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1

Catalytic One-Pot Oxetane to Carbamate Conversions: Formal
Synthesis of Drug Relevant Molecules
Wusheng Guo,a Victor Laserna,a Jeroen Rintjemaa and Arjan W. Kleija,b*
a

b

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

Received: ###
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.2015###
Abstract. Oxetanes are versatile building blocks in drugrelated synthesis to induce property-modulating effects.
Whereas related oxiranes are widely used in coupling
chemistry with carbon dioxide (CO2) to afford value-added
commodity chemicals, oxetanes/CO2 couplings remain
extremely limited despite the recent advances in the synthesis
of these four-membered heterocycles. Here we report an
effective one-pot three-component reaction (3CR) strategy for
the coupling of (substituted) oxetanes, amines and CO2 to
afford a variety of functionalized carbamates

Introduction
An upsurge in the use of oxetanes as molecular
scaffolds is currently observed in various fields of
chemical sciences.[1-4] Key areas of investigation
include their use as components of (biodegradable)
polymers,[5-7] as useful synthetic intermediates towards
more complex structures[8-11] and the incorporation of
these low molecular weight motifs into drug-like
molecules to attain improved physico-chemical
behavior.[3,12] Also, oxetane rings are found in
biologically relevant molecules such as taxol.[13]
We have become interested in the use of carbon
dioxide as a carbon feedstock in organic synthesis
thereby replacing fossil fuel based approaches.[14-17] A
successful method for CO2 conversion relies on the use
of coupling partners with a relative high free energy
(thermodynamic feasibility) combined with an
effective catalyst (kinetic feasibility) to mediate the
transformation to value added organic molecules.
Oxiranes have been often used as suitable reaction
partners and their coupling products with CO2 are
typically
cyclic[18]
or
polymeric
organic
[19,20]
carbonates.
While the field of oxirane/CO2
couplings has tremendously advanced over the years
and resulted in highly active, selective and/or
sustainable catalyst systems, the corresponding
oxetane/CO2 coupling reaction has seldom been
studied and successfully accomplished.[21-23] We
recently reported a rather general method for the
coupling of (functional) oxetanes and CO2 to produce
their six-membered organic carbonates.[24] In an effort
to capitalize further on this chemistry with the aim to

with excellent chemo-selectivity and good yields. The
process is mediated by an aluminium based catalysts under
relatively mild conditions and the developed catalytic
methodology can be applied to the formal synthesis of two
pharmaceutically relevant carbamates with the 3CR being a
key step.
Keywords: amines; carbamates; carbon dioxide; one-pot
synthesis; oxetanes

prepare more complex organic molecules with
potential in pharmaceutical chemistry, we considered
that in situ aminolysis of these carbonates could enable
the construction of useful carbamates (Scheme 1).
Generally, carbamates are highly interesting synthetic
targets due to their wide application potential as
important components of polyurethane polymers,[25]
agrochemicals[26] and pharma-ceuticals.[27]

Scheme 1. Catalytic one-pot, modular approach towards
oxetane-based carbamates.

The direct formation of carbamates from oxetanes,
CO2 and amines is rather unexplored and we are aware
of only one reported example based on the in situ
formation of a carbamate nucleophile derived from an
amine and CO2. Yoshida et al. described the formation
of hydroxy-carbamates from simple oxetane
(trimethylene oxide) and aliphatic primary or
secondary amines;[28] however, this non-catalytic
approach suffers from many limitations due to the
limited reactivity of the carbamate nucleophile.

