Effective lithiation of 3-bromopyridine: Synthesis of 3-pyridine boronic acid and variously 3-substituted pyridines

Article abstract of DOI:10.1016/S0040-4039(02)00776-1

By using toluene as a solvent, 3-lithiopyridine can be generated cleanly at -50°C. The addition of various electrophiles affords useful building blocks, such as the 3-pyridine boronic acid in 87% isolated yield.

Full text of DOI:10.1016/S0040-4039(02)00776-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4285–4287
Effective lithiation of 3-bromopyridine: synthesis of 3-pyridine
boronic acid and variously 3-substituted pyridines
Dongwei Cai,* Robert D. Larsen and Paul J. Reider
Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA
Received 19 March 2002; accepted 2 April 2002
Abstract—By using toluene as a solvent, 3-lithiopyridine can be generated cleanly at −50°C. The addition of various electrophiles
affords useful building blocks, such as the 3-pyridine boronic acid in 87% isolated yield. © 2002 Elsevier Science Ltd. All rights
reserved.
Substituted pyridines are important components of
drug candidates. Recently, we required 3-pyridine
boronic acid (1) as an intermediate in a Suzuki cross-
coupling. Although the compound is commercially
available, it is expensive (>$100/g) and often only small
quantities can be obtained. Herein, we describe an
improved process for the lithiation of 3-bromopyridine
and the preparation of 3-pyridine boronic acid, which is
capable of producing kilogram quantities of the build-
ing block. In addition the method is amenable to the
synthesis of a variety of 3-substituted pyridines in excel-
lent yields.
Because of the poor solubility of 3-pyridylmagnesium
chloride, the alternative lithium–halogen exchange was
investigated. Although 3-bromopyridine can be cleanly
converted to 3-pyridyl lithium in diethyl ether affording
a 99% assay yield of 3-pyridine boronic acid, ether is
impractical for large-scale operations. A common prob-
lem with the lithium–halogen exchange of bromopyridi-
nes in THF is the relative acidity of bromopyridines
resulting in de-protonation.6 Extremely low tempera-
tures (−100°C) are needed to minimize this side reac-
tion. In THF at −60°C with a normal addition mode, a
dark-green solution was produced. Only a 44% yield of
the boronic acid was achieved after the quench with
triisopropyl borate. To overcome the deprotonation an
inverse-addition mode was tested. The assay yield was
much better at 81%. The stability of 3-pyridyl lithium
itself in THF was very good at 5−50°C. With this
result the reaction of the anion was studied with a
variety of electrophiles.
Both magnesium– and lithium–halogen exchange of
3-bromopyridine have been reported in the literature.1,2
Although magnesium–halogen exchange offers many
advantages,1 in this specific case, isopropyl magnesium
chloride exchange did not give satisfactory results due
to poor solubility and poor conversions.3 The resulting
3-pyridylmagnesium chloride formed a very dense pre-
cipitate, which was quite unreactive with electrophiles.
Reaction with triisopropyl borate only gave a 36% yield
of pyridine boronic acid.4 The assay yield was slightly
better at 55% with a modified procedure using a 1:2
mixture of BuMgCl:BuLi,4,5 but again the solubility
was a major problem.
In addition to changing the lithiation conditions for
3-bromopyridine, the use of a non-coordinating solvent
was considered (Table 1). Normally, lithium halogen
exchange does not work well without a coordinating
solvent like THF to disassociate the BuLi aggregate. In
this case, however, the pyridine nitrogen may suitably
activate this exchange. When toluene was used as a
solvent, a nice free-flowing yellow solid of 3-pyridyl
lithium was generated. The assay yield of 3-pyridine
boronic acid was improved to 98% and the product was
isolated as a crystalline solid in 87% yield.7 Since the
boronic acid is very polar and water soluble, isolation
was difficult. Even with saturating the aqueous layer
with sodium chloride only a 70% recovery of the
product was achieved with each THF extraction. After
* Corresponding author. Tel.: 732-594-3205; fax: 732-594-1499;
e-mail: dongwei cai@merck.com
–
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00776-1

