Reaction of 2-(5-aminopyrazol-1-yl)quinoxaline 4-oxides with dimethyl acetylenedicarboxylate

The reaction of 6-chloro-2-hydrazinoquinoxaline 4-oxide 6 with ethyl 2-(ethoxymethylene)-2-cyanoacetate or (1-ethoxyethylidene)malononitrile gave 2-(5-amino-4-ethoxycarbonylpyrazol-1-yl)-6-chloroquinoxaline 4-oxide 7a or 2-(5-amino-4-cyano-3-methylpyrazol-1-yl)-6-chloroquinoxaline 4-oxide 7b , respectively. The reaction of compound 7a or 7b with dimethyl acetylenedicarboxylate resulted in the 1,3-dipolar cycloaddition reaction and then ring transformation to afford 4-(5-amino-4-ethoxycarbonylpyrazol-1-yl)-8-chloro-1,2,3-trismethoxycarbonylpyrrolo[1,2-α]quinoxaline 8a or 4-(5-amino-4-cyano-3-methylpyrazol-1-yl)-8-chloro-1,2,3-trismethoxycarbonylpyrrolo[1,2-α]quinoxaline 8b , respectively.     

Facilitated Intramolecular Conjugate Addition of Amides of 3-(3',6'-Dioxo-2',4'-dimethyl-1',4'-cyclohexadienyl)-3,3-dimethylpropionic Acid. 2. Kinetics of Degradation

The chemical stability studies of amides of 3-(3',6'-dioxo-2',4'-dimethyl-1',4'-cyclohexadienyl)-3,3-dimethylpropionic acid (Qa) [Qop(a-j)] were conducted in order to determine the utility of this redox-sensitive system as a potential prodrug promoiety or redox-sensitive protecting group in organic synthesis. This study showed that quinone propionic amides of aniline derivatives [Qop(a-d)] underwent rapid degradation in mildly acidic conditions (pH 4.5-6.0) to yield degradation products resulting from the intramolecular 1,2- or 1,4- conjugate addition of the amide nitrogen to the quinone ring. This conjugate addition was found to be specific base-catalyzed and independent of the para substituent on the aromatic ring of the amine. The predominant route of degradation yielded a five-membered ring spirolactam. By altering the nature of the amine component of the amide, these degradation reactions were prevented. Amides of Qa other than those of the aniline type [Qop(e-j)] were found to be substantially more stable and were thus proposed as the more suitable candidates for this potential redox-sensitive prodrug system and redox-sensitive protecting group for amines and alcohols in organic synthesis.     

重氮萘酮在环醚中热解反应研究

三种带有不同取代基的重氮萘酮(la～1c)在THF和二氧六环中加热分解给出不同的产物。1-重氮-4-萘酮(1a)的热解产物主要是重氮萘酮热解后产生的烯酮卡宾(2a)与环醚开环后形成的聚合物;3-甲基-1-重氮-4-萘酮(1b)的热解产物比较复杂,除冠醚类产物之外,还有烯酮卡宾对四氢呋喃和二氧六环的C-H键的插入反应产物、螺环化合物、2-甲基萘酚以及难以分离的聚合物;3-硝基-1-重氮-4-萘酮(1c)的热解产物主要是聚合物,此外还有少量C－H键的插入反应产物和2-硝基萘酚。对重氮萘酮热解反应的机理作了讨论。     

Phenylsulfanylation of 3',4'-unsaturated adenosine employing thiophenol-N-iodosuccinimide leads to 4'-phenylsulfanylcordycepin: synthesis of 4'-substituted cordycepins on the basis of substitution of the phenylsulfanyl leaving group

Upon reaction of the 3',4'-unsaturated adenosine derivative 2 with N-iodosuccinimide (NIS) and thiophenol, an unexpected electrophilic hydrophenylsulfanylation proceeded to provide 4'-phenylsulfanylcordycepin 7 in 79% yield with the ratio 7a/7b = 6.6/1. A study of the reaction mechanism revealed that hydrogen iodide (HI) generated from NIS and PhSH acted as an active species. On the basis of a deuterium experiment using PhSD, initial protonation occurred at the β face of the double bond to furnish the β-π complex III, which underwent anti addition of PhSH as a major pathway. Nucleophilic substitution of N(6)-pivaloylated 9 with various alcohols in the presence of N-bromosuccinimide (NBS) gave the respective 4'-α-alkoxycordycepins 15a-21a as the major stereoisomers. Use of DAST in place of an alcohol gave the 4'-α-fluoro analogue 23a stereoselectively. Radical-mediated carbon-carbon bond construction was also applicable to 7, giving 4'-α-allylcordycepin (24a) and 4'-α-cyanoethylcordycepin (25) derivatives.     

