Synthesis of 2,5-disubstituted-3-cyanoindoles

Article abstract of DOI:10.1016/j.tetlet.2011.11.009

An efficient synthesis of 2,5-disubstituted-3-cyanoindoles is described. This approach utilizes a highly selective iodination together with the modified Madelung reaction to generate an intermediate which can be readily transformed to more fully elaborate

Full text of DOI:10.1016/j.tetlet.2011.11.009

Tetrahedron Letters 53 (2012) 200–202
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 2,5-disubstituted-3-cyanoindoles
⇑
Mark A. Bobko, Karen A. Evans , Arun C. Kaura, Leanna E. Shuster, Dai-Shi Su
GlaxoSmithKline, Cancer Research, 1250 South Collegeville Road, Collegeville, PA 19426, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of 2,5-disubstituted-3-cyanoindoles is described. This approach utilizes a highly
selective iodination together with the modified Madelung reaction to generate an intermediate which
can be readily transformed to more fully elaborated 2,5-disubstituted-3-cyanoindole templates that were
previously difficult to access. Detailed examples and utility of this approach are presented herein.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 12 October 2011
Revised 2 November 2011
Accepted 3 November 2011
Available online 9 November 2011
Keywords:
3-Cyanoindoles
2,5-Disubstituted-3-cyanoindoles
Modified Madelung reaction
Selective iodination
Synthesis
Indoles are of great interest among the medicinal chemistry
community for their biological relevance.1 One only has to do a
search on the general indole substructure to find thousands of re-
ports on their synthesis2 and applications. More specifically, 3-
cyanoindoles are known to be of biological significance for their
use as aldosterone synthase modulators for cardiovascular dis-
ease,3 factor Xa inhibitors for antithrombotics,4 hepatitis C antivi-
rals,5 acetyl-CoA carboxylase inhibitors for type 2 diabetes,6 and
anticancer agents.7 Thus an additional method by which 3-cyano-
indoles and their derivatives could be prepared would be of great
value and utility (vide infra).8
achieve this, we investigated a variety of methods to prepare the
required indole core. Preparation of the 5-bromoindole scaffold 6
was first attempted using the Fischer indole synthesis.9 While treat-
ment of hydrazone 2 on five gram scale with polyphosphoric acid
(PPA) at high temperature afforded the indole 6 with good conver-
sion, clean separation of the product from des-bromo and di-bromo
side products on scale was difficult. An alternative approach using
Sonagashira cross-coupling conditions to form 4-bromo-2-(pyri-
din-4-ylethynyl)aniline 5, followed by ring closure with potassium
tert-butoxide proceeded in good yield.10 However, the cyanation
reaction with chlorosulfonylisocyanate to form 5-bromo-2-(pyri-
din-4-yl)-1H-indole-3-carbonitrile 7a was low yielding and poorly
reproducible.3 Protection of the indole N-1 nitrogen with a trimeth-
ylsilylethoxymethyl (SEM) group (7b) did not improve the outcome
of this cyanation. Other cyanating reagents such as potassium ferro-
cyanide required protection of the N-1 nitrogen, and were found to
be only slightly more effective.11 Disappointingly, conversion of the
bromide 7 to the coupled product was also poor. For example, com-
pound 7a was converted to 5-(isoxazol-4-yl)-2-(pyridin-4-yl)-1H-
indole-3-carbonitrile 8a in only 10% yield under standard Suzuki
cross-coupling conditions. A similar result was observed when N-
1 was SEM protected (8b). The low synthetic efficiency over multi-
ple steps in this sequence, as well as the costly 4-ethynylpyridine
starting material presented significant challenges to the synthesis
of 2,5-disubstituted-3-cyanoindoles on larger scale. In addition,
this route limited our ability to prepare diverse analogs due to
the incorporation of the 2-position substituent at the beginning of
the synthesis in the form of custom ethynyl starting materials.
The key requirements for an improved second generation syn-
thesis were to avoid a separate cyanation step and to allow for ease
of varying substituents at both the 2- and 5-positions. To address
During the course of a medicinal chemistry effort, we required
an efficient synthesis of 2-pyridyl-5-substituted-3-cyanoindoles 1
which would allow for the rapid preparation of analogs at the 5-
position.
