Palladium-catalyzed carbonylative sonogashira coupling of aryl bromides using near stoichiometric carbon monoxide

Article abstract of DOI:10.1021/ol5007289

A general procedure for the palladium-catalyzed carbonylative Sonogashira coupling of aryl bromides is reported, using near stoichiometric amounts of carbon monoxide. The method allows a broad substrate scope in moderate to excellent yields. The formed alkynone motive serves as a platform for synthesis of various heterocyclic structures, including pyrimidines. Furthermore, the presented strategy allows effective ¹³C labeling.

Full text of DOI:10.1021/ol5007289

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Carbonylative Sonogashira Coupling of Aryl
Bromides Using Near Stoichiometric Carbon Monoxide
Karoline T. Neumann,† Simon R. Laursen,† Anders T. Lindhardt,*,‡ Benny Bang-Andersen,§
and Troels Skrydstrup*,†
†Center for Insoluble Protein Structures (inSPIN), Department of Chemistry and the Interdisciplinary Nanoscience Center
(iNANO), Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark
‡Interdisciplinary Nanoscience Center (iNANO), Department of Engineering, Aarhus University, Finlandsgade 22, 8200 Aarhus N,
Denmark
§Lundbeck Research Denmark, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark
S
* Supporting Information
ABSTRACT: A general procedure for the palladium-catalyzed
carbonylative Sonogashira coupling of aryl bromides is
reported, using near stoichiometric amounts of carbon
monoxide. The method allows a broad substrate scope in
moderate to excellent yields. The formed alkynone motive
serves as a platform for synthesis of various heterocyclic structures, including pyrimidines. Furthermore, the presented strategy
allows effective 13C labeling.
lkynones are important structural motifs in organic
chemistry, as they serve as key intermediates in the
for the coupling of a heteroaromatic bromide, and only one
example was reported.
A
synthesis of many natural products.1 Furthermore, they
represent a platform for the synthesis of various heterocyclic
structures, including pyrazoles,2 pyridines,3 pyrimidines,4 and
benzodiazepines.5 Traditionally, alkynones have been prepared
by the transition-metal-catalyzed cross-coupling of acid
chlorides and terminal alkynes.6 Recently, reactions between
acid chlorides and terminal alkynes without the use of transition
metals7 have been reported. However, the general stability of
acid chlorides is limited, and they are often only accessible with
a narrow scope of functional groups.
Given our developed expertise in the application of
carbonylation chemistry performed in two-chamber reactors,
using CO generated from stable precursors,13 we decided to
investigate if the application of stoichiometric amounts of CO
would be sufficient to promote the carbonylative Sonogashira
coupling. Despite being a lower pressure protocol, a successful
outcome would simultaneously provide direct access to isotope
incorporation using 13C-labeled CO.
In this paper, we report a new protocol for the palladium-
catalyzed carbonylative Sonogashira coupling of aryl bromides
with terminal alkynes applying near stoichiometric amounts of
CO. The simple application of PdCl2 in combination with
Xantphos as the ligand at 80 °C in dioxane provides a substrate
scope with excellent functional group tolerance, including
several examples of heteroaromatic bromides. Furthermore, the
method proved adaptable to isotope labeling using 13C-labeled
CO, generated ex situ in an analogous manner to CO. Finally,
selected alkynones were transformed into their corresponding
pyrimidines, by reaction with benzamidine, illustrating the
utility of these alkynone building blocks in the synthesis of
heteroaromatic structures.
Palladium-catalyzed carbonylations of aryl halides have
within the last decades become an important transformation
in organic synthesis.8 Therefore, it has been shown that the
palladium-catalyzed carbonylative Sonogashira coupling is a
viable alternative for the synthesis of alkynones. This method
utilizes readily accessible starting materials, such as aryl halides
or pseudohalides, and shows good functional group tolerance.9
Furthermore, these carbonylative protocols can be performed
without the need of adding a copper cocatalyst, which is
normally required for the direct Sonogashira couplings. The
first palladium-catalyzed carbonylative Sonogashira coupling
was published by Kobayashi and Tanaka in 1981,10 and since
then, many groups have reported and improved this particular
transformation.11 However, until now, most protocols have
been performed using aryl iodides as electrophiles and only one
report involves the more challenging aryl bromides as
substrates. Recently, Beller and co-workers reported the first
general procedure for the carbonylative Sonogashira coupling
of aryl bromides.12 Due to a 10 bar operating pressure of
carbon monoxide, their protocol relies on the use of autoclaves.
