Chloroform amidines

N-Alkylideneamino-N-aryloxamyl chlorides N-(a-Ketoacyl)chloroform-amidines... 

The imidazole nucleus is often found in biologically active molecules,3 and a large variety of methods have been employed for their synthesis.4 We recently needed to develop a more viable process for the preparation of kilogram quantities of 2,4-disubstituted imidazoles. The condensation of amidines, which are readily accessible from nitriles,5 with a-halo ketones has become a widely used method for the synthesis of 2,4-disubstituted imidazoles. A literature survey indicated that chloroform was the most commonly used solvent for this reaction.6 In addition to the use of a toxic solvent, yields of the reaction varied from poor to moderate, and column chromatography was often required for product isolation. Use of other solvents such as alcohols,7 DMF,8 and acetonitrile9 have also been utilized in this reaction, but yields are also frequently been reported as poor. 

In conclusion, a scaleable process for the preparation of 2,4-subsituted imidazole from amidines and a-halo ketones is described. This method avoids the use of chloroform as solvent and affords the desired products in consistently good to excellent yields. 

Hydroxythiazolo[3,2-fi][l,2,4]triazoles (176, R = OH) are also available by this route. Treating 167 with methyl chloroformate (sodium hydroxide) and subsequently with sodium methoxide yields 176 (R = OH) (71GEP1942015 72GEP2032173, 72USP3682943). Thiazolo[3,2-fi][l,2,4] triazoles are also available from 2-aminothiazoles via amidines 178. Lead tetra-acetate dehydrogenation of 178 leads to 179 (94MI1). 

Carbamate-bound guanidines have been prepared by the condensation of amines with thioureas linked to insoluble supports as carbamates [519]. The direct reaction of guanidines with resin-bound carbonates or other alkoxycarbonylating agents requires the use of chloroformates or other reactive carbonic acid derivatives [520,521], Carbamate-bound amidines (Entries 7 and 8, Table 3.28) have been prepared by the reaction of amidines with resin-bound 4-nitrophenyl carbonates (0.9 mol/L amidine in DMF/DIPEA, > 4 h [522-524]). 

Wang resin bound 4-nitrophenyl carbonate is a convenient intermediate for the attachment of amines to polystyrene as carbamates (see Experimental Procedure 14.2). Aliphatic amines [82-87], ammonia [88], and amino acids [89] react exothermically with this support, whereas anilines generally require catalysis and/or long reaction times (Entry 3, Table 14.7). For the immobilization of anilines as carbamates, Wang resin derived chloroformate [90-92] generally leads to better results than resin-bound 4-nitrophenyl carbonates. Amidines also react with polystyrene-bound 4-nitrophenyl carbonates to yield /V-alkoxycarbonyl amidines (Section 3.9 [93-95]). Support-bound alkoxycarbonyl hydrazines can be prepared by treating polystyrene-bound phenyl carbonates with hydrazine [96-98]. 

Aryl-l,l-dibromo-2,3-diazabutadienes (223)145 and the JV-amino-amidine (219, R1 = Me, R2 = R3 = Ph) yield 1,3,4-triazolium bromides (220, R1 = Me, R2 = R3 = Ph, R4 = H, R5 = N=CHAr), which with ammonia in chloroform solution give novel derivatives (224) of meso-ionic l,2,4-triazol-3-imines (216). These compounds are of interest in that they belong to a new type of meso-ionic heterocycle in which the exocyclic substituent f (see Table I) is a stabilized carbanionoid residue,... 

The kinetics and mechanism of the phosphorus-catalysed dimerization of acrylonitrile to give 1,4-dicyanobut-l-ene and 2,4-dicyanobut-l-ene have been studied.114 The reactions of aryhminodimagnesium (138) with //-substituted p-cyanobenzophenones, l-cyano-9-fluorenenone, o-, m-, and p-dicyanobcnzcnes, and o-, m-, and p-nitrobenzonitriles have been examined.115 The effect of pressure on the reaction of 3 -methyl- l-(4-tolyl)triazene (139) and benzoic acid in chloroform and acetonitrile has been studied.116 The effect of acids on the rate of urethane formation from alcohols and isocyanates in the presence of alkyltin carboxylates has been examined.117 A Hammett a value has been reported for the amidine group N=CHNMe2 and used for the prediction of the basicity of sites in bifunctional amidines.118... 

Dibromo-4,4 -dicyano-a,y-diphenoxypropane (3.0 g) and anhydrous ethanol (3.0 ml) were dissolved in anhydrous chloroform (40 ml). The solution was saturated at 0°C with dry hydrogen chloride and set aside for 7 day. The iminoether hydrochloride which crystallised out, was filtered off and washed with light petroleum. The solid was added to 12% ammoniacal ethanol (47 c.c.) and the mixture was heated at 60°C for 6 hours. Solution was obtained after 3 hours and the amidine hydrochloride began to cryistallise. The mixture was ice-cooled, and the white crystalline solid was filtered off, washed with 2 N hydrochloric acid, and recrystallised twice from 0.5 N hydrochloric acid. 

