Aqueous DMF - Potassium carbonate as a substitute for thallium and silver additives in the palladium-catalyzed conversion of aryl bromides to acetyl arenes

Article abstract of DOI:10.1021/jo015599f

Highly selective palladium-catalyzed internal α-arylations of alkyl vinyl ethers with aryl and heteroaryl bromides were conveniently conducted in aqueous DMF with potassium carbonate as base and with DPPP as bidentate ligand. The corresponding acetyl arene products were, after hydrolysis, isolated in good to excellent yields. This Heck reaction procedure does not require toxic thallium or expensive silver salt additives, is promoted by water, and is suggested to proceed via charged organopalladium intermediates. Single-mode microwave irradiation was utilized in one example to shorten the reaction time.

Full text of DOI:10.1021/jo015599f

4340
J . Org. Chem. 2001, 66, 4340-4343
Aqu eou s DMF -P ota ssiu m Ca r bon a te a s a Su bstitu te for Th a lliu m
a n d Silver Ad d itives in th e P a lla d iu m -Ca ta lyzed Con ver sion of
Ar yl Br om id es to Acetyl Ar en es
Karl S. A. Vallin, Mats Larhed, and Anders Hallberg*
Department of Organic Pharmaceutical Chemistry, Uppsala University, BMC,
Box-574, SE-751 23 Uppsala, Sweden
Anders.Hallberg@farmkemi.uu.se
Received February 28, 2001
Highly selective palladium-catalyzed internal R-arylations of alkyl vinyl ethers with aryl and
heteroaryl bromides were conveniently conducted in aqueous DMF with potassium carbonate as
base and with DPPP as bidentate ligand. The corresponding acetyl arene products were, after
hydrolysis, isolated in good to excellent yields. This Heck reaction procedure does not require toxic
thallium or expensive silver salt additives, is promoted by water, and is suggested to proceed via
charged organopalladium intermediates. Single-mode microwave irradiation was utilized in one
example to shorten the reaction time.
In tr od u ction
tion of a cationic π-complex, essential for the charged
controlled R-selectivity.6
Palladium-catalyzed Heck arylation of acyclic electron-
deficient monosubstituted olefins leads predominantly to
vinylic substitution at the least hindered terminal
position.1-3 Arylation of electron-rich olefins, such as
vinyl ethers, can be controlled to deliver vinyl ethers
substituted either at the terminal â-position4 or at the
internal R-position.5 Cabri et al. demonstrated that the
employment of bidentate ligands resulted in highly
R-selective arylations of alkyl vinyl ethers.6,7 This reac-
tion, relying on the creation of cationic organopalladium
intermediates, constitutes a new, general, and efficient
entry to acetylated aromatic products from aryl triflates
or aryl halides. The related ligand-controlled highly
regioselective palladium-catalyzed R-vinylation of alkyl
vinyl ethers efficiently affords 1,3-dienes and acetals with
both classic and microwave-mediated heating.8 With aryl
or vinyl triflates, ionization occurs by spontaneous dis-
sociation of the weakly palladium(II)-coordinating triflate
counterion. Toxic thallium(I) or costly silver(I) salts were
needed as additives in the reactions where aryl bromides
were employed.6,9 This disadvantage limited the utility
of this important class of arylating agents in R-arylations,
in particular for their use in parallel synthesis and large-
scale reactions. Although the role of the thallium or silver
additives is not fully elucidated, it is proposed that these
additives promote halide abstraction9,10 and thus forma-
An alternative method to support ionization and
formation of a cationic π-complex from aryl bromides
could be to increase the polarity of the DMF-based
reaction mixture. To develop a “green” procedure we
decided to probe the potential of water as a cheap and
environmentally friendly polar additive to the Heck
cocktail.3,11,12 Very recently, Xiao demonstrated a highly
selective internal Heck arylation of butyl vinyl ether with
aryl halides in the highly polar ionic liquid 1-butyl-3-
methylimidazolium tetrafluoroborate ([bmin][BF4]).13
We herein report that an efficient conversion of aryl
bromides to acetyl arenes can be accomplished also in
absence of thallium and silver additives provided that
the arylations are conducted in a polar aqueous DMF
medium with potassium carbonate as base and 1,3-bis-
(diphenylphosphino) propane (DPPP) as ligand (eq 1). In
addition, vinyl bromides were converted into the corre-
sponding R,â-unsaturated methyl ketones via the water
promoted Heck vinylation reaction.
