Radical deoxygenation of 3-azatricyclo[2.2.1.0]heptan-5-ols to 2-azabicyclo[2.2.1]hept-5-enes and 1,2-dihydropyridines

Additions of alkyl or aryl Grignard reagents, or pyridin-3-yl-lithiums or lithium alkoxides, to exo-5,6-epoxy-7-(tert-butoxycarbonyl)-2-tosyl-7-azabicyclo[2.2.1]hept-2-ene lead to 7-substituted-1-tosyl-3-azatricyclo[2.2.1.0^2,6]heptan-5-ols. Radical deoxygenations of 7-alkyl-1-tosyl-3-azatricyclo[2.2.1.0^2,6]heptan-5-ols give 7-alkyl-4-tosyl-2-azabicyclo[2.2.1]hept-5-enes, whereas 7-aryl-1-tosyl-3-azatricyclo[2.2.1.0^2,6]heptan-5-ols give 2-(arylmethyl)-5-tosyl-1,2-dihydropyridines.     

Ring-transformation reactions of 5-hydroxy-2-oxabicyclo[3.2.0]-heptan-4-ones and 5-hydroxy-2-oxabicyclo[3.2.0]hept-6-en-4-ones

Dehydrochlorination of chlorinated 5-hydroxy-2-oxabicyclo[3.2.0]heptan-4-ones, 3a-c, which were obtained from the photo[2+2]cycloadditions between 4-hydroxy-3(2H)-furanone 1 and chloroethylenes, with triethylamine gave 2-ethenyl-3(2H)-furanones 4a,b or 2-(2-cyanoethyl)-3(2H)-furanone 4c. 2-Oxa-bicyclo[3.2.0]hept-6-en-4-ones 7 being [2+2]cycloadducts between 1 and acetylenes gave 2,3-dihydro-3-oxooxepin derivatives 8 by electrocyclic rearrangement.     

[f]-Fused purine-2,6-diones: Synthesis of new [1,3,5]- and [1,3,6]-thiadiazepino-[3,2-f]-purine ring systems

Summary 6-Phenyl-1,3-dimethyl-2,4-dioxo-1,2,3,4,8,9-hexahydro-[1,3,5]-thiadiazepino-[3,2-f]-purine (5) was obtained by a three-step synthesis from 8-mercapto-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (1) and 2-(benzoylamino)-ethyl chloride (2)via 8-(benzoylaminoethylthio)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (3) and its chloromido derivative4. The analogous 9-phenyl-1,3-dimethyl-2,4-dioxo-1,2,3,4,6,7-hexahydro-[1,3,6]-thiadiazepino-[3,2-f]-purine (7) was synthesized either from compound1 and N-(2-chloroethyl)-benzimido chloridevia N-(chloroethyl)-S-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-7H-purin-8-yl)-benzothioimide (6), or alternatively from 7-(2-benzoylaminoethyl)-8-bromo-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (9), its 8-mercapto derivative10 and the corresponding chloroimido compound11 being the intermediates.Part of this paper was presented as a preliminary report at the Congress of Czech and Slovak Chemical Societies, Olomouc, Czech Republic, September 13–16, 1993     

Photochemical Synthesis and Some Reactions of 7-Oxa-and 7-Thiatricyclo[3.2.1.03,6]octan-2-ones

