High-speed microwave-promoted hetero-Diels-Alder reactions of 2(1H)-pyrazinones in ionic liquid doped solvents

Article abstract of DOI:10.1021/jo0263216

Inter- and intramolecular hetero-Diels - Alder reactions in a series of functionalized 2(1H)-pyrazinones were investigated under controlled microwave irradiation. The cycloaddition reactions were efficiently performed in sealed tubes, utilizing either a c

Full text of DOI:10.1021/jo0263216

In recent years, the concept of speeding up synthetic
transformations by microwave activation has created a
lot of interest in the organic6 and combinatorial chemistry
community.7 In particular, the use of dedicated micro-
wave reactors that enable the rapid and safe heating of
reaction mixtures in sealed vessels under controlled
conditions with on-line temperature and pressure moni-
toring has greatly increased the general acceptance of
the microwave heating method. A very recent trend in
this area is to use ionic liquids, or mixtures of ionic
liquids and comparatively unpolar solvents, as reaction
media in microwave-heated transformations.8-11 Due to
their ionic nature, ionic liquids couple very effectively
with microwaves through an ionic conduction mecha-
nism.9 Therefore, small amounts of an ionic liquid can
be employed as additives in order to increase the dielec-
tric constant of an otherwise nonpolar solvent medium.9
In addition, ionic liquids are also known to mediate or
enhance a number of important synthetic transforma-
tions, including Diels-Alder cycloaddition reactions.12
It therefore appeared to us that a microwave/ionic
liquid strategy would be ideally suited to apply to both
inter- and intramolecular cycloaddition reactions involv-
ing the 2(1H)-pyrazinone scaffold. The hetero-Diels-
Alder reactions in this series are known to be rather
sluggish, with reaction times of many hours or even days
being quite common.2-5 In an attempt to make those
valuable synthetic transformations more useful and
applicable to a high-throughput format, we have explored
the potential rate-enhancements by microwave irradia-
tion in the presence of ionic liquids.
Our starting point in these investigations involved
intramolecular hetero-Diels-Alder reactions in a series
of alkenyl-tethered 2(1H)-pyrazinones 1a -d (Scheme 1).
Under conventional thermal conditions, reaction times
of 1-2 days have been reported for those types of
cycloaddition processes (1 f 2) involving chlorobenzene
as solvent under reflux conditions (132 °C).4 Our initial
microwave experiments were performed with pyrazinone
1a as a model substrate involving distilled 1,2-dichloro-
ethane (DCE) as solvent. DCE has been utilized success-
fully in microwave-assisted chemistry before,6 has a
considerably lower boiling point (83 °C) than chloroben-
zene (132 °C), and is therefore easier to work with. The
loss-tangent (tan δ) of DCEsgoverning the ability of the
solvent to couple with 2.45 GHz microwave irradiations
is similar to that of water (tan δ at 20 °C: DCE 0.127;
H2O 0.123).13 Therefore, DCE couples with microwaves
High -Sp eed Micr ow a ve-P r om oted
Heter o-Diels-Ald er Rea ction s of
2(1H)-P yr a zin on es in Ion ic Liqu id Dop ed
Solven ts
Erik Van der Eycken,*,† Prasad Appukkuttan,†
Wim De Borggraeve,† Wim Dehaen,†
Doris Dallinger,‡ and C. Oliver Kappe*,‡
Laboratory for Organic Synthesis, Katholieke Universiteit
Leuven, Celestijnenlaan 200F, B-3001 Heverlee, Belgium,
and Institute of Chemistry, Karl-Franzens-University Graz,
Heinrichstrasse 28, A-8010 Graz, Austria
erik.vandereycken@chem.kuleuven.ac.be;
oliver.kappe@uni-graz.at
Received August 14, 2002
Abstr a ct: Inter- and intramolecular hetero-Diels-Alder
reactions in a series of functionalized 2(1H)-pyrazinones
were investigated under controlled microwave irradiation.
The cycloaddition reactions were efficiently performed in
sealed tubes, utilizing either a combination of 1,2-dichloro-
ethane and a thermally stable ionic liquid, or 1,2-dichlo-
robenzene as reaction medium. In all cases, a significant
rate-enhancement using microwave flash heating as com-
pared to thermal heating was observed.