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D. Cai et al. / Tetrahedron Letters 43 (2002) 4285–4287
Table 1. Preparation of 3-pyridine boronic acid
Entry
Reagent
Solvent/temp. (°C)
Assayed yield (%)
a
b
c
d
e
f
Me2CHMgCl
n-BuMgCl/n-BuLi (1:2)
n-BuLi
n-BuLi (reversed addition)
n-BuLi
n-BuLi (reversed addition)
n-BuLi
THF/25
THF/−5
36
55
44
81
98
98
99
THF/−60
THF/−60
Toluene/−50
Toluene/−50
Ether/−50
e
Table 2. 3-Lithiopyridine reaction with various electrophiles
three extractions the recovery was increased to 97%.
The combined extracts were concentrated and the
product was re-dissolved in methanol/THF (1:1). The
insoluble salts were removed by filtration and the final
product was crystallized by switching the solvent from
methanol/THF to acetonitrile.
References
1. Trecourt, F.; Breton, G.; Bonnet, V.; Mongin, F.; Marsais,
F.; Queguiner, G. Tetrahedron 2000, 56, 1349.
2. (a) Negishi, E.; Luo, F.-T.; Frisbee, F.; Matsusita, H.
Heterocycles 1982, 18, 117; (b) Rubinsztajin, S.; Zeldin,
M.; Fife, W. K. Synth. React. Inorg. Met.-Org. Che. 1990,
20, 495; (c) Gilman, H.; Spatz, S. M. J. Org. Chem. 1951,
16, 1485.
3. Conversion between isopropyl magnesium chloride (1.05
equiv.) with 3-bromopyridine is around 85%. This is deter-
mined by quenching the anion with water and assaying for
the resultant pyridine and starting 3-bromopyridine.
4. (a) A major by-product was bis-pyridine boronic acid. The
double addition occurred with triisopropyl borate at room
temperature; (b) Fisher, F. C.; Havinga, E. Rec. Trav.
Chim. 1965, 84, 439.
5. Mase, T.; Houpis, I. N.; Akao, A.; Dorziotis, I.; Emerson,
K.; Hoang, T.; Iida, T.; Itoh, T.; Kamei, K.; Kato, S.;
Kato, Y.; Kawasaki, M.; Lang, F.; Lee, J.; Lynch, J.;
Maligres, P.; Molina, A.; Nemoto, T.; Okada, S.; Reamer,
Interestingly, when toluene was used as the solvent,
both normal and reversed additions gave the same
result. The pyridyl lithium, which precipitated as a
yellow solid from toluene, could be dissolved by adding
one volume of THF. This solution of 3-lithiopyridine
could conveniently be reacted with a variety of elec-
trophiles with satisfactory results (Table 2).8,9
In conclusion, we have shown that 3-lithiopyridine can
be easily generated in toluene and have demonstrated a
practical way to prepare 3-pyridine boronic acid in 87%
isolated yield. In addition this protocol can be easily
applied to the preparation of a variety of 3-substituted
pyridines.

D. Cai et al. / Tetrahedron Letters 43 (2002) 4285–4287
4287
R.; Song, J. Z.; Tschaen, D.; Wada, T.; Zewge, D.;
Volante, R. P.; Reider, P. J.; Tomimoto, K. J. Org. Chem.
2001, 66, 6775.
washed with THF/MeOH (1:1; 100 mL). The combined
filtrate and wash was concentrated. The solvent composi-
tion was switched to acetonitrile (500 mL) by distillation
whereupon the product crystallized. The solids was filtered
and dried to give 54.3 g of product as 98 wt% material in
87% yield. HPLC assay of this product was achieved with
a YMC ODS-AQ column (4.6×250) giving a 5.3 min
retention time at 1 mL/min flow rate eluting with 2%
acetonitrile/water/0.1% HClO4. 1H NMR (CD3OD, 400
MHz), l 8.76, s, 1H; 8.51, dd, J=2, 5 Hz, 1H; 8.23, d,
J=7.5 Hz, 1H, and 7.48, m, 1H; 13C NMR (D2O,
CF3COOD, 100 MHz) l, 126.1, 133.5 (broad), 140.9,
144.1, 151.0. Elemental analysis for calcd for C5H6BNO2:
C, 48.86; H, 4.92; N, 11.40; B, 8.8. Found: C, 49.58; H,
4.06; N, 11.42%. It is not unusual for a boronic acid to fail
elemental analysis since the functionality is frequently a
mixture of free boronic acid and anhydride forms. LC–MS
found 124.1 (M+H), 106.3 (M−OH). The boronic acid was
used directly in Suzuki couplings without further purifica-
tion.
6. Cai, D.; Hughes, D. L.; Verhoeven, T. R. Tetrahedron
Lett. 1996, 37, 2537.
7. Typical procedure: Toluene (600 mL) in a 2 L 3-necked
flask, equipped with an overhead stirrer, was cooled down
to −60°C. n-BuLi (2.5 M in hexane, 220 mL, 0.55 mol)
was mixed with the toluene. After the internal temperature
reached −60°C, a solution of 3-bromopyridine (79.0 g, 48.2
mL, 0.50 mol) in toluene (200 mL) was added. The inter-
nal temperature was maintained at <−50°C by controlling
the rate of addition. A yellow solid precipitated. The
resulting slurry was aged for 15–30 min, then THF (200
mL) was added slowly, keeping the internal temperature at
<−50°C. The mixture was aged for 15 min, then triiso-
propyl borate (138 mL, 0.60 mol) was added over 2 min.
The solids dissolved and a brown homogeneous solution
was obtained. The reaction solution was warmed to −15°C
and quenched with 2.7N HCl (484 mL, 1.3 mol). The
phases were separated and organic layer was washed with
water (30 mL). The aqueous layers were combined, neu-
tralized with 10N NaOH to pH 7, and extracted with THF
(3×500 mL). The organic layers were combined and con-
centrated to dryness. The resulting solid was dissolved
with THF (250 mL) and methanol (250 mL). This mixture
was filtered to remove inorganic salts and the solids were
8. Since the resulting n-BuBr can slowly react with 3-
lithiopyridine to form 3-butylpyridine in THF/toluene,
extended aging is not recommended.
9. Satisfactory analyses of the pyridine adducts were
obtained (1H and 13C NMR, elemental analysis, and LC–
MS).