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

Article abstract of DOI:10.1002/chem.201605466

Lower Lewis acidity boranes demonstrate greater tolerance to combinations of water/strong Br?nsted 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, BPh₃has improved water tolerance in the presence of alkylamines as the Br?nsted acidic adduct H₂O–BPh₃does not undergo irreversible deprotonation with aliphatic amines in contrast to H₂O–B(C₆F₅)₃. Therefore BPh₃is a catalyst for the reductive amination of aldehydes and ketones with alkylamines using silanes as reductants. A range of amines inaccessible using B(C₆F₅)₃as catalyst, were accessible by reductive amination catalysed by BPh₃via an operationally simple methodology requiring no purification of BPh₃or reagents/solvent. BPh₃has a complementary reductive amination scope to B(C₆F₅)₃with 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_avalues of the water–borane adducts and the greater susceptibility of BPh₃species towards protodeboronation. An understanding of the deactivation processes occurring using B(C₆F₅)₃and BPh₃as 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.

Full text of DOI:10.1002/chem.201605466

A Journal of
Accepted Article
Title: Expanding Water/Base Tolerant FLP Chemistry to Alkylamines
Enables Broad Scope Reductive Aminations
Authors: Michael Ingleson and Valerio Fasano
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To be cited as: Chem. Eur. J. 10.1002/chem.201605466
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10.1002/chem.201605466
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Expanding Water/Base Tolerant FLP Chemistry to Alkylamines
Enables Broad Scope Reductive Aminations
V. Fasano[a] and M. J. Ingleson[a]*
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 pKa values of the water-borane
adducts and the greater susceptibility of BPh3 species towards
protodeboronation. An understanding of the deactivation processes
occuring 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.
to the water tolerance of these fluorinated arylboranes in
the presence of certain Brønsted bases because
irreversible deprotonation of the borane-water adduct yields
an inactive (for FLP chemistry) hydroxytriarylborate anion.
Ashley, Stephan and co-workers pioneered ROH tolerant
FLP reactions and demonstrated that B(C6F5)3 could be
used for the hydrogenation of carbonyls (Scheme 1A).
Importantly, the alcohol-borane adducts are not irreversibly
deprotonated under these weakly basic conditions (which
use ethereal solvents such as 1,4-dioxane as Lewis bases
to activate H2 via an FLP mechanism).3,8 Demonstration of
the water tolerance of B(C6F5)3 was subsequently reported
proving that the hydrogenation of ketones could be
performed using non purified, “wet” reactants and solvents
(H2O-B(C6F5)3 also is not irreversibly deprotonated by
ethereal solvents).4 Recently, we reported the water
tolerance of a B(C6F5)3 catalysed system involving more
basic arylamines (conjugate acid pKa ca. 11 in MeCN,
Scheme 1B).5 In particular we found that B(C6F5)3 is able to
catalyse the reductive amination of aldehydes and ketones
with anilines using 1.2 eq. of silane as reductant.9 This
proceeds in the presence of a super-stoichiometric amount
of water derived from imine formation and the use of non-
purified solvents. An elegant extension of this approach
was recently reported using B(C6F5)3 to catalyze the
tandem Meinwald rearrangement and reductive amination
of epoxides with anilines and silanes.10 However, in the
latter, as in our work, reductive amination could not be
Introduction
Considerable progress in frustrated Lewis pair (FLP)
chemistry has been achieved in the last decade principally
using tris(pentafluorophenyl)borane, B(C6F5)3.1 Compared
to BPh3, the presence of fluorine atoms dramatically
increases the Lewis acidity.2 While high Lewis acidity is
essential in enabling certain FLP reactivity, it also poses
challenges including in the compatibility of FLPs with water
(e.g. from unpurified reactants/solvents or as a reaction by-
product) / base combinations, a topic which has attracted
recent attention.3-6 A fluorinated triarylborane with a high
Lewis acidity towards hydride (which is desirable for H-H
and Si-H bond activations) also has considerable
oxophilicity, with the corresponding triarylborane-water
adduct exhibiting much greater Brønsted acidity than water
itself.7 Indeed, the Brønsted acidity of H2O-B(C6F5)3 was
determined by Parkin and co-workers (pKa = 8.4 in MeCN)
to be comparable to HCl (8.5 in MeCN).7a This poses a limit
extended to alkylamines (conjugate acid pKa
≥
16 in MeCN)
due to the irreversible deprotonation of H2O-B(C6F5)3. Thus,
the compatibility of H2O-B(C6F5)3 with bases appear to be
limited to those bases with conjugate acids that have pKa
values
≤
12 (in MeCN). A broader amine scope catalytic
simple
reductive amination methodology using
a
triarylborane is desirable as a one-pot method (thus
preferable from an efficiency perspective) to rapidly access
amines that are ubiquitous functionalities in natural
products, pharmaceuticals and agrochemicals.
