Regioselective synthesis of 1,2-dihydropyridines by rhodium-catalyzed hydroboration of pyridines

Article abstract of DOI:10.1021/ja3002953

Pyridine undergoes addition of pinacolborane at 50 °C in the presence of a rhodium catalyst, giving N-boryl-1,2-dihydropyridine in a high yield. The selective 1,2-hydroboration also takes place in the reactions of substituted pyridines. In the reaction of 3-substituted pyridines, 3-substituted N-boryl-1,2-dihydropyridines are formed regioselectively.

Full text of DOI:10.1021/ja3002953

Communication
pubs.acs.org/JACS
Regioselective Synthesis of 1,2-Dihydropyridines by Rhodium-
Catalyzed Hydroboration of Pyridines
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
transition-metal-catalyzed hydroboration of pyridines giving N-
boryl-1,2-dihydropyridines in a regioselective manner.11 It
ABSTRACT: Pyridine undergoes addition of pinacolbor-
ane at 50 °C in the presence of a rhodium catalyst, giving
N-boryl-1,2-dihydropyridine in a high yield. The selective
1,2-hydroboration also takes place in the reactions of
substituted pyridines. In the reaction of 3-substituted
pyridines, 3-substituted N-boryl-1,2-dihydropyridines are
formed regioselectively.
should be noted that magnesium-catalyzed hydroboration of
pyridine derivatives has just been reported in the literature.12
We believe that this reaction system is also driven by the
formation of a B−N bond, although the magnesium-catalyzed
reaction provides a route to 1,4-dihydropyridine derivatives.
The hydroboration of pyridine (1a, 10 equiv) was examined
using pinacolborane (2)13 in C6D6 (Table 1). No reaction took
uch interest has been focused on the dearomatizing
Table 1. Screening of Reaction Conditions in the
Hydroboration of 1a
a
M
transformations of pyridine derivatives, which lead to
the synthesis of six-membered nitrogen-containing cyclic
compounds directly.1,2 These transformations are particularly
attractive for obtaining partially unsaturated cyclic compounds
such as 1,2-dihydropyridine derivatives, which are useful
synthetic intermediates for the synthesis of nitrogen-containing
organic molecules.2,3 As exemplified by Fowler’s NaBH4
reduction of N-(alkoxycarbonyl)pyridinium chloride,4 such
dearomatizing transformations have been achieved mainly
through formation of pyridinium salts,2 in which nucleophilic
attack to the pyridine ring is facilitated.5 Transition-metal-
catalyzed addition reactions to pyridines are also an attractive
strategy for the reduction of pyridine rings without
stoichiometric activation to form pyridinium salts, but such
simple additions to pyridine derivatives are still unexplored.
Although hydrogenation is the simplest reaction to reduce
pyridine rings, the harsh reaction conditions and overreduction
to form piperidine derivatives are often problematic.6,7
Alternatively, catalytic hydrosilylations have been developed
to obtain di- and tetrahydropyridines.8,9 However, it should be
noted that existing hydrosilylation systems have encountered
low product selectivity,8 overreaction,9a,b and a narrow
substrate scope.9c Therefore, it is highly desirable to develop
an efficient catalytic addition to pyridines that allows selective
partial reduction to dihydropyridine derivatives.
Recently, we found that pyridine derivatives undergo
addition of silylboronic esters in the presence of a palladium
catalyst to give N-boryl-4-silyl-1,4-dihydropyridines.10 This
reaction is the first catalytic addition to pyridine derivatives
to introduce non-hydrogen elements onto the carbon atoms of
the pyridine ring. We assumed that one of the driving forces of
the reaction is the formation of the boron−nitrogen bond,
which is known to be a stable covalent bond. Then, we
envisioned that use of boron-containing reagents would
promote the addition to pyridine rings by virtue of the
formation of a strong B−N bond. Herein, we describe the first
bc
,
d
c
entry
ligand
P/Rh
conv. (%)
yield (%)
3a:4
e
1
−
none
−
−
1
1
1
1
2
3
2
0
0
−
2
3
4
5
6
7
8
90
80
72
89
>99
95
44
>99
62
23
27
63
91
83
27
23:77
PPh3
1:99
PCyPh2
PCy2Ph
PCy3
26:74
87:13
91:9
PCy3
98:2
PCy3
93:7
f
g
9
PCy3
93
98:2
a
1a (2.0 mmol), 2 (0.20 mmol), [RhCl(cod)]2 (2.0 μmol), and ligand
(0−0.012 mmol) were stirred in C6D6 (0.2 mL) at 50 °C for 16 h
b
c
1
unless otherwise noted. Conversion of 2. Determined by H NMR.
d
e
Combined 1H NMR yield of 3a and 4 based on 2. In the absence of
a rhodium catalyst. 0.4 mmol scale reaction with 2 equiv of 1a in
toluene for 24 h. Isolated yield.
f
g
place at 50 °C in the absence of a rhodium catalyst (entry 1),
whereas the addition of 2 to 1a proceeded effectively in the
presence of [RhCl(cod)]2 (1.0 mol %) to give a mixture of N-
borylated 1,2-dihydropyridine 3a and 1,4-dihydropyridine 4 in
a good combined yield (entry 2). It is interesting to note that
the regioselectivity was dependent on the phosphorus ligands.