The initial synthetic approach to conivaptan HCl (1) employed by the Yamanouchi discovery group26 commenced with commercially available benzazepinone 10. Acylation of 10 with p-nitrobenzoyl chloride provided benzamide 11. Subsequent hydrogenation of 11 over palladium on carbon yielded aniline 12, which was in turn condensed with biphenyl-2-carbonyl chloride to provide bis(amide) 13. Bis(amide) 13 was subsequently heated with copper(II) bromide in boiling chloroform/ethyl acetate to furnish a-bromoketone 14. It is interesting that condensation of a-bromoketone 14 with acetamidine hydrochloride in the presence of potassium carbonate in boiling acetonitrile afforded not only the desired imidazobenzazepine product (1 53% yield, 2 steps) but also the related oxazolobenzazepine 15 (7% yield, 2 steps), which presumably resulted from nucleophilic attack of the benzazepinone oxygen on the amidine moiety followed by loss of ammonia. Separation of oxazolobenzazepine byproduct 15 from imidazobenzazepine 1 by silica gel chromatography followed by treatment of the purified imidazobenzazepine free-base with hydrochloric acid then provided conivaptan HCl (1). 

Thiadiazole S.S -dioxides (336) have been prepared by the cyclization of N-halomethylsulfonyl-amidines and -guanidines (335 Scheme 120) <70JCS(C)1429>. N-chloromethylsulfonyl-isoureas and -isothioureas (337) cyclize in the presence of base and chloroformate esters to yield the related S,S-dioxides (92) which easily undergo chlorinolysis to produce (93 Scheme 121) (see also Scheme 45) (74BSF1580). 

As mentioned above, (7-aza-3-indolyl)acetonitrile (129) was reduced catalytically to give 7-azatr3rptamine (131). Other 7-azatryptamines prepared similarly are 1-methyl, 1-benzyl, 2-methyl, and l-(2-aminoethyl). This patent also describes several other 1-, 2-, and 3-(aminoalkyl) derivatives of the four azaindole isomers. The several 4-, 5-, 6-, and 7-azaindolylalkanonitriles were also treated with hydrolylamine to give amidoximes and with hydrogen chloride in chloroform, followed by ammonia to give amidines. ... 

A, A -Diphenylformamidine 85 6 Formanilide (2.4 g, 0.02 mole) is added slowly, in small portions, to a cooled solution of PC15 (4.8 g, 0.023 mole) in chloroform (20 ml). When the reaction subsides, a chloroform solution of freshly distilled aniline (1.9 ml, 0.02 mole) is added, causing an immediate precipitation. The mixture is heated under reflux for 2.5 h, then cooled in an ice-bath and filtered. The solid amidine salt is collected, washed with cold acetone, and dried in a vacuum. The free amidine base was obtained therefrom by treatment with alcoholic sodium ethoxide solution. The crude amidine crystallizes in an ice-bath and is filtered off, washed with cold alcohol, dried, and extracted with acetone. Pouring the acetone solution into water precipitates the amidine. One more precipitation from acetone by water gives material of m.p. 140-141° (2.6 g, 66%). 

Aggarwal, V.K. and Mereu, A. (2000) Amidine-promoted addition of chloroform to carbonyl compounds. The Journal of Organic Chemistry, 65, 7211-7212. 

Chloroform/sodium hydroxide/ benzyltriethylammonium chloride Nitriles from amidines... 

Scheme 10.32. Alkylation on oxygen. Benzamide (benzenecarboxamide) is alkylated by triethyloxonium tetrafluoroborate [(CH3CH2)30 BF4 ] on oxygen in chloroform (CHCI3) solution. Subsequently, the benzimidate tetrafluoroborate salt can be aminated by treatment with ethanolic ethanamine (ethylamine, CH3CH2NH2) to produce the corresponding amidine.

Reactions. BSF is readily acylated with acid chlorides and chloroformate esters to provide Al-TMS-iV-formylamides and carbamates, respectively, which readily undergo protodesilylation (eq 17). BSF reacts with 2 equiv of an alkyl or aryl isocyanate to give l,3,5-triazine-2,4-diones in good to excellent yields (eq 18). In the case of orthocarboxamides, iV-formylform-amidines can be obtained (eq 19) ... 

Another mild method for the activation of the oxime hydroxyl group consists in its conversion into an ester moiety or, more commonly, into a sulfonate derivative. They can be rearranged into amides under basic [371] or acidic [372] conditions also involving Lewis acids [366]. Trimethylsilyl chloride [373] and chloroformate [374] in the presence of a Lewis acid can also be used. Amidines have been obtained by Beckmann rearrangement of a tosyloxime in the presence of benzotriazol [375]. 

Type D Syntheses [CNCSN].— The condensation of N-chloro-amidines (76) and potassium methyl cyanoiminodithiocarbonate (77) in chloroform below 5 C yields 2-imidoyl-3-imino-5-methylthio-A -l,2,4-thiadiazolines (78) in one stage. The reductive and hydrolytic ring cleavage of the products was briefly outlined. ... 

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