Tin-free radical cyclizations for the synthesis of 7-azaoxindoles, 7-azaindolines, tetrahydro[1,8]naphthyridines, and tetrahydro-5H-pyrido[2,3-b] azepin-8-ones

Article abstract of DOI:10.1021/ol0489649

(Chemical Equation Presented) Compounds containing a pyridine nucleus fused to a saturated nitrogen-containing ring, including 7-azaoxindoles, 7-azaindolines, tetrahydro[1,8]naphthyridines, and tetrahydro-5H-pyrido[2,3-b] azepin-8-ones, were prepared in g

Full text of DOI:10.1021/ol0489649

ORGANIC
LETTERS
2004
Vol. 6, No. 21
3671-3674
Tin-Free Radical Cyclizations for the
Synthesis of 7-Azaoxindoles,
7-Azaindolines,
Tetrahydro[1,8]naphthyridines, and
Tetrahydro-5H-pyrido[2,3-b]azepin-8-ones
Eric Bacque´,† Myriem El Qacemi,‡ and Samir Z. Zard*,‡
Laboratoire de Synthe`se Organique associe´ au CNRS, Ecole Polytechnique,
91 128 Palaiseau Cedex, France, and AVENTIS Pharma,
94 400 Vitry sur Seine, France
zard@poly.polytechnique.fr
Received June 4, 2004 (Revised Manuscript Received August 5, 2004)
ABSTRACT
Compounds containing a pyridine nucleus fused to a saturated nitrogen-containing ring, including 7-azaoxindoles, 7-azaindolines, tetrahydro-
[1,8]naphthyridines, and tetrahydro-5H-pyrido[2,3-b]azepin-8-ones, were prepared in good yield starting from various 2,6-dichloropyridines.
The method hinges on a free-radical xanthate-mediated cyclization or intermolecular addition/cyclization sequence for the construction of the
new fused rings.
For a convenient access to designed 7-azaoxindoles, which
have potential biological activity,1 it is essential that reliable,
flexible, and general synthetic methods be readily available.
However, the various synthetic routes toward these com-
pounds are limited with respect to yield and scope.
There are three general approaches to 7-azaoxindoles. The
first is the oxidative bromination of expensive 7-azaindole
derivatives followed by a zinc-mediated reduction.2 The
second requires substituted pyridines such as 2-chloronico-
tinic acid1b or 3-pyridyl acetonitrile.3 More recently, a third
process based on the carbonylation of doubly lithiated
2-pivaloylaminopyridine to give the 7-azadihydroindol-2-
one4 was reported; this method was based on the previous
lithiation studies of Turner starting from 3-methyl-2-ami-
nopyridine.5
In a previous paper, we reported an efficient approach to
indolines and indans and also described one example of a
7-azaindoline.6 Herein, we wish to report a development of
this method that leads to improved access to a wide range
† AVENTIS Pharma.
‡ Ecole Polytechnique.
(1) (a) Cheung, M.; Hunter, R. N., III.; Peel, M. R.; Lackey, K. E.
Heterocycles 2001, 55, 1583 and references therein. (b) Ting, P. C.;
Kaminski, J. J.; Sherlock, M. H.; Tom, W. C.; Lee, J. F.; Bryant, R. W.;
Watnick, A. S.; McPhail, A. T. J. Med. Chem. 1990, 33, 2697. (c) Kumar,
V.; Dority, J. A.; Bacon, E. R.; Singh, B.; Lesher, G. Y. J. Org. Chem.
1992, 57, 6995. (d) Wood, E. R.; Kuyper, L.; Petrov, K. G.; Hunter, R. N.;
Harris, P. A.; Lackey, K. Bioorg. Med. Chem. Lett. 2004, 14, 935.
(2) Marfat, A.; Carta, M. P. Tetrahedron Lett. 1987, 28, 4027.
(3) Okuda, S.; Robison, M. M. J. Am. Chem. Soc. 1959, 81, 740.
(4) Smith, K.; El-Hiti, G. A.; Pritchard, G. J., Hamilton, A. J. Chem.
Soc., Perkin Trans. 1 1999, 2299.
(5) Turner, J. A. J. Org. Chem. 1983, 48, 3401.
(6) Ly, T.-L.; Quiclet-Sire, B.; Sortais, B.; Zard, S. Z. Tetrahedron Lett.
1999, 40, 2533.
10.1021/ol0489649 CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/21/2004

