A New, Efficient Method for the Synthesis of Bisindolylmaleimides

Full text of DOI:10.1021/jo980513c

J . Org. Chem. 1998, 63, 6053-6058
6053
condensation of an indolyl-3-glyoxylyl chloride with in-
dole-3-acetimidate ester.10 Although both of these meth-
ods afford access to 7, the variable yields and the
additional chemistry required to prepare the acetimidate
or perform the ammonolysis reaction limited their po-
tential in the development of a practical approach to 1-6.
Therefore to prepare this class of compounds we sought
to identify a new, more efficient route that would afford
high yields of product, employ readily available starting
materials, and tolerate the variety of functional groups
present in 1-6. This paper describes a new, highly
efficient method to prepare symmetrical and unsym-
metrical bisindolylmaleimides 7 in 84-100% yield by
reaction of the readily available indole-3-acetamides with
methyl indolyl-3-glyoxylates using a 1.0 M solution of
KOBut in THF. The reaction is successful in the presence
of a variety of functional groups (H, alkyl, OH, NMe2,
OTr). The mechanism of this reaction is discussed.
A New , Efficien t Meth od for th e Syn th esis
of Bisin d olylm a leim id es
Margaret M. Faul,* Leonard L. Winneroski, and
Christine A. Krumrich
Lilly Research Laboratories, A Division of Eli Lilly and
Company, Chemical Process Research and Development
Division, Indianapolis, Indiana 46285-4813
Received March 18, 1998
In tr od u ction
Macrocyclic bisindolylmaleimides 1-4 have been iden-
tified as potent inhibitors of PKCâ and are currently
under development for the treatment of diabetic compli-
cations (Chart 1).1 The core structural framework re-
quired for the synthesis of 1-4 is the bisindolylmaleimide
7,2 which has also been employed in the synthesis of
indolocarbazoles staurosporine 53 and rebeccamycin 6.4
The most widely used method to prepare 7 involves
reaction of indolylmagnesium bromide with a 2,3-dihalo-
maleimide.5 Using this procedure the symmetrical bis-
indolylmaleimide 7a (R1 ) R2 ) H), a natural product
known as arcyriarubin A was prepared in two steps and
44% yield from 2,3-dichloromaleic anhydride.6 However,
for synthesis of unsymmetrical analogues (R1 and/or R2
* H) a six-step sequence is required, involving initial
monoalkylation of indolylmagnesium bromide with the
N-protected 2,3-dihalomaleimide, indole protection/alky-
lation followed by a second Grignard reaction, and a
hydrolysis/ammonolysis sequence to incorporate the ma-
leimide.7
Resu lts a n d Discu ssion
It has been reported in the literature that 4-substituted
3-hydroxymaleimides can be prepared by reaction of a
2-substituted acetamide derivative with diethyl oxalate
in strong base (KOBut) using a variety of solvents (DMF,
EtOH, and benzene).11 Encouraged by this report, we
chose to examine a synthesis of bisindolylmaleimide 7a
by condensation of indole-3-acetamide 812 with methyl
indolyl-3-glyoxylate 9 using a variety of different bases
and solvents (eq 1, Table 1). Upon condensation of 8 with
Two alternative approaches to 7 have been developed
that do not require maleimide protection. Perkin con-
densation of indole-3-acetic acid with indolyl-3-glyoxylyl
chloride affords, in 24-64% yield, the bisindolylmaleic
anhydrides,8 which are converted into the desired bis-
indolylmaleimides (R1, R2 * H), upon treatment with an
ammonium source.9 Alternatively, direct access into 7
(R1 ) H, R2 * H) can be achieved, in 42-75% yield, by
(1) (a) J irousek, M. R.; Gillig, J . R.; Gonzalez, C. M.; Heath, W. F.;
McDonald, J . H. III.; Neel, D. A.; Rito, C. J .; Singh, U.; Stramm, L. E.;
Melikian-Badalian, A.; Baevsky, M.; Ballas, L. M.; Hall, S. E.; Faul,
M. M.; Winneroski, L. L. J . Med. Chem. 1996, 39, 2664. (b) Ishii, H.;
J irousek, M. R.; Koya, D.; Takagi, C.; Xia, P.; Clermont, A.; Bursell,
S.-E.; Kern, T. S.; Ballas, L. M.; Heath, W. F.; Stramm, L. E.; Feener,
E. P.; King, G. L. Science 1996, 272, 728.
(2) Faul, M. M.; Winneroski, L. L.; Krumrich, C. A.; Sullivan, K.
A.; Gillig, J . R.; Neel, D. A.; Rito, C. J .; J irousek M. R. J . Org. Chem.
1998, 63, 1961.
(3) (a) Link, J . T.; Raghavan, S.; Danishefsky, S. J . J . Am. Chem.
Soc. 1995, 117, 552. (b) Link, J . T.; Gallant, M.; Danishefsky, S. J .;
Huber, S. J . Am. Chem. Soc. 1993, 115, 3782.
(4) (a) Nettleton, D. E.; Doyle, T. W.; Kirshnan, B.; Matsumoto, G.
K.; Clardy, J . Tetrahedron Lett. 1985, 26, 4011. (b) Kaneko, T.; Wong,
H.; Okamoto, K. T.; Clardy, J . Tetrahedron Lett. 1985, 26, 4015. (c)
Gallant, M.; Link, J . T.; Danishefsky, S. J . J . Org. Chem. 1993, 58,
343.
9 using KOBut in DMF, a 36% yield of 7a was obtained
(Table 1, entry 1). Use of NaH provided 7a in 31% yield
(Table 1, entry 2). Changing the solvent to THF, with
NaH as base, improved the yield to 56% (Table 1, entry
3). However, when a 1.0 M solution of KOBut in THF
was employed, 7a was obtained in quantitative yield
(Table 1, entry 4). The reaction was initially performed
(5) Brenner, M.; Rexhausen, H.; Steffan, B.; Steglich, W. Tetrahe-
dron 1988, 44, 2887.
