A novel one-pot procedure for the synthesis of stable dioxadiazastannepines and dioxadiazasilepines

A novel synthetic approach to seven-membered silicon- and tin-containing heterocycles has been developed. 5,6-Diaryl-1,3,4,7,2-dioxadiazastannepines 3a-l and 5,6-diaryl-1,3,4,7,2-dioxadiazasilepines 4a-l were prepared in one pot from vicinal dioximes 1a-d and diorganodichlorostannanes and diorganodichlorosilanes via dianion intermediate 2 in good yields.     

A Pd[0]-catalyzed Ullmann cross-coupling/reductive cyclization approach to C-3 mono-alkylated oxindoles and related compounds

The Pd[0]-catalyzed Ullmann cross-coupling of o-nitrohaloarenes 1a-e with the brominated heterocycles 2a-f delivers the expected products 3a-j in good to excellent yields. The reductive cyclization of such products, as well as N-acyl derivatives 3k, l, and m, has been investigated and provided the C-3 mono-substituted oxindoles 5a-d, f, g, k, and m, the direct reduction products 4i and j or indole 5l.     

Microwave-induced one-pot synthesis of 4-[3-(aryl)-1,2,4-oxadiazol-5-yl]-butan-2-ones under solvent free conditions

The synthesis of 4-[3-(aryl)-1,2,4-oxadiazol-5-yl]-butan-2-ones (5a-l) from methyl levulinate (4) and arylamidoximes (1a-l) is described. The reaction was carried out in a microwave oven without any solvent in much shorter time and in yields comparable with conventional heating.     

Benzotriazole-mediated alkoxyalkylation and acyloxyalkylation

Reactions of readily available and stable 1-(α-alkoxyalkyl)benzotriazoles type 9a,b and 10a-d with a variety of silyl enol ethers 11 or 1,3-dicarbonyl compounds 13 give the expected ketones 12a-l (60-92%), β-keto esters 14a,b (62-67%), and malonates 14c,d (79-88%) in which a tetrahydrofuran or tetrahydropyran moiety has been introduced at the α position. 1-(Benzotriazol-1-yl)alkyl esters 7 are converted by cyanide anion into cyanohydrin esters 15a-i (55-98%).     

A simple synthesis of 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles

A simple four-step synthesis of 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles 8 (or their 1H-pyrazol-3(2H)-one tautomers 8′) as the pyrazole analogues of histamine was developed. First, enamino lactam 3 was prepared as the key intermediate in two steps from 2-pyrrolidinone (1). Next, acid-catalysed ‘ring switching’ transformations of 3 with monosubstituted hydrazines 4 gave N-[(1-substituted 5-hydroxy-1H-pyrazol-4-yl)ethyl]benzamides 7a-k and N-[2-(2-heteroaryl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)ethyl]benzamides 7′l-o. Benzamides 7a-k and 7′l-o were finally hydrolysed by heating in 6 M hydrochloric acid to furnish 1-substituted 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles 8a-k and 4-(2-aminoethyl)-2-heteroaryl-1H-pyrazol-3(2H)-ones 8′l-o in good overall yields.     

Facile generation method for conjugated allenyl esters based on retro-Dieckmann-type ring-opening reactions

α-Alkynyl-α-ethoxycarbonyl cyclopentanones 1a-c and cyclohexanones 2a-c were readily synthesized by the reaction of ethyl 2-oxocyclopentanonecarboxylate 6 and ethyl 2-oxocyclohexanonecarboxylate 7 with alkynyllead triacetates 5a-c obtained from lithium acetylides 4a-c and lead tetraacetate. Treatment of 1a-c and 2a-c with 1 N KOH in THF or with n-Bu₄N⁺OEt⁻ in EtOH and THF gave the corresponding conjugated allenyl esters 8a-c, 9a-c, 10a-c, and 11a-c in good to excellent yields, respectively.     

Stereoselective tandem synthesis of oxazolo-fused pyrroloquinolines from o-alkynylaldehydes via Ag(I)-catalyzed regioselective 5-exo-dig ring closure

A tandem approach for the regio- and stereoselective synthesis of oxazolo-fused pyrroloquinolines 3a–l via the reaction of o-alkynylaldehydes 1a–i with chiral amino alcohols 2a–c under mild reaction conditions is described. The possible participation of the pyridine ring in the regioselective formation of 5-exo-dig cyclized products was supported by the controlled experiments. The structures and stereochemistry of the products were confirmed by NOESY and X-ray crystallographic studies.     

Synthesis of N,N-di(arylmethylidene)arylmethanediamines by flash vacuum pyrolysis of arylmethylazides

Flash vacuum pyrolysis of arylmethylazides 7a-d gave 2,4-diazapentadienes 5a-d in high yield (76-92%). The thermal cyclization of 5a-d gave cis-imidazolines 1a-d, further heating or Swern oxidation of 1a-d gave dehydrogenated products, imidazoles 2a-d.     

