organic molecules containing 
 bulky alkyl groups have shown great 
 potential in drug discovery and medicinal chemistry .
sterically demanding alkyl substituents such as adamantyl 
 or tert - butyl are often introduced into pharmaceuticals 
 to enhance lipophilicity and/or improve the drug s metabolic 
 stability by shielding adjacent functional groups or reactive sites 
 from enzymatic degradation .
aminoadamantanes themselves have been examined and used as antiviral 
 drugs ; however , aryl aminoadamantane 
 derivatives and other anilines based on hindered amines such as 35 ( figure 1 ) 
 remain largely unexplored , presumably due to difficulty in their preparation .
mechanism 
 of pd - catalyzed arylation of primary amines and examples 
 of bulky ,,-trisubstituted primary amines .
successful strategies that have 
 previously been used to synthesize 
 these bulky anilines employ an electrophilic amination approach .
amines 1 and 3 have been arylated through a titanium - mediated 
 coupling of the corresponding n - chloroamines with 
 grignard reagents .
additionally , there 
 are examples of transition - metal - free amination of arylboroxines and 
 copper - catalyzed amination of organozinc reagents using 3 .
recently , lalic reported an elegant 
 synthesis of hindered tertiary anilines through the copper - catalyzed 
 coupling of aryl boronic esters with o - benzoyl hydroxylamines .
while these methods are efficient , the electrophilic 
 amine must be separately prepared , and many of the nucleophiles that 
 are employed are moisture - sensitive .
a useful alternative is the palladium - catalyzed 
 c  n cross - coupling  an operationally simple and widely 
 used reaction in both industrial and academic settings .
although advances in ligand design have overcome many challenges , only a few examples of the n - arylation of hindered 
 primary amines have been reported .
amines 1 and 2 have been previously cross - coupled with catalysts with either 
 phosphines or n - heterocyclic carbenes as supporting ligands
. however , most of these reactions require moderate catalyst loadings 
 ( 15 mol % ) and elevated temperatures ( 90135 c ) 
 and , most importantly , are limited with regard to the substrate scope . 

in addition , there are no examples using more hindered and challenging 
 amine substrates such as 35 .
the 
 availability of a general method to obtain a broad range of hindered 
 anilines by a pd - catalyzed c 
herein , we describe the development of two related catalyst systems 
 that demonstrate high activity for the coupling of ,,-trisubstituted 
 primary amines 15 with a variety 
 of ( hetero)aryl halides .
these complementary systems were developed 
 through an initial ligand screen followed by a rational ligand design 
 based on the results of the kinetic analysis of the reaction ( figure 1 ) .
in 2008 
 we reported brettphos ( l1 ; table 1 ) , a biaryl(dialkyl)phosphine ligand for the pd - catalyzed 
 arylation of primary amines .
brettphos - based 
 catalyst systems often promote amination reactions at low catalyst 
 loadings and exhibit an exceptionally broad scope for both the aryl 
 halide and the primary amine .
however , 
 when we evaluated the ( 2-aminobiphenyl)palladium methanesulfonate 
 precatalyst of l1 ( p1 ) , for the coupling of 3,5-dimethoxychlorobenzene ( 6 ) with tert - octylamine ( 3 ) , the product 7 was formed in low yield ( table 1 , 
 entry 1 ) . given the size of both l1 and 3
, we felt that either amine binding ( iii , figure 1 ) or amine deprotonation ( iii  iv , figure 1 ) could be problematic . therefore , we hypothesized that the use of a 
 smaller ligand would allow for more effective coordination to the 
 pd(ii ) center and/or facilitate the approach of the base .
indeed , 
 the yield was significantly improved with the less sterically demanding and less electron - rich phbrettphos , l2 ( table 1 , entry 2 ) . furthermore , the use 
 of l3 , which lacks methoxy groups on the phosphine - containing 
 arene ring , was even more effective ( table 1 , entry 3 )
. the use of a ligand in which the distal arene of l3 had been modified by replacing the triisopropyl substituents 
 with two dimethylamino groups ( l4 ) also gave the desired 
 product in good yield ( table 1 , entry 4 ) .
the 
 catalyst derived from the corresponding dicyclohexylphosphino analogue , 
 cphos ( l5 ) , gave no product , suggesting that the relatively 
 smaller and less electron - donating phenyl groups on the phosphine 
 atom are required to promote the desired transformation .
reaction conditions : aryl halide 
 ( 0.5 mmol ) , amine ( 0.6 mmol ) , nao - t - bu ( 0.6 mmol ) , 
 1,4-dioxane ( 0.5 ml ) .
the most effective 
 precatalysts , p3 and p4 , were further evaluated 
 in reactions between 3 and 
 more complex aryl halides , and the use of p4 initially 
 gave the best results ( table 2 ) .
reaction 
 conditions : aryl halide 
 ( 0.5 mmol ) , amine ( 0.6 mmol ) , nao - t - bu ( 0.6 mmol ) , 
 1,4-dioxane ( 0.5 ml ) .
ad = adamantyl reaction conditions : 1% p , 80 c , 90 
 min .
reaction conditions : 2% p4 , 120 c , 24 h. reaction 
 conditions : 1% p4 , 100 c , 12 h.
while the results with p4 were promising , relatively 
 high temperatures ( 100120 c ) and catalyst loadings ( 13 
 mol % ) were required for the reaction to reach completion . to design 
 an improved catalyst system , we set out to qualitatively explore the 
 reaction rate dependence on each substrate using reaction progress 
 kinetic analysis ( rpka ) .
as described by blackmond , rpka is a simple , systematic method to obtain a complete picture 
 of a reaction s kinetic profile from a limited number of experiments 
 performed under synthetically relevant conditions .
this method has 
 been successfully used in a number of laboratories to elucidate the reaction mechanism of various catalytic processes . 