To circumvent the limitation of B(C6F5)3 towards
water/strong Brønsted base combinations Lewis acids that
are less oxophilic are required. These could be “hydride
selective” Lewis acids, such as Group 14 based Lewis
acids (which maintain high hydridophilicity but have lower
oxophilicity)11 or Lewis acids that are globally less Lewis
acidic (e.g., less oxophilic and less hydridophilic).12 The
latter approach was utilized by Papai, Soós and co-workers
who employed less Lewis acidic partially halogenated
triarylboranes e.g., (2,3,5,6-C6F4H)2B(2,6-C6H4Cl2), for the
catalytic hydrogenation of carbonyls in ethereal solvents
with some water tolerance demonstrated.6 Taking this
approach further, the non-halogenated triarylborane BPh3
[a]
V. Fasano and Dr. M. J. Ingleson*
School of Chemistry, University of Manchester, Manchester,
M13 9PL, UK.
Michael.ingleson@manchester.ac.uk
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201605466
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should have enhanced tolerance to water and strong base
combinations due to its lower Lewis acidity. BPh3 does
however still possess sufficient hydridophilicity to be useful
major product (by 11B and 19F NMR spectroscopy) as
expected based on relative pKa values. With no observable
deprotonation of H2O-BPh3 with BnNH2 the utility of BPh3 as
a catalyst was explored in the reductive amination of
benzaldehyde (1.0 eq.) with benzylamine (1.2 eq.), under
air using non-purified BPh3, non-purified solvents and silane
as reductant (Table 1). In this reaction, upon imine
formation, water is produced as a by-product, so both
excess (relative to BPh3) water and a good Brønsted base
(BnNH2, used in slight excess to favour imine formation) are
present in the reaction mixture.
as
a
catalyst in FLP type reactions as recently
demonstrated.13-14 While H2O-B(C6F5)3 is well documented,7
the corresponding H2O-BPh3 adduct is less studied,
particularly its ability to act as a Brønsted acid.16-19 Herein
we report an extension to the water and base tolerance of
boranes to strong amine bases, focusing, in particular on
the triarylborane catalysed reductive amination of
aldehydes/ketones with alkylamines using silanes as
reducing agents. This demonstrates that BPh3 is an
effective catalyst for the reductive amination of alkylamines
and carbonyls (Scheme 1C), including examples
challenging to reduce with borohydride salts (e.g.,
[(OAc)3BH]-). Furthermore, B(3,5-Cl2C6H3)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).
Table 1. Initial optimization of BPh3-catalysed reductive amination.
Entry
Solvent
Silane
Equiv.
Silane
1.2
Temp.
(oC)
100
100
100
100
100
60
Yield
(%)a
< 5
33
1
2
o-DCB
MeCN
o-DCB
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
PhMe2SiH
PhMe2SiH
PhMe2SiH
PhMe2SiH
PhMe2SiH
PhMe2SiH
Ph2SiH2
1.2
3
3.5
< 5
87 (80)b
35
4
5c
3.5
3.5
6
3.5
6
7
3.5
100
100
100
100
86
8
Ph2MeSiH
PhMeSiH2
PhSiH3
3.5
8
9
3.5
55
10
3.5
56
Reactions performed in sealed tubes. aYield by 1H NMR spectroscopy vs
mesitylene as internal standard. bIsolated yield. cReaction at 5 mol % catalyst
loading.
