Ruthenium-catalyzed conversion of sp3 C-O bonds in ethers to C-C bonds using triarylboroxines

Article abstract of DOI:10.1021/ol2012007

Catalytic conversion of unreactive sp³ C-O bonds in alkyl ethers to C-C bonds is described. Alkyl ethers bearing 2- or 4-pyridyl groups were coupled with triarylboroxines in the presence of a ruthenium catalyst. Triarylboroxines bearing a variety of functional groups including electron-withdrawing and -donating groups can be used for the reaction. No additional base was required for the coupling with the organoboron reagents, and base-sensitive groups can be tolerated. The reaction is considered to proceed via dehydroalkoxylation followed by addition of triarylboroxines to form C-C bonds.

Full text of DOI:10.1021/ol2012007

ORGANIC
LETTERS
Ruthenium-Catalyzed Conversion of sp3
CÀO Bonds in Ethers to CÀC Bonds
Using Triarylboroxines
2011
Vol. 13, No. 12
3254–3257
Yohei Ogiwara, Takuya Kochi,* and Fumitoshi Kakiuchi*
Department of Chemistry, Faculty of Science and Technology, Keio University,
3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan
kochi@chem.keio.ac.jp; kakiuchi@chem.keio.ac.jp
Received May 6, 2011
ABSTRACT
Catalytic conversion of unreactive sp3 CÀO bonds in alkyl ethers to CÀC bonds is described. Alkyl ethers bearing 2- or 4-pyridyl groups were
coupled with triarylboroxines in the presence of a ruthenium catalyst. Triarylboroxines bearing a variety of functional groups including electron-
withdrawing and -donating groups can be used for the reaction. No additional base was required for the coupling with the organoboron reagents,
and base-sensitive groups can be tolerated. The reaction is considered to proceed via dehydroalkoxylation followed by addition of
triarylboroxines to form CÀC bonds.
A transition-metal-catalyzed CÀC bond formation via
selective cleavage of unreactive CÀO bonds has been
rigorously investigated because of its potential utility in
organic synthesis. CÀO bonds in ethers are among the
most unreactive because alkoxides are considered poor
leaving groups.1 Concerning sp3 CÀO bonds in ethers,2À5
several catalytic conversions to CÀC bonds have been
reported, but the bonds used for the examples are limited
to relatively activated ones such as allylic2 or benzylic3 sp3
CÀO bonds.
proceed via dehydroalkoxylation, followed by coupling
with triarylboroxines to form CÀC bonds.
Initially, we envisioned that the chelation-assistance
strategy used for cleavage and functionalization of sp2
CÀO bonds in aryl ethers, reported by our group,1e,g may
be applicable to the reaction of sp3 CÀO of alkyl ethers,
and we chose 2-(2-methoxyethyl)pyridine (1a) as the sub-
strate for catalyst screening. When a reaction of 1a with
(2) Conversion of sp3 CÀO bonds in allyl ethers: (a) Takahashi, K.;
Miyake, A.; Hata, G. Bull. Chem. Soc. Jpn. 1972, 45, 230. (b) Onoue, H.;
Moritani, I.; Murahashi, S.-I. Tetrahedron Lett. 1973, 14, 121. (c)
Commercon, A.; Eourgain, M.; Delaumeny, M.; Normant, J. F.; Vil-
lieras, J. Tetrahedron Lett. 1975, 16, 3837. (d) Hayashi, T.; Konishi, M.;
Yokota, K.-I.; Kumada, M. J. Chem. Soc., Chem. Commun. 1981, 313.
(e) Miyaura, N.; Yamada, K.; Suginome, H.; Suzuki, A. J. Am. Chem.
Soc. 1985, 107, 972. (f) Lu, X.; Jiang, X. J. Organomet. Chem. 1989, 359,
139. (g) Didiuk, M. T.; Morken, J. P.; Hoveyda, A. H. J. Am. Chem. Soc.
1995, 117, 7273. (h) Nomura, N.; RajanBabu, T. V. Tetrahedron Lett.
1997, 38, 1713. (i) Chung, K.-G.; Miyake, Y.; Uemura, S. J. Chem. Soc.,
Perkin. Trans. 1 2000, 15. (j) Manabe, K.; Nakada, K.; Aoyama, N.;
Kobayashi, S. Adv. Synth. Catal. 2005, 347, 1499. (k) Yasui, H.;
Mizutani, K.; Yorimitsu, H.; Oshima, K. Tetrahedron 2006, 62, 1410.
