Copper-catalyzed radical coupling of 1,3-dicarbonyl compounds with terminal alkenes for the synthesis of tetracarbonyl compounds

Article abstract of DOI:10.1039/c6cc01942k

A novel and efficient copper-catalyzed radical cross-coupling of 1,3-dicarbonyl compounds with terminal alkenes for the synthesis of tetracarbonyl compounds with a quaternary carbon atom has been developed. Mechanistically, this transformation involves the construction of two C-C bonds and two CO bonds in a one-pot process. The reaction tolerates a wide range of functional groups and proceeds under mild conditions.

Full text of DOI:10.1039/c6cc01942k

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: M. Zhang, M.
Zhao, M. Chen, Z. Ren, Y. Wang and Z. Guan, Chem. Commun., 2016, DOI: 10.1039/C6CC01942K.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/chemcomm

Please do not adjust margins
ChemComm
Page 1 of 4
View Article Online
DOI: 10.1039/C6CC01942K
ChemComm
COMMUNICATION
Copper-catalyzed radical coupling of 1,3-dicarbonyl compounds
with terminal alkenes for the synthesis of tetracarbonyl
compounds
Received 00th January 20xx,
Accepted 00th January 20xx
Mei-Na Zhang, Mi-Na Zhao, Ming Chen, Zhi-Hui Ren, Yao-Yu Wang and Zheng-Hui Guan*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A novel and efficient copper-catalyzed radical cross-coupling of terminal alkenes for the synthesis 1,4-dicarbonyls using tert-
1,3-dicarbonyl compounds with terminal alkenes for the synthesis butyl hydroperoxide (TBHP) as the radical initiator has been
of tetracarbonyl compounds with quaternary carbon atom has developed by Wang and co-workers (Scheme 1c).11 Inspired by
been developed. Mechanistically, this transformation involves the these pioneering works, we hypothesized that radical oxidative
construction of two C-C bonds and two C=O bonds in a one-pot cross-coupling of methylene of 1,3-dicarbonyl compounds and
process. The reaction tolerates a wide range of functional groups terminal alkenes may be occurred under copper-catalyzed
and proceeds under mild conditions.
aerobic conditions. Interestingly, a tetracarbonyl compound
was observed in this transformation, which involved the
construction of two C-C bonds and two C=O bonds (Scheme
1d). Tetracarbonyl compounds are important organic
structures that are not only present in many pharmaceuticals
and food but also widely applied in fiber materials.12 However,
this class of compounds are not easily accessible by traditional
methods.13 In this paper, we have developed an efficient
copper-catalyzed aerobic radical oxidative cross-coupling of
1,3-dicarbonyl compounds with terminal alkenes for the
synthesis of tetracarbonyl compounds under mild conditions
(Scheme 1d).
Radical oxidative cross-coupling reactions have attracted
considerable attention as
a powerful method for the
construction of C-C/C-X bonds and functional molecules.1 In
recent years, radical oxidative alkenylation,2 radical oxidative
arylative-annulation,3 and radical oxidative amidation4 have
emerged. However, many of these reactions required
unfriendly radical initiators, such as peroxides, diazines, AIBN,
etc.,5 thus leading to the difficulty of product purification.
Radical cross-couplings using dioxygen as the terminal oxidant
is an ideal reaction,6 because only water was the byproduct.
Therefore, the development of efficient and selective radical
oxidative cross-couplings that prompted by dioxygen remain
highly desirable.
1,3-Dicarbonyl compounds are versatile and powerful
building blocks in organic synthesis.7 The radical coupling of
1,3-dicarbonyl compounds in C-C bond formation has been
documented.8 Oxidative cyclization of 1,3-dicarbonyl
compounds with alkenes for the synthesis of dihydrofurans
have been developed by several groups (Scheme 1a).9 CeCl3-
catalyzed aerobic radical oxidative cross-coupling of 1,3-
dicarbonyl compounds and terminal alkenes for the synthesis
of tricarbonyl compounds has been developed by Christiffers
and co-workers (Scheme 1b).10 Recently, copper/manganese
co-catalyzed oxidative coupling of simple ketones with
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of
Ministry of Education, Department of Chemistry & Materials Science, Northwest
University, Xi’an, 710127, P. R. China.
