Simple 1,3-Thiazines

Simple 1,3-Thiazines.— The stereospecific and regiospecific synthesis of 5,6-di-hydro-4 -l,3-thiazines by polar cycloaddition of thioamido-alkyl ions, generated in situ from aldehydes and thioamides, to olefins was reported in the previous Volume (see p. 712). A similar reaction with arylacetylenes PhC CRi has now been found to give mixtures of isomeric 4/f-l,3-thiazines (4) and (5) in a ratio that depends upon the nature of substituents. 

The coupling of carbonyl compounds with j3-iminodithiocarboxylic acids (see Vol. 2, p. 762), formed by the action of carbon disulphide and ammonia on cyclic ketones, has been extended to the preparation of some thiazinethiones of type (6), and a modified procedure involves the reaction of (7) with an acyl chloride to give the 1,3-thiazinethiones (8). 

A new route to 1,3-thiazinethiones with a wide variety of substituents is provided by the reaction of j8j8-dichlorovinyl aryl ketones with primary thioamides in a molar ratio of 1 2. Thus (9) reacts with thiobenzamide in boiling acetic acid to give (10), which, by sequential treatments with mercuric acetate and oxalyl chloride, can be converted into the thiazinium salt (11) 

3-Thiazinium betaines, e.g. (15), are formed in excellent yields by condensation of monosubstituted arylthioamides or trisubstituted thioureas with chlorocarbonylphenylketen, a new versatile 1,3-dielectrophilic species. Although (15) contains a masked 1,4-dipoIar system (16), it does not undergo cycloaddition reactions with acetylenic and olefinic dipolarophiles, its preferred reaction being 

Simple 1,3-Thiazines.—In connection with a study on the NH conformation in the analogues of piperidine in which a ring CH2 group is replaced by a hetero-atom, the equilibrium position of tetrahydro-l,3-thiazine [(19a) dj(l9b)] has been examined. I.r. measurements of the KNH) first overtone and electric dipole moments indicate that the predominant conformer is that with the NH axial. This preference, which applies also for tetrahydro-l,3-oxazine, may be interpreted in terms of attractive forces between the lone pair of the sulphur atom and axial NH in the conformer (19a), and repulsive rabbit ear forces between the two axial lone pairs in the conformer (19b). 

As an extension of early studies (see Vol. 2, p. 761), Sohar and Toldy have checked the reliability of i.r. and n.m.r. data in assigning tautomeric structures (20a) or (20b) to 2-arylamino-l,3-thiazines and to their N-substi-tuted derivatives by examining the spectral features of several isomer pairs (21a) and (21b), synthesized by unambiguous routes. The original papers contain a wealth of details, to which the reader is referred. 

Sohar and L. Toldy, Acta Chim. Acad. Set. Hung., 1973, 75, 99 Org. Magn. Resonance, 1972, 4, 779. 

Substituted 4,5-dihydro-6H-l,3-thiazines (27) are formed in high yields by Michael addition of thioamides, thioureas, or thiocarbamates (25) to the double bond of a 3-unsaturated aldehydes, ketones, or ketols (24) in the presence of boron trifluoride etherate and subsequent spontaneous ring-closure of the resulting intermediate (26). In some instances the products (27) can be converted into the corresponding 6H-l,3-thiazines, c.g. (28), with POCI3 in pyridine or with acid in aprotic solvents. 

Another route to bithiazinyl systems is exemplified by the thermal condensation of rubeanic acid with 2,4,6-trichlorophenyl malonate, leading 

N-acyl group with the consequence that the sulphinamide N—S bond is easily attacked by various nucleophiles. In the case of 2-alkyl(or aryl)sul-phonylthiazines it has been shown that the ring-opening process with the nucleophiles HO, RO, or RS results in the formation of derivatives of 4-sulphonylamino-m-but-2-ene sulphinates [e.g. (4) - (5)], whereas with 

Reagents i, NEtj ii, MeONa-MeOH iii, NaOH(aq)-MeOH 

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The layout of the Chapter adopted in the previous Volumes of this Series is retained, except that further restrictions on space have precluded a fuller presentation of activity in some areas, e.g. fused-ring systems incorporating the thiazine structure. Moreover, the section dealing with simple 1,2-thiazines has been omitted, as no significant work in this field has recently appeared. 

