Immobilized indolylboron as a key intermediate for solid-phase synthesis of bisindole alkaloid analogs

Article abstract of DOI:10.3987/COM-05-S(T)24

Immobilized indolylboron was easily prepared from resin-bound iodoindole and the subsequent Suzuki coupling reaction was used for the syntheses of bisindole alkaloid analogs.

Full text of DOI:10.3987/COM-05-S(T)24

HETEROCYCLES, Vol. 67, No. 1, 2006
95
HETEROCYCLES, Vol. 67, No. 1, 2006, pp. 95 - 100. © The Japan Institute of Heterocyclic Chemistry
Received, 1st July, 2005, Accepted, 24th August, 2005, Published online, 26th August, 2005. COM-05-S(T)24
IMMOBILIZED INDOLYLBORON AS A KEY INTERMEDIATE FOR
SOLID-PHASE SYNTHESIS OF BISINDOLE ALKALOID ANALOGS
Takahiro Kasahara and Yoshinori Kondo*
Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama,
Aoba-ku, Sendai 980-8578, Japan
th
Dedicated to Professor Barry M. Trost on the occasion of his 65 Birthday
Abstract – Immobilized indolylboron was easily prepared from resin-bound
iodoindole and the subsequent Suzuki coupling reaction was used for the
syntheses of bisindole alkaloid analogs.
1
Solid-phase synthesis is regarded as a very efficient method for producing combinatorial libraries and
combining solid-phase synthesis with high-throughput screening has made a significant contribution for
lead discoveries and optimization in pharmaceutical research. Contemporary synthetic reactions that use
transition metals, particularly palladium, have been employed as well established methodologies for
selective carbon-carbon bond forming reactions for solution-phase synthesis and for solid-phase
2
synthesis.
Indole rings have been found in various biologically active molecules, like a simple arylindole and
numerous studies have been done for the efficient construction and functionalization. We recently
reported a solid-phase indole synthesis using a palladium catalyzed intramolecular alkenylation or
3
amination.
4
Suzuki coupling is one of the important palladium catalyzed cross-coupling reactions in medicinal
chemistry and is suitable for synthesizing biaryl compounds. This reaction has been already applied to
5
~7
solid phase synthesis.
Many of the reported works have treated the cross coupling of immobilized
aryl halides with arylborons in solution and a limited number of examples were reported for the coupling
6
,7
reactions of immobilized arylmetals with free aryl halides in solution.
From the viewpoint of coupling
partners’ availability, the latter seems to be attractive. In this paper, we wish to report the concise
preparation of immobilized indolylboron and the subsequent arylation using palladium catalyst. The
solid-phase synthesis of bisindole alkaloid analogs using resin-bound indolylboron was accomplished.

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HETEROCYCLES, Vol. 67, No. 1, 2006
The immobilized 3-iodoindole (1) was easily prepared from indole via iodination followed by
immobilization using chlorosulfonylated polystyrene. The preparation of the immobilized indolylboron
8
9
was investigated using palladium catalyzed borylation. Murata’s borylation protocol (pinacolborane,
PdCl (dppf), Et N, in dioxane at 80 ºC) was employed to prepare the immobilized indolylboron, which
2
3
was not easily accessible by other methods.
1
) ArX, Pd[P(t-Bu)3]2
DMF, K PO
I
BPin
Ar
PdCl (dppf)
3
4
2
HBPin, Et N
80 ℃, 1 day
3
Dioxane
0 ℃, 20 h
2) t-BuOK, THF
N
N
N
8
rt, 5 h
H
O S
O2S
2
3
a-e
1
2
O
BPin =
B
O
Table 1. Arylation of Immobilized Indolylboron
c
Entry
1
ArX
Product
Yield (3 steps)
Entry
5
Product
Yield (3 steps)
ArX
I
I
3a
77%
91%
I
OMe
OMe
3c
74%
2a
3
CO2Et
6
Br
73%
60%
82%
3b
3a
3b
3c
3d
7b
8b
Br
Br
74%
88%
Br
S
4a
CO Et
I
2
3e
N
a
Cleavage condition = TBAF, reflux, 5 h bPd(PPh ) was used in place of Pd[P(t-Bu) ] .
3 4 3 2
c
Isolated yields of pure compounds after SiO column chromatography.
2
The subsequent palladium-catalyzed cross-coupling reactions with aryl halides were examined and
1
0
Pd[P(t-Bu)
3
]
2
was found to be a very active catalyst (Table 1). Since it was difficult to estimate exact
loading value (mmol/g) of the immobilized indolylboron, the three-step yield from 1 was used to evaluate
the performance of the coupling reaction with various aryl halides. The loading value of 1 was
determined as 0.86 mmol/g by cleaving the immobilized 3-iodoindole to isolate 3-iodoindole. Generally,
the reaction proceeded smoothly for both of electron rich and poor aryl halides. For the reaction of
heteroaryl halides, the better result was obtained by using Pd(PPh
3 4
) .
1
1
3
-Arylindoles have been known to be important candidates for serotonin 5-HT antagonist, and some of
2
bisindole alkaloids, which have unique structures that possess a five- or six-membered central ring shared
by two indole units and display a high degree of biological activity, have attracted the attention of
medicinal chemists. The bisindolylmaleimide subunit is present in numerous biologically active
1
2
metabolites including staurosporine and rebeccamycin.
Bisindolylmaleimides are important

