DMSO-PdI2 as a powerful oxidizing couple of alkynes into benzils: one-pot synthesis of nitrogen-containing five- or six-membered heterocycles

Article abstract of DOI:10.1016/j.tet.2008.02.081

PdI₂ in DMSO promoted the oxidation of functionalized diarylalkynes into benzil derivatives in excellent yields. This new oxidation reaction was achieved with short reaction times and low loading of palladium catalyst. This efficient catalytic

Full text of DOI:10.1016/j.tet.2008.02.081

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4287e4294
www.elsevier.com/locate/tet
DMSOePdI2 as a powerful oxidizing couple of alkynes into
benzils: one-pot synthesis of nitrogen-containing five- or
six-membered heterocycles
a
Celine Mousset , Olivier Provot , Abdallah Hamze , Jerome Bignon ,
a,
a
b
*
Jean-Daniel Brion , Mouad Alami
´
´ ˆ
a
a,
*
ˆ
a Univ Paris-Sud, CNRS, BioCIS, UMR 8076, Laboratoire de Chimie The´rapeutique, Faculte´ de Pharmacie,
rue J.B. Cle´ment F-92296 Chaˆtenay-Malabry, France
b Institut de Chimie des Substances Naturelles, CNRS, avenue de la Terrasse, F-91198 Gif sur Yvette, France
Received 25 January 2008; accepted 25 February 2008
Available online 29 February 2008
Abstract
PdI2 in DMSO promoted the oxidation of functionalized diarylalkynes into benzil derivatives in excellent yields. This new oxidation reaction
was achieved with short reaction times and low loading of palladium catalyst. This efficient catalytic process has been applied successfully to the
one-pot construction of a series of nitrogen-containing heterocycles of biological interest according to a tandem oxidationenitrogen nucleophiles
condensationecyclization.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Benzils; Palladium; DMSO; Alkynes; Oxidation; Tandem reactions; Heterocyclic compounds
1. Introduction
transformations are suitable methods with a range of simple di-
arylalkynes, many of them display low chemoselectivity and
provide low yields with substrates having sensitive functional-
ities. During the last decade, DMSO has been successfully used
as an oxidant either in the presence of CH3SO3H/HCO2H/HBr9
mixture or PdCl2.10 Typically in the latter case, the reaction is
reported to require high loading of catalyst (10 mol %) and
long reaction times, sometimes extending into days that can
seriously affect the yield and the outcome of the oxidation re-
action, particularly with substrates having strong electron-with-
drawing groups5,11 (e.g., CN, NO2) or an ortho substituent.12
Additionally, the oxidation reaction of the triple bond is far
from trivial with substrates containing a heteroaryl nucleus
including forinstance a pyridine or a pyrazole.10,13 Therefore, al-
ternative routes and more reliable procedures for the synthesis of
benzils arewelcome. The remaining challenge is to obtain highly
substituted benzils from functionalized diarylalkynes without
compromising reagent safety, simplicity, and practicality.
In the manufacture of pharmaceutical targets, increasing at-
tention is now being paid to simplification and improvement of
the existing methods. The oxidation of substituted diarylal-
kynes, readily accessible via SonogashiraeLinstrumelle (Se
L) coupling,1 constitutes one of the most versatile processes
in organic chemistry for the synthesis of benzils.2 The latter
have received a great deal of attention because of their proper-
ties and as useful synthetic intermediates in the preparation of
various heterocyclic compounds of biological interest3 includ-
ing, imidazoles or quinoxalines. The oxidation reaction has
been widely explored using various oxidant systems such as
KMnO4,4 SO3/dioxane,5 H5IO6,6 Co(OAc)2/Mn(OAc)2/NaBr,7
8
or H2O2/Fe(PA)2 (bis-(picolinato)iron(II)). Though all these
* Corresponding authors. Tel.: þ33 14683 5847; fax: þ33 14683 5828
(O.P.); tel.: þ33 14683 5887; fax: þ33 14683 5828 (M.A.).
E-mail addresses: olivier.provot@u-psud.fr (O. Provot), mouad.alami@
u-psud.fr (M. Alami).
Recently, we reported the DMSO-oxidation of functional-
ized diarylalkynes in the presence of various transition metal
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.081

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C. Mousset et al. / Tetrahedron 64 (2008) 4287e4294
salts.14 We have found that the better results were obtained us-
ing a catalytic amount (10 mol %) of environmentally friendly
FeBr3 or FeBr3/TfOH combination that act as Lewis acids to
activate the triple bond, and further allowing successive addi-
tions of DMSO. However, during this study we noticed that
substrates having a free phenolic function or a cyano group,
for instance, were resistant to the oxidation reaction, and
gave in best cases the corresponding benzils with moderate
to low yields.
In an ongoing medicinal chemistry program toward the
synthesis of substituted heterocyclic compounds,15 we re-
quired a more reliable and chemoselective procedure for the
synthesis of several benzils that could be used in situ as inter-
mediates for the elaboration of the desired target molecules.
