Cobalt(II)-Catalyzed Oxidative C-H Arylation of Indoles and Boronic Acids

Article abstract of DOI:10.1021/acs.orglett.6b03746

Co(II)-catalyzed C-H C2 selective arylation of indoles with boronic acids through monodentate chelation assistance has been achieved for the first time. The unique features of this methodology include mild reaction conditions, highly C2 regioselectivity, and employment of a Grignard reagent-free catalytic system. A wide range of substrates, including unreactive arenes, are well tolerated, which enables the construction of the coupling products efficiently. This new strategy provides an alternative and versatile approach to construct biaryls using inexpensive cobalt catalyst.

Full text of DOI:10.1021/acs.orglett.6b03746

Letter
pubs.acs.org/OrgLett
Cobalt(II)-Catalyzed Oxidative C−H Arylation of Indoles and Boronic
Acids
Xinju Zhu,‡ Jian-Hang Su,‡ Cong Du, Zheng-Long Wang, Chang-Jiu Ren, Jun-Long Niu,*
and Mao-Ping Song*
College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, P. R. China
S
* Supporting Information
ABSTRACT: Co(II)-catalyzed C−H C2 selective arylation of indoles with boronic acids through monodentate chelation
assistance has been achieved for the first time. The unique features of this methodology include mild reaction conditions, highly
C2 regioselectivity, and employment of a Grignard reagent-free catalytic system. A wide range of substrates, including unreactive
arenes, are well tolerated, which enables the construction of the coupling products efficiently. This new strategy provides an
alternative and versatile approach to construct biaryls using inexpensive cobalt catalyst.
and concerted metalation-deprotonation (CMD) process.12
he biaryl framework is a key structural motif with wide
Tapplications in pharmaceutical drugs, natural products, However, organoboronates are stable and effective coupling
and functional materials.1 The traditional synthetic method-
reagents for versatile Pd-, Rh-, and Ru-catalyzed trans-
formations, including the well-known Suzuki−Miyaura cou-
pling.13 To the best of our knowledge, cobalt-catalyzed direct
arylation of aromatics using organoboron reagents as the
coupling reagents without Grignard reagents has not been
reported. As the continuation of our interest in Co(II)-
catalyzed C−H functionalizations,12,14 we herein report the first
example of Co(II)-catalyzed regioselective C-2 arylation of
indoles with boronic acids in the absence of Grignard reagents.
We commenced our study on the coupling of 1-(pyrimidin-
2-yl)-1H-indole 1a with phenylboronic acid 2a using the N-
pyrimidine as a removable directing group. Initially, various
solvents were screened, which indicates HFIP is the best choice
to afford the desired product 3aa in 34% yield in the presence
of 20 mol % of Co(OAc)2·4H2O and 2 equiv of Mn(OAc)2·
4H2O at 90 °C for 12 h (Table 1, entry 1). Dioxane, CH3CN,
toluene, DMSO, and other alcohols led to only trace or no
desired arylated product (see the Supporting Information).
Subsequently, other cobalt catalysts, such as CoC2O4·4H2O,
Co(acac)2, and Co(acac)3 were tested, and Co(acac)2 afforded
the arylated 3aa in 65% yield (Table 1, entry 3). When the
reaction was performed at 60 °C, an increased yield of 80% was
obtained (Table 1, entry 5). Either elevated or lower
temperature was disadvantage for the reaction activity (see
the Supporting Information). However, it should be noted that
54% yield could still be achieved at 30 °C for 12 h (Table 1,
entry 6). Next, the oxidant effect on the reaction was
ology for aryl−aryl bond formation relied on transition-metal-
catalyzed cross-coupling reactions between aryl halides and
organometallic reagents.2 In the past decades, C−H arylation
has emerged as a promising and efficient alternative to form
C(sp2)−C(sp2) bonds, which is more environmentally friendly
and atom-economic.3 Meanwhile, transition-metal-catalyzed
oxidative coupling between two different C−H bonds was
also developed.4 However, up to now, the arylation of arenes
has been mostly limited to Pd and other noble transition
metals.5 To reduce the costs and toxicity, much attention has
been paid to the development of abundant and inexpensive
metals for comparable C−H arylation efficiencies.6
As a representative first-row transition metal, cobalt-based
homogeneous catalysis has been investigated extensively in view
of its versatile and unique activities in organic transformations.7
Since 2011, Shi, Ackermann, and Yoshikai have made
pioneering contributions to C−H arylation of unreactive arenes
with aryl halides or phenol-derived electrophiles catalyzed by
low-valent cobalt catalysts.8−10 To regenerate in situ active
Co−NHC complexes, Grignard regents were utilized as the
bases and reductants. Despite the above-mentioned achieve-
ments, the use of the strong Grignard reagents as the base is the
major limitation, which restricts the scope of aryl electrophiles
and leads to undesirable coupling reactions. Thus, it would
further expand the catalytic versatility of cobalt catalyst if a
Grignard reagent free condition is accomplished.11
Recently, a mixed directing-group strategy was employed to
achieve oxidative C−H/C−H bond arylation of unreactive
arenes via the combination of single-electron transfer (SET)
Received: December 16, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03746
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the desired product 3aa−3ai in moderate to excellent yields,
irrespective of electronic effects. Notably, strongly electron-
withdrawing CF3 group was tolerated to afford 3aj in 76% yield.