The readily accessible and broadly functionalized
2-azadiene system of the 2(1H)-pyrazinone scaffold1 has
been shown to offer unique opportunities for inter- and
intramolecular cycloaddition reactions with electron-rich
and electron-poor dienophiles.2 It has been demonstrated,
for example, that pharmacologically interesting com-
pounds containing a â-carbolinone or R-carboline skeleton
can be synthesized starting from 2(1H)-pyrazinone pre-
cursors via an intramolecular cycloaddition-elimination
sequence.3 Starting from alkenylpyrazinones, the tricyclic
core skeleton of the brevianamides natural products could
be synthesized via an intramolecular cycloaddition route.4
The construction of novel types of conformationally
restricted dipeptide analogues as â-turn mimetics via
intermolecular cycloaddition of these heterodienes with
ethene has also been reported recently.5 Although 2(1H)-
pyrazinones are interesting heterodienes and therefore
versatile building blocks for the generation of a number
of important product classes, their cycloaddition chem-
istry suffers from some inconveniences. In many cases
rather long reaction times at high temperatures and
sometimes high pressures are required to successfully
perform these hetero-Diels-Alder cycloadditions, restrict-
ing the practical synthetic utility of this chemistry.
(6) Lidstro¨m, P.; Tierney, J .; Wathey, B.; Westman, J . Tetrahedron
2001, 57, 9225-9283.
(7) (a) Lew, A.; Krutzik, P. O.; Hart, M. E.; Chamberlin, A. R. J .
Comb. Chem. 2002, 4, 95-105. (b) Kappe, C. O. Curr. Opin. Chem.
Biol. 2002, 6, 314-320.
† Katholieke Universiteit Leuven.
‡ Karl-Franzens-University Graz.
(1) Vekemans, J .; Pollers-Wiee¨rs, C.; Hoornaert, G. J . Heterocycl.
Chem. 1983, 919-923.
(8) Varma, R. S.; Namboodiri, V. V. Chem. Commun. 2001, 643-
644.
(2) Hoornaert, G. Bull. Soc. Chim. Belg. 1994, 103, 583-589.
(3) Tahri, A.; Buysens, K. J .; Van der Eycken, E. V.; Vandenberghe,
D. M.; Hoornaert, G. J . Tetrahedron 1998, 54, 13211-13226.
(4) De Borggraeve, W. M.; Rombouts, F. J . R.; Verbist, B. M. P.;
Van der Eycken, E. V.; Hoornaert, G. J . Tetrahedron Lett. 2002, 43,
447-449.
(9) Leadbeater, N. E.; Torenius, H. M. J . Org. Chem. 2002, 67,
3145-3148.
(10) Mayo, K. G.; Nearhoof, E. H.; Kiddle, J . J . Org. Lett. 2002, 4,
1567-1570.
(11) Vallin, K. S. A.; Emilsson, P.; Larhed, M.; Hallberg, A. J . Org.
Chem. 2002, 67, 6243-6246.
(5) De Borggraeve, W. M.; Rombouts, F. J . R.; Van der Eycken, E.
V.; Toppet, S. M.; Hoornaert, G. J . Tetrahedron Lett. 2001, 42, 5693-
5695.
(12) (a) Fischer, T.; Sethi, A.; Welton, T.; Woolf, J . Tetrahedron Lett.
1999, 40, 793-796. (b) Earle, M. J .; McCormac, P. B.; Seddon, K. R.
Green Chem. 1999, 1, 23-25.
10.1021/jo0263216 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/04/2002
7904
J . Org. Chem. 2002, 67, 7904-7907

SCHEME 1 a
F IGURE 1. Heating profiles for microwave-heated DCE (300
W maximum power, 190 °C preselected maximum tempera-
ture) doped with varying amounts of 1-butyl-3-methylimida-
zolium hexafluorophosphate (bmimPF6). Experiments were
carried out in a 5 mL sealed microwave process vial (ref 14)
containing 2 mL of DCE. Profile a: neat DCE. Profile b: 0.035
mmol of bmimPF6. Profile c: 0.075 mmol of bmimPF6. Profile
d: 0.150 mmol of bmimPF6. Profile e: 0.300 mmol of bmimPF6.
