Sequential aza-Baylis-Hillman/ring closing metathesis/aromatization as a novel route for the synthesis of substituted pyrroles

A new route to diverse 2-substituted-3-methoxycarbonyl pyrroles has been developed. Diverse SES protected alpha-methylene beta-aminoesters were obtained by a 3-component aza-Baylis-Hillman reaction. Diversity arose from the aryl aldehydes which can be used in this reaction. N-Alkylation with allyl bromide under mild conditions provided the corresponding dienes. These substituted dienes were cyclized by ring closing metathesis at room temperature or under microwave-activation with Grubbs-type II catalyst to yield SES-protected pyrroline intermediates. The final pyrroles were obtained by base-promoted dehydrodesulfinylation/aromatization. The scope of each of these reactions was explored.     

One-pot synthesis of (Z)-4-(2-bromovinyl)benezenesulfonamides by microwave-induced simultaneous debrominative decarboxylation and sulfamation of anti-2,3-dibromo-3-(4-hlorosulfonylphenyl)propanoic acid

One-pot simultaneous debrominative decarboxylation and sulfamation of anti-2,3-dibromo-3-(4-chlorosulfonylphenyl)propanoic acid in DMF (for alkyl amines) or DMF-pyridine (for aryl amines) using a diverse range of alkyl and aryl amines under microwave irradiation condition stereoselectively afforded (Z)-4-(2-bromovinyl)benzenesulfonamides in good yields.     

Synthesis of enantiomerically-enriched N-aryl amino-amides via a Jocic-type reaction

Enantiomerically-enriched secondary trichloromethyl-alcohols react with aryl amines to give enantiomerically-enriched α-N-arylamino-acid derivatives. The intermediate acid chlorides can react in situ with aryl or, regioselectively, with alkyl amines to give aryl or alkyl α-N-arylamino amides.     

The synthesis of some dialkyl 4-(3-substituted amino)phenyl-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylates

Dialkyl 4-(3-aminophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylates 1 were transformed into alkyl 4-(3-(((2-benzoylamino-2-methoxycarbonyl)ethenyl)amino)phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylates 4 and with 2,2-disubstituted-1-dimethylaminoethenes 7 into dimethyl 4-(3-(((2,2-diacyl- or 2-acyl-2-alkoxycarbonyl)ethenyl)amino)phenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylates 8 and their ethyl methyl analogues 9.     

Diphenyl disulfide and sodium in NMP as an efficient protocol for in situ generation of thiophenolate anion: selective deprotection of aryl alkyl ethers and alkyl/aryl esters under nonhydrolytic conditions

Aryl methyl ethers, methyl esters, aryl esters, and aryl sulfonates are chemoselectively deprotected under nonhydrolytic conditions by treatment with Ph(2)S(2) (0.6 equiv) and Na (1.6 equiv) in NMP under reflux or at 90 degrees C. Quantitative utilization of the 'PhS' moiety as the effective nucleophilic species represents conservation of atom economy. Other solvents such as HMPA, DMPU, DMEU, and DMF afforded comparable results. Chloro, nitro, aldehyde, alpha,alpha-diketone, and alpha,beta-unsaturated ketone functionalities remain unaffected. The deprotection was found to take place in the order aryl ester > alkyl ester > aryl alkyl ether. Substrates bearing strong electron-withdrawing groups react at a faster rate than those not having such substitution. The differences in rate of reaction has been exploited for selective deprotection for intramolecular competition. An aryl acetate/benzoate is deprotected selectively in preference to a methyl ester or aryl methyl ether. Selective deprotection of a methyl ester is observed in the presence of an aryl alkyl ether.     

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。     

Facile synthesis of 1H-pyrazolo[1,2-a]pyridazine-5,8-dione derivatives by a one-pot, three-component reactions

Protonation of the highly reactive 1:1 intermediate produced in the reaction between alkyl or aryl isocyanides and electron-deficient acetylenic esters with 3,6-dihydroxypyridazine, leads to a vinylisonitrilium cation, which undergoes an addition reaction with the conjugate base of the 3,6-dihydroxypyridazine to produce dialkyl 3-(alkyl or arylamino)-5,8-dioxo-5,8-dihydro-1H-pyrazolo[1,2-a]pyridazine-1,2-dicarboxylates in good yields at room temperature.     

