Cyclobutanes, substitution with

Sila- and Germa-cyclobutanes Substituted with Oxygen, Sulfur, Nitrogen or Phosphorus 596... 

Wehle, D. Fitjer, L. Tetrahedron Lett., 1986, 27, 5843, have succeeded in producing two conformers that are indefinitely stable in solution at room temperature. However, the other five positions of the cyclohexane ring in this case are all spiro substituted with cyclobutane rings, greatly increasing the barrier to chair-chair interconversion. 

In 1988 Heinze and Burton reported a facile synthesis of various a,p,P-trifluorostyrenes.15 These trifluorostyrene compounds were reported to be unstable to cyclodimerization at room temperature when stored neat, especially the compounds that were /lura-substituted with electron-donating substituents. They described the preparation of one compound, l,4-bis(trifluorovinyl)benzene with the observation that the material gelled when allowed to stand neat overnight. They offered the explanation that the gel was a polymer network connected with flnorinated cyclobutanes. Burton later went on to utilize this dimerization reaction for the cross-linking of polyimide thermoplastics.16... 

Thus, to achieve mirror-symmetric or centrosymmetric cyclobutane derivatives, one would start with monomers that are substituted with dichloro groups or amide functions, respectively. Both the chlorines and the amide groups can subsequently be removed readily, without affecting the stereochemistry of the ring. 

Polynitro derivatives of pentacyclo[5.4.0.0 .0 °.0 ]undecane have attracted interest as potential high-energy explosives. Molecular strain in this caged system could arise from both the constrained norbomyl moiety and the cyclobutane ring. Additional strain would be expected from nonbonding interactions if the S-endo and 1 l-endo positions were substituted with gm-dinitro groups. 

Chiral cyclobutanes can be prepared by cycloaddition of alkenes substituted with one or more chiral auxiliary groups. A diastereofacial selectivity of 95% was observed in the diethylalu-minum chloride catalyzed cycloaddition of 1,1-dimethoxyethene (36) with ( — )-dimenlhyl-3-yl fumarate (37).16 The chiral cyclobutane 38 has been used as an intermediate in the synthesis of carbocyclic oxetanocin analogs. 

Alkenes substituted with an electron-withdrawing (Z) and an electron-donating group (X) will be less reactive than the unsubstituted alkene if the substituents are vicinal (Z-C=C-X push-pull alkenes), but will generally become highly reactive when these two substituents are bound to the same carbon atom. The latter type of alkene (ZXC=CR2 1,1-captodative alkenes) readily dimerize to yield cyclobutanes and can react with 1,3-dienes to yield products of [2 + 2] and/or [2 + 4] cycloaddi-... 

Cyclobutanes can be formed by intramolecular addition of carbanions or radicals to C-C double bonds only if the latter are substituted with electron-withdrawing groups (see, e.g., Schemes 9.20 and 9.21) [81] or otherwise activated toward attack by nucleophiles. Activation by an alkynyl group or a cumulated double bond can be sufficient to promote cydobutane formation (Scheme 9.20). Unactivated alkenes, however, do not usually undergo cydization to cyclobutanes via intramolecular addition of carbanions or radicals. 

Some captodative olefins homodimerize near room temperature [141,144-146] and an intramolecular example is also known (Scheme 4) [147]. These [2 + 2]-cycloadditions are often reversible. The unfavorable entropic contribution and the strain in the cyclobutane derivative can operate in the same direction so that the cycloaddition becomes thermodynamically impossible. Even when substituted with relatively small groups, a cyclobutane can cleave back into the starting... 

While the irradiation of substituted cyclopentenones in aqueous environment gives cyclobutane dimers with a ratio of head-to-head (HH) to head-to-tail (HT) of about one, the same photoreaction in potassium decylanoate (KDC) gives the cyclobutane dimer which is almost exclusively HH (Scheme XIX) 49). The dependence of the HH/HT ratio as a function of surfactant concentration shows a dramatic increase in the ratio at the reported CMC value. The regioselectivity is attributed to the carbonyl groups being oriented in the Stem layer with the olefin extending into... 

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. ... 

Treatment of diester 10 with diethyl oxalate in the presence of base gave the disodium salt 11, which was thereafter alkylated to afford the tetrasubstituted thiophene 12. This material was subsequently used as a precursor for preparation of 3,4-dimethoxythiophene 9 <04T10671>. In a similar series of reactions involving glyoxal and suitable sulfides, several cyclobutane substituted 2,5-diacylthiophenes were synthesized <04HC26>. 

Cyclobutylidene derivatives have been regio- and stereoselec-tively reduced to substituted vinyl cyclobutanes with Pd(dba)2 and sodium formate. Heteroaryl benzylic acetates (including 2° acetates) undergo Pd-catalyzed benzylic nucleophilic substitution with malonate nucleophiles. Cyclobutanone O-benzoyloximes have been converted to a variety of nitrile derivatives using Pd(dba)2 in combination with chelating phosphines (eq 27). ... 

