Switchable C?H Alkylation of Aromatic Acids with Maleimides in Water: Carboxyl as a Diverse Directing Group

Article abstract of DOI:10.1002/cctc.201900444

A ruthenium-catalyzed protocol to access conjugate addition or decarboxylative conjugate addition of aromatic acids with maleimides has been developed. The reaction shows interesting chemoselectivity with different substituted benzoic acids. The reaction pathway of C?H alkylation is controlled by the intrinsic property of aromatic acids but not reaction conditions. Under almost the same reaction conditions, carboxyl can act as either a classical directing group or a traceless directing group, thereby generating two kinds of products, i. e., 2-alkyl substituted benzoic acids and alkyl substituted benzenes. These two reactions proceeded under mild and redox-neutral conditions in neat water under the atmosphere of air, and could be easily scaled up to grams. The decarboxylative conjugate addition, where carboxyl acts as a traceless directing group, can be realized without the addition of any ligand, silver or copper salt.

Full text of DOI:10.1002/cctc.201900444

Accepted Article
Title: Switchable C−H Alkylation of Aromatic Acids with Maleimides in
Water: Carboxyl as a Diverse Directing Group
Authors: Xian-ying Shi, Fan Pu, Zhong-Wen Liu, Lin-Yan Zhang, and
Juan Fan
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemCatChem 10.1002/cctc.201900444
Link to VoR: http://dx.doi.org/10.1002/cctc.201900444
A Journal of
www.chemcatchem.org

10.1002/cctc.201900444
ChemCatChem
FULL PAPER
Switchable C−H Alkylation of Aromatic Acids with Maleimides in
Water: Carboxyl as a Diverse Directing Group
Fan Pu,[a] Zhong-Wen Liu,[a] Lin-Yan Zhang, [a] Juan Fan,[a] and Xian-Ying Shi*[a]
Dedication ((optional))
Abstract: A ruthenium-catalyzed protocol to access conjugate
addition or decarboxylative conjugate addition of aromatic
acids with maleimides has been developed. The reaction
shows interesting chemoselectivity with different substituted
benzoic acids. The reaction pathway of C−H alkylation is
controlled by the intrinsic property of aromatic acids but not
reaction conditions. Under almost the same reaction
conditions, carboxyl can act as either a classical directing
group or a traceless directing group, thereby generating two
kinds of products, i.e., 2-alkyl substituted benzoic acids and
alkyl substituted benzenes. These two reactions proceeded
under mild and redox-neutral conditions in neat water under
the atmosphere of air, and could be easily scaled up to
grams. The decarboxylative conjugate addition, where
carboxyl acts as a traceless directing group, can be realized
without the addition of any ligand, silver or copper salt.
conjugate additions of C−H to maleimides were developed by
several research groups.[7] Ackermann and Li demonstrated
(hetero)aryl and alkenyl C−H alkylation of maleimides with
maleate esters under remarkably mild reaction conditions.[8] The
manganese-catalyzed addition of C-2 position of indoles to
maleimides has been developed by Gong and Song under
additive-free conditions.[9] Cobalt(III)-catalyzed conjugate
addition of C–H bonds in oximes and enamides to maleimides
was illuminated by Zhang and Wu successively.[10] Shi and Kim
reported Csp3−H alkylation of 8‑methylquinolines, amino acids
and peptides with maleimides, respectively.[11]
Carboxylic acids with the following advantages have been
applied extensively in C−H functionalization.[12] It widely exists in
organic molecules and can be obtained from many other
functional groups readily. The carboxyl group can be easily
transformed into diverse functional groups or be removed via
decarboxylation after directed C−H functionalization. Carboxyl
directed hydroarylations were successively achieved by
Gooßen’s group, who employ α,ß-unsaturated carbonyl
compounds, alkynes, and allyl amines as reaction partners,
respectively.[13] Moreover, all the reported reactions between
aromatic acids and maleimides delivered decarboxylative
Introduction
Succinimides are important motif found in many natural
products as well as pharmaceuticals with distinctive bioactivities
such as phensuximide, ethosuximide, and mesuximide.[1]
Succinimide moieties can be readily transferred to biologically
relevant pyrrolidines, and synthetically useful derivatives.[2] Thus,
much effort has been devoted to develop efficient methodologies
synthesizing these compounds in the past decades.[3] Recently,
the direct addition of Csp2–H bonds onto polar C=C provides a
more direct, atom- and step economical alternative to many
important compounds because all of the substrates are
incorporated into the target products.[4] As an easily available
starting material and a highly electrophilic olefin, maleimides
were frequently utilized in introducing the succinimide structures
into organic molecules to construct complex structures.[5] In this
context, Prabhu and his co-workers successively reported N-
substituted carboxamide, pyrimidinyl, azo, ketone and benzoyl
directed conjugate addition of C−H to maleimides catalyzed by
ruthenium, cobalt and rhodium catalyst, respectively.[6] Moreover,
rhodium- and cobalt-catalyzed carbonyl- or carbamoyl-directed
hydroarylation products. Prabhu disclosed
a rhodium(III)-
catalyzed C−H activation followed by conjugate addition to
maleimides, using carboxylic acid as a traceless directing
group.[14] Subsequently, Baidya and Ackermann demonstrated
ruthenium(II)-catalyzed hydroarylation of maleimides with aryl
carboxylic acids based on carboxyl-directed ortho-C−H
alkylation and concomitant decarboxylation processes,
fabricating 3-aryl succinimides, respectively (Scheme 1a).[15]
However,
these
rhodium-
or
ruthenium-catalyzed
decarboxylative alkylations have been realized only in the
organic solvent of 1,2-dichloroethane. Thus, a more sustainable
method is still highly desirable to accomplish these
transformations in a more green manner.[16] Moreover, the non-
decarboxylative hydroarylation of aromatic acids with
[a]
Fan Pu, Prof. Dr. Zhong-Wen Liu, Juan Fan, Prof. Dr. Xian-Ying Shi
Key Laboratory of Syngas Conversion of Shaanxi Province, Key
Laboratory for Macromolecular Science of Shaanxi Province, Key
Laboratory of the Ministry of Education for Medicinal Resources and
Natural Pharmaceutical Chemistry, National Engineering Laboratory
for Resource Development of Endangered Crude Drugs in
Northwest of China, School of Chemistry and Chemical Engineering,
Shaanxi Normal University, Xi’an 710062 (China)
E-mail: shixy@snnu.edu.cn
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
Scheme 1. Reactions between aromatic acids and maleimides.
