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Letter
Kinetic Resolution of α‑Tertiary Propargylic Amines through
Asymmetric Remote Aminations of Anilines
Yongkai Pan,¶ Donglei Wang,¶ Yunrong Chen, DeKun Zhang, Wei Liu, and Xiaoyu Yang*
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sı Supporting Information
*
ABSTRACT: A practical method for kinetic resolution of α-tertiary
propargylic amines has been achieved via asymmetric remote
aminations of anilines with azodicarboxylates enabled by chiral
phosphoric acid catalysis. A broad range of aryl and alkyl groups at the
α-position, as well as the substituted alkynyl and N-aryl groups were
well tolerated in these reactions, providing high kinetic resolution
performances (with an s-factor up to 111). In addition, the α-tertiary
amines bearing an α-CN group (the Strecker reaction product) could
be kinetically resolved with excellent stereoselectivity as well under
the same reaction conditions. Fruitful transformations of the chiral amination products and the recovered propargylic amines
demonstrated the power of this method in asymmetric synthesis of α-tertiary amines and their derivatives.
KEYWORDS: kinetic resolution, propargylic amines, α-tertiary amines, asymmetric remote amination, chiral phosphoric acids
E
elegant KR methods for amines and their derivatives have
been developed via asymmetric acylations,13 hydrogen-transfer
reactions,14 and others,15 almost none of them have been
successfully applied in KR of α-tertiary amines.15a Not
surprisingly, the KR of propargylic amines through chiral
thiourea-catalyzed benzoylations13f and using a stoichiometric
amount of chiral acetylating agent13i has been developed;
however, the scope was also limited to α-secondary propargylic
amines (Figure 1d). Recently, our group reported the highly
efficient kinetic resolution of 2,2-disubstituted hydroquinolines
via chiral phosphoric acid (CPA) catalyzed remote-aminations,
which represents the first efficient KR of α,α-disubstituted Nheterocycles.16 With our continuous interest in development of
novel asymmetric amination reactions of aryl amine derivatives,17 herein we disclose the first KR of α-tertiary propargylic
amines (N-aryl propargylic amines bearing N-containing
quaternary stereocenter at the α-position) by utilizing this
strategy (Figure 1e).
We commenced our study by using racemic N-Ph α-tertiary
propargylamines 1a as a model substrate and dibenzyl
azodicarboxylate 2 as an amination reagent (Table 1). Under
the catalysis of CPA TRIP (A1, 10 mol %), the KR reaction
between racemic 1a (1.0 equiv) and azodicarboxylates 2 (1.0
equiv) proceeded smoothly in CHCl3 at 20 °C to provide the
nantioenriched propargylic amines are important building
blocks in the asymmetric synthesis of numerous chiral
pharmaceuticals1 and biologically active natural products.2
Consequently, extensive efforts have been devoted to the
development of asymmetric catalytic synthesis of propargylic
amines in the last two decades.3 However, asymmetric
methods that can generate α-tertiary propargylic amines
(with an α-tetrasubstituted stereocenter) were still quite
limited. Several elegant asymmetric addition reactions of
ketimines (either using alkynyl pronucleophiles4 or alkynyl
ketimines5) were developed for asymmetric synthesis of αtertiary propargylic amines. However, the ketimine substrates
in these reactions were limited to activated ketimines, which
possessed at least one α-electron-withdrawing group (e.g., ester
and −CF3 groups) (Figure 1a). In contrast, asymmetric
additions of acetylene derived nucleophiles to unactivated
ketimines were more challenging, probably because of the low
reactivity and difficulties in stereoselectivity control. The
Ellman group6 and the Maruoka group7 reported the
asymmetric synthesis of α-tertiary propargylamines through
chiral auxiliary mediated addition of organolithium reagents to
unactivated ketimines, respectively. Although the asymmetric
catalytic version of this reaction has been achieved by
Shibasaki and co-workers through chiral Cu(I) catalysis, only
moderate enantioselectivities were afforded in these reactions
(50−78% ee, Figure 1b).8 The alternative approaches for
asymmetric synthesis of α-tertiary propargylic amines were
enantioselective propargylic aminations, however, whose scope
was limited to ethynyl epoxides,9 ethynyl lactones,10 and
ethynyl cyclic carbonates11 (Figure 1c).
