Expanding Water/Base Tolerant Frustrated Lewis Pair Chemistry to Alkylamines Enables Broad Scope Reductive Aminations

Abstract Lower Lewis acidity boranes demonstrate greater tolerance to combinations of water/strong Brønsted bases than B(C6F5)3, this enables Si−H bond activation by a frustrated Lewis pair (FLP) mechanism to proceed in the presence of H2O/alkylamines. Specifically, BPh3 has improved water tolerance in the presence of alkylamines as the Brønsted acidic adduct H2O–BPh3 does not undergo irreversible deprotonation with aliphatic amines in contrast to H2O–B(C6F5)3. Therefore BPh3 is a catalyst for the reductive amination of aldehydes and ketones with alkylamines using silanes as reductants. A range of amines inaccessible using B(C6F5)3 as catalyst, were accessible by reductive amination catalysed by BPh3 via an operationally simple methodology requiring no purification of BPh3 or reagents/solvent. BPh3 has a complementary reductive amination scope to B(C6F5)3 with the former not an effective catalyst for the reductive amination of arylamines, while the latter is not an effective catalyst for the reductive amination of alkylamines. This disparity is due to the different pK a values of the water–borane adducts and the greater susceptibility of BPh3 species towards protodeboronation. An understanding of the deactivation processes occurring using B(C6F5)3 and BPh3 as reductive amination catalysts led to the identification of a third triarylborane, B(3,5‐Cl2C6H3)3, that has a broader substrate scope being able to catalyse the reductive amination of both aryl and alkyl amines with carbonyls.


Introduction
Considerable progress in frustrated Lewis pair (FLP) chemistry has been achieved in the last decade principally using tris(pentafluorophenyl)borane, B(C 6 F 5 ) 3 . [1] Compared to BPh 3 ,t he presence of fluorine atoms dramatically increases theL ewis acidity. [2] While high Lewis acidity is essential in enabling certain FLP reactivity,i ta lso poses challenges including the compatibility of FLPs with water (e.g. from unpurified reactants/solvents or as ar eactionb y-product)/ base combinations, at opic which has attracted recent attention. [3][4][5][6] Af luorinated triarylborane with ah igh Lewisa cidity towards hydride (whichi sd esirable for HÀHa nd SiÀHb ond activations) also has considerable oxophilicity,w ith the corresponding triarylborane-water adduct exhibiting much greaterB rønsteda cidity than water itself. [7] Indeed, the Brønsted acidityo fH 2 O-B(C 6 F 5 ) 3 was determined by Parkin and co-workers (pK a = 8.4 in MeCN) to be comparable to that of HCl (8.5 in MeCN). [7a] This poses al imit to the water tolerance of thesef luorinated arylboranes in the presence of certainB rønsted bases because irreversible deprotonation of the borane-water adduct yields an inactive (for FLP chemistry) hydroxytriarylborate anion.
Ashley,S tephan, and co-workers pioneered ROH-tolerant FLP reactionsa nd demonstrated that B(C 6 F 5 ) 3 could be used for the hydrogenation of carbonyls (Scheme 1A). Importantly,the alco-hol-borane adducts are not irreversibly deprotonated under these weakly basic conditions (which use ethereal solvents such as 1,4-dioxanea sL ewis bases to activate H 2 via an FLP mechanism). [3,8] Demonstration of the water tolerance of B(C 6 F 5 ) 3 was subsequently reported proving that the hydrogenation of ketones could be performed using non-purified, "wet" reactants ands olvents (H 2 O-B(C 6 F 5 ) 3 also is not irreversibly deprotonated by ethereal solvents). [4] Recently,wer eported the water tolerance of aB (C 6 F 5 ) 3 -catalysed system involving more basic arylamines (conjugate acid pK a ca. 11 in MeCN, Scheme 1B). [5] In particular we found that B(C 6 F 5 ) 3 is able to catalyset he reductive amination of aldehydes and ketones with anilinesu sing 1.2 equivalents of silane as reductant. [9] This proceeds in the presence of as uper-stoichiometric amount of water derived from imine formation and the use of non-purified solvents. An elegant extension of this approachw as recently reported using B(C 6 F 5 ) 3 to catalyse the tandem Meinwald rearrangementa nd reductivea mination of epoxides with anilinesand silanes. [10] However,inthe latter,asinour work, reductive amination could not be extended to alkylamines( conjugate acid pK a ! 16 in MeCN) duet ot he irreversible deprotonation of H 2 O-B(C 6 F 5 ) 3 .T hus, the compatibilityo fH 2 O-B(C 6 F 5 ) 3 with bases appearst ob el imited to those bases with conjugate acids that have pK a values 12 (in MeCN). Ab roader amine scope catalytic reductivea minationm ethodology using as imple triarylborane is desirable as ao ne-pot method (thus preferable from an efficiency perspective)t or apidlya ccess amines that are ubiquitous functionalities in natural products, pharmaceuticals and agrochemicals.
