A reinvestigation of the stevens rearrangement of 1,3,4-trimethyl-1-(3,4,5-trimethoxybenzyl)-1,2,5,6-tetrahydropyridinium chloride

1,3,3-Trimethyl-2-(3,4,5-trimethoxyphenyl)-4-methylenepiperidine (XI) is prepared in an unambiguous way which involves the Refortmatsky reaction followed by ethanolysis on the N-(3,4,5-trimethoxybenzylidene)methylamine, later treatment of the resulting aminoester with ethyl acrylate, ring closure by Dieckmann reaction with decarbalkoxylation and, finally, a Wittig reaction on the piperidone obtained. The resulting methylenepiperidine XI differs in its physical and spectroscopic data from the methylene derivative IIIa obtained by the Stevens rearrangement of the 1,3,4-trimethyl-1-(3,4,5-trimethoxybenzyl)-1,2,5,6-tetrahydropyridinium chloride, whose structure must be reviewed.     

A reinvestigation of the stevens rearrangement of 1-benzyl-1,3,4-trimethyl-1,2,5,6-tetrahydropyridinium salts

Authentic samples of 1,3,3-trimethyl-2-(3,4,5-trimethoxyphenyl)-4-methylenepiperidine (Ia) and 2-(p-chlorophenyl)-1,3,3-trimethyl-4-methylenepiperidine (Ib) are prepared by Mannich condensation between 4-methyl-1-methylamino-3-pentanone hydrochloride (VI) and an aromatic aldehyde, followed by a Wittig reaction on the resulting 4-piperidone. Comparing the physical and spectroscopic properties of Ia and Ib with those of the methylene derivatives IIa and IIb obtained as by-products in the Stevens rearrangement of 1-benzyl-1,3,4-trimethyl-1,2,5,6-tetrahydropyridinium salts IIIa and IIIb, respectively, it is shown that the assignment previously made for IIa and IIb is incorrect. Spectroscopic analysis (ir, ¹H nmr, ¹³C nmr, ms) of these compounds and of its hydrogenation products VIII allows the structural and stereochemical assignment of 11a as cis-3-isopropenyl-1,3-dimethyl-2-(3,4,5-trimethoxyphenyl)pyrrolidine and of IIb as cis-2-(p-chlorophenyl)-3-isopropenyl-1,3-dimethylpyrrolidine. The formation of these rearrangement products is mechanistically interpreted as a Stevens [3,2] type process.     

Brominated trimetrexate analogues as inhibitors of pneumocystis carinii and toxoplasma gondii dihydrofolate reductase

Five previously undescribed trimetrexate analogues with bulky 2′-bromo substitution on the phenyl ring were synthesized in order to assess the effect of this structure modification on dihydrofolate reductase inhibition. Condensation of 2-[2-(2-bromo-3,4,5-trimethoxyphenyl)ethyl]-1,l-dicyanopropene with sulfur in the presence of N,N-diethylamine afforded 2-amino-5-(2′-bromo-3′,4′,5′-trimethoxybenzyl)-4-methyl-thiophene-3-carbonitrile ( 15 ) and 2-amino-4-[2-(2′-bromo-3′,4′,5′-trimethoxyphenyl)ethyl]thiophene-3-car-bonitrile ( 16 ). Further reaction with chloroformamidine hydrochloride converted 15 and 16 into 2,4-diamino-5-(2′-bromo-3′,4′,5′-trimethoxybenzyl)-4-methylthieno[2,3-d]pyrimidine ( 8a ) and 2,4-diamino-4-[2-(2′-bromo-3′,4′,5′-trimethoxyphenyl)ethylthieno[2,3-d]pyrimidine ( 12 ) respectively. Other analogues, obtained by reductive coupling of the appropriate 2,4-diaminoquinazoline-6(or 5)-carbonitriles with 2-bromo-3,4,5-trimethoxyaniline, were 2,4-diamino-6-(2′-bromo-3′,4′,5′-trimethoxyanilinomethyl)-5-chloro-quinazoline ( 9a ), 2,4-diamino-5-(2′-bromo-3′,4′,5′-trimethoxyanilinomethyl)quinazoline ( 10 ), and 2,4-diamino-6-(2′-bromo-3′,4′,5′-trimethoxyanilinomethyl)quinazoline ( 11 ). Enzyme inhibition assays revealed that space-filling 2′-bromo substitution in this limited series of dicyclic 2,4-diaminopyrimidines with a 3′,4′,5′-trimethoxyphenyl side chain and a CH₂, CH₂CH₂, or CH₂NH bridge failed to improve species selectivity against either P. carinii or T. gondii dihydrofolate reductase relative to rat liver dihydrofolate reductase.     

