Expedient Protocols for the Installation of 1,5‐Benzoazepino‐Based Privileged Templates on the 2‐Position of 1,4‐Benzodiazepine Through a Phenoxyl Spacer

An efficient novel strategy for the hetero‐annulation of 2‐chloro‐1,4‐benzodiazepine ring, substituted on its 5‐position with a carboxamido group ( 5 ), has been developed to allow the incorporation of 1,5‐benzodiazepine, 1,5‐benzothiazepine, and 1,5‐benzoxazepine ( 8 , 9 , 10 , 11 , 12 , 13 ) rings through their dimethylaminomethylene ketone intermediate ( 7 ).     

Synthesis of optically active af‐(1‐Ethyl‐3‐methylhexahydro‐1,3‐diazin‐5‐yl)‐ and N‐(1‐Ethyl‐5‐methyloctahydro‐1,5‐diazocin‐3‐yl)pyridine‐3‐carboxamides

As part of the structure‐activity relationship of the dopamine D₂ and serotonin 5‐HT₃ receptors antagonist 1, which is a clinical candidate with a broad antiemetic activity, the synthesis and dopamine D₂ and serotonin 5‐HT₃ receptors binding affinity of (R)‐5‐bromo‐N‐(1‐ethyl‐3‐methylhexahydro‐1,3‐diazin‐5‐yl)‐ and (R)‐5‐bromo‐N‐(1‐ethyl‐5‐methyloctahydro‐1,5‐diazocin‐3‐yl)‐2‐methoxy‐6‐methylaminopyridine‐3‐carboxam‐ides ( 2 and 3 ) are described. Treatment of 1‐ethyl‐2‐(p‐toluenesulfonyl)amino‐3‐methylaminopropane dihy‐drochloride ( 4a ) with paraformaldehyde and successive deprotection gave the 5‐aminohexahydro‐1,3‐diazine 6 in excellent yield. 3‐Amino‐1‐ethyl‐5‐methyloctahydro‐1,5‐diazocine ( 15 ) was prepared from 2‐(benzyloxycarbonyl)amino‐3‐[[N‐(tert‐butoxycarbonyl)‐N‐methyl]amino]‐1‐ethylaminopropane ( 9 ) through the intramolecular amidation of (R)‐3‐[N‐[(2‐benzyloxycarbonylamino‐3‐methylamino)propyl]‐N‐ethyl]aminopropionic acid trifluoroacetate ( 12 ), followed by lithium aluminum hydride reduction of the resulting 6‐oxo‐1‐ethyl‐5‐methyloctahydrodiazocine ( 13 ) in 41% yield. Reaction of the amines 6 and 15 with 5‐bromo‐2‐methoxy‐6‐methylaminopyridine‐3‐carboxylic acid furnished the desired 2 and 3 , which showed much less potent affinity for dopamine D₂ receptors than 1 .     

Synthesis of Glycaro‐1,5‐lactams and Tetrahydrotetrazolopyridine‐5‐carboxylates: Inhibitors of β‐D‐Glucuronidase and α‐L‐Iduronidase

The known glucaro‐1,5‐lactam 8 , its diastereoisomers 9 – 11 , and the tetrahydrotetrazolopyridine‐5‐carboxylates 12 – 14 were synthesised as potential inhibitors of β‐D ‐glucuronidases and α‐L ‐iduronidases. The known 2,3‐di‐O‐benzyl‐4,6‐O‐benzylidene‐D ‐galactose ( 16 ) was transformed into the D ‐galactaro‐ and L ‐altraro‐1,5‐lactams 9 and 11 via the galactono‐1,5‐lactam 21 in twelve steps and in an overall yield of 13 and 2%, respectively. A divergent strategy, starting from the known tartaric anhydride 41 , led to the D ‐glucaro‐1,5‐lactam 8 , D ‐galactaro‐1,5‐lactam 9 , L ‐idaro‐1,5‐lactam 10 , and L ‐altraro‐1,5‐lactam 11 in ten steps and in an overall yield of 4–20%. The anhydride 41 was transformed into the L ‐threuronate 46 . Olefination of 46 to the (E)‐ or (Z)‐alkene 47 or 48 followed by reagent‐ or substrate‐controlled dihydroxylation, lactonisation, azidation, reduction, and deprotection led to the lactams 8 – 11 . The tetrazoles 12 – 14 were prepared in an overall yield of 61–81% from the lactams 54, 28 , and 67 , respectively, by treatment with Tf₂O and NaN₃, followed by saponification, esterification, and hydrogenolysis. The lactams 8 – 11 and 40 and the tetrazoles 12 – 14 are medium‐to‐strong inhibitors of β‐D ‐glucuronidase from bovine liver. Only the L ‐ido‐configured lactam 10 (K_i = 94 μM ) and the tetrazole 14 (K_i = 1.3 mM ) inhibit human α‐L ‐iduronidase.     

