Thiazines cycloaddition reactions

Sulfonyl imides (78) are, like sulfenes, prepared by dehydrohalogenation of the corresponding sulfonyl chlorides (79) (usually called sulfamoyl chlorides). Like sulfenes, they take part in [2 + 2] and [4 + 2] cycloaddition reactions with electron-rich alkenes or with 1,3-dienes, yielding 1,2-thia-zetidine 1,1-dioxides (80)104 or dihydro-1,2-thiazines (81),105 respectively. 

TVA -Disulfonylsulfodiimides 244 react exothermically with butadiene to give 1-sulfo-nylimino-2-sulfonyl-3,6-dihydro-l,2-thiazines 245 (equation 130)121,122. IV-Aryl-AT-sul-fonylsulfodiimides 246 are much less reactive as dienophiles. The addition to butadiene to yield 247 takes place in boiling benzene (equation 131)123. No cycloaddition reactions of dialkyl- or diarylsulfodiimides are known. 

The reaction of 1,4-diphenylbuta-l,3-diene (2) with trithiazyl trichloride (3) yields a bi(thiadiazole) (4), an isothiazoloisothiazole (5), a dithiazolothiazine (6), and two thiazin-odithiatriazepines (7) and (8) by 1,2-, 1,3-, and 1,4-cycloaddition reactions (Scheme 2). The bridged-mode (/3-tether) tandem inter-[4 -E 2]/intra-[3 -E 2] cycloaddition of (ii)-2-methyl-2-nitrostyrene (9) with 1-butoxypenta-1,4-diene (10) produces stable tricyclic nitroso acetals (11) which afford, after reduction and protection, highly functionalized aminocyclopentanedimethanol triacetates (12) (Scheme 3). ... 

Four regioisomeric dihydrothiazine 1,1-dioxides are possible depending upon the position of the double bond. The most common examples of this subclass include 5,6-dihydro-4//-l,2-thiazine 1,1-dioxides 5, 3,4-dihydro-2//-l,2-thiazine 1,1-dioxides 6, and 3,6-dihydro-2//-l,2-thiazine 1,1-dioxides 7. Scant interest has been paid to 5,6-dihy-dro-2/7-l,2-thiazine 1,1-dioxides 8 or their substituted derivatives. Related 3,6-dihydro-2//-l,2-thiazine 1-oxides 9 are also an important subclass of compounds due to their ease of preparation via [4-f2] cycloaddition reactions. 

Theoretical calculations have been an important means of rationalizing the electronic course of hetero-Diels-Alder and related pericylic reactions for the formation of 1,2-thiazines 25 and 26. MOP AC 93 PM3 calculations have been used to deduce the regioselectivity of [4-1-2] cycloaddition reactions involving thiazinylium perchlorate 27 (Scheme 1) <1999TL1505>. Due to the higher lowest unoccupied molecular orbital (LUMO) coefficient at C-6 compared to N-2, the C-6 and S-1 behave preferentially as the dienophile double bond in cycloaddition reactions of this substrate with butadienes 28. 

The structure of A -sulfinyl compound 39 was solved using a single crystal grown by the slow evaporation of a solution of dichloromethane (DCM) and hexane (Figure 7) <2003T4651>. The A -sulfinyl compound crystallizes with two molecules in a unit cell. This work provides additional evidence for the (Z)-preference of this dienophile used in [4-1-2] cycloaddition reactions to prepare 1,2-thiazines. 

Treatment of 2-amino-5-nitrothiobenzamide with iV,iV-dimethylformamide dimethyl acetal gives 2-amino-iV-((dimethylamino)methylene)-5-nitrobenzothioamide 191 in excellent yield <2004TL5913>. Cycloaddition reaction of 191 with DMAD results in formation of dimethyl 2-(2-amino-5-nitrophenyl)-4-(dimethylamino)-4//-l,3-thiazine-5,6-dicarboxylate 192 in low yield when R = H. This is caused by cycloreversion of thiazine 192 to give dimethyl 2-((dimethylamino)methylene)-3-thioxosuccinate 193 and 2-amino-5-nitrobenzonitrile 194 (Scheme 19). When W((dimethylamino)methylene)-2-(alkylamino)-5-nitrothiobenzamides 191 (R = Me, Bn) are reacted with DMAD, the expected 4//-l,3-thiazine-5,6-dicarboxylates 195 are produced as stable compounds. 

Regiospecific, Pd(II) catalysed, cycloaddition reactions of azetidines to yield ring-enlarged products include the formation of tetrahydro-2-iminopyrimidines (e.g. 10) by reaction with carbodi-imides (95JOC253) and tetrahydro-l,3-thiazin-2-imines (e.g. 11) from isothiocyanates (95JOC3092). 

Fusion of a thiazole to pyrimidine betaines does not change the tendency of the latter for cycloaddition reactions, e.g. (306) forms adducts with alkynes (73JHC487). Similarly 1,3-thiazine betaines (399) react as 1,4-dipoles with aryl isocyanate with elimination of COS to produce pyrimidine betaines (400) (76CB3668). 

Diels -Alder reactions are widely applicable because of their versatility in building up six-mem-bered ring systems. For example. [4 + 2]-cycloaddition reactions of halogcnatcd thiazyls and 2-chloro-1,l,3.4,4-pentafluorobuta-l,3-dicne (7) furnish the corresponding 124,2-thiazines 8.63... 

