Synthesis and DFT studies of novel aryloxymaleimides via nucleophilic substitution of tosyloxy group

Article abstract of DOI:10.1016/j.molstruc.2019.04.020

Maleimide skeleton distributes widely in a great many substances, and maleimides are very useful building blocks in organic synthesis and many related disciplines, like bioconjugation. As an excellent leaving group, tosyloxy (-OTs) group are very popular

Full text of DOI:10.1016/j.molstruc.2019.04.020

Accepted Manuscript
Synthesis and DFT studies of novel aryloxymaleimides via nucleophilic substitution of
tosyloxy group
Maocai Yan, Zhen Zhang, Jinhui Zhou, Wei Li, Chunyan Zhang, Jingchang Zhang,
Huannan Wang, Xuelu Yang, Shuai Fan, Zhaoyong Yang
PII:
S0022-2860(19)30415-6
DOI:
https://doi.org/10.1016/j.molstruc.2019.04.020
MOLSTR 26392
Reference:
To appear in: Journal of Molecular Structure
Received Date: 5 September 2018
Revised Date: 12 March 2019
Accepted Date: 3 April 2019
Please cite this article as: M. Yan, Z. Zhang, J. Zhou, W. Li, C. Zhang, J. Zhang, H. Wang, X.
Yang, S. Fan, Z. Yang, Synthesis and DFT studies of novel aryloxymaleimides via nucleophilic
substitution of tosyloxy group, Journal of Molecular Structure (2019), doi: https://doi.org/10.1016/
j.molstruc.2019.04.020.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Synthesis and DFT studies of novel aryloxymaleimides via nucleophilic
substitution of tosyloxy group
Maocai Yana,*, Zhen Zhanga, Jinhui Zhoua, Wei Lia, Chunyan Zhanga, Jingchang Zhanga, Huannan Wanga,
Xuelu Yanga, Shuai Fanb, Zhaoyong Yangb,*
a School of Pharmacy, Jining Medical University, Rizhao, Shandong, 276800, China
b Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical
College, Beijing, 100050, China
* Corresponding author. Email: maocaiyan@mail.jnmc.edu.cn (Maocai Yan);
zhaoyongy@imb.pumc.edu.cn (Zhaoyong Yang)
Abstract: Maleimide skeleton distributes widely in a great many substances, and maleimides are very
useful building blocks in organic synthesis and many related disciplines, like bioconjugation. As an
excellent leaving group, tosyloxy (-OTs) group are very popular in organic synthesis; however, reports on
use of -OTs group on maleimide scaffold are very rare. In this study, 3-tosyloxymaleimide was prepared
from L-tartaric acid and used to react with various phenols or naphthols under PTC condition to give 3-
aryloxymaleimides through nucleophilic substitutions. Yields of the reaction were not high due to a
competitive transesterification reaction; however, this reaction would be practical if the side-reaction
could be suppressed by appropriate reaction conditions. The reaction mechanism was investigated by
theoretical computation. The intermediates and transition states of the reaction, as well as the potential
barrier and reaction free energy, were calculated using density functional theory (DFT), and influencing
factors of the reaction were discussed. Theoretical computations showed that this nucleophilic
substitution is favorable both kinetically and thermodynamically, while electron-withdrawing groups on
phenols are harmful to such reactions. This study will provide new knowledge and insights on the
chemical properties of maleimide and tosyloxy group, as well as the related chemical reactions.
Keywords: Maleimide; Organic synthesis; Theoretical calculations; Density functional theory; Reaction
mechanism
Introduction
Maleimide is a common scaffold of a variety of organic substances, and is also an important building
block used in chemical synthesis. Maleimide and its derivatives can be easily prepared by condensation of
maleic acid or maleic anhydride with amines, and are very useful in multiple area, especially in
bioconjugation. (1) (2) (3) (4) (5) p-Toluenesulfonyloxy (-OTs, tosyloxy) is a common functional group
widely used in organic synthesis, because it can be readily prepared from alcohols by tosylation with TsCl
and act as an excellent leaving group in substitution reactions. (6) However, application of tosyloxy group
on maleimide scaffolds were quite rarely reported. Till June 19, 2018, only 2 substances bearing a
tosyloxy group on maleimide scaffolds and 2 related references had been reported (CAS RN 903578-02-9
(7) and 873939-14-1 (8)). In our previous studies, we unexpectedly found that trans-3,4-
dihydroxypyrrolidine-2,5-dione may be converted to monotosyloxymaleimide under tosylation by
TsCl/Et3N. (9) Starting from the monotosyloxymaleimide, a number of monosubstituted maleimides
were synthesized using nucleophilic substitution reactions under mild phase transfer catalysis (PTC)
conditions. Density functional theory (DFT) was then used to investigate the mechanism of the reaction,

