Palladium-catalyzed Michael addition of indoles to α,β- unsaturated ketones in an ionic liquid

Article abstract of DOI:10.1055/s-2005-871952

The PdCl₂(CH₃CN)₂-catalyzed Michael addition reaction of indoles with α,β-unsaturated ketones in ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF₄]) to afford the corresponding 3-alkylated i

Full text of DOI:10.1055/s-2005-871952

LETTER
2003
Palladium-Catalyzed Michael Addition of Indoles to a,b-Unsaturated Ketones
in an Ionic Liquid
P
W
alladium-Catalyze
d
M
e
ichael Addi
i
tion of
-
I
ndoles
J
to
a
,
b
-Uns
u
aturated Ke
t
n
ones Li, Xu-Feng Lin, Jun Wang, Guo-Liang Li, Yan-Guang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
Fax +86(571)87951512; E-mail: orgwyg@zju.edu.cn
Received 8 May 2005
to be an excellent environmentally benign solvent for a
Abstract: The PdCl (CH CN) -catalyzed Michael addition reac-
tion of indoles with a,b-unsaturated ketones in ionic liquid 1-butyl-
2
3
2
variety of reactions.8
3
-methylimidazolium tetrafluoroborate ([bmim][BF ]) to afford the In a preliminary experiment, treatment of indole (1a)
4
corresponding 3-alkylated indoles in good yields is described. The
catalyst system PdCl (CH CN) /[bmim][BF ] can be recovered and
reused.
with 1,3-diphenylpropenone (2a) using 10 mol%
2
3
2
4
PdCl (CH CN) as catalyst in [bmim][BF ] at ambient
2
3
2
4
temperature for one hour afforded the 3-substituted indole
adduct 3a in 95% yield after column chromatography of
the reaction mixture on silica gel. The product 3a was
characterized by spectroscopic analysis. Encouraged by
Key words: palladium, indoles, Michael reaction, ionic liquid
The development of a new efficient, selective, and green this result, we studied the effect of reaction conditions on
synthetic method for the preparation of 3-substituted in- the Michael reaction for the synthesis of 3a (Table 1).
dole derivatives has attracted much attention in organic
synthesis because of its important biological activities and Table 1 Screening for Optimum Reaction Conditionsa
key role as a versatile building bock in the synthesis of
Entry
Catalyst Solvent
mol%)
Temp
(° C)
Time
(h)
Yieldb
(%)
natural products and in the design of therapeutic agents.1
The carbon–carbon bond formation at C-3 of indoles
could exploit the Michael addition reactions of indoles,
which represents one of the most important carbon–car-
bon bond-forming reactions at their C-3 position.
(
1
2
3
4
5
6
7
8
10
10
10
10
10
10
2
[bmim][BF
]
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
100
100
1
24
24
24
24
24
24
2
95
60
25
83
8
4
CH CN
3
CH Cl
2
2
Recently, a variety of methods have been explored for the
Michael addition reaction of indoles with a,b-unsaturated
MeOH
toluene
THF
2
3
ketones in the presence of protic or Lewis acids for the
preparation of 3-substituted indoles. Molecular iodine
4
was also found to efficiently catalyze this reaction. How-
50
45
94
0
ever, most of these published procedures suffer from nu-
merous drawbacks, such as the need for acidic conditions,
expensive reagents, long reaction times, or/and low yields
due to dimerization of the indoles or polymerization of the
vinyl ketones. Thus, new efficient, selective, and green
procedures are still in strong demand.
[bmim][BF4]
2
[bmim][BF4]
9
0
[bmim][BF
]
5
4
a
Conditions: 1a (1 mmol), 2a (1 mmol), and solvent (1 mL).
Isolated yield.
5
b
In 2001, Spencer et al. reported the catalytic intermolec-
ular aza-Michael reaction of enones with weak nucleo-
philic carbamates employing Lewis acidic Pd(II)
complexes. Since then, several catalytic processes have
The optimum conditions demonstrated that ionic liquid
bmim][BF ] was much more efficient than molecular sol-
[
4
6
been explored. Recently, we reported a mild and efficient
vents such as CH CN, CH Cl , MeOH, THF, and toluene
3
2
2
selective tetrahydropyranylation of primary alcohols and
deprotection of THP ethers of phenols and alcohols using
(
Table 1, entries 1–6). Furthermore, using an ionic liquid
as a solvent at high temperatures (100 °C), required less
catalyst (2 mol%) and a shorter reaction time (2 h) to give
a good yield (94%; Table 1, entries 7 and 8). However, no
Michael adduct was obtained in the absence of catalyst
PdCl (CH CN) (Table 1, entry 9).
