A Simple One‐Pot Synthesis of N‐Alkyl‐2,5‐diaryl‐1,3‐dioxol‐4‐amines

An efficient procedure for the synthesis of N‐alkyl‐2,5‐diaryl‐1,3‐dioxol‐4‐amines 3 via a one‐pot reaction of aromatic aldehydes 2 and alkyl isocyanides 1 at room temperature in good yields is described (Scheme 1, Table).     

Highly Enantioselective Aza‐Michael Reaction between Alkyl Amines and β‐Trifluoromethyl β‐Aryl Nitroolefins

The aza‐Michael addition reaction is a vital transformation for the synthesis of functionalized chiral amines. Despite intensive research, enantioselective aza‐Michael reactions with alkyl amines as the nitrogen donor have not been successful. We report the use of chiral N‐heterocyclic carbenes (NHCs) as noncovalent organocatalysts to promote a highly selective aza‐Michael reaction between primary alkyl amines and β‐trifluoromethyl β‐aryl nitroolefins. In contrast to classical conjugate‐addition reactions, a strategy of HOMO‐raising activation was used. Chiral trifluoromethylated amines were synthesized in high yield (up to 99 %) with excellent enantioselectivity (up to 98 % ee).     

One‐Pot,Four‐Component Synthesis of Novel Spiro[indeno[2,1‐b]quinoxaline‐11,4′‐pyran]‐2′‐amines

A one‐pot, four‐component reaction for the efficient synthesis of novel spiro[indeno[2,1‐b]quinoxaline‐11,4′‐pyran]‐2′‐amines by using InCl₃ is described. The syntheses are achieved by reacting ninhydrin with 1,2‐diaminobenzenes to give indenoquinoxalines, which are trapped in situ by alkyl malonates and various α‐methylencarbonyl compounds through cyclization, providing multifunctionalized spiro‐substituted indeno[2,1‐b]quinoxaline‐11,4′‐pyran‐2′‐amines.     

Microwave‐assisted synthesis of some 1,2,4‐triazol‐5‐one derivatives

A series of 3‐alkyl(aryl)‐4‐(p‐hydroxy‐phenyl)‐4,5‐dihydro‐1H‐1,2,4‐triazol‐5‐ones 2 were obtained from the reaction of alkyl (aryl) ester ethoxycarbonyl hydrazones 1 with p‐hydroxy aniline. The reaction of 1 with 1,4‐diamino benzene (1:1) to afford 3‐alkyl(aryl)‐4‐(p‐aminophenyl)‐4,5‐dihydro‐1H‐1,2,4‐triazol‐5‐ones 3 . The reaction of 3 with benzaldehyde gave 3‐alkyl(aryl)‐4‐(4′‐benzilidenamino)‐4,5‐dihydro‐1H‐1,2,4‐triazol‐5‐ones 4 . All of the above reactions occurred under microwave heating and conventional methods. Their structures were confirmed by ¹H NMR, ¹³C NMR, IR, and elemental analyses. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:38–42, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20381     

Reactivity study on morpholine‐1‐carbothioic acid (2‐phenyl‐3H‐quinazolin‐4‐ylidene) amide

Regioselective reactions of morpholine‐1‐carbothioic acid (2‐phenyl‐3H‐quinazolin‐4‐ylidene) amide ( 1 ) with electrophiles and nucleophiles were studied. The compound ( 1 ) reacts with alkyl halides in basic medium to afford S‐substituted isothiourea derivatives, with amines to give 1,1‐disubstituted‐3‐(2‐phenyl‐3H‐quinazolin‐4‐ylidene) thioureas and l‐substituted‐3‐(2‐phenyl‐quinazolin‐4‐yl) thioureas via transami‐nation reaction. The reaction of ( 1 ) with amines in the presence of H₂O₂ provided N⁴‐disubstituted‐N'⁴‐(2‐phenylquinazolin‐4‐yl)morpholin‐4‐carboximidamide via oxidative desulfurization. Estimation of reactivity sites on ( 1 ) was supported using the ab initio (HF/6‐31G**) quantum chemistry calculations. The ir, ¹H nmr, ¹³C nmr, mass spectroscopy and x‐ray identified the isolated products.     

