Syntheses of 2‐Keto‐3‐deoxy‐D‐xylonate and 2‐Keto‐3‐deoxy‐L‐arabinonate as Stereochemical Probes for Demonstrating the Metabolic Promiscuity of Sulfolobus solfataricus Towards D‐Xylose and L‐Arabinose

Practical syntheses of 2‐keto‐3‐deoxy‐D ‐xylonate (D ‐KDX) and 2‐keto‐3‐deoxy‐L ‐arabinonate (L ‐KDA) that rely on reaction of the anion of ethyl 2‐[(tert‐butyldimethylsilyl)oxy]‐2‐(dimethoxy phosphoryl) acetate with enantiopure glyceraldehyde acetonide, followed by global deprotection of the resultant O‐silyl‐enol esters, have been developed. This has enabled us to confirm that a 2‐keto‐3‐deoxy‐D ‐gluconate aldolase from the archaeon Sulfolobus solfataricus demonstrates good activity for catalysis of the retro‐aldol cleavage of both these enantiomers to afford pyruvate and glycolaldehyde. The stereochemical promiscuity of this aldolase towards these enantiomeric aldol substrates confirms that this organism employs a metabolically promiscuous pathway to catabolise the C5‐sugars D ‐xylose and L ‐arabinose.     

One‐Pot Synthesis of 3‐Acetyl‐2‐aryl‐3,4‐dihydroquinazolines from N‐[2‐(Azidomethyl)phenyl]benzamides Utilizing Intramolecular Aza‐Wittig Reaction

A new and convenient method for the preparation of 3,4‐dihydroquinazolines 5 with aryl and Ac groups at C(2) and N(3), respectively, has been developed. The key sequence is the formation of aza‐phosphorane intermediates by the reaction of N‐[2‐(azidomethyl)phenyl]benzamides 1 with Ph₃P, followed by intramolecular aza‐Wittig reaction and 3‐acetylation, which can be conducted in one‐pot.     

Efficient Synthesis of Dialkyl (2Z)‐2‐[(E)‐1‐Aryl‐2‐(3‐arylquinoxalin‐2‐yl)ethenyl]but‐2‐enedioates

The reaction of dialkyl acetylenedicarboxylates 4 with 1‐aryl‐2‐[(3‐arylquinoxalin‐2(1H)‐ylidene)ethanones 3 in the presence of Ph₃P leads to dialkyl (2Z)‐2‐[(E)‐1‐aryl‐2‐(3‐arylquinoxalin‐2‐yl)ethenyl]but‐2‐enedioates 1 in good yields.     

Synthesis of 15‐Cyano‐12‐oxopentadecano‐15‐lactone and 15‐Cyano‐ 12‐oxopentadecano‐15‐lactam

15‐Cyano‐12‐oxopentadecano‐15‐lactone was synthesized in 59% total yield starting from 2‐nitrocyclododecanone by Michael addition to acrylaldehyde, followed by reaction with trimethylsilylcyanide, hydrolysis, ring‐expansion, and Nef reaction. A two‐step, one‐pot synthesis of intermediate 2‐hydroxy‐4‐(1‐nitro‐2‐oxycyclododecyl)butanenitrile from 3‐(1‐nitro‐2‐oxocyclododecyl)propanal was developed and the conditions for the Nef reaction were studied. 15‐Cyano‐12‐oxopentadecano‐15‐lactam was synthesized in 40% total yield starting from 2‐nitrocyclododecanone by Michael addition to acrylaldehyde, followed by Strecker reaction, ring‐expansion, and Nef reaction. The conditions for the Strecker and Nef reactions were studied. The structures of the target compounds, intermediates, and by‐product were characterized by IR, ¹H‐ and ¹³C‐NMR, and elemental analysis or MS.     

First Synthesis of a C‐Homosteroid from Pregn‐4‐ene‐3,11,20‐trione

(3α,5α)‐3‐Hydroxy‐C‐homopregnane‐11,20‐dione ( 3 ) was prepared in eleven steps from the commercially available pregn‐4‐ene‐3,11,20‐trione ( 4 ) via the 11‐oxo‐13‐formyl‐12,13‐secopregnane intermediate 11 (Scheme 2). Subjection of this secopregnane to an intramolecular aldol condensation afforded the α,β‐unsaturated key intermediate C‐homopregn‐12‐en‐11‐one 12 .     

