Ketones reaction with chloroacetonitrile

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]. 

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). 

Gtycidic nitriles.20 Glycidic nitriles can be obtained in good yield by the reaction of ketones with chloroacetonitrile in aqueous sodium hydroxide with benzyltriethylammonium chloride as catalyst. 

Nucleophilic attack of tervalent phosphorus acid derivatives on the carbon atom of alkyl halides is the normal process, but sometimes the attack occurs at the halogen atom instead. This reaction is most pronounced when a stabilized carbanion may be formed, e.g. in the reaction with tetrachloromethane (equation 147). The extent of debromination of a-bromo ketones has been found to decrease in the series R2POR > RP(OR)2 > P(OR)3. Ethyl di- erf-butylphosphinite has been shown to react preferentially at the halogen atom of chloroacetonitrile, 1,2-dibromoethane and diiodomethane, to give in each case a mixture of products, e.g. equation 148. Aminophosphines are also very reactive in this respect... 

We decided to investigate one final substrate that contained our desired side chain for the intramolecular Diels-Alder cycloaddition as well as a small and removable cyano group. Our synthesis is outlined in Scheme 11. Phenol 53 was alkylated with chloroacetonitrile, then condensed to form 2-cyano benzo-furan 54. Subsequent quatemarization to 56 was accomplished with sodium hydride and a bromocrotcMiate (55) electrophile. Following phenol ether deprotection and reduction of the benzylic ketone with sodium borohydride, we were in a position to evaluate the dearomatization step. Unfortunately, all attempts to access the quinone epoxide 58 under classic or modified Adler-Becker reaction conditions failed. With these results, we closed the book on the second chapter in our vinigrol saga and went back to the drawing board. 

The B-R-9-BBN reacts with chloroacetonitrile [1] under the influence of potassium 2,6-di-t-butylphenoxide to produce the corresponding nitriles in high yield (Eq. 10.1). The reaction intermediate undergoes protonolysis readily and without adding ethanol or other protonolyzing agent as required, for example, in the synthesis of ketones under similar conditions. 

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. 

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