Enantioselective reduction of: N -alkyl ketimines with frustrated Lewis pair catalysis using chiral borenium ions

Article abstract of DOI:10.1039/c9cc02900a

Enantioselective reduction of ketimines was demonstrated using chiral N-heterocyclic carbene (NHC)-stabilised borenium ions in frustrated Lewis pair catalysis. High levels of enantioselectivity were achieved for substrates featuring secondary N-alkyl substituents. Comparative reactivity and mechanistic studies identify key determinants required to achieve useful enantioselectivity and represent a step forward in the further development of enantioselective FLP methodologies.

Full text of DOI:10.1039/c9cc02900a

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DOI: 10.1039/C9CC02900A
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Communication
Enantioselective reduction of N-alkyl ketimines with frustrated
Lewis pair catalysis using chiral borenium ions
Dan M. Mercea,a Michael G. Howlett,a Adam D. Piascik,a Daniel J. Scott,a Alan Steven,b Andrew E.
Received 00th January 20xx,
Accepted 00th January 20xx
Ashleya and Matthew J. Fuchter*,a
DOI: 10.1039/x0xx00000x
Enantioselective reduction of ketimines was demonstrated using chiral N-heterocyclic carbene (NHC)-stabilised borenium
ions in frustrated Lewis pair catalysis. High levels of enantioselectivity were achieved for substrates featuring secondary N-
alkyl substituents. Comparative reactivity and mechanistic studies identify key determinants required to achieve useful
enantioselectivity and represent a step forward in the further development of enantioselective FLP methodologies.
www.rsc.org/
The concept of ‘frustration’ continues to be useful in the FLP 1b,7f asymmetric ketimine reduction is limited to substrates
development of transition metal free Lewis acid/base pairs with with an N-aryl group. Herein we report a method to use a chiral
fascinating reactivity.1 Pioneered by Stephan and co-workers,2 borenium catalyst in the FLP reduction of N-alkyl ketimines,
‘frustration’ is often seen as a result of steric demands and this which gives good to high enantioselectivity for secondary alkyl
view currently serves as the dominant design principle.3 The ketimine substrates. We compare hydrosilylation and
frustrated Lewis pair (FLP) formalism not only applies to the hydrogenation pathways, which give important insight into the
discovery of new reactions, but also to rationalise chemistry factors that underpin good enantioselectivity. We believe these
that pre-dates the coining of the term, a notable example being results will further contribute to the development of FLP
Piers-type hydrosilylation.4 FLPs have now been exploited in catalysts for highly enantioselective reduction methodologies.
both stoichiometric and catalytic manifolds, in applications as One of the key issues with the prior designs for chiral borane
diverse as polar hydrogenation (of imines,5a carbonyls,5b FLP catalysts is the challenging synthesis required to assemble
alkenes and alkynes5c), C-H bond activation,5d and polymer the Lewis acid. We considered chiral NHC-stabilised borenium
chemistry.5e Key to this work is the reduction of substrates using ions to hold promise as alternative asymmetric FLP catalysts,
H2 and hydrosilanes, a topic that has been extensively reviewed given their effectiveness in FLP-catalysed reduction chemistry,8a
by Oestreich et al.6
and potential modularity: a large variety of chiral NHCs are
Despite many impressive developments in FLP chemistry and available.9a We chose to initially survey chiral NHCs of the IBiox
catalysis, enantioselective FLP-catalysed reduction is still class9b for generating our borenium catalysts (2a-c, Scheme 1)
significantly limited (Figure 1). Chiral borane FLPs were
pioneered by Klankermeyer and co-workers,7a followed by
ferrocene-derived boranes7b and ansa-ammonium borates7c
Figure 1. Examples of chiral FLP Lewis acid catalyst used in FLP reductions
from other groups. However, many of these catalysts showed
limited enantioselectivity. The most successful scaffold for
chiral borane FLP catalysts to date is the binaphthyl core.
Binaphthyl-derived, C6F5-substituted boranes were first
investigated by Piers and co-workers as catalysts for the
asymmetric allylstannation of aromatic aldehydes7d followed by
reports of chiral borepine catalysts (Oestreich, 1a
designs (Repo and Du; 1b7f and 1c 7g
respectively). Beside this
)
7e and acyclic
,
scaffold, a novel bicyclic bisborane has also been reported
recently by Peng, Wang et al., for N-aryl ketimine reduction.7h It
is notable amongst these examples that, with the exception of
a. Department of Chemistry, Imperial College London, Molecular Sciences Research
Hub, White City Campus, Wood Lane, London, UK, W12 0BZ
b. AstraZeneca PT&D, Charter Way, Macclesfield, UK, SK10 2NA.
c. Electronic Supplementary Information (ESI) available: Experimental and
crystallographic details. See DOI: 10.1039/x0xx00000x. Data files are openly
available (DOI: 10.14469/hpc/5645).