Temperatures were recorded on the outer surface of the glass
vial by an IR sensor.
a
(a) Isolated yield of 3. (b) Time needed for conversion of 1 to
2. (c) Time needed for conversion of 1a to 3a as spontaneous
hydrolysis of 2a occurred during the reaction.
reasonably well, leading to the heating profile displayed
in Figure 1 when irradiated in a single-mode microwave
cavity (profile a).14 Using a preselected maximum tem-
perature of 190 °C (300 W maximum power), neat DCE
can be heated to ca. 170 °C within 10 min under sealed
vessel conditions. No further increase of the temperature
(i.e., to the preselected setting of 190 °C) could be
observed on prolonged heating. Under these conditions,
the complete conversion of 1a took ca. 50 min, which
represents a considerable shortening of the reaction time
as compared to the 1-2 days required under the conven-
tional chlorobenzene reflux conditions. Note that in
contrast to heating the neat solvent (DCE, profile a), the
solution of 1a in DCE reached the 170 °C temperature
more rapidly (within ca. 3 min, profile not shown),
indicating that the 2(1H)-pyrazinone is acting as a
“molecular radiator”,15 itself absorbing some of the mi-
crowave energy. In an effort to further enhance the
maximum attainable reaction temperature (and therefore
shortening the reaction time) we have doped the solvent
with varying amounts of a room-temperature ionic liquid
(Figure 1, profiles b-e). Based on a very recent study on
the thermal stability of a variety of ionic liquids/solvent
combinations under high-temperature microwave condi-
tions,9 we have selected 1-butyl-3-methylimidazolium
hexafluorophosphate (bmimPF6) as the ionic liquid of
choice for our investigations. Adding 0.035 mmol of
bmimPF6 to the neat solvent (2 mL of DCE) the prese-
lected temperature of 190 °C could be reached within ca.
3 min upon microwave heating (Figure 1, profile b). These
results clearly demonstrate that even small amounts of
an ionic liquid are able to change the dielectric properties
of an otherwise less polar solvent sufficiently so that more
rapid heating to higher reaction temperatures becomes
possible. Increasing the amount of bmimPF6 to 0.075
mmol led, as expected, to a more rapid heating of the
reaction mixture (Figure 1, profile c). Further doubling
of the ionic liquid concentration to 0.150 mmol provided
a profile that allowed heating of the bmimPF6-doped DCE
to 190 °C within ca. 1 min (Figure 1, profile d). These
“microwave flash heating” conditions11 could only be
marginally improved by further increasing the ionic
liquid concentration (profile e). To minimize the risk of
potential contaminations or side reactions caused by the
ionic liquid,9 all the following cycloaddition studies were
carried out using this set of conditions (0.150 mmol
bmimPF6 for 2 mL of DCE, profile d). Indeed, under these
conditions the intramolecular hetero-Diels-Alder reac-
tion 1a f 3a (including the hydrolysis 2a f 3a , see
below) was completed in only 18 min For the other three
examples, similar fast transformations could be achieved
(see Scheme 1). For the hetero-Diels-Alder cycloaddition
reactions described herein we ascribe the rate-enhance-
ment on going from neat DCE (170 °C) to ionic liquid-
doped DCE (190 °C) to the 20 °C higher reaction
temperature, not to any specific effect caused by the ionic
liquid. This assumption was supported by a control
experiment where the cycloaddition/hydrolysis 1a f 3a
was performed with the 0.150 mmol bmimPF6/DCE
mixture at 170 °C. Indeed the reaction time needed for
complete conversion (ca. 40 min) was more or less iden-
tical to the experiment performed in neat DCE described
above. Evidently, the concentration or type of ionic liquid
used in our studies is not suitable for influencing the
particular Diels-Alder chemistry directly.12
The initial products of the intramolecular Diels-Alder
reactions displayed in Scheme 1 are the “imidoyl chloride”
polycycles 2.4 In general, these products are moisture
sensitive and hydrolyze to the more stable “bislactams”
3 either spontaneously (for 2a ), or by stirring in chloro-
form in the open atmosphere for 18 h.4 We discovered
that rapid hydrolysis of the intermediates 2b-d could
be achieved by addition of water (80 µL) through the
septum of the microwave process vial and resubjection
of the reaction mixture to microwave irradiation (130 °C,
5 min). The isolated overall yields of 3a -d after silica
gel chromatography were 57-77% (Scheme 1).16 These
yields are in the same range as reported for the conven-
(13) Gabriel, C.; Gabriel, S.; Grant, E. H.; Halstead, B. S. J .; Mingos,
D. M. P. Chem. Soc. Rev. 1998, 27, 213-223.
(14) For a detailed description of the single-mode microwave reactor,
see the following: Stadler, A.; Kappe, C. O. J . Comb. Chem. 2001, 3,
624-630.
