Effective palladium-catalyzed hydroxycarbonylation of aryl halides with substoichiometric carbon monoxide

Article abstract of DOI:10.1021/ja3114032

A protocol for the Pd-catalyzed hydroxycarbonylation of aryl iodides, bromides, and chlorides has been developed using only 1-5 mol % of CO, corresponding to a p_CO as low as 0.1 bar. Potassium formate is the only stoichiometric reagent, acting as a mildly basic nucleophile and a reservoir of CO. The substoichiometric CO could be delivered to the reaction from an acyl-Pd(II) precatalyst, which provides both the CO and an active catalyst, and thereby obviates the need for handling a toxic gas.

Full text of DOI:10.1021/ja3114032

Communication
pubs.acs.org/JACS
Effective Palladium-Catalyzed Hydroxycarbonylation of Aryl Halides
with Substoichiometric Carbon Monoxide
Signe Korsager, Rolf H. Taaning,* and Troels Skrydstrup*
The Center for Insoluble Protein Structures (inSPIN), Department of Chemistry and the Interdisciplinary Nanoscience Center,
Aarhus University, Gustavs Wieds Vej 14, 8000 Aarhus, Denmark
S
* Supporting Information
To promote a carbonylation reaction with substoichiometric
ABSTRACT: A protocol for the Pd-catalyzed hydroxy-
carbonylation of aryl iodides, bromides, and chlorides has
been developed using only 1−5 mol % of CO,
corresponding to a pCO as low as 0.1 bar. Potassium
formate is the only stoichiometric reagent, acting as a
mildly basic nucleophile and a reservoir of CO. The
substoichiometric CO could be delivered to the reaction
from an acyl-Pd(II) precatalyst, which provides both the
CO and an active catalyst, and thereby obviates the need
for handling a toxic gas.
addition of CO, it requires that 1 mol of CO is produced for
every mole of CO consumed. The hydroxycarbonylation of aryl
halides with formate has previously been proposed to proceed
through a formic anhydride, which spontaneously decomposes
upon heating to the carboxylic acid and CO (Scheme 1, path
Scheme 1. General Considerations for Pd-Catalyzed
Hydroxycarbonylations with Substoichiometric CO Addition
enzoic acids are common structural motifs in many natural
1
Bproducts, pharmaceuticals and agrochemicals.
Pd-cata-
lyzed hydroxycarbonylation of aryl halides represents a widely
used approach for preparing such compounds.2,3 However, this
method suffers from the handling of a highly toxic gas, carbon
monoxide, which is typically applied in large excess and high
pressures, and therefore requires specific handling measures.
Furthermore, the reaction is often conducted with water and
strong alkaline bases in polar solvents under elevated
temperatures, thereby excluding the presence of certain
functional groups. Several protocols have been developed to
circumvent these problems. For the latter, this includes the use
of nucleophiles of low basicity instead of hydroxide, which leads
to the carboxylic acid, but only after an additional hydrolysis
step.4 And for the former, several groups have developed and
applied activated formates as a source of in situ released CO.5
Nevertheless, compatibility issues between the CO generating
and the CO consuming reactions again reduce the functional
group tolerance for this transformation. Moreover, stoichio-
metric CO is produced under the reaction conditions, and as
the two coinciding reactions are not synchronized, the initial
CO pressure buildup can lead to overall safety concerns
especially with large-scale reactions. Identification of reaction
conditions, which address all of these concerns, would be of
significant value.
a).6 Hence, if reaction conditions can be identified, which are
specific for the hydroxycarbonylation step, a protocol running
on substoichiometric CO addition should be possible.
However, any CO depleting side reactions, such as reductive
carbonylation to the corresponding aldehyde (path b), would
be detrimental. To initiate the carboxylation reaction, we
envisaged that an acyl Pd(II)-complex i could provide the active
catalyst after reductive elimination of the formato intermediate.
Furthermore, it would conveniently deliver 1 equiv of CO with
respect to the palladium catalyst. Hence, throughout the
reaction course, the amount of carbon monoxide should not
exceed the catalyst concentration in solution.