To circumvent the limitation of B(C 6 F 5 ) 3 towards water/ strong Brønsted base combinations,L ewis acids that are less oxophilica re required. These could be "hydride selective" Lewis acids, such as Group 14 based Lewis acids (which maintain high hydridophilicity buth ave lower oxophilicity) [11] or Lewis acids that are globally less Lewis acidic (e.g.,l esso xophilic and less hydridophilic). [12] The latter approach was utilised by Papai, Soósa nd co-workers who employed less Lewis acidic partially halogenated triarylboranes for example, (2,3,5,6-C 6 F 4 H) 2 B(2,6-C 6 H 4 Cl 2 ), for the catalytic hydrogenation of carbonyls in ethereal solvents, with some water tolerance demonstrated. [6] Ta king this approachf urther,t he non-halogenated triarylborane BPh 3 should have enhanced tolerance to water and strong base combinations due to its lower Lewis acidity.B Ph 3 does however still possesss ufficient hydridophilicity to be useful as ac atalysti nF LP-type reactions as recently demonstrated. [13,14] While H 2 O-B(C 6 F 5 ) 3 is well documented, [7] the corresponding H 2 O-BPh 3 adduct is lesss tudied, particularly its ability to act as aB rønsted acid. [16][17][18][19] Herein we report an extension to the water and base tolerance of boranes to strong amine bases, focusing, in particularo nt he triarylborane-catalysed reductive aminationo fa ldehydes/ketones with alkylamines using silanes as reducing agents. This demonstrates that BPh 3 is an effective catalyst for the reductive amination of alkylamines and carbonyls (Scheme 1C), including examples challenging to reduce with borohydrides alts (e.g., [(OAc) 3 BH] À ). Furthermore, B(3,5-Cl 2 C 6 H 3 ) 3 is effective for the reductive amination of carbonyls and both aryl and alkylamines without requiring any inert atmosphere techniques or solvent/ reagent purification (Scheme 1D).

Results and Discussion
To determine if H 2 O-BPh 3 protonates alkylamines,B nNH 2 (conjugate acid pK a = 16.6 in MeCN) [8] was added to as olution of H 2 O-BPh 3 in [D 3 ]-MeCN. 1 HN MR spectroscopy showedc oordination of BnNH 2 to BPh 3 ,a si ndicated by a2 Hi ntegral resonance at d = 5.3 ppm (for BnNH 2 )s hiftedd ownfield from free BnNH 2 in [D 3 ]-MeCN (1.5 ppm). Identical 1 HNMR resonances are observedf or Ph 3 B-N(H) 2 Bn formed under anhydrous conditions in [D 3 ]-MeCN (for both d 11B = À1.7 ppm). Coordination of BnNH 2 to BPh 3 is reversiblea tr oom temperature as addition of benzaldehydel ed to rapid imine formation,t hus the absence of any observable [HO-BPh 3 ] À is attributed to the lower Brønsted acidity of H 2 O-BPh 3 .I nc ontrast, the additiono fB nNH 2 to H 2 O-B(C 6 F 5 ) 3 led to formation of [HO-B(C 6 F 5 ) 3 ] À as the major product (by 11 Ba nd 19 FNMR spectroscopy) as expected based on relative pK a values. With no observable deprotonation of H 2 O-BPh 3 with BnNH 2 ,t he utility of BPh 3 as ac atalystw as explored in the reductive amination of benzaldehyde (1.0 equiv) with benzylamine (1.2 equiv), under air using non-purified BPh 3 ,n on-purified solvents, and silane as reductant (Table 1). In this reaction, upon imine formation,w ater is produced as ab yproduct, so both excess( relative to BPh 3 )w ater and ag ood Brønsted base (BnNH 2 ,u sed in slight excess to favour imine formation)a re present in the reactionmixture.
