An improved protocol for the preparation of 3-pyridyl- and some arylboronic acids

Article abstract of DOI:10.1021/jo025792p

3-Pyridylboronic acid was prepared in high yield and bulk quantity from 3-bromopyridine via a protocol of lithium-halogen exchange and "in situ quench". This technique was further studied and evaluated on other aryl halides in the preparation of arylboronic acids.

Full text of DOI:10.1021/jo025792p

preparation of 3-pyridylboronic acid (3) via lithium-
halogen exchange and in situ quench with triisopropyl
borate. A brief study on the generality of this procedure
for converting aryl halides to arylboronic acids is also
reported.
An Im p r oved P r otocol for th e P r ep a r a tion
of 3-P yr id yl- a n d Som e Ar ylbor on ic Acid s
Wenjie Li,* Dorian P. Nelson,* Mark S. J ensen,
R. Scott Hoerrner, Dongwei Cai, Robert D. Larsen, and
Paul J . Reider
In our ongoing efforts to synthesize biologically active
compounds as potential therapeutic agents, we needed
to introduce a 3-pyridyl moiety onto our target. 3-Py-
ridylboronic acid (3) was the choice of reagent for this
transformation, since it is nontoxic and thermally and
air-stable.7 Although there are commercial sources for
this compound, it is available in only small quantities,
and the cost is very high. The existing literature protocol
for preparing 3-pyridylboronic acid afforded a poor yield
and required conditions not suitable for scale-up.8 In our
studies on preparing 3-pyridylboronic acid from 3-bro-
mopyridine (1), we learned that the order of addition of
the reagents was the key to a successful preparation.
When 3-bromopyridine was treated with n-butyllithium
at -78 °C followed by triisopropyl borate (2), the product
was isolated in poor yield (20-30%). The “reverse”
addition procedure, in which 3-bromopyridine was added
to a solution of n-butyllithium followed by addition of
triisopropyl borate, gave better yields, but the reaction
must be run at low temperatures (below -70 °C) in order
to get consistent results, making it inconvenient for large-
scale preparation.
Our next approach was to add n-butyllithium to a
solution of 3-bromopyridine and triisopropyl borate fol-
lowed by an acid quench (Scheme 1). This protocol has
been mentioned before, primarily in patents.9 However,
very little study and discussion about this technique has
been described. As it turned out, this sequence of addition
was superior to those previously described. Not only did
it consistently afford good yields but it also proved to be
temperature tolerant, giving the best yields (90-95%) at
-40 °C and a respectable 80% yield even at 0 °C. This
was probably because the lithium-halogen exchange on
3-bromopyridine is much faster than the reaction be-
tween n-butyllithium and triisopropyl borate. The 3-lithi-
opyridine intermediate thus generated reacts rapidly
with the borate in the reaction mixture, thereby mini-
Process Research Department, Merck Research Laboratories,
P.O. Box 2000, Rahway, New J ersey 07065
wenjie_li@merck.com; dorian_nelson@merck.com
Received April 3, 2002
Abstr a ct: 3-Pyridylboronic acid was prepared in high yield
and bulk quantity from 3-bromopyridine via a protocol of
lithium-halogen exchange and “in situ quench”. This tech-
nique was further studied and evaluated on other aryl
halides in the preparation of arylboronic acids.
Boronic acids have been widely used for cross-coupling
reactions in carbon-carbon bond formation.1,2 A typical
preparation of arylboronic acids involves a reaction