The procedure should be environmentally benign and not in-
volve the use of highly toxic and hazardous reagents. To this
end, we explored the use of PdI2 as a catalyst for the oxidation
of diarylalkynes with DMSO with the hope that its best Lewis
acid character in comparison with PdCl2, would confer to the
Pd(II) catalyst a better catalytic activity, thus reducing the re-
action times and the quantity of catalyst. Herein, we report the
results of this study and disclose that catalytic PdI2 in DMSO
can be conveniently combined with the condensation reaction
of various nitrogen nucleophiles with benzil intermediates to
prepare efficiently in a one-pot procedure nitrogen-containing
heterocycles.
To evaluate the efficiency of Pd(II) salts catalysts, first at-
tempts were carried out by using the same reaction parameters
(140 ꢀC, catalyst: 10 mol %) as we previously described in the
alkyne activation by iron bromide.14 We were pleased to ob-
serve that PdBr2 (10 mol %) efficiently catalyzed the oxidation
of 1a within 2.5 h in an excellent isolated yield and no hydro-
lyzed by-products could be detected (entry 1). In order to in-
crease the Lewis acidity of the Pd(II) catalyst, the next
experiment was achieved by adding TfOH (20 mol %) to
PdBr2. Accordingly, the oxidation occurred within only
25 min and 2a was formed in 92% yield (entry 2). Similar ex-
periments were achieved by changing PdBr2 to PdI2. We found
that PdI2 proves to be a more efficient catalyst to oxidize 1a
even without the additional help of TfOH (entries 3 and 4).
Next, the effect of the temperature was investigated. At a lower
temperature (100 ꢀC; entry 5), total disappearance of the start-
ing alkyne 1a was observed but after a prolonged reaction time
(entry 5, 2 h). We then decided to determine at 140 ꢀC the use-
ful amount of PdI2 to properly carry out this oxidation in a rea-
sonable time. Results described in entries 6e8 clearly showed
that the quantity of catalyst could be decreased to 2 mol %
without loss of efficiency, whereas a longer reaction time
was required when using only 1 mol % of PdI2. The suprem-
acy of PdI2 toward PdCl2 was clearly demonstrated in term
of shortened reaction time and efficiency by the next attempts.
Thus, replacing PdI2 by PdCl2 (2 mol %, 1 h, 140 ꢀC) induced
a lowering of the conversion rate and gave 2a in only 38%
yield (entry 9). In this case, as shown in entry 10, 8 h were re-
quired to observe total conversion of 1a, and 2a was isolated in
only 59% yield.
With optimized conditions in hand, we subsequently ex-
plored the scope of this reaction with a series of substrates,
well-known to be resistant to the oxidation reaction. As sum-
marized in Table 2, various diarylalkynes undergo efficiently
the oxidation reaction with the catalytic system PdI2/DMSO.
The representative examples in Table 2, illustrate the general-
ity of this reaction. Diarylalkynes 1b and 1c, containing elec-
tron-withdrawing groups, were oxidized, respectively, in 3 and
5 h to the corresponding benzil derivatives in excellent iso-
lated yields (entries 2 and 3). When substrate 1d containing
a free phenolic group was treated under these conditions, we
were pleased to observe that the expected p-OH substituted
benzil 2d was obtained in a good yield and in a reasonable re-
action time (entry 4). However, with alkyne 1e having a free
amino function, the reaction turned out to be less effective
even if other palladium salt sources were used (entry 5) and
gave a complex mixture of non-identified by-products. Fortu-
nately, this limitation could be circumvented by decreasing the
nucleophilicity of the nitrogen atom as we observed with an
acetamide function (entry 6, 93%). Results depicted in entries
7 and 8 clearly showed that switching the substituent’s posi-
tion on the aromatic from para to ortho did not affect the yield
of the reaction but a prolonged reaction time was required for
the oxidation of the more hindered aromatic ring.
2. Results and discussion
At first, the oxidation reaction in DMSO was studied with
the model substrate 1a bearing a p-CN group, which is usually
resistant to oxidation.14 The results summarized in Table 1 de-
scribe the effects of various palladium salts catalysts, addi-
tives, and temperature on the outcome of this reaction.
Table 1
Oxidation of diarylalkyne 1a to benzil 2a
CN
CN
PdX2 (mol%)
DMSO, T °C
O
O
1a
2a
OMe
OMe
Entry
Catalyst (mol %)
T (ꢀC)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
a
PdBr2
PdBr2/TfOH
PdI2
10
10:20
140
140
140
140
100
140
140
140
140
140
2.5
0.25
0.15
0.20
2
95
92
93
91
93
93
91
97
38
59
10
10:20
PdI2/TfOH
PdI2
PdI2
10
5
1
PdI2
PdI2
2
1
1
5
PdCl2
PdCl2
2
1
The efficiency of the PdI2/DMSO system was also demon-
strated with alkyne 1i having two carbonecarbon triple bond
as it proved to be a suitable substrate for this oxidation
2
8
Isolated yield.