the key parameter utilized in rpka is  excess  , which 
 refers to the difference between the initial concentrations of the 
 two reactants ( eq 1 ) , and the kinetic information 
 is obtained from reactions run under  different excess  
 conditions.1 we chose 
 the model reaction between aryl chloride 6 and amine 3 for our kinetic analysis using precatalyst p4 . to broaden the study , we also explored the reaction with 
 the corresponding aryl bromide 12 .
the reactions were 
 monitored in situ by reaction calorimetry along with gc analysis to 
 support the calorimetry results ( see 
 the supporting information ) .
the reaction 
 rate progress over time profiles for both aryl halides are shown together 
 in figure 2 .
it is immediately apparent that 
 the shape of the curves is different for each aryl halide and that 
 the reaction for arbr is notably faster than that for arcl .
these 
 observations suggest that the nature of the aryl halide plays a key 
 role in the kinetics of the reaction . following the rpka method
, the data may be replotted as rate vs 
 [ substrate ] to determine the rate orders of each substrate ( only the 
 most informative graphs are shown for each case ; all graphs are included 
 in the supporting information ) .
temporal reaction 
 rate profiles for the reaction of amine 3 ( 1.0 m ) and 
 arcl 6 or arbr 12 ( concentrations 
 defined by [ excess ] given in legend ; see eq 1 ) catalyzed by p4 ( 0.02 m ) .
figure 3 shows the rate vs [ arcl ] plot for 
 the two different excess experiments shown in figure 2 over the range of arcl concentrations common to both reactions . 
 at any given value of [ arcl ] ,
the concentration of amine is different 
 for the two kinetic profiles , as illustrated by the dashed line ( when 
 [ arcl ] = 0.3 m , [ amine ] = 0.8 and 0.3 m for the blue and red curves , 
 respectively ) .
an overlay of the curves at different amine concentrations 
 indicates that the rate is independent of the concentration of amine 
 for this range of concentrations .
this behavior was unexpected given 
 the steric encumbrance of 3 , which we initially predicted 
 to bind to the pd(ii ) center with difficulty and therefore be involved in the rate - determining step .
however , 
 the linear decay of the curves indicates that the reaction has a positive 
 order in [ arcl ] and that oxidative addition is ( at least partially ) 
 rate - determining .
the fact that the reactions 
 reached different maximum rates when starting at different arcl concentrations 
 ( figure 2 ) provides additional evidence for 
 a positive order in aryl halide ( since the maximum rates do not differ 
 by a factor of 2 , the order in arcl is fractional ) .
the use of a ligand 
 ( l4 ) with phenyl groups as the phosphine substituents 
 could explain the relatively slow rate of oxidative addition ( computational 
 evidence suggests that l2 has a higher energy barrier 
 than its alkyl analogue l1 for this step ) .
reaction progress kinetic profiles for the reaction of 
 arcl 6 with amine 3 plotted as rate vs [ arcl ] 
 over 
 the range of concentrations common to the two reactions .
the concentration 
 of amine 3 at the point in the reaction progress marked 
 by the dashed line is shown for each reaction .
further probing of the reaction mechanism is possible by 
 exploring 
 the behavior of aryl bromide 12 . since the rate of oxidative 
 addition is determined by the strength of the c  x bond , it was not surprising that the reaction of 12 was ca .
4 times faster than that of the aryl chloride 6 ( t1/2 = 10 min vs 46 min for 
 [ arx]0 = 0.5 m ) . in this case
, plotting the data of the 
 different excess experiments as rate vs [ amine ] for the concentrations 
 common to the two reactions provides insights into the aryl bromide 
 reaction kinetics ( figure 4 ) .
first , the overlay 
 between the curves reveals identical rates at different arbr concentrations 
 ( as illustrated by the dashed line : when [ amine ] = 0.75 m , [ arbr ] 
 = 0.25 and 0.75 m for the blue and red curves , respectively ) , indicating 
 zeroth - order kinetics in aryl halide , in contrast to the arcl case . 