For ad irect comparison with our previous work using B(C 6 F 5 ) 3 , [5] we initially performed the reactioni northo-dichlorobenzene (o-DCB)u sing 1.2 equivalents of silane. Under these conditions imine formation proceeds but no reduction was observed using 10 %m ol BPh 3 ( Table 1, entry 1). Okuda and coworkers reportedt hat BPh 3 is am ore effective catalyst for (de)hydrosilylation reactions in polar solvents such as MeCN or ni- tromethane. [13] Changing the solvent from o-DCB to MeCN now resulted in the desired product being obtainedi nm oderate yield. On increasing the amount of silane from 1.2 to 3.5 equivalents, dibenzylamine was obtained in good yield (87 %N MR yield and 80 %i solated yield). The requirement for excess silane is due to imine reduction and H 2 O/silanol dehydrosilylation occurring concurrently.T he activity of this system is not due to initial consumption of all H 2 Ob ye xcesss ilane and then imine reduction proceeding under anhydrous conditions as indicated by the absence of any induction period in this reductivea mination.T his was further confirmed by analysis of the reaction mixture after 3hours at 100 8C, at which point considerable iminer eduction had occurred (ca. 30 %) but significant water andP hMe 2 SiOH weres till present. [20] Decreasing the catalystl oading to 5mol %r esulted in al ower yield (entry 5), while 100 8Cw as found to be critical (entry 6). The applicability of other silanes was then investigated:w hile Ph 2 SiH 2 was viable in the reductivea mination (entry 7), the increase in the steric hindrance of the silane going from PhMe 2 SiH to Ph 2 MeSiH,r esulted in as ignificant drop in imine reduction (entry4 vs. 8). When smaller silanes were employed (entries 9a nd 10), dibenzylamine wast he major component among multiple products, including EtNH 2 presumablyd eriving from MeCN reduction.
With the compatibility of BnNH 2 and H 2 O-BPh 3 mixtures confirmed by the successful reductivea mination of benzaldehyde and BnNH 2 ,adirect comparison between B(C 6 F 5 ) 3 and BPh 3 wasp erformed. In our previous work we found that B(C 6 F 5 ) 3 catalysed reductive aminationso fa nilinesa nd aldehydes in o-DCB at 100 8C, but not the more basic alkylamines due to irreversible deprotonation of H 2 O-B(C 6 F 5 ) 3 . [5] To avoid any disparities arising from the solvente mployed, comparative reductivea minations using benzaldehyde and aniline or benzylaminew ith B(C 6 F 5 ) 3 or BPh 3 as catalystw ere performedi n MeCN (Table 2). Although the coordinationo fM eCN to B(C 6 F 5 ) 3 is well documented, [21] the reductivea mination of benzaldehyde and aniline still proceeded to high yield (96 %) in 1h at 100 8Co nr eplacing o-DCB with MeCN. As previously reported, 1.2 equivalents of silane is sufficient using anilinesw ith imine reduction occurring preferentially to water dehydrosilylation. Interestingly,o nr eplacing B(C 6 F 5 ) 3 with BPh 3 under identical conditions, minimal (8 %) imine reduction and minimal water dehydrosilylation wereo bserved after 1hon heating at 100 8C. As imilar outcome was observed using 0.1 equivalent BPh 3 loading and 3.5 equivalents of silane (entry 2) with al ow reductivea mination conversion even after 25 h. In contrast, in the reductivea mination of benzaldehyde/benzylamine under identicalc onditions the use of BPh 3 resultsi nan excellent conversion, whilst B(C 6 F 5 ) 3 is effectively inactive( entry 3).
