Substituted enamines

Structural formulae and nomenclature for X-ray determinations of a-substituted enamines 

TABLE 3. Heavy atom distances (A) and angles (deg) of a-substituted enamines as determined by X-ray diffraction172 

Summary of experimentally observed variations in molecular structures of 

In push-pull substituted j9-enaminones 84 to 87 due to through conjugation the C=C distance is elongated to about 1.380 A. In other push-pull systems 99 to 103 the C=C bond lengths are in the range of 1.348 to 1.405 A. In both classes the C—N distances vary between 1.303 and 1.390 A. 

In the case of doubly push-pull substituted enamines 88 to 92 and 106 to 107, instead of through conjugation a tendency to adopt a zwitterionic form is observed. This form is characterized by a very long C=C distance between 1.407 to 1.482 A, very short C—N lengths of 1.312 to 1.352 A and shows various angles of twist around the C=C bond. 

---

Risaliti et al. (22), have shown that in the addition of the electrophilic olefins to the enamines of cyclohexanone, the formation of the less substituted enamine is favored when a bulky group is present at the electrophilic carbon atom. For instance, the reaction of (8-nitrostyrene with the morpholine enamine of cyclohexanone gave only the trisubstituted isomer (30) with the substituent in the axial orientation (23). The product on hydrolysis led to the ketone (31) to which erythro configuration was assigned on the grounds illustrated in Scheme 3 (24). 

The general rule has been formulated (P) that the less substituted enamine is formed from unsymmetrical ketones such as the 2-alkylcyclohexanones. In enamine 21 the R, group and the N-alkyl groups would interfere with one another if overlap is to be maintained between the nitrogen unshared electrons and the double bond. There would be less repulsion if the isomeric enamine (22) were formed. 2-Phenylcyclohexanone and pyrrolidine with p-toluenesulfonic acid as catalyst in refluxing benzene gave enamine... 

The magnitude of the preference for the formation of the less substituted enamine from unsymmetrical ketones as expressed by the general rule given above is not entirely clear. House and Schellenbaum 48) have reported that 2-methylcyclohexanone and pyrrolidine produce a product mixture of tetra- and trisubstituted enamines in a ratio of 15 85. The estimate of this ratio was made from NMR data. In contrast Stork and co-workers (9) report the formation of 100% trisubstituted enamine as determined by NMR spectroscopy. 

Although the emphasis in this chapter has been on tbe synthesis and mechanism of formation of simple enamines, brief mention will be made of the addition of amines to activated acetylenes to indicate the interest and activity in this area of substituted enamines. Since such additions tend to be stereospecific, inclusion in this section seems apropos. The addition of amines to acetylenes has been much studied 130), but the assigning of the stereochemistry about the newly formed double bond could not be done unequivocally until the techniques of NMR spectroscopy were well developed. In the research efforts described below, NMR spectroscopy was used to determine isomer content and to follow the progress of some of the reactions. 

The intermediacy of zwitterionic species was proposed for the addition of phenylsulfenyl chloride to dimethylaminomethyl-substituted enamines (465,466). They receive support from the observed lack of stereospecific addition of methylsulfonyl chloride to cw-morpholinopropene (although the trans enamine gives only one adduct) (466). 

Heteroaromatic substituents can be incorporated onto the quinoxaline 1,4-dioxide ring system by condensing BFO with the appropriately substituted enamine, cyanomethyl, or 1,3-dicarbonylcompound. 2-Cyanomethyl-l,3-benzothiazole 27 reacted readily with BFO 1 in the presence of potassium carbonate to give the quinoxaline 1,4-dioxide 28 in good yield. 

The orbital phase theory was applied to the conformations of alkenes (a- and P-substituted enamines and vinyl ethers) [31] and alkynes [32], The conformational stabilities of acetylenic molecules are described here. 

It might be possible to add the allyl group regio-speclfIcally, using an enamine, but usually the less substituted enamine is formed preferentially. 

Owing to the predominance of the less-substituted enamine, alkylations occur primarily at the less-substituted a-carbon. Synthetic advantage can be taken of this selectivity to prepare 2,6-disubstituted cyclohexanones. The iminium ions resulting from C-alkylation are hydrolyzed in the workup procedure. 

