Cyclobutanes, preparation

To apply the decay technique, the multitritiated cyclobutane, prepared as described in the previous section, was allowed to decay for several months in gaseous systems containing, as the major component, a suitable nucleophile, such as H2O or NH3, as illustrated in Table I. 

Chiral Alcohols and Lactones. HLAT) has been widely used for stereoselective oxidations of a variety of prochiral diols to lactones on a preparative scale. In most cases pro-(3) hydroxyl is oxidized irrespective of the substituents. The method is apphcable among others to tit-1,2-bis(hydroxymethyl) derivatives of cyclopropane, cyclobutane, cyclohexane, and cyclohexene. Resulting y-lactones are isolated in 68—90% yields and of 100% (164,165). 

Extensive work in this area by the Syntex group provides additional important information with respect to the mechanistic aspects of such cycloadditions. At the same time, the method proved of considerable utility for the preparation of cyclobutane compounds bearing a wide variety of substituents. 

Fluorinated cyclobutanes and cyclobutenes are relatively easy to prepare because of the propensity of many gem-difluoroolefins to thermally cyclodimerize and cycloadd to alkenes and alkynes. Even with dienes, fluoroolefins commonly prefer to form cyclobutane rather than six-membered-ring Diels-Alder adducts. Tetrafluoroethylene, chlorotrifluoroethylene, and l,l-dichloro-2,2-difluoroethyl-ene are especially reactive in this context. Most evidence favors a stepwise diradical or, less often, a dipolar mechanism for [2+2] cycloadditions of fluoroalkenes [S5, (5], although arguments for a symmetry-allowed, concerted [2j-t-2J process persist [87], The scope, characteristic features, and mechanistic studies of fluoroolefin... 

By using freshly preeipitated copper powder at 200 °C, perfluroallenes can be prepared by the elimination of bromine fluoride or iodine fluoride from the corresponding starting matenals [70] The reaction is carried out at low pressure, 1-2 mm of Hg, and the products quickly dimenze into cyclobutane derivatives (equation 39)... 

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. 

The synthesis of 2-chloro-2,3,3-trifluorocyclobutyl acetate illustrates a general method of preparing cyclobutanes by heating chlorotrifluoroethylene, tetrafluoroethylene, and other highly fluorinated ethylenes with alkenes. The reaction has recently been reviewed.11 Chlorotrifluoroethylene has been shown to form cyclobutanes in this way with acrylonitrile,6 vinylidene chloride,3 phenylacetylene,7 and methyl propiolate.3 A far greater number of cyclobutanes have been prepared from tetrafluoroethylene and alkenes 4,11 when tetrafluoroethylene is used, care must be exercised because of the danger of explosion. The fluorinated cyclobutanes can be converted to a variety of cyclobutanes, cyclobutenes, and butadienes. 

Thermal dimerization of ethylene to cyclobutane is forbidden by orbital symmetry (Sect 3.5 in Chapter Elements of a Chemical Orbital Theory by Inagaki in this volume). The activation barrier is high E =44 kcal mof ) [9]. Cyclobutane cannot be prepared on a preparative scale by the dimerization of ethylenes despite a favorable reaction enthalpy (AH = -19 kcal mol" ). Thermal reactions between alkenes usually proceed via diradical intermediates [10-12]. The process of the diradical formation is the most favored by the HOMO-LUMO interaction (Scheme 25b in chapter Elements of a Chemical Orbital Theory ). The intervention of the diradical intermediates impfies loss of stereochemical integrity. This is a characteric feature of the thermal reactions between alkenes in the delocalization band of the mechanistic spectrum. 

One recent example of preferential [2+2] cycloaddition of dienes is the reaction of 2-siloxybutadienes with allenecarboxylates to afford cyclobutanes used for the preparation of very hindered cyclohexene systems [22]. 

It is difficult to rationalize the low yield of exp-[4]pericycline 83. The fact that a cyclobutane ring is not easily closed cannot be the reason [4], since the corresponding protected exp-[4]pericyclinone 123 [39] and the Cgo-fullerene-annelated exp-[4]rotane 128 [38] were prepared without any problems. 

The polymer = 8.19 dlg in hexafluoro-2-propanol, HFIP, solution) in Figs 1 and 2 is prepared on photoirradiation by a 500 W super-high-pressure Hg lamp for several hours and subjected to the measurements without purification. The nmr peaks in Fig. 1 (5 9.36, 8.66 and 8.63, pyrazyl 7.35 and 7.23, phenylene 5.00, 4.93, 4.83 and 4.42, cyclobutane 4.05 and 1.10, ester) correspond precisely to the polymer structure which is predicted from the crystal structure of the monomer. The outstanding sharpness of all the peaks in this spectrum indicates that the photoproduct has few defects in its chemical structure. The X-ray patterns of the monomer and polymer in Fig. 2 show that they are nearly comparable to each other in crystallinity. These results indicate a strictly crystal-lattice controlled process for the four-centre-type photopolymerization of the [l OEt] crystal. 

