Palladium-catalyzed reductive carbonylation of aryl triflates with synthesis gas

Article abstract of DOI:10.1055/s-2007-986662

A general palladium-catalyzed reductive carbonylation of aryl triflates in the presence of synthesis gas (CO/H₂) has been developed. The reaction with this most simple and environmentally benign formylation source proceeds under mild conditions and various aromatic aldehydes have been prepared in good to high yield. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-986662

LETTER
2537
Palladium-Catalyzed Reductive Carbonylation of Aryl Triflates with
Synthesis Gas
R
eductive Carbony
n
lation of Ar
n
yl Triflates
w
e
ith Synthesis
G
a
B
s
rennführer, Helfried Neumann, Matthias Beller*
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Fax +49(381)12815000; E-mail: matthias.beller@catalysis.de
Received 24 July 2007
Pd(OAc)2
OTf
CHO
Abstract: A general palladium-catalyzed reductive carbonylation
of aryl triflates in the presence of synthesis gas (CO/H2) has been
developed. The reaction with this most simple and environmentally
benign formylation source proceeds under mild conditions and var-
ious aromatic aldehydes have been prepared in good to high yield.
ligand, base
CO/H2
MeO
MeO
Scheme 1 Reductive carbonylation of the model substrate
Key words: carbonylation, palladium, aryl triflates, aldehydes, ho-
mogenous catalysis
adamantyl-n-butylphosphine (cataCXium® A), especially,
is a powerful catalyst system that is active in Heck,10
Suzuki coupling reactions,11 amination,12 and cyanation13
of aryl chlorides, as well as a-arylation of ketones with
chloroarenes.14 More recently, we successfully employed
this catalyst system in reductive carbonylations,15 as well
as in alkoxycarbonylations16 of aryl and heteroaryl bro-
mides. Encouraged by these results and in order to over-
come the limitations of known procedures, we became
interested in the formylation of aryl triflates. Herein, we
describe our investigations which led to a convenient nov-
el reductive carbonylation procedure of aryl triflates.17,18
Vinyl and aryl trifluoromethanesulfonates (triflates) offer
a highly reactive leaving group and therefore are often
used as versatile intermediates in modern organic synthe-
sis, particularly in the preparation of biologically active
compounds.1 In general, palladium-catalyzed coupling
reactions of aryl triflates allow for various functionaliza-
tions of the corresponding arene. Among the different
known coupling reactions of aryl triflates, the palladium-
catalyzed carbonylation provides in principle an elegant
and simple route to aromatic aldehydes, carboxylic acids,2
and the corresponding esters3 or amides.4
Initially, the formylation of 4-methoxyphenyl trifluoro-
methanesulfonate to give 4-methoxybenzaldehyde was
investigated as model system in the presence of eight dif-
ferent phosphine ligands (Scheme 1). Typically, all ex-
periments were carried out in a modified sixfold parallel
autoclave (reaction volume of 4 mL), which allows fast
testing of catalysts and variation of reaction conditions.
Selected results of the ligand screening are shown in
Table 1. In contrast to aryl halides19 only the bidentate
ligands 1,2-bis(diphenylphosphino)ethane (dppe) and
1,3-bis(diphenylphosphino)propane yielded the desired 4-
methoxybenzaldehyde (23–31% yield, Table 1, entries 1
and 2). Further extension of the alkyl chain of this ligand
scaffold did not improve conversion and yield. Bulky
monodentate (cataCXium® A) and bidentate (BINAP)
phosphine ligands did not lead to significant conversion
and aldehyde formation (Table 1, entries 14 and 15).
Today, a variety of catalysts are available for the alkoxy-
and aminocarbonylation of aryl triflates, but there are only
few general protocols concerning the synthetically more
interesting formylation of these substrates.