CN
Ar
N
N
H
1
We initially planned to cyanate the 3-position of the corre-
sponding 5-bromo-2-(4-pyridyl) intermediate 6, and then couple
the bromide with a variety of aryl boronic acids as the final step
(Scheme 1). This approach would facilitate efficient analog prepara-
tion by introducing diversity as the final step in the synthesis. To
⇑
Corresponding author. Tel.: +1 610 917 7764; fax: +1 610 917 6151.
E-mail address: karen.a.evans@gsk.com (K.A. Evans).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.009

M. A. Bobko et al. / Tetrahedron Letters 53 (2012) 200–202
201
Br
a
Br
Br
O
N
N
NH2
N
H
b
N
H
N
2
Br
N
N
N
H
c
I
Br
d
N
6
NH2
NH2
3
4
5
CN
N
O
CN
e (7a)
f,e (7b)
g
Br
6
N
N
O
N
N
R
N
R
B
O
7a (R=H)
7b (R=SEM)
8a (R=H)
8b (R=SEM)
O
Scheme 1. Reagents and conditions: (a) EtOH, reflux, 2 h, 85% (b) PPA, 130 °C, 73% (c) PdCl2(PPh3)2, Et3N, reflux, 43%; (d) KOt-Bu, NMP, 53%; (e) ClSO2NCO, CH3CN, 0 °C; DMF;
17–28% 7a; 0% 7b; (f) NaH, SEMCl, DMF, 90%; (g) PdCl2(dppf), K2CO3, 1,4-dioxane/water (4:1), 100 °C, 5 h, 10% 8a; <10% conversion after 16 h, 8b.
the first of these goals, the synthesis of 3-cyanoindoles can be
accomplished via application of the modified Madelung reaction12
which incorporates the 3-cyano group at the beginning of the syn-
thesis. This approach would also allow for the preparation of com-
pounds with variation at the 2-position more easily from readily
available acid chloride starting materials.
observed to be lower yielding than those with the methyl (12d)
and aryl substituents (12a–c). We also investigated the applica-
tion of this chemistry to the synthesis of 5-iodo-2-amino-3-cyan-
oindoles (Scheme 3). The desired product 12h was not found,
with the major product 14 resulting from oxidative hydrolysis
of the nitrile.15
Additionally, a synthetic sequence which utilized a more reac-
tive 5-iodoindole rather than the 5-bromoindole could be of
significant benefit in subsequent aryl cross-coupling reactions.
Gratifyingly, iodination of readily accessible (2-aminophenyl)ace-
tonitrile 9 under the mild conditions of potassium iodide and 30%
hydrogen peroxide in acetic acid13 cleanly and exclusively affor-
ded the desired para iodo intermediate 10 in 82% yield (Scheme
2). This material was then acylated with isonicotinoyl chloride
to provide 11a in 72% yield. Protection of 11a with the SEM
group, followed by ring closure with potassium tert-butoxide
via the modified Madelung reaction delivered the desired iodide
12a from 11a in 52% yield in a one-pot sequence. To our knowl-
edge, this is the first reported example of the preparation of a
highly versatile 2-substituted-3-cyano-5-iodoindole.14 Impor-
tantly, this sequence can be applied to the preparation of both
aryl and alkyl motifs at the 2-position (12a–g) as shown in Table
1. Reactions with sterically hindered alkyl R groups (12e–g) were
To demonstrate the utility of this route in preparing the desired
2,5-disubstituted-3-cyanoindoles, the iodo intermediate 12a was
coupled with a series of arylboronic acids to afford 2-pyridyl-5-
aryl-3-cyanoindoles 15a–c in 51–72% yield. The SEM group was
subsequently removed using cesium fluoride in DMF to afford
the final products 16a–c in 37–58% yield (Scheme 4).16,17
In conclusion, we have devised an efficient synthesis of 2,5-
disubstituted-3-cyanoindoles. This approach utilizes
a highly
selective and high yielding iodination followed by a one-pot
modified Madelung reaction and protection sequence to generate
the 2-substituted-3-cyano-5-iodoindole core. This protected
intermediate can then be readily transformed to generate novel
5-substituted analogs which were previously difficult to access.
