Approach to the Synthesis of Unsymmetrical/Symmetrical Maleimides via Desulfitative Arylation at Different Temperatures

Article abstract of DOI:10.1021/acs.joc.0c01323

New routes toward selective synthesis of both mono-and diaryl maleimides have been innovated. The mere requirement to this end is through the increase of temperature. The method works effectively for maleic anhydride and maleic acid as well. Also, the fir

Full text of DOI:10.1021/acs.joc.0c01323

Subscriber access provided by University of Wollongong Library
Article
An Approach to the Synthesis of Unsymmetrical/Symmetrical
Maleimides via Desulfitative Arylation at Different Temperatures
Masoumeh Abbasnia, Mehdi Sheykhan, Tahereh Ghaffari, and Elham Safari
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01323 • Publication Date (Web): 13 Aug 2020
Downloaded from pubs.acs.org on August 14, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
An Approach to the Synthesis of Unsymmetrical/Symmetrical Maleimides via
Desulfitative Arylation at Different Temperatures
7
8
9
Masoumeh Abbasnia, Mehdi Sheykhan,* Tahereh Ghaffari, and Elham Safari
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Chemistry Department, University of Guilan, P.O. Box 41335-1914, Rasht, Iran, Fax:
+981333367262, E-mail: sheykhan@guilan.ac.ir
KEYWORDS: Desulfitative arylation; maleimide; C-C bond formation; Palladium; Catalysis
ArSO2Y
Y = -Cl
ArSO2Y
O
O
O
O
O
O
Y = -Cl, -NHNH2
X
X
X
X = -NR, -O
Abstract
New routes toward selective synthesis of both mono- and diaryl maleimides have been
innovated. The mere requirement to this end is through the increase of temperature. The method
works effectively for maleic anhydride and maleic acid as well. Also, first expedient synthesis of
2-arylnaphthoquinones via the reaction of naphthoquinone with arenesulfonyl chlorides is
revealed.
Introduction
In Pd-catalysed cross couplings several contributors have been used as arylating groups. In this
2
3
4
realm, the reagents which liberate gaseous wastes such as CO1, CO2 , N2 and SO2 have
attracted great interest since the purification process are more facile. Commercially available
arenesulfonyl chlorides which are precursors of arenesulfonyl hydrazides have lately found
ACS Paragon Plus Environment
1

The Journal of Organic Chemistry
Page 2 of 33
1
2
3
4
5
6
7
8
9
widespread application in arylation reactions due to their lower price. Arylsulfonyl hydrazides
themselves are another source of arylating groups which enable one to place an aryl group on a
molecule through the extrusion of SO2 and N2 as the only waste of the reaction. In this line,
ample procedures have been disclosed showcasing the importance of these moieties in
lengthening carbon chains.4 Installation of one aryl group on another motif is a distinguished
way to construct the highly sought-after π-extended systems. Regardingly and in pursuit of our
ongoing program in C-H activations,5 we focused our attention on direct arylation of maleimides.
In this context, 3-aryl maleimides have found to act against Lewis lung carcinoma (LLC) cell
lines.6 They also show striking attributes in treatment of hypertention and liver cancer.6a
Specifically, 3-aryl-N-methyl maleimides can act as inhibitors of monoamine oxidase.7
Furthermore, they are precursors in the synthesis of Rubrolide E which is a bioactive compound
possessing antibiotic and significant cytotoxic activities.8 Scheme 1 represents some biological
active mono- and diarylated maleimides.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Some bioactive mono- and di-arylated maleimides
O
O
S
H
N
H2N
O
R
O
O
O
Cl
N H
N CH3
OH
HN
O
O
Cl
Cl
R'
NO2
GSK-3 inhibitor
COX-2 inhibitor
Glycogen syntase kinase inhibitor
HO
HO
O
O
N
O
O
O
O
N H
N CH3
OH
O
Monoamine oxidase B inhibitor
Denigrine A
(anti-tubercular agent)
Camphorataimide B
(anti-tumor)
ACS Paragon Plus Environment
2

Page 3 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Thus far all efforts for their indirect synthesis led to difunctionalized maleimidies9 and only a
few direct syntheses comprising well-established Meerwein reaction11 (Scheme 2, a), Heck
arylation10 (Scheme 2, b-d) and pre-halogenation of maleimides12 (Scheme 2, b) are available in
this realm. However, control of these reactions towards selective synthesis of 3-monoarylated
maleimides without any side reaction is still an ambitious goal and, to the best of our knowledge,
in most cases either 3-halo-4-arylhydromaleimides or 3,4-diarylmaleimides were formed as by-
products thus the yield of the main target molecule was usually unsatisfactory. Furthermore,
according to the previous literature,13 NH- and N-alkyl maleimides undergo rapid ring opening
upon exposure to bases, hence their reactions are very sensitive and must be handled diligently. It
is also worth mentioning that most transition-metals used to catalyze arylation of maleimides
yielded hydroarylated maleimides11c,14 and there are only a few reports in which the double bond
of maleimides has been conserved.12
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment
3

The Journal of Organic Chemistry
Page 4 of 33
1
2
3
4
Scheme 2. Previous methods for monoarylmaleimides
5
6
Monoarylation
Direct One-step
7
8
N2Cl
Low Yields
Mixture of Products
CuCl2 or
CuCl
ref. 11
9
(a)
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
O
O
N
N
R
R
Hazardous
Explosive
CH3
prefunctionalization
O
P
Pd2dba3
I
H3C
NEt3, THF
CH3
O
O
H3C
MW at 140 °C
(b)
O
O
+
O
O
$
N
N
R
ref. 10a
PA-Ph
R
Expensive reagent
Necessity of a ligand
PdCl2(MeCN)2
I
Bu4NCl
HCOOK
(c)
O
Low Yields
Limited Scope
O
+
O
O
$
N
ref. 10b
N
R
R
Expensive reagent
Ph
P
Pd(OAc)2
KOAc
Ethylene carbonate
I
Ph
Ph
Fe
(d)
O
N
O
+
O
O
P
$
ref. 10c
N
R
Ph
R
Expensive reagent
dppf
Necessity of a ligand
Price comparison of starting materials:
B(OH)2
SO2Cl
I
50
g
121 Euro
available from Sigma-Aldrich
product ID 78181
100
g
19.1 Euro
100 mL
100 Euro
available from Sigma-Aldrich
product ID 108138
available from Sigma-Aldrich
product ID 8.20730
On the other hand, unlike monoaryl maleimides, many indirect and direct approaches have
emerged concerning the synthesis of diarylmaleimides. Among the proposed strategies, indirect
methods have utilized non-maleimide starting materials. Phenylacetonitrile has been shown to
ACS Paragon Plus Environment
4

Page 5 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
convert into NH-free maleimide in a one-pot step-wise reaction under basic condition and with
the aid of I2 as the promoter of the reaction (Scheme 3, a-1). Also, the reaction of diarylalkynes
with amines or isocyanates under a CO atmosphere led to diarylmaliamide (Scheme 3, a-2).
When isocyanate was replaced with isocyanide, diarylmaliamide was formed in water medium
even in the absence of carbon monoxide. In a different approach, condensation of glyoxalate
ester with acetamides resulted in only NH-maliamide derivatives (Scheme 3, a-3). In contrast to
indirect methods, direct strategies15 have gained more popularity since they take advantage of
commercially available starting materials and offer simpler paths. Direct methods in which
maleimide itself is employed as the reactant is divided into two categories: step-wise reactions
and single-step reactions. The latter provide shorter routes to the favored product. Moreover, in
these approaches the need for additional reagents is obviated and superfluous, tedious
purifications are eliminated thus these reactions are more facile and cost-effective. Capretta
reported a Pd-catalysed reaction which led to diaryl maleimides in high yields albeit in high
temperatures and only by the aid of 1,3,5,7-tetramethyl-2,4,8-trioxa-6-O-methoxyphenyl-6-
phosphaadamantane as a bulky and commercially unavailable ligand.10a In the same paper,
authors prepared monoaryl maleimides in good yields but non-selectively and in mixture with
diaryl maleimides.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment
5

