Squaramide–Quaternary Ammonium Salt as an Effective Binary Organocatalytic System for Oxazolidinone Synthesis from Isocyanates and Epoxides

Article abstract of DOI:10.1002/ejoc.202000153

Squaramide–quaternary ammonium salt is illustrated as a simple, tunable, and competent metal-free binary catalytic platform for the atom-economic conversion of epoxides and isocyanates into oxazolidinones. Although, various metal catalysts have been employed for the title reaction, application of organocatalysis is scarce. At first, a rational survey of catalytic activity of several air-stable and architecturally distinct squaramides was undertaken. Thereafter, the impact on catalytic capability of different parameters, such as temperature, catalyst loading, and nature of nucleophiles, was examined. This binary organocatalytic system for the oxazolidinone synthesis, composed of a squaramide entity along with a suitable halide anion, was applied to the challenging conversion of a plethora of alkyl- and aryl-substituted epoxides– including disubstituted and enantioenriched ones– and isocyanates into the corresponding oxazolidinones in high-to-excellent yields. The time-dependent formation of oxazolidinone from epoxide and isocyanate was monitored by FTIR-ATR and ¹H NMR spectroscopy and the scalability of this process was also described. In light of ¹H NMR experiment, a hydrogen-bonding/anion-binding mechanism was proposed wherein the nucleophilic ring-opening operation, and oxo- and carbamate-anions stabilization occur cooperatively towards isocyanate fixation.

Full text of DOI:10.1002/ejoc.202000153

A Journal of
Accepted Article
Title: Squaramide/Quaternary Ammonium Salt as an Effective Binary
Organocatalytic System for Oxazolidinone Synthesis from
Isocyanates and Epoxides
Authors: Ali Rostami, Amirhossein Ebrahimi, John Husband,
Muhammad Usman Anwar, Rene Csuk, and Ahmed Al-
Harrasi
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000153
Link to VoR: http://dx.doi.org/10.1002/ejoc.202000153
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.202000153
Squaramide/Quaternary Ammonium Salt as an Effective Binary
Organocatalytic System for Oxazolidinone Synthesis from
Isocyanates and Epoxides
∗
[a]
[a]
[b]
Ali Rostami,
Amirhossein Ebrahimi, John Husband, Muhammad Usman
[a]
[c]
[a]
Anwar, Rene Csuk, Ahmed Al-Harrasi
[
a] Dr. A. Rostami, A. Ebrahimi, Dr. M. U. Anwar, Prof. Dr. A. Al-Harrasi
Natural and Medical Sciences Research Center (NMSRC), University of Nizwa, 616, Nizwa,
Sultanate of Oman
Email:
arostami@unizwa.edu.om, aharrasi@unizwa.edu.om
http://www.unizwa.edu.om/COMPMNP/
Tweeter: @NMSRC_UNizwa
[
b] Dr. J. Husband
Department of Chemistry, College of Science, Sultan Qaboos University, PO Box 36, Al-Khod
1
23, Muscat, Sultanate of Oman
[
c] Prof. Dr. R. Csuk
Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-str. 2, D-06120
Halle (Saale) Germany
This work is dedicated to Professor Hans‐Ulrich Reißig on the occasion of his 70th birthday.
1
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European Journal of Organic Chemistry
10.1002/ejoc.202000153
Abstract
Squaramide/ quaternary ammonium salt is illustrated as a simple, tunable, and competent metal-
free binary catalytic platform for the atom-economic conversion of epoxides and isocyanates into
oxazolidinones. Although, various metal catalysts have been employed for the title reaction,
application of organocatalysis is scarce. At first, a rational survey of catalytic activity of a
number of air-stable and architecturally distinct squaramides was undertaken. Thereafter, the
impact on catalytic capability of different parameters, such as temperature, catalyst loading, and
nature of nucleophiles, was examined. This binary organocatalytic system for the oxazolidinone
synthesis, composed of a squaramide entity along with a suitable halide anion, was applied to the
challenging conversion of a plethora of alkyl- and aryl-substituted epoxides− including
disubstituted and enantioenriched ones− and isocyanates into the corresponding oxazolidinones
in high-to-excellent yields. The time-dependent formation of oxazolidinone from epoxide and
1
isocyanate was monitored by FTIR-ATR and H NMR spectroscopy and the scalability of this
1
process was also described. In light of H NMR experiment, a hydrogen-bonding/anion-binding
mechanism was proposed wherein the nucleophilic ring-opening operation, and oxo- and
carbamate-anions stabilization occur cooperatively towards isocyanate fixation.
KEYWORDS: oxazolidinone, organocatalysis, hydrogen-bond donor, squaramide
2
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European Journal of Organic Chemistry
10.1002/ejoc.202000153
Introduction
Oxazolidinones constitute a valuable class of nitrogen- and oxygen-containing five-membered
heterocycles with broad applications.[1] They find applications in numerous contexts: they have
often been used as chiral auxiliaries[1a, 2] in asymmetric synthesis, as synthetic intermediates and
[3]
as building blocks in polymers,[4] and as emerging
precursors of β-aminoalcohols,
pharmacophores in medicinal chemistry.[5] N-Aryl oxazolidinones have attracted particular
interest recently as precursors to antibacterial medicines that are potent against vancomycin-
resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA).[6] They
have also exhibited medicinal action as remedies for depression and psychosis.[7] Therefore,
exploiting atom-efficient strategies towards diversity-oriented-synthesis of libraries based on the
oxazolidinone scaffold has been on the forefront of research.
In essence, the oxazolidinone core could be attained by a variety of different protocols including
[8]
cyclization reaction of α-amino acids or 1,2-amino alcohols with carbonyl derivative,
cyclocarbamations,[9] Au- and Ag-catalyzed cyclization of N-Boc-propargylic amines and
propargylic alcohols,[10] and [3 + 2] coupling between heterocumulenes and epoxides or
aziridines.[11] Among these strategies, the [3 + 2] coupling reaction of isocyanates and epoxides is
a straightforward and 100 % atom-economical method that provides a modular approach with the
ability to change substrate. Since the prominent report by Speranza and Peppel in 1958 using
onium salts,[12] a range of catalytic platforms have been reported to catalyze this process
including lanthanide salts,[13] lithium halides,[14] magnesium halides,[15] tetraphenylantimony
iodide,[16] and trialkyltin halides.[17] In addition, a great deal of effort has recently been devoted
into Lewis acidic metal complexes,[18] including those based on aluminum and chromium, all of
3
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European Journal of Organic Chemistry
10.1002/ejoc.202000153
which exhibited promising catalytic activities, yet the substrate scope was mainly limited to aryl
isocyanates.