(l) Nishikata, T.; Lipshutz, B. H. J. Am. Chem. Soc. 2009, 131, 12103.
(3) Conversion of sp3 CÀO bonds in benzyl ethers: (a) Guan, B.-T.;
Xiang, S.-K.; Wang, B.-Q.; Sun, Z.-P.; Wang, Y.; Zhao, K.-Q.; Shi, Z.-J.
J. Am. Chem. Soc. 2008, 130, 3268. (b) Wang, B.-Q.; Xiang, S.-K.; Sun,
Z.-P.; Guan, B.-T.; Hu, P.; Zhao, K.-Q.; Shi, Z.-J. Tetrahedron Lett.
2008, 49, 4310. (c) Taylor, B. L. H.; Swift, E. C.; Wartzig, J. D.; Jarvo,
E. R. J. Am. Chem. Soc. 2011, 133, 389.
Here we describe a ruthenium-catalyzed conversion of
unreactive sp3 CÀO bonds in alkyl ethers to CÀC bonds
using triarylboroxines. The reaction is considered to
(1) Conversion of sp2 CÀO bonds in ethers: (a) Heck, R. F. J. Am.
Chem. Soc. 1968, 90, 5535. (b) Wenkert, E.; Michelotti, E. L.; Swindell,
C. S. J. Am. Chem. Soc. 1979, 101, 2246. (c) Wenkert, E.; Michelotti,
E. L.; Swindell, C. S. J. Org. Chem. 1984, 49, 4894. (d) Andersson, C.-M.;
Hallberg, A. J. Org. Chem. 1988, 53, 235. (e) Kakiuchi, F.; Usui, M.;
Ueno, S.; Chatani, N.; Murai, S. J. Am. Chem. Soc. 2004, 126, 2706. (f)
Dankwardt, J. W. Angew. Chem., Int. Ed. 2004, 43, 2428. (g) Ueno, S.;
Mizushima, E.; Chatani, N.; Kakiuchi, F. J. Am. Chem. Soc. 2006, 128,
16516. (h) Guan, B.-T.; Xiang, S.-K.; Wu, T.; Sun, Z.-P.; Wang, B.-Q.;
Zhao, K.-Q.; Shi, Z.-J. Chem. Commun. 2008, 1437. (i) Tobisu, M.;
Shimasaki, T.; Chatani, N. Angew. Chem., Int. Ed. 2008, 47, 4866. (j) Yu,
D.-G.; Yu, M.; Guan, B.-T.; Li, B.-J.; Zheng, Y.; Wu, Z.-H.; Shi, Z.-J.
Org. Lett. 2009, 11, 3374. (k) Shimasaki, T.; Konno, Y.; Tobisu, M.;
Chatani, N. Org. Lett. 2009, 11, 4890.
r
10.1021/ol2012007
Published on Web 05/20/2011
2011 American Chemical Society

Monitoring of the coupling of 1a with 5a in the presence
of 3 and 4 by 1H NMR spectroscopy revealed that
2-vinylpyridine was generated during the reaction. Coupling
of 2-vinylpyridine with 5a was catalyzed by the combina-
tion of 3 and 4 in the presence of 1 equiv of MeOH to give
2aa in 37% yield. Metal-catalyzed coupling of 2- and
4-vinylpyridines and arylboronic acids has been reported
by Lautens and co-workers using a rhodium catalyst.8
Shintani and Hayashi also reported that ruthenium catalysts
can be used for 1,4-addition of boronic acids to R,β-unsatu-
rated ketones.9,10 Based on these results, we speculated that
the reaction may proceed via formation of 2-vinylpyridines
as an intermediate formed by dehydromethoxylation of 1a,
which was possibly assisted by coordination of the pyridine
nitrogen to a ruthenium or boron atom.
Table 1. Coupling of Dialkyl Ether 1a with Phenylboron Re-
agentsa
Scheme 1. Ruthenium-Catalyzed Coupling of Various Pyridy-
lethyl Ethers 1 with 5aa
a Reaction conditions: 0.5 mmol of 1a, 1.0 mmol of PhB(OR)2
(0.33 mmol in the case of 5a), 0.1 mmol of metal catalyst (0.05 mmol
in the case of 3), 0.1 mmol of ligand (if any), 0.5 mmol of additive (if any),
toluene 0.5 mL, 120 °C, 24 h. b GC yield. c 0.2 mmol of PCy3 was used.
d Not detected. e 65 h.
PhB(OH)2 was performed with RuH2(CO)(PPh3)3 as a
catalyst, only a trace amount of the desired phenylation
product2aa was detected byGCanalysis(Table1, entry 1).
