Microwave-assisted multistep synthesis of functionalized 4-arylquinolin-2(1H)-ones using palladium-catalyzed cross-coupling chemistry

Article abstract of DOI:10.1021/jo0502549

Biologically active 4-aryl-3-alkenyl-substituted quinolin-2(1H)-ones have been synthesized in a short and concise manner employing readily available 4-hydroxyquinolin-2(1H)-ones as intermediates. Key steps in the synthesis include the derivatization of th

Full text of DOI:10.1021/jo0502549

Microwave-Assisted Multistep Synthesis of Functionalized
4-Arylquinolin-2(1H)-ones Using Palladium-Catalyzed
Cross-Coupling Chemistry
Toma N. Glasnov, Wolfgang Stadlbauer, and C. Oliver Kappe*
Institute of Chemistry, Organic and Bioorganic Chemistry, Karl-Franzens-University Graz,
Heinrichstrasse 28, A-8010 Graz, Austria
oliver.kappe@uni-graz.at
Received February 8, 2005
Biologically active 4-aryl-3-alkenyl-substituted quinolin-2(1H)-ones have been synthesized in a short
and concise manner employing readily available 4-hydroxyquinolin-2(1H)-ones as intermediates.
Key steps in the synthesis include the derivatization of the quinolin-2(1H)-one cores using palladium-
catalyzed Suzuki and Heck reactions, installing the 4-aryl and 3-alkenyl substituents. All synthetic
transformations (six steps) required for the synthesis of the desired target quinolin-2(1H)-one were
carried out using controlled microwave-assisted organic synthesis.
Introduction
In recent years, an increasing interest in the synthesis
of functionalized 4-arylquinolin-2(1H)-ones 1 with prom-
ising biological properties has been observed.1-6 A num-
ber of analogues of this class of heterocyclic structure
have been reported as lead compounds or are currently
FIGURE 1. Functionalized 4-arylquinolin-2(1H)-ones with
biological activity.
* To whom correspondence should be addressed. Phone: +43-316-
380-5352. Fax: +43-316-380-9840.
(1) (a) Hewawasam, P.; Fan, W.; Ding, M.; Flint, K.; Cook, D.;
Goggings, G. D.; Myers, R. A.; Gribkoff, V. K.; Boissard, C. G.;
Dworetzky, S. I.; Starret, J. E.; Lodge, N. J. J. Med. Chem. 2003, 46,
2819-2822. (b) Boy, K. M.; Guernon, J. M.; Sit, S.-Y.; Xie, K.;
Hewawasam, P.; Boissard, C. G.; Dworetzky, S. I.; Natale, J.; Gribkoff,
V. K.; Lodge, N.; Starret, J. E. Bioorg. Med. Chem. Lett. 2004, 14,
5089-5093. (c) Hewawasam, P.; Fan, W.; Cook, D. A.; Newberry, K.
S.; Boissard, C. B.; Gribkoff, V. K., Starret, J.; Lodge, N. J. Bioorg.
Med. Chem. Lett. 2004, 14, 4479-4482. (d) Hewawasam, P. WO Patent
00/34244, 2000.
(2) Hewawasam, P.; Fan, W.; Knipe, J.; Moon, S. L.; Boissard, C.
G.; Gribkoff, V. K.; Starret, J. E. Bioorg. Med. Chem. Lett. 2002, 12,
1779-1783.
(3) (a) Angibaud, P. R.; Venet, M. G.; Filliers, W.; Broeckx, R.; Ligny,
Y. A.; Muller, P.; Poncelet, V. S.; End, D. W. Eur. J. Org. Chem. 2004,
479-486. (b) Andresen, B. M.; Couturier, M.; Cronin, B.; D’Occhio, M.;
Ewing, M. D.; Guinn, M.; Hawkins, J. M.; Jasys, V. J.; LaGreca, S. D.;
Lyssikatos, J. P.; Moraski, G.; Ng, K.; Raggon, J. W.; Stewart, A. M.;
Tickner, D. L.; Tucker, J. L.; Urban, F. J.; Vazquez, E.; Wei, L. Org.
Process Res. Dev. 2004, 8, 643-650.
undergoing clinical trials (Figure 1). Of particular inter-
est are derivatives of 3-(quinolin-3-yl)acrylates 2 and the
corresponding reduced allylic alcohols that have been
identified by Bristol-Myers Squibb (BMS) as novel and
potent maxi-K channel openers useful for the treatment
of male erectile dysfunction.1 Closely related 4-aryl-3-
aminoquinolin-2-ones were found by the same laboratory
to possess neuroprotective properties.2 Another clinically
important 4-arylquinolin-2(1H)-one is R115777 (ZAR-
NESTRA, 3).3 This 6-functionalized quinolinone deriva-
tive has emerged as a novel, selective, nonpeptide
farnesyl protein inhibitor showing in vitro activity in the
nanomolar range, and is currently undergoing human
clinical trials as an orally active antitumor agent.3
(4) Mederski, W. W. K. R.; Oswald, M.; Dorsh, D.; Christadler, M.;
Schmitges, C.-J.; Wilm, C. Biorg. Med. Chem. Lett. 1997, 7, 1883-
1886.
(5) Cappelli, A.; Mohr, G. la P.; Gallelli, A.; Rizzo, M.; Anzini, M.;
Vomero, S.; Mennuni, L.; Ferrari, F.; Makovec, F.; Menziani, M C.,
Benedetti, P. G. De B.; Giorgi, G. J. Med. Chem. 2004, 47, 2574-2586.
(6) (a) Beier, N.; Labitzke, E.; Mederski, W. W. K. R.; Radunz, H.-
E.; Ruess, K. R.-R. Heterocycles, 1994, 39, 117-131. (b) Hino, K.;
Furukawa, K.; Nagai, Y.; Uno, H. Chem. Pharm. Bull. 1980, 28, 2618-
2622. (c) Hino, K.; Kawashima, K.; Oka, M.; Nagai, Y.; Uno, H.;
Matsumoto, J.-I. Chem. Pharm. Bull. 1989, 37, 110-115.