These catalytic systems (see above) require reaction conditions involving toxic metals, laborious
catalyst synthesis, toxic solvents, high temperatures, and high catalyst loadings that eventually
limit their catalytic utilities. In addition, slow addition of isocyanates or excessive amount of
epoxides was essential to defeat the isocyanates trimerization side reaction, whereas substrate
scopes were mainly limited to terminal epoxides and aryl isocyanates. In this regard, evaluating
alternative catalytic platforms with a broad substrate scope, that fulfill growingly rigid
environmental requirements is greatly appealing.
Hydrogen-bond donor (HBD) catalytic systems− binary or bifunctional− have appeared as
exceptional organocatalytic platforms for the activation of small organic molecules through non-
covalent interactions.[19] The necessary lack of metal leftovers, and successful catalyst
elimination from the final product favor the use of such green processes over metal-catalyzed
ones. These systems represent the current state-of-the-art organocatalytic platforms for carbon
dioxide fixations,[20] yet its application in controlling cycloaddition reactions of other
heterocumulenes such as isocyanates with epoxides that requires relatively harsh reaction
conditions is still in its infancy.[21a] A pioneering work was accomplished by Toda and co-
workers in which a bifunctional tetraarylphosphonium salt catalyzes the title reaction (Scheme
1
a).[21b] An alternative process is a binary catalytic system −composed of a HBD molecule and
quaternary ammonium salt as co-catalyst− that have recently become highly favored in catalyzing
reactions of carbon dioxide. [22] They establish (a network of) hydrogen-bonds ideally tailored for
the catalytic opening of epoxides in addition to stabilization of the essential transition states via
4
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European Journal of Organic Chemistry
10.1002/ejoc.202000153
distinct hydrogen-bonding interactions. Employing such binary catalytic platforms to stabilize the
adduct of epoxide and isocyanates, while effectively guiding it towards carbon-nitrogen bond
formation is unprecedented (Scheme 1b).
Squaramide-an excellent anion-binding receptor,[23] has gained substantial consideration in
bioconjugation,[24] medicinal chemistry,[25] as an anion transporter in trans-membrane ion
channels,[23c] and lately, as a HBD in asymmetric catalysis.[19d, 26] Rivaling its analogue, thiourea,
this ditopic receptor−capable of both anion and cation binding −enjoys a modular synthesis and a
special skeleton, which is due to its rigidity, duality, double hydrogen-bond donation, extended
canted hydrogen-bond angle and acidity, provides faster reaction rates and higher
stereocontrol.[27]
After the pioneering work of Rawal’s group in 2008,[26] and with the remarkable highlight of
Kleij’s current account on squaramide-catalyzed CO
fixation,[20k] squaramide catalysis has not
2
been employed in controlling reactions of other heterocumulenes such as isocyanates.
Notably, it has been previously shown that the tetraalkylammonium halides are capable of
hydrogen-bond to the squaramide carbonyl moiety, thereby restricting the conformational
mobility of the receptor while providing more translational freedom for the halide anion.[28] Also,
in comparison to halides, oxo-anions normally have a stronger interaction and a better
stabilization with this entity, which provides a new opportunity to pre-organize both nucleophile
and substrates towards isocyanate fixation. The distinct features of this molecule (e.g. hydrogen-
bond donor-accepting abilities) motivated us to explore interactions between the squaramide,
tetraalkylammonium halide, isocyanate and epoxide (Scheme 1b).
5
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European Journal of Organic Chemistry
10.1002/ejoc.202000153
Scheme 1. Organocatalyzed [3 + 2] coupling reaction of isocyanates and epoxides
a) Prior work:
H
Cat:
O
O
PPh3
H
Y
O
R1
O
X
I
O
O
N
R2
C
R1
Me
N
R1
Toda & Suga, 2017
R2
a bifunctional catalytic system
b) This work:
Cat:
O
O
O
H
H
Y
O
R
R1
X
O
O
N
R
O
N
N
R2
H
C
H
R1
N
R1
I
Bu
4N
R2
a binary catalytic system
Continuing our curiosity in expanding new organocatalytic platforms for ring-opening
processes,[29] we sought to investigate whether squaramide −a superb anion-binding receptor with
a great double hydrogen-bond donor ability− could simultaneously participate in multiple modes
of activation and stabilization, overcoming barriers to reactivity and unsuitable equilibria. These
could be achieved via the squaramide entity by: (i) interacting reversibly with the halide anion via
bifurcated hydrogen bonds, modulating the reactivity of the anion by attenuating the electrostatic
interaction. (ii) stabilizing the oxirane-isocyanate adduct as a prelude to its use as a nitrogen
nucleophile in a subsequent carbon-nitrogen bond-forming step.
6
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European Journal of Organic Chemistry
10.1002/ejoc.202000153
In this contribution, we report, squaramide 1d and tetrabutylammonium iodide, as a simple,
metal-free, and binary catalytic system, which can mediate the [3 + 2] cycloaddition reaction of a
variety of epoxides and isocyanates under neat conditions.
Results and Discussion
Squaramides 1a-i (Figure 1) were readily prepared by condensation of a variety of aromatic and
aliphatic amines, with squarate esters in a modular and straightforward fashion, providing access
to an array of air-stable and structurally distinct catalysts.[23e, f] These catalysts vary in the type of
the substituents, the number of squaramides, and/or the level of hydrogen-bond donor ability and
acidity, thus providing the possibility to assess structure-activity relationships in these systems.
