Microwave-promoted hydroxycarbonylation in water using gaseous carbon monoxide and pre-pressurized reaction vessels

Article abstract of DOI:10.1055/s-2006-944216

The microwave-promoted hydroxycarbonylation of aryl iodides using reaction vessels pre-pressurized with CO is reported. Reactions are performed using simple palladium salts with loadings of either 0.01 mol% or 1 mol%. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-944216

LETTER
1663
Microwave-Promoted Hydroxycarbonylation in Water Using Gaseous Carbon
Monoxide and Pre-Pressurized Reaction Vessels
M
icrowave-Prom
h
oted Hydrox
a
ycarbonyla
d
tion M. Kormos, Nicholas E. Leadbeater*
Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, CT 06269-3060, USA
Fax +1(860)4862981; E-mail: nicholas.leadbeater@uconn.edu
Received 23 March 2006
oped to circumvent the problem of working with gaseous
Abstract: The microwave-promoted hydroxycarbonylation of aryl
iodides using reaction vessels pre-pressurized with CO is reported.
Reactions are performed using simple palladium salts with loadings
of either 0.01 mol% or 1 mol%.
carbon monoxide.12 Larhed and co-workers have devel-
oped and elegantly exploited the use of Mo(CO)6 as a
source of carbon monoxide in conjunction with micro-
wave heating.13 Advantages of using Mo(CO)6 as a re-
placement for gaseous CO include the fact that it is a solid
and is easily used on a small scale with commercially
available monomode microwave apparatus with no modi-
fication required. However, Mo(CO)6 is toxic and its use
results in metal waste; this being a particular problem if
the reaction is to be scaled up. We wanted to develop an
alternative strategy based around using gaseous carbon
monoxide in conjunction with the gas-loading capability
of the Synthos 3000. Since much of the chemistry we have
focused our attention on has been performed using water
as a solvent,14 we wanted first to study the palladium-
mediated hydroxycarbonylation of aryl halides in water,
forming the corresponding benzoic acids. This transfor-
mation has been reported previously using conventional
heating.15 The authors note that the reaction is very effi-
cient; a turnover number of 100,000 being reported for 4-
iodobenzoic acid holding the reaction mixture at 80 °C for
six days. Other approaches to hydroxylcarbonylation have
involved using phosphine-ligated palladium catalysts16,17
or ionic liquids as solvents (Scheme 1).18
Key words: palladium, carbonylations, catalysis, water, micro-
wave
Microwave-promoted synthesis is an area of increasing
interest in both academic and industrial laboratories.1–3 As
well as being energy-efficient,4 microwave heating can
also enhance the rate of reactions and in many cases im-
prove product yields. Also, as the field matures, people
are finding that they can perform chemistry using micro-
wave heating that cannot be achieved using ‘convention-
al’ heating methods, thus opening up new avenues for
synthesis.
Our interest has recently turned to the concept of perform-
ing microwave-promoted chemistry in vessels that have
been pre-pressurized with reactive gases. This would
broaden the application of microwave promoted synthe-
sis. It is difficult to preload commercially available micro-
wave tubes with a gas. In addition, most commercially
available single-mode microwave systems have a pres-
sure limit of 20–30 bar. With the combination of a
pressure of reactive gas and the autogenic pressure of
solvents at elevated temperatures, there is a limit to the
temperature to which reaction mixtures can be heated.
These factors have been reflected in the scarcity of reports
of organic synthesis in pre-pressurized vessels using
microwave heating.5–7 Using a newly developed dedicat-
ed multimode microwave reactor (Anton Paar Synthos
3000) it is possible to perform reactions in heavy-walled
quartz reaction vessels with operating limits of 80 bar.8
The reactor is also equipped with a gas-loading interface,
allowing the vessels to be pre-pressurized to up to 20 bar
prior to placing in the microwave cavity.9 The use of this
apparatus in the Diels–Alder reaction under an atmo-
sphere of ethene has been reported.7
O
Hal
CO, [Pd]
OH
R
R
Scheme 1
Our starting point was to use reaction conditions similar to
those developed for the Suzuki coupling in water; namely
using ligandless palladium sources as catalysts, sodium
carbonate (3.7 equiv) as a base and tetrabutylammonium
bromide (TBAB) as a phase-transfer agent.19–21 Preload-
ing reaction vessels to 14 bar with CO, we screened a
range of conditions for the conversion of 4-iodoanisole to
4-methoxybenzoic acid (anisic acid). Key results are
shown in Table 1. Palladium acetate proved to be a good
catalyst for the reaction and as a starting point we used 1
mol%. We found that the reaction worked better in the ab-
sence of a phase-transfer agent (Table 1, entries 1 and 2).
