Synthesis and reactivity of (RS)-6-chloro-7- or 9-(1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl)-7H- or 9H-purines bearing a nitrobenzenesulfonyl group on the nitrogen atom

The O,O-acetalic compounds (RS)-3-methoxy-1-[(2)- or (4)-nitrobenzenesulfonyl)]-1,2,3,5-tetrahydro-4,1-benzoxazepine have been studied in the Lewis acid-mediated condensation with 6-chloropurine. 6-Chloropurine leads to the N-7″ aminalic bond in the cyclic products and mainly to the N-9″ aminalic bond in the acyclic ones. Substitution of the chlorine atom at the 6″ position of the purine moiety is more feasible when the ring is alkylated at N-7″ than at N-9″. Exchange with a hydroxyl group is performed with water traces in deuterated dimethylsulfoxide at room temperature in a solvent-mediated process. The exchange with strong nucleophiles (e.g., thiophenol) does not need further activation.     

Design, synthesis, and cytotoxic activity of Michael acceptors and enol esters in the benzo[b]acronycine series

A series of 2-acyl-6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]acridin-7-ones (4-6) was prepared by treatment of 6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one (3) with an excess of an appropriate acyl chloride in the presence of aluminum chloride. Treatment of (+/-)-cis-1-hydroxy-2-acyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-ones (9, 10) or (+/-)-cis-1,2-diacyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-ones (2, 11) with hydrochloric acid gave the corresponding 2-acyloxy-6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]acridin-7-ones, exemplified by acetate 7 and butyrate 8. None of the Michael acceptors 4-6 showed significant antiproliferative activity. Enol esters 7 and 8 were markedly cytotoxic toward L1210 leukemia cells, with IC50 values within the same range of magnitude as (+/-)-cis-1,2-diacetoxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one (S23906-1), currently under phase I clinical trials. In contrast with S23906-1, enol esters 7 and 8 were not reactive toward purified DNA.     

Syntheses of (4,1-benzoxazepine-3-ylidene)acetic acid derivatives and their inhibition of squalene synthase

The (3,5-trans)-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid derivatives 1 have been previously identified as potent squalene synthase inhibitors. A series of (4,1-benzoxazepin-3-ylidene)acetic acid derivatives were synthesized and evaluated for their inhibition of rat and human squalene synthase, and the (E)-isomers were found to exhibit potent inhibitory activity, with the same potency as 4,1-benzoxazepine-3-acetic acid derivatives. In contrast the (Z)-isomers did not exhibit significant inhibitory activity, and the active conformation of the 4,1-benzoxazepine-3-acetic acid derivatives was deduced from the folded conformation of the (E)-isomers.     

Investigations toward the total syntheses of proapoiphine and homoproaporphine alkaloids

The reaction of 1,2,3,5-telrahydro-6-methoxy-1 -[2-(4-methoxy-1,4-eyelohexadien-1 -yl)eth-yl]-l-methyl-7-isoquinolinol ( 12 ) with hot phosphoric acid afforded (±)-tetrahydro-homoglazio-vine ( 14 ) in good yield. Similar treatment of 1,2,3,4-tetrahydro-6-methoxy-l -[2-(4-methoxy-1,4-cyelohexadien-l-yl)methyl]-2-methyl-7-isoquinolinol ( 13 ) did not produce the desired (±)-tetra-hydroglaziovine ( 18 ) but rather a mixture of diastereomeric 4,5,6,6a?,7,7a?,8,9,11, 11a?-deca-hydro-l-hydroxy-2-metlu>xy-6-methyl-10H-dibenzo[(de,g]quinolin-l-ones (16 and 17) was obtained.     

Short syntheses of 1,2,3,5-tetrahydro-5-oxopyrrolo-[1,2-a]quinoline-4-carboxylic acid and 1,2,3,4-tetrahydro-6H-6-oxopyrido[1,2-a]quinoline-5-carboxylic acid derivatives

Short and efficient syntheses of 7-fluoro-8-(4-methylpiperazin-1-yl)-1,2,3,5-tetrahydro-5-oxopyrrolo[1,2-a]-quinoline-4-carboxylic acid and 8-fluoro-9-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-6H-6-oxopyrido[1,2-a]-quinoline-5-carboxylic acid are described. Both basic heterocycles were synthesized in two steps by the condensation of a benzoylacetate with an imino ether followed by an intramolecular nucleophilic displacement cyclization reaction.     

