alkyl ( i.e. sp ) boronic esters , together with the corresponding boronic acids and trifluoroborates , represent a versatile class of crosscoupling agents that have extended significantly the utility and scope of suzuki sp processes.13 alkyl halides ( as well as pseudohalides such as tosylates ) provide access to the requisite spbased boron reagents by pd or ni,4a4c zn,4d fe4e,4f or ( and perhaps of most versatility ) the cucatalyzed borylation processes5 described first by marder and lin.5d,5f 
  our interest in this area has centered on the use of stable and readily available 1,2 and 1,3cyclic sulfamidates 1 , which have already found extensive utility as electrophiles to construct c  c , c  n and c  o bonds within heterocyclic synthesis.6 however , their utility in either direct or indirect spbased crosscoupling reactions is essentially unexplored.7 
  here we report on the application of cyclic sulfamidates 1 as substrates for cucatalyzed borylation to provide access to a range of stereochemically defined and enantiomerically pure ( aminoalkyl)boronic esters 2 
 8 ( scheme  1 ) . in mechanistic terms , however , cyclic sulfamidates , which can be viewed as alkyl pseudohalides , are differentiated from more conventional substrates , such as alkyl halides or tosylates , under cumediated borylation conditions . we evaluated initially a series of metals ( pd , ni , zn , fe ) to promote borylation , but did not achieve good turnover and yields . copper , which is also attractive for reasons of scalability , cost and low toxicity , however , proved effective with cyclic sulfamidates.9 the ( s)phenylalaninederived substrate 1a 
 6b was screened against marder 's efficient roomtemperature cucatalyzed conditions for borylation of alkyl halides ( scheme  2).5d the target boronate ester 2a was isolated by using these conditions but in poor yield ( 5  % ) and only after an extended reaction time . following an extensive evaluation of reaction conditions , we identified two necessary modifications : the optimal base ( liotbu ) and  more critically  the presence of an external iodide source ( e.g. bu4ni ) . use of these modified conditions provided boronic ester 2a 
 10 in 56  % yield at room temperature after a reaction time of 2 h. cucatalyzed borylation of 1a under ( a ) marder 's conditions for alkyl halides and ( b ) with key modifications including an external iodide source to provide boronic ester 2a . [ a ] enantiomeric purity of 2a was determined by using ( )2a from ( )1a as a standard , and no erosion of stereochemical integrity was detected by chiral hplc . replacing cui with either pd2dba3 or nii2 gave no trace of 2a , and the combination of cui and pph3 was crucial for conversion ; 2a was not observed in the absence of either of these reagents . addition of bu4ni , which had been applied successfully5d ( but also without pph3 ) to the borylation of alkyl tosylates , improved significantly the yield of 2a , and the presence of this external iodide source was critical.11 
  using the iodidemediated conditions shown in scheme  2 , we have assessed the scope of this reaction with respect to 1,2 and 1,3cyclic sulfamidates . a range of substrates across 1b  p function to provide (  and aminoalkyl)boronic esters 2b  p ( scheme  2 , table  1 ) . these include substrates with a substituent at the reacting center ( and disubstituted variants ) as an entry to secondary boronic esters ( see also scheme  4 ) . synthetic scope of cyclic sulfamidates for (  and aminoalkyl)boronic esters 2b  p . the precursor cyclic sulfamidates 1b  p are not shown explicitly but correspond directly to the products 2b  p seen here . the feasibility of a sulfonamidebased substrate depends on ring size ( compare 2e and 2 m ) . product 2h was racemic ( see text ) , and 2i was assumed to be racemic . electronwithdrawing carbonylbased nprotecting groups ( boc , cbz ) were highly preferred and essential within 1,2cyclic sulfamidates for effective conversion . in these cases , the corresponding nbenzyl , nh and nsulfonyl variants failed to give the desired boronic esters 2c  e . conventionally , 1,2cyclic sulfamidates are more reactive ( e.g. , towards ringopening with nucleophiles6 ) than the 1,3homologues ; therefore , it was interesting that here the 1,3series 1 ( n = 1 ) proved in general to be somewhat better substrates for cucatalyzed borylation ( compare yields of 2a and 2l ; 2f and 2n ) . certain benzylic substrates , such as 1q and 1r , underwent rapid decomposition ( likely oxidation or elimination ) , but the location of the benzyl moiety is important ( compare 1o to give 2o ; table  1 ) . sterically demanding substrates , such as the 4,4dimethyl variant 1s , failed to react , and subjecting the 5benzyl sulfamidate 1 t to the optimized borylation conditions led only to allylic amine 3 
 12 by competing elimination ( scheme  3 ) . substrates that failed to undergo cucatalyzed borylation . disubstituted cyclic sulfamidates 1u  w provide stereochemically defined products but , to date , are less efficient in terms of conversion and yield ( scheme  4 ) . in these cases , the major byproducts observed , 5 and 6 , resulted from c o reduction.13 nevertheless , these substrates also reflect on the nature of the mechanism of cucatalyzed borylation , which is discussed below . [ b ] stereochemistry of 2u  w was determined by oxidation ( naoh , h2o , h2o2 , 0 c ) to give the corresponding secondary alcohol as illustrated by the conversion of 2u to 4 . analogous transformations ( leading to either the same amino alcohol used to prepare the starting cyclic sulfamidate or its diastereomer ) secured the stereochemistry of boronic esters 2v and 2w ( see supporting information ) . in the cases of the product boronic esters 2u  w , the stereochemistry of the borylation process was determined by oxidation of the boronic esters to the corresponding ( and known ) secondary alcohols . this process proceeds with retention of stereochemistry at the reacting center and is illustrated here for 2u . given our initial assumptions as to the alkyl pseudohalide character of cyclic sulfamidates but their failure , for example , to undergo borylation under otherwise wellestablished conditions , we have carried out a series of experiments to gain some insight into the mechanism of cucatalyzed borylation of 2 . the role for an external iodide source was explored , prompting the obvious explanation that facile nucleophilic opening of the cyclic sulfamidate provides directly a simple alkyl iodide that reacts as expected on the basis of marder 's earlier work.5d 
