Direct access to cobaltacycles via C-H activation: N-chloroamide- enabled room-temperature synthesis of heterocycles

Article abstract of DOI:10.1021/acs.orglett.7b02632

Cobaltacycle synthesis via C-H activation has been achieved for the first time, providing key mechanistic insight into cobalt catalytic chemistry. NChloroamides are used as a directing synthon for cobalt-catalyzed roomtemperature C-H activation and construction of heterocycles. Alkynes as coupling partners allow convenient access to isoquinolones, a class of synthetically and pharmaceutically important compounds. The broad substrate scope enables a diverse range of substitution patterns to be incorporated into the heterocyclic scaffold.

Full text of DOI:10.1021/acs.orglett.7b02632

Letter
pubs.acs.org/OrgLett
Direct Access to Cobaltacycles via C−H Activation: N‑Chloroamide-
Enabled Room-Temperature Synthesis of Heterocycles
Xiaolong Yu, Kehao Chen, Shan Guo, Pengfei Shi, Chao Song, and Jin Zhu*
Department of Polymer Science and Engineering, School of Chemistry and Chemical Engineering, State Key Laboratory of
Coordination Chemistry, Nanjing National Laboratory of Microstructures, Collaborative Innovation Center of Chemistry for Life
Sciences, Nanjing University, Nanjing 210093, China
S
* Supporting Information
ABSTRACT: Cobaltacycle synthesis via C−H activation has been achieved for
the first time, providing key mechanistic insight into cobalt catalytic chemistry. N-
Chloroamides are used as a directing synthon for cobalt-catalyzed room-
temperature C−H activation and construction of heterocycles. Alkynes as coupling
partners allow convenient access to isoquinolones, a class of synthetically and
pharmaceutically important compounds. The broad substrate scope enables a
diverse range of substitution patterns to be incorporated into the heterocyclic
scaffold.
anionic ligand for expedient docking of the cobalt catalytic
center, and the N−Cl oxidizing reactivity provides a potentially
viable internal oxidation reaction pathway. Herein we report
the first direct synthesis of cobaltacycles via C−H activation
(Scheme 1a) and document N-chloroamide-enabled room-
ransition-metal-catalyzed directed C−H functionalization
Thas witnessed tremendous progress as a handy tool for
organic synthesis.1 Reaction development traditionally relies on
the use of second-row transition metal catalytic centers (e.g.,
palladium, rhodium)2−5 to effect the desired transformations.
Only recently have first-row transition metal complexes (e.g.,
cobalt)6 established their utility in catalytic synthetic contexts.
The unique electronic and steric properties associated with
these complexes promise the achievement of distinct reactivity.
Despite the synthetic progress, mechanistic understanding lags
far behind because of challenges in the isolation of elusive
intermediate species proposed in the catalytic cycle. Indeed, in
contrast to abundant examples of five-membered palladacycles
and rhodacycles,7 to date no five-membered cobaltacycle has
been directly accessed through C−H activation under bona fide
catalysis-relevant experimental settings. Only one type of five-
membered cobaltacycle8 has been synthesized through indirect
methods, starting from a catalysis-irrelevant aryl halide,
involving a key step of either transmetalation or oxidative
addition. Although this five-membered cobaltacycle has been
demonstrated to be catalytically active,8b the ad hoc synthetic
process offers no definitive proof for the occurrence of C−H
activation. The ability to directly synthesize and isolate C−H-
activated five-membered cobaltacycles is therefore still an
urgent need to advance the understanding and expand the
scope of cobalt-catalyzed C−H functionalization reactions.
We have a long-term interest in the development of novel
C−H-activation-directing synthons for achieving hitherto-
elusive mechanistic insight and synthetically useful reactivity.
In search of a directing synthon that not only can stabilize the
C−H-activated five-membered cobaltacycle but also allows for
convenient entry into the desired reaction manifold, N-
chloroamide9 has emerged as our candidate of choice by virtue
of its unique reactivity. The facile N−H deprotonation
capability (e.g., even with KF as the base) can furnish an
Scheme 1. First-Time Synthesis of Cobaltacycles via C−H
Activation and N-Chloroamide-Enabled Room-Temperature
Construction of Heterocycles
temperature (rt) construction of heterocycles (Scheme 1b).