10.1021/jo0502549 CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/02/2005
3864
J. Org. Chem. 2005, 70, 3864-3870

Multistep Synthesis of Functionalized 4-Arylquinolin-2(1H)-ones
material (Scheme 1). To obtain a suitable coupling
precursor for the Suzuki reaction, quinolinone 4 was
treated with phosphorus oxychloride (POCl3) in order to
furnish the 4-chloro derivative 5. Under conventional
thermal heating conditions, this substitution reaction is
typically carried out using POCl3 as a solvent (106 °C, 3
h).14 Employing dioxane as solvent and with controlled
microwave heating at 120 °C the substitution reaction
was completed in 25 min requiring only 2.0 equiv of the
POCl3 reagent, providing the desired quinolin-2(1H)-one
5 in 82% yield.
FIGURE 2. Modular strategy for the synthesis of 3-alkenyl-
4-arylquinolin-2(1H)-ones.
Several other biologically active 4-arylquinolin-2(1H)-
ones 1 have been described in the literature.4-6
For the subsequent palladium-catalyzed Suzuki cross-
coupling reaction of activated chloride 5, phenylboronic
acid was used as the coupling partner. This method of
synthesizing 4-arylquinolin-2(1H)-ones has so far not
been reported, although related examples can be found
in the recent literature for the preparation of 4-arylcou-
marins15 and 4-aryl-1,8-naphthyridin-2(1H)-ones.16 It is
well-known that the performance of Suzuki and other
transition-metal-catalyzed transformations can be sig-
nificantly shortened by direct in-core microwave heat-
ing.10 Taking advantage of the rapid automated process-
ing features of modern microwave reactor instrumen-
tation,17 the Suzuki reaction 5 f 6 was quickly optimized
probing different catalyst/solvent/base combinations, mo-
lar ratios of the starting materials in addition to varying
reaction time and temperature. The best conversions and
isolated product yields were achieved by using a combi-
nation of palladium acetate and triphenylphosphine as
a catalyst precursor. This allowed us to run the reaction
successfully with a comparatively low loading (0.5 mol
%) of palladium catalyst.18 A 3:1 mixture of 1,2-dimeth-
oxyethane (DME) and water proved to be the optimal
solvent combination, together with either sodium carbon-
ate or triethylamine as base. For the purpose of reaction
homogeneity and postreaction handling, triethylamine
ultimately proved to be the base of choice. The optimal
temperature/time ratio was found to be 150 °C/30 min.
If prolonged irradiation or higher temperatures were
used, more of the expected side products resulting from
homocoupling or deboronation of the boronic acid were
observed by HPLC monitoring. The presence of water in
the solvent mixture in the specified amount was also
found to be crucial for the reaction to proceed properly.
Smaller amounts or its absence led to incomplete conver-
sion; higher amounts led to partial hydrolysis of the
reactive chloroquinolinone 5 back to hydroxyquinolinone
4. Postreaction filtration through a plug of silica gel
provided an 83% isolated yield of 1-methyl-4-phenylquin-
olin-2(1H)-one (6).
A number of different synthetic pathways have been
elaborated to access 4-arylquinolin-2(1H)-ones of type 1.
In most instances, the generation of the arylquinolinone
moiety is achieved by cyclization of a suitable N-acyl-o-
aminobenzophenone precursor,1-5 or via closely related
procedures,7,8 sometimes involving the reduction of an
aryl-1,2-benzisoxazole derivative for the preparation of
the aminobenzophenone intermediate.3 Alternatively,
aroylacetanilide derivatives can be cyclized to 4-arylquin-
olin-2(1H)-ones employing suitable reagents such as
polyphosphoric acid.9
All these procedures, however, suffer from the disad-
vantage that the aryl ring attached to the C4 position of
the quinolinone core has to be introduced very early in
the overall synthetic scheme. Therefore, the preparation
of analogues, e.g., varying the aryl group at C4, is a
cumbersome and lengthy process. In this paper, we
describe a novel and flexible synthetic protocol for the
synthesis of functionalized 4-arylquinolin-2(1H)-ones
utilizing transition-metal-catalyzed carbon-carbon bond-
forming reactions. Our strategy is based on the “decora-
tion” of readily available quinolin-2(1H)-one core struc-
tures at the C4 position, using Suzuki cross-coupling
chemistry (Figure 2). To highlight the usefulness and
flexibility of this process we have applied this method
also to the synthesis of target structure 2, employing a
Suzuki/Heck reaction sequence. All synthetic manipula-
tions described herein were carried out utilizing con-
trolled sealed vessel microwave heating in both single-
mode and multimode reactors.10
Results and Discussion
The key intermediates in our overall synthetic scheme
are 4-hydroxyquinolin-2(1H)-ones. These heterocycles are
useful intermediates for many industrial products, and
several methods for their preparation have been reported
(see below).11,12 To verify the practicability of the projected
Suzuki and Heck carbon-carbon bond-forming reactions
(Figure 2), we have initially performed a model study
involving the commercially available (or easily synthe-
sized)13 4-hydroxyquinolin-2(1H)-one 4 as the starting
(13) Roschger, P.; Stadlbauer, W. Liebigs Ann. Chem. 1990, 821-
823.
(14) (a) Malle, E.; Stadlbauer, W.; Ostermann, G., Hofmann, B.; Leis,
H. J.; Kostner, G. M. Eur. J. Med. Chem. 1990, 25, 137-142. (b)
Friedla¨nder, P.; Mu¨ller, F. Ber. Dtsch. Chem. Ges. 1887, 20, 2009-
2017.
(15) (a) Beletskaya I. P.; Ganina, O. G.; Tsvetkov, A. V.; Fedorov,
A. Y.; Finet, J.-P. Synlett 2004, 15, 2797-2799. (b) Tang, Z.-Y., Hu,
Q.-S. Adv. Synth. Catal. 2004, 346, 1635-1637.
(16) Ban, H.; Muraoka, M.; Ohashi, N. Tetrahedron Lett. 2003, 44,
6021-6023.
(17) Stadler, A.; Kappe, C. O. J. Comb. Chem. 2001, 3, 624-630.
(18) For successful Suzuki coupling reactions with 50 ppb of
palladium, see: Arvela, R. K.; Leadbeater, N. E.; Sangi, M. S.;
Williams, V. A.; Granados, P.; Singer, R. D. J. Org. Chem. 2005, 70,
161-168.
(7) Park, K. K.; Lee, J. J. Tetrahedron 2004, 60, 2993-2999.
(8) Wang, J.; Discordia, R. P.; Crispino, G. A.; Li, J.; Grosso, J. A.;
Polniaszek, R.; Truc, V. C. Tetrahedron Lett. 2003, 44, 4271-4273.
(9) Huang, L.-J.; Hsieh, M.-C.; Teng, C.-M.; Lee, K.-H.; Kuo, S.-C.
