Imino chloride

Ketenimines are usually prepared from carboxyHc acid derivatives such as amides and imino chlorides via elimination and from nitriles via alkylation with alkyl haHdes under strong basic conditions (21,64). 

An alternate route to ampicillin not only circumvents the need for 6-APA but also has the advantage of providing a prodrug form of ampicillin as well as the parent compound. Reaction of benzylpenicillin (4) with the acid protecting group, 29, gives the formol ester, 30. Reaction of the product with phosphorus pentachloride leads to the corresponding imino chloride (31). 

A base-mediated type lb cyclocondensation of imino chlorides, derived from treating the corresponding A-allylamides with triphenylphosphite-chloride, provided 2-aryl- and 2,3-diarylpyrroles <06S995>. 

Treatment of the product with phosphorus oxychloride leads to a cyclodehydration reaction possibly via the imino chloride. There is thus obtained the antipsychotic compound loxapine (38-7) [39]. 

The preparation of the A -desmethyl analogue, amoxapine (39-7), illustrates an alternate approach in which the oxygen ether linkage is formed last. Reaction of the imidazolide (39-2) from 2,4-dichlorobenzoic acid (39-1) and carbonyldiimidazole with ort/zo-aminophenol (39-3) gives the benzamide (39-4). This is then converted to its imino chloride (39-5) with the ubiquitous phosphorus oxychloride. Treatment of the product with piperazine leads to the amidine (39-6), probably by an addition-elimination sequence. Copper catalyzed displacement of chlorine by phenoxide closes the ring there is thus obtained amoxapine (39-7) [40]. 

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]. 

The fusion of rings on to side d has usually been achieved via adaptations of known reactions of the imine, nitrone or imino chloride functions. Some examples are given for the l,4-benzodiazepin-2-one (202). 

Electrophilic cyclodimerization (to 26) also results when (25) is subjected to Bischler-Napieralski conditions (POCI3, reflux), presumably through reaction of pyrazole with the imino chloride intermediate (78JHC1339). 

Reaction of N,N -disubstituted imino chlorides with base to yield carbodiimides [68]. 

Amides are often cleaved with strong alkali. Fabio Prati of the University di Modena has reported (Organic Lett. 2004,6,3885) that treatment of triphenyl phosphite with chlorine at -30 "C gives a substance that reacts smoothly with amides such as 5 to give the amine 6 as the HC1 salt. The imino chloride is the intermediate, so this also provides a convenient entry to Bischler-Napieralski cyclization. 

Barker and Copeland have reported a slightly modified process for the preparation of 3 (Scheme 10). 29 was reacted with phenylchloroformate to give carbamate 33. The ring closure was affected by heating 33 in polyphosphoric acid at 100 °C to provide 31. The imino chloride 32, formed as in Scheme 9, was treated with piperazine in refluxing toluene to give 34. The piperazine 34 was then alkylated with 2-chloroethoxyethanol in the presence of Nal and Na2CO3 to afford quetiapine, which was isolated as the fumarate... 

A company in Budapest recently reported an alternative synthesis of quetiapine aimed to provide a more economical process (Scheme 11). They sought to avoid the use of imino chloride 32 as an intermediate, because it is rather unstable and is easily hydrolyzed. The carbamate 33 was reacted with l-(2-hydroxyethyl)pipera2ine to give crystalline 35 in 95% yield. The hydroxyethylpiperazine 35 was refluxed in thionyl chloride to provide crystalline chloroethylpiperazine 36 as the hydrochloride salt. Compound 36 was treated with phosphorous oxychloride and phosphorus pentoxide at reflux and 37 was isolated as a crystalline solid from diisopropyl ether in 75% yield. 

If the starting compound contains a hydroxyl group in the a position, an additional dehydration takes place and the product is an isoquinoline. Higher yields can be obtained if the amide is treated with PC15 to give an imino chloride ArCH2CH2N=CR—Cl, which is isolated... 

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