Multistep synthesis of a new tricyclic azaindole-based scaffold

Article abstract of DOI:10.1016/j.tetlet.2009.06.126

In this Letter the synthetic pathway adopted for the preparation of a new functionalized tricyclic scaffold containing the 7-azaindole moiety is presented. An intramolecular palladium-mediated reaction is described as the crucial step for a condensed seve

Full text of DOI:10.1016/j.tetlet.2009.06.126

Tetrahedron Letters 50 (2009) 5156–5158
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Tetrahedron Letters
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Multistep synthesis of a new tricyclic azaindole-based scaffold
*
Mauro Angiolini , Andrea Lombardi Borgia, Tiziano Bandiera
Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014 Nerviano, Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter the synthetic pathway adopted for the preparation of a new functionalized tricyclic scaffold
containing the 7-azaindole moiety is presented. An intramolecular palladium-mediated reaction is
described as the crucial step for a condensed seven-membered ring formation.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 4 June 2009
Revised 25 June 2009
Accepted 29 June 2009
Available online 3 July 2009
Keywords:
Azaindole
Scaffold
Palladium
Heck reaction
The chemistry of indole heterocycles is of great interest to the
pharmaceutical industry as several biological properties are associ-
ated with this chemical core in therapeutic areas such as central
nervous system, inflammation and cancer. Recently, 7-azaindoles,
which share with indoles the same [4.3]-bicyclic indene architec-
ture, but contain a second nitrogen atom in the six-membered ring,
have received increasing attention both as indole replacement and
as a scaffold endowed with peculiar physico-chemical and biolog-
ical activities (Fig. 1).1
N
H
N
H
N
indole
7-azaindole
R'
R
As part of our research activity in the field of kinase inhibitors,
we became interested in the design of new scaffolds containing the
7-azaindole core as the binding motif to kinase hinge region.2 In
particular we focused our attention on tricyclic compounds having
general formula A, where the presence of a condensed seven-mem-
bered ring makes the structure synthetically challenging to pre-
pare. (Fig. 1).
N
N
H
A
Figure 1. Chemical structures of indole, 7-azaindole and compound A.
We envisaged a retro-synthetic approach where the tricyclic
scaffold is generated by ring-closure of a suitably functionalized
7-azaindole derivative, as depicted in Scheme 1. The key step of
the synthesis is represented by the intramolecular Heck cyclization
of intermediate B between the terminal electron-poor double
bond, since R’ is a carboxylic ester function, and the aromatic ha-
lide installed at C-3 of the azaindole.3
R'
X
R'
R
4
3
R
As a first approach to compound B (R = R0 = COOMe, X = H), we
tried the introduction of a dimethyl-malonate group at C-4 posi-
tion of the 7-azaindole by a copper-mediated reaction. However
Heck
N
N
H
N
N
N
H
N
H
A
B
7-azaindole
* Corresponding author. Tel.: +39 0331581518; fax: +39 0331581347.
E-mail address: mauro.angiolini@nervianoms.com (M. Angiolini).
Present address: Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova,
Italy.
X = Br, I
Scheme 1. Retro-synthetic approach for compound A.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.126