Figure 1. Squaramide catalysts (1a−i) employed for oxazolidinone synthesis
O
O
F3C
O
O
CF3
O
O
N
H
N
H
N
H
N
H
N
H
N
H
F3C
CF3
1
a
d
1b
1e
1c
CF3
F3C
O
O
F3C
O
O
S
NO2
N
H
N
H
N
H
N
H
F3C
NH
N
H
N
H
F3C
F3C
1
f
1
O
O
O
O
N
O
O
HN
O
F3C
CF3
CF3
O
H
CF3
N
N
H
nN
H
n = 3
n = 6
HN
O
NH
HN
F
3C
NH
1
1
g
h
HN
1i
F3C
O
CF
3
CF3
CF3
F3C
7
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European Journal of Organic Chemistry
10.1002/ejoc.202000153
To evaluate the catalytic performance of these hydrogen-bond donors, we started to explore
00% atom-economic conversion of styrene oxide 2a and phenyl isocyanate 3a, as standard
substrates, into oxazolidinone 4/5a, in a process free from any generation of side products (Table
).
1
1
Table 1. Optimization of reaction conditionsa
1
O
O
O
−
+
O
Bu N X
C
4
Ph
Ph
O
N
O
N
+
+
neat
N
Ph
t (h), T (°C)
Ph
3a
Ph
Ph
2
a
4a
5a
+
N X–
Conv.b 4a:5ab
entry
1
Bu
4
t
T
(
mol %) (mol %) (h) (°C)
(%)
effect of catalyst
1
2
3
4
5
6
7
8
9
1a (5)
1a (5)
1a (5)
1a (5)
none
I (5)
Br (5)
Cl (5)
I (0)
I (5)
I (5)
I (5)
I (5)
I (5)
I (5)
I (5)
I (5)
I (5)
I (5)
12
12
12
12
12
12
12
12
12
12
12
12
12
12
50
50
50
50
50
70
50
50
50
50
50
50
50
50
45
32
8
81:19
77:23
65:35
0
0
12
20
39
41
55
14
8
19
26
15
85:15
76:24
68:32
72:28
78:12
72:28
77:23
70:30
72:28
72:28
none
1b (5)
1c (5)
1d (5)
1e (5)
1f (5)
1g (5)
1h (5)
1i (5)
1
0
1
2
3
4
1
1
1
1
effect of time and temperature
1
1
1
1
1
5
6
7
8
9
1d (5)
1d (5)
1d (5)
1d (5)
1d (5)
5
5
5
5
5
20
20
20
20
24
40
50
60
70
70
62
78
88
95
80:20
75:25
78:22
76:24
>99% 76:24
effect of catalyst loading
2
2
0
1
1d (3)
1d (6)
6
3
20
20
50
50
50
22
78:22
78:22
8
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European Journal of Organic Chemistry
10.1002/ejoc.202000153
2
2
2
2
3
4
1d (3)
1d (4)
1d (6)
3
4
6
20
20
20
50
50
50
57
69
81
72:28
72:28
72:28
a
Conditions: styrene oxide 2a (0.5 mmol), phenyl isocyanates 3a (0.5 mmol),
reaction carried out as neat. Conversion of styrene oxide 2a into 4/5a and the
ratio of 4a:5a was evaluated by H NMR spectroscopy (CDCl ) of the crude
b
1
3
reaction mixture.
Screening surveys were undertaken employing equimolar amounts of styrene oxide 2a and
phenyl isocayante 3a that were subjected to different conditions as depicted in Table 1. From the
outset, we were delighted to observe that the employed hydrogen-bond donor motif was indeed
compatible with this process: with the use of 5 mol% of N,N'-diphenylsquaramide 1a and n-
tetrabutylammonium iodide (n-TBAI) as a nucleophilic co-catalyst and under neat conditions,
1
4
5% conversion (measured by H NMR spectroscopy) of styrene oxide 2a into the corresponding
oxazolidinones 4/5a was observed; while no reaction was noticed without nucleophile (Table 1,
entries 1 and 4). Presumably, ammonium halide holds an essential role in initiating the process
by ring-opening the epoxide that is followed by cycloaddition reaction with the isocyanate. The
kind of the nucleophile has a striking outcome on reaction conversions: proceeding from iodide
to bromide and chloride significantly diminished the reaction conversion to 8% and that could be
justified by stronger hydrogen-bond accepting properties of the chloride compared to bromide
and iodide (Table 1. entries 1–3).[30] Without the hydrogen-bond donor catalyst 1a, and at 50 °C
only 12% background conversion of the oxazolidinone products 4/5a was achieved, while at
7
0 °C the background conversion was increased to 20% with the 3,5-diphenyloxazolidinone 4a as
the major product in each case (Table 1, entries 5 and 6), thus confirming the primary role of the
hydrogen-bond functionality in modulating the reactivity of the iodide and subsequent
stabilization of the anionic intermediates.[20k, 31] Generally, epoxide ring-opening happens at the
9
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European Journal of Organic Chemistry
10.1002/ejoc.202000153
less hindered carbon atom (β-cleavage), yet with respect to styrene oxide 2a, this steric bias is
[32]
outweighed by the electronic advantage at the benzylic position (α-cleavage).
To determine the influence of squaramide substitution pattern and its quantity on catalytic
activity, a range of symmetrically, non-symmetrically, di- and tri-substituted molecules (1a–i)
with sterically and/or electronically tunable structures were prepared (Figure 1). The introduction
of electron-withdrawing CF and nitro groups into the squaramide structure (1b and 1e)
3
diminished the reaction conversion to 39% and 14%, respectively (Table 1, entries 7 and 10). The
low observed conversion could presumably be due to the weakened nucleophilicity of the iodide
anion as a result of a strong hydrogen-bond interaction between this entity and the iodide
anion.[20k] Moreover, substitution with cyclohexyl groups (1c) slightly increased the reaction
conversion to 41% (Table 1, entry 8). The reaction conversion was further increased to 50% by
incorporating strong electron-withdrawing (yet poor hydrogen-bond accepting) CF moieties into
3
the phenyl group while retaining the bulky cyclohexyl substituent (1d) (Table 1, entry 9).
Electron-withdrawing groups likely enhance the acidity of the hydrogen-bond donor motif and
improves its ability to hydrogen-bonding to iodide anion while the bulky cyclohexyl substituent
diminishes such hydrogen-bonding interactions. The above cases clearly reveal that the catalytic
activity is highly responsive to the squaramide substitution patterns, and depends on the synergy
between the type of the substituents, and its acidity in controlling the reactivity of the iodide in
the ring-opening step while stabilizing the reaction intermediates. In an effort to assess the
catalytic activity of this double hydrogen-bond donor entity with thiourea, a thiourea catalyst
with a similar substitution pattern 1f was made and then employed in the title reaction. A reduced
activity of the thiourea catalyst 1f in the [3 + 2] coupling reaction of styrene epoxide 2a and
1
0
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European Journal of Organic Chemistry
10.1002/ejoc.202000153
phenyl isocyanate 3a with only 8 % conversion (Table 1, entry 11) highlights the “unique”
structural motif of the squaramide.