Bioorg. Med. Chem. 1998, 6, 1657-1662.
(10) Review: Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250-
6284 and references therein.
(11) Kappe, T.; Karem, A. S.; Stadlbauer, W. J. Heterocycl. Chem.
1988, 25, 857-862.
(12) (a) Kappe, T. Farmaco 1999, 54, 309-315. (b) Ziegler, E.; Wolf,
R.; Kappe, T. Monatsh. Chem. 1965, 96, 418-422. (c) Ziegler, E.; Junek,
H. Monatsh. Chem. 1959, 90, 762-767. (d) Junek, H.; Gelfert, K.
Monatsh. Chem. 1959, 90, 822-826;
J. Org. Chem, Vol. 70, No. 10, 2005 3865

Glasnov et al.
SCHEME 1
SCHEME 2
SCHEME 3
one isomer, which was supported by energy calculations
on both bromoquinolinones.20
Consequently, we have carried out the bromination
6 f 7 at 0 °C (17 h) in DMF in order to obtain a 92:8
selectivity in favor of the desired 3-bromo-1-methyl-4-
phenylquinolin-2(1H)-one (7), resulting in a 79% isolated
product yield of 7 after chromatography.
To install the desired acrylic ester moiety at the C3
position of the quinolinone core (Figure 2), we next
considered introducing a bromine substituent at the C3
position, resulting in a product that would be ideally set
up for a subsequent Heck vinylation. Gratifyingly, bro-
mination of quinolinone 6 with N-bromosuccinimide
(NBS)19 in a variety of solvents provided the desired
3-bromo-4-phenylquinolin-2(1H)-one (7), as well as vary-
ing amounts of the undesired 6-bromo isomer 8 (Scheme
2). Both bromoquinolinones were easily identified by
NMR spectroscopy and could be separated by automated
flash chromatography. The ease of bromination was
critically dependent on the polarity of the solvent. While
complete bromination in dioxane at room temperature
required 12 h, the same transformationsunder otherwise
identical conditionsswas achieved within 8 h in aceto-
nitrile or 4.5 h in DMF. Most important for the outcome
of the bromination, however, was the reaction tempera-
ture. Bromination with 2.5 equiv of N-bromosuccinimide
in DMF at room temperature (25 °C), for example,
provided a clean 83:17 mixture (HPLC at 215 nm) of
3-bromo- (7) and 6-bromoquinolinone (8) within 4.5 h. An
increase of the reaction temperature to 50 °C led to full
consumption of the starting material 6 within 3 h but
led to an almost equimolar ratio of bromoquinolinone
isomers (7/8 ) 55:45). The same temperature dependence
on the regiochemistry of bromination was also seen when
the brominations were carried out under microwave
conditions over a wide temperature range (60-150 °C).
In fact, performing the bromination at 100 °C (micro-
waves, 20 min) in acetonitrile (2.5 equiv of NBS) allowed
the selective preparation of the undesired 6-bromoquino-
linone isomer 8, with only trace amounts of the 3-bromo
isomer 7 being formed. Apparently, the higher reaction
temperaturesswhile allowing the brominations to be
carried out more rapidlysfavor the formation of the
thermodynamically more stable 6-bromoquinolin-2(1H)-
As a last step of our model study, the Heck vinylation
of 3-bromo-1-methyl-4-phenylquinolin-2(1H)-one (7) with
ethyl acrylate was investigated (Scheme 3). Previous
references in the literature have described Heck vinyla-
tions in a series of 3-acetoxy-3-iodoquinolin-2(1H)-ones;21
no examples related to the transformation 7 f 9 have
so far been reported. Similar to the experiments described
above for the Suzuki arylation, the reaction conditions
were optimized using automated microwave synthesis.10
After some experimentation, successful Heck vinylations
were achieved by using 3 mol % tetrakis(triphenylphos-
phine)palladium(0), 3 equiv of triethylamine as base, and
DMF as solvent. Different solvents or lower catalyst
loadings resulted in incomplete conversions. Under these
optimized conditions, full conversion to the 3-(quinolin-
3-yl)acrylate 9 was obtained within 45 min, with only
minor amounts (<5%) of debrominated quinolinone 6
being formed as a byproduct. Extractive workup provided
an 81% isolated yield of pure Heck product 9.
Having established the general feasibility of the mi-
crowave-assisted Suzuki-Heck sequence for the prepara-
tion of 3-(4-phenylquinolin-3-yl)acrylates of type 9, we
turned our attention to the synthesis of the desired
multifunctionalized target structure 2. The synthesis of
ethyl 3-[4-(5-chloro-2-methoxyphenyl)-6-(trifluoromethyl)-
1,2-dihydro-2-oxoquinolin-3-yl]acrylate (2) has been pre-
viously described by a group from BMS in 2003 and
involves more than 10 linear steps starting from 4-(tri-
fluoromethyl)aniline in its N-Boc-protected form.1 The
key step in the synthesis is a base-catalyzed cyclization
of an appropriate N-acyl-o-aminobenzophenone precur-
sor.1
Key to our synthetic protocol is the preparation of the
required 4-hydroxy-6-(trifluoromethyl)quinolin-2(1H)-one
(20) Both semiempirical (AM1, PM3) and density functional theory
calculations (B3LYP/3-21G* or 6-31G*) indicate that the 6-bromo-
quinolinone isomer is by 1.50-4.50 kcal/mol more stable than the
3-bromo isomer.
(21) (a) Reisch, J.; Bathe, A. Z. Naturforsch. 1993, 48B, 1302-1304.
(b) For Heck vinylations in a series of bicyclic 2-pyridones, see: Padwa,
A.; Sheehan, S. M.; Straub, C. S. J. Org. Chem. 1999, 64, 8648-8659.
(19) (a) Carren˜o, M. C.; Ruano, J. L. G.; Sanz, G.; Toledo, M. A.;
Urbano, A. J. Org. Chem. 1995, 60, 5328-5331. (b) Nishimura, T.;
Igarashi, J.-E.; Sunagawa, M. Bioorg. Med. Chem. Lett. 2001, 11,
1141-1144. (c) Fernandez, M.; de la Cuesta, E.; Avendan˜o, C. Synthesis
1995, 1362-1364.