The latter compound is similar to 60 (R = C02Et) in reactivity toward acenaphthylene, undergoing [4 + 2]-cycloaddition/cheleotropic elimination to the known sulhnylamine Et02C—N=S=0, which was sufficiently stable to be isolated but underwent facile cycloaddition with 2,3-dimethyl-1,3-butadiene to give the thiazine sulfoxide 65. Although 64 is a fairly reactive molecule, the reactivity in cycloaddition reactions is less than that of 60, which is in keeping with the known differences in reactivity of thiophene 1-oxide and thiophene 1,1-dioxide. 

Intermediates of type 42 may be generated by cycloaddition reactions. Thus, when the thiirene 1,1-dioxide 45 was treated with the mesoionic compound 46 at ambient temperature, the sulfone 44b was produced in high yield the thiazine dioxide 44a was prepared in a similar manner. It is noteworthy that the intermediate cycloadducts 47a and 47b lost carbon dioxide in preference to sulfur dioxide. 

The application of theoretical methods to 1,2-thiazines has been nonexistent. However, FMO theory has been used to explain the stereochemical outcome of [4 - - 2] cycloaddition reactions of N-sulfinylamine dienophiles leading to 3,6-dihydrothiazine oxides <85JCS(P2)589>. 

Benzoyl-2//-l,3-thiazines (144) and diphenylketene enter into [2 + 2] cycloaddition reactions via the imine bond, thereby providing access to thiazolo-)S-lactams (145) <85CS239>. Chloroketenes (from chloroacetyl chlorides and a tertiary amine) react in a similar manner and give chloro derivatives (146) (Scheme 27) <85BSB149>. With 6//-l,3-thiazines (147) the products are the corresponding -lactams (148) (Equation (17)) <86CJC597>. 

Dihydro-l,3-thiazine-6-thiones (262) are obtained from 2-aza-1,3-dienes (263) through cycloaddition reactions with carbon disulfide in the presence of a catalytic amount of boron trifluoride. It is probable that the initial adducts are 2,5-dihydro-1,3-thiazine-6-thiones (264), which are unstable and tautomerize to the observed products (Scheme 50) <86CC1179>. 

A detailed account of condensation reactions used in heterocyclic chemistry can be found in Section 8.2.6, in Chapter 10 [97], and, for cycloaddition reactions, in Chapter 11 [98]. A previously unknown class of compounds, spiro[3H-indole-3,2 -[41-f] pyrido[3,2-e]-l,3-thiazine]-2,4 (ll-f) diones, can be synthesized by reaction of in situ-generated 3-indolylimine with 2-mercaptonicotinic acid under the action of MW in the absence of solvent. Both neat reactions and reactions on solid supports such as silica gel, alumina etc., effectively promote the reaction whereas reactions under thermal heating conditions failed to proceed (Scheme 8.31) [99]. 

A-Sulfonylamines undergo [4+2] cycloaddition reactions with some dienes to give 1,2-thiazin-5-one 1,1-dioxides 97. 

The azido intermediate (224) can be prepared by a cycloaddition reaction using the thiazine (225) and azidoacetyl chloride in the presence of triethylamine (199). Reduction and SchifPs base formation gives (226) which can be converted to ( )-cephalothin. On the other hand introduction of the thiomethyl group followed by acylation gives (227), ideally suited for conversion to (228) and ultimately ( )-cefoxitin (200). 

In Corey and Chaykovsky s initial investigation, a cyclic ylide 79 was observed from the reaction of ethyl cinnamate with ylide 1 in addition to 32% of cyclopropane 53. In a similar fashion, an intermolecular cycloaddition between 2-acyl-3,3-bis(methylthio)acrylnitrile 80 and 1 furnished 1-methylthiabenzene 1-oxide 81. Similar cases are found in transformations of ynone 82 to 1-arylthiabenzene 1-oxide 83 and N-cyanoimidate 84 to adduct ylide 85, which was subsequently transformed to 1-methyl-lX -4-thiazin-l-oxide 86. ... 

It is well known that l,3-thiazine-4,6-diones can exist in three tautomeric forms <1960CB671, 1976KGS1042>. Cycloaddition of chlorocarbonyl ketenes with thioamides has been reported to produce only the 4-hydroxy-l,3-thiazin-6-ones, whereas the same reaction with amides gives either 4-hydroxy-1,3-oxazin-6-ones or a mixture of tautomers depending on the substituents on the starting materials <2005ARK(xv)88>. 

The diastereoselective cycloaddition of 2-phenyl-4-dimethylamino-l-thia-3-azabuta-l,3-diene with a choice of dienophiles and in the presence of a Lewis acid provides a convenient route to 5,6-dihydro-4//-l,3-thiazines <2002TL6067, 2004T1827>. The more stable /ra r-adducts are produced exclusively. The approach using (4A)-3-acryloyl-4-benzyloxazolidin-2-one 198 provides access to the chiral 5,6-dihydro-4//-l,3-thiazine 199 <2004T1827>. The exceptional level of selectivity is only achieved when magnesium bromide is used. The chiral auxiliary was removed by reaction with lithium benzoxide to give the benzyl ester 200, and reaction with catalytic amount of samarium triflate and methanol provides the methyl ester 201 (Scheme 21). 2-Substituted-5,6-dihydro-l,3-thiazines are conveniently synthesized from nitriles or thiocyanates and 4-mercapto-2-methylbutan-2-ol to produce... 

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