Ru(cod)(cot) gave a similar result (entry 2), but the use of
[RuCl2(p-cymene)]2 (3) with PPh3 increased the yield to
16% (entry 3). Catalysts of other transition metals such as
RhCl(PPh3)3 and Ni(cod)2/PCy3 were not effective for this
transformation (entries 4 and 5). The ligands were screened
for the reaction using 3 as a catalyst.6 The reaction with
P(OMe)3 resulted in a 3% yield of 2aa (entry 6), but the use of
P(OPh)3 (4) led to an increase of the yield to 25% (entry 7).
Next, other phenylboron reagents were examined for the
reaction. While the 2,2-dimethyl-1,3-propanediol ester did
not react with 1a to give 2aa (entry 8), the coupling with
triphenylboroxine (5a) provided 2aa in47% yield (entry 9).
Finally, additiveswereexaminedforthe reaction. Addition
of H2O decreased the yield (entry 10), but the reaction in
the presence of 1 equiv of MeOH or EtOH further
increased the yield to 61% and 54%, respectively (entries
11 and 12).7
a Reaction conditions: 0.50 mmol of 1, 0.33 mmol 5a, 0.05 mmol of 3,
0.10 mmol of 4, 0.5 mmol of MeOH, toluene 0.5 mL, 120 °C, 24 h. The
numbers shown are isolated yields. b Isolated yield obtained using 0.025
mmol of 3 and 0.05 mmol of 4.
Examination of various methyl ether substrates bearing
pyridyl groups was then performed (Scheme 1). The reac-
tions of substrates with 2-pyridyl- or 4-methyl-2-pyridyl
groups afforded phenylation products 2aa and 2ba in 60%
and 54% isolated yields, respectively. Increasing the steric
bulk around the pyridine nitrogen using the 6-methyl-2-
pyridyl group lowered the product yield to 38%. As we
expected that the dehydromethoxylation may be acceler-
ated as well for substrates with 4-pyridyl groups, the
reaction was also examined with several methyl ethers
bearing 4-pyridyl moieties. Although no reaction occurred
in the case of 4-(2-methoxyethyl)pyridine, the reaction
of 4-(2-methoxyethyl)-2-methylpyridine (1d) afforded
(4) Catalytic reduction of sp3 CÀO bonds in alkyl ethers: (a)
Gevorgyan, V.; Liu, J.-X.; Rubin, M.; Benson, S.; Yamamoto, Y.
Tetrahedron Lett. 1999, 40, 8919. (b) Gevorgyan, V.; Rubin, M.; Benson,
S.; Liu, J.-X.; Yamamoto, Y. J. Org. Chem. 2000, 65, 6179. (c) Yang, J.;
White, P. S.; Brookhart, M. J. Am. Chem. Soc. 2008, 130, 17509. (d)
Nichols, J. M.; Bishop, L. M.; Bergman, R. G.; Ellman, J. A. J. Am.
Chem. Soc. 2010, 132, 12554.
(5) Recent reviews on conversion of sp3 CÀX bonds in alkyl electro-
philes such as alkyl halides: (a) Glorius, F. Angew. Chem., Int. Ed. 2008,
47, 8347. (b) Terao, J.; Kambe, N. Acc. Chem. Res. 2008, 41, 1545. (c)
Rudolph, A.; Lautens, M. Angew. Chem., Int. Ed. 2009, 48, 2656.
(6) Detailed results are shown in the Supporting Information
(Table S1).
(8) Lautens, M.; Roy, A.; Fukuoka, K.; Fagnou, K.; Martin-Matute,
B. J. Am. Chem. Soc. 2001, 123, 5358.
(9) Shintani, R.; Hayashi, T. Chem. Lett. 2008, 37, 724.
(10) Reviews on addition of organoboron reagents to electron-defi-
cient olefins: (a) Hayashi, T. Synlett 2001, 879. (b) Fagnou, K.; Lautens,
M. Chem. Rev. 2003, 103, 169. (c) Hayashi, T.; Yamasaki, K. Chem. Rev.
2003, 103, 2829. (d) Shintani, R.; Hayashi, T. Aldrichim. Acta 2009, 42,
31. (e) Edwards, H. J.; Hargrave, J. D.; Penrose, S. D.; Frost, C. G.
Chem. Soc. Rev. 2010, 39, 2093.
(7) After the optimization of conditions, catalysts used for entry 2À5,
Table 1, were again tested for the reaction, but only low yields of product
2aa were obtained.