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including the transition states and intermediates, intrinsic reaction coordinates (IRC), potential barriers,
and the change of free energies; influencing factors of the reaction were also discussed.
Results and Discussion
Firstly, the commercially available L-tartaric acid was cyclized with p-methoxybenzylamine (PMB-NH2)
in xylene to give the L-tartarimide 1 (9) (10) (Scheme 1). Then 1 was treated with TsCl and Et3N in
CH2Cl2 to furnish the maleimide 2. (9) The intermediate 3 was obtained through removal of p-
methoxybenzyl (PMB) group of 2 by ceric ammonium nitrate (CAN) oxidation, and used as the starting
material of synthesis of monosubstituted maleimides (Scheme 2).
PMB
PMB
N
H
N
HOOC
HO
COOH
OH
N
a
O
O
b
O
O
c
O
O
OTs
HO
OH
OTs
L-tartaric acid
1
2
3
Scheme 1. Reactions and conditions: (a) PMB-NH2, xylene, reflux; (b) TsCl, Et3N, CH2Cl2, 0 0C ~ rt; (c)
CAN, MeCN-H2O, reflux.
It is well-known that oxygen or halogen atoms connecting to a double bond or an aromatic ring are
somewhat inert to nucleophilic substitution due to the p-π conjugation. Typical methods of substituting
OTs or halogen on aromatic rings include Ullmann reaction and its variations, like Ullmann condensation
and Goldberg reaction, catalyzed by copper or palladium. As for maleimides, nucleophilic substitutions of
halogen on maleimide without Cu or Pd catalysts have been reported (11) (12) (13) ; however, such
studies on substitution of tosyloxy group are still absent. In this study, we used various phenols to
displace the tosyloxy group of 3 to obtain the corresponding ethers (4a~4k) at the presence of K2CO3
under mild phase transfer catalysis (PTC) conditions (Scheme 2).
H
N
H
N
O
O
O
O
+
Ar-OH
+
Ar-OTs
OTs
OAr
3
4a~4k
5a~5k
Scheme 2. Reactions and conditions: K2CO3, TBAB, CH2Cl2-H2O, rt.
Generally, the reactions in Scheme 2 can be completed quickly at room temperature; however, yields of
4a~4k are relatively low (Table 1), mainly due to a competitive transesterification reaction, i.e.,
transferring of tosyl from 3 to phenols, giving the corresponding aryl tosylates (5a~5k). This side-reaction
is unsurprising since enol esters are acylating reagents. For phenol derivatives (4a~4g), the yields are
between 24.3%~47.3%; for naphthol derivatives (4h~4k), the yields differ greatly. The order of the yields
is 4h > 4i > 4j > 4k; when the Ar-OH was 2-hydroxy-1-naphthalenecarbaldehyde, no ether product 4k
was obtained, while the tosylate 5k became the only product. The lower yield of 4i is possibly due to the
steric hindrance of bromine at C-1. The strong electron-withdrawing effect of formyl group of 6-hydroxy-
2-naphthalenecarbaldehyde and 2-hydroxy-1-naphthalenecarbaldehyde probably lead to the poor yields of
4j and 4k by decreasing the nucleophilicity of naphthoxy anion; and for the latter, steric hindrance of
formyl group is also likely to play a role in preventing the formation of 4k. The yield of by-products

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5h~5k, however, are in ascending order. The reason we supposed is that the transesterification reaction
might be not as sensitive to the effects of electron-withdrawing and steric hindrance as the major reaction
is; since these two reactions are competitive, factors suppressing the major reaction will facilitate the side-
reaction.
Table 1. Structure and yield of products 4a~4k and by-products 5a~5k.
Name
Ar
Yield of Yield of
4a~4k
34.5%
42.6%
5a~5k
35.3%
37.7%
phenyl
4a
4b
43.0%
47.3%
37.6%
36.4%
4c
4d
24.3%
37.7%
38.6%
19.1%
4e
4f
H3CO
38.7%
44.7%
40.4%
34.6%
4g
4h
Br
21.9%
55.7%
4i
Br
14.0%
NA
64.3%
70.0%
4j
OHC
CHO
4k
The reaction mechanism of the formation of enol ether 4a~4k was further investigated by theoretical
computations using DFT. Possibly, this reaction may have a one-step SN2-like process, i.e., the attacking
of phenoxy anion is concerted with the leaving of the tosyloxy anion, with a transition state (TS) (6a in
Scheme 3) controlling the whole process. Alternatively, this reaction may be a two-step process,
including an addition of phenoxy anion to form a tetrahedral intermediate 6a, followed by an elimination
of tosylate anion (Scheme 3). These two mechanisms can be discriminated by whether 6a is a transition

