Mild and efficient syntheses of diverse isoindolinones from ortho-phthaldehydic acid methylthiomethyl ester

A mild and efficient method for the synthesis of diverse isoindolinones from o-phthaldehydic acid methylthiomethyl ester and aliphatic/aromatic amines has been developed. A number of nucleophiles including a hydride ion were successfully added to the intermediate Schiff's base providing isoindolinones, with or without substitution at 3-position. Conditions have also been developed for amines with an integrated nucleophilic group to react in a diverse fashion either to give isoindolinones or tricyclic γ-lactams as single diastereoisomers in very good yield.     

Syntheses and reactivities of non-symmetrical "active ester" bi-dentate cross-linking reagents having a phthalimidoyl and acid chloride, 2-benzothiazole, or 1-benzotriazole group

We have newly synthesized the non-symmetrical "phthalimidoyl active ester" bi-dentate cross-linking reagents having an acid chloride, 2-benzothiazole, or 1-benzotriazole group (i.e., 9, 15, and 16) on the basis of the reactivity study of the "active ester" model compounds, 11-14, toward the various nucleophiles and examined their reaction selectivity towards the same nucleophiles. Then, we applied for the modification of cholesterol at the more reactive site of the bi-dentate linkers to give 3β-cholesteryl 4-(phthalimidoyloxycarbonyl)butyrate (39), and the subsequent reaction of 39 with several amines, such as benzylamine, 4-chlorobenzylamine, 2-phenylethylamine, L-phenylalanine methyl ester, or diphenylalanine benzyl ester as a protein model of the cholesterol antigen.     

Solid-phase synthesis of 1,2,3,4-tetrahydroisoquinoline derivatives employing support-bound tyrosine esters in the Pictet-Spengler reaction

The solid-phase synthesis of 1,2,3,4-tetrahydroisoquinoline-3-carboxamides employing carboxyl-supported, o-alkylated tyrosine esters in a Pictet-Spengler reaction is described. Esterification of [4-(hydroxyphenyl)thiomethyl]polystyrene (Marshall resin) with ethers of N-BOC-L-tyrosine using diisopropylcarbodiimide (DIC) and 4-dimethylaminopyridine (4-DMAP) afforded the solid-supported ester derivatives. Removal of the BOC group with trifluoroacetic acid (TFA) afforded the carboxyl-supported tyrosine ester, which was then treated with paraformaldehyde and TFA to afford the desired solid-supported counterpart. Acylation of the secondary amine with arylsulfonyl chlorides followed by reaction with amines resulted in the formation of the desired 2-arylsulfonyl-7-alkoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxamides. Alternatively, the support-bound tetrahydroisoquinoline-3-carboxylate derivatives could be treated with an aldehyde and a reducing agent to give the corresponding support-bound tertiary amine. Exposure of these resin-bound products to amines afforded the corresponding 2-alkyl-7-alkoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxamides after cleavage from the resin. Alternative routes to the desired chemotypes, as well optimization of the conditions for the Pictet-Spengler reaction and the conditions for the acylation and reductive amination of the support-bound secondary amines, are also described.     

Solid-phase synthesis of 4-methylene pyrrolidines and allylic amines using palladium-activated allylic linkers

The solid-phase synthesis of 4-methylene pyrrolidines and allylic amines has been achieved using palladium-catalysed nucleophilic cleavage of allylic linkages. Six pyrrolidines were synthesised in five steps from a carboxyethyl resin 20, where the key transformations included a Lewis-acid promoted imino-Sakurai type reaction and reductive alkylation prior to the final palladium-catalysed cyclisation cleavage of the allylic carboxylate linkage. Allylic carboxylate resin 22 was also shown to undergo "traceless" cleavage using various hydride sources in the presence of catalytic palladium. A more robust allylic ether linkage was also investigated. Starting from a phenol resin 36, a number of 3-aryl-allylamines were prepared using a palladium-catalysed nucleophilic cleavage reaction.     

