Novel 2,2-bipyridine ligand for palladium-catalyzed regioselective carbonylation

Article abstract of DOI:10.1021/ol990123s

Formula presented A palladium-catalyzed highly regioselective one-step carbonylation of 2,5-dibromo-3-methylpyridine is reported. A range of alkyl esters and amides can be prepared in good yield with better than 95:5 regioselectivity via this method. Key

Full text of DOI:10.1021/ol990123s

ORGANIC
LETTERS
1999
Vol. 1, No. 5
745-747
Novel 2,2-Bipyridine Ligand for
Palladium-Catalyzed Regioselective
Carbonylation
George Guangzhong Wu,* YeeShing Wong, and Marc Poirier
Chemical Process Research and DeVelopment, Schering-Plough Research Institute,
2015 Galloping Hill Road, Kenilworth, New Jersey 07033
george.wu@spcorp.com
Received June 10, 1999
ABSTRACT
A palladium-catalyzed highly regioselective one-step carbonylation of 2,5-dibromo-3-methylpyridine is reported. A range of alkyl esters and
amides can be prepared in good yield with better than 95:5 regioselectivity via this method. Key to the high regioselectivity for the formation
aromatic amides is the introduction of a novel nonphosphine-based 2,2-bipyridine ligand. This novel reaction was scaled up smoothly in the
plant to a 130-kg batch size and facilitated the delivery of bulk material for the clinical trials of Sch 66336, a candidate for oncologic treatments.
The synthesis of Sch 663361 required an efficient method
for the preparation of secondary and tertiary 3-methyl-5-
bromo-2-pyridinecarboxyamides. Most of the reported meth-
easy access to our desired intermediate. Although underuti-
lized in industry, this reaction forms an amide in one step
and reduces the cost of goods since the starting materials
are carbon monoxide and a simple amine.3 Our major
concern was the regioselectivity, since we required the
selective reaction of the more hindered bromo group. Without
the 3-methyl group, it was reported that the 2-bromo was
more reactive toward palladium-catalyzed reactions.4
The first carbonylation reaction we carried out between
2,5-dibromo-3-methylpyridine and carbon monoxide (60 psi)
in methanol using 3 mol % of (PPh3)2PdCl2 as a catalyst
and Et3N as a base gave the desired 5-bromo-3-methyl-2-
pyridine ester and the diester in a ratio of 90:10. 2,5-
Dibromo-3-methylpyridine was initially prepared in two steps
starting from 2-amino-3-methylpyridine5 and later purchased
ods for amide formation required multistep synthesis and
did not give regioselectivity for the 2-position.2 Palladium-
catalyzed carbonylative amide formation could provide an
(1) Njoroge, F. G.; Taveras, A. G.; Kelly, J.; Remiszewski, S.; Mallams,
A. K.; Wolin, R.; Afonso, A.; Cooper, A. B.; Rane, D. F.; Liu, Y.; Wong,
J.; Vibulbhan, B.; Pinto, P.; Deskus, J.; Alvarez, C. S.; del Rosario, J.;
Connolly, M.; Wang, J.; Desai, J.; Rossman, R. R.; Bishop, W. R.; Patton,
R.; Wang L.; Kirschmeier, P.; Bryant, M. S.; Nomeir, A. A.; Lin, C. C.;
Liu, M.; McPhail, A.; Doll, R. J.; Girijavallabhan, V.; Ganguly, A. K. J.
Med. Chem. 1998, 41, 4890.
(2) (a) Wakefield, B. J. Organolithium Methods; Academic Press: New
York, 1988; p 86. (b) Fife, W. K. J. Org. Chem. 1983, 48, 1375. (c) Parham,
W. E.; Piccirilli, R. M. J. Org. Chem. Soc. 1977, 42, 257.
(3) (a) Schoenberg, A.; Bartoletti, I. Heck, R. F. J. Org. Chem. 1974,
39, 3318. (b) Heck, R. F. Palladium Reagents in Organic Syntheses;
Academic Press: New York, 1985; Chapter 4.
(4) (a) Tilley, J. W.; Zawoishi, S. J. Org. Chem. 1988, 53, 386. (b) Ernst,
A.; Gobbi, L.; Vasella, A. Tetrahedron Lett. 1996, 37, 7959. (c) After we
finished our experiments, two related papers published: Chambers, R. J.;
Marfat, A. Synth. Commun. 1997, 515. Najiba, D.; Carpentier, J.-F.;
Castanet, Y.; Biot, C.; Brocard, J.; Mortreux, A. Tetrahedron Lett. 1999,
40, 3719.
(5) Does, V.; Hertog, D. Recl. TraV. Chim. Pays-Bas, 1965, 84, 951.
10.1021/ol990123s CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/03/1999

