Enamines aromatic

Coupling of amine protons with vicinal H atoms is usually not seen in aliphatic amines because of their rapid intermolecular exchange. However, for -NH-CH moieties (enamines, aromatic amines, amides, etc.), the exchange rate is slower and splitting is often observed. The H-C-N-H coupling depends on the conformation in a similar way as the H-C-C-H coupling (see Chapter 5.1). For N-CH3 and N-CH2 groups Jhcnh ... 

The H-N-C-H coupling is not observable because of the rapid exchange of the NH protons. However, for a CH-NH-C= moiety (enamines, aromatic amines, amides, etc.) splitting is often observed. The coupling constant exhibits a dependence on the conformation analogous to that shown by vicinal H-C-C-H couplings (see p. H20). In case of free rotation ... 

Alkyl groups attached to aromatic rings are oxidized more readily than the ring in alkaline media. Complete oxidation to benzoic acids usually occurs with nonspecific oxidants such as KMnO, but activated tertiary carbon atoms can be oxidized to the corresponding alcohols (R. Stewart, 1965 D. Arndt, 1975). With mercury(ll) acetate, allyiic and benzylic oxidations are aJso possible. It is most widely used in the mild dehydrogenation of tertiary amines to give, enamines or heteroarenes (M. Shamma, 1970 H. Arzoumanian. 1971 A. Friedrich, 1975). 

Typical nucleophiles known to react with coordinated alkenes are water, alcohols, carboxylic acids, ammonia, amines, enamines, and active methylene compounds 11.12]. The intramolecular version is particularly useful for syntheses of various heterocyclic compounds[l 3,14]. CO and aromatics also react with alkenes. The oxidation reactions of alkenes can be classified further based on these attacking species. Under certain conditions, especially in the presence of bases, the rr-alkene complex 4 is converted into the 7r-allylic complex 5. Various stoichiometric reactions of alkenes via 7r-allylic complex 5 are treated in Section 4. 

Aniline (hen enamine) [62-53-3] is the simplest of the primary aromatic amines. It was first produced ia 1826 by dry distillation of indigo. In 1840 the same oily hquid was obtained by heating indigo with potash, and it was given the name aniline. The stmcture of aniline was estabUshed in 1843 with the demonstration that it could be obtained by reduction of nitrobenzene. 

An example of non-aromatic tautomerism has already been quoted (Table 13, Section 4.04.1.3.3(ii)) the equilibrium between the two enamines (152a) and (152b) is solvent and temperature dependent (70BSF3147). 

Systems usually fluonnated by electropositive fluorine reagents include acti-vated alkenes (enol ethers, enol acetates, silyl enol ethers, and enamines), activated aromatic systems, certain slightly activated carbon-hydrogen bonds, and selected organometallics. 

Fluorocylatwn of enarnines and enamides has been intensively studied by different groups [78, 79, 80 SI] The effectiveness of this particular electrophilic substitution reaction becomes obvious when the nitrogen atom of the enamine moiety is engaged in an aromatic system [82 S3] or when the olefinic system is part of an aromatic nucleus [84] (equations 37 and 38) A further extension of this reaction is demonstrated by the tnfluoracetylation of aldehyde dialkyl hydrazones [S5 86] (equation 39)... 

Similarly, fluorinated ketones are prepared and react with enamines [50], This reaction involves the intermediacy of an a,P-ethylenic ketone and leads to annelation-aromatization products [5tJ] (Table 13) (equation 37). 

Stork and Borowitz (36) have reported that the reaction of the pyrrolidine enamine of cyclohexanone with aromatic sulfonyl chloride led to the tetrasubstituted isomer of the sulfonated enamine (63). 

R, = CjHj, Rj, R3 = (0112)4] (45). Even the possibility of stabilization of the double bond by conjugation with an aromatic ring was not enough to overcome the steric repulsions. The enamine formed is probably an equilibrium product 46). 

The preparation of enamines by reduction of aromatic heterocyclic bases and their quaternary salts or of lactams is not the most useful approach (97). The lithium aluminum hydride reduction of N-acyl enamines has been used with both fruitful and unsuccessful results. A series of 3-N-acetyl -d -cholestenes (104) has been prepared by desulfurization of the appropriate thiazolidine (105) (98,99). Lithium aluminum hydride reduction of the... 

Fulvene-type enamines, which possess some nonbenzenoid aromatic character, have been synthesized by treating cyclopentadienylsodium with an amide-dimethyl sulfate eomplex (117aJ17b) or quaternary pyridinium salts (117c). One of the simplest ones produced is 6-(dimethylamino)fulvene (117a,117d). 

