Synthesis of 3-methoxyazetidines via an aziridine to azetidine rearrangement and theoretical rationalization of the reaction mechanism

The synthetic utility of N-alkylidene-(2,3-dibromo-2-methylpropyl)amines and N-(2,3-dibromo-2-methylpropylidene)benzylamines was demonstrated by the unexpected synthesis of 3-methoxy-3-methylazetidines upon treatment with sodium borohydride in methanol under reflux through a rare aziridine to azetidine rearrangement. These findings stand in contrast to the known reactivity of the closely related N-alkylidene-(2,3-dibromopropyl)amines, which are easily converted into 2-(bromomethyl)aziridines under the same reaction conditions. A thorough insight into the reaction mechanism was provided by both experimental study and theoretical rationalization.     

A convenient synthesis and spectroscopic characterization of N, N'-Bis(2-propenyl)-2,7-diazapyrenium quaternary salts

N,N'-Bis(2-propenyl)-2,7-diazapyrenium salts are synthesized in good yield from the reaction of 1,4,5,8-naphthalenetetracarboxylic dianhydride with allylamine, followed by LiAlH(4) reduction and subsequent oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). The nature of the counteranion depends on the solvent system used for recrystallization of the crude product from the final DDQ-oxidation step. X-ray analysis shows that if recrystallization is carried out in boiling CH(3)OH/H(2)O (1:1, v/v), the counteranion in the resulting deep-red crystals is always the alkoxy anion of 2-cyano-5,6-dichloro-3-hydroxy-1,4-benzoquinone, whether the final DDQ oxidation ends with addition of HClO(4) or HCl; on the other hand, if recrystallization is carried out with anhydrous acetonitrile, the product is N,N'-bis(2-propenyl)-2,7-diazapyrenium diperchlorate or dichloride depending on whether the DDQ oxidation is followed by addition of concd HClO(4) or concd HCl, respectively. Importantly, if the DDQ oxidation is quenched with HBr, Br(-) is oxidized to Br(2) by unreacted DDQ, and the resulting product is N, N'-bis(2,3-dibromopropyl)-2,7-diazapyrenium dibromide. Comparative absorption and time-resolved emission studies provide evidence for possible dimerization of N,N'-bis(2-propenyl)-2,7-diazapyrenium diperchlorate in CH(3)CN.     

Regio- and stereospecific ring opening of 1,1-dialkyl-2-(aryloxymethyl)aziridinium salts by bromide

Enantiomerically pure 2-(aryloxymethyl)aziridines are efficiently transformed into chiral N-(2-bromo-3-aryloxypropyl)amines via a regio- and stereospecific ring opening of the intermediate aziridinium salts, and the experimental results are rationalized on the basis of some high level ab initio calculations.     

A new approach towards 2-amino-1-aryloxy-3-methoxypropanes from 1-arylmethyl-2-(bromomethyl)aziridines

1-Arylmethyl-2-(bromomethyl)azirdines were converted into the corresponding 2-(aryloxymethyl)aziridines upon treatment with the appropriate potassium phenoxides in DMF/acetone in excellent yields, followed by regioselective ring opening towards N,N-di(arylmethyl)-N-(2-bromo-3-aryloxypropyl)amines using benzyl bromide in acetonitrile. Treatment of the latter β-bromoamines with sodium methoxide afforded the desired 2-amino-1-aryloxy-3-methoxypropanes as the major compounds (49-58%) besides the isomeric 3-amino-1-aryloxy-2-methoxypropanes in minor quantities (9-15%).     

