The reaction of aroyl‐substituted heterocyclic ketene aminals with aryl azides

The aroyl‐substituted heterocyclic ketene aminals 1 or 2 reacted with p‐chlorophenyl azide ( 3a ) to give the polysubstituted 1,2,3‐triazoles 4 or 5 , as well as the fused heterocycles 6 or 7 . Compounds 1 and 2 reacted with p‐nitrophenyl azide ( 3b ) much faster, and polysubstituted 1,2,3‐triazoles 8 or 9 were obtained as sole products. © 2000 John Wiley & Sons, Inc. Heteroatom Chem 11:387–391, 2000     

Synthesis of ribosylated 1,2,3‐triazole derivatives

Ribosylated 1,2,3‐triazole 4 and 5 were synthesized in moderate yields by the reaction of aroyl‐substituted heterocyclic ketene aminals 1 or 2 with 2,3,5‐tri‐O‐benzoyl‐β‐D ‐ribofuranosyl azide ( 3 ). Their structures were determined by elemental analyses and spectroscopic methods. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:487–490, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10167     

O—Maltosylation of Heterocyclic Ketene Aminals

The stereoselective synthesis of O-maltosides by reacting benzoyl-substituted heterocyclic ketene aminals 1 or 2 with acetylated maltosyl bromide 3 was investigated.Compounds 1 or 2 reacted with 3 in the presence of mercuric cyanide to give O-maltosides 4 or 5 with E-configuration.While 1 reacted with 3 in the presence of calcium hydride to give O-maltosides 6 with Zconfiguration.     

The reaction of heteroaroyl‐substituted heterocyclic ketene aminals with 2,3,4,6‐tetra‐O‐acetyl‐β‐D‐glucopyranosyl azide

The reaction of heteroaroyl‐substituted heterocyclic ketene aminals with 2,3,4,6‐tetra‐O‐acetyl‐β‐D ‐glucopyranosyl azide was investigated and a series of potential bioactive compounds, 1‐glucopyranosyl‐4‐heterocyclic‐5‐heteroaryl‐1,2,3‐triazoles, were obtained in good yields. Both the reaction rate and the yield were strongly affected by the heteroaryl and heterocyclic groups. In order to improve their water solubility, the deprotection of 1‐glucopyranosyl‐4‐heterocyclic‐5‐heteroaryl‐1,2,3‐triazole was carried out. © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:242–247, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/hc.10023     

2‐Benzothiazolyl‐N‐(arenesulfonyl)‐sulfinimidoyl fluorides

2‐Benzothiazolyl‐N‐(arenesulfonyl)‐sulfinimidoyl fluorides were synthesized by the treatment of benzothiazolyl‐2‐sulfur trifluoride with sulfonamides. The reaction of 2‐benzothiazolyl‐N‐ (p‐toluenesulfonyl)‐sulfinimidoyl fluoride with tert‐ butylamine and morpholine gave 2‐benzothiazolyl‐ N‐(arenesulfonyl)‐sulfinimidoyl amides. The reaction of 2‐benzothiazolyl‐N‐(p‐toluenesulfonyl)‐sulfinimi‐ doyl fluoride or 2‐benzothiazolyl‐¹⁵N‐(p‐tosyl)sul‐ finimidoyl fluoride with S‐trimethylsilylbenzenethiol gave di(benzothiazolyl‐2) disulfide, fluorotrimethylsi‐ lane and N,N′‐bis(p‐toluenesulfonyl)‐N,N′‐bis(phenyl‐ thio)‐hydrazine or ¹⁵N,¹⁵N′‐bis(p‐toluenesulfonyl)‐¹⁵N, ¹⁵N′‐bis(phenylthio)‐hydrazine, respectively. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:352–356, 2005; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20102     

Reaction of Pyrimidinonethione Derivatives: Synthesis of N‐Methyl‐2‐Hydrizinopyrimidine‐4‐One,Thiazolo[3,4‐b] N‐Methylpyrimidinone; 2‐(1‐Pyrazolonyl) N‐Methylpyrimidine‐4‐one and 2‐Hydrazino‐N‐Methyl Pyrimidine‐4‐One Derivatives

