Ruthenium-catalyzed decarboxylative and dehydrogenative formation of highly substituted pyridines from alkene-tethered isoxazol-5(4H)-ones

Article abstract of DOI:10.1246/cl.160480

A ruthenium-catalyzed reaction of alkene-tethered isoxazol-5(4H)-ones affording pyridines has been developed. Di-, tri-, and tetrasubstituted pyridines were obtained from various isoxazolones in good yields.

Full text of DOI:10.1246/cl.160480

CL-160480
Received: May 13, 2016 | Accepted: May 25, 2016 | Web Released: June 3, 2016
Ruthenium-catalyzed Decarboxylative and Dehydrogenative Formation of
Highly Substituted Pyridines from Alkene-tethered Isoxazol-5(4H)-ones
Kazuhiro Okamoto,* Kohei Sasakura, Takuya Shimbayashi, and Kouichi Ohe*
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University,
Katsura, Nishikyo-ku, Kyoto 615-8510
(E-mail: kokamoto@scl.kyoto-u.ac.jp, ohe@scl.kyoto-u.ac.jp)
Table 1. The reaction of isoxazolone 1a using several ruthenium
catalysts leading to pyridine 4aa
A ruthenium-catalyzed reaction of alkene-tethered isoxazol-
5(4H)-ones affording pyridines has been developed. Di-, tri-,
and tetrasubstituted pyridines were obtained from various
isoxazolones in good yields.
N
O
Ph
Ph
N
N
[Ru] (5 mol% Ru)
Me
O
+
Me
Me
Ph
toluene, 100 °C, 19 h
Me
Me
Me
3a
Keywords: Multisubstituted pyridine
| Ruthenium catalyst |
4a
Isoxazolone
1a
Entry [Ru]
Conv./%b Yield 4a/%b Yield 3a/%b
Pyridines are the most fundamental six-membered nitrogen
heterocycles that are often seen in bioactive natural products,
pharmaceuticals, and functional π-expanded materials.1 Among
various synthetic methods for pyridines, transition-metal-cata-
lyzed ring-closing approaches have emerged as alternative and
powerful methods in recent decades.2 Constructing pyridines
with substituents located at the desired position among five sites
in the structure remains challenging.
1
2
3
4
5
[RuCl2(CO)3]2
RuClH(CO)(PPh3)3
[Cp*RuCl2]2
[RuCl2(p-cymene)]2
RuCl2(PPh3)3
0
100
94
100
100
0
2
14
37
41
0
12
0
0
0
aReaction conditions: isoxazolone 1a (0.10 mmol) and [Ru] (5.0 ¯mol
b
Ru) were reacted in toluene (1.0 mL) at 100°C for 19 h. Determined
1
by H NMR with an internal standard.
Meanwhile, we have demonstrated the utilization of
isoxazol-5(4H)-ones (isoxazolones) as five-membered nitrogen-
containing heterocycles for the precursors of active organo-
nitrogen species,3 and found several types of transition-metal-
catalyzed transformation of isoxazolones4 giving N-heterocycles
via N-O bond cleavage5,6 and decarboxylation. We have already
reported that the palladium-catalyzed decarboxylative intramo-
lecular aziridination of alkene-tethered isoxazolones 1 selec-
tively afforded bicyclic aziridines 2 (Scheme 1).4a In the
iridium-catalyzed reaction of isoxazolones 1, 2H-azirines 3
were obtained selectively.4d Herein, we report a novel synthetic
method for multisubstituted pyridines 4 as decarboxylation/
dehydrogenation products, using alkene-tethered isoxazolones 1
together with a ruthenium-bipyridine catalyst.7,8
cymene)]2 and RuCl2(PPh3)3 afforded pyridine 4a in moderate
yields (37% and 41% yield, Entries 4 and 5). Based on these
results, we examined the effect of ligands using [RuCl2(p-
cymene)]2 as a catalyst precursor (Table 2). Among the various
monophosphine and bisphosphine ligands examined (Entries 1-
8), xantphos exhibited the best yield (59%; Entry 8). When
several bipyridine and terpyridine ligands were examined, they
generally worked better than phosphine ligands (Entries 9-14).
Among the bipyridine complexes tested, 5,5¤-dimethyl-2,2¤-
bipyridyl (L3) gave pyridine 4a in 70% as the best yield (69%
isolated yield, Entry 11).
