Efficient preparation of carbamates by Rh-catalysed oxidative carbonylation: unveiling the role of the oxidant

Article abstract of DOI:10.1039/c6cc09133d

The synthesis of a wide variety of carbamates from amines, alcohols and carbon monoxide has been achieved by means of a Rh-catalysed oxidative carbonylation reaction that uses Oxone as a stoichiometric oxidant. In-depth studies on the reaction mechanism shed light on the intimate role of Oxone in the catalytic cycle.

Full text of DOI:10.1039/c6cc09133d

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DOI: 10.1039/C6CC09133D
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Efficient Preparation of Carbamates by Rh-Catalysed Oxidative
Carbonylation: Unveiling the Role of the Oxidant
Received 00th January 20xx,
Accepted 00th January 20xx
Amaia Iturmendi,a Manuel Iglesias,*a Julen Munárriz,b Victor Polo,b Jesús J. Pérez-Torrentea and
Luis A. Oro*a,c
DOI: 10.1039/x0xx00000x
www.rsc.org/
The synthesis of a broad variety of carbamates from amines, reactions13 prompted us to investigate the activity of
alcohols and carbon monoxide has been achieved by means of a commercially available rhodium complexes in the synthesis of
Rh-catalysed oxidative carbonylation reaction that uses Oxone as carbamates from amines, alcohols and carbon monoxide under
stoichiometric oxidant. In-depth studies on the reaction mild conditions. Moreover, in order to broaden the synthetic
mechanism shed light on the intimate role of Oxone in the significance and scope of this reaction we assessed Oxone
catalytic cycle.
(Potassium peroxymonosulfate, KHSO5) as oxidant, which is an
inexpensive, safe and environmentally friendly reagent.13e
Initial catalytic tests aimed at evaluating the activity of various
commercially available rhodium complexes in the oxidative
carbonylation of aniline with 1-hexanol (5 equivalents). The
reaction was completed after stirring at 100 ºC in toluene for
The importance of developing new routes that permit a more
efficient and straightforward access to organic carbamates is
well illustrated by the extensive application of these molecules
as pharmaceuticals, agrochemicals or materials in the chemical
industry.1 In addition, carbamates are commonly used as
amine protecting groups and are, therefore, important
intermediates or starting materials in modern synthetic
chemistry.2
Classic approaches to the synthesis of carbamates from amines
and alcohols usually entail the use of phosgene or its
derivatives.3 Other relevant stoichiometric methods use
azides,4 isocyanates,5 and CO2 or carbonates.6 Several
catalysed processes that employ CO2 as a C1 source, amines
and alcohols have also been developed.7
18 h under a carbon monoxide atmosphere (2 bar) using [Rh(
Cl)(COD)]2, [Rh( -MeO)(COD)]2 or [Rh( -Cl)(Cl)(Cp*)]2 (COD =
cyclooctadiene; Cp* pentamethylcyclopentadienyl) as
catalysts and Oxone as oxidant (3 equivalents). The Rh(III)
catalyst, [Rh( -Cl)(Cl)(Cp*)]2, led to formation of
carbamate/urea mixtures, while [Rh( -Cl)(COD)]2 and [Rh(μ-
μ-
μ
μ
=
μ
μ
MeO)(COD)]2 afforded exclusively the carbamate in identical
isolated yields (75%). Building on these results we decided to
explore the scope of [Rh(μ-Cl)(COD)]2 as a catalyst for this
reaction using a variety of amines and alcohols.
The synthesis of carbamates by oxidative carbonylation of N–H
bonds from readily available amines and alcohols has been
achieved by means of Pd8 and Au9 catalysts under high
pressures of CO, usually above 40 bar. Noteworthy exceptions
that operate under milder conditions are the methods
reported by Orito10 and Guang.11 An alternative method for
the synthesis of carbamates by carbonylation under low CO
pressure requires the use of aromatic and aliphatic azides as
starting materials.12
Aniline can be efficiently converted into its corresponding
carbamates employing a variety of primary and secondary
alcohols without the formation of decarboxylation products or
ureas (Scheme 1). The compatibility of this methodology with
a variety of amines was also tested (Scheme 2).
The excellent activity of Rh catalysts towards carbonylation
a.Departamento Química Inorgánica – ISQCH
Universidad de Zaragoza – CSIC, 50009 Zaragoza (Spain)
E-mail: miglesia@unizar.es; oro@unizar.es.
b.Departamento Química Física – Instituto de Biocomputación y Física de Sistemas
Complejos (BIFI)
c. King Fahd University of Petroleum & Minerals (KFUPM)
Dhahran 31261 (Saudi Arabia).