Reactive sulfur species: kinetics and mechanisms of the oxidation of cysteine by hypohalous acid to give cysteine sulfenic acid

Cysteine sulfenic acid has been generated in alkaline aqueous solution by oxidation of cysteine with hypohalous acid (HOX, X = Cl or Br). The kinetics and mechanisms of the oxidation reaction and the subsequent reactions of cysteine sulfenic acid have been studied by stopped-flow spectrophotometry between pH 10 and 14. Two reaction pathways were observed: (1) below pH 12, the condensation of two sulfenic acids to give cysteine thiosulfinate ester followed by the nucleophilic attack of cysteinate on cysteine thiosulfinate ester and (2) above pH 10, a pH-dependent fast equilibrium protonation of cysteine sulfenate that is followed by rate-limiting comproportionation of cysteine sulfenic acid with cysteinate to give cystine. The observation of the first reaction suggests that the condensation of cysteine sulfenic acid to give cysteine thiosulfinate ester can be competitive with the reaction of cysteine sulfenic acid with cysteine.     

Structure based library approach to photosynthesis inhibitors:Combinatorial synthesis of hydrouracil library

Ｌｉｆｅｏｎｅａｒｔｈｄｅｐｅｎｄｓｏｎｔｈｅｃｈｅｍｉｃａｌｓｙｎｔｈｅｓｉｓ,ｓｔｏｒａｇｅａｎｄｄｅｌｉｖｅｒｙｏｆｅｎｅｒｇｙ＿ｒｉｃｈｏｒｇａｎｉｃｃｏｍｐｏｕｎｄｓｉｎｐｌａｎｔｓｏｒｇｒｅｅｎａｌｇａｅ.ＯｎｅｏｆｔｈｅｍａｉｎｓｔｅｐｓｉｎｔｈｉｓｐｒｏｃｅｓｓｉｓａｃｃｏｍｐｌｉｓｈｅｄｂｙｐｈｏｔｏｓｙｓｔｅｍＩＩ(ＰＳＩＩ),ｗｈｉｃｈｃａｔａｌｙｓｅｓｔｈｅｔｒａｎｓｆｅｒｏｆｅｌｅｃｔｒｏｎｓｆｒｏｍｗａｔｅｒｔｏｐｌａｓｔｏｑｕｉｎｏｎｅ.Ｔｈｅｓｐｅｃｉｆｉｃｉｎｈｉｂｉ…     

Dioxaborinanes with an exocyclic phosphino group

The reaction of diphenylphosphine with o-hydroxy aromatic aldehydes and a diphenylboric acid ester in the presence of tertiary amines gave ammonium 5,6-benzo-and 5,6-naphtho-4-diphenylphosphoryl-2,2-diphenyl-1, 3-dioxa-2-boratacyclohexanes. The borylation of (,2-dihydroxybenzyl)diphenylphosphine, generated in situ, with isobutyl phenylborate gave 5,6-benzo-4-diphenylphosphino-2-phenyl-1,3-dioxa-2-boracyclohexane, which, in contrast to 1,3,2,5-dioxa-boraphosphorinanes, has a high reactivity with respect to electrophilic and nucleophilic reagents and adds oxygen, sulfur, selenium, and pyridine to give the corresponding derivatives.A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Science Center, Russian Academy of Sciences, 420083 Kazan. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 1, pp. 196–200, January, 1992.     

Amination of quinolones with morpholine derivatives

The aromatic nucleophilic substitution reaction of 7-chloroquinolone carboxylic acid and its ethyl ester with cyclic amines under microwave irradiation conditions was investigated. ¹H NMR spectroscopy was used to monitor the progress of the substitution reaction. The reaction proceeded in high yield with simple cyclic amines and was less efficient for sterically more demanding bimorpholine derivatives. A Pd-catalyzed amination of quinolone carboxylic acid ethyl ester with bimorpholine derivatives provided new C-7 bimorpholino-substituted quinolone derivatives.     

Reactive sulfur species: kinetics and mechanisms of the reaction of cysteine thiosulfinate ester with cysteine to give cysteine sulfenic acid

The kinetics and mechanisms of the reaction of cysteine with cysteine thiosulfinate ester in aqueous solution have been studied by stopped-flow spectrophotometry between pH 6 and 14. Two reaction pathways were observed for pH > 12: (1) an essentially pH-independent nucleophilic attack of cysteinate on cysteine thiosulfinate ester, and (2) a pH-dependent fast equilibrium protonation of cysteine sulfenate that is followed by rate-limiting comproportionation of cysteine sulfenic acid with cysteinate to give cystine. For 6 < pH < 12, the rate-determining reaction between cysteinate and cysteine thiosulfinate ester becomes pH-dependent due to the protonation of their amine groups. Hydrolysis of cysteine thiosulfinate ester does not play a role in the aforementioned mechanisms because the rate-determining nucleophilic attack by hydroxide is relatively slow.     