The preparation of cyclobutanes via the catalytic conditions can be extremely efficient provided that the radical formed after epoxide opening is sterically shielded and cyclization promoted by the Thorpe-Ingold effect. It... 

Conlin and co-workers have also studied the fragmentation of a siletane (silacyclobutane). In this case, both the E- and Z-isomers of 1,1,2,3-tetra-methylsilane 45 were prepared and thermolyzed (Scheme 8).144 Both E-and Z-isomers of 45 led to the same products in slightly different ratios the major products were propene with silene 46, and E- and Z-2-butenes with silene 47. Silene formation was inferred from detection of the disila-cyclobutane products. During these processes, the stereochemical integrity of the compounds was largely preserved. 

In order to investigate the single electron donation process from a reduced flavin to a pyrimidine dimer or oxetane lesion, the photolyase model compounds 1-4 depicted in Scheme 4 were prepared [41, 42]. The first model compounds 1 and 2 contain a cyclobutane uracil (1) or thymine (2) dimer covalently connected to a flavin, which is the active electron donating subunit in photolyases. These model systems were dissolved in various solvents... 

Incorporation of a flavin electron donor and a thymine dimer acceptor into DNA double strands was achieved as depicted in Scheme 5 using a complex phosphoramidite/H-phosphonate/phosphoramidite DNA synthesis protocol. For the preparation of a flavin-base, which fits well into a DNA double strand structure, riboflavin was reacted with benzaldehyde-dimethylacetale to rigidify the ribityl-chain as a part of a 1,3-dioxane substructure [49]. The benzacetal-protected flavin was finally converted into the 5 -dimethoxytri-tyl-protected-3 -H-phosphonate ready for the incorporation into DNA using machine assisted DNA synthesis (Scheme 5a). For the cyclobutane pyrimidine dimer acceptor, a formacetal-linked thymine dimer phosphoramidite was prepared, which was found to be accessible in large quantities [50]. Both the flavin base and the formacetal-linked thymidine dimer, were finally incorporated into DNA strands like 7-12 (Scheme 5c). As depicted in... 

An elegant example of the use of photochemistry in complex organic synthesis is the preparation the bollweevil phenomone (sex attractant). The key step in both the Zoecon Corporation synthesis and the USDA synthesis involves the formation of a cyclobutane ring by a photoaddition reaction ... 

Similarly, the cyclobutane-fused bicyclic peroxide 19 was prepared by diimide reduction of the corresponding bicyclic endoperoxide derived from 1,3,5-cyclooctatriene (Eq. 14)31a). 

The extreme hazards involved in handling this highly reactive material are stressed. Freshly distilled material rapidly polymerises at ambient temperature to produce a gel and then a hard resin. These products can neither be distilled nor manipulated without explosions ranging from rapid decomposition to violent detonation. The hydrocarbon should be stored in the mixture with catalyst used to prepare it, and distilled out as required [1], The dangerously explosive gel is a peroxidic species not formed in absence of air, when some l,2-di(3-buten-l-ynyl)cyclobutane is produced by polymerisation [2], The dienyne reacts readily with atmospheric oxygen, forming an explosively unstable polymeric peroxide. Equipment used with it should be rinsed with a dilute solution of a polymerisation inhibitor to prevent formation of unstable residual films. Adequate shielding of operations is essential [3],... 

Cyclobutane-fused pyrimidinones 39, precursors to quinone methide intermediates, have been prepared by reaction of amidines with the cyclopropane ester 38 <06EJOC2753>. 

Radialenes represent the biggest and best known subset of the radialene family this is not surprising in view of the fact that more methods to prepare them exist than for any other class of radialenes. The major strategies are the transformation of appropriate cyclobutane derivatives, the thermal or Ni(0)-catalyzed cyclodimerization of butatrienes or higher cumulenes and the cyclotetramerization of (l-bromo-l-alkenyl)cuprates. 

Aluminum-free titanocene-methylidene can be generated by thermolysis of titana-cyclobutanes 6, which are prepared by reaction of the Tebbe reagent with appropriate olefins in the presence of pyridine bases [9]. Alternatively, the titanacyclobutanes are accessible from titanocene dichloride and bis-Grignard reagents [10] or from 71-allyl titanocene precursors [11]. The a-elimination of methane from dimethyltitanocene 7 provides a convenient means of preparing titanocene-methylidene under almost neutral conditions [12] (Scheme 14.5). 

