Copper-catalyzed α-methylenation of benzylpyridines using dimethylacetamide as one-carbon source

Article abstract of DOI:10.1021/ol500655k

The direct α-methylenation of benzylpyridines was achieved using N,N-dimethylacetamide (DMA) as a one-carbon source under copper catalysis. An intermediary species was detected at an early stage, and a possible mechanism was proposed. Additionally, α-oxygenation and dimerization of benzylpyridines could also be performed efficiently.

Full text of DOI:10.1021/ol500655k

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed α‑Methylenation of Benzylpyridines Using
Dimethylacetamide as One-Carbon Source
Masaki Itoh,† Koji Hirano,† Tetsuya Satoh,*,†,‡ and Masahiro Miura*,†
†Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
‡JST, ACT-C, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
S
* Supporting Information
ABSTRACT: The direct α-methylenation of benzylpyridines
was achieved using N,N-dimethylacetamide (DMA) as a one-
carbon source under copper catalysis. An intermediary species
was detected at an early stage, and a possible mechanism was
proposed. Additionally, α-oxygenation and dimerization of
benzylpyridines could also be performed efficiently.
Scheme 1. Copper-Catalyzed or Mediated α C−H
ariously substituted pyridines can be seen in synthesized
Vand naturally occurring bioactive compounds as well as in
organic materials and ligands for transition metals.1 Among the
potential derivatives are 2-α-styrylpyridines and their analogues,
which have recently attracted attention in the field of medicinal
chemistry because of their unique biological properties such as
inhibition of the tubulin assembly and cytotoxic activity.2 They
are also important precursors to be converted into other fine
chemicals through hydroformylation and hydroaminomethyla-
tion.3 However, synthetic approaches to such promising
compounds are so far limited. Most of the currently available
methods rely on the transition-metal-catalyzed cross-coupling4
between substrates prepared through complicated multisteps
using labile and/or toxic reagents or conventional condensation
with low substituent tolerance. To explore further application
of the class of compounds including medicinal screening,
development of new, effective processes leading to them with
simple starting materials by simple procedures is desired.
Meanwhile, transition-metal-catalyzed C−H functionalization
reactions have recently been recognized as atom- and step-
economical synthetic tools because of the needlessness of
preactivation steps for substrates such as halogenation or
metalation.5,6 By using these processes, synthetic routes to
various complex molecules can be simplified. Among them,
copper-catalyzed sp3 carbon functionalization of amines as well
as ethers at the α C−H bonds has been known to be one of
leading transformations with a relatively long history and wide
exploration.6 This type of reaction is often carried out in the
presence of an oxidant including peroxides or molecular oxygen
together with a copper catalyst. Under such oxidative
conditions, radical (A in Scheme 1) and iminium cation (B)
intermediates are formed via stepwise one-electron oxidations.
The latter intermediate is known to react with various
nucleophiles such as terminal alkynes, enols, electron-rich
heteroarenes, and arylboronic acids to form a variety of
oxidative coupling products.7
Functionalization of Amines and Ethers
As a recent intriguing example, Chang and co-workers
reported that an iminium cation generated from N,N-
dimethylformamide (DMF) in the presence of a stoichiometric
amount of copper salt under O2 couples with arylmetal reagents
and ammonium iodide to form aromatic nitriles, in which a
cyano carbon comes from DMF.8 While DMF is widely
recognized as a common solvent, it may also be employed as a
cheap, readily available one-carbon source in synthetic reactions
such as the Vilsmeier−Haack reaction.9 N,N-Dimethylaceta-
mide (DMA) is similarly popular as solvent to DMF. However,
DMA is chemically stable compared to DMF, and therefore, the
use of DMA as a one-carbon source has been less explored. In
the course of our studies of transition-metal-catalyzed C−H
functionalization,10 we found that DMA effectively undergoes
dehydrogenative sp3 C−H/sp3 C−H cross-coupling on treat-
ment with 2-benzylpyridines under copper catalysis to give 2-α-
styrylpyridine derivatives as α-methylenation products.11 While
iron-catalyzed α-methylenations of 3-substituted 2-methylqui-
noxalines and -quinolines have been recently reported,12,13
these procedures could not be applied to simple pyridine
systems. Moreover, other 1-(hetero)aryl-1-heteroarylmethanes
also underwent methylenation with various N,N-dimethyla-
mides to produce the corresponding 1-(hetero)aryl-1-hetero-
arylethenes. Besides methylenation, relevant α-oxygenation14
Received: March 3, 2014
Published: March 19, 2014
© 2014 American Chemical Society
2050
dx.doi.org/10.1021/ol500655k | Org. Lett. 2014, 16, 2050−2053

Organic Letters
Letter
and dimerization could be realized. These new findings are
described herein.
