Solid-phase synthesis of 2,3-disubstituted indoles: Discovery of a novel, high-affinity, selective h5-HT(2A) antagonist

Article abstract of DOI:10.1016/S0960-894X(00)00558-8

The application of a novel solid-phase synthesis of 2,3-disubstituted indoles utilizing a carbamate indole linker is described resulting in the identification of the novel, high-affinity, selective h5-HT(2A) antagonist 19. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0960-894X(00)00558-8

Bioorganic & Medicinal Chemistry Letters 10 (2000) 2693±2696
Solid-Phase Synthesis of 2,3-Disubstituted Indoles:
Discovery of a Novel, High-Anity, Selective h5-HT2A Antagonist
Adrian L. Smith,* Graeme I. Stevenson, Stephen Lewis, Smita Patel and Jose L. Castro
Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow,
Essex CM20 2QR, UK
Received 20 April 2000; revised 28 June 2000; accepted 30 June 2000
AbstractÐThe application of a novel solid-phase synthesis of 2,3-disubstituted indoles utilizing a carbamate indole linker is
described resulting in the identi®cation of the novel, high-anity, selective h5-HT2A antagonist 19. # 2000 Elsevier Science Ltd. All
rights reserved.
The last decade has witnessed an explosion of interest in
the solid-phase synthesis of small organic molecules as a
tool for medicinal chemists interested in accelerating the
drug discovery process through combinatorial chemistry
and automated high-speed parallel synthesis. Much of
this work has focused upon elaboration of sca€olds of
pharmaceutical relevance.1 Indoles probably represent
one of the most important of all structural classes in
drug discoveryÐhigh-anity indole ligands have been
identi®ed for a variety of G-protein coupled receptors
and a large number of drugs are indole based. Several
reports have appeared describing solid-phase synthetic
approaches to indoles,2 and we recently described some
of our studies in this area.3 We now report an extension
of these studies involving a new linker for the indole
N-H which we have successfully used for synthesizing
parallel arrays of tryptamine derivatives and which lead
to the identi®cation of the 2-arylindole 19 as a high-
anity selective antagonist for the h5-HT2A receptor.
derivative of Wang resin (1). Further functionalization
should then be possible prior to cleavage of the Wang-
carbamate linker.
Scheme 1.
The chemistry was evaluated through the synthesis of
an array of 3-(3-aminopropyl)indole derivatives 7 as
shown in Scheme 2.4,5 It was found that pre-mixing the
indole 2 (1.10 equiv) with the resin 1, azeotroping with
toluene, resuspending in toluene and treating with
potassium bis(trimethylsilyl)amide (1.05 equiv) at
78 ꢀC resulted in clean conversion to the resin-bound
indole 3.6 Removal of the silyl protecting group was
cleanly e€ected with HF±pyridine in THF to give the
alcohol 4. Activation of the alcohol and introduction of
the amino substituent proved to be somewhat problem-
atic. For example, the corresponding mesylate or tosy-
late was found to be relatively unreactive towards
nucleophilic displacement by amines and required
extensive heating for amination to occur. Under these
conditions, the indole was displaced from the resin by
nucleophilic attack of the amine on the carbamate
During the course of our work, we wished to develop
new methods for linking indoles to the solid phase in
order to allow us to rapidly explore structure±activity
relationships around indole leads. We have already
reported the use of a THP-linker for indoles which was
utilized in
a Pd(0)-mediated synthesis of 2,3-di-
substituted indoles.3 We now report the use of an alter-
native indole carbamate linker which has proven to be
extremely useful for immobilizing indole cores to resin,
allowing further functionalization prior to cleavage. The
synthetic strategy is highlighted in Scheme 1, whereby
the indole core would be deprotonated and allowed to
react with the readily available p-nitrophenylcarbonate
*Corresponding author. E-mail: adrian_smith@merck.com
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00558-8

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A. L. Smith et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2693±2696
linker. However, the alcohol 4 was readily and cleanly
converted to the more reactive tri¯ate 5, which was itself
smoothly converted to the amino derivative 6 at ambi-
ent temperature. Cleavage of the resin under the TFA
conditions usually associated with Wang resin were
problematic, presumably due to reaction of the gener-
ated carbonium ion with the indole nucleus. However,
the above observation that the indole could be cleaved
from the resin by nucleophilic displacement with amines
at elevated temperatures led to the successful use of 5%
pyrrolidine in DMF at 90 ꢀC as a means of cleavage,
with evaporation leading to essentially pure products in
many cases. An alternative hydrolytic cleavage by heat-
ing in acetic acid at 110 ꢀC was also successfully
employed, and in this case pure products were generally
obtained by lyophilization of the resulting cleavage
solution.7 With both cleavage methods, compounds
could often be puri®ed in parallel if needed by use of
SCX ion exchange chromatography8 to give analytically
pure material.