(6) Faul, M. M.; Sullivan, K. A.; Winneroski, L. L. Synthesis 1995,
1511.
(7) (a) Mayer, G.; Wille, G.; Steglich, W. Tetrahedron Lett. 1996,
37, 4483. (b) Ohkubo, M.; Nishimura, T.; J ona, H.; Honma, T.;
Morishima, H. Tetrahedron 1996, 52, 8099.
(10) Bit, R. A.; Crackett, P. H.; Harris, W.; Hill, C. H. Tetrahedron
Lett. 1993, 34, 5623.
(11) (a) Rooney, C. S.; Randall, W. C.; Streeter, K. B.; Ziegler, C.;
Cragoe, E. J . J r.; Schwam, H.; Michelson, S. R.; Williams, H. W. R.;
Eichler, E.; Duiggan, D. E.; Ulm, E. H.; Noll, R. M. J . Med. Chem.
1983, 26, 700. (b) Neel, D. A.; J irousek, M. R.; McDonald, J . H. III.
Bioorg. Med. Chem. Lett. 1998, 8, 47.
(8) Davis, P. D.; Bit, R. A.; Hurst, S. A. Tetrahedron Lett. 1990, 31,
2353.
(9) Davis, P. D.; Bit, R. A. Tetrahedron Lett. 1990, 31, 5201.
(12) Indole-3-acetamide can be purchased from the Aldrich Chemical
Co. It is also readily prepared from indole-3-acetic acid or indole-3-
acetonitrile by standard methods.
S0022-3263(98)00513-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/24/1998

6054 J . Org. Chem., Vol. 63, No. 17, 1998
Notes
Ch a r t 1
Ta ble 1. Effect of Solven t, Ba se, a n d Ad d ition Mod e on
Syn th esis of 7a fr om 8 a n d 9 (eq 1)
Sch em e 1
entry solvent
base
9 (equiv) addn modea yield (%)b
1
2
3
4
5
DMF
DMF
THF
THF
THF
KOBut
NaH
1.1
1.2
1.2
1.2
1.1
B
B
B
B
A
36
31
56
100
100
NaH
KOBut
KOBut
a
Addition mode A ) base added to reagents; B ) reagents
b
added to base. Chromatography yields.
by addition of 8 and 9 to the KOBut solution at 0 °C
(method B); however for ease of reaction, addition of the
1.0 M KOBut solution to a slurry of 8 and 9 in THF at 0
°C (method A) was preferred (Table 1, entries 4 and 5).
All reactions were quenched with concentrated HCl vide
infra and 7a isolated either directly by crystallization
from EtOH or by chromatographic purification.
acid 15 in MeOH with a Dowex 50X8100 ion-exchange
resin (Scheme 1).
Bisindolylmaleimide 7a has been converted into the
staurosporine aglycon 16 in 47% yield by a three-step
oxidative cyclization/reduction sequence (eq 2).16 Al-
Since indolyl-3-glyoxylyl chlorides were successfully
employed in the Perkin condensation, a comparison of
indolyl-3-glyoxylyl ester 9 and indolyl-3-glyoxylyl chloride
10 in the synthesis of 7a from 8 using 1.0 M KOBut in
THF was performed. Although 7a was prepared in 100%
yield from 8 and 9, the yield dropped to 68% when 10
was employed. Interestingly, Steglich has reported a
synthesis of 7a albeit in 11% yield by condensation of 8
with 10, although the reaction conditions employed were
not described.13 Similarly, reaction of N-methyl-
indole-3-acetamide 11 with 9 afforded a 92% yield of 7b
(eq 1), while the yield using 10 as the coupling partner
was only 76%. In addition to affording higher yields in
the condensation reaction indolyl-3-glyoxylyl esters are
more stable than the corresponding indolyl-3-glyoxylyl
chlorides and can be stored at room temperature for
extended periods of time. This stability also means that
they can be analyzed by HPLC facilitating monitoring
of the reaction. In addition, substitution on the glyoxylyl
ester was also tolerated and condensation of methyl (1-
methylindolyl)-3-glyoxylate 1214 with 8 or 11 afforded an
alternative approach to 7b in 87% yield and the bism-
ethylated bisindolylmaleimide 7c in 99% yield.
though previous syntheses of 16 have been limited by
low yields and multiple steps,17 this new high-yielding
synthesis of 7a will provide valuable access into this
important indolocarbazole framework.
(16) Harris, W.; Hill, C. H.; Keech, E.; Malsher, P. Tetrahedron Lett.
1993, 34, 8361.
Methyl indolyl-3-glyoxylyl esters 9 and 12 were pre-
pared in >82% yield either by (i) treatment of indole 13
or 14 in Et2O with oxalyl chloride, followed by sodium
methoxide (25 wt % solution in MeOH) at low tempera-
ture (<60 °C),15 or (ii) by refluxing the 3-indole glyoxylic
(17) (a) Sarstedt, B.; Winterfeldt, F. Heterocycles 1983, 20, 469
(seven steps, 2% yield). (b) Hughes, I.; Nolan, W. P.; Raphael, R. A. J .
Chem. Soc., Perkin Trans. I 1990, 2475 (10 steps, 11% yield). (c)
Toullec, D.; Pianetti, P.; Coste, H.; Bellevergue, P.; Grand-Perret, T.;
Ajakane, M.; Baudet, V.; Boissin, P.; Boursier, E.; Loriolle, F.;
Duhamel, L.; Charon, D.; Kirilovsky, J . J . Biol. Chem. 1991, 266, 15771
(8% for last four steps, yield of coupling not reported). (d) Fabre, S.;
Prudhomme, M.; Rapp, M. Biomed. Chem. Lett. 1992, 2, 449 (21% yield
from degradation of rebeccamycin over three steps). (e) Moody, C. J .;
Rahimtoola, K. F.; Porter, B.; Ross, B. C. J . Org. Chem. 1992, 57, 2105
(23% yield, five steps). (f) Reference 16 (14%, four steps from 2,3-
dibromomaleimide).
