Synthesis of pyrazino[1,2-a]benzimidazol-1(2H)ones via a microwave assisted Buchwald-Hartwig type reaction

Article abstract of DOI:10.1016/j.tet.2008.06.056

A convenient synthesis of substituted pyrazino[1,2-a]benzimidazol-1(2H)ones starting from 3,5-dichloropyrazinones has been accomplished. Various 3-anilino-pyrazinones were easily converted to the desired tricyclic structures by applying a microwave assisted Buchwald-Hartwig type cyclization.

Full text of DOI:10.1016/j.tet.2008.06.056

Tetrahedron 64 (2008) 8128–8133
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Synthesis of pyrazino[1,2-a]benzimidazol-1(2H)ones via a microwave assisted
Buchwald–Hartwig type reaction
,
b
a
Jo Alen a, Koen Robeyns b, Wim M. De Borggraeve a , Luc Van Meervelt , Frans Compernolle
*
a Molecular Design & Synthesis, Department of Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
b Biomolecular Architecture, Department of Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient synthesis of substituted pyrazino[1,2-a]benzimidazol-1(2H)ones starting from 3,5-di-
chloropyrazinones has been accomplished. Various 3-anilino-pyrazinones were easily converted to the
desired tricyclic structures by applying a microwave assisted Buchwald–Hartwig type cyclization.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 10 June 2008
Accepted 16 June 2008
Available online 20 June 2008
Keywords:
Buchwald–Hartwig reaction
Pyrazinone
Microwave chemistry
1. Introduction
Though no explanation was given by the authors, this could be
attributed to the strong electronegativity of the F-atom.9 At the mo-
Benzimidazoles constitute an important class within the known
drugs, e.g., the neuroleptics pimozide1 and droperidol,2 and the
highly efficient anti-ulcer agent omeprazole.3 As for the benzimid-
azoles fused with aza-aromatic ring systems, mostly pyrido[1,2-
a]benzimidazole derivatives have been reported, showing
antiviral,4 antimicrobial,5 and antiproliferative6 activities. In vitro
screening by the NCI (National Cancer Institute, Bethesda, MD, USA)
for new anticancer agents, showed product 1 (NSC 649900, Fig.1) to
be a promising lead.7 In a similar study, significant in vitro activity
against leukemia cell lines was found for the 5-arylamino-tetrahy-
drobenzimidazo[1,2-b]isoquinolines. The p-fluorophenylamino de-
rivative 2 (NSC 682011, Fig. 1) was identified as the most active
candidate in this series.8
lecularlevel thiscauses a change inlipophilicity, differentelectrostatic
interactions between molecules and inhibition of some metabolic
pathways. At the physiological level this is manifested byan improved
bioavailability,increasedselectivityfortargetorgansandinmostcases
a much lower effective dose compared to non-fluorinated analogs.
Recently pyrazino[1,2-a]benzimidazole derivatives 3 (Fig. 2)
with notable anticancer activity and potency against leukemia have
been described,10 but the area of these tricyclic systems remains
largely unexplored.
As part of our ongoing research toward the design of new pyr-
azinone containing compounds,11 we wanted to develop an effi-
cient route for the synthesis of structures 4 (Fig. 2), possessing
a strong structural similarity with 3. Bearing in mind the beneficial
influence of F-atoms on the lipophilicity, a synthetic pathway
should be found that allows a broad substitution pattern, including
one or more F-atoms.
CH3
Cl
CN
N
F
CN
N
R'
Cl
N
N
N
H
R1
N
R''
R6
Cl
O
N
N
N
N
2: NSC 682011
1: NSC 649900
3
4
R''
N
Figure 1. Pyrido[1,2-a]benzimidazoles 1 and 2, showing in vitro activity against some
leukemia and cancer cell lines.
R'
* Corresponding author. Tel.: þ3 216 327 693; fax: þ3 216 327 990.
Figure 2. Pyrazino[1,2-a]benzimidazole derivatives 3 with anticancer activity and the
proposed benzimidazolone analogs 4.
E-mail address: wim.deborggraeve@chem.kuleuven.be (W.M. De Borggraeve).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.056

J. Alen et al. / Tetrahedron 64 (2008) 8128–8133
8129
2. Results and discussion
For this study we chose dichloropyrazinones 5, 6, and 7 (Table 1)
as starting compounds. These systems can be prepared in good to
excellent yields starting from commercially available products.12 In-
troduction of the (commercially available) anilino substituent at the
reactive 3-position of the pyrazinones was performed by a method
adapted from the literature, using camphorsulfonic acid (CSA) as acid
catalyst.13 The results of this procedure, given in Table 1, suggest that
both sterical and electronic factors influence the coupling reaction.
Referring to o-bromoanilino pyrazinone 8a as the parent com-
pound (Table 1, entry 1), it is obvious that electron withdrawing
groups in para-position of the aniline’s nitrogen atom lower the
yield of the substitution reaction. This is due to a decrease in nu-
cleophilicity of the nitrogen atom, most noticeably in the case of
a CF3 (Table 1, entry 3) and a CN (Table 1, entry 4) substituent. This
observation is consistent with the yields reported in Heeres et al.
for dibromopyrazinones.13
Besides electronic factors, sterical hindrance plays an important
role as well. Substitution of the hydrogen atom in ortho-position of
the NH2 group with a methyl group causes a significant 20% drop in
yield from 71% (Table 1, entry 6) to 51% (Table 1, entry 5). Compound
8b (Table 1, entry 2) was recrystallized from methanol and charac-
terized bysingle-crystal X-rayanalysis, confirming the NMR data. An
ORTEP representation of the structure of 8b is given in Figure 3.