The cobalt catalytic chemistry allows efficient coupling of N-
chlorobenzamides with alkynes to afford isoquinolones, a class
of synthetically and pharmaceutically important compounds.10
The N−Cl bond-based catalytic process described herein differs
substantially from those documented in previous N−O bond-
derived protocols, which are synthetically restrictive, as
manifested by the requirement of rare metals (e.g., rhodium,
ruthenium),11,12 harsh reaction conditions (e.g., elevated
Received: August 24, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02632
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reaction temperature), and limited substrate scope (e.g.,
incompatibility with terminal alkynes).13
chlorobenzamide (1k). Disubstitution does not significantly
retard the reactivity (1l).
We commenced our investigation by identifying feasible
synthetic conditions for the coupling between N-chloroamides
and alkynes under cobalt catalysis. With N-chlorobenzamide
(1a) and diphenylacetylene (2a) as the substrates and with
[CoCp*(CO)I2] (10 mol %) as the catalyst precursor,
extensive screening revealed that a combination of AgOAc
(20 mol %) and KOAc (1.2 equiv) in trifluoroethanol (TFE)
can provide an optimum yield of 81% for 3,4-diphenylisoqui-
nolin-1(2H)-one (3aa) after 36 h of rt reaction.
The substrate scope for alkynes was then examined by
reaction with 1a (Scheme 2). Significantly, a broad range of
substitution patterns can be tolerated for internal and terminal
alkynes. Both electron-rich and electron-poor diarylalkynes
(2b−e) are competent for the transformation. Dialkylalkynes
(2f, 2g) exhibit essentially identical reactivity as diarylalkynes.
An internal alkyne bearing two electron-withdrawing ester
groups (2h) can also react efficiently. The reactions for aryl/
alkyl (2i) and aryl/ester (2j) unsymmetrical alkynes give a
mixture of inseparable regioisomers, whereas the regioisomers
derived from the alkyl/ester unsymmetrical alkyne (2k) can be
individually isolated. The high reactivity imparted by N-
chlorobenzamide also enables smooth reaction for terminal
alkynes. The reactivity for aryl-substituted terminal alkynes (2l,
2m) is slightly lower than that for alkyl- (2n−s) and cycloalkyl-
substituted (2t) terminal alkynes. Functional groups can be
incorporated, if desired, at the chain end of the alkyl-substituted
terminal alkynes (2u, 2v) for further synthetic manipulation.
Alternatively, the synthetic compatibility of a silyl-substituted
terminal alkyne (2w) and generation of two isolable
regioisomeric products can provide silyl group as a versatile
synthetic handle for diverse transformations.
With the optimized reaction conditions established, the
substrate scope of N-chlorobenzamides was first investigated by
reaction with 2a (Scheme 2). N-Chlorobenzamides bearing
Scheme 2. Substrate Scope of N-Chlorobenzamides and
a b
,
Alkynes
Mechanistic studies allowed the first-time synthesis of
cobaltacycles via C−H activation (Scheme 3). The reaction
Scheme 3. First-Time Synthesis of Cobaltacycles via C−H
Activation
of 1d or 1f with [CoCp*(CO)I2] afforded a C−H-activated
five-membered cobaltacycle (1d-Co or 1f-Co;14 characterized
with H NMR, 13C NMR, HRMS, and single-crystal X-ray
1
a
Reaction conditions: 1a−l (0.2 mmol), 2a−w (0.24 mmol), TFE (1.0
diffraction) (Scheme 3). 1d-Co not only can react as a
stoichiometric reagent with 2a (96% yield after 12 h) (Scheme
4, eq 1) but also can serve as an effective catalyst for the
coupling between 1d and 2a (95% yield of 3da) (Scheme 4, eq
2). The cobalt-catalyzed C−H activation leads to highly
efficient ortho H/D and D/H scrambling when starting from
1a and 1a-d5, respectively (Scheme 4, eqs 3 and 4). C−H
activation is reversible, as evidenced by (1) ortho D/H
scrambling in 3aa-d4 for a reaction between 1a-d5 and 2a
(Scheme 4, eq 5), and (2) the ability to convert 1d-Co back to
1d under HOAc (Scheme 4, eq 6). The high kinetic isotope
effect (KIE) value of 4.0 observed for the reaction between 1a/
1a-d5 and 2a is consistent with a turnover-limiting C−H
activation step (Scheme 4, eq 7). A competition reaction for N-
chlorobenzamides with different electronic characters (1b, 1d)
with 2a favors electron-poor 1d (Scheme 4, eq 8), suggesting
b
c
mL). Isolated yields are shown. Only the major regioisomer is
shown.
both electron-donating (1b, 1c) and electron-withdrawing
(1d−g) groups at the para position can react in high yield.