Ionic Liquid-Mediated Facile Synthesis and Antimicrobial Study of Thiazolo [2,3-b]Benzo[h]Quinazolines and Thiazino[2,3-b] Benzo-[h]Quinazolines

Abstract

8-Methoxy-4-phenyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione, obtained by the condensation of 2-benzylidene-6-methoxy-3,4-dihydronapthalene-1(2H)-one with thiourea, on reaction with chloroacetic acid and 3-chloropropanoic acid in the presence of the ionic liquid N-methylpyridinium tosylate furnishes 3-methoxy-7-phenyl-7,10-dihydro-5H- benzo[h]thiazolo[2,3-b]quinazoline-9(6H)-one and 3-methoxy-7-phenyl-5,6,10,11-tetrahydro- benzo[h][1,3]thiazino[2,3-b]quinazoline-9(7H)-one. Further, condensation of the thione with 1,2-dibromoethane and 1,3-dibromopropane yields 3-methoxy-7-phenyl-6,7,9,10-tetrahydro-5 H-benzo[h]thiazolo[2,3-b]quinazoline and 3-methoxy-7-phenyl-5,6,7,9,10,11-hexahydrobenzo [h][1,3]thiazino[2,3-b]quinazoline respectively. Arylidene derivatives have been obtained by two routes. The structures of the cyclized compounds have been established on the basis of elemental analysis and spectroscopic data. The synthesized compounds were screened for antimicrobial activity. Some of the compounds showed promising antimicrobial activities.     

Selenoxanthones via directed metalations in 2-arylselenobenzamide derivatives

The reaction of N, N-diethyl 4-(N', N'-dimethylamino)-2-phenylselenobenzamide (7a), N, N-diethyl 4-methoxy-2-phenylselenobenzamide (7b), N, N-diethyl 4-(N', N'-dimethylamino)-2-[(3-(N, N-dimethylamino)phenylseleno]benzamide (7c), and N, N-diethyl 4-methoxy-2-(3-methoxyphenylseleno)-benzamide (7d) with excess lithium diisopropylamide (LDA) gave 2-N, N-(dimethylamino)-9H-selenoxanthone (9a), 2-methoxy-9H-selenoxanthone (9b), 2,7-bis-N, N-(dimethylamino)-9H-selenoxanthone (9c), and 2,5-dimethoxy-9H-selenoxanthone (9d) in 70%, 59%, 23%, and 90% isolated yields, respectively. N, N-Diethyl 2-phenylselenobenzamide (2-Se) gave no reaction with LDA, t-BuLi, MeLi, or lithium 2,2,6,6-tetramethylpiperidide as base. Electron donation from the 4-substituent of benzamide derivatives 7a-7d may increase the directing ability of the carbonyl oxygen to metalate the 2-position of the arylseleno group.     

Synthesis of tetrahydrobenzoxazepine acetals with electron-withdrawing groups on the nitrogen atom. Novel scaffolds endowed with anticancer activity against breast cancer cells

Synthetic approaches that have led to (RS)-3-methoxy-N-substituded-1,2,3,5-tetrahydro-4,1-benzoxazepines with different electron-withdrawing groups, and (RS)-2-methoxy-N-trifluoroacetyl-2,3,4,5-tetrahydro-1,4-benzoxazepine are described. These novel synthons that were designed to be used as scaffolds for the preparation of new O,N-acetals as anticancer agents, unexpectedly proved to show antiproliferative activity against the MCF-7 breast cancer cell line. It has been found that substituents on the nitrogen atom have an influence on biological activity. In particular, the presence of a trifluoroacetyl moiety on the nitrogen atom leads to amides displaying interesting in vitro antitumour activities.     

