Cyclohexanone enamines

Diacetates of 1,4-butenediol derivatives are useful for double allylation to give cyclic compounds. l,4-Diacetoxy-2-butene (126) reacts with the cyclohexanone enamine 125 to give bicyclo[4.3.1]decenone (127) and vinylbicy-clo[3.2.1]octanone (128)[85,86]. The reaction of the 3-ketoglutarate 130 with cij-cyclopentene-3,5-diacetate (129) affords the furan derivative 131 [87]. The C- and 0-allylations of ambident lithium [(phenylsulfonyl)methylene]nitronate (132) with 129 give isoxazoline-2-oxide 133, which is converted into c -3-hydroxy-4-cyanocyclopentene (134)[S8]. Similarly, chiral m-3-amino-4-hyd-roxycyclopentene was prepared by the cyclization of yV-tosylcarbamate[89]. 

The reaction of vinylogous amides, or ketoaldehydes, with hydroxylamine produced 4,5,6,7-tetrahydro-l,2-benzisoxazole. A side product is the 2,1-benzisoxazole (Scheme 173) (67AHC(8)277). The ring system can also be prepared by the reaction of cyclohexanone enamines with nitrile oxides (Scheme 173) (78S43, 74KGS901). Base treatment produced ring fission products and photolysis resulted in isomerization to benzoxazoles (76JOC13). 

These steric factors are also indicated by the relative basicity of enamines derived from five-, six-, and seven-membered ketones. The five- and seven-membered enamines are considerably stronger bases, indicating better conjugation between the amine lone pair and the double bond. The reduced basicity of the cyclohexanone enamines is related to the preference for exo and endo double bonds in six-membered rings (see Section 3.10). 

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). 

Acryloyl chloride can be used to cause ring enlargement with the production of a bicyclodiketone when it is treated with a cyclohexanone enamine. This is shown by the reaction of acryloyl chloride (25) with 1-N-morpholino-1-cyclohexene (26), affording diketone 27 upon hydrolysis (32,33). 

Methyl vinyl sulfone forms 1,2-cycloaddition adducts with aldehydic enamines, both with and without 3 hydrogens (37). Simple alkylation was reported to take place when phenyl vinyl sulfone was allowed to react with cyclohexanone enamines (58,60), but it has recently been shown that phenyl vinyl sulfone also forms cyclobutane adducts (60a). 

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. 

In the reactions of arylsulfenyl chlorides with enamines one encounters an unusual result for enamine chemistry, in that the formation of 2,6-disubstituted cyclohexanone enamines predominates over the formation of monosubstitution products 474). A rationalization of this result suggests the formation of an intermediate which can act as an intramolecular electrophile in formation of the second carbon-sulfur bond. 

The potential of Fischer carbene complexes in the construction of complex structures from simple starting materials is nicely reflected in the next example. Thus, the reaction of alkenylcarbene complexes of chromium and tungsten with cyclopentanone and cyclohexanone enamines allows the di-astereo- and enantioselective synthesis of functionalised bicyclo[3.2.1]octane and bicyclo[3.3.1]nonane derivatives [12] (Scheme 44). The mechanism of this transformation is initiated by a 1,4-addition of the C -enamine to the alkenylcarbene complex. Further 1,2-addition of the of the newly formed enamine to the carbene carbon leads to a metalate intermediate which can... 

Phenyl vinyl sulfones reacted with cyclohexanone enamines 332 to afford adducts which, upon hydrolysis, gave 2-(2-phenylsulfonyl)alkylcyclohexanone 333a . However, in the reaction with phenyl styryl sulfone, two products 333b and 334 were obtained by the nucleophilic attack at the and a-carbon atoms . Steric effects, electrostatic interactions between the nitrogen atom of the enamine and the oxygen atoms of the sulfone group, and medium effects contribute to the regioselectivity of the reaction. ... 