Rhodium(III)‐Catalyzed ortho CH Heteroarylation of (Hetero)aromatic Carboxylic Acids: A Rapid and Concise Access to π‐Conjugated Poly‐heterocycles

Rh^III‐catalyzed oxidative C? H/C? H cross‐coupling between (hetero)aromatic carboxylic acids and various heteroarenes has been accomplished to construct highly functionalized ortho‐carboxy‐substituted bi(hetero)aryls. The use of a carboxy group as the directing group obviates tedious steps for installation and removal of extra directing groups, and enables a facile one‐step synthesis of ortho‐carboxy bi(hetero)aryls. The method provides opportunities for rapid assembly of a library of important fluorene and coumarin‐type poly‐heterocycles through intramolecular electrophilic substitution or oxidative lactonization. As illustrative examples, the strategy developed herein greatly streamlines accesses to a variety of appealing polyheterocycles such as DTPO (5H‐dithieno[3,2‐b:2′,3′‐d]pyran‐5‐one), CPDTO (cyclopentadithiophen‐4‐one), and indenothiophenes.     

Reaction of 2,3‐Dichloro‐1,4‐Naphthoquinone with 1‐Phenylbiguanide and 2‐Guanidinebenzimidazole

When 2,3‐dichloro‐1,4‐naphthoquinone (DCHNQ) ( 1 ) is allowed to react with 1‐phenylbiguanide (PBG) ( 2 ), 4‐chloro‐2,5‐dihydro‐2,5‐dioxonaphtho[1,2‐d]imidazole‐3‐carboxylic acid phenyl amide ( 4 ), 6‐chloro‐8‐phenylamino‐9H‐7,9,11‐triaza‐cyclohepta[a]naphthalene‐5,10‐dione ( 5 ) and 4‐dimethyl‐amino‐5,10‐dioxo‐2‐phenylimino‐5,10‐dihydro‐2H‐benzo[g]quinazoline‐1‐carboxylic acid amide ( 6 ) were obtained. While on reacting 1 with 2‐guanidinebenzimidazole (GBI) ( 3 ) the products are 3‐(1H‐benzoimidazol‐2‐yl)‐4‐chloro‐3H‐naphtho[1,2‐d]imidazole‐2,5‐dione ( 7 ) and 3‐[3‐(1H‐benzoimidazol‐2‐yl)‐ureido]‐1,4‐dioxo‐1,4‐dihydronaphthalene‐2‐carboxylic acid dimethylamide ( 8 ).     

Synthesis and conversion of 2‐(pyrazol‐1‐yl)quinoxaline 4‐oxides

The reaction of 6‐chloro‐2‐hydrazinoquinoxaline 4‐oxide 1b with acetylacetone or benzoylacetone gave 6‐chloro‐2‐(3,5‐dimethylpyrazol‐i‐yl)quinoxaline 4‐oxide 5a or 6‐chloro‐2‐(3‐methyl‐5‐phenylpyrazol‐1‐yl)quinoxaline 4‐oxide 5b , respXectively. Compound 5a or 5b was converted into the pyrrolo[1,5‐a]quinoxaline 6a or 6b , triazolo[4,3‐a]quinoxaline 9a or 9b , and tetrazolo[1,5‐a]quinoxaline 10.     

