Nickel-Catalyzed Asymmetric Propargylic Amination of Propargylic Carbonates Bearing an Internal Alkyne Group

Article abstract of DOI:10.1021/acs.orglett.8b02325

We have achieved the nickel-catalyzed asymmetric propargylic amination of propargylic carbonates bearing an internal alkyne group. A wide variety of propargylic carbonates and N-methylaniline derivatives were tolerated under the reaction conditions, providing the corresponding chiral propargylic amines in up to 97% yield with up to 97% ee.

Full text of DOI:10.1021/acs.orglett.8b02325

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nickel-Catalyzed Asymmetric Propargylic Amination of Propargylic
Carbonates Bearing an Internal Alkyne Group
Kouichi Watanabe, Yusuke Miyazaki, Masataka Okubo, Biao Zhou, Hiroaki Tsuji,*
and Motoi Kawatsura*
Department of Chemistry, College of Humanities & Sciences, Nihon University, Sakurajosui, Setagaya-ku, Tokyo 156-8550, Japan
S
* Supporting Information
ABSTRACT: We have achieved the nickel-catalyzed asym-
metric propargylic amination of propargylic carbonates bearing
an internal alkyne group. A wide variety of propargylic
carbonates and N-methylaniline derivatives were tolerated
under the reaction conditions, providing the corresponding
chiral propargylic amines in up to 97% yield with up to 97% ee.
Scheme 1. Catalytic Asymmetric Propargylic Amination of
Propargylic Alcohol Derivatives
he catalytic asymmetric propargylic substitution reaction
Thas been recognized as a powerful tool for the efficient
synthesis of chiral propargylic compounds.1 Since the pioneer-
ing work by Nishibayashi and co-workers in 2003,2 the
asymmetric propargylic substitution reaction of propargylic
alcohol derivatives with carbon- and heteroatom-centered
nucleophiles has been extensively studied using ruthenium3
and copper4 catalyst systems. However, these catalyst systems
usually could not be applicable for the reaction of propargylic
alcohol derivatives bearing an internal alkyne group,5 because a
terminal alkyne group is necessary for the formation of the
metal-allenylidene intermediates,6 which play a key role in the
substitution reaction. Therefore, the catalytic asymmetric
propargylic substitution reaction of these substrate classes is
limited to only a few examples.7 In this context, developing a
catalyst system for achieving the asymmetric propargylic
substitution reaction of propargylic alcohol derivatives bearing
an internal alkyne group is highly desirable.
Chiral propargylic amines have attracted considerable
attention because of their prevalence in synthetic intermediates
and biologically active compounds.8 The catalytic asymmetric
propargylic amination of propargylic alcohol derivatives offers
an important approach for accessing enantioenriched prop-
argylic amines.9 Although the catalytic asymmetric propargylic
amination of propargylic alcohol derivatives bearing a terminal
alkyne group has been well studied using copper catalysis
(Scheme 1, eq 1),4a−i the use of propargylic alcohol derivatives
bearing an internal alkyne group remains unexplored.10 We
describe herein the nickel-catalyzed asymmetric propargylic
amination of propargylic alcohol derivatives having an internal
alkyne group (Scheme 1, eq 2).
tAmOH at room temperature for 12 h (Table 1, entry 1).
Fortunately, the desired propargylic amine 3aa was obtained in
75% yield with 91% ee. To further improve the enantiose-
lectivity, we tested other chiral bidentate phosphine ligands
such as (R)-Tol-BINAP L2, (R)-SEGPHOS L3, and (R)-
DTBM-SEGPHOS L4 (Table 1, entries 2−4). Among these
ligands, (R)-SEGPHOS L3 showed high catalytic performance
(Table 1, entry 3). On the other hand, (S,S)-iPr-Pybox L5 and
(S,S)-tBu-BOX L6 were ineffective for the present reaction
system (Table 1, entries 5 and 6). Based on these results, we
chose (R)-SEGPHOS L3 as the chiral ligand for further
optimization studies. The amount of (R)-SEGPHOS L3 could
be reduced to 5 mol % while maintaining a high
enantioselectivity, albeit with a low yield (Table 1, entry 7).
