Strategies for the synthesis of N-(azacycloalkyl)bisindolylmaleimides: Selective inhibitors of PKCβ

Article abstract of DOI:10.1016/S0040-4020(03)00973-6

N-(Azacycloalkyl)bisindolylmaleimides 1 have been identified to be selective inhibitors of PKCβ. This manuscript will describe the synthetic approaches employed to prepare this class of compounds that resulted in development of efficient methods for prepa

Full text of DOI:10.1016/S0040-4020(03)00973-6

Tetrahedron 59 (2003) 7215–7229
Strategies for the synthesis of
N-(azacycloalkyl)bisindolylmaleimides: selective
inhibitors of PKCb
*
Margaret M. Faul, John L. Grutsch, Michael E. Kobierski, Michael E. Kopach,
Christine A. Krumrich, Michael A. Staszak, Uko Udodong, Jeffrey T. Vicenzi and
Kevin A. Sullivan
Global Chemical Process Research and Development, Lilly Corporate Center, Eli Lilly and Company, Indianapolis,
IN 46285-4813, USA
Received 14 March 2003; revised 17 June 2003; accepted 19 June 2003
Abstract—N-(Azacycloalkyl)bisindolylmaleimides 1 have been identified to be selective inhibitors of PKCb. This manuscript will describe
the synthetic approaches employed to prepare this class of compounds that resulted in development of efficient methods for preparation of
N-(azacycloalkyl) indole 5, indole-3-acetamide 8 and indole-3-glyoxylate ester 4 derivatives.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
evaluate a series of acyclic N-(azacycloalkyl)bisindolylma-
leimides 1 for their ability to inhibit PKCb (Chart 1). This
manuscript will describe our efforts to develop a general
method to prepare N-(azacycloalkyl)bisindolylmaleimides,
that enabled rapid progression of the SAR and resulted in
the selection of 1e (LY317615) for clinical evaluation
(Scheme 1).4
Most solid tumors increase in mass through the proliferation
of malignant and stromal cells, including endothelial cells,
leading to formation of a tumor vasculature. Since active
angiogenesis is a critical component of the mass expansion
of most solid tumors, this process is a valid target for
therapy. The most common and direct-acting angiogenic
factor in cancer patients is the vascular endothelial growth
factor (VEGF), and the up-regulation of VEGF receptors
has been observed in tumor-associated endothelial cells.
The signal transduction pathways of these receptors include
downstream activation of PKC, and data from numerous
assays indicate that PKC activation is directly responsible
for the VEGF signaling that leads to neovascularization.
Therefore, an inhibitor of PKC would be anticipated to
block tumor angiogenesis. The macrocyclic bisindolylma-
leimide ruboxistaurin (LY333531), a selective inhibitor of
PKCb is under evaluation in the clinic for treatment of
retinopathy associated with diabetic complications (Chart 1).
Ruboxistaurin has been shown to be effective in inhibiting
tumor growth and metastasis in a variety of tumor models,
presumably by preventing VEGF-driven angiogenesis.1–3
2. Results and discussion
Retrosynthetic analysis. We envisioned that the N-(azacy-
cloalkyl)bisindolylmaleimides 1a-i could be prepared either
(i) by condensation of indole-3-acetamide (2) or N-methyl
indole-3-acetamide (3) with substituted methyl indole-3-
glyoxylates 4b-g (strategy A, Scheme 1); or (ii) by
condensation of indole-3-glyoxylate (6) or N-methyl
Rather than pursue ruboxistaurin in the clinic as an agent for
treatment of malignant solid tumors, our goal was to
Keywords: N-(azacycloalkyl)bisindolylmaleimides; angiogenesis; vascular
endothelial growth factor.
*
Corresponding author. Tel.: þ1-3172771150; fax: þ1-3172763014;
Chart 1.
e-mail: faul_margaret_m@lilly.com
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00973-6

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M. M. Faul et al. / Tetrahedron 59 (2003) 7215–7229
Scheme 1.
indole-3-glyoxylate (7) with substituted indole-3-aceta-
mides 8b-g (strategy B).5 The key for each strategy was to
develop a general method for the synthesis of functionalized
N-(azacycloalkyl) indoles 5 and indole-3-acetamides 8. In
addition, the pyrrolidine derivative 1d contains an asymmetric
center and a route to both racemic and chiral versions of this
compound was required. This manuscript will describe our
synthetic efforts towards this class of compounds.
reported. Our goal was to develop general methodologies
for the synthesis of 5 and 8 that would allow rapid access to
a variety of N-(azacycloalkyl) bisindolymaleimide deriva-
tives for evaluation as PKCb inhibitors.
Our initial strategy was to develop a general convergent
method for synthesis of these compounds by development
of the reductive amination/cyclization chemistry (strategy C
and D, Scheme 2). Aniline (10) was prepared from ortho-
nitrotoluene (13) by a modification of the literature process
(Scheme 3).15 This improved procedure generated 10 via a
more reactive pyrrolidine enamine 14 rather than dimethy-
lenamine, which required temperatures of 130–1508C for
reaction completion. The enhanced reactivity of 14 toward
displacement resulted in a lower operating temperature
(808C) for the methanolysis step, alleviated safety concerns
due to formation of nitroso intermediates and produced an
overall cleaner purity profile. Purification by distillation
afforded (10) in .70% overall yield from 13.
Synthesis of N-(azacyclo)alkyl indole and indole-3-acet-
amide derivatives. A number of approaches to the synthesis
of N-(azacycloalkyl) indoles 5 have been reported.6–9
A
synthesis of the indole nucleus in two steps after reductive
alkylation of 2-amino-a-chloroacetophenones with ketones
has been described.10–13 Coe has also reported a Leim-
gruber–Batcho synthesis of 6-carboxyester analogs 5b-d,g
by reductive amination of aniline (10) with the correspond-
ing piperidones 9b-d,g.14 Presently, no methods for the
synthesis of 5 or 8 by reductive amination on indoline (11)
or 2,3-dihydro-1H-indole-3-acetamide (12) have been
Scheme 3.
A three step synthesis of 12 from indole-3-acetic ester has
been reported.16 However, we identified a one step method
to prepare 12 in 58% yield by reduction of 2 with
BH3·pyridine in MeOH and concentrated HCl (Eq. (1)).
Since indoline (11) is commercially available, we now had
Scheme 2.

M. M. Faul et al. / Tetrahedron 59 (2003) 7215–7229
7217
access to anilines (10), (11) and (12) to evaluate the
reductive amination chemistry.
mild oxidizing agents such as DDQ or Pd/C.19 Unfortu-
nately, DDQ oxidation of the benzyl protected indolines
derived from 9c and 9d was unsuccessful, presumably due
to competitive oxidation at the benzylic position indicating
that the choice of N-protecting group was important. Thus,
synthesis of the N-benzyl protected acetamide 8c was not
achieved.
ð1Þ
N-Alkyl piperidones and pyrrolidones 9b-d,g are commer-
cially available. Novel piperidones, e.g. N-(2-pyridinyl-
methyl)-4-piperidinone 9e were prepared via the classical
three step Dieckmann cyclization sequence (Eq. (2)).
Thus, bis Michael addition of 2 aminomethyl pyridine (17)
to ethyl acrylate (16) and Dieckmann cyclization followed
by base catalyzed decarboxylation generated 9e in 56%
overall yield.17 Although this process worked well it
required multiple steps and isolation of piperidone 9e
from aqueous media was difficult due to its high
hydrophilicity. Therefore, a more efficient one step process
for the synthesis of N-alkyl piperidones was developed that
afforded an 87% yield of 9e (as the CSA salt) by alkylation
of 4-piperidone hydrochloride monohydrate 19 with picolyl
chloride monohydrochloride 20 using Na2CO3 in refluxing
acetonitrile (Eq. (3)).18 This process also afforded a 67%
yield of N-cyclopropylmethyl piperidone 9f (Eq. (4)).18
ð5Þ
Table 1. Synthesis of N-(azacycloalkyl) indoles 5 and 8 via reductive
amination (Eq. (5))
Entry
Aniline
N-Alkyl piperidone
Yield (%)
91
83
46
76
89
92
Product
ð2Þ
1
2
3
4
5
6
10
10
10
10
10
10
9b
9c
9d
9e
9f
5b
5c
5d
5e
5f
9g
5g
7
8
9
10
11
11
11
11
9e
9b
9f
77 (2 steps)
79 (2 steps)
32 (2 steps)
87 (2 steps)
5e
5b
5f
9g
5g
ð3Þ
ð4Þ
11
12
13
14
12
12
12
12
9b
9e
9f
18 (2 steps)
50 (2 steps)
50 (2 steps)
42 (2 steps)
8b
8e
8f
9g
8g
Although this reductive amination strategy was successful,
early commitment to the N-substituent required each
product to be generated in a multi-step process. To enable
a more rapid expansion of the SAR we needed a more direct
approach to the synthesis of N-(azacycloalkyl) indoles 5 and
indole-3-acetamides 8 wherein the alkyl group could be
introduced later in the synthesis. Therefore, 4-(indol-1-yl)
piperidine (5a) and 4-(indol-1-yl-3-acetamide) piperidine
(8a) were identified as the key intermediates. Piperidine 5a
has been prepared in the patent literature by the reductive
alkylation strategy of Sugasawa.6,20 We identified a one step
synthesis of 5a in 98% yield by hydrogenation of the
corresponding N-benzyl indole 5c. The N-boc derivative 8g
was employed for preparation of 8a, since preparation of the
N-benzyl derivative was problematic during the oxidation
The reductive amination of piperidones 9 with (10), (11) and
(12) was performed by addition of the reagents to a solution
of NaBH(OAc)3 (1.5 equiv.) in HOAc (Table 1, Eq. (5)).
For reactions with (10), initial formation of the imine need
to be performed at room temperature, otherwise significant
amounts of indole and 1-acetyl indole were generated as by-
products. However, heating to 508C was required to effect
cyclization of the intermediate imine to indole 5. Using
indolines (11) and (12), oxidation to 5 or 8 was effected with

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M. M. Faul et al. / Tetrahedron 59 (2003) 7215–7229
process. Alkylation of piperidines 5a and 8a then afforded
access to a variety of N-(azacycloalkyl) indoles 5 or 8 in
good yield (Table 2, Scheme 4), without the need to
separately prepare the corresponding piperidones and
perform the reductive amination chemistry. With these
reagents available, the scope of the SAR of the N-
(azacycloalkyl) bisindolylmaleimides was expanded.
ð6Þ
Synthesis of N-(azacyclo)alkyl indole-3-glyoxylyl deriva-
tives. Methyl indole-3-glyoxylates 4 are prepared by
reaction of indole with oxalyl chloride in an organic
solvent, followed by quench of the intermediate glyoxylyl
chloride with NaOMe or MeOH.5 For the synthesis of 4b-g,
acetonitrile proved to be the optimal solvent.
Use of CH2Cl2 was avoided due to the known and observed
ability of tertiary amines to react with this solvent.21 In
addition, for substrates 5b-g the presence of a free tertiary
amine was problematic with oxalyl chloride, presumably
due to competing reactions at the tertiary nitrogen. There-
fore, to successfully prepare glyoxylate esters of indoles 5b-
g containing tertiary amines initial formation of the
monohydrochloride salts was required. Thus, treatment of
5b-g with HCl at room temperature for 1 h generated the
HCl salts. Although the HCl salts can be formed and
isolated in quantitative yield, it was more convenient for
them be prepared and used in situ. Subsequently, addition of
oxalyl chloride at 08C to a slurry of the HCl salt in
acetonitrile resulted in rapid formation of the glyoxylyl
chloride. After 2 h the reactions were quenched with MeOH
and glyoxylate esters 4b-g isolated in 65–94% yield
(Table 3, Eq. (7)). Purification of 4 by chromatography or
crystallization was necessary to remove residual dimethy-
loxalate (NMR singlet at 3.78 ppm), since this by-product
can have a negative impact on the final condensation step to
prepare 1
Scheme 4.
Table 2. Synthesis of N-(azacycloalkyl)-indoles 5 and 8 via alkylation
(Scheme 4)
Entry
Reactant
R–X
Yield (%)
Product
1
2
3
4
5
6
23
23
23
24
24
24
MeI
49a
86
97
55
69
82
5b
5f
5e
8b
8f
c-C3H5H2Br
2-Pyr-CH2Br
MeI
c-C3H5CH2Br
2-Pyr-CH2Br
8e
a
Problems with quaternary salt formation were observed for R¼Me.
Although the reductive amination approach afforded access
to the racemic N-benzyl pyrrolidine indole 5d, we were
interested in preparing the chiral variants of this compound.
Literature reports indicate that most direct approach to these
compounds via alkylation of indole with N-benzyl-3-
chloropyrrolidinol affords primarily the elimination pro-
duct.6 However, due to the commercial availability of (S)
and (R)-1-benzyl-3-hydroxypyrrolidines we sought to
explore the application of these intermediates to the
synthesis of chiral 1d derivatives. To our delight alkylation
of indole (25) or indole-3-acetamide (2) with the mesylates
26, 27 or 28 derived from racemic or chiral (S) and (R)-1-
hydroxypyrrolidines afforded an 80–86% yield of the
corresponding chiral N-(azacycloalkyl) indole derivatives
5d and 8d (Eq. (6)). In addition, since the benzyl group can
be removed and additional alkylating agents incorporated at
the pyrrolidine nitrogen, this approach provided a valuable
strategy for the synthesis of a variety of chiral N-alkyl
pyrrolidine bisindolylmaleimides.
ð7Þ
Table 3. Synthesis of N-(azacycloalkyl) indole glyoxylates 4 (Eq. (7))
Entry
Reactant
Yield (%)
Product
1
2
3
4
5
6
5b
5c
5d
5e
5f
83
94
69
86
92
67
4b
4c
4d
4e
4f
5g
4g