3866 J. Org. Chem., Vol. 70, No. 10, 2005

Multistep Synthesis of Functionalized 4-Arylquinolin-2(1H)-ones
SCHEME 4
SCHEME 5
intermediate 11. In general, benzo-substituted 4-hydroxy-
quinolin-2(1H)-ones can be obtained by cyclization of
malondianilides with suitable cyclization reagents.11,12
One of the most successful reagents reported in this
context is commercially available Eaton’s reagent, a 7.7%
solution of phosphorus pentoxide in methanesulfonic
acid.11 However, malondianilides derived from anilines
bearing strong electron-withdrawing substituents such
as the CF3 group have previously proven difficult to
cyclize, providing only moderate yields of the correspond-
ing 4-hydroxyquinolin-2(1H)-ones.11,22
The required starting material, N,N′-bis[4-(trifluoro-
methyl)phenyl]malonamide (10), was prepared in nearly
quantitative yield from malonyl dichloride and 4-(tri-
fluoromethyl)aniline following a literature procedure.23
Careful optimization of the reaction conditions demon-
strated that full conversion (HPLC at 215 nm) of the
malondianilide 10 to the quinolinone 11 could be obtained
by exposing a ca. 0.5 M solution of the starting material
in Eaton’s reagent to microwave irradiation at 120 °C
for 20 min in an argon atmosphere (Scheme 4). The
cyclization reaction proved to be rather sensitive to time,
temperature, and concentration of the reaction mixture.
Elevated reaction temperatures or prolonged microwave
irradiation resulted in a significant loss of purity, pre-
sumably due to concomitant product decomposition.
Precipitation of the crude product with ice-water fol-
lowed by dissolution in base, filtration, and repreciptation
with acid provided a 65% isolated yield of pure quinoli-
none product 11. We have also briefly investigated the
cyclization of other, more reactive malondianilides utiliz-
ing our optimized microwave protocol. As expected,11 here
the formation of the desired 4-hydroxyquinolin-2(1H)-
ones was straightforward and proceeded in high yields
(80-90%).
above) microwave conditions resulted in the formation
of the corresponding 2,4-dichloroquinoline intermediate
12 (81%), which was subsequently selectively hydrolyzed
by a methanesulfonic acid/ethanol mixture,24 again using
microwave heating at 150 °C for 20 min, providing the
desired 4-chloroquinolinone 13 in 90% yield.
After successfully obtaining the 4-chloroquinolinone 13,
we next performed the key Suzuki cross-coupling step.
Employing commercially available 5-chloro-2-methoxy-
phenylboronic acid (1.2 equiv) together with the opti-
mized protocol elaborated for the model series (see above),
we were pleased to observe near-quantitative formation
of the desired 4-arylquinolin-2(1H)-one 14 (Scheme 6).
No adjustments to the reaction conditions were required,
providing a 91% isolated product yield.
Bromination of the quinolinone substrate 14 with
N-bromosuccinimide in DMF at room temperature pro-
vided the 3-bromo derivative 15 in near-quantitative
yield, although 17 h were required to reach full conver-
sion. The reaction time could be shortened to 9-10 h by
performing the reaction at 50 °C. Here, in contrast to our
model series (cf. Scheme 2), bromination at other than
the desired C3 position of the quinolinone core was not
observed, owing to the strongly electron-withdrawing
character of the trifluoromethyl substituent. Therefore,
bromination under high-temperature microwave condi-
tions (150 °C, MeCN) allowed the preparation of the
desired 3-bromo-4-arylquinolin-2(1H)-one 14 in a signifi-
cantly reduced reaction time (50 min).
In the final step of the reaction sequence, Heck
vinylation of bromoquinolinone 15 with ethyl acrylate
provided the desired target structure 2. As with the
Suzuki protocol, no changes were required to the protocol
optimized for the model series (Scheme 3), providing the
3-(quinolin-3-yl)acrylate 2 in 90% yield after purification
by flash chromatography. As a byproduct, ca. 5% of
debrominated quinolinone 14 was isolated.
As in the model series, the 4-hydroxyquinolin-2(1H)-
one precursor 11 was then converted to the required
4-chloro derivative 13. Since selective monochlorination
at the C4 position of the N1-unblocked quinolinone 11
was not possible, a straightforward two-step chlorination/
hydrolysis sequence was employed (Scheme 5). Treat-
ment of quinolinone 11 with 2 equiv of phosphorus
oxychloride in dioxane using the previously described (see
The protocol presented herein, therefore, allows the
preparation of target structure 2 in seven steps from
4-(trifluoromethyl)aniline in an overall yield of 32%.
Importantly, all six steps described in our sequence
starting from the known malondianilide 10 were con-
ducted utilizing rapid, controlled microwave heating and
did not require any purification by recrystallization or
chromatography of the intermediate products. Typically,
the isolated intermediates had >95% purity and could
(22) In related work on the direct condensation of anilines with
substituted malonates yielding 3-substituted 4-hydroxyquinolin-2(1H)-
ones, Lange and co-workers established that 4-(trifluoromethyl)aniline
proved unreactive and that only the malondianilides could be obtained.
See: Lange, J. H. M.; Verveer, P. C.; Osnabrug, J. M.; Visser, G. M.
Tetrahedron Lett. 2001, 42, 1367-1369.
(23) Bertolini G.; Aquino, M.; Biffi, M.; d′Atri, G.; Di Pierro, F.;
Ferrario, F.; Mascagni, F.; Zaliani, A., Leoni, F. J. Med. Chem. 1997,
40, 2011-2016.
(24) (a) Rowlett, L. J. Am. Chem. Soc. 1946, 68, 1288-1290. (b)
Steinschifter, W. Ph.D. Thesis, University of Graz, 1994, pp 61 and
103. (c) Stadlbauer, W.; Prattes, S.; Fiala, W. J. Heterocycl. Chem. 1998,
35, 627-636.
J. Org. Chem, Vol. 70, No. 10, 2005 3867

Glasnov et al.