C. Mousset et al. / Tetrahedron 64 (2008) 4287e4294
4289
Table 2
PdI2 mediated oxidation of alkynes 1 into benzil derivatives 2 in DMSO
O
(2 mol%)
PdI2
Ar1
Ar1
Ar2
Ar2
DMSO, 140 °C
1
2
O
Entry
1
Akynes 1
Benzils 2
O
Time (h)
1
Yielda (%)
91
MeO
1a
2a
2b
2c
MeO
CN
CN
O
O
2
3
1b
1c
3
5
96b
93c
CO2Et
CO2Et
O
O
CHO
OH
CHO
OH
O
O
4
5
1d
1e
2d
2e
4
84
0
O
O
Me
Me
Me
Me
d
NH2
NH2
O
O
6
7
8
1f
2f
3
2
8
93
NHAc
NHAc
O
O
1g
1h
2g
2h
98d
96
OMe
OMe
O
O
Me
Me
O
MeO
MeO
O
O
9
1i
1j
2i
2j
6
9
90
O
O
O
62e
OMe
10
N
OMe
N
O
O
O
N
N
11
12
1k
1l
2k
9
57
O
O
O
2l
2
90f
58
N
N
O
O
MeO
13
1m
2m
1.5
MeO
C2H5
C2H5
O
a
Isolated yield. All new compounds exhibited satisfactory spectral properties and microanalyses.
Using PdCl2 (10 mol %) instead of PdI2 (2 mol %), 2b was obtained within 12 h in only 60% yield.
Using PdCl2 (10 mol %) instead of PdI2 (2 mol %), 2c was obtained in only 68% yield; see Ref. 12b.
No oxidation occurred when using PdCl2 (10 mol %) instead of PdI2 (2 mol %); see Ref. 12b.
A 26% yield of 2j was obtained in the presence of PdCl2 (10 mol %).
b
c
d
e
f
A 45% yield of 2l was obtained in the presence of PdCl2 (10 mol %).

4290
C. Mousset et al. / Tetrahedron 64 (2008) 4287e4294
reaction affording 2i in an excellent yield (95% per triple
bond, entry 9). In the following examples, it is interesting to
note that the reaction conditions were successfully applied to
a series of alkynes having a heteroaromatic nucleus without
any difficulty. Thus, replacing a phenyl ring by a 2-pyridyl
substituent, the procedure was still efficient and furnished
the corresponding benzil 2j in a satisfactory isolated yield
and a reasonable reaction time (entry 10). The catalytic activ-
ity of PdI2 proved to be superior to PdCl2, as the use of PdCl2
induced a lowering of the conversion rate and gave 2j in only
26% yield. When carrying out the reaction with 2,6-disubsti-
tuted pyridine 1k, we were pleased to observe that the
oxidation process occurred leading to benzil 2k in a good yield
(57% for the two triple bonds, entry 11). As expected, the
presence of a quinoline moiety on the triple bond did not
impact the outcome of the oxidation reaction and gave benzil
2l in 90% yield (entry 12), while a much lower yield was
obtained when using PdCl2 instead of PdI2 (45% not shown
in table). Finally, aliphatic arylalkyne 1m was also effective
for the reaction and its oxidation provided the enolizable
adduct 1,2-diketone 2m in a 58% non-optimized isolated yield
(entry 13).
Being given the high efficiency of this oxidation reaction,
we expected that the newly developed procedure would serve
Table 3
Tandem oxidationenitrogen nucleophiles condensationecyclization: one-pot synthesis of heterocycles 3
Entry
Akynes 1
Nitrogen-nucleophile
Heterocycles 3
Time (h) 1/[2]/3
Yielda (%)
H2N
H2N
N
N
1
1n
1g
1g
1n
1o
1n
3a
3b
3c
3d
3e
3f
2þ3
82
N
H2N
H2N
2
3
4
5
6
2þ6
2þ8
2þ3
2þ2
2þ10
80
77
88
97
96
MeO
MeO
N
OMe
N
N
Me
Me
H2N
H2N
Me
Me
OMe
H2N
H2N
Me
N
N
Me
N
H2N
NC
N
H2N
CN
CHO
NO2
N
NH4OH ,
NO2
NH
MeO
H
N
H2N
H2N
O
O
7
1p
1p
3g
3h
2þ2
2þ1
90
88
Me
OMe
OMe
NH
O
Me
MeO
H
N
H2N
H2N
S
S
8
Me
NH
O
Me
a
Isolated yield. All compounds exhibited satisfactory spectral properties and analyses.

C. Mousset et al. / Tetrahedron 64 (2008) 4287e4294
4291
OMe
as an extremely useful and quick synthetic route to obtain ni-
MeO
MeO
trogen-containing heterocyclic including quinoxaline and im-
idazole derivatives. These classes of substituted heterocyclic
compounds offer a high degree of structural diversity and
have proven to be broadly useful as biologically active com-
pounds. In this context, we were interested to investigate the
construction of these heterocyclic skeletons in a one-pot pro-
cedure as it would be economically and environmentally ad-
vantageous over multi-step syntheses.
MeO
MeO
MeO
PdI2 (1 mol%)
DMSO 140 °C
H
N
O
OMe
OH
NH
then, KOH, 140 °C
O
H2N
O
H2N
1q
MeO
3i 60%
OH
Scheme 1. One-pot synthesis of thioxoimidazolidin-2,4-dione 3i related to
combretastatin A-4 (CA-4).
Initially, the reagents and catalyst are mixed together and
experimental conditions are set up in such a way to promote
the reaction cascade. Typically, the reaction was carried out
by heating at 140 ꢀC diphenylalkyne 1n with PdI2 (2 mol %)
in DMSO in the presence of 1,2-phenylenediamine (2 equiv).
