Lewis acid mediated nucleophilic ring opening followed by cycloaddition of 2-aryl-N-tosylaziridines with carbonyl compounds: further support towards an SN2-type mechanism

A highly regioselective S_N2-type ring opening of 2-aryl-N-tosylaziridines with carbonyl compounds in the presence of a Lewis acid to afford various 1,3-oxazolidines and 1,2-amino alcohols in excellent yields and moderate to high enantioselectivity is described. The formation of non-racemic products provides convincing evidence for the S_N2-type ring opening mechanism.     

An efficient synthetic route to substituted tetrahydropyrimidines by Cu(OTf)2-mediated nucleophilic ring-opening followed by the [4+2] cycloaddition of N-tosylazetidines with nitriles

A highly efficient strategy for Cu(OTf)₂-mediated S_N2 type nucleophilic ring-opening followed by the [4+2] cycloaddition reactions of a number of 2-aryl-N-tosylazetidines with nitriles to afford a variety of substituted tetrahydropyrimidines in excellent yields is reported. The resulting tetrahydropyrimidines could easily be transformed into synthetically important 1,3-diamines by acid-catalyzed hydrolysis. The strategy has been extended to the synthesis of enantiomerically pure tetrahydropyrimidines from enantiopure disubstituted azetidines. The reaction proceeds through an S_N2 type mechanism as proposed by us earlier.     

Stereoselective synthesis of anti-2-oxazolidinones by Ph3P-CCl4-Et3N mediated SN2 cyclization of N-Boc-β-amino alcohols

Ethyl anti-4-substituted phenyl-2-oxo-1,3-oxazolidine-5-carboxylates were synthesized stereoselectively in excellent yields using the Ph₃P-CCl₄-Et₃N system by S_N2 cyclization of N-Boc-β-amino alcohols. syn to anti conversion of ethyl 4-substituted phenyl-2-oxo-1,3-oxazolidine-5-carboxylates using DBU as base is also described.     

The first iodine improved 1,3-dipolar cycloaddition: facile and novel synthesis of 2-substituted benzo[f]isoindole-4,9-diones

The first novel protocol of the synthesis of 2-substituted benzo[f]isoindole-4,9-dione framework via the one-pot, 1,3-dipolar cycloaddition of quinones, paraformaldehyde and N-substituted amino ester hydrochlorides in the present of iodine at refluxing acetonitrile was reported. All these reactions proceed with good to excellent yields. The promising results obtained 1,3-dipolar cycloaddition will have the potential application in natural product exhibiting important biological activities.     

Synthesis of novel 2-perfluoroacylcyclohexane-1,3-diones

A one-pot synthesis of 2-perfluoroalkanoylcyclohexane-1,3-diones via C-acylation of cyclohexane-1,3-diones with N-perfluoroacylimidazole as an acylating agent is reported. A reaction was examined with isolated N-trifluoroacetylimidazole and with N-perfluoroacylimidazoles generated in situ from perfluorocarboxylic acid anhydrides or perfluorocarboxylic acids.     

Regio- and stereoselective reactions of a rhodanine derivative with optically active 2-methyl- and 2-phenyloxirane

The reaction of a rhodanine derivative (=(Z)-5-benzylidene-3-phenyl-2-thioxo-1,3-thiazolidin-4-one; 1) with (S)-2-methyloxirane (2) in the presence of SiO₂ in dry CH₂Cl₂ for 10 days led to two diastereoisomeric spirocyclic 1,3-oxathiolanes 3 and 4 with the Me group at C(2) (Scheme 2). The analogous reaction of 1 with (R)-2-phenyloxirane (5) afforded also two diastereoisomeric spirocyclic 1,3-oxathiolanes 6 and 7 bearing the Ph group at C(3) (Scheme 3). The structures of 3, 4, 6, and 7 were confirmed by X-ray crystallography (Figs. 1 and 2). These results show that oxiranes react selectively with the thiocarbonyl group (CS) in 1. Furthermore, the nucleophilic attack of the thiocarbonyl S-atom at the SiO₂-activated oxirane ring proceeds with high regio- and stereoselectivity via an S_N2-type mechanism.     

A one-pot synthesis and 1,3-dipolar cycloaddition of [1,2]dithiolo[4,3-b]indole-3(4H)-thiones

Treatment of N-substituted 2-methyl-1H-indoles 1 with S₂Cl₂ and DABCO in chloroform gave the corresponding [1,2]dithiolo[4,3-b]indole-3(4H)-thiones 5 by the addition of triethylamine in high yield. 1,2-Dithiole-3-thiones 5 underwent cycloaddition with one or two DMAD equivalents to afford either 2-(3-thioxo-1,3-dihydro-2H-indol-2-ylidene)-1,3-dithioles 10 or fused 4,5-dihydrothiopyrano[3,2-b]indoles 9.     