It is interesting to see the pressure dependence of hot tritium reaction in cyclobutane C4H8. Recoil tritium attacks this molecule to give tritiated cyclobutane (substitution reaction) in an excited state, which either stabilizes by collision with a third body or decomposes into two molecules of ethylene. This is shown in the following scheme ... 

In benzene solution, the Z- and E-stilbenes 42 form approximately equal amounts of the two regioi-somers of the fra s-substituted spiro-oxetanes (e.g., 43 from 4-Me-42) with CA in yields of 80 to 88%. These addition reactions do not occur in acetonitrile solution and Z- and -4-methoxystilbenes do not photoreact with CA in either solvent. However, high yields of the fra s-spiro-oxetanes 44 are formed from CA with Z- or E-ethyl cinnamate, ethyl 3-nitrocinnamate, benzalacetone, or chalcone in both benzene and acetonitrile. In contrast, allyl ethyl ether, methyl methacrylate, vinyl acetate, styrene, and a-chlorostyrene all yield cyclobutanes 45 with CA in benzene solution but under the same conditions, indene and E-(3-bromostyrene afford spiro-oxetanes. Such variation in reaction site continues to be discussed in terms of the electron-donor/acceptor characteristics of the addends and the role of single electron transfer in the reaction pathway. 

As mentioned in the previous section, substituted norbornadienes can proceed [2+2] cycloaddition with highly reactive dienophiles (maleic imide or strained alkene) in the presence of a nickel (0) catalyst leading to the formation of cyclobutane derivatives. With less reactive dienophiles, the reaction seems to be prone to [2+ 2+ 2] cycloaddition giving homo-Diels-Alder reaction products. These two types of reactions appear to be competitive in certain cases to give a mixture of products [130-133]. 

The photosensitized dimerization of isoprene in the presence of henzil has been investigated. Mixtures of substituted cyclobutanes, cyclohexenes, and cyclooctadienes were formed and identified (53). The reaction is beheved to proceed by formation of a reactive triplet intermediate. The energy for this triplet state presumably is obtained by interaction with the photoexcited henzil species. Under other conditions, photolysis results in the formation of a methylcydobutene (54,55). 

Thermal decomposition of cis- and frans-3,6-dimethyl-3,4,5,6-tetrahydropyridazines affords propene, cis- and frans-l,2-dimethylcyclobutanes and 1-hexene. The stereochemistry of the products is consistent with the intermediacy of the 1,4-biradical 2,5-hexadienyl. The results indicate that thermal reactions of cyclic azo compounds and cyclobutanes of similar substitution proceed with similar stereospecificity when compared at similar temperatures 79JA2069). 

Thus the reactions of cyclic or acyclic enamines with acrylic esters or acrylonitrile can be directed to the exclusive formation of monoalkylated ketones (3,294-301). The corresponding enolate anion alkylations lead preferentially to di- or higher-alkylation products. However, by proper choice of reaction conditions, enamines can also be used for the preferential formation of higher alkylation products, if these are desired. Such reactions are valuable in the a substitution of aldehydes, which undergo self-condensation in base-catalyzed reactions (117,118). Monoalkylation products are favored in nonhydroxylic solvents such as benzene or dioxane, whereas dialkylation products can be obtained in hydroxylic solvents such as methanol. The difference in products can be ascribed to the differing fates of an initially formed zwitterionic intermediate. Collapse to a cyclobutane takes place in a nonprotonic solvent, whereas protonation on the newly introduced substitutent and deprotonation of the imonium salt, in alcohol, leads to a new enamine available for further substitution. 

The alkylation of enamines with nitroolefins, which gives intermediates for reductive cyclization (6S2), also provided an example of a stable cycliza-tion product derived from attack of the intermediate imonium function by the nitro anion (683). A previously claimed tetrasubstituted enamine, which was obtained from addition of a vinylsulfone to morpholinocyclohexene (314), was shown to be the corresponding cyclobutane (684). Perfluoro-olefins also gave alkylation products with enamines (685). Reactions of enamines with diazodicarboxylate (683,686) have been used diagnostically for 6-substituted cyclohexenamines. In a reaction of 2-penten-4-one with a substituted vinylogous amide, stereochemical direction was seen to depend on solvent polarity (687). 

Alkenes with electron-withdrawing groups may form cyclobutanes with alkenes containing electron-donating groups. The enamine reactions, mentioned above, are examples of this, but it has also been accomplished with tetracyanoethylene and similar molecules, which give substituted cyclobutanes when treated with alkenes of the form C=C—A, where A may be... 

Substituted cyclobutanes or benzene rings are formed by the reaction of imidazolides with suitable double-bond systems. 

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