Cyclobutanes from cycloadditions

The reaction of methyl or ethyl acrylate with the enamine of an alicyclic ketone results in simple alkylation when the temperature is allowed to rise uncontrolled in the reaction mixture (7,34,35). If the reaction mixture is kept below 30°C, however, a mixture of the simple alkylated and cyclobutane (from 1,2 cycloaddition) products are obtained (34). Upon distillation of this mixture only starting material and simple alkylated product is obtained because of the instability of the cyclobutane adduct. 

In contrast, aminoallenes, e.g. 30, undergo cydoaddition with acrylates and acrylonitrile giving cyclobutanes 31 resulting from cycloaddition to the more substituted double bond.23... 

A special case of the preparation of cyclobutanes from 1,5-dienes via valence isomerization is the use of acyclic or cyclic 1,5,7-trienes which give four-membered rings via an intramolecular [7t + 7ts2] cycloaddition (Diels-Alder reaction). This variant is illustrated for monocyclic tricnes 18 and 20 where two 71-bonds are transformed into a-bonds, resulting in tricyclic compounds 1968 and 21.09... 

Alkyl tethered alcohols such as D-mannitol and L-erythritol [20], have been used to bring cinnamyl units together for photocycloadditions. However, this probably involves cycloaddition between an excited enone moiety and the tethered alkene. Other examples of carbon linked alkenes include perhaps the earliest example of alkene+alkene photocycloaddition. Liu and Hammond [21] reported the formation of cyclobutane from the triplet irradiation of myrcene (see Sch. 11). 

Cycloaddition of electrophilic alkenes to enamines, at low temperatures and under aprotic conditions, is a well documented method for the formation of cyclobutanes from... 

The Lewis acid-promoted reactions of acrylates and propiolates with allylsilanes usually afford [2-1-2] adducts as described in the next section [470-473]. The corresponding [3-1-2] adducts are obtained as minor products although there are a few exceptions. The ratio of the two kinds of cycloadduct depends on the reaction temperature [470] - the proportion of [3-1-2] adducts increases with increasing temperature. The product ratio from cycloaddition to alkylidenemalonates and their derivatives is markedly temperature-dependent (Scheme 10.170) [474, 475]. Cyclobutanes are major products at low temperature, and [3-1-2] cycloaddition proceeds predominantly at higher temperature. In addition, the [2-1-2] cycloadducts are smoothly isomerized to the [3-1-2] adducts in the presence of a Lewis acid. This behavior clearly shows that [3-1-2] cycloaddition is thermodynamically favored. 

The photoaddition of allenic esters (31) to the enone (32) has been studied. The major products from these reactions are the dienes (33) and the cyclobutanes (34) and (35). It seems likely that the addition proceeds by the traditional biradical path to an intermediate such as (36). Dis-proportionation affords (33) while C-C bond formation yields the two cyclobutanes.The cycloaddition of isobutylene to the enone (37a) in a variety of solvents affords the adduct (38, 20-40X) and the alkylated... 

A similar problem is the determination of the amounts of cis and trans (or syn and anti) di- or polysubstituted cyclobutanes from 1,2-cycloaddition of olefins gas chromatography is frequently used in such cases - but also uv and F-nmr spectroscopy has been employed. 

The formation of cyclobutanes from alkenes by radical pathways was established by the work of Bartlett and co-workers. For example, l,l-dichloro-2,2-difluoroethene undergoes nonstereospecific cycloaddition with frflus,frans-2,4-hexadiene at 100°C to give an 82 18 mixture of diastereomeric cyclobutanes ... 

As final examples, the intramolecular cyclopropane formation from cycloolefins with diazo groups (S.D. Burke, 1979), intramolecular cyclobutane formation by photochemical cycloaddition (p. 78, 297f., section 4.9), and intramolecular Diels-Alder reactions (p. 153f, 335ff.) are mentioned. The application of these three cycloaddition reactions has led to an enormous variety of exotic polycycles (E.J. Corey, 1967A). 

Fluorinaied dienophiles. Although ethylene reacts with butadiene to give a 99 98% yield of a Diels-Alder adduct [63], tetrattuoroethylene and 1,1-dichloro-2,2-difluoroethylene prefer to react with 1,3-butadiene via a [2+2] pathway to form almost exclusively cyclobutane adducts [61, 64] (equation 61). This obvious difference in the behavior of hydrocarbon ethylenes and fluorocarbon ethylenes is believed to result not from a lack of reactivity of the latter species toward [2+4] cycloadditions but rather from the fact that the rate of nonconcerted cyclobutane formation is greatly enhanced [65]... 

In the case of enamines derived from aldehydes a cycloaddition to give a cyclobutane occurs (48-50). Thus the enamine (16) reacted with methyl acrylate in acetonitrile to give a 91 % yield of methyl 2-dimethylamino-3,3-dimethylcyclobutane carboxylate (56). Similarly, treatment of (16) with diethylmaleate at 170° gave a 70% yield of diethyl 4-dimethylamino-3,3-dimethyl-l,2-cyclobutanedicarboxylate (57), and 16 and acrylonitrile gave a 65% yield of 2-dimethylamino-3,3-dimethylcyclobutanecarbonitrile (58). 

The initial product formed when methyl vinyl ketone is mixed with an enamine [such as N,N-dimethylisobutenylamine (10)] is the dihydropyran (11) from a 1,4 cycloaddition (ll,20a,20b). The chemical reactions that the dihydropyran undergoes indicate that it is readily equilibrated with the cyclobutane isomer 12a and zwitterion 12 (11). Treatment of adduct 11 with phenyllithium gives cyclobutane 13, possibly via intermediate 12a (11). 

