Dinitrile cyclizations

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. 

In the presence of morpholine and malononitrile, the initial reaction of cyclohex-3-enal with cyanothioacetamide is followed by a condensation with the dinitrile. Cyclization follows through attack of the thiol on a nitrile function and a penta-substituted 477-thiopyran is formed (Scheme 126) <1998RJ0557, 2005RJC1537>. 

Whereas the value of this reaction lies in the forging of the N—A bond, the importance of the C—X bond formation cannot be overlooked since it is often intrinsically necessary in heterocycle formation. It is with reactions of type (2) that this chapter deals. The only previous review article pertaining to this subject is that of E. N. Zil berman4 which does not deal with heterocyclic syntheses specifically. Recent advances justify a new review of the latter area. Principally, the use of three types of reactions are discussed (a) the Ritter reaction (b) reactions involving nitrilium salts and (c) a, j-dinitrile cyclizations. All appear to be variations of the above theme. 

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 dimerization of nitriles, of which dinitrile cyclization appears to be a special case, was studied by Grundmann and his co-workers.111 They convincingly demonstrated that these compounds have the structure 181 or 182. Lazaris et al.llz have suggested that the... 

In the hydrogenation of aliphatic dinitriles, cyclization can also be an important reaction pathway.92 Saturation of succinonitrile, 45, (Eqn. 19.45) over Raney nickel gave pyrrolidine, 49, as the primary product even in the presence of ammonia. 24 Intramolecular condensation of the imine-amine intermediate is apparently a very facile reaction, taking place in preference to imine hydrogenation and the intermolecular ammonia-imine condensation. The... 

In 1904, Jocelyn Field Thorpe and co-workers conducted the first studies of the intermolecular dimerization of nitriles. A short time later, the first example of a dinitrile cyclization was described by Moore and Thorpe. Initially, all products of dinitrile cyclization reactions were characterized as imines. However, in 1955, it was determined that the product of the cyclization of adiponitrile was in actuality an enamine. The enamine structure for the product of dinitrile cyclizations has since been confirmed through numerous other studies, and makes sense chemically. The conjugated enamine would be expected to be more stable than the corresponding nonconjugated P-iminonitrile. 

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). 

An important development in pz chemistry was the successful preparation of unsymmetrical porphyrazines achieved by the cocyclization of two different dinitriles, Fig. 4. This synthetic advance was part of an effort to prepare sulfur appended porphyrazines designed to bind metal ions at the pz periphery as well as in the central cavity (4-6, 21, 22). To avoid the statistical mix of six different isomers from such cyclizations, Hoffman and co-workers (13) developed techniques to selectively prepare specific isomers. Mixed cyclizations are described in all sections of this review. 

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). 

Synthesis. Porphyrazines Mg[pz(A4)], A = S203 crown, 81a, and Mg[pz(A4)], A = S204 crown, 81e, (35%) were prepared by cyclizing the appropriate crown dinitrile 80. Compounds 81a and 81e were demetalated with trifluoroacetic acid and remetalated with either copper or manganese acetate to form compounds 81b-81d and 81f-81h (Scheme 16) (25-27). 

Synthesis. These macrocycles are prepared from seven-membered ring dinitrile complexes, 84a-84c (Scheme 17), which contain either methylene, sulfur or oxygen in the five position (129). These cyclic dinitriles are synthesized by alkylating maleonitrile dithiolate or derivatives thereof with the corresponding dihalide. The dinitriles 84a-84c can be cyclized in magnesium propoxide to form porphyrazines 85a (33%), 85b (19%), and 85c (27%) (Scheme 17), which can be demetalated with trifluoroacetic to form 86a-86c. Additionally, 86a has been remetalated with nickel (87a, 92%), copper (88a, 95%), and zinc (89a, 94%). The sulfur and oxygen derivatives 85b, 85c, 86b, and 86c are of low solubility and are not suitable for further manipulation. 

Synthesis. The synthesis of the. V-polycthcrol porphyrazines is outlined in Scheme 19. The complex Mg[pz(A4)] (95a, 18%), was prepared by cyclizing dinitrile precursor 94 with 4,7-bis(isopropyloxy)- 1,3-diaminoisoindoline... 

The products from the N-alkylation of (anilinomethylene)malonodinitriles with a-haloacetic esters and a-haloketones spontaneously cyclize to produce pyrroles (Scheme 5.3) [21]. When the A -acylated product of the reaction of the dinitrile with ethyl chloroformate is treated with an arylamine, 5-cyanopyrimidones are obtained [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... 

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. 

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. 

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