*E-mail: guanzhh@nwu.edu.cn.
†Electronic Supplementary Information (ESI) available: Detailed experimental
procedures and spectral data and copies of NMR spectra for all products. See
DOI: 10.1039/x0xx00000x
Scheme 1 Oxidative coupling of 1,3-dicarbonyl compounds with alkenes.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 4
COMMUNICATION
ChemComm
Table 1 Optimization of the reaction conditionsa
Table 2 Scope of the 1,3-dicarbonyl compoundsa
View Article Online
DOI: 10.1039/C6CC01942K
Entry
1
Catalyst
CuBr
CuI
Solvent
DMF
Yield (%)
Ph
Ph
Ph
40
0
O
O
O
O
O
O
O
O
2
DMF
O
O
O
3
CuCl
CuCl2
Cu(TFA)2
---
DMF
58
37
0
O
OnPr
Ph
Ph
Ph
OEt
OMe
4
DMF
5
DMF
3ca
, 62%
3aa, 73%
3ba, 70%
6
DMF
0
Ph
Ph
Ph
O
7
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
PEG200
NMP
24
46
73
5
O
O
O
O
O
O
O
O
8
O
O
O
9
DMSO
Toluene
CH3CN
DCE
Ph
OC8H17
Ph
OnBu
Ph
OCy
10
11
12
13b
17
19
23
3da, 75%
3ea, 60%
3fa, 68%
Ph
O
Ph
Ph
DMSO
O
O
O
O
O
O
O
O
a
Reaction conditions: 1a (0.2 mmol), 2a (0.8 mmol), catalyst (10 mol%), solvent
O
O
O
(2.0 mL), under air, 60 oC, 12 h; isolated yields. The reaction was conducted
under Ar. PEG200 = The average molecular mass of poly(ethylene glycol) is 200,
NMP = N-methyl-2-pyrrolidone.
b
Ph
O
Ph
Ph
OMe
OBn
3ia, 61%
3ga, 65%
3ha, 66%
We began our studies by using a model reaction of ethyl
acetoacetate 1a with styrene 2a in the presence of copper
catalyst under an atmosphere of air as the oxidant. We were
pleased to find that 3aa was obtained in 40% yield in the
presence of CuBr in DMF at 60 oC (Table 1, entry 1).
Encouraged by this result, further studies were performed to
improve the reaction efficiency. Screening of various catalysts,
such as CuI, CuCl, CuCl2 and Cu(TFA)2, suggested that CuCl was
the most effective catalyst for this reaction, giving the desired
3aa in 58% yield (Table 1, entries 2-5). No reaction occurred in
the absence of a copper catalyst (Table 1, entry 6). To further
improve the reaction outcome, various solvents were screened.
Further experiments showed that DMSO was the most
effective solvent, improving the yield of 3aa to 73% yield
(Table 1, entry 9). Other solvents, such as PEG200, NMP,
toluene, CH3CN and DCE were inferior (Table 1, entries 7-12).
The product 3aa was obtained in only 23% yield when the
reaction was performed under argon (Table 1, entry 13).
Ph
O
Ph
Ph
O
nPr
O
O
O
O
O
O
O
O
O
O
O
Ph
3ka, 33%
Ph
Ph
OMe
OEt
3ja, 63%
3la, 40%
a
Reaction conditions: 1 (0.2 mmol), 2a (0.8 mmol) and CuCl (10 mol%) in DMSO
(2 mL) at 60 oC under air for 12 h; isolated yields.
3ka was obtained in 33% yield, may be due to the
decomposition of aliphatic 1,3-diketones according to retro-
Claisen reaction.10 Moreover, the reaction of diethyl malonate
1l with styrene gave the desired product 3la in moderate yield.