Org. Lett., Vol. 13, No. 12, 2011
3255

phenylation product 2da in 89% isolated yield. In this case,
lowering of the catalyst loading (5 mol % of [RuCl2(p-
cymene)]2, 10 mol % of P(OPh)3) slightly improved the
product yield to 95%. The coupling of the substrate bearing
a 2-phenyl-4-pyridyl group (1e) also provided product 2ea
in 52% yield. When substrates with 2,6-dimethyl-4-pyridyl
and 4-quinolinyl groups were used for the reaction, the
corresponding phenylation products 2fa and 2ga were
obtained in 44% and 43% yields, respectively. In contrast,
the reaction of neither 3-(2-methoxyethyl)-6-methylpyri-
dine nor (2-methoxyethyl)benzene gave any corresponding
phenylation products. Therefore, the methoxyethyl group
on the aromatic ring should be on the 2- or 4-position of the
pyridine ring to achieve the phenylation.
The applicability of substrates with leaving groups other
than methoxy was also examined (Table 3). The reaction of
ethyl ether 6 with 5a proceeded to give 2da in 77% yield
(entry 1). Alcohol 7 can also be coupled with 5a in 40% yield
(entry 2). Phenoxy and acetoxy groups are generally re-
garded as better leaving groups than alkoxy groups and
these were examined for the coupling reaction. The reaction
of phenyl ether 8 provided coupling product 2da in 78%
yield (entry 3). However, ester 9 gave only 3% of the desired
product (entry 4), possibly because of the high acidity of the
generated conjugate acid or the low Lewis basicity of the
leaving group to activate boroxines.
The generality of triarylboroxines 5 was next investigated
for the coupling reaction using 1d (Table 2). A variety of
triarylboroxines bearing electron-withdrawing and -donating
groups at the para positions were coupled with methyl ether
1d to give mostly excellent yields of arylation product 2dbÀdh
(entries 1À7). One of the striking features of this reaction is
that no additional base was required for the coupling of the
organoboron reagents. This feature is demonstrated by the
result that relatively base-sensitive groups such as acetyl and
methoxycarbonyl groups are tolerated to give 96% and 71%
yields, respectively (entries 3 and 4). In the case of tris
(p-methoxyphenyl)boroxine 5h, the product yield became
moderate, and the deboronation product, anisole, was de-
tected by GC (entry 7). Meta-substituted triarylboroxines
were successfully coupled with 1d to give high yields of the
desired products (entries 8 and 9). In contrast, the reaction
with tri(o-tolyl)boroxine 5k did not give any detectable
arylation product, probably because of severe steric conges-
tion (entry 10). The coupling of 1d with tri(2-naphthyl)-
boroxine 5l proceeded smoothly to give arylation pro-
duct 2dl in 91% yield (entry 11).
Table 3. Ruthenium-Catalyzed Coupling of Substrates with
Various Oxygen Leaving Groups 6À9 with 5aa
entry
substrate
ÀOZ
GC yield (%)
1
2
3
4
6
7
8
9
ÀOEt
ÀOH
77
40
78
3
ÀOPh
ÀOAc
a Reaction conditions: 0.5 mmol of 6À-9, 0.33 mmol of 5a, 0.025 mmol
of 3, 0.05 mmol of 4, 0.5 mmol of MeOH, toluene 0.5 mL, 120 °C, 24 h.
1H NMR monitoring of the reaction of 1d with 5a showed
the generation of 2-methyl-4-vinylpyridine (10) at the early
stage of the reaction.11 Coupling of 10 with 5a can also be
catalyzed by the combination of 3 and 4 in the presence of
MeOH. When the coupling of ether 1d with 5a was per-
formed using CD3OD, formation of the corresponding
arylation product containing deuterium atoms 2da-dn was
observed (Table 4). After 1 h, significant deuterium incor-
poration was only observed at the methylene next to the
pyridine ring (C3 position).12 But after the reaction was
complete, a small increase of the amount of deuterium
atoms were observed at C1 and C2 positions as indicated
in Table 4, while the deuterium incorporation at the C3
position was slightly decreased probably via slow H/D
exchange.13 These results strongly suggest the intermediacy
of 10 for the coupling reaction.