Table 2. α-Methylenation of 1-(Hetero)aryl-1-
heteroarylmethanes 1
a
In an initial attempt, 2-benzylpyridine (1a) (0.5 mmol) was
treated in the presence of Cu(OAc)2·H2O (0.05 mmol) and
Na2S2O8 (1 mmol) in DMA (2.5 mL) at 120 °C for 4 h under
N2. As the α-methylenation product, 2-(1-phenylethenyl)-
pyridine (2a) was obtained selectively in 79% yield (entry 1 in
Table 1). Decreasing and increasing the amount of Na2S2O8
a
Table 1. α-Methylenation of 2-Benzylpyridine (1a)
b
entry
1
catalyst
solvent
DMA
temp (°C) yield of 2a (%)
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
120
120
120
120
120
120
120
140
90
79 (70)
67
65
0
c
2
DMA
d
3
DMA
4
5
6
7
8
DMA
Cu(OTf)2
DMA
85
66
41
60
39
57
56
0
CuBr2
DMA
FeCl3·6H2O
DMA
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
DMA
e
9
DMA
10
11
12
13
DMF
120
120
120
120
EtCONMe2
NMP
DMSO
0
a
Reaction conditions: 1a (0.5 mmol), catalyst (0.05 mmol), Na2S2O8
b
(1 mmol) in solvent (2.5 mL) under N2 for 4 h. GC yield based on
the amount of 1a used. Value in parentheses indicates yield after
c
d
purification. With Na2S2O8 (0.5 mmol). With Na2S2O8 (1.5 mmol).
For 8 h.
e
(0.5 and 1.5 mmol) slightly reduced the product yield (entries
2 and 3). Without the copper catalyst, the reaction did not
proceed at all (entry 4). Cu(OTf)2 showed high activity (entry
5), while CuBr2 was less effective (entry 6). In addition, FeCl3·
6H2O, which was employed for the methylenation of other
substrates,12 was found to be less effective than copper species
(entry 7). Both at 140 and 90 °C, the yield of 2a somewhat
decreased (entries 8 and 9). As the methylene carbon source,
DMF and N,N-dimethylpropanamide could also be employed.
Thus, in these solvents, 2a was obtained in 57 and 56% yields,
respectively (entries 10 and 11). In NMP and DMSO, 2a was
not formed at all (entries 12 and 13).
a
Reaction conditions: 1a (0.5 mmol), Cu(OAc)2·H2O (0.05 mmol),
Na2S2O8 (1 mmol) in DMA (2.5 mL) under N2 at 120 °C for 4 h.
Isolated yield. At 100 °C.
b
c
Under conditions using Cu(OAc)2·H2O and Na2S2O8 as
catalyst and oxidant, respectively, in DMA, the methylenation
reactions of variously substituted 2-benzylpyridines were next
examined. A series of 2-(p-substituted benzyl)pyridines 1b−f
underwent the reaction to afford the corresponding methyle-
nation products 2b−f (entries 1−5 in Table 2). The reactions
of substrates possessing electron-donating groups (entries 1
and 2) gave 2 in relatively lower yields than those with
electron-withdrawing groups (entries 3−5). 2-(m- or o-
substituted benzyl)pyridines 1g−j could also be employed for
the reaction to give 2g−j in 61−76% yields (entries 6−9).
While 1-(1-naphthyl)-1-(2-pyridyl)methane (1k) and 1-(2-
pyridyl)-1-(3-pyridyl)methane (1l) were transformed to the
corresponding methylenation products 2k and 2l smoothly
(entries 10 and 11), treatment of 1-(2-pyridyl)-1-(3-thienyl)-
methane (1l) gave 2m in a lower yield (entry 12). In the
reaction of 2-benzyl-4-methylpyridine (1n), the methylenation
took place not only on a benzylic methylene carbon but also on
a methyl carbon to give a mixture of mono- and
dimethylenation products 2n and 2n′ (entry 13). Treatment
of 2- and 4-picolines gave only trace amounts of methylenation
products (not shown); the products seem to be labile under the
present reaction conditions. 4-Benzylpyridines 1o and 1p also
underwent the methylenation to give 2o and 2p in 75 and 56%
yields, respectively (entries 14 and 15). Under the same
conditions, 3-benzylpyridine was recovered almost completely
(not shown). In addition to benzylpyridines, 2-benzylpyrimi-
dine (1q) could be used for the reaction (entry 16).