The current protocol could further expand to other types of
(hetero)aromatic and aliphatic boronic acids with arylated
product 3ak−3an obtained in moderate yields.
Table 1. Optimization of Cobalt-Catalyzed Arylation
Reaction between 1a and 2a
a
Encouraged by the above results, the scope of indole
substrates was investigated to test the generality of current
methodology (Scheme 2). To our delight, a range of substrates
b
entry
catalyst
cooxidant
temp (°C) yield (%)
1
2
3
4
5
6
7
8
9
Co(OAc)2·4H2O
CoC2O4·4H2O
Co(acac)2
Mn(OAc)2·4H2O
Mn(OAc)2·4H2O
Mn(OAc)2·4H2O
Mn(OAc)2·4H2O
Mn(OAc)2·4H2O
Mn(OAc)2·4H2O
Ag2O
90
90
90
90
60
30
60
60
60
60
34
11
65
60
80
54
9
Scheme 2. Co(II)-Catalyzed Direct Arylation of Various
a
Indoles with Phenylboronic Acid
Co(acac)3
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
PhI(OAc)2
8
Co(acac)2
O2
19
90
c
10
Co(acac)2
Mn(OAc)2·4H2O
a
Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), [Co] salt (20
mol %), cooxidant (0.4 mmol), HFIP (1.0 mL), air atmosphere, 12 h.
b
c
Isolated yield. 2a (0.4 mmol). acac = acetylacetonate, HFIP =
1,1,1,3,3,3-hexafluoro-2-propanol.
investigated, which reveals that Mn(OAc)2·4H2O was the
optimal reagent and showed highest reactivity (Table 1, entries
7−9). Moreover, it was observed that neither basic nor acidic
additives were required to fulfill the reaction (see the
Supporting Information). Lastly, the catalytic efficiency was
further improved by adjusting the amount of 2a to deliver the
corresponding product 3aa in 90% yield (Table 1, entry 10).
With the optimized conditions in hand, a variety of
functionalized boronic acids were first examined in the Co-
catalyzed C−H arylation (Scheme 1). The reaction worked well
for meta- and para-substituted arylboronic acids and delivered
Scheme 1. Co(II)-Catalyzed Direct Arylation of Indole with
a
Various Boronic Acids
a
Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), Co(acac)2 (20
mol %), Mn(OAc)2·4H2O (0.4 mmol), HFIP (1.0 mL), air
b
atmosphere, 12 h, 60 °C. Co(acac)2 (30 mol %), 80 °C.
bearing various functional groups proceeded smoothly and gave
the corresponding products in good yields. Notably, both
electron-donating and electron-withdrawing groups, including
methoxy (3ca), phenylmethoxy (3ja), methyl (3ba and 3da),
fluoro (3ea and 3ka), chloro (3fa and 3la), bromo (3ga), cyano
(3ha and 3ma), and ester (3ia) substituents were well
tolerated. Another substrate, such as pyrrole 1n, was employed,
and the corresponding products 3na was obtained in 40% yield.