For a direct comparison with our previous work using
B(C6F5)3,5 we initially performed the reaction in ortho-
dichlorobenzene (o-DCB) using 1.2 eq. of silane. Under
these conditions imine formation proceeds but no reduction
was observed using 10 % mol BPh3 (entry 1). Okuda and
co-workers reported that BPh3 is a more effective catalyst
for (de)hydrosilylation reactions in polar solvents such as
MeCN or nitromethane.13 Changing the solvent from o-DCB
to MeCN now resulted in the desired product being
obtained in moderate yield. On increasing the amount of
silane from 1.2 to 3.5 eq. dibenzylamine was obtained in
good yield (87% NMR yield and 80% isolated yield). The
requirement for excess silane is due to imine reduction and
H2O/silanol dehydrosilylation occurring concurrently. The
activity of this system is not due to initial consumption of all
H2O by excess silane and then imine reduction proceeding
under anhydrous conditions as indicated by the absence of
any induction period in this reductive amination. This was
further confirmed by analysis of the reaction mixture after 3
hours at 100oC, at which point considerable imine reduction
had occurred (ca. 30 %) but significant water and
PhMe2SiOH were still present.20 Decreasing the catalyst
loading to 5 mol % resulted in a lower yield (entry 5) while
100oC was found to be critical (entry 6). The applicability of
other silanes was then investigated: while Ph2SiH2 was
Scheme 1: Previous work (top and middle): alcohols and anilines tolerated by
fluorinated-triarylborane-water adducts; this work (inset): alkylamines tolerated
by the BPh3-OH2 adduct and both alkyl and arylamine / H2O combinations
tolerated by B(3,5-Cl2C6H3)3.
Results and Discussion
To determine if H2O-BPh3 protonates alkylamines, BnNH2
(conjugate acid pKa = 16.6 in MeCN)8 was added to a
solution of H2O-BPh3 in d3-MeCN. 1H-NMR spectroscopy
showed coordination of BnNH2 to BPh3, as indicated by a
2H integral resonance at 5.3 ppm (for BnNH2) shifted
downfield from free BnNH2 in d3-MeCN (1.5 ppm). Identical
1H NMR resonances are observed for Ph3B-N(H)2Bn
formed under anhydrous conditions in d3-MeCN (for both
δ11B = -1.7 ppm). Coordination of BnNH2 to BPh3 is
reversible at room temperature as addition of benzaldehyde
led to rapid imine formation, thus the absence of any
observable [HO-BPh3]- is attributed to the lower Brønsted
acidity of H2O-BPh3. In contrast, the addition of BnNH2 to
H2O-B(C6F5)3 led to formation of [HO-B(C6F5)3]- as the
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10.1002/chem.201605466
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Table 2. Reductive amination catalysed by BPh3 or B(C6F5)3.
viable in the reductive amination (entry 7), the increase in
the steric hindrance of the silane going from PhMe2SiH to
Ph2MeSiH, resulted in a significant drop in imine reduction
(entry 4 vs 8). When smaller silanes were employed
(entries 9 and 10), dibenzylamine was the major component
among multiple products, including EtNH2 presumably
deriving from MeCN reduction.
Entry
R
Mol %
Catal.
Equiv.
silane
Time
(h)
Yield (%)a
B(C6F5)3
BPh3
8
1
2
3
Ph
Ph
Bn
5
1.2
3.5
3.5
1
96
> 96
< 5
With the compatibility of BnNH2 and H2O-BPh3 mixtures
confirmed by the successful reductive amination of
benzaldehyde and BnNH2, a direct comparison between
B(C6F5)3 and BPh3 was performed. In our previous work we
found that B(C6F5)3 catalysed reductive aminations of
anilines and aldehydes in o-DCB at 100oC, but not the more
basic alkylamines due to irreversible deprotonation of H2O-
B(C6F5)3.5 In order to avoid any disparities arising from the
solvent employed, comparative reductive aminations using
benzaldehyde and aniline or benzylamine with B(C6F5)3 or
BPh3 as catalyst were performed in MeCN (Table 2).
Although the coordination of MeCN to B(C6F5)3 is well
documented,21 the reductive amination of benzaldehyde
and aniline still proceeded to high yield (96%) in 1 h at
100oC on replacing o-DCB with MeCN. As previously
reported 1.2 eq. of silane is sufficient using anilines with
imine reduction occurring preferentially to water
dehydrosilylation. Interestingly, on replacing B(C6F5)3 with
BPh3 under identical conditions minimal (8%) imine
reduction and minimal water dehydrosilylation were
observed after 1 h on heating at 100oC. A similar outcome
was observed using 0.1 eq. BPh3 loading and 3.5 eq. of
silane (entry 2) with a low reductive amination conversion
even after 25 h. In contrast, in the reductive amination of
benzaldehyde/benzylamine under identical conditions the
use of BPh3 results in an excellent conversion whilst
B(C6F5)3 is effectively inactive (entry 3).
