Palladium-catalyzed cross-coupling of Baylis-Hillman acetate adducts with organosilanes

Article abstract of DOI:10.1021/jo051177k

A cross-coupling reaction between acetates of Baylis-Hillman adducts and organosilanes is described. A nonconventional solvent poly(ethylene glycol) (PEG) is used as the reaction medium.

Full text of DOI:10.1021/jo051177k

Palladium-Catalyzed Cross-Coupling of Baylis-Hillman Acetate
Adducts with Organosilanes
George W. Kabalka,* Gang Dong, Bollu Venkataiah, and Chunlan Chen
Departments of Chemistry and Radiology, The University of Tennessee, Knoxville, Tennessee 37996-1600
kabalka@utk.edu
Received June 10, 2005
A cross-coupling reaction between acetates of Baylis-Hillman adducts and organosilanes is
described. A nonconventional solvent poly(ethylene glycol) (PEG) is used as the reaction medium.
Introduction
Since Hiyama demonstrated that arylfluorosilanes
undergo palladium-catalyzed cross-coupling reactions
with aryl iodides,9 the use of silicon-derived compounds
as transmetalation reagents has attracted attention
because of their low cost, ready availability, low toxicity,
and chemical stability.10 Lee and Wolf reported efficient
coupling reactions of aryl chlorides and bromides with
organotrimethoxysilanes.11 DeShong coupled vinyl and
aryl halides, aryl triflates, and allylic benzoates with
hypervalent silanes.12 Denmark and others have devel-
oped Lewis base-promoted reactions using hypervalent
silicates,13 and the use of alkenyl- and arylsilanols as
efficient coupling partners under fluoride-free condi-
tions.14
Palladium-catalyzed carbon-carbon bond formation
has become one of the most important reactions in
organic synthesis.1 It provides a highly effective method
for preparing a variety of natural products,2 supramol-
ecules,3 and liquid crystals.4 Grignard,5 organotin,6 or-
ganozinc,7 and organoboron reagents8 have all been used
as organometallic reactants in palladium-mediated cou-
pling reactions.
(1) (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
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& Sons: New York, 1995.
The Baylis-Hillman reaction provides molecules pos-
sessing hydroxyl, alkene, and electron-withdrawing groups
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Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich,
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Suzuki, K.; Kumada, M. Tetrahedron Lett. 1981, 22, 5319. (f) Hayashi,
T.; Konishi, M.; Fukushima, M.; Mise, T.; Kagotani, M.; Tajika, M.;
Kumada, M. J. Am. Chem. Soc. 1982, 104, 180. (g) Hayashi, T.;
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10.1021/jo051177k CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/12/2005
J. Org. Chem. 2005, 70, 9207-9210
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Kabalka et al.
TABLE 1. Optimization of Reaction Conditions
hydrylacrylic acid methyl ester. To increase the yield of
the desired product and suppress the formation of the
regioisomer, additional solvents were evaluated. In tolu-
ene, 25% of the regioisomer formed along with 49% of
the desired product. Due to recent interest in noncon-
ventional solvents, reactions were carried out in an ionic
liquid,butylmethylimidazoliumtetrafluoroborate(BmimBF4),
but no reaction occurred. We then investigated poly-
(ethylene glycol) (PEG) as a reaction medium.17 PEG has
been shown to be an effective polar, nonprotic solvent for
a number of organic reactions. When PEG-600 was used,
the isomerization reaction was inhibited and an excellent
yield of the coupled product was obtained at room
temperature. The quantity of TBAF was also evaluated.
One equivalent of TBAF afforded good yields (80%) but
2 equiv of TBAF led to the highest yields (92%). The
reaction also proceeded in the presence of Pd(OAc)2 when
PEG was used as solvent, and 85% of desired product
was formed.
temp time yield
entry catalysta
baseb
Pd2(dba)3 KF
Pd(OAc)2 KF
solvent
(°C)
(h)
(%)d
1
2
3
4
5
6
7
8
THF/H2Oc
50
50
50
50
50
rt
5
5
2
2
6
3
3
3
35
trace
45
49
0
92
80
85
THF/H2Oc
Pd2(dba)3 n-Bu4NF THF
Pd2(dba)3 n-Bu4NF toluene
Pd2(dba)3 n-Bu4NF BmimBF4
Pd2(dba)3 n-Bu4NF PEG
Pd2(dba)3 n-Bu4NFe PEG
Pd(OAc)2 n-Bu4NF PEG
rt
rt
a 3 mol % of Pd2(dba)3 or 5 mol % of Pd(OAc)2 (based on the
adduct). b Two equivalents of base used. c The ratio of THF/H2O
was 20/1. d Isolated yields. e One equivalent of base used.
