A-Sulfinyl dienophiles

Theoretical work on the gas-phase hetero-Diels-Alder reaction of A -sulfinyl dienophiles was used to study both endo- and o-modes of cycloaddition for both (E)-29 and (Z)-30 dienophiles at the B3LYP/6-31G level (Scheme 2) <2000JOC3997>. In summary, these calculations have predicted that (1) the A -sulfinyl dienophiles prefer the (Z)-30 orientation over (E)-29 stereochemistry by 5-7 kcalmoP, (2) the transition state is concerted but nonsynchronous, and (3) an lYo-transition state with diene 31 is favored over the fvo-approach both kinetically and thermodynamically. 

Asymmetric [4 + 2] cycloaddition reactions of A-sulfinyl compounds and dienes have been developed <2002TA2407, 2000TL3743>. Excellent enantioselectivity is observed for the preparation of product 148 by the reaction of A-sulfinyl dienophiles 146 and acyclic diene 147 catalyzed with Cu(II) and Zn(II) complexes of Evans bis(oxazolidinone) ligands (Scheme 74) <2004JOC7198>. 

One of the first examples of an excellent stereoselectivity in open-chain allylic sulfides was published in 1986 by Weinreb [208]. In this remarkable paper a diastereoselective Diels-Alder reaction of a sulfinyl dienophile with a substituted diene delivered cycloadducts as described earlier (Sect. 3.5.3, Scheme 59). After ring opening and reduction Z-olefin 362 was produced which, after S-methylation and base treatment rearranged to isomerically pure homoallyl sulfide 363. 

Two groups have recently examined enantioselective A -sulfinyl dienophile Diels-Alder reactions. In one case, Whitesell et al. found that a phenylmenthol derived N-sulfinyl carbamate adds to ( , )-2,4-hexadiene under Lewis acid catalysis to afford a single diastereomer (equation 52). If the Lewis acid was omitted, a complex mixture of cycloaddition products was obtained. Attack of the diene on the N-sulBnyl dienophile as shown in the equation would rationalize the observed results. The site of Lewis acid complexation, however, is unknown. 

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>. 

Kresze and Wagner offered a mechanistic model for the [4 + 2] cycloadditions of A-sulfinyl dienophiles to rationalize the kinetically formed regioisomeric products.10 They proposed a concerted mechanism for the reaction via a transition state which has dipolar character (Scheme 1-1). For 1-substituted dienes, transition states A and B can be considered. If R is an electron-donating group which stabilizes the cationic center, a 3-substituted product will result. If R is electron-withdrawing (e.g., C02Me), the 6-substituted isomer will be the kinetic product of the cycloaddition. A similar argument can be made for 2-substituted and more complex dienes. 

A -sulfinyl dienophiles 161 bearing electron-withdrawing groups could react with dienes 162 in Diels-Alder fashion to lead to 3,6-dihydrothiazine-l-oxides 163 (Scheme 41.34). " ... 

Weinreb SM. Synthetic methodology based upon A-sulfinyl dienophile [4+2] cycloaddition reactions. Acc. Chem. Res. 1988 21 313-318. 

The optically active a-sulfinyl vinylphosphonate 122 prepared in two different ways (Scheme 38) is an interesting reagent for asymmetric synthesis [80]. This substrate is an asymmetric dienophile and Michael acceptor [80a]. In the Diels-Alder reaction with cyclopentadiene leading to 123, the endo/exo selectivity and the asymmetry induced by the sulfinyl group have been examined in various experimental conditions. The influence of Lewis acid catalysts (which also increase the dienophilic reactivity) appears to be important. The 1,4-addition of ethanethiol gives 124 with a moderate diastereoselectivity. 

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. 

The initial work on the asymmetric [4-1-2] cycloaddition reactions of A -sulfinyl compounds and dienes was performed with chiral titanium catalysts, but low ee s were observed <2002TA2407, 2001TA2937, 2000TL3743>. A great improvement in the enantioselectivity for the reaction of AT-sulfinyl dienophiles 249 or 250 and acyclic diene 251 or 1,3-cyclohexadiene 252 was observed in the processes involving catalysis with Cu(ll) and Zn(ii) complexes of Evans bis(oxazolidinone) (BOX) ligands 253 and 254 <2004JOC7198> (Scheme 34). While the preparation of enantio-merically enriched hetero-Diels-Alder adduct 255 requires a stoichometric amount of chiral Lewis acid complex, a catalytic asymmetric synthesis of 44 is achieved upon the addition of TMSOTf. 

A -sulfinylacetamide 297 in greater than 90% yield when a catalytic amount of methyltrioxorhenium is employed. Futhermore, the hetero-Diels-Alder adduct is highly soluble in both chlorinated and ethereal solvents. A detailed investigation of the retro-Diels-Alder reaction of 298 by thermogravimetric analysis revealed an onset temperature of 120 °C and complete conversion of bicycle 298 to pentacene 296 at 160 °C, which are temperatures compatible with the polymer supports typically used in electronics applications. The electronic properties of these newly prepared OTFTs are similar to those prepared by traditional methods. Later improvements to this chemistry included the use of A -sulfinyl-/< r/-butylcarbamate 299 as the dienophile <2004JA12740>. The retro-Diels-Alder reaction of substrate 300 proceeds at much lower temperatures (130 °C, 5 min with FlTcatalyst 150 °C, Ih with no catalyst). 

