A Metal-Free Synthesis of N-Aryl Oxazolidin-2-Ones by the One-Pot Reaction of Carbon Dioxide with N-Aryl Aziridines

Article abstract of DOI:10.1002/adsc.202000175

The cost-effective TPPH₂/TBACl-catalyzed (TPPH₂=dianion of tetraphenyl porphyrin; TBACl=tetrabutyl ammonium chloride) carbon dioxide cycloaddition to N-aryl aziridines was successful in synthesizing N-aryl oxazolidin-2-ones. A cataly

Full text of DOI:10.1002/adsc.202000175

Title: A Metal-Free Synthesis of <i>N</i>-Aryl Oxazolidin-2-ones by the
One-Pot Reaction of Carbon Dioxide with <i>N</i>-Aryl Aziridines
Authors: Emma Gallo, Paolo Sonzini, Caterina Damiano, Daniela
Intrieri, and Gabriele Manca
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000175
Link to VoR: https://doi.org/10.1002/adsc.202000175

10.1002/adsc.202000175
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.202000175
A Metal-Free Synthesis of N-Aryl Oxazolidin-2-ones by the
One-Pot Reaction of Carbon Dioxide with N-Aryl Aziridines
Paolo Sonzini,a Caterina Damiano,a Daniela Intrieri,a Gabriele Mancab,* and Emma
Galloa,*
a
Department of Chemistry, University of Milan, Via Golgi 19, I-20133 Milan, Italy. +39(0)250314374,
+39(0)2503144405, e-mail: emma.gallo@unimi.it
Istituto di Chimica dei Composti OrganoMetallici, ICCOM-CNR, Via Madonna del Piano 10, I-50019 Sesto Fiorentino,
b
Italy. e-mail: gabriele.manca@iccom.cnr.it
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. The cost-effective TPPH2/TBACl-catalyzed The procedure occurred with a very high atom economy,
(TPPH2 = dianion of tetraphenyl porphyrin; TBACl = molecular nitrogen being the only by-product of the entire
tetrabutyl ammonium chloride) carbon dioxide cycloaddition tandem process.
to N-aryl aziridines was successful in synthesizing N-aryl In addition, the mechanism of catalytic cycle was
oxazolidin-2-ones. A catalytic tandem reaction was also investigated by DFT calculations.
developed, in which N-aryl aziridines were initially
synthesized and then reacted with carbon dioxide without
being purified.
Keywords: N-aryl oxazolidin-2-one; Carbon dioxide;
Aziridine; Porphyrin; DFT study
Surprisingly, the synthesis of NAOs by the direct
cycloaddition of CO2 to N-aryl aziridines was less
developed with respect to the analogous reaction
involving N-alkyl and N-benzyl aziridines.[12] The
lack of a general method for producing differently
substituted NAOs from N-aryl aziridines has been
ascribed to the lower basicity and nucleophilicity of
N-aryl with respect to N-alkyl aziridines, which
implies their limited reactivity towards CO2.[13]
Introduction
Oxazolidinones are largely used as intermediates as
well as chiral auxiliaries in organic synthesis[1] and
constitute
a
class of active pharmaceutical
molecules,[2] whose activity depends on the chemical
nature of oxazolidinone’s substituents. Excellent
pharmaceutical properties are usually observed when
a N-aryl moiety is present in the heterocycle
structure; in fact, some N-aryl oxazolidin-2-ones
(NAOs), such as Linezolid,[3] Tedizolid[4] and
Toloxatone,[5] are FDA-approved drugs for treating
bacterial and microbial infections. Consequently, a
great scientific interest has been devoted to
developing efficient procedures for synthesizing
N-aryl substituted oxazolidinones.
Among the available methodologies that are
specifically designed for synthesizing NAOs, those
involving CO2 (CO2 = carbon dioxide) as one of the
reagents is of particular interest. This is due to the
importance of using this greenhouse gas as a
renewable C1 synthetic building block.
Scheme 1. Selected examples of the CO2-based synthesis
of NAOs
Several catalytic systems have been developed and,
besides the reaction of CO2 with amino alcohols,[6]
unsaturated amines[7] and epoxy amines,[8] three-
component reactions involving CO2/epoxide/aniline[9]
or CO2/haloalkane/aniline[10] CO2/alkene/aniline[11]
combinations, have also emerged as efficient catalytic
systems for producing N-aryl oxazolidin-2-ones
(Scheme 1).