The Journal of Organic Chemistry
Page 6 of 33
1
2
3
4
Scheme 3. Various approaches to the synthesis of diarylmaleimides
5
6
7
8
9
Diarylation
a) Indirect
(1) Ar
H
N
O
O
1. I2, NaOCH3/CH3OH
Step-wise
NaOCH3
ref. 15a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CN
Only works for NH-maleimide
2. HCl
Ar
Ar
R
N
RNH2/ RNCO
RNC
+
+
CO
O
O
Ph
Ph
(2)
only one example due to limited
scope of diarylalkyne
[Rh]
Ph
Ph
H2O
ref. 9a-d
H
N
O
O
Commercially unavailable starting materials
Only works for NH-maleimide
O
O
t-BuOK
OR
Ar'
+
(3)
Ar
NH2
O
Ar
Ar'
Diarylation
b) Direct
Diarylation
i) Step-wise
X
X
1. Br2, HOAc
Pyridine
Thionyl chloride
O
O
O
O
O
O
2. NEt3, THF
3. NaOAc, HOAc, Br2
N
R
N
R
N
R
Step-wise
[Pd]
[Pd]
Ph3In
ref. 12b
[Pd]
Costly or unavailable coupling partners
Prefunctionalization needed
ref. 10a
PhBPin
ref. 15h
PhB(OH)2
Br
[Pd]
O
O
O
O
N
R
N
LG
$
R
LG = In, B(OH)2, BPin
Diarylation
ii) Single-step
This work:
SO2X
[Pd]
80 C
[Pd]
O
O
+
O
O
N
R
O
N
O
N
R
140 C


R
X = NHNH2, Cl
X = Cl
Cost-effective
Oxidant-free
Ligand-free
ACS Paragon Plus Environment
6

Page 7 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
However, construction of two aryl groups on adjacent carbons in a synperiplanar mode
imposes a major steric hindrance which is quite challenging and always within the aim of most
7
8
9
chemists. It is worth mentioning that symmetrical 3,4-diaryl maleimiedes can be exemplified as
12a,16
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
stable atropisomers at room temperature
thereby being exploited in asymmetric synthesis
and drug discovery.17 Moreover, diaryl maleimides constitute the backbone of copolymers
together with showing fluorescent properties.15f-g, 15o,18 Thus, there has been always an urge for
the synthesis of these privileged moieties. Given the foregoing, we came up with an approach to
prepare both monoaryl maleimides and diaryl maleimides selectively in a similar fashion with
the least modulation of reaction conditions.
Results and discussion
At the outset, we reacted N-methyl maleimide with p-toluenesulfonyl chloride under
Pd(OAc)2/NEt3 in acetonitrile which resulted in the 52% of the yield (Table 1, entry 1). Trying to
optimize the solvent had a destructive effect on the yield (entries 2-6). Then we took advantage
of other bases among which NaOAc acted superior to all others, yet the yield was not
satisfactory enough (entries 7-11). Hence, we then probed the role of acids in this reaction.
Although use of AcOH and p-TsOH lowered the yield, TFA built up the yield contently (entries
12-14). Use of PdCl2 instead of Pd(OAc)2 improved the yield slightly (entry 15). Then, the effect
of temperature was taken into account showing that the best temperature under which the
o
reaction can be conducted is 80 C (entries 15-16). Lowering the time of the reaction to 12 h
deteriorated the yield drastically (entry 18). Attainment of a better yield through adding different
oxidants such as K2S2O8 or metal oxidants (entries 19-21), Cs2CO3 as a base (entry 22) or PivOH
as an acid (entry 23) was futile in this process. We tested a combination of PdCl2/NaOAc both in
ACS Paragon Plus Environment
7

The Journal of Organic Chemistry
Page 8 of 33
1
2
3
4
5
6
7
8
9
the presence (entry 24) and in the absence of TFA (entry 25). In the case of PdCl2/NaOAc, the
yield obtained was higher than that of achieved from the reaction under PdCl2/NaOAc/TFA.
Based on these observations it can be suggested that the reaction proceeds via a pseudo-Heck
reaction and passes through an enolization step which can be assisted with both acids and bases.
The proposed mechanism can be corroborated more firmly by using both TFA and NaOAc in the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
reaction. After screening various conditions, PdCl2 (10%), TFA (2 equiv) in ACN under 80 C
provided the best result.
Table 1. Screening optimal conditions
Me
SO2Cl
Catalyst
Oxidant
+
O
O
N
Solvent
O
O
N
100 oC, 20 h
Me
Me
Me
Entry
Catalyst
Base
Acid
Oxidant
Solvent
Yield%a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
K2CO3
Cs2CO3
KOt-Bu
NaOAc
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
ACN
DMF
DMSO
Toluene
DMA
Dioxane
ACN
ACN
ACN
ACN
ACN
ACN
ACN
ACN
ACN
ACN
ACN
ACN
ACN
ACN
52
20
0
34
35
48
52
30
50
62
20
15
62
45
65
67b
60c
38d
62b
20b
-
-
-
K3PO4
-
-
-
-
-
-
-
-
-
-
-
HOAc
TFA
p-TsOH
TFA
TFA
TFA
TFA
TFA
-
-
-
-
-
-
-
PdCl2
PdCl2
PdCl2
PdCl2
K2S2O8
PdCl2
TFA
Cu(OAc)2.H2O
ACS Paragon Plus Environment
8

Page 9 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
21
22
23
24
25
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
-
TFA
TFA
AgOAc
ACN
ACN
ACN
ACN
ACN
20b
15b
15b
8
Cs2CO3
-
-
-
-
-
TFA/PivOH
TFA
NaOAc
NaOAc
-
38
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
Reaction conditions unless otherwise noted: N-Methyl maleimide (0.1 mmol), p-toluenesulfonyl
chloride (2 equiv), catalyst (10 mol %), base (2 equiv), acid (2 equiv), additive (2 equiv) in 0.5 mL of
solvent were heated at 100 oC for 20 h. b The reaction was run at 80 oC. c The reaction was run at 60 ºC. d
The reaction time was 12 h.
Having set the optimized conditions, we then explored the scope of the reaction (Table 2). To
this end, free N-H maleimide was reacted with different arenesulfonyl chlorides. Delightfully,
the reaction proceeded well to the desired products with benzenesulfonyl chloride and
arenesulfonyl chlorides bearing either neutral (3a-c) or electron-releasing groups (3d).
Accommodation of a methyl group at C2 position, despite imposing significant steric hindrance,
yielded the corresponding product (3e). Surprisingly, this reaction showed not only a great
tolerance towards halo groups but it also provided higher yields than other functional groups thus
paving the way for further manipulation of the prepared molecules (3f, 3g).19 We then turned our
attention to using N-methyl maleimide and employed it in the reaction with various
arenesulfonyl chlorides possessing p-methyl, p-methoxy or p-bromo groups all of which
furnished as satisfactory yields of the products as did N-H maleimide (3h-j). In addition, when 2-
naphthalenesulfonyl chloride was used as the reactant, despite the steric hindrance present in the
product between the C3-H of maleimide and C1-H of naphthalene attached to maleimide, the
reaction led to an acceptable yield (3k). N-Benzyl maleimide and N-cyclohexyl maleimide
afforded 80% and 82% yields respectively (3l, 3m). To our delight, maleic anhydride was also
reactive under standard reaction conditions yielding 3-tolyl maleic anhydride (3n). In addition,
ACS Paragon Plus Environment
9

