Synthesis and reactions of some dihydro and tetrahydro-4H-imidazo[5,4,1-ij]quinoline derivatives

Reaction of phenyl N-(8-quinolinyl)carbamate with sodium borohydride afforded 1,2-dihydro-4H-imidazo-[5,4,1-ij]quinolin-2-one, 2a . The 5,6-double bond of 2a was functionalized by reaction with nitrosyl chloride to give the nitroolefin 4 and by reaction with hypobromous acid to give the trans-bromohydrin 5 . Reaction of 5 with sodium azide led to the rearranged trans-6-azido-5-ol 7 , the structure of which was determined by ¹H nmr studies.     

Studies Directed Toward the Regioselective Carboxylation of the 4-Oxo-4,5,6,7-Tetrahydrothieno-[3,2-C]pyridine Ring System

Carboxylation of 4-oxo-4,5,6,7-tetrahydro[3,2-c]pyridine was achieved using a metallation/carbonylation strategy with desired regioselectivity provided by the existing oxo directing group.     

Imino-bridged heterocycles. I. A derivative of benzo[5,6]cyclohepta[1,2-b]pyridin-5,11-imine

The current interest in structures that contain a tricyclic framework with a nitrogen bridged central ring has prompted us to examine the synthesis of imino-bridged benzocycloheptapyridines. Treatment of 5,6-trans-dibromobenzo[5,6]cyclohepta[1,2-b]pyridin-11-one with anhydrous methyl amine in THF produced 6-β-bromo-5,6-dihydro-11α-hydroxy-12-methyl-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-5,11-imine, the first example of the desired bridged derivatives.     

Benzocycloheptapyridines. Analogs of azatadine

Certain 3-substituted derivatives of cyproheptadine ( 1a ) have been shown to possess potent pharmacological properties. The structural analogy between cyproheptadine and azatadine ( 2 ) prompted the preparation of 9-substituted derivatives of 2 and its 5,6-dehydro analog for pharmacological comparison. The 9-cyano and 9-trifluoromethylthio derivatives were prepared by direct displacement of the corresponding 9-bromo compounds. Acid hydrolysis of the nitriles generated the carboxylic acids. Oxidation of the trifluoromethylthio compounds 15a and 18a gave the epoxy sulfones 19a and 19b , which could not be deoxygenated. Therefore, the trifluoromethylsulfonyl moiety was introduced prior to the formation of the exocyclic olefin.     

Synthesis and derivatization of novel 4-aroylthiophene-and furan-2-sulfonamides

Sulfonation of 3-aroylthiophenes and furans with sulfuric acid in acetic anhydride regioselectively affords the corresponding 2,4-disubstituted heterocycle. Benzylamine derivatives of the parent sulfonamides are obtained either by Mannich reaction of aryl phenols, or via a sequence employing free radical bromination followed by selective ammonolysis. This methodology provides ready access to a wide variety of regioselectively-substituted heterocycles.     

Imino-Bridged heterocycles. V . Synthesis of 6,11-dimethyl-1 1H-benzo[5,6]cyclohepta[1,2-c]pyridin-6,11-imine by a regiospecific amide to olefin cyclization

Attempted utilization of sulfenimines 6a,b to prepare tertiary carbinamines as intermediates to the desired 6,11-dimethyl-11H-benzo[5,6]cyclohepta[1,2-c]pyridin-6,11-imine system ( 10 ) instead gave products resulting from nitrogen-sulfur bond cleavage. The preparation and use of the corresponding sulfonimine 8 , however, led to 10 through a regiospecific base-catalyzed reaction.     

Activated esters of substituted pyrazinecarboxylic acids

N-Amidino-3,5-diamino-6-chloropyrazinecarboxamide ( 1 ) has been shown to be an effective potassium sparing diuretic. Various carboxyl activating agents have been employed with 3-amino-pyrazinecarboxylic acids in an effort to synthesize analogs of 1. Stable enol esters were isolated from a number of such acids and N-t-butyl-5-methylisoxazolium perchlorate ( 12 ). Although strong bases in DMF or DMSO catalyze a competing destruction of the enol ester system, these esters are useful acylating agents for a variety of nucleophilic substrates in less polar media. Amides, esters, and thiol esters are produced in good yields under mild conditions from these activated esters.     

Imino-bridged heterocycles. III . Synthesis of mono-bridgehead substituted 11H-benzo[5,6]cyclohepta[1,2-c]pyridin-6,11-imines by regiospecific amine to olefin cyclizations

Employing regiospecific amine to endocyclic olefin and hydroxylamine to exocyclic olefin cyclizations, we have developed pathways to two isomeric, bridgehead methyl-substituted benzo[5,6]cyclohepta[1,2-c]pyridin-6,11-imines. Acid catalyzed cyclization of 5 to 6 was accomplished under exceedingly mild conditions (silica gel/chloroform), whereas, thermal cyclization of 20 to generate 21 was performed analogously to the dibenzo[a,d]cyclohepten-5,10-imine system.     

A Convenient Synthesis of 4-Aminomethyl-L-Phenylalanine

N-Boc-4-Aminomethyl-L-phenylalanine is prepared from N-Boc-4-Iodophenylalanine in 78% yield over three steps. The method features an efficient Pd-catalyzed carbonylation, oxime formation, and subsequent catalytic reduction employing an ethanol/water/acetic acid solvent system which is crucial to successful reaction.     

Carboxylic n,N-diphenylcarbamic anhydrides. New acylating agents

Carboxylic N,N-diphenylcarbamic anhydrides have been isolated from the reaction of carboxylate salts with 1-(N,N-dipheriylcarbamoyl)pyridinium chloride in aqueous or ethanolic solution. These anhydrides have been shown to be stable, crystalline derivatives and to be very reactive in acylation reactions. A comparison of pyrazinecarboxylic acid derivatives demonstrated these products to be more reactive than cyanomethyl esters or the so-called Woodward's esters, acyloxyacrylamides.