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state (one-step mechanism) or an intermediate (two-step mechanism). In quantum chemistry, this question
can be expressed as whether 6a is located at a first-order saddle point in the potential energy surface
(PES), or a local minimum in the PES; the former indicates a transition state, while the latter indicates an
intermediate.
H
N
H
H
N
O
N
O
O
O
O
O
O
+
+
TsO
OPh
OTs
OPh
OTs
6a
3
4a
Scheme 3. Proposed reaction mechanism of 3 with phenol.
The hybrid-meta GGA functional M06-2X (14) (15) with basis set 6-31+G** (16) (17) was selected for
the DFT calculations including geometry optimization, vibration analysis, and calculation of intrinsic
reaction coordinate (IRC). The M06-2X functional exhibits good performances in studies of organic
reaction mechanism, including nucleophilic addition/substitution processes. (18) (19) The combination of
M06-2X functional with the basis set 6-31G** (or with diffusion functions) is usually adequate for
theoretical studies of common organic systems (20) (21) (22) (23). For the optimized structure of
stationary points, single point energies were recalculated using double-hybrid functional B2PLYP (24)
and basis set ma-TZVP (def2-TZVP basis set (25) (26) with minimal diffuse function for heavy atoms (27)
(28)) to yield higher accuracy.
The structure of 6a was obtained by manually constructing an initial guessed structure followed by a
geometry optimization. Vibration analysis of 6a showed no imaginary frequencies, indicating 6a is not a
transition state, but an intermediate. Thus, transition states between the reactant and 6a (TS1) and
between 6a and the product (TS3) were searched and IRCs were calculated for these transition states (see
Data in Brief). Interestingly, 6a has two distinct conformational isomers (IM1 and IM2), which were
derived from IRC of TS1 and TS3, respectively, and were not interconvertible in geometry optimization
(Figure 1). IM1 and IM2 just differ in the orientation of phenyl rings, i.e., the C-OPh torsion (5-1-28-29)
and the O-Ph torsion (1-28-29-30). IM1 and IM2 were separated by a transition state (TS2), which has a
unique imaginary frequency of 41.12i. We tried to find a transition state which directly connects the
reactant to IM2, but failed. It seems that a nearly parallel position of the phenoxy anion with the
maleimide ring facilitates the nucleophilic attacking and the formation of TS1 (Figure 2, structure of the
reactant and TS1), probably due to the π-π interactions between the phenyl and maleimide ring, and leads
to the formation of IM1. However, during the leaving of tosyloxy anion, the oxygen atom of the phenoxy
group needs to reach the plane of maleimide ring, and therefore the weak interactions between the phenyl
and maleimide ring in IM1 must be broken and then the phenyl rotates outward to form IM2, which
allows the oxygen atom of the phenoxy group approaching the maleimide plane (Figure 2, structure of
TS3 and the product). Nevertheless, the transition of IM1 to TS2 is just a conformational rotation with a
potential energy barrier of only 3.2 KJ/mol, which is quite easy to accomplish.

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Figure 1. Conformational isomers of 6a (IM1, TS2, and IM2).
TS1 has only one imaginary frequency (239.05i), which corresponds to the stretch of C···OPh bond (1.94
Å); bond length of C···OTs is 1.39 Å. The long C···OPh distance in TS1 indicates the transition state is
closer to the reactant rather than to the product, and the phenoxy anion is easy to approach the carbon
atom in reaction center to form the transition state. This is in consistent with the fact that the potential
barrier from the reactant to TS1 is quite low (18.3 KJ/mol only). The only imaginary frequency of TS3 is
265.36i, corresponding to the stretch of C···OTs bond; bond length of C···OTs and C···OPh are 1.64 Å
and 1.38 Å, respectively. The low barrier between IM2 and TS3 (2.5 KJ/mol) indicates that IM2 is very
liable to decompose to form the product.
Table 2. Gibbs free energies calculated for reactant, transition states, intermediates, and product in the
reaction of 3 with phenol.a)
Single point
energy (M06-
2X)b)
Thermal correction
to
Gibbs free energy
Single point
energy
(B2PLYP)
Gibbs free
energy
Relative
energy
(KJ/mol)
Reactant -1560.166119
0.220709
0.221798
0.224744
0.225863
0.224282
0.224725
0.224045
-1560.107793
-1560.100791
-1560.108957
-1560.108790
-1560.112709
-1560.113655
-1560.158269
-1559.887084
-1559.878993
-1559.884213
-1559.882927
-1559.888427
-1559.888930
-1559.934224
123.8
145.0
131.3
134.7
120.2
118.9
0
TS1
IM1
TS2
IM2
TS3
-1560.159162
-1560.177945
-1560.176740
-1560.182231
-1560.181288
Product -1560.219515
a) Geometry optimization, vibration analysis and IRC calculation were at M06-2X/6-31+G** level. For optimized structures,
single point energies were recalculated at B2PLYP/ma-TZVP level. Each transition state has only one imaginary frequency,
while others have no imaginary frequencies after geometry optimization. Frequency scale factor of 0.9670 (29) was used in
calculating thermal correction values at 298.15K. Gibbs free energies were calculated by summing up single point energies
(B2PLYP) and the thermal correction value. All energies, except Relative energy, are given in Hartree. b) The electronic energy
barriers reported in the text were calculated using M06-2X single point energies reported here. The M06-2X single point energies
of the reactant, intermediates, and product reported here are of the optimized structures, which are slightly different to the
corresponding structures in the IRC (not optimized); so, the M06-2X single point energy barriers calculated from this Table are
slightly different to the barriers read from the IRC.

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Figure 2. Profile of free energies and structures of the stationary points along the reaction coordinate. For
clearance, all hydrogen atoms are hidden and the tosyl group is displayed in line model.
The stationary points including transition states, intermediates, reactant and product were then geometry-
optimized and calculated for Gibbs free energies (Table 2, Figure 2). Obviously, the free energy of TS3
is 1.3 KJ/mol lower than IM2 (for electronic energies, TS3 is just 2.5 KJ/mol higher); therefore, TS3 is
not a real transition state when free energies are taken into account. The free energy barrier of TS2 is just
3.4 KJ/mol; therefore, conversion from the reactant to TS1 (with a free energy barrier of 21.2 KJ/mol to
overcome) determines the speed of the whole reaction process. So, this reaction is quite easily to occur
under room temperature. The overall free energy change of the whole reaction is -123.8 KJ/mol. Also, the
free energy barrier between IM1 and TS1 is 13.7 KJ/mol, dramatically lower than the electronic energy
barrier (49.3 KJ/mol), while the barrier of forward process changed less (21.2 KJ/mol in free energy, and
18.3 KJ/mol in electronic energy). The difference in thermal correction values of free energy of the
reactant and IM1 is 10.6 KJ/mol, which is mainly contributed by the entropy difference. IM1 has a much
lower entropy than the reactant; the T·ꢀS item is -8.8 KJ/mol (T=298.15 K). The decrease of entropy
would be attributed to the loss of degree of freedom and disorder upon the joining of two molecules into
one.
The transition state of reaction of 3 with 2-hydroxy-1-naphthalenecarbaldehyde was also found and IRC
was calculated using the same parameter settings (Figure 3). The only imaginary frequency of TS1 is
299.12i, corresponding to the stretch of the newly formed C···O bond (1.84 Å). This bond length is