(13) Steglich, W. Pure. Appl. Chem. 1989, 61, 281.
(14) Downie, I. M.; Earle, M. J .; Heaney, H.; Shuhaibar, K. F.
Tetrahedron 1993, 49, 4015.
(15) At higher temperatures a side reaction resulting in formation
of the 3-indoleglyoxylic acid was observed.

Notes
J . Org. Chem., Vol. 63, No. 17, 1998 6055
Sch em e 2
The sensitivity of functional groups to this chemistry
carbonyl compound 20.19 This cyclized rapidly via an
intramolecular Perkin type condensation to hydroxy
imide 22, generated as a 5:1 trans:cis isomeric mixture.
The rate of dehydration of 22, believed to be the rate-
determining step, was found to be dependent on substi-
tution of the indole-3-acetamide only and not the sub-
stitution of the indolyl glyoxylate. For example, on
condensation of 8 and 9 using 3.0 equiv of 1.0 M KOBut
in THF, dehydration of 22 in situ to bisindolylmaleimide
7a was slow, giving only 13% of product after 3 h at room
temperature. However, when N-methylindole-3-aceta-
mide 11 was employed, under identical reaction condi-
tions, dehydration of 23 was faster, affording 77% of 7b
after 3 h. For both hydroxy imides 22 and 23 dehydra-
tion can be enhanced either (i) by addition of concentrated
HCl which facilitates dehydration by an E1 process or
(ii) by use of excess base (5-10 equiv) causing dehydra-
tion via an E2 or E1cB mechanism. The latter is
particularly important when acid sensitive functionality
is present in either indole fragment.
was explored by examining a synthesis of unsymmetrical
bisindolylmaleimide 7f, a potent inhibitor of protein
kinase C. A synthesis of this compound in five steps and
19% yield from 2,3-dichloromaleic anhydride, using the
indole Grignard chemistry previously described, has been
reported.16c We decided to examine a synthesis of 7f by
condensation of the N-substituted indole-3-acetamides
17-19 with methyl indolyl-3-glyoxylate 9 (eq 3). Reac-
In summary we have reported a new, efficient, and
very general method to prepare symmetrical and unsym-
metrical bisindolylmaleimides in 84-100% yield by con-
densation of indole-3-acetamides and methyl indole-3-
glyoxylates using a 1.0 M solution of KOBut in THF. The
reaction can tolerate a variety of functional groups (H,
alkyl, OH, OTr, and NMe2). Application of this meth-
odology to the synthesis of macrocyclic bisindolylmale-
imides 1-4, staurosporne 5, rebeccamycin 6, and other
members of the bisindolylmaleimide family are under
active investigation and will be reported in due course.
tion of N-trityloxypropylindole-3-acetamide 17 with 9
using 3.0 equiv of 1.0 M KOBut in THF afforded 7d in
91% yield. Although 7d can be deprotected to afford
alcohol 7e, it was found that 7e could also be obtained
directly, in quantitative yield, by condensation of 9 with
N-hydroxypropylindole-3-acetamide 18 using 4.0 equiv
of 1.0 M KOBut in THF. Bisindolylmaleimide 7e can be
converted into the desired bisindolylmaleimide 7f by
mesylation/amine displacement or 7f can be prepared
directly in 84% yield by condensation of N-dimethyl-
aminopropylindole-3-acetamide 1918 with 9 using 4.0
equiv of 1.0 M KOBut in THF. Therefore, using this new
methodology three alternative approaches to 7f have been
developed. The optimum synthesis affords 7f in six steps
and 51% overall yield from indole-3-acetamide 8 and
indole 13 via 17.
As described, these reactions were performed by ad-
dition of the 1.0 M solution of KOBut in THF into a pale
yellow slurry of indole-3-acetamide and indole-3-glyoxylyl
ester. During the addition of base, the reaction proceeded
through a series of notable color changes to afford the
final red solution of bisindolylmaleimide. Analysis of the
reaction of 8 with 9 by HPLC indicated that three distinct
intermediates were formed (Scheme 2). These interme-
diates were isolated and characterized. The first inter-
mediate, which was short-lived (<5 min), was the tri-
Exp er im en ta l Section
Gen er a l. Unless otherwise noted, reagents and solvents were
used as received from commercial suppliers. TLC was performed
on Kiesegel 60 F254 plates (Merck) using reagent grade solvents.
Flash chromatography was performed using Merck silica gel 60
(230-400 mesh). 1H NMR were performed at 300 MHz and 13C
NMR at 75 MHz in DMSO-d6 unless otherwise specified.
Chemical shifts are in ppm downfield from internal tetrameth-
ylsilane. Mass spectral and combustion analyses were per-
formed by the Eli Lilly and Co. Physical Chemistry Department.
Meth yl In d olyl-3-glyoxyla te (9). Preparation under basic
conditions: to a solution of indole 13 (2.00 g, 17.1 mmol) in Et2O
(20 mL) at 0-5 °C was added dropwise oxalyl chloride (1.50 mL,
17.2 mmol). The resultant yellow slurry was stirred in an ice
bath for 30 min and then cooled to -65 °C. A 25 wt % solution
of sodium methoxide in MeOH (7.80 mL, 34.1 mmol) was added
to this slurry, keeping the temperature below -60 °C. The
reaction was allowed to warm to room temperature and quenched
(18) N-Dimethylaminopropylindole-3-acetamide 19 can be prepared
in one step (approximately 60% yield) by alkylation of indole-3-
acetamide using NaH in DMF; however, it was very difficult to purify.
