Substituent-controlled domino-Knoevenagel-hetero Diels-Alder reaction—a one-pot synthesis of polycyclic heterocycles

The reaction of 2-(N-alkenyl-N-aryl)amino-4-oxo-4H-1-benzopyran-3-carbaldehyde with dimedone/Meldrum’s acid/4-hydroxycoumarin by heating in ethanol in the presence of pyridine produces polycyclic heterocycles bearing pyridine and pyran rings in a one-pot reaction. The effect of substituents on N-atom of the amino function controls the mode of reaction. Terminal alkenes prefer intramolecular Michael type reaction, but non-terminal alkenes favour Diels-Alder reaction, whereas, under similar condition, 2-(N-alkyl-N-allyl)amino-4-oxo-4H-1-benzopyran-3-carbaldehyde undergoes domino-Knoevenagel-hetero Diels-Alder reaction.     

Synthesis of pyrimidinyl arylglycines through subsequent Mitsunobu and Petasis reactions

The synthesis of highly functionalized pyrimidinyl arylglycines is presented. The highlight in our synthetic sequence includes selective O-alkylation of 2-(benzylsulfanyl)-4(3H)-pyrimidinones with N-Boc β-aminoalcohols under Mitsunobu conditions, Petasis reaction with glyoxylic acid and phenylboronic acid and nucleophilic ipso-substitution of the activated sulfur with morpholine. The unexpected spontaneous Smiles rearrangement of several pyrimidinyl amines is also discussed.     

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.     

Carbon-carbon bond formation via a tandem cationic 2-aza-Cope rearrangement-Lewis acid promoted Petasis reaction

Potassium alkynyltrifluoroborates and potassium (2-phenyl)vinyltrifluoroborates react with N-3-butenyl-(2,2-dichloro-1-propylidene)amine in the presence of BF₃·Et₂O as a Lewis acid to synthesize rearranged Mannich products. The reaction starts with a cationic 2-aza-Cope rearrangement of the imine, followed by the Lewis acid promoted borono-Mannich-type reaction on the rearranged imine to result in a new class of functionalized N-homoallylamines.     

Application of p-TSA in the one pot synthesis of N-methyl-3-nitro-aryl-benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine

A simple, efficient, eco-friendly, and cost-effective method has been developed for the synthesis of N-methyl-3-nitro-aryl-benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine derivatives using 2-aminobenzimidazole, aldehydes and (E)-N-methyl-1-(methylthio)-2-nitroethenamine, in the presence of catalytic amount of p-toluenesulfonic acid (p-TSA) in ethanol at 80?°C conditions. The advantages of this method are the use of an inexpensive and readily available catalyst, shorter reaction times, a wide range of functional group tolerance, and high yield of products via a simple experimental and work-up procedure.     

Efficient, solventless N-Boc protection of amines carried out at room temperature using sulfamic acid as recyclable catalyst

A simple, rapid, and efficient protocol for the chemoselective N-Boc protection of amines using sulfamic acid as catalyst is described. N-Boc protection of various structurally diverse aliphatic, aromatic, alicyclic, and heterocyclic amines (1°, 2°, 3°) was carried out with (Boc)₂O using sulfamic acid as catalyst (5 mol %) at room temperature under solventless conditions. The advantages of this method are simplicity, shorter reaction times (1-15 min), a cost-effective catalyst, and excellent isolated yields (90-100%); it is also environmentally benign. Moreover, the combined use of ultrasound and sulfamic acid achieves a synergic effect that is especially marked in the N-Boc protection of deactivated (sterically hindered and electron-deficient) amines. The catalyst possesses distinct advantages: ease of handling, cleaner reactions, high activity, and excellent chemoselectivity.     

Catalyst-free Mannich-type reaction of 1-(N-acylamino)alkyltriphenylphosphonium salts with silyl enolates

A catalyst-free reaction of 1-(N-acylamino)alkyltriphenylphosphonium tetrafluoroborates with silyl enolates was developed to prepare β-amino carbonyl compounds. The reported method is a useful approach for the preparation of N-protected β-amino esters as well as N-protected β-amino ketones. The starting 1-(N-acylamino)alkyltriphenylphosphonium tetrafluoroborates are readily available from N-protected α-amino acids. Therefore, the presented approach can be considered a new method for the α-homologation of N-protected α-amino acids to prepare β-amino acid derivatives.     