Furthermore, increasing the number of hydrogen-bond donor groups to bis- and tris-squaramide
had an unfavorable impact on the catalytic activity and reduced the reaction conversion to 15%
(
Table 1, entries 12–14). The observed decrease in catalytic activity is believed to be the
consequence of weakened iodide nucleophilicity as the number of hydrogen-bonding interaction
between the hydrogen-bond donor moiety and the halide anion increases.[23f] These results
highlight the imperative role of this double hydrogen-bond donor group in modulating the halide
nucleophilicity through hydrogen-bonding interactions.
The impact of three solvents with different polarities (acetonitrile, dimethylformamide, and
dimethyl sulfoxide) at 50 °C was also examined; however, none of the employed solvents
induced conversion enhancement, probably owning to their hydrogen-bond accepting character
and possible catalyst poisoning.[33] In addition, chlorinated solvent such as chlorobenzene, which
has intermediate polarity resulted in no enhancement in reaction conversion. The reaction
temperature had a significant impact on reaction kinetics. Increasing the temperature to 70 °C in
the case of aromatic epoxide 2a, and 100 °C, in the case of alkyl epoxides (2b-d), turned out to
be optimal, providing quantitative conversion of epoxides into the corresponding oxazolidinones
4
/5a-d after 24h (Table 1, entries 15–19). Notably, in the absence of catalyst 1d, and in the
presence of just n-TBAI co-catalyst at 100 °C, and after 24h, only 42% background conversion of
alkyl epoxide 2c was achieved.
Comparing entries 20, 21 and 22 in Table 1, showed that a 1:1 ratio of 1a and n-TBAI is crucial
to achieve the optimum catalytic activity while any deviation from this ratio resulted in
1
1
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European Journal of Organic Chemistry
10.1002/ejoc.202000153
conversion loss. These results suggest a cooperative effect between the two catalytic species in
ring-opening of the epoxide and/or better stabilization of the reaction intermediates. In addition,
lowering catalyst and co-catalyst loadings to 3 mol%, led to a remarkable decline in reaction
conversion while increasing their loadings by two-fold (6 mol %), provided only a slight increase
in reaction conversion (Table 1, entries 23 and 24).
The time-dependent conversion of styrene oxide 2a was examined by a set of eight similar tirals
1
in which the reactions were stopped after a specific time period and then investigated by H NMR
spectroscopy: in the presence of 1d, and after 24 h, almost quantitative conversion of styrene
oxide 2a into oxazolidinone 4/5a was noticed (see the Supporting Information, Figure S1a).
Offline attenuated total reflectance (ATR)-FTIR spectroscopy was also exploited to validate
specific bands of styrene oxide 2a, phenyl isocyanate 3a and oxazolidinone adduct 4/5a (see the
Supporting Information, Figure S1b).[16b, 17a] In line with these assessments, we monitored the
time-dependent course of the reaction by referring to the intensity of the oxazolidinone carbonyl
−
1
vibration band at 1745 cm . Throughout the reaction, the intensity of oxazolidinone carbonyl
band increased considerably and reached it‘s maximum after 24 h, while the intensity of
−
1
isocyanate asymmetric stretching vibration at 2261 cm and the epoxide ring-deformation bands
−
1
at 985 and 878 cm , decreased constantly, and effectively dissapeared after 24 h.
Motivated by these results and with a wish to evaluate the generality of the squaramide-catalyzed
coupling reaction, we examined different terminal alkyl- and aryl-substituted epoxides with
varoius
isocayantes under the optimized reaction conditions (see above) providing
oxazolidinones (4/5a–p) in high-to-excellent yields.
1
2
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European Journal of Organic Chemistry
10.1002/ejoc.202000153
As depicted in Table 2, the compatibility of the synthesis with diverse isocyanates was explored.
Styrene oxide 2a, glycidyl methacrylate 2b, and phenyl glycidyl ether 2c were chosen as typical
cases of aromatic and aliphatic epoxides, and they were screened with different aromatic
isocyanates to furnish the corresponding oxazolidinones 4/5a–p. For reactions that include
styrene oxide 2a, the thermodynamically favoured 3,5-oxazolidinones (4a–g) were consistently
the major products generated in about 2:1 to 3:1 ratios with respect to 3,4-oxazolidinones (5a–g)
(
Table 2, entries 1–6). Normally, epoxide ring-opening happens at the least substituted carbon,
yet for styrene oxide 2a, such sterically constrain bias is in competition with the more
electronically favoured ring-opening at the benzylic position.[18a-c, 32] As previously reported, in
N
cases of aryl-substituted epoxides, aryl groups favour S 1 type reaction pathway that is in
competition with S
N
2 type mechanism.[18] On the other hand, reactions involving glycidyl
methacrylate produced only 3,5-oxazolidinone (4h–n) from all isocyanates, thus revealing the
excellent regioselectivity via S 2 type mechanism offered by this strategy (Table 2, entries 8–14).
N
The yield of oxazolidinones 4/5a–n was influenced by the electronic nature of the isocyanates
employed: the highest yields observed when using electron-rich isocyanates (Table 2, entry 6);
while electron-deficient isocyanates provided lower yields
as epitomized by 3 5-
bis(trifluoromethyl)phenyl and 4-nitrophenyl isocyanates with styrene oxide (Table 2, entries 4
and 5). The lower yields by electron-deficient isocyanates strongly suggests that the rate of the
whole process is determined by the ring-closing step, which corroborates the previously reported
studies.[21b, 41] To broaden the scope of this binary catalytic system, a variety of more challenging
isocyanates[18a-c] including alkyl isocyanates 3g-h and tosyl isocyanate 3i were tested under the
optimized reaction conditions. As shown in Table 2, entries 7, and 14−16, the reaction was not
1
3
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European Journal of Organic Chemistry
10.1002/ejoc.202000153
limited to only aromatic isocyanates whereas tosyl and aliphatic isocyanates were also tolerated.
