Synthesis of ortho-cyanopyridylboronic acids and esters toward cyano-functionalized bipyridines

Article abstract of DOI:10.1055/s-2005-922772

This work describes the synthesis of ortho-cyanopyridylboronic acids and esters. Their reactivity with pyridine halides in the Suzuki cross-coupling reaction is evaluated and shows that the cyanopyridyl boronic esters appear to be more stable than their corresponding acids. These esters allowed us to synthesize new cyanobipyridine systems. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-922772

LETTER
53
Synthesis of ortho-Cyanopyridylboronic Acids and Esters toward Cyano-
Functionalized Bipyridines
S
ynthesis of ort
h
ho
-
Cyanopy
o
ridylboronic
m
A
cids and
E
sters as Cailly, Frédéric Fabis, Alexandre Bouillon, Stéphane Lemaître, Jana Sopkova, Olivieira de Santos,
Sylvain Rault*
UPRES-EA 3915: Centre d’Etudes et de Recherche sur le Médicament de Normandie, U.F.R. des Sciences Pharmaceutiques, Université de
Caen Basse-Normandie, 5 Rue Vaubénard, 14032 Caen Cedex, France
Fax +33(2)31931159; E-mail: sylvain.rault@unicaen.fr
Received 17 October 2005
CN
N
CN
N
CN
N
Abstract: This work describes the synthesis of ortho-cyanopy-
ridylboronic acids and esters. Their reactivity with pyridine halides
in the Suzuki cross-coupling reaction is evaluated and shows that
the cyanopyridyl boronic esters appear to be more stable than their
corresponding acids. These esters allowed us to synthesize new
cyanobipyridine systems.
Z
N
B(OR)2
Scheme 1 Strategy to obtain cyano-funtionalized bipyridines.
Key words: cross-coupling, lithiation, nitriles, boronic acids, bi-
pyridines
By using our previously described method for the ortho-
metallation of cyanopyridines, we easily obtained the bo-
ronic acids 1a–d in 42–70% yield with triisopropylborate
as the electrophile (Table 1, Scheme 2).12 The lowest
yield (42%) was observed for the 3-cyanopyridine and
could be explained by the lithiation in both the 2- and 4-
positions. Starting from 3-cyanopyridines, we showed
that reaction with iodine or hexachloroethane as electro-
philes gave a mixture of 2- and 4-isomers.10 Nevertheless,
with triisopropylborate only the 3-cyano-4-pyridyl boron-
ic acid (1b) has been isolated. If the 2-pyridyl boronic acid
could be formed in this reaction, its isolation was un-
successful. These results are in accordance with several
results related to the synthesis and isolation of 2-pyridyl-
boronic acid derivatives.13 Fuller and co-workers showed
that 2-pyridylboronic acids were formed but could not be
isolated because of their protodeboronation.13b
Arylboronic acids and esters are very popular in organic
synthesis both for their conversion into functional groups
such as phenols,1 aryl halides2 or nitroaryl3 compounds
and their use in Suzuki cross-coupling reactions4 or car-
bon–heteroatom bond formation.5 It is noticeable that
their pyridine counterparts did not have the same success
and have only recently been investigated,6 mainly due to
the difficulties in their purification.7 Our group has al-
ready reported the synthesis of halopyridylboronic acids
by ortholithiation reaction or metal–halogen exchange8
and their use in the Suzuki cross-coupling reaction for the
synthesis of bipyridine or polypyridine compounds such
as the natural quarterpyridine nemertelline.9 Moreover, in
a recent communication, we have reported for the first
time an efficient and general method for the synthesis of
ortho-substituted cyanopyridines via the ortholithiation of
2-, 3- and 4-cyanopyridines (Scheme 1).10 The cyano
group represents one of the most important function in
organic chemistry for its use in many transformations in-
volving nucleophilic additions, oxidations and reductions,
heterocycles synthesis. We wish to report here the synthe-
sis of ortho-cyanopyridyl boronic acids and esters and
their reactivity with halopyridines in the Suzuki cross-
coupling reaction for the construction of new cyano-func-
tionalized bipyridine systems, which could be useful for
the synthesis of polyazaheterocycles. It should be noted
that during the course of this work, Kristensen and co-
workers have reported a one-pot synthesis of neopentyl
cyanopyridylboronic esters from cyanopyridines and their
use in the synthesis of some fluoroarylcyanopyridines for
the construction of azaphenanthridines.11
CN
N
CN
B(OH)2
1) LiTMP (2 equiv), THF, –80° C, 0.75 h
2) B(Oi-Pr)3 (2.1 equiv), –80° C r.t.
