B(C6F5)3-Catalyzed Reductive Amination using Hydrosilanes

Article abstract of DOI:10.1021/acscatal.5b02896

In contrast to the established dogma that B(C₆F₅)₃ is irreversibly poisoned by excess H₂O/amine (or imine) bases, B(C₆F₅)₃ is actually a water-tolerant catalyst for the reductive amination of primary and secondary arylamines with aldehydes and ketones in "wet solvents" at raised temperatures and using only 1.2 equiv of Me₂PhSiH as reductant. Arylamines/N-arylimines do not result in the irreversible deprotonation of H₂O-B(C₆F₅)₃, allowing sufficient B(C₆F₅)₃ to be evolved at raised temperatures to effect catalytic reductions. Stronger Br?nsted basic amines such as ^tBuNH₂ (and derived imines) result in irreversible formation of [HO-B(C₆F₅)₃]^- from H₂O-B(C₆F₅)₃, precluding the formation of B(C₆F₅)₃ at raised temperatures and thus preventing any imine reduction. A substrate scope exploration using 1 mol % nonpurified B(C₆F₅)₃ and "wet solvents" demonstrates that this is an operationally simple and effective methodology for the production of secondary and tertiary arylamines in high yield, with imine reduction proceeding in preference to other possible reactions catalyzed by B(C₆F₅)₃, including the dehydrosilylation of H₂O and the reduction of carbonyl moieties (e.g., esters).

Full text of DOI:10.1021/acscatal.5b02896

Subscriber access provided by ORTA DOGU TEKNIK UNIVERSITESI KUTUPHANESI
Article
B(C6F5)3 Catalyzed Reductive Amination Using Hydrosilanes
Valerio Fasano, James E Radcliffe, and Michael James Ingleson
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.5b02896 • Publication Date (Web): 03 Feb 2016
Downloaded from http://pubs.acs.org on February 10, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
ACS Catalysis is published by the American Chemical Society. 1155 Sixteenth
Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 6
ACS Catalysis
1
2
3
4
5
6
7
8
9
B(C6F5)3 Catalyzed Reductive Amination Using Hydrosilanes
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Valerio Fasano, James E. Radcliffe, Michael J. Ingleson*
School of Chemistry, University of Manchester, Manchester, M13 9PL, United Kingdom
ABSTRACT: In contrast to the established dogma that B(C6F5)3 is irreversibly poisoned by excess H2O / amine (or imine)
bases B(C6F5)3 is actually a water tolerant catalyst for the reductive amination of primary and secondary arylamines with
aldehydes and ketones in “wet solvents” at raised temperatures
and using only 1.2 equivalents of Me2PhSiH as reductant. Ar-
ylamines / N-arylimines do not result in the irreversible depro-
tonation of H2O-B(C6F5)3 allowing sufficient B(C6F5)3 to be
evolved at raised temperatures to effect catalytic reductions.
t
Stronger Brønsted basic amines such as BuNH2 (and derived
imines) result in irreversible formation of [HO-B(C6F5)3]- from H2O-B(C6F5)3, precluding the formation of B(C6F5)3 at
raised temperatures and thus preventing any imine reduction. A substrate scope exploration using 1 mol% non-purified
B(C6F5)3 and “wet solvents” demonstrate that this is an operationally simple and effective methodology for the production
of secondary and tertiary arylamines in high yield, with imine reduction proceeding in preference to other possible reac-
tions catalyzed by B(C6F5)3 including the dehydrosilylation of H2O and the reduction of carbonyl moieties (e.g., esters).