The next step in our approach was cyclization of these key
precursors via a Buchwald–Hartwig type reaction. Traditionally
a Buchwald–Hartwig reaction14 requires long reaction times in high
boiling solvents. Strongly hindered phosphine ligands are very of-
ten used to improve yields. A very elegant synthesis of dipyrido[1,2-
a:30,20-d]imidazole (and its benzo- and aza-analogs) using either
BINAP or xanthphos in combination with Pd(OAc)2 and cesium
carbonate as base, has been described by Loones et al.15a During
a follow-up paper, reporting the synthesis of similar dipyrido[1,2-
a:20,30-d]imidazoles, it was found that cyclization required an
elevated temperature of 140 ꢀC (or alternatively switching to a
Cu-catalyst).15b
Figure 3. ORTEP representation of 8b with thermal displacement ellipsoids shown at
the 50% probability level.
benzimidazo[1,2-a]quinolines.16 In this publication the best results
were obtained using Pd(PPh3)4 as a catalyst and potassium car-
bonate as base. However, under these optimized conditions, still
a reaction time of 12 h was necessary for the reaction to go to
completion. This prompted us to adapt this procedure to micro-
wave conditions, since in the course of the past years, microwave
chemistry17 has proven its usefulness in the decoration of the
pyrazinone scaffold.18
Representative reactions were performed in a mono-mode mi-
crowave reactor that enables rapid heating of reaction mixtures in
sealed vials under controlled conditions with simultaneous moni-
toring of real-time pressure and temperature. Using a maximum
power of 150 W, precursors 8a–k were stirred at 150 ꢀC for 25 min
with 10% Pd(PPh3)4 and anhydrous potassium carbonate in DMF
(large volume to ensure high dilution, see Table 2). The high
In our case, the intramolecular reaction was performed using
the method described by Venkatesh et al. for the synthesis of
Table 2
Synthesis of compounds 4a–ka
Table 1
R1
N
R1
N
Synthesis of compounds 8a–ka
R6
Cl
O
R6
Cl
O
N
K2CO3, Pd(PPh3)4 (10%)
R1
N
R1
N
NH2
R''
R6
Cl
Br
R6
Cl
O
O
DMF, 150 °C (MW),
150 W, 25 min
N
Br
NH
N
CSA, iPrOH
+
R''
reflux, 48 h
R''
NH
N
Br
Cl
N
R'
4
R''
8
R'
R'
5: R1 = PMB, R6 = H
6: R1 = PMB, R6 = Me
7: R1 = R6 = Ph
8
R'
Entry
R1
R6
R0
R00
Product 4
Yieldb (%)
1
2
3
4
5
6
7
8
PMB
PMB
PMB
PMB
PMB
PMB
PMB
PMB
PMB
PMB
Ph
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
F
a
b
c
d
e
f
g
h
i
68
70
62
24
67
74
66
61
62
61
78
Entry
R1
R6
R0
R00
Product 8
Yieldb (%)
CF3
CN
Me
Me
OCF3
F
F
F
H
1
2
3
4
5
6
7
8
PMB
PMB
PMB
PMB
PMB
PMB
PMB
PMB
PMB
PMB
Ph
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
F
a
b
c
d
e
f
g
h
i
76
78
46
42
51
71
57
61
59
55
82
CF3
CN
Me
Me
OCF3
F
F
F
H
9
10
11
H
Ph
Cl
H
j
k
9
10
11
Reactions were performed in 10 mL glass vials sealed with an aluminum/TeflonÒ
a
H
Ph
Cl
H
j
k
crimp top containing 8a–k (0.1 mmol), K2CO3 (0.2 mmol), Pd(PPh3)4 (10 mol %), and
DMF (3 mL). The mixture was irradiated at 150 ꢀC for 25 min, using an irradiation
power of 150 W and was cooled to 50 ꢀC by gas jet cooling before the vial was
opened.
a
Reaction conditions: dichloropyrazinones 5, 6, or 7 (1 mmol), o-bromoanilino
derivative (1.5 mmol), camphorsulfonic acid (1 mmol), and isopropanol, reflux, 48 h.
b
b
Isolated yield of purified product.
Isolated yield of purified product.

8130
J. Alen et al. / Tetrahedron 64 (2008) 8128–8133
Figure 6. ORTEP representation of 4k with thermal displacement ellipsoids shown at
the 50% probability level.
Figure 4. ORTEP representation of 4a with thermal displacement ellipsoids shown at
the 50% probability level.
3. Conclusion
In conclusion, we have developed an efficient two-step pro-
cedure for the preparation of pyrazino[1,2-a]benzimidazol-
1(2H)ones, starting from easily accessible dichloropyrazinones.
This type of tricyclic compounds, with potential biological activity,
has not been reported to this date. The key step of our synthetic
route is a microwave assisted intramolecular Buchwald–Hartwig
type reaction. Two variable positions are present on the pyrazinone
part, as well as two R-groups on the benzimidazole substructure,
tolerating a wide range of electron withdrawing, electron donating,
and neutral functional groups. Under microwave irradiation, this
arylamination has a short reaction time, contributing to the overall
efficacy of this method.
temperature requirement, pointed out in previous publications,15,16
is met by using dimethylformamide as solvent.
As an example, the desired tricyclic product 4a (Table 2, entry 1)
was isolated with 68% yield. X-ray crystallography of this fused
system (crystallized from chloroform) confirmed the anticipated
structure (Fig. 4).
The probable mechanism, as suggested by Venkatesh et al.,
proceeds via a six-membered palladacycle. Reductive elimination
of this species, accompanied by N–C bond formation leads to the
desired pyrazino[1,2-a]benzimidazol-1(2H)ones (Fig. 5).16
This cyclization reaction was successfully performed on all
anilino pyrazinones, as shown in Table 2. The wide range of
variation, tolerating not only mono- but disubstitution as well,
proves the general usefulness of this reaction, as most products
can be obtained in good yields. Also in this case, electron with-
drawing functionalities seem to cause a slight decrease in yield. In
the case of a CN group in para-position, a dramatic decrease in
yield was noted. Upon standing, the resulting compound 4d
decomposed completely. Substitution of the hydrogen atom in
ortho-position does not affect the cyclization efficiency of the re-
action. Compound 4k crystallized spontaneously from CDCl3, en-
abling further characterization of this compound by single-crystal
X-ray crystallography (Fig. 6).
4. Experimental
4.1. General
Melting points are uncorrected. Infrared spectra were recorded
on a Fourier transform spectrometer. For the NMR spectra (d, ppm)
400 MHz and 300 MHz spectrometers were used. For column
chromatography 70–230 mesh silica gel was used as the stationary
phase.
4.2. Microwave irradiation experiments
All microwave irradiation experiments were carried out in
a dedicated CEM-Discover mono-mode microwave apparatus (CEM
Corporation P.O. Box 200 Matthews, NC 28106), operating at a fre-
quency of 2.45 GHz with continuous irradiation power from 0 to
300 W utilizing the standard absorbance level of 300 W maximum
power. The machine was used in the standard configuration as
delivered, including proprietary software. The reactions were car-
ried out in 10 mL glass vials sealed with an aluminum/TeflonÒ
crimp top, which can be exposed to a maximum of 250 ꢀC and
20 bar internal pressure. The temperature was measured with an IR
sensor on the outer surface of the process vial. After the irradiation
period, the reaction vessel was cooled rapidly (60–120 s) to ambi-
ent temperature by gas jet cooling.