Studies on the syntheses of analgesics. Part XXXII. An alternative synthesis of 1,2,3,4,5,6-Hexahydro-8-hydroxy-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazoeine [Studies on the syntheses of heterocyclic compounds. Part CDLXXX]

Bischler-Napieralski reaction of the amides (VIII and IX), derived from the 3-methyl-3-pentenylamine (III) with the phenylacetic acid derivatives (V ～ VII), gave the 5,6-dihydropyridines (XII and XIII), which were reduced, followed by N-benzylation, to afford the 1,2,5,6-tetrahydropyridines (XIX ～ XXI). Grewe-type cyclization of these compounds gave 3-benzyl-3-benzazocine (II), which was already converted into pentazocine (Ic). Moreover, the 1,2,5,6-tetrahydropyridines (XIX ～ XXI) were also obtained from the 2-benzylidene-1,2,5,6-tetrahydropyridine (XVII ～ XVIII) from the N-benzylamine (IV) of III via the amides (X and XI).     

6-取代苄硫基-3-(3,4,5-三甲氧基苯基)-1,2,4-三唑[3,4-b][1,3,4]噻二唑类化合物的合成与抑菌活性

以4-氨基-5-(3,4,5-三甲氧基苯基)-3-巯基-1,2,4-三唑为原料,环化得到6-巯基-3-(3,4,5-三甲氧基苯基)-1,2,4-三唑[3,4-b][1,3,4]噻二唑再与取代苄氯反应,得到9个6-取代苄硫基-3-(3,4,5-三甲氧基苯基)-1,2,4-三唑[3,4-b][1,3,4]噻二唑类衍生物3a～3i.其结构经IR,1H NMR,MS和元素分析确证.初步生物活性测试结果表明部分化合物有一定的杀菌活性.     

6-取代-3-（3，4，5-三甲氧基苯基）-1，2，4-三唑[3,4-b][1,3,4]噻二唑的合成与生物活性

以3,4,5-三甲氧基苯甲酸为原料,通过4步反应得到4-氨基-5-(3,4,5-三甲氧基苯基)-3-巯基-1,2,4-三唑,再与取代芳酸反应,得到11个6-取代-3-(3,4,5-三甲氧基苯基)-1,2,4-三唑[3,4-b][1,3,4]噻二唑衍生物5a～5k。其结构经IR,1H NMR,MS和元素分析确证。初步生物活性测试结果表明部分化合物有一定的杀菌活性。     

3-(3,4,5-三甲氧基苯基)-4-氨基-5-取代苄巯基-1,2,4-三唑的合成及其生物活性

3-(3,4,5-三甲氧基苯基)-4-氨基-5-巯基-1,2,4-三唑与取代苄氯反应合成了九个新型3-(3,4,5-三甲氧基苯基)-4-氨基-5-取代苄巯基-1,2,4-三唑(2a～2i),其结构经1H NMR,IR和MS表征.初步生物活性测试结果表明,3-(3,4,5-三甲氧基苯基)-4-氨基-5-对氯苄巯基-1,2,4-三唑(2b)对半夏立枯病菌具有抑制活性.     