Scheme 33 illustrates the difference in reactivity between triazolines obtained from cyclohexanone and cyclo-pentanone enamines. Thus, the reactions of azidophosphonates 239 with cyclohexanone enamines produce unstable aminotriazolines 240 that cannot be isolated due to their spontaneous elimination of amines to provide triazoles 241. Contrary to that, triazolines 242, derived from cyclopentanone enamines, are isolated in good yield (76-88%) and cannot be converted to the corresponding triazoles even by thermolysis <1995H(40)543>. Probably, introduction of a double bond between two five-membered rings would involve too much molecular strain. 

Although reasonable asymmetric induction has been observed in the alkylation of a chiral cyclohexanone enamine, it was noted1 in 1977 that in order to obtain higher induction in this type of reaction. Clearly what is needed is an amine with a C2 axis of symmetry . (+ )-trans-... 

It has been reported80 that cyclohexanone enamines (39) can be converted into the jS-hydroxyamines (40) by successive treatment with diborane and hydrogen peroxide. The method has been used81 to convert berberine [(41) R + R = CH202] into the ophiocarpines (42)... 

Bobbitt et al.113 reported that when benzylaminoacetaldehyde dialkyl acetals (18) are heated under reflux with concentrated hydrochloric acid and ethanol, in the presence of benzaldehyde, good yields of the 4-benzylisoquinoline derivatives (85), via the 1,2-dihydroisoquinoline (82), can be isolated. A mechanism for this reaction114 is summarized in Scheme VI. With cyclohexanone enamine and aldehydes, the intermediate has been formulated115 as 86. It was originally reported114 that an intermediate of the... 

While the Reissert reaction is a convenient method for introducing a cyano substituent into the position a to the nitrogen atom in thienopyridines, a method has been developed to introduce substituents into the position y to the nitrogen atom. Thus, acetic anhydride/ethyl cyanoacetate or benzoyl chloride/cyclohexanone enamine reagents were useful for preparing ethyl 2-(4-thieno[2,3-6]pyridyl)cyanoacetate (53) or 2-(4-thieno[2,3-6]pyridyl)cyclohexanone (54), respectively (Scheme 13) <84JHC1135, 87JHC1467). 

Complex 9 and [CpFe(o-BPXCO)CH 2C1 ] [o-BP = tri(o-biphenyl)-phosphite] were also prepared by the reaction of HC1 with [CpFe(L)-(CO)CH2OEt] (L = PPh3, o-BP) (47). Alkylation of the two complexes with sodium /crt-butyl acetoacetate and pyrroline cyclohexanone enamine yielded six of the eight possible alkylation products. The two products where L was o-BP and the nucleophile was tort-butyl acetoacetate did not form, presumably because of excessive steric hindrance. The excess of one diastereomer over the other ranged from 10 to 64%. 

As pointed out by Stork and coworkers in their definitive 1963 paper3, the reaction with electrophilic alkenes is especially successful since reaction at nitrogen is reversible. Reaction at the /2-carbon is (usually) rendered irreversible by, in the case of cyclohexanone enamines, internal proton transfer of the axial C-/2 proton to the anionic centre of the initially formed zwitterionic intermediate (34), under conditions of stereoelectronic control (Scheme 22). When this intramolecular proton transfer cannot occur in aprotic solvents, or when the product produced in protic solvents is a stronger carbon acid than adduct 35 (i.e. when Z = COR, N02), then carbon alkylation is also reversible and surprising changes in the regioselectivity of reaction may be observed (vide infra see also Section VI.D and Chapter 26). Cyclobutanes (36) and, in the case of a,/ -unsaturated... 

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)... 

Tetracyanoethylene is unusual in that it reacts with cyclohexanone enamines to give a five-membered ring instead of a cyclobutane adduct. Reaction occurs at the y-position of the enamine and an initial one-electron transfer between the two reactants is... 

Returning to the unsubstituted cyclohexanone enamine, the use of ethanol as solvent instead of benzene favours 2,6-dialkylation. In addition to the octalone dienamines this has resulted in the isolation of the tricyclic dione 149293 (Scheme 135). The same ring... 

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... 

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