M. M. Faul et al. / Tetrahedron 59 (2003) 7215–7229
7219
Synthesis of the bisindolylmaleimides strategy A. Reaction
of N-(azacycloalkyl) indole glyoxylates 4b-g with indole-3-
acetamide (2) or (3) was performed in THF using tert-KOBu
(2.2 equiv.) as base and afforded the corresponding
bisindolylmaleimides 1 in 56–83% yield (Table 4, Eq.
(8)). The tert-KOBu was added at 2108C to ensure that all
the starting glyoxylate was consumed before elimination
of the intermediate hydroximide, since this conversion
generated 1 mol of water that competitively hydrolyzed 4
into their corresponding glyoxylic acids 29. In addition, tert-
KOBu can also pick up water and generate 1 mol of KOH
and tert-butanol therefore, all reagents should be dried prior
to performing this reaction. Upon completion the reaction
was quenched with water, neutralized and cooled to 08C.
The bisindolylmaleimides precipitated from the reaction
and were isolated by filtration. At this time any glyoxylic
acid 29 formed during the process was removed. During the
work-up procedure it was important to minimize exposure
to basic pH, since competitive hydrolysis of 1 to the
corresponding anhydride 30 was observed.
ð9Þ
Table 5. Strategy B for synthesis of bisindolylmaleimides 1 (Eq. (9))
Entry
Acetamide
Glyoxylate
Yield (%)
Product
1
2
3
4
5
8b
8c
8d
8e
8g
7
7
7
7
7
54
51
77
53
80
1b
1c
1d
1e
1g
3. Conclusion
Two comparable approaches to the synthesis of N-
(azacycloalkyl)bisindolylmaleimides 1 have been ident-
ified. The first approach involves preparation of N-
(azacycloalkyl) indoles 5b-g in 2 steps by reductive
amination/oxidation from indoline (11) or in 4 steps by
reductive amination/cyclization of aniline (10). Although
this multi-step sequence can be performed individually for
each piperidone or pyrrolidinone 9, we have found it more
expedient to prepare the indolyl piperidine or pyrrolidinone
5a and use this as the key intermediate to incorporate a
variety of functional groups on the piperidine nitrogen. The
N-(azacycloalkyl) indoles 5b-g were then converted into
glyoxylate esters 4b-g and converted into the corresponding
bisindolylmaleimides 1 in 8 steps by condensation with
indole-3-acetamides (2) or (3).
In the second strategy, indole-3-acetamdes 8b-g were
generated by reductive amination/oxidation of indoline-3-
acetamide (12) with piperidones or pyrrolidinones 9. As
with the previous route, the 4-(indol-1-yl 3-acetamide)
piperidine 8a can be generated from the corresponding
N-boc analog and alkylated to expand the SAR around this
position. N-(Azacycloalkyl) acetamides 8b-g were treated
with indole glyoxylates 6 and 7 to provide an alternative
approach to bisindolylmaleimides 1 in 6 steps. These
synthetic strategies allowed preparation of a variety of
acyclic N-(azacycloalkyl)bisindolylmaleimides. From this
series of compounds 1e was identified as a potent inhibitor
of PKC and is currently being evaluated in the clinic for the
treatment of cancer.
ð8Þ
Table 4. Strategy A for synthesis of bisindolylmaleimides 1 (Eq. (8))
Entry
Acetamide
Glyoxylate
Yield (%)
Product
1
2
3
4
5
6
7
8
3
2
3
3
3
2
3
3
4b
4b
4c
4d
4e
4e
4f
83
72
73
71
75
61
56
62
1b
1i
1c
1d
1e
1h
1f
4g
1g
Synthesis of the bisindolylmaleimides strategy B. A
synthesis of 1 was also successful by reaction of the
indole-3-glyoxylate esters (6) and (7) with the correspond-
ing N-(azacycloalkyl) indole-3-acetamides 8b-g. The reac-
tions were performed in analogy to the conditions outlined
above and afforded 1 in 51–80% yield (Table 5, Eq. (9)).
The unsubstituted bisindolylmaleimide 1a was prepared in
70% yield by deprotection of 1g with concentrated HCl.
4. Experimental
Reactions were run under an atmosphere of nitrogen. TLC
was performed on Kieselgel 60 F254 plates (Merck) using
reagent grade solvents. Flash chromatography was
performed using E. M. Merck silica gel 60 (230–400

7220
M. M. Faul et al. / Tetrahedron 59 (2003) 7215–7229
mesh). The Eli Lilly and Co. Physical Chemistry Depart-
ment performed all physical chemistry analysis.
exotherm to 358C was observed. After cooling to rt,
powdered NaBH(OAc)3 (1.5 equiv.) was added in portions
over 10–15 min, keeping the reaction temperature below
308C; the NaBH(OAc)3 was rinsed in with HOAc (5 mL).
After stirring at rt for 1–4 h, the mixture was heated to 50–
1008C until the cyclization to the indole was complete. The
reaction was cooled to rt and diluted with deionized water
and organic solvent. Aqueous concentrated NaOH was
added dropwise to adjust the pH to 10–11, keeping the
reaction temperature below 258C. The layers were separ-
ated, and the aqueous layer extracted with an organic
solvent. The combined organic layers were washed with
aqueous saturated NaCl solution and dried (MgSO4). The
filtrate was concentrated in vacuo to afford the crude
product that was purified by silica gel chromatography using
the conditions described separately for each indole.
4.1. General methods for the synthesis of
N-(azacycloalkyl) indoles (5)
4.1.1. (E)-1-[2-(2-Nitrophenyl)ethenyl-pyrrolidine (14).
To a solution of 2-nitrotoluene (5.0 g, 36.5 mmol) in DMF
(20 mL) was added pyrrolidine (3.1 g, 43.8 mmol) followed
by dimethylformamide dimethylacetal (5.2 g, 43.8 mmol)
and the resulting solution was heated to 608C for 5 h, during
which time the solution turned dark. NMR analysis (CDCl3)
of a reaction aliquot showed a 3:1 ratio of 2-nitrotoluene to
desired product. The temperature was increased to 808C and
stirring continued for 17 h, after which time NMR analysis
showed no 2-nitrotoluene remained. The solution was
allowed to cool to rt and partitioned between MTBE
(100 mL) and H2O (100 mL). The aqueous layer was back-
extracted with MTBE (50 mL) and the combined extracts
were washed with aqueous saturated NaCl solution, dried
(MgSO4) and concentrated in vacuo to afford 7.45 g (94%)
14 as a dark red oil. 1H NMR (300 MHz, CDCl3) d 1.94 (m,
4H), 3.32 (m, 4H), 5.83 (d, J¼13.4 Hz, 1H), 6.93 (m, 1H),
7.23 (d, J¼13.7 Hz, 1H), 7.31 (m, 1H), 7.44 (dd, J¼8.2,
1.2 Hz, 1H), 7.83 (dd, J¼8.2, 1.2 Hz, 1H).
4.2.1. 1-(1-Methyl-piperidin-4-yl)-1H-indole (5b). Syn-
thesis via route 1. Quantities employed 10 (10.0 g,
55.2 mmol), N-methyl-piperidone 9b (7.5 mL, 61 mmol)
and NaBH(OAc)3 (17.5 g, 82.6 mmol) in HOAc (50 mL).
Following addition of NaBH(OAc)3 the reaction was stirred
at rt for 1.5 h and 1008C for 1 h. Work-up employed
deionized water (200 mL), aqueous concentrated NaOH
(70 mL) and EtOAc as the extraction solvent. Purification
using 300 g silica gel 60, 93:7 MeCl2/MeOH afforded 10.7 g
(91%) 5b. 1H NMR (400 MHz, DMSO-d6) d 7.50 (dd, 2H,
J¼7.47 Hz), 7.46 (d, 1H, J¼3.08 Hz), 7.10 (app. t, 1H,
J¼7.03 Hz), 6.99 (app. t, 1H, J¼7.47 Hz), 6.43 (d, 1H,
J¼3.08 Hz), 4.30 (m, 1H), 2.90 (m, 2H), 2.23 (s, 3H), 2.13
(m, 2H), 1.98 (m, 2H), 1.89 (m, 2H); 13C NMR (100 MHz,
DMSO-d6) d 135.0, 127.8, 124.7, 120.6, 120.2, 118.7,
109.6, 100.7, 54.6, 52.2, 45.8, 32.0; IR (CHCl3) n 3008,
2947, 2855, 2796, 2743, 1511, 1462, 1380, 1309, 1278,
1131 cm21. HRMS (ESþ) m/z calculated for C14H18N2
215.1548 (Mþ1), found 215.1542 (Mþ1).
4.1.2. 1-(2,2-Dimethoxyethyl)-2-nitrobenzene (15). Com-
pound 14 (4.4 g, 20.2 mmol) was dissolved in MeOH
(45 mL) and treated dropwise over 15 min with TMSCl
(3.3 g, 3.8 mL, 30.2 mmol). An exotherm occurred during
the addition and the dark red color mostly disappeared. The
solution was heated to reflux for 22 h, after which time
NMR analysis showed no starting material remained. The
solution was allowed to cool to rt and concentrated to an
orange-red residue. The residue was partitioned between
EtOAc (75 mL) and 5% aqueous citric acid (75 mL). The
aqueous layer was back-extracted with EtOAc (50 mL) and
the combined organic layers were washed with aqueous
saturated NaHCO3, followed by aqueous saturated NaCl and
concentrated in vacuo to afford 3.56 g (84%) 15 dark red oil.
1H NMR (300 MHz, CDCl3) d 3.25 (d, J¼5.3 Hz, 2H), 3.38
(s, 6H), 4.60 (d, J¼5.3 Hz, 1H), 7.42 (m, 2H), 7.56 (m, 1H),
7.92 (dd, J¼7.9, 1.3 Hz, 1H).
4.2.2. 1-(1-Benzyl-piperidin-4-yl)-1H-indole (5c). Syn-
thesis via route 1. Quantities employed 10 (12.1 g,
66.7 mmol), N-benzyl piperidone 9c (13.9 g, 73.4 mmol)
and NaBH(OAc)3 (22.3 g, 100 mmol) in HOAc (109 mL).
Following addition of NaBH(OAc)3 the reaction was stirred
at rt for 4 h and 508C for 15 h. Work-up employed deionized
water (130 mL), aqueous 5N NaOH (115 mL) to pH 8 and
extraction with CH2Cl2 (3£80 mL). Purification using 558 g
of silica gel 60, 80:20 hexanes/EtOAc afforded 16.2 g (83%)
5c. 1H NMR (CDCl3) d 2.09 (m, 4H), 2.23 (m, 2H), 3.09 (m,
2H), 3.61 (s, 2H), 6.53 (d, 1H, J¼3.3 Hz), 7.08–7.14 (m,
1H), 7.18–7.41 (m, 8H), 7.64 (d, 1H, J¼8.1 Hz); 13C NMR
(CDCl3) d 138.1, 135.6, 129.2, 128.9, 128.6, 128.3, 127.2,
124.1, 121.3, 121.1, 119.4, 109.3, 101.4, 63.0, 53.5, 53.1,
32.5; IR (CHCl3) n 2949, 2808, 2763, 1610, 1510, 1477,
1461 cm21. MS (ESþ) calculated for C20H22N2 m/z 290,
found 291 (Mþ1). Anal. calculated for C20H22N2: C, 82.72;
H, 7.64; N, 9.65, found: C, 82.63; H, 7.66; N, 9.66.
4.1.3. 2-(2,2-Dimethoxyethyl)-benzenamine (10). A sol-
ution of compound 15 (20.9 kg, 98.8 mol, 1.0 equiv.) in cold
MeOH (190 L) was stirred at rt under N2. A slurry of 5% Pd/
C (water wet, 2.05 kg) in cold MeOH (10 L) was charged to
the reaction mixture and rinsed in with cold MeOH (2£5 L).
The mixture was hydrogenated at rt under 25–50 psia H2 for
2–4 h. The reaction mixture was filtered through hyflo and
rinsed with MeOH (150 L). The filtrate was concentrated in
vacuo to an oil that was dissolved in MTBE (25 L) and
filtered through a 1m cartridge filter. A potency assay of the
product solution (49.3 kg) showed 35.8 wt% 10 that
represented 5.7 bkg (100% yield).
4.2.3. 1-(1-Methyl-piperidin-4-yl)-1H-indole (5d). Syn-
thesis via route 1. Quantities employed 10 (1.0 g,
4.2. Route 1 via reductive amination of aniline (10) and
N-alkyl-4-piperidones or N-alkyl-3-pyrrolidinones
5.52 mmol),
N-benzyl-3-pyrrolidinone
9c
(1.06 g,
6.05 mmol) and NaBH(OAc)3 (1.75 g, 8.26 mmol) in
HOAc (5 mL). Following addition of NaBH(OAc)3 the
reaction was stirred at rt for 1.5 h and 1008C for 2 h.
Work-up employed deionized water (20 mL), EtOAc
Aniline 10 (1.0 equiv.) was stirred as a solution in HOAc
(50 mL) at rt under N2. N-alkyl-4-piperidone or N-alkyl-3-
pyrrolidinone (1.1 equiv.) was added in one portion; an