Synthesis and Structure of O,O‐Diethyl N‐[(trans‐4‐Aryl‐5,5‐dimethyl‐2‐oxido‐2λ5‐1,3,2‐dioxaphosphorinan‐2‐yl)methyl]phosphoramidothioates

A study on the synthesis of the novel N‐(cyclic phosphonate)‐substituted phosphoramidothioates, i.e., O,O‐diethyl N‐[(trans‐4‐aryl‐5,5‐dimethyl‐2‐oxido‐2λ⁵‐1,3,2‐dioxaphosphorinan‐2‐yl)methyl]phosphoramidothioates 4a – l , from O,O‐diethyl phosphoramidothioate ( 1 ), a benzaldehyde or ketone 2 , and a 1,3,2‐dioxaphosphorinane 2‐oxide 3 was carried out (Scheme 1 and Table 1). Some of their stereoisomers were isolated, and their structure was established. The presence of acetyl chloride was essential for this reaction and accelerated the process of intramolecular dehydration of intermediate 5 forming the corresponding Schiff base 7 (Scheme 2).     

Ritter Reaction of 1‐Aryl‐1‐Fluoro‐2‐Haloethanes

Fluorinated phenethyl bromides 1,2 , and 3 , prove to be totally inert under Ritter reaction conditions in the presence of either SnCl₄ or AgNO₃, due to the strong deactivation by the gem‐difluoro unit. Subjecting 2‐bromo‐1‐fluoro‐1‐phenylethane to SnCl₄ in MeCN at elevated temperatures led to formation of 2‐methyl‐4‐phenyl‐4,5‐dihydrooxazole.     

Efficient Synthesis of Novel Coumarin‐3‐carboxamides (=2‐Oxo‐2H‐1‐benzopyran‐3‐carboxamides) Containing Lipophilic Spacers

The novel coumarin‐3‐carboxamides (=2‐oxo‐2H‐1‐benzopyran‐3‐carboxamides) 5a – 5g containing lipophilic spacers were synthesized through the Ugi‐four‐component reaction (Scheme 1). The reactions of aromatic aldehydes 1 , 4,4′‐oxybis[benzenamine] or 4,4′‐methylenebis[benzenamine] as diamine 2 , coumarin‐3‐carboxylic acid (=2‐oxo‐2H‐benzopyran‐3‐carboxylic acid; 3 ), and alkyl isocyanides 4 lead to the desired substituted coumarin‐3‐carboxamides 5a – 5g at room temperature with high bond‐forming efficiency. These novel coumarin derivatives exhibit brilliant fluorescence at 544 nm in CHCl₃.     

Synthesis of 2‐Aryl‐2,3‐dihydro‐3‐sulfanyl‐1H‐isoindol‐1‐ones by Pummerer‐Type Cyclization of N‐Aryl‐2‐(sulfinylmethyl)benzamides

An efficient method for the synthesis of 2‐aryl‐2,3‐dihydro‐3‐sulfanyl‐1H‐isoindol‐1‐ones 1 via Pummerer‐type cyclization of N‐aryl‐2‐(sulfinylmethyl)benzamides 2 is described. Thus, treatment of these sulfinyl‐benzamides 2 , easily prepared from 2‐(bromomethyl)benzoates 3 in three steps, with Ac₂O at ca. 100° resulted in the formation of the desired isoindolones 1 in generally good yields.     

Ene Reaction with Pummerer‐type Reaction Intermediate of α‐(Methylthio)‐N‐methoxy‐N‐methyl Acetamide: A New Synthesis of N‐methoxy‐N‐methyl‐(E,E)‐2,4‐dienamides

Pummerer‐type reaction intermediate 2 of α‐(methylthio)‐N‐methoxy‐N‐methyl acetamide (1) has been found to react with 1‐alkenes to afford ene adducts 3 . N‐Methoxy‐N‐methyl‐(E,E)‐2,4‐dienamides were synthesized from the adducts 3b‐f .     

Reaction of Ketene Dithioacetals with Pyrazolylcarbohydrazide： Synthesis and Biological Activities of Ethyl 5-Amino-1-（5＇-methyl-1 ＇-t-butyl-4＇-pyrazolyl）carbonyl-3-methylthio-1 H-pyrazole-4-carboxylate

The title compound, C16H23N5O3S, ethyl 5-amino-1-(5‘-methyl-1‘-t-butyl-4‘-pyrazolyl)carbonyl-3-methylthio-1H-pyrazole-4-carboxylate (5) has been synthesized by the treatment of ethyl 2-cyano-3,3-dimethylthioacrylate with 1-t-butyl-5-methyl-4-hydrazinocarbonylpyrazole (4) in refluxed ethanol. The possible mechanism of the above reaction was also discussed. The results of biological test show that the title compound has fungicidal and plant growth regulation activities.     

