An effective procedure for the acylation of azaindoles at C-3

Article abstract of DOI:10.1021/jo020135i

Conditions for attachment of acetyl chloride, benzoyl chloride, and chloromethyl oxalate to the 3-position of 4-, 5-, 6-, or 7-azaindoles were explored. Best results were achieved with an excess of AlCl₃ in CH₂Cl₂ followed

Full text of DOI:10.1021/jo020135i

SCHEME 1
An Effective P r oced u r e for th e Acyla tion of
Aza in d oles a t C-3
Zhongxing Zhang, Zhong Yang, Henry Wong,
J uliang Zhu, Nicholas A. Meanwell, J ohn F. Kadow, and
Tao Wang*
Department of Chemistry, The Bristol-Myers Squibb
Pharmaceutical Research Institute, 5 Research Parkway,
Wallingford, Connecticut 06492
condensation with an aldehyde.7 A few examples of
acylation, conducted under forcing conditions, have been
described.5,8 Moreover, with the exception of bromination,
a reliable, common procedure for derivatization of C-3 of
azaindoles has not emerged, and conditions have gener-
ally been optimized for individual azaindole substrates.
Reported strategies for the direct C-3 acylation of
azaindoles have relied upon either enhancing the nu-
cleophilicity of the azaindole or activation of the electro-
phile. As an example of the former approach, Shadrina
and co-workers heated 7-azaindole with a Grignard
reagent and dimethyl oxalate to form an R-keto ester in
64% yield.8b Sycheva and colleagues were able to prepare
a 7-azaindole derivative in 74% yield8c in ClCH2CH2Cl
at reflux by activating the electrophile, acetyl chloride,
with an excess of AlCl3. Galvez and Viladoms introduced
the acetyl moiety at C-3 of 7-azaindole using AlCl3 and
Ac2O in CS2,8d while Kato et al. accomplished a similar
transformation using AlCl3 and an acid chloride in CS2
at room temperature.8e However, all of these reactions
involved the use of elevated temperature and/or the
unpleasant solvent CS2 and, in each case, reports were
restricted to a single heterocyclic example. Consequently,
a survey of the scope and limitations of this reaction has
not been undertaken.
In pursuit of a Friedel-Crafts-type approach that
relies upon activation of the electrophile, a convenient
temperature, preferably ambient, and a replacement for
noxious CS2 as the solvent were specifically sought.
Careful screening of solvents revealed that CH2Cl2 was
the most acceptable substitute in terms of operative
simplicity and product yield. Thus, treatment of 7-aza-
indole (2) with 3-5 equiv of AlCl3 in CH2Cl2 at room
temperature followed by the addition of methyl oxalyl
chloride afforded the desired product 5 in 76% yield
(Scheme 2). It was found that a minimum of 3 equiv of
AlCl3 is required to achieve good results, but the use of
additional AlCl3 did not improve the yield further. The
requirement for greater than stoichiometric quantities
of AlCl3 could be interpreted by the formation of a
tao.wang@bms.com
Received February 26, 2002
Abstr a ct: Conditions for attachment of acetyl chloride,
benzoyl chloride, and chloromethyl oxalate to the 3-position
of 4-, 5-, 6-, or 7-azaindoles were explored. Best results were
achieved with an excess of AlCl3 in CH2Cl2 followed by the
addition of an acyl chloride at room temperature.
3-Acylated azaindoles have been reported to possess a