Irradiation (λ = 350 nm) of newly synthesized 2-acetyl- or 2-methyl-2-(alk-2-enyl)furan-3(2H)-ones 1 and 2-acetyl- or 2-methyl-2-(prop-2-enyl)thiophen-3(2H)-ones 2 affords the corresponding 1-acetyl- or 1-methyl-substituted 7-oxa- and 7-thiatricyclo[3.2.1.0^3,6]octan-2-ones 10 and 11 , respectively, via regioselective intramolecular [2 + 2] photocycloaddition in 65–95% yield (Scheme 2). The 1-acetyl-substituted O-derivatives 10b and 10c undergo ring opening on treatment with MeONa in MeOH at–78° to afford stereoselectively methyl 3-exo-acetyl-2-oxabicyclo[3.2.0]heptane-7-endo-carboxylates 12b and 12c , respectively, while a 2:1 diastereoisomeric mixture of methyl 3-acetyl-2-thiabicyclo[3.2.0]heptane-7-endo-carboxylates 13 and 14 is obtained from the corresponding S-derivative 11b . The outcome of the Huang-Minlon reduction of the 1-methyl-substituted ketones 10a and 11a is again influenced by the heteroatom in the tricycle. While 1-methyl-7-oxatricyclo[3.2.1.0^3,6]-octane ( 15 ) is the only product from the corresponding oxatricyclooctanone 10a , a 1:2 mixture of 1-methyl-7-thiatricyclo[3.2.1.0^3,6]-octane ( 16 ) and 3-methylbicyclo[3.1.1]hept-2-ene-6-endo-thiol ( 17 ) is obtained from the analogous S-compound 11a , both products stemming from a common carbanion precursor.     

Racematspaltung und Bestimmung der absoluten Konfiguration von 2, 6-disubstituierten Bicyclo [3.3.1]nonanen

Resolution and Determination of the Absolute Configuration of 2,6-Disubstituted Bicyclo[3.3.1]nonanes (±)-endo, endo-Bicyclo [3.3.1]nonane-2,6-diol was resolved via diastereomeric camphanic acid esters. Conversion of the (+)-enantiomer 2 via (+)- 5 and (+)- 6 as key intermediates gave (+) methyl 3-(3-oxocyclohexyl)-propionate ( 7 ) which independently could be prepared also from the known (+)-(R)-3-oxo-cyclohexane-carboxylic acid ( 8 ). These chemical correlations establish the absolute configuration of (+) -2 , (+) -5 and (+) -6 as well as that of (+)-bicyclo [3.3.1]nonane-2,6-dione ( 1 ) obtained by oxidation of (+) -2 . The chiroptical properties of 1 and 6 are discussed.     

2-[3-(Trifluoromethyl)phenyl]furo[3,2-b]pyrroles: synthesis and reactions

The synthesis and reactions of methyl 2-[3-(trifluoromethyl)phenyl]-4H-furo[3,2-b]pyrrole-5-carboxylate (1a) are described. Upon reaction with methyl iodide, benzyl chloride, or acetic anhydride, this compound gave N-substituted products 1b-d. By hydrolysis of compounds 1a-c, the corresponding acids 2a-c were formed, or by reaction with hydrazine-hydrate, the corresponding carbohydrazides 3a-c were formed. By heating 2-[3-(trifluoromethyl)phenly]-4H-furo[3,2-b]pyrrole-5-carboxylic acid (2a) in acetic anhydride, 4-acetyl-2-[3-(trifluoromethyl)phenyl]furo[3,2-b]pyrrole (4) was formed. By hydrolysis of 4, 2-[3-(trifluoromethyl)phenyl]-4H-furo[3,2-b]pyrrole (5a) was formed, and reactions with methyl iodide or benzyl chloride gave N-substituted products 5b-c. The reaction of 4 with dimethyl butynedioate gave substituted benzo[b]furan 6. Compound 3a reacted with triethyl orthoesters giving 7a-c, which afforded with phosphorus (V) sulphide the corresponding thiones 8a-c. The thiones 8a-c reacted with hydrazine hydrate to form hydrazine derivatives 9a-c. The reaction of triethyl orthoformiate with compounds 9a-c led to furo[2′,3′: 4,5]pyrrolo[1,2-d][1,2,4]triazolo[3,4-f][1,2,4]triazines 10a-c. Hydrazones 11a-c were formed from 3a-c and 5-[3-(trifluoromethyl)phenyl]furan-2-carboxaldehyde. The effect of microwave irradiation on some condensation reactions was compared with “classical” conditions. The results showed that microwave irradiation shortens the reaction time while affording comparable yields.     

