The preparation of a stable 2-pyridylboronate and its reactivity in the Suzuki-Miyaura cross-coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2003.11.068

The preparation and reactivity of a 2-pyridylboronate stabilised by N-phenyldiethanolamine is described. In Suzuki-Miyaura cross-coupling reactions employing this boronate, significant aryl-aryl exchange from the phosphine ligand was observed with some combinations of ligand and substrates. The amount of the exchange by-product can be minimised by appropriate choice of phosphine ligand.

Full text of DOI:10.1016/j.tetlet.2003.11.068

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 685–687
The preparation of a stable 2-pyridylboronate and its reactivity
in the Suzuki–Miyaura cross-coupling reaction
*
Paul B. Hodgson and Fabrice H. Salingue
Chemical Research and Development Department, Pfizer Global Research and Development, Pfizer Ltd, Ramsgate Road,
Sandwich, Kent CT13 9NJ, UK
Received 7 October 2003; revised 3 November 2003; accepted 14 November 2003
Abstract—The preparation and reactivity of a 2-pyridylboronate stabilised by N-phenyldiethanolamine is described. In Suzuki–
Miyaura cross-coupling reactions employing this boronate, significant aryl–aryl exchange from the phosphine ligand was observed
with some combinations of ligand and substrates. The amount of the exchange by-product can be minimised by appropriate choice
of phosphine ligand.
ꢀ
2003 Elsevier Ltd. All rights reserved.
1
A recent review highlighted the limited number of
examples of pyridyl derivatives serving as the nucleo-
phile source in Suzuki–Miyaura cross-coupling reac-
reactivity and stability of the resulting boronate, the
optimum results were obtained when N-phenyldietha-
nolamine was employed (Scheme 1).
2
;3
tions. Although there is literature precedence for the
preparation of 3- and 4-pyridylboronic acids
dialkyl(3- and 4-pyridyl)boranes, there is sparse litera-
ture relating to the preparation of 2-pyridylboron
species. This includes the synthesis of diethyl(2-
4;5
and
A one-pot process was developed to prepare the
N-phenyldiethanolamine 2-pyridylboronate, in which
2-lithiopyridine formed by reaction of n-butyllithium
and 2-bromopyridine at )70 ꢁC, was trapped in situ by
triisopropyl borate. The intermediate boronate was then
reacted with N-phenyldiethanolamine to give the prod-
6
7
pyridyl)borane as an unreactive dimer and the dimeric
8
dimethyl(2-pyridyl)borane. Methods exist for the
9
preparation of dimethyl 2-pyridylboronate and lithium
10
tri-n-propyl 2-pyridylboronate, the laboratory scale
use of 2-pyridylboronic acid glycol ester has also been
Typical procedure: Under nitrogen, a stirred solution of 2-bromo-
pyridine (843 g, 5.33 mol) and triisopropylborate (1.20 kg, 6.40 mol)
in THF (6.74 L) was cooled to 75 ꢁC. A 1.6 M solution of n-BuLi in
hexanes (4.00 L, 6.40 mol) was added at such a rate that the
temperature did not exceed )67 ꢁC. After completion of the addition,
the reaction was allowed to warm to room temperature and stirred at
this temperature for 16 h. After this time, a solution of N-phenyl-
diethanolamine (966 g, 5.33 mol) in THF (966 mL) was added and the
resulting mixture heated at reflux for 4 h. The mixture was distilled
and replaced with isopropanol until the head temperature reached
11
described.
Our initial experiments in this area confirmed literature
12
reports that 2-pyridylboronates readily hydrolyse thus
making medium and long-term storage challenging.
Herein, we describe the reactivity of a stable 2-pyridyl-
boronate that is amenable to large laboratory scale
13
preparation.
