Synthesis of C3-substituted 4-azaindoles: An easy access to 4-azamelatonin and protected 4-azatryptophan

Article abstract of DOI:10.1021/jo8011623

(Chemical Equation Presented) C3-Substituted-4-azaindoles were synthesized from pyridylacetonitriles in a two-step sequence allowing the easy introduction of a range of substituents. This strategy permits the rapid synthesis of 4-azamelatonin and a protec

Full text of DOI:10.1021/jo8011623

SCHEME 1. Synthesis of 5-Methoxy-4-azaindole by
Makosza and Co-workers
Synthesis of C3-Substituted 4-Azaindoles: An
Easy Access to 4-Azamelatonin and Protected
4-Azatryptophan
Matthieu Jeanty, Franck Suzenet,* and Ge´rald Guillaumet
Institut de Chimie Organique et Analytique (ICOA),
UMR-CNRS 6005, UniVersite´ d’Orle´ans BP 6759, rue de
Chartres, 45067 Orle´ans cedex 2, France
Friedel-Crafts acylations,6 condensations with piperidones,7 and
additions to aryl disulfides8 have been disclosed in the literature.
With the exception of halogenations and acylations, no reliable
and general procedure for derivatizing the C3 position of
azaindoles has emerged, and conditions are generally optimized
for individual substrates.
franck.suzenet@uniV-orleans.fr
ReceiVed May 29, 2008
In this paper focusing on the 4-azaindole isomer, we wish to
present a versatile approach to unprecedented C-3 substituted
4-azaindoles, with an increased scope and a high synthetic
efficiency. To this end, we have been interested in the synthesis
of 4-azaindole described by Makosza and co-workers.9 Cya-
nomethylation of 5-methoxy-3-nitropyridine via a vicarious
nucleophilic substitution of hydrogen gave pyridylacetonitrile
1a, whose subsequent heterocyclisation under hydrogenation
conditions provided the expected 4-azaindole 2 (Scheme 1).
First, we envisaged to take advantage of the acidity of the
methylene group in 1a to introduce various substituents prior
to the heterocyclisation under palladium-catalyzed hydrogena-
tion conditions. This methodology, barely applied in indole
chemistry,10 could be of particular interest for a rapid access to
C3-substituted 4-azaindoles with a wide range of functionalities.
Previous attempts by Macor et al.11 to prepare azaindoles by
this method resulted in the sole isolation of 3-methyl-4-azaindole
in only 16% yield. Although they successfully carried out
Mitsonobu reactions with 1a, the subsequent cyclization step
failed.
Since alkyl chains could not be directly introduced at the C3
position of the 4-azaindole by Friedel-Craft alkylation, we first
investigated the alkylation of pyridylacetonitriles 1a and 1b
followed by their heterocyclisation under hydrogenation condi-
tions. Results are reported in Table 1.
Deprotonation of 1a and 1b with a weak base such as
potassium carbonate and subsequent alkylation with benzyl and
primary alkyl halides afforded products 3a-3f in moderate to
C3-Substituted-4-azaindoles were synthesized from pyridy-
lacetonitriles in a two-step sequence allowing the easy
introduction of a range of substituents. This strategy permits
the rapid synthesis of 4-azamelatonin and a protected
4-azatryptophan.