1,3,4-THIADIAZOLES. REGIOSELECTIVE O-DEMETHYLATION ON DEHYDRATIVE CYCLIZATION OF 1-(3,4,5-TRIMETHOXYBENZOYL)4-SUBSTITUTED THIOSEMICARBAZIDES WITH SULPHURIC ACID

Cyclization of 1-(3,4,5-trimethoxybenzoyl)-4-substituted thiosemicarbazides 2a–g with sulphuric acid at ambient temperature afforded the selectively demethylated products 2-(4-hydroxy-3,5-dimethoxyphenyl)-5-substituted amino-1,3,4-thiadiazoles 4a–g. Meanwhile, dehydrative cyclization of 1-(3,4,5-trimethoxybenzoyl)-4-(benzyl or t-butyl)thiosemi- carbazides 2h, i with sulphuric acid yielded 2-(4-hydroxy-3,5-dimetho xyphenyl)-5-amino-1,3,4-thiadiazole 5. On the other hand, dehydration of 2h, i by heating with phosphorus oxychloride yielded 2-(3,4,5-trimethoxyphenyl)-5-amino-1,3,4-thiadiazole 6.     

Thermische Umwandlung von Phenyl-penta-2,4-dienyläthern in 4-[Penta-2,4-dienyl]-phenole als Beispiel für [5,5]-sigmatropische Umlagerungen. Vorläufige Mitteilung

The reaction between phenol and trans penta-2,4-dienyl chloride gave trans penta-2,4-dienyl Phenyl ether (I), whereas with a mixture of sorbyl chloride and 1-methylpenta-2,4-dienyl chloride, pure trans, trans hexa-2,4-dienyl phenyl ether (IV) and trans 1-methylpenta-2,4-dienyl phenyl ether (V) were obtained. The ether I gave, on heating in dilute solution at 185°, 4-(penta-2,4-dienyl)-phenol (III) as the main product, and also some 2-(2-vinylallyl)-phenol (II). The ether IV provided, on heating at 165°, in addition to the ortho CLAISEN rearrangement product VI, mainly a mixture consisting of 94% 4-(1-methylpenta-2,4-dienyl)-phenol (VIII) and only 6% 4-(hexa-2,4-dineyl)-phenol(IX). The latter product (IX) was the only para isomer produced on heating ether V, but in addition 22% of the ortho rearrangement product VII was formed. The migrations I → III, IV → VIII, and V → IX, proceeding through a ten membered transition state, are the first [5,5] sigmatropic rearrangements described.     

Synthesis of heterocycles. Part II. New routes to acetylthiadiazolines and alkylazothiazoles

Methylglyoxalyl chloride arylhydrazones (III) react with an ethanolic solution of thiourea to give 2-amino-4-methyl-5-arylazothiazoles (XII) instead of the expected 2-acetyl-4-aryl-5-imino-Δ²-1,3,4-thiadiazolines (V) which were obtained from III and potassium thiocyanate. 3-Thiocyanato-2,4-pentanedione (IV) coupled with diazotized anilines to give V. The postulated routes to formation of V and XII from III are given. Nitrosation of V gave the corresponding N-nitroso derivatives (VI) which decomposed upon refluxing in dry xylene to give 2,4-disubstituted-Δ²-1,3,4-thiadiazolin-5-ones (VII). Boiling of either V or VI with hydrochloric acid gave the hydrochloride salt (VIII). The thiadiazolines V gave the respective N-acyl derivatives (IX) and (X) with acetic anhydride and benzoyl chloride in pyridine.     

芳醛-[5-(3,4,5-三甲氧基苯基)-1,3,4-噻二唑-2-巯基]-乙酰腙衍生物的合成及生物活性研究

采用活性基团拼接法, 以2-巯基-5-(3,4,5-三甲氧基苯基)-1,3,4-噻二唑为原料, 经硫醚化、肼解、腙化反应合成了8个芳醛-[5-(3,4,5-三甲氧基苯基)-1,3,4-噻二唑-2-巯基]-乙酰腙衍生物, 并经过元素分析, IR, ¹H NMR, ¹³C NMR对其结构进行了确认. 初步生物活性测试表明, 部分化合物具有一定的抑菌生物活性.     