When the reaction was carried out at 60 °C, the desired
product 3aa was obtained in 68% yield with 95% ee (Table 1,
entry 8). Prolonging the reaction time from 12 to 48 h led to
an increase of the yield of 3aa without any loss of
enantioselectivity (Table 1, entry 9). Finally, the use of 1.5
Inspired by the nickel-catalyzed asymmetric arylation of
propargylic alcohol derivatives bearing an internal alkyne
group,7a,d we chose a nickel catalyst system for the
optimization of the reaction conditions (Table 1). We initially
examined the reaction of propargylic carbonate 1a bearing an
internal alkyne group with N-methylaniline 2a in the presence
of 2.5 mol % of Ni(cod)2 and 10 mol % of (R)-BINAP L1 in
Received: July 26, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02325
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of Reaction Conditions
Table 2. Scope of Propargylic Carbonates 1
b
c
b
c
entry
1
Ar
3
yield (%)
ee (%)
entry
L
temp (°C)
yield (%)
ee (%)
d
1
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
Ph
3aa
3ba
3ca
3da
3ea
3fa
3ga
3hb
3ia
3ja
3ka
3la
3ma
3na
96
92
80
85
74
72
90
74
85
83
90
52
92
88
95
96
96
94
95
96
94
96
94
95
91
96
79
95
1
L1
L2
L3
L4
L5
L6
L3
L3
L3
L3
rt
rt
rt
rt
rt
rt
rt
60
60
60
75
43
55
16
<1
<1
38
68
86
91
91
93
96
95
−
2
3
4
5
6
7
4-MeC6H4
4-MeOC6H4
4-CF3C6H4
4-(CO2Et)C6H4
4-FC6H4
4-BrC6H4
4-PhC6H4
3-MeC6H4
3-FC6H4
2
3
4
5
6
7
8
9
−
d
d
96
95
96
95
e
8
de
,
9
def
, ,
10
11
12
13
14
10
a
2-MeC6H4
2-FC6H4
1-naphtyl
Reaction conditions: 1a (0.2 mmol), 2a (0.5 mmol), Ni(cod)2
(0.005 mmol), L (0.02 mmol) in tAmOH (0.25 mL) at room
temperature for 12 h. Isolated yield. Determined by chiral HPLC
b
c
d
e
f
analysis. With 5.0 mol % of L3. For 48 h. With 1.5 equiv of 2a.
2-thienyl
a
Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), Ni(cod)2 (0.005
mmol), (R)-SEGPHOS (0.01 mmol) in tAmOH (0.25 mL) at 60 °C
for 48 h. Isolated yield. Determined by chiral HPLC analysis.
mmol of 1a was used. 4-Bromo-N-methylaniline 2b was used as the
amine instead of N-methylaniline 2a.
b
c
d
1
e
9−13). Propargylic carbonate 1n bearing a 2-thienyl ring can
be converted into propargylic amine 3na in 88% yield with
95% ee (entry 14). Unfortunately, our catalyst system did not
work for the reaction of propargylic carbonates having
trimethylsilyl (Ar = TMS, R = Me) and terminal alkyne
groups (Ar = H, R = Me). We also examined the reaction of
propargylic carbonate bearing a trifluoromethyl group at the
propargylic position instead of a methyl group, but the desired
propargylic amines were not formed.
