Bifunctional phase-transfer catalysts for synthesis of 2-oxazolidinones from isocyanates and epoxides

Article abstract of DOI:10.1039/d0ra00693a

A series of bifunctional phase-transfer catalysts (PTCs) were synthesized to catalyze the [3 + 2] coupling reaction of isocyanates and epoxides to afford 2-oxazolidinones in good to high yields (up to 92% yield) using PhCl as a solvent at 100 °C within 12 h. These bifunctional PTCs were easily prepared from commercially available tertiary-primary diamines and isocyanates (or isothiocyanates, mono-squaramides, respectively) in two simple steps with good modularity and demonstrated high efficiency (2.5 mol% catalyst-loading). The synergistic interaction of the quaternary ammonium salt center and hydrogen-bond donor group in the catalyst with the substrate is crucial to this atom-economic reaction.

Full text of DOI:10.1039/d0ra00693a

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Bifunctional phase-transfer catalysts for synthesis
of 2-oxazolidinones from isocyanates and
epoxides†
Cite this: RSC Adv., 2020, 10, 12360
a
a
a
b
Dong-Xiao Cui,‡ab Yue-Dan Li,‡ Ping Huang, Zhuang Tian, Yan-Yan Jia
*
a
*
and Ping-An Wang
A series of bifunctional phase-transfer catalysts (PTCs) were synthesized to catalyze the [3 + 2] coupling
reaction of isocyanates and epoxides to afford 2-oxazolidinones in good to high yields (up to 92% yield)
using PhCl as a solvent at 100 ꢀC within 12 h. These bifunctional PTCs were easily prepared from
commercially available tertiary-primary diamines and isocyanates (or isothiocyanates, mono-
squaramides, respectively) in two simple steps with good modularity and demonstrated high efficiency
(2.5 mol% catalyst-loading). The synergistic interaction of the quaternary ammonium salt center and
hydrogen-bond donor group in the catalyst with the substrate is crucial to this atom-economic reaction.
Received 22nd January 2020
Accepted 19th March 2020
DOI: 10.1039/d0ra00693a
rsc.li/rsc-advances
1 Introduction
2-Oxazolidinones and derivatives are important nitrogen and
oxygen containing heterocycles present in many chemicals with
different biological and pharmacologic activities,1–3 such as
Linezolid and Tedizolid as antibiotics (Fig. 1) to treat infections
caused by Gram-positive bacteria that are resistant to other
antibiotics.4,5 Much attention has been paid by synthetic
organic chemists to nd facile methods to 2-oxazolidinones.
There are many synthetic routes to 2-oxazolidinones, and these
methods can be divided into two types including phosgene-
involved and non-phosgene involved routes. The synthesis of
2-oxazolidinones from phosgene and vicinal amino-alcohols is
not recommended, even if the yield is excellent, but its toxicity is
extremely high.6,7 Non-phosgene involved routes to 2-oxazoli-
dinones are investigated extensively in recent years.8–10 Among
them, the ring-opening of aziridines by CO2 and “one-pot”
reaction of primary amines with epoxides and CO2 are
straightforward accesses to 2-oxazolidinones.11–15 The [3 + 2]
coupling of isocyanates with epoxides is also an atom-economic
process to provide 2-oxazolidinones, and the pioneering work
on this coupling was established by Speranza and Peppel in
1958 through phase-transfer catalysis with a high temperature
Fig. 1 Pharmaceutics containing 2-oxazolidinone motif.
found to catalyze this [3 + 2] coupling reaction,17–23 but still with
unsatisfactory results because of harsh conditions (e.g., high
catalyst-loadings, high temperature, large amount of epoxides,
or with a dropwise addition of isocyanates). In 2017, Toda and
colleagues24 have discovered an elegant route to 2-oxazolidi-
nones with high yields by using tetraarylphosphonium salts
(TAPS) as an organocatalyst. However, organocatalyzed [3 + 2]
coupling of isocyanates and epoxides to 2-oxazolidinones is still
a challenge. Herein, we presented a group of bifunctional
phase-transfer catalysts (Bif-PTCs) for synthesis of 2-oxazolidi-
nones in good yields and high efficiency (Fig. 2).