4.3. General procedure for the substitution of the 3-position
of pyrazinones with an aniline derivative
A mixture of 1 mmol dichloropyrazinones 5–7, 1.5 mmol of the
appropriate aniline derivative and 1 mmol of camphorsulfonic acid
in isopropanol was heated at reflux temperature for 48 h. The re-
action mixture was allowed to cool to room temperature and
Figure 5. Reaction mechanism of the Buchwald–Hartwig type cyclization of 8a.

J. Alen et al. / Tetrahedron 64 (2008) 8128–8133
8131
extracted with dichloromethane. After subsequently washing with
potassium carbonate solution (satd) and NaCl solution (satd), the
crude product was purified by column chromatography (silicagel,
heptane/dichloromethane 50:50).
2H), 3.81 (s, 3H); 13C NMR (CDCl3, 75 MHz,
d
): 160.0, 150.5, 146.1,
140.0, 135.6 (CH), 132.6 (CH), 130.1 (CH), 126.0, 125.2, 119.1 (CH),
117.7, 116.5 (CH), 114.6 (CH), 112.9, 106.7, 55.3 (CH3), 52.3 (CH2);
EIMS m/z (%): 446 (Mþ 81Br], 5), 444 (Mþ 79Br], 5), 121 (100);
[ [
HRMS: calcd for C19H14BrClN4O2: 443.99886; found: 443.99784.
4.3.1. 3-(2-Bromoanilino)-5-chloro-1-(4-methoxybenzyl)-2(1H)-
pyrazinone (8a)
4.3.5. 3-(2-Bromo-4,6-dimethylanilino)-5-chloro-1-
(4-methoxybenzyl)-2(1H)-pyrazinone (8e)
Yield: 76%; melting point: 184 ꢀC; IR (KBr) cmꢁ1: 1649, 1609,
1579,1553,1512; 1H NMR (CDCl3, 300 MHz,
d
): 9.06 (s,1H, NH), 8.69
Yield: 51%; melting point: 156 ꢀC; IR (KBr) cmꢁ1: 1651, 1609,
(d, 1H, J¼8.1 Hz), 7.57 (dd, 1H, J¼8.2, 1.2 Hz), 7.35 (t, 1H, J¼7.7 Hz),
1579, 1545, 1510; 1H NMR (CDCl3, 300 MHz,
d): 7.81 (s, 1H, NH), 7.30
7.29 (d, 2H, J¼7.6 Hz), 6.94 (t, 1H, J¼7.4 Hz), 6.90 (d, 2H, J¼8.7 Hz),
(d, 2H, J¼8.5 Hz), 7.29 (s, 1H), 7.02 (s, 1H), 6.92 (d, 2H, J¼8.6 Hz),
6.69 (s, 1H), 5.01 (s, 2H), 3.80 (s, 3H); 13C NMR (CDCl3, 75 MHz,
d
):
6.58 (s, 1H), 5.00 (s, 2H), 3.81 (s, 3H), 2.29 (s, 3H), 2.24 (s, 3H); 13C
159.9, 150.7, 146.6, 136.1, 132.4 (CH), 130.1 (CH), 128.4 (CH), 126.5,
125.7,124.2 (CH),119.9 (CH),114.7 (CH),114.5 (CH),113.5, 55.3 (CH3),
NMR (CDCl3, 75 MHz, d): 159.8, 150.3, 148.1, 138.3, 137.7, 131.6, 130.8
(CH), 130.7 (CH), 130.2 (CH), 126.6, 124.2, 121.5, 114.4 (CH), 113.7
52.0 (CH2); EIMS m/z (%): 421 (Mþ
[
81Br], 10), 121 (100); HRMS:
(CH), 55.3 (CH3), 51.6 (CH2), 20.7 (CH3), 19.5 (CH3); EIMS m/z (%):
calcd for C18H15BrClN3O2: 419.00362; found: 420.97422 [81Br].
449 (Mþ 81Br], 5), 447 (Mþ 79Br], 4), 121 (100); HRMS: calcd for
[ [
C20H19BrClN3O2: 447.03492; found: 447.03498.
4.3.2. 3-(2-Bromoanilino)-5-chloro-1-(4-methoxybenzyl)-6-
methyl-2(1H)-pyrazinone (8b)
4.3.6. 3-(2-Bromo-4-methylanilino)-5-chloro-1-(4-methoxy-
benzyl)-2(1H)-pyrazinone (8f)
Yield: 78%; melting point: 164 ꢀC; IR (KBr) cmꢁ1: 1649, 1609,
1579,1553,1512; 1H NMR (CDCl3, 300 MHz,
d): 8.94 (s, 1H, NH), 8.73
Yield: 71%; melting point: 153 ꢀC; IR (KBr) cmꢁ1: 1655, 1610,
(d, 1H, J¼8.2 Hz), 7.57 (d, 1H, J¼7.8 Hz), 7.36 (t, 1H, J¼7.6 Hz), 7.15 (d,
1582,1544,1512; 1H NMR (CDCl3, 300 MHz,
d): 8.96 (s,1H, NH), 8.52
2H, J¼8.2 Hz), 6.92 (t, 1H, J¼7.5 Hz), 6.86 (d, 2H, J¼8.4 Hz), 5.27 (s,
(d, 1H, J¼8.6 Hz), 7.38 (s, 1H), 7.28 (d, 2H, J¼8.6 Hz), 7.14 (d, 1H,
2H), 3.78 (s, 3H), 2.35 (s, 3H); 13C NMR (CDCl3, 75 MHz,
d): 159.2,
J¼8.1 Hz), 6.89 (d, 2H, J¼8.5 Hz), 6.65 (s, 1H), 4.99 (s, 2H), 3.79 (s,
152.0, 144.4, 136.4, 132.3 (CH), 128.3 (CH), 128.2 (CH), 126.9, 124.6,
123.7 (CH), 122.9, 119.4 (CH), 114.3 (CH), 113.2, 55.3 (CH3), 48.4
(CH2), 15.9 (CH3); EIMS m/z (%): 433 (Mþ, 1), 121 (100); HRMS: calcd
for C19H17BrClN3O2: 433.01927; found: 433.02087. Crystal data for
8b: orange-brown plate like crystals, 0.36ꢂ0.1ꢂ0.04 mm3, were
grown from methanol and belong to the triclinic space group P-1
(no. 2) with cell parameters a¼7.4520(3) Å, b¼11.8927(3) Å,
3H), 2.30 (s, 3H); 13C NMR (CDCl3, 75 MHz,
d): 159.8, 150.6, 146.5,
134.3, 133.5, 132.7 (CH), 130.0 (CH), 128.9 (CH), 126.5, 125.8, 119.8
(CH), 114.4 (CH), 114.3 (CH), 113.4, 55.27 (CH3), 51.9 (CH2), 20.5
(CH3); EIMS m/z (%): 435 (Mþ 81Br], 72), 433 (Mþ 79Br], 63), 121
[ [
(100); HRMS: calcd for
433.01962.