Universidad de Zaragoza, 50009 Zaragoza (Spain).
†Electronic Supplementary Information (ESI) available: DFT details. See
DOI: 10.1039/x0xx00000x
Scheme 1 Oxidative carbonylation of aniline with various alcohols (isolated yields after
16 h). a Isolated yield after 5 d.
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In view of the potential applicability of this methodology in the
synthesis of bioactive molecules it is significant that the
presence of carboxylic acids does not seem to thwart the
reaction, in fact, 2h is obtained in excellent yields. In addition,
compounds 2i and 2j were obtained from 2-aminopyridine and
cyclohexylamine, respectively, which demonstrates that the
catalyst performs well even with potentially chelating
substrates and with aliphatic amines.
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DOI: 10.1039/C6CC09133D
Scheme 4 Direct preparation of carbamates form imines (isolated yields).
In order to assess the scope of this methodology, a secondary
alcohol, 2-propanol, was used instead of 1-hexanol (Scheme
3). Except for 3c, 3e and 3j the expected carbamates were
Subsequently, the formation of the carbamate and
concomitant generation of H2O molecule and the
consumption of free amine from the reaction mixture would
drive the hydrolysis equilibrium toward the formation of more
amine.
a
obtained successfully, although the use of a secondary alcohol
seems to bring about somewhat lower yields in most cases,
probably due to its increased steric hindrance. In fact, bulky
amines such as ortho-substituted anilines or cyclohexylamine
are particularly affected. Remarkably, this methodology
permits the phosgene-free preparation of chlorpropham (3g),
an example of carbamate-based marketed drug.3a,12
The use of imines as starting materials also yields directly the
corresponding carbamates without the need for previous
transformation into the related amines. Compounds 1a and 1c
The mechanistic information on Rh-catalysed oxidative-
coupling reactions is limited, and the role played by the
oxidant is still a source of controversy. Moreover, the studies
published so far have focused mainly on Rh(III) catalysts that
make use of Cu(OAc)2 as stoichiometric oxidant.14,15 Recently,
various examples of alkoxycarbonylation of C–H bonds that
use Rh(I) catalysts and persulfates as the oxidant have been
reported.16 Two different mechanisms have been postulated
for this type of reactions.17 The first, proposed by Zhang et al.
for the directed alkoxycarbonylation of arenes, entails the
abstraction of a hydrido ligand, formed by previous oxidative
addition of the substrate’s C–H bond, and the proton of a
coordinated alcohol by Oxone (Scheme 5a).17a On the other
hand, a report by Li and co-workers proposes the oxidation of
were obtained by reaction of imines
4 and 5 with 1-hexanol or
2-propanol (Scheme 4). A plausible explanation for this
reaction would be that, in the presence of adventitious water,
the imines deliver in situ the corresponding amines.
[Rh(μ-Cl)(COD)]2 to a Rh(III) species by K2S2O8 as first step of
the catalytic cycle for the non-directed alkoxycarbonylation of
indenes (Scheme 5b).17b
Prompted by the scarce mechanistic knowledge on this type of
oxidations, we set off to study the role played by Oxone in the
catalytic cycle and the intimate mechanism through which the
complex or substrates interact with the oxidant.
An NMR study showed that a solution of 0.5 equivalents of
[Rh(μ
-Cl)(COD)]2, 1 equivalent of aniline, 1-hexanol and Oxone
CO
afforded complex [Rh(Cl)(CO)2(aniline)]18 under
a
atmosphere at room temperature in CD2Cl2. No further
reaction was observed upon an increase of the temperature to
50 oC. Attempts to detect CO insertion intermediates by
Scheme 2 Oxidative carbonylation of amines with 1-hexanol (isolated yields after 16 h).
reaction of [Rh(μ-Cl)(COD)]2 with aniline or 1-hexanol under a
CO atmosphere in toluene-d8 at 100 oC were unsuccessful.
However, when Oxone, 1-hexanol, aniline and 0.5 equivalents
o
of [Rh(
μ
-Cl)(COD)]2 were reacted at 100 C in toluene under a
CO atmosphere, the carbamate and [Rh(Cl)(CO)2(aniline)] were
obtained; conversely, at room temperature no carbamate
formation was observed. This suggests that, in this case, Oxone
acts before any metal-mediated substrate activation takes
place.