(15) For a discussion of the concept of molecular radiators, see, for
example: (a) Kaiser, N.-F.; Bremberg, U.; Larhed, M.; Moberg, C.;
Hallberg, A. Angew. Chem., Int. Ed. 2000, 39, 3595-3598. (b) Perreux,
L.; Loupy, A. Tetrahedron 2001, 57, 9199-9223.
J . Org. Chem, Vol. 67, No. 22, 2002 7905

is heated to 110 °C for 12 h.18 We were particularly
interested to see how the high-temperature microwave
protocol would compare with the elevated pressure
conditions.19
SCHEME 2
Our initial experiments in this series utilized again the
optimized bmimPF6/DCE conditions (Figure 1, profile d).
Since the microwave reactor setup used in the current
study14 would not allow pre-pressurization of the reaction
vessel with ethene, we saturated the solution of 2-(1H)-
pyrazinone 4a contained in the microwave process vial
with gaseous ethene at atmospheric pressure, before
sealing the vial with the standard aluminum/Teflon
crimp.14 Interestingly, microwave irradiation of this
mixture at 190 °C led to a spontaneous decomposition/
runaway reaction that caused precipitation of an in-
soluble material on the glass wall of the microwave vial.20
Therefore, we changed to conditions where the ionic
liquid was eliminated from the protocol. As a suitable
solvent we have chosen the strongly microwave absorbing
1,2-dichlorobenzene (DCB),21 allowing us to carry out the
cycloaddition chemistry in the range of 180-250 °C
utilizing microwave flash heating. For pyrazinone pre-
cursor 4a , Diels-Alder addition of ethene in the sealed
microwave vial was completed after irradiation for 40 min
at 190 °C leading to an isolated yield of 86% of pure
cycloadduct (82% under conventional thermal condi-
tions).18 Interestingly, it was not possible to further
increase the reaction rate by raising the temperature. At
temperatures above 200 °C an equilibrium between the
cycloaddition 4a f 8a and the competing retro-Diels-
Alder fragmentation process was observed. This was
confirmed by subjecting a sample of cycloadduct 8a to
microwave heating (without ethene) in DCB at 250 °C,
leading to a mixture of the 2(1H)-pyrazinone precursor
4a and the cycloadduct 8a in a ratio of ca. 1:3. For 2(1H)-
pyrazinone derivative 4b an irradiation time of 140 min
at 190 °C was required to carry the cycloaddition to
completion (89% isolated yield), in agreement with the
known decreased reactivity of this heterodiene (86%
isolated yield of 4b under conventional conditions).18 To
perform microwave-assisted protocols utilizing gaseous
reagents as described herein, it would clearly be desirable
to have a setup where a microwave compatible small-
scale reaction vessel could be pressurized with a gaseous
reagent before irradiating with microwaves. On the other
hand, note that the present microwave-assisted cycload-
SCHEME 3
tional thermal protocols (60-74%).4 However, the micro-
wave-promoted transformations described herein now
allow a more rapid and efficient one-pot access to cy-
cloadducts of type 3, that form the structural core of the
natural product brevianamide (n ) 2).4 Note that the
overall reaction times for the two-step process 1 f 2 f
3 were reduced from 2 to 3 days under conventional
conditions, to 13-20 min under microwave/ionic liquid
conditions.
