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1

Aluminium Catalysed Oxazolidinone Synthesis and their
Conversion into Functional Non-Symmetrical Ureas
Victor Laserna,a Wusheng Guoa and Arjan W. Kleija,b*
a

b

Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 – Tarragona, Spain
Fax; (+34)-977920823; Tel.: (+34)-977920247; E-mail: akleij@iciq.es
Catalan Institute of Research and Advanced Studies (ICREA), Pg. Lluís Companys 23, 08010 – Barcelona, Spain

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. An efficient and practical aluminium-catalysed
approach towards a range of functional oxazolidinones is
reported. The method is based on cheap and readily available
starting materials including terminal and internal (bicyclic)
epoxides and phenylcarbamate. The oxazolidinones serve as
highly useful synthons for the high yield preparation of
nonsymmetrical ureas by nucleophilic ring-opening affor-

Introduction
Organic ureas are ubiquitous structures in organic
chemistry and their re-emerged application potential in
various areas of chemistry has been recently
highlighted.[1] Prominent fields where ureas have
gained
importance
include
(asymmetric)
organocatalysis[2,3] and supramolecular chemistry.[4]
Organocatalytic activation of organic substrates by
means of hydrogen-bonding patterns that comprise of
the two urea NH groups has been recognized as a
powerful tool to orientate carbonyl fragments in order
to increase the efficiency of various organic
conversions. Asymmetric ureas have also been
developed successfully and applied as enantiocontrolling mediators in, for instance, the asymmetric
Strecker reaction.[5] In the context of supramolecular
applications, N,N´-disubstituted urea derivatives have
proven to be versatile building blocks for the
preparation of hydrogen-bonded supramolecular
polymers,[6,7] helical type foldamers[8] and anion
transporting molecules.[9]
There exist various synthetic methods towards
nonsymmetrical ureas although in most cases reactive
species such as carbonylimidazolide[10] or (in situ
prepared) isocyanate reagents[11-13] are required
together with air-sensitive/toxic additives[14,15] and/or
expensive metal catalysts/ligands.[12] Therefore, we set
out to explore a practical synthesis of nonsymmetrical
ureas from readily available and cheap starting
materials combined with a highly modular nature of
the reaction partners (see Scheme 1). The approach
uses oxazolidinones (cyclic carbamates) as
intermediates that allow for nucleophilic ring-opening
by suitable amines. Such an approach is not
completely without precedence,[16,17] however so far

ding the targeted urea compounds with excellent functional
group diversity, and high regio-selectivity and isolated yields
up to >99%.
Keywords: aluminium; N,Oligands;
catalysis; oxazolidinones; ureas

homogeneous

oxazolidinone type intermediates have been rarely
used for the preparation of nonsymmetrical ureas with
wide scope[18-20] and thus a more general methodology
based on these precursors derived from readily
available, cheap epoxides and phenylcarbamate
(Scheme 1) would provide an attractive and simple
route towards highly functional ureas.

Scheme 1. A modular approach towards non-symmetrical
ureas through oxazolidinone intermediates.

Jacobsen et al. recently disclosed a method for the
formation of chiral amino-alcohols through a
Co(salen) mediated enantio-selective conversion of
meso-cyclic epoxides in the presence of
phenylcarbamate as nucleophile.[21] This approach
demonstrated the use of phenylcarbamate as a cheap
and readily available reagent in the formal transfer of
an “amide” unit to an epoxide giving enantio-enriched
oxazolidinones as intermediates towards the synthesis
of chiral amino-alcohols. However, the reported
method was restricted to a limited number of cyclic
epoxides. In order to be able to develop a more general

2

method towards oxazolidinone precursors en route to
nonsymmetrical ureas, we envisioned that our
previously
reported
Lewis
acidic
Al(aminotriphenolate) catalysts would present an
alternative catalyst for oxazolidinone formation
(Scheme 1). Recently we showed that both internal as
well as terminal epoxides are easily activated towards
nucleophilic ring-opening by these catalyst systems to
form highly functional cyclic carbonates in the
presence of carbon dioxide.[22-24] In this work we will
show that these Al-catalysts provide easy access to a
wide range of oxazolidinone precursors useful for a
modular approach towards highly functionalized ureas
that are generally obtained in excellent yield and regioselectivity.