Rapid SmI2-mediated reductions of alkyl halides and electrochemical properties of SmI2/H2O/amine

Mixtures of SmI(2)/H(2)O/amine have been found to reduce alkyl halides more efficiently than SmI(2)/HMPA/alcohol mixtures at room temperature. Alkyl and aryl iodides were quantitatively reduced in <1 min and alkyl bromides in 10 min, while alkyl and aryl chlorides required more than 5 h for completion. Determination of the reaction order of Et(3)N in the reduction of 1-chlorodecane showed that the reaction order is one. Water was shown not to participate in the rate-determining step of this reduction. There was a significant change of the UV-vis spectrum and color of SmI(2) upon addition of either PMDTA or water, while no effect was observed with the addition of Et(3)N or TMEDA. Although the combination of SmI(2), water, and amines produces a very efficient reducing system, cyclic voltammetric experiments showed that the redox potential is nearly identical with that of SmI(2) alone. These results are consistent with precipitation providing the driving force for reduction. Taken together, the results of these experiments show that the combination of SmI(2)/H(2)O/amine provides a fundamentally novel and useful approach to enhance the reactivity of SmI(2).     

On the catalytic duo PdCl2(PPh3)2/AuCl(PPh3) that cannot effect a Sonogashira-type reaction: a correction

In contrast to the observation made by the Laguna group, we report that the combination of PdCl₂(PPh₃)₂ and AuCl(PPh₃) makes a unique catalytic system that allows Sonogashira-type cross-coupling of both aryl and alkyl alkynes with aryl halides in excellent yields.     

Synthesis and Properties of 3-Alkyl(aryl)-5-chloromethylisoxazoles

3-Chloro-2-isothiocyanato-1-propenyl alkyl(aryl) ketones react with hydroxylamine hydrochloride to give 3-alkyl(aryl)-5-chloromethylisoxazole. Treatment of the latter with dimethylamine and ammonium thiocyanate leads to formation of previously unknown 3-alkyl(aryl)-5-dimethylamino(or isothiocyanato)- methylisoxazoles.     

One-pot synthesis of(Z)-4-(2-bromovinyl)benezenesulfonamides by microwave-induced simultaneous debrominative decarboxylation and sulfamation of anti-2,3-dibromo-3-(4-chlorosulfonylphenyl)propanoic acid

One-pot simultaneous debrominative decarboxylation and sulfamation of anti-2,3-dibromo-3-(4-chlorosulfonylphenyl)propa-noic acid in DMF (for alkyl amines) or DMF-pyridine (for aryl amines) using a diverse range of alkyl and aryl amines under microwave irradiation condition stereoselectively afforded (Z)-4-(2-bromovinyl)benzenesulfonamides in good yields.     

(3+2) Annulation of Amidinothioureas with Binucleophile: Synthesis and Antimicrobial Activity of 3‐Phenylamino‐5‐aryl/alkyl‐1,2,4‐oxadiazole Derivatives

Herein, we report an efficient method for preparation of 3‐phenylamino‐5‐aryl/alkyl‐1,2,4‐oxadiazole by (3+2) annulation of amidinothioureas with binucleophilic hydroxylamine hydrochloride in the presence of mercury (II) chloride. Desired 3‐phenylamino‐5‐aryl/alkyl‐1,2,4‐oxadiazole was prepared in good to moderate yields. On the basis of the literature precedence, the mechanism for the formation of 3‐phenylamino‐5‐aryl/alkyl‐1,2,4‐oxadiazole is proposed. The synthesized compounds were tested for their antimicrobial activity and showed promising inhibition of Gram‐positive bacteria (Staphylococcus aureus) and fungi (Candida albicans).     