We next turned our attention to cycloaddition reactions
of 2(1H)-pyrazinones with acetylenic dienophiles. These
Diels-Alder reactions generally lead to mixtures of
pyridine and pyridone products via two competing spon-
taneous retro-Diels-Alder fragmentation pathways from
the initially formed bicyclic cycloadducts (Scheme 2).17
Employing the 2(1H)-pyrazinone precursor 4a as model
substrate we have studied the cycloaddition reaction with
dimethylacetylenedicarboxylate (DMAD) under the mi-
crowave/ionic liquid conditions used above (190 °C, DCE/
bmimPF6). Utilizing the microwave protocol (10 equiv of
DMAD), pyridine 6 and pyridone 7 were obtained in 82%
and 2% isolated yield, respectively, after only 5 min of
microwave irradiation.16 These results are consistent in
terms of product yields and ratios, with the data obtained
under thermal conditions where DMAD was utilized as
the solvent under reflux conditions (140 °C, 30 min).17
The third cycloaddition route investigated in the 2(1H)-
pyrazinone series involved the Diels-Alder cycloaddition
reaction of the heterocyclic pyrazinone heterodienes 4a ,b
with ethene, leading to the bicyclic cycloadducts 8a ,b
(Scheme 3). Under conventional conditions, these cy-
cloaddition reactions have to be carried out in an auto-
clave applying 25 atm ethene pressure before the setup
(18) Loosen, K. P.; Tutonda, M. G.; Khorasani, M. F.; Compernolle,
F.; Hoornaert, G. J . Tetrahedron 1991, 47, 9259-9268.
(19) For the use of gaseous reagents in microwave-assisted pro-
cesses, see, for example: Tanner, D. D.; Kandanarachchi, P.; Ding,
Q.; Shao, H.; Vizitiu, D.; Franz, J . A. Energy Fuels 2001, 15, 197-
204.
(20) CAUTION! This precipitate resulted in extreme microwave
absorption accompanied by a rapid increase in pressure that resulted
in an automatic shut-down of the microwave reactor, and caused
thermal cracks to appear on the glass vial. We assume that an ionic
liquid-initiated polymerization of ethene had occurred, that caused
precipitation of strongly microwave absorbing ionic liquid-doped
polyethylene on the glass vial. In the absence of the ionic liquid a
normal heating pattern was observed. For examples of ionic liquid-
initiated polymerizations of olefins, see, the following: (a) Hong, K.;
Zhang, H.; Mays, J . W.; Visser, A. E.; Brazel, C. S.; Holbrey, J . D.;
Reichert, W. M.; Rogers, R. D. Chem. Commun. 2002, 1368-1369. (b)
Zhang, H.; Hong, K.; Mays, J . W. Macromolecules 2002, 35, 5738-
5741. (c) Hlatky, G. G Patent WO 0181436, 2001.
(16) All products were indentified and characterized on the basis of
their 1H NMR spectrum and comparison with authentic materials.
(17) Tutonda, M., Vanderzande, D., Hendrickx, M., Hoornaert, G.
Tetrahedron 1990, 46, 5715-5732.
(21) (a) Bose, A. K.; Banik, B. K.; Lavlinskaia, N.; J ayaraman, M.;
Manhas, M. S. Chemtech 1997, 27, 18-24. (b) Strohmeier, G. A.;
Kappe, C. O. J . Comb. Chem. 2002, 4, 154-161.
7906 J . Org. Chem., Vol. 67, No. 22, 2002

) 6 Hz, 1H), 1.87 (dd, J ) 14, 6 Hz); 13C NMR (CDCl3, 75 MHz)
δ 169.0, 167.3, 138.9, 129.3, 126.8, 124.3, 91.4, 73.3, 63.7, 42.8,
28.6, 26.2; EIMS m/z 258 (M+, 4), 137 (M+ - PhNHCHO, 100).
Da ta for 3c: yield 57%; IR (KBr) 1698 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 7.32-7.21 (m, 5H), 6.73 (br s, 1H), 4.87 (d,
J ) 14 Hz, 1H), 4.33 (d, J ) 14 Hz, 1H), 4.14-4.10 (m, 1H),
3.80-3.73 (m, 2H), 2.04-1.87 (m, 3H), 1.86-1.74 (m, 1H), 1.67-
1.49 (m, 2H), 1.24 (dbrd, J ) 12, 5 Hz, (<1 Hz), 1H); 13C NMR
(CDCl3, 100 MHz) δ 170.0, 168.5, 136.0, 128.9, 128.2, 128.1, 83.5,
67.1, 58.3, 48.6, 35.6, 30.3, 25.6, 24.0; CIMS m/z 287 (MH+).
