Synthesis of 2,2'-bipyridyl-type compounds via the Suzuki-Miyaura cross-coupling reaction

Article abstract of DOI:10.1002/jhet.5570440213

(Chemical Equation Presented) 2,2′-Bipyridyl-type compounds may be prepared by Suzuki-Miyaura coupling of a 2-pyridylboronic ester with 2-haloazines and -azoles. Ten examples are presented with yields of 47 to 84%. Both arylbromides and arylchlorides undergo the coupling, but the reaction is sensitive to ring substitution adjacent to the halogen.

Full text of DOI:10.1002/jhet.5570440213

Mar-Apr 2007
363
Synthesis of 2,2'-Bipyridyl-Type Compounds via
the Suzuki-Miyaura Cross-Coupling Reaction
Nicholas A. Jones, James W. Antoon, Alfred L. Bowie, Jr., J. Brian Borak and Erland P. Stevens*
Department of Chemistry, Davidson College, Box 7120, Davidson, NC 28035-7120
Received May 31, 2005
O
N
+
N
N
B
PdCl2(PPh3)2
CuI, DMF
N
N
X
O
Ph
K3PO4, 100º
X = Cl, Br
47-84%
10 examples
2,2'-Bipyridyl-type compounds may be prepared by Suzuki-Miyaura coupling of a 2-pyridylboronic
ester with 2-haloazines and –azoles. Ten examples are presented with yields of 47 to 84%. Both
arylbromides and arylchlorides undergo the coupling, but the reaction is sensitive to ring substitution
adjacent to the halogen.
J. Heterocyclic Chem., 44, 363 (2007).
Stille [4-7] and Negishi [2,8-12] couplings. A singular
bipyridine synthesis by a Hiyama coupling has also been
reported [13]. A problem for the Suzuki-Miyaura coupling
in these instances is a general unavailability of heteroaryl-
boronic acid derivatives of type 9 (Figure 2) [14]. Various
2-pyridylboronic esters [15-19] (10) as well as related 5-
tetrazolyl- (11) [20] and 2-oxazolylboronic acids (12) [12]
are reportedly unstable. Couplings of 2-pyridylboronic acid
derivatives are virtually unknown [21,22]. In contrast, 3-
[23-28] and 4-pyridylboronic acid derivatives [24,26] and
their couplings are relatively well-established.
INTRODUCTION
2,2'-Bipyridines (1) and related compounds with a bis-
imine subunit (2) are widely used as bidentate transition-
metal ligands and sometimes also show biological activity.
Typical examples of useful compounds containing subunit 2
include a ligand for iron(II) detection (3) [1] and fungicide 4
[2] (Figure 1).
N
N
N
N
Ph
N
(1)
(2)
N
B(OR)2
(9)
N
N
N
B(OR)2
(10)
N
N
Ph
N
O
N
N
B(OH)2
N
N
N
N
N
B(OH)2
(11)
N
(3)
(4)
(12)
Figure 1. Bipyridyl-type structures
Figure 2. Reportedly unstable 2-pyridyl-type boronic acid derivatives
Compounds containing substructure
2 are often
Recently, successful and scalable syntheses of 2-
pyridylboronic acid 10 (R = H) [16] and boronic ester 13
[15] have been disclosed (Figure 3). Furthermore, boronic
ester 13 has been shown to be stable during prolonged
storage and is now commercially available [29].
Surprisingly, neither 10 nor 13 have been studied for their
use in cross-couplings for the preparation of bipyridyl-
type compounds. We are now disclosing our efforts to
synthesize bipyridines and related compounds with the
newly accessible 2-pyridylboronic ester 13.
prepared by palladium-catalyzed processes such as the
Stille, Negishi, Hiyama, and Suzuki-Miyaura couplings.
These reactions require an arylmetal (6) and an arylhalide
(5) (Scheme 1) [3]. Of the four coupling methods, the
Suzuki-Miyaura reaction is a particularly attractive route
because of the mildness of the reaction and stability of the
arylboronic acid (6, M = B(OH)2).
Scheme 1
M =
Pd0
B(OR)2 (Suzuki)
ZnX (Negishi)
SnR3 (Stille)
+
+
Ar-X
Ar'-M
Ar-Ar'
MX
(5)
(6)
(7)
(8)
O
SiR3 (Hiyama)
N
B
N
O
Ph
Despite advantages of the Suzuki-Miyaura coupling,
bipyridines and related heterocyclic biaryls with
connections of type 2 are almost exclusively prepared by
(13)
Figure 3. Stable, isolable 2-pyridylboronic acid derivative