Investigations of the stereoselectivity of the intramolecular Diels-Alder reaction of a spiculoic acid model system

Model linear precursors to the spiculoic acids were prepared and underwent thermally induced IMDA reactions. The configuration of C5 in the stereotriad was found to dominate any inherent endo/exo selectivity of the IMDA reaction. The isomer (2E,5S)-20 underwent the IMDA to give the spiculoic acid stereochemistry in 84% yield and 94% ds. The required stereotriads were synthesised using stereoselective substrate-controlled aldol reactions; an anti-boron aldol reaction, controlled by the π-facial preference of (S)-2-benzoyloxypentan-3-one ((S)-27) led to (5R)-(22) and a syn-titanium aldol reaction, under the stereocontrol of a chiral N-acylthiazolidinethione (42) led to (5S)-(22). Chain extension using standard Wittig, HWE and ‘modified’ Julia olefinations installed the diene and dienophile components giving the linear precursors to the IMDA reactions.     

A novel access to pyrido[4,3-d]pyrimidine scaffold via Staudinger/intramolecular aza-Wittig reaction of 5-acyl-4-(β-azidoalkyl)-1,2,3,4-tetrahydropyrimidin-2-ones

A general four-step approach to 1,2,3,7,8,8a-hexahydropyrido[4,3-d]pyrimidin-2-ones via Staudinger/intramolecular aza-Wittig reaction of 5-acyl-4-(β-azidoalkyl)-1,2,3,4-tetrahydropyrimidin-2-ones promoted by PPh₃ was developed. Synthesis of the starting pyrimidinones included preparation of 3-azidoaldehydes by the addition of hydrazoic acid to α,β-unsaturated aldehydes, transformation of 3-azidoaldehydes into N-[(3-azido-1-tosyl)alkyl]ureas followed by the reaction with enolates of dibenzoylmethane, benzoylacetone, acetylacetone, or ethyl 2,4-dioxo-4-phenylbutanoate and dehydration of the resulting products under acidic conditions.     

Operationally convenient asymmetric synthesis of (S)- and (R)-3-amino-4,4,4-trifluorobutanoic acid: Part II. Enantioselective biomimetic transamination of 4,4,4-trifluoro-3-oxo-N-[(R)-1-phenylethyl]butanamide

An asymmetric synthesis of (S)- and (R)-3-amino-4,4,4-trifluorobutanoic acid via DBU-catalyzed asymmetric 1,3-proton shift transfer reaction of (Z)-3-[(R)-1-phenylethylamino]-4,4,4-trifluoro-N-[(R)-1-phenylethyl]but-2-enamide has been developed. The intermediate Schiff base (S,R′)-9 was found to be relatively configurationally stable under the highly basic reaction conditions allowing preparation of the target amino acid in high chemical yield and enantioselectivity. This method was demonstrated to be practical for large (>25 g) scale synthesis of the target β-amino acid.     

Synthesis of C5-substituted imidazolines

5-(Hydroxymethyl)-3-(t-butyloxycarbonyl)imidazoline 2 was prepared in four steps from 2,3-diaminopropionic acid in 72% overall yield. Mitsunobu reaction with a series of phenol derivatives gave the corresponding 5-(aryloxymethyl)-3-(t-butyloxycarbonyl)imidazolines 8a-l. Phthalimide and N-benzyl trifluoroacetamide also reacted.     

Ugi three-component coupling reaction for the synthesis of 2-(6-oxo-11-phenyl-7,8-dihydrobenzo[b]pyrrolo[1,2-d][1,4]diazocin-5(6H)-yl)-2-phenylacetamide derivatives

A three-component, four center Ugi reaction of 3-(1-(2-aminophenyl)-5-phenyl-1H-pyrrol-2-yl)propanoic acid with aromatic aldehyde and t-butyl isocyanide has been achieved to produce a novel class of N-tert-butyl-2-(6-oxo-11-phenyl-7,8-dihydrobenzo[b]pyrrolo[1,2-d][1,4]diazacine-5(6H)-yl)-2-phenylacetamides in moderate to good yields.     

Cyanamide: a convenient building block to synthesize 4-aryl-2-cyanoimino-3,4-dihydro-1H-pyrimidine systems via a multicomponent reaction

4-Aryl-2-cyanoimino-3,4-dihydro-1H-pyrimidine derivatives were prepared using a multicomponent reaction by reacting a mixture of arene or heteroarenecarbaldehyde, 1,3-dicarbonyl compounds, and cyanamide under acidic conditions. The novelty of this approach derives from its use of cyanamide as a building block in a four-component Biginelli-type reaction. Varying the reaction conditions led to the formation of either N-(2-imino-6-phenyl-1,3,5-oxadiazinan-4-ylidene) cyanamide or 3,4-dihydropyrimidin-2(1H)-one. The type of heterocycle skeleton synthesized depends on the nature of the acid catalyst as well as the reaction conditions employed.     