Encouraged by our success in the nickel-catalyzed
asymmetric propargylic amination, we next investigated the
reaction of propargylic carbonate 1a with various aniline
derivatives 2 (Table 3). N-Methylaniline derivatives 2b−e
having para-substituents (Me, MeO, F, Br) on their phenyl
rings were smoothly reacted with propargylic carbonate 1a
under the optimized reaction conditions, providing the
corresponding propargylic amines 3ab−ae in high yields with
excellent enantioselectivity (Table 3, entries 1−4). The
reaction of N-methylaniline derivatives 2f and 2g, which
possess meta-substituents on their phenyl rings, afforded
propargylic amines 3af and 3ag in 91% and 40% yields with
95% and 96% ee, respectively (Table 3, entries 5 and 6). When
N-methylaniline derivatives 2h and 2i were used as the amine
source, the desired products 3ah and 3ai were obtained with
excellent enantioselectivity, albeit with low yields (Table 3,
entries 7 and 8). The present catalyst system was also effective
not only for N-methylaniline derivatives but also N-benzylani-
line 2j and indoline 2k (Table 3, entries 9 and 10). Aniline 2l
also underwent the reaction to furnish the amination product
3al in 24% yield with 90% ee (Table 3, entry 11).
equiv of N-methylaniline 2a afforded the propargylic amine
3aa in 91% yield with 95% ee (Table 1, entry 10).
With the optimized reaction conditions in hand, we
examined the applicability of the asymmetric nickel catalysis
with respect to propargylic carbonates 1 bearing a wide variety
of internal alkyne groups using N-methylaniline 2a as the
amine source (Table 2). The reaction of propargylic carbonate
1a could be conducted on a 1 mmol scale, affording the desired
product 3aa without any loss of the catalytic performance
(Table 2, entry 1). The reaction of propargylic carbonates 1b−
e bearing electron-donating and -withdrawing substituents on
their phenyl rings proceeded well to give the corresponding
propargylic amines 3ba−ea in 74−92% yields with 94−96% ee
(Table 2, entries 2−5). Propargylic carbonates 1f and 1g
having fluoro and bromo atoms were tolerated under the
reaction conditions to furnish the desired products 3fa and 3ga
in 72% and 90% yields with 96% and 95% ee, respectively
(Table 2, entries 6 and 7). The reaction of a biphenyl-group-
containing substrate 1h with 4-bromo-N-methylaniline 2b
instead of N-methylaniline 2a gave the desired product 3hb in
74% yield with 96% ee, and the absolute configuration of 3hb
was determined to be R by an X-ray crystallographic analysis
(Table 2, entry 8). 3-Methyl phenyl (1i), 3-fluorophenyl (1j),
2-methyl phenyl (1k), 2-fluorophenyl (1l), and 1-naphthyl
(1m) substituents showed no significant effect during the
catalysis. Thus, chiral propargylic amines 3ia−ma were
obtained in 52−92% yields with 79−96% ee (Table 2, entries
We propose the possible reaction pathways and stereo-
chemical models as shown in Scheme 2. Initially, the addition
of (R)- and (S)-propargylic carbonate 1a to the nickel(0)
species would occur in an anti fashion,11 giving η1-
allenylnickels I and II.12 Although the epimerization process
in the present asymmetric nickel catalysis is still unclear, we
B
DOI: 10.1021/acs.orglett.8b02325
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
group on the γ carbon atom of the η1-allenylnickel II and the
phenyl group on the phosphine moiety of (R)-SEGPHOS.
To support these suggested reaction pathways, we examined
preliminary mechanistic studies as shown in Scheme 3. When
Table 3. Scope of Amines 2
Scheme 3. Reaction of Chiral Propargylic Carbonates for
Preliminary Mechanistic Studies
a
b
c
entry
2
Ar
R
3
yield (%) ee (%)
1
2
3
4
5
6
7
8
9
2c
2d
2e
2b
2f
2g
2h
2i
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-BrC6H4
3-MeC6H4
3-FC6H4
2-MeC6H4
2-FC6H4
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Bn
−
3ac
3ad
3ae
3ab
3af
3ag
3ah
3ai
92
97
82
76
91
46
18
19
86
73
24
95
95
95
96
95
96
96
97
89
94
90
a
Reaction conditions: (R)- or (S)-1a (0.2 mmol), 2 (0.3 mmol),
Ni(cod)2 (0.005 mmol), DPEPHOS or (R)-SEGPHOS (0.01 mmol)
in tAmOH (0.25 mL) at 60 °C for 48 h.