M. Angiolini et al. / Tetrahedron Letters 50 (2009) 5156–5158
SiMe3
5157
O
O
N
O
OMe
OEt
I
EtO
a
b, c, d
e, f
N
N
H
N
H
N
N
N
H
N
Boc
1
2
3
4
Scheme 2. Reagents and conditions: (a) TEA, CuI, trimethylsilylacetylene, PdCl2(Ph3P)2, rt, 2 h, 80%; (b) BH3ꢁSMe2, THF, cyclohexene, 0 °C to rt, 1.5 h; (c) NaHCO3, H2O2, 0 °C to rt,
18 h; (d) EtOH, H2SO4, rt, 18 h, 55% over three steps; (e) THF, DMAP, (Boc)2O, rt, 6 h, 70%; (f) THF, LiHMDS 1 M in THF, 2-bromomethyl-acrylic acid methyl ester, ꢀ78 °C, 1 h, 90%.
Table 1
the reaction did not work at all prompting us to design a new syn-
Experimental conditions for the Heck reaction.
thetic pathway.4
Entry
1
2
3
4
We then turned to a Sonogashira coupling reaction between 4-
iodo-azaindole 1 and trimethylsilylacetylene. The coupling worked
satisfactorily affording compound 2 in 80% yield, as reported in
Scheme 2. The intermediate 2 was manipulated through several
steps aiming to convert the triple bond into an aryl-acetic moiety.
Thus, hydroboration of the triple bond followed by an oxidative
work-up with hydrogen peroxide and sodium bicarbonate fur-
nished the corresponding aryl-acetic compound, which in turn
was converted into the ethyl ester 3 with ethanol in the presence
of sulfuric acid as catalyst. The protection of the nitrogen in posi-
tion 1 as Boc-derivative made possible a highly efficient alkylation
of the benzylic position at C-4 with LiHMDS as base at ꢀ78 °C and
bromomethyl-acrylic acid methyl ester, affording the highly func-
tionalized compound 4 in good yield (Scheme 2).5–7
Solvent
Catalyst
% Cat.
Halogen
Base
DMF
Pd(PPh3)4
5
I
Ag3PO4
90
Trace
DMF
Pd(OAc)2
10
Br
K2CO3
90
Toluene
Pd(OAc)2
DMF–H2O
Herrmann
7
Br
Bu4NOAc
130
30
5
I
TEAa
90
—
T (°C)
Yield (%)
20
a
The reaction was carried out in the presence of P(o-Tolyl)3.
O
O
O
OMe
OMe
O
With derivative 4 in our hands, an electrophilic addition at C-3
position allowed the introduction of the halogen atom necessary
for the planned intramolecular Heck reaction. Deprotection of the
Boc group with trifluoroacetic acid and reaction with NBS or NIS
in dry DMF afforded the corresponding bromo- or iodo-derivatives
5a–b in 70% yield, enabling us to finally carry out the cyclization
step for seven-membered ring formation (Scheme 3).
EtO
Br
EtO
a
N
N
H
N
N
H
5a
6
Several cyclization attempts were carried out on both the 3-bro-
mo- and 3-iodo-derivatives 5a and 5b using different conditions
and catalysts as summarized in Table 1.
The data confirmed that the seven-membered ring cyclization,
as expected, was a critical step and the Herrmann–Beller catalyst,
a palladacycle derivative commercially available, allowed the iso-
lation of the tricyclic scaffold 6 in 30% yield in a DMF–water sol-
vent mixture at 130 °C and with Bu4NOAc, as depicted in Scheme 4.
The direction of cyclization is controlled by the electron-with-
drawing nature of the carboxylic ester function installed on the
oTol
oTol
O
O
P
Pd
Pd
P
O
O
oTol
oTol
Herrmann-Beller catalyst
Scheme 4. Reagents and conditions: (a) DMF–H2O 5:1, 7% Herrmann–Beller
catalyst, 130 °C, Bu4NOAc, 8 h, 30%.
O
O
OMe
O
O
terminal double bond, which determined the endo closure and for-
mation of the seven-membered ring. A different catalyst such as
palladium-(bis)acetate also gave the expected product but only
with 20% yield in DMF as solvent and K2CO3 as base. Finally palla-
dium tetrakis furnished only a trace of the product 6 when the
compound 5b was the substrate for cyclization. In fact in this case
the reaction led to the corresponding de-ionidated compound as
the main reaction by-product. In any case, the bromo-derivative
5a revealed to be the best substrate for the cyclization step.8,9
At this point our synthetic scheme required the selective trans-
formation of the two ester moieties, aiming to prepare an initial
derivative as a model compound for testing activities. Thus we car-
ried out, through a fast trans-esterification reaction to the corre-
OMe
EtO
EtO
X
a, b or c
N
N
H
N
N
Boc
4
5a
5b
Br
I
Scheme 3. Reagents and conditions: (a) DCM, TFA, rt, 4 h, 90%; (b) DMF, NBS, rt, 1 h,
70%; (c) DMF, NIS, rt, 1 h, 70%.