6‐Aryl‐5‐cyano‐4‐pyrimidinone‐2‐thion derivatives 1a‐c reacted with methyl iodide (1:2) to give the corresponding 2‐S,N‐dimethyl pyrimidine‐4‐one derivatives 2a‐c . Compounds 2a‐c were in turn, reacted with hydrazine hydrate to give the sulfur free reaction products 3a‐c . These reaction products were taken as the starting materials for the synthesis of several new heterocyclic derivatives. Reaction of 3a‐c with acetic anhydride and formic acid gave pyrimido triazines 4a‐c and 7a‐c , respectively. Their reactions with active methylene containing reagents gave the corresponding 2‐(1‐pyrazonyl)‐N‐methyl pyrimidine derivatives 9a‐c and 10a‐c , respectively. Their reactions with aromatic aldehydes afforded the corresponding 2‐hydrazono pyrimidine derivatives 11a‐c . The structure of these reactions products were established based on both elemental analysis and spectral data studies.     

Acylation of Heterocyclic Ketene Aminals with Propionyl Chloride

Heterocyclic ketene aminals 1 or 2 reacted with propionyl chloride to give both the mono-N-and C-acylated products 4 and 5 or 6 and 7. While N-methyl heterocyclic ketene aminals 3 reacted with propionyl chloride under the same condition, the reaction took place in complexity. Besides N-and C-acylation, the O-attack and heterocyclic ring cleavage also occurred to give products 8 and 9.     

Synthesis and Biological Screening of 2‐Substituted 5,6‐Dihydro‐5‐oxo‐ 4H‐1,3,4‐oxadiazine‐4‐propanenitriles and of Their Intermediates

To evaluate the effect of substituents on biological activities of electron‐rich N‐containing heterocycles, the variably 2‐substituted 5,6‐dihydro‐5‐oxo‐4H‐1,3,4‐oxadiazine‐4‐propanenitriles 26 – 33 were synthesized and evaluated for antibacterial, antifungal, and enzyme‐inhibition activities. The target compounds were obtained from alkyl 4‐ or 3‐hydroxy benzoates 1 and 2 , respectively, and from methyl indoleacetate 3 . The phenolic OH group of benzoates 1 and 2 were substituted with p‐toluenesulfonyl (→ 4 and 5 ), benzoyl (→ 6 and 7 ), and benzyl groups (→ 8 and 9 ) and then converted to 5,6‐dihydro‐5‐oxo‐4H‐1,3,4‐oxadiazine‐4‐propanenitriles. To establish structure‐activity relationships (SAR), a pharmacological screening of the intervening intermediates was also conducted, which revealed that the intermediate hydrazide 11 possesses significant antimicrobial and MAO‐A inhibiting properties and intermediates 12, 24, 28 , and 29 appreciable antifungal activities. Compound 7 inhibits α‐chymotrypsin.     

Low‐valent Titanium Induced Reductive Coupling of O‐Nitrophenylazide with Benzoyl Substituted Ketene Dithioacetals: a Novel Synthesis of 4‐Aryl‐2‐methylthio‐3Z7‐l,5‐benzodiazepines

Treated with the low‐valent titanium derived from TiCl₄/Sm system, o‐nitrophenylazide could produce the intermediate 2 in situ, which reacted with benzoyl substituted ketene dithioacetals to afford 4‐aryl‐2‐methylthio‐3H‐1,5‐benzodiazepines in good yields under mild and neutral conditions.     

THE RADICAL NUCLEOPHILIC SUBSTITUTION REACTION OF HETEROCYCLIC KETENE AMINALS WITH 2,4-DINITROHALOBENZENES

The anion of heterocyclic ketene aminals reacted with 2,4-dini-tro-halobenzenes to give an arylated product through the radical nucleo-philic substitution confirmed by ESR spectroscopy,ESR-spin trapping techni-que,and depression of the reaction rate by the addition of inhibitor.     

