Pd-catalyzed decarbonylative heck olefination of aromatic carboxylic acids activated in situ with di-tert-butyl dicarbonate

Article abstract of DOI:10.1055/s-2002-34227

The first protocol for a direct Heck olefination of aromatic carboxylic acids has been developed. By treatment with commercially available di-tert-butyl dicarbonate, the carboxylic acids are converted in situ into the mixed anhydrides, which in the presen

Full text of DOI:10.1055/s-2002-34227

LETTER
1721
Pd-Catalyzed Decarbonylative Heck Olefination of Aromatic Carboxylic
Acids Activated in situ with Di-tert-butyl Dicarbonate
P
d-Catalyze
d
D
u
ecarbonylati
k
ve
H
eck
O
le
a
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Fax +49(208)3062985; E-mail: goossen@mpi-muelheim.mpg.de
Received 11 July 2002
Our new strategy to make use of the widely available aro-
matic carboxylic acids as aryl sources for Heck olefina-
tions was to utilize the mixed anhydrides of carbonic and
aromatic carboxylic acids as reactive intermediates
Abstract: The first protocol for a direct Heck olefination of aroma-
tic carboxylic acids has been developed. By treatment with com-
mercially available di-tert-butyl dicarbonate, the carboxylic acids
are converted in situ into the mixed anhydrides, which in the
presence of a palladium catalyst react with olefins to give styrene (Scheme 1). Such anhydrides are easily formed just by
derivatives. As by-products, only volatile CO and CO2 along with
mixing carboxylic acids 1 with dialkyl dicarbonates such
tert-butanol are formed, making the work-up of the reaction
as di-tert-butyl dicarbonate (Boc2O) 3, a popular protect-
products particuarly easy. A mixture of PdCl2, LiCl and -picoline
ing agent for amines.9,10 During this activation process,
was identified to be the most effective catalyst system.
CO2 and one equivalent of the alcohol are released. It has
previously been reported that certain Pd-complexes selec-
Key words: carboxylic acids, catalysis, palladium, Heck reaction,
di-tert-butyl dicarbonate
tively insert into the acyl-oxygen-bond of such com-
pounds.11 Thus, a catalytic cycle consisting of the
oxidative addition of the mixed anhydride to give an acyl
The Heck olefination is a powerful transformation that has
Pd monoalkylcarbonate complex, exchange of the alkyl-
found many applications in organic chemistry. Due to its
carbonate e.g. for a halide, extrusion of CO to give an aryl
high tolerance for functional groups, it is often used in the
complex, insertion of an olefin into the aryl-Pd-bond, and
synthesis of natural products and synthetic drugs.1 Over
finally release of the product via -hydride elimination
the last decade, several highly active catalyst systems
appeared to be feasible. In the overall process, only CO,
have been developed.2 Usually, aryl halides are employed
CO2 and an alcohol are formed as byproducts.
as starting materials, but other aryl sources such as aryl
We chose the reaction of benzoic acid 1a/Boc2O 3 with
styrene 2a as our model system (Scheme; R, Ar = Ph) and
triflates,3 diazonium salts,4 sulfonyl halides5 and aroyl
chlorides6 have been used as well. However, all these sub-
screened various Pd-complexes under different conditions
strates require stoichiometric amounts of base and thus,
in order to identify a suitable catalyst system for the de-
equivalent amounts of waste salts are produced. The first
sired conversion. Selected results are displayed in
base- and salt-free Heck olefination was developed by de
Table 1.
Vries et al. using carboxylic anhydrides as aryl sources.7
In analogy to the Pd-catalyzed olefination of carboxylic
anhydrides or phenol esters, the presence of halide ions is
crucial for the activity of the Pd catalyst (entries 1–8).7,8
This is probably due to the fact that halide ligands facili-
tate the decarbonylation of the acyl groups on the palladi-
um. In this respect, LiCl proved to be the most effective
halide source.12 Stabilizing ligands such as phosphines or
amines avoid agglomeration of the palladium and, thus,
increase the catalyst lifetime. However, they significantly
reduce the activity of the catalyst (entries 9–11). The best
In this reaction variant, one equivalent of carboxylic acid
is released which can, in principle, be converted back into
the starting anhydride. We recently disclosed the first de-
carbonylative Heck olefination of phenol esters, which are
more conveniently accessible than carboxylic anhy-
drides.8 However, the necessity to generate the starting
materials in an extra reaction step and separate the olefin
products from the carboxylic acids or phenols are practi-
cal disadvantages of these processes for small-scale appli-
cations.
Scheme 1 Heck olefination of carboxylic acids.
Synlett 2002, No. 10, Print: 01 10 2002.
Art Id.1437-2096,E;2002,0,10,1721,1723,ftx,en;G19302st.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1722