Solid-phase synthesis of 4(1H)-quinolone and pyrimidine derivatives based on a new scaffold-polymer-bound cyclic malonic acid ester

An efficient method for the preparation of polymer-bound cyclic malonic acid ester starting from Merrifield resin has been developed. Reaction of the resin-bound cyclic malonic acid ester with triethyl orthoformate and subsequent double substitution with nucleophilic reagents, such as arylamine, urea, thiourea, 2-aminobenzothiazoles, or isothiosemicarbazones, afforded the corresponding polymer-bound substituted aminomethylene cyclic malonic acid esters, which upon thermal treament led to 4(1H)-quinolones, 3-substituted uracils and thiouracils, 4H-pyrimido[2,1-b]benzothiazol-4-ones, and 1-(N-alkylidene or benzylideneamino)-1,6-dihydro-2-methylthio-6-oxo-pyrimidines, depending on the structures of the nucleophilic reagents.     

An efficient organocatalyzed multicomponent synthesis of diarylmethanes via Mannich type Friedel-Crafts reaction

We have developed an efficient organocatalyzed, multicomponent synthesis of diarylmethane derivatives from tertiary aromatic amines, formaldehyde and 2-naphthols via Mannich type Friedel-Crafts reaction. Several organocatalysts such as (−)-chinchonidine, l-proline, l-thiaproline, and l-pipecolonic acid have been screened for the reaction but the best results were obtained with l-proline. In this Mannich type Friedel-Crafts alkylation, tertiary aromatic amines react with formaldehyde-proline adduct to generate 1-(4-(dimethylamino)benzyl)pyrrolidinium-2-carboxylate intermediate, which undergoes nucleophilic addition to give substituted diarylmethanes in excellent yields.     

Synthesis of substituted 3-aminospiro-4-but-2-enolides

Previously unknown 3-N-alkylamino-, 3-N,N-dialkylamino-4-but-2-enolides containing spirocyclic moiety have been synthesized by nucleophilic addition of amines at the triple bond of methyl ester of β-(1-hydroxycyclohexyl)propiolic acid or by the reaction of amines with the corresponding 3-methoxy-4-but-2-enolide. N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 117913, Russia. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1330–1335, October, 1999.     

Nitropyrazoles 20. Synthesis and transformations of 1-methoxymethyl-3,4,5-trinitropyrazole

1-Methoxymethyl-3,4,5-trinitropyrazole, synthesized from 3,4,5-trinitropyrazole by the action of methoxymethyl chloride, was involved into the nucleophilic substitution reaction with N-nucleophiles (aliphatic amines, hydrazine derivatives). The reaction was effected regioselectively with substitution of the nitro group at position 5 in good yields. The thus obtained 5-R-substituted compounds under acid hydrolysis conditions give N-unsubstituted 5-R-3,4-dinitropyrazoles.     

Investigation of the reaction of 1-methyl-2,5-dichloro-3,4-diformylpyrrole with amines

The reaction of 1-methyl-2,5-dichloro-3,4-diformylpyrrole with amines of the aliphatic series leads to products of replacement of one chlorine atom. With aromatic amines the reaction takes place at one of the formyl groups to give aminals. The latter in the presence of excess amine readily give bisazomethines of 1-methyl-2-chloro-5-arylamino-3, 4-diformylpyrrole, which can also be obtained directly by the reaction of dichlorodiformylpyrrole with arylamines. It is shown that in this case one of the formyl groups and the adjacent chlorine atom react initially, after which the second formyl group reacts. The chlorine atom in bisazomethines of 1-methyl-2-chloro-5-arylamino-3,4-diformylpyrrole has high nucleophilic lability and is easily replaced by a hydroxy group or a piperidine residue.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1489–1493, November, 1981.     

Synthesis of Nicotinic Acid Derivatives by the Reaction of Salts of 1-Alkyl-4,6-dimethyl-2-pyrimidinylacetic Acid Esters with Amines

A study was carried out on the enamine rearrangement of iodoalkylates of the ethyl ester of 4,6-dimethyl-2-pyrimidinylacetic acid to give ethyl esters of 2-alkylamino-4,6-dimethylnicotinic acid, which proceeds upon the action of various amines. The reaction with amines containing an alkyl substituent different from that at the quaternized nitrogen atom of the pyrimidinium salt leads to the formation of products of rearrangement and transamination. In the presence of water, the rearrangement is accompanied by the formation of the ethyl ester of 1,2-dihydro-2-oxo-4,6-dimethylnicotinic acid.     