Exploring the Border between Concerted and Two‐Step Pathways of 1,3‐Dipolar Cycloadditions of Organic Azides to Cyclic Ketene N,X‐Acetals. – Synthesis and 15N‐NMR Spectra of Zwitterions and Spirocyclic Cycloadducts

Cyclic ketene N,X‐acetals 1 are electron‐rich dipolarophiles that undergo 1,3‐dipolar cycloaddition reactions with organic azides 2 ranging from alkyl to strongly electron‐deficient azides, e.g., picryl azide ( 2L ; R¹=2,4,6‐(NO₂)₃C₆H₂) and sulfonyl azides 2M – O (R¹=XSO₂; cf. Scheme 1). Reactions of the latter with the most‐nucleophilic ketene N,N‐acetals 1A provided the first examples for two‐step HOMO(dipolarophile)–LUMO(1,3‐dipole)‐controlled 1,3‐dipolar cycloadditions via intermediate zwitterions 3 . To set the stage for an exploration of the frontier between concerted and two‐step 1,3‐dipolar cycloadditions of this type, we first describe the scope and limitations of concerted cycloadditions of 2 to 1 and delineate a number of zwitterions 3 . Alkyl azides 2A – C add exclusively to ketene N,N‐acetals that are derived from 1H‐tetrazole (see 1A ) and 1H‐imidazole (see 1B , C ), while almost all aryl azides yield cycloadducts 4 with the ketene N,X‐acetals (X=NR, O, S) employed, except for the case of extreme steric hindrance of the 1,3‐dipole (see 2E ; R¹=2,4,6‐(^tBu)₃C₆H₂). The most electron‐deficient paradigm, 2L , affords zwitterions 16D , E in the reactions with 1A , while ketene N,O‐ and N,S‐acetals furnish products of unstable intermediate cycloadducts. By tuning the electronic and steric demands of aryl azides to those of ketene N,N‐acetals 1A , we discovered new borderlines between concerted and two‐step 1,3‐dipolar cycloadditions that involve similar pairs of dipoles and dipolarophiles: 4‐Nitrophenyl azide ( 2G ) and the 2,2‐dimethylpropylidene dipolarophile 1A (R, R=H, ^tBu) gave a cycloadduct 13 H , while 2‐nitrophenyl azide ( 2 H ) and the same dipolarophile afforded a zwitterion 16A . Isopropylidene dipolarophile 1A (R=Me) reacted with both 2G and 2 H to afford cycloadducts 13G , J ) but furnished a zwitterion 16B with 2,4‐dinitrophenyl azide ( 2I) . Likewise, 1A (R=Me) reacted with the isomeric encumbered nitrophenyl azides 2J and 2K to yield a cycloadduct 13L and a zwitterion 16C , respectively. These examples suggest that, in principle, a host of such borderlines exist which can be crossed by means of small structural variations of the reactants. Eventually, we use ¹⁵N‐NMR spectroscopy for the first time to characterize spirocyclic cycloadducts 10 – 14 and 17 (Table 6), and zwitterions 16 (Table 7).     

Formation of N‐Heterocyclic Carbenes by Tautomerization of Mesomeric Betaines: Cyclic Boron Adducts and Palladium Complexes From 2‐(Imidazolium‐1‐yl)phenolates

2‐(Imidazolium‐1‐yl)phenolates are conjugated heterocyclic mesomeric betaines in tautomeric equilibrium with the corresponding N‐heterocyclic carbenes (NHCs), 3‐(2‐hydroxyphenyl)‐imidazol‐2‐ylidenes. The carbene tautomers can be trapped as thiones (X‐ray analysis). Moreover, bis(triphenylphosphine)palladium(II) dichloride in THF trapped the carbene tautomer as a palladium complex without participation of the phenolate group (X‐ray analysis). The corresponding anionic NHCs, 2‐phenolate‐substituted imidazol‐2‐ylidenes, can be trapped by triethylborane or triphenylborane to form 4,4‐diethyl‐ or 4,4‐diphenyl‐4H‐benzo[e]imidazo[2,1‐c][1,4,2]oxaza‐borininium‐4‐ides, respectively (two X‐ray analyses). These tricyclic systems are the first representatives of a new heterocyclic ring system. The results of DFT calculations concerning the HOMO/LUMO profiles and partial charges are also presented.     

