Chloroacetonitrile, reaction

Although not fully characterized, 2-carbethoxy-4-hydroxythiazole (230a), R, = C02Et, R2 = H, apparently results from the reaction of chloroacetonitrile with ethyl thiooxamate (2), Ri = C02Et (417). a-Chlorothioacids (232) condensed with thiobenzamide in the presence of carbon disulfide (542) yield the corresponding 2-phenyl-4-hydroxy-thiazole (234). The same product was obtained from 233 (Scheme 121). 

Very few 4-aminothiazoles have been synthetized directly. The reaction of a-halonitriles with thioamides generally fails and only extensive decomposition results. However, the benzene sulfonic ester of mandelonit-rile reacts with thiobenzamide to give 2,5-diphenyl-4-aminothiazole (257), Ri = R2 = Ph, in 37% yield (Scheme 132) (417) Similarly, a-cyano-a-acetylthioacetamide condensed with a-chloroacetonitrile give 257, Ri = CH(CN)CH3 and R2 = H (804). 

Akabori and Saito obtained 6-methoxy-3-indolylacetonitrile (231) from 6-methoxyindole and chloroacetonitrile by the Grignard reaction/ and Wieland et al. prepared 5 methoxy-3-indolylaceto-... 

Dimethylindole magnesium iodide reacts with chloroacetonitrile in ether to give 3-cyanomethyl-2,3-dimethylindolenine (234). Majima and Hoshino obtained 3-(2-cyanoethyl)lndole (235) by the action of -chloropropionitrile on indole magnesium iodide. The reaction was slower with -chloropropionitrilc than with chloro-aoetonitrile. 3-(3-Cyano-w-propyl)indole (236), required as an intermediate in the synthesis of 3-indolyl-y-w-butyric acid, was prepared, but not isolated, by the action of y-chloro-w-butyronitrile on indole magnesium iodide. ... 

Davies et al. have described the synthesis of 2,4-diamino-selena-zole (4), by the reaction of selenourea with chloroacetonitrile. The... 

Alkylation of the tetrahydropyridine, 52 (obtained by reaction of a suitable protected derivative of 4-piperidone followed by dehydration and deprotection), with chloroacetonitrile affords 53, Reduction of the cyano group gives the diamine (54). Reaction of this intermediate with the S-methyl ether of thiourea affords guancycline (55). 

Reaction of highly functionalized pyridine 126 with chloroacetonitrile 127 or ct-halocarbonyl compounds under phase-transfer conditions furnished pyrrolo[2,3-r/ thieno[2,3-3]pyridine 128 (Equation 31) <2000PS(163)29>. 

Simlilar conclusions are indicated for the reaction product obtained from dichloro-acetonitrile and trichloroborane. For the product obtained from chloroacetonitrile and trichloroborane, however, a nitrile-borane structure is found which, according to the authors 481, might depend critically on the reaction conditions. 

The reaction of 135 with the 1,2-dioxane derivative 136 yielded the derivative of the fused ring system 137 in moderate yield (43—46%) <2000JHC269>. Vainilavicius et al. have transformed 135 with chloroacetonitrile to the alkylated derivative 138 and with ethyl bromoacetate to 139 <2001M825>. They found that 139 could be ring-closed to 140 in high yield, whereas 138 when treated with sodium methoxide gave 141 in poor yield. Direct routes to 140 and 141 starting from 135 have also been elaborated. 

The Darzens reaction between aldehydes and ketones with activated halomethyl compounds is an effective route to oxiranes under phase-transfer catalytic conditions and the catalyst has a profound stereochemical control of the substituents (see Chapter 12). The reaction has been conducted in high yield under liquidtliquid and solidrliquid two-phase conditions with a range of halomethyl compounds [e.g. 25-30], Ketones tend to be much slower in their reaction and benzylic ketones undergo alkylation with chloroacetonitrile in preference to the Darzens reaction [25]. 

The formation of cyclopropanes from 7C-deficient alkenes via an initial Michael-type reaction followed by nucleophilic ring closure of the intermediate anion (Scheme 6.26, see also Section 7.3), is catalysed by the addition of quaternary ammonium phase-transfer catalysts [46,47] which affect the stereochemistry of the ring closure (see Chapter 12). For example, equal amounts of (4) and (5) (X1, X2 = CN) are produced in the presence of benzyltriethylammonium chloride, whereas compound (4) predominates in the absence of the catalyst. In contrast, a,p-unsatu-rated ketones or esters and a-chloroacetic esters [e.g. 48] produce the cyclopropanes (6) (Scheme 6.27) stereoselectively under phase-transfer catalysed conditions and in the absence of the catalyst. Phenyl vinyl sulphone reacts with a-chloroacetonitriles to give the non-cyclized Michael adducts (80%) to the almost complete exclusion of the cyclopropanes. 

Cyclopropanation reactions of chloroalkanes with jt-deficient alkenes under basic phase-transfer catalysed conditions have been observed. Thus, for example, chloroacetic esters and chloroacetonitriles undergo Michael-type reactions with acrylic esters and acrylonitriles, the products of which cyclize to give cyclopropanes (see Section 6.4). 

A degree of stereoselective control of the course of a reaction, which is absent or different from that prevalent when the reaction is conducted in the absence of quaternary ammonium salts, may be achieved under standard phase-transfer catalysed reaction conditions. The reactions, which are influenced most by the phase-transfer catalyst, are those involving anionic intermediates whose preferred conformations or configurations can be controlled by the cationic species across the interface of the two-phase system. For example, in the base-catalysed Darzens condensation of aromatic aldehydes with a-chloroacetonitriles to produce oxiranes (Section 6.3), the intermediate anion may adopt either of the two conformations, (la) or (lb) which are stabilized by interaction across the interface by the cations (Scheme 12.1) [1-4]. 