L. J. Gooßen et al.
LETTER
balance between these two effects is observed for -pi- matic carboxylic acids can be converted with different
coline, which sufficiently stabilizes the palladium to avoid olefins in good yields (Table 2). Even electron-rich car-
precipitation and loss of catalytic activity while still per- boxylic acids, which are less reactive in the alternative re-
mitting reasonable reaction rates.
action protocols via anhydrides or phenol esters,7,8 gave
high yields in this new transformation (e.g. 4h–l). A
strong preference for the formation of the trans 1,2-ole-
fins is observed, in analogy to conventional Heck reac-
tions. The reaction was also successfully performed on
larger scale (4a).
Table 1 Effects of the Conditions on the Product Distributiona
Entry Pd source Additive Ligand
Conv. (%) Sel.f (%)
1
2
Pd(OAc)2
Pd(acac)2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
-
-
0
0
0
0
In summary, our new protocol allows the first in situ acti-
vation and direct Heck olefination of aromatic carboxylic
acids. Therefore, one reaction step is saved in comparison
to previously reported procedures. The reaction protocol
involves only commercially available, air-stable chemi-
cals and produces only volatile by-products. It is, there-
fore, particularly useful for small-scale applications in
research and drug discovery.
-
-
3
-
-
4
KBr
NaBr
LiBr
NaCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
-
5
-
10
25
0
95
95
6
-
7
-
8
-
40
45
55
95
10
95
85
50
90
95
95
Representative Experimental Procedure
9
PPh3
Preparation of stilbene 4a: A 20 mL flask was charged with palladi-
um chloride (0.03 mmol, 5.30 mg), lithium chloride (0.10 mmol,
4.30 mg), benzoic acid (1.00 mmol, 122 mg), di-tert-butyl dicar-
bonate (1.00 mmol, 218 mg), styrene (1.20 mmol, 150 L), -pi-
coline (0.30 mmol, 27.0 L) and dry NMP (5 mL). The reaction
mixture was briefly purged with argon and heated to 120 °C. An ex-
cess of di-tert-butyl dicarbonate (436 mg, 2.00 mmol) in NMP (1
mL) was slowly added via syringe pump over several hours. After
16 hours, the crude reaction mixture was diluted with toluene (30
mL) and washed with 2 N HCl (15 mL), water (15 mL), and satu-
rated aqueous NaHCO3 (15 mL). The organic layer was dried over
MgSO4, the volatiles were removed in vacuo and the residue was
filtered through a small plug of SiO2 using hexane as eluent yielding
4a (145 mg, 80%) and small quantities of its regioisomers. The
product was characterized via 1H-, 13C NMR and HRMS. The ana-
lytical data was identical with that reported in literature.
10
11
12b
13c
14d
15e
-picoline
isoquinoline 46
-picoline
-picoline
-picoline
-picoline
20
35
90
53
a Conditions: 1.00 mmol benzoic acid, 1.20 mmol styrene, 1.00 mmol
BOC2O, 0.03 mmol catalyst, 5 mL N-methylpyrrolidone, 0.10 mmol
ligand, 0.10 mmol additive, 120 °C, 16 h.
b DMF as the solvent.
c DMPU as the solvent.
d Slow addition of 2.00 mmol BOC2O.
e 160 °C, 2 h, slow addition of BOC2O.
Acknowledgement
f Sideproducts: homoanhydride and tert-butylester.
We thank Professor Dr. M. T. Reetz for generous support and con-
stant encouragement and the DFG, FCI and BMBF for financial
support.
Amides such as DMF or NMP proved to be the optimal
solvents, probably due to their ability to stabilize Pd-com-
plexes in solution (entries 10 and 12). The optimal reac-
tion temperature was 120 °C: at lower temperatures, the
reaction is rather slow and at higher temperatures, the
mixed anhydrides are not stable enough, so that side prod-
ucts such as homoanhydrides are formed. Especially for
electron defficient carboxylic acids decarboxylation of
the mixed anhydrides under formation of tert-butyl esters
is observed. Due to the thermal instability of the carbonic
acid derivatives, it is beneficial to add Boc2O in excess.
Slow addition of Boc2O over the entire reaction time fur-
ther improved the yield of the desired stilbene (entries 14
and 15).
References
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Synlett 2002, No. 10, 1721–1723 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Pd-Catalyzed Decarbonylative Heck Olefination
1723
Table 2 Heck Olefination of Carboxylic Acids
Comp.
Structure
Yield (%)b
80 (78)d
Sel.c
18:1
Comp.
Structure
Yield (%)b
65
Sel.c
4a
4h
11:1
4b
4c
48
87
10:1
13:1
4i
4j
45
45
19:1
14:1
4d
4e
4f
66
72
78
16:1
20:1
14:1
4k
4l
71
81
51
20:1
19:1
23:1
4m
4g
88
28:1
4n
80
5:1e
a Conditions: 1.00 mmol carboxylic acid, 1.20 mmol olefin, 3.00 mmol BOC2O, 0.03 mmol PdCl2, 0.10 mmol LiCl, 0.10 mmol -picoline,
5 mL N-methylpyrrolidone, 120 °C, 16 h.
b Isolated yields.
c Ratio of 1,2-:1,1-substituted olefins.
d On 25 mmol scale.
e Mixture of isomers
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Synlett 2002, No. 10, 1721–1723 ISSN 0936-5214 © Thieme Stuttgart · New York