Unfortunately, under these conditions, no significant formation
of the desired quinoxaline 3a was observed, even after pro-
longed stirring, owing to probable nitrogen-oxidation side re-
actions. We then decided to achieve this transformation in
a sequential way by heating DMSO in a first step, 1n with
PdI2 (2 mol %) then, by introducing 1,2-phenylenediamine
(2 equiv) in a second step. Thus under the protocol described
above, we were pleased to observe that the tandem sequence
worked very well and provided the desired quinoxaline 3a in
82% yield. The results summarized in Table 3 show that this
tandem oxidationenitrogen nucleophiles condensationecycli-
zation was highly effective with a variety of diarylalkynes and
nitrogen nucleophile reagents including anilines, NH4OH,
urea. Thus, quinoxalines 3bee variously substituted (Me,
OMe, CN) were synthesized according to the procedure de-
scribed above in good yields ranging from 77% (entry 3) to
97% (entry 5). Moreover, this protocol is also convenient as
it opens up an easy access to substituted imidazoles. As ex-
pected (entry 6), imidazole 3f was obtained in an excellent
96% yield from alkyne 1n (1 equiv), 4-nitrobenzaldehyde
(1 equiv), and NH4OH (10 equiv). Interestingly, when alkyne
1p was heated in DMSO in the presence of PdI2, the corre-
sponding 1,2-diketone, which upon refluxing with urea or
thiourea cyclized to form in good yields the imidazolidin-
2,4-dione 3g and thioxoimidazolidin-2,4-dione 3h, respec-
tively (entries 7 and 8). Altogether, these results demonstrated
the efficiency of this tandem oxidationenitrogen nucleophiles
condensationecyclization to provide in a one-pot way a broad
variety of nitrogen-containing heterocycles of biological
interest.
3. Conclusion
In summary, we successfully described a simple, rapid, and
high yielding synthesis of functionalized benzils from diarylal-
kynes using the couple PdI2/DMSO. The chemoselectivity of
this procedure, which requires low loading of catalyst, must
be underlined as different substituents on the aromatic rings
were tolerated as well as nitrogen-containing heterocycles’ nu-
cleus. More interestingly, the procedure can be extended to the
one-pot preparation of various heterocyclic compounds (qui-
noxalines, imidazoles, imidazolidine-2,4-diones.) based on
a tandem oxidationenitrogen nucleophiles condensationecy-
clization. Variation is allowed in each of the partners, thus
making a wide range of accessible heterocycles. This process
is not only of interest for combinatorial synthesis of heterocy-
cles, but in many cases, also offers considerable synthetic ad-
vantages in term of yield, selectivity, and simplicity of the
reaction procedure.
4. Experimental
4.1. Instrumentation
The compounds were all identified by usual physical
methods, i.e., 1H NMR, 13C NMR, IR, and elemental analysis.
1H and 13C NMR spectra were measured in CDCl3 with
1
a Bruker Avance 300 (300 MHz). H chemical shifts are re-
ported in parts per million from an internal standard TMS or
of residual chloroform (7.27 ppm). The following abbrevia-
tions are used: m (multiplet), s (singlet), d (doublet), t (triplet),
dd (doublet of doublet). 13C chemical shifts are reported in
parts per million from the central peak of deuteriochloroform
(77.14). IR spectra were measured on a Bruker Vector 22 spec-
trophotometer (neat, cmꢁ1). Mass spectra were obtained with
a Esquire LC Bruker spectrometer. Analytical TLC was per-
formed on Merck precoated silica gel 60F plates. Merck silica
gel 60 (230e400 mesh) was used for column chromatography.
Finally, starting from the alkyne 1q the newly developed
one-pot procedure have been successfully used for the synthe-
sis of the thioxoimidazolidin-2,4-dione 3i having both a 3,4,5-
trimethoxyphenyl and a 3-hydroxy-4-methoxyphenyl rings
(Scheme 1). The latter may be regarded as an analogue of
the natural combretastatin A-4 (CA-4),16 well-known to act
as both antimitotic and as a selective inhibitor of tumor vascu-
lature growth. Compound 3i was evaluated for cytoxicity in
human colon cancer HCT116 cells and was compared in con-
temporaneous experiment to the CA-4. Unfortunately, the
newly synthesized compound was significantly less potent
(IC50¼100 mM) in the growth inhibition assay in HCT116 cells
than CA-4 (IC50¼2 nM) and was no further studied.
Melting points (mp) were recorded on a Buchi B-450 appara-
¨
tus and were uncorrected.
4.2. General procedure for the preparation of benzils 2aep
from alkynes
A mixture of alkyne 1 (1 mmol) and PdI2 (7.2 mg;
0.02 mmol) in 7 mL of DMSO was stirred at 140 ꢀC for an ap-
propriate time (see Table 2). After cooling to room tempera-
ture, H2O (15 mL) was added and the mixture was extracted

4292
C. Mousset et al. / Tetrahedron 64 (2008) 4287e4294
with EtOAc (3ꢂ15 mL). Organic layers were then washed
with an aqueous saturated NH4Cl solution, dried, and concen-
trated. The crude mixture was then purified by column chro-
matography on silica gel to give benzil compounds 2.
