1,3-Thiazines nucleophiles

A majority of the compounds encountered in this class of heterocycles exist as A -dioxides. The nomenclature for such compounds is somewhat ambiguous as the terms sultam, sulfonamide, and 1,2-thiazine 1,1-dioxide have all been used to describe these molecules. The reactivity of 1,2-thiazine 1,1-dioxides 4 (as the 22/-tautomer) has been thoroughly investigated and much of this work has been described in Chapter 6.06 of CHEG-II(1996) <1996CHEC-II(6)349>. This S(vi)-oxidized compound 4 undergoes both nucleophilic and electrophilic attack, which are often non-regioselective. 

Fully conjugated species are somewhat rare in the 1,2-thiazine class of heterocycles. These molecules are comprised of two separate subclasses, the first of which includes the highly reactive 1,2-thiazinylium salts. Although these salts, such as 27, have in some cases been isolated, they readily react regioselectively at C-6 with a variety of nucleophiles including sodium alkoxides 76, silyl enol ethers 77, sodium malonates 78, and sodium thiophenoxide 79 (Scheme 10) <2001T8965>. 

A variety of methods exist for the formation of 1,2-thiazines via the construction of an S-N bond by nucleophilic attack of nitrogen onto a sulfur-bearing leaving group. For example, the reaction of aryl bromide 189 with potassium thiocyanate in the presence of copper(l) iodide and triethylamine affords benzothiazine 190, although in low yield and as a mixture with indoline by-product 191 (Equation 28) <2000JOC8152>. 

Thiazine 283 has been prepared through the nucleophilic ring opening of fused bicyclic aziridine isothiazoli-dine 1,1-dioxide 284 with MeOH in the presence of BF3-OEt2 (Equation 40) <20000L2327, 2004JOC6377>. 

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>. 

Perfluoro(3-isothiocyanato-2-methyl-2-pentene) reacts with N-nucleophiles to produce a series of fluoroalkyl-substituted 6/f-l,3-thiazines <1997RJO720>. The acid-catalyzed cyclization of thioureas immobilized on Wang (X = O) or Rink resin (X = NH) provides a convenient route to a wide range of 2-amino-4/7-benzothiazine derivatives 212 (Scheme 23) <20000L3667>. The thioureas are obtained in four steps from 2-nitrocinnamic acids. A general synthesis of 2-alkylidene-4-imino-l,4-dihydrobenzo-l,3-thiazines 213-215 involves treatment of 2-isothiocyanato-benzonitrile with acidic methylene compounds under basic conditions <2003SL1503>. The ( )-isomers are the predominant isomers formed. 

Nucleophilic attack occurs most readily at the 3-carbon of 277-1,4-thiazines, and makes them susceptible toward hydrolysis. 3,5-Diphenyl-l,4-thiazine 108 and its 2,6-dimethyl derivative 191 were both hydrolyzed with dilute acid (Equation 9) <1968017>. 

Nucleophilic substitution at the 3-carbon of 2/7-1,4-thiazines 192 <1969JHC247> and 193 <1992CPB1025> and nucleophilic addition to the 3-carbon of 2/7-1,4-benzothiazine 194 <1999TL2565> have been reported (Scheme 15). The catalyst used in the reaction of 194 is prepared from praseodymium(lll) isopropoxide and (R)-binaphthol. 

If a carboxylic acid ester side chain is introduced at the 3-position of a thiazine with a free NH group, lactam formation may occur <1987J(P1)1027>. Compound 78 is a result of lactam formation, and the synthesis of similar compounds is shown in Scheme 44 (Section 8.09.7). Reactions where the nitrogen reacts with a side chain introduced by a nucleophilic attack at the 3-carbon of 277-dihydrothiazines are shown in Schemes 6 and 27. 

Examples of nucleophilic attack at the saturated 2-carbon of dihydro-l,4-thiazines, which may be assisted by the neighboring sulfur atom, are shown below. The nucleophiles include water, which was used in the acid-catalyzed hydrolysis of the ketal in 236 (Equation 21) <1982S424>, methanol in the conversion of 214 into a monothioacetal (Equation 22) <1982JHC131>, ethanol and dimethylaniline, which both reacted with 237 (Scheme 29) <1982TL4963>, and triethyl phosphite that was used to convert 238 into the phosphonate 239 required for Wadsworth-Emmons reaction (Equation 23) <2004BML1477>. Compound 240 reacted with both methanol and methanethiol (Equation 24) <1990JME1898>. 

Conjugation to the free electron pair of the thiazine nitrogen makes these 3-substituents nucleophilic. The first example is reaction of 42 <1968CHE322> and its 2-ethoxycarbonyl derivatives <1983JME559> with triethyl-oxonium tetrafluoroborate (Scheme 42). Another is the reaction of 27 with hexamethyldisiloxane to give 112 (Equation 31) <1988JME1575>. 