A number of control experiments were conducted to obtain
mechanistic insight for the methylenation of 1 (Scheme 2).
2051
dx.doi.org/10.1021/ol500655k | Org. Lett. 2014, 16, 2050−2053

Organic Letters
Letter
intermediate F, rather than E, was unexpectedly detected along
with 2a (24%) by GC−MS analysis of the reaction mixture.
Once formed, F disappeared during the progress of reaction.
Fortunately, F could be isolated from the mixture, and the
structure was unambiguously confirmed by NMR. Treatment of
F under standard conditions gave 2a in 95% yield (Scheme 2d).
In contrast, treatment of separately prepared E under same
conditions gave only a trace amount of 2a, most of E being
recovered (94%) (see the Supporting Information). These
results indicate that the present reaction proceeds involving
intermediary formation of F through nucleophilic addition of D
to an iminium cation G (Scheme 2e),16 which seems to be
generated from dimethylamine and C.17 Dimethylamine may
be formed by hydration18 of N,N-dimethylamides. In spite of
these considerations, other possible pathways including a
radical process through the coupling of A (Scheme 1) with
1-phenyl-1-pyridylmethyl radical cannot be excluded.
Scheme 2. Investigation for Mechanistic Insights
In the absence of the oxidant Na2S2O8, 1 could be converted
into other products. Treatment of 1a (0.5 mmol) in the
presence of Cu(OAc)2·H2O (0.05 mmol) under air in DMA
(2.5 mL) at 120 °C for 48 h led to oxygenation at the α-
position to produce phenyl pyridyl ketone (3) in 89% yield
(Scheme 3a). On the other hand, the use of a stoichiometric
Scheme 3. Oxygenation and Dimerization of 1
amount of Cu(OAc)2·H2O in the reaction of 1a brought about
exclusive formation of dimerization product 4a in 82% yield as
a mixture of diastereomers (meso/dl = 1:1) (Scheme 3b).
Treatment of 1o under same conditions gave a separable
mixture of diastereomers of 4o. Expectedly, the reaction of
symmetrical 1r gave 4r as a single product in 82% yield.
In summary, we have demonstrated that the copper-catalyzed
α-methylenation and α-oxygenation as well as copper-mediated
dimerization of benzylpyridines can be realized efficiently. In
the methylenation, an N-methyl group of DMA or DMF was
incorporated as the one-carbon source to produce α-
styrylpyridine derivatives, which are of interest for their unique
biological properties.
Initially, this reaction was expected to proceed via initial
generation of iminium cation C by the oxidation with
Cu(OAc)2·H2O and Na2S2O8, subsequent nucleophilic addition
by a benzylcopper species D generated in situ, and final
dehydroamidation15 to form a methylenation product, as
shown in Scheme 2a.
It was confirmed that the methylene unit in the produced 2 is
from the N-methyl group of N,N-dimethylamides. Thus, the
reaction of 1a in DMF-d7 gave 2a-d2 in 55% yield (Scheme 2b).
In this case, partial deuteration at the α-position of recovered
1a (35% recovery, 1a-d0:1a-d1:1a-d2 = 39:49:12) was observed.
This indicates that formation of D shown in Scheme 2a is
reversible. At an early stage (30 min) of the reaction of 1a in
DMA under standard conditions, a small amount (12%) of
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, additional results, and character-
ization data of products. This material is available free of charge
via the Internet at http://pubs.acs.org.
2052
dx.doi.org/10.1021/ol500655k | Org. Lett. 2014, 16, 2050−2053

Organic Letters
Letter
(c) Murata, S.; Teramoto, K.; Miura, M.; Nomura, M. J. Chem. Res.,
Synop. 1993, 434. (d) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2004, 126,
11810. (e) Li, Z.; Li, C.-J. Org. Lett. 2004, 6, 4997. (f) Li, Z.; Li, C.-J. J.
Am. Chem. Soc. 2005, 127, 3672. (g) Li, Z.; Li, C.-J. J. Am. Chem. Soc.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: satoh@chem.eng.osaka-u.ac.jp.
*E-mail: miura@chem.eng.osaka-u.ac.jp.