Nickel-catalyzed organozinc-induced unexpected 1,3-migration of tert-butyl from sulfur to carbon in N-tert-butanesulfinyl iminoacetates

The nickel-catalyzed reaction for an unexpected 1,3-migration of tert-butyl from sulfur to carbon, upon treatment of functionalized N-tert-butanesulfinyl iminoacetate in the presence of organozinc reagent, was developed. The generality has been explored by considering the flexibility in the structure of each reactive component, organozinc halide and N-tert-butanesulfinyl iminoacetate.     

Rational use of substituted N-allyl and N,N-diallylanilines in the stereoselective synthesis of novel 2-alkenyltetrahydro-1-benzazepines

Two new series of 1,4-epoxy-2-exo-vinyl(isopropenyl)tetrahydro-1-benzazepines and cis-2-vinyl(isopropenyl)-4-hydroxytetrahydro-1-benzazepines were prepared by an efficient three/four-step route from available substituted N,N-diallylanilines and mono N-allylanilines. The amino-Claisen rearrangement and the sequential oxidation/intramolecular 1,3-dipolar cycloaddition reactions were used as the key steps in this synthesis. All the synthesized compounds were fully characterized by IR, GC-MS and NMR techniques.     

Efficient three-component reactions of α-thiocyanato ketones stereoselectively forming E-3-aroylidene-2-oxindole derivatives

A new three-component reaction of α-thiocyanato ketones under microwave irradiation for the stereoselective synthesis of 25 examples of E-3-aroylidene-2-oxindole derivatives has been described. The domino reaction simultaneously installs C–S and C–C bonds through continuous [3+2] cycloaddition/ring opening of in situ generated 1,3-oxathiolanes/S_N2-type reaction sequence.     

Synthesis of 5-aminoisoxazolines from N-allyl compounds and nitrile oxides via tandem isomerization-1,3-dipolar cycloaddition

A new strategy for the synthesis of derivatives of 5-aminoisoxazolines via tandem catalytic isomerization (of N-allyl systems to N-(1-propenyl) systems)—1,3-dipolar cycloaddition (of a stable nitrile oxide to N-(1-propenyl) systems) is presented. Rhodium and ruthenium complexes, Verkade’s superbase, and 18-crown-6/KOH system were used for the syntheses of the N-(1-propenyl) systems. 4-P-substituted isoxazoline was also synthesized via cycloaddition of diphenyl(1-propenyl)phosphine (prepared via isomerization of allyldiphenylphosphine) to 2,6-dichlorobenzonitrile oxide. All cycloadditions were regioselective but not stereoselective and not concerted. Cycloaddition to all N-(1-propenyl) systems yielded 5-N-substituted isoxazolines, but cycloaddition to P-(1-propenyl) system lead to the formation of a 4-P-regioisomer. This difference in regioselectivity is predicted by opposite FMO reactivity indices calculated for model compounds: N-(1-propenyl)amine and N-(1-propenyl)phosphine.     

The stereoselective addition of titanium(IV) enolates of 1,3-oxazolidin-2-one and 1,3-thiazolidine-2-thione to cyclic N-acyliminium ion. The total synthesis of (+)-isoretronecanol

(+)-Isoretronecanol (1) has been prepared in four steps and 36% overall yield via the diastereoselective addition of the titanium(IV) enolate derived from N-4-chlorobutyryl-1,3-thiazolidine-2-thione (3) to N-Boc-2-methoxypyrrolidine (5), which afforded 2-substituted pyrrolidine 7 in 84% yield (8:1 diastereoisomeric ratio), followed by reductive recovery of the chiral auxiliary and cyclization.     

N-Arylation of 4-fluoro-5-trimethylsilyl-1H-pyrazole

The 1,3-dipolar cycloaddition reaction of fluoro(trimethylsilyl)acetylene prepared in situ with an excess of diazomethane smoothly proceeded to give the corresponding 4-fluoro-5-trimethylsilyl-1H-pyrazole in 84% yield. The copper iodide-catalyzed N-arylation of the fluorinated pyrazole with a variety of aryl iodides afforded N-aryl-4-fluoropyrazoles as desilylation products in good to excellent yields.     

Stereoselective radical cyclizations of N-(2-halobenzoyl)-cyclic ketene-N,X(X=O, S)-acetals

2-Alkyloxazolines and 2-alkylthiazolines react with 2-halobenzoyl chlorides to form N-(2-halobenzoyl)-cyclic ketene-N,O-acetals and N-(2-halobenzoyl)-cyclic ketene-N,S-acetals in excellent yields, respectively. These ketene acetals readily undergo stereocontrolled aryl radical cyclizations to afford the central six-membered rings of substituted-2,3,10,10α-tetrahydrooxazolo[3,2-b]isoquinolin-5-ones and their 2,3,10,10α-tetrahydrothiazolo[3,2-b]isoquinolin-5-one analogs. The tertiary N,O- and N,S-radicals formed upon aryl radical reaction at the ketene-N,X(X=O, S)-acetal double bond appear to have reasonable stability. The stereoselectivity in hydrogen abstractions by these intermediate radicals from both Bu₃SnH and (Me₃Si)₃SiH was investigated. The N,S-heterocyclic fused ring products may have potential medical value.     