酰氨基硫脲及相关杂环衍生物的研究XXIX: 2-(3'-溴苯胺基)-5-[5'-氨基-1'-(4"-氯苯基)-1',2',3'-三唑-4'-基]-1,3,4-噻二唑的晶体结构

经1-[5'-氨基-1'-(4"-氯苯基)-1',2',3'-三唑-4'-甲酰基]-4-(3'-溴苯基)-3-氨基硫脲在浓硫酸作用下制得2-(3'-溴苯胺基)-5-[5'-氨基-1'-(4"-氯苯基)-1',2',3'-三唑-4'-基]-1,3,4-噻二唑化合物。该化合物的晶体结构经X射线衍射分析确定, 化合物属三斜晶系, P1空间群, a=1.1784(2), b=1.4455(2),c=1.1353(1)nm; α=100.68(1), β=109.50(1), γ=79.89(1)°; V=1.7779nm^3; 分子式C~1~6H~1~1BrClN~7S, Mr=448.75; Dc=1.673g/cm^3, Z=4,μ=58.16cm^-^1, 最终偏离因子R=0.084, Rw=0.086。分析化合物的键长, 键角数据表明, 该分子具有离域π键结构。     

3, 6-二取代-均三唑并[3, 4-b]-1, 3, 4-噻二唑的合成

研究了2-苯基-1, 2, 3-三唑-4-羧酸(1)与3-烷基/芳基-4-氨基-5-巯基-1, 2, 4-三唑(2a～o)在POCl~3催化下, 脱水缩合得到15个新的3-烷基/芳基-6-(2'-苯基-1', 2', 3'-三唑-4'-基)均三唑并[3,4-b]-1, 3, 4-噻二唑类化合物(3a～o)。     

Synthesis of 3-alkoxycarbonylaminomethylcarbonylamino-4-benzoyl-1,2-dihydropyridines and their cyclization to 5-phenyl-1,3,8,9-tetrahydro-2H-pyrido[3,4-e]-1,4-diazepin-2-ones

The regiospecific reaction of 3-benzyloxycarbonylaminomethylcarbonylamino-4-benzoylpyridine (6a) , or 3-t-butoxycarbonylaminomethylcarbonylamino-4-benzoylpyridine (6b) , with either acetyl chloride or ethyl chloroformate, and either n-butylmagnesium chloride or phenylmagnesium bromide afforded the respective 1-acetyl (or ethoxycarbonyl)-2-n-butyl (or phenyl)-3-benzyloxy (or t-butoxy) carbonylaminomethylcarbonylami-no-4-benzoyl-1,2-dihydropyridines 7 in 60-75% yield. Reaction of 1-acetyl (or ethoxycarbonyl)-2-n-butyl (or phenyl)-3-t-butoxycarbonylaminomethylcarbonyl-4-benzoyl-1,2-dihydropyridines 7b, 7f, 7d, 7h with trifluoroacetic acid gave the corresponding 5-phenyl-8-acetyl (or ethoxycarbonyl)-9-n-butyl (or phenyl)-1,3,8,9-tetrahydro-2H-pyrido[3,4-e]-1,4-diazepin-2-ones 8a, 8b, 8c, 8d respectively in 45–63% yield. N¹-Methylation of 5-phenyl-8-acetyl-9-n-butyl (or phenyl)-1,3,8,9-tetrahydro-2H-pyrido[3,4-e]-1,4-diazepin-2-ones 8a, 8b using sodium hydride and iodomethane yielded the corresponding N¹-methyl derivatives 9a (48%) and 9b (54%). Oxidation of 5,9-diphenyl-8-ethoxycarbonyl-1,3,8,9-tetrahydro-2H-pyrido[3,4-e]-1,4-diazepin-2-one (8d) using p-chloranil afforded 1,3-dihydro-5,9-diphenyl-2H-pyrido[3,4-e]-1,4-diazepin-2-one (10) . 5-Phenyl-8-acetyl-9-n-butyl-1,3,8,9-tetrahydro-2H-pyrido[3,4-e]-1,4-diazepin-2-one (8a) and the corresponding 8-ethoxycarbonyl analog 8c exhibited weak anticonvulsant activity indicating that 8a and 8c may be acting at the same site as the 7-halo-1,4-benzodiazepin-2-one class of compounds.     

