BINOL-catalyzed highly enantioselective terminal alkyne additions to aromatic aldehydes.

Article abstract of DOI:10.1021/ol025825n

[reaction: see text] The readily available BINOL ligand in combination with Ti(O(i)Pr)(4) was found to catalyze the highly enantioselective reaction (92-98% ee) of terminal alkynes with aromatic aldehydes that contain a variety of substituents and substitution patterns. After the preparation of the zinc acetylide reagent, the catalytic asymmetric addition to aldehydes proceeded at room temperature with excellent stereocontrol. This simple catalyst system is practical for the asymmetric synthesis of chiral propargylic alcohols.

Full text of DOI:10.1021/ol025825n

ORGANIC
LETTERS
2
002
Vol. 4, No. 11
855-1857
BINOL-Catalyzed Highly Enantioselective
Terminal Alkyne Additions to Aromatic
Aldehydes
1
David Moore and Lin Pu*
Department of Chemistry, UniVersity of Virginia, CharlottesVille, Virginia 22904-4319
lp6n@Virginia.edu
Received March 5, 2002
ABSTRACT
i
The readily available BINOL ligand in combination with Ti(O Pr)
4
was found to catalyze the highly enantioselective reaction (92−98% ee) of
terminal alkynes with aromatic aldehydes that contain a variety of substituents and substitution patterns. After the preparation of the zinc
acetylide reagent, the catalytic asymmetric addition to aldehydes proceeded at room temperature with excellent stereocontrol. This simple
catalyst system is practical for the asymmetric synthesis of chiral propargylic alcohols.
4
Optically active propargylic alcohols are versatile precursors
for the synthesis of many chiral organic compounds.
tives. In recent years, optically pure BINOL has become a
cheap and broadly applicable chiral compound. Direct use
of the unmodified BINOL ligand in combination with metal
salts in asymmetric catalysis has resulted in a series of
exciting discoveries. Among these are the nitro aldol
1
Addition of metalated terminal alkynes to carbonyls is a very
useful method to generate various types of propargylic
alcohols. Recently, Carreira and co-workers discovered a
highly enantioselective catalyst based on the chiral amino
5
6
7
reaction, the allylstannane addition, the ene reaction, the
2
alcohol 1 for the alkynylzinc addition to aliphatic aldehydes.
Other chiral compounds have also been used to carry out
(1) Selected examples: (a) Modern Acetylene Chemistry; Stang, P. J.;
Diederich, F., Eds.; VCH: Weinheim, 1995. (b) Marshall, J. A.; Wang, X.
J. J. Org. Chem. 1992, 57, 1242-1252. (c) Fox, M. E.; Li, C.; Marino, J.
P., Jr.; Overman, L. E. J. Am. Chem. Soc. 1999, 121, 5467-5480. (d) Myers,
A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492-4493. (e) Trost, B.
M.; Krische, M. J. J. Am. Chem. Soc. 1999, 121, 6131-6141. (f) Roush,
W. R.; Sciotti, R. J. J. Am. Chem. Soc. 1994, 116, 6457-6458. (g) Corey,
E. J.; Cimprich, K. A. J. Am. Chem. Soc. 1994, 116, 3151-3152.
(
2) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687-
the asymmetric reaction of terminal alkynes with carbonyl
compounds, but only limited enantioselectivity has been
9688.
(3) (a) Li, Z.; Upadhyay, V.; DeCamp, A. E.; DiMichele, L.; Reider, P.
Synthesis 1999, 1453-1458. (b) Ishizaki, M.; Hoshino, O. Tetrahedron:
Asymmetry 1994, 5, 1901-1904. (c) Lu, G.; Li, X.; Zhou, Z.; Chan, W.
L.; Chan, A. S. C. Tetrahedron: Asymmetry 2001, 12, 2147-2152. (d)
Niwa, S.; Soai, K. J. Chem. Soc., Perkin Trans. 1 1990, 937-943. (e)
Tombo, G. M. R.; Didier, E.; Loubinoux, B. Synlett 1990, 547-548. (f)
For a review, see: Pu, L.; Yu, H. B. Chem. ReV. 2001, 101, 757-824.