(19) Isolated from the reaction by addition of 1.0 equiv of KOBut in
THF followed by rapid quench with concentrated HCl (37%).

6056 J . Org. Chem., Vol. 63, No. 17, 1998
Notes
by addition of water (10 mL). A solid, which precipitated out of
solution, was isolated by filtration and dried under vacuum at
room temperature to give 3.21 g (93%) of 9.
g, 6.30 mmol) in THF (10 mL), with 1.0 M KOBut (17.2 mL, 17.2
mmol). The reaction was quenched with concentrated HCl (37%,
8 mL) and diluted with EtOAc (125 mL), and the organic layers
were washed with water (2 × 100 mL) and saturated aqueous
sodium chloride (25 mL), dried (MgSO4), and filtered. Purifica-
tion was achieved using a gradient of 2:1 to 1:1 hexanes:EtOAc
to give 2.04 g (100%) of 7a as dark red crystals. Crude 3,4-(3-
indolyl)-1H-pyrrole-2,5-dione can also be crystallized directly
from the reaction using EtOH to give a stiochiometric ethanol
monosolvate in high purity (>99%) and yield (88%): 1H NMR
(300 MHz, DMSO-d6) δ 11.6 (s, 2H), 10.9 (s, 1H), 7.70 (s, 1H),
7.69 (s, 1H), 7.33 (d, 2H, J ) 8.07 Hz), 6.94 (t, 2H, J ) 7.34 Hz),
6.77 (d, 2H, J ) 8.00 Hz), 6.59 (t, 2H, J ) 7.72 Hz), 4.33 (t, 1H,
J ) 5.04 Hz), 3.45-3.37 (m, 2H), 1.02 (t, 3H, J ) 7.00 Hz); 13C
NMR (75 MHz, DMSO-d6) δ 172.6, 135.6, 128.7, 127.4, 125.1,
121.2, 120.5, 118.9, 111.3, 105.2, 30.2, 18.1; IR (KBr) v 3395,
3353, 1701 cm-1; UV (EtOH) λ 464 nm (ꢀ 8443), 376 nm (ꢀ 5591),
277 nm (ꢀ 12176); MS (FD) m/z 327 (M+, 100%). Anal. Calcd
for the ethanol solvate C22H19N3O3: C, 70.76; H, 5.13; N, 11.25.
Found: C, 70.97; H, 5.22; N, 11.12.
Preparation under acidic conditions: a 100 mL round-bottom
flask, fitted with a Dean-Stark apparatus containing 4 Å
molecular sieves, was charged with 3-indoleglyoxylic acid 15
(1.00 g, 5.29 mmol), anhydrous MeOH (40 mL), and Dowex 50X8-
100 ion-exchange resin (1.00 g). After 1 h at reflux the reaction
was cooled to room temperature. Acetone (20 mL) was added,
and the reaction was reheated to dissolve the product. The resin
was removed by filtration and the product crystallized from 20
mL of MeOH (0 °C) to afford 880 mg (82%) of 9: 1H NMR (300
MHz, DMSO-d6) δ 12.39 (bs, 1H), 8.41 (s, 1H), 8.16-8.10 (m,
1H), 7.55-7.49 (m, 1H), 7.29-7.21 (m, 2H), 3.86 (s, 3H); 13C
NMR (75 MHz, DMSO-d6) δ 179.5, 164.8, 139.1, 137.5, 126.3,
124.6, 123.6, 121.9, 113.5, 113.2, 53.2; IR (KBr) v 3215, 1732
cm-1; UV (EtOH) λ 324 nm (ꢀ 9582), 267 (ꢀ 9399), 255 nm (ꢀ
9582); MS (FD) m/z 203 (M+, 100%). Anal. Calcd for C11H9-
NO3: C, 65.02; H, 4.46; N, 6.89. Found: C, 64.93; H, 4.25; N,
7.03.
Meth yl (1-Meth ylin d olyl-3)-glyoxyla te (12). To a solution
of 1-methylindole 14 (2.00 g, 15.2 mmol) in Et2O (20 mL) at 0-5
°C was added dropwise oxalyl chloride (1.30 mL, 14.9 mmol).
The resultant yellow slurry was stirred in an ice bath for 30
min and then cooled to -65 °C. A 25 wt % solution of sodium
methoxide in MeOH (7.0 mL, 30.6 mmol) was added to this
slurry keeping the temperature below -60 °C. The reaction was
allowed to warm to room temperature and quenched by addition
of water (10 mL). The solid, which precipitated out of solution,
was isolated by filtration and dried under vacuum at room
temperature to give 2.93 g (89%) of 12: 1H NMR (300 MHz,
DMSO-d6) δ 8.47 (s, 1H), 8.16-8.13 (m, 1H), 7.60-7.57 (m, 1H),
7.36-7.26 (m, 2H), 3.89 (s, 3H), 3.86 (s, 3H); 13C NMR (75 MHz,
DMSO-d6) δ 178.7, 164.6, 142.2, 138.1, 126.6, 124.5, 123.9, 121.9,
112.0, 111.8, 53.1, 34.1; IR (KBr) v 1728 cm-1; UV (EtOH) λ 327
nm (ꢀ 10586), 260 nm (ꢀ 10603); MS (FD) m/z 217 (M+, 100%).
Anal. Calcd for C12H11NO3: C, 66.35; H, 5.10; N, 6.45. Found:
C, 66.29; H, 5.39; N, 6.65.
