Weak Coordinating Carboxylate Directed Rhodium(III)-Catalyzed C-H Activation: Switchable Decarboxylative Heck-Type and [4 + 1] Annulation Reactions with Maleimides

Article abstract of DOI:10.1021/acs.orglett.9b01412

A weakly coordinating carboxylate directing group assisted C-H activation with maleimides leading to novel and switchable decarboxylative Heck-type and [4 + 1] annulation products catalyzed by Rh(III) has been reported. In these reactions, solvents play a

Full text of DOI:10.1021/acs.orglett.9b01412

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Weak Coordinating Carboxylate Directed Rhodium(III)-Catalyzed C−
H Activation: Switchable Decarboxylative Heck-Type and [4 + 1]
Annulation Reactions with Maleimides
Mahadev Sharanappa Sherikar and Kandikere Ramaiah Prabhu*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India
S
* Supporting Information
ABSTRACT: A weakly coordinating carboxylate directing group assisted C−H activation with maleimides leading to novel and
switchable decarboxylative Heck-type and [4 + 1] annulation products catalyzed by Rh(III) has been reported. In these
reactions, solvents play a vital role in switching the selectivity. An aprotic solvent, THF, leads to the decarboxylative Heck-type
product while the protic solvent, TFE, results in the [4 + 1] annulation product. The methodology shows high functional group
tolerance.
ransition-metal-catalyzed directed functionalization for
the construction of carbocyclic and heterocyclic mole-
substituted maleimides are prepared by reacting an amine with
maleic anhydride, whereas obtaining 3-substituted maleimide
derivatives by employing the C−H activation strategy is not
easy and rare.5,11 One of the early syntheses of 3-substituted
maleimides was reported by Vogl in 1955 using arene
diazonium salt and a Cu(II)-catalyst.12a Later in 2011,
Capretta reported a Suzuki coupling reaction of 3-bromoma-
leimide with phenylboronic acid.12b In 2015, Zhou reported
coupling of maleimide with aryl iodide under Pd-catalysis
(Scheme 1).12c The carboxylic acid is known as a weak
coordinating directing group for various synthetic trans-
T
cules is gaining much attention in organic synthesis.1
Maleimide, succinimide, and spirocyclic pyrrolidine motifs
are an important class of compounds, which are present in
various natural products and biologically active molecules and
have high utility in pharmaceuticals.2 Several potent drug
molecules, such as antimicrobials, anticonvulsants, and
inhibitors, contain the maleimide ring as a core feature (Figure
1).3 One of the great advantages of maleimide and succinimide
Scheme 1. Comparison with Previous Work
Figure 1. Molecules containing maleimide ring.
rings is that they can be easily converted into heterocyclic
compounds such as pyrrolidines and γ-lactams.4 In C−H
activation, generally, maleimide undergoes 1,4-addition re-
action due to a rigid bicyclic intermediate of the succinimide
ring, which is lacking a β-hydrogen that is synperiplanar.
Consequently, succinimide cannot undergo β-hydride elimi-
nation.5 Therefore, a vast majority of reports are on the 1,4-
addition reaction of maleimide with aromatic compounds
using different directing groups and transition metal
catalysts.4d,6,7 Maleimide is also known to undergo 1,1-type,8
[3 + 2],9 and [4 + 2]10 annulation reactions. Generally,
Received: April 23, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01412
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
formations under C−H activation conditions.13,14 The
transition-metal-catalyzed decarboxylative hydroarylation of
maleimide using acid as a directing group is known under
Rh(III)- and Ru(II)-catalysis.15 However, decarboxylative
Heck-type and 1,1-type annulation reactions of maleimide
with benzoic acid are not known. We considered using a base
in the reaction can avoid the quenching of the metallacycle and
thereby the formation of the corresponding Heck-type product
can be facilitated. If this idea is successful, the reaction can be
fine-tuned to obtain a [4 + 1] annulation product, without
undergoing the decarboxylation.