M. M. Faul et al. / Tetrahedron 59 (2003) 7215–7229
7221
(10 mL), aqueous concentrated NaOH to pH 10–11 and
extraction with additional EtOAc. Purification using 50 g
silica gel 60, CH2Cl2 to 98:2 CH2Cl2/MeOH afforded 0.70 g
(46%) of 5d. 1H NMR (300 MHz, DMSO-d6) d 7.58 (d, 1H,
J¼8.2 Hz), 7.49 (d, 2H, J¼3.0 Hz), 7.36–7.20 (m, 5H),
7.09 (dt, 1H, J¼8.2, 1.3 Hz), 6.99 (t, 1H, J¼7.5 Hz), 6.42
(d, 1H, J¼3.5 Hz), 5.13–5.08 (m, 1H), 3.65 (q, 2H,
J¼12.8 Hz), 2.98–2.93 (m, 1H), 2.76 (d, 2H, J¼6.0 Hz),
2.49–2.38 (m, 2H); 13C NMR (75 MHz, DMSO-d6) d
139.3, 135.7, 128.8, 128.6, 128.5, 127.2, 126.2, 121.2,
120.7, 119.3, 110.4, 101.3, 60.0, 59.6, 54.2, 53.3, 32.2; IR
(CHCl3) n 3009, 2798, 1611, 1511, 1480, 1461, 1348, 1311,
1230 cm21; HRMS (ES) m/z calculated for C19H20N2
277.1705 (Mþ1), found 277.1696. Anal. calculated for
C19H20N2 C, 67.92, H, 3.17, N, 8.80, found C, 67.86, H,
3.02, N, 8.74.
13C NMR (CDCl3) d 135.6, 128.5, 124.0, 121.2, 121.0,
120.0, 119.4, 109.2, 101.4, 63.6, 53.4, 53.2, 53.1, 32.4, 8.4,
4.0; IR (CHCl3) n 3007, 2948, 2930, 2780, 1672, 1610,
1510, 1477, 1461, 1307 cm21. HRMS (ES) m/z calculated
for C17H22N2 255.1861 (Mþ1), found 255.1850.
4.2.6. 4-Indol-1-yl-piperidine-1-carboxylic acid tert-
butyl ester (5g). Synthesis via route 1. Quantities
employed 10 (4.13 g, 22.8 mmol), N-(tert-butoxycarbo-
nyl)-4-piperidone 9g (5.00 g, 25.1 mmol) and NaBH(OAc)3
(7.25 g, 34.2 mmol) in HOAc (38 mL). Following addition
of NaBH(OAc)3 the reaction was stirred at 508C for 18 h.
Work-up employed aqueous saturated NaHCO3 (250 mL)
and CH2Cl2 (3£50 mL). Purification by silica gel chroma-
tography using 4:1 hexanes/EtOAc afforded 6.30 g (92%)
1
5g. H NMR (300 MHz, DMSO-d6) d 7.56–7.53 (m, 2H),
7.48 (d, 1H, J¼3.3 Hz), 7.13, app. t, 1H, J¼7 Hz), 7.02, app.
t, 1H, J¼8 Hz), 6.45 (d, 1H, J¼3.3 Hz), 4.55 (m, 1H), 4.13
(bd, 1H, J¼12.4 Hz), 2.95 (m, 3H), 1.90 (m, 4H), 1.44 (s,
9H); 13C NMR (75 MHz, DMSO-d6) d 153.8, 135.2, 127.9,
124.9, 120.8, 120.4, 119.0, 109.9, 100.9, 78.8, 52.2, 31.9,
28.1; IR (CHCl3) n 3009, 2981, 2862, 1685, 1477, 1462,
1453, 1427, 1368, 1311, 1245, 1165 cm21. MS (FDþ) m/z
calculated for C18H24N2O2 300.4, found 300.4. Anal.
calculated for C18H24N2O2 C, 71.9; H 8.05; N, 9.32,
found: C, 72.2; H, 8.05; N, 9.29.
4.2.4. 1-(1-Pyridin-2-yl methyl-piperidin-4-yl)-1H-indole
(5e). Synthesis via route 1. Quantities employed 10 (866 g,
4.78 mol),
N-(2-pyridinylmethyl)-4-piperidinone
9e
(1.00 kg, 5.26 mol) and NaBH(OAc)3 (1.52 kg, 7.71 mol)
in HOAc (5 L). Following addition of NaBH(OAc)3 the
reaction was stirred at rt for 4 h and 50–608C for 24–48 h.
Work-up employed deionized water (20 L), EtOAc (8.5 L),
aqueous 50% NaOH (6 L) to pH 9.5–10 and extraction with
additional EtOAc (2£8 L). No chromatographic purification
required. The organic layer was concentrated in vacuo to a
thick oil. IPA (20 L) was added and the mixture was
reconcentrated in vacuo to remove residual EtOAc. IPA
(20 L) was added and the resulting slurry was concentrated
in vacuo until crystallization began. The slurry was stirred at
rt for 6–24 h, then cooled to 0–58C for 2–3 h. The product
was isolated by filtration, rinsed with cold IPA (2£1.5 L)
4.3. Route 2 via reductive amination of indoline (11) and
1-alkyl-4-piperidone
Indoline 11 (1.0 equiv.) was stirred as a solution in HOAc at
rt under N2; an exotherm to 348C was observed. After
cooling to rt, N-alkyl-4-piperidone (1.1 equiv.) was added in
one portion; an exotherm to 358C was observed. After
cooling to rt, powdered NaBH(OAc)3 (1.5 equiv.) was
added in portions over 10–15 min, keeping the reaction
temperature below 308C; the NaBH(OAc)3 was rinsed in
with HOAc. After stirring for 1 h at rt, the reaction was
diluted with deionized water and organic solvent. Aqueous
concentrated NaOH was added dropwise to adjust the pH to
10–11, keeping the reaction temperature below 408C. The
layers were separated and the aqueous layer extracted. The
combined organic layers were washed with aqueous
saturated NaCl solution and dried (MgSO4). The drying
agent was removed by filtration and rinsed with EtOAc. The
filtrate was concentrated in vacuo to afford the crude
indoline intermediate.
1
and dried at 508C to afford 1.06 kg (76%) 5e. H NMR
(300 MHz, DMSO-d6) d 8.50 (d, 1H, J¼4.9 Hz), 7.78 (dt,
1H, J¼7.5, 1.9 Hz), 7.54–7.43 (m, 4H), 7.26 (dt, 1H, J¼4.9,
1.1 Hz), 7.12 (t, 1H, J¼7.6 Hz), 6.98 (t, 1H, J¼7.4 Hz), 6.44
(d, 1H, J¼3.0 Hz), 4.41–4.30 (m, 1H), 3.68 (s, 2H), 2.98 (d,
2H, J¼12.0 Hz), 2.32 (dt, 2H, J¼11.5, 2.5 Hz), 2.08–1.90
(m, 4H); 13C NMR (75 MHz, DMSO-d6) d 158.6, 148.7,
136.4, 135.3, 128.0, 124.9, 122.7, 122.1, 120.8, 120.4,
118.9, 109.7, 100.8, 63.6, 52.5, 32.0; IR (CHCl3) n 2952,
2808, 1591, 1571, 1476, 1461, 1451, 1434, 1369, 1342,
1309, 1252, 1146, 1126, 997, 991 cm21; MS (FD)
calculated for C19H21N3 291, found m/z (Mþ1) 292
(100%). Anal. calculated for C19H21N3 C, 78.32, H, 7.26,
N, 14.42, found C, 78.36, H, 7.19, N, 14.55.
4.2.5. 1-(1-Cyclopropylmethyl-piperidin-4-yl)-1H-indole
(5f). Synthesis via route 1. Quantities employed 10
(805 mg, 4.44 mmol), N-cyclopropylmethyl-3-pyrrolidi-
none 9f (750 mg, 4.89 mmol) and NaBH(OAc)3 (1.42 g,
6.70 mmol) in HOAc (4 mL). Following addition of
NaBH(OAc)3 the reaction was stirred at rt for 1.5 h and
1008C for 1 h. Work-up employed deionized water (22 mL),
EtOAc (6 mL), aqueous concentrated NaOH to pH 10–11,
and extraction with additional EtOAc. Purification using
50 g silica gel 60, 95:5 CH2Cl2/MeOH afforded 1.01 g
(89%) of 5f as a red oil. 1H NMR (CDCl3) d 0.15 (m, 2H),
0.57 (m, 2H), 0.94 (m, 1H), 2.15 (m, 6H), 2.35 (d, 2H,
J¼6.3 Hz), 3.27 (m, 2H), 4.25 (m, 1H), 6.53 (dd, 1H, J¼0.6,
2.7 Hz), 7.10 (dt, 1H, J¼0.9, 8.1 Hz), 7.20 (m, 1H), 7.26 (m,
1H), 7.40 (dd, 1H, J¼0.6, 7.8 Hz), 7.64 (td, 1H, J¼8.1 Hz);
A solution of the indoline in THF was stirred at 0–58C
under N2. A solution of DDQ (1.0 equiv.) in THF was
prepared and added dropwise to the reaction, keeping the
temperature below 108C. The dark, thick reaction was
allowed to warm to rt and stirred overnight (21 h).
Additional DDQ was added as needed in order to drive
the reaction to completion. After stirring 1 h, the reaction
mixture was diluted with an organic solvent and water.
Aqueous 5N NaOH was added dropwise to adjust the pH
to 10–11, keeping the reaction temperature below 258C.
The layers were separated and the aqueous layer extracted.
The combined organic layers were washed with
aqueous saturated NaCl solution and dried (MgSO4). The
drying agent was removed by filtration and rinsed.
The filtrate was concentrated in vacuo to afford crude