To this end, we decided to explore the solid-phase
synthesis of 2-aryltryptamines 18 according to Scheme 3.
The tryptophol derivative 13 was cleanly brominated in
the indole 2-position by lithiation with lithium 2,2,6,6-
tetramethylpiperidide9 followed by treatment with
BrCF2CF2Br to give 14. Removal of the tert-butyloxy-
carbonyl group was e€ectively carried out using sodium
methoxide to give the relatively unstable free 2-bromo-
indole 15. This could be loaded onto the p-nitrophenyl-
carbonate derivative of Wang resin (1) as previously
described to give the resin-bound 2-bromoindole 16.
Table 1. Yields of products 7 with a range of amines HNR2, together
with yields of dimer
Example
Amine HNR2
Yield 7a
(%)
Yield dimera
(%)
8
51
35
The scope and eciency of the chemistry is illustrated in
Table 1. For primary amines HNR2, variable amounts
of the indole dimer resulting from cross-linking of the
mono-alkylated amine 6 with a neighbouring resin-
bound tri¯ate were observed. This was particularly
noticeable with relatively unreactive amines such as
aniline. This was not problematic with secondary
amines, and uniformly high yields of these were
obtained with a wide range of amines.
9
10
11
12
75
86
91
91
15
0
0
0
aIsolated yield based upon initial loading of p-nitrophenylcarbonate
resin 1, utilizing 5% pyrrolidine in DMF cleavage at 90 ꢀC for 4 h.
Having established the chemistry for introduction of
3-(aminoalkyl)indole substituents on solid phase, we
wished to extend this chemistry in order to allow the
introduction of substituents into the indole 2-position.
Scheme 3. Reagents: (i) LiTMP (2 equiv), THF,
78 ꢀC then
BrCF2CF2Br (2 equiv); (ii) NaOMe, MeOH, 20 ꢀC; (iii) 1, KHMDS,
toluene, 78 ! 20 ꢀC, 30 min; (iv) Ar-B(OH)2, Pd(PPh3)4, Na2CO3,
THF±H2O, 100 ꢀC, 16 h; or Ar-SnMe3, Pd(PPh3)4, toluene, 105 ꢀC,
16 h; (v) PPTS, 10% EtOH±DCE; (vi) Tf2O, 2,6-di-tert-butyl-4-
methylpyridine, CH2Cl2, 20 ꢀC, 30 min; (vii) HNR2 (4 equiv), CH2Cl2,
20 ꢀC, 1 h; (viii) AcOH, 110 ꢀC, 4 h.
Scheme 2. Reagents:ꢀ(i) 1, KHMDS, toluene, 78 ! 20 ꢀC, 30 min;
(ii) HFꢁ py, THF, 20 C, 30 min; (iii) Tf2O, 2,6-di-tert-butyl-4-methyl-
pyridine, CH2Cl2, 20 ꢀC, 2Â30 min; (iv) HNR2 (4 equiv), CH2Cl2,
20 ꢀC, 1 h; (v) 5% pyrrolidine, DMF, 90 ꢀC, 4 h; (vi) AcOH, 110 ꢀC,
4 h.