Synthesis of 4,5-Dihydroisoxazoles Bearing Phosphonate Moiety

Abstract

Introduction of phosphoryl group usually leads to the improvement of biological activity of the parent molecule. A facile synthetic route was introduced based on an intramolecular silylnitronate-olefin cyclo-addition (ISOC) reaction. Thus, 3-(β-diethoxyphosphoryl)-ethyl-5-methoxycarbonyl - 4,5 -dihydroisoxazole (1), 3-(α-diethoxyphosphoryl- α -substituted methyl) - 5 - methoxycarbonyl - 4,5 - dihydroisoxazole (2) and 3 - methyl - 4 -alkyl(aryl) - 5 - bisphosphoryl - 4,5 - dihydroisoxazole (3) were prepared from diethyl methylphosphonate, diethylphosphite and methylene bisphosphonate respectively after treatment with BuLi or LDA and appropriate nitroalkene followed by ClSiMe₃. Condensation of but - 3 - en - 1 - yl phosphonate with nitroalkene, followed by ClSiMe₃, led to the stereoselective synthesis of fused carboisoxazole derivatives (4). In the case of aryl substituted α- nitroalkene, the reaction undergoes stereoselectively due to the formation of transition state of the least steric hindrance during the Michael addition step, which gave rise to the exclusive formation of erythro isomers. With alkyl substituted α- nitroalkenes, the diastereoselectivity was not obvious as the result of minor steric difference of the related groups. It seems necessary to point out that the stereochemistry involved in the ISOC reaction is quite different from an intramolecular nitrile-oxide olefin cycloaddition (INOC) process presumably due to the formation of transition states with diverse steric environments. Since 4,5-dihydroisoxazole derivatives are synthetic equivalent of β- hydroxy ketones, 1,3 - diketones, γ- aminoalcohols, α β- unsaturated ketones, the present contribution should expand the field of applications of 4,5 -dihydroisoxazole derivatives in the natural products synthesis by building block strategy.     

New Approaches to the Synthesis of 4‐(2‐Aminophenyl)‐1,3‐dihydro‐2H‐imidazol‐2‐ones and 3‐Ureidoindoles and a Study of Their Interconversion

3‐Alkyl/aryl‐3‐ureido‐1H,3H‐quinoline‐2,4‐diones ( 2 ) and 3a‐alkyl/aryl‐9b‐hydroxy‐3,3a,5,9b‐tetrahydro‐1H‐imidazo[4,5‐c]quinoline‐2,4‐diones ( 3 ) react in boiling concentrated HCl to give 5‐alkyl/aryl‐4‐(2‐aminophenyl)‐1,3‐dihydro‐2H‐imidazol‐2‐ones ( 6 ). The same compounds were prepared by the same procedure from 2‐alkyl/aryl‐3‐ureido‐1H‐indoles ( 4 ), which were obtained from the reaction of 3‐alkyl/aryl‐3‐aminoquinoline‐2,4(1H,3H)‐diones ( 1 ) with 1,3‐diphenylurea or by the transformation of 3a‐alkyl/aryl‐9b‐hydroxy‐3,3a,5,9b‐tetrahydro‐1H‐imidazo[4,5‐c]quinoline‐2,4‐diones ( 3 ) and 5‐alkyl/aryl‐4‐(2‐aminophenyl)‐1,3‐dihydro‐2H‐imidazol‐2‐ones ( 6 ) in boiling AcOH. The latter were converted into 1,3‐bis[2‐(2‐oxo‐2,3‐dihydro‐1H‐imidazol‐4‐yl)phenyl]ureas ( 5 ) by treatment with triphosgene. All compounds were characterized by ¹H‐ and ¹³C‐NMR and IR spectroscopy, as well as atmospheric pressure chemical‐ionisation mass spectra.     

Amidrazones. 6 . Synthesis of 1,2,4-thiadiazoles by thermolysis of N3-thiocarbamoylamidrazone ylides

Reaction of N³-unsubstituted amidrazone ylides ( 1a and 1b ) with alkyl or aryl isothiocyanates gives N³-thiocarbamoylamidrazone ylides ( 2 ). Thermolysis of 2 gives 3-alkyl(or aryl)-5-alkyl(or aryl)amino-1,2,4-thiadiazoles ( 3a-i ).     

某些含芳碲基或烷碲基的1, 4-苯醌和1, 4-萘醌衍生物

四氯-1,4-苯醌(1)和2,3-二氯-1,4-萘醌(2)中的氯相当活泼,能和许多亲核试剂反应,如醇和酚;硫醇和硫酚;胺及许多含NH的杂环化合物。1和2与磷亲核试剂的反应也是已知的,本文报道1及2和芳碲基或烷碲基亲试剂的反应。     

