Enamines tetrasubstituted

The increase in the proportion of the tetrasubstituted isomer in the cases of the morpholine and piperidine enamines of 2-methylcyelohexanone has been ascribed to both steric and electronic factors. The authors propose that the overlap of the electron pair on the nitrogen atom and the v electrons of the double bond is much more important in the case of the pyrrolidine enamines and much less with the others. Support for this postulate was provided by the NMR spectra of these enamines, wherein the chemical shifts of the vinylic protons of the pyrrolidine enamines were at a higher field than those of the corresponding morpholine and piperidine enamines by 20-27 Hz. The greater amount of overlap or electron delocalization, in the case of pyrrolidine enamine, is in accord with the postulate of Brown et al. (7- ) that the double bond exo to the five-membered ring is more favored than the double bond exo to the six-membered ring. 

Since the overlap requirements with the piperidine and morpholine enamine are much less stringent, the steric in terference in the tetrasubstituted... 

Another case in point is the N-methylaniline enamine of 2-methylcyclo-hexanone (22), which has been reported 15) to consist exclusively of the tetrasubstituted isomer. Here the electron pair on the nitrogen atom could... 

Morpholine enamine of 2- -propylcyclohexanone has been shown (16) by NM R spectroscopy to be a 2 3 mixture of tri- and tetrasubstituted isomers. 

The tetrasubstituted isomer of the morpholine enamine of 2-methyl-cyclohexanone (20) because cf the diminished electronic overlap should be expected to exhibit lower degree of enamine-type reactivity toward electrophilic agents than the trisubstituted isomer. This was demonstrated to be the case when the treatment of the enamine with dilute acetic acid at room temperature resulted in the completely selective hydrolysis of the trisubstituted isomer within 5 min. The tetrasubstituted isomer was rather slow to react and was 96% hydrolyzed after 22 hr (77). The slowness might also be due to the intermediacy of quaternary iminium ion 23, which suffers from a severe. 4< strain 7,7a) between the equatorial C-2 methyl group and the methylene group adjacent to the nitrogen atom, 23 being formed by the stereoelectronically controlled axial protonation of 20. 

That the methyl group in the less substituted isomer of the enamine (20) is axial was borne out by the work of Johnson et al. (18) in the total synthesis of the glutarimide antibiotic //-dehydrocycloheximide (24). The acylation of the morpholine enamine of 2,4-dimethylcyclohexanone (25) with 3-glutarimidylacetylchloride (26), followed by the hydrolysis of the intermediate product (27) with an acid buffer, led to the desired product in 35 % yield. The formation of the product in a rather low yield could most probably be ascribed to the relatively low enamine-type aetivity exhibited by the tetrasubstituted isomer, which fails to undergo the acylation reaction, and also because in trisubstituted isomer one of the CHj groups is axial. Since the methyl groups in the product are trans to each other, the allylic methyl group in the less substituted isomer of the enamine should then be in the axial orientation. 

Danishafsky and Feldman (21) have shown that the cyclization of the aminoketone (28) led to the internal enamine (29), which lacks the steric interaction of the type existent in the enamines of 2-alkycyclohexanones. In this case, the tetrasubstituted isomer was favored over the trisubstituted one by a factor of 4 1, which may be ascribed to the double bond being in the exo position in the latter case. 

However, when the bulky substituent is no longer present at the electrophilic carbon atom, the addition of the olefin to the morpholine enamine of cyclohexanone leads largely to the tetrasubstituted isomer. For instance the reaction of this enamine with phenyl vinyl sulfone gave a 1 3 mixture of... 

Reaction of the pyrrolidine enamine of cyclohexanone with phenyl vinyl sulfone afforded a 9 1 mixture of the tri- and tetrasubstituted isomers (2(5). The preference of the less substituted isomer in this case is in keeping with the greater overlap requirement between the n electrons of the double bond and the electron pair on the nitrogen atom, since the double bond exo to the five-membered ring is much more favored than the double bond exo to the six-membered ring. It is, however, hard to explain the formation of largely the trisubstituted isomer with the piperidine enamine of cyclohexanone, where both of the rings involved are six-membered. 

Risaliti et al. (2J) have also studied the addition of 2-nitropropene, which also lacks any substituent at the electrophilic carbon atom, to the morpholine enamine of cyclohexanone. The product, as expected, was the tetrasubstituted isomer, the formation of which may be envisioned via the transition state (42). 

The reaction of the morpholine enamine of cyclohexanone with phenyl isothiocyanate led only to the tetrasubstituted isomer of the monoadduct (54), which failed to add any more of the phenyl isothiocyanate. The formation of only the tetrasubstituted isomer has been attributed by Hunig et al. (37) to the stronger conjugation of the C=S group with the enamine double bond than that of the C=0 group in the enamine (49). 

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). 

Morpholine enamine of methyl isopropyl ketone prepared by this method was found to be a 3 7 mixture of di- and tetrasubstituted isomers (126 and 127). 

The alkylation of enamines with nitroolefins, which gives intermediates for reductive cyclization (6S2), also provided an example of a stable cycliza-tion product derived from attack of the intermediate imonium function by the nitro anion (683). A previously claimed tetrasubstituted enamine, which was obtained from addition of a vinylsulfone to morpholinocyclohexene (314), was shown to be the corresponding cyclobutane (684). Perfluoro-olefins also gave alkylation products with enamines (685). Reactions of enamines with diazodicarboxylate (683,686) have been used diagnostically for 6-substituted cyclohexenamines. In a reaction of 2-penten-4-one with a substituted vinylogous amide, stereochemical direction was seen to depend on solvent polarity (687). 

