From Cyclobutyl Derivatives

Conversion of oximes derived from cyclobutyl ketones to amides represents the classic Beckmann rearrangement. One example of this reaction is the formation of optically active 7,7-dimethyl-2-azabicyclo[4.1.1]octan-3-one (1) from 6,6-dimethylbicyclo[3.1.1]heptan-2-one oxime, which is readily derived from /3-pinene.40... 

SCHEME 12. Isodesmic reactions based on cyclobutyl derivatives 49-52. Reaction energies from MINDO/3 (first entry) and EHT calculations (second entry) in kcal mol173... 

On the other hand, cyclobutyl compounds are not obtained from cyclopropylmethyl derivatives with carbenium ion stabilizing substituents on the carbinyl carbon. For example, reactions of methylcyclopropyl methanol (101) with acidic reagents led to unrearranged or on further heating to 3-penten-l-yl derivatives (equation 70) . 

Changing the medium drastically from water to pentane, does not significantly affect the reaction course, and the cyclopropane derivatives still account for ca. 94 % of the products in this reaction . On the other l nd, cyclobutyl derivatives are the sole products in the acid-catalyzed hydration of 3-methylbicyclobutanecarbonitrile (equation 54) and in the methanolysis of methyl 3-methylbicyclobutanecarboxylate (equation 55) . ... 

There are very few examples of ring contraction from cyclobutyl to cyclopropyl. Irradiation of a benzene solution of 2-diazo-3,4-bis(diphenylmethylene)cyclobutanone (60) in the presence of water, methanol, 2-propanol or aniline afforded the carboxylic acid derivatives (61) in 13, 87, 75 and 45% yield respectively. Thermolysis of an aqueous dioxane solution of (60) surprisingly gave (61 XR = OH) in higher yield (52% equation 20). ... 

Both the selenoxide and the selenonium ylide routes have been applied to cyclobutyl derivatives, themselves readily available 57) from selenoacetals of cyclo-butanones on one hand and primary alkyl halides, epoxides, or carbonyl compounds on the other. 

The solvolysis of both cyclopropylcarbinyl and cyclobutyl derivatives proceeds with rearrangement to give mixtures of cyclopropylcarbinyl (515), cyclobutyl (516), and allylcarbinyl derivatives (517)401,402. Under certain conditions the product distributions are very similar, starting from either (57. ) or (514) (Table 16). These data... 

Table 16. Products from S jl reactions of cyclopropylcarbinyl and cyclobutyl derivatives...

Another example, pubhshed by scientists from Parke-Davis, relates to a series of dipeptoid analogs of chole-cystokinin. These compounds are a-methyl-tryptophan derivatives, N-substituted by carbamic esters of cyclanols with ring sizes increasing from cyclobutyl to cyclodo-decyl (Figure 14.3). Here again an optimal size was found (cyclononyl). 

It is interesting to note that the latter result is exceptional since l,l-bis(phenyl-seleno)cyclopropane is the only selenoacetal derived from ketones to be at least partially cleaved under these conditions and even the homologous cyclobutyl derivative is inert under these conditions. This may be due to the extra stabilization introduced by the cyclopropyl ring. The case of 2-decy 1-1,1-bis(methylseleno)cyclo-propane merits further comment. It is difficult to assess whether the cleavage of the carbon-selenium bond occurs on the methylseleno moiety cis or tram to the alkyl group, since this organometallic leads to a mixture of the two possible stereoisomers on further reaction with electrophiles (Scheme 16). 

It is also evident from the data of Bly et al. (95), Jacobs and Macomber (91), and Garry and Vessiere (99) that neopentyl-type homoallenic systems do not yield cyclopropyl derivatives upon solvolysis, in contrast to the unsubstituted parent system. If they have no substituents at Cj or C3, neopentyl homoallenic substrates yield rearranged acyclic olefins and rearranged solvent-incorporated products exclusively. If they carry an alkyl substituent at Ci, they give both rearranged and unrearranged acyclic products. If a substituent is present on C3 besides the acyclic derivatives, cyclobutyl products also are formed. 

The construction of cyclopentanones can take several avenues based upon the concepts evolving from use of small ring conjunctive reagents. A very simple one is a-cuparenone (183) which can be thought to derive by a ring expansion of a cyclobutyl carbinyl system as in 184 (Scheme 8) 110,1U). If X. is an anion stabilizing... 

Scheme 3 - Product distribution from solvolysis of cyclopropylcarbinyl cyclobutyl and allylcarbinyl derivates.

Archibald and co-workers have explored the synthesis of polynitrocyclobutanes and then-derivatives. The synthesis of these compounds via the nucleophilic substitution of cyclobutyl halides with nitrite anion was ruled out at an early stage because displacement in this system is too slow for practical use. This is a consequence of the molecular strain in the cyclobutane ring, which causes carbon atoms to deviate from sp hybridization towards sp character. 

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