Sulfinyl Dienophiles

The only paper concerning catalysis by Lewis acids of the Diels-Alder reactions of these simple sulfinyl ethylenes was due to Ronan and Kagan [20], who studied the influence of TMSOTf in the reaction of compound (S)-l with cyclo-pentadiene and furane. In the first case, the reaction occurs at 0°C in 3 h, giving an 89 11 mixture of endo and exo adducts (overall yield 60%) with very high n-facial selectivity (de 92%). The high efficiency of the catalyst increasing the reactivity of 1 also made possible its reaction with furan, which evolved with low endo/exo selectivity (55 45) and lower 7r-facial selectivity (de 70%) than that observed with cyclopentadiene. These excellent results were nevertheless, eclipsed by those reported in the same paper [20] concerning the activation of 

Reactions of compound 8a with butadiene, 2,3-dimethylbutadiene, and isoprene required more drastic conditions (150°C, autoclave) [24]. In the case of isoprene, a 60 40 regioisomeric mixture was obtained (the major product being the para-adduct). The influence of Lewis acid catalysis on the reaction of cyclopentadiene with different ethynyl aryl sulfoxides [Ar =p-Tolyl, o-nitrophenyl, and l(2-methoxynaphthyl)] has been recently reported [25].Dienophilicities of acetylenic sulfoxides were greatly enhanced by the presence of various Lewis acids (the effect being greater with stronger Lewis acid), but the stereoselectivity was scarcely affected by the catalysis. 

From the above results it can be inferred that sulfinyl ethylenes are not good dienophiles because of their low reactivity and poor stereoselectivity. In order to improve both of these factors, different electron-withdrawing groups (able to increase dienophilic reactivity and to restrict conformational movement around the C-S bond, thus improving the stereoselectivity) were incorporated into the double bond. They are presented in the sections below, classified according to the number and kind of the additional activating groups present in the vinyl sulfoxide moiety. 

---

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. 

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. 

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-... 

Numerous studies have dealt with different types of sulfur-containing hetero-dienophiles. Thus, hetero Diels-Alder reactions of N -sulfinyl dienophiles have been thoroughly studied by Weinreb et al. [454] the resulting cycloadducts represent useful and versatile intermediates in the synthesis of homoallylic amines [455] or pyrroles [456]. Further work using this type of S = N dienophiles... 

Asymmetric hetero Diels-Alder reactions of N-sulfinyl dienophiles with chiral dienes have been found to proceed with very good induced diastereoselec-tivities [459]. 

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>. 

The reaction of AT-sulfinyl dienophiles with 1,3-dienes yields 3,6-dihydrothia-zine 1-oxides (compare the corresponding reactions with sulfur diimides. Sect. 3.1), which can be ring opened with carbon nucleophiles to yield allylic sulfoxides ready to undergo the ME rearrangement. The seminal paper on this chemistry by Weinreb appeared in 1984 (Scheme 57) [67,140]. 

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... 

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. 

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). ... 

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. 

Weinreb, S. M. Synthetic methodology based upon N-sulfinyl dienophile [4 + 2]-cycloaddition reactions. Acc. Chem. Res. 1988, 21,313-318. 

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>. 

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. 

The first examples of intramolecular Af-sulfinyl dienophile cycloadditions have recently been reported by Weinreb et al. Treatment of ( , )-... 

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)]. ... 

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. 

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... 

---