up to 200 C.16 Aer that, several metallic catalysts have been
ꢀ
2 Results and discussion
2.1. The preparation of bifunctional phase-transfer catalysts
(Bif-PTCs)
aDepartment of Medicinal Chemistry, School of Pharmacy, The Fourth Military
Medical University, Changle West Road 169, Xi'an, 710032, P. R. China. E-mail:
ping_an1718@outlook.com
The synthesis and applications of bifunctional phase-transfer
catalysts are very attractive to academies and industries for
their high efficiency and environmental sustainability.25–29
These Bif-PTCs usually contain both one quaternary onium salt
center and at least one hydrogen-bonding donor group in their
bDepartment of Pharmacy, Xijing Hospital, Fourth Military Medical University,
Changle West Road 15, Xi'an 710032, P. R. China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra00693a
‡ Co-rst authors. These two authors have the same contribution to this work.
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the synthetic process of thiourea-containing Bif-PTCs (Bif-PTC-8
and 9), Boc-protection and deprotection were used to avoid S-
alkylation in quaternization by benzyl bromide.32 Squaramide-
containing Bif-PTC-10 can be easily prepared from coupling of
mono-ester of squaramide with 2-(pyrrolidin-1-yl)ethan-1-
amine and then quaternization by benzyl bromide. The struc-
tures of these Bif-PTCs are listed in Fig. 3, and all Bif-PTCs are
characterized by their NMR and HRMS.31
2.2. The [3 + 2] coupling of isocyanates and epoxides by Bif-
PTCs
Inspired by Toda and colleagues' work, a free O–H of TAPS plays
a role as hydrogen-bonding donor in activation of epoxides,
these above prepared Bif-PTCs also contain free N–H in their
structures, we deduced that these Bif-PTCs could be used as
organocatalysts for synthesis of 2-oxazolidinones from the
coupling of epoxides and isocyanates.
At rst, we chose the coupling of phenyl glycidyl ether 1a and
p-chlorobenzene isocyante 2a as a model reaction for optimi-
zation of reaction conditions, and the results are shown in
Table 1. It was found that without catalyst leads to no reaction
(entry 1 vs. 3). When TBAB was used as catalyst, 2-oxazolidinone
3aa was obtained in very low yield with the recovery of the
substrate epoxide 1a (entry 2). Bif-PTCs with electron-donating
groups at phenyl ring (such as para-Me or 3,5-diMe, Bif-PTC-3,
4, 6 and 7) have shown low catalytic activities to this [3 + 2]
cycloaddition and produced 3aa in low yields (entries 5, 6, 8 and
9, 38–45%). The catalysts with a urea group demonstrate better
performance than catalysts with a thiourea or squaramide
group in this [3 + 2] coupling reaction (entry 3 vs. entries 10–12).
Bif-PTC-1 is the best catalyst to provide 2-oxazolidinone 3aa in
85% yield under standard reaction conditions. Instead of PhCl
as solvent, when the coupling of 1a and 2a were carried out in
toluene, NMP or 1,4-dioxane, the yield of 3aa is decreased
signicantly (entry 3 vs. entries 13–15).
Fig. 2 Phase-transfer catalysts for synthesis of 2-oxazolidinones.
structures. The hydrogen-bonding donor groups include
hydroxyl (–OH), (thio)urea and squaramide. Recently, we have
reported catalytic asymmetric amination of b-nitrostyrenes by
chiral Bif-PTCs in high yields and enantioselectivties.30 We have
also developed a group of Bif-PTCs for catalyzed cycloaddition
of CO2 with epoxides to produce cyclic carbonates in good to
excellent yields.31 For our continuous effort on the synthesis and
applications of Bif-PTCs, we have prepared a series of quater-
nary ammonium salts with one hydrogen-bonding donor for
catalyzed [3 + 2] coupling of isocyanates and epoxides to 2-
oxazolidinones. From commercially available tertiary-primary
diamines, Bif-PTC-1–10 were prepared in moderate to good
yields through 2–4 steps. These catalysts featured by simple
preparation, high modularity and good stability. There are only
two simple steps including coupling reaction of tertiary-primary
diamines with isocyanates and following quaternization to
afford urea-containing Bif-PTCs (Bif-PTC-1–7) in good yield. In
Increase of catalyst-loading from 2.5 mol% to 5 mol% and
10 mol%, the yield of 3aa is promoted slightly (entry 3 vs. entries
16 and 17). When the reaction temperature was set at 60 ꢀC and
room temperature (r.t.), the yield of 3aa was dropped to 45%
Fig. 3 The chemical structures of Bif-PTC-1–10.