KEYWORDS: “frustrated Lewis pairs”, water tolerance, reductive amination, metal-free, amines
Catalyst tolerance to H2O is essential for reductive
aminations as imine (or enamine) formation produces an
1. INTRODUCTION
The past decade has witnessed spectacular advances in
metal-free catalytic reductions, particularly using “frus-
trated Lewis pairs” (FLPs).1 Numerous advances built on
the pioneering work of Piers (using hydrosilanes)2 and
Stephan (using H2)3 have led to B(C6F5)3, 1, being estab-
lished as a versatile reduction catalyst.1,4 Whilst 1 and its
derivatives are effective metal-free catalysts for the reduc-
equivalent of H2O. However, borane Lewis acids such as 1
are highly oxophilic10 and readily bind water which leads
to a significant enhancement in its Brønsted acidity.11 In
the presence of an appropriate Brønsted base 1-OH2 un-
dergoes deprotonation to form [1-OH]- which is catalyti-
cally inactive. In recent notable work water (and alcohol)
tolerant reductions catalyzed by 1 (and derivatives) have
been reported. However, to date these processes are lim-
ited to the reduction of weak Brønsted bases (relative to
imines/amines) such as carbonyl moieties to alcohols.12
Water tolerant reductions of systems containing more
Brønsted basic functional groups (e.g., anilines) catalyzed
by 1 have not been reported due to the perception that
irreversible deprotonation of 1-OH2 would occur poison-
ing the catalyst.12 Herein we report that B(C6F5)3 is toler-
ant of excess water / arylamines functioning as an effec-
tive catalyst for the reductive amination of a range of ar-
ylamines using only 1.2 equivalents of silane as reductant.
2d,
4
tion of imines,1,
including enantioselective variants,5
these procedures require prior synthesis and isolation of
the imine and rigorous exclusion of H2O in the subse-
quent reduction process. The latter necessitates anhy-
drous solvents and inert conditions, or the in-situ removal
of low levels of H2O from “wet” solvents/reagents using
sacrificial hydrides or molecular sieves (Scheme 1, right).6
These requirements have limited the wider uptake of 1 as
a catalyst and also prevents the use of 1 as a catalyst for
reductive amination where the imine is formed (along
with an equivalent of H2O) and reduced in-situ. Reductive
amination is a one-pot method thus preferable from an
efficiency perspective and facilitates rapid access to
amines that are ubiquitous functionalities in natural
products, pharmaceuticals and agrochemicals (such as
Imatinib).7 Whilst transition metal catalysts have been
used for reductive aminations,8 a metal-free FLP catalyzed
process using H2 or Si-H as reductant has limited prece-
dence; to the best of our knowledge only one example
using 1 has been reported in which aniline/ hexanal for-
mally undergo reductive amination to afford the amine in
moderate (42 %) conversion. However, this process uses
five Si-H equivalents, presumably effecting H2O dehy-
drosilylation and generating anhydrous conditions.9
SCHEME 1: B(C6F5)3 catalyzed reductive amination (left)
and hydrosilylation of purified imine (right).
ACS Paragon Plus Environment

ACS Catalysis
Page 2 of 6
1
2
3
4
5
6
7
8
9
In a control reaction containing PhNH2 but in the ab-
2. RESULTS
sence of benzaldehyde (precluding imine formation) the
dehydrosilylation of H2O in o-DCB catalyzed by 1 does
proceed at 100oC. Nevertheless, in these reductive amina-
tions 1.2 equiv. of Me2PhSiH is sufficient for imine reduc-
tion, indicating imine reduction is kinetically favored over
the dehydrosilylation of H2O. Attempts to replace the
hydrosilane reductant with H2 (ca. 4 atm.) under identical
reductive amination conditions failed to produce any
amine (entry 9). However, as the reduction of isolated
benzylideneaniline with 5 mol% purified 1 and ca. 4 atm.
H2 in anhydrous o-DCB was found to be extremely slow
and low yielding at 100oC α-methylbenzylideneaniline
was utilized as an alternative test substrate. Under anhy-
drous conditions this imine is reduced in good conversion
using 10 mol% purified 1 and ca. 4 atm. H2 (> 95% after 48
h at 100oC). In contrast, combining acetophenone and
aniline with 10 mol% 1 under ca. 4 atm. H2 and heating for
As part of our ongoing investigations into water toler-
ant carbon Lewis acids in FLPs a control reaction combin-
ing 5 mol% 1, 1 equiv. of benzaldehyde and 1.2 equiv. of
both aniline and Me2PhSiH in ortho-dichlorobenzene (o-
DCB) was investigated. Me2PhSiH was used for direct
comparison to the previously reported hydrosilylation of
N-benzylideneaniline under anhydrous conditions.2d At
20oC there was significant imine formation (> 90 %) but
no reductive amination and no consumption of the silane,
indicating 1 is effectively poisoned (Table 1, entry 1). How-
ever, heating led to formation of the reduced product, N-
benzylaniline, in good conversion. Subsequently, the re-
ductive amination was found to proceed efficiently using
non-purified (“wet”) o-DCB and non-purified 1 under am-
bient atmosphere at raised temperatures (Table 1 entries 2
and 3). Analogous reductive amination reactivity was ob-
served when repeating the reaction in “wet” CH2Cl2 (entry
4), “wet” THF (entry 5) and “wet” cyclopentyl methyl
ether (CPME) (entry 6) even with only 1 mol% of non-
purified 1 under ambient conditions (entry 7). Whilst
CPME is a more attractive solvent from a green chemistry
perspective13 o-DCB was utilized hereon as it facilitates in-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
24 hours at 100oC led to no reductive amination (by H
NMR spectroscopy). The analogous reductive amination
of acetophenone and aniline using 1 mol% 1 and 1.2 equiv.
