COtab: Expedient and Safe Setup for Pd-Catalyzed Carbonylation Chemistry

Article abstract of DOI:10.1021/acs.orglett.9b01423

Bench-stable tablets (COtabs) have been developed for the rapid and safe production of carbon monoxide. The tablets can be made in less than 5 min without the use of a glovebox and only require a stock solution of an amine base to liberate a specific quantity of CO in a two-chamber system. The COtabs were tested in five different carbonylation reactions and provided similar yields compared to literature procedures. Finally, a gram-scale reaction was conducted, as well as ¹³C-isotope labeling of the anticancer drug, olaparib.

Full text of DOI:10.1021/acs.orglett.9b01423

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
COtab: Expedient and Safe Setup for Pd-Catalyzed Carbonylation
Chemistry
Hugo P. Collin,†,§,∇ Wallace J. Reis,†,∥,∇ Dennis U. Nielsen,*,† Anders T. Lindhardt,⊥
Marcelo S. Valle,§ Rossimiriam P. Freitas,∥ and Troels Skrydstrup*,†
†Department of Chemistry, Interdisciplinary Nanoscience Center (iNANO), Carbon Dioxide Activation Center (CADIAC), Aarhus
University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark
§
̂
Departamento de Ciencias Naturais, Universidade Federal de Sao
̃
Joao
del-Rei, Sao Joao del-Rei, MG 36301-160, Brazil
̃ ̃ ̃
∥
̂
Departamento de Química, ICEx, UFMG, Av. Pres. Antonio Carlos, 6627, Pampulha, Belo Horizonte, MG 31270-901, Brazil
⊥
́
Danish Technological Institute, Life Science Division, Kongsvang Alle 29, 8000 Aarhus C, Denmark
S
* Supporting Information
ABSTRACT: Bench-stable tablets (COtabs) have been
developed for the rapid and safe production of carbon
monoxide. The tablets can be made in less than 5 min without
the use of a glovebox and only require a stock solution of an
amine base to liberate a specific quantity of CO in a two-
chamber system. The COtabs were tested in five different
carbonylation reactions and provided similar yields compared
to literature procedures. Finally, a gram-scale reaction was
conducted, as well as 13C-isotope labeling of the anticancer
drug, olaparib.
ransition-metal-catalyzed carbonylation chemistry is a
demonstrate the applicability of these tablets in five different
Tpowerful methodology for installing carbonyl groups into
organic molecules.1 Although carbon monoxide (CO) is a
useful C1-building block, the inherent toxic properties of this
gaseous molecule raise several safety concerns. To avoid
potential gas leaks while handling pressurized cylinders, the
utility of CO-releasing molecules has seen a tremendous
increase during the past decade.2 In 2011, we reported on the
ex situ formation of CO from a crystalline acid chloride
(COgen), which enabled the safe liberation of this diatomic
molecule in a two-chamber system (COware).3 Since then, we
have reported on numerous carbonylative transformations
utilizing this setup.4 Although the safety concern can be
eliminated by applying this strategy in small-scale reactions, it
is still not without its drawbacks as the methodology requires
an inert atmosphere, and therefore, reactions are set up in a
glovebox. Furthermore, the ex situ formation of CO requires
five components (COgen, Pd-source, phosphine ligand, base,
and solvent), which makes it time-consuming to conduct
several reactions at once. Since gloveboxes may not be
standard equipment in all chemistry laboratories, and time is
often an issue for compound synthesis in pharmaceutical
companies, we became interested in finding solutions to
increase the utility of COgen in order to make the CO release
more user-friendly.
carbonylative transformations using the double-chamber
system, COware, as well as the possibility for its facile
exploitation in 13C-isotope labeling and a gram-scale reaction.
Handling of moisture-sensitive compounds can be simplified
by submerging the reagent in a protective matrix (Scheme 1).
A common example is sodium hydride, which is commercial-
ized as a 60% mixture in mineral oil. Similar to this concept,
pyrophoric reagents such as potassium hydride5 or triethyla-
Scheme 1. Air- and Moisture-Sensitive Reagents/Catalysts
Embedded in Paraffin/Mineral Oil
In this paper, we report on air-stable tablets (COtabs) that
can be rapidly produced without special precautions and which
release CO by merely adding a stock solution of base. We
Received: April 24, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01423
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
luminum6a can be handled in air by utilizing paraffin wax. Air-
sensitive catalysts such as chromium(III) complexes for
ethylene oligomerization7 or metathesis-catalysts based on
the work from Schrock and Hoveyda6 or Grubbs8 can also
successfully be embedded in paraffin wax to avoid catalyst
decomposition in air. In 2015, Buchwald and co-workers
reported on the use of hollow paraffin wax capsules containing
air-sensitive Pd catalysts and reagents for conducting coupling
reactions without the need for a glovebox.9 Following this
report, Garg published on a similar strategy for handling the
air-sensitive Ni(0) source, Ni(cod)2.10 Finally, Wu utilized the
encapsulation method for performing multicomponent reac-
tions with thiols, thereby avoiding catalyst poisoning and the
foul smell often associated with these compounds.11 These
protocols point to the important feature that simple solutions
can be employed to solve troublesome challenges in the
laboratory. Although useful, and commercially available for
most cases, the compounds depicted in Scheme 1 still require a
glovebox for storage before being embedded in the protective
matrix.