After determining the optimal conditions, we examined the
scope of substituted isoxazolones. The di-, tri-, and tetrasub-
stituted pyridines from various isoxazolones were obtained in
moderate to good yields (Table 3). Isoxazolones 1b-1f, which
possess various aromatic substituents at the R1 position, p-
methoxy-, p-trifluoromethyl-, and p-bromophenyl groups as well
as 2-naphthyl and 2-thienyl groups, all reacted to afford the
corresponding pyridines 4b-4f in 43-66% yields. The reaction
of isoxazolones 1g-1i, which possess various aromatic sub-
stituents at the R3 or R4 position, also afforded pyridines 4g-4i.
The reaction of isoxazolones having four substituents at R1-R4
positions gave tetrasubstituted pyridines 4j-4l. Isoxazolone 1m,
which possesses two olefinic moieties, was also successfully
converted to pyridine 4m, with one olefinic moiety intact.
The structure of pyridine 4h was confirmed by X-ray crystallo-
graphic analysis.9
We first examined the reactions of 1a using several types of
ruthenium catalyst precursors (Table 1). Ruthenium carbonyl
complexes did not show eminent catalytic activity for pyridine
formation (Entries 1 and 2). A [Cp*RuCl2]2 as a catalyst
afforded pyridine 4a in 14% yield (Entry 3). Both [RuCl2(p-
N
O
R1
R2
R1
R2
N
Ru cat.
Pd cat.
N
Me
R1
O
intramolecular
aziridination
pyridine
formation
Me
Me
R2
2
4
This work
1
Ir cat.
ring contraction
N
Me
R1
R2
Interestingly, vinylpyridine 4n (dehydrogenative product)
was not observed at all when using isoxazolone 1n, having a
conjugate diene moiety. Instead, ethylpyridine 4n¤ (non-dehy-
drogenative product) was selectively obtained in 65% yield
(eq 1). In the present system, both dehydrogenative and non-
3
Scheme 1. Transition-metal-catalyzed transformation of alkene-
tethered isoxazol-5(4H)-ones giving various nitrogen-containing
heterocycles.
988 | Chem. Lett. 2016, 45, 988–990 | doi:10.1246/cl.160480
© 2016 The Chemical Society of Japan

Table 2. Ligand screening for ruthenium-catalyzed formation of
pyridine 4a from isoxazolone 1aa
Table 3. Substrate scope for ruthenium-catalyzed formation of
pyridine 4 from isoxazolone 1a
N
[RuCl2(p-cymene)]2
(2.5 mol%)
N
O
O
R1
Ph
Me
Me
[RuCl2(p-cymene)]2 (2.5 mol%)
L3 (5 mol%)
R1
R2
N
R4
R3
Ph
N
N
ligand (X mol%)
Me
O
O
+
R2
R3
Ph
toluene, 100 °C, 19 h
toluene, 100 °C, 19 h
Me
Me
Me
4
3a
4a
1
R4
1a
Me
Me
X
Me
Me
N
S
N
N
N
N
N
N
N
N
N
N
Me
Me
L1
L2
L5
L3
Me
4e 66%
Me
Me
Me
Ph
4a (X = H)
4b (X = OMe) 60%
4c (X = CF3) 58%
69%
4f 43%
N
N
N
4d (X = Br)
64%
N
N
Br
Me
Me
L4
L6
Ph
N
N
Ph
Me
N
Entry
Ligand
X
Yield of 4a/%b Yield of 3a/%b
Me
Ph
Me
4h 65%
Ph
1
2
3
4
5
6
7
8
9
10
11
12
13
14
PPh3
P(4-MeOC6H4)3
P(4-CF3C6H4)3
P(2-MeC6H4)3
dppe
dpph
dppf
xantphos
L1
L2
L3
L4
L5
15
15
15
15
5
42
36
38
42
20
35
38
59
64
59
70 (69)c
40
64
59
0
0
0
4g 66%
4i 50%
0
Ph
N
Ph
Ph
N
Me
Me
Ph
N
Ph
N
55
33
0
0
6
0
0
0
0
5
5
5
5
5
5
5
5
Me
Me
Me
Me
4j 62%
4k 69%
4l 53%
4m 74%
aReaction conditions: isoxazolone 1 (0.20 mmol) and [Ru] (10 ¯mol
Ru) were reacted in toluene (2.0 mL) at 100°C for 19 h.