Me2PhSiH as reductant proceeded rapidly to give the de-
sired amine (entry 11). The disparity between H2 and
Me2PhSiH reactions is attributed to kinetic factors as sim-
ilar 19F NMR spectra are observed (see SI) indicating that 1
is not irreversibly poisoned in either case (consistent with
hydrosilylation being rapid under anhydrous conditions
whilst hydrogenation with ca. 4 atm. H2 is slow even in
the absence of H2O). A drastic rate retardation by 20
equiv. of H2O with respect to 1 was also observed in the
recently reported water tolerant carbonyl hydrogena-
tion.12c Borane 1 is essential as whilst 1-OH2 forms readily
in wet solvents and has a pKa similar to HCl,11 the use of a
range of strong Brønsted acids (including H2SO4, HNO3,
HCl and CF3COOH, with the latter previously used to
promote hydrosilane reductions of C=O)14 as catalysts at 5
mol% loading led to no reductive amination of benzalde-
hyde/aniline/Me2PhSiH mixtures on heating to 100oc (20
h). The ability of 1 to catalyze reductive aminations ex-
pands the limited list of examples where B(C6F5)3 can be
used for σ-bond activation in the presence of excess H2O
/ base mixtures to moderately basic arylamines and N-
arylimines.12 Although it is significant that more basic
1
situ monitoring of the aliphatic region of the H NMR
spectra enabling rapid substrate screening. The catalyzed
reductive amination is proceeding in the presence of > 100
equiv. H2O (relative to B(C6F5)3 due to the presence of
H2O from the condensation reaction and from the “wet”
solvent”) as only 1.2 equiv. of Me2PhSiH is utilized, insuf-
ficient to both dry the reaction mixture (by dehydrosilyla-
tion of H2O) and reduce the imine.
Table 1. Reductive amination catalyzed by B(C6F5)3a
R
Solvent Temp
(oC)a
Time B(C6F5)3
Yield
(%)b
(h)
(mol %)
1
2
H
H
o-DCB
o-DCB
o-DCB
CH2Cl2
THF
20
60
20
2
5
5
5
5
5
5
1
0
52
94
80
90
96
95
90
0
t
amines, e.g., BuNH2 do not undergo reductive amination
3
H
100
60
0.25
2
catalyzed by 1 using Me2PhSiH under identical conditions.
4
H
To provide more insight, particularly into the amine
disparity the model reaction was analyzed at each stage
by 1H, 19F and 11B NMR spectroscopy (Fig. 1). This was per-
formed with 5 mol% 1 (see SI) and stoichiometric 1 (to
facilitate observation of 11B resonances). The 19F NMR
spectra for both loadings of 1 reveal the same major spe-
cies are present at each stage, albeit with the resonances
for 1-OH2 shifting depending on the ratio of 1 : H2O as
previously reported.11 On combination of equimolar ani-
line and 1-OH2 in “wet” o-DCB two compounds are ob-
served; 1-NH2Ph and [1-OH]- (Fig. 1, spectrum b). A
change in their relative ratio is then observed on addition
of 1 eq. of benzaldehyde, with [1-OH]- increasing (spec-
trum c). At this point significant N-benzylideneaniline is
5c
H
80
1.5
0.5
1
6
H
CPME
CPME
o-DCB
o-DCB
o-DCB
o-DCB
100
100
100
100
100
100
7
H
8
H
0.5
24
24
1.5
1
9d
10d
11
H
5
5
1
Me
Me
0
64
a = reactions run in sealed tubes under ambient atmosphere
using “wet” solvents and non-purified 1. b = conversion by 1H
NMR spectroscopy Vs. mesitylene as internal standard c =
0.95 eq. of Me2PhSiH. d = ca. 4 atm. H2 as reductant.