Selective 1,4-hydroboration (3a:4 = 1:99) was catalyzed by a
Rh/PPh3 catalyst generated in situ from [RhCl(cod)]2 and
PPh3 (P/Rh = 1), although the yield was low owing to the
Received: January 11, 2012
Published: February 9, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
formation of unidentified byproducts (entry 3). In contrast, 1,2-
hydroboration selectively took place in high yields, when the
reaction was carried out using rhodium catalysts bearing
PCy2Ph (entry 5) and PCy3 (entry 6). Finally, we found that a
rhodium catalyst bearing PCy3 (P/Rh = 2) was the most
effective catalyst for 1,2-hydroboration of 1a. The adduct was
obtained in an 83% yield in a 3a:4 ratio of 98:2 (entry 7). On
the other hand, use of 3 equiv of PCy3 decreased the reaction
rate (entry 8). By using a Rh/PCy3 (P/Rh = 2) catalyst,
hydroboration could be carried out under the reduced
stoichiometry of 1a (2 equiv), affording 3a in 93% isolated
yield with high isomeric purity (entry 9).14
of a large excess of 1j (entry 9). The established catalytic
conditions were applicable to hydroboration of 3,5-lutidine
(1k) and 3,4-lutidine (1l), leading to the high-yield formation
of the corresponding 1,2-dihydropyridines 3k and 3l,
respectively (entries 10 and 11). The regioselectivity in the
hydroboration of 1l was again very high, and the regioisomeric
product was not observed at all. Regioselective 1,2-hydro-
boration also took place in the reaction of methyl 6-
methylnicotinate (1m), giving 3m in high yield (entry 12).
However, 2,6-lutidine did not react with 2 at all under the
conditions.
A possible catalytic cycle for the hydroboration of pyridine is
assumed based on the general mechanism for the rhodium-
catalyzed hydroboration of alkynes and alkenes (Scheme 1).11
Substituted pyridines 1b−1m were subjected to hydro-
boration using the Rh/PCy3 (P/Rh = 2) catalyst in toluene
at 50 °C (Table 2).14 The reaction of 2 with 4-picoline (1b),
Scheme 1. Possible Reaction Mechanism
Table 2. Rhodium-Catalyzed 1,2-Hydroboration of
Substituted Pyridines 1b−1m
a
b
entry
R1
R2
R3
R4
yield (%)
1
2
H
H
H
H
Me
Et
Ph
CF3
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
1b
1c
1d
1e
1f
92 (3b)
82 (3c)
The oxidative addition of the B−H bond of 2 to Rh(I), as well
as coordination of pyridine, gives complex A. Insertion of
pyridine into the Rh−H bond takes place at the 1,2-positions of
the pyridine ring with the Rh−N bond formation to give
borylrhodium amide B. Finally, reductive elimination from B
results in the formation of dihydropyridine and regeneration of
Rh(I).
N-Boryl-1,2-dihydropyridines 3 are expected to be a new
class of building blocks for the synthesis of six-membered
nitrogen-containing cyclic compounds. We tested a conversion
of 3 to the corresponding N-acyl derivatives, which are difficult
to synthesize by Fowler’s reduction (Scheme 2).15 A C6D6
H
c
d
3
H
85 (3d)
4
5
6
H
92 (3e)
90 (3f)
91 (3g)
Me
H
OMe
F
H
H
1g
1h
1i
c
d
7
H
H
72 (3h)
c
e
8
cf
,
CO2Me
H
H
H
78 (3i, 3i′)
d
9
H
Me
H
1j
58 (3j)
10
11
12
Me
H
1k
1l
96 (3k)
88 (3l)
75 (3m)
Me
Me
H
H
cf
,
CO2Me
Me
1m
a
1 (0.80 mmol), 2 (0.40 mmol), [RhCl(cod)]2 (4.0 μmol), and PCy3
(0.016 mmol) were stirred in toluene (0.2 mL) at 50 °C for 24 h.
b
c
d
Isolated yield based on 2. Carried out in C6D6. 1H NMR yield
Scheme 2. Acylation of N-Boryl-1,2-dihydropyridines
e
based on 2. Combined yield of a 33:67 mixture of 3i and the regio-
f
isomer 3i′ (R3 = CO2Me, R1 = R2 = R4 = H). 10 equiv of 1 (4.0 mmol)
were used.
