2-Chloroacrylonitrile

With a,p-dihalo- or a-halo-a,p-unsaturated carbonyl derivatives A significant number of examples exist in which a,P-dihalogenated carbonyl derivatives undergo reactions with thioglycolates in the presence of base to produce thiophenes. " The reactions have been shown to occur through intermediate a-halo-a,P-unsaturated carbonyl derivatives produced by the elimination of HX. Thus the use of a-halo-a,P unsaturated carbonyl systems in place of the a,P-dihalocarbonyl compounds was found to efficiently provide thiophenes upon reaction with thioglycolates. In a modification of the work of Fiesselmann, readily accessible methyl-2-chloroacrylate 23 and 2-chloroacrylonitrile 24 have been used in this sense to provide 25 and 26, respectively. 

Further investigations revealed that the disubstituted indolo[3,2-fl]carbazoles 117a-b may be conveniently obtained in moderate yields simply by heating 115 with dimethyl or diethyl acetylenedicarboxylate in xylene, while the use of lower-boiling solvents (benzene, toluene) led to the formation of the presumed intermediate Michael adducts 118a-b as the major products. The reaction of 115 with 2-chloroacrylonitrile furnished the indolo[3,2-fl]carbazole derivative 119 where aromatizaticRi did not take place (99T2371). 

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-... 

Chloro-2-[A -methyl-Af -(thien-2-ylmethylene)hydrazino]quinoxaline 4-oxide (288, R = H) with 2-chloroacrylonitrile gave 8-chloro-4-hydroxy-l-methyl-... 

To mention a few synthetic appHcations of trialkylsilanols, trimethylsilanol 4 adds readily to 2-chloroacrylonitrile in diethyl ether in the presence of triethylamine as triethylammonium trimethylsilanolate followed by ehmination of triethylamine hydrochloride to give 99 [32] (cf. discussion of the strongly nucleophihc properties of ammonium trimethylsilanolate 155 in Section 4.2.1). The stable potassium trimethylsilanolate 97 has also been used for the saponification of esters (Section 4.7). Dimethylphenylsilanol 100 adds readily to a,y9-unsaturated carbonyl compounds such as methyl vinyl ketone 764 in the presence of Pd(OAc)2 in a Heck-Suzuki-type reaction to give the sihcon-free /9-phenylmethylvinylketone 101 [33]. 

With stirring and cooling triethylamine (25.3 g) is added dropwise to a solution of trimethylsilanol 4 (22.5 g) and 2-chloroacrylonitrile (22.0 g) in dry ether. The reaction mixture is then stirred for 7-8 h at 30-35 °C. The precipitated triethylammo-nium chloride is removed by filtration, the filtrate is concentrated, and the residue is distilled in vacuo (b.p. 85-86°C/6mm) to give 21.4 g (95%) 2-methoxyacryloni-trile 99 [32] (Scheme 3.15). 

A) Synthesis of A ring system Retrosynthetic analysis of cyclohexanone 2a leads to diene 5 and 2-chloroacrylonitrile 6 as a ketene equivalent (Scheme 13.6.2) as the starting materials. 

Also, in the form of N-(2-pyridylcarbonyl)proline Pro undergoes 1,3-dipolar cycloaddition with 2-chloroacrylonitrile to give two tetracyclic products and 61b in 5% yield (85TL5447). When Pro-OMe was heated with methyl cinnamate and benzaldehyde in toluene for several hours, two iso-... 

However, use of a less reactive reagent where [R = R =(CH2)4, (CH2)s, (CH2)20(CH2)2] led to the isolation of products 61 and 62, with a reduction in the yields of the desired cycloadducts. The product 62 arises from Michael addition of the liberated methanethiol to A-methylmaleimide. The protocol was further extended to olefinic dipolarophiles with dimethyl fiimurate, dimethyl maleate, fumaronitrile, and 2-chloroacrylonitrile leading to the corresponding adducts, although these dipolarophiles proved somewhat less reactive with reduced yields being observed. Where applicable, the alkene configuration was reflected in the relative stereochemistry of the cycloadducts (Fig. 3.5). 

Nan ya et al. (97) also reported the synthesis of isoindolediones by the reaction of miinchnones with 1,4-benzoquinones. Reactions with an unsymmetrical mtinchnone were not regioselective. Several groups have examined the reactions of miinchnones with unsaturated nitriles, including 2-chloroacrylonitrile (98), cinna-monitrile (78,99) and fumaronitrile (78) to give unexpected products in several cases. Eguchi and co-workers (100) smdied the cycloaddition of several mtinch-nones with electron-deficient trifluoromethylated olehns. Thus, miinchnones 176... 

Nitrodienes undergo intermolecular Diels-Alder reactions with appropriate dienophiles. The resulting nitro compounds can then be cyclized via a nitrile oxide intermediate.49 Thus, the 2-chloroacrylonitrile Diels-Alder adduct of 8-nitro-l,3-octadiene was prepared and cyclized to give (105) as a 3 1 mixture of diastereomers (Scheme 30). The Diels-Alder adduct of dimethyl acetylenedicarboxylate and 8-nitro-l,3-octadiene cyclized exclusively at the conjugated double bond, activated by the ester groups. Similarly, the quinone Diels-Alder adduct (106) cyclized at the conjugated double bond reduction of the conjugated double bond permitted cyclization on the cycloalkenyl double bond. 

This type of synthesis has been described earlier in the formation of 2,3-dihydro-l/7-l,2-diazepino[3,4-A]quinolines by 1,5-dipolar cycloaddition of quinoxalin-4-oxides with 2-chloroacrylonitrile <1996GHEC-II(9)113>. 

A highly enantioselective and diastereoselective addition of trisubstituted carbon donors, such as (166), to 2-chloroacrylonitrile (167), catalysed by bifunctional Cin- chona alkaloid catalysts, e.g. (169), has been reported as the first example of an asymmetric cascade that includes conjugate addition and protonation with efficient (g) catalytic control at two non-adjacent stereocentres (168).218... 

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