All of the reactions proceeded without kinetic resolution of the racemic epoxides.
Table 2. Cycloaddition of epoxide 2a, 2b and 2c with various isocyanatesa
(
5 mol %)
O
O
O
C
1
d
−
O
(5 mol %)
+
R2
R2
Bu N I
4
O
N
O
N
+
R1
N
R2
neat
−
R1
R1
2
4 h, 70 100 °C
2
3
4
5
(
R =), a: Ph, b: CH
2
2OCOC(CH3
2, c: CH2
OPh
1
)=CH
Entry
Isocyanate
Product
Yieldb
%
4:5c
O
O
1
88
86
82
74:26
O
N
O
N
N
C O
3
a
Ph 4a
5a Ph
O
O
Cl
Cl
2
3
78:22
71:29
Cl
N
C
O
O
N
N
O
N
3
b
Ph 4b
5b Ph
O
O
O
F
F
F
N
C
O
O
N
3c
Ph 4c
5c Ph
1
4
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European Journal of Organic Chemistry
10.1002/ejoc.202000153
CF3
CF
3
O
O
F3C
O
N
O
N
7
8
70:30
N
C O
CF3
CF
3
3d
4
5
Ph
4d
5d Ph
F3C
O
O
NO2
NO
2
O
N
O
N
O N
N C O
2
7
6
65:35
82:18
3
e
Ph 4e
5e Ph
O
O
6
7
8
90
44
95
O
N
O
N
N
C
O
O
3
f
Ph 4f
5f Ph
O
O
68:32
100:0
N
C
O
N
O
N
3
g
Ph 4g
5g Ph
O
O
N
N
C O
3
a
O
4h
O
O
Cl
9
89
100:0
O
N
Cl
N C O
3b
O
O
4i
1
5
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European Journal of Organic Chemistry
10.1002/ejoc.202000153
O
F
1
0
86
100:0
O
N
F
N C O
3c
O
O
4j
CF3
O
F3C
1
1
O
N
81
100:0
N
C O
CF3
3d
O
O
4k
F3C
O
NO2
O
N
O N
N C O
12
13
14
2
85
92
49
100:0
100:0
100:0
3
e
O
4l
O
O
O
N
N
C O
3
f
O
O
4m
O
O
N
N
C O
3
g
O
4n
O
1
6
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European Journal of Organic Chemistry
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O
O
N
N
C
O
8
2
1
1
5
6
100:0
3
h
O
4o
Ph
O
O
O
O
N
S
O
S
1
00:0
O
94
N
C O
4p
O
3i
Ph
a
Conditions: epoxide 2 (0.2 mmol), isocyanate 3 (0.2 mmol), reaction carried out as neat.
d (5 mol %), n-TBAI (5 mol %), 100 °C, 24 h. In case of epoxide 2a, the reaction was
1
b
c
heated to 70 °C. Yields refer to product isolated by column purification. The ratio of
4
1
a:5a was evaluated by H NMR spectroscopy (CDCl ) of the crude reaction mixture.
3
Next, a series of different terminal epoxides 2 were assessed in reaction with the aryl- and alkyl-
substituted isocyanates 3a and 3b, respectively. Epoxides 2b–d bearing alkoxy and halo groups
underwent epoxide ring-opening exclusively at the less-substituted carbon atom to furnish the
corresponding 3,5-oxazolidinones in high yields and regioselectivity (Table 3, entries 1–3). The
observed regioselectivity could be justified by favourbale steric constrain observed in the case of
alkyl-substituted epoxides (2b-d): nucleophilic attack occures at the less hindered carbon atom
of an aliphatic epoxide by an S 2 type mechanism (preferred attack on the methylene carbon).
N
Surprisingly, tert-butyl isocyanate 3b, a challenging case due to both the unfavorable steric and
stereo electronic factors, was also well-tolerated under this catalytic system (Table 3, entries 4–6).
1
7
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European Journal of Organic Chemistry
10.1002/ejoc.202000153
Table 3. Cycloaddition of isocyanate 3a and 3b with various epoxidesa
(
5 mol %)
O
O
O
C
1
d
−
O
(5 mol %)
+
R2
R2
Bu N I
4
O
N
O
N
+
R1
N
R2
neat
R1
R1
24 h, 100 °C
2
3
4
5
(
R =),
2
a
: Ph, b: t-Bu
3
Entry
Epoxide
Product
Yieldb 4:5c
%
O
O
Ph
94
100:0
N
O
1
2
O
O
4q
2b
O
O
Ph
93
100:0
O
N
O
Ph
2
c
4r
O
Ph
O
O
Ph
3
91
45
100:0
100:0
Cl
O
N
2d
4
s
Cl
O
4
O
O
N
O
O
4t
2b
1
8
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European Journal of Organic Chemistry
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O
5
O
48
48
100:0
100:0
O
N
O
Ph
4
u
2
c
O
Ph
O
O
6
O
N
Cl
2d
4v
Cl
a
Conditions: epoxide 2 (0.2 mmol), isocyanate 3 (0.2 mmol), 1d (5 mol %), n-TBAI (5
b
mol %), 100 °C, 24 h, reaction carried out as neat. Yields refer to product isolated by
column purification. c The ratio of 4a:5a was evaluated by H NMR spectroscopy
1
(
CDCl ) of the crude reaction mixture.
