Enantioselective Rhodium-Catalyzed Alkenylation of Aliphatic Imines

Article abstract of DOI:10.1021/acs.orglett.7b02737

An efficient, enantioselective rhodium-catalyzed addition of potassium alkenyltrifluoroborates to N-nosyl aliphatic imines has been realized. Good reaction yields and excellent enantioselectivities (94-99% ee) were obtained for a variety of aliphatic imines and nucleophilic alkenyltrifluoroborates. An active rhodium-diene catalyst and the precise reaction condition control proved to be pivotal for success.

Full text of DOI:10.1021/acs.orglett.7b02737

Letter
pubs.acs.org/OrgLett
Enantioselective Rhodium-Catalyzed Alkenylation of Aliphatic Imines
Xue-Wei Qian,†,§ Ze-Jian Xue,†,§ Qian Zhao,‡ Zhe Cui,† Ya-Jing Chen,† Chen-Guo Feng,*,†,‡
and Guo-Qiang Lin*,†,‡
†Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, P.R. China
‡Jiangsu Key Laboratory of Chiral Drug Development, Jiangsu Aosaikang Pharmaceutical Co., Ltd., Nanjing, Jiangsu 211112, P.R.
China
S
* Supporting Information
ABSTRACT: An efficient, enantioselective rhodium-catalyzed
addition of potassium alkenyltrifluoroborates to N-nosyl
aliphatic imines has been realized. Good reaction yields and
excellent enantioselectivities (94−99% ee) were obtained for a
variety of aliphatic imines and nucleophilic alkenyltrifluor-
oborates. An active rhodium-diene catalyst and the precise
reaction condition control proved to be pivotal for success.
hiral, α-branched amines are commonly found in many
knowledge, rhodium-catalyzed enantioselective alkenylation of
aliphatic imines has not been realized yet.
C
biologically active molecules and natural products.1 The
rhodium-catalyzed, asymmetric addition of organoboron re-
agents to imines serves as a powerful strategy to access these
interesting compounds.2 Since the first example was reported by
Tomioka’s group in 2004,3a in which rhodium-catalyzed,
enantioselective addition of arylboronic acids to arylimines was
realized, significant effort has been devoted to expanding the
substrate scope of this transformation.3−7 The utilization of
aliphatic imines and alkenylboron reagents represents two
important leaps toward this goal. Due to the relatively lower
stability of aliphatic imines, the study of their addition reaction
lagged far behind the aromatic imines. In 2009, Ellman and co-
workers first reported the addition of arylboronic acids to
aliphatic imines using a rhodium/bisphosphine catalyst.4a Later,
this reaction was greatly improved by our group with the
discovery of an efficient catalytic system based on an active
rhodium/diene catalyst.4b Recently, Yamamoto and co-workers
reported a rhodium/bis(phosphoramidite) catalytic system for
this reaction.4c On the other hand, despite the obvious
advantages brought by the introduction of the alkenyl moiety,
examples with alkenylboron reagents were rather scarce. In 2001,
Shintani, Hayashi, and co-workers provided a single example, in
which an alkenylboron reagent was first used in the rhodium-
catalyzed, enantioselective imine addition.5a Soon, a systematic
research with cyclic aromatic imines was described by Lam and
co-workers.5b For the alkenylation of less active acyclic imines,
the Wu group5c and our group5d independently achieved this
enantioselective addition in 2014.
Scheme 1. Rhodium-Catalyzed Asymmetric Alkenylation of
Aliphatic Imines
Encouraged by our previous success in asymmetric addition
reactions with rhodium/chiral bicyclo[3.3.0]octadiene com-
plexes,9,10 we sought to explore these catalysts further in the
addition reactions with more challenging substrates. Herein, we
describe our development of an elegant catalytic system for the
highly enantioselective addition of potassium alkenyltrifluor-
oborates to aliphatic imines (Scheme 2).
