A general and efficient palladium-catalyzed alkoxycarbonylation of phenols to form esters through in situ formed aryl nonaflates

Article abstract of DOI:10.1002/chem.201103797

Esters made easy! A general and efficient methodology for the palladium-catalyzed alkoxycarbonylation of in situ formed aryl nonaflates has been developed (see scheme). Both homo- and cross-esterifications are possible. DPPF=1,1′-bis(diphenylphosphino)ferrocene. Copyright

Full text of DOI:10.1002/chem.201103797

COMMUNICATION
DOI: 10.1002/chem.201103797
A General and Efficient Palladium-Catalyzed Alkoxycarbonylation of
Phenols To Form Esters through In Situ Formed Aryl Nonaflates
Xiao-Feng Wu,[a, b] Helfried Neumann,[b] and Matthias Beller*[b]
Dedicated to Professor Christian Bruneau on the occasion of his 60th birthday
The synthesis of carboxylic acid esters has attracted the
interest of organic chemists for more than 100 years. The
most common strategy for their preparation involves the
stoichiometric activation of the parent acid to form a more
reactive acyl halide, anhydride, or activated ester that is
amenable to subsequent nucleophilic substitution.[1] An in-
teresting and complementary transformation is the palladi-
um-catalyzed carbonylation of aryl halides, which makes use
of CO as an inexpensive and easily available C1 source.[2,3]
Originally, these carbonylation reactions were established in
the mid 1970s by the pioneering work of Heck and co-work-
ers.[4] Since that time, palladium-catalyzed carbonylations of
haloarenes have found numerous applications in organic
synthesis, and even in related industrial processes that have
been realized on a >1000 ton scale, such as the alkoxycar-
bonylation of a benzylic alcohol in the synthesis of ibupro-
fen.[5]
more stable than the corresponding triflates; on the other,
they are more reactive than the corresponding mesylates or
toyslates.[9,10] Moreover, C4F9SO2F, which is used as the main
reagent for aryl nonaflate synthesis, is relatively inexpensive,
stable in air, not sensitive to moisture, and can be stored at
room temperature.[11] As a consequence of these interesting
properties of aryl nonaflates, we report here a general pro-
tocol for the palladium-catalyzed alkoxycarbonylation of in
situ formed aryl nonaflates with phenols and aliphatic alco-
hols. Additionally, this approach is also applied for homoes-
terification, yielding esters with identical residues.
At the start of our investigation, the carbonylation of
phenol was studied as a model system in the presence of
[{PdACTHNURGTNE(GNU cinnamyl)Cl}2] and different ligands at 1008C and
under an atmosphere of CO (5 bar). Activation of the sub-
strate occurred by adding 0.5 equivalents of C4F9SO2F (with
respect to phenol) in toluene.
For more than a decade, our group has been interested in
the advancement of the palladium-catalyzed carbonylation
of aryl halides.[6] Recent examples include the development
As shown in Table 1, the use of monodentate ligands,
such as PPh3, PCy3, and PACHTUNTGRENUNG(o-tolyl)3, gave only low yields, or
none at all, of the desired phenyl benzoate (Table 1, en-
tries 1–3). To our delight, the application of bidentate phos-
phine ligands provided moderate to good yields of the de-
sired product (Table 1, entries 4–12). Interestingly, bidentate
ligands with larger bite angles gave improved product yields,
whereas the more electron-donating ligands resulted in
lower yields of the ester (Table 1, entries 9 and 10). Decreas-
ing the catalyst loading to 0.5 mol% of the palladium com-
plex still led to a 73% yield of phenyl benzoate (Table 1,
entry 13). However, a further decrease of the catalyst con-
centration to 0.25 mol% Pd provided only 51% of the de-
sired product. Notably, a good yield of phenyl benzoate was
achieved even at either 1 bar CO or 808C (Table 1, en-
tries 15 and 16).
Based on our experimental data and former mechanistic
studies of palladium-catalyzed carbonylations of aryl hal-
ides,[12] the reaction mechanism for this homoesterification is
proposed in Scheme 1. After in situ generation of the
phenyl nonaflate, oxidative addition to the [Pd0Ln] species
occurred. After coordination and insertion of CO, the termi-
nal ester is formed by nucleophilic attack of phenol (R=
Ph). Under the assistance of base, the active Pd0 catalyst is
regenerated and the catalytic cycle may start again. Never-
theless, the reaction of a cationic benzoylpalladium(II) spe-
cies with phenol and NEt3 to form benzoylpalladium(II)
À
of carbonylative activation of C H bonds in heteroarenes to
form ketones,[6c] the aminocarbonylation with ammonia to
give primary amides,[6j,k] and the carbonylative vinylation to
to give alkenones.[6b,h] Based on this work, we became inter-
ested in the carbonylation of activated phenols. In addition
to aryl halides, phenols are frequently found in pharmaceuti-
cals, agrochemicals, polymers, and natural products.[7] Grati-
fyingly, phenols can be easily transformed into aryl sulfo-
nates, which offer a highly reactive leaving group.[8] Conse-
quently, they have been used as versatile intermediates in
modern organic synthesis, particularly in the preparation of
biologically active compounds.
Among the different classes of aryl sulfonate, aryl nona-
flates offer interesting properties. On the one hand, they are
[a] Dr. X.-F. Wu
Department of Chemistry, Zhejiang Sci-Tech University
Xiasha Campus, Hangzhou, Zhejiang Province, 310018 (P.R. China)
[b] Dr. X.-F. Wu, Dr. H. Neumann, Prof. Dr. M. Beller
Leibniz-Institut fꢀr Katalyse e.V. an der Universitꢁt Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
Fax : (+49)381-1281-5000
E-mail: matthias.beller@catalysis.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103797.
Chem. Eur. J. 2012, 18, 3831 – 3834
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3831

