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“This is the peer reviewed version of the following article: Angew. Chem. Int. Ed. 2018, 57 (35), 11203-11207, which has been
published in final form at DOI: 10.1002/anie.201803967. This article may be used for non-commercial purposes in accordance with
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COMMUNICATION
Organocatalyzed Domino [3+2] Cycloaddition/Payne-Type
Rearrangement using Carbon Dioxide and Epoxy Alcohols
Sergio Sopeña,[a] Mariachiarra Cozzolino,[a] Cristina Maquilón,[a] Eduardo C. Escudero-Adán,[a] Marta
Martínez Belmonte,[a] and Arjan W. Kleij*[a][b]

Abstract: An unprecedented organocatalytic approach towards
highly substituted cyclic carbonates from tri- and tetra-substituted
oxiranes and carbon dioxide has been developed. The protocol
involves the use of a simple and cheap superbase under mild,
additive- and metal-free conditions towards the initial formation of a
less substituted carbonate product that equilibrates to a tri- or even
tetra-substituted cyclic carbonate under thermodynamic control. The
latter are conveniently trapped in situ providing overall a new domino
process for synthetically elusive heterocyclic scaffolds. Control
experiments provide a rationale for the observed cascade reactions,
which demonstrate high similarity with the well-known Payne
rearrangement of epoxy alcohols.

biosynthetic pathways exist towards these complex structures, no
synthetic methodologies towards tetra-substituted cyclic
carbonates from epoxides and CO2 have been reported to date.
Therefore, the discovery of new concepts that can alleviate the
problems associated with the formation of these highly substituted
cyclic carbonates can revive new potential of these heterocycles
in synthetic organic chemistry.

The chemistry of cyclic organic carbonates has been developed
to a high level of sophistication over the years.[1] In particular,
these heterocyclic structures were initially targeted for application
as electrolytes of lithium ion batteries and useful precursors
towards polycarbonate polymers.[2] More recently, focus has
shifted to the use of cyclic carbonates as synthetic precursors for
a range of fine-chemical and pharma-relevant scaffolds.[3] In this
respect, both the functionalization and the degree of substitution
of the cyclic carbonate ring has proven to be crucial to develop
catalytic procedures that allow for enantio- or diastereoselective
transformations including the formation of allylic compounds,[4]
heterocyclic scaffolds[5] and macrocyclic compounds[6] among
others.[7] Therefore, synthetic methodologies that give easy
access to highly substituted and functionalized cyclic carbonates
have gained much importance over the last years and are crucial
towards further advancing these synthetic blocks.
The most popular and straightforward approach towards
cyclic carbonate synthesis is the [3+2] cycloaddition of CO2 to
epoxides under Lewis acid catalysis. [8] Despite the considerable
progress noted over the years in this field, the use of tri- and even
tetrasubstituted epoxides as coupling partners has been
extremely challenging due to the steric requirements of these
reactions.[9] The relevance of highly substituted carbonates is
illustrated by the occurrence of several natural compounds such
as the triterpenoid carbonate Chukvelutin D and the
sesquiterpenoid carbonate Hololeucin (Scheme 1a).[10] While

[a]

[b]

S. Sopeña, M. Cozzolino, Dr. E. C. Escudero-Adán, Dr. Marta
Martínez Belmonte, Prof. Dr. A. W. Kleij, Institute of Chemical
Research of Catalonia (ICIQ), the Barcelona Institute of Science and
Technology, Av. Països Catalans 16, 43007 - Tarragona, Spain
E-mail: akleij@iciq.es
Prof. Dr. A. W. Kleij
Catalan Institute of Research and Advanced Studies (ICREA), Pg.
Lluís Companys 23, 08010 Barcelona, Spain
Supporting information for this article is given via a link at the end of
the document

Scheme 1. (a) Naturally occurring cyclic carbonates Chukvelutin D and
Hololeucin with their cyclic carbonate fragments in red. (b) Base-assisted Payne
rearrangement of epoxy alcohols. (c) New organocatalytic approach towards
elusive tri- and tetra-substituted cyclic carbonates. Cat stands for catalyst.