To achieve the decarboxylative Heck-type product, the
optimization study began with the reaction of benzoic acid
with N-ethyl maleimide (2a) in the presence of a Rh(III)-
catalyst (5 mol %), AgBF4 (20 mol %) as an activator, and
Cu(OAc)2·H2O (1 equiv) as an oxidant in THF at 120 °C
(entry 1, Table 1). However, this reaction was futile, and the
Table 1). Our attempts to improve the yield of the desired
decarboxylative Heck-type product 3aa were not successful.
Thus, we thought it would be beneficial to use the salt of
benzoic acid to improve the yield of the desired decarbox-
ylative Heck-type product.
On the basis of this, reactions of sodium, potassium, and
lithium salts of benzoic acid (1a) with N-ethyl maleimide (2a)
and 5 mol % of a Rh(III)-catalyst, AgBF4 as an activator, and
Cu(OAc)2·H2O (1 equiv) as an oxidant in THF at 120 °C
(entries 3−5, Table 1) were performed. These reactions
resulted in the formation of decarboxylative Heck-type product
3aa in 60%, 40%, and 66% yields, respectively (entries 3−5,
Table 1). As the Li salt of benzoic acid furnished a better yield,
further optimizations were carried out using the Li salt of the
acid. Decreasing the amount of Cu(OAc)2·H2O to 0.75 equiv
resulted in the formation of 3aa in 70% NMR yield (entry 6),
whereas further lowering the amount of Cu(OAc)2·H2O
furnished 3aa (62%, entry 7). The yield of 3aa was enhanced
to 79% by loading of the Rh(III)-catalyst to 7.5 mol % (entry
8). A further increase in catalyst loading to 10 mol % furnished
the product 3aa in 74% yield (entry 9). Changing the solvent
from THF to a protic solvent, TFE, furnished 3aa in 7% yield
along with [4 + 1] annulation product 4aa in 18% yield (entry
10). A similar reaction in DCE as a solvent afforded the
product 3aa in 21% yield (entry 11). Employing AgOAc and
CuCO3 as oxidants instead of Cu(OAc)2·H2O led to the
formation of 3aa in 54% and 57% yields, respectively (entries
12 and 13). Among these conditions, we observed that the
combination of Cu(OAc)2·H2O and THF solvent was ideal for
affording decarboxylative Heck-type product 3aa in good yield
(79%, entry 8).
As seen in entry 10, the reaction in a protic solvent (TFE)
furnished the corresponding [4 + 1] annulated product 4aa in
18% yield. Therefore, we directed our optimization efforts
toward obtaining the annulated product exclusively. Thus, the
reaction of lithium benzoate (1a) and N-ethyl maleimide (2a),
with 5 mol % of a Rh(III)-catalyst, AgSbF6, and Cu(OAc)2·
H2O in TFE at 100 °C was performed, which furnished the
annulated product 4aa in 25% yield along with the Heck-type
product 3aa in 5% yield (entry 14, Table 1). Sodium benzoate
under the same reaction conditions furnished the annulated
4aa product in 47% yield along with the Heck-type product
3aa in 4% yield (entry 15). Quite interestingly, this reaction
also led to a double C−H activation of benzoic acid furnishing
alkenylation as well as annulation of the benzoic acid forming
the product 5aa in 10% yield. To obtain the annulated product
4aa, exclusively, the stoichiometry of the reaction had been
altered. Therefore, 1.5 equiv of sodium benzoate 1a was
reacted with 1 equiv of maleimide 2a. This reaction led to the
formation of the annulated product 4aa in 50% yield (entry
16). To our delight, when 2 equiv of sodium benzoate was
used, the reaction proceeded well furnishing the annulated
product 4aa in 67% yield along with a minor amount of the
Heck-type product 3aa (13%, entry 17). By increasing the
catalyst loading to 7.5 mol %, a mixture of annulated product
4aa and the Heck-type product 3aa was obtained in 57% and
11% yields, respectively (entry 18). The reaction in HFIP, a
more polar and acidic solvent as compared to TFE, afforded
the corresponding annulated product 4aa exclusively, albeit in
low yield (44%, entry 19). The reaction in methanol was not
helpful (entry 20, see the Supporting Information for detailed
screening studies).