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Table 1 The screening of coupling reaction conditions for 2-oxazolidinone
Entrya
Bif-PTCs
Solvent
Temp.
Time
Yieldc (%)
1
2
3
4
5
6
7
8
None
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
Toluene
NMPd
1,4-Dioxane
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
100 ꢀ
100 ꢀ
100 ꢀ
100 ꢀ
100 ꢀ
C
C
C
C
C
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
8 h
0
TBABb (2.5 mol%)
12
85
84
45
40
80
46
38
24
26
36
70
Trace
32
87
92
22
45
0
Bif-PTC-1 (2.5 mol%)
Bif-PTC-2 (2.5 mol%)
Bif-PTC-3 (2.5 mol%)
Bif-PTC-4 (2.5 mol%)
Bif-PTC-5 (2.5 mol%)
Bif-PTC-6 (2.5 mol%)
Bif-PTC-7 (2.5 mol%)
Bif-PTC-8 (2.5 mol%)
Bif-PTC-9 (2.5 mol%)
Bif-PTC-10 (2.5 mol%)
Bif-PTC-1 (2.5 mol%)
Bif-PTC-1 (2.5 mol%)
Bif-PTC-1 (2.5 mol%)
Bif-PTC-1 (5 mol%)
Bif-PTC-1 (10 mol%)
Bif-PTC-1 (2.5 mol%)
Bif-PTC-1 (2.5 mol%)
Bif-OC-1e (2.5 mol%)
Bif-OC-1/TBAB (2.5 mol%)
Bif-OC-1/TBAF (2.5 mol%)
Bif-OC-1/TBAI (2.5 mol%)
Bif-PTC-1 (2.5 mol%)
Bif-PTC-1 (2.5 mol%)
100 ꢀC
100 ꢀ
100 ꢀ
100 ꢀ
C
C
C
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
100 ꢀC
100 ꢀ
100 ꢀ
100 ꢀ
100 ꢀ
100 ꢀ
100 ꢀ
C
C
C
C
C
C
100 ꢀC
r.t.
60 ꢀ
C
100 ꢀ
100 ꢀC
100 ꢀ
100 ꢀC
100 ꢀ
100 ꢀC
C
75
0
72
56
33
C
C
4 h
a
0.2 mmol of 1a and 0.21 mmol of 2a in 2 mL PhCl were stirred under inert atmosphere. b TBAB ¼ (n-Bu)4N+Brꢁ. c Isolated yield based on 1a. d NMP
e
¼ 1-methylpyrrolidin-2-one. Bif-OC-1 is the precursor (without quaternization) of Bif-PTC-1.
and 22%, respectively (entry 3 vs. entries 18 and 19). By using moderate to good yields. The scope of substrates was shown in
Bif-OC-1 (the precursor of Bif-PTC-1, without quaternization) as Fig. 4. It was found that arylisocyanates contain one electron-
a catalyst, the corresponding 2-oxazolidin-one 3aa was not ob- donating group (p-Me) can afford corresponding 2-oxazolidi-
tained through the coupling process (entry 20). However, when nones in high to excellent yields (examples 3ab, 3bb, 3cb, 3db
the catalytic amount of Bif-OC-1 and TBAB were used, 3aa was and 3eb vs. the others). The glycidol-derivated epoxides provide
obtained in 75% yield (entry 21). Switching TBAB to TBAF, no 2-oxazolidinones in better yields than styrene oxides (3fc vs.
