A convenient synthetic route to substituted pyrrolo[2,3-b]pyridines via a novel ethylene-bridged compound

Article abstract of DOI:10.1016/j.tetlet.2015.10.031

A convenient synthetic route to 4-substituted pyrrolo[2,3-b]pyridines is presented. The novel ethylene bridged compound 1,2-bis(4-azidopyrrolo[2,3-b]pyridinyl)ethene was prepared and further derivatized. The novel synthesis was applied in the preparation of 3-cyano-4-hydroxypyrrolo[2,3-b]pyridine.

Full text of DOI:10.1016/j.tetlet.2015.10.031

Tetrahedron Letters 56 (2015) 6606–6609
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A convenient synthetic route to substituted pyrrolo[2,3-b]pyridines
via a novel ethylene-bridged compound
Birgit Wilding a, Carina Vidovic b, Norbert Klempier a,b,
⇑
a Austrian Centre of Industrial Biotechnology (acib) c/o Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, 8010 Graz, Austria
b Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, 8010 Graz, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient synthetic route to 4-substituted pyrrolo[2,3-b]pyridines is presented. The novel ethylene
bridged compound 1,2-bis(4-azidopyrrolo[2,3-b]pyridinyl)ethene was prepared and further derivatized.
The novel synthesis was applied in the preparation of 3-cyano-4-hydroxypyrrolo[2,3-b]pyridine.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 6 August 2015
Revised 2 October 2015
Accepted 7 October 2015
Available online 9 October 2015
Keywords:
Pyrrolo[2,3-b]pyridine
7-Azaindole
1,2-Bis(pyrrolo[2,3-b]pyridinyl)ethene
Ethylene-bridge
Pyrrolo[2,3-b]pyridines (7-azaindoles) are widely investigated
for their promising biological activities as indole and purine bioi-
sosteres. The pyrrolo[2,3-b]pyridine scaffold has been reported in
various kinase inhibitors, as the ring heteroatoms are known to
form hinge interactions in the kinase ATP binding site.1 Several
pyrrolo[2,3-b]pyridines have been reported as selective inhibitors
of different isoforms of Janus kinase (JAK).2 The complex pyrrolo
[2,3-b]pyridine BMS-911543 is currently undergoing clinical trials
as selective JAK-2 inhibitor.3
In contrast to indoles, the pyrrolo[2,3-b]pyridine scaffold is
found in only few natural products, for example, the variolins.
Variolins, alkaloids isolated from the Antarctic marine sponge
Kirkpatrick varialosa, are potent cyclin-dependent kinase (CDK)
inhibitors. Variolin B is an efficient activator of apoptosis, showing
potent cytotoxic activity against a variety of human cancer cell
lines, including those overexpressing P-glycoprotein, a cell efflux
pump responsible for the resistance of cancerous cells to many
chemotherapy agents.4,5
synthesized for the investigation of the substrate scope of nitrile
reductase queF.
Pyrrolo[2,3-b]pyridines are mostly synthesized starting from
substituted pyridine precursors,9–11 although syntheses starting
from pyrrole precursors have also been reported.12 Various routes
known from indole synthesis, such as the Fischer, Madelung, or
Reissert syntheses, are limited by their narrow scope, drastic reac-
tion conditions, and poor yields.5 Palladium catalyzed reactions
have proven an invaluable tool in the synthesis of pyrrolo[2,3-b]
pyridines.10 Most notably, a number of pyrrolo[2,3-b]pyridines
have been prepared by Sonogashira coupling of a 3-halosubstituted
2-aminopyridine. The resulting alkynylpyridines were then reacted
under a variety of conditions to give the desired pyrrolo[2,3-b]
pyridines.11
Here, we report a novel synthetic route for the preparation of
4-substituted pyrrolo[2,3-b]pyridines. 1,2-Bis(4-azidopyrrolo[2,3-b]
pyridinyl)ethene (Schemes 1 and 2) was serendipitously discovered
as product of the condensation reaction of 2-amino-4-azidopyridine
with chloroacetaldehyde. 1,2-Bis(4-azidopyrrolo[2,3-b]pyridinyl)
ethene (2) was then used as a starting point for the subsequent
synthesis of 3,4-disubstituted pyrrolo[2,3-b]pyridines, including the
desired 3-cyano-4-hydroxypyrrolo[2,3-b]pyridine.
We have been interested in the biocatalytic synthesis and
transformation of nitriles since several years.6 Recently, we have
investigated nitrile reductase queF,7 an unprecedented enzyme
catalyzing the reduction of a nitrile group to the corresponding
amine.8 3-Cyano-4-hydroxypyrrolo[2,3-b]pyridine is a close struc-
tural analogue of the natural substrate, 2-amino-5-cyanopyrrolo
[2,3-d]pyrimidin-4-one, of nitrile reductase queF and was thus
We have previously used the condensation reactions of chloro-
acetaldehyde with an appropriately substituted pyrimidine precur-
sor for the synthesis of pyrrolo-7b and thieno[2,3-d]pyrimidines13
(see Electronic supplementary information) and intended to apply
this reaction for the synthesis of pyrrolo[2,3-b]pyridines. The reac-
tion of chloroacetaldehyde with 2-amino-4-hydroxypyridine did
⇑
Corresponding author. Tel.: +43 316 873 32445; fax: +43 316 873 32402.
E-mail address: klempier@tugraz.at (N. Klempier).
http://dx.doi.org/10.1016/j.tetlet.2015.10.031
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

