Diethylammonium iodide as catalyst for the metal-free synthesis of 5-aryl-2-oxazolidinones from aziridines and carbon dioxide

Article abstract of DOI:10.1039/d1ob00458a

The catalytic potential of ammonium halide salts was explored in the coupling reaction of a model aziridine with carbon dioxide, highlighting the superior activity of [NH2Et2]I. Then, working at room temperature, atmospheric CO2 pressure and in the absenc

Full text of DOI:10.1039/d1ob00458a

Organic &
Biomolecular Chemistry
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PAPER
Diethylammonium iodide as catalyst for the
metal-free synthesis of 5-aryl-2-oxazolidinones
from aziridines and carbon dioxide†
Cite this: Org. Biomol. Chem., 2021,
19, 4152
Giulio Bresciani, a,b Marco Bortoluzzi,
*
b,c Guido Pampaloni a,b and
a,b
Fabio Marchetti
*
The catalytic potential of ammonium halide salts was explored in the coupling reaction of a model aziri-
dine with carbon dioxide, highlighting the superior activity of [NH2Et2]I. Then, working at room tempera-
ture, atmospheric CO2 pressure and in the absence of solvent, the [NH2Et2]I-catalyzed synthesis of a
series of 5-aryl-2-oxazolidinones was accomplished in good to high yields and excellent selectivity, from
2-aryl-aziridines with N-methyl or N-ethyl groups. NMR studies and DFT calculations outlined the pivotal
role of both the diethylammonium cation and the iodide anion. The proposed method represents a con-
venient choice for obtaining a limited number of valuable molecules for which more complex and more
expensive catalytic systems have been reported even in recent years.
Received 9th March 2021,
Accepted 19th April 2021
DOI: 10.1039/d1ob00458a
rsc.li/obc
urized conditions are often required and a catalyst is strictly
necessary, either metal based15,16 or not.17,18
Introduction
The employment of carbon dioxide as a sustainable, non-toxic
In fact, the catalyst-free synthesis of 5-aryl-2-oxazolidinones
and largely available C1 synthon for organic synthesis, repla- from aziridines has been forced at temperatures above 100 °C
cing hazardous compounds, has witnessed an increasing and at 3.5–10.0 MPa CO2 pressure, affording products in
advance in recent years.1 In this setting, oxazolidinones are 30–90% yields;19 in the absence of a catalyst, drastic con-
five-membered heterocyclic compounds that are key precursors ditions are avoided only using a special apparatus (high-speed
for the manufacture of bioactive chemicals,2,3 and synthetic ball milling).20
processes exploiting CO2 fixation routes have been intensively
Most of the metal-catalysed reactions, and even some orga-
investigated.2a,4 In general, the available methods require the nocatalytic systems,18,21 require a Lewis base additive to facili-
use of a catalyst, unless high pressure of CO2 or supercritical tate the aziridine ring opening, and tetrabutylammonium
conditions are employed.5 A variety of suitable unsaturated halides have been widely employed in this regard.16 The direct
organic substrates (e.g. amines and amino-alcohols6,7) and catalytic effect of simple halide salts has been sparingly inves-
also appropriate combinations of reactants have been evalu- tigated, and in some cases (tetraalkyl)ammonium halides
ated for their coupling with carbon dioxide, such as epoxide/ alone have revealed some potential to promote the aziridine/
amine,8 alkyne/amine,9 aniline/1,2-dibromoethane,10 alkene/ CO2 coupling. Working at ambient conditions, 2-methyl-aziri-
amine11
and
amine/(2-bromo-1-aryl)dimethylsulfonium dine was converted to 4-methyl-1,3-oxazolidin-2-one in organic
salts.12 The use of aziridines for their direct coupling with CO2 solvent by means of [NBu4]X (X = Cl, Br, I), Scheme 1A, and
is appealing from the point of view of the atom economy,13 [NBu4]Br in THF solution revealed to be the best choice (95%
but is featured by a high activation barrier;14 therefore, press- yield). The alternative use of lithium/sodium halides needed a
considerably higher amount of salt (20% mol) to provide satis-
fying yields, which are increased upon addition of 18-crown-
aUniversity of Pisa, Department of Chemistry and Industrial Chemistry,
6.22 Similarly, the carboxylation of a small series of aziridines
Via Moruzzi 13, I-56124 Pisa, Italy
bCIRCC, via Celso Ulpiani 27, I-70126 Bari, Italy.
