Hafnium trifluoromethanesulfonate [Hf(OTf)4]-catalyzed conjugate addition of indoles to α,β-enones

Article abstract of DOI:10.1055/s-2005-872694

Hafnium trifluoromethanesulfonate [Hf(OTf)₄]- and scandium trifluoromethanesulfonate [Sc(OTf)₃]-catalyzed conjugated addition of 3-position of indoles to several enones proceeded in acetonitrile as solvent. Especially, Hf(OTf)_4<

Full text of DOI:10.1055/s-2005-872694

2492
LETTER
Hafnium Trifluoromethanesulfonate [Hf(OTf)4]-Catalyzed Conjugate
Addition of Indoles to a,b-Enones
H
f(OTf) -Catalyze
d
Ao
t
oles to
o
Enones i Kawatsura,*a Sachiko Aburatani,b Junichi Uenishib
4
a
Department of Materials Science, Faculty of Engineering, Tottori University, Koyama, Tottori 680-8552, Japan
b
Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8412, Japan
Fax +81(857)315179; E-mail: kawatsur@chem.tottori-u.ac.jp
Received 4 July 2005
10
activity in water.9 Herein, we report that the Sc(OTf)3
Abstract: Hafnium trifluoromethanesulfonate [Hf(OTf)4]- and
scandium trifluoromethanesulfonate [Sc(OTf)3]-catalyzed conju-
gated addition of 3-position of indoles to several enones proceeded
in acetonitrile as solvent. Especially, Hf(OTf)4 exhibited high cata-
lytic activity and gave the conjugate addition product in good yield.
catalyzed the indole addition to enones in MeCN solvent,
and furthermore, Hf(OTf)411 exhibited a high catalytic ac-
tivity even at a lower catalyst loading for this reaction.
We examined the reaction of indole (1a) and methyl vinyl
ketone (2a) using some Lewis acid catalysts in MeCN
(Scheme 1, Table 1). The reaction with 10 mol%
Sc(OTf)3 proceeded smoothly and gave 90% of the conju-
gate addition product (entry 1). The reaction rate was fast-
er than other reported catalysts, and the amount of
Sc(OTf)3 was reduced to 5 mol% without decreasing the
yield (entry 2). On the other hand, Hf(OTf)4 showed a re-
ally high reactivity for this reaction. The reaction using
the 10 mol% catalyst was complete only in ten minutes.
The reaction with Sc(DS)3 also finished in ten minutes, al-
though the reaction yield was lower than that with
Hf(OTf)4 (entries 3 and 4). Thus, Hf(OTf)4 was a very
effective catalyst for this conjugate addition of indoles to
enones, and the reaction with 1 mol% of Hf(OTf)4
proceeded efficiently to give the product in 90% yield
(entry 5).
Key words: hafnium trifluoromethanesulfonate, conjugate addi-
tions, Lewis acids, indoles, enones, catalysis
Indoles are the key components of many drugs and some
biologically active compounds, and the development of
new forming methods leading to indole derivatives has
attracted much attention in organic synthesis.1 Especially,
3-substituted indoles exhibit several biological activities,
and are versatile intermediates for the synthesis of several
indole derivatives.2 Based on these reasons, there are sev-
eral addition reactions of indoles to enones,3 and recently
the Lewis acid-catalyzed conjugate addition of the 3-posi-
tion of indoles to enones had been reported by several
groups. The reaction using a Lewis acid requires careful
control to prevent side reactions such as the dimerization
or polymerization of indoles. For example, Bi(NO)3,4
The results of the 5-substituted indoles (1b and 1c) and 1-
methyl indole (1d) addition to several enones catalyzed by
Hf(OTf)4 compared to Sc(OTf)3 are summarized in
Table 2. In all cases, the reation with Hf(OTf)4 was faster
than the reaction with Sc(OTf)3. The reaction of the 5-sub-
stituted indoles to methyl vinyl ketone (2a) smoothly pro-
ceeded with Sc(OTf)3 (entries 1 and 3), and the same
