Silylative Reductive Amination of α,β-Unsaturated Aldehydes: A Convenient Synthetic Route to β-Silylated Secondary Amines

Article abstract of DOI:10.1002/chem.201800958

Described here is a reductive amination/hydrosilylation cascade of α,β-unsaturated aldehydes mediated by a Lewis acidic borane catalyst. The present reaction system provides an one-pot synthetic route towards β-silylated secondary amines that have not been accessible by other previous catalysis. Comparative ¹H NMR studies on the silylative reduction of enimines revealed that steric bulkiness of primary amine reactants strongly affects both catalytic efficiency and regioselectivity. This strategy was applicable to a broad range of substrates and amenable to one-pot gram-scale synthesis. Moreover, a diastereoselective introduction of the β-silyl group was also found to be feasible (d.r. up to 71:29).

Full text of DOI:10.1002/chem.201800958

A Journal of
Accepted Article
Title: Silylative Reductive Amination of a,b-Unsaturated Aldehydes: A
Convenient Synthetic Route to b-Silylated Secondary Amines
Authors: Sukbok Chang, Eunae Kim, and Sehoon Park
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Silylative Reductive Amination of -Unsaturated Aldehydes: A
Convenient Synthetic Route to -Silylated Secondary Amines
Eunae Kim, Sehoon Park,* and Sukbok Chang*
Abstract: Described herein is a reductive amination/hydrosilylation
cascade of -unsaturated aldehydes mediated by a Lewis acidic
borane catalyst. The present reaction system provides an one-pot
synthetic route towards-silylated secondary amines that have not
1
been accessible via other precedent catalysis. Comparative H NMR
studies on the silylative reduction of enimines revealed that steric
bulkiness of primary amine reactants strongly affects both catalytic
efficiency and regioselectivity. This strategy was applicable to a broad
range of substrates and amenable to one-pot gram-scale synthesis.
Moreover, a diastereoselective introduction of the -silyl group was
also found to be feasible (dr. up to 71:29).
-Unsaturated carbonyls are highly useful building blocks in
organic synthesis.[1] This is probably due to their versatile
reactivities based on a LUMO-lowering activation pathway.[2]
Given such an intrinsic electronic property, -unsaturated
carbonyls undergo conjugate addition by a number of nucleophilic
organo(metallic) compounds, providing formally reduced products
to form a new sp3 carbon-Nu bond (Nu: = nucleophiles based on
H, C, N, etc.).[3] Among various transformations, remote
functionalization of -unsaturated aldehydes via enimines or
dienamines as a key intermediate has drawn a considerable
attention in (asymmetric) organic synthesis (Scheme 1a).[4-5]
Scheme 1. a) Functionalizations of -unsaturated aldehydes via enimines or
dienamines. b) B(C6F5)3-catalyzed silylative reduction cascades of pyridines
Despite of such numerous utilization of -unsaturated carbonyls,
and conjugated nitriles. c) Silylative reductive amination of conjugated
there have been no reports on the reductive amination[6] of -
aldehydes leading to -silylated secondary amines (this work).
unsaturated carbonyls leading to silylated amines.
On the other hand, we previously reported the boron-
In mechanistic studies, we found that the -silylation takes place
catalyzed silylative reduction of quinolines, pyridines, and
via an enamine intermediate formed by an initial B(C6F5)3-
conjugated nitriles, affording a diverse range of aza compounds
mediated 1,4-hydrosilylation.
having a sp3 CSi bond beta to the nitrogen atom (Scheme 1b).[7]
In this context, we envisioned that -unsaturated aldimines
that can be conveniently generated through a condensation
reaction of conjugated aldehydes with primary amines, would
undergo a C(sp3)Si bond-forming reduction cascade under the
[ ]
*
Dr. S. Park, Prof. Dr. S. Chang
Department of Chemistry, Korea Advanced Institute of Science and
Technology (KAIST), Daejeon 34141 (Republic of Korea)
and
Center for Catalytic Hydrocarbon Functionalizations, Institute for
Basic Science (IBS), Daejeon 34141 (Republic of Korea)
E-mail: sehoonp@kaist.ac.kr,
B(C6F5)3 catalysis.[8] Described herein is the silylative reductive
amination of -unsaturated aldehydes, providing -silylated
secondary amines in one-pot (Scheme 1c). This work represents
the first example of reductive amination with concomitant
incorpotation of a silyl group. A variety of combinations of readily
accessible aldehydes and primary amines enabled us to
synthesize a wide range of -silylated amines in high yields. The
reaction path of a silylative reduction of conjugated imines were
elucidated: an N-bulky substituent of substrates leads to 1,4-
hydrosilylation, while a less bulky group on the N atom causes the
formation of 1,2-addition intermediate as a minor path. The
present one-pot strategy was amenable to the gram-scale
synthesis and also to the diastereoselective silylative reduction.
