New efficient synthesis of 1H-imidazo-[4,5-c]quinolines by a sequential Van Leusen/Staudinger/aza-Wittig/carbodiimide-mediated cyclization

A new efficient synthesis of multisubstituted 1H-imidazo-[4,5-c]quinoline derivatives via sequential van Leusen/Staudinger/aza-Wittig/carbodiimide-mediated cyclization was developed. Azides 4, obtained from Van Leusen reaction of 2-azidobenzaldehyde 1, amine 2 and TosMIC (tosylmethyl isocyanide) 3, reacted with triphenyl phosphine to produce iminophosphorane 5. A tandem aza-Wittig reaction of iminophosphorane 5 with isocyanate generated 1H-imidazo-[4,5-c]quinoline 7 through carbodiimide intermediate 6 in moderate to good yield.     

Lewis acid-catalyzed Friedel-Crafts/Michael cascade reaction of N,N-dialkyl-3-vinylanilines with N-tosylaziridines for the stereoselective synthesis of highly functionalized tetrahydroisoquinolines

A Lewis acid-catalyzed Friedel-Crafts/Michael cascade reaction between N-dialkyl-3-vinylanilines and N-tosylaziridines has been developed for the stereoselective synthesis of tetrahydroisoquinolines (THIQs). The reaction using Gd(OTf)₃ as the Lewis acid catalyst was tolerant to the various N-dialkyl-3-vinylaniline and N-tosylaziridine substrates and provided access to 28 new, highly functionalized THIQs in typically high yields with moderate- to- excellent diastereoselectivities.     

A simple and one-pot synthesis of 2,3,4,5-tetrasubstituted 4,5-dihydro-3H-1,4-benzodiazepines

2,3,4,5-Tetrasubstituted 4,5-dihydro-3H-1,4-benzodiazepines were synthesized in one-pot by a new sequential Ugi 4CC/Staudinger/aza-Wittig reaction, starting from easily accessible o-azidobenzaldehyde, α-amino ketone hydrochloride, isocyanide and carboxylic acid.     

First example of the cascade acylation/IMDAV/ene reaction sequence,leading to N-arylbenzo[f]isoindole-4-carboxylic acids possessing anti-viral activity

The reaction between readily accessible N-aryl-3-phenylallylamines and maleic anhydride led to unexpected products – polysubstituted hydrogenated benzo[f]isoindole-4-carboxylic acids. This transformation proceeds through a previously unknown sequence of steps: N-acylation of the allylamine with maleic anhydride, intramolecular Diels-Alder reaction of the vinylarene in the intermediate N-maleamide, and Alder-ene reaction of the products of the previous two steps. Selected benzo[f]isoindoles displayed antiviral activity.     

Domino pericyclic reactions of acyclic conjugated (E,Z,E,E)-tetraenes

Acyclic conjugated (E,Z,E,E)-tetraenes, upon thermolysis, undergo a domino pericyclic process involving 6π electrocyclisation of the (E,Z,E)-triene moiety to give the corresponding cis-disubstituted 5-vinyl-1,3-cyclohexadienes, followed by an intramolecular Diels-Alder reaction with the vinyl side chain to give tricyclo[3.2.1.0^2,7]oct-3-enes.     

Competitive thermal ene reaction and Diels-Alder reactions of 2-[N-(alk-2-enyl)benzylamino]-3-vinylpyrido[1,2-a]pyrimidin-4(4H)-ones

Thermal reaction of 2-[N-(alk-2-enyl)benzylamino]-3-(2-substituted and 2,2-disubstituted)vinylpyrido[1,2-a]pyrimidin-4(4H)-ones gave azepine, the desired ene products, and/or pyran derivatives. The formation of the latter was responsible for the [4+2] cycloaddition reaction between the α,β-unsaturated ester carbonyl moiety as a diene part and the alkenylamino moiety as an ene one. The reaction features depended upon the kinds of substituents both on the vinyl and alkenyl counterparts; strongly electron-withdrawing substituents on the vinyl moiety or an electron-donating substituent on the alkenyl one changed the reaction feature from the ene reaction to the hetero Diels-Alder reaction.     

Short diastereoselective synthesis of cis- and trans-hexahydropyrido[2,1-a]isoindole derivatives

A new and highly stereoselective access to 4,10b-trans or 4,10b-cis hexahydropyrido[2,1-a]isoindole derivatives is reported, both requiring an intramolecular Mannich-type reaction as key step. The cis diastereoisomer is obtained in three steps from a 2-alkyl benzaldehyde through the stereoselective formation of a 2,6-cis-disubstituted piperidine, while the trans stereomer is efficiently obtained, in a single step, if a 2-formyl benzoic acid is involved in the Mannich cyclization process.     

