The synthesis of thiaolivacine and related compounds

1,5-Dimethylbenzothieno[2,3-g]isoquinoline (thiaolivacine) has been prepared from the nitro-vinyl derivative of 4-methyl-3-dibenzothiophenecarboxaldehyde. Using the same aldehyde, 4-des-methylisothiaolivacine was prepared by formation of the Schiff's base with aminoacetaldehyde diethyl acetal followed by cyclization. Similar methods yielded the pyrido-N-isomer, 1-des-methylthiaolivacine, from 4-methyl-2-dibenzothiophenecarboxaldehyde. The thiaolivacine parent unsubstituted ring system, benzothieno[2,3-g]isoquinoline, was prepared from 2-dibenzothio-pheneearboxaldehyde by the aminoacetaldehyde approach, as was the corresponding oxygen analog, benzofuro[2,3-g]isoquinoline, from 2-dibenzofurancarboxaldehyde. The 100 MHz spectra of these fused isoquinolines are recorded and correlated.     

Synthesis of diallyl‐containing polyimide and the effect of allyl groups on properties

A diallyl‐containing bisphenol, 1,1‐bis(3‐allyl‐4‐hydroxyphenyl)‐1‐(6‐oxido‐6H ‐dibenzo [c,e][1,2] oxaphosphorin‐6‐yl) ethane ( 1 ), was prepared by a two‐step procedure. Then, a diallyl‐containing diamine, 1,1‐bis(3‐allyl‐4‐(4‐aminophenoxy)‐phenyl)‐1‐(6‐oxido‐6H‐dibenzo [c,e][1,2] oxaphosphorin‐6‐yl)ethane ( 3 ), was prepared from the nucleophilic substitution of ( 1 ) with 4‐fluoronitrobenzene, followed by the reduction by Fe/HCl. A flexible polyimide ( 4 ) with curable diallyl linkages was prepared from the condensation of ( 3 ) and 4,4′‐oxydiphthalic anhydride in m‐cresol in the presence of isoquinoline. Curing polyimide ( 4 ) at 300 °C leads to thermosetting polyimide ( 5 ). We discussed the amounts of allyl group on T_g, coefficient of thermal expansion, and thermal stability of thermosetting polyimides, and found that thermal properties and dimensional stability of thermosetting polyimides increase with the amounts of cured allyl moieties. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 513–520     

Synthesis of thermosetting polyetherimide‐containing allyl groups

An allyl‐containing diphenol, 1‐(3‐allyl‐4‐hydroxyphenyl)‐1‐(4‐hydoxyphenyl)‐1‐(6‐oxido‐6H ‐dibenz[c,e][1,2]oxaphosphorin‐6‐yl)ethane (1) , was prepared from a one‐pot reaction of 9,10‐dihydro‐oxa‐10‐phosphaphenanthrene‐10‐oxide, 4‐hydroxyacetophenone, and 2‐allylphenol in the presence of p‐toluenesulfonic acid monohydrate. Then, an allyl‐containing dietheramine, 1‐(4‐(4‐aminophenoxy)phenyl)‐1‐(3‐allyl 4‐(4‐aminophenoxy)‐phenyl)‐1‐(6‐oxido‐6H‐dibenz[c,e][1,2] oxaphosphorin‐6‐yl)ethane (3) , was prepared from the nucleophilic substitution of (1) with 4‐fluoronitrobenzene, followed by the reduction of the dinitro groups by Fe/HCl. A flexible polyetherimide (PEI) (4) with a curable characteristic was prepared from the condensation of (3) and 4,4′‐oxydiphthalic anhydride (ODPA) in m‐cresol in the presence of isoquinoline. Curing PEI (4) at 300 °C leads to PEI (5) , which exhibits much a higher T_g value (307 °C) and a lower coefficient of thermal expansion (CTE) (29 ppm/°C) than PEI (4) (T_g = 253 °C, CTE 52 ppm/°C). © 2013 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013     

Synthesis of 2,3,10,11 -tetraalkoxy-substituted tetrahydrobenzo [a] naphtho [1,2-g] quinolizines

2 Four3,10,11-tetraalkoxy-substituted 5,6,15,15a-tetrahydro-8H-benzo[a]naphtho[1,2-g]-quinolizines were prepared by the Pictet-Spengler cyclization of the respective 1-(6,7-dialkoxy-2-naphthylmethyl)-6,7-dialkoxy-1,2,3,4-tetrahydroisoquinolines. The latter compounds were obtained by a chemical reduction of the corresponding dihydro compounds, which, in turn, were formed by a Bischler-Napieralski cyclization of the appropriate amides.     