sbchang@kaist.ac.kr
E. Kim
Department of Chemistry, Korea Advanced Institute of Science and
Technology (KAIST), Daejeon 34141 (Republic of Korea),
Center for Catalytic Hydrocarbon Functionalizations, Institute for
Basic Science (IBS), Daejeon 34141 (Republic of Korea)
and
Korea Research Institute of Chemical Technology (KRICT), Daejeon
34114 (Republic of Korea)
Supporting information for this article can be found under:
https://doi.org/
1
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Table 1: Screen of reaction conditions.[a]
Table 2: Scope of silylative reductive amination of -unsaturated aldehydes.[a]
Silane
(equiv)
T
[oC]
t
[h]
Yields of
1/1’[%][b]
Entry
Solvent
1
2
PhMe2SiH (4)
CDCl3
CDCl3
85
85
6
15
15
15
15
15
15
15
3
59/25
85/<1
77/<1
55/<1
7/65
PhMe2SiH (4)
Et2SiH2 (4)
3
CDCl3
85
4
Ph2SiH2 (4)
CDCl3
85
5
Et3SiH (4)
CDCl3
85
6
PhMe2SiH (4)
PhMe2SiH (4)
PhMe2SiH (4)
PhMe2SiH (4)
PhMe2SiH (4)
PhMe2SiH (4)
PhMe2SiH (4)
PhMe2SiH (2)
PhMe2SiH (3)
CDCl3
25
<1/90
9/73
7
CDCl3
45
8
CDCl3
60
33/50
89/<1
83/<1
86/<1
78/<1
79/<1
85/<1
9
CDCl3
110
110
110
110
110
110
10
11
12
13
14
toluene-d8
benzene-d6
C6D5Cl
CDCl3
3
3
3
3
[a] Reaction conditions: for step (i) conjugated aldehydes (0.5 mmol) and anilines (1
equiv) in CHCl3 (0.4 mL) in the presence of molecular sieve 4Å (200 mg) at 25 oC,
6~20 h; for step (ii) B(C6F5)3 (0.025 mmol, 5 mol%), PhMe2SiH (2 mmol, 4 equiv) in
CHCl3 (0.1 mL) at 110 oC for 5 h. Isolated as an NH form upon silica-column
chromatography. [b] Et2SiH2 (4 equiv) used instead of PhMe2SiH. [c] Crude NMR
yields determined by 1H NMR on the basis of 1,1,2,2-tetrachloroethane (TCE) as an
internal standard.
CDCl3
3
[a] Reaction conditions: for step (i) cinnamaldehyde (0.5 mmol) and aniline (1 equiv)
in solvent (0.4 mL) in the presence of molecular sieve 4Å (200 mg) at 25 oC, 6~20 h;
for step (ii) B(C6F5)3 (0.025 mmol, 5 mol% relative to cinnamaldehyde), silane (1~2
mmol, 2~4 equiv relative to cinnamaldehyde), solvent (0.1 mL) at 25~110 oC, 3~15 h.
Conversion of an aldimine was >99%. [b]Determined by 1H NMR of the crude reaction
mixture on the basis of 1,1,2,2-tetrachloroethane (TCE) as an internal standard.