Asymmetric Proline‐Catalyzed Addition of Aldehydes to 3H‐Indol‐3‐ones: Enantioselective Synthesis of 2,3‐Dihydro‐1H‐indol‐3‐ones with Quaternary Stereogenic Centers

The proline‐catalyzed addition of various aliphatic aldehydes to sterically hindered 2‐aryl‐substituted 3H‐indol‐3‐ones affords 2,2‐disubstituted 2,3‐dihydro‐1H‐indol‐3‐one derivatives with excellent enantioselectivities. In addition, the synthesis of a chiral derivative, (S)‐2‐(2‐bromophenyl)‐2,3‐dihydro‐2‐(2‐hydroxyethyl)‐1H‐indol‐3‐one, which can be used as an intermediate for the preparation of the natural product hinckdentine A was accomplished with a high level of enantioselectivity.     

Molecular Iodine Catalyzed One‐pot Aza‐Diels‐Alder Reaction under Solvent‐free Conditions

Catalyzed by molecular iodine at room temperature, under solvent‐free conditions, a two component aza‐Diels‐Alder cyclization of N‐vinyl‐2‐pyrrolidinone with N‐arylimine gave tetrahydroquinoline derivatives in good yields and high stereo‐selectivity. And three components aza‐Diels‐Alder reaction of N‐vinyl‐2‐pyrrolidinone, anilines and indole‐3‐carbaldehydes under the same condition afford only cis‐product in good yields.     

The Reaction of (N‐Isocyanimino)triphenylphosphorane with Biacetyl in the Presence of Aromatic Carboxylic Acids: Efficient One‐Pot Three‐Component Reaction for the Synthesis of 3‐(5‐Aryl‐1,3,4‐oxadiazol‐2‐yl)‐3‐hydroxybutan‐2‐one Derivatives

Reactions of biacetyl (=butane‐2,3‐dione) with (N‐isocyanimino)triphenylphosphorane in the presence of aromatic carboxylic acids proceed smoothly at room temperature and under neutral conditions to afford 3‐(5‐aryl‐1,3,4‐oxadiazol‐2‐yl)‐3‐hydroxybutan‐2‐one derivatives in high yields.     

A series of (E)‐5‐(arylideneamino)‐1‐tert‐butyl‐1H‐pyrrole‐3‐carbonitriles and their reduction products to secondary amines: syntheses and X‐ray structural studies

An efficent access to a series of N‐(pyrrol‐2‐yl)amines, namely (E)‐1‐tert‐butyl‐5‐[(4‐chlorobenzylidene)amino]‐1H‐pyrrole‐3‐carbonitrile, C₁₆H₁₆ClN₃, (7a), (E)‐1‐tert‐butyl‐5‐[(2,4‐dichlorobenzylidene)amino]‐1H‐pyrrole‐3‐carbonitrile, C₁₆H₁₅Cl₂N₃, (7b), (E)‐1‐tert‐butyl‐5‐[(pyridin‐4‐ylmethylene)amino]‐1H‐pyrrole‐3‐carbonitrile, C₁₅H₁₆N₄, (7c), 1‐tert‐butyl‐5‐[(4‐chlorobenzyl)amino]‐1H‐pyrrole‐3‐carbonitrile, C₁₆H₁₈ClN₃, (8a), and 1‐tert‐butyl‐5‐[(2,4‐dichlorobenzyl)amino]‐1H‐pyrrole‐3‐carbonitrile, C₁₆H₁₇Cl₂N₃, (8b), by a two‐step synthesis sequence (solvent‐free condensation and reduction) starting from 5‐amino‐1‐tert‐butyl‐1H‐pyrrole‐3‐carbonitrile is described. The syntheses proceed via isolated N‐(pyrrol‐2‐yl)imines, which are also key synthetic intermediates of other valuable compounds. The crystal structures of the reduced compounds showed a reduction in the symmetry compared with the corresponding precursors, viz. Pbcm to P from compound (7a) to (8a) and P2₁/c to P from compound (7b) to (8b), probably due to a severe change in the molecular conformations, resulting in the loss of planarity observed in the nonreduced compounds. In all of the crystals, the supramolecular assembly is controlled mainly by strong (N,C)—H…N hydrogen bonds. However, in the case of (7a)–(7c), C—H…Cl interactions are strong enough to help in the three‐dimensional architecture, as observed in Hirshfeld surface maps.     

