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

Chapter 13. Aromatic Substitution: Nucleophilic and Organometallic

13.C. Reactions

In the first part of this section, reactions are classified according to attacking species, with all leaving groups considered together, except for hydrogen and N₂⁺, which are treated subsequently. Finally, a few rearrangement reactions are discussed.

13.C.i. All Leaving Groups Except Hydrogen and N₂⁺

A. Oxygen Nucleophiles

13-1 Hydroxylation of Aromatic Compounds

Hydroxy-de-halogenation

Direct hydroxylation of aryl halides to give phenols generally requires the presence of activating groups or exceedingly strenuous reaction conditions.⁹⁶ When the reaction is carried out at high temperatures, cine substitution is observed, indicating a benzyne mechanism.⁹⁷ However, phenols are prepared from aryl halides using KOH and a Pd catalyst at 100 °C.⁹⁸ Formation of phenols is possible using AgNO₃ with microwave irradiation,⁹⁹ or CuI.¹⁰⁰ There is a hydrogen peroxide promoted hydroxylation of aryl halides with metal hydroxide salts.¹⁰¹ Other microwave-promoted phenol-forming reactions are known.¹⁰²

A slightly related reaction involves the amino group of naphthylamines where can be replaced by a hydroxyl group after treatment with aq bisulfite.¹⁰³ The scope is greatly limited; the amino group, with very few exceptions may be NH₂ or NHR and must be on a naphthalene ring. The reaction is reversible (see 13-6), and both the forward and reverse reactions are called the Bucherer reaction.

An indirect method for conversion of an aryl halide to a phenol involves initial conversion to an organometallic, followed by oxidation to the phenol. For the conversion of aryl Grignard reagents to phenols, a good procedure is the use of trimethyl borate followed by oxidation with H₂O₂ in acetic acid¹⁰⁴ (see Reaction 12-31). Phenols have been obtained from unactivated aryl halides by treatment with borane and a metal (e.g., lithium), followed by oxidation with alkaline H₂O₂.¹⁰⁵ Arylboronic acids [ArB(OH)₂] are oxidized by aq H₂O₂ to give the corresponding phenol.¹⁰⁶ The reaction of an aromatic compound with a borane in the presence of an Ir catalyst, followed by oxidation with aq Oxone, gave the corresponding phenol.¹⁰⁷ Aryllithium reagents have been converted to phenols by treatment with oxygen.¹⁰⁸ In a related indirect method, arylthallium bis(trifluoroacetates) (prepared by Reaction 12-23) can be converted to phenols by treatment with lead tetraacetate followed by triphenylphosphine, and then dilute NaOH.¹⁰⁹ Diarylthallium trifluoroacetates undergo the same reaction.¹¹⁰

OS I, 455; II, 451; V, 632. Also see, OS V, 918.

13-2 Alkali Fusion of Sulfonate Salts

Oxido-de-sulfonato-substitution

Aryl sulfonic acids can be converted, through their salts, to phenols, by alkali fusion. In spite of the extreme conditions, the reaction gives fairly good yields, except when the substrate contains other groups that are attacked by alkali at the fusion temperatures. Milder conditions can be used when the substrate contains activating groups, but the presence of deactivating groups hinders the reaction. The mechanism is not clear, but a benzyne intermediate has been ruled out by the finding that cine substitution does not occur.¹¹¹

OS I, 175; III, 288.

13-3 Replacement by OR or OAr

Alkoxy-de-halogenation

This reaction is similar to 13-1 and, like that one, generally requires activated substrates.^96,112 With unactivated substrates, side reactions predominate, although aryl methyl ethers have been prepared from unactivated chlorides by treatment with MeO⁻ in HMPA.¹¹³ This reaction gives better yields than 13-1 and is used more often. A good solvent is liquid ammonia. Aryl chlorides react with phenol and KOH with microwave irradiation to give the diaryl ether.¹¹⁴ Potassium phenoxide reacts with iodobenzene in an ionic solvent at 100°C with CuCl.¹¹⁵ Sodium methoxide reacted with o- and p-fluoronitrobenzenes ~10⁹ times faster in NH₃ at −70°C than in MeOH.¹¹⁶ Phase-transfer catalysis has also been used.¹¹⁷ Phenols reacted with aryl fluorides¹¹⁸ or aryl chlorides¹¹⁹ to give the diaryl ether. Intramolecular versions are known that produce benzofurans.¹²⁰ Heating aryl iodides and phenols in an ionic liquid forms ethers.¹²¹ In addition to halides, leaving groups can be other OR, or even OH.¹²²

For aroxide nucleophiles, the reaction is promoted by Cu salts,¹²³ and activating groups need not be present. This method of preparation of diaryl ethers is called the Ullmann ether synthesis¹²⁴ and should not be confused with the Ullmann biaryl synthesis (13-11). The reactivity order is typical of nucleophilic substitutions, despite the presence of the Cu salts.¹²⁵ Copper-catalyzed coupling is known using ligand and additive-free conditions.¹²⁶ Because aryloxycopper(I) reagents (ArOCu) react with aryl halides to give ethers, it has been suggested that they are intermediates in the Ullmann ether synthesis.¹²⁷ Indeed, high yields of ethers can be obtained by reaction of ROCu or ArOCu with aryl halides.¹²⁸ Aryl halides are converted to aryl ethers with aliphatic alcohols in the presence of suitable Cu salts.¹²⁹

An increasingly important variation of this reaction couples an alkoxide and an aryl halide to give aryl ethers in the presence of a Pd catalyst and a suitable ligand.¹³⁰ Ligand effects are important in such reactions.¹³¹ A Pd catalyzed, intramolecular displacement of an aryl halide with a pendant alkoxide unit leads to dihydrobenzofurans.¹³² Nickel catalysts have also been used.¹³³ Aryl iodides react with phenols in the presence of K₂CO₃, CuI, and Raney nickel alloy.¹³⁴ An Fe catalyzed etherification reaction is known.¹³⁵

In a related reaction, acid salts (RCOO⁻) are sometimes used as nucleophiles.¹³⁶ Unactivated substrates have been converted to carboxylic esters in low-to-moderate yields under oxidizing conditions.¹³⁷ The following chain mechanism, called the S_ON2 mechanism,¹³⁸ has been suggested¹³⁸:

OS I, 219; II, 445; III, 293, 566; V, 926; VI, 150; X, 418.

B. Sulfur Nucleophiles

13-4 Replacement by SH or SR

Aryl thiols and thioethers can be prepared by reactions that are similar to 13-1 and 13-3.¹³⁹ Activated aryl halides generally give good results, but side reactions are occasionally important. Some reagents give the thiol directly. 4-Bromonitrobenzene reacts with Na₃SPO₃, in refluxing methanol, to give 4-nitrothiophenol, for example.¹⁴⁰

Diaryl sulfides can be prepared by the use of .¹⁴¹ Even unactivated aryl halides react with if polar aprotic solvents (e.g., DMF,¹⁴² DMSO¹⁴³ 1-methyl-2-pyrrolidinone,¹⁴⁴ or HMPA)¹⁴⁵ are used, though the mechanisms are still mostly or entirely nucleophilic substitution. 2-Iodothiophene reacts directly with thiophenol to give 2-(phenylthio)thiophene.¹⁴⁶

Metal-catalyzed reactions of aryl halides and thiols lead to thioethers. Perhaps the most common metal used nowadays is Pd.¹⁴⁷ Copper catalysts have been used,¹⁴⁸ including catalysis in aqueous media,¹⁴⁹ and also Ni¹⁵⁰ or In¹⁵¹catalysts. Copper-catalyzed coupling is known using ligand- and additive-free conditions.¹⁵² Aryl iodides react with dialkyl disulfides and a nickel catalyst to give aryl alkyl sulfides.¹⁵³ Diaryl sulfides can also be prepared (in high yields) by treatment of unactivated aryl iodides with ArS⁻ in liquid ammonia under irradiation.¹⁵⁴ The mechanism in this case is probably S_RN1. The reaction (with unactivated halides) has also been carried out electrolytically, with a Ni catalyst.¹⁵⁵ In the presence of a Pd catalyst, thiophenols react with diaryliodonium salts (Ar₂I⁺⁻BF₄) to give the unsymmetrical diaryl sulfide.¹⁵⁶

Other sulfur nucleophiles also react with activated aryl halides:

Arylboronic acids [ArB(OH)₂] react with thiols and copper(II) acetate to give the corresponding alkyl aryl sulfide.¹⁵⁷ Arylboronic acids also react with N-methylthiosuccinimide, with a Cu catalyst, to give the aryl methyl sulfide.¹⁵⁸

Aryl sulfones have been prepared from sulfinic acid salts, aryl iodides, and CuI.¹⁵⁹ A Pd catalyzed arylation of sulfenate anions leads to aryl sulfoxides.¹⁶⁰The copper-catalyzed reaction of NaO₂SMe and aryl iodides give the aryl methyl sulfone,¹⁶¹ and aryl sulfones have been prepared from arylboronic acids using a Cu catalyst.¹⁶² A similar synthesis of diaryl sulfones has been reported using a Pd catalyst.¹⁶³

Aryl selenides (ArSeAr and ArSeAr') can be prepared by similar methodology. Symmetrical diaryl selenides were prepared by the reaction of iodobenzene with diphenyl diselenide (PhSeSePh), in the presence of Mg and a Cu catalyst.¹⁶⁴ Aryl halides react with tin selenides (ArSeSnR₃), with a Cu catalyst, to give the diaryl selenide,¹⁶⁵ and a CuS–Fe catalyst was also used.¹⁶⁶

Thiocyanates have been generated from unactivated aryl halides using charcoal supported copper(I) thiocyanate.¹⁶⁷

OS I, 220; III, 86, 239, 667; V, 107, 474; VI, 558, 824. Also see, OS V, 977.

C. Nitrogen Nucleophiles

13-5 Replacement of Halogen by NH₂, NHR, or NR₂

Amino-de-halogenation

Amido-de-halogenation

Activated aryl halides react with ammonia and primary and secondary amines to give the corresponding arylamines. Primary and secondary amines usually give better results than ammonia, with piperidine especially reactive. Picryl chloride (2,4,6-trinitrochlorobenzene) is often used to form amine derivatives. 2-Chloronitrobenzene also reacts with aniline derivatives directly with microwave irradiation.¹⁶⁸ Other leaving groups in this reaction may be NO₂,¹⁶⁹ N₃, OSO₂R, OR, SR, N=NAr (where Ar contains electron-withdrawing groups)¹⁷⁰ and even NR₂.¹⁷¹ Aryl triflates react directly with secondary amines in N-methylpyrrolidine solvent using microwave irradiation.¹⁷² Aniline derivatives react with activated aromatic rings, in the presence of tetrabutylammonium fluoride and under photolysis conditions, to give a N,N-diarylamine.¹⁷³ Arylation of amines with aryl halides has also been done in ionic liquids¹⁷⁴ and in supercritical CO₂.¹⁷⁵ Flow reactor technology has been used for the direct, uncatalyzed amination of 2-chloropyridine.¹⁷⁶

Aryl halides can be converted to amines by the use of NaNH₂, NaNHR, or NaNR₂.¹⁷⁷ Lithium dialkylamides also react with aryl halides to give the N-arylamine.¹⁷⁸ With amide base reagents, the benzyne mechanism generally operates, so cine substitution (Sec. 13.A.iii, category 2) is often found. The amide base is usually generated by reaction of the amine with an organolithium reagent, but other bases may be used. The reaction of an amine, an aryl halide, and potassium tert-butoxide generates the N-aryl amine.¹⁷⁹ Triarylamines have been prepared in a similar manner from ArI and Ar′₂NLi, even with unactivated ArI.¹⁸⁰

Aryl fluorides react in the presence of KF–alumina and 18-crown-6 in DMSO.¹⁸¹ Aryl fluorides react with amines in the presence of potassium carbonate/DMSO and ultrasound,¹⁸² and aryl chlorides react on basic alumina with microwave irradiation.¹⁸³ 2-Fluoropyridine reacts with R₂NBH₃Li to give the 2-aminoalkylpyridine.¹⁸⁴ 2,4-Dinitrofluorobenzene, known as Sanger's reagent, is used to tag the amino end of a peptide or protein chain.¹⁸⁵

The reaction of amines with aryl halides can be done under milder conditions using a catalyst to initiate or mediate the reaction. Both amines (aliphatic and aniline derivatives)¹⁸⁶ and amide bases¹⁸⁷ have been coupled to aryl halides using Pd catalysts and an appropriate ligand.¹⁸⁸ A considerable amount of work¹⁸⁹ has been done to vary the nature of the ligand and the Pd catalyst, as well as the base.¹⁹⁰ Work to discern the mechanism of this reaction has also received considerable attention.¹⁹¹ This amination has come to be called the Buchwald–Hartwig Cross-Coupling Reaction.

Polymer-supported Pd catalysts,¹⁹² polymer-bound phosphine ligands used in conjunction with a Pd catalyst,¹⁹³ and polymer-bound amines¹⁹⁴ have been used for N-arylation. These reactions have been done in ionic liquids using a Pd catalyst.¹⁹⁵ Palladium-catalyzed amination of aryl halides has been reported using microwave irradiation.¹⁹⁶ Catalysts are available for the amination of aryl halides in aqueous media.¹⁹⁷ The Pd-catalyzed amination of aryl substrates is not limited to halides, and the reaction with mesylates lead to arylamines.¹⁹⁸ Arylamines with chiral substituents on nitrogen can be prepared using a Pd-catalyst with optically active ligands.¹⁹⁹

Aniline derivatives have been prepared by the reaction of aryl chlorides with silylamines (Ph₃SiNH₂) using lithium hexamethyldisilazide and a Pd catalyst.²⁰⁰ Amines react with Ph₂I⁺BF₄⁻, in the presence of Pd catalysts,²⁰¹ or a CuI catalyst²⁰² to give the N-phenyl amine. Aminoalkylation of heteroaromatic rings is possible, as in the reaction of 3-bromothiophene with a primary amine and a Pd catalyst.²⁰³ 2-Halopyridines react to give the 2-aminoalkyl pyridine.²⁰⁴

Copper catalysts have been used for the reaction of amines or aniline derivatives with aryl halides.²⁰⁵ The selectivity of O- versus N-arylation for reactions of amino alcohols has been discussed.²⁰⁶ Copper-catalyzed amination reactions can be done in aqueous media using 2-dimethylaminoethanol as a ligand.²⁰⁷ Ammonium salts serve as a nitrogen source in some cases.²⁰⁸ In the Goldberg reaction, an aryl bromide reacts with an acetanilide in the presence of K₂CO₃ and CuI to give an N-acetyldiarylamine, which can be hydrolyzed to a diarylamine: ArBr + Ar′NHAc → ArAr′NAc.²⁰⁹

Nickel catalysts have been used in the reaction of aryl halides with N-alkyl aniline derivatives²¹⁰ and also with aliphatic amines.²¹¹N-Arylation was also accomplished with butyllithium and a secondary amine using Ni/C-diphenylphosphinoferrocene (dppf).²¹² An intramolecular reaction of a pendant aminoalkyl unit with an aryl chloride moiety, catalyzed by Ni(0) gave a dihydroindole.²¹³ An arylbismuth reagent reacts with aliphatic amines, in the presence of copper(II) acetate, to give an N-arylamine.²¹⁴ Diarylzinc reagents give the N-aryl amine in the presence of a Cu²¹⁵ or a Ni catalyst²¹⁶. Aryl halides also react with Zn(NTMS₂)₂ in the presence of a Pd catalyst to give arylamines.²¹⁷ Iron-catalyzed arylation reactions are known.²¹⁸ A Mo(CO)₆ mediated, Pd catalyzed reaction is known for allylamines and aryl halides.²¹⁹

Intramolecular versions of this reaction generate bicyclic or polycyclic amines.²²⁰ An example is the conversion of 16 to the tetrahydroquinoline.²²¹ Larger ring amines can be prepared using this approach: 8- and even 12-membered.

Arylboronic acids react with aliphatic amines²²² or aq ammonia²²³ in the presence of a Cu catalyst. N-Aryl imides have been prepared by similar methodology, from arylboronic acids.²²⁴ Trifluoroarylboronates react with copper(II) acetate and then an aliphatic amine to give the N-phenylamine.²²⁵ Primary aromatic amines (ArNH₂) were converted to diaryl amines (ArNHPh) by treatment with Ph₃Bi(OAc)₂²²⁶ and a Cu powder catalyst.²²⁷

The metal-catalyzed reaction with ammonia or amines likely proceeds by the S_NAr mechanism.²²⁸ This reaction, with phase-transfer catalysis, has been used to synthesize triarylamines.²²⁹ In certain cases, the S_RN1 mechanism has been found (Reaction 10-26). When the substrate is a heterocyclic aromatic nitrogen compound, still a different mechanism [the S_N(ANRORC) mechanism], involving opening and reclosing of the aromatic ring, has been shown to take place.²³⁰

There are a number of indirect approaches for the preparation of aryl amines. Activated aromatic compounds can be directly converted to the N-aryl amine in high yield with hydroxylamine in the presence of strong bases.²³¹ Aryl halides can be converted to the corresponding Grignard reagent (Reaction 12-38). Subsequent reaction with allyl azide followed by hydrolysis leads to the corresponding aniline derivative.²³² Aryl Grignard reagents react with nitroaryl compounds to give, after reduction with FeCl₃/NaBH₄, a diaryl amine.²³³ Aryl halides can be converted to the aryllithium via halogen–lithium exchange or hydrogen–lithium exchange (Reactions 12-38 and 12-39).

The use of transition metal catalysts allows aryl halides to react with the nitrogen of amides or carbamates to give the corresponding N-aryl amide or N-aryl carbamate. Amides react with aryl halides in the presence of a Pd²³⁴ or a Cu catalyst.²³⁵N-Aryl lactams are prepared by the reaction of a lactam with an aryl halide in the presence of a Pd catalyst.²³⁶ β-Lactams also react.²³⁷ The reaction of 2-oxazolidinones with aryl halides in the presence of a Pd catalyst gave the N-aryl-2-oxazolidinone.²³⁸N-Aryl amides are prepared from amides using PhSi(OMe)₃/Cu(OAc)₂/Bu₄NF.²³⁹N-Boc hydrazine derivatives (BocNHNH₂) gave the N-phenyl derivative [BocN(Ph)NH₂] when reacted with iodobenzene and a catalytic amount of CuI and 10% of 1,10-phenanthroline.²⁴⁰ 3-Bromothiophene was converted to the 3-amido derivative with an amide and CuI-dimethylethylenediamine.²⁴¹N-(2-Thiophene)-2-pyrrolidinone was similarly prepared from 2-iodothiophene, the lactam, and a copper catalyst.²⁴²N-Arylation of urea is possible using a Cu catalyst.²⁴³

The transition metal catalyzed couplings of primary or secondary phosphines with aryl halides or sulfonate esters to give arylphosphines is known.²⁴⁴ The Pd catalyzed conversion of aryl halides to aryl phosphines using (trimethylsilyl)diphenylphosphine tolerates many functional groups (not those that are easily reducible, e.g., aldehydes, because Zn metal²⁴⁵ is often used as a coreagent), but it is mainly limited to aryl iodides.²⁴⁶ Diphenylphosphine reacts with aryl iodides and a copper catalyst to give the triarylphosphine.²⁴⁷ Aryl iodides also react with a secondary phosphine and 5% Pd/C to give the P-arylphosphine.²⁴⁸ Tertiary phosphines can be used via aryl–aryl exchange, as in the reaction of an aryl triflate and triphenylphosphine and a Pd catalyst, for example, gave the arylphosphonium salt (ArPPh₃).²⁴⁹ Aryl iodides can also be used.²⁵⁰

OS I, 544; II, 15, 221, 228; III, 53, 307, 573; IV, 336, 364; V, 816, 1067; VII, 15. OS III, 664. OS X, 423.

13-6 Replacement of a Hydroxy Group by an Amino Group

Amino-de-hydroxylation

The reaction of naphthols with ammonia and sodium bisulfite is called the Bucherer reaction. Primary amines can be used instead of ammonia, in which case N-substituted naphthylamines are obtained. In addition, primary naphthylamines can be converted to secondary (ArNH₂ + RNH₂ + NaSO₃ → ArNHR), by a transamination reaction. The mechanism of the Bucherer reaction amounts to a kind of overall addition–elimination, via 18 and 19.²⁵¹

The first step in either direction consists of addition of NaHSO₃ to one of the double bonds of the ring, which gives an enol from 17 (or enamine from 20) that tautomerizes to the keto form 18 (or imine form, 19). The conversion of 18 to 19 (or vice versa) is an example of Reaction 16-13 (or 16-2). Evidence for this mechanism was the isolation of 18²⁵² and the demonstration that for β-naphthol treated with ammonia and HSO₃⁻, the rate of the reaction depends only on the substrate and on HSO₃⁻, indicating that ammonia is not involved in the rate-determining step.²⁵³ If the starting compound is a β-naphthol, the intermediate is a 2-keto-4-sulfonic acid compound, so the sulfur of the bisulfite in either case attacks meta to the OH or NH₂.²⁵⁴

Hydroxy groups on benzene rings can be replaced by NH₂ groups if they are first converted to aryl diethyl phosphates. Treatment of these with KNH₂ and potassium metal in liquid ammonia gives the corresponding primary aromatic amines.²⁵⁵ The mechanism of the second step is S_RN1.²⁵⁶

OS III, 78.

D. Halogen Nucleophiles

13-7 The Introduction of Halogens

Halo-de-halogenation, and so on

It is possible to replace a halogen on an aromatic ring by another halogen²⁵⁷ if the ring is activated. In such cases, there is equilibrium, which is usually shifted in the desired direction by the use of an excess of added halide ion.²⁵⁸A phenolic hydroxy group can be replaced by chloro with PCl₅ or POCl₃, but only if the ring is activated. Unactivated phenols give phosphates when treated with POCl₃: 3 ArOH + POCl₃ → (ArO)₃PO. Phenols, even unactivated ones, can be converted to aryl bromides by treatment with Ph₃PBr₂²⁵⁹ (see Reaction 10-47) and to aryl chlorides by treatment with PhPCl₄.²⁶⁰

Halide exchange is particularly useful for putting fluorine into a ring, since there are fewer alternate ways of doing this than for the other halogens. Activated aryl chlorides give fluorides when treated with KF in DMF, DMSO, or dimethyl sulfone.²⁶¹ Reaction of aryl halides with Bu₄PF/HF is also effective for exchanging a halogen with fluorine.²⁶²

Halide exchange can also be accomplished with copper halides. Since the leaving-group order in this case is I > Br > Cl F, which means that iodides cannot normally be made by this method, the S_NAr mechanism is probably not operating.²⁶³ However, aryl iodides have been prepared from bromides, by the use of Cu supported on charcoal or Al₂O₃,²⁶⁴ with an excess of NaI and a Cu catalyst,²⁶⁵ and by treatment with excess KI and a Ni catalyst.²⁶⁶Interestingly, aryl chlorides have been prepared from aryl iodides using 2 molar equivalents of NiCl₂ in DMF, with microwave irradiation.²⁶⁷ Aryl and vinyl triflates can be converted to the corresponding bromide or chloride using a Pd catalyst.²⁶⁸

Aryl iodides²⁶⁹ and fluorides can be prepared from arylthallium bis(trifluoroacetates) (see Reaction 12-23), indirectly achieving the ArH → ArI and ArH → ArF conversions. The bis(trifluoroacetates) react with KI to give ArI in high yields.²⁷⁰ Aryllead triacetates [ArPb(OAc)₃] can be converted to aryl fluorides by treatment with BF₃–etherate.²⁷¹ Treatment of PhB(OH)₂ with NIS gives iodobenzene.²⁷² Arylboronic acids (Reaction 12-28) can be converted to the corresponding aryl bromides by reaction with 1,3-dibromo-5,5-dimethylhydantoin and 5 mol% NaOMe.²⁷³ Other aryl halides can be prepared using 1,3-dihalo-5,5-dimethylhydantoins.

OS III, 194, 272, 475; V, 142, 478; VIII, 57; 81, 98.

The reduction of phenols and phenolic esters and ethers is discussed in Reactions 19-38 and 19-35. The reaction ArX → ArH is treated in 11-39, although, depending on reagent and conditions, it can be nucleophilic or free radical substitution, as well as electrophilic.

E. Carbon Nucleophiles²⁷⁴

Some formations of new aryl–carbon bonds formed from aryl substrates have been considered in Reactions 10-57, 10-68, 10-76, and 10-77.

13-8 Cyanation of Aromatic Rings

Cyano-de-halogenation

Cyano-de-metalation

The reaction between aryl halides and cuprous cyanide is called the Rosenmund–von Braun reaction.²⁷⁵ Reactivity of the aryl halide is in the order I > Br > Cl > F, indicating that the S_NAr mechanism does not apply.²⁷⁶ Cyanides (e.g., KCN and NaCN) do not react with aryl halides, even activated ones, but this reaction has been done in ionic liquids using CuCN.²⁷⁷ The reaction has also been done in water using CuCN, a phase-transfer catalyst, and microwave irradiation.²⁷⁸l-Proline has been used to promote the reaction.²⁷⁹

Aryl halides react with metal cyanides, often with another transition metal catalyst, to give aryl nitriles (aryl cyanides). Alkali cyanides convert aryl halides to nitriles²⁸⁰ in dipolar aprotic solvents in the presence of Pd(II) salts²⁸¹or Cu²⁸² or Ni²⁸³ complexes. In the presence of a Pd- catalyst,²⁸⁴ several cyanide-containing compounds react with aryl halides. Several different sources of cyanide may be used with the Pd catalyzed reaction, including: Zn(CN)₂,²⁸⁵CuCN,²⁸⁶ sodium cyanoborohydride/catechol,²⁸⁷ potassium ferricyanide,²⁸⁸ and KCN.²⁸⁹ Microwave irradiation has been used to facilitate Pd catalyzed cyanation.²⁹⁰ Aryl triflates may be used in aryl cyanation reactions, as well as aryl halides.²⁹¹ Benzylthiocyanate reacts with boronic acids to give aryl cyanides in a “cyanide-free” reaction, catalyzed by a Pd complex and mediated by Cu(I).²⁹² Cyanation reactions catalyzed by copper salts are common.²⁹³ Aryl bromides react with Ni(CN)₂ with microwave irradiation to give ArCN.²⁹⁴ A nickel complex also catalyzes the reaction between aryl triflates and KCN to give aryl nitriles.²⁹⁵ Iridium-catalyzed borylation of arenes also leads to aryl nitriles.²⁹⁶

Alternative procedures are available. One uses excess aq KCN followed by photolysis of the resulting complex ion [ArTl(CN)₃⁻] in the presence of excess KCN.²⁹⁷ Alternatively, arylthallium acetates react with Cu(CN)₂ or CuCN to give aryl nitriles.²⁹⁸ Yields from this procedure are variable, ranging from almost nothing to 90 or 100%.