Copper-mediated C-H activation/C-S cross-coupling of heterocycles with thiols

We report the synthesis of a series of aryl- or alkyl-substituted 2-mercaptobenzothiazoles by direct thiolation of benzothiazoles with aryl or alkyl thiols via copper-mediated aerobic C-H bond activation in the presence of stoichiometric CuI, 2,2'-bipyridine and Na(2)CO(3). We also show that the approach can be extended to thiazole, benzimidazole, and indole substrates. In addition, we present detailed mechanistic investigations on the Cu(I)-mediated direct thiolation reactions. Both computational studies and experimental results reveal that the copper-thiolate complex [(L)Cu(SR)] (L: nitrogen-based bidentate ligand such as 2,2'-bipyridine; R: aryl or alkyl group) is the first reactive intermediate responsible for the observed organic transformation. Furthermore, our computational studies suggest a stepwise reaction mechanism based on a hydrogen atom abstraction pathway, which is more energetically feasible than many other possible pathways including β-hydride elimination, single electron transfer, hydrogen atom transfer, oxidative addition/reductive elimination, and σ-bond metathesis.     

Heck arylations of pent-4-enoates or allylmalonate using a palladium/tetraphosphine catalyst

The Heck reaction of aryl halides with functionalised alk-1-enes should be a powerful method for the synthesis of functionalised (E)-1-arylalk-1-ene derivatives. The major problem of this reaction is the palladium-catalysed migration of the carbon-carbon double bond along the alkyl chain when there are no substituents on the C3 carbon of the alk-1-enes. We observed that for the arylation of ethyl pent-4-enoate, ethyl 2-methylpent-4-enoate or dimethyl allylmalonate this migration could be partially or completely controlled using appropriate reaction conditions. The ramification on the alkyl chain and the substituents on the aryl halide have also an important influence on this migration. Moreover, the cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane/1/2[PdCl(C₃H₅)]₂ system catalyses this reaction with a wide range of aryl bromides using very high ratio substrate/catalyst in good yields.     

Lewis-acid-catalyzed rearrangement of arylvinylidenecyclopropanes: significant influence of substituents and electronic nature of aryl groups

Lewis-acid-catalyzed reactions of arylvinylidenecyclopropanes having three substituents at the corresponding cyclopropyl rings have been investigated thoroughly. The reaction products are highly dependent on the substituents at the corresponding cyclopropyl rings and the electronic nature of the aryl groups. For arylvinylidenecyclopropanes bearing two alkyl groups at the C-1 position (R1, R2, R3=aryl; R4=H; R5, R6=alkyl), naphthalene derivatives were formed in the presence of Lewis-acid Eu(OTf)3 in DCE at 40 degrees C. For arylvinylidenecyclopropanes in which R1, R2, R3=aryl and R4, R5=alkyl (syn/anti isomeric mixtures), the corresponding 6aH-benzo[c]fluorine derivatives were formed in the syn-configuration via a double intramolecular Friedel-Crafts reaction when all of the aryl groups do not have electron-withdrawing groups or the corresponding indene derivatives were obtained via an intramolecular Friedel-Crafts reaction as long as one electron-deficient aryl group was attached. For arylvinylidenecyclopropanes in which R1, R2, R3, R4=aryl and R5=alkyl or H, the corresponding indene derivatives were obtained exclusively via a sterically demanding intramolecular Friedel-Crafts reaction. Lewis-acid effects and mechanistic insights have been discussed on the basis of experimental investigations.     

Study of direction of cyclization of 1‐azolil‐4‐aryl/alkyl‐thiosemicarbazides

On a four series of 1‐azolil‐4‐aryl/alkyl‐thiosemicabazides, a study on the influence of azole moiety on the capability for intramolecular cyclization and its direction was carried out. It was found that for 4‐aryl/alkyl‐thiosemicabazides with triazole, imidazole, or pyrrole moiety at N‐1 nitrogen atom possible products were only s‐triazoles, both in alkaline and acidic medium. Successful dehydrocyclization of 1‐azolil‐4‐aryl/alkyl‐thiosemicarbazides leading to a thiadiazole has been documented only for a series of 1‐(4‐methyl‐1,2,3‐thiadiazol‐5‐yl‐carbonyl)‐4‐aryl/alkyl‐thiosemicarbazides. It can be speculative that the determination of pK_a value of oxygen atom of 1‐azolil‐4‐aryl/alkyl‐thiosemicarbazide can be a very valuable parameter in the prediction of the possibility of dehydrocyclization to form thiadiazole. © 2010 Wiley Periodicals, Inc. Heteroatom Chem 21:521–532, 2010; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.20643