7222
M. M. Faul et al. / Tetrahedron 59 (2003) 7215–7229
product that was purified using the conditions specified for
each indole.
silica gel 60, CH2Cl2 to 95:5 CH2Cl2/MeOH afforded 0.35 g
(35%) 5f.
4.3.1. 1-(1-Methyl-piperidin-4-yl)-1H-indole (5b). Syn-
thesis via route 2. Indoline formation employed indoline 11
(2.50 mL, 22.3 mmol) in HOAc (13 mL), 1-methyl-4-
piperidone (3.00 mL, 24.4 mmol) and NaBH(OAc)3
(7.09 g, 33.5 mmol). Following addition of NaBH(OAc)3
the reaction was stirred at rt for 1 h. Work-up employed
deionized water (50 mL), EtOAc (10 mL) and aqueous
concentrated NaOH to pH 10–11. The filtrate was
concentrated in vacuo to afford 4.59 g (95%) crude indoline.
4.3.4. 4-Indol-1-yl-piperidine-1-carboxylic acid tert-
butyl ester (5g). Synthesis via route 2. Indoline formation
employed indoline 11 (11.9 g, 100 mmol), N-(tert-butox-
ycarbonyl)-4-piperidone 9g (29.9 g, 150 mmol) in HOAc
(150 mL) and NaBH(OAc)3 (31.8 g, 150 mmol). Following
addition of NaBH(OAc)3 the reaction was stirred at rt for
1 h. Work-up employed aqueous 5N NaOH (500 mL) to pH
8 and EtOAc (500 mL). After re-extraction with EtOAc the
filtrate was concentrated in vacuo to afford crude indoline
that was purified by silica gel chromatography (7:1 hexanes/
EtOAc) to afford 29.9 g (99%) of purified indoline.
Indole formation employed indoline intermediate (4.20 g,
19.4 mmol) in THF (40 mL) and DDQ (4.41 g, 19.4 mmol)
in THF (20 mL). Reaction was stirred at rt for 24 h.
Additional DDQ (1.32 g, 5.81 mmol) was required to drive
the reaction to completion. Work-up employed deionized
water (50 mL), EtOAc (50 mL), aqueous 5N NaOH to pH
10–11 and additional EtOAc. Purification using 100 g silica
gel 60, 95:5 CH2Cl2/MeOH!93:7 CH2Cl2/MeOH afforded
3.46 g (83%) of 5b.
Indole formation employed indoline intermediate (29.5 g,
97.4 mmol) in THF (300 mL) and DDQ (22.1 g, 97.4 mmol)
in THF (100 mL). Reaction was stirred at 0–58C for 45 min.
Work-up employed aqueous NaHCO3 (4£300 mL), EtOAc
(700 mL) and aqueous saturated NaCl (2£300 mL). Purifi-
cation using silica gel 60, 6:1 hexanes/EtOAc afforded
25.9 g (88%) 5g.
4.3.2. 1-(1-Pyridin-2-yl methyl-piperidin-4-yl)-1H-indole
(5e). Synthesis via route 2. Indoline formation employed
indoline 11 (1.50 g, 12.6 mmol), 9e (2.63 g, 13.8 mmol) in
HOAc (7.5 mL) and NaBH(OAc)3 (4.01 g, 18.9 mmol).
Following addition of NaBH(OAc)3 the reaction was
stirred at rt for 3 h. Work-up employed deionized water
(40 mL), EtOAc (20 mL), aqueous concentrated NaOH
to pH 10–11 and additional EtOAc (20 mL). The filtrate
was concentrated in vacuo to afford crude indoline that
was purified by silica gel chromatography (150 g silica 60,
88:12 EtOAc/MeOH) to afford 3.14 g (85%) of purified
indoline.
4.4. Route 3 via alkylation of 1-(4-piperidinyl)-1H-indole
(5a)
Indole 5a (1.0 equiv.) and powdered K2CO3 (1.2 equiv.)
were stirred as a slurry in DMF at rt under N2-blanket. The
alkylating agent (1.1 equiv.) was added in one portion. The
reaction was allowed to cool gradually to rt and stirred
overnight. The reaction mixture was partitioned between an
organic solvent and water. The layers were separated and
the aqueous layer was extracted with organic solvent. The
combined organic layers were washed with aqueous
saturated NaCl and dried (MgSO4). The drying agent was
removed by filtration and rinsed. The filtrate was concen-
trated in vacuo and the crude product was purified by silica
gel chromatography using the conditions specified for each
indole.
Indole formation employed indoline intermediate (1.50 g,
5.11 mmol) in THF (15 mL) and DDQ (1.28 g, 5.64 mmol)
in THF (7 mL). Reaction was stirred at 0–58C for 1 h.
Work-up employed aqueous NaHCO3 (30 mL), EtOAc
(30 mL), aqueous 5N NaOH to pH 10–11 and additional
EtOAc. Purification using 50 g silica gel 60, 95:5 EtOAc/
MeOH afforded 1.34 g (90%) of 5e.
4.4.1. 1-(1-Methyl-piperidin-4-yl)-1H-indole (5b). Syn-
thesis via route 3. Quantities employed indole 5a (1.93 g,
9.64 mmol), powdered K2CO3 (1.60 g, 11.6 mmol) in DMF
(14 mL) and dimethylsulfate (1.00 mL, 10.6 mmol). Work-
up employed deionized water (20 mL) and EtOAc (20 mL).
Purification using 50 g silica gel 60, 93:7 CH2Cl2/MeOH
afforded 1.00 g (49%) 5b, as an oil that crystallized upon
standing.
4.3.3. 1-(1-Cyclopropylmethyl-piperidin-4-yl)-1H-indole
(5f). Synthesis via route 2. Indoline formation employed
indoline 11 (0.79 g, 6.6 mmol), N-(cyclopropylmethyl)-4-
piperidone 9f (1.11 g, 7.24 mmol) in HOAc (5 mL) and
NaBH(OAc)3 (2.11 g, 9.96 mmol). Following addition of
NaBH(OAc)3 the reaction was stirred at rt for 1 h. Work-up
employed deionized water (20 mL), EtOAc (10 mL), aqueous
concentrated NaOH to pH 10–11 and additional EtOAc
(20 mL). Thefiltrate wasconcentratedinvacuo toaffordcrude
indoline. Purification using 50 g silica gel 60, 90:10 EtOAc/
MeOH) to afford 1.54 g (90%) of purified indoline.
4.4.2. 1-(1-Pyridin-2-yl methyl-piperidin-4-yl)-1H-indole
(5e). Synthesis via route 3. Quantities employed indole 5a
(0.78 g, 3.89 mmol), powdered K2CO3 (1.18 g, 8.54 mmol)
in DMF (5.5 mL) and 2-picolyl chloride monohydrochlor-
ide 20 (0.75 g, 4.3 mmol). Reaction was stirred at rt for 3 h
and 508C for 2 h. Work-up employed deionized water
(24 mL) and CH2Cl2 (25 mL). Purification using 50 g silica
gel 60, EtOAc to 95:5 EtOAc/MeOH afforded 1.10 g (97%)
5e.
Indole formation employed indoline intermediate (1.00 g,
3.90 mmol) in THF (10 mL) and DDQ (974 mg, 4.29 mmol)
in THF (5 mL). Reaction was stirred at rt for 24 h.
Additional DDQ added (385 mg, 1.70 mmol) and reaction
stirred for 1 h Work-up employed aqueous NaHCO3
(15 mL), EtOAc (15 mL), aqueous 5N NaOH to pH 10–
11 and additional EtOAc (10 mL). Purification using 150 g
4.4.3. 1-(1-Cyclopropylmethyl-piperidin-4-yl)-1H-indole
(5f). Synthesis via route 3. Quantities employed indole 5a
(3.4 g, 17 mmol), powdered K2CO3 (2.82 g, 20.4 mmol) in
DMF (20 mL) and (bromomethyl)cyclopropane (1.82 mL,

M. M. Faul et al. / Tetrahedron 59 (2003) 7215–7229
7223
18.8 mmol). The reaction was stirred at 608C for 1 h. Work-
up employed deionized water (50 mL) and Et2O (3£30 mL).
Purification using 189 g silica gel, 98:2 to 95:5 CH2Cl2/
MeOH afforded 3.75 g (86% yield) 5f as a yellow oil.
in one portion. The hydrochloride salt of 5b precipitated.
The very thick slurry was heated to 508C for 5–10 min to
then slowly cooled to 215 to 2108C, during which time the
slurry remained thin and stirred well. Oxalyl chloride
(3.10 mL, 35.5 mmol, 1.5 equiv.) was added dropwise,
keeping the reaction temperature below 258C for 1–2 h.
The slurry became very thick and was diluted with ACN
(50 mL) and allowed to warm to rt. After the reaction was
complete the mixture was cooled to 0–58C. MeOH (10 mL)
was added dropwise, keeping the reaction temperature
below 108C. The resulting violet solution was allowed to
warm to rt until the methanolysis reaction was complete,
then it was cooled to 5–108C. Aqueous 2N NaOH (60 mL)
was added dropwise to adjust the pH to 9.5–10, keeping the
reaction temperature below 258C. The layers were separated
and the aqueous layer was extracted with EtOAc. The
combined organic layers were washed with aqueous
saturated NaCl solution and dried (MgSO4). The drying
agent was removed by filtration and rinsed with EtOAc. The
filtrate was concentrated in vacuo and the crude product
purified using 200 g silica gel 60, 85:15:1 EtOAc/MeOH/
4.4.4. 1-Piperidin-4-yl-1H-indole (5a).6 Route 1 from 1-
[1-(phenylmethyl)-4-piperidinyl]-1H-indole (5c). Indole
5c (5.00 g, 17.2 mmol) was dissolved in MeOH (80 mL) and
added to a slurry of 10% Pd/C (0.4 g) in toluene (4 mL). The
mixture was hydrogenated (50 psi) for 20 h. The catalyst
was removed by filtration through hyflo and carefully rinsed
with MeOH. The filtrate was concentrated in vacuo to afford
1
3.40 g (98%) 5a. H NMR (CDCl3) d 1.60 (br s, 1H), 1.88
(dd, 1H, J¼4.2, 12.4 Hz), 1.97 (dd, 1H, J¼3.9, 12.0 Hz),
2.10 (m, 2H), 2.84 (dt, 2H, J¼2.4, 12.3 Hz), 3.27 (m, 2H),
4.35 (m, 1H), 6.53 (d, 1H, J¼0.6, 3.3 Hz), 7.10 (m, 1H),
7.20 (m, 1H), 7.24 (m, 1H), 7.40, (dd, 1H, J¼0.6, 8.1 Hz),
7.64 (td, 1H, J¼0.9, 8.1 Hz). 13C NMR (CDCl3) d 135.4,
128.6, 128.2, 124.0, 121.5, 121.2, 119.4, 109.3, 101.4, 53.7,
46.3, 33.8; IR (CHCl3) n 3008, 2953, 1602, 1510, 1477,
1461, 1319, 1309 cm21. HRMS (ESþ) m/z calculated for
C13H16N2 201.1391 (Mþ1), found 201.1393 (Mþ1).
1
c.NH4OH) to afford 5.81 g (83%) 4b as a solid. H NMR
(400 MHz, DMSO-d6) d 8.48 (s, 1H), 8.18 (app d, 1H), 7.74
(app d, 1H), 7.32 (m, 2H), 4.47 (m, 1H), 3.89 (s, 3H), 2.93
(app d, 2H), 2.24 (s, 3H), 2.17–1.93 (m, 6H); 13C NMR
(100 MHz, DMSO-d6) d 178.2, 163.6, 137.0, 136.2, 125.8,
123.6, 123.1, 121.2, 121.2, 111.6, 111.4, 54.2, 53.6, 52.6,
45.7, 31.6; IR (CHCl3) n 3019, 2949, 2851, 2792, 2739,
4.5. Route 2 from 1,1-dimethylethyl ester 4-(1H-indol-1-
yl)1-piperidinecarboxylic acid (5g)
Indole 5g (30 g, 100 mmol) was stirred at rt as a solution in
EtOAc (150 mL). Trifluoroacetic acid (38.5 mL, 500 mmol)
was added dropwise over 10–15 min during which time an
exotherm to 308C was observed. The dark solution was
heated to 608C for 12 h, then allowed to cool to rt overnight.
The solution was cooled to 108C and water (150 mL) added.
Aqueous 50% NaOH was added dropwise to adjust the pH
to 10–11 keeping the temperature below 308C. The aqueous
layer was extracted with EtOAc and the combined organic
layers dried (MgSO4). The drying agent was removed by
filtration, rinsed with EtOAc and the filtrate was concen-
trated to dryness to obtain 14 g (70%) 5a.
1728, 1640, 1517, 1462, 1380, 1280, 1183, 1141 cm21
.
Anal. calculated for C17H20N2O3: C, 67.98; H, 6.71; N,
9.33, found: C, 68.15, H, 6.72. N, 9.33. HRMS (ES) m/z
(Mþ1) calculated for C17H20N2O3 301.1552, found
301.1543.
4.7.2. [1-(1-Benzyl-piperidin-4-yl)-1H-indol-3-yl]-oxo-
acetic acid methyl ester (4c). A mixture of 5c (6.00 g,
20.7 mmol) in dry ACN (54 mL) was cooled to 08C.
5.72 M HCl in ACN (3.8 mL, 21.73 mmol, 1.05 equiv.)
was added and the reaction mixture stirred for 10 min at
0–108C and 1 h at rt. After cooling to 2108C, oxalyl
chloride (3.60 mL, 41.3 mmol. 2.00 equiv.) was added
dropwise at 210 to 08C over 15 min to obtain an orange
mixture. The mixture was stirred for 1 h at 08C. MeOH
(12 mL) was added and the resulting red solution was
stirred for 30 min at 08C, then partitioned between cold
water (100 mL) and EtOAc (80 mL). The pH was adjusted
to 7 with 5N NaOH (22 mL). The layers were separated
and the aqueous layer was extracted with EtOAc
(2£30 mL). The combined organic solution was washed
with aqueous saturated NaCl (100 mL), dried (Na2SO4)
and concentrated in vacuo to an oil. Purification using
180 g silica gel 60 (60:40 to 50:50 hexanes/EtOAc)
followed by trituration with hexanes (2 mL) afforded
4.6. Alternative procedure for the synthesis 1-(1-methyl-
piperidin-4-yl)-1H-indole (5d) via alkylation of indole
(25) with 1-benzyl-3-mesyloxy pyrrolidine (26)
NaH (300 mg, 7.63 mmol) was slurried in DMF (5 mL) and
cooled to 08C. Indole 25 (850 mg, 7.30 mmol) was added as
a solution in DMF (5 mL) and the reaction was allowed to
stir at rt for 1 h. The reaction was then cooled to 08C. 1-
Benzyl-3-mesyloxypyrrolidine 2622–24 (1.50 g, 5.87 mmol)
in DMF (5 mL) was added dropwise and the reaction heated
to 508C for 20 h. After cooling to rt the reaction was diluted
with EtOAc and washed with water (3£). The organic layer
was washed with aqueous saturated NaCl, dried (MgSO4)
and the solvent was removed in vacuo to give an oil that
was purified by silica gel chromatography (1:1:0.5
hexanes/CH2Cl2/EtOAc) to afford 1.30 g 5d (80%) as a
yellow oil.
1
7.33 g (94%) 4c. H NMR (CDCl3) d 2.15–2.25 (m, 6H),
3.11 (m, 2H), 3.61 (s, 2H), 3.95 (s, 3H), 4.30 (m, 1H),
7.26–7.45 (m, 8H), 8.46 (m, 1H), 8.51 (s, 1H); 13C NMR
(DMSO-d6) d 178.6, 164.0, 138.3, 137.2, 136.4, 128.7,
128.0, 127.8, 126.8, 125.9, 123.8, 123.3, 121.4, 111.8,
111.4, 61.8, 53.9, 52.5, 51.9, 31.6; IR (CHCl3) n 1729,
1643, 1517, 1462, 1281, 1267, 1192, 1142, 1062 cm21
.
MS (ES) m/z calculated for C23H24N2O3 376, found 377
(Mþ1). Anal. calculated for C23H24N2O3: C, 73.38; H,
6.42; 7.44, found: C, 73.09; H, 6.41; N, 7.36.
4.7. Synthesis of glyoxylyl esters
4.7.1. [1-(1-Methyl-piperidin-4-yl)-1H-indol-3-yl]-oxo-
acetic acid methyl ester (4b). To solution of 5b (5.00 g,
23.3 mmol) in ACN (50 mL) and MTBE (50 mL) at rt was
added 4 M HCl in dioxane (5.90 mL, 23.6 mmol, 1.0 equiv.)

