Cp?Co(III)-Catalyzed C-H Alkylation with Maleimides Using Weakly Coordinating Carbonyl Directing Groups

Article abstract of DOI:10.1021/acs.orglett.8b00761

A novel protocol for ortho-C-H alkylation of aromatic and heteroaromatic ketones and esters under Cp?Co(III) catalysis has been developed for the first time. The reaction proceeds through initial cyclometalation via weak chelation-assisted C-H bond activation, followed by coordination of activated alkene, insertion between Co-C, and protodemetalation.

Full text of DOI:10.1021/acs.orglett.8b00761

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Cp*Co(III)-Catalyzed C−H Alkylation with Maleimides Using Weakly
Coordinating Carbonyl Directing Groups
Rajib Mandal, Balakumar Emayavaramban, and Basker Sundararaju*
Fine Chemical Laboratory, Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, Uttar Pradesh, India
*
S Supporting Information
ABSTRACT: A novel protocol for ortho-C−H alkylation of
aromatic and heteroaromatic ketones and esters under
Cp*Co(III) catalysis has been developed for the first time.
The reaction proceeds through initial cyclometalation via weak
chelation-assisted C−H bond activation, followed by coordi-
nation of activated alkene, insertion between Co−C, and
protodemetalation.
egioselective C−H bond functionalization catalyzed by
possibly due to ineffective formation of the key metallacyclic
intermediate with weakly coordinating directing groups.
In our continuing efforts focused on developing efficient
weakly coordinating directing groups for C−H bond functiona-
R
transition metals has attracted much attention since the
pioneering work by Murai and co-workers on the formation of
1
,2
C−C and C−heteroatom bonds. Recent advances in green and
sustainable chemistry demand that chemists explore less-
expensive and earth-abundant 3d late-transition metals for C−
7i,k,l
lization,
we report the Cp*Co(III)-catalyzed 1,4-addition of
maleimides to ortho-C−H bonds of ketones and esters under
3
redox-neutral conditions, leading to various biologically active
H bond functionalization. In this regard, Cp*Co(III) has
1
0,11
succinimides (Scheme 1c);
the latter are commonly used as
emerged as an excellent catalyst since the pioneering work by
12a
12b
antidepressants and anticonvulsants,
e.g., phensuximide,
4
,5
Matsunaga and Kanai. One of the drawbacks of this otherwise
very popular Cp*Co(III) catalytic system is the overdependence
of strongly coordinating directing groups such as thio, pyridyl,
amino, amido, etc. for chelate-assisted C−H bond functionaliza-
ethosuximide, mesuximide, etc. The results presented herein are
significant from the points of view of atom efficiency and redox
neutrality. Given that ketone and ester functionalities are widely
distributed in organic compounds, the protocol described herein
should allow their ready C−H functionalization under mild
conditions.
6
tions (Scheme 1a). The use of substrates containing weakly
coordinating directing groups has been less explored with first-
row transition metals, in particular, with Co(III), and only a few
reports have to date been documented (Scheme 1b). This is
Initially, ortho-C−H bond alkylation of aryl ketone 1a was
explored with maleimide 2a in the presence 10 mol% of
Cp*Co(CO)I and 20 mol% of AgSbF , with metal carboxylate
7
−9
2
6
Scheme 1. Overview of C−H Bond Functionalization with
Cp*Co(III)
(10−30 mol %) in 1,2-dichloroethane (DCE) (0.1 M) as the
solvent at 120 °C (Table 1). Remarkably, the expected alkylation
product 3aa was isolated in 24% yield with sodium pivalate after
2
4 h (entry 1). Inspired by this result, the influence of other metal
carboxylates, namely, sodium/potassium acetate, was also
examined (entries 2−3). Indeed, sodium acetate was found to
be the best, leading to 3aa in an isolated yield of 39%.