N
1a–d
Scheme 2 Synthesis of ortho-cyanopyridyl boronic acids 1a–d. See
Table 1 for starting materials and yields.
With the newly synthesized cyanopyridylboronic acids,
we undertook the synthesis of 3-nitro[2,3¢]bipyridyl-4¢-
carbonitrile (2). Starting from the 4-cyano-3-pyridylbo-
ronic acid (1a) and the commercially available 2-chloro-
3-nitropyridine, we used known conditions for the Suzuki
cross-coupling reactions reported on these type of struc-
ture: K2CO3 as base, Pd(PPh3)4 as catalyst in a toluene–
ethanol mixture.14 Unfortunately, the yield in isolated
coupled product was only 5% (Scheme 3). The close
proximity of the electron-withdrawing cyano group may
facilitate the competitive protodeboronation reaction as
already described by Suzuki in the benzene series.15 In-
deed, significant amount of 4-cyanopyridine was present
SYNLETT 2006, No. 1, pp 0053–0056
0
5.
0
1.
2
0
0
6
Advanced online publication: 16.12.2005
DOI: 10.1055/s-2005-922772; Art ID: G33905ST
© Georg Thieme Verlag Stuttgart · New York

54
T. Cailly et al.
LETTER
Table 1 Boronic Acids 1a–d Starting Materials and Yields
CN
N
CN
N
O
B
Yield (%)a
70
pinacol, MgSO4
B(OH)2
Starting material Product
Compd
O
toluene, overnight, 12 h
CN
CN
1a
1a–d
4a–d
B(OH)2
Scheme 5 Synthesis of boronic esters 4a–d. See Table 2 for starting
N
N
materials and yields.
1b
42
B(OH)2
CN
CN
Table 2 Starting Materials and Yields for Boronic Esters 4a–d
N
Starting materials Products
Compd
Yield (%)a
80
N
1c
65
53
B(OH)2
CN
CN
4a
B(OH)2
CN
N
O
B
N
N
CN
CN
N
O
1d
N
B(OH2)
CN
Cl
4b
78
B(OH)2
N
Cl
CN
O
O
a Isolated yields.
B
CN
N
on the crude mixture. By using the more stable 3-pyridyl-
boronic acid with the 2-chloro-3-nitropyridine, the cou-
pling product 3 was obtained in 60% yield. Replacing
Pd(PPh3)4 by PdCl2(PPh3)2 allowed us to significantly
increase the yield to 70% (Scheme 4).
N
4c
82
77
B(OH)2
CN
O
B
N
O
N
CN
CN
4d
B(OH2)
CN
CN
N
K2CO3 (2.1equiv),
5% Pd(PPh3)4
B(OH)2
+
NO2
Cl
O
O
B
N
toluene–EtOH (10/1),
100 °C, 24 h
N
N
NO2
N
Cl
CN
N
2
1a 1.1 equiv
1 equiv
Yield 5%
Cl
Scheme 3 Reaction of 1a and 2-chloro-3-nitropyridine in Suzuki
cross-coupling.
a Isolated yields.
We then tried to achieve the synthesis of 3-nitro-[2,3¢]bi-
pyridyl-4¢-carbonitrile (2) using the boronic ester 4a un-
der several coupling conditions (Scheme 6, Table 3). The
coupled product 2 was obtained by using our initial con-
ditions [Pd(PPh3)4, K2CO3, PhMe/EtOH] in 50% yield.
Although the cyanoboronic esters remained subject to
protodeboronation, they appeared to be more stable than
the corresponding acids.
K2CO3 (2.1 equiv)
toluene–EtOH (10:1)
100 °C, 24 h
N
B(OH)2
+
NO2
N
5% Pd(PPh3)4 Yield 60%
Cl
NO2
N
N
5% PdCl2(PPh3)2 Yield 70%
3
1.1 equiv
1 equiv
Scheme 4 Reaction of 3-pyridylboronic acid and 2-chloro-3-nitro-
pyridine in Suzuki cross-coupling.