10
25
35
10
25
87
Reactions performed in sealed tubes. aYield by 1H NMR spectroscopy vs
mesitylene.
To better understand the disparities between PhNH2 and
BnNH2 in reductive aminations catalysed by BPh3 a number
of control reactions were performed. A solution of BPh3 in
anhydrous MeCN was heated at 100oC sealed under air,
with no significant reaction (e.g., protodeboronation)
observed. However, adding 10 eq. of water to this solution
led to significant protodeboronation after 2 hours at 100oC
(PhB(OH)2, Ph2B(OH) and PhH observed by 1H and 11B
NMR spectroscopy) presumably via an intramolecular
protodeboronation process from H2O-BPh3 as recently
calculated for H2O-B(C6F5)3.23 Having identified that H2O-
BPh3 can undergo protodeboronation to produce
catalytically inactive products the effect of amine basicity on
protodeboronation was investigated. The addition of 10 eq.
of PhNH2 to a solution of H2O-BPh3 (made by mixing 1 eq.
of BPh3 with 10 eq. of water in MeCN to approximate the
catalysis conditions) did not prevent protodeboronation on
heating. Notably, when 10 eq. of the more basic BnNH2 was
added to an identical solution containing H2O-BPh3,
protodeboronation proceeded to a significantly lower extent
1
(by monitoring the appearance of benzene in the H NMR
spectrum and by 11B NMR spectroscopy). Even upon
heating at 100oC for 20 hours (Figure 1) four coordinate
It should be noted that during reductive aminations using
BPh3 as catalyst four coordinate boron species (such as
imine
ꢀ
BPh3 and amine
ꢀ
BPh3) and 11B resonances
LꢀBPh3 compounds were still the dominant species with
BnNH2 in contrast to that with PhNH2.
consistent with Ph2BOH and PhB(OH)2 are all observed.
Importantly, attempts to catalyse the reductive amination of
benzaldehyde / benzylamine with PhB(OH)2, Ph2B(OH) or
Ph3BOH- (whilst not observed the latter is feasibly present
in low concentration through a small degree of H2O-BPh3
deprotonation) in place of BPh3 led to very low conversions
(e.g., ca. 10% using Ph2BOH) after 25 h at 100oC in MeCN.
The use of Brønsted acids such as HCl and HNO3 also
resulted in minimal reductive amination. Combined these
control reactions indicate the importance of the
triarylborane as the catalyst in this process, presumably for
activation of the silane via established (for B(C6F5)3)
mechanistic pathways.22
Figure 1. 11B-NMR spectra of H2O-BPh3 or H2O-BPh3/amine 1:10:10
immediately on mixing (left) and after heating at 100oC for 20 h in d3-MeCN.
Blue (no amine), green (+ PhNH2), red (+ BnNH2).
The disparity between PhNH2 and BnNH2 in reductive
amination catalyzed by BPh3 will be due to different amine
(or imine) basicity, however this will affect a number of
processes, therefore to identify the origin of this disparity a
number of control reactions were performed. The disparity
is not due to the less nucleophilic imine derived from
aniline/benzaldehyde leading to
a significantly greater
barrier to an SN2 type reaction with the R3Si-H-BPh3
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10.1002/chem.201605466
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species. This was confirmed by the fact that under
NMR spectrum at 5.7 ppm for the NH2 group) reacts with
equimolar water as indicated by a drastic shift in the 1H
NMR spectrum to a broad resonance at 2.1 ppm (integral
four for the combined NH2 / OH2 resonance). This suggests
an equilibrium between Ph(H)2N-BPh3 and H2O-BPh3
consistent with the more rapid protodeboronation observed.
