Polycondensed heterocycles. II. A new preparative route to 11-Oxo-5H,11H-pyrrolo[2,1-c][1,4]benzothiazepine

6-Methylthio-10-oxo-5H,10H-pyrrolo[1,2-b]isoquinoline 11 was isolated in an attempted synthesis of 11-oxo-5H,11H-pyrrolo[2,1-c][1,4]benzothiazepine 1 from 1-(2-methylthiobenzyl)pyrrole-2-carboxylic acid chloride 9 , obtained using as starting material o-methylthiobenzyl bromide 3 and passing through 1-(2-methylthiobenzyl)pyrrole-2-carbonitrile 5 , by cyclization with aluminum chloride. However the successful demethylation with sodium in dimethylacetamide of 1-(2-methylthiobenzyl)pyrrole-2-carboxyamide 12 , formed by hydrolysis of nitrile 5 , allowed us to prepare by another way the corresponding thiol 13 and consequently the 1-(2-mercaptobenzyl)pyrrole-2-carboxylic acid 14 , which when subjected to intramolecular ring closure by CDI in place of DCC gave 1 in higher yield, 69% instead of 43%. Finally, the direct cyanation of 1-(2-ethoxycarbonylthiobenzyl)pyrrole 16 , prepared utilizing the 1-(2-mercaptobenzyl)pyrrole 15 obtained by demethylation of the corresponding thioanisol 4 which was carried out as above, afforded the unexpected 1-(2-ethylthio-benzyl)pyrrole-2-carbonitrile 17 .     

Heterocycles with a benzothiadiazepine moiety. 3. Synthesis of imidazo[5,1-d]pyrrolo[1,2-b][1,2,5]benzothiadiazepine 9,9-dioxide

The synthesis of imidazo[5,1-d]pyrrolo[1,2-b][1,2,5]benzothiadiazepine 9,9-dioxide ( 5 ), a novel sulfur-containing tetracyclic benzodiazepine, is reported starting from pyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-diox-ide ( 6 ) by cycloaddition of tosylmethyl isocyanide to the azomethine double bond. Pyrrolobenzothiadiazepine 6 was obtained by iron powder/acetic acid reduction of 1-(2-nitrobenzenefulfonyl)pyrrole-2-carboxaldehyde ( 7 ) and subsequent ring closure of intermediate aminoaldehyde or by cyclization of 1-(2-formamidobenzene-sulfonyl)pyrrole ( 8 ) with phosphorus oxychloride via a Bischler-Napieralski reaction. Formylation of 1-(2-ami-nobenzenesulfonyl)pyrrole with acetic-formic anhydride gave 8. The structure of 5 was confirmed by oxidation with activated manganese dioxide of dihydro derivative 9 , obtained through cyclization of 11-amino-methyl-10,11-dihydropyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-dioxide ( 10 ) with triethyl orthoformate. The last compound was prepared alternatively by catalytic reduction of nitro derivative 11 , obtained by addition of nitromethane to pyrrolobenzothiadiazepine 6 , or by lithium aluminum hydride/sulfuric acid reduction of amide 13 , synthesized starting from ethyl 10,11-dihydropyrrolo[1,2-b][1,2,5]benzothiadiazepine-11-carboxyl-ate 5,5-dioxide.     

Experimental antiulcer drugs. 3. Some unusual transformations of the cyclopenta[c] pyrroles

The cyclopenta[c]pyrrole-4-carbonitrile ( 3 ) is transformed by hyrlroxylamine in hot alcohol to 4,5,6,6a-tetrahydro-l-imino-3,5,5,6a-tetramethyl-4-cyclopenta[c]pyrrole methyl ketone oxime ( 5 ) in contrast to the cyclopentapyrrole 10 which afforded 1,2-diacetyl-3,3,5,5-tetramethyl-cyclopentene dioxime ( 11 ). The cyclopenta[c]pyrrole-4-carboxamide 1 (R = C₆H₅) yielded the isomeric 2a,3,4,4a,5,6,6a,6b-octahydro-2a,4,4,6a-tetramethyl-5-(phenylimino)pentaleno[1,6-bc]-pyrrol-2-(1H)one ( 12 ) in hot dilute hydrochloric acid or hot 99% phosphoric acid. The amide 1 (R = C₆H₅) was transformed in the solid state by oxygen over a period of several months to a mixture of the isomeric anils, 13 and 14 of 1,7-diacetyl-7-hydroxy-4,6,6-trimethyl-2-azabicyclo-[2.2.l.]heptan-3-one( 16 ).     