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significantly shorter than the TS1 of 4a (1.94 Å), indicating that the naphthoxy anion will need to
overcome much more resistance to reach a closer position to the center carbon atom to form the transition
state. Obviously, the strong electron-withdrawing effect of the formyl group at ortho- position decreases
the electronegativity of the oxygen atom, and therefore it needs to be much closer (than the phenoxy
anion) to the center carbon atom to reach a balance with the leaving group (tosyloxy). This agrees with
the fact that the potential barrier (37.6 KJ/mol, electronic energy) is significantly higher than that of 4a
(18.3 KJ/mol). The Gibbs free energy barrier of the forward process was calculated at the same
computation level to 4a (Table 3) to be 31.4 KJ/mol, higher than 4a (21.2 KJ/mol), whereas the free
energy barrier for the reverse process is 7.4 KJ/mol, lower than 4a (13.7 KJ/mol). These data clearly
demonstrated that formation of 4k is more difficult than 4a. Even so, such a reaction would be able to
proceed easily at room temperature, assuming the absence of the competitive transesterification reaction,
which is apparently very easier to proceed.
Figure 3. Comparison of transition state and IRC of 4a and 4k.
Table 3. Gibbs free energy changes in the reaction of 3 with 2-hydroxy-1-naphthalenecarbaldehyde.a)
Single point
energy (M06-
2X)
Thermal
correction to
Gibbs free energy
Single point
energy
(B2PLYP)
Gibbs free
energy
Relative
energy
(KJ/mol)
Reactant -1827.0553572
0.272080
0.271086
0.272069
-1826.9746736 -1826.7025936
-1826.9617225 -1826.6906365
0
31.4
24.0
TS1
IM1
-1827.0410351
-1827.0525356
-1826.965520
-1826.6934510
a) All parameter settings in the calculation were the same to those in Table 2.
Conclusion
In this study, nucleophilic displacement reactions of tosyloxy group on maleimide scaffold was explored.
The nucleophiles were different phenols and naphthols, and the reactions were carried out at the presence
of K2CO3 under mild PTC conditions. Usage of tosyloxy group on maleimides was very rarely reported,
and this study is attempting to provide a preliminary exploratory research and to discover the potential
issues in such reactions. The reaction mechanism and influencing factors were explored by theoretical
computations using DFT, based on the experimental results. The free energy barrier and free energy of
reaction showed that these nucleophilic substitution reactions were favorable both thermodynamically and

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kinetically. However, the yield of the reactions were low to moderate, primarily attributed to the
competitive transesterification reaction. Nevertheless, this reaction still could be of practical value if
suitable reaction conditions are found to suppress the undesirable transesterification reaction. Further
computational and experimental studies in this area are still underway and will be reported upon new
progress.
Experimental Details
1. Chemical synthesis
General methods: 1 and 2 were prepared according to our previous studies. (9) CAN were from Aladdin
Chemical Reagents (Shanghai, China). Phenols and naphthols were purchased from Aladdin Chemical
Reagents or IVKeyan (Shanghai, China). Other reagents were from Fuyu Fine Chem (Tianjin, China).
Boiling range of petroleum ether used in this study is 60-90 0C. Pre-coated silica gel GF254 plates
(Qingdao Haiyang Chemical, Qingdao, China) were used in TLC. Preparative column chromatography
was performed using silica gel (100-200 mesh). NMR spectra were recorded on Bruker Avance III-400 or
AscendTM 600 spectrometers. HRMS spectra were determined using Bruker Daltonics maXis UHR-TOF
with ESI ionization source.
1.1. 3-Tosyloxymaleimide (3)
2 (19.10 g, 49.3 mmol) and CAN (93.73 g, 171 mmol) were suspended in MeCN-H2O (279 ml : 31 ml),
and the mixture was stirred and refluxed until TLC (4:1, petroleum ether-EtOAc) showed the reaction had
completed. The mixture was cooled down to room temperature, to which water (800 ml) was slowly
added. The mixture was then left overnight to allow the product to precipitate. After filtration, the
obtained solid was subject to column chromatography (8:1, petroleum ether-EtOAc) to furnish 3 (9.52 g,
35.6 mmol) as a light yellow powder. Yield: 72.2%. 1H NMR (600 MHz, CDCl3): 2.49 (s, 3H, PhCH3),
6.30 (d, 1H, J=1.2, H-4), 7.34 (br, 1H, NH), 7.43 (m, 2H, Ar-H), 7.90 (m, 2H, Ar-H); 13C NMR (400
MHz, CDCl3): 21.9, 110.3, 128.8, 130.5, 130.8, 147.5, 149.3, 163.7, 167.4; HRMS m/z: [M+NH4]+
calculated 285.0540, found 285.0540; [M+Na]+ calculated 290.0094, found 290.0091.
1.2. General procedure of synthesis of 3-aryloxymaleimide (4a~4k)
3 (300 mg, 1.12 mmol), Ar-OH (2.04 mmol), and TBAB (50 mg) were dissolved in CH2Cl2 (15 ml), to
which a K2CO3 aqueous solution (K2CO3 300 mg in H2O 2.5 ml) was added. The mixture was stirred
vigorously at room temperature until TLC (4:1, petroleum ether-EtOAc) showed the reaction had
completed. The mixture was then diluted by CH2Cl2 (15 ml) and washed by water (25 ml × 3) and dried
over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and subject to a silica gel
column chromatography (15:1 ~ 7:1, petroleum ether-EtOAc) to give the desired 3-aryloxymaleimides
(4a~4k) and the by-products aryl tosylates (5a~5k). (For 4-(2-methoxyethyl)phenol, 5e was firstly eluted
by 10:1 petroleum ether-acetone, and then 4e was collected using 7:1 petroleum ether-EtOAc.)
3-Phenoxymaleimide (4a): white solid, yield 34.5%. 1H NMR (600 MHz, CDCl3): 5.31 (d, 1H, J=1.8, H-
13
4), 7.19-7.21 (m, 2H, Ar-H), 7.31-7.34 (m, 1H, Ar-H), 7.45-7.48 (m, 2H, Ar-H), 7.67 (br, 1H, NH); C
NMR (400 MHz, CDCl3): 100.5, 119.8, 127.0, 130.4, 153.8, 159.6, 165.4, 169.3; HRMS: m/z [M+Na]+
calculated 212.0318, found 212.0319.
Phenyl tosylate (5a) (30) (31) (32): white solid, yield 35.3%.

