Copper/Manganese Cocatalyzed Oxidative Coupling of Vinylarenes with Ketones

Article abstract of DOI:10.1021/acs.orglett.5b02116

A novel copper/manganese cocatalyzed direct oxidative coupling of terminal vinylarenes with ketones via C(sp³)-H bond functionalization following C-C bond formation has been developed using tert-butyl hydroperoxide as the radical initiator. Various ketones underwent a free-radical addition of terminal vinylarenes to give the corresponding 1,4-dicarbonyl products with excellent regioselectivity and efficiency through one step. A possible reaction mechanism has been proposed.

Full text of DOI:10.1021/acs.orglett.5b02116

Letter
pubs.acs.org/OrgLett
Copper/Manganese Cocatalyzed Oxidative Coupling of Vinylarenes
with Ketones
Xing-Wang Lan,† Nai-Xing Wang,*,† Wei Zhang,† Jia-Long Wen,† Cui-Bing Bai,† Yalan Xing,*,‡
and Yi-He Li†
†Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China
‡Department of Chemistry, William Paterson University of New Jersey, 300 Pompton Road, Wayne, New Jersey 07470, United States
S
* Supporting Information
ABSTRACT: A novel copper/manganese cocatalyzed direct oxidative coupling of terminal vinylarenes with ketones via C(sp3)−
H bond functionalization following C−C bond formation has been developed using tert-butyl hydroperoxide as the radical
initiator. Various ketones underwent a free-radical addition of terminal vinylarenes to give the corresponding 1,4-dicarbonyl
products with excellent regioselectivity and efficiency through one step. A possible reaction mechanism has been proposed.
irect difunctionalization of alkenes1 is an important
1, (1)). However, the alkenyl peroxides are labile so that these
Dstrategy for the synthesis of complex molecules. In compounds are difficult to use directly for the synthesis of
particular, transition-metal-catalyzed direct oxidative coupling
of alkenes2 has been developed as a fascinating and powerful
Scheme 1. Direct Difunctionalization of Terminal
approach for preparing carbonyl compounds. In this context,
the direct difunctionalization of alkenes to introduce both a
carbonyl group and another functional group such as ethers,3
alcohols,4 amides,5 and phosphonates6 has been extensively
studied recently. Direct C(sp3)−H bond functionalization is
highly attractive, but it has been scarcely developed.7 Therefore,
it is still a challenge to develop the direct and regioselective
difunctionalization of alkenes via C(sp3)−H bond functional-
ization for the efficient synthesis of compounds containing
multifunctional groups.2a,8
Vinylarenes with Unactivated Ketones
1,4-Dicarbonyl compounds are versatile scaffolds for the
synthesis of carbocyclic and heterocyclic compounds, and
significant efforts have been devoted to the development of the
synthesis of this valuable synthon.9 Recently, Huang and Xie9d
reported a cascade carbo-carbonylation reaction of alkenes with
ketones to generate 1,4-dicarbonyl compounds using organo-
catalyst and transition-metal catalyst via a SOMO enamine.
Wan and co-workers9f reported a different method for the
formation of 1,4-dicarbonyls which involves a radical process; in
particular, a Co-catalyzed alkene addition/trapping/Korn-
blum−DeLaMare rearrangement was employed. Very recently,
Klussmann and co-workers10 discovered a multicomponent
radical addition of unactivated ketones and tert-butyl hydro-
peroxide to vinylarenes via Brønsted acid catalyzed formation of
ketone radicals for the synthesis of alkenyl peroxides (Scheme
complex molecules or pharmaceuticals. We envisioned that the
direct and regioselective difunctionalization of alkenes to
provide dual carbonyl groups could be realized in a single
procedure via a free-radical pathway. Herein, we present the
copper/manganese-cocatalyzed direct oxidative coupling of
vinylarenes with ketones via C(sp3)−H bond functionalization
Received: July 22, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02116
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
to generate 1,4-dicarbonyls (Scheme 1, (2)). Compared to
Klussmann’s work, this work avoided the use of environ-
mentally unfriendly strong acid and used a one-pot reaction to
give 1,4-dicarbonyls. To the best of our knowledge, this is first
report of the direct oxidative coupling of simple vinylarenes
with ketones via C(sp3)−H bond functionalization to assemble
the synthetically versatile 1,4-dicarbonyls in one pot.