Subsequently, screening of different cobalt precursors was
initiated, which led to identification of a cobalt monomer as
the best catalyst (entries 4−6). Further investigation revealed
that an equimolar amount of acetate with cobalt is crucial to
obtain 3aa (entries 7−9). Finally, an excellent yield (93%) of 3aa
was achieved when the solvent employed was 0.2 M under the
standard conditions (entry 10). Later, different solvents, lower
temperatures, and changes in catalyst loading were found to be
ineffective in affording 3aa in better yields (entries 11−13).
Received: March 10, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00761
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Reaction Optimization
Scheme 2. Scope of Ketones
b
AgSbF6
(x mol %)
MCO2R
(x mol %)
yield
entry
[Co] (x mol %)
(%)
1
2
3
4
5
6
Cp*Co(CO)I (10)
AgSbF (20) NaOPiv (30)
24
37
39
15
11
n.d.
2
6
Cp*Co(CO)I (10)
AgSbF (20) KOAc (30)
2
6
Cp*Co(CO)I (10)
AgSbF (20) NaOAc (30)
2
6
[Cp*CoI ] (5)
AgSbF (20) NaOAc (30)
2
2
6
[Cp*CoCl ] (5)
AgSbF (20) NaOAc (30)
2
2
6
+
−
[Cp*Co(CH CN) ] SbF
6
−
NaOAc (30)
3
3
(5)
7
8
9
Cp*Co(CO)I (10)
AgSbF (20) NaOAc (10)
74
33
10
2
6
Cp*Co(CO)I (10)
AgSbF (20)
−
2
6
Cp*Co(CO)I (10)
AgSbF (20) NaOAc (50)
2
6
c
10
11
12
13
14
Cp*Co(CO)I (10)
AgSbF (20) NaOAc (10)
93
2
6
d
Cp*Co(CO)I (10)
AgSbF (20) NaOAc (10)
32
2
6
Cp*Co(CO)I (5)
AgSbF (10) NaOAc (10)
76
2
6
e
Cp*Co(CO)I (10)
AgSbF (20) NaOAc (10)
60
2
6
Cp*Co(CO)I (10)
−
NaOAc (10)
n.d.
2
a
All reactions were carried out under an argon atmosphere, unless
otherwise stated, using 1a/2a/[Co]/[Ag]/[MCO R] in 0.2/0.3/0.02/
2
b
c
0
.04/0.02−0.06 mmol at 120 °C in DCE (0.1 M). Isolated yield. 1
d e
mL of DCE (0.2 M) was used. TFE was used as solvent. Reaction
was performed at 100 °C. DCE = 1,2-Dichloroethane; TFE = 2,2,2-
trifluoroethanol; n.d. = not determined.
However, ionization of Co with a silver salt was found to be
crucial for the reaction to proceed (entry 14).
To evaluate the scope of the reaction, various aryl ketones were
examined (Scheme 2). Electron-donating groups (Me, OMe, and
t
Bu) as well as electron-withdrawing groups (Br and Cl) at the
para-position were well tolerated, and the expected alkylated
products were isolated in excellent yields (3bb−3fb). Next, we
examined the regioselectivity of the reaction by employing m-
methyl- and m-methoxy-substituted arenes (1g and 1h). While
the former gave exclusively the product derived from the less
hindered site, the latter yielded a mixture of two separable
isomers in a 1.54:1 ratio (3hb:3hb′) with the major product
corresponding to the one derived from C−H alkylation
occurring at the less hindered site. Similarly, alkylation occurred
at the less hindered site when 2-naphthyl ketone (1i) was
employed. The reaction could also be extended to hetero-
aromatics such as 2-thiophenyl ketone, leading to the
corresponding product 3jb in very good yield. Next, we
investigated the influence of sterics at the α-position of the
(3ab−3ae). Even substituted arenes employed in place of alkyl
groups did not alter the outcome of the reactions (3af−3ah).