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3-(4-tert-Butylphenoxy)maleimide (4b): white solid, yield 42.6%. 1H NMR (600 MHz, CDCl3): 1.34 (s,
9H, t-Bu), 5.33 (d, 1H, J=1.2, H-4), 7.10-7.12 (m, 2H, Ar-H), 7.23 (br, 1H, NH), 7.43-7.46 (m, 2H, Ar-H);
13C NMR (400 MHz, CDCl3): 30.3, 33.6, 99.3, 118.1, 126.2, 149.0, 150.5, 158.7, 164.4, 168.4; HRMS:
m/z [M+Na]+ calculated 268.0944, found 268.0947.
4-tert-Butylphenyl tosylate (5b) (33): white solid, yield 37.7%.
3-(4-Isopropylphenoxy)maleimide (4c): white solid, yield 43.0%. 1H NMR (400 MHz, CDCl3): 1.26 (d,
6H, J=6.8, CH3×2), 2.95 (m, 1H, CHMe2), 5.32 (s, 1H, H-4), 7.09-7.12 (m, 2H, Ar-H), 7.27-7.31 (m, 2H,
Ar-H), 7.60 (br, 1H, NH); 13C NMR (400 MHz, CDCl3): 24.0, 33.7, 100.3, 119.5, 128.2, 147.7, 151.8,
159.8, 165.5, 169.5; HRMS: m/z [M+Na]+ calculated 254.0788, found 254.0793.
4-Isopropylphenyl tosylate (5c) (33): colorless liquid, yield 37.6%.
3-(3,4-Dimethylphenoxy)maleimide (4d): white solid, yield 47.3%. 1H NMR (400 MHz, CDCl3): 2.27 (s,
3H, CH3), 2.28 (s, 3H, CH3), 5.29 (s, 1H, H-4), 6.91 (m, 1H, Ar-H), 6.96 (m, 1H, Ar-H), 7.18 (m, 1H, Ar-
H), 7.58 (br, 1H, NH); 13C NMR (400 MHz, CDCl3): 19.3, 20.0, 100.2, 116.7, 120.6, 131.1, 135.4, 139.1,
151.8, 159.9, 165.5, 169.6; HRMS: m/z [M+Na]+ calculated 240.0631, found 240.0637.
3,4-Dimethylphenyl tosylate (5d) (33) : white solid, yield 36.4%.
1
3-(4-(2-Methoxyethyl)phenoxy)maleimide (4e): white solid, yield 24.3%. H NMR (400 MHz, CDCl3):
2.91 (t, 2H, J=6.8, PhCH2), 3.37 (s, 3H, OCH3), 3.63 (t, 2H, J=6.8, OCH2), 5.32 (d, 1H, J=1.6, H-4), 7.10-
7.13 (m, 2H, Ar-H), 7.29-7.33 (m, 2H, Ar-H), 7.40 (br, 1H, NH); 13C NMR (400 MHz, CDCl3): 35.5,
58.8, 73.1, 100.4, 119.6, 130.7, 138.1, 152.2, 159.7, 165.3, 169.2; HRMS: m/z [M+Na]+ calculated
270.0737, found 270.0737.
4-(2-Methoxyethyl)phenyl tosylate (5e) (34): colorless liquid, yield 38.6%.
3-(2,3,5-Trimethylphenoxy)maleimide (4f): white solid, yield 37.7%. 1H NMR (600 MHz, CDCl3): 2.08
(s, 3H, CH3), 2.28 (s, 3H, CH3), 2.30 (s, 3H, CH3), 5.13 (d, 1H, J=1.2, H-4), 6.76 (s, 1H, Ar-H), 6.93 (s,
1H, Ar-H), 7.15 (br, 1H, NH); 13C NMR (600 MHz, CDCl3): 11.7, 20.0, 20.9, 100.5, 117.7, 124.5, 129.3,
136.9, 139.3, 152.1, 159.8, 165.1, 169.1; HRMS: m/z [M+Na]+ calculated 254.0788, found 254.0786.
2,3,5-Trimethylphenyl tosylate (5f) (35): white solid, yield 19.1%.
1
3-(5,6,7,8-Tetrahydro-2-naphthoxy)maleimide (4g): white solid, yield 38.7%. H NMR (600 MHz,
CDCl3): 1.79-1.83 (m, 4H, H-6’, H-7’), 2.77 (t, 4H, J=6.0, H-5’, H-8’), 5.31 (d, 1H, J=1.2, H-4), 6.87-
6.90 (m, 2H, Ar-H), 7.11 (m, 1H, Ar-H), 7.28 (br, 1H, NH); 13C NMR (600 MHz, CDCl3): 22.7, 22.9,
28.9, 29.5, 100.3, 116.6, 119.7, 130.8, 135.9, 139.6, 151.5, 159.9, 165.3, 169.2; HRMS: m/z [M+Na]+
calculated 266.0788, found 266.0791.
5,6,7,8-Tetrahydro-2-naphthyl tosylate (5g) (33) : colorless liquid, yield 40.4%.
1
3-(1-Naphthoxy)maleimide (4h): dark red solid, yield 44.7%. H NMR (600 MHz, CDCl3): 5.19 (d, 1H,
J=1.8), 7.31-7.33 (m, 1H), 7.49-7.51 (m, 1H), 7.55-7.59 (m, 3H), 7.82-7.83 (m, 1H), 7.92-7.96 (m, 2H);
13C NMR (150 MHz, CDCl3): 101.1, 116.0, 120.9, 125.3, 125.4, 127.1, 127.2, 127.3, 128.2, 135.0, 149.8,
159.8, 165.2, 169.1; HRMS: m/z [M+Na]+ calculated 262.0475, found 262.0473.
1-Naphthyl tosylate (5h) (33) : white solid, yield 34.6%.
3-(1,6-Dibromo-2-naphthoxy)maleimide (4i): white solid, yield 21.9%. 1H NMR (400 MHz, DMSO-d6):
5.65 (s, 1H, H-4), 7.78-7.80 (m, 1H, Ar-H), 7.93-7.96 (m, 1H, Ar-H), 8.17-8.21 (m, 2H, Ar-H), 8.48-8.49