This article is protected by copyright. All rights reserved.

10.1002/cctc.201900444
ChemCatChem
FULL PAPER
has also not been reported, which may be due to its high
tendency towards the competitive transformations such as the
cascade cyclization and the decarboxylation.
Table 1. Selected results for optimizing reaction conditions.[a]
Water as an environmentally benign, nonflammable, and
nontoxic reaction medium has been attracted considerable
attention in sustainable C−H bond functionalizations.[17] A few
examples of ruthenium-catalyzed hydroarylations in water have
been demonstrated,[14] including the direct addition of amides
and aromatic acids with conjugated alkenes, the intramolecular
hydroarylation of arenes with olefins, and annulations of alkynes
by benzamides and heteroaromatic acids.[13c, 18]
Based on these understandings and our continuous interest in
C−H functionalizations in water,[18f] herein we describe a
ruthenium(II)-catalyzed protocol to access conjugate addition or
decarboxylative conjugate addition of aromatic acids with
maleimides under mild and redox-neutral conditions in benign
water as a reaction medium (Scheme 1b). Carboxyl can serve
as either a classical directing group or a traceless directing
group, which is controlled by the intrinsic property of aromatic
acids but not reaction conditions. The reaction is
environmentally friendly, operationally simple, and not sensitive
to air. Noteworthy, although carboxyl as a classical or a
traceless directing group has been extensively studied,[12] the
reaction pathway controlled by the intrinsic property of aromatic
acids but not reaction conditions has never been reported.
Entry
additive
Solvent
Yield (%)[b]
3a 3a’
1
2
-
H2O
H2O
67
76
45
70
44
54
45
58
61
24
trace
trace
0
6
9
NaH2PO4
Na2HPO4
KH2PO4
3
H2O
11
9
4
H2O
5
K2HPO4
H2O
13
14
10
11
13
trace
0
6
NaOAc
H2O
7
HCOONa
PivONa·H2O
KOAc
H2O
8
H2O
9
H2O
10
11
12
13
14
15
NaH2PO4
NaH2PO4
NaH2PO4
NaH2PO4
NaH2PO4
NaH2PO4
THF
1,4-dioxane
DME
DCE
0
0
toluene
CH3CN
0
0
0
0
[a] Reactions were carried out with 1a (0.1 mmol), 2a (0.15 mmol),
[RuCl2(p-cymene)]2 (5 mol%), additive (0.5 equiv), solvent (0.5 mL) at
85 °C for 24 h, under air. [b] Determined by 1H NMR analysis of the
crude reaction mixture using 1,3,5-trimethoxybenzene as internal
standard.
Results and Discussion
We initiated our study by reacting 2-toluic acid (1a) with N-
methyl maleimide (2a) via the catalysis of [RuCl2(p-cymene)]2 (5
mol%) in neat water under atmosphere of air. The conjugate
addition product 3a was formed in 67% yield at 85 oC
accompanied with 6% yield of decarboxylative product 3a’
(Table 1, entry 1). Then, the amount of the catalyst, reaction
time and temperature were tested. Unfortunately, variation of
these parameters did not enhance the yield of 3a. Gratifyingly, it
was found that the yield could be increased to 76% by the
addition of NaH2PO4 (Table 1, entry 2). On the contrary, other
alkali salts such as Na2HPO4, KH2PO4, K2HPO4, NaOAc,
HCOONa, PivONa·H2O, and KOAc are less efficient in this
transformation (Table 1, entries 3-9). To our surprise, the
utilization of commonly used organic solvents such as THF, 1,4-
dioxane, DME, DCE, toluene, and CH3CN afforded
unsatisfactory yield of 3a (Table 1, entries 10-15).