(1) Heck, R. F. Org React. 1982, 27, 345-390.
(2) De Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994,
33, 2379-2411.
Resu lts
(3) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009-
3066.
In the initial experiments we reacted 1-bromo naph-
thalene (1e) with butyl vinyl ether (2a ) in DMF with
(4) Larhed, M.; Andersson, C. M.; Hallberg, A. Acta Chem. Scand.
1993, 47, 212-217.
(5) Hallberg, A.; Westfelt, L.; Holm, B. J . Org. Chem. 1981, 46,
5414-5415.
(10) Karabelas, K.; Westerlund, C.; Hallberg, A. J . Org. Chem. 1985,
(6) Cabri, W.; Candiani, I.; Bedeschi, A.; Penco, S.; Santi, R. J . Org.
Chem. 1992, 57, 1481-1486.
50, 3896.
(11) Bumagin, N. A.; More, P. G.; Beletskaya, I. P. J . Organomet.
Chem. 1989, 371, 397-401.
(7) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2-7.
(8) Vallin, K. S. A.; Larhed, M.; J ohansson, K.; Hallberg, A. J . Org.
Chem. 2000, 65, 4537-4542.
(12) Wang, J . X.; Hu, Z.; Wei, B. G.; Bai, L. J . Chem. Res. S 2000,
484-485.
(9) Grigg, R.; Loganathan, V.; Santhakumar, V.; Sridharan, V.;
Teasdale, A. Tetrahedron Lett. 1991, 32, 687-690.
(13) Xu, L. J .; Chen, W. P.; Ross, J .; Xiao, J . L. Org. Lett. 2001, 3,
295-297.
10.1021/jo015599f CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/22/2001

Pd-Catalyzed Conversion of Aryl Bromides to Acetyl Arenes
J . Org. Chem., Vol. 66, No. 12, 2001 4341
Ta ble 1. Regioselective In ter n a l Ar yla tion a n d Vin yla tion of Vin yl Eth er s w ith Or ga n o Ha lid esa
entry
aryl halide or vinyl bromide
olefin
H2O/DMF
time (h)
temp °Cb
4/3c
isolated yield 5 (%)d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
4-MeO-PhBr
4-MeO-PhBr
4-MeO-PhBr
PhBr
PhBr
PhBr
PhBr
PhBr
PhBr
PhBr
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1c
1d
1e
1e
1f
2a
2a
2a
2a
2a
2a
2a
2a
0.0/12.5
0.75/12.5
1.5/12.5
0.0/12.5
0.75/12.5
1.5/12.5
1.5/12.5e
1.5/12.5f
1.5/12.5
1.5/12.5
1.5/12.5
1.5/12.5
1.5/12.5
1.5/12.5
3.0/12.5
1.5/12.5
3.0/12.5
1.5/12.5
1.5/12.5
3.0/12.5
3.0/12.5
6.0/12.5
3.0i/12.5
1.5/12.5
3.0/12.5
3.0/12.5
3.0/12.5
1.5/12.5
1.5/12.5
1.5/12.5m
1.5/12.5m
16
16
16
86
16
16
48
48
16
16
40
16
16
16
16
66
16
240
86
86
16
16
30
240
16
16
48
48
16
168
40
80
80
80
80
80
80
80
80
80
80
80
80
80
80
100
80
100
80
100
80
100
100
100
80
100
100
100
100
80
99/1
99/1
99/1
99/1
99/1
99/1
99/1
99/1
99/1
99/1
99/1
99/1
99/1
98/2
98/2
96/4
99/1
93/7
99/1
99/1
99/1
99/1
99/1
99/1
99/1
99/1
99/1
99/1
99/1
98/2
96/4
5a 93
5a 95
5a 92
5b 89
5b 87
5b 82
5b 86
5b 89
5b 85
5b 85
5b 73
5c 94
5d 88
5e 96
5e 92
5f 81
5f 71
5g 48
5g 62
5g 54
5g 70
5g 45
5g 61
5h 66j
5h 86
5i 64
2b
2c
PhBr
2d g
2a
4-Me-PhBr
2-Me-PhBr
1-Br-naphthyl
1-Br-naphthyl
4-Cl-PhBr
4-Cl-PhBr
4-F3C-PhBr
4-F3C-PhBr
4-F3C-PhBr
4-F3C-PhBr
4-F3C-PhBr
4-F3C-PhBr
4-NC-PhBr
4-NC-PhBr
3-Br-pyridyl
4-Br-pyridylk
3-Br-thienyl
1-I-naphthyl
R-Br-styrene
R-keto-vinyl-Brl
2a
2a
2a h
2a
1f