The Journal of Organic Chemistry
Page 10 of 33
1
2
3
4
5
6
7
8
9
when arenesulfonyl hydrazides were used instead of arenesulfonyl chlorides, comparable yields
were achieved which extended the scope of this reaction even more (Table 2).
Table 2. Substrate scope for construction of 3-aryl maleimides a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R'
SO2Cl
R'
PdCl2
TFA
or
+
O
O
2
N
R
1
ACN, air
O
O
N
R
3
SO2NHNH2
80 °C, 20 h
R'
2'
t-Bu
Me
MeO
O
O
O
O
H
N
H
N
H
N
H
N
O
O
O
O
b
3a
3b
3c
, 94(69) %
, 68(62)%
Cl
, 92%
3d
, 75(82)%
Br
Me
O
O
O
O
H
N
H
H
N
N
Me
N
Me
O
O
3f
O
O
3e
, 58(47)%
, 97%
O
3g
, 95%
3h,
67(57)%
Br
Me
Me
MeO
O
O
N
O
O
Me
N
N
Me
N
O
O
O
3k
, 60%
3l
8)
, 82(6 %
3i
3j
, 70%
, 65%
Me
Me
O
O
N
O
O
O
3n
3m
, 68(59)%
, 80(70)%
a
Standard reaction conditions: Maleimide or maleic anhydride 1 (0.1 mmol), arenesulfonyl
chloride 2 (2.0 equiv), PdCl2 (10 mol %), TFA (2 equiv) in 0.5 mL ACN were heated at 80 °C
for 20 h. b The yields in parenthesis were attained when arenesulfonyl hydrazides were used in
the place of arenesulfonyl chlorides.
When maleic acid as the starting material was subjected to p-toluenesulfonyl chloride, a
concomitant dehydration/arylation took place giving rise to 3-tolyl maleic anhydride. This
ACS Paragon Plus Environment
10

Page 11 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
outcome gives one the opportunity to use maleic acid as a surrogate for maleic anhydride without
any need for very high temperatures (Scheme 4, 3n). In the next step, we utilized
naphthoquinone in the place of maleimides. As opposed to prior work,20 using our modified
conditions, no sulfonyl naphthoquinone was formed but rather an extrusion of SO2 occurred
which culminated in 3-aryl naphthoquinone (Scheme 4, 6a-c).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. The reaction of a) maleic acid and b) 1,4-naphthoquinone with arenesulfonyl
chlorides
O
SO2Cl
Me
O
(a)
(b)
PdCl2 (10 mol%)
TFA (2 equiv.)
ACN, air
HO
HO
O
+
80 oC, 20 h
O
O
Me
4
3n,
59%
O
R'
O
SO2Cl
PdCl2 (10 mol%)
K2CO3 (2 equiv.)
ACN, air
+
O
100 oC, 20 h
O
R'
R'= Me, 6a,
OMe, 6b,
t-Bu, 6c,
56%
5
60%
60%
Unpredictably, when checking the different parameters of optimization table, it was found out
o
that only with increasing the temperature to 140 C and without any other deviation from
standard conditions, a new product was formed; i.e. symmetrical 3,4-diphenyl maleimide (Table
3, 7a). To the best of our knowledge, due to the high reactivity of both C3 and C4 of
maleimides, the majority of previous reports on functionalization of this motif encountered
serious difficulties attaining either monoaryl- or diaryl-maleimides selectively and in most cases
a mixture of both products was gained. Having said that, we managed to get access to each series
only through temperature control without any unwanted interfering side-products (Table 3).
ACS Paragon Plus Environment
11

The Journal of Organic Chemistry
Page 12 of 33
1
2
3
4
5
6
7
Table 3. Substrate scope for construction of 3,4-diaryl maleimides a
8
9
R'
R'
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
SO2Cl
PdCl2 (10 mol%)
TFA (2 equiv.)
ACN, air
+
O
O
N
R
O
O
N
R
7
R'
140 C, 5 h
2
1
t-Bu
t-Bu
Me
Me
O
O
O
O
N
O
O
N
N
H
H
H
7a
b
7c
, 72%
, 75%
7 , 65%
Br
Br
Cl
Cl
O
O
O
O
O
O
N
N
H
N
H
Me
7f
, 68%
7d
7e
, 78%
, 80%
O
O
O
O
N
N
7g
7h
, 68%
, 70%
a
All reactions were run under the following conditions: Maleimide 1 (0.1 mmol),
arenesulfonyl chloride 2 (2.0 equiv), PdCl2 (10 mol %), TFA (2 equiv) in 0.5 mL ACN were
heated under air at 140 °C for 5 h.
To show the generality of this reaction, we exposed maleimide to various arenesulfonyl
chlorides with different functional groups such as methyl, tert-butyl, halide groups (Cl and Br)
which all led to the desired products in good yields (7b-e). Then, we replaced free N-H
maleimide with other N-substituted maleimides namely N-methyl, N-benzyl and N-cyclohexyl
ACS Paragon Plus Environment
12

Page 13 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
maleimides. Although we faced a slight fall in the yields comparing to N-H maleimide, the yields
were still satisfactory thus it can be claimed that this method offers more privileges than previous
methods and can be a preferred substitute for them (7f-h). Also, methanesulfonyl chloride and
ethanesulfonyl chloride were tested under our reaction conditions to widen the scope of reaction
but these reactions did not yielded any products and the starting materials remained intact at the
end of the reaction.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
A tentative mechanism for this reaction is outlined in Scheme 5. As was previously put forth
21
by Doucet we assumed that in the first step Pd(II) is converted to Pd(IV) through oxidative
addition into ArSO2-Cl bond. Extrusion of SO2 followed by a carbopalladation furnishes
intermediate I which rapidly converts into its palladium-enolate tautomer II. Then, due to more
stability of intermediate III, the enol form tautomerizes to its keto form.22 Although the three
intermediates are in equilibrium, it must have been intermediate I from which β-hydride
elimination proceeded since only in this intermediate palladium and H are placed on adjacent
carbons and in a syn mode which is an essential requirement for elimination. Pd(IV) formed in
this step then undergoes a reductive elimination and restores Pd(II) to the cycle. The second
arylation takes place via the same mechanism this time with 3-arylmaleimide in place of
maleimide itself as the starting material.
It is worth mentioning that except for the literature reports that referred to a Pd(II)/Pd(IV)
cycle for the mechanism of the palladium-catalyzed desulfitative reactions,4a,21b there are some
reports that proposed a Pd(0)/Pd(II) cycle in the same issue.23 In addition, in the case of entries
1-2 and 4-6 of the Table 1, in which triehtyl amine was used as the additive of the reaction, the
mechanism might have passed through a Pd(0) which then undergoes an oxidative-addition into
ACS Paragon Plus Environment
13

The Journal of Organic Chemistry
Page 14 of 33
1
2
3
4
5
6
the S-Cl bond. Therefore, the reaction might involve either Pd(0)/Pd(II) or Pd(II)/(IV)
intermediates and we cannot refuse any of them at this time.
7
8
9
Scheme 5. Plausible mechanism for regioselective C-3 arylation and 3,4-diarylation of
maleimides
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ar
Ar
ArSO2Cl
O
O
PdII
N
R
H
Ar
H
Ar
H
PdIVCl
Ar
Ar
O
Ar
O
PdIVCl
O
Ar
O
OPdIVCl
ArSO2PdIVCl
O
N
N
N
R
(V)
R
(IV)
R
(VI)
SO2
ArSO2PdIVCl
H
Ar
ArPdIVCl
H
ArSO2Cl
PdII
O
O
H
N
R
O
O
N
R
ClPdIV
O
Ar
Ar
ClPdIV
O
Ar
ClPdIVO
O
O
O
N
N
N
R
(III)
R
R
(I)
(II)
To demonstrate practicability of the invented new synthetic methods, the reaction of p-
toluenesulfonyl chloride with N-benzyl maleimide performed in 0.3 mmol, 1 mmol and 3 mmol
scales under monoarylation condition. Investigation showed that going to 0.3 mmol scale does
not reduce the conversion but in larger scales it smoothly decreases. The reactions proceeded to
the desired product 3l in acceptable yields (Scheme 6).
ACS Paragon Plus Environment
14