A reaction temperature of 165 °C is optimal; increasing
this temperature has no effect on product yield (Table 1,
Palladium-mediated carbonylation chemistry is an im-
portant tool in the synthetic chemist’s portfolio.10,11 When
transferring this chemistry from conventional to micro-
wave heating a number of approaches have been devel-
SYNLETT 2006, No. 11, pp 1663–1666
1
2
.0
7
.2
0
0
6
Advanced online publication: 04.07.2006
DOI: 10.1055/s-2006-944216; Art ID: S04306ST
© Georg Thieme Verlag Stuttgart · New York

1664
C. M. Kormos, N. E. Leadbeater
LETTER
entry 3). Reduction of the base by half has a deleterious We decided to screen a range of substrates in the reaction
effect on the product yield (Table 1, entry 4). Using using both 1 mol% Pd(OAc)2 and 0.01 mol% palladium
Herrmann’s palladacycle22 instead of palladium acetate derived from our ICP standard. The results are shown in
offered no advantage in terms of product yield (Table 1, Table 2. Only aryl iodides can be coupled using the meth-
entry 5). Since in our Suzuki protocol we showed that odology; aryl bromides are unreactive (Table 2, entry 2).
very low catalyst loadings could be used,19 we decided to
Table 2 Hydroxycarbonylation of Aryl Halides in Watera
examine the effect of reducing catalyst loading in the
carbonylation reaction. When working in water, a major
O
problem can be precipitation of palladium from a stock
solution, particularly when working with a salt such as
palladium acetate. This is avoided by using an acid stabi-
I
MW, CO
OH
[Pd], Na2CO3, H2O
R
R
lized stock solution such as that purchased as an ICP stan-
dard for palladium. This can be diluted accordingly to
give solutions of the desired concentrations. Using this,
we found that the catalyst loading can be decreased to
0.01 mol% with a 14% decrease in product yield (Table 1,
entries 6 and 7). No starting material remained at the end
of the reaction hence extension of reaction time to im-
prove product yields would have no effect. Moving to
catalyst loadings lower that 0.01 mol% had a significant
detrimental effect (Table 1, entries 8 and 9).
Entry
Aryl halide
Product yield
1% Pd(OAc)2 0.01% Pd soln
OMe
1
2
3
4
86
0
72
I
0
OMe
Br
I
69
82
80
59
Me
Table 1 Optimization of Conditions for the Hydroxycarbonylation
Reaction
COMe
O
I
MW, CO
I
I
OH
5
6
92
59
80
–
[Pd], base, H2O
MeO
MeO
Entry Reaction conditionsa,b
Yield (%)
65
CF3
NO2
NH2
F
1
2
3
4
5
6
7
8
9
1 mol% Pd(OAc)2, 3.7 equiv Na2CO3, 1 equiv
TBAB, 165 °C, 20 min
I
I
7
8
54
60
77
70
68
15
–
1 mol% Pd(OAc)2, 3.7 equiv Na2CO3,
no TBAB, 165 °C, 20 min
86
80
67
87
72
70
64
52
1 mol% Pd(OAc)2, 3.7 equiv Na2CO3,
no TBAB, 200 °C, 20 min
–
1 mol% Pd(OAc)2, 1.9 equiv Na2CO3,
no TBAB, 165 °C, 20 min
I
9
70
74
63
–
1 mol% Herrmann’s palladacycle, 3.7 equiv
Na2CO3, no TBAB, 165 °C, 20 min
I
10
11
12
Me
0.1 mol% Pd soln, 3.7 equiv Na2CO3,
no TBAB, 165 °C, 20 min
I
0.01 mol% Pd soln, 3.7 equiv Na2CO3,
no TBAB, 165 °C, 20 min
MeO
0.001 mol% Pd soln, 3.7 equiv Na2CO3,
no TBAB, 165 °C, 20 min
I
0.0001 mol% Pd soln, 3.7 equiv Na2CO3,
no TBAB, 165 °C, 20 min
I
N
a Reactions were run in a sealed tube, preloaded with 14 bar CO, using
2 mmol aryl halide, 7.4 mmol Na2CO3, and 10 mL H2O. An initial mi-
crowave irradiation power of 800 W was used, the temperature being
ramped from r.t. to 165 °C and held until a total reaction time of 20
min had elapsed.
