motivated by potential applications in 
 biomedical research and 
 other disciplines , substantial effort 
 has been dedicated to the development of methods for the preparation 
 of organofluorine compounds . in the case 
 of alkyl fluorides ,
advances have been described in the catalytic 
 enantioselective synthesis of stereogenic centers that bear a fluorine 
 substituent , particularly  to a 
 carbonyl group .
although most studies have addressed the generation 
 of secondary stereocenters , a few reports 
 have examined the establishment of tertiary centers ; currently , the 
 latter methods are largely limited to either cyclic or doubly activated 
 acyclic -fluorocarbonyl compounds . to 
 the best of our knowledge , no general catalytic enantioselective process 
 has been discovered for the synthesis of simple tertiary -fluorinated 
 acyclic ketones . during the past decade
, we have developed an 
 array of nickel - catalyzed 
 asymmetric cross - coupling methods , employing racemic alkyl electrophiles 
 as reaction partners ; to date , all of the electrophiles have been 
 secondary , with z = h ( eq 1 ) .
we have now begun to explore enantioselective couplings of other 
 families of electrophiles , beginning with geminal dihalides ( eq 1 ; z = f , x = halide ) ; such h  f substitutions can have a dramatic impact on reactivity 
 and/or ee . if a suitable catalyst could 
 achieve selective cleavage of the c
 x bond , along with efficient 
 and highly enantioselective c  c bond formation , then this would 
 enable the catalytic asymmetric synthesis of tertiary alkyl fluorides.1 in view of the high interest in the enantioselective synthesis 
 of -fluorocarbonyl compounds , as well as the excellent 
 functional - group compatibility of negishi reactions , we chose to examine the coupling of -halo--fluoroketones 
 with organozinc reagents . in this article
, we describe the first catalytic 
 asymmetric cross - coupling that employs geminal dihalides as electrophiles , 
 specifically , a nickel / bis(oxazoline)-catalyzed stereoconvergent negishi 
 arylation of racemic -bromo--fluoroketones to generate 
 tertiary -fluorinated acyclic ketones ( eq 2).2
at the time 
 that we began our investigation in 2011 , we were not 
 aware of any precedent for selective nickel - catalyzed cross - couplings 
 of -halo--fluoro compounds .
however , during the course 
 of our studies , ando reported diastereoselective kumada reactions 
 of -bromo--fluoro--lactams with aryl grignard 
 reagents , employing a nicl2glyme / bis(oxazoline ) catalyst that we had described for enantioselective 
 couplings of aryl grignard reagents with -bromoketones .
unfortunately , our attempts to apply 
 our previous methods for kumada and 
 negishi arylations 
 to the cross - coupling of the racemic -bromo--fluoroketone 
 illustrated in table 1 were unsuccessful ( < 2% 
 yield ) .
however , through the appropriate choice of reaction parameters , 
 we were able to achieve the desired -arylation and to generate 
 the tertiary alkyl fluoride with very good enantioselectivity ( 97% 
 ee ; table 1 , entry 1 ) .
nicl2glyme 
 and bis(oxazoline ) l * are commercially available and 
 air - stable . all data 
 are the average of two 
 experiments .
a negative 
 ee value signifies that 
 the major product of the reaction is the opposite ( r ) enantiomer .
the yields 
 were determined through 
 analysis by f nmr spectroscopy , with the aid of an internal 
 standard .
table 1 provides information on the impact 
 of various reaction parameters on the efficiency of this catalytic 
 asymmetric synthesis of tertiary alkyl fluorides . in the absence of 
 nicl2glyme or of ligand
l * , essentially 
 no carbon  carbon bond formation is observed ( entries 2 and 
 3 ) .
the cis phenyl substituent in the 5 position of the oxazolines 
 plays an important role in enantioselectivity and yield ( entry 4 ) , 
 as does the substitution on the one - carbon linker that bridges the 
 oxazolines ( entries 5 and 6 ) .
a variety of pybox and 1,2-diamine ligands furnish inferior results ( e.g. , 
 entries 7 and 8) .
the use of less catalyst or less nucleophile leads 
 to a modest decrease in yield , although no erosion in ee ( entries 
 9 and 10 ) . under our optimized conditions ,
phmgcl is not a useful 
 coupling partner ( entry 11 ) , whereas good enantioselectivity but less - efficient 
 cross - coupling is observed when ph2zn serves as the nucleophile 
 ( entry 12 ) . conducting the negishi reaction at room temperature or 
 with a single
solvent causes a small drop in ee and a substantial 
 loss in yield ( entries 1315 ) .