A Facile One-Step Synthesis of New Types of 8-Thiazolyl and 8-Thiadiazinyl Coumarins

N-[4-(7-Methoxy-4-methyl-2-oxo-2H-chromen-8-yl)-thiazol-2-yl]-guanidine ( 2 ) has been prepared by the condensation of 4-methyl-7-methoxy-8-(2-bromoacetyl)coumarin ( 1 ) with guanylthiourea. 4-Methyl-7-methoxy-8-[2-(N′-(1-phenyl-ethylideneisopropylidene)-hydrazino]-thiazol-4-yl]chromen-2-ones ( 3 , 4 , and 5 ) have been prepared by reaction of 4-methyl-7-methoxy-8-(2-bromoacetyl) coumarin ( 1 ) and thiosemicarbazide in presence of acetophenone or acetone without any solvent. The formation of these compounds was further confirmed by the condensation of acetophenone/acetone thiosemicarbazones with 4-methyl-7-methoxy-8-(2-bromoacetyl)coumarin ( 1 ) in anhydrous ethanol in a two-step process. Similarly 8-[2-[N′-(benzylidene)hydrazine]-thiazol-4-yl]-7-methoxy-4-methyl-chromen-2-ones ( 6 , 7 , and 8 ) have been prepared by the condensation of 4-methyl-7-methoxy-8-(2-bromoacetyl)chromen-2-one with thiosemicarbazide and various aromatic aldehydes in a single step without any solvent. The formation of these compounds was further confirmed by the condensation of appropriately substituted benzaldehyde thiosemicarbazones with 4-methyl-7-methoxy-8-(2-bromoacetyl)coumarin in anhydrous ethanol. 4-Methyl-7-methoxy-8-(2-bromoacetyl) chromen-2-one (1) upon condensation with 3,5-dimercapto-4-amino-s-triazole in anhydrous ethanol resulted in the formation of 8-(3-mercapto-3H-[1,2,4]triazolo[3,4-b]thiadiazin-6-yl)-7-methoxy-4-methyl chromen-2-one (9). This compound ( 9 ) on reaction with various alkyl and phenacyl halides in anhydrous ethanol gave corresponding 4-methyl-7-methoxy-8-[3-(2-oxo-substituted sulphanyl)-7H-[1,2,4]triazolo[3,4-b]thiadiazin-6-yl]chromen-2-ones ( 10 to 18 ). The structures of newly prepared compounds have been confirmed from analytical and spectral data.     

Studies on the syntheses of heterocyclic compounds—CDLXXXIV : One-step synthesis of dibenzoindolizinium salt and phenolic aporphine by benzyne reaction

An indisputable benzyne reaction of 1-(5-bromo-2,4-dimethoxybenzyl)-1,2,3,4-tetrahydro-7-hydroxy-6-methoxy-2-methylisoquinoline (1) with NaNH₂ in liquid NH₃ afforded 1-hydroxy-2,8,10-trimethoxy-6-methylaporphine (4) and 5,6,12,12a-tetrahydro-2-hydroxy-3,9,11-trimethoxy-7-methyldibenzo[b,g]indolizinium salt (6).     

Synthesis of certain 3-alkoxy-1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidines structurally related to adenosine,inosine and guanosine

Several 3-alkoxysubstituted pyrazolo[3,4-d]pyrimidine ribonucleosides structurally related to adenosine, inosine and guanosine have been prepared by the direct glycosylation of preformed aglycon precursor containing a 3-alkoxy substituent. Ring closure of 5(3)-amino-3(5)-ethoxypyrazole-4-carboxamide ( 6b ) with either formamide or potassium ethyl xanthate gave 3-ethoxyallopurinol ( 7b ) and 3-ethoxy-6-thioxopyrazolo[3,4-d]-pyrimidin-4(5H,7H)-one ( 10 ), respectively. Methylation of 10 gave the corresponding 6-methylthio derivative 15 . Similar ring annulation of 5(3)-methoxypyrazole-4-carboxamide ( 6a ) with formamide afforded 3-methoxyallopurinol ( 7a ). Treatment of 5(3)-amino-3(5)-methoxypyrazole-4-carbonitrile ( 5a ) with formamidine acetate furnished 4-amino-3-methoxypyrazolo[3,4-d]pyrimidine ( 4 ). High-temperature glycosylation of 7b with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose in the presence of boron trifluoride etherate gave a 2:1 mixture of N-1 and N-2 glycosyl blocked nucleosides 11b and 13b . Deprotection of 11b and 13b with sodium methoxide gave 3-ethoxy-1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4(5H)-one ( 12b ) and the corresponding N-2 glycosyl isomer 14b , respectively. Similar glycosylation of either 4 or 7a , and subsequent debenzoylation gave exclusively 4-amino-3-methoxy-1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidine ( 9 ) and 3-methoxy-1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4-(5H)-one ( 12a ), respectively. The structural assignment of 12a was made on the basis of single-crystal X-ray analysis. Application of this general glycosylation procedure to 15 gave the corresponding N-1 glycosyl derivative 16 as the sole product, which on debenzoylation afforded 3-ethoxy-6-(methylthio)-1-(3-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4(5H)-one ( 17 ). Oxidation of 16 and subsequent ammonolysis furnished the guanosine analog 6-arnino-3-ethoxy-1-β-D-ribofuranosylpyrazolo[3,4-d]-pyrimidin-4(5H)-one ( 19 ). Similarly, starting from 3-methoxy-4,6-bis(methylthio)pyrazolo[3,4-d]pyrimidine ( 20 ), 6-amino-3-methoxy-1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4(5H)-one ( 23 ) was prepared.     

