BINOL-Salen-catalyzed highly enantioselective alkyne additions to aromatic aldehydes

Article abstract of DOI:10.1021/ol0498139

(Equation presented) The BINOL-Salen compound (-)-1 can catalyze the addition of both aryl- and alkylalkynes to aromatic aldehydes at room temperature with high enantioselectivity (86-97% ee). The conditions for this catalytic process are both mild and simple. Unlike most other BINOL-based catalysts, using ligand (-)-1 not only avoids heating or cooling but also does not require the addition of Ti(OⁱPr)₄.

Full text of DOI:10.1021/ol0498139

ORGANIC
LETTERS
2004
Vol. 6, No. 6
1065-1068
BINOL−Salen-Catalyzed Highly
Enantioselective Alkyne Additions to
Aromatic Aldehydes
Zi-Bo Li and Lin Pu*
Department of Chemistry, UniVersity of Virginia, CharlottesVille, Virginia 22904-4319
lp6n@Virginia.edu
Received February 1, 2004
ABSTRACT
The BINOL−Salen compound (−)-1 can catalyze the addition of both aryl- and alkylalkynes to aromatic aldehydes at room temperature with
high enantioselectivity (86−97% ee). The conditions for this catalytic process are both mild and simple. Unlike most other BINOL-based
i
catalysts, using ligand (−)-1 not only avoids heating or cooling but also does not require the addition of Ti(OPr)4.
The catalytic asymmetric alkyne addition to carbonyl com-
pounds has attracted intense research activity in recent years
because this process can provide a very convenient route to
chiral propargylic alcohols that have diverse synthetic
applications.1-3 Among the catalytic methods developed for
the asymmetric alkyne addition to aldehydes,4-10 two are
currently considered the most practical. One was developed
by Carreira and co-workers, which used N-methylephedrin,
Zn(OTf)2, and Et3N.5 In this method, the zinc alkynylides
were generated in situ in the presence of substoichiometric
amounts of Zn(II) salts. The other method was developed
by us,6,7a-c which used 1,1′-bi-2-naphthol (BINOL), Et2Zn,
and Ti(OiPr)4. The alkynylzincs in this method were gener-
ated by treating terminal alkynes with Et2Zn. The chiral
(1) (a) Marshall, J. A.; Wang, X. J. J. Org. Chem. 1992, 57, 1242-