2a h
2a
1g
1g
1g
1g
1g
1g
1h
1h
1i
1j
1k
1l
1m
1n
2a
2a
2a h
2a h
2a h
2a
2a h
2a h
2a h
2a
5j 62
5k 66
5e 82
5l 23
2a
2a
2a
40
80
5m 18
a
The reactions were performed in 5.0 mmol scale under a nitrogen atmosphere in sealed Pyrex tubes with 1.0 equiv of 1; 2.5 equiv of
2, 0.030 equiv of Pd(OAc)2, 0.066 equiv of DPPP, 1.2 equiv of K2CO3, 0.0-6.0 mL of water, and 12.5 mL of dry DMF. Oil bath. c R/â,
b
Determined by GC/MS and 1H NMR. Purity >95% by GC/MS. e 2.5 equiv of LiCl was added. f 2.5 equiv of LiBr was added. 0.75 equiv
d
g
h
i
j
k
l
of 2d was utilized. 5.0 equiv of 2a was utilized. Water was exchanged with MeOH. Only 88% conversion of 1h . HCl salt. 2-Bromo-
m
4,4-dimethyl-2-cyclohexen-1-one. Dry DMSO instead of dry DMF, 1.0 mmol scale.
triethylamine as base, but omitted the thallium additive.
An R/â (4/3) selectivity of 75/25 was encountered, corro-
borating the low regioselectivity in absence of thallium
salts previously reported.6,14 Addition of water to this
reaction medium resulted in a very slow reaction.15
However, we found that substitution of triethylamine for
potassium carbonate as base and use of a 3.0/12.5 water/
DMF solvent system produced an high regioselectivity
of 98/2. An analogous Heck cocktail with water, potas-
sium carbonate, and triethylamine also delivered a regio-
selective and smooth reaction (4/3 ) 96/4).16
Ch a r t 1
The preparative results from the vinylation reactions
with high regioselectivities of a series of aryl, heteroaryl
and vinyl halides (1a -n ) with alkyl vinyl ethers (2a -d ,
Chart 1) in the water/DMF medium are presented in
Table 1. The corresponding aryl methyl ketones (5a -k )
were isolated after acidic treatment in good to excellent
yields in all of the investigated reactions (eq 1). To afford
smooth and selective transformations, the addition of
water was needed with all aryl bromides except for the
electron-rich 1a . Increased water content in the reaction
medium enhanced the reaction rates in general. With the
electron-poor 1f-j, a larger amount of water and/or
higher reaction temperature was found to be crucial for
high R-selectivities (entries 16-22, 24-27). In addition,
water could be exchanged by methanol without loss of
selectivity (entry 23). Five equivalents of olefin 2a were
necessary for complete conversion of the aryl bromides
in the reactions with 3.0-6.0 mL of water.
The nitrogen-functionalized vinyl ethers 2b and 2c
undergoes â-arylation via nitrogen-palladium coordina-
tion in the presence of monodentate ligands or under
ligand-less conditions.4 Utilizing the aqueous DMF/
potassium carbonate/DPPP system, the phenylations
resulted in high selectivity of the R-position of the vinyl
ethers (entries 9 and 10). Furthermore, double phenyl-
ation of the bis vinyl ether 2d (only 0.75 equiv of olefin)
provided 5b in good yield (73%, entry 11).