N
O
[RuCl2(p-cymene)]2
(2.5 mol%)
L3 (5 mol%)
Ph
Me
Me
Ph
N
Ph
N
O
Me
ð1Þ
L6
5
0
toluene, 100 °C, 19 h
Me
Me
4n' 65%
Me
Me
aReaction conditions: isoxazolone 1a (0.10 mmol) and [Ru] (5.0 ¯mol
Ru) were reacted in toluene (1.0 mL) at 100 °C for 19 h. Determined
by H NMR with an internal standard. Isolated yield.
1n
4n not formed
b
1
c
N
O
N
H2
R1
R2
100
80
60
40
20
0
R1
R3
[Ru]
O
A
R2
H
[Ru]
H
N
[Ru]
O
4
1
R1
R2
H
R3
H
[Ru]
N
O
path a
R1
R3
[Ru]
R3
R1
CO2
[Ru]
N
B
R1
R3
N
G
N
R3
0
200
400
600
time/min
800
1000
1200
R2
H
R2
E
R1
H
R2
H
R2
[Ru]
R3
C
[Ru]
3
N
N
Figure 1. Time-dependent distribution of isoxazolone 1a (blue
dots), azirine 3a (green dots), and pyridine 4a (red dots).
R1
path b R2
R3
R1
R3
H
R2
F
H
dehydrogenative processes are possible depending on the
substrate, which implies that the hydrogen transfer may be
adjusted by the ruthenium dihydrogen species.
D
Scheme 2. Proposed mechanism for ruthenium-catalyzed pyr-
idine formation.
The reaction in a deuterated solvent (toluene-d8) was then
1
monitored with H NMR (Figure 1). In the beginning, isoxazo-
lone 1a was consumed quickly and disappeared within 1 h. As
isoxazolone 1a was consumed upon heating, 2H-azirine 3a was
generated in 93% yield within 2 h, and then 2H-azirine 3a was
converted to pyridine 4a gradually. These observations clearly
indicate that 2H-azirine 3a is produced at an early stage prior to
pyridine formation.10,11
um catalyst A followed by the formation of 2H-azirine 3 passes
through the similar mechanism as described in our previous
paper.4d Then, imido complex D can undergo the cyclization in
two possible pathways. [2+2] Cycloaddition of the N=Ru bond
with the C=C bond forms aza-ruthenacycle E, which undergoes
β-hydride elimination to form intermediate G (path a). On the
other hand, 1,5-hydrogen shift from intermediate D forms
dienyliminido complex F, which undergoes electrocyclization to
A proposed mechanism for the present reaction is described
(Scheme 2). Generation of intermediates C and D from rutheni-
Chem. Lett. 2016, 45, 988–990 | doi:10.1246/cl.160480
© 2016 The Chemical Society of Japan | 989

H
N
Eur. J. 2010, 16, 12052.
[RuCl2(p-cymene)]2
(2.5 mol%)
N
O
3
For recent examples of transition-metal-catalyzed cyclization reactions
of organic azides affording N-heteroaromatic compounds, see: a) D. J.
Gorin, N. R. Davis, F. D. Toste, J. Am. Chem. Soc. 2005, 127, 11260.
b) B. J. Stokes, H. Dong, B. E. Leslie, A. L. Pumphrey, T. G. Driver,
J. Am. Chem. Soc. 2007, 129, 7500. c) S. Chiba, Y.-F. Wang, G.
Lapointe, K. Narasaka, Org. Lett. 2008, 10, 313. d) M. Shen, B. E.
Leslie, T. G. Driver, Angew. Chem., Int. Ed. 2008, 47, 5056. e) Y.-F.
Wang, S. Chiba, J. Am. Chem. Soc. 2009, 131, 12570. f) K. Sun, S. Liu,
P. M. Bec, T. G. Driver, Angew. Chem., Int. Ed. 2011, 50, 1702. g) B. J.
Stokes, S. Liu, T. G. Driver, J. Am. Chem. Soc. 2011, 133, 4702. h) Y.-F.
Wang, K. K. Toh, E. P. J. Ng, S. Chiba, J. Am. Chem. Soc. 2011, 133,
6411. i) Y.-F. Wang, K. K. Toh, J.-Y. Lee, S. Chiba, Angew. Chem., Int.
