Palladium-catalyzed regioselective silaboration of pyridines leading to the synthesis of silylated dihydropyridines

Article abstract of DOI:10.1021/ja2020229

The addition of silylboronic esters to pyridine takes place in toluene at 50 °C in the presence of a palladium catalyst to give N-boryl-4-silyl-1,4- dihydropyridines in high yield. The regioselective 1,4-silaboration also proceeds in the reaction of 2-picoline and 3-substituted pyridines, whereas 4-substituted pyridines undergo 1,2-silaboration to give N-boryl-2-silyl-1,2- dihydropyridines regioselectively.

Full text of DOI:10.1021/ja2020229

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pubs.acs.org/JACS
Palladium-Catalyzed Regioselective Silaboration of Pyridines Leading
to the Synthesis of Silylated Dihydropyridines
Kazuyuki Oshima, Toshimichi Ohmura,* and Michinori Suginome*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku,
Kyoto 615-8510, Japan
S Supporting Information
b
Table 1. Screening of Reaction Conditions in the Silabora-
tion of 1aa
ABSTRACT: The addition of silylboronic esters to pyr-
idine takes place in toluene at 50 °C in the presence of a
palladium catalyst to give N-boryl-4-silyl-1,4-dihydropyri-
dines in high yield. The regioselective 1,4-silaboration also
proceeds in the reaction of 2-picoline and 3-substituted
pyridines, whereas 4-substituted pyridines undergo 1,2-
silaboration to give N-boryl-2-silyl-1,2-dihydropyridines
regioselectively.
temp
conv. of
2 (%)b
yield of
3a (%)b
entry
1c none
catalyst precursor
(°C)
atalytic reactions for the functionalization and transforma-
tion of pyridine and its derivatives have gained much
50
50
50
50
50
25
80
50
50
50
0
0
0
(η3-C3H5)PdCl(PPh3)
(η3-C3H5)PdCl(PCyPh2)
(η3-C3H5)PdCl(PCy2Ph)
(η3-C3H5)PdCl(PCy3)
(η3-C3H5)PdCl(PCy3)
(η3-C3H5)PdCl(PCy3)
[(η3-C3H5)PdCl]2
(η3-C3H5)PdCl(PCy3) þ PCy3
0
45
93
C
2
3
4
5
6
7
8
9
attention in synthetic organic chemistry.1 A particular difficulty
lies in the addition reactions of pyridine, which give functiona-
lized dihydropyridine derivatives. Although such conversions can
be achieved by some stoichiometric reactions using alkali metals2
or strong nucleophiles such as organolithiums,3 applications of
these reactions are limited because of the harsh reaction condi-
tions and the instability of the products. Conversion of pyridine
to more reactive pyridinium salts has been used as an alternative
way to transform pyridine into dihydropyridines.4 The transi-
tion-metal-catalyzed addition reaction of unactivated pyridine has
been recognized as a rather difficult reaction and is much less
explored.5 Hydrogenation6 and hydrosilylation,7ꢀ9 both of
which allow the introduction of hydride onto the pyridine ring,
are the only successful catalytic processes reported to date. It
would be highly attractive to establish a new catalytic addition
reaction by which a non-hydrogen functional group can be
introduced onto the carbon atoms of pyridine.
36
77
83 (>99d) 79 (94e)
0
>99
0
0
44
0
f
g
0
0
g
10 Pd(dba)2 þ PCy3
91
85
a Conditions: 1a (1.0 mmol), 2 (0.10 mmol), Pd catalyst (2.0 μmol)
were stirred in C6D6 (0.2 mL) at 50 °C for 24 h. b 1H NMR yield based
on 2. c Carried out in the absence of Pd. d Conversion after 96 h.
e Isolated yield for a 0.4 mmol scale reaction in toluene for 96 h. f 1.0 mol %
dimer was used. g 2.0 mol %.
the boryl group onto the nitrogen atom and the silyl group onto
the C4 carbon atom.12 Although PCy2Ph and PCy3 were both
effective for the silaboration (entries 4 and 5), we decided that
PCy3 was the ligand of choice because the reaction proceeded
more cleanly (entry 5). Full conversion of 2 was achieved at a
prolonged reaction time (96 h) at 50 °C in toluene, and 3a was
isolated in 94% yield (entry 5). No reaction took place at 25 °C
(entry 6), and a reduced yield was observed at 80 °C (entry 7). The
complex consisting of palladium and PCy3 in a 1:1 ratio
was crucial for high catalyst activity. A phosphine-free palladium
complex did not work as a catalyst (entry 8), and additional PCy3
completely shut down the catalytic activity (entry 9). A catalyst
generated in situ from Pd(dba)2 and PCy3 (P:Pd = 1:1) showed
comparable efficiency to (η3-C3H5)PdCl(PCy3) (entry10), indicat-
ing that the reaction proceeds via a mechanism involving Pd(0).
During our ongoing study of catalytic silaboration of unsatu-
rated hydrocarbons,10 we fortuitously found that a pyridine ring
can undergo addition of silylboronic esters in the presence of a
catalyst. Here we describe a palladium-catalyzed addition of
silylboronic esters to pyridines. The reaction achieves the
dearomatizing conversion of pyridines to dihydropyridines un-
der mild conditions, with the introduction of a silyl group on a
carbon atom of the pyridine ring.
Pyridine (1a, 10 equiv) was reacted with Me2PhSiꢀB(pin)
(2) in C6D6 in the presence of (η3-C3H5)PdCl(L) (L = tertiary
phosphine)11 (2.0 mol %) as a catalyst precursor (Table 1). No
reaction took place when the reaction was carried out at 50 °C in
the absence of palladium or even in the presence of a palladium
catalyst bearing PPh3 (entries 1 and 2). In sharp contrast, the
reaction proceeded with a palladium catalyst bearing cyclohexyl-
substituted phosphines (entries 3ꢀ5). The reaction gave dihy-
dropyridine derivative 3a through regioselective introduction of
Received: March 5, 2011
Published: April 21, 2011
r
2011 American Chemical Society
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|