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given our previous work on such NHCs,9c and the fact that the
corresponding borohydride 3a has been shown to act as a
stoichiometric enantioselective reducing agent towards
ketones.10a During the early phases of our project, Stephan,
Crudden, Melen and co-workers reported the attempted
asymmetric reduction of ketimines using borenium 2d as part of
a large screening effort of chiral borenium FLP catalysts.8b
Catalyst 2d hydrogenated N-phenyl ketimine 4a with poor
selectivity (56:44 e.r.), and showed no activity towards N-benzyl
ketimine 4b, even under 102 atm H2 pressure (298K, CH2Cl2).8b
Given this outcome, we sought to further understand how the
reducing agent, catalyst components (NHC, borenium
counterion, etc.) and ketimine substrate could be developed to
enable good reactivity and enantioselectivity.
Borenium catalyst 2a was prepared from hydride 3a by
treatment with HNTf2 in 73% yield on gram scale.10bǂ The
borenium ion nature of 2a was confirmed by 11B NMR
spectroscopy (δ = 73 ppm (br), CD2Cl2), DOSY NMR studies
(Dc/Da = 1.06),10b,11 and X-ray crystallography on the isolated
species (see ESI). Compound 2a displayed good solubility in
halogenated solvents: chloroform, dichloromethane, and 1,2-
Table 1. Hydrosilylation development
View Article Online
DOI: 10.1039/C9CC02900A
Entry Cat. Subst. Solvent
Conv. (Time)
e.r. (R:S)a
65:35
57:43
64.5:35.5
57:43
59:41
38.5:61.5
19:81
21:79
10:90
10:90
1b
2
3
4
5d
6
7
8
2a
2bc
2cc
2a
2a
2a
2a
2a
2a
2a
4a
4a
4a
4a
4a
4b
4b
4c
4c
4c
Toluene
Toluene
Toluene
1,2-DFB
1,2-DFB
Toluene
1,2-DFB
Toluene
98% (44 h)
71% (24 h)
100% (24 h)
100% (19 h)
89% (286 h)
100% (6 h)
100% (34 h)
53% (74 h)
9
10d
1,2-DFB 100% (145 h)
1,2-DFB 68% (316 h)
Reactions were carried out on 0.375 mmol scale (0.63 M), conversion to
amine product(s) assessed by NMR; Unless otherwise stated the hydrosilane
used was PhMe2SiH; products 5 were obtained following workup with MeOH
and chromatography; a. determined by chiral HPLC, the N-acetylated
derivative of 5c was used; enantiomers assigned by comparison of optical
rotation values with the literature. b. reaction carried out with stirring on
double the scale; c. catalyst formed in situ from the corresponding
borohydride and HNTf2; d. hydrosilane used was Ph2MeSiH.
difluorobenzene
(1,2-DFB).
A
Gutmann-Beckett
measurement,12 which provides a measure of Lewis acidity in
terms of an acceptor number (AN), revealed 2a to be a weaker
Lewis acid (AN = 70.7) than the common FLP borane B(C6F5)3 (AN
= 78.113). We additionally synthesised borenium catalysts 2b
and 2c which vary in steric bulk of the chiral NHC (Scheme 1)
and investigated counterions more coordinating than NTf2.
However, a preliminary assessment of NHC-borenium ions with
OTf, OMs, or OTs counterions revealed that such complexes are
unable to cleave H2 in combination with ketimine substrates
(Figure S13), due to coordination of the counterion of the
borenium (see ESI).
reactivity was observed using PhMe2SiH and a catalyst loading
of 4 mol%, which is comparable to other studies (Figure 1).