by lithium iodide, in THF solution at room temperature and
normal CO2 pressure, required a stoichiometric amount of salt
(1.5 equivalents vs. aziridine), Scheme 1B; the addition of
hexamethylphosphoramide (HMPA) as a co-solvent improved
the regioselectivity of the reaction.23 On the other hand, rela-
tively low amounts of LiBr efficiently operate under drastic
conditions.24–26
E-mail: fabio.marchetti1974@unipi.it, markos@unive.it; https://people.unipi.it/
fabio_marchetti1974/
cUniversity of Venezia “Ca’ Foscari”, Department of Molecular Science and
Nanosystems, Via Torino 155, I-30170 Mestre (VE), Italy
†Electronic supplementary information (ESI) available: NMR studies, DFT opti-
mized structures, NMR spectra. Cartesian coordinates of the DFT-optimized
structures are collected in a separated .xyz file. See DOI: 10.1039/d1ob00458a
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Results and discussion
We studied the coupling between 1-methyl-2-phenylaziridine
and carbon dioxide as model reaction, and several
a
ammonium salts were evaluated as possible catalysts by 1H
NMR spectroscopy. The results of this study are compiled in
Table 1. The reaction was conducted in the absence of solvent
at ambient temperature and atmospheric pressure of CO2 from
a balloon. Fixing the catalyst concentration to 2 mol%,
3-methyl-5-phenyloxazolidin-2-one was produced in variable
yields after 24 hours. Tetramethylammonium iodide and tetra-
hexylammonium bromide revealed totally inactive, while other
tetraalkylammonium iodides and [NBu4]Br led to the for-
mation of the desired product in 15–29% yields. This fact
suggests that a balance between steric and electronic factors
related to the nitrogen substituents is crucial to provide
activity. Moreover, iodide salts manifested higher efficiency
than the homologous chlorides and bromides (compare runs
3–5 and 12–14). Overall, ammonium iodides performed as the
best catalysts of the series with [NH2Et2]I leading to the
highest yield of product (78%, run 14).
Scheme 1 Overview of previously investigated aziridine/CO2 coupling
reactions promoted by (alkyl)ammonium halides and alkali metal halides
in mild conditions. (A) Catalyst (equivalents vs. aziridine, yield): [NBu4]Cl
(0.02, 22%), [NBu4]Br (0.02, 10–95%), [NBu4]I (0.02, 63%), LiCl (0.20,
traces), LiBr (0.20, 74%), LiI (0.20, 32%), NaBr (0.20, 37%), NaBr (0.20 +
0.05 18-crown-6, 76%), KBr (0.20 + 0.05 18-crown-6, 62%); solvent:
THF, MeCN or MeOH; pCO2 = 1 atm; T = 0–40 °C; reaction time =
24 h.22 (B) Catalyst (equivalents vs. aziridine, yield): LiI (1.5, 83–99%), LiI
(1.0 + 1.0 HMPA, 88–91%); solvent: THF; pCO2 = 1 atm; T = room temp-
erature; reaction time = 4 h.23 (C) Catalyst (equivalents vs. aziridine,
yield): [NH4]Cl (1.0, 0%), [NH4]Br (1.0, 0%), [NH4]I (1.0, 94%), LiCl (1.0,
33%), LiBr (1.0, 76%), LiI (1.0, 85%), NaCl (1.0, 0%), NaBr (1.0, 27%), NaI
(1.0, 83%); solvent: THF; pCO2 = 3 atm; T = room temperature; reaction
time = 4 h; the use of [NH4]I (5 mol%) at pCO2 = 4 atm provided 98%
yield of product after 2 h; I/II ratio variable between 66/34 and 99/1.27
Table 1 Synthesis of 3-methyl-5-phenyloxazolidin-2-one from 1-methyl-
2-phenylaziridine and carbon dioxide
Aziridine
(mg, mmol)
Catalyst,
mol% (mg)
t
Yielda
(%)
A range of halide salts was explored for carrying out the car-
boxylation of N-benzyl-2-methylaziridine in THF at room temp-
erature and 4 atm of CO2 pressure (Scheme 1C).27 Two regio-
isomers were generally obtained, and ammonium iodide per-
formed better than lithium and sodium salts under stoichio-
metric conditions. Ammonium iodide was efficient also in a
catalytic amount, and its favourable action was attributed to
the preliminary formation of an aziridinium cation.
This scenario prompted us to systematically investigate the
catalytic potential of alkylammonium halides in the synthesis
of oxazolidinones from aziridines via CO2 fixation, with a par-
ticular focus on partially alkylated ammonium species, which,
to the best of our knowledge, have never been evaluated here-
tofore. No solvent, room temperature and atmospheric
pressure of carbon dioxide were adopted as fixed experimental
conditions, due to sustainability issues. Note that working
under 1 atm CO2 pressure is an added value also for safety
reasons, allowing to conduct the synthesis using common lab-
oratory glassware and a simple, safe and cheap balloon tech-
nique, without the needing of any pressurized equipment.
The results of this work will be presented, including DFT
calculations giving insight into the higher performance pro-
vided by the use of a dialkylammonium halide as catalyst.
