Synthesis of (3-indolyl)heteroaromatics by Suzuki-Miyaura coupling and their inhibitory activity in lipid peroxidation

Article abstract of DOI:10.3987/COM-02-S64

A variety of (3-indolyl)heteroaromatic compounds were synthesized by Suzuki-Miyaura coupling of 3-indolylboronic acid and halogenated heteroaromatics. 2-(3-Indolyl)thiophene showed potent inhibitory activity against lipid peroxidation by rat liver microsome.

Full text of DOI:10.3987/COM-02-S64

HETEROCYCLES, Vol. 59, No. 2, 2003, pp. 473 - 476, Received, 27th August, 2002
SYNTHESIS OF (3-INDOLYL)HETEROAROMATICS BY SUZUKI-
MIYAURA COUPLING AND THEIR INHIBITORY ACTIVITY IN
LIPID PEROXIDATION
Atsushi Nishida,* Naoki Miyashita, Mihoko Fuwa, and Masako Nakagawa
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho,
Inage-ku, Chiba 263-8522, Japan
Abstract - A variety of (3-indolyl)heteroaromatic compounds were synthesized by
Suzuki-Miyaura coupling of 3-indolylboronic acid and halogenated
heteroaromatics. 2-(3-Indolyl)thiophene showed potent inhibitory activity against
lipid peroxidation by rat liver microsome.
Martefragin A (1) is an indole alkaloid isolated from a sea algae, Martensia fragilis Harvey, collected at
Toyama Bay in Japan.1 Since 1 showed potent inhibitory activity against lipid peroxidation (30-fold more
potent inhibitor than α-tocopherol) by rat liver microsome, it was expected to be a new lead compound in
the development of anti-oxidant drugs. We have already reported the first asymmetric total synthesis of 1
and its stereoisomers. This total synthesis allowed us to determine the absolute stereochemistry of the
natural product, as shown in Scheme 1.2
Scheme 1
-
OOC
BnOOC
BnOOC
NH
N
N
O
O
O
+
NH
HN
HN
N
H
N
H
N
H
Boc
Boc
Oxidative
Cyclization
Martefragin A (1)
An efficient method for synthesizing analogs of martefragin A using a solid-phase synthesis was also
developed and some analogs were found to be more potent inhibitors than the natural product.3 A
preliminary study on the structure-activity relationship showed that the presence of an indole ring is
essential for its biological activity.4 Therefore, we turned our attention to the effect of heteroaromatics
connected to the C3 position of indole. Using the same procedure for the synthesis of martefragin A,
thiazole and imidazole analogs of martefragin A were prepared and both showed potent activities. To
investigate the effects of structurally diverse heteroaromatic rings, a new strategy for synthesizing (3-
indolyl)heteroaromatics was required. We report here a Suzuki-Miyaura coupling reaction of 3-
indoleboronic acid with halogenated heteroaromatic compounds.
Coupling reactions at the 3-position of indoles were widely studied using 3-indolylzinc derivatives by
Sakamoto5 and Bosch.6 Stille coupling reactions of 3-tributylstannylindole and halo aromatics or 3-iodo-
indole with tributylstannylimidazole derivatives were also studied by Ortar7 and Hibino.8 The introduction

of simple phenyl and alkenyl groups at the C2 and C3 positions of indole by Suzuki-Miyaura coupling has
been reported recently.9,10 In the synthesis of an indole alkaloid, topsentin, Ohta used Suzuki-Miyaura
coupling, and a 3-(3-indolyl)imidazole derivative was obtained in 79% yield using N-silylated 3-
indolylboronic acid and a protected 3-bromoimidazole derivative.11 Interestingly, the reverse combination
of bromide and boronic acid gave the same product in only 7% yield.
We chose Ohta' s protocol to construct a library of indole substituted heteroaromatics, since a wide variety
of halogenated heteroaromatic compounds are available commercially (Scheme 2).
Scheme 2
HetAr-X
Halo Hetero-
aromatics
t
1) BuLi
HetAr
B(OH)2
Br
4
THF
Pd(PPh3)4
base
solvent
2) B(OR)3
N
P
N
P
N
P
N
P
N
P
3a
: P=TBS
5
8
2a
: P=TBS
2b: P=TIPS
: P=TBS
3b: P=TIPS
6: P=TIPS
7: P=H
(P=TBS or TIPS)
N
N
c
a
:
:
b
d
:
:
COOMe
O
N
S
S
N
HetAr
N
Me
f
:
e
g
:
:
OMe
N
Table 1. Coupling Reactions of 3 with 4
a
c
a
c
HetAr-X
Conditions Product (%)
HetAr-X
Conditions Product (%)
N
N
5a (59)
6a (82)
6a (86)
5d (61)
6d (75)
6d (71)
A
B
C
A
B
C
4a
4e
Br
I
S
Br
Me
5a (64)
6a (75)
6a (64)
5e (67)
6e (77)
6e (76)
A
B
C
A
B
C
4b
4c
4f
S
Br
Br
N
N
5b (58)
6b (70)
6b (69)
5f (71)
6f (80)
6f (76)
A
B
C
A
B
C
4g
Br
COOMe
O
N
5g (32)
6g (78)
6g (75)
N
S
5c (57)
6c (81)
A
B
C
A
B
C
4d
4h
OMe
Br
b
6c (0)
Br
a Condition A: 2a, B(OMe) , Pd(PPh ) (5 mol%), aq. satd. Na CO , benzene-MeOH, reflux; Condition
3
3 4
2
3
B: 2b, B(OiPr) , Pd(PPh ) (3 mol%), aq. satd. Na CO , benzene-MeOH, reflux; Condition C: 2b,
3
3 4
2
3
B(OiPr) , Pd(PPh ) (3 mol%), LiOH-Na CO , aq. THF, rt, one-pot procedure. b 7c was obtained in 31%
3
3 4
2
3
yield. c The yields from 2.
N-TBS-3-Bromoindole (2a) was prepared from indole by the standard procedure in high yield.6,11
Lithiation of 2a by tBuLi followed by reaction with trimethyl borate gave N-TBS-indolyl-3-boronic acid
(3a). Although 3a could be isolated from the crude product by precipitation, it readily decomposed to N-
TBS-indole. Therefore, crude 3a was used directly in the following coupling reaction. According to Ohta' s