Kinetic resolution (KR) of amines12 is a practical method to
produce enantioenriched amines. Although a number of
© 2021 American Chemical Society
Received: May 24, 2021
Revised: June 21, 2021
Published: June 25, 2021
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Letter
Table 1. Optimizations of Reaction Conditionsa
entry
cat
sol.
time
(h)
ersb
erpb
Cc
(%)
sd
1
2
3
4
5
6
7
8
9
10
11
12
13e
14f
15f,g
A1
A2
A3
A4
A5
A6
A7
A8
A8
A8
A8
A8
A8
A8
A8
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
Tol
DCM
CCl4
Et2O
CHCl3
CHCl3
CHCl3
24
60
48
24
3
24
24
3
8
8
8
24
8
24
72
56:44
53:47
51:49
71:29
75:25
60.5:39.5
60:40
91:9
65:35
71:29
91:9
54.5:45.5
90:10
94:6
84:16
86:14
71.5:28.5
53:47
73.5:26.5
89.5:10.5
81.5:18.5
83:17
90.5:9.5
85.5:14.5
88:12
89:11
84:16
92:8
96:4
96.5:3.5
15
12
25
47
39
25
23
50
30
36
51
11
49
49
42
6.8
2.6
1.1
4.1
14
5.4
5.9
24
7.9
11
20
5.6
29
66
59
Figure 1. Asymmetric synthesis of α-tertiary propargylic amines.
a
Reactions were performed using 1a (0.1 mmol), 2 (0.1 mmol), CPA
catalysts (0.01 mmol), and 3 Å molecular sieves (30 mg) in solvents
(1 mL) at the designated temperature. bDetermined by HPLC
analysis on a chiral stationary phase. cConversion (C) = ees/(ees +
eep). ds = ln[(1 − C)(1 − ees)]/ln[(1 − C)(1 + ees)]. eAt 0 °C. fAt −
30 °C. gWithout 3 Å molecular sieves.
aniline para-amination product 3 with 86:14 enantiomeric
ratio (er) and the recovered 1a with 56:44 er, corresponding to
a selectivity factor (s)18 of 6.8 (entry 1). Next, a variety of
BINOL-derived CPA catalysts were screened in this reaction
(entries 2−7). Encouragingly, the 3,3′-di(9-anthracenyl)substituted CPA A7 gave an improved s-factor of 14 and a
faster reaction rate as well (entry 5). Switching the chiral
scaffold form BINOL-type to H8-BINOL-type resulted in
better kinetic resolution performance, corresponding to an sfactor of 24 (entry 8). A range of solvents were also examined
in this reaction (entries 9−12), which indicated the CHCl3 still
as the optimal solvent. As the faster reaction rate enabled by
CPA A8, the reaction temperature was further decreased to
give improved selectivities (entries 13−14), and the reaction at
−30 °C provided the optimal KR performance, with an s-factor
of 66 (entry 14, 24 h). The role of 3 Å molecular sieves (MS)
was also studied, and it was found that the absence of MS led
to markedly decreased reaction rate (entry 15). Other
commercial available azodicarboxylates were also examined in
this reaction, which generally gave poor reactivities and KR
performances (see Table S1 in Supporting Information for
details).
With the optimal KR conditions in hand, the scope of αtertiary propargylic amines and various substitutions at the αposition were first investigated (Scheme 1). A range of paraand meta-substituted phenyl groups (including both electrondonating and electron-withdrawing groups) at the α-position
of propargylic amines were evaluated (1b−1f), which were
well tolerated with the standard conditions, providing excellent
kinetic resolution performances (s-factor up to 85). The
disubstituted phenyl (1g), 2-naphthyl (1h), and 2-thienyl (1i)
groups were also amenable variants under these conditions.
However, the ortho-substituted phenyl group was not tolerated
in this reaction, which gave markedly diminished KR
performance (see 1u in Scheme S1 in Supporting Information). The absolute configurations of the chiral products were
assigned by analogy to recovered (R)-1a, whose structure was
unambiguously determined by X-ray crystallography.19 Next, a
series of alkyl groups other than the methyl group at the 1position of propargylic amine 1 were also examined, which
suggested that both primary alkyl groups (1j−1m) and
sterically demanding secondary alkyl group (1n) were
compatible with this kinetic resolution reaction.
