Convenient synthesis of arylpropargyl aldehydes and 4-aryl-3-butyn-2-ones from arylacetylenes and amide acetals

The reaction of arylacetylenes 1 and N,N-dimethylformamide dimethylacetal (2a, DMF-DMA) afforded the corresponding arylpropargyl aldehydes 3 in moderate yields. Similarly, the reaction of 1 and N,N-dimethylacetamide dimethylacetal (2b, DMA-DMA) gave 4-aryl-3-butyn-2-ones 4.     

Facile and clean synthesis of α-alkenoyl ketene-(S,S)-acetals via the aldol condensation reactions in water

The aldol condensation reactions of α,α-diacetyl ketene-(S,S)-acetals, 1a and 1b, with aromatic aldehydes 2 in the presence of NaOH in water have been investigated. At room temperature, the base-mediated condensations proceed smoothly to afford the corresponding mono-condensed products, α-alkenoyl ketene-(S,S)-acetals 3, in high yields. At reflux temperature, the reactions produce high yields of symmetric double condensed α,α-dialkenoyl ketene-(S,S)-acetals 4 when 2 equiv of aldehyde are employed. Moreover, compounds 3 can condense with a different aldehyde to give unsymmetric double condensed α,α-dialkenoyl ketene-(S,S)-acetals 5.     

Aminoalkylation of nitriles by iminium ions generated in situ

Aminoalkylation of a series of primary and secondary nitriles with N-(α-aminoalkyl)benzotriazoles 1 (derived from a variety of secondary amines and aldehydes) proceeds smoothly providing the corresponding β-aminoalkyl nitriles 5a-j in 66-97% yields.     

A new method for the synthesis of 2-cyclopenten-1-one-5-carboxylic ester derivatives via Rh2(OAc)4-mediated intramolecular C-H insertion reaction of 4Z-β-vinyl-α-diazo β-ketoesters

2-Cyclopenten-1-one-5-carboxylic ester derivatives 14 are synthesized in a four-step-reaction sequence starting from alkynyl aldehydes 9 via 4Z-β-vinyl-α-diazo β-ketoesters intermediate 8. The synthetic method for 8 is described. When the δ substituent is an alkyl group, Rh(II)-mediated decomposition of the diazo compounds 8 led to an intramolecular C-H insertion to afford 2-cyclopenten-1-one-5-carboxylic ester derivatives 14 in high yields. When the δ substituent is an aryl group, 2-hydroxynaphthoate 15 is obtained exclusively. In both cases, no Wolff rearrangement product was observed.     

Original reaction of p-nitrobenzyl chloride with aldehydes using tetrakis(dimethylamino)ethylene (TDAE)

A series of disubstituted diarylethanols was prepared in moderate to good yields by reaction of p-nitrobenzyl chloride (1) with various aromatic aldehydes (2-12) in presence of tetrakis(dimethylamino)ethylene (TDAE).     

Facile synthesis of 4-phenylquinolin-2(1H)-one derivatives from N-acyl-o-aminobenzophenones

An efficient synthesis of 4-phenylquinolin-2(1H)-one derivatives has been achieved in a one-pot reaction from N-acyl-o-aminobenzophenones 1a-c (a: acyl=acetyl; b: acyl=propanoyl; c: acyl=heptanoyl) using NaH as a base. Treatment of 1 with NaH provided the quinolones 2a-c with 62-83% yields, whereas the reaction in the presence of alkyl iodide (alkyl=methyl, ethyl, n-octyl) gave the corresponding N-alkylated quinolones 3a-g in 75-95% yields. The alkylation reaction of 4-phenylquinolin-2(1H)-one 2a with alkyl halide gave a mixture of N-alkylated and O-alkylated products. Comparison of IR and NMR data of the N-alkylated and O-alkylated compounds with those of 2a-c indicated that 2a-c exist as the lactam form.     

Original synthesis of oxiranes via TDAE methodology: reaction of 2,2-dibromomethylquinoxaline with aromatic aldehydes

We report herein the reaction of 2,2-dibromomethylquinoxaline 2 with aromatic aldehydes 3a-g in the presence of TDAE. These reactions lead to a mixture of cis/trans-isomers of corresponding oxiranes 4a-g in good yields. The stereoselectivity of the reaction was sensitive to steric hindrance.     