Ed. 2011, 50, 5927. j) S. Chiba, Synlett 2012, 21, and references therein.
a) K. Okamoto, T. Oda, S. Kohigashi, K. Ohe, Angew. Chem., Int. Ed.
2011, 50, 11470. b) K. Okamoto, T. Shimbayashi, E. Tamura, K. Ohe,
Chem.®Eur. J. 2014, 20, 1490. c) T. Shimbayashi, K. Okamoto, K. Ohe,
Synlett 2014, 25, 1916. d) K. Okamoto, T. Shimbayashi, M. Yoshida, A.
Nanya, K. Ohe, Angew. Chem., Int. Ed. 2016, 55, 7199.
Ph
Ph
Ph
L3 (5 mol%)
Ph
Ph
N
O
+
toluene, 100 °C, 19 h
[Ru]
Me
Me
5o 74%
Me
1o
4o 19%
N
H
Ph
Me
Scheme 3. Preferential formation of indole 5o from alkene-
tethered isoxazolone 1o.
4
5
6
[RuCl2(p-cymene)]2
H
(2.5 mol%)
L3 (5 mol%)
N
N
O
Ph
Me
Ph
(2)
O
toluene, 100 °C, 19 h
Ph
1p
Me
5p 70%
For reviews on the transition-metal-catalyzed reactions involving N-O
bond cleavage of the oxime derivatives, see: a) M. Kitamura, K.
Narasaka, Chem. Rec. 2002, 2, 268. b) K. Narasaka, M. Kitamura,
Eur. J. Org. Chem. 2005, 4505. c) H. Huang, J. Caia, G.-J. Deng, Org.
Biomol. Chem. 2016, 14, 1519.
form intermediate G (path b). Finally, β-hydride elimination
from intermediate G produces pyridine 4 and ruthenium
dihydride H that regenerates catalyst A with the release of
molecular hydrogen.12
The reaction of isoxazolone 1o afforded indole 5o in 74%,
together with pyridine 4o in 19% (Scheme 3). Indole formation
can be explained by assuming the insertion of the anticipated
ruthenium-nitrene intermediate into the C-H bond of a phenyl
group. Moreover, the isoxazolone without an olefinic moiety (1p)
selectively afforded indole 5p in 70% yield (eq 2). These results
indicate that the formation of indoles via the intramolecular C-H
insertion proceeds efficiently and is preferred to the cyclization
with the internal olefin moiety leading to pyridines.
In summary, we have developed a ruthenium-catalyzed
decarboxylative and dehydrogenative pyridine formation from
isoxazol-5(4H)-ones. Multisubstituted pyridines were synthe-
sized selectively. Depending on the substituents of the starting
isoxazolones, indoles were obtained as major components by
the intramolecular C-H insertion reaction. Further investigations
for the expansion of the present catalytic system towards the
synthesis of more useful N-heterocycles are currently under way
in our laboratory.
For examples of transition-metal-catalyzed transformation of acyclic
oxime esters into pyridines, see: a) H. Tsutsui, K. Narasaka, Chem. Lett.
2001, 526. b) S. Liu, L. S. Liebeskind, J. Am. Chem. Soc. 2008, 130,
6918. c) K. Parthasarathy, M. Jeganmohan, C.-H. Cheng, Org. Lett.
2008, 10, 325. d) P. C. Too, Y.-F. Wang, S. Chiba, Org. Lett. 2010, 12,
5688. e) T. K. Hyster, T. Rovis, Chem. Commun. 2011, 47, 11846.
f) J. M. Neely, T. Rovis, J. Am. Chem. Soc. 2013, 135, 66. g) R. M.
Martin, R. G. Bergman, J. A. Ellman, J. Org. Chem. 2012, 77, 2501.
h) T. Gerfaud, L. Neuville, J. Zhu, Angew. Chem., Int. Ed. 2009, 48,
572. i) Z.-H. Ren, Z.-Y. Zhang, B.-Q. Yang, Y.-Y. Wang, Z.-H. Guan,
Org. Lett. 2011, 13, 5394. j) R. K. Chinnagolla, S. Pimparkar, M.
Jeganmohan, Org. Lett. 2012, 14, 3032. k) Y. Yoshida, T. Kurahashi, S.
Matsubara, Chem. Lett. 2012, 41, 1498. l) M.-N. Zhao, R.-R. Hui, Z.-H.