Table 1. Palladium-catalyzed alkoxycarbonylation of in situ formed
phenyl nonaflate.[a]
Table 2. Palladium-catalyzed alkoxycarbonylation of in situ formed aryl
nonaflates: Homoesterification reactions.[a]
Entry
Ligand
([mol%])
CO
[bar]
T
[8C]
Yield
[%][b]
Entry
Phenol
Ester
Yield
[%][b]
G
N
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
PPh3 (4)
PCy3 (4)
5
5
5
5
5
5
5
5
5
5
5
5
5
5
1
5
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
18
0
0
1
2
3
80
92
88
P
N
DPPE (2)
DPPP (2)
DPPB (2)
DPEphos (2)
Xantphos (2)
DPPF (2)
DtBPF (2)
DIOP (2)
BINAP (2)
DPPF (1)
DPPF (0.5)
DPPF (2)
DPPF (2)
62
78
80
78
81
83
63
60
83
73[c]
51[d]
80
79
4
5
90
93
[a] [{PdACHTUNGTRENNUNG(cinnamyl)Cl}2] (1 mol%, 0.01 mmol), ligand, toluene (2 mL),
phenol (2 mmol), C4F9SO2F (1 mmol), NEt3 (2 mmol), CO, 16 h; Cy=cy-
clohexyl, DPPE=1,2-bis(diphenylphosphino)ethane, DPPP=1,3-bis(di-
phenylphosphino)propane,
DPPB=1,4-bis(diphenylphosphino)butane,
DPEphos=bis(2-diphenylphosphinophenyl)ether, Xantphos=4,5-bis(di-
phenylphosphino)-9,9-dimethylxanthene, DPPF=1,1’-bis(diphenylphos-
phino)ferrocene,
DtBPF=1,1’-bis(di-tert-butylphosphino)ferrocene,
DIOP=(+)-2,3-ortho-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphos-
phino)butane, BINAP=(R)-(+)-(1,1’-binaphthalene-2,2’-diyl)bis(diphe-
nylphosphine). [b] Yields were determined by GC using hexadecane as
the internal standard and based on 1 mmol of phenol. [c] [{Pd-
ACHTUNGTRENNUNG(cinnamyl)Cl}2] (0.5 mol%, 0.005 mmol). [d] [{PdACHTUNTGNER(NUGN cinnamyl)Cl}2] (0.25
mol%, 0.0025 mmol).
6
7
76
89
8
9
80
63
60
72
10
11
Scheme 1. Proposed reaction mechanism.
phenoxide as a stable intermediate (and Et3NH+NfOÀ)
cannot be ruled out. In the latter case, final reductive elimi-
nation would give the ester and regenerate the active Pd0
species.
12
85
[a] [{Pd
(cinnamyl)Cl}2]
(1 mol%,
0.01 mmol),
DPPF
(2 mol%,
0.02 mmol), toluene (2 mL), phenol (2 mmol), C4F9SO2F (1 mmol), NEt3
(2 mmol), CO (1 bar), 1008C, 16 h. [b] Isolated yields.
Having suitable reaction conditions in hand, we decided
to test the generality of our protocol by using 1 mol% of
the palladium complex under 1 bar of CO at 1008C. The ho-
moesterification of various phenols is shown in Table 2. The
corresponding esters were isolated in good to excellent
yields for reactions of electron-rich phenols (Table 2, en-
tries 2–8). Methoxy- and methylthio-substituents were toler-
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Chem. Eur. J. 2012, 18, 3831 – 3834