Notably,d uring reductive aminations using BPh 3 as catalyst four-coordinate boron species (such as imine!BPh 3 and amine!BPh 3 )a nd 11 Br esonances consistentw ith Ph 2 BOH and PhB(OH) 2 are all observed. Importantly,a ttempts to catalyse the reductive amination of benzaldehyde/benzylamine with PhB(OH) 2 ,P h 2 B(OH) or Ph 3 BOH À (whilstn ot observedt he latter is feasibly present in low concentration through as mall degree of H 2 O-BPh 3 deprotonation) in place of BPh 3 led to very low conversions( e.g.,c a. 10 %u sing Ph 2 BOH) after 25 ha t1 00 8C in MeCN. The use of Brønsted acids such as HCl and HNO 3 also resultedi nm inimal reductive amination. Combined these control reactions indicate the importance of the triarylborane as the catalysti nt his process, presumably for activation of the silane via established (for B(C 6 F 5 ) 3 )m echanistic pathways. [22] To better understand the disparities between PhNH 2 and BnNH 2 in reductivea minationsc atalysed by BPh 3 ,an umber of control reactions were performed. As olution of BPh 3 in anhydrous MeCN was heated at 100 8Cs ealed under air,w ith no significant reaction (e.g.,p rotodeboronation) observed. However,a dding 10 equivalents of water to this solution led to significant protodeboronation after 2hours at 100 8C( PhB(OH) 2 , Ph 2 B(OH) and PhH observed by 1 Ha nd 11 BNMR spectroscopy) presumably via an intramolecular protodeboronation process from H 2 O-BPh 3 as recently calculated for H 2 O-B(C 6 F 5 ) 3 . [23] Havingi dentified that H 2 O-BPh 3 can undergo protodeboronation to produce catalytically inactivep roducts the effect of amine basicity on protodeboronationwas investigated. The addition of 10 equivalents of PhNH 2 to as olutiono fH 2 O-BPh 3 (made by mixing 1equivalents of BPh 3 with 10 equivalents of water in MeCN to approximate the catalysis conditions) did not prevent protodeboronation on heating.N otably,w hen 10 equivalents of the more basic amine BnNH 2 was added to an identical solutionc ontaining H 2 O-BPh 3 ,p rotodeboronation proceeded to as ignificantlyl ower extent (by monitoring the appearance of benzene in the 1 HNMR spectrum and by 11 BNMR spectroscopy). Even upon heating at 100 8Cf or 20 hours (Figure 1) four-coordinate L!BPh 3 compounds were still the dominant speciesw ith BnNH 2 in contrast to that with PhNH 2 .
The disparity between PhNH 2 and BnNH 2 in reductive amination catalyzed by BPh 3 will be due to different amine (or imine) basicity,h owever this will affect an umber of processes, therefore to identify the origin of this disparity an umber of control reactions were performed. The disparity is not duet ot he less nucleophilic imine derived from aniline/benzaldehydel eading to as ignificantly greaterb arriert oa nS N 2t ype reaction with the R 3 Si-H-BPh 3 species. This was confirmed by the fact that under anhydrous conditions using catalytic BPh 3 and stoichiometric PhMe 2 SiH, N-benzylidene aniline and N-benzylidene benzylamine wereb oth reduced (Scheme2,l eft). However, . Although no silylated amine was observed during reductive amination, the exact nature of the iminiumc ation could not be unambiguously defined in this process due to the fast hydrolysis of silylated amine under thesec onditions. Nevertheless, furtherc ontrol reactions showedt hat both protonated N-benzylidene aniline and N-benzylidene benzylamine were reduced by [HBPh 3 ] À (consistent with Okuda andc o-workersr eport on imine hydroboration catalyzed by [HBPh 3 ] À salts) . [24] There was no evidence for differing degrees of side reactions (such as evolution of PhH (by protodeboronation)) or significant differences in the rate of reduction during the control reactions with the iminium cations (Scheme 2, right). Whilst the iminium cations derived from N-benzylidene aniline do undergo slower reductions (than those derived from N-benzylidene benzylamine)t his should only result in longerr eactiont imes being required for complete reductive amination using PhNH 2 /benzaldehyde under BPh 3 catalysis. However,t his is not observed, as no further increase in conversion is observed on longerr eaction times in reductive aminations.C ombined theseo bservations indicatet hat the differencei nr eactivity is due to more rapid catalystd ecomposition in the presence of PhNH 2 relative to BnNH 2 andn ot any intrinsic barrier to N-benzylidene aniline reduction.
