Enamines, also

HAOOAOIN-ISSIOORIOES Ouinoxaline synthesis Synthesis ot quinoxaiine dioxides trom benzoiurazan oxide and ketone enoiates or enamines (also known as Beirut reaction). 

The structure of the protonated enamines has been investigated by infrared spectroscopy. On protonation there is a characteristic shift of the band in the double-bond stretching region to higher frequencies by 20 to 50 cm with an increased intensity of absorption (6,13,14a). Protonated enamines also show absorption in the ultraviolet at 220-225 m/x due to the iminium structure (14b). This confirms structure 5 for these protonated enamines, because a compound having structure 4 would be expected to have only end absorption as the electrons on nitrogen would not be available for interaction with the n electrons of the double bond. 

Enamines also react with electrophilic alkenes to give conjugate addition products. The addition reactions of enamines of cyclohexanones show a strong preference for attack from the axial direction.319 This is anticipated on stereoelectronic grounds because the tt orbital of the enamine is the site of nucleophilicity. 

Several enamines also participate in these cycloaddition reactions. For example, the addition of methyl lithium to benzaldehyde 5 and the sequential introduction of the vinylogous amide and magnesium bromide results in the cycloaddition elimination product chromene 63 (method G, Fig. 4.33).27 The introduction of methyl magnesium bromide to a solution of the benzaldehyde 5 and two equivalents of the morpholine enamine produces the cycloadduct 64 in 70% yield with better than 50 1 diastereoselectivity (method F). Less reactive enamides, such as that used by Ohwada in Fig. 4.4, however, fail to participate in these conditions. 

Enamines also react with electrophilic alkenes. This aspect of their chemistry will be described in Section 1.10. 

Enamines also can be acylated on the a C with acid chlorides. 

In addition to preparation of arylhydrazones from the carbonyl compounds and an arylhydrazine, the Japp-Klingemann reaction of arenediazonium ions with enolates and enamines is an important method for preparation of arylhydrazones. This method provides a route to monoarylhydrazones of a-dicarbonyl compounds from /3-keto acids and to the hydrazones of pyruvate esters from / -keto esters. Enamines also give rise to monoarylhydrazones of a-diketones. Indolization of these arylhydrazones provides the expected 2-acyI-or 2-alkoxycarbonyl-indoles (equations 95-97). 

Benzo[6]furans and 2,3-dihydrobenzo[6]furans have been obtained by condensation of quinones with compounds having an active methylene group (B-74MI31201) and 2-aminobenzo[6 ]furan derivatives are obtained with malononitrile (68M2359). The reaction of p-benzoquinone with enamines also affords benzo[6]furans. 

The reaction of a,/3-unsaturated carbonyl compounds with enamines also leads to dihydropyrans, although it is not always possible to isolate these since they react further to give either ring-opened by-products or bicyclic derivatives arising from a Stork annelation. There has been considerable discussion on the mechanism of this reaction, although the initial nucleophilic attack of the enamine on the /3-carbon of the diene is not in doubt (63JA207). It is possible that a zwitterionic species is involved, either as an intermediate or merely in equilibrium with the dihydropyran (67JCS(C)226). 

Enamines also react with diketene to form chromones (60JCS26). One drawback to this method is the use of 2,3-dihydro-Ar,Ar-dimethyl-p-toluidine, prepared by Birch reduction of the aromatic amine, and the consequent need to aromatize the reduced chromone which is the initial product. 

In addition to acyclic and monocyclic enamines, bicyclic and tricyclic enamines also undergo cycloaddition with dihalocarbenes. Endocyclic enamines , such as pyrrole and indole, add dichforocarbene and the adducts rapidly undergo ring cleavage to afford 3-chloropyridine and 3-chloroquinoline, respectively, in moderate yields (c/. Section 4.7.3.9).75-77... 

Ionized enamines also play an important role in the El-induced decomposition of more complex molecules. 