this observation is confirmed by the fact that the reactions achieve 
 identical maximum rates ( 0.03 m / min ) for different initial 
 concentrations of aryl bromide ( figure 2 ) . 

second , the rate appears to be relatively insensitive to the concentration 
 of amine .
the nearly horizontal curves show the rate slightly decreasing 
 over the range of amine concentrations from 0.9 to 0.5 m , suggesting 
 zeroth - order kinetics in [ amine ] . since oxidative addition of aryl 
 bromides is faster , the rate - determining step of the reaction has 
 shifted to a subsequent step in the catalytic cycle , which is independent 
 of both [ arbr ] and [ amine ] .
therefore , 
 for the reaction of aryl bromide 12 and amine 3 with precatalyst p4 , reductive elimination is most 
 likely the rate - determining step .
reaction progress kinetic profiles for 
 the reaction of arbr 12 with amine 3 plotted 
 as rate vs [ amine ] over 
 the range of concentrations common to the two reactions .
the concentration 
 of arbr 12 at the point in the reaction progress marked 
 by the dashed line is shown for each reaction . at approximately 40% conversion ,
the initial zeroth - order 
 regime 
 shown in figure 4 gives way to a slow linear 
 decay in reaction rate for the [ excess ] = 0 m reaction ( equal amounts 
 of aryl bromide 12 and amine 3 ; see the supporting information for the full graph ) .
this 
 behavior corresponds to initial saturation kinetics in [ amine ] . as the concentration of amine 3 decreases , amine binding to the pd(ii ) center becomes slower than 
 reductive elimination and , therefore , rate - determining .
the 
 kinetic analysis of the reactions with two different aryl halides 
 suggests that , to improve the catalyst system , oxidative addition 
 and reductive elimination need to be accelerated . modifying the ligand 
 to make it both more electron - rich ( faster oxidative addition ) and 

larger ( faster reductive elimination ) might result in faster rates 
 for each step .
we reasoned that switching 
 from a biaryl(diaryl)phosphine - type ligand to the ( dialkyl)phosphino 
 analogue ( figure 5 ) would accomplish both requirements . 