Synthesis of some 5-aryl-2,2′-dipyrromethenes as analogs of prodigiosin

Three new dipyrromethenes have been synthesized as analogs of prodigiosin: 3-methoxy-5-phenyl-2,2′-dipyrromethene (10a) , 3-methoxy-4 -pentyl-5-phenyl-5′-methyl-2,2′-dipyrromethene (10b) , and 3-methoxy-4′-pentyl-5′-methyl-5-(2″-thienyl)-2,2′-dipyrromethene (10c). The Michael addition of ethyl glycinate to an appropriate arylidenemalonate, quenched with ethyl chloroformate and followed by a Dieckmann cyclization gave diethyl 1-ethoxycarbonyl-3-oxo-5-phenyl and thienylpyrrolidine-2,4-dicarboxylate, 2a and 2b. Methylation of the highly enolic keto-esters, followed by oxidation to N-ethoxycarbonylpyrroles led, after appropriate elaboration of the pyrrole nucleus, to 2-phenyl- and 2-thienyl-4-methoxypyrroles. The acid catalyzed condensation of these arylmethoxypyrroles with either pyrrole-2-carboxaldehyde or 5-methyl-4-pentylpyrrole-2-carboxaldehyde led to 10a, 10b and 10c.     

Pyrrolo[1,2-d]triazines-1,2,4. II. Etude des pyrrolo[1,2-d]triazinones-1 et -4

The synthesis of 1,2-dihydro-1-oxopyrrolo[1,2-d]-1,2,4-triazines was achieved by rearrangement of 2-pyrrolyloxadiazoles under alkaline conditions or by cyclisation of pyrrole N-ethoxymethylidene hydrazides. The cyclisation of the N-carbethoxy hydrazone of the pyrrole-2-carboxaldehyde gave the 3,4-dihydro-4-oxopyrrolo[1,2-d]-1,2,4-triazine. Electrophilic substitution reactions of the 1- and 4-pyrrolotriazinones were made either on the lactam nitrogen with methyl sulphate, benzyl chloride and monochloroacetic acid or on the pyrrole ring with bromine and nitric acid. The structure of the derivatives was determined by ¹H nmr.     

Bone collagen cross-links: a convergent synthesis of (+)-deoxypyrrololine.

A convergent total synthesis of (+)-deoxypyrrololine (Dpl, 4), a putative cross-link of bone collagen, is described starting from a commercially available L-glutamic acid derivative, (4S)-5-(tert-butoxy)-4-[(tert-butoxycarbonyl)amino]-5- oxopentanoic acid (16). Condensation of aldehyde (S)-(-)-17 with nitro compound (S)-(-)-27, both of which were prepared from a common precursor (S)-16, gave the alpha-hydroxynitro compound 28, which upon acetylation afforded alpha-acetoxynitro compound 14 in good yield. Subsequent condensation and cyclization of alpha-acetoxynitro compound 14 with benzyl isocyanoacetate (15) in the presence of DBU in THF gave the key pyrrole intermediate (S,S)-(-)-12 in 57% yield. N-Alkylation of pyrrole (S,S)-(-)-12 with iodide (S)-(-)-13 using t-BuOK in THF afforded the 2-benzyloxycarbonyl-1,3,4-substituted pyrrole derivative (-)-29 in 42% yield. Removal of the protective groups in (-)-29 followed by hydrogenolysis and decarboxylation afforded the cross-link (+)-Dpl (4) in good overall yield. The synthesis of an analogue (S)-(+)-24 and formation of a novel tetrahydroindole derivative (-)-31 are also described.     

Synthesis of 3-(2-Aminoethyl)pyrrole Derivatives

3-(2-Di-n-propylaminoethyl)pyrrole (1a) was prepared in good yield by reduction of pyrrole-3-(N,N-di-n-propylglyoxamide) (9) with lithium aluminum hydride. 3-(2-Di-n-propylaminoethyl)-5-acetylpyrrole (1b) was prepared by first acetylation of 1-p-toluenesulfonyl-3-(2-di-n-propylaminoethyl)pyrrole (6) followed by hydrolysis of the p-toluenesulfonyl substituent. The starting material 6 was prepared by homologation of 1-(p-toluenesulfonyl)pyrrole-3-carboxaldehyde (3) to the corresponding acetaldehyde followed by reductive amination of the latter.     