rationalized that pressing the reagents together under high
pressure into a tablet might be an alternative but good
solution. We therefore mixed COgen, HBF4P(tBu)3 (0.5 mol
%), and Pd(OAc)2 (0.5 mol %) in a mortar,13 which provided
a uniformly distributed powder (COgen premix)14 upon
grinding that could be compressed into a tablet (COtab) using
a hydraulic press (Scheme 2b). The time efficiency of the
process should be stressed as it takes less than 5 min to make a
tablet.15 The issue of the base was solved by preparing a 0.25
M solution of Cy2NMe in dioxane.
With the COtabs in hand, we decided to test the efficiency
of the tablets and compare them to carbonylation reactions set
up in a glovebox with COgen. By using CO as the limiting
reagent, amide 1 could be isolated in a nearly quantitative yield
(95%) using either a glovebox procedure or COtabs set up in a
fumehood (Scheme 3).3,16
Scheme 3. Aminocarbonylations Performed in a Glovebox
a
with COgen or with COtabs on a Benchtop
Inspired by these reports, we sought to develop a similar
protocol for a glovebox-free and practical generation of CO in
a two-chamber system. We initially chose the paraffin wax
capsules designed by Buchwald as the delivery system. The
goal was to include all reagents (Scheme 2a) into a single
Scheme 2. CO Generation from COgen
a
For specific reaction conditions, see the Supporting Information.
Excited by these results, we evaluated other amino-
carbonylations as depicted in Scheme 3.17 Boc-protected
hydrazine could be employed as a potent nucleophile resulting
in high isolated yields for 2.18 A precursor for the antipsychotic
drug, quetiapine (3),19 was synthesized through an intra-
molecular aminocarbonylation. Nikethamide (4, respiratory
stimulant),20 the melanoma PET tracer 5,21 and moclobemide
(6, antidepressant)22 could all be isolated in high yields.
Importantly, COtabs provided a similar result compared to the
reactions set up in a glovebox.
Aminocarbonylation reactions are among the most reliable
carbonylation reactions due to the lack of a competing direct
reaction, in this case the Buchwald−Hartwig amination.23 In
order to demonstrate the efficiency of the COtabs, we
therefore turned our attention to more CO-sensitive reactions,
whereby the direct coupling is challenging to suppress
(Scheme 4). This was demonstrated by the synthesis of
three alkynones (7−9) via a carbonylative Sonogashira
reaction24 whereby COtabs provided similar yields compared
to the glovebox procedure. The carbonylative Mizoroki−Heck
reaction was also achieved in the preparation of compounds
capsule to render the process more time-efficient. Since the
active Pd(0) catalyst can be formed in situ from Pd(OAc)2 and
the HBF4 salt of P(tBu)3 as reported by Fu, a glovebox was not
required.12 Liquid tertiary amine bases such as DIPEA or
Cy2NMe are usually the best choice for the decarbonylation of
COgen under the previously reported conditions, which in this
setup would not be applicable. Screening of a range of solid
bases revealed 1-cyclohexyl-4-tosylpiperazine to be a promising
candidate (results not shown). However, fitting all reagents
into a single hollow wax capsule proved to be challenging, and
removal of the wax residues from the two-chamber system was
likewise tedious. Discouraged by this, we decided to pursue the
development of a more traditional approach. As the mass of
the reagents was problematic for the paraffin capsule, we
B
DOI: 10.1021/acs.orglett.9b01423
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
As a final demonstration of the applicability of COtabs, the
anticancer drug olaparib (20)33 was prepared with a carbon-13
isotope label merely by employing a COtab composed of 13C-
labeled COgen (Scheme 5).34 A gram-scale synthesis of the
Scheme 4. Carbonylative C−C Bond-Forming Reactions
Comparing Glovebox Conditions with COtab and
a
BenchTop Conditions
Scheme 5. Scale-up and 13C-Labeling of Olaparib
drug in a yield of 91% could be obtained by adding 10 COtabs
(5 mmol of CO) to a larger COware system (see the
Supporting Information for experimental details).