A Novel,One‐Pot Four‐Component Route to 2′‐Thioxo‐2′,3′‐dihydrospiro[indole‐3,6′‐[1,3]thiazin]‐2‐one Derivatives

An efficient route to 2′,3′‐dihydro‐2′‐thioxospiro[indole‐3,6′‐[1,3]thiazin]‐2(1H)‐one derivatives is described. It involves the reaction of isatine, 1‐phenyl‐2‐(1,1,1‐triphenyl‐λ⁵‐phosphanylidene)ethan‐1‐one, and different amines in the presence of CS₂ in dry MeOH at reflux (Scheme 1). The alkyl carbamodithioate, which results from the addition of the amine to CS₂, is added to the α,β‐unsaturated ketone, resulting from the reaction between 1‐phenyl‐2‐(1,1,1‐triphenyl‐λ⁵‐phosphanylidene)ethan‐1‐one and isatine, to produce the 3′‐alkyl‐2′,3′‐dihydro‐4′‐phenyl‐2′‐thioxospiro[indole‐3,6′‐[1,3]thiazin]‐2(1H)‐one derivatives in excellent yields (Scheme 2). Their structures were corroborated spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS) and by elemental analyses.     

Quinolone analogues 1. A convenient synthesis of 1‐alkyl‐4‐oxo‐1,4‐dihydropyridazino[3,4‐b]quinoxaline‐3‐carboxylic acids

The reaction of the alkylhydrazinoquinoxaline N‐oxides 2a‐d with dimethyl acetylenedicarboxylate gave the dimethyl 1‐alkyl‐1,5‐dihydropyridazino[3,4‐b]qumoxaline‐3,4‐dicarboxylates 3a‐d , whose reaction with nitrous acid effected the C₄‐oxidation to afford the dimethyl 1‐alkyl‐4‐hydroxy‐1,4‐dihydropyridazino‐[3,4‐b]quinoxaline‐3,4‐dicarboxylates 4a‐d , respectively. The reaction of compounds 4a‐d with 1,8‐diazabicyclo[5.4.0]‐7‐undecene in ethanol provided the ethyl 1‐alkyl‐4‐oxo‐1,4‐dihydropyridazino[3,4‐b]quinoxa‐line‐3‐carboxylates 5a‐d , while the reaction of compounds 4a‐d with potassium hydroxide furnished the 1‐alkyl‐4‐oxo‐1,4‐dihydropyridazino[3,4‐b]quinoxaline‐3‐carboxylic acids 6a‐d , respectively. Compounds 6c,d were also obtained by the reaction of compounds 5c,d with potassium hydroxide, respectively.     

Arenesulfonylheterocycles (I): Synthesis and reactions of 2‐benzenesulfonyl‐4,5‐dichloropyridazin‐3‐ones with amines

The direct sulfonylation of 4,5‐dichloropyridazin‐3‐ones with some benzenesulfonyl chlorides in the presence of base in tetrahydrofuran gave only the corresponding N‐sulfonylated product. The reaction of 2‐benzenesulfonyl‐4,5‐dichloropyridazin‐3‐ones with some aliphatic amines under neutral conditions afforded 5‐alkylamino‐2‐benzenesulfonyl‐4‐chloropyridazin‐3‐ones and/or the corresponding N‐alkyl‐benzenesulfonamides.     

Rapid Synthesis of 2‐Alkanol‐substituted Pyrrolo[2,3‐b]quinoxalines from Propargylic Alcohols via Copper‐free Sonogashira Coupling Reaction at Room Temperature

A practical and efficient procedure is established for the synthesis of 2‐alkanol‐substituted pyrrolo[2,3‐b]quinoxalines by the reaction of N‐alkyl‐3‐chloroquinoxaline‐2‐amines with propargylic alcohols. The reaction is carried out in the absence of any copper salt but in the presence of a catalytic amount of Pd(PPh₃)₂Cl₂ at room temperature. The Sonogashira coupling reaction step in this procedure is fast, producing clean products with high yields without contamination by unwanted homocoupling Glaser reaction products. The synthesized pyrroloquinoxaline derivatives are also screened against the three bacterial strains Micrococcus luteus, pseudomonas aeruginosa, and Bacillus subtilis.     