For further extending the substrate scope, we have
investigated the reaction of various terminal alkenes with ethyl
acetoacetate 1a as well, and the results are illustrated in Table
3. Styrene with both electron-donating and electron-
withdrawing substituents on the benzene rings displayed
similar reactivity in the reaction. Various styrenes bearing
methyl, tert-butyl, methoxy, fluoro, chloro and bromo
substituents were transformed efficiently into their
With the optimized conditions in hand, we set out to
explore the scope of the 1,3-dicarbonyl compounds (Table 2).
It was discovered that ethyl, methyl, n-propyl, n-butyl, n-octyl,
cyclohexyl, allyl and benzyl acetoacetate were all well
tolerated and afforded the desired products 3aa-3ha in 60%-
corresponding products 3ab-3ah in good to excellent yields. In
75% yields. The α-ethyl-substituted and α-propyl-substituted
1,3-dicarbonyl compounds 1i and 1j proceeded smoothly to
afford the desired products 3ia and 3ja in good yields.
However, when the symmetric diketone 1k was subjected
under the standard reaction conditions, the desired product
addition, the styrene possessing an acetoxyl group also
reacted well to give the corresponding product 3ae in 60%
yield. However, ortho-chloro substitution on the aromatic ring
of the styrene led to a poor yield. And 2,4,6-trimethyl substitu-
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 3 of 4
ChemComm
COMMUNICATION
Table 3 Scope of the terminal alkenesa
View Article Online
DOI: 10.1039/C6CC01942K
t-Bu
MeO
O
O
O
O
O
O
O
O
O
O
O
O
OEt
OEt
OEt
Scheme 2 Control experiments.
t-Bu
OMe
3ac, 81%
3ab, 67%
AcO
3ad, 65%
12 h. However, ethyl 2-acetyl-4-oxo-4-phenylbutanoate
isolated in 17% yield along with the desired product 3aa in
25% yield, at 2 h. And the reaction of with styrene gave 3aa
in 77% yield at 20 h, with 18% recovery of the 2-acetyl-4-oxo-
4-phenylbutanoate (eqn (3)). This result revealed that the
D was
F
Br
D
O
O
O
D
O
O
O
O
O
O
O
reaction proceeded through oxidative coupling of ethyl acetoa-
O
O
OEt
OEt
OEt
OAc
F
Br
3ae, 60%
3af, 77%
3ag, 61%
Cl
Cl
O
O
O
O
O
O
O
O
O
O
O
O
Cl
OEt
OEt
OEt
Cl
3ah, 58%
3ai, 30%
3aj, 0%
a
Reaction conditions: 1a (0.2 mmol), 2 (0.8 mmol) and CuCl (10 mol%) in DMSO
(2 mL) at 60 oC under air; isolated yields.
ted styrene reacted with 1a failed to obtain the desired
product 3aj. These results indicated that the transformation
was sensitive to the steric effect of the terminal alkenes.
Furthermore, no reaction occurred when aliphatic alkenes
were employed as the substrate, such as 1-octene and
allylbenzene.
In order to gain more insight into the reaction mechanism,
control experiments were carried out (Scheme 2). First, no
desired product 3aa was obtained when acetophenone and 1a
was conducted under standard conditions (eqn (1)), thus ruling
out the possibility of Wacker oxidation process. Furthermore,
the reactions were quenched at 2 h and at 12 h (eqn (2)). The
product 3aa was obtained, as the sole product, in 73% yield, at
Scheme 3 Plausible mechanism of the reaction.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3

Please do not adjust margins
ChemComm
Page 4 of 4
COMMUNICATION
ChemComm
Chem. Int. Ed., 2011, 50, 5034; (c) J. Liu, Z. Liu, P. Liao, L.
cetate 1a with styrene 2a to give 2-acetyl-4-oxo-4-
Zhang, T. Tu and X. Bi, Angew. CheDmO.I:I1n0t..10E3Vd9ie./,Cw62ACr0tiCc1l0e51O,9n45li2n4Ke
,
phenylbutanoate
D, followed by the coupling of D with
10618.
another molecular styrene. Further, when a radical-trapping
reagent, (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO),
was added to the reaction (eqn (4)). Formation of 3aa was
completely suppressed, implying that the reaction proceeds
through a radical pathway.