Total synthesis of 2',3',4',5',5' '-(2)h(5)-ribonucleosides: the key building blocks for NMR structure elucidation of large RNA

The diastereospecific chemical syntheses of uridine-2',3',4',5',5' '-(2)H(5) (21a), adenosine-2',3',4',5',5' '-(2)H(5) (21b), cytidine-2',3',4',5',5' '-(2)H(5)(2)H(5) (21c), and guanosine-2',3',4',5',5' '-(2)H(5) (21d) (>97 atom % (2)H at C2', C3', C4', and C5'/C5' ') have been achieved for their use in the solution NMR structure determination of oligo-RNA by the Uppsala "NMR-window" concept (refs 4a-c, 5a, 6), in which a small (1)H segment is NMR-visible, while the rest is made NMR-invisible by incorporation of the deuterated blocks 21a-d. The deuterated ribonucleosides 21a-d have been prepared by the condensation of appropriately protected aglycone with 1-O-acetyl-2,3,5-tri-O-(4-toluoyl)-alpha/beta-D-ribofuranose-2,3,4,5,5'-(2)H(5) (19), which has been obtained via diastereospecific deuterium incorporation at the C2 center of appropriate D-ribose-(2)H(4) derivatives either through an oxidation-reduction-inversion sequence or a one-step deuterium-proton exchange in high overall yield (44% and 24%, respectively).     

2-芳胺基-5-[5'-氨基-1'-(4''-氯苯基)-1', 2', 3'-三唑-4'-基]——-1, 3, 4-恶二唑的合成

利用1-[5'-氨基-1'-(4'-氯苯基)-1', 2', 3'-三唑-4'-甲酰基]-4-芳基氨基硫脲在汞盐Hg(OAc)2-HOAc中加热缩合, 制得11种新的2-芳胺基-5-[5'-氨基-1'-(4'-氯苯基)-1', 2', 3'-三唑-4'-基]---1, 3, 4-恶二唑。所有化合物的结构经元素分析, IR、MS以及1H NMR确认。选择代表物作生测试验, 结果表明, 2b, 2k中MIC3.1mg/L时, 对大肠杆菌及金黄色葡萄球菌繁殖有明显抑制。     

Selenium heterocycles. XXXVII . Synthesis of 4-(thiazol-4-yl)-1,2,3-selenadiazoles and 4-(selenazol-4-yl)-1,2,3-selenadiazoles

Starting from readily available 2-substituted-4-formylthiazoles and selenazoles, a series of 4-(2-aryl-4-selenazolyl)-1,2,3-selenadiazoles I and 4-(2-substituted-4-thiazolyl)-1,2,3-selenadiazoles II were prepared. Pyrolysis of compound II afforded (2-substituted-4-thiazolyl) acetylenes VII. Addition of potassium hydroxide pellets to an alcoholic solution of II gave 2-substituted-1,4-diselenafulvenes VIII. Decomposition of compound II with base followed by the addition of carbon disulfide gave 5-substituted 2-thioxo-1,3-thiaselenoles XI.     