7224
M. M. Faul et al. / Tetrahedron 59 (2003) 7215–7229
4.7.3. [1-(1-Benzyl-pyrrolidin-3-yl)-1H-indol-3-yl]-oxo-
acetic acid methyl ester (4d). Indole 5d (3.00 g,
10.9 mmol) was dissolved in Et2O (30 mL) and 1 M
solution of HCl, 1N in Et2O (10.9 mL, 10.9 mmol) added
dropwise, forming a slurry that was allowed to stir at rt for
1 h. The slurry was filtered and dried to afford 3.20 g (94%)
of the HCl salt as an off-white solid. The HCl salt (3.00 g,
9.60 mmol) was dissolved in CH2Cl2 (30 mL) and cooled to
08C. Oxalyl chloride (1.68 mL, 19.2 mmol) was added
dropwise, and the reaction allowed to come to rt and stirred
for 1.5 h. It was then cooled to 2608C. A 25% solution of
NaOMe in MeOH (11.0 mL, 48.0 mmol) was added
dropwise and after 1.5 h at 2608C the reaction warmed to
rt. Aqueous saturated NH4Cl and CH2Cl2 were added and
the layers separated. The combined organics were washed
with aqueous saturated NaCl and dried (MgSO4). The
solvent was removed in vacuo to give a yellow oil that was
purified through a silica gel filter pad (95:5 EtOAc/MeOH)
to afford 2.40 g 4d (69%). 1H NMR (300 MHz, DMSO-d6) d
8.65 (s, 1H), 8.18 (d, 1H, J¼7.0 Hz), 7.84 (d, 1H,
J¼7.3 Hz), 7.46–7.19 (m, 7H), 5.26 (bs, 1H), 3.92 (s,
3H), 3.89–3.64 (m, 2H), 3.31–2.99 (m, 2H), 2.76–2.71 (m,
1H), 2.60–2.50 (m, 1H), 2.43–2.34 (m, 1H), 2.04–1.93 (m,
1H); 13C NMR (75 MHz, CDCl3) d 137.8, 136.2, 128.5,
128.4, 127.2, 123.8, 123.4, 122.8, 110.3, 59.7, 59.5, 55.5,
53.0, 52.7, 35.6, 32.5; IR (CHCl3) n 2961, 2802, 1728, 1642,
1518, 1275, 1262, 1142, 1096, 1076, 1040, 1027, 1016,
809 cm21. HRMS (ESþ) calculated for C22H23N2O3
363.1708, found m/z (Mþ1) 363.1701 (100%).
1192, 1142, 1062 cm21
C22H23N3O3 377, found m/z (Mþ1) 378 (100%). Anal.
calculated for C22H23N3O3 C, 70.01, H, 6.14, N, 11.13,
found C, 69.71; H, 6.22; N, 11.21.
.
MS (FD) calculated for
4.7.5. Methyl N-(1-(cyclopropylmethyl)-4-piperidinylin-
dolyl)-3-glyoxylate (4f).
A solution of 5f (3.37 g,
13.3 mmol) in dry ACN (35 mL) was cooled to 08C and
treated with 3.42 M HCl in ACN (4.07 mL, 13.9 mmol,
1.05 equiv.). The solution was stirred for 10 min at 08C and
1 h at rt. Upon cooling to 2108C, oxalyl chloride (2.30 mL,
26.4 mmol, 2.00 equiv.) was added dropwise over 10 min at
08C. The resulting orange solution was stirred for 1 h at 08C,
then MeOH (7.7 mL) added. After 0.5 h the solution was
poured into water (60 mL) and the pH adjusted to 8 with 5N
NaOH (17 mL). The mixture was extracted with EtOAc
(4£30 mL). The combined organic layers were washed with
aqueous saturated NaCl (50 mL), dried (Na2SO4), filtered
and concentrated in vacuo to an oil. Purification using 190 g
silica gel 60 (98:2 to 95:5 CH2Cl2/MeOH) afforded 4.18 g
1
(92%) 4f. H NMR (CDCl3) d 0.15 (m, 2H), 0.57 (m, 2H),
0.92 (m, 1H), 2.22 (m, 6H), 2.35 (d, 2H, J¼6.9 Hz), 3.30 (m,
2H), 3.94 (s, 3H), 4.30 (m, 1H), 7.35 (m, 2H), 7.40 (m, 1H),
8.46 (m, 1H), 8.52 (s, 1H); 13C NMR (DMSO-d6) d 178.6,
164.0, 137.3, 136.4, 125.9, 123.8, 123.2, 121.4, 111.8,
111.4, 62.5, 54.0, 52.5, 52.0, 31.6, 8.4, 3.7; IR (CHCl3) n
1729, 1642, 1517, 1462, 1276, 1192, 1141 cm21. MS
calculated for C20H24N2O3 340, found (ES) m/z 340.20.
Anal. calculated for C20H24N2O3: C, 70.56; H, 7.10; N,
8.22, found C, 70.66; H, 7.09; N, 8.30.
4.7.4. Oxo-[1-(1-pyridin-2-ylmethyl-piperidin-4-yl)-1H-
indol-3-yl]-acetic acid methyl ester (4e). Anhydrous HCl
(130 g, 3.57 mol, 1.0 equiv.) was bubbled into a mixture of
5e (1.05 kg, 3.60 mol, 1.0 equiv.) in ACN (9.3 L) at 0–
208C. The mixture was stirred for 30 min, then cooled to
210 to 08C. Oxalyl chloride (914 g, 7.20 mol, 2.0 equiv.)
was added dropwise to the reaction mixture at 210 to 08C.
The reaction was stirred at 210 to 08C for 2 h. MeOH
(2.1 L) was added dropwise at 210 to 08C and the reaction
stirred at that temperature for 1 h. The reaction mixture was
slowly added to a mixture of cold (0–108C) aqueous 5 wt%
NaHCO3 solution (20 L) and cold EtOAc (13 L). The pH of
the mixture was adjusted to 7–8 with aqueous 2N NaOH
(2 L). The layers were separated and the aqueous layer
extracted with EtOAc (10 L). The combined organic layers
were washed with dilute aqueous NaCl solution (10 L) and
concentrated in vacuo. The concentrate was dissolved in
EtOAc (7 L) and treated with 4e seed crystals (0.5 g). After
stirring 30–60 min to allow significant crystallization,
heptane (10 L) was added dropwise over 60–90 min. The
mixture was concentrated in vacuo to remove 5 L of solvent.
The product slurry was stirred at 0–108C for 1–2 h, filtered
and rinsed with heptane (2£2.5 L), then dried in a vacuum
4.7.6. 4-(3-Methoxyoxalyl-indol-1-yl)-piperidine-1-car-
boxylic acid tert-butyl ester (4g). Oxalyl chloride
(1.53 mL, 1.76 mmol, 1.06 equiv.) was added dropwise to
a solution of 5g (500 mg, 1.66 mmol) in Et2O (22 mL) at
08C. The reaction was stirred for 90 min at 08C then cooled
to 2708C. MeOH (0.169 mL, 4.16 mmol) was added and
the resulting yellow slurry allowed to warm to rt. After
stirring at rt for 3 h the mixture was concentrated in vacuo
and the residue dissolved in CH2Cl2 (25 mL). The organic
layer was washed with aqueous saturated NaHCO3 (25 mL),
aqueous saturated NaCl, dried (MgSO4), filtered, and
concentrated in vacuo. Purification by silica gel chroma-
tography (2:1 hexanes/EtOAc) afforded 430 mg (67%) 4g.
1H NMR (300 MHz, DMSO-d6) d 8.52 (s, 1H), 8.20 (d, 1H,
J¼7.3 Hz), 7.79 (d, 1H, J¼7.3 Hz), 7.41–7.26 (m, 2H),
4.79–4.63 (m, 1H), 4.16 (bd, 2H, J¼11.0 Hz), 3.90 (s, 3H),
3.13–2.81 (m, 2H), 2.09–1.80 (m, 4H), 1.40 (s, 9H); 13C
NMR (75 MHz, DMSO-d6) d 178.8, 164.0, 153.7, 137.3,
136.4, 125.8, 123.8, 123.4, 121.4, 111.4, 78.9, 53.5, 52.5,
31.5, 28.1; IR (CHCl3) n 3030, 2981, 2955, 2935, 2863,
1728, 1687, 1644 cm21. MS (ESþ) m/z calculated for
C21H26N2O5 386.2, found 386.2 (Mþ). Anal. calculated for
C21H26N2O5 C, 65.3; H, 6.78; N, 7.25, found: C, 65.0; H,
6.81; N, 7.21.
1
oven at 50–608C to yield 1.176 kg (86.5%) 4e. H NMR
(300 MHz, DMSO-d6) d 8.52 (s, 1H), 8.50 (dd, 1H, J¼4.8,
1.6 Hz), 8.17 (dd, 1H, J¼5.9, 1.7 Hz), 7.80–7.74 (m, 2H),
7.49 (d, 1H, J¼7.7 Hz), 7.36–7.24 (m, 3H), 4.57–4.50 (m,
1H), 3.89 (s, 3H), 3.67 (s, 2H), 2.98 (bd, 2H, J¼11.8 Hz),
2.33 (bt, 2H, J¼9.1 Hz), 2.11–1.97 (m, 4H); 13C NMR
(75 MHz, DMSO-d6) d 178.6, 164.0, 158.5, 148.7, 137.2,
136.4, 125.9, 124.8, 123.8, 123.3, 122.7, 122.1, 121.3,
111.8, 111.4, 63.4, 53.7, 52.5, 52.1, 31.6; IR (CHCl3) n
2954, 1728, 1642, 1517, 1462, 1436, 1280, 1268, 1255,
4.8. Indole-3-acetamide synthesis
4.8.1. 2-(2,3-Dihydro-1H-indol-3-yl)-acetamide (12).
Indole-3-acetamide 2 (45.0 g, 0.258 mol) was dissolved in
MeOH (225 mL) and cooled to 0–58C. 12N HCl (123 mL,
1.48 mol, 5.7 equiv.) was added dropwise, keeping the
reaction temperature below 258C. The reaction was cooled