Moreover, this protocol was not restricted to pyrimidine
directing group. The pyridine equipped indoles 1o−1t could
still react with 2a effectively to provide the arylated products in
57−90% yields.
The current Co-catalyzed C−H transformation could further
be extended to arene-containing substrates, which delivered the
arylated product 5a−5c in 46−60% yields (Scheme 3). Overall,
compared with other metal catalysts, similar efficiencies could
be achieved for indole substrates, while lower yields were
achieved for unreactive arenes with limited substrate scopes.
To gain insight into the reaction mechanism, a set of control
experiments was conducted (Scheme 4). In the competitive
studies, when an equimolar mixture of 1a and [D1]-1a was
a
Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), Co(acac)2 (20
mol %), Mn(OAc)2·4H2O (0.4 mmol), HFIP (1.0 mL), air
atmosphere, 12 h, 60 °C. 2 (0.8 mmol), Co(acac)2 (30 mol %), 48 h.
b
B
DOI: 10.1021/acs.orglett.6b03746
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Co(II)-Catalyzed Direct Arylation of Arene-
Containing Substrates
Scheme 5. Proposed Reaction Mechanism
a
a
Reaction conditions: 4 (0.2 mmol), 2a (0.4 mmol), Co(acac)2 (20
mol %), Mn(OAc)2·4H2O (0.4 mmol), HFIP (1.0 mL), air
b
c
atmosphere, 12 h, 60 °C. Co(acac)2 (30 mol %), 80 °C. 2a (0.8
mmol), Co(acac)2 (30 mol %), 48 h.
Scheme 4. Mechanistic Studies
presence of Mn(OAc)2·4H2O as the cooxidant under an air
atmosphere. This methodology enables the facile construction
of various arylated indoles, which is operationally convenient,
cost-effective, and Grignard reagent-free. The pyrimidine
auxiliary could be easily removed under the basic hydrolysis.
This protocol could provide new insight into Co-catalyzed
arylation, which paves the way for other types of inexpensive
Co-catalyzed C−C cross-coupling reactions.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03746.
Experimental procedures and NMR spectra data for new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
employed, a kinetic isotope effect (KIE) value of 1.4 was
obtained. Also, a KIE value of 2.0 was observed between 1a or
[D1]-1a with 2a, respectively, in the parallel experiments, which
indicates that Co-catalyzed C−H bond cleavage is the rate-
determining step (Scheme 4, eq 1). In the absence of
Mn(OAc)2·4H2O, the employment Co(acac)2 alone led to no
desired product, while 11% yield was obtain when Co(acac)3
was utilized under the Ar atmosphere. In the presence of
Co(acac)2, no product was detected when Mn(OAc)2·4H2O
was introduced under Ar, while 3aa was isolated in 18% yield
with Mn(OAc)3·4H2O applied (Scheme 4, eq 2). These results
indicate that the reaction probably commenced from an in situ
generated Co(III) species in the presence of Mn(OAc)2·4H2O
and oxygen (from air).12 Next, when the radical quencher,
including TEMPO, BHT, or BQ, was added, no desired
product 3aa was formed, which implies that a SET pathway
might be involved during the reaction (Scheme 4, eq 3).
On the basis of the above mechanistic studies and previous
reports,12 a plausible catalytic cycle is illustrated in Scheme 5.
Initially, oxygen oxidized MnII to MnIII or MnIV complex, which
reacted with CoII to generate CoIII species. Next, complex 1a
underwent a CMD process to produce intermediate I. The
reaction between phenylboronic acid 2a and MnIII provided a
phenyl radical,15 which attacked the intermediate I to form
intermediate II. Lastly, the desired product 3aa was obtained by
reductive elimination, accompanied by the regeneration of CoII
to fulfill the catalytic cycle.
■
*E-mail: niujunlong@zzu.edu.cn.
*E-mail: mpsong@zzu.edu.cn.
ORCID
Mao-Ping Song: 0000-0003-3883-2622
Author Contributions
‡X.Z. and J.-H.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The work described in this letter was supported by the National
Natural Science Foundation of China (Nos. 21502173,
21272217) and Outstanding Young Talent Research Fund of
Zhengzhou University (No. 1521316002).
REFERENCES
■
(1) (a) Wencel-Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369.
