March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (2013)

Chapter 18. Rearrangements

18.F. Reactions

The reactions in this chapter are classified into three main groups and 1,2-shifts are considered first. Within this group, reactions are classified according to (1) the identity of the substrate atoms A and B and (2) the nature of the migrating group W. The cyclic rearrangements are in the second group. The third group consists of rearrangements that cannot be fitted into either of the first two categories.

Reactions in which the migration terminus is on an aromatic ring have been treated under aromatic substitution. These are Reactions 11-27–11-32, 11-36, 13-30-13-32, and, partially, 11-33, 11-38, and 11-39. Double-bond shifts have also been treated in other chapters, although they may be considered rearrangements (Sec. 8.A and Reactions 12-4, and 12-2). Other reactions that may be regarded as rearrangements are the Pummerer (19-83) and Willgerodt(19-84) reactions.

18.F.i. 1,2-Rearrangements

A. Carbon-to-Carbon Migrations of R, H, and Ar

18-1 Wagner–Meerwein and Related Reactions

1/Hydro,1/hydroxy-(2/→1/alkyl)- migro- elimination, and so on

Wagner-Meerwein rearrangements were first discovered in reactions of bicyclic terpenes, and most of the early development of this reaction was with these compounds.⁹⁶ An example is the conversion of isoborneol to camphene. It fundamentally involves a 1,2-alkyl shift of an intermediate carbocation, (e.g., 52 → 53). When alcohols are treated with acids, simple substitution (e.g., Reaction 10-48) or elimination (Reaction 17-1) usually accounts for most or all of the products. But in many cases, especially where two or three alkyl or aryl groups are on the β carbon, some or all of the product is rearranged. These rearrangements have been called Wagner–Meerwein rearrangements, although this term is nowadays reserved for relatively specific transformations (e.g., isoborneol to camphene and related reactions). As pointed out previously, the carbocation that is a direct product of the rearrangement must stabilize itself, and most often it does this by the loss of a hydrogen β to it, so the rearrangement product is usually an alkene.⁹⁷ If there is a choice of protons, Zaitsev's rule (Sec. 17.A.i, category 3) governs the direction, as expected. Sometimes a different positive group is lost instead of a proton. Less often, the new carbocation reacts with a nucleophile instead of losing a proton. The nucleophile may be the water that is the original leaving group, in which case the product is a rearranged alcohol; or it may be some other species present (solvent, added nucleophile, etc.).

Rearrangement is usually predominant in neopentyl and neophyl types of substrates, and with these types normal nucleophilic substitution is difficult (normal elimination is of course impossible). Under S_N2 conditions, substitution is extremely slow⁹⁸; and under S_N1 conditions, carbocations are formed that rapidly rearrange. However, free radical substitution, unaccompanied by rearrangement, can be carried out on neopentyl systems, although, as seen previously (Sec. 18.C), neophyl systems undergo rearrangement as well as substitution.

Examples of carbocation rearrangements are found in simpler systems (e.g., neopentyl chloride, example a) and even 1-bromopropane (example b). These examples illustrate the following points:

1. Hydride ion can migrate. In example b, it was hydride that shifted, not bromine:

2. The leaving group does not have to be H₂O, but can be any departing species whose loss creates a carbocation, including N₂ from aliphatic diazonium ions⁹⁹ (see the section on leaving groups in nucleophilic substitution in Sec. 10.A.ii, category 1). Rearrangement may follow when the carbocation is created by addition of a proton or other positive species to a double bond.

3. Example b illustrates that the last step can be substitution instead of elimination.

4. Example a illustrates that the new double bond is formed in accord with Zaitsev's rule.

2-Norbornyl cations (see 52), besides displaying the 1,2-shifts of a CH₂ group previously illustrated for the isoborneol → camphene conversion, are also prone to rapid hydride shifts from the 3 to the 2 position (known as 3,2-shifts). These 3,2-shifts usually take place from the exo side¹⁰⁰; that is, the 3-exo hydrogen migrates to the 2-exo position.¹⁰¹ This stereoselectivity is analogous to the behavior previously seen for norbornyl systems, namely, that nucleophiles attack norbornyl cations from the exo side (Sec. 10.C.i, category 4) and that addition to norbornenes is also usually from the exo direction (Sec. 15.B.iii).

For rearrangements of alkyl carbocations, the direction of rearrangement is usually toward the most stable carbocation (or radical), which is tertiary > secondary > primary, but rearrangements in the other direction have also been found,¹⁰² and the product is sometimes a mixture corresponding to an equilibrium mixture of the possible carbocations. The Wagner–Meerwein rearrangement has been observed for a secondary to a secondary carbocation rearrangement, leading to some controversy. Winstein¹⁰³ described norbornyl cations in terms of the resonance structures represented by the nonclassical ion 54.¹⁰⁴ This view was questioned, primarily by Brown,¹⁰⁵ who suggested that the facile rearrangements could be explained by a series of fast 1,3-Wagner–Meerwein shifts.¹⁰⁶ There is considerable evidence, however, that the norbornyl cation rearranges with σ participation,¹⁰⁷ and there is strong NMr evidence for the nonclassical ion in superacids at low temperatures.¹⁰⁸

As alluded to above, the term “Wagner–Meerwein rearrangement” is not precise. Some use it to refer to all the rearrangements in this section and in Reaction 18-2. Others use it only when an alcohol is converted to a rearranged alkene. Many use the term only for rearrangements that involve a nonclassical carbocation intermediate. Terpene chemists call the migration of a methyl group the Nametkin rearrangement. The term retropinacol rearrangement is often applied to some or all of these. Fortunately, this disparity in nomenclature does not seem to cause much confusion. Catalytic asymmetric Wagner–Meerwein shifts have been observed.¹⁰⁹ An asymmetric, Pd catalyzed Wagner–Meerwein shift has been reported with allenic alcohols.¹¹⁰

Several of these rearrangements sometimes occur in one molecule, either simultaneously or in rapid succession. A spectacular example is found in the triterpene series. Friedelin is a triterpenoid ketone found in cork. Reduction gives 3β-friedelanol (55). When this compound is treated with acid, 13(18)-oleanene (56) is formed.¹¹¹ In this case, seven 1,2-shifts take place. Loss of H₂O from position 3 leaves a positive charge, and

the following shifts occur: hydride from 4 to 3; methyl from 5 to 4; hydride from 10 to 5; methyl from 9 to 10; hydride from 8 to 9; methyl from 14 to 8; and methyl from 13 to 14. This leaves a positive charge at position 13, which is stabilized by loss of the proton at the 18 position to give 56. All these shifts are stereospecific, the group always migrating on the side of the ring system on which it is located; that is, a group above the “plane” of the ring system (indicated by a solid line in 55) moves above the plane, and a group below the plane (dashed line) moves below it. It is probable that the seven shifts are not all concerted, although some of them may be, for intermediate products can be isolated.¹¹² As an illustration of point 2 (see above), it may be mentioned that friedelene, derived from dehydration of 55, also gives 56 on treatment with acid.¹¹³

Some alkanes undergo Wagner–Meerwein rearrangements if treated with Lewis acids and a small amount of initiator. An interesting application of this reaction is the conversion of tricyclic molecules to adamantane and its derivatives.¹¹⁴ It has been found that all tricyclic alkanes containing 10 carbons are converted to adamantane by treatment with a Lewis acid, (e.g., AlCl₃). If the substrate contains > 10 carbons, alkyl-substituted adamantanes are produced. The IUPAC name for these reactions is Schleyer adamantization. Two examples are the AlCl₃-mediated reactions of 57 and 58.

If 14 or more carbons are present, the product may be diamantane or a substituted diamantane.¹¹⁵ These reactions are successful because of the high thermodynamic stability of adamantane, diamantane, and similar diamond-like molecules. The most stable of a set of C_nH_m isomers (called the stabilomer) will be the end product if the reaction reaches equilibrium.¹¹⁶ Best yields are obtained by the use of “sludge” catalysts¹¹⁷ (i.e., a mixture of AlX₃ and tert-butyl bromide or sec-butyl bromide).¹¹⁸ Though it is certain that these adamantane-forming reactions take place by nucleophilic 1,2 shifts, the exact pathways are not easy to unravel because of their complexity.¹¹⁹ Treatment of adamantane-2-¹⁴C with AlCl₃ results in total carbon scrambling on a statistical basis.¹²⁰

As already indicated, the mechanism of the Wagner–Meerwein rearrangement is usually nucleophilic. Free radical rearrangements are also known (see Section 18.A), though virtually only with aryl migration. However, carbanion mechanisms (electrophilic) have also been found.⁹⁴ Thus Ph₃CCH₂Cl treated with sodium gave Ph₂CHCH₂Ph along with unrearranged products.¹²¹ This is called the Grovenstein-Zimmerman rearrangement. The intermediate is Ph₃CCH₂⁻, and the phenyl moves without its electron pair. Only aryl and vinylic,¹²² and not alkyl, groups migrate by the electrophilic mechanism (see the introductory section preceding Sec. 18.A) and transition states or intermediates analogous to 41 and 42 are likely.¹²³

OS V, 16, 194; VI, 378, 845.

18-2 The Pinacol Rearrangement

1/ O-Hydro,3/hydroxy-(2/→3/alkyl)- migro-elimination

When 1.2-diols (vic-diols; glycols) are treated with acids,¹²⁴ they rearrange to give aldehydes or ketones, although elimination without rearrangement can also be accomplished. This reaction is called the pinacol rearrangement; the reaction gets its name from a prototype compound pinacol (Me₂COHCOHMe₂), which is rearranged to pinacolone (Me₃CCOCH₃).¹²⁵ In this type of reaction, reduction can compete with rearrangement.¹²⁶ The reaction has been accomplished many times, with alkyl, aryl, hydrogen, and even ethoxycarbonyl (CO₂Et)¹²⁷ as migrating groups. In most cases, each carbon has at least one alkyl or aryl group, and the reaction is most often carried out with tri- and tetrasubstituted glycols. As mentioned earlier, glycols in which the four R groups are not identical can give rise to more than one product, depending on which group migrates (see Sec. 18.A.iii for a discussion of migratory aptitudes). A noncatalytic reaction is possible in supercritical water.¹²⁸

Stereodifferentiation is possible in this reaction.¹²⁹ When TMSOTf was used to initiate the reaction, it was shown to be highly regioselective.¹³⁰ Mixtures are often produced, and which group preferentially migrates may depend on the reaction conditions as well as on the nature of the substrate. Thus the action of cold, concentrated sulfuric acid on 59 produces mainly the ketone 60 (methyl migration), while treatment of 59 with acetic acid containing a trace of sulfuric acid gives mostly 61 (phenyl migration).¹³¹ If at least one R is hydrogen, aldehydes can be produced as well as ketones. Generally, aldehyde formation is favored by the use of mild conditions (lower temperatures, weaker acids), because under more drastic conditions the aldehydes may be converted to ketones (Reaction 18-4). The reaction has been carried out in the solid state, by treating solid substrates with HCl gas or with a solid organic acid.¹³²

The mechanism involves a simple 1,2-shift. The ion 62 (where all four R groups are Me) has been trapped by the addition of tetrahydrothiophene.¹³³ A migration takes place from the tertiary position because carbocations stabilized by an oxygen atom are even more stable than tertiary alkyl cations (Sec. 5.A.ii). In addition, the new carbocation can immediately stabilize itself by losing a proton.

It is obvious that other compounds in which a positive charge can be placed on a carbon α to one bearing an OH group can also give this rearrangement. This is true for β-amino alcohols, which rearrange on treatment with nitrous acid (this is called the semipinacol rearrangement), for iodohydrins, for which the reagent is mercuric oxide or silver nitrate, for β-hydroxyalkyl selenides [R¹R²C(OH)C(SeR⁵)R³R⁴],¹³⁴ and for allylic alcohols,¹³⁵ which can rearrange on treatment with a strong acid that protonates the double bond. A related rearrangement is the Et₂Zn mediated rearrangement of bromohydrins to give ketones.¹³⁶

A similar rearrangement is given by epoxides, when treated with acidic reagents (e.g., BF₃–etherate or MgBr₂–etherate), 5M LiClO₄ in ether,¹³⁷ InCl₃,¹³⁸ Bi(OTf)₃,¹³⁹ or sometimes by heat alone.¹⁴⁰ Epoxides are converted to aldehydes or ketones on treatment with certain metallic catalysts¹⁴¹ including treatment with iron complexes,¹⁴² IrCl₃,¹⁴³ or with BiOClO₄.¹⁴⁴ Base-induced rearrangement is also known, but the products are usually different.¹⁴⁵

The Meinwald rearrangement converts epoxides to carbonyl compounds.¹⁴⁶ Several reagents mediate this transformation, including Cu compounds.¹⁴⁷ A closely related reaction of vinyl epoxides gives alkenyl ketones upon treatment with Ga compounds.¹⁴⁸ It has been shown that epoxides are intermediates in the pinacol rearrangements of certain glycols.¹⁴⁹ Among the evidence for the mechanism given is that Me₂COHCOHMe₂, Me₂COHC(NH₂)Me₂, and Me₂COHCClMe₂ gave the reaction at different rates (as expected), but yielded the same mixture of two products, pinacol and pinacolone, indicating a common intermediate.¹⁵⁰

A good way to prepare β-diketones consists of heating α,β-epoxy ketones at 80–140 °C in toluene with small amounts of (Ph₃P)₄Pd and dppe.¹⁵¹ Epoxides are converted to 1,2-diketones with Bi, DMSO, O₂ and a catalytic amounts of Cu(OTf)₂ at 100 °C.¹⁵² α,β-Epoxy ketones are also converted to 1,2-diketones with a Ru catalyst¹⁵³ or an Fe catalyst.¹⁵⁴ Epoxides with an α-hydroxyalkyl substituent give a pinacol rearrangement product in the presence of a ZnBr₂¹⁵⁵ or Tb(OTf)₃¹⁵⁶ catalyst to give a γ-hydroxy ketone.

Oxaziridines are converted to ring-expanded lactams under photochemical conditions.¹⁵⁷N-Tosyl aziridines with an α-hydroxyalkyl substituent give a pinacol rearrangement product in the presence of Lewis acids (e.g., SmI₂), in this case a keto-N-tosyl amide.¹⁵⁸

β-Hydroxy ketones can be prepared by treating the silyl ethers (63) of α,β-epoxy alcohols with TiCl₄.¹⁵⁹

OS I, 462; II, 73, 408; III, 312; IV, 375, 957; V, 326, 647; VI, 39, 320; VII, 129. See also, OS VII, 456.

18-3 Expansion and Contraction of Rings

Demyanov ring contraction; Demyanov ring expansion

When a positive charge is formed on an alicyclic carbon, migration of an alkyl group can take place to give ring contraction, producing a ring that is one carbon smaller than the original, as in the interconversion of the cyclobutyl cation and the cyclopropylcarbinyl cation (64). Note that this change involves conversion of a

secondary to a primary carbocation. In a similar manner, when a positive charge is placed on a carbon α to an alicyclic ring, ring expansion can take place.¹⁶⁰ The new carbocation, and the old one, can then give products by combination with a nucleophile (e.g., the alcohols shown above), or by elimination, so that this reaction is a special case of 18-1. Often, both rearranged and unrearranged products are formed, so that, for example, cyclobutylamine and cyclopropylmethylamine give similar mixtures of the two alcohols shown above on treatment with nitrous acid (a small amount of 3-buten-1-ol is also produced). When the carbocation is formed by diazotization of an amine, the reaction is called the Demyanov rearrangement,¹⁶¹ but of course similar products are formed when the carbocation is generated in other ways. The expansion reaction has been performed on rings of C₃–C₈,¹⁶² but yields are best with the smaller rings, where relief of small-angle strain provides a driving force for the reaction. Strain is apparently much less of a factor in the cyclobutyl–cyclopropylmethyl interconversion (for a discussion of this interconversion, see Sec. 10.C.i). The influence of substituents on this rearrangement has been examined.¹⁶³ Note that a hybrid of a [1,2]-sigmatropic hydrogen shift (also See 18-29) and a two-electron-electrocyclic ring opening has been discovered for cyclopropylcarbinyl cations that was labeled as a “hiscotropic” rearrangement.”¹⁶⁴ The contraction reaction has been applied to four-membered rings and to rings of C₆–C₈, but contraction of a cyclopentyl cation to a cyclobutylmethyl system is generally not feasible because of the additional strain involved.

A related rearrangement involves cyclopropyl propargylic alcohols, which gives an alkylidene cyclobutanone in the presence of Ag and Au catalysts,¹⁶⁵ or Ru and In catalysts.¹⁶⁶ Cyclopropylcarbinyl rearrangements are catalyzed by ionic liquids under solvent-free conditions.¹⁶⁷ Methylenecyclopropanes rearrange to cyclobutenes in the presence of 1 atm of CO and Pt catalyst¹⁶⁸ or a Pd catalyst, mediated by a Cu catalyst.¹⁶⁹ Arylvinylidenecyclopropanes rearrange to bicyclic systems in the presence of a Lewis acid.¹⁷⁰

Ring expansions of certain hydroxyamines (e.g., 65) are analogous to the semipinacol rearrangement (Reaction 18-2). This reaction is called the Tiffeneau–Demyanov ring expansion. These have been performed on rings of C₄–C₈and the yields are better than for the simple Demyanov ring expansion. A similar reaction has been used to expand rings of from five to eight members.¹⁷¹ In this case, a cyclic bromohydrin of the form 66 is treated with a Grignard reagent, which, acting as a base, removes the OH proton to give the alkoxide 67. When 67 is heated to reflux, ring enlargement occurs. The reaction has been done with 66 in which at least one R group is phenyl or methyl,¹⁷² but fails when both R groups are hydrogen.¹⁷³

A positive charge generated on a three-membered ring gives “contraction” to an allylic cation, as shown.¹⁷⁴

As seen in Section 10.G.i, category 7, this is the reason nucleophilic substitutions are not feasible at a cyclopropyl substrate. The reaction is often used to convert cyclopropyl halides and tosylates to allylic products, especially for the purpose of ring expansion, an example being the conversion of 68 to 69.¹⁷⁵ The stereochemistry of these cyclopropyl cleavages is governed by the principle of orbital symmetry conservation (for a discussion, see Reaction 18-27, the Möbius–Hückel method).

Three-membered rings can also be cleaved to unsaturated products in at least two other ways. (1) Upon pyrolysis, cyclopropanes can undergo “contraction” to propenes.¹⁷⁶ In the simplest case, cyclopropane gives propene when heated to 400–500 °C. The mechanism is generally regarded¹⁷⁷ as involving a diradical

intermediate¹⁷⁸ (recall that free radical 1,2-migration is possible for diradicals, Sec. 18.C). (2) The generation of a carbene or carbenoid carbon in a three-membered ring can lead to allenes, and allenes are often prepared in

this way.¹⁷⁹ Flash vacuum pyrolysis of 1-chlorocyclopropene thermally rearranges to chloroallene.¹⁸⁰ One way to generate such a species is treatment of a 1,1-dihalocyclopropane with an alkyllithium compound (Reaction 12-39).¹⁸¹In contrast, the generation of a carbene or carbenoid at a cyclopropylmethyl carbon gives ring expansion.¹⁸²

Some free radical ring enlargements are also known, an example being¹⁸³:

This reaction has been used to make rings of 6, 7, 8, and 13 members. A possible mechanism is

This reaction has been extended to the expansion of rings by three or four carbons, by the use of a substrate containing (CH₂)_nX (n = 3 or 4) instead of CH₂Br.¹⁸⁴ By this means, 5-, 6-, and 7-membered rings were enlarged to 18–11-membered rings. A β-keto ester (e.g., 2-carboxyethyl cyclohexanone) is converted to 3-carboxyethyl cylcoheptanone when treated with CF₃CO₂ZnCH₂I.¹⁸⁵

OS III, 276; IV, 221, 957; V, 306, 320; VI, 142, 187; VII, 12, 114, 117, 129, 135; VIII, 179, 467, 556, 578.

18-4 Acid-Catalyzed Rearrangements of Aldehydes and Ketones

1/Alkyl,2/alkyl-interchange, and so on

Rearrangements of this type, where a group α to a carbonyl “changes places” with a group attached to the carbonyl carbon, occur when migratory aptitudes are favorable.¹⁸⁶ The R², R³, and R⁴ groups may be alkyl or hydrogen. Certain aldehydes have been converted to ketones, and ketones to other ketones (though more drastic conditions are required for the latter), but no rearrangement of a ketone to an aldehyde (R¹ = H) has so far been reported. There are two mechanisms,¹⁸⁷ each beginning with protonation of the oxygen and each involving two migrations. In one pathway, the migrations are in opposite directions¹⁸⁸:

In the other pathway, the migrations are in the same direction. The actual mechanism of this pathway is not certain, but an epoxide (protonated) intermediate¹⁸⁹ is one possibility¹⁹⁰:

If the reaction is carried out with ketone labeled in the C=O group with , the first pathway predicts that the product will contain all the in the C=O carbon, while in the second pathway the label will be in the α carbon (demonstrating migration of oxygen). The results of such experiments¹⁹¹ have shown that in some cases only the C=O carbon was labeled, in other cases only the α carbon, while in still others both carbons bore the label, indicating that in these cases both pathways were in operation. With α-hydroxy aldehydes and ketones, the process may stop after only one migration (this is called the α-ketol rearrangement).

The α-ketol rearrangement can also be brought about by base catalysis, but only if the alcohol is tertiary, since if R¹ or R² = hydrogen, enolization of the substrate is more favored than rearrangement.

