Selenium dioxide oxidations of dialkyl-3H-azepines: the first synthesis of 2-azatropone from oxidation of 2, 5-Di-tert-butyl-3H-azepine

Oxidation reactions of 2,5- and 3,6-di-tert-butyl-3H-azepines (1 and 2) with selenium dioxide (SeO(2)) were performed. The oxidation of 1 with SeO(2) gave 3-tert-butyl-7,7-dimethyl-4-oxo-octa-2,5-dienal 3 in 36% yield, 4-tert-butyl-5-(3,3-dimethyl-2-oxo-butylidene)-1, 5-dihydro-pyrrol-2-one 4 in 13% yield, 2, 6-di-tert-butyl-2-pyridinecarbaldehyde 5 in 12% yield, and 4, 7-di-tert-butyl-2H-azepin-2-one (2-azatropone) 6 in 6% yield, respectively. Oxidation of 2 with SeO(2) gave 2, 2-dimethyl-1-[2-(5-tert-butyl)-pyridyl]propanol 7 in 55% yield, and 3,6-di-tert-butyl-2H-azepine 8 in 5% yield, respectively. We found that selenium dioxide oxidation of 1 affords 4-oxo-octa-2,5-dienal 3 by a new ring cleavage reaction of 1, and we described the first synthesis of 2-azatropone 6 from this oxidation of 1. In the case of 2, pyridylpropanol 7 was obtained as the major product. We now report in detail result of these oxidation reactions, which have led to the synthesis of a novel azatropone derivative.     

Nitroimidazoles. IX. Synthesis of 2-acetyl-1-methyl-5-nitroimidazole

Manganese dioxide oxidation of 2-hydroxymethyl-1-methyl-5-nitroimidazole (6) gave 1-methyl-5-nitroimidazole-2-carboxaldehyde (7) in high yield. Reaction of diazomethane with 7 afforded the title compound 1 in low yield. Treatment of ethyl acid malonate with two equivalents of isopropylmagnesium bromide in THF and subsequent addition to 1-methyl-5-nitroimidazole-2-carbonylimidazolide (12) yielded ethyl (1-methyl-5-nitroimidazole-2-carbonyl)acetate (10) in 70% yield. Hydrolysis and decarboxylation of compound 10 gave the desired compound 1 in 97% yield.     

Studies on pyrazines. 9 . The facile synthesis of pyrazine 1-oxides substituted at C-2 with cyano,methoxycarbonyl and carboxy groups

The peroxysulfuric acid oxidation of 2-cyanopyrazine ( 1 ) gave its 1-oxide 3 (18% yield) and pyrazinecarb-oxamide (8% yield), while that of methyl pyrazinecarboxylate ( 2 ) provided the 1- and 4-oxides in 15 and 7% yields, respectively. On the other hand, pyrazinecarboxylic acid 1-oxide ( 7 ) was prepared by condensation of 2-methylpyrazine 1-oxide ( 8 ) with benzaldehyde followed by oxidative cleavage (47% overall yield).     

Synthesis of (-)-quinocarcin by directed condensation of alpha-amino aldehydes

An enantioselective synthesis of the natural antiproliferative agent quinocarcin was achieved by the directed condensation of optically active alpha-amino aldehyde intermediates. Condensation of the N-protected alpha-amino aldehyde 1, prepared in eight steps (19% yield) from (R,R)-pseudoephedrine glycinamide, with the C-protected alpha-amino aldehyde derivative 2, prepared in seven steps (34% yield) from (R,R)-pseudoephedrine glycinamide, afforded the corresponding imine in quantitative yield. Without isolation, direct treatment of this imine intermediate with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and hydrogen cyanide led to cleavage of the fluorenylmethoxycarbonyl (Fmoc) protective group followed by addition of cyanide (Strecker reaction) to form the bis-amino nitriles 3 as a mixture of diastereomers, in 91% yield. Treatment of the diastereomers 3 with trimethylsilyl cyanide and zinc chloride in 2,2,2-trifluoroethanol at 60 degrees C led to stepwise cyclization to form the tetracyclic product 4 (42% yield from 1 and 2). The latter intermediate was transformed into (-)-quinocarcin (1) in five steps (45% yield). The yield of quinocarcin was 19% from 1 and 2 (7 steps), and 4% from pseudoephedrine glycinamide (15 steps).     