Scheme 2.11 shows some examples of Robinson annulation reactions. Entries 1 and 2 show annulation reactions of relatively acidic dicarbonyl compounds. Entry 3 is an example of use of 4-(trimethylammonio)-2-butanone as a precursor of methyl vinyl ketone. This compound generates methyl vinyl ketone in situ by (3-eliminalion. The original conditions developed for the Robinson annulation reaction are such that the ketone enolate composition is under thermodynamic control. This usually results in the formation of product from the more stable enolate, as in Entry 3. The C(l) enolate is preferred because of the conjugation with the aromatic ring. For monosubstituted cyclohexanones, the cyclization usually occurs at the more-substituted position in hydroxylic solvents. The alternative regiochemistry can be achieved by using an enamine. Entry 4 is an example. As discussed in Section 1.9, the less-substituted enamine is favored, so addition occurs at the less-substituted position. 

Synthetic use can be made of the potent electrophilic properties of ADC compounds by transforming the initial adducts into heterocyclic products. For example, reaction of DEAZD with enamine 92 gives the substitution product 93 in quantitative yield. Further treatment of this initial adduct with acid, followed by base hydrolysis leads to benzoxazol-2-ones. The dimethyl substituted enamine (92, R = Me) gives the rare, but isolable 6//-benzoxazol-2-one ring system (Scheme 13).147... 

The enamines derived from cyclohexanones have been of particular interest. The pyrrolidine enamine is most frequently used for synthetic applications. In the enamine mixture formed from pyrrolidine and 2-methylcyclohexanone, structure 6 is predominant.67 The tendency for the less substituted enamine to predominate is quite general. A steric effect is responsible for this preference. Conjugation between the nitrogen atom and the 7i orbitals of the double bond favors coplanarity of the bonds that are darkened in the structures. A serious nonbonded repulsion (A1,3 strain) destabilizes isomer 7. Furthermore, in isomer 6 the methyl group adopts a quasi-axial conformation to avoid steric interaction... 

Aminoallyl carbanions, obtained by deprotonation of enamines or allylamines, are well-known homoenolate equivalents, since electrophilic attack occurs, in most cases, highly regiose-lectively to give the 3-substituted enamines, hydrolysis of which leads to the corresponding carbonyl compounds15 24,25. 

From a more synthetic perspective, reaction of the aUtenylmagnesium derivatives with electrophiles is very interesting. Indeed, if the intermediates could be trapped with electrophiles, the reaction would provide a novel route to the preparation of nitrogen-containing heterocycles having a fully substituted enamine structure. This expectation proved to be possible (Table... 

TABLE 11. Synthesis of phenothiazine having a fully substituted enamine structure (181)... 

Owing to the low reactivity of substituted enamines, reaction (2) is useful mainly for the preparation of monoalkylated ketones. 

Cyclic ketones react faster than the aliphatic ketones in the order cyclo-pentanone > cyclohexanone > higher-membered cyclic ketones. a-Substi-tuted ketones give the less substituted enamines, which in turn could be alkylated to put a substituent on this position of the ketone [51] (Eq. 11). 

Simpler alkenylmorpholines, such as 4-vinylmorpholine (148), would seem to be interesting heterocyclic monomers. While monomer (148) is unstable, substituted enamines such as 1-morpholino-l-butene (149) have been incorporated into copolymers with acrylonitrile. Copolymers containing up to 30% of units derived from monomer (148), however, may be prepared according to Scheme 45 (70MI11102). 

Resin-bound amines can be converted into imines [710,711] or enamines by reaction with carbonyl compounds (Entries 6 and 7, Table 3.39). Resin-bound enamines have also been prepared by Michael addition of resin-bound secondary amines to acceptor-substituted alkynes [712], by Hg(II)-catalyzed addition of resin-bound secondary amines to unactivated alkynes [713], by addition of C-nucleophiles to resin-bound imino ethers [714], and by chemical modification of other resin-bound enamines [712,713,715], Acceptor-substituted enamines ( push-pull alkenes) are not always susceptible to hydrolytic cleavage by TFA alone and might require aqueous acids to undergo hydrolysis [716]. 

The addition of amines to electron-poor alkynes leads to the formation of enamines (Entry 11, Table 10.6). These acceptor-substituted enamines are more stable towards hydrolysis than enamines derived from unsubstituted ketones. Alkynes devoid of electron-withdrawing groups do not react smoothly with amines, and usually require Hg(II) catalysis to be converted to resin-bound enamines (Entry 12, Table 10.6). 