364
N. A. Jones, J. W. Antoon, A. L. Bowie, Jr., J. B. Borak and E. P. Stevens
Vol 44
RESULTS AND DISCUSSION
The couplings of 13 were performed on both bromo-
and chloroazines (Table 1). Arylchlorides are generally
less reactive than bromides in palladium-catalyzed
couplings. However, substitution of the chloride on an
imine-type carbon and the π-deficient nature of azine
rings makes the chlorine-carbon bond sufficiently reactive
for palladium(0) insertion without requiring special
ligands on the palladium catalyst [30].
Three couplings involved dihaloazines (Table 1, Entries
6, 7, and 8). By GC-MS analysis of the crude reaction
mixture, none of the products, themselves being
haloazines, showed evidence of reacting with excess 13.
Only 2,4-dichloropyrimidine (25) raises the question of
regioselectivity of the coupling. The structure of product
26 was assigned based on other palladium-catalyzed
couplings of 25 in the literature [31].
Couplings of 2-haloazines. Through the convenient
procedure described by Hodgson [15], ample quantities of
2-pyridylboronic ester 13 were readily available.
Couplings of 13 with haloazines afforded 2,2'-bipyridine-
type products in modest to excellent yields (Scheme 2 and
Table 1). Couplings were performed with 5 mol%
PdCl2(PPh3)2 and 1.1 equivalents of boronic ester 13
relative to the haloazine. Published couplings of 13 call
for 2.0 equivalents of the boronic ester. Using a smaller
excess still provides good yields while simplifying
purification. The reactions were generally complete
within a few hours at 100º.
Scheme 2
Not all haloazines could be successfully coupled with
boronic ester 13. Failed haloazines include 1-chloro-
isoquinoline (29) and 6-bromopurine (30) (Figure 4).
Both are sterically hindered at the halogen-bearing carbon
13
N
N
PdCl2(PPh3)2
CuI, DMF
K3PO4
N
X
product
haloazine
Table 1. Products from couplings of 2-pyridylboronic ester 13 with 2-haloazines
Entry
2-Haloazine
Cross-coupled product
Reaction time (h)
Yield (%)
74
N
1
2
3
1
N
N
Br
(14)
(1)
N
8
2
64
84
N
N
N
Cl
(15)
(17)
(16)
N
N
N
N
Cl
(18)
N
N
N
N
N
4
1
61
Cl
(19)
(20)
Ph
Ph
N
N
5
6
7
8
7
6
1
3
77
54
53
74
N
N
N
Cl
Br
Cl
(21)
(23)
(25)
(22)
(24)
(26)
N
N
Br
N
N
Br
N
N
N
N
N
N
Cl
Cl
Cl
Cl
N
N
N
Cl
(27)
(28)