Page 15 of 33
The Journal of Organic Chemistry
1
2
3
4
Scheme 6. Gram-scale synthesis of monoaryl maleimides
5
6
7
8
9
Me
O
SO2Cl
O
O
N
standard conditions
+
N
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
0.3 mmol
1 mmol
3 mmol
0.07 g (80%)
0.20 g (71%)
0.49 g (59%)
Conclusion
In summary, a direct mono- and di-arylation on maleimides through concomitant Pd-catalysed
two C-H functionalizations is achieved which provides an expedient access to 3-aryl- and 3,4-
diaryl maleimides. This reaction is beneficial due to its simplicity and easily accessible starting
materials. It is also noteworthy that temperature is the only factor that would do good and come
into play for selective synthesis of either mono- or diaryl-maleimides. Good tolerance towards
different functional groups and a wide scope renders this approach an alluring synthetic method
as a replacement for the prior multi-step or single-step precedents.
Experimental Section
General Methods and Materials
All commercially available reagents were used without further purification. Unless noted
otherwise, all reagents were purchased from Acros Organics and Merck Millipore. TLC was
1
conducted on silica gel 250 micron, F254 plates. HNMR spectra were recorded at room
ACS Paragon Plus Environment
15

The Journal of Organic Chemistry
Page 16 of 33
1
2
3
4
5
6
7
8
9
temperature on a Bruker 400 and 500 MHz spectrometers, using DMSO-d6 and acetone-d6 as
solvent. Chemical shifts are reported in ppm with TMS as an internal standard. 13CNMR spectra
are referenced from the solvent central peak. Chemical shifts are given in ppm. N-
benzylmaleimide and N-cyclohexylmaleimide were prepared using the instructions given in
previous papers.24
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Typical procedure for the synthesis of 3-aryl-1H-pyrrole-2,5-diones (3a-3n)
In a vial charged by maleimide (3 mmol, 291 mg), benzenesulfonyl chloride (2 equiv, 6 mmol,
1.056 g), palladium chloride (10 mol%, 0.3 mmol, 53.1 mg) and TFA (6 equiv, 6 mmol, 684
mg), was added acetonitrile (7 mL) and capped. The resulting mixture was heated in an oil bath
o
at 80 C for 20 h. After washing the mixture with 10% brine solution and extraction with
dichloromethane, the organic layer was dried over sodium sulfate and evaporated under reduced
pressure. The organic residue was purified by a silica loaded column chromatography with 1:20
ethyl acetate in n-hexane as eluent. Recrystallization of the product using n-hexane gave pure 3-
phenyl-1H-pyrrole-2,5-dione 3a as off-white solid (280 mg), 54% yield.
Typical procedure for the synthesis of 2-arylnaphthalene-1,4-diones (6a-6c)
Naphthoquinone (1 mmol, 158 mg), p-toluenesulfonyl chloride (1 equiv, 1 mmol, 190 mg),
palladium chloride (10 mol%, 0.1 mmol, 17.7 mg), potassium carbonate (2 equiv, 2 mmol, 276
o
mg) in acetonitrile (5 mL), was stirred at 100 C for 20 h in a reaction vessel. The mixture was
washed with 10% brine solution and then extracted with dichloromethane. The organic layer was
dried over sodium sulfate and evaporated under reduced pressure. The organic residue was
purified by a silica loaded column chromatography with 1:20 ethyl acetate in n-hexane as eluent.
Recrystallization of the product using n-hexane gave pure 2-(p-tolyl)naphthalene-1,4-dione 6a as
white solids (139 mg), 56% yield.
ACS Paragon Plus Environment
16

Page 17 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Typical procedure for the synthesis of 3,4-diaryl-1H-pyrrole-2,5-diones (7a-7h)
Maleimide (1 mmol, 97 mg), benzenesulfonyl chloride (2 equiv, 2 mmol, 352 mg), palladium
chloride (10 mol%, 0.1 mmol, 17.7 mg) and TFA (2 equiv, 2 mmol, 228 mg), was added
acetonitrile (5 mL) and capped. The resulting mixture was heated in an oil bath at 140 oC for 5 h.
The mixture was washed with 10% brine solution, extracted with dichloromethane the organic
layer was dried over sodium sulfate and evaporated under reduced pressure. The organic residue
was purified by a silica loaded column chromatography with 1:20 ethyl acetate in n-hexane as
eluent. Recrystallization of the product using n-hexane gave pure 3,4-diphenyl-1H-pyrrole-2,5-
dione 7a as pale-yellow solid (187 mg), 75% yield.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
3-Phenyl-1H-pyrrole-2,5-dione (3a); 54% yield (280 mg). White solid, mp. 160-162 C,
1HNMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.95-7.97 (m, 2H), 7.47-7.48 (m, 3H) 7.14 (s,
1H). Known compound.11c
3-p-Tolyl-1H-pyrrole-2,5-dione (3b); 41% yield (230 mg). White crystalline solid, mp. 174-176
1
oC, HNMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 8.0 Hz, 2H) 7.37 (s, 1H), 7.29 (d, J = 8.0 Hz,
2H), 6.69 (s, 1H), 2.43 (s, 3H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 172.8, 172.3, 143.6,
141.4, 129.9, 129.0, 126.5, 125.0, 21.5. Anal. Calcd for C11H9NO2: C, 70.58; H, 4.85; N, 7.48.
Found: C, 70.67; H, 4.91; N, 7.53.
3-(4-tert-Butylphenyl)-1H-pyrrole-2,5-dione (3c); 52% yield (357 mg). Pale green sheet
1
crystalline solid, mp. 188-192 oC, HNMR (500 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.89 (dd, J =
13
6.5, 2.0 Hz, 2H), 7.48 (dd, J = 7.0, 2.0 Hz, 2H) 7.07 (s, 1H), 1.28 (s, 9H). C{1H} NMR (125
MHz, DMSO-d6) δ 172.9, 172.5, 154.3, 143.7, 129.1, 126.8, 126.3, 125.5, 35.3, 31.4. Anal.
Calcd for C14H15NO2: C, 73.34; H, 6.59; N, 6.11. Found: C, 73.25; H, 6.55; N, 6.04.
3-(4-Methoxyphenyl)-1H-pyrrole-2,5-dione (3d); 46% yield (267 mg). Yellow solid, mp. 128-
130 oC, 1HNMR (500 MHz, DMSO-d6) δ 10.86 (s, 1H), 7.97 (d, J = 8.5 Hz, 2H), 7.03 (d, J = 9.0
Hz, 2H), 6.99 (s, 1H), 3.80 (s, 3H). Known compound.11c
ACS Paragon Plus Environment
17