Results and Discussion
We first set out to test a small series of
Al(aminotriphenolate) complexes A-C (Figure 1) in
the synthesis of oxazolidinone 1 under various
conditions (Table 1) using the coupling of cyclohexene
oxide (CHO) and phenylcarbamate as a benchmark
reaction. The reaction without the addition of catalyst
does not proceed at 50ºC (entry 1), and at 70ºC only
low conversion of the phenylcarbamate reagent is
noted. In general we found that those reactions that
were carried out at this latter temperature (entries 2,
58 and 1415) caused (partial) decomposition of the
carbamate reagent and the white precipitates noted
could be isolated and assigned to the formation of
1,3,5-triazine-2,4,6(1H, 3H, 5H)-trione, a cyclic
structure supported by 1H, 15N, 13C NMR and IR
analysis (see Supporting Information).

Figure 1. Al-catalysts AC used in this work.

Therefore, we decided to optimize further the catalysis
conditions at 50ºC using various catalysts, catalyst
loadings and amount of the epoxide (CHO). Alcatalyst A performs much better than B (cf., entries 58) but its use results in moderate substrate conversion
levels at 50ºC (entries 3 and 4). Much better activity
was noted for the chloride-substituted Al-complex C
for which a loading of 2.5 mol% and an equimolar
amount of epoxide (entry 11) already provided 81%
conversion. Further increasing the epoxide/carbamate
ratio to 2 led to nearly full conversion (95%) with a
high isolated yield (89%) for the oxazolidinone
product (entry 9). Therefore, the reaction conditions of

this latter entry seem to be rather ideal for the synthesis
of oxazolidinone 1.

Table 1. Screening of catalyst structures A-C and reaction
conditions in the synthesis of oxazolidinone 1 from
cyclohexene oxide and phenylcarbamate.[a]
CHO
T
Conv.[b]
[mmol]
[ºC]
[%]
1
1.0
50
0


2
1.0
70
17[c]


3
2.5
1.0
50
41
A
4
5.0
1.0
50
47
A
5
2.5
1.0
70
94[c]
A
6
5.0
1.0
70
99[c]
A
7
2.5
1.0
70
10[c]
B
8
5.0
1.0
70
15[c]
B
9
2.5
1.0
50
95(89)[d]
C
10
5.0
1.0
50
99
C
11
2.5
0.5
50
81
C
12
2.5
0.75
50
84
C
13
2.5
2.0
50
99
C
14
1.0
1.0
70
99[c]
C
15
2.5
1.0
70
99(71)[c,d]
C
[a]
General conditions: 0.5 mmol phenylcarbamate, catalyst
A-C (05 mol%), 18 h, CH3CN. [b] Conversion determined
by 1H NMR (CDCl3) based on phenol formation. [c] White
precipitate noted. [d] Isolated yield of oxazolidinone product
in brackets.
Entry

Cat.

Amount
[mol%]

Once discovered the best conditions for the conversion
of CHO into product 1 using the most effective Al
catalyst (i.e., C), we then started to investigate the
scope of this process (Scheme 2). In general, this Almediated synthesis allows for a wide range of
(functional) groups to be present in the epoxide
substrate including alkene (2 and 4), alkyl halide (5),
arylbromide (9), epoxidic (8), alkyne (13) and ether
(10 and 13-15) groups. Of further note are the
syntheses of oxazolidinones 11 and 16 and compounds
13 that comprise of an (a)cyclic dialkyl-substituted
pattern. The alternative formation of acyclic and cyclic
4,5 and 5,5´disubstituted oxazolidinone regioisomers
from
aziridenes/CO2[25-27],
[28,29]
epoxide/isocyanate
or propargylic amine/CO2[30]
substrate combinations typically require harsher
reaction conditions, a higher loading of catalyst and/or
the use of stoichiometric/expensive additives and more
elaborative procedures. The method disclosed here
towards oxazolidinones 116 is operationally simple
and allows for high conversion under attractive
reaction conditions (50ºC, 2 mol% of catalyst). The
majority of the oxazolidinone compounds could be
isolated in good yields (up to 91%) and high regioselectivity for the 5isomer was noted with some

3

exceptions (cf., the synthesis of 9, 12 and 16). Since
these reactions occur with inversion of configuration
at the carbon centre at the initial stage of the reaction
(i.e., nucleophilic attack of the carbamate reagent onto
the epoxide-Al complex), those reactions that involve
cis-configured carbon centres in the oxirane unit give
rise to oxazolidinones with a trans disposition (cf.,
syntheses of 1-3 and 11a). Thus these conversions
proceed with formal inversion unlike the reactions
between isocyanates and epoxides.[29]

dual character: the aminotriphenolate ligand acts here
as a proton relay mediator increasing the nucleophilic
character of the alkoxide which allows a more efficient
ring-closing to occur releasing the final
(configurationally inverted) product and a phenoxide
as a leaving group.[31] The formation of phenol, as a
result of the phenoxide abstracting a proton, is easily
recognized in the reaction mixture and thus allows for
following the course of the process (see Table 1,
Scheme 3).