To the best of our knowledge, only the
(salen)chromium(III)/DMAP-catalyzed (DMAP
=
N,N-dimethyl-4-aminopyridine)
synthesis
of
N-phenyl oxazolidin-2-ones[12a] and the last step of
the Toloxatone synthesis, promoted by a dimeric
1
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10.1002/adsc.202000175
Advanced Synthesis & Catalysis
aluminium (III) Schiff base complex,[12b] occurred by
the direct CO2 cycloaddition to a N-aryl aziridine
compound (Scheme 2).
synthesizing N-alkyl oxazolidin-2-ones.[14a] Even if a
very good 2a/2b regioisomeric ratio was obtained,
the modest values of the aziridine conversion and
oxazolidinone selectivity indicated a limited catalytic
efficiency of the ruthenium bis-imido catalyst (Table
1, entry 1). The reaction produced, alongside the
desired N-aryl-oxazolidin-2-ones 2a/2b in a low yield,
other side-products which were not characterized.
Interestingly, when Ru(TPP)(NAr)2 was replaced
with TPPH2, the aziridine conversion of 20 % was
observed (Table 1, entry 2) and this value increased
to 61 % by running the reaction in THF (Table 1,
entry 3) where CO2 is better solubilized. Thus, in
order to assess the role of TPPH2 in the catalytic
cycle, the reaction was run in the presence of TBACl
alone and obtained results indicated that TPPH2 was
responsible for a better 2a/2b regioisomeric ratio
(compare entries 3 and 4 of Table 1). In addition,
TPPH2 had a positive effect on the reaction rate, as
proved by the larger aziridine conversion, which was
observed after 6 hours of reaction (Table 1, entries 3
and 4, values in parenthesis).
Recently, we reported a ruthenium porphyrin-
based catalytic procedure for synthesizing N-alkyl
oxazolidin-2-ones[14] and, during our efforts to apply
the same procedure for synthesizing NAOs, we
discovered that the reaction was efficiently promoted
by the low-cost TPPH2/TBACl catalytic system
(TPPH2 = tetraphenyl porphyrin; TBACl = tetrabutyl
ammonium chloride). The presence of a transition
metal complex was not required.
Results and Discussion
Synthetic study
We report here the optimization and study scope of
the synthesis of N-aryl oxazolidin-2-ones, which were
obtained either by reacting CO2 with purified N-aryl
aziridines or by applying a cost-effective, tandem
procedure. The latter methodology consists in the
Ru(TPP)CO-catalyzed synthesis of N-aryl aziridines
that were converted, without being purified, into
corresponding NAOs by the TPPH2/TBACl-catalyzed
cycloaddition of CO2.
No aziridine conversion was observed by only
using TPPH2 underlining the essential role of TBACl.
Albeit the catalytic activity of tetrabutylammonium
halides was already reported in the synthesis of
N-alkyl oxazolidin-2-ones,[15] the efficiency of the
sole TBACl in promoting the formation of NAOs has
never been reported. Lower or no catalytic efficiency
was
observed
when
either
PPNCl
(bis(triphenylphosphine)iminium chloride) (Table 1,
entry 5) or DMAP (Table 1, entry 6) was employed
as the co-catalyst.
Table 1. Synthesis of oxazolidin-2-ones 2a/2b[a]
entry cat./co-cat.
conv.
%
sel. 2a/2b
%
[b]
[b]
ratio
1[c]
Ru(TPP)(NAr)2
60
40
97:3
/TBACl
2[c]
3
4
TPPH2/TBACl
TPPH2/TBACl
-/TBACl
20
90
90:10
90:10
74:26
65:35
-
61 (20[d]) 80
63 (5[d])
49
-
79
78
-
5
6
TPPH2/PPNCl
TPPH2/DMAP
[a] Reaction conditions: 0.11 M THF N-aryl aziridine
solution in a steel autoclave for 15 h at 100°C, 1.2 MPa
CO2 and cat./co-cat./aziridine = 1:10:100. [b] Determined
by H NMR by using 2,4-dinitrotoluene as the internal
standard. [c] Benzene as the reaction solvent. [d] After 6
hours.
