Copper-catalysed oxidative Csp3-H methylenation to terminal olefins using DMF

Article abstract of DOI:10.1039/c4cc02275k

A copper-catalysed direct oxidative Csp³-H methylenation to terminal olefins using DMF as one carbon source was developed. In this reaction, various functional groups were well tolerated, thus providing a simple way to construct arylvinylketones and arylvinylpyridines. The preliminary mechanistic investigations revealed that CH₂ was from DMF (N-CH₃).

Full text of DOI:10.1039/c4cc02275k

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Copper-catalysed oxidative Csp3–H
methylenation to terminal olefins using DMF†
Cite this: Chem. Commun., 2014,
50, 7636
Jianming Liu,‡ab Hong Yi,‡a Xin Zhang,b Chao Liu,a Ren Liu,b Guoting Zhanga and
Aiwen Lei*a
Received 27th March 2014,
Accepted 20th May 2014
DOI: 10.1039/c4cc02275k
www.rsc.org/chemcomm
A copper-catalysed direct oxidative Csp3–H methylenation to terminal and the environmental impact of these reagents have hindered
olefins using DMF as one carbon source was developed. In this its further application. Therefore, seeking a simple, available
reaction, various functional groups were well tolerated, thus providing carbon source is highly desirable. As one of the most common
a simple way to construct arylvinylketones and arylvinylpyridines. The polar solvents, N,N-dimethylformamide (DMF) is known to be
preliminary mechanistic investigations revealed that CH2 was from employed as a cheap, readily available multipurpose building
DMF (N–CH3).
block in organic reactions for various units, such as –CO,
–NMe2, –Me, –CHO, etc.7 Nevertheless, using DMF as one
The terminal alkenes represent some of the most important synthons carbon source to realize the oxidative Csp3–H methylenation
in organic synthesis, and they are widely present in biologically active to terminal alkenes is still not well developed. Recently,
natural products and material molecules.1 The synthesis of terminal the direct Csp3–H methylenation of quinolines with DMAc
alkenes has been extensively studied. Traditional methods to prepare pioneered by Wang and Xu provided a rapid and straightforward
terminal alkenes usually involved two pathways: the first way is the access to the 2-vinylquinolines.8 Herein, we successfully realized
anionic reactions developed by Wittig, Johnson, and Peterson.2 the copper-catalysed direct oxidative Csp3–H methylenation of
However, stoichiometric quaternary phosphorus salts are required. arylketones and 1-aryl-1-pyridinemethanes9 using DMF as one
The other way is utilizing transition-metal-catalysed cross-coupling carbon source which provides a simple way to construct terminal
reactions including Suzuki reaction (aryl halides and alkenylboronic olefins (Scheme 1).
acids), Stille reaction (aryl halides and vinylstannanes) and Heck
To probe the feasibility of our proposed study, we chose
reaction (aryl halides and olefins) to synthesize terminal alkenes 2-phenylacetophenone (1a) and DMF as model substrates to
using palladium catalysts.3 Considering the principle of atom- evaluate the parameters (Table 1). When the reaction was
economic, sustainable and environment-friendly organic synthesis, performed in DMF at 100 1C under a N2 atmosphere using
it is highly desirable to develop a simple and practical protocol to FeCl3ꢀ6H2O as the catalyst, the desired product (2a) was not
construct terminal alkenes.
observed (Table 1, entry 1). Then we began to apply the copper
Recently, transition-metal-catalysed C–H functionalization salts as catalysts, and we were pleased to get the target product
has attracted considerable attention because it offers more albeit with low yield (Table 1, entry 2). After screening different
efficient ways for the construction of complex chemical frame- copper catalysts, Cu(TFA)2ꢀxH2O improved the yield to 88%,
works.4 The construction of CQC from the widely available whereas other copper catalysts, such as Cu(acac)2, CuBr2,
C–H bond will undoubtedly have great significance in organic CuSO4, Cu(NO3)2, CuI, CuBr and CuCl were less effective
synthesis using a simple C1 source as the carbon linkage. (Table 1, entries 3–10). Only 3% product was obtained when
Traditionally, CH2Br2 and HCHO,6 as the one carbon linkage, the reaction was carried out in the absence of a copper catalyst
5
have been utilized to construct these terminal alkenes by (Table 1, entry 12). However, the oxidant Na2S2O8 showed less
functionalization of Csp3–H compounds. However, the toxicity
a College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072,
P. R. China. E-mail: aiwenlei@whu.edu.cn; Tel: +86-27-68754672
b School of Chemistry and Chemical Engineering, Henan Normal University,
Xinxiang, Henan 453007, P. R. China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 Copper-catalysed oxidative methylenation of Csp3–H arylketones
c4cc02275k
and 1-aryl-1-pyridinemethanes using DMF as one carbon source.
‡ Jianming Liu and Hong Yi contributed equally to this work.
7636 | Chem. Commun., 2014, 50, 7636--7638
This journal is ©The Royal Society of Chemistry 2014