Run
Catalyst
(° C)
1
2
3
4
5
6
7
8
(133, 1.00)
(135, 1.01)
(130, 0.98)
(133, 1.00)
(136, 1.02)
(130, 0.98)
(133, 1.00)
(135, 1.01)
(136, 1.02)
(133, 1.00)
(136, 1.02)
(133, 1.00)
(130, 0.98)
(130, 0.98)
(135, 1.01)
(133, 1.00)
(133, 1.00)
(130, 0.98)
(136, 1.02)
(133, 1.00)
(136, 1.02)
(130, 0.98)
(136, 1.02)
(136, 1.02)
[NMe4]I
[NEt4]I
[NBu4]Cl
[NBu4]Br
[NBu4]I
[NBu4]I
[NBu4]I
[NHex4]Br
[NMe3Bn]I
[NHEt3]I
[NH2Me2]I
[NH2Et2]Cl
[NH2Et2]Br
[NH2Et2]I
[NH2Et2]I
[NH2Et2]I
[NH2Et2]I
[NH2Et2]I
[NH2iEt2]I
[NH2 Pr2]I
[NH3Me]I
[NH3Et]I
[NH3Cy]I
[NH4]I
2 (4.0)
2 (5.2)
2 (5.4)
2 (6.4)
1 (3.8)
2 (7.2)
5 (15)
2 (8.8)
2 (5.6)
2 (4.6)
2 (3.5)
2 (2.2)
2 (3.0)
2 (3.9)
1 (2.0)
5 (10)
21
21
21
21
21
21
21
21
21
21
21
21
21
21
21
21
0
35
21
21
21
21
21
21
0
15
5
20
30
29
65
Traces
26
74
70
0
25
78
66
82
50
53
75
72
58
67
68
73
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
5 (10)
5 (9.8)
10 (20)
2 (4.6)
2 (3.2)
2 (3.4)
2 (4.6)
2 (2.9)
Experimental conditions: no solvent; pCO2 = 1 atm; t = 24 hours
a Calculated as integral ratio between the 1H NMR signals of ring CH
(product) and 1,1,2,2-tetrachloroethane as standard
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Different concentrations of diethylammonium iodide and
tetrabutylammonium iodide were then tested: the best result
was obtained by using [NH2Et2]I in a concentration of 5 mol%
(yield = 82%, run 16). An appreciable influence of the tempera-
ture was observed, and working at room temperature (ca.
21 °C) resulted to be the most favourable choice, presumably
representing a compromise between slow kinetics (low temp-
erature) and side reactions (high temperature).
Organic & Biomolecular Chemistry
Table 2 Carboxylation of aziridines to 5-aryl-2-oxazolidinones cata-
lysed by [NH2Et2]I under solventless and ambient conditions
Run
1
Aziridine (mg, mmol)
Oxazolidinone
Yielda (%)
0
2
3
20
0
Using the optimal reaction parameters found for the model
reaction, we extended the catalytic study to the carboxylation
of a series of 2-arylaziridines (Table 2). In general, variable
yields were recognized, mainly depending on the nature of the
nitrogen substituent. More precisely, the carboxylation of 1-H-
2-arylaziridines did not work or provided low yields of the
corresponding cyclic products after 24 hours (runs 1–4). This
result is probably ascribable to the prevalent occurrence of
side aziridine polymerization.28 On the other hand, the reac-
tions involving 1-methyl-2-arylaziridines led to the formation
of the oxazolidinones in 76–85% yields, including the first syn-
thesis of 3-methyl-5-(4-fluorophenyl)oxazolidin-2-one via the
aziridine/CO2 route (runs 5–8). The Me/Et replacement at nitro-
gen leads to a lower conversion, and the products were
detected in 28–66% yields, including the unprecedented
3-ethyl-5-(4-fluorophenyl)oxazolidin-2-one (runs 9–12). 1H
NMR analyses outlined the formation of aziridine oligomeriza-
tion species and piperazines as by-products, consistently to
previous findings.29
On further increasing the steric hindrance of the aziridine
N-substituent (isopropyl, n-butyl, cyclohexyl, tosyl), no reaction
took place. Moreover, the results shown in Table 2 evidence
some role of the aryl para-substituent, although a clear corre-
lation between its electronic and steric properties and the yield
values seems hard to be rationalized.
The synthesis, from the respective aziridine, of the products
indicated in Table 2 is not a trivial task, since more expensive/
elaborated catalytic systems and eventually drastic experi-
mental conditions have been reported, even recently, for the
same reactions. Note that ammonium halides are often
employed as co-catalysts, in a range of concentrations compar-
able to that adopted here for [NH2Et2]I.
4
5
6
17
82
76
7
8
85
81
In order to figure out possible differences in the mecha-
nism of action of different catalysts, the interaction between
equimolar amounts of 1-methyl-2-phenylaziridine and two
selected ammonium iodides was NMR investigated. Thus,
solutions of the aziridine in CD3CN were treated with [NBu4]I
and [NH2Et2]I, respectively. The addition of [NBu4]I did not
9
28
50
1
determine any appreciable change in the H NMR resonances
10
of the two mixed species over 4 days (Fig. S1†). Then, the
expected formation of 3-methyl-5-phenyloxazolidin-2-one was
cleanly observed upon bubbling CO2 to the solution (no
additional information was achieved by carrying out the reac-
tion directly under CO2 atmosphere). Conversely, mixing di-
ethylammonium iodide and 1-methyl-2-phenylaziridine
resulted in a downfield shift (from 3.15 to 2.98 ppm) and an
increase of the intensity of the signal due to the ammonium
protons (Fig. S2†). This variation is ascribable to the occur-
11
52
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Table 2 (Contd.)
tion with carbon dioxide leading to 3-methyl-5-phenyloxazoli-
din-2-one, catalysed by ammonium halides. Preliminary calcu-
lations indicate that the three-membered cycle is not opened
by the direct attack of iodide or bromide on the phenyl-substi-
tuted carbon. Therefore, the presence of an acidic species able
to interact with the nitrogen atom appears of paramount
importance for the subsequent coupling with CO2.24,31 Carbon
dioxide itself is a possible acid, and in fact, the transition state
for the aziridine ring-opening reaction by iodide in the pres-
ence of one CO2 molecule was found (N-CO2 bond length =
1.497 Å). This transition state is 36.5 kcal mol−1 higher than
the free reactants and presumably involved in the case of the
reaction promoted by [NBu4]I, being the tetrabutylammonium
cation unable to interact with the aziridine/iodide system, in
agreement with NMR studies (see above).