Solvent‐free synthesis of 5‐methyl‐7‐aryl‐4,7‐dihydrotetrazolo[1,5‐a]pyrimidine‐6‐carboxylic esters catalyzed by sulfamic acid

The solvent‐free synthesis of 5‐methyl‐7‐aryl‐4,7‐dihydrotetrazolo[1,5‐a]pyrimidine‐6‐carboxylic esters was performed and effectively catalyzed by sulfamic acid. Compared with conventional methods, this protocol features mild reaction conditions and high yields. Furthermore, it is solvent‐free and thus eco‐friendly.     

Cytotoxicities and Topoisomerase I Inhibitory Activities of 2‐[2‐(2‐Alkynylphenyl)ethynyl]benzonitriles, 1‐Aryldec‐3‐ene‐1,5‐diynes,and Related Bis(enediynyl)arene Compounds

The activities of a series of acyclic enediynes, 2‐(6‐substituted hex‐3‐ene‐1,5‐diynyl)benzonitriles ( 1 – 5 ) and their derivatives 7 – 23 were evaluated against several solid tumor cell lines and topoisomerase I. Compounds 1 – 5 show selective cytotoxicity with Hepa cells, and 2‐[6‐phenylhex‐3‐ene‐1,5‐diynyl]benzonitrile ( 5 ) reveals the most‐potent activity. Analogues 8 – 10 and 13 – 22 also have the same effect with DLD cells; 1‐[(Z)‐dec‐3‐ene‐1,5‐diynyl)‐4‐nitrobenzene 21 shows the highest activity among them. Moreover, 1‐[(Z)‐dec‐3‐ene‐1,5‐diynyl]‐2‐(trifluoromethyl)benzene ( 20 ) exhibits the strongest inhibitory activity with the Hela cell line. Derivatives 9, 10, 18 , and 23 display inhibitory activities with topoisomerase I at 87 μM . The cell‐cycle analysis of compound 5 , which induces a significant blockage in S phase, indicates that these novel enediynes probably undergo other biological pathways leading to the cytotoxicity, except the inhibitory activity toward topoisomerase I.     

7‐Amino‐2‐methylsulfanyl‐1,2,4‐triazolo[1,5‐a]pyrimidine‐6‐carboxylic acid as the dimethylformamide and water monosolvates at 293 K

The molecular structure of 7‐amino‐2‐methylsulfanyl‐1,2,4‐triazolo[1,5‐a]pyrimidine‐6‐carboxylic acid is reported in two crystal environments, viz. as the dimethylformamide (DMF) monosolvate, C₇H₇N₅O₂S·C₃H₇NO, (I), and as the monohydrate, C₇H₇N₅O₂S·H₂O, (II), both at 293 (2) K. The triazolo[1,5‐a]pyrimidine molecule is of interest with respect to the possible biological activity of its coordination compounds. While the DMF solvate exhibits a layered structural arrangement through N...O hydrogen‐bonding interactions, the monohydrate displays a network of intermolecular O...O and N...O hydrogen bonds assisted by cocrystallized water molecules and weak π–π stacking interactions, leading to a different three‐dimensional supramolecular architecture. Based on results from topological analyses of the electron‐density distribution in X—H...O (X = O, N and C) regions, hydrogen‐bonding energies have been estimated from structural information only, enabling the characterization of hydrogen‐bond graph energies.     

Facile preparation of 7,11‐di(4‐nitrobenzenesulfonyl)‐diaza‐1,4‐dioxa‐7,11‐spiro[4,7]dodecan‐9‐one

Compound 1 as a key intermediate for the synthesis of 3,3,7,7‐tetrakis‐(difluoroamino)octahydro‐1,5‐dinitro‐1,5‐diazocine (HNFX) and 3,3‐bis(difluoroamino)octahydro‐1,5,7,7‐tetranitro‐1,5‐diazocine (TNFX) is described. Cycloalkylation of 3 with 1,3‐dibromopropan‐2‐ol ( 4 ) afforded 1,5‐protected‐1,5‐diazocine 2 , followed by chromic acid oxidation to ketone 1 in good yield.     