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13
(m, 1H, Ar-H), 11.09 (br, 1H, NH); C NMR (100 MHz, DMSO-d6): 102.8, 113.1, 120.9, 121.9, 129.2,
130.1, 131.0, 131.3, 132.1, 133.9, 149.8, 158.1, 166.7, 171.0; HRMS: m/z [M+Na]+ calculated 419.8664,
found 419.8665.
1
1,6-Dibromo-2-naphthyl tosylate (5i): white solid, yield 55.7%. H NMR (600 MHz, CDCl3): 2.44 (s,
3H), 7.30 (m, 2H), 7.48 (m, 1H), 7.62 (m, 1H), 7.68 (m, 1H), 7.80 (m, 2H), 7.96 (m, 1H), 8.02 (m, 1H);
13C NMR (150 MHz, CDCl3): 21.8, 116.3, 121.3, 122.9, 128.0, 128.8, 129.3, 129.9, 130.1, 131.3, 131.4,
132.7, 133.5, 145.3, 145.9; HRMS: m/z [M+NH4]+ calculated 473.9192, found 473.9196.
1
3-(6-Formyl-2-naphthoxy)maleimide (4j): white solid, yield 14.0%. H NMR (600 MHz, DMSO-d6):
5.77 (d, 1H, J=1.2, H-4), 7.66-7.68 (m, 1H, Ar-H), 7.96-7.98 (m, 1H, Ar-H), 8.03 (m, 1H, Ar-H), 8.12 (m,
1H, Ar-H), 8.32 (m, 1H, Ar-H), 8.66 (m, 1H, Ar-H), 10.16 (s, 1H, CHO), 10.95 (br, 1H, NH); 13C NMR
(400 MHz, DMSO-d6): 102.6, 117.1, 121.0, 123.9, 129.4, 130.9, 133.0, 134.4, 134.8, 137.3, 154.2, 158.2,
167.1, 171.4, 193.4; HRMS: m/z [M+H]+ calculated 268.0604, found 268.0601.
1
6-Formyl-2-naphthyl tosylate (5j): white solid, yield 64.3%. H NMR (600 MHz, CDCl3): 2.45 (s, 3H,
CH3), 7.22-7.24 (m, 1H, Ar-H), 7.31-7.33 (m, 2H, Ar-H), 7.54 (m, 1H, Ar-H), 7.74-7.75 (m, 2H, Ar-H),
7.83-7.85 (m, 1H, Ar-H), 7.93-7.97 (m, 2H, Ar-H), 8.31 (m, 1H, Ar-H), 10.14 (s, 1H, CHO); 13C NMR
(150 MHz, CDCl3): 21.8, 120.2, 122.6, 123.9, 128.5, 129.1, 130.0, 131.1, 131.5, 132.2, 133.9, 134.5,
136.7, 145.8, 149.5, 191.8; HRMS: m/z [M+H]+ calculated 327.0686, found 327.0686.
1-Formyl-2-naphthyl tosylate (5k) (36): white solid, yield 70.0%.
2. Theoretical computation
All theoretical computations were performed using Gaussian 09 (37). SMD implicit solvent model (38) of
dichloromethane was used in all calculations. Geometry optimization, vibration analysis, and IRC
calculation were done at M06-2X/6-31+G** level; single point energies were recalculated for the
optimized structures using functional B2PLYP and basis set def2-TZVP (with minimal diffuse function
for heavy atoms). Gibbs free energies were obtained by summing up the single point energy (B2PLYP
level) with the thermal correction value. The frequency scale factor of 0.9670 (29) was used in calculation
of the thermal correction values. Imaginary frequencies of transition states reported here have not been
scaled. IRCs were calculated using LQA method, and the Hessian matrix was recalculated every 5 steps.
The step size of IRC was 0.05 Bohr; 300 steps at maximum in each direction were calculated, and all
IRCs completed within 300 steps.
Acknowledgement
This work was supported by A Project of Shandong Province Higher Educational Science and
Technology Program (J17KA260 and J15LM13), The Natural Science Foundation of Shandong Province
(ZR2016BL05), and funding programs of Jining Medical University (Support Funding JY2016KJ002Z).
Data in Brief
The NMR spectra of the novel aryloxymaleimide compounds and the computational data (including
coordinates of the stationary points and IRCs) may be found in Data in Brief.

