Isothiazole cycloaddition reaction

Lithioisothiazoles are readily prepared by the action of butyllithium, and the isothiazole ring is desulfurized by Raney nickel (see Section 4.02.1.8). Few cycloaddition reactions are known. 

Few isothiazoles undergo simple cycloaddition reactions. 4-Nitroisothiazoles add to alkynes (see Section 4.17.7.4). With 5-thiones (84) and dimethyl acetylenedicarboxylate, addition to both sulfur atoms leads to 1,3-dithioles (85) (77SST(4)339, 80H(14)785, 81H(16)156, 81H(16)595). Isothiazol-3-one 1-oxide and the corresponding 1,1-dioxide give normal adducts with cyclopentadiene and anthracene (80MI41700), and saccharin forms simple 1 1 or 1 2 adducts with dimethyl acetylenedicarboxylate (72IJC(B)881). 

Isothiazole-4,5-dicarboxylic acid, 3-phenyl-dimethyl ester synthesis, S, 150 Isothiazole-5-glyoxylic acid ethyl ester reduction, 6, 156 Isothiazole-4-mercurioacetate reactions, 6, 164 Isothiazole-5-mercurioacetate reactions, 6, 164 Isothiazoles, 6, I3I-I75 acidity, 6, 141 alkylation, 6, 148 aromaticity, S, 32 6, 144-145 basicity, 6, I4I biological activity, 6, 175 boiling points, 6, I43-I44, 144 bond fixation, 6, 145 bond orders, 6, I32-I34 calculated, 6, 133 bromination, S, 58 6, 147 charge densities, 6, 132-134 cycloaddition reactions, 6, 152 desulfurization, S, 75 6, 152 deuteration, S, 70... 

Individual aspects of nitrile oxide cycloaddition reactions were the subjects of some reviews (161 — 164). These aspects are as follows preparation of 5-hetero-substituted 4-methylene-4,5-dihydroisoxazoles by nitrile oxide cycloadditions to properly chosen dipolarophiles and reactivity of these isoxazolines (161), 1,3-dipolar cycloaddition reactions of isothiazol-3(2//)-one 1,1-dioxides, 3-alkoxy- and 3-(dialkylamino)isothiazole 1,1-dioxides with nitrile oxides (162), preparation of 4,5-dihydroisoxazoles via cycloaddition reactions of nitrile oxides with alkenes and subsequent conversion to a, 3-unsaturated ketones (163), and [2 + 3] cycloaddition reactions of nitroalkenes with aromatic nitrile oxides (164). 

The meso-ionic l,3>2-oxathiazol-5-ones (169) show an interesting range of reactions with nucleophiles including ammonia, primary amines, and aqueous alkali. They also react with l,3-dipolarophiles, including dimethyl acetylenedicarboxylate and methyl propiolate, yielding isothiazoles (171) and carbon dioxide. 1,3-Dipolar cycloaddition reactions with alkenes such as styrene, dimethyl maleate, and methyl cinnamate also lead to isothiazoles (171) directly. BicycUc intermediates (cf. 136) were not isolable these cycloaddition reactions with alkenes giving isothiazoles involve an additional dehydrogenation step. 

Rees and co-workers in their study of the reactions of trithiazyl trichloride in the preparations of heterocyclic compounds have noted that the isothiazolo[5,4-, isothiazole compound 140 was produced in low yield on reaction with conjugated dienes, along with the other heterocyclic systems 142-145 in much higher yields (Equation 28). Since it is known that trithiazyl trichloride is in thermal equilibrium with its monomer NSCl (Equation 29), the authors propose the so-called criss-cross cycloaddition reaction (Equation 30) which has been reported for azabu-tadienes, but this represents the first example of such a criss-cross cycloaddition to an all-carbon diene <1998CC1207>. 

Few examples of functionalization on the benzene ring of benzisothiazole have been reported (see Section 4.05.7.2). Studies on the reactivity of unsaturated chains in cycloaddition reactions have been reported (see Section 4.05.7.3). The high reactivity of 4-vinylisothiazolin-3-one A-oxides in Diels-Alder cycloadditions, both as diene and dienophile, is illustrated by their tendency to dimerize. 5-Vinylisothiazole A,A-dioxides react at the vinyl function with different 1,3-dipoles. Isothiazolo-3-sulfolenes 265 give an o-quinodimethane which can be trapped with a dienophile. Different isothiazole derivatives substituted with a carbon chain functionalized with heteroatoms have been prepared as ligands for the formation of complexes. 3-Oxocamphorsulfonimide reacts with the anion of alkynes and several studies on the reactivity of the products with electrophiles are reported. 