Reactions of N- and C-alkenylanilines: VI. Synthesis of 6-methyl-2-[(E or Z)-1-propenyl]anilines and the corresponding anilides and their reaction with bromine

Isomerization of 2-allyl-6-methylaniline by the action of potassium hydroxide at 300°C afforded cis and trans isomers of 2-methyl-6-(1-propenyl)aniline which were converted into the corresponding carbamates by treatment with ethyl chloroformate. Ethyl 2-methyl-6-(1-propenyl)phenylcarbamates reacted with bromine to give mixtures of 4-(1-bromoethyl)-8-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and ethyl 2- methyl-6-(1,2-dibromopropyl)phenylcarbamates. Treatment of the same compounds with N-bromosuccinimide resulted in formation of 2-ethoxy-4H-3,1-benzoxazine derivatives. The reaction of N-{6-methyl-2-[(Z)- 1-propenyl]-phenyl}methanesulfonamide gave a mixture of stereoisomeric N-[6-methyl-2- (1,2-dibromopropyl)-phenyl]-methanesulfonamides.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 12, 2004, pp. 1815–1818.Original Russian Text Copyright © 2004 by Afonkin, Sotnikov, Gataullin, Spirikhin, Abdrakhmanov.For communication V, see [1].     

An efficient and facile one-pot synthesis of propargylamines by three-component coupling of aldehydes, amines, and alkynes via C-H activation catalyzed by NiCl2

NiCl₂ was found to be a highly efficient and effective catalyst for the one-pot three-component (A³) coupling of aldehydes, amines, and alkynes to produce propargylamines in nearly quantitative yields. Structurally divergent aldehydes, amines, and alkynes were converted into the corresponding propargylamines. No co-catalyst or activator is needed and water is the only byproduct of this novel protocol.     

Iridium complex-catalyzed allylic amination of allylic esters

Iridium complex-catalyzed allylic amination of allylic carbonates was studied. The solvent strongly affected the catalytic activity. The use of a polar solvent such as EtOH is essential for obtaining the products in high yield. The reaction of (E)-3-substituted-2-propenyl carbonate and 1-substituted-2-propenyl carbonate with pyrrolidine in the presence of a catalytic amount of [Ir(COD)Cl](2) and P(OPh)(3) (P/Ir = 2) gave a branch amine with up to 99% selectivity. Both secondary and primary amines could be used for this reaction. When a primary amine was used, selective monoallylation occurred. No diallylation product was obtained. The reaction of 1,1-disubstituted-2-propenyl acetate with amines exclusively gave an alpha,alpha-disubstituted allylic amine. This reaction provides an alternative route to the addition of an organometallic reagent to ketimines for the preparation of such amines. The reaction of (Z)-3-substituted-2-propenyl carbonate with amines gave (Z)-linear amines with up to 100% selectivity. In all cases, no (E)-linear amine was obtained. The selectivities described here have not been achieved in similar palladium complex-catalyzed reactions.     

Alkylation of pyridinecarbaldehyde oximes with epoxy compounds

O-and N-Alkylation products were obtained by reactions of pyridine-2-,-3-, and-4-carbaldehyde oximes with enantiomerically pure and racemic epoxy compounds (1,2-epoxypropane, 1-phenyl-1,2-epoxyethane, 1-chloro-2,3-epoxypropane, and 1-bromo-2,3-epoxypropane) in the presence of bases and under conditions of phase-transfer catalysis. A series of new amino alcohols was synthesized by condensation of amines with products of O-alkylation of pyridinecarbaldehyde oximes with 1-halo-2,3-epoxypropanes. Published in Russian in Zhurnal Organicheskoi Khimii, 2007, Vol. 43, No. 3, pp. 450–454. The text was submitted by the authors in English.     

A concise synthesis of furostifoline by tetrabutylammonium fluoride-promoted indole ring formation

Furostifoline, a furo[3,2-a]carbazole alkaloid, was synthesized in 10% overall yield in four steps from 2-acetyl-3-bromofuran. The key step of this synthesis was the 2-substituted indole formation with tetrabutylammonium fluoride (TBAF) from 2-(2-propenyl)-3-((2-ethoxycarbonylamino)phenylethynyl)furan, which was easily prepared from ethyl 2-ethynylphenylcarbamate with 3-bromo-2-(2-propenyl)furan by the Sonogashira reaction.     

