Synthesis of 5-bromopyridyl-2-magnesium chloride and its application in the synthesis of functionalized pyridines

Article abstract of DOI:10.1021/ol0400589

(Chemical Equation Presented) The 5-bromopyridyl-2-magnesium chloride (2), which was not accessible previously, was efficiently synthesized for the first time via an iodomagnesium exchange reaction with 5-bromo-2-iodopyridine (1). This reactive intermediate was allowed to react with a variety of electrophiles to afford a range of useful functionalized pyridine derivatives. Application of this methodology to 5-bromo-2-iodo-3-picoline provided a simple and economical synthesis of a key intermediate for the preparation of Lonafarnib, a potent anticancer agent.

Full text of DOI:10.1021/ol0400589

ORGANIC
LETTERS
2004
Vol. 6, No. 26
4905-4907
Synthesis of
5-Bromopyridyl-2-magnesium Chloride
and Its Application in the Synthesis of
Functionalized Pyridines
Jinhua J. Song,* Nathan K. Yee, Zhulin Tan, Jinghua Xu, Suresh R. Kapadia, and
Chris H. Senanayake
Department of Chemical DeVelopment, Boehringer Ingelheim Pharmaceuticals Inc.,
900 Old Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877-0368
jsong@rdg.boehringer-ingelheim.com
Received October 1, 2004
ABSTRACT
The 5-bromopyridyl-2-magnesium chloride (2), which was not accessible previously, was efficiently synthesized for the first time via an iodo-
magnesium exchange reaction with 5-bromo-2-iodopyridine (1). This reactive intermediate was allowed to react with a variety of electrophiles
to afford a range of useful functionalized pyridine derivatives. Application of this methodology to 5-bromo-2-iodo-3-picoline provided a simple
and economical synthesis of a key intermediate for the preparation of Lonafarnib, a potent anticancer agent.
During our process development of a drug candidate, we
required an efficient and practical method for the synthesis
of 5-bromo-2-metalated-pyridine. A literature survey showed
that metal-halogen exchange reactions of 2,5-dibomo-
pyridines have recently received considerable attention1-6
due to the apparent usefulness of metalated halopyridines in
the synthesis of pyridine-containing natural products as well
as novel therapeutic agents.
Parham first reported that lithiation of 2,5-dibromopyridine
occurred selectively at the C(5) position (n-BuLi, -100 °C,
(1) Parham, W. E.; Piccirlli, R. M. J. Org. Chem. 1977, 42, 257.
(2) Bolm, C.; Ewald, M.; Felder, M.; Schlingloff, G. Chem. Ber. 1992,
125, 1169.
Figure 1.
(3) (a) Romero-Salguero, F. J.; Lehn, J.-M. Tetrahedron Lett. 1999, 40,
859. (b) Wicha, J.; Masnyl, M. Heterocycles 1981, 16, 521. (c) Alderweir-
eldt, F. C.; Vrijens, I., Esmans, E. L.; Wotring, L. L.; Townsend, L. B.;
Balzarini, J.; De Clereq, E. Nucleosides Nucleotides 1989, 8, 891.
improved and utilized this reaction in the synthesis of novel
(4) Wang, X.; Rabbat, P.; O’Shea, P.; Tillyer, R.; Grabowski, E. J. J.;
THF, Figure 1).1 Subsequently, Bolm2 and others3 have
2,2′-bipyridines. More recently, Wang et al. described a C(2)-
selective monolithiation of 2,5-dibromopyridine with n-
BuLi.4 They have found that by judiciously choosing the
solvent (toluene) and running the reaction at very low
concentration (0.017-0.085 M) under cryogenic conditions
(-50 to -78 °C), the 5-bromo-2-lithiopyridine could be
Reider, P. J. Tetrahedron Lett. 2000, 41, 4335.
(5) Trecourt, F.; Breton, G.; Bonnet, V.; Mongin, F.; Marsais, F.;
Queguiner, G. Tetrahedron Lett. 1999, 40, 4339.
