Heck cross-couplingg reaction of 3-iodoindazoles with methyl acrylate: A mild and flexible strategy to design 2-azatryptamines

Article abstract of DOI:10.1016/S0040-4039(00)00624-9

In order to design 2-azabioisosteres of tryptamine, serotonin or melatonin, the conditions of the Heck coupling reaction of 3-iodoindazoles with methyl acrylate are studied. This reaction authorizes the synthesis of 3-indazolylpropenoates as key intermediates to prepare 3-indazolylpropionic acids and 3-indazolylethylamines. The flexible synthetic strategy allows molecular diversity. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00624-9

Tetrahedron Letters 41 (2000) 4363±4366
Heck cross-coupling reaction of 3-iodoindazoles with
methyl acrylate: a mild and ¯exible strategy to design
2-azatryptamines
Valerie Collot, Didier Varlet and Sylvain Rault*
Â
Centre d'Etudes et de Recherche sur le Medicament de Normandie, UFR des Sciences Pharmaceutiques,
Â
5, rue Vaubenard, 14032 Caen, France
Received 20 March 2000; accepted 14 April 2000
Abstract
In order to design 2-azabioisosteres of tryptamine, serotonin or melatonin, the conditions of the Heck
coupling reaction of 3-iodoindazoles with methyl acrylate are studied. This reaction authorizes the synthesis
of 3-indazolylpropenoates as key intermediates to prepare 3-indazolylpropionic acids and 3-indazolylethyl-
amines. The ¯exible synthetic strategy allows molecular diversity. # 2000 Elsevier Science Ltd. All rights
reserved.
Although indazole is an azabioisostere of indole, very few publications are devoted to its
chemistry in comparison with the indole. However, some indazole derivatives such as 7-NI (nitric
oxide synthase inhibitor),1 YC-1 (guanylyl cyclase activator),2 granisetron (5HT-3 receptor
antagonist),3 lonidamine (cytotoxic modulator)4 or SE063 (HIV protease inhibitor),5 are already
considered as leads in medicinal chemistry. Aimed at studying mild and ¯exible strategies to
design new indazole libraries, we recently published a very ecient Suzuki cross-coupling reaction
leading to 3-arylindazoles.6 We report here a general and versatile pathway leading to 3-indazolyl-
propionic acid (3-(1H-indazol-3-yl)-propionic acid) and 3-indazolylethylamine (2-(1H-indazol-3-yl)-
ethylamine) via a Heck cross-coupling reaction of 3-iodoindazoles with methyl acrylate in the
presence of a catalytic amount of dichloro[1,10-bis(diphenylphosphino)ferrocene]palladium(II)
(PdCl2(dppf)).
3-Iodoindazoles 2 are obtained by direct iodination of indazoles 1 modifying6 the method
previously described by Bocchi and Palli.7
Preliminary attempts of coupling reaction from 3-iodoindazoles 2 demonstrated the necessity
of a protecting group in the N-1 position. When the cross-coupling reaction was conducted from
unprotected indazoles 2, it led only to the Michael adducts 12 without reaction at the 3 position
* Corresponding author. E-mail: rault@pharmacie.unicaen.fr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00624-9