3
[18, 21b]
The reaction with challenging 1,2-disubstituted epoxides −a case that is problematic−
was
examined and to our delight, the reactions proceeded smoothly to provide the corresponding
oxazolidinones in moderate yields, albeit at much slower reaction rates (Scheme 2). The reaction
of cis-stilbene oxide 2e, proceeded to give a mixure of cis- and trans-oxazolidinone 4w in 31%
yield, with the major isomer holding the cis configuration (trans/cis isomeric ratio: 40:60,
1
observable by H NMR). Adding to this, the reaction of trans-stilbene oxide provided a mixture
of cis- and trans-oxazolidinones in 65 % yield, yet with the major isomer holding the trans
1
configuration (trans/cis isomeric ratio: 80:20, observable by H NMR). Crystals of compounds
appropriate for X-ray analysis were grown from slow evaporation of ethyl acetate solution. The
following crystal structures unambiguously revealed the cis and trans configurations (see The
1
13
Experimental Section and Crystallographic Information File). In addition, the H and C NMR
data corroborate the previously reported analysis for cis- and trans-isomers of oxazolidinone.[17b,
3
4]
The fact that these reactions were partially stereospecific implies the conversion of stilbene
1
9
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European Journal of Organic Chemistry
10.1002/ejoc.202000153
oxides into the corresponding oxazolidinones could occur via competing pathways, including
double inversion and/or S 1 type manifolds. A similar stereochemical result has been reported
N
earlier for the reaction of 1,2-disubstituted epoxides and heterocumulenes.[18a-c, 35]
Scheme 2. Reactions with 1,2-disubstituted epoxides.a
(
10 mol %)
O
O
O
1d
+
−
O
Ph
Ph
C
Bu N I
4
(10 mol %)
neat
O
N
O
N
(
a) Ph
Ph
N
-
Ph
Ph
Ph
Ph
Ph
96 h, 100 °C
31%
cis 2e
3a
-
-
cis 4w
trans 4w
(X-ray)
:
cis trans
(60:40)
(
10 mol %)
O
O
O
1d
+
−
O
C
Bu N I
Ph
Ph
4
(10 mol %)
neat
O
N
O
N
(
b) Ph
Ph
N
-
Ph
96 h, 100 °C
38 %
Ph
Ph
Ph
Ph
trans 2e
-
-
3a
cis 4w
trans 4w
X-ray)
20:80)
(
:
cis trans
(
a
Conditions: epoxide 2e (1 mmol), isocyanate 3a (1 mmol), reaction carried out as neat.
Yields refer to product isolated by column purification. The ratio of cis:trans was evaluated by
1
H NMR spectroscopy (CDCl ) of the crude reaction mixture.
3
To better understand the reaction pathway, optically pure (R)- and (S)-(+)-glycidyl benzyl ether
was examined under the optimized reaction conditions to evaluate the chirality transfer from the
epoxides (Scheme 3). We isolated the oxazolidinone adduct 4x in 99% enantiomeric excess (ee)
in each case, with retention of configuration starrting from epoxides with a similar ee values,
2
0
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European Journal of Organic Chemistry
10.1002/ejoc.202000153
providing evidence for iodide-mediated-ring-opening of the epoxide from the less-hindered
2 pathway (preferred attack on the methylene carbon).[36] This binary catalytic
position via S
N
platform provides an entry to enantioenriched oxazolidinones without stereochemical erosion.
Scheme 3. Synthesis of optically active compoundsa
O
(
5 mol %)
1
d
O
Ph
+
−
O
N
O
Bu N I
C
4
(5 mol %)
Ph
O
(a)
N
neat
O
-
4
x
2f
24 h, 100 °C
(S)
1%
(S)-
Ph
Ph
9
(99% ee)
3a
(99% ee)
O
(5 mol %)
1
d
O
Ph
+
−
O
N
O
Bu N I
C
4
(5 mol %)
Ph
O
(b)
N
neat
O
2
f
24 h, 100 °C
-
(
R)-
Ph
Ph
4
x
(
R)
(
99% ee)
3a
9
0%
(99% ee)
a
Conditions: epoxide 2f (0.2 mmol), isocyanate 3a (0.2 mmol), 1d (5 mol %), n-TBAI (5
mol %), 100 °C, 24 h, reaction carried out as neat. Yields refer to product isolated by
column purification. Enantiomeric excess (ee) was analyzed using chiral HPLC (see the
Supporting Information for further details).
A scale up experiment was carried out to highlight the practicality of this catalytic system
(
Scheme 4a). In this experiment, under the optimized reaction conditions, a mixture of phenyl
glycidyl ether epoxide (2c) (50 mmol) and phenyl isocyanate 3a (50 mmol) were converted to the
corresponding oxazolidinone 4r in 90 % isolated yield after column chromatography on silica gel.
As shown in scheme 4b, the applicability of this process was further expanded to the synthesis of
2
1
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European Journal of Organic Chemistry
10.1002/ejoc.202000153
Toloxatone (4z), an antidepressant agent that acts as a selective and reversible inhibitor of
monoamine oxidase-A (MOA) [37] using previously reported strategy.[21b]
Scheme 4. (a) A scale up reaction with substrates 2c and 3a. (b) Synthesis of Toloxatone 4zb
a
(
5 mol %)
O
1
d
O
C
N
+
−
O
Bu N I (5 mol %)
Ph
4
O
N
+
PhO
(a)
neat
Ph
3a
24 h, 100 °C
PhO
2c
4r
90 %
(50 mmol)
(12.0 g)
O
C
N
(
5 mol %)
O
1
d
+
−
O
Bu N I
4
(5 mol %)
O
N
+
Cl
neat
4 h, 100 °C
5 %
2
Cl
2d
3f
4y
9
(b)
O
O
1. KOAc, DMF
O
N
O
N
2
. K CO , EtOH
2
3
6
5 %
HO
Cl
(4z)
over 2 steps
4y
Toloxatone
a
Conditions: (a) epoxide 2c (50 mmol), isocyanate 3a (50 mmol), 1d (5 mol %), n-TBAI
(
5 mol %), 100 °C, 24 h, reaction carried out as neat. Yields refer to product isolated by
b
column purification. Conditions: (b) first step: epoxide 2d (2 mmol), isocyanate 3a (2
mmol), 1d (5 mol %), n-TBAI (5 mol %), 100 °C, 24 h, reaction carried out as neat;
Second step: KOAc (10.0 mmol), DMF (10 mL); K
2
CO (10.0 mmol), EtOH (10 mL).