reactions were catalyzed by Hf(OTf)4 in a much shorter
7
8
Bi(OTf)3,5 InBr3,6 InCl3 and Yb(OTf)3 have been report-
ed as useful Lewis acid catalysts for this reaction. Howev-
er, the reaction usually demands over a 10 mol% catalyst
and requires several hours. Also, Kobayashi and co-work-
er reported Sc(DS)3 (DS = dodecyl sulfate) catalyzed the
conjugate addition of indoles to a,b-enones in water, how-
ever, they also reported Sc(OTf)3 exhibited a low catalytic
3aa: R1 = H, R2 = H, R3 = H, R4 = Me
R3
O
O
R2
3ab: R1 = H, R2 = H, R3 = Me, R4 = Ph
3ba: R1 = H, R2 = CN, R3 = H, R4 = Me
3ca: R1 = H, R2 = OMe, R3 = H, R4 = Me
3da: R1 = Me, R2 = H, R3 = H, R4 = Me
R3
R4
R4
R2
2a,b
NR1
catalyst
2a: R3 = H, R4 = Me
2b: R3 = Me, R4 = Ph
+
3ac: R1 = H, R2 = H, n = 0
3ad: R1 = H, R2 = H, n = 1
3ae: R1 = H, R2 = H, n = 2
3cd: R1 = H, R2 = OMe, n = 1
3dc: R1 = Me, R2 = H, n = 0
3dd: R1 = Me, R2 = H, n = 1
3de: R1 = Me, R2 = H, n = 2
MeCN, r.t.
NR1
1a–d
2c: n = 0
2d: n = 1
2e: n = 2
n
n
R2
O
O
1a: R1 = H, R2 = H
1b: R1 = H, R2 = CN
1c: R1 = H, R2 = OMe
1d: R1 = Me, R2 = H
NR1
Scheme 1
SYNLETT 2005, No. 16, pp 2492–2494
0
4
.1
0
.2
0
0
5
Advanced online publication: 21.09.2005
DOI: 10.1055/s-2005-872694; Art ID: U21105ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Hf(OTf)4-Catalyzed Addition of Indoles to Enones
2493
Table 1 Catalytic 1,4-Addition of Indole 1a to Methyl Vinyl
Ketone (2a)a
reaction time and gave similar yields (entries 2 and 4).
The reaction of 1-methyl indole was also catalyzed by
Hf(OTf)4 and gave the conjugate addition product in good
yield (entry 6). The pheny 1-propenyl ketone (2b) was
also usable for this reaction (entries 7–10). Cyclic enones
(2c,d) were also good Michael acceptors under these cat-
alytic conditions (entries 11–16). For the indoles (1a), 1-
methyl indole (1d) and the 5-substituted indoles (1b,c)
also react with cyclic enones (2c,d) and gave the
corresponding products in good yield (entries 17–24). In
some cases, the reaction with Hf(OTf)4 gave a lower yield
than when using of Sc(OTf)3 due to the dimerization and/
or polymerization of indoles, but the rate of the con-
version was much faster than with Sc(OTf)3.
Entry
Catalyst
Time
2 h
Yield (%)b
1
2
3
4
5
Sc(OTf)3 (10 mol%)
Sc(OTf)3 (5 mol%)
Sc(DS)c (10 mol%)
Hf(OTf)4 (10 mol%)
Hf(OTf)4 (1 mol%)
90
90
76
85
90
24 h
10 min
10 min
2 h
a All reactions were carried out in MeCN at r.t.
b Isolated yield by silica gel column chromatography.
c DS = dodecyl sulfate.
Table 2 Hf(OTf)4- or Sc(OTf)3-Catalyzed 1,4-Addition of Indoles 1a–d to Enones 2a–ea
Entry
1
1
2
Product 3
3ba
3ba
3ca
Catalyst
Time
30 min
10 min
4 h
Yield (%)b
85
1b
1b
1c
1c
1d
1d
1a
1a
1d
1d
1a
1a
1a
1a
1a
1a
1b
1b
1c
1c
1d
1d
1d
1d
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2c
2c
2d
2d
2e
2e
2d
2d
2d
2d
2c
2c
2d
2d
Sc(OTf)3
Hf(OTf)4
Sc(OTf)3
Hf(OTf)4
Sc(OTf)3
Hf(OTf)4
Sc(OTf)3
Hf(OTf)4
Sc(OTf)3
Hf(OTf)4
Sc(OTf)3
Hf(OTf)4
Sc(OTf)3
Hf(OTf)4
Sc(OTf)3
Hf(OTf)4
Sc(OTf)3
Hf(OTf)4
Sc(OTf)3
Hf(OTf)4
Sc(OTf)3
Hf(OTf)4
Sc(OTf)3
Hf(OTf)4
2
83
3
56
4
3ca
10 min
2 h
50
5
3da
3da
3ab
3ab
3db
3db
3ac
88
6
10 min
3 h
82
7
62
8
15 min
30 min
15 min
72 h
80
9
50
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
90
57
3ac
9 h
57
3ad
3ad
3ae
4 h
94
30 min
3 h
70
90
3ae
10 min
72 h
99
3bd
3bd
3cd
3cd
3dc
3dc
3dd
3dd
39
2 h
70
6 h
69
20 min
17 h
68
73
1 h
85
30 min
15 min
70
66
a All reactions were carried out with 10 mol% of catalyst in MeCN at r.t., and were stopped when indoles were consumed.
b Isolated yield by silica gel column chromatography.
Synlett 2005, No. 16, 2492–2494 © Thieme Stuttgart · New York