18-5 The Dienone–Phenol Rearrangement

2/ C→5/ O-Hydro,1/ C→2/ C-alkyl-bis -migration

Cyclohexadienone derivatives that have two alkyl groups in the 4 position undergo, on acid treatment,¹⁹² 1,2-migration of one of these groups from 70 to give the phenol. Note that a photochemical version of this reaction has been observed.¹⁹³ The driving force in the overall reaction (the dienone–phenol rearrangement) is of course creation of an aromatic system.¹⁹⁴ Note that 70 and 71 are arenium ions (Sec. 5.A.ii), the same as those generated by attack of a phenol on an electrophile.¹⁹⁵ Sometimes, in the reaction of a phenol with an electrophile, a kind of reverse rearrangement (called the phenol–dienone rearrangement) takes place, though without an actual migration.¹⁹⁶ An example is

18-6 The Benzil–Benzilic Acid Rearrangement

1/ O-Hydro,3/oxido-(1/→2/aryl)- migro-addition

When treated with base, α-diketones rearrange to give the salts of α-hydroxy acids, a reaction known as the benzil–benzilic acid rearrangement (benzil is PhCOCOPh; benzilic acid is Ph₂COHCO₂H).¹⁹⁷ A Rh catalyzed version of this reaction has also been reported.¹⁹⁸ Though the reaction is usually illustrated with aryl groups, it can also be applied to aliphatic diketones¹⁹⁹ and to α-keto aldehydes. The use of an alkoxide instead of hydroxide gives the corresponding ester directly,²⁰⁰ although alkoxide ions that are readily oxidized (e.g., OEt⁻ or OCHMe₂⁻) are not useful here, since they reduce the benzil to a benzoin. The mechanism is similar to the rearrangements in Reaction 18-1–18-4, but there is a difference: The migrating group does not move to a carbocation. The first step is attack of the base at the carbonyl group, the same as the first step of the tetrahedral mechanism of nucleophilic substitution (Sec. 16.A.i) and of many additions to the C=O bond (Chapter 16):

The mechanism has been intensely studied,¹⁸⁸ and there is much evidence for it.²⁰¹ The reaction is irreversible.

OS I, 89.

18-7 The Favorskii Rearrangement

2/Alkoxy-de-chloro(2/→1/alkyl)- migro-substitution

The reaction of α-halo ketones (chloro, bromo, or iodo) with alkoxide ions²⁰² to give rearranged esters is called the Favorskii rearrangement.²⁰³ The use of hydroxide ions or amines as bases leads to the free carboxylic acid (salt) or amide, respectively, instead of the ester. Cyclic α-halo ketones give ring contraction, as in the conversion of 72 to 73.

The reaction has also been carried out on α-hydroxy ketones²⁰⁴ and on α,β-epoxy ketones, which give β-hydroxy acids.²⁰⁵ The fact that an epoxide gives a reaction analogous to a halide indicates that the oxygen and halogen are leaving groups in a nucleophilic substitution step.

Investigation of the mechanism²⁰⁶ of the Favorskii rearrangement has led to proposals for at least five different mechanisms. However, the finding²⁰⁷ that 74 and 75 both give 76 (this behavior is typical) shows that any mechanism where the halogen leaves and R¹ takes its place is invalid, since in such a case 74 would be expected to give 76 (with PhCH₂ migrating), but 75 should give PhCHMeCOOH (with CH₃ migrating). That is, in the case of 75, it was PhCH that migrated and not methyl. Another important result was determined by radioactive labeling. Chloroketone (72), in which C-1 and C-2 were equally labeled with , was converted to 73. The product was found to contain 50% of the label on the carbonyl carbon, 25% on C-1, and 25% on C-2.²⁰⁸ Now the carbonyl carbon, which originally carried half of the radioactivity, still had this much, so the rearrangement did not directly affect it. However, if the C-6 carbon had migrated to C-2, the other half of the radioactivity would be only on C-1 of the product:

On the other hand, if the migration had gone the other way (if the C-2 carbon had migrated to C-6), then this half of the radioactivity would be found solely on C-2 of the product. The fact that C-1 and C-2 were equally labeled showed that both migrations occurred, with equal probability. Since C-2 and C-6 of 72 are not equivalent, this means that there must be a symmetrical intermediate.²⁰⁹ The type of intermediate that best fits the circumstances is a cyclopropanone,²¹⁰ and the mechanism (for the general case) is formulated (replacing R¹ of our former symbolism with CHR⁵R⁶, since it is obvious that for this mechanism an α hydrogen is required on the non-halogenated side of the carbonyl):

The intermediate corresponding to 78, in the case of 72, is a symmetrical compound, and the three-membered ring can be opened with equal probability on either side of the carbonyl, accounting for the results with ¹⁴C. In the general case, 78 is not symmetrical and should open on the side that gives the more stable carbanion.²¹¹ This accounts for the fact that 74 and 75 give the same product. The intermediate in both cases is 77, which always opens to give the carbanion stabilized by resonance. The cyclopropanone intermediate (78) has been isolated in the case where R² = R⁵ = t-Bu and R³ = R⁶ = H,²¹² and it has also been trapped.²¹³ Also, cyclopropanones synthesized by other methods have been shown to give Favorskii products on treatment with NaOMe or other bases.²¹⁴

The mechanism discussed is in accord with all the facts when the halo ketone contains an α hydrogen on the other side of the carbonyl group. However, ketones that do not have an α hydrogen also rearrange to give the same type of product in what is usually called the quasi-Favorskii rearrangement. The quasi-Favorskii rearrangement cannot take place by the cyclopropanone mechanism. The mechanism that is generally accepted (called the semibenzilic mechanism²¹⁵) is a base-catalyzed pinacol rearrangement-type mechanism similar to that of 18-6. This mechanism requires inversion at the migration terminus and this has been found.²¹⁶ It has been shown that even where there is an appropriately situated α hydrogen, the semibenzilic mechanism may still operate.²¹⁷

An interesting analogue of the Favorskii rearrangement treats a ketone, (e.g., 4-tert-butylcyclohexanone), without an α-halogen with Tl(NO₃)₃ to give 3-tert-butylcyclopentane-1-carboxylic acid.²¹⁸

OS IV, 594; VI, 368, 711.

18-8 The Arndt–Eistert Synthesis

In the Arndt–Eistert synthesis, an acyl halide is converted to a carboxylic acid with one additional carbon.²¹⁹ The first step of this process is Reaction 16-89. The actual rearrangement occurs in the second step after treatment of the diazo ketone with water and silver oxide or with silver benzoate and triethylamine. This rearrangement is called the Wolff rearrangement.²²⁰ It is the best method of increasing a carbon chain by one from a carboxylic acid (see Reaction 10-75 and 16-30). If an alcohol (R′OH) is used instead of water, the ester (RCH₂CO₂R′) is isolated.²²¹ Similarly, treatment with ammonia gives the amide. Other catalysts are sometimes used (colloidal Pt, Cu, etc.), but occasionally the diazo ketone is simply heated or photolyzed in the presence of water, an alcohol, or ammonia, with no catalyst at all using ultrasound.²²² The photolysis method²²³ often gives better results than the Ag catalysis method. Of course, diazo ketones prepared in any other way also give the rearrangement.²²⁴ The reaction is of wide scope. The R group may be alkyl or aryl and may contain many functional groups including unsaturation, but not including groups acidic enough to react with CH₂N₂ or diazo ketones (e.g., Reaction 10-5 and 10-19). Sometimes the reaction is performed with other diazoalkanes (i.e., R′CHN₂) to give RCHR′COOH. The reaction has been used for ring contraction of cyclic diazo ketones²²⁵ (e.g., 79).²²⁶

An asymmetric variation converted ketones to esters using an azaferrocene catalyst.²²⁷

The mechanism is generally regarded as involving formation of a carbene.²²⁸ It is the divalent carbon that has the open sextet and to which the migrating group brings its electron pair:

The actual product of the reaction is thus the ketene, which then reacts with water (15-3), an alcohol (15-5), or ammonia or an amine (15-8). Particularly stable ketenes²²⁹ (e.g., Ph₂C=C=O) have been isolated and others have been trapped in other ways (e.g., as β-lactams,²³⁰ reaction 16-96). The purpose of the catalyst is not well understood, though many suggestions have been made. This mechanism is strictly analogous to that of the Curtius rearrangement(Reaction 18-14). Although the mechanism as shown above involves a free carbene and there is much evidence to support this,²³¹ it is also possible that at least in some cases the two steps are concerted and a free carbene is absent.

When the Wolff rearrangement is carried out photochemically, the mechanism is basically the same,²²³ but another pathway can intervene. Some of the ketocarbene originally formed can undergo a carbene–carbene rearrangement, through an oxirene intermediate.²³² This was shown by labeling experiments, where

diazoketones labeled in the carbonyl group gave rise to ketenes that bore the label at both C=C carbons.²³³ In general, the smallest degree of scrambling (and thus of the oxirene pathway) was found when R′ = H. An intermediate believed to be an oxirene has been detected by laser spectroscopy.²³⁴ The oxirene pathway is not found in the thermal Wolff rearrangement. It is likely that an excited singlet state of the carbene is necessary for the oxirene pathway to intervene.²³⁵ In the photochemical process, ketocarbene intermediates, in the triplet state, have been isolated in an Ar matrix at 10–15 K, where they have been identified by UV–visible, IR, and ESR spectra.²³⁶ These intermediates went on to give the rearrangement via the normal pathway, with no evidence for oxirene intermediates.

The diazo ketone can exist in two conformations, called s-(E) and s-(Z). Studies have shown that Wolff rearrangement takes place preferentially from the s-(Z) conformation.²³⁷

OS III, 356; VI, 613, 840.

18-9 Homologation of Aldehydes and Ketones

Methylene-insertion

Aldehydes and ketones²³⁸ can be converted to their homologues with diazomethane.²³⁹ Several other reagents²⁴⁰ are also effective, including Me₃SiI, and then silica gel.²⁴¹ With the diazomethane reaction, formation of an epoxide (16-46) is a side reaction. Superficially, this reaction appears to be similar to the insertion of carbenes into C–H bonds, (Reaction 12-21, and IUPAC names it as an insertion), but the mechanism is quite different. However, it is a true rearrangement and no free carbene is involved. The first step is an addition to the C=O bond:

The betaine (80) can sometimes be isolated. As shown in Reaction 16-46, intermediate 80 can also go to the epoxide. The evidence for this mechanism has been summarized in the review by Gutsche.²³⁹ Note that this mechanism is essentially the same as in the apparent “insertions” of oxygen (Reaction 18-19) and nitrogen (Reaction 18-16) into ketones.

1,3-Diketones are converted to 1,4-diketones upon treatment with CF₃CO₂ZnCH₂I.²⁴² In a related reaction, alkenes insert into aldehydes in the presence of a Rh catalyst to give the corresponding ketone.²⁴³

Aldehydes give fairly good yields of methyl ketones; that is, hydrogen migrates in preference to alkyl. The most abundant side product is not the homologous aldehyde, but the epoxide. However, the yield of aldehyde at the expense of methyl ketone can be increased by the addition of methanol. If the aldehyde contains electron-withdrawing groups, the yield of epoxides is increased and the ketone is formed in smaller amounts, if at all. Ketones give poorer yields of homologous ketones. Epoxides are usually the predominant product here, especially when one or both R groups contain an electron-withdrawing group. The yield of ketones also decreases with increasing length of the chain. The use of a Lewis acid increases the yield of ketone.²⁴⁴ Cyclic ketones,²⁴⁵ three membered²⁴⁶ and larger, behave particularly well and give good yields of ketones with the ring expanded by one.²⁴⁷ Aliphatic diazo compounds (RCHN₂ and R₂CN₂) are sometimes used instead of diazomethane, with the expected results.²⁴⁸ Ethyl diazoacetate can be used analogously, in the presence of a Lewis acid or of triethyloxonium fluoroborate,²⁴⁹ to give a β-keto ester, (e.g., 81).

When unsymmetrical ketones were used in this reaction (with BF₃ as catalyst), the less highly substituted carbon preferentially migrated.²⁵⁰ The reaction can be made regioselective by applying this method to the α-halo ketone, in which case only the other carbon migrates.²⁵¹ The ethyl diazoacetate procedure has also been applied to the acetals or ketals of α,β-unsaturated aldehydes and ketones.²⁵²

Bicyclic ketones can be expanded to form monocyclic ketones in the presence of certain reagents. Treatment of a bicyclo[4.1.0]hexan-4-one derivative with SmI₂ led to a cyclohexanone.²⁵³ The SmI₂ also converts α-halomethyl cyclic ketones to the next larger ring ketone²⁵⁴ and cyclic ketones to the next larger ring ketone in the presence of CH₂I₂.²⁵⁵

Another homologation reaction converts an aldehyde to its tosyl hydrazone, and subsequent reaction with an aldehyde and NaOEt/EtOH give a ketone.²⁵⁶ The reaction of an aldehyde with vinyl acetate and Ba(OH)₂ gives the homologated conjugated aldehyde.²⁵⁷

OS IV, 225, 780. For homologation of carboxyl acid derivatives, see OS IX, 426

B. Carbon-to-Carbon Migrations of Other Groups

18-10 Migrations of Halogen, Hydroxyl, Amino, and so on

Hydroxy-de-bromo- cine-substitution, and so on

When a nucleophilic substitution is carried out on a substrate that has a neighboring group (Sec. 10.C) on the adjacent carbon, a cyclic intermediate can be generated that is opened on the opposite side, resulting in migration of the neighboring group. In the example shown above (NR₂ = morpholino),²⁵⁸ the reaction took place via an aziridinium salt (82) to give an α-amino-β-hydroxy ketone. Sulfonate esters and halides can also migrate in this reaction.²⁵⁹

α-Halo and α-acyloxy epoxides undergo ready rearrangement to α-halo and α-acyloxy ketones, respectively.²⁶⁰ These substrates are prone to rearrange, and often do so upon standing without a catalyst, although an acid catalyst is necessary in some cases. The reaction is essentially the same as the rearrangement of epoxides shown in 18-2, except that halogen or acyloxy is the migrating group (as shown above; however, it is also possible for one of the R groups (alkyl, aryl, or hydrogen) to migrate instead, and mixtures are sometimes obtained). In a related reaction, α-bromoaziridines undergo rearrangement to the isomerized α-bromoaziridine in the presence of MgBr₂.²⁶¹

In the presence of a Cu catalyst, alkenyl epoxides (vinyl oxiranes) rearrange to a 2,5-dihydrofuran.²⁶² Alkenyl thiiranes are similarly converted to 2,5-dihydrothiophenes with a Cu catalyst.²⁶³

Allylic alcohols migrate to give a new allylic alcohol in the presence of a Re catalyst. An example is the conversion of 83 to 84.²⁶⁴ Variations using Rh²⁶⁵ or Ir²⁶⁶ catalysts are known, and methanesulfonic acid catalyzes the isomerization.²⁶⁷ In the presence of a Ru catalyst, an allylic alcohol was isomerized to an aliphatic ketone.²⁶⁸ There is a similar Au catalyzed isomerization of allylic acetates.²⁶⁹

The Meyer–Schuster Rearrangement is an acid-catalyzed rearrangement of a propargyl alcohol to a conjugated carbonyl compound.²⁷⁰ Rearrangement was also catalyzed by a cationic Rh–bisphosphane complex.²⁷¹ An Au catalyzed rearrangement of ethoxyalkynyl carbinols gave α,β-unsaturated esters.²⁷² The base-induced isomerization of a propargylic alcohol gave a conjugated ketone,²⁷³ and a combination of Mo–Au led to rapid 1,3-rearrangement of propargyl alcohols.²⁷⁴ An Au–Ag catalyzed reaction with propargyl esters gave a 2-O-pivaloyl conjugated aldehyde.²⁷⁵ A similar reaction with a Pt catalyst converted a 1-ethoxy propargylic ester to a 2-carboethoxy conjugated ketone.²⁷⁶ An Au catalyzed isomerization of allenyl carbinol esters is also known.²⁷⁷

18-11 Migration of Boron

Hydro,dialkylboro-interchange, and so on

Boranes are prepared by the reaction of BH₃ (B₂H₆) or an alkylborane with an alkene (15-16). When a nonterminal borane is heated at temperatures ranging from 100 to 200 °C, the boron moves toward the end of the chain.²⁷⁸The reaction is catalyzed by small amounts of borane or other species containing B–H bonds. The boron can move past a branch, for example,

but not past a double branch, for example,

The reaction is an equilibrium: 85, 86, and 87 each gave a mixture containing ~40% 85, 1% 86, and 59% 87. The migration can go quite a long distance, including a migration of 11 positions.²⁷⁹ If the boron is on a cycloalkyl ring, it can move around the ring; if any alkyl chain is also on the ring, the boron may move from the ring to the chain, ending up at the end of the chain.²⁸⁰ The reaction is useful for the migration of double bonds in a controlled way (see 12-2). The mechanism may involve a π complex, at least partially.²⁸¹

18-12 The Neber Rearrangement

Neber oxime tosylate-amino ketone rearrangement

α-Amino ketones can be prepared by treatment of ketoxime tosylates with a base (e.g., ethoxide or pyridine).²⁸² This reaction is called the Neber rearrangement. The R group is usually aryl, although the reaction has been carried out with R = alkyl or hydrogen. The R′ group may be alkyl or aryl, but not hydrogen. The Beckmann rearrangement (Reaction 18-17) and the abnormal Beckmann reaction (elimination to the nitrile, Reaction 17-30) may be side reactions, although these generally occur in acid media. A similar rearrangement is given by N,N-dichloroamines of the type RCH₂CH(NCl₂)R′, where the product is also RCH(NH₂)COR′.²⁸³ The mechanism of the Neber rearrangement involves an azirine intermediate (88).²⁸⁴ The best evidence for this mechanism is that the azirine intermediate has been isolated.^285, In contrast to the Beckmann rearrangement, this one is sterically indiscriminate:²⁸⁶Both a syn and an anti ketoxime give the same product. The mechanism, as shown above, consists of three steps. However, it is possible that the first two steps are concerted, and it is also possible that what is shown as the second step is actually two steps: loss of OTs to give a nitrene, and formation of the azirine. In the case of the dichloroamines, HCl is first lost to give RCH₂C(=NCl)R′, which then behaves analogously.²⁸⁷N-Chloroimines prepared in other ways also give the reaction.²⁸⁸ Indoles have been prepared via a Neber rearrangement.²⁸⁹

OS V, 909; VII, 149.

C. Carbon-to-Nitrogen Migrations of R and Ar

The reactions in this group are nucleophilic migrations from a carbon to a nitrogen atom. In each case, the nitrogen atom either has six electrons in its outer shell (and thus invites the migration of a group carrying an electron pair) or else loses a nucleofuge concurrently with the migration (Sec. 18.A.i). Reactions 18-13–18-16 are used to prepare amines from acid derivatives. Reactions 18-16 and 18-17 are used to prepare amines from ketones. The mechanisms of Reaction 18-13–18-16 (with carboxylic acids) are very similar and follow one of two patterns:

Some of the evidence²⁹⁰ is (1) configuration is retained in R (Sec. 18.A.ii); (2) the kinetics are first order; (3) intramolecular rearrangement is shown by labeling; and (4) no rearrangement occurs within the migrating group, for example, a neopentyl group on the carbon of the starting material is still a neopentyl group on the nitrogen of the product.

In many cases, it is not certain whether the nucleofuge X is lost first, creating an intermediate nitrene²⁹¹ or nitrenium ion, or whether migration and loss of the nucleofuge are simultaneous, as shown above.²⁹² It is likely that both possibilities can exist, depending on the substrate and reaction conditions.

18-13 The Hofmann Rearrangement

Bishydrogen-(2/→1/ N-alkyl)- migro-detachment (formation of isocyanate)

In the Hofmann rearrangement, an unsubstituted amide is treated with sodium hypobromite (or sodium hydroxide and bromine, which is essentially the same thing) to give an isocyanate, but this compound is seldom isolated²⁹³since it is usually hydrolyzed under the reaction conditions. The final isolated product is a primary amine that has one carbon fewer than the starting amide.²⁹⁴ The R group may be alkyl or aryl, but if it is an alkyl group of more than about six or seven carbons, low yields are obtained unless Br₂ and NaOMe are used instead of Br₂ and NaOH.²⁹⁵ Another modification uses NBS/NaOMe.²⁹⁶ Under these conditions, the product of addition to the isocyanate is the carbamate (RNHCOOMe, Reaction 16-8), which is easily isolated or can be hydrolyzed to the amine.²⁹⁷ A mixture of NBS and DBU (see Reaction 17-13) in methanol gives the carbamate,²⁹⁸ as does electrolysis in methanol.²⁹⁹

Side reactions when NaOH is the base are formation of ureas (RNHCONHR) and acylureas (RCONHCONHR) by addition, respectively, of RNH₂ and RCONH₂ to RNCO (16-20). If acylureas are desired, they can be made the main products by using only one-half of the usual quantities of Br₂ and NaOH. Another side product, but only from primary R, is the nitrile derived from oxidation of RNH₂ (Reaction 19-5).

Imides react to give amino acids, (e.g., phthalimide gives o-aminobenzoic acid). α-Hydroxy and α-halo amides give aldehydes and ketones by way of the unstable α-hydroxy- or α-haloamines. However, a side product with an α-halo amide is a gem-dihalide. Ureas analogously give hydrazines.

The mechanism follows the pattern outlined in the discussion preceding Reaction 18-13.

