A concise synthesis of all four possible benzo[4,5]furopyridines via palladium-mediated reactions.

Article abstract of DOI:10.1021/ol0260425

[reaction: see text] By taking advantage of the alpha- and gamma-activation of chloropyridines as well as palladium-mediated reactions, all four possible benzo[4,5]furopyridine tricyclic heterocycles, benzo[4,5]furo[2,3-b]pyridine, benzo[4,5]furo[2,3-c]py

Full text of DOI:10.1021/ol0260425

ORGANIC
LETTERS
2002
Vol. 4, No. 13
2201-2203
A Concise Synthesis of All Four
Possible Benzo[4,5]furopyridines via
Palladium-Mediated Reactions
Wen Song Yue and Jie Jack Li*
Department of Chemistry, Pfizer Global Research and DeVelopment,
2800 Plymouth Road, Ann Arbor, Michigan 48105
jack.li@pfizer.com
Received April 18, 2002
ABSTRACT
By taking advantage of the r- and γ-activation of chloropyridines as well as palladium-mediated reactions, all four possible benzo[4,5]-
furopyridine tricyclic heterocycles, benzo[4,5]furo[2,3-b]pyridine, benzo[4,5]furo[2,3-c]pyridine, benzo[4,5]furo[3,2-c]pyridine, and benzo[4,5]-
furo[3,2-b]pyridine, are efficiently synthesized from 2-chloro-3-iodopyridine, 3-chloro-4-stannylpyridine, 4-chloro-3-iodopyridine, and 2-chloro-
3-hydroxypyridine, respectively.
The advent of palladium chemistry has exerted a profound
impact on the synthesis of heterocycles.1 During the course
of our research, we investigated the utility of palladium
chemistry in the synthesis of benzo[4,5]furopyridines. These
heterocycles often display important biological activities2 and
are also useful biosteres for dibenzofuran. Ames and Opalko
synthesized benzo[4,5]furo[2,3-b]pyridine (2) in 10% yield
employing an intramolecular Heck reaction of 2-(2-bromo-
phenoxy)pyridine.3 Abramovitch et al. also reported the
synthesis of 2 via a six-step sequence from an N-(aryloxy)-
pyridinium salt.4 Furthermore, Lai and co-workers adapted
an SNAr cyclization strategy to prepare benzo[4,5]furo[2,3-
c]pyridine (5) in 63% yield from 3-fluoro-4-(2-methoxy-
phenyl)-pyridine.5 Herein we report our efforts in ac-
complishing an efficient synthesis of benzo[4,5]furo[2,3-b]-
pyridine (2), benzo[4,5]furo[2,3-c]pyridine (5), benzo[4,5]-
furo[3,2-c]pyridine (7), and benzo[4,5]furo[3,2-b]pyridine
(10) via palladium-mediated reactions6 while taking advan-
tage of the R- and γ-activation of chloropyridines.
The synthesis of benzo[4,5]furo[2,3-b]pyridine (2) was
readily achieved. 2-Chloro-3-iodopyridine7 was prepared in
65% yield by lithiation of 2-chloropyridine followed by
treatment with I2. Because of the R-activation, a result of
the inductive effect of the N-atom on the pyridine ring,
chemoselective SNAr displacement of the 2-chloro substituent
with a nucleophile was expected to proceed smoothly. As
illustrated in Scheme 1, refluxing 2-chloro-3-iodopyridine
with sodium o-iodophenoxide, derived from exposing iodo-
phenol to NaH, in DMF gave heterobiaryl ether 1 in 87%
Scheme 1. Synthesis of Benzo[4,5]furo[2,3-b]pyridine (2)
(1) (a) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry;
Pergamon: Amsterdam, 2000. (b) Li, J. J. In Alkaloids, Chemical and
Biological PerspectiVes; Pelletier, S. W., Ed.; Pergamon: Oxford, 1999;
Vol. 14, pp 437-503. (c) Stanforth, S. P. Tetrahedron 1998, 54, 263-303.
(d) Godard, A.; Marsais, F.; Ple´, N.; Trecourt, F.; Turck, A.; Que´guiner,
G. Heterocycles 1995, 40, 1055-1091. (e) Undheim, K.; Benneche, T. AdV.
Heterocycl. Chem. 1995, 62, 305-418. (f) Kalinin, V. N. Synthesis 1992,
413-432. (g) Undheim, K.; Benneche, T. Heterocycles 1990, 30, 1155-
1193. (h) Sakamoto, T.; Kondo, Y.; Yamanaka, H. Heterocycles 1988, 27,
2225-2249.