C19H17BrClN3O2: 433.01927; found:
c¼11.9346(4) Å,
a
¼61.5520(10)ꢀ,
b
¼78.646(2)ꢀ,
g
¼72.080(2)ꢀ,
4.3.7. 3-[2-Bromo-4-(trifluoromethoxy)anilino]-5-chloro-1-
(4-methoxybenzyl)-2(1H)-pyrazinone (8g)
V¼883.26(5) Å3, Z¼2, rcalcd¼1.635 g/cm3,
2
qmax¼142ꢀ,
m(Cu
K
a
)¼1.858 cmꢁ1. Data were collected on a Bruker SMART 6000
Yield: 57%; melting point: 118 ꢀC; IR (KBr) cmꢁ1: 1647, 1610,
detector, Cu K
a
(l¼1.54178 Å), crossed Go¨bel mirrors, T¼100 K;
1585, 1546, 1508; 1H NMR (CDCl3, 400 MHz,
d): 9.02 (s, 1H, NH),
8734 reflections were measured of which 3219 independent. The
data were corrected for Lorentz, absorption and polarization ef-
fects. The structure was solved by directs methods. Full matrix
least-squares refinement based on jF2j was performed. Hydrogen
atoms were placed at calculated positions with temperature factors
20% higher than those of the parent atoms. The refinement (237
8.74 (d, 1H, J¼9.2 Hz), 7.46 (d, 1H, J¼2.2 Hz), 7.28 (d, 2H, J¼8.6 Hz),
7.25 (td, 1H, J¼9.2, 3.2 Hz), 6.89 (d, 2H, J¼8.7 Hz), 6.71 (s, 1H), 5.00
(s, 2H), 3.79 (s, 3H); 13C NMR (CDCl3, 100 MHz,
d): 160.0, 150.5,
146.4, 144.0 (d, J¼2 Hz), 135.1, 130.1 (CH), 126.4, 125.5, 125.3 (CH),
121.0 (CH), 120.4 (q, J¼256 Hz), 120.2 (CH), 115.2 (CH), 114.5 (CH),
113.2, 55.3 (CH3), 52.1 (CH2); EIMS m/z (%): 503 (Mþ, 14), 121 (100);
HRMS: calcd for C19H14BrClF3N3O3: 502.98591; found: 502.97605.
parameters) converged to an R1 value of 4.95%, uR2 of 10.94%, max./
min. residual electron density 0.14/ꢁ0.61 e Åꢁ3. Crystallographic
data (excluding structure factors) for compound 8b have been de-
posited with the Cambridge Crystallographic Data Centre as sup-
plementary publication number CCDC-660796.
4.3.8. 3-(2-Bromo-4-fluoroanilino)-5-chloro-1-(4-methoxy-
benzyl)-2(1H)-pyrazinone (8h)
Yield: 61%; melting point: 134 ꢀC; IR (KBr) cmꢁ1: 1650, 1610,
1571,1552,1507; 1H NMR (CDCl3, 300 MHz,
d): 8.92 (s,1H, NH), 8.65
4.3.3. 3-[2-Bromo-4-(trifluoromethyl)anilino]-5-chloro-1-
(4-methoxybenzyl)-2(1H)-pyrazinone (8c)
(dd, 1H, J¼9.1, 5.6 Hz), 7.32 (t, 1H, J¼2.8 Hz), 7.28 (d, 2H, J¼8.2 Hz),
7.08 (td, J¼8.5, 2.7 Hz), 6.89 (d, 2H, J¼8.4 Hz), 6.69 (s, 1H), 5.00 (s,
Yield: 46%; melting point: 132 ꢀC; IR (KBr) cmꢁ1: 1659, 1611,
2H), 3.79 (s, 3H); 13C NMR (CDCl3, 75 MHz,
d): 159.9, 157.7 (d,
1578, 1549, 1531, 1513; 1H NMR (CDCl3, 400 MHz,
d
): 9.19 (s, 1H,
J¼246 Hz), 150.5, 146.4, 132.6, 130.0 (CH), 126.4, 125.6, 120.7 (d,
J¼7 Hz, CH), 119.5 (d, J¼26 Hz, CH), 115.0 (d, J¼21 Hz, CH), 114.7
(CH), 114.4 (CH), 113.4 (d, J¼9 Hz), 55.3 (CH3), 52.0 (CH2); EIMS m/z
NH), 8.84 (d,1H, J¼8.9 Hz), 7.82 (d, 1H, J¼1.3 Hz), 7.60 (dd,1H, J¼8.7,
1.1 Hz), 7.29 (d, 2H, J¼8.6 Hz), 6.90 (d, 2H, J¼8.6 Hz), 6.75 (s, 1H),
5.02 (s, 2H), 3.80 (s, 3H); 13C NMR (CDCl3, 100 MHz,
d
): 160.1, 150.6,
(%): 439 (Mþ 81Br], 12), 437 (Mþ 79Br], 11), 121 (100); HRMS: calcd
[ [
146.4, 139.1, 130.1 (CH), 129.5 (q, J¼4 Hz, CH), 126.3, 125.7 (q,
J¼33 Hz), 125.6 (q, J¼3 Hz, CH), 125.4, 123.3 (q, J¼270 Hz), 119.3
(CH), 115.9 (CH), 114.6 (CH), 113.0, 55.3 (CH3), 52.2 (CH2); EIMS m/z
for C18H14BrClFN3O2: 436.99419; found: 436.99384.
4.3.9. 3-(2-Bromo-4,6-difluoroanilino)-5-chloro-1-(4-methoxy-
benzyl)-2(1H)-pyrazinone (8i)
(%): 489 (Mþ 81Br], 36), 487 (Mþ 79Br], 28), 121 (100); HRMS: calcd
[ [
for C19H14BrClF3N3O2: 486.99100; found: 486.99129.