In contrast to the plethora of natural products containing an
indole moiety, only few incorporate an azaindole ring. This
bioisoster of indole possessing remarkable physicochemical and
pharmacological properties now attracts increasing interest from
the chemistry community.1
The fusion of an electron-deficient pyridine ring with a pyrrole
ring, forming an azaindole, alters the electronic properties of
the π-system, rendering such heteroaromatic rings less reactive
than indoles toward electrophilic reagents. As a consequence,
direct functionalization at the C3 position with electrophiles is
not as straightforward as for indoles. To date, few examples of
nitrations,2 halogenations,3 formylations,4 Mannich reactions,5
(1) (a) Song, J. J.; Reeves, J. T.; Gallou, F.; Tan, Z.; Yee, N. K.; Senanayake,
C. H. Chem. Soc. ReV. 2007, 36, 1120. (b) Me´rour, J.-Y.; Joseph, B. Curr. Org.
Chem 2001, 5, 471, and references therein. (c) Popowycz, F.; Routier, S.; Joseph,
B.; Me´rour, J.-Y. Tetrahedron 2007, 63, 1031. (d) Popowycz, F.; Me´rour, J.-
Y.; Joseph, B. Tetrahedron 2007, 63, 8689. (e) Prokopov, A. A.; Yakhontov,
L. N. Khim. Farm. Zh. 1994, 28, 30 CAN 122: 31364. (f) Hyaric, M.; Viera de
Almeida, M.; Nora de Souza, M. V. Quim. NoVa 2002, 25, 1165. (g) For
physicochemical properties see: Wu, P.-W.; Hsieh, W.-T.; Cheng, Y.-M.; Wei,
C.-Y.; Chou, P.-T. J. Am. Chem. Soc. 2006, 128, 14426. (h) Cash, M. T.;
Schreiner, P. R.; Phillips, R. S. Org. Biomol. Chem. 2005, 3, 3701.
(2) Bychikhina, N. N.; Azimov, V. A.; Yakhontov, L. N. Khim. Geterotsikl.
Soedin. 1982, 3, 356; Chem. Abstr. 1982, 97, 6190.
(3) (a) Papageorgiou, C.; Camenisch, G.; Borer, X. Bioorg. Med. Chem. Lett.
2001, 11, 1549. (b) Gallou, F.; Reeves, J. T.; Tan, Z.; Song, J. J.; Yee, N. K.;
Harcken, C.; Liu, P.; Thomson, D.; Senanayake, C. H. Synlett 2007, 2, 211.
(4) (a) Van de Poe¨l, H.; Guillaumet, G.; Viaud-Massuard, M.-C. Tetrahedron
Lett. 2002, 43, 1205. (b) 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.
(7) (a) Macor, J. E.; Newman, M. E. Heterocycles 1990, 31, 805. (b) Filla,
S. A.; Mathes, B. M.; Jonhson, K. W.; Phebus, L. A.; Cohen, M. L.; Nelson,
D. L.; Zgombick, J. M.; Erickson, J. A.; Schenck, K. W.; Wainscott, D. B.;
Branchek, T. A.; Schaus, J. M. J. Med. Chem. 2003, 46, 3060.
(8) Ahmed, M.; Briggs, M. A.; Bromidge, S. M.; Buck, T.; Campbell, L.;
Deeks, N. J.; Garner, A.; Gordon, L.; Hamprecht, D. W.; Holland, V.; Johnson,
C. N.; Medhurst, A. D.; Mitchell, D. J.; Moss, S. F.; Powles, J.; Seal, J. T.;
Stean, T. O.; Stemp, G.; Thompson, M.; Trail, B.; Upton, N.; Winborn, K.;
Witty, D. R. Bioorg. Med. Chem. Lett. 2005, 15, 4867.
(9) Makosza, M.; Danikiewicz, W.; Wojciechowski, K. Liebigs Ann. Chem.
1988, 203.
(10) (a) Walker, G. N. J. Am. Chem. Soc. 1955, 77, 3844. (b) Snyder, H. R.;
Merica, E. P.; Force, C. G.; White, E. G. J. Am. Chem. Soc. 1958, 80, 4622. (c)
Walker, G. N. J. Med. Chem. 1965, 8, 583. (d) Marino, J. P.; Hurt, C. R. Synth.
Commun. 1994, 24, 839. (e) Humphrey, G. R.; Kuethe, J. T. Chem. ReV. 2006,
106, 2875. (f) Belley, M.; Sauer, E.; Beaudoin, D.; Duspara, P.; Trimble, L. A.;
Dube´, P. Tetrahedron Lett. 2006, 47, 159. (g) Belley, M.; Beaudoin, D.; Duspara,
P.; Sauer, E.; St-Pierre, G.; Trimble, L. A. Synlett 2007, 19, 2991. (h) Belley,
M.; Beaudoin, D.; St-Pierre, G. Synlett 2007, 19, 2999.