between an organoborate and an organometal (Li or Mg)
species, usually prepared by magnesium insertion or
lithium-halogen exchange of the corresponding aryl
halides.3 This method has its limitations, however. First,
it is difficult to apply this method to substrates bearing
functional groups not compatible with organolithium
reagents such as esters and nitriles. Second, some
aryllithium intermediates are intrinsically unstable, as
in the case of many aromatic heterocycles.4 Alternately,
arylboronic esters can be prepared from aryl halides or
aryl triflates via a palladium-catalyzed cross-coupling
reaction with tetraalkoxydiboron or dialkoxyhydrobo-
rane.5,6 These methods tolerate a wide range of functional
groups. However, they are not suitable for large-scale
synthesis because tetraalkoxydiboron and dialkoxyhy-
droborane are expensive. In this note we report a revised
procedure for a high-yielding, reproducible, and scalable
(1) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995,
95, 2457-2483. (b) Suzuki, A. J . Organomet. Chem. 1999, 576, 147-
168. (c) Suzuki, A. Pure Appl. Chem. 1994, 66, 213-222. (d) Suzuki,
A. Pure Appl. Chem. 1991, 63, 419-422.
(7) For application of 3-pyridylboronic acid in cross-coupling reac-
tions, see: (a) Enguehard, C.; Hervet, M.; Allouchi, H.; Debouzy, J .-
C.; Leger, J .-M.; Gueiffier, A. Synthesis 2001, 4, 595-600. (b) Li, J . J .;
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Guillaneux, D.; Nguyen, T.; Wong, P. L.; Snieckus, V. J . Org. Chem.
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(9) (a) DeCamp, A. E.; Grabowski, E. J . J .; Huffman, M. A.; Xavier,
L. C.; Ho, G.-J .; Mathre, D. J .; Yasuda, N. Preparation of 2-Aryl
Carbapenems. PCT Int. Appl. WO 9531461, 1995. (b) DeCamp, A.;
Dolling, U. H.; Li, Y.; Rieger, D. L.; Yasuda, N.; Xavier, L. C. Boron
Containing Intermediates Useful in the Preparation of Carbapenems.
U.S. Patent 5338875, 1994. (c) Yasuda, N.; Huffman, M. A.; Ho, G.-J .;
Xavier, L. C.; Yang, C.; Emerson, K. M.; Tsay, F.-R.; Li, Y.; Kress, M.
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E.; Mathre, D. J .; Douglas, A. W.; Dolling, U.-H.; Grabowski, E. J . J .;
Reider, P. J . J . Org. Chem. 1998, 63, 5438-5446. (d) Singh, A.; Chen,
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Arylsulfonylboronic Acids, Haloarenes, and Aminoisoxazoles. PCT Int.
Appl. WO 0056685, 2000.
(2) For recent developments of the Suzuki reaction and its industrial
application, see: (a) Littke, A. F.; Dai, C.; Fu, G. C. J . Am. Chem. Soc.
2000, 122, 4020-4028. (b) Bei, X.; Turner, H. W.; Weinberg, W. H.;
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Wolfe, J . P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38, 2413-
2416. (d) Zhang, C.; Huang, J .; Trudell, M. L.; Nolan, S. P. J . Org.
Chem. 1999, 64, 3804-3805. (e) Littke, A. F.; Fu, G. C. Angew. Chem.,
Int. Ed. 1998, 37, 3387-3388. (f) Old, D. W.; Wolfe, J . P.; Buchwald,
S. L. J . Am. Chem. Soc. 1998, 120, 9722-9723. (g) Smith, G. B.;
Dezeny, G. C.; Hughes, D. L.; King, A. O.; Verhoeven, T. R. J . Org.
Chem. 1994, 59, 8151-8156.
(3) (a) Gerrard, W. The Chemistry of Boron; Academic: New York,
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(5) (a) Ishiyama, T.; Murata, M.; Miyaura, N. J . Org. Chem. 1995,
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Tetrahedron Lett. 1997, 38, 3447-3450.
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10.1021/jo025792p CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/13/2002
5394
J . Org. Chem. 2002, 67, 5394-5397