We began our investigations by exploiting styrene 1 and
acetone 2 as model substrates under various reaction conditions
(Table 1). After screening a series of transition-metal catalysts
entry 15). Interestingly, further exploration showed that a
decent yield was obtained when MnCl2·4H2O was employed as
a cocatalyst (Table 1, entry 18), but other additives cannot
provide more excellent results (Table 1, entries 16, 17, and 19,
and Supporting Information). To our delight, a 71% yield was
achieved when the reaction time was prolonged to 72 h under
the optimal conditions (Table 1, entry 20). Finally, by
comparison of several control experiments (Table 1, entries
21−25), we further defined the optimal conditions for this
transformation, indicating that catalysts, base, and radical
initiator are crucial in this reaction, although the α-C−H of
ketone possesses some reactivity, and the reaction is not
sensitive to air. Several other common radical initiators, such as
DTBP, BPO, and DDQ, gave low or no activity, and TBHP
(5.5 M solution in decane) as radical initiator gave a 50% yield
(see the Supporting Information).
Table 1. Selected Results for Screening the Optimal
a
Reaction Conditions
With the optimal conditions in hand, the substrate scope of
this reaction was investigated by testing various terminal
vinylarenes 1 and ketones 2 (Scheme 2). First, a series of
b
entry
catalyst
cocatalyst
base
Et3N
yield (%)
1
FeCl3·6H2O
NiCl2·6H2O
MnCl2·4H2O
CuCl2
22
18
8
Scheme 2. Substrate Scope for the Reaction of Alkenes with
a
2
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
DBU
t-BuOK
K2CO3
pyridine
DBU
DBU
DBU
DBU
DBU
DBU
DBU
Ketones
3
4
0
5
CuBr2
15
10
18
24
11
17
46
<5
trace
trace
43
45
47
54
50
71
44
15
<10
0
6
CuI
7
CuSO4·5H2O
Cu(OTf)2
Cu(ClO4)2
Cu(OAc)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
8
9
10
11
12
13
14
c
15
16
17
18
19
NiCl2·6H2O
FeCl3·6H2O
MnCl2·4H2O
CuBr2
d
20
MnCl2·4H2O
e
21
22
f
23
DBU
DBU
DBU
24
g
25
Cu(OTf)2
MnCl2·4H2O
53
a
Reaction conditions: styrene 1 (0.5 mmol, 1 equiv), acetone 2 (3
mL), catalyst (5 mol %), cocatalyst (5 mol %), base (1.5 equiv),
aqueous TBHP (4 equiv, 70% in water) in seal tube at 60 °C for 24 h.
b
c
Isolated yields. 10 mol % of 1,10-phenanthroline was employed.
d
e
f
a
Reaction within 72 h. 20 mol % of Cu(OTf)2. Without aqueous
Reaction conditions: alkenes 1 (0.5 mmol, 1 equiv), ketones 2 (3
g
TBHP (70% in water). Open flask (in air).
mL), Cu(OTf)2 (5 mol %), MnCl2·4H2O (5 mol %), DBU (1.5
equiv), aqueous TBHP (4 equiv, 70% in water) at 60 °C.
(Table 1, entries 1−10, and Supporting Information), a 24%
yield of the desired 1,4-dicarbonyl product 3 was achieved in
the presence of 1.5 equiv of Et3N and 4 equiv of TBHP (70% in
water) using Cu(OTf)2 as catalyst (Table 1, entry 8). To
improve the yield, several other bases, including DBU, t-BuOK,
K2CO3, and pyridine, were examined (Table 1, entries 11−14).
Gratifyingly, switching the base to DBU enhanced the reaction
efficiency to furnish 46% yield of the product under the same
conditions, while other bases were less effective. However,
when 10 mol % of 1,10-phenanthroline as additive was added
to the reaction, the reaction yield was not improved (Table 1,
substituted terminal vinylarenes was explored for reaction with
acetone in sealed tubes as shown in Scheme 2. Styrenes having
electron-withdrawing substituents such as halogen substituents
(F-, Cl-, and Br-) at the para-position afforded the desired
products in moderate yields (41%, 63%, and 53%, respectively).