Scheme 1. Radical Sequence Plan
Scheme 2. Preparation of Radical Precursors and of
7-Azaoxindoles
of nitrogen containing rings fused to a pyridine nucleus,
including 7-azaoxindoles. This new synthetic route involves
a free-radical-mediated cyclization onto the pyridine ring as
the key step.7
As part of our work on the free-radical xanthate-mediated
chemistry, a radical cyclization onto the pyridine ring
appeared to us as a potentially general approach toward
compounds of such considerable pharmaceutical interest.
Radical cyclizations using xanthates have numerous advan-
tages such as experimental simplicity, the absence of heavy
or toxic metals, and compatibility with a wide range of
functionality since the conditions are mild and neutral.7b
In the present case, the xanthate precursor III would be
produced from an aminopyridine I by reaction with chloro-
acetyl chloride to give an amide II followed by displacement
of the chlorine with potassium O-ethyldithiocarbonate. Thus,
upon exposure to lauroyl peroxide (DLP) in 1,2-dichloro-
ethane (DCE) or chlorobenzene, radical IV is generated from
the xanthate group and should cyclize onto the aromatic ring
to give a new radical V which can be aromatized into
azaoxindole VI by oxidation with the peroxide (Scheme 1).
Our initial studies in this area started with benzylami-
nopyridine. Unfortunately, under standard conditions to form
the chloroacetamide derivative, the reaction afforded unex-
pectedly betaine VII, a compound described earlier in the
literature.8 The formation of this product is certainly a
consequence of the high nucleophilicity of the pyridine
nitrogen.
2). With the higher boiling n-butylamine, the yield was much
better (74%). Unfortunately, with the bulkier tert-butylamine,
the reaction was much slower and the yield disappointingly
low (5%). Nevertheless, we secured enough material to carry
out some preliminary experiments, which turned out to be
successful (vide infra). Thus, the need for a precursor
increased, and we decided to improve the synthesis of the
2-amino-6-chloropyridines. We eventually found that heating
2,6-dichloropyridine with tert-butylamine at 180 °C in a
sealed tube for 4 days gave the desired aminopyridine 2b in
more than 99% yield (Scheme 2). The reaction was very
clean despite the harsh conditions, which were applied to
other amines and to more substituted dichloropyridines such
as 2,4,6-trichloropyridine. All of these derivatives were
readily converted into the corresponding xanthates 4.
We were indeed pleased to find that addition of lauroyl
peroxide to a refluxing solution of compounds 4 in DCE or
chlorobenzene furnished 7-azaoxindoles in good yield. Our
results are displayed in Scheme 2.
In addition to successfully blocking the deleterious nu-
cleophilic activity of the pyridine nitrogen, the chlorine in
position 6 provides a handle for further transformations. It
can of course be reductively removed but may also be
exploited for a new aromatic nucleophilic substitution or for
various transition-metal-mediated couplings.
3-Substituted analogues may be accessed by Knoevenagel
condensation of the azaoxindoles with aldehydes or ketones
or by alkylation of the derived anion.
To circumvent this unwanted reaction, we decided to place
a chlorine at the 6-position of the pyridine ring to sterically
and electronically decrease the nucleophilicity of the nitrogen.
2-Amino-6-chloropyridines are accessible by substitution of
commercially available 2, 6-dichloropyridine. Thus, heating
the latter in refluxing cyclopropylamine afforded 2-(N-
cyclopropylamino)-6-chloropyridine in 11% yield (Scheme
(7) (a) For a review on radical additions to aromatics, see: Studer, A.
In Radicals in Organic Synthesis; Renaud, P., Sibi, M., Eds.; Wiley VCH:
Weinhem, 2001; Vol. 2, pp 62-80. (b) For a review on the radical chemistry
of xanthates, see: Zard, S. Z. Angew. Chem., Int. Ed. Engl. 1997, 36, 672.
(8) Hulinska, H.; Budesinsky, M.; Holubek, J.; Matousova, O.; Frycova,
H.; Protiva, M. Collect. Czech. Chem. Commun. 1989, 54, 1376.
7-Azaindolines are pharmaceutically important com-
pounds9 and act often as precursors of 7-azaindoles, which
have an even greater pharmaceutical potential, in particular
3672
Org. Lett., Vol. 6, No. 21, 2004