however , our initial ligand screen ( table 1 ) showed that cphos ( l5 ) gave no product , suggesting 
 this ligand was too large and/or too electron - rich .
we thus prepared 
 ligands with one phenyl group and one alkyl group ( figure 5 ) . by incorporating one large alkyl group
, we could 
 increase the electron density and size of the ligand , while keeping 
 the smaller aryl group should still allow amine binding and deprotonation 
 to proceed at a rapid rate .
we synthesized two biaryl(alkyl)phenyl 
 ligands in which one of 
 the phenyl groups on the phosphine of l4 is replaced 
 with either a cyclohexyl ( l6 ) or a tert - butyl ( l7 ) group ( table 3 ; see 
 the supporting information for details 
 on the preparation of the ligands ) .
the corresponding precatalysts p6 and p7 were prepared and examined under identical 
 conditions used in our previous ligand assessment ( table 1 ) . as hypothesized , the hybrid ( alkyl)phenyl phosphines l6 and l7 provided superior catalysts .
a system 
 based on ligand l7 proved optimal , giving full conversion 
 of 6 in less than 30 min at 70 c ( table 3 , entry 3 ) .
reaction conditions : aryl halide 
 ( 0.5 mmol ) , amine ( 0.6 mmol ) , nao - t - bu ( 0.6 mmol ) , 
 1,4-dioxane ( 0.5 ml ) . to understand 
 the difference between l4 and l7 , we investigated 
 the kinetics of the reactions between 
 aryl halides 6 and 12 and amine 3 using a catalyst based on l7 under the same reaction 
 conditions used for p4 ( 2% pd , 70 c ) .
the use of 
 ligand l7 dramatically accelerated the rate of the reaction : t1/2 = 2.6 and 1.9 min for 6 and 12 , respectively , whereas the half - lives with p4 were 46 and 10 min for 6 and 12 ( [ arx]0 = 0.5 m ; see the supporting information for details ) . to perform accurate calorimetric kinetic studies of 
 the improved system , we adjusted the reaction conditions by reducing 
 the catalyst loading ( from 2 to 0.5 mol % ) and the temperature for 
 the aryl bromide ( from 70 to 60 c ) .
more consistent results were observed at lower catalyst loadings 
 through in situ generation of an oxidative addition complex from ( cod)pd(ch2tms)2 , ligand l7 , and aryl halide 
 than through the use of precatalyst p7 as the pd source .
in addition , it was found that better results 
 were obtained in the presence of an extra equivalent of l7 ( with respect to the palladium catalyst ) , which was extended to 
 the general reaction conditions ( table 4 ) .
reaction conditions : aryl halide 
 ( 1 mmol ) , amine ( 1.2 mmol ) , nao - t - bu ( 1.2 mmol ) , 
 1,4-dioxane ( 1 ml ) .
even with the sharply reduced 
 catalyst concentration 
 ( and reduced temperature for the arbr substrate ) , the rate of these 
 reactions was ca
. 1 order of magnitude greater than that of the reactions 
 with precatalyst p4 ( figures 2 and 6 ) temporal reaction rate profiles for the 
 reaction of amine 3 ( 1.0 m ) and arcl 6 or 
 arbr 12 ( concentrations 
 defined by [ excess ] given in legend ; see eq 1 ) .
note a : pd(l7 ) is an oxidative addition complex generated 
 in situ from ( cod)pd(ch2tms)2 , l7 , and 12 ( see the supporting information for details ) .
figure 7 shows the data from the different 
 excess experiments for aryl chloride 6 as rate vs [ arcl ] 
 over the range of arcl concentrations common to both reactions .
although 
 the reaction has a more complex profile than with p4 , 
 the nonhorizontal shape of the curves and the different maximum rates 
 ( 0.124 and 0.02 m / min for the blue and the red curves , respectively ) 
 imply that there is a positive order in aryl chloride and thus that 
 oxidative addition remains , at least partially , the rate - determining 
 step ( the reaction has a fractional order in [ arcl ] ) .
in contrast 
 to the arcl reactions with p4 , the two curves are not 
 overlaid , which could indicate a positive reaction order in [ amine ] 
 ( the reactions have different rates at different amine concentrations ) . 
 however , the convex shape of the rate curves ( particularly explicit 
 for the red curve ) is typically a hallmark of catalyst deactivation
. the likelihood of rate dependence on [ amine ] 
 vs catalyst deactivation can be deconvoluted with a quantitative assessment . 