A practical access to novel 2-amino-5-arylidene-1,3-thiazol-4(5H)-ones via sulfur/nitrogen displacement under solvent-free microwave irradiation

A new effective approach to the synthesis of a small library of 2-amino-5-arylidene-1,3-thiazol-4(5H)-ones was reported using solvent-free reaction conditions under microwave irradiation. In the first step, rhodanines were subjected to Knoevenagel condensation with aryl aldimines according to a facile one-pot protocol. Then the (5Z)-5-arylidene rhodanine derivatives were transformed directly into the corresponding 2-amino-1,3-thiazol-4(5H)-ones by sulfur/nitrogen displacement reaction under microwaves with retention of configuration and good overall yields.     

Synthesis of C1-symmetric chiral tripodal oxazolines through an oxazoline exchange reaction with amino alcohols

Various C₁-symmetric chiral tripodal tris(oxazolines) with two different oxazoline units were synthesized from chiral C₃-symmetric tris(oxazolines) through an oxazoline exchange reaction with amino alcohols in the presence of zinc chloride. Evaluation of the new oxazolines as chiral molecular receptor showed that some of the receptors have chiral discrimination ability.     

AcOH-catalyzed aza-Michael addition/N-nitrosation: An efficient approach to CF2HCH2-containing N-nitrosoamines

A simple and highly efficient protocol for the AcOH-catalyzed three-component reaction among nitroalkenes, difluoroethylamine and tert-butyl nitrite through cascade aza-Michael addition/N-nitrosation has been developed. A range of CF₂HCH₂-containing N-nitrosoamines were obtained in good to excellent yields. This approach features easily available cheap materials, without using additional organic solvents, simple operation under room temperature, gram scalable preparation and functionally diverse products.     

Efficient synthesis of 6-aryl-4-trifluoromethyl/ethoxycarbonyl-2H-pyran-2-ones through self-condensation of penta-2,4-dienenitriles

An efficient synthesis of two new series of 6-aryl-4-trifluoromethyl-2H-pyran-2-ones and 6-aryl-4-carboxyethyl-2H-pyran-2-ones, obtained through the self-condensation reaction of 5-aryl-5-methoxy-3-(trifluoromethyl)penta-2,4-dienenitriles 3 and ethyl 4-aryl-2-(cyanomethylene)-4-methoxybut-3-enoates 4 respectively, is reported. The self-condensation reaction of the enoates 4 was performed in water in the presence of hydrochloric acid whereas the self-condensation reaction of the penta-2,4-dienenitriles 3 required the use of zinc bromide and hydrochloric acid in order to give the respective 2H-pyran-2-ones. Products were obtained up to 97% yield.     

New synthetic strategy for preparation of the anticoagulant drug Rivaroxaban via an asymmetric Henry reaction

A new synthetic approach towards the anticoagulant drug (S)-Rivaroxaban was described. This reaction sequence involved six steps overall, starting from commercially available and inexpensive N-(4-aminophenyl)morpholin-3-one. The stereogenic centre was introduced by an asymmetric Henry reaction catalysed by the complex of copper(II) acetate and (2R,5S)-2-(pyridine-2-yl)imidazolidine-4-one with 87% ee. The individual reaction steps proceeded with high yields and did not require any unusual or expensive reagents.     

Novel and efficient synthesis of triazolobenzodiazepine analogues through the sequential Ugi 4CR-click-N-arylation reactions

An efficient approach for the synthesis of N-alkyl-2-aryl-2-(6-oxo-4H-benzo[f][1,2,3]triazolo[1,5-a][1,4]diazepin-5(6H)-yl)acetamides is described. The protocol involves Ugi four-component reaction of 2-bromobenzoic acid, propargylamine, aldehydes and isocyanides followed by in situ sequential click reaction of azide ion with triple bond and N-arylation reaction to afford desired products in good to excellent yields.     