Addition of difluorocarbene to 4',5'-unsaturated nucleosides: synthesis and deoxygenation reactions of difluorospirocyclopropane nucleosides

Synthetic routes to 4'-(2,2-difluorospirocyclopropane) analogues of adenosine, cytidine, and uridine are described. Treatment of 2',3'-O-isopropylidene-4',5'-unsaturated compounds derived from adenosine and uridine with difluorocarbene (generated from PhHgCF3 and NaI) gave diastereomeric mixtures of the 2,2-difluorospirocyclopropane adducts. Stereoselectivity resulting from hindrance by the isopropylidene group favored addition at the beta face. Removal of base and sugar protecting groups gave new difluorospirocyclopropane nucleoside analogues. The protected uridine analogue was converted into its cytidine counterpart via a 4-(1,2,4-triazol-1-yl) intermediate. Stannyl radical-mediated deoxygenation of the 3'-O-TBS-2'-thionocarbamate derivatives gave the 2'-deoxy products of direct hydrogen transfer. In contrast, identical treatment of the 2'-O-TBS-3'-thionocarbamate isomers resulted in opening of the vicinal difluorocyclopropane ring upon generation of a C3' radical followed by homoallylic hydrogen transfer to give 4'-(1,1-difluoroethyl)-3',4'-unsaturated nucleoside derivatives. Structural aspects and biological effect considerations are discussed.     

3-(2'-苯基-1', 2', 3'-连三唑-4'-基)-6-烷基/芳基-均三唑并[3, 4-b]-1, 3, 4-噻二唑的合成

研究了3-(2'-苯基-1', 2', 3'-连三唑-4'-基)-4-氨基-5-巯基-1, 2, 4-三唑(1)与取代苯甲酸和脂肪酸(2a-r)在POCl3催化下的反应, 共合成得到18个新的3-(2'-苯基-1', 2', 3'-连三唑-4'-基)-6-烷基/芳基-均三唑并[3, 4-b]-1, 3, 4-噻二唑(3a-r), 经元素分析,IR, 1H NMR和MS进行了结构确证。     

Solution self-assembly, spontaneous deprotonation, and crystal structures of bipyrazolate-bridged metallomacrocycles with dimetal centers

A series of nanosized cavity-containing bipyrazolate-bridged metallomacrocycles with dimetal centers, namely, {[(bpy)M]8L4}(NO3)8 [L=3,3',5,5'-tetramethyl-4,4'-bipyrazolyl, Pd, Pt; 1,4-bis-4'-(3',5'-dimethyl)-pyrazolylbenzene), Pd; and 1,4-bis-4'-(3',5'-dimethyl)-pyrazolylbiphenyl, Pd], {[(phen)M]8L4}(NO3)8 [L=3,3',5,5'-tetramethyl-4,4'-bipyrazolyl, Pd, Pt; 1,4-bis-4'-(3',5'-dimethyl)-pyrazolylbenzene, Pd; and 1,4-bis-4'-(3',5'-dimethyl)-pyrazolylbiphenyl, Pd], {[(bpy)Pd]6L3}(NO3)6 [L=1,4-bis-4'-(3',5'-dimethyl)-pyrazolylbenzene,], {[(phen)Pd]6L3}(NO3)6 [L=1,4-bis-4'-(3',5'-dimethyl)-pyrazolylbenzene,], {[(bpy)Pd]4L2}(NO3)4 [L=1,3-bis-4'-(3',5'-dimethyl)-pyrazolylbenzene, and 1,2-bis-4'-(3',5'-dimethyl)-pyrazolylbenzene,], and {[(phen)Pd]4L2}(NO3)4 [L=1,3-bis-4'-(3',5'-dimethyl)-pyrazolylbenzene, and 1,2-bis-4'-(3',5'-dimethyl)-pyrazolylbenzene,] (where bpy=2,2'-bipyridine and phen=1,10-phenanthroline) have been synthesized through a directed self-assembly approach that involves spontaneous deprotonation of the 1H-bipyrazolyl ligands in aqueous solution. These complexes, with weak Pd(II)...Pd(II) or Pt(II)...Pt(II) interactions, have been characterized by elemental analysis, 1H and 13C NMR, cold-spray ionization or electrospray ionization mass spectrometry, UV-visible spectroscopy, and luminescence spectroscopy. Complexes and have also been characterized by single-crystal X-ray diffraction analysis.     

