Assisted tandem palladium(II)/palladium(0)-catalyzed C-and N-Arylations of quinoxalin-2(1H)-ones in water

Article abstract of DOI:10.1002/adsc.201400662

A straightforward assisted tandem palladium(II)-and palladium(0)-catalyzed direct C-3 and N-4 arylation of quinoxalin-2(1H)-ones with boronic acids and aryl halides in water as safe and cheap solvent is reported. This environmentally friendly catalytic protocol is compatible with a wide range of functional groups and allows construction of various biologically important quinoxalin-2(1H)-one backbones.

Full text of DOI:10.1002/adsc.201400662

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DOI: 10.1002/adsc.201400662
Assisted Tandem Palladium(II)/Palladium(0)-Catalyzed C- and N-
Arylations of Quinoxalin-2(1H)-ones in Water
Amandine Carrꢀr,a Jean-Daniel Brion,a Mouad Alami,a,* and Samir Messaoudia,*
a
University Paris-Sud, CNRS, BioCIS-UMR 8076, Laboratoire de Chimie Thꢁrapeutique, Equipe Labellisꢁe Ligue Contre
Le Cancer, LabEx LERMIT, Facultꢁ de Pharmacie, 5 rue J.-B. Clꢁment, Chꢂtenay-Malabry, 92296 France
Fax : (+33) 146-83-58-28; e-mail: samir.messaoudi@u-psud.fr or mouad.alami@u-psud.fr
Received: July 9, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400662.
Abstract: A straightforward assisted tandem palla- functional groups and allows construction of various
dium(II)- and palladium(0)-catalyzed direct C-3 and biologically important quinoxalin-2(1H)-one back-
N-4 arylation of quinoxalin-2(1H)-ones with boronic bones.
acids and aryl halides in water as safe and cheap sol-
vent is reported. This environmentally friendly cata- Keywords: assisted tandem catalysis; C-arylation; N-
lytic protocol is compatible with a wide range of arylation; palladium catalysis; quinoxalinones
[4a]
À
Introduction
catalysis for the construction of two C C bonds.
Moreover, there are no known examples that employ
À
À
Quinoxalin-2(1H)-ones are present in many com- palladium to form C C and C N bonds in two differ-
pounds of enormous practical importance, ranging ent catalytic cycles. As part of our continuing efforts
from pharmaceutical agents to material science.[1] Tai- to develop efficient methods to functionalize hetero-
loring the properties of these compounds to satisfy cycles via transition-metal catalysis,[5] we became in-
their specific functions necessitates the development terested in the possibility of applying our recently dis-
of news synthetic methods. These methods should be closed Pd(II)-catalyzed C-3 arylation of quinoxalin-
capable of regioselectively introducing a variety of 2(1H)-one 1a with arylboronic acids[6] to a new assist-
substituents bearing diverse functional groups to the ed tandem Pd(II) and Pd(0)-catalyzed C-3 and N-4 ar-
desired heterocyclic scaffold in high efficiency within ylations of this type of heterocycle in a single opera-
a minimum of steps. Among the strategies able to ad- tion (Scheme 1). The hypothesis was that a reducing
dress this challenge, tandem catalysis, which involves agent could be used to trigger the necessary change in
two or more catalytic cycles in a single reactor, is rec- mechanism. Thus, in situ reduction of a Pd(II) catalyst
ognized as a powerful tool in several areas of organic which is able to perform reductive C-3 arylation of 1a
chemistry, including natural product synthesis, drug (Scheme 1, cycle 1), into a Pd(0) species, by introduc-
discovery, and processes for constructing heterocy- tion of appropriate ligands such as a phosphine,[7] can
cles.[2,3] This approach has emerged as an atom-eco- effectively catalyze a Buchwald-Hartwig N-4 arylation
nomic strategy and has several advantages over multi- of 3a in the presence of an aryl halide (Scheme 1,
step syntheses, including time- and cost-savings, atom cycle 2). From the synthetic viewpoint, this coupling
economy, waste reduction and reduced energy con- should be the shortest and the most efficient route to
sumption.