Synthesis of Certain 3-Aminopyrazolo[5,4-b]pyridine and 3,4-Substituted Pyrido[2′,3′：3,4]pyrazolo[5,1-c][1,2,4]triazine Derivatives

2-Thioxo-1,2-dihydropyridine derivatives 2a, 2b were reacted with methyl iodide to give 2-methylthiopyridines 3a, 3b, which were reacted with hydrazine hydrate to produce 3-aminopyrazolo[5,4-b]pyridines 4a, 4b. Compounds 4a, 4b were diazotized to afford the corresponding diazonium salts 5a, 5b, which were reacted with some active methylene compounds 6a-6h to give the corresponding pyrido[2′,3′ ： 3,4]pyrazole[5,1-c][1,2,4]triazines 7-14.     

Total synthesis of a novel 2-thiabicyclo[3.2.0]heptan-6-one analogue of penicillin N

A route has been developed which allows synthesis of novel cyclobutanone analogues of penicillin. This is illustrated by the synthesis of (1R,4R,5R,5′R,7S)-(1b) and (1S,4S,5S,5′R,7R)-7-[5′-amino-5′-carboxy]pentanamido]-2-thiabicyclo[3.2.0]heptan-6-one-4-carboxylate (1a), an analogue of penicillin N. The key steps in the synthesis were the formation of the bicyclic structure via a [2+2] cycloaddition and the introduction of nitrogen at C7 via an intramolecular nitrene insertion.     

Synthesis and reactions of 11H‐benzo[b]pyrano[3,2‐f]indolizines an pyrrolo[3,2,1‐ij]pyrano[3,2‐c]quinolines

2‐Methyl‐3H‐indoles 1 cyclize with two equivalents of ethyl malonate 2 to form 4‐hydroxy‐11H‐benzo[b]pyrano[3,2‐f]indolizin‐2,5‐diones 3, whereas 2‐mefhyl‐2,3‐dihydro‐1H‐indoles 9 give under similar conditions regioisomer 8‐hydroxy‐5‐methyl‐4,5‐dihydro‐pyrrolo[3,2,1‐ij]pyrano[3,2‐c]quinolin‐7,10‐diones 10 . The pyrone rings of 3 and 9 can be cleaved either by alkaline hydrolysis to give 7‐acetyl‐8‐hydroxy‐10H‐pyrido[1,2‐a]indol‐6‐ones 4 or 5‐acetyl‐6‐hydroxy‐2‐methyl‐1,2‐dihydro‐4H‐pyrrolo‐[3,2,1‐ij]quinolin‐4‐ones 11 , respectively. Chlorination of 3 and 9 with sulfurylchloride gives under subsequent ring opening 7‐dichloroacetyl‐8‐hydroxy‐10H‐pyrido[1,2‐a]indol‐6‐ones 5 or 5‐dichloracetyl‐6‐hydroxy‐2‐methyl‐1,2‐dihydro‐4H‐pyrrolo[3,2,1‐ij]quinolin‐4‐ones 12 . The dichloroacetyl group of 5 can be reduced with zinc to 7‐acetyl‐8‐hydroxy‐10H‐pyrido[1,2‐a]indol‐6‐ones 7. Treatment of the acetyl compounds 4, 7 and 11 with 90% sulfuric acid cleaves the acetyl group and yields 8‐hydroxy‐10H‐pyrido[1,2‐a]‐indol‐6‐ones 6 and 8 , and 6‐hydroxy‐2‐methyl‐1,2‐dihydro‐4H‐pyrrolo[3,2,1‐ij]quinolin‐4‐ones 13 . Reaction of dichloroacetyl compounds 12 with sodium azide yields 6‐hydroxy‐2‐methyl‐5‐(1H‐tetrazol‐5‐ylcarbonyl)‐1,2‐dihydro‐4H‐pyrrolo[3,2,1‐ij]quinolin‐4‐ones 14 via intermediate geminal diazides.     

Novel transformations of two kinds of chlorinated photo [2 + 2] cycloadducts of 2-pyrone-5-carboxylate

Novel reactions of 7,7-dichloro- and 7,7,8-trichloro-3-oxo-2-oxabicyclo[4.2.0]oct-4-ene-6-carboxylates 5 with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in alcohol gave pyrano[4,3-b]pyran-2,5-diones 8 via (Z)-(2H-pyran-2-on-3-yl)butenoates 7. On the other hand, the same treatment of 7,7,8-trichloro-2-oxo-3-oxabicyclo-[4.2.0]oct-4-ene-5-carboxylate 6b afforded 2-oxo-3-oxabicyclo[4.2.0]oct-4,7-diene-5-carboxylate 14 via cyclobutene formation and S_N2′ displacement by attack of the alkoxy anion.     