we can consider relative rates of the two reactions at any given concentration 
 of arcl and amine , with 
x  and  y  as the reaction orders in [ arcl ] and [ amine ] , 
 respectively , and kobs as the observed 
 rate constant , which contains the catalyst concentration ( eq 2 ) .
choosing 
 [ arcl ] = 0.5 m , we see from figure 7 that [ amine ] 
 = 1.0 m for the blue curve ( the beginning of the reaction ) and 0.5 
 m for the reaction in red ( 50% conversion ) and that their relative 
 rates differ by a factor of 5 ( eq 3 ) . if kobs is identical for the two runs , y is calculated 
 to be greater than 2 ( eq 4a ) , which is not mechanistically reasonable . 

if the reaction is in fact zeroth - order in [ amine ] ( y = 0 ) , eq 4b indicates that kobs for 
 the red curve has been deactivated by a factor of 5 at 50% conversion . 

although this mathematical argument can not entirely exclude rate dependence 
 on [ amine ] , catalyst deactivation is a more likely explanation on 
 the basis of the shape of the curves and the fact that different maximum 
 rates are obtained for different arcl concentrations .
reaction progress kinetic 
 profiles for the reactions of arcl 6 with amine 3 plotted as rate vs [ arcl ] over 
 the range of concentrations common to the two reactions .
the concentration 
 of amine 3 at the point in the reaction progress marked 
 by the dashed line is shown for each reaction .
note a : pd(l7 ) is an oxidative addition complex generated in situ from ( cod)pd(ch2tms)2 , l7 , and 12 ( see 
 the supporting information for details ) .
lastly , the data for the cross - coupling 
 between aryl bromide 12 and amine 3 with 
 a catalyst based on l7 , shown in figure 6 , reveal the fastest 
 reactions run in this work ( even at 60 c ) .
the curves show an 
 uncommon shape in which the rates reach their maximum at ca .
2535% 
 conversion , which suggests a delay in the catalyst entering the catalytic 
 cycle .
in addition , as in the reaction with aryl chloride 6 , unusual behavior is observed at the end of the reactions : the curves 
 decay , displaying a convex shape ( see the supporting 
 information for the full graph ) , presumably due to catalyst 
 decomposition . thus , it seems that the catalyst based on l7 has a transient nature in such a fast reaction and does not establish 
 a persistent steady - state kinetics behavior to allow further rpka 
 analysis .
however , since both different excess reactions with aryl 
 bromide 12 reach the same maximum rate independent of 
 their initial concentration , it can be inferred that the reaction 
 is likely zeroth - order in arbr as with precatalyst p4 .
to gain a deeper insight into the differences between l4 and l7 , we prepared oxidative addition complexes [ l4pd(4-cnph)br ] ( 13 ) and [ l7pd(4-cnph)br ] ( 14 ) as air - stable yellow solids and analyzed them by single - crystal 
 x - ray crystallography ( figure 8) . similar to 
 what has been previously observed with biaryl(dialkyl)phosphine ligands , 
 the complexes possess a slightly distorted square planar geometry 
 at pd .
as has been observed with l5 , the dimethylamino substituents were not coplanar with the 
 aryl ring to which they are attached , indicating that no conjugation 
 of the nitrogen lone pairs with the aromatic -system is occurring . 

thus , the dimethylamino groups should be considered as overall electron - withdrawing 
 by induction rather than electron - donating .
this could assist the 
 binding of bulky and electron - rich amines by rendering the pd center 
 more electrophilic .
x - ray structures of oxidative addition 
 complexes 13 and 14 and relevant bond lengths . 