Ortho substitution is also synthetically compatible (1h, 1i), with
a diminished product yield observed for a bulkier substituent.
Meta-substituted N-chlorobenzamides show reactivity similar to
that of the para-substituted ones, but the reactions can be
complicated by varied regioselectivity patterns. The placement
of a methyl group at the meta position (1j) results in exclusive
reactivity at the sterically more accessible site, thus allowing the
delivery of a single regioisomer as the product. However, the
transformation is less selective for a meta-fluoro-substituted N-
B
DOI: 10.1021/acs.orglett.7b02632
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Mechanistic Studies of Cobalt-Catalyzed
Coupling of N-Chloroamides with Alkynes
Scheme 5. Mechanistic Proposal for Cobalt-Catalyzed
Coupling of N-Chloroamides with Alkynes
in the destabilized CoV complex is substituted with I−, and C−I
reductive elimination proceeds subsequently.
In summary, the direct synthesis of cobaltacycles via C−H
activation has been achieved for the first time, providing elusive
mechanistic insight into cobalt-catalyzed C−H functionaliza-
tion reactions. An N-chloroamide directing synthon strategy
has been developed for cobalt-catalyzed rt construction of
heterocycles. Alkynes as coupling partners allow efficient access
to isoquinolones. The broad substrate scope offers the ability to
incorporate a diverse range of substitution patterns into the
heterocycle scaffold. The intriguing versatile reactivity identified
herein will inspire the development of more transition-metal-
catalyzed, synthetically unique transformations based on highly
reactive C−H-activation-directing synthons.
ASSOCIATED CONTENT
* Supporting Information
■
S
that C−H activation occurs through a concerted metalation−
deprotonation mechanism.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02632.
Taken together, these results indicate that mechanistically,
CoIII-enabled turnover-limiting C−H activation occurs first,
followed by CoIII-to-CoV oxidation (high-valent RhV has been
previously invoked in rhodium-catalyzed C−H functionaliza-
tion reactions15). Subsequent consecutive alkyne migratory
insertion and C−N reductive elimination provide the target
product and allow the regeneration of CoIII (Scheme 5). The
proposal of the CoIII-to-CoV oxidation pathway is consistent
with the high oxidizing reactivity of the N−Cl bond, as
demonstrated by the ability to convert 1d-Co into 4-
fluorophthalimide (1d-1) (see the Supporting Information).
Two bond cleavage sites can be conceived for the initiation of
this reaction cascade, i.e., the N−Cl bond and the Co−(CO)
bond. The formation of 1d-1 is consistent with the N−Cl bond
as the reactivity launching site and the following reaction
pathway: CoIII-to-CoV oxidation by the N−Cl bond leading to
destabilization of the carbonyl ligand (due to less efficient back-
bonding to the π-acidic ligand from the electron-poor CoV
center), migratory insertion of the carbonyl ligand into the
Co−C bond, and C−N reductive elimination. This proposal is
further supported by the identification of 4-fluoro-2-iodoben-
zamide (1d-2) as a product when 1d-Co is reacted with KI (see
the Supporting Information). In this case, the carbonyl ligand
Experimental procedures and product characterization
(PDF)
1
Copies of the H and 13C NMR spectra of selected
products (PDF)
Crystallographic data for 1d-Co (CIF)
Crystallographic data for 1f-Co (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jinz@nju.edu.cn.
ORCID
Jin Zhu: 0000-0003-4681-7895
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge support from the National Natural
Science Foundation of China (21425415, 21274058) and the
National Basic Research Program of China (2015CB856303).
C
DOI: 10.1021/acs.orglett.7b02632
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Chem. 2014, 79, 6123. (d) Yang, F.; Ackermann, L. J. Org. Chem. 2014,
79, 12070.
