Imino chloride formation

Yet another approach to these compounds consists of substituting the piperazine ring onto the preformed heterocyclic moiety. Ullman condensation of the substituted thiosalyciclic acid (40-1) with ort/zo-chloronitrobenzene results in the displacement of chlorine by thiophenoxide and the formation of the thioether (40-2). The nitro group in this last intermediate is then reduced to an aniline (40-3) the resulting amino acid is then cyclized thermally to the lactam (40-4). Treatment of that with phosphorus oxychloride gives the imino chloride (40-5). Reaction with N-methylpiperazine leads to the replacement of chlorine by nitrogen and the formation of clothiapine (40-6) [39]. 

For a review of the formation and reactions of imino chlorides, see Bonnett, R., in Patai, S. The Chemistry of the Carbon-Nitrogen Double Bond, Wiley, NY, 1970, pp. 597-662. 

The mechanism is not fully understood, but it is very similar to the mechanism of the Gattermann-Koch formylation. The first step is the formation of a nitrilium chloride that is subsequently transformed to an imino chloride from which the reactive species, the iminium ion is generated. 

Enzymatic 7-ACA splitting procedures [for general review, see 261] have been developed and commercialized by companies like Asahi Chemical, Hoechst, and Novartis. The replacement of the hitherto employed chemical deacylation processes like the imino ether (Figure 1.1-3) or the nitrosyl chloride method [262] resulted in a cost reduction of 80% and a decrease of the waste volume by a factor 100 from 311 to 0.3 tons per 1-ton 7-ACA. Chlorinated hydrocarbons like dimethyl aniline and methylene cloride as well as heavy metal ions can be completely avoided. Instead of zinc salt formation, multiple silylation, formation of the imino chloride, imino ether, and finally an imino ether hydrolysis, the side chain is removed in two enzymatic steps (Figure 1.1-3). 

Participation by sulfur has also been noted in attempts to hydrolyze the imino chloride functionality of penicillin intermediates, e.g., as in (66), to amide groups. Treatment of (66) with silver nitrate or aqueous acid resulted in the formation of three products, (67)-(69). Their formation can be rationalized as shown in Eq. (20). ... 

Considerable effort has been expended in exploring the scope of ke-tenimine formation as it pertains to the introduction of 7(6)-methoxy substituents. Carrol et al. (1974) reported the facile construction of ke-tenimines derived from penicillin G and demonstrated deuterium incorporation at C-6 by base-catalyzed exchange of a related imino chloride. Workers at Sankyo later reported a method (Sugimura et al., 1976) by which an imine 145 was produced from an a-haloimino chloride (144) via base-catalyzed 1,4-elimination. The resulting imine was stereospe-cifically converted to methoxyketenimine 146 by the addition of meth-oxide anion (—78°C). Exposure to lithium methoxide at -20°C then led to iminoether 147, which was transformed to amide 148 by a new reaction with trimethylchlorosilane and I equiv of quinoline. 

A 1,5-bond cleavage reaction which involves a 6,5-elimination rather than nitrogen participation has been reported. - The penicillin imino-chloride (130) rearranges to oxazole (132) on treatment with triethylamine a 6,5-elimination followed by jS-lactam ring-opening and oxazole formation has been proposed as the likely pathway. ... 

In an interesting variation on this theme, the bis acid chloride of diethylmalonate (138) is condensed with the 0-methyl ether of urea to afford the imino ether of the barbituric acid (139). Heating this ether at 200°C results in 0 to N migration of the methyl group and formation of metharbital (140). ... 

The pharmacological versatility of this general substitution strategy is further illustrated by diazonium coupling of 14 with 2-nitrobenzenediazonium chloride to produce biarylal-dehyde 18. Formation of the oxime with hydroxylamine is followed by dehydration to the nitrile. Reaction with anhydrous methanolic hydrogen chloride leads to imino ether and addition-elimination of ammonia leads to the antidepressant amid-ine, nitrafudam (20). ... 