Metal-free methods have been reported. For example, conversion of an aromatic compound to the corresponding iminium salt used POCl₃ and DMF, and subsequent reaction with molecular iodine in aq ammonia gave the nitrile.²⁹⁹ An indirect method involves the reaction of an aromatic ring with tert-butyllithium, particularly when there is a directing group (see Reaction 13-17), followed by reaction with PhOCN (phenyl cyanate) to give the aryl nitrile.³⁰⁰ Aromatic ethers (ArOR)³⁰¹ have been photochemically converted to ArCN.

OS III, 212, 631.

13-9 Coupling of Aryl and Alkyl Organometallic Compounds with Functionalized Aryl Compounds

Aryl-de-halogenation, and so on

A number of methods involving transition metals have been used to prepare unsymmetrical biaryls³⁰² (see also, Reaction 13-11). The uncatalyzed coupling of aryl halides and metalated aryls (particularly aryllithium reagents) is also known, including cyclization of organolithium reagents to aromatic rings.³⁰³ Noncatalyzed coupling reactions of aryllithium reagents and haloarenes can proceed via the well-known aryne route, but a novel addition–elimination pathway is possible when substituents facilitate a chelation-driven nucleophilic substitution pathway.³⁰⁴ Such noncatalyzed coupling reactions often proceed with high regioselectivity and high yield.³⁰⁴ 2-Bromopyridine reacts with pyrrolidine, at 130 °C with microwave irradiation, to give 2-(2-pyrrolidino)pyridine.³⁰⁵ Aryl iodides undergo homocoupling to give the biaryl by heating with triethylamine in an ionic liquid.³⁰⁶ Note that alkyl bromides are coupled to pyrrolidine by heating in an ionic liquid.³⁰⁷

Palladium-catalyzed coupling reactions that generate biaryls are increasingly important in synthesis. Aryl halides undergo homocoupling to give the biaryl with a Pd³⁰⁸ or a Ni catalyst.³⁰⁹ Aryl iodides have been coupled to form symmetric biphenyls with a Pd catalyst,³¹⁰ and homocoupling occurs with aryl triflates under electrolysis conditions with a Pd catalyst.³¹¹ A recyclable Pd catalyst for use in ionic liquids has been developed.³¹² Other alternative solvents include PEG.³¹³

Thiophene derivatives,³¹⁴ pyrrole,³¹⁵ azoles,³¹⁶ quinoline,³¹⁷ and indolizine³¹⁸ have been coupled to aryl halides using a Pd catalyst. Fused polycyclic aromatic compounds can also be prepared from halobiaryls.³¹⁹Trimethylsilylpyridine derivatives are coupled to aryl halides in the presence of a Pd catalyst.³²⁰ A related reaction is the Pd catalyzed decarboxylative coupling of arylcarboxylic acids with aryl iodides.³²¹

Palladium catalysts are often used in conjunction with another metal compound or complex. Arylgermanium compounds are coupled with aryl iodides using tetrabutylammonium fluoride and a Pd catalyst.³²² Homocoupling of triphenylbismuth is known,³²³ as well as the coupling of arylbismuth reagents to aryliodonium salts³²⁴ and to aryltin compounds³²⁵ with Pd compounds or complexes. Aryl triflates were coupled to triphenylbismuth using a Pd catalyst.³²⁶ Specialized arylbismuth compounds have been used with a Pd catalyst to convert aryl chlorides to biaryls.³²⁷ An aryltin–aryl halide coupling has been done in ionic liquids.³²⁸ Aryl halides react with cyclopentadiene and Cp₂ZrCl₂ and a Pd catalyst to give pentaphenylcyclopentadiene.³²⁹ The homocoupling of arylzinc iodides with a Pd catalyst has been reported.³³⁰ In a related reaction, arylsulfonyl chlorides also react with ArSnBu₃ with Pd and Cu catalysts to give the biaryl.³³¹

Aryl triflates (halides) couple with ArZn(halide) reagents in the presence of a Ni catalyst.³³² A homocoupling-type reaction was reported in which PhSnBu₃ was treated with 10% CuCl₂, 0.5 equiv of iodine, and heated in DMF to give biphenyl.³³³ Similar coupling was accomplished with aryltellurium compounds.³³⁴ A Co(II) catalyzed cross-coupling of arylcopper compounds with aryl halides gives the corresponding biaryl.³³⁵ Another homocoupling reaction of pyridyl bromides was reported using NiBr₂ under electrolytic conditions. Both alkylmanganese compounds (RMnCl)³³⁶ and Ph₃In³³⁷ react with aryl halides or aryl triflates to give the arene. Aryl halides also react with phenols to form biaryls using a Rh catalyst.³³⁸ Diaryliodonium salts react with PhPb(OAc)₃ and a Pd catalyst to give the biaryl.³³⁹ Coupling of trialkylbismuth compounds with aryl halides leads to the arene in the presence of a Pd catalyst.³⁴⁰ A cross-coupling reaction of benzylindium compounds and aryl halides in the presence of a Pd catalyst has been reported.³⁴¹

Grignard reagents couple with aryl halides without a Pd catalyst, by the benzyne mechanism,³⁴² but metal-catalyzed reactions are known. Typical catalysts include Fe,³⁴³ Ni³⁴⁴ Co,³⁴⁵ or Ti,³⁴⁶ and Pd- catalyzed reactions are important.³⁴⁷ Aryl Grignard reagents react with aryltrimethylammonium triflates in the presence of a Pd catalyst to give the corresponding biaryl.³⁴⁸ Arylmagnesium halides couple with aryl tosylates in the presence of a Pd catalyst to give unsymmetrical biaryls,³⁴⁹ and to halopyridines to give the arylated pyridine.³⁵⁰ Aryl Grignard reagents are coupled to aryliodonium salts, with ZnCl₂ and a Pd catalyst, to give the biaryl.³⁵¹

The coupling reaction of an excess of a Grignard reagent (RMgX) with methoxy aromatic compounds, when the aromatic ring contains multiple alkoxy groups, proceeds with replacement of the OMe group by R.³⁵² Aryl sulfones were coupled with aryl Grignard reagents in the presence of a Ni catalyst.³⁵³

Unsymmetrical binaphthyls were synthesized by photochemically stimulated reaction of naphthyl iodides with naphthoxide ions in an S_RN1 reaction.³⁵⁴ Methyl chloroacetate coupled with aryl iodides under electrolysis conditions, using a Ni catalyst.³⁵⁵ Unsymmetrical biaryls were prepared from two aryl iodides using a CuI catalyst and microwave irradiation.³⁵⁶

It is possible to couple metalated alkyl compounds to aryl compounds. Alkyl halides³⁵⁷ are coupled to aryl halide using a Ni catalyzed reductive cross coupling.³⁵⁸ Organozinc compounds, available by reaction of an alkyl halide and zinc metal, are coupled to aryl halides using a Pd- catalyst.³⁵⁹ Specialized alkyl indium complexes have been used with a Pd catalyst to give arenes.³⁶⁰ Iron complexes have been used for coupling reactions.³⁶¹ Triarylbismuth compounds are coupled with aryl bromides in the presence of a Pd catalyst.³⁶² Organolithium reagents are coupled to aryl bromides in the presence of a Ni catalyst,³⁶³ as are arylzinc compounds.³⁶⁴ The lithium enolate anion of an ester was coupled to an aryl halide using a Pd catalyst.³⁶⁵ Other ketones can be coupled to aryl triflates, in the presence of a Pd catalyst, and with good enantioselectivity.³⁶⁶

OS VI, 916; VIII, 430, 586; X, 9, 448.

13-10 Arylation and Alkylation of Alkenes

Alkylation or Alkyl-de-hydrogenation, and so on

Arylation of alkenes³⁶⁷ is an important reaction using an “arylpalladium” reagent, typically generated in situ from an aryl halide or other suitably functionalized aromatic compound and a Pd catalyst.³⁶⁸ The Pd catalyzed aryl–alkene coupling reaction is known as the Heck reaction.³⁶⁹ Mizoroki³⁷⁰ had earlier described the coupling between iodobenzene and styrene to form stilbene in methanol at 120 °C in the presence of potassium acetate and a palladium chloride catalyst leading some to call this the Mizoroki–Heck reaction. The reaction works best with aryl iodides, but conditions are available for aryl bromides and aryl chlorides.³⁷¹ Aryldiazonium salts (see Reactions 13-25 and 13-26) have also been used.³⁷² Activated aromatic compounds couple readily,³⁷³ but unactivated aromatic compounds often require special reaction conditions. The Heck reaction can be done with heterocyclic compounds,³⁷⁴ and heteroaryl halides can be used in the coupling reaction.³⁷⁵ Intramolecular Heck reactions are increasingly important.³⁷⁶ A silane-tethered, intramolecular Heck reaction is known.³⁷⁷ Other nucleophiles can be coupled to aryl halides.³⁷⁸

Phosphine–free catalysts,³⁷⁹ halogen-free reactions,³⁸⁰ and base-free reactions³⁸¹ have been developed for the Heck reaction. Improvements to the Pd catalyst system are constantly being reported,³⁸² including polymer-supported³⁸³ silca-supported,³⁸⁴ and recoverable catalysts.³⁸⁵ Considerable work has been done to study and improve the ligand.³⁸⁶ Efforts have been made to produce a homogeneous catalyst for the Heck reaction.³⁸⁷ The Heck reaction can be done in aq media,³⁸⁸ in perfluorinated solvents,³⁸⁹ in polyethylene glycol,³⁹⁰ in neat tricaprylmethylammonium chloride,³⁹¹ and in supercritical CO₂ (See Sec. 9.D.ii).³⁹² The reaction has been done on solid support,³⁹³including Montmorillonite clay,³⁹⁴ glass beads,³⁹⁵ on a reverse-phase silica support,³⁹⁶ and using microwave irradiation.³⁹⁷ A microwave irradiated Heck coupling was done in water using a Pd catalyst.³⁹⁸ A noncatalytic reaction was reported using supercritical water.³⁹⁹ The effects of high pressure have been studied.⁴⁰⁰ The Heck reaction has also been done in ionic liquids,⁴⁰¹ and it is known that the nature of the halide is important in such reactions.⁴⁰² Ionic liquids have been shown to actually promote the Heck reaction.⁴⁰³

Ethylene is the most reactive alkene, and increasing substitution lowers the reactivity. Coupling generally takes place at the less highly substituted side of the double bond.⁴⁰⁴ Unlike the diazonium coupling reaction in Reaction 13-26, the Heck reaction is not limited to activated substrates. Both electron-deficient alkenes (e.g., acrylates),⁴⁰⁵ and electron-rich alkenes⁴⁰⁶ undergo the Heck reaction. The substrate can be an unactivated alkene,⁴⁰⁷ and the alkene can contain a variety of functional groups (e.g., esters, ether,⁴⁰⁸ enol ethers,⁴⁰⁹ enamides,⁴¹⁰ carboxyl, phenolic, or cyano groups).⁴¹¹ The aryl halide or aryl triflate can be coupled to dienes,⁴¹² allenes,⁴¹³ allylic acetates,⁴¹⁴ allylic silanes,⁴¹⁵ allylic amines,⁴¹⁶ vinyl phosphonate esters,⁴¹⁷ and with terminal alkynes.⁴¹⁸ Aryliodonium salts can be coupled to conjugated alkenes in a Heck-like manner using a Pd catalyst.⁴¹⁹ Double-coupling reactions have been reported, generating diaryl aromatic compounds.⁴²⁰ Heck-type reactions have been reported with imines.⁴²¹

Control of regiochemistry is a serious problem in the coupling to unsymmetrical alkenes. Some regioselectivity can be obtained by the use of alkenes attached to an auxiliary coordinating group,⁴²² or by using special ligands and acrylate or styrene as substrates.⁴²³ Neighboring-group effects play a role in the Heck reaction.⁴²⁴ Steric effects are thought to control regioselectivity,⁴²⁵ but electronic influences have also been proposed.⁴²⁶ It has been shown that the presence of steric effects generally improves 1,2-selectivity, and that electronic effects can be used to favor 1,2- or 2,1-selectivity.⁴²⁷ A 1,4-Pd migration between the o- and o′-positions of biaryls has been observed in organopalladium intermediates derived from o-halobiaryls.⁴²⁸ Migration of the double bond is a problem in some cases, and reaction conditions play a significant role in such migrations.⁴²⁹ It has been reported that double-bond isomerization can be suppressed in intramolecular Heck reactions done in supercritical CO₂ (see Sec. 9.D.ii).⁴³⁰

The Pd catalyzed reactions are usually stereospecific,⁴³¹ yielding products expected from syn addition followed by syn elimination.⁴³² Because the product is formed by an elimination step, with suitable substrates, double-bond migration can occur, resulting in allylic rearrangement (as in the reaction of cyclopentene and iodobenzene to give 21).⁴³³ Asymmetric Heck reactions are known,⁴³⁴ including asymmetric intramolecular Heck reactions.⁴³⁵Dihydrofurans react with aryl triflates and a Pd catalyst that includes a chiral ligand, to give the 5-phenyl-3,4-dihydrofuran with good enantioselectivity.⁴³⁶ A similar reaction was reported for an N-carbamoyl dihydropyrrole.⁴³⁷

An addition–elimination mechanism (addition of ArPdX followed by elimination of HPdX) operates in most cases.⁴³⁸ In the conventionally accepted reaction mechanism,⁴³⁹ which is shown,⁴⁴⁰ a four-coordinate arylPd(II) intermediate (a palladacycle)⁴⁴¹ is formed by oxidative addition of the aryl halide to a Pd(0) complex prior to olefin addition.⁴⁴² This description suggests that cleavage of the dimeric precursor complex, reduction

of Pd²⁺, and ligand dissociation combine to give a viable catalytic species.⁴⁴³ σ-Alkyl Pd(II) intermediates are thought to be involved.⁴⁴⁴ An analysis of reaction kinetics under dry conditions was reported.⁴³⁵ In this study, the mechanism requires a first-order dependence on olefin concentration, and anomalous kinetics may be observed when the rate-limiting step is not directly on the catalytic cycle.⁴³⁵ The mechanism requires a proton abstraction step, and there are substituent effects for this step.⁴⁴⁵ A mechanistic study has been reported for the Pd catalyzed decarboxylative reaction of alkenes and arylcarboxylic acids.⁴⁴⁶ The kinetics and mechanism of the Heck reaction promoted by a C–N palladacycle has been studied.⁴⁴⁷ The mechanistic implications of asymmetric Heck reactions have been examined.⁴⁴⁸

There are a number of variations of this reaction, including the use of transition metal catalysts other than Pd. Rhodium-catalyzed Heck reactions are known,⁴⁴⁹ and there are Co-,⁴⁵⁰ Ru-,⁴⁵¹ and Ni catalyzed variations.⁴⁵² Iron-mediated arylation of alkenes has been reported,⁴⁵³ and vinylgermanes are coupled to aryl halides with a Pd catalyst.⁴⁵⁴ Aryl chlorides were coupled to conjugated esters using a RuCl₃•3 H₂O, in an atmosphere of O₂ and CO.⁴⁵⁵ Aryl halides have been coupled to allenyltin compounds (C=C=C-SnR₃).⁴⁵⁶ Divinylindium chloride [(CH₂=CH)₂InCl] reacted with an aryl iodide in aq THF with a Pd catalyst to give the styrene derivative.⁴⁵⁷ Trialkenylindium reagents reacted similarly with aryl halides in the presence of a Pd catalyst.⁴⁵⁸ Arylzinc chlorides (ArZnCl) were coupled to vinyl chlorides using a Pd catalyst,⁴⁵⁹ and vinyl zinc compounds were coupled to aryl iodides.⁴⁶⁰ In the presence of trimethylsilylmagnesium chloride, primary alkyl halides coupled to aryl alkenes to give the substituted alkene (R′–CH=CHAr), using a Co catalyst.⁴⁶¹

Potassium vinyltrifluoroborates can be coupled to aryl halides in Heck-like coupling reactions.⁴⁶² Likewise, the reaction of aryltrifluoroborates with vinyl halides, in the presence of a Pd catalyst, leads to the aryl alkene.⁴⁶³ In a related reaction, alkyltrifluoroborates react with aryl halides in the presence of a Pd and a Rh catalyst.⁴⁶⁴

Although related to chemistry found in Reaction 10-57, metal-catalyzed alkylation reactions are easily viewed as Heck-like reactions. For that reason, they are discussed here. Alkyl halides are coupled to alkenes to form substituted alkenes using a Co catalyst, promoted by Me₃SiCH₂MgCl.⁴⁶⁵ Alkylation requires that the alkyl group lacks a β-hydrogen, and the reaction is successful for the introduction of methyl, benzyl, and neopentyl groups.⁴⁶⁶However, vinylic groups, even those possessing β-hydrogen atoms, have been successfully introduced (to give 1,3-dienes) by the reaction of the alkene with a vinylic halide in the presence of a trialkylamine and a Pd(0) catalyst.⁴⁶⁷

OS VI, 815; VII, 361; 81, 42, 54, 63, 263

13-11 Homo-Coupling of Aryl Halides: The Ullmann Reaction

de-halogen-coupling

The coupling of aryl halides with copper is called the Ullmann reaction.⁴⁶⁸ The reaction is clearly related to Reaction 13-9, but involves aryl copper intermediates. The reaction is of broad scope and has been used to prepare many symmetrical and unsymmetrical biaryls.⁴⁶⁹ When a mixture of two different aryl halides is used, there are three possible products, but often only one is obtained. The best leaving group is iodo, and the reaction is most often done on aryl iodides, but bromides, chlorides, and even thiocyanates have been used. New ligands have been developed to promote the reaction, including an air-stable diazaphospholane ligand.⁴⁷⁰ The Cu catalyst has been immobilized.⁴⁷¹Intramolecular reactions are known.⁴⁷² The coupling reaction can be applied to heterocyclic compounds.⁴⁷³

The effects of other groups on the ring are not easily predicted. The nitro group is strongly activating, but only in the ortho (not meta or para) position.⁴⁷⁴ Both R and OR groups activate in all positions. Not only do OH, NH₂, NHR, and NHCOR inhibit the reaction, as would be expected for aromatic nucleophilic substitution, but so do CO₂H (but not CO₂R), SO₂NH₂, and similar groups for which the reaction fails completely. These groups inhibit the coupling reaction by causing side reactions.

The mechanism is not known with certainty. It seems likely that it is basically a two-step process, similar to that of the Wurtz reaction (10-56), which can be represented schematically by

Organocopper compounds have been trapped by coordination with organic bases.⁴⁷⁵ In addition, aryl copper compounds (ArCu) have been independently prepared and shown to give biaryls (Ar–Ar′) when treated with aryl iodides (Ar′I).⁴⁷⁶ A similar reaction has been used for ring closure⁴⁷⁷: Copper-catalyzed coupling of aryl halides and heterocycles has been reported.⁴⁷⁸

An important alternative to the Ullmann method is the use of certain Ni complexes.⁴⁷⁹ Aryl halides (ArX) can also be converted to Ar–Ar⁴⁸⁰ by treatment with activated Ni metal,⁴⁸¹ with Zn and Ni complexes,⁴⁸² with aq alkaline sodium formate, Pd–C and a phase-transfer catalyst,⁴⁸³ and in an electrochemical process catalyzed by a Ni complex.⁴⁸⁴

An asymmetric Ullmann reaction has been reported.⁴⁸⁵

OS III, 339; V, 1120.

13-12 Coupling of Aryl Compounds with Arylboronic Acid Derivatives

Aryl-de-halogenation, and so on

Aryl-de-boronylation, and so on

Arylboronic acids are coupled to aryl halides using a Pd catalyst to give the arene in what is called Suzuki coupling (or Suzuki–Miyaura coupling).⁴⁸⁶ Aryl triflates react with arylboronic acids [ArB(OH)₂, Reaction 12-28],⁴⁸⁷ or with organoboranes,⁴⁸⁸ in the presence of a Pd catalyst.⁴⁸⁹ Even hindered boronic acids give good yields of the coupled product.⁴⁹⁰ Homocoupling of arylboronic acids has been reported.⁴⁹¹ Some aromatic compounds are so reactive that a catalyst may not be required. Using tetrabutylammonium bromide, phenylboronic acid was coupled to 2-bromofuran without a catalyst.⁴⁹²

Different conditions (including additives and solvent) for the reaction have been reported,⁴⁹³ often focusing on the Pd catalyst⁴⁹⁴ or the ligand.⁴⁹⁵ Phosphine-⁴⁹⁶ and ligand-free conditions⁴⁹⁷ have been developed. Recyclable catalysts have been developed.⁴⁹⁸ Catalysts have been developed for deactivated aryl chlorides.⁴⁹⁹ Suzuki coupling has also been done in ionic liquids,⁵⁰⁰ in supercritical CO₂⁵⁰¹ (see Sec. 9.D.ii), and there are solvent-free procedures.⁵⁰² Several procedures for coupling in aqueous media have been reported.⁵⁰³ The reaction has been done neat on alumina,⁵⁰⁴ and on alumina with microwave irradiation.⁵⁰⁵ Several procedures have been reported using microwave irradiation.⁵⁰⁶ Modifications to the basic procedure include tethering the aryl triflate⁵⁰⁷ or the boronic acid⁵⁰⁸ to a polymer, allowing a polymer-supported Suzuki reaction. Polymer-bound Pd complexes have been used.⁵⁰⁹There is even a Pd free cross-coupling.⁵¹⁰

Arylboronic acids have been coupled to vinyl halides⁵¹¹ or vinyl tosylates⁵¹² using a Pd catalyst. Halogenated heteroaromatic compounds react, as do aryl carbamates, carbonates and sulfamates,⁵¹³ and aryl phosphoramides.⁵¹⁴Aryl sulfonates have been used.⁵¹⁵ Arylboronic acids couple with aryl sulfonate esters.⁵¹⁶ Many different heterocycles have been arylated.⁵¹⁷ 4-Pyridylboronic acids have been used.⁵¹⁸ 3-Iodopyridine reacted with NaBPh and palladium acetate, with microwave irradiation, to give 3-phenylpyridine.⁵¹⁹

A variety of functional groups are compatible with Suzuki coupling, including Ar₂P=O,⁵²⁰ CHO,⁵²¹ C=O of a ketone,⁵²² CO₂R,⁵²³ cyclopropyl,⁵²⁴ NO₂,⁵²⁵ CN, and halogen substituents.⁵²⁶ Vinyl halides react with arylboronic acids to give alkenyl derivatives (vinyl arenes, C=C–Ar),⁵²⁷ in what is clearly a Heck-like reaction. In a variation, vinylboronic acids coupled to aryl halides to give the vinyl-coupling product.⁵²⁸ Vinylboronic acids have been coupled to aryldiazonium salts (see Reaction 13-25) without added base, using a Pd catalyst with an imidazolium ligand.⁵²⁹

Alkylation can accompany arylation if alkyl halides are added, as in the conversion of iodobenzene to 2,6-dibutylbiphenyl.⁵³⁰ Alkyl groups may be coupled to aryls, as in the Pd catalyzed reaction of arylboronic acids with benzylic carbonates.⁵³¹ Arylboronic acids also couple with alkyl halides using either a palladium(II) acetate⁵³² or a Ni catalyst.⁵³³ Conversely, arylboronic acids can be coupled to aliphatic halides.⁵³⁴ Arylboronic acids can be coupled to allylic alcohols as well.⁵³⁵ Benzylic phosphonates have also been used.⁵³⁶ Double Suzuki coupling reactions are known.⁵³⁷ An alkyl–alkyl coupling reaction has been classified as a Suzuki cross-coupling reaction.⁵³⁸ The reaction of an arylboronic acid and 1,2-dibromoethane, with KOH and a Pd catalyst, leads to the styrene derivative.⁵³⁹

Since many biaryls are chiral due to atropisomerism (see Sec. 4.C, category 5), the use of a chiral catalyst, and/or a chiral ligand can lead to enantioselectivity in the Suzuki coupling.⁵⁴⁰

For a mechanistic viewpoint,⁵⁴¹ the Suzuki coupling proceeds via oxidative addition of areneboronic acids to give a Pd species, followed by 1,2-arene migration to an electron-deficient Pd atom, eventually leading to very fast reductive elimination to afford biaryls.⁵⁴² This mechanism is illustrated.⁵⁴³ Several intermediates of the oxidative coupling process have been identified by electrospray ionization mass spectrometry.⁵⁴⁴ Palladium peroxo complexes have been shown to be key intermediates.⁵⁴⁵

Other transition metals have been employed in these coupling reactions, sometimes as cocatalysts. Arylboronic acids have been coupled to conjugated alkenes to give the aryl–alkene coupling product using a Pd catalyst,⁵⁴⁶ a Ru catalyst with copper(II) acetate,⁵⁴⁷ a Ni catalyst,⁵⁴⁸ or a Rh catalyst.⁵⁴⁹ Aryl boronic acids are coupled with aryl ammonium salts to give the biaryl, with a Ni catalyst.⁵⁵⁰ Allylic acetates have been coupled to arylboronic acids using nickel bis(acetylacetonate) and diisobutylaluminum hydride.⁵⁵¹ Arylboronic acids (Reaction 12-28) were shown to react directly with benzene in the presence of Mn(OAc)₃.⁵⁵² Aryl halides couple with ArB(IR′₂) species with a Pd catalyst.⁵⁵³ Iron catalysts have been developed for coupling with alkyl halides.⁵⁵⁴ Arylboronic acids couple with the phenyl group of Ph₂TeCl₂ with a Pd catalyst.⁵⁵⁵ Tributyltin aryl compounds were coupled to the aryl group of Ar₂I⁺BF₄⁻ with a Ni catalyst.⁵⁵⁶

Suzuki-type coupling reactions have been reported involving acyl halides. When arylboronic acids were reacted with benzoyl chloride and PdCl₂, the product was the diaryl ketone.⁵⁵⁷ This coupling reaction was also accomplished using a Pd(0) catalyst.⁵⁵⁸ Cyclopropylboronic acids couple with benzoyl chloride, in the presence of Ag₂O and a Pd catalyst, to give the cyclopropyl ketone.⁵⁵⁹ A Ni catalyst has been used,⁵⁶⁰ and Ph₃P/Ni/C–BuLi has also been used.⁵⁶¹ Arylboronic acids have also been coupled to anhydrides,⁵⁶² and the methoxy group of anisole derivatives has been replaced with phenyl using phenylboronic acid and a Ru catalyst.⁵⁶³

Arylborates (see Reaction 12-28), ArB(OR)₂, can be used in place of the boronic acid.⁵⁶⁴ The coupling reaction of aryl iodide (22) with boronate (23), for example, gave biaryl 24.⁵⁶⁵ Base-free conditions, using nitrogen ligands, have been reported.⁵⁶⁶ Aryl and heteroarylboroxines (25) can be coupled to aryl halides using a Pd catalyst.⁵⁶⁷ Vinylboranes have been coupled to aryl iodides to give the aryl alkene, in the presence of a Pd catalyst.⁵⁶⁸Organoboranes are coupled to aryl halides with a Pd catalyst.⁵⁶⁹

In a useful variation, aryltrifluoroborates (ArBF₃⁺ X⁻) (Reaction 12-28), are coupled to aryl halides with a Pd catalyst to give the biaryl.⁵⁷⁰ Alkyltrifluoroborates⁵⁷¹ (RBF₃K, see Reaction 12-28) react with aryl triflates⁵⁷² aryl halides,⁵⁷³ or aryliodonium salts⁵⁷⁴ with a Pd catalyst, to give the arene. In a related reaction, vinyltrifluoroborates (C=C–BF₃⁺ X⁻ see Reaction 12-28), are coupled to aryl halides with a Pd catalyst to give the styrene derivative.⁵⁷⁵Suzuki coupling with trifluoroborates has also been done using microwave irradiation.⁵⁷⁶ Aryltellurides have been used in this reaction.⁵⁷⁷ A Pd catalyzed reaction with enamino ketones, mediated by Cu(II) salts, led to coupling to give the aryl derivative.⁵⁷⁸ Ruthenium catalysts have also been used.⁵⁷⁹

OS 75, 53, 61

The coupling reactions of alkylboronic acids are covered in Reaction 13-17.

