176
Published on the web January 30, 2010
Regioselective Oxidation of Pyrrole Derivatives with DDQ and Its Synthetic Application
Ryoji Iwamoto, Yutaka Ukaji,* and Katsuhiko Inomata*
Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University,
Kakuma, Kanazawa 920-1192
(Received November 20, 2009; CL-091033; E-mail: inomata@cacheibm.s.kanazawa-u.ac.jp)
t-Butyl 4-alkyl-1H-pyrrole-2-carboxylates were oxidized with
Cl
Cl
DDQ in the presence of MeOH at the ¡-position of the alkyl
substituent at the C-4 position regioselectively to afford 4-
acylpyrrole derivatives. On the other hand, treatment of the
pyrroles with DDQ in the presence of AcOH furnished the
corresponding 4-(1-acetoxyalkyl)pyrroles. The resulting 4-
(acetoxymethyl)pyrrole reacted with various nucleophiles to afford
the functionalized pyrrole derivatives in good yields.
OR
H
1
1
O
2
O
2
R
R
R
R
ROH
DDQ
NC
CN
1
E
E
N
(R = Me)
N
H
4
Cl
Cl
OMe
MeO OMe
H
OMe
O
O
2
1
2
1
2
R
R
R
R
R
1
R
MeOH
+
NC
CN
We have been studying the total syntheses of natural and
unnatural bilin chromophores of phytochromes,1 and have
succeeded in synthesizing phytochromobilin (P¯B), phycocya-
nobilin (PCB), modified PCBs, biliverdin (BV) and its analogs
including sterically locked derivatives in free acid forms by
developing efficient methods for the preparation of each pyrrole
ring and a new coupling reaction between them.1 During the
course of syntheses of different types of locked chromophores, it
was necessary to prepare various pyrroles that have arbitrary-
length side chains and a wide variety of functional groups.2 In
the previous syntheses, the side chains and functional groups
originated from aldehydes and/or nitro compounds through a
modified Barton reaction. It would be ideal for the synthesis of
locked chromophores if the various types of pyrroles could
be available from a common pyrrole by simple manipulation.
Herein we describe a regioselective oxidation of t-butyl 4-
alkylpyrrole-2-carboxylates with DDQ3 and its application
toward the synthesis of various types of functionalized pyrroles.
First, t-butyl 3-[2-(allyloxycarbonyl)ethyl]-4-methyl-1H-
pyrrole-2-carboxylate (1a), which is a useful synthon for the
B,C-ring components of bilin chromophores,1 was treated with
1.2 equiv of DDQ in the presence of 10 equiv of MeOH.4,5
The regioselectively oxidized product, 4-formylpyrrole 2a, was
obtained in 42% yield and 39% of unreacted 1a was recovered,6
while the expected 4-(methoxymethyl)pyrrole 4a (R = Me,
R1 = H, R2 = CH2CO2Allyl in Scheme 1) was not detected
(Table 1, Entry 1). When 3.0 equiv of DDQ was used, 2a was
obtained in 77% yield (Entry 2). The oxidation of 3-ethyl-4-
methylpyrrole-2-carboxylate 1b also afforded the 4-formyl-
pyrrole 2b in good yield (Entry 3). In the case of 3,4-dimethyl-
pyrrole 1c, 4-formylpyrrole 2c7 was obtained in 25% yield
accompanied by 52% of the dimerized by-product 3. 3,4-
Diethylpyrrole 1d was oxidized regioselectively to give 4-
acetylpyrrole 2d7 in poor yield (Entry 5). When the reaction was
carried out at lower temperature, the reaction was sluggish but
2d was obtained in improved yield (Entry 6). The 4-formyl-
pyrrole 2a-2c might be produced by further oxidation of
the initially formed intermediate, 4-(methoxymethyl)pyrrole 4
(R = Me),5 to 5 followed by hydrolysis (Scheme 1). During
the oxidation of 1d, formation of 4-(1-methoxyethyl)pyrrole
4d (R, R1, R2 = Me), which was readily hydrolyzed to 4-(1-
hydroxyethyl)pyrrole 4d (R = H, R1, R2 = Me) in an attempt to
E
E
E
− H
N
H
N
H
N
H
t
5
(E = CO Bu)
2
work-up
2
Scheme 1.
Table 1. Oxidation of t-butyl 1H-pyrrole-2-carboxylates 1 with DDQ in
the presence of MeOH
O
1
1
2
2
R
R
R
R
DDQ (n equiv)
MeOH (10 equiv)
E
E
CH Cl , rt, Time
N
N
2
2
1
2
H
H
Entry
R1
H
R2
E
n
Time
2/%
t
1
2
3
4
5
6b
7
8
CH2CO2Allyl
CO2 Bu
a
1.2
3.0
3.0
3.0
3.0
3.0
3.0
3.0
43 h
43 h
9 h
7 h
2 h
4 d
4 d
47 h
42
77
72
25a
14
66
25
54
t
H
H
CH3
CH3
H
CH3
CO2 Bu
b
c
d
t
CO2 Bu
t
CO2 Bu
H
CH3
CH3
H
Ts
Ts
e
f
aBy-product
3 was obtained in
O
52% yield. bThe reaction was
carried out at ¹20 °C for 3 d and
at ¹10 °C for 1 d.
t
BuO C
2
N
H
t
CO Bu
2
N
H
3
isolate, was observed on TLC and gradually consumed during
the progress of the reaction. This observation supports the
stepwise oxidation mechanism via 4-(1-methoxyalkyl)pyrroles 4
as shown in Scheme 1. The oxidation of 4-methyl-2-tosylpyrrole
derivative 1e, possessing a tosyl group instead of an ester group,
proceeded sluggishly to give 4-formyl-2-tosylpyrrole 2e in low
yield (Entry 7). In the case of 4-ethyl-2-tosylpyrrole derivative
1f, 2f was obtained in 54% yield (Entry 8).
Thus, if the electron density of the ¡-oxygen of the 4-alkyl
group of intermediary pyrrole 4 is decreased, the second
oxidation to 5 could be suppressed. Actually, when the oxidation
of 1a was carried out with 1.0 equiv of DDQ in the presence of
AcOH (R = Ac in Scheme 1) instead of MeOH, 4-(acetoxy-
methyl)pyrrole 6a was regioselectively obtained in 46% yield
and 11% of 1a was recovered (Table 2, Entry 1). When 1.5
Chem. Lett. 2010, 39, 176-177
© 2010 The Chemical Society of Japan