Syntheses of Examples of the 5,6-dihydro-4H-[1,2,3]triazolo[4,5,1-ij]quinoline, 4,5,6,7-tetrahydro[1,2,3]triazolo[4,5,1-jk][1,4]benzodiazepine,and 5,6,7,8-tetrahydro-4H-[1,2,3]triazolo[4,5,1-kl][1]benzazocine ring systems

Lithiation of 1-vinylbenzotriazole 9 with n-BuLi (2 equiv) generates dianion 10, which upon subsequent reaction with 1,2- and 1,4-diketones affords 14 and 13, representatives of the 5,6-dihydro-4H-[1,2,3]triazolo[4,5,1-ij]quinoline 1 and 5,6,7,8-tetrahydro-4H-[1,2,3]triazolo[4,5,1-kl][1]benzazocine 2 ring systems, respectively. Reactions of dianion 10 with isocyanates give 15a,b, which contain the 4,5,6,7-tetrahydro[1,2,3]triazolo[4,5,1-jk][1,4]benzodiazepine 3 ring system.     

Furopyridines. XIII. Reaction of 2-methylfuro[2,3-b]-, -[3,2-b]-, -[2,3-c]- and -[3,2-c]pyridines with lithium diisopropylamide

Lithiation of 2-methylfuro[2,3-b]- 1a , -[2,3-c]- 1c and -[3,2-c]pyridine 1d with lithium diisopropylamide at ?75° and subsequent treatment with deuterium chloride in deuterium oxide afforded 2-monodeuteriomethyl compounds 2a, 2c and 2d , while 2-methylfuro[3,2-b]pyridine 1b gave a mixture of 1b, 2b , 2-methyl-3-deuteriofuro[3,2-b]pyridine 2′b and 2-(1-proynyl)pyridin-3-ol 5 . The same reaction of 1a at ?40° gave 3-(1,2-propadienyl)pyridin-2-ol 3 and 3-(2-propynyl)pyridin-2-ol 4 . Reaction of the lithio intermediates from 1a, 1c and 1d with benzaldehyde, propionaldehyde and acetone afforded the corresponding alcohol derivatives 6a, 6c, 6d, 7a, 7c, 7d, 8a, 8c and 8d in excellent yield; while the reaction of lithio intermediate from 1b gave the expected alcohols 6b and 8b in lower yields accompanied by formation of 3-alkylated compounds 9, 11, 12 and compound 5 . While reaction of the intermediates from 1a, 1b and 1d with N,N-dimethylacetamide yielded the 2-acetonyl compounds 13a, 13b and 13d in good yield, the same reaction of 1c did not give any acetylated product but recovery of the starting compound almost quantitatively.     

Condensed Thienopyrimidines. 14. Synthesis of 10H-Thiopyrano[4',3':4',5']thieno[2',3':4,5]pyrimido[2,3-c]-1,2,4-triazines

Reaction of a substituted 2-aminothienothiopyran with methyl(phenyl) isothiocyanate, intramolecular cyclization of the obtained N'-methyl(phenyl) thioureido derivatives, and work up of the cyclization products with hydrazine hydrate gave 2-hydrazinodihydrothiopyranothienopyrimidines. Treatment of the latter with pyruvic acid gave the novel 10H-thiopyrano[4',3':4',5']thieno[2',3':4,5]pyrimido[2,3-c]-1,2,4-triazines.     

Influence of the beta-alkoxy group on the diastereoselectivity of Aldol reactions of tetrahydro-4H-thiopyran-4-one with 4-Alkoxytetrahydro-2H-thiopyran-3-carboxaldehydes