Oxidative C-H amination has been an area of intensive research since the publication of CHEC-II(1996). This methodology has been applied to the synthesis of a variety of 1,2-thiazine 1,1-dioxides. In the simple cases, substrates containing an aromatic C-H can be cyclized in the presence of hypervalent iodine. For instance, the reaction of A-methoxy(2-arylethane)sulfonamide 202 with [hydroxyl(tosyloxy)iodo]benzene rapidly affords benzenesulfon-amide 203 in excellent yield (Equation 30) <20030BC1342> see also <2000JOC926> and <2000JOC8391>. 

We have described (88TL4855) a simple synthesis of pyridin-2-ones by a two-step annulation of 2 with aliphatic acid chlorides (Scheme 27). The acylation of aminoazadienes 2 in pyridine furnished 4-amidoyl-l-azabutadienes 107 in high yields (85JOC802) lithium diisopropylamide-catalyzed aldol-type cyclization of 107 afforded pyridin-2-ones 108 in 83-94% yield. Extension of this reaction to methanesulfonyl chloride permitted preparation of open-chain derivatives 109 in 88-90% yield, which in turn cyclized in the presence of lithium diisopropylamide to 2//-l,2-thiazines 110 in 82-92% yield (89TL4705). Earlier work by the Komatsu-Ohshiro group showed that the reaction of simple 1-azadienes... 

Simple bond energy calculations show that 2H- 1,2-oxazines and -thiazines are unstable relative to the corresponding open chain iminoaldehydes and iminothioaldehydes, and thus they only find expression in the form of transient species. Early claims for the synthesis of 2H- 1,2-oxazines have not been authenticated, and, for example, the reaction between 4-nitrosodimethylaniline and tetracyclone does not give the oxazine (1) as was once thought, but rather the isomeric lactam (2), although it is likely that the oxazine is formed as an intermediate (Scheme 1) (64TL1569). 

Simple alkyl-substituted dihydro-1,4-thiazines are readily converted into the corresponding 5-monoxides atmospheric oxidation is sometimes sufficient, although side reactions may also occur. The cyclohexene derivative (99), for instance, affords not only the oxide (100) but also the spiro compound (101) probably generated by ring contraction of a hydroperoxide intermediate (Scheme 42) <73US(B)(8)34l>. 

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... 

The simple addition product 3-mercaptodecanal 14 is obtained as the main product. On standing this compound changed into a viscous odorless oil of structure 15. As expected [M>] compound 14 reacts in the presence of NH3 and acetaldehyde to thiazine derivatives 16 and 17 as indicated in Figure 6. 

Thiazine analogues have received a great deal of attention partly because they may arise by chemical transformations from penicillins (73CC226,74JCS(P1)1572>. A simple synthesis of this ring system is shown below. 

Very simple and straightforward alkylation of NH-heterocycles (NaH, Cl(CH2) SMe, = 2 or 3, 68-86%) permits one-pot preparation of pyrrole and carbazole sulfide models for the reaction with triflic anhydride <2003S1191>. Cyclization of the (l/7-pyrrol-l-yl)alkyl sulfides 1470 obtained leads to 2,3-dihydropyrrolo[2,l- ][l,3]thiazole 1472 and 3,4-dihydro-2/7-pyrrolo[2,T ][l,3]thiazine 1473 via intermediate l-methyl-2,3-dihydropyrrolo[2,l-/ ][l,3]thiazol-1-ium or l-methyl-3,4-dihydro-27/-pyrrolo[2,T ][l,3]thiazin-Tium salts 1471 (n = Z or 3), respectively, that were isolated in high yields in most cases (Scheme 281) <2003S1191>. 