1252. (b) Henderson, M. A.; Heathcock, C. H. J. Org. Chem. 1988, 53,
4736-4745. (c) Fox, M. E.; Li, C.; Marino, J. P., Jr.; Overman, L. E. J.
Am. Chem. Soc. 1999, 121, 5467-5480.
(2) (a) Nicolaou, K. C.; Webber, S. E. J. Am. Chem. Soc. 1984, 106,
5734-5736. (b) Chemin, D.; Linstrumelle, G. Tetrahedron 1992, 48, 1943-
1952. (c) Corey, E. J.; Niimura, K.; Konishi, Y.; Hashimoto, S.; Hamada,
Y. Tetrahedron Lett. 1986, 27, 2199-2202. (d) Vourloumis, D.; Kim, K.
D.; Petersen, J. L.; Magriotis, P. A. J. Org. Chem. 1996, 61, 4848-4852.
(3) (a) Evans, D. A.; Halstead, D. P.; Allison, B. D. Tetrahedron Lett.
1999, 40, 4461. (b) Trost, B.; Krische, M. J. J. Am. Chem. Soc. 1999, 121,
6131-6141. (c) Roush, W. R.; Sciotti, R. J. J. Am. Chem. Soc. 1994, 116,
6457-6458. (d) Burgess, K.; Jennings, L. D. J. Am. Chem. Soc. 1991, 113,
6129-6139.
ligands in both methods are commercially available and
inexpensive. They can conduct the highly enantioselective
(7) Other reports on BINOL-catalyzed alkyne additions involving both
R2Zn and Ti(OiPr)4: (a) Lu, G.; Li, X.; Chan, W. L.; Chan, A. S. C. J.
Chem. Soc., Chem. Commun. 2002, 172-173. (b) Li, X.-S.; Lu, G.; Kwok,
W. H.; Chan, A. S. C. J. Am. Chem. Soc. 2002, 124, 12636-12637. (c)
Lu, G.; Li, X.-S.; Chen, G.; Chan, W. L.; Chan, A. S. C. Tetrahedron:
Asymmetry 2003, 14, 449-452. (d) Liu, Q.-Z.; Xie, N.-S.; Luo, Z.-B.; Cui,
X.; Cun, L.-F.; Gong, L. Z.; Mi, A.-Q.; Jiang, Y. Z. J. Org. Chem. 2003,
68, 7921-7924. (e) Moore, D.; Huang, W.-S.; Xu, M.-H.; Pu, L.
Tetrahedron Lett. 2002, 43, 8831-8834. (f) Mashall, J. A.; Bourbeau, M.
P. Org. Lett. 2003, 5, 3197-3199.
(4) For reviews, see: (a) Pu, L. Tetrahedron 2003, 59, 9873-9886. (b)
Pu, L.; Yu, H. B. Chem. ReV. 2001, 101, 757-824.
(5) (a) Frantz, D. E.; Fa¨ssler, R.; Tomooka, C. S.; Carreira, E. M. Acc.
Chem. Res. 2000, 33, 373-381. (b) Anand, N. K.; Carreira, E. M. J. Am.
Chem. Soc. 2001, 123, 9687-9688.
(6) (a) Gao, G.; Moore, D.; Xie, R.-G.; Pu, L. Org. Lett. 2002, 4, 4143-
4146. (b) Moore, D.; Pu, L. Org. Lett. 2002, 4, 1855-1857.
10.1021/ol0498139 CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/26/2004

