Low ligand loading, highly enantioselective addition of phenylacetylene to aromatic ketones catalyzed by Schiff-base amino alcohols

Article abstract of DOI:10.1021/ol060526+

Schiff-base amino alcohols 7a,b derived from L-phenylglycine through three simple steps are found to be highly effective for the enantioselective addition of phenylacetylene to aromatic ketones. When the loading of 7b was 1 mol %, an ee value of up to 95% was obtained. However, when 7b was lowered to 0.1 mol %, a high ee value of 85% was still achieved. A practical solution to synthesize the optically active tertiary propargylic alcohols was described.

Full text of DOI:10.1021/ol060526+

ORGANIC
LETTERS
2006
Vol. 8, No. 11
2277-2280
Low Ligand Loading, Highly
Enantioselective Addition of
Phenylacetylene to Aromatic Ketones
Catalyzed by Schiff-Base Amino
Alcohols
Chao Chen,† Liang Hong,† Zhao-Qing Xu,† Lei Liu,† and Rui Wang*,†,‡
Department of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou
UniVersity, Lanzhou, Gansu 730000, China, and State Key Laboratory for Oxo
Synthesis and SelectiVe Oxidation, Lanzhou Institute of Chemical Physics, Chinese
Academy of Sciences, Lanzhou, Gansu 730000, China
wangrui@lzu.edu.cn
Received March 3, 2006
ABSTRACT
Schiff-base amino alcohols 7a,b derived from L-phenylglycine through three simple steps are found to be highly effective for the enantioselective
addition of phenylacetylene to aromatic ketones. When the loading of 7b was 1 mol %, an ee value of up to 95% was obtained. However, when
7b was lowered to 0.1 mol %, a high ee value of 85% was still achieved. A practical solution to synthesize the optically active tertiary propargylic
alcohols was described.
The catalytic enantioselective formation of new C-C bonds
is an important class of organic reactions.1 Among them,
the asymmetric addition of terminal alkynes to carbonyl
compounds and formation of the chiral propargylic alcohols
have been very intense research fields in recent years. Some
excellent work has been reported in the field of the
asymmetric addition of alkynes to aldehydes with high ee
values.2 However, the practical asymmetric alkynylation of
ketones to form optical tertiary propargylic alcohols is facing
a challenge because of the reduced propensity of ketones to
coordinate to Lewis acids,3 and few catalysts were found to
be effective in promoting the asymmetric addition of
alkynylzinc to ketones. P. G. Cozzi first reported that a Zn-
(2) (a) Pu, L. Tetrahedron 2003, 59, 9873. (b) Cozzi, P. G.; Hilgraf, R.;
Zimmermann, N. Eur. J. Org. Chem. 2004, 4095. (c) Anand, N. K.; Carreira,
E. M. J. Am. Chem. Soc. 2001, 123, 9687-9688. (d) Frantz, D.; Fassler, E.
R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122, 1806-1807. (e) Lu, G.;
Li, X.; Chan, W. L.; Chan, A. S. C. Chem. Commun. 2002, 172. (f) Li, X.;
Lu, G.; Kwok, W. H.; Chan, A. S. C. J. Am. Chem. Soc. 2002, 124, 12636.
(g) Boyall, D.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2002, 4, 2605-
2606. (h) Moore, D.; Pu, L. Org. Lett. 2002, 4, 1855. (i) Gao, G.; Moore,
D.; Xie, R. G.; Pu, L. Org. Lett. 2002, 4, 4143. (j) Gao, G.; Xie, R. G.; Pu,
L. Proc. Natl. Acad. Sci. 2004, 101, 5417. (k) Takita, R.; Yakura, K.;
Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 13760. (l) Gao,
G.; Wang, Q.; Yu, X. Q.; Xie, R. G.; Pu, L. Angew. Chem., Int. Ed. 2006,
45, 122. (m) Trost, B. M.; Weiss, A. H.; Wangelin, J. v. J. Am. Chem. Soc.
2006, 128, 8. (n) Emmerson, D. P. G.; Hems, W. P.; Davis, B. G. Org.
Lett. 2006, 8, 207.
† Lanzhou University.
‡ Chinese Academy of Sciences.
(1) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley:
New York, 1994. (b) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Compre-
hensiVe Asmmetric Catalysis; Springer: Berlin, 1999.
10.1021/ol060526+ CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/02/2006