Table 1
Reaction yield for the conversion of compounds 11a–h to 12a–h
CN
CN
CN
O
CN
a
I
I
b
I
R
NH2
N
NH2
N
H
R
O
9
10
11a-h
12a-h
Si
CN
CN
I
I
O
N
c
Compounds
R
Yield (%)
N
N
H
12a
12b
12c
12d
12e
12f
4-Pyridyl
3-Pyridyl
4-CO2Me-phenyl
Methyl
iso-Propyl
tert-Butyl
52
33
43
47
26
24
4
O
N
11a
12a
Si
Scheme 2. Reagents and conditions: (a) KI, 30% H2O2, HOAc, 1 h, 82% (15 g scale);
(b) isonicotinoyl chloride, DIEA, DCM, 72%; (c) NaH, SEMCl, THF, 30 min, then KOt-
Bu, 30 min, 52%.
12g
12h
Cyclohexyl
Morpholino
0

202
M. A. Bobko et al. / Tetrahedron Letters 53 (2012) 200–202
CN
CO2H
O
CN
I
I
I
a, b
c
O
10
N
O
N
H
N
N
H
N
N
H
O
O
13
12h, 0%
14,
15%
Scheme 3. Reagents and conditions: (a) NaHCO3, DCM/water (1:1), phosgene (20% solution in toluene), 1 h, 92%; (b) morpholine, DCM, rt, 3 h, 79%; (c) NaH, TMSCl, THF,
30 min, rt, then KOt-Bu, 20 h, rt.
CN
CN
CN
I
Ar
Ar
b
a
N
N
N
N
N
N
H
O
O
Si
Si
12a
15a, Ar = 4-pyridyl
15b, Ar = 3-pyridyl
15c, Ar = 2-furanyl
16a, Ar = 4-pyridyl
16b, Ar = 3-pyridyl
16c, Ar = 2-furanyl
Scheme 4. Reagents and conditions: (a) ArB(OH)2, PdCl2(dppf), K2CO3, dioxane/H2O, 100 °C lw, 1 h, 51–72%; (b) CsF, DMF, 125–130 °C, 2.5 h, 37–58%.
ppm: 5.41 (s, 2H), 6.53 (d, J = 8.34 Hz, 1H), 7.30 (dd, J = 8.59, 2.02 Hz, 1H), 7.39
(d, J = 2.02 Hz, 1H), NH2 protons not resolved. (2-Amino-5-
The useful synthetic approach reported herein can be applied to
the synthesis of a variety of 2,5-disubstituted-3-cyanoindoles.
iodophenyl)acetonitrile (10) (258 mg, 1.0 mmol) was dissolved in 10 mL of
DCM. 4-Pyridinecarbonyl chloride (178 mg, 1.0 mmol) was added, followed by
DIEA (0.35 mL, 2.0 mmol). After 16 h at rt, the reaction mixture was
concentrated in vacuo. Purification by automated flash chromatography (12 g
silica gel, 2–10% MeOH in DCM, 40 min gradient) afforded 11a as a grayish
powder (260 mg, 72%). 1H NMR (400 MHz, DMSO-d6) d ppm: 4.01 (s, 2H), 7.26
(d, J = 8.34 Hz, 1H), 7.78 (dd, J = 8.34, 2.02 Hz, 1H), 7.82–7.93 (m, 3H), 8.76–
8.87 (m, 2H), 10.48 (s, 1H). N-[2-(Cyanomethyl)-4-iodophenyl]-4-
pyridinecarboxamide (11a) (2.65 g, 7.3 mmol) was dissolved in 5 mL of THF
and cooled to 0 °C. NaH (60% oil dispersion, 0.32 g, 8.0 mmol) was added. After
5 min, SEMCl (1.42 mL, 8.0 mmol) was added and the reaction mixture was
allowed to stir for 30 min at room temperature. KOt-Bu (95%, 0.95 g, 8.0 mmol)
was then added and the reaction mixture was stirred for another 30 min. The
reaction was quenched with water (5 mL). The resulting mixture was stirred
for 5 min and concentrated in vacuo to near dryness. The residue was taken up
in ethyl acetate (400 mL), and washed with water (2 Â 250 mL), satd NH4Cl
(2 Â 250 mL), and brine (1 Â 100 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Purification by automated flash chromatography (200 g
Acknowledgment
The authors thank Minghui Wang for his assistance with the
2-D NMR spectra.