The Journal of Organic Chemistry
Page 18 of 33
1
2
3
4
5
6
7
8
9
o
3-o-Tolyl-1H-pyrrole-2,5-dione (3e); 37% yield (207 mg). White solid, mp. 148-150 C,
1HNMR (500 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.65-7.71 (m, 1H), 7.39
(d, J = 7.5 Hz, 1H), 7.34 (t, J = 7.0 Hz, 1H), 2.31 (s, 3H). 13C{1H} NMR (125 MHz, DMSO-d6)
δ 172.7, 172.5, 145.5, 137.7, 131.2, 130.7, 130.0, 129.3, 129.2, 126.2, 20.9. Anal. Calcd for
C11H9NO2: C, 70.58; H, 4.85; N, 7.48. Found: C, 70.50; H, 4.91; N, 7.42.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-(4-Bromophenyl)-1H-pyrrole-2,5-dione (3f); 57% yield (429 mg). Yellow solid, mp. 184-186
oC, 1HNMR (500 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.92 (dd, J = 7.0, 2.0 Hz, 2H), 7.69 (dd, J =
7.0, 2.0 Hz, 2H), 7.20 (s, 1H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 171.3, 170.5, 142.7,
132.0, 130.5, 128.8, 126.1, 124.8. Anal. Calcd for C10H6BrNO2: C, 47.65; H, 2.40; N, 5.56.
Found: C, 47.58; H, 2.31; N, 5.51.
3-(4-Chlorophenyl)-1H-pyrrole-2,5-dione (3g);) 60% yield (372 mg). Yellow solid, mp. 180-
182 oC, 1HNMR (500 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.5
Hz, 2H), 7.20 (s, 1H). Known compound.11c
1-Methyl-3-p-tolyl-1H-pyrrole-2,5-dione (3h); 49% yield (295 mg). Greenish white crystalline
o
1
solid, mp. 110-112 C, HNMR (500 MHz, DMSO-d6) δ 7.93 (d, J = 8.0 Hz, 2H), 7.31 (d, J =
8.0 Hz, 2H), 7.21 (s, 1H), 2.92 (s, 3H), 2.36 (s, 3H). Known compound.25
3-(4-Methoxyphenyl)-1-methyl-1H-pyrrole-2,5-dione (3i); 47% yield (305 mg). Yellow
o
1
crystalline solid, mp. 142-145 C, HNMR (400 MHz, DMSO-d6) δ 8.04 (dd, J = 6.8, 2.0 Hz,
2H), 7.15 (s, 1H), 7.08 (dd, J = 7.2, 2.0 Hz, 2H), 3.84 (s, 3H), 2.93 (s, 3H). 13C{1H} NMR (100
MHz, DMSO-d6) δ 171.5, 171.2, 161.9, 142.8, 130.8, 129.1, 121.9, 114.9, 55.9, 23.7. Anal.
Calcd for C12H11NO3: C, 66.35; H, 5.10; N, 6.45. Found: C, 66.25; H, 5.06; N, 6.49.
3-(4-Bromophenyl)-1-methyl-1H-pyrrole-2,5-dione (3j); 41% yield (326 mg). White solid, mp.
128-130 oC, 1HNMR (500 MHz, DMSO-d6) δ 7.95 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H),
13
7.33 (s, 1H), 2.28 (s, 3H). C{1H} NMR (125 MHz, DMSO-d6) δ 170.4, 170.2, 141.5, 131.9,
131.5, 130.3, 125.9, 124.6, 23.6. Anal. Calcd for C11H8BrNO2: C, 49.65; H, 3.03; N, 5.26.
Found: C, 49.69; H, 2.99; N, 5.19.
1-Methyl-3-(naphthalen-3-yl)-1H-pyrrole-2,5-dione (3k); 45% yield (320 mg). Yellow solid,
mp. 144-146 °C, 1HNMR (300 MHz, DMSO-d6) δ 8.66 (s, 1H), 7.81-7.91 (m, 4H), 7.46-7.50 (m,
ACS Paragon Plus Environment
18

Page 19 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
2H), 7.05 (s, 1H), 2.91 (s, 1H). 13C{1H} NMR (75 MHz, DMSO-d6) δ 167.1, 166.5, 146.1, 132.6,
131.2, 129.4, 129.2, 128.8, 128.6, 128.3, 126.9, 126.8, 124.9, 124.9, 124.7, 23.6. Anal. Calcd for
C15H11NO2: C, 75.94; H, 4.67; N, 5.90. Found: C, 75.88; H, 4.74; N, 5.82.
7
8
9
1-Benzyl-3-p-tolyl-1H-pyrrole-2,5-dione (3l); 59% yield (490 mg). Pale yellow solid, mp. 92-94
oC, 1HNMR (500 MHz, DMSO-d6) δ 7.93 (d, J = 8.0 Hz, 2H), 7.30-7.34 (m, 4H), 7.26-7.27 (m,
4H), 4.64 (s, 2H), 2.34 (s, 3H). Known compound.26
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-Cyclohexyl-3-p-tolyl-1H-pyrrole-2,5-dione (3m); 52% yield (419 mg). Pale yellow solid, mp.
104-106 oC, 1HNMR (500 MHz, DMSO-d6) δ 7.91 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H),
7.17 (s, 1H), 3.80-3.87 (m, 1H), 2.36 (s, 1H), 1.93-2.01 (m, 2H), 1.78 (d, J = 13.0 Hz, 2H), 1.64
(t, J = 13.0 Hz, 3H), 1.23-1.35 (m, 3H). Known compound.27
o
1
3-p-Tolylfuran-2,5-dione (3n); 38% yield (214 mg). White solid, mp. 98-100 C, HNMR (400
MHz, Acetone-d6) δ 8.03 (d, J = 8.0 Hz, 2H), 7.74 (s, 1H), 7.41 (d, J = 8.0 Hz, 2H), 2.44 (s, 3H).
Known compound.28
o
2-p-Tolylnaphthalene-1,4-dione (6a); 56% yield (139 mg). Yellow solid, mp. 101-103 C,
1HNMR (400 MHz, DMSO-d6) δ 8.11-8.09 (m, 1H), 8.02-8.04 (m, 1H), 7.69-7.71 (m, 2H), 7.41
(d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 6.98 (s, 1H), 2.3 (s, 3H). Known compound.29
2-(4-Methoxyphenyl)naphthalene-1,4-dione (6b); 60% yield (160 mg). Yellow solid, mp. 114-
o
1
116 C, HNMR (500 MHz, DMSO-d6) δ 8.07-8.08 (m, 1H), 8.00-8.01 (m, 1H), 7.87-7.90 (m,
2H), 7.61 (d, J = 9.0 Hz, 2H), 7.10 (s, 1H), 7.03 (d, J = 8.5 Hz, 2H), 3.82 (s, 3H). Known
compound.30
2-(4-tert-Butylphenyl)naphthalene-1,4-dione (6c); 60% yield (174 mg). Yellow solid, mp. 122-
o
1
125 C, HNMR (500 MHz DMSO-d6) δ 8.06-8.08 (m, 1H), 7.99-8.01 (m, 1H), 7.87-7.89 (m,
2H), 7.54 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.12 (s, 1H), 1.30 (s, 9H). Known
compound.31, 9d
ACS Paragon Plus Environment
19

The Journal of Organic Chemistry
Page 20 of 33
1
2
3
4
5
6
3,4-Diphenyl-1H-pyrrole-2,5-dione (7a); 75% yield (218 mg). Yellow crystalline solid, mp.
o
1
171-173 C, HNMR (500 MHz, DMSO-d6) δ 11.36 (s, 1H), 7.48-7.51 (m, 6H), 7.45-7.47 (m,
4H). Known compound.32
7
8
9
o
3,4-Di-p-tolyl-1H-pyrrole-2,5-dione (7b); 65% yield (181 mg). Yellow solid, mp. 170-172 C,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1HNMR (500 MHz, DMSO-d6) δ 11.16 (s, 1H), 7.24 (d, J = 8.0 Hz, 4H), 7.17 (d, J = 8.5 Hz,
4H), 2.29 (s, 6H). Known compound.10a,15c
3,4-bis(4-tert-Butylphenyl)-1H-pyrrole-2,5-dione (7c); 72% yield (200 mg). Green-yellow solid,
o
1
mp. 212-216 C, HNMR (500 MHz, DMSO-d6) δ 11.20 (s, 1H), 7.42 (d, J = 8.0 Hz, 4H), 7.35
(d, J = 8.0 Hz, 4H), 1.28 (s, 18 H). 13C{1H} NMR (125 MHz, DMSO-d6) δ 172.3, 152.6, 136.2,
129.8, 126.5, 125.7, 35.0, 31.4. Anal. Calcd for C24H27NO2: C, 79.74; H, 7.53; N, 3.87. Found:
C, 79.81; H, 7.59; N, 3.84.
3,4-bis(4-Chlorophenyl)-1H-pyrrole-2,5-dione (7d); 78% yield (248 mg). Yellow crystalline
solid, mp. 208-210 oC, 1HNMR (500 MHz, DMSO-d6) δ 11.32 (s, 1H), 7.47 (dt, J = 8.5, 2.5 Hz,
4H), 7.36 (dt, J = 8.5, 2.5 Hz, 4H). Known compound.10a,15c
3,4-bis(4-Bromophenyl)-1H-pyrrole-2,5-dione (7e); 80% yield (295 mg). Yellow crystalline
solid, mp. 172-174 oC, 1HNMR (500 MHz, DMSO-d6) δ 11.30 (s, 1H), 7.61 (d, J = 8.5 Hz, 4H),
13
7.30 (d, J = 8.5 Hz, 4H). C{1H} NMR (125 MHz, DMSO-d6) δ 171.8, 136.5, 132.3, 132.2,
128.3, 124.0. Anal. Calcd for C16H9Br2NO2: C, 47.21; H, 2.23; N, 3.44. Found: C, 47.25; H,
2.31; N, 3.52.
1-Methyl-3,4-diphenyl-1H-pyrrole-2,5-dione (7f); 68% yield (251 mg). Yellow crystalline solid,
mp. 138-141 oC, 1HNMR (500 MHz, DMSO-d6) δ 7.48-7.50 (m, 4H), 7.36-7.42 (m, 6H), 3.19 (s,
3H). Known compound.15a
1-Benzyl-3,4-diphenyl-1H-pyrrole-2,5-dione (7g); 70% yield (258 mg). Yellow solid, mp. 98-
o
1
102 C, HNMR (500 MHz, DMSO-d6) δ 7.36-7.41 (m, 15H), 4.75 (s, 2H). Known
compound.15b
1-Cyclohexyl-3,4-diphenyl-1H-pyrrole-2,5-dione (7h); 68% yield (226 mg). Green-yellow
crystalline solid, mp. 140-142 oC, 1HNMR (500 MHz, DMSO-d6) δ 7.65-7.71 (m, 2H), 7.34-7.40
ACS Paragon Plus Environment
20