With the optimized reaction conditions in hand, the present
conjugate addition reaction was then carried out between a
series of substituted benzoic acids and N-methyl maleimide. As
can be seen in Table 2, this methodology was applicable to
diverse aromatic acids irrespective of the nature of their
substituents. Ortho-substituted benzoic acids bearing electron-
donating groups, such as C2H5, Ph, PhCH2, PhCH2CH2, all
delivered the addition products in moderate to good yields (3b-
3e, 50-74%). 2-Iodobenzoic acid showed lower reactivity in this
reaction affording 3f in 39% yield. However, 2-ethoxybenzoic
acid generated rather low yield of addition product (8% NMR
yield). Strong electron-withdrawing groups such as CF3 and NO2
were also tolerated. 2-(Trifluoromethyl)benzoic acid produced
moderate yields (3g, 55%). While 2-nitrobenzoic acid afforded
addition products in a lower yield of 25% (NMR yield). For meta-
substituted substrates such as 3-toluic acid and 3-
(trifluoromethyl)benzoic acid, better regioselectivity occurring in
a less hindered C−H bond was observed (3h-3i). However,
when para-substituted benzoic acids including CH3, CH3O, Cl,
Br, I, CF3 and NO2 were employed, a trace amount of addition
products was detected. Moreover, all cyano substituted benzoic
acids including 2-, 3- or 4-cyanobenzoic acids showed a poor
reactivity. Disubstituted aromatic acids, such as 2,3- and 2,4-
disubstituted benzoic acids, were also applicable in this
transformation affording the target products in moderate to good
yields (3j-3o, 50-70%).
Several maleimides were used to examine the compatibility of
this on water conjugate addition with 2-toluic acid, 2-
ethylbenzoic acid and 2-benzylbenzoic acid, respectively.
Unprotected maleimide, i.e., N−H maleimide, led to the desired
products in good isolated yields (3p of 60% and 3q of 70%).
Substrates with protecting groups of ethyl afforded the expected
products in moderate to good yields (3r-3t, 56-74%). To our
delight, N-substituted maleimides bearing bulky protecting
groups such as tertiary butyl and benzyl, also delivered the
corresponding products in moderate to good yields (3u-3y, 50-
70%). As for this transformation, decarboxylative addition
products were observed as side products (see Supporting
This article is protected by copyright. All rights reserved.

10.1002/cctc.201900444
ChemCatChem
FULL PAPER
Table 3. Substrate scope for decarboxylative conjuage addition.[ a]
Table 2. Substrate scope for conjugate addition. [ a]
[a] Reaction conditions: aromatic acids (0.2 mmol), maleimides (0.3 mmol),
[RuCl2(p-cymene)]2 (5 mol%), NaH2PO4 (0.1 mmol), deionized water (0.6 mL),
85 °C, 24 h, isolated yield.
Information Table S1).
Surprisely, the reaction between 2-phenoxybenzoic acid and
N-methyl maleimide under this catalytic system generated 1-
methyl-3-(3-phenoxyphenyl)pyrrolidine-2,5-dione (4a) in a 74%
isolated yield in water and air. The process involves carboxyl-
directed conjugate addition of C−H bond to the polar double
bond of maleimide with concerted decarboxylation, in which
carboxyl acts as a traceless directing group. Although the
rhodium or ruthenium-catalyzed decarboxylative hydroarylation
of maleimides were demonstrated by Ackermann, Ramaiah and
Mahiuddin Baidya,[14-15] respectively, the reactions all proceeded
in the organic solvent of DCE. Baidya also used [Ru(p-
cymene)Cl2]2 as the catalyst, however, phosphorus ligand of
Cy3PO is required in catalytic system.[15b] In viewing that water
is the most abundant compound on the earth surface, and is
regarded as a green solvent, various conditions including the
amount of catalyst, additive, reaction time and reaction
temperature were examined to further improve the yield of 4a.
Shortening the reaction time to 16 h, the isolated yield of 4a was
[a] Reaction conditions: aromatic acids (0.2 mmol), maleimides (0.3 mmol),
[RuCl2(p-cymene)]2 (5 mol%), NaH2PO4 (0.1 mmol), deionized water (0.6 mL),
85 °C, 16 h, isolated yield.
still 74%. No improved yield was observed in other reaction
conditions. Then, the applicability of this decarboxylative
hydroarylation of maleimides to establish 3-aryl succinimides in
water and air was investigated.
Firstly, the substrate scope was examined with respect to the
aromatic acids and N-methyl maleimide. It was found that this
decarboxylative conjugate addition depended greatly on the
substituent and its position. 2-Ethoxylbenzoic acid proceeded
smoothly to afford the desired product in a moderate yield
accompanied by 40% unreacted 2-ethoxybenzoic acid (4b, 51%).
This article is protected by copyright. All rights reserved.

10.1002/cctc.201900444
ChemCatChem
FULL PAPER
2- and 3-fluorobenzoic acid also worked well in the
decarboxylative reaction and provided moderate yields of
products (4c-4d, 65-66%). To our surprise, in the case of 3-
fluorobenzoic acid, the decarboxylative alkylation occurred at the
sterically hindered position. Moreover, 5-halogen substituted 2-
toluic acids, 2,5-dimethoxyl benzoic acid, and 5-halogen
substituted 2-methoxylbenzoic acids performed well under the
reaction conditions providing the product in moderate to
excellent yields regardless of steric hindrance effect (4e-4l, 48-
93%). The reaction is compatible with sensitive functional group,
such as hydroxyl (4m, 86%). However, benzoic acid proved to
be a poor substrate for decarboxylative reaction, providing
decarboxylative product in a rather low NMR yield of 18% (4w)
accompanied by 6% NMR yield of conjugate addition product
(3z). Very interestingly, when 2-alkyl benzoic acids, 3-toluic acid,
2,3-disubstituted benzoic acids, and 4-disubstituted benzoic
acids were utilized to react with N-methyl maleimide under
almost the same reaction conditions, non-decarboxylative
conjugate addition products were isolated as main products but
not decarboxylative products. These results illuminate that the
main product under the present catalytic system is determined
by the intrinsic property of aromatic acids but not reaction
conditions. Moreover, the good to excellent selectivity of non-
decarboxylative or decarboxylative products was observed in
these two transformations (See Supporting Information Table S1
and S2).
was treated in the absence of N-methyl maleimide (Scheme 2a).