On the basis of the results summarized in Table 1, the
optimal reaction conditions for coupling phenyltriethoxy-
silane with Baylis-Hillman acetate adducts were found
to be 3 mol % of Pd2(dba)3 and 2 equiv of TBAF in PEG-
600 at room temperature.
in close proximity, which makes them valuable in a
number of stereoselective processes.15 We recently dem-
onstrated that potassium organotrifluoroborates can be
employed in palladium-catalyzed cross-coupling reactions
with Baylis-Hillman acetate adducts.16 In view of the
similarities between boron and silicon chemistry, the
cross-coupling reactions of Baylis-Hillman acetate ad-
ducts with silicon reagents were explored with use of
palladium catalysis. We wish to report the successful
palladium-catalyzed coupling of organosilanes with Bay-
lis-Hillman acetate adducts and related reagents.
Study of the Reaction Scope. With an optimal set
of reaction conditions established, the versatility of the
reaction was then surveyed. Baylis-Hillman acetate
adducts derived from reactions of aryl aldehydes, het-
eroaryl aldehydes, and aliphatic aldehydes with methyl
acrylate, acrylonitrile, or R,â-unsaturated cyclic ketones
were subjected to the new coupling reaction process.
Coupling of Baylis-Hillman Adducts Derived
from Methyl Acrylate and Acrylonitrile. The reac-
tions of various Baylis-Hillman acetate adducts derived
from methyl acrylate were investigated first. The results
are summarized in Table 2 (entries 1-9). Aryl- and
heteroarylsilanes readily participate in the reaction
(entries 10-12). The reaction yields are very good in the
absence of electron withdrawing groups on the aromatic
moiety of the adduct (Table 2, entry 9). The reaction is
highly stereoselective. The stereochemistry of the prod-
ucts was established by comparing NMR parameters for
the olefinic and methylene protons for the products with
literature values.18 The ratio of E/Z isomers was deter-
mined by 1H NMR analysis. The ratio was normally
found to be exceed 90/10 even for aliphatic Baylis-
Hillman adducts.
Results and Discussion
Optimization of Reaction Conditions. The reaction
of methyl 3-acetoxy-3-phenyl-2-methylenepropanoate with
phenyltriethoxysilane was chosen as the model system
to define the optimum reaction conditions (Table 1).
When the coupling reaction was performed in THF/H2O
in the presence of 3 mol % of Pd2(dba)3 and 2 equiv of
KF at 50 °C for 5 h, only a 35% yield of desired product
was obtained. When the catalyst was changed to Pd-
(OAc)2, the yield decreased. Better results were achieved
when KF was replaced by tetrabutylammonium fluoride
(TBAF) as the silane activator. Treatment of a Baylis-
Hillman adduct (0.5 mmol) with phenyltriethoxysilane
(0.65 mmol) in the presence of 3 mol % of Pd2(dba)3 and
2 equiv of TBAF produced 45% of the desired cross-
coupled product, 27% of the regioisomer, and 2-benz-
The protocol was then applied to reactions between two
3-acetoxy-2-methylenealkanenitriles 4 and p-tolyltri-
ethoxysilane. The desired coupling did not occur at room
temperature but the product was obtained after heating
the reaction mixture to 50 °C (Figure 1). The reactions
afforded products with excellent stereoselectivity. Inter-
estingly, for Baylis-Hillman nitrile adducts, the Z isomer
was the major product. This inversion in stereochemistry
(13) (a) Chuit, C.; Corriu, R. J. P.; Reye, C.; Young, J. C. Chem. Rev.
1993, 93, 1371. (b) Kobayashi, S.; Nishio, K. J. Am. Chem. Soc. 1995,
117, 6392. (c) Kobayashi, S.; Yasuda, M.; Hachiya, I. Chem. Lett. 1996,
407. (d) Denmark, S. E.; Winter, S. B. D.; Su, X. P.; Wong, K. T. J.
Am. Chem. Soc. 1996, 118, 7404. (e) Denmark, S. E.; Wong, K. T.;
Stavenger, R. A. J. Am. Chem. Soc. 1997, 119, 2333. (f) Denmark, S.
E.; Winter, S. B. D. Synlett 1997, 1087. (g) Denmark, S. E.; Stavenger,
R. A.; Wong, K. T.; Su, X. P. J. Am. Chem. Soc. 1999, 121, 4982. (h)
Denmark, S. E.; Stavenger, R. A. J. Am. Chem. Soc. 2000, 122, 8837.
