Arylation of enamines

The reactions of enamines with positively activated olefins have been extended to arylations with / -quinones (350,362-369) and quinone sulfoni-mides (365-368,370). Thus a new pathway for the facile formation of benzofurans and indoles became available. 

In the arylations of enamines with very reactive aryl halides (352,370) such as 2,4-dinitrochlorobenzene, the closely related mechanistic pathway of addition of the enamine to the aromatic system, followed by elimination of halide ion, can be assumed. The use of n-nitroarylhalides furnishes compounds which can be converted to indolic products by reductive cycliza-tion. Less reactive aryl halides, such as p-nitrochlorobenzene, lead only to N-arylation or oxidation products of the enamines under more vigorous conditions. 

Diaryliodonium salts also reacted with enamines to give a-aryl ketones in low yields (370). 

While pyridine and quinoline N-oxides do not react directly with enamines, they have been found to form a-pyridyl and 2-quinolinyl-2 -cyclohexanones in good yields after prior acylation (371,372). 

In the reactions of benzyne with enamines, arylated enamines or amino-benzocyclobutenes can be obtained, depending on reaction conditions and the structure of the enamine. Thus the presence of a proton source such as a secondary amine will favor the enamine product through capture of the zwitterionic intermediate, whereas in the absence of protons one sees 

---

Arylation of enamines with p-benzoquinones takes a somewhat different course (70). The enamine (16) reacts exothermally with p-benzoquinone in benzene solution to give 2-(dimethylamino)-2,3-dihydro-3,3-dimethyl-5-benzofuranol (92). The reaction of enamines with quinone dibenzenesul-fonimide proceeds similarly (68). The product from the enamine (28) is the tetrahydrocarbazole derivative (93). 

C-Arylation also takes place with other reactive halides, e.g. heterocyclic 2-chloro-5-nitropyridine 4-chloro-3-nitropyridine, and 2-chloro-4,5-dicarbethoxypyrimidine. 2,4-Dinitrofluorobenzene leads to resinous products, because it is too reactive. Arylation of enamines with less reactive halides occur solely at nitrogen. Treatment of 1 -pyrrolidino-1-cyclohexene with 4-nitrochlorobenzene at elevated temperatures affords iV-4-nitrophenylpyrrolidine. The first step probably consists... 

Arylation of enamines can also be achieved with iodonium salts 234 (Eq. 8) but the yields are low. 

A number of methods for the C-arylation of enamines have been reported, but most have serious limitations. Highly reactive aryl halides, such as 2,4-dinitrochlorobenzene, react with pyrrolidine enamines of cyclic ketones to give the a-arylated ketone on hydrolysis131-135 (Scheme 49). The method fails with less reactive halides, such as... 

A number of related couplings have been reported during the synthesis of alkaloids, such as oxocrinine and cryptoplurine [26], the intramolecular coupling of diarylamines to dibenzazepine, and dibenzazocine structures [27], synthesis of galanthamine [28] and phe-nanthropyrrolidines [29], and the intramolecular arylation of enamines [30]. 

Arylation of enamines with activated aromatic halides (128) is possible. It is of interest to note, however, that less reactive (harder) aryl halides could effect substitution at the nitrogen of enamines. 

Triethylamine a-Arylketones by C-arylation of enamines with active halides... 

The arylation of morpholinocyclohexene with 2- or 4-chloroquinoline N-oxide or 4-chloropyridine N-oxide and benzoyl chloride led to cyclohexanone a-substituted with the respective chloroquinolines or 4-chloropyridine (691). 2,4-Dinitrofluorobenzene reacted with 2-benzylidene-3-methylbenzothiazoline to give the enamine arylation product (672). 

The reactions of enamines as 1,3-dipolarophiles provide the most extensive examples of applications to heterocyclic syntheses. Thus the addition of aryl azides to a large number of cyclic (596-598) and acyclic (599-602) enamines has led to aminotriazolines which could be converted to triazoles with acid. Particular attention has been given to the direction of azide addition (601,603). While the observed products suggest a transition state in which the development of charges gives greater directional control than steric factors, kinetic data and solvent effects (604-606) speak against zwitterionic intermediates and support the usual 1,3-dipolar addition mechanism. 

