Cobalt(III)- and Rhodium(III)-Catalyzed C-H Amidation and Synthesis of 4-Quinolones: C-H Activation Assisted by Weakly Coordinating and Functionalizable Enaminone

Article abstract of DOI:10.1021/acs.orglett.7b00583

Cobalt(III) and rhodium(III) catalysts exhibited complementary scope in C-H amidation of aryl enaminones. The amidation reactions proceeded with broad scope under the assistance of a weakly coordinating and bifunctional enaminone directing group. The electrophilicity of the enaminone group can be further utilized in subsequent hydrolysis-cyclization reactions to afford NH 4-quinolones in telescoping reactions.

Full text of DOI:10.1021/acs.orglett.7b00583

Letter
pubs.acs.org/OrgLett
Cobalt(III)- and Rhodium(III)-Catalyzed C−H Amidation and Synthesis
of 4‑Quinolones: C−H Activation Assisted by Weakly Coordinating
and Functionalizable Enaminone
Fen Wang,†,∥,§ Liang Jin,†,‡,§ Lingheng Kong,† and Xingwei Li*,†
†Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
‡School of Chemistry and Chemical Engineering, Dalian University of Technology, Dalian 116023, China
S
* Supporting Information
ABSTRACT: Cobalt(III) and rhodium(III) catalysts exhibited
complementary scope in C−H amidation of aryl enaminones.
The amidation reactions proceeded with broad scope under the
assistance of a weakly coordinating and bifunctional enaminone
directing group. The electrophilicity of the enaminone group
can be further utilized in subsequent hydrolysis−cyclization reactions to afford NH 4-quinolones in telescoping reactions.
iridium-catalyzed amidation of a variety of sp2 and sp3 C−H
he C−N linkage is one of the most important bonds in
1
Tpharmaceuticals and organic functional molecules. Tradi- bonds using this reagent. These early C−H amidation systems
resorted to arenes assisted by nonfunctionalizable directing
groups, and consequently, only simple amidation was realized.
Shortly afterward, Li,9 Zhu,10 Glorius,11 Ackermann,12 and
others13 extended it to amidation−cyclization systems where
participation of a nucleophilic NH directing group allowed
synthesis of quinazolines and their N-oxides.9−12 Despite the
progress, the DGs have been mostly limited to nitrogen
chelators, while weakly coordinating DGs have been only
occasionally used and are mostly limited to secondary
benzamides.5b,8b,14 On the other hand, ketone carbonyl groups
are readily functionalizable, but they have been rarely applied in
C−H activation due to their low coordinating ability.15 We
reasoned that the carbonyl group in enaminones is more
polarized and more coordinating, and it may accommodate C−
H amidation. Furthermore, enaminone contains both nucleo-
philic and electrophilic sites and can be readily functionalized in
postcoupling manipulations to allow for cyclization as have
been recently demonstrated by Zhu in C−H activation
(Scheme 1).16 We now report cobalt- and rhodium-catalyzed
C−H amidation of enaminones and synthesis of 4-quinolones
under operationally simple conditions.
tional methods to construct C−N bonds include the Goldberg
reaction, the Buchwald−Hartwig coupling, and the Chan−Lam
coupling.2 Although very efficient, these methods require the
employment of functionalized arene starting materials. In the
past decades, the C−H activation strategy has been extensively
explored, which takes advantage of readily available arene
substrates.3 Thus, C−H activation has provided an important
avenue to access C−N bonds in high atom- and step-economy,4
and a variety of nucleophilic and electrophilic amination/
amidation reagents have been developed (Scheme 1).5,6
In 2015, Chang applied dioxazolone as an amidating reagent
for the C−H amidation of arenes for the first time (Scheme 1).7
Later, Chang and others8 realized rhodium-, cobalt-, and
Scheme 1. Nitrogenation Reagents and C−H Activation of
Enaminone
We initiated our investigation with the optimization studies
on the coupling of enaminone 1a and dioxazolone 2a (Table
1). The expected amidation reaction proceeded in the presence
of a rhodium catalyst, but the yield was only moderate (entry
1). While the yield was lower using a CoCp*(CO)I2/AgSbF6