Since our cyanopyridylboronic acids did not seem to be
the ideal partner for the Suzuki cross-coupling reaction,
we decided to synthesize their pinacol esters, considered
as more stable16 and easier to characterize species. The es-
terification of all our cyanoboronic acids were carried out
with standard conditions; pinacol and MgSO4 in toluene at
room temperature overnight.17 The pinacol esters 4a–d
were all obtained in 77–82% yield (Scheme 5, Table 2).18
The crystallization of the 2-cyano derivative allowed us to
record X-ray data and to confirm their structure.19
CN
O
B
CN
N
N
NO2
Cl
O
+
24 h
NO2
N
N
2
4a 1.1 equiv
1 equiv
Scheme 6 Reaction of 4a and 2-chloro-3-nitropyridine in Suzuki
cross-coupling reaction. See Table 3 for yields and conditions.
Synlett 2006, No. 1, 53–56 © Thieme Stuttgart · New York

LETTER
Synthesis of ortho-Cyanopyridylboronic Acids and Esters
55
pinacol esters appears to be more appropriate, and al-
lowed us to achieve the synthesis of original cyano-fun-
tionalized bipyridines. These original cyanobipyridine
scaffolds are now available to develop a standard nitrile
chemistry, and their use in the synthesis of new azahetero-
cycles is currently under investigation.
Table 3 Conditions and Yields for Suzuki Cross-Coupling Reaction
between 4a and 2-Chloro-3-nitropyridine
Base (2.1 equiv) Solvent (reflux) Catalyst (5%)
Yield (%)a
K2CO3
Toluene–EtOH Pd(PPh3)4
Toluene–EtOH PdCl2(PPh3)2
Toluene–EtOH Pd(PPh3)4
50
25
25
42
K2CO3
Na2CO3
Acknowledgment
Na2CO3
Toluene
Pd(PPh3)4
We thank the Servier Laboratories and the ‘Conseil Régional de
Basse-Normandie’ for their financial support, Dr. Rémy Legay for
mass spectrometry and Dr. Nicolas Saettel for the manuscript pre-
paration.
a Isolated yields.
To achieve the synthesis of cyano-functionalized bipy-
ridines, we used the available boronic esters 4a–d in
Suzuki cross-coupling reactions using bromo- and iodo-
pyridines under the same conditions. This allowed us to
obtain original cyanobipyridines 5a–d in 40–60% yield
(Scheme 7, Table 4).14
References and Notes
(1) (a) Webb, K. S.; Levy, D. Tetrahedron Lett. 1995, 36, 5117.
(b) Voisin, A. S.; Bouillon, A.; Lancelot, J. C.; Rault, S.
Tetrahedron 2005, 61, 1427. (c) Brown Ripin, D. H.; Cai,
W.; Brenek, S. J. Tetrahedron Lett. 2000, 41, 5817.
(2) Thiebes, C.; Prakash, G. H. S.; Petasis, N. A.; Olah, G. A.
Synlett 1998, 141.
(3) (a) Prakash, G. K. S.; Panja, C.; Mathew, T.; Surampundi,
V.; Petasis, N. A.; Olah, G. A. Org. Lett. 2004, 6, 2205.
(b) Salzbrunn, S.; Simon, J.; Prakash, G. K. S.; Petasis, N.
A.; Olah, G. A. Synlett 2000, 1485.
CN
O
B
CN
N
K2CO3 (2.1 equiv),
5% Pd(PPh3)4
z
N
O
+
N
z
N
toluene–EtOH (10:1),
reflux 24 h
(4) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(b) Tyrrell, E.; Brookes, P. Synthesis 2003, 469.
(5) (a) Chan, D. M. T.; Monaco, K. L.; Wang, R. P.; Winters, M.
P. Tetrahedron Lett. 1998, 39, 2933. (b) Lam, P. Y. S.;
Clark, C. G.; Saubern, S.; Adams, J.; Chan, D. M. T.;
Combs, A. Tetrahedron Lett. 1998, 39, 2941. (c) Lam, P. Y.
S.; Vincent, G.; Clark, C. G.; Deudon, D.; Jadhav, P. K.
Tetrahedron Lett. 2001, 42, 3415. (d) Herradura, P. S.;
Pendola, K. A.; Guy, R. K. Org. Lett. 2000, 2, 2019.
(6) (a) Parry, P. R.; Wang, C.; Batsanov, A. S.; Bryce, M. R.;
Tarbit, B. J. Org. Chem. 2002, 67, 7541. (b) Sutherland, S.;
Gallagher, T. J. Org. Chem. 2003, 68, 3352. (c) Thompson,
A. E.; Hughes, G.; Batsanev, A. S.; Bryce, M. R.; Parry, P.
R.; Tarbit, B. J. Org. Chem. 2005, 70, 388. (d) Cioffi, C. L.;
Spencer, W. T.; Richards, J. J.; Herr, R. J. J. Org. Chem.