Scheme 3. Proposed mechanism leading to formal inversion
in cis-2,3-dimethyloxirane.

Scheme 2. Synthesis of oxazolidinones 116 from various
epoxides and phenylcarbamate catalysed by Alaminotriphenolate complex C (2 mol%). Reported here are
isolated yields after column purification; selectivities refer
to regio-isomers formed in the case of terminal epoxide
conversion (note: only the major isomer is shown).

This inversion pathway was further substantiated by
the synthesis of 11b (cis diastereoisomer of 11a; dr >
99%) that was prepared from the trans-epoxide.
The envisioned mechanism involves a nucleophilic
attack of the phenyl carbamate on the coordinated
epoxide producing a reactive alkoxide which is
stabilized by the Al complex (Scheme 3) displaying

The oxazolidinones 1-16 serve as useful precursors
towards the formation of highly functional,
nonsymmetrical ureas as shown in Scheme 4.
Treatment of the respective oxazolidinone precursor
with a suitable amine (1.24 equiv) allows for
isolation of the urea product in high yield and chemoselectivity. The aminolysis of the oxazolidinone
occurs with exclusive preference for scission of the
NHC=O bond. The formation of ureas 17-24, 27 and
28 from bicyclic oxazolidinones proceeds generally
under mild reaction conditions in the presence of a
small excess of amine reagent in CH3CN solvent. This
procedure is attractive, practical and proceeds with full
conversion of the starting materials. In the case where
oxazolidinones derived from terminal epoxides are
used as starting materials (i.e., 25, 26 and 29-32), the
aminolysis reaction required generally higher
temperature, longer reaction times and a larger excess
of amine reagent (4 equiv) under solvent-free
conditions. In the latter cases, somewhat lower isolated
yields are noted (up to 73%).
The scope demonstrated in Scheme 3 illustrates that
highly functionalized ureas can be prepared including
those incorporating pyrrolidine (17), alkene (19, 23, 25
and 29), alkyne (20 and 31), heterocyclic (17, 24, 25,
27, 31 and 32), alkyl amine (28) and vicinal diol (26)
groups. Note that urea 26 is derived from the
oxazolidinone 5 which is based on the initial use of
epichlorohydrin. The longer reaction time needed to
convert 5 into 26 resulted in effective hydrolysis of the
alkyl chloride fragment which is in line with the
recorded NMR data and mass spectrometric analysis
(see Supporting Information).

4

Figure 2. X-ray molecular structure determined for urea 27.
Selected interatomic distances (Å) and angles (º) with esd´s
in parentheses: N(1A)-C(1A) = 1.366(5), N(2A)-C(1A) =
1.356(5), C(1A)-O(1A) = 1.248(5), N(2A)-C(6A) =
1.449(5); N(1A)-C(1A)-N(2A) = 117.8(4), N(1A)-C(1A)O(1A) = 120.4(4), N(2A)-C(1A)-O(1A) = 121.8(4).

The diversity of functional groups in the presented
scope of urea products has potential in post-synthetic
modifications as shown in Scheme 5. To demonstrate
further use of these scaffolds, urea 13 was subjected to
“click” chemistry conditions using benzyl azide as
coupling partner: this afforded the triazole 34
smoothly in 91% yield.[32] The use of click reactions to
functionalize
polymer
supports
or
other
macromolecular structures is interesting for
catalytic[33] and supramolecular applications[34,35] and
therefore this chemistry combined with suitable urea
synthons opens up new opportunities in
aforementioned areas.

Scheme 4. Synthesis of nonsymmetrical ureas 1732 from
oxazolidinone precurcors and primary/secondary amines.
Reported yields are isolated ones after column
purification/crystallization.

Both primary as well as secondary amines (cf.,
syntheses of 17, 22, 27 and 32) react smoothly with the
oxazolidinone precursors further amplifying the
potential scope of this urea formation reaction. The
molecular structure of urea 27 (Figure 2) was
determined by X-ray diffraction. Compound 27 was
derived from oxazolidinone 1. Thus, the relative
configuration of the urea and the free alcohol groups
(trans) is further testament of the proposed inversion
mechanism as depicted in Scheme 3.

Scheme 5. Synthetic potential of urea 13.