Theoretical Study on Gas—phase Pyrolytic Reactions of N—Ethyl,Isopropyl and N—t—Butyl Substituted 2—Aminopyrazine

Density functional theory (DFT) and ab initio methods were used to study gas‐phase pyrolytic reaction mechanisms of iV‐ethyl, N‐isopropyl and N‐t‐butyl substituted 2‐aminopyrazine at B3LYP/6–31G* and MP2/6–31G*, respectively. Single‐point energies of all optimized molecular geometries were calculated at B3LYP/6–311 + G(2d,p) level. Results show that the pyrolytic reactions were carried out through a unimolecular first‐order mechanism which were caused by the migration of atom H(17) via a six‐member ring transition state. The activation energies which were verified by vibrational analysis and correlated with zero‐point energies along the reaction channel at B3LYP/6–311 + G(2d,p) level were 252.02 kJ. mo^?1 (N‐ethyl substituted), 235.92 kJ‐mol^?1 (N‐t‐isopropyl substituted) and 234.27 kJ‐mol^?1 (N‐t‐butyl substituted), respectively. The results were in good agreement with available experimental data.     

THE SECONDARY REACTION IN THE CONDENSATION OF 1-METHYL-2-METHYLTHIO-IMIDAZOLINE WITH ACTIVE METHYLENE COMPOUNDS

Mono-substituted heterocyclic ketene aminals are formed by the reactionof 1-methyl-2-methylthio-imidazoline with active methylene compoundscontaininq an acetyl or benzoyl group by the elimination of both amethylthio and an acyl group.This is resulted by the secondary reactioof the produced methanethiol to attack the more active carbonyl group.     

Regiospecific Synthesis of N-Sulfanilyl Heterocyclic Ketene Aminals

Heterocyclic ketene aminals 1 or 2 reacted with N-acetylsulfanilyl chloride 3 in the presence of sodium hydride to afford N-sulfanilyl heterocyclic ketene aminals 4 or 5 regiospecifically.     

An Efficient One‐Pot Four‐Component Synthesis of Functionalized Imidazo[1,2‐a]pyridines

An efficient one‐pot four‐component protocol for the synthesis of imidazo[1,2‐a]pyridines was developed by condensing ethane‐1,2‐diamine ( 2 ), 1,1‐bis(methylthio)‐2‐nitroethene ( 1 ), aldehydes 3 , and activated methylene compounds in EtOH under reflux conditions (Tables 1–3). The features of this procedure are operational simplicity, good yields of products, in situ preparation of heterocyclic ketene aminals (HKA), and catalyst‐free conditions.     

Syntheses of N‐[3‐(1‐methyl‐1H‐2‐imidazolyl)propyl]benzamides and N‐[3‐(1‐methyl‐1H‐2‐imidazolyl)propyl]benzenesulfonamides

A series of substituted N‐(4‐substituted‐benzoyl)‐N‐[3‐(1‐methyl‐1H‐imidazol‐2‐yl)propyl]amines ( 13 ) and N‐arylsulfonyl‐N‐[3‐(1‐methyl‐1H‐imidazol‐2‐yl)propyl]amines ( 14 ) were prepared from the reaction of 3‐(1‐methyl‐1H‐imidazol‐2‐yl)propan‐1‐amine ( 7 ) with substituted benzoyl chloride or substituted‐benzene sulfonyl chloride respectively. Compound 7 was prepared by two independent methods.     