7
PdCl (CH CN) as catalyst. As a part of our interest in
2
3
2
palladium-catalyzed reactions, herein we describe a new
catalyst system PdCl (CH CN) /[bmim][BF ] which
2
3
2
4
could promote efficiently the conjugate addition reaction
of indoles with a,b-unsaturated ketones. The air- and
2
3
2
Under the optimized reaction conditions, a variety of in-
doles 1 and a,b-unsaturated ketones 2 were tested using
moisture-stable ionic liquid [bmim][BF ] has been found
4
2
1
.0 mol% PdCl (CH CN) as a catalyst in [bmim][BF ] at
00 °C for two hours (Scheme 1). The results are
2 3 2 4
9
SYNLETT 2005, No. 13, pp 2003–2006
Advanced online publication: 12.07.2005
DOI: 10.1055/s-2005-871952; Art ID: U13905ST
1
9
.0
8
.2
0
0
5
summarized in Table 2. Indole (1a) reacted with a,b-un-
saturated ketones 2a–j to afford the corresponding 3-sub-
©
Georg Thieme Verlag Stuttgart · New York

2
004
W.-J. Li et al.
LETTER
O
stituted indole derivatives 3a–j in good to excellent yields
2
mol% PdCl2(CH3CN)2
(
Table 2, entries 1–10). Various substituted indoles 1b–e
X
+
R1
R2
[
bmim][BF4], 100 °C , 2 h
could also react smoothly with different a,b-unsaturated
ketones to provide the desired addition products 3l–s in
good yields (Table 2, entries 12–19), although the strong-
ly electron-deficient 5-nitroindole (Table 2, entry 18) and
7-nitroindole (Table 2, entry 19) required a longer reac-
tion time (6 h) and an increased catalyst concentration (10
mol%).
N
H
1a–e
2a–k
O
R2
R1
X
N
H
3a–s
Scheme 1
Table 2 Palladium-Catalyzed Michael Addition of Indoles 1a–e with a,b-Unsaturated Ketones 2a–ka
Entry
1
Indoles
a,b-Unsaturated ketones
Products
Yields (%)b
94
O
3a
N
H
1
a
2a
2b
2c
2
3
4
1a
1a
1a
O
O
O
3b
3c
3d
85
89
85
Br
Me
Cl
2
2
2
d
O
5
6
7
1a
1a
1a
3e
3f
75
80
82
e
f
O
O
O
O
3g
OBn
2
g
h
8
9
1a
1a
1a
O
3h
3i
95
95
92
O
O
F
2
O
F
Cl
2
i
1
0
O
3j
Cl
2
j
Synlett 2005, No. 13, 2003–2006 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Michael Addition of Indoles to a,b-Unsaturated Ketones
2005
a
Table 2 Palladium-Catalyzed Michael Addition of Indoles 1a–e with a,b-Unsaturated Ketones 2a–k (continued)
Entry
Indoles
a,b-Unsaturated ketones
Products
Yields (%)b
1
1
1a
O
3k
94
OMe
2
k
1
2
Br
2a
3l
94
N
H
1
b
1
1
1
3
4
5
1b
2c
2j
3m
3n
3o
84
90
96
1b
3
H CO
2a
N
H
1
c
1
1
1
6
7
8
1c
2d
2h
2a
3p
3q
3r
91
93
80
1c
2
O N
N
H
1
d
1
9
2a
3s
73
N
H
NO2
1
e
a
Ratio of 1/2/PdCl (CH CN) = 1:1:0.02, [bmim][BF ] at 100 °C for 2 h (1.0 mmol scale).
Yields refer to a single run and are given for isolated products.
2
3
2
4
b
We also examined other a,b-unsaturated compounds like EtOAc and Et O. The rest of the viscous ionic liquid and
2
aldehydes, nitriles, and esters, however, it was found that PdCl (CH CN) was dried under reduced pressure and re-
2
3
2
indole (1a) did not undergo a Michael reaction with 2l–n used in three further runs with only a gradual decrease in
even by using 10 mol% PdCl (CH CN) as a catalyst in activity. The yields obtained by using the recycled cata-
2
3
2
[
bmim][BF ] at 100 °C for six hours, as shown in lyst system resulted in longer reaction times (3–5 h) in or-
4
Scheme 2. Thus, the catalyst system PdCl (CH CN) / der to be able to achieve yields comparable to those
2
3
2
[
bmim][BF ] can only promote the Michael addition reac- obtained in the first run.