HETEROCYCLES, Vol. 67, No. 1, 2006
97
candidates for selectively inhibiting Protein Kinase C (PKC) and recent SAR studies have dramatically
1
3
improved the potency and selectivity for PKC with structures such as GF 109203X.
N-alkylated structure showed biological activities, we designed a synthetic route so that monoalkylation
Since the
could be easily performed.
The precursor of the central block for bisindolylmaleimide,
1
4
dibromomaleimide (4), was synthesized according to the reported procedure.
For the solid-phase
synthesis, the borylation of immobilized 3-iodoindole with pinacolborane in the presence of a palladium
catalyst, followed by Suzuki coupling gave the immobilized mono-coupling product (5). The bromide
(
5) was then treated with excess N-lithioindole to yield the immobilized bisindolylmaleimide (7). The
bisindolylmaleimide (7) was treated with excess MeI in the presence of Cs CO to give the
monomethylated compound. Finally the immobilized bisindole was cleaved by TBAF and
2
3
mono-methylated bisindolylmaleimide (8) was synthesized in 38% yield from the immobilized
iodoindole in 5 steps (Scheme 1).
Scheme 1. Solid-Phase Synthesis of Bisindolylmaleimide Derivative
Me
N
Me
N
O
O
O
O
I
BPin
PdCl (dppf)
4
2
HBPin, Et N
3
Br
Br
Br
Pd(PPh3)4
Dioxane
0 ℃, 20 h
N
N
N
8
Tl CO
2 3
O S
2
O S
2
O S
2
DMF
1
2
5
Me
N
Me
N
O
O
O
O
6
N
Li
1) MeI, Cs CO
2
3
THF
2) TBAF, THF
N
O S
N
N
N
H
H
Me
2
7
8
In summary, 3-aryl- and heteroaryl- indoles were synthesized using an immobilized indolylboron as a key
intermediate. The methodology was also extended for the solid-phase synthesis of bisindolylmaleimide.
ACKNOWLEDGMENT
This work was partly supported by a Grant-in Aid for Scientific Research (No.16390002 and
No.16033208) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
REFERENCES AND NOTES