SCHEME 6
SCHEME 7
assisted syntheses discussed in this paper were typically
performed on a comparatively small scale (0.3-2.0 mmol,
<5 mL processing volume) in single-mode microwave
reactors.17 Recently, several authors have reported in-
dependently the feasibility of directly scaling reaction
conditions from small-scale single-mode to larger scale
multimode batch microwave reactors (10-500 mL) with-
out reoptimization of the reaction conditions.27,28 There-
fore, many of the microwave reactions described herein
were also performed on a larger scale (up to 16 mmol, 56
mL processing volume) in multimode batch reactors27 in
order to access larger product quantities. Importantly, a
reoptimization of reaction conditions was not necessary,
and products were obtained in similar yields and purities
as on a small scale (see the Experimental Section).
be carried on without purification in the next step. From
the standpoint of generating diversity, the modular and
flexible “scaffold decoration” strategy (Figure 2) should
allow the rapid preparation of a multitude of 4-arylquin-
olin-2(1H)-one analogues, given the large number of
commercially available boronic acids. This represents a
clear improvement over existing synthetic approaches to
this compound class starting from N-acyl-o-aminobenzo-
phenones.1-5 Naturally, other high-speed microwave-
assisted transition metal-catalyzed transformations may
also be accessible from the 4-chloroquinolin-2(1H)-one
building blocks.10,25
To emphasize this point we have carried out microwave-
assisted aminocarbonylation reactions with 6-bromo-4-
phenylquinolin-2(1H)-one 8. Introduction of a carbonyl
group at the C6 position of the quinolinone core may
provide an entry into intermediates for the synthesis of
the nonpeptide farnesyl protein inhibitor ZARNSESTRA
(3).3 Employing the recently reported conditions for
performing microwave-assisted aminocarbonylations,26
using molybdenum hexacarbonyl as a solid source of
carbon monoxide and Herrmann’s palladacycle (5 mol %)
in combination with Fu’s salt [(t-Bu)3PH‚BF4] as a
catalyst system, the anticipated quinoline-6-carboxamide
16 was obtained (Scheme 7). Thus, microwave irradiation
of arylbromide 8 with benzylamine in acetonitrile as
solvent at 170 °C for 25 min provided a 61% yield of
amide 16 after chromatographic workup.
Conclusion
In summary, we have developed an efficient synthetic
approach for the synthesis of 4-aryl-substituted quinolin-
2(1H)-ones, a class of compounds with interesting biologi-
cal activities. The method could be extended to the
synthesis of 3-alkenyl-substituted analogues allowing
access to important pharmaceutical target structures.
The described sequential Suzuki/Heck scaffold decoration
method allows the introduction of substituents late in the
synthetic scheme, therefore greatly facilitating the prepa-
ration of 2(1H)-quinolinone analogues with diversity at
the C4 and/or the C3 position (combinatorial libraries).
Almost all of the synthetic steps described in this paper
were carried out by controlled microwave irradiation,
including the six-step conversion of malondianilide 10 to
the target quinolinone 2 involving a number of different
chemical manipulations.
(27) Stadler, A.; Yousefi, B. H.; Dallinger, D.; Walla, P.; Van der
Eycken, E.; Kaval, N.; Kappe, C. O. Org. Process Res. Dev. 2003, 7,
707-716.
(28) (a) Iqbal, M.; Vyse, N.; Dauvergne, J.; Evans, P. Tetrahedron
Lett. 2002, 43, 7859-7862. (b) Stadler, A.; Pichler, S.; Horeis, G.;
Kappe, C. O. Tetrahedron 2002, 58, 3177-3183. (c) Lehmann, F.;
Pilotti, Å; Luthman, K. Mol. Diversity 2003, 7, 145-152. (d) Shackel-
ford, S. A.; Anderson, M. B.; Christie, L. C.; Goetzen, T.; Guzman, M.
C.; Hananel, M. A.; Kornreich, W. D.; Li, H.; Pathak, V. P.; Rabinovich,
A. K.; Rajapakse, R. J.; Truesdale, L. K.; Tsank, S. M.; Vazir, H. N. J.
Org. Chem. 2003, 68, 267-275. Andappan, M. M. S.; Nilsson, P.; von
Schenck, H.; Larhed, M. J. Org. Chem. 2004, 69, 5212-5218.
Finally, it should be emphasized that during the
reaction optimization phase most examples of microwave-
(25) Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002, 35,
717-727.
(26) (a) Wannberg, J.; Larhed, M. J. Org. Chem. 2003, 68, 5750-
5753. (b) Herrero, M. A.; Wannberg, J.; Larhed, M. Synlett 2004, 2335-
2338.
3868 J. Org. Chem., Vol. 70, No. 10, 2005

Multistep Synthesis of Functionalized 4-Arylquinolin-2(1H)-ones
for 4.5 h at room temperature and the resulting dark yellow
solution subsequently poured onto 15 mL of ice-water. After
being stirred for 5 min, the precipitate was filtered, washed
with water, and dried. Evaporation of the solvent followed by
flash chromatography (petroleum ether/ethyl acetate ) 2:1)
of the crude reaction mixture produced 99 mg (75%) of pure
product 7 as white solid: mp 176-177 °C (ethanol); IR (KBr)
Experimental Section
General Methods. TLC analysis was performed on pre-
coated plates. 1H NMR spectra were obtained on a 360 or 500
MHz instrument, 13C NMR spectra were recorded on a 360
MHz instrument at 90 MHz. FTIR spectra were recorded using
KBr pellets. Low-resolution mass spectra were obtained in the
atmospheric pressure chemical ionization (positive or negative
APCI) mode. Analytical HPLC analysis was carried out on a
C18 reversed-phase analytical column (119 × 3 mm, particle
size 5 µm) at 25 °C using a mobile phase A (water/acetonitrile
90:10 (v/v) + 0.1% TFA) and B (acetonitrile + 0.1% TFA) at a
flow rate of 0.5 mL/min. The following gradient was applied:
linear increase from solution 30% B to 100% B in 7 min, hold
at 100% solution B for 2 min. All chromatographic product
purification was performed with an automated flash chroma-
tography system employing prepacked silica cartridges/sam-
plets.
Microwave Irradiation Experiments. Small-scale mi-
crowave-assisted synthesis was carried out in an Emrys
synthesizer single-mode microwave cavity producing controlled
irradiation at 2450 MHz (Biotage AB, Uppsala).17 Reaction
times refer to hold times at the temperatures indicated, not
to total irradiation times. The temperature was measured with
an IR sensor on the outside of the reaction vessel. The large-
scale microwave syntheses were carried out in a Synthos 3000
multimode batch reactor from Anton Paar GmbH (Graz),
utilizing an eight-vessel quartz rotor system following the
previously published general protocols.27 Reaction times were
extended by 5-10 min compared to the small-scale runs in
order to ensure full conversion. Reaction temperatures were
monitored by a gas balloon thermometer inside one reference
vessel.