CuBr‐catalysed one‐pot multicomponent synthesis of 3‐substituted 2‐thioxo‐2,3‐dihydroquinazolin‐4(1H)‐one derivatives

A novel methodology is presented for the synthesis of 3‐substituted 2‐thioxo‐2,3‐dihydroquinazolin‐4(1H)‐one derivatives based on an efficient tandem multicomponent reaction using copper bromide as catalyst. This methodology is based on the multicomponent one‐pot reaction of methyl 2‐bromobenzoate, phenylisothiocyanate derivatives and sodium azide in the presence of copper bromide and l ‐proline under basic conditions. To show the generality of the method, various phenylisothiocyanates bearing electron‐donating or electron‐withdrawing functionalities were used and the desired products were obtained in high isolated yields.     

One‐Pot Synthesis of 4‐(Alkylamino)‐1‐(arylsulfonyl)‐3‐benzoyl‐1,5‐ dihydro‐5‐hydroxy‐5‐phenyl‐2H‐pyrrol‐2‐ones via a Multicomponent Reaction

An effective route to novel 4‐(alkylamino)‐1‐(arylsulfonyl)‐3‐benzoyl‐1,5‐dihydro‐5‐hydroxy‐5‐phenyl‐2H‐pyrrol‐2‐ones 10 is described (Scheme 2). This involves the reaction of an enamine, derived from the addition of a primary amine 5 to 1,4‐diphenylbut‐2‐yne‐1,4‐dione, with an arenesulfonyl isocyanate 7 . Some of these pyrrolones 10 exhibit a dynamic NMR behavior in solution because of restricted rotation around the C? N bond resulting from conjugation of the side‐chain N‐atom with the adjacent α,β‐unsaturated ketone group, and two rotamers are in equilibrium with each other in solution ( 10 ? 11 ; Scheme 3). The structures of the highly functionalized compounds 10 were corroborated spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS), by elemental analyses, and, in the case of 10a , by X‐ray crystallography. A plausible mechanism for the reaction is proposed (Scheme 4).     

Synthesis of Benzimidazoles by Phosphine‐Mediated Reductive Cyclisation of ortho‐Nitro‐anilides

Heating ortho‐nitro‐anilides 1 – 3 and 2‐methyl‐N‐(3‐nitropyridin‐2‐yl)propanamide ( 5 ) with 4 equiv. of a phosphine led to the 2‐substituted benzimidazoles 6 – 8 and to the imidazo[4,5‐b]pyridine 10 , respectively, in yields between 45 and 85%. Heating 1 with (EtO)₃P effected cyclisation and N‐ethylation, leading to the 1‐ethylbenzimidazole 6b . The slow cyclisation of the N‐pivaloylnitroaniline 2b allowed isolation of the intermediate phosphine imide 11 that slowly transformed into the 1H‐benzimidazole 7b . The structure of 11 was established by crystal‐structure analysis. While the N‐methylated ortho‐nitroacetanilide 3 cyclised to the 1,2‐dimethyl‐1H‐benzimidazole ( 8 ), the 2‐methylpropananilide 4 was transformed into 1‐methyl‐3‐(1‐methylethyl)‐2H‐benzimidazol‐2‐one ( 9 ).     

An Efficient Synthesis of 3‐(1H‐Tetrazol‐5‐yl)coumarins (=3‐(1H‐Tetrazol‐5‐yl)‐2H‐1‐benzopyran‐2‐ones) via Domino Knoevenagel Condensation,Pinner Reaction,and 1,3‐Dipolar Cycloaddition in Water

A novel straightforward synthesis of 3‐(1H‐tetrazol‐5‐yl)coumarins (=3‐(1H‐tetrazol‐5‐yl)‐2H‐1‐benzopyran‐2‐ones) 6 via domino Knoevenagel condensation, Pinner reaction, and 1,3‐dipolar cycloaddition of substituted salicylaldehydes (=2‐hydroxybenzaldehydes), malononitrile (propanedinitrile), and sodium azide in H₂O is reported (Scheme 1 and Table 2). This general protocol provides a wide variety of 3‐(1H‐tetrazol‐5‐yl)coumarins in good yields under mild reaction conditions.     

NO migration from N‐methyl‐N‐nitrosobenzene‐sulfonamide to 3,6‐dibromocarbazole: Concerted or stepwise reaction path?

The NO migration from N‐methyl‐N‐nitrosobenzene‐sulfonamide to 3,6‐dibromocarbazole was proposed in a recent literature to follow a stepwise reaction path. However, the present density functional theory calculations at the MP2/6–31G(d,p)//B3LYP/6–31G(d,p) level show that this reaction exclusively proceeds via a concerted mechanism involving a four‐membered ring transition state. The calculated barrier is in good agreement with the experimental finding. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2007