In the initial attempts, the addition of (E)-styrylboronic acid to
N-4-nosyl-protected alkylimine 1a was carried out under the
previous successful reaction conditions for arylboronic acids.4b
Unfortunately, a significantly lower reaction yield and
enantioselectivity were obtained in contrast to the excellent
results with phenylboronic acid, which may be partly attributed
The addition of alkenylboron reagents to aliphatic imines
would provide not only chiral alkylalkenylamines but also chiral
dialkylamines by a further simple hydrogenation step. However,
only rhodium-catalyzed, diastereoselective reactions using chiral
aliphatic N-tert-butanesulfinyl imines have been reported by
Ellman and co-workers (Scheme 1).8 To the best of our
Received: September 1, 2017
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.7b02737
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Organic Letters
Letter
Using the optimized conditions, the scope of alkylimine was
explored (Scheme 3). Good reaction yield and enantioselectivity
Scheme 2. Preliminary Results in the Rhodium-Catalyzed
Asymmetric Alkenylation of Aliphatic Imines
Scheme 3. Rhodium-Catalyzed Asymmetric Alkenylation of
a
Aliphatic Imines
to the lower stability of alkenylboronic acids under the reaction
conditions.11,12
Accordingly, the boronic acids were replaced by the more
stable trifluoroborates13 in the following screening process, and
some representative results were summarized in Table 1. In the
a
Table 1. Optimization of Reaction Conditions
b
c
rhodium loading
(mol %)
temp
(°C)
additive
(equiv)
time
(h)
yield
ee
entry
(%)
(%)
1
3
3
70
80
60
70
70
70
70
70
70
70
70
70
70
70
MeOH (5)
MeOH (5)
MeOH (5)
MeOH (3)
MeOH (2)
EtOH (3)
iPrOH (3)
tBuOH (3)
H2O (3)
tBuOH (3)
tBuOH (3)
tBuOH (3)
tBuOH (3)
tBuOH (3)
6
42
30
22
67
66
66
44
80
59
81
80
89
88
27
97
97
97
97
96
94
95
97
91
97
97
98
97
96
2
6
3
3
6
4
3
6
5
3
6
a
6
3
6
Reactions conditions: 1 (0.20 mmol), 2 (0.40 mmol), [Rh(OH)-
7
3
6
(L1)]2 (0.005 mmol), and 4 Å molecular sieves (150 mg) in dioxane
(2 mL) at 70 °C for 30 min. Yields refer to isolated product.
Enantiomeric excesses were determined by chiral HPLC analysis.
8
3
6
9
3
6
b
c
Reaction was run in 1 mmol scale. Not detected.
10
11
12
13
3
0.5
0.17
0.5
0.5
0.5
3
5
were observed when acetaldehyde-derivatized imine with a
shorter chain length was used (3ba). However, alkylimines with
longer chain length gave decreased reaction yields, accompanied
by a slight variation in enantioselectivity (3ca−3ea). An imine
bearing a terminal BnO group was also a competent substrate,
albeit with reduced reaction yield and enantioselectivity (3fa).
Improved enantioselectivities were achieved with α- or β-
branched alkylimines, which could be attributed to the beneficial
effect of the increased steric hindrance in the substrates (3ga and
3ha). The same trend was also observed when cyclic alkylimines
bearing three-, five-, or six-membered rings were examined (3ia−
3ka).15
Next, the scope of alkenyltrifluoroborates was examined in the
addition to imine 1a. Introduction of chlorine substituent to
different positions of the phenyl ring of (E)-styryltrifluoroborate
2a resulted in a slight loss in reaction yield, albeit with almost
equally high enantioselectivities (3ab and 3ac). In contrast, a
slight loss in enantioselectivity was observed when the phenyl
ring was replaced by a flexible linear alkyl chain (3ad and 3ae).
Methyloxy (3ag), benzyloxy (3ah) and CO2Me (3ai) groups
were well tolerated, providing the desired products in high yields
with excellent enantioselectivities. While the reaction of α-
branched or trisubstituted trifluoroborate also proceeded well,
notably in higher reaction yields with cyclic alkenylboronates
(3aj−3am), the unsubstituted vinyltrifluoroborate failed to give
any observable product (3an).16
10
5
d
14
a
Unless otherwise noted, reactions were carried out with 1a (0.20
mmol), 2a (0.40 mmol), 4 Å molecular sieves (150 mg) in dioxane (2
b
mL). Yields were determined by 1H NMR spectroscopy using
c
CBr2H2 as an internal standard. Determined by chiral HPLC analysis.
d
Without 4 Å molecular sieves.
presence of the active rhodium−diene complex ([Rh(OH)-
(L1)]2), molecular sieves, and proton source, the addition of (E)-
styryltrifluoroborate 2a to alkylimine 1a proceeded at 70 °C to
give the desired product in 42% yield with excellent
enantioselectivity (entry 1). Either increasing or decreasing the
reaction temperature resulted in lower reaction yield (entries 2
and 3). The proton source and its quantity can affect both the
reaction yield and enantioselectivity, and 3 equiv of t-BuOH
proved to be optimal (entries 4−9). A careful examination of
reaction time indicated that the reaction could actually go to
completion within 10 min (entry 11), and we chose to run the
reaction for 30 min to ensure the full conversion of starting
material in the following study (entries 10). The reaction yield
can be further improved to 89% by increasing the catalyst loading
to 5 mol % (entry 12). Interestingly, we noticed a profound
impact of molecular sieves on the reaction yield, and only 27%
yield was obtained without this additive (entry 14).14
B
DOI: 10.1021/acs.orglett.7b02737
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ORCID
The N-nosylamide 3aa can easily be transformed to the
corresponding free amine 4 by treatment with classic 2-
thioglycolic acid (TGA)/LiOH at room temperature (eq 1).5d
In addition, 3aa can be hydrogenated under benign reaction
conditions, providing a N-nosyl-protected chiral dialkylamine 5
(eq 2).