A. L. Smith et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2693±2696
2695
Considerable e€ort was spent investigating the intro-
duction of the 2-aryl substituent (16!17). Suzuki-type
reactions10,11 were examined utilizing the Pd(0)-medi-
ated coupling of arylboronic acids with the 2-bromo-
indole 16. A number of reaction condition variants were
examined, but the standard Pd(PPh3)4/Na2CO3/aqu-
eous THF conditions proved to be amongst the best.
Double couplings were required to push the reaction to
completion, and under these conditions some hydrolysis
of the indole±resin linkage was observed. This resulted
in somewhat reduced overall yields of the ®nal products
18, although they were generally obtained with good
purity.
Removal of the THP protecting group from the 2-aryl-
indoles 17 was readily accomplished with PPTS, and the
resulting resin-bound 2-aryltryptophols were converted
through to the desired 2-aryltryptamines 18 without
incident using the previously described chemistry. An
indication of the overall relative eciencies of the
Suzuki and Stille coupling routes is given in Table 2.
With ecient solid-phase chemistry now available for
synthesizing arrays of 2-aryltryptamine derivatives, a
number of such libraries were synthesized and screened
in various assays within Merck. One such assay was
against the cloned human 5-HT2A receptor with the
cloned human D2 receptor being used as a counter-
screen, looking for antagonists showing selectivity for
5-HT2A over D2 for the possible development of an
atypical neuroleptic. This revealed that compound 19 is
a high-anity antagonist14 16 at the h5-HT2A receptor
with good selectivity over hD2 activity (Table 3), com-
parable to the selective h5-HT2A antagonist MDL
100,907 reported to be in phase III clinical trials for
chronic schizophrenia.18 The development of the series
based upon 19 as part of a selective 5-HT2A antagonist
medicinal chemistry program will be described in
subsequent communications.
The corresponding Stille coupling with aryl-
stannanes10,12 proved to be a better reaction, often pro-
ceeding to completion with a single coupling reaction
and not su€ering the partial resin linker hydrolysis
observed under the Suzuki reaction conditions. This
reaction is, however, hampered by the lack of commer-
cially available arylstannanes which generally had to be
prepared via reaction of aryl Grignards with
Me3SnCl.13
Table 2. Comparison of Suzuki and Stille couplings on solid-phase
synthesis of 2-aryltryptamine derivatives (HNR2=piperidine)
Reagent
Number of couplings
Puritya
(%)
Yieldb
(%)
Acknowledgements
The authors thank Drs. J. Crawforth and M. Rowley
for supplying the tert-butyldimethylsilyl derivative of
5-¯uorohomotryptophol 2.
2
2
2
2
1
1
92
94
89
84
94
89
45
47
44
35
65
61
References and Notes
1. (a) James, I. W. Annu. Rep. Comb. Chem. Mol. Diversity
1999, 2, 129. (b) Hermkens, P. H. H.; Ottenheijm, H. C. J.;
Rees, D. Tetrahedron 1996, 52, 4527.
2. (a) Kraxner, J.; Arlt, M.; Gmeiner, P. Synlett 2000, 125. (b)
Zhang, H.-C.; Ye, H.; Moretto, A. F.; Brum®eld, K. K.;
Maryano€, B. E. Org. Lett. 2000, 2, 89. (c) Zhang, H.-C.;
Brum®eld, K. K.; Jaroskova, L.; Maryano€, B. E. Tetra-
hedron Lett. 1998, 39, 4449. (d) Collini, M. D.; Ellingboe, J.
W. Tetrahedron Lett. 1997, 38, 7963. (d) Fagnola, M. C.;
Candiani, I.; Visentin, G.; Cabri, W.; Zarini, F.; Mongelli, N.;
Bedeschi, A. Tetrahedron Lett. 1997, 38, 2307. (e) Zhang,
H.-C.; Brum®eld, K. K.; Maryano€, B. E. Tetrahedron Lett.
1997, 38, 2439. (f) Zhang, H.-C.; Maryano€, B. E. J. Org.
Chem. 1997, 62, 1804.
aHPLC purity of crude product produced by AcOH cleavage
(230 nm).
bIsolated yield of puri®ed product based upon initial loading of p-
nitrophenylcarbonate resin 1.
