Expedient preparation of trifluoromethyl-substituted benzofuranols

Direct access to 3-trifluoromethyl-substituted benzofuranols is presented. The products are obtained in good yields from commercially available salicylaldehydes by using in situ generated trifluoromethyl diazomethane and boron trifluoride as an activator. As shown in a representative example, the products can be transformed into the corresponding trifluoromethyl-substituted benzofurans.     

Preparation of 1H‐pyrazole‐5‐carboxamides from dilithiated C(α), N‐phenylhydrazones and lithiated ethyl oxanilates or lithiated ethyl oxamate

Dilithiated C(α), N‐phenylhydrazones were prepared in excess lithium diisopropylamide and condensed with either ethyl oxanilate, ethyl 4′‐chlorooxanilate, or ethyl oxamate to give intermediates that were quenched and acid cyclized to substituted lH‐pyrazole‐5‐carboxamides.     

Efficient synthesis of pyrimido[5,4‐c]pyridazines and of thiino[2,3‐d]pyrimidines based on an aza‐wittig reaction/heterocyclization strategy

A simple one‐pot and efficient method is described for the synthesis of pyrimido[5,4‐c]pyridazines 5 and of thiino[2,3‐d] pyrimidines 15 by a domino process involving an aza‐Wittig reaction/heterocyclization. The iminophosphorane 2 reacted with phenylisocyanate, followed by heterocyclization on addition of amines to give the corresponding guanidine intermediates 4 . The guanidine intermediates were cyclized in the presence of catalytic amount of sodium ethoxide to pyrimido[5,4‐c]pyridazines 5 . Similarly, iminophosphorane 12 reacted with phenylisocyanate and amines to give thiino[2,3‐d]pyrimidines 15 in moderate yields. Furthermore, pyridazino[4,3‐d]oxazines 10 and thiino[2,3‐d]oxazines 19 were synthesized by the intremolecular aza‐Wittig reaction of phosphazenes 2 and 12 , respectively, with acid chlorides followed by heterocylization via imidoyl chloride intermediates. J. Heterocyclic Chem., (2012).     

The preparation of N-(1H-pyrazol-3-yl)arylamides and 1H-pyrazol-3-amines from polylithiated C(α),N-thiosemicarbazones and C(α),N-semicarbazones

C(α),N-Thiosemicarbazones or C(α),N-semicarbazones were polylithiated with excess lithium diiso-propylamide, and the resulting cyclized intermediates were condensed with aromatic esters to afford N-(1H-pyrazol-3-yl)arylamides. The polylithiated intermediates were also quenched with aqueous acid to give 5-substituted, 1H-pyrazol-3-amines.     

Reactions of dilithiooximes,dilithiophenylhydrazones and trilithiohydrazones with nitriles. Acid-cyclization to isoxazoles or pyrazoles

Certain C(α)O-dilithiooximes, C(α)N-dilithiophenylhydrazones, and C(α)N,N-trilithiohydrazones were treated with a variety of nitriles. The intermediates were not isolated, but cyclized with acid to give isoxazoles or pyrazoles.     

Synthesis of 4-aminothieno[2,3-b] pyridine-5-carboxylie acids

2-Amino-3-cyanothiophenes were reacted with ethyl aminocrotonate in the presence of catalytic amounts of p-toluensulfonic acid. The intermediates 2-[N-(3′-ethoxycarbonyl-2′-propenylamino]-3-cyanothiophenes obtained were cyclized with sodium ethoxide to give the desired ethyl 4-aminothieno[2,3-b] pyridine-5-carboxylate. Hydrolysis of the latter aminoesters afforded 4-aminothieno[2,3-b]pyridine-5-carboxylic acid. The overall yields were about 80%.     

Synthesis of 4-thiocarbamoyl-5-aminopyrazoles

Aryl and t-butylhydrazines react with 2-cyano-3-ethoxythiocrotonamide affording 2-cyano-3-aryl-t-butylhy-drazinothiocrotonamides. These intermediates can be easily cyclized to 4-thiocarbamoyl-5-aminopyrazoles by heating a few minutes in a strong base. Alkylhydrazines react with 2-cyano-3-ethoxythiocrotonamide yielding directly a mixture of the cyclized compounds 4-cyano-5-aminopyrazoles and 4-thiocarbamoyl-5-aminopyr-azoles.     

