Circular dichroism spectra of 1,2,3,4,5,6-Hexahydro-2,6-methano-3-benzazocines

Circular dichroism curves of levorotatory 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-8-ol derivatives have been determined and correlated with stereochemical features. Compounds with the rectus configuration at C-6 were found to exhibit negative extrema for the long wavelength phenolic π → π* transition. The remaining Cotton effects have been ascribed to specific aromatic π → π* transitions.     

A regiospecific synthesis of 8-Methoxy-1,2,3,4,5,6-hexahydro-1,6-methano-3-benzazocines

A regiospecific synthesis of the 6-methoxy-1,2,3,4,5,6-hexahydro-1,6-methano-3-benzazocine system is reported.     

Syntheses of analgesics. Part XXX.. Conformational studies of diastereoisomeric quaternary ammonium salts of 1,2,3,4,5,6-Hexahydro-2,6-methano-3-benzazocines

The configuration of the quaternary ammonium salts (Va and Vb) from 3-benzyl-1,2,3,4,5,6-hexahydro-8-hydroxy-6,11-dimethyl-2,6-methano-3-benzazocine. (II) and 3-methyl-2-butenyl bromide was determined spectroscopically. Moreover, configurational studies on 3-benzyl (VIa and VIb) and 3-(3-methyl-2-butenyl)benzazocinium bromides (VIIa and VIIb) were also achieved.     

Synthesis of 1α and 1β-acylamino and alkylamino-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines and related compounds

The synthesis of series of 1α and 1β-alkylamino-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines from the corresponding acylamino intermediates is described. Cyclization of the 1β-chloromethylamido derivative 20 to the novel bridged benzomorphan 21 occurred whereas the corresponding 1β-chloromethylamido derivative 19 failed to cyclize for steric reasons. In addition several related 1α-acylamidomethyl- and 1β-alkyl-aminomethyl benzomorphans are reported.     

Synthesis of 1,5-methano-3-benzazocines by intramolecular Buchwald-Hartwig arylation of 2-piperidinones

A conceptually novel route to 1,5-methano-3-benzazocines based on an intramolecular Buchwald-Hartwig arylation was developed. The reaction required the use of the zinc enolate of the piperidinone substrates. These substrates, piperidin-2-ones with a 2-bromobenzyl substituent in the 5-position were prepared by reductive amination of 4-formyl esters. The latter could be obtained via Michael addition of enamines, derived from 3-arylpropanals, to ethyl acrylate.     

Syntheses of benzomorphan and related compounds. Part III. An alternate synthesis of 3-substituted-1,2,3,4,5,6-hexahydro-8-hydroxy-2,6-methano-6,11-dimethyl-3-benzazocine

Reduction of the appropriate Schiff bases gave 5-benzylamino-3-methyl-2-pentene (XVII) and l-benzylamino-3-methylpentane (XVIII), the condensation of which with methyl 3-(4-methoxyphenyl)-2,3-epoxypropionate afforded a mixture of the isomeric 1-benzyl-2-(4-methoxy-benzyl)-3,4-dimethyl-4-hydroxypiperidines (XIXa and XIXb). The piperidinols were heated with hydrobromic acid, respectively, to afford 3-benzyl-1,2,3,4,5,6-hexahydro-8-hydroxy-2,6-methano-6,11-dimethyl-3-benzazocine (II). Since the conversion of II to pentazocine (Ic) had already been accomplished, an alternate synthesis of Ic was achieved.     

Synthesis of 1,5-methano-2-benzazocines from 3-hydroxy-1,3-dimethyl-6-phenyl-4-piperidone

Reaction of 3e-hydroxy-1e,3a-dimethyl-6e-phenyl-4-piperidone with cyanoacetic ester affords 6e,8a-dimethyl-2-oxo-5e-phenyl-3-cyanofuro[2,3-c]piperidine, the epoxide of which undergoes intramolecular cyclization on treatment with 80% H₂SO₄, to give 1,2,5,6-tetrahydro-2-endo-4-dimethyl-1,5-methano-6-oxo-2-benzazocin-3-ene. It has been found that the latter is formed via the intermediate 3-hydroxy-6e,8a-dimethyl-2-oxo-5e-phenylfuro[2,3-c]piperidine.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1371–1374, October, 1986.     

Syntheses of the opioid substructures 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine and 2,3,4,5-tetrahydro-1,5-methano-1H-2-benzazepine

Concise syntheses of 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine (12) and 2,3,4,5-tetrahydro-1,5-methano-1H-2-benzazepine (18) are described and involve an intramolecular Friedel-Crafts alkylation and an intramolecular Heck cyclization as their respective key ring-forming steps.     