Synthesis and analgesic activity of novel heterocycles, [1]benzothiopyrano[3,4-b]pyrrole derivatives

In order to develop analgesic compounds possessing a sulfur atom in the alicyclic ring, novel cis-fused heterocycles, [1]benzothiopyrano[3,4-b]pyrrole derivatives (II) were synthesized via a unique cyclization reaction starting from 4-(4-methoxyphenylthio)-2-butanone (1) or 6-methoxy-3,4-dihydro-2H-1-benzothiopyran-4-one (7). The analgesic effects of benzothiopyranopyrroles (16, 18) were measured by means of the writhing test. The phenolic derivative 18 completely inhibited the appearance of writhing at the dose of 50 mg/kg, but the methoxy derivative 16 had no analgesic effect.     

Synthesis of enantiopure (R,R)- and (S,S)-cis-2,3-propanoprolines

A novel approach to the synthesis of an enantiopure bicyclic proline analogue, hexahydrocyclopenta[b]pyrrole-6a(1H)-carboxylic acid (‘2,3-propanoproline’), has been developed. The method relied on tandem Strecker-nucleophilic cyclization reaction of 2-(2-bromoethyl)cyclopentanone. The overall synthetic scheme included six steps and resulted in 18% overall yield of both enantiomers of the title amino acid.     

Carboxyketenes, methyleneketenes, vinylketenes, oxetanediones, ynols, and ylidic ketenes from Meldrum's acid derivatives

It has been documented that 5-methylene-Meldrum's acid derivatives (1, 12 ) and their enols (2, 13) can undergo fragmentation to malonic anhydrides (4, 19 ), carboxyketenes (3, 16) and methyleneketene (5, 21 , 35 ), as well as cyclization to pyrrole-3-one and thiophene-3-one derivatives 11a,b (but not furan-3-ones 11c ) under the conditions of flash vacuum thermolysis (FVT). Here we report theoretical calculations at the B3LYP/6-311 + G(2d, p) and G3X(MP2) levels of theory, which allow a rationalization of these observations. The calculated activation barriers for these reactions are all of the order of 37-40 kcal mol(-1). Hydroxyacetylenes (alkynols) 7 are sometimes observed in FVT reactions of Meldrum's acid derivatives. Their formation is now explained as an FVT reaction of the carboxyketenes (e.g. 3-->7 and 32-->34) with a calculated activation barrier of ca. 39 kcal mol(-1). The cyclization of alkylamino- and alkylthio-substituted methyleneketenes 8a,b to pyrrolone and thiophenone derivatives 11a,b is found to be energetically very feasible under FVT conditions, and even in some cases in solution, with activation barriers of 33-39 kcal mol(-1). This cyclization takes place via the fleeting ylidic ketene intermediates 9a,b,25, and 37a,b, which exist in very shallow energy minima. Alkoxy-substituted methyleneketenes 8c do not cyclize in this manner due to the rather high, but in principle not impossible, activation barriers for the initial 1,4-H shifts to the ylidic ketenes 9c (ca. 47 kcal mol(-1)).     

Direct synthesis of pyrrole nucleosides by the stereospecific sodium salt glycosylation procedure

A stereospecific high-yield glycosylation of preformed fully aromatic pyrroles has been accomplished for the first time. Reaction of the sodium salt of pyrrole-2-carbonitrile ( 1a ) and pyrrole-2,4-dicarbonitrile ( 1b ) with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranose ( 2 ) gave exclusively the corresponding blocked nucleosides with β-anomeric configuration 3a and 3b , which on deprotection gave 1-(2-deoxy-β-D-erythro-pentofuranosyl) derivatives of 1a ( 3c ) and 1b ( 3d ). Functional group transformation of 3c and 3d provided a number of 2-monosubstituted 4a-c and 2,4-disubstituted 4d-f derivatives of 1-(2-deoxy-β-D-erythro-pentofuranosyl)pyrrole. Similar glycosylation of the sodium salt of 1a and 1b with 1-chloro-2,3,5-tri-O-benzyl-α-D-arabinofuranose ( 5 ) and further functional group transformation of the intermediate blocked nucleosides 6a and 6b provided 1-β-D-arabinofuranosyl derivatives of pyrrole-2-carboxamide ( 7b ) and pyrrole-2,4-dicarboxamide ( 7d ). The synthetic utility of this glycosylation procedure for the preparation of 1-β-D-ribofuranosylpyrrole-2-carbonitrile ( 12 ) has also been demonstrated by reacting the sodium salt of 1a with 1-chloro-2,3-O-isopropylidene-5-O-(t-butyl)dimethylsilyl-α-D-ribofuranose ( 10 ) and subsequent deprotection of the blocked intermediate 11 . This study provided a convenient route to the preparation of aromatic pyrrole nucleosides.     

