S. R. Gilbertson et al. / Tetrahedron Letters 42 (2001) 365–368
367
Ph2P
Pd2(DBA)3
ligand
OTf
H
H
N
N
+
+
N
BOC
O
O
O
O
O
1
0
1
7
8
8'
Ph2P
Ligand 10
Ligand 11
Benzene, (i-Pr)2NEt, RT, 3 days
Benzene, (i-Pr)2NEt, RT, 24h
43% conversion, less than 5 %ee
89% conversion, 7%ee
N
O
1
1
(
iPr)2N
Scheme 3.
OTf
Pd2(dba)3
ligand 5
H
OTf
Pd2(dba)3
Ligand 5,
CO2Et
+
CO2Et
O
O
+
O
Benzene, (i-Pr)2NEt
75°C, 24 hours
O
benzene, 75ºC
13
(iPr)2NEt
17
80% 46% ee
1
12
1
16
3
days
95% 82% ee
OTf
Pd (dba)
Ligand 5
2
3
Pd2(dba)3
ligand 5
H
OTf
C H
+
+
O
6
13
O
C6H13
solvent, 75ºC
base
Benzene, (i-Pr)2NEt
75°C, 24 hours
14
12
15
1
18
19
83% 27% ee
Benzene,(i-Pr)2NEt 2 days 14% (conv.) 73%ee
Dioxane, Bu4-NOAc 2 days 85% (conv.) 12%ee
Scheme 4.
around the metal increases the rate of the Heck reac-
tion. With this in mind a ligand where the carbamate-
protecting group on the proline nitrogen was replaced
with a urea was also tested (11). That ligand provided a
catalyst with good activity but unfortunately low
selectivity.
and (3 mol%) in degassed solvent was stirred at the
reaction temperature. The progress of the reaction was
monitored by GC and TLC. Upon completion, the
mixture was diluted with additional diethyl ether and
washed with water and brine, dried and evaporated.
Additional substrates were examined to determine if
this ligand system is reasonably general. Reaction of
aryl triflate 12 with dihydrofuran gives good selectivity
and high conversion at 75°C (Scheme 4). The reaction
of cyclopentene with phenyl triflate gave fair selectivity
in benzene but with low conversion, while in dioxane
the conversion was higher but the selectivity was low.
Two acyclic triflates were also tested. Both of these
molecules proceeded with good rate but gave the
Acknowledgements
This work was partially supported by NIH R01
GM56490-04 and Washington University. We also
gratefully acknowledge the Washington University
High-Resolution NMR Facility, partially supported by
NIH 1S10R02004, and the Washington University
Mass Spectrometry Resource Center, partially sup-
ported by NIHRR00954, for their assistance.
2
9
product in only moderate selectivity.
The asymmetric Heck reaction is a transformation that
has considerable promise. Once catalyst systems can be
found that, perform the reaction with good selectivity,
under mild conditions, and on a variety of substrates
this reaction will be a valuable tool for synthetic or-
ganic chemists. This paper illustrates that this proline
based system has some application in this reaction.
Also the study of the reaction in different solvents and
with a variety of bases should serve as a guide for
others working in this area. Obtaining high selectivity
in this reaction is complicated by the problem of iso-
merization of the double bond of the product. We have
observed that the amount of isomerization can be con-
trolled by both the solvent and the base used in this
reaction.
References
1. Heck, R. F. In Palladium-Catalyzed Vinylation of Or-
ganic Alides; Dauben, W. G., Ed.; John Wiley & Sons:
New York, 1982; Vol. 27, pp. 345–390.
2. Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn.
1971, 581.
3. Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5518.
4. Shibasaki, M.; Boden, C. D. J.; Kojima, A. Tetrahedron
1997, 53, 7371–7395.
5. Overman, L. E.; Rucker, P. V. Heterocycles 2000, 52,
1297–1314.
6. Overman, L. E. Pure Appl. Chem. 1994, 66, 1423–1430.
7
. Madin, A.; O’Donnell, C. J.; Oh, T.; Old, D. W.; Over-
man, L. E.; Sharpe, M. J. Angew. Chem., Int. Ed. 1999,
38, 2934–2936.
General procedure: A mixture of triflate, alkene (5 mol
equiv.), base (3 equiv.), Pd (dba) (1.5 mol%) and lig-
2
3