Study on 1,3,5‐Triazine Chemistry in Dehydrocondensation: Gauche Effect on the Generation of Active Triazinylammonium Species

The reaction of 2‐chloro‐4,6‐dimethoxy‐1,3,5‐triazine (CDMT) with various nitrogen‐containing compounds, particularly tertiary amines (tert‐amines), has been studied for the preparation of 2‐(4,6‐dimethoxy‐1,3,5‐triazinyl)trialkylammonium salts [DMT‐Am(s)]. DMT‐Ams derived from aliphatic tert‐amines exhibited activity for the dehydrocondensation between a carboxylic acid and an amine to form an amide in a model reaction. Based on a conformational analysis of DMT‐Ams and tert‐amines by NMR and X‐ray diffraction methods, we concluded that a β‐alkyl group maintained in a gauche relationship with the nitrogen lone pair of tert‐amines significantly hinders the approach of CDMT to the nitrogen. Thus, trimethylamine and quinuclidine without such alkyl groups readily react with CDMT whereas triethylamine, possessing two or three such gauche β‐alkyl groups in the stable conformations, does not react at all. The theory of “gauche β‐alkyl group effect” proposed here provides useful guidelines for the preparation of DMT‐Ams possessing various tertiary amine moieties. An investigation of the dehydrocondensation activity of tert‐amines in a CDMT/tert‐amine system that involves in situ generation of DMT‐Am, showed that the gauche effect of the β‐alkyl group becomes quite pronounced; the yield of the amide decreases significantly with tert‐amines possessing an unavoidable gauche β‐alkyl group. Thus, the tert‐amine/CDMT systems are useful for judging whether tert‐amines can readily react with CDMT without isolation of DMT‐Ams.     

Disulfonimide‐Catalyzed Asymmetric Reduction of N‐Alkyl Imines

A chiral disulfonimide (DSI)‐catalyzed asymmetric reduction of N‐alkyl imines with Hantzsch esters as a hydrogen source in the presence of Boc₂O has been developed. The reaction delivers Boc‐protected N‐alkyl amines with excellent yields and enantioselectivity. The method tolerates a large variety of alkyl amines, thus illustrating potential for a general reductive cross‐coupling of ketones with diverse amines, and it was applied in the synthesis of the pharmaceuticals (S)‐Rivastigmine, NPS R‐568 Hydrochloride, and (R)‐Fendiline.     

Efficient New Synthesis of N‐Arylbenzo[b]furo[3,2‐d]pyrimidin‐4‐amines and Their Benzo[b]thieno[3,2‐d]pyrimidin‐4‐amine Analogues via a Microwave‐Assisted Dimroth Rearrangement

A useful and rapid access to libraries of N‐arylbenzo[b]furo[3,2‐d]pyrimidin‐4‐amines ( 1 ) and their novel benzo[b]thieno[3,2‐d]pyrimidin‐4‐amine analogues ( 2 ) was investigated for the first time. Title compounds were obtained via microwave‐accelerated condensation and Dimroth rearrangement of suitable anilines with N′‐(2‐cyanaryl)‐N,N‐dimethylformimidamides obtained by reaction of benzo[b]furane and benzo[b]thiophene precursors with N,N‐dimethylformamide dimethyl acetal. This work also demonstrates that well‐controlled parameters offer comfortable use of microwave technology and are both safe and beneficial to the environment. Some products obtained in this article exhibit interesting in vitro antiproliferative effects.     