2

Among these limitations are the restricted scope in
oxetanes (only two) and thus the eventual carbamate
products that can be prepared, the harsh reaction
conditions (100120ºC, 40 bar) and long reaction
times (up to 72 h). Furthermore, the yields (most
examples are <31%) of the hydroxy-carbamates were
significantly compromised and competitive formation
of amino-alcohols was noted which were actually
found to be the major products. We envisioned that an
efficient catalyst for the intermediate formation of a
six-membered carbonate and in situ aminolysis could
help to drastically improve the direct formation of
carbamates from oxetanes, amines and CO2. This
would amplify the scope of reaction partners and
address the sustainability of the process by allowing
lower temperature/pressure conditions for effective
formation of the target carbamates. Previously we used
such catalyst systems for highly efficient and
demanding oxirane/CO2 coupling reactions focusing
on the formation of either cyclic[29,30] or polycarbonate structures.[31]
Here we describe a highly efficient methodology for
the one-pot catalytic formation of functionalized
carbamates from various (substituted) oxetanes, CO2
and primary/secondary amines in good yields. The
applied Al-catalysis offers faster reactions,
significantly reduced by-product formation and for the
majority of the examples environmentally more
benign reaction conditions (70ºC, 10 bar). The
developed catalytic process towards these oxetanebased carbamates was also successfully applied
towards the formal synthesis of Carisoprodol and the
mono-carbamate of Felbatol, two carbamate-derived
drug molecules.

strategy did not produce the desired carbamate in high
yield. For instance, carbamate 2 was prepared only in
a low yield of 35%; we therefore modified the one-pot
synthesis for 2 and added the amine at a later stage of
the reaction (i.e., a sequential approach; Experimental
Section)
without
isolating
the
carbonate
intermediate.[32] This afforded an appreciable increase
in isolated yield (65%) and apparently for some of the
oxetane/amine combinations the formation of the
intermediate six-membered carbonate (Scheme 1) was
hampered; the much shorter total reaction time
required for the sequential preparation of 2, 4, 5, and 8
(16 h) is support for this postulation.[33]

Results and Discussion
We first examined simple oxetane as coupling partner
towards carbamates using a 3CR approach
(Experimental Section) having the amine already
present at the start of the reaction. The amine reagent,
present in stoichiometric amounts, could potentially
coordinate to the catalyst thereby deactivating it and
shut down catalytic turnover. However, in general Odonor ligands such as oxetanes have excellent
coordination ability to main group metal complexes
used herein and therefore we expected that the
presence of the amine would only marginally affect the
kinetics of the catalytic formation of the carbonate
intermediate.
We previously described that six-membered
carbonates can be efficiently prepared using an Al(III)
aminotriphenolate complex having tBu substituents on
the periphery of the ligand and having an axial ligation
site for oxetane activation.[24] Thus, this complex was
first probed in the coupling of oxetane, several amines
and CO2 to afford their corresponding carbamate
products 1-8 (Figure 1). These carbamates were
produced in synthetically useful yields of up to 91%
(cf., synthesis of 6). However, we noted that for the
formation of carbamates 2, 4, 5 and 8 this one-pot

Figure 1. Substrate scope investigated using oxetane
(trimethylene oxide) as coupling partner: synthesis of
carbamates 1-8. General conditions: [Al] is the tBu-derived
Al(III) complex (see above), 4 mmol scale, MEK 1.0 mL,
time/temperature indicated. TBAI/TBAB stands for
tetrabutylammonium iodide/bromide. Note that for
carbamates 2, 4, 5 and 8 the time indicated in brackets is a
combination of (1) prior carbonate formation, and (2)
subsequent aminolysis. All yields are of the isolated
products after column purification.

3

A variety of functionalities are readily introduced
into these carbamates including pyridyl (1), cyclic
amide (2), olefinic (4 and 6) and morpholinyl (5)
groups. These results show that the one-pot approach
is indeed feasible towards oxetane based carbamates
and therefore we decided to extend the synthesis
towards carbamates derived from various 3,3´disubsituted and 3-mono-substituted oxetanes.
Table 1. Screening study towards carbamate formation
using 3,3´-dimethyloxetane, benzyl amine and CO2 as
substrates.[a]

Entry

Cat.

