Sulfinyl Dienophile Cycloadditions

As stated in the Introduction, iV-sulfinyl compounds bearing electron-withdrawing substituents react as heterodienophiles. Arylsulfinyl derivatives usually require heating for a reaction to occur, whereas other types of iV-sulfinyl dienophiles wQl 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.  

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

Entry Dienophile Diene Conditions Product Yield Ref. 

Weinreb and co-workers have also utilized A -sulfinyl-8-phenylmenthol 

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

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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. 

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>. 

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... 

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. 

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. 

The Weinreb group has recently examined the reaction of chiral N-sulfinyl dienophile 23, prepared from (+)-camphor, with 1,3-cyclohex-adiene (Scheme 1-VlII). Whereas the uncatalyzed cycloaddition afforded a mixture of diastereomeric adducts, the reaction promoted by TiCU gave a single adduct 24 having the 35,6ft 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-VlII). 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 transiticm state, 24 wiU result. 

The first report on the use of enantiomerically pure sulfinyl dienophiles in Diels-Alder cycloadditions was by Maignan and Raphael [156], who utilized (+)-(R)-p-tolyl vinyl sulfoxide (26a) as an optically active dienophile (Scheme 5.58). A mixture of endo (177a) and (177b) and exo (178a) and (178b) diastereoisomers were formed as a result of poor selectivity. 

It has been shown that the sulfinyl group present as chiral auxiliary either in dienophiles or in dienes is very useful for controlling the enantio- and diastereofacial selectivity in the asymmetric Diels-Alder reaction [43]. A wide variety of enantiomerically pure cyclohexadienedicarboxylates has been produced by cycloaddition of the sulfinylmaleate 39 with several dienes under catalyzed... 

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. 

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