(5) Yakhontov, L. N.; Azimov, V. A. Khim. Geterotsikl. Soedin. 1970, 6,
32; Chem. Abstr. 1970, 72, 121396.
(6) Zhang, Z.; Yang, Z.; Wong, H.; Zhu, J.; Meanwell, N. A.; Kadow, J. F.;
Wang, T. J. Org. Chem. 2002, 67, 6226.
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7390 J. Org. Chem. 2008, 73, 7390–7393
10.1021/jo8011623 CCC: $40.75 2008 American Chemical Society
Published on Web 08/26/2008

TABLE 1. Direct Alkylation of Pyridylacetonitriles 1a and 1b
Followed by 4-Azaindole Ring Formation
SCHEME 2. Solvent Effect on the Cyclisation of 3e
SCHEME 3. Michael Additions on Pyridinylacetonitrile 1a
Followed by 4-Azaindoles Ring Formation
base such as LDA did not result in any improvement. Finally,
Michael additions with acrylonitrile and ethyl acrylate were
accomplished under smooth conditions in moderate to good
yields employing benzyltrimethylammonium methoxide.13 Sub-
sequent heterocyclisation afforded azaindoles 7a and 7b in 43%
and 36% yield, respectively.
To further extend the scope of this methodology, Knoevenagel
condensations on 1a and 1b were also carried out. Results of
the condensation and the subsequent 4-azaindole ring formation
are reported in Table 2. Most of the aromatic aldehydes
employed in the Knoevenagel condensation reacted in high
yields (up to 97%, Table 2, entry 5). The subsequent 4-azaindole
ring formation was carried out in yields ranging between 41%
and 55% (Table 2, entries 1-5). However, with indole-3-
carboxaldehyde (Table 2, entry 6), we did not manage to isolate
any product. Modification of the reaction time or the solvent
(ethyl acetate) did not improve the reactivity. The steric
hindrance of the indole ring could be ruled out as the reason
for the failure of the cyclization (Table 2, entry 6 vs entry 2
with the naphthalene ring) and we incriminated the heteroaroa-
tom present on the aldehyde. This hypothesis was confirmed
when pyrrole-2-carboxaldehyde (Table 2, entry 7) and thiophene-
2-carboxaldehyde (Table 2, entry 8) were employed, since none
of the conditions used allowed formation of the desired products.
The lack of reactivity may be due to the electron-rich character
of these heterocycles, which prevents addition of the amine onto
the nitrile.
To emphasize the great interest of this methodology for the
rapid synthesis of biologically active compound analogues, we
performed the synthesis of 4-azamelatonin 10 and protected
4-azatryptophan 12.
In the literature, a synthesis of 4-azamelatonin has been
reported in six steps with an overall yield of 3.6%.14 Employing
our strategy, key azaindole 4f was readily obtained. Hydrogena-
tion of 4f with Raney nickel as catalyst in acetic anhydride gave
successfully 4-azamelatonin 10 in only four steps with an overall
yield of 17% (Scheme 4).
a After a column flash chromatography. b 0.5 equiv of K2CO3 was
used in DMF as solvent. c DMF/CH3CN mixture was used as solvent.
d EtOH/MeOH mixture was used as solvent. e EtOH was used as
solvent.
high yields. Several solvents and reaction temperatures were
screened to minimize the formation of the bis-alkylated deriva-
tives responsible for the moderate yields (Table 1, entries 3 and
6). Intermediates 3a-3f were then hydrogenated to provide the
corresponding C3-alkylated 4-azaindoles in reasonable yields.
Adding acetic acid as cosolvent increased the rate of the
conversion but did not improve the yields. This strategy proved
to be compatible with functional groups present on the side chain
(Table 1, entries 5 and 6) and rapidly afforded original
4-azaindoles in moderate to good yields.
It is important to note that the nature of the solvent is crucial.
Indeed, as already documented in the literature with phenylac-
etonitriles,12 the cyclization of 3e in ethyl acetate furnished
exclusively the tetrahydro-naphtyridine ring (Scheme 2).