The first step is an example of Reaction 12-52 and intermediate N-halo amides (89) have been isolated. Compound 89 is acidic because of the presence of two electron-withdrawing groups (acyl and halo) on the nitrogen, and in the second step, 89 loses a proton to the base. It is possible that the third step is actually two steps: loss of bromide to form a nitrene, followed by the actual migration, but most of the available evidence favors the concerted reaction.³⁰⁰A similar reaction can be effected by the treatment of amides with lead tetraacetate.³⁰¹ Among other reagents that convert RCONH₂ to RNH₂ (R = alkyl, but not aryl) are phenyliodosyl bis(trifluoroacetate) [PhI(OCOCF₃)₂]³⁰² and hydroxy(tosyloxy)iodobenzene [PhI(OH)OTs].³⁰³

A variation of the Hofmann rearrangement treated a β-hydroxy primary amide with PhI(O₂CCF₃)₃ in aq acetonitrile, giving an isocyanate via –CON-I, which reacts with the hydroxyl group intramolecularly to give a cyclic carbamate.³⁰⁴ Note that carbamates are converted to isocyanates by heating with Montmorillonite K-10.³⁰⁵

OS II, 19, 44, 462; IV, 45; VIII, 26, 132.

18-14 The Curtius Rearrangement

Dinitrogen-(2/→1/ N-alkyl)- migro-detachment

The Curtius rearrangement involves heating acyl azides to yield isocyanates.³⁰⁶ The reaction gives good yields of isocyanates, since no water is present to hydrolyze them to the amine. Of course, they can be subsequently hydrolyzed, and indeed the reaction can be carried out in water or alcohol, in which case the products are amines, carbamates, or acylureas, as in 18-13.³⁰⁷ This is a very general reaction and can be applied to almost any carboxylic acid: aliphatic, aromatic, alicyclic, heterocyclic, unsaturated, and containing many functional groups. Acyl azides can be prepared as in Reaction 10-43 or by treatment of acylhydrazines (hydrazides) with nitrous acid (analogous to Reaction 12-49). The Curtius rearrangement is catalyzed by Lewis acids or protic acids, but these are usually not necessary for good results.

The mechanism is similar to that in Reaction 18-13 to give an isocyanate. Also note the exact analogy between this Reaction and 18-8. However, in this case, there is no evidence for a free nitrene and it is probable that the conversion is concerted.³⁰⁸

Alkyl azides can be similarly pyrolyzed to give imines, in an analogous reaction³⁰⁹:

The R groups may be alkyl, aryl, or hydrogen, although if hydrogen migrates, the product is the unstable R₂C=NH. The mechanism is essentially the same as that of the Curtius rearrangement. However, in pyrolysis of tertiary alkyl azides, there is evidence that free alkyl nitrenes are intermediates.³¹⁰ The reaction can also be carried out with acid catalysis, in which case lower temperatures can be used, although the acid may hydrolyze the imine (16-2). Cycloalkyl azides give ring expansion as shown.³¹¹

Aryl azides also give ring expansion on heating, for example,³¹²

OS III, 846; IV, 819; V, 273; VI, 95, 910. Also see, OS VI, 210.

18-15 The Lossen Rearrangement

Hydro,acetoxy-(2/→1 N-alkyl)- migro-detachment

The O-acyl derivatives of hydroxamic acids³¹³ give isocyanates when treated with bases or sometimes even just on heating, in a reaction known as the Lossen rearrangement.³¹⁴ The mechanism is similar to that of Reaction 18-13and 18-14:

In a similar reaction, aromatic acyl halides are converted to amines in one laboratory step by treatment with hydroxylamine-O-sulfonic acid.³¹⁵

A chiral Lossen rearrangement is known.³¹⁶

18-16 The Schmidt Reaction

There are actually three reactions called by the name Schmidt reaction, involving the addition of hydrazoic acid to carboxylic acids, aldehydes and ketones, and alcohols and alkenes.³¹⁷ The most common is the reaction with carboxylic acids, illustrated above.³¹⁸ Sulfuric acid is a common catalyst, but Lewis acids have also been used. Good results are obtained for aliphatic R, especially for long chains. When R is aryl, the yields are variable, being best for sterically hindered compounds like mesitoic acid. This method has the advantage over Reaction 18-13 and 18-14 in that there is just one laboratory step from the acid to the amine, but conditions are more drastic.³¹⁹ Under the acid conditions employed, the isocyanate is virtually never isolated.

The reaction between a ketone and hydrazoic acid is a method for “insertion” of NH between the carbonyl group and one R group, converting a ketone into an amide.³²⁰

Either or both of the R groups may be aryl. In general, dialkyl ketones and cyclic ketones react more rapidly than alkyl aryl ketones, and these more rapidly than diaryl ketones. The latter require sulfuric acid and do not react in concentrated HCl, which is strong enough for dialkyl ketones. Dialkyl and cyclic ketones react sufficiently faster than diaryl or aryl alkyl ketones or carboxylic acids or alcohols so that these functions may be present in the same molecule without interference. Cyclic ketones give lactams³²¹: With alkyl aryl ketones, it is the aryl group that generally migrates to the nitrogen, except when the alkyl group is bulky.³²²

The reaction has been applied to a few aldehydes, but rarely. With aldehydes the product is usually the nitrile (Reaction 16-16). Even with ketones, conversion to the nitrile is often a side reaction, especially with the type of ketone that gives 17-30. A useful variation of the Schmidt reaction treats a cyclic ketone with an alkyl azide (RN₃)³²³ in the presence of TiCl₄, generating a lactam.³²⁴ An intramolecular Schmidt reaction gives bicyclic amines.³²⁵ Another variation treats a silyl enol ether of a cyclic ketone with TMSN₃ and photolyzes the product with UV light to give a lactam.³²⁶ An α–azido cyclic ketone rearrangement to lactams under radical conditions (Bu₃SnH/AIBN).³²⁷

Alcohols and alkenes react with HN₃ to give alkyl azides,³²⁸ which in the course of reaction rearrange in the same way as discussed in Reaction 18-14.³⁰⁹ The Mitsunobu Reaction (10-17) can be used to convert alcohols to alkyl azides, and an alternative reagent for azides [(PhO)₂PON₃], for use in the Mitsunobu is now available.³²⁹ In the presence of an Au catalyst, an acetylenic azide was converted to a pyrrole derivative.³³⁰ An intramolecular Schmidt reaction gives bicyclic lactams in the presence of MeAlCl₂.³³¹

There is evidence that the mechanism with carboxylic acids³²⁰ is similar to that of Reaction 18-14, except that it is the protonated azide that undergoes the rearrangement³³²:

The first step is the same as that of the A_AC1 mechanism (Reaction 16-59, which explains why good results are obtained with hindered substrates. The mechanism with ketones involves formation of a nitrilium ion (82), which reacts with water.

Intermediates (e.g., 90) have been independently generated in aqueous solution.³³³ Note the similarity of this mechanism to those of “insertion” of CH₂ (Reaction 18-9) and of O (Reaction 18-19). The three reactions are essentially analogous, both in products and in mechanism.^334,320 Also note the similarity of the latter part of this mechanism to that of the Beckmann rearrangement (Reaction 18-17).

OS V, 408; VI, 368; VII, 254; X, 207. See also, OS V, 623.

18-17 The Beckmann Rearrangement

Beckmann oxime–amide rearrangement

When oximes are treated with PCl₅ or a number of other reagents, they rearrange to substituted amides in a reaction called the Beckmann rearrangement.³³⁵ Reagents used include concentrated H₂SO₄ acid, formic acid, liquid SO₂, silica gel,³³⁶ RuCl₃,³³⁷ Y(OTf)₃,³³⁸ I₂,³³⁹ HgCl₂,³⁴⁰ triphosphazene,³⁴¹ bromodimethylsulfonium bromide–ZnCl₂,³⁴² neat with FeCl₃,³⁴³ cyanuric acid,³⁴⁴ and polyphosphoric acid.³⁴⁵ Simply heating the oxime of benzophenone neat leads to N-phenyl benzamide.³⁴⁶ The reaction has been done in supercritical water³⁴⁷ and in ionic liquids.³⁴⁸ A polymer-bound Beckman rearrangement has been reported.³⁴⁹ Microwave assisted Beckmann rearrangements are known.³⁵⁰ Note that the reaction of an imine with BF₃·OEt₂ and m-chloroperoxybenzoic acid leads to a formamide.³⁵¹

The oximes of cyclic ketones give ring enlargement and form the lactam,³⁵² as in the formation of caprolactam (see Reaction 18-16) from the oxime of cyclohexanone. Solvent-free reactions are known.³⁵³ Cyclic ketones can be converted directly to lactams in one laboratory step by treatment with NH₂OSO₂OH and formic acid (Reaction 16-14 takes place first, then the Beckmann rearrangement).³⁵⁴

Of the groups attached to the carbon of the C=N unit, the one that migrates in the Beckman rearrangement is generally the one anti to the hydroxyl, and this is often used as a method of determining the configuration of the oxime. However, it is not unequivocal. It is known that with some oximes the syn group migrates and that with others, especially where R and R′ are both alkyl, mixtures of the two possible amides are obtained. However, this behavior does not necessarily mean that the syn group actually undergoes migration. In most cases, the oxime undergoes isomerization under the reaction conditions before migration takes place.³⁵⁵ The scope of the reaction is quite broad and R and R′ may be alkyl, aryl, or hydrogen. However, hydrogen very seldom migrates, so the reaction is not generally a means of converting aldoximes to unsubstituted amides (RCONH₂). This latter conversion can be accomplished, however, by treatment of the aldoxime with nickel acetate under neutral conditions³⁵⁶ or by heating the aldoxime for 60 h at 100 °C after it has been adsorbed onto silica gel.³⁵⁷ As in the case of the Schmidt rearrangement (Reaction 18-16), when the oxime is derived from an alkyl aryl ketone, it is generally the aryl group that preferentially migrates.³⁵⁸

Not only do oximes undergo the Beckmann rearrangement, but so also do esters of oximes with many acids, organic and inorganic. A side reaction with many substrates is the formation of nitriles (the “abnormal” Beckmann rearrangement, Reaction 17-30). The O-carbonates of imines (e.g., Ph₂C=N–OCO₂Et) react with BF₃·OEt₂ to give the corresponding amide in this case N-phenyl benzamide.³⁵⁹

In the first step of the mechanism, the OH group is converted by the reagent to a better leaving group, for example, proton acids convert it to OH₂⁺. After that, the mechanism³⁶⁰ follows a course analogous to that for the Schmidt reaction of ketones (18-16) from the formation of nitrilium ion (92) on³⁶¹: Alternative modes of reaction are possible. For example, when PCl₅ is used to induce the reaction, a N-O-PCl₄ species is formed, which generates 92. Intermediates of the form 92 have been detected by NMR and UV spectroscopy.³⁶² The rearrangement has also been found to take place by a different mechanism, involving formation of a nitrile by fragmentation, and then addition by a Ritter Reaction (16-91).³⁶³ Beckmann rearrangements have also been carried out photochemically.³⁶⁴ A computational study compared converted versus stepwise mechanisms for the Beckmann rearrangement, and found that proton relay between the substrate and the solvent molecules controls the reaction, and migration and N–O bond scission occur simultaneously.³⁶⁵

If the rearrangement of oxime sulfonates is induced by organoaluminum reagents,³⁶⁶ the nitrilium ion intermediate (92) is captured by the nucleophile originally attached to the Al. By this means an oxime can be converted to an imine, an imino thioether (R–N=C–SR), or an imino nitrile (R–N=C–CN).³⁶⁷ In the last case, the nucleophile comes from added trimethylsilyl cyanide. In the presence of LiI, 2-benzyloxypyridine is converted to N-benzyl-2-pyridone.³⁶⁸

In a related reaction, treatment of spirocyclic oxaziridines with MnCl(tpp) (tpp = triphenylphosphine, ligand)³⁶⁹ or photolysis³⁷⁰ leads to a lactam.

OS II, 76, 371; VIII, 568.

18-18 Stieglitz and Related Rearrangements

Methoxy-de- N-chloro-(2/→1/ N-alkyl)- migro-substitution, and so on

In addition to the reactions discussed at 18-13–18-17, other rearrangements are known in which an alkyl group migrates from C to N. Certain bicyclic N-haloamines (e.g., N-chloro-2-azabicyclo[2.2.2]octane, above), undergo rearrangement when solvolyzed in the presence of silver nitrate.³⁷¹ This reaction is similar to the Wagner–Meerwein rearrangement (18-1) and is initiated by the silver-catalyzed departure of the chloride ion.³⁷² Similar reactions have been used for ring expansions and contractions, analogous to those discussed for Reaction 18-3.³⁷³ An example is the conversion of 1-(N-chloroamino)cyclopropanols to β-lactams.³⁷⁴ Methyl prolinate was converted to the 2-piperidone upon treatment with SmI₂ and pivalic acid–THF.³⁷⁵

The name Stieglitz rearrangement is generally applied to the rearrangements of trityl N-haloamines and

hydroxylamines. These reactions are similar to the rearrangements of alkyl azides (18-14), and the name Stieglitz rearrangement is also given to the rearrangement of trityl azides. Another similar reaction is the rearrangement undergone by tritylamines when treated with lead tetraacetate (Ar₃CNH₂ → Ar₂C=NAr.³⁷⁶

D. Carbon-to-Oxygen Migrations of R and Ar

18-19 The Baeyer–Villiger Rearrangement³⁷⁷

Oxy-insertion

The treatment of ketones with peroxyacids (e.g., peroxybenzoic or peroxyacetic acid or with other peroxy compounds in the presence of acid catalysts, gives carboxylic esters by migration of an alkyl group oxygen³⁷⁸ and the carboxylic acid parent of the peroxyacid as a byproduct. In other words, there is a C → O rearrangement, and the reaction is called the Baeyer–Villiger rearrangement.³⁷⁹ A particularly good reagent is peroxytrifluoroacetic acid. Reactions with this reagent are rapid and clean, giving high yields of product, although it is often necessary to add a buffer (e.g., Na₂HPO₄), to prevent transesterification of the product with trifluoroacetic acid that is also formed during the reaction. The reaction is often applied to cyclic ketones to give lactones.³⁸⁰ Hydrogen peroxide has been used to convert cyclic ketones to lactones using a catalytic amount of MeReO₃³⁸¹ or a diselenide catalyst.³⁸²Heterogeneous catalysts are used for the Baeyer–Villiger reaction.³⁸³ Transition metal catalysts have been used with peroxyacids to facilitate the oxidation.³⁸⁴ Polymer-supported peroxy acids have been used,³⁸⁵ and solvent-free Bayer–Villiger reactions are known.³⁸⁶ Potassium peroxomonosulfate supported on acidic silica gel has been used.³⁸⁷

Enantioselective synthesis³⁸⁸ of chiral lactones from achiral ketones has been achieved by the use of enzymes³⁸⁹ and other asymmetric reactions are known.³⁹⁰ Chiral Pd complexes give chiral lactones from cyclic ketones with high enantioselectively.³⁹¹ Other chiral catalysts include those based on Al.³⁹² Baeyer–Villiger oxidation of chiral substrates with m-chloroperoxybenzoic acid (mcpba) also leads to chiral lactones.³⁹³

For acyclic compounds, R′ must usually be secondary, tertiary, or vinylic, although primary R′ has been rearranged with peroxytrifluoroacetic acid,³⁹⁴ with I₂–H₂O₂,³⁹⁵ BF₃–H₂O₂,³⁹⁶ and with K₂S₂O₈–H₂SO₄.³⁹⁷ For unsymmetrical ketones, the approximate order of migration is tertiary alkyl > secondary alkyl, aryl > primary alkyl > methyl. Since the methyl group has a low migrating ability, the reaction provides a means of cleaving a methyl ketone (R′COMe) to produce an alcohol or phenol (R′OH, by hydrolysis of the ester R′OCOMe). The migrating ability of aryl groups is increased by electron-donating and decreased by electron-withdrawing substituents.³⁹⁸ There is a preference of anti- over gauche migration.³⁹⁹

Enolizable β-diketones do not react. α-Diketones can be converted to anhydrides.⁴⁰⁰ With aldehydes, migration of hydrogen gives the carboxylic acid, and this is a way of accomplishing Reaction 19-23. Migration of the other group would give formates, but this seldom happens, though aryl aldehydes have been converted to formates with H₂O₂ and a selenium compound⁴⁰¹ (see also, the Dakin Reaction in 19-11).

The mechanism⁴⁰² is similar to those of the analogous reactions with hydrazoic acid (18-16 with ketones) and diazomethane (18-8):

One important piece of evidence for this mechanism was that benzophenone– gave ester entirely labeled in the carbonyl oxygen, with none in the alkoxyl oxygen.⁴⁰³ Carbon-14 isotope-effect studies on acetophenones have shown that migration of aryl groups takes place in the rate-determining step,⁴⁰⁴ demonstrating that migration of Ar is concerted with departure of OCOR².⁴⁰⁵ It is hardly likely that migration would be the slow step if the leaving group departed first to give an ion with a positive charge on an oxygen atom, which would be a highly unstable species.

18-20 Rearrangement of Hydroperoxides

C-Alkyl- O-hydroxy-elimination

Hydroperoxides (R = alkyl, aryl, or hydrogen) can be cleaved by proton or Lewis acids in a reaction whose principal step is a rearrangement.⁴⁰⁶ The reaction has also been applied to peroxy esters (R₃COOCOR′), but less often. When aryl and alkyl groups are both present, migration of aryl dominates. It is not necessary actually to prepare and isolate hydroperoxides. The reaction takes place when the alcohols are treated with H₂O₂ and acids. Migration of an alkyl group of a primary hydroperoxide provides a means for converting an alcohol to its next lower homolo (RCH₂OOH → CH₂=O + ROH).

The mechanism is as follows⁴⁰⁷:

The last step is hydrolysis of the unstable hemiacetal. Alkoxycarbocation intermediates (93, R = alkyl) have been isolated in superacid solution⁴⁰⁸ at low temperatures, and their structures proved by NMr.⁴⁰⁹ The protonated hydroperoxides could not be observed in these solutions, evidently reacting immediately on formation.

OS V, 818.

E. Nitrogen-to-Carbon, Oxygen-to-Carbon, and Sulfur-to-Carbon Migration

18-21 The Stevens Rearrangement

Hydron-(2/ N→1/alkyl)- migro-detachment

In the Stevens rearrangement,⁴¹⁰ a quaternary ammonium salt containing an electron-withdrawing group Z on one of the carbons attached to the nitrogen is treated with a strong base (e.g., NaOR or NaNH₂) to give a rearranged tertiary amine. The Z group may be RCO, ROOC, or phenyl.⁴¹¹ The most common migrating groups are allylic, benzylic, benzhydryl, 3-phenylpropargyl, and phenacyl, though even methyl migrates to a sufficiently negative center. Migration of aryl is rare, but has been reported.⁴¹² When an allylic group migrates, it may or may not involve an allylic rearrangement within the migrating group (see Reaction 18-35), depending on the substrate and reaction conditions. The reaction has been used for ring enlargement,⁴¹³ illustrated by the rearrangement of 94.

The mechanism has been the subject of much study.⁴¹⁴ The rearrangement is intramolecular, as shown by cross-over experiments, by labeling,⁴¹⁵ and by the fact that retention of configuration is found at R¹.⁴¹⁶ The first step is loss of the acidic proton to give the ylid (95), which has been isolated.⁴¹⁷ The finding⁴¹⁸ that CIDNP is observed⁴¹⁹ in many instances shows that in these cases the product is formed directly from a free-radical precursor. The following radical pair mechanism was proposed⁴²⁰:

The radicals do not drift apart because the solvent cage holds them together. According to this mechanism, the radicals must recombine rapidly in order to account for the fact that R¹ does not racemize. Other evidence in favor of mechanism a is that in some cases small amounts of coupling products (R¹–R¹) have been isolated,⁴²¹ which would be expected if some √R¹ leaked from the solvent cage. However, not all the evidence is easily compatible with mechanism a.⁴²² It is possible that another mechanism (b), similar to mechanism a, but

involving ion pairs in a solvent cage instead of radical pairs, operates in some cases. A third possible mechanism would be a concerted 1,2-shift,⁴²³ but the orbital symmetry principle requires that this take place with inversion at R¹.⁴²⁴ (see Reaction 18-30 and [1,5]-migration). Since the actual migration takes place with retention, it cannot, according to this argument, proceed by a concerted mechanism. However, in the case where the migrating group is allylic, a concerted mechanism can also operate (Reaction 18-35). An interesting finding compatible with all three mechanisms is that optically active allylbenzylmethylphenylammonium iodide (asymmetric nitrogen, see Sec. 4.C, category 3) gave an optically active product⁴²⁵:

The Sommelet–Hauser rearrangement competes when Z is an aryl group (see Reaction 13-31). Hofmann elimination competes when one of the R groups contains a β hydrogen atom (Reaction 17-7 and 17-8).

Sulfur ylids containing a Z group give an analogous rearrangement (see the reaction), sometimes referred to as a Stevens rearrangement.⁴²⁶ In this case too, there is much evidence (including CIDNP) that a radical-pair cage mechanism is operating,⁴²⁷ except that when the migrating group is allylic, the mechanism may be different (see Reaction 18-35).

Another reaction with a similar mechanism⁴²⁸ is the Meisenheimer rearrangement,⁴²⁹ in which certain tertiary amine oxides rearrange on heating to give substituted hydroxylamines (see reaction).⁴³⁰ The migrating group R¹ is almost always allylic or benzilic.⁴³¹ Both R² and R³ may be alkyl or aryl, but if one of the R groups contains a β hydrogen, Cope elimination (Reaction 17-9) often competes. In a related reaction, when 2-methylpyridine N-oxides are treated with trifluoroacetic anhydride, the Boekelheide reaction occurs to give 2-hydroxymethylpyridines.⁴³²

Certain tertiary benzylic amines, when treated with BuLi, undergo a rearrangement analogous to the Wittig rearrangement (Reaction 18-22, e.g., PhCH₂NPh₂ → Ph₂CHNHPh).⁴³³ Only aryl groups migrate in this reaction.