The 5-bromo derivative 136 was the key starting material for the preparation of both classes of compounds. It was obtained from 135 (R = H) by addition of bromine to the C4-C5 double bond followed by ehmination of HBr, which can be spontaneous or induced by TEA. Stdle reaction on 136 (BusSnR, (Ph3P)2BnClPd) performed in toluene afforded the vinyl compoimd 137 (70%), the ethenyl derivative 138 (86%), and the aryl or heteroaryl compounds 139 (45-70%). Isothiazoles 140 fimctionahsed at C-5 with an isoxa-zoline ring were prepared by a regioselective cycloaddition reaction starting from the vinyl derivative 137 and nitrile oxides [46]. 

Nitrile sulfides are well suited for the synthesis of isothiazoles incorporating the C=N-S unit via their 1,3-dipolar cycloaddition reactions with double or triple-bonded dipolarophiles. Benzonitrile sulfide 210 is readily prepared from decarboxylation of oxathiazolone 209 using microwave irradiation <05SC807>. Subsequent cycloadditions to dimethyl acetylene-dicarboxylate (DMAD) and dimethyl fumarate afford 211 and 212, respectively. In the case of ethyl propiolate, a 1 1 regioisomeric mixture of phenylisothiazoles 213 and 214 is obtained. 

The mesoionic oxathiazoliuraolate (3) underwent a cycloaddition reaction with 2-tert-butyl-6,6-dimethylfulvene (4) in a [ 4tt + 2 t ] manner to give the isothiazole (6) by extrusion of carbon dioxide from the initially formed cycloadduct (5) and then spontaneous dehydrogenation <97X9921>. 

TABLE 4.17. 1,3-DIPOLAR CYCLOADDITION REACTIONS OE IN SITU-GENERATED MUNCHNONES AND ISOTHIAZOLE 1,1-DIOXIDE 241 ... 

A heavily substituted non-classical thienol3,4-c]isothiazole (175) has been prepared in almost quantitative yield by the cyclization of the dibenzoylisothiazole (174) with phosphorus pentasulphide (Scheme 15). The precursor (174) is itself synthesized, albeit in low yield, from the oxathiazolium-olate (173), by a process akin to that described earlier (p. 286). The thiophen ring (but not the isothiazole ring) in (175) behaves as a masked ylide, and it undergoes cycloaddition reactions such as with dimethyl acetylenedicarboxylate, when the 2,1-benzisothiazole (178) is... 

Even heterocyclic carbon-carbon double bonds undergo the [3+2] cycloaddition reaction with azides, as exemplified by the reaction of isothiazol-1,1-dioxides with aryl- and benzyl azides . 

Fordyce et al. (2010) have enveloped an improved method for the synthesis of isothiazoles and 1,2,4-thiadiazoles. The 1,3-dipolar cycloaddition reactions of nitrile sulfides, generated by microwave-assisted decarboxylation of 1,3,3-oxathiazal-2-ones have been studied. The adducts l,2,4-thiadiazole-5-carboxylates were synthesized by cycloaddition of the nitrite sulfides to ethyl cyanoformate. 

Diethylamino-4-(4-methoxyphenyl)-isothiazole 5,5-dioxide 6 is (95T(51)2455) a highly reactive partner in 1,3-dipolar cycloadditions with several dipoles. Azomethine yhdes, such as oxazolones 7 and miinchnones 8, afforded with 6 bicychc pyrrolo[3,4-d]isothiazole 5,5-dioxides 9, 10, 11 in satisfactory yield. The regioselectivity of the reaction was excellent. The thermal behavior of these new bicychc systems was investigated. When heated at their melting point or shghtly above, triarylpyrroles 12, 13 were obtained through SOj and AtiV-diethylcyanamide ehmination. 

As reported before (see Section 4.14.6.1, Scheme 19), thermolysis of oxathiazolines (169) proceeds via a retro 1,3-dipolar cycloaddition to produce the carbonyl compound and the nitrile sulfide intermediate. Trapping reactions have been carried out with DMAD, ECF (ethyl cyano formate), and benzonitrile to give respectively isothiazoles (170) and thiadiazoles (171) and (172). However in two particular cases (R = 4-MeOC6H4, 4-ClCgH4, thermolysis in the presence of benzonitrile gives (172) and the thiadiazole (173) in very low yields. It has been suggested that the latter arises... 

Irradiation of 2-phenylbenzoxazole forms a head-to-tail dimer, 1,3-diazetidine 436, whereas benzoxazole itself, in the presence of oxygen, gives the dimeric product, 437. Isothiazoles yield lactams 438 on reaction with diphenylketene. Benzotriazole and its 2-alkyl derivatives undergo photochemical ( > 290 nm) [2 + 2] cycloaddition to maleinimides to give adducts 439 <20020L1487>. 

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