Microwave-assisted carbonylation and cyclocarbonylation of aryl iodides under ligand free heterogeneous catalysis

Article abstract of DOI:10.1021/jo9021315

"Chemical Equation Presented" Carbonylation reaction is a very effective transformation for the synthesis of esters, amides, and heterocyclic compounds. Heterogeneous catalyzed carbonylation reactions can be carried out using the association of Pd/C and microwave dielectric heating. Alkoxy carbonylation can be performed, with stoichiometric amounts of different primary and secondary alcohols in DMF in the presence of DBU as the base. Analogously, iodobenzene, CO, and amines can be transformed into the corresponding amides in good yields after a simple filtration to remove the catalyst. Pd/C was also successfully employed in microwave-assisted cyclocarbonylation of o-iodoaniline with acyl chlorides to give benzoxazinones. Pd/ C can be recycled two times without, a considerable difference in the reaction yields.

Full text of DOI:10.1021/jo9021315

pubs.acs.org/joc
Microwave-Assisted Carbonylation and Cyclocarbonylation of Aryl
Iodides under Ligand Free Heterogeneous Catalysis
Jessica Salvadori, Evita Balducci, Silvia Zaza, Elena Petricci,* and Maurizio Taddei
ꢀ
Dipartimento Farmaco Chimico Tecnologico, Universita degli Studi di Siena, Via A. Moro,
I-53100 Siena, Italy
petricci@unisi.it
Received November 3, 2009
Carbonylation reaction is a very effective transformation for the synthesis of esters, amides, and
heterocyclic compounds. Heterogeneous catalyzed carbonylation reactions can be carried out using the
association of Pd/C and microwave dielectric heating. Alkoxy carbonylation can be performed with
stoichiometric amounts of different primary and secondary alcohols in DMF in the presence of DBU as
the base. Analogously, iodobenzene, CO, and amines can be transformed into the corresponding amides
in good yields after a simple filtration to remove the catalyst. Pd/C was also successfully employed in
microwave-assisted cyclocarbonylation of o-iodoaniline with acyl chlorides to give benzoxazinones. Pd/
C can be recycled two times without a considerable difference in the reaction yields.
Introduction
to a solid support such as activated carbon (charcoal),
zeolites and molecular sieves, metal oxides (silica, alumina,
MgO, ZnO, TiO2, ZrO2), clays, alkali and alkaline earth salts
(CaCO3, BaSO4, BaCO3, SrCO3), porous glass, organic
polymers, or polymers embedded in porous glass.3-6 Differ-
ent Pd nanoparticels are also active catalytic systems due to
their large surface area,7 and some of them have been also
used in continuous-flow systems.7d Normally, supported Pd
Palladium-catalyzed reactions are largely applied to many
synthetic transformations for the assembly of a wide range of
important molecules in pharmaceutical, agricultural, and
natural product chemistry. Using homogeneous palladium
catalysis, high reaction rate, turnover numbers (TON), and
high selectivities and yields are often possible after addition
of opportune ligands, such as phosphines, amines, carbenes,
or dibenzylideneacetones (dba).1 However, the main draw-
back of homogeneous catalysis is associated with separation
and reuse (recycle) of the catalyst. This condition leads to a
loss of expensive metal (and ligands) and to the presence of
metal impurities in the products. The complete removal of
residual metals is a huge problem especially for pharmaceu-
tical products where carryover of metal impurities may cause
serious problems in the production of many formulations.2
In order to address these problems, heterogeneous Pd
catalysis is a promising option. Pd(0) or Pd(II) can be fixed
(3) Blaser, H.-U.; Indolese, A.; Schnyder, A.; Steiner, H.; Studer, M.
J. Mol. Catal. A: Chem. 2001, 173, 3–18.
(4) For a review on the use of Pd/C, see: (a) Seki, M. Synthesis 2006,
2975–2992. (b) Zhao, F.; Bhanage, B. M.; Shirai, M.; Arai, M. Chem.;Eur.
J. 2000, 6, 843–848.
(5) (a) Biffis, A.; Zecca, M.; Basato, M. J. Mol. Catal. A: Chem. 2001, 173,
249–274. (b) Mehnert, C. P.; Weaver, D. W.; Ying, J. Y. J. Am. Chem. Soc.
1998, 120, 12289–12296. (c) Djakovitch, L.; Koehler, K. J. Am. Chem. Soc.
2001, 123, 5990–5999.
(6) (a) Varma, R. S.; Naicker, K. P.; Liesen, P. J. Tetrahedron Lett. 1999,
40, 2075–2078. (b) Li, J.; Mau, A. W. H.; Strauss, C. R. Chem. Commun.
1997, 1275–1276.
(7) (a) Reetz, M. T.; de Vries, J. G. Chem. Commun. 2004, 1559–1563.
(b) Bhattacharya, S.; Srivastava, A.; Sengupta, S. Tetrahedron Lett. 2005, 46,
3557–3560. (c) Astruc, D.; Lu, F.; Aranzaes, J. R. Angew. Chem., Int. Ed.
2005, 44, 7852–7872. (d) Solodenko, W.; Wen, H.; Leue, S.; Stuhlmann, F.;
€
Sourkouni-Argirusi, G.; Jas, G.; Schonfeld, H.; Kunz, U.; Kirschning, A.
Eur. J. Org. Chem. 2004, 3601–3610.
(1) Liebscher, Y.; Liebscher, J. Chem. Rev. 2007, 107, 133–173.