Chemistry of thienopyridines. XXXIX. Synthesis of benzothieno[2,3-h]isoquinoline and related studies

Benzo[b]thiophene-2-carboxaldehyde undergoes condensation with 4-methylpyridine and with 2-methylquinoline to produce trans-diarylethenes (52% and 76%, respectively). The former alkene photocyclizes in cyclohexane to yield [1]benzo[2,3-h]isoquinoline (35%), while the latter alkene does not give successful, analogous cyclization.     

Synthesis of 8,9-dialkoxy-substituted tetrahydrobenz[h] isoquinolines

6,7-Dimethoxy-2-naphthylethylamine, prepared by the diborane reduction of 6,7-dimethoxy-2-naphtlialeneacetamide, underwent a Pictet-Spengler cyclization to form 8,9-dimethoxy-1,2,3,4-tetrahydrobenz[h]isoquinoline. This compound is identical with that obtained by reduction of the corresponding dihydrobenzisoquinoline prepared from formamide cyclization. 6,7-Dialkoxy-2-naphthaleneacetic acids, the key intermediates for the preparation of these amides, were obtained from 6,7-dialkoxy-2-acetonaphthones by a modified Willgerodt reaction.     

Synthesis of cycloproparenes via aromatization of 7-Oxanorbornenes with Low-Valent titanium

1H-Cyclopropa[b]naphthalene 3c and the 2,7-diphenyl-substituted derivative 3a have been synthesized via cycloaddition of the appropriate isobenzofurans 1a and 1b to 1-bromo-2-chlorocyclopropene and aromatization of the adducts with low-valent Ti. The same procedure afforded the 2,7-dimethyl-H-cyelopropa[g]isoquinoline ( 15 ), but failed for the parent azacompound. Reaction of adducts of furans to 1-bromo-2-chlorocyclopropenes with low-valent Ti produced mixtures of cyclopropabenzenes 19 and 1,6-dihalogeno-1,3,5-cycloheptatrienes 18 . The latter could be converted to cyclopropabenzenes with BuLi.     

Synthesis of Functionalized Cycloprop[f]indenes via the Carbene Addition Route

The synthesis of 4,5-dihydro-1H,3H-cycloprop[f]inden-4-ol ( 1 ) and diethyl 4,5-dihydro-1H,3H-cycloprop[f]-indene-4,4-dicarboxylate ( 26 ) starting from diene 4 is described. The cyclopentene ring is constructed by condensation of diethyl malonate to the dibromide 21 . The key-step in the synthesis of 1 consists in a twofold Curtius degradation of 22 , with subsequent reduction of the carbonyl group and aromatization. The skeleton of the isomer 31 is synthesized via cycloaddition of butadiene to cyclopent-4-ene-1,3-dione ( 7 ) and addition of dichlorocarbene to the adduct 27 after ketalisation. The attempted synthesis of dihydrocycloprop[f]indene ( 2 ) by base-induced elimination of several appropriately substituted precursors failed.     