4.2.5. 1-(2-Methoxyphenyl)-2-p-tolylethane-1,2-dione 2h
Yield: 98%. Yellow solid, mp: 98e101 ꢀC. TLC: Rf 0.38
(cyclohexane/EtOAc, 80:20, SiO2). IR (neat) nmax/cmꢁ1
:
1660, 1599, 1485, 1466, 1438, 1266, 1203, 1178, 1161, 1114,
1018, 883, 831, 732, 703. 1H NMR (CDCl3, 300 MHz, 298 K):
d 7.93 (dd, 1H, J¼7.8, 1.8 Hz), 7.73 (d, 2H, J¼8.4 Hz), 7.52e
7.47 (m, 1H), 7.20 (d, 2H, J¼8.4 Hz), 7.05e7.00 (m, 1H),
6.84 (d, 1H, J¼8.4 Hz), 3.48 (s, 3H), 2.40 (s, 3H). 13C NMR
(CDCl3, 75 MHz, 298 K): d 194.7 (CO), 193.3 (CO), 160.4
(C), 144.7 (C), 136.3 (CH), 130.5 (CH), 130.4 (C), 129.4
(4CH), 123.9 (C), 121.4 (CH), 112.3 (CH), 55.6 (CH3), 21.8
(CH3). MS (ESI): m/z 277 (MþNa)þ.
4.2.1. 1-(4-Methoxyphenyl)-2-(4-cyanophenyl)ethane-1,2-
dione 2a
Yield: 91%. Yellow solid, mp: 164e166 ꢀC. TLC: Rf 0.81
(CH2Cl2, SiO2). IR (neat) nmax/cmꢁ1: 2940, 2229, 1674,
1650, 1597, 1570, 1510, 1427, 1408, 1312, 1267, 1213, 1166,
1
1048, 1028, 884, 841, 781, 745. H NMR (CDCl3, 300 MHz,
298 K): d 8.09 (d, 2H, J¼8.7 Hz), 7.95 (d, 2H, J¼9.0 Hz),
7.80 (d, 2H, J¼8.7 Hz), 7.00 (d, 2H, J¼9.0 Hz), 3.91 (s, 3H).
13C NMR (CDCl3, 75 MHz, 298 K): d 192.6 (C), 191.4
(C]O), 165.4 (C]O), 136.1 (C), 132.6 (2CH), 132.5 (2CH),
130.2 (2C), 125.5 (C), 117.6 (2C), 114.5 (2CH), 55.7
(OCH3). MS (APCI): m/z 266 (MþH)þ.
4.2.6. 1,4-Bis(phenylglyoxalyl)benzene 2i
Yield: 90%. Yellow solid, mp: 124e125 ꢀC. TLC: Rf 0.19
(cyclohexane/CH2Cl2, 80:20, SiO2). IR (neat) nmax/cmꢁ1
1665, 1596, 1582, 1502, 1449, 1406, 1307, 1203, 1181, 1000,
:
1
936, 880, 831, 790, 725, 710. H NMR (CDCl3, 300 MHz,
298 K): d 8.10 (s, 4H), 7.96 (d, 4H, J¼7.5 Hz), 7.68 (t, 2H,
J¼7.5 Hz), 7.52 (t, 4H, J¼7.8 Hz). 13C NMR (CDCl3,
75 MHz, 298 K): d 193.3 (2CO), 193.2 (2CO), 137.0 (2C),
135.2 (2C), 132.4 (2CH), 130.2 (4CH), 130.9 (4CH), 129.1
(4CH). MS (ESI): m/z 343 (MþH)þ.
4.2.2. Ethyl 4-(2-oxo-2-phenylacetyl)benzoate 2b
Yield: 96%. Yellow solid, mp: 75e77 ꢀC. TLC: Rf 0.48 (cy-
clohexane/EtOAc, 60:40, SiO2). IR (neat) nmax/cmꢁ1: 1719,
1670, 1596, 1580, 1503, 1450, 1408, 1368, 1273, 1206, 1177,
1105, 1018, 887, 847, 782, 734, 711. 1H NMR (CDCl3,
300 MHz, 298 K): d 8.15 (d, 1H, J¼8.4 Hz), 8.02 (d, 2H,
J¼8.4 Hz), 7.96 (d, 2H, J¼7.5 Hz), 7.66 (t, 1H, J¼7.5 Hz),
7.51 (t, 2H, J¼7.5 Hz), 4.40 (q, 2H, J¼7.2 Hz), 1.39 (t, 3H,
J¼7.2 Hz). 13C NMR (CDCl3, 75 MHz, 298 K): d 193.8
(CO), 193.7 (CO), 165.3 (C), 136.0 (C), 135.7 (CH), 135.1
(CH), 132.7 (C), 130.0 (2CH), 129.9 (2CH), 129.7 (2CH),
129.1 (2CH), 61.6 (CH2), 14.2 (CH3). MS (APCI): m/z 283
(MþH)þ.