Scheme 2. (A) Transition metal- and (B) metal free-
mediated CO2 cycloaddition to N-aryl aziridines
1
The reaction of 1-(3,5-bis(trifluoromethyl)phenyl)-2-
phenylaziridine (1) with CO2 (Table 1) was first run
in the presence of Ru(TPP)(NAr)2/TBACl catalytic
Considering the importance of applying such a
convenient method for synthesizing NAOs, the
TPPH2/TBACl-based methodology was investigated
in detail. Reaction parameters of the model
system (Ar
= 3,5-(CF3)2C6H3), by using the
experimental conditions already employed for
2
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10.1002/adsc.202000175
Advanced Synthesis & Catalysis
cycloaddition of CO2 to 1 were systematically tuned
in order to magnify the catalytic performance (Figure
1) (see SI for experimental details). First, a series of
catalytic reactions was performed by using the
experimental conditions reported in Table 1 and
changing the aziridine concentration from 7.5 x 10-2
to 2.0 mol/L.
regioisomeric ratios up to 99 %, 99 % and 96:4,
respectively.
Data reported in Table 2 suggested that the
reaction productivity was related to both electronic
and steric factors. The presence of EWG as R group
had a beneficial effect on the reaction outcome. In
fact, the quantitative conversion of aziridine into the
corresponding axazolid-2-one was observed when the
nitrogen atom was bonded either to the
3,5-(CF3)2C6H3 (Table 2, entry 1) or 4-(NO2)2C6H4
aromatic group (Table 2, entry 2). In these cases, the
reaction productivity was not greatly influenced by
the electronic characteristics of Ar’ group linked to
the aziridine carbon atom. In fact, good aziridine
conversions and product selectivities were achieved
by introducing whether EDG (Table 2, entries 3-5) or
a halogen atom (Table 2, entry 6) onto the Ar’ moiety.
A slight decrease on the reaction performance was
observed by inserting into the molecule the very
strong electron-deficient C6F5 substituent as the Ar’
group (Table 2, entry 7). It is interesting to note that
the reaction worked well also when EWGs were
present on Ar’ (Ar’ = C6F5) and R was an EDG (R =
tBu); in fact oxazolidin-2-one 16a/16b was obtained
from 15 with very good conversion (92 %) and
selectivity (86 %) as well as regioselectivity (16a/16b
= 91:9) (Table 2, entry 8). This result suggested that
the presence of two groups with opposite electronic
features can induce the polarization of the aziridine
C-N bond, independently on the position where they
are located. We propose that, regardless of how the
stretching of the aziridine C-N bond is produced, the
bond polarization facilitates the C-N bond cleavage
and in turn the CO2 cycloaddition. This hypothesis
could explain the slight decrease of the reaction
productivity, which was observed in the synthesis of
14a/14b when both the nitrogen and carbon aziridine
atoms linked aryl moieties bearing EWGs (entry 7).
When Ar’ = Ph, the bond polarization increased by
enhancing the electron-withdrawing nature of the R
substituent on the N-aryl group. Thus, in accordance
to what is stated above, better catalytic efficiencies
were observed by moving from OMe to a chlorine
substituent, as the R group on the para position of the
aryl moiety (entries 9-12). The dependence of the
reaction productivity on the electronic characteristic
of R was more pronounced when R was placed in
ortho or meta position with respect to the nitrogen
atom. In fact, while an acceptable yield of oxazolidin-
2-ones 26a/26b (60 % yield) was still observed by
reacting aziridine 25 with CO2 (entry 13), only traces
of oxazolidin-2-ones deriving from aziridine 27 were
formed (entry 14), due to the negative coupling of
electronic and steric effects.
90
100
100
a
80
70
60
50
b
c
80
60
40
20
0
85
70
55
40
25
0
0,3 0,6 0,9 1,2 1,5 1,8 2,1
0,0
0,5
1,0
1,5
2,0
20
50
80 110 140
[aziridine] (mol/L)
CO2 pressure (MPa)
T ( C)
Figure 1. Optimization of reaction’s experimental
conditions
As shown in Figure 1a, the best yield/regioisomeric
ratio combination was observed by using 1.5 mol/L
of aziridine 1 in THF (86 % yield, 2a/2b = 86:14).
Next, five different reactions were conducted by
using experimental conditions of Table 1, except for
the aziridine concentration that was fixed at 1.5
mol/L, and applying five different CO2 pressures
(Figure 1b). The oxazolidin-2-one yield increased up
to 86 % (2a/2b=86:14) at 1.2 MPa CO2 and then the
efficiency of the process dropped by further raising
the CO2 pressure. This effect can be due to a small
volumetric expansion,[16] which caused an aziridine
dilution with a consequent negative effect on the
catalytic performance (see catalytic effect of the
aziridine molarity in Figure 1a).
