Asymmetrie copper-catalyzed propargylic substitution reaction of propargylic acetates with enamines

Article abstract of DOI:10.1021/ol901891u

Enamines served as carbon-nucleophiles for the first time In the Cu-catalyzed asymmetric propargylic substitution reaction of propargylic acetates, providing corresponding chiral β-ethynyl-substituted ketones In high yields and In good to high enantioselectivity.

Full text of DOI:10.1021/ol901891u

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4612-4615
Asymmetric Copper-Catalyzed
Propargylic Substitution Reaction of
Propargylic Acetates with Enamines
Ping Fang and Xue-Long Hou*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
xlhou@mail.sioc.ac.cn
Received August 14, 2009
ABSTRACT
Enamines served as carbon-nucleophiles for the first time in the Cu-catalyzed asymmetric propargylic substitution reaction of propargylic
acetates, providing corresponding chiral ꢀ-ethynyl-substituted ketones in high yields and in good to high enantioselectivity.
The diverse transformations of the alkyne moiety into other
functional groups make the propargylic substitution reaction an
attractive protocol in the construction of complex molecules.1
Nicholas reported the reaction of electron-rich aromatic com-
pounds with a stoichiometric amount of Co-complex in 1977.2
Murahashi realized the propargylic substitution reaction of
propargyl esters with amines by using a catalytic amount of
CuCl.3 Since then, great progress has been made. Nowadays,
a variety of metal- and organo-catalysts have been used as
catalysts effectively, and amines, amides, thiols, ketones, and
many others have served as nucleophiles, providing correspond-
ing propargyl derivatives.4 However, the asymmetric version
of the reaction with a catalytic amount of chiral catalyst had
not been realized for a long time. The breakthrough was made
by Nishibayashi, who reported the first successful example of
an asymmetric propargylic substitution reaction of propargylic
alcohols with acetone catalyzed by the Ru complex, up to 82%
ee being realized.5 Recently, van Maarseveen and Nishibayashi
independently realized Cu-catalyzed asymmetric propargylic
substitution of propargylic acetates with amines as nucleophiles,
affording corresponding chiral amines in up to 88% and 89%
ee, respectively.6 Despite these great achievements, the asym-
metric catalytic version of the reaction is still rare; in particular,
the carbon-nucleophile has been limited in the use of acetone
and aromatic compounds.5,7 Asymmetric catalytic propargylic
substitution reactions with carbon-nucleophiles are still a far
(1) (a) Hudrlik, P. F.; Hudrlik, A. M. In The Chemistry of the Carbon-
Carbon Triple Bond; Patai, S., Ed.; Wiley: Chichester, 1978; Chapter 7, p
199. (b) Trost, B. M. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4. (c) Kennedy-Smith,
J. J.; Young, L. A.; Toste, F. D. Org. Lett. 2004, 6, 1325. (d) Luzung,
M. R.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 15760. (e) Magnus, P.
Tetrahedron 1994, 50, 1397. (f) Mukai, C.; Moharram, S. M.; Kataoka,
O.; Hanaoka, M. J. Chem. Soc., Perkin Trans. 1 1995, 2849. (g) Jacobi,
P. A.; Murphree, S.; Rupprecht, F.; Zheng, W. J. Org. Chem. 1996, 61,
2413. (h) Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L.
J. Am. Chem. Soc. 1997, 119, 4353.
(4) For reviews, see: (a) Nishibayashi, Y.; Uemura, S. Curr. Org. Chem.
2006, 10, 135. (b) Kabalka, G. W.; Yao, M.-L. Curr. Org. Synth. 2008, 5,
28. (c) Nishibayashi, Y.; UemuraS. In: Metal Vinylidenes and Allenylidenes
in Catalysis: From ReactiVity to Applications in Synthesis; Bruneau, C.,
Dixneuf, P. H., Eds.; Wiley-VCH: Weinheim, 2008; Chapter 7. (d)
Ljungdahl, N.; Kann, N. Angew. Chem., Int. Ed. 2009, 48, 642.
(2) Lockwood, R. F.; Nicholas, K. M. Tetrahedron Lett. 1977, 18, 4163.