ACS Paragon Plus Environment

Page 3 of 6
ACS Catalysis
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Figure 1. 19F NMR spectra in wet o-DCB (with a capillary
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. 19F NMR spectra in wet o-DCB (with a capillary
insert of d6-DMSO) of the in-situ reaction mixture showing
a) 1 eq. B(C6F5)3.xH2O b) + 1 eq. aniline c) + 1 eq. benzalde-
hyde d) heated at 100oC for 18 h e) + 1.2 eq. Me2PhSiH after
heating to 100oC for 2 hr.
insert of d6-DMSO) of the in-situ reaction mixture showing
t
a) 1 eq. B(C6F5)3.xH2O + 1 eq. BuNH2 b) + 1 eq. benzaldehyde
c) heated at 100oC for 2 h d) + 1.2 eq. Me2PhSiH after heating
to 100oC for 2 hr.
1
observed in the H NMR spectrum indicating a reduction
at 100oC for 24 hours (there is no consumption of silane
by 29Si NMR spectroscopy). This confirms that [1-OH]-
does not react with Me2PhSiH at raised temperatures. The
effective poisoning of catalyst 1 is further indicated by the
imine free reaction where mixtures of 1-OH2 / tBuNH2 /
Me2PhSiH in “wet” o-DCB do not lead to H2O dehydrosi-
lylation or consumption of any silane even on prolonged
heating at 100oC. Dehydrosilylation therefore does not
proceed in the presence of stoichiometric tBuNH2 whereas
in the concentration of aniline and an increase in that of
H2O consistent with the observed change in the 1-NH2Ph
: [1-OH]- ratio. It should be noted that coordination of N-
benzylideneaniline to 1 is not observed at any point
throughout this reaction sequence. Anion [1-OH]- corre-
11
sponds to an B resonance at -4.8 ppm (observed in the
stoichiometric in 1 reaction), significantly upfield from 1-
15
OH2 (δ11B +4.6 ppm in difluorobenzene),12d,
whilst 1-
NH2Ph has a δ11B = -6.4 ppm (See SI). Aniline dissociates
rapidly from 1 at room temperature (confirmed by the
addition of benzaldehyde to 1-NH2Ph leading to rapid
imine formation), therefore the persistence of 1-NH2Ph in
the reaction mixture is not due to kinetic factors. A con-
clusion further supported by heating the reaction mixture
to 100oC for 18 h (spectrum d) which led to changes in the
ratio of 1-NH2Ph and [1-OH]- along with slow formation
of C6F5H (by 19F NMR spectroscopy), crucially significant
amounts of 1-NH2Ph and [1-OH]- both remained after
heating. The addition of Me2PhSiH to the reaction mix-
ture and further heating then resulted in imine reduction
(by 1H NMR spectroscopy). The activity observed in these
sequential reactions at both 100 and 5 mol% loadings is
attributed to 1-NH2Ph or [1-OH]- (after protonation to
form 1-OH2) releasing a critical concentration of the ac-
tive catalyst 1 at raised temperatures.
