Ring opening of N-hydroxyphthalimide to construct phenylurea derivatives

Article abstract of DOI:10.1080/00397911.2021.1919709

Arylurea and their analogues have been one of the most ubiquitous backbone during the past century, and extensive studies have been conducted to establish practical synthetic methods for their derivatives. In particular, it is an effective pathway to synthesize arylureas by using commercially available phthalimide compounds. Reported herein is a triethoxyphosphine promoted ring-opening of the N-hydroxyphthalimide (NHPI) by the nucleophilic attack of amines. This transformation shows a wide range of functional-group tolerance under mild reaction conditions.

Full text of DOI:10.1080/00397911.2021.1919709

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Ring opening of N-hydroxyphthalimide to
construct phenylurea derivatives
Yinhui Wu, Bin Lv, Yanan Zhang, Pan Gao, Min Zhang & Yu Yuan
To cite this article: Yinhui Wu, Bin Lv, Yanan Zhang, Pan Gao, Min Zhang & Yu Yuan (2021) Ring
opening of N-hydroxyphthalimide to construct phenylurea derivatives, Synthetic Communications,
51:13, 2025-2033, DOI: 10.1080/00397911.2021.1919709
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SYNTHETIC COMMUNICATIONSV
2021, VOL. 51, NO. 13, 2025–2033
https://doi.org/10.1080/00397911.2021.1919709
Ring opening of N-hydroxyphthalimide to construct
phenylurea derivatives
Yinhui Wua, Bin Lva, Yanan Zhanga, Pan Gaoa, Min Zhangb, and Yu Yuana
b
aSchool of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, China; Affiliated
Hospital of Yangzhou University, Yangzhou, China
ABSTRACT
ARTICLE HISTORY
Received 17 September 2020
Arylurea and their analogues have been one of the most ubiquitous
backbone during the past century, and extensive studies have been
conducted to establish practical synthetic methods for their deriva-
tives. In particular, it is an effective pathway to synthesize arylureas
by using commercially available phthalimide compounds. Reported
herein is a triethoxyphosphine promoted ring-opening of the N-
hydroxyphthalimide (NHPI) by the nucleophilic attack of amines. This
transformation shows a wide range of functional-group tolerance
under mild reaction conditions.
KEYWORDS
N-hydroxyphthalimide;
phenylurea; ring-opening
reaction; construction of
C–N bond
GRAPHICAL ABSTRACT
Introduction
Arylurea derivatives represent a vital class of organic building blocks of pharmaceutical
chemicals for some anticancer drugs,[1] and are also applied in pesticides widely.[2]
Recently, the cleavage of N-substituted phthalimides has been regarded as a straightfor-
ward way to access the arylurea derivatives.[3] Many methods have been developed for
ring-opening reaction or ring expansion reaction of N-substituted phthalimides.[4] The
presence of the metal catalysts can effectively broke the phthalimide skeleton to achieve
the ring opening or ring expansion reaction.[5] Few examples have been reported on the
cleavage of N-substituted phthalimides to construct the backbone of arylureas.
Furthermore, the synthesis of arylureas also attracted attention in the decades, metal
catalysts and hash reaction conditions were necessary for the synthesis of the arylur-
eas.[6] In 1999, Gutschow developed a method to synthesize phenylurea compounds in
acetone under reflux conditions using sulfonate as a leaving group in phthalimides
(Scheme 1a).[7] In 2010, Sheikh and his coworkers also synthesized phenylurea
CONTACT Min Zhang
494784309@qq.com
Affiliated Hospital of Yangzhou University, Yangzhou 225009, China;
Yu Yuan
yyuan@yzu.edu.cn School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou
225009, China.
Supplemental data for this article can be accessed on the publisher’s website
ß 2021 Taylor & Francis Group, LLC