Michael addition of chiral formaldehyde N,N-dialkylhydrazones to activated cyclic alkenes

The nucleophilic conjugate addition of chiral formaldehyde N,N-dialkylhydrazones 1 to doubly activated cyclic alkenes 2-8 proceeds smoothly to afford the corresponding Michael adducts 14, 16, 18, 20, 22, 24, and 25 in variable yields and selectivities. The reactions take place either spontaneously or in the presence of MgI₂ as a mild Lewis acid depending on the type of substrate. Release of the chiral auxiliary was achieved by transformation of the hydrazone moiety into acetals, dithioacetals or nitriles.     

An efficient microwave assisted synthesis of novel class of Rhodanine derivatives as potential HIV-1 and JSP-1 inhibitors

(Z)-5-(2-(1H-Indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one (7a-q) derivatives have been synthesized by the condensation reaction of 3-phenyl-2-thioxothiazolidin-4-ones (3a-h) with suitably substituted 2-(1H-indol-3-yl)-2-oxoacetaldehyde (6a-d) under microwave condition. The thioxothiazolidine-4-ones were prepared from the corresponding aromatic amines (1a-e) and di-(carboxymethyl)-trithiocarbonyl (2). The aldehydes (6a-h) were synthesized from the corresponding acid chlorides (5a-d) using HSnBu₃.     

Synthesis and photochromic behaviour of new methyl induced linear and angular thieno-2H-chromenes

New methyl induced linear and angular thieno-2H-chromenes 4, 5 and 6 were prepared by reaction of new methylated 6-hydroxybenzo[b]thiophenes 2 (a, b and c) and propargylic alcohols 3a and 3b, using acidic Alumina Brockmann I as catalyst and drying agent. Compounds 2 were prepared in good to excellent yields in a ‘one pot’ three step reaction from the corresponding bromo compounds 1. The photochromic behaviour of compounds 4, 5 and 6b was evaluated with the aid of a classical set of spectrokinetic parameters, and compared to reference compounds that are benzoannellated in the 5,6 and 6,7 positions of the chromene (naphthopyrans) and also to thieno-2H-chromenes 7 and 8, previously prepared, which are analogues of 5a. The resistance to fatigue (photodegradation) under continuous irradiation was also evaluated.     

Reactions of 4-substituted 5H-1,2,3-dithiazoles with primary and secondary amines: fast and convenient synthesis of 1,2,5-thiadiazoles, 2-iminothioacetamides and 2-oxoacetamides

The treatment of 5H-1,2,3-dithiazole-5-thiones 1 in chloroform under reflux and 5H-1,2,3-dithiazol-5-ones 2 in THF at room temperature with primary aliphatic amines and benzylamine afforded 1,2,5-thiadiazole-3(2H)-thiones 3 and 1,2,5-thiadiazol-3(2H)-ones 6, respectively. The structure of dithiazolone 3f was confirmed by X-ray diffraction analysis. The reaction of dithiazolone 2e bearing an electron-donating methyl group in the 4-position gave 2-oxoacetamide 7e in high yield. The reaction of thiones 1 with secondary aliphatic amines in DMSO yielded 2-iminothioacetamides 8 in moderate yields together with elemental sulfur. Interestingly, the treatment of dithiazolones 2 with secondary amines under the same conditions afforded 2-oxoacetamides 9—the products of the hydrolysis of corresponding imino derivatives 10, which was isolated as 10b. A general mechanism was proposed for the formation of the products.     

A novel method for (Z)-stereoselective preparation of CF3-substituted enediynes and their coupling reactions

Trifluoromethylated enynyl sulfones 3 were reacted with 2-4 equiv of phenyl, n-hexyl, trimethylsilyl, or triisopropylsilyl substituted ethynyllithium reagents in THF or ether at 0 °C to give trifluoromethylated enediynes 6 (Z)-stereoselectively in 41-96% yields. The reactions of β-fluoro-β-trifluoromethylvinyl sulfone 5 with same ethynyllithium reagents (4 equiv) afforded the corresponding enediynes 6 in 41-90% yields. The cross-coupling reactions of 6 bearing TMS group with aryl iodides in the presence of Pd(PPh₃)₂Cl₂, Ag₂CO₃, and n-Bu₄NBr provided the corresponding enediynes 6 in 20-71% yields. Dimerization of (Z)-6 bearing TMS group in the presence of CuBr₂ and K₂CO₃ yielded dimer (Z,Z)-7 in good yield.     

