Subject reactions with nitriles

Individual aspects of nitrile oxide cycloaddition reactions were the subjects of some reviews (161 — 164). These aspects are as follows preparation of 5-hetero-substituted 4-methylene-4,5-dihydroisoxazoles by nitrile oxide cycloadditions to properly chosen dipolarophiles and reactivity of these isoxazolines (161), 1,3-dipolar cycloaddition reactions of isothiazol-3(2//)-one 1,1-dioxides, 3-alkoxy- and 3-(dialkylamino)isothiazole 1,1-dioxides with nitrile oxides (162), preparation of 4,5-dihydroisoxazoles via cycloaddition reactions of nitrile oxides with alkenes and subsequent conversion to a, 3-unsaturated ketones (163), and [2 + 3] cycloaddition reactions of nitroalkenes with aromatic nitrile oxides (164). 

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. 

Only a few reports have described the application of optically active nitrile oxides in 1,3-dipolar cycloadditions (65-70). A general trend for these reactions is that moderate-to-poor diastereoselectivities are obtained when it is attempted to control the stereoselectivity using a chiral nitrile oxide. In one of the few recent examples, the chiral nitrile oxide 43, derived from Al-formylnorephenedrine and 3-methylnitrobutene, was subjected to reaction with diethyl fumerate (Scheme 12.16) (69). Compound 44 was obtained as the major product of this reaction as a 75 25 mixture with its diastereomer. 

Primary amides can also be generated in situ from nitriles. Thus, one-pot synthesis of A -acyl-a-amino acids by Pd-catalyzed amidocarbonylation of alkyl- and arylnitriles has been developed.For example, acetonitrile was hydrolyzed to acetamide first and subjected to the reaction with cyclohexanecarbaldehyde in the same reaction vessel to give A-acetyl-2-cyclohexylglycine 13 in 92% yield (Equation (2)). This process is... 

Finally, C. J. Easton, C. M. M. Hughes, G. P. Savage, and G. W. Simpson (Adelaide and Melbourne, Australia) review the cycloaddition reactions of nitrile oxides with alkenes. Although previous reviews of this subject have appeared, the synthetic potential of this reaction has recently been the object of intensive study. 

Dideoxynucleosides show potent anti-retroviral activity against HIV-specific reverse transcriptase80-83. In particular, 2, 3 -dideoxy-3 -C-cyano-2 -substituted thymidine derivatives (33 A and 33 B) with a free 5 -hydroxy function (R1 = H) are potential inhibitors of the HIV-reverse transcriptase-promoted c-DNA synthesis. As these compounds have yet to be prepared by another method, the 3 -ene-nitrile 3284 was subjected to conjugate addition reactions with ammonia, primary amines, secondary amines and carbon nucleophiles. Most of these nucleophilic amine addition reactions give either the trans-isomer 33 A as the sole product (e.g., reaction with pyrrolidine, piperidine, morpholine), or as the major product along with the c/s-isomer (e.g., reaction with methylamine, benzylamine), except for the reaction with ammonia where the cts-isomer 33B is formed as the major product84. 

Isoxazole-supported selenium resins, produced via 1,3-dipolar cycloaddition of nitrile oxides with propargyl selenium resin, were subjected to a-alkylation reactions with various electrophiles, leading to 3-aryl-5-i4-substituted ethenylisoxazoles in satisfactory yields (62-78%) and purity (90-99%). Compound 238 gave olefin 240, through selenoxide elimination from the a-alkylation product 239 (Scheme 56) <2003OL4649>. 

The reactions of phosgene with nitriles have been the subject a series of publications [1343,1544,2227,2228,2230] and the general reactions of acyl chlorides (including the special... 

The second synthesis (398) is an extraordinarily simple and direct one, in which the protected tetracyclic indoloquinolizidine aldehyde 741, obtained as two C-14 epimers and prepared as shown in Scheme 113, was subjected to cleavage of the 3,A b-bond by reaction with benzyl chloroform-ate in aqueous tetrahydrofuran. The resulting C-3 alcohol was converted into the corresponding nitrile 742, which was again obtained as a mixture of C-14 epimers, regardless of whether the starting material 741 was either... 

The chemistry of heterocyclic N-oxides prior to 1970 has been the subject of an extensive review,117 but most of their reactions with benzyne have been studied more recently. In N-oxides the disposition of bonds at the nitrogen atom can be linear (nitrile oxides), trigonal (nitrones), or tetrahedral (tertiary... 

D Auria and Racioppi have reported that the arylacrylonitriles (11) undergo facile (2+2)-cycloaddition when subjected to benzophenone-sensitized irradiation in acetonitrile solution. The products obtained from this treatment and the yields obtained are shown under the appropriate structures in Scheme 3. Again a mixture of addition types is encountered in line with results obtained from the cycloaddition reactions with the cinnamic acids. Dimerization of the nitrile (12) was also studied and yielded the two adducts (13) and (14). Irradiation of 3-(estran-16-yl)acrylates and 2-(estran-16-yl)vinyl ketones brings about the formation of dimers and also isomerization of the unsaturated side chains. ... 

A,A-Disubstituted 4-amino-1,1-dicyanobuta-1,3-dienes were obtained from ylidene-malononitriles by reactions with triethyl orthoformate and amines232. Furfurylidenemalono-nitriles have been subjected to various reactions to form different open-chain derivatives, which are useful intermediates. So 157 was reacted with ketene thioacetal 158 to yield furylhexadienonitriles 15923. ... 

The reaction of nitriles with water to form amides was also found to be catalyzed by complex 1 [23]. This is a commercially relevant reaction since amides are used as lubricants, detergent additives, drug stabilizers, etc. [24]. In aqueous solution this complex was found to be in equilibrium with [Cp 2Mo(OH)(H20] (2), and this monomer was proposed to be the active hydration catalyst The hydration was proposed to occur by an intramolecular attack of a hydroxide ligand on a coordinating nitrile. The reaction occurred under mild conditions, preventing the autocatalytic formation of acrylamide. Although this system allows the hydration of simple and functionalized nitriles, including acrylonitrile, which is hydrated exclusively at the C N position, its major drawback resides in the fact that the reactions are subject to product inhibition. 

Acylhydrazones, R CH=N-NHCOR , undergo stereoselective Mannich reactions with silyl ketene acetals to give j8-hydrazido esters, using activation by a chiral silicon Lewis acid. Alternatively, the use of silyl ketene imine gives a /3-hydrazido nitrile. Enantioselective (5)-l-amino-2-methoxymethylpyrrolidine (SAMP) hydrazone alkylation of aldehydes and ketones is the subject of a computational study, providing a useful screening method for possible new candidates. " ... 

Nitriles, cyanamides, and cyanates have been subjected to efficient [4 4- 2] cycloaddition reactions with acylketenes to give 1,3-oxazin-4-ones... 

Synthesis of BW-4030W92 (232) started from 2,3-dichlorobenzaldehyde (262) which was transformed into nitrile 263 (Scheme 62) [238]. Compound 263 which reacted with ethyl diethoxyacetate - t-BuOK and then - ethyl iodide to give enol ether 264. Reaction of 264 with guanidine afforded pyrimidine derivative 265, which upon deprotection gave aldehyde 266. Compound 266 was reduced with sodium borohydride and then subjected to reaction with diethylaminosulphur... 

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