2j
2k
2l
3aj
3ak
3al
d
10
11
−
Ph
H
a
Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), Ni(cod)2 (0.005
mmol), (R)-SEGPHOS (0.01 mmol) in tAmOH (0.25 mL) at 60 °C
the reaction of (R)- or (S)-1a with N-methylaniline 2a was
carried out in the presence of 2.5 mol % of Ni(cod)2 and 5 mol
% of DPEphos, an almost racemic 3aa was obtained.
Furthermore, both (R)- and (S)-1a were converted into (R)-
3aa under the optimized reaction conditions.14 These results
suggest that the epimerization of the η1-allenylnickel species
would proceed via the propargylic cation intermediates.1c The
involvement of a μ−η3-allenyl/propargyl dinuclear complex15
and a radical species16 could not be ruled out. The detailed
mechanistic studies are under investigation.
b
c
for 48 h. Isolated yield. Determined by chiral HPLC analysis.
d
Indoline was used as the amine.
Scheme 2. Plausible Reaction Pathways and Stereochemical
Models
In conclusion, we have accomplished the nickel-catalyzed
asymmetric propargylic amination of propargylic carbonates
bearing internal alkyne groups. A wide array of the propargylic
carbonates can be transformed into the corresponding chiral
propargylic amines in good yields with excellent enantiose-
lectivities. Our nickel catalyst system enabled access to chiral
propargylic amines bearing internal alkyne groups that are
difficult to prepare using the conventional catalytic methods.
Detailed mechanistic studies and further application of our
catalyst system to other asymmetric transformations are
currently underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02325.
Experimental details and procedures; mechanistic
studies; X-ray crystal structure of 3hb; NMR spectra;
HPLC chromatograms (PDF)
Accession Codes
CCDC 1815699 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
assume that the epimerization would take place between the
η1-allenylnickels I and II via a propargylic cation intermediate
III.13 During the subsequent reaction of these two
intermediates with N-methylaniline 2a, the γ carbon atom of
the η1-allenylnickel I is attacked by the amine from its Re-face
through the favored TS1, thus leading to (R)-3aa as a major
stereoisomer. On the other hand, the reaction of the η1-
allenylnickel II with the amine through TS2 seems to be
disfavored due to the steric repulsion between the methyl
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: tsuji@chs.nihon-u.ac.jp.
*E-mail: kawatsur@chs.nihon-u.ac.jp.
C
DOI: 10.1021/acs.orglett.8b02325
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
(6) For examples, see: (a) Nishibayashi, Y.; Wakiji, I.; Hidai, M. J.
Am. Chem. Soc. 2000, 122, 11019. (b) Nishibayashi, Y.; Wakiji, I.;
Ishii, Y.; Uemura, S.; Hidai, M. J. Am. Chem. Soc. 2001, 123, 3393.
(c) Sakata, K.; Nishibayashi, Y. Catal. Sci. Technol. 2018, 8, 12 and
also see refs 4d and 13.
Biao Zhou: 0000-0002-4138-9425
Hiroaki Tsuji: 0000-0002-8899-3435
Motoi Kawatsura: 0000-0002-8341-6866
(7) (a) Smith, S. W.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 12645.
(b) Motoyama, K.; Ikeda, M.; Miyake, Y.; Nishibayashi, Y. Eur. J. Org.
Chem. 2011, 2011, 2239. (c) Sinisi, R.; Vita, M. V.; Gualandi, A.;
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Sun, J.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 2966. For copper-
catalyzed stereospecific propargylic arylation of chiral propargylic
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in-Aid for Scientific
Research (C) from the Japan Society for the Promotion of
Science (17K05794). We thank Mr. Mikihiro Saito (Nihon
university) for his experimental support.
́
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D
DOI: 10.1021/acs.orglett.8b02325
Org. Lett. XXXX, XXX, XXX−XXX