Facile and efficient synthesis of 4-azidotetrafluoroaniline: a new photoaffinity reagent

p-Azidotetrafluoroaniline (1) was synthesized in 65-73% yield by two different methods employing a stable carbamate intermediate. The first method trapped the intermediate isocyanate generated via a modified Curtius rearrangement with 2-methyl-2-propanol or 2-(trimethylsilyl)ethanol to form the stable carbamates 2d and 2e, respectively. Benzoic acid 2c was first converted to its acid chloride with PCl(5). Displacement of the chloride by NaN(3) in acetone/water formed the acyl azide. Thermal rearrangement followed by the addition of the appropriate alcohols provided the carbamates. The acid labile carbamate 2d was deprotected with HCl/AcOH to provide 1, while trifluoroacetic acid was required to deprotect 2e and afford 1. In the second path, 1 was synthesized in five steps from pentafluoronitrobenzene (3a) in 65% overall yield. Compound 3a was converted into 4-azidotetrafluoronitrobenzene (3b) with NaN(3) in 93% yield and was used without further purification to form 1, 4-diaminotetrafluorobenzene (3c) by Sn/HCl reduction in 85% yield. The mono-9-fluorenylmethoxycarbonyl (FMOC) derivative 3d was formed from 3c with FMOC-Cl and pyridine in EtOAc in 92% yield. Diazotization of 3d under anhydrous conditions with TFA/NaNO(2) and NaN(3) gave 3e in 87% yield. The aryl azide was formed with concurrent nitration of the 2-position of the fluorenyl system. The protecting group was removed with piperidine to afford 1 in 93% yield. Irradiation of 1 with 254 nm light in cyclohexane gave cyclohexylamine 11, diamine 3c, and azobenzene 12 as the primary products. The formation of C-H insertion product 11 indicates that 1 forms a singlet nitrene upon photolysis. Two heterobifunctional photoaffinity reagents iodoacetamide 9 and dansyl derivative 10 were prepared.     

Efficient Two-Step Synthesis of 11,11′-Dithiobis[1-(2-bromo-2-methylpropionyloxy)undecane], a Conventional Initiator for Grafting Polymer Brushes from Gold Surfaces via ATRP

11,11′-Dithiobis[1-(2-bromo-2-methylpropionyloxy)undecane], a conventional initiator for grafting polymers from gold surfaces, was synthesized in two steps from 11-mercapto-1-undecanol in 88–92% overall yield. Oxidative dimerization of 11-mercapto-1-undecanol with a catalytic amount of sodium iodide and 30% hydrogen peroxide in ethyl acetate proceeded in 96% yield. Esterification with 2-bromoisobutyryl bromide in dichloromethane was clean and almost quantitative (92% yield) with pyridine used as base, whereas triethylamine gave a messy reaction (64% yield). Alternatively, esterification with 2-bromo-2-methyl-propanoic acid in dichloromethane occurred readily under Steglich's conditions with N,N′-dicyclohexylcarbodiimide (DCC) and a catalytic amount of dimethylaminopyridine (DMAP; 88% yield).     

An Asymmetric Synthesis of L-694,458, a Human Leukocyte Elastase Inhibitor, via Novel Enzyme Resolution of beta-Lactam Esters

A convergent synthesis of [S-(R,S)]-2-[4-[(4-methylpiperazin-1-yl)carbonyl]phenoxy]-3,3-diethyl-N-[1-[3,4-(methylenedioxy)phenyl]butyl]-4-oxo-1-azetidinecarboxamide (L-694,458, 1), a potent human leukocyte elastase inhibitor, was achieved via chiral synthesis of key intermediates: (S)-3,3-diethyl-4-[4'-[(N-methylpiperazin-1-yl)carbonylphenoxy]-2-azetidinone (2) and (R)-alpha-propylpiperonyl isocyanate (3). Synthesis of beta-lactam 2 was achieved by a novel enantioselective lipase hydrolysis of ester 5 to produce (S)-3,3-diethyl-4-(4'-carboxyphenoxy)-2-azetidinone (6) (60% yield, three cycles, 93% ee) with isolation, epimerization, and recycling of the undesired (R)-ester 5. Isocyanate 3 was prepared by chiral addition of Zn(n-Pr)(2) to piperonal (98% yield, 99.2% ee), azide displacement and reduction to (R)-alpha-propylpiperonylamine (11) (58% yield, 85% ee), crystallization as the D-pyroglutamic acid salt (92% yield, 98.2% ee), and isocyanate formation (98% yield) with phosgene.     