Encouraged by these first successful attempts, we investigated
what the outcome of a Michael addition/hydrogenation sequence
with 1a would be (Scheme 3).
Despite the potential pharmacological and biological proper-
ties of a 4-aza analogue of tryptophan, the synthesis of such a
Our first attempt toward a 1,4-addition with 1a using
potassium carbonate was unsuccessful. The use of a stronger
(13) Comoy, C.; Marot, C.; Podona, T.; Baudin, M.-L.; Morin-Allory, L.;
Guillaumet, G.; Pfeiffer, B.; Caignard, D.-H.; Renard, P.; Rettori, M.-C.; Adam,
G.; Guardiola-Lemaˆıtre, B. J. Med. Chem. 1996, 39, 4285.
(12) (a) Kotzamani, H. K. J. Heterocycl. Chem. 1995, 32, 947. (b) Makosza,
M.; Stalewski, J. Tetrahedron 1995, 51, 7263.
(14) Maze´as, D.; Guillaumet, G.; Viaud, M.-C. Heterocycles 1999, 50, 1065.
J. Org. Chem. Vol. 73, No. 18, 2008 7391

SCHEME 4. New Synthesis of the 4-Azamelatonine 10a
TABLE 2. Knoevenagel Condensations on Pyridyl-acetonitriles
Followed by 4-Azaindoles Ring Formation
a Reagents and conditions: (i) 4-chlorophenoxyacetonitrile, tBuOK, THF,
-10 °C; (ii) BrCH2CN, K2CO3, DMF; (iii) H2, Pd/C, EtOH/AcOH; (iv)
H2, Raney Ni, Ac2O.
SCHEME 5. Synthesis of Protected 4-Azatryptophan 12
4-azaindoles. Moreover, most of the starting pyridylacetonitriles
being commercially available or readily obtained,15 the method
appears to be quite general. This strategy has also proved to be
very useful for the synthesis of aza-analogues of biologically
active compounds.
Experimental Section
General Procedure for Direct Alkylations. 2-Cyanomethyl-6-
methoxy-3-nitropyridine 1a or 2-cyanomethyl-3-nitropyridine 1b
was dissolved in the appropriate solvent (see Table 1). Potassium
carbonate was added to this solution, and the corresponding alkyl
halide was introduced dropwise. After stirring for a few hours, the
solution was slightly acidified to pH 4 with a 1 N HCl solution.
The mixture was extracted twice with ethyl acetate, dried over
MgSO4, and concentrated. The crude material was purified by flash
column chromatography with the appropriate eluent.
2-(3-Nitropyridin-2-yl)-3-phenylpropionitrile (3a). The desired
product was obtained according to the general procedure using 200
mg (1.22 mmol) of compound 1b, 338 mg (2.45 mmol) of
potassium carbonate, and 117 µL (1.22 mmol) of benzyl bromide
in 5 mL of acetonitrile. The solution was stirred for 3 h at room
temperature. The product was isolated with petroleum ether/ethyl
acetate (8/2 then 6/4) as eluent as a white solid (80%). Mp ) 146
1
°C. IR (thin film, NaCl): 2220, 1596, 1523, 1350 cm-1. H NMR
(250 MHz, CDCl3): δ 3.36 (d, J ) 7.5 Hz, 2H), 5.10 (t, J ) 7.5
Hz, 1H), 7.26-7.33 (m, 5H), 7.54 (dd, J ) 8.5 Hz, J ) 4.6 Hz,
1H), 8.37 (dd, J ) 8.5 Hz, J ) 1.5 Hz, 1H), 8.94 (dd, J ) 4.6 Hz,
J ) 1.5 Hz, 1H). 13C NMR (62.5 MHz, CDCl3): δ 39.6, 39.8, 118.6,
124.3, 127.8, 129.0, 129.3, 133.6, 135.9, 144.6, 149.7, 153.9. HRMS
calcd for C14H11N3O2 [M + H]+: 254.0930, found 254.0937.
