Copper-catalyzed enantioselective propargylic substitution of propargylic acetates with enamines

Article abstract of DOI:10.1039/c4ra09431j

With the use of chiral tridentate P,N,N ligand, copper-catalyzed enantioselective propargylic substitution of propargylic acetates with enamines has been achieved, giving the corresponding propargylic ketones in high yields and with excellent enantioselec

Full text of DOI:10.1039/c4ra09431j

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Copper-catalyzed enantioselective propargylic
substitution of propargylic acetates with enamines†
Cite this: RSC Adv., 2014, 4, 53216
a
b
Bo Wang,ab Chunxiao Liu and Hongchao Guo
*
Received 28th August 2014
Accepted 8th October 2014
DOI: 10.1039/c4ra09431j
www.rsc.org/advances
With the use of chiral tridentate P,N,N ligand, copper-catalyzed b-keto acid could undergo asymmetric propargylic substitution
enantioselective propargylic substitution of propargylic acetates with reaction to give chiral propargylic-substituted products. Among
enamines has been achieved, giving the corresponding propargylic various nucleophiles, enamine is a quite attractive one. It can be
ketones in high yields and with excellent enantioselectivities.
used as a variation of the a-carbanions of ketones, avoiding
using a strong base in the reaction process.8 In 2009, Hou and
coworkers rst used enamines as carbon nucleophiles in
asymmetric propargylic substitution reactions.7d Using CuClO4/
(R)-Cl-MeOBIPHEP as the catalyst, the reaction of propargylic
alcohol acetate with enamines worked efficiently under mild
conditions to give the corresponding chiral b-ethynyl-
substituted ketones in high yields and in good to high enan-
tioselectivities. However, the enantioselectivities of the reac-
tions were not very satisfactory. The ees of the chiral products
except for two cases were below 90%. Therefore novel chiral
catalyst with better enantioselectivity for this reaction is highly
desirable. Recently, chiral tridentate P,N,N ligands have been
used in the propargylic substitution and cycloaddition
reactions of propargylic alcohol derivatives, giving the corre-
sponding products in high yields and excellent enantiose-
lectivities.9 In this context, we explored the application of chiral
tridentate P,N,N ligand in propargylic substitution of
propargylic acetates with enamines (Scheme 1). Herein, we
reported in the presence of chiral tridentate P,N,N ligand,
The propargylic substitution reaction of propargylic alcohol as
well as its derivatives with nucleophiles is one of the most useful
tools for the synthesis of various alkyne moiety-containing
molecules,1 which could easily be further transformed into
useful complex compounds.2 Since Nicholas and coworkers
reported Co-mediated propargylic substitution reaction of
propargylic alcohol in 1977,3 many metal catalytic systems such
as Ti, Fe, Ni, Cu, Ru, Pd, Re, Bi, Sc, Ir, Pt, and Au, have
successfully been developed.1 A wide range of nucleophiles such
as carbon, oxygen, sulfur, and nitrogen can be used in the
reaction. Owing to very signicant value of chiral propargylic-
substituted products in organic synthesis, asymmetric cata-
lytic propargylic substitution reaction of propargylic alcohol
derivatives with nucleophiles has attracted much attention in
recent years.4 In 2003, using thiolate-bridged diruthenium
complexes as chiral catalyst, Hidai, Uemura, and co-workers
achieved the rst catalytic asymmetric propargylic substitu-
tion reaction of propargylic alcohol with acetone.5 Although
only up to 35% ee was obtained in the reaction, the work trig-
gered the researcher's intense interest to asymmetric catalytic
propargylic substitution reaction. In the past decade, a few
metal catalysts such as Ru6 and Cu7 for asymmetric propargylic
substitution reaction have been discovered. In the presence of
these catalysts, a variety of nucleophiles such as ketone,
aromatic compounds, alkene, aldehyde, amine, enamine and
aState Key Laboratory Breeding Base of Green Pesticide and Agricultural
Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering,
Ministry of Education, Guizhou University, Huaxi District, Guiyang 550025, China
bDepartment of Applied Chemistry, China Agricultural University, Beijing 100193,
China. E-mail: hchguo@cau.edu.cn
† Electronic supplementary information (ESI) available: Characterization data
spectra of all products. See DOI: 10.1039/c4ra09431j
Scheme
acetates with enamines.
1 Cu-catalyzed propargylic substitution of propargylic
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copper-catalyzed highly enantioselective propargylic substitu- reactions were carried out in MeOH at 0 C in the presence of
tion of propargylic acetates with enamines for synthesis of Cu(CH3CN)4ClO4 (5 mol%), tridentate P,N,N ligand (L) (7.5
chiral propargylic ketones.
mol%) and the base i-Pr2NEt.
In the initial experiments, using the tridentate P,N,N ligand
Under the optimized conditions, we examined the scope of
(L) as chiral ligand,9e,10 we studied propargylic substitution of propargylic acetate and enamine. As indicated in Table 2,
propargylic acetate (1a) with enamine (2a) (Table 1). Since propargylic substitution of various propargylic acetate (1) with