IR kinetic spectroscopy investigation of the CH4 + O(1D) reaction

The branching of the title reaction into several product channels has been investigated quantitatively by laser infrared kinetic spectroscopy for CH(4) and CD(4). It is found that OH (OD) is produced in 67 +/- 5% (60 +/- 5%) yield compared to the initial O((1)D) concentration. H (D) product is produced in 30 +/- 10%(35 +/- 10%). H(2)CO is produced in 5% yield in the CH(4) system (it was not possible to measure the CD(2)O yield in the CD(4) case). D(2)O is produced in 8% yield in the CD(4) system (it was not feasible to measure the H(2)O yield). The ratio of the overall rate constant of the CD(4) reaction to the overall rate constant of the O((1)D) + N(2)O reaction was determined to be 1.2(5) +/- 0.1. A measurement of the reaction of O((1)D) with NO(2) gave 1.3 x 10(-10) cm(3) molecule(-1) s(-1) relative to the literature values for the rate constants of O((1)D) with H(2) and CH(4). Hot atom effects in O((1)D) reactions were observed.     

褪黑激素的合成与表征

以吲哚为起始原料,经4步反应合成了褪黑激素(MLT) 吲哚(1)在甲醇中羟基化得到5-羟基吲哚(2),(2)同2-氯乙胺在乙酸乙酯中进行胺乙基化反应得到5-羟基色胺(3),(3)与硫酸二甲酯在甲苯中对羟基进行醚化,得到5-甲氧基色胺(4),(4)经乙酰化得到产物MLT,收率80%     

Nitroimidazoles. VI. Syntheses of 1-methyl-2-(1,3,4-thiadiazol-2-yl)-5-nitroimidazole and 1-methyl-2-(1,3,4-oxadiazol-2-yl)-5-nitroimidazole

Starting from readily available 1-methyl-5-nitroimidazole-2-carboxylic acid hydrazide (1), 1-methyl-2-(1,3,4-thiadiazol-2-yl)-5-nitroimidazole (4) and 1-methyl-2-(1,3,4-oxadiazol-2-yl)-5-nitroimidazole (10) were prepared. The reaction of 1 with formic acid gave 1-(1-methyl-5-nitroimidazole-2-carboxyl)-2-(formyl)hydrazine ( 8 ) in high yield. Refluxing of the latter with phosphorus pentasulfide in xylene yielded compound 4 in 50% yield. Reaction of compound 8 with phosphorus pentoxide afforded compound 10 in 60% yield.     

三种O－异戊烯基苯丙素类天然产物的首次合成

以香草醛为起始原料，经O－异戊烯基化、Witting反应、水解、还原、氧化等 反应步骤，首次合成了三种苯丙素天然产物boropinalA（1），boropinalC（2） boropinicAcid（3）,有化合物结构均由核磁共振氢谱，质谱及红外光谱确证，用 X射线衍射法测定了3的晶体及分子结构。     

6,7-二氢-5H-1-氮茚的合成研究

以价廉易得的己二酸二甲酯为原料, 在甲醇钠的催化下, 通过Dieckmann缩合反应得到2-氧代环戊烷羧酸甲酯, 收率82.2%; 2-氧代环戊烷羧酸甲酯再与丙烯腈在40%(质量比)苄基三甲基氢氧化铵甲醇溶液存在下, 经Michael加成制得1-(2-氰乙基)-2-氧代环戊烷羧酸甲酯, 收率82.5%; 进一步酸性脱羧得到3-(2-氧代环戊基)丙腈, 收率84.0%; 将脱羧产物通入装有Ni-Cu/γ-Al2O3催化剂的固定床反应器中, 催化环合最终得到6,7-二氢-5H-1-氮茚, 反应总收率33.8%.     

