Synthesis of 4- and 6-azaindoles via the fischer reaction

Article abstract of DOI:10.1021/ol902139r

Contrary to the common idea that Fischer indole cyclization often cannot be effectively applied to the synthesis of the corresponding azaindoles, we show that this approach can be actually very efficient for the formation of 4- and 6-azaindoles bearing an electron-donating group on the starting pyridylhydrazines. Two 4-azaindole natural product analogues were synthesized in a few steps and very good overall yields.

Full text of DOI:10.1021/ol902139r

ORGANIC
LETTERS
2009
Vol. 11, No. 22
5142-5145
Synthesis of 4- and 6-Azaindoles via the
Fischer Reaction
Matthieu Jeanty, Je´roˆme Blu, Franck Suzenet,* and Ge´rald Guillaumet
Institut de Chimie Organique et Analytique (ICOA), UniVersite´ d’Orle´ans,
UMR-CNRS 6005, BP 6759, rue de Chartres, 45067 Orle´ans cedex 2, France
franck.suzenet@uniV-orleans.fr
Received May 19, 2009
ABSTRACT
Contrary to the common idea that Fischer indole cyclization often cannot be effectively applied to the synthesis of the corresponding azaindoles,
we show that this approach can be actually very efficient for the formation of 4- and 6-azaindoles bearing an electron-donating group on the
starting pyridylhydrazines. Two 4-azaindole natural product analogues were synthesized in a few steps and very good overall yields.
Azaindoles are prevalent substructures in naturally occurring
and synthetic molecules displaying biological as well as
physicochemical activities. In the context of drug discovery,
these scaffolds have already shown their potential for
example as bioisosteres of the most biologically privileged
indole ring system. Consequently, the development of
efficient ways to prepare these compounds constitutes an
active and essential area of research.1
Among these classical approaches to the formation of
indole systems, the most well-known and versatile Fischer
indole cyclization8 (scheme 1) has rarely been applied to
Scheme 1. Fischer Synthesis of Indoles
Most of the methods used to form azaindoles have been
inspired, over the years, by various synthetic strategies
developed for indole ring formation. These methods include
the Madelung-type cyclization,2 the Reissert-type procedure,3
the Leimgruber-Batcho reaction,4 the Lorenz-type cycliza-
tion,5 palladium-catalyzed heteroannulations,6 and the Bartoli
sequence.7
azaindole chemistry. This fact can be attributed to the
unfavorable electron-deficient character of the pyridine ring
in the [3,3]-sigmatropic rearrangement step of heterocycliza-
tion.9
Thus, very few examples of Fischer indole syntheses have
been reported for the formation of azaindoles. Although the
(1) For general reviews about synthesis and reactivity of azaindoles,
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2007, 63, 1031. (b) Popowycz, F.; Me´rour, J.-Y.; Joseph, B. Tetrahedron
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6, 775. (c) Dodd, R. H.; Doisy, X.; Potier, P. Heterocycles 1989, 28, 1101.
(d) Curtis, N. R.; Kulagowski, J. J.; Leeson, P. D.; Ridgill, M. P.; Emms,
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Dodd, R. H.; Ouanne`s, C.; Robert-Gre´co, M.; Potier, P. J. Med. Chem.
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Curtis, N. R.; Kulagowski, J. J.; Leeson, P. D.; Ridgill, M. P.; Emms, F.;
Freedman, S. B.; Patel, S. Bioorg. Med. Chem. Lett. 1999, 9, 585. (d) Park,
S. S.; Choi, J.-K.; Yum, E. K.; Ha, D.-C. Tetrahedron Lett. 1998, 39, 627.
(e) Xu, L.; Lewis, I. R.; Davidsen, S. K.; Summers, J. B. Tetrahedron Lett.
1998, 39, 5159. (f) Ujjainwalla, F.; Warner, D. Tetrahedron Lett. 1998,
39, 5355. (g) Fang, Y.-Q.; Yuen, J.; Lautens, M. J. Org. Chem. 2007, 72,
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K. J. J. Chem. Soc., Chem. Commun. 1975, 493. (b) Mahadevan, I.;
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10.1021/ol902139r CCC: $40.75
Published on Web 10/19/2009
 2009 American Chemical Society

