Sonogashira cross-coupling reaction of 3-iodoindazoles with various terminal alkynes: A mild and flexible strategy to design 2-aza tryptamines

Article abstract of DOI:10.1016/S0040-4039(02)00393-3

This paper describes a Sonogashira-type cross-coupling reaction of 3-iodoindazoles with various terminal alkynes as a general route to 3-alkynylindazoles. The coupling reaction is illustrated by the preparation of new indazolylpropiolic or propargylic derivatives. Scope and limitation of the method are outlined.

Full text of DOI:10.1016/S0040-4039(02)00393-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2695–2697
Sonogashira cross-coupling reaction of 3-iodoindazoles with
various terminal alkynes: a mild and flexible strategy to design
2-aza tryptamines
Anca Arnautu,a Vale´rie Collot,a Javier Calvo Ros,b Carole Alayrac,b Bernhard Witulskib,* and
Sylvain Raulta,*
aCentre d’Etudes et de Recherche sur le Me´dicament de Normandie, UFR des Sciences Pharmaceutiques, 5 rue Vaube´nard,
14032 Caen Cedex, France
bFachbereich Chemie der Universita¨t Kaiserslautern, Erwin Schro¨dinger Strasse, D-67663 Kaiserslautern, Germany
Received 15 January 2002; revised 22 February 2002; accepted 25 February 2002
Abstract—This paper describes a Sonogashira-type cross-coupling reaction of 3-iodoindazoles with various terminal alkynes as a
general route to 3-alkynylindazoles. The coupling reaction is illustrated by the preparation of new indazolylpropiolic or
propargylic derivatives. Scope and limitation of the method are outlined. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
the synthesis of 3-alkynylindazoles. An indepth survey
of the literature did not show such a study. For this
purpose, we applied the most straightforward methods
for the preparation of arylalkynes which is the palla-
dium-catalyzed coupling of terminal alkynes with aryl-
halides described for the first time by Sonogashira et al.
in 1975.10
Although indazole is the 2-azabioisostere of indole,
very few publications are devoted to its chemistry in
comparison with the indole. However, some indazole
derivatives such as 7-NI,1 7-MI2 (nitric oxide synthase
inhibitors), YC
1
(guanylyl cyclase activator),3
granisetron (5HT-3 receptor antagonist),4 lonidamine
(cytotoxic modulator)5 or SE063 (HIV protease
inhibitor)6 are already considered as leads in medicinal
chemistry. Aiming at studying mild and flexible strate-
gies to design new indazole librairies, we recently pub-
lished a very efficient Suzuki cross-coupling reaction
leading to 3-arylindazoles7 and a general and versatile
pathway leading to 3-indazolylpropionic acid and
derivatives via a Heck cross-coupling reaction of 3-
iodoindazoles.8 We also depicted that these reactions
could be carried out selectively or together with N-
arylations.9
As a part of our research program on the design of
2-aza bioisosteres of tryptamine, serotonin or mela-
tonin, we planned to develop an efficient method for
Scheme 1. Reagents and conditions: (i) (1) HBF4 aq. 50%, (2)
NaNO2 aq, 0°C; (ii) AcOK, 18-crown-6, CHCl3, rt; (iii) I2,
KOH, DMF, rt.
* Corresponding authors. Tel.: +33-2-31-93-41-69; fax: +33-2-31-93-
11-88; e-mail: rault@pharmacie.unicaen.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00393-3

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A. Arnautu et al. / Tetrahedron Letters 43 (2002) 2695–2697
the fact that these alkynes are often difficult to prepare
and to purify. For our own part we chose to adapt a
method firstly described by Papanastassiou19 (DCC in
CH2Cl2) and details concerning our method will be
published elsewhere. In our hands the methods using
mixed anhydride or acid chloride as intermediate were
able to produce sufficiently pure carboxamides.
To go further, we finally studied this cross coupling
reaction of 3-iodoindazoles with N,N-dimethyl- or N-
tosyl propargylamines. As expected, the results were very
good with quantitative couplings to give the indazolyl
propargylamines 16–23. The result was the same for the
N-tosylpentynylamine to give 24.
Scheme 2. (i) TosCl, t-BuOK, THF, 7 h (85%) or (Boc)2O,
All these results are summarized in Table 1.
DMAP,TEA,CH3CN,3h(88%);(ii)
, PdCl2(PPh3)2
(5 mol%), Et3N, CuI, DMF, rt; (iii) MeONa, MeOH, rt.
Table 1. Sonogashira cross-coupling reactions of 3-iodoin-
dazoles
2. Results and discussion
Most of the syntheses of the indazole derivatives reported
in the literature proceed from benzene precursors, in
which the pyrazole moiety was generated by ring closure
starting from isatines, phenylhydrazines or o-toluidi-
nes.11–13 Amongst these reactions, we found that the most
common ones proceed by a phase transfer catalyzed
reaction
from
o-methylbenzendiazonium
tetra-
fluoroborates.2,14 5-Methoxyindazole 3a and 5-bromoin-
dazole 3b were prepared in this way (Scheme 1).
3-Iodoindazoles 4a–d bearing either electron-withdraw-
ing or electron-donating substituents in position 5 were
obtained by direct iodination of indazoles 3 modifying7
the method previously described by Bocchi15 (Scheme 1).
As for our precedent work concerning the Heck cross-
coupling reaction of 3-iodoindazoles with acrylic deriva-
tives,8 our preliminary attempts of coupling reaction
from 4d with 1-propioloylpyrrolidine according to the
classical conditions of Sonogashira coupling demon-
strated the need for protecting the nitrogen group in the
N-1 position. Indeed, without protection there is no
coupling in position 3 and the product of the reaction is
mainly the adduct on N-1. On the other hand, when the
same reaction was conducted from the N-protected-3-
iodoindazoles 5–10, the reactions generally ran quickly
with high yield affording the indazolylpropiolamides
11–23 (Scheme 2).
These good results have to be compared with the lack of
reactivity of the methyl propiolate, which in our hands
and various conditions never gave the desired methylin-
dazolyl propiolate. Indeed, it has been documented that
terminal acetylenes containing an electron-withdrawing
group directly attached to the ethynyl carbon atom react
poorly with aryl halides.17,18 This obvious difference of
reactivity between ester and carboxamide acetylene
derivatives during the cross coupling reactions seems to
have not been well documented and we found only one
description of Sonogashira reactions using propiolamide
itself and N-methylpropiolamide.18 The lack of a more
detailed investigation on the cross coupling capability of
electron deficient propiolic amides is undoubtedly due to
All reactions were carried out according to the general procedure.20