Scheme 3 Oxidative carbonylation of amines with 2-propanol (isolated yields after 16
h).
Scheme 5 Differences between the role played by the oxidant in the mechanisms
proposed by Zhang and Li.
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DOI: 10.1039/C6CC09133D
Fig. 1 DFT calculated Gibbs free energy profile (in kcal·mol–1 and relative to A and isolated molecules) for the Rh-catalysed oxidative carbonylation of amines.
methanol molecule interacts with Oxone by a hydrogen bond
to give adduct B’. This triggers the oxidation of Rh(I) to Rh(III)
by means of a concerted transition state (TSB’D) in which
Oxone deprotonates the methanol ligand and transfers the
–
hydroxo group to the metal. Simultaneously, release of HSO4
and formation of
The presence of the OH ligand allows for the deprotonation of
the coordinated amine, thus affording the aquo-complex via
TSDE, surmounting an energetic barrier of 8.1 kcalmol-1.
Carbonylation and isomerisation of gives Rh(III)-amido
complex . The downslope pathway thereafter (Fig. 2) entails
the migratory insertion of the carbonyl ligand into the M–N
bond, thus forming intermediate Finally, reductive
D upon coordination of aniline take place.
E
E
F
G.
elimination of the carbamoyl (RNHC(O)-) and alkoxo (RO-)
ligands, according to transition state TSGH, affords the
Fig. 2 DFT calculated Gibbs free energy profile (in kcal·mol–1 and relative to A and
corresponding carbamate and regenerates the catalyst (
after exchange of the carbonyl ligand by aniline.
A)
isolated molecules) for Rh-catalysed oxidative carbonylation of amines.
Noteworthy, the relatively low energy span calculated for the
In order to shed light on the reaction mechanism,
computational study at the DFT level was performed using the
B3LYP-D3 functional, considering [Rh(Cl)(CO)2(aniline)] as the
a
catalytic cycle (23.0 kcal·mol–1) from intermediate
D
to the
transition state TSFG does not seem to justify the high
temperatures required for this reaction. This apparent
inconsistency, however, is in accord with the almost negligible
solubility of Oxone in organic solvents and the ensuing
reactivity problems reported in the literature.19 Therefore, the
reaction rate probably depends on the concentration of Oxone
in the solution, which increases at higher temperatures. In this
regard, we performed the synthesis of 1a (Scheme 1) in the
presence of a phase transfer catalyst, namely 4 mol% of
catalyst (A) and MeOH as the alcohol. Fig. 1 shows the most
plausible mechanism of action of Oxone according to the
theoretical calculations and experimental data. Two related
pathways can be postulated. In the first, Oxone interacts
directly with [Rh(Cl)(CO)2(aniline)] (blue lines) while, in the
second, previous substitution of aniline by MeOH is required
(red lines). In both cases, the oxidation of the Rh centre and
the deprotonation of the substrate (alcohol or aniline) take
place according to a concerted mechanism at the beginning of
the catalytic cycle,‡ prior to substrate activation or migratory
insertion.§ Under the reaction conditions both reaction
pathways may occur simultaneously although the second path
(red lines) features a slightly lower activation barrier. This
mechanism entails that, after formation of A’, the coordinated
tetrabutylammonium tetrafluoroborate, which acts as
a
surfactant that solubilises Oxone. In this case, the reaction
takes place at 50 ºC; however, ca. 40% of aldehyde was
obtained as a by-product due to alcohol oxidation.
In conclusion, we have disclosed a Rh(I)-catalysed three-
component reaction that allows for the preparation of
carbamates from amines (or imines), alcohols and carbon
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Inesi, V. Mucciante and L. Rossi, J. Org. Chem. 1998, 63
,
monoxide under mild conditions, affording water and KHSO4 as
the only reaction by-products. This process is catalysed by the
commercially available complex [Rh(μ-Cl)(COD)]2 in the
1337−1338; d) W. D. McGhee, D. P. RiDleOyI,: 1M0..10E3.V9Ci/eCwh6rAiCrstCtic0lae9nO1dn3l3inKDe.
M. Christ, Organometallics 1993, 12, 1429−1433; e) R. N.
Salvatore, J. A. Ledger and K. W. Jung, Tetrahedron Lett.