4
tion of indoles with a,b-unsaturated ketones.
PdCl (CH CN) is a known Lewis acid catalyst, however,
2
3
2
We attempted to recycle the PdCl (CH CN) / the generation of protic acids through hydrolysis of metal
2
3
2
[
bmim][BF ] system, and found that the catalyst system complexes is a known, but often underestimated phenom-
4
could be easily recovered after completion of the reaction enon in Lewis acid catalysis. Recently, Spencer et al.10
and reused in subsequent reactions. Since the products demonstrated that protons, rather than metal ions, were
were weakly soluble in the ionic phase, they were easily the active catalysts in PdX (CH CN) -mediated hetero-
2
3
2
separated by thoroughly extracting the mixture with Michael addition reactions in molecular solvents with a
small amount of water, and their NMR experiments did
not reveal interactions between the carbonyl of a,b-unsat-
10 mol% PdCl2(CH3CN)2
R
+
Ph
urated ketones and Lewis acid PdX (CH CN) . In our in-
[
bmim][BF4], 100 °C , 6 h
2
3
2
N
vestigations, we also tested the Brønsted acidity of
PdX (CH CN) by using a weak base 4-methyl-2,6-di-
H
R = CHO, 2l
1a
2
3
2
R = CN,
2m
Ph
R
R = CO2Et, 2n
tert-butylpyidine (MDBP), which can distinguish be-
tween Brønsted (protonic) and Lewis acids because it only
binds to protons and is unable to coordinate to metal ions
2+
11
N
H
like Pd due to the bulky tert-butyl groups. It was found
that the catalyst system PdCl (CH CN) /[bmim][BF ] did
no product
2
3
2
4
not work for the Michael addition of 1a and 2a in the pres-
ence of 11 mol% MDBP (Scheme 3). In the absence of
Scheme 2
Synlett 2005, No. 13, 2003–2006 © Thieme Stuttgart · New York

2
006
W.-J. Li et al.
LETTER
(3) (a) Harrington, P. E.; Kerr, M. A. Synlett 1996, 1047.
O
1
0 mol% PdCl2(CH3CN)2
no
reaction
(b) Harrington, P.; Kerr, M. A. Can. J. Chem. 1998, 76,
1256. (c) Loh, T. P.; Wei, L. L. Synlett 1998, 975. (d) Loh,
T. P.; Pei, J.; Lin, M. Chem. Commun. 1996, 2315.
(e) Yadav, J. S.; Abraham, S.; Reddy, B. V. S.; Sabitha, G.
Synthesis 2001, 2165. (f) Bandini, M.; Cozzi, P. G.;
Giacomini, M.; Melchiorre, P.; Selva, S.; Umani-Ronchi, A.
J. Org. Chem. 2002, 67, 3700. (g) Arcadi, A.; Bianchi, G.;
Chiarini, M.; Anniballe, G.; Marinelli, F. Synlett 2004, 944.
+
Ph
Ph
11 mol% MDBP
N
[
bmim][BF4], r.t., 3 h
Me
H
1a
2a
MDBP
N
t-Bu
t-Bu
(
h) Ji, S. J.; Wang, S. Y. Synlett 2003, 2074. (i) Zhan, Z. P.;
Yang, R. F.; Lang, K. Tetrahedron Lett. 2005, 46, 3859.
j) Srivastava, N.; Banik, B. K. J. Org. Chem. 2003, 68,
109. (k) Agnusdei, M.; Bandini, M.; Melloni, A.; Umani-
Scheme 3
(
2
MDBP, however, the Michael addition occurred smoothly
under the same conditions and the acidity of the medium
Ronchi, A. J. Org. Chem. 2003, 68, 7126. (l) Evans, D. A.;
Scheidt, K. A.; Fandrik, K. R.; Wai Lam, H.; Wu, J. J. Am.
Chem. Soc. 2003, 125, 10780. (m) Bartoli, G.; Bartolacci,
M.; Bosco, M.; Foglia, G.; Giuliani, A.; Marcantoni, E.;
Sambri, L.; Torregiani, E. J. Org. Chem. 2003, 68, 4594.