(2) Welch, C. J.; Albaneze-Walker, J.; Leonard, W. R.; Biba, M.; Da
Silva, J.; Henderson, D.; Laing, B.; Mathre, D. J.; Spencer, S.; Bu, X.; Wang,
T. Org. Process Res. Dev. 2005, 9, 198–205.
DOI: 10.1021/jo9021315
r
Published on Web 02/25/2010
J. Org. Chem. 2010, 75, 1841–1847 1841
2010 American Chemical Society

Salvadori et al.
JOCArticle
catalysts require more drastic reaction conditions than
homogeneous ones, but this does not cause problems as far
as the stability of the catalysts is concerned. The somewhat
lower activity can be compensated by using higher tempera-
tures and catalyst loadings. Among heterogeneous Pd
sources, palladium activated on carbon (Pd/C) is a commer-
cially available, inexpensive palladium catalyst used only for
hydrogenations before the 1990s.8 More recently, different
coupling procedures5 for carbon-carbon, carbon-oxygen,
and carbon-nitrogen bond formation in the presence of Pd/
C have been published.1,9-11 In comparison with other
expensive and air-sensitive Pd catalysts, Pd/C is more easily
handled and can be recovered from the reaction mixture by
simple filtration and reused. It is very stable under acid and
basic conditions and has a much higher surface area than
alumina- and silica-supported catalysts. It is now the domi-
nant heterogeneous catalyst for industrial application of Pd-
catalyzed reactions.
Palladium-catalyzed carbonylation of aryl halides in the
presence of nucleophiles is an important atom-economic
reaction that can be applied to the synthesis of a wide range
of arylcarbonyl compounds12 such as ketones, carboxylic
acids, esters, or amides that can be easily obtained either in
solution12b,13 or in the solid phase.12e Most of the carbonyla-
tion procedures reported in the literature are based on the use
of homogeneous Pd catalysts in the presence of phosphine
ligands.14 However, an excess of phosphine is often required
to avoid catalyst deactivation, and its separation from the
reaction products and regeneration is usually difficult, limit-
ing the applicability of carbonylation procedures.15
reported the use of Pd/C to obtain aromatic esters. The
procedure has been efficiently applied to the synthesis of
polymers using 150 psi of carbon monoxide and heating the
reaction mixture at 150 °C for 6 h. Moreover, an excess of
nucleophile as well as the use of toxic benzene were required
to run the reaction to completion. Chen and Xia18b recently
extended the application of Pd/C to alkoxycarbonylation
and carbonylative Sonogashira coupling reactions of aryl
iodides in the absence of copper and phosphine ligands. The
procedure for alkoxycarbonylation required a pressure of
CO from 72 to 300 psi and temperature of 130 °C. Moreover,
the nucleophile was used as the solvent, limiting the applica-
tion of the procedure to nonvolatile alcohols. On the other
hand, the use of a more sophisticated heterogeneous cata-
lysts for aminocarbonylation reaction of aryl halide has been
ꢀ
recently investigated in a continuous flow reactor by Csajagi
and co-workers.19
Despite its well-known toxicity, CO is a very valuable and
convenient reagent for a variety of reasons: (i) it is thermally
quite stable and yet chemically reactive, and (ii) it is an
inexpensive carbon source, which can be incorporated into a
variety of organic compounds in its entirety without produ-
cing any undesirable byproduct. Since its toxicity problem
can satisfactorily be dealt with in many instances, CO can be
considered an environmentally friendly and convenient C
source in an overall sense.12a,20 Mo(CO)6 is a potential
alternative source of CO that was applied to the traditional
and microwave-assisted synthesis of amides, esters, and
carboxylic acids starting from aryl halides or triflates.21
However, Mo(CO)6 is highly toxic, and its (over)stoichio-
metric use results in extreme metal waste, a potential pro-
blem in scale-up.22 Recently, Leadbeater and Kormos first
reported microwave-promoted hydroxy- and alkoxycarboxy-
lation of aryl iodides using heavy-walled quartz reaction
vessels prepressurized with CO in the presence of Pd(OAc)2
as catalyst; in addition, in this procedure the nucleophile of the
reaction is the solvent.23
Only one patent and three papers report the use of Pd/C in
the carbonylation of aryl halides for the synthesis of car-
boxylic acids or esters.16-18 Sugi and co-workers18a first
(8) For recent applications of hydrogenation using Pd/C, see: (a) Du, R.;
Zhu, C.; Zhang, P.; Fan, R. Synth. Commun. 2008, 38, 2889–2897. (b) Mori,
A.; Mizusak, T.; Kawase, M.; Maegawa, T.; Monguchi, Y.; Takao, S.;
Takagi, Y.; Sajiki, H. Adv. Synth. Catal. 2008, 350, 406–410. (c) Kumar,
G. D. K.; Baskaran, S. J. Org. Chem. 2005, 70, 4520–4523.
(9) (a) Hagiwara, H.; Shimizu, Y.; Hoshi, T.; Suzuki, T.; Ando, M.;
Ohkubo, K.; Yokoyamac, C. Tetrahedron Lett. 2001, 42, 4349–4351. (b) El
Mi, B.; Vasapollo, G.; Alper, H. J. Org. Chem. 1993, 58, 4739–4741.
(10) Beller, M.; Morandi, W. A.; Eckert, M.; Neumann, H. Tetrahedron
Lett. 1999, 40, 4523–4526.
Lately, improvements in design of commercial microwave
ovens for organic synthesis allowed the controlled introduc-
tion of gases inside the reaction tube that can be considered
as a potential autoclave. With this kind of apparatus,
hydroformylation,24 hydroaminomethylation,25 hydrogena-
tion,26 and hydroxy-,23a alkoxy-,23b and aminocarbonyla-
tion27 have been performed under mild conditions.28 Taking
(11) Lin, Y.-S.; Alper, H. Angew. Chem., Int. Ed. 2001, 40, 779–781.
