Palladium-Catalyzed Carboxy-Alkynylation of Propargylic Amines Using Carbonate Salts as Carbon Dioxide Source

Article abstract of DOI:10.1002/ejoc.201900500

A palladium-catalyzed multicomponent reaction of propargylic amines, alkynyl bromides and cesium hydrogen carbonate to access oxazolidinones is reported. In contrast to previous reports, only a slight excess of cesium hydrogen carbonate is used as a surrogate of carbon dioxide. The reaction gives access to oxazolidinones bearing alkyl- and aryl polysubstituted enynes in good yield and very high E stereoselectivity.

Full text of DOI:10.1002/ejoc.201900500

A Journal of
Accepted Article
Title: Palladium-Catalyzed Carboxy-Alkynylation of Propargylic Amines
Using Carbonate Salts as Carbon Dioxide Source
Authors: Phillip D. G. Greenwood and Jerome Waser
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900500
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900500
Supported by

10.1002/ejoc.201900500
European Journal of Organic Chemistry
COMMUNICATION
Palladium-Catalyzed Carboxy-Alkynylation of Propargylic Amines
Using Carbonate Salts as Carbon Dioxide Source
Phillip D. G. Greenwood and Jerome Waser*[a]
Abstract:
A
palladium-catalyzed multi-component reaction of
with a carbonate salt as source of CO2 in a reaction or acting
directly as a nucleophile/electrophile.[3a,b,12] In 1996, Costa and
co-workers developed an organic super base catalysed
carboxylation of propargylic amines. This publication contained a
single example of the use of a tetramethylguanidinium carbamate
amine complex as a carrier for CO2.[3a] In a subsequent work two
years later they showed the use of sodium hydrogen carbonate
as the CO2 source.[3b] The reaction between epoxide and sodium
hydrogen carbonate catalysed by tetrabutylammonium bromide
was also developed as a viable pathway to access cyclic
carbonates.[12] Trost and co-workers reported the use of
carbonates in the palladium-catalyzed enantioselective ring-
opening of vinyl epoxides to give either diols or cyclic
carbonates.[13]
propargylic amines, alkynyl bromides and cesium hydrogen
carbonate to access oxazolidinones is reported. In contrast to
previous reports, only a slight excess of cesium hydrogen carbonate
is used as surrogate of carbon dioxide. The reaction gives access to
oxazolidinones bearing alkyl- and aryl polysubstituted enynes in good
yield and very high E stereoselectivity.
Introduction
The utilisation of the greenhouse gas CO2 has attracted
significant interest over recent years.[1] For the organic chemistry
community, focus has been on incorporating CO2 into organic
molecules for the synthesis of valuable compounds and
commodity chemicals.[2] As an important application, insertion of
CO2 into propargylic amines to form oxazolidinones has been
achieved using a range of diverse conditions (Scheme 1).[3,4]
Transformations without metal catalysts require harsh or
specialized conditions, such as super bases[3a-d] or super critical
CO2.[3e,f] A number of transition-metal catalysed processes
allowing milder r eaction conditions have been developed using
ruthenium[4a] palladium,[4b,c] silver,[4d-i] gold[4j,k] and zinc[4l] catalysts,
as well as a copper substituted ionic liquid.[4m] In all of these
reported methods, the addition of CO2 has been combined with
protonation of the triple bond in the propagylic amines, resulting
in the formation of a C-O and a C-H bond (Scheme 1A).[5]
Recently the Nevado group demonstrated through the use of
palladium catalysis that a carboxylation-arylation sequence can
be performed as part a new multicomponent synthesis of
oxazolidinones (Scheme 1B).[6] Using gaseous CO2 at
atmospheric pressure, they obtained tetra-substituted alkenes via
C-O and C-C bond formation, allowing for a broader range of
oxazolidinones to be synthesised. Developing efficient methods
to access oxazolidinones is important, as they are useful as
intermediates[7] or chiral auxiliaries[8] in organic synthesis. They
are also found in agrochemicals and antibacterial drugs[9] and
their material properties have even been exploited for applications
in lithium battery technology.[10]
Scheme 1. Synthesis of oxazolidinones from propargylic amines.
As most carboxylation reactions, the developed approaches
are usually based on the use of gaseous CO2, which is convenient
as it is widely available. However, the use of a gas leads to
inefficient mass transport at the gas/liquid interface,[11] resulting in
a poor atom economy. For example, a 1 mmol reaction with a 2
litre balloon of CO2 has an excess of 89 equivalents of CO2.