Asymmetric synthesis of 3-substituted unsaturated prolines from chiral sulfoximine substituted allyl titanium(IV) complexes

An asymmetric synthesis of the 3-substituted Δ^3,4-unsaturated prolines 7a-e and 3-substituted 4-methylene prolines 14a-c starting from the corresponding γ,δ-unsaturated α-amino acids 4a-e and 11a-c, respectively, is described. Amino acid derivatives 4a-e and 11a-d were obtained through aminoalkylation of the corresponding sulfoximine substituted allyl titanium(IV) complexes 2a-e and 10a-d, respectively, with the N-tert-butylsulfonyl imino ester 3. Activation of sulfoximines 4a-e and 11a-c through methylation of the sulfoximine group followed by a KF mediated isomerization of the vinyl aminosulfoxonium salts 5a-e and 12a-c, respectively, to the corresponding allyl aminosulfoxonium salt 6a-e and 13a-c, respectively, and a subsequent intramolecular nucleophilic substitution of the allylic aminosulfoxonium group afforded the enantio- and diastereomerically pure proline derivatives in medium to high yields.     

An efficient substituent dependent synthesis of congested pyridines and pyrimidines

An efficient and versatile synthesis of various congested pyridines 3a-h, 6a,b, 8a-n, 10a-g, and 16a,b, and (pyrimidin-4-yl)acetonitriles 13a-g has been delineated by base catalyzed ring transformation of suitably functionalized 2H-pyran-2-ones 1a-h, 5, 7, and 15 by formamidine acetate 2a, acetamidine hydrochloride 2b, S-methylisothiourea 9a, pyrazol-1-yl-carboxamidine 9b, and arylamidine hydrochloride 12 separately in the presence of powdered KOH in dry DMF.     

Synthesis and characterization of boronates derived from non-symmetric amino-bis-phenols

The condensation of 2-[[(2-hydroxyphenyl)amino]methyl]-phenols (1a-1e) with different arylboronic acids led to 12 new monomeric boronates of the type 2-aryl-dibenzo[d,h]-6-aza-1,3-dioxa-2-boracyclononene (2a-2l). The boronates were characterized by ¹H-, ¹³C-, ¹¹B- and 2D-NMR experiments, FT infrared, mass spectra and elemental analyses. The stereochemistry of the H-N → B-Ph fusion is always cis, as established through the NMR spectra, as well as the X-ray structures of four boronates (2a, 2e, 2f and 2l). Hydrogen bonds between the amine proton and the oxygen ester of the five- membered ring are present in three X-ray structures (2a, 2e and 2f), while the supramolecular structure in the derivative possessing a primary amine (2l) is built up through the protons present in this moiety instead of the proton from the H-N → B-Ph fragment.     

Columnar/smectic metallomesogens derived from heterocyclic benzoxazoles

The synthesis, mesomorphic behavior, and optical properties of two new series of metal complexes 1a,b-M (M=Pd, Cu, Zn) derived from benzoxazoles 2a,b are reported. The crystal and molecular structures of mesogenic 5-decyloxy-2-(6-decyloxybenzooxazol-2-yl)phenol and nonmesogenic bis[5-octyloxy-2-(6-octyloxybenzooxazol-2-yl) phenol]Pd(II) were determined by means of X-ray structural analysis. Two benzoxazoles 2a exhibited monotropic SmA phases, and all benzoxazoles 2b were nonmesogenic. On the other hand, metal complexes 1a-M exhibited distinctly different mesomorphism from complexes 1b-M. Complexes 1a-Pd formed SmC phases; complexes 1a-Cu and 1a-Zn formed crystal phases. In contrast, complexes 1b-Zn exhibited columnar phases, and complexes 1b-Cu and 1b-Pd were nonmesogenic. The difference of the mesomorphism in 1a-M and 1b-M was probably attributed to the geometry and/or the overall molecular shape created by 2a and 2b. The electronic configuration of metal ion might play an important role in forming the mesophases. The fluorescent properties of these compounds were also examined.     

Efficient synthesis of cephalotaxine- and deoxyharringtonine analogues by a trimethylaluminium-mediated domino reaction

The synthesis of cephalotaxine- and cephalotaxine amide analogues 14a-c and 16a-c as well as of the deoxyharringtonine analogues 5a,b was performed employing a trimethylaluminium-mediated domino reaction of 9a-c and 8 to give the spirocyclic compounds 7a-c, which was followed by a palladium catalyzed α-arylation.     