M. M. Faul et al. / Tetrahedron 59 (2003) 7215–7229
7225
to 0–108C. Borane–pyridine complex (88.6 mL, 0.877 mol,
3.4 equiv.) was added dropwise, keeping the reaction
temperature below 258C. The reaction was stirred for 1 h at
rt, then cooled to 08C. Water (450 mL) was slowly added
keeping the temperature ,258C. 50% NaOH (97 mL,
1.85 mol, 7.2 equiv.) was added dropwise to adjust the pH to
8. The product was extracted into EtOAc (3£225 mL) and
washed with aqueous saturated NaHCO3 (225 mL) and
aqueous saturated NaCl (225 mL). The organic layer was
dried (MgSO4) filtered and concentrated in vacuo. Purification
by silica gel chromatography (95:5 to 90:10 EtOAc/MeOH)
afforded 26.5 g (58%) racemic 12. 1H NMR (300 MHz,
DMSO-d6) d 7.34 (bs, 1H), 7.01 (d, 1H, J¼6.95 Hz), 6.90
(app. t, 1H, J¼7.5 Hz), 6.83 (bs, 1H), 6.54–6.47 (m, 2H), 5.39
(s, 1H), 3.57–3.45(m, 2H),3.12–3.03(m, 1H),2.52–2.45(m,
1H), 2.28–2.20 (m, 1H); 13C NMR (75 MHz, DMSO-d6) d
172.9, 152.0, 131.7, 127.2, 123.6, 116.7, 108.4, 52.4, 40.0,
38.1; IR (CHCl3) n 3529, 3410, 3010, 2857, 1681, 1609, 1592,
1488, 1465 cm21. HRMS (ES) m/z calculated for C10H12N2O
176.0950, found 176.0950.
A solution of the crude indoline intermediate in THF was
stirred at 0–58C under N2. A solution of DDQ (1.0 equiv.)
in THF was prepared and added dropwise to the reaction
keeping the reaction temperature below 108C. The dark,
thick reaction was allowed to warm to rt and stirred
overnight (21 h). Upon completion aqueous 5N NaOH was
added dropwise to adjust the pH to 10–11 keeping the
reaction temperature below 258C. The layers were separated
and the aqueous layer extracted. The combined organic
layers were washed with aqueous saturated NaCl and dried
(MgSO4). The drying agent was removed by filtration and
the filtrate concentrated in vacuo to afford crude product that
was purified using the conditions specified for each indole.
4.9.1. 2-[1-(1-Methyl-piperidin-4-yl)-1H-indol-3-yl]-
acetamide (8b). Synthesis via route 1. Indoline formation
employed indoline 12 (2.00 g, 11.3 mmol) in HOAc
(10 mL) 1-methyl-4-piperidone (1.55 mL, 12.6 mmol) and
powered NaBH(OAc)3 (3.59 g, 16.9 mmol). Work-up
employed deionized water (50 mL) and EtOAc (20 mL).
Yield of crude indoline was 2.29 g (74%).
4.8.2. 2-(1-Piperidin-4-yl-1H-indol-3-yl)-acetamide (8a).
Compound 8g (1.38 g, 3.86 mmol) was stirred at rt as a
slurry in EtOAc (28 mL). 4 M HCl in dioxane (19 mL,
76 mmol, 20 equiv.) was added dropwise over 5 min. The
resulting dark purple slurry was stirred at rt overnight. The
mixture was cooled to 10–158C and deionized water
(15 mL) added. The pH of the biphasic solution was
adjusted to 10–11 with aqueous 50% NaOH. The product
was extracted with EtOAc (3£), adding solid NaCl to the
aqueous layer to help the extraction process. The combined
organic layers were dried (MgSO4), filtered and rinsed with
EtOAc. The filtrate was concentrated in vacuo to obtain
410 mg (41%) 8a as a solid (note: suspect yield loss to
Indole-3-acetamide formation employed indoline inter-
mediate (2.0 g, 7.32 mmol) in THF (20 mL) and DDQ
(1.68 g, 7.4 mmol) in THF (20 mL). Work-up employed
aqueous 5N NaOH until pH 10–1 and EtOAc. Overall yield
1
(obtained in two crops) 0.46 g (24%). H NMR (400 MHz,
DMSO-d6) d 7.54 (d, 1H, J¼7.91 Hz), 7.45 (d, 1H,
J¼8.35 Hz), 7.29 (app bs, 2H), 7.09 (t, 1H, J¼7.03 Hz),
6.98 (t, 1H, J¼7.03 Hz), 6.81 (bs, 1H), 4.26 (m, 1H), 3.45 (s,
2H), 2.89 (app bd, 2H), 2.23 (s, 3H), 2.13 (m, 2H), 1.99–
1.83 (m, 4H); 13C NMR (100 MHz, DMSO-d6) d 172.3,
135.2, 127.4, 123.2, 120.7, 118.9, 118.3, 109.5, 108.7, 54.6,
52.1, 45.8, 39.6, 39.5, 32.5, 32.0. HRMS (ES) m/z calculated
for C16H21N3O 272.1763 (Mþ1), found 272.1753.
1
aqueous layer). H NMR (400 MHz, DMSO-d6) d 7.53 (d,
1H, J¼7.91 Hz), 7.47 (d, 1H, J¼8.35 Hz), 7.31 (bs, 1H),
7.27 (s, 1H), 7.09 (app. t, 1H, J¼7.91 Hz), 6.98 (app. t, 1H,
J¼7.03 Hz), 6.82 (bs, 1H), 4.34 (m, 1H), 3.46 (s, 2H), 3.05
(m, 3H), 2.67 (m, 2H), 1.86 (m, 2H), 1.82–1.69 (m, 2H);
13C NMR (100 MHz, DMSO-d6) d 172.4, 135.0, 127.3,
123.2, 120.6, 118.9, 118.2, 109.5, 108.6, 53.0, 45.6, 33.6,
32.5; IR (KBr) n 3304, 3104, 2944, 2914, 2824, 2737, 1687,
1464 cm21. HRMS (ES) m/z calculated for C15H19N3O
258.1606 (Mþ1), found 258.1602.
4.9.2. 2-[1-(1-Pyridin-2-ylmethyl-piperidin-4-yl)-1H-
indol-3-yl]-acetamide (8e). Synthesis via route 1. Indoline
formation employed 12 (2.00 g, 11.3 mmol), 1-pyridin-2-yl
methyl-piperidin-4-one 9e (2.38 g, 12.5 mmol) in HOAc
(10 mL), and powdered NaBH(OAc)3 (3.59 g, 16.9 mmol).
After stirring for 3–4 h at rt, the reaction was diluted with
deionized water (50 mL), EtOAc (50 mL) and MeOH
(5 mL). Purification by silica gel chromatography (90:10:1
EtOAc/MeOH/c.NH4OH), followed by reslurry of the
product in 9:1 EtOAc/MeOH (10 vol.) afford 3.00 g (75%)
of the indoline intermediate.
4.9. General methods for the synthesis of N-
(azacycloalkyl) indole-3-acetamides (8). Route 1 via
reductive amination/oxidation of 2-(2,3-dihydro-1H-
indol-3-yl)-acetamide (12) and 1-alkyl-4-piperidones
Indole-3-acetamide formation employed indoline inter-
mediate (3.00 g, 8.56 mmol) in THF (45 mL) and DDQ
(2.04 g, 8.98 mmol) in THF (15 mL). Work-up employed
deionized water (75 mL), followed by aqueous 5% NaHCO3
solution (75 mL) but the product did not precipitate. The
mixture was partially concentrated in vacuo to remove the
organic solvent. MTBE (50 mL) was added and the biphasic
mixture stirred at 508C for 10–15 min to precipitate the
product. The slurry was cooled to rt, filtered, rinsed with
water and MTBE to isolate the solid. The solid was
reslurried in 5:1 EtOAc/MeOH at 508C for 10–15 min,
cooled to rt, filtered, rinsed with 5:1 EtOAc/MeOH and
dried to afford 1.96 g (66%) 8e. 1H NMR (300 MHz,
DMSO-d6) d 8.51 (app. d, 1H), 7.79 (app. t, 1H,
J¼7.69 Hz), 7.59–7.41 (m, 3H), 7.38–7.20 (m, 3H), 7.13
2-(2,3-Dihydro-1H-indol-3-yl)-acetamide 12 (1.0 equiv.) in
HOAc was stirred at rt for 20–30 min to obtain a solution,
then 1-alkyl-4-piperidone (1.1 equiv.) was added in one
portion. After cooling to rt, powdered NaBH(OAc)3
(1.5 equiv.) was added in portions over 10–15 min, keeping
the reaction temperature below 308C. After stirring for 1–
2 h at rt, the reaction was diluted with deionized water and
an organic solvent. Aqueous concentrated NaOH was added
dropwise to adjust the pH to 10–11 keeping the reaction
temperature below 358C. The precipitated product was
isolated by filtration and rinsed with water and an organic
solvent. The solid was dried in a vacuum oven at 508C to
afford the intermediate indoline.

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M. M. Faul et al. / Tetrahedron 59 (2003) 7215–7229
(t, 1H, J¼7.32 Hz), 7.01 (t, 1H, J¼7.32 Hz), 6.84 (bs, 1H),
4.32 (m, 1H), 3.70 (s, 2H), 3.48 (s, 2H), 2.98 (app. d, 2H),
2.33 (m, 2H), 2.07–1.88 (m, 4H); 13C NMR (75 MHz,
DMSO-d6) d 172.7, 158.6, 148.7, 136.4, 135.5, 127.6,
123.4, 122.7, 122.1, 120.9, 119.0, 118.5, 109.6, 108.9, 63.5,
52.5, 52.3, 32.4; IR (KBr) n 3377, 3159, 3111, 2945, 2794,
2758, 1676, 1585, 1463, 1385, 1362, 1342 cm21. HRMS
(ES) m/z calculated for C21H24N4O 349.2028 (Mþ1), found
349.2022.
Indole formation employed indoline intermediate (82.3 g,
0.229 mol) in THF (590 mL) and DDQ (52.0 g, 0.229 mol)
in THF (145 mL). Work-up employed EtOAc and saturated
aqueous NaHCO3 solution. The product precipitated in the
separatory funnel, causing bad emulsions and the solids
were then filtered. The first crop of product was rinsed with
EtOAc and water and dried to afford 36.3 g (44%) 8g The
filtrate was re-extracted to afford a second crop of product.
Overall yield 69.6 g (85%) 8g. 1H NMR (300 MHz, DMSO-
d6) d 7.55 (d, 1H, J¼7.69 Hz), 7.50 (d, 1H, J¼8.42 Hz),
7.31 (s, 1H), 7.27 (bs, 1H), 7.12 (app. t, 1H, J¼7.0 Hz), 7.01
(app. t, 1H, J¼8.1 Hz), 6.82 (bs, 1H), 4.53–4.51 (m, 1H),
4.13–4.09 (bm, 2H), 3.46 (app. s, 2H), 2.99–2.92 (bm, 2H),
1.94–1.91 (bm, 2H), 1.84–1.74 (m, 2H), 1.43 (s, 9H); 13C
NMR (75 MHz, DMSO-d6) d 172.6, 153.8, 135.4, 127.6,
123.4, 120.9, 119.1, 118.5, 109.6, 109.0, 78.7, 59.7, 52.0,
42.8, 32.4, 32.0, 28.3, 28.1, 20.7, 14.0; IR (CHCl3) n 3515,
3400, 1681, 1575, 1463, 1427 cm21. HRMS (ES) m/z
calculated for C20H27N3O3 357.2054, found 357.2052.
4.9.3. 2-[1-(1-Cyclopropylmethyl-piperidin-4-yl)-1H-
indol-3-yl]-acetamide (8f). Synthesis via route 1. Indoline
formation employed 12 (1.18 g, 6.70 mmol), 1-cyclopro-
pylmethyl-piperidin-4-one 9f (1.13 g, 7.38 mmol) in HOAc
(5 mL) and powdered NaBH(OAc)3 (2.13 g, 10.1 mmol).
Reaction was stirred at rt for 1 h. Work-up involved
deionized water (20 mL) and EtOAc (10 mL). The filtrate
was concentrated in vacuo to afford the crude indoline
intermediate as a solid that was triturated with MTBE
(53 mL) and dried to afford 1.68 g (81%) of purified
indoline intermediate.
4.10. Route 2 via alkylation of 2-(1-piperidin-4-yl-1H-
indol-3-yl)-acetamide (8a)
Indole-3-acetamide formation employed indoline inter-
mediate (1.00 g, 3.19 mmol) in THF (10 mL) and a solution
of DDQ (797 mg, 3.51 mmol) in THF (5 mL). Purification
using 100 g silica gel 60 (80:20:1 EtOAc/MeOH/c.NH4OH)
afforded 620 mg (62%) of 8f. 1H NMR (400 MHz, DMSO-
d6) d 7.47 (d, 1H, J¼7.47 Hz), 7.40 (d, 1H, J¼8.35 Hz),
7.20 (app. bs, 2H), 7.04 (d, 1H, J¼7.47 Hz), 6.93 (d, 1H,
J¼7.47 Hz), 6.76 (bs, 1H), 4.22 (m, 1H), 3.40 (s, 2H), 3.05
(m, 2H), 2.22–2.07 (m, 4H), 1.95–1.83 (m, 4H), 0.81 (m,
1H), 0.42 (m, 2H), 0.05 (m, 2H); 13C NMR (100 MHz,
DMSO-d6) d 172.3, 135.2, 127.4, 123.2, 120.7, 118.9,
118.3, 109.5, 108.6, 62.7, 52.6, 52.4, 39.6, 39.6, 39.4, 32.5,
32.1, 8.6, 3.9; IR (KBr) n 3301, 3129, 2925, 2782, 1670,
1611, 1464, 1408, 1286, 1227 cm21. HRMS (ES) m/z
calculated for C19H25N3O 312.2076 (Mþ1), found
312.2066.
(1-Piperidin-4-yl-1H-indol-3-yl)-acetamide 8a (1 equiv.)
and powdered K2CO3 (1.2 equiv.), were stirred as a slurry
in DMF at 0–58C under N2-blanket. The alkylating agent
(1.2 equiv.) was added in one portion. The cooling bath was
removed and the reaction was allowed to stir at rt until
complete. The reaction was quenched with deionized water
and after stirring for 2 h, the product was isolated using the
conditions specified.
4.10.1. 2-[1-(1-Methyl-piperidin-4-yl)-1H-indol-3-yl]-
acetamide (8b). Synthesis via route 2. Quantities
employed (1-piperidin-4-yl-1H-indol-3-yl)-acetamide 8a
(257 mg, 1.0 mmol), powdered K2CO3 (166 mg,
1.20 mmol) in DMF (4 mL) and iodomethane (0.075 mL,
1.20 mmol) was added in one portion and the reaction
stirred for 3 h. Additional iodomethane (0.02 mL,
0.32 mmol) was added and the reaction stirred at rt for 2 h
until complete. Work-up employed deionized water (4 mL).
The product was isolated by filtration, rinsed with minimal
2:1 water/DMF and dried to afford 150 mg (55%) 8b.
4.9.4. 4-(3-Carbamoylmethyl-indol-1-yl)-piperidine-1-
carboxylic acid tert-butyl ester (8g). Synthesis via route
1. Indoline formation employed 2-(2,3-dihydro-1H-indol-3-
yl)-acetamide 12 (45.0 g, 0.255 mol), 1-(tert-butoxycarbo-
nyl)-4-piperidone (55.9 g, 0.281 mol) in HOAc (360 mL)
and powdered NaBH(OAc)3 (81.1 g, 0.383 mol) in HOAc
(45 mL, 0.79 mol). Work-up employed deionized water
(1 L), followed by aqueous concentrated NaOH (371 mL,
7.09 mol). The product oiled out of solution and was
dissolved with EtOAc (500 mL) and MeOH (100 mL).
Additional concentrated NaOH (35 mL, 0.67 mol) was
added to adjust the pH to 10. The product precipitated
from solution. The thick slurry was stirred for 1 h at rt,
then filtered and rinsed with water and EtOAc (minimal).
The white solid was dried overnight to afford 67.3 g
(73%) of the indoline intermediate. The filtrate was re-
extracted with EtOAc and water and concentrated in
vacuo to a solid (34 g), that was triturated with MTBE
(150 mL), filtered and dried to afford an additional 15.4 g
(17%) indoline intermediate. A third crop of 5.9 g (6%)
was isolated from the MTBE filtrate by concentrating to
dryness, adding cold MTBE (minimal), filtering and
rinsing with cold MTBE. The total yield was 88.6 g
(96%) of indoline intermediate.
4.10.2. 2-[1-(1-Pyridin-2-ylmethyl-piperidin-4-yl)-1H-
indol-3-yl]-acetamide (8e). Synthesis via route 2. Quan-
tities employed piperidin-4-yl-1H-indol-3-yl-acetamide 8a
(225 mg, 0.874 mmol), powdered K2CO3 (266 mg,
1.92 mmol, 2.2 equiv.) in DMF (3.4 mL) and 2-picolyl
chloride monohydrochloride 20 (160 mg, 0.975 mmol). The
reaction was stirred at rt overnight, then at 508C for 1 h.
Work-up employed deionized water (5 mL). After stirring
1–2 h the product was isolated by filtration, rinsed with
water and dried to afford 250 mg (82%) 8e.
4.10.3. 2-[1-(1-Cyclopropylmethyl-piperidin-4-yl)-1H-
indol-3-yl]-acetamide (8f). Synthesis via route 2. Quan-
tities employed piperidin-4-yl-1H-indol-3-yl-acetamide 8a
(210 mg, 0.816 mmol), powdered K2CO3 (135 mg,
0.977 mmol) in DMF (3.2 mL) and (bromomethyl)cyclo-
propane (0.090 mL, 0.928 mmol). Upon heating to 508C for
3 h the reaction was incomplete and additional (bromo-
methyl)cyclopropane (0.115 mL, 1.19 mmol) was added.