4364
(Scheme 1). In contrast, when the same reaction was conducted from the N-protected-3-iodoindazoles
3, the coupling reaction was very ecient a€ording the propenoates 4.
Scheme 1. Heck cross-coupling reaction of 3-iodoindazoles with methyl acrylate. Reagents and conditions: (i) I2, KOH,
DMF, rt, 2 h (90%); (ii) methyl acrylate, PdCl2(dppf), TEA, TBAI, DMF, 50ꢀC, 2 h; (iii) PhCH2Br or TosCl, t-BuOK,
THF, 8 h (85%) or (Boc)2O, DMAP, TEA, CH3CN, 3 h (88%)
It must be pointed out that the Boc-protecting group was stable during this coupling reaction
in contrast to Tos which was partially cleaved. This is why Boc should be preferred as the labile-
protecting group. On the other hand, PdCl2(dppf) catalyst8 in a mixture of DMF:H2O containing
TEA and tetrabutylammonium iodide (TBAI) (Method A) was found to be superior9 to the
10
traditional Heck-coupling catalyst Pd(OAc)2/PPh3 (Method B) (Table 1).
Table 1
Eciency of various conditions on the formation of 3-indazolylpropenoates 4
Several attempts of reduction of the ethylenic double bond of 4 with sodium borohydride in the
presence of nickel(II) chloride hexahydrate11 showed that a preliminary cleavage of the Boc group
was necessary to prevent the formation of a mixture of protected and unprotected compounds

4365
during this reaction. So, prior to the reduction, the cleavage was easily realized with sodium
methoxide in methanol at room temperature to give the unprotected methyl propenoates 5 which
then were reduced to give the methyl 3-indazolylpropionates 6. Saponi®cation of the ester at
room temperature in an aqueous sodium hydroxide solution gave the 3-indazolylpropionic acids
7 (Scheme 2) in about 46% yield from the parent indazoles.
Scheme 2. Synthesis of 3-indazolylpropionic acids 7. Reagents and conditions: (i) MeONa, MeOH, rt, 1 h (100%); (ii)
.
NaBH4, NiCl2 6H2O, MeOH, rt, 6 h (85%); (iii) NaOH 6N, THF, rt, 6 h (95%)
Furthermore, in order to obtain 3-indazolylethylamine derivatives, we studied the conditions of
the Curtius rearrangement of 7a. At this stage the formation of the carbonyl azide via the mixed
anhydride needed the protection of N-1. Fortunately, we found that the N-1 protection and the
formation of the carbonyl azide could be achieved in one step, by adjusting the reaction condi-
tions. Thus, when the formation of the mixed anhydride intermediate was achieved with 2
equivalents of ethyl chloroformate in the presence of 2 equivalents of triethylamine, the reaction
gave quantitatively the protection of N-1 with the ethoxycarbonyl group. Treatment of this non-
isolated intermediate with 1 equivalent of sodium azide gave quantitatively the stable N-1-protected
propionyl azide 8a (Scheme 3).
Scheme 3. Synthesis of 3-indazolylethylamines. Reagents and conditions: (i) ClCO2Et (2 equiv.), TEA (2 equiv.), ace-
tone, 0ꢀC, NaN3 (>95%); (ii) n-butanol, 115ꢀC, 10 min (>95%); (iii) MeONa, MeOH, rt (95%); (iv) KOH 6N, DME,
re¯ux, 12 h (>95%)
Due to the relative stability of this carbonyl azide, the Curtius rearrangement was conducted at
115ꢀC in boiling n-butanol, leading quantitatively to the bis-protected 3-indazolylethylamine 9a.
Then the two protecting groups were cleaved selectively. Treatment of 9a with sodium methoxide
in methanol at room temperature produced the cleavage of the ethoxycarbonyl group to give the
monoprotected butyloxycarbonylethylamine 10a.12 Finally, deprotection of 10a was achieved in a
mixture of aqueous potassium hydroxide solution and DME at re¯ux overnight. The four-step
sequence of the rearrangement of the carboxylic acid 7a into amine 11a is quasi-quantitative.
In conclusion, the Heck cross-coupling reaction of 3-iodoindazoles with methyl acrylate
authorizes, in mild conditions, the design of new libraries of 2-aza analogues of indole derivatives

4366
with potent interest in medicinal chemistry. At each step the reaction conditions were adjusted to
be automated and to reach molecular diversity. Application of this strategy to the preparation of
serotonin and melatonin analogues will be published elsewhere with the biological results.
Acknowledgements
This work was supported by Conseil Regional de Basse-Normandie (Caen, France).
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1
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