(3) Imada, Y.; Yuasa, M.; Nakamura, I.; Murahashi, S.-I. J. Org. Chem.
1994, 59, 2282.
10.1021/ol901891u CCC: $40.75
Published on Web 09/22/2009
 2009 American Chemical Society

less explored field,8,9 though the corresponding allylic
substitution reaction has been investigated in detail and
widely used in organic synthesis.1,10 In the course of our
research on the palladium-catalyzed asymmetric allylic
alkylation reaction, we have demonstrated the use of “hard”
carbon-nucleophiles in palladium-catalyzed allylic alkyla-
tion.11 Upon the basis of these results, the propargylic
substitution reaction with carbon nucleophiles was investi-
gated. In this communication, we report our preliminary
results of the copper-catalyzed asymmetric propargylic
substitution reaction using enamines as carbon nucleophiles.
To the best of our knowledge, this is the first report of metal-
catalyzed asymmetric propargylic substitution involving
enamines.
Table 1. Influence of the Parameters on the Reactiona
entry
1
ligand
base
yield (%)b
ee (%)c
1d
2d
3d
4d
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21e
1a
1a
1a
1a
1a
1b
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
L1
L2
L3
L4
L4
L4
L4
L4
L4
L4
L4
L4
L5
L6
L7
L8
L9
L10
L11
L12
L8
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
-
K2CO3
Et3N
pyridine
DBU
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
76
73
72
59
62
63
90
65
NR
86
complex
trace
88
74
74
93
50
27
9
10
40
54
53
72
65
-
70
-
-
71
Initially, we examined the reaction of propargylic acetate 3a
with acetophenone 2 in the presence of 10 mol % of CuI as
catalyst and LDA as base at 0 °C. However, no desired product
was provided. Considering that the enamines have widely been
used successfully as the equivalent of enolates,12 the enamine
3a was tested in the reaction (eq 1). It was found that the
reaction of 1a and 3a in MeOH with 5 mol % of CuClO4
(MeCN)4 as catalyst afforded the product in 10% yield, while
2,6-bis(oxazolinyl)pyridine L1 was used as ligand and product
4a was provided in 76% yield and in 27% ee. With these results
in hand, the influence of the parameters on the reaction was
investigated further (eq 1, Table 1).
4
62
79
5
12
59
61
81
77
61
85
88
a Molar ratio: 3a/1/base/CuClO4·(MeCN)4/L ) 1/2/4/0.05/0.05. b Isolated
yield. c Determined by HPLC. d Run at rt. e Run at -15 °C.
The results revealed that the ligand with a different type
of coordination atom showed its great impact on the
enantioselectivity of the reaction. The enantioselectivity of
the reaction was lower when the PYBOX L1-L313a (Figure
1) were used, which was improved greatly if P,P-ligand
BINAP was used (entry 4 vs entries 1-3). The enantiose-
lectivity of the reaction increased from 40% to 54% further
if the reaction proceeded at 0 °C (entry 5 vs entry 4). The
substituent on nitrogen of enamines 1 is another important
factor not only on the enantioselectivity but also on the
reactivity of the reaction. The reaction provided product 4a
in 90% yield with 72% ee when diethylamino alkene 1c was
used, while both yield and ee value decreased if morpholinyl
and pyrrolidinyl alkenes 1a and 1b were used, respectively
(entry 7 vs entries 5 and 6). The investigation of the solvent
effect showed that the MeOH is the only choice. Very poor
Figure 1. Structure of the ligands.
yields were provided or no reaction took place if other
common solvents, including THF, DME, MeCN, toluene,
CH2Cl2, DMF, and EtOH, were used in the reaction of 1c
(5) (a) Inada, Y.; Nishibayashi, Y.; Uemura, S. Angew. Chem., Int. Ed.
2005, 44, 7715. (b) Nishibayashi, Y.; Onodera, G.; Inada, Y.; Hidai, M.;
Uemura, S. Organometallics 2003, 22, 873.