4.2.7. 1-(4-Methoxyphenyl)-2-(pyridine-2-yl)ethane-1,2-
dione 2j
Yield: 62%. Brown solid, mp: 97e98 ꢀC. TLC: Rf 0.22 (cy-
clohexane/EtOAc, 70:30, SiO2). IR (neat) nmax/cmꢁ1: 1696,
1666, 1597, 1575, 1511, 1464, 1440, 1424, 1312, 1258, 1225,
1
1169, 1113, 1060, 1022, 995, 890, 843, 812, 795, 746. H
NMR (CDCl3, 300 MHz, 298 K): d 8.63 (d, 1H, J¼4.5 Hz),
8.15 (d, 1H, J¼7.8 Hz), 7.92e7.88 (m, 3H), 7.50e7.46 (m,
1H), 6.87 (d, 2H, J¼9 Hz), 3.90 (s, 3H). 13C NMR (CDCl3,
75 MHz, 298 K): d 195.4 (CO), 194.6 (CO), 164.5 (C),
151.9 (C), 149.9 (CH), 137.4 (CH), 132.1 (2CH), 128.1
(CH), 126.4 (C), 123.3 (CH), 114.4 (2CH), 55.7 (CH3). MS
(ESI): m/z 242 (MþH)þ.
4.2.3. Ethyl 4-(2-oxo-2-phenylacetyl)benzaldehyde 2c
Yield: 93%. Yellow solid, mp: 73e75 ꢀC. TLC: Rf 0.35 (cy-
clohexane/EtOAc, 80:20, SiO2). IR (neat) nmax/cmꢁ1: 1704,
1669, 1595, 1576, 1501, 1450, 1418, 1385, 1304, 1202, 1180,
1
1014, 881, 822, 791, 752, 719. H NMR (CDCl3, 300 MHz,
4.2.8. 1-Phenyl-2-(quinolin-3-yl)ethane-1,2-dione 2l
298 K): d 10.11 (s, 1H), 8.12 (d, 2H, J¼8.4 Hz), 7.95e8.02
(m, 4H), 7.67 (tt, 1H, J¼7.2, 1.2 Hz), 7.52 (m, 2H). 13C
NMR (CDCl3, 75 MHz, 298 K): d 193.5 (CO), 193.4 (CO),
191.2 (CHO), 139.9 (C), 136.9 (C), 135.2 (CH), 132.5 (C),
130.3 (2CH), 130.0 (2CH), 129.9 (4CH), 129.1 (2CH). MS
(APCI): m/z 283 (MꢁH)ꢁ.
Yield: 90%. Yellow solid, mp: 127e129 ꢀC. TLC: Rf 0.33
(cyclohexane/EtOAc, 80:20, SiO2). IR (neat) nmax/cmꢁ1
:
1665, 1616, 1594, 1570, 1495, 1450, 1420, 1374, 1319, 1298,
1259, 1209, 1172, 1127, 1000, 974, 926, 894, 840, 787, 760,
744, 716. 1H NMR (CDCl3, 300 MHz, 298 K): d 9.47 (s,
1H), 8.71 (d, 1H, J¼2.1 Hz), 8.16 (d, 1H, J¼8.4 Hz), 8.04e
8.01 (m, 2H), 7.90e7.82 (m, 2H), 7.70e7.59 (m, 2H),
7.55e7.49 (m, 2H). 13C NMR (CDCl3, 75 MHz, 298 K):
d 193.0 (CO), 192.7 (CO), 150.3 (C), 149.1 (C), 140.1 (CH),
135.2 (CH), 133.0 (CH), 132.5 (C), 130.1 (2CH), 129.6
(2CH), 129.5 (2CH), 127.9 (CH), 126.4 (C), 125.3 (C). MS
(ESI): m/z 262 (MþH)þ.
4.2.4. N-(4-(2-Oxo-2-p-tolylacetyl)phenyl)acetamide 2f
Yield: 93%. Yellow solid, mp: 123e125 ꢀC. TLC: Rf 0.38
(cyclohexane/EtOAc, 60:40, SiO2). IR (neat) nmax/cmꢁ1
3323, 1671, 1589, 1526, 1410, 1371, 1318, 1265, 1220, 1169,
:
1
1121, 1017, 887, 851, 766, 745. H NMR (CDCl3, 300 MHz,
298 K): d 8.22 (s, 1H), 7.80e7.74 (m, 4H), 7.57 (d, 2H,
J¼7.5 Hz), 7.21 (d, 2H, J¼7.8 Hz), 2.34 (s, 3H), 2.10 (s, 3H).
13C NMR (CDCl3, 75 MHz, 298 K): d 194.7 (CO), 193.7
(CO), 169.1 (NHCO), 146.4 (C), 144.1 (C), 131.3 (2CH),
130.4 (C), 130.0 (2CH), 129.7 (2CH), 129.3 (C), 119.2
(2CH), 24.7 (CH3), 21.9 (CH3). MS (APCI): m/z 282 (MþH)þ.