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HETEROCYCLES, Vol. 67, No. 1, 2006
1
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011.
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. N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457.
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. (a) B. A. Lorsbach and M. J. Kurth, Chem. Rev., 1999, 99, 1549. (b) S. Bräse, J. H. Kirchhoff, and J.
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7
8
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. (a) M. Murata, S. Watanabe, and Y. Masuda, J. Org. Chem., 1997, 62, 6458. (b) M. Murata, T.
6
Oyama, S. Watanabe, and Y. Masuda, J. Org. Chem., 2000, 65, 164. (c) Piettre et al. and Tempest
7
et al. reported palladium catalyzed borylation of immobilized aryl halides using Miyaura’s
8
protocol (bispinacolatodiboron, PdCl
2
(dppf), KOAc, in DMF or DMSO at 80 ºC).
1
1
1
0. (a) I. D. Hills, M. R. Netherton, and G. C. Fu, Angew. Chem., Int. Ed., 2003, 42, 5749. (b) A. F.
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1. J. K. Perregaard and K. Andersen, Eur. Pat. Appl., 470039, May 2, 1992 (Chem. Abstr., 1992, 116,
2
35431u).
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Masuma, J. Antibiot., 1977, 30, 275. (b) J. T. Link, S. Raghavan, and S. J. Danishefsky, J. Am.
Chem. Soc., 1995, 117, 552. (c) J. L. Wood, B. M. Stoltz, S. N. Goodman, and K. Onwueme, J. Am.
Chem. Soc., 1997, 119, 9652. (d) D. E. Nettleton, T. W. Doyle, and B. Krishnan, Tetrahedron Lett.,
1
985, 26, 4011. (e) T. Kaneko, H. Wong, K. T. Okamoto, and J. Clardy, Tetrahedron Lett., 1985,
6, 4015. (f) M. Gallant, J. T. Link, and S. J. Danishefsky, J. Org. Chem., 1993, 58, 343.
2
1
1
3. (a) D. Toullec, P. Pianetti, H. Coste, P. Bellevergue, T. Grand-Perret, M. Ajakane, V. Baudet, P.
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2
66, 15771.
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Org. Chem., 1998, 63, 2646.

HETEROCYCLES, Vol. 67, No. 1, 2006
99
1
5. Procedure for the Preparation of Immobilized 3-Iodoindole (1): A mixture of indole (1.75 g,
5.0 mmol) and KOH (3.20 g, 57 mmol) in DMF ( 20 mL) was stirred for 10 min. Then iodine
4.10 g, 16.1 mmol) was added, and the mixture was stirred for 30 min. The mixture was poured
into the solution (H O 200 mL, 25% NH aq 4 mL, Na 200 mg), and the precipitation was
1
(
2
3
2 2 5
S O
separated by filtration. The precipitation was dissolved in DMF, and 60% NaH ( 610 mg, 15.3
mmol) was added at 0 ºC. The mixture was stirred for 30 min at rt and polystyrene sulfonyl
chloride (1.97 mmol/g, 2.61 g, 5.14 mmol) was added at 0 ºC. The mixture was stirred slowly at
room temperature for 16 h. Saturated aqueous NH
4
Cl was added, and the resin was separated by
O (two
filtration and washed with THF (three times), H O (three times), MeOH (three times), Et
2
2
times). The resin was dried in vacuo to afford 2.72 g of 1. The loading (mmol/g) of 1 was
derived from 3-iodoindole generated from cleavage of 1. A mixture of resin 1 (240.6 mg) and
t-BuOK (532.5 mg, 4.7 mmol) in THF (5 mL) under an argon atmosphere was stirred at rt for 3 h.
Saturated aqueous NH Cl (10 mL)was added, and the resin was separated by filtration and washed
4
with THF (three times), H
2
O (three times), AcOEt (three times). The aqueous phase was extracted
. The evaporation of the organic phase gave
with AcOEt, and organic phase was dried over MgSO
4
the crude product, and the crude product was purified by chromatography on silica gel using
hexane/AcOEt (9:1) to afford 50.3 mg of 3-iodoindole. The loading of 1 was estimated as 0.860
mmol/g.
1
6. Procedure for the preparation of immobilized indolylboron (2): In a sealed tube, Et
mL, 0.810 mmol) and pinacolborane (0.095 mL, 0.635 mmol) were added into a mixture of resin (1)
171.3 mg, 0.1473mmol), PdCl dppf complex with dichloromethane (1:1) (12.6 mg 0.01543 mmol),
3
N (0.115
(
2
and dioxane (1.5 mL), and the mixture was heated at 80 ºC for 20 h under an argon atmosphere.
The resin was separated by filtration and washed with THF (three times), MeOH (three times),
CHCl
indolylboron (2).
7. General procedure of solid-phase Suzuki coupling using resin (2) (Table 1): In a sealed tube, the
mixture of resin (2), K PO (100.6 mg, 0.4739 mmol), Pd[P(t-Bu) (8.5 mg, 0.01663 mmol),
-iodoanisole (Entry 5, 176.4 mg, 0.7537 mmol), and DMF (2.5 mL) was heated at 80 ºC for 1 day
3 2
(three times), Et O (two times). The resin was dried in vacuo to afford the immobilized
1
3
4
3 2
]
4
under an argon atmosphere. The resin was separated by filtration and washed with THF (three
times), H O (three times), MeOH (three times), CHCl (three times), Et O (two times). The resin
2
3
2
was dried in vacuo to afford the immobilized arylindole. The resin of the immobilized arylindole
and t-BuOK (177.7 mg, 1.583 mmol) in THF (5 mL) was stirred at rt for 6 h under an argon
atmosphere. Saturated aqueous NH
4
Cl was added into the mixture. The resin was separated by
O (three times), AcOEt (three times). The
filtration, and washed with THF (three times), H
2