T
[ºC]

t
[h]

Yield of
9
[%][c]
0
0
0
9
6
0
50

75
30

75
30

90
60

PPNI 5
75
30
TBAB 5
75
30
PPNI 5
75
18+10
PPNI
75
18+10
2.5
8[b]
AltBu
PPNI 5
60
18+10
53
9[b]
AltBu
PPNI 5
75
18+10
71
10
AltBu
PPNI 5
90
18+10
75[d]
[a]
General conditions: 2.5 mol% [AltBu], 1.0 mL MEK,
p(CO2)º = 10 bar. [b] 3 equiv of oxetane used. [c] NMR yield
using mesitylene as internal standard. [d] Isolated yield.
1
2
3
4
5[b]
6
7


AltBu
AltBu
AltBu
AltBu

AltBu

Co-cat.
[mol%]

Before investigating this part of the substrate scope
in more detail, we evaluated the feasibility of both the
3CR and sequential one-pot approach for a preselected combination of 3,3´-dimethyloxetane, benzyl
amine and CO2 (see Table 1). In the absence of Al
complex (AltBu) and/or nucleophile no conversion was
observed (entries 13).[33] The 3CR synthesis using
both the Al-complex and PPNI (PPN =
bistriphenylphosphine-iminium) only gave low yield
of carbamate 9 (entries 45;  9%). Then the
sequential approach was probed and the presence of
only the nucleophile PPNI did not afford any product
(entry 6), whereas the additional presence of AltBu
(entries 710) gave carbamate 9 in up to 75% yield
after some further optimization of the reaction
temperature and the catalyst/nucleophile ratio. The
data obtained in these screening studies clearly show
that for the more lethargic, substituted oxetanes[34] the
sequential approach towards carbamates is most
appropriate.
To further substantiate the hypothesis that the lower
reactivity of these substituted oxetanes is responsible
for the low conversion noted in these cases with amine
addition at the beginning of the one-pot approach,
some further control experiments were carried out.
When simple oxetane (i.e., trimethylene oxide) was

treated with allyl amine using AltBu as catalyst (2.5
mol%), TBAB as nucleophile (5 mol%) at 75ºC for 18
h in the absence of CO2 (cf., synthesis of 4, Figure 1),
full conversion was noted to the amino-alcohol
product evidenced by 1H NMR analysis. This result
unambiguously demonstrates that for this combination
of reaction partners the chemo-selectivity towards the
carbamate 4 may be compromised due to competitive
aminolysis of the oxetane substrate. The isolated yield
of 4 was indeed significantly improved from 34 to 76%
by addition of the amine at a later stage of the reaction
(sequential approach) allowing first for six-membered
carbonate formation avoiding amino-alcohol sideproducts.
We also subjected 3,3´-dimethyloxetane to similar
reaction conditions described in entry 8 (Table 1)
using benzyl amine and 5 mol% of PPNI without
adding CO2 and monitored possible conversion by 1H
NMR analysis. After 18 h, only the starting materials
could be detected and no amino-alcohol was thus
formed. This latter result is in line with the lower
reactivity of substituted oxetanes compared to parent
oxetane. The observed lower carbamate yields when
using substituted oxetanes through a 3CR approach is
thus not related to competitive amino-alcohol
formation as shown in the synthesis of 4.

Figure 2. Investigated scope for substituted oxetanes:
synthesis of carbamates 10-17. General conditions: [Al] is
the tBu-derived Al(III) complex (see above), 4 mmol scale,
MEK 1.0 mL, time/temperature indicated. TBAI/TBAB
stands for tetrabutylammonium iodide/bromide, PPN =

4

bis(triphenylphosphine)iminium. All yields are of the
isolated products after column purification.

5

The scope in oxetane partners was then amplified
(see Figure 2) and various 3,3´-disubtituted substrates
were subjected to the one-pot sequential approach to
afford carbamates 1017 in isolated yields of up to
71% (cf., synthesis of 13). It should be noted that these
conversions are highly challenging and therefore in
some of the reported transformations higher reaction
temperatures/pressures were unavoidable such as in
the case of 12, 13, 15 and 16. The conversion of
substituted
oxetanes
greatly
amplifies
the
opportunities in carbamate synthesis and highly
functionalized scaffolds are accessible through this
catalytic protocol; remarkably, the ester fragment in 15
was tolerated and this carbamate was isolated in 48%
yield. Other useful groups such as a long-tail internal
olefin (13) and 2-thiophenylyl (16) were also easily
introduced.

carbamate formation reaction developed herein. The
key hydroxy-carbamate intermediate 20 (48% yield)
was finally converted virtually quantitatively into
Carisoprodol 21 by treatment with trichloroacetyl
isocyanate.[3638] Carbamate 24, obtained in 70% yield
from oxetane 23 using a similar catalytic carbamate
formation as used for 20, was treated with ammonium
cerium(IV)nitrate (CAN) to remove the 4-methoxybenzyl group (PMB)[39] and gave the hemi-carbamate
25 of Felbatol in 95% yield. For Carisoprodol, the
original route[40] is based on stepwise carbamation of
2-methyl-2-propyl-1,3-propanediol involving the use
of phosgene or phosgene-derived dialkylcarbamate
reagents. Thus, the newly developed protocol provides
an alternative way of producing carbamate-derived
pharmaceuticals using catalytic chemistry.