A nucleophilic attack of an N-tethered phenethyl substituent is shown in Scheme 50. The protonated thiazine ring brings about an intramolecular electrophilic aromatic substitution on the aryl substituent, whether this is a phenyl <1992CHE832> or a veratryl ring <1980JHC449>. 

Sulfur atom can act as a nucleophile or an electrophile in ring closure. Nucleophilic behavior can be seen in the hydrolysis of the H-2 receptor antagonist ranitidine 261, which gives thiazine 262 as the main product (Scheme 51) <1987J(P1)951>. 

A variety of N,S-bis(nucleophiles) react with unsaturated 5(47/)-oxazolones to produce triazolo-l,3-thiazin -ones 570 and 1,3-thiazin-4-ones 572. Mechanistically, Michael addition of the bis(nucleophile) to 569 and 571 followed by ring opening with concomitant cyclization leads to the observed products. 

Reactions of pyrimido[4,5-3] [l,4]thiazines were discussed in CHEC-II(1996) <1996CHEC-II(7)737> more recently, reported reactions of this system involve nucleophilic substitution in a number of guises. Hemiaminals at C-3 react with ammonium acetate to form aminals (Equation 166) <1999CHE97>. The formation of acyl hydrazides from pyrimido[4,5-3][l,4]thiazine-2-carboxylic acids, along with their subsequent conversion to acyl azides and Curtius... 

A general type of [3 + 3] heterocyclization involves initial nucleophilic attack on the electrophilic three-membered heterocycle by a 1,3-electrophile-nucleophile. Aziridines (330) with either a-mercapto ketones (329) or with a mixture of a ketone and sulfur give 5,6-dihydro-1,4-thiazines (330 — 331 — 332). Azirines (333) can be used for the preparation of pyrazinones (334) from ot-amino esters R2CH(NH2)C02Et and of 1,4-oxazinones from a-hydroxy esters (83TL1153). 

Simple 6H- 1,3-oxazines and -thiazines are commonly encountered as intermediates in the reactions of oxazinium and thiazinium salts with nucleophiles (see Section 2.27.2.2.3). Additionally there is a considerable interest in 6//-1,3-thiazines as intermediates in the synthesis of cephem antibiotics (see Section 2.27.3.24) and many approaches have been... 

Phenacylisothiazolium salts were prepared by fusion of isothiazoles with phenacyl bromide (85BSB149). Treatment of the salt with pyridine afforded the 2-benzoyl-2//-l,3-thiazines (44) via intramolecular nucleophilic attack on the sulfur atom (Scheme 25). 

In this sequence, substitution by 1 mol of dimethylamine first replaces the benzylmercaptan leading to 5-acetyl-2-dimethylamino-6//-l,3-thiazine (197). The thiazine then undergoes attack by dimethylamine excess at C-6, leading to the thiourea (198). The benzylmercaptan liberated in the first reaction may act as a nucleophile (BzS",H2NMe2+), and a different thiourea substituted by dimethylamino and benzylthio groups is obtained. The action of pyrrolidine on 1,3-thiazine-4-ones (194) can be seen as a Michael addition followed by elimination of H2S. In acidic media, the linear compound obtained is cyclized to the pyrimidone (200) (Scheme 80)... 

The reaction of 1,3-dithietane 92f substituted with a diethylphosphoryl group with G-nucleophiles is analogous to the previously reported reaction. Its condensation with different C-nucleophiles, such as cyclic and acyclic a-carbonyl-methylenes and a-carbonylhydrazones, gave a number of [2,l-3]fused phosphono-substituted thioxopyranes 97, 100, 103, 107, oxadiazine 109, and thiazine 105 (Scheme 12), which are of potential biological interest <2002PS1885>. 

Benzo-l,3-thioxin-4-thione (148) reacts with phenylhydrazine to form the dithiole hydrazone (149), which must arise by initial nucleophilic attack at the thione function (80T3309). The l,3-thiazine-2,4-dione (150) possesses a three-carbon unit with an attached sulfur atom. Thionation with phosphorus pentasulfide gives the unsubstituted l,2-dithio e-3-thione (3b) (70AjC5l>. 

It has long been known that oxidation of phenothiazine and its C-substituted derivatives in aqueous acid yields the red 3H-pheno-thiazin-3-ones (phenothiazones). This reaction proceeds by a nucleophilic attack of water on the intermediate phenazathionium cations. The pathway of Scheme 5, after Shine and Mach, describes the route in detail. 

Dichlorophenothiazine-5-oxide - and 1,3,7-trichloropheno-thiazine-5,5-dioxide were obtained on treating phenothiazine with HCl in the presence of H2O2, reactions which were interpreted as nucleophilic substitutions. 

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