Da ta for 3d : yield 77%; IR (KBr) 1710, 1690 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 7.41-7.22 (m, 5H), 7.09 (s, 1H), 4.38-4.35
(m, 1H), 4.13 (ddd, J ) 10, 2, 1 Hz, 1H), 3.97 (ddd, J ) 10, 10,
1 Hz, 1H), 2.52 (ddd, J ) 13, 10, 5 Hz, 1H), 2.26-2.16 (m, 1H),
2.07-1.99 (m, 1H), 1.89-1.76 (m, 1H), 1.72-1.60 (m, 2H), 1.54
(ddd, J ) 13, 5, 1 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 170.4,
167.3, 139.8, 129.2, 127.3, 124.8, 84.5, 64.0, 62.3, 35.1, 30.9, 26.6,
25.5; EIMS m/z 272 (M+, 10), 153 (M+ - PhNCO, 100), 151 (M+
- PhNHCHO, 70); HRMS exact mass for C15H16N2O3 272.1161,
found 272.1162.
ditions do not require a significant ethene pressure
(measured total pressure in the microwave vial at 190
°C 1-2 bar), but are nevertheless significantly faster
than the earlier published autoclave methods (25 atm
ethene pressure at 110 °C for 12 h (4a ) and 16 h (4b)).
We believe that this is a consequence of the higher
reaction temperatures utilized in the microwave protocol,
compensating for the lower pressure.
In conclusion, we have demonstrated that inter- and
intramolecular hetero-Diels-Alder reactions of function-
alized 2(1H)-pyrazinones can be carried out rapidly
utilizing microwave flash heating. For these transforma-
tions, low-boiling solvents such as 1,2-dichloroethane,
doped with small amounts of an ionic liquid are generally
ideal reaction media as they allow very rapid heating by
microwaves in sealed vessels in combination with a
facilitated reaction workup. In addition, we have shown
that the use of a gaseous reagent in a sealed vessel
microwave experiment may provide an alternative, more
efficient method to carry out synthetic transformations
in comparison to standard autoclave protocols. Significant
rate-enhancements for both inter- and intramolecular
hetero-Diels-Alder reactions were observed comparing
the standard protocols to the microwave-heated trans-
formations. In all the investigated Diels-Alder additions,
yields and product distributions were very similar to
what has been observed under conventional thermal
conditions.
P r oced u r e for th e Syn th esis of Com p ou n d s 6 a n d 7. A
solution of the 3-cyano-2(1H)-pyrazinone 4a17 (100 mg), bmimPF6
(15 µL), and dimethyl acetylenedicarboxylate (532 µL) in 1,2-
dichloroethane (1 mL; freshly distilled) is irradiated for 5 min
at 190 °C preselected maximum temperature. Experiments were
carried out in a 2 mL sealed microwave process vial. The reaction
was worked up by diluting the mixture with CH2Cl2. The
mixture was subsequently washed with a saturated solution of
NaHCO3 and brine, and the organic layer was dried over
anhydrous Na2SO4. After filtration and evaporation of the
solvent, the crude products 6 and 7 were purified by column
chromatography over silica gel using a gradient elution selecting
different mixtures of hexane/ethyl acetate as the eluent ranging
from 100% hexane-to-a ratio of 6:4. Both compounds were
identified on the basis of their NMR spectra and comparison
with authentic materials. For spectral data of compounds
synthesized under conventional heating conditions, see ref 17.
Da ta for 6: yield 82%; mp 92-93 °C (lit.17 mp 93 °C); 1H NMR
(CDCl3, 400 MHz) δ 7.93 (s, 1H), 4.03 (s, 3H), 3.91 (s, 3H); EIMS
m/z 254 (M+, 14), 222 (100).
Exp er im en ta l Section
Gen er a l Meth od s. For a general description of methods and
microwave irradiation procedures, see ref 14. All cycloaddition
products have previously been characterized, and the data
obtained corresponded satisfactorily with NMR and MS data,
and comparison with authentic samples.
1
Da ta for 7: yield 2%; mp 158 °C (lit.17 mp 158 °C); H NMR
Gen er a l P r oced u r e for th e Syn th esis of Cycloa d d u cts
3a -d . A solution of the corresponding 3-alkenyl(oxy)-2(1H)-
pyrazinone 1b-d 4 (100 mg) and bmimPF6 (30 µL, 0.15 mmol)
in 1,2-dichloroethane (2 mL; freshly distilled) is irradiated at
190 °C preselected maximum temperature (see Scheme 1 for
irradiation times). Experiments were carried out in a 5 mL
sealed microwave process vial. Then water (80 µL) is added
through the septum of the microwave process vial and the
reaction mixture is heated at 130 °C preselected maximum
temperature for an additional 5 min. The reaction was worked
up by diluting the mixture with CH2Cl2. The mixture was
subsequently washed with a saturated solution of NaHCO3 and
brine and the organic layer was dried over anhydrous Na2SO4.