Synthesis of 2,5,7‐Triaryl‐4,7(6,7)‐dihydropyrazolo[1,5‐a]pyrimidine‐3‐carbonitriles by Reaction of 5(3)‐Amino‐3(5)‐aryl‐1H‐pyrazole‐4‐carbonitriles with Chalcones

The reaction of 5(3)‐amino‐3(5)‐aryl‐1H‐pyrazole‐4‐carbonitriles with 1,3‐diaryl‐2‐propen‐1‐ones (chalcones) in refluxing DMF leads to 2,5,7‐triaryl‐4,7(6,7)‐dihydropyrazolo[1,5‐a]pyrimidine‐3‐carbonitriles. In DMSO solution, the latter exist in equilibrium of two tautomeric 4,7‐dihydropyrazolo[1,5‐a]pyrimidines and 6,7‐dihydropyrazolo[1,5‐a]pyrimidines in various ratios, depending on the nature of aryl substituents in chalcone building blocks.     

First synthesis of 2‐(2,4,4‐trimethyl‐3,4‐dihydro‐2H‐benzo[h]chromen‐2‐yl)‐1‐naphthol and 3‐(2,4,4‐trimethyl‐3,4‐dihydro‐2H‐benzo[g]chromen‐2‐yl)‐2‐naphthol from 1‐ and 2‐naphthol derivatives

Two new structurally isomeric, 2‐(2,4,4‐trimethyl‐3,4‐dihydro‐2H‐benzo[h]chromen‐2‐yl)‐1‐naphthol ( 1 ) and 3‐(2,4,4‐trimethyl‐3,4‐dihydro‐2H‐benzo[g]chromen‐2‐yl)‐2‐naphthol ( 3 ) have been synthesized from 2‐acetyl‐1‐naphthol and ethyl‐3‐hydroxy‐2‐naphthoate, respectively, involving Grignard reaction, dehydration of the corresponding tertiary alcohols, and hetero Diels–Alder dimerization. The two benzochromenes ( 1 and 3 ) have been fully characterized by IR, NMR, and HRESIMS data. Their structures are further supported by crystallography of their corresponding acetates ( 2 and 4 ). J. Heterocyclic Chem., (2011).     

Hetaryl‐1,5 Benzodiazepines—Part I: Synthesis of 3‐pyrimidinyl‐ and Imidazolyl‐1,5‐benzodiazepines

Nucleophilic substitution of 3‐bromo‐4‐phenyl‐1H‐[1,5]benzodiazepin‐2‐one ( 1 ) with thiourea or guanidine in presence of potassium carbonate afforded 1,5‐benzodiazepin‐3‐ylimidothiocarbamate 2 or 1,5‐benzodiazepin‐3‐ylguanidine 3 , respectively. Pyrimidylthiobenzodiazepines 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 were obtained via the reaction of compound 2 with malononitrile dimer, diethyl malonate, methylenemalononitriles, or a mixture of an aldehyde and β‐keto esters or acetylacetone, catalyzed using ceric ammonium nitrate. Reaction of compound 2 or 3 with α‐halo esters, nitriles, and/or ketones afforded imidazoles 14 , 15 , 16 , 17 , 18 , 19 , 20 , respectively.     

Study of the Reaction of 5‐Aryl‐7‐hydrazino‐2‐phenylpyra‐zolo[1,5‐c]pyrimidines with 1,3‐Dicarbonyl Compounds

A novel synthetic method for the preparation of 5‐aryl‐7‐(3,5‐dimethyl‐1H‐pyrazol‐1‐yl)‐2‐phenylpyrazolo[1,5‐c]‐pyrimidines and 1‐(5‐aryl‐2‐phenylpyrazolo[1,5‐c]pyrimidin‐7‐yl)‐3‐methyl‐1H‐pyrazol‐5‐ols is provided by condensative cyclization of 5‐aryl‐7‐hydrazino‐2‐phenylpyrazolo[1,5‐c]pyrimidines with 1,3‐dicarbonyl compounds. The study of the more reactive position for electrophilic substitusion reactions on such ring system was also achieved.     