7
6 ꢁC (distilling 11.3 L and adding in 8.4 L of isopropanol during the
As there is literature precedent for diol and thiol
process). The mixture was cooled to room temperature and stirred
for 12 h. After this time the mixture was filtered, the solid washed
with isopropanol (1.7 L) and dried in vacuo overnight at 40 ꢁC to give
14
derivatives stabilising boronic acids, a screen was
conducted using lithium triisopropyl 2-pyridylboronate
as the starting material. In terms of the physical form,
1
1605 g of the N-phenyldiethanolamine 2-pyridylboronate. H NMR
(
CD
.33 (t, J ¼ 6:07 Hz, 5H (4 · 1.25)), 3.52 (t, J ¼ 6:07 Hz, 5H
3
OD, 300 MHz), d (ppm) 1.14 (d, J ¼ 6:14 Hz, 9.3H (6 · 1.55)),
3
(
4 · 1.25)), 3.72 (sept, J ¼ 6:14 Hz, 1.55H), 6.60 (t, J ¼ 7:23 Hz,
Keywords: 2-Pyridylboronate; N-Phenyldiethanolamine; Suzuki–
Miyaura cross-coupling; Tris(o-tolyl)phosphine; Palladium(II)acetate.
1.25H), 6.76 (d, J ¼ 8:90 Hz, 2.5H (2 · 1.25)), 7.10 (m, 1H), 7.20 (dd,
J ¼ 7:23, 8.90 Hz, 2.5H (2 · 1.25)), 7.4–7.6 (m, 2H), 8.39 (m, 1H).
z
*
Corresponding author. Tel.: +44-1304-645786; fax: +44-1304-655-
86; e-mail: paul_hodgson@sandwich.pfizer.com
Hence the effective molecular weight was calculated as 404 g/mol
giving a yield of approximately 75%.
5
0
040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.068

686
P. B. Hodgson, F. H. Salingue / Tetrahedron Letters 45 (2004) 685–687
N-phenyl-
diethanolamine
Br
B(OiPr) .Li
O
B(OiPr)3
3
N
B
O
N
n-BuLi
THF
N
IPA
N
Theoretical structure of the
N-phenyldiethanolamine
2-pyridylboronate
Scheme 1.
Table 1. Reactivity of N-phenyldiethanolamine 2-pyridylboronate with selected aryl halides
Pd(OAc) , PPh3
2
N-phenyldiethanolamine
+
+ X
R
2
-pyridylboronate
2
CuI, K CO3
N
N
R
THF
Product 1
By-product 2
a
a
Entry
R
X
1 (%)
2 (%)
1
2
3
4
5
6
7
3-CN
I
84
82
88
89
47
54
74
10
70
2
4-NO
2-CH
2
I
Trace
2
3
I
2,6-(CH
4-OMe
3
)
2
I
Trace
24
I
4-NH
2
I
14
4-CH
4-CH
4-NO
3
I
26
1.5
Trace
b
8
3
Br
Br
9
2
a
Isolated yield.
With 4-bromotoluene the reaction was heated at 100 ꢁC to achieve complete reaction.
b
uct boronate in approximately 75% yield on a 4 molar
scale. The exact structure was not determined but NMR
showed the presence of both isopropyl and N-phenyldi-
ethanolamine groups in the product, while the presence
of a stoichiometric level of lithium was determined by
ICP-AES. As the stoichiometry of the stabilising groups
varies with the reaction conditions, the effective molec-
ular weight of the N-phenyldiethanolamine 2-pyridyl-
boronate was calculated following analysis by H NMR
prior to further reaction. It was shown that the first stage
of the reaction can also be performed at )10 ꢁC giving
rise to a product containing higher levels of both iso-
propyl and N-phenyldiethanolamine.