The first catalytic formylation reaction of enol triflates
was reported by Baillargeon and Stille in 1986 using tin
hydride and carbon monoxide.5 Under relatively mild
conditions (50 °C, 1–3 atm of CO, and 2.5–3.5 h reaction
time) few a,b-unsaturated aldehydes were prepared in
good yields. Later on, the original work of Stille has been
improved by employing organosilanes instead of tin
hydride as hydrogen donor.6
Only little work has been done using synthesis gas (CO/
H2), which represents the most simple and cheap formyla-
tion source. To the best of our knowledge, only Holzapfel
et al. reported a reductive carbonylation of (hetero)aryl
triflates with CO/H2.7 However, the main drawback of this
protocol is the limited scope explored.
After having found a suitable ligand for the model system,
we investigated the influence of base more carefully
(Table 1, entries 2–9). Among the different amines tested,
pyridine gave the best results (57% yield; 79% selectivity)
(Table 1, entry 4). In general, inorganic bases, for exam-
ple K2CO3, gave full conversion, but only low selectivity
for the aldehyde. Here, the carboxylic acid is produced as
major side product.
For some years, we have been interested in the develop-
ment of practical Pd catalysts and their use in different
coupling reactions.8 As examples we developed novel bi-
arylphosphines and adamantylphosphines.9 Palladium/di-
Figure 1 demonstrates the influence of the synthesis gas
pressure and the substrate concentration on the yield
of the model system. At lower CO/H2 pressure (5 bar)
SYNLETT 2007, No. 16, pp 2537–2540
Advanced online publication: 12.09.2007
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1
.1
0
.2
0
0
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DOI: 10.1055/s-2007-986662; Art ID: G22007ST
© Georg Thieme Verlag Stuttgart · New York

2538
A. Brennführer et al.
LETTER
50–92% are obtained. In addition to the model substrate,
aryl triflates with different functional groups in the para
position are formylated successfully. In general, electron-
rich substituents (e.g., p-tolyl triflate, 3,5-di-tert-butyl-
phenyl triflate) decrease the reactivity compared to elec-
tron-deficient substrates (e.g., p-trifluoromethylphenyl
triflate, p-chlorophenyl triflate). The protocol works
well also for 1-naphthyl triflate, 2-naphthyl triflate, and 3-
trifluoromethyl-sulfonyloxyestra-1,3,5(10)-trien-17-one
(Table 2, entries 11, 12, 16). The presence of ortho sub-
stituents led to a decreased yield of the corresponding
aldehyde since these triflates are less reactive towards
formylation than the corresponding para isomers. Never-
theless, prolonging the reaction time from 24 hours to 60
hours, o-tolualdehyde is obtained in 85% yield (Table 2,
entry 3). Unfortunately, a change in reaction time and syn-
thesis gas mixture did not improve the yield of o-formyl-
benzonitrile (Table 2, entry 14).
Table 1 Palladium-Catalyzed Formylation of 4-Methoxyphenyl
Trifluoromethanesulfonatea
Entry Ligand
Base
Conversion Yield Selectivity
(%)b
(%)b
23
31
36
57
36
8
(%)b
29
33
36
79
78
10
9
1
2
dppe
Et3N
Et3N
79
dppp
94
3
dppp
TMEDA 100
4
dppp
Pyridine
Bn3N
73
46
85
100
100
100
16
20
8
5
dppp
6
dppp
DABCO
K2CO3
Cs2CO3
NaOAc
Et3N
7
dppp
9
8
dppp
6
6
9
dppp
10
0
10
0
From a synthetic perspective it is noteworthy that the
reductive carbonylation of 4-methoxyphenyl trifluoro-
methanesulfonate can be carried out in situ as well.
10c
11
12
13
14
15d
dppb
dpppentane
dpphexane
dppf
Et3N
0
0
Without optimization the one-pot sulfonylation–carbon-
ylation sequence furnished 4-methoxybenzaldehyde in
44% yield (Scheme 2; Table 2, entry 1). This constitutes,
to the best of our knowledge, the first one-pot carbony-
lation of a phenol derivative.