€
(12) (a) Brennfuhrer, A.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed.
€
ꢀ
2009, 48, 4114–4133. (b) Skoda-Foldes, R.; Kollar, L. Curr. Org. Chem. 2002,
6, 1097–1119. (c) El Ali, B.; Alper, H. Synlett 2000, 161–171. (d) Ma, S.; Wu,
B.; Jiang, X. J. Org. Chem. 2005, 70, 2588–2593. (e) Takahashi, T.; Inoue, H.;
Tomida, S.; Doi, T. Tetrahedron Lett. 1999, 40, 7843–7846.
ꢀ
ꢀ
ꢀ
ꢀ
(13) Beller, M.; Cornils, B.; Frohning, C. D.; Kohlpaintner, C. W. J. Mol.
Catal. A: Chem. 1995, 104, 17–85.
(14) For an example of homogeneous catalyzed carbonylation reaction in
the presence of phosphine ligands, see: (a) Sans, V.; Trezeciak, A.-M.; Luis,
(19) Csajagi, C.; Bercsek, B.; Niesz, K.; Kovacs, I.; Szekelyhidi, Z.; Bajko,
Z.; Urge, L.; Darvas, F. Org. Lett. 2008, 10, 1589–1592.
(20) Handbook of Organopalladium Chemistry for Organic Synthesis;
Wiley: New York, 2002; Vol. 2.
ꢀ
S.; Ziolkowski, J. J. Catal. Lett. 2006, 109, 37–41. (b) Wallow, T. I.; Novak,
(21) (a) Wu, X. Y.; Larhed, M. J. Org. Chem. 2005, 70, 3094–3098. (b)
Wannberg, J.; Larhed, M. J. Org. Chem. 2003, 68, 5750–5753. (c) Odell,
L. R.; Savmarker, J.; Larhed, M. Tetrahedron Lett. 2008, 49, 6115–6118.
(22) (a) Wan, Y.; Altermann, M.; Larhed, M.; Hallberg, A. J. Org. Chem.
2002, 67, 6232–6235. (b) Wan, Y.; Altermann, M.; Larhed, M.; Hallberg, A.
J. Comb. Chem. 2003, 5, 82–84.
B. M. J. Org. Chem. 1994, 59, 5034–5037. (c) Urata, H.; Maekawa, H.;
Takahashi, S.; Fuchikami, T. Tetrahedron Lett. 1991, 56, 4320–4322. (d)
Beller, M.; Eckert, M. Angew. Chem., Int. Ed. 2000, 39, 1010–1027. (e) Frisch,
A. C.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674–688. (f) Ozawa, F.;
Sugimoto, T.; Yamamoto, T.; Yamamoto, A. Organometallics 1984, 3, 692–
ꢀ
697. (g) Takacs, A.; Acs, P.; Farkas, R.; Kokotos, G.; Kollar, L. Tetrahedron
2008, 64, 9874–9878.
ꢀ
(23) (a) Kormos, C. M.; Leadbeater, N. E. Synlett 2006, 1663–1666. (b)
Kormos, C. M.; Leadbeater, N. E. Org. Biomol. Chem. 2007, 5, 65–68.
(24) Mann, A.; Petricci, E.; Rota, A.; Schoenfelder, A.; Taddei, M. Org.
Lett. 2006, 8, 3725–3727.
(25) Petricci, E.; Salvadori, J.; Mann, A.; Taddei, M. Tetrahedron Lett.
2007, 48, 8501–8504.
(15) Ionic liquids have been used as well for the recycling of the catalyst;
for an example of the use of ionic liquids in carbonylation reactions, see: (a)
Zhu, B.; Jiang, X. Synlett 2006, 2795–2798. (b) Lancaster, M. Green Chem. R.
Soc. Chem. 2002. (c) Riisagera, A.; Fehrmann, R.; Haumann, M.; Wasserscheid,
P. Top. Catal. 2006, 40, 91–102.
(26) (a) Piras, L.; Genesio, E.; Ghiron, C.; Taddei, M. Synlett 2008, 1125–
1128. (b) Vanier, G. S. Synlett 2007, 131–135.
(16) Eisenstadt, A. European Patent EP0461322, 1990.
(17) Tambade, P. J.; Patil, Y. P.; Bhanushali, M. J.; Bhanage, B. M.
Tetrahedron Lett. 2008, 49, 2221–2224.
(27) Cardullo, F.; Donati, D.; Merlo, G.; Paio, A.; Petricci, E.; Taddei,
M. Syntlett 2009, 47–50.
(18) (a) Ramesh, C.; Nakamura, R.; Kubota, Y.; Miwa, M.; Sugi, Y.
Synthesis 2003, 501–504. (b) Chen, J. J.; Xia, C. J. Catal. 2008, 253, 50–56.
(28) For a review on the argument, see: Petricci, E.; Taddei, M. Chem.
Today 2007, 25, 40–45.
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TABLE 1. Temperature of Different Solvents Reached after Microwave Irradiation in the Presence and Absence of Homogeneous and Heterogeneous
Palladium Catalystsa
solvent
bp (°C)
tan δ
T (pure solvent) (°C)
T with Pd(OAc)2b (°C)
T with Pd/Cb (°C)
DT (°C)
DMF
THF
toluene
CCl4
153
66
111
76
0.161
0.047
0.040
n.d.
139
89
66
62
140
97
70
67
183
132
118
93
44
43
52
31
aSingle-mode sealed vessel microwave irradiation, 150 W constant magnetron output power, 1 mL of solvent, sealed 10 mL Pyrex reaction vessel,
magnetic stirring, external sensor. Temperature was monitored by an external IR sensor; starting temperature 30 °C. b0.05 mmol.