br 
 angle (  ) , which decreased 
 from 86.5 to 83.2. we infer that this geometric difference 
 also applies to the amido complexes iv ( figure 1 ) , bringing the two groups to be connected closer 
 in 14 than in 13 and therefore facilitating 
 reductive elimination .
we next set out to examine the substrate scope of the reaction 
 with p7 .
we were able to reduce catalyst loadings from 
 12% p4 to 0.5 mol % p7 and the temperature 
 from 100120 to 80 c for many substrates ( table 4 ) .
more challenging substrates 
 required 1 mol % pd and 100 c ( e.g. , with 30 or 33 ) . a variety of electron - deficient , electron - rich , and heteroaryl 
 chlorides and bromides
esters and nitriles ( 32 , 34 ) were 
 tolerated under the reaction conditions , although free n  h 
 heterocycles and enolizable ketones were not compatible .
protic substrates 
 such as phenols , carboxylic acids , and amides were also successfully 
 coupled by using 2 equiv of base ( 23 , 25 , and 29 ) .
as previously reported , nitrogen - containing 
 five - membered heterocycles are challenging , albeit important , substrates .
however , replacing the methyl 
 group with a trityl protecting group led to the clean formation of 31 .
reactions using ortho - substituted substrates and/or 
 tritylamine 5 were sluggish with p7 , and 
 the use of p4 provided better results in these cases 
 ( table 5 ) .
this system allowed for the preparation 
 of extremely 
 hindered secondary anilines as 2,6-disubstituted aryl halides ( 35 ) and substrates bearing large ortho substituents ( 36 ) were successfully coupled in high yields . additionally , 
 certain heteroaryl halides such as 5-chloro-2,1,3-benzothiadiazole 
 and 4-methyl-3-bromothiophene gave better results using p4 ( 40 , 42 ; 1015% yields were obtained 
 using p7 ) . for activated 2-halopyridines and pyrazine 
 ( 41 , 44 , 45 ) the corresponding 
 aro - t - bu byproduct was also observed but was easily separated from the desired compound .
weaker 
 inorganic bases ( cs2co3 , k3po4 , or k2co3 ) that could circumvent this 
 issue were found to be ineffective in promoting the desired transformation . 

nonetheless , a wide variety of substrates , including aryl halides 
 containing base - sensitive functional groups , were coupled with deliberate 
 choice of the supporting ligand ( l7 or l4 ) reaction conditions : aryl halide 
 ( 1 mmol ) , amine ( 1.2 mmol ) , nao - t - bu ( 1.2 mmol ) , 
 1,4-dioxane ( 1 ml ) .
in summary , we have developed a general method for the cross - coupling 
 of hindered primary amines with a range of ( hetero)aryl chlorides 
 and bromides .
this transformation occurs under mild conditions and 
 provides the desired products in high yields utilizing two catalyst 
 systems .
ligand l7 was designed after analysis of the 
 reaction mechanism using the rpka method . rather than amine binding
, 
 it was found that oxidative addition for aryl chlorides and reductive 
 elimination for aryl bromides with the initial catalyst based on ligand l4 were rate - determining .
these observations lead to the development 
 of l7 , a biaryl(alkyl)arylphosphine ligand that greatly 
 accelerated the reaction with both aryl halides .
l7 is 
 the first example of a hybrid ( alkyl)aryl ligand that provides superior 
 results as compared to its analogues with identical alkyl- or arylphosphorus 
 substituents , offering another tunable 
 site for better control of catalyst activity .
we anticipate that this 
 methodology will find applications in both academic and pharmaceutical 
 settings , and we expect the new class of biarylphosphine ligands reported 
 here to influence our future design of ligands .
 we 
 report the pd - catalyzed arylation of very hindered ,,-trisubstituted 
 primary amines . 
 kinetics - based mechanistic analysis and rational design 
 have led to the development of two biarylphosphine ligands that allow 
 the transformation to proceed with excellent efficiency . 
 the process 
 was effective in coupling a wide range of functionalized aryl and 
 heteroaryl halides under mild conditions . 