Yield: 59%; melting point: 138 ꢀC; IR (KBr) cmꢁ1: 1650, 1607,
1580, 1550, 1512; 1H NMR (CDCl3, 300 MHz,
d): 7.71 (s, 1H, NH), 7.29
4.3.4. 3-Bromo-4-{[6-chloro-4-(4-methoxybenzyl)-3-oxo-3,4-
dihydro-2-pyrazinyl]amino}benzonitrile (8d)
(d, 2H, J¼8.7 Hz), 7.21 (dt, 1H, J¼7.8, 2.2 Hz), 6.95 (m, 1H), 6.91 (d,
2H, J¼8.6 Hz), 6.65 (s,1H), 5.00 (s, 2H), 3.81 (s, 3H); 13C NMR (CDCl3,
Yield: 42%; melting point: 261 ꢀC; IR (KBr) cmꢁ1: 1660, 1611,
100 MHz,
d
): 160.7 (dd, J¼250, 13 Hz), 160.0, 158.2 (dd, J¼255,
1576,1552,1512; 1H NMR (CDCl3, 300 MHz,
d
): 9.27 (s,1H, NH), 8.87
13 Hz), 150.1, 147.7, 130.1 (CH), 126.4, 126.3, 122.4 (dd, J¼12, 4 Hz),
121.4 (dd, J¼15, 4 Hz), 115.8 (dd, J¼25, 4 Hz, CH), 115.0 (CH), 114.5
(CH), 104.6 (t, J¼25 Hz, CH), 55.3 (CH3), 51.7 (CH2); EIMS m/z (%):
(d, 1H, J¼8.5 Hz), 7.84 (d, 1H, J¼1.7 Hz), 7.64 (dd, 1H, J¼8.5, 1.7 Hz),
7.30 (d, 2H, J¼8.5 Hz), 6.92 (d, 2H, J¼8.5 Hz), 6.81 (s, 1H), 5.04 (s,

8132
J. Alen et al. / Tetrahedron 64 (2008) 8128–8133
455 (Mþ, 12), 121 (100); HRMS: calcd for C18H13BrClF2N3O2:
454.98477; found: 454.98436.
refinement (273 parameters) converged to an R1 value of 3.10%, uR2
of 8.07%, max./min. residual electron density 0.05/ꢁ0.24 e Åꢁ3
.
Crystallographic data (excluding structure factors) for compound
4a have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC-660795.
4.3.10. 3-(2-Bromo-6-chloro-4-fluoroanilino)-5-chloro-1-
(4-methoxybenzyl)-2(1H)-pyrazinone (8j)
Yield: 55%; melting point: 198 ꢀC; IR (KBr) cmꢁ1: 1655, 1612,
1583, 1544,1509; 1H NMR (CDCl3, 400 MHz,
d
): 7.76 (s, 1H, NH), 7.34
4.4.2. 4-Chloro-2-(4-methoxybenzyl)-3-methylpyrazino[1,2-
a]benzimidazol-1(2H)-on (4b)
(dd,1H, J¼7.6, 2.8 Hz), 7.29 (d, 2H, J¼8.6 Hz), 7.21 (dd, J¼7.9, 2.8 Hz),
6.91 (d, 2H, J¼8.6 Hz), 6.64 (s,1H), 5.01 (s, 2H), 3.83 (s, 3H); 13C NMR
Yield: 70%; melting point: 206 ꢀC; IR (KBr) cmꢁ1: 1665, 1638,
(CDCl3,100 MHz,
d
): 160.4 (d, J¼252 Hz),160.0,150.1,147.8, 134.5 (d,
1612, 1515; 1H NMR (CDCl3, 300 MHz,
d
): 8.39 (d, 1H, J¼8.1 Hz), 8.04
J¼11 Hz), 130.6 (d, J¼4 Hz), 130.2 (CH), 126.5, 126.3, 124.1 (d,
J¼11 Hz), 119.2 (d, J¼25 Hz, CH), 116.9 (d, J¼25 Hz, CH), 114.9 (CH),
114.6 (CH), 55.3 (CH3), 51.7 (CH2); EIMS m/z (%): 471 (Mþ, 5), 121
(100); HRMS: calcd for C18H13BrCl2FN3O2: 470.95522; found:
470.95657.
(d, 1H, J¼7.7 Hz), 7.47 (m, 2H), 7.19 (d, 2H, J¼8.3 Hz), 6.84 (d, 2H,
J¼8.2 Hz), 5.38 (s, 2H), 3.76 (s, 3H), 2.42 (s, 3H); 13C NMR (CDCl3,
75 MHz, d): 159.1, 154.5, 143.5, 139.7, 131.3, 128.2 (CH), 127.9, 125.4
(CH), 124.9 (CH), 122.4, 122.0 (CH), 115.1 (CH), 114.3 (CH), 109.2, 55.2
(CH3), 47.2 (CH2), 15.5 (CH3); EIMS m/z (%): 353 (Mþ, 49), 121 (100);
HRMS: calcd for C19H16ClN3O2: 353.09310; found: 353.09232.
4.3.11. 3-(2-Bromoanilino)-5-chloro-1,6-diphenyl-2(1H)-
pyrazinone (8k)
4.4.3. 4-Chloro-2-(4-methoxybenzyl)-7-(trifluoromethyl)-
pyrazino[1,2-a]benzimidazol-1(2H)-one (4c)
Yield: 82%; melting point: 176 ꢀC; IR (KBr) cmꢁ1: 1643, 1611,
1574, 1547, 1505; 1H NMR (CDCl3, 300 MHz,
d): 9.15 (s, 1H, NH), 8.84
Yellow precipitate. Yield: 62%; melting point: 205 ꢀC; IR
(d, 1H, J¼8.0 Hz), 7.59 (d, 1H, J¼7.8 Hz), 7.40 (t, 1H, J¼7.6 Hz), 7.26–
(KBr) cmꢁ1: 1673, 1639; 1610, 1511; 1H NMR (CDCl3, 300 MHz,
d):
7.13 (m, 8H), 7.06 (d, 2H, J¼6.9 Hz), 6.97 (t, 1H, J¼7.3 Hz); 13C NMR
8.62 (s, 1H), 8.13 (d, 1H, J¼8.7 Hz), 7.75 (d, 1H, J¼8.5 Hz), 7.33 (d, 2H,
(CDCl3, 75 MHz, d): 151.5, 145.8, 137.1, 136.2, 132.5 (CH), 131.7, 130.9
J¼8.3 Hz), 6.91 (d, 2H, J¼8.3 Hz), 6.71 (s, 1H), 5.16 (s, 2H), 3.81 (s,
(CH), 129.0 (CH), 128.7 (CH), 128.4 (CH), 128.1 (CH), 126.8, 125.1,
124.2 (CH), 119.9 (CH), 113.5; EIMS m/z (%): 451 (Mþ, 12), 372 (51);
HRMS: calcd for C22H15BrClN3O: 451.00870; found: 451.00625.