Acylation with aromatic acid chlorides was believed to occur on carbon 91). The dibenzoylation of the enamine (113) with benzoyl chloride in the presence of triethylamine has, however, been shown to give a mixture of three products (92). The major components are the cis and Irons isomers of the O-acylated enamino ketone (Ola and b) and the minor isomer is the 2,6-diacylated enamine (132). 

The aromatic sulfonyl chlorides which have no a-hydrogen and thus cannot form sulfenes give acylic sulfones. Thus 1-piperidinopropene on reaction with benzene sulfonyl chloride (9J) gave 2-benzenesulfonyl-l-piperidinopropene (153). Similarly the enamine (28) reacts with p-toluene-sulfonyl chloride to give the 2-p-toluenesulfonylcyclohexanone (154) on hydrolysis (/OS). 

This method of bromination has been employed in the selective bromination (777) of the ketone (167). While direct bromination results in bromination not only in the position alpha to the ketone but also in the aromatic ring, bromination of the enamine (168) and subsequent hydrolysis gave only the monobrominated product (169). 

The enamines of cyclic ketones, on reaction with aliphatic and aromatic aldehydes, give good yields of the 2-monoalkylidene derivative of the corresponding ketones (J28). The first step in the reaction appears to be the... 

The intermediacy of dipolar species such as 186 has been demonstrated by reaction of enamines with 2-hydroxy-1-aldehydes of the aromatic series (129). The enamine (113) reacts in benzene solution at room temperature with 2-hydroxy-1-naphthaldehyde to give the crystalline adduct (188) in 91 % yield. Oxidation with chromium trioxide-pyridine of 188 gave 189 with p elimination of the morpholine moiety. Palladium on charcoal dehydrogenation of 189 gave the known 1,2-benzoxanthone (129). 

Aldehyde enamines react with aromatic diazonium salts in two ways, depending on the degree of substitution at the enamine earbon (130). Thus the piperidine enamine of butyraldehyde (60) reacted with p-nitrophenyl-diazonium chloride to give the p-nitrophenylhydrazone of the a-keto aldehyde (190). 

In most reviews of enamine chemistry the reactions of iminium salts are scattered throughout the review and are consequently not covered in a comprehensive manner. This chapter will be an attempt to look at reactions that, at one stage or another, proceed by nucleophilic addition to the iminium intermediate. The subject of enamines has been reviewed 1-4) and certain aspects of iminium salt chemistry such as reduction of aromatic quaternary salts have been treated in detail (5). Consequently, the reduction of aromatic quaternary salts with complex hydrides will be presented here only briefly. Although the literature (especially 1950-1967) has been checked with care, the author can make no claim to completeness. The... 

The previous sections have dealt with stable C=N-I- functionality in aromatic rings as simple salts. Another class of iminium salt reactions can be found where the iminium salt is only an intermediate. The purpose of this section is to point out these reactions even though they do not show any striking differences in their reactivity from stable iminium salts. Such intermediates arise from a-chloroamines (133-135), isomerization of oxazolidines (136), reduction of a-aminoketones by the Clemmensen method (137-139), reductive alkylation by the Leuckart-Wallach (140-141) or Clarke-Eschweiler reaction (142), mercuric acetate oxidation of amines (46,93), and in reactions such as ketene with enamines (143). 

Lukes studied the reaction of N-methyl lactams with Grignard reagents. With the five- (39-42) and six-membered (43-47) rings, 2,2-dialkylated bases (16, = 1,2) are formed as by-products in addition to the l-methyl-2-alkyl pyrrolines (15, = 1) or l-methyl-2-alkyl piperideines (15, =2). Aromatic Grignard reagents afford only the unsaturated bases, probably because of steric factors (48,49). Separation of enamines and 2,2-dialkylated amines from each other can be easily achieved since the perchlorates of the enamines and the picrates of 2,2-dialkylated bases crystallize readily. Therefore enamines can be isolated as crystalline perchlorates and the 2,2-dialkylated bases as crystalline picrates. Some authors who repeated the reactions isolated only pyrrolines (50,57) or, by contrast, 2,2-dialkylated bases (52). This can be explained by use of unsuitable isolation techniques by the authors. 

Tertiary pyrrolines (49, = 1) and piperideines (49, = 2) (if R = H and the enamine can exist in the monomeric form or if R = aryl) evidently possess an endocyclic -double bond (79,155,156). The stretching frequency of the double bond can be lowered to 1620-1635 cm by conjugation with an aromatic substituent. The double bond of an analogous compound with aliphatic substituents in position 2 may occupy either the endo or the exo position. Lukes and co-workers (157) have shown that the majority of the five-membered-ring compounds, traditionally formulated with the double bond in a position, possess the structure of 2-alkylidene derivatives (50) with an exocyclic double bond, infrared absorption at 1627 cm . Only the 1,2-dimethyl derivative (51) is actually a J -pyrroline, absorbing at 1632 cm . For comparison, l,3,3-trimethyl-2-methylene pyrrolidine (52) with an unambiguous exocyclic double bond has been prepared (54). 