Furthermore, increased pressures of CO (30 bar) were required
As the starting point for the optimization, the coupling of 4-
bromoanisole with 4-ethynyltoluene was chosen (Table 1).
Based on preliminary work performed in our group, the
combination of PdCl2 with triethylamine in dioxane was
applied. CO was generated ex situ from COgen by applying the
two-chamber reactor (COware) previously reported.13 With
Received: March 9, 2014
Published: April 4, 2014
© 2014 American Chemical Society
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Table 1. Ligand Screening of the Carbonylative Sonogashira
Reaction
Scheme 1. Scope of the Carbonylative Sonogashira Coupling
with Aryl Bromides
a
ab
,
b
entry
ligand (mol %)
conversion (%)
1
2
3
4
5
6
7
8
HBF4(tBu)3P (10.0)
HBF4PCy3 (10.0)
CataCXium A (10.0)
PPh3 (10.0)
37
0
27
25
trace
P(o-Tol)3 (10.0)
Xantphos (5.0)
dppf (5.0)
c
>95 (90)
25
dppp (5.0)
trace
50
d
9
Xantphos (2.5)
a
Chamber A: COgen (0.75 mmol), HBF4(tBu)3P (1 mol %),
Pd(cod)Cl2 (1 mol %), Cy2NMe (1.5 mmol) in dioxane (3 mL).
Chamber B: 4-bromoanisole (0.5 mmol), 4-ethynyltoluene (0.75
mmol), PdCl2 (5 mol %), ligand (x mol %), Et3N (1.5 mmol) in
b
c
1
dioxane (3 mL). Determined by H NMR. Isolated yield shown in
d
brackets. Using 2.5 mol % of PdCl2.
this setup in hand, different ligands were tested, the results of
which are shown in Table 1.
First, alkyl phosphine ligands were tested, as these were
previously shown to provide good conversions of both aryl
iodides and aryl bromides (Table 1, entries 1−3).9g,12,14
However, in this case, these ligands did not provide satisfactory
conversions. Another attempt was undertaken using PPh3, a
typically applied ligand in the carbonylative Sonogashira
reaction with aryl iodides (Table 1, entry 4). However, only
low conversion of 4-bromoanisole was observed, presumably
due to a difficult oxidative addition step using PPh3 as ligand.
Changing to the more active ligand P(o-Tol)3 only provided
trace amounts of 1 (Table 1, entry 5).
Using the bidentate ligand, Xantphos provided full
conversion to the desired product (Table 1, entry 6), with a
90% isolated yield of the desired alkynone (1). Other bidentate
ligands, such as dppf and dppp, proved less reactive (Table 1,
entries 7 and 8). Lowering the ligand and catalyst loadings only
afforded 50% conversion (Table 1, entry 9).
Having developed optimal reaction conditions for the
carbonylative Sonogashira coupling of aryl bromides, we
explored the scope of the reaction by examining combinations
of various aryl bromides and terminal alkynes (Scheme 1).
Electron-rich aryl bromides were coupled successfully in high
yields (compounds 2, 10, and 11), including 4-bromoaniline,
which could be successfully isolated in a 72% yield (compound
6). Electron-deficient aryl bromides were also coupled to the
desired alkynone structures in yields ranging from 82 to 98%
(compounds 3−5, 7, 12, 14, and 15). The use of aryl bromides
carrying ortho substituents turned out to be more challenging,
but by increasing the reaction temperature to 100 °C and
applying DIPEA as the base, we could secure the desired
products in moderate to good yields (compounds 8, 13, 16,
and 17). Both free anilines and Boc-protected anilines were
tolerated under the developed conditions with isolated yields
ranging from 72 to 95% (compounds 6, 10, 16, and 18).
Especially the motive found in compound 16 is interesting as it
provides an expedient access to various quinolone structures.15
a
Chamber A: COgen (0.75 mmol), HBF4(tBu)3P (1 mol %),
Pd(cod)Cl2 (1 mol %), Cy2NMe (1.5 mmol) in dioxane (3 mL).