2004, 69, 2210.
X
1.1 equiv
1 equiv
Scheme 7 Synthesis of cyano-functionalized bipyridines 5a–d. See
Table 4 for starting materials and yields.
Table 4 Yields and Starting Materials for the Synthesis of Cyano-
Functionalized Bipyrines 5a–d
Boronic Pyridine
esters halides
Products
Yield
(%)a
N
4a
4b
5a
5b
55
58
N
CN
Br
Br
N
(7) Cai, D.; Larsen, R. D.; Reider, P. J. Tetrahedron Lett. 2002,
43, 4285.
N
N
CN
(8) (a) Bouillon, A.; Lancelot, J. C.; Collot, V.; Bovy, P. R.;
Rault, S. Tetrahedron 2002, 58, 2885. (b) Bouillon, A.;
Lancelot, J. C.; Collot, V.; Bovy, P. R.; Rault, S.
Tetrahedron 2002, 58, 3323. (c) Bouillon, A.; Lancelot, J.
C.; Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron 2002, 58,
4369.
(9) Bouillon, A.; Voisin, A. S.; Robic, A.; Lancelot, J. C.;
Collot, V.; Rault, S. J. Org. Chem. 2003, 68, 10178.
(10) Cailly, T.; Fabis, F.; Lemaître, S.; Bouillon, A.; Rault, S.
Tetrahedron Lett. 2005, 46, 135.
N
4c
5c
40b
60
N
Cl
N
N
Cl
F
I
N
CN
CN
4d
5d
F
(11) Hansen, H. M.; Lysén, M.; Begtrup, M.; Kristensen, J.
Tetrahedron 2005, 61, 9955.
Cl
N
Br
(12) Typical Procedure for Obtention of ortho-Cyano-
pyridylboronic Acids 1a–d.
N
To a stirred solution under N2 of 2,2,6,6-tetramethyl-
piperidine (20.2 mmol, 3.4 mL) in THF (40 mL) was added
at –30 °C 2.5 M n-BuLi (19.2 mmol, 7.7 mL). The solution
was allowed to reach 0 °C, kept under stirring during 15 min
and cooled to –80 °C. 2-Cyanopyridine (9.6 mmol, 1 g) in
THF (20 mL) was slowly added to the mixture over 15 min.
After 30 min of stirring at –80 °C, a solution of triisopropyl-
borate (20.2 mmol, 4.66 mL) in THF (10 mL) was slowly
a Isolated yields.
b A significant amount of pyridine-2-carboxamide was also isolated.
In conclusion, we have successfully synthesized ortho-cy-
anopyridylboronic acids. While they seem to be unstable
under Suzuki cross-coupling conditions, the use of their
Synlett 2006, No. 1, 53–56 © Thieme Stuttgart · New York

56
T. Cailly et al.
LETTER
added over 15 min and the resulting mixture stirred for 30
min. The solution was then allowed to warm slowly to r.t.
The mixture was quenched with 40 mL of H2O and washed
3 times with Et2O (75 mL). The aqueous layer was then
acidified to pH 6 by addition of 3 M HCl, extracted with
EtOAc (5 × 100 mL), and the organic layer was evaporated
to give the 2-cyano-3-pyridylboronic acid (1c) as a white
powder (yield 65%); mp >220 °C. 1H NMR (400 MHz,
CD3OD): d = 7.62 (dd, 3J = 4.8 Hz, 3J = 7.7 Hz, 1 H), 8.09
(dd, 3J = 7.7 Hz, 4J = 1.7 Hz, 1 H), 8.67 (dd, 3J = 4.7 Hz,
4J = 1.7 Hz, 1 H), 8.82 (br s, 2 H). IR (KBr): 3225, 2260
(CN), 1581, 1563, 1451, 1332, 1195, 1157, 1080, 1038, 772,
637, 559 cm–1.
CDCl3): d = 108.69, 116.05, 123.51, 123.55, 123.67, 131.57,
135.73, 148.85, 151.24, 153.20, 154.06. IR (KBr): 3429,
3093, 3015, 2228 (CN), 1721, 1593, 1585, 1471, 1418,
1400, 1195, 1013, 864, 809, 745, 711, 643, 543 cm–1.
HRMS: m/z calcd: 182.0718; found: 182.0719.