N‐Heterocyclic Carbene Iron(III) Porphyrin‐Catalyzed Intramolecular C(sp3)–H Amination of Alkyl Azides

Metal‐catalyzed intramolecular C?H amination of alkyl azides constitutes an appealing approach to alicyclic amines; challenges remain in broadening substrate scope, enhancing regioselectivity, and applying the method to natural product synthesis. Herein we report an iron(III) porphyrin bearing axial N‐heterocyclic carbene ligands which catalyzes the intramolecular C(sp³)–H amination of a wide variety of alkyl azides under microwave‐assisted and thermal conditions, resulting in selective amination of tertiary, benzylic, allylic, secondary, and primary C?H bonds with up to 95 % yield. 14 out of 17 substrates were cyclized selectively at C4 to give pyrrolidines. The regioselectivity at C4 or C5 could be tuned by modifying the reactivity of the C5–H bond. Mechanistic studies revealed a concerted or a fast re‐bound mechanism for the amination reaction. The reaction has been applied to the syntheses of tropane, nicotine, cis‐octahydroindole, and leelamine derivatives.     

Three‐Component Synthesis of Spiro[indoline‐3,4′‐pyrazolo[3,4‐b]pyridines] under Microwave Irradiation

A domino three‐component strategy with high efficiency for the synthesis of spiro[indoline‐3,4′‐pyrazolo[3,4‐b ]pyridines] from easily available isatins, pyrazol‐5‐amines and β‐ketonitriles under microwave heating. During reaction process, HOAc plays dual roles as reaction media as well as a Brønsted acid‐promoter. Flexible structural modification, broad functional group compatibility and mild reaction conditions make this strategy a useful and attractive process of library generation for drug discovery.     

Efficient One‐Pot Synthesis of Alkyl 2‐(Dialkylamino)‐4‐phenylthiazole‐5‐carboxylates and Single‐Crystal X‐Ray Structure of Methyl 2‐(Diisopropylamino)‐4‐phenylthiazole‐5‐carboxylate

The reaction between secondary amines, benzoyl isothiocyanate, and dialkyl acetylenedicarboxylates (=dialkyl but‐2‐ynedioates) in the presence of silica gel (SiO₂) led to alkyl 2‐(dialkylamino)‐4‐phenylthiazole‐5‐carboxylates in fairly high yields. The structures of the products were confirmed by their IR, ¹H‐ and ¹³C‐NMR, and mass spectra, and by a single‐crystal X‐ray structure determination.     

Microwave‐Assisted Synthesis of Novel 2,4‐Dihydro‐5‐[4‐(trifluoromethyl)phenyl]‐3H‐1,2,4‐triazol‐3‐ones and Potentiometric Determination of Their pKa in Nonaqueous Solvents

The novel 4‐amino‐ or 4‐aryl‐substituted 2,4‐dihydro‐5‐[(4‐trifluoromethyl)phenyl]‐3H‐1,2,4‐triazol‐3‐ones 3a – 3g were synthesized by reaction of N‐(ethoxycarbonyl)‐4‐(trifluoromethyl)benzenehydrazonic acid ethyl ester ( 2 ) and primary amines or hydrazine by microwave irradiation. Compounds 3a – 3g were potentiometrically titrated with tetrabutylammonium hydroxide (Bu₄NOH) in four nonaqueous solvents, i.e., ⁱPrOH, ^tBuOH, MeCN, and N,N‐dimethylformamide (DMF). Also half‐neutralization potential values and the corresponding pK_a values were determined in all cases.     

Microwave‐assisted Synthesis of 6‐{(5‐Aryl‐1,3,4‐oxadiazol‐2‐yl)methyl}‐6H‐indolo[2,3‐b]quinoxalines

An efficient and convenient synthesis of a new series of 2‐{(6H‐indolo[2,3‐b]quinoxalin‐6‐yl)methyl}‐5‐aryl‐1,3,4‐oxadiazoles from readily available 1,2‐diaminobenzene and isatins under microwave irradiation conditions was disclosed. The 6‐{(5‐aryl‐1,3,4‐oxadiazol‐2‐yl)methyl}‐6H‐indolo[2,3‐b]quinoxalines were also prepared by the thermal cyclo‐condensation reaction of 2‐(6H‐indolo[2,3‐b]quinoxalin‐6‐yl)acetohydrazides with carboxylic acids in refluxing POCl₃. The microwave‐assisted synthesis was rapid and resulted in higher yield of the products at lower operating temperature with reduced waste generation in comparison with the thermal reaction protocol.     