The 11B NMR spectra are inconclusive for this system as
H2O-BPh3 and Ph3B-N(H)2Ph have extremely similar
chemical shifts whilst the slow exchange regime is not
reached even at -38oC in d3-MeCN.
anhydrous
conditions
using
catalytic
BPh3
and
stoichiometric PhMe2SiH, N-benzylidene aniline and N-
benzylidene benzylamine were both reduced (Scheme 2,
left). However, under catalytic reductive amination
conditions the key electrophile could be the silylated
iminium cation (if the BPh3 activated silane is directly
attacked by the imine) or the protonated iminium cation (via
imine protonation by [R3Si-OH2][HBPh3] formed from initial
attack by H2O on R3Si-H-BPh3). Although no silylated amine
was observed during reductive amination, the exact nature
of the iminium cation could not be unambiguously defined in
this process due to the fast hydrolysis of silylated amine
under these conditions. Nevertheless, further control
reactions showed that both protonated N-benzylidene
aniline and N-benzylidene benzylamine were reduced by
[HBPh3]- (consistent with Okuda and co-workers report on
imine hydroboration catalyzed by [HBPh3]- 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) this should only result in
longer reaction times being required for complete reductive
amination using PhNH2/benzaldehyde under BPh3
catalysis. However, this is not observed with no further
increase in conversion observed on longer reaction times in
reductive aminations. Combined these observations
indicate that the difference in reactivity is due to more rapid
catalyst decomposition in the presence of PhNH2 relative to
BnNH2 and not any intrinsic barrier to N-benzylidene aniline
reduction.
With the disparity between BnNH2 and PhNH2 in reductive
aminations catalyzed with BPh3 clarified we next
investigated the highly Brønsted basic but less nucleophilic
amine tBuNH2. Significantly, tBuNH2 and PhNH2 have
similar Mayr nucleophilicity values in MeCN (N = 12.35 and
12.64, respectively),25 but the conjugate acid of BuNH2 has
t
a pKa of 18.4. Under standard conditions (3.5 eq. silane, 10
t
mol % BPh3, MeCN) the reductive amination of BuNH2 and
benzaldehyde proceeded to a 93 % conversion after 25 h at
100oC. Again the 11B NMR spectrum after 25 h was
dominated by four coordinate boron species with minimal
PhB(OH)2 and Ph2B(OH) observed. To investigate the
origin of the enhanced stability of BPh3 in the presence of
tBuNH2 the 1H and 11B NMR spectra of BPh3 / tBuNH2 / H2O
mixtures was examined which revealed broad resonances
at 25oC, (e.g., a H resonance at 3.7 ppm) shifted downfield
t
with respect to BuNH2 and H2O-BPh3 (1.3 and 2.6 ppm,
respectively). Cooling this solution to below -10oC resulted
1
t
in the appearance of BuN(H)2-BPh3, however, this was a
minor component (ca. 10%). The major resonance in the 1H
NMR spectrum was still broad with a chemical shift not
consistent with H2O-BPh3 or free tBuNH2, instead it is
assigned as H2O-BPh3 and [HOBPh3][H3NtBu] in fast
exchange a process which was not frozen out at -38oC in
d3-MeCN. Based on these observations feasible key
processes occurring in-situ in the reductive amination
reactions are summarised in Scheme 3.
Scheme 2: N-benzylidene amines reduction.
As BPh3 decomposition most probably proceeds via H2O-
BPh3 (based on its fast protodeboronation) reducing the
concentration of this species in solution should be key to
provide enhanced catalytic activity. At least two scenarios
are feasible for achieving this: (i) the more basic species
(BnNH2 or its derived imine) retards protodeboronation by
deprotonating H2O-BPh3 resulting in a different catalyst
resting state, [HO-BPh3]-, that is more stable to
protodeboronation; (ii) the more nucleophilic amine / imine
(e.g., BnNH2 or its derived imine) forms a Lewis adduct
Scheme 3: Feasible key reactions in reductive amination reaction
mixtures. L.B. = Lewis bases. E1 = H, E2 = R3Si or E1 = R3Si, E2 = H.
LꢀBPh3 which is more stable to protodeboronation than
Ph3B-OH2. Based on the in-situ NMR data for H2O-
BPh3/BnNH2 the latter is more probable as only Bn(H)2N-
BPh3 is observed with no [Ph3B-OH]- detectable. In
contrast, with the less basic/nucleophilic aniline the adduct
Ph(H)2N-BPh3 (which when formed under anhydrous
Upon heating, enough BPh3 is generated from a Lewis
adduct or the hydroxyborate to activate the silane to
nucleophilic attack. Nucleophilic attack leads to the
formation of [HBPh3]- that in turn would reduce the iminium
cation (either silylated or protonated) by hydride transfer
1
conditions has a characteristic integral 2H singlet in the H
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thus regenerating the catalyst. The protodeboronation
pathway deactivates the catalyst, and is a process which
most probably proceeds from H2O-BPh3. The concentration
of this species can be minimized in solution by using
stronger bases/nucleophiles which lead to formation of
compete H2O for reaction with the borohydride, whereas
with less electrophilic imines the rates of water/silanol
dehydrosilylation and iminium cation reduction are
comparable hence excess silane is required. Reductive
amination also proceeded in the presence of a terminal C-C
triple bond without significant reduction of the latter (1i), or
any observable side reactivity e.g., dehydroboration.1d
LBꢀBPh3 or [LB-H][HOBPh3] (LB = amine or imine). It
should be noted that in the presence of both BnNH2 and N-
benzylidene benzylamine BPh3 binds the former
preferentially. As the optimal catalysis conditions uses a
slight excess of amine the continued presence of free
amine presumably helps reduce the quantity of H2O-BPh3
present and thus limit protodeboronation.