7
8
(a) C. Richter, B. Voigt and R. Mahrwald, RSC Adv., 2015, 5,
45571; (b) J. Yang, A. Mao, Z. Yue, W. Zhu, X. Luo, C. Zhu, Y.
Xiao and J. Zhang, Chem. Commun., 2015, 51, 8326.
(a) H. Wang, L.-N. Guo and X.-H. Duan, Org. Lett., 2013, 15
,
5254; (b) Y.-Y. Liu, X.-H. Yang, J. Yang, R.-J. Song and J.-H. Li,
Chem. Commun., 2014, 50, 6906; (c) H. Jiang, Y. Cheng, Y.
Zhang and S. Yu, Org. Lett., 2013, 15, 4884; (d) M. Mondal
Based on the above experimental results, a plausible
reaction mechanism was proposed in Scheme 3. First, the
and U. Bora, RSC Adv., 2013, 3, 18716; (e) Z.-F. Lu, Y.-M. Shen,
oxidation of the 1,3-dicarbonyl compound
single electron transfer to generate copper enolate
converted to free radical . The single-electron inserts into
terminal styrene to cause C-C propagation, which is further
oxidized by O2 to form D 9b,10,11,14
As before, the intermediate
can be further transformed to afford the final product 3aa
through the same process.
1
by Cu(II) via a
J.-J. Yue, H.-W. Hu and J.-H. Xu, J. Org. Chem., 2008, 73, 8010;
(f) C. A. Correia and C.-J. Li, Tetrahedron Lett., 2010, 51, 1172;
(g) Y.-F. Wang, K. K. Toh, S. Chiba and K. Narasaka, Org. Lett.,
2008, 10, 5019; (h) S. Guo, Q. Wang, Y. Jiang and J.-T. Yu, J.
Org. Chem., 2014, 79, 11285.
A, which is
B
.
9
(a) S. Tang, K. Liu, Y. Long, X. Gao, M. Gao and A. Lei, Org.
Lett., 2015, 17, 2404; (b) X. Zhang, W. Dai, W. Wu and S. Cao,
Org. Lett., 2015, 17, 2708; (c) P. Li, J. Zhao, C. Xia and F. Li,
Org. Lett., 2014, 16, 5992.
D
In summary, we have developed a novel and efficient Cu-
catalyzed aerobic radical oxidative cross-coupling of 1,3-
dicarbonyl compounds and terminal alkenes for the synthesis
of tetracarbonyl compounds. The reaction is characterized by a
simple procedure and only atmospheric air as an oxidant. The
reaction tolerates a wide range of functional groups and
proceeds under mild conditions. Further scope and
mechanistic studies of the reaction are underway.
This work was supported by generous grants from the
National Natural Science Foundation of China (21472147,
21272183), and the Fund of the Rising Stars of Shanxi Province
(2012KJXX26).
10 (a) M. R
Ö
ssle, T. Werner, A. Baro, W. Frey and J. Christoffers,
ssle, T.
Angew. Chem. Int. Ed., 2004, 43, 6547; (b) M. R
Ö
Werner, W. Frey and J. Christoffers, Eur. J. Org. Chem., 2005,
5031.
11 X.-W. Lan, N.-X. Wang, W. Zhang, J.-L. Wen, C.-B. Bai, Y. Xing
and Y.-H. Li, Org. Lett., 2015, 17, 4460.
12 P. Haberz, F. Rodriguez-Castaneda, J. Junker, S. Becker, A.
Leonov and C. Griesinger, Org. Lett., 2006, 8, 1275.