(6) (a) Detz, R. J.; Delville, M. M. E.; Hiemstra, H.; van Maarseveen,
J. H. Angew. Chem., Int. Ed. 2008, 47, 3777. (b) Hattori, G.; Matsuzawa,
H.; Miyake, Y.; Nishibayashi, Y. Angew. Chem., Int. Ed. 2008, 47, 3781.
(c) Hattori, G.; Yoshida, A.; Miyake, Y.; Nishibayashi, Y. J. Org. Chem.,
DOI: 10.1021/jo901064n.
(7) Catalytic asymmetric propargylation with aromatic compounds: (a)
Matsuzawa, H.; Miyake, Y.; Nishibayashi, Y. Angew. Chem., Int. Ed. 2007,
46, 6488. (b) Matsuzawa, H.; Kanao, K.; Miyake, Y.; Nishibayashi, Y. Org.
Lett. 2007, 9, 5561. (c) Kanao, K.; Miyake, Y.; Nishibayashi, Y. Organo-
metallics 2009, 28, 2920.
Org. Lett., Vol. 11, No. 20, 2009
4613

and 3a with CuClO4/BINAP as catalyst at 0 °C (not shown
in Table 1). The base also showed its effect on the reaction.
The reaction afforded product 4a in 65% yield with 65% ee
in the absence of base (entry 8), while the use of Et3N
provided the same results as that of DIPEA (entry 10 vs entry
7). However, worse results were given when K2CO3, pyri-
dine, and DBU were used as base (entries 9, 11, and 12).
The screen of P,P-ligands showed that (S)-tol-binap L5 with
steric hindrance on the P atom afforded the product in a little
bit lower ee (entry 13). Even worse enantioselectivity was
given if (S)-xylyl-binap L6, (S)-Duphos L9,13b and (R,R)-
(-)-2,3-bis(tert-butylmethylphosphino)quinoxaline L1013c
were used, respectively (entries 14, 17, and 18). Product 4a
with similar ee was obtained when the ligands L7, L11, and
L12 were used (entries 15, 19, and 20), and the ee value
increased to 79% if (R)-Cl-MeO-biphep L8 was the ligand
(entry 16). The investigation of the impact of different Cu-
salts provided that CuClO4 is the best choice among the Cu-
salts we screened, including CuI, CuTc, CuCl, Cu(OAc)2,
and Cu(OTf)2 (not shown in Table 1). The studies on the
temperature effect on the reaction showed that lower tem-
perature was in favor of product in higher ee (entry 4 vs
entry 5 and entry 16 vs entry 21). The influence of the leaving
group of the propargyl compound was also studied. It was
found that the alkyne was decomposed if the Ac group in
3b was replaced by CF3CO-, ClCH2CO-, and pyridinyl-2
CO- groups (not shown in Table 1).
Table 2. Enantioselective Cu-Catalyzed Propargylic Substitution
Reaction of Propargylic Acetates 3 with Enamines 1a
entry
1, R
3, Ar
4, yield (%)b ee (%)c
1
2
3
4
5
6
c, Ph
c, Ph
c, Ph
c, Ph
c, Ph
c, Ph
c, Ph
c, Ph
c, Ph
c, Ph
a, 4-MeOC6H4
b, Ph
a, 88
b, 77
c, 83
d, 95
e, 67
f, 88
g, 73
h, 65
i, 95
81
85
84
82
80
80
85
85
73
67
80
80
78
77
87
85
86
91
84
82
85
85
90
c, 3-MeC6H4
d, 4-MeC6H4
e, 3-MeOC6H4
f, 4-FC6H4
g, 4-ClC6H4
h, 4-BrC6H4
i, 1-naphthyl
j, 2-furyl
b, Ph
b, Ph
b, Ph
b, Ph
b, Ph
7d
8d
9
10
11
12
13
14
15
16
17
18
19
20
21d
22d
23d
j, 80
l, 57
d, 4-MeOC6H4
e, 4-MeC6H4
i, 2-naphthyl
j, 2-furyl
m, 72
n, 85
o, 55
p, 81
q, 70
r, 67
s, 61
t, 40
u, 63
v, 79
w, 58
x, 59
f, 4-FC6H4
g, 4-ClC6H4
h, 4-BrC6H4
k, 4-NO2C6H4
l, 3-pyridyl
m, 2,4-Cl2C6H3 b, Ph
f, 4-FC6H4
b, Ph
b, Ph
b, Ph
b, Ph
c, 3-MeC6H4
f, 4-ClC6H4
c, 3-MeC6H4
f, 4-FC6H4
k, 4-NO2C6H4
a Molar ratio: 3a/1/base/CuClO4.(MeCN)4/L ) 1/2/4/0.05/0.05. b Isolated
yield. c Determined by HPLC. d The reaction was performed at -5 °C.