As BPh 3 decomposition most probably proceeds via H 2 O-BPh 3 (based on its fast protodeboronation), reducing the concentration of this speciesi ns olution should be key to provide enhanced catalytic activity.A tl east two scenarios are feasible for achieving this:i )the more basic species( BnNH 2 or its derived imine) retardsp rotodeboronation by deprotonating H 2 O-BPh 3 resulting in ad ifferent catalyst resting state, [HO-BPh 3 ] À , that is more stable to protodeboronation;i i) the more nucleophilic amine/imine( e.g.,B nNH 2 or its derived imine) forms aL ewis adduct L!BPh 3 ,w hich is more stable to protodeboronation than Ph 3 B-OH 2 .B ased on the in situ NMR data for H 2 O-BPh 3 /BnNH 2 the latter is more probable as only Bn(H) 2 N-BPh 3 is observed with no [Ph 3 B-OH] À detectable. In contrast, with the less basic/nucleophilic aniline,t he adduct Ph(H) 2 N-BPh 3 (whichw hen formed under anhydrous conditions has acharacteristic integral 2H singlet in the 1 HNMR spectrum at d = 5.7 ppm for the NH 2 group) reacts with equimolar water as indicatedb yadrastic shift in the 1 HNMR spectrum to ab road resonance at d = 2.1 ppm (integral four for the combined NH 2 / OH 2 resonance). This suggests an equilibrium between Ph(H) 2 N-BPh 3 and H 2 O-BPh 3 consistent with the more rapid protodeboronation observed. The 11 BNMR spectra are inconclusive for this system as H 2 O-BPh 3 andP h 3 B-N(H) 2 Ph have extremely similar chemical shifts, whilst the slow exchange regime is not reached even at À38 8Cin[ D 3 ]-MeCN.
Upon heating, enough BPh 3 is generated from aL ewis adduct or the hydroxyborate to activate the silane to nucleophilic attack. Nucleophilic attack leads to the formation of [HBPh 3 ] À that in turn would reduce the iminium cation (either silylatedo rp rotonated) by hydride transfer thusr egenerating the catalyst. The protodeboronation pathway deactivates the catalyst, and is ap rocess whichm ost probablyp roceeds from H 2 O-BPh 3 .T he concentration of this species can be minimized in solutionb yu sing strongerb ases/nucleophiles which lead to formationo fL B !BPh 3 or [LB-H][HOBPh 3 ]( LB = amine or imine). Notably,i nt he presence of both BnNH 2 and N-benzylidene benzylamine, BPh 3 binds the former preferentially.A st he optimal catalysis conditions uses as light excess of amine, the continued presence of free amine presumably helps reduce the quantity of H 2 O-BPh 3 present and thus limit protodeboronation.
With an understandingo ft he limitations of using BPh 3 for catalytic reductive amination,t he substrate scope was then explored with the reactions performed under air,u sing non-purified solvent and reactants with everything combined at the start in an operationally simple process (Table 3).