Page 21 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
(m, 8H), 3.88-3.95 (m,1H), 1.97-2.04 (m, 2H), 1.79 (d, J = 11.5 Hz, 2H), 1.60-1.64 (m, 2H),
1.32-1.36 (m, 4H). Known compound.12c
7
8
ASSOCIATED CONTENT
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Supporting Information. Copies of 1H and 13C{1H} NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Chemistry Department, University of Guilan, P.O. Box 41335-1914, Rasht, Iran, Fax:
+981333367262, E-mail: sheykhan@guilan.ac.ir
Orchid
Mehdi Sheykhan: 0000-0002-1438-7643
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by research council of the University of Guilan.
References
(1)
For some examples see: (a) Meng, G.; Szostak, M. General Olefin Synthesis by the
Palladium‐Catalyzed Heck Reaction of Amides: Sterically Controlled Chemoselective N-
C Activation, Angew. Chem. Int. Ed. 2015, 54, 14518-14522; (b) Liu, C.; Ji, C-L.; Qin,
Z-X.; Hong, Xin.; Szostak, M. Synthesis of Biaryls via Decarbonylative Palladium-
Catalyzed Suzuki-Miyaura Cross-Coupling of Carboxylic Acids, iScience 2019, 19, 749-
ACS Paragon Plus Environment
21

The Journal of Organic Chemistry
Page 22 of 33
1
2
3
4
5
6
7
8
9
759; (c) Liu, C.; Szostak, M. Decarbonylative cross-coupling of amides, Org. Biomol.
Chem. 2018, 16, 7998-8010 and all references therein; (d) Zhou, P. -X.; Shi, S.; Wang, J.;
Zhang, Y.; Li, C.; Ge, C. Palladium/copper-catalyzed decarbonylative heteroarylation of
amides via C–N bond activation, Org. Chem. Front., 2019, 6, 1942-1947; (e) Liu, L.;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Zhou, D.; Liu, M.; Zhou, Y.; Chen, T. Palladium-Catalyzed Decarbonylative
Alkynylation of Amides, Org. Lett. 2018, 20, 2741-2744; (f) Luo, Z.; Xiong, L.; Liu,
T.; Zhang, Y.; Lu, S.; Chen, Y.; Guo, W.; Zhu, Y.; Zeng, Z. Palladium-Catalyzed
Decarbonylative Suzuki-Miyaura Coupling of Amides To Achieve Biaryls via C-N Bond
Cleavage, J. Org. Chem. 2019, 84, 10559-10568; (g) Zhou, T.; Ji, C-L.; Hong, X.;
Szostak, M. Palladium-catalyzed decarbonylative Suzuki-Miyaura cross-coupling of
amides by carbon-nitrogen bond activation, Chem. Sci. 2019, 10, 9865-9871.
(2)
For some representative examples see: (a) Cornella, J.; Larrosa, I. Decarboxylative
Carbon-Carbon bond-forming transformations of (hetero)aromatic carboxylic acids,
Synthesis 2012, 44, 653-676; (b) Myers, A. G.; Tanaka, D.; Mannion, M. R. Development
of a decarboxylative palladation reaction and its use in a Heck-type olefination of arene
carboxylates, J. Am. Chem. Soc. 2002, 124, 11250-11251; (c) Hu, P.; Zhang, M.; Jie, X.;
Su, W. Palladium-catalyzed decarboxylative C-H bond arylation of thiophenes, Angew.
Chem. Int. Ed. 2012, 51, 227-231; (d) Xie, K.; Yang, Z.; Zhou, X.; Li, X.; Wang, S.; Tan,
Z.; An, X.; Guo, C-C. Pd-catalyzed decarboxylative arylation of thiazole, benzoxazole
and polyfluorobenzene with substituted benzoic acids, Org. Lett. 2010, 12, 1564-1567;
(e) Pei, K.; Jie, X.; Zhao, H.; Su, W. Palladium-catalyzed decarboxylative C-H bond
arylation of furans, Eur. J. Org. Chem. 2014, 4230-4233; (f) Zhou, J.; Hu, P.; Zhang, M.;
ACS Paragon Plus Environment
22

Page 23 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Huang, S.; Wang, M.; Su, W. A versatile catalyst for intermolecular direct arylation of
indoles with benzoic acids as arylating reagents, Chem. Eur. J. 2010, 16, 5876-5881.
(a) Zhu, M.-K.; Zhao, J.-F.; Loh, T.-P. Palladium-catalyzed C-C bond formation of
arylhydrazines with olefins via carbon-nitrogen bond cleavage, Org. Lett. 2011, 13, 6308-
6311; (b) Li, M.; Ye, Y. Palladium-catalyzed sp2 C-H arylation of azoarenes with
arylhydrazines, ChemCatChem, 2015, 7, 4137-4142; (c) Zhao, Y.; Song, Q. Palladium-
catalyzed aerobic oxidative cross-coupling of arylhydrazines with terminal alkynes,
Chem. Commun. 2015, 51, 13272-13274.
(3)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4)
For reviews in this field see: (a) Bheeter, C. B.; Chen, L.; Soulé J.-F.; Doucet, H.
Regioselectivity in palladium-catalysed direct arylation of 5-membered ring
heteroaromatics. Catal. Sci. Technol. 2016, 6, 2005-2049; (b) Yuan, K.; Soulé, J.-F.;
Doucet, H. Functionalization of C-H Bonds via Metal-Catalyzed Desulfitative Coupling:
An Alternative Tool for Access to Aryl- or Alkyl-Substituted (Hetero)arenes. ACS Catal.
2015, 5, 978-991; (c) Ortgies, D. H.; Hassanpour, A.; Chen, F.; Woo, S.; Forgione, P.
Desulfination as an Emerging Strategy in Palladium‐Catalyzed C-C Coupling Reactions.
Eur. J. Org. Chem. 2016, 408-425; (d) Modha, S. G.; Mehta V. P.; Van der Eycken, E. V.
Transition metal-catalyzed C-C bond formation via C-S bond cleavage: an overview.
Chem. Soc. Rev. 2013, 42, 5042-5055 and references therein.
(5)
(a) Sheykhan, M.; Shafiee-Pour, M.; Abbasnia, M. C-H Activation under the Guise of
Diels-Alder Reaction: Annulation toward the Synthesis of Benzo[e]isoindole-1,3-diones.
Org. Lett. 2017, 19, 1270-1273; (b) Khoobi, M.; Molaverdi, F.; Jafarpour, F.; Abbasnia,
M.; Kubicki, M.; Shafiee, A. A one-pot domino C-H, C-C activation in coumarins: a fast
track to 2,3-diaryl benzo[b]furans. Chem. Commun. 2015, 51, 11713-11716; (c)
ACS Paragon Plus Environment
23