Isocyanides, when heated in the gas phase or in nonpolar solvents, undergo a 1,2-intramolecular rearrangement to nitriles (RNC → RCN).⁴³⁴ In polar solvents, the mechanism is different.⁴³⁵

18-22 The Wittig Rearrangement⁴³⁶

Hydron-(2/ O→1/alkyl)- migro-detachment

The rearrangement of ethers upon treatment with alkyllithium reagents is called the Wittig rearrangement (not to be confused with the Wittig Reaction, 16-44) and is similar to 18-21.⁴¹¹ However, a stronger base is required (e.g., phenyllithium or sodium amide). The R and R′ groups may be alkyl,⁴³⁷ aryl, or vinylic.⁴³⁸ Also, one of the hydrogen atoms may be replaced by an alkyl or aryl group, in which case the product is the salt of a tertiary alcohol. Migratory aptitudes here are allylic, benzylic > ethyl > methyl > phenyl.⁴³⁹ The stereospecificity of the 1,2-Wittig rearrangement has been discussed.⁴⁴⁰ The following radical-pair mechanism⁴⁴¹ (similar to mechanism a of Reaction 18-21) is likely, after removal of the proton by the base. One of the

the radical pair is a ketyl. Evidence for this mechanism includes (1) the rearrangement is largely intramolecular; (2) migratory aptitudes are in the order of free-radical stabilities, not of carbanion stabilities⁴⁴² (which rules out an ion-pair mechanism similar to mechanism b of Reaction 18-21); (3) aldehydes are obtained as side products⁴⁴³; (4) partial racemization of R′ has been observed⁴⁴⁴ (the remainder of the product retained its configuration); (5) cross-over products have been detected⁴⁴⁵; and (6) when ketyl radicals and R√ radicals from different precursors were brought together, similar products resulted.⁴⁴⁶ However, there is evidence that at least in some cases the radical-pair mechanism accounts for only a portion of the product, and some kind of concerted mechanism can also take place.⁴⁴⁷ Most of the above investigations were carried out with systems where R′ is alkyl, but a radical-pair mechanism has also been suggested for the case where R′ is aryl.⁴⁴⁸ When R′ is allylic a concerted mechanism can operate (Reaction 18-35).

When R is vinylic it is possible, by using a combination of an alkyllithium and t-BuOK, to get migration to the γ carbon (as well as to the α carbon), producing an enolate that, on hydrolysis, gives an aldehyde⁴⁴⁹:

An aza-Wittig rearrangement is also known.⁴⁵⁰ Other [2,3]-rearrangements are discussed in Reaction 18-35.

There are no OS references, but see OS VIII, 501, for a related reaction.

F. Boron-to-Carbon Migrations⁴⁵¹

For another reaction involving boron-to-carbon migration, see 10-73.

18-23 Conversion of Boranes to Alcohols

Oxidation of trialkylboranes (see Reaction 15-16) uses NaOH and H₂O₂, which react to give the hydroperoxide anion, (HOO⁻). Reaction of the organoborane with basic H₂O₂ (via HOO⁻) leads to an ate-complex, and subsequent B → O rearrangement of an alkyl group on boron to a peroxy oxygen, with expulsion of hydroxide, leads to a borate, and then an alcohol after hydrolysis. The proposed mechanism⁴⁵² is shown in which a trialkylborane is converted to 3 molar equivalents of the alcohol, along with boric acid.

Using the hydroboration reaction in 15-16, this procedure converts alkenes to an anti-Markovnikov borane, and oxidation leads to the anti-Markovnikov alcohol. An example is the conversion of methylcyclopentene to trans-2-methylcyclopentanol.⁴⁵³ Formation of the organoborane proceeds via a cis-addition of B–H, placing the boron trans to the methyl group, and stereoselective oxidation and B → O rearrangement leads to retention of configuration in the alcohol, as shown.

Trialkylboranes can be prepared from alkenes by Reaction 15-16, and they react with carbon monoxide⁴⁵⁴ at 100–125 °C in the presence of ethylene glycol to give the 2-bora-1,3-dioxolanes (96), which are easily oxidized (Reaction 12-27) to tertiary alcohols.⁴⁵⁵ The R groups may be primary, secondary, or tertiary, and may be the same or different.⁴⁵⁶ Yields are high and the reaction is quite useful, especially for the preparation of sterically hindered alcohols (e.g., tricyclohexylcarbinol, 97 and tri-2-norbornylcarbinol, 98), which are difficult to prepare by Reaction 16-24. Heterocycles in which boron is a ring atom react similarly (except that high CO pressures are required), and cyclic alcohols can be obtained from these substrates.⁴⁵⁷ The preparation of such heterocyclic boranes was discussed at Reaction 15-16. The overall conversion of a diene or triene to a cyclic alcohol has been described by H.C. Brown as “stitching” with boron and “riveting” with carbon.

The mechanism has been shown to be intramolecular by the failure to find cross-over products when mixtures of boranes are used.⁴⁵⁸ The following scheme, involving three boron-to-carbon migrations, to 99 and then to 100 has been suggested.

The purpose of the ethylene glycol is to intercept the boronic anhydride (100), which otherwise forms polymers that are difficult to oxidize. As will be seen in Reaction 18-23 and 18-24, it is possible to stop the reaction after only one or two migrations have taken place.

There are two other methods for achieving the conversion R₃B → R₃COH, which often give better results: (1) treatment with α,α-dichloromethyl methyl ether and the base lithium triethylcarboxide⁴⁵⁹ (2) treatment with a suspension of sodium cyanide in THF followed by reaction of the resulting trialkylcyanoborate (101) with an excess (>2 equiv) of trifluoroacetic anhydride.⁴⁶⁰ All the above migrations take place with retention of configuration at the migrating carbon.⁴⁶¹

Several other methods for the conversion of boranes to tertiary alcohols are also known.⁴⁶²

If the reaction between trialkylboranes and carbon monoxide (18-23) is carried out in the presence of water followed by addition of NaOH, the product is a secondary alcohol. If H₂O₂ is added along with the NaOH, the corresponding ketone is obtained instead.⁴⁶³ Various functional groups (e.g., OAc, COOR, CN) may be present in R without being affected,⁴⁶⁴ although if they are in the α or β position relative to the boron atom, difficulties

may be encountered. The use of an equimolar amount of trifluoroacetic anhydride leads to the ketone rather than the tertiary alcohol.⁴⁶⁵ By this procedure thexylboranes (RR′R²B, where R² = thexyl) can be converted to unsymmetrical ketones (RCOR′).⁴⁶⁶ Variations of this methodology have been used to prepare optically active alcohols.⁴⁶⁷ For another conversion of trialkylboranes to ketones see Reaction 18-26.⁴⁶⁸

OS VII, 427. Also see, OS VI, 137.

18-24 Conversion of Boranes to Primary Alcohols, Aldehydes, or Carboxylic Acids

When the reaction between a trialkylborane and carbon monoxide (18-23) is carried out in the presence of a reducing agent (e.g., lithium borohydride or potassium triisopropoxyborohydride), the reduction agent intercepts the intermediate (99), so that only one boron→carbon migration takes place, and the product is hydrolyzed to a primary alcohol or oxidized to an aldehyde.⁴⁶⁹ This procedure wastes two of the three R groups, but this problem can be avoided by the use of B-alkyl-9-BBN derivatives (see Reaction 15-16). Since only the 9-alkyl group migrates, this method permits the conversion in high yield of an alkene to a primary alcohol or aldehyde containing one more carbon.⁴⁷⁰ When B-alkyl-9-BBN derivatives are treated with CO and lithium tri-tert-butoxyaluminum hydride,⁴⁷¹ other functional groups (e.g., CN and ester) can be present in the alkyl group without being reduced.⁴⁷² Boranes can be directly converted to carboxylic acids by reaction with the dianion of phenoxyacetic acid.⁴⁷³

Boronic esters [RB(OR′)₂] react with methoxy(phenylthio)methyllithium [LiCH(OMe)SPh] to give salts, which, after treatment with HgCl₂, and then H₂O₂, yield aldehydes.⁴⁷⁴ This synthesis has been made enantioselective, with high ee values (>99%), by the use of an optically pure boronic ester,⁴⁷⁵ for example:

18-25 Conversion of Vinylic Boranes to Alkenes

The reaction between trialkylboranes and iodine to give alkyl iodides was mentioned at 12-31. When the substrate contains a vinylic group, the reaction takes a different course,⁴⁷⁶ with one of the R′ groups migrating to the carbon, to give alkenes.⁴⁷⁷ The reaction is stereospecific in two senses: (1) if the groups R and R″ are cis in the starting compound, they will be trans in the product; (2) there is retention of configuration within the migrating group R′.⁴⁷⁸Since vinylic boranes can be prepared from alkynes (Reaction 15-16), this is a method for the addition of R′ and H to a triple bond. If R² = H, the product is a (Z)-alkene. The mechanism is believed to involve an iodonium intermediate, (e.g., 102) and attack by iodide on boron. When R′ is vinylic, the product is a conjugated diene.⁴⁷⁹

In another procedure, the addition of a dialkylborane to a 1-haloalkyne produces an α-halo vinylic borane (103).⁴⁸⁰ Treatment of 103 with NaOMe gives the rearrangement shown, and protonolysis of the product produces the (E)-alkene.⁴⁷⁸ If R is a vinylic group, the product is a 1,3-diene.⁴⁸¹ If one of the groups is thexyl, the other migrates.⁴⁸² A combination of both of the procedures described above results in the preparation of trisubstituted alkenes.⁴⁸³

18-26 Formation of Alkynes, Alkenes, and Ketones from Boranes and Acetylides

A hydrogen directly attached to a triple-bond carbon can be replaced in high yield by an alkyl or an aryl group, by treatment of the lithium acetylide with a trialkyl- or triarylborane, followed by reaction of the lithium alkynyltrialkylborate (104) with iodine.⁴⁸⁴ The R′ group may be primary or secondary alkyl as well as aryl, so the reaction has a broader scope than the older Reaction 10-74.⁴⁸⁵ The R group may be alkyl, aryl, or hydrogen, although in the last-mentioned case satisfactory yields are obtained only if lithium acetylide-ethylenediamine is used as the starting compound.⁴⁸⁶ Optically active alkynes can be prepared by using optically active thexylborinates (RR²BOR′, R² = thexyl, where R is chiral) and LiCCSiMe₃.⁴⁸⁷ The reaction can be adapted to the preparation of alkenes⁴⁸⁸ by treatment of 104 with an electrophile (e.g., propanoic acid⁴⁸⁹ or tributyltin chloride).⁴⁹⁰ The reaction with Bu₃SnCl produces the (Z)-alkene stereoselectively.

Treatment of 104 with electrophiles (e.g., methyl sulfate, allyl bromide, or triethyloxonium borofluoride), followed by oxidation of the resulting vinylic borane, gives a ketone (illustrated for methyl sulfate)⁴⁹¹:

Note that there are reactions that involve N → O rearrangements, including those mediated by silicon.⁴⁹²

18.F.ii. Non-1,2 Rearrangements

A. Electrocyclic Rearrangements

18-27 Electrocyclic Rearrangements of Cyclobutenes and 1,3-Cyclohexadienes

(4) seco-1/4/Detachment; (4) cyclo-1/4/Attachment

(6) seco-1,6/Detachment; (6) cyclo-1/6/Attachment

Cyclobutenes and 1,3-dienes can be interconverted by treatment with UV light or with heat.⁴⁹³ These are 4π-electrocyclizations. The thermal reaction is generally not reversible (although exceptions⁴⁹⁴ are known), and many cyclobutenes have been converted to 1,3-dienes by heating at temperatures between 100 and 200 °C.⁴⁹⁵ Benzocyclobutenes also undergo electrocyclic ring opening,⁴⁹⁶ as do benzocyclobutanones.⁴⁹⁷ The photochemical conversion can in principle be carried out in either direction, but most often 1,3-dienes are converted to cyclobutenes rather than the reverse, because the dienes are stronger absorbers of light at the wavelengths used.⁴⁹⁸ In a similar reaction, 1,3-cyclohexadienes interconvert with 1,3,5-trienes, but in this case the ring-closing process is generally favored thermally and the ring-opening process photochemically, but exceptions are known in both directions.⁴⁹⁹ Substituent effects can lead to acceleration of the electrocyclization process.⁵⁰⁰ Torquoselectivity in cyclobutene ring-opening reaction has been examined.⁵⁰¹

Examples of these types of reactions include:

Ref. 502

An interesting example of 1,3-cyclohexadiene→1,3,5-triene interconversion is the reaction of norcaradienes to give cycloheptatrienes.⁵⁰³ This is a 6π-electrocyclization, and it has been catalyzed by Lewis acids.⁵⁰⁴ Norcaradienes give this reaction so readily (because they are cis-1,2-divinylcyclopropanes, see Reaction 18-32) that they cannot generally be isolated, though some exceptions are known⁵⁰⁵ (see also, 15-64).

These reactions, called electrocyclic rearrangements,⁵⁰⁶ take place by pericyclic mechanisms. The evidence comes from stereochemical studies, which show a remarkable stereospecificity whose direction depends on whether the reaction is induced by heat or light. For example, it was found for the thermal reaction that cis-3,4-dimethylcyclobutene gave only cis,trans-2,4-hexadiene, while the trans isomer gave only the trans–trans-diene⁵⁰⁷:

This is evidence for a four-membered cyclic transition state and arises from conrotatory motion about the C-3–C-4 bond.⁵⁰⁸ It is called conrotatory because both movements are clockwise (or both counterclockwise). Because both rotate in the same direction, the cis isomer gives the cis–trans-diene.⁵⁰⁹ The other possibility (disrotatory motion) would have one moving clockwise while the other moves counterclockwise; the cis isomer would have given the cis–cis-diene (shown) or the trans–trans-diene. If the motion had been disrotatory, this would still have been evidence for a cyclic mechanism. If the mechanism were a diradical or some other kind of noncyclic process, it is likely that no stereospecificity of either kind would have been observed. The reverse

reaction is also conrotatory. In contrast, the photochemical cyclobutene: 1,3-diene interconversion is disrotatory in either direction.⁵¹⁰ On the other hand, the cyclohexadiene: 1,3,5-triene interconversion shows precisely the opposite behavior. The thermal process is disrotatory, while the photochemical process is conrotatory (in either direction). These startling results are a consequence of the symmetry rules mentioned in Section 15-60, the FOM.⁵¹¹ As in the case of cycloaddition reactions, we will use the FOM and Möbius–Hückel approaches.⁵¹²

The Frontier Orbital Method (FOM)⁵¹³

As applied to these reactions, the FOM may be expressed: A σ bond will open in such a way that the resulting p orbitals will have the symmetry of the highest occupied π orbital of the product. In the case of cyclobutenes, the HOMO of the product in the thermal reaction is the χ₂ orbital (Fig. 18.1). Therefore, in a thermal process, the cyclobutene must open so that on one side the positive lobe lies above the plane, and on the other side below it. Thus the substituents are forced into conrotatory motion (Fig. 18.2). On the other hand, in the photochemical process, the HOMO of the product is now the χ₃ orbital (Fig. 18.1), and in order for the p orbitals to achieve this symmetry (the two plus lobes on the same side of the plane), the substituents are forced into disrotatory motion.

Fig. 18.1 Symmetries of the X₂ and X₃^∗ orbitals of a conjugated diene

Fig. 18.2 Thermal opening of 1,2-diethylcyclobutene. The two hydrogens and two methyls are forced into conrotatory motion so that the resulting p-orbitals have the symmetry of the HOMO of the diene.

This reaction may be considered from the opposite direction (ring closing). For this direction, the rule is that those lobes of orbitals that overlap (in the HOMO) must be of the same sign. For thermal cyclization of butadienes, this requires conrotatory motion (Fig. 18.3). In the photochemical process, the HOMO is the χ₃ orbital, so that disrotatory motion is required for lobes of the same sign to overlap.

Fig. 18.3 Thermal ring closing of a 1,3-diene. Conrotatory motion is required for two + lobes to overlap.

The Möbius–Hückel Method

As seen in Reaction 15-60, the Möbius–Hückel Method, a basis set of p orbitals is chosen and inspected for sign inversions in the transition state. Figure 18.4 shows a basis set for a 1,3-diene. It is seen that disrotatory ring closing (Fig. 18.4a) results in overlap of plus lobes only, while in conrotatory closing (Fig. 18.4b) there is one overlap of a plus with a minus lobe. In the first case, there are zero sign inversions, while in the second there is one sign inversion. With zero (or an even number of) sign inversions, the disrotatory transition state is a Hückel system, and so is allowed thermally only if the total number of electrons is 4n + 2 (Sec. 15-60, the Möbius–Hückel Method). Since the total here is 4, the disrotatory process is not allowed. On the other hand, the conrotatory process, with one sign inversion, is a Möbius system, which is thermally allowed if the total number is 4n. The conrotatory process is therefore allowed thermally. For the photochemical reactions, the rules are reversed: A reaction with 4n electrons requires a Hückel system, so only the disrotatory process is allowed.

Fig. 18.4 The 1,3-diene–cyclobutene interconversion. The orbitals shown are not molecular orbitals, but a basis set of p atomic orbitals. (a) Disrotatory ring closure gives zero sign inversion. (b) Conrotatory ring closure gives one sign inversion. We could have chosen to show any other basis set (another basis set would have two plus lobes above the plane and two below, etc.). This would change the number of sign inversion, but the disrotatory mode would still have an even number of sign inversions, and the conrotatory mode an odd number, whichever basis set was chosen.

Both the FOM and the Möbius–Hückel methods can also be applied to the cyclohexadiene: 1,3,5-triene reaction⁵¹⁴; in either case the predicted result is that for the thermal process, only the disrotatory pathway is allowed, and for the photochemical process, only the conrotatory. For example, for 1,3,5-hexatriene, the symmetry of the HOMO is

In the thermal cleavage of cyclohexadienes, then, the positive lobes must lie on the same side of the plane, requiring disrotatory motion:

Disrotatory motion is also necessary for the reverse reaction, in order that the orbitals that overlap may be of the same sign:

All these directions are reversed for photochemical processes, because in each case a higher orbital, with inverted symmetry, is occupied.

In the Möbius–Hückel approach, diagrams similar to Fig. 18.4 can be drawn for this case. Here too, the disrotatory pathway is a Hückel system and the conrotatory pathway a Möbius system, but since six electrons are now involved, the thermal reaction follows the Hückel pathway and the photochemical reaction the Möbius pathway.

In the most general case, four possible products can arise from a given cyclobutene or cyclohexadiene: two from the conrotatory and two from the disrotatory pathway. For example, conrotatory ring opening of 105 gives either 106 or 107, while disrotatory opening gives either 108 or 109. The orbital-symmetry rules indicate when a given reaction will operate by the conrotatory and when by the disrotatory mode, but not which of the two possible conrotatory or disrotatory pathways will be followed. Often, however, it is possible to make such

predictions on steric grounds. For example, in the opening of 105 by the disrotatory pathway, 108 arises when groups A and C swing in toward each other (clockwise motion around C-4, counterclockwise around C-3), while 109 is formed when groups B and D swing in and A and C swing out (clockwise motion around C-3, counterclockwise around C-4). This observation leads to a prediction that when A and C are larger than B and D, the predominant or exclusive product will be 109 rather than 108. Predictions of this kind have largely been borne out.⁵¹⁵ There is evidence, however, that steric effects⁵¹⁶ are not the only factor, and that electronic effects also play a role, and their role may be even greater.⁵¹⁷ An electron-donating group stabilizes the transition state when it rotates outward, because it mixes with the LUMO; if it rotates inward, it mixes with the HOMO, destabilizing the transition state.⁵¹⁸ The compound 3-formylcyclobutene provided a test. Steric factors would cause the CHO (an electron-withdrawing group) to rotate outward; electronic effects would cause it to rotate inward. The experiment showed inward rotation.⁵¹⁹

Cyclohexadienes are of course 1,3-dienes, and in certain cases it is possible to convert them to cyclobutenes instead of to 1,3,5-trienes.⁵²⁰ An interesting example is found in the pyrocalciferols. Photolysis of the syn isomer (110) (or of the other syn isomer, not shown) leads to the corresponding cyclobutene,⁵²¹ while photolysis of the anti isomers (one of them is 111) gives the ring-opened 1,3,5-triene (112). This difference in behavior is at first sight remarkable, but is easily explained by the orbital-symmetry rules. Photochemical ring opening to a 1,3,5-triene must be conrotatory. If 110 were to react by this pathway, the product would be the triene 112, but this compound would have to contain a trans-cyclohexene ring (either the methyl group or the hydrogen would have to be directed inside the ring). On the other hand, photochemical conversion to a cyclobutene must be disrotatory, but if 111 were to give this reaction, the product would have to have a trans-fused ring junction. Compounds with such ring junctions are known (Sec. 4.K.iii), but are very strained. Stable trans-cyclohexenes are unknown (Sec. 4.Q.iii). Thus, 110 and 111give the products they do owing to a combination of orbital-symmetry rules and steric influences.