Synthesis of cycl[3.2.2]azine and benzo[g]cycl[3.2.2]azine derivatives by use of the [2 + 8] cycloaddition reaction of indolizines and dimethyl acetylenedicarboxylate

The reaction of 1-ethoxycarbonylmethylpyridinium bromides 5a-k with nitro ketene dithioacetal, 1,1-bis-(methylthio)-2-nitroethylene ( 2 ), in the presence of triethylamine in ethanol gave the desired ethyl 2-methyl-thioindolizine-3-carboxylates 3a-k in good yields, along with ethyl 2-methylthio-1-nitroindolizine-3-carboxyl-ates 4a-d . Deesterification of 3 using sodium hydroxide in methanol followed by treatment with polyphosphoric acid gave the corresponding 2-methylthioindolizines 5a-d in good yields. The desulfurization of 5 with Raney-nickel in ethanol occurs smoothly to give the 1,2,3-unsubstituted indolizines 6a-c (a , parent indolizine; b , 8-methylindolzine; c , 6,8-dimethylindolizine). Similarly, pyrrolo[2,1-a]isoquinoline ( 19 ) was also synthesized. These indolizine and pyrrolo[1,2-a]isoquinoline derivatives were allowed to react with dimethyl acetylene to give the corresponding cycl[3.2.2]azine and benzo[g]cycl[3.2.2]azine derivatives in good results.     

Polycondensed heterocycles. IV. synthesis of 1,4-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzothiazine

A method for the synthesis of the title compound 3 consisted of an intramolecular cyclization in a stannic chloride catalyzed Friedel-Crafts reaction of N-(2-methylthiophenyl)-5-oxoproline chloride 10 , prepared by chlorination of the corresponding acid 9 obtained by hydrolysis of its ethyl ester 8 . Condensation of 2-methylthioaniline 4 with diethyl bromomalonate 5 afforded diethyl 2-methylthioanilinomalonate 6 which gave 8 either directly by reaction with ethyl acrylate or by alkylation with ethyl β-bromopropionate or ethyl acrylate and cyclization of resulting triethyl 2-(2-methylthio)anilino-2-carboxyglutarate 7 . This method was not convenient because of the poor yield of 3 (14%). On the other hand, cyclization of N-(2-mercaptophenyl)-5-oxoproline 14 with DCC and DMAP provided 3 in 45% yield. Oxidation with m-CPBA of the esters 11 and 8 , demethylation via the Pummerer rearrangement of the respective sulphoxides 12 and 17 with TFAA and oxidation with iodine of resulting N-(2-mercap-tophenyl)-5-oxoproline esters 13 and 18 gave the corresponding disulphides 16 and 19 . Hydrolysis of these latter compounds and reduction of the resulting bis[2-[2-(hydroxycarbonyl)-5-oxo-1-pyrrolidinyl]phenyl] disulphide 15 with sodium dithionite afforded the required 14 . Deprotection of t-butyl ester 13 with TFA at 55° to obtain 14 led to 3 in 42% yield. Finally the Pummerer rearrangement of N-(2-methylsulphinylphenyl)-5-oxo-proline 20 yielded the mixture of 14 and 15 .     

Synthesis of some new fused coumarin derivatives

2-Hydrazino-4-hydroxy-5H- [1] -benzopyrano- [ 4,3-d ] -pyrim-idin-5-one (3) was prepared via condensation of 2 with hy-drazine hydrate. Treatment of 3 with methylene chloride, ethyl chloroformate, ethyl chloroacetate and benzaldehyde yielded the corresponding 2 - ( substituted ) hydrazino - 4 -hydro-xy-5H-[1]-benzopyrano-[4, 3-d]-pyrimidin-5-one (4, 5, 6, and 10), followed by cyclization of 4, 5 and 6 with dimethyl fonnamide and fused sodium acetate under reflux, while compound 10 was cyclized with bromine and sodium acetate in acetic acid. Compound 3 reacted with β-(toloyl) acrylic acid, ethyl α-cyano-p-methoxytinnamate, diethyl mal-onate and acetyl chloride affording the corresponding 2-(substituted) hydrazino-4-hydroxy-5H-[1]-benzopyrano-[4, 3-d]-pyrimidin-5-one (12, 13, 14, 15 and 16).     