The same reaction conducted in the presence of N-methyl
maleimide displayed a significant H/D scrambling in the product
[Dn]-3z and [Dn]-4w (Scheme 2b). These results suggest that a
reversible cyclometalation mode was involved.[19] The kinetic
isotope effect was investigated via competition and parallel
experiments within 15 min, respectively. A KIE of 3.1 (parallel
experiment and kH/kD= 7.6 (competition experiment) were
observed (Scheme 3a and 3b), which illuminates that the C‒H
bond cleavage might be related with the rate determining step.[20]
We next examined the scope of maleimides in decarboxylative
conjugate addition with 5-fluoro-2-methoxybenzoic acid in neat
water. Similar to conjugate addition, maleimide, N-ethyl, N-
cyclohexyl, N-2-carboxyethyl and N-benzyl maleimide could be
efficiently converted into the corresponding decarboxylative
products in good to excellent yields (4n-4q, 4s, 66-84%).
Unexpectedly, N-tert-butyl maleimide displayed good activity
despite steric hindrance (4r, 80%). In addition to N-alkyl
maleimide, phenyl and substituted phenyl such as 4-
hydroxyphenyl and 4-bromophenyl, employed in place of alkyl
groups did not affect the outcome of the reaction (4t-4v, 50-
81%). In most cases, the high conversion of aromatic acids was
observed. Moreover, almost no conjugate addition product was
detected (see Supporting Information Table S2).
Scheme 3. The experiments to determine the kinetics isotopic.
Further experiments were carried out to probe the possible
reaction mechanism. First, experiments were performed with
D2O as the solvent. 98% Deuterium incorporation was observed
at the two ortho positions of the carboxyl when the benzoic acid
Scheme 4. Reaction of 3-aryl succinimde under standard reaction conditions.
To test whether direct conjugate addition product is an
intermediate to form decarboxylative product, we prepared 3-
fluoro-6-methyl-2-(1-methyl-2,5-dioxopyrrolidin-3-yl)benzoic acid
(4e’) and treated it under standard reaction conditions (Scheme
4). However, 4e was not detected after the reaction, indicating
that the decarboxylative conjugate addition product are not
produced via a sequence of conjugate addition followed by
protodecarboxylation.
Scheme 2. Probing the reversibility of the C‒H activation step.
On the basis of these observations as well as previous reports
This article is protected by copyright. All rights reserved.

10.1002/cctc.201900444
ChemCatChem
FULL PAPER
about ruthenium-catalyzed carboxyl-directed C‒H activation and
carboxyl as
expected products of 3a and 4j was obtained in satisfactory
isolated yields of 76% and 88%, respectively (Scheme 6). In
addition, the synthesis of spirosuccinimide (5a), which is of
potent interest in medicinal chemistry, was successfully
demonstrated in a short time via intramolecular dehydrogenation
of 3a (Scheme 7).
a a plausible
traceless directing group,[21-22]
mechanism for the present conjugate addition and
decarboxylative conjugate addition was depicted in Scheme 5.
Firstly, the dimer [RuCl2(p-cymene)]2 catalyst dissociates to a
coordinatively unsaturated monomer A, which undergoes
cyclometallation with carboxyl to generate five-membered
ruthenium-cyclic intermediate B. Ru species in B coordinates to
the maleimides followed by migratory insertion affording
ruthenacycle D. Ruthenacycle D could proceed by two pathways.
Direct protonolysis of D releases conjugate addition products 3a-
3z. The alternative pathway affords decarboxylative conjugate
products 4a-4v via decarboxylation of D and subsequent
protonolysis. Under this catalytic system, the substrates
determine the main reaction pathway of intermediate D.
Scheme 7. Synthesis of spirosuccinimide.
Conclusions
In summary, we have developed a ruthenium-catalyzed
switchable reaction to obtain either a conjugate addition product
or a decarboxylative conjugate addition product from easily
accessible aromatic acids and maleimides. A variety of different
aryl substituted succinimides were obtained in moderate to
excellent yields. It is interesting to note that aromatic acid plays
a pivotal role in the chemoselectivity but not reaction conditions.
The use of water as solvent under atmosphere of air makes this
approach very environmentally friendly and practical. Given the
mild and redox-neutral conditions in neat water, operational
simplicity, easily scale-up to gram level, these methods may find
applications in the synthesis of related complex structures.
Experimental Section
Scheme 5. A plausible reaction mechanism.
