Thiazines acid chlorides

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... 

Oxazine and -thiazine betaines (59) are prepared by reacting malonyl chlorides with secondary amides or thioamides respectively (Scheme 18). Carbon suboxide can be used instead of the acid chlorides, giving salts unsubstituted at C-5 (72S312). 

A number of halogenated derivatives of 155, 160, and 165 have been prepared.129 For example, the thieno-1,2-thiazine analog 166 has been converted to eneamine derivative 167 which has been acylated (phosgene/ triethylamine) to afford acid chloride 168. Treatment of 168 with 2-aminopyridine gave 169 (Eq. 36). This process is completely analogous to the 1,2-benzothiazine synthesis depicted in Eq. (6). 

Pfister and co-workers130 have also prepared the three isomeric thieno-l,2-thiazin-3-one ring systems. The acid chloride 171 of 3-(2-N-methylsulfamoyl)thiopheneacetic acid (170) with sodium bicarbonate gave 3,4-dihydro-2-methyl-3-oxo-2//-thieno[3,2-e]-l,2-thiazine 1,1-dioxide (172) (Eq. 37). 

Thioxo-3,4,5,6-tetrahydro-l,3-thiazin-4-ones (57) are A-acylated by acid chlorides in the presence of triethylamine to give 3-acyl-2-thioxo-3,4,5,6-tetrahydro-l,3-thiazin-4-ones (58) (Equation... 

Acid chlorides react at the nitrogen atom of 5,6-dihydro-2-thioxo-l,3-thiazin-4(3if)-ones (see Section 6.07.4.2), and the same regioselectivity is obtained if these substrates are reacted with trichloromethylsulfenyl chloride in the presence of either sodium hydride or triethylamine, but in the absence of bases attack is directed to the sulfur atom and the products are 5,6-dihydro-2-dithio-... 

Six-membered Rings.—Diels-Alder cyclizations using heterodienophiles provide a useful route to 1,2-thiazine derivatives immonium salts (300) derived from 7V-sulphinylmethylamine react across the N=S grouping. 1,3-Thiazinones are prepared " by reaction of thia-acylisocyanates (301) with enamines and enol ethers, and the formation of this ring system is also possible by reaction of JV-monosubstituted dithiocarbamates with a,/8-unsaturated acid chlorides. The reaction involves a series of equilibria, N- to S-transacylation, and cyclization reactions. 

Thiocyanato acid chlorides (333) cyclize in the presence of hydrogen chloride to 2-chloro-l,3-thiazin-4-ones (334). ... 

Thiazine blue Chloride, in T-00136 Thioindigo 5,5 -disulfonic acid, T-00164 >Tolonium chloride, in T-00189 Toluylene blue Chloride, in T-00190... 

For the synthesis of the benzosulfonamide subclass of 1,2-thiazines, introduction of the sulfonyl chloride has been effected by treatment of electron-rich aromatic compounds with chlorosulfonic acid. Such is the case for 1,2-benzothiazine 1,1-dioxides 181 which have been accessed from phenylethylamines 182 in 67-92% yields via intermediate 183 (Scheme 23) <1998SC2137>. 

Aminopropanols, when reacted with cyanogen bromide, also afford 2-amino-(or imino)-dihydro-1,3-oxazines (Scheme 90) (64ZOB3427), and related thiazines are formed when allylic isothiouronium salts (207) are cyclized with trifluoroacetic acid and stannic chloride. The necessary starting materials are synthesized from aldehydes or ketones by the action of vinylmagnesium chloride and subsequent treatment of the product allyl alcohols (206) first with hydrogen chloride and then with a thiourea (Scheme 91) (77JHC717). 

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). 

Diones are normally synthesized from /3-hydroxy acids in two steps first, conversion into carbamates by reaction with sodium cyanate, and then cyclization with thionyl chloride (Scheme 103) (54JCS839). Alternative preparations utilize oxetanes, which may be combined either with isocyanates in the presence of boron trifluoride (68JAP6808278) or with S-alkylthioureas (Scheme 104) (69ZOR1844). In the last example the initial products are imines (224) which may readily be hydrolyzed to the required diones. Similar methods can be applied to the synthesis of tetrahydro-l,3-thiazine-2,4-diones, and, for instance, the 4-oxo-2-thioxo derivative (225) is obtained from /3-propiolactone and dithiocarbamic acid (Scheme 105) (48JA1001). 

Some reduced derivatives of imidazo[2,l-b]-l,3-thiazin-4-one have been described. For example, the reaction of 2-mercaptobenzimidazole with acry-loyl chlorides results in TAs 188 (91MI2). A similar iodine-containing compound (R = H) was synthesized by the cyclization of acid 189 (92MI2) (Scheme 66). 

A number of methods employ an imidazole-2-thione or related compound with a bifunctional reagent to build the thiazine ring in one or two steps. Treatment of (682) with acrylyl chloride directly produced (683) (64JOC1720). Substituting acrylic acid under catalysis allows isolation of the S-alkylated intermediate, which cyclized to (683) upon heating (64JOC1715). 

H-1,4-Thiazines are weak bases (Section 11,D,5), and the parent compound is reported to form salts with picric acid, chloroplatinic acid, and hydrogen chloride. Alkylation, to give the thiazinium iodide 25, occurred when the thiazine 15 was treated with methyl iodide the derivative 25 is the only known example of a 4//-l,4-thiazinium salt. 

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