When
aliphatic
aldehydes
(n-butyraldehyde
and
propionaldehyde) were used, full consumption of the in-situ
formed imine was observed, but the desired product was
only a minor component due to over-alkylation to the
tertiary amine or enamine isomerization reactions, as
reported for B(C6F5)3.5 However, when ketones were
utilised, the reaction was successful, allowing a secondary
carbon centre to be attached to the nitrogen (1j-k). Notably,
the reductive amination of acetophenone and benzylamine
is challenging with widely used reducing agents e.g.,
Na[triacetoxyborohydride] (Na[(OAc)3BH], 55 % yield after
10 days),26 in contrast using BPh3/silane 1j is produced
higher yield in shorter reaction times. The reductive
amination of 1-acetyl-1-cyclohexene and morpholine to
yield 1l is also challenging using [(OAc)3BH]- (only 10 %
yield after 4 days),26 but it proceeds to 87 % yield using
BPh3/silane. This demonstrates that the BPh3 catalysed
process is applicable to systems where established
borohydride reductive amination approaches struggle.
Furthermore, the formation of 1l shows the compatibility of
this methodology with C-C double bonds. The inclusion of
With an understanding of the limitations of using BPh3
for catalytic reductive amination, the substrate scope was
then explored with the reactions performed under air, using
non-purified solvent and reactants with everything
combined at the start in an operationally simple process
(Table 3).
Table 3. Substrates screening of the reductive amination.
n
substituents on benzylamine, as well as the use of BuNH2
as another C-primary amine, was also realized (e.g. 1m-o),
although using the latter amine over-alkylation also
occurred to some extent (e.g. forming nBu2NBn). C-
secondary amines, such as cyclo-hexylamine and
t
isopropylamine, or a C-tertiary amine BuNH2, gave good
conversions to the desired products (1p-r). It is noteworthy
that a common product could be formed from a different
combination of aldehyde/amine (e.g. 1k and 1p), offering
two retrosynthetic strategies. Finally, when a secondary
amine such as BnN(H)Me was used in combination with an
enolizable ketone the reaction still proceeds successfully to
form 1s in excellent yield. It should be emphasized that
these amines are not accessible by reductive amination
using B(C6F5)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, using 10 mol % of
unpurified BPh3 in non-purified acetonitrile and using
PhMe2SiH as reductant (Scheme 4). Combining all the
reactants at the start and heating the reaction mixture at
100oC for 25 hours enabled the desired product to be
isolated in a 90 % isolated yield (1.1 g).
a
Reactions performed in sealed tubes.
b Isolated yield. c 48 h. d 40 h. e 30 h.
1H-NMR yields vs mesitylene.
A range of functionalized benzaldehydes were amenable
in the reductive amination with benzylamine, with good in-
situ conversions and 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, the reaction was less tolerant to nitro substituents
(due to trans-imination and formation of dibenzylamine
observed as the major by-product). It is noteworthy that
when EWGs are present in the para position of
benzaldehyde (e.g. –CO2Me or -CN), minimal siloxane (and
silanol) were observed after 25 h (by 1H and 29Si NMR
spectroscopy), with significant reduction of the imine still
occurring. Furthermore > 50 % imine reduction to 1f was
observed with only 1.2 eq. of silane after 25 h. This
indicates that more electrophilic imines effectively out
Scheme 4: Gram-scale synthesis of N-benzyl-1-adamantylamine
.
