Aryl halides with enamines

Aryl halides with a halogen activated by electron-withdrawing groups react with pyrrolidine enamines of cyclic ketones (68) to give the a-arylated ketones after hydrolysis. The enamine (28) with 2,4-dinitrochlorobenzene gave an excellent yield of 2(2,4-dinitrophenyl)cyclohexanone (88). The... 

Condensation of aryl halides with various active methylene compounds is readily promoted by catalytic action of palladium to give the corresponding arene derivatives containing a functionalized ethyl group [7]. Yamanaka et al. extended this chemistry to haloazoles including oxazoles, thiazoles and imidazoles [8]. Thus, in the presence of Pd(Ph3P)4,2-chlorooxazole was refluxed with phenylsulfonylacetonitrile and NaH to form 4,5-diphenyl-a-phenylsulfonyl-2-oxazoloacetonitrile, which existed predominantly as its enamine tautomer. In a similar fashion, 4-bromooxazole and 5-bromooxazole also were condensed with phenylsulfonylacetonitrile under the same conditions. 

Pyrrolidinocyclohexene added under N2 to a cooled soln. of l-chloro-2,4-di-nitrobenzene and triethylamine in methylene chloride, allowed to stand 24 hrs. at room temp., coned, in vacuo, the residue stirred into 3 -HCl, and the product isolated after 24 hrs. -> 2-(2,4-dinitrophenyl) cyclohexanone. Y 92%.—Very reactive aryl halides attack enamines by C-arylation to give a-arylketones on hydrolysis while with less reactive aryl halides N-arylation and cleavage to N-arylated sec. amines occur. F. e. s. M. E. Kuehne, Am. Soc. 54, 837 (1962). 

Allylic amines are coupled to halides giving either allylic amines or enamines depending on the reaction condition. Reaction of steroidal dienyl triflate with Boc-diprotected allylamine affords allylamine. Use of AcOK as a base is crucial for the clean coupling[102]. The tert-allylic amine 123 reacts with an aryl halide to give the enamine 125 in DMF and allylic amine 124 in nonpolar solvents[103]. 

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. 

Stork Enamine Synthesis A reaction leading to the formation of an a-alkyl or a-carbonyl compound from an alkyl or aryl halide reacting with an enamine. 

The monoarylated enamine can then be acylated to form a mixture of 2-acyl-2-arylcyclohexanone and 2-aryl-6-acylcyclohexanone. This was held to indicate that arylation affords two enamines, 62 and 63, which differ only in the position of the double bond. The reaction involving acyl halides could be explained under the assumption that in the more probable enamine structure (with conjugation through the free electron pair on nitrogen, the double bond, and the aromatic ring) it is the hydrogen atom on C(6) which is more acidic. 

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 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... 

Besides Michael additions the mild reaction conditions of CIR are also compatible with cycloadditions. Since chalcones can also be considered as heterodienes, Diels-Alder reactions with inverse electron demand are suitable elementary steps that are applicable for heterocycle synthesis. Therefore, after CIR of electron-deficient (hetero)aryl halides 11 and (hetero)aryl propargyl alcohols 12, (hetero) cyclic and acyclic morpholino enamines 98 are added and, finally, after adding... 

The method is quite useful for particularly active alkyl hahdes, such as allylic, benzyhc, and propargyhc halides, and for a-halo ethers and esters. Other primary and secondary halides can show sluggish reactivity. The react of enamines with benzotriazole derivatives has been reported. Tertiary hahdes do not give the reaction at all since, with respect to the halide, this is nucleophilic substitution and ehmination predominates. The reaction can also be applied to activated aryl halides (e.g., 2,4-dinitrochlorobenzene see Chapter 13), to epoxides, and to activated alkenes, such as acrylonitrile. The latter is a Michael-type reaction (15-24) with respect to the alkene. 

The initial success of the inverse electron demand [4 + 2]cycloaddition reaction of electron deficient, 1,2,4-triazine (61) with a-aryl enamine (60) to formulate the 4-arylpyridine forms the basis of a complementary approach to the CDE ring system of lavendamycin. In this strategy the oxidative insertion of aryl halide bond to provide the p-carboline derivative in the presence of palladium (0) was the notable feature. In a recently published article by Boger, a total synthesis of lavendamycin starting from the precursor 63 has been presented. The utility of... 

Various cyclic compounds can be prepared by the reaction of ketones with bifunctional aryl halides. The jS-naphthol derivative 52 was obtained by a-arylation of dibenzyl ketone (14) with o-bromobenzaldehyde derivative 51, followed by aldol condensation [38], Also the indole derivative 54 was synthesized by the reaction of cyclohexanone with 2-iodoaniline (53). Formation of 54 may be explained by enamine formation at first, followed by intramolecular Mizoroki-Heck reaction, rather than via a-arylation [39],... 

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. 

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... 

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. 

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

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