General Procedure for 1,4-Additions. 2-Cyanomethyl-6-meth-
oxy-3-nitropyridine 1a or 2-cyanomethyl-3-nitropyridine 1b was
dissolved in methanol under argon, and then a catalytic amount of
benzyltrimethylammonium methoxide (40 wt % solution in metha-
nol) was added to this solution. The Michael acceptor was added
dropwise, and the mixture was stirred at 50 °C during the
appropriate time (see Table 2). The crude was diluted with ethyl
acetate and washed with a 1 N HCl solution, brine, and finally
with water. The organic layer was dried over MgSO4 and
concentrated. The crude material was purified by flash column
chromatography with the appropriate eluent.
a Degradation products were obtained.
compound has never been described, to the best of our
knowledge, in the literature. Applying our sequence, pyridine
1b was alkylated with methyl 2-acetamidoacrylate (Michael
acceptor), and the resulting product was subjected to the
heterocyclization conditions to furnish protected 4-azatryptophan
12 in two steps (Scheme 5).
In summary, we have described a straightforward preparation
of C3-substituted 4-azaindoles by means of the functionalization
of pyridylacetonitriles. This method can be used with a wide
range of electrophiles allowing the synthesis of unprecedented
(15) Katz, R. B.; Voyle, M. Synthesis 1989, 314.
7392 J. Org. Chem. Vol. 73, No. 18, 2008

Methyl 4-Cyano-4-(6-methoxy-3-nitropyridin-2-yl)butanoate
(6a). The desired product was obtained according to the general
procedure using 200 mg (1.03 mmol) of compound 1a, 200 µL
(0.5 mmol) of benzyltrimethylammonium methoxide, and 97 µL
(1.08 mmol) of methyl acrylate in 10 mL of methanol. The solution
was stirred for 1.5 h at 50 °C. The product was isolated with
petroleum ether/ethyl acetate (8/2) as eluent as a white solid (80%).
Mp ) 102 °C. IR (thin film, NaCl): 2944, 2247, 1733, 1596, 1334,
1023 cm-1. 1H NMR (250 MHz, CDCl3): δ 2.40 (dd, J ) 7.3 Hz,
J ) 6.9 Hz, 2H), 2.67 (t, J ) 7.3 Hz, 2H), 3.68 (s, 3H), 4.11 (s,
3H), 5.09 (t, J ) 6.9 Hz, 1H), 6.86 (d, J ) 9.1 Hz, 1H), 8.35 (d,
J ) 9.1 Hz, 1H). 13C NMR (62.5 MHz, CDCl3): δ 28.2, 31.2, 36.6,
52.0, 55.3, 112.0, 118.3, 136.9, 138.6, 149.4, 165.5, 172.2. HRMS
calcd for C12H13N3O5 [M + H]+: 302.0753, found 302.0759.
General Procedure for Knoevenagel Condensations. 2-Cya-
nomethyl-6-methoxy-3-nitropyridine 1a or 2-cyanomethyl-3-nitro-
pyridine 1b was dissolved in absolute ethanol (generally 5 mL for
200 mg of substrate). To this solution were added the aldehyde
and one drop of piperidine. The mixture was stirred overnight then
filtered. The solid was washed with a small amount of diethyl ether
and dried under vacuum.
3-Benzyl-1H-pyrrolo[3,2-b]pyridine (4a). The desired product
was obtained according to the general procedure using 800 mg (3.16
mmol) of compound 3a, in 40 mL of the ethanol/acetic acid mixture.
The solution was hydrogenated for 5.5 h at 35 °C. The product
was isolated with petroleum ether/ethyl acetate (1/1) as eluent as a
white solid (53%). Mp ) 155 °C. IR (thin film, NaCl): 1493, 1455,
1
1413, 1288 cm-1. H NMR (400 MHz, CDCl3): δ 4.22 (s, 2H),
7.01-7.28 (m, 7H), 7.58 (d, J ) 6.8 Hz, 1H), 8.46 (bs, 1H), 9.31
(bs, 1H). 13C NMR (100 MHz, CDCl3): δ 30.3, 116.5, 116.9, 118.5,
126.0, 126.5, 128.4, 128.9, 129.4, 141.3, 142.7, 145.1. HRMS calcd
for C14H12N2 [M + H]+: 209.1079, found 209.1080.
