Chloronitrile

Pasinszki and Westwood investigated the dimerization of chloronitrile oxide CICNO to 3,4-dichloro-l,2,5-oxadiazole-2-oxide 78 (Scheme 48) [98JPC(A) 4939]. From B3-LYP/6-31G calculations, they conclude that the reaction path can be characterized as a typical Firestone-type cycloaddition, a two-step mechanism with a C—C bond forming characterizing the first reaction step. The activation... 

The solution is cooled and then diluted with 450 cc. of water. The oily layer of chloronitrile is collected in about 80 cc. of chloroform and Separated from the water solution. The chloroform solution is washed with about 125-150CC. of calcium chloride solution (prepared by adding one volume of water to an equal volume of a saturated solution of crystallized calcium chloride) and once with 125-150 cc. of water, and then dried over fused calcium chloride. 

The action of aqueous potassium hydroxide on chloronitrile 14 in DMSO at 25-30°C accomplishes the hydrolysis of the chloronitrile moiety and furnishes ketone 13 in a yield of 80%. Treatment of a solution of ketone 13 in CH2CI2 with mCPBA and sodium bicarbonate results in a selective Baeyer-Villiger oxidation to give bicyclic lactone 12 in >95% yield. It is noteworthy that the Baeyer-Villiger oxidation is completely regioselective and that the... 

A key transformation in Corey s prostaglandin synthesis is a Diels-Alder reaction between a 5-(alkoxymethyl)-l,3-cyclopenta-diene and a ketene equivalent such as 2-chloroacrylonitrile (16). As we have already witnessed in Scheme 3, it is possible to bring about a smooth [4+2] cycloaddition reaction between 5-substituted cyclopentadiene 15 and 2-chloroacrylonitrile (16) to give racemic 14 as a mixture of epimeric chloronitriles. Under these conditions, the diastereomeric chloronitriles are both produced in racemic form because one enantiotopic face of dienophile 16 will participate in a Diels-Alder reaction with the same facility as the other enantiotopic face. In subsequent work, Corey s group demonstrated that racemic hydroxy acid 11, derived in three steps from racemic 14 (see Scheme 3), could be resolved in a classical fashion with (+)-ephe-... 

This reaction is illustrative of a general procedure for the alkylation of active methylene functions in the presence of concentrated aqueous alkali catalyzed by tetraalkylammonium salts. This catalytic method has been used to alkylate arylacetonitriles with monohaloalkanes,2 dihaloalkanes,3 a-chloroethers,4 chloronitriles,.5 haloacetic acid esters,6 and halonitro aromatic compounds.7 It has also been used to alkylate ketones,8 lf/ indene,9 9i/-fluorene,ll) and the Reissert compound.11 The reaction is inhibited by alcohols and by iodide ion.2... 

The literature synthesis of the racemic 2-azidonitrile (80) by diazotisation of the 5-amino-1,2,3-thiadiazole (78) could not be repeated the 2-chloronitrile (79) was the only product obtained from the reaction <96TA607>. 

The synthetic utility of the D-A reaction can be expanded by the use of dienophiles that contain masked functionality and are the synthetic equivalents of unreactive or inaccessible compounds. (See Section 13.1.2 for a more complete discussion of the concept of synthetic equivalents.) For example, a-chloroacrylonitrile shows satisfactory reactivity as a dienophile. The a-chloronitrile functionality in the adduct can be hydrolyzed to a carbonyl group. Thus, a-chloroacrylonitrile can function as the equivalent of ketene, CH2=C=0,63 which is not a suitable dienophile because it has a tendency to react with dienes by [2 + 2] cycloaddition, rather than the desired [4 + 2] fashion. 

We entered this field when we studied the photoisomerization of simply substituted nitrile oxides 138 (R = Cl, Br, CN).188 Matrix irradiation yields the corresponding isocyanates 144. In the case of chloronitrile oxide besides the absorptions of chloroisocyanate189 the bands of chloronitrene190 also appear. It can be assumed that the nitrile oxide-isocyanate rearrangement starts with the ring closure 138 - 140.191192... 