(i) Denmark, S. E.; Fujimori, S. Org. Lett. 2002, 4, 3473. (j) Denmark,
S. E.; Fujimori, S. Org. Lett. 2002, 4, 3477. (k) Denmark, S. E.; Sweis,
R. F. Acc. Chem. Res. 2002, 35, 835.
(17) PEG is soluble in solvents, such as CH2Cl2, CHCl3, tetrahy-
drofuran, CH3OH, and H2O at room temperature. It can be precipitated
from these solutions by the addition of diethyl ether, hexane, or tert-
butyl methyl ether. Physical properties of PEG-600: mp 20-25 °C,
viscosity (210 F) ) 10.5 cSt. See: (a) Zhao, X.; Metz, W. A.; Sieber, F.;
Janda, K. D. Tetrahedron Lett. 1998, 39, 8433. (b) Fu, Y.; Etienne, M.
A.; Hammer, R. P. J. Org. Chem. 2003, 68, 9854.
(18) (a) Basavaiah, D.; Muthukumaran, K.; Sreenivasulu, B. Syn-
thesis 2000, 545. (b) Mason, P. H.; Emsile, N. D. Tetrahedron 1994,
50, 12001. (c) Shanmugam, P.; Singh, P. R. Synlett 2001, 1314.
(14) (a) Denmark, S. E.; Sweis, R. F. J. Am. Chem. Soc. 2001, 123,
6439. (b) Denmark, S. E.; Ober, M. H. Org. Lett. 2003, 5, 1357.
(15) (a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev.
2003, 103, 811. (b) Drewes, S. E.; Ross, G. H. P. Tetrahedron 1988,
44, 4653. (c) Basavaiah, D.; Dharmarao, P.; Suguna H. R. Tetrahedron
1996, 52, 8001.
(16) Kabalka, G. W.; Venkataiah, B.; Dong, G. Org. Lett. 2003, 5,
3803.
9208 J. Org. Chem., Vol. 70, No. 23, 2005

Cross-Coupling of Baylis-Hillman Acetate Adducts
TABLE 2. Coupling of Various Baylis-Hillman Acetate
TABLE 3. Coupling of Various Baylis-Hillman Adducts
Derived from r,â-unsaturated Cycloalkenones with
Triethoxysilanes
Adducts with Organosilanesa
yield
entry
R
R′
phenyl
phenyl
phenyl
phenyl
phenyl
product (%)b E/Z
yield
(%)
1
2
phenyl
3a
3b
3c
3d
3e
3f
3g
3h
3i
92 93/7
91 99/1
89 95/5
87 94/6
78 99/1
94 99/1
86 92/8
85 90/10
62 96/4
86 97/3
92 98/2
70 93/7
entry
R
n
R′
product
p-chlorophenyl
p-tolyl
1-naphthyl
2-furyl
p-methoxyphenyl phenyl
2-chlorophenyl
n-octyl
1
2
3
4
5
6
7
phenyl
phenyl
phenyl
phenyl
phenyl
2-methoxyphenyl
2-methoxyphenyl
1
1
2
2
2
2
2
phenyl
9a
9b
9c
9d
9e
9f
51
53
70
66
77
61
65
3
p-tolyl
4
phenyl
p-tolyl
p-chlorophenyl
phenyl
p-tolyl
5
6
7
phenyl
8
phenyl
9g
9
p-nitrophenyl
phenyl
phenyl
10
11
12
p-tolyl
3j
3k
3l
phenyl
phenyl
p-chlorophenyl
2-thienyl
a Reactions carried out at room temperature for 3 h with 2 equiv
of Bu4NF. b Isolated yield.
FIGURE 3. Coupling of 5-acetoxycyclopent-1-enecarboxylic
acid ethyl ester.
The substituents on the aromatic ring of organosilane
only slightly affected the reaction yields.
FIGURE 1. Coupling of Baylis-Hillman nitrile adducts.
Coupling of Functionally Substituted Allylic Cy-
cloalkenol Acetates with Organotriethoxysilanes.
Allylic cycloalkenol acetates are important synthetic
precursors in organic and medicinal chemistry. For
example, Casara utilized them as key precursors in the
synthesis of cyclopentanecarboxylic acid matrix metal-
loproteinase (MMP) inhibitors.19 Amri converted allylic
cycloalkenol acetates to alkylcarbethoxycycloalkenes as
the key step in a short synthesis of (()-mitsugashiwa-
lactone. 20,21
FIGURE 2. Coupling of Baylis-Hillman adduct derived from
vinyl ketone.
To extend the scope of the new reaction, the reaction
of a 5-acetoxycyclopent-1-enecarboxylic acid ethyl ester
(10) was investigated (Figure 3). The reaction proceeded
at 50 °C to produce good yields of product 11.
was noted in an earlier trifluoroborate study that also
resulted in slightly higher product yields.16
Coupling of Baylis-Hillman Adducts Derived
from Acylic and Cyclic r,â-Unsaturated Ketones.
The reaction of adduct 6 (derived from methyl vinyl
ketone) with organosilanes was then investigated (Figure
2). The coupling reaction proceeded smoothly in excellent
(90%) yield. No regioisomer formation was observed in
the reaction, only the desired SN2′ product, 7, was formed.