Synthesis of 4,10-dihydro-4,10-dioxo-1H[1]benzothiopyrano[3,2-B]pyridine and 7-oxo-7,13-dihydro[1]benzothiopyrano[2,3-b]-1,5-benzodiazepine

3-Amino-4H-1-benzothiopyran-4-one (3-aminothiochromone) was easily prepared by reaction of 3-bromo-thiochromen-4-one with sodium azide in methanol-water. Condensation of 3-aminothiochromone with diethyl ethoxymethylenemalonate and with dimethyl acetylenedicarboxylate gave intermediates, which were thermally cyclized to give 4,10-dihydro-4,10-dioxo-1H[1]benzothiopyrano[3,2-b]pyridinecarboxylates. 3-Formyl-thiochromone was condensed with o-phenylenediamine to give 7-oxo-7,13-dihydro[1]benzothiopyrano[2,3-b]-1,5-benzodiazepine.     

Preparation of substituted 1,2‐Dihydro‐3H‐pyrazol‐3‐ones from polylithiated 2′‐phenylphenylacetohydrazides and aromatic esters

Several 2′‐phenylphenylacetohydrazides were polylithiated with excess lithium diisopropylamide, and the resulting intermediates were condensed with several aromatic esters to afford C‐acylated intermediates that were not usually isolated, but acid cyclized directly to 1,4,5‐trisubstituted, 1,2‐dihydro‐3H‐pyrazol‐3‐ones.     

The preparation of 4,5-dihydro-2H-benz[e]indazoles from dilithiated 2-tetralone phenylhydrazone and aromatic esters

The phenylhydrazone of 2-tetralone was dilithiated with excess lithium diisopropylamide followed by condensation with several aromatic esters, and the resulting intermediates were acid cyclized to 4,5-dihydro-2H-benz[e]indazoles.     

Substituted 2,3,4,5-tetrahydro-1H-3-benzazepine and 2,3,4,5-tetrahydro-1H-naphth[1,2-d] azepine derivatives

The multi-step synthetic procedures to prepare a number of 2,3,4,5-tetrahydro-1H-benzazepine derivatives 1 through a series of intermediates are described. The condensation of arylaldehydes 2 with 2-nitropropanes 3 gave nitroalcohols 4 which were reduced to alcohol amines 5 . The condensation of 5 with arylacetaldehydes 6 gave imino derivatives 7 which on reduction with borohydride gave secondary amines 8 . By employing different methods, alcohol amines 5 were condensed with arylacetic acids 9 to give amides 10 which were then reduced to amines 8 . On treatment with mineral acids, amines 8 were cyclized to the target compounds 1 . Biological activities of 1 are also briefly discussed.     

Synthesis of 4,10-dihydro-4,10-dioxo-1H-[1]-benzopyrano[3,2-b]pyridine, 4,5-Dihydro-4,5-dioxo-1H-[1]-benzopyrano[2,3–6]pyridine and 1,5-Dihydro-1,5-dioxo-4H-[1]-benzopyrano[3,4-b]pyridine derivatives from aminobenzopyrones

3-Aminochromone and 3-aminocoumarin were condensed with diethyl ethoxymethylenemalonate and with dimethyl acetylenedicarboxylate to give intermediates, which were thermally cyclized to give 4,10-dihydro-4,10-dioxo-lH-[1]-benzopyrano[3,2-b]pyridinecarboxylates and 1,5-dihydro-1,5-dioxo-4H-[1]-benzopyrano-[3,4-b]pyridinecarboxylates. 2-Aminochromone was converted to 4,5-dihydro-4,5-dioxo-1H-[1]-benzopyrano-[2,3-b]pyridinecarboxylate via an intermediate condensation product with diethyl ethoxymethylenemalonate. These esters were hydrolyzed to the corresponding carboxylic acids (21, 30, 36, 50, and 60). Attempts to prepare 4,5-dihydro-4,5-dioxo-1H-[1]-benzopyrano[4,3-b]pyridinecarboxylates from 4-aminocoumarin were unsuccessful.     