In the course of our research program towards the creation of
more complex cyclic carbonate structures,[7d, 9a+d, 11] we reasoned
that the base-assisted isomerization of 2,3-epoxy alcohols known
as the Payne rearrangement (Scheme 1b)[12] offers a
paradigmatic scenario towards the synthesis of highly substituted
cyclic carbonates. We recently reported a substrate-controlled
divergent synthesis of cyclic carbonates and carbamates from
epoxy alcohols and amines, respectively, under Al(III)
catalysis.[13] This work showed the potential of the Al-catalyst to

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act as a bifunctional entity with built-in proton-relay capabilities,
and further demonstrated a crucial role for the alcohol unit of the
substrate. We envisioned that a proper organocatalyst could
combine both (1) proton-shuttling potential thereby mediating the
synthesis of the cyclic carbonate from an epoxy alcohol and CO2,
and (2) induce subsequently a base-assisted Payne-type
rearrangement of the hydroxymethyl-substituted cyclic carbonate.
By selectively trapping of the more reactive hydroxy-methyl
substituted carbonate (Scheme 1c), a simple and conceptually
novel route towards structurally elusive tri- and tetrasubstituted
cyclic carbonates would become available. Herein we present a
new metal- and nucleophile-free one-pot domino strategy
generally applicable towards [3+2] cycloadditions involving highly
substituted epoxy alcohols and CO2 as substrates. As far as we
are aware, this catalytic process is unprecedented in product

scope as there are no previous reports on formation of
tetrasubstituted cyclic carbonates from epoxides, even more so
under organocatalytic conditions.
First, we decided to test our hypothesis with a range of Ncontaining bases using glycidol A as a benchmark substrate
(Scheme 2a). Under relatively mild conditions (45 ºC, 10 bar) and
importantly in the absence of an external nucleophile, the cyclic
carbonate 1 could be easily prepared in up to 95% yield (85%
isolated) using DBU as catalyst. Several other N-bases were also
productive in the synthesis of 1 including DMAP (90%), TMG
(95%), MTBD (90%) and TBD (91%), see Scheme 2b. In order to
be able to select a catalyst suitable for more challenging
substrates (Scheme 2c), (R,R)-phenyl glycidol B was probed
under suitable reaction conditions (for details: see Tables S1 and
S2). Interestingly, for this internal epoxide, TBD and DBU showed
the best catalytic features towards the formation of carbonates 2a
and 2b, and DBU was finally selected as the preferred catalyst to
investigate the conversion of trisubstituted epoxide C (Scheme
2d).[14]
Interestingly, when similar conditions were applied as for the
mono- and di-substituted epoxide conversions (45 ºC, 10 bar, 10
mol% DBU), quantitative conversion of C into carbonates 3a and
3b was achieved (3a:3b = 7:3). Since 3a cannot be obtained
through classical nucleophilic ring opening of the epoxide, its
formation is therefore ascribed to an equilibration between 3a and
3b under the experimental conditions with a key role for DBU. This
hypothesis could be confirmed as the isolated mixture of cyclic
carbonates was selectively and quantitatively converted into the
acetyl-protected, tri-substituted carbonate 4 (84% isolated yield)
in the presence of DBU/AcIm.[15] Remarkably, the formation of 4
from C through a one-pot domino sequence was also successfully
probed and provided the carbonate in 86% yield. These results
imply that the acetylation step is faster for the primary alcohol with
a dynamic kinetic resolution between 3a and 3b under basic
conditions to provide elusive CO2 derived heterocycles.
Furthermore, benzylated C was not converted by DBU in the
presence of CO2, pointing at a crucial role for the alcohol unit in
this conversion (see SI page S93 for details).