Journal of the American Chemical Society
COMMUNICATION
Table 2. 1,4-Silaboration of Pyridines 1aꢀfa
Table 3. 1,2-Silaboration of Pyridines 1g, 1h, and 8aa
entry
R1
R2
Me
1
SiꢀB
time (h)
yield (%)b
92 (3b)
entry
R3
Me
1 or 8
SiꢀB
time (h)
yield (%)b
1c
2c
3c,d
4c,d
5c
6g
7g
8g
H
1b
1c
1d
1e
1f
2
2
2
2
2
4
4
4
96
96
96
96
96
24
24
24
1c
2c
3e
4e
1g
1h
1h
8a
2
2
4
4
96
96
24
24
79 (6a), 72d (9a)
81 (6b), 69d (9b)
93 (7a)
H
OMe
Ph
95 (3c)
Ph
H
79e (3d), 59f (8d)
72e (3e), 62f (8e)
no reaction
90 (5a)
Ph
H
CO2Me
H
SiMe2Ph
91 (7b)
a Conditions: pyridine (0.80 or 4.0 mmol), silylboronic ester (0.40
Me
H
mmol), and (η3-C3H5)PdCl(PCy3) (8.0 μmol) were stirred in C6D6
H
1a
1b
1f
(0.2 mL) at 50 °C. b 1H NMR yield based on 2 or 4. 1 (4.0 mmol)
c
H
Me
89 (5b)
was used. d Isolated yield based on 2 after conversion to 2-silylpyridine 9
(see eq 4). e 1 (0.80 mmol) was used.
Me
H
90 (5c)
a Conditions: 1 (0.80 or 4.0 mmol), 2 or 4 (0.40 mmol), and (η3-
C3H5)PdCl(PCy3) (8.0 μmol) were stirred in toluene (0.2 mL) at
50 °C. b Isolated yield based on 2 or 4. c 1 (4.0 mmol) was used. d Carried
out in C6D6. e 1H NMR yield based on 2. f Isolated yield based on 2 after
conversion to 4-silylpyridine 8 (see eq 3). g 1 (0.80 mmol) was used.
The dihydropyridines obtained by the silaboration are ex-
pected to show unique reactivities.4,14 The reactions of Me2PhSi-
substituted 3 and 6 with benzaldehyde (1 equiv) resulted in
aromatization of the dihydropyridine cores to give silylated
pyridines 8 and 9, respectively, in high yields (eqs 2ꢀ4).15 As
mentioned above, some dihydropyridine derivatives (3d, 3e, 6a,
and 6b) that were difficult to isolate were directly converted into
the pyridine derivatives for isolation (eqs 3 and 4).
Various pyridines 1aꢀf were subjected to the silaboration
using the Pd/PCy3 catalyst system (Table 2). The reactions of 2
with 3-picoline (1b) and 3-methoxypyridine (1c) proceeded
smoothly to give the corresponding 1,4-adducts 3b and 3c in
high yields (entries 1 and 2). The silaboration with 2 was also
applicable to 3-phenylpyridine (1d) and methyl nicotinate (1e),
resulting in efficient formation of 3d and 3e, respectively (entries
3 and 4). Because these 1,4-dihydropyridine derivatives were
difficult to separate from the remaining 1, isolation was carried
out after conversion to 4-silylpyridines 8 via reaction with
benzaldehyde (see below). In contrast to the successful silaboration
of 3-substituted pyridines, 2-picoline (1f) did not react with 2 at all
under the same reaction conditions (entry 5). A silylboronic ester
413 bearing chlorine on the silicon atom was found to be more
reactive than 2 (entries 6ꢀ8). The additions of 4 to 1a and 1b were
complete within 24 h and gave the corresponding 1,4-adducts