M. M. Faul et al. / Tetrahedron 59 (2003) 7215–7229
7227
The reaction slurry was stirred at rt overnight. And
quenched with deionized water (3.5 mL). After stirring 1 h
the product was isolated by filtration, rinsed with minimal
2:1 water/DMF and dried to afford 174 mg (69%) 8f.
thesis via strategy A. Quantities employed 4c (4.00 g,
10.6 mmol), 7 (2.00 g, 10.6 mmol) in dry THF (15 mL) and
tert-KOBu (23.4 mL, 23.4 mmol). Yield after filtration
1
4.00 g (73%) 1c as a red/orange solid. H NMR (DMSO-
d6) d 1.84 (m, 3H), 2.17 (m, 2H), 2.48 (m, 1H), 2.87 (d, 2H,
J¼11.4 Hz), 3.32 (s, 2H), 3.84 (s, 3H), 4.40 (m, 1H), 6.57
(m, 2H), 6.76 (t, 1H, J¼7.2 Hz), 7.03 (m, 3H), 7.30 (m, 5H),
7.41 (d, 1H, J¼8.4 Hz), 7.54 (d, 1H, J¼8.7 Hz), 7.64 (s,
1H), 7.86 (s, 1H), 10.93 (s, 1H); 13C NMR (DMSO-d6) d
172.9, 172.8, 138.3, 136.6, 135.4, 133.4, 128.7, 128.1,
128.0, 126.8, 126.6, 126.1, 125.1, 121.6, 121.4, 121.3,
119.6, 119.5, 110.1, 110.0, 105.4, 104.5, 61.8, 52.9, 52.0,
32.8, 31.7. IR (KBr) n 3133, 3108, 3051, 3024, 2940, 2661,
1726, 1702, 1625, 1606, 1531, 1452, 1373, 1327, 1241,
1212 cm21. HRMS (ES) m/z (Mþ1) calculated for
C33H30N4O2 515.2447, found 515.2455.
4.10.4. 2-[1-(1-Benzyl-pyrrolidin-3-yl)-1H-indol-3-yl]a-
cetamide (8d). NaH (7.80 g, 196 mmol) was slurried in
DMF (100 mL) and cooled to 08C. Indole-3-acetamide 2
(22.7 g, 131 mmol) was added as a solution in DMF (100 mL)
and the reaction was allowed to stir at rt for 1 h. The reaction
was cooled back to 08C. 1-Benzyl-3-mesyloxy pyrrolidine 26
(50.0 g, 196 mmol) in DMF (100 mL) was added and the
reaction was heated to 508C for 20 h. After cooling to rt, the
reaction was diluted with EtOAc and washed with water (3£).
The organic layer was washed with aqueous saturated NaCl,
dried (MgSO4) and the solvent was removed in vacuo to give
an oil. Purification by silica gel chromatography (1:1 hexanes/
acetone) afforded 37.6 g (86%) 8d as a yellow oil. 1H NMR
(300 MHz, DMSO-d6) d 7.56 (d, 2H, J¼7.9 Hz), 7.42–7.22
(m, 7H), 7.10 (t, 1H, J¼7.1 Hz), 7.00 (t, 1H, J¼7.9 Hz), 6.86
(bs, 1H), 5.08–5.05 (m, 1H), 3.66 (q, 2H, J¼13.2 Hz), 3.49 (s,
2H), 2.99–2.94 (m, 1H), 2.79–2.76 (m, 2H), 2.51–2.40 (m,
1H), 1.97–1.90 (m, 1H); 13C NMR (75 MHz, DMSO-d6) d
172.6, 138.8, 135.5, 128.4, 128.2, 127.7, 126.8, 124.9, 124.4,
120.9, 118.9, 118.4, 109.8, 109.0, 59.4, 59.1, 53.6, 52.8, 32.4,
31.7; IR (CHCl3) n 3516, 3401, 2799, 1675, 1575, 1463, 1454,
1366, 1350 cm21. MS (FD) calculated for C21H23N3O 333,
found m/z (Mþ1) 334 (100%). Anal. calculated for
C21H23N3O C, 75.65, H, 6.95, N, 12.60, found C, 75.64, H,
6.92, N, 12.84.
4.11.3. 3-(1-Methyl-1H-indol-3-yl)-4-[1-[1-benzyl-4-pyr-
rolidinyl]-1H-indol-3-yl]-1H-pyrrole-2,5-dione (1d).
Synthesis via strategy A. Quantities employed 4d
(4.20 g, 11.6 mmol), 3 (2.18 g, 11.6 mmol) in THF
(50 mL) and tert-KOBu (57.9 mL, 57.9 mmol). Purifi-
cation after work-up by silica gel chromatography (4:1
CH2Cl2/EtOAc) afforded 4.09 g 1d (71%) as a bright red
1
solid. H NMR (300 MHz, DMSO-d6) d 10.94 (s, 1H),
7.91 (d, 1H, J¼5.3 Hz), 7.81 (d, 1H, J¼4.9 Hz), 7.60 (dt,
1H, J¼7.9, 4.9 Hz), 7.32–7.23 (m, 4H), 7.14–7.02 (m,
4H), 6.86–6.81 (m, 1H), 6.66–6.56 (m, 2H), 5.09 (bs,
1H), 3.80 (s, 3H), 3.43–3.33 (m, 2H), 2.75–2.38 (m,
4H), 2.19–2.14 (m, 1H), 1.79–1.72 (m, 1H); 13C NMR
(75 MHz, DMSO-d6) d 172.8, 138.8, 136.7, 135.5, 133.3,
129.4, 128.1, 128.1, 127.5, 126.9, 126.7, 125.9, 124.9,
124.8, 121.6, 121.3, 119.6, 119.4, 110.2, 110.0, 105.5,
104.4, 59.4, 58.7, 53.7, 52.2, 32.8, 32.1, 14.0; IR (CHCl3)
n 1762, 1715, 1532, 1463, 1374, 1359, 1336, 1310, 1245,
1230 cm21. MS (FD) calculated for C32H28N4O2 500,
found m/z (Mþ1) 501 (100%). Anal. calculated for
C32H28N4O2 C, 76.78, H, 5.64, N, 11.19, found C, 76.58,
H, 5.82, N, 10.96.
4.11. General method for the synthesis of
bisindolylmaleimides
A slurry of the indolyl-3-glyoxylate (1.1 equiv.) and indole-
3-acetamide (1.0 equiv.) in THF were stirred under a N2-
blanket and cooled to 2158C. tert-KOBu (1.0 M solution in
THF, 2.2 equiv.) was added dropwise, keeping the reaction
temperature below 258C. The cooling bath was removed
and the reaction allowed to warm to rt, then heated to 458C
for 1–2 h until complete. The reaction solution was cooled
to rt overnight, then partitioned between EtOAc and
aqueous 5% NaHCO3 solution. The product crystallized
from the biphasic mixture. It was filtered and rinsed and
dried to yield the desired product.
4.11.4. 3-(1-Methyl-1H-indol-3-yl)-4-[1-[1-(2-pyridinyl-
methyl)-4-piperidinyl]-1H-indol-3-yl]-1H-Pyrrole-2,5-
dione (1e). Synthesis via strategy A. Quantities employed
4e (779 mg, 2.06 mmol), 3 (377 mg, 2.00 mmol) in THF
(5.7 mL) and tert-KOBu (14.4 mL, 4.4 mmol). After work-
up the product precipitated and was filtered and rinsed with
cold 3:1 water/THF to afford 772 mg (75%) 1e as an orange
solid. 1H NMR (300 MHz, DMSO-d6) d 10.94 (s, 1H), 8.49
(d, 1H, J¼4.0 Hz), 7.87 (s, 1H), 7.77 (dt, 1H, J¼7.6,
1.8 Hz), 7.66 (s, 1H), 7.56 (d, 1H, J¼8.5 Hz), 7.44 (t, 2H,
J¼7.6 Hz), 7.26 (t, 1H, J¼7.3 Hz), 7.15–7.00 (m, 3H), 6.77
(t, 1H, J¼7.5 Hz), 6.64–6.54 (m, 2H), 4.48–4.35 (m, 1H),
3.86 (s, 3H), 3.65 (s, 2H), 2.89 (bd, 2H, J¼12.0 Hz), 2.29
(bt, 2H, J¼8.2 Hz), 1.98–1.76 (m, 4H); 13C NMR (75 MHz,
DMSO-d6) d 172.8, 172.8, 158.5, 148.7, 136.6, 136.4,
135.4, 133.4, 128.1, 127.9, 126.6, 126.1, 125.1, 124.9,
122.6, 122.0, 121.6, 121.3, 121.2, 119.6, 119.5, 110.2,
110.0, 105.5, 104.4, 63.5, 52.7, 52.2, 32.8, 31.8; IR (CHCl3)
n 2951, 1760, 1717, 1532, 1463, 1354, 1336, 1244,
1133 cm21. MS (FD) calculated for C32H29N5O2 515,
found m/z (Mþ1) 516 (100%). Anal. calculated for
C32H29N5O2 C, 74.54, H, 5.67, N, 13.58, found C, 74.68,
H, 5.96, N, 13.38.
4.11.1. 3-(1-Methyl-1H-indol-3-yl)-4-[1-(1-methyl-piper-
idin-4-yl)-1H-indol-3-yl]-pyrrole-2,5-dione (1b). Syn-
thesis via strategy A. Quantities employed 4b (1.00 g,
3.33 mmol), 3 (628 mg, 3.34 mmol) in THF (10 mL) and
tert-KOBu (7.4 mL, 7.4 mmol). Yield after filtration 1.21 g
1
(83%) 1b as an orange solid. H NMR (300 MHz, DMSO-
d6) d 10.89 (bs, 1H), 7.85 (s, 1H), 7.59 (s, 1H), 7.53 (d, 1H,
J¼8.35 Hz), 7.41 (d, 1H, J¼7.91 Hz), 7.06 (m, 3H), 6.77 (t,
1H, J¼7.47 Hz), 6.60 (t, 1H, J¼7.91 Hz), 6.52 (d, 1H,
J¼7.91 Hz), 4.34 (m, 1H), 3.85 (s, 3H), 2.82 (m, 2H), 2.19
(s, 3H), 2.10 (m, 2H), 1.79 (m, 4H); IR (CHCl3) n 3007,
2945, 2851, 2793, 1606, 1489, 1473, 1379, 1275, 1249,
1125, 1068, 1024 cm21. HRMS (ES) m/z (Mþ1) calculated
for C27H26N4O2 439.2134, found 439.2100.
4.11.2. 3-[1-(1-Benzyl-piperidin-4-yl)-1H-indol-3-yl]-4-
(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione (1c). Syn-