Synthesis and in vitro evaluation of N-(Bromobut-3-en-2-yl)-7-methoxy-1,2,3,4-tetrahydroacridin-9-amine as a cholinesterase inhibitor with regard to Alzheimer's disease treatment

A new tacrine based cholinesterase inhibitor, N-(bromobut-3-en-2-yl)-7-methoxy-1,2,3,4-tetrahydroacridin-9-amine (1), was designed and synthesized to interact with specific regions of human acetylcholinesterase and human butyrylcholinesterase. Its inhibitory ability towards cholinesterases was determined and compared to tacrine (THA) and 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine (7-MEOTA). The assessment of IC50 values revealed 1 as a weak inhibitor of both tested enzymes.     

Methods for the synthesis of 5,6,7,8-tetrahydro-1,8-naphthyridine fragments for alphaVbeta3 integrin antagonists

The preparation of 3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propan-1-amine 2a and 3-[(7R)-7-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl]propan-1-amine 2b, key intermediates in the synthesis of alpha(V)beta(3) antagonists, is described. The syntheses rely on the efficient double Sonogashira reactions of 2,5-dibromopyridine 3 with acetylenic alcohols 4a/4b and protected propargylamines 10a-e followed by Chichibabin cyclizations of 3,3'-pyridine-2,5-diyldipropan-1-amines 9a/9b.     

3-acyl-1,5-benzodiazepines in the reactions of 5,5-dimethyl-2-formylcyclohexane-1,3-dione with certain 1,2-diaminobenzenes

Reaction of 5,5-dimethyl-2-formylcyclohexane-1,3-dione with 4-methyl-, 4-benzoyl-, and 4-nitro-1,2-diaminobenzenes gave the corresponding 2-(2-amino-4-methylphenylaminomethylene)-, 2-(2-amino-5-benzoylphenylaminomethylene)-, and 2-(2-amino-5-nitrophenylaminomethylene)-5,5-dimethylcyclohexane-1,3-diones. When treated with hydrochloric acid, they cyclize to 7-methyl-, 8-benzoyl-, and 8-nitro-3,3-dimethyl-2,3,4,5-tetrahydro-1H-dibenzo[b,e][1,4]diazepinon hydrochlorides. Under hydrolytic conditions the salts of 3,3,7-trimethyl-2,3,4,5-tetrahydro-1H-dibenzo[b,e][1,4]diazepinone and 3,3-dimethyl-2,3,4,5-tetrahydro-1H-dibenzo[b,e][1,4]diazepinone undergo the C₁₁−N₁₀ bond cleavage to give N-(2-aminophenyl)- and N-(2-amino-5-methylphenyl)-substituted 3-amino-2-formyl-5,5-dimethylcyclohex-2-enones. Ring opening of the hydrochlorides of 8-benzoyl-, and 3,3-dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-dibenzo[b,e][1,4]diazepinones occurs at the C−N₅ bond and gives the starting enamines. Riga Technical University, Riga LV-1658, Latvia; Translated from Khimiya Geterotsiklicheskikh Soedinenii, N. 5, pp. 696–700, May, 1999.     