Palladium-Catalyzed Alkoxycarbomylation
COMMUNICATION
Table 3. Palladium-catalyzed alkoxycarbonylation of in situ formed
phenyl nonaflate with different alcohols.[a]
ated under our conditions and gave good yields of the re-
spective esters. As well as electron-rich phenols, phenols
with electron-withdrawing substituents can be applied in this
reaction. Hence, fluoro-, trifluoromethyl-, and trifluorome-
thoxy-substituted phenols were transformed into the desired
esters in moderate to good yields (60–72%) by applying this
one-pot methodology (Table 2, entries 9–11). Furthermore,
a benzoyl-functionalized phenol resulted in an 85% yield of
the corresponding ester (Table 2, entry 12). A possible
reason for the decreased yields for the homoesterification of
electron-poor phenols could be the lower stability of the
corresponding aryl nonaflates, which are more prone to
non-selective decomposition reactions. It is worth mention-
ing that we also tested 4-hydroxypyridine as a substrate, but
unfortunately no ester product was detected.
Entry
Alcohol
Ester
Yield
[%][b]
1
2
87
89
3
75
Clearly, the cross-coupling of two different phenols or
a phenol and an aliphatic alcohol is a more interesting reac-
tion for organic synthesis than these homoesterification re-
actions. Key to the success of this type of cross-esterification
process is the addition of the second alcohol after the initial
formation of the aryl nonaflate. In general, adding the
second alcohol one hour after mixing the other reagents was
sufficient and allowed for the selective activation and cou-
pling reaction (Table 3). Notably, both electron-donating
and electron-withdrawing groups were tolerated under our
conditions and good yields of the biaryl esters were obtained
(Table 3, entries 1–5). As well as different phenols, metha-
nol, 2-propanol, tert-butyl alcohol, and benzyl alcohol were
coupled successfully under the same conditions and the cor-
responding benzoates were isolated in 40–82% yields
(Table 3, entries 6–9).
4
5
85
82
6
7
8
methanol
68
60
40
2-propanol
tert-butyl alcohol
In conclusion, a novel methodology for the palladium-cat-
alyzed alkoxycarbonylation of phenols has been developed.
Activation of the phenols occurs through the convenient in
situ generation of aryl nonaflates. Both electron-donating
and electron-withdrawing substituents on the aryl and ester
component are tolerated and 21 different esters were isolat-
ed in good yields. Notably, not only homoesterification, but
also the cross-coupling of two different phenols or cross-
coupling of phenol with aliphatic alcohols are possible
under these reaction conditions.
9
82
[a] [{Pd
(cinnamyl)Cl}2]
(1 mol%,
0.01 mmol),
DPPF
(2 mol%,
0.02 mmol), toluene (2 mL), phenol (1 mmol), C4F9SO2F (1 mmol), NEt3
(2 mmol), RT, 1 h; then, alcohol (1 mmol), CO (1 bar), 1008C 16 h.
[b] Isolated yields.
were evaporated with adsorption on silica gel and the crude product was
purified by column chromatography using n-heptane and n-heptane/
AcOEt (18:1) as the eluent.
Typical reaction procedure for the alkoxycarbonylation of in situ formed
phenyl nonaflate with other alcohols: [{PdACTHUNTRGNEU(GN cinnamyl)Cl}2] (1 mol%,
Experimental Section
0.01 mmol), DPPF (2 mol%), and phenol (1 mmol) were transferred into
a vial (4 mL reaction volume) equipped with a septum, a small cannula,
and a stirring bar. After the vial was purged with argon, toluene (distilled
from sodium ketyl, 2 mL), C4F9SO2F (1 mmol), and NEt3 (2 mmol) were
injected into the vial by syringe. After stirring at room temperature for
1 h, the respective alcohol (1 mmol) was added by syringe. The vial was
then placed in an alloy plate, which was transferred into a 300 mL auto-
clave (4560 series from Parr Instruments), under an argon atmosphere.
After flushing the autoclave three times with CO, the pressure was ad-
justed to 1 bar and the reaction was performed for 16 h at 1008C. After
the reaction, the autoclave was cooled to room temperature and the pres-
sure was carefully released. Water (6 mL) was added to the reaction mix-
ture and the solution was extracted 3–5 times with ethyl acetate (2–
3 mL). The combined extracts were evaporated with adsorption on silica
gel and the crude product was purified by column chromatography using
n-heptane and n-heptane/AcOEt (18:1) as the eluent.
Typical reaction procedure for the carbonylation reaction of in situ
formed phenyl nonaflate with phenol: [{PdACTHUNTRGNEU(GN cinnamyl)Cl}2] (1 mol%,
0.01 mmol), DPPF (2 mol%), and phenol (2 mmol) were transferred into
a vial (4 mL reaction volume) equipped with a septum, a small cannula,
and a stirring bar. After the vial was purged with argon, toluene (distilled
from sodium ketyl, 2 mL), C4F9SO2F (1 mmol), and NEt3 (2 mmol) were
injected into the vial by syringe. The vial was then placed in an alloy
plate, which was transferred into a 300 mL autoclave (4560 series from
Parr Instruments), under an argon atmosphere. After flushing the auto-
clave three times with CO, the pressure was adjusted to 1 bar and the re-
action was performed for 16 h at 1008C. After the reaction, the autoclave
was cooled to room temperature and the pressure was carefully released.
Water (6 mL) was added to the reaction mixture and the solution was ex-
tracted 3–5 times with ethyl acetate (2–3 mL). The combined extracts
Chem. Eur. J. 2012, 18, 3831 – 3834
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3833

M. Beller et al.
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Acknowledgements
The authors thank the state of Mecklenburg–Vorpommern and the Bun-
desministerium fꢀr Bildung und Forschung (BMBF) for financial support.
We also thank Dr. W. Baumann and Dr. C. Fischer (all LIKAT) for ana-
lytical support.
Keywords: aryl nonaflate
palladium · phenols
·
carbonylation
·
esters
·
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Received: December 2, 2011
Revised: January 11, 2012
Published online: February 29, 2012
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