1-Meth ylin d ole-3-a ceta m id e (11). To a suspension of NaH
(3.33 g, 83.3 mmol, 60% mineral oil dispersion) in DMF (20 mL)
was added dropwise a solution of 3-indolylacetonitrile (10.0 g,
64.0 mmol) in DMF (50 mL). The reaction was stirred at room
temperature for 30 min and then cooled to 0-5 °C. A solution
of methyl iodide (13.6 g, 95.8 mmol) in DMF (30 mL) was added
dropwise. The reaction was stirred at room temperature for 3
h and then quenched with EtOAc (300 mL), washed with
aqueous 0.5 N HCl (400 mL), dried (MgSO4), and filtered. The
solvent was removed in vacuo to give 16.3 g (100%) of 1-methyl
3-indolylacetonitrile that was carried on without purification.
To a solution of crude 1-methylindole-3-acetonitrile (16.3 g, 95.0
mmol) and tetrabutylammonium bromide (4.13 g, 12.8 mmol)
in CH2Cl2 (100 mL) at 0 °C was added a 30% aqueous solution
of hydrogen peroxide (33 mL) followed by an aqueous 20 wt %
solution of NaOH (26 mL). The reaction was stirred at room
temperature overnight, diluted with CH2Cl2 (650 mL), and
washed with aqueous 1 N HCl (500 mL) and water (500 mL),
dried (MgSO4), and filtered. The solvent was removed in vacuo
to give a thick slurry to which was added hexanes (100 mL).
Filtration using 1:1 CH2Cl2:hexanes (100 mL) as a rinse afforded
8.45 g (70%) of 11: 1H NMR (300 MHz, DMSO-d6) δ 7.50 (d,
1H, J ) 7.78 Hz), 7.32 (d, 1H, J ) 8.21 Hz), 7.27 (bs, 1H), 7.11-
7.05 (m, 2H), 6.95 (t, 1H, J ) 7.40 Hz), 6.79 (bs, 1H), 3.68 (s,
3H), 3.4 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ 173.8, 137.5,
129.1, 128.6, 122.0, 119.9, 119.3, 110.4, 109.4, 22.2, 33.2; IR
(KBr) v 3436, 3175, 1624 cm-1; UV (EtOH) λ 287 nm (ꢀ 5853),
223 nm (ꢀ 32896); MS (FD) m/z 188 (M+, 100%). Anal. Calcd
for C11H12N2O: C, 70.19; H, 6.43; N, 14.88. Found: C, 70.02;
H, 6.17; N, 14.99.
3-[(1-Meth yl)-3-in d olyl]-4-(3-in d olyl)-1H-p yr r ole-2,5-d i-
on e (7b). From 1-methyl indole-3-acetamide 11: the general
procedure was followed using 11 (1.00 g, 5.31 mmol) and 9 (1.30
g, 6.40 mmol) in THF (10 mL) with 1.0 M KOBut (15.9 mL, 15.9
mmol). The reaction was quenched with concentrated HCl (37%,
8 mL) and diluted with EtOAc (150 mL), and the organic layer
was washed with water (100 mL) and saturated aqueous sodium
chloride (25 mL), dried (MgSO4), and filtered. Purification was
achieved using a gradient of 2:1 to 1:1 hexanes:acetone to give
1.66 g (92%) of 7b.
From methyl (1-methylindolyl-3)-glyoxylate 12: the general
procedure was followed using 8 (1.00 g, 5.74 mmol) and 12 (1.50
g, 6.91 mmol) in THF (10 mL), with 1.0 M KOBut (17.2 mL, 17.2
mmol). The reaction was quenched with concentrated HCl (37%,
8 mL) and diluted with EtOAc (150 mL) and the organic layer
was washed with water (100 mL) and saturated aqueous sodium
chloride (25 mL), dried (MgSO4), and filtered. Purification was
achieved using a gradient of 2:1 to 1:1 hexanes:acetone to give
1.71 g (87%) of 7b: 1H NMR (300 MHz, DMSO-d6) δ 11.6 (s,
1H, NH), 10.9 (s, 1H, NH), 7.79 (s, 1H), 7.69 (d, 1H, J ) 2.55
Hz), 7.38 (d, 1H, J ) 8.19 Hz), 7.34 (d, 1H, J ) 8.11 Hz), 6.97
(qn, 2H), 6.81 (d, 1H, J ) 7.98), 6.69 (d, 1H, J ) 7.87), 6.63-
6.57 (m, 2H), 3.82 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 174.3,
137.9, 137.3, 134.4, 130.4, 128.8, 128.7, 127.1, 126.9, 123.0, 122.9,
122.5, 122.3, 120.9, 120.6, 113.1, 111.4, 107.0, 106.1, 34.2; IR
(KBr) ν 3347, 3190, 1754, 1691 cm-1; UV (EtOH) λ 466 nm (ꢀ
8415), 376 nm (ꢀ 5513), 278 nm (ꢀ 10733); MS (FD) m/z 341 (M+,
100%). Anal. Calcd for C21H15N3O2: C, 73.89; H, 4.43; N, 12.31.
Found: C, 73.31; H, 4.57; N, 12.27.
3,4-[(1-Meth yl)-3-in d olyl]-1H-p yr r ole-2,5-d ion e (7c). The
general procedure was followed using 11 (1.00 g, 5.31 mmol) and
12 (1.38 g, 6.35 mmol) in THF (10 mL), with 1.0 M KOBut (15.9
mL, 15.9 mmol). The reaction was quenched with 1 N HCl (25
mL). The product precipitated out of solution and was isolated
by filtration after 15 min to give 1.88 g (99%) of 7c: 1H NMR
(300 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.79 (s, 2H), 7.41 (d, 2H, J
) 8.22 Hz), 7.02 (t, 2H, J ) 7.06 Hz), 6.74 (d, 2H, J ) 7.95),
6.63 (t, 2H, J ) 7.54 Hz), 3.84 (s, 6H); 13C NMR (75 MHz, DMSO-
d6) δ 172.9, 136.4, 132.9, 126.9, 125.8, 121.6, 121.0, 119.4, 109.9,
104.6, 32.8; IR (KBr) v 3411, 3127, 3058, 1710 cm-1; UV (EtOH)
λ 470 nm (ꢀ 6219), 376 nm (ꢀ 3991), 283 nm (ꢀ 7385); MS (FD)
m/z 355 (M+, 100%). Anal. Calcd for C22H17N3O2: C, 74.35; H,
4.82; N, 11.82. Found: C, 74.25; H, 5.03; N, 11.55.