4-ethylpyridine (1c), and 4-phenylpyridine (1d) proceeded
effectively to give the corresponding 1,2-hydroboration
products 3b−3d in high yields (entries 1−3). Electron deficient
4-trifluoromethylpyridine (1e) was also applicable to the
hydroboration, leading to the high-yield formation of the
corresponding 1,2-dihydropyridine 3e (entry 4). Remarkably,
hydroboration of 3-substituted pyridines such as 3-picoline
(1f), 3-methoxypyridine (1g), and 3-fluoropyridine (1h) gave
1,2-hydroboration products 3f−3h with high regioselectivity, in
which a hydrogen atom was selectively introduced to the more
sterically congested 2-position (entries 5−7). In contrast, the
reaction of methyl nicotinate (1i) gave a 33:67 mixture of 3i
and the regioisomer 3i′ (R3 = CO2Me, R1 = R2 = R4 = H),
although an ester group, which could not survive under the
magnesium-catalyzed conditions,12 was tolerable (entry 8). The
hydroboration of 2-picoline (1j) also took place in a 1,2-
addition fashion to afford 3j in moderate yield in the presence
solution of dihydropyridines 3d obtained by the hydroboration
of 1d was treated with acetyl and pivaloyl chlorides (1.1 equiv)
in a one-pot manner. The reactions gave N-acetyl- and N-
pivaloyl-1,2-dihydropyridines 5a and 5b in 73% and 71%
overall yields, respectively. According to the one-pot procedure,
3-fluorinated 3h could also be acylated to afford N-acetyl 6a
and N-pivaloyl 6b. It should be noted that the acylation of the
B−N bond could be successfully achieved in the presence of 4-
phenylpyridine (1d, 1.2 equiv), whereas use of pyridine or
triethylamine led to the formation of complex mixtures.
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Journal of the American Chemical Society
Communication
(2) For reviews on dihydropyridines, see: (a) Eisner, U.; Kuthan, J.
Chem. Rev. 1972, 72, 1. (b) Stout, D. M.; Meyers, A. I. Chem. Rev.
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J. Chem. Soc., Perkin Trans. 1 2002, 1141. (e) Edraki, N.; Mehdipour,
A. R.; Khoshneviszadeh, M.; Miri, R. Drug Discovery Today 2009, 14,
1058.
We separately examined a Diels−Alder reaction of 3 (Scheme 3).
A C6D6 solution of 3 was reacted with N-methylmaleimide
Scheme 3. Diels−Alder Reaction of N-Boryl-1,2-
dihydropyridines
(3) For examples of 1,2-dihydropyridines utilized in synthesis of
natural products and biologically active compounds, see: (a) Wender,
P. A.; Schaus, J. M.; White, A. W. J. Am. Chem. Soc. 1980, 102, 6157.
(b) Marazano, C.; Goff, M.-T. L.; Fourrey, J.-L.; Das, B. C. J. Chem.
Soc., Chem. Commun. 1981, 389. (c) Raucher, S.; Bray, B. L. J. Org.
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1990, 55, 6028. (e) Polniaszek, R. P.; Dillard, L. W. J. Org. Chem.
1992, 57, 4103. (f) Comins, D. L.; Brooks, C. A.; Al-awar, R. S.;
Goehring, R. R. Org. Lett. 1999, 1, 229. (g) Zhao, G.; Deo, U. C.;
Ganem, B. Org. Lett. 2001, 3, 201. (h) Satoh, N.; Akiba, T.;
Yokoshima, S.; Fukuyama, T. Angew. Chem., Int. Ed. 2007, 46, 5734.
(i) Barbe, G.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 13873.
(4) Fowler, F. W. J. Org. Chem. 1972, 37, 1321.
(5) The direct conversion of unactivated pyridine to dihydropyridine
derivatives requires strong nucleophiles such as organolithiums or use
of alkali metals. For examples, see: (a) Evans, J. C. W.; Allen, C. F. H.
Org. Synth. 1938, 18, 70. (b) Sulzbach, R. A. J. Organomet. Chem. 1970,
24, 307.
(6) Successful catalytic partial hydrogenation is limited to the
pyridines bearing a carbonyl functional group at the C3 position,
which gives isolable carbonyl-conjugated 1,2-dihydropyridines and
1,4,5,6-tetrahydropyridines. For examples, see: (a) Freifelder, M. J.
Org. Chem. 1964, 29, 2895. (b) Quan, P. M.; Quin, L. D. J. Org. Chem.
1966, 31, 2487. (c) Eisner, U. J. Chem. Soc. D, Chem. Commun. 1969,
1348.
(7, 1.5 equiv). The Diels−Alder reaction took place at room
temperature to give N-borylated 2-azabicyclo[2.2.2]octane
(isoquinuclidine)16 derivatives with high efficiency. These
compounds were isolated in 62−81% total yields after acylation
of the B−N bond with pivaloyl chlorides in the presence of 1d.