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References
1. Corrêa, R.; Rosa, P. W.; Bella Cruz, A.; Savi, A. O. S.; Cechinel Filho, V.; Nunes, R. J. Synthesis and Antibacterial Activity
of Citraconimides. Pharmaceutical Sciences 1996, 2 (8), 353-355.
2. Mederski, W. W. K. R.; Baumgarth, M.; Germann, M.; Kux, D.; Weitzel, T. A convenient synthesis of 4-aminoaryl
substituted cyclic imides. Tetrahedron Lett 2003, 44 (10), 2133-2136.
3. Koniev, O.; Wagner, A. Developments and recent advancements in the field of endogenous amino acid selective bond
forming reactions for bioconjugation. Chem Soc Rev 2015, 44 (15), 5495–5551.
4. Francis, M. B.; Carrico, I. S. New frontiers in protein bioconjugation. Current Opinion in Chemical Biology 2010, 14 (6),
771–773.
5. Beck, A.; Goetsch, L.; Dumontet, C.; Corvaïa, N. Strategies and challenges for the next generation of antibody–drug
conjugates. Nature Reviews Drug Discovery 2017, 16, 315–337.
6. Smith, M.; March, J. Advanced Organic Chemistry, 6th ed.;, 2007; pp 501-502.
7. Poschenrieder, H.; Stachel, H.-D.; Eckl, E.; Jax, S.; Polborn, K.; Mayer, P. Functionalized imides by regioselective
ozonation. Helvetica Chimica Acta 2006, 89 (5), 971-982.
8. Bretschneider, T.; Es-Sayed, M.; Fischer, R.; Kather, K.; Malsam, O.; Konze, J.; Loesel, P.; Sanwald, E.; Hempel, W.
Preparation of 1H-pyrrole-2,5-dione derivatives as insecticides and acaricides. PCT Int. Appl. 2006, WO 2006007998.
9. Yan, M.; Zhang, Z.; Zhou, J.; Li, W.; Fan, S.; Yang, Z. Conversion of 3,4-Dihydroxypyrrolidine-2,5-Dione to Maleimide
through Tosylation and Mechanism Study by DFT. Computational Chemistry 2018, 6, 47-56.
10. Zheng, J. L.; Liu, H.; Zhang, Y. F.; Zhao, W.; Tong, J. S.; Ruan, Y. P.; Huang, P. Q. A study on the racemization step in the
synthesis of pyrrolidinols via cyclic α-hydroxyimides. Tetrahedron: Asymmetry 2011, 22, 257–263.
11. Hajjaj, B.; Shah, A.; Bell, S.; Shirran, S. L.; Botting, C. H.; Slawin, A. M. Z.; Hulme, A. N.; Lovett, J. E. Synthesis of Next-
Generation Maleimide Radical Labels. Synlett 2016, 27 (16), 2357 - 2361.
12. Lynch, D. M.; Crovetti, A. J. Reactions of Dichloromaleimides with Alcohols, Phenols, and Thiols. J Heterocyclic Chem
1972, 9, 1027-1032.
13. Marculescu, C.; Kossen, H.; Morgan, R. E.; Mayer, P.; Fletcher, S. A.; Tolner, B.; Chester, K. A.; L.H., J.; Baker, J. R.
Aryloxymaleimides for cysteine modification, disulfide bridging and the dual functionalization of disulfide bonds. Chem
Commun 2014, 50, 7139-7142.
14. Zhao, Y.; Truhlar, D. G. The M06 Suite of Density Functionals for Main Group Thermochemistry, Thermochemical Kinetics,
Noncovalent interactions, Excited States, and Transition Elements. Theor Chem Acc 2008, 120, 215–241.
15. Zhao, Y.; Truhlar, D. G. Density Functionals with Broad Applicability in Chemistry. Acc Chem Res 2008, 41, 157-167.
16. Rassolov, V. A.; Pople, J. A.; Ratner, M. A.; Windus, T. L. 6-31G* basis set for atoms K through Zn. J Chem Phys 1998,
109 , 1223-1229.
17. Rassolov, V. A.; Ratner, M. A.; Pople, J. A.; Redfern, P. C.; Curtiss, L. A. 6-31G* Basis Set for Third-Row Atoms. J Comp
Chem 2001, 22 , 976-984.
18. Goerigk, L.; Hansen, A.; Bauer, C.; Ehrlich, S.; Najibia, A.; Grimme, S. A look at the density functional theory zoo with the
advanced GMTKN55 database for general main group thermochemistry, kinetics and noncovalent interactions. Phys Chem
Chem Phys 2017, 19, 32184-32215.
19. Wang, Y.; Wei, D.; Zhang, W. Recent Advances on Computational Investigations of NHeterocyclic Carbene Catalyzed