TABLE 2. Solvent Evaluation on Microwave-Assisted Alkoxycarbo-
nylation of Iodobenzene Using EtOH as Nucleophile
in account that Pd/C efficiently couples with microwave
irradiation because of its strong microwave absorbing sup-
port (charcoal),26b,29 the optimization of a methodology for
microwave-assisted carbonylation reactions using Pd/C as
catalyst was investigated. In fact, during microwave dielec-
tric heating, Pd/C could be consider as a passive heating
element allowing very high temperatures to be reached on
catalyst surface and, by conduction, in the reaction medium.
Its use could be considered particularly favorable regarding
the high temperatures usually required for a wide range of
heterogeneous catalyzed reactions. Consequently, we
decided to investigate the use of Pd/C in the presence of
gaseous carbon monoxide under microwave dielectric heat-
ing for carbonylation reaction with stoichiometric amount of
nucleophile. A wide range of different procedures for the
synthesis of carboxylic acids, esters, amides, and heterocyclic
compounds was studied using aryl iodides as substrates.
entry
solvent
base
conversion (%) (yield, %)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
EtOH
THF
THF
K2CO3
K2CO3
Cs2CO3
DIPEA
K2CO3
Cs2CO3
DIPEA
K2CO3
Cs2CO3
DIPEA
TEA
>99 (90)
3
6
16
THF
toluene
toluene
toluene
DCE
DCE
DCE
DCE
DMF
DMF
DMF
DMF
DMF
2
33
32
93
>99 (88)
7
38
K2CO3
Cs2CO3
DIPEA
TEA
Results and Discussion
In order to qualitatively compare the efficiency of heating
Pd/C with homogeneous Pd catalyst (i.e., Pd(OAc)2) under
microwave dielectric heating, some simple experiments
were carried out by irradiating DMF, CCl4, toluene, and
THF at 150 W for 1 min in the presence of Pd catalysts and
recording the reaction temperature detected by the IR
sensor (Table 1).
DBU
>99 (95)
by investigating the transformation of iodobenzene into the
corresponding ethyl benzoate (Table 2).12,18,31
First, EtOH was used as the solvent, as reported in
classical Pd/C and carbonylation reactions,18,23 using
K2CO3 as the base, at 170 psi of CO. Ester 2 was obtained
in quantitative yield after 20 min of irradiation by micro-
waves at 130 °C (entry 1, Table 2). With the aim of using the
nucleophile in stoichiometric amounts, the effects on the
reaction of different parameters (solvent, base, temperature,
and pressure) were examined. In THF and in the presence of
inorganic (entries 2 and 3, Table 2) or organic bases (entry 4,
Table 2), only a very poor conversion was observed. The
reaction did not run at all in toluene (entries 5-7, Table 2) or
in 1,2-dichloroethane in the presence of K2CO3 (entry 8,
Table 2). Only traces of 2 were detected when Cs2CO3 was
used, whereas in the presence of organic bases such as
DIPEA and TEA product 2 was obtained in no more than
30% yield (entries 10 and 11, Table 2). Finally, DMF was
found to be the best solvent for this transformation. In
association with K2CO3, it gave 93% conversion of 1
(entry 12, Table 2), and a higher conversion was observed
using Cs2CO3 (entry 13 in Table 2). However, product 2 was
recovered only in a 88% yield for the contemporary forma-
tion of biphenyl derivative. On the other hand, the associa-
tion of DMF with DIPEA or TEA gave a decrease in the
conversion (entries 14 and 15, Table 2). Finally, the best
These data do not give any information about the tem-
perature on the surface of the heterogeneous catalyst, but
they can give an idea of the reaction temperature behavior in
the presence of strongly microwave absorbing catalysts.29,30
It is known that solvents with low tan δ values (CCl4,
toluene, or THF) are only slightly heated by microwaves,
and in fact, in the absence of the metal, a low heating was
observed after long irradiation, probably due to the use of
incompletely microwave-transparent vessels. On the other
hand, DMF easily reaches higher temperatures after only
1 min of irradiation. Marginally higher temperatures were
reached after addition of Pd(OAc)2 (0.05 mmol) to all the
solvents investigated, indicating that the presence of the
palladium salt itself does not increase the temperature of
the reaction mixture under microwaves dielectric heating.
When the same amount of Pd/C was added to the solvents, a
very high increase of the temperature (from 31 to 52 °C in
1 min depending on the solvent) was observed.
Starting from these data, the possibility of using Pd/C in
microwave-assisted carbonylation procedures was evaluated
(29) Kappe, C. O.; Dallinger, D.; Murphree S. S. Pratical Microwave
Synthesis for Organic Chemists Wiley 2009.
(30) For more informations on how correctly detect temperature during
microwave irradiation: (a) Kremsner, J. M.; Kappe, C. O. J. Org. Chem.
2006, 71, 4651–4658. (b) Herrero, M. A.; Kremsner, J. M.; Kappe, C. O.
J. Org. Chem. 2008, 73, 36–47.
(31) Barnard, C. F. Org. Proc. Res. Dev. 2008, 12, 566–574.
J. Org. Chem. Vol. 75, No. 6, 2010 1843

Salvadori et al.
