Electron-deficient nitrile derivatives

As a direct route for the constructing carbon-carbon bonds, catalytic asymmetric Michael additions with various carbon-based nucleophiles including malonic esters, cyanide, electron-deficient nitrile derivatives, a-nitroesters, nitroalkanes, Horner-Wadsworth-Emmons reagent, indoles, and silyl enol ethers have attracted considerable attention. 

The 1,3-dipolar cycloaddition reaction of nitrile sulfides with nitriles yields 3,5-disubstituted 1,2,4-thiadiazoles of unequivocal structure. This method has received considerable attention in recent years. Electron deficient nitriles such as tosyl cyanide afford high yields of 5-tosyl derivatives (341) (Equation (53) see also Scheme 61) <93JHC357). 

The alluring possibility to form reactive 1,3-dipoles from suitable precursors in situ using light was further extended to nitrile ylides. These dipoles can be generated photochemically from the corresponding 2//-azirines (Fig. 10) [58]. This methodology was employed by Lin and coworkers to modify an azirine-containing protein with electron-deficient fumarate derivatives [59]. 

Nitro compounds have been converted into various cyclic compounds via cycloaddition reactions. In particular, nitroalkenes have proved to be useful in Diels-Alder reactions. Under thermal conditions, they behave as electron-deficient alkenes and react with dienes to yield 3-nitrocy-clohexenes. Nitroalkenes can also act as heterodienes and react with olefins in the presence of Lewis acids to yield cyclic alkyl nitronates, which undergo [3+2] cycloaddition. Nitro compounds are precursors for nitrile oxides, alkyl nitronates, and trialkylsilyl nitronates, which undergo [3+2]cycloaddition reactions. Thus, nitro compounds play important roles in the chemistry of cycloaddition reactions. In this chapter, recent developments of cycloaddition chemistry of nitro compounds and their derivatives are summarized. 

In the presence of Bu OK, (benzotriazole-l-yl)methyl isocyanide (BetMIC) 697 undergoes alkylation on the methylene group to give isocyanide 698. The anion derived from 698, upon its treatment with Bu OK, adds to the electron-deficient double bonds of ajl-unsaturated ketones, esters or nitriles to produce pyrroles 699. A similar reaction of isocyanide 698 with Schiff bases provides imidazoles 700. In both cases, use of unsubstituted isonitriles 697 in the reactions leads to heterocycles 699 and 700 with R1 = H (Scheme 108) <1997H(44)67>. 

N-Substituted amides derived from 2-chloro- or4-chloronicotinic acid react with CH-acidic nitriles in the presence of base to yield amino derivatives of [l,6]naphthytid-5(6//)-ones and [2,7]naphthyrid-l(2//)-ones <1997JHC397>. 3-(l-Alkylamino)pyridines react with electron-deficient alkynes (acetylene dicatboxylates) in the presence of acid to give l,2-dihydro[2,7]naphthyridine-3,4-dicarboxylates in up to 72% yield compounds unsubstituted at C-1 were readily oxidized with potassium permanganate to naphthyridine-l-ones <2005TL3953>. 

Diazadienes 314 (R2 = Ph) afforded, in the same way, good yields of bis-trifluoromethyl dihydroquinazolines 335, as reported by Burger and Penninger (Scheme 74). However, N-unsubstituted heterodienes 314 (R2 = H) yielded upon heating with aromatic nitriles symmetrical triazine derivatives 336 through a [4 + 2] cycloaddition (78S524). Muchowski and co-workers have employed the related 2-trichloromethyl-4-dimethyl-amino-1,3-diaza-l, 3-butadienes 337 for synthesizing 2-trichloromethylpyr-imidines 338 in 38-98% yield by cyclization with electron-deficient acetylenes moreover, triazine 339 was obtained in 80% yield in the reaction of... 

The Strecker reaction is defined as the addition of HCN to the condensation product of a carbonyl and amine component to give a-amino nitriles. Lipton and coworkers reported the first highly effective catalytic asymmetric Strecker reaction, using synthetic peptide 43, a modification of Inoue s catalyst (38), which was determined to be inactive for the Strecker reactions of aldimines (see Scheme 6.5) [62], Catalyst 43 provided chiral a-amino nitrile products for a number of N-benzhydryl imines (42) derived from substituted aromatic (71-97% yield 64->99% ee) and aliphatic (80-81% yield <10-17% ee) aldehydes, presumably through a similar mode of activation to that for hydrocyanations of aldehydes (Table 6.14). Electron-deficient aromatic imines were not suitable substrates for this catalyst, giving products in low optical purities (<10-32% ee). The a-amino nitrile product of benzaldehyde was converted to the corresponding a-amino acid in high yield (92%) and ee (>99%) via a one-step acid hydrolysis. 

SnCU-promoted addition of malonates and bromomalonates to simple nitriles (not electron-deficient) gives a,/8-dehydro-/3-amino acid derivatives (Eq. 44) [74]. SnCU is the Lewis acid of choice for the condensation of aroyl chlorides with sodium isocyanate, affording aroyl isocyanates in 70-85 % yields [75]. Non-aromatic acyl chlorides react under more variable reaction conditions. 

The double bonds of electron-deficient olefins (carbonyl compounds, nitriles, sulfones, sulfoxides, nitro derivatives, etc.) have a low-lying LUMO that can allow the attack of various nucleophiles. The nucleophiles can be neutral or negatively charged heteroatomic species, or they can be carbon species such as organometal-lic reagents or enolates. In the case of heteroatomic nucleophiles, asymmetric additions can be performed in the presence of chiral catalysts, with chiral reagents, or with substrates bearing chiral residues. 

Most pyrimidine carbonitriles show normal nitrile chemistry reductive reactions to methylamines by metal hydrides, hydrolytic reactions, reduction to aldehydes and formation of ketones with Grignard reagents. However, in highly electron-deficient pyrimidines, competition may arise between addition to an electrophilic substituent and the electrophilic pyrimidine ring. In the 5-cyano derivative (426), specific attack of organometallics is in the 4-position, with formation of the dihydro derivatives (427) instead of a ketone <83ACS(B)6I3>. 

The [Ir(ppy)2bpy] complex photo-catalyses inter- and intramolecular C-H functionalisation reactions of tertiary amines under the visible light irradiation. Oxygen behaves as a chemical switch, triggering different reaction pathways and leading to different products from the same starting material. In anaerobic conditions, the intermolecular addition of iV,iV-dimethyl-anilines to electron-deficient alkenes yields y-amino nitriles. Aerobic conditions, on the other hand, favour a radical addition/ cyclisation reaction, leading to tetrahydroquinoline derivatives. The intramolecular version of the radical addition produces unexpectedly indole-3-carboxaldehyde derivatives. ... 

The photocycloaddition of 2tf-azirines to electron-deficient olefins produces d -pyrrolines as primary photoproducts. Some of the dipolarophiles used include acrylic esters, acrylonitriles, fumaric and maleic esters, methyl allenecarboxylate, norbornene, and l,2-dicyanocyclobutene. Similarly, styrenes and vinylpyridines undergo smooth photocycloaddition to 2H-azirines. Addition of acetylene derivatives to the transient nitrile ylide gives 2H-pyrroles (18, 20) which rearrange to pyrroles (19) if the C-2 atom is monosubstituted. 3-Phenyl-2/f-azirines have been found to cycloadd to vinylphosphonium salts and to vinyl sulfones. The initial adducts (22 and 24) undergo ready loss of the phosphorous or sulfur substituent to give 2H-pyrroles (23 and 25). ... 

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