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). 

The deprotonation of an iminium ion (formula A in Figure 7.27) to give an enam-ine is reversible under the usual reaction conditions. Therefore, the most stable enam-ine possible is produced preferentially. Figure 7.28 emphasizes this using the example of an enamine formation from a-methylcyclohexanone (i.e., from an asymmetrical ketone). The enamine with the trisubstituted double bond is produced regioselectively and not the enamine with the tetrasubstituted double bond. Since the stability of olefins usually increases with an increasing degree of alkylation, this result is at first... 

In the pyrrolidine enamine of 2-methyl-4-f-butylcyclohexanone the methyl group is largely axial15. The morpholine enamine of 2-methyl-4-f-butylcyclohexanone exists as an isomeric equilibrium mixture of 54% trisubstituted enamines 55 and 56 and 46% tetrasubstituted enamine 57. The distribution between quasiequatorial and quasiaxial trisubstituted isomers is 1 1 (i.e. the mixture contains 27% of each)15. 

The situation is rendered even more complex when an unsymmetrical ketone is used as the enamine precursor, since then a mixture of enamines is formed. If the ketone is a-substituted, as with 2-alkylcyclohexanones, a mixture of the more substituted or tetrasubstituted (It) and the less-substituted (la) enamine isomers is usually obtained, in acid catalysed equilibrium (Scheme 2). 

For tetrasubstituted enamine double bonds the situation is less clear. The stereoselectivity depends to a very large extent on the nature of the C2-substituent (R) and varies from being completely non-stereoselective (R = CH3)34 to completely axial stereoselective [R = N(C02Et)NHC02Et]39-41. 

Two explanations have been suggested for this anomalous result83,84. Huffman and coworkers84 have proposed that the 2,2-disubstituted cyclohexanone (38) is derived directly from a 2,6-disubstituted enolate intermediate by simultaneous alkylation at C2 and dealkylation at C6. This is in effect a S 2 mechanism for which there is no precedent in enamine chemistry (Scheme 24). The basis for this suggestion is the anomalous solvent-dependent annulation of 2-substituted cyclohexanone enamines with methyl vinyl ketone (MVK) and the assumption that direct C-alkylation of a tetrasubstituted enamine is improbable for it is known that there is considerably less overlap of the unshared electrons on nitrogen with the n system of the double bond in this isomer relative to the more stable trisubstituted isomer, thereby greatly decreasing the rate of alkylation . 

The authors assume this reflects the rotamer population of the zwitterionic intermediate and that 51 arises by abstraction of an equatorial proton (Scheme 36). However, this would be more likely to occur via a twist conformation which could arise, at least in part, from equatorial attack on the enamine. Interestingly the tetrasubstituted enamine (51) crystallized from the reaction mixture and was shown on heating in benzene, without added acid catalyst, to revert to the same mixture of 51 and 52. This presumably reflects the greater carbon acidity of a methylene alpha to a sulphone group which can therefore catalyse the interconversion or cause reversion to enamine followed by re-alkylation100. 

Similar results were obtained with enamines of acyclic ketones such as desoxybenzoin. Nitrostyrene gave only the less substituted mono-alkylated enamine and hence the / -nitro-a-phenylethyl ketone on hydrolysis117. Surprisingly 2-nitropropene gives mainly the tetrasubstituted cyclohexanone enamine106. A hexahydrobenzo-l,2-oxazine-7V-oxide (55) was isolated at low temperatures (in 80% yield) which rearranged at room temperature to a mixture of alkylated enamine isomers107 (Scheme 39). 

Oxidation of enamines derived from cyclic and acyclic ketones with thallium triacetate in equivalent amount leads to the formation of the corresponding 2-acetoxy ketones75 (Scheme 52). The reactions are stereoselective (the antiparallel attack of the oxidizing agent is preferred over a parallel attack on 3- and 4-/-butylcyclohexanone enamines) and the attack occurs preferentially at the tetrasubstituted enamine double bond, when there is more than one possibility due to isomerism. 

The anomalous products may be obtained by conversion of enamines 85 and 91 to the corresponding enolates 86 and 92 due to the effect of external base or the tetrasubstituted enamine, followed by attack on a second molecule of methyl vinyl ketone affording isomeric enolates 87 and 93. Protonation of these enolates would afford precursors to enones 88 (cis alkyl groups) and 94 (trans alkyl groups). 

This catalytic cascade was first realized using propanal, nitrostyrene and cinnamaldehyde in the presence of catalytic amounts of (9TMS-protected diphenylprolinol ((.S )-71,20 mol%), which is capable of catalyzing each step of this triple cascade. In the first step, the catalyst (S)-71 activates component A by enamine formation, which then selectively adds to the nitroalkene B in a Michael-type reaction (Hayashi et al. 2005). The following hydrolysis liberates the catalyst, which is now able to form the iminium ion of the a, 3-unsaturated aldehyde C to accomplish in the second step the conjugate addition of the nitroalkane (Prieto et al. 2005). In the subsequent third step, a further enamine reactivity of the proposed intermediate leads to an intramolecular aldol condensation. Hydrolysis returns the catalyst for further cycles and releases the desired tetrasubstituted cyclohexene carbaldehyde 72 (Fig. 8) (Enders and Hiittl 2006). 

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