Synthesis of methyl esters of 5-amino-4-(substituted amino)-2-methylthio-7H-pyrrolo[2,3d]-pyrimidine-6-carboxylic acids

The optimum route for the synthesis of methyl esters of N-[(4-substituted amino)-5-cyano-2-methylthiopyrimidin-6-yl]amino acids (which are starting materials for preparing the methyl esters of the corresponding 5-amino-4-(substituted amino)pyrrolo[2,3-d]pyrimidine-6-carboxylic acids) is via subsequent reactions of 4,6-dichloro-2-methylthiopyrimidine-5-carbonitrile with amines and methyl glycinate. In some examples, the reaction of methyl N-(4-chloro-2-methylthio-6-pyrimidinyl)aminoacetate with amines occurs to give the corresponding acid amides. The previously unknown synthesized derivatives of pyrimidin-6-yl amino acids and 4,5-diaminopyrrolo[2,3-d]pyrimidine- 6-carboxylic acids possess fungicidal properties.Vilnius University, Vilnius 2006, Lithuania. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No 7, pp. 955–961, July, 2000.     

Synthesis of certain alkenyl purines and purine analogs

Synthesis of alkenyl derivatives of certain purines and purine analogs is described. Direct alkylation of the sodium salt of 6-chloropurine (1) either with 1-bromo-2-pentene or 4-bromo-2-methyl-2-butene in N,N-dimethylformamide furnished N-7, 4a and N-9, 3a , 3b alkenyl derivatives. Similar alkylation of 2-amino-6-chloropurine (2) provided the corresponding N-7, 4c-4e and N-9, 3c-3e alkenyl derivatives. Acid hydrolysis of these chloro derivatives 3a-3e, 4a,c-e furnished the corresponding alkenyl hypoxan-thines 6a, 6b and 7a or alkenyl guanines 6c-6e and 7c-7e. Treatment of 3a-3d with thiourea in absolute ethanol provided the corresponding 6-thio derivatives 5a-5d. Alkylation of the sodium salt of either purine-6-carboxamide (8) or 1,2,4-triazole-3-carboxamide (10) gave mainly one isomer 9a, 9b and 11a, 11b. The direct alkylation of pyrrolo[2,3-d]pyrimidin-4(3H)-one (12) gave N-3 alkenyl derivatives 13a, 13b , and the N-7 alkenyl derivatives 16a, 16b have been prepared starting from the 4-chloro derivative 14 . Synthesis of 2-amino-7-(2-penten-1-yl)pyrrolo[2,3-d]pyrimidin-4(3H)-one (19a) has been accomplished starting from 2-amino-4-methoxypyrrolo[2,3-d]pyrimidine (17) . These alkenyl derivatives were found to be devoid of anti-HCMV activity in vitro.     

C(3)-alkylation and cyclization of pyrazino[1,2-b]isoquinolin-4-ones

To avoid the epimerization of the C(11a)-stereocenter previously observed in 6,11a-cis-pyrazino[1,2-b]isoquinolin-1,4-diones, we present in this paper the C(3)-alkylation of 1-methoxy-pyrazino[1,2-b]isoquinolin-4-ones to obtain all-cis derivatives through a very reliable protocol. The success of the acid-promoted cyclization to get pentacyclic (R₃=arylmethyl) or tetracyclic (R₃=2-bromo-2-propenyl) compounds is dependent on the nature of the C(3)-unsaturated chain and of the N-substituent, but these limitations have been overcome by using trifluoromethanesulfonic as a superacid catalyst. The C-(3)-alkylation of pyrazino[1,2-b]isoquinolin-4-one is also studied.     