Therefore, it is sometimes advantageous to have a solid CO2
source to enable easier handling and better reaction efficiency. In
this context, a limited number of examples have been reported
Herein, we describe a convenient method for the palladium
catalysed three-component synthesis of oxazolidinones from
propargylic amines with cesium hydrogen carbonate as the C1
source instead of gaseous CO2 (Scheme 1C). Alkynyl bromide 1
was used as a third partner, resulting in a new stereoselective
synthesis of highly substituted enynes.[14]
[a]
Phillip Greenwood, and Prof. Dr. Jerome Waser
Laboratory of Catalysis and Organic Synthesis
Ecole Polytechnique Fédérale de Lausanne
EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne (CH)
Fax: (+)41 21 693 97 00
Results and Discussion
While working on the palladium catalysed oxyalkynylation of
propargylic
amines
tethered
by
trifluoroacetaldehyde
E-mail: jerome.waser@epfl.ch
Homepage: http://lcso.epfl.ch/
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900500
European Journal of Organic Chemistry
COMMUNICATION
derivatives,[15] an unexpected side reaction was observed: When
the reaction of propargylic amine 2a with silyl alkynyl bromide 1
and half acetal 3 was examined, oxazolidinone product 5a was
observed in addition to the expected product 4 (Scheme 2). This
was confusing, as there was no obvious source of CO2 in the
reaction. When the reaction was performed in the absence of
hemiacetal tether with or without a balloon of CO2, exclusive
formation of oxazolidinone 5a was observed. The formation of 5a
could be finally suppressed to give 4 in high yield by the use of
non-carbonate bases, establishing the latter as the source of the
CO2 group. When considering the lack of reports in the use of
carbonate salts in the palladium-catalyzed multi-component
synthesis of oxazolidinones, combined with the fact that enynes
were never reported as products, we decided to optimize the
formation of 5a. CsHCO3 was finally identified as the best CO2
source, with a palladium-DPEPhos complex as catalyst in DCE at
60 °C (Table 1, entry 1). Under these conditions, product 5a was
obtained in 77% isolated yield.
moved on to propargylic amines bearing aromatic groups on the
alkyne.
N-benzyl-3-phenylprop-2-yn-1-amine
with
an
unsubstituted phenyl ring gave enyne 5g in 81% yield.
Substituting the nitrogen with a methyl group gave 5h with a
reduced yield of 66%. 4-Methoxy (5i), 4-trifluromethyl (5j) and 3-
bromo (5k) substituents were tolerated on the aryl ring, giving
moderate to good yields. Introducing two methyl substituents at
the meta positions (5l) had no detrimental effect on the reaction.
Finaly, a propargylic amine with a heteroaromatic thiophene
group on the alkyne gave enyne 5m in 47% yield. Substrates with
aromatic substituents on the alkyne required increased reaction
temperatures and longer reaction time to reach full conversion. All
reactions gave a single isomer of the product and the E
configuration of the olefin was established by X-ray analysis on
compound 5g.[17] The configuration of the other compounds was
assumed to be the same based on the similar NMR spectra.
Table 1. Optimisation of the carboxylation-alkynylation of 2a.[a]
Scheme 2. Unexpected formation of oxazolidinone 5a observed during the
tethered oxyalkynylation of propargylic amine 2a.
Entry
1
Changes to Standard conditions
none
5a (%)[b]
2a(%)
80 (77)[c]
40
<14
64
64
2
Not surprisingly, the structure of the base had a strong
impact on the outcome of the reaction. The carbonate salts of both
cesium and rubidium gave the desired product albeit with modest
yield (entry 2). The use of salts of smaller cations gave poor yields
and calcium and barium carbonates gave no product formation at
all (entry 3). A higher temperature of 75 °C (entry 4), and a lower
temperature of 50 °C (entry 5) both led to a lower yield of 64%,
with the latter giving incomplete conversion. The choice of ligand
played a central role in the oxyalkynylation reaction using
hemiacetal tether 3.[15,16] Therefore, we examined again the most
successful ligands from the previous protocol (DCEPhos,
XantPhos and dppf). However, they led to the the formation of
oxazolidinone 5a in low yields only (entries 6-8). Different solvents
(entries 9-11) and palladium sources were also explored (see
Supporting Information), but none of the changes provided any
improvement. Both the palladium loading (entry 12) and the
equivalence of base (entry 13) could be decreased. However, this
led to longer reaction time and incomplete conversion. Finally,
when the reaction was carried out with a balloon of CO2, the same
yield was obtained (entry 14). The addition of 4Å molecular sieves
had no influence on the reaction outcome (entry 15). The
transformation was clean and only starting material and product
were observed.