Although the effect of quaternary ammonium salts on the stereochemistry of the two-phase condensation reaction of a-chloroacetonitrile with acrylonitriles to form cyclopropanes [4, 7] is not as pronounced as with the Darzens reaction, it can be rationalized in an analogous manner (Scheme 12.2). In the absence of the catalyst, the more highly stabilized anion (4a) is favoured leading to the preferential production of the cis isomer (5). As with the Darzens reaction, addition of the catalyst causes diffusion of the anions (4a) and (4b), as ion-pairs, into the bulk of the organic phase where their relative stabilities are similar and a more equal ratio of the two isomeric cyclopropanes (5) and (6) results (Table 12.2). 

Catalysis of the C-alkylation of 5-methyoxy-l,3-dimethyloxindole with chloroacetonitrile by A-(3,4-dichlorobenzyl)cinchoninium or quininium chloride leads in good yield to the (5)-3-alkylatcd derivative (78% ee), which provides an efficient stereospecific route to the anticholinesterase agent, (-)-physostigmine [9]. Other analogous alkylation reactions have been reported [10]. 

The condensation of 5-amino-3-methyl-l,2,4-thiadiazole (118) with aliphatic or aromatic nitriles yields 1 1 adducts, which are, according to their H NMR spectra, equilibrium mixtures of (119) and (120) (Scheme 28) <82AHC(32)285>. These adducts are produced by a bond switch at the n-hypervalent sulfur in (121). X-ray analysis of the adduct formed from the reaction of (118) with chloroacetonitrile showed the adduct to exist as (122) in the crystals <81AX(B)185>. Further examples of this type of bond switch at rc-hypervalent sulfur are observed in the reaction of 5-imino-1,2,4-thiadiazolines with various electrophilic reagents (Section 4.08.6.1). 

The extensively studied Appel s salt can be produced by prolonged chlorination of acetonitrile with S2CI2 (Scheme 24) <85CB1632>. For preparative purposes chloroacetonitrile gives the best yield (85%). Another simple method for synthesis of Appel s salt may be provided by reaction of S2CI2 with ethylamine (yield and conditions of the process not disclosed) <85PS(23)277>. 

Reactions of the salts 79-81 with chloroacetonitrile, methyl chloroacetate, chloroacetone, or substituted phenacyl bromide yield different products the thiazoles 90 are formed in excellent yield from the reaction with 79 (Equation 1) and when salts 80 and 81 are treated with phenacyl bromide, thiazolopyridine 91 and benzoxazine derivative 92 are formed, respectively <2004H(63)2319>. 

Replacement of the pyridine ring by a more strongly basic ethylpiperidine moiety leads to the antiarrhythmic dmg disobutamide (55-5). The synthesis of this compound also involves successive carbanion alkylation reactions. Thus, reaction of the anion from ortho-chloroacetonitrile (55-1) with A-(2-chloroethyl) piperidine gives the intermediate (55-3) alkylation of the anion from this leads to (55-4). Hydrolysis with sulfuric acid completes the preparation of disobutamide (55-5) [56]. 

The two major routes to 3,4-dihydro-2JT-l,5-benzodioxepins (274) from (273) and (275) are applicable to a wide range of substituted derivatives. The 3-oxo derivative, important as a perfume odorant, can be prepared via the reaction of 1,2-dihydroxybenzene with chloroacetonitrile (75CJC2279) or via a Dieckmann cyclization (74USP3799892). 

Practical syntheses of chloroacetonitrile depend upon dehydration of chloroacetamide with phosphorus pentoxide. The present method uses a liquid reaction medium in previous procedures the dry reagents were heated in the absence of solvent or liquid medium. ... 

To an ice-cooled solution of the nitrile, in absolute alcohol (see Table II above) is added dry hydrogen chloride until 1.1 moles has been taken up. The resulting solution is allowed to stand at 0°C for the times shown in Table II, column 2. After this time, ether is added in the amounts shown in column 3 for the purpose of preventing the formation of a hard cake of the salt. In the case of very reactive nitriles such as acetonitrile and chloroacetonitrile it is advisable to have the ether present before the hydrogen chloride is added in order to prevent solidification of the reaction mixture. After allowing the reaction mixture to stand for 15-20 hr in a refrigerator, it is cooled to —30°C to hasten crystallization. The product salt is filtered, washed with cold (—40°C) ether, and dried... 

Bromine trifluoride is also used to convert the cyano group in acetonitrile, chloroacetonitrile, and propionitrile into the trifluoromethyl substituent. The reaction is carried out using hydrofluoric acid as a solvent.126... 

Production, use and human exposure Halogenated acetonitriles are not produced on an industrial scale. Chloroacetonitrile has been used on a limited basis in the past as a pesticide. Several halogenated acetonitriles have been detected in chlorinated drinking-water in a number of countries as a consequence of the reaction of chlorine with natural organic substances present in untreated water. The only known route of human exposure is through chlorinated drinking-water (lARC, 1991). 

Benzothiazepines can be constructed from substrates of type (376) and an appropriate C—C— N fragment thus, 2,3-dihydro-1,4-benzothiazepin-5-one (377) can be prepared by reaction of (376 R = OH) with aziridine. The reaction of 2-mercaptoaryl ketone (376 R=Ph) with 2-bromoethylamine is a two-stage process intermediate (378) cyclizes in the presence of pyridine to give (379). The reaction of (376 R=OMe) with chloroacetonitrile in the presence of alcohols (R OH) gives (380) (740PP287). 

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