synthesis of a variety of propargylic alcohols. Limitations
have also been identified for these methods. Carreira’s
method can catalyze the alkyne addition to aliphatic alde-
hydes with high enantioselectivity, but it is not catalytic for
the addition to benzaldehyde. Our BINOL method can
catalyze the alkyne addition to aromatic, aliphatic, and R,â-
unsaturated aldehydes with high enantioselectivity,6,7f but it
requires the use of both Et2Zn and Ti(OiPr)4. Therefore, the
search of efficient catalysts continues for the asymmetric
alkyne additions. Herein, we report our finding of a highly
enantioselective alkyne addition to aromatic aldehydes
catalyzed by a BINOL-Salen ligand in the absence of
Ti(OiPr)4.
BINOL-Salens are a class of compounds made from the
condensation of the 3-aldehyde function of BINOL with
amines. Since 1993, Katsuki has used BINOL-Salen-based
manganese complexes for the asymmetric epoxidation of
alkenes.11 In recent years, Kozlowski has further developed
BINOL-Salen-based bifunctional metal complexes for asym-
metric catalysis.12 We prepared enantiomerically pure
BINOL-Salen ligands 1-4 by using Kozlowski’s method.12
Compounds (-)-1 and (+)-1 are a pair of enantiomers.
Compounds (-)-1/2 and 3/4 are two pairs of diastereomers
with the configuration of the chiral carbon centers inverted.
We also prepared the macrocyclic BINOL-Salen 5 by
following Brunner’s procedure.13
Scheme 1. Asymmetric Reaction of Phenylacetylene with
Benzaldehyde
by the sequential treatment of phenylacetylene with Et2Zn,
a chiral ligand, and then benzaldehyde (Scheme 1). As the
results summarized in Table 1 show, compound (-)-1 gave
the highest enantioselectivity among the five ligands. The
low enantioselectivity of compound 2 indicated a mismatched
chirality between the BINOL units and the chiral carbon
centers. Replacement of the cyclohexyl groups of (-)-1 with
the diphenyl groups of 3 and 4 also gave very low
enantioselectivity. The macrocycle 5 was a poor chiral ligand
for this reaction.
Table 1. Results for the Reaction of Phenylacetylene with
Benzaldehyde in the Presence of Ligands (-)-1-5 and Et2Zn in
Toluene at Room Temperature
phenylacetylene
(equiv)
Et2Zn
ee
entry
ligand
(equiv)
(%)
1
2
3
4
5
(-)-1 (15 mol %)
2 (15 mol %)
3 (15 mol %)
4 (15 mol %)
5 (15 mol %)
2.1
2.1
2.1
2.1
2.1
2.0
2.0
2.0
2.0
2.0
79
<10
<10
13
17
We then explored the conditions for the use of ligand (-)-1
in the reaction of phenylacetylene with benzaldehyde. Table
2 summarizes these experiments. In entries 1-4, various
solvents including toluene, THF, diethyl ether, and methylene
chloride were tested, among which, toluene was found to
be the best. Increasing the amount of phenylacetylene versus
Et2Zn led to reduction in enantioselectivity (entry 5). This
indicated that the phenylethynyl ethylzinc intermediate, as
shown in Scheme 1, should be more favorable in the addition
to the aldehyde than bisphenylethynylzinc that could be
generated from the reaction of excess phenylacetylene with
Et2Zn. Reducing the amount of ligand (-)-1 from 15 to 11
mol % in entry 6 led to reduction in ee. Increasing the amount
(9) (a) Lu, G.; Li, X. S.; Jia, X.; Chan, W. L.; Chan, A. S. C. Angew.
Chem., Int. Ed. 2003, 42, 5057-5058. (b) Jiang, B.; Chen, Z.-L.; Xiong,
W.-N. J. Chem. Soc., Chem. Commun. 2002, 1524-1525. (c) Xu, Z. Q.;
Wang, R.; Xu, J. K.; Da, C. S.; Yan, W. J.; Chen, C. Angew. Chem., Int.
Ed. 2003, 42, 5747-5749.
(10) Corey, E. J.; Cimprich, K. A. J. Am. Chem. Soc. 1994, 116, 3151-
3152.
(11) (a) Sasaki, H.; Irie, R.; Katsuki, T. Synlett 1993, 300-302. (b)
Katsuki, T. Coord. Chem. ReV. 1995, 140, 189-214.
Compounds 1-5 were used to catalyze the reaction of
phenylacetylene with benzaldehyde in the presence of Et2Zn.
The reactions were conducted at room temperature in toluene
(12) (a) DiMauro, E. F.; Kozlowski, M. C. Org. Lett. 2001, 3, 1641-
1644. (b) Annamalai, V.; DiMauro, E. F.; Carroll, P. J.; Kozlowski, M. C.
J. Org. Chem. 2003, 68, 1973-1981. (c) DiMauro, E. F.; Kozlowski, M.
C. Organometallics 2002, 21, 1454-1461.
(8) A BINOL derivative-catalyzed alkyne addition without using titanium
was reported but with lower enantioselectivity than this work: Xu, M.-H.;
Pu, L. Org. Lett. 2002, 4, 4555-4557.
(13) (a) Brunner, H.; Schiessling, H. Angew Chem., Int. Ed. Engl. 1994,
33, 125-126. (b) Brunner, H.; Schiessling, H. Bull. Soc. Chim. Belg. 1994,
103, 119-126.
1066
Org. Lett., Vol. 6, No. 6, 2004