The low isolated yield in entry 22 (45% of 5g) is a
consequence of an accelerated dehalogenation process
that was observed at high water content. Contrary to the
internal couplings with aryl bromides, the analogous aryl
iodides delivered essentially nonselective product mix-
tures of 3 and 4 under water/DMF/potassium carbonate
conditions.17 The only exception to this lack of selectivity
was experienced with naphthyl iodide 1l which was
(14) Andersson, C.-M.; Hallberg, A.; Daves, G. D. J . Org. Chem.
1987, 52, 3529-3536.
(15) A noncomplete conversion of 1e was observed after 4 days at
80 °C (water/DMF ) 1.5/12.5). The major product was the correspond-
ing methyl ketone 5e.
(16) The reaction was performed according to entry 15 in Table 1
but with an extra addition of 1.2 mmol of triethylamine.

4342 J . Org. Chem., Vol. 66, No. 12, 2001
Vallin et al.
vinylated successfully and with high regioselectivity
(entry 29). Vinylation of R-bromostyrene (1m ) gave the
expected R,â-unsaturated methyl ketone after hydrolysis
but in a low yield (23%) due to homocoupling and
formation of 1,3-diphenyl-1-butyn-3-ene.18,19 Apparently,
1m eliminates hydrobromic acid to give phenylacetylene
which undergoes a subsequent Sonogashira coupling with
unreacted 1m . Rapid dehalogenation of 2-bromo-4,4-
dimethyl-2-cyclohexen-1-one (1n ) explains the low yield
of 5m (entry 31).8
to increase the polarity. In fact, the polarity of the
reaction system might be determining whether the
reaction will proceed in a neutral or cationic Heck-
pathway with aryl bromides (Overman’s hidden gate).3,24
The potential importance of an aryl palladium hydroxide
species,3,25,26 that might play a pivotal role for the
outcome of the reaction, can at present not be excluded,
although the selectivity with electron-rich bromides do
not rely on the presence of water (Table 1, entries 1 and
4).
Unfortunately, the couplings reported in Table 1
require long reaction times, which is a drawback for rapid
combinatorial applications. By exploiting the single-mode
microwave heating technique,20-23 the reaction time for
the phenylation of 2a could be shortened to 1 h at 122
°C in a microwave synthesizer (eq 2). Attempts to
truncate the reaction time further, by raising the reaction
temperature, did not improve the outcome and led to a
substantial loss of regioselectivity.
Furthermore in two experiments in Table 1 (entries 7
and 8), the influence of different halide salts on the
reaction was investigated. The effect of both the LiCl and
LiBr additives was a retained regioselectivity but de-
creased reaction rate compared to the standard reaction
in entry 6.27 Thus, it is reasonable to assume that the
ionic pathway was partly impeded by the formation of a
neutral palladium(II) halide intermediate.
The poor regioselectivities encountered with aryl io-
dides is most likely a consequence of the formation of a
neutral oxidative addition complex with a palladium-
coordinating iodide.6 The relatively high trans effect
exerted by the iodide28 can promote a dissociation of one
of the phosphorus atoms in the bidentate ligand and
induce the subsequent generation of a neutral π-complex.
Therefore, after insertion and hydridopalladium halide
elimination, a higher extent of linear 3 is formed.
Discu ssion
By addition of water as an ionization-accelerating
additive, we had initially hoped to increase the scope of
this protocol to include also internal R-arylations of
noncyclic N-alkylated enamides. The low regioselectivi-
ties encountered in aqueous DMF/potassium carbonate/
DPPP-mediated reactions of aryl bromides with this class
of olefins (typically R/â )70/30) were in sharp contrast
to the excellent selectivities reported in the DPPP-
controlled enamide/aryl triflate couplings (R/â ) 100/0).7
This unexpected result suggested to us that the olefin
itself could lend assistance for the transition between the
neutral and cationic mechanism. Thus, it seems that the
enamides disfavor the cationic reaction path by being less
efficient at trapping the trivalent cationic palladium
complex formed in an equilibrium mixture (path A, a
dissociative ligand-exchange process, eq 4). Another
explanation could be that in an apical attack (path B,
an associative ligand-exchange process), the incoming
enamide might not exchange the bromide as readily as
the more reactive vinyl ethers do.
