Imino-bridged heterocycles. II. Regiospecific synthesis of the 11H-benzo[5,6]cyclohepta[1,2-c]pyridin-6,11-imine and 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5,10-imine systems

Regiospecific synthetic pathways for two of the eight isomeric benzocycloheptapyridinimines have been developed based upon intramolecular acid catalyzed additions between an amine function and an internal olefin. The requisite amines were generated from known tricyclic ketones by ketimine formation followed by sodium borohydride reduction.     

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.     

New heterocyclic systems. Benzo[4,5]cyclohepta[1,2-b]pyrrole and benzo[5,6]cyclohepta[1,2-f]pyrrolizidine derivatives

The synthesis of the polycyclic pyrrole acetic acids 9e, 13e and 13g by multistep processes from 1-bromo-4-phenylbutan-2-one ( 6c ) is reported. An instance of the use of the 2-chloroethyl moiety as a pyrrole nitrogen protecting group is described. The α-methylaminoketone ( 6e ) was synthesised by a novel two step process from 6c and methyl N-methylformimidate ( 12 ).     

Imino-bridged heterocycles. VI . An unusual bridge structure resulting from an attempted ritter reaction in the benzo[5,6]cyclohepta[1,2-c]pyridine system

An attempt to generate a tertiary carbinamine from 1 , through use of the Ritter reaction, resulted in the formation of the new bridged system 2 . This product apparently resulted from an intramolecular cyclization of the 5,6 olefin to the C-11 nitrilium ion of 4 , followed by a second Ritter reaction at C-6.     

The preparation of the benzo[4,5]cyclohepta[1,2-b]pyrazine and benzo[4,5]cyclohepta[1,2-b]quinoxaline systems

Benzo[4,5]cyclohepta[1,2-b]quinoxaIine 2 , benzo[4,5]cyclohepta[1,2-b]pyrazine 3a and benzo[4,5]cyclohepta[1,2-b]quinoxaline 4 were prepared from 4,5-benzotropolone and 1,2-phenylenediamine, ethylenediamine and 1,2-diaminocyclohexane, respectively. Compound 3a was methylated to 3b .     

Derivatives of benzo[5,6]cyclohepta[1,2-b]thiophene. Synthesis of 2,3,7,8-tetrahydro-3-oxothieno[1,2-b]cyclohepta[5,6,7-de]isoquinoline and 1,2,3,7,8,11b-hexahydro-3-oxothieno[1,2-b]cyclohepta[5,6,7-de]isoquinoline

The synthesis of the title compounds was carried out by cyclization via isocyanate of (E)-4,5-dihydro-10H-benzo[5,6]cyclohepta[1,2-b]-thiophene-10-ylideneacetic acid and 4,5-dihydro-10H-benzo[5,6]cyclohepta[1,2-b]-thiophene-10-ylacetic acid respectively, which were obtained by the Wadsworth-Emmons modification of the Wittig reaction of 4,5-dihydro-10H-10-oxobenzo[5,6]cyclohepta[1,2-b]thiophene and triethyl phosphonacetate. The structures of these new compounds are described.     

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.     

A new route to benzo[4,5]cyclohepta[1,2-b]naphthalenes: synthesis of radermachol

[formula: see text] Condensation of 3-phenylsulfonyl-1,3-isobenzofuranone (3) with benzocyclohept-6,7-en-5-ones such as 4 and 15 provides a straightforward, general method for synthesis of functionalized benzo[4,5]cyclohepta[1,2-b]naphthalenes (e.g., 5 and 16). This finding was used to achieve a brief and efficient preparation of 6,7-benzo-3,4-(1,4-dimethoxy-2,3-naphtho)-1,5-dioxosuberane (2), an established intermediate to the naturally occurring red pigment radermachol (1).     

Derivatives of benzo[4,5]cyclohepta[1,2-b]thiophene 3. Synthesis of 2,3,6,7-tetrahydro-3-oxobenzo[1,2]cyclohepta[3,4,5-hi]thieno[3,4-c]pyridine and 2,3,7,8-tetrahydro-3-oxothieno[2,1-b]cyclohepta[5,6,7-de]isoquinoline

The title compounds 3 and 4 were synthesized by cyclization via isocyanate of the Z and E-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophene-4-ylidenacetic acids 8 and 9 , which in turn were prepared by the Wadsworth-Emmons reaction of ketone 5 with triethyl phosphonacetate followed by separation and independent hydrolysis of the corresponding esters 6 and 7 . The structures of these new compounds as well as the configurations of their isomeric precursors are described.     

Derivatives of benzo[4,5]cyclohepta[1,2-b]thiophene. 4. Synthesis of 1-(9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-yl)-3-alkylaminoazetidines

Thirteen 1-(9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-yl)-3-alkylaminoazetidines 11 have been synthesized in three steps from 4-amino-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophene ( 6 ), which was obtained from the reduction of either 4-azido 4 or 4-hydroxyimino 5 derivatives. All the compounds have been evaluated as potential antidepressive agents.     