3-[1-(3-O′-Tr iph en ylm eth ylpr opyl)-3-in dolyl]-4-(3-in dolyl)-
1H-p yr r ole-2,5-d ion e (7d ). The general procedure was fol-
lowed using 17 (1.00 g, 2.10 mmol) and 9 (0.51 g, 2.51 mmol) in
THF (10 mL), with 1.0 M KOBut (6.30 mL, 6.30 mmol). The
reaction was diluted with EtOAc (125 mL), washed with water
(100 mL) and saturated aqueous sodium chloride (25 mL), dried
(MgSO4), and filtered. Purification was achieved using 1:1
hexanes:acetone to give 1.20 g (91%) of 7d as a foam: 1H NMR
(300 MHz, DMSO-d6) δ 11.59 (bs, 1H), 10.87 (bs, 1H), 7.61 (d,
1H, J ) 2.67 Hz), 7.50 (s, 1H), 7.37-7.15 (m, 17H), 6.91 (q, 2H,
J ) 8.15 Hz), 6.73 (d, 1H, J ) 7.98 Hz), 6.61-6.55 (m, 2H), 6.42
(t, 1H, J ) 7.75 Hz), 4.30 (t, 2H, J ) 6.42 Hz), 2.93 (t, 2H, J )
5.62 Hz), 1.94-1.91 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ
172.9, 143.8, 135.9, 135.5, 131.9, 129.0, 128.1, 127.8, 127.6, 127.1,
Gen er a l P r oced u r e for th e P r ep a r a tion of Bisin d olyl-
m a leim id es. To a suspension of the indole-3-acetamide and
methyl indolyl-3-glyoxylate in THF at 0 °C was added 1.0 M
KOBut in THF. The reaction was allowed to come to room
temperature and stirred for 3 h. The reaction was quenched
(for conditions see individual examples), extracted, and purified
by flash chromatography.
3,4-(3-In d olyl)-1H-p yr r ole-2,5-d ion e (7a ). The general
procedure was followed using 8 (1.00 g, 5.74 mmol) and 9 (1.28

Notes
J . Org. Chem., Vol. 63, No. 17, 1998 6057
126.9, 125.8, 125.1, 121.5, 121.4, 121.2, 121.0, 119.4, 119.1, 111.6,
110.0, 105.5, 104.8, 86.0, 59.8, 42.7, 29.8; IR (KBr) v 3385, 3054,
1757, 1701 cm-1; UV (EtOH) λ 465 nm (ꢀ 7597), 377 nm (ꢀ 4916),
278 nm (ꢀ 9971); HRMS calcd for C42H33N3O3 627.2522, found
627.2528.
3-[1-(3-Hyd r oxyp r op yl)-3-in d olyl]-4-(3-in d olyl)-1H-p yr -
r ole-2,5-d ion e (7e). From 1-(3-O′-triphenylmethylpropyl)in-
dole-3-acetamide 17: the general procedure was followed using
17 (1.00 g, 2.10 mmol) and 9 (510 mg, 2.51 mmol) in THF (10
mL), with 1.0 M KOBut (6.30 mL, 6.30 mmol). The reaction was
quenched with concentrated HCl (37%, 8 mL), heated to reflux
for 1 h to detritylate the alcohol, and diluted with EtOAc (125
mL). The organic layer was washed with water (100 mL) and
saturated aqueous sodium chloride (25 mL), dried (MgSO4), and
filtered. Purification was achieved using 1:1 hexanes:acetone
to give 660 mg (82%) of 7e.
From 1-(3-hydroxypropyl)-indole-3-acetamide 18: the general
procedure was followed using 18 (1.56 g, 6.71 mmol) and 9 (2.73
g, 13.4 mmol) in THF (15 mL), with 1.0 M KOBut (26.9 mL, 26.9
mmol). The reaction was quenched with concentrated HCl (37%,
10 mL) and diluted with EtOAc (300 mL), and the organic layer
was washed with water (2 × 200 mL) and saturated aqueous
sodium chloride (50 mL), dried (MgSO4), and filtered. Purifica-
tion was achieved using a gradient of 2:1 to 1:1 hexanes:acetone
to give 2.55 g (100%) of 7e as a foam: 1H NMR (300 MHz,
DMSO-d6) δ 11.62 (bs, 1H), 10.86 (bs, 1H), 7.71 (s, 1H), 7.68 (s,
1H), 7.41 (d, 1H, J ) 8.24 Hz), 7.31 (d, 1H, J ) 8.11 Hz), 6.94
(qn, 2H), 6.78 (d, 1H, J ) 7.91 Hz), 6.69 (d, 1H, J ) 8.00 Hz),
6.63-6.52 (m, 2H), 4.58 (t, 1H, J ) 4.95 Hz), 4.23 (t, 2H, J )
6.73 Hz), 3.35-3.26 (m, 2H), 1.81 (t, 2H, J ) 6.35 Hz); 13C NMR
(75 MHz, DMSO-d6) δ 173.0, 172.9, 136.0, 135.8, 132.2, 132.0,
129.2, 128.0, 127.2, 126.1, 125.3, 121.6, 121.2, 121.0, 119.5, 119.3,
111.8, 110.2, 105.6, 105.0, 42.8, 32.8, 29.7; IR (KBr) v 3502, 3180,
3051, 1751, 1693, 1528 cm-1; UV (EtOH) λ 466 nm (ꢀ 8147), 378
nm (ꢀ 5382), 278 nm (ꢀ 10364); HRMS calcd for C23H19N3O3
386.1505, found 386.1501.