Et3N
0
0
Et3N
49
18
1
0
0
BINAP
Et3N
0
0
cataCXium® A Et3N
0
0
In conclusion, we have demonstrated that aryl triflates are
successfully carbonylated with available and environmen-
tally benign synthesis gas in the presence of Pd/dppp. The
shown palladium-catalyzed reductive carbonylation
represents a useful method for the synthesis of aromatic
aldehydes from readily available phenols.
a Reaction conditions: 4-methoxyphenyl trifluoromethanesulfonate
(0.5 mmol), Pd(OAc)2 (1.5 mol%), ligand (2.25 mol%), base (1.5
equiv), 2-butoxyethyl ether (0.7 equiv; internal standard), DMF
(2 mL), CO/H2 (5 bar, 1:1), 100 °C, 16 h.
b Determined by gas chromatography.
c Toluene as solvent.
d 4.5 mol% cataCXium® A.
Acknowledgment
The authors thank S. Giertz, Dr. H. Klein, and S. Buchholz for ex-
cellent technical and analytical assistance, as well as Dr. R. Jackstell
and Dr. T. Schareina (all at Leibniz Institute for Catalysis) for
providing ligands and complexes. Generous financial support from
Mecklenburg-Vorpommern, the Fonds der Chemischen Industrie,
the Bundesministerium für Bildung und Forschung (BMBF), and
the DFG (Leibniz Prize) is gratefully acknowledged.
References and Notes
(1) (a) Frenette, R.; Hutchinson, J. H.; Léger, S.; Thérien, M.;
Brideau, C.; Chan, C. C.; Charleson, S.; Ethier, D.; Guay, J.;
Jones, T. R.; McAuliffe, M.; Piechutta, H.; Riendeau, D.;
Tagari, P.; Girard, Y. Bioorg. Med. Chem. Lett. 1999, 9,
2391. (b) Henley, P. D.; Kilburn, J. D. Chem. Commun.
1999, 1335. (c) Miller, W. H.; Bondinell, W. E.; Cousins, R.
D.; Erhard, K. F.; Jakas, D. R.; Keenan, R. M.; Ku, T. W.;
Figure 1 Influence of synthesis gas pressure and substrate concen-
tration on the yield of 4-methoxybenzaldehyde
decreasing the substrate concentration significantly im-
proved the yield of 4-methoxybenzaldehyde.
OH
OTf
CHO
Tf2O, pyridine
Pd(OAc)2, dppp
Further investigations showed that this effect is mini-
mized when a higher synthesis gas pressure (>10 bar) is
used.
OMe
OMe
OMe
Next, we studied the scope and limitations of the catalyst
system (Table 2). In general, product yields in between
Scheme 2 In situ synthesis of 4-methoxybenzaldehyde18
Synlett 2007, No. 16, 2537–2540 © Thieme Stuttgart · New York

LETTER
Reductive Carbonylation of Aryl Triflates with Synthesis Gas
2539
Table 2 Scope and Limitations of the Catalyst Systema
Newlander, K. A.; Ross, S. T.; Haltiwanger, R. C.; Bradbeer,
J.; Drake, F. H.; Gowen, M.; Hoffman, S. J.; Hwang, S.-M.;
James, I. E.; Lark, M. W.; Lechowska, B.; Rieman, D. J.;
Stroup, G. B.; Vasko-Moser, J. A.; Zembryki, D. L.;
Azzarano, L. M.; Adams, P. C.; Salyers, K. L.; Smith, B. R.;
Ward, K. W.; Johanson, K. O.; Huffman, W. F. Bioorg. Med.
Chem. Lett. 1999, 9, 1807. (d) Xiang, A. X.; Watson, D. A.;
Ling, T.; Theodorakis, E. A. J. Org. Chem. 1998, 63, 6774.
(e) Wang, L.; Shen, W. Tetrahedron Lett. 1998, 39, 7625.
(f) Ma, D.; Tian, H.; Sun, H.; Kozikowski, A. P.;
Pshenichkin, S.; Wroblewski, J. T. Bioorg. Med. Chem. Lett.
1997, 7, 1195. (g) Fretz, H. Tetrahedron Lett. 1996, 37,
8475. (h) Shishido, K.; Goto, K.; Miyoshi, S.; Takaishi, Y.;
Shibuya, M. J. Org. Chem. 1994, 59, 406. (i) Thompson, S.
