Sulfoximine coupling

Examples of coupling reactions of ort/ro-bromobenzoate ester 80 or ortho-bromobenzonitrile 87 with sulfoximine (7 )-77a were also reported (Scheme 23a/b). In these cases only coupling occurred. However, the products could be converted into the 2,1-benzothiazines 82 and 85 by treatment with a strong base. 

The Harmata group also found that certain ort/w-bromocinnamates underwent a Michael addition during the course of the Buchwald-Hartwig reaction. This one-pot process produced the same products as the two step process and with the same, complete stereoselectivity. For example, this was first observed with bromocinnamate 107, where the reaction with (7 )-77b afforded a 53% yield of sulfoximine 108 as well as a 36% yield of benzothiazine 95 under standard coupling conditions (Scheme 27). The cyclization was attributed to a buttressing effect of the ortho-methoxy in bromocinnamate 107. This presumably favored a conformation that placed the methyl group of its sulfoximine functionality near the p-carbon of the a,P-unsaturated ester, thus favoring cyclization. 

The reaction of ortho- uh tituxed chlorophenyl ketones in the [3+3] coupling reaction generally requires long reactions times and results in poor yields of the 1,2-thiazine products. A microwave-assisted reaction of chloroaryl ketones 272 with sulfoximine 268 has been developed which provides the cyclized products 273 in improved yields after two cycles of treatment with the Pd-catalyst (Scheme 39) <2004TL5233>. 

We have developed asymmetric syntheses of isocarbacyclin [3] (Scheme 1.3.2) and cicaprost [4] (Scheme 1.3.3) featuring a Cu-mediated allylic alkylation of an allyl sulfoximine [5-7] and a Ni-catalyzed cross-coupling reaction of a vinyl sulf-oximine [8-10], respectively, transformations that were both developed in our laboratories. The facile synthesis of an allyl sulfoximine by the addition-elimination-isomerization route aroused interest in the synthesis of sulfonimidoyl-sub-stituted aiiyititanium complexes of types 1 and 2 (Fig. 1.3.2) and their application as chiral heteroatom-substituted allyl transfer reagents [11]. 

The initial observation indicating that such C-arylation was indeed feasible stemmed from an attempted palladium-catalyzed double N-arylation reaction (for details of this type of coupling reaction, see below). With the objective of preparing C2-symmetric bissulfoximine 28, dibromonaphthalene 29 was treated with an excess of sulfoximine 9 under standard coupling conditions using [Pd2dba3]/ BINAP as a catalyst in the presence of a base and, to our surprise, cyclic sulf-oximine 30 was obtained in excellent yield (Scheme 2.1.1.8) [30]. 

Hartwig-Buchwald, Suzuki, and Stille type cross-coupling reactions with key intermediate 46 led to a wide range of substituted sulfoximines such as 47-49 [37]. In order to demonstrate the synthetic utility of the resulting products, pseudo tripeptide 50 was prepared from a related intermediate. 

To our delight we found that palladium-catalyzed cross-couplings between sulfoximines and aryl halides (or aryl nonaflates) work very well, affording N-arylated products in high yield [45]. Generally, Buchwald s Pd(OAc)2/BlNAP catalyst system (with CS2CO3 and toluene at 100 °C) was applied, and thereby a variety of N-aryl sulfoximines 58 - including enantiopure ones - were prepared (Scheme 2.1.1.17). 

Subsequently, a copper-catalyzed cross-coupling [with substoichiometric amounts of copper(l) iodide and N,N -dimethylethylenediamine (DMEDA)] between aryl halides and sulfoximines was developed [52]. In this case, both aryl bromides and aryl iodides reacted well. For the conversion of the former substrates an in-situ copper-catalyzed aryl Finkelstein reaction [53] had to be performed first, as shown in Scheme 2.1.1.22 for the preparation of 64 starting from bromobenzene (62). 

The synthesis of phosphino sulfoximine 97 relied significantly on the successful development of methods pursued in parallel in our group. Whereas palladium-catalyzed cross-couplings between 53 and 98 proceeded in low yield, the copper catalysis with a combination of copper(l) iodide and cesium acetate worked well, affording 99 in up to 83% yield [78]. The resulting phosphine oxides 99 were then reduced to the corresponding phosphines 97 using a mixture of trichlorosilane and triethylamine (Scheme 2.1.1.33). 

Subsequently, palladium-catalyzed couplings between aryl halides and sulfoximines were also used by Gais, Harmata, and others. For example, see M. Harmata, S. K. Ghosh, Org. Lett. 

The group of Harmata has explored a route that can be used to effectively couple aryl chlorides with methylphenylsulfoximines [100]. Using palladium acetate and rac-binap with a large excess of aryl chlorides as coupling partners and cesium carbonate as the base, yields of 10-94% were attained after one or two 1.5-hour irradiation periods at 135 °C. Switching to an aryl tri-flate, and using a surplus of the sulfoximines (five equivalents) furnished an impressive 94% yield (Scheme 32). 

Whereas the T1 linker involves immobilization of a diazonium salt on an amine resin, the T2 linker is the reversal of this concept. An immobilized diazonium salt 73 was prepared from Merrifield resin 70 in two steps subsequent addition of primary and secondary amines generated triazenes 74. Attachment of hydroxylamine, hydrazines, sulfoximines, and phenols (to give azo coupling products) proceeds equally well (Scheme 6.1.16). 

These vinyl sulfoximines undergo nickel-catalyzed cross-coupling reactions with organometallic reagents to give optically active alkenes (see Section V.D for details). 

Palladium-catalyzed coupling of dibromoarene and sulfoximine gives 1,5,6-oxithiazocine 138 ring system in 69% yield (Equation 25 <2002SL832>). The reaction sequence involves an intramolecular N-arylation followed by intramolecular ring closure. 

A new chiral benzothiazine ligand 205 was synthesized by Harmata and co-workers <06JOC3650>. It could be converted into a chiral molecular receptor 207 in a simple way. This chiral species 207 could be used as a new class of chiral molecular tweezers. The synthesis of 205 commenced with the protection of the commercially available compound 202, which was then coupled with (K -sulfoximine 77b using the one-pot, one-operation procedure <99AG(E)2419> affording enantiomerically pure benzothiazine 204. This was followed by deprotection to produce benzothiazine 205 in good yield. 

Application of a polymer-supported enantiopure sulfoximine in stereoselective conversion into hydroxysulfones has been reported (Scheme 12.30) [13, 41]. The chiral sulfoximine resin was prepared by coupling the sulfoximine potassium salt 78, in the presence of tetrabutylammonium bromide (TBAB), to Merrifield resin. Hydroxyalkylation of the polymer-bound sulfoximine 79 at the a-position with benzaldehyde and propanal furnished the hydroxysulfoximine resin 80. Oxidative cleavage gave hydroxysulfones 81 in 81 and 84% yield and enantiomeric excesses of 24 and 26% ee. 

Similarly, N-arylsulfoximines and related species have been prepared by Pd-catalyzed coupling of a sulfoximine with aryl chlorides under the influence of microwave irradiation [72], Appropriately functionalized systems gave rise to benzo-thiazines directly in a one pot process. 

---