无外加催化剂条件下邻取代芳香醛与5, 5-二甲基-1, 3-环己二 酮的反应研究

在DMF溶剂中,不外加催化剂使邻取代芳香醛(1)与5,5-二甲基-1,3-环己二酮(2)发生缩合和加成反应生成3,3,6,6-四甲基-4a-羟基-9-芳基-1,8-二氧代-2,3,4,4a,5,6,7,8,9,9a-十氢化-1H-氧杂蒽(3a-3d)。在同样条件下,邻羟基芳香醛与5,5-二甲基-1,3-环己二酮则发生缩合、加成和脱水反应生成3,3-二甲基-9-(5,5-二甲基-3-羟基-2-环己烯-1-酮-2-基)-1-氧代-2,3,4,9-四氢化-1-氧杂蒽(4a-4b)。用单晶X-射线分析法确定了产物3a和4a的晶体结构。     

The synthesis of 2-benzazocines using ring-closing metathesis as a key step

A number of protected 7-isopropoxy-8-methoxy-1,2,3,6-tetrahydro-2-benzazocines were synthesized from 2-allyl-3-isopropoxy-4-methoxybenzaldehyde using ring-closing metathesis as the key step. In addition, two 9-isopropoxy-8-methoxy-3,6-dihydro-2-benzazocines were synthesized from 5-isopropoxy-4-methoxy-2-[(1E)-3-phenyl-2-propenyl]benzaldehyde, which in turn was obtained from the thermal Claisen-Cope rearrangement of 4-methoxy-3-{[(2E)-3-phenyl-2-propenyl]oxy}benzaldehyde. Finally, five of the 2-benzazocine compounds were tested for anti-cancer activity.     

Mechanism of the Catalytic Activity of Nucleophiles in the Stepwise Hydrolysis and Condensation Reactions of Tetramethoxysilane

Active ingredients : A model for the simplest hydrolysis reaction is applied to all stages of stepwise hydrolysis and condensation taking place during a sol–gel process. The picture shows the molecular structures of the transition states of the ammonia‐ (left) and OH^?‐promoted (right) condensation reactions of two Si(OH)₄ molecules, including an additional water molecule.

     

1,3-dipolar cycloaddition chemistry for the preparation of novel indolizinone-based compounds

[Chemical reaction: See text] Starting from methyl 5-oxo-6-trifluoromethanesulfonyloxy-1,2,3,5-tetrahydroindolizine-8-carboxylate, obtained by a Rh(II)-catalyzed 1,3-dipolar cycloaddition reaction of 1-(2-benzenesulfonyl-2-diazoacetyl)pyrrolidin-2-one and methyl acrylate, several indolo- and furano-fused indolizinones were efficiently prepared. In the first case, a palladium-mediated C-N coupling of the triflate with a variety of substituted anilines provided the desired methyl 5-oxo-6-(arylamino)-1,2,3,5-tetrahydroindolizine-8-carboxylates in high yield. Methyl 6-(2-bromophenylamino)-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylate as well as its decarboxylated analogue, 6-(2-bromophenylamino)-2,3-dihydro-1H-indolizin-5-one, were synthesized in excellent yield and were found to undergo an intramolecular Heck cyclization to give 1,2,3,6-tetrahydroindolizino[6,7-b]indol-5-ones. To prepare furano-fused indolizinones, methyl 6-hydroxy-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylate was etherified with different allyl halides, and the resultant allyl ethers were subjected to a thermal Claisen rearrangement to give the corresponding methyl 7-allyl-6-hydroxy-5-oxo-1,2,3,4-tetrahydroindolizine-8-carboxylates. Cyclization under Wacker oxidation conditions afforded methyl 2-methyl-8-oxo-5,6,7,8-tetrahydro-1-oxa-7a-aza-s-indacene-4-carboxylates in near-quantitative yield.     

Enamine condensation on derivatives of aleuritic acid and synthesis of (Z)-9-tricosene (muscalure), its (E)-isomer,and (E)-13-heptacosene

Enamine condensation on (9RS,10RS)-9,10,16-triacetoxy hexadecanoyl chloride as Well as (7RS,8RS)-7,8-diacetoxy pentadeca-1,15-dioyl chloride using 1-morpholino-1-cyclohexene led to chain elongated products with 22 and 27 carbon atoms respectively. The former was converted into (Z)-9-tricosene and its (E)-isomer while the latter led to a synthesis of (E)-13-heptacosene.