Then, reaction parameters optimized up to now
(1.5 mol/L of 1 and 1.2 MPa CO2) were used to study
the effect of the temperature on the catalytic
efficiency (Figure 1c). By raising the reaction
temperature to 125°C, the aziridine was completely
converted into oxazolidin-2-one with 99 % yield and
a 2a/2b regioisomeric ratio of 86:14 (Table 2, entry
1). A further increment of the reaction temperature
did not cause any additional positive effect. This
good result was maintained by decreasing the
reaction time from 15 to 8 hours and halving the
TBACl amount (from 10 % to 5 %). In this last case
the positive effect of TPPH2 was evident, as proven
by the lower performance observed by using 5 mol %
of TBACl alone (conv. = 84 %, sel. = 72 %, 2a/2b =
80:20 versus conv. = 99 %, sel. = 99 %, 2a/2b =
86:14 observed in the presence of TPPH2 too). The
replacement of THF with the more eco-friendly
2-MeTHF solvent, which derives from natural
sources,[17] was responsible for worse catalytic results
(conv. = 99 %, sel. = 81 % 2a/2b = 80:20)
Although aziridine 28, showing 3,5-(Cl)2C6H3
substituent on the nitrogen atom (Table 2, entry 15),
efficiently reacted with CO2 forming 29a/29b,
oxazolidin-2-ones 31a/31b were obtained only in
moderate selectivity (30 %) by using aziridine 30,
which shows 3,5-(NO2)2C6H3 group on the nitrogen
atom (Table 2, entry 16). Unexpectedly, 31a/31b
Thus, the optimized experimental conditions of
TPPH2/TBACl/aziridine = 1:5:100, 1.5 mol/L of
aziridine, 1.2 MPa CO2, 125°C and 8 h were
employed for studying the reaction scope (see SI for
experimental details). The procedure was effective
for synthesizing oxazolidin-2-ones reported in Table
2 with aziridine conversions, product selectivities and
3
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10.1002/adsc.202000175
Advanced Synthesis & Catalysis
compounds were obtained together with many other
uncharacterized side-products.
Ru(TPP)CO-catalyzed reaction of aryl azide with a
styrene derivative forming the corresponding
aziridine and then, after checking the aziridine yield
by 1H NMR spectroscopy and evaporating the
reaction solvent to dryness, the residue was
solubilized in THF and transferred into the autoclave
Next, the reactivity of aziridines having Ar’ = Ph
and R’ = Me was investigated and, as reported in
entries 17 and 18 of Table 2, the presence of two
substituents on both carbon atoms of the aziridine
ring had a negative effect on both the conversion and
selectivity values. In accordance to the dependence of
the reaction productivity on the electronic feature of
the N-Ar moiety, the negative effect was more
where
the
TPPH2/TBACl-mediated
CO2
cycloaddition to aziridine yielded the desired
oxazolidin-2-one.
In order to investigate the applicability of the
pronounced when R was an EDG (compare entries 17, methodology, the tandem protocol was applied for
R = 3,5-(CF3)2 and 18, R = 4-tBu of Table 2). Finally,
1-(3,5-bis(trifluoromethyl)phenyl)-2-methyl-2-
phenylaziridine 36, deriving from the reaction of
-methyl styrene and 3,5-bis(trifluoromethyl)phenyl
azide, was tested in the reaction with CO2. The lack
of the oxazolidin-2-one formation suggested that the
ring-opening reaction involved the more substituted
carbon atom which, in this case cannot be attacked by
the nucleophilic species due to the high steric
hindrance.
Except in one case (Table 2, entry 13), all the
reactions reported in Table 2 occurred with a a/b
regioselectivity higher than 77:24 and the convenient
a/b ratio allowed us to easily isolate the desired
oxazolidin-2-one isomer a by chromatographic
purification (see SI).
synthesizing oxazolidin-2-ones 2a/2b, 18a and 37a
(Scheme 3). To evaluate the influence of unreacted
reagents on the catalytic performance, we
intentionally tested the tandem syntheses of product
2a/2b and 18a as case studies. The two N-aryl azides,
forming corresponding aziridines 1 and 17, show a
very different reactivity (while 1 was obtained in
99 % yield, aziridine 17 was only formed in 65 %
yield) and also the transformation of 1 and 17 into
2a/2b and 18a, respectively occurred with a very
different efficiency (entries 1 and 9 of Table 2). As
reported in Scheme 3, 2a/2b and 18a compounds
were obtained with yields and a/b regioselectivities
very similar to those obtained by using purified
aziridines (compare entries 1 and 9 of Table 2 with
values reported in Scheme 3) to indicate that the
tandem procedure was efficient as well as the two-
step process.