B. Wilding et al. / Tetrahedron Letters 56 (2015) 6606–6609
6607
N3
N
N3
N
N3
N
O
NOH
N
N
N
N
N
N
Cl
N
N3
N
a
b
c
d
NH2
NH2
N
N
N
O
NOH
1
N3
N3
N3
2
4
3
N3
NH2
CN
CN
NH2
OH
N
N
N
CN
CN
N
N
N
e
f
g
h
N
N
N
N
N
N
H
H
CN
CN
7
8
N3
NH2
5
6
Scheme 1. Synthesis of 5-cyano-4-hydroxypyrrolo[2,3-b]pyrimidine. Reagents and conditions: (a) sodium azide, DMF, ammonium formate, 120 °C, yield 53%; (b)
chloroacetaldehyde, sodium acetate trihydrate, water, 60 °C, yield 78%; (c) POCl3, DMF, yield 54%; (d) hydroxylamine hydrochloride, ethanol, aq NaOH, yield 82%; (e) (1) acetic
anhydride, (2) acetic acid, reflux, yield 17%; (f) Pd/C, THF, hydrogen, yield 87%; (g) NaIO4, NaClO2, OsO4, acetonitrile, water, yield 57%; (h) NaNO2, acetic acid, water, 100 °C,
yield 87%.
NH2
N3
N
molecule of chloroacetaldehyde to the desired product. With
increasing reaction time, only the amount of byproduct increased
to up to 50% conversion after four hour reaction time, while the
amount of the desired product 4-aminopyrrolo[2,3-b]pyridine
could not be increased.
We then investigated 2-amino-4-azidopyridine (1) as the
starting material for the condensation reaction with chloroacetalde-
hyde. Unexpectedly, 1,2-bis(4-azidopyrrolo[2,3-b]pyridinyl)ethene
(2) was formed as the only product and was initially isolated in 54%
yield. The yield was further improved by a brief optimization of the
reaction conditions to 78% (Scheme 1). The preparation of an ethy-
lene-bridged pyrrolo[2,3-b]pyridine has so far not been reported
in the literature. The ethylene bridge acts as an atom efficient pro-
tecting group of the pyrrole nitrogen, thereby offering advantages
over the unprotected pyrrolo[2,3-b]pyridine.
1,2-Bis(4-azidopyrrolo[2,3-b]pyridinyl)ethene (2) was a useful
starting material for a number of subsequent reactions (Scheme 2).
The azide group was reduced to give 1,2-bis(4-aminopyrrolo[2,3-b]
pyridinyl)ethene (9) in 88% yield. Compound 9 could be interesting
for further derivatization, for example, in amide couplings,
Buchwald–Hartwig type cross-couplings, or reductive aminations.
Chlorination and bromination in position 5 of 1,2-bis(4-azidopy-
rrolo[2,3-b]pyridinyl)ethene (2) was readily achieved to give
compounds 10 and 11. These halide substituted compounds are
particularly interesting as starting materials in palladium
catalyzed reactions. The ethylene bridge of 1,2-bis(4-azidopyrrolo
[2,3-b]pyridinyl)ethene (2) was cleaved by dihydroxylation and
periodate cleavage in a one pot procedure using sodium chlorite
for the re-oxidation of the osmium tetraoxide. Dihydroxylation
and periodate cleavage of the ethylene bridge of compound 2
results in a formyl group on the pyrrole nitrogen. The use of basic
work up conditions with isopropanol/sodium hydroxide14
quantitatively cleaved the formyl group, giving 4-azidopyrrolo
[2,3-b]pyridine (12) as the only product in one step from the
bridged compound 2.
X
N
N
N
N
N
N
a
b
N
X
N3
N
N3
NH2
9
10
11 X=Br
X=Cl
N
N
N
N3
N3
O
2
d
c
N3
N
N
N
N
N
H
N
O
12
N3
3
Scheme 2. Reactions starting from 1,2-bis(4-azidopyrrolo[2,3-b]pyridinyl)ethene
(2). Reagents and conditions: (a) Pd/C, ethanol, 25 bar hydrogen, steel autoclave,
yield 88%; (b) NBS, THF, rt, yield 49% or NCS, THF, rt, yield 78%; (c) POCl3, DMF, yield
54%; (d) NaIO4, NaClO2, OsO4, acetonitrile, water, yield 54%.
not give the expected 4-hydroxypyrrolo[2,3-b]pyridine as
product, but 1-(2-chloroethenyl)-4-hydroxypyrrolo[2,3-b]pyridine.
Protection of the hydroxyl group as methoxy group gave a complex
mixture of undesired products in the condensation reaction.
The reaction of chloroacetaldehyde with 2,4-diaminopyridine
gave the desired product 4-aminopyrrolo[2,3-b]pyridine in 15%
yield and a byproduct resulting from the condensation of a second
Formylation of pyrrolo[2,3-b]pyridines in position 5 is most
commonly achieved using the Duff,15 or Vilsmeier–Haack16

