Cycloadditions alkenes, isocyanates

Abstract The main computational studies on the formation of (3-lactams through [2+2] cycloadditions published during 1992-2008 are reported with special emphasis on the mechanistic and selectivity aspects of these reactions. Disconnection of the N1-C2 and C3-C4 bonds of the azetidin-2-one ring leads to the reaction between ketenes and imines. Computational and experimental results point to a stepwise mechanism for this reaction. The first step consists of a nucleophilic attack of the iminic nitrogen on the sp-hybridized carbon atom of the ketene. The zwitterionic intermediate thus formed yields the corresponding (3-1 actant by means of a four-electron conrotatoty electrocyclization. The steroecontrol and the periselectivity of the reaction support this two-step mechanism. The [2+2] cycloaddition between isocyanates and alkenes takes place via a concerted (but asynchronous) mechanism that can be interpreted in terms of a [n2s + (n2s + n2s)] interaction between both reactants. Both the regio and the stereochemistry observed are compatible with this computational model. However, the combination of solvent and substituent effects can result in a stepwise mechanism. 

The [2+2] Cycloaddition Between Isocyanates and Alkenes 3.1 General Mechanism... 

As in the case of the reaction between ketenes and imines, the [2+2] cycloaddition between isocyanates and alkenes [106, 107] can take place via concerted and stepwise mechanisms. However, with the exception of highly nucleophilic alkenes (vide infra), concerted mechanisms were postulated, since isocyanates are suitable candidates to act as antarafacial partners in thermal [2+2] cycloadditions (Fig. 1). Aside from the [n2s + n2J mechanism, in principle [n2s + (A + A) [108] and [A + (A + A s)] [109] mechanisms can be envisaged (Fig. 5). 

Both concerted and stepwise mechanisms have been proposed for these reactions although the experimental facts can be readily accounted for by the formation of a 1,4-dipolar intermediate (27 Scheme 27). The reaction rates are markedly increased in polar solvents. The cycloadditions of isocyanates to alkenes are always regiospecific, the reaction taking place so as to form the most stable 1,4-dipole. 

Jochims [134] and Hassan s [135] groups reported the efficient use of l-aza-2-azoniaallene salts 119 and 0-acetylated j6-D-glucopyranosyl isothiocyanate 89 for the preparation of glucopyranosylimino-l,3,4-thiadiazoles 121 and 122. These salts, prepared from chloroalkylazo derivatives 118 and antimony (V) chloride, can undergo 1,3-dipolar cycloadditions with multiple bonds-containing compounds, such as alkynes, alkenes, isocyanates, isothio-... 

The common methods for the S5mthesis of p-lactams are cycloaddition reactions such as the Staudinger s ketene-imine cycloadditions, ester enolate-imine cycloadditions, alkyne-nitrone cycloadditions (Kinugasa reaction), alkene-isocyanate cycloadditions, and Torii s cyclocarbonylation of allyl halides with imines. Several cyclizahon reactions of p-amino esters, p-amino acids, p-hydroxamate esters, and a-diazocarbonyls have been developed for the formation of p-lactam ring. N,N-Disubstituted a-haloamides cyclize by C3-C4 bond formation leading to the formation of P-lactam ring. 

The [2+2] cycloaddition of isocyanates 23 and alkenes 24 also stereospecihcally delivers cw-P-lactams 25 (Scheme 41.5) " ... 

Electron-deficient alkenes add stereospecifically to 4-hydroxy-THISs with formation of endo-cycloadducts. Only with methylvinyl-ketone considerable amounts of the exo isomer are produced (Scheme 8) (16). The adducts (6) may extrude hydrogen sulfide on heating with methoxide producing 2-pyridones. The base is unnecessary with fumaronitrile adducts. The alternative elimination of isocyanate Or sulfur may be controlled using 7 as the dipolarenOphile. The cycloaddition produces two products, 8a (R = H, R = COOMe) and 8b (R = COOMe, R =H) (Scheme 9) (17). Pyrolysis of 8b leads to extrusion of furan and isocyanate to give a thiophene. The alternative S-elimi-nation can be effected by oxidation of the adduct and subsequent pyrolysis. 