Table 1. Optimization Studies
yield
entry
1
2
X
Cu(OAc)2·H2O (equiv)
solvent
3aa
4aa
5aa
H
H
Na
K
Li
Li
Li
Li
Li
Li
Li
Li
Li
Li
Na
Na
Na
Na
Na
Na
1
1
1
1
1
0.75
0.50
0.75
0.75
0.75
0.75
AgOAc (0.75)
CuCO3 (0.75)
0.75
0.75
0.75
THF
THF
THF
THF
THF
THF
THF
THF
THF
TFE
DCE
THF
THF
TFE
TFE
TFE
−
−
−
−
−
−
−
−
−
−
18
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
10
−
−
−
−
−
c
33
60
40
66
70
62
79
74
07
21
54
57
05
04
07
13
11
−
3
4
5
6
7
d
8
e
9
10
11
12
13
14
15
−
25
47
50
67
57
44
30
f
16
g
17
0.75
0.75
0.75
0.75
TFE
TFE
HFIP
MeOH
d
18
19
20
08
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol) [RhCp*Cl2]2 (5
mol %), AgBF4 (4 times the amount of catalyst) and X = Li (for
entries 1−9), AgSbF6 (4 times the amount of catalyst) and X = Na
(for entries 10−15), temp (120 °C and 100 °C for entries 1−13 and
b
1
14−20, respectively). Yields based on H NMR using trimethox-
c
ybenzene as an internal standard. K2CO3 (1 equiv) used.
[RhCp*Cl2]2 (7.5 mol %). [RhCp*Cl2]2 (10 mol %). 1a (0.3
mmol) and 2a (0.2 mmol). 1a (0.4 mmol), 2a (0.2 mmol).
d
e
f
g
starting materials were intact during the reaction conditions.
To increase the reactivity of the acid in the reaction, K2CO3
has been used as a base, as the corresponding carboxylate ion
can bind with the metals more effectively. As expected, this
reaction using K2CO3 (1 equiv) resulted in the formation of
decarboxylative Heck-type product 3aa in 33% yield (entry 2,
B
DOI: 10.1021/acs.orglett.9b01412
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
With these optimization studies, the scopes of the Heck-
type, as well as the annulation reactions, were studied using the
conditions noted in entries 8 and 17 (Table 1), respectively.
The reactions of lithium benzoate 1a with N-ethyl, benzyl,
phenyl, and N-(4-methoxy) phenyl substituted maleimide
derivatives were facile furnishing the corresponding decarbox-
ylative Heck-type products 3aa−3ad in 72−77% yields
(Scheme 2). Similarly, the reaction of lithium benzoate 1a
After exploring the scope of decarboxylative Heck-type
products, the substrate scope for the [4 + 1] annulation
reaction was investigated (Scheme 3). The reaction of N-ethyl
a
Scheme 3. Substrate Scope for [4 + 1] Annulation Reaction
a
Scheme 2. Substrate Scope for Heck-Type Reaction
a
Reaction conditions: Air, 1a (0.4 mmol), 2a (0.2 mmol),
[RhCp*Cl2]2 (5 mol %), AgSbF6 (20 mol %), Cu(OAc)2·H2O (75
b
c
mol %), TFE (2 mL), temp 100 °C, time 1 h. Isolated yields. 8
mmol scale reaction.
a
Reaction conditions: Air, 1a (0.2 mmol), 2a (0.3 mmol),
and N-isopropyl substituted maleimides with sodium benzoate
(1a) produced the corresponding [4 + 1] annulation products
4aa and 4ab in 62% and 63% yields, respectively. N-Ethyl
maleimide 2a reacted well with sodium salts of 4-methox-
ybenzoic acid, 4-methylbenzoic acid, and 4-chlorobenzoic acid
furnishing the corresponding annulated products 4ba, 4ca, and
4da in 50%, 55%, and 41% yields, respectively. The reaction of
2a with acid salts of m-methyl and m-bromo benzoic acids
afforded the corresponding annulated products 4ea and 4fa in
50% and 46% yields, respectively. The reaction of 2a with m-
methoxy benzoic acids salt led to the annulations at both ortho-
positions and furnished a regioisomeric mixture of annulated
products 4ga and 4ga′ in a ratio of 72:28 as an inseparable
mixture in 54% yield. Sterically hindered acid salts such as
ortho-anisic acid salt underwent a smooth annulation with 2a
forming the product 4ha in 47% yield along with
decarboxylative Heck-type product 3ca (see in Scheme 2) in
25% isolated yield. 1-Naphthoic acid salt also furnished the
corresponding annulated product 4ia in 60% yield.16
Interestingly, the Heck-type reaction of lithium benzoate
with N-benzyl maleimide and N-phenyl maleimide furnished
biologically active molecules. As seen in Figure 1, compounds
3ab and 3ac are a potent antimicrobial and inhibitor of
monoglyceride lipase, respectively. The scale-up reaction (8
mmol scale) of the Heck-type reaction of N-ethyl maleimide
with lithium benzoate furnished the Heck-product 3aa in 56%
yield (Scheme 2). Similarly, the reaction of sodium benzoate
with N-ethyl maleimide under annulation conditions afforded
the corresponding annulated product 4aa in 39% yield
(Scheme 3).