Considering our expertise in synthesizing N-aryl
aziridines,[18] we developed a tandem procedure in
order to improve the reaction sustainability. The first
step of the tandem reaction consisted in the
Table 2. Study of the reaction scope[a]
entry N-aryl aziridine
conv. %[b]
sel. %[c]
a/b ratio[b]
1
2
3
4
5
6
7
8
1, Ar’ = Ph, R’ = H, R = 3,5-(CF3)2
3, Ar’ = Ph, R’ = H, R = 4-NO2
99
99
99
98
99
99
80
92
85
95
99
97
99
80
94
99
73
70
99
99
90
86
90
99
80
86
23
57
50
74
60
<9
99
30
71
40
2a/2b = 86:14
4a/4b = 78:22
6a/6b = 80:20
8a/8b = 99:1
5, Ar’ = 4-tolyl, R’ = H, R = 3,5-(CF3)2
7, Ar’ = 4-(tBu)C6H4, R’ = H, R = 3,5-(CF3)2
9, Ar’ = 4-(Me)C6H4, R’ = H, R = 4-NO2
11, Ar’ = 4-(Br)C6H4, R’ = H, R = 3,5-(CF3)2
13, Ar’ =C6F5, R’ = H, R = 3,5-(CF3)2
15, Ar’= C6F5, R = 4-tBu
10a/10b = 85:15
12a/12b = 80:20
14a/14b = 82:18
16a/16b = 91:9
18a/18b = 99:1
20a/20b = 96:4
22a/22b = 90:10
24a/24b = 89:11
26a/26b = 64:36
-
9
17, Ar’ = Ph, R’ = H, R = 4-OMe
10
11
12
13
14
15
16
17
18
19, Ar’ = Ph, R’ = H, R = 4-tBu
21, Ar’ = Ph, R’ = H, R = 4-Br
23, Ar’ = Ph, R’ = H, R = 4-Cl
25, Ar’ = Ph, R’ = H, R = 2-NO2
27, Ar’ = Ph, R’ = H, R = 3-OMe
28, Ar’ = Ph, R’ = H, R = 3,5-Cl2
30, Ar’ = Ph, R’ = H, R = 3,5-(NO2)2
32, Ar’ = Ph, R’ = Me, R = 3,5-(CF3)2
34, Ar’ = Ph, R’ = Me, R = 4-tBu
29/29b = 81:19
31a/31b = 77:24
33a/33b = 94:6
35a/35b = 83:17
[a] Reaction conditions: 1.5 M THF N-aryl aziridine solution in a steel autoclave for 8 h with TPPH2/TBACl/aziridine =
1
1:5:100 at 125°C and 1.2 MPa of CO2. [b] Determined by H NMR using 2,4-dinitrotoluene as the internal standard.
[c] Isolated by flash chromatography
4
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10.1002/adsc.202000175
Advanced Synthesis & Catalysis
Previous theoretical studies on the oxazolidinone
formation either investigated the active role of metals
in activating aziridine towards the CO2 nucleophilic
attack[20] or modelled uncatalyzed reactions.[21] In
these latter cases, very high energy barriers were
calculated (ca. 50 kcal mol-1) emphasizing the
positive effect of a metal catalyst on the reaction
efficiency. In all the reported DFT studies, N-alkyl
aziridines were considered as the starting materials.
Since computational data on the CO2 cycloaddition
to N-aryl aziridines promoted by an organocatalyst
has not been reported yet, we started our investigation
(see Computational Details for more information) by
modelling the most plausible arrangements and
interactions between all the involved reactants,
namely TBACl, TPPH2, N-aryl aziridine (1) and CO2.
Fixing the porphyrin macrocycle, as the ‘ground floor’
of these molecular architectures, the formation of
different adducts between TPPH2 and alternatively
CO2 (adduct 38a), TBACl (adduct 38b) and aziridine
(1) (adduct 38c) were evaluated without introducing
any structural simplification (Figure 2).
Scheme 3. Tandem synthesis of oxazolidin-2-ones 2a/2b,
18a and 37a
It should be underlined that the tandem reaction was
effective when the aziridination occurred without a
complete azide conversion, as in the case of the less
reactive 4-(OMe)C6H4N3 azide, whose reaction with
styrene formed corresponding aziridine 17 in a non-
quantitative yield. In this latter case, the crude of the
aziridine formation, containing both Ru(TPP)CO and
unconverted N-aryl azide, was treated as described
above and compound 18a was obtained with values
comparable to those reported in entry 9 of Table 2.
