5- -4-chloro-1,2,3-dithiazoles

Cyano-4-quinazolinones (4-oxo-3,4-dihydro-2-quinazolinecarbonitriles) 975 are available from 2-[A -(chloro-dithiazole)imino]benzoate esters 973 by reaction with primary aliphatic amines at room temperature <1998JHC659, 2002H(57)1471, 2002TL3993, 2005TL7477>. 

The sole recent example of this synthesis involved the complex reaction of 1,2-benzenediamine (348) with 4-chloro-5-cyano-l,2,3-dithiazol-l-ium chloride (349)... 

If benzamidine is replaced by benzamidoxime, then the 4-oxide derivative 107 is obtained as a minor product (8%) together with 4-chloro-l,2,3-dithiazol-5-one 108 (32%) and the 5-thione 109 (15%) (Equation 30). The formation of the 4-oxide, as opposed to the isomeric 2-oxide, was confirmed by mass spectral and 15N NMR data. The yield of the 4-oxide product could be improved by using an O-acyl benzamidoxime in place of benzamidoxime <1999J(P1)2243>. 

Cyclic disulfanes also undergo cleavage reactions. 5,5-Difluoro-3-chloro-l,2,4-dithiazole reacts with chlorine to give various sulfenyl chlorides depending on temperature ... 

An extensively studied and highly important 1,2,3-dithiazole - 4,5-dichloro-l,2, 3-dithiazol-l-ium chloride (Appel salt) 145 (R = Cl) - was first prepared by Appel and coworkers in 1985 by chlorination of chloroacetonitiile by sulfur monochloride in dichloromethane (1985CB1632) and it has been the most convenient procedure to date. Appel salt can be obtained also by prolonged chlorination of acetonitrile itself, or by the sulfur monochloride reaction with ethylamine the yields and experimental conditions were not disclosed (1985PS277). Recently, a series of mono-substituted acetonitriles were converted to 5-substituted-4-chloro-l,2,3-dithiazolium chlorides 145 (1999CC531,... 

The 6//-l,3-thiazin-6-iminium hydroperchlorate salts 78-81 give interesting products when treated with nucleophiles <2003H(60)2273>. Hydrolysis of 6-imino-6//-l,3-thiazine hydroperchlorate 78 affords (2Z,4Z)-2-cyano-5-hydroxy-5-phenyM-azapenta-2,4-dienethioamide 82 in excellent yield, while treatment with morpholine gives 2-(morpholinomethylene)malononitrile 83 and thiobenzamide. The 5-(ethoxycarbonyl) -(methylthio)-2-aryl-6/7-l,3-thiazin-6-iminium salts 79 and 80 react with hydroxide or morpholine to afford ethyl 4-(methylthio)-2-aryl-6-thioxo-l,6-dihydropyrimidine-5-carboxylates 84 and 85. In the case of the 4-chloro analogue 80, the (Z)-ethyl 2-(5-(4-chlorophenyl)-37/-l,2,4-dithiazol-3-ylidene)-2-cyanoacetate 87 is also formed for the reaction with sodium hydroxide. The 1,2,4-dithiazoles 86 and 87 can be obtained as the sole product when 79 and 80 are treated with sodium acetate in DMSO. Benzoxazine 88 is isolated when the iminium salt 81 is treated with morpholine or triethylamine. Nitrile 89 is formed as a ( /Z)-mixture when 6-imino-67/-l,3-thiazine hydroperchlorate 79 is reacted with triethylamine and iodomethane in methanol <2003H(60)2273>. 

A series of 3-substituted 5-cyano-l,2,4-thiadiazoles 76 have been prepared in varying yields (21-92%) via reaction of nitrogen nucleophiles with 4-chloro-5-isoxazolylimino-5W-l,2,3-dithiazoles 75 <99H811>. 

Kim et al. [103] have shown that spiro-(3-lactams 128 (Scheme 32) obtained by a facile synthesis, serves as a precursor for the synthesis of hitherto unknown (3-lactams undergoing cleavage of the bond between S-l and S-2 with nucleophiles. Treatment of 5-substitutedimino-4-chloro-5//- l, 2,3-dithiazoles 126 with 2-chloro-2-phenylacetyl chloride 127 in the presence of triethylamine afforded spiro-(3-lactams 128. 

Scheme 32 Synthesis of spiro-fl-lactams using 5-substitutedimino-4-chloro-5//-l,2,3-dithiazoles and 2-chloro-2-phenylacetyl chloride...