The reactivity of the N-phenyldiethanolamine 2-pyr-
idylboronate was then studied. Several aryl halides were
§
screened (Table 1) and in some cases a significant
quantity of 2-phenylpyridine was isolated. Good yields
of the desired product were obtained with aryl iodides
substituted with electron withdrawing groups (Table 1,
entries 1 and 2). With electron donating groups on the
aryl iodide the reaction produced two major products,
the anticipated 2-arylpyridine 1 and the corresponding
phenyl by-product 2 (Table 1, entries 5–7). For aryl
1
à
à
1
The boronate was analysed by H NMR in CD
number of N-phenyl groups (x) and the number of isopropyl groups
y) relative to the number of pyridyl groups. For use in further
3
OD, measuring the
(
§
Procedure for the Suzuki reaction: A suspension of aryl halide
reactions the effective molecular weight of the N-phenyldiethanol-
amine 2-pyridylboronate was calculated using the following formula:
(
10.8 mmol), the N-phenyldiethanolamine 2-pyridylboronate
21.6 mmol), PPh (0.57 g, 2.17 mmol), Pd(OAc) (0.12 g, 0.53 mmol),
CO (3.99 g, 21.6 mmol) and CuI (0.82 g, 4.30 mmol) in THF
38 mL) was heated to reflux under nitrogen until the reaction was
(
3
2
K
2
3
ðMW of 2-pyridylboronÞ þ ðMW of N-phenyldiethanolamine ꢀ 2Þ
(
ꢁ
x þ ðMW of isopropanol ꢀ 1Þ ꢁ y:
judged complete by HPLC. The reaction was cooled to rt, filtered
through a filter agent, evaporated to dryness and purified by column
chromatography using ethyl acetate/heptane as eluent. Appropriate
fractions were combined, evaporated to dryness and the product(s)
That is,
MW ¼ 89 þ ð179 ꢁ xÞ þ ð59 ꢁ yÞ:
As lithium is a minor component of the N-phenyldiethanolamine 2-
pyridylboronate with respect to molecular weight, lithium was not
included in the effective molecular weight calculation.
1
identified by H NMR, MS and microanalysis. In some cases the
1
ratio of products was obtained by H NMR of the combined mixture
of product and by-product.

P. B. Hodgson, F. H. Salingue / Tetrahedron Letters 45 (2004) 685–687
Table 2. Effect of the phosphine ligand on the reaction
687
Ar
Pd(OAc) , PAr
2
3
N-phenyldiethanolamine
+
+ I
R
2
-pyridylboronate
N
CuI, K CO
2
3
N
R
THF
Product 1
By-product 2
a
Ratio of the 2-arylpyridine (1)/by-product (2)
Aryl iodide
PPh
3
P(o-tolyl)
3
P(p-tolyl)
3
P(p-anisole)
3
4
-CH
-OMe
3
82/18
77/23
99.9/0.1
>99.9/<0.1
N/A
72/28
92/8
N/A
4
N/A: Product and by-product are identical.
a
Ratio as determined by HPLC.
iodides with ortho substitution, the formation of 2 was
negligible (Table 1, entries 3 and 4) and the data indicate
that with aryl bromides, electron withdrawing groups
are required in order to obtain good yields (Table 1,
entries 8 and 9).
References and notes
1. Tyrrell, E.; Brookes, P. Synthesis 2003, 469.
. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
. Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
. (a) Cai, D.; Larsen, R. D.; Reider, P. J. Tetrahedron Lett.
002, 43, 4285; (b) Li, W.; Nelson, D. P.; Jensen, M. S.;
Hoerrner, R. S.; Cai, D.; Larsen, R. D.; Reider, P. J. J.
Org. Chem. 2002, 67, 5394.
. Mitchell, M. B.; Wallbank, P. J. Tetrahedron Lett. 1991,
2
3
4
2
Aryl–phenyl exchange from the phosphine ligand,
resulting in the formation of the by-product 2 is well
15
known and can be rationalised by an aryl–phenyl ex-
change in the intermediate palladium(II) complex and
5
3
2, 2273.
16
subsequent coupling with the 2-pyridyl boronate.