1-Methyl-4-chloroquinolin-2(1H)-one (5). To 300 mg (1.7
mmol) of 4-hydroxyquinoline-2(1H)-one 4 in a 10 mL micro-
wave process vial were added 520 mg (3.4 mmol, 320 µL) of
POCl3 and 2 mL of anhydrous dioxane. After that, the mixture
was stirred for 2 min at room temperature to allow complete
homogenization. The sealed vial was heated by microwave
irradiation for 25 min at 120 °C. After cooling to ambient
temperature, the mixture was poured onto 20 mL of ice-water.
The resulting solution was neutralized with 0.5 M KOH. After
being stirred for 20 min, the precipitate was filtered, washed
with water, and dried to give 257 mg (82%) of quinolinone 5:
mp 117-119 °C (lit.14b mp 117.5 °C); 1H NMR (360 MHz,
DMSO-d6) δ 3.59 (s, 3H), 6.9 (s, 1H), 7.37 (t, J ) 7.56, 1H),
7.59 (d, J ) 8.49, 1H), 7.72 (t, J ) 7.71, 1H), 7.91 (d, J ) 7.91,
1H); MS (pos. APCI) m/z 195 (29, M + 2), 193 (100, M+).
Microwave scale-up was performed on a 16 mmol scale
providing an 80% product yield.
1-Methyl-4-phenylquinolin-2(1H)-one (6). A mixture of
121 mg (0.625 mmol) of 4-chloro-1-methylquinolin-2(1H)-one
(5), 82 mg (0.688 mmol, 1.1 equiv) of phenylboronic acid, 190
mg (1.88 mmol, 260 µL, 3 equiv) of Et3N, 0.7 mg (0.003 mmol,
0.5 mol %) of Pd(OAc)2, and 3.3 mg (0.0125 mmol, 2 mol %) of
PPh3 was dissolved in 1.5 mL of DME/water (3:1). The reaction
mixture was stirred for 5 min and then heated by microwave
irradiation for 30 min at 150 °C. The resulting solution was
subsequently treated with charcoal and filtered through a
small plug of silica gel (3 g). The silica plug was washed twice
with an additional amount of 2 mL of DME. Evaporation of
the solvent produced 119 mg (83%) of quinolinone 6 as a
yellow-white solid: mp 146-148 °C (ethanol) (lit.7 mp 146 °C);
IR (KBr) νmax 1665, 1586, 1452, 1377, 1318 cm-1; 1H NMR (360
MHz, CDCl3) δ 3.08 (s, 3H), 6.70 (s, 1H), 7.19 (t, J ) 7.4 Hz,
1H), 7.43-7.60 (m, 8H); MS (pos. APCI) m/z 235 (100, M + 1).
Anal. Calcd for C16H13NO: C, 81.68; H, 5.57; N, 5.95. Found:
C, 81.45; H, 5.64; N, 5.84. Microwave scale-up was performed
on a 11.5 mmol scale providing a 80% product yield.
1
νmax 1645, 1595, 1547, 1490, 1443, 1412, 1305 cm-1; H NMR
(360 MHz, CDCl3) δ 3.90 (s, 3H), 7.13-7.17 (m, 2H), 7.28-
7.30 (m, 2H), 7.43-7.61 (m, 5H); 13C NMR (90 MHz, CDCl3) δ
31.2, 114.3, 119.1, 121.5, 122.5, 128.4, 128.5, 128.6, 130.8,
137.3, 138.8, 150.5, 158.2; MS (pos. APCI) m/z 315 (60, M +
2), 313 (100, M), 234 (10, M - 79). Anal. Calcd for C16H12BrNO:
C, 61.17; H, 3.85; N, 4.45. Found: C, 60.96; H, 3.77 N, 4.44.
6-Bromo-1-methyl-4-phenylquinoline-2(1H)-one (8). A
mixture of 100 mg (0.425 mmol) of 1-methyl-4-phenylquinolin-
2(1H)-one (6) and 267 mg (1.5 mmol, 2.5 equiv) of NBS was
dissolved in 1.5 mL of MeCN. The reaction mixture was stirred
for 1 min at room temperature and subsequently heated by
microwave irradiation at 100 °C for 20 min. After being cooled
to ambient temperature, the mixture was poured onto 15 mL
of ice-water and stirred for 5 min. The precipitate was filtered,
washed with water, and dried to give 125 mg (95%) of
3-bromoquinolinone 8: mp 177-179 °C (ethanol); 1H NMR
(500 MHz, CDCl3) δ 3.75 (s, 3H), 6.69 (s, 1H), 7.31 (d, J ) 8.6
Hz, 1H), 7.39-7.67 (m, 7H); 13C NMR (90 MHz, CDCl3) δ 31.4,
115.5, 116.0, 120.5, 122.8, 128,4, 128.9, 130.4, 133.5, 136.6,
137.8, 149.4, 158.0; MS (pos. APCI) m/z 315 (100, M + 2), 313
(97, M), 235 (27, M - 78). Anal. Calcd for C16H12BrNO: C,
61.17; H, 3.85; N, 4.45. Found: C, 60.86; H, 3.64; N, 4.34.
Ethyl 3-(1,2-Dihydro-1-methyl-2-oxo-4-phenylquinolin-
3-yl)acrylate (9). To 100 mg (0.32 mmol) of 3-bromo-1-methyl-
4-phenylquinolin-2(1H)-one (7) in a 5 mL microwave process
vial were added 50 mg (0.5 mmol, 54 µL, 1.5 equiv) of ethyl
acrylate, 101 mg (1.0 mmol, 140 µL, 3.0 equiv) of Et3N, 11 mg
(0.01 mmol, 3 mol %) of Pd(PPh)3, and 1.5 mL of anhydrous
DMF. The reaction mixture was stirred for 5 min and
subsequently heated by microwave irradiation at 150 °C for
45 min. After being cooled to ambient temperature, the
mixture was purified by flash chromatography (petroleum
ether/ethyl acetate ) 1:1) to give 89 mg (81%) of quinolinone
9: mp 154-156 °C (methanol); IR (KBr) νmax 1703, 1634, 1608,
1310, 1273 cm-1; 1H NMR (360 MHz, CDCl3) δ 1.23 (t, J ) 7.1
Hz, 3H), 3.84 (s, 3H), 4.13 (q, J ) 7.1 Hz, 2H), 7.18-7.58 (m,
11H); MS (pos. APCI) m/z 333 (100), 287 (70, M - 46), 259
(15, M - 74). Anal. Calcd for C20H16NO3: C, 75.66; H, 5.74; N,
4.20. Found: C, 75.58; H, 5.58; N, 4.10.
6-(Trifluoromethyl)-4-hydroxyquinolin-2(1H)-one (11).