Much lower energy barriers were obtained on considering
[NH2Et2]+ as Brønsted acid. The computed reaction profiles for
the formation of 3-methyl-5-phenyloxazolidin-2-one by
[NH2Et2]X (X = Br, I) are shown in Fig. 1. Coherently with NMR
experiments (see above), the cation gives hydrogen bond inter-
action with the aziridine, with modest Gibbs energy variation
with respect to the reactants (step a, Fig. S3†). The nucleophilic
Run
12
Aziridine (mg, mmol)
Oxazolidinone
Yielda (%)
66
Experimental conditions: aziridine ca. 1 mmol (no solvent); catalyst:
[NH2Et2]I, 5 mol%; pCO2 = 1 atm; t = 24 hours. a Calculated as integral
ratio between the 1H NMR signals of ring CH (product) and 1,1,2,2-tet-
rachloroethane as standard.
rence of N–H⋯N hydrogen bonding between the diethyl-
ammonium cation and the aziridine nitrogen, as previously
described for analogous systems.30 After 15 hours in the
absence of CO2, a complicated mixture of products was
detected, presumably derived from oligomerization and cycli-
zation processes;29a this fact highlights the major activating
power towards the aziridine of [NH2Et2]I compared to [NBu4]I.
1-Methyl-2-phenylaziridine was selected as a model sub-
strate for the computational investigation of the coupling reac-
Fig. 1 Computed reaction profiles for the conversion of 1-methyl-2-phenylaziridine and carbon dioxide to 3-methyl-5-phenyloxazolidin-2-one,
catalysed by [NH2Et2]X (X = Br, red; X = I, violet). C-PCM/ωB97X/def-SVP calculations, ε = 8.9. Gibbs energy values (kcal mol−1) are referred to the
free reactants.
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attack of X− to the C(Ph) carbon atom affords the first transition of these species. Here, we have carried out a screening study
state of the reaction (step b, Fig. S4†), then the ammonium evidencing diethylammonium iodide as a convenient catalyst
acidic hydrogen is transferred to the aziridine. The consequent for the regiospecific conversion of 2-arylaziridines, bearing
ring-opening species (step c, Fig. S5†) is best described as a sec- small N-alkyl substituents, to the corresponding 5-aryl-2-oxazo-
ondary amine with hydrogen bond interaction with diethyl- lidinones under environmentally benign conditions (room
amine. The bromide-derivative is about 9.2 kcal mol−1 more temperature and atmospheric CO2 pressure). Combined, NMR
stable than the corresponding iodide-one, due to the higher and DFT results suggest that the optimal activity provided by
stability of the C–Br bond with respect to C–I. The nitrogen [NH2Et2]I arises from its nature of Brønsted acid associated
atom of the amino group is able to attack CO2, assisted by with a satisfying strength of the conjugate base, and the rela-
hydrogen bond interaction with diethylamine. The non-proto- tive weakness of the carbon-iodine bond, favouring the final
nated oxygen atom can give intramolecular nucleophilic attack cyclization step of the reaction.
to the halido-substituted carbon (step f, Fig. S8†). This is fol-
Although the applicability of the present method is not
lowed by generation of the oxazolidinone ring with strong nega- broad and has not been extended to 2-alkyl-aziridines, it pro-
tive Gibbs energy variation, the [NH2Et2]+ cation binding the vides a clear advance, in terms of simplicity and sustainability,
carbonyl moiety via hydrogen bond (step g, Fig. S9†).
for the synthesis of a series of valuable molecules with respect
In summary, DFT outcomes point out multiple roles played to existing literature procedures.
by the diethylammonium cation in the catalytic reaction, and
in particular: (1) the initial protonation of the aziridine nitro-
gen to trigger the ring-opening and stabilize the intermediate
amine species; (2) the hydrogen bond interaction with the
amine, facilitating the nucleophilic attack towards CO2; (3) the
Experimental section
General details
Operations were conducted in air. CO2 (99.99%) was purchased
protonation of the carbamate formed after interaction with
CO2; (4) the deprotonation of the O–H moiety during the final
cyclization step. The convenience in the use of [NH2Et2]+ prob-
ably relies on a compromise between the good Brønsted acidic
character (otherwise absent in [NBu4]+), favouring the protona-
tion steps, and the satisfying basicity of the conjugated base
provided by the two ethyl substituents, favouring the hydrogen
bond formation and deprotonation steps.