Synthesis of (+)-1,3:2,5-dianhydroviburnitol ((+)-(1R,2R,3S,5R,6S)-4,7-dioxatricyclo[3.2.1.03,6]octan-2-ol)

Epoxidation of (?)-(1R,2R,4R)-2-endo-cyano-7-oxabicyclo[2.2.1]hept-5-en-2-exo-yl acetate ((?)-5) followed by saponification afforded (+)-(1R,4R,5R,6R)-5,6-exo-epoxy-7-oxabicyclo[2.2.1]heptan-2-one ((+)-7). Reduction of (+)-7 with diisobutylaluminium hydride (DIBAH) gave (+)-1,3:2,5-dianhydroviburnitol ( = (+)-(1R,2R,3S,4R,6S)-4,7-dioxatricyclo[3.2.1.0^3,6]octan-2-ol; (+)-3). Hydride reductions of (±)-7 were less exo-face selective than reductions of bicyclo[2.2.1]heptan-2-one and its derivatives with NaBH₄, AlH₃, and LiAlH₄ probably because of smaller steric hindrance to endo-face hydride attack when C(5) and C(6) of the bicyclo-[2.2.1]heptan-2-one are part of an exo oxirane ring.     

Synthesis and Biological Activities of 7‐Arylazo‐7H‐pyrazolo[5,1‐c][1,2,4] Triazol‐6(5H)‐Ones and 7‐Arylhydrazono‐7H‐[1,2,4]triazolo[3,4‐b] [1,3,4]thiadiazines

Two series of 7‐arylazo‐7H‐3‐(2‐methyl‐1H‐indol‐3‐yl)pyrazolo[5,1‐c][1,2,4]triazol‐6(5H)‐ones 4 and 7‐arylhydrazono‐7H‐3‐(2‐methyl‐1H‐indol‐3‐yl)‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazines 7 were prepared via reactions of 4‐amino‐3‐mercapto‐5‐(2‐methyl‐1H‐indol‐3‐yl)‐1,2,4‐triazole 1 with ethyl arylhydrazono‐chloroacetate 2 and N‐aryl‐2‐oxoalkanehydrazonoyl halides 5 , respectively. A possible mechanism is proposed to account for the formation of the products. The biological activity of some of these products was also evaluated.     

Synthesis of 1-p-Methoxyphenyl and 1-p-Methoxyphenyl-4-methylbicyclo-[2.2.1]heptan-7-one. The Oxidation of 7-Hydroxy-1-p-methoxyphenyl-4-methylbicyclo[2.2.1]heptan-7-carboxylic Acid with Lead Tetraacetate

A simple synthetic route to 1-p-methoxyphenyl and 1-p-methoxyphenyl-4-methylbicyclo [2.2.1]heptan-7-one 6b,a has been developed through benzilic acid rearrangement of the bicyclo[2.2.1]octandiones 2b,a. The oxidation of 7-hydroxy-1-p-methoxyphenyl-4-methylbicyclo[2.2.1]heptan-7-carboxylic acid 3a with lead tetraacetate gives the carbolactone 7a which is also formed by the reaction of the ketone 6a with m-chloroperbenzoic acid.     

Zur Synthese des 6,7-Dihydro-15-hydroxy-7,7-dimethylbenzo[2,3] (1,6)-naphthyridino[5,6-b]chinazolin-9-ons

The reaction of1,1-dimethyl-3-oxobutylisothiocyanate1 with methyl anthranilate takes place via the 2-(2-thioxopyrimidine-1)-benzoic methylester2 a, which is rearranged to the methyl thioxopyridineanthranilate3 a. 3 a is alkylated by methyl anthranilate to the corresponding methylthio-product4 a, which reacts with anthranilic acid via5a to the benzo [1,6]naphthyridino[5,6-b]-chinazoline6. 6 can also be synthesized by condensation of 2-methylthiopyridines9 a, b with anthranilic acid and 4-dimethylaminpyridine-2-thione8a with methyl anthranilate resp.