Synthesis of 11-bromo-9-methyl-6-methylene-3-methylthio-5,6,9,10-tetrahydro-8H-[1,2,4]triazolo[3′,4′;3,4]pyrazino[1,2-c]pyrimidine-8,10-dione from 4-allyl-1-(3-methyl-2,4-dioxo-1,2,3,4-tetrahydro-6-pyrimidinylcarbonyl)thiosemicarbazide

4-Allyl-1-(3-methyl-2,4-dioxo-1,2,3,4-tetrahydro-6-pyrimidinylcarbonyl)thiosemicarbazide is cyclized in alkaline medium into 4-allyl-3-(3-methyl-2,4-dioxo-1,2,3,4-tetrahydro-6-pyrimidinyl)-1,2,4-triazoline-3-thione, which is converted on alkylation with iodomethane into the methylthio derivative. Reaction of the latter with bromine occurs with formation of 3-(5-bromo-3-methyl-2,4-dioxo-1,2,3,4-tetrahydro-6-pyrimidinyl)-4-(2,3-dibromopropyl)-5-methylthio-1,2,4-triazole, dehydrobromination of which with potassium carbonate leads to formation of the first representative of a new heterocyclic system, viz. 11-bromo-9-methyl-6-methylene-3-methylthio-5,6,9,10-tetrahydro-8H-[1,2,4]triazolo[3,4:3,4]pyrazino[1,2-c]pyrimidine-8,10-dione.Vilnius University, Vilnius 2734, Lithuania. e-mail: sigitas.tumkevicius@chf.vu.lt. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 67–70, January, 1999.     

Preparation of functionalized primary chiral amines and amides via an enantioselective three-component synthesis of propargylamines

A general preparation of functionalized primary chiral amines and amides from propargylamines has been developed. The chirality is established by an enantioselective three-component reaction of an aldehyde, a terminal alkyne and a secondary amine in the presence of copper(I) bromide/Quinap as the catalytic system leading to chiral propargylamines in high yields and enantioselectivities. Functionalization and reduction leads to various primary amines and amides.     

超声萃取/气相色谱-串联质谱法同时测定纺织品中6种禁用有机磷阻燃剂

以丙酮为萃取溶剂,建立了超声萃取/气相色谱-串联质谱同时测定纺织品中6种禁用有机磷阻燃剂的分析方法.6种禁用有机磷阻燃剂三-(1-氮杂环丙基)氧化膦( TEPA)、三-(2-氯乙基)磷酸酯(TCEP)、三-(2,3-二氯丙基)磷酸酯(TDCP)、二-(2,3-二溴丙基)磷酸酯(DDBPP)、三-(邻甲苯基)磷酸酯(TO...     

Synthesis of d- and l-2,3-trans-3,4-cis-4,5-trans-3,4-dihydroxy-5-hydroxymethylproline and tripeptides containing them

Enantiomerically pure (-)-(1R,4R,5R,6S)- and (+)-(1S,4S,5S,6R)-7-(tert-butoxycarbonyl)-5,6-exo-isopropylidenedioxy-7-azabicyclo[2.2.1]hept-2-one ((-)-3 and (+)-3) have been obtained from the Diels-Alder adduct of N-(tert-butoxycarbonyl)pyrrole and 2-bromo-1-(p-toluenesulfonyl)acetylene, including the Alexakis optical resolution of ketone (+/-)-3 via formation of cyclic aminals with (1R,2R)-diphenylethylenediamine. Compounds (-)-3 and (+)-3 were converted into d- and l-2,3-trans-3,4-cis-4,5-trans-N-(tert-butoxycarbonyl)-5-hydroxymethyl-3,4-isopropylidenedioxyprolines (-)-4 and (+)-4, respectively. Applying the Boc and Fmoc strategies of peptide synthesis, these compounds were used to construct two tripeptides containing the d- or l-2,3-trans-3,4-cis-4,5-trans-3,4-dihydroxy-5-hydroxymethylproline.     

