Other Reactions Leading to Cyclobutanes

The ring-opened intermediates, which are known as oxyallyl cations, can also be generated by a number of other reaction processes.97 98 99 100 

For reviews, see W. T. Brady in The Chemistry of Ketenes, Allenes, and Related Compounds, S. Patai, ed., John Wiley Sons, New York, 1980, Chapter 8 W. T. Brady, Tetrahedron 37 2949 (1981). 

Intramolecular ketene cycloadditions are possible if the ketene and alkene functionalities can achieve an appropriate orientation.108 

Cyclobutanes can also be formed by nonconcerted processes involving zwitterionic intermediates. The combination of an electron-rich alkene (enamine, enol ether) and a very electrophilic one (nitro- or polycyanoalkene) is required for such processes. 

The stereochemistry of these reactions depends on the lifetime of the dipolar intermediate, which, in turn, is influenced by the polarity of the solvent. In the reactions of enol ethers with tetracyanoethylene, the stereochemistry of the enol ether portion is retained in nonpolar solvents. In polar solvents, cycloaddition is nonstereospecific, as a result of a longer lifetime for the zwitterionic intermediate.112 

Ketenes are especially reactive in [2 + 2] cycloadditions, and an important reason is that they offer a low degree of steric interactions in the transition state. Another reason is the electrophilic character of the ketene LUMO. The best yields are obtained in reactions in which the ketene has an electronegative substituent, such as halogen. Simple ketenes are not very stable and usually must be generated in situ. The most common method for generating ketenes for synthesis is by dehydrohalogenation of acyl chorides. This is usually done with an amine such as triethylamine. Other activated carboxylic acid derivatives, such as acyloxypyridinium ions, have also been used as ketene precursors  

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Two questions immediately arise. First, why do some of these reactions lead to cyclohexenes and others to cyclobutanes And secondly, are the two new bonds formed simultaneously in one step or separately in two distinct steps ... 

The isodesmic reaction conserves the number of bonds of a given formal type. This is accomphshed by choosing reference molecules that contain two heavy atoms, preserving the formal bond between them. The four C-C bonds of cyclobutane are preserved in the reference as four ethane molecules. Cyclobutene, having one C=C and three C-C bonds, needs a molecule of ethene and three molecules of ethane as reference. The two C-0 bond and two C-C bonds of oxetane translate into two molecules of ethanol and two molecules of ethane. Balancing the reaction to conserve all other bonds leads to the isodesmic Reactions 3.9i-3.11i. 

One of the most prevalent examples of reaction involving DNA excited states is pyrimidine-pyrimidine dimer formation. Thymine and cytosine are the two pyrimidine bases present in DNA, and pyrimidine-pyrimidine dimers can form between any combination of these two bases. The most common of these is the thymine-thymine (TT) dimer [4-7]. Two types of TT dimers are known (shown in Fig. 13.1). The first, and sole focus of this chapter due to its prevalence, is called cyclobutane pyrimidine dimer (CPD) and is formed by the [2-1-2] addition of the C5-C6 double bonds. The second is called the 6 photoadduct and is formed by the addition of the C5-C6 double bond on one thymine to the C4-04 double bond on the other. This leads to an oxetane intermediate that subsequently rearranges to form the 6-4 product. Both of these photoproducts are thought to form starting with initial excitation to a state. There is some debate in the literature... 

The direct irradiation of the parent coumarin in the presence of alkenes results only in an inefficient photodimerization and [2 + 2]-photocycloaddition. Lewis acid coordination appears to increase the singlet state lifetime, and leads to improved yields in the stereospecific [2 + 2]-photocycloaddition [95]. Alternatively, triplet sensitization can be employed to facilitate a [2 + 2]-photocycloaddition. Yields of intramolecular [2 + 2]-photocycloadditions remain, however, even with electron-rich alkenes in the medium range at best. The preference for HT addition and for formation of the exo-product is in line with mechanistic considerations discussed earlier for other triplet [2 + 2]-photocycloadditions [96, 97]. Substituted coumarins were found to react more efficiently than the parent compound, even under conditions of direct irradiation. 3-Substituted coumarins, for example, 3-methoxy-carbonylcoumarin [98], are most useful and have been exploited extensively. The reaction of 3-ethoxycarbonylcoumarin (100) with 3-methyl-l-butene yielded cleanly the cyclobutane 101 (Scheme 6.36) with a pronounced preference for the exo-product (d.r. = 91/9). Product 101 underwent a ring-opening/ring-closure sequence upon treatment with dimethylsulfoxonium methylide to generate a tetrahydrodibenzofur-an, which was further converted into the natural product ( )-linderol A (102) [99]. 

One of the best-studied solid-state reactions is the photopolymerization of distyrylpyrazine (9) and related compounds to give crystalline polymers containing cyclobutane rings (Scheme 10). This reaction is reminiscent of Schmidt s early work on cinnamic acids, although the presence of two double bonds per monomer can lead to oligomeric or polymeric rather than solely dimeric products. The four-center reaction of 9, and other related polymerizations, have been reviewed in detail by Hasegawa, who has played a central role in the study of these systems... 

Cyclobutanes may be converted to alkenes thermally, the reverse of the [2 + 2] cycloaddition reaction. These retroaddition or cycloreversion reactions have important synthetic applications and offer further insights into the chemical behavior of the 1,4-diradical intermediates involved they may proceed to product alkenes or collapse to starting material with loss of stereochemistry. Both observations are readily accommodated by the diradical mechanism. Generation of 1,4-tetramethylene diradicals in other ways, such as from cyclic diazo precursors, results in formation of both alkenes and cyclobutanes, with stereochemical details consistent with kinetically competitive bond rotations before the diradical gives cyclobutanes or alkenes. From the tetraalkyl-substituted systems (5) and (6), cyclobutane products are formed with very high retention stereospecificity,while the diradicals generated from the azo precursors (7) and (8) lead to alkene and cyclobutane products with some loss of stereochemical definition. ... 

Two major side reactions compete with the coupling reaction protonation of the radical anion followed by further reduction and protonation leading to the saturated dihydro product, and polymerization induced by the basic dianion formed by coupling of two radical anions. Other, less typical reaction pathways include reaction between a radical anion and a molecule of substrate. Scheme 2, dimerization of two radicals formed by protonation of the initial radical anion. Scheme 3, or, infrequently, cleavage of the radical anion followed by coupling. However, for radical anions derived from monoactivated alkenes, the pathway in Scheme 2 has only been unequivocally established as a major pathway in a few cases in which the final zero-electron product is a cyclobutane, that is, a cycloaddition product. 

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