a Reactions were run in a sealed tube, preloaded with 14 bar CO, using
2 mmol 4-iodoanisole and 10 mL H2O. An initial microwave irradia-
tion power of 1000 W was used, the temperature being ramped from
r.t. to that shown.
b For clarity, changes in reaction conditions from entry 1 are noted in
bold.
Synlett 2006, No. 11, 1663–1666 © Thieme Stuttgart · New York

LETTER
Microwave-Promoted Hydroxycarbonylation
1665
extracted with Et2O (3 × 15 mL). The organic washings were
combined, dried over MgSO4 and the Et2O removed on a rotary
evaporator. This left the crude product, which was isolated and
yield determined by NMR spectroscopy using an internal standard.
Product characterization was by comparison of NMR data with that
in the literature.
A range of aryl iodides can be converted to the benzoic
acids including ortho-substituted examples (Table 2,
entries 10 and 11). Generally, product yields are higher
when using the higher catalyst loading, the exceptions be-
ing 2- and 4-iodotoluene (Table 2, entries 3 and 10). We
find that a representative heteroaromatic substrate gives
only moderate yields of the desired product (Table 2, en-
try 12). This is attributed in part to competitive decompo-
sition as well as to the difficulty in isolating the acid
product from the reaction mixture.
Acknowledgment
The University of Connecticut is thanked for funding. Anton Paar
GmbH is thanked for equipment support.
In summary, we have presented here a methodology for
the microwave-promoted hydroxycarbonylation of aryl
iodides using reaction vessels pre-pressurized with CO. It
offers an alternative to using solid CO sources. A concern
about using carbon monoxide gas in microwave vessels
has been the issue of leakage. Here we show that, with the
proper apparatus, the use of carbon monoxide gas is
quick, easy, and safe.
References and Notes
(1) A number of books on microwave-promoted synthesis have
been published recently: (a) Kappe, C. O.; Stadler, A.
Microwaves in Organic and Medicinal Chemistry; Wiley-
VCH: Weinheim, 2005. (b) Microwave-Assisted Organic
Synthesis; Lidström, P.; Tierney, J. P., Eds.; Blackwell:
Oxford, 2005. (c) Microwaves in Organic Synthesis; Loupy,
A., Ed.; Wiley-VCH: Weinheim, 2002. (d) Hayes, B. L.
Microwave Synthesis: Chemistry at the Speed of Light; CEM
Publishing: Matthews NC, 2002.
Description of the Microwave Apparatus
(2) For a recent review, see: Kappe, C. O. Angew. Chem. Int. Ed.
2004, 43, 6250.
A commercially available multimode microwave unit was used for
the reactions. The instrument is equipped with two magnetrons with
combined continuous microwave output power from 0 to 1400 W.
Heavy-walled quartz reaction vessels (80 mL capacity, up to 60 mL
working volume) were used. These vessels are dedicated for reac-
tions at high pressure (up to 80 bar). The quartz vessels were capped
with special seals and a protective PEEK cap and then were placed
inside protecting air-cooling jackets made of PEEK. The seals com-
prise a release valve that could be manually operated. The individ-
ual vessels were placed in an eight-position rotor and fixed in place
by screwing down the upper rotor plate, and the rotor was finally
closed with a protective hood. The vessels, once placed and secured
in the rotor with the hood attached, were loaded with carbon
monoxide using a commercially available gas-loading kit, access
being via a bayonet link. They were pressurized directly from a
carbon monoxide cylinder to 14 bar (ca. 200 psi). The rotor was then
placed into the microwave cavity. The temperature was monitored
using an internal gas balloon thermometer placed in one reference
vessel and additionally by exterior IR thermography. Pressure was
monitored by a simultaneous hydraulic pressure-sensing device for
all vessels, with recording of the highest pressure level and pressure
increase. Reaction vessels were stirred by means of a rotating mag-
netic plate located below the floor of the microwave cavity and a
Teflon-coated magnetic stir bar in the vessel. At the end of a reac-
tion, any remaining pressure was vented by releasing the venting
screw on each reaction vessel whilst still in the rotor access being
via frontal holes in the rotor lid.