3H); 13C NMR (CDCl3, 100 MHz,
d): 160.1, 152.9, 145.3, 142.5, 130.4,
130.1 (CH), 127.2 (q, J¼33 Hz), 126.9, 124.2 (q, J¼271 Hz), 122.9 (CH),
122.3 (q, J¼3 Hz, CH), 115.7 (CH), 114.7 (CH), 112.4 (q, J¼4 Hz, CH),
110.5 (C), 55.3 (CH3), 50.6 (CH2); EIMS m/z (%): 409 (Mþ, 14), 407
(Mþ, 46), 121 (100); HRMS: calcd for C19H13ClF3N3O2: 407.06484;
found: 407.06436.
4.4. General procedure for the Buchwald–Hartwig type
reaction of anilino pyrazinones under microwave irradiation
Anilino pyrazinones 8a–k (0.1 mmol), 0.2 mmol K2CO3 and
10 mol % Pd(PPh3)4 were put in a 10 mL glass vial equipped with
a small magnetic stirring bar. To this was added dimethylform-
amide (3 mL) and the vial was tightly sealed with an aluminum/
TeflonÒ crimp top. The mixture was then irradiated for 25 min at
150 ꢀC using a maximum irradiation power of 150 W. After com-
pletion of the reaction, the vial was cooled to 50 ꢀC by gas jet
cooling before it was opened. After evaporation of the solvent and
extraction with dichloromethane, the crude product was purified
by column chromatography (silicagel, heptane/ethylacetate 70:30
or dichloromethane/methanol 98:2).
4.4.4. 4-Chloro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydro-
pyrazino[1,2-a]benzimidazole-7-carbonitrile (4d)
Yield: 24%; 1H NMR (CDCl3, 300 MHz,
d): 8.72 (s, 1H), 8.12 (d, 1H,
J¼8.5 Hz), 7.75 (d, 1H, J¼8.5 Hz), 7.33 (d, 2H, J¼8.4 Hz), 6.91 (d, 2H,
J¼8.3 Hz), 6.74 (s, 1H), 5.16 (s, 2H), 3.81 (s, 3H).
4.4.5. 4-Chloro-2-(4-methoxybenzyl)-7,9-dimethylpyrazino[1,2-
a]benzimidazol-1(2H)-one (4e)
Yield: 67%; melting point: 204 ꢀC; IR (KBr) cmꢁ1: 1674, 1508; 1H
NMR (CDCl3, 300 MHz,
1H), 6.88 (d, 2H, J¼8.4 Hz), 6.56 (s,1H), 5.12 (s, 2H), 3.79 (s, 3H), 2.74
(s, 3H), 2.49 (s, 3H); 13C NMR (CDCl3, 100 MHz,
): 159.8, 153.3,
d): 7.89 (s, 1H), 7.32 (d, 2H, J¼8.6 Hz), 7.13 (s,
d
4.4.1. 4-Chloro-2-(4-methoxybenzyl)pyrazino[1,2-a]benzimidazol-
1(2H)-one (4a)
140.9, 139.4, 135.7, 131.6, 131.0, 130.1 (CH), 127.9 (CH), 127.3, 114.8
(CH), 114.5 (CH), 111.1 (CH), 110.9, 55.3 (CH3), 50.3 (CH2), 22.2 (CH3),
17.0 (CH3); EIMS m/z (%): 367 (Mþ, 80), 121 (100); HRMS: calcd for
Yield: 68%; melting point: 225 ꢀC; IR (KBr) cmꢁ1: 1670, 1510; 1H
NMR (CDCl3/MeOD, 400 MHz,
d
): 8.30 (d, 1H, J¼8.4 Hz), 7.99 (d, 1H,
C20H18ClN3O2: 367.10875; found: 367.10844.
J¼8.2 Hz), 7.51 (td, 1H, J¼7.6, 0.6 Hz), 7.44 (td, 1H, J¼7.8, 0.7 Hz),
7.33 (d, 2H, J¼8.6 Hz), 6.89 (d, 2H, J¼8.6 Hz), 6.71 (s, 1H), 5.12 (s,
4.4.6. 4-Chloro-2-(4-methoxybenzyl)-7-methylpyrazino[1,2-
a]benzimidazol-1(2H)-one (4f)
2H), 3.79 (s, 3H); 13C NMR (CDCl3/MeOD, 100 MHz,
d): 159.7, 153.1,
143.0, 140.3, 130.8, 129.9 (CH), 127.1, 125.6 (CH), 125.2 (CH), 121.6
(CH), 114.9 (CH), 114.3 (CH), 114.2 (CH), 110.8, 55.1 (CH3), 50.2 (CH2);
EIMS m/z (%): 339 (Mþ, 63), 121 (100); HRMS: calcd for
Yield: 74%; melting point: 187 ꢀC; IR (KBr) cmꢁ1: 1671, 1635,
1608, 1512; 1H NMR (CDCl3, 300 MHz,
d
): 8.05 (s, 1H), 7.89 (d, 1H,
J¼8.4 Hz), 7.31 (d, 3H, J¼8.2 Hz), 6.88 (d, 2H, J¼8.2 Hz), 6.57 (s, 1H),
5.12 (s, 2H), 3.79 (s, 3H), 2.53 (s, 3H); 13C NMR (CDCl3, 75 MHz,
):
C
18H14ClN3O2: 339.07745; found: 339.0785. Crystal data for 4a:
d
transparent plate like crystals, 0.5ꢂ0.2ꢂ0.1 mm3, were grown from
chloroform and belong to the monoclinic space group P21/c (no. 14)
with cell parameters a¼11.15320(10) Å, b¼7.52900(10) Å,
159.7, 153.3, 141.7, 140.1, 135.5, 131.2, 130.0 (CH), 127.5 (CH), 127.3,
121.5 (CH), 114.5 (CH), 114.4 (CH), 113.6 (CH), 110.8, 55.3 (CH3), 50.1
(CH2), 22.2 (CH3); EIMS m/z (%): 353 (Mþ, 59), 121 (100); HRMS:
calcd for C19H16ClN3O2: 353.09310; found: 353.09434.