protocol, 3a was reacted with 2 equivalents of 2-bromothiophene (4a) in the presence of 5 mol% of
Pd(PPh ) and Na CO in aqueous MeOH-benzene (Condition A, Table 1). The mixture was refluxed for
3 4
2
3
1 h to give 2-(N-TBS-3-indolyl)thiophene (7a) in 59% yield from 2a along with bis-indole (8, P=TBS,
2%) and N-TBS-indole (16%). The coupling of 3a with 2-iodothiophene (4b) slightly improved the yield.
Under these conditions, brominated heteroaromatics (4c-h) were coupled with 2a, and the results are
shown in Table 1.
Several problems were observed during the reaction under Condition A. First, when the reaction was slow,
a considerable amount of desilylated indoles were formed which deactivated the catalyst. Another problem
was the formation of N-TBS-indole, which was produced by the decomposition of 3-indolylboronic acid
and by protonation of 3-lithioindole. Since trimethyl borate contains a variable amount of methanol, which
is difficult to remove from the reagent, we next used triisopropyl boronate.10 The protecting group on
indole was changed to a triisopropylsilyl (TIPS) group.10 Thus, 2b was converted to 3b using triisopropyl
borate and reacted with 4a-h. Under these optimized conditions (Condition B) the amount of catalyst could
be reduced to 3 mol%. The yields of all of the coupling products were increased.
Next, we investigated a one-pot procedure without isolation of 3-indolylboronic acid. Thus, after the
reaction of lithiated N-TIPS-indole with triisopropyl boronate was quenched by adding aqueous Na CO ,
2
3
halogenated heteroaromatic compounds and the catalyst were added to the reaction mixture (Condition C).
The coupling reaction proceeded at room temperature to give the product in a yield comparable to that under
Condition B. The reaction using 2-bromoimidazole gave a complex reaction mixture under all three
conditions.
Scheme 3
B(OH)
HetAr(Br)
Br
2
1) t BuLi
HetAr(Br)
9
2
HetAr
+
2) B(OiPr)
N
TIPS
3
N
TIPS
N
TIPS
N
TIPS
Pd(PPh )
3 4
Na CO aq.
2
3
2
aq. MeOH-
benzene
reflux
2b
3b
11
10
Table 2 Coupling Reaction of 3b and Dibromoheteroaromatics (9)
run
time Molar Ratio of
HetAr(Br)
Product (%)
2
(h)
2b : 9
10
11
1
2
1.5
3
1 : 2
69
1
13
84
9a
9b
9c
Br
S
Br
Br
2.5 : 1
Br
3
4
5
25
1 : 2
5 : 1
67
8
5
89
S
5
6
2
2
1 : 2
2.5 : 1
84
0
3
94
Br
Br
N
The coupling reaction using dibromoheteroaromatics (9) also proceeded under Condition B (Table 2).
Depending on the ratio of 2b and 9, the reaction formed either mono-coupling product (10) or bis-coupling
product (1 1).

Among the resulting (3-indolyl)heteroaromatics, 6a-6g were desilylated by tetrabutylammonium fluoride to
give 7a-7g in high yield. The relative inhibitory activities of 7a-7g against lipid peroxidation by rat liver
microsome1 are shown in Table 3. Except for pyrimidyl derivative (7d), most of the indole-substituted
heteroaromatic compounds showed inhibitory activity. Among the compounds tested, 2-(3-indolyl)-
thiophene (7a) was 2.5 times more active than the parent compound (1).
Table 3 Relative Inhibitory Activities of (3-Indolyl)heteroaromatics against Lipid
Peroxidation by Rat Liver Microsome
1
7a
7b
7c
7d
7e
7 f
Relative
Activity
1
2.5
0.84
0.58
0.01
0.48
0.70
ACKNOWLEDGEMENT
This research was supported by a Grant-in-Aid for Scientific Research on Priority Areas (A) "Exploitation
of Multi-Element Cyclic Molecules" from the Ministry of Education, Culture, Sports, Science, and
Technology. The authors thank Drs. H. Saito and H. Tamaoki, Lead Chemical, Co., Ltd., for their helpful
discussions and assistance in biological testing.
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