View Article Online
Communication
ChemComm
Table 1 Impact of reaction parameters on Cu-catalysed oxidative cou-
pling of benzophenone (1a) with DMFa
Table 3 Scope of a-methylenation of 1-(hetero)aryl-1-heteroarylmethanes (3)a
Entry
Catalyst
Oxidant
Yieldb (%)
1c
2
3
4
5
6
7
8
9
10
11d
12
13d
FeCl3ꢀ6H2O
CuCl2ꢀ2H2O
Cu(acac)2
CuBr2
Cu(OTf)2
CuSO4
Cu(NO3)2
CuI
CuBr
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
Na2S2O8
n.d.
24
11
30
69
57
3
29
27
28
88
3
CuCl
Cu(TFA)2ꢀxH2O
—
Cu(TFA)2ꢀxH2O
63
a
Reaction conditions: 1a (0.50 mmol), catalyst (20 mol%), oxidant
b
(1.0 mmol), DMF (2.0 mL), 100 1C, N2, 24 h. Yield determined by GC
analysis. n.d. = not detected. 30 mol% catalyst, 2.0 equiv. oxidant
were used.
a
c
d
Reaction conditions: 1 (0.50 mmol), Cu(TFA)2ꢀxH2O (30 mol%),
K2S2O8 (2.0 mmol), DMF (2.0 mL), 100 1C, N2, 24 h, isolated yield.
efficiency with a yield of 63% (Table 1, entry 13). From these
experiments, we determined the optimized conditions to be:
Cu(TFA)2ꢀxH2O (30 mol%), K2S2O8 (2.0 equiv.), DMF, 100 1C, 24 h.
With the optimal conditions established, various arylketones
were investigated and the results are summarized in Table 2.
Compound 1b with a p-OMe group on the aryl group was
transformed into the desired product in 79% yield (2b). In
addition, the C–Br group was well tolerated in this reaction
providing the possibility for further functionalization (2c–2e).
Furthermore, 2,3-dihydro-1H-inden-1-one and 6-methoxy-2,3-
dihydro-1H-inden-1-one were also suitable for this reaction
(2f and 2g). Unfortunately, direct oxidative coupling of chroman-
2-one and 2-(2-oxo-2-phenylethyl)-isoindoline-1,3-dione with DMF
did not give the desired product (2h and 2i).
Encouraged by these promising results, we further applied
the substrates of copper-catalysed a-methylenation reaction to
substituted benzylpyridines. To our delight, good to excellent
yields were obtained with various benzylpyridines (Table 3).
Both benzyl and 4-(4-chlorobenzyl)-pyridine reacted with DMF
under the standard conditions to afford the coupling products in
good yields (4a and 4b). Similarly, benzyl and 2-(4-chlorobenzyl)-
pyridine coupled well with DMF to construct the substituted
pyridines (4c and 4d). Substrates containing electron-donating
groups provided higher yields than the substrates containing
electron-withdrawing groups (4e–4f). The 2-(1-([1,10-biphenyl]-4-yl)-
vinyl)pyridine was similarly found to be a suitable substrate for
this transformation and gave the desired products in good yield
(4g). The reaction of 4-(pyridin-2-ylmethyl)benzonitrile afforded the
desired product (4h) in 66% yield.
Table 2 Scope of a-methylenation of arylketones (1)a
To gain some insights into the mechanism, several experiments
were carried out under the optimized conditions. In order to
confirm the resource of CH2, we used d7-DMF as the solvent to
perform this reaction, the results turned out that the deuterium
product was obtained in 90% (Scheme 2a) and the ratio of
deuterium-labelled is more than 99%. In addition, different
amides were employed to test this notable transformation. Inter-
estingly, a-methylenation of 1,2-diphenylethanone was found
to occur only in the presence of N,N-dimethylformamide and
N,N-dimethylacetamide (Scheme 2b). These two results demon-
strated that the carbon source was from the N-methyl of DMF.
Based on the above results, a proposed mechanism is depicted in
Fig. S3 (ESI†). Furthermore, the operando IR was monitored to
investigate this oxidative reaction presented in Scheme 2c. From
the 3D kinetic behavior profile of this reaction, we observed an
a
Reaction conditions: 1 (0.50 mmol), Cu(TFA)2ꢀxH2O (30 mol%),
K2S2O8 (1.0 mmol), DMF (2.0 mL), 100 1C, N2, 24 h, isolated yield.
b
K2S2O8 (2.0 mmol) was used.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 7636--7638 | 7637