Ren, Y.-Y. Wang, Z.-H. Guan, Org. Lett. 2014, 16, 3082. m) M. Zheng,
P. Chen, W. Wu, H. Jiang, Chem. Commun. 2016, 52, 84.
Peters et al. has reported a palladium-catalyzed reaction of isoxazol-
5(4H)-ones affording pyridines. See: S. Rieckhoff, T. Hellmuth, R.
Peters, J. Org. Chem. 2015, 80, 6822.
For ruthenium-catalyzed reductive cyclization of nitroarenes forming
N-heteroaromatic compounds, see: a) M. Akazome, T. Kondo, Y.
Watanabe, J. Chem. Soc., Chem. Commun. 1991, 1466. b) M. Akazome,
T. Kondo, Y. Watanabe, Chem. Lett. 1992, 769. c) M. Akazome, T.
Kondo, Y. Watanabe, J. Mol. Catal. 1993, 80, 383. d) M. Akazome, T.
Kondo, Y. Watanabe, J. Org. Chem. 1993, 58, 310. e) M. Akazome, T.
Kondo, Y. Watanabe, J. Org. Chem. 1994, 59, 3375.
7
8
Supporting Information is available on http://dx.doi.org/
10.1246/cl.160480.
9
See Supporting Information for the crystallographic data of pyridine 4h.
The CIF file (CCDC 1474698) can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
References and Notes
1
a) Comprehensive Heterocyclic Chemistry III, ed. by A. R. Katritzky,
C. A. Ramsden, E. F. V. Scriven, R. J. K. Taylor, Elsevier, Oxford, U.K.,
2008, Vol. 7. b) J. A. Bull, J. J. Mousseau, G. Pelletier, A. B. Charette,
Chem. Rev. 2012, 112, 2642, and references therein.
10 For examples of pyridine formation from 2H-azirines, see: a) T. Izumi,
H. Alper, Organometallics 1982, 1, 322. b) N. S. Y. Loy, A. Singh, X.
Xu, C.-M. Park, Angew. Chem., Int. Ed. 2013, 52, 2212. c) A. Prechter,
G. Henrion, P. F. dit Bel, F. Gagosz, Angew. Chem., Int. Ed. 2014, 53,
4959. d) Y. Jiang, C.-M. Park, Chem. Sci. 2014, 5, 2347. e) Y. Jiang,
C.-M. Park, T.-P. Loh, Org. Lett. 2014, 16, 3432.
11 The reaction of isolated 2H-azirine 3a under the present reaction
conditions also afforded pyridine 4a in 70% yield. In contrast, the
thermal reaction of 2H-azirine 3a in toluene at 100 °C did not afford
pyridine 4a at all. These results indicate that the formation of both 2H-
azirine 3 and pyridine 4 will proceed by the ruthenium catalysis.
12 To clarify the mechanism, we have investigated some hydrogen
scavengers such as p-phenylstyrene, tert-butylethylene, and aceto-
phenone. No hydrogenation products were obtained under the present
reaction conditions.
2
For recent reviews, see: a) I. Nakamura, Y. Yamamoto, Chem. Rev. 2004,
104, 2127. b) Heterocycles from Transition Metal Catalysis, ed. by A.
Kotschy, G. Timári, Springer, Netherlands, 2005. doi:10.1007/1-4020-
3692-2. c) B. Heller, M. Hapke, Chem. Soc. Rev. 2007, 36, 1085.
d) D. M. D’Souza, T. J. J. Müller, Chem. Soc. Rev. 2007, 36, 1095. e) J. J.
Song, J. T. Reeves, F. Gallou, Z. Tan, N. K. Yee, C. H. Senanayake,
Chem. Soc. Rev. 2007, 36, 1120. f) I. V. Seregin, V. Gevorgyan, Chem.
Soc. Rev. 2007, 36, 1173. g) J.-M. Weibel, A. Blanc, P. Pale, Chem. Rev.
2008, 108, 3149. h) M. Álvarez-Corral, M. Muñoz-Dorado, I.
Rodríguez-García, Chem. Rev. 2008, 108, 3174. i) N. T. Patil, Y.
Yamamoto, Chem. Rev. 2008, 108, 3395. j) A. S. Dudnik, N. Chernyak,
V. Gevorgyan, Aldrichimica Acta 2010, 43, 37. k) M. D. Hill, Chem.®
990 | Chem. Lett. 2016, 45, 988–990 | doi:10.1246/cl.160480
© 2016 The Chemical Society of Japan