We believe that the high R-preference encountered in
the internal couplings of aryl bromides in water/DMF
with potassium carbonate as base is attributed to the
generation of a key cationic aryl palladium π-intermedi-
ate (6) via displacement of the bromide. We speculate
that such ionization could be facilitated in the highly
polar reaction system. A likely reaction path for the
aqueous Heck procedure is presented in eq 3. The greater
the contribution of a cationic complex 6, the higher the
overall reaction rate and selectivity. We interpret the
powerful effect from the non-amine carbonate base as a
consequence of an increased ionic strength in the me-
dium. The addition of water to the reaction mixture
increases the concentration of dissolved potassium car-
bonate. Furthermore, electron-poor aryl bromides are not
capable of completely converting 1 and 2 into the charged
intermediate 6 unless a large portion of water is added
(17) Low R-selectivities were encounted with the following aryl
iodides: 4-methoxyiodobenzene (R/â ) 85/15), iodobenzene (R/â ) 72/
28), 4-bromoiodobenzene (R/â ) 79/21), 4-(trifluoromethyl)iodobenzene
(R/â ) 73/27).
(18) Andersson, C.-M.; Hallberg, A. J . Org. Chem. 1989, 54, 1502-
(21) Larhed, M.; Hallberg, A. J . Org. Chem. 1996, 61, 9582-9584.
(22) Gabriel, C.; Gabriel, S.; Grant, E. H.; Halstead, B. S. J .; Mingos,
D. M. P. Chem. Soc. Rev. 1998, 27, 213-223.
(23) Kaiser, N. F. K.; Bremberg, U.; Larhed, M.; Moberg, C.;
Hallberg, A. Angew. Chem., Int. Ed. 2000, 39, 3596-3598.
1505.
(19) Temperatures above 40 °C resulted in reduced regioselectivity.
(20) Strauss, C. R.; Trainor, R. W. Aust. J . Chem. 1995, 48, 1665-
1692.

Pd-Catalyzed Conversion of Aryl Bromides to Acetyl Arenes
J . Org. Chem., Vol. 66, No. 12, 2001 4343
phino)propane (DPPP), and potassium carbonate were pur-
chased from commercial suppliers and were used directly as
received. The vinyl ethers 2b and 2c were prepared as
previously described using a mercury(II)-catalyzed transetheri-
fication procedure.4 Bromo-4,4-dimethyl-2-cyclohexen-1-one
(1n ) was prepared by literature procedure.31 DMF and DMSO
was stored over activated 4 Å molecular sieves.
Gen er a l P r oced u r e for th e Th er m a l r-Ar yla tion of
Vin yl Eth er 2a -d (Ta ble 1). A mixture of the corresponding
aryl halide (5.0 mmol), vinyl ether (3.75-25.0 mmol), Pd(OAc)2
(0.0334 g, 0.150 mmol), DPPP (0.136 g, 0.330 mmol), K2CO3
(0.83 g, 6.0 mmol), 0.400 g naphthalene (internal standard),
lithium halide (when present), and 0.0-6.0 mL water (or 3.0
mL methanol) in 12.5 mL of DMF was stirred under N2 in a
sealed tube (for reaction time, temperature, and amount of
water, see Table 1). Samples were periodically taken and
partitioned between diethyl ether and 0.1 M NaOH. The
organic layers were dried over K2CO3(s) before analyses by GC/
MS. After complete consumption of the starting aryl halide,
the reaction was cooled to room temperature and hydrolyzed
by adding 20 mL of 5% HCl for 30 min. All reactions were
worked up by extraction with CH2Cl2 and 10% K2CO3 (aq).
The products 5a -k were purified by column chromatography
on silica gel. Eluents: isohexane/ethyl acetate.