JOCArticle
TABLE 3. Influence of Time, Temperature, And Pressure on Micro-
wave-Assisted Alkoxycarbonylation
TABLE 4. Generalization of Microwave-Assisted Alkoxycarbonyla-
tion Reaction Using Different Alcohols
a
%
entry
T (°C)
time (min)
CO (psi)
1
2
Ph-Ph
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
140
140
130
130
130
130
130
130
130
130
130
120
120
120
120
100
10
20
15
10
20
10
20
20
10
10
20
10
10
10
20
10
170
170
170
170
130
130
100
80
80
20
20
170
150
100
20
61
35
5
4
7
12
1
99
>99
94
98
70
66
10
1
1
1
3
84
98
95
2
1
1
4
1
99
89
20
1
7
76
98
89
170
10
aDetermined by GC/MS.
conversion and reaction yields were obtained in DMF using
DBU as the base (entry 16, table 2).
Fixing DMF/DBU as the best couple solvent/base condi-
tions for stoichiometric alkoxycarbonylation, the influence
of time, temperature, and pressure of CO was also investi-
gated (Table 3).
Higher reaction temperatures (140 °C) were tested with the
aim to complete the reaction in shorter times, but poor
conversions were observed after 10 and 20 min with a
growing amount of bipheyl formed together with other
byproducts (entries 1 and 2, Table 3). Different attempts
were done at 130 °C at different pressures of CO. Using 170
psi, a full conversion was obtained after 10 min of irradia-
tion, and 2 was present as the only reaction product without
biphenyl and other byproduct (entries 3 and 4, Table 3). It is
interesting to note that also at 130 psi of CO a full conversion
is possible in 10 min with high recovery of 2 after a simple
acid workup (entry 6, Table 3). When heating was prolonged
to 20 min, some products derived from degradation of DBU
and DMF were formed lowering the yield of the ester 2 (entry
5, Table 3). Decreasing the pressure (100, 80, and 20 psi), a
strong reduction of the conversion was observed (entry
7-11, Table 3). However, lowering the temperature to
120 °C, at 170 psi of CO and irradiating for 10 min, it was
possible to obtain compound 2 in good yield. Further
reduction of the temperature (entry 16, Table 3) as well as
reduction of CO pressure (entries 13-15, Table 3) dramati-
cally lowered the product formed. In conclusion, optimal
conditions for alkoxycarbonylation of aryl iodides with
stoichiometric amount of EtOH were microwave dielectric
heating for 10 min in the presence of 10% Pd/C and DBU in
DMF at 130 °C under 130 psi of CO.33
a2 equivof 1 was used. bNo improvement in reaction yields is observed
after irradiation for longer times because of dehalogenation of 1. See
reference 32.
the corresponding ester derivatives 4a-p (Table 4). EtOH,
MeOH, and BuOH gave 4a-e in almost quantitative yields
(entries 1-5, Table 4) as phenol, cyclohexylethanol, and
norborneol that gave esters 4k-n in very good yield. It is
interesting to note that using menthol as starting material
longer reaction times are required in order to obtain 4o in
satisfactory yields (entries 17 and 18, Table 4).
Using benzyl alcohol, the corresponding ester 4f was
obtained in only 74% yield (entry 6, Table 4). In the case
of substrates like tatradodecanol, i-PrOH, and cyclohexanol,
no full conversion was possible (entries 7-11, Table 4). As
these substrates may be different from EtOH, the reaction
The best reaction conditions found on the model substrate
were applied to different aryl iodides and alcohols to obtain
(32) Perry, R. J.; Turner, S. R. J. Org. Chem. 1991, 56, 6573–6579.
(33) (a) The catalyst can be used two times without changing in the reaction
yield. A decrease in the reaction yield was observed using Pd/C four times: 2 was
in fact isolated in 40% yield. (b) Similar results were obtained using bis-
(dibenzyldeneacetone)Pd(0) as homogeneous catalyst, but 15 min of irradiation
by microwaves is necessary to obtain full conversion. Using Pd(OAc)2, as
previously reported by Leadbeater and Kormos,23 a large excess of nuclephile is
necessary to obtain comparable yields as well as higher pressures of CO (160 psi)
and longer reaction times (20 min).
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Salvadori et al.
JOCArticle
TABLE 5. Microwave-Assisted Aminocarbonylation Reaction
TABLE 6. Microwave-Assisted Pd/C-Catalyzed Cyclocarbonylation
Primary and secondary amines are good substrates for this
transformation as well as aniline (entries 1-9, Table 5).
However, using deactivated 2-nitro-5-chloroaniline only
traces of expected amide 6j were obtained.27
aConversion detected by GC-MS.
Another interesting application of Pd-catalyzed insertion
of CO is the cyclocarbonylation of o-iodoanilines with acid
chlorides reported by Alper and co-workers;34-37 this one-
pot procedure yielding 2-substituted 4H-3,1-benzoxazin-4-
ones was achieved using Pd(OAc)2 as the catalyst, at 300 psi
of CO and in the presence of DIPEA, heating at 130 °C for
24 h. A good conversion was also possible at lower reaction
temperatures (100 °C), but the addition of an opportune
ligand appeared to be necessary. We were pleased to observe
that when 2-iodoaniline was irradiated with benzoyl chloride
for 30 min, at 130 °C in the presence of CO (130 psi) Pd/C and
was also tried using Cs2CO3 in the place of DBU but with
insufficient results. However, a good conversion of tetra-
dodecanol and cyclohexanol into esters 4g and 4l was
observed when 2 equiv of iodobenzene were employed as
dehalogenation reaction appeared to be faster than alkoxy-
lation reaction (entries 8 and 14, Table 4). Acceptable yields
of 2-propanol esters 4h-j were finally obtained after 15-20
min of irradiation (entries 9-1,1 Table 4). When t-BuOH
was used, the corresponding ester was obtained only in 20%
yield (entry 20, Table 4).