3
observed. Thus, one of the current challenges in this area
is to develop generally enantioselective as well as practical
catalysts for the reaction of terminal alkynes especially with
aromatic aldehydes.
In our laboratory, we are interested in studying the
applications of 1,1′-bi-2-naphthol (BINOL) and its deriva-
(
4) (a) Pu, L. Chem. ReV. 1998, 98, 2405-2494. (b) Huang, W.-S.; Hu,
Q.-S.; Pu, L. J. Org. Chem. 1998, 63, 1364-1365. (c) Yu, H.-B.; Hu, Q.-
S.; Pu, L. J. Am. Chem. Soc. 2000, 122, 6500-6501.
1
0.1021/ol025825n CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/01/2002

Table 1. Results for the Reaction of Phenylacetylene with Benzaldehyde (Tol ) toluene)
i
Ti(O Pr)4
BINOL
(mol %)
temp for
step 2
major
ee of 3
entry
conditions for step 1
solvent in step 2
Tol (5 mL)
CH2Cl2 (5 mL)
THF (5 mL)
ether (5 mL)
CH2Cl2 (5 mL)
CH2Cl2 (5 mL)
CH2Cl2 (5 mL)
(mol %)
product
(%)
1
2
3
4
5
6
7
Tol (5 mL), BINOL, rt
25
25
25
25
25
25
25
10
10
10
10
10
10
10
rt
rt
rt
rt
rt
rt
rt
4
4
4
4
4
4
4
∼85
∼88
∼70
∼78
∼85
ND
CH2Cl2 (5 mL), BINOL, rt
THF (5 mL), BINOL, rt
ether (5 mL), BINOL, rt
CH2Cl2 (5 mL), reflux
CH2Cl2 (5 mL), BINOL, reflux
CH2Cl2 (5 mL), BINOL
ND
i
Ti(O Pr)4, reflux
8
9
Tol (5 mL), reflux
Tol (1 mL), reflux
Tol (1 mL), reflux
Tol (1 mL), reflux
Tol (1 mL), reflux
Tol (1 mL), reflux
Tol (1 mL), reflux
Tol (1 mL), reflux
Tol (2 mL), reflux
Tol (2 mL), reflux
Tol (2 mL), reflux
Tol (2 m L), r eflu x
Tol (5 mL)
25
25
25
25
25
100
10
50
25
25
25
50
10
10
10
10
10
10
10
20
10
10
10
20
rt
rt
0 °C
42 °C
12 °C
rt
rt
rt
rt
rt
3
3
3
3
3
3
3
3
3
3
3
3
80
85
62
48
78
87
70
91
92
90
80
96
Tol (1 mL) + CH2Cl2 (4 mL)
Tol (1 mL) + CH2Cl2 (4 mL)
Tol (1 mL) + CH2Cl2 (4 mL)
Tol (1 mL) + CH2Cl2 (4 mL)
Tol (1 mL) + CH2Cl2 (4 mL)
Tol (1 mL) + CH2Cl2 (4 mL)
Tol (1 mL) + CH2Cl2 (4 mL)
Tol (2 mL) + CH2Cl2 (8 mL)
Tol (2 mL) + CH2Cl2 (18 mL)
Tol (2 mL) + CH2Cl2 (48 mL)
Tol (2 m L) + CH2Cl2 (8 m L)
1
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
9
rt
r t
Diels-Alder reaction, and others.9,10 In a number of cases,
8
from the work described below. Both procedures have their
own practical advantages.