The photochemical synthesis of novel heterocyclic compounds from s-triazolo[4,3-b]pyridazine (II)

s-Triazolo[4,3-b Jpyridazine (I) photochemically reacted with dihydropyran; 2,3-dihydro-p-dioxin; 2,5-dihydrofuran; 2,5-dimethoxy-2,5-dihydrofuran; and 1,3-dioxep-5-ene to give a new series of substituted pyrrolo[1,2-b]-.s-triazoles (II-IX). In most reactions, two or more products were formed. The following compounds have been prepared from I: 9-methylene-4a,5,6,7,8a,9-hexahydropyrano[2,3 :4,5]pyrrolo[1,2-b]-s-triazole (Ha), the corresponding 9-cyanomethyl product (III), and 9-methylene-4a,7,8,8a-tetrahydro-6H,9H-pyrano[3′,2′:4,5]pyrrolo[1,2-b]-s-triazole (IIb) from dihydropyran; 9-methylene-4a,6,7,8a-tetrahydro-9H-p-dioxino[2′,3′:4,5]-pyrrolo[1,2-6]-s-triazole (IV) from 2,3-dihydro-p-dioxin; 8-methylene-4a,5,7a,8-tetrahydro-7H-furo[3′,4′:4,5]pyrrolo[1,2-b]-s-triazole (V) and the corresponding 8-cyanomethyl product (VI) from 2,5-dihydrofuran; 8-cyanomethyl-5,7-dimethoxy-4a,5,7a,8-tetrahydro-7H-furo[3′,4′:4,5]-pyrrolo[1,2-6]-s-lriazole (VII) from 2,5-dimethoxy-2,5-dihydrofuran; and 10-methylene-4a,5,9a,10-tetrahydro-9H-[1,3]dioxepino[5′,6′:4,5]pyrrolo[1,2-b]-s-triazole (VIII) and the corresponding 10-cyanomethyl product (IX) from 1,3-dioxep-5-ene. The addition of several other compounds (1,2,3,6-tetrahydropyridine, 1-acetylimidazole, 3-sulfolene, 2,3-dihydro-p-dithiin, and vinylene carbonate) was attempted, but no reactions were observed.     

Synthesis and debenzoylation products of two perbenzoylated 2-substituted 5-D-galactosyl-1,3,4-oxadiazoles

The synthesis of 2-(p-chlorophenyl)-5-[1′,2′,3′,4′,5′-penta-O-benzoyl-D-galactopentitol-1-yl]-1,3,4-oxadiazole is described. Its debenzoylation gave an equilibrium mixture of the 1,3,4-oxadiazole derivative without protection of the hydroxyl group and the N-benzoyl-D-galactono-1,4-lactonehydrazone. A similar equilibrium was observed by debenzoylation of 2-phenyl-5-[1′,2′,3′,4′,5′-penta-O-benzoyl-D-galactopentitol-1-yl]-1,3,4-oxadiazole. The ¹H, ¹³C nmr and ms spectra of these compounds are presented.     

The reaction of aroylhydrazines with N-phenylsulfonylarenehydrazonoyl chlorides. A route to substituted 4-amino-(4H)-1,2,4-triazoles and 1,3,4-oxadiazoles

Treatment of N-phenylsulfonylarenehydrazonoyl chlorides (II) with equivalent amounts of aroylhydrazines (III) in ethanol gave 3,5-diaryl-4-phenylsulfonylamino-1,2,4-triazoles (IV). Reaction of II with two equivalents of III in tetrahydrofuran gave 2,5-diaryl-1,3,4-oxadiazoles (V), in addition to IV. Addition of triethylamine to II or its mixture with III yielded only the tetrazenes (VIII). The possible pathways leading to IV-V and VIII are discussed. J. Chem. Soc., 14, 1089 (1977)     