Compared to alkoxycarbonylation,12a there are only a few
reports on aminocarbonylation reactions even if the condi-
tions for both transformations are similar, reflecting the
similarity in their mechanism. Therefore, the use of amines
as nuclephiles was investigated as well. Starting from 1 and
3a-c, aryl amides 6a-j were obtained in good yields
after only 15 min of irradiation by microwaves using
Pd/C as catalyst, in the presence of DBU in DMF at
130 °C (Table 5).
(34) Larksarp, C.; Alper, H. Org. Lett. 1999, 1, 1619–1622.
(35) Zheng, Z.; Alper, H. Org. Lett. 2008, 10, 829–832.
(36) (a) Lu, S.-M.; Alper, H. J. Am. Chem. Soc. 2008, 130, 6451–6455. (b)
Rescourio, G.; Alper, H. J. Org. Chem. 2008, 73, 1612–1615. (c) Ali, B.;
Alper, H. Synlett 2000, 161–171. (d) Khumtaveeporn, K.; Alper, H. Acc.
Chem. Res. 1995, 28, 414–422.
(37) (a) Church, T. L.; Byrne, C. M.; Lobkovsky, E. B.; Coates, G. W.
J. Am. Chem. Soc. 2007, 129, 8156–8162. (b) Church, T. L.; Getzler, Y. D. Y.
L.; Byrne, C. M.; Coates, G. W. Chem. Commun. 2007, 657–674. (c)
Vasapollo, G.; Mele, G. Curr. Org. Chem. 2006, 10, 1397–1421.
J. Org. Chem. Vol. 75, No. 6, 2010 1845

Salvadori et al.
JOCArticle
DIPEA in DMF, the expected compound 14a was obtained
in 82% yield (entry 1, Table 6).
Ethyl 4-Fluorobenzoate (4c). See ref 41.
Methyl Benzoate (4d). See ref 42.
Butyl Benzoate (4e). See ref 43.
It is interesting to note that the use of homogeneous
palladium sources like Pd(OAc)2 or Pd(PPh3)2Cl2 under
our reaction conditions gave only traces of product 14a with
the formation of N-phenylbenzamide as the main product.
Cyclocarbonylation with different acyl chlorides or acid
activated as hydroxysuccinimido derivatives gave com-
pounds 14a-f in good yields (Table 6). It is worth noting
that when activated acid 11 was the starting material a
complete isomerization of double bond in the final product
was observed (entry 4, Table 6).
In conclusion, the association of Pd/C and microwave
dielectric heating allowed the rapid alkoxy and amino car-
bonylation of aryl iodides in the presence of a heterogeneous
catalyst. Different alcohols and amines can be used in
stoichiometric amounts, increasing the potential of the reac-
tion limited until now to the use of the alcohol as the reaction
solvent. The versatility of Pd/C as heterogeneous catalyst for
carbonylation reaction is also confirmed by the possibility to
carry out cyclohydrocarbonylation producing benzoxazi-
nones. The catalyst can be reused at least two times without
changing in the reaction yields.61
Benzyl Benzoate (4f). See ref 44.
Pentadecyl Benzoate (4g). See ref 45.
Isopropyl Benzoate (4h). See ref 46.
Isopropyl 4-Methoxybenzoate (4i). See ref 47.
Ethyl Isopropyl Terephthalate (4j). 1H NMR (400 MHz,
CDCl3) δ: 8.03 (m, 4H); 5.21 (q, 1H, J = 7 Hz); 4.34 (q, 2H,
J = 7.2 Hz); 1.35 (m, 9H). 13C NMR (400 MHz, CDCl3) δ:
165.8; 165.2; 134.6; 134.0; 129.1; 68.93; 61.32; 21.2; 14.25.
Purification by column chromatography (eluent: petroleum
ether/AcOEt 9:1). Yield: 70%. Anal. Calcd for C13H16O4: C,
66.09; H, 6.83; O, 27.09. Found: C, 66.12; H, 6.78; O, 27.02.
Phenyl Benzoate (4k). See ref 48.
Cyclohexyl Benzoate (4l). See ref 49.
2-Cyclohexylethyl Benzoate (4m). See ref 50.
Bicyclo[2.2.1]heptan-2-yl Benzoate (4n). 1H NMR (400 MHz,
CDCl3) δ: 8.10 (d, 2H, J = 7.6 Hz); 7.49-7.58 (m, 3H); 5.15
(m, 1H); 1.63 (m, 2H); 1.39 (m, 4H); 1.26 (m, 1H); 1.12 (m, 1H);
0.33 (m 2H). GC/MS: m/z 105. tR: 16.4 min. Yield: 96%. Anal.
Calcd for C14H16O2: C, 77.75; H, 7.46; O, 14.80. Found: C,
77.69; H, 7.42; O, 14.82.
4-Isopropyl-2-methylcyclohexyl Benzoate (4o). 1H NMR (400
MHz, CDCl3) δ: 8.02 (d, 2H, J = 7.6 Hz); 7.50-7.52 (m, 1H);
7.39-7.40 (m, 2H); 4.89-4.92 (m, 1H); 1.72-1.72 (m, 2H); 1.65
(m, 2H); 1.23 (m, 1H); 1.09-1.12 (m, 2H); 0.89-0.91 (m, 9H).
