Thiazine Derivatives

An antibiotic, ansathiazin (394), was isolated from Streptomyces albo-longus, the structure followed from its transformations and spectroscopic data (86E1167). 

Synthetically, 7-methyl- 395 was obtained from 4-methyl-1,2-benzoquinone and 2-aminoethanethiol (70JHC555) and 3-oxo analogs of 395 were prepared from azidobenzoquinones and ethyl mercaptoacetate (73TL4695). Dibenzo and benzo or naphtho analogs of 395 were prepared from 2-arylamino- 

From 3-chloro-l,4- or -1,2-naphthoquinones and sodium sulfide, the ben-zolog of 395, and with o-aminothiophenol the isomeric quinone 396, were prepared (71ZOR1031 86JCS(P1)2233). Compound 396 rapidly isomerizes 

4-benzoquinone with sodium sulhde and subsequent oxidation with oxygen (27MI1). 2,3-Dichloro- and 2-anilino-3-chloro-1,4-naphthoquinone reacted with sodium sulfide to produce the pentacyclic quinone 398. The compound, when heated in nitrobenzene or in acetic/nitric acid, extrudes sulfur and compound 61 (R = Ph) is formed (23CB1291). 

---

Adducts from various quaternary salts have been isolated, in reactions with aldehydes, a-ketoaldehydes, dialkylacylphosphonates and dialkyl-phosphonates, isocyanates, isothiocyanates, and so forth (Scheme 15) (36). The ylid (11) resulting from removal of a Cj proton from 3.4-dimethyl-S-p-hydroxyethylthiazolium iodide by NEtj in DMF gives with phenylisothiocyanate the stable dipolar adduct (12) that has been identified by its NMR spectrum and reactional product, such as acid addition and thiazolidine obtention via NaBH4 reduction (Scheme 16) (35). It must be mentioned that the adduct issued from di-p-tolylcarbodiimide is separated in its halohydrogenated form. An alkaline treatment occasions an easy ring expansion into a 1,4-thiazine derivative (Scheme 17) (35). 

But when the reaction is carried out in an aqueous solution of sodium hydrogen carbonate, extension of the ring occurs with formation of dihydro-l,4-thiazine derivative (Scheme 19). the structure of which has been established by mean of NMR and infrared spectra (41). 

Takamizawa et al. developed a general ring-expansion reaction of heterocycles that, applied to thiazolium salts, yields 1,4-thiazines (496, 497) thiamine (220) reacts with dialkyl acylphosphonates (221) to give the tricyclic 1,4-thiazine (222) (498), which is easily hydrolyzed to dihydro-1,4-thiazinone (223) (499) (Scheme 106). In the case of thiazolium slats containing no functional groups (224), 1,4-thiazine derivatives (226) were directly obtained in fairly good yields (Scheme 107). 

Looking for novel 1,3-thiazines with biological interest, Dandia and coworkers have recently prepared fused pyrido-1,3-thiazine derivatives by treatment of in situ generated 3-indolyHmine derivatives with 2-mercaptonicotinic... 

Shionogi [211] has filed a patent application on a series of thiazine derivatives no compounds are specifically claimed. The thiazine derivative (322) was active in vivo in the formalin-induced licking-and-biting model in ICR mice with an ED50 of 1.5mg/kg after oral dosing. 

Soviet workers have studied reactions between iV-sulfinylamines and 1,3-dienes 1,2-thiazine derivatives (e.g., 64) were formed.82,83 An earlier... 

Thiazine derivatives have been obtained by reactions of primary thioamides with a,p-unsaturated ketones (Scheme 26).53... 

Basic hydrolysis of the [l,2,4]triazolo[5,l-3][l,3]thiazine derivative 77 was described to yield triazole-thione 78, the reaction proceeding in 59% yield <2005ZOR1092>. Related partially saturated triazolothiazines 79 were also subjected to ring-opening reaction aqueous hydrolysis afforded the acid 80 <2004KGS1256>, whereas reaction of 79 with hydrazine hydrate yielded the acid hydrazine 81 <2004ZOR260>. Both transformations took place in high yields. 

AN—N bond cleavage can be obtained by tion of 4-//-l,3-thiazine derivatives in a the cathodic reduction of some mesoionic slightly basic medium leads to a ring... 

For the preparation of cephems from a protected t-butyl ce-methoxygly-cinate thioamide and an orthoamide, an azathiadiene was formed which afforded the 1,3-thiazine derivative after cycloaddition of acrolein (Scheme 42) (89JOC2889). 

No pyrido[l,2-6][l,2]thiazine derivative has been the subject of theoretical or experimental structural studies. 

The reaction mode depends mainly on the choice of the base and reaction conditions, but route B is usually more common. Thus, tetrahydro-l,4-thiazine derivative 157 the structure of which was proved by X-ray crystal structure analysis (Fig. 7) [22b] was obtained in the reaction of the chloro ester 1-Me with 2-aminoethanethiol (156) using K2CO3 or EtgN as a base in 43 and 20% yield, respectively (Scheme 49) [22b, 26]. In the latter case, the secondary amino group in the primary tetrahydrothiazine product 157 underwent Michael addition to a second molecule of 1-Me to give 2-[r-(spirocyclopropanetetrahydrothiazinyl) cyclopropyl]-2-chloroacetate 158 (14% yield). When KOH in the presence of di-benzo-18-crown-6 was employed, however, the seven-membered heterocycles 155 (42%) and 159 (48%) were obtained upon reaction of 1-Me with 1,3-pro-panedithiol and 2-aminoethanethiol, respectively (Scheme 49) [26]. 

