Dihydrothiazines preparation

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. 

Solvolysis of Diels-Alder adducts provides a useful means of preparing a variety of nitrogen-containing compounds. For instance, the hydrolysis of A Cbz or A -Ts bicylic sulfonamides 44 and 112 with NaOH affords the homoallylic carbamate 113 and sulfonamide 114, respectively (Scheme 12) <2000TL3743, 2002TA2407>. Related hydrolysis reactions have also been reported with monocyclic 1,2-dihydrothiazine oxides <2004JOC7198>. 

Deprotonation of a dihydrothiazine ring, followed by a reaction with an electrophile, is most straightforward in benzothiazin-3-ones (general structure 35), which are deprotonated at the 2-position by lithium diisopropyl amide (LDA). The enolate can then react with a variety of electrophiles including deuterium oxide, methyl iodide, and aldehydes <1982T3059>. Compound 70 was prepared in this manner from 2,4-dimethyldihydro-l,4-benzothiazin-3-one (Equation 27) <1985T569>. 

Dehydration of dihydrothiazines is possible using either Pummerer reaction or 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ), and compound 107 was prepared by both routes from 249 (Scheme 38) <1985JOC413>. 

Dihydrothiazines are useful in the formation of cephems and the derivative (205), for example, was prepared from the bromoester (204) and ethyl thioformate specifically for this purpose (B-80MI22701). 

Y-Sulfinyl carbamate 7 and 1,3-cyclohexadiene react in the presence of titanium(IV) chloride at - 50 °C to give a 9 1 mixture of diastereomeric 3,6-dihydrothiazine S-oxides 11 differing in the configuration at sulfur. The N-sulfinyl carbamate 10, prepared from a (+)-camphor derived alcohol, however, reacts with 1,3-cyclohexadiene to form exclusively one cycloadduct100. 

Until recently, dihydrothiazine oxides had not found much use in synthesis. Recently, Weinreb and coworkers have exploited some of the known reactions of these adducts, along with some new transformations, in stereoselective preparation of some complex nitrogen-containing molecules. One useful transformation of these adducts is the hydrolysis/retro-ene elimination of sulfur dioxide shown in equation (53). Thus dihydrothiazine oxide (120), prepared from ( , )-tetramethylbutadiene, underwent hydrolysis to allylic sulfinic acid (121) which suffered a retro-ene reaction via the chair-like conformation... 

The compound (which had a dihydrothiazine ring fused to the P-lactam core) showed resistance to P-lactamases and was less toxic than benzylpenicillin. The discovery that the basic building block, namely 7-aminocephalosporanic acid (7-ACA), could be synthesised, led to the preparation of numerous cephalosporin derivatives eg cephalothin, cephaloglycin (orally active), cefaclor and cefuroxime (Figure 7). 

By 1959, Rolinson and coworkers completed the isolation of the penicillin nucleus, 6-aminopenicil-lanic acid, (Figure 1) in quantity. At about the same time the p-lactam-dihydrothiazine structure for the cephalosporin C was proposed [2] and confirmed subsequently by X-ray crystallographic analysis. In 1962, Morin and coworkers established a chemical method for the production of 7-aminocephalosporanic acid (Figure 1) from cephalosporin C in quantity. These developments opened the way to the preparation of... 

Usually, precursors of type 52 are stable, readily prepared compounds. Thus the derivative 52a was converted into the dihydrothiazine 53a when... 

The reactions of a-mercapto ketones with aziridines have been used to prepare derivatives of the dihydrothiazines 50 and 51 for example,... 

Dihydrothiazines may be prepared by the action of elemental sulfur and aziridine upon ketones " the outcome of the reaction is markedly dependent upon the structure of the ketone. Thus with symmetrical ketones of type 62, e.g., pentan-3-one, heptan-4-one, cyclopentanone, cyclohexanone, and cyclooctanone, dihydrothiazines of type 63 were obtained in high yields symmetrical thiazolidines of type 64 were also formed as minor by-products. 

The dihydrothiazine 105b has also been prepared from D-penicillamine and methyl 2-chloro-3-oxopropionate. In principle, its synthesis may involve a cyclization of type 93 or the dehydration of an intermediate of... 

An example of a cyclization of type 122 is provided by the conversion of the betaine 124, prepared from 5-(2-hydroxyethyl)-3,4-dimethylthiazolium iodide and phenyl isothiocyanate, into the dihydrothiazine 125 in the presence of sodium hydroxide a likely reaction pathway is suggested... 

The most widely used method for the preparation of dihydrothiazine oxides involves the oxidation of the parent dihydrothiazines with sodium periodate or w-chloroperbenzoic In certain in-... 

The reactions of a-mercapto ketones with aziridines have been used to prepare derivatives of the dihydrothiazines 50 and 5144-47 for example, 2-mercaptopentan-3-one and 3-mercapto-3-methylbutan-2-one afforded the compounds 60a and 61a with aziridine, and the derivatives 60b and 61b with 2-methylaziridine. In general, good yields of dihydrothiazines are obtained by this route. 

The most widely used method for the preparation of dihydrothiazine oxides involves the oxidation of the parent dihydrothiazines with sodium periodate or w-chloroperbenzoic acid.79,95,98,100-102,113.114 jn certajn jn stances, oxygen will act as the oxidant for example, the sulfoxide 187 was formed when a cyclohexane solution of the compound 117 was exposed to the air.44,46,86 The mechanism of this reaction, in which the thiazolidine 186 was a co-product, has already been discussed (Section V,C,2,b). 

These A-sulfinyl Diels-Alder reactions are also highly stereoselective, giving products of syn addition to the 1,3-diene. The same holds true for the sulfur diimide cycloadditions . The stereoselectivity with respect to the dienophile is not very well known because the stereochemistry of sulfur in the starting A-sulfinyl dienophile and in the resulting thiazine derivatives has usually not been determined. A representative sample of the stereoselective preparation of 3,6-dihydrothiazine 1-oxides and 1-imines is shown in Scheme 34 <84JA786i, 84JA7867>. 

Scheme 42). Using the same methodology, the dihydrothiazine (216) was used to prepare the... 

The Weinreb group investigated the hydrolysis of dihydrothiazine oxide 39, prepared from ( , )-tetramethylbutadiene, which was demonstrated to afford only sulfonamide 40 having an E double bond and the erythro configuration [Eq. (18)]. 

The Weinreb group has recently developed stereoselective methodology for synthesis of unsaturated vicinal diamine derivatives from dihydrothiazine imines.49 For example, when cycloadduct 54 prepared from (E, )-2,4-hexadiene was treated with phenylmagnesium bromide followed by trimethyl phosphite, E-threo vicinal diamine 57 was formed cleanly in good yield [Ea. <27)1. 

New rearrangements of 2-imino-2//-l-benzopyran-3-carboxamides, on their treatment with anthranilic acid, have been revealed. 4-Quinazolinones (72) have been prepared by rearrangement of 4-imino-4//-3,l-benzoxazines (71) via amidine carboxamides, while dihydrothiazines such as (73) which are disubstituted at C(7) have been observed to undergo a cyclization-ring contraction reaction with substituted acrylic acids to yield pyrroles (74). This interesting transformation has been accounted for by the route outlined in Scheme 23. 

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