Intramolecular Diamination and Alkoxyamination of Alkenes with N-Sulfonyl Ureas With N-Iodosuccinimide

Reaction of N-δ-alkenyl-N'-sulfonyl urea 1 with N-iodosuccinimde (NIS; 2 equiv) and a catalytic amount of AgOTf (20 mol %) at room temperature led to intramolecular alkoxyamination to form bicyclic isourea 2a in 95% isolated yield. In comparison, reaction of 1 with NIS and sodium bicarbonate (1 equiv) at room temperature led to isolation of bicyclic imidazolidin-2-one 2b in 91% yield. These NIS-mediated alkoxyamination and diamination protocols were effective for a range of N-δ-alkenyl-N'-sulfonyl ureas to form the corresponding heterobicyclic compounds in good yield with high chemoselectivity and good to excellent diastereoselectivity.     

Electrophilic addition of alcohols to 1-vinyl-2-phenylazopyrroles and unexpected formation of 2-methylquinoline

1-Vinyl-2-phenylazopyrroles react with alcohols in the presence of acids or PdCl₂ to give 1-(1-alkoxyethyl)-2-phenylazopyrroles in up to 49% yield. In the presence of trifluoroacetic acid 2-methylquinoline unexpectedly formed (yield up to 26%) involving into the reaction the phenylazo and 1-vinyl groups.     

Studies on the synthesis of heterocyclic compounds. Part IV. Further investigation of the pschorr reaction with some pyrazole derivatives

Thermal decomposition of the diazonium sulfate derived from N-methyl-(1-phenyl-3-methylpyrazol-5-yl)-2-aminobenzamide afforded products formulated as 1-phenyl-3-methyl[2]benzopyrano[4,3-c]pyrazol-5-one (yield 10%), 1,4-dimethyl-3-phenylpyrazolo[3,4-c]isoquinolin-5-one (yield 10%), N-methyl-(1-phenyl-3-methylpyrazol-5-yl)-2-hydroxybenzamide (yield 8%) and 4′-hydroxy-2,3′-dimethyl-1′-phenylspiro[isoindoline-1,5′-[2]-pyrazolin]-3-one (yield 20%). Decomposition of the diazonium sulfate derived from N-methyl-(1,3-diphenylpyrazol-5-yl)-2-aminobenzamide gave products formulated as 7,9-dimethyldibenzo[e,g]pyrazolo[1,5-a][1,3]-diazocin-10-(9H)one (yield 8%), 4-methyl-1,3-diphenylpyrazolo[3,4-c]isoquinolin-5-one (yield 7%) and 4′-hydroxy-2-methyl-1′,3′-diphenylspiro[isoindoline-1,5′-[2]pyrazolin]3-one (yield 10%). The spiro compounds 6a,b underwent thermal and acid-catalysed conversion into the hitherto unknown 2-benzopyrano[4,3-c]pyrazole ring system 7a,b in good yield. Analytical and spectral data are presented which supported the structures proposed.     

Development of an enantioselective synthetic route to neocarzinostatin chromophore and its use for multiple radioisotopic incorporation

A convergent, enantioselective synthetic route to the natural product neocarzinostatin chromophore (1) is described. Synthesis of the chromophore aglycon (2) was targeted initially. Chemistry previously developed for the synthesis of a neocarzinostatin core model (4) failed in the requisite 1,3-transposition of an allylic silyl ether when applied toward the preparation of 2 with use of the more highly oxygenated substrates 27 and 54. An alternative synthetic plan was therefore developed, based upon a proposed reduction of the epoxy alcohol 58 to form the aglycon 2, a transformation that was achieved in a novel manner, using a combination of the reagents triphenylphosphine, iodine, and imidazole. The successful route to 1 and 2 began with the convergent coupling of the epoxydiyne 15, obtained in 9 steps (43% overall yield) from D-glyceraldehyde acetonide, and the cyclopentenone (+)-14, prepared in one step (75-85% yield) from the prostaglandin intermediate (+)-16, affording the alcohol 22 in 80% yield and with > or =20:1 diastereoselectivity. The alcohol 22 was then converted into the epoxy alcohol 58 in 17 steps with an average yield of 92% and an overall yield of 22%. Key features of this sequence include the diastereoselective Sharpless asymmetric epoxidation of allylic alcohol 81 (98% yield); intramolecular acetylide addition within the epoxy aldehyde 82, using Masamune's lithium diphenyltetramethyldisilazide base (85% yield); selective esterification of the diol 84 with the naphthoic acid 13 followed by selective cleavage of the chloroacetate protective group in situ to furnish the naphthoic acid ester 85 in 80% yield; and elimination of the tertiary hydroxyl group within intermediate 88 using the Martin sulfurane reagent (79% yield). Reductive transposition of the product epoxy alcohol (58) then formed neocarzinostatin chromophore aglycon (2, 71% yield). Studies directed toward the glycosylation of 2 focused initially on the preparation of the N-methylamino --> hydroxyl replacement analogue 3, an alpha-D-fucose derivative of neocarzinostatin chromophore, formed in 42% yield by a two-step Schmidt glycosylation-deprotection sequence. For the synthesis of 1, an extensive search for a suitable 2'-N-methylfucosamine glycosyl donor led to the discovery that the reaction of 2 with the trichloroacetimidate 108, containing a free N-methylamino group, formed the alpha-glycoside 114 selectively in the presence of boron trifluoride diethyl etherate. Subsequent deprotection of 114 under mildly acidic conditions then furnished the labile chromophore (1). The synthetic route was readily modified for the preparation of singly and doubly (3)H- and (14)C-labeled 1, compounds unavailable by other means, for studies of the mechanism of action of neocarzinostatin in vivo.     

