sulfonamides and sulfones 
 serve both as useful intermediates in 
 organic synthesis and as important target 
 molecules in their own right . for example , enantioenriched 
 secondary benzylic sulfonamides and sulfones display a range of biological 
 activity ( e.g. , protein tyrosine phosphatase inhibitor , antisepsis agent , and -secretase inhibitor ) .
however , to the best of our knowledge , there 
 are no methods for the direct catalytic asymmetric synthesis of such 
 sulfonamides , and just a few for such sulfones
. one potential route to these compounds is the stereoconvergent 
 coupling of a racemic -halosulfonamide / sulfone with an appropriate 
 nucleophile ( eq 1 ) . during the past several 
 years
, we have described an array of nickel - catalyzed enantioselective 
 cross - couplings of secondary alkyl electrophiles . whereas couplings 
 of activated electrophiles ( a leaving group  
 to a carbonyl , aryl , alkenyl , alkynyl , or cyano group ) proceed in 
 good ee with a variety of nucleophiles ( alkyl- , aryl- , and alkenylmetal ) , reactions of unactivated electrophiles have been 
 limited , with three exceptions , to alkylmetals , specifically alkyl-(9-bbn ) reagents.1 because -halosulfonyl 
 compounds are generally poor substrates 
 for sn2 reactions , and the sulfonyl group does not effectively 
 stabilize an adjacent radical ( bond dissociation energy for a c  h 
 bond of dimethylsulfone : 99 kcal / mol ) , we view them as unactivated alkyl electrophiles .
herein , we report 
 the first examples of the stereoconvergent cross - coupling of unactivated 
 alkyl electrophiles with nucleophiles other than organoboranes , as 
 well as the first general method for their coupling with aryl- or 
 alkenylmetal reagents ; in particular , we describe nickel / bis(oxazoline)-catalyzed 
 cross - couplings of racemic -bromosulfonamides and -sulfones 
 with organozinc and organozirconium reagents , thereby furnishing secondary 
 benzylic and allylic sulfonamides and sulfones in good enantiomeric 
 excess ( eq 2).2
upon investigating a variety of reaction 
 parameters , we determined 
 that a nickel / bis(oxazoline ) catalyst 
 can achieve the cross - coupling of an -bromosulfonamide with 
 an arylzinc reagent in very good ee and yield at 20 c 
 ( table 1 , entry 1 ) ; nicl2glyme 
 and bis(oxazoline ) l1 ( ( r , r ) and ( s , s ) ) are commercially available . 

all previous reports of stereoconvergent negishi reactions of racemic 
 electrophiles have employed activated coupling partners .
the yield was 
 determined through 
 gc analysis with the aid of a calibrated internal standard .
essentially no cross - coupling 
 is observed in the absence of nicl2glyme ( table 1 , entry 2 ) , and 
 a low yield of the desired product is obtained if ligand l1 is omitted ( entry 3 ) . at room temperature , the coupling proceeds 
 in good ee , but hydrodebromination predominates over c  c bond 
 formation .
the corresponding valine - derived bis(oxazoline ) ( l2 ) is nearly as effective as phenylglycine - derived l1 ( entries 1 and 5 ) , whereas removal of the gem - dimethyl 
 substituents on the linker between the oxazolines of l1 leads to a substantial drop in efficiency ( entry 6 ) .
although pybox 
 ligands are often the ligand of choice for nickel - catalyzed stereoconvergent 
 negishi reactions , pybox l4 is not effective for this particular cross - coupling , nor is a 1,2-diamine 
 ligand ( entries 7 and 8) .
the use of phmgbr in 
 place of phzni leads to a small loss in ee and a substantial loss 
 in yield ( entry 9 ) . when the catalyst loading is reduced in half , 
 no erosion in enantioselectivity
is observed , although the yield falls 
 by a modest amount ( entry 10 ) .
the process is somewhat oxygen - sensitive 
 ( entry 11 ; 66% conversion ) but not particularly moisture - sensitive 
 ( entry 12 ) . under these conditions
, we can achieve stereoconvergent 
 negishi 
 cross - couplings of a variety of racemic -bromosulfonamides 
 with phzni to generate highly enantioenriched benzylic sulfonamides 
 ( table 2 ) .
the 
 nitrogen of the sulfonamide can bear either an alkyl or an aryl substituent , 
 with little impact on ee or yield ( entries 15 ) .
furthermore , 
 the r side chain can include functional groups and can 
 be either primary ( entries 68 ) or secondary ( entry 9 ) , although 
 in the case of the latter a diminished yield is observed . on a gram 
 scale , the cross - coupling illustrated in entry 2 proceeds in 92% ee 
 and 98% yield .
the conditions 
 that we developed for stereoconvergent negishi reactions 
 of -bromosulfonamides ( table 2 ) can 
 be applied without modification to the corresponding sulfones ( table 3 ) .
thus , the r substituent can range in steric 
 demand from methyl to t - butyl ( entries 14 ) , 
 and it can be aromatic ( entry 5 ) . with respect to the r group , it may be linear or branched ( entries 15 ) .