6. (a) Cai, W.; Ripin, D. H. B. Synlett 2002, 273; (b)
Terashima, M.; Kakimi, H.; Ishikura, M.; Kamata, K.
Chem. Pharm. Bull. 1983, 31, 4573; (c) Ishikura, M.;
Mano, T.; Oda, I.; Terashima, M. Heterocycles 1984, 22,
To determine whether variation of the phosphine ligand
minimised formation of the exchange by-product, four
triarylphosphine ligands [PPh , P(o-tolyl) , P(p-tolyl) ,
2
471.
3
3
3
7
8
9
. Murafuji, T.; Mouri, R.; Sugihara, Y.; Takakura, K.;
Mikata, Y.; Yano, S. Tetrahedron 1996, 52, 13933.
. Hodgkins, T. G.; Powell, D. R. Inorg. Chem. 1996, 35,
3
P(p-anisyl) ] were investigated in the reaction (Table 2).
The best reaction profile was obtained when tris(o-
tolyl)phosphine was used. In the reaction with 4-iodo-
anisole, the product was isolated in 85% yield and only a
trace of the exchange by-product was observed. Use of
trialkyl ligands [P(n-Bu) , P(t-Bu) or P(cyclohexyl) ] led
2
140.
. (a) Sindkhedkar, M. D.; Mulla, H. R.; Wurth, M. A.;
Cammers-Goodwin, A. Tetrahedron 2001, 57, 2991; (b)
Fernando, S. R. L.; Maharoof, U. S. M.; Deshayes, K. D.;
Kinstle, T. H.; Ogawa, M. Y. J. Am. Chem. Soc. 1996, 118,
5783.
3
3
3
to a slower reaction rate, but formation of 2-alkylpyri-
dine or 2-phenylpyridine by-products was not observed.
1
1
1
0. Dube, D.; Fortin, R.; Friesen, R.; Wang, Z.; Gauthier, J.
Y. World Patent 9,803,484, 1998; Chem. Abstr. 1998, 128,
140614.
1. Geissler, H.; Haber, S.; Meudt A.; Vollmuller, F.; Scherer,
S. World Patent 0,104,076, 2001; Chem. Abstr. 2001, 134,
In summary, a scalable process for the formation of a
stable
17
2-pyridylboronate is described along with
examples of the reactivity of this material. In cases when
a high level of the by-product generated by aryl–phenyl
exchange was formed using triphenylphosphine as the
ligand, it was shown that using tris(o-tolyl)phosphine
greatly reduced the level of by-product formation.
8
6165.
2. Fischer, F. C.; Havinga, E. Recl. Trav. Chim. Pays-Bas
974, 93, 21.
1
13. The preparation of the N-phenyldiethanolamine 2-pyr-
idylboronate and reaction with one substrate are described
in: Boulton, L. T.; Crook, R. J.; Pettman, A. J.; Walton,
R. World Patent 03,011,829, 2003; Chem. Abstr. 2003, 138,
1
70247.
4. (a) Caron, S.; Hawkins, J. M. J. Org. Chem. 1998, 63,
054; (b) Gravel, M.; Thompson, K. A.; Zak, M.; Berube,
C.; Hall, D. J. Org. Chem. 2002, 67, 3.
5. (a) Kong, K. C.; Cheng, C. H. J. Am. Chem. Soc. 1991,
1
1
1
2
1
13, 6313; (b) OÕKeefe, D. F.; Dannock, M. C.; Marcuc-
Acknowledgements
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6. Segelstein, B. E.; Butler, T. W.; Chenard, B. L. J. Org.
Chem. 1995, 60, 12.
The authors thank Andrew Bibb, Robert Crook and
Neal Sach for screening potential stabilising ligands and
Adrian Davis and Catriona Thom for performing ana-
lytical studies.
17. A 10-month-old batch, that had been stored in double
polyethylene bags in a HDPE drum, was used for this
study.