(6) Mase, T.; Houpis, I. N.; Akao, A.; Dorziotis, I. K.; Hoang, T.; Iida,
T.; Itoh, T.; Kamei, K.; Kato, S.; Kato, Y.; Kawasaki, M.; Lang, F.; Lee,
J.; Lynch, J.; Maligres, P.; Monila, A.; Nemoto, T.; Okada, S.; Reamer,
R.; Song, J. Z.; Tschaen, D.; Wada, T.; Zewge, D.; Volante, R. P.; Reider,
P. J.; Tomimoto, K. J. Org. Chem. 2001, 66, 6775.
10.1021/ol0400589 CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/18/2004

obtained as the major product. The selectivity, ranging from
6:1 to 34:1, is highly dependent on the concentration, reaction
temperature and reaction time. Higher concentration and
higher reaction temperature gave rise to increased 5-lithiation
product as well as decomposition of the resulting lithiated
bromopyridines. The authors also noted that the ratio of C(5)
and C(2) isomers of lithiopyridines varies over the time due
to lithium migration between two positions. The observed
intrinsic instability of 5-bromo-2-lithiopyridine presents a
major limitation for large-scale applications.
Magnesium-halogen exchange was also tested on 2,5-
dibromopyridine. Queguiner et al. has reported that treatment
of 2,5-dibromopyridine with i-PrMgCl led to the preferential
formation of 2-bromopyridyl-5-magnesium chloride (9:1).5
Mase et al. have used ate complex n-Bu3MgLi to effect the
Mg-Br exchange reaction of 2,5-dibromopyridine.6 Again,
the metalation occurred at the C(5) position selectively.
Therefore, despite recent advances described above, access
to the isomeric 5-bromopyridyl-2-magnesium halide remains
a synthetic challenge. In this Letter, we report the first
efficient synthesis of such an intermediate via an iodo-
magnesium exchange reaction with 5-bromo-2-iodopyridine
and its synthetic utilities.
The 5-bromo-2-iodopyridine (1) represents an ideal starting
point for the synthesis of 2,5-disubstituted pyridines. Re-
cently, we have reported an efficient method for the
preparation of this compound from 2,5-dibromopyridine via
an I-Br exchange reaction (NaI, AcCl, CH3CN, reflux), and
we have demonstrated its superiority to 2,5-dibromopyridine
in carbonylation reactions.7 We thought it was a logical step
to also investigate its reactivities in the metal-halogen
exchange reactions. When 5-bromo-2-iodopyridine was
treated with n-BuLi in THF at -78 °C, the lithiation occurred
instantly to afford 5-bromo-2-lithiopyridine. However, as
observed by Wang,4 the lithiated pyridine starts to decompose
in a short period of time, especially at higher temperature.
This stability issue precludes any practical application of this
process on manufacturing scales. In addition, the unavoidable
isomeric byproduct resulting from C(5) lithiopyridine proved
to be difficult to remove during purifications. Therefore, it
is imperative for us to have a highly selective method for
C(2) carbanion formation.
formed within 30 min. Upon quenching with MeOH-d4,
3-bromopyridine was recovered with >95% D incorporation
at the position para to bromine, which was indicative of the
formation of the desired 5-bromopyridyl-2-magnesium chlo-
ride (2). A slight overcharge of i-PrMgCl does not lead to
lower yields. This is in contrast to the lithiation reaction,
where an excess of n-BuLi resulted in the formation of bis-
lithiated species, thus lowering the yield of the desired
monolithiopyridine. The iodo-magnesium exchange reaction
also proceeded smoothly in CH2Cl2 and toluene. It is worth
noting that the Grignard reagent is soluble in CH2Cl2 and
the solution can be conveniently transferred via cannulation
if reverse addition is desired. The complete C(2) selectivity
in this reaction indicates that the higher reactivity of iodide
vs bromide overcomes the opposing relative regioselectivity
inherent to the pyridine ring system.