Notes
́
2005, 127, 6968. (h) Basle, O.; Li, C.-J. Org. Lett. 2008, 10, 3661.
(i) Huang, L.; Zhang, X.; Zhang, Y. Org. Lett. 2009, 11, 3730.
(j) Shirakawa, E.; Uchiyama, N.; Hayashi, T. J. Org. Chem. 2011, 76,
25. (k) Huang, L.; Niu, T.; Wu, J.; Zhang, Y. J. Org. Chem. 2011, 76,
1759.
The authors declare no competing financial interest.
(8) (a) Kim, J.; Choi, J.; Shin, K.; Chang, S. J. Am. Chem. Soc. 2012,
134, 2528. (b) Wang, Z.; Chang, S. Org. Lett. 2013, 15, 1990. For
palladium-catalyzed versions, see: (c) Kim, J.; Chang, S. J. Am. Chem.
Soc. 2010, 132, 10272. (d) Ding, S.; Jiao, N. J. Am. Chem. Soc. 2011,
133, 12374.
ACKNOWLEDGMENTS
■
We thank Prof. Dr. N. Tohnai, Osaka University, for X-ray
crystal-structure analysis and helpful discussions. This work was
partly supported by Grants-in-Aid from MEXT, JSPS, and JST,
Japan.
(9) Ding, S.; Jiao, N. Angew. Chem., Int. Ed. 2012, 51, 9226 and
references therein.
(10) (a) Nishino, M.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem.,
Int. Ed. 2012, 51, 6993. (b) Nishino, M.; Hirano, K.; Satoh, T.; Miura,
M. J. Org. Chem. 2011, 76, 6447. (c) Kitahara, M.; Umeda, N.; Hirano,
K.; Satoh, T.; Miura, M. J. Am. Chem. Soc. 2011, 133, 2160. For
reviews, see ref 5d,m,n.
REFERENCES
■
(1) Recent reviews: (a) Bull, J. A.; Mousseau, J. J.; Pelletier, G.;
Charette, A. B. Chem. Rev. 2012, 112, 2642. (b) Ritchie, T. J.;
Macdonald, S. J. F.; Peace, S.; Pickett, S. D.; Luscombe, C. N. Med.
Chem. Commun. 2012, 3, 1062.
(2) For example, see: (a) Lawson, M.; Hamze, A.; Peyrat, J.-F.;
Bignon, J.; Dubois, J.; Brion, J.-D.; Alami, M. Org. Biomol. Chem. 2013,
11, 3664. (b) Froimowitz, M.; Gu, Y.; Dakin, L. A.; Nagafuji, P. M.;
Kelley, C. J.; Parrish, D.; Deschamps, J. R.; Janowsky, A. J. Med. Chem.
2007, 50, 219.
(3) (a) Ahmed, M.; Buch, C.; Routaboul, L.; Jackstell, R.; Klein, H.;
Spannenberg, A.; Beller, M. Chem.Eur. J. 2007, 13, 1594.
(b) Lazzaroni, R.; Settambolo, R.; Rocchiccioli, S.; Paganelli, S.;
Marchetti, M. J. Organomet. Chem. 2005, 690, 1699. (c) Lazzaroni, R.;
Settambolo, R.; Prota, G.; Botteghi, C.; Paganelli, S.; Marchetti, M.
Inorg. Chim. Acta 2004, 357, 3079. (d) Botteghi, C.; Paganelli, S.;
Bigini, L.; Marchetti, M. J. Mol. Catal. 1994, 93, 279.
(4) (a) Nunez, A.; Abarca, B.; Cuadro, A. M. J. Org. Chem. 2009, 74,
4166. (b) Hansen, A. L.; Ebran, J.-P.; Gogsig, T. M.; Skrydstrup, T.
Chem. Commun. 2006, 4137. (c) Chen, S.-H. Tetrahedron Lett. 1997,
38, 4741.
(5) Selected reviews for transition-metal-catalyzed C−H functional-
ization: (a) Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A. Acc.
Chem. Res. 2012, 45, 814. (b) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu,
J.-Q. Acc. Chem. Res. 2012, 45, 788. (c) Mitchell, E. A.; Peschiulli, A.;
Lefevre, N.; Meerpoel, L.; Maes, B. U. W. Chem.Eur. J. 2012, 18,
10092. (d) Hirano, K.; Miura, M. Chem. Commun. 2012, 48, 10704.
(e) Patureau, F. W.; Wencel-Delord, J.; Glorius, F. Aldrichimica Acta
2012, 45, 31. (f) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc.