Secondary N-alkyl-substituted maleimides such as N-cyclohexyl-
and 2-methylbenzylmaleimides also afforded the corresponding
products in good-to-excellent yields (3ai−3aj). Indeed, the
unprotected maleimide as a coupling partner also led to 1,4-
addition product 3ak in good isolated yield. The possible bis-
alkylation was investigated with maleimide 2l in a one-pot
procedure. As desired, bis-1,4-addition product 3al was isolated
using excess aryl ketone and an ethyl-bridged maleimide dimer as
the limiting substrate. Further, we have tested other activated
olefins, among which only acrylate gave moderated alkylation
product (3am−3ao) using 50 mol % of pivalic acid as an additive
in place of sodium acetate.
t
carbonyl group through systematic replacement of the bulky Bu
i
group with Pr, Ph, Et, and Me. Under the standard conditions,
corresponding alkylated products 3kb−3nb were isolated in
moderate-to-good yields. We further subjected various commer-
cially available aryl ketones to alkylations using maleimide.
Indeed, the reactions occurred smoothly providing the 1,4-
addition products 3ob−3sb in good-to-excellent yields. Finally,
we also tested a cyclic ketone such as 5-dibenzosuberenone 1t,
which afforded the monoalkylated product 3tb in an excellent
yield of 92%.
Subsequently, esters as weakly coordinating directing groups
were examined for 1,4-addition of maleimide, as shown in
Scheme 4. A brief screening of the reaction conditions using ethyl
benzoates revealed that TFE was the best solvent for the success
We further studied the scope of maleimides 2, as depicted in
Scheme 3. Substrates with various protecting groups such as Me,
i
Et, Bu, and Bn afforded the expected products in excellent yields
B
DOI: 10.1021/acs.orglett.8b00761
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Scope of Activated Olefins
Scheme 6. Control Experiments
Scheme 7. Proposed Mechanism
a
b
Standard conditions were used. 50 mol % of PivOH used in place of
NaOAc
Scheme 4. Ester as a Weakly Coordinating Directing Group
of the reactions, leading to ortho-alkylated ethylbenzoates in
moderate to good yields (5ab−5db).
Scheme 5. Overcoming the Limitation by the presence of
Strong Coordinating Groups
C−H bond activation (Scheme 6a). Second, H/D exchange
experiments were carried out without 2a using deuterated
trifluoroethanol as an external deuterium source, leading to
significant deuterium exchange with 1a, suggesting that the C−H
activation is reversible (Scheme 6b(i)).
Last, the reaction between 1a and 2a under the standard
reaction conditions revealed deuterium incorporation in 16%
and 19% for diastereotopic hydrogens at the C-3 position of the
maleimide and in 47% yield at the ortho-position of the arene,
which suggests that initial C−H activation is reversible and that
the active catalyst is regenerated via protodemetalation.
Based on the results described above, and previous literature
Also, the competition reaction between strong and weakly
coordinating groups under our optimized reaction conditions
was investigated using aza-indolyl-substituted arylketone, as
shown in Scheme 5. The results showed that ketone is favored as
a directing group over pyridine, possibly due to the favored five-
membered metallocyle rather than the six-membered one.
To establish the mechanism, several preliminary control
experiments were carried out as shown in Scheme 6. First, an
intermolecular competitive experiment was carried out with an
equimolar amount of an arene source (1c/1e) and maleimide 2b
under the standard conditions providing 3cb/3eb in a 1.78:1
ratio, suggesting that the reaction proceeds through electrophilic
7
,9
reports, we propose the plausible reaction mechanism, as
shown in Scheme 7. Accordingly, cationic cobalt(III) complex A
can undergo initial ligand exchange with carbonyl derivatives 1/
4, followed by carboxylate-assisted reversible cyclometalation to
intermediate C. Coordination of maleimide, followed by
6l
insertion between Co−C and subsequent re-entry of “CO”,
C
DOI: 10.1021/acs.orglett.8b00761
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
can lead to seven-membered metallocycle E. This may further
undergo protodemetalation to afford the 1,4-addition product 3/
Chem., Int. Ed. 2016, 55, 5577. (d) Sun, B.; Yoshino, T.; Matsunaga, S.;
Kanai, M. Chem. Commun. 2015, 51, 4659. (e) Li, J.; Ackermann, L.
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5
and regenerate the cobalt(III) active species for the next cycle.