The scope of the alkynyl and N-aryl substitutions of the
propargylic amine substrates was also examined under the
optimal kinetic resolution conditions (Scheme 2). A series of
substituents at the acetylene site were investigated, which
indicated that both the aryl/heteroaryl groups (1o and 1p) and
the alkyl group (1q) were compatible with these conditions,
providing both the amination products and recovered SM with
high enantioselectivities. In addition, the substituted N-aryl
groups were also screened, which suggested that the 3substituted anilines (1r and 1s) and 3,5-disubstituted aniline
(1t) could be well tolerated under the standard conditions;
however, the 2-substituted aniline only afforded poor KR
performance (see 1v in Scheme S1 in Supporting Information).
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Scheme 1. Scope for KR of α-Tertiary Propargylic Amines
Regarding α-Substitutionsa
Letter
Scheme 2. Scope for KR of α-Tertiary Propargylic Amines
Regarding Alkynyl and N-aryl Substitutionsa
a
Reactions were run with 1 (0.2 mmol), 2 (0.2 mmol) with CPA (S)A8 (0.02 mmol, 10 mol %) in CHCl3 (2 mL) at designated
temperatures in the presence of activated 3 Å molecular sieves (100
mg) for 18−48 h. Isolated yields were reported. Er values were
determined by HPLC analysis on a chiral stationary phase. s = ln[(1 −
C)(1 − ees)]/ln[(1 − C)(1 + ees)]. Conversion (C) = ees/(ees + eep).
b
At −10 °C. cAt −20 °C. dAt −50 °C.
Scheme 3. KR of α-Tertiary Allylic Amine, Strecker
Reaction Product, and N,N-Disubstituted Propargylic
Amine
a
Reactions were run with 1 (0.2 mmol), 2 (0.2 mmol) with CPA (S)A8 (0.02 mmol, 10 mol %) in CHCl3 (2 mL) at −30 °C in the
presence of activated 3 Å molecular sieves (100 mg) for 19−72 h.
Isolated yields were reported. Er values were determined by HPLC
analysis on a chiral stationary phase. s = ln[(1 − C)(1 − ees)]/ln[(1
− C)(1 + ees)]. Conversion (C) = ees/(ees + eep). bAt −20 °C. cAt 0
°C. dAt −40 °C.
With the excellent kinetic resolution performances afforded
for a wide array of α-tertiary propargylic amines, we turned our
attention to the kinetic resolution of other types of racemic αtertiary amines by utilizing this asymmetric amination strategy
(Scheme 3). However, using the optimal KR conditions on
racemic α-tertiary allylic amine 4a produced the recovered 4a
and the amination product 5a in almost racemic form,
suggesting extremely poor kinetic resolution performance
(Scheme 3a). Interestingly, the KR of α-tertiary amine 6a
bearing an α-cyano group (the Strecker reaction product)
using the standard conditions provided the recovered (S)-6a in
52% yield with 93:7 er and the amination product 7a in 46%
yield with 99:1 er, corresponding to an excellent s-factor of 276
without optimizations (Scheme 3b). Together with the
excellent KR performances for α-tertiary propargylic amines,
these results clearly implied that the sp-hybrid substituents at
the α-position of these α-tertiary amines were critical for the
stereodiscrimination of the three non-hydrogen substituents
with the chiral catalyst, which may be attributed to the unique
shape of these groups or the presence of additional interaction
with the catalyst. In addition, the KR of N-Me-N-Phsubstituted propargylic amine 8a was studied under the
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Letter
CAN readily provided the free primary amine, isolated as its
benzoylated analogue 12a in 44% yield (two steps) with 93:7
er. In addition, the transformations of the versatile alkynyl
group in the recovered propargylic amines (R)-1a were also
studied. The cyclization of (R)-1a enabled by Au(I)-catalyst
provided the dihydroquinoline 13a bearing α,α-disubstitutions
(Scheme 4d). On the other hand, the [3 + 2] cycloaddition of
(R)-1a with BnN3 in the presence of Cu(I)-catalyst gave the
triazole product 14a in 71% yield with 92.5:7.5 er. Reduction
of the acetylene group of (R)-1a with LiAlH4 afforded the
corresponding α-tertiary allylic amine (R)-4a with retained
enantiopurity (Scheme 4e), which could not be accessed via
the KR of racemic allylic amines as shown in Scheme 3a.