(13) Sivakumar, G.; Vijeta, A.; Jeganmohan, M. Chem. - Eur. J. 2016,
REFERENCES
■
(1) (a) Ackermann, L. Chem. Rev. 2011, 111, 1315. (b) Segawa, Y.;
Itami, K.; Maekawa, T. Angew. Chem., Int. Ed. 2015, 54, 66. (c) Cheng,
C.; Hartwig, J. F. Chem. Rev. 2015, 115, 8946. (d) Zheng, Q.-Z.; Jiao,
N. Chem. Soc. Rev. 2016, 45, 4590. (e) Labinger, J. A. Chem. Rev. 2017,
117, 8483. (f) Kim, D.-S.; Park, W.-J.; Jun, C.-H. Chem. Rev. 2017, 117,
8977.
(2) (a) He, J.; Wasa, M.; Chan, K. S. L.; Yu, J.-Q. J. Am. Chem. Soc.
2013, 135, 3387. (b) Chan, K. S. L.; Wasa, M.; Chu, L.; Laforteza, B.
N.; Miura, M.; Yu, J.-Q. Nat. Chem. 2014, 6, 146. (c) Park, Y.; Kim, Y.;
Chang, S. Chem. Rev. 2017, 117, 9247. (d) Baudoin, O. Acc. Chem. Res.
2017, 50, 1114.
(3) (a) Wang, H.; Tong, H.-R.; He, G.; Chen, G. Angew. Chem., Int.
Ed. 2016, 55, 15387. (b) Fu, H.; Shen, P.-X.; He, J.; Zhang, F.; Li, S.;
Wang, P.; Liu, T.; Yu, J.-Q. Angew. Chem., Int. Ed. 2017, 56, 1873.
(c) Yang, Y.; Gao, P.; Zhao, Y.; Shi, Z. Angew. Chem., Int. Ed. 2017, 56,
3966.
22, 5899.
(14) CCDC 1555149 (1d-Co) and CCDC 1562390 (1f-Co) contain
the supplementary crystallographic data for this paper. These data are
provided free of charge by The Cambridge Crystallographic Data
Centre.
(15) (a) Xu, L.; Zhu, Q.; Huang, G.; Cheng, B.; Xia, Y. J. Org. Chem.
2012, 77, 3017. (b) Guo, W.; Zhou, T.; Xia, Y. Organometallics 2015,
34, 3012. (c) Park, Y.; Heo, J.; Baik, M.-H.; Chang, S. J. Am. Chem. Soc.
2016, 138, 14020. (d) Yang, Y.-F.; Houk, K. N.; Wu, Y.-D. J. Am.
Chem. Soc. 2016, 138, 6861. (e) Wu, J.-Q.; Zhang, S.-S.; Gao, H.; Qi,
Z.; Zhou, C.-J.; Ji, W.-W.; Liu, Y.; Chen, Y.; Li, Q.; Li, X.; Wang, H. J.
Am. Chem. Soc. 2017, 139, 3537.
(4) (a) Oi, S.; Fukita, S.; Inoue, Y. Chem. Commun. 1998, 2439.
(b) Zhao, X.; Yu, Z. J. Am. Chem. Soc. 2008, 130, 8136. (c) Vogler, T.;
Studer, A. Org. Lett. 2008, 10, 129. (d) Wang, F.; Yu, S.; Li, X. Chem.
Soc. Rev. 2016, 45, 6462.
(5) (a) Zhou, S.; Wang, J.; Wang, L.; Song, C.; Chen, K.; Zhu, J.
Angew. Chem., Int. Ed. 2016, 55, 9384. (b) Hummel, J. R.; Boerth, J. A.;
Ellman, J. A. Chem. Rev. 2017, 117, 9163. (c) Kim, H.; Chang, S.
Angew. Chem., Int. Ed. 2017, 56, 3344. (d) Zhao, Y.; Li, S.; Zheng, X.;
Tang, J.; She, Z.; Gao, G.; You, J. Angew. Chem., Int. Ed. 2017, 56,
4286. (e) Hyster, T. K.; Rovis, T. J. Am. Chem. Soc. 2010, 132, 10565.
(f) Morimoto, K.; Itoh, M.; Hirano, K.; Satoh, T.; Shibata, Y.; Tanaka,
K.; Miura, M. Angew. Chem., Int. Ed. 2012, 51, 5359.
(6) (a) Grigorjeva, L.; Daugulis, O. Angew. Chem., Int. Ed. 2014, 53,
10209. (b) Gandeepan, P.; Cheng, C.-H. Acc. Chem. Res. 2015, 48,
1194. (c) Moselage, M.; Li, J.; Ackermann, L. ACS Catal. 2016, 6, 498.