羟甲基环氧树脂的“邻位效应”的探讨

邻位羟甲基环氧树脂由于在其缩水甘油醚基的邻位引入了羟甲基而使环氧基反应活性提高。本文合成了邻位和对位羟甲基苯基缩水甘油醚作为模型化合物,通过差热分析和红外光谱研究了它们与4,4′-二氨基二苯甲烷的反应,并对Schwarzer提出的“邻位效应”进行了探讨。     

A novel [60]fullerene amino acid for use in solid-phase peptide synthesis

[see structure]. A fullerene derivative containing a free amino group has been condensed with N-Fmoc-L-glutamic acid alpha-tert-butyl ester to give a C60-functionalized amino acid. The carboxylic end of this amino acid has been deprotected in acidic conditions, and the resulting acid has been used for solid-phase peptide synthesis. The final peptide, cleaved from the resin, was very soluble in water solutions and showed antimicrobial activity against two representative bacteria.     

Kinetics of amide formation through carbodiimide/N-hydroxybenzotriazole (HOBt) couplings

The kinetics of formation of amide, 4, from the corresponding carboxylic acid by reaction with the isopropyl ester of methionine (MIPE), mediated by carbodiimide EDCI, 1, and HOBt, 2, have been studied in 1-methyl-2-pyrrolidinone (NMP) using reaction calorimetry. The reaction rates have been found to be independent of the concentration of HOBt, showing that the rate-determining step is the reaction between the carboxylic acid and EDCI to give the corresponding O-acylisourea. The pH dependence of the observed rate constants for O-acylisourea formation is consistent with a second-order reaction between doubly protonated EDCI (EDCIH2(2+), 6) and the carboxylate group. The observed rate constants fall sharply at high pH, as the fraction of EDCI as EDCIH2(2+) continues to fall strongly, whereas the carboxylic acid group is already fully ionized. The rate constant, kP, for reaction between the carboxylate group of acid, 3, and EDCIH2(2+) has a value of kP = 4.1 x 10(4) M(-1) s(-1) at 20 degrees C, some 10(5) times higher than similar rate constants measured in water. The subsequent catalytic cycle, involving reaction of O-acylisourea with HOBt to give HOBt ester, which then reacts with the amine to give the amide with regeneration of HOBt, determines the product distribution. In the case of the amino acid, 3, reaction of the O-acylisourea with MIPE to give amide, 4, is increasingly favored at higher pH values over that with the less basic internal aromatic amine of 3 to give the diamide 5.     

2,4-Dihydroxy-5,6-dihydropyrimidine derivatives

The reaction of dihydroorotic acid and its butyl ester with amines was studied. Depending on the basicity and three-dimensional structure of the amines, the amidation of the ester group may be accompanied by cleavage of the pyrimidine ring at the 3,4-bond to form ureidosuccinic acid or its monoamide.The reaction products have been previously described [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1141–1145, August, 1972.     

REACTIONS OF N-(p-CHLOROSULFONYLPHENYL)MALEIMIDE

Abstract

N-Phenylmaltimide reacted with chlorosulfonic acid to give an excellent yield of the sulfonyl chloride (1), which with dimethylamine or aniline (2 equivs.) afforded the corresponding sulfonamides (2,3). However, use of more dimethylamine (4 equivs.) caused opening of the imido ring and addition to the double bond to yield the dimethylamide (12). Similar reaction with diethylamine in methanol resulted in nucleophilic ring-opening by the solvent leading to the methyl ester (13). Analogous reactions with morpholine, pyrrolidine and piperidine (3 equivs.) proceeded with addition and substitution to give 7–9. N-(p-chlorosulfonylphenyl)-3,4-dichloromaleimide (15) reacted with amines with substitution of both the 3- and sulfonyl chlorine atoms to give the sulfonamides (16–21).

3-Chloro-4-phenoxy-N-phenylmaleimide reacted with chlorosulfonic acid to give the bis-sultonyl chloride (22); condensation with dimethylamine caused displacement of the 4-(p-chlorosulfonyl-phenoxy) group to give 16. The various reactions are discussed and the structures of the products confirmed by microanalytical and spectroscopic data. The results of preliminary biological screening against 4 fungi and 2 enzymes are included.