Having demonstrated that an acyclic vinyl ketone
derived Baylis-Hillman adduct underwent coupling with
phenyltriethoxysilane, reactions of Baylis-Hillman ad-
ducts 8 derived from R,â-unsaturated cycloalkenones
were examined. The reaction of 8 with various aryltri-
ethoxysilanes proceeded such that the aryl group of the
aryltriethoxysilane replaced the acetoxy group at its
original position (SN2 coupling). This reaction has not
been reported previously. Representative results of the
cross-coupling reaction of a variety of cyclic ketone
derived Baylis-Hillman adducts, 8, are summarized in
Table 3. Adducts derived from 2-cyclohexenone produced
higher yields than those derived from 2-cyclopentenones.
Conclusion
An efficient palladium-catalyzed coupling reaction of
aryltrialkoxysilanes with various Baylis-Hillman acetate
adducts has been developed. PEG is the most effective
solvent in that it suppresses the formation of regioiso-
mers. The coupling reaction of Baylis-Hillman adducts
(19) Le Diguarher, T.; Chollet, A.-M.; Bertrand, M.; Hennig, P.;
Raimbaud, E.; Sabatini, M.; Guilbaud, N.; Pierre, A.; Tucker, G. C.;
Casara, P. J. Med. Chem. 2003, 46, 3840.
(20) Amri, H.; Rambaud, M.; Villieras, J. Tetrahedron 1990, 46,
3535.
(21) Amri, H.; Villieras, J. Tetrahedron Lett. 1987, 28, 5521.
(22) (a) Aggarwal, V. K.; Mereu, A. Chem. Commun. 1999, 2311.
(b) Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J. Org. Chem. 2003, 68,
692. (c) Reddy, M. V. R.; Rudd, M. T.; Ramachandran, P. V. J. Org.
Chem. 2002, 67, 5382. (d) Takano, S.; Yamane, T.; Takahashi, M.;
Ogasawara, K. Tetrahedron: Asymmetry 1992, 3, 837. (e) Luo, S.;
Zhang, B.; He, J.; Janczuk, A.; Wang, P. G.; Cheng, J.-P. Tetrahedron
Lett. 2002, 43, 7369.
J. Org. Chem, Vol. 70, No. 23, 2005 9209

Kabalka et al.
and then stirred at room temperature for 3 h. The mixture
was extracted with ether (4 × 5 mL) and the combined organic
layers were dried over anhydrous MgSO4. After removal of the
solvent under reduced pressure, purification of the residue by
flash chromatography over silica gel with 5% ethyl acetate in
hexanes gave the desired product 3a (116 mg, 92%) as a
colorless oil: 1H NMR (CDCl3) δ 7.94 (s, 1H), 7. 34-7.18 (m,
10H), 3.95 (s, 2H), 3.72 (s, 3H); 13C NMR (CDCl3) δ 168.5,
140.9, 139.3, 135.2, 130.5, 129.1, 128.7, 128.5, 128.4, 127.8,
126.0, 52.0, 33.1. Anal. Calcd for C17H16O2: C, 80.93; H, 6.39.
Found: C, 80.87; H, 6.40.
derived from unsaturated cyclic ketones with silanes was
also studied. Adducts derived from methyl acrylate,
acrylonitrile, and vinyl ketones couple with organosilanes
to give allylic rearranged (SN2′) products whereas adducts
derived from unsaturated cyclic ketones gave SN2 prod-
ucts. The observed results for the acyclic adducts are
comparable to those obtained utilizing the organotrifluo-
roborate reagents.16 Interestingly, reactions involving the
unsaturated cyclic ketones are only successful utilizing
silane reagents. Application of this chemistry to asym-
metric reactions is currently under investigation.
Acknowledgment. We wish to thank the U.S.
Department of Energy and the Robert H. Cole Founda-
tion for support of this research.
Experimental Section
Preparation of 2-Benzyl-3-phenylacrylic Acid Methyl
Ester (3a): Representative Procedure. To a solution of
3-acetoxy-3-phenyl-2-methylenepropanoate (117 mg, 0.50 mmol),
phenyltriethoxysilane (156 mg, 0.65 mmol), and 3 mol % of
Pd2(dba)3 (16 mg, 0.015 mmol) in PEG-600 (3 mL) contained
in a 25 mL round-bottomed flask fitted with a rubber septum
was added tetrabutylammonium fluoride in THF (1.0 mL, 1.0
M, 1.0 mmol) via syringe. The flask was purged with nitrogen
Supporting Information Available: 1H NMR and 13C
NMR spectra along with the general synthetic procedure for
all compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO051177K
9210 J. Org. Chem., Vol. 70, No. 23, 2005