Pyrrolo[1,2-d]triazines-1,2,4. I. Dérivés pyrroliques

Pyrrole hydrazides and hydrazones were synthesized from pyrrole-2-carboxylic acid and pyrrole-2-carboxaldehyde, The 2-pyrrolyloxadiazoles and thiadiazoles were obtained by cyclising the pyrrole hydrazides with phosphorus oxychloride and tetraphosphorus decasulphide. These derivatives have been used for the synthesis of pyrrolo[1,2-d]-1,2,4-triazines by cyclisation or rearrangement.     

Synthesis and antioxidant assay of new nicotinonitrile analogues clubbed thiazole,pyrazole and/or pyridine ring systems

A series of novel nicotinonitrile derivatives were synthesized by hybridization with thiazole, pyrazole, and pyridine ring systems using 4-aminobenzohydrazide as link-bridge. The synthetic strategy of nicotinonitrile-thiazole analogues involves cyclization of the precursor N-phenyl thiosemicarbazide derivative 4 with chloroacetic acid and phenacyl bromide. The reaction of hydrazide 3 with acetylacetone and/or ethyl acetoacetate was applied as a synthetic route for accessing 2-((4-(pyrazole-1-carbonyl)phenyl)amino)-nicotinonitrile derivatives 9–10 . The 2-((4-(4-thiazolylidene-pyrazole-1-carbonyl)-phenyl)amino)nicotinonitriles 14–15 were obtained via a nucleophilic addition of pyrazolone 10 to phenyl isothiocyanate followed by cyclization with chloroacetone, phenacyl chloride, and/or ethyl bromoacetate. The 6-amino-4-aryl-3,5-dicyano-2-oxo-1-(4-substitutedbenzamido)-pyridines 19 were synthesized by Knoevenagel condensation N′-(2-cyanoacetyl)-benzohydrazide derivative 16 with substituted benzaldehydes followed by heating with malononitrile. All synthesized products were evaluated for their antioxidant potentialities using of 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical cation delcolorization assay. The nicotinonitrile-thiazole hybrid 6b was found the most promising antioxidant agent with inhibition activity 86.27%.     

Synthesis of thio- and furan-fused heterocycles: furopyranone,furopyrrolone, and thienopyrrolone derivatives

We report herein the synthesis of a novel class of compounds, ethyl 4-oxo-4H-furo[3,2-c]pyran-6-yl carbonate, (7E)-7-[(dimethylamino)methylene]-4H-furo[3,2-c]pyran-4,6(7H)-dione, 5-oxo-N-phenyl-2,5-dihydro-4H-furo[3,2-b]pyrrole-4-carboxamide, and 5-oxo-N-phenyl-5,6-dihydro-4H-thieno[3,2-b]pyrrole-4-carboxamide starting from the corresponding acid derivatives. Intramolecular cyclization in the presence of thionyl chloride formed the target fused ring systems. Additional transformation was seen in the cyclization of furan-fused heterocycle. A mechanism was proposed based on experimental and computational findings.     

N-桥连芳基吡咯类衍生物的合成、晶体结构及杀虫杀螨活性研究

以1-溴甲基-2-(4-氯苯基)-3-氰基-4-溴-5-三氟甲基吡咯为起始原料合成了3个新颖的N-桥连芳基吡咯类衍生物5a～5c. 通过氢谱、红外、元素分析及X射线单晶衍射确证了结构. 发现当2-(4-氯苯基)-3-氰基-4-溴-5-三氟甲基吡咯分别与S2Cl2, SCl2, 次磺酰氯, 亚磺酰氯反应时, 均未得到预期的N桥连产物, 却得到了Br被S取代的非预期产物. 杀虫杀螨活性结果显示目标产物5a～5c对东方粘虫、尖音库蚊幼虫、朱砂叶螨具有选择性, 如5a对东方粘虫具有很好的杀虫活性, 5a和5b在0.5 mg•g－1浓度下对尖音库蚊的杀虫活性为100%, 5b对朱砂叶螨具有很好的杀螨活性, 达到了商品化品种溴虫氰的水平.     