SCHEME 1
SCHEME 2
would be quenched by borate immediately after they were
formed and, therefore, gave boronic acids in good yields.
In contrast, the sequential addition method gave better
yield in entries 10-13. This may indicate that these
aryllithium species were relatively stable, so the sequen-
tial addition of borate had no adverse effect. In fact, in
entries 10-13 significant amounts of unreacted aryl
bromides were observed in the in situ quench method,
whereas the sequential addition method consumed all the
aryl bromides. This suggests that the generation of the
aryllithium with these substrates was relatively slow,
therefore allowing n-butyllithium to react competitively
with triisopropyl borate.
mizing the chance for 3-lithiopyridine to undergo unde-
sired side reactions. The product was isolated by crystal-
lization from acetonitrile in the form of boroxin 4.10 The
optimized procedure was easily scaled up to produce 1
kg of crystalline boroxin 4, which functioned very well
in a palladium-catalyzed cross-coupling reaction with aryl
halides. The characterization of boroxin 4 was difficult,
however, due to the presence of varying amounts of
hydrates. Therefore, boroxin 4 was converted to its
pinacol ester 5, which was fully characterized.11
To study the general scope of this “in situ quench”
protocol, we applied it to several other aryl halides in
the preparation of arylboronic acids (Scheme 2). The
yields were compared to those observed using the tradi-
tional sequential addition method in which aryl halides
were treated with n-butyllithium followed by addition of
the borate.12 As shown in Table 1, the in situ quench
procedure gave better yields in several heterocyclic
systems (entries 1-4). This method also worked better
in the presence of functional groups that are sensitive to
organolithium species (entries 7-9). It could be assumed
that the aryllithium species generated from these sub-
strates either were labile or might undergo side reactions.
In the in situ quench procedure, the aryllithium species
In conclusion, the revised procedure for lithium-
halogen exchange with in situ quench with borate offers
an efficient alternative for preparing some arylboronic
acids from corresponding aryl halides, especially in
substrates that are sensitive to organolithium species.
Exp er im en ta l Section
Gen er a l. All reactions were performed under nitrogen. THF
and toluene were dried using 4 Å molecular sieves overnight.
Commercially available reagents were used without further
purification.
3-P yr id ylbor oxin (4). A 1 L, three-necked flask equipped
with a temperature probe, an overhead stirrer, and a septum
was charged with toluene (320 mL) and THF (80 mL) and put
under a nitrogen atmosphere. The flask was charged with
triisopropyl borate (55.4 mL, 240 mmol) and 3-bromopyridine
(19.3 mL, 200 mmol). The mixture was cooled to -40 °C using
a dry ice/acetone bath. n-Butyllithium (2.5 M in hexanes, 96 mL,
240 mmol) was added dropwise via a syringe pump over 1 h,
and the mixture was stirred for an additional 0.5 h while the
temperature was held at -40 °C. The acetone/dry ice bath was
removed, and the reaction mixture was then allowed to warm
to -20 °C before a 2 N HCl solution (200 mL) was added. When
the mixture reached room temperature, it was transferred to a
1 L separatory funnel and the aqueous layer (pH ≈ 1) was cut
into a 500 mL Erlenmeyer flask. While the aqueous layer was
stirred, its pH was adjusted to 7 using a 5 N NaOH solution (≈
30 mL). A white solid product precipitated as the pH approached
7. This mixture was then saturated with 50 g of NaCl, trans-
ferred to a 1 L separatory funnel, and extracted three times with
THF (250 mL portions). The combined THF extracts were
evaporated in vacuo to provide a solid. The solid was taken up
in acetonitrile (80 mL) for crystallization. The resulting slurry
was heated to 70 °C, stirred for 30 min, and allowed to cool
slowly to room temperature before it was cooled to 0 °C using
an ice bath. After the slurry was stirred at 0 °C for 30 min, the
solid was collected on a fritted glass funnel. The solid was
washed with cold acetonitrile (5 °C, 15 mL) and dried under
vacuum to afford 19.61 g of white solid. A satisfactory melting
point for this solid could not be obtained. 1H NMR (400 MHz,
CD3OD) δ 8.62 (br, 1 H), 8.56-8.54 (m, 1 H), 8.45 (d, 1 H, J )
7.2 Hz), 7.74 (t, 1 H, J ) 6.6 Hz). Anal. Calcd for C15H12B3O3N3‚
(10) (a) Hoye, T. R.; Mi, L. Tetrahedron Lett. 1996, 37, 3097-3098.
(b) Mohri, S.-I.; Stefinovic, M.; Snieckus, V. J . Org. Chem. 1997, 62,
7072-7073.
(11) During the preparation of this manuscript, a nonaqueous
workup procedure for the preparation of arylboronic esters was
reported: Wong, K.-T.; Chien, Y.-Y.; Liao, Y.-L.; Lin, C.-C.; Chou, M.-
Y.; Leung, M.-K. J . Org. Chem. 2001, 67, 1041-1044.
(12) Gen er a l P r oced u r e for th e Sequ en tia l Ad d ition Meth od .
A 50 mL round-bottomed flask equipped with a temperature probe, a
magnetic stirrer, and a septum was charged with toluene (16 mL) and
THF (4 mL) and put under a nitrogen atmosphere. The flask was
charged with aryl halide (10 mmol). The solution was cooled to -70
°C using a dry ice/acetone bath. n-Butyllithium (2.5 M in hexanes, 4.8
mL, 12 mmol) was added dropwise via a syringe pump over 1 h. After
the mixture was stirred for an additional 0.5 h, triisopropyl borate
(2.8 mL, 12 mmol) was added while the temperature was held at -70
°C. The acetone/dry ice bath was then removed, and the reaction
mixture was allowed to warm to -20 °C before a 2 N HCl solution (10
mL) was added. When the mixture reached room temperature, it was
transferred to a 100 mL separatory funnel and the layers were
separated. The organic layer was assayed by HPLC and the yield was
determined by comparison with
product.
a standard solution of authentic
(13) (a) Dack, K. V.; Whitlock, G. A. Preparation of N-hydroxytet-
rahydropyridylsulfonylacetamides and related compounds as matrix
metalloprotease inhibitors. PCT Int. Appl. WO 9929667, 1999. (b)
Gronowitz, S.; HO¨ rnfeldt, A.-B.; Kristjansson, V.; Musil, T. Chem. Scr.
1986, 26, 305-309.
J . Org. Chem, Vol. 67, No. 15, 2002 5395

