Iminochloride

Because of the structural requirements of the bielectrophile, fully aromatized heterocycles are usually not readily available by this procedure. The dithiocarbamate (159) reacted with oxalyl chloride to give the substituted thiazolidine-4,5-dione (160) (see Chapter 4.19), and the same reagent reacted with iV-alkylbenzamidine (161) at 100-140 °C to give the 1 -alkyl-2-phenylimidazole-4,5-dione (162) (see Chapter 4.08). Iminochlorides of oxalic acid also react with iV,iV-disubstituted thioureas in this case the 2-dialkylaminothiazolidine-2,4-dione bis-imides are obtained. Thiobenzamide generally forms linear adducts, but 2-thiazolines will form under suitable conditions (70TL3781). Phenyliminooxalic acid dichloride, prepared from oxalic acid, phosphorus pentachloride and aniline in benzene, likewise yielded thiazolidine derivatives on reaction with thioureas (71KGS471). 

Early attempts to produce cephalosporin analogs by varying the 7-acylamino substituent were frustrated because, in contrast to previous experience with penicillins, a good method for producing the necessary 7-amino compound (33a) could not be found. This problem was finally solved when it was discovered that diazotization of the a-aminoadipyl residue produces an iminolactone (33b) which can be hydrolyzed to the free amine in good yield. Subsequently an improved procedure was developed which involves silylation of the carboxyl groups followed by reaction with phosphorus pentachloride to yield iminochloride (33c)... 

Ingham proposed the following sequence to explain the formation of oxazole products following his study of the reaction of benzaldehyde with mandelonitrile and hydrogen chloride. In the event, addition of hydrogen chloride to the cyanide is the first step providing the intermediate iminochloride 5 (Ari = Ph), which upon reaction with benzaldehyde affords oxazole 2 (Ari, Ar2 = Ph) via intermediate 6 (Ari, Ar2 = Ph). 

Condensation of Af-aryliminochlorides with malonic ester followed by thermal cyclization, as initially reported by Just, was found to be a general method for the preparation of 2, 3, 4-substituted quinolines. Various substituents on the aryl ring of the iminochloride proved uneventful, even though the conditions required to generate the iminochloride utilized PCI5. 

In the Meth-Cohn quinoline synthesis, the acetanilide becomes a nucleophile and provides the framework of the quinoline (nitrogen and the 2,3-carbons) and the 4-carbon is derived from the Vilsmeier reagent. The reaction mechanism involves the initial conversion of an acylanilide 1 into an a-iminochloride 11 by the action of POCI3. The a-chloroenamine tautomer 12 is subsequently C-formylated by the Vilsmeier reagent 13 derived from POCI3 and DMF. In examples where acetanilides 1 (r = H) are employed, a second C-formylation of 14 occurs to afford 15 subsequent cyclisation and... 

It was found inadvisable to use more than four molecules of form-amide [ (47) when R = H] per molecule of anthranilic acid and the condensation produces best results when the mixture is heated at 120 -130°C for 2 hr followed by further heating at 170°-180 C for 2 hr. Other variants of this reaction involve the use of ammonium o-acylaminobenzoates, anthranilic acid in the presence of nitriles and acetic anhydride, o-acetamidonitrile with acetic anhydride or hydrogen peroxide, anthranilic esters and aliphatic or aromatic amides or amidines, isatoic anhydride with amides or amidines, and anthranilic esters with aryl iminochlorides in acetoned The mechanism proposed by Bogert and Gotthelf has had experimental supporR and is represented in Scheme 12. 

Tile easy availability of (di)nitronaphthyridones, in which the lactam part can easily be converted into an iminochloride, has successfully led to preparation of the parent (di)nitronaphthyridines by removal of the chloro atom. For that purpose the chloro atom in the 2- and 4-chloro derivative of the 3-nitro-l,5-, -1,6-, and -1,8-naphthyridines (78a-78e) was first substituted with tosylhydrazine to give the corresponding tosyl-hydrazide, which then was hydrolyzed in alkaline solution into the corresponding 3-nitro-l,5-, -1,6-, and -1,8-naphthyridines (79a, 79b, and 79c). 

The ketone synthesis of Houhen and Hoesch, which is based on the principle of the Gattermann reaction, proceeds very smoothly and gives very favourable results, especially in the case of polyhydric phenols. In this synthesis nitriles are used. Here it is the iminochlorides R—C=NH which are converted into ketimines and then into ketones, a... 

An arylamidine found subsequently to have anti-arrythmic activity was actually synthesized in the hope of producing a hypoglycemic agent. Iminochloride 198 is prepared from the corresponding benzamide and the chlorine i displaced with n-amylpiperidine to... 

Finally, replacement of the methylene bridge by a sulfur bridge leads to compoxmds such as 117 and 123 which are major tranquilizers. Thus, Ullmann condensation of thiosalicylic acid 112 with ortho-chloronitrobenzene affords thioether 113 the nitro group is then reduced to the aniline (114). Cycliza-tion as above leads to the lactam 115, which is then converted to the iminochloride derivative (116). Condensation with N-methylpiperazine affords clothiapine... 

Action of hydroxylamine on N-acylated amidines, iminochlorides and iminoethers [C]... 

It has been found [25f) that acyliminoethers which are more easily available than iminochlorides or amidines, also yield oxadiazoles when treated with hydroxylamine at 0° C. 

The chemistry of imidates and their methods of synthesis have been reviewed [32], Imidates are mainly available via the Pinner synthesis, via iminochlorides, from amides, from aldehydes and ketones, and via unsaturated systems [32]. 

Aminopyridine (32) with PhCOCHBrPh gives (33), and 2-aminobenzothiazole (34) with iminochloride (35) gives (36). 

The synthesis of thieno[3,4-6][ 1,5]benzothiazepin-10(9/7)-ones (60) was carried out by cyclizing mercaptans 59 in the presence of polyphosphoric acid the reaction afforded compounds 60 and benzothiazoles 61 in approximately equal amounts. Lactams 60 were transformed into 10-piperazinyl derivatives 63 directly on treatment in refluxing toluene with piperazines or through the formation of iminochloride intermediates 62, which then reacted with an excess of piperazines under the same experimental... 

Dihydropyrido[2,3-6][l,5]benzothiazepin-5(6//)-ones (104) were obtained by cyclocondensation of 5 and 2-chloronicotinic acid (103) the reaction of compounds 104 with phosphorus oxychloride and phosphorus pentachloride afforded the corresponding iminochlorides which were refluxed in toluene with piperazines and triethylamine to give compounds 105. These products showed antihistaminic, orexigenic, and antianaphy-... 

The chemical synthesis of 7-ACA (Fig. 3) is a classical organic route, which uses equimolar amounts of chemicals. A preferred process is the so-called iminoha-lide/iminoether deacylation route, involving formation of the iminochloride by reaction with PCI5, conversion into the iminoether by treatment with alcohol and hydrolysis with water [7]. Highly purified cephalosporin C, isolated, for example as the zinc salt, is required as a dried solid as the starting material. 

In the standard form of this route, a carboxylic acid is heated with the orffto-disubstituted benzene orf/to-amino-phenol, -thiophenol or -aniline. An iminoether will react at a much lower temperature and iminochlorides, generated in situ using the acid, triphenylphosphine and hot carbon tetrachloride, can be used for benzimidazole or benzoxazole synthesis. Orthoesters with a KSF clay is a highly recommended variant and can be used for the synthesis of all three unsubstituted benzo-l,3-azoles. ... 

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