benzene, and chlorobenzene were viable to give 1 in 78~86% in
addition to chloroform (entries 1012). Reducing the silane
quantity brought about slightly lower yield of 1 relative to that with
4 equiv of silane (entries 1314).[10]
At the outset of this study, we conducted an optimization study
using cinnamaldehyde as a standard substrate for the one-pot
silylative reductive amination cascade (Table 1). A condensative
reaction of cinnamaldehyde with aniline in the presence of
molecular sieve was found to be facile in various solvents to
With the optimal conditions in hand, the scope of the one-pot
silylation cascade was explored (Table 2). Electronic variation in
the aniline moiety had marginal effects in leading -silylated
products (13) in good to high yields. The -unsaturated
aldimines obtained from alkyl amines smoothly underwent
silylative reduction to furnish 4 and 5 in 91% and 85%,
respectively. Notably, facile formation of 4 was achieved when
Et2SiH2 was employed instead of PhMe2SiH. Next, aryl-
substituted acrylaldehydes with electronic and steric variations in
the aryl moiety were subjected to the B(C6F5)3-catalyzed silylative
reduction conditions. The m- or p-methyl substituted aryl group
had no significant effects on the product yields (1, 78% vs. 6, 81%;
8, 84%), while an o-methyl substituent in the aryl moiety gave
slightly lower yield (7, 70%). These results imply that the present
catalysis is sensitive to the sterics of the aryl-moiety in substrates
(also vide infra). The reaction of a series of acrylaldehydes
bearing a haloaryl group smoothly proceeded in the presence of
B(C6F5)3 catalyst to afford the corresponding -silylated products
in 70~90% (915). Substrates having a p-phenoxyaryl or
anthracene group reacted with PhMe2SiH to give the desired -
silylated secondary amines in 75% (16) and 84% (17) respectively,
upon silica-column chromatography.[11]
o
quantitatively afford an enimine (completed in 6 h at 25 C).[9]
Upon completion of the conjugate imine formation, the
B(C6F5)3/silane system under variable conditions was applied to
the in situ formed imine solution. The reaction with PhMe2SiH (4
equiv) in the presence of B(C6F5)3 (5 mol%) smoothly proceeded
at 85 oC to result in a mixture of N-(2-silyl-3-phenylpropyl)aniline
1 and N-(3-phenyl-1-propenyl)aniline 1’ in 59% and 25% in 6 h,
respectively, and the yield of 1 reached up to 85% in 15 h (Table
1, entries 12). This result indicates that the cascade reaction
proceeds via an N-(3-phenyl-1-propenyl)aniline intermediate 1’.
Increasing steric bulkiness of silanes led to lower efficiency: a
reaction with Et2SiH2 furnished 1 in 77% yield (entry 3), whereas
bulkier silanes, Ph2SiH2 and Et3SiH were less reactive to afford 1
in 55% and 7%, respectively (entries 45). It is noteworthy that
the reaction with Et3SiH afforded 65% of 1’ as a major product,
suggesting that the -silylation on 1’ is a turnover-limiting step
(vide infra). Reaction temperature turned out to be crucial to the
catalytic efficiency: the reaction at a range of 25 to 60 oC produced
1 in inferior yield but yielded 1’ in 50~90% (entries 68), while
elevating temperature to 110 oC improved the catalytic efficiency
to attain 89% of 1 in 3 h (entry 9). The optimal solvent for both the
condensation and silylative steps was next examined: toluene,
2
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Table 3: Scope of silylative reduction of -unsaturated aldimines.[a]
0.5
0.4
0.3
0.2
0.1
0
0.6
0.5
0.4
0.3
0.2
0.1
0
0
10
20
30
40
50
60
0
10
20
30
40
50
60
Scheme 2. 1H NMR monitoring of the silylative reduction of N-phenyl (a,c)
and N-tert-butyl (b,d) enimines under the borane catalysis.
of conjugated imines bearing an alkyl-substituent at the C2 to C4
position did not afford the desired -silylated amines under the
standard conditions. Instead, an exhaustive product lacking a sp3
CSi bond was formed from C2- or C4-methyl-enimines, while a
C3-methyl substitued enimine was converted mainly to the
respective 1,2-addition product.
To understand the reaction behavior in more detail, the
silylative reduction of two representative enimine substrates was
set for the 1H NMR-led progress monitoring (Scheme 2). The
reaction of an N-phenyleneimine with PhMe2SiH (4 equiv)
proceeded to attain a quantitative conversion in 10 min at 35 oC,
giving rise to a mixture of 1,4-product 1’ (75%) and 1,2-product 1”
(15%). At this stage, the -silylated product 1 was not formed yet.
Upon elevating temperature to 110 oC, the in situ formed 1’ begun
to slowly be reduced to the -silylated product 1 (16%) with
disappearance of the 1,2-product 1” over 50 min at 110 oC
(Scheme 2a,c). These observations provide some insights: (i) an
imine intermediate undergoes mainly 1,4-addition, while 1,2-
addition also takes place as a minor path; and (ii) the sp3 -CSi
bond formation is rate-limiting.
[a] Reaction conditions: conjugated imines (0.5 mmol), B(C6F5)3 (0.025 mmol, 5 mol%),
silane (2 mmol, 4 equiv) in CHCl3 (0.5 mL) at 110 oC for 5 h. Isolated as an NH or N-
Ts form. [b] Yields over two steps. [c] Crude NMR yields determined by 1H NMR on
the basis of 1,1,2,2-tetrachloroethane (TCE) as an internal standard. [d] An exhaustive
reduction product as a major was formed. [e] An 1,2-addition product was formed as
a major.
