Chloromethyl with sodium cyanide

Another way to synthesize ibuprofen consists of the chloromethylation of Ao-butylben-zene, giving 4-Ao-butylbenzylchloride (3.2.24). This product is reacted with sodium cyanide, making 4-Ao-butylbenzyl cyanide (3.2.25), which is alkylated in the presence of sodium amide by methyl iodide into 2-(4-iAo-butylbenzyl)propionitrile (3.2.26). Hydrolysis of the resulting product in the presence of a base produces ibuprofen (3.2.23). 

Phenyl-4-methyl-7azaindole-3-carboxaldehyde (148, B = H, R = Ph Scheme 10) was reduced with sodium borohydride to the 3-hydroxymethyl compound (145, R = H, R = Ph) in quantitative yield,whereas the 6-chloro compound (145, R = C1, R = H) was obtained in only 10 % yield. Treatment of 145 (R = H, R =Ph) with thionyl chloride gave the 3-chloromethyl compound (146), isolated in 99 % yield as the hydrochloride. With sodium bicarbonate in water, the 3-chloromethyl salt (146) is hydrolyzed rapidly back to the hydroxymethyl compound (145). An attempt to synthesize the 3-acetonitrile (147) by heating the 3-chloromethyl salt (146) with sodium cyanide in ethanol produced only the bisazaindolylmethylene ether (50%). Use of acetone cyanohydrin gave the acetonitrile (147) (50 %). It was hydrolyzed to give l-phenyl-4-methyl-7-azaindole-... 

Three tetracyclic systems, triphenylene, benz(c)phenanthrene and chrysene can be derived by angular benzannelation of phenanthrene and hence these hydrocarbons may be synthesized from corresponding phenanthreneacetonitriles. The phenanthrene-1-acetonitrile (81) used for the preparation of the chrysenes (82) was obtained from phenanthrene-l-carbonitrile (72a) in a sequence of conventional steps hydrolysis to the acid (84%) by KOH in triglycol, reduction to the carbinol (82%) by sodium dihydrido-bis(methoxyethoxy)aluminate, conversion by thionyl chloride in benzene to the chloromethyl derivative (98%), and finally reaction of the latter with sodium cyanide in DMSO to (81) (94%). 

To achieve a further benzannelation, benzo(b)thiophen-7-carbonitrile (196 b) has been converted by a four-step sequence — hydrolysis by KOH in cellosolve (150°, 1 h), reduction of the acid by sodium bis(methoxyethoxy)aluminiumdi-hydride, action of thionyl chloride on the carbinol, and reaction of the chloromethyl compound with sodium cyanide in DMSO — in a 75% overall yield to the oily benzo(b)thiophen-7-acetonitrile (197), which finally afforded the naphtho(l,2-b)-thiophen-9-carbonitriles (198a, b) ... 

The reaction of chloromethyl aryl ethers with nucleophilic reagents has been described by Barber et al Thus, by reaction with thiourea, potassium thiocyanate, or sodium cyanide, there arc obtained aryloxyalkylisothiouronium salts, aryloxyalkyl thiocyanates, and aryloxyalkylacetonitriles, respectively. The reaction of chloromethyl aryl ethers with butyllithium leads to an aryloxycarbene which on reaction with olefins gives aryloxy-cyclopropanes. The ethers react with triphenylphosphine and a base to give phcnoxymethylene ylides which arc useful in con-... 

The 4,10,16-triaza-18-crown-6 macrocycle shown above was first prepared by Lehn and coworkers (Graf and Lehn, 1975 Lehn, 1985) and was an important intermediate for the synthesis of the first macrotetracyclic polyethers (Canceill et al., 1982 Kotzyba-Hibert et al., 1981 Pratt et al., 1988). The key step in this synthesis was conversion of A-tosyldiethanolamine [TsN(CH2CH20H)2] into the diacid dichloride, TsN(CH2CH20CH2C0Cl)2. As shown above, this conversion was accomplished by reaction with chlo-roacetic acid followed by oxalyl chloride (method A) (Miller et al., 1989) or by chloromethylation, sodium cyanide, hydrolysis and conversion of the diacid to the diacid dichloride (method B) (Graf and Lehn, 1981). The third hypothetical method to the diacid dichloride shown above starts with tosylamide and 5-chloro-3-oxa-l-pentanol followed by Jones oxidation and thionyl chloride (method C) (Qian et al., 1990). 

CHLOROMETHYL CYANH)E (107-14-2) ClCHjCN Forms explosive mixture with air (flashpoint 133°F/56°C Fire Rating 2). Contact with water, steam, or strong acid, or acid fiimes produce toxic hydrogen cyanide gas. Violent reaction with strong oxidizers. Incompatible with sodium nitrate, lithium alanate. Thermal decomposition releases toxic hydrogen cyanide and hydrogen chloride gas. On small fires, use dry chemical powder (such as Purple-K-Powder), foam, or COj extinguishers. 