3-[1-(3-Dim et h yla m in op r op yl)-3-in d olyl]-4-(3-in d olyl)-
1H-p yr r ole-2,5-d ion e (7f). From 1-(dimethylaminopropyl)-
indole-3-acetamide 19: the general procedure was followed using
19 (600 mg, 2.31 mmol) and 9 (940 mg, 4.63 mmol) in THF (10
mL), with 1.0 M KOBut (9.30 mL, 9.30 mmol). The reaction was
diluted with EtOAc (100 mL) and the organic layer washed with
water (2 × 75 mL) and saturated aqueous sodium chloride (25
mL), dried (MgSO4), and filtered. The product was crystallized
directly after workup with acetone (8 mL) to give 0.80 g (84%)
of 7f.
From 3-[1-(3-hydroxypropyl)-3-indolyl]-4-(3-indolyl)-1H-pyr-
role-2,5-dione (7e): a suspension of 7e (41.8 g, 109 mmol) in
CH2Cl2 (1.20 L) was treated with pyridine (26.3 mL, 326 mmol)
and methanesulfonic anhydride (22.7 g, 130 mmol) and stirred
for 2.5 h at room temperature. The reaction was then quenched
using aqueous 0.1 N HCl (3.26 L), and the organic layer was
washed with water (1500 mL) and saturated aqueous sodium
chloride (500 mL), dried (MgSO4), and filtered. The solvent was
removed in vacuo to give 50.0 g (99%) of 3-[1-(methanesulfonyl-
propyl)-3-indolyl]-4-(3-indolyl)-1H-pyrrole-2,5-dione that was
used directly: 1H NMR (300 MHz, DMSO-d6) δ 11.64 (bs, 1H),
10.88 (bs, 1H), 7.72 (d, 1H, J ) 2.70 Hz), 7.71 (s, 1H), 7.44 (d,
1H, J ) 8.25 Hz), 7.32 (d, 1H, J ) 8.12 Hz), 6.99 (t, 1H, J )
7.63 Hz), 6.92 (t, 1H, J ) 7.46 Hz), 6.81 (d, 1H, J ) 7.98 Hz),
6.68-6.54 (m, 3H), 4.29 (t, 2H, J ) 6.75 Hz), 4.10 (t, 2H, J )
6.09 Hz), 3.11 (s, 3H), 2.09 (t, 2H, J ) 6.41 Hz); 13C NMR (75
MHz, DMSO-d6) δ 172.8, 135.9, 135.6, 131.6, 129.2, 128.2, 126.8,
126.0, 125.1, 121.8, 121.6, 121.2, 120.8, 119.6, 119.2, 111.7, 110.0,
105.4, 105.3, 67.3, 42.0, 36.5, 29.2; IR (KBr) v 3469, 1760, 1717,
1618, 1392, 1176 cm-1; UV (EtOH) λ 462 nm (ꢀ 7567), 379 nm
(ꢀ 5211), 279 nm (ꢀ 11428), 207 nm (ꢀ 49965); HRMS calcd for
Hz), 7.01-6.90 (m, 2H), 6.83 (d, 1H, J ) 7.96 Hz), 6.69-6.61
(m, 2H), 6.54 (t, 1H, J ) 7.54 Hz), 4.21 (t, 2H, J ) 6.48 Hz),
2.06-2.03 (bs, 8H), 1.81-1.77 (m, 2H); 13C NMR (75 MHz,
DMSO-d6) δ 173.1, 173.0, 136.0, 135.8, 132.0, 129.3, 127.9, 127.1,
126.1, 125.2, 121.7, 121.6, 121.2, 120.9, 119.5, 119.2, 111.8, 110.1,
105.6, 105.0, 45.1, 43.6, 30.7, 27.5; IR (KBr) v 3394, 1701 cm-1
;
UV (EtOH) λ 466 nm (ꢀ 4085), 378 nm (ꢀ 2640), 347 nm (ꢀ 1831),
277 nm (ꢀ 5376); HRMS calcd for C25H25N4O2 413.1978, found
413.1975.
N-(1H-In dol-3-ylacetyl)-r-oxo-1H-in dole-3-acetam ide (20).
A solution of 8 (1.00 g, 5.74 mmol) and 9 (1.28 g, 6.30 mmol) in
THF (10 mL) was cooled to 0 °C under N2, treated with 1.0 M
KOBut (11.5 mL, 11.5 mmol), and then quenched immediately
with concentrated HCl (8 mL). The reaction was worked up
extractively using EtOAc and water, and the mixture was
purified by chromatography using a gradient of 2:1 to 1:1
hexanes:acetone to give 0.25 g (13%) of the major HPLC product
identified as 20 (Rf ) 0.46, 1:1 hexanes:acetone): 1H NMR (300
MHz, DMSO-d6) δ 12.28 (bs, 1H), 12.27 (bs, 1H), 11.38 (bs, 1H),
8.29 (d, 1H, J ) 2.82 Hz), 8.08 (d, 1H, J ) 6.74 Hz), 7.51-7.46
(m, 2H), 7.32 (d, 1H, J ) 8.04 Hz), 7.27-7.21 (m, 3H), 7.05 (t,
1H, J ) 7.29 Hz), 6.95 (t, 1H, J ) 7.35 Hz), 3.90 (s, 2H); 13C (75
MHz, DMSO-d6) δ 181.6, 171.3, 137.2, 136.6, 136.0, 127.2, 125.5,
124.3, 123.5, 122.5, 121.06, 120.9, 118.5, 118.4, 112.5, 111.7,
111.4, 106.6, 33.3; IR (KBr) ν 3348, 3217, 3058, 1762 cm-1; MS
(FAB) calcd for C20H15N3O3 345, found [M + H]+ of m/z 346
(100%).