The Journal of Organic Chemistry
Page 24 of 33
1
2
3
4
5
6
7
8
9
Jafarpour, F.; Ayoubi-Chianeh, M.; Abbasnia M.; Azizzade, M. A new route to π-
extended polycyclic aromatic hydrocarbons via cross-dehydrogenative coupling. Catal.
Sci. Technol. 2017, 7, 2930-2934; (d) Jafarpour, F.; Abbasnia, M. A Regioselective
Metal-Free Construction of 3-Aroyl Coumarins by Csp2-H Functionalization. J. Org.
Chem. 2016, 81, 11982-11986.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(6)
(a) Boukouvalas, J.; Albert, V.; Loach, R. P.; Lafleur-Lambert, R. Unified route to
asymmetrically substituted butenolide, maleic anhydride, and maleimide constituents of
Antrodia camphorate. Tetrahedron 2012, 68, 9592-9597; (b) Cheng, C. -F.; Lai Z. -C.;
Lee, Y. -J. Total synthesis of (±)-camphorataimides and (±)-himanimides by
NaBH4/Ni(OAc)2 or Zn/AcOH stereoselective reduction. Tetrahedron 2008, 64, 4347-
4353; (c) Nakamura, N.; Hirakawa, A.; Gao, J.-J.; Kakuda, H.; Shiro, M.; Komatsu, Y.;
Sheu C.-C.; Hattori, M. five new maleic and succinic acid Derivatives from the mycelium
of Antrodia camphorata and their cytotoxic effects on LLC tumor cell line. J. Nat. Prod.
2004, 67, 46-48; (d) Stewart, S. G.; Polomska M. E.; Lim, R. W. A concise synthesis of
maleic anhydride and maleimide natural products found in Antrodia camphorate.
Tetrahedron Lett. 2007, 48, 2241-2244; (e) Chien, S.-C.; Chen, M.-L.; Kuo, H.-T.; Tsai,
Y.-C.; Lin, B.-F.; Kuo, Y.-H. Anti-inflammatory activities of new succinic and maleic
derivatives from the fruiting body of Antrodia camphorate. J. Agric. Food Chem. 2008,
56, 7017-7022; (f) Wu, M.-D.; Cheng, M.-J.; Wang, B.-C.; Yech, Y.-J.; Lai, J.-T.; Kuo,
Y.-H.; Yuan, G.-F.; Chen, I.-S. Maleimide and maleic anhydride derivatives from the
mycelia of Antrodia cinnamomea and their nitric oxide inhibitory activities in
Macrophages. J. Nat. Prod. 2008, 71, 1258-1261.
ACS Paragon Plus Environment
24

Page 25 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(7)
Manley-King, C. I.; TerréBlanche, G.; Castagnoli Jr., N.; Bergh, J. J.; Petzer, J. P.
Inhibition of monoamine oxidase B by N-methyl-2-phenylmaleimides. Bioorg. Med.
Chem. 2009, 17, 3104-3110.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(8)
(9)
Kar, A.; Argade, N. P. A Facile synthesis of Rubrolide E. Synthesis 2005, 2284-2286.
(a) Kondo, T.; Nomura, M.; Ura, Y.; Wada K.; Mitsudo, T.-A. Ruthenium-catalyzed [2 +
2 + 1] cocyclization of isocyanates, alkynes, and CO enables the rapid synthesis of
polysubstituted maleimides. J. Am. Chem. Soc. 2006, 128, 14816-14817; (b) Zhu, F.; Li,
Y.; Wang, Z.; Wu, X.-F. An efficient Rhodium‐catalyzed carbonylative annulation of
internal alkynes and anilines to produce maleimides. ChemCatChem 2016, 8, 3710-3713;
(c) Inoue, S.; Fukumoto, Y.; Chatani, N. A Chelation-assisted transformation:ꢀ Synthesis
of maleimides by the Rh-catalyzed carbonylation of alkynes with pyridin-2-
ylmethylamine. J. Org. Chem. 2007, 72, 6588-6590; (d) Hu, W.; Zheng, J.; Li, J.; Liu, B.;
Wu, W.; Liu, H.; Jiang, H. Assembly of polysubstituted maleimides via Palladium-
catalyzed cyclization reaction of alkynes with isocyanides. J. Org. Chem. 2016, 81,
12451-12458; (e) Bae, Y. K.; Cho, C.S. Palladium‐catalyzed carbonylative cyclization of
β‐bromo‐α,β‐unsaturated carboxylic acids with 2,2‐dimethylhydrazine leading to
1‐(dimethylamino)‐1H ‐pyrrole‐2,5‐diones. Appl. Organometal. Chem. 2014, 28, 225-
229; (f) Gao, Q.; Wu, X.; Li, Y.; Liu, S.; Meng X.; Wu, A. Iodine‐promoted sequential
C(sp3)-H functionalization reactions: An Annulation strategy for the construction of
3‐methylthio‐4‐arylmaleimides. Adv. Synth. Catal. 2014, 356, 2924-2930.
(10) (a) Rondestvedt Jr, C. S.; Vogl, O. Arylation of unsaturated systems by free radicals. II.
Arylation of maleimide by diazonium salts. J. Am. Chem. Soc. 1955, 77, 2313-2315; (b)
Rondestvedt Jr., Kalm, C. S. M. J.; Vogl, O. Arylation of unsaturated systems by free
ACS Paragon Plus Environment
25

The Journal of Organic Chemistry
Page 26 of 33
1
2
3
4
5
6
7
8
9
radicals. VII. The Meerwein reaction. V. Further arylations of maleimides. ultraviolet
spectra of arylmaleimides, arylmaleic anhydrides and arylmaleo and fumaronitriles. J.
Am. Chem. Soc. 1956, 78, 6115-6120; (c) Yanga, Z.-H.; Chena, Z.-H.; Ana, Y.-L.; Zhao,
S.-Y. Selective and tunable synthesis of 3-arylsuccinimides and 3-arylmaleimides from
arenediazonium tetrafluoroborates and maleimides. RSC Adv. 2016, 6, 23438-23447.
(a) Awuah, E.; Capretta, A. Development of methods for the synthesis of libraries of
substituted maleimides and α,β-Unsaturated-γ-butyrolactams. J. Org. Chem. 2011, 76,
3122-3130; (b) Roshchin, A. I.; Polunin, E. V. Synthesis of 2-arylmaleimides via the
Heck reaction. Mendeleev Commun. 2008, 18, 332-333; (c) Lim, L.H.; Zhou, J. A
challenging Heck reaction of maleimides. Org. Chem. Front. 2015, 2, 775-777.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(11)
(12) (a) Ambrogi, M.; Ciogli, A.; Mancinelli, M.; Ranieri, S.; Mazzanti, A. Atropisomers of
arylmaleimides: stereodynamics and absolute configuration. J. Org. Chem. 2013, 78,
3709-3719; (b) Bouissane, L.; Sestelo, J. P.; Sarandeses, L. A. Synthesis of 3,4-
disubstituted maleimides by selective cross-coupling reactions using Indium
organometallics. Org. Lett. 2009, 11, 1285-1288; (c) Onimura, K.; Matsushima, M.;
Nakamura, M.; Tominaga, T.; Yamabuki, K.; Oishi, T. Synthesis and fluorescent
properties of model compounds for conjugated polymer containing maleimide units at the
main chain. J. Polym. Sci. Part A: Polym. Chem. 2011, 49, 3550-3558.
(13) (a) Barradasst, R. G.; Etcher E.; Porter, J. D. The hydrolysis of maleimide in alkaline
solution. Can. J. Chem. 1976, 54, 1400-1404; (b) Matsui, S.; Aida, H. Hydrolysis of
some N-alkylmaleimides. J. Chem. Soc. Perkin Trans. 2, 1978, 0, 1277-1280.
(14) (a) Bettadapur, K. R.; Lanke, V.; Prabhu, K. R. A deciduous directing group approach for
the addition of aryl and vinyl nucleophiles to maleimides. Chem. Commun. 2017, 53,
ACS Paragon Plus Environment
26