3aa is found by TLC checking (entry 22), and replacing TBAB 3ga), it may due to the electron-withdrawing effect of aryl rings.
with TBAI, the yield of 3aa is 72% (entry 23). This may due to the
A plausible mechanism for Bif-PTCs catalyzed [3 + 2]
better nucleophilicity and leaving property of Brꢁ than Fꢁ. The coupling of isocyanate and epoxide is proposed in Fig. 5. At the
dual role of Brꢁ in the catalytic cycle is a good nucleophile for beginning, the epoxide 1 is activated by Bif-PTC-1 through
ring-opening of epoxide and also a good leaving group during hydrogen-bonding interaction between two N–H and O atom to
the cyclization. The combined use of TBAB and urea with form intermediate A, which undergoes nucleophilic attack from
electron-withdrawing group (such as CF3) is alternative to the Brꢁ to give intermediate B, intermediate B attacks isocyanate 2
coupling of epoxides and isocyanates to form 2-oxazolidinones. to yield intermediate C, the intramolecular ring-closing of
The decrease of reaction time resulted in the decrease of yields intermediate C provides 2-oxazolidinone 3 with a release of Bif-
of 3aa (entries 24 and 25). Based on these above screening, the PTC-1 to take apart in the next catalytic cycle. It was found that
optimal conditions are listed as follows: 2.5 mol% of Bif-PTC-1 isocyanates and epoxides are less soluble in PhCl, so the PTCs
as catalyst, PhCl as solvent, the reaction mixture was stirred at may play a role as a substrate-to-solvent transfer agent. In
100 ꢀC for 12 h. With the optimal reaction conditions in hand, addition, Brꢁ in PTCs as a nucleophile attacks epoxide to make
various isocyanates (1b–f) and epoxides (2b–f) were used as ring-opening process in this catalytic cycle. In order to show the
substrates to produce a number of 2-oxazolidinones (3aa–fc) in application of this above [3
+ 2] coupling reaction,
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Fig. 4 The Bif-PTC-1 catalyzed synthesis of 2-oxazolidinones.
Scheme 1 The preparation of a intermediate for Linezolid.
3 Experimental
3.1. General
1H NMR and 13C NMR spectra were measured in CDCl3, solu-
tion on a Bruker AV-400 spectrometer using TMS as an internal
reference. Coupling constant (J) values are given in Hz. Multi-
plicities are designated by the following abbreviations: s,
singlet; d, doublet; t, triplet; q, quartet; br, broad; m, multiplet.
High-resolution mass spectra (HRMS) were performed on
a Bruker microTOF-Q II Mass Spectrometer with ES ionization
(ESI). All commercially available reagents were used as received.
Thin-layer chromatography on silica (with GF254) was used to
monitor all reactions. Products were puried by ash column
Fig. 5 The plausible catalytic cycle for Bif-PTCs catalyzed [3 + 2]
coupling reaction.
a intermediate 6 of a potent antibiotic Linezolid was directly
prepared in 53% yield by the coupling of epoxide 4 and isocy-
anate 5 under standard reaction conditions (Scheme 1).
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chromatography on silica gel purchased from Qingdao Haiyang
Chemical Co., Ltd. The preparation and characterization data of
all bifunctional phase-transfer catalysts (Bif-PTCs) were found
in our previous report.31
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isoxazolidinones 3
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0.20 mmol of epoxide 1, 2.7 mg of Bif-PTC-1 (2.5 mol%), and
0.21 mmol of isocyanate 2 in 2.0 mL PhCl was stirred for 12 h at
100 ꢀC under inert atmosphere. The solvent was evaporated
under reduced pressure and the residue was puried by a ash
column chromatography (petroleum ether: ethyl acetate ¼ 2 : 1
to 1 : 3) to yield corresponding 2-oxazolidinones 3. The char-
acterization data of products were found in ESI.†
4 Conclusions
In conclusion, 2-oxazolidinones have been prepared through
[3 + 2] coupling reactions of isocyanates and epoxides in the
presence of 2.5 mol% bifunctional phase-transfer catalysts
(Bif-PTCs) in good to excellent yields. These hydrogen-bonding
donor containing Bif-PTCs can be easily prepared from
commercially available tertiary-primary diamines and iso(thio)
cyanates or mono-squaramide. Furthermore, an intermediate of
Linezolid was also obtained in 53% yield by this simple
manipulation. The synthesis of 2-oxazolidinone-containing
bioactive molecules by using this strategy are underway in our
laboratory.
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Conflicts of interest
There are no conicts to declare.
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Acknowledgements
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We thank the National Natural Science Foundation of China
(21372259 and 81503028) for nancial support.
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