4.3. General procedure for the preparation of quinoxalines
3aee from alkynes 1
Following the procedure described for benzils 2, and after
cooling, a DMSO solution of the arylenediamine (2 mmol,

C. Mousset et al. / Tetrahedron 64 (2008) 4287e4294
4293
2 equiv) was added to the mixture and heated at 140 ꢀC for the
appropriate reaction time (see Table 3). After cooling to room
temperature, H2O (15 mL) was added, and the mixture was ex-
tracted with EtOAc (3ꢂ15 mL). Organic layers were then
washed with an aqueous saturated NH4Cl solution, dried,
and concentrated. The crude mixture was then purified by col-
umn chromatography on silica gel to give quinoxalines 3aee.
2,3-Diphenylquinoxaline 3a17 (yield: 82%) and 6-methyl-
2,3-diphenylquinoxaline 3d18 (yield: 88%), which are known
compounds gave satisfactory data.
were added to the mixture and heated at 140 ꢀC for 12 h. After
cooling, the crude was concentrated and extracted with
CH2Cl2 (3ꢂ15 mL). Organic layers were then washed with
an aqueous saturated NH4Cl solution, dried, and concentrated.
The crude mixture was then purified by column chromatogra-
phy on silica gel to give 3f (Yield: 96%). Spectral data of 3f
were identical to those previously reported.19
4.5. Synthesis of compounds 3gei
Following the procedure described for benzils 2, and after
cooling, a solution of urea or thiourea (2 mmol, 2 equiv) and
KOH (3 mL, 1.2 M) were added to the mixture and heated
at 140 ꢀC for the appropriate reaction time (see Table 3). After
cooling, H2O (15 mL) was added, and the mixture was ex-
tracted with EtOAc (3ꢂ15 mL). Organic layers were then
washed with an aqueous saturated NH4Cl solution, dried,
and concentrated. The crude mixture was then purified by col-
umn chromatography on silica gel to give 3gei.
4.3.1. 2-(4-Methoxyphenyl)-3-phenylquinoxaline 3b
Yield: 80%. Orange oil. TLC: Rf 0.57 (CH2Cl2, 70:30,
SiO2). IR (neat) nmax/cmꢁ1: 3062, 2934, 2837, 2226, 1606,
1578, 1558, 1537, 1513, 1477, 1463, 1444, 1418, 1394, 1344,
1293, 1222, 1175, 1142, 1128, 1112, 1077, 1058, 1025, 978,
1
907, 837, 808, 785, 761, 727. H NMR (CDCl3, 300 MHz,
298 K): d 8.30e8.17 (m, 2H), 7.76e7.70 (m, 2H), 7.57e
7.54 (m, 2H), 7.49 (d, 2H, J¼8.8 Hz), 7.37e7.35 (m, 2H),
6.83 (d, 2H, J¼8.8 Hz), 3.81 (s, 3H). 13C NMR (CDCl3,
75 MHz, 298 K): d 160.1 (C), 153.3 (C), 152.9 (C), 141.2
(C), 140.9 (C), 139.3 (2C), 131.3 (2CH), 129.7 (CH), 129.6
(2CH), 129.5 (CH), 129.1 (CH), 129.0 (CH), 128.6 (CH),
128.2 (2CH), 113.6 (2CH), 55.2 (CH3). MS (APCI): m/z 313
(MþH)þ.
4.5.1. 5-(4-Methoxyphenyl)-5-p-tolylimidazolidine-2,4-
dione 3g
Yield: 90%. Yellow solid, mp: 214e218 ꢀC. TLC: Rf 0.35
(cyclohexane/EtOAc, 60:40, SiO2). IR (neat) nmax/cmꢁ1
:
3193, 2359, 1776, 1698, 1608, 1508, 1420, 1299, 1251,
1175, 1119, 1035, 973, 926, 757, 718. 1H NMR (CD3COCD3,
300 MHz, 298 K): d 9.96 (s, 1H), 8.22 (s, 1H), 7.39 (d, 2H,
J¼9.0 Hz), 7.36 (d, 2H, J¼9.0 Hz), 7.22 (d, 2H, J¼9.0 Hz),
6.96 (d, 2H, J¼9.0 Hz), 3.81 (s, 3H), 2.34 (s, 3H). 13C NMR
(CD3COCD3, 75 MHz, 298 K): d 175.6 (CO), 160.4 (C),
156.6 (CO), 138.6 (C), 138.4 (C), 133.1 (C), 129.9 (2CH),
129.0 (2CH), 127.7 (2CH), 114.6 (2CH), 71.4 (C), 55.6
(OCH3), 21.0 (CH3). MS (ESI): m/z 319 (MþNa)þ.
4.3.2. 2-(4-Methoxyphenyl)-6,7-dimethyl-3-phenyl-
quinoxaline 3c
Yield: 80%. Brown oil. TLC: Rf 0.21 (cyclohexane/EtOAc,
90:10, SiO2). IR (neat) nmax/cmꢁ1: 1606, 1578, 1514, 1481,
1461, 1416, 1398, 1344, 1296, 1249, 1208, 1174, 1110, 1061,
1
1026, 972, 909, 870, 837, 810, 776, 758. H NMR (CDCl3,
300 MHz, 298 K): d 7.85 (s, 2H), 7.53e7.46 (m, 2H), 7.45
(d, 2H, J¼8.8 Hz), 7.36e7.33 (m, 3H), 6.81 (d, 2H,
J¼8.8 Hz), 3.81 (s, 3H), 2.50 (s, 6H). 13C NMR (CDCl3,
75 MHz, 298 K): d 159.9 (C), 152.4 (C), 152.0 (C), 140.3
(C), 140.2 (C), 140.1 (C), 139.9 (C), 139.6 (C), 131.7 (C),
131.2 (2CH), 129.7 (2CH), 128.4 (CH), 128.2 (2CH), 128.1
(CH), 128.0 (CH), 113.6 (2CH), 55.2 (CH3), 20.4 (2CH3).