Folic acid analogs. Modifications in the benzene-ring region. 5. 2′,6′-diazafolic acid

The synthesis of 2′,6′-diazafolic acid was accomplished by the condensation of 2-acetylamino-4(3H)pteridinone-6-earboxaldehyde (XIV) with diethyl N-[(5-amino-2-pyrimidinyl)carbonyl]-L-glutamate (XIII) followed by reduction of the anil double bond and alkaline hydrolylic cleavage of the N²-acetyl and ethyl ester protecting groups. Intermediate XIII was prepared by starling with 5-nitro-2-styrylpyrimidine (VI) and proceeding via 5-arnino-2-styrylpyrimidine (IX). The henzyloxycarbonyl derivative of IX was prepared and oxidized to the corresponding 5-benzyloxycarbonylaminopyrimidine-2-carboxylic acid (XI). The coupling of XI with diethyl L-glutamate followed by hydrogenolysis of the henzyloxycarbonyl function afforded the desired intermediate XIII. 2′,6′-Diazafolic acid was a potent inhibitor of Streptococcus faecium and displayed marginal activity against leukemia 1,1210 in mice.     

Bisindoles. 38. Synthesis of Some Derivatives of 1H,6H-Indolo[7,6-g]indole

1H,6H,2,3,7,8-Tetramethylindolo[7,6-g]indole and 1H,8H,2,3,4,5,9,10,11,12-octahydrocarbazolo[3,2-c]carbazole were synthesized by the condensation of 1,5-naphthylenedihydrazine with alkyl ketones followed by cyclization of the obtained hydrazones without isolation. The respective N,N-dibenzyl derivatives were obtained by benzylation of the alkyl-substituted compounds. A new spirocyclic system was synthesized by nucleophilic addition of 2,3,3,7,8,8-hexamethylindolenino[7,6-g]indolenine to 2',3'-dimethoxycarbonylspirofluorenecyclopropene.     

Generation of N‐Heterocycles via Tandem Reactions of N ′‐(2‐Alkynylbenzylidene)hydrazides

As a powerful synthon, N ′‐(2‐alkynylbenzylidene)hydrazides have been utilized efficiently for the construction of N‐heterocycles. Since N ′‐(2‐alkynylbenzylidene)hydrazides can easily undergo intramolecular 6‐endo cyclization promoted by silver triflate or electrophiles, the resulting isoquinolinium‐2‐yl amides can proceed through subsequent transformations including [3 + 2] cycloaddition, nucleophilic addition, and [3 + 3] cycloaddition. Several unexpected rearrangements via radical processes were observed in some cases, which afforded nitrogen‐containing heterocycles with molecular complexity. Reactive partners including internal alkynes, arynes, ketenimines, ketenes, allenoates, and activated alkenes reacted through [3 + 2] cycloaddition and subsequent aromatization, leading to diverse H‐pyrazolo[5,1‐a]isoquinolines with high efficiency. Nucleophilic addition to the in situ generated isoquinolinium‐2‐yl amide followed by aromatization also produced H‐pyrazolo[5,1‐a]isoquinoline derivatives when terminal alkynes, carbonyls, enamines, and activated methylene compounds were used as nucleophiles. Isoquinoline derivatives were obtained when indoles or phosphites were employed as nucleophiles in the reactions of N ′‐(2‐alkynylbenzylidene)hydrazides. A tandem 6‐endo cyclization and [3 + 3] cycloaddition of cyclopropane‐1,1‐dicarboxylates with N ′‐(2‐alkynylbenzylidene)hydrazides was observed as well. Small libraries of these compounds were constructed. Biological evaluation suggested that some compounds showed promising activities for inhibition of CDC25B, TC‐PTP, HCT‐116, and PTP1B.

     

A new synthesis of dibenzo[b,g][1,5]naphthyridine-6,12(5H,1H)dione (epindolidione)

A new convenient synthesis of dibenzo[b,g][1,5]naphthyridine-6,12(5H,11H)dione starting from N-phenylglycine ethyl ester is described. Ester condensation of N-phenylglycine ethyl ester with diethyl oxalate followed by reaction with aniline under acid catalysis gave a mixture of diethyl dianilinomaleate and diethyl dianilinofumarate in 54% yield. Upon heating this mixture in a high-boiling inert solvent, 3-anilino-2-ethoxycarbonyl-4-quinolone was obtained in 72% yield. Final ring closure of the quinolone derivative using polyphosphoric acid gave the epindolidione.     