range of biological activities including the potential for
the treatment of inflammation, asthma, anxiety, depres-
sion, sleeping disorders, Alzheimer’s disease, migraine,
and pain.1 In an ongoing medicinal chemistry project, we
directed our efforts toward developing practical method-
ology for acylating at the 3-position of 4-, 5-, 6-, and
7-azaindoles.
The acylation of indole (1) at C-3 is a well documented
process that takes advantage of the electron-rich nature
of this position, which can be viewed as possessing
enamine-like character.2 However, we have observed that
when one carbon atom of the benzene ring of indole is
replaced by a nitrogen atom, acylation at the 3-position
is considerably more difficult. For example, the reaction
of 7-azaindole (2) with oxalyl chloride in Et2O was
unproductive while indole (1), under the same conditions,
provided the corresponding 3-acylated indole 3 in excel-
lent yield (Scheme 1).3
The inertness of the 3-position of azaindole when
compared to that of indole is presumably the result of
the electron-deficient nature of the pyridine moiety,
which reduces the overall nucleophilicity of the hetero-
cyclic system. This would be further exacerbated by the
potential of oxalyl chloride, which is typically used in
excess, to acylate the pyridine nitrogen atom. As a
consequence, documented examples of the direct func-
tionalization of the 3-position of azaindoles are restricted
to halogenation,4 Mannich reactions,5 carbonylation,6 and
(1) (a) Cassidy, F.; Hughes, I.; Rahman, S. S.; Hunter, D. J . WO
96/11929 April 25, 1996. (b) Scherlock, M. H.; Tom, W. C. US 5,023,265
J une 11, 1991. (c) Mantovanini, M.; Melillo, G.; Daffonchio, L. WO 95/
04742 February 16, 1995.
(2) Ottoni, O.; Neder, A. d. V. F.; Bias, A. K. B.; Cruz, R. P. A.;
Aquino, L. B. Org. Lett. 2001, 3, 1005 and references therein.
(3) Shaw, K. N. F.; McMillan, A.; Gudmundson, A. G.; Armstrong,
M. D. J . Org. Chem. 1958, 23, 1171.
(4) (a) Kelly, T. A.; McNeil, D. W.; Rose, J . M.; David, E.; Shih, C.-
K.; Crob, P. M. J . Med. Chem. 1997, 40, 2430. (b) Sakamoto, T.; Satoh,
C.; Kondo, Y.; Yamanaka, H. Heterocycles 1992, 34, 2379. (c) Mahade-
van, I.; Rasmussen, M. J . Heterocycl. Chem. 1992, 29, 359. (d) Alvarez,
M.; Fernandez, D.; J oule, J . A. Synthesis 1999, 615.
(5) Doisy, X.; Dekhane, M.; Hyaric, M. L.; Rousseau, J .-F.; Singh,
S. K.; Tan, S.; Guilleminot, V.; Schoemaker, H.; Sevrin, M.; George,
P.; Potier, P.; Dodd, R. H. Bioorg. Med. Chem. 1999, 7, 921.
(6) Robinson, M. M.; Robinson, B. L. J . Am. Chem. Soc. 1956, 78,
1247.
(7) Cornia, M.; Casiraghi, G.; Zetta, L. J . Org. Chem. 1991, 56, 5466.
(8) (a) Kato, M.; Ito, K.; Nishino, S.; Yamakuni, H.; Takasugi, H.
Chem. Pharm. Bull. 1995, 43, 1351. (b) Shadrina, L. P.; Dormidontov,
Yu. P.; Ponomarev, V, G.; Lapkin, I. I. Khim. Geterotsikl. Soedin. 1987,
1206. (c) Sycheva, T. V.; Rubtsov, N. M.; Sheinker, Yu. N.; Yakhontov,
L. N. Khim. Geterotsikl. Soedin. 1987, 100. (d) Galvez, C.; Viladoms,
P. J . Heterocycl. Chem. 1982, 19, 665. (e) Kato, M.; Ito, K.; Nishino,
S.; Yamakuni, H.; Takasugi, H. Chem. Pharm. Bull. 1995, 45, 1351.
10.1021/jo020135i CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/20/2002
6226
J . Org. Chem. 2002, 67, 6226-6227

