50
Chemistry Letters Vol.36, No.1 (2007)
Alkylation of N-Protecting Group-free Indole with Vinyl Ketones Using Iron Salt Catalyst
Toshiyuki Itoh,ꢀ Hiroyuki Uehara, Koji Ogiso, Shun Nomura, Shuichi Hayase, and Motoi Kawatsura
Department of Materials Science, Faculty of Engineering, Tottori University,
4-101 Koyama-minami, Tottori 680-8552
(Received September 14, 2006; CL-061059; E-mail: titoh@chem.tottori-u.ac.jp)
Table 1. Alkylation of indole (1) with vinyl ketones 2a
Indole was reacted with vinyl ketones in the presence of
3 mol % of iron(II) tetrafluoroborate in acetonitrile or ionic
liquids to give 3-alkylated product in an excellent yield. 2,3-Di-
alkylated indole was also obtained when the reaction was carried
out using an excess amount of methyl vinyl ketone with the same
catalyst; the results were significantly dependent on the reaction
medium and both methanol and ionic liquid were found to be
good solvents for double alkylation of indole.
Vinyl ketone 2
R2
Entry
Solvent
Time/h Yield of 3c/%
R1
1
2
3
4
5
6
7
8
9
a:
a:
a:
b:
b:
b:
c:
c:
d:
H
H
H
H
H
H
H
H
CH3
CH3
CH3CNb
CH3CN
2
2
75
71
CH3
[bmim][TFSI]
CH3CN
2
86
66
n-C5H11
n-C5H11
n-C5H11
4
[bmim][PF6]
[bmim][TFSI]
2
76
2
62
78
PhCH2CH2 [bmim][PF6]
PhCH2CH2 [bmim][TFSI]
1
3
92
86
Iron is recognized as an economical and pollution free metal
source.1 We have developed several types of iron salt-catalyzed
reactions: the intramolecular cyclization of cyclopropanone-
dithioacetals,2 [2 þ 2]-cycloaddition of trans-anethol,3 and
[2 þ 3]-type cycloaddition of styrene derivatives with 1,4-ben-
zoquinone; it was then established that the reaction was greatly
accelerated in an ionic liquids (ILs) solvent system.4,5 We further
discovered that the Michael-type addition of ꢀ-ketoesters with
ꢁ,ꢀ-unsaturated ketones was catalyzed by iron(II) tetrafluorobo-
–(CH2)2–
–(CH2)2–
–(CH2)2–
CH3CN
CH3CN
CH3CN
48
24
24
10d d:
11e d:
94 (2% ee)f
83 (3% ee)f
a1.5 equiv. vs substrate was used. bDry air (5 mL/mmol vs substrate) was
bubbled into the solvent prior to the reaction. cIsolated yield. dThe reaction
was carried out in the presence of 3 mol % of the Jacobsen ligand. eThe
reaction was carried out in the presence of 3 mol % of pybox ligand. The
enantiomeric excess was determined by HPLC analysis using Chiralcel OD
(i-PrOH:n-Hexane = 9:1).
f
.
rate (Fe(BF4)2 6H2O) under air conditions and demonstrated
the reaction was conducted in CH2Cl2, CH3Cl, Et2O, THF,
toluene, or benzene. Unfortunately, however, there was also no
reaction when ethyl acrylate, acrylonitrile, or nitroethene was
used as acceptor. We initially performed the reaction using
CH3CN in which dry air was bubbled prior to the reaction,6
but no significant modification of the reaction efficiency was
recorded. Therefore, further reactions were carried out under
only air atmospheric conditions. The results of reactions using
various types of ketones in CH3CN or ionic liquid solvent sys-
tems are summarized in Table 1.
The ionic liquid solvent system gave better results than
those in CH3CN solvent for these reactions, and 3a was obtained
in 86% yield in [bmim][TFSI] solvent, respectively (Entry 3).
Excellent results were obtained when 2c (R1 ¼ H, R2 ¼
PhCH2CH2) was used as acceptor in [bmim][TFSI] solvent
system and 5c (R1 ¼ H, R2 ¼ PhCH2CH2) was obtained in
92% yield (Entry 8). Indole also reacted with cyclopentenone
2d (R1, R2 = –(CH2)2–) and 3d was obtained in 86% yield
(Entry 9). Since chiral Lewis acid-mediated enantioselective
alkylation was reported,8f we tested the reaction in the presence
of two types of chiral ligands, the (R,R)-Jacobsen10 or (S,S)-bis-
(oxazolinyl)pyridine (pybox) ligand.11 However, no enantiose-
lectivity was obtained even when these optically active ligands
were employed for these reactions, though excellent chemical
yields of 3d were recorded (Entries 10 and 11). Further, the
reaction was completely inhibited by addition of 1 equiv. of
TEMPO. These results may suggest that the reaction takes place
without influence of the ligand via the radical cation pathway,
though TEMPO is reported to bind with the iron(III) cation
and inactivate the catalytic property.12
that recyclable use of catalyst was possible when the reaction
was carried out in a 1-butyl-3-methylimidazolium bis(trifluoro-
methylsulfonyl)imide ([bmim][TFSI]) solvent system.6 The
Lewis acid-mediated Friedel–Crafts-type alkylation of indole
with unsaturated carbonyl compounds has attracted growing
interest over the past few years.7,8 We anticipated that the same
type of product might be obtained if indole 1 was subjected to
.
the reaction with vinyl ketones 2 using Fe(BF4)2 6H2O as cata-
lyst (Eq 1). To our delight, the desired product 3 was indeed
obtained in good to excellent yield. Further, even the double-
alkylated product 4 was produced when the reaction was carried
out in the presence of excess amount of acceptor methyl vinyl
ketone. Here, we wish to report the iron salt-catalyzed novel
alkylation of indole.9
O
R1
R1
1.2 equiv.
O
R2
2
R2
(1)
N
•
Fe(BF4)2 6H2O (3 mol%)
N
H
3
H
CH3CN or ILs, rt under air
1
Typically, the reaction was carried out as follows: to a solu-
tion of indole (1) (59 mg, 0.5 mmol) and 3-buten-2-one (2a)
(53 mg, 1.5 equiv.) in acetonitrile (CH3CN) (0.5 mL) was added
.
Fe(BF4)2 6H2O (5.0 mg, 3 mol %) and the mixture was stirred at
room temperature (rt) under an air atmosphere for 2 h. The reac-
tion mixture was extracted with ether and subsequent purifica-
tion using silica gel thin layer (TLC) chromatography to afford
the product 3a (R1 ¼ H, R2 ¼ Me)7b (66 mg, 0.35 mmol) in
71% yield (Entry 2, Table 1). Very simple alkylation of indole
was thus accomplished. The reaction proceeded smoothly in
CH3CN or ionic liquids solvent and no reaction took place when
3
Interestingly, the reaction using Fe(ClO4)3–Al2O3 as
catalyst gave 2,3-dialkylated product 4a in low yield of 12%
Copyright Ó 2007 The Chemical Society of Japan
Itoh, Toshiyuki