4-Azamelatonin (10). In a hydrogenation reactor, 823 mg (4.42
mmol) of compound 4f was dissolved in 30 mL of acetic anhydride.
To this solution were added 544 mg (6.63 mmol) of sodium acetate
and a catalytic amount of Raney nickel. The mixture was
hydrogenated for 24 h under 60 psi of hydrogen at room temper-
ature. The crude was then filtered through a short plug of celite.
After the addition of 60 mL of ethyl acetate to the filtrate, acetic
anhydride was quenched by the addition of a saturated solution of
Na2CO3. The organic layer was separated, and the aqueous layer
was extracted with a further 40 mL of ethyl acetate. The organic
layers were combined, washed with water, dried over MgSO4, and
then concentrated. The residue was purified by flash column
chromatography with ethyl acetate as eluent, and the desired product
was obtained as a slightly brown solid (72%). Mp ) 144 °C
(recrystallized from ethyl acetate) (lit.14 mp )155-156 °C (pen-
(Z)-2-(6-Methoxy-3-nitropyridin-2-yl)-3-phenylacrylonitrile
(8a). The desired product was obtained according to the general
procedure using 200 mg (1.03 mmol) of 2-cyanomethyl-6-methoxy-
3-nitropyridine 1a and 105 µL (1.03 mmol) of benzaldehyde. The
product was obtained as a yellow solid (75%). Mp ) 166 °C. IR
1
(thin film, NaCl): 3082, 2240, 1573, 1504, 1467, 1321 cm-1. H
tane)). IR (thin film, NaCl): 2945, 1731, 1520, 1320, 1020 cm-1
.
NMR (250 MHz, CDCl3): δ 4.09 (s, 3H), 6.87 (d, J ) 9.0 Hz,
1H), 7.49-7.52 (m, 3H), 7.73 (s, 1H), 7.94-7.98 (m, 2H), 8.28
(d, J ) 9.0 Hz, 1H).13C NMR (62.5 MHz, CDCl3): δ 55.1, 108.8,
112.0, 115.9, 129.2, 130.1, 131.9, 132.9, 136.5, 147.0, 149.4, 165.0.
HRMS calcd for C15H11N3O3 [M + H]+: 282.0879, found 282.0870.
The stereochemistry of the double bond was determined by
calculation from Table of Spectral Data for Structure Determination
of Organic Compounds (Pretsh, E.; Clerc, T.; Seibl, J.; Simmon,
W. Springer-Verlag: New York, 1998): δ (H-Z isomer) ) 7.54 ppm
vs δ (H-E isomer) ) 7.31 ppm.
1H NMR (400 MHz, CDCl3): δ 1.94 (s, 3H), 2.98 (t, J ) 6.0 Hz,
2H), 3.55-3.59 (m, 2H), 4.02 (s, 3H), 6.62 (d, J ) 8.6 Hz, 1H),
7.14 (d, J ) 2.4 Hz, 1H), 7.36 (bs, 1H), 7.58 (d, J ) 8.6 Hz, 1H),
8.53 (bs, 1H). 13C NMR (100 MHz, CDCl3): δ 23.5, 24.1, 41.9,
53.4, 105.7, 114.1, 122.4, 125.0, 125.1, 141.7, 160.0, 170.4. HRMS
calcd for C12H15N3O2 [M + H]+: 234.1243, found ) 234.1250.
Acknowledgment. The authors acknowledge Les Labora-
toires Servier for financial support (M.J.).
General Procedure for Hydrogenations. In a hydrogenation
reactor, the pyridylacetonitrile was dissolved in an ethanol/acetic
acid (25/1, v/v) mixture. Palladium on carbon (15 wt %) was added,
and the mixture was hydrogenated under 75 psi of hydrogen. The
crude material was then filtered through a plug of celite and
concentrated. This crude material was purified by flash column
chromatography with the appropriate eluent.
Supporting Information Available: General and chemical
information plus experimental procedures and copies of 1H and
13C NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO8011623
J. Org. Chem. Vol. 73, No. 18, 2008 7393