copper catalyst has been demonstrated to be a good catalyst for N,N-diethyl-1-phenylethenamine (2a) worked very well to give
propargylic substitution of propargylic acetate (1a) with the propargylic substitution ketones in high yield (75–95%) and
enamine (2a),7d several copper salts were examined with meth- excellent enantioselectivities (95–98% ee) (entries 1–11). Both
anol as the solvent. To our delight, in the presence of 5 mol% of electron-donating and electron-withdrawing substituents on
Cu(OAc)2 and 7.5 mol% of chiral ligand (L), propargylic acetate the benzene ring of propargylic acetates were well tolerated in
(1a) was treated with enamine (2a) in methanol for 12 h to give the propargylic substitution reactions, and the substitution
the corresponding product 3aa in 52% yield and 76% ee pattern had no signicant inuence on the activity and stereo-
(entry 1). Using Cu(OTf)2 as the catalyst, the product could be selectivity (entries 1–9). In addition, 2-naphthyl and 2-thienyl
obtained in 70% yield and 73% ee (entry 2). The yield was propargylic acetates (1j and 1k) were also compatible substrates
markedly increased, at the same time, the enantioselectivity (entries 10–11). 2-Naphthyl substituted propargylic acetate (1j)
nearly did not degraded. But the copper salts such as CuCl and carried out propargylic substitution with enamine (2a),
CuI were sluggish, resulting in the propargylic substitution providing the corresponding product in 85% yield and 96% ee
product in poor yield with poor or moderate ee (entries 3, 4). In (entry 10). 2-Thienyl substituted propargylic acetate (1k)
particular, using 5 mol% of Cu(CH3CN)4ClO4, the product 3aa underwent the reaction to give the substitution product in 76%
was obtained in 75% yield and 93% ee (entry 5). The solvent yield and 96% ee (entry 11). Aer investigation of the scope of
screening revealed that other solvents such as THF, toluene, propargylic acetates, different enamines were evaluated in
CH2Cl2, acetone and acetonitrile are not compatible with this asymmetric
propargylic
substitution
reaction
with
reaction. Using these solvents, no product or trace of product 1-phenylprop-2-yn-1-yl acetate (1a). A broad range of aromatic
was observed on the TLC (entries 6–10). Through lowering the enamines with electron-donating and electron-withdrawing
reaction temperature to 0 ꢀC, the yield and ee were increased to
90% and 97%, respectively (entry 11). According to these
screening results, the following propargylic substitution
Table 2 Cu-catalyzed enantioselective propargylic substitution of
propargylic acetates (1) with enamines (2)a
Table 1 Screening of the reaction conditionsa
Entry R1
R2
3
Yieldb (%) Eec (%)
1
2
3
4
5
6
7
8
Ph (1a)
4-MeC6H4 (1b)
4-OMeC6H4 (1c) Ph (2a)
Ph (2a)
Ph (2a)
3aa 90
3ba 92
3ca 95
3da 86
3ea 75
3fa 88
3ga 95
3ha 83
3ia 80
3ja 85
3ka 76
3ab 81
97
97
95
96
97
98
97
96
96
96
96
96
96
96
96
97
96
4-FC6H4 (1d)
2-ClC6H4 (1e)
3-ClC6H4 (1f)
4-ClC6H4 (1g)
4-BrC6H4 (1h)
4-CF3C6H4 (1i)
2-naphthyl (1j)
2-thienyl (1k)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
4-MeC6H4 (2b)
4-OMeC6H4 (2c) 3ac 88
4-FC6H4 (2d)
3-ClC6H4 (2e)
4-ClC6H4 (2f)
4-BrC6H4 (2g)
Entry
[Cu]
Solvent
T
Yieldb (%)
Eec (%)
1
2
3
4
5
6
7
8
Cu(OAc)2
Cu(OTf)2
CuCl
MeOH
MeOH
MeOH
MeOH
MeOH
THF
Toluene
CH2Cl2
Acetone
CH3CN
MeOH
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0 ꢀ
52
70
25
30
76
73
8
55
9
CuI
10
11
12
13
14
15
16
17
CuClO4
CuClO4
CuClO4
CuClO4
CuClO4
CuClO4
CuClO4
75
93
n.r.d
n.r.
Trace
Trace
n.r.
90
n.d.e
n.d.
n.d.
n.d.
n.d.
97
3ad 83
3ae 87
3af 86
3ag 80
9
10
11
C
Ph (1a)
a
Reactions of 1a (0.5 mmol), 2a (1.0 mmol), copper salt (0.025 mmol), L
a
(0.038 mmol) and i-Pr2NEt (1.2 mmol) were carried out in 4.0 mL of
Reactions of 1 (0.5 mmol), 2 (1.0 mmol), Cu(CH3CN)4ClO4 (0.025
b
solvent for 12 h. CuClO4
¼
Cu(CH3CN)4ClO4. Isolated yields. mmol), L (0.038 mmol) and i-Pr2NEt (1.2 mmol) were carried out in
c
b
c
Determined by chiral HPLC analysis. The absolute conguration was 4.0 mL of MeOH at 0 ꢀC for 12 h. Isolated yields. Determined by
determined by comparing the optical rotation with the data in ref. 9e. chiral HPLC analysis. The absolute conguration was determined by
d
n.r. ¼ No reaction. e n.d. ¼ Not determined.
comparing the optical rotation with the data in ref. 9e.
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substituents were employed under the optimal reaction condi-
tions, affording the corresponding products in 80–88% yields
with uniformly excellent enantioselectivities (96–97% ee)
(entries 12–17).
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Conclusions
In summary, using a chiral tridentate P,N,N ligand, we have
developed Cu-catalyzed enantioselective propargylic substitu-
tion of propargylic acetates with enamines to give the prop-
argylic ketones in high yields with excellent enantioselectivities.
The reaction proceeds smoothly under mild conditions and
provides an expedient access to highly valuable chiral prop-
argylic ketone compounds.
Acknowledgements
This study was supported by the National S&T Pillar Program of
China (No. 2012BAK25B03). Prof. Xiangping Hu in the Dalian
Institute of Chemical Physics is gratefully acknowledged for the
constructive discussion and for providing the chiral ligand.
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