Hydrazonyl chlorides

The pyrazolone-3-carboxyhc acid (71) has been isolated by reaction of oxazolone (70) with hydrazonyl chloride (eq. 18) (46). 

F-Dibenz[/),/]azepines enter into 1,3-dipolar cycloadditions with diarylnitrilimines 14, generated in situ from hydrazonyl chlorides, to give dibenzo[7>,/]pyrazolo[3,4-rf]azepines, e.g. 15, in good yields.233... 

The synthesis of pyrazoIo[5,l-c][l,2,4]triazines was effected (77JHC227 80JHC209) by the preparation of the hydrazonyl chlorides... 

Cyclization of hydrazonyl chloride 797 with aniline gave triazolotriazine 798 (R2 = PhNH) (80JHC209). Cyclization of 797 was also effected by the action of sodium acetate to give 798 (R2 = Cl) (83JHC285). Cyclization of 799 by the action of sulfuric acid gave a triazolotriazine formulated as 800 or 801 (83JHC285). 

Spiro[3H-indole-3,5(4.H)-(l,2,4)triazoline]-2-one derivatives 204 have been obtained using microwave irradiation in the reaction between imines of isatin 203 and nitrile imines generated in situ from the corresponding hydrazonyl chlorides 199 (Scheme 9.63). The yields are in the range 85-95% and the reaction is complete within 5 min [110]. Similar reactions performed under thermal conditions were complete in 6-10 h and yields decreased to 20-30%. However, when the reaction was performed at ambient temperature, the products were obtained in excellent yields but only after a prolonged reaction time (30 h). 

A mild and greener approach to the synthesis of 1,2,4-triazoles by the dipolar cycloaddition of nitrilimines with nitriles has been reported. The nitrilium intermediates were generated in situ from hydrazonyl chlorides 120 and reacted with the nitriles in a one-pot process. Yields of the 1,3,5-trisubstituted products 121a-o were good in the majority of cases (Equation 37 and Table 20) <2005H(65)1183>. 

Reaction of ethyl 5-amino-3-methylthio-l//-pyrazol-4-carboxylate 267 with sodium nitrite in the presence of hydrochloric acid gives the diazo intermediate 268, which on treatment with active methylenic compounds such as ethyl a-chloroacetate or a-chloroacetylacetone affords the hydrazonyl chlorides 269 and 270, respectively, whose reaction with triethylamine in refluxing ethanol convert them into ethyl 4-hydro-2-methylthiopyrazolo[5,l-c]-[l,2,4]triazole-3,6-dicarboxylate 271 and ethyl 6-acetyl-4-hydro-2-methylthiopyrazolo[5,l-c][l,2,4]triazole-3-carboxy-late 272 (Scheme 23) <2001MI1>. 

Benzothiazol-2-ylcarbonylhydroximoyl chloride 255 reacts with 2-aminobenzimidazole in refluxing ethanol to give (2-benzothiazolyl)-2-oxoacetic-(2-benzimidazolyl)hydrazonyl chloride as the presumed intermediate that cyclizes in situ to 3-(benzothiazol-2-yl)carbonyl-l/7-[l,2,4]triazolo[4,3- ]benzimidazole 278 (Scheme 26) <1997T17461>. 

Of the general methods for the generation of transient nitrile imines for use in synthesis (19), perhaps the most convenient are the base-induced dehydrochlorination of hydrazonyl chlorides and the oxidation of hydrazones. Developments in both of these areas have either increased the convenience of the method or given a deeper insight into the reaction mechanism. 

Silver carbonate, when used as the base in the dehydrochlorination of hydrazonyl chlorides, has a unique effect in enhancing yields and favoring particular modes of reaction, for example, in the promotion of the tandem intermolecular-intramolecular synthesis of macrocycles 302 discussed in Section 7.3.2.4 (73). Such differences have led to some investigations into the mechanism of its reaction. In this work (74), the hydrazonyl chloride 134 was reacted with 2 M equiv of silver carbonate in the presence of various allylic alcohols. 

In recent work, a homochiral substituent has been incorporated into the reactant to allow the separation of enantiomerically pure products. Thus, the homochiral reactant 288, prepared from (5)-1-phenylethylamine, gave a pair of diastereoisomers (289) and (290) that were separated by chromatography and identified via X-ray crystallography (178). The nitrile imine was generated by the hydrazonyl chloride-base route. The reaction showed only modest stereoselectivity that favored 289 when silver carbonate was used as the base but it was found that this was reversed when triethylamine was used. However, this was not the case for a related reaction (179). 

Reactants with long tethers (e.g., 300) can also take an alternative path involving hrst an intermolecular cycloaddition with the hydrazonyl chloride precursor to give 301 followed by an intramolecular cycloaddition to give the hL(pyrazolocy-clophanes) (302) (73). Byproducts of this type were also been reported in earlier work (183,188). 

The reactions of nitrile imines with nucleophilic reagents in which the addition is followed by cyclization of the primary product, provide a useful route to heterocycles. In most of these reactions, the experiments were carried out by the treatment of hydrazonyl chlorides, as nitrile imine precursors, with triethylamine in the presence of the nucleophilic reagent. The originators generally made the assumption that it was nitrile imines rather than the hydrazonyl chlorides that were the reacting species. 

Scott et al. [70TL4083 72JHC(P1)2224] reported the condensation of hydrazonyl chlorides of type 63 with 1,2-diaminoethane in aqueous diox-ane to produce 3-aryl-5,6,7-trihydroimidazolo[2,l-c] 1,2,4-triazoles (65). Fusion of an imidazole ring onto a triazole nucleus was the approach used (78UKZ725) in the reaction of 3-amino-2-methyl-5-substituted-l,2,4-triazole (66) with a-haloketones in the presence of perchloric acid to give l-methylimidazolo-[2,l-c]l,2,4-triazolium ions (67). 

McCarthy and co-workers [275] prepared nitrile imines in situ by exposing two hydrazonyl chlorides (210) to basic conditions, and these underwent [2 -i- 3]-cy-cloaddition reaction -with solid-supported-enamines derived from a Merrifield-based piperazine resin and the selected phenylacetaldehyde (209) (Scheme 46). Pyrazoles (212) were then obtained after cleavage from the resin under mildly acidic conditions, the resin functioning as a traceless linker. 

Hydrazonyl chlorides have been employed in the synthesis of 1,2,4-triazoles. Intermolecular cyclization of hydrazonyl chlorides 166 with nitriles catalyzed by ytterbium(I) triflate afforded a series of 1,3,5-trisubstituted-1,2,4-triazoles 167 in good yields <05SC1435>. Dipolar cycloadditions between hydrazonyl chlorides 168 and nitriles in aqueous sodium bicarbonate in the presence of a surfactant provided mild conditions for the syndesis of l-aryl-5-substituted-... 

From (V- 2-[(Cyanomethyl)sulfanyl phenyl hydrazonyl Chlorides (Fragments S - Arene - N - N - C)... 

Diazotization of appropriate 2-substituted arylammes and subsequent coupling with a-halo ketones 1 affords the hydrazonyl chloride 2. When 2 is treated with excess triethylamine in refluxing benzene, the 4,1,2-benzothiadiazines 4a-c and 6a, b are formed.114 The reaction proceeds via the intermediates 3 and 5. On heating 2 for 4-5 hours, the cyanomethyl group of 5 is split off and the 4,1,2-benzothiadiazines 6 a, b are formed. For further syntheses of 4,1,2-benzothiadiazines using this method, see refs 115 and 116. 

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