5158
M. Angiolini et al. / Tetrahedron Letters 50 (2009) 5156–5158
O
O
OMe
O
OMe
O
a
EtO
MeO
N
N
N
N
H
H
6
6a
O
O
OMe
O
OH
O
HO
HN
b, c
N
N
N
H
N
H
7
8
Scheme 5. Reagents and conditions: (a) THF–H2O–MeOH 3:1:1, LiOH, rt, 72 h, 85%; (b) DCM, TEA, TBTU, benzylamine, rt, 2 h, 85%; (c) LiOH, MeOH, rt, 18 h, 80%.
2. (a) Seefeld, M. A.; Rouse, M. B.; McNulty, K. C.; Sun, L.; Wang, J.; Yamashita, D. S.;
sponding dimethyl ester intermediate 6a, the complete and selec-
tive hydrolysis of the more reactive aliphatic ester with 2 equiv of
Luengo, J. I.; Zhang, S. Y.; Minthorn, E. A.; Concha, N. O.; Heerding, D. A. Bioorg.
Med. Chem. Lett. 2009, 19, 2244–2248; (b) Kim, K. S.; Zhang, L.; Schmidt, R.; Cai,
LiOH in a methanol–water–THF mixture. The reaction was quite
clean and furnished slowly the monoacid compound 7 in good
yield by a simple one-pot procedure. Subsequent coupling of inter-
mediate 7 with benzylamine in DCM with TBTU and further hydro-
Z. W.; Wei, D.; Williams, D. K.; Lombardo, L. J.; Trainor, G. L.; Xie, D.; Zhang, Y.;
An, Y.; Sack, J. S.; Tokarski, J. S.; Darienzo, C.; Kamath, A.; Marathe, P.; Zhang, Y.;
Lippy, J.; Jeyaseelan, R., Sr.; Wautlet, B.; Henley, B.; Gullo-Brown, J.; Manne, V.;
Hunt, J. T.; Fargnoli, J.; Borzilleri, R. M. J. Med. Chem. 2008, 51, 5330–5341; (c)
Tang, J.; Hamajima, T.; Nakano, M.; Sato, H.; Dickerson, S. H.; Lackey, K. E. Bioorg.
Med. Chem. Lett. 2008, 18, 4610–4614; (d) Casuscelli F.; Casale, E.; Faiardi, D.;
Piutti, C.; Mongelli, N.; Traquandi, G. Patent Application EP2002836, 2008.
3. (a) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971, 44, 581; (b) Heck, R.
F., ; Nolley, J. P., Jr. J. Org. Chem. 1972, 37, 2320–2322; (c) Beletskaja, P. I.;
Cheprakov, A. V. Chem. Rev. 2000, 100, 3009–3066.
4. (a) Yip, S. F.; Cheung, H. Y.; Zhou, Z.; Kwong, F. Y. Org. Lett. 2007, 9, 3469–3472;
(b) Hennessy, E. J.; Buchwald, S. L. Org. Lett. 2002, 4, 269–272.
5. Caldwell, J. J.; Cheung, K. M.; Collins, I. Tetrahedron Lett. 2007, 48, 1527–1529.
6. Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874–922.
7. (a) Torisu, K.; Kobayashi, K.; Iwahashi, M.; Nakai, Y.; Onoda, T.; Nagase, T.;
Sugimoto, I.; Okada, Y.; Matsumoto, R.; Nanbu, F.; Ohuchida, S.; Nakai, H.; Toda,
M. Bioorg. Med. Chem. 2004, 12, 4685–4700; (b) Alemany, C.; Bach, J.; Garcia, J.;
Lopez, M.; Rodriguez, A. B. Tetrahedron 2000, 56, 9305–9312.
lysis of the
a,b-unsaturated ester moiety with 10 equiv of LiOH
afforded the representative amide monoacid derivative 8, proving
that the new tricyclic scaffold can also be easily functionalized
by simple chemical manipulation (Scheme 5).
In conclusion, we have described the preparation of a new func-
tionalized tricyclic scaffold containing the 7-azaindole core by a
multistep synthesis. The crucial cyclization reaction to the seven-
membered ring was accomplished in acceptable yield by employ-
ing the Herrmann–Beller palladacycle catalyst. The two carboxylic
ester functions could be differentiated taking advantage of the
8. (a) Herrmann, W. A.; Brossmer, C.; Öfele, K.; Reisinger, C. P.; Priermeier, T.;
Beller, M.; Fischer, H. Angew. Chem. 1995, 107, 1989–1992; (b) Herrmann, W. A.;
Brossmer, C.; Öfele, K.; Reisinger, C. P.; Priermeier, T.; Beller, M. Chem. Eur. J.
1997, 3, 1354–1367; (c) Tietze, L. F.; Schirok, H.; Wöhrmann, M.; Schrader, K.
Eur. J. Org. Chem. 2000, 2433–2444.
9. Experimental procedure for the synthesis of compound 6 by the intramolecular Heck
reaction: To a 0.025 M solution of compound 5a (0.736 mmol, 1 equiv) in a
mixture of 5:1 DMF–H2O under argon atmosphere, the catalyst (0.05 mmol,
0.07 equiv) and NBu4AcO (2.65 mmol, 3.6 equiv) were added. The mixture was
stirred at 130 °C for 8 h and treated with ethyl acetate, dried over Na2SO4, and
evaporated to dryness. The crude was purified by flash column chromatography
(AcOEt/hexane 1:1) affording the title compound as white solid in 30% yield.
MS–ESI for C16H17N2O4 (MH+): 301.18; MS–ESI for C16H15N2O4 (MHꢀ): 299.16.
1H NMR (400 MHz, CDCl3): d 1.18 (t, 3H, J = 5.5 Hz), 2.92 (d, 1H, J = 5.8 Hz), 3.84
(s, 3H), 4.15 (m, 3H), 4.37 (dd, 1H, J = 5.8 and 1.2 Hz), 7.22 (d, 1H, J = 5.1 Hz), 7.64
(s, 1H), 7.85 (s, 1H), 8.17 (d, 1H, J = 5.1 Hz), 12.11 (br s, 1H).
higher reactivity of the saturated vis-a-vis the a,b-unsaturated es-
ter. In fact complete and selective hydrolysis of the aliphatic ester
led to the versatile intermediate 7. This compound is amenable to
further manipulation by exploiting the chemistry of carboxylic
functional group, thus opening opportunities for a diversity-ori-
ented synthesis. Moreover the tricyclic scaffold represents a novel
pharmacophore with attractive and original profile.
References and notes
1. (a) Bartberger, M. D.; Sukits, S.; Wilde, C.; Soukup, T. Synthesis 2008, 201–214;
(b) Popowycz, F.; Routier, S.; Joseph, B.; Mérour, J. Y. Tetrahedron 2007, 63, 1031–
1064; (c) Mérour, J. Y.; Benoît, J. Curr. Org. Chem. 2001, 5, 471–506.