OS CV, 102, 467; OS 81, 89.

13-13 Aryl–Alkyne Coupling Reactions

Alkynyl-de-halogenation, and so on

When aryl halides react with copper acetylides to give 1-aryl alkynes, the reaction is known as Stephens–Castro coupling.⁵⁸⁰ Both aliphatic and aromatic substituents can be attached to the alkyne unit, and a variety of aryl iodides have been used. Benzonitrile was shown to react with alkynyl zinc bromides, with a Ni catalyst and after electrolysis to give the diarylalkyne, where the cyano unit was replaced with an alkyne unit.⁵⁸¹

A Pd catalyzed variation is known in which an aryl halide reacts with a terminal alkyne to give 1-aryl alkynes is called Sonogashira coupling.⁵⁸² Terminal aryl alkynes react with aryl iodides and Pd(0)⁵⁸³ to give the corresponding diaryl alkyne,⁵⁸⁴ but monoalkynes are easily prepared.⁵⁸⁵ Aryl iodides are more reactive than aryl fluorides.⁵⁸⁶ Alkynes can be coupled to heteroaromatic compounds.⁵⁸⁷ As with all of the metal-catalyzed reactions in this chapter, work has been done to vary reaction conditions, including the catalyst,⁵⁸⁸ the ligand,⁵⁸⁹ the solvent, and additives.⁵⁹⁰ There are copper-⁵⁹¹ and ligand-free variations.⁵⁹² Transition metal free coupling has been reported using a 2,2,6,6-tetramethylpiperidine-N-oxyl radical as an oxidant.⁵⁹³ Variations include Sonogashira coupling in water, without Cu,⁵⁹⁴ and other reactions are done in aqueous media.⁵⁹⁵ The coupling has been done in aq polyethylene glycol,⁵⁹⁶ and in ionic liquids.⁵⁹⁷ Microwave irradiation is an important tool in this reaction.⁵⁹⁸ Sonogashira coupling was reported on microbeads,⁵⁹⁹ with nanoparticulate nickel powder,⁶⁰⁰ and the aryl iodide was tethered to a polymer for a solid-state reaction.⁶⁰¹ Polymer-supported catalysts are known.⁶⁰² A variation scavenged the triphenylphosphine byproduct by addition of Merrifield resin.⁶⁰³

Coupling of the alkynes to form a diyne (see Reaction 14-16) can be a problem is some cases, although the aryl–alkyne coupling usually predominates.⁶⁰⁴ There are many variations. Alkyl groups are coupled to alkynes under Sonogashira conditions, including unactivated secondary alkyl halides.⁶⁰⁵ Coupling propargyl bromide and an aryl iodide, in the presence of an amine, gives the aryl aminomethylalkyne.⁶⁰⁶ 4-Chloroacetophenone reacts with 1-phenylethyne, showing that the carbonyl group is compatible with this reaction.⁶⁰⁷ Arenediazonium salts can be used for the coupling reaction.⁶⁰⁸ Similar Pd catalyzed coupling of bromoalkynes with heterocycles also leads to the alkynyl derivative.⁶⁰⁹ Ynamides are coupled using cooper-free conditions.⁶¹⁰

There are variations of the Sonogashira reaction that use other metals as catalysts or cocatalysts. A Pd free reaction is known, using Cu complexes as the catalyst.⁶¹¹ An In catalyzed reaction is known that does not use Cu, Pd, or phosphine ligands.⁶¹² Gold(I) has been used to catalyze Sonogashira reactions,⁶¹³ and there are Ni⁶¹⁴ and Fe catalyzed⁶¹⁵ reactions. Silver iodide has been used to catalyze the reaction.⁶¹⁶ Conversion of 1-lithioalkynes to the corresponding alkynyl zinc reagent allows coupling with aryl iodides when a Pd catalyst is used.⁶¹⁷ A 1-lithioalkyne was directly coupled to aryl bromides in the presence of B(OiPr)₃ and a Pd catalyst,⁶¹⁸ where an alkynylboronic acid was generated in situ. Lithium alkynyltrimethylborates are coupled to aryl chlorides as well.⁶¹⁹ Terminal alkynes are coupled to acylpyridinium salts in the presence of a Cu catalyst, giving a product with high enantioselectivity when a chiral ligand is used.⁶²⁰ Coupling with alkynyl tin compounds is known.⁶²¹ A triphenylstibine [Ph₃Sb(OAc)₂] was used to transfer a phenyl group to the alkyne carbon of PhCCSiMe₃, using Pd and CuI catalysts.⁶²²

A variation of this aryl–alkyne coupling reaction reacted methylthioalkynes (R–CC–SMe) with arylboronic acids and a Pd catalyst to give the aryl alkyne (R–CC–Ar).⁶²³ The boron trifluoride induced Pd catalyzed cross-coupling reaction of 1-aryltriazenes with areneboronic acids has been reported.⁶²⁴ Aryl halides are coupled to alkynyltrifluoroboronates (R–CC–BF₃K, Reaction 12-28) using a Pd catalyst.⁶²⁵ Aryl iodides were also coupled to lithium alkynyl borate complexes, Li[R–CC–B(OR′)₃], to give the aryl alkyne.⁶²⁶

Diaryliodonium salts react with terminal alkynes to give the phenyl alkyne.⁶²⁷ A variation couples the phenyl group of Ph₂I⁺OTf⁻ with an en-yne using a Pd catalyst.⁶²⁸ Aryl sulfonate esters can be coupled to terminal alkynes using a Pd catalyst in polymethylhydrosiloxane.⁶²⁹

OS 11, 2009, 234.

13-14 Arylation at a Carbon Containing an Active Hydrogen

Bis(ethoxycarbonyl)methyl-de-halogenation, and so on

The arylation of compounds of the form ZCH₂Z′ is analogous to Reaction 10-67, where Z is defined as an electron-withdrawing group (ester, cyano, sulfonyl, etc.). Activated aryl halides generally give good results.⁶³⁰ Treatment with an aryl halide in liquid ammonia containing Na or K, for example, leads in the formation of 26 and 27.⁶³¹ When the solution is irradiated with near-UV light, but Na or K is omitted, the same products are

obtained (though in different proportions).⁶³² In either case, other leaving groups can be used instead of halogens (e.g., NR₃⁺, SAr) and the mechanism is the S_RN1 mechanism. N-Heterocyclic carbene ligands in the presence of alkoxide bases lead to coupling of ketones and aryl halides, at the α-position of the ketone.⁶³³ The reaction can also take place without an added initiator. The reaction of 2-fluoroanisole and KHMDS, and 4 equiv of 2-cyanopropane, leads to substitution of the fluorine atom by CMe₂CN.⁶³⁴ β-Keto esters were coupled to aryl fluorides using CsOH and a chiral quaternary ammonium salt, leading to the aryl substitution product with good enantioselectivity.⁶³⁵

Even unactivated aryl halides can be employed if the reaction is carried out in the presence of a strong base (e.g., NaNH₂⁶³⁶ or LDA). Compounds of the form ZCH₂Z′, and even simple ketones⁶³⁷ or carboxylic esters have been arylated in this manner. The reaction with unactivated halides proceeds by the benzyne mechanism and represents a method for extending the malonic ester (and similar) syntheses to aromatic compounds. The base performs two functions: It removes a proton from ZCH₂Z′ and catalyzes the benzyne mechanism. The reaction has been used for ring closure, as in the formation of indole 28.⁶³⁸

A similar reaction was reported using a Pd catalyst.⁶³⁹ Nitroethane was converted to 2-phenylnitroethane using bromobenzene and a Pd catalyst.⁶⁴⁰ Palladium catalysts have been developed for the α-arylation of ketones.⁶⁴¹ α-Arylation of esters has been accomplished using Pd catalysts.⁶⁴² Malonate esters are coupled unactivated aryl halides using a Pd catalyst.⁶⁴³ Bis-(sulfones) [CH₂(SO₂Ar)₂], react with aryl halides in the presence of a Pd catalyst.⁶⁴⁴Iron(II) salts have also been used to initiate this reaction.⁶⁴⁵ The coupling of active methylene compounds and unactivated aryl halides can also be done with copper halide catalysts¹⁰³ (the Hurtley reaction).⁶⁴⁶ Similar coupling was accomplished with CH₂(CN)₂ and a Ni catalyst.⁶⁴⁷ A variation of α-arylation reacts α-halocarbonyl compounds with arylboronic acids, in the presence of a Ni catalyst.⁶⁴⁸ Malonic and β-keto esters can be arylated at the α-carbon in high yields by treatment with aryllead tricarboxylates [ArPb(OAc)₃],⁶⁴⁹ with triphenylbismuth carbonate (Ph₂BiCO₃),⁶⁵⁰ and other Bi reagents.⁶⁵¹ In a related process, manganese(III) acetate was used to convert a mixture of ArH and ZCH₂Z′ to ArCHZZ′.⁶⁵² Arylzinc reagents have also been used.⁶⁵³

Enolate ions of ketones react with PhI in the dark.⁶⁵⁴ In this case, it has been suggested⁶⁵⁵ that initiation takes place by formation of a radical (e.g., 29).

This is a SET mechanism (see Sec. 10.B). The photostimulated reaction has also been used for ring closure.⁶⁵⁶ In certain instances of the intermolecular reaction, there is evidence that the leaving group exerts an influence on the product ratios, even when it has already departed at the time that product selection takes place.⁶⁵⁷

The reaction of the enolate anions of ketones and aldehydes, generated in situ by addition of a suitable base, with aryl halides can be accomplished by treatment with a Pd catalyst.⁶⁵⁸ Formation of an enolate anion of a conjugated ketone (cyclohexenone) via reaction with LDA (see Sec. 8.F, category 7), in the presence of Ph₃BiCl₂, leads to the α-phenyl conjugated ketone (6-phenylcyclohex-2-enone).⁶⁵⁹ An ester reacted with TiCl₄ and N,N-dimethylanline to give the para-substitution product (Me₂N–Ar–2Et).⁶⁶⁰ Nickel-catalyzed α-arylation of ketone enolate anions is also known.⁶⁶¹ The enolate anion of lactams will react with aryl halides in the presence of a Pd catalyst via the 3-aryl lactam.⁶⁶² When the enolate anion of a ketone is generated in the presence of a Pd catalyst and a chiral phosphine ligand, the α-aryl ketone is formed with good enantioselectivity.⁶⁶³

OS V, 12, 263; VI, 36, 873, 928; VII, 229.

13-15 Conversion of Aryl Substrates to Carboxylic Acids, Their Derivatives, Aldehydes, and Ketones⁶⁶⁴

Alkoxycarbonyl-de-halogenation, and so on

Carbonylation of aryl halides⁶⁶⁵ and aryl triflates⁶⁶⁶ with CO, an alcohol and a base (which gives an alkoxide), and a Pd catalyst, gives carboxylic esters. Similar carbonylation reactions are possible with alkyl halides. Aryl carboxylic acids were also prepared from aryl iodides by heating in DMF with lithium formate, LiCl, acetic anhydride, and a Pd catalyst.⁶⁶⁷ Even very sterically hindered alkoxides can be used to produce the corresponding ester.⁶⁶⁸The use of H₂O, RNH₂, or an alkali metal or calcium carboxylate⁶⁶⁹ instead of ROH, gives the carboxylic acid,⁶⁷⁰ amide,⁶⁷¹ or mixed anhydride, respectively.⁶⁷² Ester formation via carbonylation was done is supercritical CO₂ (see Sec. 9.D.ii).⁶⁷³ Microwave promoted carbonylation reactions have been reported.⁶⁷⁴

Variations including a silica-supported Pd reagent have been used to convert iodobenzene to butyl benzoate, in the presence of CO and butanol.⁶⁷⁵ 2-Chloropyridine was converted to the butyl pyridine 2-carboxylate with this procedure.⁶⁷⁶ Dicobalt octacarbonyl [Co₂(CO)₈] may be used as a surrogate reagent for CO.⁶⁷⁷ Heating an aryl iodide, CO in ethanol and DBU, with a Pd catalyst, gave the ethyl ester of the aryl carboxylic acid.⁶⁷⁸ A similar result was obtained when an aryl iodide was heated in ethanol with triethylamine, CO, and Pd/C.⁶⁷⁹ Phenols and aryl halides react with a Pd catalyst, and carbonylation leads to the phenyl ester.⁶⁸⁰ Arylthallium bis(trifluoroacetates) [ArTl(O₂CCF₃)₂, (see Reaction 12-23], can be carbonylated with CO, an alcohol, and a PdCl₂ catalyst to give esters.⁶⁸¹ Note that seleno esters (ArCOSeAr) were prepared from aryl iodides, CO, PhSeSnBu₃, and a Pd catalyst.⁶⁸²Aminocarbonylation reactions are known.⁶⁸³

Modification of this approach allows the synthesis of ketones, and aryl iodides can be converted to aldehydes.⁶⁸⁴ Aryl ketones can be prepared from aryltrimethylsilanes (ArSiMe₃) and acyl chlorides in the presence of AlCl₃.⁶⁸⁵Aryllithium and Grignard reagents react with iron pentacarbonyl to give aldehydes ArCHO.⁶⁸⁶ The reaction of CO with aryllithium may occur by electron transfer.⁶⁸⁷ Aryl iodides are converted to unsymmetrical diaryl ketones on treatment with arylmercury halides and nickel carbonyl: ArI + Ar′HgX + Ni(CO)₄ → ArCOAr′.⁶⁸⁸ Aryl iodides are carbonylated to give the aryl alkyl ketone with CO and R₃In.⁶⁸⁹ Aryl iodides are coupled with aryl acid chlorides in the presence of an In complex to form a diaryl ketone.⁶⁹⁰ Organomercury compounds undergo a similar reaction.⁶⁹¹ The aryllead reagent [PhPb(OAc)₂] was converted to benzophenone using NaOMe, CO, and a Pd catalyst.⁶⁹² Aryl iodides containing an ortho substituent with a β-cyano group that served as the source of a carbonyl group, was converted to a bicyclic ketone with a Pd catalyst at 130 °C in aq DMF.⁶⁹³

Diaryl ketones can also be prepared by coupling aryl iodides with phenylboronic acid (Reaction 12-28), in the presence of CO and a Pd catalyst.⁶⁹⁴ This reaction has been extended to heteroaromatic systems, with the preparation of phenyl 4-pyridyl ketone from phenylboronic acid and 4-iodopyridine.⁶⁹⁵ 2-Bromopyridine as coupled with phenylboronic acid, CO, and a Pd catalyst to give phenyl 2-pyridyl ketone.⁶⁹⁶ Carbonylation of an alkyne and an aryl halide, with CO and Pd and Cu catalysts, gave the alkynyl ketone RCC(C=O)Ar.⁶⁹⁷

13-16 Arylation of Silanes

Silyl and Silyloxy-de-halogenation, Aryl-de-silylation, and so on

In the presence of transition metal catalysts (e.g., Pd), trialkoxysilanes [HSi(OR)₃] react with aryl halides to give the corresponding arylsilane.⁶⁹⁸ This transformation is an alternative to the Suzuki coupling (Reaction 13-12).⁶⁹⁹The influence of silicon substituents on the cross-coupling reaction has been studied.⁷⁰⁰ A similar reaction was reported using a Rh catalyst.⁷⁰¹ Similar coupling of aryl halides with trialkylsilanes (HSiR₃) in the presence of a Pd,⁷⁰²or Rh catalyst,⁷⁰³ or PtO₂⁷⁰⁴ gives the arylsilane. Cyclic alkoxysilanes are prepared using Pd catalyzed cross-coupling reactions.⁷⁰⁵ Vinylsilanes are coupled to aryl halides to give the aryl alkene.⁷⁰⁶ Disilanes have also been employed, using a Pd catalyst.⁷⁰⁷ Arylsilanes can be coupled to aryl iodides using a Pd catalyst⁷⁰⁸ and in aqueous media.⁷⁰⁹ Arylsilanes react with alkyl halides to give the corresponding arene, in the presence of a Pd catalyst.⁷¹⁰

Other variations include the conversion of vinyl silanes to styrene derivatives upon treatment with Bu₄NF (TBAF), an aryl iodide and a Pd catalyst.⁷¹¹ Arylsilanes were coupled to alkenes to give the styrene derivative using palladium acetate in an oxygen atmosphere,⁷¹² or TBAF and an Ir catalyst.⁷¹³ Aryl iodides can be coupled to 1-methyl-1-vinyl- and 1-methyl-1-(prop-2-enyl)silacyclobutane with desilyation, using a Pd catalyst and TBAF, to give the corresponding styrene derivative.⁷¹⁴ Aryl silanes can be coupled to aryl iodides using Ag₂O and a Pd catalyst,⁷¹⁵ and arylsiloxanes [ArSi(OR)₃] are coupled to aryl halides with TBAF and a Pd catalyst.⁷¹⁶ 1-Trialkylsilylalkynes (R₃Si–CC–R′) were coupled to aryl iodides using a Pd catalyst.⁷¹⁷

An alternative approach reacts aryllithium reagents with siloxanes [Si(OR)₄], to give the aryl derivative ArSi(OR)₃.⁷¹⁸ Biaryl derivatives are similarly prepared from aryl halides.⁷¹⁹ Arylsiloxanes are similarly coupled at the ortho position of anilide derivatives.⁷²⁰

The reaction of NaBPh₄ (sodium tetraphenylborate) and a silyl dichloride (Ph₂SiCl₂) gives biphenyl.⁷²¹

13.C.ii. Hydrogen as Leaving Group⁷²²

13-17 Alkylation and Arylation

Alkylation or Alkyl-de-hydrogenation, and so on

The alkylation of aromatic rings was introduced, in part, in Reaction 10-57. The reaction of an aromatic ring with an organolithium reagent can give H–Li exchange to form an aryllithium. This reaction tends to be slow if there are activating substituents on the aryl halide, or in the absence of diamine additives.⁷²³ When heteroatom substituents are present as in 30, however, the reaction is facile and the Li goes into the 2 position (as in 31).⁷²⁴ This regioselectivity can be quite valuable synthetically, and is now known as directed ortho metalation⁷²⁵ (see Reaction 10-57). Subsequent reaction with a suitable electrophilic agent (e.g., D₂O) leads to 32 in this case. Aryllithium reagents give arylation. The reaction occurs by an addition–elimination mechanism and the adduct can be isolated.⁷²⁶ Upon heating of the adduct, elimination of LiH occurs and an alkylated product is obtained. With respect to C-2, the first step is the same as that of the S_NAr mechanism. The difference is that the unshared pair of electrons on the nitrogen combines with the lithium, so the extra pair of ring electrons has a place to go: It becomes the new unshared pair on the nitrogen.

With TMEDA/n-butyllithium mediated arene lithiation reactions, the viability of directive effects (complex-induced proximate effects) has been questioned,⁷²⁷ although it is not clear if this extends to other systems (particularly when there is a strong coordinating group (e.g., carbamate).⁷²⁸ The 2 position is much more acidic than the 3 position (see Table 8.1), but a negative charge at C-3 is in a more favorable position to be stabilized by the Li⁺. Lithiation reactions do not necessarily rely on a complex-induced proximity effect.⁷²⁹N,N-Dialkyl aryl-O-sulfamates are substrates for ortho metalation.⁷³⁰ Phenylaziridines also undergo this reaction.⁷³¹ Formation of the ortho arylmagnesium compound has been accomplished with bases of the form (R₂N)₂Mg.⁷³² A directed meta metalation has been reported, using alkali metal mediated zincation.⁷³³ Note that the substrate-dependent mechanism of the ortho lithiation of aryloxazolines using butyllithium has been studied.⁷³⁴

Benzene, naphthalene, and phenanthrene have been alkylated with alkyllithium reagents, although the usual reaction with these reagents is Reaction 12-22,⁷³⁵ and Grignard reagents have been used to alkylate naphthalene.⁷³⁶ The addition–elimination mechanism apparently applies in these cases too. A protected form of benzaldehyde (protected as the benzyl imine) has been similarly alkylated at the ortho- position with butyllithium.⁷³⁷ The alkylation of heterocyclic nitrogen compounds⁷³⁸ with alkyllithium reagents is called Ziegler alkylation. The reaction of 2-chloropyridine with 3 equiv of butyllithium–Me₂NCH₂CH₂OLi and then iodomethane gave 2-chloro-6-methylpyridine.⁷³⁹Note that H–Li exchange can be faster than Cl–Li exchange. Treatment of 2-chloro-5-phenylpyridine with tert-butyllithium leads to lithiation on the phenyl ring rather than Li–Cl exchange, and subsequent treatment with dimethyl sulfate gave 2-chloro-5-(2-methylphenyl)pyridine.⁷⁴⁰ The reaction of N-triisopropylsilyl indole with tert-butyllithium and then iodomethane gave the 3-methyl derivative.⁷⁴¹ Heteroaromatic compounds can be alkylated. Pyrrole, for example, reacts with an allylic halide and zinc to give primarily the 3-substituted pyrrole.⁷⁴²

Mercuration of aromatic compounds⁷⁴³ can be accomplished with mercuric salts, most often Hg(OAc)₂,⁷⁴⁴ to give ArHgOAc. This is ordinary electrophilic aromatic substitution and takes place by the arenium ion mechanism (Sec. 11.A.i).⁷⁴⁵ Aromatic compounds can also be converted to arylthallium bis(trifluoroacetates) [ArTl(OOCCF₃)₂] by treatment with thallium(III) trifluoroacetate⁷⁴⁶ in trifluoroacetic acid.⁷⁴⁷ These arylthallium compounds can be converted to phenols, aryl iodides or fluorides (Reaction 12-31), aryl cyanides (Reaction 12-34), aryl nitro compounds,⁷⁴⁸ or aryl esters (Reaction 12-33). The mechanism of thallation appears to be complex, with electrophilic and electron-transfer mechanisms both taking place.⁷⁴⁹ Transient metalated aryl complexes can be formed that react with another aromatic compound. Aryl iodides reacted with benzene to form a biaryl in the presence of an Ir catalyst.⁷⁵⁰Aniline derivatives reacted with TiCl₄ to give the para-homo coupling product (R₂N–Ar–Ar–NR₂).⁷⁵¹

Aromatic nitro compounds can be methylated with dimethyloxosulfonium methylid⁷⁵² or the methylsulfinyl carbanion (obtained by treatment of DMSO with a strong base)⁷⁵³:

The reactions with the sulfur carbanions are especially useful, since none of these substrates can be methylated by the Friedel–Crafts procedure (Reaction 11-10).

A different kind of alkylation of nitro compounds uses carbanion nucleophiles that have a chlorine at the carbanionic carbon. The following process takes place:⁷⁵⁴

This type of process is called vicarious nucleophilic substitution of hydrogen.⁷⁵⁵ The Z group is electron withdrawing (e.g., SO₂R, SO₂OR, SO₂NR₂, COOR, or CN); it stabilizes the negative charge. The carbanion attacks the activated ring ortho or para to the nitro group.⁷⁵⁶ Hydride ion (H⁻) is not normally a leaving group, but in this case the presence of the adjacent Cl allows the hydrogen to be replaced. Hence, Cl is a “vicarious” leaving group. Other leaving groups have been used (e.g., OMe and SPh), but Cl is generally the best. Many W groups in the ortho, meta, or para positions do not interfere. The reaction is also successful for di- and trinitro compounds, for nitronaphthalenes,⁷⁵⁷ and for many nitro heterocycles, may also be used.⁷⁵⁸ When the nucleophile is Br₃C⁻ or Cl₃C⁻, the product is ArCHX₂, which can easily be hydrolyzed to ArCHO.⁷⁵⁹ This is therefore an indirect way of formylating an aromatic ring containing one or more NO₂ groups, which cannot be done by any of the formylations mentioned in Reaction 11-1–11-18.

Replacement of an amino group is possible. When aniline derivatives were treated with allyl bromide and tert-butyl nitrite (t-BuONO), the aryl–allyl coupling product was formed (Ar–NH₂ → Ar–CH₂CH=CH₂).⁷⁶⁰

For the introduction of CH₂SR groups into phenols, see Reaction 11-23. See also, Reaction 14-19.

OS II, 517.