In the reaction of salicylic acid thioamide 419 with 2-cyano-3,3-bis(methylsulfanyl)acrylate under acidic conditions, a 2-(o-hydroxyphenyl)-6-imino-l,3-thiazine derivative was obtained as a perchlorate salt 420 on treatment with phenacyl bromide, this underwent a ring transformation to yield 4-benzoylmethylthio-27/-l,3-benzoxazin-2-ylidene-substituted ethyl cyanoacetate 421 (Scheme 81) <2003H(60)2273, 2004H(63)2319>. 

Fully conjugated 1,2-thiazines have been prepared with both S(ll) and S(vi) oxidation states. While the zwitterionic compound 11 has been known for some time <1984CHECI(3)995, 1996CHEC-II(6)349>, thiazinylium salts 12 have only recently been prepared. Both fully unsaturated 1,2-thiazine derivatives are considered to be nonaromatic due to poor p-d Jt-bonding. Eurthermore, the six-membered ring of l-alkyl-l,2-thiazine 1-oxide 11 is not planar, but instead exists in a puckered, half-boat conformation thereby precluding aromaticity <1978CC197>. 

Single crystal X-ray analysis has proved to be valuable for the determination of the stereochemistry of chiral 1,3-thiazine derivatives and provided support for the mechanisms in stereoselective reactions <2001EJ03553, 2001EJ03025, 2002TL6067, 2004T1827>. 

Table 1 Proton NMR data for some 1,3-thiazine derivatives...

A convenient route to 2-alkylthio-4-alkyl-4-hydroxy-5,6-dihydro-4/7-l,3-thiazine derivatives 176 is the reaction of A-alkyldithiocarbamates with a,/3-unsaturated ketones in the presence of boron trifluoride etherate at 0°C (Scheme 15) <2002HAC377>. The predominant diastereomer displayed a m-relationship between the hydroxyl group and the C-4 substituent. Subsequent dehydration led to two isomeric products 177 and 178 with an equilibrium mixture resulting in a ratio of 94 6 in the case of 2-benzylthio-4-hydroxy-4-methyl-5,6-dihydro-4/7-l,3-thiazine. 2-Phenyl-4-alkyl-4-hydroxy-5,6-dihydro-4/7-l,3-thiazine derivatives are similarly prepared by reacting thio-benzamide with o ,/3-unsaturated ketones at room temperature <2002EJP307>. 

Reactions of jy -3-A -acylamino alcohols with 1 equiv of LR give the corresponding jy -5,6-dihydro-l,3-thiazine derivatives 222 in 40-88% yield (Scheme 26) <2001EJ03553>. Similarly, the /r -3-A -acylamino alcohols give access to the 6-dihydro-1,3-thiazine derivatives. 

A good variety of compounds have been prepared and characterized allowing us to obtain reliable information on the chemical shifts of saturated and unsaturated ring protons. A selection of different structures are shown in Table 4. The thiazine derivatives have been organized in groups for comparison. The effects of saturation (54, 105, 106), substituents of variable electronegativity (107, 108), increasing oxidation state of sulfur (121, 122, 27-29), and deprotonation (109-111) can be observed. 

Some information has been obtained on the fragmentation patterns of 1,4-thiazine derivatives. A group of 2- and 3-substituted A-methylated benzothiazines with the general structure 2 (R = Me) lost a methyl radical in electron impact mass spectrometry at 70eV (Scheme 2) <1982J(P1)831>. 

The nitrogen of 2/7-dihydrothiazines reacts readily with alkyl or acyl halides in the presence of a base. Table 8 contains a selection of N-alkylations and N-acylations performed on dihydro-1,4-thiazine derivatives. 

In some reactions with thiocarbonyl ylides, 1,3-thiazine derivatives are formed by a series of consecutive reactions. For example, the interception of 3-thioxocy-clobutanone (5)-methylide (69) with thiobenzamide results in the formation of the bicyclic 1,3-thiazine (176) (100a) (Scheme 5.50). A conceivable intermediate is the 1,3-adduct 175 as shown in Scheme 5.50. 

Similarly the thione 172 is formed from the dithioester 171, which is obtained from the thiazine derivative 170 (71JCS(C)1610). 

In the anancomeric thiazine derivatives (shown in Table V), however, the trans-fused compound shows two equal couplings of 145 Hz and the cis-fused compound two equal couplings of 149 Hz.101 These results and others102 suggest caution in the use of this parameter in conformational assignments. 

Dihydro-1,3-thiazine derivatives (208) and (210) are prepared by the addition of alkyl propiolates to thioureas and dithiocarbamic acids respectively. In the latter case it is necessary to cyclize the initial products (209) with acetic anhydride (Scheme 96) (70AJC51). Ring expansion of isothiazolium chlorides (211) by the action of potassium cyanide provides a route to imine derivatives (212 Scheme 97) (79TL1281). 

For 4//-thiazine-4-ones (78), two maxima are generally noted one between 233 and 258 nm and the other between 278 and 298 nm [66TL3225 77LA1249 78JCS(P1)1428]. The differences in the long-wave maxima between amino and imino structures in the UV spectra are not usually substantial, with the exception of the dirnethylamino derivative (79) (82CCC3268). This compound (X max = 330 nm) shows a bathochromic shift of 60-80 nm compared to all other thiazine derivatives, probably due... 

---