Palladium-catalyzed cross-coupling of cyclopropylmethyl N-tosylhydrazones with aromatic bromides: an easy access to multisubstituted 1,3-butadienes

Direct synthesis of 1,1-disubstitued 1,3-butadienes has been efficiently realized from the cross-coupling of cyclopropylmethyl N-tosylhydrazones with aromatic bromides by means of PdCl₂(MeCN)₂ as catalyst. 1,1,4-Trisubstitued 1,3-butadiene derivatives were obtained in up to 70% yields through a one-pot procedure catalyzed by Pd(OAc)₂ in the presence of excessive amount of aromatic bromides. The present methodology provides an easy and efficient route to multisubstituted 1,3-butadienes.     

A novel one-pot synthesis of hydroximoyl chlorides and 2-isoxazolines using N-tert-butyl-N-chlorocyanamide

Treatment of aldoximes with N-tert-butyl-N-chlorocyanamide gave hydroximoyl chlorides in quantitative yields in less than a minute, which on dehydrohalogenation in the presence of triethylamine gave the corresponding nitrile oxides. The nitrile oxides underwent 1,3-dipolar addition to dipolarophiles and gave 2-isoxazolines in excellent yields under mild conditions.     

Highly diastereoselective 1,3-dipolar cycloaddition of nonstabilized azomethine ylides to 3-nitro-2-trihalomethyl-2H-chromenes: synthesis of 1-benzopyrano[3,4-c]pyrrolidines

Reactions of 3-nitro-2-trifluoro(trichloro)methyl-2H-chromenes, including 2-unsubstituted derivatives, with N-alkyl-α-amino acids (sarcosine, proline) and paraformaldehyde proceed diastereoselectively to give 1-benzopyrano[3,4-c]pyrrolidines in good yields as a result of a 1,3-dipolar cycloaddition of the intermediate nonstabilized azomethine ylide at the Δ³-bond of the chromene system.     

A convenient synthetic route to 2-aryl-N-tosylazetidines and their ZnX2 (X = I, OTf) mediated regioselective nucleophilic ring opening reactions: synthesis of γ-iodoamines and tetrahydropyrimidines

A general and convenient synthetic route to various 2-aryl-N-tosylazetidines has been described. Their ZnX₂ (X = I, OTf) mediated nucleophilic ring opening with halides and [4+2] cycloaddition reactions with various nitriles have been achieved to afford γ-iodoamines and substituted tetrahydropyrimidines, respectively, in good to excellent yields. A mechanism for the cycloaddition reaction is proposed.     

Heteroaromatic annulation studies on 2-[bis(methylthio)methylene]-1,3-indanedione: efficient routes to indenofused heterocycles

2-[Bis(methylthio)methylene]-1,3-indanedione has been shown to be a useful three carbon 1,3-dielectrophilic synthon for the highly efficient regiospecific synthesis of a variety of indenofused five- and six-membered heterocycles via heteroaromatic annulation. The methodology has been further elaborated to the corresponding N,S-acetals leading to amino substituted heterocycles, thus providing further point of diversity in the newly synthesized heterocyclic frameworks. Further, the facile access to cytotoxic indeno[2,1-c]quinolin-7-ones and the novel polycyclic heteroaromatics demonstrates the versatility of heteroaromatic annulation protocol via α-oxoketene-S,S-acetal in generating novel biologically important polycyclic heteroaromatics.     

Unexpected course of rearrangement of substituted S-(1(3H)-isobenzofuranone-3-yl)isothiuronium bromides

Three series of S-(1(3H)-isobenzofuranone-3-yl)isothiuronium bromides differing in substitution at the isothiuronium moiety (none, one or two methyl groups) and at the benzene ring were prepared and characterized. These salts were then treated with various bases (acetate, triethylamine, Na₂CO₃) to give either 1-hydroxy-3-oxo-1,3-dihydro-2H-isoindol-2-carbothioamides or the product of S to N isobenzofuranone-3-yl migration, i.e., 1,3-dimethyl-1-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)thioureas. If ammonia was used in reaction with N,N′-dimethyl isothiuronium salts then 3-hydroxy-2,3-dihydro-1H-isoindol-1-ones were formed together with 1,3-dimethyl-1-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)thioureas in parallel reaction with the yields increasing with ammonia concentration. The formation of isoindolones takes place in two steps with an aldehyde intermediate, which can be trapped with N,N-dimethylhydrazine.