General Information
1H NMR spectra and 13C NMR spectra were measured on a 400 MHz
spectrometer or 600 MHz spectrometer (13C NMR 100 MHz or 150 MHz),
with tetramethylsilane (TMS) as the internal standard at room
temperature. Chemical shifts are given in δ relative to TMS, with the
coupling constants J given in Hz. High-resolution mass spectra (HRMS)
were obtained from a Bruker Compass-Maxis instrument (ESI). All
solvents were dried and/or distilled by standard methods. All reagents
were purchased from commercial sources and used without further
purification. All work-up and purification procedures were carried out with
analytical reagent solvents. D5-benzoic acid was prepared according to
previous report.[23]
General procedure for ruthenium-catalyzed conjugate
addition of aromatic acids with maleimides
An oven-dried reaction vessel was charged with [RuCl2(p-cymene)]2 (Ru*,
6.1 mg, 5 mol%, 0.01 mmol), aromatic acids (0.2 mmol), maleimides (0.3
mmol), NaH2PO4 (12.0 mg, 0.1 mmol), deionized water (0.6 mL). The
mixture was stirred under air at 85 °C (oil bath temperature) for 24 h.
After cooling to room temperature, the mixture was diluted with EtOAc (5
mL) and filtered through a short silica gel pad. The filter cake was further
flushed with EtOAc (3 × 5 mL). The combined solution was concentrated
under vacuum, and the residue was purified by a preparative thin-layer
chromatography to afford the corresponding product.
Scheme 6. Gram-scale preparation of 3a and 4j.
To further explore the practicality of these two on water
reactions, 10 mmol and 4 mmol scale reactions of 2-toluic acid
and 5-fluoro-2-methoxybenzoic acid were carried out with N-
methyl maleimide, respectively. We were pleased to find that the
This article is protected by copyright. All rights reserved.

10.1002/cctc.201900444
ChemCatChem
FULL PAPER
General procedure for ruthenium-catalyzed decarboxylative
conjugate addition of aromatic acids with maleimides
An oven-dried 50 mL Schlenk tube was charged with 5-fluoro-2-
methoxybenzoic acid (0.6802 g, 4 mmol), N-methyl maleimide (0.6666 g,
6 mmol), [RuCl2(p-cymene)]2 (Ru*, 0.1225 g, 0.2 mmol), NaH2PO4
(0.2400 g, 2 mmol), and deionized water (12 mL). The mixture was
stirred at 85 °C (oil bath temperature) in air for 16 h. Then, the reaction
mixture was concentrated to give a crude product, which is purified by
silica-gel column chromatography using hexanes/EtOAc (5/1) to yield
compound 4j (0.836 g, 88%).
An oven-dried reaction vessel was charged with [RuCl2(p-cymene)]2 (Ru*,
6.1 mg, 5 mol%, 0.01 mmol), aromatic acids (0.2 mmol), maleimides (0.3
mmol), NaH2PO4 (12.0 mg, 0.1 mmol), deionized water (0.6 mL). The
mixture was stirred under air at 85 °C (oil bath temperature) for 16 h.
After cooling to room temperature, the mixture was diluted with EtOAc (5
mL) and filtered through a short silica gel pad. The filter cake was further
flushed with EtOAc (3 × 5 mL). The combined solution was concentrated
under vacuum, and the residue was purified by a preparative thin-layer
chromatography to afford the corresponding product.
Experimental procedure for the synthesis of 4e’.
An oven-dried reaction vessel was charged with [RuCl2(p-cymene)]2 (Ru*,
3.1 mg, 5 mol%, 0.005 mmol), 5-fluoro-2-methylbenzoic acid (0.0154 g,
0.1 mmol), N-methyl maleimide (0.0166 g, 0.15 mmol), deionized water
(0.5 mL). The mixture was stirred under air at 85 °C (oil bath
temperature) for 24 h. After cooling to room temperature, the mixture was
diluted with EtOAc (5 mL) and filtered through a short silica gel pad. The
filter cake was further flushed with EtOAc (3 × 5 mL). The combined
solution was concentrated under vacuum, and the residue was purified
by a preparative thin-layer chromatography to afford 4e’.
Ortho deuteration experiment
[RuCl2(p-cymene)]2 (Ru*, 3.1 mg, 5 mol%, 0.005 mmol), benzoic acid
(12.2 mg, 0.1 mmol), NaH2PO4 (6.0 mg, 0.05 mmol), deuterium water
(0.3 mL), were successively added to a reaction vessel equipped with a
stir bar. The mixture was stirred at 85 °C (oil bath temperature) for 24 h.
The resulting mixture was cooled to room temperature, filtered through a
short column of silica gel. The solvent was removed under reduced
pressure and the amount of ortho-deuterated benzoic acid was
determined by the relative ratio of peak area.
Experimental
procedures
for
the
synthesis
of
spirosuccinimide.
KIE experiment (parallel experiments)
An oven-dried reaction vessel was charged with 3a (24.7 mg, 0.1 mmol),
CuCl (4.9 mg, 0.05 mmol), N,N-dimethylformamide (0.6 mL). The vessel
was heated at 140 °C (oil bath temperature) for 15 min under air. When
the reaction was complete, the resulting mixture was cooled to room
temperature, and filtered through a short silica gel pad. Then, the mixture
was concentrated in vacuo to give a residue, which was purified by
preparative thin-layer chromatography (TLC) on silica gel to afford the
corresponding product.
[RuCl2(p-cymene)]2 (Ru*, 3.1 mg, 5 mol%, 0.005 mmol), benzoic acid
(12.2 mg, 0.1 mmol), N-methyl maleimide (16.7 mg, 0.15 mmol),
NaH2PO4 (6.0 mg, 0.05 mmol), deionized water (0.3 mL), were
successively added to a reaction vessel equipped with a stir bar. In
another reaction vessel, D5-benzoic acid (12.7 mg, 0.1 mmol) was used
instead of benzoic acid. The two reactions were stirred at 85 °C (oil bath
temperature) for 5 min, 7.5 min, 10 min 12.5 min, 15 min respectively.