MS (APCI): m/z 341 (MþH)þ.
4.5.2. 5-(4-Methoxyphenyl)-2-thioxo-5-p-tolylimidazolidin-
4-one 3h
Yield: 88%. Orange oil. TLC: Rf 0.28 (cyclohexane/EtOAc,
60:40, SiO2). IR (neat) nmax/cmꢁ1: 3196, 1721, 1692, 1608,
1508, 1389, 1301, 1248, 1163, 1121, 1028, 928, 816, 735.
1H NMR (CD3COCD3, 300 MHz, 298 K): d 10.59 (s, 1H),
9.75 (s, 1H), 7.09 (d, 2H, J¼8.9 Hz), 7.06 (d, 2H,
J¼8.4 Hz), 6.98 (d, 2H, J¼8.4 Hz), 6.72 (d, 2H, J¼8.9 Hz),
3.55 (s, 3H), 2.08 (s, 3H). 13C NMR (CD3COCD3, 75 MHz,
298 K): d 182.2 (CS), 175.9 (CO), 160.6 (C), 139.1 (C),
136.8 (C), 131.5 (C), 130.0 (2CH), 129.0 (2CH), 127.6
(2CH), 114.8 (2CH), 74.1 (C), 55.6 (OCH3), 21.0 (CH3).
MS (ESI): m/z 312.8 (MþH)þ.
4.3.3. 4-(3-Phenyl-quinoxalin-2-yl)benzonitrile 3e
Yield: 97%. Yellow solid, mp: 168e170 ꢀC. TLC: Rf 0.49
(cyclohexane/EtOAc, 70:30, SiO2). IR (neat) nmax/cmꢁ1
:
1
2225, 1477, 1342, 1057, 1022, 976, 844, 813, 775, 723. H
NMR (CDCl3, 300 MHz, 298 K): d 8.12 (m, 2H), 7.75 (m,
2H), 7.65e7.50 (m, 4H), 7.50e7.28 (m, 5H). 13C NMR
(CDCl3, 75 MHz, 298 K): d 153.1(C), 151.3 (C), 143.6 (C),
141.5 (C), 141.1 (C), 138.3 (C), 132.1 (2CH), 130.8 (CH),
130.6 (2CH), 130.5 (CH), 129.8 (2CH), 129.3 (3CH), 128.6
(2CH), 118.6 (C), 112.5 (CN). MS (APCI): m/z 308 (MþH)þ.
4.5.3. 5-(3-Hydroxy-4-methoxyphenyl)-5-(3,4,5-trimethoxy-
phenyl)imidazolidine-2,4-dione 3i
Yield: 60%. White solid, mp: 240 ꢀC. TLC: Rf 0.35 (cyclo-
hexane/EtOAc, 60:40, SiO2). IR (neat) nmax/cmꢁ1: 3377, 3224,
2937, 1769, 1716, 1591, 1509, 1462, 1414, 1399, 1333, 1272,
1227, 1129, 1104, 1016, 1003, 859, 823, 810, 754, 735, 686.
1H NMR (CD3COCD3, 300 MHz, 298 K): d 9.70 (s, 1H),
8.05 (s, 1H), 7.55 (s, 1H), 6.80e6.68 (m, 5H), 3.70 (s, 3H),
3.64 (s, 6H), 3.60 (s, 3H). 13C NMR (CD3COCD3, 75 MHz,
4.4. Synthesis of 2-(4-nitrophenyl)diphenylimidazole 3f
Following the procedure described for benzils 2, and after
cooling, an AcOH (25 mL) solution of NH4OAc (10 mmol,
10 equiv, 0.77 g) and 4-nitrobenzaldehyde (1.2 mmol, 0.18 g)

4294
C. Mousset et al. / Tetrahedron 64 (2008) 4287e4294
4. (a) Deng, X.; Mani, N. S. Org. Lett. 2006, 8, 269; (b) Lee, D.; Chang, V. S.
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298 K): d 175.2 (CO), 156.2 (CO), 154.2 (2C), 148.3 (C),
147.3 (C), 136.3 (2C), 134.2 (C), 118.7 (CH), 114.9 (CH),
112.1 (CH), 105.6 (2CH), 71.3 (C), 60.5 (OCH3), 56.5 (2
OCH3), 56.2 (OCH3). MS (ESI): m/z 319 (MþNa)þ.
5. Rogatchov, V. O.; Filimonov, V. D.; Yusubov, M. S. Synthesis 2001, 1001.
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Acknowledgements
The CNRS is gratefully acknowledged for support of this
research. Thanks also to the MNSER for a doctoral fellowship
to C.M.
10. Yusubov, M. S.; Zholobova, G. A.; Vasilevsky, S. F.; Tretyakov, E. V.;
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