the combination of BINOL with a Ti(IV) complex has shown
We first studied the asymmetric reaction of phenyl-
acetylene with benzaldehyde. This reaction involves two
steps: (1) treatment of phenylacetylene with diethylzinc with
i
or without BINOL and Ti(O Pr)
4
; (2) addition of benzalde-
(Scheme 1). The first step
i
hyde, (S)-BINOL and Ti(O Pr)
4
high catalytic activity as well as excellent enantioselectivity.6
-9
We have investigated the asymmetric alkynylzinc addition
Scheme 1. Reaction of Phenylacetylene with Benzaldehyde in
i
catalyzed by BINOL and Ti(O Pr)
4
and found that this simple
i
the Presence of Diethylzinc, (S)-BINOL, and Ti(O Pr)
4
catalyst system is highly enantioselective for the reaction of
aromatic aldehydes. During the preparation of this paper,
Chan and co-workers independently reported the use of
BINOL and a partially hydrogenated BINOL in combination
i
with Ti(O Pr)
4
(1.5 equiv versus aldehyde) to carry out the
reaction of phenylacetylene with a variety of aldehydes in
11
the presence of dimethylzinc at 0 °C. They also observed
that BINOL showed high enantioselectivity for a few
aldehydes, but their experimental procedure is very different
(
5) (a) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. Engl.
1
1
1
997, 36, 1236-1256. (b) Mikami, K.; Matsukawa, S. J. Am. Chem. Soc.
993, 115, 7039-7040. (c) Mikami, K.; Matsukawa, S. J. Am. Chem. Soc.
994, 116, 4077-4078.
probably generates the zinc phenylacetylide intermediate 2
which can then add to benzaldehyde in the presence of the
catalyst. In this reaction, besides the desired propargylic
alcohol 3, the side product 4 was observed under certain
conditions as the result of the ethyl addition to benzaldehyde.
Table 1 summarizes our attempts for this reaction. In these
experiments, 1.1 mmol of phenylacetylene was reacted with
1.0 mmol of diethylzinc and 0.5 mmol of benzaldehyde. We
found that in order to generate 3 as the major product and
avoid the ethyl addition side product 4, it was necessary to
reflux phenylacetylene with diethylzinc in toluene in step 1
(6) (a) Keck, G. E.; Tatbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993,
1
15, 8467-8468. (b) Costa, A. L.; Piazza, M. G.; Tagliavini, E.; Trombini,
C.; Umani-Ronchi, A. J. Am. Chem. Soc. 1993, 115, 7001-7002. (c) Aoki,
S.; Mikami, K.; Terada, M.; Nakai, T. Tetrahedron 1993, 49, 1783-1792.
(
7) Mikami, K. Pure Appl. Chem. 1996, 68, 639-644.
(8) (a) Mikami, K.; Terada, M.; Motoyama, Y.; Nakai, T. Tetrahedron:
Asymmetry 1991, 2, 643-646. (b) Mikami, K.; Motoyama, Y.; Terada, M.
J. Am. Chem. Soc. 1994, 116, 2812-2820.
(
9) (a) Mori, M.; Nakai, T. Tetrahedron Lett. 1997, 38, 6233-6236. (b)
Zhang, F.-Y.; Yip, C.-W.; Cao, R.; Chan, A. S. C. Tetrahedron: Asymmetry
1
997, 8, 585-589.
10) Sakane, S.; Maruoka, K.; Yamamoto, H. Tetrahedron Lett. 1985,
6, 5535-5538.
11) Lu, G.; Li, X.; Chan, W. L.; Chan, A. S. C. J. Chem. Soc., Chem.
Commun. 2002, 172-173.