10.1021/ol0260425 CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/01/2002

yield. Subsequent Stille-Kelly reaction8 of ether 1 using
hexamethylditin in the presence of catalytic PdCl2‚(Ph3P)2
in refluxing xylene furnished benzo[4,5]furo[2,3-b]pyridine
(2)9 in 90% yield.
The Stille coupling of 4-chloro-3-tributylstannylpyridine
and o-iodophenol under the same conditions for the trans-
formation 3 f 4 led to two products in 70% combined yield.
The major product was the desired adduct 6, along with the
cyclized product, benzo[4,5]furo[3,2-c]pyridine (7) as a
minor product (Scheme 3, route a). The discrepancy of
The synthesis of benzo[4,5]furo[2,3-c]pyridine (5) began
with preparation of stannane 3 (Scheme 2). Applying
Scheme 3. Synthesis of Benzo[4,5]furo[3,2-c]pyridine (7)
Scheme 2. Synthesis of Benzo[4,5]furo[2,3-c]pyridine (5)
Gribble’s ortho-lithiation tactic,10 3-chloropyridine was
deprotonated at the most acidic position, C(4). Subsequent
exposure of the resulting 3-chloro-4-lithiopyridine to tri-
butyltin chloride gave 3-chloro-4-tributylstannylpyridine (3).
The Stille coupling of stannane 3 with o-iodophenol in the
presence of catalytic PdCl2‚(Ph3P)2 and CuI in refluxing DMF
then produced heterobiaryl 4 in 63% yield. Only small
amounts of 4 were observed when the reaction was carried
out using THF, dioxane, or toluene as the solvent. Finally,
the intramolecular SNAr etherification was accomplished by
treatment of biaryl 4 with NaOt-Bu in refluxing DMSO to
afford benzo[4,5]furo[2,3-c]pyridine (5)11 in 57% yield.
reactivities between heterobiaryls 4 and 6 relies upon the
fact that the 4-chloro substituent on 6 is more activated as a
result of γ-activation than the 3-chloro substituent on 4.
Subjecting the reaction mixture to NaOt-Bu in refluxing
DMSO furnished benzo[4,5]furo[3,2-c]pyridine (7)12 in only
34% yield. As a consequence, an alternative route to 7 was
pursued.
4-Chloro-3-iodopyridine was prepared in 65-80% yield
by ortho-lithiation of 4-chloropyridine followed by treatment
with iodine (Scheme 3, route b).13 Taking advantage of the
γ-activation, also a consequence of the inductive effect of
the N-atom on the pyridine ring, regioselective SNAr
displacement of the 4-chloro substituent was accomplished
by refluxing 4-chloro-3- iodopyridine with sodium o-
iodophenoxide in DMF to construct heterobiaryl ether 8 in
(2) Wakelin, L. P. G.; Waring, M. J. In ComprehensiVe Medicinal
Chemistry; Sammes, P. G., Ed.; Pergamon: Oxford, 1990, pp 703-724.
(3) Ames, D. E.; Opalko, A. Tetrahedron 1984, 40, 1919-1925.
(4) Abramovitch, R. A.; Inbasekaran, M. N.; Kato, S.; Radzikowska, T.
A.; Tomask, P. J. Org. Chem. 1983, 48, 690-695.
(5) Lai, L.-L.; Lin, P.-Y.; Huang, W.-H.; Shiao, M.-J.; Hwu, J. R.
Tetrahedron Lett. 1994, 35, 3545-3546.
(6) Farina, V.; Krishnamurthy, V.; Scott, W. J. The Stille Reaction;
Wiley: New York, 1998.
(7) Guillier, F.; Nivoliers, F.; Godard, A.; Marsais, F.; Queguiner, G.
Tetrahedron Lett. 1994, 35, 6489-6492.
