Cyclohexanone enamines substituted

A substituted a,/3-unsaturated aldehyde, cinnamaldehyde, has been observed to undergo the same type of two-step 1,3-cycloaddition reaction with a cyclohexanone enamine as acrolein does, forming in this case a stereo-isomeric mixture of substituted bicycloaminoketones in excellent yield (29a,31a,31b). 

The reactions of pyrrolidinocyelohexenes with acid have also been Considered from a stereochemical point of view. Deuteration of the 2-methylcyclohexanone enamine gave di-2-deuterio-6-methylcyclohexanone under conditions where ds-4-/-butyI-6-methyIpyrrolidinocycIohexene was not deuterated (2J4). This experiment supported the postulate of Williamson (2JS), which called for the axial attack of an electrophile and axial orientation of the 6 substituent on an aminocyclohexene in the transition state of such enamine reactions. These geometric requirements explain the more difficult alkylation of a cyclohexanone enamine on carbon 2, when it is substituted at the 6 position, as compared with the unsubstituted case. 

The arylation of morpholinocyclohexene with 2- or 4-chloroquinoline N-oxide or 4-chloropyridine N-oxide and benzoyl chloride led to cyclohexanone a-substituted with the respective chloroquinolines or 4-chloropyridine (691). 2,4-Dinitrofluorobenzene reacted with 2-benzylidene-3-methylbenzothiazoline to give the enamine arylation product (672). 

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 . 

Reaction of 3-substituted cyclohexanone enamines with / -nitrostyrene gives, on hydrolysis, a mixture of 6- and 2-alkylated ketones (59 and 57 ratio 4 1, respectively). Since the 6-alkylated ketone (59) is formed in much greater amount than enamine (58)... 

Diethyl azodicarboxylate (DAD) behaves like a reactive electrophilic alkene and attack on a substituted cyclohexanone enamine can occur from an axial or equatorial direction depending on the steric effects in the transition state. For example, DAD reacts with 159 to give 160 by equatorial attack, together with 161 (ratio 1 9), whereas the... 

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 hydrolysisSurprisingly 2-nitropropene gives mainly the tetrasubstituted cyclohexanone enamine . A hexahydrobenzo-l,2-oxazine-A-oxide (55) was isolated at low temperatures (in 80% yield) which rearranged at room temperature to a mixture of alkylated enamine isomers (Scheme 39). 

The preference for attack at the Cg-position can clearly be attributed to developing gauche butane interactions with the R-substituent for axial attack at C2, thus necessitating equatorial attack at Cj with consequent increase in the activation energy owing to developing non-bonded twist interactions in 60 (Scheme 41). In contrast to j9-nitrostyrene, 1-nitropropene undergoes both axial and equatorial attack on both 3- and 4-substituted cyclohexanone enamines, except for reaction at C2 of the 3-substituted enamine where only equatorial attack occurs . 

Whitesell and Felman therefore concluded that an amine with a C2 axis of symmetry was required in order to ensure that the same side of the cyclohexene ring was shielded from attack whichever conformation of the enamine underwent alkylation. The en-antioselectivity was thereby considerably increased, but in the opposite chiral sense, by using the cyclohexanone enamine derived from ( + )-/mnj-2,5-dimethylpyrrolidine. This was assumed to have the S, S-configuration based on the results of the alkylation (Scheme 70). Optical yields of 82-93% ee were obtained. Also noteworthy was the low level of dialkylation observed (4-7%) and the fact that formation of enamine 77 was at least ten times faster using type 3A molecular sieves compared to 4A molecular sieves. Similar methodology has been applied to the alkylation of 4-substituted cyclohexanone enamines to give mainly the less stable trans disubstituted cyclohexanone s . 

Application of this annulation reaction to substituted cyclohexanone enamines has led to the observation of some remarkable solvent-dependent regjoselectivity effects. Thus, the pyrrolidine enamine of 2-methylcyclohexanone underwent annulation with MVK to give only the expected A "-2-octalone, derived from the more reactive less substituted enamine isomer, in both benzene and methanol as solvents (Scheme 130). However, the corresponding reaction with 2,5-disubstituted cyclohexanone enamines shows dramatic solvent and stoichiometry effects. For example, the pyrrolidine enamine (130a) of 2-methyl-5 isopropenylcyclohexanone (dihydrocarvone) on reaction with one or two equivalents of MVK in benzene, or with one equivalent of MVK in methanol, gave the exi>ected product (131) exclusively. However, with five equivalents of MVK in methanol the unexpected product (132) derived from the less reactive more substituted enamine (130b) was obtained exclusively (Scheme 131). 

The presence of 1,3-diaxial interaction between the C-2 alkyl group and the C-4 axial hydrogen atom is reflected in the rate of enamine formation of 2-substituted cyclohexanone. It has been shown by Hunig and Salzwedel (20) that even under forcing conditions, the yield of pyrrolidine and morpholine enamines of 2-methylcyclohexanone does not exceed 58%, whereas the C-2 unsubstituted ketones underwent enamine formation under rather milder conditions in better than 80 % yield. 

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). 

In a similar manner the addition of ethyl azodicarboxylate to the morpholine enamine of cyclohexanone furnished the less substituted isomer (34) with the substituent in the axial orientation (2, 26). 

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. 

Campbell and Jung (34) have reported that the reaction of 2 moles of o-halo-substituted benzoyl chloride with the morpholine enamine of cyclohexanone gave the corresponding 2,2-dibenzoyI derivative (57). 

The piperidine, pyrrolidine, and morpholine enamines of cyclohexanone substituted in the 3-position by methyl, phenyl, and l-butyl have been prepared (49). The complexity of the NMR spectra in the ethylenic hydrogen region indicated a mixture of isomeric enamines. Estimation of the per cent of each isomer by examination of the NMR spectra was not possible, nor were the isomeric enamines separable by vapor-phase chromatography. 

In the acylation of enamines derived from 3-substituted cyclohexanones, 6-acylated products were favored over 2-acylated products (398), thus revealing another selective enamine reaction sequence. The use of oxalyl bromide for the acylation of enamines has also been described (399). 

The Michael additions of chiral cycloalkanone imines or enamines, derived from (FV l-l-phcnyl-ethanamine or (5)-2-(methoxymethyl)pyrrolidine, are highly diastereofacially selective reactions providing excellent routes to 2-substituted cycloalkanones. This is illustrated by the addition of the enamine of (S)-2-(methoxymethyl)pyrrolidine and cyclohexanone to 2-(aryl-methylene)-l,3-propanedioates to give, after hydrolysis, the (2 5,a.S )-oxodicstcrs in 35-76% yield with d.r. (2 S,aS)/(2 S,a/ ) 94 6- > 97 3 and 80-95% ee214. 

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. 

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... 

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). 

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>... 

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