Yield: 75%. Anal. Calcd for C17H24O2: C, 78.42; H, 9.29; O,
12.29. Found: C, 78.48; H, 9.31; O, 12.25.
Experimental Section
General Remarks. 1HNMR and 13C NMR spectra were
recorded on a 400 MHz instrument at 400 and at 200 MHz,
respectively. GC/MS analysis was performed using a CP 8944
column (30 m ꢀ 0.250 mm ꢀ 0.39 mm). After 5 min at 90 °C, the
temperature was increased in 10 °C/min steps up to 280 °C and
kept at 300 °C for 4 min. All reactions are performed in a CEM
Discover microwave oven equipped with a 10 mL tube for
reactions under pressure and an external IR sensor to the detect
the reaction temperature during the irradiation (CEM
Corporation). This glass vial, tested for resisting up to 250 psi
(17 bar, 1723 KPa), is provided with a tube connection to an
external pressure controlling system equipped with a valve and
an exit tube for venting the vial at the end of the reaction. The
exit tube was connected to a cylinder containing CO through a
three-way connector equipped with two taps to pressurized the
system before microwave irradiation. All products synthesized
in this study have been characterized by 1H NMR and MS
analysis.
tert-Butyl Benzoate (4p). See ref 60.
Morpholino(phenyl)methanone (6a). See ref 51.
(4-Methoxyphenyl)(morpholino)methanone (6b). See ref 52.
Ethyl 4-(morpholine-4-carbonyl)benzoate (6c). 1H NMR (400
MHz, CDCl3) δ: 8.02 (d, 2H, J = 7.5 Hz); 7.39 (d, 2H, J = 7.5
Hz); 4.31 (q, 2H, J = 7.2 Hz); 3.21-3.70 (m, 8H); 1.32 (t, 3H,
J = 7.5 Hz). 13C NMR (400 MHz, CDCl3) δ: 169.3; 165.7; 139.4;
131.6; 129.8; 127.0; 66.7; 61.2; 14.2. Yield: 90%. Anal. Calcd for
C14H17NO4: C, 63.87; H, 6.51; N, 5.32; O, 24.31. Found: C,
63.82; H, 6.57; N, 5.39; O, 24.38.
N-(4-Methoxybenzyl)benzamide (6d). See ref 53.
4-Methoxy-N-(4-methoxybenzyl)benzamide (6e). 1H NMR
(400 MHz, CDCl3) δ: 8.39 (d, 2H, J = 7.2 Hz); 7.48 (bs, 1H);
7.21-7.25 (m, 2H); 6.80-6.92 (m, 4H); 4.49 (d, 2H, J = 6 Hz);
3.86 (s, 3H); 3.76 (s, 3H). Yield: 60%. Anal. Calcd for
C16H17NO3: C, 70.83; H, 6.32; N, 5.16; O, 17.69. Found: C,
70.88; H, 6.39; N, 5.13; O, 17.74.
General Procedure for the Synthesis of Esters 2 and 4a-o and
Amides 6a-i. A solution of the aryl iodide (0.50 mmol) and the
alcohol or amine (0.50 mmol) in DMF (1 mL) was placed in a 10
mL tube for microwave reactions. DBU (224 μL, 1.50 mmol)
and Pd/C 10% (10 mg, 0.01 mmol) were added, and the solution
was submitted to pressurized CO (130 psi) and inserted in the
cavity of a Discover System (CEM Corp.). After being heated
for 20 min at 130 °C at 150 W (value previously settled on the
microwave oven), the tube was cooled and the internal gas
pressure released. The reaction mixture was filtered, diluted
with 1 N HCl, and extracted with EtOAc. The organic layer were
washed several times with H2O, dried over anhydrous Na2SO4,
and evaporated in vacuo after filtration. The product obtained
was purified by flash chromatography (eluent: PE/AcOEt 9:1,
esters; PE/AcOEt 6:1 amides).
Ethyl 4-(4-Methoxybenzylcarbamoyl)benzoate (6f). 1H NMR
(400 MHz, CDCl3) δ: 7.97 (d, 2H, J = 8.4 Hz); 7.78 (d, 2H, J =
8.4 Hz); 7.16-7.20 (m, 2H); 6.74-6.85 (m, 2H); 4.51 (d, 2H, J =
5.6 Hz); 4.32 (q, 2H, J = 7.2 Hz); 3.71 (s, 3H); 1.35 (t, 3H, J =
5.6 Hz). 13C NMR (400 MHz, CDCl3) δ: 166.7; 165.8; 159.9;
139.5; 138.1; 132.9; 129.7; 129.6; 127.1; 120.0; 113.5; 112.8; 61.3;
55.1; 44.1; 14.2. Yield: 75%. Anal. Calcd for C18H19NO4: C,
(41) Bowden, T. S.; Watkins, T. F. J. Chem. Soc. 1940, 1249–1254.
(42) Bradley, W.; Robinson, R. J. Am. Chem. Soc. 1930, 52, 1558–1565.
(43) Newman, M.; Fones, W, S. J. Am. Chem. Soc. 1947, 69, 1046–1047.
(44) Eilel, E. L.; Anderson, R. P. J. Am. Chem. Soc. 1952, 74, 547–549.
(45) Breusch, F. L; Baykut, F. Istanbul Univ. Fen. Fak. Mecmuasi Ser. C
1961, 26, 6–11.
(46) Silva, S. Bull. Soc. Chim. Fr. 1869, 12, 224–227.
(47) Kuhn, L. P. J. Am. Chem. Soc. 1949, 71, 1575–1577.
(48) Gilman, H.; Vernon, C. C. J. Am. Chem. Soc. 1926, 48, 1063–1066.
(49) Friess, S. L.; Farnham, N. J. Am. Chem. Soc. 1950, 72, 5518–5521.
(50) Jin, S.; Holub, D. P.; Wustrow, D. J. Tetrahedron Lett. 1998, 39,
3651–3654.
Ethyl Benzoate (2). See ref 38.
Ethyl 4-Methoxybenzoate (4a). See ref 39.
Diethyl Terephthalate (4b). See ref 40.
(51) Atherton, R. F.; Openshaw, H. T.; Todd, A. R. J. Chem. Soc. 1945,
660–663.