3
Further studies for the hydrogen-bonding interaction of epoxide and the squaramide entity as well
as it’s hydrogen-bonding interaction with the iodide nucleophile was demonstrated in a series of
2
2
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European Journal of Organic Chemistry
10.1002/ejoc.202000153
1H NMR experiments (see the Supporting Information, Figure S3). These experiments were
achieved employing solutions of styrene oxide 2a and n-TBAI added to a 0.2 M solution of 1d
in DMSO-d at room temperature. Negligible downfield shifts (from δ = 10.02 ppm to 10.11
6
ppm) and (from δ = 7.72 ppm to 7.77 ppm) of the two distinctive 1d N-H proton signals were
observed as excess amount of epoxide 2a (ten equivalents) was added to a solution of 1d in
DMSO-d . It seems that the interaction between squaramide 1d and epoxide 2a is typically weak,
6
a phenomenon that was previously observed by Kleij and co-workers.[20k] On the other hand,
when an equivalent of tetrabutylammonium iodide (n-TBAI) was added to a solution of 1d in
DMSO-d
6
, clear downfield shifts of the two characteristic N-H protons (from δ = 10.02 ppm to
1
0.96 ppm) and (from δ = 7.72 ppm to 8.50 ppm) were observed which pinpoints the anion-
binding properties of this double hydrogen-bond donor entity. In addition, similar downfield
shifts of the two ortho-protons of the 3,5-bis(trifluoromethyl)-phenyl moiety (δ = 7.98 ppm to
8
.25 ppm) were also observed. These downfield shifts bodes well with the squaramide N-H
acidities , catalytic activities, and anion-binding properties.[23, 39] These data suggest that the
[
38]
[27]
styrene oxide 2a is unable to compete with the iodide anion to form a hydrogen-bonded complex
2
a:1d,[40] indicating squaramide’s catalytic activity is mostly related to its control on the
reactivity of the ion-pair through anion binding as well as its hydrogen-bonding stabilization of
oxoanionic intermediates that form after iodide-mediated ring-opening of the epoxide.
We have inferred a mechanism similar to the previously proposed ones in which a hydrogen-
bond donor entity could participate in anion-binding processes during the course of the
reaction;[20k, 41] modulating the reactivity of the anion while stabilizing the reaction intermediates
(
Scheme 5). First, the squaramide 1 binds reversibly to the iodide anion of the n-TBAI which is
2
3
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European Journal of Organic Chemistry
10.1002/ejoc.202000153
present in an equimolar ratio with respect to the host (Scheme 5, I) while epoxide, that is present
in excess, is unlikely to compete for binding to 1 in the presence of iodide. Second, an iodide-
mediated ring-opening reaction of epoxide furnishes a hydrogen-bond-stabilized iodoohydrin
intermediate (Scheme 5, II). The in situ formed oxo-anions via epoxide ring-opening could easily
displace the iodide nucleophile in the 1a:I complex[20j-k, 41], providing 1a-stabilized oxo-anion
complex. Subsequent inclusion of isocyanate into the iodoohydrin entity results in a
squaramide—stabilized carbamate intermediate (Scheme 5, IV). Lastly, the catalytic cycle is
completed with an intramolecular ring closure of the carbamate intermediate producing the
oxazolidinone 4/5 and regenerating the host 1. Since iodide binding to 1 is significant, the host-
−
−
guest assembly 1:n-TBAI can be assumed as the resting state of this catalytic system: the host 1
captures the iodide anion that is liberated in the ring-closing step while furnishing the
oxazolidinone adduct.
2
4
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European Journal of Organic Chemistry
10.1002/ejoc.202000153
O
N
O
N
R
R
H
H
Bu +Bu
N
I
Bu
Bu
O
O
Bu
I
Bu
+
R
N
O
R
N
Bu
N
Bu
O
N
H
H
R1
O
I
R2
R1
R1
O
O
R
Bu +Bu
N
Bu Bu II
I
Bu IV
Bu
O
+
N
N
Bu R2
H
Bu
N
N
I
H
R
C
I
O
O
R1
R1
R2
R
N
O
H
N
O
Bu
Bu
Bu H
Bu
+
O
N
N
R
O
III
Scheme 5. Proposed catalytic cycle for squaramide/n-TBAI-catalyzed [3 + 2] cycloaddition of
isocyanates and epoxides.
2
5
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European Journal of Organic Chemistry
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Conclusions
Organocatalysis is an emerging and promising catalytic platform that effectively catalyzes
reactions of heterocumulenes for the preparation of heterocycles. The binary organocatalytic
system −composed of a squaramide entity along with a suitable halide anion− developed here
successfully catalyzes the [3 + 2] cycloaddition of isocyanates and epoxides towards the
preparation of oxazolidinones.
This simple and tunable catalytic system is highly efficient for the synthesis of aryl- and alkyl N-
substituted oxazolidinones in addition to the disubstituted and enantioenriched ones from a broad
range of epoxides and isocyanates in high-to-excellent yields. This metal- and solvent-free
platform causes halide nucleophilic ring-opening operation, and isocyanate insertion to occur in a
cooperative manner producing oxazolidinones without resort to slow addition of isocyanates or
excess amount of epoxides. A hydrogen bonding-anion binding mechanism was proposed in
which the double hydrogen-bond donor catalyst could simultaneously participate in multiple
modes of activation and stabilization. Efforts in development of other organocatalytic systems for
the mild fixation of isocyanate are underway in our laboratory.
Experimental Section
Materials and general methods. Squaramide 1a-i were prepared under argon atmosphere using
Schlenk techniques and [3 + 2] cycloaddition reactions were carried out in drum vials. Stainless
steel syringes were used to transfer air and moisture-sensitive liquids. Flash chromatography was
performed using silica gel 60 (230-400 mesh) from Merck. Thin layer chromatography was
performed on glass plates precoated with 0.25 mm Kieselgel 60 F254 (Merck). Epoxides 2a-f,
isocyanates 3a-i, aniline, 3,5-bis(trifluoromethyl)aniline, 4-nitroaniline, 3,4-diethoxy-3-
2
6
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European Journal of Organic Chemistry
10.1002/ejoc.202000153
cyclobutene-1,2-dione, cyclohexyl amine, 3,5 bis(trifluoromethyl) phenyl isothiocyanate, 1,6
diaminohexane, tris(2-aminoethyl)amine, was purchased from Sigma Aldrich. Tetrabutyl
ammonium iodide, tetrabutyl ammonium bromide, tetrabutyl ammonium chloride, 1,3
diaminopropane, was purchased from Merck. Zinc trifluoromethanesulfonate was purchased from
Alfa Aesar. All other reagents were purchased from commercial sources, unless otherwise noted.
Solvents were purchased from Merck. Distilled water was obtained from an in-house supply.