Dimethyl Acetylenedicarboxylate in Reactions with Substituted 3‐(2‐aminophenyl)‐6‐R1‐1,2,4‐triazin‐5‐(2H)‐ones: Structure and Properties of the Products

The article describes unusual [5 + 1]‐cyclocondensations of dimethyl acetylenedicarboxylate (DMAD), in which this reagent uncharacteristically acts as a 1,1‐biselelectrophilic agent. Reactions of DMAD with 1,5‐bisnucleophilic 3‐(2‐aminophenyl)‐6‐R¹‐1,2,4‐triazin‐5(2H)‐ones yielded triazinoquinazoline‐derived diesters. The latter was shown to react with nucleophiles: hydrazine cleaved the pyrimidine ring of the diesters to give anilines, while ester hydrolysis furnished corresponding carboxylic acids.     

Oxazepines and thiazepines. 41 . Synthesis of 4‐aryl‐2,3‐dihydro‐2‐styryl‐1,5‐benzothiazepines by the reaction of (E,E)‐cinnamylideneacetophenones with 2‐aminothiophenol and their conversion into 2,2‐disubstituted 3‐acetyl‐2,3‐dihydrobezothiazoles

New 4‐aryl‐2,3‐dihydro‐2‐styryl‐1,5‐benzothiazepines 8–13 have been synthesized by an acid catalyzed reaction of 2‐arninothiophenol ( 1 ) and (E,E)‐cinnamylideneacetophenones 2–7. Ring contraction of 1,5‐benzothiazepines 8–13 provided 2,2‐disubstituted 3‐acetyl‐2,3‐dihydrobenzothiazoles 14–19 under acetylating conditions.     

Synthesis and Antimicrobial Activity of Racemic 1,5‐Diols: 2‐(1,3‐Diaryl‐3‐hydroxypropyl)cyclohexan‐1‐ol Derivatives

A series of novel racemic 2‐(1,3‐diaryl‐3‐hydroxypropyl)cyclohexan‐1‐ol derivatives were synthesized from 1,5‐diketones. All the synthesized compounds were characterized by spectroscopic methods. The antibacterial activities of obtained chiral 1,5‐diols were investigated against four Gram‐positive and three Gram‐negative bacteria by determining of minimum inhibitory concentrations (MICs) in vitro. Compounds 3b , 3c , and 3d were found to be active against Enterococcus faecalis and Escherichia coli. In addition, compound 3j were found to be moderately active against all tested bacterial strains.     

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.     

Synthesis of some novel pyrazolo[1,5‐a]pyrimidine, 1,2,4‐triazolo[1,5‐a]pyrimidine,pyrido[2,3‐d]pyrimidine,pyrazolo[5,1‐c]‐1,2,4‐triazine and 1,2,4‐triazolo[5,1‐c]‐1,2,4‐triazine derivatives incorporating a thiazolo[3,2‐a]benzimidazole moiety

E‐3‐(N,N‐Dimethylamino)‐1‐(3‐methylthiazolo[3,2‐a]benzimidazol‐2‐yl)prop‐2‐en‐1‐one ( 2 ) was synthesized by the reaction of 1‐(3‐methylthiazolo[3,2‐a]benzimidazol‐2‐yl)ethanone ( 1 ) with dimethylformamide‐dimethylacetal. The reaction of 2 with 5‐amino‐3‐phenyl‐1H‐pyrazole ( 4a ) or 3‐amino‐1,2,4‐(1H)‐triazole ( 4b ) furnished pyrazolo[1,5‐a]pyrimidine and 1,2,4‐triazolo[1,5‐a]pyrimidine derivatives 6a and 6b , while the reaction of enaminone 2 with 6‐aminopyrimidine derivatives 7a,b afforded pyrido[2,3‐d]pyrimidine derivatives 9a,b , respectively. The diazonium salts 11a or 11b coupled with compound 2 to yield the pyrazolo[5,1‐c]‐1,2,4‐triazine and 1,2,4‐triazolo[5,1‐c]‐1,2,4‐triazine derivatives 13a and 13b . Some of the newly synthesized compounds exhibited a moderate effect against some bacterial and fungal species.