Isothiazolo pyridines

There are nine different ways of constructing fused isoxazolo- or isothiazolo-pyridines. These are the main groups into which such compounds have been classified (Chart 1). 

Four additional isomeric isothiazolo-pyridine ring-systems have been synthesized by annelating the isothiazole ring to the pre-formed pyridine ring. 

Chloro-a,/3-unsaturated aldehydes condense with ammonium thiocyanate to give isothiazoles (76EGP122249). 2,3-Diphenylcyclopropenone reacts with iV-sulfinyl-cyclohexylamine in the presence of nickel tetracarbonyl to give the isothiazolin-3-one 1-oxide (197) (79SST(5)345). Cholesteryl acetate reacts with trithiazyl trichloride in pyridine to give the isothiazolo steroid (198) (77JCS(P1)916). 

Isothiazolo[3,4-d]pyridin-4(5H)-one, 3,6-dialkyl-applications, 6, 644 2H-Isothiazolo[2,3-a]pyrimidine synthesis, 6, 640 Isothiazolo[4,3-d]pyrimidine synthesis... 

Isoxazolo[2,3-4]pyridines 44, isothiazolo[2,3-4]pyridines 46, and their fully saturated derivatives 45 and 47 (Scheme 16) were discussed in CHEC(1984) <1984CHEC(6)613> and CHEC-II(1996) <1996CHEC-II(8)249>. Very little information was available on the isothiazolo[2,3- ]pyridine ring system while most of the informations given on the oxygenated parent, isoxazolo[2,3- ]pyridines, concerned the fully saturated system. Careful examination of the literature clearly shows that the situation did not change much almost no references have been reported on isothiazolo[2,3- ]pyridines and most of the work done in the last decade concerns the synthesis and reactivity of hexahydro-isoxazolo[2,3- ] pyridines 45. Therefore, this chapter will briefly describe the new reactions of fully conjugated systems and will focus on the partially/completely saturated derivatives. 

The performance of several semi-empirical (modified neglect of diatomic overlap (MNDO), AMI, PM3, and SAMI) and ab initio (Hartree-Fock (FIF) and MP2/6-31G ) methods for determining structural and electronic factors of a series of isothiazolo[5,4-b]pyridines was compared by Martinez-Merino et al. <1996T8947>. They found that most of the semi-empirical methods calculated reasonable molecular structures when compared to the actual X-ray structures (compounds 3-5) (see, for example. Table 1 for selected bond lengths of compound 3). Flowever, the dipole moments were not reproducible using these methods. 

Some general observations for 4-nitroimidazo[4,5- ]pyridin-2-ones, imidazo[4,5- ]pyridine-2-thiones, imidazo[4,5-f]pyridine-2-thiones, imidazo[4,5- ]quinolin-2-ones, isothiazolo[5,4- ]pyridine-2-thiones, and 3/f-l,2-dithiolo[4,3-f]pyridine-3-thiones are reported in <1996CHEC-II(7)283>. The majority of compounds in this review have been isolated using standard chromatographic techniques. 

No further advances in the reactions of isothiazolo[4,5-f]pyridines have been reported since the original chapter in 1996CHEC-II(7)283. 

Coupling of the isothiazolo[5,4- ]pyridine 114 with compound 115 affords useful compounds as serine protease inhibitors (Equation 25) <2003JME4428>. 

A range of isothiazolo[5,4-3]pyridines were prepared by cyclization of thiopyridines with iodine/sodium carbonate (Equation 68) <2000FA669>. 

In the attempted synthesis of isothiazolo[5,4-3]pyridin-3(2//)-one 1,1-dioxide 172, direct oxidation of isothi-azolo[5,4-/ ]pyridin-3(2//)-one with either Oxone /MeOH, 3-chloroperoxybenzoic acid/CH2Cl2, or KMn04/AcOH did not afford the desired product. However, this compound was synthesized in good yield by treatment of 173 with chlorine in aqueous HCl and subsequent reaction with ammonia in ethanol (Scheme 14) <1996T8947>. 

The aza-Diels-Alder reaction has been used to form isothiazolo[4,5-/ ]pyridines <1996CHEC-II(7)283> in a highly diastereoselective manner (Equation 69) <2004AGE2001, 2004JOG8429>. 

Reaction of isothiazolo[5,4-/ ]pyridines, such as 189, affords the corresponding pyridothiazines 190 by rearrangement, although only general yields were reported (Equations 80) <2002FA737>. 

The isothiazolo[4,5- ]pyridine 204 has been utilized as a important intermediate in the asymmetric synthesis of (—)-methyl palustramate 205 <2004JOC8429>. 

Isothiazolo[5,4-7]pyridines, such as 189, are key intermediates in the synthesis of pyridothiazine 1,1-dioxides, which have CNS antioxidant properties <2002FA737>. 

No further reports were found for isoxazolo[5,4- ]pyridines, isoxazolo[4,5- ]pyridines, isoxazolo[4,5- ]pyridines, isothiazolo[4,3- ]pyridines, isothiazololSjd- lpyndines, isothiazolo[4,5- ]pyridines, dithiolo[4,3- ]pyridines, dithiolo[4,3- ]pyridines, dithiolo[3,4- ]pyridines, dithiolo[3,4- ]pyridines, thiopyrano[4,3-<7]isoxazoles, thiopyr-ano[3,4- ]pyrazoles, thiopyrano[4,3- ]pyrazoles, thiopyrano[2,3-c]pyrazoles or selenopyrano[2,3-< ]pyrazoles. 

A novel synthesis of isothiazolo[3,4-4]pyrimidines 395 in high yields via reaction of 393 with 394 in dichloro-methane in the presence of pyridine at room temperature has been reported (Equation 60) <20030L507>. 

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