1
Proton nuclear magnetic resonance ( H NMR) spectra and carbon nuclear magnetic resonance
(13
C NMR) spectra were recorded on a Bruker DRX-300 (300 MHz), Varian Mercury-500 (500
MHz) and Bruker DRX-600 (600 MHz) spectrometers. Chemical shifts for protons (δ scale) are
reported in parts per million (ppm) downfield from tetramethylsilane and are referenced to
residual protium in the NMR solvent (DMSO: δ 2.50, CDCl
are reported in parts per million downfield from tetramethylsilane and are referenced to the
carbon resonances of the solvent (DMSO: δ 39.51, CDCl : δ 77.23). Data represented as follows:
3
: δ 7.26). Chemical shifts for carbon
3
chemical shift, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet), coupling constants (J value) in Hertz (Hz), and number of protons. Conversion was
measured by the ratio of epoxide compared to those of corresponding oxazolidinones. Infrared
(
IR) spectra were obtained on a Thermo/Nicolet NEXUS 470 instrument equipped with a single-
bounce diamond / ZnSe ATR accessory, either in the solid state or as neat liquids, as indicated.
–1
Spectral features are tabulated as follows: wavenumber (cm ); intensity (s-strong, m-medium, w-
weak, br-broad). High-resolution mass spectra (HRMS) and HPLC were obtained on an Agilent
technologies 6530 Q-TOF-LC-MS. All optical rotations [α]20 analyses were performed on a
D
KRUSS P300 polarimeter instrument. Optical rotations are measured at the wavelength of the
2
7
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European Journal of Organic Chemistry
10.1002/ejoc.202000153
sodium D-line (589.3 nm) at a temperature of 20 °C, with reference to a layer 1 dm thick of a
solution containing 0.01 g of the substance per 1 milliliter.
Preparation of symmetrically substituted squaramides. Squaramides 1a-c were prepared
according to the previously reported procedures.[23e, 42]
3
,4-Bis(phenylamino)cyclobut-3-ene-1,2-dione (1a). Synthesized according to the previously
reported procedure:[23e] to a stirred solution of 3,4-diethoxycyclobut-3-ene-1,2-dione (397 µl, 2
mmol, 1 equiv) and zinc trifluoromethanesulfonate (146 mg, 0.4 mmol, 20 mol %) in toluene /
DMF 19:1 (2 mL) was added aniline (201 µl, 2.2 mmol, 1.1 equiv). The solution was heated to
1
00 °C and stirred for 12 h. When the solution was cooled to room temperature, a white
precipitate was observed and isolated by decanting the solvent. The solid was further washed
with methanol (3 x 5 mL), and each time it was shaken vigorously and centrifuged to remove the
methanol. The resulting solid was further refluxed with isopropanol to eliminate any traces of
1
DMF and further dried in vacuo yielding 1a as a white solid (470 mg, 1.78 mmol, 89% yield). H
NMR and C NMR spectra were in agreement with the previously reported spectrum.[23e] 1H
NMR (600 MHz, DMSO-d ) δ 9.87 (br, 2H), 7.48 (d, J = 7.8 Hz, 4H), 7.37 (t, J = 7.8 Hz, 4H),
.08 (t, J = 7.8 Hz, 2H); C NMR (151 MHz, DMSO) δ 181.6, 165.6, 138.5, 129.4, 123.4,
18.5.
,4-Bis(3,5-bis(trifluoromethyl)-phenylamino)cyclobut-3-ene-1,2-dione (1b). Squaramide 1b was
13
6
H
1
3
7
1
C
3
prepared in (922 mg, 1.72 mmol, 86% yield) as a white solid by following the procedure for the
1
13
preparation of 1a. H NMR and C NMR spectra were in agreement with the previously reported
spectrum: [23e] 1H NMR (600 MHz, DMSO-d
) δ
10.43 (br, 2H), 7.90 (s, 4H), 7.68 (s, 2H); C
13
6
H
2
8
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European Journal of Organic Chemistry
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NMR (151 MHz, DMSO-d
6
) δ
C
181.7, 166.2, 141.2, 131.5 (q, J = 33 Hz), 123.4 (q, J = 273. Hz),
1
18.1, 115.4.
,4-Bis(cyclohexlamino)cyclobut-3-ene-1,2-dione (1c). to
3
a
stirred solution of 3,4-
diethoxycyclobut-3-ene-1,2-dione (397 µl, 2 mmol, 1 equiv) in methanol (2 mL) was added
cyclohexylamine (252 µl, 2.2 mmol, 1.1 equiv) at room temperature. The solution was stirred for
1
2
2 h at room temperature. The precipitated solid was filtered and washed with di ethyl ether (2 ×
1
ml) and dried in vacuo yielding 1c as a white solid (498 mg, 1.80 mmol, 90% yield). H NMR
and C NMR spectra were in agreement with the previously reported spectrum: [42] 1H NMR
600 MHz, DMSO-d ) δ 7.31 (s, 2H), 3.74 (s, 2H), 1.86 (d, J = 8.9 Hz, 4H), 1.72 – 1.62 (m,
H), 1.53 (d, J = 12.4 Hz, 2H), 1.27 (m, 8H), 1.20 – 1.11 (m, 2H); C NMR (151 MHz, DMSO-
) δ 181.8, 167.0, 52.0, 33.7, 24.8, 24.0.
13
(
6
H
1
3
4
d
6
C
Preparation of unsymmetrically substituted squaramides. [23e, 43]
-(3,5-bis(trifluoromethyl)-phenylamino)-4-ethoxycyclobut-3-ene-1,2-dione (II). To a stirred
3
solution of 3,4-diethoxycyclobut-3-ene-1,2- dione (I) (0.814 ml, 5.5 mmol 1.1 equiv) and zinc
trifluoromethanesulfonate (400 mg, 1.1 mmol, 20 mol %) in ethanol (10 mL) at room
temperature was added 3,5-bis(trifluoromethyl)aniline (0.781 ml, 5 mmol, 1 equiv). The solution
was stirred overnight at room temperature, then the mixture was concentrated under reduced
pressure and purified by flash column chromatography (silica gel, 1 : 0 → 7 : 3 n-
hexanes/ethylacetate) and dried in vacuo to afford 3-(3,5-bis(trifluoromethyl)-phenylamino)-4-
1
ethoxycyclobut-3-ene-1,2-dione (II) as white solid (2.2 g, 4.6 mmol, 92% yield). H NMR and
13C NMR spectra were in agreement with the previously reported spectrum: [43] 1
H NMR (600
2
9
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