Conclusion
We here disclose a simple but effective two-step
method for the formation of highly functional,
nonsymmetrical ureas from easy to prepare
oxazolidinones. The cyclic carbamates are derived
from cheap and readily available epoxides and
phenylcarbamate mediated through Al-catalysis. The
method is further characterized by its operational
simplicity and wide scope in ureas that can be attained.

5

Further to this, these functional ureas may serve as
suitable scaffolds in organic synthesis which can be
post-modified using “click” type reactions as
demonstrated herein.

Experimental Section

Accreditation 2014-2018 (SEV-2013-0319) and project CTQ201460419-R for support. W.G. thanks the CELLEX foundation for
financial support and V.L. wishes to acknowledge the Generalitat
de Catalunya for an FI fellowship. Eduardo C. Escudero-Adán and
Dr. Eddy Martin are thanked for the X-ray crystallographic
analysis.

References

Oxazolidinone Synthesis
Typically, phenyl carbamate (1 mmol), the epoxide (2
mmol), the aluminium catalyst (2 mol%) and acetonitrile (2
mL) were introduced into a glass vial (5 ml) equipped with
a stirring bar. The vial was closed and introduced into a
silicon oil bath preheated at the desired reaction temperature
(5070ºC) and stirred for 18 h. Once the reaction mixture
had cooled down to r.t. the product was purified by flashcolumn chromatography following analysis. Full
characterization data and copies of relevant spectra are
provided in the Supporting Information.
Urea Synthesis
Typically, the oxazolidinone (0.5 mmol) was introduced
into an HPLC vial equipped with a stirring bar. For the
oxazolidinones based on bicyclic scaffolds, the amine
reagents were introduced (usually 1.2 equiv but was risen to
1.8 equiv when dealing with volatile amines) with addition
of acetonitrile (0.2 mL) and heated to the desired
temperature (50ºC) for 18 h. Once the reaction mixture had
cooled down to r.t. the pure product was isolated by
evaporation of the excess of amine, and the crude ureas
recrystallized from dichloromethane (ureas 20, 21, 23, 24,
27 and 28) or purified by flash column chromatography. The
oxazolidinones with monocyclic scaffolds were treated with
the respective amine reagent (4 equiv) under neat conditions
and heated to 70ºC for 66 h. The products were then isolated
by recrystallization from dichloromethane (for urea 29) or
purified by flash column chromatography. Full
characterization data and copies of relevant spectra are
provided in the Supporting Information.
Crystallographic Studies
The measured crystal was stable under atmospheric
conditions; nevertheless it was treated under inert conditions
immersed in perfluoro-polyether as protecting oil for
manipulation. Data Collection: measurements were made
on a Bruker-Nonius diffractometer equipped with an
APPEX II 4K CCD area detector, a FR591 rotating anode
with Mo Kα radiation, Montel mirrors and a Kryoflex low
temperature device (T = −173 °C). Full-sphere data
collection was used with ω and φ scans. Programs used:
Data collection Apex2 V2011.3 (Bruker-Nonius 2008), data
reduction Saint+Version 7.60A (Bruker AXS 2008) and
absorption correction SADABS V. 2008−1 (2008).
Structure Solution: SHELXTL Version 6.10 (Sheldrick,
2000) was used.[36] Structure Refinement: SHELXTL-97UNIX VERSION. Crystal data for 27: C11H20N2O3, Mr =
228.29, triclinic, P-1, a = 6.4520(13) Å, b = 9.1250(18) Å,
c = 20.031(4) Å,  = 92.00º,  = 92.90º,  = 90.06º, V =
1177.1(4) Å3, Z = 4, ρ = 1.288 mg·M−3,  = 0.094 mm−1, 
= 0.71073 Å, T = 100(2) K, F(000) = 496, crystal size = 0.15
 0.04  0.01 mm, (min) = 1.018°, (max) = 27.67°, 5421
reflections collected, 5421 reflections unique, GoF = 1.061,
R1 = 0.0812 and wR2 = 0.1951 [I > 2σ(I)], R1 = 0.1438 and
wR2 = 0.2367 (all indices), min/max residual density =
−0.716/0.718 [e·Å−3]. Completeness to θ(27.67°) = 98.9%.
CCDC number 1405849.

Acknowledgements
We thank ICIQ, ICREA and the Spanish Ministerio de Economía y
Competitividad (MINECO) through Severo Ochoa Excellence

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7

FULL PAPER
Expedient Synthesis of Functionalized NonSymmetrical Ureas from Oxazolidinone Precursors
Adv. Synth. Catal. 2015, 357, Page – Page
Victor Laserna, Wusheng Guo, Arjan W. Kleij*

8