Dihydrothiazine oxide 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>. 

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... 

Another useful reaction of these Diels-Alder adducts is shown in equation (54). Dihydrothiazine oxide (123) from ( . )-2,4-hexadiene can be opened with a Grignard reagent to allylic sulfoxide (124) which undergoes a stereoselective 2,3-sigmatropic rearrangement via the envelope-like transition state conformation shown, having a quasi-equatorial methyl group to afford sulfenate ester (125). Desulfurization of (125) provides E)-threo smino alcohol derivative (126) in excellent overall yield. If ( ,Z)-2,4-hexadiene is used, the E)-erythro epimer of (126) is formed cleanly. 

In addition to their involvement in oxidation reactions, thiazinium ions of type 138 intervene in the interconversion of 3-hydroxy and 3-aIkoxy dihydrothiazines. - For example, compound 139b was converted into 13S by aqueous hydrochloric acid. 

An unusual Pummerer-Iike reaction has been reported to occur when certain 3-hydroxymethyl dihydrothiazine oxides are treated with acetyl chloride. For example, the compounds 212 and 213 were convert into the bicyclic derivative 180b, which was isolated as a 4 1 mixture of diastereoisomers. The reaction probably occurs by a pathway similar to that depicted in Scheme 9. 

Only two reactions leading to the formation of ring-opened products have been reported for dihydrothiazine oxides. Thus when treated with acetyl chloride, the sulfoxide 221 was converted into the oxazolinone 235, probably by way of the intermediate 234. Raney nickel has been shown to effect the desulfurization of the compound 236, to give the oxazolidine 237. ... 

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). 

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>. 

There are several well-known transformations of 3,6-dihydrothiazine oxides and 3,6-dihydrothiazine imines. In most of these reactions, either the cyclic sulfinamide moiety and/or the carbon-carbon double bond is involved. For example, a 3,6-dihydrothiazine oxide can be hydrolyzed under either acidic or basic conditions to afford a homoallylic amine derivative [Eq. (17)]. 

Similarly, treatment of a dihydrothiazine oxide with thiophenoxide ion and thiophenol yielded an intermediate thiosulfinate ester, which underwent further reaction to produce a disulfide [Eq. (23)]. 

The cycloaddition of 7V-sulfinyl compounds with dienes gives dihydrothiazine oxides, which are precursors of homoallyl amines or pyrroles. Reactions of these reactive dienophiles in the presence of SnCU or TiCU yield the adducts diastereoselectively under mild reaction conditions. 

Finally, reaction of a dihydrothiazine oxide with vinylmagnesium bromide at -60 °C, followed by workup, afforded a sulfine as a single diastereoisomer. The reaction presumably occurred via ring opening of the sulfur Diels-Alder adduct to a vinyl sulfoxide, followed by isomerization [124]. Although the stereochemistry was not identified, the structure depicted below was postulated (Scheme 9.24). 

Diels-Alder Reactions. 7V-Sulfinyl compound (1) is an effective dienophlle in the regioselective [4 + 2] cycloaddition of unsymmetrical dienes. For example, 2-substituted dienes were found to yield only 5-substituted dihydrothiazine oxides (eq 9). The cycloaddltlon of (1) with simple 1-substituted 1,3-dienes is often dependent on the reaction temperature. At low temperatures, 3-substltuted dihydrothiazine oxides are usually formed as kinetic products, but at higher temperatures the more stable 6-substituted heterocycles are produced (eq 10). ... 

Because the integrity of the dihydrothiazine ring and its C-4 carboxyl substituent is crucial to useful antimicrobial activity, reactions involving this part of the cephalosporin molecule are usually undesirable. The possibilities for sulfur oxidation or alkylation, substitution at C-2 which is adjacent to both sulfur and a double bond, double bond isomerization and addition reactions, and the influence of a free carboxylic acid must all be considered in designing reactions to selectively modify other cephalosporin functionalities. 

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. 

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>. 

A-Sulfinyl amides function as dienophiles in the Diels Alder reaction and with suitably substituted dienes yield 3,6-dihydrothiazine 1-oxides containing two stereogenic carbon atoms bonded to the sulfinyl sulfur and nitrogen93 recent studies have shown that the reaction occurs in a stepwise fashion via dipolar intermediates94. 

The reaction of ( , )-2,4-octadecadienyl carbamate with thionyl chloride in pyridine at 15 "C yields only one stereoisomer of the corresponding dihydrothiazine 5-oxide via an /V-sultinyl carbamate intermediate which undergoes intramolecular Diels-Alder reaction with complete stereoselecti vity 96. 

The high pressure reaction also woiks well with -silyl dienophile (119). This process allows easy access to 3,6-dihydrothiazine 1-oxides which are unsubstituted on nitrogen. 

Although the dehydrogenation of dihydrothiazines of type lib, which are readily available compounds (Section V,B), may provide a useful route to thiazines, few examples have been reported. However, studies in the author s laboratory have shown that the compound 18a was converted into the thiazine 19 in good yield by lead tetraacetate in benzene. A further example is provided by the transformation, in boiling toluene, of the dihydrothiazine 18b into the bis(thiazine) 20 the product, however, was isolated only in 12% yield. The formation of the thiazinium chloride 23, from the reaction of the penicillin sulfoxide 21 with phenylacetyl chloride in acetone exposed to the air, constitutes a remarkable oxidative rearrangement. It seems likely that the dihydrothiazine 22, formed by the route suggested in Scheme 1,... 

There are numerous examples in which dihydrothiazines are converted into their 1-oxides and 1,1-dioxides these reactions are discussed in Sections VI,B,1 and VII,B,1, respectively. 

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