Whereas carbenoid character is definitely present in metalated alkyl vinyl ethers, lithiated alkyl and aryl vinyl sulfides and thioesters, which are easily available by hydrogen-lithium exchange, do not display carbenoid-typical reactions . They rather behave like nucleophilic reagents, so that their discussion is beyond the scope of this overview despite their utility in synthesis The same appiies to various derivatives of enamines, deprotonated in the vinyiic a-nitrogen position - . 

In related asymmetric Michael-additions of enamine (206) and 2-aryl- 1-nitro-ethylenes, only one of the four possible enantiomerically pure diastereomers was formed 204). Hydrolysis of the crude primary products furnished a-alkylated cyclohexanones of > 90 % enantiomeric excess 204). 

Oxidation of enamines.1 Oxidation of enamines of cyclic ketones in the presence of BFj etherate results in a Favorski type rearrangement to esters of contracted cycloalkanoic acids. A related reaction also occurs with enamines of aryl methyl ketones. 

Reaction of aryl azide with cis-trans mixtures of enamines yields, under kinetically controlled conditions, only the trans-triazolines, as shown by NMR studies. At higher temperatures or in the presence of acid, however, the trans-triazoline epimerizes to give a cis-trans equilibrium mixture the isomer ratio at equilibrium is dictated by steric repulsions in the triazoline ring, and the size of the substituents does not seem to exert a significant effect.211 The proposed mechanism involves the breaking of the N-l/C-5 bond (Scheme 54), although an N-l/N-2 rupture is equally feasible. 

Olefinic double bonds substituted with one or more electron-withdrawing groups show significant dipolarophilic activity in cycloaddition reactions with organic azides,43,276-278 similar to the electron-rich double bonds of enamines and enol ethers the reactivity is less pronounced in azide additions compared to that observed in diazomethane reactions.7 The first triazolines reported resulted by the action of aryl azides on benzoquinones.1,279-281 As a rule, stereospecific cis additions occur,32 which are usually unidirectional except in the case of methacrylic derivatives67 and certain alkenes bearing... 

Chloro-3-aryl- (9) and 2-amino-3-aiylpyridine (10) can be formed by cyclization of enamine (11) under acidic or basic conditions respectively (Scheme 6) <95JOC(60)3750>. 

Interest in the use of pyrylium salts in synthesis continues. 2-Methylpyridinium salts are converted into the 2-arylpyridinium compound on reaction with 2,4,6-triarylpyrylium salts in the presence of base. The methylpyridinium salt is deprotonated to the anhydrobase which behaves as an enamine, attacking the pyrylium salt at C-2, promoting a ring opening - ring closure sequence which culminates in the effective arylation of the pyridinium salt. 

The complicated reaction of 1-pyrrolidino-l-cyclohexene with quinonebenzenesulfonimide may begin with arylation of the enamine system.234 The final product of the strongly exothermic reaction is a substituted tetrahvdrocarbazole (66). 

The scope of this reaction appeared to be limited to dialkylamides and electron-neutral aryl halides. For example, nitro-, acyl-, methoxy-, and dimethylamino-substituted aryl halides gave poor yields upon palladium-catalyzed reaction with tributyltin diethylamide. Further, aryl bromides were the only aryl halides to give any reaction product. Vinyl bromides gave modest yields of enamines in some cases. Only unhindered dialkyl tin amides gave substantial amounts of amination product. The mechanism did not appear to involve radicals or benzyne intermediates. 

A study on the scope of the reaction applied to different types of carbonyl compounds (aldehydes, cyclic ketones and some substituted alkyl aryl ketones75) has been published. Two different secondary amines (pyrrolidine, morpholine) were used. Titanium tetrachloride on various supports (e.g. A1203) acted as effective dehydrating agents for the preparation of enamines from hindered ketones and secondary amines76. 

An unexpected synthesis of enamines has been observed. Treatment of hexahydro-benzazocinium halides 120 (R = H, Me R = Alkyl, R1 = Me, Et) with sodium in liquid ammonia gave 70-86% of E-4-aryl-l-(dialkylamino)-l-butenes (121)527. 

Condensation of enamines with perfluoroarenes, such as perfluorobenzene, perfluor-otoluene, bromopentafluorobenzene and perfluoropyridine, leads after hydrolysis to the formation of a-perfluoroaryl ketones137. C-Arylation may be followed by intramolecular N-arylation thus leading to fluorinated tetrahydrocarbazoles (Scheme 51). The C-versus-N initial arylation ratio is very dependent on the amine moiety and was best for diethylamine enamines. 

---