t
it does in the presence of PhNH2. Heating the BuNH2
containing reaction mixture to 100oC only leads to de-
composition of [1-OH]- to C6F5H and unidentified boron
species. The reactivity disparity is attributed to the great-
t
er Brønsted basicity of BuNH2 / benzylidene-tbutylamine
relative to aniline which does not irreversibly deprotonate
1-OH2 (scheme 2, left). Reversible deprotonation of 1-OH2
is essential for catalytic activity as it enables the release of
sufficient 1 at raised temperatures (from 1-OH2 or 1-
NH2Ph). These observations are related to the recent re-
ports on water tolerant carbonyl hydrogenation using 1
and weakly basic conditions where the key factor is also
the deprotonation of 1-OH2 being reversible.12
Previously, N-benzylidene-tbutylamine has been hy-
drosilylated using catalytic 1 and Me2PhSiH under anhy-
drous conditions.2d Attempting the reductive amination
t
of BuNH2 and benzaldehyde with 1-OH2 / Me2PhSiH re-
sulted in no reduction under a range of conditions. Exam-
ination of the 19F NMR spectrum of 1/tBuNH2 mixtures in
“wet” o-DCB (Fig. 2 spectrum a) revealed that [1-OH]- was
the major C6F5 containing species observable (with and
without benzaldehyde, Fig. 2 spectrum b) and after heat-
ing to 100oC became the only B(C6F5)3 containing species
observable (Fig. 2 spectrum c). Significant N-benzylidene-
SCHEME 2: Disparate equilibrium positions on combin-
ing aniline or tbutylamine with benzaldehyde and 1 in wet
o-DCB.
It is noteworthy that the basicity and the nucleophilic-
ity of the amine are both important. The conjugate acids
1
tbutylamine was observed in the H NMR spectrum con-
n
of BuNH2 and tBuNH2 have similar pKa values (10.59 and
firming imine formation. Under these conditions [1-OH]-
forms effectively irreversibly as indicated by the absence
of imine reduction on addition of Me2PhSiH and heating
10.55, respectively),16 and their respective imines will be of
similar Brønsted basicity to each other, yet these two
amines result in different outcomes. On combination of 1,
nBuNH2 and benzaldehyde 1-nBuN=C(H)Ph is the major
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 6
1
2
3
4
5
6
7
8
9
product observed by NMR spectroscopy. This is not a ki-
bined at the start), compatibility with green solvents
netic product as adding nBuNH2 / benzaldehyde to 1-OH2
initially forms predominantly [1-OH]- but subsequent
heating to 100oC produces mixtures containing predomi-
nantly 1-nBuN=C(H)Ph (along with C6F5H). The lower
(CPME) and the low catalyst loading. With the require-
ments for reductive amination in hand the scope of this
process catalyzed by 1 mol% non-purified 1 and using 1.2
eq. of Me2PhSiH in wet o-DCB was explored (Table 2).
n
t
steric bulk of butyl relative to butyl presumably makes
the dative bond in 1-nBuN=C(H)Ph stronger and thus
alters the relative energetics, the equilibrium position and
thus the species observed post heating to 100oC. Irrespec-
tive of this, nBuNH2/benzaldehyde mixtures do not un-
dergo reductive amination catalyzed by 1 (or 1-OH2). This
is attributed to N-benzylidene-nbutylamine coordinating
strongly to 1 (19F resonances for 1-nBuN=C(H)Ph persist
on prolonged heating in the presence of Me2PhSiH). This
observation is consistent with previous reports in which 1
does not catalyze the hydrosilylation of the sterically
similar imine benzylidene-methylamine under anhydrous
conditions due to its strong coordination to 1.2d
Table 2: Reductive amination substrate scope
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
These NMR spectroscopic studies allow the key re-
quirements for successful reductive amination using 1 /
Me2PhSiH at raised temperatures to be defined as: (i) the
amine and corresponding imine need to be of sufficiently
low Brønsted basicity to reversibly deprotonate 1-OH2
and (ii) the amine and imine need to be of sufficiently low
nucleophilicity to reversibly bind to 1. When these re-
quirements are fulfilled a critical concentration of 1 is
present at high temperatures to activate the silane to nu-
cleophilic attack as previously elucidated.2e-g, 17 The nucle-
ophile attacking R3Si-H-B(C6F5)3 may be an imine or H2O,
the latter forming [Me2PhSi-OH2][H-1] which could then
protonate the imine. The silylated or protonated iminium
cation would then be reduced by hydride transfer from [1-
H]- (Scheme 3). Attempts to observe intermediates (e.g.,
silylated iminium cations or silylated amines) at a range
of temperatures were not successful as the hydrolysis of
Me2PhSi-protected amines is rapid under these conditions
even at 20oC; thus either mechanism could be operating
at 100oC (scheme 3). The expected silicon by-products,
Me2PhSiOH and (PhMe2Si)2O are observed by 29Si NMR
spectroscopy. Attempts to observe a silylated intermedi-
ate with bulkier silanes, for example Ph3SiH, were also
unsuccessful. Furthermore, hydrolysis of N-SiPh3 substi-
tuted amines also occurs more rapidly than the reductive
amination reaction using Ph3SiH under these conditions.