(15) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1991, 207.
(16) (a) Mattesson, D. S. J. Organomet. Chem. 1999, 581, 51.
(b) Urawa, Y.; Naka, H.; Miyazawa, M.; Souda, S.; Ogura,
K. J. Organomet. Chem. 2002, 653, 269.
(17) (a) Wong, K. T.; Chien, Y. Y.; Liao, Y. L.; Lin, C. C.; Chou,
M. Y.; Leung, M. K. J. Org. Chem. 2002, 67, 1041.
(b) Chan, D. M. T.; Monaco, K. L.; Li, R.; Bonne, D.; Clark,
C. G.; Lam, P. Y. S. Tetrahedron Lett. 2003, 44, 3863.
(c) Kristensen, J.; Lysén, M.; Vedso, P.; Begtrup, M. Org.
Lett. 2001, 3, 1435.
(13) (a) Fischer, F. C.; Havinga, E. Recl. Trav. Chim. Pays-Bas
1974, 93, 21. (b) Fuller, A. A.; Hester, H. R.; Salo, E. V.;
Stevens, E. P. Tetrahedron Lett. 2003, 44, 2935.
(18) Typical Procedure for the Synthesis of ortho-Cyano-
pyridylboronic Esters 4a–d.
(14) Typical Procedure for Suzuki Cross-Coupling 2, 3, 5a–d.
A three-necked flask, equipped with a septum inlet, a reflux
condenser and a thermometer, was degassed with argon and
charged with 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-
yl)nicotinonitrile (4b, 1.6 mmol, 0.36 g), K2CO3 (3.3 mmol,
0.46 g) and Pd(PPh3)4 (0.08 mmol, 91 mg). A degassed
solution of 3-bromopyridine (1.5 mmol, 0.15 mL) in a
toluene–EtOH mixture (10 mL, 1 mL) was added rapidly
through the septum inlet with a syringe. The mixture was
heated to 100 °C for 24 h (TLC monitoring) under stirring.
The flask was poured in H2O (30 mL), and extracted with
EtOAc (3 × 50 mL). The organic layer was then washed with
brine, dried with MgSO4, filtered, and evaporated.
A solution of the 2-cyano-3-pyridylboronic acid (1c, 4.3
mmol, 1 g), pinacol (4.3 mmol, 0.52 g) and MgSO4 (3 g) in
toluene (25 mL) was stirred overnight (TLC monitoring).
The suspension was filtered and the resulting solution
washed with brine (3 × 15 mL). Evaporation of the organic
layer gave the pure product 4c as yellow crystals (yield
82%); mp 66 °C. 1H NMR (400 MHz, CDCl3): d = 1.39 (s,
12 H), 7.48 (dd, 3J = 4.8 Hz, 3J = 7.8 Hz, 1 H), 8.18 (dd,
3J = 7.8 Hz, 4J = 1.7 Hz, 1 H), 8.75 (dd, 3J = 4.7 Hz, 4J = 1.7
Hz, 1 H). 13C NMR (100 MHz, CDCl3): d = 24.80, 85.33,
117.19, 125.71, 143.41, 152.31. IR (KBr): 3053, 2979, 2238
(CN), 1582, 1557, 1458, 1361, 1145, 1130, 1074, 1041, 962,
837, 778, 662, 561 cm–1. Anal. Calcd for C12H15BN2O2 (%):
C, 62.65; H, 6.57; N, 12.18. Found: C, 62.41; H, 6.88; N,
11.74.
[3,4¢]Bipyridinyl-3¢-carbonitrile was isolated as a white
powder 5b (yield 58%) by column chromatography using
EtOAc–cyclohexane (1:1) and EtOAc as eluants; mp
180 °C. 1H NMR (400 MHz, CDCl3): d = 7.49–7.53 (m, 2
H), 8.01 (ddd, 3J = 8.0 Hz 4J = 2.4 Hz 4J = 1.7 Hz, 1 H), 8.79
(dd, 3J = 4.8 Hz 4J = 1.7 Hz, 1 H), 8.83 (d, 4J = 2.4 Hz, 1 H),
8.89 (d, 3J = 5.1 Hz, 1 H), 9.02 (s, 1 H). 13C NMR (100 MHz,
(19) Crystallographic data for the structural analysis have been
deposited with the Cambridge Crystallographic Data Centre,
publication number: CCDC 288826.
Synlett 2006, No. 1, 53–56 © Thieme Stuttgart · New York