An interesting bifunctional system with a combination of In(OTf)3 and benzoyl-quinine 65 was developed in p-lactam formation reaction from ketenes and an imino ester by Lectka [Eq. (13.40)]. High diastrereo- and enantioselectivity as well as high chemical yield were produced with the bifunctional catalysis. In the absence of the Lewis acid, polymerization of the acid chloride and imino ester occurred, and product yield was moderate. It was proposed that quinine activates ketenes (generated from acyl chloride in the presence of proton sponge) as a nucleophile to generate an enolate, while indium activates the imino ester, which favors the desired addition reaction (66) ... 

Two other ways of making levamisole differ only in the method of making l-(2-phenyl-2-hydroxyethyl)-2-imino-l,3-thiazolidine (38.1.28). One of them begins with a reaction of styrene oxide and 2-imino-l,3-thiazolidine and subsequent treatment of the resulting product (38.1.28) with thionyl chloride and then with acetic anhydride, which leads to the formation of tetramizole [25]. 

L abbe and Vermeulen have proposed salts of type (105) as key intermediates in the reactions of 5-aminothiatriazole (10) with acyl chlorides (Scheme 19) <81BSB89>. The intermediate is expected to undergo cyclization to 3-imino-A -l,2,4-oxathiazoline (106) followed by reaction with a second molecule of acyl chloride to give the corresponding thiapentalene (107). The formation of the 1,2,4-thiadiazole (104) was explained as a result of an addition of V-acetylcyanamide (108), formed by extrusion of nitrogen and loss of sulfur from 5-acetamido-1,2,3,4-thiatriazole, to the key intermediate... 

In the condensations of o-aminohenzyl alcohol 376 or anthranilic acid 401 with 4,5-dichloro-l,2,3-dithiazolium chloride (Appel s salt) 402, imino-l,2,3-dithiazoles 403 were formed. Heating of the imino alcohol 403 (X = H2) in THE in the presence of NaH afforded an 11 1 mixture of 3,1-benzoxazine 404 and 3,1-benzothiazine 405 in moderate yield. Thermal cyclization of imino acid 403 (X = 0) resulted nearly quantitatively in formation of 3,1-henzoxazin-4-one 406 (Scheme 76) <1995CC1419, 1995J(P 1)2097, 1997SL704>. 

Cyclocarbonylation of o-iodophenols 503 with isocyanates or carbodiimides and carbon monoxide in the presence of a catalytic amount of a palladium catalyst (tris(dibenzylideneacetone)dipalladium(O) Pd2(DBA)3) and l,4-bis(di-phenylphosphino)butane (dppb) resulted in formation of l,3-benzoxazine-2,4-diones 504 or 2-imino-l,3-benzoxazin-4-ones 505 (Scheme 94). The product yields were dependent on the nature of the substrate, the catalyst, the solvent, the base, and the phosphine ligand. The reactions of o-iodophenols with unsymmetrical carbodiimides bearing an alkyl and an aryl substituent afforded 2-alkylimino-3-aryl-l,3-benzoxazin-4-ones 505 in a completely regioselective manner <1999JOC9194>. On the palladium-catalyzed cyclocarbonylation of o-iodoanilines with acyl chlorides and carbon monoxide, 2-substituted-4f/-3,l-benzoxazin-4-ones were obtained <19990L1619>. 

The second arm of the scheme involves first a reaction of the (3-beta ketoester (7-1) with nitrous acid. The first product from nitrosation on the activated carbon spontaneously rearranges to afford oxime (7-2). Treatment with acetyl chloride then affords the (9-acylated oxime (7-3). Condensation of that compound with the imino ether from propionitrile leads to the formation of the imidazole (7-4). 

Fused pyrroles have been prepared by the condensation of an amino group with a suitably positioned carbonyl function. Thus, reduction of ethyl (3-nitro-2-thienyl)pyruvate (226) with tin(IV) chloride gave 5-ethoxycarbonyl thieno[3,2-6]pyrrole (47), by the spontaneous cyclization of the intermediate amino derivative (227 Scheme 76) (64JOC2160). The formation of indolo[3,2-6]indole (229), a dibenzannelated pyrrolopyrrole, by the cyclization of (228) with tin(IV) chloride (Scheme 77) is an example of a case where reduction of the imino function in the starting material is necessary before cyclization will occur (78AHC(22)183). 

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