5a and 5b in high yields (entries 6 and 7). It should be noted that 4
reacted even with 2-picoline (1f) to afford 5c in high yield (entry 8).
Silaboration of 4-substituted pyridines was then examined
(Table 3). We found that the 1,2-additions of 2 to 4-picoline (1g)
and 4-phenylpyridine (1h) proceeded to give the corresponding
N-boryl-2-silyl-1,2-dihydropyridines 6a and 6b regioselectively
in high yields (entries 1 and 2). The silaboration of 1h took place
more efficiently when the reaction was carried out using 4 (entry 3).
4-(Dimethylphenylsilyl)pyridine (8a), which was prepared
via silaboration of 1a followed by treatment with benzaldehyde
(see eq 2), also underwent silaboration with 4, giving disilylated
7b (entry 4).
A possible catalytic cycle for the silaboration of pyridine is
proposed in Scheme 1. Oxidative addition of the silylboronic
ester to Pd(0) and coordination of pyridine gives complex A.16
Regioselective insertion of pyridine into the PdꢀB bond with
introduction of the boryl group onto the nitrogen atom forms
π-allylpalladium complex B.17 Finally, reductive elimination
from B results in the formation of the dihydropyridine and
regeneration of Pd(0). Formation of the stable BꢀN bond may
facilitate the formation of B in the catalytic cycle.18
Quinoline (1i) also reacted with 4 under the Pd/PCy3-
catalyzed conditions, giving the 1,4-adduct 5d as the major
product (81%) (eq 1).
In conclusion, we have established a new class of catalytic
addition reactions that achieves dearomatizing conversion of
pyridines to functionalized dihydropyridines. Regioselective
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Journal of the American Chemical Society
COMMUNICATION
Scheme 1. Possible Reaction Mechanism
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N-boryldihydropyridines are now under investigation in our
laboratory.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details and char-
b
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charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
ohmura@sbchem.kyoto-u.ac.jp; suginome@sbchem.kyoto-u.ac.jp
(10) For recent contributions on silaboration, see: (a) Ohmura, T.;
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Masuda, K.; Suginome, M. J. Am. Chem. Soc. 2008, 130, 1526.
(c) Ohmura, T.; Taniguchi, H.; Suginome, M. Org. Lett. 2009, 11, 2880.
(d) Ohmura, T.; Oshima, K.; Taniguchi, H.; Suginome, M. J. Am. Chem.
Soc. 2010,132, 12194. For recent reviews, see:(e) Beletskaya, I.; Moberg,
C. Chem. Rev. 2006, 106, 2320. (f) Burks, H. E.; Morken, J. P. Chem.
Commun. 2007, 4717. (g) Ohmura, T.; Suginome, M. Bull. Chem. Soc.
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’ ACKNOWLEDGMENT
K.O. acknowledges JSPS for fellowship support.
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