CHLOROMETHYL CYANIDE (107-14-2) Forms explosive mixture with air (flash point 133°F/56°C). Contact with steam or acids produces hydrogen cyanide gas. Violent reaction with strong oxidizers. Incompatible with sodium nitrate, lithium alanate. 

By emulsion polymerization of styrene with chloromethylated styrene in the presence of divinylbenzene and hexadecyltrimethylammonium bromide as a surfactant, latex particles of the copolymer were synthesized with a diameter of 0.08-0.2 m [67,68]. The copolymer was transformed directly to phosphonium salts by boiling the emulsion with tributylphosphine for 24 h. The stirring rate over 510-670 rpm did not affect the rate constants of catalyzed, interfacial transfer reactions of the aqueous solution of sodium cyanide with 1-bromooctane at 90 °C and with benzyl bromide at 80 °C in toluene in the presence of the above catalysts. The catalyst activity increased with an increase in the latex particle size. 

The chemical operations described in the literature to introduce or into citric acid molecule are based essentially on the Grimaux and Adam synthesis. Labeled citric acid was prepared by Wilcox et al. [35] in the reaction of Na CN with 3-chloro-2-carboxy-2-hydroxybutyric acid and the formed nitrile was hydrolyzed directly with hydrochloric acid. From this solution, citric acid was isolated in the form of calcium citrate and finally converted to the acid. An alternative procedme was proposed by Rothchild and Fields [36] to obtain trimethyl citrate from labeled sodium cyanide and di-chloromethyl glycolate. A more complex synthesis of C labeled citric acid is described by Winkel et al. [39]. They used labeled methyl acetate and acetyl chloride (in the presence of hthium 1,1,1,3,3,3,-hexamethyldisilazide, [(CH3)2Si]2NLi which was dissolved in tetrahydiofuran) to obtain methyl acetoac-etate. It reacts in the presence of lithium diisopropylamide, [(CH3)2CH]2NLi, also dissolved in tetrahydrofuran, with dimethyl carbonate to give dimethyl 1,3-ace-tonedicaiboxylate. It is dicarboxylated by the action of bisulfite and potassium cyanide is converted to 3-cyano-3-hydroxy-l,5 pentanedioate and finally hydrolyzed by hydrochloric acid to citric acid. 

Although phase transfer catalysis is certainly an important and extremely versatile tool for the chemical modification of chloromethyl polystyrene, it is not necessarily always the best method as excellent results can also be obtained for some nucleophilic displacements when DMF or even DMSO (at low temperature to avoid oxidation to the carboxaldehyde polymer) are used as solvent for the nucleophile. For example, we prefer to use a solution of sodium cyanide in DMF to prepare cyanomethyl polystyrene from I rather than using a different solvent and phase transfer conditions, and we routinely prepare iodomethyl polystyrene from I by reaction with sodium or potassium iodide in acetone rather than under the conditions of Gozdz (Ref. 25). Recent work by Bied-Charreton et al. (Ref. 32) has also shown that excellent results could be obtained even under classical conditions in the transformation of I into its malononitrile derivative if the chloromethylated polymer is first transformed into the more reactive iodomethyl derivative this is in sharp contrast with earlier data from the same laboratory (Ref. 33). 

MetHoxym0thyl ethers of phenols. These ethers are readily prepared by reaction of chloromethyl methyl ether with a suspension of the dry sodium salt of a phenol in benzene or toluene. They are useful as protective groups because they are stable to alkali, to potassium cyanide, to Grignard reagents, and to n-butyllithium, but can be hydrolyzed when desired by very gentle treatment with acid. They are cleaved more easily than the corresponding benzyl ethers. Examples of synthetic uses are as follows. 

A plausible mechanism for the reaction includes several organometallic species that are sensitive to reactive moieties elsewhere in the molecule. If a chloro, chloromethyl, or mesyloxymethyl substituent is attached vicinal to the 1,1 -dibromo moiety, efficient ring opening occurs prior to carbonylation and P,y- and y, -unsaturated acid derivatives are formed. Reductive carbonylation has also been achieved with 1,1-dibromocyclopropanes using an excess of pentacarbonyliron in dimethylformamide with added methanol or sodium methoxide, or cobalt(II) chloride and nickel(ll) cyanide under phase-transfer conditions in a carbon monoxide atmosphere. However, the yield of cyclopropanecarboxylic acid derivatives is low, and when pentacarbonyliron is used the amount of monobromides is fairly high. ... 

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