[RhCp*Cl2]2 (7.5 mol %), AgBF4 (30 mol %), Cu(OAc)2·H2O
b
c
(0.75 equiv), THF (2 mL), temp 120 °C, time 3 h. Isolated yields. 8
mmol scale reaction.
with N-(4-acetyl) phenyl and N-(methyl-4-benzoate) sub-
stituted maleimide furnished the corresponding Heck-type
products 3ae and 3af in moderate yields (52% and 52%,
respectively). The reaction of unsubstituted maleimide with
lithium benzoate 1a afforded the corresponding decarbox-
ylative Heck-type product 3ag in 77% good yield. The
decarboxylative Heck-type reaction of N-ethyl maleimide 2a
with the Li salt of m-toluic acid occurred at both the ortho- and
para- positions forming the corresponding regioisomers 3ba
and 3ba′ in a 9:1 ratio as an inseparable mixture in 70% yield.
The reaction of the lithium salt of 2-methoxybenzoic acid with
2a gave the corresponding decarboxylative Heck-product 3ca
in 48% yield. The reaction of 2a with acid salts having electron-
donating groups such as OMe and an electron-withdrawing
group such as NO2 and Cl on the phenyl ring of the acid
furnished the products 3da−3fa in 57−62% yield. Likewise,
the reactions of 2a with carboxylic acid salts that have −CHO
and COCH3 groups at the para-position of the phenyl ring of
the acid afforded the products 3ga and 3ha in 40% and 48%
yields, respectively. The reaction of 2a with a 3,4,5-trimethoxy
substituted acid salt derivative displayed good reactivity
forming 3ia in 61% yield. However, the reaction of 2a with
1-naphthoic acid salt rendered the product 3ja in 26% yield.
The Li salt of 2-fumaric acid and cinnamic acid failed to
furnish the corresponding decarboxylative Heck-type product.
C
DOI: 10.1021/acs.orglett.9b01412
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Letter
The D2O labeling experiment has been performed to gain
insight into the reaction mechanism (Scheme 4). The reaction
To the best of our knowledge, this is the first report of
decarboxylative Heck-type and 1,1-type annulation reactions of
maleimide with benzoic acid. Some products obtained by
Heck-type reactions are also biologically active molecules.
Scheme 4. Deuteration Study
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.9b01412.
Experimental procedures, characterization data, and
spectra for all compounds (PDF)
of the Li salt of 3,4,5-trimethoxy benzoic acid with D2O in the
absence of maleimide under decarboxylative Heck-type
reaction conditions furnished dideuterated product 6 in 75%
yield with deuterium incorporation of 65% at both ortho-
positions of the acid derivative. This deuterium labeling
experiment indicates that the C−H activation step may be
reversible.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: prabhu@iisc.ac.in.
ORCID
Based on the literature precedence,5,8c a plausible reaction
mechanism is shown in Scheme 5. The [RhCp*Cl2]2 generates
Kandikere Ramaiah Prabhu: 0000-0002-8342-1534
Notes
Scheme 5. Plausible Mechanism
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by SERB (EMR/2016/006358),
New-Delhi, Indian Institute of Science, and R. L. Fine Chem.
We thank Dr. A. R. Ramesha (R. L. Fine Chem) for useful
discussions.
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