(3) For other reviews on the general area of microwave-
promoted organic synthesis, see: (a) Larhed, M.; Moberg,
C.; Hallberg, A. Acc. Chem. Res. 2002, 35, 717. (b) Lew,
A.; Krutzik, P. O.; Hart, M. E.; Chamberlain, A. R. J. Comb.
Chem. 2002, 4, 95. (c) Lidström, P.; Tierney, J. P.; Wathey,
B.; Westman, J. Tetrahedron 2001, 57, 9225.
(4) Gronnow, M. J.; White, R. J.; Clark, J. H.; Macquarrie, D. J.
Org. Process Res. Dev. 2005, 9, 516.
(5) Milijanic, O.; Vollhardt, K. P. C.; Whitener, G. D. Synlett
2003, 29.
(6) Specially designed reactors have been used for gas phase
catalysis under microwave irradiation. See ref. 7 and
references therein.
(7) Kaval, N.; Dehaen, W.; Kappe, C. O.; Van der Eycken, E.
Org. Biomol. Chem. 2004, 2, 154.
(8) Synthos 3000 available from Anton Paar GmbH
(www.anton-paar.com).
(9) For an overview of the apparatus, see: Stadler, A.; Yousefi,
B. H.; Dallinger, D.; Walla, P.; Van der Eycken, E.; Kaval,
N.; Kappe, C. O. Org. Process Res. Dev. 2003, 7, 707.
(10) For a review of palladium-mediated carbonylation
chemistry, see: Skoda-Földes, R.; Kollár, L. Curr. Org.
Chem. 2002, 6, 1097.
(11) For examples, see: (a) Magerlein, W.; Indolese, A. F.;
Beller, M. Angew. Chem. Int Ed. 2001, 40, 2856.
(b) Albaneze-Walker, J.; Bazaral, C.; Leavey, T.; Dormer, P.
G.; Murry, J. A. Org. Lett. 2004, 6, 2097. (c) Calo, V.;
Giannoccaro, P.; Nacci, A.; Monopoli, A. J. Organomet.
Chem. 2002, 645, 152. (d) Ramesh, C.; Nakamura, R.;
Kubota, Y.; Miwa, M.; Sugi, Y. Synthesis 2004, 501.
(12) For a general review of alternatives to CO gas, see:
Morimoto, T.; Kakiuchi, K. Angew. Chem. Int. Ed. 2004, 43,
5580.
Typical Procedure for the Hydroxycarbonylation of 4-Iodoani-
sole.
In an 80 mL quartz tube was placed 4-iodoanisole (468 mg, 2.0
mmol), Na2CO3 (0.785 g, 7.4 mmol), Pd(OAc)2 (4.5 mg, 0.02
mmol, 1 mol%) and H2O (10 mL). The vessel was sealed and loaded
onto the rotor. Three other vessels were prepared similarly. Each
vessel was pressurized to 14 bar with CO. The loaded rotor was sub-
jected to a maximum of 1000 W microwave power in a ramp to
165 °C and then held at this temperature until a total reaction time
of 20 min had elapsed. The reaction mixture was stirred continuous-
ly and the pressure peaked at approximately 30 bar. Upon comple-
tion, the reaction vessels were allowed to cool to 50 °C, this taking
around 20 min. Any remaining pressure was vented in a fume cup-
board and then the vessels were removed from the rotor. The con-
tents acidified with HCl to pH 1–3. The aqueous solution was
(13) For examples, see: (a) Lagerlund, O.; Larhed, M. J. Comb.
Chem. 2006, 8, 4. (b) Wu, X.; Larhed, M. Org. Lett. 2005, 7,
3327. (c) Wu, X. Y.; Nilsson, P.; Larhed, M. J. J. Org.
Chem. 2005, 70, 346. (d) Wannberg, J.; Larhed, M. J. Org.
Chem. 2003, 68, 5750.
(14) For a review see: Leadbeater, N. E. Chem. Commun. 2005,
2881.
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LETTER
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Synlett 2006, No. 11, 1663–1666 © Thieme Stuttgart · New York