Reinvestigation of the stevens rearrangement of 1-benzyl-1,3,4-trimethyl-1,2,5,6-tetrahydropyridinium salts. II. Synthesis of 2-aryl-3-isopropenyl-1,3-dimethylpyrrolidines

cis-2-Aryl-3-isopropenyl-1,3-dimethylpyrrolidines Ha and IIb have been synthesized by an unambiguous way, thus confirming the structure of the methylene derivatives obtained as by-products in the Stevens rearrangement of 1-benzyl-1,3,4-trimethyl-1,2,5,6-tetrahydropyridinium salts Ia and Ib. The synthesis is based on the acid-induced intramolecular cyclization between an iminium salt and the α-position of a ketal group. Thus, condensation between amino ketal XXI, prepared via Gabriel synthesis from 5-chloro-3-methyl-2-pentanone, and the appropriate aldehyde afforded imines XXI. Their treatment with dry hydrogen chloride followed by acid hydrolysis and methylation gave 3-acetylpyrrolidines IV, which were transformed into the isopropenyl derivatives II by reaction with methyl-lithium and further dehydration.     

New routes to aroylthiadiazolines and arylazothiazoles from phenylglyoxalyl bromide arylhydrazones and phenacyl thiocyanate

Reaction of phenylglyoxalyl bromide arylhydrazones (III) with thiourea in ethanol produces 2-amino-4-phenyl-5-arylazothiazoles (XI) instead of the expected 2-benzoyl-4-aryl-5-imino-Δ^2?1,3,4-thiadiazolines (V) obtained from III and potassium thiocyanate. Phenacyl thiocyanate (IV) couples with diazotized anilines to give V. The mechanisms of formation of V and XI from VI and III, respectively, are postulated. Nitrosation of V gives the corresponding N-nitroso derivatives (VII), which decompose upon refluxing in xylene to give 2,4-disubstituted Δ² ?1,3,4-thiadiazolin-5-ones (VIII). The thiadiazolines V give the respective N-aeyl derivatives IX and X with acetic anhydride and benzoyl chloride in pyridine.     

Synthesis and characterization of some nitrogen heterocycles from d-galactose derivatives

The tetrazoles 5-(6′-acetamido-6′-deoxy-1′,2′:3′,4′-di-O-isopropylidene-D-glycero-α-D-galactohexopyranos-6′-yl)tetrazole ( 1 ) and 5-(6′-acetamido-6′-deoxy-1′,2′:3′,4′–di-O-isopropylidene-L-glycero-α-D-galacto-hexopyranos-6′-yl)-tetrazole ( 2 ) were synthesized by the 1,3-dipolar cycloaddition reaction of the epimeric α-acetamidonitriles 5 and 6 , respectively, with sodium azide. Reaction of tetrazole 1 with acetic anhydride in the presence of pyridine afforded the N-acetyl-1,3,4-oxadiazole derivative 3 and the N-acetylacetamido-1,3,4-oxadiazole derivative 7 . The N-acetylacetamido-1,3,4-oxadiazole derivative ( 8 ) was isolated when the tetrazole 2 was allowed to react under the same conditions. The physical and spectroscopic data of the five new compounds 1, 2, 3, 7 and 8 are presented.     