1
a = yield calculated by H NMR spectroscopy using mesity-
lene as an internal standard. b = 1.5 h. c = isolated yield. d =
20 h.
A range of functionalized benzaldehydes were com-
patible (2a – 2f) with in-situ conversions and isolated
yields (e.g., 2d) moderate to good. Diaryl, aryl-alkyl and
dialkyl ketones (2g - 2i) were amenable to reductive ami-
nation. However, acetaldehyde and butyraldehyde pro-
duced complex mixtures in which the desired product
was only a minor component. The inclusion of electron
withdrawing and electron donating substituents on the
aromatic aldehyde and the aniline was also realized (e.g.,
2j -2m). It is notable that the more Brønsted basic and
nucleophilic p-methoxyaniline (PMP) was viable in reduc-
tive amination under these conditions, albeit requiring 1.5
h. The longer reaction time is attributable to a lower con-
centration of catalyst 1 at raised temperatures, with in-situ
19F NMR spectroscopy revealing a higher proportion of [1-
SCHEME 3: Proposed reductive amination pathways.
Despite being slower than the reduction of isolated N-
benzylideneaniline under anhydrous conditions,2d
B(C6F5)3 catalyzed reductive amination is attractive due to
the simplicity of the procedure (all reactants are used as
received without any additional purification and com-
ACS Paragon Plus Environment

Page 5 of 6
ACS Catalysis
1
2
3
OH]- (relative to 1-NH2Aryl) for p-methoxyaniline com-
mines (and their derived imines) do not irreversibly
deprotonate H2O-B(C6F5)3 and do not form strong dative
bonds to B(C6F5)3, two outcomes that would otherwise
preclude catalysis. This operationally simple reductive
amination methodology represents a rare example of
B(C6F5)3 being effective for σ-bond activation in the pres-
ence of (super) stoichiometric H2O and moderate
Brønsted bases. Furthermore, it extends significantly the
Lewis bases compatible with H2O-B(C6F5)3 (i.e. that form
[HO-B(C6F5)3]- reversibly) to arylamines, N-arylimines,
quinolines and PMes3.
4
5
6
7
8
9
pared to that observed for aniline (pre-heating). This is
consistent with the greater Brønsted basicity of PMP.
Compatibility with PMP is significant as it generates a
masked N-H moiety which can be readily deprotected to
provide access to the parent primary amine. The reduc-
tive amination of
a secondary arylamine also was
achieved, with in-situ enamine formation and reduction
proceeding in good yield (2o). Nitro groups on the aryla-
mine are also amenable (2p) but in lower yield due to an
imine formation equilibrium position favoring benzalde-
hyde (significant carbonyl reduction is observed). We also
explored functional groups that may interfere with reduc-
tive amination catalyzed by 1. This revealed that reductive
amination proceeds in preference to ester hydrosilylation
(2q)2 and that exogenous base (in the form of a substitut-
ed quinoline) is compatible (2r). It should be noted that
the formation of 2r required 20 h at 100oc with the addi-
tional Brønsted base shifting the equilibrium position
towards [1-OH]- thereby reducing the quantity of 1 pre-
sent at high temperature.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ASSOCIATED CONTENT
Supporting Information. Full experimental details and
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* Michael J. Ingleson
Michael.ingleson@manchester.ac.uk
To probe further the effect of exogenous base on the
reductive amination methodology an equivalent of PMes3
was added as a non-nucleophilic base to the reaction of /
PhNH2 / benzaldehyde / Me2PhSiH catalyzed by 5 mol %
1. This resulted in a drastic change to the 19F NMR spec-
trum pre-heating (relative to the PMes3 free reaction)
with only [1-OH]- observed ([HPMes3]+ is also observed in
the 31P NMR spectrum). Nevertheless, on heating this
mixture to 100oC reductive amination still proceeds, albeit
slowly, indicating that the protonation of [1-OH]- by
[HPMes3]+ also proceeds under these conditions to gener-
ate 1-OH2 and subsequently catalytically active 1.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version
of the manuscript.