(salen), 1, promoted alkynylation of ketones with moderate
enantioselectivities as a pioneering study.4 He considered that
the success of this addition ascribed to the salen-metal
complex which could behave as a bifunctional Lewis acid-
Lewis base catalyst. In the same year, Chan and co-workers
described the alkynylzinc addition to ketones with very high
ee values in the presence of chiral camphorsulfonamide
ligand 2 and a stronger Lewis acid Cu(OTf)2.5 Almost at the
same time, Cozzi6 and we7d developed an asymmetric
addition of alkynylation of ketones in the presence of BINOL
3 and Ti (Figure 1). We found the 1:1 ratio of BIONL/Ti
with high ee values and good yields in low loading of the
ligand, and to the best of our knowledge, 1 mol % was the
lowest amount reported in this reaction.
It is well-known that alkyl2Zn does not react with simple
ketones without another Lewis acid’s assistance because of
the low activity of the carbonyl in ketones. Recently, Cozzi
reported that MeZnCtCPh could be directly added to the
simple ketones without a ligand (Scheme 1).8 It was because
Scheme 1. Alkynylation of Ketones in the Presence of
Alkynylzinc
the electron-withdrawing nature of the alkynyl affected
the zinc center in MeZnCtCPh, thus increasing the polarity
of the C-Zn bond and the Lewis acidity of the metal to a
great extent. This kind of zinc complex has enough Lewis
acidity to activate the carbonyl group in the ketone.
Therefore, it can make this kind of addition work success-
fully. On the basis of the facts mentioned above, we
attempted to perform the enantioselective addition of phe-
nylacetylene to ketones without adding any other stronger
Lewis acid except zinc.
The Schiff-base amino alcohols9 were easily prepared from
L-phenylglycine in three simple steps with overall yields of
up to 70% and 73%, respectively (Scheme 2). At first, 5
mol % of 7a and 7b was employed in the asymmetric
addition of phenylacetylene to acetophenone in the presence
of diethylzinc. The reaction was completed in 14 h at room
temperature. Ligand 7b which has a much bulkier substitute
gave a better result. Then, the solvent effect on this process
using 7b was probed. Low enantioselectivity and a slow
reaction time were found in CH2Cl2. Hexane gave the best
ee and yield. In the reaction, we found that the ligand was
not completely dissolved in hexane, and perhaps, a smaller
amount of ligand could serve as a catalyst with the same
result. Therefore, we attempted to decrease the loading of
the ligand to 1 mol %. To our surprise, the ee was up to
Figure 1. Structure of ligands for the asymmetric addition of
alkynylation of ketones.
was necessary for a stronger Lewis acid. Although advances
have been achieved, high loadings of ligands (usually 20
mol %) had to be used to achieve good to excellent
enantioselectivities. Therefore, we report here an example
of a highly efficient chiral ligand which could catalyze the
enantioselective addition of alkynylzinc to simple ketones
(3) Selected references on the enantioselective organozinc addition to