The reactivity of 5-bromopyridyl-2-magnesium chloride
(2) was examined through reactions with a variety of
electrophiles (Table 1).8 The Grignard intermediate was
reacted with DMF to furnish the aldehyde (3a) in excellent
yield (90%). As a comparison, the same aldehyde (3a) was
synthesized in only 49% yield via the intermediacy of
5-bromo-2-lithiopyridine.4 Weinreb amides (entries 3 and 4)
reacted smoothly with 2 to afford the corresponding ketones
(3b9 and 3c). Due to the high electrophilicity of the pyridyl
trifluoromethyl ketone, it was isolated as its hydrate (3c).
Butyraldehyde condensed with the Grignard intermediate to
give the alcohol (3d) in 70% yield. Direct cyanation of the
C(2) position of the pyridine ring was achieved by reacting
5-bromopyridyl-2-magnesium chloride (2) with TsCN. This
result is noteworthy because according to a recent report,10
5-bromo-2-lithiopyridine4 failed to react with TsCN to give
5-bromo-2-cyanopyridine (3e).
The Grignard intermediate also coupled nicely with the
iminium trifluoroacetate to afford the amine (3f)11 directly
in 82% yield. The carbon-sulfur bond formation using
(8) Representative Procedure. In a 22 L, three-neck, round-bottom
flask equipped with mechanical stirrer, 1 kg (3.52 mol) of 5-bromo-2-
iodopyridine (1) was dissolved in 5 L of THF. The solution was cooled to
-15 to -10 °C. Then, 1.9 L (3.8 mol, 1.08 equiv) of 2 M i-PrMgCl was
added at a rate to keep the internal temperature below 0 °C (1 h). The
reaction mixture became a brown suspension. After the reaction mixture
was stirred between -15 to 0 °C for 1 h, 400 mL (5.16 mol, 1.5 equiv) of
anhydrous DMF was added at a rate to keep the internal temperature below
0 °C. After the reaction mixture was stirred at these temperatures for 30
min, the cooling bath was removed and allowed to warm to room
temperature over 1 h. The reaction mixture was then cooled to 0 °C, and 4
L of 2 N HCl aqueous solution was added at a rate to keep the internal
temperature below 25 °C. The mixture was stirred for 30 min. The pH was
adjusted to pH 6-7 by adding about 150 mL of 2 N NaOH aqueous solution.
The layers were separated; the THF layer was concentrated to give the
dark brown wet solids, and the aqueous layer was extracted with 3 L of
CH2Cl2. The CH2Cl2 layer was used to dissolve the residue obtained from
the THF layer, and the resulting solution was washed with water (2 L x 2).
The combined organic layer was dried by stirring with MgSO4 (400 g) for
30 min and filtered. Evaporation of solvents gave 589 g (90% yield) of the
desired aldehyde (3a) as a brownish-yellow solid.
(9) (a) Couve-Bonnaire, S.; Carpentier, J.-F.; Mortreux, A.; Castanet,
Y. Tetrahedron 2003, 59 (16), 2793. (b) Couve-Bonnaire, S.; Carpentier,
J.-F.; Mortreux, A.; Castanet, Y. Tetrahedron Lett. 2001, 42 (22), 3689.
(10) Markevitch, D. Y.; Rapta, M.; Hecker, S. J.; Renau, T. E. Synth.
Commun. 2003, 33, 3285.
(11) Boschelli, D. H.; Wang, Y.; Boschelli, F. C.; Berger, D. M.; Zhang,
N.; Powell, D. W.; Ye, F.; Yamashita, A.; Demorin, F. F.; Wu, B.; Tsou,
H.-R.; Overbeek-Klumpers, E. G.; Wissner, A. U.S. Patent 2002026052,
2002.
To overcome these problems associated with lithio-
pyridines, we focused our attention on magnesium-halogen
exchange reaction for two reasons: (a) aryl Grignard reagents
are typically more stable and less basic than aryllithium, and
(b) it is unlikely that Mg will migrate to C(5) from the C(2)
position once formed.
It has been shown by Queguiner5 as well as Mase6 that,
for the same halogen comparison (as in 2,5-dibromopyridine),
the C(5) position is strongly favored in the Mg-halogen
exchange reaction. On the other hand, the proposed use of
an iodide instead of a bromide at the C(2) position in the
present study would enhance the reactivity of the position R
to the nitrogen.