(
[bmim][BF ]) was found to increase (pH changed from 7
4
to 3). These results strongly suggest that the presence of
Brønsted acids is crucial for the Michael reaction. Fur-
thermore, it was also found that a small amount of hydro-
chloric acid (a drop of concd HCl for per mmol of
substrate) instead of PdCl (CH CN) could indeed pro-
(
n) Shi, M.; Cui, S. C.; Li, Q. J. Tetrahedron 2004, 60, 6679.
(
4) (a) Wang, S. Y.; Ji, S. J.; Loh, T. P. Synlett 2003, 2377.
(b) Banik, B. K.; Fernandez, M.; Alvarez, C. Tetrahedron
Lett. 2005, 46, 2479.
2
3
2
mote the Michael reaction {[bmim][BF ] at 100 °C for 3
4
(
(
5) Gaunt, M. J.; Spencer, J. B. Org. Lett. 2001, 3, 25.
6) (a) Kobayashi, S.; Kakumoto, K.; Sugiura, M. Org. Lett.
h} to give about a 50% yield, although the direct use of
hydrochloric acid resulted in some byproducts including
oligomerized indoles. Based on these facts, it is possible
that protons from the partial hydrolysis of
PdCl (CH CN) in [bmim][BF ] (with a very small
2002, 4, 1319. (b) Wabnitz, T. C.; Spencer, J. B.
Tetrahedron Lett. 2002, 43, 3891. (c) Xu, L. W.; Xia, C. G.;
Hu, X. X. Chem. Commun. 2003, 2570. (d) Xu, L. W.; Li,
L.; Xia, C. G.; Zhou, S. L.; Li, J. W.; Hu, X. X. Synlett 2003,
2337. (e) Rivastava, N.; Banik, B. K. J. Org. Chem. 2003,
2
3
2
4
amount of water) act as the active catalysts in our Michael
reaction.
68, 2109. (f) Takasu, K.; Nishida, N.; Ihara, M. Synlett 2004,
1844.
In summary, we have developed a novel and general
method for the synthesis of 3-substituted indole deriva-
tives via a PdCl (CH CN) -catalyzed Michael reaction of
(7) Wang, Y. G.; Wu, X. X.; Jiang, Z. Y. Tetrahedron Lett.
2004, 45, 2973.
(8) (a) Chauvin, Y.; Olivier, H. CHEMTECH 1995, 25, 26.
b) Seddon, K. R. J. Chem. Technol. Biotechnol. 1997, 68,
51. (c) Welton, T. Chem. Rev. 1999, 99, 2071.
d) Wasserscheid, P.; Keim, W. Angew. Chem. Int. Ed. 2000,
9, 3772. (e) Sheldon, R. Chem. Commun. 2001, 2399.
2
3
2
(
3
(
3
indoles with a,b-unsaturated ketones in [bmim][BF ]. The
4
method offers several advantages including mild reaction
conditions, high selectivity, good yields, as well as facile
procedures. Furthermore, the catalyst system could be re-
covered and reused. We are currently investigating and
developing the enantioselective Michael reaction by using
chiral ligands in this catalytic system.
(
9) Indoles 3; General Procedure. The appropriate indole 1
(1.0 mmol), a,b-unsaturated ketone 2 (1.0 mmol), and PdCl2
(CH CN) (2 mol%) were mixed in [bmim][BF ] (1 mL).
3
2
4
The mixture was stirred at 100 °C under N for the
2
appropriate time and the reaction was monitored by TLC.
After completion, the products were separated by thorough
Acknowledgment
extraction with a mixture of EtOAc–Et O. The solvent was
2
evaporated and pure 3-substituted indole derivatives 3 were
obtained by silica gel column chromatography with hexane–
EtOAc (3:1). The ionic liquid containing PdCl (CH CN)
This work was financially supported by the Teaching and Research
Award Program for Outstanding Young Teachers in Higher Educa-
tion Institutions of MOE, P.R.C.
2
3
2
was dried under vacuum for the next run. All products gave
satisfactory spectroscopic and analytical data.
Representative compound 3a: Yield 94%, pale pink solid,
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f
–
1 1
3
407 (NH), 1675 (C=O) cm . H NMR (500 MHz, CDCl ):
(
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1
6
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3
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(
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[
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23 19
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Synlett 2005, No. 13, 2003–2006 © Thieme Stuttgart · New York