To 250 mg (0.64 mmol) of N,N′-bis[(4-trifluoromethyl)phenyl]-
malonamide (10) in a 5 mL microwave process vial was added
1.5 mL of Eaton’s reagent (CAS 39394-84-8). The vial was
capped and the mixture stirred for 10 min under argon
atmosphere. The sealed vial was heated by microwave irradia-
tion at 120 °C for 20 min. After being cooled to room
temperature, the resulting dark-colored solution was poured
onto ice-water, and the formed precipitate filtered by suction.
The product was dissolved in 100 mL of 0.5 M NaOH, and
after being sitrred for 1 h, the turbid solution was filtered and
the filtrate subsequently acidified with 2 M HCl. The formed
precipitate was filtered, washed with water, and dried to give
96 mg (65%) of quinolinone 11: mp > 330 °C (2-propanol); IR
1
(KBr) νmax 1660, 1640, 1611, 1594, 1562 cm-1; H NMR (360
MHz, DMSO-d6) δ 5.98 (s, 1H), 7.41 (d, J ) 8.7 Hz, 1H), 7.81
(d, J ) 8.7 Hz, 1H), 8.02 (s, 1H), 11.57 (s, 1H), 11.76 (s, 1H);
MS (neg. APCI) m/z 229 (100, M), 228 (30, M - 1), 187 (16,
M - 42). Anal. Calcd for C10H6F3NO2: C, 52.41; H, 2.64; N,
6.11. Found: C, 52.67; H, 2.56; N, 6.01. Microwave scale-up
was performed on a 3.85 mmol scale providing a 63% product
yield.
3-Bromo-1-methyl-4-phenylquinolin-2(1H)-one (7). A
mixture of 100 mg (0.425 mmol) of 1-methyl-4-phenylquinolin-
2(1H)-one 6 and 267 mg (1.5 mmol, 2.5 equiv) of NBS was
dissolved in 3 mL of DMF. The reaction mixture was stirred
2,4-Dichloro-6-(trifluoromethyl)quinoline (12). To 300
mg (1.3 mmol) of 6-(trifluoromethyl)-4-hydroxyquinoline-2(1H)-
one (11) in a 10 mL microwave process vial were added 390
J. Org. Chem, Vol. 70, No. 10, 2005 3869

Glasnov et al.
1
mg (2.6 mmol, 240 µL) of POCl3 and 2 mL of anhydrous
dioxane. After that, the mixture was stirred for 2 min at room
temperature to allow complete homogenization. The sealed vial
was heated by microwave irradiation for 15 min at 120 °C.
After being cooled to ambient temperature, the mixture was
poured onto 20 mL of ice-water. The formed solution was
neutralized with 0.5 M KOH. After being stirred for 20 min,
the precipitate was filtered, washed with water, and dried to
give 280 mg (81%) of quinolinone 11: mp 98-100 °C (ethanol);
(KBr) νmax 1678, 1625, 1610, 1491, 1312 cm-1; H NMR (360
MHz, CDCl3) δ 3.75 (s, 3H), 7.06 (d, J ) 8.9 Hz, 1H), 7.16 (d,
J ) 2.4 Hz, 1H), 7.35 (s, 1H), 7.52 (dd, 6.4, 2.5 Hz, 1H), 7.67
(d, J ) 8.6 Hz 1H), 7.78 (d, J ) 8.1 Hz, 1H), 12.56 (s, 1H); MS
(pos. APCI) m/z 435 (22, M + 4), 433 (M + 2), 431 (60, M), 353
(25, M - 78). Anal. Calcd for C17H10BrClF3NO2: C, 47.20; H,
2.33; N, 3.2. Found: C, 47.20; H, 2.16; N, 3.18.
Ethyl 3-[4-(5-Chloro-2-methoxyphenyl)-6-(trifluoro-
methyl)-1,2-dihydro-2-oxoquinolin-3-yl]acrylate (2). To
145 mg (0.33 mmol) of 3-bromo-4-(5-chloro-2-methoxyphenyl)-
6-(trifluoromethyl)quinolin-2(1H)-one 15 in a 5 mL microwave
process vial were added 50 mg (0.5 mmol, 54 µL, 1.5 equiv) of
ethyl acrylate, 101 mg (1.0 mmol, 140 µL, 3 equiv) of Et3N, 11
mg (0.01 mmol, 3 mol %) of Pd(PPh)3, and 1.5 mL of anhydrous
DMF. The reaction mixture was stirred for 5 min and
subsequently heated by microwave irradiation for 45 min at
150 °C. After being cooled to ambient temperature, the mixture
was poured onto 10 mL of ice-water and stirred for 5 min.
Then the yellow precipitate was filtered, washed with water,
and dried. Evaporation of the solvent after flash chromatog-
raphy (petroleum ether/ethyl acetate ) 1:4) produced 133 mg
(90%) of quinolinone 2 as a white solid: mp 235-237 °C
IR (KBr) νmax 1574, 1562, 1451 cm-1 1H NMR (360 MHz,
;
DMSO-d6) δ 8.18-8.24 (m, 3H), 8.49 (s, 1H); MS (pos. APCI)
m/z 269 (18, M + 4), 267 (M + 2), 265 (M), 231 (22, M - 34),
198 (8, M - 68). Anal. Calcd for C10H4Cl2F3N: C, 45.15; H,
1.52; N, 5.26. Found: C, 45.05; H, 1.38; N, 5.12. Microwave
scale-up was performed on a 7 mmol scale providing a 81%
product yield.
4-Chloro-6-(trifluoromethyl)quinoline-2(1H)-one (13).
To 500 mg (2.0 mmol) of 2,4-dichloro-6-(trifluoromethyl)-
quinoline (12) in a 10 mL microwave process vial were added
385 mg (4.0 mmol, 260 µL) of MeSO3H and 4 mL of EtOH.
The reaction mixture was stirred for 10 min and subsequently
heated by microwave irradiation for 20 min at 150 °C. After
being cooled to ambient temperature, the mixture was poured
onto 20 mL of ice-water and stirred for 20 min. The precipitate
was filtered, washed with water, and dried to give 441 mg
(90%) of quinolinone 13: mp 206-208 °C (toluene); IR (KBr)
νmax 3174, 1676, 1632, 1597 cm-1; 1H NMR (360 MHz, DMSO-
d6) δ 6.98 (s, 1H), 7.54 (d, J ) 8.8 Hz, 1H), 7.95 (d, J ) 8.9 Hz,
1H), 8.07 (s, 1H), 12.38 (s, 1H); MS (neg. APCI) m/z 249 (30,
M + 2), 247 (100, M). Anal. Calcd for C10H5ClF3NO: C, 48.51;
H, 2.04; N, 5.66. Found: C, 48.47; H, 1.87; N, 5.62.