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The results discussed above indicate that B(C6F5)3 and
BPh3 have complementary tolerance to water / amine
combinations in reductive aminations (Figure 2). B(C6F5)3 is
a viable catalyst for aryl amines (conjugate acids pKa < 12
in MeCN) but not alkylamines (conjugate acids pKa > 16 in
MeCN) due to irreversible deprotonation of H2O-B(C6F5)3
with the latter. In contrast, BPh3 is a viable reductive
amination catalyst for alkylamines but not arylamines due to
more rapid protodeboronation in the presence of the latter.
We were thus interested in exploring an amine with an
intermediate pKa, specifically the reductive amination of
benzaldehyde and benzhydrylamine (conjugate acid pKa 15
in MeCN)27 was performed with both these boranes using
acids to release BPh3 compounds.28 Furthermore, we
recently observed decomposition of Na[B(3,5-Cl2C6H3)4]
(termed Na[BArCl] herein) in wet solvents on heating. To
confirm that Na[BArCl] decomposition by protonolysis
generates B(3,5-Cl2C6H3)3 species the strong Brønsted acid
HNTf2 was added to NaBArCl. This resulted in the
appearance of a major new resonance at 67 ppm in the 11B
NMR spectrum assigned as B(3,5-Cl2C6H3)3, with this
chemical
shift
consistent
with
other
reported
tri(chloroaryl)boranes.29 Applying this in-situ B(3,5-Cl2C6H3)3
generation procedure (using an excess of Na[BArCl]
relative to HNTf2 to preclude any trace Brønsted acid
remaining as strong Brønsted acids can also activate Si-H
bonds)30 B(3,5-Cl2C6H3)3 catalyzed the reductive amination
of benzaldehyde and benzhydrylamine to give the desired
product in good yield (Scheme 5). The use of both B(C6F5)3
and BPh3 as catalysts under these conditions gave low
conversions.
10 mol
% catalyst loading. In all cases the in-situ
conversions were only moderate at best (less than 30%)
under a range of conditions with both boranes (e.g., in
MeCN or o-DCB at 100oC), indicating that an amine whose
conjugate acid has a pKa between 12 - 16 is particularly
challenging for both boranes. Again in-situ analysis
revealed that with BPh3 significant protodeboronation
proceeded upon heating (by 11B NMR spectroscopy), whilst
with B(C6F5)3 the deactivation was due to the effectively
irreversible deprotonation of H2O-B(C6F5)3 (by 11B / 19F
NMR spectroscopy).
Scheme 5. Reductive amination with benzaldehyde and benzylhydryl-
amine using B(C6F5)3, BPh3 or B(3,5-C6H3Cl2)3 (generated in situ) as
catalyst.
Seeking
an
operationally
simpler process
the
decomposition of Na[BArCl] by action of H2O was
investigated as a route to generate B(3,5-Cl2C6H3)3 in-
situ.31,
32
This approach was successful for the catalytic
reductive amination of benzhydrylamine and benzaldehyde
using 10 mol% Na[BArCl] in o-DCB (Scheme 6) with all
manipulations performed in air using non-purified
solvent/reagents. Weakly coordinating solvents are
essential as attempts using MeCN as solvent led to no
reductive amination. The solvent dependency is attributed
to the formation of [(H2O)xNa]+ species in o-DCB which
have enhanced Brønsted acidity (relative to H2O) and are
thus key to effecting anion protodeboronation and
generation of the triarylborane, as previously discussed for
NaBPh4.28 In contrast in MeCN the solvent is presumably
solvating the Na cations, resulting in a less Brønsted acidic
solution and no anion protodeboronation.
Figure
2: Water/amine tolerance of B(C6F5)3 and BPh3 under the
reductive amination reaction conditions.
Given the respective limitations of B(C6F5)3 and BPh3
a
single triarylborane that is a viable catalyst for the reductive
amination of both aryl and alkyl amines (including
benzhydrylamine) was targeted. To have a broad amine
scope the triarylborane must form a H2O-BAryl3 adduct that
is both more resistant to protodeboronation than H2O-BPh3
and less Brønsted acidic than H2O-B(C6F5)3. Furthermore, a
triarylborane that does not contain ortho halogen aryl
substituents is desirable as ortho substituents increase the
steric bulk around boron and thus can significantly hinder
amine/imine coordination to boron.12 The latter is actually
desired in this process as it reduces the concentration of
With an in-situ catalyst generation protocol in hand a
brief amine substrate scope exploration was undertaken.