Concerning the halide counteranion, the comparison of the
two reaction profiles in Fig. 1 can be rationalized based on the
two different carbon–halogen bond strengths: it is worth remind-
ing that too stable intermediates are as detrimental to catalysis
as too high energy intermediates. Thus, the greater stability of
the C–Br bond lowers the energy barrier of the first step, and the
carbamic acid (step e) is much more stable for X = Br (rather
than X = I) compared to the reactants (ΔG = −7.5 kcal mol−1).
The stability of such an intermediate presumably slows down the
final cyclization step, requiring C–Br bond cleavage, and this
feature represents a possible explanation for the lower catalytic
activity exhibited by [NH2Et2]Br with respect to [NH2Et2]I.
from Rivoira, while other reactants and solvents were commer-
cial products (Merck, TCI Europe or Strem) of the highest
purity available, and stored under N2 as received. Solvents
(Merck) were distilled before use over appropriate drying
agents. 2-Arylaziridines17b and [NH3Cy]I32 were prepared
according to the respective literature procedures. NMR spectra
were recorded at 298 K with a Bruker Avance II DRX 400 instru-
ment equipped with a BBFO broadband probe. 1H and 13C
chemical shifts were referenced to the non-deuterated aliquot
of the solvent,33 while 19F chemical shifts were referenced to
an external standard (CFCl3). Elemental analyses were per-
formed on a Vario MICRO cube instrument (Elementar).
i
Synthesis and characterization of [NH2 Pr2]I
An excess of hydrogen iodide (ca. 20 mmol from a 57%
aqueous solution) was added dropwise to diisopropylamine
(1.00 mL, 7.14 mmol) in a Schlenk tube. The mixture was
stirred for 30 minutes, then ethanol (5 mL) was added. The
liquid phase was removed, and the precipitate was washed
with diethyl ether (3 × 10 mL) and then dried under vacuum. A
second crop of product was recovered from the initial solution
by re-crystallization using diethyl ether as non-solvent (15 mL)
at −30 °C. Total yield 1.55 g, 95%. Anal. calcd for C6H16NI: C,
31.46; H, 7.04; N, 6.11. Found C, 31.61; H, 7.09; N, 6.04. 1H
NMR (CDCl3): δ/ppm = 8.29 (br, 2H, NH2), 3.66 (m, 1H, CH),
1.61 (d, 3JHH = 6.7 Hz, 6H, CH3).
Conclusions
The development of sustainable synthetic routes to access
2-oxazolidones exploiting CO2 fixation is currently of large
interest. In particular, the aziridine/CO2 coupling reaction is
an atom economic process but possessing a high activation
barrier, whereby a wide range of catalysts has been proposed.
Nonambient temperature and/or pressure are often required
and elaborated catalytic systems have been reported, including
Synthesis, isolation and NMR characterizaion of 2-aryl-
aziridines
General procedure.17b Under N2 flux, a 250 mL round
the use of tetrabutylammonium halides as co-catalysts, when bottom flask containing a solution of Me2S (ca. 65 mmol) in
working under mild conditions. In this context, the catalytic dry CH3CN (15 mL) was cooled to 0 °C. To this solution, Br2
potential of ammonium halides alone has been barely (ca. 40 mmol) in dry CH2Cl2 (35 mL) was added dropwise over
explored, despite the easy availability and relatively low toxicity 15 minutes, thus [Me2SBr]Br formed as orange precipitate.12
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3
The system was stirred for further 30 minutes, then the appro- (m, 1H, CH); 2.14 (d, 1H, CH2, JHH = 6.2); 1.63 (d, 1H, CH2,
priate alkene (ca. 80 mmol) was added dropwise and the 3JHH = 3.1); 1.06 (br, 1H, NH).
resulting mixture was stirred for 2 hours at 0 °C. White solid
1-Methyl-2-(4-chlorophenyl)aziridine.35 From (2-bromo-1-(4-
[BrCH2C(SMe2)(4-C6H4R)]Br was recovered by filtration, chlorophenyl)ethyl)dimethylsulfonium bromide (6.18 mmol)
washed with Et2O (3 × 15 mL) and dried under vacuum. A and NH2Me (40% aqueous solution). Colourless liquid. Yield
portion of this solid (ca. 6 mmol) was dissolved in water 746 mg, 72% 1H NMR (CDCl3): δ/ppm = 7.27–7.14 (m, 4H,
(30 mL) and the selected amine (6 eq.) was added dropwise. C6H4); 2.48 (s, 3H, NMe); 2.24 (m, 1H, CH); 1.85 (d, 1H, CH2,
The mixture was stirred overnight at room temperature, 3JHH = 3.0); 1.63 (d, 1H, CH2, 3JHH = 6.7).
extracted with Et2O (3 × 20 mL) and dried over Na2SO4. The
1-Ethyl-2-(4-chlorophenyl)aziridine.17b From (2-bromo-1-(4-
volatiles were removed under vacuum and the residue was chlorophenyl)ethyl)dimethylsulfonium bromide (5.92 mmol)
chromatographed on a silica column; a mixture of ethyl and NH2Et (2 M tetrahydrofuran solution). Colourless liquid.
acetate and petroleum ether (40–60 °C) (from 1 : 10 to 1 : 6 v/v), Yield 742 mg, 69%. 1H NMR (CDCl3): δ/ppm = 7.38–7.22 (m,
added of triethylamine (5% v/v), as eluent allowed to isolate 4H, C6H4); 2.44 (m, 2H, NCH2); 2.25 (m, 1H, CH); 1.82 (d,
3
the aziridine product.