2
Cs2CO3 or Rb2CO3 as base[d]
Other carbonates[e] as base[d]
at 75 °C
<9
3
30-40
4
5
at 50 °C
7
6
DCEPhos instead of DPEPhos
XantPhos instead of DPEPhos
dppf instead of DPEPhos
Chlorobenzene instead of DCE
Trifluorotoluene instead of DCE
Chloroform instead of DCE
half catalyst loading
15
50
20
46
5
7
4
8
50
3
9
10
11
12
13
14
15
41
40
68
69
80
76
4
5
1 equivalent base
5
With a CO2 balloon
-
In presence of 4Å MS
-
[a] Reaction conditions: 0.10 mmol 2a, 0.13 mmol 1, 0.20 mmol CsHCO3 in
DCE at 60 °C. [b] NMR yields using p-difluorobenzene as internal standard.
[c] Isolated yield. [d] Reactions run at 75 °C [e] Li2CO3, Na2CO3, K2CO3,
NaHCO3, CaCO3, and BaCO3 were examined.
With the optimised conditions in hand, we moved on to study
the scope of the reaction (Scheme 3). We start by looking at
aliphatic groups on the nitrogen; para-methoxy benzyl and
ferrocenylmethyl protected propagylic amines were used
succesfully in the reaction to give 5b and 5c. On the alkyne, a
primary benzyl (5d) and a secondary cyclopropyl (5e) groups
were both well tolerated in the reaction. The tert-butyl substituted
enyne 5f was obtained in lower yields and required longer
reaction times and higher temperature for full conversion. We then
When
a
terminal acetylene substrate, N-benzyl
propynylamine, was subjected to the same reaction conditions,
only trace amounts of carboxylation product was observed. The
use of substrates with substituents at the propargylic position or
an attempt of carboxy-arylation as well as carboxy-alkynylation
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900500
European Journal of Organic Chemistry
COMMUNICATION
with aryl- or alkyl- substituted bromoalkynes were also not
successful, even with the ligands applied to these classes of
substrates in the aminal-tethered oxyalkynylation reaction (trifuryl
phosphine and RuPhos). These reactions were also performed
under CO2 atmosphere, but the carboxylation products were still
not observed.
We propose therefore an alternative pathway for the mechanism
of this reaction (Scheme 4B). First, oxidative addition of the
palladium(0) complex on alkynyl bromide
1
generates
palladium(II) complex I. Coordination of the alkyne substrate
leads then to activation of the triple bond (II).[18] This step most
probably requires first dissociation of the bromide anion to
generate a more reactive cationic palladium intermediate with a
The mechanism that is generally proposed for the
carboxylation of propargylic amines involves the nucleophilic
attack of the nitrogen onto the carbon of CO2 to give a carbamate
anion which then undergoes a 5-exo-dig cyclisation onto the triple
bond activated by palladium (Scheme 4A). In our case, this seems
unlikely, as the carbon of the hydrogen carbonate anion is much
less electrophilic and the reaction also works with carbonates. It
may be possible that the carbonate is undergoing decomposition
under the reaction conditions to produce CO2. However, this
seems unlikely as the yields obtained would be very high for the
generation of only one or two equivalents of CO2 gas.
Furthermore, many palladium-catalyzed reactions use carbonate
bases under similar conditions, but report of CO2 incorporation
remains exceedingly rare, speaking against an efficient
generation of gaseous CO2 from the carbonates.
free coordination site.[19] The carbonate attacks as
a
nucleophile,[13,20] to give trans oxy-palladation intermediate III.
Intramolecular nucleophilic attack by the nitrogen gives with
elimination of water gives then vinyl palladium complex IV.
Reductive elimination finally leads to the observed product. In this
scenario, the oxypalladation step would probably not occur with
high regioselectivity, but may be reversible. Fast formation of the
oxazolidinone product is possible only for the drawn regioisomer.
Alternatively, hydrogen bonding between the amine and the
carbonate may direct the attack of the nucleophile. Further
investigation will be needed to support this mechanism
hypothesis.
Scheme 4. Proposed mechanism for the carboxy-alkynylation reaction.
Conclusions
In summary, we have presented an unprecedented palladium
catalyzed carboxylation-alkynylation reaction using
a solid
inorganic hydrogen carbonate source of CO2. It gives access to
highly substituted enynes substrates with very high
stereoselectivity. The exceptional efficiency of the reaction may
suggest an interesting mechanism pathway, which should be
more strongly supported by further studies.