Table 2. Ruthenium-Catalyzed Coupling of Ether 1d with Var-
ious Triarylboroxines 5a
Ar
product
isolated yieldb (%)
1
p-NO2C6H4
p-CF3C6H4
p-AcC6H4
2db
2dc
2dd
2de
2df
2dg
2dh
2di
2dj
88
93
95
71
91
97
51
96
87
ndd
91
2
3
4c
5
p-MeOC(O)C6H4
p-BrC6H4
6
p-MeC6H4
7
p-MeOC6H4
m-MeC6H4
m-MeOC6H4
o-MeC6H4
8
9
10
11
2dk
2dl
2-naphthyl
a Reaction conditions: 0.5 mmol of 1d, 0.33 mmol of 5, 0.025 mmol of
Figure 1. Possible reaction pathway for the ruthenium-catalyzed
coupling of 1d with 5a.
3, 0.05 mmol of 4, 0.5 mmol of MeOH, toluene 0.5 mL, 120 °C, 24 h.
b Isolated yield. c 0.5 mmol of 5. d Not detected.
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Org. Lett., Vol. 13, No. 12, 2011

Table 4. Coupling of 1d with 5a in the Presence of CD3ODa
incorporated D atomsb,c
C2 (1H)
entry
time (h)
conversionb (%)
isolated yield (%)
C1 (3H)
C3 (2H)
1
2
1
37
13
ndd
ndd
0.73D
0.51D
24
quant
quant
0.25D
0.07D
a Reaction conditions: 0.5 mmol of 1a, 0.33 mmol of 5a, 0.025 mmol of 3, 0.05 mmol of 4, 0.5 mmol of CD3OD, toluene 0.5 mL, 120 °C. b Determined
by 1H NMR analyses. c Deuterium incorporation was also confirmed by 2H NMR analyses. d Not detected.
Although the detailed mechanism is unclear at this point, a
possible mechanism of the coupling reaction is shown in
Figure 1 using 1d and 5a as a substrate. First, both the
pyridine nitrogen and ethereal oxygen coordinate to a ruthe-
nium or boron atom.14 Dehydroalkoxylation of 1d is facili-
tated by the coordination and proceeds to give vinylpyridine
10. The presence of methanol assists transmetalation of the
phenyl group from the boron atom to the ruthenium com-
plex, and carboruthenation of 10, followed by protodemeta-
lation, proceeds to give phenylation product 2da.
In summary, an unprecedented catalytic conversion of
unreactive sp3 CÀO bonds in alkyl ethers to CÀC bonds
was described. Alkyl ethers bearing a 2- or 4-pyridyl group
were coupled with triarylboroxines in the presence of a
ruthenium catalyst. Triarylboroxines bearing a variety of
functional groups including electron-withdrawing and -
donating groups can be used for the reaction. No addi-
tional base was required for the coupling with organobor-
on reagents and base-sensitive groups can be tolerated. 1H
NMR monitoring of the reaction indicated that it proceeds
via a novel mechanism for catalytic functionalization of
ethers, dehydroalkoxylation, followed by coupling with
triarylboroxines to form CÀC bonds. Further studies are
in progress to develop catalytic functionalization of other
types of alkyl ethers using the dehydroalkoxylation/cou-
pling strategy.
(11) Vinylpyridine 10 was not observed when the reaction was
performed without either 3 and 5a. Heating ether 1d in toluene at
120 °C also failed to give 10. These results suggest both ruthenium
complex 3 and boronate 5a are required for efficient formation of
vinylpyridine intermediate 10.
(12) Selective deuterium incorporation at the C3 position was also
observed for the reaction of vinylpyridine 10 with 5a. See the Supporting
Information for details.
(13) The slow H/D exchange at the C1 and C2 positions was sup-
ported by the result that deuterium incorporation at these positions was
observed for 2da when the reaction of 1d with 5d was performed in the
presence of 2da. See the Supporting Information for details.
(14) When ether 1d was mixed with ruthenium complex 3 and
phosphite 4 in toluene-d8, a low-field shift (0.24 ppm) of the 1H NMR
signal was observed for the proton at the 6-position on the pyridine ring.
The 1H NMR spectrum of a mixture of 1d and boroxine 5a also showed a
significant low-field shift (0.26 ppm) of the pyridyl proton at the
6-position as well as high-field shifts of the protons around the etheral
oxygen up to 0.09 ppm. The results suggest that both the nitrogen and
the oxygen of substrate 1d can interact with the ruthenium catalyst or
boroxines under the conditions for the catalytic reaction.
Acknowledgment. This work was supported, in part, by a
Grant-in-Aid for Scientific Research from the Ministry of Ed-
ucation, Culture, Sports, Science and Technology (MEXT),
Japan, and by The Science Research Promotion Fund.
Supporting Information Available. Experimental proce-
dures and spectroscopic data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 12, 2011
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