Unexpectedly, when the CF3- or NO2-substituted styrene was
used as a substrate in the reaction, the yield was dramatically
reduced to low or even trace. In addition, the m- and o-bromo-
substituted styrenes were also examined, and the order of their
reactivity was as follows: para > meta > ortho. Obviously, the
B
DOI: 10.1021/acs.orglett.5b02116
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
position of substituents impacted the yield of the reaction.
Styrenes having electron-donating substituents such as CH3-,
CH3O- and t-Bu- also smoothly generated the corresponding
products. Unfortunately, no product was formed when the
NH2-substituted styrene was employed as a substrate. We
believed strong electron-donating and electron-withdrawing
groups such as amino and nitro groups on the aromatic ring
inhibit the reaction. Similarly, we also found that most previous
works rarely involved strong electron-withdrawing and
electron-donating groups.10,11 Finally, we speculated that this
transformation was affected by both electronic and steric
factors. Afterward, several ketones were also studied for
reaction with typical vinylarenes in an open flask (in air), and
most substrates were suitable for this protocol. From primary
acetone to secondary diethyl ketone, moderate yields were
obtained (3n−p). In addition, cyclohexanone and cyclo-
pentanone were also smoothly converted to the corresponding
products, giving moderate yields of products (3q−s). However,
the tertiary diisopropyl ketone led to only trace amounts of
product 3t, and we speculated the lack of reactivity could be
due to steric effects. Then the methyl acetoacetate was also
tested, and we found that it selectively gave the desired product
3u in a 55% yield. Moreover, 3v was generated in 40% yield
from acetophenone and styrene.
for the copper/manganese cocatalyzed difunctionalization of
terminal vinylarenes is outlined in Scheme 4. Initially, tert-
Scheme 4. Possible Mechanistic Pathways
However, in the process of investigation of substrate scope,
we found an unexpected result that when acetyl acetone was
used as a substrate under the same conditions, no desired
product was obtained. In addition, α-methylstyrene and
acetone under the same conditions only gave 80% yield of
the alkene cleavage product acetophenone (Scheme 3).
butyloxy radical and hydroxyl radical (eq 1) are generated with
the assistance of copper/manganese catalysts.12 A fast
equilibrium exists between tert-butyloxy radical and the tert-
butylperoxyl radical (eq 2),13 and then tert-butyloxy radical
and/or hydroxyl radical abstract a hydrogen radical from
ketones to generate the α-ketone radicals (eq 3). Subsequently,
addition of the α-ketone radicals to the styrene double bond
leads to a transient radical A (eq 4), which combines with
hydroxyl radical or tert-butylperoxyl radical to generate
intermediate B3,10 or B′2,14 (eq 5). Finally, intermediate B or
B′ can form the target product in the presence of metal
catalysts or DBU (eq 6).
Scheme 3. Two Unexpected Results
In summary, we have developed a copper/manganese-
cocatalyzed direct oxidative coupling of terminal vinylarenes
with ketones via C(sp3)−H bond functionalization to generate
1,4-dicarbonyls. Various ketones and terminal vinylarenes can
be smoothly converted into the corresponding products in
moderate yields with good functional group tolerance. This
strategy offers a new method to synthesize useful functionalized
complex molecules directly using simple and inexpensive
reactants. A free-radical pathway was involved in this method.
Further studies regarding the detailed mechanism are currently
underway in our laboratory.