  two substrates were investigated by directly comparing the reactivity of the cyclic sulfamidate and the equivalent alkyl iodide ( scheme  5 ) . as discussed above , 1,2cyclic sulfamidate 1a underwent cumediated borylation to give 2a in 56  % yield at room temperature after 2 h [ scheme  5 ( a ) ] . the corresponding primary iodide 7 failed to react appreciably at room temperature ; however , boronic ester 2a was obtained in essentially the same yield following heating at 80 c for 18 h. cyclic sulfamidate vs. alkyl iodide ; comparison of relative reaction rates and yields . ( b ) differential yields at room temperature after a fixed time ( 2 h ) . ( c ) generation , isolation of nsulfate 9 and conversion to boronic ester 2k . the 1,3variant 1k provided an alternative perspective of this differential reactivity . while 1k gave boronic ester 2k in 77  % yield at room temperature after 2 h , the corresponding alkyl iodide 8 led to 40  % of 2k under the same conditions but with added iodide [ scheme  5 ( b ) ] . these results both suggest that a simple alkyl iodide ( 7 or 8) is not an intermediate in the conversion of cyclic sulfamidates to the corresponding boronic esters . further insight into this process was gleaned from closer study of the initial reaction of the cyclic sulfamidate with iodide . exposure of 1k to nai ( in the presence of et3n , which was essential to retain the nsulfate unit ) in anhydrous acetone gave the hydrolytically sensitive nsulfate 9 as a colorless solid [ scheme  5 ( c ) ] . subsequent exposure of isolated 9 
 14 to the standard cumediated borylation procedure gave 2k in 77  % yield , which parallels the observation in scheme  5 ( b ) . from this we conclude that the nsulfated iodide 9 is the key intermediate and , additionally , that the presence of the nsulfate moiety favorably influences the subsequent cucatalyzed borylation , based on the comparison to a simple primary alkyl iodide . the mechanism of cucatalyzed borylation of aryl and alkyl halides has been probed,15 and there is some but not definitive evidence for the intermediacy of alkyl radicals . our studies support the likely involvement of radical species , at least with respect to the carbon center . using 1 equiv . of tempo as a radical trap with 1f as the cyclic sulfamidate substrate , we isolated adduct 10 in 37  % yield and observed no borylation ( i.e. ester 2f ) product [ scheme  6 ( a ) ] . cyclohexa1,4diene also completely suppressed boronic ester formation from 1f , although we were unable to isolate an adduct in this case.13 
  ( a ) use of tempo as a cradical trap and ( b ) loss of enantiomeric integrity for a 5methyl1,2cyclic sulfamidate on borylation . further support for a radical mechanism comes from use of enantiomerically pure 5substituted 1,2cyclic sulfamidate 1h [ scheme  6 ( b ) ] . coppercatalyzed borylation of ( r)1h under standard conditions gave a 56  % isolated yield of racemic secondary boronic ester 2 g , a result that was confirmed by using racemic 1h as a control to validate chiral hplc analysis of the products.14 it is also pertinent to reflect on the stereochemical results shown in scheme  4 for disubstituted 1,2 and 1,3cyclic sulfamidates . borylation of trans1u gave boronic ester 2u in 45  % yield , the stereochemistry of which was established by stereospecific oxidation to give the known alcohol 4 . in this case , although stereochemically clean , the original configuration at the c5 stereocenter was lost . similarly , the cisconfigured 1,3cyclic sulfamidates 1v and 1w gave retention and inversion , respectively , at the borylating center ( c6 ) , where the outcome at the intermediate carbon radical is subject to a high level of internal diasteromeric control . in these latter cases , although yields were moderate ( and competitive reduction was seen ) , no trace of the diastereomeric boronic esters was detected . we have developed a variant of coppercatalyzed borylation that is suited to the exploitation of readily available cyclic sulfamidates and extends the scope of the copperbased procedures to synthesize stereochemically defined alkylboronic esters . cyclic sulfamidates are readily available and offer access to enantiomerically ( or diastereomerically ) pure ( aminoalkyl)boronic esters suitable for further exploitation in crosscoupling processes . while our initial premise was that cyclic sulfamidates would perform as pseudohalides ( cf . , tosylates ) and undergo borylation under wellestablished conditions , that proved not to be the case . there are substratespecific features , such as the intermediacy of an nsulfated iodide that clearly imbue cyclic sulfamidates with major advantages over the corresponding ( i.e. , simple aminobased ) alkyl halides . another important aspect is the key requirement of an nacylated cyclic sulfamidate ; nalkyl / benzyl or nsulfonyl analogues are not efficient substrates in our hands . further studies are required to probe the role of the nacyl moiety , but this may , like the nsulfate , serve to activate the reacting c  o bond and/or provide a ligand for any intermediate copper species . the involvement of radical intermediates in this chemistry can lead to loss of stereochemistry at the reacting c  o center , but the outcome is substratedependent and can provide good overall levels of stereocontrol .
abstractcyclic sulfamidates undergo borylation under coppercatalyzed conditions using b2pin2 to give enantiomerically ( and diasteromerically ) defined ( aminoalkyl)boronic esters . 
 external iodide is essential , but the intermediacy of simple alkyl iodides has been excluded ; nsulfated intermediates are key in the borylation sequence . based on stereochemical studies and trapping experiments 
 , the involvement of carboncentered radicals under these coppercatalyzed conditions appears likely .