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B. Wilding et al. / Tetrahedron Letters 56 (2015) 6606–6609
reaction. The Duff reaction was originally reported for the prepara-
tion of 3- and 5-formylsalicylic acids.17 The reaction proceeds in a
series of equilibrium reactions. A secondary amine is formed with
hexamethylenetetramine, which is then dehydrogenated to Schiff
bases by heating in acetic acid. The Schiff bases can then be
hydrolyzed to give aldehydes. 4-Azidopyrrolo[2,3-b]pyridine (12)
was used as the starting material for Duff and Vilsmeier–Haack
formylation reactions. 4-Azido-3-formylpyrrolo[2,3-d]pyridine
was obtained using both formylation conditions. Yields and
product purity were relatively low, in particular for the
Duff reaction. In contrast, the Vilsmeier–Haack formylation of
can be found, in the online version, at http://dx.doi.org/10.1016/j.
tetlet.2015.10.031.
References and notes
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1,2-bis(4-azidopyrrolo[2,3-b]pyridinyl)ethene
formylated product 3 in 54% and high purity.
(2)
gave
the
The ethylene bridged pyrrolo[2,3-b]pyridine system was benefi-
cial in the formylation reaction, consequently we decided to pro-
ceed with the bridged pyrrolo[2,3-b]pyridine 3. The subsequent
step to give the oxime 1,2-bis(4-azido-3-(hydroxyiminomethyl)
pyrrolo[2,3-b]pyridin-1-yl)ethene proceeded in excellent yield of
82% and gave the (E)/(Z)-isomers in a ratio of 1.6:1. Dehydration
of the oxime to the corresponding nitrile (5) was carried out with
acetic anhydride. The (Z)-oxime was quantitatively converted into
the nitrile, as observed by NMR, however the (E)-oxime was
O-acetylated under the reaction conditions. The O-acetylated
(E)-oxime was then converted into the nitrile (5) by reflux in acetic
acid.
Cyano groups in position 3 of pyrrolo[2,3-b]pyridines have
been introduced by dehydration of the oxime,18 or
palladium catalyzed C–H cyanation.19,20 Direct cyanation with
chloro-sulfonylisocyanate has been reported for a number of
heterocycles including indoles.21 Direct cyanation of 1,2-bis
(4-azidopyrrolo[2,3-b]pyridinyl)ethene (2) was not successful in
our hands, while formylation proceeded in good yield and purity.
The azide group in 1,2-bis(4-azido-3-cyanopyrrolo[2,3-b]
pyridin-1-yl)ethene (5) was reduced to the corresponding amino-
group in a hydrogenation reaction with platinum or palladium
on charcoal as the catalyst. Higher yields were obtained using
palladium on charcoal. Cleavage of the ethylene bridge was carried
out analogously as for 1,2-bis(4-azidopyrrolo[2,3-b]pyridin-1-yl)
ethene (2) and similar yields of 57% were observed. In the final
step, the 4-amino substituent was converted into a hydroxyl group
in a diazotization reaction. The desired product 3-cyanopyrrolo
[2,3-b]pyridine was obtained in 87% yield.
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We have presented a novel synthetic route for the preparation
of 4-substituted pyrrolo[2,3-b]pyridines, via the novel ethylene-
bridged compound 1,2-bis(4-azidopyrrolo[2,3-b]pyridinyl)ethene.
1,2-Bis(4-azidopyrrolo[2,3-b]pyridinyl)ethene was shown to be a
useful starting material for a number of subsequent reactions.
3-Cyano-4-hydroxypyrrolo[2,3-b]pyridine was successfully pre-
pared using this novel synthetic route.
Acknowledgments
The authors would like to thank Cornelia Hojnik for skillful
assistance in the laboratory. This work has been supported by
the Federal Ministry of Science, Research and Economy (BMWFW),
the Federal Ministry of Traffic, Innovation and Technology (BMVIT),
the Styrian Business Promotion Agency SFG, the Standortagentur
Tirol and ZIT—Technology Agency of the City of Vienna through
the COMET-Funding Program managed by the Austrian Research
Promotion Agency FFG.
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Supplementary data
Supplementary data (synthetic procedures and characterization
data, including graphical NMR spectra) associated with this article
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