Chen-Guo Feng: 0000-0001-9899-9489
Author Contributions
§X.-W.Q. and Z.-J.X. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from National Natural Science Foundation of
China (21472212, 21361162001) and the Strategic Priority
Research Program (B) (XDB20000000) of the Chinese
Academy of Sciences is acknowledged. We acknowledge Dr.
Han-Qing Dong (Arvinas Inc.) for his help in the preparation of
this manuscript, and Mr. Jiao-Long Meng (Jiangsu Aosaikang
Ltd.) for his help in the paper revision.
The absolute configuration of 3aa was determined unambig-
uously to be R by X-ray crystallographic structure analysis. This
stereoselectivity could be explained by the model depicted in
Scheme 4, which originates from Hayashi’s model for the
arylation of arylimine catalyzed by the rhodium−diene catalyst.3b
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In conclusion, we discovered an efficient rhodium catalytic
system for the highly enantioselective alkenylation of aliphatic
imines. Various alkenyltrifluoroborates with different branch
structures and functional groups could successfully react with a
variety of aliphatic imines, providing the desired products in
good yields and excellent enantioselectivities. The key to the
success is the utilization of an active diene−rhodium catalyst as
well as the precise control of reaction conditions. Our developed
transformation provides a modular synthetic approach, not only
for chiral alkylalkenylamines but also for chiral dialkylamines.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02737.
(7) For examples on catalytic rhodium-catalyzed 1,2-addition of
allylboron reagents to aromatic imines, see: (a) Luo, Y.; Hepburn, H. B.;
Chotsaeng, N.; Lam, H. W. Angew. Chem., Int. Ed. 2012, 51, 8309.
(b) Martínez, J. I.; Smith, J. J.; Hepburn, H. B.; Lam, H. W. Angew.
Chem., Int. Ed. 2016, 55, 1108.
Experimental procedures, compound characterization
data (PDF)
X-ray data for compound 3aa (CIF)
(8) (a) Brak, K.; Ellman, J. A. J. Am. Chem. Soc. 2009, 131, 3850.
(b) Brak, K.; Ellman, J. A. J. Org. Chem. 2010, 75, 3147.
(9) For reviews of chiral diene ligands, see: (a) Defieber, C.;
Grutzmacher, H.; Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47, 4482.
(b) Shintani, R.; Hayashi, T. Aldrichimica Acta 2009, 42, 31. (c) Feng,
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: fengcg@sioc.ac.cn
*E-mail: lingq@sioc.ac.cn
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DOI: 10.1021/acs.orglett.7b02737
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Letter
C.-G.; Xu, M.-H.; Lin, G.-Q. Synlett 2011, 2011, 1345. (d) Feng, X.; Du,
H. Asian J. Org. Chem. 2012, 1, 204.
(10) For seminal references on chiral bicyclo[3.3.0]octadiene ligands,
see: (a) ref 3e. (b) Helbig, S.; Sauer, S.; Cramer, N.; Laschat, S.; Baro, A.;
Frey, W. Adv. Synth. Catal. 2007, 349, 2331.
(11) Lennox, A. J. J. G.; Lloyd-Jones, C. J. Am. Chem. Soc. 2012, 134,
7431.
(12) A blank test was carried out to compare the stability of (E)-
styrylboronic acid and phenylboronic acid, which showed a much faster
degradation of the (E)-styrylboronic acid in the reaction conditions. See
the Supporting Information for details.
(13) For reviews on organotrifluoroborates, see: (a) Darses, S.; Genet,
J.-P. Chem. Rev. 2008, 108, 288. (b) Molander, G. A.; Sandrock, D. L.
Curr. Opin. Drug Discovery Dev. 2009, 12, 811. (c) Molander, G. A. J. Org.
Chem. 2015, 80, 7837.
(14) Several other chiral bicyclo[3.3.0]octadiene ligands were
evaluated but did not afford better results than the used diene L1. See
the Supporting Information for details.
(15) Cyclohexanecarboxaldehyde-derived imines with N-Boc or N-
diphenylphosphinoyl protecting group were also tested but failed to
afford desired products.
(16) The (Z)-styryltrifluoroborate was tested to afford the addition
product in <10% yield and as an inseparable Z/E mixture (Z/E = 2:1).
D
DOI: 10.1021/acs.orglett.7b02737
Org. Lett. XXXX, XXX, XXX−XXX