A convenient synthesis of 2-cyano-3-substituted indoles

Article abstract of DOI:10.1055/s-2004-835627

A new and mild method for the synthesis of 2-cyano-3-substituted indoles is described which is effective on N-unsubstituted indoles.

Full text of DOI:10.1055/s-2004-835627

2806
LETTER
A Convenient Synthesis of 2-Cyano-3-Substituted Indoles
A
Convenient
o
S
ynthesis of
p
2-Cyano-3-S
h
ubstituted In
i
doles e Denison, Stephen T. Hilton*1
School of Chemical and Pharmaceutical Sciences, Kingston University, Penrhyn Road, Kingston-upon-Thames, Surrey, KT1 2EE, UK
Fax +44(20)76797524; E-mail: S.Hilton@ucl.ac.uk
Received 3 September 2004
i, ii
Abstract: A new and mild method for the synthesis of 2-cyano-3-
substituted indoles is described which is effective on N-unsubstitut-
ed indoles.
H
N
N
H
N
SO2
Ph
O
Key words: electrophilic cyanation, cyanoindoles, heterocycles,
Lewis acids, nitriles
4
5
iii
iv
Substituted cyanoindoles are important intermediates in
the synthesis of heteroaromatic molecules and have found
some use in the synthesis of biologically active com-
pounds.2,3 Incorporation of the nitrile functionality into
substituted indoles has been accomplished via a variety of
methods which often involve multi-step routes and harsh,
expensive or toxic reagents.2,4–15 During our investiga-
tions into the synthesis of monoterpene indole alkaloids
and spirocyclic oxindoles via nucleophilic free-radical
chemistry, it was necessary to incorporate an electron
withdrawing cyano-group at the 2-position of our 3-sub-
stituted indole precursors.16,17 The initial synthetic route
was based on Vilsmeier formylation of protected indole 1,
followed by oxime formation and dehydration
(Scheme 1). However, the formylation step gave low
yields (ca. 50%) and required extensive purification of the
product.
N
H
CN
N
CN
SO2Ph
7
6
Scheme 2 Reagents and conditions: (i) LDA, THF, –78 °C,
PhSO2Cl (85%); (ii) LDA, THF, –78 °C, t-BuNCO (68%); (iii)
POCl3, PhH (83%); (iv) NaH–PhSH, THF, reflux (72%).
the 2-cyano protected indole 6 in 83% yield. Treatment
with sodium thiophenoxide finally gave the desired 2-cy-
ano-3-methylindole 7 (Scheme 2).14
The main drawback involved in the synthesis of both 3-
substituted-2-cyanoindoles was the need for early protec-
tion of the indole nitrogen. As a result of the multistep
syntheses and low overall yields obtained in the synthesis
of our substituted 2-cyanoindoles we decided to investi-
gate alternative methods for the introduction of the nitrile
functionality into indole. Herein we now report a new
approach to 3-substituted-2-cyanoindoles.
CO2Me
CO2Me
i
N
N
Our initial investigation was based on the reaction be-
tween indole-3-acetic acid methyl ester 8 and tert-butyl
isocyanate. There are two possible means whereby the re-
action can be encouraged: (i) activation of indole, (already
achieved by Gribble and Katritzky via lithiation at the C-
2 position of indole)5,10 (ii) activation of the isocyanate.
An example of this is the use of chlorosulfonyl isocyan-
ate,4 which has a strong electron-withdrawing group on
the isocyanate nitrogen making it very reactive and thus
more difficult to work with. However, we felt that tert-
butyl isocyanate could be activated by the use of a Lewis
acid. Addition of 1 equivalent of boron trifluoride diethyl
etherate to a solution of 8 and tert-butyl isocyanate result-
ed in a 62% yield of amide 9 (Scheme 3). Following the
initial success, we optimised the reaction conditions by in-
creasing the amount of Lewis acid used to 2 equivalents
and carried out the reaction in dichloromethane at 0 °C,
which gave the amide 9 in 97% yield.18 This was sub-
sequently converted to the 2-cyanoindole ester 10 by heat-
ing a solution of the amide 9 at reflux with POCl3 in either
benzene or toluene (77%).19 Electron-donating groups at
C-5 are commonly found in biologically-active indole
Me
1
Me
O
2
ii, iii
CO2Me
N
CN
Me
3
Scheme 1 Reagents and conditions: (i) DMF–POCl3, 40 °C (48%);
(ii) NH2OH, Et3N (99%); (iii) Ac2O, pyridine, reflux (73%).
In related studies, we had previously synthesised 3-meth-
yl-2-cyano indole 7 following the reported method of
Gribble and co-workers.10 This involved protection and
activation of 3-methylindole 4 as a phenylsulfonamide de-
rivative, followed by treatment with LDA and tert-butyl
isocyanate to give the amide 5 in 68% yield. Subsequent
treatment with phosphorous oxychloride in benzene gave
SYNLETT 2004, No. 15, pp 2806–2808
Advanced online publication: 08.11.2004
DOI: 10.1055/s-2004-835627; Art ID: D26704ST
© Georg Thieme Verlag Stuttgart · New York
0
7
.1
2
.2
0
0
4