TABLE 1. P r ep a r a tion of Ar ylbor on ic Acid s fr om Ar yl Ha lid es
a
Yields were determined by HPLC assay. b Products show 1H NMR data and HPLC retention times consistent with commercial authentic
samples (entries 1, 3, and 5-13). c Product shows 1H NMR data consistent with the literature (ref 13a). Product shows 1H NMR data
d
consistent with the literature (ref 13b). e In this entry, 2 equiv of n-butyllithium was used.
0.5H2O: C, 55.65; H, 4.05; N, 12.98. Found: C, 55.51; H, 4.10;
N, 12.88. The yield based on this formula was 91%.
Gen er a l In Situ Qu en ch P r oced u r e for th e P r ep a r a tion
of Ar ylbor on ic Acid s. A 50 mL round-bottomed flask equipped
with a temperature probe, a magnetic stirrer, and a septum was
charged with toluene (16 mL) and THF (4 mL) and put under a
nitrogen atmosphere. The flask was charged with triisopropyl
borate (2.8 mL, 12 mmol) and aryl halide (10 mmol). The mixture
was cooled to -70 °C using a dry ice/acetone bath. n-Butyl-
lithium (2.5 M in hexanes, 4.8 mL, 12 mmol) was added dropwise
via a syringe pump over 1 h, and the mixture was stirred for an
additional 0.5 h while the temperature was held at -70 °C. The
acetone/dry ice bath was removed, and the reaction mixture was
then allowed to warm to -20 °C before a 2 N HCl solution (10
mL) was added. When the mixture reached room temperature,
it was transferred to a 100 mL separatory funnel and the layers
were separated. Both the organic and aqueous layers were
assayed by HPLC, and the yield was determined by comparison
with a standard solution of authentic product.
3-P yr id ylbor on ic Acid P in a col Ester (5). A 1 L three-
necked flask equipped with a stir bar, a nitrogen inlet adapter,
and a Dean-Stark trap with a condenser was charged with
3-pyridylboroxin 4‚0.5H2O (10.0 g, 30.8 mmol), pinacol (13.5 g,
114 mmol), and toluene (400 mL). The solution was heated with
a 120 °C oil bath and refluxed using a Dean-Stark apparatus
for 2.5 h. The reaction was finished when the solution went from
cloudy white to clear. The solution was then concentrated in
vacuo to provide a solid. This solid was taken up in cyclohexane
(50 mL) and crystallized by holding the suspension at 85 °C for
30 min and then allowing the temperature to slowly return to
room temperature. The slurry was filtered, and the solid was
washed with cyclohexane (10 mL) and dried under vacuum to
afford 15.39 g of 5 as a white solid (81% from 4, 72% from
3-bromopyridine). Mp: 103-106 °C. 1H NMR (400 MHz, CDCl3)
δ 8.95 (br, 1 H), 8.67 (dd, 1 H, J ) 1.8, 4.9 Hz), 8.06 (dt, 1 H, J
) 1.8, 7.5 Hz), 7.29-7.26 (m, 1 H), 1.36 (s, 12 H). 13C NMR (100
MHz, CDCl3) δ 155.4, 151.9, 142.3, 124.0, 123.1, 84.2, 24.9. Anal.
Calcd for C11H16BO2N: C, 64.43; H, 7.86; N, 6.83; B, 5.27.
Found: C, 64.16; H, 7.72; N, 6.62; B, 5.35.
Isola tion for En tr ies 1, 2, a n d 4. The aqueous layers were
neutralized to pH ≈ 7 using a 5 N NaOH solution followed by
extraction with THF (×3). The combined THF extracts were
evaporated in vacuo to provide solids, which were recrystallized
5396 J . Org. Chem., Vol. 67, No. 15, 2002

from acetonitrile. The recrystallized products gave satisfactory
1H NMR spectra.
Isola tion for En tr ies 3 a n d 5-13. The organic layers were
evaporated in vacuo to provide solids, which were recrystallized
from acetonitrile. The recrystallized products gave satisfactory
1H NMR spectra.
Ack n ow led gm en t. We thank Prof. Barry Trost and
Dr. Nobuyoshi Yasuda for their helpful discussions and
suggestions. We also thank Ms. Vicky Vydra for melting
point data.
J O025792P
J . Org. Chem, Vol. 67, No. 15, 2002 5397