Introducing difluoromethylene sulfonamide group via nucleophilic addition of difluoromethylene anion with aromatic aldehydes

A new fluorine-containing synthon, R¹COCF₂SO₂R² (2, R¹, R²=morpholino, piperidino, etc.), was developed for the introduction of difluoromethylene sulfonamide or difluoromethylene group. Under different conditions, 2 reacted readily with aromatic aldehydes to give the corresponding difluoromethylene-containing alcohols or diols in moderate to good yields in the presence of potassium tert-butoxide. Difluoromethylene sulfonamide group was introduced into organic compounds directly for the first time by this method.     

Novel and efficient approach to (Z)-4-trifluoroethylidene-1,3-dioxolane derivatives via (trifluoromethyl)ethynylation of ketones and aldehydes

Perfluoroalkylated 4-trifluoroethylidene-1,3-dioxolanes 2a-p were prepared in quantitative yields from the reaction of new stable (trifluoromethyl)ethynylation reagent 1a with TBAF at −15 °C for 10 min, followed by treatment with phenyl perfluoroalkylated ketones at room temperature. The use of aldehydes under the same reaction condition afforded 1,3-dioxolanes 2q-r in good yields. The reaction of 1a with TBAF, followed by treatment with aldehydes or ketones at −15 °C for 10 min and then with trifluoroacetophenone at room temperature provided 1,3-dioxolane derivatives 2s-t in good yields. Tetrabutylammonium trifluoropropynylide [II] was treated with benzaldehyde derivatives at −15 °C for 10 min, followed by treatment with trifluoroacetophenone, to give the corresponding 1,3-dioxolanes 2u-z and 1,3-dioxines 3u-z with different reaction condition.     

Development of a Double Allylboration Reagent Targeting 1,5-syn-(E)-Diols: Application to the Synthesis of the C(23)-C(40) Fragment of Tetrafibricin

Interest in the synthesis of the C(23)-C(40) fragment 2 of tetrafibricin prompted us to develop a new method for the synthesis of 1,5-syn-(E)-diols. Toward this end, the kinetically controlled hydroboration of allenes 6, 33, ent-39, 42, and 45 with the Soderquist borane 25R were studied. Tetrabutylammonium allenyltrifluoroborate 45 gave superior results and was utilized in a double allylboration sequence with two different aldehydes to provide the targeted 1,5-syn-(E)-diols in generally high yields (72-98%), and with high enantioselectivity (>95% ee), diastereoselectivity (dr >20:1), and (E)/(Z) selectivity (>20:1). This new method was applied to the synthesis of the C(23)-C(40) fragment 2 of tetrafibricin.     

Synthesis of indenes by ytterbium-catalyzed carboalkoxylation/Friedel-Crafts reaction of arylidenecyclopropanes with acetals

Ytterbium-catalyzed tandem carboalkoxylation/Friedel-Crafts reaction of arylidenecyclopropanes 1 with acetals 2 afforded the corresponding indene derivatives 3 in good to high yields. For example, in the presence of 10 mol % of Yb(OTf)₃ the reaction of 1-phenylbenzylidenecyclopropane 1a with the dimethyl acetals of benzaldehyde 2a, p-tolualdehyde 2b, and p-anisaldehyde 2c gave 1,3-diphenyl-2-(2-methoxyethyl)indene 3a, 2-(2-methoxyethyl)-3-phenyl-1-(p-tolyl)indene 3b, and 1-(p-anisyl)-2-(2-methoxyethyl)-3-phenylindene 3c in 82%, 80%, and 80% yields, respectively.     