Treatment of allylic amine (R)-4a with PhBr under Pdcatalysis generated the aziridines 15a with excellent diastereoselectivity (>25:1 dr),20 which would be a useful building
block for further derivatizations.
In conclusion, we disclose the first kinetic resolution of αtertiary propargylic amines through chiral phosphoric acidcatalyzed asymmetric remote aminations of anilines with
azodicarboxylates, which represents a practical method to
produce α-tertiary propargylic amines without bearing αactivation groups. A wide array of aryl and alkyl groups at the
α-position, as well as the alkynyl and N-aryl variants of the
propargylic amines were well compatible in these reactions,
providing excellent KR performances (with s-factors up to
111). Moreover, the α-tertiary amines bearing an α-CN group
(the Strecker reaction product) could be kinetically resolved
with excellent stereoselectivity as well under the same reaction
conditions. Gram-scale reaction and fruitful transformations of
the chiral amination products and the recovered propargylic
amines demonstrated the utilities of this kinetic resolution
method in asymmetric synthesis of α-tertiary amines and their
derivatives.
standard conditions, which gave the products with extremely
low conversion and s-factor, suggesting the critical role of the
hydrogen-bonding interaction between the NH group of the
substrate and the PO moiety of the CPA catalyst (Scheme
3c).
To demonstrate the practicability of these KR reactions, the
large-scale KR of racemic propargylic amine 1a (1.1 g, 5.0
mmol) with reduced CPA catalyst loading (5 mol %) at −20
°C proceeded smoothly to provide the amination product 3a
in 48% yield with 94:6 er and recovered (R)-1a in 51% yield
with 92:8 er, corresponding to an s-factor of 41 (Scheme 4a).
Scheme 4. Gram-Scale KR Reaction and Derivatizations of
Chiral Products
■
ASSOCIATED CONTENT
* Supporting Information
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.1c02331.
Full experiments and characterization data including 1H
and 13C NMR spectra and HPLC for the synthesized
products (PDF)
■
Crystallographic data for (R)-1a (CIF)
AUTHOR INFORMATION
Corresponding Author
Xiaoyu Yang − School of Physical Science and Technology,
ShanghaiTech University, Shanghai 201210, China;
orcid.org/0000-0002-0756-0671; Email: yangxy1@
shanghaitech.edu.cn
The derivatizations of the chiral amination products were also
studied to showcase the utilities of these methods. Notably,
treatment of the amination product 3a with basic conditions at
70 °C facilely removed the para-hydrazine motif to return the
chiral starting material (S)-1a, thus realizing the enantiodivergent synthesis of α-tertiary propargylic amine 1a (Scheme
4b). Furthermore, catalytic hydrogenation of 3a using Raney
Ni as catalyst provided the free 1,4-phenyldiamine derivative
10a in 84% yield, with concomitant hydrogenation of the
acetylene group (Scheme 4c). Diazotization of 10a with
NaNO2 followed by treatment with NaI gave the paraiodonation product 11a, which would be useful for further
derivatizations. Additionally, the N-aryl group could be
removed under oxidative conditions; treatment of 10a with
Authors
Yongkai Pan − School of Physical Science and Technology,
ShanghaiTech University, Shanghai 201210, China
Donglei Wang − School of Physical Science and Technology,
ShanghaiTech University, Shanghai 201210, China;
University of Chinese Academy of Sciences, Beijing 100049,
China; Shanghai Institute of Organic Chemistry, Shanghai
200032, China
Yunrong Chen − School of Physical Science and Technology,
ShanghaiTech University, Shanghai 201210, China
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Catalysis: An Anion Binding Approach to the Kinetic Resolution of
DeKun Zhang − School of Physical Science and Technology,
ShanghaiTech University, Shanghai 201210, China
Wei Liu − School of Physical Science and Technology,
ShanghaiTech University, Shanghai 201210, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.1c02331
Author Contributions
¶
Y.P. and D.W. contributed equally.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
We gratefully acknowledge NSFC (Grant Nos. 21702138,
21901162) and ShanghaiTech University start-up funding for
financial support. The authors thank the support from
Analytical Instrumentation Center (# SPST-AIC10112914),
SPST, ShanghaiTech University, and Dr. Na Yu for the X-ray
crystallographic analysis.
■
Letter
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