c¼18.4666(2) Å,
b
¼96.8370(10)ꢀ,
V¼1539.66(3) Å3,
Z¼4,
rcalcd¼1.466 g/cm3, 2qmax¼142ꢀ,
m(Cu K
a
)¼1.858 cmꢁ1, Data were
collected on a Bruker SMART 6000 detector, Cu K
a
(l¼1.54178 Å),
4.4.7. 4-Chloro-2-(4-methoxybenzyl)-7-(trifluoromethoxy)-
pyrazino[1,2-a]benzimidazol-1(2H)-one (4g)
crossed Go¨bel mirrors, T¼100 K; 15,760 reflections were measured
of which 2935 independent. The data were corrected for Lorentz,
absorption and polarization effects. The structure was solved by
directs methods. Full matrix least-squares refinement based on jF2j
was performed. Hydrogen atoms were placed at calculated posi-
tions with temperature factors 20% higher than those of the parent
atoms and the X–H bond distances were free to refine. The
Yield: 66%; melting point: 169 ꢀC; IR (KBr) cmꢁ1: 1669, 1632,
1514; 1H NMR (CDCl3, 300 MHz,
d): 8.20 (s, 1H), 8.04 (d, 1H,
J¼9.0 Hz), 7.41 (d, 1H, J¼8.7 Hz), 7.32 (d, 2H, J¼8.3 Hz), 6.90 (d, 2H,
J¼8.3 Hz), 6.66 (s, 1H), 5.15 (s, 2H), 3.80 (s, 3H); 13C NMR (CDCl3,
100 MHz,
d
): 160.0, 153.0, 146.3 (d, J¼1 Hz), 141.94, 141.88, 130.7,
130.1 (CH), 127.0, 123.2 (CH), 120.6 (q, J¼256 Hz), 119.9 (CH), 115.4

J. Alen et al. / Tetrahedron 64 (2008) 8128–8133
8133
(CH), 114.6 (CH), 110.3, 107.4 (CH), 55.3 (CH3), 50.4 (CH2); EIMS m/z
(%): 426 (Mþ, 24), 121 (100); HRMS: calcd for C19H13ClF3N3O3:
423.05975; found: 423.05916.
atoms were placed at calculated positions with temperature factors
20% higher than those of the parent atoms and the X–H bond dis-
tances were free to refine. The refinement (244 parameters) con-
verged to an R1 value of 3.87%,
uR2 of 9.40%, max./min. residual
4.4.8. 4-Chloro-7-fluoro-2-(4-methoxybenzyl)pyrazino[1,2-
a]benzimidazol-1(2H)-one (4h)
electron density 0.49/ꢁ0.28 e Åꢁ3. Crystallographic data (excluding
structure factors) for compound 4k have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publi-
cation number CCDC-661575.
Yield: 61%; melting point: 229 ꢀC; IR (KBr) cmꢁ1: 1667, 1637,
1608, 1513; 1H NMR (CDCl3, 400 MHz,
d
): 7.97 (d, 1H, J¼9.2 Hz), 7.96
(dd, 1H, J¼9.3, 2.2 Hz), 7.31 (d, 2H, J¼8.6 Hz), 7.27 (td, 1H, J¼9.1,
2.3 Hz), 6.89 (d, 2H, J¼8.7 Hz), 6.62 (s, 1H), 5.12 (s, 2H), 3.79 (s, 3H);
Acknowledgements
13C NMR (CDCl3, 100 MHz,
d
): 160.3 (d, J¼243 Hz), 159.9, 153.1, 141.2
(d, J¼3 Hz), 140.1, 130.8 (d, J¼14 Hz), 130.1 (CH), 127.1, 123.2 (d,
The authors thank the F.W.O. (Fund for Scientific Research-
Flanders (Belgium)) for financial support. We are grateful to B.
Demarsin for HRMS measurements and to K. Duerinckx for assist-
ing with the NMR measurements. J.A. and W.M.D.B. (Postdoctoral
Fellows of the F.W.O.-Flanders) thank the F.W.O. for the fellowships
received. W.M.D.B. also thanks the F.W.O. for a ‘Krediet aan
Navorsers’.
J¼10 Hz, CH), 115.1 (CH), 114.8 (CH), 114.6 (CH), 110.3, 100.7 (d,
J¼30 Hz, CH), 55.3 (CH3), 50.3 (CH2); EIMS m/z (%): 359 (Mþ
[
37Cl],
20), 357 (Mþ, 67), 121 (100); HRMS: calcd for C18H13ClFN3O2:
357.06803; found: 357.06755.
4.4.9. 4-Chloro-7,9-difluoro-2-(4-methoxybenzyl)pyrazino[1,2-
a]benzimidazol-1(2H)-one (4i)
Yield: 62%; melting point: oil; IR (NaCl) cmꢁ1: 1671, 1508; 1H
NMR (CDCl3, 400 MHz,
J¼8.6 Hz), 7.02 (td, 1H, J¼9.7, 2.1 Hz), 6.89 (d, 2H, J¼8.6 Hz), 6.66 (s,
1H), 5.12 (s, 2H), 3.80 (s, 3H); 13C NMR (CDCl3, 100 MHz,
): 160.0,
159.9 (dd, J¼245, 10 Hz), 154.6 (dd, J¼260, 14 Hz), 152.8, 141.2 (d,
J¼3 Hz), 132.2, 130.1 (CH), 129.9, 126.9, 115.8 (CH), 114.6 (CH), 110.0,
101.7 (dd, J¼29, 21 Hz, CH), 97.1 (dd, J¼29, 5 Hz, CH), 55.3 (CH3),
50.5 (CH2); EIMS m/z (%): 375 (Mþ, 100), 121 (33); HRMS: calcd for
d
): 7.82 (dt, 1H, J¼8.9, 1.0 Hz), 7.31 (d, 2H,
Supplementary data
d
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.06.056.
References and notes
C
18H12ClF2N3O2: 375.05861; found: 375.05812.
1. Pinder, R. M.; Brogden, R. N.; Sawyer, P. R.; Speight, T. M.; Spencer, R.; Avery,
G. S. Drugs 1976, 12, 1–40.
4.4.10. 4,9-Dichloro-7-fluoro-2-(4-methoxybenzyl)pyrazino[1,2-
a]benzimidazol-1(2H)-one (4j)
2. Chambers, R. A.; Druss, B. G. J. Clin. Psychiatry 1999, 60, 664–667.
3. Holt, S.; Howden, C. W. Dig. Dis. Sci. 1991, 36, 385–393.
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5. (a) Badawey, E.-S. A. M.; Gohar, Y. Il Farmaco 1992, 47, 489–496; (b) Hammad,
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6. (a) Koenigsmann, M.; Zafferani, M.; Danhauser-Rield, S.; Reuti, B.; Houlihan,
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9. Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications;
Wiley-Interscience: New York, NY, 2004.