Scheme 3. Preparation of 2-Chloro-6-aminopyridines
Scheme 4. Synthesis of 7-Azaindolines and
Tetrahydro[1,8]naphthyridines
as pertains their antiinflammatory properties.10 However, it
is a somewhat inaccessible class of derivatives. Recently, a
free-radical-mediated aryl amination has been described
whereby an aryl radical, generated by tributyltin hydride,
adds to the nitrogen of an azomethine bond to give an
azaindoline.11 A second approach involving a directed ortho-
metalation of aminopyridines has been described to access
annulated pyridines derivatives.12
We have found that xanthate chemistry allows an expedi-
ent and especially versatile radical synthesis of azaindolines.
The method employs cheap, nontoxic, and easy to handle
compounds. Thus, treatment of 2,6-dichloropyridine with an
excess of allylamine produced in a quantitative yield the
2-allylamino-6-chloropyridine, which was protected by an
acetyl group before being subjected to the radical steps
(Scheme 3). Indeed, an addition-cyclization sequence using
xanthate derivatives provided the desired 7-azaindolines in
good yield (Scheme 4).
of great pharmaceutical importance,16 for instance, since
several drugs possess this backbone. Yet, very few proce-
dures have been reported for the synthesis of such com-
pounds. The usual route involves a regioselective hydroge-
nation of naphthyridines which are prepared via a Skraup17
or a Friedla¨nder reaction.18 An optimized intramolecular
Chichibabin reaction was also applied to access these bicyclic
heterocycles.19
In our case, all we had to do was to add one more carbon
to the side chain. Thus, 2-homoallylamino-6-chloropyridine
(7, n ) 2) was prepared in good yield by reacting 2,6-
dichloropyridine with excess 3-butenylamine in a sealed tube
at 140 °C. The addition of S-cyanomethyl-O-ethyl xanthate
gave an excellent yield of the corresponding adduct 9f (97%),
which underwent a smooth ring closure upon exposure to
stoichiometric amounts of lauroyl peroxide providing the
expected tetrahydronaphthyridine 10f in 72% yield. The
synthesis of 10g represents another example.
The tremendous flexibility of this approach is demon-
strated by the variety of the xanthates 8 that can be used
(examples 10a-e in Scheme 4). Furthermore, the oxazoli-
dinone derivative 10c can give rise to a wide library of
amides when treated with various amines.13 Compound 10b
is also of great interest since can be involved in a Hantzsch-
type14 reaction to form thiazole derivatives, which are known
as bioisosteres of pyridine rings. Its chlorine atom can also
be substituted by a xanthate group and engaged in a new
radical addition onto another olefinic trap.15
The unique advantages of the xanthate technology can be
appreciated in connection with the preparation of larger fused
rings. 1,2,3,4-Tetrahydro[1,8]naphthyridine derivatives are
(9) (a) Desarbre, E.; Me´rour, J.-Y. Tetrahedron Lett. 1996, 37, 43. (b)
Taylor, E. C.; Pont, J. L. Tetrahedron Lett. 1987, 28, 379.(c) Beattie, D.
E.; Crossley, R.; Curran, A. C. W.; Hill, D. G.; Lawrence, A. E. J. Med.
Chem. 1977, 20, 718.(d) Robison, M. M.; Robison, B. L.; Butler, F. P. J.
Am. Chem. Soc. 1959, 81, 743.
(10) Marminon, C.; Pierre´, A.; Pfeiffer, B.; Pe´rez, V.; Le´once, S.; Renard,
P.; Prudhomme, M. Bioorg. Med. Chem. 2003, 11, 679 and references
therein.
Finally, we examined the possibility of constructing a
pyridine fused to a seven-membered ring. Derivatives of
tetrahydro-5H-pyrido[2,3-b]azepin-8-ones are very rare,20 and
a simple, efficient route to such structures would significantly
(11) Viswanathan, R.; Mutnick, D.; Johnston, J. N. J. Am. Chem. Soc.
2003, 125, 7266.
(12) Davies, A. J.; Brands, K. M. J.; Cowden, C. J.; Dolling, U.-H.;
Lieberman, D. R. Tetrahedron Lett. 2004, 45, 1721 and references therein.
(13) Kunieda, T.; Higuchi, T.; Abe, Y.; Hirobe, M. Tetrahedron 1983,
39, 3253.
(14) Hantzsch, S. Justus Liebigs Ann. Chem. 1889, 250, 269. For a recent
pharmaceutical use of thiazoles, see: Cosford, N. D. P.; Tehrani, L.; Roppe,
J.; Schweiger, E.; Smith, N. D.; Anderson, J.; Bristow, L.; Brodkin, J.;
Jiang, X.; McDonald, I.; Rao, S.; Washburn, M.; Varney, M. A. J. Med.
Chem. 2003, 46, 204.
(16) For a recent pharmaceutical use of this class of compounds, see:
Hutchinson, J. H.; Halczenko, W.; Brashear, K. M.; Breslin, M. J.; Coleman,
P. J.; Duong, L. T.; Fernandez-Metzler, C.; Gentile, M. A.; Fisher, J. E.;
Hartman, G. D.; Huff, J. R.; Kimmel, D. B.; Leu, C. T.; Meissner, R. S.;
Merkle, K.; Nagy, R.; Pennypacker, B.; Perkins, J. J.; Prueksaritanont, T.;
Rodan, G. A.; Varga, S. L.; Wesolowski, G. A.; Zartman, A. E.; Rodan, S.
B.; Duggan, M. E. J. Med. Chem. 2003, 46, 4790.
(17) For a recent review on the Skraup reaction, see: Hamada, Y.;
Takeuchi, I. Yakugaku Zasshi 2000, 120, 206.
(18) For a review on the Friedla¨nder reaction, see: Cheng, C.-C.; Yan,
S. J. Org. React. 1982, 28, 37.
(15) Bergeot, O.; Corsi, C.; El Qacemi, M.; Zard, S. Z. Unpublished
results.
(19) Palucki, M.; Hughes, D. L.; Yasuda, N.; Yang, C.; Reider, P. J.
Tetrahedron Lett. 2001, 42, 6811.
Org. Lett., Vol. 6, No. 21, 2004
3673