Synthesis of new heterocyclic phenols: 9-Hydroxypyrido[1,2-a]pyrimidin-4-one and Derivatives

9-Hydroxypyrido[1,2-a]pyrimidin-4-one ( 5 ) was prepared by condensation of 2-amino-3-hydroxypyridine with isopropylidene aminomethylenemalonate. The reaction first led to an enaminoester intermediate which underwent cyclization by heating at 250° affording the new heterocyclic phenol 5 . A similar condensation performed on 2-amino-3-benzyloxypyridine yielded the corresponding benzylic ether which can be easily debenzylated to 5 by hydrogenolysis. Furthermore 2-amino-3-benzyloxypyridine condensed with diethyl ethoxymethylenemalonate gave 9-benzyloxy-3-ethoxycarbonylpyrido[1,2-a]pyrimidin-4-one which was also debenzylated to the corresponding free phenol.     

A new synthesis of imidazo[1,2-a]pyridine and imidazo[2,1-a]isoquinoline derivatives

A new synthesis of imidazo[1,2-a]pyridine and imidazo[2,1-a]isoquinoline derivatives 4 and 8 , respectively by 1,5-dipolar cyclization reactions of stabilized pyridinium N-ylides 3a-e or isoquinolinium N-ylide 7 is described. The starting N-ylides 3a-e and 7 are prepared by the reaction of the corresponding pyridinium salts 1a-e or isoquinolinium salts 6 with N-bis(methylthio)methylene-p-toluenesulfonamide (2) .     

Cyclization of Nitriles: LIX. Synthesis and Properties of 1-(2-Thienyl)-4-cyano-5,6,7,8-tetrahydro-3(2H)- isoquinolinethione Derivatives. Molecular and Crystal Structure of 3-Isobutylsulfanyl-1-(2-thienyl)-4-cyano-5,6,7,8- tetrahydroisoquinoline

By condensation of 2-(2-thenoyl)-1-cyclohexanone with cyanothioacetamide a new compound of aseries of chalcogen-containing isoquinolines with a thiophene fragment in its structure was prepared. It wasdemonstrated that alkylation of the compound with haloalkanes, their derivatives, in particular with thosehaving electron-withdrawing substituents furnished 3-alkylthio-4-cyano-5,6,7,8-tetrahydroisoquinolines.Some of the latter underwent cyclization into 3-amino-2-R-5-(2-thienyl)-6,7,8,9-tetrahydrothieno[2,3-c]isoquinoline.     

Base- and acid-catalyzed condensation reactions of reissert compounds with vinylpyridines

The hydrochloric acid-catalyzed condensation of 2-p-anisoyl-1,2-dihydroisoquinaldonitrile ( 3 ) with 2-vinylpyridine gave 2-(1-isoquinolyl)-3-(2-pyridyl)-5-p-anisylpyrrole ( 4 ), and the corresponding reaction of 3 with 4-vinylpyridine afforded 2-(1-isoquinolyl)-3-(4-pyridyl)-5-p-anisylpyrrole (5). The condensation of the lithium salt of 3 with 4-vinylpyridine gave α-(4-pyridyl)-β-(1-iso-quinolyl)-p-methoxypropiophenone ( 10 ), which was cyclized to 2-(4-pyridyl)-3-p-anisylpyrrolo-[2,1-a]isoquinoline (7) by the action of concentrated hydrochloric acid. 2-(4-Pyridyl)-3-phenyl-pyrrolo[2,1-a]isoquinoline ( 6 ) and 2-(2-pyridyl)-3-p-anisylpyrrolo[2,1-a]isoquinoline ( 8 ) were prepared by analogous sequences of reactions.     

A strategy to access fused triazoloquinoline and related nucleoside analogues

Fused triazoloquinolines have been prepared starting from (E)-3-(2-nitrophenyl)-1-aryl-prop-2-en-1-ones and sugar or benzyl azides in a sequential [3+2] cycloaddition reaction, followed by one pot Pd–C assisted reduction, cyclization and aromatization. The triazolyl fused quinolines with N¹-glycosyl substituents as unnatural nucleosides have inherent potential to generate a library of compounds for bioevaluations.