Indole- and pyrrole-sulfonium ylides

Electrophilic substitution of indole and pyrrole with sulfoxides and acid anhydrides leads to the formation of indole-3-sulfonium salts and pyrrole-2-sulfonium salts. These are deprotonated with potassium carbonate to give indole-3-sulfonium ylides and pyrrole-2-sulfonium ylides. An indole-2-sulfonium ylide was obtained by methylation and subsequent deprotonation of 2-(methylthiol)indole.     

Tuning the anion binding properties of calixpyrroles by means of p-nitrophenyl substituents at their meso-positions

Extended cavity calix[4]pyrroles and a calix[6]pyrrole were synthesized by cyclization of 5-methyl-5-(4-nitrophenyl)dipyrromethane with acetone in the presence of acid. The solid-state structures of the novel macrocycles were determined by X-ray crystallography. The host-guest chemistry of these receptors towards halide ions was investigated in solution by ¹H NMR titration techniques and compared with those of the meso-octamethylcalix[4]pyrrole and meso-dodecamethylcalix[6]pyrrole. The binding of chloride anions was observed to occur with different affinities on the two faces of the novel calix[6]pyrrole derivative described here.     

Practical synthesis of (R)-4-mercaptopyrrolidine-2-thione from L-aspartic acid. Preparation of a novel orally active 1-beta-methylcarbapenem, TA-949

A facile and economical synthesis of a novel orally active 1-beta-methylcarbapenem, TA-949 (1), is described. The key process involves an efficient synthesis of the C-2 side chain (R)-4-mercaptopyrrolidine-2-thione 2 from L-aspartic acid and the construction of the 1-beta-methylcarbapenem skeleton. The mercapto group of 2 with an R-configuration was formed via deaminative bromination of the amino group of L-aspartic acid beta-methyl ester hydrochloride 12 followed by a complete S(N)2-type substitution with potassium benzenemethanethiolate. High-yield amination and cyclization of the chloride 15 to the pyrrolidin-2-one 16 was accomplished by a simple treatment with ammonia. Thiation of 16 and the Birch reduction of the resultant thiolactam 18 provided the C-2 side chain 2 in high yield with the asymmetric center retained as such. The side chain 2 was installed into the 1-beta-methylcarbapenem skeleton either by coupling with the vinyl phosphate 5 or by the use of the counterattack strategy involving the Dieckmann-type cyclization of the thioester 8. Removal of the protective groups of the coupling product 6 followed by esterification provided TA-949 (1) in high yield.     

Synthesis of 1-Substituted Pyrrole-3-carboxaldehydes

The Vilsmeier-Haack formylation is the route most frequently employed for the introduction of a formyl group into the 2 or 3 position of a pyrrole ring.^2,3 Factors affecting the extent of substitution in the 2 and 3 positions in N-substituted pyrroles under Vilsmeier-Haack conditions have been investigated and the product distribution appears mainly to be the result of steric interactions.^4,5 Although it is relatively simple to introduce a formyl residue into the 2-position of a pyrrole nucleus, considerable molecular manipulation must normally be undertaken to prepare pyrrole-3-carboxaldehydes which do not bear substituents in the 2 and 5 positions of the pyrrole ring.⁶ An alternative method is the generation of isomeric mixtures of pyrrole-2-carboxaldehyde and pyrrole-3-carboxaldehyde by the acid mediated rearrangement of t h e corresponding pyrrole-2-carboxaldehydes.     

The reaction of methyl pyrrole-2-carboxylate with epoxides

Potassium methyl pyrrole-2-carboxylate and styrene oxide are shown to yield trans-1-styrylpyrrole-2-carboxylic acid (dry conditions) and 1-(2-hydroxy-2-phenylethyl)pyrrole-2-carboxylic acid (moist conditions). The hydroxy acid yields 1H-3-phenyl-3,4-dihydropyrrolo[2.1-c]-[1.4]oxazin-1-one, on treatment with polyphosphoric acid. Vinyl acids were also obtained from the potassium pyrrole ester and ethylene oxide, propylene oxide, and cis- and trans-stilbene oxide; the latter two compounds yielded stereospecific products. A pyrrolo[2.1-c]-[1.4]benzoxazinone was obtained from cyclohexene oxide. The photo chemical isomerization of the trans-1-styryl acid and the attempted conversion into lactones is described.