Ar ange of functionalised benzaldehydes were amenable in the reductive amination with benzylamine, with good in situ conversionsa nd isolated yields (1a-e). It is noteworthy that ester and cyano substituents were compatible, with no evidence for their reduction under these conditions (1f, g). However,t he reactionw as less tolerant to nitro substituents (due to trans-imination and formation of dibenzylamine observed as the major by-product). It is noteworthy that when electronwithdrawing groupsa re presenti nt he para positiono fb enzaldehyde( e.g. -CO 2 Me or -CN), minimal siloxane( and silanol) were observed after 25 h( by 1 Ha nd 29 Si NMR spectroscopy), with significant reduction of the imine still occurring. Furthermore > 50 %i mine reduction to 1f was observed with only 1.2 equivalents of silane after 25 h. This indicates that more electrophilic iminese ffectively out compete H 2 Of or reaction with the borohydride, whereas with less electrophilic imines the rates of water/silanol dehydrosilylation andi miniumc ation reduction are comparable hence excess silane is required. Reductive aminationalso proceeded in the presence of aterminal CÀCt riple bond without significant reduction of the latter (1i), or any observable side reactivity,f or example, dehydroboration. [1d] When aliphatic aldehydes (n-butyraldehyde and propionaldehyde)w ere used, full consumptiono ft he in situ formedi mine was observed, butt he desired product was only am inor component duet oo ver-alkylation to the tertiary amine or enamine isomerization reactions, as reported for B(C 6 F 5 ) 3 . [5] However,w hen ketones were utilised, the reaction was successful, allowing as econdary carbon centre to be attached to the nitrogen (1j,k). Notably,t he reductive aminationo fa cetophenone and benzylamine is challenging with widely used reducing agents such as Na[triacetoxyborohydride] (Na[(OAc) 3 BH],5 5% yield after 10 days), [26] in contrast using BPh 3 /silane 1j is produced in higher yield in shorter reaction times. The reductivea mination of 1-acetyl-1-cyclohexenea nd morpholine to  yield 1l is also challenging using [(OAc) 3 BH] À (only 10 %y ield after 4d ays), [26] but it proceeds to 87 %y ield using BPh 3 /silane. This demonstrates that the BPh 3 -catalysed process is applicable to systemsw here established borohydrider eductivea mination approaches struggle. Furthermore,t he formation of 1l shows the compatibility of this methodology with CÀCd ouble bonds. The inclusion of substituents on benzylamine, as well as the use of nBuNH 2 as another C-primary amine, was also realized (e.g. 1m-o), althoughu sing the latter amine over-alkylation also occurred to some extent (e.g. forming nBu 2 NBn). C-secondary amines,s uch as cyclo-hexylaminea nd isopropylamine, or aC -tertiary amine tBuNH 2 ,g ave good conversions to the desired products (1p-r). It is noteworthy that ac ommon product could be formed from ad ifferent combination of aldehyde/ amine (e.g. 1k and 1p), offering two retrosynthetic strategies. Finally,w hen as econdary amine such as BnN(H)Me was used in combination with an enolizablek etone the reaction still proceeds successfully to form 1s in excellent yield. It should be emphasized that these amines are not accessible by reductive aminationu sing B(C 6 F 5 ) 3 as catalyst due to it being limited to aniline derivatives. To demonstrate scalability the reductive amination of benzaldehyde and 1-adamantylamine was performed on gram-scale under air,u sing 10 mol %o funpurified BPh 3 in non-purified acetonitrile and using PhMe 2 SiH as reductant (Scheme 4). Combining all the reactants at the starta nd heatingt he reaction mixture at 100 8Cf or 25 hours enabled the desired product to be isolated in a9 0% isolated yield (1.1 g).