Mar-Apr 2007
Synthesis of 2,2'-Bipyridyl-Type Compounds
365
relative to the haloazines in Table 1. Attempts to affect
the coupling with improved catalyst ligands such as
Buchwald’s S-Phos were not successful and resulted in
recovery of unreacted starting haloazine under a variety of
conditions [23].
Scheme 4
O
O
O
O
B
B
N
N
O
O
(36)
N
B
Br
PdCl2(PPh3)2
DMF, K3PO4
N
Br
(37)
(35)
N
N
N
N
N
PdX
N
H
N
Cl
(29)
N
N
N
(38)
N
(30)
+
H
N
N
Figure 4. Haloazines in failed couplings
(39)
(40)
homocoupling
protodeboronation
(not observed)
(observed)
Couplings of 2-haloazoles. Two haloazoles, 2-chloro-
benzoxazole (31) and 2-chlorobenzothiazole (32), were
cross-coupled with boronic ester 13 (Scheme 3). The
yields in these two couplings are somewhat lower than the
reactions in Table 1. Relative to benzene, azoles are π-
excessive, a property that slows insertion of palladium(0)
into the carbon-chlorine bond. Insertion of palladium is
the rate-determining step of the Suzuki-Miyaura reaction
[32]. Slowing of the insertion step may result in partial
decomposition of the marginally stable 2-pyridylboronic
ester 13 at the elevated reaction temperature.
unsuccessful. All attempts were based on deprotonation of
the azole ring and quenching the resulting anion with a
borate ester (Scheme 5) [34]. Our difficulty with imine-
type boronic esters derived from azoles is in agreement
with both our experience with these compounds [18] and
reports from other research groups [12,20].
Scheme 5
Scheme 3
B(OiPr)3
O
BuLi
N
N
N
N
N
B
N Ph
Li
N
X
N
X
N
THF, -78º
then
13
O
OH
OH
N
Cl
PdCl2(PPh3)2
CuI, DMF
K3PO4
PhN
(40)
(41)
(not observed)
31 (X = O)
32 (X = S)
33 (X = O), 47%
34 (X = S), 67%
EXPERIMENTAL
In agreement with the above findings, haloazoles such
as 2-bromo-1-methylimidazole (35) fail to react with
bis(pinacolato)diboron (36) in homocoupling reactions
(Scheme 4). Only the protodeboronation product (40) is
observed. 1-Methylimidazole (40) likely arises via
putative boronic ester intermediate 37. Because of the
very electron-rich azole ring in 35, palladium insertion to
form 38 is slow. The available concentration of 38 to
couple with 37 is therefore very low, and boronic ester 37
decomposes by protodeboronation. Steric effects from the
1-methyl group of 35 may also play a role in this failed
reaction. In contrast to 35, 2-bromopyridine (14) readily
undergoes homocoupling under identical reaction
conditions [18].
NMR spectra were recorded on JEOL JNM-ECP 300 or 400
MHz spectrometers. Chemical shifts are reported in ppm (δ)
relative to tetramethylsilane as an internal standard. IR spectra
were recorded on a MIDAC Series M spectrometer. MS (EI)
were recorded on a Varian 3800 Gas Chromatograph-Saturn
2000 Mass Spectrometer system operating at 11.7 eV. Melting
ranges were taken on an Electrothermal Mel-Temp and are
uncorrected. Elemental analyses of compounds unreported in the
literature were performed by Quantitative Technologies, Inc. of
Whitehouse, NJ. Merck precoated silica gel 60 F254 plates were
used for TLC analysis, and Merck 60 silica gel was used for
column chromatography. Chromatography solvents were mixed
on a v/v basis. All reagents and solvents were purchased from
commercial sources and used without further purification.
General Suzuki-Miyaura cross-coupling procedure.
According to the procedure of Hodgson [15], the haloazine or –
azole (1.0 mmol) was dissolved in N,N-dimethylformamide (10
mL) with boronic ester 13 (450 mg, 1.1 mmol),
bis(triphenylphosphine)palladium II dichloride (35 mg, 0.05
mmol), anhydrous tribasic potassium phosphate (385 mg, 2.0
mmol), and copper I iodide (95 mg, 0.5 mmol). The reaction was
heated to 100 ºC with stirring until all starting material had been
Based upon Hodgson’s procedure for preparing 2-
pyridylboronic ester 13 [15], the synthesis of other imine-
type boronic esters (9), especially those based upon
azoles, was investigated. Azole-based boronic esters of
type 9 are essentially unknown in the literature [33].
Unfortunately, our efforts to produce boronic esters from
1-methylimidazole (40) and benzothiazole were