3JHH = 3.2, 1H, CH2); 1.64 (d, JHH = 6.7 Hz, 1H, CH2,); 1.18 (t,
2-Phenylaziridine.17b
From
(2-bromo-1-phenylethyl)di- 3JHH = 7.2 Hz, 3H, CH3).
methylsulfonium bromide (6.10 mmol) and NH3 (30%
2-(4-Fluorophenyl)aziridine.34 From (2-bromo-1-(4-fluoro-
aqueous solution). Colourless liquid. Yield 363 mg, 50% 1H phenyl)ethyl)dimethylsulfonium bromide (6.15 mmol) and
NMR (CDCl3): δ/ppm = 7.37–7.23 (m, 5H, Ph); 3.05 (m, 1H, NH3 (30% aqueous solution). Colourless liquid. Yield 388 mg,
3
3
1
CH); 2.29 (d, JHH = 6.0 Hz, 1H, CH2); 1.77 (d, JHH = 2.9 Hz, 46%. H NMR (CDCl3): δ/ppm = 7.39–7.24 (m, 4H, C6H4); 3.07
3
3
1H, CH2).
1-Methyl-2-phenylaziridine.17b From (2-bromo-1-pheny- 3.1 Hz, 1H, CH2); 1.23 (br, 1H, NH).
lethyl)dimethylsulfonium bromide (6.25 mmol) and NH2Me 1-Methyl-2-(4-fluorophenyl)aziridine. From (2-bromo-1-(4-
(m, 1H, CH); 2.30 (d, JHH = 6.3 Hz, 1H, CH2); 1.78 (d, JHH =
(40% aqueous solution). Colourless liquid. Yield 599 mg, 72%. fluorophenyl)ethyl)dimethylsulfonium bromide (6.28 mmol)
1H NMR (CDCl3): δ/ppm = 7.37–7.21 (m, 5H, Ph); 2.50 (s, 3H, and NH2Me (40% aqueous solution). Colourless liquid. Yield
3
NMe); 2.28 (m, 1H, CH); 1.91 (d, JHH = 3.2 Hz, 1H, CH2); 1.63 475 mg, 50%. 1H NMR (CDCl3): δ/ppm = 7.17, 6.97 (m, 4H,
(d, 3JHH = 6.7 Hz, 1H, CH2).
C6H4); 2.47 (s, 3H, NMe); 2.24 (m, 1H, CH); 1.84 (d, 1H, CH2,
1-Ethyl-2-phenylaziridine.17b From (2-bromo-1-phenylethyl) 3JHH = 3.4); 1.60 (d, 1H, CH2, JHH = 6.6). 13C NMR (CDCl3): δ/
dimethylsulfonium bromide (6.00 mmol) and NH2Et (2 M ppm = 162.0 (d, 1JCF = 244.5 Hz, CF); 136.0 (d), 127.6 (d), 115.1
tetrahydrofuran solution). Colourless liquid. Yield 600 mg, (d) (C6H4); 47.9 (NCH3); 41.7 (CH); 39.3 (CH2). 19F NMR
68%. 1H NMR (CDCl3): δ/ppm = 7.40–7.24 (m, 5H, Ph); (CDCl3): δ/ppm = −116.2. Anal. Calcd for C9H10FN: C, 71.50; H,
3
3
2.53–2.44 (m, 2H, NCH2); 2.34 (m, 1H, CH); 1.94 (d, JHH = 3.2 6.67; N, 9.26. Found: C, 71.43; H, 6.75; N, 9.23.
3
3
Hz, 1H, CH2); 1.68 (d, JHH = 6.7 Hz, 1H, CH2); 1.26 (t, JHH
=
1-Ethyl-2-(4-fluorophenyl)aziridine. From (2-bromo-1-(4-
7.2 Hz, 3H, CH3).
fluorophenyl)ethyl)dimethylsulfonium bromide (5.96 mmol)
2-(p-Tolyl)aziridine.34 From (2-bromo-1-(p-tolyl)ethyl)di- and NH2Et (2 M tetrahydrofuran solution). Colourless liquid.
methylsulfonium bromide (6.00 mmol) and NH3 (30% Yield 581 mg, 59%. Colourless liquid. 1H NMR (CDCl3): δ/ppm
aqueous solution). Colourless liquid. Yield 344 mg, 43%. 1H = 7.38–7.22 (m, 4H, C6H4); 2.44 (q, JHH = 7.2 Hz, 2H, NCH2);
3
3
NMR (CDCl3): δ/ppm = 7.14 (m, 4H, C6H4); 3.00 (m, 1H, CH); 2.29 (m, 1H, CH); 1.86 (d, 1H, CH2, JHH = 3.2); 1.65 (d, 1H,
2.35 (s, 3H, C6H4Me); 2.18 (m, 1H, CH2); 1.81 (m, 1H, CH2); CH2, JHH = 6.7); 1.20 (t, 3H, CH3, JHH = 7.2); 13C NMR
3
3
1.68 (br, 1H, NH) ppm.