Acknowledgments
Scheme 3. Scope of the carboxylation-alkynylation reaction. [a] Product
isolated with 1-7.5% dba as impurity. Substrates with aromatic alkynyl groups
required 24-48 h at 75 °C.
This work is supported by the Swiss National Science Foundation
(No. 200021_159920), the European Research Council (ERC
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900500
European Journal of Organic Chemistry
COMMUNICATION
Consolidator Grant No. 771170 and EPFL. We thank Dr. R.
Scopelliti and Dr. F. F. Tirani from ISIC at EPFL for X-ray analysis.
J. Waser, Org. Lett. 2017, 19, 3548; d) U. Orcel, J. Waser, Chem. Sci.
2017, 8, 32
[17] The data is available at the Cambridge Crystallographic Data Center
(ccdc number: 1905359). For an example of highly stereoselective
nickel-catalyzed bifunctionalization of alkynes with carbon dioxide, see:
X. Wang, Y. Liu, R. Martin, J. Am. Chem. Soc. 2015, 137, 6476.
[18] R. Chinchilla, C. Nájera, Chem. Rev. 2014, 114, 1783.
[19] We thank the reviewer for highlighting this point. Potentially, the scope
of the reaction could be further improved by increasing the amount of
more reactive cationic palladium intermediates. In fact, carboxy-arylation
with phenyl iodide was observed in about 30% yield with silver
tetrafluoroborate as additive (see Supporting Information). This
preliminary result is promising for further extending the scope of the
methodology.
Keywords: palladium catalysis • alkynes • heterocycles • carbon
dioxide • multi-component reactions
[1]
a) D. L. Tomasko, H. Li, D. Liu, X. Han, M. J. Wingert, L. J. Lee, K. W.
Koelling, Ind. Eng. Chem. Res. 2003, 42, 6431; K. Sumida, D. L. Rogow,
J. A. Mason, T. M. McDonald, E. D. Bloch, Z. R. Herm, T. H. Bae, J. R.
Long, Chem. Rev. 2012, 112, 724-781. b) M. Poliakoff, W. Leitner, E. S.
Streng, Faraday Discuss. 2015, 183, 9; c) E. Alper, O. Y. Orhan,
Petroleum 2017, 3, 109; d) E. I. Koytsoumpa, C. Bergins, E. Kakaras, J.
Supercrit. Fluids 2018, 132, 3.
[20] a) N. Bosworth, P. Magnus, R. Moore, J. Chem. Soc., Perkin Trans. 1
1973, 2694; b) B. J. Lüssem, H.-J. Gais, J. Am. Chem. Soc. 2003, 125,
6066; c) F. D. Bobbink, W. Gruszka, M. Hulla, S. Das, P. J. Dyson, Chem.
Commun. 2016, 52, 10787.
[2]
[3]
a) T. Sakakura, J.-C. Choi, H. Yasuda, Chem. Rev. 2007, 107, 2365; b)
M. Cokoja, C. Bruckmeier, B. Rieger, W. A. Herrmann, F. E. Kuhn,
Angew. Chem., Int. Ed. 2011, 50, 8510; c) Q. Liu, L. P. Wu, R. Jackstell,
M. Beller, Nature Commun. 2015, 6; d) A. Tortajada, F. Julia-Hernandez,
M. Borjesson, T. Moragas, R. Martin, Angew. Chem., Int. Ed. 2018, 57,
15948.
a) M. Costa, G. P. Chiusoli, M. Rizzardi, Chem. Commun. 1996, 27,
1699; b) M. Costa, G. P. Chiusoli, D. Taffurelli, G. Dalmonego, J. Chem.
Soc. Perkin Trans. 1 1998, 1, 1541; c) R. Nicholls, S. Kaufhold, B. N.
Nguyen, Cat. Sci. Technol. 2014, 4, 3458; d) N.-K. Kim, H. Sogawa, K.
Yamamoto, Y. Hayashi, S. Kawauchi, T. Takata, Chem. Lett. 2018, 47,
1063; e) Y. Kayaki, M. Yamamoto, T. Suzuki, T. Ikariya, Green Chem.
2006, 8, 1019; f) C. Bertolotti, M. Selva, R. Maggi, E. Orlandini, G. Sartori,
C. Oro, Tetrahedron Lett. 2007, 48, 2131; g) For a review, See: S.
Arshadi, E. Vessally, M. Sobati, A. Hosseinian, A. Bekhradnia, J. CO2
Util. 2017, 19, 120.