View Article Online
ChemComm
Communication
In addition, the operando IR showed that the inductive period
was not referred in this reaction. Further detailed mechanistic
investigations are currently underway in our laboratory.
This work was supported by the 973 Program (2012CB725302),
the NSFC (21390400, 21025206, 21103044, 21272180 and
21302148), and the Research Fund for the Doctoral Program of
Higher Education of China (20120141130002) and the Program for
Changjiang Scholars and Innovative Research Team in University
(IRT1030).
Notes and references
1 (a) R. F. Heck and J. P. Nolley, J. Org. Chem., 1972, 37, 2320–2322;
(b) I. P. Beletskaya and A. V. Cheprakov, Chem. Rev., 2000, 100,
3009–3066; (c) A. B. Dounay and L. E. Overman, Chem. Rev., 2003,
103, 2945–2964; (d) C. Peng, Y. Wang and J. Wang, J. Am. Chem. Soc.,
2008, 130, 1566–1567.
2 (a) G. Wittig and G. Geissler, Justus Liebigs Ann. Chem., 1953, 580,
44–57; (b) C. R. Johnson and R. C. Elliott, J. Am. Chem. Soc., 1982, 104,
7041–7044; (c) C. R. Johnson, J. R. Shanklin and R. A. Kirchhoff,
J. Am. Chem. Soc., 1973, 95, 6462–6463; (d) D. J. Peterson, J. Org.
Chem., 1968, 33, 780–784.
3 (a) A. F. Littke and G. C. Fu, J. Am. Chem. Soc., 2001, 123, 6989–7000;
(b) X. Han, B. M. Stoltz and E. J. Corey, J. Am. Chem. Soc., 1999, 121,
7600–7605; (c) E. Peyroux, F. Berthiol, H. Doucet and M. Santelli, Eur.
J. Org. Chem., 2004, 1075–1082; (d) M. T. Reetz, G. Lohmer and
R. Schwickardi, Angew. Chem., Int. Ed., 1998, 37, 481–483.
4 (a) R. Giri, B.-F. Shi, K. M. Engle, N. Maugel and J.-Q. Yu, Chem. Soc.
Rev., 2009, 38, 3242–3272; (b) P. B. Arockiam, C. Bruneau and
P. H. Dixneuf, Chem. Rev., 2012, 112, 5879–5918; (c) D. Alberico,
M. E. Scott and M. Lautens, Chem. Rev., 2007, 107, 174–238;
(d) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110, 1147–1169;
(e) Y. Yang, K. Cheng and Y. Zhang, Org. Lett., 2009, 11, 5606–5609;
( f ) S. Guo, B. Qian, Y. Xie, C. Xia and H. Huang, Org. Lett., 2010, 13,
522–525; (g) N. Kuhl, M. N. Hopkinson, J. Wencel-Delord and
F. Glorius, Angew. Chem., Int. Ed., 2012, 51, 10236–10254; (h) C. Liu,
H. Zhang, W. Shi and A. Lei, Chem. Rev., 2011, 111, 1780–1824.
5 Y.-S. Hon, T.-R. Hsu, C.-Y. Chen, Y.-H. Lin, F.-J. Chang, C.-H. Hsieh
and P.-H. Szu, Tetrahedron, 2003, 59, 1509–1520.
Scheme 2 Investigation for mechanistic insights.
obvious decrease in absorption of the substrate (1a) at 761 cmꢁ1
At the same time, the peak of the product (2a) increased at
a wavenumber of 782 cmꢁ1. Therefore, this reaction occurred
without any inductive period from the result of operando IR.
In conclusion, we have demonstrated a copper-catalysed
direct oxidative Csp3–H methylenation of arylketones and
1-aryl-1-pyridinemethanes using DMF as one carbon source.
This protocol provided a direct way for functionalization of
Csp3–H compounds. This method presented a simple way to
.
´
´
´˜
´
6 (a) J. L. G. Ruano, M. A. Fernandez-Ibanez, J. A. Fernandez-Salas,
´
´
´
´
M. C. Maestro, P. Marquez-Lopez and M. M. Rodrıguez-Fernandez,
¨
J. Org. Chem., 2008, 74, 1200–1204; (b) A. Erkkila and P. M. Pihko,
J. Org. Chem., 2006, 71, 2538–2541.
7 (a) S. Ding and N. Jiao, Angew. Chem., Int. Ed., 2012, 51, 9226–9237;
(b) J. Muzart, Tetrahedron, 2009, 65, 8313–8323; (c) Y. Li, D. Xue,
W. Lu, C. Wang, Z.-T. Liu and J. Xiao, Org. Lett., 2014, 16, 66–69.
8 (a) S.-J. Lou, D.-Q. Xu, D.-F. Shen, Y.-F. Wang, Y.-K. Liu and Z.-Y. Xu,
Chem. Commun., 2012, 48, 11993–11995; (b) Y. Li, F. Guo, Z. Zha and
Z. Wang, Chem. – Asian. J., 2013, 8, 534–537.
synthesize arylvinylketones and arylvinylpyridines which shows 9 When we are preparing this manuscript, a similar report on the
methylenation of benzylpyridines was just reported. However,
the substrates scope of our reaction can be further applied to simple
aryl-ketones. M. Itoh, K. Hirano, T. Satoh and M. Miura, Org. Lett.,
promising potential in biological activities and pharmaceutical
applications. Preliminary mechanistic investigations confirmed
that the product CH2 is from the N–CH3 of solvent DMF.
2014, 16, 2050–2053.
7638 | Chem. Commun., 2014, 50, 7636--7638
This journal is ©The Royal Society of Chemistry 2014