To confirm the radical mechanism, two radical inhibitors,
tetramethylpiperidin-1-oxyl (TEMPO) and 2,6-di-tert-butylphe-
nol (BHT), were introduced to the reaction: 2.0 equiv of
radical inhibitors resulted in a very low yield, and no reaction
occurred when 4.0 equiv of radical inhibitor was used, which
provided good evidence to support a radical pathway for the
reaction (see the Supporting Information). To verify the
mechanism, we have also tried to use the intermediated tert-
butylperoxide B to directly transform to the desired product
under the standard conditions, and a 82% yield of the desired
product was obtained, implying B functions as a major reaction
intermediate in this transformation. Meanwhile, a 17% yield of
the desired product was achieved when benzyl alcohol B′ was
used as a substrate under the same conditions, indicating B′ can
be partly oxidized to 1,4-dicarbonyl product (see the
Supporting Information). On the basis of our experimental
results and previous reports,3,4,10,12−14 a tentative mechanism
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02116.
Experimental procedures and copies of spectra for all the
compounds (PDF)
C
DOI: 10.1021/acs.orglett.5b02116
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(11) (a) Wang, J.; Liu, C.; Yuan, J. W.; Lei, A. W. Angew. Chem., Int.
Ed. 2013, 52, 2256. (b) Majji, G.; Guin, S.; Rout, S. K.; Behera, A.;
Patel, B. K. Chem. Commun. 2014, 50, 12193. (c) Zhu, Y. F.; Wei, Y. Y.
Chem. Sci. 2014, 5, 2379.
(12) (a) Wei, W. T.; Song, R. J.; Li, J. H. Adv. Synth. Catal. 2014, 356,
1703. (b) Wei, W. T.; Yang, X. H.; Li, H. B.; Li, J. H. Adv. Synth. Catal.
2015, 357, 59.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: nxwang@mail.ipc.ac.cn. Tel: +86-10-82543575. Fax:
+86-10-62554670.
*E-mail: xingy@wpunj.edu
Notes
(13) Singh, R.; Allam, B. K.; Singh, N.; Kumari, K.; Singh, S. K.;
Singh, K. N. Org. Lett. 2015, 17, 2656.
(14) Zhang, J. X.; Wang, Y. J.; Zhang, W.; Wang, N. X.; Bai, C. B.;
Xing, Y. L.; Li, Y. H.; Wen, J. L. Sci. Rep. 2014, 4, 7446.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this research was provided by the Natural
Science Foundation of China (21172227).
REFERENCES
■
(1) For recent examples, see: (a) Taniguchi, T.; Fujii, T.; Ishibashi,
H. J. Org. Chem. 2010, 75, 8126. (b) Xue, Q. C.; Xie, J.; Xu, P.; Hu, K.
D.; Cheng, Y. X.; Zhu, C. J. ACS Catal. 2013, 3, 1365. (c) Jiang, X. Y.;
Qing, F. L. Angew. Chem., Int. Ed. 2013, 52, 14177. (d) Lu, Q. Q.;
Zhang, J.; Wei, F. L.; Qi, Y.; Wang, H. M.; Liu, Z. L.; Lei, A. W. Angew.
Chem., Int. Ed. 2013, 52, 7156. (e) Sun, X.; Li, X. Y.; Song, S.; Zhu, Y.
C.; Liang, Y. F.; Jiao, N. J. Am. Chem. Soc. 2015, 137, 6059. (f) Yang,
Y.; Liu, Y. L.; Jiang, Y.; Zhang, Y.; Vicic, D. A. J. Org. Chem. 2015, 80,
6639. (g) Yang, B.; Xu, X. H.; Qing, F. L. Org. Lett. 2015, 17, 1906.
(h) Li, Y.; Hartmann, M.; Daniliuc, C. G.; Studer, A. Chem. Commun.
2015, 51, 5706. (i) Wickens, Z. K.; Guzman
Angew. Chem., Int. Ed. 2015, 54, 236.
́
, P. E.; Grubbs, R. H.
(2) For recent examples and reviews, see: (a) Liu, W. P.; Li, Y. M.;
Liu, K. S.; Li, Z. P. J. Am. Chem. Soc. 2011, 133, 10756. (b) Kuhl, N.;
Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Angew. Chem., Int.
Ed. 2012, 51, 10236. (c) Deb, A.; Manna, S.; Modak, A.; Patra, T.;
Maity, S.; Maiti, D. Angew. Chem., Int. Ed. 2013, 52, 9747. (d) Wu, X.
F.; Fang, X. J.; Wu, L. P.; Jackstell, R.; Neumann, H.; Beller, M. Acc.