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Y. WU ET AL.
Scheme 1. Strategies for synthesis of benzoyl urea compounds.
compounds under alkaline conditions at room temperature while sulfonate or ester
groups were employed as leaving groups (Scheme 1b),[8] and the careful mechanism
research shows that the formation of the product goes through a Lossen-type rearrange-
ment. Inspired by Schmidt[9] and our previous research,[10] we wondered if the reduci-
bility of phosphites could efficiently promote amines to break the nitrogen-oxygen bond
directly. Hence, in our work N-hydroxyphthalimide was chosen to react with morpho-
line in the presence of phosphites to produce arylylurea compounds.
Results and discussion
The investigation was initiated by the utilization of N-hydroxyphthalimide 1a (1.0 eq.)
and morpholine 2a (5.0 eq.) in the presence of triethyl phosphite (2.0 eq.) at 110 ꢀC in
toluene. Fortunately, the corresponding products 3aa could be obtained in 52% yield
(Table 1, entry 1). The reaction depended on the amount of triethyl phosphite, so 77%
and 89% yield of 3aa were obtained with 3.0 and 5.0 eq. of triethyl phosphite, respect-
ively (Table 1, entry 2 and 3). Meanwhile, it was found that no reaction was carried out
without triethyl phosphite (Table 1, entry 4). Then we tested the amount of morpholine,
the reduction of morpholine induced the yield to drop down (Table 1, entries 5–7).
Interestingly, the reaction efficacy was dramatically enhanced by decreasing the reaction
temperature (Table 1, entries 8–10), which provided 3aa in 98% yield at 50 ꢀC (entry
10). When the temperature is further reduced to room temperature, the reaction cannot
proceed (entry 11). Other phosphites complexes such as P(OMe)3, P(OPh)3,
HOP(OMe)2 and HOP(OEt)2 were less efficient for this reaction (Table 1, entries

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Table 1. Optimization the reaction conditionsa.
Entry
Morpholine/eq.
Add./eq.
Add.
T/ ꢀC
Yieldb/%
1
2
3
4
5
6
7
8
5.0
5.0
5.0
5.0
3.0
2.0
1.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
2.0
3.0
5.0
0.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
110
110
110
110
110
110
110
100
80
50
r.t.
50
50
52
77
89
NR
88
72
trace
90
92
98
trace
60
9
10
11
12
13
14
15
16
P(OEt)3
P(OEt)3
P(OMe)3
P(OPh)3
HOP(OMe)2
HOP(OEt)2
OP(OEt)3
77
72
81
NR
50
50
50
aReaction conditions: 1a (0.3 mmol), 2a (1.5 mmol), additive, in Toluene (2.0 mL), air, 12 h.
bIsolated yield.
12–15). Nevertheless, when the reaction was carried out using OP(OEt)3, we did not
observe any target product (Table 1, entries 16).
With the optimized reaction conditions in hand, the nucleophilic ring-opening reac-
tions of N-hydroxyphthalimide 1a with a broad range of secondary amines 2 were then
explored (Scheme 2). It was found that aliphatic secondary amines could react with
N-hydroxyphthalimide in moderate conditions to excellent yields smoothly. Methyl sub-
stituted amines connecting with different substituent groups including methyl, ethyl,
propyl, isopropyl, benzyl, and cyclohexyl were good substrates for this ring-opening
reaction. Two long chains substituted secondary amine 2h also could react with N-
hydroxyphthalimide, but the yield is a bit low due to the steric hindrance effect of the
groups. Moreover, pyrrolidine 2i and piperidine 2j can also react with N-hydroxyphtha-
limide to obtain the desired product and the yield is considerable. Additionally, we
made attempt to use primary amides to carry out the reaction. Unfortunately, we did
not get the product we wanted. The reason of it is that primary amine is not basic
enough to open the ring of NHPI.
Next, some substituted N-hydroxyphthalimides were reacted with morpholine under
the standard reaction condition (Scheme 3). It was found that two isomers were
obtained using meta substituted N-hydroxyphthalimides, and the ratio of two isomers is
about 1:1. Affected by steric hindrance, when methyl is substituent, the ratio of the two
products is 9:10 3ba; when chlorine is substituent, the ratio of the two products is 10:16