Using optimized reaction conditions, the scope of the
reaction was examined (eq 2, Table 2).14 Generally, a wide
in good to high yields with 67-91% ee. Either enamines 1
or electrophiles 3 having electron-withdrawing groups af-
forded products in higher enantioselectivity (entries 6-8 for
3, 15-18 and 20-23 for 1). Replacing the phenyl group by
a naphthyl group in either the enamine or propargyl
compound gave the product in higher yields but a little bit
lower ee (entries 9 and 13 vs entry 2). Higher ee (84%) was
given when heteroaromatic substrate 1l was used, albeit the
yield was lower (entry 19) while the ee value was lower if
heteroaromatic propargyl acetate 3j was the reagent (entry
10). It is worth noting that enamine 1n derived from
range of enamines 1 and propargyl acetates 3 were suitable
for the reaction, affording propargylic-substituted products
(8) Some examples of the propargylation using stoichiometric chiral
metal complex or via substrate-induction: (a) Nishibayashi, Y.; Imajima,
H.; Onodera, G.; Uemura, S. Organometallics 2005, 24, 4106. (b) Ru-
benbauer, P.; Herdtweck, E.; Strassner, T.; Bach, T. Angew. Chem., Int.
Ed. 2008, 47, 10106.
(14) Typical procedure for the Cu-catalyzed asymmetric propargylic
substitution reaction of N,N-diethyl-1-phenylethenamine 1c with pro-
pargylic acetate 3a: To a flame-dried Schlenk tube with CuClO4·(CH3CN)4
(3.3 mg, 0.01 mmol) and (R)-Cl-MeO-biphep (6.9 mg, 0.01 mmol) was
added anhydrous methanol (1.0 mL) under argon, and the resulting mixture
was stirred at rt for 30 min. The flask was kept at -15 °C, 3a (35 mg, 0.20
mmol), and N,N-diethyl-1-phenylethenamine 1c (70 mg, 0.40 mmol) and
diisopropylethylamine (103 mg, 0.80 mmol) in anhydrous methanol (1.0
mL) were added. The mixture was stirred at -15 °C, monitored by TLC.
After completion, the reaction mixture was quenched with buffer of NaOAc/
HOAc (1.0 mL), and the resulting solution was stirred for 10 min at rt.
Water was added (5.0 mL) and extracted with Et2O (20 mL × 3). The
combined organic layer was washed with brine and dried over anhydrous
MgSO4. The solvent was removed under reduced pressure, and the residue
was purified by preparative TLC (hexane/ethyl acetate ) 10/1) to give
product 4a (46.7 mg, 88% yield). 1H NMR (300 MHz, CDCl3): δ 7.95-7.92
(m, 2H), 7.58-7.26 (m, 5H), 6.89-6.84 (m, 2H), 4.40 (dt, J ) 7.1, 2.4
Hz, 1H), 3.78 (s, 3H), 3.56 (dd, J ) 17.1, 7.8 Hz, 1H), 3.34 (dd, J ) 17.0,
6.8 Hz, 1H), 2.26 (d, J ) 3 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 196.88,
158.62, 136.60, 133.26, 132.61, 128.59, 128.48, 128.09, 114.03, 85.63,
70.80, 55.24, 47.10, 31.81. HRMS: calcd. for C18H16O2, 264.1150. Found:
264.1148. [R]D20 +4.8 °(c 1.01, CHCl3). The optical purity was determined
by HPLC analysis: Chiralcel OD, hexane/iPrOH ) 98/2, flow rate ) 0.6
mL/min, λ ) 230 nm, retention time: 22.7 min (major) and 26.0 min (minor),
81% ee.