Substrate 4a was reduced with low enantioselectivity and a
slight preference for the R product enantiomer (Table 1, entries
1 and 4). The use of a bulkier hydrosilane (entries 5 and 10) led
to a reduced reaction rate with similar enantioselectivity. More
promising results were obtained however when the substrate
was changed to an N-alkyl derivative. Although N-benzyl
substrate 4b exhibited excellent reactivity in toluene (entry 6),
only low enantioselectivity was observed. Interestingly, the
major enantiomer obtained (S) was of opposite configuration to
that obtained for substrate 4a. While toluene versus 1,2-DFB
gave comparable results for 4a, 1,2-DFB gave an increased
enantioselectivity (e.r. 81:19, S:R, entry 7) in the reduction of
4b. Increasing the bulk of the N-alkyl substituent further
improved enantioselectivity. Notably, N-cyclohexyl substrate 4c
gave a high enantioselectivity (e.r. 90:10, S:R, entry 9)
comparable with other leading chiral borane FLP catalysts
(Figure 1). Similar enantioselectivity was observed for catalysts
2a-c.
With appropriate chiral NHC-borenium catalysts
2 in hand, we
surveyed the enantioselective hydrosilylation of N-aryl ketimine
4a and N-alkyl ketimines 4b and 4c (Table 1). Good to excellent
Scheme 1. Catalyst synthesis and literature model substrates (Tf = SO2CF3)
Given these promising results, substrate scope was further
explored in the enantioselective hydrosilylation of N-alkyl
ketimines using 2a (Table 2). Catalyst 2a showed comparably
high enantioselectivity (e.r. 90:10 – 93:7) in the reduction of a
range of bulky secondary N-alkyl ketimines (Table 2, entries 1-
4). Although primary N-alkyl substituents gave slightly lower
selectivity (Table 2, entries 5, 6), we highlight that the
enantioselectivity observed (e.r. 79:21 – 82:18, entries 5 and 6)
is comparable to the only other example of FLP asymmetric
reduction of N-alkyl ketimines.7f While a bulky substituent on
2 | J. Name., 2012, 00, 1-3
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acetophenone (4c,e) gave good reactivity and enantioselectivity
(e.r. 90:10, Table 3 entries 1 and 2). Lowering the pressure to
Table 2. Hydrosilylation substrate scope
View Article Online
DOI: 10.1039/C9CC02900A
10 bar H2 dramatically reduced the reaction rate. In agreement
with the results of Stephan, Crudden, Melen and co-workers,8b
hydrogenation of substrate 4a occurred with much lower
enantioselectivity (e.r. 59:41, entry 3). Consistent with our
results for hydrosilylation, substrate 4i only gave moderate
enantioselectivity (e.r. 65:35, entry 4). Changing the steric bulk
of the nitrogen substituent to be either larger (entry 5) or
smaller (entries 6 and 7) resulted in a substantial drop in
product yield.
It is notable that the enantioselectivity observed for substrates
4a and 4c is analogous, regardless of whether a hydrosilane or
H2 was used. Oestreich and co-workers have previously shown
that borane-promoted imine reduction using hydrosilanes can
Entry Subst.
Ar
Ph
Ph
Ph
2-Np
Ph
Ph
Ph
Ph
R’
H
H
H
H
H
H
H
Me
R
Conv.
100%
91%
Yield
91%f
47%
71%
75%
~100%
79%
-
e.r. (S:R)a
90:10
90:10
90:10
93:7
1b
2
3
4c,d
5c,e
6
4c
4d
4e
4f
4b
4g
4h
4i
c-Hex
i-Pr
c-Pent 100%
c-Hex
Bn
Bu
77%
97%
100%
0%
82:18
79:21
-
7
8
CHPh2
c-Hex
61%
62%
64:36g
occur via hydride addition to silyl-iminium
6
and proto-iminium
Reactions were carried out on 0.375 mmol scale (0.63 M), conversion to amine
product(s) assessed by NMR; Unless otherwise stated solvent was 1,2-DFB,
and the reaction time was 34 h; products 5 were obtained following workup
with MeOH and chromatography. a. determined using chiral HPLC following
acetylation; enantiomers assigned by comparison of optical rotation values
with the literature. b. 145 h. c. reaction solvent was DCM. d. 31 h. e. 2 h. f.
~11% (PhMe2Si)2O impurity. g. enantiomers not assigned.
7
intermediates; the latter also involves the formation of silyl-
enamine intermediate
8
(Figure 3).14 Monitoring the
hydrosilylation of substrate 4c using 2a by NMR indicated a
comparable mechanism to be operative here (See ESI, Figure
S6,7,11). Given the operation of both reduction pathways, and
the comparison with hydrogenation–where polar reduction can
only occur via a proto-iminium
7
intermediate–it would appear
that the nature of the imine activating group (+SiR3 or H) has
little or no effect on enantioselectivity. Furthermore, it suggests
that improvements in enantioselectivity are due to better
substrate/catalyst matching and not due to a potential change
in mechanism between hydrogenation and hydrosilylation. The
successful enantioselective reduction using catalyst 2a appears
to be mostly a result of the presence of a bulky alkyl substituent
on the nitrogen atom of the ketimine.