(b) Segawa, Y.; Maekawa, T.; Itami, K. Angew. Chem., Int. Ed. 2015, 54,
66−81.
(2) (a) de Meijere, A., Diederich, F., Eds. Metal-Catalyzed Cross-
Coupling Reactions; Wiley-VCH: Weinheim, 2004. (b) Ackermann, L.,
Ed. Modern Arylation Methods; Wiley-VCH: Weinheim, 2009.
(c) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.;
Resmerita, A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2011, 111, 1346.
(d) Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.;
Snieckus, V. Angew. Chem., Int. Ed. 2012, 51, 5062−5085.
In conclusion, we have developed a Co(acac)2-catalyzed
oxidative C2 arylation of indoles with boronic acids in the
C
DOI: 10.1021/acs.orglett.6b03746
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(3) For selective reviews of transition-metal catalyzed C−H
arylations, see: (a) Baudoin, O. Chem. Soc. Rev. 2011, 40, 4902.
(b) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed.
2009, 48, 9792. (c) Hussain, I.; Singh, T. Adv. Synth. Catal. 2014, 356,
1661. (d) Chen, Z.; Wang, B.; Zhang, J.; Yu, W.; Liu, Z.; Zhang, Y.
Org. Chem. Front. 2015, 2, 1107. (e) Rao, W.-H.; Shi, B.-F. Org. Chem.
Front. 2016, 3, 1028.
C.; Zhu, X.; Li, P.-X.; Zhang, J.-H.; Niu, J.-L.; Song, M.-P. Org. Lett.
2016, 18, 3610.
(15) For the formation of a phenyl radical in the presence of
Mn(acac)2·2H2O and oxygen, see: Wang, H.; Yu, Y.; Hong, X.; Xu, B.
Chem. Commun. 2014, 50, 13485.
(4) For selective reviews of oxidative coupling between two different
C−H bonds, see: (a) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev.
2011, 111, 1780. (b) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (c) Girard,
S. A.; Knauber, T.; Li, C.-J. Angew. Chem., Int. Ed. 2014, 53, 74.
(5) For selective reviews, see: (a) Alberico, D.; Scott, M. E.; Lautens,
M. Chem. Rev. 2007, 107, 174. (b) Daugulis, O.; Do, H.-Q.;
Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. For other
representative examples, see (c) Nishikata, T.; Abela, A. R.; Huang,
S.; Lipshutz, B. H. J. Am. Chem. Soc. 2010, 132, 4978. (d) Karthikeyan,
J.; Haridharan, R.; Cheng, C.-H. Angew. Chem., Int. Ed. 2012, 51,
12343. (e) Luo, J.; Preciado, S.; Larrosa, L. J. Am. Chem. Soc. 2014,
136, 4109. (f) Zheng, J.; Zhang, Y.; Cui, S. Org. Lett. 2014, 16, 3560.
(g) Wang, L.; Qu, X.; Li, Z.; Peng, W.-M. Tetrahedron Lett. 2015, 56,
3754. (h) Tiwari, V. K.; Kamal, N.; Kapur, M. Org. Lett. 2015, 17,
1766. (i) Sollert, C.; Devaraj, K.; Orthaber, A.; Gates, P. J.; Pilarski, L.
T. Chem. - Eur. J. 2015, 21, 5380. (j) Yang, Y.; Qiu, X.; Zhao, Y.; Mu,
Y.; Shi, Z. J. Am. Chem. Soc. 2016, 138, 495. (k) Biafora, A.; Krause, T.;
Hackenberger, D.; Belitz, F.; Gooβen, L. J. Angew. Chem., Int. Ed. 2016,
55, 14752. (l) Nareddy, P.; Jordan, F.; Brenner-Moyer, S. E.; Szostak,
M. ACS Catal. 2016, 6, 4755. (m) Wang, H.-W.; Cui, P.-P.; Sun, W.-
Y.; Yu, J.-Q. J. Org. Chem. 2016, 81, 3416. (n) Tu, D.; Cheng, X.; Gao,
Y.; Yang, P.; Ding, Y.; Jiang, C. Org. Biomol. Chem. 2016, 14, 7443.
(6) (a) Do, H.-Q.; Kashif Khan, R. M.; Daugulis, O. J. Am. Chem. Soc.