Synthesis of 4-(5-Chloro-2-methoxyphenyl)-6-(trifluo-
romethyl)quinolin-2(1H)-one (14). A mixture of 155 mg
(0.625 mmol) of 4-chloro-6-(trifluoromethyl)quinolin-2(1H)-one
13, 127 mg (0.688 mmol, 1.1 equiv) of 5-chloro-2-methoxyphen-
yl boronic acid, 190 mg (1.88 mmol, 260 µL, 3 equiv) of Et3N,
0.7 mg (0.003 mmol, 0.5 mol %) of Pd(OAc)2, and 3.3 mg (0.0125
mmol, 2 mol %) of PPh3 was dissolved in 1.5 mL of DME/water
(3:1). The reaction mixture was stirred for 5 min and subse-
quently heated by microwave irradiation for 30 min at 150
°C. The resulting solution was subsequently treated with
charcoal and filtered through a small plug of silica gel (3 g).
The silica plug was washed twice with an additional amount
of 2 mL of DME. Evaporation of the solvent produced 201 mg
(91%) of quinolinone 14 as a yellow-white solid: mp 147-148
°C (methanol); IR (KBr) νmax 1671, 1489, 1315, 1264 cm-1; 1H
NMR (360 MHz, DMSO-d6) δ 3.68 (s, 3H), 6.53 (s, 1H), 7.25
(d, J ) 7.2 Hz, 2H), 7.41 (d, J ) 2.6 Hz, 1H), 7.52-7.59 (m,
2H), 7.83 (d, J ) 8.7 Hz, 1H), 12.23 (s, 1H); MS (pos. APCI)
m/z 355 (44, M + 2), 353 (100, M), 338 (12, M - 15). Anal.
Calcd for C17H11ClF3NO2: C, 57.72; H, 3.13; N, 3.96. Found:
C, 57.61; H, 3.15; N, 3.99. Microwave scale-up was performed
on a 4.0 mmol scale providing a 90% product yield.
3-Bromo-4-(5-chloro-2-methoxyphenyl)-6-(trifluoro-
methyl)quinolin-2(1H)-one (15). To 150 mg (0.425 mmol)
of 4-(5-chloromethoxyphenyl)-6-trifluoromethyl)quinolin-2(1H)-
one 14 in a 10 mL microwave process vial were added 187 mg
(1.06 mmol, 2.5 equiv) of NBS and 3 mL of MeCN. The reaction
mixture was heated by microwave irradiation for 50 min at
150 °C. The solvent was evaporated and the residue recrystal-
lized from ethanol to give 159 mg (87%) of brominated
quinolinone 15 as a white solid: mp 252-254 °C (ethanol); IR
(methanol); IR (KBr) νmax 1711, 1664, 1625, 1488, 1283 cm-1
;
1H NMR (360 MHz, CDCl3) δ 1.31 (t, J ) 7.1 Hz, 3H), 3.72 (s,
3H), 4.22 (q, J ) 7.1 Hz, 2H), 7.06 (d, J ) 8.9 Hz, 1H), 7.14 (d,
J ) 2.6 Hz, 1H), 7.27-7.60 (m, 5H), 7.77 (d, J ) 1.4 Hz, 1H)
12.07 (s, 1H); MS (pos. APCI) m/z 454 (37, M + 2), 451 (100,
M), 405 (62, M - 46). Anal. Calcd for C22H17ClF3NO4: C, 58.48;
H, 3.79; N, 3.10. Found: C, 58.54; H, 3.51; N, 3.06.
N-Benzyl-1,2-dihydro-1-methyl-2-oxo-4-phenylquino-
line-6-carboxamide (16). A mixture of 50 mg (0.16 mmol) of
6-bromo-1-methyl-4-phenylquinolin-2(1H)-one (8), 73 mg of
DBU (0.48 mmol, 72 µL, 3 equiv), 52 mg of benzylamine (0.48
mmol, 53 µL, 3 equiv), 43 mg of Mo(CO)6, 70 mg of (t-Bu)3PH‚
BF4, and 7.5 mg (0.008 mmol, 2 mol %) of Herrmann’s
palladacycle was dissolved in 2 mL of MeCN. The reaction
mixture was stirred for 5 min and then heated by microwave
irradiation for 25 min at 170 °C. The resulting solution was
purified by flash chromatography using a 1:1 mixture of
petroleum ether/EtOAc to afford 36 mg (61%) of quinoline-6-
carboxamide (16) as a yellowish solid: mp >350 °C (ethanol);
IR (KBr) νmax 1642, 1582, 1538 cm-1 1H NMR (360 MHz,
;
CDCl3) δ 3.7 (s, 3H), 4.43 (d, J ) 5.53 Hz, 2H), 6.5 (s, 1H),
7.28 (m, 5H), 7.52 (m, 5H), 7.7 (d, J ) 9.11, 1H), 8.03 (s, 1H),
8.18 (d, J ) 8.59, 1H), 9.12 (t, J ) 5.64, 1H); 13C NMR (90
MHz, CDCl3) δ 29.9, 39.9, 115.7, 119.5, 121.5, 127.2, 127.6,
128.1, 128.7, 129.3, 129.5, 136.7, 140.0, 142.3, 150.9, 161.1,
165.8; MS (pos. APCI) m/z 369 (31, M + 1), 368 (100, M), 278,
(6, M - 90). Anal. Calcd. for C24H20N2O2: C, 78.24; H, 5.47;
N, 7.60. Found: C, 78.44; H, 5.23; N, 7.56.
Acknowledgment. We thank the Austrian Science
Fund (FWF, I18-N07) and the Austrian Academic
Exchange Service (O¨ AD) for financial support. We thank
Dr. W. M. F. Fabian for performing the computational
studies and Prof. Dr. H. Sterk for recording 2D NMR
spectra. The provision of microwave reactors from
BiotageAB (Uppsala) and Anton Paar GmbH (Graz) is
gratefully acknowledged.
JO0502549
3870 J. Org. Chem., Vol. 70, No. 10, 2005