Preliminary experiments were conducted with aryl iodide 1
employing the two-chamber system (COware) and 9-
methylfluorene-9-carbonyl chloride (COgen) as the stoichio-
metric CO precursor,7,8 in order to identify appropriate
catalytic conditions for the selective transformation of aryl
halides to the corresponding carboxylic acids (Table 1). The
reaction conditions used potassium formate and 1.5 equiv of
CO. Of the ligands tested, the bulky monodentate phosphine
ligands, such as P(tBu)3, P(oTol)3, tBu-Brettphos, or bidentate
phosphine ligands, including dppb, dppf, diPrpf or tBu-
In this Communication, we report the first reaction
conditions for the Pd-catalyzed hydroxycarbonylation of aryl
halides, which perform well with addition of substoichiometric
carbon monoxide as low as only 1−5 mol %. Furthermore, to
simplify the operating conditions, we exploit air stable acyl
palladium(II) precatalysts, which deliver not only the active
catalyst, but also the necessary substoichiometric amount of
CO required to initiate the carbonylation reaction.
Received: November 20, 2012
Published: February 11, 2013
© 2013 American Chemical Society
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Table 1. Screening Ligands for the Hydroxycarbonylation of
a
Aryl Iodide 1
Figure 1. 13C- and 31P NMR spectra of complex 13C-4 and single
crystal x-ray structure of complex 4.
absence of external CO,10 in light of the high selectivity for
carboxylic acid formation observed for entry 6 in Table 1 with
1.5 equiv of CO. However, to our delight, the addition of a
stoichiometric amount of dtbpf with respect to the Pd-acyl
complex 4 provided a highly active catalyst, which performed
the carbonylation reactions without CO addition. Changing the
solvent to Me-THF remarkably allowed the carboxylation to be
run at only a 1 mol % catalyst loading with a 98% isolated yield
of 2 (Table 2).11 Other iodides tested also performed admirably
providing carboxylic acids 5−8 in good yields.
Table 2. Synthesis of Carboxylic Acids 2, 5−8 from Aryl
a
Iodides
a
Chamber 1: 2 (0.5 mmol), Pd(dba)2 (25 μmol), ligand
(monodentate: 50 μmol, bidentate: 25 μmol), HCO2K (1 mmol),
TBAI (0.15 mmol, phase transfer catalyst), dioxane (3 mL). Chamber
2: COgen (0.75 mmol), Cy2NMe (1.5 mmol), Pd(dba)2 (38 μmol),
b
P(tBu)3·HBF4 (38 μmol), dioxane (3 mL) at 80 °C for 18 h. Based
c
on 1H NMR analysis. The reductive dehalogenation of 2 was
observed in 10% with dppf and 22% with tBu-Brettphos.
Josiphos, provided high selectivities for the carboxylic acid 2
over the reductive carbonylation product, aldehyde 3. However,
complete selectivity for 2 and the best yield was secured with
dtbpf (entry 8).
a
Aryl iodide (0.50 mmol), 4 (5.0 μmol), dtbpf (5.0 μmol), HCO2K (1
To investigate the use of an acyl Pd(II) precatalyst, we first
prepared complex 4 due to known similar acyl complexes in the
literature bearing a P(tBu)3 ligand.9 This was easily achieved
from the reaction of Pd(PtBu3)2 with phenyl iodide and 2.5
equiv of CO or 13CO (generated from COgen and 13COgen,
respectively), yielding 4 and 13C-4 in good yields as air-stable
solids (Scheme 2). Synthesis of 13C-4 allowed for the rapid
mmol), Me-THF (3 mL) at 80 °C for 18 h.
A series of aryl bromides operated well using this precatalyst
(Table 3). For substrates with electron donating substituents, a
higher catalyst loading (5 mol %) was required to reach full
conversion. Gratifyingly, ortho-substituents on the aromatic
ring, such as methoxy, fluorine, or methyl, were also tolerated
(compounds 8, 15, 18 and 25). In addition, heterocyclic
compounds were equally adaptable to the applied reaction
conditions as illustrated with compounds 13, 14, 16, and 22−
24.
Scheme 2. Synthesis of Acyl Pd(II) Complexes 4 and 13C-4
Finally, Table 4 reveals that aryl chlorides with electron
withdrawing groups can be transformed to their corresponding
carboxylic acids 5, 6, and 26 in near quantitative yield. To
obtain full conversion, the reaction temperature was raised to
120 °C and a higher boiling solvent, diglyme, was applied.12
Lastly, benzyl chloride proved to be a good substrate for these
transformations generating phenylacetic acid (27) in an 85%
yield.