(8) (a) Kelly, T. R.; Li, Q.; Bhushan, V. Tetrahedron Lett. 1990, 31,
161-164. (b) Grigg, R.; Teasdale, A.; Sridharan, V. Tetrahedron Lett. 1991,
32, 3859-3862. (c) Sakamoto, T.; Yasuhara, A.; Kondo, Y.; Yamanaka,
H. Heterocycles 1991, 36, 2597-2600. (d) Fukuyama, Y.; Yaso, H.;
Nakamura, K.; Kodama, M. Tetrahedron Lett. 1999, 40, 105-108. (e)
Seiders, T. J.; Baldridge, K. K.; Elliott, E. L.; Grube, G. H.; Siegel, J. S. J.
Am. Chem. Soc. 1999, 121, 7439-7440. (f) Iyoda, M.; Miura, M. I.; Sasaki,
S.; Kabir, S. M. H.; Kuwatani, Y.; Yoshida, M. Tetrahedron Lett. 1997,
38, 4581-4582. (g) Iwaki, T.; Yasuhara, A.; Sakamoto, T. J. Chem. Soc.,
Perkin Trans. 1 1999, 1505-1510.
(11) Data for 5: mp ) 93-95 °C; Rf ) 0.28 (1:1 hex/EtOAc); IR (KBr,
cm-1) 3042, 1626, 1577, 1450, 1421, 1182, 1016, 823, 750, 728; 1H NMR
(CDCl3) δ 8.97 (s, 1H), 8.57 (d, J ) 6.0 Hz, 1H), 8.00 (d, J ) 7.7 Hz, 1H),
7.84 (d, J ) 7.0 Hz, 1H), 7.60 (m, 2H), 7.60 (t, J ) 7.0 Hz, 1H); 13C NMR
(CDCl3) 156.8, 152.9, 143.0, 134.4, 130.9, 129.8, 123.4, 122.3, 122.0, 115.0,
122.4; MS (ACPI) m/z 169.9 (M+ + 1). Anal. Calcd for C11H7NO: C,
78.09; H, 4.17; N, 8.28. Found: C, 77.92; H, 4.26; N, 8.16.
(9) Data for 2: mp ) 68-69 °C; Rf ) 0.47 (1:1 hex/EtOAc); 1H NMR
(CDCl3) δ 8.43 (dd, J ) 1.8, 5.1 Hz, 1H), 8.24 (dd, J ) 1.7, 7.6 Hz, 1H),
7.93 (m, 1H), 7.61 (m, 1H), 7.30 (m, 2H); 13C NMR (CDCl3) δ 163.4,
154.7, 146.6, 129.8, 128.5, 123.6, 122.6, 121.5, 119.3, 117.1, 112.4; MS
(ACPI) m/z 170.1 (M+ + 1). Anal. Calcd for C11H7NO: C, 78.09; H, 4.17;
N, 8.28. Found: C, 77.96; H, 4.22; N, 8.19.
(10) (a) Gribble, G. W.; Saulnier, M. G. Tetrahedron Lett. 1980, 21,
4137-4140. (b) Gribble, G. W.; Saulnier, M. G. Heterocycles 1993, 35,
151-169. (c) Mallet, M.; Que´guiner, G. Tetrahedron 1982, 38, 3035-
3042. (d) Mallet, M.; Que´guiner, G. Tetrahedron 1986, 42, 2253-2262.
(12) Data for 7: mp ) 72-74 °C.; Rf ) 0.20 (1:1 hex/EtOAc); 1H
NMR (CDCl3) δ 9.02 (s, 1Η), 8.43 (d, J ) 5.6 Hz, 1H), 7.78 (d, J ) 7.8
Hz, 1H), 7.38 (d, J ) 8.0 Hz, 1H), 7.29 (m, 2H), 7.18 (t, J ) 7.6 Hz, 1H);
13C NMR (CDCl3) δ 161.2, 156.1, 147.7, 143.8, 128.5, 124.1, 121.8, 121.3,
107.1; MS (ACPI) m/z 170.0 (M+ + 1). Anal. Calcd for C11H7NO: C,
78.09; H, 4.17; N, 8.28. Found: C, 78.02; H, 4.13; N, 8.17.
(13) Cho, S. Y.; Kim, S. S.; Park, K.-H.; Kang, S. K.; Choi, J.-K.; Hwang,
K.-J.; Yum, E. K. Heterocycles 1996, 43, 1641-1652.