Synthesis and antifolate activity of 2,4-diamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine analogues of trimetrexate and piritrexim

2,4-Diamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines with di- and trimethoxyaralkyl substitution at the 6-position were synthesized from the N⁶-unsubstituted compound and appropriate aralkyl bromides in N,N-dimethylformamide solution containing a catalytic amount of sodium iodide. An improved method of preparation of 2,4-diamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine from 2-amino-6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one was also developed, in which N² was protected by reaction with pivalic anhydride and the resulting product was subjected consecutively to reaction with 4-chlorophenylphosphorodichloridate and 1,2,4-triazole, ammonolysis to replace the 4-imidazolido group and remove the N²-pivaloyl group, and catalytic hydrogenolysis to remove the 6-benzyl group. In assays of the ability of the products to inhibit dihydrofolate reductase from Pneumocystis carinii, and Toxoplasma gondii, and rat liver the most active of the compounds tested was 2,4-diamino-6-(2′-bromo-3′,4′,5′-trimethoxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. The concentration of this compound needed to inhibit enzyme activity by 50% was 0.51 μM against the P. carinii enzyme, 0.09 μM against the T. gondii enzyme, and 0.35 μM against the rat enzyme. Thus, there was selectivity of binding to T. gondii enzyme, but not P. carinii enzyme, relative to rat enzyme. 2′,5′-Dimethoxybenzyl analogues were less active than the corresponding 3′,4′,5′-trimethoxybenzyl analogues, and compounds with a CH₂CH₂ or CH₂CH₂CH₂ bridge were less active than those with a CH₂ bridge. 2,4-Diamino-6-(2′-bromo-3′,4′,5′-trimethoxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine showed greater selectivity than trimetrexate or piritrexim for the P. carinii and T. gondii enzyme, but was less selective than trimethoprim or pyrimethamine. However its molar potency against both enzymes was greater than that of trimethoprim, the antifolate most commonly used, in combination with sulfamethoxazole, for initial treatment of opportunistic P. carinii and T. gondii infections in patients with AIDS and other disorders of the immune system.     

New tetracyclic compounds containing the β-carboline moiety

Oxidation of 1-methyl-3-methoxycarbonyl-β-carboline with selenium dioxide gave 1-formyl-3-methoxycarbonyl-β-carboline II . Compound II reacted with acetic or propionic anhydride to give easily the 2-methoxycarbonyl-6H-indolo[3,2,1-d,e][1,5]naphthyridin-6-ones III ; reaction of II with some primary amines led to the formation of the Schiff bases IV , which were reduced to the 1-aminomethyl-3-methoxycarbonyl-β-carbolines V with sodium borohydride. Cyclization of V with aqueous formaldehyde led to the pyrimido[3,4,5-lm]pyrido[3,4-b]indoles VI . Analogously, cyclization with formaldehyde, acetone or 1,1′-carbonyldiimidazole of the 3-aminomethyl- 1,2,3,4-tetrahydro-β-carbolines VIII , obtained by reaction of 3-methoxycarbonyl-1,2,3,4-tetrahydro-β-carboline VII with amines followed by lithium aluminium hydride reduction of the resulting amides, gave the imidazo[1′,5′-1,6]pyrido[3,4-b]indoles IX and X . Dieckmann cyclization of 3-methoxycarbonyl-2-[(3-ethoxycarbonyl)-1-propyl]-1,2,3,4-tetrahydro-β-carboline XI led to a 1:1 mixture of the β-ketoesters XII and XIII , which underwent deethoxycarbonylation to 5,6,8,9,10,11,11a,12-octahydroindolo[3,2-b]quinolizin-11-one XIV . Finally, the polyphosphoric acid (or esters) catalyzed cyclization of the N-acyl derivatives XVI of 3-hydrazinocarbonyl-β-carboline XV led smoothly to the 3-(1,3,4-oxadiazol-2-yl)-β-carbolines XVII .     

Reaction of N1,N2-diarylacetamidines with (2,4,7-trinitro-9H-fluoren-9-ylidene)propanedinitriles

Novel spiro[fluorene-9,4′-(1′,2′,3′,4′-tetrahydropyridine)]-5′-carbonitriles 6a-c have been obtained from the reaction of N¹,N²-diarylacetamidines 1a-c with (2,4,7-trinitro-9H-fluoren-9-ylidene)propanedinitrile ( 2 ) in ethyl acetate solutions at ambient temperature for 6a,b or under reflux for 6c , respectively.