Yield: 61%; melting point: oil; IR (NaCl) cmꢁ1: 1674, 1637, 1608,
1515; 1H NMR (CDCl3, 400 MHz,
d
): 7.95 (dd, 1H, J¼8.8, 2.2 Hz), 7.36
(dd, 1H, J¼9.1, 2.2 Hz), 7.31 (d, 2H, J¼8.6 Hz), 6.90 (d, 2H, J¼8.6 Hz),
6.66 (s, 1H), 5.12 (s, 2H), 3.80 (s, 3H); 13C NMR (CDCl3, 100 MHz,
):
d
160.1, 159.6 (d, J¼245 Hz), 152.8, 141.4 (d, J¼2 Hz), 137.9, 131.1 (d,
J¼15 Hz), 130.2 (CH), 128.2 (d, J¼13 Hz), 127.0, 115.9 (CH), 115.4 (d,
J¼29 Hz, CH), 114.7 (CH), 110.0, 99.7 (d, J¼29 Hz, CH), 55.3 (CH3),
50.6 (CH2); EIMS m/z (%): 391 (Mþ, 13), 121 (100); HRMS: calcd for
C
18H12Cl2FN3O2: 391.02906; found: 391.02959.
10. Demirayak, S.; Abu Mohsen, U.; Karaburun, A. C. Eur. J. Med. Chem. 2002, 37,
255–260.
4.4.11. 4-Chloro-2,3-diphenylpyrazino[1,2-a]benzimidazol-1(2H)-
one (4k)
11. (a) De Borggraeve, W. M.; Verbist, B. M. P.; Rombouts, F. J. R.; Pawar, V. G.;
Smets, W. J.; Kamoune, L.; Alen, J.; Van der Eycken, E. V.; Compernolle, F.;
Hoornaert, G. J. Tetrahedron 2004, 60, 11597–11612; (b) Pawar, V. G.; De Borg-
graeve, W. M. Synthesis 2006, 17, 2799–2814; (c) Alen, J.; Smets, W. J.; Dobr-
zan´ ska, L.; De Borggraeve, W. M.; Compernolle, F.; Hoornaert, G. J. Eur. J. Org.
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12. Vekemans, J.; Pollers-Wiee¨rs, C.; Hoornaert, G. J. J. Heterocycl. Chem. 1983, 20,
919–923.
13. Heeres, J.; de Jonge, M. R.; Koymans, L. M. H.; Daeyaert, F. F. D.; Vinkers, M.; Van
Aken, K. J. A.; Arnold, E.; Das, K.; Kilonda, A.; Hoornaert, G. J.; Compernolle, F.;
Yield: 78%; melting point: 174 ꢀC; IR (KBr) cmꢁ1: 1672, 1511; 1H
NMR (CDCl3, 300 MHz,
d
): 7.60 (d, 1H, J¼8.6 Hz), 7.41 (td, 1H, J¼7.7,
1.2 Hz), 7.26 (d, 1H, J¼2.5 Hz), 7.25–7.16 (m, 6H), 7.13 (dd, 2H, J¼6.6,
3.0 Hz), 7.06 (dd, 2H, J¼6.8, 1.0 Hz), 6.98 (td, 1H, J¼7.7, 1.4 Hz); 13C
NMR (CDCl3, 75 MHz, d): 151.5, 145.8, 137.2, 136.2, 132.5 (CH), 131.7,
130.9 (CH), 129.0 (CH), 128.7 (CH), 128.4 (CH), 128.10 (CH), 128.06
(CH), 126.8, 125.2, 124.2 (CH), 120.0 (CH), 113.6; EIMS m/z (%): 371
(Mþ, 100); 336 (37); HRMS: calcd for C22H14ClN3O: 371.08254;
found: 371.08292. Crystal data for 4k: translucent block like crys-
tals, 0.4ꢂ0.3ꢂ0.2 mm3, were grown from CDCl3 and belong to the
monoclinic space group C2/c (no. 15) with cell parameters
´
Cegla, M.; Azzam, R. A.; Andries, K.; de Bethune, M.-P.; Azijn, H.; Pauwels, R.;
Lewi, P. J.; Janssen, P. A. J. J. Med. Chem. 2005, 48, 1910–1918.
14. (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131–209; (b) Yang, B.
H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125–146; (c) Wolfe, J. P.;
Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805–818; (d)
Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046–2067.
15. (a) Loones, K. T. J.; Maes, B. U. W.; Dommisse, R. A.; Lemie`re, G. L. F. Chem.
Commun. 2004, 2466–2467; (b) Loones, K. T. J.; Maes, B. U. W.; Meyers, C.;
Deruytter, J. J. Org. Chem. 2006, 71, 260–264.
16. Venkatesh, C.; Sundaram, G. S. M.; Ila, H.; Junjappa, H. J. Org. Chem. 2006, 71,
1280–1283.
17. (a) Hayes, B. L. Microwave Synthesis: Chemistry at the Speed of Light; CEM:
Matthews, NC, 2002; (b) Microwave-Assisted Synthesis of Heterocycles; Van der
Eycken, E., Kappe, C. O., Eds.; Springer: Berlin, Heidelberg, New York, NY, 2006.
18. (a) Kaval, N.; Bisztray, K.; Dehaen, W.; Kappe, C. O.; Van der Eycken, E. Mol.
a¼24.20(4) Å,
b¼8.510(13) Å,
c¼18.22(2) Å,
b
¼112.21(7)ꢀ,
V¼3474(9) Å3, Z¼8, rcalcd¼1.422 g/cm3,
2
qmax¼141.4ꢀ,
m(Cu
K
a
)¼1.858 cmꢁ1, Data were collected on a Bruker SMART 6000
detector, Cu K
a
(l¼1.54178 Å), crossed Go¨bel mirrors, T¼100 K;
14,751 reflections were measured of which 2963 independent. The
data were corrected for Lorentz, absorption and polarization ef-
fects. The structure was solved by directs methods. Full matrix
least-squares refinement based on jF2j was performed. Hydrogen
´
Diversity 2003, 7, 125–133; (b) Alen, J.; Dobrzanska, L.; De Borggraeve, W. M.;
Compernolle, F. J. Org. Chem. 2007, 72, 1055–1057.