earliest attempts can be traced back to 1913,10 the first
positive result for 4-azaindoles appeared in the 1940s with
the synthesis of 5-chloro-2-methyl-4-azaindole in 12%
yield.11
deprotection proceeding in situ) (Table 1). Linear and cyclic
alkyl ketones as well as alkylketals were efficient substrates
In 1957, Fischer reactions were reported to run in the
absence of acid12 or in the presence of ZnCl2 by heating
13
Table 1. Aza-Fischer Cyclization from 1 and Ketones or Ketals
to 180-250 °C. These harsh thermal conditions have proved
unpopular for the preparation of azaindoles,14 and the
published results remained moderate in terms of yields,
chemical functions tolerance, and/or isomers formation
selectivity. Over the past 20 years, despite sporadic examples
of azaindole ring formation via the Fischer reaction,15
this method is still perceived as inappropriate for the
synthesis of azaindoles.16 In this Letter, we wish to counteract
this ide´e rec¸ue and show the extraordinary efficiency of
Fischer cyclization for the formation of 4- and 6-azaindoles.
Considering that Fischer indole syntheses are often more
efficient when involving arylhydrazines bearing electron-
donating groups,17 we started our investigation on the aza-
Fischer cyclization with 6-methoxypyrid-3-ylhydrazine 1. At
this stage, it is worth noting that the absence of symmetry
in 1 could allow the formation of two azaindole isomers
(Scheme 2).
Scheme 2
.
Expected Isomers in the Azaindole Fischer Synthesis
from Pyrid-3-ylhydrazines
We first treated pyridylhydrazine 1, prepared by formation
and reduction of the corresponding diazonium salt,18 with
valeraldehyde in refluxing aqueous H2SO4 (4 wt %). After
2 h, we successfully isolated the 4-azaindole isomer 2 in
80% yield with no detectable amounts of the 6-azaindole
isomer as determined by NMR (Scheme 3).
a Isolated yield after column chromatography. b Degradation products
were observed.
Scheme 3
.
Synthesis of 5-Methoxy-3-propyl-4-azaindole 2 via
the Fischer Reaction
(entries 1-4). Nonsymmetric pentan-2-one was treated
through the thermodynamic ene-hydrazine isomer to furnish
only azaindole 6 (entry 4). The azaindole isomer resulting
from cyclization through the terminal CH3 of the methylke-
tone was not observed. This lack of reactivity was confirmed
with acetophenone (entry 6) and protected acetaldehyde
(entry 5), no azaindole being recovered. The reaction was
also applicable in the presence of functional groups (entries
7-9). Interestingly, using protected 4-chlorobutanal, we did
not recover the expected azatryptamine as observed for indole
series,19 but we isolated the hydroxy derivative 8 resulting
Evaluation of various carbonyl derivatives showed that this
strategy is effective for a range of ketones or ketals (aldehyde
(7) Zhang, Z.; Yang, Z.; Meanwell, N. A.; Kadow, J. F.; Wang, T. J.
Org. Chem. 2002, 67, 2345.
(8) For reviews, see: (a) Humphrey, G. R.; Kuethe, J. T. Chem. ReV.
2006, 106, 2875. (b) Hughes, D. L. Org. Prep. Proc. Int. 1993, 25, 607.
(c) Ganem, B. Acc. Chem. Res. 2009, 42, 463.
(11) Takahashi, T.; Saikachi, H.; Goto, H.; Shimamura, S. J. Pharm.
Soc. Jpn. 1944, 64, 7.
(9) (a) Dollinger, M.; Henning, W.; Kirmse, W. Chem. Ber. 1982, 115,
2309. (b) Crooks, P. A.; Robinson, B. Can. J. Chem. 1969, 47, 2061.
(10) (a) Perkin, W. H.; Robinson, R. J. Chem. Soc. 1913, 1973. (b)
Fargher, R. G.; Furness, R. J. Chem. Soc. 1915, 688.
(12) Fitzpatrick, J. T.; Hiser, R. D. J. Org. Chem. 1957, 22, 1703.
(13) (a) Abramovitch, R. A.; Adams, K. A. Can. J. Chem. 1962, 40,
864, and references therein. (b) Ficken, G. E.; Kendall, J. D. J. Chem. Soc.
1959, 3202.
Org. Lett., Vol. 11, No. 22, 2009
5143