It is interesting to note that the corresponding N-acetyldihy-
dropyridine 6a did not react with 7 under the identical reaction
conditions, suggesting that N-borylated dihydropyridine is
much more reactive in the Diels−Alder reaction than the corre-
sponding N-acyl derivatives.
In conclusion, we have established an efficient method for a
dearomatizing conversion of unactivated pyridines to 1,2-
dihydropyridines via rhodium-catalyzed hydroboration. Regio-
selective formation of N-boryl-1,2-dihydropyridines has been
achieved using a rhodium catalyst bearing PCy3 as a ligand. N-
Boryl-1,2-dihydropyridines have been used in a Diels−Alder
reaction to form an isoquinuclidine structure and found to be
more reactive than the corresponding N-acetyl-1,2-dihydropyr-
idines. Synthetic applications utilizing the N-borylated 1,2-
dihydropyridines, as well as mechanistic details of the reaction,
are now under investigation in our laboratory.
(7) For examples of catalytic hydrogenation of pyridines to form
piperidine derivatives, see: (a) Hamilton, T. S.; Adams, R. J. Am. Chem.
Soc. 1928, 50, 2260. (b) Adkins, H.; Kuick, L. F.; Farlow, M.; Wojcik,
B. J. Am. Chem. Soc. 1934, 56, 2425. (c) Freifelder, M.; Stone, G. R. J.
Org. Chem. 1961, 26, 3805. For a recent example of asymmetric
hydrogenation, see: (d) Glorius, F.; Spielkamp, N.; Holle, S.; Goddard,
R.; Lehmann, C. W. Angew. Chem., Int. Ed. 2004, 43, 2850. See also ref
1a and 1b.
(8) For heterogeneous catalyst conditions, see: Cook, N. C.; Lyons, J.
E. J. Am. Chem. Soc. 1966, 88, 3396.
(9) For homogeneous catalyst conditions, see: (a) Hao, L.; Harrod, J.
F.; Lebuis, A.-M.; Mu, Y.; Shu, R.; Samuel, E.; Woo, H.-G. Angew.
Chem., Int. Ed. 1998, 37, 3126. (b) Harrod, J. F.; Shu, R.; Woo, H. G.;
Samuel, E. Can. J. Chem. 2001, 79, 1075. (c) Gutsulyak, D. V.; van der
Est, A.; Nikonov, G. I. Angew. Chem., Int. Ed. 2011, 50, 1384. For a
commentary, see: (d) Osakada, K. Angew. Chem., Int. Ed. 2011, 50,
3845.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and characterization data of the products.
This material is available free of charge via Internet at http://
pubs.acs.org.
(10) Oshima, K.; Ohmura, T.; Suginome, M. J. Am. Chem. Soc. 2011,
133, 7324.
AUTHOR INFORMATION
(11) For reviews on transition-metal-catalyzed hydroboration, see:
(a) Burgess, K.; Ohlmeyer, M. J. Chem. Rev. 1991, 91, 1179.
(b) Beletskaya, I.; Pelter, A. Tetrahedron 1997, 53, 4957. (c) Crudden,
C. M.; Edwards, D. Eur. J. Org. Chem. 2003, 4695. (d) Carroll, A.-M.;
O’Sullivan, T. P.; Guiry, P. J. Adv. Synth. Catal. 2005, 347, 609.
(e) Brown, J. M. In Modern Rhodium-Catalyzed Organic Reactions;
Evans, P. A., Ed.; Wiley-VCH: Weinheim, 2005; p 33.
■
Corresponding Author
ohmura@sbchem.kyoto-u.ac.jp; suginome@sbchem.kyoto-u.ac.jp
Notes
The authors declare no competing financial interest.
(12) Arrowsmith, M.; Hill, M. S.; Hadlington, T.; Kociok-Kohn, G.;
Weetman, C. Organometallics 2011, 30, 5556.
(13) Tucker, C. E.; Davidson, J.; Knochel, P. J. Org. Chem. 1992, 57,
̈
ACKNOWLEDGMENTS
K.O. acknowledges JSPS for fellowship support.
■
3482.
REFERENCES
(14) The N-borylated dihydropyridines 3 are air and moisture
sensitive. Isolation of 3a−3c, 3e−3g, 3k, and 3l, which are derived
from pyridines with low boiling points, was carried out as follows:
After hydroboration, the reaction mixture was treated with activated
charcoal. Filtration of the mixture under an atmosphere of nitrogen
resulted in a rhodium-free colorless solution. The solution was
concentrated in vacuo to remove volatiles including starting pyridines.
Methyl nicotinate derived 3i + 3i′ and 3m could be purified by
■
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Journal of the American Chemical Society
Communication
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