commercially.6 Carbonylation with alkylamines proceeded
even more smoothly and gave better than 95:5 regioselec-
tivity as determined by both HPLC and NMR analyses. This
better selectivity was apparently due to the stronger nucleo-
philicity of amines than alcohols. The synthetic versatility
of the carbonylation met the challenge of the preparation of
a variety of amides in a single step for our process
optimization. As shown in Table 1, the reaction worked well
dropped accordingly to between 24 and 50%. Anilines with
electron-donating substituents gave better selectivity and
yield than those bearing electron-withdrawing groups. It was
further observed that the regioselectivity deteriorates with
time and eventually bisamides become the dominant product.
This, coupled with the fact that no 5-monoamide was
observed, suggested a sequential reaction mechanism. This
may account for the lower selectivity with anilines since their
reaction rates were three times slower than those for
alkylamines. Thus, we first sought to shorten the reaction
time with aniline by varying the base. (PPh3)2PdCl2 (3 mol
%) was used as a catalyst for this study. As shown in Table
2, the stronger the base the faster the reaction rate. However,
both the regioselectivity and the yield deteriorate with the
base strength.
Table 1. Regioselective Carbonylation
Table 2. Base Effect
We then studied the ligand effect on the regioselectivity
using 1.4 equiv of DBU as a base. We thought that initial
Pd coordination with the pyridine nitrogen followed by
insertion to the neighboring Br-C bond accounted for the
selectivity and that a weaker ligand should enhance the
selectivity. In fact, pyridine is known to coordinate with
palladium and forms stable complexes.7 Examination of the
effect of several ligands on the selectivity validated our
thinking, and these results are summarized in Table 3. While
a strong ligand such as Bu3P completely inhibits the
carbonylation, reaction without any ligand such as palladium
on carbon also gives only a trace of product. The lack of
with both primary and secondary amines as well as with
cyclic amines. For alkylamines, the reaction time was 6 h
and the isolated yields ranged from 59 to 72%. Over 20
amides were prepared via this regioselective carbonylation
and some of the representative examples are listed in Table
1.
Table 3. Ligand Effect
Further studies indicated that aromatic amides are better
suited for our synthetic efforts toward Sch 66336. The
regioselectivity, however, decreased from 95:5 for alkyl-
amines to about 70:30 for anilines, and the isolated yields
Bipyridine
bipyridine
Bipyridine
(6) D & O Chemicals, Inc. 401 South Van Brunt Street, Englewood, NJ
07631.
746
Org. Lett., Vol. 1, No. 5, 1999

reactivity with Bu3P may come from the decrease in reaction
rate of the migratory insertion step. It is clear from Table 3
that we need a ligand that is weak enough not to inhibit the
coordination of 2,5-dibromo-3-methylpyridine with pal-
ladium and strong enough to keep palladium in solution. We
shifted our attention away from the ubiquitous phosphine-
based ligand and selected 2,2-bipyridine8 for this task. This
novel ligand improved the regioselectivity from 75:25 to 98:2
for aromatic amides. It was also observed that less polar
solvents such as toluene give better selectivity than polar
ones such as MeCN or DMF. The amount of catalyst used
can be further dropped from 3 to 0.5 mol % without
sacrificing the yield.
A simple workup procedure was developed for the
isolation of amides as described in ref 9. Under the optimized
conditions, the isolated yields for amides derived from aniline
and 4-chloroaniline increased from 55% and 40% to 82%
and 72%, respectively. As shown in Table 4, the solution
yield for N-methylphenyl amide 15 also improved from 35%
to 66%. The reaction with aniline was scaled up successfully
and safely in the plant and produced more than 600 kg of
bulk intermediate for our antitumor project.
In summary, we have developed a palladium-catalyzed
regioselective carbonylation and applied it to the manufacture
of a pharmaceutical intermediate. This reaction replaced
multiple steps in previous syntheses and reduced the cost
significantly.
Acknowledgment. We thank the staff of Analytical
Department for assays, Zhixian Ding, Xing Chen, and Doris
Schumacher for their support and help, and our plant
engineers and operators for a successful scale-up.
Supporting Information Available: Experimental pro-
1
cedures, full characterization data, and H and 13C NMR
spectra for compounds 1-15. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL990123S
(7) Stephenson, T. A.; Morehouse, S. M.; Powell, A. R.; Heffer, J. P.;
Wilkinson, G. J. Chem. Soc. 1965, 3632.
(8) Recently, chrial derivatives of 2,2-bipyridine were used as chiral
ligands for palladium reactions: Chelucci, G.; Pinna, G. A.; Saba, A.
Tetrahedron: Asymmetry 1998, 9, 531.
(9) Representative Experimental Section. To a 4-L autoclave were
added sequentially 250 g (950 mmol) of 2,5-dibromo-3-methylpyridine, 6.7
g (30 mmol) of Pd(OAc)2, 5.0 g (32 mmol) of 2,2-bipyridine, 2.5 L of
toluene, 127 mL (1.1 mol) of aniline, and 194 mL (1.4 mol) of DBU. The
autoclave was sealed, evacuated, purged with nitrogen, and charged with
CO to 80 psi. The mixture was heated to 65 °C for about 40 h while keeping
the pressure at 80 psi, cooled to 25 °C, and filtered through a pad of Celite
with aid of water. The layers were separated, and the organic layer was
concentrated. Crystallization of the residue from 2-PrOH gave the desired
amide in 76-82% isolated yield.The purity of the isolated product was
>98% and the solution yield was 90% as determined by HPLC.
Table 4. Carbonylation with 2,2-Bipyridine Ligand
Bipyridine
Org. Lett., Vol. 1, No. 5, 1999
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