Rev. 2011, 40, 5068. (g) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius,
F. Chem. Soc. Rev. 2011, 40, 4740. (h) Kuninobu, Y.; Takai, K. Chem.
Rev. 2011, 111, 1938. (i) Ackermann, L. Chem. Rev. 2011, 111, 1315.
(j) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(k) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110,
624. (l) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 46, 677.
(m) Satoh, T.; Miura, M. Chem.Eur. J. 2010, 16, 11212. (n) Satoh,
T.; Miura, M. Synthesis 2010, 3395. (o) Chen, X.; Engle, K. M.; Wang,
D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (p) Daugulis,
O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074.
(q) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013. (r) Park, Y. J.; Park,
J.-W.; Jun, C.-H. Acc. Chem. Res. 2008, 41, 222. (s) Seregin, I. V.;
Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173. (t) Alberico, D.; Scott,
M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (u) Godula, K.; Sames,
D. Science 2006, 312, 67.
(11) Copper-catalyzed reactions of amine N-oxides with alkanes were
reported: (a) Taniguchi, Y.; Kitamura, T.; Fujiwara, Y.; Horie, S.;
Takaki, K. Catal. Today 1997, 36, 85. (b) Taniguchi, Y.; Horie, S.;
Takaki, K.; Fujiwara, Y. J. Organomet. Chem. 1995, 504, 137.
(12) (a) Lou, S.-J.; Xu, D.-Q.; Shen, D.-F.; Wang, Y.-F.; Liu, Y.-K.;
Xu, Z.-Y. Chem. Commun. 2012, 48, 11993. (b) Li, Y.; Guo, F.; Zha, Z.;
Wang, Z. Chem.Asian J. 2013, 8, 534.
(13) A rhodium-catalyzed methylation at the α-position of
acetophenones using DMF has also been recently reported: Li, Y.;
Xue, D.; Lu, W.; Wang, C.; Liu, Z.-T.; Xiao, J. Org. Lett. 2014, 16, 66.
(14) Recent representative examples: (a) de Houwer, J.; Tehrani, K.
A.; Maes, B. U. W. Angew. Chem., Int. Ed. 2012, 51, 2745. (b) Pieber,
B.; Kappe, C. O. Green Chem. 2013, 15, 320. (c) Nakanishi, M.; Bolm,
C. Adv. Synth. Catal. 2007, 349, 861.
(15) Cox, M.; Prager, R. H.; Svensson, C. E. Aust. J. Chem. 2003, 56,
887.
(16) Iminium cations such as G can also be formed from
formaldehyde and secondary amines. However, the reactions of thus
formed Mannich reagents with benzylpyridines were less effective in
the absence of any catalyst: Moehrie, H.; Pycior, M.; Lessel, J. Sci.
Pharm. 1996, 64, 569. Actually, treatment of 1a (0.5 mmol) with
paraformaldehyde (2 mmol) and N-hexyl-N-methylamine (1 mmol) in
the presence of Na2S2O8 (1 mmol) at 120 °C for 4 h gave only 6% of
2a, most of 1a being consumed by unidentified reactions.
(17) (a) Lao, Z.-Q.; Zhong, W.-H.; Lou, Q.-H.; Li, Z.-J.; Meng, X.-B.
Org. Biomol. Chem. 2012, 10, 7869. (b) Xia, Q.; Chen, W. J. Org. Chem.
2012, 77, 9366.
(18) Cho, S. H.; Kim, J. Y.; Lee, S. Y.; Chang, S. Angew. Chem., Int.
Ed. 2009, 48, 9127.
(6) (a) Girard, S. A.; Knauber, T.; Li, C.-J. Angew. Chem., Int. Ed.
2014, 53, 74. (b) Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012,
41, 3464. (c) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111,
1780. (d) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215.
(e) Scheuermann, C. J. Chem.Asian J. 2010, 5, 436. (f) Li, C.-J. Acc.
Chem. Res. 2009, 42, 335.
(7) For example, see: (a) Murata, S.; Suzuki, K.; Tamatani, A.; Miura,
M.; Nomura, M. J. Chem. Soc., Perkin Trans. 1 1992, 1387. (b) Murata,
S.; Teramoto, K.; Miura, M.; Nomura, M. Heterocycles 1992, 34, 1177.
2053
dx.doi.org/10.1021/ol500655k | Org. Lett. 2014, 16, 2050−2053