In conclusion, we have demonstrated an efficient, redox-
neutral, waste-free Co-catalyzed 1,4-addition of C−H bonds of
ketone and ester to maleimide in good-to-excellent isolated
yields. The reaction permits good site selectivity, broad substrate
scope, and excellent functional group tolerance. We have further
shown that the selective C−H alkylation directed by a ketone
group is preferred even in the presence of a strongly coordinating
group, which allows the applicability of the reaction to a large
body of target molecules.
5
4, 4508. (h) Patel, P.; Chang, S. ACS Catal. 2015, 5, 853. (i) Hummel, J.
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(7) For selected examples using a weakly coordinating directing group
́ ́
with Cp*Co(III), see: (a) Lu, Q.; Vasquez-Cespedes, S.; Gensch, T.;
Glorius, F. ACS Catal. 2016, 6, 2352. (b) Lerchen, A.; Knecht, T.;
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ASSOCIATED CONTENT
Supporting Information
■
1
5170. (c) Wang, H.; Lorion, M. M.; Ackermann, L. Angew. Chem., Int.
*
S
Ed. 2016, 55, 10386−10390. (d) Sun, B.; Yoshino, T.; Kanai, M.;
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00761.
Moselage, M.; Gonzal
f) Kong, L.; Yu, S.; Zhou, X.; Li, X. Org. Lett. 2016, 18, 588. (g) Zhang,
Z.-Z.; Liu, B.; Xu, J.-W.; Yan, S.-Y.; Shi, B.-F. Org. Lett. 2016, 18, 1776.
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́
ez, M. J.; Ackermann, L. ACS Catal. 2016, 6, 2705.
(
Experimental methods, optimization of reaction con-
ditions, and other supplementary data (PDF)
(
2
AUTHOR INFORMATION
Corresponding Author
2016, 52, 1338. (j) Ghorai, J.; Reddy, A. C. S.; Anbarasan, P. Chem. - Eur.
J. 2016, 22, 16042. (k) Kalsi, D.; Laskar, R. A.; Barsu, N.; Premkumar, J.
R.; Sundararaju, B. Org. Lett. 2016, 18, 4198. (l) Mandal, R.;
Sundararaju, B. Org. Lett. 2017, 19, 2544.
■
*
E-mail: basker@iitk.ac.in.
ORCID
(8) For a recent review on ketone directed C−H bond functionaliza-
tion, see: Huang, Z.; Lim, H. N.; Mo, F.; Young, M. C.; Dong, G. Chem.
Soc. Rev. 2015, 44, 7764 and references therein.
Basker Sundararaju: 0000-0003-1112-137X
Notes
(9) For selected examples using ketone as a weakly coordinating
directing group, see: (a) Gandeepan, P.; Parthasarathy, K.; Cheng, C.-H.
J. Am. Chem. Soc. 2010, 132, 8569. (b) Patureau, F. W.; Besset, T.; Kuhl,
N.; Glorius, F. J. Am. Chem. Soc. 2011, 133, 2154. (c) Jeganmohan, M.;
Padala, K. Org. Lett. 2011, 13, 6144. (d) Mo, F.; Trzepkowski, L. J.;
Dong, G. Angew. Chem., Int. Ed. 2012, 51, 13075. (e) Bhanuchandra, M.;
Ramu Yadav, M.; Rit, R. K.; Kuram, M. R.; Sahoo, A. K. Chem. Commun.
2013, 49, 5225. (f) Li, G.; Wan, L.; Zhang, G.; Leow, D.; Spangler, J.; Yu,
J.-Q. J. Am. Chem. Soc. 2015, 137, 4391. (g) Kim, J.; Chang, S. Angew.
Chem., Int. Ed. 2014, 53, 2203. (h) Bettadapur, K. R.; Lanke, V.; Prabhu,
K. R. Org. Lett. 2015, 17, 4658.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support provided by SERB (EMR/2016/000136) to
carry out this research is gratefully acknowledged. B.S. wishes to
thank to IITK for a PK Kelkar fellowship. R.M. and B.E. are
thankful to CSIR and IITK for their fellowships.
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Org. Lett. XXXX, XXX, XXX−XXX