Olefins conjugated with electron-withdrawing groups other than a carbonyl group undergo reactions with enamines in a manner similar to the carbonyl-conjugated electrophilic alkenes described above. Namely, they condense with an enamine to form a zwitterion intermediate from which either 1,2 cycloaddition to form a cyclobutane ring or simple alkylation can take place. 

Nitroolefins also offer the possibilities of 1,2 cycloaddition (37,57) or simple alkylation (57-59) products when they are allowed to react with enamines. The reaction of nitroethylene with the morpholine enamine of cyclohexanone led primarily to a cyclobutane adduct in nonpolar solvents and to a simple alkylated product in polar solvents (57). These products are evidently formed from kinetically controlled reactions since they cannot be converted to the other product under the conditions in which the other... 

From a preparative point of view, the photochemical [2 + 2] cycloaddition is the most important of the photochemical reactions especially the cycloaddition involving enones. The [2 + 2] cycloaddition is the method of choice for the construction of cyclobutane derivatives as well as cyclobutane units within larger target molecules. 

A key step in the synthesis in Scheme 13.11 was a cycloaddition between an electron-rich ynamine and the electron-poor enone. The cyclobutane ring was then opened in a process that corresponds to retrosynthetic step 10-IIa 10-IIIa in Scheme 13.10. The crucial step for stereochemical control occurs in Step B. The stereoselectivity of this step results from preferential protonation of the enamine from the less hindered side of the bicyclic intermediate. 

Cyclopentadiene adds to dimethylmaleic anhydride to produce cyclobutane dimer (84) and two products from l,4-cycloaddition<97) ... 

Endo product (86) is thought to result from thermal addition and is probably not a photoproduct. Cyclohexadiene yields cyclobutanes (87)—(89) and 1,4-cycloaddition product (90) with dimethylmaleic anhydride(87> ... 

The observation that the overwhelming product from the cycloaddition of 3 to 1,3-butadiene (12) is a cyclobutane derivative 31 and the proportion of the [4 -I- 2] adduct increases in the order 12 < 26 6 is in accord with the increasing diene reactivity in this series. Whereas cyclopentadiene readily combines with most dienophiles at low temperatures, 1,3-butadiene, mainly owing to its predominant s-trans conformation, enters into [4 + 2] cycloadditions only at elevated temperatures. 

The cycloadditions in entries 1-3 are still believed to occur via a diradical stepwise pathway, as confirmed by obtaining a thermodynamic 78 22 trans/cis mixture of dispirooctanes 536 from frans-dicyanoethylene (533) (entry 3) [13b, 143], The cycloaddition to tetracyanoethylene (131) in the absence of oxygen gives only low yields of the [2 + 2] adduct, due to the simultaneous formation of products 542 and 543 (Scheme 74) [13b]. Still, the formation of the cyclobutanes 537 and 542 is noteworthy, since the reactions of TCNE with phenyl substituted MCPs exclusively afford methylenecyclopentane derivatives [37,144], The reaction is thought to occur via dipolar intermediates 539-541 formed after an initial SET process (Scheme 74) [13b]. The occurrence of intermediates 540 and 541 has been confirmed by trapping experiments [13b]. 

The Lewis acid catalyst 53 is now referred to as the Narasaka catalyst. This catalyst can be generated in situ from the reaction of dichlorodiisopropoxy-titanium and a diol chiral ligand derived from tartaric acid. This compound can also catalyze [2+2] cycloaddition reactions with high enantioselectivity. For example, as depicted in Scheme 5-20, in the reaction of alkenes bearing al-kylthio groups (ketene dithioacetals, alkenyl sulfides, and alkynyl sulfides) with electron-deficient olefins, the corresponding cyclobutane or methylenecyclobu-tene derivatives can be obtained in high enantiomeric excess.18... 

Several other types of photochemical reactions involving unsaturated carbohydrates have been reported. One of these is38 photochemical, E -Z isomerization of the groups attached to a double bond (see Scheme 5). A second is the internal cycloaddition between two double bonds connected by a carbohydrate chain.39-41 Although the carbohydrate portion of the molecule is not directly involved in this cycloaddition, its presence induces optical activity in the cyclobutane derivatives produced photochemically. Finally, a group of acid-catalyzed addition-reactions has been observed for which the catalyst appears to arise from photochemical decomposition of a noncarbohydrate reactant.42-44... 

So summarizing we see that in thermal [2 + 2] cycloaddition, a supra-supra process is geometrically possible but symmetry forbidden. But in supra-antar process, symmetry is allowed but geometrically difficult. Now we have to explain how the photochemical formation of cyclobutane takes place from 2n components. 

A cycloaddition reaction produces a ring of atoms by forming two new G-bonds, for example the formation of a cyclobutane dimer from two alkene molecules. The direct photoreaction involves the concerted reaction of the singlet Jtpt ) excited state of one alkene with the ground state of the other. Stereospecific reactions in which the dimers preserve the ground-state geometry occur when liquid cis- or trans-but-2-ene are irradiated at low temperature ... 

An interesting reaction that has been developed over the past decade is the application of (2 + 2)-cycloaddition reactions to the synthesis of cyclophanes49. One of the earliest examples of this is the selective conversion of the bis(arylalkenes) 112 into the adducts 113. The yield of product is dependent to some extent on the chain length separating the aryl groups and the best yield of 41% is obtained when the separation includes four methylene units (n = 4). Lower yields are recorded with the other derivatives. Mixtures of products are formed when the m-isomers 114 are used. This affords 115 and 116. The yields of these are better than those obtained from the p-isomers 11250 51. Nishimura and coworkers52 have examined the ease with which such cyclobutanes, e.g. 115, n = 2,... 

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