A related process is the Bergmann cyclization,⁵²² where an ene–diyne cyclizes to a biradical (103) and then aromatizes as shown. Simply heating the en–diyne will usually lead to aromatization via this pathway.⁵²³ Quinones can be formed via Bergman cyclization⁵²⁴ and there are other synthetic applications.⁵²⁵ The role of vinyl substitution has been examined.⁵²⁶ An aza-Bergman cyclization is known.⁵²⁷

The 1,3-diene-cyclobutene interconversion can even be applied to benzene rings. For example,⁵²⁸ photolysis of 1,2,4-tri-tert-butylbenzene (114) gives 1,2,5-tri-tert-butyl[2.2.0]hexadiene (115, a Dewar benzene).⁵²⁹ The reaction owes its success to the fact that once 115 is formed, it cannot, under the conditions used, revert to 114 by either a thermal or a photochemical route. The orbital-symmetry rules prohibit thermal conversion of 115 to 114 by a pericyclic mechanism, because thermal conversion of a cyclobutene to a 1,3-diene must be conrotatory, and conrotatory reaction of 115 would result in a 1,3,5-cyclohexatriene containing one trans double bond (116), which is of course too strained to exist. Compound 115 cannot revert to 114 by a photochemical pathway either, because light of the frequency used to excite 114 would not be absorbed by 115. This is another example of a molecule that owes its stability to the orbital-symmetry rules (see Reaction 15-63). Pyrolysis of 115 does give 114, probably by a diradical mechanism.⁵³⁰ In the case of 117 and 118, the Dewar benzene is actually more stable than the benzene. Compound 117 rearranges to 118 in 90% yield at 120 °C.⁵³¹ In this case, thermolysis of the benzene gives the Dewar benzene (rather than the reverse), because of the strain of four adjacent tert-butyl groups on the ring.

A number of electrocyclic reactions have been carried out with systems of other sizes, [(e.g., conversion of the 1,3,5,7-octatetraene (119) to the cyclooctatriene (120)].⁵³² The stereochemistry of these reactions can be predicted in a similar manner. The results of such predictions can be summarized according to whether the number of electrons involved in the cyclic process is of the form 4n or 4n + 2 (where n is any integer including zero).

Thermal Reaction

Photochemical Reaction

4n

Conrotatory

Disrotatory

4n + 2

Disrotatory

Conrotatory

Although the orbital-symmetry rules predict the stereochemical results in almost all cases, it is necessary to recall (Reaction 15-60, the Möbius–Hückel Method) that they only say what is allowed and what is forbidden, but the fact that a reaction is allowed does not necessarily mean that the reaction takes place, and if an allowed reaction does take place, it does not necessarily follow that a concerted pathway is involved, since other pathways of lower energy may be available.⁵³³ Furthermore, a “forbidden” reaction might still be made to go, if a method of achieving its high activation energy can be found. This was, in fact, done for the cyclobutene–butadiene interconversion (cis-3,4-dichlorocyclobutene gave the forbidden cis,cis- and trans,trans-1,4-dichloro-1,3-butadienes, as well as the allowed cis, trans isomer) by the use of IR laser light.⁵³⁴ This is a thermal reaction. The laser light excites the molecule to a higher vibrational level (Sec. 7.A.i), but not to a higher electronic state.

As is the case for [2 + 2]-cycloaddition reactions (15-63), certain forbidden electrocyclic reactions can be made to take place by the use of metallic catalysts.⁵³⁵ An example is the silver ion-catalyzed conversion of tricyclo[4.2.0.0^2.5]octa-3,7-diene to cyclooctatetraene⁵³⁶:

This conversion is very slow thermally (i.e., without the catalyst) because the reaction must take place by a disrotatory pathway, which is disallowed thermally.⁵³⁷ In another example, the major thermal product from the barrelene anion is a rearranged allyl anion that is formed by disrotatory cleavage of the cyclopropyl ring, a formally Woodward–Hoffmann-forbidden process.⁵³⁸

The ring opening of cyclopropyl cations (Sec. 10.G.i, category 7 and Reaction 18-3) is an electrocyclic reaction and is governed by the orbital symmetry rules.⁵³⁹ For this case, the rule is invoked that the σ bond opens in such a way that the resulting p orbitals have the symmetry of the highest occupied orbital of the product, in this case,

an allylic cation. Recall that an allylic system has three molecular orbitals (Sec. 2.C, category 3). For the cation, with only two electrons, the highest occupied orbital is the one of lowest energy (HOMO). Thus, the cyclopropyl cation must undergo a disrotatory ring opening in order to maintain the symmetry. Note that, in contrast, ring opening of the cyclopropyl anion must be conrotatory,⁵⁴⁰ since in this case it is the next orbital of the allylic system that is the highest occupied, and this has the opposite symmetry.⁵⁴¹ However, it is difficult to generate a free cyclopropyl cation (Sec. 10.G.i, category 7), and it is likely that in most cases, cleavage of the σ bond is concerted with departure of the leaving group in the original cyclopropyl substrate. This, of course, means that the σ bond provides anchimeric assistance to the removal of the leaving group (an S_N2 type process), and we would expect that such assistance should come from the back side. This has an important effect on the direction of ring opening. The orbital-symmetry rules require that the ring opening is disrotatory, but as seen above, there are two disrotatory pathways and the rules do not indicate which is preferred. But the fact that the σ orbital provides assistance from the backside means that the two substituents that are trans to the leaving group must move outward, not inward.⁵⁴² Thus, the disrotatory pathway that is followed is the one shown in B, not the one shown in B′, because the former puts the electrons of the σ bond on the side opposite

that of the leaving group.⁵⁴³ Strong confirmation of this picture⁵⁴⁴ comes from acetolysis of endo- (121) and exo-bicyclo[3,1,0]hexyl-6-tosylate (112). The groups trans to the tosylate must move outward. For 121, this means that the two hydrogen atoms can go outside the framework of the six-membered ring, but for 122 they

are forced to go inside. Consequently, it is not surprising that the rate ratio for solvolysis of 121/122 was found to be >2.5 × 10⁶ and that at 150 °C, 122 did not solvolyze at all.⁵⁴⁵ This evidence is kinetic. Unlike the cases of the cyclobutene (1,3-diene and cyclohexadiene) 1,3,5-triene interconversions, the direct product here is a cation, which is not stable but reacts with a nucleophile and loses some of its steric integrity in the process, so that much of the evidence has been of the kinetic type rather than from studies of product stereochemistry. However, it has been shown by investigations in superacids (Sec. 5.A.ii), where it is possible to keep the cations intact and to study their structures by NMR, that in all cases studied the cation that is predicted by these rules is in fact formed.⁵⁴⁶

OS V, 235, 277, 467; VI, 39, 145, 196, 422, 427, 862; IX, 180.

18-28 Conversion of One Aromatic Compound to Another

(6) cyclo-de-hydrogen-coupling (Overall transformation)

Stilbenes can be converted to phenanthrenes by irradiation with UV light⁵⁴⁷ in the presence of an oxidizing agent, (e.g., dissolved molecular oxygen, FeCl₃, or iodine).⁵⁴⁸ The reaction is a photochemically allowed conrotatory⁵⁴⁹conversion of a 1,3,5-hexatriene to a cyclohexadiene, followed by removal of two hydrogen atoms by the oxidizing agent. The intermediate dihydrophenanthrene has been isolated.⁵⁵⁰ The actual reacting species must be the cis-stilbene, but trans-stilbenes can often be used, because they are isomerized to the cis isomers under the reaction conditions. The reaction can be extended to the preparation of many fused aromatic systems, for example⁵⁵¹:

though not all such systems give a reaction.⁵⁵² The use of substrates containing heteroatoms (e.g., PhN=NPh) allows the formation of heterocyclic ring systems.

Isomerization of biphenylene to benzo[a]pentalene⁵⁵³ is a well-known benzene ring contraction rearrangement,⁵⁵⁴ driven by relief of strain in the four-membered ring. Related to this process is the flash vacuum pyrolysis (FVP) of the alternant polycyclic aromatic hydrocarbon benzo[b]biphenylene at 1100 °C, which gives fluoranthene, a nonalternant polycyclic aromatic hydrocarbon, as the major product at 1100 °C in the gas phase.⁵⁵⁵ The mechanism used explain that this isomerization involves equilibrating diradicals of 2-phenylnaphthalene, which rearrange by the net migration of a phenyl group to give equilibrating diradicals of 1-phenylnaphthalene, one isomer of which then cyclizes to fluoranthene.

Another transformation of one aromatic compound to another is the Stone–Wales rearrangement of pyracyclene (123),⁵⁵⁶ which is a bond-switching reaction. The rearrangement of bifluorenylidene (124) to dibenzo[g,p]chrysene (125) occurs at temperatures as low as 400 °C and is accelerated in the presence of decomposing iodomethane, a convenient source of methyl radicals.⁵⁵⁷ This result suggested a radical rearrangement. This rearrangement is believed to occur by a radical-promoted mechanism consisting of a sequence of homoallyl-cyclopropylcarbinyl rearrangement steps.⁵⁵⁸

B. Sigmatropic Rearrangements

A sigmatropic rearrangement is defined⁵⁵⁹ as migration, in an uncatalyzed intramolecular process, of a σ bond, adjacent to one or more π systems, to a new position in a molecule, with the π systems becoming reorganized in the process. Examples are

The order of a sigmatropic rearrangement is expressed by two numbers set in brackets: [i,j]. These numbers can be determined by counting the atoms over which each end of the σ bond has moved. Each of the original termini is given the number 1. Thus in the first example above, each terminus of the σ bond has migrated from C-1 to C-3, so the order is [3,3]. In the second example, the carbon terminus has moved from C-1 to C-5, but the hydrogen terminus has not moved at all, so the order is [1,5].

18-29 [1,j]-Sigmatropic Migrations of Hydrogen

1/→3/Hydrogen-migration; 1/→5/Hydrogen-migration

Many examples of thermal or photochemical rearrangements in which a hydrogen atom migrates from one end of a system of π bonds to the other have been reported,⁵⁶⁰ although the reaction is subject to geometrical constraints. Isotope effects play a role in sigmatropic rearrangements, and there is evidence for a kinetic silicon isotope effect.⁵⁶¹ Pericyclic mechanisms are involved,⁵⁶² and the hydrogen must, in the transition state, be in contact with both ends of the chain at the same time. This means that for [1,5] and longer rearrangements, the molecule must be able to adopt the cisoid conformation. Furthermore, there are two geometrical pathways by which any sigmatropic rearrangement can take place, illustrated for the case of a [1,5]-sigmatropic rearrangement,⁵⁶³ starting with a substrate of the form 126, where the migration origin is an asymmetric carbon atom and U ≠ V. In one of the two pathways, the hydrogen moves along the top or bottom face of the π system. This is called suprafacial migration. In the other pathway, the hydrogen moves across the π system, from top to bottom, or vice versa. This is antarafacialmigration. Altogether, a single isomer like 126 (different rotamers) can give four products. In a suprafacial migration, H can move across the top of the π system (as drawn above) to give the (R,Z)-isomer, or it can rotate 180 ° and move across the bottom of the π system to give the (S,E)- isomer.⁵⁶⁴ The antarafacial migration can similarly lead to two diastereomers, in this case the (S,Z)- and (R,E)-isomers.

In any given sigmatropic rearrangement, only one of the two pathways is allowed by the orbital-symmetry rules; the other is forbidden. To analyze this situation, first use a modified frontier orbital approach.⁵⁶⁵ Imagine that in the transition state C, the migrating H atom breaks away from the rest of the system, which is treated as if it were a free radical.

Note that this is not what actually takes place; it is imagined in order to analyze the process. In a [1,3]-sigmatropic rearrangement, the imaginary transition state consists of a hydrogen atom and an allyl radical. The latter species (Sec. 2.C, category 3) has three π orbitals, but the only one that is of concern, the HOMO, which, in a thermal rearrangement is D. The electron of the hydrogen atom is of course in a 1s orbital, which has only one lobe. The rule governing sigmatropic migration of hydrogen is the H must move from a plus to a plus or from a minus to a minus lobe, of the HOMO; it cannot move to a lobe of opposite sign.⁵⁶⁶ The only way this can happen in a thermal [1,3]-sigmatropic rearrangement is by an antarafacial migration. Consequently, the rule predicts that antarafacial thermal [1,3]-sigmatropic rearrangements are allowed, but the suprafacial pathway is forbidden. However, in a photochemical reaction, promotion of an electron means that E is now the HOMO; the suprafacial pathway is now allowed and the antarafacial pathway is forbidden.

A similar analysis of [1,5]-sigmatropic rearrangements shows that in this case the thermal reaction must be suprafacial and the photochemical process antarafacial. For the general case, with odd-numbered j, [1,j]-suprafacial migrations are allowed thermally when j is of the form 4n + 1, and photochemically when j has the form 4n − 1; the opposite is true for antarafacial migrations.

As expected, the Möbius–Hückel method leads to the same predictions. Here, examine the basis set of orbitals shown in F and G for [1,3]- and [1,5]-rearrangements, respectively. A [1,3]-shift involves four electrons, so an allowed thermal pericyclic reaction must be a Möbius system (15-60, the Möbius–Hückel Method) with one or an odd number of sign inversions. As can be seen in F, only an antarafacial migration can achieve this. A [1,5]-shift, with six electrons, is allowed thermally only when it is a Hückel system with zero or an even number of sign inversions; hence it requires a suprafacial migration.⁵⁶⁷

The actual reported results bear out this analysis. Thus a thermal [1,3]-migration is allowed to take place only antarafacially, but such a transition state would be extremely strained, and thermal [1,3]-sigmatropic migrations of hydrogen are unknown.⁵⁶⁸ On the other hand, the photochemical pathway allows suprafacial [1,3]-shifts, and a few such reactions are known, an example being the photochemical rearrangement of 127 to 128.⁵⁶⁹ Substituents influence the efficacy of the [1,3]-hydrogen shift.⁵⁷⁰

The situation is reversed for [1,5]-hydrogen shifts. In this case, the thermal rearrangements, being suprafacial, are quite common, while photochemical rearrangements are rare.⁵⁷¹ Two examples of the thermal reaction are

Ref. 572

Ref. 573

Note that the first example bears out the stereochemical prediction made earlier. Only the two isomers shown were formed. In the second example, migration can continue around the ring. Migrations of this kind are called circumambulatory rearrangements,⁵⁷⁴ and such migrations are known for cyclopentadiene,⁵⁷⁵ pyrrole, and phosphole derivatives.⁵⁷⁶ Geminal bond participation has been observed in pentadienes,⁵⁷⁷ the effects of phenyl substituents have been studied,⁵⁷⁸ and the kinetics and activation parameters of [1,5]-hydrogen shifts have been examined.⁵⁷⁹ The [1,5]-hydrogen shifts are also known with vinyl aziridines.⁵⁸⁰ A Ru catalyzed cycloisomerization of en-1-ynes leads to cyclic dienes.⁵⁸¹

The rare [1,4]-hydrogen transfer has been observed in radical cyclizations.⁵⁸² With respect to [1,7]-hydrogen shifts, the rules predict the thermal reaction to be antarafacial.⁵⁸³ Unlike the case of [1,3]-shifts, the transition state is not too greatly strained, and an example of such rearrangements is the formation of 129 and 130.⁵⁸⁴ Photochemical [1,7]-shifts are suprafacial and, not surprisingly, many of these have been observed.⁵⁸⁵

The orbital symmetry rules also help to explain the unexpected stability of certain compounds (see Reaction 15-63, preceding Reaction 15-64 and 18-27, the Möbius–Hückel Method). Thus, 130 could, by a thermal [1,3]-sigmatropic rearrangement, easily convert to toluene, which of course is far more stable because it has an aromatic sextet. Yet 130 has been prepared and is stable at dry ice temperature and in dilute solutions.⁵⁸⁶

Analogues of sigmatropic rearrangements in which a cyclopropane ring replaces one of the double bonds are also known, for example,⁵⁸⁷

The reverse reaction has also been reported.⁵⁸⁸ 2-Vinylcycloalkanols⁵⁸⁹ undergo an analogous reaction, as do cyclopropyl ketones (see 18-33, preceding 18-34 for this reaction).

18-30 [1,j]-Sigmatropic Migrations of Carbon

[1,3] migration of alkyl

Ref. 590

[1,5] migration of phenyl

Ref. 591

Sigmatropic migrations of alkyl or aryl groups⁵⁹² are less common than the corresponding hydrogen migrations.⁵⁹³ When they do take place, there is an important difference. Unlike a hydrogen atom, whose electron is in a 1sorbital with only one lobe, a carbon free radical has its odd electron in a p orbital that has two lobes of opposite sign. Therefore, if the imaginary transition states for this case are drawn (see above), a thermal suprafacial [1,5]-process (Fig. 18.5) is observed, and symmetry can be conserved only if the migrating carbon moves in such a way that the lobe that was originally attached to the π system remains attached to the π system.

Fig. 18.5 Hypothetical orbital movement for a thermal [1,5]-sigmatropic migration of carbon. To move from one negative lobe, the migrating carbon uses only its own negative lobe, retaining its configuration.

This can happen only if configuration is retained within the migrating group. On the other hand, thermal suprafacial [1,3]-migration (Fig. 18.6) can take place if the migrating carbon switches lobes. If the migrating carbon was originally bonded by its minus lobe, it must now use its plus lobe to form the new C–C bond. Thus, configuration in the migrating group will be inverted. From these considerations, suprafacial [1,j]-sigmatropic rearrangements in which carbon is the migrating group should always be allowed, both thermally and photochemically, but thermal [1,3]-migrations⁵⁹⁴ will proceed with inversion and thermal [1,5]-migrations with retention of configuration within the migrating group. More generally, suprafacial [l,j]-migrations of carbon in systems where j = 4n − 1 proceed with inversion thermally and retention photochemically, while systems where j = 4n + 1 show the opposite behavior. Where antarafacial migrations take place, all these predictions are of course reversed.

Fig. 18.6 Hypothetical orbital movement for a thermal [1,3]-sigmatropic migration of carbon. The migrating carbon moves a negative to a positive lobe, requiring it to switch its own bonding lobe from negative to positive, inverting its configuration.

The first laboratory test of these predictions was the pyrolysis of deuterated endo-bicyclo[3.2.0]hept-2-en-6-yl acetate (131), which gave the exo-deuterio-exo-norbornyl acetate (132).⁵⁹⁵ Thus, as predicted by the orbital symmetry rules, this thermal suprafacial [1,3]-sigmatropic reaction took place with complete inversion at C-7. Similar results have been obtained in a number of other cases.⁵⁹⁶ However, similar studies of the pyrolysis of the parent hydrocarbon of 131, labeled with D at C-6 and C-7, showed that while most of the product was formed with inversion at C-7, a significant fraction (11–29%) was formed with retention.⁵⁹⁷ Other cases of lack of complete inversion are also known.⁵⁹⁸ A diradical mechanism has been invoked to explain such cases.⁵⁹⁹ There is strong evidence for a radical mechanism for some [1,3]-sigmatropic rearrangements.⁶⁰⁰ Photochemical suprafacial [1,3]-migrations of carbon have been shown to proceed with retention, as predicted.⁶⁰¹

Although allylic vinylic ethers generally undergo [3,3]-sigmatropic rearrangements (Reaction 18-33), they can be made to give the [1,3] kind, to give aldehydes, for example,

by treatment with LiClO₄ in diethyl ether.⁶⁰² In this case, the C–O bond undergoes a 1,3-migration from the O to the end vinylic carbon. When the vinylic ether is of the type ROCR′=CH₂, ketones (RCH₂COR′) are formed. There is evidence that this [1,3]-sigmatropic rearrangement is not concerted, but involves dissociation of the substrate into ions.⁶⁰²

Thermal suprafacial [1,5]-migrations of carbon have been found to take place with retention,⁶⁰³ but also with inversion.⁶⁰⁴ A diradical mechanism has been suggested for the latter case.⁶⁰⁴

Simple nucleophilic, electrophilic, and free radical 1,2-shifts can also be regarded as sigmatropic rearrangements (in this case, [1,2]-rearrangements). As previously discussed (see discussion in introductory section preceding 18.A) similar principles applied to such rearrangements show that nucleophilic 1,2-shifts are allowed, but the other two types are forbidden unless the migrating group has some means of delocalizing the extra electron or electron pair. The mechanism of the forbidden [3s,5s]-sigmatropic shift has been examined.⁶⁰⁵

18-31 Conversion of Vinylcyclopropanes to Cyclopentenes

The thermal expansion of a vinylcyclopropane to a cyclopentene ring⁶⁰⁶ is a special case of a [1,3]-sigmatropic migration of carbon, although it can also be considered an internal [_π2 + _σ2]-cycloaddition reaction (see 15-63). It is known as a vinylcyclopropane rearrangement.⁶⁰⁷ The reaction has been carried out on many vinylcyclopropanes bearing various substituents in the ring⁶⁰⁸ or on the vinyl group and has been extended to 1,1-dicyclopropylethene⁶⁰⁹and (both thermally⁶¹⁰ and photochemically⁶¹¹) to vinylcyclopropenes. This

rearrangement can be catalyzed by Rh and Ag compounds, and has been used to form rings.⁶¹² Two competing reactions are the homodienyl [1,5]-shift (if a suitable H is available, see 18-29), and simple cleavage of the cyclopropane ring, leading in this case to a diene (see 18-3).

Flash vacuum pyrolysis of the trimethylsilyl ether of cyclopropylcarbinyl alcohols gives ring expanded ketones.⁶¹³ Various heterocyclic analogues⁶¹⁴ are also known, as in the rearrangement of aziridinyl amides (133).⁶¹⁵Cyclopropyl ketones can be treated with tosylamine and a Zr catalyst, which converts the imine formed in situ to a pyrroline.⁶¹⁶ N-Cyclopropylimines undergo rearrangement to cyclic imines (pyrrolines) under photochemical conditions.⁶¹⁷P-Vinyl phosphiranes (the P analogue of cyclopropanes with P in the ring) under a similar rearrangement, and the mechanism has been studied.⁶¹⁸

Vinylcyclobutanes can be converted to cyclohexenes,⁶¹⁹ but larger ring compounds do not generally give the reaction.⁶²⁰ Tricyclo[4.1.0.0^2.5]heptanes rearrange to give nonconjugated cycloheptadienes.⁶²¹ The bicyclo[2.1.0]pentane derivatives undergo this reaction.