K.; Heathcock, C. H. J. Org. Chem. 1992, 57, 5979.
(2) (a) Lesma, G.; Sacchetti, A.; Silvani, A. Synthesis 2006,
594. (b) Cacchi, S.; Fabrizi, G.; Goggiamani, A. Org. Lett.
2003, 5, 4269. (c) Cacchi, S.; Lupi, A. Tetrahedron Lett.
1992, 33, 3939.
Entry Aryl triflate
Temp Conversion Yield Selectivity
(°C) (%)b
(%)b (%)b
1c
2
100
100
85
98
44 52
80 81
MeO
OTf
OTf
3d
80
85
85 99
45 45
Me
4
100 100
5
100
99
76 77
92 92
Me
OTf
O
6c
80 100
OTf
Me
7
80
97
91 93
87 87
(3) (a) Iwamoto, H.; Yukimasa, Y.; Fukazawa, Y. Tetrahedron
Lett. 2002, 43, 8191. (b) Lin, S.-K.; Rasetti, V. Helv. Chim.
Acta 1995, 78, 857. (c) Kraus, G. A.; Maeda, H.
Tetrahedron Lett. 1994, 35, 9189. (d) Ohta, T.; Ito, M.;
Inagaki, K.; Takaya, H. Tetrahedron Lett. 1993, 34, 1615.
(e) Dolle, R. E.; Schmidt, S. J.; Kruse, L. I. J. Chem. Soc.,
Chem. Commun. 1987, 904.
Cl
OTf
8d
80 100
F3C
OTf
OTf
9
100
68
53 79
(4) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron
Lett. 1986, 27, 3931.
(5) Baillargeon, V. P.; Stille, J. K. J. Am. Chem. Soc. 1986, 108,
452.
(6) (a) Hashimoto, A.; Shi, Y.; Drake, K.; Koh, J. T. Bioorg.
Med. Chem. 2005, 13, 3627. (b) Hennequin, L. F. A.;
Halsall, C. T. WO 026156, 2005. (c) Nemoto, T.; Ohshima,
T.; Shibasaki, M. Tetrahedron 2003, 59, 6889. (d) Morera,
E.; Ortar, G.; Varani, A. Synth. Commun. 1998, 28, 4279.
(e) Kotsuki, H.; Datta, P. K.; Suenaga, H. Synthesis 1996,
470.
10
100 100
80 100
65 65
50 50
OTf
OTf
11
(7) Holzapfel, C. W.; Ferreira, A. C.; Marais, W. J. Chem. Res.
2002, 5, 218.
(8) For a personal account, see: Zapf, A.; Beller, M. Chem.
Commun. 2005, 431.
(9) See, for example: (a) Harkal, S.; Rataboul, F.; Zapf, A.;
Fuhrmann, C.; Riermeier, T. H.; Monsees, A.; Beller, M.
Adv. Synth. Catal. 2004, 346, 1742. (b) Harkal, S.;
Michalik, D.; Zapf, A.; Jackstell, R.; Rataboul, F.;
Riermeier, T. H.; Monsees, A.; Beller, M. Tetrahedron Lett.
2005, 46, 3237.
(10) Ehrentraut, A.; Zapf, A.; Beller, M. Synlett 2000, 1589.
(11) Zapf, A.; Ehrentraut, A.; Beller, M. Angew. Chem. Int. Ed.
2000, 39, 4153.
OTf
OTf
12
80 100
69 69
41 86
13d
80
48
Br
OTf
14d,e
15d
80 100
16 16
67 70
CN
80
96
90
TfO
OTf
H
(12) (a) Tewari, A.; Hein, M.; Zapf, A.; Beller, M. Tetrahedron
2005, 61, 9705. (b) Ehrentraut, A.; Zapf, A.; Beller, M.
J. Mol. Catal. 2002, 182-183, 515.
(13) Schareina, T.; Zapf, A.; Mägerlein, W.; Müller, N.; Beller,
M. Tetrahedron Lett. 2007, 48, 1087.
O
Me
H
16f
100
49 55
H
(14) Ehrentraut, A.; Zapf, A.; Beller, M. Adv. Synth. Catal. 2002,
344, 209.