This experiment indicated that the outcome of the
second step of the tandem procedure was not affected
by the presence of any reaction components
previously used for the synthesis of N-aryl aziridine,
including Ru(TPP)CO, which did not have any
catalytic influence in the CO2 cycloaddition.
38a
38c
It is worth noting that the tandem procedure was
also effective for synthesizing, as the only
regioisomer, oxazolidin-2-one 37a, which is a potent
anti-inflammatory, being a Δ-5 desaturase (D5D)
inhibitor[19] (Scheme 3). Although a modest reaction
productivity (35 % yield) was observed, this result is
noteworthy in view of the in vitro pharmaceutical
activity of 37a, which has previously been obtained
from corresponding epoxide in the very low yield of
3-4 %.[19]
38b
Figure 2. Optimized structures of adducts between TPPH2
and CO2 (38a), TBACl (38b) and N-aryl aziridine 1 (38c).
Hydrogen atoms are omitted for clarity.
We can envisage a general application of the
tandem methodology for synthesizing NAOs for the
following reasons: i) The presence of Ru(TPP)CO
doesn’t compromise the CO2 cycloaddition to N-aryl
aziridine; ii) The styrene excess, which is required in
the aziridination step, can either be eliminated during
the solvent evaporation (when low-boiling liquid
styrenes are used) or separated during the
chromatographic purification of oxazolidin-2-one;
iii) When the ArN3 consumption is incomplete, the
residual azide amount doesn’t alter the oxazolidin-2-
one formation and it can be easily removed during the
chromatographic purification of oxazolidin-2-one.
The formation of the adduct 38a was discharged in
view of its endergonicity (+3.5 kcal mol-1) as well as
the long distance between the porphyrin core and CO2
in the optimized structure (3.11 Å). On the other hand,
the formation of 38c, although feasible from an
energy viewpoint (-4.8 kcal mol-1), was also excluded
since all the investigations of its further evolution
into the final N-aryl oxazolidin-2-one 2 failed. It
worth noting that an adduct similar to 38c was
optimized by T. Ema et al. in the study of the
calix[4]pyrrole-catalyzed cyclic carbonate synthesis
by the reaction of epoxide with CO2.[22] In this case,
the adduct stability was ascribed to the establishment
of hydrogen-bonding interactions between the oxygen
atom of epoxide and the pyrrolic protons of the
macrocyclic molecule. Conversely, the presence of
hydrogen bonds was not detected in 38c due to the
long distance (2.66 Å, Figure 2) between NH
Theoretical investigation of the N-aryl oxazolidin-2-
one formation.
In order to shed some light on the catalytic role of
porphyrin TPPH2 in the CO2 cycloaddition into
N-aryl aziridines, a DFT study was carried out.
5
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10.1002/adsc.202000175
Advanced Synthesis & Catalysis
moieties of the tetrapyrrolic core and the aziridine
nitrogen atom.
chloride anion, since its NBO calculated charge
of -0.94 in 39 became -0.20 in 41.
On these bases, the computational analysis was
performed by considering 38b the starting adduct
(Figure 2), whose formation was estimated to be
exergonic by -7.5 kcal mol-1. The presence of the
peripheral meso-phenyl substituents was responsible
for the establishment of a tridimensional arrangement
where the TBACl salt was lodged through weak
cooperative electrostatic interactions, which were
well considered by using B97D functional.[23]
Next, the adduct 39, which derived by the reaction
of 38b with aziridine 1, was optimized with a free
energy gain of -0.9 kcal mol-1 (Figure 3).
39TS
41
Figure 4. Optimized structure of transition state 39TS and
adduct 41. Hydrogen atoms are omitted for clarity.
Similarly to what observed in the cyclic carbonate
formation catalyzed by the calix[4]pyrrole/TBAI
binary system,[22] adduct 41 was 17.2 kcal mol-1
higher in free energy than the starting 39. This result
suggested that the productive formation of the final
oxazolidinone might be due to following more
favorable steps, involving the CO2 activation and the
ring-closing process (see below).
The negatively charged nitrogen N2 atom of 41
was able to activate a CO2 molecule with the
consequent formation of adduct 42 with a N2-C3 bond
of 1.52 Å and a bent O1C3O and O1C1Cl
arrangements (129.6° and 120.6, respectively).