we have examined 
 the scope of arylzinc nucleophiles that participate 
 in this method for the catalytic asymmetric synthesis of benzylic 
 sulfonamides and sulfones ( table 4 ) .
electron - rich 
 and electron - poor arylzinc reagents are suitable partners , as is a 
 heteroarylzinc reagent , furnishing the desired product in very good 
 ee .
especially noteworthy is our observation that o - substituted phenylzinc reagents can be employed with both sulfonamide- 
 and sulfone - based electrophiles ( entries 57 and 911 ) ; 
 in our previous studies of nickel - catalyzed enantioselective arylations , o - substituted nucleophiles have generally been poor coupling 
 partners . all data are the average of two 
 experiments .
amount of arzni : 
 2.0 equiv ; amount 
 of catalyst : 20% nicl2glyme , 26% ( r , r)-l1 .
next , we sought to expand the scope of stereoconvergent 
 cross - couplings 
 of -bromosulfonamides and -sulfones to include a second family 
 of nucleophiles , specifically , alkenylmetal reagents .
we determined 
 that , whereas reactions of alkenylzinc reagents proceed 
 in poor yield using the method described above , alkenylzirconium reagents serve as suitable nucleophiles under modified conditions 
 ( table 5 ) .
thus , an array 
 of allylic sulfonamides and sulfones can 
 be synthesized with good enantioselectivity in the presence of functional 
 groups such as a thiophene and a primary alkyl chloride .
we have suggested that , for at least 
 some nickel - catalyzed cross - couplings 
 of alkyl electrophiles , an alkyl radical may be generated during the 
 oxidative - addition step of the catalytic cycle . in the case of electrophiles that bear an appropriately positioned 
 pendant olefin , we have observed complete cyclization of the putative 
 radical onto the olefin in some instances , and no cyclization in another . in order to gain insight into the mechanism of the stereoconvergent 
 arylations described herein , we investigated the negishi reaction 
 of an -bromosulfonamide bearing a pendant olefin ( eq 3 ) . at 70%
conversion 
 of the electrophile , we observe a 38% yield of the direct ( uncyclized ) 
 cross - coupling product ( 8) and a 17% combined yield of 
 cyclized cross - coupling products ( 9).3 cyclopentane derivatives cis-9 and trans-9 are each an 1:1 
 mixture of 
 diastereomers ( differing in the relative stereochemistry at the deuterium - bearing 
 carbon ) , consistent with the expectation for cyclization of radical 
 intermediate 10 ( but not for a simple organometallic 
 pathway involving only -migratory insertion and then reductive 
 elimination ) .
our observation that uncyclized cross - coupling product 8 has deuterium only in the trans position suggests that , 
 when intermediate 10 does cyclize , the process is irreversible .
simple 5-hexenyl radical cyclizations proceed with first - order 
 rate constants of 10 s. although , to the best of our knowledge , the 
 rate of cyclization of sulfonamide - substituted radical 10 has not been determined , it is very likely to be significantly slower 
 than diffusion ( 10 s ) .
our observation of cyclized , cross - coupled 
 products ( 9 ) therefore represents evidence that a nickel - catalyzed 
 asymmetric cross - coupling process may include a noncage radical pathway . 

consistent with this suggestion , the ratio of uncyclized ( d)/cyclized ( c ) product changes as the concentration 
 of catalyst changes ( figure 1 ) .
dependence of the ratio of uncyclized ( d)/cyclized ( c ) 
 product 
 on the concentration of nickel .
we have developed methods for the enantioselective 
 synthesis of 
 secondary sulfonamides and sulfones , specifically , nickel - catalyzed 
 negishi arylations and alkenylations of racemic -bromosulfonamides 
 and -sulfones with readily available organozinc and organozirconium 
 reagents ; with regard to stereoconvergent couplings of unactivated alkyl electrophiles , previous examples had been limited 
 to organoboron nucleophiles and , with the exception of three isolated 
 examples , to alkylation reactions . in terms of mechanism , 
 a cyclization / stereochemical probe has provided evidence for a radical 
 intermediate that has a sufficient lifetime to escape the solvent 
 cage and cyclize irreversibly under the coupling conditions .
additional 
 studies directed at elucidating the mechanisms of cross - coupling reactions 
 of alkyl electrophiles , as well as expanding the scope of such processes , 
 are underway .
 the 
 development of efficient methods for the generation of enantioenriched 
 sulfonamides and sulfones is an important objective for fields such 
 as organic synthesis and medicinal chemistry ; however , there have 
 been relatively few reports of direct catalytic asymmetric approaches 
 to controlling the stereochemistry of the sulfur - bearing carbon of 
 such targets . in this report 
 , we describe nickel - catalyzed stereoconvergent 
 negishi arylations and alkenylations of racemic -bromosulfonamides 
 and -sulfones that furnish the desired cross - coupling product in very 
 good ee and yield for an array of reaction partners . 
 mechanistic studies 
 are consistent with the generation of a radical intermediate that 
 has a sufficient lifetime to diffuse out of the solvent cage and to 
 cyclize onto a pendant olefin . 
Introduction
Results and Discussion
Conclusions