Funding Sources
The University of Manchester
The EPSRC (EP/M023346/1 and EP/K03099X/1)
The Royal Society.
ACKNOWLEDGMENT
Finally, the scope of the methodology was further ex-
tended to form biologically important N-substituted iso-
indolinones starting from 2-carboxybenzaldehyde and
aniline.18 This process involves an amination / amidation
sequence and was successful on a gram scale using 5 mol
% non-purified 1 and 1.2 equiv. Me2PhSiH in “wet” o-DCB
to produce N-Ph-isoindolinone in 92 % yield (1.24 g,
scheme 4) isolated without column chromatography.
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 to MJI).
REFERENCES
(1) For recent reviews on FLP chemistry see: (a) Stephan, D. W. J.
Am. Chem. Soc. 2015, 137, 10018-10032. (b) Stephan, D. W., Erker,
G. Angew. Chem. Int. Ed. 2015, 54, 6400-6441. (c) Stephan, D. W.
Acc. Chem. Res. 2015, 48, 306-316. (d) Oestreich, M., Hermeke, J.,
Mohr J. Chem. Soc. Rev. 2015, 44, 2202-2220 (e) Topics in Current
Chemistry: Frustrated Lewis Pairs I-II; Erker, G., Stephan, D. W.,
Eds.; Springer-Verlag: Berlin, Heidelberg, 2013.
(2) For pioneering studies on Si-H activation with B(C6F5)3 see:
(a) Parks, D. J, Piers, W. E. J. Am. Chem. Soc. 1996, 118, 9440-
9441. (b) Blackwell, J. M., Foster, K. L., Beck, V. H., Piers, W. E. J.
Org. Chem. 1999, 64, 4887-4892 (c) Parks, D. J., Blackwell, J. M.,
Piers, W. E. J. Org. Chem. 2000, 65, 3090-3098. (d) Blackwell, J.
M., Sonmor, E. R., Scoccitti, T., Piers, W. E. Org. Lett. 2000, 2,
3921-3923. For subsequent notable mechanistic studies see: (e)
Rendler, S., Oestreich, M. Angew. Chem., Int. Ed. 2008, 47, 5997-
6000. (f) Hermeke, J., Mewald M., Oestreich, M. J. Am. Chem.
Soc. 2013, 135, 17537-17546. (g) Houghton, A. F., Hurmalainen, J.,
Mansikkamäki, A., Piers, W. E., Tuononen, H. M. Nat. Chem.
2014, 6, 983-988.
O
(i), (ii)
+
H2N
N
OH
1.24 g
(92%)
O
O
Scheme 4: Catalyzed formation of N-Ph-isoindolinone. (i)
“wet” o-DCB, 15 mins (ii) 5 mol% 1-OH2, 1.2 eq. Me2PhSiH,
100oC 1 h.
CONCLUSION
In summary, B(C6F5)3 is a highly effective and water
tolerant catalyst for the reductive amination of primary
and secondary arylamines at raised temperatures using
non-purified solvents and reagents. This process uses only
1.2 equiv. of Me2PhSiH thus under these conditions imine
reduction is faster than H2O dehydrosilylation. The key to
this successful reductive amination is the fact that aryla-
(3). For pioneering studies on H2 activation with B(C6F5)3 see: (a)
Welch, G. C., San Juan, R. R., Masuda, J. D., Stephan, D. W. Sci-
ence 2006, 314, 1124-1126. (b) Chase, P. A., Welch, G. C., Jurca, T.,
ACS Paragon Plus Environment

ACS Catalysis
Page 6 of 6
1
2
3
4
5
6
7
8
9
Stephan, D. W. Angew. Chem., Int. Ed. 2007, 46, 8050-8053. (c)
Welch, G. C., Stephan, D. W. J. Am. Chem. Soc. 2007, 129, 1880-
1881. (d) Spies, P., Schwendemann, S., Lange, S., Kehr, G., Fröh-
lich R., Erker, G. Angew. Chem., Int. Ed. 2008, 47, 7543-7546
(4) For recent reviews on FLP hydrogenations see: (a) Shi, L.,
Zhou, Y.-G., ChemCatChem. 2015, 7, 54-56. (b) Hounjet, L. J.,
Stephan, D. W. Org. Process Res. Dev. 2014, 18, 385-391. (c)
Paradies, J., Angew. Chem., Int. Ed. 2014, 53, 3552-3557
(5) (a) Chen, D., Klankermayer, J. Chem. Commun. 2008, 2130-
2131. (b) Hog, D. T., Oestreich, M. Eur. J. Org. Chem. 2009, 5047-
5056. (c) Chen, D., Wang, Y., Klankermayer, J. Angew. Chem.,
Int. Ed. 2010, 49, 9475-9478. (d) Sumerin, V., Chernichenko, K.,
Nieger, M., Leskelä, M.; Rieger, B., Repo, T. Adv. Synth. Catal.
