Concise and Efficient Synthesis of 4-Fluoro-1H-pyrrolo[2,3-b]pyridine

Article abstract of DOI:10.1021/ol036030z

(Equation presented) Two routes describing the preparation of 4-fluoro-1H-pyrrolo[2,3-b]pyridine (4a) from 1H-pyrrolo[2,3-b]pyridine N-oxide (1) are presented. Regioselective fluorination was achieved using either the Balz-Schiemann reaction or lithium-halogen exchange.

Full text of DOI:10.1021/ol036030z

ORGANIC
LETTERS
2003
Vol. 5, No. 26
5023-5025
Concise and Efficient Synthesis of
4-Fluoro-1H-pyrrolo[2,3-b]pyridine
,†
Carl Thibault,* Alexandre L’Heureux,† Rajeev S. Bhide,‡ and Re´jean Ruel†
Department of DiscoVery Chemistry, Pharmaceutical Research Institute, Bristol-Myers
Squibb, 100 bouleVard de l’Industrie, Candiac, Que´bec, Canada, J5R 1J1, and
P.O. Box 4000, Princeton, New Jersey 08543-4000
carl.thibault@bms.com
Received October 16, 2003
ABSTRACT
Two routes describing the preparation of 4-fluoro-1H-pyrrolo[2,3-b]pyridine (4a) from 1H-pyrrolo[2,3-b]pyridine N-oxide (1) are presented.
Regioselective fluorination was achieved using either the Balz−Schiemann reaction or lithium−halogen exchange.
Azaindoles are indole surrogates of great interest in synthetic
organic and medicinal chemistry. While there are limited
literature references on the chemical reactivity of 7-aza-
indoles, their synthesis has been the subject of a number of
recent reviews.1 The regioselective synthesis of 7-azaindoles,
functionalized on the pyridine ring, remains a major chal-
lenge that has been addressed so far by two general
approaches: (1) formation of the pyrrole ring via the
cyclization of an appropriately functionalized pyridine
precursor and (2) ring substitution starting from 7-azaindole
N-oxide (1).1 In the course of an ongoing research program,
we required an efficient synthesis of 4-fluoro-1H-pyrrolo-
[2,3-b]pyridine (4a), which to our knowledge was unprec-
edented (Scheme 1).
The drawback of the electrophilic fluorination of neutral
aromatics is that it typically gives mixtures of mono- and
polyfluorinated products. On the other hand, the Balz-
Schiemann reaction provides regioselective monofluorinated
aryl fluorides via the controlled thermal decomposition of a
diazonium tetrafluoroborate salt.
Scheme 1a
The challenge in the synthesis of compound 4a resides in
the need for selective aromatic fluorination at C-4. Aromatic
fluorination reactions are usually achieved either by the
Balz-Schiemann reaction2,3 or via electrophilic fluorination.4
† Bristol-Myers Squibb, 100 boulevard de l’Industrie, Candiac, Que´bec,
Canada, J5R 1J1.
‡ P.O. Box 4000, Princeton, New Jersey 08543-4000.
(1) Me´rour, J. Y.; Joseph, B. Curr. Org. Chem. 2001, 5, 471 and
references cited therein.
(2) (a) Balz, G.; Schiemann, G. Ber. 1927, 60, 1186. (b) Milner, J. D.
Synth. Commun. 1992, 22 (1), 73. (c) Laali, K. K.; Gettwert, V. J. J. Fluorine
Chem. 2001, 107, 31.
a Reagents and conditions: (a) CH3SO2Cl, DMF. (b) (1) N-
allylamine, Pd(OAc)2, (o-biphenyl)PCy2, NaOt-Bu, 1,4-dioxane, 100
°C; (2) 10% Pd/C, CH3SO3H, EtOH, 80 °C. (c) 48% aq HBF4,
NaNO2, 23 °C.
(3) Reviews: (a) Roe, A. Org. React. 1949, 5, 193. (b) Suschitzky, H.
AdV. Fluorine Chem. 1965, 4, 1.
10.1021/ol036030z CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/04/2003