In addition to the synthesis of /1-dicarbonyl compounds3,25, the acylation of enamines also gives access to a wide variety of acyclic, carbocyclic and heterocyclic systems. The course of the reaction is often critically dependent upon the type of enamine used, on the substituents present in the two reagents, and on the experimental conditions, such as temperature, solvent, presence of added tertiary amine, etc. In contrast to alkylation, A-acylation is readily reversible. Since enamines are stronger bases than the C-acylated enamines, half an equivalent of the enamine is lost by salt formation in their reaction with acid chlorides. This can be avoided by addition of a tertiary amine179, but this in... 

Under these conditions the stereoselectivity is higher, as the attack of the reagent occurs equatorially, leading to axial amines (72-92%). A comparison with the results of reduction of 4-f-butylcyclohexanone shows a complete inversion of stereoselectivity (16-27% of equatorial attack). Reductions of 2-alkylcyclohexanone enamines also proceed with high stereoselectivity, leading predominantly to the cis amines in the six-membered ring derivatives (66-96%), and almost exclusively in the case of the five-membered enamines (95-98%) (Scheme 84). The A1,3 strain112 in fact would shift the conformational equilibrium towards the axial (or pseudo xial) orientation of the substituent. 

Enamines also act as useful intermediates for the acylation of aldehydes or ketones at a-position (Scheme 3.21). 

For other examples of ostensibly similar cycloadditions, however, quite different stereochemical results have been obtained, ranging from complete loss (116 + 117 - 118 the frauj-propenyl enamine also gives adduct 118 ) - to complete retention of stereochemistry tetramethoxyethylene reacts with (107) to give only the [2 + 2] adduct (119). ... 

Enamines also undergo condensation with aldehydes to give a,(3-unsaturated ketones on hydrolysis. ... 

Synthesis of quinoxaline N,N -dioxides from benzofurazan oxides and ketone enolates or enamines (also known as the Beirut reaction) (see 1st edition). 

Thermolysis of 1,2,4-triazines with a side-chain terminal nitrile group leads to the formation of condensed pyrazines <89JOCl245>. This reaction involves cycloaddition of the nitrile dienophile across C-3 and C-6 of the 1,2,4-triazine followed by aromatization of the intermediate cycloadduct by extrusion of the N—N bridge. As a typical example, the 5,6-diphenyl-1,2,4-triazine (167) is fused under nitrogen at 225-235°C to form the condensed pyrazine (168) in 71% yield (Equation (21)). Intermolecular cyclization of oxadiazinones with enamines also yields condensed pyrazines. The bicyclic intermediates lose carbon dioxide to generate 1,4-diazadienes, which aromatize to the... 

Momiyama and Yamamoto [50] found that cyclic achiral enamines also react with nitrosobenzene in the presence of chiral carboxylic acids to produce the 0-nitroso aldol product (Scheme 12.3). The best result was obtained with piperidine enamine 16 and (S)-l-naphthyl glycolic acid 17. 

As noted in Table 19.1, enamines also participate in Michael reactions as illustrated by the addition of the enamine of cyclohexanone to acrylonitrile, CH2=CHCN. 

In a similar manner, enamines also reacted with the corresponding 1,2- or 1,3-Af-substituted diamines 1-3 under the effect of a rhodium catalyst with moderate to excellent iso-regioselectivity (Figure 5.22) [94]. 

The reaction of NO with the double bonds of enamines also produces compounds containing the diazeniumdiolate functional group bound to carbon, and some of the compounds prepared in this way have the potential to serve as spontaneous NO donors [43]. The compounds chosen for study were enamines 1-4 derived from condensation of cyclopentanone or cyclohexanone with morpholine or pyrrolidine. When these enamines were dissolved in acetonitrile and treated with NO gas (5-atm pressure) at room temperature, a vigorous exothermic reaction resulted, accompanied by high uptake of NO and formation of a brown precipitate. Attempts to isolate the solid precipitates often resulted in rapid decomposition, with the release of large volumes of gaseous NO. At -78 °C in diethyl ether, the reaction of 4-(l-cyclohexen-l-yl) morpholine (IX) afforded a good yield of crystalline NO addition product (X) ... 

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