the presence of water ( 0.1 equiv ) 
 has essentially no impact on the course of the reaction ( entry 16 ) , 
 whereas running the reaction under air results in decreased yield 
 ( entry 17 ) .
our optimized conditions can be applied to the catalytic 
 asymmetric 
 negishi arylation of a variety of racemic -bromo--fluoroketones , 
 furnishing tertiary alkyl fluorides in generally good ee ( table 2 ) .
the r group of the 
 ketone can vary in size , although a lower ee is observed with a bulky 
 isopropyl substituent ( entries 16 ) .
high enantioselectivity 
 is typically obtained whether the aromatic group ( ar ) is para- , meta- , 
 or ortho - substituted , and whether it is electron - rich or electron - poor 
 ( entries 716 ) ; we have not previously observed high ee in 
 related nickel - catalyzed cross - couplings with ortho - substituted ar 
 groups ( entries 14 and 15 ; previously : 75% ee ) .
functional groups such as an 
 olefin , alkyl chloride , aryl methyl ether , and aryl fluoride are compatible with the reaction conditions .
the scope of this 
 method for the catalytic asymmetric synthesis 
 of tertiary alkyl fluorides is also fairly broad with respect to the 
 nucleophile ( arzncl ; table 3 ) .
thus , para- and meta- ( but not ortho- ) substituted arylzinc reagents are suitable cross - coupling 
 partners , furnishing the desired -fluoroketone in good ee . 

electron - rich as well as electron - poor nucleophiles can be employed ; 
 in the case of the latter , a reaction temperature of 20 c , 
 rather than 25 c , is optimal .
a silyl ether , aryl chloride , 
 and aryl bromide are compatible with 
 the coupling conditions .
this method for the selective cross - coupling 
 of a geminal dihalide 
 electrophile is not limited to -bromo--fluoroketones . 
 under similar conditions
, a racemic -chloro--fluoroketone 
 also reacts with an arylzinc reagent to generate a tertiary alkyl 
 fluoride in good ee ( eq 3 ) .
in contrast , in 
 the case of related cross - couplings , -chlorocarbonyl compounds 
 were not suitable reaction partners.3 the enantioenriched organofluorine cross - coupling products 
 can 
 be derivatized with high stereoselectivity .
for example , nucleophilic 
 additions of allyl and aryl nucleophiles to the carbonyl group proceed 
 with > 20:1 dr to generate densely functionalized adducts ( eqs 4 and 5).4 moreover , regioselective baeyer  villiger 
 oxidation of the 
 enantioenriched -fluoroketones can be achieved , thereby providing 
 access to either an alkyl ester or an aryl ester by controlling the 
 relative migratory aptitudes of the ketone substituents ( eqs 6 and 7 ) .
this oxidation 
 thereby enables , to our knowledge , the first asymmetric synthesis 
 of acylated fluorohydrins ( eq 6 ) , as well as an indirect method for the catalytic 
 enantioselective synthesis of tertiary -fluoroesters ( eq 7 ) and amides.6
in summary , we have developed the first catalytic 
 asymmetric cross - coupling 
 method that employs geminal dihalides as electrophiles .
specifically , 
 we have established that nickel / bis(oxazoline)-catalyzed stereoconvergent 
 negishi reactions of racemic -halo--fluoroketones provide 
 access to enantioenriched tertiary alkyl fluorides , thereby complementing 
 earlier catalytic asymmetric methods for the synthesis of organofluorine 
 compounds , which have typically focused on the generation of secondary 
 alkyl fluorides .
the -fluoroketones that are produced in these 
 negishi couplings can be transformed into a variety of interesting 
 families of organofluorine target molecules .
additional investigations 
 of catalytic enantioselective cross - couplings of alkyl electrophiles 
 are underway .
 the 
 development of new approaches to the construction of fluorine - containing 
 target molecules is important for a variety of scientific disciplines , 
 including medicinal chemistry . in this article 
 , we describe a method 
 for the catalytic enantioselective synthesis of tertiary alkyl fluorides 
 through negishi reactions of racemic -halo--fluoroketones , 
 which represents the first catalytic asymmetric cross - coupling that 
 employs geminal dihalides as electrophiles . 
 thus , selective reaction 
 of a c  br ( or c  cl ) bond in the presence of a c  f 
 bond can be achieved with the aid of a nickel / bis(oxazoline ) catalyst . 
 
 the products of the stereoconvergent cross - couplings , enantioenriched 
 tertiary -fluoroketones , can be converted into an array of 
 interesting organofluorine compounds . 
Introduction
Results and Discussion
Conclusions