catalyst system in DCE (entry 2), introduction of NaOAc
additive improved the efficiency (entries 5−7). Further
screening returned KOAc as an optimal base additive (entry
8) and 1,4-dioxane as the best solvent (entry 7). In contrast, an
acid additive turned out to be essentially ineffective (entries 3
Received: February 26, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00583
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Letter
a
Table 1. Optimization Studies
b
entry
catalyst (mol %)
additive (equiv)
solvent
DCE
yield (%)
c
1
[RhCp*Cl2]2/AgSbF6
CoCp*(CO)I2/AgSbF6
CoCp*(CO)I2/AgSbF6
CoCp*(CO)I2/AgSbF6
CoCp*(CO)I2/AgSbF6
CoCp*(CO)I2/AgSbF6
CoCp*(CO)I2/AgSbF6
CoCp*(CO)I2/AgSbF6
CoCp*(CO)I2/AgSbF6
CoCp*(CO)I2/AgSbF6
CoCp*(CO)I2/AgSbF6
CoCp*(CO)I2/AgSbF6
CoCp*(CO)I2/AgSbF6
CoCp*(CO)I2/AgNTf2
AgSbF6
64
50
2
3
4
5
DCE
HOAc (2.0)
PivOH (2.0)
NaOAc (0.3)
NaOAc (0.3)
NaOAc (0.3)
KOAc (0.3)
AgOAc (0.2)
KOAc (0.3)
KOAc (0.5)
KOAc(0.3)
DCE
64
DCE
47
DCE
73
d
6
DCE
78
7
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
89
8
93
9
69
10
11
68
84
e
12
d
85
13
KOAc (0.3)
NaOAc(0.3)
KOAc (0.3)
69
14
15
trace
NR
a
Unless otherwise noted, all reactions were carried out using 1a (0.20 mmol), 2a (0.30 mmol), and a cobalt catalyst (10 mol %) in the presence of a
b
c
silver additive (20 mol %) in a solvent (2.0 mL) at 100 °C for 12 h under Ar. Isolated yield. [RhCp*Cl2]2 (4 mol %) and AgSbF6 (16 mol %) were
used. The reaction temperature is 120 °C. The reaction temperature is 80 °C.
d
e
and 4). Decreasing the loading of the catalyst, variation of the
amount of KOAc additive, or lowering the temperature all
resulted in somewhat lower yield. Thus, the following optimal
reaction conditions (conditions A) have been established for
further studies: Cp*Co(CO)I2 (10 mol %), AgSbF6 (20 mol
%), and KOAc (30 mol %) in 1,4-dioxane at 100 °C for 12 h.
With the optimized reaction conditions in hand, we next
examined the scope of this system (Scheme 2). The scope of
enaminone was explored in the coupling with 2a. It was found
that enaminones bearing an electron-donating (3ba, 3ca),
-withdrawing (3ga), or halogen group (3ea, 3fa, 3ha) at the
para position generally coupled under the cobalt-catalyzed
conditions in excellent yields. To our surprise, a para t-Bu-
substituted enaminone failed to undergo any coupling with 2a,
and this negative effect has been observed in our previous
indole synthesis via Rh(III)-catalyzed C−H activation of N-
pyridylanilines.17 The low yield of Co(III) catalysis is probably
due to catalyst decomposition. Gratifyingly, this limitation was
resolved when typical Rh(III)-catalyzed amidation conditions
were applied (conditions B), and the desired product (3da) was
isolated in good yield. Introduction of meta Me and OMe
groups is also tolerated, and the coupling occurred at the less
hindered position (3ja, 3ka). Interestingly, the coupling of a
meta fluoro-substituted enamonine afforded two products. The
C−H activation at the less hindered site gave a regular
amidated product 3na, while C−H activation at the more
hindered ortho site delivered an N-benzoyl-4-quinolone (4na)
as a result of further nucleophilic cyclization of the
corresponding amide intermediate. This scenario of amida-
tion−cyclization was also observed in the coupling of an acetal-
fused enaminone (4oa), indicative of the intrinsic stereo-
electronic effect of these two substrates. Introduction of a m-Cl
group or a fused benzene ring was also allowed (3la and 3ma),
but only under the Rh(III)-catalyzed conditions, and the
amidated products were isolated in good to high yield. The
reaction proved sensitive to steric perturbation at the ortho
Scheme 2. Scope of Enaminones in Amidation
position. Nevertheless, an o-fluoro-substituted enaminone
reacted with moderate efficiency under our Rh(III)-catalyzed
conditions (3ia). Furthermore, the C−H activation was not
limited to a benzene ring; a thiophene-based enaminone also
B
DOI: 10.1021/acs.orglett.7b00583
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Letter
reacted in high efficiency under the cobalt-catalyzed conditions
(3pa).