Bicyclic keto esters can easily be prepared by a process called a,a -annulation.29 Thus, treatment of the enamine of cyclopentanone (64) with ethyl a-(bromomethyl)acrylate (98) affords, after work-up, the bicyclic keto ester (99) in 80% yield (equation IS).2911 The mechanism probably involves an initial Michael addition and elimination (or a simple Sn2 or Sn2 alkylation) followed by an intramolecular Michael addition of the less-substituted enamine on the acrylate unit. The use of the enamine of 4,4-bis(ethoxycarbonyl)cyclohexanone (100 equation 26) with (98) gives a 45% yield of the adaman-tanedione diester (101) (yield based on 100 70% when based on 98) via a,a -annulation followed by Dieckmann condensation.29 Enamines of heterocyclic ketones can also serve as the initial nucleophiles, e.g. (102) and (103) give (105) via (104), formed in situ, in 70% yield (Scheme 11 ).29>... 

For the indole, methyl sustitution at the 2-position (i.e. 71) appears to sterically block C—C annulation vs C—N annulation (Scheme 46)126a. Note also that electrochemical methods are only useful for the substituted vinylindoles, as unsubstituted indoles passivate the working electrode. The results of cycloadditions of substituted enamines 66 and 69 to vinylindoles 65 and 71 are summarized in Tables 7 and 8. 

Di- and tri-substituted enamines of aldehydes have been generated under mild conditions (1 h, 0°C, 1.2 equiv. of amine).278 Although easily isolable, they can be conveniently employed in situ. The reaction is chemoselective (ketones present are not affected), it tolerates sensitive groups such as acetals and silyl ethers, and it works for both aliphatic and aromatic aldehydes. 

The API nizatidine contains an enamine functionality (Fig. 59). Degradation of the enamine functionality under acid and basic conditions yields the subsequent amine. After irradiation with a mercury lamp in an aqueous solution, nizatidine degraded to the corresponding urea compound from the addition of water to the nitro-substituted enamine followed by cleavage (consistent with the enamine photochemistry scheme, Figure 58) (98). 

The hydrazine 89 is made from the amine by nitrosation and reduction and the keto-acid 90 is available as levulinic acid. Now comes the big question when the Fischer indole synthesis is carried out on the hydrazone 91 which enamine is formed, the one we want 92, or the one we don t want 93 Since the Fischer indole is an acid- (or Lewis acid-) catalysed reaction we expect the more substituted enamine 92 to be favoured. 

A recent example of this reaction is the photo-irradiation of mixtures of benzaldehyde and substituted enamines to give 3-amino oxetanes with very high diastereoselectivities in favor of the fir-product <1999JOC1265>. High regio- and stereoselectivity were again achieved in reactions between monosubstituted benzils and 2-morpholinopropenenitrile... 

Steroidal, alicyclic or aromatic annulated pyridines were prepared via a microwave-assisted, base-catalyzed Henry reaction of /1-formyl enamides and nitromethane on an alumina support [97]. Highly substituted tri- and tetrasubstituted pyridines were synthesized in a Bohlmann-Rahtz reaction from ethyl /3-amino crotonate and various alkynones. The reaction involved a Michael addition-cyclodehydration sequence and was effected in a single synthetic step under microwave heating conditions [98]. An alternative approach towards polysubstituted pyridines was based on a reaction sequence involving an inverse electron-demand Diels-Alder reaction between various enamines 45 and 1,2,4-triazines 44 (Sect. 3.6), followed by loss of nitrogen and subsequent elimination-aromatization. Enamines 45 were formed in situ from various ketones and piperidine under one-pot microwave dielectric heating conditions [99]. Furthermore, a remarkable acceleration of the reaction speed (from hours and days to minutes) was observed in a microwave-assisted cycloaddition. Unsymmetrically substituted enamines 45 afforded mixtures of regioisomers (Scheme 35). 

Fritsch and Weingarten 386 have studied the electrooxidation of 22 substituted enamines by cyclic voltammetry and ESR spectroscopy. Oxidation potentials of these strong electron donors may be as low as -0,901 V (vs.S.C.E.). The life times of the initially formed radical cations range from 0,005 sec to days depending on the efficiency of reactive site blocking or stabilization by substituents. Coupling constants from the ESR spectra indicate that the unpaired electron is polarized away from the dimethylamino substituents. The opposite is true for the... 

In the preparation of enamines from a-substituted ketones, e.g. 2-alkylcyclohexanones, the less-substituted enamine is always formed because of steric interactions77. This makes possible the introduction of a... 

The original ketone here is unsymmetrical, so two enamines are possible. However, the formation of solely the less substituted enamine is typical. The outcome may be explained as the result of thermodynamic control enamine formation is reversible so the less hindered enamine predominates. 

For the more substituted enainine, steric hindrance forces the enamine to lose planarity, and destabilizes it. The less substituted enamine, on the other hand, is rather more stable. Note how the preference for the less substituted enamine is opposite to the preference for a more substituted enol. 

---