+
the nitrogen atom improves enantioselectivity, excessive bulk
prevents reaction (Table 2, entry 7). Extending the aliphatic
chain that derives from the ketone component of the ketimine
(substrate 4i) also leads to a reduction in enantioselectivity.
Given the competency of catalyst 2a for the asymmetric
hydrosilylation of N-alkyl ketimines, we additionally assessed
the potential to use H2 as the reductant. Increasing the catalyst
loading to 10 mol% allowed for a range of substrates to be
hydrogenated (Table 3). Similarly to hydrosilylation, the
reduction of secondary N-alkyl ketimines derived from
In conclusion, we have explored the use of chiral IBiox NHC-
stabilised borenium scaffolds for the enantioselective
hydrosilylation and hydrogenation of ketimine substrates. In
contrast with prior results of borenium-mediated FLP
reductions,8b we have discovered that optimisation of the
reaction conditions allowed synthetically useful levels of
enantioselectivity to be achieved for a range of substrates. The
best results were obtained for substrates featuring secondary
N-alkyl substituents; substrates that are poorly explored in prior
enantioselective FLP reductions. For such substrates, the level
of enantioselectivity obtained is competitive with other chiral
borane catalysts (Figure 1) and comparable for both
hydrosilylation and hydrogenation, with higher reactivity
observed for the former. In future work, we believe that further
optimization of chiral NHC-borenium catalysts may be possible
to build upon the results described herein. For example, in
preliminary work we have investigated the potential to use a
borenium catalyst with the very weakly coordinating counterion
Table 3. Hydrogenation substrate scope
Entry Subs.
R’
H
H
H
Me
H
R
Conv. Yield e.r. (S:R)a
1
2b,c
3d
4
4e
4c
4a
4i
c-Pent 100%
c-Hex
Ph
c-Hex
CHPh2
Bn
67%
66%
91%
36%
-
90:10
89:11
41:59
65:35e
-
-
-
99%
100%
67%
0%
5
6
7
4h
4b
4g
H
H
8%
-
Bu
11%
-
Reactions carried out on a 0.375 mmol scale (0.63 M) using SPR (screening
pressure reactor) equipment, conversion to amine product assessed by NMR;
a. determined using chiral HPLC following acetylation; enantiomers assigned
by comparison of optical rotation values with the literature; b. At 10 bar H2,
NMR tube (re-pressurised after 192 h): 97%, 212 h, e.r. 90:10. c. for the
reaction carried out in DCM an e.r. value of 91:9 was obtained. d. 4 mol% 2a,
90 bar H2, 24 h. e. enantiomers not assigned.
{Al[O(CF3)3]4},15 given the need for
a non-coordinating
counterion for effective catalysis (vide supra). We observed
slightly improved enantioselectivity (e. g. product 5c, e.r. =
90:10 NTf2 counterion, 95:5 {Al[O(CF3)3]4} counterion see ESI,
Table S12). We believe our results pave the way for future
developments in enantioselective asymmetric reductions using
FLP catalysts.
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Y.-X. Chen, J. Am. Chem. Soc., 2014, 136, 1774–1777; Q. Wang,
View Article Online
Figure 3. Lewis acid catalysed hydrosilylation using a borenium cation. For a full
mechanism see reference 14 and Figure S8.
W. Zhao, S. Zhang, J. He, Y. Zhang and E. Y.-X. Chen, ACS Catal.,
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We wish to thank the EPSRC and AstraZeneca for Ph. D. funding
(CASE studentship to DMM). MJF would like to thank the EPSRC
for an Established Career Fellowship (EP/R00188X/1). AEA
would like to thank the Royal Society for a University Research
Fellowship (UF/160395). We would also like to thank Kevin
Leslie and Fiona Bell (AstraZeneca) for technical support.
8
9
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DOI: 10.1039/C9CC02900A
Effective enantioselective reduction of ketimines has been demonstrated by ‘frustrated’ Lewis pair
catalysis using an IBiox-stabilised borenium cation.
O
O
N
N
iPr
iPr
NTf2
B
R
R
N
HN
H2 or PhMe2SiH
Ar
Ar
O
O
For R = alkyl
N
N
Up to 93:7 e.r.
iPr
iPr
B
H