Then the two reaction mixtures were filtered through a short column of
1
silica gel. The solvent was then removed under reduced pressure and H
NMR used 1,3,5-trimethoxybenzene as the internal standard. Thus the
KIE was found to be 3.1.
Acknowledgements
The authors are grateful to the National Natural Science
Foundation of China (Grant No. 21776171, 21636006 and
21572122), the Fundamental Research Funds for the Central
Universities (Grant No. GK201906005 and GK201901001) for
providing financial supports.
KIE experiment (intermolecular competition)
[RuCl2(p-cymene)]2 (Ru*, 3.1 mg, 5 mol%, 0.005 mmol), benzoic acid
(6.1 mg, 0.05 mmol), D5-benzoic acid (6.4 mg, 0.05 mmol), N-methyl
maleimide (16.7 mg, 0.15 mmol), NaH2PO4 (6.0 mg, 0.05 mmol),
deionized water (0.3 mL), were successively added to a reaction vessel
equipped with a stir bar. The mixture was stirred at 85 °C (oil bath
temperature) for 15 min. Then the reaction mixtures were filtered through
a short column of silica gel. The solvent was then removed under
reduced pressure and 1H NMR used 1,3,5-trimethoxybenzene as the
internal standard. Thus the KIE was found to be 7.6.
Keywords: on water reaction • ruthenium catalysis• conjugate
addition •
[1]
a) K. Kamiński, J. Obniska, I. Chlebek, B. Wiklik, S. Rzepka, Bioorg.
Med. Chem. 2013, 21, 6821–6830; b) M. Crider, T. M. Kolczynski, K. M.
Yates, J. Med. Chem. 1980, 23, 324–326; c) J. Uddin, K. Ueda, E. R. O.
Siwu, M. Kita, D. Uemura, Bioorg. Med. Chem. 2006, 14, 6954–6961; d)
H. P. Cho, D. W. Engers, D. F. Venable, C. M. Niswender, C. W.
Lindsley, P. J. Conn, K. A. Emmitte, A. L. Rodriguez, ACS Chem.
Neurosci. 2014, 5, 597−610; e) J. Wrobel, A. Dietrich, S. A. Woolson, J.
Millen, M. McCaleb, M. C. Harrison, T. C. Hohman, J. Sredy, D.
Sullivan, J. Med. Chem. 1992, 35, 4613−4627.
Experimental procedure for the synthesis of 3a on 10 mmol
scale
An oven-dried 100 mL Schlenk tube was charged with 2-methylbenzoic
acid (1.3600 g, 10 mmol), N-methyl maleimide (1.6665 g, 15 mmol),
[RuCl2(p-cymene)]2 (Ru*, 0.3062 g, 0.5 mmol), NaH2PO4 (0.5999 g, 5
mmol), and deionized water (30 mL). The mixture was stirred at 85 °C (oil
bath temperature) in air for 24 h. Then, the reaction mixture was
concentrated to give a crude product, which is purified by silica-gel
column chromatography using hexanes/EtOAc/AcOH (2/1/0.05) to yield
compound 3a (1.875 g, 76%).
[2]
[3]
H. Gali, K. R. Prabhu, S. R. Karra, K. V. Katti, J. Org. Chem. 2000, 65,
676−680.
a) Z. Han, P. Li, Z. Zhang, C. Chen, Q. Wang, X. Q. Dong, X. Zhang,
ACS Catal. 2016, 6, 6214−6218; b) P. Williamson, A. Galván, M. J.
Gaunt, Chem. Sci. 2017, 8, 2588−2591; c) N. Barsu, S. K. Bolli, B.
Sundararaju, Chem. Sci. 2017, 8, 2431−2435.
Experimental procedure for the synthesis of 4h on 4 mmol
scale.
This article is protected by copyright. All rights reserved.

10.1002/cctc.201900444
ChemCatChem
FULL PAPER
[4]
[5]
For reviews, see: a) F. Kakiuchi, S. Murai, Acc. Chem. Res. 2002, 35,
[15] a) N. Y. P. Kumar, T. Rogge, S. R. Yetra, A. Bechtoldt, E. Clot, L.
Ackermann, Chem. Eur. J. 2017, 23, 17449−17453; b) M. Baidya, A.
Mandal, H. Sahoo, S. Dana, M. Baidya, Org. Lett. 2017, 19, 4138−4141.
[16] R. N. Butler, A. G. Coyne, Chem. Rev. 2010, 110, 6302−6337.
[17] a) C. I. Herrerías, X. Yao, Z. Li, C. J. Li, Chem. Rev. 2007, 107,
2546−2562; b) B. Li, P. H. Dixneuf, Chem. Soc. Rev. 2013, 42,
5744−5767.
826−834; b) L. Yang, H. Huang, Chem. Rev. 2015, 115, 3468−3517; c)
V. Ritleng, C. Sirlin, M. Pfeffer, Chem. Rev. 2002, 102, 1731−1769.
a) K. R. Bettadapur, M. S. Sherikar, V. Lanke, K. R. Prabhu, Asian J.
Org. Chem. 2018, 7, 1338−1342; b) N. Muniraj, K. R. Prabhu, Org. Lett.