TABLE 1. Acyla tion of Aza in d oles a t C-3
F IGURE 1.
SCHEME 2
complex between the azaindole and AlCl3. Presumably,
the first equivalent of AlCl3 is consumed in coordinating
to the pyridine nitrogen atom, a complex in which the
pKa of the pyrrole NH will be lowered. Reaction with the
second equivalent of AlCl3 may lead to deprotonation and
the formation of the aluminum salt depicted in Figure 1
as the reactive species. The third equivalent of AlCl3
forms an “ate complex” with the acyl chloride, the active
intermediate during Friedel-Crafts reactions.
Encouraged by this result, these conditions were
examined with isomeric azaindoles that, in turn, were
prepared either according to literature procedures9 or by
application of a Bartoli-type process.10 Reaction with a
variety of acid chlorides under similar conditions pro-
ceeded smoothly in all cases at room temperature to
produce products in moderate to high yield, as sum-
marized in Table 1.
In general, 5- and 7-azaindoles provided C-3 acylated
products in higher yields than 4- and 6-azaindoles, a
trend that appears to be consistent with the electron-
withdrawing effect of the pyridine-like nitrogen atom on
the pyrrole moiety. In the 4- and 6-azaindole ring
systems, the olefin element of the pyrrole moiety is more
directly conjugated with the pyridine-like nitrogen atoms,
an electronic effect that will reduce its overall nucleo-
philicity.
In summary, we have reported general conditions for
the C-3 functionalization of 4-, 5-, 6-, and 7-azaindoles
with acid chlorides. This method is attractive due to the
simplicity of the operational procedure, the mildness of
the conditions, and the applicability to all of the isomeric
azaindoles.
and 6-azaindole were prepared according to documented proce-
dures.9,10 1H and 13C NMR spectra were obtained at 500 MHz
with samples dissolved in CD3OD, CDCl3, or DMSO-d6.
Acyla tion of Aza in d ole: P r ep a r a tion of Meth yl (5-
Aza in d ol-3-yl)oxoa ceta te, Com p ou n d 11. 5-Azaindole (0.5 g,
4.2 mmol) was added to a stirred suspension of AlCl3 (2.8 g, 21.0
mmol) in CH2Cl2 (100 mL). After the mixture was stirred at room
temperature for 1 h, methyl oxalyl chloride (2.5 g, 21.0 mmol)
was added dropwise and the resulting mixture stirred for 8 h.
MeOH (20 mL) was added cautiously to quench the reaction,
the solvents were removed under vacuum, and the residual solid
was purified by silica gel chromatography using a mixture of
EtOAc and MeOH (10:1) as eluent to afford the acylated product
(0.60 g, 70%).
Exp er im en ta l Section
Gen er a l Meth od s. Aluminum chloride, 7-azaindole, acetyl
chloride, benzoyl chloride, and methyl oxalyl chloride (Table 1)
are commercially available and were used as received. 4-, 5-,
Ack n ow led gm en t. We are very grateful to Ms.
Marie D’Andrea for assistance in obtaining exact MS
spectra.
(9) (a) Mahadevan, I.; Rasmussen, M. J . Hetereocycl. Chem. 1992,
29, 359. (b) Hands, D.; Bishop, B.; Cameron, M.; Edwards, J . S.;
Cottrell, I. F.; Wright, S. H. B. A Synthesis 1996, 877.
(10) (a) Zhang, Z.; Yang, Z.; Kadow, J . F.; Meanwell, N. A.; Wang,
T. J . Org. Chem. 2002, 67, 2345. (b) Bartoli, G.; Palmieri, G.; Bosco,
M.; Dalpozz, R. Tetrahedron Lett. 1989, 30, 2129. (c) Bosco, M.;
Dalpozzo, R.; Bartoli, G.; Palmieri, G.; Petrini, M. J . Chem. Soc., Perkin
Trans. 2 1995, 657. (d) Dobson, D.; Todd, A.; Gilmore, J . Synth.
Commun. 1991, 21, 611. (e) Dobbs, A. B.; Voyle, M.; Whittall, N. Synlett
1999, 1594.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
and HRMS data of compounds 5-16. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O020135I
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