Most notably, the triarylborane derived in-situ from
Na[BArCl] was able to catalyze the reductive amination of
benzaldehyde with PhNH2, BnNH2 and tBuNH2 amines
whose conjugates acids span the pKa range from 10.6 to
18.4 in MeCN. This indicates a reduced acidity of the
corresponding H2O-B(3,5-Cl2C6H3)3 adduct (relative to that
of H2O-B(C6F5)3) and an improved stability of B(3,5-
Cl2C6H3)3 species to protodeboronation (relative to BPh3).
The amount of silane required for good conversion to the
reductive amination product was explored and again found
to depend on the imine electrophilicity, with the more
electrophilic imine (derived from aniline) reduced using only
H2O-BAryl3
in
solution
thus
also
helps
limits
protodeboronation. Given these requisites B(3,5-Cl2C6H3)3
was selected and its synthesis via the protolytic
decomposition of its tetraarylborate salt was utilized as the
borate salt is air and moisture stable as a solid in contrast
to the free triarylboranes (see subsequent discussion).
Tetraarylborate anion decomposition has significant
precedence for [BPh4]- salts which react with Brønsted
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10.1002/chem.201605466
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1.2 eq. of silane, whilst the less electrophilic imines again
required an excess of silane due to competitive
dehydrosilylation reactions.
H2O-B(C6F5)3 undergoing irreversible deprotonation by stronger
Brønsted basic amines such as alkylamines. Finally, a third
triarylborane, B(3,5-Cl2C6H3)3, of intermediate Lewis acidity,
was shown to be effective for the reductive amination of a
range of amines whose conjugate acids span pKa values of
10.6 to 18.5 in MeCN. Furthermore, in-situ tetraarylborate
anion decomposition by H2O in non-coordinating solvents
represents
a
simple route to generate the active
triarylborane catalyst from a readily accessible bench stable
precursor. The reductive amination methodologies presented
herein are operationally simple (e.g. no purification of any
materials / solvent is required and the reactions are performed
under air) and are applicable to gram-scale and complex
molecule synthesis.
Scheme 6: Reductive aminations under air employing Na[BArCl] as precursor
catalyst.
The ability to use Na[BArCl] as a precursor to the active
triarylborane catalyst has practical advantages since it is
readily synthesized and is bench stable for at least 6
months. In contrast, whilst BPh3 is commercially available
its storage as a solid under ambient atmosphere leads to
gradual decomposition (even after only 14 days significant
PhB(OH)2 and Ph2B(OH) are observed by 11B NMR
spectroscopy). This negatively impacts conversion; for
example using pristine BPh3 gives 87% conversion of
benzaldehyde and benzylamine to the reductive amination
product whereas the same batch of BPh3 stored as a solid
in air for 2 weeks results in only 52 % conversion when
used as the catalyst under otherwise identical conditions. In
contrast, Na[BArCl] stored as a solid for 6 months in air
shows no deterioration in reductive amination catalytic
activity. Thus Na[BArCl] is a useful 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.
Acknowledgements
This work was made possible by financial support from the
University of Manchester, the EPSRC (EP/M023346/1 and
EP/K03099X/1), and the Royal Society (for the award of a
University Research Fellowship). Additional research data
supporting this publication are available as supplementary
information accompanying this publication. Dr Alex Pulis is
thanked for useful discussions.
Keywords: “frustrated Lewis pairs” • water tolerance • reductive
amination • protodeboronation • boron
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10.1002/chem.201605466
Chemistry - A European Journal
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Entry for the Table of Contents
FULL PAPER
“Basically” different: BPh3 has a higher tolerance
to H2O and alkylamine combinations than
B(C6F5)3, due to the lower Brønsted acidity of H2O-
BPh3. This extends the water/base tolerance of
FLP systems to strong bases (conjugate acid pKa
= 18.5). With weaker amine bases H2O-BPh3
undergoes proto-deboronation. B(3,5-Cl2C6H3)3, a
borane of intermediate Lewis acidity, was shown to
be effective for the reductive amination of a range
of amines whose conjugate acids span pKa values
of 10.6 to 18.5 in MeCN.
V. Fasano and M. J. Ingleson*
Page No. – Page No.
Expanding Water/Base Tolerant
FLP Chemistry to Alkylamines
Enables Broad Scope Reductive
Aminations
Irreversible
deprotonation
of H2O-B(C6F5)3
Protodeboronation
of BPh3 species
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