(3R-tr a n s)-3-H yd r oxy-3,4-d i-1H -in d ol-3-yl-2,5-p yr r oli-
d in ed ion e a n d (3S-cis)-3-Hyd r oxy-3,4-d i-1H-in d ol-3-yl-2,5-
p yr r olid in ed ion e (22). A solution of 8 (1.00 g, 5.74 mmol) and
9 (1.28 g, 6.30 mmol) in THF (10 mL) was cooled to 0 °C under
N2, treated with 1.0 M KOBut (31.6 mL, 31.6 mmol), and then
quenched with water after 15 min. The reaction was worked
up extractively using EtOAc and water, and the mixture was
purified by chromatography using CH2Cl2 treated with 0-5%
MeOH to give 0.42 g (21%) of the major HPLC products20
identified as 22 (Rf ) 0.22, 9:1 CH2Cl2:MeOH). The diastereo-
mers 22 were separated by preparative HPLC using a 25 cm
Kromsil C18 (13 µm) DT0048 column with 40% ACN in a water
mobile phase, 1.0 mL/min, 240 nm at ambient temperature to
give 0.11 g of the major diastereomer and 0.02 g of the minor
diastereomer as determined by HPLC. 22 (major-trans): 1H
NMR (300 MHz, DMSO-d6) δ 11.55 (s, 1H), 11.06 (d, 1H, J )
2.09 Hz), 11.03 (d, 1H, J ) 1.88 Hz), 7.61 (d, 1H, J ) 7.93 Hz),
7.42-7.31(m, 3H), 7.24 (d, 1H, J ) 2.42 Hz), 7.15-6.97 (m, 4H),
6.85 (dt, 1H, J ) 7.49 Hz, 0.88 Hz), 6.19 (s, 1H), 4.77 (s, 1H);
13C (75 MHz, DMSO-d6) δ 178.9, 177.5, 136.8, 135.9, 127.9, 125.8,
124.9, 123.7, 121.2, 120.7, 120.1, 119.2, 118.7, 118.3, 115.2, 111.6,
111.3, 105.8, 77.0, 51.8; IR (KBr) ν 3405, 3400, 3059, 1781, 1719
cm-1; MS (FAB) calcd for C20H15N3O3 345, found [M + H]+ of
m/z 346 (100%). 22 (minor-cis): 1H NMR (300 MHz, DMSO-d6)
δ 11.69 (s, 1H), 10.75 (d, 1H, J ) 2.13 Hz), 10.59 (d, 1H, J )
1.91 Hz), 7.50 (d, 1H, J ) 7.71 Hz), 7.37 (d, 1H, J ) 8.01 Hz),
7.11 (t, 2H, J ) 7.55 Hz), 7.00 (d, 1H, J ) 2.60 Hz), 6.96-6.75
(m, 4H), 6.69 (d, 1H, J ) 2.44 Hz), 6.61 (d, 1H), 4.79 (s, 1H); 13
C
(75 MHz, DMSO-d6) δ 179.3, 176.7, 136.0, 135.3, 127.4, 125.0,
124.1, 123.8, 120.6, 120.5, 120.0, 118.9, 118.2, 113.0, 111.3, 111.0,
106.8, 80.1, 53.6; MS (FAB) Calcd for C20H15N3O3 345, found
[M + H]+ of m/z 346 (100%). Both compounds gave identical
fragmentation pathways by positive ion EI-MS including loss
of 18 mass units (H2O). The minor diastereomer produced a
cross-peak between the methine proton at 4.79 ppm and the
hydroxyl proton at 6.61 ppm in the NOESY spectrum indicative
of a cis-orientation, while no cross-peak was present in NOESY
spectrum of the major trans-diastereomer.
C
24H21N3O5S 463.1202, found 463.1191.
A suspension of mesylate (70.4 g, 152 mmol) in THF (1.02 L)
Ack n ow led gm en t. We are grateful to Professors
Marvin Miller and Bill Roush for helpful discussions
during the course of this work. We would like to thank
was treated with a 40% aqueous solution of dimethylamine (423
mL, 3.75 mol), and the solids were dissolved immediately to give
a solution which was stirred at room temperature for 16 h. The
reaction was diluted with CH2Cl2 (1.50 L), and the organic layer
was washed with water (2 × 1.00 mL). The solvent was removed
in vacuo to give 60.0 g (96%) of 7f: 1H NMR (300 MHz, DMSO-
d6) δ 11.65 (bs, 1H), 10.88 (s, 1H), 7.75 (d, 1H, J ) 2.58 Hz),
7.66 (s, 1H), 7.37 (d, 1H, J ) 8.22 Hz), 7.16 (d, 1H, J ) 8.12
(20) HPLC conditions: Zorbax SB-CN 4.6 mm × 25 cm column with
40/60 THF/0.1% trifluoroacetic acid in water mobile phase (isocratic,
22 °C) at 1 mL/min and 233 nm. Elution times: tR 9 ) 6.6 min, tR 8 )
3.9 min, tR 7a ) 11.7 min, tR 22 (major trans-diastereomer) ) 9.5 min,
tR 22 (minor cis-diastereomer) ) 10.3 min, tR 20 ) 17.6 min.

6058 J . Org. Chem., Vol. 63, No. 17, 1998
Notes
Su p p or tin g In for m a tion Ava ila ble: Complete analytical
and spectroscopic characterization for 17, 18, and 19 (4 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
Mr. J oe Kennedy and Mr. J ohn Bowers for purification
of cis and trans isomers 22. Ms. Karen McCune, Mr.
Gary Cooke, Dr. Doug Dorman, Mr. K. Wayne Taylor,
Mr. David Reed, Mr. J ames Osbourne, and Mr. Craig
Kemp, of Eli Lilly and Co. Pharmaceutical and Analyti-
cal chemistry, are acknowledged for contributions to the
characterization of 22.
J O980513C