Table 3.
3. Smith, A. L.; Stevenson, G. I.; Swain, C. J.; Castro, J. L.
Tetrahedron Lett. 1998, 39, 8317.
4. Step i was carried out in a round bottom ¯ask; step ii was
carried out in a PTFE ¯ask; steps iii±vii were carried out using
an Advanced Chemtech ACT 496 solid-phase synthesis robot.
5. Solid-phase reactions were monitored by di€use re¯ectance
FT-IR spectroscopy.
Ki (nM)
6. The resin 1 (2.97 g, 0.59 mmol/g) and indole 2 (590 mg,
1.92 mmol) were mixed in a 100 mL round bottom ¯ask and
azeotroped with toluene (10 mL) on a rotary evaporator.
Failure to do this may result in hydrolysis during the next step.
Toluene (20 mL) was added, and the ¯ask cooled to 78 ꢀC.
Potassium bis(trimethylsilyl)amide (3.70 mL of a 0.5 M solu-
tion in toluene) was added dropwise, and the reaction was
then allowed to warm to room temperature over 30 min. The
resin was ®ltered washing successively with toluene, CH2Cl2,
a
b
Compound
h5-HT2A
hD2
19
MDL 100,907
2.7
0.3
900
1300
aDisplacement of [3H]-ketanserin from CHO cells stably expressing
h5-HT2A receptors.15
bDisplacement of [3H]-spiperone from CHO cells stably expressing
hD2 receptors.17

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A. L. Smith et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2693±2696
MeOH and Et2O and dried to give 3.27 g of resin 3
(0.52 mmol/g). IR indicated complete conversion of 1 to 3
(CˆO signal). The resin was treated with Ac2O:pyr-
idine:CH2Cl2 (1:3:5) for 30 min in order to cap any Wang resin
resulting from hydrolysis of 1.
7. The pyrrolidine cleavage method leaves small amounts of
bis-pyrrolidine urea as an impurity in the cleaved products.
The AcOH cleavage method acetylates unprotected alcohols,
but otherwise is generally clean.
8. The sample was loaded in MeOH onto a Varian SCX ben-
zenesulfonic acid ion exchange solid-phase extraction column,
washed with MeOH, and the compound then eluted o€ with
2 M NH3 in MeOH.
9. LiTMP was found to be much more e€ective than LDA at
lithiation of the indole 2-position.
12. McKean, D. R.; Parrinello, G.; Renaldo, A. F.; Stille, J.
K. J. Org. Chem. 1987, 52, 422.
13. Al-Diab, S. S. Inorg. Chim. Acta 1989, 160, 93.
14. In h5-HT2A transfected CHO cells, compound 19 alone at
1 mM had no e€ect but antagonized the 5-HT mediated accu-
mulation of inositol phosphates.
15. Berg, K. A.; Clarke, W. P.; Salistad, C.; Saltzman, A.;
Maayani, S. Mol. Pharmacol. 1994, 46, 477.
16. Freedman, S. B.; Harley, E. A.; Iverson, L. L. Br. J.
Pharmacol. 1988, 93, 437.
17. Patel, S.; Freedman, S. B.; Chapman, K. L.; Emms, F.;
Fletcher, A. E.; Knowles, M.; Marwood, R.; McAllister, G.;
Myers, J.; Patel, S.; Curtis, N.; Kulagowski, J. J.; Leeson, P.
D.; Ridgill, M.; Graham, M.; Matheson, S.; Rathbone, D.;
Watt, A. P.; Bristow, L. J.; Rupniak, N. M. J.; Baskin, E.;
Lynch, J. J.; Ragan, C. I. J. Pharm. Exp. Ther. 1997, 283, 636.
18. Sorbera, L. A.; Silvestre, J.; Castaner, J. Drugs Future
1998, 23, 955.
10. Reactions were carried out in a Quest 210 solid-phase
reactor under a N2 atmosphere.
11. Suzuki, A. J. Organomet. Chem. 1999, 576, 147.