(CDCl3): δ/ppm = 161.9 (d, 1JCF = 244.6 Hz, CF); 136.3 (d), 127.8
1-Methyl-2-(p-tolyl)aziridine.35 From (2-bromo-1-(p-tolyl) (d), 115.1 (d) (C6H4); 55.8 (NCH2), 40.5 (CH); 37.5 (CH2); 14.5
ethyl)dimethylsulfonium bromide (5.95 mmol) and NH2Me (CH3). 19F NMR (CDCl3): δ/ppm = −116.3. Anal. Calcd for
(40% aqueous solution). Colourless liquid. Yield 613 mg, 70% C10H12FN: C, 72.70; H, 7.32; N, 8.48. Found: C, 72.75; H, 7.37;
1H NMR (CDCl3): δ/ppm = 7.16 (m, 4H, C6H4); 2.52 (s, 3H, N, 8.43.
3
NMe); 2.37 (s, 3H, C6H4Me); 2.28 (m, 1H, CH); 1.92 (d, JHH
3.2 Hz, 1H, CH2); 1.64 (d, 3JHH = 6.7 Hz, 1H, CH2).
=
Synthesis and NMR characterization of 5-aryloxazolidin-2-ones
1-Ethyl-2-(p-tolyl)aziridine.17b From (2-bromo-1-(p-tolyl)
General procedure. The appropriate amount of ammonium
ethyl)dimethylsulfonium bromide (6.30 mmol) and NH2Et (2 salt (according to Table 1) was introduced into a Schlenk tube,
M tetrahydrofuran solution). Colourless liquid. Yield 660 mg, which was evacuated by a vacuum pump and then filled with
1
65%. H NMR (CDCl3): δ/ppm = 7.13 (m, 4H, C6H4); 2.52–2.36 CO2. The vacuum/CO2 sequence was repeated twice. Under a
(m, 2H, NCH2); 2.33 (s, 3H, C6H4Me); 2.28 (m, 1H, CH); 1.89 stream of carbon dioxide, the selected aziridine (ca. 1 mmol)
3
3
(m, 1H, CH2); 1.64 (d, JHH = 6.7 Hz, 1H, CH2); 1.20 (t, JHH
7.2 Hz, 3H, CH3).
=
was added, and the resulting mixture was stirred for 24 hours
at room temperature under atmospheric pressure of carbon
2-(4-Chlorophenyl)aziridine.36 From (2-bromo-1-(4-chloro- dioxide from a balloon. A precise amount of 1,1,2,2-tetrachlor-
phenyl)ethyl)dimethylsulfonium bromide (6.06 mmol) and oethane (ca. 0.2 mL) was added as internal standard, then an
NH3 (30% aqueous solution). Colourless liquid. Yield 539 mg, aliquot (ca. 0.1 mL) of the mixture was mixed with CDCl3
1
1
58% H NMR (CDCl3): δ/ppm = 7.23–7.10 (m, 4H, C6H4); 2.92 (0.5 mL) in an NMR tube. Yield values were determined by H
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3
3
NMR spectroscopy and are referenced to 1,1,2,2- 4H, C6H4); 5.46 (t, JHH = 8.1 Hz, 1H, CH); 3.90, 3.42 (t, JHH
=
tetrachloroethane.
8.4 Hz, 2H, CH2); 2.93 (s, 3H, CH3).
3-Ethyl-5-(4-fluorophenyl)oxazolidin-2-one. From 1-ethyl-2-
5-Phenyloxazolidin-2-one.17b
From
2-phenylaziridine
1
(120 mg, 1.01 mmol) and carbon dioxide. H NMR (CDCl3): δ/ (4-fluorophenyl)aziridine (163 mg, 0.987 mmol) and carbon