To demonstrate the flexibility of the current synthetic route to
-silyl amines, we next examined the B(C6F5)3-catalyzed silylative
reduction of various -unsaturated aldimines (Table 3). A series
of substrates possessing an alkyl-substituted aniline moiety were
initially tested. ortho-Alkyl substituent(s) on the aniline moiety
rendered the reaction sluggish, thus requiring to use Et2SiH2, a
more reactive hydrosilane reagent to give reasonable yields of the
desired products (1821, 71~88%). Alkyl substituents at the other
position(s) on the aniline unit had a minimal impact, which allowed
for smooth conversion (2224, 83~87%). Substrates bearing an
N-naphthyl or -biphenyl group were also reacted under the
standard conditions to give 25 and 26 in 86% and 81%,
respectively. The present reaction was found to be almost
insensitive to electronic factors since electronic variations in both
aniline and aldehyde units brought about all similar product yields
comparable to that of 1 (2732, 82~89% vs. 1, 85%). Reactions
of enimine substrates having a series of N-alkyl groups were
performed to reveal that Et2SiH2 was more effective relative to
PhMe2SiH, leading to good to high yields of the desired products
3336 (62~91%). It is noteworthy that a substrate bearing an N-
tBu group was more reactive than substrates bearing a less bulky
N-alkyl unit under the identical conditions (36, 91% vs. 34, 62%).
This result suggests that a borane species that binds to an amine
unit is in an off-cycle resting state.[7a-d] Unfortunately, a reaction
On the other hand, the reaction of an N-tBu-imine showed
somewhat distinctive reaction profiles (Scheme 2b,d). In fact, this
imine was rapidly converted to give a mixture of 1,4-product 36'
(77%) and the desired product 36 (12%) within 1 min. Prolonged
o
reaction up to 1 h at 23 C, the enamine intermediate 36' was
completely consumed to eventually afford 36 in 88% yield.[12] This
result clearly indicates that steric bulkiness of an N-substituent of
enimines strongly influences both reaction rate and
regioselectivity for the addition of a SiH bond.
Based on the above observations and our previous reports,[7a-
c] a reaction pathway for the B(C6F5)3-mediated silylative reduction
of -unsaturated aldimines is proposed in Scheme 3. B(C6F5)3
catalyst is assumed to form an adduct A with an aldimine
substrate as a resting species,[13] which is dissociated into an
aldimine and an active species of borane-silane adduct B.[14]
A
silyl transfer from B to an aldimine substrate will take place to form
an iminium ion bearing a borohydride anion C. The nucleophilic
borohydride attack is presumed to occur selectively at the C-4
3
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Scheme 3. Proposed mechanism of the B(C6F5)3-catalyzed hydrosilylation
cascade of -unsaturated aldimines.
Scheme 4. a) Gram-scale synthesis of -silylated amines. b) Fleming-Tamao
oxidation of the silylated product. c) Diastereoselective -silylative reduction of
-unsaturated aldimines in one-pot.
position of C to form an enamine species D when the N-
t
substituent is bulky (e.g. R = Bu). However, when the N-
substituent is less bulky (e.g. R= Ph), a hydride transfer to the C-
2 position will also take place as a minor path leading to the
formation of an allylamine E.[13a] The 1,4-addition intermediate D
is suggested to undergo the turnover-limiting -selective
hydrosilylation via an intermediate F to give G, while the 1,2-
addition intermediate E is assumed to be hydrosilylated to furnish
G as well. The saturated amine H as a minor product is
considered to be formed through intermediates D and E.[15]
Finally, the synthetic utility of the present catalysis was
explored (Scheme 4). The one-pot silylative reductive amination
cascade could be carried out on a gram-scale without difficulty to
provide a series of -silylated secondary amines (1, 10, and 17)
in 77~82% yields (Scheme 4a). 1 synthesized from the parent
aldimine under the borane catalysis was subjected to the Fleming-
Tamao oxidation conditions,[16] giving rise to an N-tosylated -
amino alcohol (1-OH) in 47% total yield (Scheme 4b).
Acknowledgements
This research was supported by the Institute for Basic Science
(IBS-R010- D1). We thank Dr. Narasimhulu Gandhamsetty for his
initial experimental assistance.
Conflict of interest
The authors declare no conflict of interest.