probably from chlorine substitution prior to Fischer cycliza-
tion. Finally, using a nonsymmetric ketone, the competing
formation of two different stable ene-hydrazine intermediates
was observed, and the regioselectivity of the cyclization
seemed to be oriented by steric effects (entry 9).
These excellent results prompted us to investigate the
influence of the methoxy group on the starting pyridylhy-
drazine 1 in achieving this cyclization. We first replaced the
methoxy group with a hydrogen atom. Attempts to synthesize
the corresponding hydrazine were plagued by the formation
of a complex mixture of products, probably due to the lack
of stability of the hydrazine function. At this stage, the
corresponding highly stable bisphenylhydrazone 10 was
synthesized and led to a total absence of cyclization after
24 h (Scheme 4). A similar assessment was noted when the
accordance with literature results.11,13 On the basis of these
mechanistic considerations, the success of Fischer aza-
indolization may be predicted with simple rules: pyridylhy-
drazine substrates bearing an electron-donating group on a
position ortho or para to the hydrazine function could
preferably help the heterocyclization in position 2 of the
pyridine ring (or position 4 if position 2 is already substi-
tuted) in refluxing aqueous H2SO4 (4 wt %).
To check the relevance of these rules, we first used
3-hydrazinyl-2-methoxypyridine 12,23 expected to be a
favorable substrate for Fischer cyclization. Cyclohexanone
and protected phenylacetaldehyde were refluxed in aqueous
H2SO4 (4 wt %) for 2 h with 12, and the corresponding
6-azaindoles were indeed isolated in 55% and 60% yields,
respectively (Scheme 6).
Scheme 6. Favorable 6-Azaindoles Aza-Fischer Synthesis
Scheme 4. Substituent Effects on the Aza-Fischer Cyclization
On the other hand, the expected unfavorable substrate
2-hydrazinyl-6-methoxypyridine 15, obtained by aromatic
nucleophilic substitution of the 2-chloro-6-methoxy-py-
ridine with hydrazine, was treated with cyclohexanone.
As postulated, the 7-azaindole product was not isolated
under the previously defined experimental conditions
(Scheme 7).
methoxy group is meta to the hydrazone function (compound
11).20
From all of these considerations, the following mechanism
was postulated to explain the crucial role played by the
electron-donating group on the increased reactivity and high
regioselectivity of the cyclization process (Scheme 5).
Scheme 5. Proposed Mechanism
Scheme 7. Unfavorable 7-Azaindole Aza-Fischer Synthesis
To check whether other electron-donating groups would
be suitable for this Fischer cyclization, we introduced the
(15) (a) Bernardino, A. M.; Ain Khan, M.; de Oliveira Gomes, A.
Heterocycl. Commun. 2000, 6, 463. (b) Helissey, P.; Parrot-Lopez, H.;
Renault, J.; Cros, S.; Paoletti, C. Eur. J. Med. Chem. 1987, 22, 277. (c)
Shindo, H.; Fujishita, T.; Sasatani, T.; Chomei, N.; Takada, S. Heterocycles
1989, 29, 899. (d) Ain Khan, M.; da Rocha, J. F. J. Heterocycl. Chem.
1978, 15, 913. (e) Bisagni, E.; Nguyen, C. H.; Pierre´, A.; Pe´pin, O.; de
Cointet, P.; Gros, P. J. Med. Chem. 1988, 31, 398. (f) Chen, Y.; Chung,
C.; Chen, I.; Chen, P.; Jeng, H. Bioorg. Med. Chem. 2002, 10, 2705. (g)
Nguyen, C. H.; Bisagni, E. Tetrahedron 1987, 43, 527. (h) Bisagni, E.;
Ducrocq, C.; Civier, A. Tetrahedron 1976, 32, 1383. (i) Hung, N. C.;
Bisagni, E. Tetrahedron 1986, 42, 2303. (j) Nguyen, C.; Lhoste, J.-M.;
Lavelle, F.; Bissery, M.-C.; Bisagni, E. J. Med. Chem. 1990, 33, 1519.
(16) Only very recently, Lachance and colleagues described the 6-aza-
indole synthesis under thermal conditions. Lachance, N.; Bonhomme-
Beaulieu, L.-P.; Joly, P. Synthesis 2009, 721.
Following the generally accepted pathways for Fischer
indole synthesis formulated by Robinson and Robinson in
1924,21 the mesomeric effect of the methoxy group is thought
to promote the N-N bond cleavage (push effect).9,17,22
Concomitantly, the pyridinium nitrogen may help the new
C-C bond formation (pull effect).
Therefore, a tandem push-pull effect could explain the
unusual reactivity of this aza-indolization (Scheme 5), the
cyclization at the R-position of the pyridine ring being in
(17) (a) Ishii, H. Acc. Chem. Res. 1981, 14, 275. (b) Hughes, D. L.
Org. Prep. Proc. Int. 1993, 25, 607.
(14) (a) Okuda, S.; Robison, M. J. Am. Chem. Soc. 1959, 81, 740. (b)
Kelly, A. H.; McLeod, D. H.; Parrick, J. Can. J. Chem. 1965, 43, 296. (c)
Kelly, A. H.; Parrick, J. Can. J. Chem. 1966, 44, 2455. (d) Crooks, P. A.;
Robinson, B. Can. J. Chem. 1969, 47, 2061.
(18) Regan, J.; Capolino, A.; Cirillo, P. F.; Gilmore, T.; Graham, A. G.;
Hickey, E.; Kroe, R.; Madwed, J.; Moriak, M.; Nelson, R.; Pargellis, C. A.;
Swinamer, A.; Torcellini, C.; Tsang, M.; Moss, N. J. Med. Chem. 2003,
46, 4676.
5144
Org. Lett., Vol. 11, No. 22, 2009