References and notes
1. (a) Sharma, V.; Kumar, P.; Pathak, D. J. Heterocycl. Chem. 2010, 47, 491–502; (b)
Rodrigues de Sa Alves, F.; Barreiro, E. J.; Fraga,, C. A. M. Mini-Rev. Med. Chem.
2009, 9, 782–793.
2. (a) Patil, S. A.; Patil, R.; Miller, D. D. Curr. Med. Chem. 2011, 18, 615–637. and
references therein; (b) Cacchi, S.; Fabrizi, G.; Goggiamani, A. Org. Biomol. Chem.
2011, 9, 641–652; (c) Ziegert, R. E.; Knepper, K.; Brase, S. Targets Heterocyclic.
Syst. 2005, 9, 230–253.
silica gel, 0–10% methanol/DCM, 50 min gradient) afforded 12a (1.8 g, 52%). 1
H
3. Adams, C.; Hu, Q.-Y.; McGuire, L.W.; Papillon, J. PCT Int. Appl. WO 2009156462
A2 20091230, 2009.
NMR (400 MHz, DMSO-d6) d ppm: À0.15 to À0.11 (m, 9H), 0.71–0.78 (m, 2H),
4. Wallnoefer, H. G.; Liedl, K. R.; Fox, T. J. Comput. Chem. 2011, 32, 1743–1752.
5. Gu, Z. PCT Int. Appl. WO 2010118009 A1 20101014, 2010.
6. Chonan, T.; Tanaka, H.; Yamamoto, D.; Yashiro, M.; Oi, T.; Wakasugi, D.; Ohoka-
Sugita, A.; Io, F.; Koretsune, H.; Hiratate, A. Bioorg. Med. Chem. Lett. 2010, 20,
3965–3968.
7. Grewal, G.; Oza, V. PCT Int. Appl. WO 2008059238 A1 20080522, 2008.
8. Reddy, B. V.; Subba; Begum, Z.; Reddy, Y.; Jayasudhan; Yadav, J. S. Tetrahedron
Lett. 2010, 51, 3334–3336. and references therein.
9. Franco, L. H.; Palermo, J. A. Chem. Pharm. Bull. 2003, 51, 975–977.
10. Majumdar, K. C.; Mondal, S. Tetrahedron Lett. 2007, 48, 6951–6953.
11. Yan, G.; Kuang, C.; Zhang, Y.; Wang, J. Org. Lett. 2010, 12, 1052–1055. Using
these conditions, we observed formation of compound 7b from compound 6 in
25–36% conversion.
3.37–3.44 (m, 2H), 5.60 (s, 2H), 7.73–7.79 (m, 4H), 8.08 (s, 1H), 8.84–8.89 (m,
2H).
In
a
5 mL
microwave
vial,
5-iodo-2-(4-pyridinyl)-1-({[2-
(trimethylsilyl)ethyl]oxy}methyl)-1H-indole-3-carbonitrile (12a) (100 mg,
0.21 mmol), 4-pyridinylboronic acid (38.8 mg, 0.32 mmol) and potassium
carbonate (87 mg, 0.63 mmol) were taken up in 5 mL of 4:1 dioxane/water.
