Nitriles, reductive cleavage

The reductive capability of CgK has been a subject of interest (LA). Uses for CgK include the reductive cleavage of carbon-sulfur bonds (S5), the reductive alkylation of nitriles and esters (S6), and the reductive alkylation of aldehydes and ketones (S7). The activity of CgK has... 

A nitrile oxide generated from a sugar derived aldoxime 30 underwent INOC reaction to the chiral pyranoisoxazoline 31 (Eq. 4) [20]. Reductive cleavage of isoxazoline 31 followed by acetylation provided the tetrasubstituted pyran 32. 

A total synthesis of functionalized 8,14-seco steroids with five- and six-membered D rings has been developed (467). The synthesis is based on the transformation of (S)-carvone into a steroidal AB ring moiety with a side chain at C(9), which allows the creation of a nitrile oxide at this position. The nitrile oxides are coupled with cyclic enones or enol derivatives of 1,3-diketones, and reductive cleavage of the obtained cycloadducts give the desired products. The formation of a twelve-membered ring compound has been reported in the cycloaddition of one of the nitrile oxides with cyclopentenone and as the result of an intramolecular ene reaction, followed by retro-aldol reaction. 

This chapter deals mainly with the 1,3-dipolar cycloaddition reactions of three 1,3-dipoles azomethine ylides, nitrile oxides, and nitrones. These three have been relatively well investigated, and examples of external reagent-mediated stereocontrolled cycloadditions of other 1,3-dipoles are quite limited. Both nitrile oxides and nitrones are 1,3-dipoles whose cycloaddition reactions with alkene dipolarophiles produce 2-isoxazolines and isoxazolidines, their dihydro derivatives. These two heterocycles have long been used as intermediates in a variety of synthetic applications because their rich functionality. When subjected to reductive cleavage of the N—O bonds of these heterocycles, for example, important building blocks such as p-hydroxy ketones (aldols), a,p-unsaturated ketones, y-amino alcohols, and so on are produced (7-12). Stereocontrolled and/or enantiocontrolled cycloadditions of nitrones are the most widely developed (6,13). Examples of enantioselective Lewis acid catalyzed 1,3-dipolar cycloadditions are summarized by J0rgensen in Chapter 12 of this book, and will not be discussed further here. 

Dipolar cycloaddition reactions between nitrile oxides and aUcenes produce 2-isoxazolines. Through reductive cleavage of the N—O bond of the 2-isoxazohnes, the resulting heterocycles can be readily transformed into a variety of important synthetic intermediates such as p-hydroxy ketones (aldols), p-hydroxy esters, a,p-unsaturated carbonyl compounds, y-amino alcohols, imino ketones and so forth (7-12). 

Because only one stable electroactive product arises from the reduction of /7-chlorobenzonitrile, the interpretation of the cyclic voltammetric behavior is relatively straightforward. The fact that electron attachment to halogen-containing compounds frequently results in the cleavage of the carbon-halogen bond immediately suggests benzonitrile as a possible product. The similarity between the cyclic voltammetric behavior of benzonitrile and that of the p-chlorobenzo-nitrile reduction product supports this prediction (see Fig. 21.1). 

The indolyl nitro compound (98) was converted to the corresponding nitrile oxide, which cyclized to afford an inseparable mixture of isoxazolidines (99) and (100 Scheme 2S).46 These were acetylated and the THP group replaced by a mesyl group at which point the desired 3-isomer could be separated. Elimination via a selenide intermediate provided the alkenylisoxazoline (101), which was converted to an isoxazolinium salt and reduced with LAH to give an N-methylisoxazolidine. Reductive cleavage with aluminum amalgam provided (+)-paliclavine. 

Dihydroisoxazoles can be formed by stereoselective 1,3-dipolar cycloaddition of nitrile oxides, for example, to enantiopure allylic alcohols, and these products can be converted into -amino acids 510 by a characteristic nucleophilic addition to the C=N bond in 509 followed by reductive cleavage of the N—O bond and oxidative cleavage of the diol moiety. The facial selectivity in the nucleophilic addition is dictated by the C(5) substituent (Scheme 109), e.g., <2003JA6846, 2004SL1409, 2005JA5376>. 

When recent advances in the chemistry of isoxazoles were reviewed by Kochetkov and Sokolov1 in this Series in 1963 (and by Quilico2 in 1962), the main features of isoxazole chemistry had been established. Since then some important new discoveries have been made, but probably the most significant advances have concerned the exploitation of the known features of their chemistry in synthesis. Particularly noteworthy developments include the further application of the cycloaddition of nitrile oxides in the synthesis of isoxazoles (Section II,C and D), the use of isoxazolium salts in peptide synthesis (Section III,B,2), syntheses involving the products of reductive cleavage of isoxazoles as intermediates (Section III,D and E) and annelation reactions via deprotonation of alkylisoxazoles (Section 1II,E). 

Trifluoropropcnc itself reacts regioselectively with various nitrile oxides, even nonaromatic nitrile oxides. The latter arc prepared in one step from oximes and A -chlorosuccin-imide, or in a two-step sequence with isolation of the hydroximoyl chlorides. Cycloadducts, obtained at room temperature in the presence of triethylamine, are then converted into trilluoro- 8-hydroxy ketones 9 by reductive cleavage. The reaction with a dipole substituted by a group derived from L-phcnylalanine allows the preparation of chiral ketones. ... 

Reductive cleavage with TMSCl/Nal of fused systems such as pyrano- and furo[3,4-cjisoxazole derivatives 18 gave predominantly polysubstituted isoxazoles 19, as key intermediates for further elaborations <03H1625>. Pyranoisoxazole derivatives 18a have been prepared by intramolecular 1,3-DC of nitrile oxides 21, obtained by treatment with n-... 

For the direct conversion of aliphatic nitriles to aldehydes, the best nonhydride method appears to be that of Fischli. The nitrile is treated with a large excess of activated zinc and a catalytic amount (0.1 equiv.) of aquocobalamine in acetic acid/water (4 1) at room temperature for several hours. Using this method, a variety of aliphatic aldehydes were obtained in yields which were generally very satisfactory. As examples, the aldehydes (48), (49) and (50) were produced in yields of 63%, 82% and 90%, respectively. Aldehyde (50) was also formed from the unsaturated nitrile (51) under the same conditions. The proposed mechanism is shown in Scheme 15, the key steps being the attack of cob(l)alamine on the nitrile to give intermediate (52) and the reductive cleavage of the latter by the zinc. It was suggested that the product aldehyde was not reduced because the adduct between itself and cob(l)alamine is, for electronic reasons, less stable than (52). 

The electrochemical cleavage of nitriles can also be performed in anhydrous amine media [146], making possible C-CN bond cleavage in aliphatic nitriles, such as cyclohep-tanecarbonitrile and heptanecarbonitrile. This reaction was interpreted as due to reductive cleavage by solvated electrons. This reaction has also been accomplished with electrogenerated solvated electrons [147]. 

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