Adduct 42 (Figure 5) was exergonically formed
by -1.7 kcal mol-1 with the calculated CO2 IR
vibration at 1674 cm-1. At this point, one of the two
oxygen atoms of CO2, namely O1, was responsible for
the ring-closing process with the consequent
formation of 2a and the chloride anion release.
The transition state 42TS of this final step was
located and it showed an almost linear O1-C1-Cl
arrangement (ca. 173.2°) and O1∙∙∙C1 and C1∙∙∙Cl
distances of 2.14 and 2.32 Å, respectively (O1∙∙∙C1
and C1∙∙∙Cl distances in 42 were 3.83 and 1.89 Å,
respectively). The free energy barrier, associated to
the process, was estimated to be + 11.3 kcal mol-1.
Figure 3. Optimized structure of the adduct 39. Hydrogen
atoms are omitted for clarity.
The comparison between 39 and 40, which is formed
between TBACl and 1 in the absence of TPPH2 (see
SI), highlighted the beneficial role of the porphyrin.
In fact, while the adduct 39 is exergonically achieved
(-8.4 kcal mol-1), the formation of adduct 40 was
endergonic by +3.5 kcal mol-1. Next, the reaction
proceeded by the ring-opening process due to the
nucleophilic attack of the chloride anion to the
aziridine C1 atom, which is 1.13 Å closer than C2 to
Cl- ion (Figure 3).
The transition state 39TS of the ring-opening step
was located and the N2-C1 bond distance, which was
1.47 Å in adduct 39, elongated to 2.23 Å in 39TS
(Figure 4). Contemporary, the chloride anion
efficiently exerted its nucleophilic action, since the
Cl∙∙∙C1 distance was significantly shortened by ca.
1.29 Å (from 3.73 Å in 39 to 2.44 Å in 39TS). The
free energy barrier, associated to the formation of
39TS, was estimated to be +23.5 kcal mol-1.
After the transition state, the reaction evolved
through the minimum 41 (Figure 4) with a free
energy gain of -6.3 kcal mol-1, compared to 39TS. In
adduct 41, the Cl-C1 bond of 1.94 Å was formed and
the N2∙∙∙C1 distance elongated up to 2.48 Å, allowing
the formation of an open C1C2N2 chain. While the
nitrogen N2 atom, of the original aziridine cycle,
increased its negative charge (the NBO, natural bond
orbital, calculated charge[24] was -0.68 in 41 and -0.48
in 39), an opposite trend was observed for the
42
42TS
Figure 5. Optimized structure of 42 and transition state
42TS. Hydrogen atoms are omitted for clarity.
6
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10.1002/adsc.202000175
Advanced Synthesis & Catalysis
The production of the final compound 2a occurred by
the free energy gain of -28.1 kcal mol-1 and the
restoration of the initial adduct 38b, able to activate a
new aziridine molecule 1 to restart another catalytic
cycle. The complete free energy profile of the
formation of 2a is shown in Figure 6.
Finally, a tandem reaction, which did not require
the purification of N-aryl aziridine, was developed.
The tandem methodology allowed the synthesis of the
pharmaceutically active N-aryl oxazolidin-2-one 37a
in a yield higher than that reported in literature.
The very high sustainability and atom-economy of
the procedure is assured by merging the virtuous use
of CO2, as a raw material, with the conversion of
N-aryl azides into NAOs by producing benign
molecular nitrogen as the only stoichiometric by-
product of the two-step procedure. Note that also the
aziridination step of the tandem procedure was
efficiently catalyzed by a commercially available
compound.
42TS
39TS
CO2
+
11.3
6.3
41
42
23.5
28.1
1.7
TBACl
+
TPPH2
1
+
7.5
38b
0.9
39
Experimental Section
38b +
2a
SI contains experimental details for the synthesis and
characterization of all products, copies of NMR spectra
and the coordinates and free energies of all the optimized
structures.
General synthesis of N-aryl oxazolidin-2-ones reported
in Table 2: In a 2.0 mL glass liner equipped with a screw
cap and glass wool, tetraphenylporphyrin (2.3 mg,
3.75 x 10-3 mmol), tetrabutyl ammonium chloride (5.2 mg,
3.75 x 10-2 mmol) and aziridine (3.75 x 10-1 mmol) were
dissolved in THF (0.25 mL). The reaction mixture was
cooled to -78°C and the vessel was transferred into a
stainless-steel autoclave; three vacuum-nitrogen cycles
were performed and 1.2 MPa CO2 was charged at room
temperature. The autoclave was placed in a preheated oil
bath at 125°C and stirred for 8 h, then it was cooled at
room temperature and slowly vented. The solvent was
evaporated to dryness and the crude analyzed by 1H NMR
spectroscopy by using 2,4-dinitrotoluene as the internal
standard. The product was isolated by flash
chromatography (silica gel, n-hexane/ethyl acetate = 9:1).