Regioselective synthesis of novel 4-aryl-2-ethylthio-7-methyl pyrazolo[1,5-a]-[1,3,5]-triazines

Pyrazolo[1,5-a]-[1,3,5]-triazines 6a-d were obtained by an efficient one-step reaction from S,S-diethyl aroyliminodithiocarbonates 4a-d and 5-amino-3-methylpyrazole 5 or by an alternative two-step reaction from 5 and aroyl isothiocyanates 8a-d to give initially the thiourea derivatives 9a-d, which after S-ethylation and cyclization afforded compounds 6a-d. The intermediate 7a isolated from reaction between 4a and 5 permitted us to establish the orientation.     

Synthesis of novel lariat azathia crown macrocycles containing two triazole rings and bis crown macrocycles containing four triazole rings

The 13-hydroxy macrocycles 7a-d were prepared in 40-50% yields by the condensation of 1,ω-bis(4-amino-1,2,4-triazol-3-ylsulfany)alkanes 2a-d with 1,3-bis(2-formyphenoxy)-2-propanol (9). Acylation of 7a-d with 2-chloroacetylchloride gave the corresponding esters 11a,b. Amination of 11a,b with different amines in acetone furnished exclusively the target lariat macrocycles 12a,b and 13 in 60-70% yields. Reaction of 2 equiv. of the macrocycles 11a,b with 1 equiv. of piperazine afforded the novel bis macrocyles 14a,b in 50-60% yields. Reduction of 7a-d with NaBH₄ afforded the corresponding 13-hydroxyazathia crown ethers 15a-d in 65-70% yields.     

Synthesis of a new class of azathia crown macrocycles containing two 1,2,4-triazole or two 1,3,4-thiadiazole rings as subunits

A series of new 1,2/1,3-bis[o-(N-methylidenamino-5-aryl-3-thiol-4H-1,2,4-triazole-4-yl)phenoxy]alkane derivatives 3a-d and bis[o-(N-methylidenamino-2-thiol-1,3,4-thiadiazole-5-yl)phenoxy]alkanes 6a-c were prepared by condensation of 4-amino-5-(aroyl)-4H-1,2,4-triazole-3-thiols 2a-b or 2-amino-5-mercapto-1,3,4-thiadiazole with bis-aldehydes 1a-c. Further reaction of compounds 3a-d and 6a-c with dibromoalkanes afforded the new macrocycles 5a-f and 8a-d. The cyclization does not require high dilution techniques and provides the expected azathia macrocycles in good yields, ranging from 55% to 68%.     

Synthesis of poly-substituted pyrroles starting from the Baylis-Hillman adducts

We synthesized poly-substituted pyrrole derivatives 4a-e, 7a-c and 10a-d from the reaction of phenacyl bromide and the aza-Baylis-Hillman adducts 1a-d or their rearranged derivatives 5a-e. The pyrroles were synthesized via the successive N-alkylation, Michael addition, elimination of p-toluenesulfinic acid and oxidative aromatization processes.     

New synthesis of 2-trifluoromethyl-2,3-dihydro-1H-quinolin-4-ones

N-(1-Ethoxy-2,2,2-trifluoroethyl)anilines 2a-2f, prepared from trifluoroacetaldehyde ethyl hemiacetal and aniline, readily reacted with diethyl malonate in the presence of sodium hydride, giving substituted products 5a-5f in high yields. Compounds 5a-5f subjected to hydrolysis and decarboxylation under specified conditions yielded the 4,4,4-trifluorobutyric acids 6a-6e or 7. Direct ring-closure of 6a-6e with polyphosphoric acid gave 2-trifluoromethyl-2,3-dihydro-1H-quinolin-4-ones 9a-9e.     

Catalyst- and steric-controlled alkenylation via chemoselective C-H activation and C-Br activation in Heck reaction of methyl 1-(2-bromoaryl)-3-(2-furyl/thienyl)-5-oxopyrrolidine-2-carboxylates and diethyl 1-(2-bromoaryl)-3-(2-furyl/thienyl)-5-oxopyrrolidine-2,2-dicarboxylate derivatives

Pd(II)-catalyzed alkenylation of methyl 1-(2-bromoaryl)-3-(2-furyl/thienyl)-5-oxopyrrolidine-2-carboxylate derivatives 1(a-d) resulted in the formation of 3(a-d) exclusively via C-H activation in the heteroaryl moiety. Similar observations were observed for the corresponding diester analogues 4(a-d) to form 5(a-d). Normal Heck reaction, however, was observed in the case of 1(a-f) to furnish 2(a-f) when the reaction was carried out with Pd(0) catalyst generated in situ. Pd(0)-catalyzed vinylation of 4(a-f) via C-Br oxidation, however, failed due to steric reason.     

Synthesis and transformations of sulfur-substituted indolizidines and quinolizidines

3-Sulfolenes 1a-b underwent [4+2] cycloaddition reactions with p-toluenesulfonyl isocyanate to give tetrahydropyridinones 3a-b. Through N-detosylation of 3a-b and subsequent intramolecular cyclization, indolizidine 5a and quinolizidine 5b were synthesized. Useful functional group transformations of compounds 5a-b were also investigated.