Th er m a l r-Vin yla tion of 1m a n d 1n w ith Vin yl Eth er
2a . The vinylation of 2a was performed as described under
General Procedure for the Thermal R-Arylation of Vinyl Ether
2a-d but in a 1.0 mmol scale using vinyl bromides 1m and
1n and employing DMSO instead of DMF as organic solvent.
The products 5l and 5m were purified as described for the
acetyl arenes.
Micr ow a ve Hea ted In ter n a l r-P h en yla tion of 2a w ith
Br om oben zen e (eq 2). The microwave-assisted phenylation
of 2a was performed as described under General Procedure
for the Thermal R-Arylation of Vinyl Ether 2a-d but in a 1.0
mmol scale in a Smith process vial. The reaction temperature
was 122 °C with a microwave irradiation time of 60 min. The
product 5b was purified as described for the conventionally
heated products.
Con clu sion
In summary, we have demonstrated that aryl and
heteroaryl bromides are efficiently converted to the
corresponding acetyl arenes in high yields and selectivi-
ties by conducting the reactions in an aqueous DMF
medium with potassium carbonate as base. The devel-
oped Heck process merits attention due to the convenient,
nonexpensive, and environmentally benign experimental
procedure.
Exp er im en ta l Section
Gen er a l. H NMR and 13C NMR spectra were recorded in
CDCl3 at 270 and 67.8 MHz. Mass spectra were recorded at
an ionizing voltage of 70 eV (EI). The GC/MS was equipped
1
with
a
HP-1 (25 m × 0.20 mm) capillary column. The
regioisomers were assumed to have the same GC/MS response
factor. All nonmicrowave reactions were conducted under
nitrogen in heavy-walled Pyrex tubes sealed with a screwcap
fitted with a Teflon gasket silicon septum. Microwave heating
was performed under nitrogen in a (Smith Synthesizer) single-
mode microwave cavity, from Personal Chemistry AB, produc-
ing continuous irradiation at 2450 MHz. Both conventional
and microwave-mediated reactions were performed with mag-
netic stirring. All reactions were allowed to proceed until
complete consumption of the starting aryl or vinyl halide,
utilizing an appropriate choice of thermal heating time or
microwave irradiation time and temperature. Column chro-
matography was performed using commercially available silica
gel 60 (particle size: 0.040-0.063 mm, Merck). The isolated
acetyl arenes (5a -k ) and R,â-unsaturated methyl ketones (5l,
5m ) are commercially available or have previously been
characterized, and the data obtained corresponded satisfactory
with MS and NMR literature data.6,14,29,30
Ma ter ia ls. The vinyl ethers 2a and 2d , aryl and vinyl
halides 1a -m , palladium(II) acetate, 1,3-bis(diphenylphos-
(24) Ashimori, A.; Bachand, B.; Calter, M. A.; Govek, S. P.; Overman,
L. E.; Poon, D. J . J . Am. Chem. Soc. 1998, 120, 6488-6499.
(25) Crisp, G. T.; Gebauer, M. G. Tetrahedron 1996, 52, 12465-
12474.
(26) Suzuki, A. J . Organomet. Chem. 1999, 576, 147-168.
(27) In a separate experiment with 1b and 2a , LiI (2.5 equiv) was
found to decrease the reaction rate more strongly than LiCl and LiBr
(73% conversion of 1b after 3 days, 4/3 ) 99/1).
(28) Appelton, T. G.; Clark, H. C.; Manzer, L. E. Coord. Chem. Rev.
1973, 10, 335-422.
(29) Meyer, W. L.; Brannon, M. J .; Burgos, C.; Goodwin, T. E.;
Howard, R. W. J . Org. Chem. 1985, 50, 438-447.
(30) Najera, C.; Sansano, J . M. Tetrahedron 1990, 46, 3993-4002.
Ack n ow led gm en t. We gratefully acknowledge the
financial support from the Swedish Natural Science
Research Council and the Swedish Research Council for
Engineering Sciences. We would like to thank Personal
Chemistry AB for providing the microwave cavity.
J O015599F
(31) Bordwell, F. G.; Wellman, K. M. J . Org. Chem. 1963, 28, 2544-
2547.