2494
M. Kawatsura et al.
LETTER
We have examined some amine ligands for this reaction
and found tridentate amine ligands having a pyridine unit
largely improved the chemical yield without a formation
of bisindole. The reaction of 1a with 2b in the presence of
10 mol% of Hf(OTf)4 and 12 mol% of ligand 4 (Figure 1)
was complete within ten minutes and gave 3ab in a quan-
titative yield. On the other hand, that in the presence of
ligand 5 was complete in 30 minutes and 3ab was ob-
tained quantitatively. These tridentate amine ligands were
also effective for reactions with cyclic enones (2c and 2d).
The reaction of 2c and 2d with 1a using ligand 4 gave the
conjugate addition product in 95% (1 h) and 98% isolated
yield (0.5 h), respectively. However, an asymmetric in-
duction was observed in less than 5% in all cases.
References
(1) Sundberg, R. J. The Chemistry of Indoles; Academic Press:
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H
H
H
H
Ph
N
N
Ph Ph
N
N
Ph
N
N
Me
Me
Me
Me
Me
Me
Me
Me
4
5
Figure 1
In summary, we have demonstrated that Hf(OTf)4 is an
effective catalyst for the conjugate addition of indoles to
a,b-enones. The reaction proceeded within several min-
utes and gave products in good yield. Also we discovered
that tridentate amine ligands increase the yield of this cat-
alytic reaction. The development of asymmetric variants
for these reactions will be the subject of future work.12
(8) (a) Harrington, P. E.; Kerr, M. A. Synlett 1996, 1047.
(b) Harrington, P. E.; Kerr, M. A. Can. J. Chem. 1998, 76,
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(9) Manabe, K.; Aoyama, N.; Kobayashi, S. Adv. Synth. Catal.
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(10) Reviews for Sc-centered Lewis acid in organic synthesis,
see: (a) Fukuzawa, S.-I. In Lewis Acid Reagents; Yamamoto,
H., Ed.; Oxford University Press: Oxford, 1999, 185.
(b) Kobayashi, S. In Lewis Acids in Organic Synthesis, Vol.
2; Yamamoto, H., Ed.; Wiley-VCH: Weinheim, 2000, 883.
(11) Reviews for Hf-centered Lewis acid in organic synthesis,
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Ed.; Oxford University Press: Oxford, 1999, 177.
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General Procedure
A mixture of indole 1 (0.1 mmol), enone 2 (0.15 mmol), and
Hf(OTf)4 (10 mol%) in MeCN (0.5 mL) was stirred at r.t. for the
appropriate time (see Table 1 and Table 2). After complete conver-
sion, as indicated by TLC, the reaction mixture was diluted with
H2O and extracted with EtOAc. The combined organic layers were
dried over MgSO4, concentrated in vacuo, and purified by column
chromatography on silica gel to afford the pure product 3 (see
Table 1 and Table 2).
Synlett 2005, No. 16, 2492–2494 © Thieme Stuttgart · New York