Table 2. Conditions for the Reaction of Phenylacetylene with
Benzaldehyde in the Presence of Ligand (-)-1
Table 3. Results for the Alkyne Additions to Aldehydes
Catalyzed by (-)-1
ligand
phenyl-
acetylene
(equiv)
(-)-1
T
R2Zn
ee
entry (mol %) (°C) solvent
(equiv)
(%)
1
2
3
4
5
6
7
8
9
15
15
15
15
15
11
22
30
30
22
22
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
toluene
THF
ether
2.1
2.1
2.1
2.1
3.0
2.0
2.0
2.0
3.0
2.0
2.0
Et2Zn (2.0)
Et2Zn (2.0)
Et2Zn (2.0)
Et2Zn (2.0)
Et2Zn (2.0)
Et2Zn (2.0)
Et2Zn (2.0)
Et2Zn (2.0)
Et2Zn (3.0)
Et2Zn (2.0)
79
57
39
29
45
71
87
87
87
80
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
tolu en e
10
11
r t
Me2Zn (2.0) 92
of ligand (-)-1 to 22 mol % in entry 7 gave enhanced ee,
but further increasing the amount of the ligand to 30 mol %
did not lead to a further increase in ee (entry 8). In entry 9,
the amounts of ligand (-)-1, phenylenacetylene, and Et2Zn
were increased, but no effect on the enantioselectivity was
observed. Reducing the reaction temperature from room
temperature to 0 °C gave reduced enantioselectivity (entry
10). Replacement of Et2Zn with Me2Zn boosted the enan-
tioselectivity to 92% ee (entry 11). The configuration of the
propargylic alcohol product was S as determined by compar-
ing with the literature.10
We also used (+)-1 to catalyze the reaction of phenyl-
acetylene with benzaldehyde. Under the conditions of entry
11 in Table 2, (+)-1 gave the propargylic alcohol product
with 92% ee. The configuration of the product was R, the
enantiomer of the product from (-)-1 as expected.
Earlier, Cozzi found that Jacobsen’s Salen ligand 6 could
catalyze the alkyne addition to ketones with up to 81% ee.14
We tested the use of 6 in the asymmetric phenylacetylene
addition to benzaldehyde by applying the conditions of entry
11 in Table 2. However, only 39% ee was observed. This
shows that BINOL units of ligand (-)-1 are necessary for
the high enantioselectivity.
a (+)-1 was used.
aldehyde gave excellent stereocontrol as well (entry 10). Very
good enantioselectivity was also observed for the reaction
of an alkenyl alkyne with benzaldehyde (entry 19).
In summary, we have discovered that the BINOL-Salen
compound (-)-1 can catalyze the addition of both aromatic
and aliphatic alkynes to aromatic aldehydes with high
enantioselectivity. The conditions of this catalytic process
are both mild and simple. Unlike most other BINOL-based
(15) A typical experimental procedure for the alkyne addition to
aldehydes catalyzed by (-)-1 is given below. Under nitrogen, an alkyne
(0.5 mmol) and Me2Zn (0.5 mmol) were added to a 10 mL flask containing
toluene (1 mL, distilled over sodium). After the solution was stirred at room
temperature for 1 h, ligand (-)-1 (0.054 mmol, 38.2 mg) was added and
the mixture stirred for another 1 h. Then, an aldehyde (0.25 mmol) was
added and the reaction was allowed to proceed at room temperature for 18
h. Water was added to quench the reaction, and the mixture was extracted
with diethyl ether and dried with sodium sulfate. After column chroma-
tography on silica gel eluted with 2-10% ethyl acetate in hexanes, the
propargylic alcohol product was isolated. The enantiomeric purity of the
product was determined by using HPLC Chiralcel OD column.
Ligand (-)-1 was used to catalyze the reaction of alkynes
with a variety of aldehydes by applying the optimized
conditions of entry 11 in Table 2.15 As shown by the results
summarized in Table 3, high enantioselectivity has been
achieved for the addition of both aromatic and aliphatic
alkynes to aromatic aldehydes. The addition to a vinyl
(14) Cozzi, P. G. Angew. Chem., Int. Ed. 2003, 42, 2895-2898.
Org. Lett., Vol. 6, No. 6, 2004
1067

catalysts,6-8 using ligand (-)-1 not only avoids heating or
Supporting Information Available: Conditions to de-
termine the enantiomeric purity of the propargyl alcohol
products are provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
cooling but also does not require the addition of Ti(OiPr)4.
Acknowledgment. We thank the National Institutes of
Health (R01GM58454/R01EB002037) for partial support of
this research.
OL0498139
1068
Org. Lett., Vol. 6, No. 6, 2004