Crystal structure of 6,11-dihydro-6,11-methano-5H-benzo[5,6]cyclohepta[1,2-b]pyridinol-11

X-ray structure of 6,11-dihydro-6,11-methano-5H-benzo[5,6]cyclohepta[1,2-b]pyridinol-11 is determined.     

Heterocycles. Part XII. Synthesis of new benzo[6,7]cyclohepta[1,2-d]pyrimidine

Selected 2-arylidene-1-benzosuberones I were condensed with guanidine hydrochloride to give the corresponding substituted 2-aminopyrimidines II and III respectively. Condensation of chalcones I with benz-amidine hydrochloride revealed the formation of the corresponding substituted 2-phenylpyrimidines IV. The structure of all products was substantiated by chemical and spectroscopic methods.     

Adducts of phenanthrene 9,10-imine and of benz[a]anthracene 5,6-imine to some nitrogen heterocycles

N-4-Pyridinyl-, N-2-quinolinyl-, and 2-pyrazinylphenanthrene 9,10-imines 4–6 , as well as N-4-pyridinyl- and N-2-pyrazinylbenz[a]anthracene 5,6-imines 12 and 13 were prepared by sodium hydride-mediated interaction of the parent arene imines, 1 and 10 , and the respective chloropyridine, chloroquinoline or chloropyrazine. N-Nicotynoyl-, N-2-pyridinoyl- and N-6-quinolinoylphenanthrene 9,10-imines 7–9 were obtained by interaction of N-trimethylsilylphenanthrene 9,10-imine ( 2 ) and the appropriate pyridine- or quinolinecarbonyl chlorides. Reaction of N-methylsulfonylphenanthrene 9,10-imine with thymine, cytosine, 5-fluorocytosine, purine, 6-chloropurine and adenine afforded, in the presence of either potassium carbonate or 1,5-diazabicyclo[3.4.0]non-5-ene, adducts 16–22 , respectively. The structures of the adducts were conformed by multinuclear nmr and by NOESY and C-H correlation 2D nmr spectrometry.     

Benzodifurans. I. The synthesis of benzo[1,2-b:5,4-b]difuran and some methyl analogs

The first parent benzodifuran (XVI) and three di- and trimethylated derivatives have been synthesized and screened for erythemal activity (negative response). Two benzodifurans were prepared from resorcinol and 2-methylresorcinol by acetylation, Fries rearrangement, alkylation of the resulting 4,6-diacetylresorcinols with ethyl bromoacetate, saponification, and then cyclization of the (4,6-diacetyl-1,3-phenylenedioxy)diacetic acids. Another was prepared from the Claisen rearrangement product of 1,3-bis(allyloxy)-2-methylbenzene by acetylation, bromina-tion, and cyclization. Ozonolysis of the Claisen rearrangement product gave additional support to the formulation of o-hydroxyphenylaeetaldehydes as cyclic hemiacetals. The parent benzodifuran was synthesized from 5-formyI-6-hydroxybenzofuran, which was prepared in two steps from 5-bromo-6-methoxybenzofuran. Alkylation of the former with ethyl bromoacetate, saponification, and cyclization furnished benzo[1,2-b.5,4-b ]difuran. The ultraviolet and nuclear magnetic resonance spectra of the four benzodifurans are compared.     

Synthesis of 3H[1,2]diazepino[5,6-b]indole and 3H[1,2]diazepino[4,5-b]indole derivatives

The synthesis of two new derivatives of 3H[1,2]diazepino[5,6-b]indole, 5 and 11 , and one new derivative of 3H[1,2]diazepino[4,5-b]indole, 16 , are described. Compound 5 was obtained by the reaction of methyl 2-(3-methoxycarbonyl-1-methylindole)acetate 2 , with hydrazine. Compound 11 was obtained in two ways from ethyl 2-(1-methylindole)acetate ( 8 ) by formylation and reaction with hydrazine. Compound 16 was obtained treating 3-(2-ethoxycarbonylindole)acetonitrile ( 14 ) with hydrazine.     

Studies on the benzo[1,2]cyclohepta[3,4,5-d,e]isoquinoline ring system

The syntheses of various oxidation states of the novel benzo[1, 2]cyclohepta[3, 4, 5-d, e]-isoquinoline ring system is described. The ring system was obtained by the Schmidt rearrangement, with exclusive alkyl migration, of 1, 6, 7, 11b-tetrahydro - 2H - dibenz-[cd,h]azulen-2-one and by a Bischler-Napieralski reaction of suitable derivatives of 10, 11-dihydro-5H-dibenzo[a, d]cycloheptene - 5 - methylamine. 4, 5, 10, 11 - Tetramethoxy derivatives of the new ring system were best prepared by a Pictet-Spengler reaction of the appropriate amine.