contribute to the study of their chemistry and pharmacologi-
cal profile. We explored two complementary routes. The first
involved xanthate 4c which, in the presence of allyl acetate,
underwent preferentially an intermolecular addition to give
adduct 11 in 51% yield instead of ring closing to the
azaindoline 5c as described above. This is a remarkable result
since it indicates that ring closure to the pyridine ring is
relatively slow (but nevertheless feasible through the xanthate
approach) and can be overtaken by an intermolecular addition
even to an unactivated olefin such as allyl acetate. This
dichotomy in the reactivity translates in practice into a great
flexibility for the introduction of variety into the structures.
Ring closure starting from 11 occurred in a modest but still
useful yield to give 12 (34%). The second approach involved
addition of a xanthate to compound 13 followed by ring
closure to the seven-membered ring, which occurred surpris-
ingly efficiently. Compound 15 was thus obtained in 59%
yield (Scheme 5).
Scheme 5. Two Routes toward
Tetrahydro-5H-pyrido[2,3-b]azepin-8-ones
In summary, we have presented some of our preliminary
results relating to the synthesis of pyridine derivatives where
the heteroaromatic ring is fused to five-, six-, or even seven-
membered nitrogen-containing heterocycles. None of the
yields have been optimized; nevertheless, this approach is
far more general and flexible than traditional routes. It should
now be possible to access simply and cheaply a vast number
of hitherto unknown structures of high pharmaceutical
interest.
Acknowledgment. We thank Aventis Pharma for gener-
ous financial support to one of us (M.E.).
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(20) (a) Jo¨ssang-Yanagida, A.; Gansser, C. J. Heterocycl. Chem. 1978,
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39. (c) Pa¨tzel, M.; Ushmajev, A.; Liebscher, J.; Granik, V.; Grisik, S.;
Polievktov, M. J. Heterocycl. Chem. 1992, 29, 1067. (d) Seitz, G.; Dietrich,
S.; Go¨rge, L.; Richter, J. Tetrahedron Lett. 1986, 27, 2747.
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