When a THF solution of 5-bromo-2-iodopyridine (1) was
treated with i-PrMgCl or c-pentylMgCl at 0 °C, a slurry was
(7) Song, J. J.; Yee, N. K. J. Org. Chem. 2001, 66, 605.
4906
Org. Lett., Vol. 6, No. 26, 2004

Table 1. Synthesis of 5-Bromo-2-Substituted Pyridines
Figure 2.
i-PrMgCl in THF for 45 min at 0 °C. Addition of phenyl
isocyanate into the reaction mixture afforded an 86% yield
of the desired amide (5), which has been employed as a key
intermediate in the large-scale synthesis of Lonafarnib, a
potent anticancer agent.14 The previously reported synthesis
of this important intermediate14c involved a selective carbon-
ylation reaction with 2,5-dibromo-3-picoline (4), which
required the use of 80 psi of CO, 3 mol % Pd(OAc)2, 3.3
mol % 2,2′-bipyridine, as the ligand and 40 h at 65 °C for
the reaction to complete. Therefore, the current method
provides a much simpler and more economical alternative
than the carbonylation approach.
In summary, magnesium-iodine exchange reaction of
5-bromo-2-iodopyridine (1) was found to occur smoothly at
the C(2) position to furnish the corresponding metalated
intermediates in excellent yield with complete regioselec-
tivity. The current method provides the first synthesis of
5-bromopyridyl-2-magnesium chloride (2) that was not
accessible previously. Compared to the reported lithiation
reactions,4 the present protocol obviated high dilution and
cryogenic requirements, avoided the formation of the iso-
meric byproducts, and has been successfully carried out on
a multikilogram scale in a pilot plant. In terms of suitability
and practicality for large-scale production, 5-bromopyridyl-
2-magnesium chloride (2) is clearly a superior reagent in
replacing the unstable 5-bromo-2-lithiopyridine for synthesis
of 2,5-disubstituted pyridines. This protocol was successfully
applied to the synthesis of a key intermediate for an
anticancer agent, Lonafarnib, further demonstrating the utility
of this methodology.
a Electrophile was introduced at -78 °C. bReverse addition of methylene
chloride solution of Grignard intermediate into a solution of iminium salt
was required.
Supporting Information Available: Experimental pro-
cedures for synthesis of 3-bromo-6-deuteriopyridine and
compounds 1, 5, 6, and 3a-h and 1H NMR data, including
the reproduction of 1H NMR spectra for 3-bromo-6-
deuteriopyridine and compounds 1, 5, 6, and 3a-h. This
material is available free of charge via the Internet at
http://pubs.acs.org.
phenyl disulfide was equally successful to furnish compound
3g.12 Treating 5-bromopyridyl-2-magnesium chloride (2) with
TMSCl gave an 84% yield of 5-bromo-2-trimethylsilyl-
pyridine (3h), which was synthesized in only 51% yield via
lithiopyridine.4
This chemistry was further extended to 5-bromo-2-iodo-
3-picoline (6, Figure 2).13 The corresponding pyridyl Grig-
nard intermediate (7) was obtained cleanly by treatment with
OL0400589
(12) Abramovitch, R. A.; Helmer, F.; Liveris, M. J. Org. Chem. 1969,
34, 1730.
(13) 5-Bromo-2-iodo-3-picoline (6) was synthesized according to the
general method in ref 7 (see Supporting Information).
(14) (a) Kuo, S.-C.; Chen, F.; Hou, D.; Kim-Meade, A.; Bernard, C.;
Liu, J.; Levy, S.; Wu, G. G. J. Org. Chem. 2003, 68, 4984. (b) Poirier, M.;
Chen, F.; Bernard, C.; Wong, Y.-S.; Wu, G. G. Org. Lett. 2001, 3, 3795.
(c) Wu, G. G.; Wong, Y.-S.; Poirier, M. Org. Lett. 1999, 1, 745.
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