Our first approach to the synthesis of 4a took advantage
of a regioselective Balz-Schiemann fluorination reaction,
which required the synthesis of the intermediate amine 3b.5
Recently, Benoˆıt and Gingras have developed the regio-
selective chlorination at C-4 of 1H-pyrrolo[2,3-b]pyridine
7-oxide (1), using methanesulfonyl chloride in DMF.6
Attempted thermal nucleophilic substitution of the resulting
chloride 2 using N-allylamine or sodium azide was unsuc-
cessful. Cottam and co-workers7 have demonstrated that the
thermal nucleophilic substitution of chloride 2 worked only
with secondary alkylamines or N-alkylanilines, from which
deprotection to give the primary amine would not be trivial.
It was therefore apparent to us that an alternative approach
was necessary.
provided the first practical synthesis of 4-fluoro-1H-pyrrolo-
[2,3-b]pyridine (4a) in a four-step sequence in 29% overall
yield. Since a more efficient and scalable synthesis was
required, alternative approaches were subsequently explored.
For example, we intensively examined alternative chlorine
displacement reactions using 4-chloro-1H-pyrrolo[2,3-b]-
pyridine-7-oxide (5a) and 7-benzyl-4-chloro-1H-pyrrolo[2,3-
c]pyridin-7-ium bromide12 (5b) together with various nu-
cleophilic fluorine sources (Scheme 2).13,14 These attempts
Scheme 2
Fortunately, it was found that a Buchwald palladium-
catalyzed amination8 using chloride 2 and N-allylamine gave
allylamine 3a in 76% yield. Subsequent deallylation,9 using
palladium on carbon in acidic alcohol solution, provided 1H-
pyrrolo[2,3-b]pyridin-4-ylamine 3b in 95% yield, after
purification on SCX-silica gel.10 The amine 3b was then
submitted to the Balz-Schiemann reaction conditions. In
previously reported Balz-Schiemann reactions, the diazonium
tetrafluoroborate intermediate can typically be isolated and
subsequent pyrolysis gives the desired fluoroaromatic com-
pound.2,3 In our case, diazonium tetrafluoroborate salt was
generated from the amine 3b at 0 °C2b and decomposition
occurred spontaneously in the 48% tetrafluoroboric acid
solution in water at room temperature, affording a 1:1.3
mixture of fluoride 4a and 1H-pyrrolo[2,3-b]pyridine-4-ol
(4b). This type of side reaction is typically not observed in
the Balz-Schiemann transformation, because the dediazo-
niation step proceeds in the absence of water at high
temperature.2,3 However, in this case, the desired fluoride
compound 4a was isolated in 40% yield from the mixture
by basic aqueous extractions. Using other reaction conditions,
we were able to preclude the formation of alcohol 4b, but
this did not result in an improved isolated yield of 4a. For
example, when the diazonium tetrafluoroborate was isolated
at low temperature (-5 °C) and the decomposition was
carried out at 85 °C in toluene, only a 25% isolated yield of
the fluoride 4a was obtained. Similarly, other conditions
using HPF6,2b NOBF4,2b NOPF6,2b and t-BuONO11 were
attempted but did not improve the yield of fluoride 4a.
Nevertheless, the Balz-Schiemann route described above
proved to be unsuccessful, with either starting material
recovery or decomposition occurring. We then tried increas-
ing the leaving group capacity from a chloride to a bromide.
Adapting the regioselective chlorination conditions found by
Benoˆıt and Gingras,6 we synthesized 4-bromo-1H-pyrrolo-
[2,3-b]pyridine (6) by treating the N-oxide 1 with methane-
sulfonyl bromide15 in DMF. Interestingly, this bromination
was not as regioselective as the corresponding chlorination
and the desired bromide 6 was obtained in only 13% yield.
The N-oxide16 5c was prepared from 6, but unfortunately
all attempts to displace the bromide failed.
We then decided to use bromide 7 in a lithium-halogen
exchange reaction, followed by treatment with electrophilic
fluorine reagent, to generate a 4-fluoro derivative (Scheme
3).17 As part of this approach, the development of an
improved preparation of 6 was undertaken. It was found that
treatment of N-oxide 1 with methanesulfonic anhydride and
tetramethylammonium bromide in DMF gave a mixture (8:
1:1) of the 4-bromo-, 6-bromo- and 4,6-dibrominated com-
pounds. The desired 4-bromo-1H-pyrrolo[2,3-b]pyridine (6)
crystallized from the reaction mixture in 54% yield, following
addition of water and neutralization to pH 7 using aqueous
(4) For recent reviews: (a) Taylor, S. D.; Kotoris, C. C.; Hum, G.
Tetrahedron 1999, 55, 12431. (b) Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem.
ReV. 1996, 96, 1737 and references cited therein.
(5) (a) Meade, E. A.; Beauchamp, L. M. J. Heterocycl. Chem. 1996, 33,
303. (b) Antonini, I.; Claudi, F.; Cristalli, G.; Franchetti, P.; Grifantini,
M.; Martelli, S. J. Med. Chem. 1982, 25, 1258. (c) Schneller, S. W.; Luo,
J.-K. J. Org. Chem. 1980, 45, 4045.
(6) Benoˆıt, S.; Gingras, S. Processes for the preparation of antiviral
7-azaindole derivatives. U.S. Provisional Patent 60/367,401, 2003.
(7) Girgis, N. S.; Larson, S. B.; Robins, R. K.; Cottam, H. B. J.
Heterocycl. Chem. 1989, 26, 317.
(11) (a) Clark, R. D.; Berger, J.; Garg, P.; Weinhardt, K. K.; Spedding,
M.; Kilpatrick, A. T.; Brown, C. M.; MacKinnon, A. C. J. Med. Chem.
1990, 33, 591. (b) Mirsadeghi, S.; Prasad, G. K. B.; Whittaker, N.; Thakker,
D. R. J. Org. Chem. 1989, 54, 3091.
(12) Hannah, J.; Johnson, C. R.; Wagner, A. F.; Walton, E. J. Med. Chem.
1982, 25, 457.
(13) Vlasov, V. M. J. Fluorine Chem. 1993, 61, 193.
(14) (a) Aksenov, V. V.; Vlasov, V. M.; Moryakina, I. M.; Rodionov,
P. P.; Fadeeva, V. P.; Chertok, V. S.; Yakobson, G. G. J. Fluorine Chem.
1985, 28, 73. (b) Starks, C. M.; Liotta, C. Phase Transfer Catalysis;
Academic Press: New York; 1978.
(8) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J.
Org. Chem. 2000, 65, 1158.
(15) Block, E.; Aslam, M.; Eswarakrishnan, V.; Gebreyes, K.; Hutch-
inson, J.; Iyer, R.; Laffitte, J.-A.; Wall, A. J. Am. Chem. Soc. 1986, 108,
4568.
(16) N-Oxide was formed in 94% yield upon treatment of 4-bromo-7-
azaindole 6 with a solution of 32% peracetic acid/acetic acid in ethyl acetate.
(17) (a) Differding, E.; Ofner, H. Synlett 1991, 187. (b) Barnes, K. D.;
Hu, Y.; Hunt, D. A. Synth. Commun. 1994, 24, 1749. (c) Zajc, B. J. Org.
Chem. 1999, 64, 1902.
(9) (a) Jaime-Figueroa, S.; Liu, Y.; Muchowski, J. M.; Putman, D. G.
Tetrahetron Lett. 1998, 39, 1313. Other deallylation conditions attempted
did not improve yield; see other conditions in ref 9a and: (b) Garro-Helion,
F.; Merzouk, A.; Guibe´, F. J. Org. Chem. 1993, 58, 6109.
(10) On a larger scale, purification could also be done using Dowex 50W
X 4 resin.
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Org. Lett., Vol. 5, No. 26, 2003