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HETEROCYCLES, Vol. 67, No. 1, 2006
aqueous phase was extracted with AcOEt, and organic phase was washed with brine and dried over
4
MgSO . The evaporation of the organic phase gave the crude product, and the crude product was
purified by chromatography on silica gel using hexane/AcOEt (92:8)-(85:15) to afford 24.2 mg
(
Entry 5, 74% from 1) of 3-(4-methoxyphenyl)-1H-indole.
1
1
8. 3-Phenyl-1H-indole (Table 1, Entries 1, 3): H NMR (CDCl
3
, 400 MHz) δ 7.17-7.30 (m, 3H),
7
2
.33 (d, J = 2.4 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.67 (dd, J = 8.0, 1.2 Hz,
+
H), 7.94 (d, J = 8.0 Hz, 1H), 8.18 (br s, 1H); MS (EI) m/z: (rel intensity): 193 (M , 100%), 165
11N: 193.0891. Found: 193.0907.
-(1H-Indol-3-yl)benzoic acid ethyl ester (Table 1, Entries 2, 4): H NMR (CDCl
(
25); HRMS (EI) Calcd for C14H
1
4
3
, 400 MHz)
δ 1.42 (t, J = 6.8 Hz, 3H), 4.40 (q, J = 6.8 Hz, 2H), 7.22 (dt, J = 7.6, 1.0 Hz, 1H), 7.27 (dt, J = 7.6,
1
7
2
2
3
3
1
.0 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 2.8 Hz, 1H), 7.74 (d, J = 8.2 Hz, 2H), 7.96 (d, J =
+
.6 Hz, 1H), 8.11 (d, J = 8.2, Hz, 2H), 8.41 (br s, 1H); MS (EI) m/z (rel intensity): 265 (M , 100%),
2
37 (32), 220 (32), 165 (14), 149 (14); HRMS (EI) Calcd for C17H15NO : 265.1103. Found:
65.1084.
1
-(4-Methoxyphenyl)-1H-indole (Table 1, Entries 5, 6): H NMR (CDCl
3
, 400 MHz) δ 3.86 (s,
H), 6.99 (d, J = 8.0 Hz, 2H), 7.17 (t, J = 8.0 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 7.29 (d, J = 1.6 Hz,
H), 7.41 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.89 (d, J = 8.0 Hz, 1H), 8.17 (1H, br s); MS
+
(
EI) m/z (rel intensity): 223 (M , 100%), 208 (69), 180 (12), 152 (10), 111 (13); HRMS (EI) Calcd
for C15
H13NO: 223.0997. Found: 265.0987.
1
3
7
1
3
7
-Thiophen-2-yl-1H-indole (Table 1, Entry 7): H NMR (CDCl
3
, 600 MHz) δ 7.07-7.08 (m, 1H),
+
.18-7.25 (m, 6H), 7.88 (br s, 1H), 7.96 (d, J = 7.2 Hz, 1H); MS (EI) m/z (rel intensity): 199 (M ,
00%), 171 (14); HRMS (EI) Calcd for C12
H
9
NS: 199.0456. Found 199.0428.
1
-Pyridin-2-yl-1H-indole (Table 1, Entry 8): H NMR (CDCl , 600 MHz) δ 7.08-7.11 (m, 1H),
3
.20-7.24 (m, 2H), 7.29 (d, J = 7.8 Hz, 1H), 7.63-7.64 (m, 1H), 7.67-7.68 (m, 2H), 8.27 (d, J = 7.8
+
Hz, 1H), 8.65 (d, J = 4.8 Hz, 1H), 9.43 (br s, 1H); MS (EI) m/z (rel intensity): 194 (M , 100%), 166
(
10 2
18), 149 (13), 83 (21); HRMS (EI) Calcd for C13H N : 194.0844. Found: 199.0830.