C3,N4-diarylated dihydroquinoxalin-2(1H)-ones 4a
One of the subfamilies of this strategy is “assisted for the purpose of a medicinal chemistry screening
tandem catalysis,” in which one precatalyst was used program. To the best of our knowledge, there is no
in different oxidation states to preform two mechanis- report describing the formation of 4 using this strat-
tically distinct bond forming reactions in the presence egy. Herein, we report our success on the develop-
of a reagent that triggers this change in mechanism.[2] ment of such a protocol.
However, in contrast to the much more developed
areas of tandem catalysis, reports of assisted tandem
catalysis are rare,[4] and to the best of our knowledge,
there is only one report based on Pd-assisted tandem
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Scheme 1. Pd(II)-catalyzed C3-arylation and Pd(0)-catalyzed N4-arylation through an assisted tandem process using a reduc-
tive trigger.
Table 1. Optimization coupling reaction of 1a with
PhB(OH)2 under various conditions[a]
Results and Discussion
To achieve our goal successfully, we initially studied
the first step in order to control the exclusive forma-
tion of 3a. Very recently, we reported with a single
example that achieving the reaction of 1a with phe-
nylboronic acid under our optimized conditions
[Pd(OAc)2, phenanthroline in DMF at 1208C, argon
atmosphere], enabled the selective formation of 3-
phenyl-3,4-dihydroquinoxalin-2(1H)-one 3a, however,
contaminated with 2a in a 92/8 ratio (68% yield of
3a).[6] To circumvent the formation of 2a in favor of
3a exclusively, and optimize the yield of 3a, an exten-
sive screening of various reaction parameters (palladi-
um, ligand and solvent) was conducted (Table 1). Op-
timal conditions were found to require the use of
Pd(OAc)2 (5 mol%), 2,2’-bipyridine (7.5 mol%) in
water at 808C for 16 h under an argon atmosphere
(entry 12). Accordingly, the desired product 3a was
isolated in a 95% yield.
In line of our hypothesis to achieve a tandem pro-
cess, when the first coupling is complete, subsequent
addition of bromobenzene (1.1 equiv), KOH (4 equiv)
and Xphos or P(tBu)3·HBF4 (10 mol%) provided C-
3,N-4 diarylated quinoxalin-2(1H)-one 4a in yields up
to 84% (Scheme 2, Eq.2). The success of this tandem
Entry Pd.cat
L
Solvent
Conv[g] (%)
2a/1a/3a
1[a]
2[a]
3[a]
4[a]
5[a]
6[a]
7[a]
8[a]
9[a]
Pd(OAc)2
bipy
-
-
MeNO2
MeNO2
MeNO2
MeNO2
10/33/57
0/100/0
0/100/0
16/10/74
17/5/78
0/80/20
10/5/85
PdCl2(bipy)
PdCl2(phen)
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Phen
5(NO2)Phen MeNO2
Xphos[b]
bipy
MeNO2
H2O
tAmOH 0/100/0
bipy
bipy
EtOH
0/100/0
21/0/79
10/4/86
3/4/93[h]
5/13/82
7/17/76
6/4/90[i]
10[a] Pd(OAc)2
11[c] Pd(OAc)2
12[d] Pd(OAc)2
13[e] Pd(OAc)2
14[f] Pd(OAc)2
15[d] Pd(OAc)2
5(NO2)Phen H2O
bipy
bipy
bipy
bipy
bipy
H2O
H2O
H2O
H2O
MeNO2
[a]
Conditions: quinoxalinone 1a (0.5 mmol), boronic acid
(1.5 equiv), palladium (10 mol%), ligand (10 mol%), sol-
vent (2 mL) under argon at 808C for 16 h.
XPhos (20 mol%) was used.
2,2ꢄ-Bipyridine (bipy, 15 mol%) was used.
Pd(OAc)2 (5 mol%) and bipy (7.5 mol%) were used.
Pd(OAc)2 (5 mol%) and bipy (10 mol%) were used.
Pd(OAc)2 (2.5 mol%) and bipy (3.5 mol%) were used.
The ratio was determined by 1H NMR on the crude
product.
[b]
[c]
[d]
[e]
[f]
À
À
C C and C N bond formation demonstrates that the
ligand phosphine added[8] can act as the reductive
trigger to form a Pd(0) species from a Pd(II) and can
initiate a new reaction for converting 3a into 4a
through the N-arylation coupling process.