Scheme 4. Telescoping Synthesis of NH Isoquinolones
The scope of dioxazolone substrates was next explored using
1a as a coupling partner (Scheme 3). Introduction of both
Scheme 3. Scope of Dioxazolones in Amidation Reaction
3aa with a simple hydrazine or a phenylhydrazine afforded a
pyrazole in good to high yield, with the amide functionality
being intact (eq 1).
Several experiments have been performed to briefly probe
the mechanism (Scheme 5). H/D exchange experiment has
Scheme 5. Preliminary Mechanistic Studies
electron-donating and -withdrawing groups to the ortho, meta,
and para positions of the 3-aryldioxazolone is fully tolerated,
and the amidated product was isolated in moderate to excellent
yield as the sole coupled product (3ab−an, 46−94%), although
a relatively lower yield was observed for an o-Me substituted
dioxazolone (3an) due to steric effect. The incorporated
halogen and cyano groups should allow further manipulation of
the coupled products. In addition, the 3-aryldioxazolone has
been extended to 3-heteroaryl (3ao) and -alkyl (3ap)
substitution with essentially no loss of coupling efficiency.
Although the amidated product failed to undergo cyclization
in situ in most cases, we reasoned that this can be possible
under ex situ conditions. Although attempts to cyclize product
3aa met with failure when catalyzed by Lewis acidic metals such
as Au(I) or Au(III), treatment of 3aa with hydrochloric acid led
to formation of an NH quinolone 5a in 92% yield as a result of
hydrolysis−cyclization. In contrast, treatment of thiophene-
based amination product 3pa, however, gave no desired
product. Nevertheless, these two processes have been
successfully combined in a telescoping synthesis for seven
examples (Scheme 4). Thus, the two-stage synthesis of NH
quinolones was realized in good to high yield. In these
reactions, both electron-donating and -withdrawing groups at
the para and meta positions of the enaminone substrate were
well tolerated. Besides formation of quinolones, heating amide
been performed between enaminone 1a and CD3COOD under
conditions A in the absence of any amidating reagent. 1H NMR
analysis of the recovered (94% yield) enaminone revealed slight
H/D exchange (10% D) at both ortho positions, and no
exchange at any other position has been observed, indicative of
relevancy of C−H activation. To further understand this C−H
activation process, the kinetic isotope effect has been measured
using both a side-by-side reaction (KIE = 4.9) and an
intermolecular competition reaction (KIE = 5.7). Consistent
large values of KIE have been obtained from these two
reactions, suggesting that C−H activation is involved in the
turnover-limiting process (see the SI for a proposed catalytic
cycle).
C
DOI: 10.1021/acs.orglett.7b00583
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
356, 1443. (j) Ackermann, L. Acc. Chem. Res. 2014, 47, 281. (k) Chen,
Z.; Wang, B.; Zhang, J.; Yu, W.; Liu, Z.; Zhang, Y. Org. Chem. Front.
2015, 2, 1107. (l) Song, G.; Li, X. Acc. Chem. Res. 2015, 48, 1007.
(4) For reviews on C−H amination reactions, see: (a) Cho, S. H.;
Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068.
(b) Collet, F.; Lescot, C.; Dauban, P. Chem. Soc. Rev. 2011, 40, 1926.
(c) Jeffrey, J. L.; Sarpong, R. Chem. Sci. 2013, 4, 4092. (d) Shin, K.;
Kim, H.; Chang, S. Acc. Chem. Res. 2015, 48, 1040. (e) Louillat, M.-L.;
Patureau, F. W. Chem. Soc. Rev. 2014, 43, 901. (f) Jiao, J.; Murakami,
K.; Itami, K. ACS Catal. 2016, 6, 610. (g) Subramanian, P.; Rudolf, G.
C.; Kaliappan, K. P. Chem. - Asian J. 2016, 11, 168. (h) Park, Y.; Kim,
Y.; Chang, S. Chem. Rev. 2017, DOI: 10.1021/acs.chemrev.6b00644.
(5) For selected examples using organic azides as the amino source,
see: (a) Kim, J.; Park, S.; Ryu, J.; Cho, S.; Kim, S.; Chang, S. J. Am.
