Hydrogenation Accompanied by Cyclization

Primary and secondary y- and 8-aminonitriles may lead to ring closure to form five-and six-membered compounds, respectively. For example, the hydrogenation of 2-nitro- or 2-amino-4,5-dimethoxyphenylacetonitrile with Raney Ni gives 5,6-dimethoxyindole (eq. 7.58).109 

Hydrogenation of phthalonitrile over Raney Ni does not give the corresponding diamine, but isoindoline in 91-98% yields due to extensive occurrence of cyclization (eq. 7.59).110 Likewise, hydrogenation of succinonitrile and glutaronitrile leads to the formation of pyrrolidines and piperidines, respectively. 

Hydrogenation in a dilute solution is also effective to suppress the cyclization. Thus, when succinonitrile was hydrogenated in THF-NH3 over Raney Co and CaO at 120°C and 20 MPa H2, an 88% yield of 1,4-butanediamine was obtained by adding a THF solution of succinonitrile drop by drop during a 100-min period.113 When hydrogenation was carried out in usual way, the yield of the 1,4-diamine decreased to 72.7%. 

Cyclization also occurs extensively with glutaronitriles. In hydrogenation of 1,3-dicyano-2-propanol with Raney Ni, the formation of 4-hydroxypiperidine predominated over the formation of l,5-diamino-3-propanol even in the presence of liquid ammonia.114 Hydrogenation in the absence of ammonia further increased the yield of the piperidine (eq. 7.62). Adiponitrile was transformed to azacycloheptane in high selectivity in the hydrogenation over y-Al203-supported Ni catalysts in a continuous process at 170°C and 0.1 MPa H2 in the absence of ammonia.115 

Cyclization occurs readily in the hydrogenation of o-phenylenediacetonitrile where the seven-membered benzotetrahydroazepine is formed in 54% yield over a nickel catalyst.116 Similarly, in hydrogenation of 4,5-bis(cyanomethyl)veratrole (13) with Raney Ni, the desired 4,5-bis(2-aminomethyl)veratrole (14) was obtained in only a 25% yield together with a 38% yield of the benzotetrahydroazepine 15 (eq. 7.63).117 

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In some instances, ring contraction is accompanied by cyclization to indole derivatives. For example, l-aryl-6-oxo-l,4,5,6-tetrahydropyridazines with a carboxyl or methyl group at position 3 give indoles when treated with an ethanolic solution saturated with hydrogen chloride or in the presence of BF3 etherate. 

A very efficient, stereospecific synthesis of DL-ribose was based26 on the use of l,l-diethoxy-5-(tetrahydropyran-2-yloxy)-2-pentyn-3-ol as the substrate. Catalytic hydrogenation of this alkyne to the cts-alkene was accompanied by cyclization, to give 2-ethoxy-2,5-dihydro-5-(tetra-hydropyran-2-yloxy)furan (35). cis-Hydroxylation of the double bond in 35 was effected with potassium permanganate, yielding the ethyl DL-ribofuranoside derivative 36, which was hydrolyzed to DL-ribose. 

Hydrogenation of 1,4- and 1,5-diketones over platinum metals may be accompanied by cyclization to give tetrahydrofurans and terahydropyrans, respectively.133,134 The hydrogenation of 2,6-heptanedione over Pt-C at 200°C in cyclohexane gave 40% of 2,6-dimethyltetrahydropyran, together with 43% of 3-methylcyclohexanone and 15% of 3-methylcyclohexanol, which resulted by an intramolecular aldol condensation and subsequent hydrogenation.134... 

Another example of a transannular cyclization that occurs in the solid state is provided by the epoxy alcohol 31. This compound is stable when dissolved in organic solvents and in 0.25N sulfuric acid. However, the crystals transform rapidly to 32. Although the process is accompanied by partial melting, it appears to be a true solid-state one. Interestingly, the reaction is slowed down appreciably when the dry crystals are covered with ether. Hydrogen bromide is eliminated in the reaction and it may be that an acid-catalyzed process is also occurring in the presence of solvent this process may be slowed down by the dissolution of the decomposition products in the solvent (77). 

Ionic hydrogenation of the same bicyclic diene 382 by Et3SiH in the presence of CF3COOH at room temperature or at 80 °C via ions 387 and 388 is accompanied by transannular cyclizations (equation 139)192. The behavior of diene 382 under Ritter reaction conditions (MeCN, H2SO4) reveals new possibilities to control the transannular cyclizations (equation 140)193. Depending on the sulfuric acid concentration, the reaction temperature and the presence of a nucleophilic solvent, these transformations can be directed to the formation of either the bicyclic amides 389 and 390 having the precursor structure or the tricyclic products 391193. 

The direct cyclization of 5-styrylpyrazole-4-carboxylic acids can be accomplished only if N-1 is substituted by methyl [83H(20)1581]. Otherwise, the three-step route (hydrogenation, cyclization, and dehydrogenation) remains an alternative (Section II,A,l,a). An exception is the cyclization of phenylbenzofuranpropionic acids which forms dibenzofurotropone systems this reaction is accompanied by spontaneous dehydrogenation [78IJC(B)567],... 

Formation of a 1,2-diazocine by cyclization or ring closure has been almost exclusively accomplished by formation of the N=N or N-N bond by coupling of open-chain dinitro or diamino compounds. Reaction of o.o -dinitrodiphenylethane with zinc accompanied by hydrogen chloride (09CR401) or barium hydroxide (75MI4) yielded 8 or its N-oxide, respectively. The latter compound and the N,N -dioxide of 8 were formed by oxidative and reductive coupling of o.o -diamino- and o.o -dinitrodiphe-... 

Indole synthesis.3 A general indole synthesis involves reaction of an o-nitrotoluene derivative with dimethylformamide dimethyl acetal in refluxing DMF with removal of the methanol to form a nitro N,N-dimethyl enamine. Reduction of the nitro group is accompanied by spontaneous cyclization to an indole. Catalytic hydrogenation is generally preferred for this step. 

Change of solvent to benzene also yields these dimers which are accompanied by the adducts (78) and the furan (79). The adducts (78) are formed via a hydrogen abstraction pathway. The photochemical isomerization of the spirocyclopropane derivatives (80) affords the carbazole derivatives (81). This reaction involves ring-opening of a cyclopropyl bond followed by cyclization of the resultant biradical. An oxidative step must also be operative. 

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