The results discussed above indicate that B(C 6 F 5 ) 3 and BPh 3 have complementary tolerance to water/amine combinations in reductivea minations ( Figure 2). B(C 6 F 5 ) 3 is av iable catalyst for aryl amines (conjugate acids pK a < 12 in MeCN) butn ot alkylamines (conjugate acids pK a > 16 in MeCN) due to irreversible deprotonation of H 2 O-B(C 6 F 5 ) 3 with the latter.I nc ontrast, BPh 3 is av iable reductivea mination catalyst for alkylamines but not arylamines due to more rapid protodeboronation in the presence of the latter.W ew ere thus interested in exploring an amine with an intermediate pK a ,s pecifically the reductive amination of benzaldehyde and benzhydrylamine (conjugate acid pK a 15 in MeCN) [27] was performed with both these boranes using 10 mol %c atalyst loading. In all cases the in situ conversionsw ereo nly moderatea tb est (lesst han 30 %) under ar ange of conditions with both boranes (e.g.,i nM eCN or o-DCB at 100 8C), indicating that an amine whose conjugate acid has ap K a between 12-16i sp articularly challenging for both boranes. Again in situ analysisr evealed that with BPh 3 significant protodeboronation proceeded upon heating (by 11 BNMR spectroscopy), whilst with B(C 6 F 5 ) 3 the deactivation was due to the effectively irreversible deprotonation of H 2 O-B(C 6 F 5 ) 3 (by 11 B/ 19 FNMR spectroscopy). Given the respective limitations of B(C 6 F 5 ) 3 and BPh 3 ,asingle triarylborane that is av iable catalystf or the reductive amination of both aryl and alkyl amines (including benzhydrylamine) was targeted. To have ab road amine scope, the triarylborane must form aH 2 O-BAryl 3 adduct that is both more resistant to protodeboronation than H 2 O-BPh 3 and less Brønsted acidic than H 2 O-B(C 6 F 5 ) 3 .F urthermore, at riarylboranet hat does not contain ortho-halogen aryl substituents is desirable, as ortho substituents increase the steric bulk aroundb oron and thus can significantly hindera mine/imine coordination to boron. [12] The latter is actually desired in this process as it reduces the concentrationo fH 2 O-BAryl 3 in solution, thus also helpingt o limit protodeboronation. Given these requisites B(3,5-Cl 2 C 6 H 3 ) 3 was selected and its synthesis via the protolytic decomposition of itst etraarylborate salt was utilised as the borate salt is air and moisture stable as as olidi nc ontrast to the free triarylboranes (see subsequent discussion). Te traarylborate anion decomposition has significant precedence for [BPh 4 ] À salts which react with Brønsted acids to release BPh 3 compounds. [28] Furthermore, we recently observed decomposition of Na[B(3,5-Cl 2 C 6 H 3 ) 4 ]( termed Na[BArCl] herein) in wet solvents on heating.
To confirm that Na[BArCl] decomposition by protonolysisg enerates B(3,5-Cl 2 C 6 H 3 ) 3 species, the strongB rønsted acid HNTf 2 was added to NaBArCl. This resulted in the appearance of am ajor new resonance at d = 67 ppm in the 11 BNMR spectrum assigned as B(3,5-Cl 2 C 6 H 3 ) 3 ,w ith this chemical shift consistent with other reported tri(chloroaryl)boranes. [29] Applying this in situ B(3,5-Cl 2 C 6 H 3 ) 3 generation procedure (using an excess of Na[BArCl] relative to HNTf 2 to preclude any trace Brønsted acid remaining as strong Brønsted acids can also activate SiÀH bonds), [30] B(3,5-Cl 2 C 6 H 3 ) 3 catalyzed the reductive amination of benzaldehyde andb enzhydrylamine to give the desired product in good yield (Scheme 5). The use of both B(C 6 F 5 ) 3 Scheme4.Gram-scale synthesis of N-benzyl-1-adamantylamine. Scheme5.Reductive amination with benzaldehyde and benzylhydrylamine using B(C 6 F 5 ) 3, BPh 3 or B(3,5-C 6 H 3 Cl 2 ) 3 (generated in situ) as catalyst. Seeking an operationally simpler process, the decomposition of Na[BArCl] by action of H 2 Ow as investigated as ar oute to generate B(3,5-Cl 2 C 6 H 3 ) 3 in situ. [31,32] This approach was successful for the catalytic reductive amination of benzhydrylamine and benzaldehyde using 10 mol %N a [BArCl] in o-DCB (Scheme6), with all manipulations performed in air using nonpurifieds olvent/reagents. Weakly coordinating solvents are essentiala sa ttempts using MeCN as solventl ed to no reductive amination.T he solvent dependency is attributed to the formation of [(H 2 O) x Na] + species in o-DCB that have enhanced Brønsteda cidity (relative to H 2 O) and are thus key to effecting anion protodeboronationa nd generation of the triarylborane, as previously discussed for NaBPh 4 . [28] In contrast in MeCN, the solventi sp resumably solvating the Na cations,r esulting in al ess Brønsted acidic solution and no anion protodeboronation.