To a solution of the titanocene(II) reagent 29 in THF (42 mL) in a 300-mL round-bottomed flask, prepared from titanocene dichloride (6.54 g, 26.3 mmol), magnesium turnings (0.766 g, 31.5 mmol), triethyl phosphite (8.96 mL, 52.5 mmol), and finely powdered 4 A molecular sieves (1.31 g) according to the procedure described above, was added a solution of l,l-bis(phenylthio)cyclobutane (63 2.29 g, 8.40 mmol) in THF (14 mL). The reaction mixture was stirred for 15 min. and then a solution of (S)-isopropyl 3-phenylpro-panethioate (91 1.46 g, 7.00 mmol) in THF (21 mL) was injected dropwise over a period of 10 min. The reaction mixture was refluxed for 1 h, then cooled, whereupon 1 m aq. NaOH solution (150 mL) was added. The insoluble materials produced were removed by filtration through Celite and washed with diethyl ether. The aqueous layer was separated and extracted with diethyl ether. The combined ethereal extracts were dried (Na2S04), filtered, and concentrated. The residual liquid was purified by column chromatography (silica gel, hexane) to afford 1.33 g (77%) of (l-isopropylthio-3-phenylpropan-1 -ylidene) cyclobutane (92). 

The ring expansion of cyclobutane derivatives to other carbocycles remains to be one of the most powerful tool in synthetic organic chemistry. Cyclobutanones are exceptionally facile starting materials for the preparations of y-lactones as well as cyclopentanones. 

Strained molecules such as cyclopropanes and cyclobutanes have emerged as important intermediates in organic synthesis. We have already demonstrated here that cyclobutane derivatives can indeed serve as starting materials for the synthesis of natural as well as unnatural products. Unlike cyclopropanes, which can be prepared asymmetrically in a number of ways 175 -182>, the asymmetric synthesis of cyclobutane derivative has received less attention, and, to our best knowledge, very few reports were recorded recently 183). Obviously, the ready availability of chiral cyclobutane derivatives would greatly enhance their usefulness in the enantioselective synthesis of natural products. The overcome of this last hurdle would allow cyclobutane derivatives to play an even more important role in synthetic organic chemistry. 

A new method, reported by Pearlman (262), for the preparation of Woodward s key building block also constitutes a new synthesis of reserpine as well as deserpidine. In the key step of the synthesis an internal (2ir + 2-tt] photocycliza-tion of dienone 518 gave cyclobutane derivative 519 with the established stereochemistry. Methanolysis and subsequent peracid treatment of 520 yielded lactone ester 521. Repeated methanolysis and retroaldol fission of the cyclobutane... 

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... 

Cyelobutanone has been prepared by (1) reaction of diazomethane with ketene,4 (2) treatment of methylenecyclobutane with performic acid, followed by cleavage of the resulting glycol with lead tetraacetate,s (3) ozonolysis of methylenecyclobutane, (4) epoxidation of methylene-cyclopropane followed by acid-catalyzed ring expansion,7 and (5) oxidative cleavage of cyclobutane trimethylene thioketal, which in turn is prepared from 2-(co-chloropropyl)-l,3-dithiane.8... 

The present procedure9 represents another synthesis of cyelobutanone through the unique acetylenic bond participation in solvolysis. Cyclobutane derivatives prepared in this way include 2-methyl-, 2-ethyl-, 2-isopropyl-, and 2-trifluoromethylcyclobutanone from the corresponding acetylenic compounds.10... 

The product of the reaction may be still further broken down by eliminating the second carboxyl group. (Preparation of cyclobutane from the dicarboxylic ester formulated above.)... 

Bidentate chiral water-soluble ligands such as (S,S)-2,4-bis(diphenyl-sulfonatophosphino)butane BDPPTS (Fig. 2) or (R,R) 1,2-bis(diphenylsul-fonatophosphinomethyl)cyclobutane have been prepared [25]. Their palladium complexes catalyze the synthesis of chiral acids from various viny-larenes and an ee of 43% has been reached for p-methoxystyrene with the BDPPTS ligand. Furthermore, recycling of the aqueous phase has shown that the regio- and enantioselectivity are maintained and that no palladium leaches. 

Penta-alkylphosphorane intermediates are also inferred from the products of the reaction of these ylides with silacyclobutane, from which hydrogen is eliminated.44 However, the cyclobutane ring is left intact when the reaction is carried out with more bulky ylides (Scheme 10).46 Silicon- and germanium-substituted allenes have been prepared by the reaction of monometallated ketens with stable ylides, e.g. (43).46... 

The second example is an intermolecular crystal-state reaction. Cross-conjugated 1,5-disubstituted 1,4-dien-3-ones in solution undergo both cis-trans photoisomerization and photodimerization, yielding complex mixtures of products, including die all-trans-substituted cyclobutane 2 in the case of 1,5-diphenyl-1,4-pentadien-3-one. In contrast, dienones such as 3a in whose crystals adjacent molecules lie parallel and strongly overlapped react in the solid to give 3b as the sole photoproduct. This isomerically pure tricyclic diketone results, formally, from an eight-center dimerization. It is not formed in the reaction in solution, and could be prepared by other methods only with considerable difficulty (4). 

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