(
2
(
entry 8). This condition may be more favorable for the
(
3
b
formation of the zinc acetylide 2. Treatment of phenyl-
1856
Org. Lett., Vol. 4, No. 11, 2002

acetylene with diethylzinc at lower temperatures in various
i
4
solvents with or without BINOL and Ti(O Pr) in step 1
Table 2. Results for the Terminal Alkyne Additions to
Aldehydes in the Presence of Diethylzinc, (S)-BINOL, and
mainly led to the side product 4 (entries 1-7). Comparison
of entry 5 with entry 8 revealed that although refluxing in
toluene in step 1 gave much higher yield of 3, the enantio-
selectivity was higher when the reaction was carried out in
i
Ti(O Pr)
4
CH
2
Cl
2
. Therefore, we tested the use of a combined solvent
Cl for step 2. Indeed, higher enantio-
of toluene and CH
2
2
selectivity was achieved in entry 9 than entry 8. We also
varied the temperature in step 2 in order to optimize the
reaction condition. However, only reduced enantioselectivity
was observed at either higher or lower temperatures (entries
10-12). Thus, the room-temperature condition seems most
suitable for the reaction. We found that increasing the amount
i
of Ti(O Pr)
entry 13) and reducing Ti(O Pr)
selectivity (entry 14). Increasing both Ti(O Pr)
4
only gave slightly increased enantioselectivity
i
(
4
decreased the enantio-
i
4
and BINOL
led to significantly higher enantioselectivity (entry 15). We
then studied the effect of the reagent concentration on this
reaction. In entry 16, the amount of solvent was doubled
which improved this reaction over entry 9. However, further
diluting the reaction mixture reduced the enantioselectivity
(entries 17, 18). Finally, by combining the conditions in entry
15 with entry 16, we obtained the optimized enantioselec-
tivity (96% ee) and yield in entry 19. No side product was
observed in this experiment.
The optimized procedure for the reaction of benzaldehyde
with phenylacetylene is given here. Under nitrogen, phenyl-
acetylene (1.1 mmol, 121 µL) and diethylzinc (1.0 mmol,
a
1
102 µL) were added to a 25 mL flask containing toluene (2
Determined by H NMR.
mL, distilled over sodium). This solution was heated under
reflux for 5 h during which a white precipitate was generated.
It was then combined with (S)-BINOL (0.10 mmol, 28.6 mg,
aldehyde which showed excellent enantioselectivity. This
reaction is particularly useful, since the triisopropylsilyl group
in the resulting chiral propargylic alcohol 5 can be easily
removed for further derivatization.
>
99% ee) and CH
2 2
Cl (8 mL, dried with activated alumina
and stored over molecular sieves). After the mixture was
i
stirred at room temperature for 15 min, Ti(O Pr)
4
(0.25 mmol,
74 µL) was added and the stirring continued for another hour.
Benzaldehyde (0.5 mmol, 50 µL) was then added, and the
reaction mixture was stirred for 4 h. Concentrated ammonium
chloride was added to quench the reaction, and the mixture
2 2
was extracted with CH Cl and dried with sodium sulfate.
In summary, the readily available BINOL ligand has been
found to catalyze the highly enantioselective reaction of
terminal alkynes with aromatic aldehydes that have a variety
of substituents as well as substitution patterns. After the
preparation of the zinc acetylide reagent, the catalytic
asymmetric addition to aldehydes proceeds at room temper-
ature with excellent stereocontrol. This simple catalyst system
is practical for the asymmetric synthesis of chiral propargylic
alcohols containing aromatic rings.
After column chromatography on silica gel using 2-10%
ethyl acetate in hexanes to elute, compound 3 was isolated
in 77% yield. The enantiomeric purity of the propargylic
alcohol product 3 was determined to be 96% ee by using an
HPLC Chiralcel OD column. The configuration of this
propargylic alcohol was R as determined by comparing its
optical rotation with the literature data.1g
The above procedure was applied to the reaction of
terminal alkynes with a variety of aromatic aldehydes. As
the results summarized in Table 2 show, highly enantio-
selective reactions of phenylacetylene with ortho-, meta-, or
para-substituted benzaldehydes containing electron-donating
or electron-withdrawing substituents have been achieved by
using the BINOL-based catalyst (entries 1-9). The additions
to 2-naphthaldehyde and 1-naphthaldehyde also gave very
high enantioselectivity (entries 10 and 11). In entry 12, we
studied the reaction of triisopropylsilylacetylene with benz-
Acknowledgment. We thank the partial support for this
research from the donors of the Petroleum Research Fund,
administered by the American Chemical Society.
Supporting Information Available: The conditions to
determine the enantiomeric purity of the propargylic alcohol
products are provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL025825N
Org. Lett., Vol. 4, No. 11, 2002
1857