Chem. Soc. 2012, 134, 9110. (b) Ryu, J.; Kwak, J.; Shin, K.; Lee, D.;
Chang, S. J. Am. Chem. Soc. 2013, 135, 12861. (c) Hwang, H.; Kim, J.;
Jeong, J.; Chang, S. J. Am. Chem. Soc. 2014, 136, 10770. (d) Zheng, Q.;
Liang, Y.; Qin, C.; Jiao, N. Chem. Commun. 2013, 49, 5654.
(e) Thirunavukkarasu, V.; Raghuvanshi, K.; Ackermann, L. Org. Lett.
2013, 15, 3286. (f) Yu, D.; Suri, M.; Glorius, F. J. Am. Chem. Soc. 2013,
135, 8802. (g) Liu, B.; Li, B.; Wang, B. Chem. Commun. 2015, 51,
16334. (h) Yadav, M.; Rit, R.; Sahoo, A. Org. Lett. 2013, 15, 1638.
(6) (a) Kim, H.; Shin, K.; Chang, S. J. Am. Chem. Soc. 2014, 136,
5904. (b) Suzuki, C.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2015,
17, 1597. (c) Huang, X.; Wang, Y.; Lan, J.; You, J. Angew. Chem., Int.
Ed. 2015, 54, 9404. (d) Grohmann, C.; Wang, H.; Glorius, F. Org. Lett.
2012, 14, 656. (e) Gwon, D.; Hwang, H.; Kim, H. K.; Marder, S. R.;
Chang, S. Chem. - Eur. J. 2015, 21, 17200. (f) Albone, D. P.;
Challenger, S.; Derrick, A. M.; Fillery, S. M.; Irwin, J. L.; Parsons, C.
M.; Takada, H.; Taylor, P. C.; Wilson, D. J. Org. Biomol. Chem. 2005,
3, 107. (g) Yu, S.; Wan, B.; Li, X. Org. Lett. 2013, 15, 3706.
(h) Grohmann, C.; Wang, H.; Glorius, F. Org. Lett. 2013, 15, 3014.
(i) Zhu, D.; Yang, G.; He, J.; Chu, L.; Chen, G.; Gong, W.; Chen, K.;
Eastgate, M. D.; Yu, J.-Q. Angew. Chem., Int. Ed. 2015, 54, 2497. (j) Yu,
S.; Tang, G.; Li, Y.; Zhou, X.; Lan, Y.; Li, X. Angew. Chem., Int. Ed.
2016, 55, 8696. (k) Yu, S.; Li, Y.; Zhou, X.; Wang, H.; Kong, L.; Li, X.
Org. Lett. 2016, 18, 2812. (l) Zou, M.; Liu, J.; Tang, C.; Jiao, N. Org.
Lett. 2016, 18, 3030. (m) Shi, L.; Wang, B. Org. Lett. 2016, 18, 2820.
(7) Park, Y.; Park, K. T.; Kim, J. G.; Chang, S. J. Am. Chem. Soc. 2015,
137, 4534.
In summary, we have applied enaminone as a weakly
coordinating directing group to realize the amidation of a broad
scope of arenes. Cobalt and rhodium catalysts are both efficient
for this transformation, and they offered complementary scope
of substrates. In most cases, only simple amidation was
achieved. Occasionally, the C−H amidation was followed by
cyclization to give N-acyl 4-quinolones under the catalytic
conditions. The enaminone acts as an electrophilic directing
group as in subsequent hydrolysis−cyclization reactions to
afford diverse NH quinolones in telescoping reactions. Given
the broad scope of substrates, ready functionalization of the
enaminone, and diversity of the coupled products, this method
may find applications in the synthesis of complex structures.
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.7b00583.
Detailed experimental procedures, characterization of
new compounds, and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xwli@dicp.ac.cn.
ORCID
Xingwei Li: 0000-0002-1153-1558
Present Address
∥(F.W.) School of Chemistry, University of Manchester,
Manchester M13 9PL, UK.
Author Contributions
§F.W. and L.J. contributed equally.
Notes
(8) (a) Wang, H.; Tang, G.; Li, X. Angew. Chem., Int. Ed. 2015, 54,
13049. (b) Park, J.; Chang, S. Angew. Chem., Int. Ed. 2015, 54, 14103.
(c) Barsu, N.; Rahman, M. A.; Sen, M.; Sundararaju, B. Chem. - Eur. J.
2016, 22, 9135. (d) Park, Y.; Heo, J.; Baik, M.-H.; Chang, S. J. Am.