13 A. Leonov, B. Voigt, F. Rodriguez-CastaÇeda, P. Sakhaii and C.
Griesinger, Chem. Eur. J., 2005, 11, 3342.
14 (a) S. E. Allen, R. R. Walvoord, R. Padilla-Salinas and M. C.
Kozlowski, Chem. Rev., 2013, 113, 6234; (b) J. Zhang, J. Jiang,
D. Xu, Q. Luo, H. Wang, J. Chen, H. Li, Y. Wang and X. Wan,
Angew. Chem. Int. Ed., 2014, 53, 1; (c) P. Liu, J.-L. Liu, H.-S.
Wang, Y.-M. Pan, H. Liang and Z.-F. Chen, Chem. Commun.,
2014, 50, 4795; (d) H. Yan, L. Lu, G. Rong, D. Liu, Y. Zheng, J.
Chen and J. Mao, J. Org. Chem., 2014, 79, 7103; (e) K. Cheng,
L. Huang and Y. Zhang, Org. Lett., 2009, 11, 2908.
Notes and references
1
(a) C. Liu, D. Liu and A. Lei, Acc. Chem. Res., 2014, 47, 3459;
(b) J. Jeffrey, F. R. Petronijević and D. W. C. MacMillan, J. Am.
Chem. Soc., 2015, 137, 8404; (c) G. J. Choi and R. R. Knowles,
J. Am. Chem. Soc., 2015, 137, 9226; (d) C. C. Nawrat, C. R.
Jamison, Y. Slutskyy, D. W. C. MacMillan and L. E. Overman, J.
Am. Chem. Soc., 2015, 137, 11270; (e) D. C. Miller, G. J. Choi,
H. S. Orbe and R. R. Knowles, J. Am. Chem. Soc., 2015, 137
13492; (f) X. Shang and Z. Liu, Acta Chim. Sinica., 2015, 73
1275.
,
,
2
3
(a) W. Liu, L. Li, Z. Chen and C.-J. Li, Org. Biomol. Chem., 2015,
13, 6170; (b) J. Wang, C. Liu, J. Yuan and A. Lei, Angew. Chem.
Int. Ed., 2013, 52, 2256.
(a) L. Lv, S. Lu, Q. Guo, B. Shen and Z. Li, J. Org. Chem., 2015,
80, 698; (b) P. Li, J. Zhao, C. Xia and F. Li, Org. Lett., 2014, 16
,
5992.
4
5
J. Liu, Q. Liu, H. Yi, C. Qin, R. Bai, X. Qi, Y. Lan and A. Lei,
Angew. Chem. Int. Ed., 2014, 53, 502.
(a) Y. Li, B. Liu, H.-B. Li, Q. Wang and J.-H. Li, Chem. Commun.,
2015, 51, 1024; (b) Y. Zhu and Y. Wei, Chem. Sci., 2014, 5,
2379; (c) F. Teng, S. Sun, Y. Jiang, J.-T. Yu and J. Cheng, Chem.
Commun., 2015, 51, 5902; (d) X.-H. Ouyang, R.-J. Song, C.-Y.
Wang, Y. Yang and J.-H. Li, Chem. Commun., 2015, 51, 14497;
(e) K. C. Majumdar and P. Debnath, Tetrahedron, 2008, 64
,
9799; (f) T. Akindele, K.-I. Yamada and K. Tomioka, Acc. Chem.
Res., 2008, 42, 345; (g) J. Hui, Y. Shi, T. Li, J. Wu and Z. Fu,
RSC Adv., 2015, 5, 44326; (h) M. Conte and V. Chechik, Chem
Commun., 2010, 46, 3991; (i) J. Iqbal, B. Bhatia and N. K.
Nayyar, Chem. Rev., 1994, 94, 519; (j) B. B. Snider, Chem.
Rev., 1996, 96, 339.
(a) J. Lai, L. Tian, X. Huo, Y. Zhang, X. Xie and S. Tang, J. Org.
Chem., 2015, 80, 5894; (b) L. Tebben and A. Studer, Angew.
6
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins