Substrate-Controlled Product Divergence: Conversion of CO2 into Heterocyclic Products

Article abstract of DOI:10.1002/anie.201511521

Substituted epoxy alcohols and amines allow substrate-controlled conversion of CO₂ into a wide range of heterocyclic structures through different mechanistic manifolds. This new approach results in an unusual scope of CO₂-derived products by initial activation of CO₂ through either the amine or alcohol unit, thus providing nucleophiles for intramolecular epoxy ring opening under mild reaction conditions. Control experiments support the crucial role of the amine/alcohol fragment in this process with the nucleophile-assisted ring-opening step following an S_Ni pathway, and a 5-exo-tet cyclization, thus leading to heterocyclic scaffolds.

Full text of DOI:10.1002/anie.201511521

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International Edition: DOI: 10.1002/anie.201511521
German Edition: DOI: 10.1002/ange.201511521
CO2 Fixation
Substrate-Controlled Product Divergence: Conversion of CO2 into
Heterocyclic Products
Jeroen Rintjema, Roel Epping, Giulia Fiorani, Eddy Martín, Eduardo C. Escudero-Adµn, and
Arjan W. Kleij*
Abstract: Substituted epoxy alcohols and amines allow sub-
strate-controlled conversion of CO2 into a wide range of
heterocyclic structures through different mechanistic mani-
folds. This new approach results in an unusual scope of CO2-
derived products by initial activation of CO2 through either the
amine or alcohol unit, thus providing nucleophiles for intra-
molecular epoxy ring opening under mild reaction conditions.
Control experiments support the crucial role of the amine/
alcohol fragment in this process with the nucleophile-assisted
ring-opening step following an SNi pathway, and a 5-exo-tet
cyclization, thus leading to heterocyclic scaffolds.
frequently used as high-energy reaction partners for CO2-
based synthesis, and considerable achievement in the prep-
aration of organic carbonates and derived molecules has been
achieved in the last decade.[7] However, the challenging
coupling of highly substituted epoxides and CO2 necessi-
tates the quest for an alternate and mechanistically distinct
methodology.
[8]
Recently, we proposed that hydroxy- and amino-substi-
tuted oxetanes can be catalytically coupled at remarkably low
temperatures with CO2 through elusive alkyl carbonic acid
intermediates to afford five- or six-membered carbonates/
carbamates in the absence of external nucleophiles.[9] Further
to this, other groups have communicated on (noncatalytic)
approaches using stoichiometric additives in combination
with substrates having pendent hydroxy/amine groups.[10] We
envisioned that epoxy alcohols and amines would serve as
ideal substrates to develop an efficient substrate-controlled
catalytic approach, as these scaffolds combine high accessi-
bility, easy synthesis, and a broad molecular diversity
(Scheme 1, right).[11] This new catalytic approach towards
the coupling of epoxy alcohols and CO2 would trigger an
alternative mechanism leading to intramolecular nucleophilic
attack (SNi) of a hemiester of a carbonic acid, thus accessing
a wider scope of potential products. Since the conventional
mechanism (Scheme 1, left) would be initiated by an external
nucleophile and require different reaction conditions, both
mechanistic routes would be accessible and provide a con-
ceptually new approach towards product diversity from
a single epoxy alcohol or amine substrate.
T
he global challenge regarding future fossil fuel depletion
has motivated the chemical community to invent new
methodologies for alternative conversions of carbon feed-
stocks into basic and fine-chemical targets. While CO2 is
mainly considered an environmental hazard because of the
ever-increasing emissions from human activities into our
atmosphere, it also represents a cheap and accessible carbon-
based building block with great potential in organic syn-
thesis.[1] Despite this potential, progress in this area of
research is still rather limited to a handful of coupling
À
À
reactions which are prominently based on C O and C N
bond formations.[2] Although catalysis has been recognized as
a key sustainable technology enabling more efficient CO2
conversion,[3] it often relies on metal-mediated activation of
a co-reactant rather than CO2 itself, thereby limiting its use in
a more amplified portfolio of chemical reactions.[4] Direct
substrate involvement in the activation of the CO2 molecule is
truly scarce and typically requires the use of stoichiometric
amounts of additives,[5] or the involvement of substrates which
have limited scope and/or accessibility.[6]
We first established general reaction conditions using the
simplest epoxy alcohol (i.e., glycidol) and a Lewis acid based
on aluminium(III)-centred aminotriphenolate complexes (A–
To solve this challenge, the use of cheap molecular
scaffolds which induce activation of CO2 and guide alter-
native new mechanistic approaches towards its conversion is
appealing. This approach would create a new conceptual
framework for CO2 use and valorization. Epoxides have been
[*] J. Rintjema, R. Epping, Dr. G. Fiorani, Dr. E. Martín,
E. C. Escudero-Adµn, 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)
Scheme 1. Mechanistic divergence in the coupling between CO2 and
ither epoxy alcohols or amines leading to product diversity. LA=Lewis
acid, Nu=nucleophile.
Supporting information for this article can be found under http://dx.
doi.org/10.1002/anie.201511521.
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D; see Table 1 and Table S1 in the Supporting Information) in
stitution patterns, using C as the catalyst. In general, scope,
the absence of an external nucleophile: these reactions
conditions are related to the hydroxy oxetane conversions
reported previously.[9] At 508C after 14 hours we found that
the aluminium-catalyst C (Table S1, entry 3) gives the highest
conversion (89%) and selectivity (> 99%). Whereas the
complex D shows higher reactivity (Table S1, entry 4; > 99%
conversion), the reaction mixture was complex, possibly
resulting from polyether formation. The formation of the
carbonate 1 is sluggish at 258C (Table S1, entry 5) but is
virtually complete in 1 hour when raising the reaction
temperature to 758C (Table S1, entry 7). Benzyl protection
of the alcohol unit in glycidol (Table S1, entry 6) shuts down
catalysis, thus hinting at a key role for the free alcohol to
mediate an alternative pathway towards the carbonate.
Surprisingly, the formation of 1 also proceeds without any
Lewis acid present (Table S1, entries 9 and 10) but with
significantly slower kinetics than in the presence of C.
Next we examined reaction conditions to trigger the
alternative mechanism using 1-(oxiran-2-yl)ethanol (Table 1):
if successful this would give direct evidence for an alternative
pathway leading to structurally divergent organic carbonates
as depicted in Scheme 1. The use of a nucleophile only
(TBAB) at low temperature favors the conventional product I
(Table 1, entry 1). A combination of both C and TBAB gives
improved reactivity, but a mixture of products of the types I
and II (entry 2) was observed. Delightedly, complete selec-
tivity towards the alternative carbonate product (II) is
achieved at 508C in the absence of an external nucleophile
(entry 3).
with respect to the carbonates/carbamates, which can be
attained through this substrate-mediated CO2 activation is
diverse and the targeted products 1–13 (Figure 1) were
obtained in good yields of up to 95% upon isolation, and
with high chemoselectivity.[12,13] Notably, this alternative
synthetic method for carbonates allows formation of highly
challenging 4,5-di- (5 and 7) and 4,4,5-trisubstitutions (8, 9, 12
and the spirocompound 13) on the cyclic carbonate ring,
including the use of terpene-based scaffolds (6 derived from
2,3-epoxy-geraniol). Interestingly, when epoxy amines are
used as substrates only the 5-substituted isomer is formed (10
and 11), and is in contrast to the known (catalytic) couplings
between aziridines and CO2 which often result in the
formation of regioisomeric mixtures.[14] The chemoselectivity
for both 12 (54%) and 13 (75%) was compromised by the
competitive formation of the carbonate product mediated
through the conventional mechanism (Scheme 1).[15] To the
best of our knowledge, the trisubstituted carbonates cannot
be obtained by using a conventional approach for catalytic
CO2/epoxide couplings, thus demonstrating the added value
of this new methodology.
Table 1: Screening of suitable reaction conditions to trigger an alter-
native mechanism leading to formation of the carbonate type II.[a]
Entry Cat. [mol%] Co-cat. [mol%] T [8C] t [h] Conv. [%][b] I/II[b]
1
2
3
–
TBAB (5.0)
TBAB (5.0)
–
25
25
50
40
14
14
55
>99
>99
81:19
22:78
0:100
C (1.0)
C (1.0)
[a] Reaction conditions: 1-(oxiran-2-yl)ethanol (1.0 mmol),
p(CO2)8=10 bar, 1.0 mL MEK (methyl ethyl ketone). [b] Determined by
1H NMR (CDCl3) spectroscopy. TBAB=tetra-n-butylammonium iodide.
The results presented in Table 1 and Table S1 suggest that
organic carbonates may indeed be accessed through an
alternative mechanism based on in situ formation of CO2-
derived nucleophiles (Scheme 1). Therefore, we decided to
expand the scope of carbonates/carbamates by examination
of epoxy alcohols and amines with more challenging sub-
Figure 1. Synthesis of highly substituted organic carbonates and carba-
mates (1–13) from epoxy alcohols/amines and CO2.[13]
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Having validated that an alternative mechanism towards
organic carbonate formation through the use of epoxy
alcohols/amines can be selectively induced, we next set out
to explore the possibility of an unprecedented product
divergence from a single epoxy alcohol/amine substrate
(Figure 2). In essence, the different mechanisms leading to
the formation of organic carbonates should be triggered
under different reaction (temperature) conditions and by
using different additives. We were pleased to find that indeed
access to both types of carbonate products from simple and
accessible precursors (14–17) could be achieved in good
yields. Notably, the use of a natural product (sclareol,
a bicyclic diterpenol) shows that the approach is also feasible
with more complicated scaffolds. For both sclareol carbonates
16 (X-ray structure determined)[16] and 17 the formation of
diastereoisomeric mixtures arises from the sclareol epoxida-
tion stage, with apparently some higher degree of stereocon-
trol in the preparation of 17.
5-substituted isomer, and is in line with the proposed intra-
molecular pathway presented in Scheme 1. The presence of
an N-aryl group in the epoxy amine substrate expands upon
the potential of this chemistry as it provides a simple entry to
pharmaceutically relevant 5-substituted oxazolidinones such
as toloxatone (21; 74% yield; X-ray structure determined),[16]
which is a known antidepressant. Interestingly, there are
several structurally highly related oxazolidinone molecules
which are used as antimicrobials and the easy formation of 21
gives promise to the synthesis of new types of bioactive
compounds using CO2 as a co-reactant.
To support the formation of a nucleophile derived from an
epoxy alcohol and CO2, we closely examined the formation of
the carbonate product 4 (Figure 3). Enantiopure (2R,3R)-
(+)-3-phenylglycidol (96%) was converted with 94% selec-
tivity into 4 (86% yield, one diastereoisomer). The other two
Figure 3. More detailed investigation into the diastereoselective forma-
tion of cyclic carbonate 4 and its benzyl-protected derivative 22.
components of the reaction mixture were the other diaste-
reoisomer (3%) and the standard carbonate product (3%),
which were separated from 4 by chromatography. Note that
this reaction also proceeds in the presence of cesium
carbonate, though with preferential formation of the
expected, disubstituted carbonate product.[5b] Overall the
reaction follows a diastereoselective pathway (d.r. = 97:3).
The absolute configuration [(2R,3S)] of 4 was determined by
X-ray crystallographic analysis of its O-benzyl-protected
derivative 22 (see the Supporting Information)[16] and
showed a formal inversion at one of the carbon centers.
This inversion suggests that a nucleophilic substitution takes
place prior to isolation (Walden inversion), and is in line with
the mechanistic proposal in Scheme 1 which presents a formal
5-exo-tet-type cyclization. Moreover, the selective formation
of the 5-substituted oxazolidinone products 10, 11, and 21
additionally supports the involvement of an intramolecular
nucleophilic attack on the epoxide prior to product formation.
In summary, we report a simple and practical method for
a new substrate-controlled CO2 conversion process which
allows product divergence from epoxy alcohols/amines. The
different carbonate/carbamate products can be accessed
through different mechanistic manifolds which are simply
triggered by tuning of the reaction temperature/pressure and
use of suitable nucleophilic/base additives. Such control
allows new, unexplored uses of CO2 in organic synthesis
through substrate-driven activation of this renewable carbon
Figure 2. Product divergence from four epoxy alcohols/amines, thus
giving access to the compounds 14–21. For all reactions 2 mol% [AltBu
and p(CO2)8=10 bar were used unless indicated otherwise. Details:
14, 5 mol% TBAB, 258C, 60 h, conv. 95%, sel. 85%; 15, 808C, 40 h,
30 bar, conv. >99%, sel. 93%; 16, 5 mol% TBAB, 508C, 14 h, 30 bar,
conv. >99%, sel. 79%; 17, 10 mol% TBACl, 758C, 14 h, conv. >99%,
sel. 79%; 18, 5 mol% TBAB, 758C, 14 h, conv. >99%, sel. 97%; 19,
10 mol% DIPEA, 508C, 40 h, 30 bar, conv. >99%, sel. 77%; 20,
5 mol% TBAB, 308C, 40 h, conv. >99%, sel. 81%; 21, 2 mol% TBAB,
758C, 14 h, conv. >99%, sel. 81%.[13] Ts =4-toluenesulfonyl.
]
The use of epoxy amines (Figure 2, below) also gives
product divergence potential (18–21), and leads to the
formation of either cyclic carbonate or carbamate scaffolds.
The use of tosyl-protected epoxy amines is challenging since
the amine will be rather unreactive toward the formation of
a nucleophilic intermediate based on CO2 (Scheme 1, alter-
native pathway). However, we found that the addition of
a suitable base (DIPEA) allows access to the carbamate 18 in
an appreciable yield of 65% with full selectivity towards the
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progress to expand this principle to other readily available
organic scaffolds to further capitalize on the potential of this
alternative raw carbon material in chemical synthesis.
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Acknowledgements
We thank ICIQ, ICREA, and the Spanish Ministerio de
Economía y Competitividad (MINECO) through the project
CTQ-2014–60419-R, and the Severo Ochoa Excellence
Accreditation 2014–2018 through the project SEV-2013-
0319. Dr. Noemí Cabello, Sofía Arnal, and Vanessa Martínez
are acknowledged for the mass analyses. G.F. acknowledges
financial support from the European Community through
a Marie Curie Intra-European Fellowship (FP7-PEOPLE-
2013-IEF, project RENOVACARB, Grant Agreement no.
622587).
Keywords: carbon dioxide fixation · heterocycles ·
homogeneous catalysis · Lewis acids · small ring systems
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Angew. Chem. 2016, 128, 4040–4044
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a
detailed discussion and explanation see the Supporting
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Information.
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Data Centre.
Received: December 11, 2015
Revised: January 28, 2016
Published online: February 19, 2016
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