Total synthesis of 2,6-dimethylergolin-8α-amines

A stereoselective total synthesis of the racemic form of the 2,6-dimethylergolin-8ã-amine derivative III , previously obtained semi-synthetically from lysergic acid, is described. Starting from the commercially available tricyclic lactam 1 , the 9,10-didehydroergoline skeleton containing an angular Me group in position 3 (see 18 ) is built up in several steps applying a Woodward D-ring annelation sequence. The introduction of the 8-amino group is achieved with complete diastereoselectivity to give exclusively the 8ã-derivative 22. Subsequently, a Wagner-Meerwein-type migration of the angular Me group yields the 2-methylated 9,10-didehydroergoline derivative 31. The feasibility of this key transformation was tested on the two model systems 4 and 7 prior to the evaluation of the total synthesis. A stereoselective Birch reduction to the trans-fused ergoline, and deacetylation/acylation conclude the total synthesis of the racemic target compound 34. In addition, the resolution of an early intermediate (see 3 ) by chromatography on a chiral stationary phase is presented which demonstrates that the described total synthesis could also be used for the preparation of the biologically active (5R,8S,10R)-enantiomer III .     

Facile synthesis of fused purines from 8-aminotheophylline

Fused purines 3a-f were prepared by one-step from 8-aminotheophylline ( 1 ) and α,ω-dibromoalkanes in N, N-dimethylformamide in the presence of sodium hydride. Reaction of 3c-e with chloroacetyl chloride followed by treatment with dimethylamine gave 6a-c . A one-step reaction of 1 with ethyl bromopropionate gave 1,3-dimethyl-1,2,3,4,6,7,8,9-octahydropyrimido[2,1-f]purine-2,4,8-trione ( 7b ). Facile syntheses of 7a, c, d from 1 were also carried out.     

Facile synthesis and herbicidal evaluation of 4H-3,1-benzoxazin-4-ones and 3H-quinazolin-4-ones with 2-phenoxymethyl substituents

Series of 4H-3,1-benzoxazin-4-ones and 3H-quinazolin-4-ones with phenoxy-methyl substituents were rationally designed and easily synthesized via one-pot N-acylation/ring closure reactions of anthranilic acids with 2-phenoxyacetyl chlorides to yield the 4H-3,1-benzoxazin-4-ones, and subsequently substituted with amino derivatives to obtain the 3H-quinazolin-4-ones. The herbicidal evaluation was performed on the model plants barnyard grass (a monocotyledon) and rape (a dicotyledon), and most of the title compounds displayed high levels of phytotoxicity. The active substructure and inhibitory phenotype analysis indicated that these compounds could be attributed to the class of plant hormone inhibitors. A docking study of several representative compounds with the hormone receptor TIR1 revealed an appreciable conformational match in the active site, implicating these compounds are potential lead hits targeting this receptor.     

Facile and convenient synthesis of 2,6-disubstituted 4H-1,3-oxazin-4-one derivatives

Facile and convenient methods for the preparation of a variety of 2,6-disubstituted 4H-1,3-oxazin-4-ones 3 by three complementary methods are described. Treatment of the branched aliphatic imidate 2c,d with diketene 1 in the presence of a catalytic amount of acetic acid affords 2-substituted 6-methyl-1,3-oxazin-4-ones 3c,d , whereas the unbranched imidate 2b,e gave oxazines 3b,e and pyrimidines 4b,e (Method A). The reaction of acyl Meldrum's acid 5 with imidate 2 afford 2,6-disubstituted oxazine 3, though the alkylimidate with acetyl Meldrum's acid yielded 3 and 5-acetyl-1,3-oxazine-4,6-dione 8 (Method B). The cylodehydration of acylacetylcarboxamide 13 with acid, such as 70% perchloric acid or fluorosulfonic acid, afforded 1,3-oxazines 3 (Method C).     

Facile and general synthesis of quaternary 3-aminooxindoles

A novel approach to the valuable quaternary 3-aminooxindole skeleton is reported on the basis of intramolecular arylation of enolates of substituted amino acids. The reaction tolerates dialkyl- and arylalkylamines as well as a range of carbon substituents (primary and secondary alkyl, aryl). The cyclization of N-indolyl-substituted substrates is accompanied by direct C-H arylation of the indole, leading to indolo-fused benzodiazepines.     

γ-Radiolysis of 5-fluorouracil and 5-fluorouridine derivatives having sulfur-containing substituents

γ-Radiolysis reactions of eight 5-fluorouracil (5-FU) derivatives having sulfonyl group-containing substituents at the 1-position and five 5-fluorouridine (5-FUR) derivatives having thioureido group-containing substituents were studied under the conditions where hydrated electron (e_aq^?) and hydroxyl radical (HO·) become the principal reactive species. The 5-FU and 5-FUR derivatives were radiolyzed to give 5-FU and 5-FUR, respectively. The efficiency of the reactions depended upon the nature of reactive species and also upon the nature of substituents. The reactivity features of the γ-radiolysis reactions are discussed.