3
ppm = 7.43–7.34 (m, 5H, Ph); 6.54 (br, 1H, NH); 5.61 (t, JHH
8.4 Hz, 1H, CH); 3.97, 3.54 (t, 3JHH = 8.4 Hz, 2H, CH2).
=
dioxide. In this case, the reaction mixture was dissolved in the
minimum volume of ethyl acetate, and this solution was
3-Methyl-5-phenyloxazolidin-2-one.17b,12 From 1-methyl-2- charged on a silica column. A mixture of ethyl acetate and pet-
1
phenylaziridine (133 mg, 1.00 mmol) and carbon dioxide. H roleum ether (40–60 °C) (from 1 : 10 to 1 : 4 v/v), added of tri-
NMR (CDCl3): δ/ppm = 7.41–7.26 (m, 5H, Ph); 5.48 (t, JHH
3
=
ethylamine (5% v/v), was used as eluent to collect the fraction
3
8.6 Hz, 1H, CH); 3.91, 3.44 (t, JHH = 8.6 Hz, 2H, CH2); 2.92 (s, corresponding to the product. Yield 132 mg, 64%. Anal. Calcd
3H, CH3). for C11H12FNO2: C, 63.15; H, 5.78; N, 6.69. Found: C, 63.20; H,
3-Ethyl-5-phenyloxazolidin-2-one.12,17b From 1-ethyl-2-phe- 5.77; N, 6.63. 1H NMR (CDCl3): δ/ppm = 7.34–7.30, 7.07–7.03
nylaziridine (148 mg, 1.00 mmol) and carbon dioxide. 1H NMR (m, 4H, C6H4); 5.45 (t, JHH = 8.3 Hz, 1H, CH); 3.91 (t, JHH
=
3
3
3
3
(CDCl3): δ/ppm = 7.29–7.20 (m, 5H, Ph); 5.33 (t, JHH = 8.7 Hz, 8.3 Hz, 1H, CH2); 3.41–3.25 (m, 3H, CH2 + NCH2); 1.15 (t, JHH
3
1
1H, CH); 3.80 (t, JHH = 8.7 Hz, 1H, CH2); 3.30–3.15 (m, 3H, = 7.3 Hz, 3H, CH3). 13C NMR (CDCl3): δ/ppm = 162.7 (d, JCF
=
CH2 + NCH2); 1.04 (t, 3JHH = 7.2 Hz, 3H, CH3).
246.6 Hz, CF); 161.5 (CvO); 134.6 (d), 127.5 (d), 115.8 (d)
5-(p-Tolyl)oxazolidin-2-one.12,37 From 2-(p-tolyl)aziridine (C6H4); 73.72 (CH); 51.5 (CH2); 38.8 (NCH2); 12.4 (CH3).
(136 mg, 1.02 mmol) and carbon dioxide. 1H NMR (CDCl3): 19F NMR (CDCl3): δ/ppm = −112.9.
δ/ppm = 7.31–7.22 (m, 4H, C6H4); 6.22 (br, 1H, NH); 5.60 (t,
3
DFT calculations
3JHH = 8.4 Hz, 1H, CH); 3.97, 3.56 (t, JHH = 8.4 Hz, 2H, CH2);
2.39 (s, 3H, CH3).
The ground- and transition state structures were optimized
3-Methyl-5-(4-tolyl)oxazolidin-2-one.12,16d From 1-methyl-2- using the hybrid B3PW91 DFT functional39 in combination
(p-tolyl)aziridine (150 mg, 1.02 mmol) and carbon dioxide. with Ahlrichs’ split-valence-polarized basis set, with ECP on
1H NMR (CDCl3): δ/ppm = 7.27–7.21 (m, 4H, C6H4); 5.46 the iodine atom.40 The C-PCM implicit solvation model was
3
3
(t, JHH = 8.4 Hz, 1H, CH); 3.90, 3.45 (t, JHH = 8.4 Hz, 2H, added to ωB97X calculations, considering a dielectric constant
CH2); 2.94 (s, 3H, NCH3); 2.38 (s, 3H, C6H4CH3).
ε = 8.9.41 The stationary points were characterized by IR simu-
3-Ethyl-5-(4-tolyl)oxazolidin-2-one.12,17b From 1-ethyl-2-(p- lations (harmonic approximation), from which zero-point
tolyl)aziridine (165 mg, 1.02 mmol) and carbon dioxide. vibrational energies and thermal corrections (T = 25 °C) were
1H NMR (CDCl3): δ/ppm = 7.20–7.13 (m, 4H, C6H4); 5.39 (t, obtained. The software used was Gaussian 09.42 Cartesian
3JHH = 8.3 Hz, 1H, CH); 3.83 (t, JHH = 8.6 Hz, 1H, CH2); coordinates of the DFT-optimized structures are collected in a
3
3.38–3.25 (m, 3H, CH2 + NCH2), 2.30 (s, 3H, C6H4CH3); 1.12 separated .xyz file.
(t, 3JHH = 7.3 Hz, 3H, CH2CH3).
5-(4-Chlorophenyl)oxazolidin-2-one.12,37 From 2-(4-chloro-
phenyl)aziridine (150 mg, 0.976 mmol) and carbon dioxide. Conflicts of interest
1H NMR (CDCl3): δ/ppm = 7.39–7.29 (m, 4H, C6H4); 6.49 (br,
3
3
There are no conflicts to declare.
1H, NH); 5.58 (t, JHH = 8.4 Hz, 1H, CH); 3.97, 3.49 (t, JHH
=
8.4 Hz, 2H, CH2).
3-Methyl-5-(4-chlorophenyl)oxazolidin-2-one.12,38
From
Acknowledgements
1-methyl-2-(4-chlorophenyl)aziridine (165 mg, 0.984 mmol)
1
and carbon dioxide. H NMR (CDCl3): δ/ppm = 7.38–7.28 (m,
The University of Pisa is acknowledged for funding
(PRA_2020_39).
3
3
4H, C6H4); 5.45 (t, JHH = 8.3 Hz, 1H, CH); 3.91, 3.40 (t, JHH
=
8.3 Hz, 2H, CH2); 2.92 (s, 3H, CH3).
3-Ethyl-5-(4-chlorophenyl)oxazolidin-2-one.12,15a
From
1-ethyl-2-(4-chlorophenyl)aziridine (183 mg, 1.01 mmol) and
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