13-18 Amination of Nitrogen Heterocycles

Amination or Amino-de-hydrogenation

Pyridine and other heterocyclic nitrogen compounds can be aminated with alkali metal amides in a process called the Chichibabin reaction.⁷⁶¹ The attack is always in the 2 position unless both such positions are filled, in which case the 4 position is attacked. Substituted alkali metal amides (e.g., RNH⁻ and R₂N⁻), have also been used. The mechanism is probably similar to that of Reaction 13-17. The existence of intermediate ions (e.g., 33)

(from quinoline) has been demonstrated by NMR spectra.⁷⁶² A pyridyne type of intermediate was ruled out by several observations including the facts that 3-ethylpyridine gave 2-amino-3-ethylpyridine⁷⁶³ and that certain heterocycles that cannot form an aryne could nevertheless be successfully aminated. Nitro compounds do not give this reaction,⁷⁶⁴ but they have been aminated (ArH → ArNH₂ or ArNHR) via the vicarious substitution principle (see Reaction 13-17), using 4-amino- or 4-alkylamino-1,2,4-triazoles as nucleophiles.⁷⁶⁵ The vicarious leaving group in this case is the triazole ring. Note, however, that 3-nitropyridine was converted to 6-amino-3-nitropyridine by reaction with KOH, hydroxylamine, and ZnCl₂.⁷⁶⁶

Analogous reactions have been carried out with hydrazide ions (R₂NNH⁻).⁷⁶⁷ A mixture of NO₂ and O₃, with excess NaHSO₃, converted pyridine to 3-aminopyridine.⁷⁶⁸ For other methods of aminating aromatic rings, see Reaction 11-6.

There are no Organic Syntheses references, but see OS V, 977, for a related reaction.

13.C.iii. Nitrogen as Leaving Group

The diazonium group can be replaced by a number of groups.⁷⁶⁹ Some of these are nucleophilic substitutions, with S_N1 mechanisms (Sec. 10.A.ii), but others are free radical reactions and are treated in Chapter 14. The solvent in diazonium group reactions is usually water. With other solvents it has been shown that the S_N1 mechanism is favored by solvents of low nucleophilicity, while those of high nucleophilicity favor free radical mechanisms.⁷⁷⁰ The N₂⁺group⁷⁷¹ can be replaced by Cl⁻, Br⁻, and CN⁻, by a nucleophilic mechanism (see OS IV, 182), but the Sandmeyer reaction is much more useful (Reaction 14-20). Transition metal catalyzed reactions are known involving aryldiazonium salts, and diazonium variants of the Heck reaction (13-10) and Suzuki coupling (13-12) were mentioned previously. As mentioned in Section 13.B.i, it must be kept in mind that the N₂⁺ group can activate the removal of another group on the ring. In a few cases, nitrogen groups (e.g., nitro or ammonium) can be replaced.

13-19 Diazotization

When primary aromatic amines are treated with nitrous acid, diazonium salts are formed.⁷⁷² The reaction also occurs with aliphatic primary amines, but aliphatic diazonium ions are extremely unstable, even in solution (see Sec. 10.G.iii). Aromatic diazonium ions are more stable, because of the resonance interaction between the nitrogen atoms and the ring:

Incidentally, 34 contributes more than 35, as shown by bond-distance measurements.⁷⁷³ In benzenediazonium chloride, the C–N distance is ~1.42 Å, and the N–N distance ~1.08 Å,⁷⁷⁴ and these values fit more closely to a single and a triple bond than to two double bonds (see Table 1.5). Even aromatic diazonium salts are unstable at temperatures other than about <5 °C. A few are more stable (e.g., the diazonium salt obtained from sulfanilic acid), which is stable up to 10 or 15 °C. Diazonium salts are usually prepared in aqueous solution and used without isolation.⁷⁷⁵ While it is possible to prepare solid diazonium salts (see Reaction 13-23), many dry diazonium salts are explosive if not handled with great care and extreme caution should be exercised. The stability of aryl diazonium salts can be increased by crown ether complexion.⁷⁷⁶

For aromatic amines, the reaction is very general. Halogen, nitro, alkyl, aldehyde, sulfonic acid, and so on, groups do not interfere. Since aliphatic amines do not react with nitrous acid below a pH of ~3, it is even possible, by working at a pH ~1, to diazotize an aromatic amine without disturbing an aliphatic amino group in the same molecule.⁷⁷⁷

If an aliphatic amino group is α to a COOR, CN, CHO, COR, and so on, and has a hydrogen, treatment with nitrous acid gives not a diazonium salt, but a diazo compound.⁷⁷⁸ Such diazo compounds can also be prepared, often more conveniently, by treatment of the substrate with isoamyl nitrite (Me₂CHCH₂CH₂ONO) and a small amount of acid.⁷⁷⁹ Certain heterocyclic amines also give diazo compounds rather than diazonium salts.⁷⁸⁰

Despite the fact that diazotization takes place in acid solution, the actual reactive species is not the salt of the amine, but is the small amount of free amine present.⁷⁸¹ Because aliphatic amines are stronger bases than aromatic ones that at pH values <3 there is not enough free amine present for the former to be diazotized, while the latter still undergo the reaction. In dilute acid, the actual attacking species is N₂O₃, which acts as a carrier of NO⁺. Evidence is that the reaction is second order in nitrous acid and, at sufficiently low acidities, the amine does not appear in the rate expression.⁷⁸² Under these conditions the mechanism is

Other evidence exists for this mechanism.⁷⁸³ Other attacking species can be NOCl, H₂NO₂⁺, and at high acidities even NO⁺. Nucleophiles (e.g., Cl⁻, SCN⁻, and thiourea) catalyze the reaction by converting the HONO to a better electrophile (e.g., HNO₂ + Cl⁻ + H⁺ → NOCl + H₂O).⁷⁸⁴

N-Aryl ureas are converted to the aryldiazonium nitrate upon treatment with NaNO₂ and H₂SO₄ in dioxane⁷⁸⁵ or with DMF–NO₂ in DMF.⁷⁸⁶

There are many preparations of diazonium salts listed in Organic Syntheses, but they are always prepared for use in other reactions. They are listed under reactions in which they are used. The preparation of aliphatic diazo compounds can be found in OS III, 392; IV, 424. See also, OS VI, 840.

13-20 Hydroxylation of Aryldiazonium Salts

Hydroxy-de-diazoniation

This reaction is formally analogous to 13-1, but with a N₂⁺ leaving group rather than a halide. Water is usually present whenever diazonium salts are made, but at these temperatures (0–5°C) the reaction proceeds very slowly. When it is desired to have OH replace the diazonium group, the excess nitrous acid is destroyed and the solution is usually boiled. Some diazonium salts require even more vigorous treatment, for example, boiling with aq H₂SO₄ or with trifluoroacetic acid containing potassium trifluoroacetate.⁷⁸⁷ The reaction can be performed on solutions of any diazonium salts, but hydrogen sulfates are preferred to chlorides or nitrates, since in these cases there is competition from the nucleophiles Cl⁻ or NO₃⁻.

A better method, which is faster, avoids side reactions, takes place at room temperature, and gives higher yields consists of adding Cu₂O to a dilute solution of the diazonium salt dissolved in a solution containing a large excess of Cu(NO₃)₂.⁷⁸⁸ Aryl radicals are intermediates when this method is used. It has been shown that aryl radicals are at least partly involved when ordinary hydroxy-de-diazoniation is carried out in weakly alkaline aqueous solution.⁷⁸⁹Decomposition of arenediazonium tetrafluoroborates in F₃CSO₂OH gives aryl triflates directly, in high yields.⁷⁹⁰

OS I, 404; III, 130, 453, 564; V, 1130.

13-21 Replacement by Sulfur-Containing Groups

Mercapto-de-diazoniation, and so on

These reactions are convenient methods for incorporating a sulfur-containing group onto an aromatic ring. With Ar′S⁻, diazosulfides (Ar–N=N–S–Ar′) are intermediates,⁷⁹¹ which can in some cases be isolated.⁷⁹² Thiophenols can be made as shown above, but more often the diazonium ion is treated with EtO–CSS⁻ or S₂²⁻, which give the expected products, and these are easily convertible to thiophenols. Aryldiazonium salts are prepared by the reaction of an aniline derivative with an alkyl nitrite (RONO), and when formed in the presence of dimethyl disulfide (MeS–SMe), the product is the thioether (Ar–S–Me).⁷⁹³ Aryl triflates have been converted to the aryl thiol using NaST(P5) and a Pd catalyst, followed by treatment with tetrabutylammonium fluoride⁷⁹⁴ (see also, Reaction 14-22).

OS II, 580; III, 809 (but see OS V, 1050). Also see, OS II, 238.

13-22 Replacement by Iodine

Iodo-de-diazoniation

One of the best methods for the introduction of iodine into aromatic rings (see Reaction 13-7) is the reaction of diazonium salts with iodide ions.⁷⁹⁵ Analogous reactions with chloride, bromide, and fluoride ions give poorer results, and Reactions 14-20 and 13-23 are preferred for the preparation of aryl chlorides, bromides, and fluorides. However, when other diazonium reactions are carried out in the presence of these ions, halides are usually side products. Aniline has also been converted to fluorobenzene by treatment with t-BuONO and SiF₄ followed by heating.⁷⁹⁶ A related reaction between PhN=N–NR₂ and iodine gave iodobenzene.⁷⁹⁷

The actual attacking species is probably not only I⁻ if it is I⁻ at all. The iodide ion is oxidized (by the diazonium ion, nitrous acid, or some other oxidizing agent) to iodine, which in a solution containing iodide ions is converted to I₃⁻; this is the actual attacking species, at least partly. This was shown by isolation of ArN₂⁺ I₃⁻ salts, which, on standing, gave ArI.⁷⁹⁸ From this, it can be inferred that the reason the other halide ions give poor results is not that they are poor nucleophiles but rather they are poor reducing agents (compared with iodide). There is also evidence for a free radical mechanism.⁷⁹⁹

The hydroxyl group of a phenol can be replaced with iodine. The reaction of phenol with a boronic ester and a Pd catalyst, followed by reaction with NaI and chloramine-T (see Reaction 15-52) converts phenol to iodobenzene.⁸⁰⁰Arylboronic acids are converted to the aryl fluoride with Selectfluor, in the presence of a Pd catalyst.⁸⁰¹

OS II, 351, 355, 604; V, 1120.

13-23 The Schiemann Reaction

Fluoro-de-diazoniation (overall transformation)

Heating diazonium fluoroborates (the Schiemann or Balz–Schiemann reaction) is by far the best way to introduce fluorine into an aromatic ring.⁸⁰² In the most common procedure, the tetrafluoroborate salts are prepared by diazotizing as usual with nitrous acid and HCl and then adding a cold aqueous solution of NaBF₄, HBF₄, or NH₄BF₄. A precipitate forms, which is dried, and the salt is heated in the dry state. These salts are unusually stable for diazonium salts, and the reaction is usually successful (since diazonium salts are generally unstable, care should be exercised any time a diazonium salt is dried). In general, any aromatic amine that can be diazotized will form a BF₄⁻salt, usually with high yields. The diazonium fluoroborates can be formed directly from primary aromatic amines with tert-butyl nitrite and BF₃–etherate.⁸⁰³ The reaction has also been carried out on ArN₂⁺ PF₆⁻ ArN₂⁺ SbF₆⁻, and ArN₂⁺ AsF₆⁻ salts, in many cases with better yields.⁸⁰⁴ Aryl chlorides and bromides are commonly prepared by the Sandmeyer reaction (14-20). In an alternative procedure, aryl fluorides are prepared by treatment of aryltriazenes Ar–N=N–NR₂ with 70% HF in pyridine.⁸⁰⁵

The mechanism is of the S_N1 type. That aryl cations are intermediates was shown by the following experiments⁸⁰⁶: Aryl diazonium chlorides are known to arylate other aromatic rings by a free radical mechanism (see Reaction 13-27). In radical arylation it does not matter whether the other ring contains electron-withdrawing or electron-donating groups; in either case a mixture of isomers is obtained, since the attack is not by a charged species. If an aryl radical were an intermediate in the Schiemann reaction and the reaction were run in the presence of other rings, it should not matter what kinds of groups were on these other rings: Mixtures of biaryls should be obtained in all cases. But if an aryl cation is an intermediate in the Schiemann reaction, compounds containing meta-directing groups (i.e., meta-directing for electrophilic substitutions), should be meta arylated and those containing ortho–para directing groups should be ortho and para arylated, since an aryl cation should behave in this respect like any electrophile (see Chapter 11). Experiments have shown⁸⁰⁷ that such orientation is observed, demonstrating that the Schiemann reaction has a positively charged intermediate. The attacking species, in at least some instances, is not F⁻ but BF₄⁻.⁸⁰⁸

OS II, 188, 295, 299; V, 133.

13-24 Conversion of Amines to Azo Compounds

N-Arylimino-de-dihydro-bisubstitution

Aromatic nitroso compounds combine with primary arylamines in glacial acetic acid to give symmetrical or unsymmetrical azo compounds (the Mills reaction).⁸⁰⁹ A wide variety of substituents may be present in both aryl groups. Unsymmetrical azo compounds have also been prepared by the reaction between aromatic nitro compounds (ArNO₂) and N-acyl aromatic amines (Ar′NHAc).⁸¹⁰ The use of phase-transfer catalysis increased the yields.

13-25 Methylation, Vinylation, and Arylation of Diazonium Salts

Methyl-de-diazoniation, and so on

A methyl group can be introduced into an aromatic ring by treatment of diazonium salts with tetramethyltin and a Pd catalyst.⁸¹¹ The reaction has been performed with Me, Cl, Br, and NO₂ groups on the ring. A vinylic group can be introduced with CH₂=CHSnBu₃. When an aryl amine is treated with tert-butyl hyponitrite (t-BuONO) and allyl bromide, the nitrogen is displaced to give the allyl–aryl compound.⁸¹²

Aryl diazonium salts can be used coupled with alkenes in a Heck-like reaction (Reaction 13-10).⁸¹³ Other reactive aryl species also couple with aryldiazonium salts in the presence of a Pd catalyst.⁸¹⁴ A Suzuki-type coupling (Reaction 13-12) has also been reported using arylboronic acids, aryldiazonium salts, and a Pd catalyst.⁸¹⁵

Aryltrifluoroborates (Reaction 12-28) react with aryldiazonium salts in the presence of a Pd catalyst to give the corresponding biaryl.⁸¹⁶ See Reaction 13-12. Arylborate esters also react using a Pd catalyst, and the aryl diazonium unit reacts faster than an aryl halide.⁸¹⁷

13-26 Arylation of Activated Alkenes by Diazonium Salts: Meerwein Arylation

Arylation or Aryl-de-hydrogenation

Alkenes activated by an electron-withdrawing group (Z may be C=C, halogen, C=O, Ar, CN, etc.) can be arylated by treatment with a diazonium salt and a cupric chloride⁸¹⁸ catalyst. This is called the Meerwein arylation reaction.⁸¹⁹ Addition of ArCl to the double bond (to give Z(Cl)C–CHAr) is a side reaction (15-46). In an improved procedure, an arylamine is treated with an alkyl nitrite (generating ArN₂⁺in situ) and a copper(II) halide in the presence of the alkene.⁸²⁰

The mechanism is probably of the free radical type, with Ar√ (36) forming as in Reaction 14-20, and then halogen transfer to give 37 or elimination to give 38.⁸²¹

The radical 36 can react with cupric chloride by two pathways, one of which leads to addition and the other to substitution. Even when the addition pathway is taken, however, the substitution product may still be formed by subsequent elimination of HCl. Note that radical reactions are presented in Chapter 14, but the coupling of an alkene with an aromatic compound containing a leaving group prompted its placement here. Note the similarity to the Heck reaction in Reaction 13-10.

OS IV, 15.

13-27 Arylation of Aromatic Compounds by Diazonium Salts

Arylation or Aryl-de-hydrogenation

When the normally acidic solution of a diazonium salt is made alkaline, the aryl portion of the diazonium salt can couple with another aromatic ring. Known as the Gomberg or Gomberg–Bachmann reaction,⁸²² it has been performed on several types of aromatic rings and on quinones. Yields are not high (usually <40%) because of the many side reactions undergone by diazonium salts, although higher yields have been obtained under phase-transfer conditions.⁸²³ The conditions of the Meerwein reaction (13-26), treatment of the solution with a copper-ion catalyst, have also been used, as has the addition of sodium nitrite in DMSO (to benzenediazonium tetrafluoroborate).⁸²⁴When the Gomberg–Bachmann reaction is performed intramolecularly as in the formation of 39, either by the alkaline solution or by the copper-ion procedure, it is called the Pschorr reaction⁸²⁵ and yields are usually somewhat higher. Still higher yields have been obtained by carrying out the Pschorr reaction electrochemically.⁸²⁶ The Pschorr reaction has been carried out for Z = CH=CH, CH₂CH₂, NH, C=O, CH₂, and quite a few others. A rapid and convenient way to diazotize the amine substrate uses isopropyl nitrite in the presence of sodium iodide, in which case the ring-closed product is formed in one step.⁸²⁷ Palladium-catalyzed arylation of arenediazonium salts are known.⁸²⁸

Other compounds with nitrogen–nitrogen bonds have been used instead of diazonium salts. Among these are N-nitroso amides [ArN(NO)COR], triazenes,⁸²⁹ and azo compounds. Still another method involves treatment of an aromatic primary amine directly with an alkyl nitrite in an aromatic substrate as solvent.⁸³⁰

In each case, the mechanism involves generation of an aryl radical from a covalent azo compound. In acid solution, diazonium salts are ionic and their reactions are polar. When they cleave, the product is an aryl cation (see Sec. 13.A.i). However, in neutral or basic solution, diazonium ions are converted to covalent compounds, and these cleave to give free radicals (Ar√ and Z√). Note that radical reactions are presented in Chapter 14, but the coupling of an aromatic ring with an aromatic compound containing a leaving group prompted its placement here. Note the similarity to the Suzuki Reaction in 13-12.

Under Gomberg–Bachmann conditions, the species that cleaves is the anhydride (40).⁸³¹

The aryl radical thus formed attacks the substrate to give the aryl cation⁸³² intermediate 42 (see Sec. 14.A.iii), from which the radical 41 abstracts hydrogen to give the product (43). N-Nitroso amides probably rearrange to N-acyloxy compounds (44), which cleave to give aryl radicals.⁸³³ There is evidence that the reaction with alkyl nitrites also involves attack by aryl radicals.⁸³⁴

The Pschorr reaction can take place by two different mechanisms, depending on conditions: (1) attack by an aryl radical (as in the Gomberg–Bachmann reaction) or (2) attack by an aryl cation (similar to the S_N1 mechanism discussed in Sec. 13.A.ii).⁸³⁵ Under certain conditions the ordinary Gomberg–Bachmann reaction can also involve attack by aryl cations.⁸³⁶

OS I, 113; IV, 718.

13-28 Aryl Dimerization with Diazonium Salts

De-diazonio-coupling; Arylazo-de-diazonio-substitution

When diazonium salts are treated with cuprous ion (or with Cu and acid, in which case it is called the Gatterman method), two products are possible. If the ring contains electron-withdrawing groups, the main product is the biaryl, but the presence of electron-donating groups leads mainly to the azo compound. This reaction is different from Reaction 13-27 (and from 19-14) in that both aryl groups in the product originate from ArN₂⁺, that is, hydrogen is not a leaving group in this reaction. The mechanism probably involves free radicals.⁸³⁷

OS I, 222; IV, 872. Also see, OS IV, 273.

13-29 Replacement of Nitro

Alkyl-de-nitration, Hydroxy and alkoxy-de-nitration, Halo-de-nitration

In some cases, the nitrogen group of an aromatic nitro compound can be replaced with an alkyl group. The reaction of 1,4-dinitrobenzene with potassium tert-butoxide in the presence of BEt₃, for example, gave 4-ethylnitrobenzene.⁸³⁸

Other nucleophiles can replace a nitrogen-containing group. The reaction of hydroxide with Ar–Y, where Y = nitro,⁸³⁹ azide, NR₃⁺, and so on gives the corresponding phenol. This latter reaction works with alkoxide nucleophiles to give the corresponding aryl ether. The nitro can be replaced with chloro by use of NH₄Cl, PCl₅, SOCl₂, HCl, Cl₂, or CCl₄. Some of these reagents operate only at high temperatures and the mechanism is not always nucleophilic substitution. Activated aromatic nitro compounds can be converted to fluorides with fluoride ion.⁸⁴⁰

The reaction of vinyl nitro compounds (C=C–NO₂) and aryl iodide to give the styrene compound (C=C–Ar) was reported using BEt₃ and exposure to air.⁸⁴¹

13.C.iv. Rearrangements

13-30 The von Richter Rearrangement

Hydro-de-nitro-cine-substitution

When aromatic nitro compounds are treated with cyanide ion, the nitro group is displaced and a carboxyl group enters with cine substitution (Sec. 13.A.iii), always ortho to the displaced group, never meta or para. The scope of this reaction, called the von Richter rearrangement, is variable.⁸⁴² As with other nucleophilic aromatic substitutions, the reaction gives best results when electron-withdrawing groups are in ortho and para positions, but yields are low, usually <20% and never >50%.

At one time, it was believed that a nitrile (ArCN) was an intermediate, since cyanide is the reagent and nitriles are hydrolyzable to carboxylic acids under the reaction conditions (16-4). However, a remarkable series of results proved this belief to be in error. Bunnett and Rauhut⁸⁴³ demonstrated that α-naphthyl cyanide is not hydrolyzable to α-naphthoic acid under conditions at which β-nitronaphthalene undergoes the von Richter rearrangement to give α-naphthoic acid. This proved that the nitrile could not be an intermediate. It was subsequently demonstrated that N₂ is a major product of the reaction.⁸⁴⁴ It had previously been assumed that all the nitrogen in the reaction was converted to ammonia, which would be compatible with a nitrile intermediate, since ammonia is a hydrolysis product of nitriles. At the same time it was shown that NO₂⁺ is not a major product. The discovery of nitrogen indicated that a nitrogen–nitrogen bond must be formed during the course of the reaction. Rosenblum proposed a mechanism in accord with all the facts⁸⁴³:

Note that 46 is a stable compound: Hence, it should be possible to prepare it independently and to subject it to the conditions of the von Richter rearrangement. This was done and the correct products are obtained.⁸⁴⁵ Further evidence is that when 45 (Z = Cl or Br) was treated with cyanide in , half the oxygen in the product was labeled, showing that one of the oxygen atoms of the carboxyl group came from the nitro group and one from the solvent, as required by this mechanism.⁸⁴⁶

13-31 The Sommelet–Hauser Rearrangement

Benzylic quaternary ammonium salts, when treated with alkali metal amides, undergo a rearrangement called the Sommelet–Hauser rearrangement.⁸⁴⁷ Since the product is a benzylic tertiary amine, it can be further alkylated and the product again subjected to the rearrangement. This process can be continued around the ring until an ortho position is blocked.⁸⁴⁸

The rearrangement occurs with high yields and can be performed with various groups present in the ring.⁸⁴⁹ The reaction is most often carried out with three methyl groups on the nitrogen, but other groups can also be used, though if a β-hydrogen is present, Hofmann elimination (Reaction 17-7) often competes. The Stevens rearrangement (Reaction 18-21) is also a competing process.⁸⁵⁰ When both rearrangements are possible, the Stevens rearrangement is favored at high temperatures and the Sommelet–Hauser at low temperatures.⁸⁵¹ The mechanism is:

The benzylic hydrogen is most acidic and is the one that first loses a proton to give the ylid (47). However, 48, which is present in a smaller amount, is the species that undergoes the rearrangement, shifting the equilibrium in its favor. This mechanism is an example of a [2,3]-sigmatropic rearrangement (see Reaction 18-35). Another mechanism that might be proposed is one in which a methyl group actually breaks away (in some form) from the nitrogen and then attaches itself to the ring. That this is not so was shown by a product study.⁸⁵² If the second mechanism were true, 49 should give 50, but the first mechanism predicts the formation of 51, which is what was actually obtained.⁸⁵³

The mechanism as shown can lead only to an ortho product. However, a small amount of para product has been obtained in some cases.⁸⁵⁴ A mechanism⁸⁵⁵ in which there is a dissociation of the ArC–N bond (similar to the ion-pair mechanism of the Stevens rearrangement, Reaction 18-21) has been invoked to explain the para products that are observed.

Sulfur ylids containing a benzylic group (analogous to 48) undergo an analogous rearrangement.⁸⁵⁶

OS IV, 585.

13-32 Rearrangement of Aryl Hydroxylamines

1/C-Hydro-5/N-hydroxy-interchange

Aryl hydroxylamines treated with acids rearrange to aminophenols.⁸⁵⁷ Although this reaction (known as the Bamberger rearrangement) is similar in appearance to Reactions 11-28–11-32, the attack on the ring is not electrophilic but nucleophilic. The rearrangement is intermolecular, with the following mechanism:

Among the evidence⁸⁵⁸ for this mechanism are the facts that other products are obtained when the reaction is run in the presence of competing nucleophiles (e.g., p-ethoxyaniline) when ethanol is present, and that when the para position is blocked, compounds similar to 53 are isolated. In the case of 2,6-dimethylphenylhydroxylamine, the intermediate nitrenium ion (52) was trapped, and its lifetime in solution was measured.⁸⁵⁹ The reaction of 52 with water was found to be diffusion controlled.⁸⁶⁰

There is a base-mediated rearrangement of aromatic hydroxamic acids to anilines.⁸⁶¹

OS IV, 148.

13-33 The Smiles Rearrangement

The Smiles rearrangement actually comprises a group of rearrangements that follow the pattern given above.⁸⁶² A specific example is the reaction of 54 with hydroxide to give 55.

Smiles rearrangements are simply intramolecular nucleophilic substitutions. In the example given, SO₂Ar is the leaving group and ArO⁻ is the nucleophile. The nitro group serves to activate its ortho position. Halogens also serve as activating groups.⁸⁶³ The ring at which the substitution takes place is nearly always activated, usually by ortho or para nitro groups. Here X is usually S, SO, SO₂,⁸⁶⁴ O, or CO₂, and Y is usually the conjugate base of OH, NH₂, NHR, or SH. The reaction has even been carried out with Y = CH₂⁻ (phenyllithium was the base here).⁸⁶⁵

The reaction rate is greatly enhanced by substitution in the 6 position of the attacking ring, for steric reasons. For example, a methyl, chloro, or bromo group in the 6 position of 54 caused the rate to be ~10⁵ times faster than when the same groups were in the 4 position,⁸⁶⁶ although electrical effects should be similar at these positions. The enhanced rate comes about because the most favorable conformation of the molecule can adapt to suit the bulk of the 6-substituent is also the conformation required for the rearrangement. Thus, less entropy of activation is required.