Keywords: reductive amination
hydrosilylation • -unsaturated compounds • selectivity
• Lewis acidic borane •
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enantiomerically enriched amine unit. While a series of -silylated
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ratios (up to 71:29) at the present stage, further comprehensive
screening of the chiral anciliaries may allow us to achieve high
diastereoselectivity of the -silylated amines (Scheme 4c).
In summary, we have for the first time developed the silylative
reductive amination cascade of -unsaturated aldehydes in
one-pot, providing a broad range of secondary amines bearing a
sp3 CSi bond beta to the nitrogen atom. The present catalysis is
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1
convenient and selective even in gram-scale synthesis. The H
NMR study clearly suggests a sequential hydrosilylation cascade
under kinetic differentiation, and that the N-substituent has an
impact on the catalytic reactivity and selectivity. Asymmetric
induction by a chiral feature present in the substrate enables to
synthesize enantioriched -silylated secondary amines in good
yields.
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Tetrahedron, 2002, 58, 8247; h) M. Oestreich, J. Hermeke, J. Mohr,
Chem. Rev. Soc. 2015, 44, 2202.
[7]
[8]
Although a few examples of catalytic reductions of enimines or enamines
with silanes have been reported, these provide a mixture of allyl- and/or
saturated amines that do not bear sp3 CSi bond(s), see: a) Y. Misumi,
H. Seino, Y. Mizobe, J. Am. Chem. Soc. 2009, 131, 14636; b) Y. Corre,
W. Iali, M. Hamdaoui, X. Trivelli, J.-P. Djukic, F. Agbossou-Niedercorn,
C. Michon, Catal. Sci. Technol. 2015, 5, 1452; c) B. S. Takale, S. M. Tao,
X. Q. Yu, X. J. Feng, T. Jin, Ming, B, Y. Yamamoto, Org. Lett. 2014, 16,
2558; d) M. Tan, Y. Zhang, Tetrahedron Lett. 2009, 50, 4912.
[9]
a) A. D. J. Calow, J. J. Carbó, J. Cid, E. Fernández, A. Whiting, J. Org.
Chem. 2014, 79, 5163; b) R. G. Bergman, D. A. Colby, J. Ellman, J. Am.
Chem. Soc. 2008, 130, 3645.
.
[10] In most catalytic entries in Table 1, N-silyl-(3-phenylpropyl)aniline as an
undesired product was observed in 10~20%.
[11] In an attempt to enable a direct silylative reductive amination, a reaction
of cinnamyaldehyde, aniline (1 equiv), and PhMe2SiH (2 equiv) in the
presence of catalytic B(C6F5)3 (5 mol%) was performed at 100 oC for 15
h in toluene, disclosing that neither enimine/enamine intermediates nor
the -silylated product 1 were formed.
[12] The above two reactions in Scheme 2 generated the undesired exhaustive
reduction products in approximately 10% yields.
[13] The catalytic amount of an adduct of B(C6F5)3 with N-phenyleneimine was
observed by 1H NMR during the catalytic turnovers, see: a) J. M.
Blackwell, E. R. Sonmor, T. Scoccitti, W. E. Piers, Org. Lett. 2000, 2,
3921; b) J. M. Blackwell, W. E. Piers, M. Parvez, R. McDonald,
Organometallics 2002, 21, 1400.
[14] a) D. J. Parks, W. E. Piers, J. Am. Chem. Soc. 1996, 118, 9440; b) D. J.
Parks, J. M. Blackwell, W. E. Piers, J. Org. Chem. 2000, 65, 3090; c) A.
Y. Houghton, J. Hurmalainen, A. Mansikkamki, W. E. Piers, H. M.
Tuononen, Nat. Chem. 2014, 6, 983.
[15] N. Gandhamsetty, S. Park, S. Chang, Synlett 2017, 28, 2396.
[16] a) K. Tamao, N. Ishida, T. Tanaka, M. Kumada, Organometallics 1983, 2,
1694; b) M. Rubin,T. Schwier, V. Gevorgyan, J. Org. Chem. 2002, 67,
1936.
5
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10.1002/chem.201800958
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Eunae Kim, Sehoon Park,* Sukbok
Chang*
Page No. – Page No.
Title
Silylative Reductive Amination of -
Unsaturated Aldehydes: A Convenient
Synthetic Route to -Silylated
Secondary Amines
Silylative reductive amination of -unsaturated aldehydes has been first realized under the
borane catalysis, providing a wide range of combinatorial structures of secondary amines
bearing a sp3 CSi bond beta to the nitrogen atom in high yields. Monitoring of the reaction
progress revealed that the N-substituent of an amine unit has a significant impact on both
reaction rate and regioselectivity.
6
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