Synthesis of 5H-pyridazino[4,5-b]indoles and their benzofurane analogues utilizing an intramolecular Heck-type reaction

The title ring systems were prepared from pyridazin-3(2H)-one precursors in novel, efficient pathways. 2-Methylbenzo[b]furo[2,3-d]pyridazin-1(2H)-one was synthesized via a regioselective nucleophilic substitution reaction of a 2-methyl-4,5-dihalopyridazin-3(2H)-one with phenol followed by an intramolecular Heck-type reaction. The same molecule and its 6-phenyl analogue were also prepared via reaction of 2-methyl-5-iodopyridazin-3(2H)-one or 2-methyl-5-chloro-6-phenylpyridazin-3(2H)-one, respectively, with 2-bromophenol or 2-iodophenol followed by Pd-catalyzed cyclodehydrohalogenation. Moreover, a new approach for the synthesis of 2-methyl-2,5-dihydro-1H-pyridazino[4,5-b]indol-1-ones was also elaborated utilizing a Heck-type ring closure reaction on 5-[(2-bromophenyl)amino]-2-methylpyridazin-3(2H)-ones which were obtained via Buchwald-Hartwig amination of 2-methyl-5-halopyridazin-3(2H)-ones with 2-bromoaniline.     

Synthesis of cis bis-β-lactams via Staudinger cycloaddition reaction using C2-symmetric 1,2-diamines

An efficient stereoselective synthesis of bis-β-lactams via cycloaddition reaction (Staudinger reaction) of ketenes with bisimines derived from C₂-symmetric 1, 2-diamines is described. The reaction provided diastereomeric mixture of meso and C₂-symmetric cis-bis-β-lactams with higher selectivity for meso-bis-β-lactams.     

1,2-Disubstituted cyclohexane nucleosides: comparative study for the synthesis of cis and trans adenosine analogues

A new class of adenosine analogues with 1,2-disubstituted carbocycles (with cis and trans stereochemistry) have been synthesized. Construction of the base on the amino group of (±)-cis-(2-aminocyclohexyl)methanol was more efficient than the Mitsunobu condensation between the purine base and protected (±)-trans-(2-hydroxymethyl)cyclohexanol. The latter strategy gave the final compound with cis stereochemistry in a short number of steps with the overall yield depending on the nature of the protecting group on the hydroxymethyl group of the diol. However, Mitsunobu condensation between a purine base and the protected (±)-cis-(2-hydroxymethyl)cyclohexanol is not an ideal method to obtain trans purine derivatives because the elimination reaction is faster than the substitution reaction.     

N-Allyl-1,3-oxazines via a facile keto-ene/cyclization tandem reaction

The intramolecular keto-ene/cyclization tandem reaction of γ-N-allylamino ketones is an effective means of producing 1,3-oxazines. The reaction usually requires high temperatures and/or pressures. We discovered that N,N-diallyl amines undergo the reaction at lower temperatures than their monoallyl analogs. An extreme example, 1-N,N-diallylamino-9,10-anthraquinone, undergoes the keto-ene reaction near ambient temperature. In the case of 1-N,N′-dialkylaminoanthraquinones, electron deficient ene components can even be used, allowing the preparation of a broad spectrum of oxazines. Furthermore, the N-allyl-1,3-oxazine can be easily deallylated to produce a 1,3-oxazine that contains a secondary amine.     

Hydrophosphonylation of chiral hexahydroquinoxalin-2(1H)-one derivatives as an effective route to new bicyclic compounds: Aminophosphonates,enamines and imines

A series of new aminophosphonate and phosphonic acid derivatives of hexahydroquinoxalin-2(1H)-ones and tetrahydroquinoxalin-2(1H)-ones were synthesised via hydrophosphonylation of the corresponding bicyclic imines with various dialkyl or diaryl H-phosphonates, H-phosphinates or H-phosphine oxides as phosphorus nucleophiles. The utility of the obtained compounds was demonstrated by their application as a source of phosphonate carbanion in the Horner-Wadsworth-Emmons (HWE) reaction leading to new bicyclic amines with an exocyclic, and unexpectedly, also endocyclic double bond depending on the structure of the aldehyde used.     

Stereoselective synthesis of new bicyclic N,O-iso-homonucleoside analogues

The synthesis of two new bicyclic nucleoside analogues is reported. These compounds are iso-homonucleoside and are synthesised through a 1,3-dipolar cycloaddition of an enantiopure cyclic nitrone to protected allyl acohol and subsequent introduction of thymine by a Mitsunobu reaction.     

One-pot synthesis of quinolin-2-(1H)-ones via tandem Ugi-Knoevenagel condensations

A new application of the Ugi reaction in the synthesis of heterocyclic compounds is described. Substituted quinolin-2-(1H)-ones are formed in one-pot sequential Ugi four-component condensation and intramolecular Knoevenagel cyclization between o-acylanilines, aldehydes, malonic or tosylacetic acids and cyclohexyl isocyanide.