Synthesis and Spectral Characterization of Some Novel Phosphonyl‐ and Phosphoryl Pyrazole Compounds

1,3‐Diphenyl‐1H‐pyrazole‐4‐carbaldehyde ( 1 ) reacted with aniline, 2‐substituted anilines, and P,P‐dimethylphosphinic hydrazide in the presence of diethyl phosphite to give acyclic α‐aminophosphonate 2 , cyclic α‐aminophosphonates 4–6 , and α‐hydrazinophosphonate 7 , respectively. Also, treatment of aldehyde 1 with cyanoaceto‐hydrazide, acetophenone, and malononitrile afforded the condensation products 8 , 16 , and 21 , respectively, which in turn, reacted with diethyl phosphite and P,P‐dimethylphosphinic hydrazide. The reaction of diethyl phosphite with the hydrazone 8 and chalcone 16 yielded the novel phosphorus heterocycles 13 and 18 , respectively, while its reaction with the dicyanoarylidene 21 produced the dicyanopyrazolyl phosphonate 22 . On the other hand, treatment of the hydrazone 8 with P,P‐dimethylphosphinic hydrazide gave the unexpected P,P‐dimethylphosphinic hydrazone 15 , which reacted with diethyl phosphite forming α‐hydrazinophosphonate 7 . Furthermore, the interesting N‐phosphoryl pyrazoles 20 and 24 were resulted in good yield via cycloaddition of P,P‐dimethylphosphinic hydrazide to the chalcone 16 and dicyanoarylidene 21 , respectively. Structures of all newly synthesized compounds were confirmed by considering the data of IR spectroscopy, MS, and ¹H‐, ¹³C‐, and ³¹P‐NMR spectroscopy, as well as that of elemental analyses.     

Studies on organophosphorus compounds: Synthesis and reactions of [1,2,4,3]triaza‐phospholo[4,5‐a]quinoxaline derivative

2,4‐Bis‐(4‐methoxyphenyl)‐1,3,2,4‐dithiadiphosphetane‐2,4‐disulfide (Lawesson's reagent) ( 1 ) reacted with 2‐hydrazino‐3‐methyl‐quinoxaline ( 2 ) to give [1,2,4,3]‐triazaphospholo[4,5‐a]quinoxaline derivative 3 . The Mannich reaction using different amines on compound 3 gave Mannich bases 4a–d . Also, compound 3 reacted with formaldehyde to give the corresponding 2‐hydroxymethyl derivative 5 , which upon reaction with thionyl chloride gave the corresponding chloromethyl derivative 6 . Treatment of compound 6 with some thiols yielded the corresponding sulfides 7a–d . Acylation of compound 3 gave acylated compounds 8a,b . Compound 9 , which was prepared through the reaction of compound 3 with ethyl cyanoacetate, was investigated as a starting material for the synthesis of some new heterocyclic systems 10–13 . Also, reaction of compound 9 with carbon disulfide and 2 equivalents of methyl iodide in a one‐pot reaction yielded the corresponding ketene‐S,S‐acetal 14 , which in turn reacted with bidentates to give some new heterocycles 15–17 . © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:520–529, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20473     

1,3‐cycloadditions of pyridinium N‐arylimides

The title compounds (5a: Ar = C₆H5, 5b: Ar = 2‐pyridyl) are 1,3‐dipoles of the azomethine imine type; their 1,3‐cycloadditions are accompanied by the loss of the pyridinium resonance energy. As a consequence, the interaction with electron‐deficient ethylenes gives rise to cycloaddition/cycloreversion equilibria, in contrast to the cycloadditions of isoquinolinium N‐arylimides; enamines do not react with 5. The cycloadducts of 5a to dimethyl maleate, fumaronitrile, and acrylonitrile are N^β‐dienyl‐phenylhydrazines, which undergo a hydrazo rearrangement affording aminals derived from a tetracyclic system. Like enamines, the dienehydrazine system of the cycloadducts reacts with dimethyl acetylenedicarboxylate by [2 + 2] cycloaddition and electrocyclic ring opening furnishing tetrahydropyrrolo[3,2‐a]azocine derivatives. © 1999 John Wiley & Sons, Inc. Heteroatom Chem 10: 79–88, 1999