Nitrile imines cyclizations

Another 1,7-dipolar cyclization leading to 1,2-benzodiazepines, but with the difference that a C-C bond is formed, is the ring closure of the nitrile imines 15 to give 17 by a [1,5]-sigmatropic shift of hydrogen in the intermediates 16. The nitrile imines are generated from the (2-vinylphenyl)hydrazonoyl chlorides 14."8 120... 

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. 

Benzothiadiazines (158) are prepared by cyclization of the chlorohydrazones (212) on treatment with triethylamine (81JCS(Pl)2245). The reaction probably involves intramolecular nucleophilic attack by sulfur on a nitrile imine intermediate, since (212) does not cyclize on heating alone. Intramolecular aromatic sulfonation gives 1,2,4-benzothiadiazine 1,1-dioxides (214). Thus treatment of (213) with aluminum trichloride leads to cyclization with bond formation between sulfur and the aromatic ring (79JCS(P1)1043). 

The mesoionic compounds known as sydnones serve as cyclic azomethine imines. Thus, sydnone (167), isolable after preparation from die corresponding nitrosamine, underwent cyclization as an azomethine imine at 20-35 C (Scheme 52).86 Photolysis of sydnones also results in cyclization but through nitrile imine intermediates vide infra). 

Nitrile imine cycloadditions provide access to pyrazolines and pyrazoles. Intramolecular cyclizations to alkynes were first reported in 1974.88 Perhaps the most useful method for generation of nitrile imines involves 1,3-elimination of hydrogen chloride from an a-chlorohydrazone. Tetrazoles and sydnones are also precursors to nitrile imines. 

Nitrile imines can have the alkenyl group attached at either end of the 1,3-dipole, through carbon or nitrogen. Predominantly 1,3-cyclizations have been observed although a few 1,1 -cyclizations have been reported. 

Nitrile imines can cyclize to 1,1-cycloadducts if the dipole-dipolarophile parallel plane approach is unfavorable. Thus, cyclopropanes (175a-b) were independently obtained on short-term reaction of the chlorohydrazone precursors with silver carbonate (Scheme 55).93 Longer reaction times afforded a 3 1 b a ratio from either precursor the products were shown to equilibrate. Heating of cyclopropanes (175a-b) afforded a benzodiazepine. 

The nitrile imine (176), containing a cyclic dipolarophile, cyclized to a tricyclic pyrazoline in 73% yield.89... 

Numerous alkynyl nitrile imines have been shown to undergo cyclization. Typical examples are the preparation of pyrazoles (177) and (178 Scheme 56).90-94... 

Heterocyclic hydrazonyl halides which possess an amino-hydrogen undergo ring closure via 1,3-dipolar nitrile imines which can also be written as 1,5-dipolar ions. 1,5-Electro-cyclization then gives the fused product (Scheme 13). The method has been used for the preparation of 6,7-dihydro-3-aryl-5H-imidazo[2,l-c]-s-triazoles (72JCS(P2)1887),... 

Although in most cyclization reactions the 5(4//)-oxazolones react as 1,3-dipolar reactants (azo-methine ylides) through the mesoionic tautomers, they serve as dipolarophiles with nitrile imines <92H(34)315>. The nitrile imines, generated by the thermal decomposition of tetrazoles (82), add across the 2,3 double bond to generate triazoles (83) after further reaction (Scheme 26). Since the 5(4//)-oxazolones with a hydrogen at position 4 are in equilibrium with the 5(2//)-oxazolones under the reaction conditions, the addition of the nitrile imine also occurs across the 3,4-double bond of these compounds to afford an isomeric triazole (84). Pyrazines (85), which are products of the thermal decomposition of 5(4 0 Oxazolones <76HCA2149>, as well as diarylethylenes (86), are also formed. 

In contrast to the condensed thiatriazinedioxide (Chapter 8.26), the synthetic potential and reactivity of these thiatriazine derivatives has not been widely explored. Prolonged refluxing of (4) in acetic acid led to the cleavage of the tetrazine ring leading to nitrile imine intermediate (5). The intermediate (5) readily underwent intramolecular cyclization to 8-amino-1,2,4-triazolo[4,3-a]pyrimidin-7(8//)-ones (6) (Scheme 1) <87JOC2220>. 

Until recently the products of all nitrile cyclizations by the Thorpe reaction had been formulated as imines, although the products were found in 1955 to be better written as the enamine structure. In order to verify the reaction mechanism of the Thorpe reaction, the solid-state reaction of 84 and Bu OK was monitored by measurement of IR spectra in Nujol mulls. As the reaction proceeds (Scheme 14), the CN absorption of 84 at 2250 cm" decreases and a new CN absorption of the imine intermediate (87) arises at 2143 cm As 87 is converted into 88 by a proton migration, the CN absorption of 87 at 2143 cm" disappears, and only the CN absorption of 88 at 2189 cm remains finally [13]. 

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