Page 27 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
6251-6254; (b) Liu, S.-L.; Li, Y.; Guo, J.-R.; Yang, G.-C.; Li, X.-H.; Gong, J.-F.; Song.
M.-P. An Approach to 3-(Indol-2-yl)succinimide derivatives by Manganese-catalyzed C-
H activation. Org. Lett. 2017, 19, 4042-4045; (c) Mandal, A.; Sahoo, H.; Dana S.;
Baidya, M. Ruthenium(II)-catalyzed hydroarylation of maleimides using carboxylic acids
as a traceless directing group. Org. Lett. 2017, 19, 4138-4141; (d) Shintani, R.; Duan,
W.-L.; Nagano, T.; Okada, A.; Hayashi, T. Chiral Phosphine-olefin bidentate ligands in
asymmetric catalysis: Rhodium-catalyzed asymmetric 1,4-addition of aryl boronic acids
to maleimides. Angew. Chem. Int. Ed. 2005, 44, 4611-4614; (e) Ji, J.; Yang, Z.; Liu, R.;
Ni, Y.; Lin, S.; Pan, Q. Pd(II)/bipyridine catalyzed conjugate addition of arylboronic
acids to α,β-unsaturated amides. Tetrahedron Lett. 2016, 57, 2723-2726; (f) Bettadapur,
K. R.; Lanke, V.; Prabhu, K. R. Ru(II)-catalyzed C-H activation: Ketone-directed novel
1,4-addition of ortho C-H bond to maleimides. Org. Lett. 2015, 17, 4658-4661; (g) Lv,
N.; Liu, Y.; Xiong, C.; Liu, Z.; Zhang, Y. Cobalt-catalyzed oxidant-free spirocycle
synthesis by liberation of hydrogen. Org. Lett. 2017, 19, 4640-4643; (h) Han, S. H.; Kim,
S.; De, U.; Mishra, N. K.; Park, J.; Sharma, S.; Kwak, J. H.; Han, S.; Kim, H. S.; Kim, I.
S. Synthesis of succinimide-containing chromones, naphthoquinones, and xanthones
under Rh(III) catalysis: Evaluation of anticancer activity. J. Org. Chem. 2016, 81, 12416-
12425; (i) Shintani, R.; Duan, W.-L.; Hayashi, T. Rhodium-catalyzed asymmetric
construction of quaternary carbon stereocenters:ꢀ Ligand-dependent regiocontrol in the
1,4-addition to substituted maleimides. J. Am. Chem. Soc. 2006, 128, 5628-5629; (j)
Berhal, F.; Wu, Z.; Genet, J.-P.; Ayad, T.; Ratovelomanana-Vidal, V. Rh-catalyzed
asymmetric 1,4-addition of arylboronic acids to α,β-unsaturated ketones with difluorphos
and synphos analogues. J. Org. Chem. 2011, 76, 6320-6326.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment
27

The Journal of Organic Chemistry
Page 28 of 33
1
2
3
4
5
6
7
8
9
(15) (a) Yeh, H.-C.; Wu, W.-C.; Wen, Y.-S.; Dai, D.-C.; Wang, J.-K.; Chen, C.-T. Derivative
of α,β-Dicyanostilbene:ꢀ Convenient precursor for the synthesis of diphenylmaleimide
compounds, E-Z isomerization, crystal structure, and solid-state fluorescence. J. Org.
Chem. 2004, 69, 6455-6462; (b) Jafarpour, F.; Shamsianpour, M. Palladium-catalyzed
cross-dehydrogenative coupling of maleimides with simple arenes: A fast track to highly
substituted maleimides. RSC Adv. 2016, 6, 103567-103570; (c) Jafarpour, F.;
Shamsianpour, M.; Issazadeh, S.; Dorrani, M.; Hazrati, H. Palladium-catalyzed direct
arylation of maleimides: A simple route to bisaryl-substituted maleimides. Tetrahedron
2017, 73, 1668-1672; (d) Liu, T.-Z.; Chen, Y. Synthesis, optical and electrochemical
properties of luminescent polymers containing 1,2-diphenylmaleimide and thiophene
segments. Polymer 2005, 46, 10383-10391; (e) Chan, L.-H.; Lee, Y.-D.; Chen, C.-T.
Achieving saturated red photoluminescence and electroluminescence with readily
synthesized maleimide-arylamine copolymers. Tetrahedron 2006, 62, 9541-9547; (f)
Yahyaoui, A. E.; Felix, G.; Heynderickx, A.; Moustrou, C.; Samat, A. Convenient
synthesis of photochromic symmetrical or unsymmetrical bis(heteroaryl)maleimides via
the Suzuk-Miyaura cross-coupling reaction. Tetrahedron 2007, 63, 9482-9487; (g) Xie,
H.-D.; Ho, L. A.; Truelove, M. S.; Corry, B.; Stewart, S. G. Fluorescent triphenyl
substituted maleimide derivatives: Synthesis, spectroscopy and quantum chemical
calculations. J. Fluoresc. 2010, 20, 1077-1085.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(16) Barrett, S.; Bartlett, S.; Bolt, A.; Ironmonger, A.; Joce, C.; Nelson, A.; Woodhall, T.
Configurational Stability of Bisindolylmaleimide Cyclophanes: From conformers to the
first configurationally stable, atropisomeric bisindolylmaleimides. Chem. Eur. J. 2005,
11, 6277-6285.
ACS Paragon Plus Environment
28

Page 29 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(17) (a) Kumarasamy, E.; Raghunathan, R.; Sibi, M.P.; Sivaguru, J. Nonbiaryl and
heterobiaryl atropisomers: Molecular templates with promise for atropselective chemical
transformations. Chem. Rev. 2015, 115, 11239-11300; (b) Bringman, G.; Mortimer, A.
J.P.; Keller, P. A.; Gresser, M. J.; Garner J.; Breuning, M. Atroposelective synthesis of
axially chiral biaryl compounds. Angew. Chem. Int. Ed. 2005, 44, 5384-5427; (c) Zask,
A.; Murphy, J.; Ellestad, G.A. Biological stereoselectivity of atropisomeric natural
products and drugs. Chirality 2013, 25, 265-274; (d) LaPlante, S. R.; Fader, L. D.;
Fandrick, K. R.; Fandrick, D. R.; Hucke, O.; Kemper, R.; Miller, S. P. F.; Edwards, P. J.
Assessing atropisomer axial chirality in drug discovery and development. J. Med. Chem.
2011, 54, 7005-7022; (e) LaPlante, S. R.; Edwards, P. J.; Fader, L. D.; Jakalian, A.;
Hucke, O. Revealing atropisomer axial chirality in drug discovery. Chem. Med. Chem.
2011, 6, 505; (f) Clayden, J.; J. Moran, W.; Edwards P. J.; LaPlante, S. R. The challenge
of atropisomerism in drug discovery. Angew. Chem. Int. Ed. 2009, 48, 6398-6401.
(18) (a) Chan, L.-H.; Juang, S.-Y.; Chen M.-C.; Lin, Y.-J. A new series of random conjugated
copolymers containing 3,4-diphenyl-maleimide and thiophene units for organic
photovoltaic cell applications. Polymer 2012, 53, 2334-2346; (b) Afanasenko, A. M.;
Boyarskaya, D. V.; Boyarskaya, I. A.; Chulkova, T. G.; Grigoriev, Y.M.; Kolesnikov,
I.E.; Avdontceva, M. S.; Panikorovskii, T.L.; Panin, A.I.; Vereshchagin, A. N.; Elinson,
M. N. Structures and photophysical properties of 3,4-diaryl-1H-pyrrol-2,5-diimines and
2,3-diarylmaleimides. J. Mol. Struct. 2017, 1146, 554-561; (c) Chan, L.-H.; Lee, Y.-D.;
Chen, C.-T. 3,4-Diphenylmaleimide-thiophene-fluorene copolymers for polymeric
orange–red light-emitting diodes. Org. Electron. 2006, 7, 55-59; (d) Zhao, Y.; Lin, Z.;
Zhou, Z.; Yao, H.; Lv, W.; Zhen, H.; Ling, Q. White light-emitting devices based on star-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment
29