methylsulfanyl electron-donating group on the 2-chloro-5-
nitropyridine 16. Reduction of the nitro group into the amine
1724 followed by hydrazine synthesis according to the
standard procedure allowed Fischer cyclization with valer-
aldehyde to afford 5-methylsulfanyl-4-azaindole 18 in 57%
yield (Scheme 8).
Finally, to show the great interest of this methodology in
term of simplicity, step economy, and efficiency, we
performed the synthesis of the 4-azaindole analogue 22 of
the well-known melatonin neurohormone27 in 69% yield over
only two steps from 1 (Scheme 10). We then focused on the
Scheme 10. Synthesis of 4-Azamelatonin and 4-Azaglycozoline
Scheme 8
.
Methylsulfanyl Group in the Fischer Azaindole
Synthesis
To further extend the scope of this efficient synthesis of
4- and 6-azaindoles, the methoxy group of 2 was treated with
BBr3,25 and the resulting 5-hydroxy-4-azaindole 19 was
isolated in 69% yield and afterward transformed in the
corresponding triflate derivative 20 with Tf2O (Scheme 9).26
anticancer carbazoles series and synthesized in two steps
from 1 the 4-aza analogue 24 of the natural glycozoline
(extracted from the root bark of Glycosmis pentaphylla)28
(Scheme 10).
In summary, we have shown that Fischer indole synthesis
can indeed be used efficiently for the synthesis of 4- and
6-azaindoles and thus presents most of the advantages known
and recognized for this cascade cyclization. The ubiquity of
the indoles in natural products combined with the pharma-
ceutical relevance of this heterocyclic substructure should
render this approach broadly useful to develop azaindole
analogues. Work is in progress to extend the scope of this
efficient synthesis.
Scheme 9
.
Toward a Wider Scope of Subsituents in the
Azaindole Core
Acknowledgment. The authors acknowledge Les Labo-
ratoires Servier for financial support (M.J.).
At this stage, the triflate moiety could allow the introduction
of numerous substituents.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(19) Grandberg, I. I.; Zuyanova, T. I.; Afonina, N. I.; Ivanova, T. A.
Dokl. Akad. Nauk SSSR 1967, 176, 583.
(20) We first confirmed that hydrazone A reacts as well as hydrazine 1
with valeraldehyde to successfully furnish azaindole 2 (scheme).
OL902139R
(25) Larraya, C.; Guillard, J.; Renard, P.; Audinot, V.; Boutin, J. A.;
Delagrange, P.; Bennejean, C.; Viaud-Massuard, M.-C. Eur. J. Med. Chem.
2004, 39, 515.
This result is in accordance with a report by Buchwald and colleagues:
Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120,
6621.
(26) Mouaddib, A.; Joseph, B.; Hasnaoui, A.; Merour, J.-Y. Synthesis
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Murakami, Y. J. Chem. Soc., Perkin Trans. 1 1989, 2407.
(23) See the Supporting Information.
(24) Takemoto, T.; Eda, M.; Okada, T.; Sakashita, H.; Matzno, S.;
Gohda, M.; Ebisu, H.; Nakamura, N.; Fukaya, C.; Hiara, M.; Eiraku, M.;
Yamanouchi, K.; Yokoyama, K. J. Med. Chem. 1994, 37, 18.
(27) Azamelatonin synthesis was recently described in 4 steps in 17%
overall yield: Jeanty, M.; Suzenet, F.; Guillaumet, G. J. Org. Chem. 2008,
73, 7390. For the first synthesis of 4-azamelatonin, see: Maze´as, D.;
Guillaumet, G.; Viaud, M.-C. Heterocycles 1999, 50, 1065.
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D. P. Phytochemistry 1969, 8, 769.
Org. Lett., Vol. 11, No. 22, 2009
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