After filtration and evaporation of the solvent the crude product
was purified by column chromatography over silica gel using
ethyl acetate as the eluent. For compound 1a , it is not necessary
to add water as spontaneous hydrolysis of 2a occurs during
reaction. All compounds were identified on the basis of their
NMR and MS spectra and comparison with authentic materials.
For spectral data of compounds synthesized under conventional
heating conditions, see ref 4.
(CDCl3, 400 MHz) δ 8.41 (s, 1H); 7.38 (m, 5H), 4.01 (s, 3H), 3.80
(s, 3H); EIMS m/z 312 (M+, 96), 281 (52), 253 (100).
P r oced u r e for th e Syn th esis of Cycloa d d u cts 8a ,b. A
solution of the corresponding 2(1H)-pyrazinone 4a ,b5 (50 mg)
in 1,2-dichlorobenzene (5 mL) is saturated with ethene by
passing the gas through the solution for 30 min at atmospheric
pressure. The solution is irradiated at 190 °C preselected
maximum temperature (see body text for irradiation times).
Experiments were carried out in a 5 mL sealed microwave
process vial. The reaction was worked up by evaporating the
1,2-dichlorobenzene. The crude product was purified by column
chromatography over silica gel using a gradient elution selecting
different mixtures of hexane/ethyl acetate as the eluent ranging
from 100% hexane-to-a ratio of 6:4. Both compounds were
identified on the basis of their NMR spectra and comparison
with authentic materials. For spectral data of compounds
synthesized under conventional heating conditions, see ref 5. In
case of the imidoyl chloride 8b, hydrolysis to the corresponding
bislactam occurred during chromatography.
Da ta for 8a : Yield 86%; 1H NMR (CDCl3, 400 MHz) δ 7.52-
7.22 (m, 5H), 4.93 (dd, 1H), 2.72-2.05 (m, 4H); EIMS m/z 259
(M+, 3), 119 (PhNCO+, 100).
Da ta for 8b: yield 89%; 1H NMR (CDCl3, 400 MHz) δ 7.54-
7.25 (m, 5H), 4.97 (m, 1H), 2.52-1.94 (m, 4H); EIMS m/z 268
(M+, 5), 149 (M+ - PhNCO, 87), 119 (PhNCO+, 100).
Da ta for 3a : yield 74%; mp 141-142 °C (lit.4 mp 142 °C); IR
(KBr) 1700 cm-1 1H NMR (CDCl3, 400 MHz) δ 7.34-7.23 (m,
;
5H), 6.68 (br s, 1H), 4.92 (d, J ) 15 Hz, 1H), 4.38 (ddd, J ) 9, 8,
1 Hz, 1H), 4.30 (ddd, J ) 10, 8, 6 Hz, 1H), 4.27 (d, J ) 15.0 Hz,
1H), 3.88 (ddd, J ) 5, 2, 1 Hz, 1H), 2.48-2.35 (m, 1H), 2.30-
2.24 (m, 1H), 1.89 (m, 2H), 1.55 (ddd, J ) 14, 7, 1 Hz, 1H); 13C
NMR (CDCl3, 100 MHz) δ 169.5, 168.7, 136.1, 128.9, 128.1, 128.0,
91.4, 73.0, 60.1, 48.3, 43.3, 28.5, 26.1; CIMS m/z 273 (MH+).
Da ta for 3b: yield 67%; mp 255 °C (lit.4 mp 254 °C); IR (KBr)
1704 cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.46-7.22 (m, 5H), 6.21
(br s, 1H), 4.50-4.29 (m, 3H), 2.73-2.48 (m, 2H), 2.38 (br
quintuplet(dddd), J ) 6 Hz, 1H), 2.03 (br quintuplet (dddd), J
Ack n ow led gm en t. We thank PersonalChemistry
AB (Uppsala, Sweden) for the use of the SmithSynthe-
sizer. We are also grateful to the Research Fund
Katholieke Universiteit Leuven for financial support.
J O0263216
J . Org. Chem, Vol. 67, No. 22, 2002 7907