With an in situ catalyst generation protocol in hand, ab rief amine substrate scope exploration wasu ndertaken. Most notably,t he triarylborane derived in situ from Na[BArCl] wasa ble to catalyse the reductivea mination of benzaldehydew ith PhNH 2 ,B nNH 2 ,a nd tBuNH 2 amines whose conjugate acids span the pK a range from 10.6 to 18.4 in MeCN. This indicates ar educed acidity of the corresponding H 2 O-B(3,5-Cl 2 C 6 H 3 ) 3 adduct (relative to that of H 2 O-B(C 6 F 5 ) 3 )a nd an improved stability of B(3,5-Cl 2 C 6 H 3 ) 3 species to protodeboronation (relative to BPh 3 ). The amounto fs ilane requiredf or good conversion to the reductive amination product wase xplored anda gain found to depend on the imine electrophilicity,w ith the more electrophilic imine (derived from aniline) reduced using only 1.2 equivalentso fs ilane, whilst the less electrophilic imines again required an excessofs ilane due to competitive dehydrosilylationreactions.
The ability to use Na[BArCl]a sap recursor to the active triarylboranec atalysth as practical advantages since it is readily synthesized and is bench stable for at least 6months. In contrast, whilst BPh 3 is commerciallya vailable itss toragea sas olid under ambient atmosphere leads to gradual decomposition (even after only 14 days significant PhB(OH) 2 and Ph 2 B(OH) are observed by 11 BNMR spectroscopy). This negatively impacts conversion;f or example using pristine BPh 3 gives 87 %c onversion of benzaldehyde and benzylamine to the reductive amination product whereas the same batch of BPh 3 stored as as olid in air for 2weeks results in only 52 %c onversion when used as the catalyst under otherwise identicalc onditions. In contrast, Na[BArCl] stored as as olid for 6months in air shows no deterioration in reductive amination catalytic activity.T hus Na [BArCl] is au seful bench-stable catalyst precursor for reductive aminations, with its utility further demonstrated in the rapid synthesis of the more complex drug molecule Piribedil (used in the treatment of Parkinson's disease) [33] in good yield (Scheme 7) under air using non-purified reagents/solvents.

Conclusions
In summary,BPh 3 has ahighertolerance to H 2 Oand alkylamine combinationst han B(C 6 F 5 ) 3 ,d ue to the lower Brønsted acidity of H 2 O-BPh 3 .T his extends the water/base tolerance of FLP systems to strong bases (conjugate acid pK a = 18.5). This enables the utilisation of BPh 3 as ac atalystf or the reductivea mination of aldehydes and ketones with many different aliphatic amines,r anging from C-primary to C-tertiary.T his system is even effective for the reductivea mination of substrates that are challenging with conventionalb orohydrides (e.g., [(OAc) 3 BH] À ). BPh 3 andB (C 6 F 5 ) 3 exhibit complementary amine scope in reductive aminations, with the former limited by the protodeboronation of H 2 O-BPh 3 in the presence of weaker amine Brønsted bases/nucleophiles, while the latteri sl imited by H 2 O-B(C 6 F 5 ) 3 undergoing irreversible deprotonation by stronger Brønsted basic aminess uch as alkylamines.F inally, athirdtriarylborane, B(3,5-Cl 2 C 6 H 3 ) 3 ,ofintermediate Lewis acidity,w as shown to be effective for the reductive amination of ar ange of amines whose conjugate acids span pK a values of 10.6 to 18.5 in MeCN. Furthermore, in situ tetraarylborate anion decomposition by H 2 Oi nn on-coordinating solvents represents as imple route to generatet he active triarylborane catalyst from ar eadily accessible bench-stable precursor.T he reductive amination methodologies presented herein are operationally simple (e.g. no purification of any materials/solvent is requireda nd the reactions are performed under air) and are applicable to gram-scalea nd complex molecule synthesis.