Although the Smiles rearrangement is usually carried out on compounds containing two rings, this need not be the case, as in the formation of 56.⁸⁶⁷

In this case the, sulfenic acid (56) is unstable⁸⁶⁸ and the actual products isolated were the corresponding sulfinic acid (RSO₂H) and disulfide (R₂S₂).

In the Smiles rearrangement, the nucleophile Y is most often the conjugate base of SH, SO₂NHR, SO₂NH₂, NH₂, NHR, OH, and OR. There are few examples where Y is a carbanion, and the most common example is probably the Truce–Smiles rearrangement, where L–YH is an o-tolyl group.⁸⁶⁹ The prototypical Truce–Smiles rearrangement requires use of a strong base to form the benzylic carbanion that undergoes the rearrangement. When sulfone (57) was treated with butyllithium, for example, deprotonation led to the benzylic lithium compound (58). Truce–Smiles rearrangement led to 59, and hydrolysis gave the sulfinic acid (60).⁸⁷⁰ Truce–Smiles rearrangements with stabilized benzylic carbanions are known,⁸⁷⁰ and rearrangements of carbanions in general fall under this category.⁸⁷¹ Relatively few examples have been reported, however.⁸⁷² Truce–Smiles rearrangements of sulfones that proceed through a six-membered transition state have been reported.⁸⁷³ In another example, displacement of an activated aryl fluoride with o-hydroxyacetophenone gave a product that was C-arylated adjacent to the ketone.⁸⁷⁴

Notes

1. See Zoltewicz, J.A. Top. Curr. Chem. 1975, 59, 33.

2. See Fairlamb, I.J.S. Tetrahedron 2005, 61, 9661.

3. Acevedo, O.; Jorgensen, W.L. Org. Lett. 2004, 6, 2881.

4. See Miller, J. Aromatic Nucleophilic Substitution, Elsevier, NY, 1968. For reviews, see Bernasconi, C.F. Chimia 1980, 34, 1; Acc. Chem. Res. 1978, 11, 147; Bunnett, J.F. J. Chem. Educ. 1974, 51, 312; Ross, S.D. in Bamford, C.H.; Tipper, C.F.H. Comprehensive Chemical Kinetics, Vol. 13, Elsevier, NY, 1972, pp. 407–431; Buck, P. Angew. Chem, Int. Ed. 1969, 8, 120; Buncel, E.; Norris, A.R.; Russell, K.E. Q. Rev. Chem. Soc. 1968, 22, 123; Bunnett, J.F. Tetrahedron 1993, 49, 4477; Zoltewicz, J.A. Top. Curr. Chem. 1975, 59, 33.

5. See Barrett, I.C.; Kerr, M.A. Tetrahedron Lett. 1999, 40, 2439.

6. Also see Wu, Z.; Glaser, R. J. Am. Chem. Soc. 2004, 126, 10632; Terrier, F.; Mokhtari, M.; Goumont, T.; Hallé, J.-C.; Buncel, E. Org. Biomol. Chem. 2003, 1, 1757.

7. Meisenheimer, J. Liebigs Ann. Chem. 1902, 323, 205; Jackson, C.L.; see Jackson, C.L.; Gazzolo, F.H. Am. Chem. J. 1900, 23, 376; Jackson, C.L.; Earle, R.B. Am. Chem. J., 1903, 29, 89.

8. For heteroatom nucleophiles see Gallardo, I.; Guirado, G.; Marquet, J. J. Org. Chem. 2002, 67, 2548.

9. See Buncel, E.; Crampton, M.R.; Strauss, M.J.; Terrier, F. Electron Deficient Aromatic- and Heteroaromatic-Base Interactions, Elsevier, NY, 1984; Illuminati, G.; Stegel, F. Adv. Heterocycl. Chem. 1983, 34, 305; Terrier, F. Chem. Rev. 1982, 82, 77; Strauss, M.J. Acc. Chem. Res. 1974, 7, 181; Hall, T.N.; Poranski, Jr., C.F. in Feuer, H. The Chemistry of the Nitro and Nitroso Groups, pt. 2, Wiley, NY, 1970, pp. 329–384; Foster, R.; Fyfe, C.A. Rev. Pure Appl. Chem. 1966, 16, 61.

10. Crampton, M.R.; Gold, V. J. Chem. Soc. B 1966, 893. See Buncel, E.; Crampton, M.R.; Strauss, M.J.; Terrier, F. Electron Deficient Aromatic- and Heteroaromatic-Base Interactions, Elsevier, NY, 1984, pp. 15–133.

11. Destro, R.; Gramaccioli, C.M.; Simonetta, M. Acta Crystallogr. 1968, 24, 1369; Ueda, H.; Sakabe, M.; Tanaka, J.; Furusaki, A. Bull. Chem. Soc. Jpn. 1968, 41, 2866; Messmer, G.G.; Palenik, G.J. Chem. Commun. 1969, 470.

12. Grossi, L. Tetrahedron Lett. 1992, 33, 5645.

13. Bunnett, J.F.; Garbisch, Jr., E.W.; Pruitt, K.M. J. Am. Chem. Soc. 1957, 79, 385. See Gandler, J.R.; Setiarahardjo, I.U.; Tufon, C.; Chen, C. J. Org. Chem. 1992, 57, 4169.

14. See Fernndez, I.; Frenking, G.; Uggerud, E. J. Org. Chem. 2010, 75, 2971.

15. Chiacchiera, S.M.; Singh, J.O.; Anunziata, J.D.; Silber, J.J. J. Chem. Soc. Perkin Trans. 2 1987, 987.

16. Bernasconi, C.F.; de Rossi, R.H.; Schmid, P. J. Am. Chem. Soc. 1977, 99, 4090.

17. Bunnett, J.F.; Sekiguchi, S.; Smith, L.A. J. Am. Chem. Soc. 1981, 103, 4865.

18. See Nudelman, N.S. J. Phys. Org. Chem. 1989, 2, 1. See also, Nudelman, N.S.; Montserrat, J.M. J. Chem. Soc. Perkin Trans. 2 1990, 1073.

19. Jain, A.K.; Gupta, V.K.; Kumar, A. J. Chem. Soc. Perkin Trans. 2 1990, 11.

20. Ayrey, G.; Wylie, W.A. J. Chem. Soc. B 1970, 738.

21. Bacaloglu, R.; Blaskó, A.; Bunton, C.A.; Dorwin, E.; Ortega, F.; Zucco, C. J. Am. Chem. Soc. 1991, 113, 238; Crampton, M.R.; Davis, A.B.; Greenhalgh, C.; Stevens, J.A. J. Chem. Soc. Perkin Trans. 2 1989, 675.

22. See Muscio, Jr., O.J.; Rutherford, D.R. J. Org. Chem. 1987, 52, 5194.

23. Quiñonero, D.; Garau, C.; Rotger, C.; Frontera, A.; Ballester, P.; Costa, A.; Deyà. P.M. Angew. Chem. Int. Ed. 2002, 41, 3389.

24. Himeshima, Y.; Kobayashi, H.; Sonoda, T. J. Am. Chem. Soc. 1985, 107, 5286.

25. See Glaser, R.; Horan, C.J.; Nelson, E.D.; Hall, M.K. J. Org. Chem. 1992, 57, 215.

26. Aryl iodonium salts Ar₂I⁺ also undergo substitutions by this mechanism (and by a free radical mechanism).

27. Also see Lorand, J.P. Tetrahedron Lett. 1989, 30, 7337.

28. See Ambroz, H.B.; Kemp, T.J. Chem. Soc. Rev. 1979, 8, 353.

29. Stang, P.J.; Rappoport, Z.; Hanack, M.; Subramanian, L.R. Vinyl Cations, Academic Press, NY, 1979. See Hanack, M. Pure Appl. Chem. 1984, 56, 1819; Rappoport, Z. Reactiv. Intermed. (Plenum) 1983, 3, 427; Ambroz, H.B.; Kemp, T.J. Chem. Soc. Rev. 1979, 8, 353. See also, Charton, M. Mol. Struct. Energ. 1987, 4, 271; Glaser, R.; Horan, C.J.; Lewis, M.; Zollinger, H. J. Org. Chem. 1999, 64, 902.

30. See Zollinger, H. Angew. Chem, Int. Ed. 1978, 17, 141; Swain, C.G.; Sheats, J.E.; Harbison, K.G. J. Am. Chem. Soc. 1975, 97, 783, 796; Burri, P.; Wahl, Jr., G.H.; Zollinger, H. Helv. Chim. Acta 1974, 57, 2099; Richey, Jr., H.G.; Richey, J.M. in Olah, G.A.; Schleyer, P.v.R. Carbonium Ions, Vol. 2, Wiley, NY, 1970, pp. 922–931; Miller, J. Aromatic Nucleophilic Substitution, Elsevier, NY, 1968, pp. 29–40.

31. Lewis, E.S.; Miller, E.B. J. Am. Chem. Soc. 1953, 75, 429.

32. Swain, C.G.; Sheats, J.E.; Gorenstein, D.G.; Harbison, K.G. J. Am. Chem. Soc. 1975, 97, 791.

33. See Apeloig, Y.; Arad, D. J. Am. Chem. Soc. 1985, 107, 5285.

34. See Williams, D.L.H.; Buncel, E. Isot. Org. Chem. Vol. 5, Elsevier, Amsterdam, The Netherlands, 1980, pp. 147, 212; Zollinger, H. Pure Appl. Chem. 1983, 55, 401.

35. Lewis, E.S.; Kotcher, P.G. Tetrahedron 1969, 25, 4873; Lewis, E.S.; Holliday, R.E. J. Am. Chem. Soc. 1969, 91, 426; Tröndlin, F.; Medina, R.; Rüchardt, C. Chem. Ber. 1979, 112, 1835.

36. Bergstrom, R.G.; Landell, R.G.M.; Wahl, Jr., G.H.; Zollinger, H. J. Am. Chem. Soc. 1976, 98, 3301.

37. Szele, I.; Zollinger, H. Helv. Chim. Acta 1981, 64, 2728.

38. Ravenscroft, M.D.; Skrabal, P.; Weiss, B.; Zollinger, H. Helv. Chim. Acta 1988, 71, 515.

39. See Hoffmann, R.W. Dehydrobenzene and Cycloalkynes, Academic Press, NY, 1967; Gilchrist, T.L. in Patai, S.; Rappoport, Z. The Chemistry of Functional Groups, Supplement C pt. 1, Wiley, NY, 1983, pp. 383–419; Bryce, M.R.; Vernon, J.M. Adv. Heterocycl. Chem. 1981, 28, 183; Levin, R.H. React. Intermed. (Wiley) 1985, 3, 1; Fields, E.K. in McManus, S.P. Organic Reactive Intermediates, Academic Press, NY, 1973, pp. 449–508.

40. Roberts, J.D.; Semenow, D.A.; Simmons, H.E.; Carlsmith, L.A. J. Am. Chem. Soc. 1965, 78, 601.

41. See Hess, Jr., B.A. Eur. J. Org. Chem. 2001, 2185.

42. Wentrup, C. Austr. J. Chem. 2010, 63, 979.

43. See Kitamura, T.; Meng, Z.; Fujiwara, Y. Tetrahedron Lett. 2000, 41, 6611; Kawabata, H.; Nishino, T.; Nishiyama, Y.; Sonoda, N. Tetrahedron Lett. 2002, 43, 4911. Microwave spectroscopy can be used to detect benzynes: see Godfrey, P.D. Austr. J. Chem. 2010, 63, 1061.

44. See Suwinski, J.; Swierczek, K. Tetrahedron 2001, 57, 1639.

45. See Gilman, H.; Avakian, S. J. Am. Chem. Soc. 1945, 67, 349. For a table of many such examples, see Bunnett, J.F.; Zahler, R.E. Chem. Rev. 1951, 49, 273, p. 385.

46. Riggs, J.C.; Ramirez, A.; Cremeens, M.E.; Bashore, C.G.; Candler, J.; Wirtz, M.C.; Coe, J.C.; Collum, D.B. J. Am. Chem. Soc. 2008,130, 3406.

47. Bunnett, J.F.; Kearley, Jr., F.J. J. Org. Chem. 1971, 36, 184.

48. See Kalendra, D.M.; Sickles, B.R. J. Org. Chem. 2003, 68, 1594.

49. See Pellissier, H.; Santelli, M. Tetrahedron 2003, 59, 701.

50. See Gaviña, F.; Luis, S.V.; Costero, A.M.; Gil, P. Tetrahedron 1986, 42, 155.

51. Chapman, O.L.; Mattes, K.; McIntosh, C.L.; Pacansky, J.; Calder, G.V.; Orr, G. J. Am. Chem. Soc. 1973, 95, 6134. For the IR spectrum of pyridyne trapped in a matrix, see Nam, H.; Leroi, G.E. J. Am. Chem. Soc. 1988, 110,4096. See Brown, R.D.; Godfrey, P.D.; Rodler, M. J. Am. Chem. Soc. 1986, 108, 1296.

52. DeProft, F.; Schleyer, P.v.R.; van Lenthe, J.H.; Stahl, F.; Geerlings, P. Chem. Eur. J. 2002, 8, 3402.

53. Nash, J.J.; Nizzi, K.E.; Adeuya, A.; Yurkovich, M.J.; Cramer, C.J.; Kenttämaa, H.I. J. Am. Chem. Soc. 2005, 127, 5760.

54. For reviews of hetarynes, see van der Plas, H.C.; Roeterdink, F. in Patai, S.; Rappoport, Z. The Chemistry of Functional Groups, Supplement C, pt. 1, Wiley, NY, 1983, pp. 421–511; Reinecke, M.G. Tetrahedron 1982, 38, 427; den Hertog, H.J.; van der Plas, H.C. Adv. Heterocycl. Chem. 1971, 40, 121; Kauffmann, T.; Wirthwein, R. Angew. Chem, Int. Ed. 1971, 10, 20.

55. Hamura, T.; Ibusuki, Y.; Sato, K.; Matsumoto, T.; Osamura, Y.; Suzuki, K. Org. Lett. 2003, 5, 3551.

56. Kim, J.K.; Bunnett, J.F. J. Am. Chem. Soc. 1970, 92, 7463, 7464.

57. See Rossi, R.A.; de Rossi, R.H. Aromatic Substitution by the S_RN1 Mechanism, American Chemical Society, Washington, 1983; Savéant, J. Adv. Phys. Org. Chem. 1990, 26, 1; Norris, R.K. in Patai, S.; Rappoport, Z. The Chemistry of Functional Groups, Supplement D, pt. 1, Wiley, NY, 1983, pp. 681–701; Chanon, M.; Tobe, M.L. Angew. Chem, Int. Ed. 1982, 21, 1; Rossi, R.A. Acc. Chem. Res. 1982, 15, 164. Also see Rossi, R.A.; Pierini, A.B.; Palacios, S.M. Adv. Free Radical Chem. (Greenwich, Conn.) 1990, 1, 193; Costentin, C.; Hapiot, P.; Médebielle, M.; Savéant, J.-M. J. Am. Chem. Soc. 1999, 121, 4451.

58. The symbol T is used for electron transfer.

59. See Amatore, C.; Pinson, J.; Savéant, J.; Thiébault, A. J. Am. Chem. Soc. 1981, 103, 6930.

60. Bunnett, J.F. Acc. Chem. Res. 1978, 11, 413.

61. Savéant, J.-M. Tetrahedron 1994, 50, 10117.

62. See Cornelisse, J.; de Gunst, G.P.; Havinga, E. Adv. Phys. Org. Chem. 1975, 11, 225; Cornelisse, J. Pure Appl. Chem. 1975, 41, 433; Pietra, F. Q. Rev. Chem. Soc. 1969, 23, 504, p. 519.

63. See Savéant, J. Acc. Chem. Res. 1980, 13, 323. See also, Alam, N.; Amatore, C.; Combellas, C.; Thiébault, A.; Verpeaux, J.N. J. Org. Chem. 1990, 55, 6347.

64. Swartz, J.E.; Bunnett, J.F. J. Org. Chem. 1979, 44, 340, and references cited therein.

65. Galli, C.; Gentili, P.; Guarnieri, A. Gazz. Chim. Ital., 1995, 125, 409.

66. Borosky, G.L.; Pierini, A.B.; Rossi, R.A. J. Org. Chem. 1992, 57, 247.

67. Manzo, P.G.; Palacios, S.M.; Alonso, R.A. Tetrahedron Lett. 1994, 35, 677.

68. Galli, C.; Gentili, P. J. Chem. Soc. Perkin Trans. 2 1993, 1135.

69. Marquet, J.; Jiang, Z.; Gallardo, I.; Batlle, A.; Cayón, E. Tetrahedron Lett. 1993, 34, 2801. Also see, Keegstra, M.A. Tetrahedron 1992, 48, 2681.

70. Rossi, R.A.; Palacios, S.M. Tetrahedron 1993, 49, 4485.

71. Marquet, J.; Casado, F.; Cervera, M.; Espín, M.; Gallardo, I.; Mir, M.; Niat, M. Pure Appl. Chem. 1995, 67, 703.

72. With meta substituents, electron-withdrawing groups also increase the rate: See Nurgatin, V.V.; Sharnin, G.P.; Ginzburg, B.M. J. Org. Chem, USSR 1983, 19, 343.

73. See Miller, J. Aromatic Nucleophilic Substitution, Elsevier, NY, 1968, pp. 61–136.

74. For reviews of reactivity of nitrogen-containing heterocycles, see Illuminati, G. Adv. Heterocycl. Chem. 1964, 3, 285; Shepherd, R.G.; Fedrick, J.L. Adv. Heterocycl. Chem. 1965, 4, 145.

75. See Albini, A.; Pietra, S. Heterocyclic N-Oxides, CRC Press, Boca Raton, FL, 1991, pp. 142–180; Katritzky, A.R.; Lagowski, J.M. Chemistry of the Heterocyclic N-Oxides, Academic Press, NY, 1971, pp. 258–319, 550–553.

76. Bunnett, J.F.; Zahler, R.E. Chem. Rev. 1951, 49, 273, pp. 308.

77. Miller, J.; Parker, A.J. Aust. J. Chem. 1958, 11, 302.

78. Berliner, E.; Monack, L.C. J. Am. Chem. Soc. 1952, 74, 1574.

79. See de Boer, T.J.; Dirkx, I.P. in Feuer, H. The Chemistry of the Nitro and Nitroso Groups, pt. 1, Wiley, NY, 1970, pp. 487–612.

80. Fluorine significantly activates ortho and meta positions, and slightly deactivates para positions (see Table 13.1): See Chambers, R.D.; Seabury, N.J.; Williams, D.L.H.; Hughes, N. J. Chem. Soc. Perkin Trans. 1 1988, 255.

81. See Yakobson, G.G.; Vlasov, V.M. Synthesis 1976, 652; Kobrina, L.S. Fluorine Chem. Rev. 1974, 7, 1.

82. See Balas, L.; Jhurry, D.; Latxague, L.; Grelier, S.; Morel, Y.; Hamdani, M.; Ardoin, N.; Astruc, D. Bull. Soc. Chim. Fr. 1990, 401.

83. See Bartoli, G.; Todesco, P.E. Acc. Chem. Res. 1977, 10, 125; a list of σ⁻ values in Table 9.4.

84. From Roberts, J.D.; Vaughan, C.W.; Carlsmith, L.A.; Semenow, D.A. J. Am. Chem. Soc. 1956, 78, 611. See Hoffmann, R.W. Dehydrobenzene and Cycloalkynes, Academic Press, NY, 1973, pp. 134–150.

85. Wotiz, J.H.; Huba, F. J. Org. Chem. 1959, 24, 595. See also, Biehl, E.R.; Razzuk, A.; Jovanovic, M.V.; Khanapure, S.P. J. Org. Chem. 1986, 51, 5157.

86. See Miller, J. Aromatic Nucleophilic Substitution, Elsevier, NY, 1968, pp. 137–179.

87. See Furukawa, N.; Ogawa, S.; Kawai, T.; Oae, S. J. Chem. Soc. Perkin Trans. 1 1984, 1839.

88. See Beck, J.R. Tetrahedron 1978, 34, 2057. See also, Effenberger, F.; Koch, M.; Streicher, W. Chem. Ber. 1991, 24, 163.

89. Loudon, J.D.; Shulman, N. J. Chem. Soc. 1941, 772; Suhr, H. Chem. Ber. 1963, 97, 3268.

90. Kobrina, L.S.; Yakobson, G.G. J. Gen. Chem. USSR 1963, 33, 3238.

91. Reinheimer, J.D.; Taylor, R.C.; Rohrbaugh, P.E. J. Am. Chem. Soc. 1961, 83, 835; Ross, S.D. J. Am. Chem. Soc. 1959, 81, 2113; Litvinenko, L.M.; Shpan'ko, L.V.; Korostylev, A.P. Doklad. Chem. 1982, 266, 309.

92. See Miller, J. Aromatic Nucleophilic Substitution, Elsevier, NY, 1968, pp. 180–233.

93. From Bunnett, J.F.; Zahler, R.E. Chem. Rev. 1951, 49, 273, p. 340; Sauer, J.; Huisgen, R. Angew. Chem. 1960, 72, 294, p. 311; Bunnett, J.F. Annu. Rev. Phys. Chem. 1963, 14, 271.

94. See Amatore, C.; Combellas, C.; Robveille, S.; Savéant, J.; Thiébault, A. J. Am. Chem. Soc. 1986, 108, 4754, and references cited therein.

95. Seeliger, F.; Błaej, S.; Bernhardt, S.; Mkosza, M.; Mayr, H. Chemistry: European J. 2008, 14, 6108.

96. See Fyfe, C.A. in Patai, S. The Chemistry of the Hydroxyl Group, pt. 1, Wiley, NY, 1971, pp. 83–124.

97. This benzyne mechanism is also supported by labeling experiments: Bottini, A.T.; Roberts, J.D. J. Am. Chem. Soc. 1957, 79, 1458; Dalman, G.W.; Neumann, F.W. J. Am. Chem. Soc. 1968, 90, 1601.

98. Anderson, K.W.; Ikawa, T.; Tundel, R.E.; Buchwald, S.L. J. Am. Chem. Soc. 2006, 128, 10694. Also see Schulz, T.; Torborg, C.; Schäffner, B.; Huang, J.; Zapf, A.; Kadyrov, R.; Börner, A.; Beller, M. Angew. Chem. Int. Ed.2009, 48, 918; Sergeev, A.G.; Schulz, T.; Torborg, C.; Spannenberg, A.; Neumann, H.; Beller, M. Angew. Chem. Int. Ed. 2009, 48, 7595.

99. Hashemi, M.M.; Akhbari, M. Synth. Commun. 2004, 34, 2783.

100. Maurer, S.; Liu, W.; Zhang, X.; Jiang, Y.; Ma, D. Synlett 2010, 976. See also Jing, L.; Wei, J.; Zhou, L.; Huang, Z.; Li, Z.; Zhou, X. Chem. Commun. 2010, 4767.

101. Cantrell, Jr., W.R.; Bauta, W.E.; Engles, T. Tetrahedron Lett. 2006, 47, 4249.

102. Kormos, C.M.; Leadbeater, N.E. Tetrahedron 2006, 62, 4728.

103. See Seeboth, H. Angew. Chem, Int. Ed. 1967, 6, 307; Gilbert, E.E. Sulfonation and Related Reactions; Wiley, NY, 1965, pp. 166–169.

104. Hawthorne, M.F. J. Org. Chem. 1957, 22, 1001. For other procedures, see Lewis, N.J.; Gabhe, S.Y. Aust. J. Chem. 1978, 31, 2091; Hoffmann, R.W.; Ditrich, K. Synthesis 1983, 107.

105. Pickles, G.M.; Thorpe, F.G. J. Organomet. Chem. 1974, 76, C23.

106. Simon, J.; Salzbrunn, S.; Prakash, G.K.S.; Petasis, N.A.; Olah, G.A. J. Org. Chem. 2001, 66, 633. Also see Xu, J.; Wang, X.; Shao, C.; Su, D.; Cheng, G.; Hu, Y. Org. Lett. 2010, 12, 1964.

107. Maleczka, Jr., R.E.; Shi, F.; Holmes, D.; Smith III, M.R. J. Am. Chem. Soc. 2003, 125, 7792.

108. Parker, K.A.; Koziski, K.A. J. Org. Chem. 1987, 52, 674. See Taddei, M.; Ricci, A. Synthesis 1986, 633; Einhorn, J.; Luche, J.; Demerseman, P. J. Chem. Soc. Chem. Commun. 1988, 1350.

109. Taylor, E.C.; Altland, H.W.; Danforth, R.H.; McGillivray, G.; McKillop, A. J. Am. Chem. Soc. 1970, 92, 3520.

110. Taylor, E.C.; Altland, H.W.; McKillop, A. J. Org. Chem. 1975, 40, 2351.

111. Buzbee, L.R. J. Org. Chem. 1966, 31, 3289; Oae, S.; Furukawa, N.; Kise, M.; Kawanishi, M. Bull. Chem. Soc. Jpn. 1966, 39, 1212.

112. See Gujadhur, R.; Venkataraman, D. Synth. Commun. 2001, 31, 2865.

113. Testaferri, L.; Tiecco, M.; Tingoli, M.; Chianelli, D.; Montanucci, M. Tetrahedron 1983, 39, 193.

114. Rebeiro, G.L.; Khadilkar, B.M. Synth. Commun. 2003, 33, 1405.

115. Chauhan, S.M.S.; Jain, N.; Kumar, A.; Srinivas, K.A. Synth. Commun. 2003, 33, 3607.

116. Kizner, T.A.; Shteingarts, V.D. J. Org. Chem, USSR 1984, 20, 991.

117. Artamanova, N.N.; Seregina, V.F.; Shner, V.F.; Salov, B.V.; Kokhlova, V.M.; Zhdamarova, V.N. J. Org. Chem, USSR 1989, 25, 554.