The diastereoselectivity of the aldol reaction of tetrahydro-4H-thiopyran-4-one (3) with 1,4-dioxa-8-thiaspiro[4.5]decane-6-carboxaldehyde (9a) under a variety of conditions is examined. Under optimized conditions, three of the four possible diastereomers from this aldol reaction can be obtained selectively (3-16:1). Reactions of 9a with the Li, B, Mg(II), and Ti(IV) enolates of 3 and with the corresponding trimethylsilyl enol ether 4b in the presence of BF(3) x OEt(2), SnCl(4), or TiCl(4) as promoters gave the Felkin adducts exclusively (>95%) as mixtures of syn (11a) and anti (12a) diastereomers. Use of the "amine-free" Li enolate of 3 gave 12a with a much higher diastereoselectivity (9:1) and yield (70%) than that obtained using the lithium diisopropylamide-generated Li enolate of 3 (2-3:1; 15-40%). The TiCl(4)-promoted reaction of 4b with 9a gave 11a with excellent selectivity (16:1). In contrast, the MgBr(2) x OEt(2)-promoted reaction of 4b with 9a gave the anti-Felkin adducts exclusively as a 3:1 mixture of syn (13a)/anti (14a) diastereomers. Similar aldol reactions of 3 with the cis and trans isomers of 4-(methoxy)methoxytetrahydro-2H-thiopyran-3-carboxaldehyde (9b and 9c) were examined to probe the influence of the ketal protecting group in 9a on the observed aldol diastereoselectivity. The results are rationalized by applying Evans' stereochemical model for merged 1,2- and 1,3-asymmetric induction (non-chelation), with the exception of the MgBr(2) x OEt(2)-promoted reactions of 4b with 9a, 9b, and 9c, which are accommodated by assuming chelation control. Comparison of the reactions of 9a, 9b, and 9c suggests that the ketal group in 9a uniquely allows high levels of either Felkin or anti-Felkin selectivity to be achieved.     

Dibenzo[b,e][1,4]diazepin-1-Ones,Synthesis and Derivatization

Several linearly fused tricyclic 6,7,6-systems were prepared. Reaction of 1,2-diamino-4-nitrobenzene with 5,5-dimethylcyclohexan-1,3-dione gave 3-(2-amino-5-nitroaniIino)-5,5-dimethylcyclohex-2-en-1-one (8) . Reaction of 8 and its analogue 6 with various aldehydes gave 2,3,4₎5,10,11-hexahydro-3,3-dimethyl-11-substituted-1H-dibenzo[b,e][1,4]diazepin-1-ones 9 and 10 . Acetylation of 9 and 10 gave the corresponding N-acetyl derivatives. Spectral data of the products are discussed.     

Furopyridines. VII. Preparation and hydrolysis of 2-cyano and 3-cyano derivatives of furo[3,2-b]-, furo[2,3-c]- and furo[3,2-c]pyridine

This paper describes the preparation and hydrolysis of 2-cyano and 3-cyano derivatives of furo[3,2-b]-, furo[2,3-c]- and furo[3,2-c]pyridine. Treatment of furopyridines 1a , 1b and 1c with n-butyllithium in hexane-tetrahydrofuran at -70° and subsequent addition of N,N-dimethylformamide yielded 2-formyl derivatives 2a , 2b and 2c. Dehydration of the oximes 4a , 4b and 4c of 2a , 2b and 2c gave 2-cyano compounds 5a , 5b and 5c , which were hydrolyzed to give 2-carboxylic acids, 6a, 6b and 6c , respectively. Reaction of 3-bromo compounds 7a , 7b and 7c with copper(I) cyanide in N,N-dimethylformamide afforded 3-cyano derivatives 8a , 8b and 8c. Alkaline hydrolysis of 8a , 8b and 8c gave compounds formed by fission of the 1-2 bond of furopyridines 9a , 9b and 9c , while acidic hydrolysis gave the corresponding carboxamides, 10a , 10b and 10c.     

Synthesis, resolution, and renal vasodilation activity of novel DA1 agonists: 4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline derivatives.

7,8-Dihydroxy-4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline (1) and 4-(3,4-dihydroxyphenyl)-7-hydroxy-8-methyl-1,2,3, 4-tetrahydroisoquinoline (2) are potent renal vasodilators which selectively stimulate DA1 (peripheral dopamine receptor-1) receptors. Especially, (S)-(-)-1 is the most potent. Its DA1 agonist activity is about 10 times stronger than dopamine for increasing renal blood flow in anesthetized dogs. The renal and cardiovascular effects of (S)-(-)-1 may be suitable for the treatment of patients with renal insufficiency, heart failure and hypertension.