Substituent effects in the optical spectra of simple alkyl and arylpheno-thiazine radicals have been reported by Biehl et... 

In the first edition of Comprehensive Heterocyclic Chemistry (CHEC-I) 1,3-thiazines and 1,3-oxazines were reviewed together indeed, much of their chemistry is similar, providing justification for this arrangement. However, there are areas in which this is not so, and in this edition the two types of heterocycle are treated separately. This allows a more focused approach, but as Quiniou and Guilloton <90AHC(50)85> have already pointed out, one feature which complicates any survey of 1,3-thiazines is the interrelationship of these compounds to cephalosporins. The literature dealing with cephems and related systems is vast and requires individual treatment, so here the emphasis is on the synthesis and reactions of simple 1,3-thiazines and their benzo derivatives. Other fused systems are not included unless their chemistry illustrates some important property of the 1,3-thiazine heterocycle itself. 

A significant number of 1,3-thiazine derivatives have been subjected to x-ray crystallographic analysis. Thus, it has been shown that the atoms of the unsaturated chromophore of simple 6H-l,3-thiazines lie in the same plane, with the methylene group at C-6 out of the plane <86CJC597, 87BSF149>, and that in the solid state 4-hydroxy-l,3-thiazin-6-ones (13) are preferred to 4,6-diones (12) <86MI... 

Thiazine containing alkaloids are relatively rare in Nature, but they range in structural complexity from simple monocyclic derivatives such as chondrine and benzothiazines such as the aplidinones, to more complex tri- and polycyclic compounds exemplified by ansafhiazin and the shermilamines. On the other hand, the simplest N,S-heterocycle - the 5-membered thiazole - is relatively common in Nature, and, for example, plays a vital role in the function of thiamine (vitamin Bi). Thiazole rings also occur in important biologically active natural products such as the epothilones (Figure 1). 

The sulfone group is relatively rare in natural products, but a simple example is the l,4-thiazine-l,l-dioxide 10 (Figure 2), isolated from the marine sponge Anchinoe tenacior (94TL2421). The structure was assigned on the basis of NMR spectroscopy, but has yet to be confirmed by S5mthesis. 

This short review has highlighted the wide range of 1,4-thiazines that occur in Nature. The N,S-heterocycle appears in a number of guises, notably as simple monocyclic di- or tetrahydro derivatives with all possible oxidation levels at sulfur, as benzothiazinones, and as thiazine-S,S-dioxides fused to quinones. The review also shows that many of these interesting heterocyclic compounds are yet to succumb to synthesis, and we hope that the article will stimulate further work in this area. 

In a similar manner as used for 1,2-dione/diamine condensations, Kaupp carried out stoichiometric mechanochemical reactions of o-mercaptoanihne 86 with ninhydrin in the three reaction cascade (substitution, cyclization, and elimination), which gave the salt of 10a-hydroxyindeno[2,l-( ]benz[l,4]thiazin-l l(10a//)-one 89 (Schane4.23) [15], Washing of product with NaHC03 was the simple woricup in this efQcient sol-vent-free synthetic protocol. 

Simple 1,3-Thiazines.— The reported formation of 1,3-thiazines (13) by the addition of thioureas to dimethyl acetylenedicarboxylate has been re-examined independently by two groups who have unequivocally confirmed earlier studies indicating the five-membered 1,3-thiazoline structures (14) for all condensation products (c/. Chapter 13) in this series. 

Monocyclic 1,4-Thiazines.—Remarkably little has been published recently on the chemistry of simple 1,4-thiazines. As an extension of early studies, Carson and co-workers now report the isolation and structure of the new isomeric 3-carboxyl-1,4-thiazine S -oxides (63) and (64) from the oxidation... 

Benzo-l,4-thiazines and Related Compounds.—The condensation of 2-aminothiols with simple o-benzoquinones has been studied as a model... 

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