2011, 353, 2093-2110 (e) Chen, D., Leich, V., Pan, F., Klankermay-
er, J. Chem. Eur. J. 2012, 18, 5184-5187. (f) Mewald, M., Oestreich,
M. Chem. Eur. J. 2012, 18, 14079-14084. (g) Liu, Y., Du, H. J. Am.
Chem. Soc. 2013, 135, 6810-6813. (i) Zhu, X., Du, H, Org. Biomol.
Chem. 2015, 13, 1013-1016.
(6) (a) Thomson, J. W., Hatnean, J. A., Hastie, J. J.; Pasternak, A.,
Stephan, D. W., Chase, P. A. Org. Process Res. Dev. 2013, 17, 1287-
1292. (b) Mahdi, T., Stephan, D. W. Angew. Chem., Int. Ed. 2015,
54, 8511-8514.
(7) Lawrence, S. A., Amines: Synthesis Properties and Applica-
tions; Cambridge, University Press, Cambridge, 2004.
(8) For transition metal catalyzed reductive aminations using
hydrosilanes see: Zheng, J., Roisnel, T., Darcel, C., Sortais, J.-B.
ChemCatChem. 2013, 5, 2861-2864 and references therein.
(9) Fu, M.-C., Shang, R., Cheng, W.-M., Fu. Y. Angew. Chem., Int.
Ed. 2015, 54, 9042-9046.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(10) Britovsek, G. J. P., Ugolotti, J., White, A. J. P. Organometal-
lics 2005, 24, 1685-1691.
(11) Bergquist, C., Bridgewater, B. M., Harlan, C. J., Norton, J. R.
Friesner, R. A., Parkin, G. J. Am. Chem. Soc. 2000, 122, 10581-
10590
(12) For alcohol tolerant FLP reductions see: (a) Scott, D. J.,
Fuchter, M. J., Ashley, A. E., J. Am. Chem. Soc. 2014, 136, 15813-
15816. (b) Mahdi, T., Stephan, D. W. J. Am. Chem. Soc. 2014, 136,
15809-15812. For water tolerant FLP reductions see: (c) Gyömöre,
A., Bakos, M., Földes, T., Pápai, I., Domján, A., Soós, T. ACS
Catal. 2015, 5, 5366-5372. (d) Scott, D. J., Simmons, T. R., Law-
rence, E. J., Wildgoose, G. G., Fuchter, M. J., Ashley, A. E. ACS
Catal. 2015, 5, 5540-5544.
(13) McGonagle, F. I., MacMillan, D. S., Murray, J., Sneddon, H.
F., Jamieson, C., Watson, A. J. B. Green Chem. 2013, 15, 1159-1165.
(14) Doyle, M. P., West, C. T. J. Org. Chem. 1975, 40, 3835–3838
(15) (a) Hewavitharanage, P., Danilov, E. O., Neckers, D. C. J.
Org. Chem. 2005, 70, 10653-10659. (b) Bibal, C., Santini, C. C.,
Chauvin, Y., Vallee, C., Olivier-Bourbigou, H. Dalton Trans.
2008, 37, 2866-2870.
(16) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463 (b)
Bordwell, F. G.,
http://www.chem.wisc.edu/areas/reich/pkatable/index.htm.
(17) Piers, W. E., Marwitz, A. J. V., Mercier, L. G., Inorg. Chem.
2011, 50, 12252-12262.
(18) Kumar, V., Sharma, S., Sharma, U., Singh B., Kumar, N.
Green Chem. 2012, 14, 3410-3414.
ACS Paragon Plus Environment