(d) Liang, Y.; Jiao, N. Angew. Chem., Int. Ed. 2016, 55, 4035. (e) Yu,
X.; Chen, K.; Yang, F.; Zha, S.; Zhu, J. Org. Lett. 2016, 18, 5412.
(f) Shi, P.; Wang, L.; Chen, K.; Wang, J.; Zhu, J. Org. Lett. 2017, 19,
2418. (g) Chavan, L. N.; Gollapelli, K. K.; Chegondi, R.; Pawar, A. B.
Org. Lett. 2017, 19, 2186.
(7) (a) Racowski, J. M.; Gary, J. B.; Sanford, M. S. Angew. Chem., Int.
Ed. 2012, 51, 3414. (b) Park, Y.; Park, K. T.; Kim, J. G.; Chang, S. J.
Am. Chem. Soc. 2015, 137, 4534. (c) Zhou, S.; Wang, J.; Zhang, F.;
Song, C.; Zhu, J. Org. Lett. 2016, 18, 2427. (d) Wu, Y.; Zhou, B. Org.
Lett. 2017, 19, 3532. (e) Yu, X.; Chen, K.; Wang, Q.; Guo, S.; Zha, S.;
Zhu, J. Angew. Chem., Int. Ed. 2017, 56, 5222.
(8) (a) Ikemoto, H.; Yoshino, T.; Sakata, K.; Matsunaga, S.; Kanai,
M. J. Am. Chem. Soc. 2014, 136, 5424. (b) Sanjose-
D.; Garcia-Roca, A.; Martin, E.; Benet-Buchholz, J.; Per
́
Orduna, J.; Gallego,
ez-Temprano,
́
M. H. Angew. Chem., Int. Ed. 2017, DOI: 10.1002/anie.201704744.
(9) (a) Grohmann, C.; Wang, H.; Glorius, F. Org. Lett. 2012, 14, 656.
(b) Ng, K.-H.; Zhou, Z.; Yu, W.-Y. Chem. Commun. 2013, 49, 7031.
(c) Vanjari, R.; Guntreddi, T.; Singh, K. N. Org. Lett. 2013, 15, 4908.
(d) Ng, F.-N.; Zhou, Z.; Yu, W.-Y. Chem. - Eur. J. 2014, 20, 4474.
(e) Xie, W.; Yoon, J. H.; Chang, S. J. Am. Chem. Soc. 2016, 138, 12605.
(10) (a) Chen, C.-Y.; Chang, F.-R.; Pan, W.-B.; Wu, Y.-C.
Phytochemistry 2001, 56, 753. (b) Nagarajan, M.; Morrell, A.; Fort,
B. C.; Meckley, M. R.; Antony, S.; Kohlhagen, G.; Pommier, Y.;
Cushman, M. J. Med. Chem. 2004, 47, 5651. (c) Ruchelman, A. L.;
Houghton, P. J.; Zhou, N.; Liu, A.; Liu, L. F.; LaVoie, E. J. J. Med.
Chem. 2005, 48, 792. (d) Miura, T.; Yamauchi, M.; Murakami, M. Org.
Lett. 2008, 10, 3085.
(11) (a) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F. J. Am.
Chem. Soc. 2011, 133, 2350. (b) Guimond, N.; Gorelsky, S. I.; Fagnou,
K. J. Am. Chem. Soc. 2011, 133, 6449. (c) Ye, B.; Cramer, N. Science
2012, 338, 504. (d) Liu, H.; An, Z.; He, J. ACS Catal. 2014, 4, 3543.
(e) Su, B.; Wei, J.-B.; Wu, W.-L.; Shi, Z.-J. ChemCatChem 2015, 7,
2986.
(12) (a) Ackermann, L.; Fenner, S. Org. Lett. 2011, 13, 6548. (b) Li,
B.; Ma, J.; Wang, N.; Feng, H.; Xu, S.; Wang, B. Org. Lett. 2012, 14,
736. (c) Yadav, M. R.; Rit, R. K.; Shankar, M.; Sahoo, A. K. J. Org.
D
DOI: 10.1021/acs.orglett.7b02632
Org. Lett. XXXX, XXX, XXX−XXX