2019, 21, 1068−1072; c) W. Miura, K. Hirano, M. Miura, Org. Lett. 2015,
17, 4034−4037; d) S. Sharma, S. H. Han, Y. Oh, N. K. Mishra, S. H.
Lee, J. S. Oh, I. S. Kim, Org. Lett. 2016, 18, 2568−2571; e) N. Lv, Y.
Liu, C. Xiong, Z. Liu, Y. Zhang, Org. Lett. 2017, 19, 4640−4643; f) R.
Manoharan, M. Jeganmohan, Org. Lett. 2017, 19, 5884−5887; g) C.
Zhu, J. Luan, J. Fang, X. Zhao, X. Wu, Y. Li, Y. Luo, Org. Lett. 2018, 20,
5960−5963; h) Z. H. Yang, Z. H. Chen, Y. L. Ana, S. Y. Zhao, RSC Adv.
2016, 6, 23438−23447; i) J. Ji, Z. Yang, R. Liu, Y. Ni, S. Lin, Q. Pan,
Tetrahedron Lett. 2016, 57, 2723−2726; j) H. Zhao, X. Shao, T. Wang,
S. Zhai, S. Qiu, C. Tao, H. Wang, H. Zhai, Chem. Commun. 2018, 54,
4927−4930; k) M. Tamizmani, B. Ramesh, M. Jeganmohan, J. Org.
Chem. 2018, 83, 3746−3755; l) S. Manna, A. P. Antonchick, Chem. Eur.
J. 2017, 23, 7825−7829; m) S. H. Han, N. K. Mishra, M. Jeon, S. Kim,
H. S. Kim, S. Y. Jung, Y. H. Jung, J. M. Ku, I. S. Kim, Adv. Synth. Catal.
2017, 359, 3900−3904.
[18] a) J. Li, L. Ackermann, Org. Chem. Front. 2015, 2, 1035–1039; b) K.
Mukherjee, E. Ramesh, K. Ghosh, A. K. Sahoo, Asian J. Org. Chem.
2018, 7, 1380 –1384; c) L. Ackermann, S. Fenner, Org. Lett. 2011, 13,
6548–6551; d) K. S. Singh, S. G. Sawant, P. H. Dixneuf,
ChemCatChem 2016, 8, 1046–1050; e) W. J. Han, F. Pu, C. J. Li, Z. W.
Liu, J. Fan, X. Y. Shi, Adv. Synth. Catal. 2018, 360, 1358−1363.
[19] W. Xie, J. Yang, B. Wang, B. Li, J. Org. Chem. 2014, 79, 8278−8287; b)
P. Duan, X. Lan, Y. Chen, S. S. Qian, J. J. Li, L. Lu, Y. Lu, B. Chen, M.
Hong, J. Zhao, Chem. Commun. 2014, 50, 12135−12138; c) L.
Ackermann, A. V. Lygin, N. Hofmann, Angew. Chem. 2011, 123,
6503−6506; Angew. Chem. Int. Ed. 2011, 50, 6379−6382; d) L. Wang,
L. Ackermann, Org. Lett. 2013, 15, 176−179.
[20] a) H. Zhang, K. Wang, B. Wang, H. Yi, F. Hu, C. Li, Y. Zhang, J. Wang,
Angew. Chem. 2014, 126, 13450–13454; Angew. Chem. Int. Ed. 2014,
53, 13234–13238; b) Y. Xia, Z. Liu, S. Feng, Y. Zhang, J. B. Wang, J.
Org. Chem. 2015, 80, 223–236; c) M. Zhang, H. J. Zhang, T. Han, W.
Ruan, T. B. Wen, J. Org. Chem. 2015, 80, 620–627; d) X. Geng, C.
Wang, Org. Lett. 2015, 17, 2434–2437; e) Y. Álvarez-Casao, C. A. M. R.
van Slagmaat, G. K. M. Verzijl, L. Lefort, P. L. Alsters, M. Á.
Fernández-Ibáñez, ChemCatChem 2013,10, 2620−2626.
[6]
[7]
a) P. Keshri, K. R. Bettadapur, V. Lanke, K. R. Prabhu, J. Org. Chem.
2016, 81, 6056−6065; b) N. Muniraj, K. R. Prabhu, ACS Omega 2017,
2, 4470−4479; c) N. Muniraj, K. R. Prabhu, J. Org. Chem. 2017, 82,
6913−6921; d) K. R. Bettadapur, V. Lanke, K. R. Prabhu, Org. Lett.
2015, 17, 4658−4661; e) V. Lanke, K. R. Bettadapur, K. R. Prabhu, Org.
Lett. 2015, 17, 4662−4665; f) M. S. Sherikar, R. Kapanaiah, V. Lanke,
K. R. Prabhu, Chem. Commun. 2018, 54, 11200−11203.
a) J. T. Yu, R. Chen, H. Jia, C. Pan, J. Org. Chem. 2018, 83,
12086−12093; b) C. Pan, Y. Wang, C. Wu, J. T. Yu, Org. Biomol. Chem.
2018, 16, 693−697; c) Q. He, T. Yamaguchi, N. Chatani, Org. Lett.
2017, 19, 4544−4547; d) R. Mandal, B. Emayavaramban, B.
Sundararaju, Org. Lett. 2018, 20, 2835−2838; e) S. Sharma, S. H. Han,
H. Jo, S. Han, N. K. Mishra, M. Choi, T. Jeong, J. Park, I. S. Kim, Eur. J.
Org. Chem. 2016, 3611−3618.