Chamber B: aryl bromide (0.5 mmol), alkyne (0.75 mmol), PdCl2 (5
mol %), Xantphos (5 mol %), Et3N (1.5 mmol) in dioxane (3 mL).
b
c
Isolated yields. Reaction conducted at 100 °C using DIPEA (1.5
d
mmol) as base in both chambers. Starting from 1,1′-biphenyl triflate.
The substrate scope also demonstrates that a variety of
terminal alkynes can be tolerated; aromatic alkynes with ortho
and para substituents and aliphatic alkynes perform well under
the catalytic conditions (e.g., compounds 3, 4, 20, and 21).
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Scheme 3. Synthesis of 13C-Labeled Pyrimidines from
Selected Carbonylative Sonogashira Products
TIPS-protected acetylene also underwent successful coupling,
affording 19 in an excellent 98% isolated yield. Finally,
substituting the aryl bromide for the corresponding aryl triflate
did not impede the carbonylative coupling (compound 22).
Next, attention was turned to the heteroaromatic bromides
as electrophiles in the coupling (Scheme 2). Applying N-Boc-
ab c
, ,
Scheme 2. Scope of the Carbonylative Sonogashira Coupling
a b
,
with Heteroaryl Bromides
a
Carbonylative Sonogashira. Chamber A: COgen (0.75 mmol),
HBF4(tBu)3P (1 mol %), Pd(cod)Cl2 (1 mol %), Cy2NMe (1.5
mmol) in dioxane (3 mL). Chamber B: aryl bromide (0.5 mmol),
alkyne (0.75 mmol), PdCl2 (5 mol %), Xantphos (5 mol %), Et3N (1.5
b
mmol) in dioxane (3 mL). Pyrimidine synthesis: alkynone (0.3
a
Chamber A: COgen (0.75 mmol), HBF4(tBu)3P (1 mol %),
Pd(cod)Cl2 (1 mol %), Cy2NMe (1.5 mmol) in dioxane (3 mL).
Chamber B: aryl bromide (0.5 mmol), alkyne (0.75 mmol), PdCl2 (5
mol %), Xantphos (5 mol %), Et3N (1.5 mmol) in dioxane (3 mL).
mmol), benzamidine hydrochloride (0.36 mmol), Na2CO3 (0.72
c
d
mmol) in MeCN (2 mL) and H2O (0.3 mL). Isolated yields. From
18a, Scheme 1 From 26a, Scheme 2.
e
b
c
Isolated yields. Using 13COgen (0.75 mmol).
accessed before. Finally, this setup is highly suitable for 13C
isotope labeling by applying 13COgen as the CO precursor.
protected bromoindoles furnished the alkynones in good
overall yields (compounds 24 and 28). Different bromo-
pyridines were also tolerated in moderate to excellent yields
(compounds 23, 25, and 26). Using 2-bromobenzothiophene
as the electrophile yielded the desired product 27 in a 60%
isolated yield. Finally 2-bromothiophene was successfully
coupled to alkynone 29 in a 73% yield.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and copies of all the H NMR and 13C
1
NMR spectra for all the coupling products. This material is
available free of charge via the Internet at http://pubs.acs.org.
Finally, to illustrate the applicability of the synthesized
alkynones, it was decided to synthesize pyrimidines and their
labeled counterparts. The synthesis of the intermediary
alkynone structures was carried out using 13C-labeled
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: lindhardt@eng.au.dk.
*E-mail: ts@chem.au.dk.
Notes
13COgen (compounds 18b and 26b, Scheme 3). Muller and
̈
co-workers have demonstrated how to access various hetero-
cyclic structures starting from the alkynone motif.2b,4 Hence,
employing their method provided an efficient route to highly
substituted pyrimidines in only two steps with overall good
yields (Scheme 3).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
In conclusion, we have developed a new and efficient
procedure for the carbonylative Sonogashira coupling of various
aryl- and heteroaryl bromides. Noteworthy, is the excellent
functional group tolerance, illustrating the generality of the
developed procedure. The substrate scope also includes several
examples of heteroaromatic bromides, which have not been
We appreciative the generous financial support of this work
from the Danish National Research Foundation (Grant No.
DNRF59), the Villum Foundation, the Danish Council for
Independent Research: Technology and Production Sciences,
the Carlsberg Foundation, the Lundbeck Foundation, and
Aarhus University.
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Letter
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