Scheme 2. [a] Screening of various N-containing bases to convert glycidol A
and CO2 into its respective cyclic carbonate. Conditions used: glycidol (8.0
mmol), N-base (5.0 mol%), mesitylene (10 mol%), MEK (5.0 mL), 45 ºC, 10 bar,
18 h. [b] All reported yields for 1, 2a/2b and 3a/3b are based on NMR
measurements using mesitylene as internal standard, unless noted otherwise.
Details: (i) Polyether (3%) was also formed. (ii) Isolated yield after
chromatographic purification. [c] Comparison between DMAP, TBD and DBU in
the synthesis of carbonates 2a and 2b from (R,R)-phenyl glycidol. The
combined NMR yield for 2a+2b is reported. [d] DBU-catalyzed conversion of
trisubstituted epoxide C. Details: (iii) DBU (1 equiv), acetyl imidazole (AcIm; 1.5
equiv), rt, 1.5 h; isolated yields are reported.

The successful synthesis of carbonate 4 inspired us to
examine the generality of this domino process using primarily triand tetra-substituted epoxides (Figure 1). Thus, we probed more
functional epoxide precursors towards the preparation of 58 and
found that in all these cases the trisubstituted OAc-protected
carbonates could be selectively formed and in high isolated yields
(7590%). Importantly, the presence of additional double bond or
epoxide groups did not interfere with the chemo-selectivity of
these conversions, and only the conversion of the epoxy alcohol
fragments was observed. For 5 (as observed in the synthesis of
4) a one-pot procedure was feasible and provided a higher yield
of the carbonate. For all subsequent syntheses (cf., 613) we
therefore used the one-pot three step sequence. Delightfully, the
tetra-substituted carbonates 913 could also be prepared
conveniently in appreciable yields (4078%) and represent the
first examples of [3+2] cycloadditions between tetra-substituted
epoxides and CO2.[16] Whereas the spiro-carbonates 9‒11 were
obtained under relatively mild conditions, products 12 and 13

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required harsher reaction settings. The molecular structure of 11b
was also confirmed by X-ray analysis.[17]
In order to further support the mechanistic proposal that a
Payne-like rearrangement takes place between carbonate
products, we carried out a number of control experiments
(Scheme 3). First the conversion of trisubstituted epoxide C was
probed in the absence of CO2 to see whether classical Payne
rearrangement occurs prior to carbonate formation, but no
conversion of C into the mono-substituted epoxy alcohol D
(Scheme 3a) was observed. This implies that the presence of
(electrophilic) CO2 is required for the domino conversion leading
to the trisubstituted carbonate product. Different pre-isolated
mixtures of carbonates 3a and 3b (40:60 and 92:8) were then
subjected to the general catalytic conditions (Scheme 3b), and
both equilibrated to a 70:30 ratio. This observation supports the
view that the formation of the mixture of carbonates is basemediated and follows initial formation of 3b from epoxy alcohol C.

showed the intermediate presence of carbonate mixtures prior to
protection. The selective formation of 16, was compromised by
the presence of an electron-withdrawing phenyl group that
enables a faster protection than isomerization rate of the
intermediate mixture of carbonates. Consequently, a lower ratio
(83:17) between the protected tri- and mono-substituted
carbonate was formed.[18] The X-ray molecular structure
determined for 16 unequivocally revealed the trisubstituted nature
of the cyclic carbonate product.[17]

Scheme 3. Mechanistic control reactions to support the unique, organocatalytic
Payne-type rearrangement at the carbonate level.

Figure 1. Scope in cyclic carbonates using a domino [3+2]
cycloaddition/rearrangement sequence in the presence of DBU and AcIm.
Reaction conditions: [a] epoxide (1.0 mmol), DBU (10 mol%), MEK (5.0 mL), 45
ºC, p(CO2)º = 10 bar, 18 h; then DBU (1 equiv.), AcIM (1.5 equiv.), r.t., 1.5 h.

Similar types of protected trisubstituted carbonates 1417
(Scheme 3c) were also conveniently and selectively derived from
mono-substituted epoxides having a tertiary alcohol unit, and

To show that the organocatalytic approach towards the
preparation of these highly substituted cyclic carbonates is
distinct from metal-mediated approaches, a bis-epoxide (Scheme
3d) was subjected to the same conditions in the presence of an
Al-based aminotriphenolate complex[13] and the reaction mixture
compared with the one obtained by using DBU as catalyst.
Whereas in the latter case selective conversion of the epoxy
alcohol is achieved, the use of the Al-complex leads to a complex
mixture of products while converting both epoxy groups (see
Supporting Information). The organocatalytic approach therefore
allows for a regio-selective epoxide transformation, and offers
potential to address subsequent conversion of the remaining
oxirane unit.

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In conclusion, a new domino process has been developed
towards the elusive coupling of tri- and tetrasubstituted epoxides
and CO2 by an organocatalytic strategy. This novel reactivity
allows for the synthesis of otherwise elusive cyclic carbonates
under mild reaction conditions, is operationally friendly and allows
for regio-selective formation of mono-carbonates using bis- or trisepoxy-based substrates. This substrate-controlled conversion of
carbon dioxide offers access to new, functional heterocyclic
scaffolds with amplified potential in synthetic chemistry.

Acknowledgements
We thank the CERCA Program/Generalitat de Catalunya, ICREA,
the Spanish MINECO (CTQ2017-88920-P and SEV-2013-0319),
and AGAUR (2017-SGR-232). S. S. thanks Covestro for support.
Dr. Marta Giménez and Cristina Rivero are thanked for help with
the high-pressure reactions and Dr. Noemí Cabello for the MS
measurements.

[6]

[7]

[8]

[9]

Keywords: carbon dioxide • domino process • epoxy alcohols •
organocatalysis • Payne rearrangement
[1]

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Note that the known, nucleophilic bromide-based catalyst TBAB showed
a combined yield of only 7% for 2a/2b (2a:2b = 55:45), see the
Supporting Information for details. This demonstrates that the in situ
formation of a nucleophilic species derived from the epoxy alcohol
substrate is far more effective than the use of an external nucleophile.
Primary alcohols can be easily protected using AcIm, see: a) H.
Hagiwara, K. Morohashi, T. Suzuki, M. Ando, I. Yamamoto, M. Kato,
Synth. Commun. 1998, 28, 2001-2006; b) R. C. Pratt, B. G. G. Lohmeijer,
D. A. Long, R. M. Waymouth, J. L. Hedrick, J. Am. Chem. Soc. 2006,
128, 4556-4557.
For the one-pot reactions towards 913 typically we found 8:2 ratios
between the desired tetra-substituted carbonate and a disubstituted one
contrary to the syntheses of trisubstituted carbonate products 48. This
observation indicates that the acetyl-protection (third step in the one-pot
synthesis) is more competitive because of a slower base-induced
equilibration of both carbonates. For this reason most of the unprotected
tetrasubstituted carbonates were directly isolated.
For details, see CCDC 1832243 and 1832244.
Pure trisubstituted carbonate 21 was isolated (30%) as a single
diastereoisomer (dr >99:1) by chromatographic separation; note,
however, that initially quantitative formation of a mixture of both the triand monosubstituted carbonate occurred (ratio tri/mono = 83:17, dr =
57:43 for the trisubstituted product).

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Entry for the Table of Contents:

COMMUNICATION
No Payne, no gain: A domino [3+2]
cycloaddition/Payne type rearrangement allows for the synthesis of
elusive heterocycles from carbon
dioxide and epoxy alcohols. This
attractive,
metal-free
and
operationally
simple
approach
affords
a
wide
range
of
substitutionally dense and functional
cyclic carbonates. The mechanistic
manifold towards these scaffolds
shows resemblance with the Payne
rearrangement of epoxy alcohols as
shown
by
various
control
experiments.

Sergio Sopeña, Mariachiarra Cozzolino,
Cristina Maquilón, Eduardo C. EscuderoAdán, Marta Martínez Belmonte and Arjan W.
Kleij*

Page No. – Page No.

Organocatalyzed Domino [3+2]
Cycloaddition/Payne-Type Rearrangement
using Carbon Dioxide and Epoxy Alcohols