Conclusion
Summarising, we here describe a new catalytic method
for the formation of highly functionalized carbamates
using a one-pot methodology based on the threecomponent coupling between (substituted) oxetanes,
primary/secondary amines and CO2 under effective
Al-catalysis. This procedure does not require the
isolation of the intermediate six-membered carbonates
before aminolysis and greatly amplifies the scope
towards these carbamate scaffolds.
The developed catalytic chemistry has also shown
to be of use in the preparation of carbamate-derived
drug molecules (cf. synthesis of Carisoprodol and the
hemi-carbamate of Felbatol) and thus provides an
interesting new route towards pharmaceutically
relevant molecules through challenging coupling
chemistry that involves oxetanes and CO2. We believe
that this approach may help to further capitalize on the
application of oxetane building blocks in medicinal
chemistry combined with the use of a renewable
carbon feedstock (CO2) and beyond.

Experimental Section
Method A: 3CR synthesis of carbamates:
Scheme 2. Formal synthesis of Carisoprodol 21 and the
mono-carbamate of Felbatol 25 using in the key step the Alcatalysed carbamate formation from an intermediate
oxetane, amine and CO2.

The successful approach towards the oxetane based
carbamates 117 prompted us to apply the newly
developed catalytic process towards more relevant
carbamate-based
drug
precursors
including
Carisoprodol (21) and the mono-carbamate of Felbatol
(25), see Scheme 2. Both syntheses start of by using
commercially available diols 18 and 22. These diols
can be easily converted into their oxetane derivatives
19 and 23, respectively, by a known
lithiation/tosylation-lithiation/cyclization sequence[35]
in appreciable yields. These oxetanes 19 and 23 then
served as starting point for the catalytic one-pot

The respective amine (4.0 mmol, 1 eq.), oxetane (12 mmol,
3 eq.), Al-complex (AltBu, 0.52%), TBAB/PPNCl and
MEK (l mL) were charged into a 30 mL stainless steel
autoclave. The autoclave was then subjected to three cycles
of pressurization and depressurization with carbon dioxide
(5 bar), before final stabilization of the pressure at 10 bar.
The autoclave was sealed and heated to 60100ºC and left
stirring for the required time. Then the autoclave was cooled
to r.t. and depressurized. After the reaction, the analytically
pure carbamate product was isolated by flash
chromatography.