(52) Yoshinao, T.; Yoshimi, Y.; Zen-ichi, Y. Synthesis 1983, 474–476.
(53) Buck, J. S.; Ide, W. S. J. Am. Chem. Soc. 1931, 53, 1536–1542.
(38) Lachman, A. J. Am. Chem. Soc. 1924, 46, 708–723.
(39) Buck, J. S.; Ide, W. S. J. Am. Chem. Soc. 1932, 54, 4349–4364.
(40) Reimer, M; Downes, H. R. J. Am. Chem. Soc. 1921, 43, 945–951.
1846 J. Org. Chem. Vol. 75, No. 6, 2010

Salvadori et al.
JOCArticle
68.99; H, 6.11; N, 4.47; O, 20.42. Found: C, 68.91; H, 6.19; N,
4.39; O, 20.48.
80%. Anal. Calcd for C13H15NO2: C, 71.87; H, 6.96; N, 6.45; O,
14.73. Found: C, 71.82; H, 6.92; N, 6.50; O, 14.78.
4-Fluoro-N-(4-methoxybenzyl)benzamide (6g). See ref 54.
N-Phenylbenzamide (6h). See ref 55.
4-Fluoro-N-phenylbenzamide (6i). See ref 56.
2-Benzyl-4H-benzo[d][1,3]oxazin-4-one (14c). See ref 58.
(E)-2-(Prop-1-enyl)-4H-benzo[d][1,3]oxazin-4-one (14d). See
ref 59.
General Procedure for the Synthesis of Cycles 14a-f. A
solution of the o-iodoaniline (0.50 mmol) and acyl chloride
(0.75 mmol) in DMF (1 mL) was placed in a 10 mL tube for
microwave reactions. DIPEA (261 μL, 1.50 mmol) and Pd/C
10% (10 mg, 0.01 mmol) were added, and the solution was
submitted to pressurized CO (130 psi) and inserted in the cavity
of a Discover System (CEM Corp.). After being heated for 30
min at 130 °C at 150 W (value previously settled on the
microwave oven), the tube was cooled and the internal gas
pressure released. The reaction mixture was filtered, diluted
with 1 N HCl, and extracted with CH2Cl2. The organic layer
were washed several times with H2O, dried with dry Na2SO4,
and evaporated in vacuo after filtration. The product obtained
was purified by flash chromatography using a 3:2 mixture of PE/
AcOEt as eluent.
(E)-2-Styryl-4H-benzo[d][1,3]oxazin-4-one (14e). 1H NMR
(400 MHz, CDCl3) δ: 8.15 (d, J = 8.4 Hz, 1H); 7.61-7.73
(m, 2H); 7.21-7.59 (m, 7H); 6.73-6.69 (m, 2H). LC/MS: 271
[M þ 1]þ (yield 78%). Anal. Calcd for C16H11NO2: C, 77.10; H,
4.45; N, 5.62; O, 12.84. Found: C, 77.06; H, 4.51; N, 5.57; O, 12.89.
2-tert-Butyl-4H-benzo[d][1,3]oxazin-4-one (14f). 1H NMR
(400 MHz, CDCl3) δ: 8.25 (d, 1H, J = 8 Hz); 7.35 (m, 1H); 7.21
(d, 1H, J = 7.2); 7.04 (m, 1H); 1.32 (s, 3H). 13C NMR (400 MHz,
CDCl3) δ: 169.3; 162.7; 136.8; 130.2; 127.1; 123.6; 122.2; 37.8; 27.77
(yield 70%). Anal. Calcd for C12H13NO2: C, 70.92; H, 6.45; N,
6.89; O, 15.74. Found: C, 70.99; H, 6.37; N, 6.92; O, 15.78.
Acknowledgment. This work was financially supported by
MIUR (Rome) within the PRIN project 2006.
2-Phenyl-4H-benzo[d][1,3]oxazin-4-one (14a). See ref 57.
2-Neopentyl-4H-benzo[d][1,3]oxazin-4-one (14b). 1H NMR
(400 MHz, CDCl3) δ: 8.15 (d, J = 8.4 Hz, 1H); 7.73 (t, J =
6.8 Hz, 1H); 7.48 (d, J = 8.4 Hz, 1H); 7.15 (t, J = 6.8 Hz, 1H);
2.54 (s, 2H); 1.09 (s, 9H). GC/MS: m/z 128. tR: 16.5 min. Yield:
Supporting Information Available: NMR spectra and GC/
MS. This material is available free of charge via the Internet at
http://pubs.acs.org.
(58) Arcus, C. L.; Marks, R. E. J. Chem. Soc. 1956, 1627–1633.
(59) Bain, D. I.; Smalley, R. K. J. Chem. Soc. 1968, 1593–1597.
(60) Price, C. C.; Lincoln, D. C. J. Am. Chem. Soc. 1951, 73, 5836–5838.
(61) The catalyst was recovered by filtration using membrane filter after
the carbonylation of iodobenzene. Recovered catalyst was used for the
reaction under the same condition; the conversions determined by GC-MS
were as follows (see the Supporting Information for more details): >99%
(first time), 98% (second time), and 7% (third time).
(54) Yu, M. S.; Curran, D. P.; Nagashima, T. Org. Lett. 2005, 7, 3677–
3680.
(55) Chan, D. M. T. Tetrahedron Lett. 1996, 37, 9013–9016.
(56) Sanford, J. K.; Blair, F. T.; Arroya, J.; Sherk, K. W. J. Am. Chem.
Soc. 1945, 67, 1941–1943.
(57) Arcus, C. L.; Coombs, M. M. J. Chem. Soc. 1953, 3698–3700.
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