118. See Agejas, J.; Bueno, A.B. Tetrahedron Lett. 2006, 47, 5661.

119. Chaouchi, M.; Loupy, A.; Marque, S.; Petit, A. Eur. J. Org. Chem. 2002, 1278.

120. Chen, C.-y.; Dormer, P.G. J. Org. Chem. 2005, 70, 6964.

121. Luo, Y.; Wu, J.X.; Ren, R.X. Synlett 2003, 1734.

122. Oae, S.; Kiritani, R. Bull. Chem. Soc. Jpn. 1964, 37, 770; 1966, 39, 611.

123. See Hosseinzadeh, R.; Tajbakhsh, M.; Mohadjerani, M.; Alikarami, M. Synlett 2005, 1101.

124. Naidu, A.B.; Raghunath, O.R.; Prasad, D.J.C.; Sekar, G. Tetrahedron Lett. 2008, 49, 1057; Naidu, A.B.; Sekar, G. Tetrahedron Lett. 2008, 49, 3147. See Moroz, A.A.; Shvartsberg, M.S. Russ. Chem. Rev. 1974, 43, 679; Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428.

125. Weingarten, H. J. Org. Chem. 1964, 29, 977, 3624. See Cai, Q.; Zou, B.; Ma, D. Angew. Chem. Int. Ed. 2006, 45, 1276.

126. Chang, J.W.W.; Chee, S.; Mak, S.; Buranaprasertsuk, P.; Chavasiri, W.; Chan, P.W.H. Tetrahedron Lett. 2008, 49, 2018.

127. Kawaki, T.; Hashimoto, H. Bull. Chem. Soc. Jpn. 1972, 45, 1499.

128. Whitesides, G.M.; Sadowski, J.S.; Lilburn, J. J. Am. Chem. Soc. 1974, 96, 2829.

129. Lipshutz, B.H.; Unger, J.B.; Taft, B.R. Org. Lett. 2007, 9, 1089; Maiti, D.; Buchwald, S.L. J. Org. Chem. 2010, 75, 1791; Maiti, D.; Buchwald, S.L. J. Am. Chem. Soc. 2009, 131, 17423; Tlili, A.; Monnier, F.; Taillefer, M. Chemistry: Eur. J. 2010, 16, 12299; Zhao, D.; Wu, N.; Zhang, S.; Xi, P.; Su, X.; Lan, J.; You, J. Angew. Chem. Int. Ed. 2009, 48, 8729.

130. Parrish, C.A.; Buchwald, S.L. J. Org. Chem. 2001, 66, 2498; Torraca, K.E.; Huang, X.; Parrish, C.A.; Buchwald, S.L. J. Am. Chem. Soc. 2001, 123, 10770.

131. Burgos, C.H.; Barder, T.E.; Huang, X.; Buchwald, S.L. Angew. Chem. Int. Ed. 2006, 45, 4321.

132. Kuwabe, S.-i.; Torraca, K.E.; Buchwald, S.L. J. Am. Chem. Soc. 2001, 123, 12202.

133. Manolikakes, G.; Dastbaravardeh, N.; Knochel, P. Synlett 2007, 2077.

134. Xu, L.-W.; Xia, C.-G.; Li, J.-W.; Hu, X.-X. Synlett 2003, 2071.

135. Bistri, O.; Correa, A.; Bolm, C. Angew. Chem. Int. Ed. 2008, 47, 586.

136. See Desai, L.V.; Stowers, K.J.; Sanford, M.S. J. Am. Chem. Soc. 2008, 130, 13285.

137. Jönsson, L.; Wistrand, L. J. Org. Chem. 1984, 49, 3340.

138. First proposed by Alder, R.W. J. Chem. Soc. Chem. Commun. 1980, 1184.

139. See Peach, M.E. in Patai, S. The Chemistry of the Thiol Group, pt. 2, Wiley, NY, 1974, pp. 735–744.

140. Bieniarz, C.; Cornwell, M.J. Tetrahedron Lett. 1993, 34, 939.

141. See Palomo, C.; Oiarbide, M.; López, R.; Gómez-Bengoa, E. Tetrahedron Lett. 2000, 41, 1283.

142. Testaferri, L.; Tiecco, M.; Tingoli, M.; Chianelli, D.; Montanucci, M. Synthesis 1983, 751. See Tiecco, M.; Testaferri, L.; Tingoli, M.; Chianelli, D.; Montanucci, M. J. Org. Chem. 1983, 48, 4289.

143. Bradshaw, J.S.; South, J.A.; Hales, R.H. J. Org. Chem. 1972, 37, 2381.

144. Caruso, A.J.; Colley, A.M.; Bryant, G.L. J. Org. Chem. 1991, 56, 862; Shaw, J.E. J. Org. Chem. 1991, 56, 3728.

145. Cogolli, P.; Maiolo, F.; Testaferri, L.; Tingoli, M.; Tiecco, M. J. Org. Chem. 1979, 44, 2642. See also, Testaferri, L.; Tingoli, M.; Tiecco, M. Tetrahedron Lett. 1980, 21, 3099; Suzuki, H.; Abe, H.; Osuka, A. Chem. Lett. 1980, 1363.

146. Lee, S.B.; Hong, J.-I. Tetrahedron Lett. 1995, 36, 8439.

147. Fernández-Rodríguez, M.A.; Shen, Q.; Hartwig, J.F. J. Am. Chem. Soc. 2006, 128, 2180.

148. Sperotto, E.; van Klink, G.P.M.; de Vries, J.G.; van Koten, G. J. Org. Chem. 2008, 73, 5625; Zhu, D.; Xu, L.; Wu, F.; Wan, B. Tetrahedron Lett. 2006, 47, 5781; Feng, Y.-S.; Li, Y.-Y.; Tang, L.; Wu, W.; Xu, H.-J. Tetrahedron Lett. 2010, 51, 2489; Feng, Y.; Wang, H.; Sun, F.; Li,Y.; Fu, X.; Jin, K. Tetrahedron 2009, 65, 9737.

149. Rout, L.; Saha, P.; Jammi, S.; Punniyamurthy, T. Eur. J. Org. Chem. 2008, 640.

150. Gómez-Benítez, V.; Baldovino-Pantaleón, O.; Herrera-Álvarez, C.; Toscano, R.A.; Morales-Morales, D. Tetrahedron Lett. 2006, 47, 5059; Yoon, H.-J.; Choi, J.-W.; Kang, H.; Kang, T.; Lee, S.-M.; Jun, B.-H.; Lee, Y.-S. Synlett 2010, 2518.

151. Reddy, V.P.; Swapna, K.; Kumar, A.V.; Rama Rao, K. J. Org. Chem. 2009, 74, 3189.

152. Buranaprasertsuk, P.; Chang, J.W.W.; Chavasiri, W.; Chan, P.W.H. Tetrahedron Lett. 2008, 49, 2023.

153. Tankguchi, N. J. Org. Chem. 204, 69, 6904.

154. Bunnett, J.F.; Creary, X. J. Org. Chem. 1974, 39, 3173, 3611.

155. Meyer, G.; Troupel, M. J. Organomet. Chem. 1988, 354, 249.

156. Wang, L.; Chen, Z.-C. Synth. Commun. 2001, 31, 1227.

157. Herradua, P.S.; Pendola, K.A.; Guy, R.K. Org. Lett. 2000, 2, 2019.

158. Savarin, C.; Srogl, J.; Liebeskind, L.S. Org. Lett. 2002, 4, 4309.

159. Suzuki, H.; Abe, H. Tetrahedron Lett. 1995, 36, 6239.

160. Maitro, G.; Vogel, S.; Prestat, G.; Madec, D.; Poli, G. Org. Lett. 2006, 8, 5951.

161. Baskin, J.M.; Wang, Z. Org. Lett. 2002, 4, 4423.

162. Kar, A.; Sayyed, I.A.; Lo, W.F.; Kaiser, H.M.; Beller, M.; Tse, M.K. Org. Lett. 2007, 9, 3405.

163. Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Parisi, L.M.; Bernini, R. J. Org. Chem. 2004, 69, 5608.

164. Taniguchi, N.; Onami, T. J. Org. Chem.2004, 69, 915; Taniguchi, N.; Onami, T. Synlett 2003, 829.

165. Beletskaya, I.P.; Sigeev, A.S.; Peregudov, A.S.; Petrovlskii, P.V. Tetrahedron Lett. 2003, 44, 7039.

166. Li, Y.; Wang, H.; Li, X.; Chen, T.; Zhao, D. Tetrahedron 2010, 66, 8583.

167. Clark, J.H.; Jones, C.W.; Duke, C.V.A.; Miller, J.M. J. Chem. Soc. Chem. Commun. 1989, 81. See also, Yadav, J.S.; Reddy, B.V.S.; Shubashree, S.; Sadashiv, K. Tetrahedron Lett. 2004, 45, 2951.

168. Xu, Z.-B.; Lu, Y.; Guo, Z.-R. Synlett 2003, 564. See Li, W.; Yun, L.; Wang, H. Synth. Commun. 2002, 32, 2657.

169. See Yang, T.; Cho, B.P. Tetrahedron Lett. 2003, 44, 7549.

170. Kazankov, M.V.; Ginodman, L.G. J. Org. Chem, USSR 1975, 11, 451.

171. Sekiguchi, S.; Horie, T.; Suzuki, T. J. Chem. Soc. Chem. Commun. 1988, 698.

172. Xu, G.; Wang, Y.-G. Org. Lett. 2004, 6, 985.

173. Hertas, I.; Gallardo, I.; Marquet, J. Tetrahedron Lett. 2000, 41, 279.

174. Yadav, J.S.; Reddy, B.V.S.; Basak, A.K.; Narsaiah, A.V. Tetrahedron Lett. 2003, 44, 2217.

175. Smith, C.J.; Tsang, M.W.S.; Holmes, A.B.; Danheiser, R.L.; Tester, J.W. Org. Biomol. Chem. 2005, 3, 3767.

176. Hamper, B.C.; Tesfu, E. Synlett 2007, 2257.

177. See Heaney, H. Chem Rev. 1962, 62, 81, see p. 83.

178. Tripathy, S.; Le Blanc, R.; Durst, T. Org. Lett. 1999, 1, 1973. See Kanth, J.V.B.; Periasamy, M. J. Org. Chem. 1993, 58, 3156.

179. Shi, L.; Wang, M.; Fan, C.-A.; Zhang, F.-M.; Tu, Y.-Q. Org. Lett. 2003, 5, 3515.

180. Neunhoeffer, O.; Heitmann, P. Chem. Ber. 1961, 94, 2511.

181. Smith III, W.J.; Sawyer, J.S. Tetrahedron Lett. 1996, 37, 299.

182. Magdolen, P.; Meciarová, M.; Toma, S. Tetrahedron 2001, 57, 4781.

183. Kidwai, M.; Sapra, P.; Dave, B. Synth. Commun. 2000, 30, 4479.

184. Thomas, S.; Roberts, S.; Pasumansky, .L; Gamsey, S.; Singaram, B. Org. Lett. 2003, 5, 3867.

185. Sanger, F The Biochem. J. 1945, 39, 507.

186. Ali, M.H.; Buchwald, S.L. J. Org. Chem. 2001, 66, 2560; Kuwano, R.; Utsunomiya, M.; Hartwig, J.F. J. Org. Chem. 2002, 67, 6479; Reddy, Ch.V.; Kingston, J.V.; Verkade, J.G. J. Org. Chem. 2008, 73, 3047; Shen, Q.; Hartwig, J.F. Org. Lett. 2008, 10, 4109.

187. Harris, M.C.; Huang, X.; Buchwald, S.L. Org. Lett. 2003, 4, 2885. See Coldham, I.; Leonori, D. Org. Lett. 2008, 10, 3923; Shen, Q.; Hartwig, J.F. J. Am. Chem. Soc. 2006, 128, 10028. For a discussion about the influence of water on this reaction, see Dallas, A.S.; Gothelf, K.V. J. Org. Chem. 2005, 70, 3321.

188. See Anderson, K.W.; Tundel, R.E.; Ikawa, T.; Altman, R.A.; Buchwald, S.L. Angew. Chem. Int. Ed. 2006, 45, 6523.

189. Gajare, A.S.; Toyota, K.; Yoshifuji, M.; Ozawa, F. J. Org. Chem. 2004, 69, 6504; Huang, X.; Anderson, K.W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S.L. J. Am. Chem. Soc. 2004, 125, 6653; Singer, R.A.; Tom, N.J.; Frost, H.N.; Simon, W.M. Tetrahedron Lett. 2004, 45, 4715; Smith, C.J.; Early, T.R.; Holmes, A.B.; Shute, R.E. Chem. Commun. 2004, 1976.

190. See Singh, U.K.; Strieter, E.R.; Blackmond, D.G.; Buchwald, S.L. J. Am. Chem. Soc. 2002, 124, 14104. For a study of rate enhancement by the added base, see Meyers, C.; Maes, B.U.W.; Loones, K.T.J.; Bal, G.; Lemière, G.L.F.; Dommisse, R.A. J. Org. Chem. 2004, 69, 6010.

191. See Strieter, E.R.; Buchwald, S.L. Angew. Chem. Int. Ed. 2006, 45, 925; Fors, B.P.; Davis, N.R.; Buchwald, S.L. J. Am. Chem. Soc. 2009, 131, 5766.

192. Guinó, M.; Hii, K.K. Tetrahedron Lett. 2005, 46, 7363. See Inasaki, T.; Ueno, M.; Miyamoto, S.; Kobayashi, S. Synlett 2007, 3209.

193. Parrish, C.A.; Buchwald, S.L. J. Org. Chem. 2001, 66, 3820.

194. Weigand, K.; Pelka, S. Org. Lett. 2002, 4, 4689.

195. See Grasa, G.A.; Viciu, M.S.; Huang, J.; Nolan, S.P. J. Org. Chem. 2001, 66, 7729.

196. Jensen, T.A.; Liang, X.; Tanner, D.; Skjaerbaek, N. J. Org. Chem. 2004, 69, 4936.; Loones, K.T.J.; Maes, B.U.W.; Rombouts, G.; Hostyn, S.; Diels, G. Tetrahedron 2005, 61, 10338.

197. Xu, C.; Gong, J.-F.; Wu, Y.-J. Tetrahedron Lett. 2007, 48, 1619.

198. So, C.M.; Zhou, Z.; Lau, C.P.; Kwong, F.Y. Angew. Chem. Int. Ed. 2008, 47, 6402.

199. Tagashira, J.; Imao, D.; Yamamoto, T.; Ohta, T.; Furukawa, I.; Ito, Y. Tetrahedron Asymmetry 2005, 16, 230.

200. Huang, X.; Buchwald, S.L. Org. Lett. 2001, 3, 3417.

201. Kang, S.-K.; Lee, H.-W.; Choi, W.-K.; Hong, R.-K.; Kim, J.-S. Synth. Commun. 1996, 26, 4219. See Carroll, M.A.; Wood, R.A. Tetrahedron 2007, 63, 11349.

202. Kang, S.-K.; Lee, S.-H.; Lee, D. Synlett 2000, 1022.

203. Ogawa, K.; Radke, K.R.; Rothstein, S.D.; Rasmussen, S.C. J. Org. Chem. 2001, 66, 9067.

204. Junckers, T.H.M.; Maes, B.U.W.; Lemière, G.L.F.; Dommisse, R. Tetrahedron 2001, 57, 7027; Basu, B.; Jha, S.; Mridha, N.K.; Bhuiyan, Md.M.H. Tetrahedron Lett. 2002, 43, 7967.

205. Choudary, B.M.; Sridhar, C.; Kantam, M.L.; Venkanna, G.T.; Sreedhar, B. J. Am. Chem. Soc. 2005, 127, 9948; Shafir, A.; Buchwald, S.L. J. Am. Chem. Soc. 2006, 128, 8742; Wolf, C.; Liu, S.; Mei, X.; August, A.T.; Casimir, M.D. J. Org. Chem. 2006, 71, 3270; Jiang, D.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2007, 72, 672; Wang, H.; Li, Y.; Sun, F.; Feng, Y.; Jin, K.; Wang, X. J. Org. Chem. 2008, 73, 8639; Cai, Q.; Zhu, W.; Zhang, H.; Zhang, Y.; Ma, D. Synthesis 2005, 496. For a ligand-free reaction, see Yong, F.F.; Teo, Y.-C. Synlett 2010, 3068.

206. Shafir, A.; Lichtor, P.A.; Buchwald, S.L. J. Am. Chem. Soc. 2007, 129, 3490. For an amination using aq ammonia, see Meng, F.; Zhu, X.; Li, Y.; Xie, J.; Wang, B.; Yao, J.; Wan, Y. Eur. J. Org. Chem. 2010, 6149.

207. Lu, Z.; Twieg, R.J. Tetrahedron Lett. 2005, 46, 2997.

208. Kim, J.; Chang, S. Chem. Commun. 2008, 3052.

209. See Renger, B. Synthesis 1985, 856.

210. Wolfe, J.P.; Buchwald, S.L. J. Am. Chem. Soc. 1997, 119, 6054; Lipshutz, B.H.; Ueda, H. Angew. Chem. Int. Ed. 2000, 39, 4492.; Brenner, E.; Schneider, R.; Fort, Y. Tetrahedron 2002, 58, 6913; Chen, C.; Yang, L.-M. J. Org. Chem. 2007, 72, 6324.

211. Manolikakes, G.; Gavryushin, A.; Knochel, P. J. Org. Chem. 2008, 73, 1429; Gao, C.-Y.; Cao, X.; Yang, L.-M. Org. Biomol. Chem. 2009, 7, 3922.

212. Tasler, S.; Lipshutz, B.H. J. Org. Chem. 2003, 68, 1190.

213. Omar-Amrani, R.; Thomas, A.; Brenner, E.; Schneider, R.; Fort, Y. Org. Lett. 2003, 5, 2311.

214. Fedorov, A.Yu.; Finet, J.-P. J. Chem. Soc. Perkin Trans. 1 2000, 3775.

215. Berman, A.M.; Johnson, J.S. J. Am. Chem. Soc. 2004, 126, 5680.

216. Berman, A.M.; Johnson, J.S. Synlett 2005, 1799.

217. Lee, D.-Y.; Hartwig, J.F. Org. Lett. 2005, 7, 1169.

218. Guo, D.; Huang, H.; Xu, J.; Jiang, H.; Liu, H. Org. Lett. 2008, 10, 4513; Correa, A.; Bolm, C. Angew. Chem. Int. Ed. 2007, 46, 8862; Correa, A.; Carril, M.; Bolm, C. Chemistry: European J. 2008, 14, 10919.

219. Appukkuttan, P.; Axelsson, L.; Van der Eycken, E.; Larhed, M. Tetrahedron Lett. 2008, 49, 5625.

220. See Jordan-Hore, J.A.; Johansson, C.C.C.; Gulias, M.; Beck, E.M.; Gaunt, M.J. J. Am. Chem. Soc. 2008, 130, 16184; Kuwahara, A.; Nakano, K.; Nozaki, K. J. Org. Chem. 2005, 70, 413.

221. See Bunnett, J.F.; Hrutfiord, B.F. J. Am. Chem. Soc. 1961, 83, 1691. Also see Hoffmann, R.W. Dehydrobenzene and Cycloalkynes, Academic Press, NY, 1973, pp. 150–164.

222. Chiang, G.C.H.; Olsson, T. Org. Lett. 2004, 6, 3079; Lan, J.-B.; Zhang, G.-L.; Yu, X.-Q.; You, J.-S.; Chen, L.; Yan, M.; Xie, R.-G. Synlett 2004, 1095.

223. Jiang, Z.; Wu, Z.; Wang, L.; Wu, D.; Zhou, X. Can. J. Chem. 2010, 88, 964.

224. Chernick, E.T.; Ahrens, M.J.; Scheidt, K.A.; Wasielewski, M.R. J. Org. Chem. 2005, 70, 1486.

225. Quach, T.D.; Batey, R.A. Org. Lett. 2003, 5, 4397.

226. See Finet, J. Chem. Rev. 1989, 89, 1487.

227. See Barton, D.H.R.; Yadav-Bhatnagar, N.; Finet, J.; Khamsi, J. Tetrahedron Lett. 1987, 28, 3111.

228. See Bethell, D.; Jenkins, I.L.; Quan, P.M. J. Chem. Soc. Perkin Trans. 1 1985, 1789; Paine, A.J. J. Am. Chem. Soc. 1987, 109, 1496.

229. Gauthier, S.; Fréchet, J.M.J. Synthesis 1987, 383.

230. See van der Plas, H.C. Tetrahedron 1985, 41, 237; Acc. Chem. Res. 1978, 11, 462.

231. See Chupakhin, O.N.; Postovskii, I.Ya. Russ. Chem. Rev. 1976, 45, 454, p. 456.

232. Kabalka, G.W.; Li, G. Tetrahedron Lett. 1997, 38, 5777.

233. Sapountzis, I.; Knochel, P. J. Am.Chem. Soc. 2002, 124, 9390.

234. Kitagawa, O.; Takahashi, M.; Yoshikawa, M.; Taguchi, T. J. Am. Chem. Soc. 2005, 127, 3676; Fors, B.P.; Dooleweerdt, K.; Zeng, Q.; Buchwald, S.L. Tetrahedron 2009, 65, 6576. For an intramolecular reaction, see Yang, B.H.; Buchwald, S.L. Org. Lett. 1999, 1, 35.

235. Hosseinzadeh, R.; Tajbakhsh, M.; Mohadjerani, M.; Mehdinejad, H. Synlett 2004, 1517.

236. Browning, R.G.; Badaringarayana, V.; Mahmud, H.; Lovely, C.J. Tetrahedron 2004, 60, 359; Deng, W.; Wang, Y.-F.; Zou, Y.; Liu, L.; Guo, Q.-X. Tetrahedron Lett. 2004, 45, 2311. Also see Klapars, A.; Huang, X.; Buchwald, S.L. J. Am. Chem. Soc. 2002, 124, 7421; Ferraccioli, R.; Carenzi, D.; Rombolà, O.; Catellani, M. Org. Lett. 2004, 6, 4759.

237. Also see Klapars, A.; Parris, S.; Anderson, K.W.; Buchwald, S.L. J. Am. Chem. Soc. 2004, 126, 3529.

238. Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Zappia, G. Org. Lett. 2001, 3, 2539.

239. Lam, P.Y.S.; Deudon, S.; Hauptman, E.; Clark, C.G. Tetrahedron Lett. 2001, 42, 2427.

240. Wolter, M.; Klapars, A.; Buchwald, S.L. Org. Lett. 2001, 3, 3803.

241. Padwa, A.; Crawford, K.R.; Rashatasakhon, P.; Rose, M. J. Org. Chem. 2003, 68, 2609.

242. Kang, S.-K.; Kim, D.-H.; Park, J.-N. Synlett 2002, 427.

243. Nandakumar, M.V. Tetrahedron Lett. 2004, 45, 1989.

244. Gelpke, A.E.S.; Kooijman, H.; Spek, A.L.; Hiemstra, H. Chem. Eur. J. 1999, 5, 2472; Ding, K.; Wang, Y.; Yun, H.; Liu, J.; Wu, Y.; Terada, M.; Okubo, Y.; Mikami, K. Chem. Eur. J. 1999, 5, 1734; Vyskocil, S.; Smrcina, M.; Hanus, V.; Polasek, M.; Kocovsky, P. J. Org. Chem. 1998, 63, 7738; Martorell, G.; Garcias, X.; Janura, M.; Saá, J.M. J. Org. Chem. 1998, 63, 3463; Lipshutz, B.H.; Buzard, D.H.; Yun, C.S. Tetrahedron Lett. 1999, 40, 201.

245. Ager, D.J.; Laneman, S. Chem. Commun. 1997, 2359.

246. Tunney, B.H.; Stille, J.K. J. Org. Chem. 1987, 52, 748.

247. Van Allen, D.; Venkataraman, D. J. Org. Chem. 2003, 68, 4590.

248. Stadler, A.; Kappe, C.O. Org. Lett. 2002, 4, 3541.

249. Kwong, F.Y.; Lai, C.W.; Chan, K.S. Tetrahedron Lett. 2002, 43, 3537.

250. Marcoux, D.; Charette, A.B. J. Org. Chem. 2008, 73, 590.

251. Rieche, A.; Seeboth, H. Liebigs Ann. Chem. 1960, 638, 66.

252. Rieche, A.; Seeboth, H. Liebigs Ann. Chem. 1960, 638, 43, 57.

253. Kozlov, V.V.; Veselovskaia, I.K. J. Gen. Chem. USSR 1958, 28, 3359.

254. Rieche, A.; Seeboth, H. Liebigs Ann. Chem. 1960, 638, 76.

255. Rossi, R.A.; Bunnett, J.F. J. Org. Chem. 1972, 37, 3570.

256. See Scherrer, R.A.; Beatty, H.R. J. Org. Chem. 1972, 37, 1681.

257. For a list of reagents, with references, see Larock, R.C. Comprehensive Organic Transformations, 2nd ed., Wiley–VCH, NY, 1999, pp. 671–672.

258. Sauer, J.; Huisgen, R. Angew. Chem. 1960, 72, 294, p. 297.

259. Schaefer, J.P.; Higgins, J. J. Org. Chem. 1967, 32, 1607.

260. Bay, E.; Bak, D.A.; Timony, P.E.; Leone-Bay, A. J. Org. Chem. 1990, 55, 3415.

261. Kimura, Y.; Suzuki, H. Tetrahedron Lett. 1989, 30, 1271. See Dolby-Glover, L. Chem. Ind. (London) 1986, 518.

262. Uchibori, Y.; Umeno, M.; Seto, H.; Qian, Z.; Yoshioka, H. Synlett 1992, 345.

263. Bacon, R.G.R.; Hill, H.A.O. J. Chem. Soc. 1964, 1097, 1108. See also, Clark, J.H.; Jones, C.W.; Duke, C.V.A.; Miller, J.M. J. Chem. Res. (S) 1989, 238.