The reaction rate has also been greatly increased by the addition of a one-electron oxidant tris-(4-bromophenyl)aminium hexafluoroantimonate (Ar₃N√⁺ SbF₆⁻, Ar = p-bromophenyl).⁶²² This reagent converts the substrate to a cation radical, which undergoes ring expansion much faster.⁶²³

The mechanisms of these ring expansions are not certain. Both concerted⁶²⁴ and diradical⁶²⁵ pathways have been proposed,⁶²⁶ and it is possible that both pathways operate, in different systems.

For the conversion of a vinylcyclopropane to a cyclopentene in a different way, see OS 68, 220.

18-32 The Cope Rearrangement

(3/4/)→(1/6/)- sigma-Migration

When 1,5-dienes are heated, a [3,3]-sigmatropic rearrangement known as the Cope rearrangement (not to be confused with the Cope elimination Reaction, 17-9) occurs to generate an isomeric 1,5-diene.⁶²⁷ When the diene is symmetrical about the 3,4-bond, the reaction gives a product identical with the starting material⁶²⁸:

Therefore, a Cope rearrangement can be detected only when the diene is not symmetrical about this bond. Any 1,5-diene gives the rearrangement; for example, 3-methyl-1,5-hexadiene heated to 300 °C gives 1,5-heptadiene.⁶²⁹However, the reaction takes place more easily (lower temperature required) when there is a group on the C-3 or C-4 with leads to the new double bond being substituted. The reaction is reversible⁶³⁰ and produces an equilibrium mixture of the two 1,5-dienes, which is richer in the thermodynamically more stable isomer. However, the equilibrium can be shifted to the right for 3-hydroxy-1,5-dienes,⁶³¹ because the product tautomerizes to the ketone or aldehyde:

This reaction of 3-hydroxy-1,5-dienes is called the oxy-Cope rearrangement,⁶³² and has proved highly useful in synthesis.⁶³³ The oxy-Cope rearrangement is greatly accelerated (by factors of 10¹⁰–10¹⁷) if the alkoxide is used rather than the alcohol (the anionic oxy-Cope rearrangement),⁶³⁴ where the direct product is the enolate ion, which is hydrolyzed to the ketone. A metal-free reaction using a phosphazene base has been reported.⁶³⁵ The silyloxy-Cope rearrangement has proven to be quite useful.⁶³⁶ An antibody-catalyzed oxy-Cope reaction is known,⁶³⁷ and the mechanism and origins of catalysis for this reaction have been studied.⁶³⁸ Sulfur substituents also lead to rate enhancement of the oxy-Cope rearrangement.⁶³⁹ Note that 2-oxonia Cope rearrangements have been implicated in Prins cyclization reactions (16-54).⁶⁴⁰ A highly diastereoselective oxonia-Cope rearrangement proceeded using a chiral aldehyde with a chiral conjugated ester.⁶⁴¹

aza-Cope rearrangements are also known.⁶⁴² There is an enantioselective aza-Cope rearrangement.⁶⁴³ There is also a 1,2-oxaza-Cope rearrangement. Involving esters and alkyl nitrites.⁶⁴⁴ In amino-Cope rearrangements, the solvent plays a role in the regioselectivity of the reaction.⁶⁴⁵ It has been suggested that this latter reaction does not proceed solely by a concerted [3.3]-sigmatropic rearrangement.⁶⁴⁶

The 1,5-diene system may be inside a ring or part of an allenic system⁶⁴⁷ (the example shown illustrates both of these situations).⁶⁴⁸ However, the reaction does not take place when one of the double bonds is part of

an aromatic system (e.g., 4-phenyl-1-butene).⁶⁴⁹ When the two double bonds are in vinylic groups attached to adjacent ring positions, the product is a ring four carbons larger. This has been applied to divinylcyclopropanes and divinylcyclobutanes, as shown.⁶⁵⁰ Indeed, cis-1,2-divinylcyclopropanes give this rearrangement so rapidly

that they generally cannot be isolated at room temperature,⁶⁵¹ but exceptions are known.⁶⁵² Note that divinyloxiranes, divinylphosphiranes, and divinylthiiranes undergo similar rearrangements.⁶⁵³ When heated, 1,5-diynes are converted to 3,4-dimethylenecyclobutenes (134).⁶⁵⁴ A rate-determining Cope rearrangement is followed by a very rapid electrocyclic (18-27) reaction.

The interconversion of 1,3,5-trienes and cyclohexadienes (in Reaction 18-27) is very similar to the Cope rearrangement, but in 18-27, the 3,4-bond goes from a double to a single bond rather than from a single bond to no bond. Like [2 + 2]-cycloadditions (Reaction 15-63), Cope rearrangements of simple 1,5-dienes can be catalyzed by certain transition metal compounds. For example, the addition of a Pd catalyst causes the reaction to take place at room temperature.⁶⁵⁵

As indicated with the arrows, the mechanism of the uncatalyzed Cope rearrangement is a simple six-centered pericyclic process.⁶⁵⁶ Since the mechanism is so simple, it has been possible to study some rather subtle points, among them the question of whether the six-membered transition state is in the boat or the chair form.⁶⁵⁷ For the case of 3,4-dimethyl-1,5-hexadiene, it was demonstrated conclusively that the transition state is in the chair form. This was shown by the stereospecific nature of the reaction: The meso isomer gave the cis–trans product, while the (±) diastereomer gave the trans–trans-diene.⁶⁵⁸ If the transition state is in the chair form (taking the meso isomer, e.g.), one methyl must be “axial” and the other “equatorial” and the product must be the

cis–trans-alkene. There are two possible boat forms for the transition state of the meso isomer. One leads to a trans–trans product; the other to a cis–cis-alkene. For the (±) pair, the predictions are just the opposite: There is just one boat form, and it leads to the cis–trans-alkene, while one chair form (“diaxial” methyls) leads to the cis–cis product and the other (“diequatorial” methyls) predicts the trans–trans product. Thus the nature of the products obtained demonstrates that the transition state is a chair and not a boat.⁶⁵⁹ While 3,4-dimethyl-1,5-hexadiene is free to assume either the chair or boat (it prefers the chair), other compounds are not so free. Thus 1,2-divinylcyclopropane (see above) can react only in the boat form, demonstrating that such reactions are possible.⁶⁶⁰

Because of the nature of the transition state⁶⁶¹ in the pericyclic mechanism, optically active substrates with a stereogenic carbon at C-3 or C-4 transfer the chirality to the product (see Reaction 18-33 for an example in the mechanistically similar Claisen rearrangement).⁶⁶² There are many examples of asymmetric [3,3]-sigmatropic rearrangements.⁶⁶³

Not all Cope rearrangements proceed by the cyclic six-centered mechanism.⁶⁶⁴ Thus cis-1,2-divinylcyclobutane (see above) rearranges smoothly to 1,5-cyclooctadiene, since the geometry is favorable. The trans isomer also gives this product, but the main product is 4-vinylcyclohexene (resulting from Reaction 18-31). This reaction can be rationalized as proceeding by a diradical mechanism (see 135),⁶⁶⁵ although it is possible that at least part of the cyclooctadiene produced comes from a prior epimerization of the trans- to the cis-divinylcyclobutane followed by Cope rearrangement of the latter.⁶⁶⁶

It has been suggested that another type of diradical two-step mechanism may be preferred by some substrates.⁶⁶⁷ Indeed, a nonconcerted Cope rearrangement has been reported.⁶⁶⁸ In this pathway,⁶⁶⁹ the 1,6-bond is formed before the 3,4-bond breaks:

This is related to the Bergman cyclization that was introduced in Reaction 18-27.

It was pointed out earlier that a Cope rearrangement of the symmetrical 1,5-hexadiene gives 1,5-hexadiene. This is a degenerate Cope rearrangement (Sec. 18.A.ii). Bicyclo[5.1.0]octadiene (136) undergoes a similar rearrangement.⁶⁷⁰ At room temperature, the NMR spectrum of this compound is in accord with the structure shown on the left. At 180 °C, it is converted by a Cope reaction to a compound equivalent to itself. The interesting thing is that at 180 °C the NMR spectrum shows that what exists is an equilibrium mixture of the two

structures. That is, at this temperature the molecule rapidly (faster than 10³ times per second) changes back and forth between the two structures. This is called valence tautomerism and is quite distinct from resonance, even though only electrons shift⁶⁷¹ (see Sec. 2.N for other types of tautomerism). The positions of the nuclei are not the same in the two structures. Molecules like 136 that exhibit valence tautomerism (in this case, at 180 °C) are said to have fluxional structures. It may be recalled that cis-1,2-divinylcyclopropane does not exist at room temperature because it rapidly rearranges to 1,4-cycloheptadiene (see above), but in 136 the cis-divinylcyclopropane structure is frozen into the molecule in both structures. Several other compounds with this structural feature are also known. Of these, bullvalene (137) is especially interesting. The Cope rearrangement shown for 137 changes the position of the cyclopropane ring from 4,5,10 to 1,7,8. But the molecule could also have undergone rearrangements to put this ring at 1,2,8 or 1,2,7. Any of these could then undergo several Cope

rearrangements. In all, there are or >1.2 million tautomeric forms, and the cyclopropane ring can be at any three carbons that are adjacent. Since each of these tautomers is equivalent to all the others, this has been called an infinitely degenerate Cope rearrangement. Bullvalene has been synthesized and its NMR spectrum was determined.⁶⁷² At −25 °C, there are two peaks with an area ratio of 6 : 4. This is in accord with a single nontautomeric structure. The six protons are the vinylic protons and the four protons are the allylic ones. But at 100 °C, the compound shows only one NMR peak, indicating that the compound rapidly interchanges its structure among 1.2 million equivalent forms.⁶⁷³ The NMR spectrum of bullvalene also shows only one peak at 100 °C.⁶⁷⁴

Another compound for which degenerate Cope rearrangements result in equivalence for all the carbons is hypostrophene (138).⁶⁷⁵ In the case of the compound barbaralane (139)⁶⁷⁶ (bullvalene in which one CH=CH has been replaced by a CH₂), there are only 2 equiv tautomers.⁶⁷⁷ However, NMR spectra indicate that even at room temperature a rapid interchange of both tautomers is present, although by about −100 °C this has slowed to the point where the spectrum is in accord with a single structure. In the case of semibullvalene (140) (barbaralane in which the CH₂ has been removed), not only is there a rapid interchange at room temperature, but even at −110 °C.⁶⁷⁸ Compound 140 has the lowest energy barrier of any known compound capable of undergoing the Cope rearrangement.⁶⁷⁹

The molecules taking part in a valence tautomerization need not be equivalent. Thus, NMR spectra indicate that a true valence tautomerization exists at room temperature between the cycloheptatriene (141) and the norcaradiene (142).⁶⁸⁰ In this case, one isomer (142) has the cis-1,2-divinylcyclopropane structure, while the other does not. In an analogous interconversion, benzene oxide⁶⁸¹ and oxepin exist in a tautomeric equilibrium at room temperature.⁶⁸²

Bullvalene and hypostrophene are members of a group of compounds all of whose formulas can be expressed by the symbol (CH)₁₀.⁶⁸³ Many other members of this group are known. Similar groups of (CH)_n compounds exist for other even-numbered values of “n”.⁶⁸⁵ For example, there are 20 possible (CH)₈⁶⁸⁴ compounds,⁶⁸⁵ and five possible (CH)₆ compounds,⁶⁸⁶ all of which are known: benzene, prismane (Sec. 4.Q.i), Dewar benzene (see Reaction 18-27, the Möbius–Hückel Method), bicyclopropenyl,⁶⁸⁷ and benzvalene.⁶⁸⁸

An interesting example of valence tautomerism is the case of 1,2,3-tri-tert-butylcyclobutadiene (Sec. 2.K.ii). There are two isomers, both rectangular, and NMR spectra show that they exist in a dynamic equilibrium, even at −185 °C.⁶⁸⁹

18-33 The Claisen Rearrangement⁶⁹⁰

Allylic aryl ethers, when heated, rearrange to o-allylphenols in a reaction called the Claisen rearrangement.⁶⁹¹ If both ortho positions are filled, the allylic group migrates to the para position (this is often called the para-Claisen rearrangement).⁶⁹² There is no reaction when the para and both ortho positions are filled. Migration to the meta position has not been observed. In the ortho migration, the allylic group always undergoes an allylic shift. That is, as shown above, a substituent α to the oxygen is now γ to the ring (and vice versa). On the other hand, in the para migration there is never an allylic shift: The allylic group is found exactly as it was in the original ether. Compounds with propargylic groups (i.e., groups with a triple bond in the appropriate position) do not generally give the corresponding products.

The mechanism is a concerted pericyclic [3,3]-sigmatropic rearrangement⁶⁹³ and accounts for all these facts. For the ortho rearrangement,

Evidence is the lack of a catalyst, the fact that the reaction is first order in the ether, the absence of cross-over products when mixtures are heated, and the presence of the allylic shift, which is required by this mechanism. The allylic shift for the ortho rearrangement (and the absence of one for the para) has been demonstrated by ¹⁴C labeling, even when no substituents are present. Studies of the transition state geometry have shown that, like the Cope rearrangement, the Claisen rearrangement usually prefers a chair-like transition state.⁶⁹⁴ A retro-Claisen rearrangement is known and its mechanism has been examined.⁶⁹⁵

When the ortho positions have no hydrogen, a second [3,3]-sigmatropic migration (a Cope reaction) follows:

and the migrating group is restored to its original structure. Intermediates of structure 143 have been trapped by means of a Diels–Alder reaction (15-60).⁶⁹⁶ The rearrangement of aryl allyl ethers is facilitated by Ag–KI in hot acetic acid,⁶⁹⁷ and by AlMe₃ in water.⁶⁹⁸ A solid-phase reaction of polymer-bound substrate undergoes the Claisen rearrangement with microwave irradiation.⁶⁹⁹

Allylic ethers of enols (allylic vinylic ethers, 144) also undergo the Claisen rearrangement⁷⁰⁰; in fact, it was discovered with these compounds first.⁷⁰¹ In these cases of course, the final tautomerization does not take place even when R′ = H, since there is no aromaticity to restore, and ketones are more stable than enols.⁷⁰² Catalytic Claisen rearrangements of allyl vinyl ethers are well known.⁷⁰³ The use of water as solvent accelerates the reaction.⁷⁰⁴Microwave induced reactions on silica gel⁷⁰⁵ and in ionic liquids⁷⁰⁶ are known The mechanism is similar to that with allylic aryl ethers.⁷⁰⁷ In the presence of a chiral Cu complex, Claisen rearrangements proceed with good enantioselectivity.⁷⁰⁸ N-Heterocyclic carbenes catalyzed an enantioselective Claisen rearrangement.⁷⁰⁹ A chiral hydrogen-bond donor has been used for enantioselective Claisen rearrangements.⁷¹⁰ A chiral allylic ether gave an enantioselective Claisen rearrangement with an Ir catalyst.⁷¹¹

Since the Claisen rearrangement mechanism does not involve ions, it should not be greatly dependent on the presence or absence of substituent groups on the ring.⁷¹² This is the case. Electron-donating groups increase the rate and electron-withdrawing groups decrease it, but the effect is small, with the p-amino compound reacting only ~10–20 times faster than the p-nitro compound.⁷¹³ However, solvent effects⁷¹⁴ are greater: Rates varied over a 300-fold range when the reaction was run in 17 different solvents.⁷¹⁵ An especially good solvent is trifluoroacetic acid, in which the reaction can be carried out at room temperature.⁷¹⁶ Most Claisen rearrangements are performed without a catalyst, but AlCl₃ or BF₃ are sometimes used.⁷¹⁷ In this case, it may become a Friedel–Crafts reaction, with the mechanism no longer cyclic,⁷¹⁸ and ortho, meta, and para products may be obtained.

Allyl allene ethers undergo a Claisen rearrangement when heated in DMF to give the expected diene with a conjugated aldehyde unit.⁷¹⁹ Butenolides with a β-allylic ether unit undergo Claisen rearrangement–Conia reaction⁷²⁰cascade to give an oxaspiroheptane with β-keto lactone comprising the five-membered ring.⁷²¹ Allylic esters of β-keto acids undergo a Claisen rearrangement in what is known as the Carroll rearrangement⁷²² (also called the Kimel–Cope rearrangement⁷²³), and the reaction can be catalyzed by a Ru complex.⁷²⁴ An asymmetric Carroll rearrangement was catalyzed by a chiral Pd complex.⁷²⁵

Heating an allylic alcohol with N,N-dimethylacetamide dimethyl acetal yields a transient intermediate, and subsequent Claisen rearrangement gives an amide in a sequence that is known as the Eschenmoser variant or the Eschenmoser–Claisen rearrangement.⁷²⁶ This reaction has also been called the Meerwein–Eschenmoser Claisen rearrangement.⁷²⁷ An enantioselective version has been reported using a chiral Pd complex.⁷²⁸

The enolate anions (145) of allylic esters (formed by treatment of the esters with LICA) rearrange to γ,δ-unsaturated acids.⁷²⁹ Alternatively, the silylketene acetal [R³R²C=C(OSiR₃)OCH₂CH=CHR¹] may be used instead of 145.⁷³⁰This rearrangement also proceeds at room temperature. By either procedure, the reaction is called the Ireland–Claisen rearrangement.⁷³¹ Note the presence of the negative charge in 145. As with the oxy-Cope rearrangement (in Reaction 18-34), negative charges generally accelerate the Claisen reaction,⁷³² although the extent of the acceleration can depend on the identity of the positive counterion.⁷³³ The reaction proceeds with good syn selectivity in many cases.⁷³⁴ The Ireland–Claisen rearrangement has been made enantioselective by converting 145 to an enol borinate in which the boron is attached to a chiral group.⁷³⁵ The Ireland–Claisen rearrangement can be done with amide derivatives also.⁷³⁶

As just mentioned, asymmetric Claisen rearrangement reactions are well known.⁷³⁷ Chiral Lewis acids have been designed for this purpose.⁷³⁸ In general, asymmetric [3,3]-sigmatropic rearrangements are well known.⁷³⁹

A number of analogues of the Claisen rearrangement are known, for example, rearrangement of ArNHCH₂CH=CH₂,⁷⁴⁰ of N-allylic enamines (R₂C=CRNRCR₂CR=CR₂)⁷⁴¹ of allylic imino esters [RC(OCH₂CH=CH₂)=NR]⁷⁴²(these have often been rearranged with transition metal catalysts⁷⁴³), and of RCH=NRCHRCH₂CH=CH₂. These rearrangements of nitrogen-containing compounds can be called aza-Claisen rearrangements,⁷⁴⁴ but are sometimes called aza-Cope rearrangements,⁷⁴⁵ as described in Reaction 18-32. A Pd catalyzed aza-Claisen has been reported.⁷⁴⁶ An important contribution to this variation is the rearrangement of trichloroacetimidate derivatives of prochiral (Z)-2-alken-1-ols, usually with a Pd catalyst, to give chiral allylic esters.⁷⁴⁷ There is a catalytic enantioselective aza-Cope rearrangement.⁷⁴⁸ A so-called amine-Claisen rearrangement was reported for N-allyl indoles, when heated in the presence of BF₃√OEt₂.⁷⁴⁹ An azo-Cope rearrangement, CH₂=CHCR₂′)CR₂′N=NAr → R₂′C=CHCH₂NArN=CR₂², has been reported.⁷⁵⁰ In a related reaction, allylic phorphorimidates undergo [3,3]-sigmatropic rearrangement.⁷⁵¹

The conversion of allylic aryl thioethers, (ArSCH₂CH=CH₂) to o-allylic thiophenols is not feasible, because the latter are not stable,⁷⁵² but react to give bicyclic compounds.⁷⁵³ However, many allylic vinylic sulfides do give the rearrangement (the thio-Claisen rearrangement).⁷⁵⁴ Allylic vinylic sulfones (e.g., H₂C=CRCH₂–SO₂–CH=CH₂) rearrange, when heated in the presence of ethanol and pyridine, to unsaturated sulfonate salts (CH₂=CRCH₂CH₂CH₂SO₃⁻), produced by reaction of the reagents with the unstable sulfene intermediates CH₂=CRCH₂CH₂CH=SO₂.⁷⁵⁵ Allylic vinylic sulfoxides rapidly rearrange at room temperature or below.⁷⁵⁶ Chiral vinyl sulfoxides undergo Claisen rearrangement with good enantioselectivity.⁷⁵⁷

Ethers with an alkyl group in the γ position (ArO–C–C=C–R systems) sometimes give abnormal products, with the β carbon becoming attached to the ring⁷⁵⁸:

It has been established that these abnormal products do not arise directly from the starting ether, but are formed by a further rearrangement of the normal product⁷⁵⁹:

This rearrangement, which has been called an enolene rearrangement, a homodienyl [1,5]-sigmatropic hydrogen shift (see Reaction 18-29), and a [1,5]-homosigmatropic rearrangement, involves a shift of three electron pairs over seven atoms. It has been found that this “abnormal” Claisen rearrangement is general and can interconvert the enol forms of systems of the types 146 and 147 through the cyclopropane intermediate (148).⁷⁶⁰

OS III, 418; V, 25; VI, 298, 491, 507, 584, 606; VII, 177; VIII, 251, 536.