7228
M. M. Faul et al. / Tetrahedron 59 (2003) 7215–7229
4.11.5. 3-[1-[1-(Cyclopropylmethyl)-4-piperidinyl]-1H-
indol-3-yl]-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-
dione (1f). Synthesis via strategy A. Quantities employed
4f (3.94 g, 11.6 mmol), 3 (2.18 g, 11.6 mmol) in THF
(16 mL) and tert-KOBu (25.5 mL). After work-up the
product precipitated was filtered and rinsed with water to
calculated for C26H24N4O2Cl C, 67.90, H, 5.26, N, 12.18,
found C, 67.96, H, 5.46, N, 12.01.
4.11.8. 3-(1H-Indol-3-yl)-4-[1-(1-pyridin-2-ylmethyl-
piperidin-4-yl)-1H-indol-3-yl]-pyrrole-2,5-dione (1h).
Synthesis via strategy A. Quantities employed 4e (3.00 g,
7.95 mmol), 2 (1.26 g, 7.23 mmol) in THF (60 mL) and tert-
KOBu (36.1 mL, 36.1 mmol). After work-up the product
was recrystallized from hot MeOH (30 mL, 0.8 vol.) to give
2.43 mg (61%) 1h. 1H NMR (300 MHz, DMSO-d6) d 11.67
(d, 1H, J¼2.22 Hz), 10.91 (s, 1H), 8.51 (d, 1H, J¼4.03 Hz),
7.80 (d, 1H, J¼2.93 Hz), 7.77 (td, 1H, J¼7.69 Hz, 1.46 Hz),
7.69 (s, 1H), 7.55 (d, 1H, J¼8.05 Hz), 7.47 (d, 1H,
J¼7.69 Hz), 7.39 (d, 1H, J¼8.05 Hz), 7.26 (app. d, 1H,
J¼6.95, 5.49 Hz), 7.10–6.90 (m, 3H), 6.80–6.55 (m, 3H),
4.50–4.30 (m, 1H), 3.66 (s, 2H), 3.37 (s,.2H), 2.93 (d, 2H,
J¼11.34 Hz), 2.31 (dd, 2H, J¼10.98, 8.42 Hz), 1.85 (m,
2H); 13C NMR (75 MHz, DMSO-d6) d 172.9, 172.8, 158.5,
148.7, 136.4, 136.0, 135.4, 129.4, 128.3, 128.2, 127.0,
126.0, 124.8, 122.6, 122.1, 121.6, 121.5, 121.3, 121.0,
119.7, 119.3, 111.7, 110.2, 105.4, 105.4, 63.5, 53.8, 52.5,
1
afford after drying 3.1 g (56%) 1f as an orange solid. H
NMR (DMSO-d6) d 0.06 (m, 2H), 0.44 (m, 2H), 0.82 (m,
1H), 1.80 (m, 4H), 2.18 (m, 4H), 3.03 (d, 2H, J¼11.1 Hz),
3.84 (s, 3H), 4.35 (m, 1H), 6.52 (m, 1H), 6.60 (t, 1H,
J¼7.5 Hz), 6.77 (t, 1H, J¼7.5 Hz), 7.05 (m, 3H), 7.41 (d,
1H, J¼8.1 Hz), 7.53 (d, 1H, J¼8.4 Hz), 7.62 (s, 1H), 7.86
(s, 1H), 10.92 (s, 1H); 13C NMR (DMSO-d6) d 135.4, 133.4,
128.1, 121.6, 121.4, 121.2, 119.6, 119.5, 110.1, 110.0, 52.1,
32.8, 31.6, 8.3, 3.7; IR (KBr) n 1748, 1703, 1531, 1464,
1330, 1215 cm21. MS (ES) m/z calculated for C30H30N4O2
478, found Mþ1¼ 479. Anal. calculated for C30H30N4O2:
C, 75.29; H, 6.32; N, 11.70, found: C, 75.03; H, 6.25; N,
11.42.
4.11.6. 1,1-Dimethylethyl ester 4-[3-[2,5-dihydro-4-(1-
methyl-1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]-1H-
indol-1-yl]-1-piperidinecarboxylic acid (1g). Synthesis
via strategy A. Quantities employed 4g (2.66 g,
6.88 mmol), 3 (1.29 g, 6.88 mmol) in Et2O (25 mL) and
tert-KOBu (20.7 mL, 20.7 mmol). Purification, after work-
up, by silica gel chromatography (2:1 hexanes/EtOAc)
afforded 2.23 g (62%) 1g as a red foam. 1H NMR
(300 MHz, DMSO-d6) d 10.92 (s, 1H), 7.88 (s, 1H), 7.64
(s, 1H), 7.59 (d, 1H, J¼8.4 Hz), 7.42 (d, 1H, J¼8.4 Hz),
7.12–6.99 (m, 3H), 6.79 (app. t, 1H, J,8 Hz), 6.62 (app. t,
1H, J,7 Hz), 6.53, (d, 1H, J¼7.7 Hz), 4.67–4.54 (m, 1H),
4.12–4.05 (m, 2H), 3.86 (s, 3H), 3.02–2.82 (m, 2H), 1.88
(bd, 2H, J¼12.1 Hz), 1.72–1.55 (m, 2H), 1.41, (s, 9H); 13C
NMR (75 MHz, DMSO-d6) d 172.8, 172.7, 153.7, 136.6,
135.3, 133.4, 128.2, 128.1, 126.6, 126.1, 125.1, 121.6,
121.5, 121.4, 121.2, 119.7, 119.5, 110.1, 110.0, 105.6,
104.4, 78.8, 59.7, 52.4, 32.8, 31.6, 28.0. IR (CDCl3) n 3543,
3491, 3197, 3047, 3007, 2976, 1755, 1702, 1630,
1609 cm21. HRMS (ES) exact mass calculated for
C31H32N4O4 Mþ 524.2424, found 524.2442. Anal. calcu-
lated for C31H32N4O4, C, 70.9; H, 6.15; N, 10.7, found; C,
70.5; H, 6.43. N, 10.1.
52.3, 31.8; IR (KBr) n 3323, 1751, 1698, 1614, 1530 cm21
.
HRMS (ES) exact mass calculated for C31H27N5O2 Mþ
501.2165, found 501.2165.
4.11.9. 3-(1H-Indol-3-yl)-4-[1-(1-methyl-piperidin-4-yl)-
1H-indol-3-yl]-pyrrole-2,5-dione (1i). Synthesis via strat-
egy A. Quantities employed 4b (1.00 g, 3.33 mmol), 2
(580 mg, 3.33 mmol) in THF (10 mL) and tert-KOBu
(17.4 mL, 7.4 mmol). After work-up 1.02 g (72%) 1i was
isolated as an orange solid. 1H NMR (300 MHz, DMSO-d6)
d 11.7 (bs, 1H), 10.9 (bs, 1H), 7.77 (s, 1H), 7.62 (s, 1H), 7.52
(d, 1H, J¼8.35 Hz), 7.38 (app d, 1H), 7.05 (m, 2H), 6.95 (m,
1H), 6.75 (t, 1H, J¼7.47 Hz), 6.6 (m, 2H), 4.34 (m, 1H),
2.83 (app d, 2H), 2.19 (s, 3H), 2.10 (m, 2H), 1.85 (m, 4H);
13C NMR (75 MHz, DMSO-d6) d 135.8, 135.2, 128.2,
127.9, 126.8, 125.8, 124.6, 121.4, 121.3, 121.2, 120.8,
119.5, 119.1, 110.0, 105.3, 105.2, 54.3, 52.5, 45.7, 40.0,
39.9, 39.8, 39.6, 39.2, 39.2, 31.7; IR (KBr) n 3339, 3125,
3040, 2942, 2800, 2671, 1702, 1616, 1531, 1462, 1340,
1304, 1231, 1199, 1128 cm21. HRMS (ES) m/z (Mþ1)
calculated for C26H24N4O2 425.1978, found 425.1995.
4.11.10. 3-(1-Methyl-1H-indol-3-yl)-4-[1-(1-methyl-
piperidin-4-yl)-1H-indol-3-yl]-pyrrole-2,5-dione (1b).
Synthesis via strategy B. Quantities employed 8b
(106 mg, 0.391 mmol), 7 (85 mg, 0.391 mmol) in THF
(2 mL) and tert-KOBu, (0.862 mL, 0.862 mmol). After
work-up the product was filtered, rinsed with water and
EtOAc,thendriedtoafford92 mg(54%)1basanorangesolid.
4.11.7. 3-(1-Methyl-1H-indol-3-yl)-4-(1-piperidin-4-yl-
1H-indol-3-yl)-pyrrole-2,5-dione (1a). Concentrated HCl
(2.74 mL, 33.2 mmol, 15 equiv.) was added to a solution of
1g (1.16 g, 2.21 mmol) in EtOAc (11 mL) at reflux. The
reaction mixture was stirred at reflux for 2 h then cooled to
08C, filtered and rinsed with EtOAc. The red product was
1
dried at 508C in vacuo to give 710 mg (70%) 1a. H NMR
(300 MHz, DMSO-d6) d 10.98 (s, 1H), 9.46 (bs, 1H), 9.23
(bs, 1H), 7.88 (s, 1H), 7.68 (d, 1H, J¼8.4 Hz), 7.62 (s, 1H),
7.42 (d, 1H, J¼8.1 Hz), 7.10–6.94 (m, 4H), 6.75 (app. t, 1H,
J,7 Hz), 6.65–6.54 (m, 2H), 4.90–4.75 (m, 1H), 3.88 (s,
3H), 3.40 (d, 2H, J¼11.7 Hz), 3.10 (app. t, 2H, J,11 Hz),
2.31–2.12 (m, 1H), 2.11–2.00 (m, 1H); 13C NMR (75 MHz,
DMSO-d6) d 172.8, 136.5, 135.1, 133.4, 128.3, 127.6,
126.2, 126.1, 125.3, 121.8, 121.7, 121.3, 121.1, 119.8,
119.5, 110.4, 110.1, 105.9, 104.4, 50.3, 42.7, 32.9, 28.3,
28.2; IR (KBr) n 3110, 2887, 2762, 2677, 2487, 1750,
1697 cm21. MS (ES) calculated for C26H24N4O2Cl 459.96
(–HCl¼423.51), found m/z (M2HCl) 423.24. Anal.
4.11.11. 3-[1-(1-Benzyl-piperidin-4-yl)-1H-indol-3-yl]-4-
(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione (1c). Syn-
thesis via strategy B. Quantities employed 8c (160 mg,
0.460 mmol), 7 (100 mg, 0.460 mmol) in THF (3 mL) and
tert-KOBu (1.00 mL, 1.00 mmol). The reaction was heated
to 458C for 2 h but was incomplete (stalled at the
intermediate hydroxyimide stage). Additional tert-KOBu
(1.74 mL, 1.74 mmol) was added but further heating for 2 h
was still incomplete. However, the reaction was quenched
and worked up via the standard procedure. Purification
using 50 g silica gel 60 (1:1 CH2Cl2/EtOAc) to afford
121 mg (51%) 1c.

M. M. Faul et al. / Tetrahedron 59 (2003) 7215–7229
7229
5. Faul, M. M.; Winneroski, L. L.; Krumrich, C. A. J. Org. Chem.
1998, 63, 6053–6058.
4.11.12. 3-(1-Methyl-1H-indol-3-yl)-4-[1-[1-benzyl-4-
pyrrolidinyl]-1H-indol-3-yl]-1H-pyrrole-2,5-dione (1d).
Synthesis via strategy B. Quantities employed 8d (25.0 g,
75.0 mmol), 7 (17.0 g, 78.7 mmol) in THF (250 mL) and
tert-KOBu (375 mL, 375 mmol). Purification, after work-
up, by silica gel chromatography (4:1 CH2Cl2/EtOAc)
afforded 22.4 g 1d (60%) as a bright red solid.
6. Sasakura, K.; Adachi, M.; Sugasawa, T. Synth. Commun.
1988, 18, 265–273.
7. Sugasawa, T.; Adachi, M.; Sasakura, K.; Kitagawa, A. J. Org.
Chem. 1979, 44, 578–586.
8. Sugasawa, T.; Toyoda, T.; Adachi, M.; Sasakura, K. J. Am.
Chem. Soc. 1978, 100, 4842–4852.
9. Adachi, M.; Sasakura, K.; Sugasawa, T. Chem. Pharm. Bull.
1985, 33, 1826–1835.
4.11.13. 3-(1-Methyl-1H-indol-3-yl)-4-[1-[1-(2-pyridinyl-
methyl)-4-piperidinyl]-1H-indol-3-yl]-1H-pyrrole-2,5-
dione (1e). Synthesis via strategy B. Quantities employed
8e (697 mg, 2.00 mmol), 7 (447 mg, 2.06 mmol) in THF
(5.7 mL) and tert-KOBu (4.4 mL, 4.4 mmol). After work-up
the product precipitated was filtered and rinsed with cold 3:1
water/THF to afford 550 mg (53%) 1e as an orange solid.
10. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff,
C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849–3862.
11. Abdel-Magid, A. F.; Maryanoff, C. A.; Carson, K. G.
Tetrahedron Lett. 1990, 31, 5595–5598.
12. Douglas, A. W.; Abramson, N. L.; Houpis, I. N.; Karady, S.;
Molina, A.; Xavier, L. C.; Yasuda, N. Tetrahedron Lett. 1994,
35, 6807–6810.
4.11.14. 1,1-Dimethylethyl ester 4-[3-[2,5-dihydro-4-(1-
methyl-1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]-1H-
indol-1-yl]-1-piperidinecarboxylic acid (1g). Synthesis
via strategy B. Quantities employed 8g (450 mg,
1.26 mmol), 7 (274 mg, 1.26 mmol) in THF (5 mL) and
tert-KOBu, (2.80 mL, 2.80 mmol). Purification, after work-
up, using 50 g silica gel 60 (1:1 EtOAc/heptane) afforded
528 mg (80%) 1g.
13. Houpis, I. N.; Molina, A.; Douglas, A. W.; Xavier, L.; Lynch,
J.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1994, 35,
6811–6814.
14. Coe, J. W.; Vetelino, M. G.; Bradlee, M. J. Tetrahedron Lett.
1996, 37, 6045–6048.
15. Arai, E.; Tokuyama, H.; Linsell, M. S.; Fukuyama, T.
Tetrahedron Lett. 1998, 39, 71–74.
16. Zhang, J.-L.; Cai, M.-S. Huaxue Xuebao 1996, 84–89.
17. Hosken, G. D.; Hancock, R. D. J. Chem. Soc., Chem. Commun.
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