TfO
(15) Klaus, S.; Neumann, H.; Zapf, A.; Strübing, D.; Hübner, S.;
Almena, J.; Riermeier, T. H.; Groß, P.; Sarich, R.; Krahnert,
W.-R.; Rossen, K.; Beller, M. Angew. Chem. Int. Ed. 2006,
45, 154.
(16) Neumann, H.; Brennführer, A.; Groß, P.; Riermeier, T. H.;
Almena, J.; Beller, M. Adv. Synth. Catal. 2006, 348, 1255.
(17) Aryl triflates were prepared from the corresponding phenols
by a well-established method: Echavarren, A. M.; Stille, J.
K. J. Am. Chem. Soc. 1987, 109, 5478.
a Reaction conditions: aryl triflate (1 mmol), Pd(OAc)2 (1.5 mol%),
dppp (2.25 mol%), pyridine (1.5 equiv), 2-butoxyethyl ether (0.7
equiv; internal standard), DMF (2 mL), CO/H2 (20 bar, 1:1), 24 h.
b Determined by gas chromatography.
c In situ synthesis of 4-methoxybenzaldehyde.
d Reaction time 60 h.
e CO/H2 (3:1): 20 bar.
f Isolated yield.
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A. Brennführer et al.
LETTER
(18) A 50 mL round-bottom flask was charged with 4-methoxy-
phenol (1.86 g, 15 mmol) and sealed with a septum.
Subsequently, pyridine (15 mL) was added. The clear
solution was cooled to 0 °C and trifluoromethanesulfonic
anhydride (2.8 mL, 17 mmol) was added dropwise. The
resulting orange solution was stirred over night at r.t.
Another 10 mL Schlenk flask was charged with Pd(OAc)2
(50.5 mg, 1.5 mol%), 1,3-bis(diphenylphosphino)propane
(139.2 mg, 2.25 mol%), DMF (5 mL), and 2-butoxyethyl
ether (2.61 mL, internal GC standard). Both solutions were
combined and transferred to a 100 mL autoclave of the 4560
series from Parr Instruments® under argon atmosphere. After
flushing the autoclave three times with CO/H2 (1:1), 20 bar
of synthesis gas were adjusted at ambient temperature and
the reaction was performed for 24 h at 100 °C. Before and
after the reductive carbonylation an aliquot of the reaction
mixture was subjected to GC analysis for determination of
yield and conversion.
(19) For previous work on palladium-catalyzed carbonylations of
aryl halides applying CO, see for example: (a) Ashfield, L.;
Barnard, C. F. J. Org. Process Res. Dev. 2007, 11, 39.
(b) Cai, M.-Z.; Zhao, H.; Zhou, J.; Song, C.-S. Synth.
Commun. 2002, 32, 923. (c) Schnyder, A.; Beller, M.;
Mehltretter, G.; Nsenda, T.; Studer, M.; Indolese, A. F. J.
Org. Chem. 2001, 66, 4311. (d) Bates, R. W.; Gabel, C. J.;
Ji, J.; Rama-Devi, T. Tetrahedron 1995, 51, 8199.
(e) Hartman, G. D.; Halczenko, W. Synth. Commun. 1991,
21, 2103. (f) Mutin, R.; Lucas, C.; Thivolle-Cazat, J.;
Dufaud, V.; Dany, F.; Basset, J. M. J. Chem. Soc., Chem.
Commun. 1988, 896. (g) See ref. 5. (h) Pri-Bar, I.;
Buchman, O. J. Org. Chem. 1984, 49, 4009.
(i) Baillargeon, V. P.; Stille, J. K. J. Am. Chem. Soc. 1983,
105, 7175. (j) Schoenberg, A.; Heck, R. F. J. Am. Chem.
Soc. 1974, 96, 7761.
Synlett 2007, No. 16, 2537–2540 © Thieme Stuttgart · New York