Peptide thioester preparation based on an N-S acyl shift reaction mediated by a thiol ligation auxiliary

Formation of peptide thioesters, based on an N to S acyl shift mediated by an auxiliary, N-4,5-dimethoxy-2-mercaptobenzyl (Dmmb) group, under acidic conditions, is described. The protected peptide was assembled on a hydroxymethylphenylacetamidomethyl resin via an N-Dmmb-amino acid residue according to standard Fmoc solid-phase peptide synthesis following treatment with trifluoroacetic acid. The peptide α-thioester was released from the resin by reaction with 2-mercaptoethanesulfonic acid in the presence of N,N-diisopropylethylamine.     

Synthesis of pseudopeptidic (S)-6-amino-5-oxo-1,4-diazepines and (S)-3-benzyl-2-oxo-1,4-benzodiazepines by an Ugi 4CC Staudinger/aza-Wittig sequence

Sequential Ugi reaction between p-substituted arylglyoxals, alkylamines, cyclohexyl isocyanide and 3-azido-(S)-2-(tert-butoxycarbonylamino)propanoic acid, followed by a Staudinger/aza-Wittig cyclization in the presence of triphenylphosphine, gave rise to enantiomerically pure N-cyclohexyl 4-alkyl-2-aryl-5-oxo-(S)-6-(tert-butoxycarbonylamino)-4,5,6,7-tetrahydro-1H-1,4-diazepine-3-carboxamides, that can be useful for new drug design. By the same sequence, p-substituted benzaldehydes, 2-aminobenzophenone, cyclohexyl isocyanide and (S)-3-phenyl-2-azidopropionic acid gave rise to N-cyclohexyl 2-((S)-3-benzyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-yl)-(R/S)-2-arylacetamides.     

Three-component synthesis of new unsymmetrical oxindoles via Friedel-Crafts type reaction

The synthesis of 2-(3-(4-(dimethylamino)phenyl)-2-oxoindolin-3-yl)-1H-indene-1,3(2H)-diones as new unsymmetrical oxindoles via a Friedel-Crafts type three-component reaction of 1,3-indandion, N,N-dimethylaniline and isatins in ethanol in the presence of LiClO₄ is reported.     

Chemoselective aminomethylation of bifunctional substrates: carbonyl versus phenolic hydroxyl,carbonyl versus pyrazole and pyrrole versus phenolic hydroxyl as competing activating groups

Chemoselectivity in the Mannich reaction for three different types of bifunctional substrates has been investigated. 1-Hydroxy-2-naphthalenylethanone affords either phenolic Mannich bases at high pH (free amines), or ketonic Mannich bases at low pH (amine hydrochlorides), whereas the use of N,N-dimethylmethyleneiminium chloride as a preformed dimethylaminomethylation reagent gave the phenolic Mannich base. 1-Aryl-3-(1H-pyrazol-1-yl)-1-propanones undergo aminomethylation at position 4 of the pyrazole ring, and not at the methylene group α to the carbonyl function, regardless of the reaction conditions. 4-(2,5-Dimethyl-1H-pyrrol-1-yl)phenol is aminomethylated chemoselectively on the pyrrole ring under mild reaction conditions.     

Microwave-induced domino-Knoevenagel-hetero Diels–Alder reaction—an easy route to di[1]benzopyrano[2,3-b:4′,3′-d]pyridine

MW-irradiation of a well-ground equimolar mixture of 2-(N-alkynyl-N-aryl)aminochromone-3-carbaldehyde and dimedone underwent domino-Knoevenagel-hetero Diels–Alder (DKHDA) reaction for nonterminal alkynes, whereas conventional heating of the above reaction mixture in ethanol in the presence of pyridine accomplished alkyne-carbonyl metathesis (ACM) reaction or both ACM and DKHDA reaction. Here is the first example of an organo-catalyzed ACM reaction.     

Concise [4+3] cycloaddition reaction of pyrroles leading to tropinone derivatives

A concise [4+3] cycloaddition reaction of pyrroles with 2-(silyloxy)allyl cations has been developed. The oxyallyl cations stabilized with a methylthio group or geminal methyl groups were generated from the corresponding allylic alcohols under the influence of a Brönsted acid (Tf₂NH), respectively. The use of N-nosyl-protected pyrroles as the four-carbon unit was found to give tropinone derivatives in high yield.     

Synthesis of new 2,5-diamino-1,3-thiazole and 2-thiohydantoin derivatives by condensation of N-(2-Aryl-1-chloro-2-oxoethyl) carboxamides with thioureas

N-(2-Aryl-1-chloro-2-oxoethyl) carboxamides react under mild conditions with thiourea, N-alkyl-and N-arylthioureas, and various N,N′-disubstituted thioureas, following the Hantzsch reaction scheme. The reactions are selective, and the resulting 2,5-diamino-1,3-thiazole derivatives undergo recyclization acid followed by hydrolysis to give substituted 2-thiohydantoins on heating with hydrochloric acid in ethanol.