18-34 The Fischer Indole Synthesis

When arylhydrazones of aldehydes or ketones are treated with a catalyst, elimination of ammonia takes place and an indole is formed, in the Fischer indole synthesis.⁷⁶¹ Zinc chloride is a commonly used catalyst, but dozens of others, including other metal halides, proton and Lewis acids, and certain transition metals have also been used. Microwave irradiation has been used to facilitate this reaction.⁷⁶² The reaction has been done using an AlCl₃ complex as an ionic liquid,⁷⁶³ and solid-phase Fischer indole syntheses are known.⁷⁶⁴ Aniline derivatives react with α-diazoketones, in the presence of a Rh catalyst, to give indoles as well.⁷⁶⁵ Arylhydrazones are easily prepared by the treatment of aldehydes or ketones with phenylhydrazine (Reaction 16-2) or by aliphatic diazonium coupling (Reaction 12-7). However, it is not necessary to isolate the arylhydrazone. The aldehyde or ketone can be treated with a mixture of phenylhydrazine and the catalyst; this is now common practice. In order to obtain an indole, the aldehyde or ketone must be of the form RCOCH₂R′ (R = alkyl, aryl, or hydrogen). Vinyl ethers (e.g., dihydrofuran) serve as an aldehyde surrogate when treated with phenylhydrazine and a catalytic amount of aq H₂SO₄ to give an 3-substituted indole.⁷⁶⁶

At first glance, the reaction does not seem to be a rearrangement. However, the key step of the mechanism⁷⁶⁷ is a [3,3]-sigmatropic rearrangement⁷⁶⁸:

There is much evidence for this mechanism, for example, (1) the isolation of 153,⁷⁶⁹ (2) the detection of 152 by and NMR,⁷⁷⁰ (3) the isolation of side products that could only have come from 151,⁷⁷¹ and (4) -labeling experiments showing that it was the nitrogen farther from the ring that is eliminated as ammonia.⁷⁷² The main function of the catalyst seems to be to speed the conversion of 149 to 150. The reaction can be performed without a catalyst.

OS III, 725; IV, 884. Also see, OS IV, 657.

18-35 [2,3]-Sigmatropic Rearrangements

(2/ S-3/)→(1/5/)- sigma-Migration

Sulfur ylids bearing an allylic group are converted to unsaturated sulfides on heating.⁷⁷³ This is a concerted [2,3]-sigmatropic rearrangement⁷⁷⁴ and has also been demonstrated for the analogous cases of nitrogen ylids⁷⁷⁵ and the conjugate bases of allylic ethers (in the last case it is called a [2,3]-Wittig rearrangement).⁷⁷⁶ It has been argued that the [2,3]-Wittig rearrangement demands severe deformation of the molecule in order to proceed.⁷⁷⁷ It has been shown that SmI₂ induces a [2,3]-Wittig rearrangement.⁷⁷⁸ The reaction has been extended to certain other systems,⁷⁷⁹ even to an all-carbon system.⁷⁸⁰

Treatment of an α-(N-allylic amino) ketone with NaH led to 2-allylic α-amino ketones via a [2,3]-rearrangement.⁷⁸¹ In the presence of a chiral ligand on nitrogen,⁷⁸¹ or with a chiral additive,⁷⁸² good asymmetric induction is possible. Vinylaziridines undergo [2.3]-sigmatropic rearrangement.⁷⁸³

Since the reactions involve migration of an allylic group from a sulfur, nitrogen, or oxygen atom to an adjacent negatively charged carbon atom, they are special cases of the Stevens or Wittig rearrangements (18-21 and 18-22). However, in this case the migrating group must be allylic (in 18-21 and 18-22 other groups can also migrate). Thus, when the migrating group is allylic, there are two possible pathways: (1) the radical-ion or ion-pair mechanisms (18-21 and 18-22) and (2) the concerted pericyclic [2,3]-sigmatropic rearrangement. These are easily distinguished since the latter always involves an allylic shift (as in the Claisen rearrangement), while the former pathway does not.

Of these reactions, the [2,3]-Wittig rearrangement in particular has often been used as a means of transferring chirality. The product of this reaction has potential stereogenic centers at C-3 and C-4 (if R⁵ ≠ R⁶), and if the starting ether is optically active because of a stereogenic center at C-1, the product may be optically active as well. Many examples are known in which optically active ethers were converted to a product that was optically active because of chirality at C-3, C-4, or both.⁷⁸⁴ If a suitable stereogenic center is present in R¹ (or if a functional group in R¹ can be so converted), then stereocontrol over three contiguous stereogenic centers can be achieved. Stereocontrol of the new double bond (E or Z) has also been accomplished.

If an OR or SR group is attached to the negative carbon, the reaction becomes a method for the preparation of β,γ-unsaturated aldehydes, because the product is easily hydrolyzed.⁷⁸⁵

Another [2,3]-sigmatropic rearrangement converts allylic sulfoxides to rearranged allylic alcohols by treatment with a thiophilic reagent (e.g., trimethyl phosphite).⁷⁸⁶ This is the Mislow–Evans rearrangement. In this case, the migration is from sulfur to oxygen. [2,3]-Oxygen-to-sulfur migrations are also known.⁷⁸⁷ The Sommelet–Hauser rearrangement discussed in Reaction 13-31 is also a [2,3]-sigmatropic rearrangement.

OS VIII, 427.

18-36 The Benzidine Rearrangement

When hydrazobenzene is treated with acids, it rearranges to give ~70% 4,4′-diaminobiphenyl (154, benzidine) and ~30% 2,4′-diaminobiphenyl. This reaction is called the benzidine rearrangement and is general for N,N′-diarylhydrazines.⁷⁸⁸ Usually, the major product is the 4,4′-diaminobiaryl, but four other products may also be produced: the 2,4′-diaminobiaryl, already referred to, the 2,2′-diaminobiaryl, and the o- and p-arylaminoanilines (called semidines). The 2,2′- and p-arylaminoaniline compounds are formed less often and in smaller amounts than the other two side products. Usually, the 4,4′-diaminobiaryl predominates, except when one or both para positions of the diarylhydrazine are occupied. However, the 4,4′-diamine may still be produced even if the para positions are occupied. If SO₃H, CO₂H, or Cl (but not R, Ar, or NR₂) is present in the para position, it may be ejected. With dinaphthylhydrazines, the major products are not the 4,4′-diaminobinaphthyls, but the 2,2′ isomers. Another side reaction is disproportionation to ArNH₂ and ArN=NAr. For example, p,p′-PhC₆H₄NHNHC₆H₄Ph gives 88% disproportionation products at 25 °C.⁷⁸⁹

The mechanism has been exhaustively studied and several mechanisms have been proposed.⁷⁹⁰ At one time, it was believed that NHAr broke away from ArNHNHAr and became attached to the para position to give the semidine, which then went on to product. The fact that semidines could be isolated lent this argument support, as did the fact that this would be analogous to the rearrangements considered in Chapter 11 (Reaction 11-28–11-32). However, this theory was proved incorrect when it was discovered that semidines could not be converted to benzidines under the reaction conditions. Cleavage into two independent pieces (either ions or radicals) has been ruled out by many types of cross-over experiments, which always showed that the two rings of the starting material are in the product; that is, ArNHNHAr′ gives no molecules (of any of the five products) containing two Ar groups or two Ar′ groups, and mixtures of ArNHNHAr and Ar′NHNHAr′ give no molecules containing both Ar and Ar′. An important discovery was the fact that, although the reaction is always first order in substrate, it can be either first⁷⁹¹ or second⁷⁹² order in [H⁺]. With some substrates the reaction is entirely first order in [H⁺], while with others it is entirely second order in [H⁺], regardless of the acidity. With still other substrates, the reaction is first order in [H⁺] at low acidities and second order at higher acidities. With the latter substrates fractional orders can often be observed,⁷⁹³ because at intermediate acidities, both processes take place simultaneously. These kinetic results seem to indicate that the actual reacting species can be either the monoprotonated substrate ArNHNH₂Ar or the diprotonated ArNH₂NH₂Ar.

Most of the proposed mechanisms⁷⁹⁴ attempted to show how all five products could be produced by variations of a single process. An important breakthrough was the discovery that the two main products are formed in entirely different ways, as shown by isotope-effect studies.⁷⁹⁵ When the reaction was run with hydrazobenzene labeled with at both nitrogen atoms, the isotope effect was 1.022 for formation of 154, but 1.063 for formation of 2,4′-diaminobiphenyl. This showed that the N–N bond is broken in the rate-determining step in both cases, but the steps themselves are obviously different. When the reaction was run with hydrazobenzene labeled with at a para position, there was an isotope effect of 1.028 for formation of 154, but essentially no isotope effect (1.001) for formation of 2,4′-diaminobiphenyl. This can only mean that for 154 formation of the new C–C bond and breaking of the N–N bond both take place in the rate-determining step; in other words, the mechanism is concerted. The following [5.5]-sigmatropic rearrangement accounts for this⁷⁹⁶:

The diion 155 was obtained as a stable species in superacid solution at −78 °C by treatment of hydrazobenzene with FSO₃H–SO₂ (SO₂ClF).⁷⁹⁷ Although the results just given were obtained with hydrazobenzene, which reacts by the diprotonated pathway, monoprotonated substrates have been found to react by the same [5,5]-sigmatropic mechanism.⁷⁹⁸ Some of the other rearrangements in this section are also sigmatropic. Thus, formation of the p-semidine takes place by a [1,5]-sigmatropic rearrangement,⁷⁹⁹ and the conversion of 2,2′-hydrazonaphthalene to 2,2′-diamino-1,1′-binaphthyl by a [3,3] sigmatropic rearrangement.⁸⁰⁰

2,4′-Diaminobiphenyl is formed by a completely different mechanism, though the details are not known. There is rate-determining breaking of the N–N bond, but the C–C bond is not formed during this step.⁸⁰¹ The formation of the o-semidine also takes place by a nonconcerted pathway.⁸⁰² Under certain conditions, benzidine rearrangements have been found to go through radical cations.⁸⁰³

C. Other Cyclic Rearrangements

18-37 Metathesis of Alkenes (Alkene or Olefin Metathesis)⁸⁰⁴

Alkene metathesis

When alkenes are treated with certain catalysts they are converted to other alkenes in a reaction in which one set of alkylidene groups (R¹R²C=) have become interchanged with other alkylidene groups (R³R⁴C=) by a process schematically illustrated by the equilibrium reaction shown below. In an early example shown above, 2-pentene (either cis, trans, or a cis–trans mixture) is converted to a mixture of ~50% 2-pentene, 25% 2-butene, and 25% 3-hexene. Nowadays, superior catalysts and experimental procedures have made this reaction synthetically useful (see below). The reaction is reversible⁸⁰⁵ and the alkene starting material and products exist in equilibrium, so the same mixture can be obtained by starting with equimolar quantities of 2-butene and 3-hexene.⁸⁰⁶ The reaction is called metathesis of alkenes or alkene metathesis (olefin metathesis).⁸⁰⁷ In general, the reaction can be applied to a single unsymmetrical alkene, giving a mixture of itself and two other alkenes, or to a mixture of two alkenes, in which case the number of different molecules in the product depends on the symmetry of the reactants. In the example, a mixture of R¹R²C=CR¹R² and R³R⁴C=CR³R⁴ gives rise to only one new alkene (R¹R²C=CR³R⁴), while in the most general case, the reaction of two alkenes (R¹R²C=CR³R⁴ and R⁵R⁶C=CR⁷R⁸) can give a mixture of 10 alkenes: the original 2 + 8 new ones. In early work, W, Mo,⁸⁰⁸ or Re complexes were used, and with simple alkenes the proportions of products are generally statistical,⁸⁰⁹ which limited the synthetic utility of the reaction since the yield of any one product is low. In some cases, one alkene may be more or less thermodynamically stable than the rest, so that the proportions are not statistical in all cases.

It is possible to shift the equilibrium to favor certain products. For example, 2-methyl-1-butene gives rise to ethylene and 3,4-dimethyl-3-hexene. By allowing the gaseous ethylene to escape, the yield of 3,4-dimethyl-3-hexene can be raised to 95%.⁸¹⁰ This example shows that it is possible to tailor the substrate to include two terminal alkenes that lead to ethylene as a product, whose escape from the reaction drives the equilibrium to product.

The development of better catalysts has revolutionized this reaction,⁸¹¹ making it one of the most important methods available for modern synthesis. Both homogeneous⁸¹² and heterogeneous⁸¹³ catalysts have been used for this reaction. Of the many homogeneous catalysts, Ru complexes are the most important,⁸¹⁴ and important heterogeneous catalysts include oxides of Mo, W, and Re deposited on alumina or silica gel.⁸¹⁵ The major breakthrough in these catalysts was the development of catalysts that are relatively air stable. Three important catalysts are metal carbene complexes 156⁸¹⁶ and 157⁸¹⁷ (Grubbs catalyst I and II; Mes = mesityl, respectively), and 158 (the Shrock catalyst).⁸¹⁸ Catalyst 157 can be generated in situ from air stable precursors.⁸¹⁹

The synthetic importance⁸²⁰ of ring-closing and ring-opening metathesis reactions has, in part, led to the ongoing development of new catalysts.⁸²¹ Catalysts have been developed that are compatible with both water and methanol.⁸²² The reaction is compatible with the presence of other functional groups⁸²³ (e.g., other alkene units,⁸²⁴ carbonyl units,⁸²⁵ the alkene unit of conjugated esters,⁸²⁶ butenolides⁸²⁷ and other lactones,⁸²⁸ amines,⁸²⁹ amides,⁸³⁰sulfones,⁸³¹ phosphine oxides,⁸³² sulfonate esters,⁸³³ and sulfonamides,⁸³⁴ see 149).⁸³⁵ Ether groups,⁸³⁶ including vinyl ethers,⁸³⁷ vinyl halides,⁸³⁸ vinyl silanes,⁸³⁹ vinyl sulfones,⁸⁴⁰ allylic ethers,⁸⁴¹ and thioethers⁸⁴² are also compatible.

Asymmetric ring-closing metathesis reactions have been reported,⁸⁴³ and chiral metathesis catalysts are continually being developed.⁸⁴⁴ The enantioselective synthesis of bicyclic lactams from dienyl lactams used a chiral Mo catalyst.⁸⁴⁵ Asymmetric ring-opening metathesis has also been reported.⁸⁴⁶

Recyclable catalysts have been developed,⁸⁴⁷ and the reaction has been done in ionic liquids,⁸⁴⁸ supercritical CO₂⁸⁴⁹ (Sec. 9.D.ii), and in aqueous media.⁸⁵⁰ Microwave-induced ring-closing metathesis⁸⁵¹ and also cross-metathesis reactions⁸⁵² are known. Polymer-bound Ru⁸⁵³ and Mo catalysts⁸⁵⁴ have been used, and catalyst 157 has been immobilized on PEG.⁸⁵⁵ Efficient methods have been developed for the removal of Ru byproducts from metathesis reactions that include the use of a scavenger resin,⁸⁵⁶ and removal by aqueous extraction.⁸⁵⁷

By choice of the proper catalyst, the reaction has been applied to terminal and internal alkenes, straight chain or branched. The effect of substitution on the ease of reaction is CH₂= > RCH₂CH= > R₂CHCH= > R₂C=.⁸⁵⁸ Note that isomerization of the C=C unit can occur after metathesis,⁸⁵⁹ but methods have been developed to prevent this, including addition of 2,6-dichlorobenzoquinone.⁸⁶⁰ Cross-metathesis⁸⁶¹ (or symmetrical homo-metathesis⁸⁶²) of alkenes to give new alkenes can be accomplished. Monosubstituted alkenes react faster than disubstituted alkenes.⁸⁶³ A double metathesis reaction of a diene (also called domino⁸⁶⁴ or tandem metathesis⁸⁶⁵) with conjugated aldehydes has been reported,⁸⁶⁶ and a triple metathesis was reported to for a dihydropyran with two dihydropyran substituents.⁸⁶⁷ Cross-metathesis of vinylcyclopropanes leads to an alkene with two cyclopropyl substituents.⁸⁶⁸ Vinylcyclopropane-alkyne metathesis reactions have been reported.⁸⁶⁹ Cyclic alkenes can be opened, usually with polymerization using metathesis catalysts. Ring-opening metathesis generates dienes from cyclic alkenes.⁸⁷⁰ Allenes undergo a metathesis reaction to give symmetrical allenes.⁸⁷¹ An interesting variation reacts an α,ω-diene with a cyclic alkene. The combination of ring-opening metathesis and ring-closing cross-metathesis leads to ring expansion to give a macrocyclic nonconjugated diene.⁸⁷² Note that an alkane metathesis reaction is known.⁸⁷³

Dienes can react intermolecularly or intramolecularly.⁸⁷⁴ Intramolecular reactions generate rings, including small rings,⁸⁷⁵ usually alkenes or dienes. Alkene metathesis can be used to form very large rings, including 21-membered lactone rings.⁸⁷⁶ Diynes undergo both cross-metathesis and ring-closing metathesis.⁸⁷⁷ Diynes can also react intramolecularly to give large-ring alkynes.⁸⁷⁸ Metathesis with vinyl-cyclopropyl-alkynes is also known, producing a ring-expanded product (see 159).⁸⁷⁹ Vinyl halides undergo metathesis reactions.⁸⁸⁰

Two cyclic alkenes react to give dimeric dienes,⁸⁸¹ for example,

With many catalysts, the products can then react with additional monomers and with each other, so that polymers are produced, and the cyclic dienes are obtained only in low yield. The reaction between a cyclic and a linear alkene can give a ring-opened diene⁸⁸²:

The reaction has also been applied to internal alkynes⁸⁸³:

and some success has been reported for terminal triple bonds.⁸⁸⁴ As noted above, molecules with a terminal alkene and a terminal alkyne react quite well (ene-yne metathesis).⁸⁸⁵ Intramolecular reactions of a double bond with a triple bond are known⁸⁸⁶ and a tetracyclic tetraene has been prepared from a poly-yne-diene.⁸⁸⁷ Cross-metathesis of terminal alkynes and terminal alkenes (en-ynes)⁸⁸⁸ to give a diene has also been reported.⁸⁸⁹ Enyne metathesis generates 1,3-dienes.⁸⁹⁰

The generally accepted mechanism is a chain mechanism,⁸⁹¹ involving the intervention of a metal–carbene complex (160 and 161)⁸⁹² and a four-membered ring containing a metal⁸⁹³ (162–165).⁸⁹⁴ In the cross-metathesis reaction shown as an example, R₂C=CR₂ reacts with R¹₂C=CR¹₂ in the presence of a metal catalyst (M). Initial reaction with the catalyst leads to the two expected metal carbenes, (160 and 161). Metal carbene (161) can react with both alkenes to form metallocyclobutanes 162 and 163. Each of these intermediates loses the metal to form the alkenes, the product of metathesis (R₂C=CR¹₂) and one of the original alkenes. In a likewise manner, 160 reacts with each alkene to form metallocyclobutanes 164 and 165, which decomposes to R₂C=CR₂ and the metathesis product. It has been shown that the phosphine-containing methylidene complexes decompose to methylphosphonium salts,⁸⁹⁵

OS 80, 85; 81, 1.

18-38 Metal-Ion-Catalyzed σ-Bond Rearrangements

Many highly strained cage molecules undergo rearrangement when treated with metallic ions [e.g., Ag⁺, Rh(I), or Pd(II)].⁸⁹⁶ The bond rearrangements observed can be formally classified into two main types: (Type 1)

[2 + 2]-ring openings of cyclobutanes and (Type 2) conversion of a bicyclo[2.2.0] system to a bicyclopropyl system. The molecule cubane supplies an example of each type (see above). Treatment with Rh(I) complexes converts cubane to tricyclo[4.2.0.0^2.5]octa-3,7-diene (166),⁸⁹⁷ an example of type 1, while Ag⁺ or Pd(II) causes the second type of reaction, producing cuneane.⁸⁹⁸ Other examples are the conversion of 167 to 168, and formation of 159, the 9,10-dicarbomethyoxy derivative of snoutane (pentacyclo[3.3.2.0^2,4.0^3,7.0^6,8]decane).