Facile synthesis of 2‐alkylthio‐5‐phenylmethylene‐4H‐imidazol‐4‐ones

2‐Alkylthio‐5‐phenylmethylidene‐4H‐imidazol‐4‐ones 4 were synthesized by S‐alkylation of 2‐thioxo‐3‐alkyl(aryl)‐4‐imidazolidinones 3 , which were obtained via cyclization of isothiocyanates 2 with aliphatic(aromatic) primary amines. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:348–351, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10160     

Tandem Hydroformylation/Reductive Amination of 3‐Allyl‐2‐methylquinazolin‐4(3H)‐one

The 3‐allyl‐2‐methylquinazolin‐4(3H)‐one ( 1 ), a model functionalized terminal olefin, was submitted to hydroformylation and reductive amination under optimized reaction conditions. The catalytic carbonylation of 1 in the presence of Rh catalysts complexed with phosphorus ligands under different reaction conditions afforded a mixture of 2‐methyl‐4‐oxoquinazoline‐3(4H)‐butanal ( 2 ) and α,2‐dimethyl‐4‐oxoquinazoline‐3(4H)‐propanal ( 3 ) as products of ‘linear’ and ‘branched’ hydroformylation, respectively (Scheme 2). The hydroaminomethylation of quinazolinone 1 with arylhydrazine derivatives gave the expected mixture of [(arylhydrazinyl)alkyl]quinazolinones 5 and 6 , besides a small amount of 2 and 3 (Scheme 3). The tandem hydroformylation/reductive amination reaction of 1 with different amines gave the quinazolinone derivatives 7 – 10 . Compound 10 was used to prepare the chalcones 11a and 11b and pyrazoloquinazolinones 12a and 12b (Scheme 4).     

Comparative metabolite profiling of carboxylic acids in rat urine by CE‐ESI MS/MS through positively pre‐charged and 2H‐coded derivatization

A new approach to the selective comparative metabolite profiling of carboxylic acids in rat urine was established using CE‐MS and a method for positively pre‐charged and ²H‐coded derivatization. Novel derivatizing reagents, N‐alkyl‐4‐aminomethyl‐pyridinum iodide (alkyl=butyl, butyl‐d9 or hexyl), containing quaternary amine and stable‐isotope atoms (deuterium), were introduced for the derivatization of carboxylic acids. CE separation in positive polarity showed high reproducibility (0.99–1.32% RSD of migration time) and eliminated problems with capillary coating known in CE‐MS anion analyses. Essentially complete ionization and increased hydrophobicity after the derivatization also enhanced MS detection sensitivity (e.g. formic acid was detected at 0.5 pg). Simultaneous derivatization of one sample using two structurally similar reagents, N‐butyl‐4‐aminomethyl‐pyridinum iodide (BAMP) and N‐hexyl‐4‐aminomethyl‐pyridinum iodide, provided additional information for recognizing a carboxylic acid in an unknown sample. Moreover, characteristic fragmentation acquired by online CE‐MS/MS allowed for identification and categorization of carboxylic acids. Applying this method on rat urine, we found 59 ions matching the characteristic patterns of carboxylic acids. From these 59, 32 ions were positively identified and confirmed with standards. For comparative analysis, 24 standard carboxylic acids were derivatized by chemically identical but isotopically distinct BAMP and N‐butyl‐d9‐4‐aminomethyl‐pyridinium iodide, and their derivatization limits and linearity ranges were determined. Comparative analysis was also performed on two individual urine samples derivatized with BAMP and N‐butyl‐d9‐4‐aminomethyl‐pyridinium iodide. The metabolite profiling variation between these two samples was clearly visualized.