Synthesis and Transformations of Ethyl (Z)-2-(2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)-3-(dimethylamino)propenoate

Ethyl (Z)-2-(2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)-3-(dimethylamino)propenoate was prepared in one step from ethyl (2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)acetate and bis(dimethylamino)-tert-butoxymethane and treated with various amines and hydrazines to afford the corresponding amino substituted products. Reactions of the titled compound with N,N'-, C,N-, and C,O'-ambident nucleophiles in refluxing acetic acid furnished the corresponding fused pyrimidinones, quinolizinones, and pyranones.     

Fluorinated pyrido[2,3-c]pyridazines. II. Synthesis and antibacterial activity of 1,7-disubstituted 6-fluoro-4(1H)-oxopyrido[2,3-c]pyridazine-3- carboxylic acids

Chemical modification of pyridonecarboxylic acid antibacterials with a 1,8-naphthyridine ring, such as enoxacin and tosufloxacin, to their 2-aza derivatives was studied. A new series of 1,7-disubstituted 6-fluoro-4(1H)-oxopyrido[2,3-c]pridazine-3-carboxylic acids (25-27) was prepared by a route involving either alkylation of ethyl 6-fluoro-4(1H)-oxo-7-(p-tolylthio)pyrido[2,3-c]pyridazine-3-carbox ylate (7) or intramolecular cyclization of ethyl 2-(2,6-dichloro-5-fluoronicotinoyl)-2-[2-(p-fluorophenyl)hydraz ono]acetate, (20), followed by displacement reaction with cyclic amines at C-7; the N-1 substituent in these compounds included of ethyl, 2-fluoroethyl and p-fluorophenyl groups, and the C-7 functional group comprised variously-substituted piperazines and pyrrolidines. Antibacterial activities of these compounds were markedly inferior to those of enoxacin and tosufloxacin.     

Preparation of 2- and 4-arylmethyl N-substituted and N,N-disubstituted anilines via a "green", multicomponent reaction

[reaction: see text] A new, green, regioselective, one-step, multicomponent reaction of an aldehyde possessing a nonenolizable carbonyl function, cyclohex-2-enone (or a derivative thereof), and primary or secondary amines afforded 2-N-substituted arylmethyl anilines or 4-N,N-disubstituted arylmethyl anilines, respectively. Yields and regioselectivities were good. Evidence for a pathway involving imine and iminium intermediates is presented along with examples demonstrating amenability of the process to combinatorial chemistry.     

Synthesis of enantiomerically pure 1,2-diamine derivatives of 7-azabicyclo[2.2.1]heptane. New leads as glycosidase inhibitors and rigid scaffolds for the preparation of peptide analogues

Enantiomerically pure alcohols (-)- and (+)-7-tert-butoxycarbonyl-6-endo-p-toluenesulfonyl-7-azabicyclo[2.2.1]hept-2-en-5-endo-ol ((-)-11 and (+)-11) have been obtained from the Diels-Alder adduct of N-(tert-butoxycarbonyl)pyrroel and 2-bromo-1-p-toluenesulfonylacetylene, including a resolution method. These two alcohols were converted into (+)- and (-)-5-exo-amino-7-(tert-butoxycarbonyl)-2,3-exo-isopropylidenedioxy-7-azabicyclo[2.2.1]heptane ((+)-18 and (-)-18) and (+)- and (-)-5-endo-amino-7-(tert-butoxycarbonyl)-2,3-exo-isopropylidenedioxy-7-azabicyclo[2.2.1]heptane ((+)-19 and (-)-19) after adequate functionalization and desulfonylation steps. The corresponding conformationally constrained bicyclic 1,2-diamines (+)-4, (-)-4, (+/-)-5, (+/-)-6, (+)-7, and (-)-7 were obtained from the protected precursors 18 and 19 and evaluated as glycosidase inhibitors. Diamines (+)-4, (-)-4, (+)-6, and (-)-6 can be seen as new nonpeptide molecular scaffolds for the design of peptide analogues.