The vial was flushed with nitrogen and PdCl2(dppf) (15.4 mg, 0.02 mmol) was
added and the vial capped. The reaction mixture was heated in the microwave
at 100 °C for 1 h, then stirred with brine at rt. After 5 min, the dioxane layer
was separated and concentrated in vacuo. Purification by automated flash
chromatography (12 g silica gel, 0–10% MeOH in DCM, 40 min gradient)
afforded 15a (65 mg, 72%). 1H NMR (400 MHz, CHLOROFORM-d) d ppm: 0.00 (s,
9H), 0.96 (t, 2H), 3.62 (t, J = 7.83 Hz, 2H), 5.51 (br s, 2H), 7.61–7.99 (m, 6H), 8.15
(br s, 1H), 8.60–9.04 (m, 4H). In a 2 dram teflon-capped vial, 2,5-di-4-pyridinyl-
12. (a) Orlemans, E. O. M.; Schreuder, A. H.; Conti, P. G. M.; Verboom, W.;
Reinhoudt, D. N. Tetrahedron 1987, 43, 3817–3826; (b) Wacker, D. A.;
Kasireddy, P. Tetrahedron Lett. 2002, 43, 5189–5191.
13. Reddy, K. S. K.; Narender, N.; Rohitha, C. N.; Kulkarni, S. J. Synth. Commun. 2008,
38, 3894–3902.
14. We found only one example of a related 2-aryl-3-cyano-5-bromoindole. See
Yu, W.; Du, Y.; Zhao, K. Org. Lett. 2009, 11, 2417–2420.
15. DiBiase, S. A.; Wolak, R. P., Jr.; Dishong, D. M.; Gokel, G. W. J. Org. Chem. 1980,
45, 3630–3634.
16. Experimental procedure for the synthesis of 16a: (2-Aminophenyl)acetonitrile
(9) (2.64 g, 20.0 mmol) was dissolved in 50 mL of acetic acid. KI (3.65 g,
22.0 mmol) was added followed by dropwise addition of 30% H2O2 (2.24 mL,
22.0 mmol). The reaction mixture was then stirred under nitrogen for 90 min,
poured into 200 mL of 0.1 M sodium thiosulfate solution, and extracted with
ethyl acetate (3 Â 200 mL). The organic fractions were combined, washed with
0.1 M sodium thiosulfate (2 Â 200 mL), satd sodium bicarbonate (2 Â 200 mL)
and brine (2 Â 200 mL), dried over sodium sulfate, filtered, and concentrated in
vacuo. Purification by automated flash chromatography (400 g silica gel, 25%
ethyl acetate/hexanes) afforded 10 (3.5 g, 68%). 1H NMR (400 MHz, DMSO-d6) d
1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-indole-3-carbonitrile
(15a)
(65 mg, 0.15 mmol) was dissolved in 1 mL of DMF and CsF (116 mg,
0.76 mmol) was added. The vial was capped and heated to 130 °C for 2.5 h.
The reaction mixture was cooled to room temperature, filtered, and purified by
automated reversed phase HPLC (Gilson, 5–55% ACN/water, 0.1% TFA, 7 min
gradient) to afford 16a as
a
bright yellow solid (47 mg, 58%). 1H NMR
(400 MHz, METHANOL-d4) d ppm: 7.87 (d, J = 8.59 Hz, 1H), 8.05 (dd, J = 8.84,
1.77 Hz, 1H), 8.29 (br s, 2H), 8.44 (d, J = 1.26 Hz, 1H), 8.50 (d, J = 5.81 Hz, 2H),
8.75–9.19 (m, 4H), NH not resolved. Anal. calcd for C19H12N4Á2C2HF3O2: C,
52.68; H, 2.69; N, 10.68 . Found: C, 52.21; H, 2.42; N, 9.66 (di-TFA salt).
17. Our work in related areas has shown that incorporating a protecting group
strategy could be critical to the success of utilizing this template for further
elaboration using other metal-catalyzed cross-coupling reactions. For example,
in a related series of 2-amino-3-cyano-6-bromo indole analogs, we observed
that alkylation at N-1 was critical for the successful completion of 6-position
coupling with alkyltrifluoroborates, as well as with amines. In these cases, no
reaction was observed when the indole nitrogen was left unprotected, whereas
good conversion was observed when the indole nitrogen was protected.