[21] a) H. Miura, S. Terajima, T. Shishido, ACS Catal. 2018, 8, 6246−6254;
b) C. S. Wang, P. H. Dixneuf, J. F. Soule, ChemCatChem 2017, 9,
3117−3120; c) Y. Kommagalla, V. B. Mullapudi, F. Francis, C. V.
Ramana, Catal. Sci. Technol. 2015, 5, 114−117; d) P. B. Arockiam, C.
Fischmeister, C. Bruneau, P. H. Dixneuf, Angew. Chem. 2010, 122,
6779−6782; Angew. Chem. Int. Ed. 2010, 49, 6629−6632; e) Z. Wu, S.
Chen, C. Hu, Z. Li, H. Xiang, X. Zhou, ChemCatChem 2013, 5,
2839−2842.
[8]
[9]
Z. Zhang, S. Han, M. Tang, L. Ackermann, J. Li, Org. Lett. 2017, 19,
3315−3318.
[22] a) A. Biafora, B. A. Khan, J. Bahri, J. M. Hewer, L. J. Gooßen, Org. Lett.
2017, 19, 1232−1235; b) L. Huang, A. Biafora, G. Zhang, V. Bragoni, L.
J. Gooßen, Angew. Chem. 2016, 128, 7047−7051; Angew. Chem. Int.
Ed. 2016, 55, 6933−6937; c) X. Y. Shi, X. F. Dong, J. Fan, K. Y. Liu, J.
F. Wei, C. J. Li, Sci. China Chem. 2015, 58, 1286−1291.
S. L. Liu, Y. Li, J. R. Guo, G. C. Yang, X. H. Li, J. F. Gong, M. P. Song,
Org. Lett. 2017, 19, 4042−4045.
[10] a) W. Yu, W. Zhang, Y. Liu, Z. Liu, Y. Zhang, Org. Chem. Front. 2017,
4, 77−80; b) X. Chen, J. Ren, H. Xie, W. Sun, M. Sun, B. Wu, Org.
Chem. Front. 2018, 5, 184−188.
[23] H. A. Chiong, Q. N. Pham, O. Daugulis, J. Am. Chem. Soc. 2007, 129,
9879−9884.
[11] a) B. B. Zhan, Y. Li, J. W. Xu, X. L. Nie, J. Fan, L. Jin, B. F. Shi, Angew.
Chem. 2018, 130, 5960 –5964; Angew. Chem. Int. Ed. 2018, 57, 5858–
5862; b) S. Han, J. Park, S. Kim, S. H. Lee, S. Sharma, N. K. Mishra, Y.
H. Jung, I. S. Kim, Org. Lett. 2016, 18, 4666−4669.
[12] For recent reviews, see: a) Y. Yang, K. Li, Y. Cheng, D. Wan, M. Li, J.
You, Chem. Commun. 2016, 52, 2872−2884; b) G. Shi, Y. Zhang, Adv.
Synth. Catal. 2014, 356, 1419−1442; c) M. P. Drapeau, L. J. Gooßen,
Chem. Eur. J. 2016, 22, 18654−18677; d) S. D. Sarkar, W. Liu, S. I.
Kozhushkov, L. Ackermann, Adv. Synth. Catal. 2014, 356, 1461−1479;
e) L. Ackermann, Acc. Chem. Res. 2014, 47, 281−295; f) M. Font, J. M.
Quibell, G. J. P. Perry, I. Larrosa, Chem. Commun. 2017, 53,
5584−5597; g) Y. Wei, P. Hu, M. Zhang, W. Su, Chem. Rev. 2017, 117,
8864−8907.
[13] a) G. Zhang, Z. Hu, F. Belitz, Y. Ou, N. Pirkl, L. J. Gooßen, Angew.
Chem. 2019, 131, DOI: 10.1002/ange.201901309; Angew. Chem. Int.
Ed. 2019, 58, DOI: 10.1002/anie.201901309; b) X. Q. Hu, Z. Hu, A. S.
Trita, G. Zhang, L. J. Gooßen, Chem. Sci. 2018, 9, 5289–5294; c) G.
Zhang, F. Jia, L. J. Gooßen, Chem. Eur. J. 2018, 24, 4537–4541; d) L.
Huang, A. Biafora, G. Zhang, V. Bragoni, L. J. Gooßen, Angew. Chem.
2016, 128, 7047–7051, Angew. Chem. Int. Ed. 2016, 55, 6933–6937; e)
X. Q. Hu, Z. Hu, G. Zhang, N. Sivendran, L. J. Gooßen, Org. Lett.
2018, 20, 4337–4340.
[14] K. R. Prabhu, K. R. Bettadapur, V. Lanke, K. R. Prabhu, Chem.
Commun. 2017, 53, 6251−6254.
This article is protected by copyright. All rights reserved.

10.1002/cctc.201900444
ChemCatChem
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 1:
FULL PAPER
Text for Table of Contents
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
((Insert TOC Graphic here: max.
width: 5.5 cm; max. height: 5.0 cm))
Layout 2:
FULL PAPER
Fan Pu, Zhong-Wen Liu, Juan Fan, and
Xian-Ying Shi*
Page No. – Page No.
Switchable
C−H
Alkylation
of
Aromatic Acids with Maleimides in
Water: Carboxyl as
Directing Group
a
Diverse
Text for Table of Contents
This article is protected by copyright. All rights reserved.