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Y. WU ET AL.
Scheme 2. Reaction substrate scope of secondary amine. Reaction conditions: 1a (0.3 mmol), 2
(1.5 mmol), P(OEt)3 (1.5 mmol), in Toluene (2.0 mL), air, 50 ꢀC, 12 h.
3ca; but when bromine is substituent, the ratio of the two products is 8:10 3da, it is
affected not only by the steric effect but also by the electronic effect. However, while
ortho substituted N-hydroxyphthalimides was used as substrates, unique product was
formed in the system usually. When chlorine and bromine are substituents, only one
product is generated 3ea, 3fa. When methyl is used as a substituent, almost only one
product is generated 3ga. According to the experiments above, we believe that the
regioselectivity is mainly affected by steric hindrance.

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Scheme 3. Scope of phthalimides.a Reaction conditions: 1 (0.3 mmol), 2a (1.5 mmol), P(OEt)3
(1.5 mmol), in Toluene (2.0 mL), air, 50 ꢀC, 12 h.
To propose the possible reaction mechanism, we conducted another two experiments.
One is in an oxygen atmosphere and the other is in a nitrogen atmosphere (Scheme
4a). We found that more than 81% yield could be obtained in an oxygen atmosphere,
but it did not react in a nitrogen atmosphere. Based on the above experiments and
existing literature,[11] we proposed the possible reaction mechanism (Scheme 4b). At the
beginning, The NHPI was oxygenated by air to form the hydroperoxyl radical and
nitroxylate radical (PINO), which could react with triethyl phosphite to form the inter-
mediate B. Then triethyl phosphate was removed from the intermediate B to generate
intermediate C. The intermediate C combined with hydroperoxyl radical to form the
intermediate D. Subsequently, morpholine attacked the carbonyl group in the inter-
mediate D to open the hetero ring, and the intermediate E was obtained selectively due
to the steric hindrance. Afterwards, triethyl phosphite attacked the intermediate E and
another triethyl phosphate was removed from intermediate F to generate the intermedi-
ate G. The intermediate H was produced by Hoffmann rearrangement reaction.[12]
Consequently, the other morpholine attacked the intermediate H to form the prod-
uct 3aa.
In conclusion, we developed a ring-opening reaction of N-hydroxyphthalimide with
aliphatic secondary amines in the presence of phosphite ester in high yields under mild

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Y. WU ET AL.
Scheme 4. Proposed mechanism.
reaction conditions. The reaction underwent a rearrangement reaction. It is a simple
method to achieve the construction of C-N bond and carbamide backbone with easily
available raw materials.

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Experimental section
In a typical process, N-hydroxyphthalimide (0.3 mmol), morpholine (1.5 mmol), and tri-
ethyl phosphite (1.5 mmol) were stirred in freshly distilled toluene. The mixture was
stirred at 50 ꢀC under air for 12–15 h. Upon the completion of the reaction, the solvent
was removed. The crude mixture was directly subjected to column chromatography on
silica gel using petrol ether/ethyl acetate as eluent to give the desired products.
Physical and spectral data of 3aa
1
NMR: H NMR (400 MHz, CDCl3) d 8.81 (s, 1H), 8.14 (d, J ¼ 8.4 Hz, 1H), 7.41 ꢁ 7.36
(m, 1H), 7.18 ꢁ 7.16 (m, 1H), 7.02 ꢁ 6.98 (m, 1H), 3.74 ꢁ 3.64 (m, 12H), 3.48 ꢁ 3.46 (m,
4H). 13C NMR (100 MHz, CDCl3) d 170.05, 154.57, 139.05, 131.22, 127.55, 122.13,
121.52, 121.46, 77.32, 77.20, 77.00, 76.68, 66.80, 66.43, 43.89. HRMS m/z (ESI): calcd for
C16H21N3NaO4 (M þ Na)þ 342.1424, found 342.1462.
1
Full experimental details including all information, H and 13C NMR spectra, HRMS
data have been provided in Supporting information as a separate file.
Funding
The present research was financially supported by Natural Science Foundation of Jiangsu
Province [BK20161328].
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