264. Clark, J.H.; Jones, C.W. J. Chem. Soc. Chem. Commun. 1987, 1409.

265. Klapars, A.; Buchwald, S.L. J. Am. Chem. Soc. 2002, 124, 14844.

266. Yang, S.H.; Li, C.S.; Cheng, C.H. J. Org. Chem. 1987, 52, 691.

267. Arvela, R.K.; Leadbeater, N.E. Synlett 2003, 1145.

268. Shen, X.; Hyde, A.M.; Buchwald, S.L. J. Am. Chem. Soc. 2010, 132, 14076.

269. See Merkushev, E.B. Synthesis 1988, 923; Russ. Chem. Rev. 1984, 53, 343.

270. Taylor, E.C.; Kienzle, F.; McKillop, A. Org. Synth. VI, 826; Taylor, E.C.; Katz, A.H.; Alvarado, S.I.; McKillop, A. J. Organomet. Chem. 1985, 285, C9. See Usyatinskii, A.Ya.; Bregadze, V.I. Russ. Chem. Rev. 1988, 57, 1054; Taylor, E.C.; Altland, H.W.; McKillop, A. J. Org. Chem. 1975, 40, 2351.

271. De Meio, G.V.; Pinhey, J.T. J. Chem. Soc. Chem. Commun. 1990, 1065.

272. Thiebes, C.; Prakash, G.K.S.; Petasis, N.A.; Olah, G.A. Synlett 1998, 141.

273. Szumigala, Jr., R.H.; Devine, P.N.; Gauthier, Jr., D.R.; Volante, R.P. J. Org. Chem. 2004, 69, 566.

274. See Artamkina, G.A.; Kovalenko, S.V.; Beletskaya, I.P.; Reutov, O.A. Russ. Chem. Rev. 1990, 59, 750.

275. See Ellis, G.P.; Romney-Alexander, T.M. Chem. Rev. 1987, 87, 779.

276. See Connor, J.A.; Leeming, S.W.; Price, R. J. Chem. Soc. Perkin Trans. 1 1990, 1127.

277. Wu, J.X.; Beck, B.; Ren, R.X. Tetrahedron Lett. 2002, 43, 387.

278. Arvela, R.K.; Leadbeater, N.W.; Torenius, H.M.; Tye, H. Org. Biomol. Chem. 2003, 1, 1119.

279. Wang, D.; Kuang, L.; Li, Z.; Ding, K. Synlett 2008, 69.

280. For a list of reagents that convert aryl halides to cyanides, with references, see Larock, R.C. Comprehensive Organic Transformations, 2nd ed., Wiley–VCH, NY, 1999, pp. 1705–1709.

281. Takagi, K.; Sasaki, K.; Sakakibara, Y. Bull. Chem. Soc. Jpn. 1991, 64, 1118.

282. Connor, J.A.; Gibson, D.; Price, R. J. Chem. Soc. Perkin Trans. 1 1987, 619.

283. Sakakibara, Y.; Okuda, F.; Shimobayashi, A.; Kirino, K.; Sakai, M.; Uchino, N.; Takagi, K. Bull. Chem. Soc. Jpn. 1988, 61, 1985.

284. See Stazi, F.; Palmisano, G.; Turconi, M.; Santagostino, M. Tetrahedron Lett. 2005, 46, 1815; Zhu, Y.-Z.; Cai, C. Eur. J. Org. Chem. 2007, 2401.

285. Marcantonio, K.M.; Frey, L.F.; Liu, Y.; Chen, Y.; Strine, J.; Phenix, B.; Wallace, D.J.; Chen, C.-y. Org. Lett. 2004, 6, 3723. See Erker, T.; Nemec, S. Synthesis 2004, 23.

286. Sakamoto, T.; Ohsawa, K. J. Chem. Soc. Perkin Trans. 1 1999, 2323.

287. Jiang, B.; Kan, Y.; Zhang, A. Tetrahedron 2001, 57, 1581.

288. Mariampillai, B.; Alliot, J.; Li, M.; Lautens, M. J. Am. Chem. Soc. 2007, 129, 15372; Weissman, S.A.; Zewge, D.; Chen, C. J. Org. Chem. 2005, 70, 1508; Schareina, T.; Zapf, A.; Mägerlein, W.; Müller, N.; Beller, M. Tetrahedron Lett. 2007, 48, 1087; Velmathi, S.; Leadbeater, N.E. Tetrahedron Lett. 2008, 49, 4693.

289. Yang, C.; Williams, J.M. Org. Lett. 2004, 6, 2837.

290. Chobanian, H.R.; Fors, B.P.; Lin, L.S. Tetrahedron Lett. 2006, 47, 3303.

291. Zhu, Y.-Z.; Cai, C. Synth. Commun. 2008, 38, 2753; Yeung, P.Y.; So, C.M.; Lau. C.-P.; Kwong, F.Y. Angew. Chem. Int. Ed. 2010, 49, 8918.

292. Zhang, Z.; Liebeskind, L.S. Org. Lett. 2006, 8, 4331.

293. Cristau, H.-J.; Ouali, A.; Spindler, J.-F.; Taillefer, M. Chemistry: European J. 2005, 11, 2483.

294. Arvela, R.K.; Leadbeater, N.E. J. Org. Chem. 2003, 68, 9122.

295. Chambers, M.R.I.; Widdowson, D.A. J. Chem. Soc. Perkin Trans. 1 1989, 1365; Takagi, K.; Sakakibara, Y. Chem. Lett. 1989, 1957.

296. Liskey, C.W.; Liao, X.; Hartwig, J.F. J. Am. Chem. Soc. 2010, 132, 11389.

297. Taylor, E.C.; Altland, H.W.; McKillop, A. J. Org. Chem. 1975, 40, 2351.

298. Uemura, S.; Ikeda, Y.; Ichikawa, K. Tetrahedron 1972, 28, 3025.

299. Ushijima, S.; Togo, H. Synlett 2010, 1067; Ushijima, S.; Togo, H. Synlett 2010, 1562.

300. Sato, N. Tetrahedron Lett. 2002, 43, 6403.

301. Letsinger, R.L.; Colb, A.L. J. Am. Chem. Soc. 1972, 94, 3665.

302. Alberico, D.; Scott, M.E.; Lautens, M. Chem. Rev. 2007, 107, 174.

303. See Clayden, J.; Kenworthy, M.N. Synthesis 2004, 1721.

304. See Becht, J.-M.; Gissot, A.; Wagner, A.; Mioskowski, C. Chem. Eur. J. 2003, 9, 3209.

305. Narayan, S.; Seelhammer, T.; Gawley, R.E. Tetrahedron Lett. 2004, 45, 757.

306. Park, S.B.; Alper, H. Tetrahedron Lett. 2004, 45, 5515.

307. Jorapur, Y.R.; Lee, C.-H.; Chi, D.Y. Org. Lett. 2005, 7, 1231.

308. Silveira, P.B.; Lando, V.R.; Dupont, J.; Monteiro, A.L. Tetrahedron Lett. 2002, 43, 2327; Kuroboshi, M.; Waki, Y.; Tanaka, H. Synlett 2002, 637. See also, Venkatraman, S.; Li, C.-J. Org. Lett. 1999, 1, 1133.

309. Leadbeater, N.E.; Resouly, S.M. Tetrahedron Lett. 1999, 40, 4243.

310. Penalva, V.; Hassan, J.; Lavenot, L.; Gozzi, C.; Lemaire, M. Tetrahedron Lett. 1998, 39, 2559.

311. de Franca, K.W.R.; Navarro, M.; Léonel, É; Durandetti, M.; Nédélec, J.-Y. J. Org. Chem. 2002, 67, 1838.

312. Wang, R.; Twamley, B.; Shreeve, J.M. J. Org. Chem. 2006, 71, 426.

313. Wang, L.; Zhang, Y.; Liu, L.; Wang, Y. J. Org. Chem. 2006, 71, 1284.

314. Glover, B.; Harvey, K.A.; Liu, B.; Sharp, M.J.; Tymoschenko, M.F. Org. Lett. 2003, 5, 301.

315. See Rieth, R.D.; Mankand, N.P.; Calimano, E.; Sadighi, J.P. Org. Lett. 2004, 6, 3981.

316. Sezen, B.; Sames, D. Org. Lett. 2003, 5, 3607.

317. Quintin, J.; Franck, X.; Hocquemiller, R.; Figadère, B. Tetrahedron Lett. 2002, 43, 3547.

318. Park, C.-H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan, V. Org. Lett. 2004, 6, 1159.

319. Liu, Z.; Zhang, X.; Larock, R.C. J. Am. Chem. Soc. 2005, 127, 15716.

320. Napier, S.; Marcuccio, S.M.; Tye, H.; Whittaker, M. Tetrahedron Lett. 2008, 49, 6314. See also, Denmark, S.E.; Smith, R.C.; Chang, W.-T.T.; Muhuhi, J.M. J. Am. Chem. Soc. 2009, 131, 3104.

321. Wang, Z.; Ding, Q.; He, X.; Wu, J. Tetrahedron 2009, 65, 4635.

322. Nakamura, T.; Kinoshita, H.; Shinokubo, H.; Oshima, K. Org. Lett. 2002, 4, 3165.

323. Ohe, T.; Tanaka, T.; Kuroda, M.; Cho, C.S.; Ohe, K.; Uemura, S. Bull. Chem. Soc. Jpn. 1999, 72, 1851.

324. Kang, S.-K.; Ryu, H.-C.; Kim, J.-W. Synth. Commun. 2001, 31, 1021.

325. Wang, J.; Scott, A.I. Tetrahedron Lett. 1996, 37, 3247; Kim, Y.M.; Yu, S. J. Am. Chem. Soc. 2003, 125, 1696.

326. Rao, M.L.N.; Yamazaki, O.; Shimada, S.; Tanaka, T.; Suzuki, Y.; Tanaka, M. Org. Lett. 2001, 3, 4103.

327. Yamazaki, O.; Tanaka, T.; Shimada, S.; Suzuki, Y.; Tanaka, M. Synlett 2004, 1921.

328. Grasa, G.A.; Nolan, S.P. Org. Lett. 2001, 3, 119.

329. Dyker, G.; Heiermann, J.; Miura, M.; Inoh, J.-I.; Pivsa-Ast, S.; Satoh, T.; Nomura, M. Chem. Eur. J. 2000, 6, 3426.

330. With NCS, Hossain, K.M.; Kameyama, T.; Shibata, T.; Takagi, K. Bull. Chem. Soc. Jpn. 2001, 74, 2415. See also, Venkatraman, S.; Li, C.-J. Tetrahedron Lett. 2000, 41, 4831.

331. Dubbaka, S.R.; Vogel, P. J. Am. Chem. Soc. 2003, 125, 15292.

332. Chen, C. Synlett 2000, 1491. See Walla, P.; Kappe, C.O. Chem. Commun. 2004, 564.

333. Kang, S.-K.; Baik, T.-G.; Jiao, X.H.; Lee, Y.-T. Tetrahedron Lett. 1999, 40, 2383.

334. Kang, S.-K.; Lee, S.-W.; Kim, M.-S.; Kwon, H.S. Synth. Commun. 2001, 31, 1721.

335. Korn, T.J.; Knochel, P. Angew. Chem. Int. Ed. 2005, 44, 2947.

336. Cahiez, G.; Luart, D.; Lecomte, F. Org. Lett. 2004, 6, 4395.

337. Pérez, I.; Sestelo, J.P.; Sarandeses, L.A. J. Am. Chem. Soc. 2001, 123, 4155.

338. Bedford, R.B.; Limmert, M.E. J. Org. Chem. 2003, 68, 8669.

339. Kang, S.-K.; Choi, S.-C.; Baik, T.-G. Synth. Commun. 1999, 29, 2493.

340. Gagnon, A.; Duplessis, M.; Alsabeh, P.; Barabé, F. J. Org. Chem. 2008, 73, 3604.

341. Chupak, L.S.; Wolkowski, J.P.; Chantigny, Y.A. J. Org. Chem. 2009, 74, 1388.

342. Du, C.F.; Hart, H.; Ng, K.D. J. Org. Chem. 1986, 51, 3162.

343. Cahiez, G.; Chaboche, C.; Mahuteau-Betzer, F.; Ahr, M. Org. Lett. 2005, 7, 1943.

344. Yoshikai, N.; Mashima, H.; Nakamura, E. J. Am. Chem. Soc. 2005, 127, 17978.

345. Korn, T.J.; Cahiez, G.; Knochel, P. Synlett 2003, 1892.

346. Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K. Tetrahedron 2000, 56, 9601.

347. Manabe, K.; Ishikawa, S. Synthesis 2008, 2645.

348. Reeves, J.T.; Fandrick, D.R.; Tan, Z.; Song, J.J.; Lee, H.; Yee, N.K.; Senanayake, C.H. Org. Lett. 2010, 12, 4388.

349. Roy, A.H.; Hartwig, J.F. J. Am. Chem. Soc. 2003, 125, 8704.

350. Bonnet, V.; Mongin, F.; Trècourt, F.; Quèguiner, G.; Knochel, P. Tetrahedron Lett. 2001, 42, 5717.

351. Wang, L.; Chen, Z.-C. Synth. Commun. 2000, 30, 3607.

352. Kojima, T.; Ohishi, T.; Yamamoto, I.; Matsuoka, T.; Kotsuki, H. Tetrahedron Lett. 2001, 42, 1709.

353. Clayden, J.; Cooney, J.J.A.; Julia, M. J. Chem. Soc. Perkin Trans. 1 1995, 7.

354. Beugelmans, R.; Bois-Choussy, M.; Tang, Q. Tetrahedron Lett. 1988, 29, 1705. See Pierini, A.B.; Baumgartner, M.T.; Rossi, R.A. Tetrahedron Lett. 1988, 29, 3429.

355. Durandetti, M.; Nédélec, J.-Y.; Périchon, J. J. Org. Chem. 1996, 61, 1748.

356. He, H.; Wu, Y.-J. Tetrahedron Lett. 2003, 44, 3445.

357. For a review of coupling reactions using various metals, see Terao, J.; Kambe, N. Acc. Chem. Res. 2008, 41,1545.

358. Everson, D.A.; Shrestha, R.; Weix, D.J. J. Am. Chem. Soc. 2010, 132, 920.

359. Hama, T.; Culkin, D.A.; Hartwig, J.F. J. Am. Chem. Soc. 2006, 128, 4976.

360. Shenglof, M.; Gelman, D.; Heymer, B.; Schumann, H.; Molander, G.A.; Blum, J. Synthesis 2003, 302.

361. Sherry, B.D.; Fürstner, A. Acc. Chem. Res. 2008, 41,1500.

362. Rao, M.L.N.; Banerjee, D.; Jadhav, D.N. Tetrahedron Lett. 2007, 48, 2707.

363. Jhaveri, S.B.; Carter, K.R. Chemistry: European J. 2008, 14, 685.

364. Wang, L.; Wang, Z.-X. Org. Lett. 2007, 9, 4335.

365. Moradi, W.A.; Buchwald, S.L. J. Am. Chem. Soc. 2001, 123, 7996.

366. Liao, X.; Weng, Z.; Hartwig, J.F. J. Am. Chem. Soc. 2008, 130, 195.

367. See Heck, R.F. Palladium Reagents in Organic Syntheses, Academic Press, NY, 1985, pp. 179–321; Ryabov, A.D. Synthesis 1985, 233; Heck, R.F. Org. React. 1982, 27, 345; Moritani, I.; Fujiwara, Y. Synthesis 1973, 524. See Cabri, W.; Candiani, I. Accts. Chem. Res. 1995, 28, 2.

368. See Heck, R.F. Acc. Chem. Res. 1979, 12, 146; Kozhevnikov, I.V. Russ. Chem. Rev. 1983, 52, 138. See also, Spencer, A. J. Organomet. Chem. 1983, 258, 101; Andersson, C.; Karabelas, K.; Hallberg, A.; Andersson, C. J. Org. Chem. 1985, 50, 3891; Larock, R.C.; Johnson, P.L. J. Chem. Soc. Chem. Commun. 1989, 1368.

369. See Alonso, F.; Beletskaya, I.P.; Yus, M. Tetrahedron 2005, 61, 11771.

370. Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn 1971, 4, 581.

371. See Littke, A.F.; Fu, G.C. Angew. Chem. Int. Ed. 2002, 41, 4176.

372. Roglans, A.; Pla-Quintana, A.; Moreno-Mañas, M. Chem. Rev. 2006, 106, 4622;

373. Myers, A.G.; Tanaka, D.; Mannion, M.R. J. Am. Chem. Soc. 2002, 124, 11250.

374. Pyridines: Draper, T.L.; Bailey, T.R. Synlett 1995, 157.

375. See Park, S.B.; Alper, H. Org. Lett. 2003, 5, 3209. See also, Zeni, G.; Larock, R.C. Chem. Rev. 2004, 104, 2285.

376. See Firmansjah, L.; Fu, G.C. J. Am. Chem. Soc. 2007, 129, 11340. Also see, Echavarren, A.M.; Gómez-Lor, B.; González, J.J.; de Frutos, Ó. Synlett 2003, 585.

377. Mayasundari, A.; Young, D.G.J. Tetrahedron Lett. 2001, 42, 203.

378. For a review, see Prim, D.; Campagne, J.-M.; Joseph, D.; Andrioletti, B. Tetrahedron 2002, 58, 2041.

379. Consorti, C.S.; Zanini, M.L.; Leal, S.; Ebeling, G.; Dupont, J. Org. Lett. 2003, 5, 983; Senra, J.D.; Malta, L.F.B.; de Souza, A.L.F.; Medeiros, M.E.; Aguiar, L.C.S.; Antunes, O.A.C. Tetrahedron Lett. 2007, 48, 8153.

380. Hirabayashi, K.; Nishihara, Y.; Mori, A.; Hiyama, T. Tetrahedron Lett. 1998, 39, 7893.

381. Ruan, J.; Li, X.; Saidi, O.; Xiao, J. J. Am. Chem. Soc. 2008, 130, 2424; Martinez, R.; Voica, F.; Genet, J.-P.; Darses, S. Org. Lett. 2007, 9, 3213.

382. Selvakumar, K.; Zapf, A.; Beller, M. Org. Lett. 2002, 4, 3031; Feuerstein, M.; Doucet, H.; Santelli, M. Tetrahedron Lett. 2002, 43, 2191. For the use of palladium nanoparticles, see Calò, V.; Nacci, A.; Monopoli, A.; Laera, S.; Cioffi, N. J. Org. Chem. 2003, 68, 2929. See Lindh, J.; Enquist, P.-A.; Pilotti, Å.; Nilsson, P.; Larhed, M. J. Org. Chem. 2007, 72, 7957. See also Seki, M. Synthesis 2006, 2975.

383. Kim, J.-H.; Kim, J.W.; Shokouhimehr, M.; Lee, Y.-S. J. Org. Chem. 2005, 70, 6714.

384. Polshettiwar, V.; Molnár, Á. Tetrahedron 2007, 63, 6949.

385. Karimi, B.; Enders, D. Org. Lett. 2006, 8, 1237; Ambulgekar, G.V.; Bhanage, B.M.; Samant, S.D. Tetrahedron Lett. 2005, 46, 2483; Papp, A.; Galbács, G.; Molnár, Á. Tetrahedron Lett. 2005, 46, 7725; Li, H.; Wang, L.; Li, P. Synthesis 2007, 1635.

386. See Qadir, M.; Möchel, T.; Hii, K.K. Tetrahedron 2000, 56, 7975. Also see Tani, M.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2004, 69, 1221; Yang, D.; Chen, Y.-C.; Zhu, N.-Y. Org. Lett. 2004, 6, 1577; Eberhard, M.R. Org. Lett. 2004, 6, 2125; Liu, J.; Li, S.; Xie, H.; Zhang, S.; Lin, Y.; Xu, J.; Cao, J. Synlett 2005, 1885; Schultz, T.; Pfaltz, A. Synthesis 2005, 1005; Iranpoor, N.; Firouzabadi, H.; Tarassoli, A.; Fereidoonnezhad, M. Tetrahedron 2010, 66, 2415.

387. Nair, D.; Scarpello, J.T.; White, L.S.; dos Santes, L.M.F.; Vankelecom, I.F.J.; Livingston, A.G. Tetrahedron Lett. 2001, 42, 8219.

388. See Botella, L.; Nájera, C. J. Org. Chem. 2005, 70, 4360; Zhang, Z.; Zha, Z.; Gan, C.; Pan, C.; Zhou, Y.; Wang, Z.; Zhou, M.-M. J. Org. Chem. 2006, 71, 4339; Bhattacharya, S.; Srivastava, A.; Sengupta, S. Tetrahedron Lett.2005, 46, 3557.

389. Moineau, J.; Pozzi, G.; Quici, S.; Sinou, D. Tetrahedron Lett. 1999, 40, 7683.

390. Chandrasekhar, S.; Narsihmulu, Ch.; Sultana, S.S.; Reddy, N.R. Org. Lett. 2002, 4, 4399.

391. Perosa, A.; Tundo, P.; Selva, M.; Zinovyev, S.; Testa, A. Org. Biomol. Chem. 2004, 2, 2249.

392. Early, T.R.; Gordon, R.S.; Carroll, M.A.; Holmes, A.B.; Shute, R.E.; McConvey, I.F. Chem. Commun. 2001, 1966. See Kayaki, Y.; Noguchi, Y.; Ikariya, T. Chem. Commun. 2000, 2240.

393. Franzén, R. Can. J. Chem. 2000, 78, 457.

394. Ramchandani, R.K.; Uphade, B.S.; Vinod, M.P.; Wakharkar, R.D.; Choudhary, V.R.; Sudalai, A. Chem. Commun. 1997, 2071.

395. Tonks, L.; Anson, M.S.; Hellgardt, K.; Mirza, A.R.; Thompson, D.F.; Williams, J.M.J. Tetrahedron Lett. 1997, 38, 4319.

396. Anson, M.S.; Mirza, A.R.; Tonks, L.; Williams, J.M.J. Tetrahedron Lett. 1999, 40, 7147.

397. Arvela, R.K.; Leadbeater, N.E. J. Org. Chem. 2005, 70, 1786; Leadbeater, N.E.; Williams, V.A.; Barnard, T.M.; Collins, Jr., M.J. Synlett 2006, 2953; Declerck, V.; Martinez, J.; Lamaty, F. Synlett 2006, 3029; Zhu, M.; Song, Y.; Cao, Y. Synthesis 2007, 853; Du, L.-H.; Wang, Y.-G. Synth. Commun. 2007, 37, 217. See Nilsson, P.; Gold, H.; Larhed, M.; Hallberg, A. Synthesis 2002, 1611.

398. Wang, J.-X.; Liu, Z.; Hu, Y.; Wei, B.; Bai, L. Synth. Commun. 2002, 32, 1607.

399. Zhang, R.; Sato, O.; Zhao, F.; Sato, M.; Ikushima, Y. Chem. Eur. J. 2004, 10, 1501.

400. Buback, M.; Perkovic, T.; Redlich, S.; de Meijere, A. Eur. J. Org. Chem. 2003, 2375.

401. Hagiwara, H.; Sugawara, Y.; Isobe, K.; Hoshi, T.; Suzuki, T. Org. Lett. 2004, 6, 2325; Handy, S.T. Synlett 2006, 3176; Jung, J.-Y.; Taher, A.; Kim, H.-J.; Ahn, W.-S.; Jin, M.-J. Synlett 2009, 39; Zhou, L.; Wang, L. Synthesis2006, 2653; Iranpoor, N.; Firouzabadi, H.; Azadi, R. Eur. J. Org. Chem. 2007, 2197; Cárdenas, J.C.; Fadini, L.; Sierra, C.A. Tetrahedron Lett. 2010, 51, 6867.

402. Handy, S.T.; Okello, M. Tetrahedron Lett. 2003, 44, 8395.

403. Mo, J.; Xu, L.; Xiao, J. J. Am. Chem. Soc. 2005, 127, 751.

404. Heck, R.F. J. Am. Chem. Soc. 1969, 91, 6707; 1971, 93, 6896.

405. Xu, Y.-H.; Lu, J.; Loh, T.-P. J. Am. Chem. Soc. 2009, 131, 1372.

406. Mo, J.; Xiao, J. Angew. Chem. Int. Ed. 2006, 45, 4152.

407. Yokota, T.; Tani, M.; Sakaguchi, S.; Ishii, Y. J. Am. Chem. Soc. 2003, 125, 1476.

408. Larhed, M.; Hallberg, A. J. Org. Chem. 1996, 61, 9582.

409. Battace, A.; Zair, T.; Doucet, H.; Santelli, M. Tetrahedron Lett. 2006, 47, 459; Andappan, M.M.S.; Nilsson, P.; von Schenck, H.; Larhed, M. J. Org. Chem. 2004, 69, 5212. For a review pertaining to enol ethers, see Daves, Jr., G.D. Adv. Met. Org. Chem. 1991, 2, 59.

410. Liu, Z.; Xu, D.; Tang, W.; Xu, L.; Mo, J.; Xiao, J. Tetrahedron Lett. 2008, 49, 2756.

411. See Daves, Jr., G.D.; Hallberg, A. Chem. Rev. 1989, 89, 1433.

412. Jeffery, T. Tetrahedron Lett. 1992, 33, 1989.

413. Chang, H.-M.; Cheng, C.-H. J. Org. Chem. 2000, 65, 1767.

414. Mariampillai, B.; Herse, C.; Lautens, M. Org. Lett. 2005, 7, 4745.

415. Jeffery, T. Tetrahedron Lett. 2000, 41, 8445.

416. Olofsson, K.; Larhed, M.; Hallberg, A. J. Org. Chem. 2000, 65, 7235; Wu, J.; Marcoux, J.-F.; Davies, I.W.; Reider, P.J. Tetrahedron Lett. 2001, 42, 159.

417. Kabalka, G.W.; Guchhait, S.K.; Naravane, A. Tetrahedron Lett. 2004, 45, 4685.

418. Kundu, N.G.; Pal, M.; Mahanty, J.S.; Dasgupta, S.K. J. Chem. Soc. Chem. Commun. 1992, 41. See also, Heck, R.F. Palladium Reagents in Organic Syntheses, Academic Press, NY, 1985, pp. 299–306.

419. Xia, M.; Chen, Z.C. Synth. Commun. 2000, 30, 1281.

420. Handy, S.T.; Wilson, T.; Muth, A. J. Org. Chem. 2007, 72, 8496.

421. Li, Z.; Fu, Y.; Zhang, S.-L.; Guo, Q.-X.; Liu, L. Chemistry: Asian J. 2010, 5, 1475.

422. Nilsson, P.; Larhed, M.; Hallberg, A. J. Am. Chem. Soc. 2001, 123, 8217 and earlier references therein.

423. Ludwig, M.; Strömberg, S.; Svensson, M.; Åkermark, B. Organometallics 1999, 18, 970.

424. Oestreich, M. Eur. J. Org. Chem. 2005, 783.

425. Collman, J.P.; Hegedus, L.S.; Norton, J.R.; Finke, R.G. Principles and Applications of Organotransition Metal Chemistry, 2nd ed., University Science Books, Mill Valley, CA, 1987; Cornils, B.; Herrmann, A.W., Eds., Applied Homogeneous Catalysis with Organometallic Compounds, Wiley, NY, 1996; Vol. 2; Heck, R.F. Acc. Chem. Res. 1979, 12, 146.

426. Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2.

427. von Schenck, H.; Akermark, B.; Svensson, M. J. Am. Chem. Soc. 2003, 125, 3503.

428. Campo, M.A.; Zhang, H.; Yao, T.; Ibdah, A.; McCulla, R.D.; Huang, Q.; Zhao, J.; Jenks, W.S.; Larock, R.C. J. Am. Chem. Soc. 2007, 129, 6298.

429. Fall, Y.; Berthiol, F.; Doucet, H.; Santelli, M. Synthesis 2007, 1683.

430. Shezad, N.; Clifford, A.A.; Rayner, C.M. Tetrahedron Lett. 2001, 42, 323.

431. Su, Y.; Jiao, N. Org. Lett. 2009, 11, 2980.

432. Heck, R.F. J. Am. Chem. Soc. 1969, 91, 6707; See Masllorens, J.; Moreno-Mañas, M.; Pla-Quintana, A.; Plexats, R.; Roglans, A. Synthesis 2002, 1903. See Tan, Z.; Negishi, E. Angew. Chem. Int. Ed. 2006, 45, 762.

433. Larock, R.C.; Baker, B.E. Tetrahedron Lett. 1988, 29, 905. Also see, Larock, R.C.; Gong, W.H.; Baker, B.E. Tetrahedron Lett. 1989, 30, 2603.

434. Wu, W.-Q.; Peng, Q.; Dong, D.-X.; Hou, X.-L.; Wu, Y.-D. J. Am. Chem. Soc. 2008, 130, 9717.

435. Lapierre, A.J.B.; Geib, S.J.; Curran, D.P. J. Am. Chem. Soc. 2007, 129, 494. See Dounay, A.B.; Overman, L.E. Chem. Rev. 2002, 102, 2945.

436. Gilbertson, S.R.; Xie, D.; Fu, Z. J. Org. Chem. 2001, 66, 7240; Gilbertson, S.R.; Fu, Z. Org. Lett. 2001, 3, 161; Hennessy, A.J.; Connolly, D.J.; Malone, Y.M.; Buiry, P.J. Tetrahedron Lett. 2000, 41, 7757.

437. Servino, E.A.; Correia, C.R.D. Org. Lett. 2000, 2, 3039.

438. Heck, R.F.; Nolley, Jr., J.P. J. Org. Chem. 1972, 3720; Henriksen, S.T.; Norrby, P.-O.; Kaukoranta, P.; Andersson, P.G. J. Am. Chem. Soc. 2008, 130, 10414.

439. Heck, R.F. Comprehensive Organic Synthesis Vol. 4, Trost, B.M.; Fleming, I., Eds., Pergamon, Oxford, NY, 1991, p. 833; de Meijere, A.; Meyer, F.E. Angew. Chem. Int. Ed. 1994, 33, 2379; Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2; Crisp, G.T. Chem. Soc. Rev. 1998, 27, 427.

440. See Diederich, F.; Stang, P.J., Eds. Metal-Catalyzed Cross-Coupling Reactions, Wiley–VCH, Weinheim, 1998; Heck, R.F. Palladium Reagents in Organic Syntheses, Academic Press, NY, 1985.

441. Masselot, D.; Charmant, J.P.H.; Gallagher, T. J. Am. Chem. Soc. 2006, 128, 694.

442. See Amatore, C.; Godin, B.; Jutand, A.; Lemaître, F. Chemistry: European J. 2007, 13, 2002.

443. Rosner, T.; Pfaltz, A.; Blackmond, D. G. J. Am. Chem. Soc. 2001, 123, 4621.

444. For related work, see Kalyani, D.; Sanford, M.S. J. Am. Chem. Soc. 2008,130, 2150.

445. García-Cuadrado, D.; de Mendoza, P,; Braga, A.C.; Maseras, F.; Echavarren, A.M. J. Am. Chem. Soc. 2007, 129, 6880.

446. Tanaka, D.; Romeril, S.P.; Myers, A.G. J. Am. Chem. Soc. 2005, 127, 10323.

447. Consorti, C.S.; Flores, F.R.; Dupont, J. J. Am. Chem. Soc. 2005, 127, 12054.

448. Hii, K.K.; Claridge, T.D.W.; Brown, J.M.; Smith, A.; Deeth, R.J. Helv. Chim. Acta 2001, 84, 3043.

449. Kurahashi, T.; Shinokubo, H.; Osuka, A. Angew. Chem. Int. Ed. 2006, 45, 6336.

450. Zhou, P.; Li, Y.; Sun, P.; Zhou, J.; Bao, J. Chem. Commun. 2007, 1418; Amatore, M.; Gosmini, C.; Périchon, J. Eur. J. Org. Chem. 2005, 989.

451. Matsuura, Y.; Tamura, M.; Kochi, T.; Sato, M.; Chatani, N.; Kakiuchi, F. J. Am. Chem. Soc. 2007, 129, 9858.

452. Inamoto, K.; Kuroda, J.; Danjo, T.; Sakamoto, T. Synlett 2005, 1624; Denmark, S.E.; Butler, C.R. Chem. Commun. 2009, 20.

453. Wen, J.; Zhang, J.; Chen, S.-Y.; Li, J.; Yu, X.-Q. Angew. Chem. Int. Ed. 2008, 47, 8897; Liu, W.; Cao, H.; Lei, A. Angew. Chem. Int. Ed. 2010, 49, 2004.

454. Torres, N.M.; Lavis, J.M.; Maleczka, Jr., R.E. Tetrahedron Lett. 2009, 50, 4407.

455. Weissman, H.; Song, X.; Milstein, D. J. Am. Chem. Soc. 2001, 123, 337.

456. Huang, C.-W.; Shanmugasundaram, M.; Chang, H.-M.; Cheng, C.-H. Tetrahedron 2003, 59, 3635.

457. Takami, K.; Yorimitsu, H.; Shinokubo, H.; Matsubara, S.; Oshima, K. Org. Lett. 2001, 3, 1997.

458. Lehmann, U.; Awasthi, S.; Minehan, T. Org. Lett. 2003, 5, 2405.

459. Dai, C.; Fu, G.C. J. Am. Chem. Soc. 2001, 123, 2719.

460. Jalil, A.A.; Kurono, N.; Tokuda, M. Synlett 2001, 1944.

461. Ikeda, Y.; Makamura, T.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2002, 124, 6514.

462. Molander, G.A.; Brown, A.R. J. Org. Chem. 2006, 71, 9681. Also see Alacid, E.; Njera, C. J. Org. Chem. 2009, 74, 2321.

463. Molander, G.A.; Fumagalli, T. J. Org. Chem. 2006, 71, 5743.

464. Molander, G.A.; Jean-Gérard, L. J. Org. Chem. 2007, 72, 8422.

465. Affo, W.; Ohmiya, H.; Fujioka T.; Ikeda, Y.; Nakamura, T.; Yorimitsu, H.; Oshima, K.; Imamura, Y.; Mizuta, T.; Miyoshi, K. J. Am. Chem. Soc. 2006, 128, 8068.

466. Heck, R.F. J. Organomet. Chem. 1972, 37, 389; Heck, R.F.; Nolley, Jr., J.P. J. Org. Chem. 1972, 3720.

467. Kim, J.I.; Patel, B.A.; Heck, R.F. J. Org. Chem. 1981, 46, 1067; Heck, R.F. Pure Appl. Chem. 1981, 53, 2323. See also, Jeffery, T. J. Chem. Soc. Chem. Commun. 1991, 324; Larock, R.C.; Gong, W.H. J. Org. Chem. 1989, 54, 2047. Also see Varma, R.S.; Naicker, K.P.; Liesen, P.J. Tetrahedron Lett. 1999, 40, 2075.

468. See Fanta, P.E. Synthesis 1974, 9; Goshaev, M.; Otroshchenko, O.S.; Sadykov, A.S. Russ. Chem. Rev. 1972, 41, 1046.

469. See Bringmann, G.; Walter, R.; Weirich, R. Angew. Chem, Int. Ed. 1990, 29, 977. Also see, Meyers, A.I.; Price, A. J. Org. Chem. 1998, 63, 412.

470. Yang, M.; Liu, F. J. Org. Chem. 2007, 72, 8969.

471. Wu, Q.; Wang, L. Synthesis 2008, 2007.

472. See for example, Karimipour, M.; Semones, A.M.; Asleson, G.L.; Heldrich, F.J. Synlett, 1990, 525.

473. D'Angelo, N.D.; Peterson, J.J.; Booker, S.K.; Fellows, I.; Dominguez, C.; Hungate, R.; Reider, P.J.; Kim, T.-S. Tetrahedron Lett. 2006, 47, 5045.

474. Forrest, J. J. Chem. Soc. 1960, 592.

475. Lewin, A.H.; Cohen, T. Tetrahedron Lett. 1965, 4531.

476. See Mack, A.G.; Suschitzky, H.; Wakefield, B.J. J. Chem. Soc. Perkin Trans. 1 1980, 1682.

477. Salfeld, J.C.; Baume, E. Tetrahedron Lett. 1966, 3365; Lothrop, W.C. J. Am. Chem. Soc. 1941, 63, 1187.

478. Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404.

479. See Lourak, M.; Vanderesse, R.; Fort, Y.; Caubere, P. J. Org. Chem. 1989, 54, 4840, 4844; Iyoda, M.; Otsuka, H.; Sato, K.; Nisato, N.; Oda, M. Bull. Chem. Soc. Jpn. 1990, 63, 80. For a review of the mechanism, see Amatore, C.; Jutand, A. Acta Chem. Scand. 1990, 44, 755.

480. For a list of reagents, with references, see Larock, R.C. Comprehensive Organic Transformations, 2nd ed., Wiley–VCH, NY, 1999, pp. 82–84.

481. Matsumoto, H.; Inaba, S.; Rieke, R.D. J. Org. Chem. 1983, 48, 840; Chao, C.S.; Cheng, C.H.; Chang, C.T. J. Org. Chem. 1983, 48, 4904.

482. Takagi, K.; Hayama, N.; Sasaki, K. Bull. Chem. Soc. Jpn. 1984, 57, 1887.

483. Bamfield, P.; Quan, P.M. Synthesis 1978, 537.

484. Meyer, G.; Rollin, Y.; Perichon, J. J. Organomet. Chem. 1987, 333, 263.

485. Nelson, T.D.; Meyers, A.I. J. Org. Chem. 1994, 59, 2655; Nelson, T.D.; Meyers, A.I. Tetrahedron Lett. 1994, 35, 3259.

486. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; Alonso, F.; Beletskaya, I.P.; Yus, M. Tetrahedron 2008, 64, 3047; Doucet, H. Eur. J. Org. Chem. 2008, 2013; Molander, G.A.; Yun, C.-S. Tetrahedron 2002, 58, 1465. See Kotha, S.; Lahiri, K.; Kasshinath, D. Tetrahedron 2002, 58, 9633.

487. Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513; Badone, D.; Baroni, M.; Cardomone, R.; Ielmini, A.; Guzzi, U. J. Org. Chem. 1997, 62, 7170. See Torrell, E.; Brookes, P. Synthesis 2003, 469.

488. Fürstner, A.; Seidel, G. Synlett, 1998, 161.

489. For a review, see Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 2419.

490. Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207.

491. Lei, A.; Zhang, X. Tetrahedron Lett. 2002, 43, 2525; Parrish, J.P.; Jung, Y.C.; Floyd, R.J.; Jung, K.W. Tetrahedron Lett. 2002, 43, 7899.

492. Bussolari, J.C.; Rehborn, D.C. Org. Lett. 1999, 1, 965.

493. Fairlamb, I.J.S.; Kapdi, A.R.; Lee, A.F. Org. Lett. 2004, 6, 4435; Arentsen, K.; Caddick, S.; Cloke, G.N.; Herring, A.P.; Hitchcock, P.B. Tetrahedron Lett. 2004, 45, 3511; Artok, L.; Bulat, H. Tetrahedron Lett. 2004, 45, 3881, Arcadi, A.; Cerichelli, G.; Chiarini, M.; Correa, M.; Zorzan, D. Eur. J. Org. Chem. 2003, 4080.

494. See Schweizer, S.; Becht, J.-M.; Le Drian, C. Org. Lett. 2007, 9, 3777; Burns, M.J.; Fairlamb, I.J.S.; Kapdi, A.R.; Sehnal, P.; Taylor, R.J.K. Org. Lett. 2007, 9, 5397; Guo, M; Jian, F.; He, R. Tetrahedron Lett. 2006, 47, 2033; Li, J.-H.; Zhu, Q.-M.; Xie, Y.-X. Tetrahedron 2006, 62, 10888; Kantam, M.L.; Subhas, M.S.; Roy, S.; Roy, M. Synlett 2006, 633; Alonso, D.A.; Cívicos, J.F.; Nájera, C. Synlett 2009, 3011; You, E.; Li, P.; Wang, L. Synthesis 2006, 1465; Felpin, F.-X.; Ayad, T.; Mitra, S. Eur. J. Org. Chem. 2006, 2679; Lee, D.-H.; Jung, J.-Y.; Lee, I.-M.; Jin, M.-J. Eur. J. Org. Chem. 2008, 356; Subhas, M.S.; Racharlawar, S.S.; Sridhar, B.; Kennady, P.K.; Likhar, P.R.; Kantam, M.L.; Bhargava, S.K. Org. Biomol. Chem. 2010, 8, 3001; Bhayana, B.; Fors, B.P.; Buchwald, S.L. Org. Lett. 2009, 11, 3954; Nishikata, T.; Abela, A.R.; Huang, S.; Lipshutz, B.H. J. Am. Chem. Soc. 2010, 132, 4978; Guo, M.; Zhang, Q. Tetrahedron Lett. 2009, 50, 1965. For a discussion of catalysts in this reaction, see Barder, T.E.; Walker, S.D.; Martinelli, J.R.; Buchwald, S.L. J. Am. Chem. Soc. 2005, 127, 4685. For a precatalyst that is useful with unstable 2-heteroaryl boronic acids, see Kinzel, T.; Zhang, Y.; Buchwald, S.L. J. Am. Chem. Soc. 2010, 132, 14073.

495. So, C.M.; Yeung, C.C.; Lau, C.P.; Kwong, F.Y.J. Org. Chem. 2008, 73, 7803; Lipshutz, B.H.; Petersen, T.B.; Abela, A.R. Org. Lett. 2008, 10, 1333; Dai, W.-M.; Zhang, Y. Tetrahedron Lett. 2005, 46, 1377; Villemin, D.; Jullien, A.; Bar, N. Tetrahedron Lett. 2007, 48, 4191; Lai, Y.-C.; Chen, H.-Y.; Hung, W.-C.; Lin, C.-C.; Hong, F.-E. Tetrahedron 2005, 61, 9484; Kuriyama, M.; Shimazawa, R.; Shirai, R. Tetrahedron 2007, 63, 9393; Mai, W.; Gao, L. Synlett 2006, 2553; Ghosh, R.; Adarsh, N.N.; Sarkar, A. J. Org. Chem. 2010, 75, 5320.

496. Mino, T.; Shirae, Y.; Sakamoto, M.; Fujita, T. J. Org. Chem. 2005, 70, 2191; Liu, L.; Zhang, Y.; Wang, Y. J. Org. Chem. 2005, 70, 6122; Yamamoto, Y.; Suzuki, R.; Hattori, K.; Nishiyama, H. Synlett 2006, 1027; Mino, T.; Kajiwara, K.; Shirae, Y.; Sakamoto, M.; Fujita, T. Synlett 2008, 2711; Zhang, G. Synthesis 2005, 537; Cui, X.; Qin, T.; Wang, J.R.; Liu, L.; Guo, Q.-X. Synthesis 2007, 393.

497. Liu, L.; Zhang, Y.; Xin, B. J. Org. Chem. 2006, 71, 3994; Korolev, D.N.; Bumagin, N.A. Tetrahedron Lett. 2006, 47, 4225; Li, J.-H.; Li, J.-L.; Xie, Y.-X. Synthesis 2007, 984; Saha, D.; Chattopadhyay, K.; Ranu, B.C. Tetrahedron Lett. 2009, 50, 1003; da Conceição Silva, A.; Senra, J.D.; Aguiar, L.C.S.; Simas, A.B.C.; de Souza, A.L.F.; Malta, L.F.B.; Antunes, O.A.C. Tetrahedron Lett. 2010, 51, 3883; Zhou, W.-J.; Wang, K.-H.; Wang, J.-X.; Gao, Z.-R. Tetrahedron 2010, 66, 7633.

498. Li, J.-H.; Liu, W.-J.; Xie, Y.-X. J. Org. Chem. 2005, 70, 5409; Felpin, F.-X. J. Org. Chem. 2005, 70, 8575; Masllorens, J.; González, I.; Roglans, A. Eur. J. Org. Chem. 2007, 158.

499. Zapf, A.; Ehrentraut, A.; Beller, M. Angew. Chem. Int. Ed. 2000, 39, 4153.

500. See Calò, V.; Nacci, A.; Monopoli, A.; Montingelli, F. J. Org. Chem. 2005, 70, 6040; Yang, C.-H.; Tai, C.C.; Huang, Y.-T.; Sun, I.-W. Tetrahedron 2005, 61, 4857; Hagiwara, H.; Ko, K.H.; Hoshi, T.; Suzuki, T. Chem. Commun. 2007, 2838; Xin, B.; Zhang, Y.; Liu, L.; Wang, Y. Synlett 2005, 3083.

501. Early, T.R.; Gordon, R.S.; Carroll, M.A.; Holmes, A.B.; Shute, R.E.; McConvey, I.F. Chem. Commun. 2001, 1966.

502. Li, J.-H.; Deng, C.-L.; Xie, Y.-X. Synth. Commun. 2007, 37, 2433.

503. For a review, see Franzén, R.; Xu, Y. Can. J. Chem. 2005, 83, 266. See Jiang, N.; Ragauskas, A.J. Tetrahedron Lett. 2006, 47, 197; Arvela, R.K.; Leadbeater, N.E.; Mack, T.L.; Kormos, C.M. Tetrahedron Lett. 2006, 47, 217; Hattori, H.; Fujita, K.; Muraki,T.; Sakaba, A. Tetrahedron Lett. 2007, 48, 6817; Del Zotto, A.; Amoroso, F.; Baratta, W.; Rigo, P. Eur. J. Org. Chem. 2009, 110; Xu, K.; Hao, X.-Q.; Gong, J.-F.; Song, M.-P.; Wu, Y.-J. Austr. J. Chem. 2010, 63, 315.

504. Kabalka, G.W.; Pagni, R.M.; Hair, C.M. Org. Lett. 1999, 1, 1423. See Basu, B.; Das, P.; Bhuiyan, Md.M.H.; Jha, S. Tetrahedron Lett. 2003, 44, 3817.

505. Villemin, D.; Caillot, F. Tetrahdron Lett. 2001, 42, 639.

506. Chanthavong, F.; Leadbeater, N.E. Tetrahedron Lett. 2006, 47, 1909; Arvela, R.K.; Leadbeater, N.E.; Sangi, M.S.; Williams, V.A.; Granados, P.; Singer, R.D. J. Org. Chem. 2005, 70, 161; Miao, G.; Ye, P.; Yu, L.; Baldino, C.M. J. Org. Chem. 2005, 70, 2332; Arvela, R.K.; Leadbeater, N.E. Org. Lett. 2005, 7, 2101; Baxendale, I.R.; Griffiths-Jones, C.M.; Ley, S.V.; Tranmer, G.K. Chemistry: European J. 2006, 12, 4407; Yan, J.; Zhu, M.; Zhou, Z. Eur. J. Org. Chem. 2006, 2060.

507. Blettner, C.G.; König, W.A.; Stenzel, W.; Schotten, T. J. Org. Chem. 1999, 64, 3885. For other reactions on solid support, see Franzén, R. Can. J. Chem. 2000, 78, 957.

508. Hebel, A.; Haag, R. J. Org. Chem. 2002, 67, 9452.

509. Kantam, M.L.; Roy, M.; Roy, S.; Sreedhar, B.; Madhavendra, S.S.; Choudary, B.M.; De, R.L. Tetrahedron 2007, 63, 8002; Schweizer, S.; Becht, J.-M.; Le Drian, C. Tetrahedron 2010, 66, 765; Islam, M.; Mondal, P.; Tuhina, K.; Hossain, D.; Roy, A.S. Chem. Lett. 2010, 39, 1200.

510. Guo, Y.; Young, D.J.; Hor, T.S.A. Tetrahedron Lett. 2008, 49, 5620.

511. Poondra, R.R.; Fischer, P.M.; Turner, N.J. J. Org. Chem. 2004,69, 6920.

512. Wu, J.; Zhu, Q.; Wang, L.; Fathi, R.; Yang, Z. J. Org. Chem. 2003, 68, 670.

513. Quasdorf, K.W.; Riener, M.; Petrova, K.V.; Garg, N.K. J. Am. Chem. Soc. 2009, 131, 17748. See Antoft-Finch, A.; Blackburn, T.; Snieckus, V. J. Am. Chem. Soc. 2009, 131, 17750.

514. Zhao, Y.-L.; Li, Y.; Li, Y.; Gao, L.-X.; Han, F.-S. Chemistry: Eur. J. 2010, 16, 4991.

515. Zhang, W.; Chen, C.H.-T.; Lu, Y.; Nagashima, T. Org. Lett. 2004, 6, 1473; Riggleman, S.; DeShong, P. J. Org. Chem. 2003, 68, 8106.

516. So, C.M.; Lau, C.P.; Chan, A.S.C.; Kwong, F.Y. J. Org. Chem. 2008, 73, 7731; So, C.M.; Lau, C.P.; Kwong, F.Y. Angew. Chem. Int. Ed. 2008, 47, 8059.

517. Lane, B.S.; Sames, D. Org. Lett. 2004, 6, 2897; Denmark, S.E.; Baird, J.D. Org. Lett. 2004, 6, 3649; Prieto, M.; Zurita, E.; Rosa, E.; Muñoz, L.; Lloyd-Williams, P.; Giralt, E. J. Org. Chem. 2004, 69, 6812; Dvorak, C.A.; Rudolph, D.A.; Ma, S.; Carruthers, N.I. J. Org. Chem. 2005, 70, 4186; Kudo, N.; Perseghini, M.; Fu, G.C. Angew. Chem. Int. Ed. 2006, 45, 1282; Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li, B.-J.; Li, Y.-Z.; Shi, Y.-J. Angew. Chem. Int. Ed. 2008, 47, 1473.

518. Morris, G.A.; Nguyen, S.T. Tetrahedron Lett. 2000, 42, 2093.

519. Villemin, D.; Gómez-Escalonilla, M.J.; Saint-Clair, J.-F. Tetrahedron Lett. 2001, 42, 635.

520. Baillie, C.; Chen, W.; Xiao, J. Tetrahedron Lett. 2001, 42, 9085.

521. Phan, N.T.S.; Brown, D.H.; Stgring, P. Tetrahedron Lett. 2004, 45, 7915.

522. Baillie, C.; Zhang, L.; Xiao, J. J. Org. Chem. 2004, 69, 7779.

523. Mutele, I.; Suna, E. Tetrahedron Lett. 2004, 45, 3909.

524. Ma, H.-r.; Wang, X.-L.; Deng, M.-z. Synth. Commun. 1999, 29, 2477.

525. Tao, B.; Boykin, D.W. J. Org. Chem. 2004, 69, 4330; Li, J.-H.; Liu, W.-J. Org. Lett. 2004, 6, 2809.

526. Colacot, T.J.; Shea, H.A. Org. Lett. 2004, 6, 3731; DeVasher, R.B.; Moore, L.R.; Shaughnessy, K.H. J. Org. Chem. 2004, 69, 7919.

527. Shen, W. Synlett 2000, 737.

528. Peyroux, E.; Berthiol, F.; Doucet, H.; Santelli, M. Eur. J. Org. Chem. 2004, 1075.

529. Andrus, M.B.; Song, C.; Zhang, J. Org. Lett. 2002, 4, 2079.

530. Catellani, M.; Motti, E.; Minari, M. Chem. Commun. 2000, 157. See Yin, J.; Buchwald, S.L. J. Am. Chem. Soc. 2000, 122, 112051.

531. Kuwano, R.; Yokogi, M. Org. Lett. 2005, 7, 945.

532. Kirchhoff, J.H.; Netherton, M.R.; Hills, I.D.; Fu, G.C. J. Am. Chem. Soc. 2002, 124, 13662.

533. Zhou, J.; Fu, G.C. J. Am. Chem. Soc. 2004, 126, 1340.

534. Bandgar, B.P.; Bettigeri, S.V.; Phopase, J. Tetrahedron Lett. 2004, 45, 6959.

535. Tsukamoto, H.; Sato, M.; Kondo, Y. Chem. Commun. 2004, 1200; Kayaki, Y.; Koda, T.; Ikariya, T. Eur. J. Org. Chem. 2004, 4989.

536. McLaughlin, M. Org. Lett. 2005, 7, 4875.

537. Habashneh, A.Y.; Dakhil, O.O.; Zein, A.; Georghiou, P.E. Synth. Commun. 2009, 39, 4221.

538. Lu, Z.; Fu, G.C. Angew. Chem. Int. Ed. 2010, 49, 6676.

539. Lando, V.R.; Moneitro, A.L. Org. Lett. 2003, 5, 2891.

540. Navarro, O.; Kelly, III, R.A.; Nolan, S.P. J. Am. Chem. Soc. 2003, 125, 16194; Baudoin, O. Eur. J. Org. Chem. 2005, 4223.

541. See Esponet, P.; Echavarren, A.M. Angew. Chem. Int. Ed. 2004, 43, 4704.

542. Moreno-Mañas, M.; Pérez, M.; Pleixats, R. J. Org. Chem. 1996, 61, 2346.

543. See Metal–Catalyzed Cross–Coupling Reactions, Diederich, F.; Stang, P.J. Wiley–VCH, Weinheim, 1998, p. 212.