2-Benzazepines. 7. Synthesis of pyrimido[5,4-d][2]benzazepines

Two novel syntheses of pyrimido[5,4-d][2]benzazepines are described. The first synthesis started with 3-phenylphthalide which in three steps was converted to a functionalized pyrimidine which was cyclized to give the 2-benzazepine ring system. The second approach used o-benzoylbenzoic acid methyl ester as the starting material, which in four steps was converted to a functionalized pyrimidine which was cyclized to give a 2-benzazepine. Pyrimido[5,4-d][2]benzazepines have been found to have activity in standard central nervous system (CNS) pharmacological tests.     

The Preparation Of 2-[4,5-Dihydro-3-Aryl-5-Isoxazolyl]-Phenols From C(α),O-Dilithiooximes and Lithiated Hydroxyaryl Aldehydes

C(a), O-Oximes were dilithiated in excess lithium diisopropylamide, and the resulting intermediates were condensed with lithiated hydroxyphenyl aldehydes and related materials and cyclized with acid to afford 2-[4,5-dihydro-3-aryl-5-isoxazolyl]phenols, substituted 4,5-dihydroisoxazoles (2-isoxazolines).     

The preparation of heterocyclic materials from 2-isocyanatobenzoyl chloride and difunctional nucleophiles

2-Isocyanatobenzoyl chloride was treated with difunctional nucleophiles such as o-phenylenediamine, 1,8-diaminonaphthalene, o-aminothiophenol, and thioacetamide. The diaminonucleophiles gave intermediates which were thermally cyclized, and the other nucleophilic reagents gave heterocyclic materials directly.     

Oxidative cyclization of 2-aryl-3-arylamino-2-alkenenitriles to N-arylindole-3-carbonitriles mediated by NXS/Zn(OAc)2

A variety of 2-aryl-3-arylamino-2-alkenenitriles were converted to N-arylindole-3-carbonitriles in a one-pot manner through NBS- or NCS-mediated halogenation followed by Zn(OAc)(2)-catalyzed intramolecular cyclization. It is postulated that the process involves the formation of arylnitrenium ion intermediates, which undergo the electrophilic aromatic substitution to give the cyclized N-arylindole product.     

The chemistry of 2H-3,1-benzoxazine-2,4(1H)-dione (isatoic anhydride). 18. A short synthesis of swietenidin A

N-Methylisatoic anhydrides react with the lithium enolate of ethyl methoxyacetate at low temperatures to produce intermediates which, when cyclized, afford 4-hydroxy-3-methoxy-2(1H)-quinolinones. By this route, 3-methoxy-N-methylisatoic anhydride ( 8 ) can be converted to the alkaloid swietenidin A (2) in 71% yield.     

A new synthesis of 2-substituted benzofurans and benzothiophens: Novel fragmentation reactions of simple alkyl groups

Flash vacuum pyrolysis of (2-methoxy- and (2-methylthiobenzoyl)alkylidenetriphenylphosphoranes results in loss of Ph₃PO and methyl radical; cyclisation of the resulting radical intermediates leads to benzofurans and benzothiophens in which the 2-substituents have undergone novel fragmentation processes.     

Preparation of 4-pyrimidinetliiones from acyl lsothiocyanate-enamine adducts

Adducts formed from benzoyl isothiocyanate and l-morpholinocyclopentene or β-(N,N-diethylamino)styrene and that prepared from acetyl isothiocyanate and l-pyrrolidinoeyclopen-tene gave 4-pyrimidinethiones when treated with primary amines or ammonia. In some cases intermediates, the products of amine exchange, were isolated. These intermediates were readily cyclized to 4-pyrimidinethiones with dilute alkali.     

Preparation of 2-[1-Phenyl-1H-pyrazol-5-yl]benzoic Acids from Dilithiated C(α),N-Phenylhydrazones and Methyl Hydrogen Phthalate

Select C(α),N-phenylhydrazones were dilithiated with excess lithium diisopropylamide to their dianion-type intermediates followed by condensation with methyl hydrogen phthalate. The resulting C-acylated hydrazones were not isolated but acid cyclized directly to afford new substituted 2-(1-phenyl-1H-pyrazol-5-yl)benzoic acids.