Chloro-l,2,3-dithiazoles 41 and 42 show strong ultraviolet (UV) absorption at Amax 423—431 nm (logs 3.8—4.0) and a weaker absorption at Amax 330nm (loge3.2-3.3) <1998J(P1)2505>. 

The IR spectrum of 4-chloro-l,2,3-dithiazole-5-thione 41 shows strong bands at 1041, 1029, and 1013cm 1 in the region for sulfine symmetric and asymmetric stretching <1998J(P1)2505>. 

Primary and secondary alkylamines have been used for the preparation of iV-alkyl- and V,lV-dialkylcyanothio-formamides, respectively, in the reaction with 4-chloro-l,2,3-dithiazole-5-thione 41 (Equation 20) <1996TL3709>. 4-Chloro-l,2,3-dithiazole-5-one 99 in the reaction with mono- and di-alkylamines afforded N,N -disubstituted ureas in moderate to good yields (Equation 21) <2001TL8197>. The reaction was proposed to be similar to the corresponding thione 41 but displacement of a cyano group by another molecule of alkylamine accompanies this conversion. 

Treatment of 5-arylimino-4-chloro-l,2,3-dithiazoles 56 with in situ-generated (chloro)phenylketene gave azetidi-none-l,2,3-dithiazoles 137 in high to moderate yields through [2+2] cycloaddition to the N=C-Ar imine bond (Scheme 23) <2001CC1412>. 

Compound 553, obtained from Apple s salt 552 or from 4-chloro-l,2,3-dithiazole-5-thione, reacts with several nucleophiles affording highly functionalized 5-cyano isothiazoles 554 in a very short and simple synthesis from readily available materials <1997J(P 1)3345, 1998J(P1)77, 2002J(P1)1236>. 

Arylimino-4-chloro-57/-l,2,3-dithiazole 558 reacts with (chloro)phenylketene in CH2CI2 at room temperature affording spiro compounds 559, which undergo decomposition in the presence of primary and secondary alkylamines giving bis(2-oxo-azetidin-4-yl)trisulfides, which, in turn, with an excess of -propylamine are converted into the isothiazolones 560 <2001CC1412>. 

Aryl isothiocyanates The reaction of arylamines with the reagent affords 5-(A(-aryliinino)-4-chloro-l,2,3-dithiazoles which are decomposed to give ArN=C=S by a Grignard reagent. 

The reaction of methylenetriphenylphosphorane with epichlorohydrin followed by addition of butyllithinm and an aldehyde in toluene provides alkylidenecyclo-butanols in moderate to good yield (Scheme 3). Similar reactions have previously been reported to afford alkylidenecyclo-propylmethanols (61) and the current report demonstrates that the reaction is highly base- and solvent-dependent. Further studies of the kinetics and mechanism of the addition of cyclopentadienylidenetriphenylphosphorane to tetrahalo-p-benzoquinones have included the reaction with tetraiodo-p-benzoquinone to give the 2,5-disubstituted quinone (62). Initial attack on sulfur is presumably involved in the reaction of two equivalents of stabilised phosphoranes with 5-arylimino-4-chloro-5H-1,2,3-dithiazoles (63) to give a mixture of N-arylcyanothioformamides (64) and, as the major product, the novel ylides (65). In one example the structure of (65) was confirmed by X-ray crystallography. 

Kim and co-workers used dithiazoles to prepare 3-substituted 2-cyanoquinazolinones. Treatment of methyl anthranilate with Appel s salt in the presence of two equivalents of pyridine fiimished the corresponding methyl-A -(4-chloro-5//-1,2,3-dithiazol-5-ylidene)anthranilate (not shown). Further reaction of the ylidene with methyl amine provided the desired cyanoquinazoline in 73% yield. This work set the framework for Besson and co-workers synthesis of a tricyclic congener of desoxyvasicinone, a compound with cytotoxicity against a murine leukemia P-388 cell line. 

The synthesis of 6-fluoro-2-cyanoquinolone 26 from 4-fluoroaniline 16 is shown in Scheme 8. 4,5-Dichloro-5H-l,2,3-dithiazohum chloride 23 reacts with the Meldrum acid to form 5-(4-chloro-5H-l,2,3-dithiazol-5-yhdene)-2,2-dimethyl-l,3-dioxan-4,6-dione 24, which on treatment with 4-fluoroanihne 16 is transformed into 5-[(arylamino)(cyano)methylene]-2,2-dimethyl-l,3-dioxan, 6-dione 25 in high yield. Heating of compound 25 in biphenyl ether results in the formation of 2-cyanoquinolone 26 [14,15]. 

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