ketones: (a) Ramo´n, D. J.; Yus, M. Angew. Chem., Int. Ed. 2004, 43, 284.
(b) Betancort, J. M.; Garc´ıa, C.; Walsh, P. J. Synlett 2004, 749. (c) Dosa,
P. I.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 445. (d) Ramo´n, D. J.; Yus,
M. Tetrahedron Lett. 1998, 39, 1239. (e) Ramo´n, D. J.; Yus, M. Tetrahedron
1998, 54, 5651. (f) Garc´ıa, C.; LaRochelle, L. K.; Walsh, P. J. J. Am. Chem.
Soc. 2002, 124, 10970. (g) Jeon, S.-J.; Walsh, P. J. J. Am. Chem. Soc. 2003,
125, 9544. (h) Garc´ıa, C.; Walsh, P. J. J. Org. Chem. 2003, 68, 3641. (i)
Li, H.; Garc´ıa, C.; Walsh, P. J. Proc. Natl. Acad. Sci. 2004, 101, 5425. (j)
Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 6538. (k) Jeon, S.-J.; Li,
H.; Garc´ıa, C.; LaRochelle, L. K.; Walsh, P. J. J. Org. Chem. 2005, 70,
448. (l) Saito, B.; Katsuki, T. Synlett 2004, 1557.
(8) Cozzi, P. G.; Rudolph, J.; Bolm, C.; Norrby, P. O.; Tomasini, C. J.
Org. Chem. 2005, 70, 5733.
(9) Selected references for the salen-schiff base as chiral catalysts: (a)
DiMauro, E. F.; Kozlowski, M. C. J. Am. Chem. Soc. 2002, 124, 12668-
12669. (b) DiMauro, E. F.; Kozlowski, M. C. Org. Lett. 2002, 4, 3781-
3784. (c) Li, Z. B.; Pu, L. Org. Lett. 2004, 6, 1065-1068. (d) Dahmen, S.
Org. Lett. 2004, 6, 2113-2116. (e) Nagata, T.; Yorozu, K.; Yamada, T.;
Mukaiyama, T. Angew. Chem., Int. Ed. Engl. 1995, 34, 2145. (f) Belokon,
Y. R.; Caveda-Cepas, S.; Green, B.; Ikonnikov, N. S.; Khrustalev, V. N.;
Larichev, V. S.; Moscalenko, M. A.; North, M.; Orizu, C.; Tararov, V. I.;
Tasinazzo, M.; Timofeeva, G. I.; Yashkina, L. V. J. Am. Chem. Soc. 1999,
121, 3968-3971. (g) Belokon, Y. R.; North, M.; Parsons, T. Org. Lett.
2000, 2, 1617. (h) Cameron, P. A.; Gibson, V. C.; Irvine, D. J. Angew.
Chem., Int. Ed. 2000, 39, 2141-2144. (i) Shimizu, K. D.; Cole, B. M.;
Krueger, C. A.; Kuntz, K.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1704. (j) Yun, H. Y.; Wu, Y. J.; Wu, K. L.; Zhou,
D. Y. Tetrahedron Lett. 2000, 41, 10263-10266. (k) Taylor, M. S.; Zalatan,
D. N.; Lerchner, A. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127,
1313-1317.
(4) Cozzi, P. G. Angew. Chem., Int. Ed. 2003, 42, 2895.
(5) Lu, G.; Li, X. S.; Jia, X.; Chan, W. L.; Chan, A. S. C. Angew. Chem.,
Int. Ed. 2003, 42, 5057.
(6) Cozzi, P. G.; Alesi, S. Chem. Commun. 2004, 2448.
(7) Selected recent examples of our group: (a) Xu, Z. Q.; Wang, R.;
Xu, J. K.; Da, C. S.; Yan, W. J.; Chen, C. Angew. Chem., Int. Ed. 2003,
42, 5747. (b) Xu, Z. Q.; Chen, C.; Xu, J. K.; Miao, M. B.; Yan, W. J.;
Wang, R. Org. Lett. 2004, 6, 1193. (c) Kang, Y. F.; Liu, L.; Wang, R.;
Zhou, Y. F.; Yan, W. J. AdV. Synth. Catal. 2005, 347, 243. (d) Zhou, Y.
F.; Wang, R.; Xu, Z. Q.; Yan, W. J.; Liu, L.; Kang, Y. F.; Han, Z. J. Org.
Lett. 2004, 6, 4147. (e) Ni, M.; Wang, R.; Han, Z. J.; Mao, B.; Da, C. S.;
Liu, L.; Chen, C. AdV. Synth. Catal. 2005, 347, 1659. (f) Liu, L.; Wang,
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Gong, M. Z. J. Org. Chem. 2005, 70, 1084.
2278
Org. Lett., Vol. 8, No. 11, 2006

