Cyclization of dinitriles

Preparative routes to 5/7-dibenz[6,e]azepine-6,11 -diones (morphanthridinediones) are based mainly on the cyclization of 2-aminobenzophenone-2 -carboxylic acids and their derivatives (55LA(594)89). Studies on a-aminodiphenyImethane-2 -carboxylic acid reveal that cyclization to 5,11 -dibenz[6,e ]azepinone (188) is much slower at room temperature than the cyclizations of the analogous 2-aminobiphenyl-2 -carboxylic acid and the 2 -aminobiphenylacetic acid (189), which at room temperature cyclize spontaneously to phenanthridone and dibenz[f>,d]azepin-6-one (190) respectively (61JOC1329). The hydrogen bromide-induced cyclization of dinitriles (Scheme 16) is adaptable to the synthesis of 2-amino-7-bromo-3//-azepines and 5H-dibenz[c,e]azepin-7-ones (67JOC3325). Apparently, for unsymmetrical dinitriles cyclization is such as always to give the azepine with the bromo substituent attached to the carbon of the a,j8-unsaturated nitrile as exemplified in Scheme 16. 

ZIEGLER METHOD. Cyclization of dinitriles at high dilution in dialkyl ether in the presence of ether-soluble metal alkylanilide and hydrolysis of the resultant imino-nitril with formation of macrocvclic ketones in good yields. 

The reagent is used in the Ziegler cyclization of dinitriles. The greatly simplified technique of Kohler and Schroeder was used by Fry and Fieser" and by Cope and... 

KAISER-JOHNSON-MIDDLETON Dinitrilecyclization Synthesis of heterocycles by cyclization of dinitriles by means of HBr(see 1st edition). 

The Thorpe-Ziegler reaction has been widely utilized in the synthesis of natural products. Deslongchamps and co-workers used the cyclization for construction of the D-ring of the stemodane skeleton in the natural product (-(-)-maritimol. (+)-Maritimol (36), isolated from Stemodia maritime was used as a Caribbean folk medicine for the treatment of venereal diseases. Cyclization of dinitrile 34 was followed by acidic hydrolysis to yield tetracycle 35, The synthesis of 35 represented a formal synthesis of the natural product, as this intermediate could be elaborated to 36 using conditions developed by Piers and co-workers. ... 

Lithium alkoxides play an important role in the oligomeric cyclization of dinitriles in the synthesis of phthalocyanines. The combination of potassium alkoxide-crown ether complex in a hydrocarbon solvent gives a very powerful catalyst for production of vinyl ethers from alcohols and acetylene (Eq. 7.9). ... 

Porphyrazines (pz), or tetraazaporphyrins, are compounds that can be viewed as porphyrin variants in which the meso carbon atoms are replaced with nitrogen atoms, as Fig. 1 shows (1). This difference intrinsically gives porphyrazines discrete physiochemical properties from the porphyrins. In addition, despite their similar molecular architecture, porphyrazines are prepared by an entirely different synthetic route than porphyrins—by template cyclization of maleonitrile derivatives, as in Fig. 2, where the open circle with the A in it represents the peripheral substituent of the pz—rather than by the condensation of pyrrole and aldehyde derivatives (1). The pz synthetic route allows for the preparation of macrocycles with chemical and physical properties not readily accessible to porphyrins. In particular, procedures have been developed for the synthesis of porphyrazines with S, N, or O heteroatom peripheral functionalization of the macrocycle core (2-11). It is difficult to impossible to attach the equivalent heteroatoms to the periphery of porphyrins (12). In addition, the preparation and purification of porphyrazines that bear two different kinds of substituents is readily achievable through the directed cocyclization of two different dinitriles, Fig. 3 (4, 5, 13). 

Following the reports of sulfur appended porphyrazines, Fitzgerald et al. (28) reported a facile synthesis of alkyl appended porphyrazines in 1991, preparing the dialkyl dinitrile precursors from alkynes via a Rosenmund von Braun reaction. Later, these types of dinitriles were used in mixed cyclizations to prepare porphyrazines with three dipropyl substituents (6,29). An intriguing extension was the... 

Porphyrazines are typically synthesized by a templated cyclization of substituted dinitriles, Fig. 2 (2). The most common divalent metal used as the template for this reaction is Mg2+, usually as the butoxide or propoxide, although other group 1(1 A) and 2(IIA) metals have been reported (41). Mixed cyclizations, which utilize two different dinitriles, Fig. 3, in principal, would give a statistical mixture of six different products or isomers. The truly enabling synthetic foundation for modem pz chemistry is the development of strategies directed toward the synthesis... 

M[pz(A3B)]. The preparation of unsymmetrical (A3B) porphyrazines can be achieved by a mixed cyclization of two different substituted dinitriles however, as outlined in Section II, the result of this method is a statistical mix of the six possible isomers formed by all possible combinations of dinitriles. To avoid such a result, it has been shown that stacking the stoichiometry to favor one of the two dinitrile precursors will result in the formation of mostly A4 and A3B (4, 21). 

A very popular route to piperid-4-ones is by a Dieckmann or Thorpe cyclization of appropriate diesters or dinitriles. In most cases the nitrogen atom is tertiary, to avoid the formation of amides as by-products. A simple example is provided by the synthesis of the piperidone ester (129) which, after hydrolysis and decarboxylation, gives the piperid-4-one (130) (45JOC277). The diesters are available by addition of amines to acrylates and so the two ester fragments can be different. For the production of AT-benzoylpiperid-4-one (132) the whole operation from benzamide and ethyl acrylate to the ester (131) can be achieved... 

Okamoto et a/.156 cyclized the dinitriles (86 R = CN, R2 = H) by heating in 15° hydrochloric acid to obtain pyrido[l,2-a]pyrimidine-3-carboxylic acids (89 R2 = H). 2-Aminopyridinium chloride and ethoxymethylene-malononitrile at 110CC yielded 3-cyano-4-imino-4H-pyrido[l,2-a]pyrimi-dine (87 R1 = R2 = H, X = NH) and compound 91. Under similar conditions, 2-amino-3-methylpyridine gave a noncyclized product of type 91. 

Only a limited number of dinitriles which would lead to nonaromatic systems on cyclization have been studied thus far. 

TABLE X. Pyridines Prepared by Hydrogen Halide Cyclization of 1,3-Dinitriles... 

The preparation of derivatives (167) of this ring system by the action of halogen acids on dicyanoguanidines (166) was reported by Kaiser and Roemer107,108 in 1953. Their patents undoubtedly represent the first specific applications of dinitrile cyclization to the synthesis of a heterocyclic system. Excellent yields of 167 were... 

The carbanion generated from the dinitrile 24 causes a Smiles-type nucleophilic rearrangement to produce new anions 25 and 26. The tandem intramolecular cyclization of the latter affords dihydrothiophene 27. Thieno[2,3-3][l,6]naphthyridine 28 is derived from 27 in four steps (Scheme 6) <1995H(41)1307>. 

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