2001, 42, 6023−6025.
presence of Oxone. This methodology shows a good tolerance
to several functional groups and is compatible with primary
and secondary alcohols. Theoretical and experimental data
suggest that Oxone plays a dual role as base and oxidant, thus
allowing for initial oxidation of the Rh(I) pre-catalyst to a Rh(III)
species—this step being essential to achieve substrate
activation. Remarkably, this transformation requires previous
coordination of the alcohol because its deprotonation and the
7
8
a) M. Abla, J. C. Choi and T. Sakakura, Chem. Commun. 2001,
2238−2239; b) M. Abla, J. C. Choi and T. Sakakura, Green
Chem. 2004, 6, 524−525; c) S. L. Peterson, S. M. Stucka and
C. J. Dinsmore, Org. Lett. 2010, 12, 1340−1343; d) A. Julián,
V. Polo, E. A. Jaseer, F. J. Fernández-Alvarez and L. A. Oro,
ChemCatChem 2015,
carbamates).
7, 3895–3902 (preparation of silyl
a) B. Gabriele, G. Salerno, R. Mancuso and M. Costa, J. Org.
Chem. 2004, 69, 4741–4750; b) F. Shi, Y. Deng, T. SiMa and
H. Yang, J. Catal. 2001, 203, 525–528; c) A. K. Ghosh and M.
Brindisi, J. Med. Chem. 2015, 58, 2895−2940; d) S. Fukuoka,
M. Chono and M. Kohno, J. Org. Chem. 1984, 49, 1458–1460;
e) H. Alper and F. W. Hartstock, J. Chem. Soc., Chem.
Commun., 1985, 1141–1142; f) S. Fukuoka, M. Chono and
Masashi Kohno, J. Chem. Soc., Chem. Commun., 1984, 399–
400; g) B. Gabriele, R. Mancuso, G. Salerno and M. Costa,
Top. Organomet. Chem. 2006, 18, 239–271.
oxidation of the metal centre occur by
mechanism.
a concerted
Acknowledgements
This work was supported by the Spanish Ministry of Economy
and Competitiveness (MINECO/FEDER) (CONSOLIDER INGENIO
CSD2009-0050, CTQ2013-42532-P and CTQ2015-67366-P
projects) and the DGA/FSE-E07. The support from KFUPM-
University of Zaragoza research agreement and the Centre of
Research Excellence in Petroleum Refining & KFUPM is
gratefully acknowledged. V. P. acknowledges the support of
BIFI-ZCAM. J. M. thanks the support from the Ministry of
Education Culture and Sports (FPU14/06003).
9
F. Shi and Y. Deng, Chem. Commun., 2001, 443–444.
10 a) K. Orito, M. Miyazawa, T. Nakamura, A. Horibata, H.
Ushito, H. Nagasaki, M. Yuguchi, S. Yamashita, T. Yamazaki,
M. Tokuda, J. Org. Chem. 2006, 71, 5951–5958.
11 b) Z.-H. Guan, H. Lei, M. Chen, Z.-H. Ren, Y. Bai and Y.-Y.
Wanga, Adv. Synth. Catal. 2012, 354, 489–496.
12 L. Rena and N. Jiao Chem. Commun., 2014, 50, 3706–3709.
13 a) J. P. Collman, L. S. Hegedus, J. R. Norton, R. G. Finke,
Principles and Applications of Organotransition Metal
Chemistry; University Science Books: Mill Valley, CA, 1978; b)
Hartwig, J. F.; Organotransition metal chemistry-from
bonding to catalysis. University Science Books. 2009, 753
,
Notes and references
757–578; c) F. J. Fernández-Alvarez, M. Iglesias, L. A. Oro and
V. Passarelli, in Comprehensive Inorganic Chemistry II, ed. J.
Reedijk and K. Poeppelmeier, Vol 8. Oxford: Elsevier; 2013. p.
399–432; d) Z.-H. Guan, Z.-H. Ren, S. M Spinella, S. Yu, Y.-M.
Liang and X. Zhang, J. Am. Chem. Soc. 2009, 131, 729–733; e)
R. Lang, J. Wu, L. Shi, C. Xi and F. Li, Chem. Commun., 2011,
47, 12553–12555; B. Liu, F. Hu, and B.-F. Shi, ACSCatal. 2015,
‡ The use of 3-chloroperoxybenzoic acid as oxidant with or
without an external base (K2SO4 or DMAP) fails to afford the
corresponding carbamates, which suggests that oxidant and
base act according to a concerted mechanism.