     

A series of novel acyclic nucleosides. II. Synthesis of acyclic nucleosides bearing an imidazo[4,5-d] [1,3]oxazine ring

Novel acyclic nucleosides 3a,b,c where N-1 of acyclovir is replaced by oxygen atom were prepared. Thus, 1-[(2-acetoxyethoxy)methyl]-5-amino-4-ethoxycarbonylimidazole ( 9 ) was treated with ethoxycarbonyl isothiocyanate or benzoyl isothiocyanate to give 11e,f . Methylation of the latter with methyl iodide afforded S-methylisothiourea derivative 12f which was treated with alkali and subsequently the mixture was neutralized to give 5-amino-3-[(2-hydroxyethoxy)methyl]-3H-imidazo[4,5-d][1,3]oxazin-7-one ( 3a ). Compounds 3b,c were obtained by treatment of acetic anhydride or propionic anhydride with sodium 5-amino-1-[(2-hydroxyethoxy)methyl]imidazole-4-carboxylate ( 7 ) which was prepared via 5-amino-[(2-acetoxyethoxy)methyl]-imidazole-4-carboxamide ( 5 ). Evaluation of acyclic oxanosine analogs for cytotoxicity and activity against herpes simplex virus type 1 (HSV-1) revealed that all the derivatives tested were inactive, but cytotoxicity were similar or less as compared to that of acyclovir.     

Synthesis of Novel Isoxazolyl 1,6-Dithia-4,9-diazaspiro[4,4]nonane-3,8-diones and 1-Oxa-6-thia-2,4,9-triazaspiro[4,4]non-2-ene-8-ones

The key intermediates, 3-(5-methyl-3-isoxazolyl)-2-arylimino-1,3-thiazolan-4-ones (3), were obtained from 3-amino-5-methylisoxazole (1) by reaction with chloroacetyl chloride followed by treatment with aryl isothiocyanates. Cyclocondensation of 3 with mercapto acetic acid furnished novel isoxazolyl 1,6-dithia-4,9-diazaspiro[4,4]nonane-3,8-diones (4). Cycloaddition of 3 with benzonitrile oxides afforded novel isoxazolyl 1-oxa-6-thia-2,4,9-triazaspiro[4,4]non-2-ene-8-ones (5).     

Highly Efficient [3 + 2] Cycloaddition: Click Synthesis of Novel 1H‐indol‐3‐yl‐benzo[d]imidazole Bis‐triazoles

A series of novel 1‐((1H‐1,2,3‐triazol‐4‐yl)methyl)‐2‐(1‐((1H‐1,2,3‐triazol‐4‐yl)methyl)‐5‐substituted‐1H‐indol‐3‐yl)‐6‐substituted‐1H‐benzo[d]imidazoles 5a – i have been prepared using click chemistry as an ideal strategy where [3 + 2] cycloaddition of azides with terminal alkynes has been developed as the target compounds. In route‐II, 5‐substituted‐1H‐indole‐3‐carbaldehydes 1a – c react with 5‐substituted orthophenylenediamine 8 to give desired products, that is, 6‐substituted‐2‐(5‐substituted‐1H‐indol‐3‐yl)‐1H‐benzo[d]imidazole 6a – i . Here, 6a – i react with 2 equiv of propargylbromide 7 to give novel 6‐substituted 2‐(5‐substituted‐1‐(prop‐2‐yn‐1‐yl)‐1H‐indol‐3‐yl)‐1‐(prop‐2‐yn‐1‐yl)‐1H‐benzo[d]imidazole 4a – i . 4a – i were reacted with 2 equiv of NaN₃ in t‐butanol/water (1:2) and add catalytic amount of CuSO₄.5H₂O. Stir the reaction mixture at room temperature to get the target products 5a – i . Here, obtained products contain four rings, that is, one indole, two triazoles, and one benzimidazole. The main advantages of this method are short reaction times, easy workup, higher yields (88–92%), and no by‐products formation.     