366
N. A. Jones, J. W. Antoon, A. L. Bowie, Jr., J. B. Borak and E. P. Stevens
Vol 44
consumed as determined by gc. Additional small portions of
palladium catalyst (10 mg) and 13 (100 mg) were added if the
reaction required over 3 h for completion. The mixture was
diluted in ether, washed with water or dilute sodium chloride
(5x), dried (magnesium sulfate), filtered, and concentrated in
vacuo. Column chromatography of the residue afforded the
purified product.
ºC) [40].
Acknowledgment. We thank the Petroleum Research Fund
(35968-GB1) and Research Corporation (CC5241) for financial
support. We also thank the Department of Chemistry at
Winthrop University for use of its NMR spectrometer during a
time of maintenance on our own instrument.
2,2'-Bipyridine (1). White solid (74%), Rf 0.20 (50% ethyl
acetate/50% hexanes); mp 69-70 ºC (lit. mp 72 ºC) [35].
2-(2-Pyridinyl)quinoline (16). White solid (64%), Rf 0.22
(25% ethyl acetate/75% hexanes); mp 96-97 ºC (lit. mp 98 ºC)
[36].
2-(2-Pyridinyl)quinazoline (18). White solid (84%), Rf 0.23
(25% ethyl acetate/75% hexanes); mp 113-114 ºC (lit. mp 86-87
ºC) [37]; IR (film) 3051 (w), 3003 (w), 1591 (m), 1551 (m),
1493 (s), 1479 (m), 1403 (m), 1367 (m), 1130 (m), 1061 (s) cm-
1. 1H NMR (deuteriochloroform) δ 9.97 (s, 1H), 8.79 (d, 1H, J =
4.8 Hz), 8.60 (d, 1H, J = 8.1 Hz), 8.20-8.14 (m, 2H), 7.92 (tt,
1H, J = 8.1, 1.8 Hz), 7.84-7.76 (m, 2H), 7.45-7.40 (m, 1H). 13C
NMR (deuteriochloroform) δ 154.5, 150.1, 149.4, 144.1, 142.5,
141.8, 137.2, 130.2, 130.1, 129.7, 129.3, 124.6, 122.1. MS (EI,
11.7 eV) m/z (rel int) 208 (15), 207 (M+, 100), 105 (60), 79 (21),
78 (15), 51 (15), 50 (22). Anal. calcd for C13H9N3: C, 75.35; H,
4.38; N, 20.28. Found: C, 75.18; H, 4.20; N, 20.18.
2-Pyridinylpyrazine (20). White solid (61%), Rf 0.26 (25%
ethyl acetate/75% hexanes); mp 55-56 ºC (lit. mp 57-58 ºC) [7].
3-Phenyl-6-(2-pyridinyl)pyridazine (22). White solid (77%),
Rf 0.25 (20% ethyl acetate/80% hexanes); mp 160 ºC (lit. mp
155-157 ºC) [7].
6-Bromo-2,2'-bipyridine (24). White solid (54%), Rf 0.50
(20% ethyl acetate/80% hexanes); mp 69-70 ºC (lit. mp 71-72
ºC) [38]; IR (film) 3038 (w), 3009 (w), 1579 (s), 1548 (s), 1424
(w), 1399 (m), 1153 (w), 1126 (w), 1071 (w), 1040 (w), 986 (m)
cm-1. 13C NMR (deuteriochloroform) δ 157.3, 154.5, 149.2,
141.6, 139.2, 137.0, 128.0, 124.2, 121.5, 119.7.
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Synthesis of 2,2'-Bipyridyl-Type Compounds
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