A series of calpain I inhibitors such as 184 were prepared in a similar fashion from a-chloronitrile 185 in four steps (Scheme 24) <2001JME3488>. The key steps of this synthesis are the aforementioned Friedel-Crafts-type reaction of chloronittile 185 with CISO3H and a one-pot amidation/N-alkylation of dichloride 186 which furnishes the benzosulfonamide core 188 of these inhibitors via intermediate 187. 

Pyrazolo[3,4-. ]pyridines have also been formed by reaction of the appropriate chloronitrile pyridine (Equation 50) <2002BML2925>. Pyrazolo[3,4-. ]pyridines can be prepared by oxidative cyclization with PIFA (Equation 51 Table 27) <1997SC2217>. 

Pyrazolo[3,4-r-]pyridines have been formed by cyclization of the chloronitrile 155 with hydrazine hydrate in good yield (Equation 56) <2003BML1581>. Townsend and co-workers have reported the preparation of 3-substituted... 

Synthesis of isoxazolo[5,4- ]pyridines can be carried out from the corresponding chloronitrile intermediate 165 (Equation 64) <2002BML2925> or by deprotonation of an oxime with subsequent cyclization and expulsion of chloride (Equation 65) <1996JA10803>. Ring closure onto the nitrile in 166 by treatment with sodium hydroxide affords the isoxazolo[5,4- ]pyridine 167 in low yield (Equation 66) <1999JOC8479>. 

A new synthesis of pyrrolizidine, which is based on the reaction of bis-tertiary glycols with co-chloronitriles, was reported by Meyers and Libano.28 The method involves three steps (a) condensation of 2,5-dimethyl-2,5-hexanediol (48) with 4-chlorobutyronitrile in the presence of sulfuric acid to give a derivative of A 1-pyrroline (49), (6) reduction of 49 with sodium borohydride to give the corresponding pyrrolidine (50), and (c) intramolecular cyclization of the pyrrolidine in the presence of alkali to give the pyrrolizidine derivative 51. The three-step synthesis was performed without isolation of the intermediate products. 

Amino-1,2,4-triazines (678) can be prepared from the chloronitriles (677) and ammonia <78HC(33)189, p.249) or from the nitrosopyrazoles (676) by treatment with phosphorus pentachloride and then ammonia <58T(3)209). 

Nitriles may be prepared by dehydration of aldoximes an attempt to effect a Beckmann rearrangement on the oxime (481) of 5-methoxy-4-oxopyran-2-carboxaldehyde gives the nitrile (482) but under milder conditions only the chloride (483) and the chloronitrile (484) are obtained (75JHC219). 

Interestingly, Yamada and co-workers (58) have shown that the silver ion-promoted rearrangement of the chloronitrile isomers 157 and 159 yields the tricyclic isomeric cyanoketones 158 and 160 respectively. 

The versatility of this approach was further expanded when Meyers and Libano20,21 showed that, using chloronitriles, azabicyclic compounds (12, n = 2, 3, or 4) can be obtained in good yields after two additional steps. 

The synthesis of homologs of this tricyclic compound in which ring B is four- or five-membered was also carried out, using the appropriate chloronitriles.22 The yields in these cases are somewhat better, being 50 and 54% respectively. 

In 1993, Corey reported the first synthesis of paeoniflorin.56 The core of paeoniflorin was constructed using a Sml2-mediated Reformatsky-type reaction (Scheme 7.16). Treatment of a-chloronitrile 31 with Sml2 gave cyclobutanol 32 in excellent yield. The sensitivity of cyclobutanol 32 to base precluded the use of more conventional aldol-type cyclisations.56... 

The aminal function embedded in hexahydropyrrolo[l,2- 7]imidazoles 646 (Scheme 155) renders them prone to equilibration and eliminations under basic conditions. For example 646 (E = CN, C02Me) undergoes epimerization 647 upon storage or exposure to basic alumina. In the case of chloronitrile 648, a 2,4-disubstituted pyrrole is readily formed under mild conditions <1998J(P1)2061>. 

Electrogenerated nickel(O) bipyridine complexes serve as catalysts for a number of syntheses (a) formation of ketones from acyl halides and either alkyl or aryl halides [319], (b) production of, )/-unsaturated esters via coupling of a -haloesters with aryl or vinyl halides [320], (c) coupling of a-chloroesters or a-chloronitriles with carbonyl... 

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