6

Method B: sequential synthesis of carbamates:
The respective oxetane (4.0 mmol, 1 eq.), Al-complex (AltBu,
0.52.5%), TBAB/PPNCl and MEK (l mL) were charged
into a 30 mL stainless steel autoclave. The autoclave was
then subjected to three cycles of pressurization and
depressurization with carbon dioxide (5 bar), before final
stabilization of the pressure at 10 bar. The autoclave was
sealed and heated to 75110ºC and left stirring for the
required time. Then the autoclave was cooled to r.t. and
depressurized. Hereafter, the respective amine (1.2 equiv for
non-volatile amines and 3 equiv for volatile amines) was
added into the reaction mixture and the autoclave was sealed
and heated to 75110ºC for 10 h. Finally, the autoclave was
cooled down to room temperature again, and the analytically
pure carbamate product was then isolated by flash
chromatography.
Synthesis of carbamate (6)
The product was obtained through the 3CR approach using
1.5 mol% [AltBu], 2.5 mol% PPNI and performing the
reaction at 70ºC and 10 bar for 60 h. Carbamate 6 was
isolated after column purification in 91% yield. Note: the
product is unstable when kept in the presence of air. 1H
NMR (300 MHz, CDCl3): δ = 5.19 (t, J = 6.5 Hz, 1H), 5.07
(t, J = 6.7 Hz, 1H), 4.61 (br s, 1H), 4.24 (m, 2H), 3.80-3.76
(m, 2H), 3.67 (s, 2H), 2.36 (br s, 1H), 2.12-1.97 (m, 4H),
1.83 (m, 2H), 1.68 (s, 3H), 1.66 (s, 3H), 1.60 (s, 3H);
13
C1H NMR (101 MHz, CDCl3): δ = 157.19, 139.83,
131.89, 123.92, 120.23, 61.66, 59.00, 58.97, 39.56, 32.44,
26.49, 25.79, 17.80, 16.34; IR (neat):  = 1688 cm-1
(NC(=O)O); HRMS (ESI): m/z calcd. 278.1727 (M+Na)+,
found: 278.1738.
Synthesis of carbamate (13)
The product was obtained through the sequential approach
using 4.0 mol% [AltBu], 7.0 mol% PPNI and performing the
first step of the conversion at 75ºC and 40 bar for 24 h. The
second step, after addition of the amine, was carried out at
75ºC for 10 h. The carbamate 13 was isolated after column
purification in 71% yield. 1H NMR (500 MHz, CDCl3): δ =
7.36-7.28 (m, 5H), 5.37-5.35 (m, 2H), 4.70 (br s, 1H), 4.70
(s, 2H), 4.12-4.05 (m, 2H), 3.44 (m, 2H), 3.38-3.37 (m, 2H),
3.18-3.14 (m, 2H), 3.04 (br s, 1H), 2.06-1.96 (m, 4H), 1.48
(m, 2H), 1.32-1.26 (m, 22H), 0.91 (s, 3H), 0.89-0.87 (m,
3H); 13C1H NMR (101 MHz, CDCl3): δ = 157.30, 138.28,
130.11, 129.90, 128.51, 127.76, 127.61, 81.91, 74.54, 73.66,
66.65, 66.50, 41.27, 41.08, 29.90, 29.87, 29.83, 29.65, 29.45,
29.39, 27.35, 27.32, 26.87, 23.83, 17.26, 14.25; IR (neat): 
= 1699 cm-1 (NC(=O)O); HRMS (ESI): m/z calcd. 526.3867
(M+Na)+, found: 526.3859.
For the experimental details and analytical data of all other
carbamates, and copies of relevant NMR/IR spectra see the
Supporting Information.

Acknowledgements
We thank ICIQ, ICREA, and the Spanish Ministerio de Economía
y Competitividad (MINECO) through project CTQ2014-60419-R,
and support through Severo Ochoa Excellence Accreditation
2014–2018 (SEV-2013-0319). WG thanks the Cellex Foundation
for supporting his postdoctoral fellowship and VL thanks the
Generalitat de Catalunya for a FI pre-doctoral fellowship. Dr.
Marta Gimínez and Cristina Rivero are thanked for their help
regarding the high-pressure experiments.

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NMR; mesitylene as internal standard) with traces of
the carbamate product 7. Note that carbamate
formation in the absence of an external nucleophile
using 3,3´-dimethyloxirane (Table 1, entries 2 and 3)
does not lead to any product formation. This clearly
demonstrates that carbamate nucleophiles possibly
derived from amines and CO2 are incompetent towards
oxetane ring-opening under the reaction conditions
used.
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[32] Conditions used in this approach: 2.5 mol% [AltBu], 5.0
mol% TBAB, 75ºC, 10 bar.

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J. Org. Chem. 1998, 63, 9932.

[33] Please note that CO2 and alkyl amines may give rise to
carbamate nucleophiles themselves. However, when
we carried out the synthesis of compound 7 (Figure 1)
based on the simplest oxetane in the absence of TBAI,
we found only amino alcohol product (7% yield by

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8

FULL PAPER
Catalytic One-Pot Oxetane to Carbamate
Conversions: Formal Synthesis of Drug Relevant
Molecules
Adv. Synth. Catal. 2015, 357, Page – Page
Wusheng Guo, Victor Laserna, Jeroen Rintjema
and Arjan W. Kleij*

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