Figure 6. Free energy profile of the catalytic formation of
N-aryl oxazolidin-2-one 2a.
As shown in Figure 6, the highest encountered free
energy barrier of 23.5 kcal mol-1 was much lower
than those reported for uncatalyzed processes (ca. 50
kcal mol-1)[21b] to confirm the role of TPPH2 in
facilitating the catalytic cycle.
The reaction between aziridine 1 with CO2,
forming oxazolidin-2-one 2a, was exergonic
by -2.2 kcal mol-1. The achieved value is consistent
with others reported in literature for similar processes,
such as the (salen)Cr-catalyzed aziridine/CO2
coupling reaction, where the corresponding N-alkyl
oxazolidin-2-one was located at -3.9 kcal mol-1, with
respect to the starting reagents.[20a]
General synthesis of N-aryl oxazolidin-2-ones by the
tandem procedure: In a Schlenk flask, Ru(TPP)(CO)
(0.25 g, 3.37 x 10-2 mmol), the desired styrene (8.40 mmol)
and N-aryl azide (1.68 mmol) were refluxed in benzene (50
mL). After 4.0 h, two mL of the solution were taken, dried
1
in vacuo and analyzed by H NMR spectroscopy after
adding 2,4-dinitrotoluene as the internal standard in order
to determine the aziridine yield. When the reaction was
complete, the solvent was evaporated to dryness in vacuo,
the crude dissolved in the opportune THF volume (the
aziridine concentration has to be 1.5 M) and transferred a
2.0 mL glass liner equipped with a screw cap and glass
wool. Next, tetraphenylporphyrin and tetrabutyl
ammonium chloride were added and, after cooling
to -78°C, the vessel was transferred into a stainless-steel
autoclave. Three vacuum-nitrogen cycles were performed
and 1.2 MPa CO2 was charged at room temperature. The
autoclave was placed in a preheated oil bath at 125°C,
stirred for 8 h, then cooled to room temperature and slowly
vented. The solvent was evaporated to dryness and the
crude analyzed by 1H NMR spectroscopy by using
2,4-dinitrotoluene as the internal standard. The product
was isolated by flash chromatography (silica gel,
n-hexane/ethyl acetate = 9:1).
Conclusion
In conclusion, we here report the cost-effective
synthesis of differently substituted NAOs by using
the TPPH2/TBACl-based eco-friendly synthetic
procedure. The reactivity which was observed in the
presence of TBACl alone deserves a particular
attention to better evaluate the real efficiency of the
employed catalytic systems. In our case, the addition
of 1.0 mol % of TPPH2 had a positive effect on the
reaction productivity and this result is noteworthy in
view of the low cost, commercial availability and no
toxicity of the porphyrin catalyst.
The DFT study of the reaction underlined the
beneficial effect of TPPH2 on the synthesis of the
oxazolidin-2-ones through the formation of stable
adducts. In the presence of TPPH2 the free energy
barrier of the reaction was halved with respect those
reported for the uncatalyzed CO2 coupling to N-alkyl
aziridines.
Computational Details. All the minima and transition
states along the Potential Energy Surface were isolated and
[23]
characterized at B97D-DFT level of theory
within the
Gaussian 16 package.[25] The inclusion of the dispersion
forces into the functional was important for taking into
account the weak interactions between the different
reactants in the formation of adducts. All the optimized
structures were validated as minima or transition states by
the vibrational frequencies calculations. All the
7
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10.1002/adsc.202000175
Advanced Synthesis & Catalysis
calculations were based on the CPCM model[26] for the
tetrahydrofuran, the solvent that was experimentally used.
The 6-31G basis set, with the addition of the polarization
functions (d, p) was adopted.
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We gratefully acknowledge the University of Milan-Italy for the
Transition Grant 2015/2017 – Horizon 2020.
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Advanced Synthesis & Catalysis
FULL PAPER
A Metal-Free Synthesis of N-Aryl Oxazolidin-2-
ones by the One-Pot Reaction of Carbon Dioxide
with N-Aryl Aziridines
Adv. Synth. Catal. Year, Volume, Page – Page
Paolo Sonzini, Caterina Damiano, Daniela Intrieri,
Gabriele Manca,* Emma Gallo*
10
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