LETTER
A Convenient Synthesis of 2-Cyano-3-Substituted Indoles
2807
derivatives and there was concern that reaction may occur boron trifluoride enables the more conveniently handled
in the benzene ring of such indoles. However, reaction of reagent, tert-butyl isocyanate to be used and the synthesis
11 gave the corresponding amide 12 in good yield (80%), can also be conducted on a relatively large scale (ca. 100
which was then converted to the nitrile 13 in excellent g for 8) and with a significant reduction in the number of
yield (92%). In the case of 14 where the indole nitrogen steps previously required.
carries a methyl group, only 60% of the corresponding
amide 15 was isolated. Presumably, the N-alkyl group re-
duces the nucleophilicity of the C-2 position of indole, re-
Acknowledgment
We wish to thank Professor Keith Jones for his advice and for
giving us the opportunity to carry out this research.
sulting in lower yields of amide 15. The resultant amide
was readily converted to the N-protected 2-cyanoindole
ester 16 (88%). In the case of 3-methylindole 4, amide 17
was prepared in 85% yield, and then converted to 2-cy-
ano-3-methylindole 7 in 90% yield. Thus in contrast to
our previous 4-step synthesis of 7, only 2 steps were re-
quired and no protecting group strategy was necessary.
References
(1) New address: S. T. Hilton, Chemistry Department,
Christopher Ingold Laboratories, University College
London, 20 Gordon Street, London, WC1H 0AJ, UK.
(2) Bernardi, L.; Bosisio, G.; Mantegani, S.; Sapini, O.;
Temperilli, A.; Salvati, P.; di Salle, E.; Arcari, G.; Bianchi,
G. Arzneim.-Forsch. 1983, 33, 1094.
(3) Fukami, T.; Yamakawa, T.; Niiyama, K.; Kojima, H.;
Amano, Y.; Kanda, F.; Ozaki, S.; Fukuroda, T.; Ihara, M.;
Yano, M.; Ishikawa, K. J. Med. Chem. 1996, 39, 2313.
(4) Satake, K.; Yano, K.; Fujiwara, M.; Kimura, M.
Heterocycles 1996, 43, 2361.
(5) Katritzky, A. R.; Akutagawa, K.; Jones, R. A. Synth.
Commun. 1988, 18, 1151.
(6) Seifert, K.; Härtling, S.; Johne, S. Tetrahedron Lett. 1983,
24, 2841.
(7) Tamura, Y.; Adachi, M.; Kawasaki, T.; Yasuda, H.; Kita, Y.
J. Chem. Soc., Perkin Trans. 1 1980, 1132.
(8) Sakamoto, T.; Ohsawa, K. J. Chem. Soc., Perkin Trans. 1
1999, 2323.
An unexpected result occurred in the case of 18 where we
obtained a 1:2 ratio of 19:20 (85%) using standard condi-
tions. Heating the reaction mixture at reflux did not
change the ratio of products. Although it is well estab-
lished that there is competition between N- and C-acyla-
tion in indole derivatives, given the results obtained with
compounds 4, 8 and 11, it is possible that the acetoxy
group participates in the reaction in some way. The amide
19 could be isolated from the mixture by chromatography
in moderate yield (25%) and was converted to the 2-cy-
ano-3-substituted indole 21 in good yield (79%).
In summary, we have developed a new, mild and efficient
synthesis of 2-cyano-3-substituted indoles in two steps,
which is effective on N-unsubstituted indoles. The use of
R
R
R
CO2Me
CO2Me
CO2Me
CN
i
ii
H
N
N
H
N
H
N
H
O
8; R=H
11; R=OMe
9; R=H (97%)
12; R=OMe (80%)
10; R=H (77%)
13; R=OMe (92%)
CO2Me
CO2Me
CO2Me
i
ii
ii
H
N
N
N
N
CN
Me
Me
O
Me
14
15 (60%)
16 (88%)
i
H
N
N
H
N
H
N
H
CN
O
4
17 (85%)
7 (90%)
OAc
OAc
OAc
i
H
N
N
H
N
H
N
O
O
N
H
18
19
20
ii
(1:2, 85% combined)
OAc
N
H
CN
21 (79%)
Scheme 3 Reagents and conditions: (i) BF3·OEt2, CH2Cl2, t-BuNCO, 0 °C; (ii) POCl3, PhH, reflux.
Synlett 2004, No. 15, 2806–2808 © Thieme Stuttgart · New York