Other isocyanates undergo [2 + 2] cycloaddition, but only with very electron rich alkenes. Thus phenyl isocyanate gives /3-lactams with ketene acetals and tetramethoxyethylene. With enamines, unstable /3-lactams are formed if the enamine has a /3-H atom, ring opened amides are produced 2 1 adducts are also found. Photochemical addition of cis- and traH5-stilbene to phenyl isocyanate has also been reported (72CC362). 

Like the similar cycloaddition of ketenes to alkenes (15-61), most of these reactions probably take place by the di-ionic mechanism c (p. 1078). P-Lactams have also been prepared in the opposite manner by the addition of enamines to isocyanates ... 

Ketenes and isocyanates also undergo facile [6 + 2]-photocycloaddition with metal complexed cyclic polyenes. Irradiation of 232 in the presence of diphenylketene gave 256 in good yield (Scheme 58)120. This should be contrasted with the normal behavior of ketenes toward alkenes, which typically involves [2 + 2]-cycloaddition. Isocyanates such as 257 work as well. The adducts are produced in high yields and have considerable potential in synthesis. 

The intramolecular nitrile oxide-alkene cycloaddition sequence has been used for the assembly of a great variety of natural products. A target that has received special attention is that of taxol (156), undoubtedly due to its unique structural features, its potent anticancer activity, and its hmited availability from natural sources (318,319). In 1984 Kozikowski et al. found that the treatment of nitro dienone 158 (obtained from the p-benzoquinone derivative 157) with p-chlorophe-nyl isocyanate under Mukaiyama conditions afforded the unexpected eight-mem-bered ring 159, which is related to ring B of taxol (156) (Scheme 6.79). 

Silyl-substituted diazoketones 29 cycloadd with aryl isocyanates to form 1,2,3-triazoles 194 (252) (Scheme 8.44). This reaction, which resembles the formation of 5-hydroxy-l,2,3-triazoles 190 in Scheme 8.43, has no analogy with other diazocarbonyl compounds. The beneficial effect of the silyl group in 29 can be seen from the fact that related diazomethyl-ketones do not react with phenyl isocyanate at 70 °C (252). Although the exact mechanistic details are unknown, one can speculate that the 2-siloxy-1-diazo-1-alkene isomer 30 [rather than 29 (see Section 8.1)] is involved in the cycloaddition step. With acyl isocyanates, diazoketones 29 cycloadd to give 5-acylamino-l,2,3-thiadiazoles 195 by addition across the C=S bond (252), in analogy with the behavior of diazomethyl-ketones and diazoacetates (5). 

N-Vinyl heterocumulenes represent a new, highly reactive 2-azadiene species, which react, in general, with electron-rich alkenes and alkynes. Accordingly, we think it is of interest to complement the utility of electron-poor 2-azadienes in [4 + 2] cycloadditions by showing some examples involving A-vinyl isocyanates, -isothiocyanates, -carbodiimides, and -ketenimines. 

Ring fused products can be elaborated from isoxazolines (80S757). Several nitrocyclo-alkenes (516) were prepared and reacted with phenyl isocyanate to generate the intermediate nitrile oxides which underwent internal cycloaddition to afford the tricyclic isoxazolines (517). Cleavage of the N—O bond by hydrogenation in the presence of a catalytic amount of Raney nickel and subsequent hydrolysis afforded the /3-ketol (518 Scheme 113). 

Isoxazoles and their partially or fully saturated analogs have mainly been prepared, both in solution and on insoluble supports, by 1,3-dipolar cycloadditions of nitrile oxides or nitrones to alkenes or alkynes (Figure 15.10). Nitrile oxides can be generated in situ on insoluble supports by dehydration of nitroalkanes with isocyanates, or by conversion of aldehyde-derived oximes into a-chlorooximes and dehydrohalogenation of the latter. Nitrile oxides react smoothly with a wide variety of alkenes and alkynes to yield the corresponding isoxazoles. A less convergent approach to isoxazoles is the cyclocondensation of hydroxylamine with 1,3-dicarbonyl compounds or a,[3-unsatu-rated ketones. 

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