A conventional and solid-state synthesis,biological activity,and molecular docking studies of 6-arylbenzo[4,5]imidazo[1,2-a] [1,8]naphthyridin-10-ols

An effective, practical, and simple approach toward the preparation of highly-substituted 6-arylbenzo[4, 5]imidazo[1,2-a][1,8]naphthyridin-10-ols 6(a-h) by the reaction of 3-aryl-1,8-naphthyridin-2-amines 3(a-h) with benzoquinone 4 in acid catalyzed cyclization under solid-state method, as well as conventional conditions, has been described. The products are obtained in good yields and in a solid of high purity. The major advantages of solid states are easy workup, low costs, short reaction time, good efficacy, and environment-friendly procedure. The newly synthesized compounds were thoroughly characterized using spectral data and elemental analyses. All compounds were screened for their biological evaluation. Predominantly 6b and 6c compounds showed the highest antibacterial activity. Moreover, all the synthesized compounds were docked against topoisomerase II DNA gyrase enzyme.     

Synthesis of potential metabolites of the brain imaging agents methyl (1R,2S,3S,5S)-3-(4-Iodophenyl)-8-alkyl-8-azabicyclo[3.2.1]octane-2-carboxylate

The synthesis of potential hydroxy metabolites of the brain imaging agents methyl (1R,2S,3S,5S)-3-(4-iodophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate and methyl (1R,2S,3S,5S)-3-(4-iodophenyl)-8-(3-fluoropropyl)-8-azabicyclo[3.2.1]octane-2-carboxylate are reported. The nitration of iodophenyltropanes 1 or 2 with nitronium tetrafluoroborate afforded the nitro compounds 3 or 4 which were reduced with iron powder to the corresponding amino compounds 5 and 6 . The final hydroxylated products 7 and 8 were obtained via a modified Sandmeyer reaction.     

Polynuclear Iron and Rhodium Complexes of 7-Oxa[2.2.1]hericene (2,3,5,6-tetramethylidenebicyclo[2.2.1]heptan-7-one)

μ-Carbonyl(Rh? Rh)di(η⁵-indenyl)[(2R,3S)-C,2,3,C-η-(2,3,4,5-tetramethylidenebicyclo[2.2.1]heptan-7-one)]]-dirhodium(I)(Rh? Rh) (7) and cis-μ-[(2R,3S,5R,6S))-C,2,3,C-η:C,5,6,C-η-(2,3,5,6-tetramethylidenebicyclo[2.2.1]heptan-7-one)]bis[μ-carbonyldi(η⁵-indenyl)dirhodium(I)(Rh? Rh)] ( 8 ) have been prepared. Complex 7 reacts with Fe₂(CO)₉ in hexane/MeOH and gives cis-μ-[(2R,3S,5R,6S] ( 9 ), trans-μ-[(2R,3S,5S,6R)-C,2,3,C-η: C,5,6, C-η-(2,3,5,6-tetramethylidenebicyclo[2.2.1]heptan-7-one)-μ-carbonyldi(η⁵-indenyl)dirhodium(I)(Rh? Rh)-(tricarbonyliron) ( 10 ), and, μ-carbonyl(Rh? Rh)[(2R,3S)-C,2,3,C-η-(2,3-dimethyl-5,6-dimethylidenebicyclo-[2.2.1]hept-2-en-7-one)]di(η⁵-indenyl)dirhodium(I)(Rh? Rh) ( 11 ). Treatment of 7-oxa[2.2.1]hericene ( 4 ) with Fe₂(CO)₉ or (cyclooctene)₂Fe(CO)₃ gave a 1:2 mixture of cis-μ-[(2R,3S,5R,6S)-] ( 12 ) and trans-μ-[(2R,3S,5S,6R)-C,2,3,C-η:C,5,6,C-η-(2,3,5,6-tetramethylidenebicyclo[2.2.1]heptan-7-one)]bis(tricarbonyliron)( 13 ).