2008, 130, 15185. (b) Phipps, R. J.; Gaunt, M. J. Science 2009, 323,
1593. (c) Ilies, L.; Kobayashi, M.; Matsumoto, A.; Yoshikai, N.;
Nakamura, E. Adv. Synth. Catal. 2012, 354, 593. (d) Nishino, M.;
Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2012, 51, 6993.
(e) Shang, R.; Ilies, L.; Matsumoto, A.; Nakamura, E. J. Am. Chem. Soc.
2013, 135, 6030. (f) Cheng, Y.; Wu, Y.; Tan, G.; You, J. Angew. Chem.,
Int. Ed. 2016, 55, 12275. (g) Zhao, S.; Liu, B.; Zhan, B.-B.; Zhang, W.-
D.; Shi, B.-F. Org. Lett. 2016, 18, 4586.
(7) For selective reviews of cobalt-catalyzed C−H functionalizations,
see: (a) Hess, W.; Treutwein, J.; Hilt, G. Synthesis 2008, 22, 3537.
(b) Yoshikai, N. Synlett 2011, 2011, 1047. (c) Tilly, D.; Dayaker, G.;
Bachu, P. Catal. Sci. Technol. 2014, 4, 2756. (d) Pellissier, H.; Clavier,
H. Chem. Rev. 2014, 114, 2775. (e) Gao, K.; Yoshikai, N. Acc. Chem.
Res. 2014, 47, 1208. (f) Gandeepan, P.; Cheng, C.-H. Acc. Chem. Res.
2015, 48, 1194. (g) Yoshikai, N. ChemCatChem 2015, 7, 732.
(h) Ackermann, L. J. Org. Chem. 2014, 79, 8948. (i) Wei, D.; Zhu, X.;
Niu, J.-L.; Song, M.-P. ChemCatChem 2016, 8, 1242. (j) Moselage, M.;
Li, J.; Ackermann, L. ACS Catal. 2016, 6, 498.
(8) Li, B.; Wu, Z.-H.; Gu, Y.-F.; Sun, C.-L.; Wang, B.-Q.; Shi, Z.-J.
Angew. Chem., Int. Ed. 2011, 50, 1109.
(9) (a) Song, W.; Ackermann, L. Angew. Chem., Int. Ed. 2012, 51,
8251. (b) Punji, B.; Song, W.; Shevchenko, G. A.; Ackermann, L.
Chem. - Eur. J. 2013, 19, 10605. (c) Li, J.; Ackermann, L. Chem. - Eur. J.
2015, 21, 5718. (d) Mei, R.; Ackermann, L. Adv. Synth. Catal. 2016,
358, 2443.
(10) Gao, K.; Lee, P.-S.; Long, C.; Yoshikai, N. Org. Lett. 2012, 14,
4234.
(11) Hu, L.; Gui, Q.; Chen, X.; Tan, Z.; Zhu, G. Org. Biomol. Chem.
2016, 14, 11070.
(12) Du, C.; Li, P.-X.; Zhu, X.; Suo, J.-F.; Niu, J.-L.; Song, M.-P.
Angew. Chem., Int. Ed. 2016, 55, 13571.
(13) Lennox, A. J. J.; Lloyd-Jones, G. C. Chem. Soc. Rev. 2014, 43,
412.
(14) (a) Zhang, L.-B.; Hao, X.-Q.; Zhang, S.-K.; Liu, Z.-J.; Zheng, X.-
X.; Gong, J.-F.; Niu, J.-L.; Song, M.-P. Angew. Chem., Int. Ed. 2015, 54,
272. (b) Zhang, L.-B.; Hao, X.-Q.; Liu, Z.-J.; Zheng, X.-X.; Zhang, S.-
K.; Niu, J.-L.; Song, M.-P. Angew. Chem., Int. Ed. 2015, 54, 10012.
(c) Zhang, L.-B.; Zhang, S.-K.; Wei, D.; Zhu, X.; Hao, X.-Q.; Su, J.-H.;
Niu, J.-L.; Song, M.-P. Org. Lett. 2016, 18, 1318. (d) Hao, X.-Q.; Du,
D
DOI: 10.1021/acs.orglett.6b03746
Org. Lett. XXXX, XXX, XXX−XXX