New regiospecific isothiazole C–C coupling chemistry

Abstract

Regioselective palladium catalysed coupling reactions are achieved in good to high yields, starting from either 3,5-dichloro- or 3,5-dibromoisothiazole-4-carbonitriles 1 and 2, providing 3-halo-5-(hetero/aryl, alkenyl and alkynyl)isothiazoles 3, 4, 6-9 from Stille couplings, 3-halo-5-(hetero/arylethynyl)isothiazoles 14-19 from Sonogashira and 5,5'-bi(3-chloroisothiazole-4-carbonitrile) (13) from an Ullmann type coupling. 3,5-Dibromoisothiazole-4-carbonitrile 2 is more reactive than the dichloroisothiazole-4-carbonitrile 1 and effective enough for Stille, Negishi and Sonogashira couplings. 5,5-Bi(3-chloroisothiazole-4-carbonitrile) (13) is prepared by a palladium catalysed Ullmann coupling from 3-chloro-5-iodoisothiazole-4-carbonitrile (11). A variety of 3-substituted isothiazoles (3-substituents = Cl, Br, OMs, OTs and OTf) are less reactive and fail to give successful Suzuki couplings at the isothiazole C-3 position. The 3-iodo-5-phenyl-isothiazole-4-carbonitrile (28), prepared via Sandmeyer iodination, participates successfully in Suzuki, Ullmann type, Stille, Negishi and Sonogashira coupling reactions. All products are fully characterized.

The conversion of isothiazoles into pyrazoles using hydrazine

“…11 Recently we tried to prepare 3-hydrazino-5-phenylisothiazole-4-carbonitrile 3 from 3-chloro-5-phenylisothiazole-4-carbonitrile 1 using neat anhydrous hydrazine but obtained in quantitative yield 3-amino-5-phenylpyrazole-4-carbonitrile 2 (Scheme 1). 12 This pyrazole, first prepared by treating [2-methoxy(phenyl)methylene]-malononitrile with hydrazine monohydrate, 13 when in solution is in a dynamic solvent dependent prototropic equilibrium [14][15][16][17] with isomer 5-amino-3-phenylpyrazole-4-carbonitrile. No attempt to differentiate between prototropic isomers will be presented here.…”

The Conversion of 5,5′-Bi(1,2,3-dithiazolylidenes) into Isothiazolo[5,4-d]isothiazoles

“…Moreover our efforts to carry out Suzuki-Miyaura [PhB(OH) 2 (3 equiv), KF (3.5 equiv), 18-crown-6 (0.5 equiv), Pd(OAc) 2 (10 mol %), PhMe, 110 °C], Stille [PhSnBu 3 (3 equiv), Pd(Oac) 2 (10 mol %), DMF, 100 °C or Pd Superstable (10 mol %), PhMe, 110 °C] or Sonogashira couplings [phenylacetylene (2.2 equiv), Et 3 N (4 equiv), PdCl 2 (Ph 3 P) 2 (5 mol %), MeCN, 100 °C] led to only traces of product and mainly gave degradation of the ring system. The difficulty in displacing isothiazole C3 chlorides has been previously reported [45,46,47]. Analysis of the reaction mixtures (TLC) revealed S 8 (TLC) supporting ring cleavage, presumably owing to a thiophilic attack.…”

Synthesis of 5-Substituted 3-Amino-1H-Pyrazole-4-Carbonitriles as Precursors for Microwave Assisted Regiospecific Syntheses of Pyrazolo[1,5-a]Pyrimidines

“…δ H = 9 and 10 ppm. There are alternative procedures described in the literature for the preparation of 8a,b by treating arylmethylenemalononitrile with hydrazine [ 9 , 10 ] or via transformation of isothiazoles and isoxazoles into pyrazoles 8a,b using hydrazines [ 11 ]. In the present article, the condensation reaction of 3-amino-1 H -4-pyrazolecarbonitrile derivatives 8a-c with enaminone 2c and enaminonitrile 9, recently prepared in our laboratory [ 12 ], is examined.…”