Thiopyrans are produced in high yield by the microwave-induced one-pot reaction between a,/ -unsaturated ketones, dienophilic alkynes, and Lawesson s reagent. The equivalent thermal reaction is unsuccessful <2006TL4925>. Calculations at the G3MP2B3 level show that the introduction of a 5-methyl substituent into n -sul I cnyl-. a-sulfinyl-, and ct-sulfonyl- hex-5-enyl radicals shifts the regioselectivity of cyclization to the 6-endo products, tetrahydrothiopyran derivatives <2006JOC9595>. 

The complete 7r-facial selectivity observed for these reactions, which is probably the highest so far reported with acyclic sulfinyl dienophiles, can be rationalized by assuming that conformational equilibrium around the C-S bond was completely restricted as a consequence of an important dipolar repulsion between cyano and sulfinyl groups. It determines that the latter one adopts the s-... 

As expected, the major product was the frans-annulated compound 2-188 which should be formed via an exo-E-zzz-zfz-transition structure with an attack of the dienophile anti to the bulky tolyl group. An ezzdo-Z-anfz-orientation which would also lead to the trans-product can be excluded because of its strain [54]. The reaction of the corresponding a -sulfinyl-a,/ -unsaturated ketone 2-189 displayed a much lower induced diasteroselectivity (Fig. 2-53) [170b]. 

The hetero-DielsAlder reaction of A-sulfinyl 141 (X = 0 or NR) or thionitrosoarene 144 dienophiles with dienes 142 is the main method for the formation of 3,6-dihydro-2//-l,2-thiazine 1-oxides 143 or 3,6-dihydro-2//-1,2-thiazines 145 (Scheme 73) . The mechanistic and stereochemical aspects of this reaction are covered in detail in GHEC-II . In general, thionitrosoarenes 144 are transient in nature, rather difficult to prepare, and thus have a limited role in the synthesis of 1,2-thiazines. On the other hand, A-sulfinyl compounds 141 and related sulfur diimines are more stable and are isolable species. The common method of preparation of the A-sulfinyl compounds involves treatment of an amine or amide with SOCl2 and base. 

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. 

In 2002 the same author demonstrated the usefulness of this method in a rather demanding context including an intramolecular cycloaddition with an W-sulfinyl urea as a new type of N-sulfinyl dienophile (Scheme 60) [144]. As key steps in the total synthesis of freshwater cyanobacterial hepatotoxins, ( , )-diene 238 was transformed into N-sulfinyl urea 239 which immediately cycloadds intramolecularly yielding tricycle 240 as a single isomer in excellent yield. After reaction with phenylmagnesium bromide the intermediate allylic sulfoxide rearranges cleanly to diastereomerically pure allylic alcohol... 

Preparation of Suliinyl Dienophiles. This sulfinyl ester was also used to prepare optically active sulfinyl dienophiles by a Knoevenagel-type condensation of Glyoxylic Acid (eq 7). ... 

One synthetic problem in aza Diels-Alder reactions is the stability of imines under the influence of Lewis acids. It is desirable that the Lewis acid-activated imines are immediately trapped by dienes or dienophiles. In 1989, Sisko and Weinreb reported a convenient procedure for the aza Diels-Alder reaction of an aldehyde, a 1,3-diene, and A-sulfinyl p-toluenesulfonamide via A -sulfonyl imine produced in situ—a stoichiometric amount of BF3 OEt2 was used as a promoter [28a]. 

Weinreb et al. have found a similar lack of stereoselectivity in the cycloaddition of cyclohexadiene and iV-sulfinylbenzyl carbamate." The mechanistic situation is further complicated in these cases by the fact that one cannot determine whether the ( )- or (Z)-sulfinyl dienophile is the reacting species. 

The Weinreb group has recently examined the reaction of chiral N-sulfinyl dienophile 23, prepared from (+)-camphor, with 1,3-cyclohex-adiene (Scheme 1-VIII). Whereas the uncatalyzed cycloadcUtion afforded a mixture of diastereomeric adducts, the reaction promoted by TiCU gave a single adduct 24 having the 35,6/ configuration. Stereochemistry at sulfur in this compound could not be determined. As in the phenylmenthol series, one can reasonably consider two reacting dienophile conformations 23A and 23B (Scheme 1-VIU). If conformer 23A is attacked by the diene in an endo manner from the most exposed face, the observed adduct 24 will be formed. Similarly, if conformer 23B reacts with cyclohexadiene via an exo transition state, 24 will result. 

This transformation has been extended to a number of other AT-substituted adducts of AT-sulfinyl dienophiles, - although yields of product are quite variable depending on the nature of the substituents. Russian workers have found that A/ -acyldihydrothiazine oxides can be converted to dihydro-1,3-oxazines in good yield (Scheme 1-X), perhaps via the ho-moallylic amine derivative [cf. Eq. (17)]. ... 

As stated in the Introduction, N-sulfinyl compounds bearing electron-withdrawing substituents react as heterodienophiles. Arylsulfinyl derivatives usually require heating for a reaction to occur, whereas other types of N-sulfinyl dienophiles will often cycloadd near room temperature or below. In fact, these cycloadditions are sometimes dangerously exothermic when run in the absence of a solvent, and usually an inert solvent such as benzene, toluene, or cyclohexane is used.2 ... 

A number of representative examples of N-sulfinyl dienophile cycloadditions can be found in Table 1-1. As noted above, some adducts undergo... 

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