§ Alternative mechanisms where substrate activation precedes
Rh(I)→Rh(III) oxidation by Oxone or Rh(I)→Rh(III) oxidation by
Oxone occurs without substrate coordination show higher
activation energies (see ESI).
5
, 1863−1881; f) A. Iturmendi, P. J. Sanz Miguel, S. A.
Popoola, A. A. Al-Saadi, M. Iglesias and L. A. Oro, Dalton
Trans. 2016, 45, 16955–16965.
1
A. K. Ghosh and M. Brindisi, J. Med. Chem. 2015, 58,
14 For computational studies see: a) I. Funes-Ardoiz and F.
Maseras, Angew. Chem. Int. Ed. 2016, 55, 2764–2767; b) L.
Xu, Q. Zhu, G. Huang, B. Cheng and Y. Xia, J. Org. Chem.
2012, 77, 3017–3024; c) N. Quiñones, A. Seoane, R. García-
2895−2940.
2
for examples see: a) O. Dangles, F. Guibd and G. Balavoine, J.
Org. Chem. 1987, 52, 4984–4993; b) A. Merzouk, F. Guibé
and A. Loffet Tetrahedron Lett. 1992, 33, 477–480; c) G.
Hancock, I.J. Galpin, B.A. Morgan, 1982, 23, 249–252.
Fandiño, J. L. Mascareñas and M. Gulías, Chem. Sci. 2013, 4,
2874–2879; d) D. L. Davies, C. E. Ellul, S. A. Macgregor and C.
L. McMullin, J. Am. Chem. Soc. 2015, 137, 9659–9669; d) J.
Jiang, R. Ramozzi and K. Morokuma, Chem. Eur. J. 2015, 21
11158–11164.
3
For examples see: a) T. A. Unger in Pesticides Synthesis Book,
Ed. W. Andrew, Noyes Publications, New Jersey, 1996; b) H.
Babad and A. G. Zeiler, Chem. Rev. 1973, 73, 75–91; c) S. M.
Rahmathullah, J. E. Hall, B. C. Bender, D. R. McCurdy, R. R.
,
15 For experimental studies see: a) L. Li, W. W. Brennessel and
W. D. Jones, Organometallics 2009, 28, 3492–3500; b) N.
Wang, B. Li, H. Song, S. Xu and B. Wang, Chem. Eur. J. 2013,
19, 358–364.
Tidwell and D. W. J. Boykin, Med. Chem. 1999, 42
,
3994−4000; d) N. A. Roberts, J. A. Martin, D. Kinchington, A.
V. Broadhurst, J. C. Craig, I. B. Duncan, S. A. Galpin, B. K.
Handa, J. Kay, A. Krohn, R. W. Lambert, J. H. Merrett, J. S.
Mills, K. E. B. Parkes, S. Redshaw, A. J. Ritchie, D. L. Taylor, G.
J. Thomas and P. J. Machin, Science 1990, 248, 358−361; e)
H. Eckert and B. Forster, Angew. Chem., Int. Ed. Engl. 1987,
26, 894−895.
16 B. Liu, F. Hu and B.-F. Shi, ACS Catal. 2015, 5, 1863−1881.
17 a) Z.-H. Guan, Z.-H. Ren, S. M. Spinella, S. Yu and Y.-M. Liang,
Zhang, X. J. Am. Chem. Soc. 2009, 131, 729−733; b) R. Lang, J.
L. Wu, L. J. Shi, C. G. Xia, and F. W. Li, Chem. Commun. 2011,
47, 12553−12555.
4
5
6
E. F. V. Scriven and K. Turnbull, Chem. Rev. 1988, 88,
18 D. N. Lawson and G. Wilkinson, J. Chem. Soc. 1965, 1900–
1907.
19 a) E. P. Bulman Page and B. R. Buckley in Mechanisms in
Homogeneous and Heterogeneous Epoxidation Catalysis, Ed.:
S. T. Oyama, Elsevier, Oxford, 2008, pp. 177–217; b) B. M.
Trost, R. Braslau, J. Org. Chem., 1988, 53, 532–537.
297−368.
G. Raspoet and M. T. Nguyen J. Org. Chem. 1998, 63, 6878–
6885.
a) M. Yoshida, Na. Hara and S. Okuyama, Chem. Commun.,
2000, 151–152; b) T. Tsuda, K. Watanabe, K. Miyata, H.
Yamamoto and T. Inorg. Chem. 1981, 20, 2728−2730; c) A.
4 | J. Name., 2012, 00, 1-3
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