Wittig reaction with ion-supported Ph3P

Ion-supported Ph₃P, 4-(diphenylphosphino)benzyltrimethylammonium bromide A and N-methyl-N-[4-(diphenylphosphino)benzyl]pyrrolidinium bromide B, were used for the Wittig reaction. Ion-supported phosphonium salts A1 and B1, which were prepared from the reactions of ion-supported Ph₃P A and B with ethyl bromoacetate, respectively, reacted with aromatic and aliphatic aldehydes in the presence of K₂CO₃ to give the corresponding α,β-unsaturated ethyl esters in good yields with high purity by simple filtration of the reaction mixture and subsequent removal of the solvent from the filtrate. Similarly, ion-supported phosphonium salts A2 and B2, which were prepared from the reactions of ion-supported Ph₃P A and B with p-methylbenzyl bromide, respectively, reacted with aromatic and aliphatic aldehydes in the presence of NaH to provide the corresponding p-methylstyrene derivatives in good yields with high purity by simple filtration of the reaction mixture and the subsequent removal of the solvent from the filtrate. In both reactions, the co-product, ion-supported Ph₃PO, could be obtained quantitatively by simple filtration, and was converted into the corresponding ion-supported Ph₃P A and B again in high yields using dimethyl sulfate, followed by the reduction with LiAlH₄. Recovered and regenerated ion-supported Ph₃P A and B could be reused for the same Wittig reaction while maintaining good yields of ethyl (E)-3-(4′-chlorophenyl)-2-propenoate and 1-(4′-chlorophenyl)-2-(4″-methylphenyl)ethene with high purity by simple filtration and removal of the solvent from the filtrate.     

Copper-mediated coupling of aminopurines and aminopyrimidines with arylboronic acids

Selective N-arylation of aminopurines and aminopyrimidines 1-3 with arylboronic acids 4-6 was explored using copper(II) acetate and the corresponding N-arylated purine and pyrimidine derivatives 7-15 were obtained in moderate to good yields.     

Solvent-free reactions of fullerenes and N-alkylglycines with and without aldehydes under high-speed vibration milling

The solvent-free reactions of fullerenes and N-alkylglycines with and without aldehydes (RCHO) 2a-e under high-speed vibration milling (HSVM) conditions have been investigated. Fulleropyrrolidines 4a-e (C₆₀(CH₂N(CH₃)CHR), R=H (4a), C₆H₅ (4b), p-NO₂-C₆H₄ (4c), p-CH₃O-C₆H₄ (4d), p-(CH₃)₂N-C₆H₄ (4e)) were obtained in moderate yields from reactions of C₆₀ with aldehydes 2a-e and N-methylglycine (Prato reaction). In all these solvent-free reactions, 4a was found to be formed besides 4b-e, indicating that fullerenes can react with N-substituted glycines in the absence of aldehyde to give fulleropyrrolidines. For this novel reaction, a possible reaction mechanism involving an electron transfer process has been proposed. Intrigued by this observation, the dependence of the yield on the reagent ratio for the reaction of C₆₀ with paraformaldehyde and/or N-methylglycine was examined to search the optimal conditions. The reaction of C₇₀ with paraformaldehyde and/or N-methylglycine under HSVM conditions was also studied and was found to give the positional isomers of [70]fulleropyrrolidines.     

Preparation of new pyrido[3,4-b]thienopyrroles and pyrido[4,3-e]thienopyridazines

Two new types of pyrido-fused tris-heterocycles (1a,b and 2a,b) have been prepared from 3-aminopyridine in five/six steps. A synthetic strategy for the preparation of the novel pyrido[3,4-b]thieno[2,3- and 3,2-d]pyrroles (1a,b) and pyrido[4,3-e]thieno[2,3- and 3,2-c]pyridazines (2a,b) has been studied. The Suzuki cross coupling of the appropriate 2- and 3-thienoboronic acids (3,4) and 4-bromo-3-pyridylpivaloylamide (9) afforded the biaryl coupling products (10,11) in high yields (85%). Diazotization of the hydrolysed (2-thienyl)-coupling product (12) and azide substitution gave the 3-azido-4-(2-thienyl)pyridine intermediate (72%, 14). 3-Azido-4-(3-thienyl)pyridine (15) was prepared by exchanging the previous order of reactions. The desired β-carboline thiophene analogues (1a,b) were obtained via the nitrene by thermal decomposition of the azido precursors (14,15). By optimising conditions for intramolecular diazocoupling, the corresponding pyridazine products (72-83%, 2a,b) were afforded.