fluoride 8 in 84% yield. It is worth noting that the yield
obtained for this heteroaryllithium fluorination is particularly
high in comparison with related examples reported in the
literature.17 Finally, deprotection using tetrabutylammonium
fluoride provided fluoride 4a in quantitative yield. This route
provided rapid, efficient, and scalable access to 4-fluoro-7-
azaindole 4a in 45% overall yield.
Scheme 3 a
In conclusion, two routes have been developed for the
synthesis of 4-fluoro-1H-pyrrolo[2,3-b]pyridine (4a). The
first synthetic approach features a Balz-Schiemann trans-
formation proceeding at room temperature. A second ap-
proach features efficient lithium-halogen exchange of the
corresponding bromide 7, followed by quenching with an
electrophilic fluorine source. These approaches afford new
fluorinated azaindoles for which there is very little precedent
in the literature. Further studies on the use of 4-fluoro-7-
azaindole 4a and related compounds will be reported in due
course.
a Reagents and conditions: (a) (CH3SO2)2O, (CH3)4NBr, DMF;
(b) NaH, TIPS-Cl, THF, 65 °C; (c) t-BuLi, NFSI, THF, -78 °C.
sodium hydroxide. Bromide 6 was then protected (to avoid
subsequent lithiation at C-218) as the N-triisopropylsilyl
derivative in quantitative yield. Lithium-halogen exchange
of bromide 7 using tert-butyllithium19 in THF at -78 °C,
followed by addition of N-fluorobenzenesulfimide,17 gave
Acknowledgment. We wish to thank Drs. Francis Beau-
lieu, Serge Benoˆıt, Edward Ruediger, and Ste´phane Gingras
for helpful discussions.
(18) (a) Griffen, E. J.; Roe, D. G.; Snieckus, V. J. Org. Chem. 1995, 60,
1484. (b) Beswick, P. J.; Greenwood, C. S.; Mowlem, T. J.; Nechvatal, G.;
Widdowson, D. A. Tetrahedron 1988, 44, 7325. (c) Sundberg, R. J.; Russell,
H. F. J. Org. Chem. 1973, 41, 3324. (d) Iwao, M. Heterocycles 1993, 36,
29. (e) Bray, B. L.; Mathies, P. H.; Naef, R.; Solas, D. R.; Tidwell, T. T.;
Artis, D. R.; Muchowski, J. M. J. Org. Chem. 1990, 55, 6317.
(19) A >1.5 M solution of tert-butyllithium in pentane was used to avoid
the precipitation of N-fluorobenzenesulfimide.
Supporting Information Available: Detailed experi-
mental procedures and full characterization data for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL036030Z
Org. Lett., Vol. 5, No. 26, 2003
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