2808
S. Denison, S. T. Hilton
LETTER
(9) Tokuyama, H.; Kaburagi, Y.; Chen, X.; Fukuyama, T.
Synthesis 2000, 429.
(10) Gribble, G. W.; Barden, T. C.; Johnson, D. A. Tetrahedron
1988, 44, 3195.
(11) Yamada, F.; Fukui, Y.; Shinmyo, D.; Somei, M.
Heterocycles 1993, 35, 99.
(12) Nagasaki, I.; Suzuki, Y.; Iwamoto, K.; Higashino, T.;
Miyashita, A. Heterocycles 1997, 46, 443.
(13) Hughes, T. V.; Cava, M. P. J. Org. Chem. 1999, 64, 313.
(14) Lin, C.; Fang, J. J. Chin. Chem. Soc. (Taipei) 1993, 40, 571.
(15) Fiumana, A.; Jones, K. Chem. Commun. 1999, 1761.
(16) Hilton, S. T.; Ho, T. C. T.; Pljevaljcic, G.; Schulte, M.;
Jones, K. Chem. Commun. 2001, 209.
(8.00 g, 97%); mp 159.5–160.5 °C; Rf = 0.31 (3:1, hexane–
EtOAc); (m/z calcd for C16H20N2O3 [M+]: 288.1474. Found:
288.1473 [M+]). IR: nmax = 3273.1 (NH), 1720.1 (CO2CH3),
1638.0 (CONHt-Bu) cm–1. 1H NMR: (300 MHz, CDCl3):
d = 1.91 [9 H, s, C(CH3)3], 3.75 (3 H, s, OCH3), 3.98 (2 H, s,
CH2CO2CH3), 7.17 (1 H, td, J = 8.0 and 1.0 Hz, C-5H), 7.29
(1 H, td, J = 8.0 and 1.0 Hz, C-6H), 7.53 (1 H, d, J = 8.0 Hz,
C-7H), 7.70 (1 H, d, J = 8.0 Hz, C-4H), 8.13 (1 H, br s, NH),
10.68 (1 H, br s, CONH). 13C NMR (75 MHz, CDCl3): d =
29.04 [C(CH3)3], 31.05 (CH2CO2CH3), 52.17 [C(CH3)3],
52.68 (CO2CH3), 106.86 (C-3), 112.27 (C-7), 119.53 (Ar-C-
H), 120.13 (Ar-C-H), 124.15 (Ar-C-H), 127.76 (quaternary
C), 131.32 (quaternary C), 135.36 (C-7a), 161.89 (CONH),
173.80 (CO2CH3). MS: m/z (%) = 288.15 (87.6) [M+],
215.04 (95.4), 200.05 (92.1), 188.07 (56.1), 183.03 (62.1),
156.04 (89.5), 128.05 (100.0), 58.16 (67.4).
(17) Hilton, S. T.; Ho, T. C. T.; Pljevaljcic, G.; Jones, K. Org.
Lett. 2000, 2, 2639.
(18) Representative Procedure: (2-t-Butylcarbamoyl-1H-
indol-3-yl)-acetic Acid Methyl Ester (9): Boron trifluoride
diethyl etherate (7.2 mL, 8.1 g, 57.5 mmol) was added to a
stirred solution of indole-3-acetic acid methyl ester (8, 5.4 g,
28.8 mmol) and freshly distilled t-butyl isocyanate (4.9 mL,
4.3 g, 43.1 mmol) in CH2Cl2 (40 mL) at 0 °C. The reaction
was allowed to stir for 18 h whereupon organic solvent was
removed under reduced pressure and the residue taken up in
CH2Cl2 (100 mL) and washed with a solution of sat. NH4Cl
(100 mL). The aqueous phase was extracted with CH2Cl2
(2 × 100 mL) and the combined organic extracts washed
with brine (200 mL), dried (MgSO4), filtered and organic
solvent removed under reduced pressure. The crude product
was purified by flash column chromatography (3:1, hexane–
EtOAc) to give amide 9 as colourless crystalline needles
(19) Representative Procedure: (2-Cyano-1H-indol-3-yl)-
acetic Acid Methyl Ester (10): A solution of ester 9 (48.90
g, 0.20 mol) and phosphorus oxychloride (50.0 mL, 82.30 g,
0.54 mol) in benzene (300 mL) was heated under reflux for
7 h. Organic solvent was removed under reduced pressure
and the residue partitioned between CH2Cl2 (200 mL) and a
solution of sat. NaHCO3 (200 mL) and stirred for 1 h. The
organic layer was separated and the aqueous phase extracted
with CH2Cl2 (3 × 200 mL). The combined organic extracts
were washed with brine (200 mL), dried (MgSO4), filtered
and solvent removed under reduced pressure. The crude
product was purified by flash column chromatography (5:1,
hexane–EtOAc) to give nitrile 10 as a colourless crystalline
solid (26.87 g, 77%); mp 88.0–89.5 °C.9
Synlett 2004, No. 15, 2806–2808 © Thieme Stuttgart · New York