The simplest examples of this type of compound are enamines derived from the quinuclidine skeleton (67). The formulation of enamines of qflmuclidine in a inesomeric form would violate Bredt s rule. Actually, the ultraviolet spectrum of 2,3-benzoquinuclidine shows that there exists no interaction of aromatic ring tt electrons and the nitrogen-free electron pair (160,169). The overlap of the olefinic tt orbital and the lone pair orbital on nitrogen is precluded. 

From the preparative point of view, reactions of heterocyclic aromatic compounds with nucleophilic reagents are very important, especially the reactions of their quaternary salts containing a formal enamine grouping in the molecule. 

Heterocyclic enamines A -pyrroline and A -piperideine are the precursors of compounds containing the pyrrolidine or piperidine rings in the molecule. Such compounds and their N-methylated analogs are believed to originate from arginine and lysine (291) by metabolic conversion. Under cellular conditions the proper reaction with an active methylene compound proceeds via an aldehyde ammonia, which is in equilibrium with other possible tautomeric forms. It is necessary to admit the involvement of the corresponding a-ketoacid (12,292) instead of an enamine. The a-ketoacid constitutes an intermediate state in the degradation of an amino acid to an aldehyde. a-Ketoacids or suitably substituted aromatic compounds may function as components in active methylene reactions (Scheme 17). 

Formally analogous to the foregoing Grignard additions are the intramolecular condensations of amides with aromatic systems, found in the Bischler-Napieralski reaction 101), which is of particular interest in isoquinoline and indole alkaloid syntheses (102). Condensations of amidines with reactive methylene compounds also led to enamines (103-106). 

Aromatic enamines were prepared by dehydroha logenation of /3-bromo-amines with strong base. While trans enamines were thus formed, one obtained mostly cis enamines from rearrangement of the corresponding allylic amines under similar reaction conditions (646). Vicinal endiamines were obtained from S-dichloroamines and lithium amides (647). 

Extensions of the enamine alkylation to a-tetralones have also been used (245-248), but product yields were lower, presumably due to steric crowding in a transition state where generation of an imonium salt gives rise to a repulsion between a methylene group on nitrogen and a peri aromatic proton. 

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. 

An interesting rearrangement which is based on the intramolecular acylation of an enamine by an ester is found in the aromatization of the adduct derived from N-methylpyrrole and an acetylenedicarboxylic ester (407,408). 

Reactions of enamines with selenium dioxide gave low yields of enamino ketones (J8). Aromatization of cyclohexanone derived enamines eould be largely prevented by the use of aeetonitrile as solvent for the reaction. Even then, yields were eonsiderably below the limit of 50%, imposed by the generation of an equivalent of water. 

From the oxidation of enamines with aromatic nitro compounds a-keto-enamines were obtained in modest yields (70J). Photooxygenation led to cleavage of the enamine double bond (706,707). 

The coupling of enamines with aromatic diazonium salts has been used for the syntheses of monoarylhydrazones of a-diketones (370,488-492) and a-ketoaldehydes (488,493). Cleavage of the initial enamine double bond and formation of the phenylhydrazone of acetone and acetophenone has been reported with the enamines of isobutyraldehyde and 2-phenylpropionalde-hyde. Rearrangement of the initial coupling product to the hydrazone tautomer is not possible in these examples. 

Extensions of 1,3-dipolar additions of aromatic azides (720,721) to other enamines (636), and particularly to the enamine tautomer of SchilTs bases, were explored (722,723). Further nitrone additions were reported (724,725) and a double nitrile oxide added to an endiamine (647). Cyanogen azide and enamines gave cyanoamidines through rearrangement (726). 

A unique method to generate the pyridine ring employed a transition metal-mediated 6-endo-dig cyclization of A-propargylamine derivative 120. The reaction proceeds in 5-12 h with yields of 22-74%. Gold (HI) salts are required to catalyze the reaction, but copper salts are sufficient with reactive ketones. A proposed reaction mechanism involves activation of the alkyne by transition metal complexation. This lowers the activation energy for the enamine addition to the alkyne that generates 121. The transition metal also behaves as a Lewis acid and facilitates formation of 120 from 118 and 119. Subsequent aromatization of 121 affords pyridine 122. 

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