Type 1

Ref. 899

Type 2⁹⁰⁰

Ref. 901

The mechanisms of these reactions are not completely understood, although relief of strain undoubtedly supplies the driving force. The reactions are thermally forbidden by the orbital-symmetry rules, and the role of the catalyst is to provide low-energy pathways so that the reactions can take place. Type 1 reactions are the reverse of the catalyzed [2 + 2] ring closures discussed at Reaction 15-63. The following mechanism, in which Ag⁺ attacks one of the edge bonds, has been suggested for the conversion of 167 to 168.⁹⁰²

Simpler bicyclobutanes can also be converted to dienes, but in this case the products usually result from cleavage of the central bond and one of the edge bonds.⁹⁰³ For example, treatment of 170 with AgBF₄,⁹⁰⁴

or [(π-allyl)PdCl]₂⁹⁰⁵ gives a mixture of the two dienes shown, resulting from a formal cleavage of the C-1–C-3 and C-1–C-2 bonds (note that a hydride shift has taken place). Dienes can also be converted to bicyclobutanes under photochemical conditions.⁹⁰⁶

18-39 The Di-π-methane and Related Rearrangements

Di-π-methane rearrangement

1,4-Dienes carrying alkyl or aryl substituents on C-3⁹⁰⁷ can be photochemically rearranged to vinylcyclopropanes in a reaction called the di-π-methane rearrangement.⁹⁰⁸ An example is conversion of 171 to 172.⁹⁰⁹ For most 1,4-dienes, it is only the singlet excited state that gives the reaction; triplet states generally take other pathways.⁹¹⁰ For unsymmetrical dienes, the reaction is regioselective. For example, 173 gave 174, not 175:⁹¹¹

The mechanism can be described by the diradical pathway given⁹¹² (the C-3 substituents act to stabilize the radical), although the species shown are not necessarily intermediates, but may represent transition states. It has been shown, for the case of certain substituted substrates, that configuration is retained at C-1 and C-5 and inverted at C-3.⁹¹³

The reaction has been extended to allylic benzenes⁹¹⁴ (in this case C-3 substituents are not required), to β,γ-unsaturated ketones⁹¹⁵ (the latter reaction, which is called the oxa-di-π-methane rearrangement,⁹¹⁶ generally occurs only from the triplet state), to β,γ-unsaturated imines,⁹¹⁷ and to triple-bond systems.⁹¹⁸

When photolyzed, 2,5-cyclohexadienones can undergo a number of different reactions, one of which is formally the same as the di-π-methane rearrangement.⁹¹⁹ In this reaction, photolysis of the substrate 176 gives the bicyclo[3.1.0]hexenone (181). Although the reaction is formally the same (note the conversion of 171 to 172),

the mechanism is different from that of the di-π-methane rearrangement, because irradiation of a ketone can cause an n → π∗ transition, which is of course not possible for a diene lacking a carbonyl group. The mechanism⁹²⁰ in this case has been formulated as proceeding through the excited triplet states 178 and 179. In step 1, the molecule undergoes an n → π∗ excitation to the singlet species 177, which cross to the triplet 178. Step 3 is a rearrangement from one excited state to another. Step 4 is a π∗→ n electron demotion (an intersystem crossing from T₁ → S₀, see Sec. 7.A.vi, category 4). The conversion of 180 to 181 consists of two 1,2-alkyl migrations (a one-step process would be a 1,3-migration of alkyl to a carbocation center): The old C-6–C-5 bond becomes the new C-6–C-4 bond and the old C-6–C-1 bond becomes the new C-6–C-5 bond.⁹²¹

2,4-Cyclohexadienones also undergo photochemical rearrangements, but the products are different, generally involving ring opening.⁹²²

18-40 The Hofmann–Löffler and Related Reactions

A common feature of the reactions in this section⁹²³ is that they serve to introduce functionality at a position remote from functional groups already present. As such, they have proved very useful in synthesizing many compounds, especially in the steroid field (see also, Reactions 19-2 and 19-17). When N-haloamines in which one alkyl group has a hydrogen in the 4 or 5 position are heated with sulfuric acid, pyrrolidines, or piperidines are formed, in a reaction known as the Hofmann–Löffler reaction (also called the Hofmann–Löffler–Freytag reaction).⁹²⁴ The R′ group is normally alkyl, but the reaction has been extended to R′ = H by the use of concentrated sulfuric

acid solution and ferrous salts.⁹²⁵ The first step of the reaction is a rearrangement, with the halogen migrating from the nitrogen to the 4 or 5 position of the alkyl group. It is possible to isolate the resulting haloamine salt, but usually this is not done, and the second step, the ring closure (Reaction 10-31), takes place. The reaction is most often induced by heat, but this is not necessary, and irradiation and chemical initiators (e.g., peroxides) have been used instead. The mechanism is of a free radical type, with the main step involving an internal hydrogen abstraction.⁹²⁶

A similar reaction has been carried out on N-halo amides, which give γ-lactones⁹²⁷:

Another related reaction is the Barton reaction,⁹²⁸ by which a methyl group in a unique position relative to an OH group can be oxidized to a CHO group. The alcohol is first converted to the nitrite ester. Photolysis of the nitrite results in conversion of the nitrite group to the OH group and nitrosation of the methyl group. Formation of a radical and with the methyl group in the appropriate position, hydrogen-atom transfer via a six-center transition state leads to a nitrite. Hydrolysis of the oxime tautomer gives the aldehyde, for example⁹²⁹

This reaction takes place only when the methyl group is in a favorable steric position.⁹³⁰ The mechanism is similar to that of the Hofmann–Löffler reaction.⁹³¹

This is one of the few known methods for effecting substitution at an angular methyl group. Not only CH₃ groups but also alkyl groups of the form RCH₂ and R₂CH can give the Barton reaction if the geometry of the system is favorable. An RCH₂ group is converted to the oxime R(C=NOH), which is hydrolyzable to a ketone, or to a nitroso dimer, while an R₂CH group gives a nitroso compound [R₂C(NO)]. With very few exceptions, the only carbons that become nitrosated are those in the position δ to the original OH group, indicating that a six-membered transition state is necessary for the hydrogen abstraction.⁹³²

OS III, 159.

D. Noncyclic Rearrangements

18-41 Hydride Shifts

The example shown is typical of a transannular hydride shift. The 1,2-diol is formed by a normal epoxide hydrolysis reaction (10-7).⁹³³ For a discussion of 1,3 and longer hydride shifts, see Sec. 18.B.

18-42 The Chapman Rearrangement

1/ O→3/ N-Aryl-migration

In the Chapman rearrangement, N,N-diaryl amides are formed when aryl imino esters are heated.⁹³⁴ Best yields are obtained in refluxing tetraethylene glycol dimethyl ether (tetraglyme),⁹³⁵ although the reaction can also be carried out without any solvent at all. Many groups may be present in the rings (e.g., alkyl, halo, OR, CN, and CO₂R). Aryl migrates best when it contains electron-withdrawing groups. On the other hand, electron-withdrawing groups in Ar² or Ar³ decrease the reactivity. The products can be hydrolyzed to

diarylamines, and this is a method for preparing these compounds. The mechanism probably involves an intramolecular⁹³⁶ aromatic nucleophilic substitution, resulting in a 1,3 oxygen-to-nitrogen shift via a species (e.g., 182). Aryl imino esters can be prepared from N-aryl amides by reaction with PCl₅, followed by treatment

of the resulting imino chloride (183) with an aroxide ion.⁹³⁷ Imino esters with any or all of the three groups being alkyl also rearrange, but they require catalysis by H₂SO₄ or a trace of methyl iodide or methyl sulfate.⁹³⁸ The mechanism is different, involving an intermolecular process.⁹³⁹ This is also true for derivatives for formamide (Ar² = H).

18-43 The Wallach Rearrangement

The conversion of azoxy compounds (e.g., 184), upon acid treatment, to p-hydroxy azo compounds (e.g., 185, or sometimes the o-hydroxy isomers⁹⁴⁰) is called the Wallach rearrangement.⁹⁴¹ When both para positions are occupied, the o-hydroxy product may be obtained, but ipso substitution at one of the para positions is also possible.⁹⁴² The following facts are known for the proposed mechanism⁹⁴³: (1) The para rearrangement is intermolecular.⁹⁴⁴(2) When the reaction was carried out with an azoxy compound in which the N–O nitrogen was labeled with , both nitrogens of the product carried the label equally,⁹⁴⁵ demonstrating that the oxygen did not have a preference for migration to either the near or the far ring. This shows that there is a symmetrical intermediate. (3) Kinetic studies show that two protons are normally required for the reaction.⁹⁴⁶ The following mechanism,⁹⁴⁷ involving the symmetrical intermediate (187), has been proposed to explain the facts.⁹⁴⁸ It has proved possible to obtain 186 and 187 as stable species in superacid solutions.⁷⁹⁷ Another mechanism, involving an intermediate with only one positive charge, has been proposed for certain substrates at low acidities.⁹⁴⁹

A photochemical Wallach rearrangement⁹⁵⁰ is also known: The product is the o-hydroxy azo compound, the OH group is found in the farther ring, and the rearrangement is intramolecular.⁹⁵¹

18-44 Dyotropic Rearrangements

1/ C-Trialkylsilyl,2/ O-trialkylsilyl-interchange

A dyotropic rearrangement⁹⁵² is an uncatalyzed process in which two σ bonds simultaneously migrate intramolecularly.⁹⁵³ There are two types. The above is an example of type 1, which consists of reactions in which the two σ bonds interchange positions. In type 2, the two σ bonds do not interchange positions. An example is

Some other examples are

Type 1

Ref. 954

Type 1

Ref. 955

Type 2

Ref. 956

A useful type 1 example is the Brook rearrangement,⁹⁵⁷ a stereospecific intramolecular migration of silicon from carbon to oxygen that occurs for (α-hydroxybenzyl)trialkylsilanes (188) in the presence of a catalytic amount of base.⁹⁵⁸ Formation of a Si–O bond rather than the Si–C bond drives the rearrangement, which is believed to proceed via formation of 189, and does proceed with inversion of configuration at carbon and retention of configuration at silicon.⁹⁵⁹ A reverse Brook rearrangement is also known.⁹⁶⁰ The reaction has been extended to other systems. A homo-Brook rearrangement has also been reported.⁹⁶¹ Another variation is the aza-Brook rearrangement of α-(silylallyl)amines.⁹⁶² The Brook rearrangement has been used in synthesis involving silyl dithianes.⁹⁶³ A Brook rearrangement mediated [6 + 2]-annulation has been used for the construction of eight-membered carbocycles.⁹⁶⁴

The Brook rearrangement has been used in two important synthetic applications, a multicomponent coupling protocol initiated by a Brook rearrangement involving silyl dithianes as mentioned, and anion relay chemistry (ARC) involving a Brook rearrangement. An example of the former is the conversion of the 2-silyl dithiane (190) to the anion with tert-butyllithium followed by ring opening of an epoxide to give 191.⁹⁶⁵ Treatment with HMPA triggers a solvent-controlled Brook rearrangement that gives a new dithiane anion (192), which then reacts with a different epoxide to give the final product 193. An example of the anion relay chemistry treats dithiane (194) with n-butyllithium, and then 195 to give 196.⁹⁶⁶ Subsequent treatment with a variety of electrophiles (e.g., allyl bromide, in HMPA), leads to 197 via a Brook rearrangement, and then alkylation of the resultant dithiane anion. This reaction can be initiated by nucleophiles other than dithiane anion.

Notes

1. de Mayo, P. Rearrangements in Ground and Excited States, 3 Vols., Academic Press, NY, 1980; Stevens, T.S.; Watts, W.E. Selected Molecular Rearrangements, Van Nostrand-Reinhold, Princeton, 1973; Collins, C.J.; Eastham, J.F. in Patai, S. The Chemistry of the Carbonyl Group, Vol. 1, Wiley, NY, 1966, pp. 761–821. See also, the series Mechanisms of Molecular Migrations.

2. Vogel, P. Carbocation Chemistry; Elsevier, NY, 1985, pp. 323–372; Shubin, V.G. Top. Curr. Chem. 1984, 116/117, 267; Saunders, M.; Chandrasekhar, J.; Schleyer, P.v.R. in de Mayo, P. Rearrangements in Ground and Excited States, Vol. 1, Academic Press, NY, 1980, pp. 1–53; Kirmse, W. Top. Curr. Chem. 1979, 80, 89. For reviews of rearrangements in vinylic cations, see Shchegolev, A.A.; Kanishchev, M.I. Russ. Chem. Rev. 1981, 50, 553; Lee, C.C. Isot. Org. Chem. 1980, 5, 1.

3. It was first postulated by Whitmore, F.C. J. Am. Chem. Soc. 1932, 54, 3274.

4. The IUPAC designations depend on the nature of the steps. For the rules, see Guthrie, R.D. Pure Appl. Chem. 1989, 61, 23, pp. 44–45.

5. Dostrovsky, I.; Hughes, E.D. J. Chem. Soc. 1946, 166.

6. Borodkin, G.I.; Shakirov, M.M.; Shubin, V.G.; Koptyug, V.A. J. Org. Chem. USSR 1978, 14, 290, 924.

7. Brouwer, D.M.; Hogeveen, H. Prog. Phys. Org. Chem. 1972, 9, 179, see pp. 203–237; Olah, G.A.; Olah, J.A. in Olah, G.A.; Schleyer, P.v.R. Carbonium Ions, Vol. 2, Wiley, NY, 1970, pp. 751–760, 766–778. For a discussion of the rates of these reactions, see Sorensen, T.S. Acc. Chem. Res. 1976, 9, 257.

8. Brouwer, D.M. Recl. Trav. Chim. Pays-Bas 1968, 87, 210; Saunders, M.; Hagen, E.L. J. Am. Chem. Soc. 1968, 90, 2436.

9. Ahlberg, P.; Jonsäll, G.; Engdahl, C. Adv. Phys. Org. Chem. 1983, 19, 223; Leone, R.E.; Barborak, J.C.; Schleyer, P.v.R. in Olah, G.A.; Schleyer, P.v.R. Carbonium Ions, Vol. 4, Wiley, NY, 1970, pp. 1837–1939; Leone, R.E.; Schleyer, P.v.R. Angew. Chem. Int. Ed. 1970, 9, 860.

10. Campbell, A.; Kenyon, J. J. Chem. Soc. 1946, 25, and references cited therein.

11. See Kirmse, W.; Gruber, W.; Knist, J. Chem. Ber. 1973, 106, 1376; Borodkin, G.I.; Panova, Y.B.; Shakirov, M.M.; Shubin, V.G. J. Org. Chem. USSR 1983, 19, 103.

12. See Cram, D.J. in Newman, M.S. Steric Effects in Organic Chemistry, Wiley, NY, 1956; pp. 251–254; Wheland, G.W. Advanced Organic Chemistry, 3rd ed., Wiley, NY, 1960, pp. 597–604.

13. Bernstein, H.I.; Whitmore, F.C. J. Am. Chem. Soc. 1939, 61, 1324. For other examples, see Tsuchihashi, G.; Tomooka, K.; Suzuki, K. Tetrahedron Lett. 1984, 25, 4253.

14. See Meerwein, H.; van Emster, K. Ber. 1920, 53, 1815; 1922, 55, 2500; Meerwein, H.; Gérard, L. Liebigs Ann. Chem. 1923, 435, 174.

15. See Winstein, S.; Morse, B.K. J. Am. Chem. Soc. 1952, 74, 1133.

16. Collins, C.J.; Benjamin, B.M. J. Org. Chem. 1972, 37, 4358, and references cited therein.

17. Mosher, H.S. Tetrahedron 1974, 30, 1733. See also, Guthrie, R.D. J. Am. Chem. Soc. 1967, 89, 6718.

18. Shiner, Jr., V.J.; Imhoff, M.A. J. Am. Chem. Soc. 1985, 107, 2121.

19. Racho, J.; Goedken, V.; Walborsky, H.M. J. Org. Chem. 1989, 54, 1006. An opposing view: Kirmse, W.; Feyen, P. Chem. Ber. 1975, 108, 71; Kirmse, W.; Plath, P.; Schaffrodt, H. Chem. Ber. 1975, 108, 79.

20. Skell, P.S.; Starer, I.; Krapcho, A.P. J. Am. Chem. Soc. 1960, 82, 5257.

21. Karabatsos, G.J.; Orzech, Jr., C.E.; Meyerson, S. J. Am. Chem. Soc. 1964, 86, 1994.

22. Saunders, M.; Vogel, P.; Hagen, E.L.; Rosenfeld, J. Acc. Chem. Res. 1973, 6, 53; Lee, C.C. Prog. Phys. Org. Chem. 1970, 7, 129; Collins, C.J. Chem. Rev. 1969, 69, 543. See also, Cooper, C.N.; Jenner, P.J.; Perry, N.B.; Russell-King, J.; Storesund, H.J.; Whiting, M.C. J. Chem. Soc. Perkin Trans. 2 1982, 605.

23. Karabatsos, G.J.; Orzech, Jr., C.E.; Fry, J.L.; Meyerson, S. J. Am. Chem. Soc. 1970, 92, 606.

24. Lee, C.C.; Cessna, A.J.; Ko, E.C.F.; Vassie, S. J. Am. Chem. Soc. 1973, 95, 5688. See also, Lee, C.C.; Reichle, R. J. Org. Chem. 1977, 42, 2058 and references cited therein.

25. Karabatsos, G.J.; Hsi, N.; Meyerson, S. J. Am. Chem. Soc. 1970, 92, 621. See also, Karabatsos, G.J.; Anand, M.; Rickter, D.O.; Meyerson, S. J. Am. Chem. Soc. 1970, 92, 1254.

26. Karabatsos, G.J.; Fry, J.L.; Meyerson, S. J. Am. Chem. Soc. 1970, 92, 614. See also, Lee, C.C.; Zohdi, H.F. Can. J. Chem. 1983, 61, 2092.

27. Saunders, M.; Jaffe, M.H.; Vogel, P. J. Am. Chem. Soc. 1971, 93, 2558; Saunders, M.; Vogel, P. J. Am. Chem. Soc. 1971, 93, 2559, 2561; Kirmse, W.; Loosen, K.; Prolingheuer, E. Chem. Ber. 1980, 113, 129.

28. Kirmse, W.; Ratajczak, H.; Rauleder, G. Chem. Ber. 1977, 110, 2290.

29. Brouwer, D.M.; Hogeveen, H. Recl. Trav. Chim. Pays-Bas 1970, 89, 211; Majerski, Z.; Schleyer, P.v.R.; Wolf, A.P. J. Am. Chem. Soc. 1970, 92, 5731.

30. See Koptyug, V.A.; Shubin, V.G. J. Org. Chem. USSR 1980, 16, 1685; Wheland, G.W. Advanced Organic Chemistry, 3rd ed., Wiley, NY, 1960, pp. 573–597.

31. See Cram, D.J. in Newman, M.S. Steric Effects in Organic Chemistry, Wiley, NY, 1956, pp. 270–276. For an interesting example, see Nickon, A.; Weglein, R.C. J. Am. Chem. Soc. 1975, 97, 1271.

32. See McCall, M.J.; Townsend, J.M.; Bonner, W.A. J. Am. Chem. Soc. 1975, 97, 2743; Brownbridge, P.; Hodgson, P.K.G.; Shepherd, R.; Warren, S. J. Chem. Soc. Perkin Trans. 1 1976, 2024.

33. Grimaud, J.; Laurent, A. Bull. Soc. Chim. Fr. 1967, 3599.

34. See Fischer, A.; Henderson, G.N. J. Chem. Soc., Chem. Commun. 1979, 279, and references cited therein. See also, Marx, J.N.; Hahn, Y.P. J. Org. Chem. 1988, 53, 2866.

35. See Pilkington, J.W.; Waring, A.J. J. Chem. Soc. Perkin Trans. 2 1976, 1349; Korchagina, D.V.; Derendyaev, B.G.; Shubin, V.G.; Koptyug, V.A. J. Org. Chem. USSR 1976, 12, 378; Wistuba, E.; Rüchardt, C. Tetrahedron Lett.1981, 22, 4069; Jost, R.; Laali, K.; Sommer, J. Nouv. J. Chim. 1983, 7, 79.

36. Bachmann, W.E.; Ferguson, J.W. J. Am. Chem. Soc. 1934, 56, 2081.

37. Le Drian, C.; Vogel, P. Helv. Chim. Acta 1987, 70, 1703; Tetrahedron Lett. 1987, 28, 1523.

38. For a review, see Berson, J.A. Angew. Chem. Int. Ed. 1968, 7, 779.

39. Berson, J.A.; Poonian, M.S.; Libbey, W.J. J. Am. Chem. Soc. 1969, 91, 5567; Berson, J.A.; Donald, D.S.; Libbey, W.J. J. Am. Chem. Soc. 1969, 91, 5580; Berson, J.A.; Wege, D.; Clarke, G.M.; Bergman, R.G. J. Am. Chem. Soc. 1969, 91, 5594, 5601.

40. See Collins, C.J. Acc. Chem. Res. 1971, 4, 315; Collins, J.A.; Glover, I.T.; Eckart, M.D.; Raaen, V.F.; Benjamin, B.M.; Benjaminov, B.S. J. Am. Chem. Soc. 1972, 94, 899; Svensson, T. Chem. Scr. 1974, 6, 22.

41. See Collins, C.J. Chem. Soc. Rev. 1975, 4, 251.

42. See Kirmse, W.; Günther, B. J. Am. Chem. Soc. 1978, 100, 3619.

43. Skell, P.S.; Reichenbacher, P.H. J. Am. Chem. Soc. 1968, 90, 2309.

44. Reineke, C.E.; McCarthy, Jr., J.R. J. Am. Chem. Soc. 1970, 92, 6376; Smolina, T.A.; Gopius, E.D.; Gruzdneva, V.N.; Reutov, O.A. Doklad. Chem. 1973, 209, 280.

45. See Fry, J.L.; Karabatsos, G.J. in Olah, G.A.; Schleyer, P.v.R. Carbonium Ions, Vol. 2, Wiley, NY, 1970, p. 527.

46. See Kirmse, W.; Knist, J.; Ratajczak, H. Chem. Ber. 1976, 109, 2296.

47. Skell, P.S.; Maxwell, R.J. J. Am. Chem. Soc. 1962, 84, 3963. See also, Skell, P.S.; Starer, I. J. Am. Chem. Soc. 1962, 84, 3962.

48. Hudson, H.R.; Koplick, A.J.; Poulton, D.J. Tetrahedron Lett. 1975, 1449; Fry, J.L.; Karabatsos, G.J. in Olah, G.A.; Schleyer, P.v.R. Carbonium Ions, Vol. 2, Wiley, NY, 1970, p. 527.

49. Saunders, M.; Stofko, Jr., J.J. J. Am. Chem. Soc. 1973, 95, 252.

50. See Cope, A.C.; Martin, M.M.; McKervey, M.A. Q. Rev. Chem. Soc. 1966, 20, 119.

51. Prelog, V.; Küng, W. Helv. Chim. Acta 1956, 39, 1394.

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