Several observations suggested that the conversion from aryl
halides to benzoic acids was indeed a carbonylation reaction.
First, transformation of aryl iodide 1 to carboxylic acid 2 could
be run using a catalyst generated from Pd(dba)2 and dtbpf with
5 mol % carbon monoxide generated from COgen applying the
two chamber system. Again, only the use of dtbpf proved
assignment of the cis-relationship between the acyl and
phosphine ligand as demonstrated by the small coupling
constant of 4.9 Hz in the 13C NMR and 31P NMR spectra
(Figure 1). This assignment was confirmed by the single crystal
X-ray structure of 4 revealing a T-shaped complex as seen for
analogous acyl complexes with the P(tBu)3 ligand (Figure 1).9
Unfortunately, similar attempts to prepare the complex bearing
the ligand dtbpf were fruitless.
Surprisingly, complex 4 could not catalyze the hydroxy-
carbonylation of iodide 1 with potassium formate in the
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Table 3. Synthesis of Carboxylic Acids 5, 6 and 8−25 from
Scheme 3. Scale-Up Experiments
a
Aryl Bromides
mL of CO present at all times, corresponding to a CO partial
pressure of only 0.1 bar.
In conclusion, a mild protocol for the Pd-catalyzed
hydroxycarbonylation of aryl halides has been developed
using only 1−5 mol % loadings of carbon monoxide. This
transformation works well with a number of aryl iodides and
bromides, as well as aryl chlorides possessing electron poor
substituents. The substoichiometric amounts of CO could be
delivered to the reaction using an acyl-Pd(II) precatalyst, such
as complex 4, which also provides the active metal catalyst. This
approach obviates the need for handling gaseous CO from a
cylinder. Further work is in progress to examine other
carbonylation reactions, which can run with the addition of
only substoichiometric carbon monoxide.
CCDC 905027 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, by e-mailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge
CB2 1EZ, U.K.; fax: +44 1223 336033.
a
Aryl bromide (0.50 mmol), 4 (5.0 μmol), dtbpf (5.0 μmol), HCO2K
b
(1 mmol), 2-Me-THF (3 mL) at 80 °C for 18 h. 4 (25 μmol), dtbpf
(25 μmol).
Table 4. Synthesis of Carboxylic Acids 5, 6, 26 and 27 from
Aryl Chlorides and Benzyl Chloride
a
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H NMR and 13C NMR spectra for all the coupling
a
Aryl chloride (0.50 mmol), 4 (25 μmol), dtbpf (25 μmol), HCO2K
products, as well as details on experimental procedures. This
material is available free of charge via the Internet at http://
pubs.acs.org.
b
(1 mmol), diglyme (3 mL) at 120 °C for 18 h. 80 °C for 18 h.
effective with the addition of low CO loadings. And second, the
volume of the headspace in the reaction flask proved important
for an efficient reaction suggesting that CO dissociates from the
Pd complex and diffuses into the headspace. Through pressure
measurements, we have observed that for effective trans-
formation the partial pressure should reach a minimum of 0.1
bar. Reducing the CO partial pressure leads to lower
conversions. As predicted, the same measurements revealed
that the increase in the pressure of the overall system
corresponds to the amount of 4 added, which is maintained
throughout the reaction course (see Supporting Information).13
This carboxylation protocol was next applied to the gram
scale synthesis of benzamide 30, a potent and selective human
A2A receptor antagonist (Scheme 3).14 Prodrug derivatives of
30 are currently under evaluation as drug candidates for the
treatment of Parkinson’s disease.14 Hydroxycarboxylation of
aryl bromide 28 was successfully performed on a 60 mmol scale
providing carboxylic acid 29 in an 81% isolated yield (11 g). 29
could readily be transformed into the corresponding amide 30
with 2-aminothiazole in the presence of EDC/Oxyma. It should
be noted that the hydroxycarbonylation was run with only 14.5
AUTHOR INFORMATION
Corresponding Author
ts@chem.au.dk; rt@chem.au.dk
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are deeply appreciative of generous financial support from
the Danish National Research Foundation, the Danish Council
for Strategic Research, the Carlsberg Foundation, the Villum
Foundation, the Lundbeck Foundation and Aarhus University.
The authors are grateful to Dr. Jacob Overgaard for the X-ray
crystallographic analysis.
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