Scheme 2. Preparation of Schiff-Base Amino Alcohols from
Table 2. Asymmetric Addition of Phenylacetylene to Various
Ketones Promoted by Ligand 7ba-c
L-Phenylglycine
ligand
(mol %)
yieldd
(%)
eee
(%)
entry
ketones
acetophenone
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
70
83
77
62
70
76
70
63
76
80
90
94
95
94
94
92
90
90
90
77
2′-fluoroacetophenone
2′-naphthacetophenone
1′-naphthacetophenone
2′-methoxyacetophenone
4′-methylacetophenone
4′-fluoroacetophenone
4′-chloroacetophenone
3′-methylacetophenone
benzalacetone
10
a Ligand/ketones/Et2Zn/phenylacetylene ) 0.01:1:2:2. b All the reactions
were conducted at -18 °C in 1 mL of hexane. c All the reactions were
carried out for 48-60 h for aromatic ketones and for 24 h for R,â-
unsaturated ketones. d Yield of isolated product. e The enantiomeric excess
was determined by HPLC on a chiralcel OD-H column.
81% at room temperature (Table 1, entry 5). Encouraged by
these results, we studied the effects of the temperature.
Lowering the reaction temperature from room temperature
to 0 °C led to an increasing ee (Table 1, entry 6), and at
-18 °C, the best result was obtained (Table 1, entry 7). When
the amount of diethylzinc was increased from 1.2 to 5 equiv,
the ee was slightly influenced (entries 8-11).
Under the optimized conditions, catalyst 7b loading as low
as 1 mol % has been successfully used for the asymmetric
addition of phenylacetylene to various aromatic ketone
reactions. Acetophenone and related derivatives were excel-
lent substrates for the catalyst (Table 2). Moreover, 2-naph-
thacetophenone gave the best enantiomeric excess (95% ee,
Table 2, entry 3). When the R,â-unsaturated ketone was used
as the substrate, a moderate enantiomeric excess was
achieved (Table 2, entry 10). In contrast to aromatic ketones,
aliphatic ketones are reactive using the catalyst 7b and a
moderate enantiomeric excess was obtained.10
In addition, to test the power of the ligand 7b, we further
lowered the loading of 7b to 0.1 mol % and up to 85% ee
was achieved (Table 3, entry 8). Studies of the mechanism
Table 3. Asymmetric Addition of Phenylacetylene to Ketones
Promoted by the Ligand 7b with Lower Loadinga,b
yieldc eed
entry
ketones
ketones/ligand
(%)
(%)
1
2
3
4
5
6
7
8
acetophenone
acetophenone
100
1000
100
1000
100
1000
100
1000
70
67
83
80
77
70
62
65
90
80
94
80
95
84
94
85
Table 1. Asymmetric Addition of Phenylacetylene to
2′-fluoroacetophenone
2′-fluoroacetophenone
2′-naphthacetophenone
2′-naphthacetophenone
1′-naphthacetophenone
1′-naphthacetophenone
Acetophenone Catalyzed by Schiff-Base Amino Alcoholsa
time Et2Znb yieldc eed
a Unless otherwise specified, the reaction was run in 1 mL of hexane
under argon for 48 h with 1 M Et2Zn in hexane. b Ketones/ligand ) 1000
were performed at room temperature. c Yield of isolated product. d The
enantiomeric excess was determined by HPLC on chiralcel OD-H column.
entry ligand mol % solvent T (°C) (h)
(mL)
(%) (%)
1
2
3
4
5
6
7
8
9
7a
7b
7b
7b
7b
7b
7b
7b
7b
7b
7b
7b
5
5
5
5
1
1
1
1
1
1
1
1
toluene rt
toluene rt
CH2Cl2 rt
hexane rt
hexane rt
14
14
14
14
48
48
48
48
48
48
48
48
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.3
0.75
1.0
1.25
0.5
90
92
67
94
75
71
70
63
75
73
70
71
78
83
47
86
81
84
90
87
88
85
84
83
of the reaction and the application of this catalyst system in
other asymmetric catalytic reactions are in progress.
hexane
0
hexane -18
hexane -18
hexane -18
hexane -18
hexane -18
hexane -18
In summary, we have reported that an easily prepared
Schiff-base amino alcohol is highly efficient for asymmetric
addition of phenylacetylene to aromatic ketones when the
loading of 7b is 1 mol %. This system does not need to add
any other stronger Lewis acid except zinc, and the alky-
nylzinc must be prepared in advance. To the best of our
knowledge, 7b is the most efficient chiral ligand for the
10
11
12e
a Unless otherwise specified, the substrate of acetophenone was run on
a 0.25 mmol scale in 1 mL of hexane under argon. b 1 M Et2Zn in hexane.
c Yield of isolated product. d The enantiomeric excess was determined by
HPLC on a chiralcel OD-H column. e The reaction was performed in 0.5
mL of 1 M Et2Zn in hexane.
(10) Methyl isobutyl ketone (-18 °C in 1 mL of hexane, 7b/ketone/Et2-
Zn/ phenylacetylene ) 0.01:1:2:2, 61% ee).
Org. Lett., Vol. 8, No. 11, 2006
2279

enantioselective addition of alkynylzinc to simple ketones
from the standpoint of low loading of ligands.
Supporting Information Available: The character-
izations of ligand 7 and the products are provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was supported by the grants
from the National Natural Science Foundation of China (Nos.
20372028, 20472026, and 20525206) and Chang Jiang
Program of the Ministry of Education of China.
OL060526+
2280
Org. Lett., Vol. 8, No. 11, 2006