[4]
a) T. Mitsudo, Y. Hori, Y. Yamakawa, Y. Watanabe, Tetrahedron Lett.
1987, 28, 4417; b) M. Shi, Y. M. Shen, J. Org. Chem. 2002, 67, 16; c) P.
Brunel, J. Monot, C. E. Kefalidis, L. Maron, B. Martin-Vaca, D. Bourissou,
ACS Catal. 2017, 7, 2652; d) S. Yoshida, K. Fukui, S. Kikuchi, T. Yamada,
Chem. Lett. 2009, 38, 786; e) M. Yoshida, T. Mizuguchi, K. Shishido,
Chem. Eur. J. 2012, 18, 15578; f) T. Ishida, R. Kobayashi, T. Yamada,
Org. Lett. 2014, 16, 2430; g) K. Sekine, R. Kobayashi, T. Yamada, Chem.
Lett. 2015, 44, 1407; h) N. Sugiyama, M. Ohseki, R. Kobayashi, K.
Sekine, K. Saito, T. Yamada, Chem. Lett. 2017, 46, 1323; i) Z. Chang, X.
Jing, C. He, X. Liu, C. Duan, ACS Catal. 2018, 8, 1384; j) S. Hase, Y.
Kayaki, T. Ikariya, ACS Catal. 2015, 5, 5135; k) K. I. Fujita, K. Inoue, J.
Sato, T. Tsuchimoto, H. Yasuda, Tetrahedron 2016, 72, 1205; l) X. Liu,
M. Y. Wang, S. Y. Wang, Q. Wang, L. N. He, ChemSusChem 2017, 10,
1210; m) M.-Y. Wang, Q.-W. Song, R. Ma, J.-N. Xie, L.-N. He, Green
Chem. 2016, 18, 282.
[5]
[6]
[7]
With the exception of ref. 4g,h, which report the formation of a C-O and
a C-halogen bond.
P. García-Domínguez, L. Fehr, G. Rusconi, C. Nevado, Chem. Sci. 2016,
7, 3914.
a) K. Benakli, C. X. Zha, R. J. Kerns, J. Am. Chem. Soc. 2001, 123, 9461-
9462; b) S. Gibson, H. K. Jacobs, A. S. Gopalan, Tetrahedron Lett. 2011,
52, 887.
[8]
[9]
D. A. Evans, J. Bartroli, T. L. Shih, J. Am. Chem. Soc. 1981, 103, 2127.
a) D. J. Diekema, R. N. Jones, Lancet 2001, 358, 1975; b) M. R.
Barbachyn, C. W. Ford, Angew. Chem., Int. Ed. 2003, 42, 2010; c) N.
Pandit, R. K. Singla, B. Shrivastava, Int. J. Med. Chem. 2012, 2012, 1.
[10] N. Nanbu, K. Hagiyama, M. Takehara, M. Ue, Y. Sasaki,
Electrochemistry 2010, 78, 450.
[11] A. Broderick, M. A. Rocha, Y. Khalifa, M. B. Shiflett, J. T. Newberg, J.
Phys. Chem. B 2019, 123, 2576.
[12] Nishikubo, T.; Kameyama, A.; Sasano, M. J. Polym. Sci. A 1994, 32, 301.
[13] B. M. Trost, E. J. McEachern, J. Am. Chem. Soc. 1999, 121, 8649.
[14] For an iodination-cross-coupling approach for the synthesis of
oxazolidinone enynes, see: T. F. Tam, E. Thomas, A. Krantz,
Tetrahedron Lett. 1987, 28, 1127.
[15] P. D. G. Greenwood, E. Grenet, J. Waser, Chem. Eur. J. 2019, 3010.
[16] a) U. Orcel, J. Waser, Angew. Chem., Int. Ed. 2015, 54, 5250; b) U. Orcel,
J. Waser, Angew. Chem., Int. Ed. 2016, 55, 12881; c) B. Muriel, U. Orcel,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900500
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Catalysis
Phillip D. G. Greenwood and Jerome
Waser*
Page No. – Page No.
Palladium-Catalyzed Carboxy-
Alkynylation of Propargylic Amines
Using Carbonate Salts as Carbon
Dioxide Source
A palladium-catalyzed multi-component reaction of propargylic amines, alkynyl
bromides and cesium hydrogen carbonate to access oxazolidinones is reported. In
contrast to previous reports, only a slight excess of cesium hydrogen carbonate is
used as surrogate of carbon dioxide.
This article is protected by copyright. All rights reserved.