In conclusion, we have developed small tablets (COtabs)
that can liberate CO in the presence of a stock solution of
Cy2NMe. The tablets can easily be prepared by mixing COgen,
Pd(OAc)2, and HBF4P(tBu)3 in a mortar and pressing the
resulting powder in a hydraulic press. The formation of these
tablets can be accomplished without precautions to exposure
to air, and the tablets can be stored in a bottle without any
trace of decomposition being observed.35 The use of COtabs
was demonstrated in five different carbonylation reactions, and
the same efficiency for these transformations was obtained
compared to the original literature. Furthermore, 13C-isotope
labeling, as well as gram-scale synthesis, was also demonstrated.
We anticipate that this glovebox-free carbonylation protocol
will be of great utility for chemists without access to specialized
equipment, such as a glovebox or CO-containing cylinders,
who wish to carry out Pd-catalyzed carbonylation reactions.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01423.
Experimental procedures, product characterization and
spectral data (PDF)
a
For specific reaction conditions, see the Supporting Information.
AUTHOR INFORMATION
Corresponding Authors
■
10−12 as demonstrated in Scheme 4.25 Furthermore, by
utilizing conditions favoring the carbonylative Suzuki−Miyaura
reaction,26 precursors for suprofen (NSAID)27 and benzodia-
zepines28 (compounds 13 and 14) could be obtained, as well
as the blood cholesterol lowering drug fenofibrate (15).29
Finally, three different types of carbonylative α-arylation
reactions were successfully demonstrated, resulting in the
formation of 1,3-diketones 16 and 17,30 the pyrazine-
containing ketone 18,31 and the 1,3-ketoamide 19.32 Gratify-
ingly, using COtabs for a glovebox-free alternative did not lead
to a loss of efficiency compared to the original procedure.
*E-mail: dun@chem.au.dk.
*E-mail: ts@chem.au.dk.
ORCID
Hugo P. Collin: 0000-0001-9483-7183
Dennis U. Nielsen: 0000-0002-4521-5991
Troels Skrydstrup: 0000-0001-8090-5050
Author Contributions
∇H.P.C. and W.J.R. contributed equally.
C
DOI: 10.1021/acs.orglett.9b01423
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Notes
Letter
which might provide an alternative solution for laboratories that do
not have access to a hydraulic press.
The authors declare the following competing financial
interest(s): A.T.L. and T.S. are co-owners of SyTracks A/S,
which commercializes the two-chamber system (COware) and
COgen premix.
(15) The developed COtabs do not offer significant advantages
regarding stability or reproducibility compared to adding the
components individually. However, conducting several carbonylation
reactions at once can be realized more rapidly using COtabs.
(16) Using Pd(OAc)2 instead of Pd(dba)2 as the precatalyst for CO-
formation setup in a fumehood did not have an effect on the yield, as
1 was produced in an identical yield.
(17) For carbonylation reactions set up in a fumehood that rely on
air-sensitive phosphine ligands, we employed the corresponding
Buchwald generation 4 precatalyst. For examples, see: (a) Bruno, N.
C.; Niljianskul, N.; Buchwald, S. L. J. Org. Chem. 2014, 79, 4161−
4166. (b) Friis, S. D.; Skrydstrup, T.; Buchwald, S. L. Org. Lett. 2014,
16, 4296−4299.
(18) Andersen, T. L.; Caneschi, W.; Ayoub, A.; Lindhardt, A. T.;
Couri, M. R. C.; Skrydstrup, T. Adv. Synth. Catal. 2014, 356, 3074−
3082.
ACKNOWLEDGMENTS
■
This study was financed in part by the Coordenaca
̧
o
̃
de
́
Aperfeic
̧oamento de Pessoal de Nivel Superior - Brasil
(CAPES) - Finance Code 001. We thank the Danish National
Research Foundation (Grant No. DNRF118), NordForsk
(85378), and Aarhus University for financial support. We
thank Nicolai Mogensen, Mathias Flinker, and Jakob Kumke
for initial results (all from Department of Chemistry,
Interdisciplinary Nanoscience Center (iNANO), Carbon
Dioxide Activation Center (CADIAC), Aarhus University)
(former students). We are grateful to Prof. Bo Brummerstedt
Iversen and Dr. Peter Hald (Department of Chemistry,
Interdisciplinary Nanoscience Center (iNANO), Center for
Materials Crystallography, Aarhus University) for assistance
with the hydraulic press for preparing the COtabs.
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D
DOI: 10.1021/acs.orglett.9b01423
Org. Lett. XXXX, XXX, XXX−XXX