Chem. Soc. 2016, 138, 14020. (e) Jeon, M.; Mishra, N. K.; De, U.;
Sharma, S.; Oh, Y.; Choi, M.; Jo, H.; Sachan, R.; Kim, H. S.; Kim, I. S.
J. Org. Chem. 2016, 81, 9878. (f) Mishra, N. K.; Oh, Y.; Jeon, M.; Han,
S.; Sharma, S.; Han, S. H.; Um, S. H.; Kim, I. S. Eur. J. Org. Chem.
2016, 2016, 4976.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the NSFC (Nos. 21472186 and
21525208) and the Fund for New Technology of Methanol
Conversion of Dalian Institute of Chemical Physics (Chinese
Academy of Sciences) is gratefully acknowledged.
(9) (a) Wang, F.; Wang, H.; Wang, Q.; Yu, S.; Li, X. Org. Lett. 2016,
18, 1306. (b) Wang, Q.; Wang, F.; Yang, X.; Zhou, X.; Li, X. Org. Lett.
2016, 18, 6144.
(10) Wang, J.; Zha, S.; Chen, K.; Zhang, F.; Song, C.; Zhu, J. Org.
Lett. 2016, 18, 2062.
(11) Wang, X.; Lerchen, A.; Glorius, F. Org. Lett. 2016, 18, 2090.
(12) Wang, H.; Lorion, M.; Ackermann, L. Angew. Chem., Int. Ed.
2016, 55, 10386.
(13) Huang, J.; Huang, Y.; Wang, T.; Huang, Q.; Wang, Z.; Chen, Z.
Org. Lett. 2017, 19, 1128.
REFERENCES
■
(1) (a) Kim, J.; Movassaghi, M. Acc. Chem. Res. 2015, 48, 1159.
(b) San
́
chez, C.; Men
́
dez, C.; Salas, J. A. Nat. Prod. Rep. 2006, 23,
1007. (c) Hili, R.; Yudin, A. K. Nat. Chem. Biol. 2006, 2, 284.
(d) Kibayashi, C. Chem. Pharm. Bull. 2005, 53, 1375.
(2) (a) Guram, A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116,
7901. (b) Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116,
5969. (c) Sanjeeva Rao, K.; Wu, T.-S. Tetrahedron 2012, 68, 7735.
(d) Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K.
Tetrahedron Lett. 2001, 42, 3415.
(3) For a recent review on transition-metal-catalyzed direct C−H
functionalization, see: (a) Chen, X.; Engle, K. M.; Wang, D. H.; Yu, J.-
Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (b) Colby, D. A.; Bergman,
R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (c) Yeung, C. S.; Dong,
V. M. Chem. Rev. 2011, 111, 1215. (d) Song, G.; Wang, F.; Li, X.
Chem. Soc. Rev. 2012, 41, 3651. (e) Neufeldt, S. R.; Sanford, M. S. Acc.
Chem. Res. 2012, 45, 936. (f) Li, B.-J.; Shi, Z.-J. Chem. Soc. Rev. 2012,
(14) Ryu, J.; Shin, K.; Park, S. H.; Kim, J. Y.; Chang, S. Angew. Chem.,
Int. Ed. 2012, 51, 9904.
(15) (a) Muralirajan, K.; Parthasarathy, K.; Cheng, C.-H. Angew.
Chem., Int. Ed. 2011, 50, 4169. (b) Kim, J.; Kim, J.; Chang, S. Chem. -
Eur. J. 2013, 19, 7328. (c) Liu, X.; Li, X.; Liu, H.; Guo, Q.; Lan, J.;
Wang, R.; You, J. Org. Lett. 2015, 17, 2936.
(16) Zhou, S.; Wang, J.; Wang, L.; Song, C.; Chen, K.; Zhu, J. Angew.
Chem., Int. Ed. 2016, 55, 9384.
41, 5588. (g) Bruckl, T.; Baxter, R. D.; Ishihara, Y.; Baran, P. S. Acc.
̈
(17) Chen, J.; Song, G.; Pan, C.-L.; Li, X. Org. Lett. 2010, 12, 5426.
Chem. Res. 2012, 45, 826. (h) Hartwig, J. F. Acc. Chem. Res. 2012, 45,
864. (i) Kuhl, N.; Schroder, N.; Glorius, F. Adv. Synth. Catal. 2014,
̈
D
DOI: 10.1021/acs.orglett.7b00583
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