合成1,2-环十二二酮的新方法

以十二烷二酸（１）为原料,与甲醇酯化生成十二烷二酸二甲酯（２）,收率为８６５％。化合物２经偶联 缩合得１,２ 二三甲基硅氧基环十二烯（３）,收率为６３１％。利用溴氧化化合物３得到１,２ 环十二二酮（４）淡黄色晶体,收率７９％,全过程收率达４３.１％,是合成１,２ 二酮的新方法。目标化合物结构经红外光谱、核磁共振氢谱和碳谱表征确认。     

合成双酚AF的新方法

由六氟丙酮三水合物和苯胺,经缩合、重氮化、水解、Friedel-Crafts烷基化等4步反应在常压下合成了双酚 AF。首先,以五氧化二铌为催化剂,在 n (HFA•3H₂O) : n (aniline) : n (Nb₂O₅) = 2 : 1 : 0.1,回流 6 h 条件下,合成出中间体（Ⅰ）,收率高达96.3%。然后在重氮化温度为 ﹣2 ～ 2 ℃,硫酸质量分数为 14.7%,n (Ⅰ) : n (H₂SO₄) : n (NaNO₂) = 1 : 4.1 : 1.1,及水解时硫酸质量分数为 50%,n (H₂SO₄) : n (Ⅰ) = 11.0 : 1、108～112 ℃反应 1.5 ～ 2 h 的优化条件下,化合物Ⅰ经重氮化、水解后以 92.7%的高收率得到中间体 2-（4-羟基苯）六氟异丙醇（Ⅱ）;再在甲磺酸存在下,化合物Ⅱ与苯酚经Friedel-Crafts烷基化反应以 72.4% 的收率合成了目标产物双酚 AF（Ⅲ）,总收率为 64.6%（以苯胺为基准计算）。     

从邻苯二酚合成3,4-亚甲二氧基苯甲醇

胡椒醇;从邻苯二酚合成3;4-亚甲二氧基苯甲醇     

2-(4′-Fluorophenyl)imidazole. Nitration studies

Reactions of 2-(4′-fluorophenyl)imidazole ( 1 ) and related compounds under various nitrating conditions are discussed. With 90% nitric acid in 20% oleum at ?10°, 1 affords 2-(4′fluorophenyl)-4(5)-nitroimidazole ( 2 ) in 80% yield. Reaction of 2 with the same reagents at 25° affords 2-(4′-fluoro-3′-nitrophenyl)-4(5)-nitroimidazole ( 4 ) in 90% yield, whereas with 90% nitric acid in acetic acid at 95°, 2 affords 4,5-dinitro-2-(4′-fluorophenyl)imidazole ( 5 ) in 80% yield. Reaction of 1 with 70% nitric acid in concentrated sulfuric acid at 25° affords 2-(4′-fluorophenyl)-5-hyroximinoimidazolin-4-one ( 6 ), which rearranges and hydrolyzes to 5-(4′-fluorophenyl)-1,2,4-oxadiazole-3-carboxylic acid. A discussion of these reactions is presented.