ACCEPTED MANUSCRIPT
Cycloaddition/Annulation Reactions: Mechanism and Origin of Selectivities. ChemCatChem 2018, 10, 338-360.
20. Shi, Q.; Zhang, W.; Wang, Y.; Qu, L.; Wei, D. Insights into the isothiourea-catalyzed asymmetric [4 + 2] annulation of
phenylacetic acid with alkylidene pyrazolone. Org Biomol Chem 2018, 16, 2301–2311.
21. Li, X.; Tang, M.; Wang, Y.; Wang, Y.; Li, Z.; Qu, L. B.; Wei, D. Insights into the N-Heterocyclic Carbene (NHC)-Catalyzed
Intramolecular Cyclization of Aldimines: General Mechanism and Role of Catalyst. Chem Asian J 2018, 13, 1710-1718.
22. Li, X.; Wang, Y.; Wang, Y.; Tang, M.; Qu, L. B.; Li, Z.; Wei, D. Insights into the N-Heterocyclic Carbene (NHC)-Catalyzed
Oxidative γ-C(sp3)−H Deprotonation of Alkylenals and Cascade [4 + 2] Cycloaddition with Alkenylisoxazoles. J Org Chem
2018, 83, 8543-8555.
23. Shi, Q.; Wang, Y.; Wang, Y.; Qu, L. B.; Qiao, Y.; Wei, D. Insights to N-heterocyclic carbene-catalyzed [3 + 4] annulation
reactions of 2-bromoenals with N-Ts hydrazones. Org Chem Front 2018, 5, 2739-2748.
24. Grimme, S. Semiempirical hybrid density functional with perturbative second-order correlation. J Chem Phys 2006, 124 ,
034108.
25. Weigend, F.; Ahlrichs, R. Balanced basis sets of split valence, triple zeta valence and quadruple zeta valence quality for H to
Rn: Design and assessment of accuracy. Phys Chem Chem Phys 2005, 7, 3297-3305.
26. Weigend, F. Accurate Coulomb-fitting basis sets for H to Rn. Phys Chem Chem Phys 2006, 8, 1057-1065.
27. Zheng, J.; Xu, X.; Truhlar, D. G. Minimally augmented Karlsruhe basis sets. Theor Chem Acc 2011, 128 (3), 295–305.
28. Papajak, E.; Zheng, J.; Xu, X.; Leverentz, H. R.; Truhlar, D. G. Perspectives on Basis Sets Beautiful: Seasonal Plantings of
Diffuse Basis Functions. J Chem Theory Comput 2011, 7 (10), 3027-3034.
29. Alecu, I. M.; Zheng, J.; Zhao, Y.; Truhlar, D. G. Computational Thermochemistry: Scale Factor Databases and Scale Factors
for Vibrational Frequencies Obtained from Electronic Model Chemistries. J Chem Theory Comput 2010, 6, 2872-2887.
30. Sakurai, N.; Mukaiyama, T. A New Preparative Method Of Aryl Sulfonate Esters By Using Cyclic Organobismuth Reagents.
Heterocycles 2007, 74, 771-790.
31. Naoto, S.; Teruaki, M. New Preparative Method of Aryl Tosylates by Using Organobismuth Reagents. Chemistry Letters
2007, 36 (7), 928-929.
32. Miller, S. C. Profiling Sulfonate Ester Stability: Identification of Complementary Protecting Groups for Sulfonates. J Org
Chem 2010, 75, 4632–4635.
33. Huang, H.; Wu, Y.; Zhang, W.; Feng, C.; Wang, B. Q.; Cai, W. F.; Hu, P.; Zhao, K. Q.; Xiang, S. K. Copper-Catalyzed
Regioselective C-H Sulfonyloxylation of Electron-Rich Arenes with p-Toluenesulfonic Acid and Sulfonyloxylation of
Aryl(mesityl)iodonium Sulfonates. J Org Chem 2017, 82, 3094−3101.
34. Jones, C. S.; Bull, S. D.; Williams, J. M. J. DBN hexafluorophosphate salts as convenient sulfonylating and phosphonylating
agents. Org Biomol Chem 2016, 14, 8452–8456.
35. Nayak, S. K. A Facile Route to the Deprotection of Sulfonate Esters and Sulfonamides with Low Valent Titanium Reagents.
Synthesis 2000, No. 11, 1575–1578.
36. Lei, X.; Jalla, A.; Shama, M. A. A.; Stafford, J. M.; Cao, B. Chromatography-Free and Eco-Friendly Synthesis of Aryl
Tosylates and Mesylates. Synthesis 2015, 47, 2578–2585.
37. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; etal. Gaussian 09, Gaussian, Inc., Wallingford CT.
38. Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal Solvation Model Based on Solute Electron Density and on a
Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions. J Phys Chem B

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2009, 113 (18), 6378–6396.

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Nucleophilic substitutions of tosyloxy group on maleimide can occur easily
Transesterification is a significant side-reaction when phenols are used
This substitution reaction is favorable both kinetically and thermodynamically
Electron-withdrawing groups on phenols are harmful to the substitution reaction