Nitrile Derivatives

These compounds and their derivatives can be manufactured using relatively simple equipment compared to that required for the fatty nitrile derivatives. Cyclization of amidoamines to imidazolines requires higher reaction temperatures and reduced pressures. Prices of imidazolines are therefore high. 

Although hydrogenation of A-benzylideneaniline in the presence of 11 afforded the corresponding product (eq. 1 in Scheme 11), the a,(3-unsaturated ketone was converted into a mixture of unsaturated and saturated alcohols in the 42 56 ratio (eq. 2 in Scheme 11). Several substrates (nitrile derivatives, epoxides, esters, internal alkynes, and terminal alkenes), which are shown in Fig. 4, are not hydrogenated in this catalytic system. 

Imidates 60 were prepared in two steps by first reacting nitrile derivatives with various alcohols. The condensation of the obtained iminoester with appropriate acetyl chloride resulted in the formation of the title compounds 60a-c (Scheme 12). The structures of the products 60 were elucidated by means of spectroscopic analysis. 

In 1978, Sugasawa et al., at Shionogi Pharmaceutical Co. reported ortho-selective Friedel-Craft acylation with free anilines with nitrile derivatives [4]. Sugasawa reported that the reaction requires two different Lewis acids (BC13 and A1C13) and does not proceed when N,N-dialkyl anilines are used. He proposed that boron bridging between nitriles and anilines led to exclusive ortho-acylation but a conclusive mechanism was not elucidated. The report did not offer any reason why two different Lewis acids were required and why the reaction did not progress with N,N-dialkyl anilines. Therefore, we initiated mechanistic studies. 

Three approaches to the synthesis of 4-amino-5-unsubstituted imidazoles (71) have been described and are summarized in Scheme 7. These are (a) reduction of 4-nitroimidazoles (72) (b) hydrolysis of carbamates and amides (73) (c) cyclization of nitrile derivatives (74). 

Treatment of a methanolic solution of the nitrile derivatives (81 R1 = CH2CN, R2 = CONH2) [prepared in two steps from the calcium antagonist compound (81 R1 = R2 = H)] with sodium hydride resulted in facile cyclization, giving the 4-aminoimidazol-2-one derivative (82) (53%) (90JMC1805). 

Table 8 Preparation of 1,3,4-thiadiazoles from thiohydrazide and nitrile derivatives...

Treatment of isoxazoline-fiised [60]fullerene 48 with NaOMe in the presence of MeOH gave the p-hydroxy nitrile derivative 49 in good yield <00SL361>. The synthesis of the enantiomerically pure cyclopropane amino acid 51 covalently attached to a fulleroisoxazoline has been achieved . 

Additions to quinoline derivatives also continued to be reported last year. Chiral dihydroquinoline-2-nitriles 55 were prepared in up to 91% ee via a catalytic, asymmetric Reissert-type reaction promoted by a Lewis acid-Lewis base bifunctional catalyst. The dihydroquinoline-2-nitrile derivatives can be converted to tetrahydroquinoline-2-carboxylates without any loss of enantiomeric purity <00JA6327>. In addition the cyanomethyl group was introduced selectively at the C2-position of quinoline derivatives by reaction of trimethylsilylacetonitrile with quinolinium methiodides in the presence of CsF <00JOC907>. The reaction of quinolylmethyl and l-(quinolyl)ethylacetates with dimethylmalonate anion in the presence of Pd(0) was reported. Products of nucleophilic substitution and elimination and reduction products were obtained . Pyridoquinolines were prepared in one step from quinolines and 6-substituted quinolines under Friedel-Crafts conditions <00JCS(P1)2898>. 

The photochemical reaction can also proceed via the triplet state and in this case no cyclization is observed. Especially when acetophenone is added as a triplet sensitizer, 41 is not formed. Remarkable is the observation that in the presence of anthracene or pyrene as triplet quencher, the yield of the cyclization product 41 was not enhanced and that nitrene insertion into CH bonds of anthracene or pyrene was observed. When the photochemical cyclization reaction was performed with the tosyl azide derivative 42a or the azido nitrile derivative 42b (Scheme 6), only low yields of the tricyclic amide 41 (32% from 42a, 9% from 42b, respectively) were obtained <2001JCS(PI)2476>. 

The (aziridin-l-ylimino)phosphoranes (57) react with ketens to give nitrile derivatives, presumably from an intermediate ketenimine by breaking the N—N bond and migration of the aziridinyl group.60 They also react with acyl halides and... 

The only cationic surfactant (Fig. 23) found in any quantity in the environment is ditallow dimethylammonium chloride (DTDMAC), which is mainly the quaternary ammonium salt distearyldimethylammonium chloride (DSDMAC). The organic chemistry and characterization of cationic surfactants has been reported and reviewed [330 - 332 ]. The different types of cationic surfactants are fatty acid amides [333], amidoamine [334], imidazoline [335], petroleum feed stock derived surfactants [336], nitrile-derived surfactants [337], aromatic and cyclic surfactants [338], non-nitrogen containing compounds [339], polymeric cationic surfactants [340], and amine oxides [341]. 

The last nitrile derivative to be examined is cimetidine (11.93), in which the CN group is attached to a guanidino function. While cimetidine cannot be strictly classified as an aliphatic or aromatic nitrile, it nevertheless resembles aromatic nitriles in two ways there are no H-atoms at C(a) to allow oxidative denitrilation, and the electrons of the CN group are delocalized over the moiety to which it is attached. 

Furazan- and furoxan-carboxylic acids are thermally and hydrolytically unstable decomposing to a-(hydroxyimino)nitriles, but their amide, ester, halide, and nitrile derivatives are readily accessible and all undergo the expected functional group interconversions. Dicyanofuroxan reacts with hydroxylamine to give the fused oxazino compound (63) and the pyridazino analogue (64) is similarly formed with hydrazine <82H(19)1063>. 

Although the conversion of an amide to a nitrile may be considered a standard reaction, the conversion of 62 to 63 by treatment with POCI3 represents the synthesis of one of the very few examples of such a nitrile derivative (Equation 25) <2004IZV1257>. 

Antiviral 2,5-disubstituted imidazo[4,5-f]pyridines have been reported for the treatment of hepatitis C <2007BML390, 2007BML5111>. A method for the preparation of substituted l//-imidazo[4,5-f]pyridines as immune response modifiers has been reported <2007W0092641>. 6-Phenyl-l//-imidazo[4,5-f]pyridine-4-carbo-nitrile derivatives have been reported to act as cathepsin K and S inhibitors <2007USP179138>. Imidazo[4,5-4pyridine derivatives have also been prepared as C3A receptor antagonists <2007W0034277>. 

Transformation of both the ester and nitrile derivatives 726 or 727 into pyrano[2,3-t7 pyridazines 728 or 729, respectively, by treatment with dilute HCl at room temperature involved nucleophilic displacement of the morpholine group by the hydroxyl group with an acidic hydrolysis followed by intramolecular iminolactonization and then hydrolysis of the formed imino group to a carbonyl group. Compounds 726 and 727 were prepared by Vilsmeier-Haack formylation of 2-methyl-5-morpholino-3(2/7)-pyridazinone 724 followed by condensation of the resulting product 725 with either ethyl a-cyanoacetate or malononitrile in EtOH (Scheme 34) <1994H(37)171>. 

Iodo-7-methylbenzo[l,2-/ 4,3- ]dithiophene 65 undergoes nucleophilic substitution on reaction with copper cyanide in DMF to produce the nitrile derivative 66 (Equation 10) <1997TL457>. 

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