(9) Some examples of propargylations other than nucleophilic substitu-
tion: (a) Fukamizu, K.; Miyake, Y.; Nishibayashi, Y. J. Am. Chem. Soc.
2008, 130, 10498. (b) Smith, S. W.; Fu, G. C. J. Am. Chem. Soc. 2008,
130, 12645.
(10) For some reviews: (a) HelmchenG. In Asymmetric SynthesissThe
Essentials; Christmann, M., Bra¨se, S., Eds.; Wiley-VCH: Weinheim, 2007;
p 95. (b) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921. (c)
Lu, Z.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 258.
(11) (a) You, S.-L.; Hou, X.-L.; Dai, L.-X.; Zhu, X.-Z. Org. Lett. 2001,
3, 149. (b) You, S.-L.; Zhu, X.-Z.; Hou, X.-L.; Dai, L.-X. Acta Chim. Sin.
2001, 59, 1667. (c) Yan, X.-X.; Liang, C.-G.; Zhang, Y.; Hong, W.; Cao,
B.-X.; Dai, L.-X.; Hou, X.-L. Angew. Chem., Int. Ed. 2005, 44, 6544. (d)
Zheng, W.-H.; Zheng, B.-H.; Zhang, Y.; Hou, X.-L. J. Am. Chem. Soc.
2007, 129, 7718. (e) Zhang, K.; Peng, Q.; Hou, X.-L.; Wu, Y.-D. Angew.
Chem., Int. Ed. 2008, 47, 1741. (f) Liu, W.; Che, D.; Zhu, X.-Z.; Wan,
X.-L.; Hou, X.-L. J. Am. Chem. Soc. 2009, 131, 8734.
(12) Pappoport, Z., Ed. The Chemistry of Enamines; Wiley: Chichester,
1994.
(13) (a) Nishiyama, H.; Sakaguchi, H.; Nakamura, T.; Horihata, M.;
Kondo, M.; Itoh, K. Organometallics 1989, 8, 846. (b) Burk, M. J. J. Am.
Chem. Soc. 1991, 113, 8518. (c) Imamoto, T.; Sugita, K.; Yoshida, K. J. Am.
Chem. Soc. 2005, 127, 11934.
4614
Org. Lett., Vol. 11, No. 20, 2009

aliphatic cyclohexanone was also a suitable substrate,
providing the product in 33% yield with 72% ee and 10:1
dr when using OBz as the leaving group (eq 3). However,
the aliphatic
In summary, we have described the first example of
copper-catalyzed enantioselective propargylic substitution
reactions of propargylic acetates with enamines to afford
ꢀ-ethynyl-substituted ketones with good to high yield and
enantioselectivity. Further investigations on extending the
reaction scope using other types of enamines and applications
of this method in organic synthesis as well as on the
understanding of the reaction mechanism are in progress.
Acknowledgment. Financially supported by the Major
Basic Research Development Program (2006CB806106),
National Natural Science Foundation of China (20532050,
20872161 and 20821002), Chinese Academy of Sciences,
Croucher Foundation of Hong Kong, and Science and
Technology Commission of Shanghai Municipality. This
paper is dedicated to Professor You Qi Tang on the occasion
of his 90th birthday.
(benzyl-substituted) propargyl acetate and 1,3-diphenyl-2-
propynyl acetate, a propargylic acetate bearing an internal
alkyne moiety, could not react at all.
The absolute configuration of product 4a was determined
as (S) by reducing the acetylene group of 4a to the ethyl
group and comparing the sign of optical rotation of product
with that of known compound reported in the literature.15
Supporting Information Available: Detailed experimen-
tal procedures and analytic data, 1H and 13C NMR and HPLC
spectra for 4. This material is available free of charge via
the Internet at http://pubs.acs.org.
¨
(15) Isleyen, A.; Dogan, O. Tetrahedron: Asymmetry 2007, 18, 679.
OL901891U
Org. Lett., Vol. 11, No. 20, 2009
4615