A. Arnautu et al. / Tetrahedron Letters 43 (2002) 2695–2697
2697
We have to point out that the influence of the nature of
the substituents of the indazole on the benzene moiety
seems to have a very poor influence on the course of the
coupling reaction. Importantly, when this substituent is
a bromine atom, as for 9, cross couplings conducted at
room temperature are totally selective in position 3
without any double cross coupling products. However,
a second palladium-catalyzed cross coupling reaction
seems to be possible under more drastic conditions—
reactions that are currently investigated by us. Another
general comment concerning the N-protected group
could be as follows: Boc protection seems to be better
than Tos one. Indeed, we observed that Boc protecting
group was stable during this coupling reaction in con-
trast to Tos, which was partially cleaved as it can be
noted by comparison of the results in entries 6–7 or
10–11. Finally, the Boc group can be easily removed by
treatment with sodium methoxide in methanol at room
temperature.
Erickson-Viitanen, S.; Ko, S. S. Bioorg. Med. Chem. Lett.
1999, 9, 3217–3220.
7. Collot, V.; Dallemagne, P.; Bovy, P. R.; Rault, S. Tetra-
hedron 1999, 55, 6917–6922.
8. Collot, V.; Varlet, D.; Rault, S. Tetrahedron Lett. 2000,
41, 4363–4366.
9. Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron Lett. 2000,
41, 9053–9057.
10. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetra-
hedron Lett. 1975, 16, 4467–4770; reviews: Metal-cata-
lyzed Cross Coupling Reactions; Diederich, F.; Stang, P.
J., Eds.; Wiley-VCH: London, 1998; (b) Brandsma, L.;
Vasilevsky, S. F.; Verkruijsse, H. D. Application of Tran-
sition Metal Catalysts in Organic Synthesis; Springer:
Berlin, 1998.
11. Elderfield, R. C. In Heterocyclic Compounds; Elderfield,
R. C., Ed.; John Wiley & Sons, Inc.: New York, 1957;
Vol. 5, p. 162.
12. Behr, L. C.; Fusco, R.; Jarobe, C. H. In Pyrazoles,
Pyrazolines, Pyrazolidines, Indazoles and Condensed
Rings; Wiley, R. H., Ed.; International Wiley Science:
New York, 1969; p. 289.
13. Elguero, J. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R.; Rees, C. W., Eds.; Pergamon Press:
New York, 1984; Vol. 5, p. 167.
In conclusion, the Sonogashira cross-coupling reaction
of 3-iodoindazoles with various propiolic or propargylic
derivatives appears as a general method to prepare new
building blocks of interest in medicinal chemistry, as
for example new aza analogues of tryptamine deriva-
tives. Biological studies concerning these compounds
are currently in progress.
14. Bartsch, R. A.; Yang, I. W. J. Het. Chem. 1984, 21,
1063–1064.
15. Bocchi, V.; Palla, G. Synthesis 1982, 1096–1097.
16. Wrzeciono, U.; Pietkiewicz, K.; Niewegglowska, W.;
Michalska, W. Pharmazie 1979, 34, 20–22.
Acknowledgements
17. (a) Yoneda, N.; Matsuoka, S.; Miyaura, N.; Fukuhara,
T.; Suzuki, A. Bull. Chem. Soc. Jpn. 1990, 63, 2124–2126;
(b) Sakamoto, T.; Shiga, F.; Yasuhara, A.; Uchiyama,
D.; Kondo, Y.; Yamanaka, H. Synthesis 1992, 746–749;
(c) Kundu, N. G.; Dasqupta, S. K. J. Chem. Soc., Perkin
Trans. 1 1993, 2657–2663; (d) for a recent study of
Sonogashira couplings between electron deficient alkynes
and diaryliodonium salts, see: Radhakrishnan, U.; Stang,
P. J. Org. Lett. 2001, 3, 859–860.
The authors thank the Conseil Re´gional de Basse-Nor-
mandie and FEDER (Fonds Europe´ens de De´veloppe-
ment Economique Re´gional) for their financial support.
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20. General procedure for the preparation of N-protected
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