2202
Org. Lett., Vol. 4, No. 13, 2002

89% yield. Employing the Stille-Kelly conditions,8 di-iodide
8 was treated with hexamethylditin in the presence of
catalytic PdCl2‚(Ph3P)2 in refluxing xylene to give benzo-
[4,5]furo[3,2-c]pyridine (7) in 92% yield.
The assembly of benzo[4,5]furo[3,2-b]pyridine (10) proved
to be a challenging enterprise. Several initial routes that
applied the Stille coupling strategy were either too lengthy
or met with failure. An “intramolecular aryl-Heck” reaction15
eventually allowed us to successfully prepare tricycle 10.
As depicted in Scheme 4, commercially available 2-chloro-
ether 9 in 74% yield.14 Subsequently, the heteroaryl-aryl
C-C bond connection was achieved using an intramolecular
aryl-Heck reaction under Jeffery’s ligand-free conditions.16
The desired benzo[4,5]furo[3,2-b]pyridine (10)17 was isolated
in 64% yield.
In conclusion, by taking advantage of the R- and γ-activa-
tion of chloropyridines and utilizing palladium-mediated
reactions, we have synthesized all four possible benzofuro-
pyridines: benzo[4,5]furo[2,3-b]pyridine (2), benzo[4,5]furo-
[2,3-c]pyridine (5), benzo[4,5]furo[3,2-c]pyridine (7), and
benzo[4,5]furo[3,2-b]pyridine (10). Our method provides an
alternative to literature methods where metalation of pyridine
was followed by palladium-catalyzed coupling approach for
pyridine derivative synthesis.18 The aforementioned success
is also a testimony to the utility of palladium chemistry as a
powerful tool in solving otherwise lengthy synthetic problems
with great efficiency.
Scheme 4. Synthesis of Benzo[4,5]furo[3,2-b]pyridine (10)
Acknowledgment. The authors are indebted to Mr.
Roderick J. Sorenson for helpful discussions on bismuth
chemistry and to Drs. Michelle M. Bruendl and Drago R.
Sliskovic for proofreading the manuscript.
Supporting Information Available: 1H and 13C NMR
spectra of benzo[4,5]furopyridines 2, 5, 7, and 10. This
material is available free of charge via the Internet at
http://pubs.acs.org.
3-hydroxypyridine was phenylated using triphenylbismuth(V)
diacetate in the presence of Cu(II) pivaloate to provide diaryl
OL0260425
(14) (a) Elliott, G. I.; Konopelski, J. P. Tetrahedron 2001, 57, 5683-
5705. (b) Harada, T.; Ueda, S.; Yoshida, T.; Inoue, A.; Takeuchi, M.;
Ogawa, N.; Oku, A.; Shiro, M. J. Org. Chem. 1994, 59, 7575-7576. (c)
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Shibaike, K.; Akamatsu, H.; Hori, A.; Abe, H.; Takeuchi, Y. Synthesis 2002,
237-241.
(16) Jeffery’s conditions: (a) Jeffery, T. J. Chem. Soc., Chem. Commun.
1984, 1287-1289. (b) Jeffery, T. Tetrahedron Lett. 1999, 40, 1673-1676.
(c) Jeffery, T. Tetrahedron Lett. 1998, 39, 5751-5754. (d) Jeffery, T. AdV.
Met.-Org. Chem. 1996, 5, 153-260. (e) Jeffery, T. Tetrahedron 1996, 52,
10113-10130. (f) Jeffery, T. Tetrahedron Lett. 1994, 35, 4103-4106.
(17) Data for 10: mp ) 62-64 °C; Rf ) 0.46 (1:1 hex/EtOAc); 1H
NMR (CDCl3) δ 8.40 (dd, J ) 3.7, 0.9 Hz, 1H), 8.15 (dt, J ) 7.6, 0.7 Hz,
1H), 7.72 (dd, J ) 7.1, 0.8 Hz, 1H), 7.50-7.27 (m, 4H); 13C NMR (CDCl3)
δ 157.9, 150.1, 145.4, 144.3, 129.4, 123.8, 123.1, 121.45, 121.36, 118.8,
112.3; MS (ACPI) m/z 170.0 (M+ + 1).
(18) Li, J. J. In Progresses in Heterocyclic Chemistry; Gribble, G. W.,
Gilchrist, T. L., Eds.; Pergamon: Oxford, 2000; Vol. 12, pp 37-56.
Org. Lett., Vol. 4, No. 13, 2002
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