Chem. Res. 2014, 47, 1041. (e) Liu, C.; Liu, D.; Lei, A. W. Acc. Chem.
Res. 2014, 47, 3459. (f) Yan, H.; Lu, L. H.; Rong, G. W.; Liu, D. F.;
Zheng, Y.; Chen, J.; Mao, J. C. J. Org. Chem. 2014, 79, 7103.
(g) Chatalova-Sazepin, C.; Wang, Q.; Sammis, G. M.; Zhu, J. P. Angew.
Chem., Int. Ed. 2015, 54, 5443. (h) Yang, L.; Huang, H. M. Chem. Rev.
2015, 115, 3468.
(3) Cheng, K.; Huang, L. H.; Zhang, Y. H. Org. Lett. 2009, 11, 2908.
(4) Cheng, J. K.; Loh, T. P. J. Am. Chem. Soc. 2015, 137, 42.
(5) Yang, X. H.; Wei, W. T.; Li, H. B.; Song, R. J.; Li, J. H. Chem.
Commun. 2014, 50, 12867.
(6) Wei, W.; Ji, J. X. Angew. Chem., Int. Ed. 2011, 50, 9097.
(7) For recent examples, see: (a) Antonchick, A. P.; Burgmann, L.
Angew. Chem., Int. Ed. 2013, 52, 3267. (b) Liu, D.; Liu, C.; Li, H.; Lei,
A. W. Angew. Chem., Int. Ed. 2013, 52, 4453. (c) Liu, D.; Liu, C.; Li,
H.; Lei, A. W. Chem. Commun. 2014, 50, 3623. (d) Li, Z. J.; Zhang, Y.;
Zhang, L. Z.; Liu, Z. Q. Org. Lett. 2014, 16, 382. (e) Zhou, L. L.; Tang,
S.; Qi, X. T.; Lin, C. T.; Liu, K.; Liu, C.; Lan, Y.; Lei, A. W. Org. Lett.
2014, 16, 3404. (f) Ke, J.; Tang, Y. L.; Yi, H.; Li, Y. L.; Cheng, Y. D.;
Liu, C.; Lei, A. W. Angew. Chem., Int. Ed. 2015, 54, 6604. (g) Liu, D.;
Li, Y. X.; Qi, X. T.; Liu, C.; Lan, Y.; Lei, A. W. Org. Lett. 2015, 17, 998.
(h) Bunescu, A.; Wang, Q.; Zhu, J. P. Org. Lett. 2015, 17, 1890.
(8) (a) Taniguchi, T.; Sugiura, Y.; Zaimoku, H.; Ishibashi, H. Angew.
Chem., Int. Ed. 2010, 49, 10154. (b) Majji, G.; Guin, S.; Rout, S. K.;
Behera, A.; Patel, B. K. Chem. Commun. 2014, 50, 12193.
(9) (a) Matsumoto, S.; Okubo, Y.; Mikami, K. J. Am. Chem. Soc.
1998, 120, 4015. (b) Yoo, E. J.; Wasa, M.; Yu, J. Q. J. Am. Chem. Soc.
́
2010, 132, 17378. (c) Fernandez, M.; Uria, U.; Vicario, J. L.; Reyes, E.;
Carrillo, L. J. Am. Chem. Soc. 2012, 134, 11872. (d) Xie, J.; Huang, Z.
Z. Chem. Commun. 2010, 46, 1947. (e) Liu, C.; Deng, Y.; Wang, J.;
Yang, Y. Y.; Tang, S.; Lei, A. W. Angew. Chem., Int. Ed. 2011, 50, 7337.
(f) Zhang, F.; Du, P.; Chen, J. J.; Wang, H. X.; Luo, Q.; Wan, X. B.
Org. Lett. 2014, 16, 1932.
(10) Schweitzer-Chaput, B.; Demaerel, J.; Engler, H.; Klussmann, M.
Angew. Chem., Int. Ed. 2014, 53, 8737.
D
DOI: 10.1021/acs.orglett.5b02116
Org. Lett. XXXX, XXX, XXX−XXX