[g]
[h]
[i]
Prompted by these exciting results, we subsequently
investigated the substrate scope for this tandem cata-
95% of isolated product 3a.
90% of isolated product 3a.
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Scheme 2. Pd(II)-catalyzed C3-arylation and Pd(0)-catalyzed N4-arylation through an assisted tandem process using phos-
phine ligand as a reductive trigger.
lytic process by systematically varying the boronic Conclusions
acids, the aryl halides and the quinoxalin-2(1H)-one
substrates. Gratifyingly, all the tandem C- and N-ary- In conclusion, we successfully developed an efficient
lations proceeded cleanly and selectively in good to and practical catalytic protocol based on Pd(II)- and
excellent yields. As illustrated in Scheme 3, a variety P(0)-catalyzed tandem process for C-3 and N-4 aryla-
of electron-rich and electron-deficient, para- and tion/alkenylation of various quinoxalin-2(1H)-ones
meta-substituted aryl boronic acids effectively under- with arylboronic acids and aryl/alkenyl halides in
go reaction with quinoxalin-2(1H)-one 1a in concert a safe and green water reaction media. The protocol
with bromobenzene in yields up to 95% (products exhibited a broad substrate scope with respect to the
4a-c and 4e-h). In addition, the sterically demanding coupling partners, thus providing an attractive
ortho substitution pattern was tolerated toward method to access a large molecular diversity of 3-aryl-
tandem coupling reaction of 1a, furnishing compound 4-aryl(alkenyl)-dihydroquinoxalin-2(1H)-ones
4d having an ortho methoxy group. Notably, heteroar- biological interest.
ene boronic acids such as thiophen-3-ylboronic acid
4
of
failed in this reaction and starting material 1a was re-
covered unchanged. Interestingly, both bromobenzene Experimental Section
and chlorobenzene reacted well in this tandem cou-
pling providing 4a in good yields (81–84%), whereas General experimental methods
the yield decreased until 59% when iodobenzene was
The compounds were all identified by usual physical meth-
used as a coupling partner.[9]
ods, that is, H NMR, 13C NMR (J-MOD), IR, MS (ESI). H
and 13C NMR spectra were measured in CDCl3 or
[D6]DMSO with either Bruker Avance-300. 1H chemical
shifts are reported in ppm from an internal standard TMS
or of residual chloroform (7.27 ppm). The following abrevia-
tion are used: m (multiplet), s (singlet), bs (broad singlet), d
(doublet), t (triplet) dd (doublet of doublet), td (triplet of
doublet), q (quadruplet), qui (quintuplet), sex (sextuplet).
13C chemical shifts are reported in ppm from the central
peak of deuteriochloroform (77.14). IR spectra were mea-
sured on a Bruker Vector 22 spectrophotometer. MS were
recorded on a Micromass spectrometer. Analytical TLC was
performed on Merck precoated silica gel 60F plates. Merck
silica gel 60 (0,015–0,040 mm) was used for column chroma-
tography. Melting points were recorded on a Bꢅchi B-450
apparatus and are uncorrected.
1
1
As illustrated in Scheme 4, when quinoxalin-2(1H)-
one 1a and phenylboronic acid were used as coupling
partners, various aryl bromides including those having
sensitive functional groups (e.g., esters, enolizable ke-
tones) undergo N-arylation in this tandem catalytic
process in high yields. Aryl bromides containing para
and meta electron-donating or electron-withdrawing
substituents were readily coupled with 1a and phenyl-
boronic acid to give products 4j–q in good to excel-
lent yields. Extending this method to the tandem C3-
arylation and N4-alkenylation of 1a was also success-
ful furnishing the desired dihyquinoxalin-2(1H)-one
4r in a good 81% yield.
Finally, this tandem process was successfully ex-
panded to the coupling of a series of quinoxalin-
2(1H)-ones as well as related heterocycles (e.g., ben-
zo[g]quinoxalin-2(1H)-one) with various arylboronic
acids and aryl/styryl halides (Scheme 5) providing
compounds 4s–z, 4ab and 4ac in yields up to 96%.
General procedure for the tandem reaction between
quinoxalin-2(1H)-ones, arylboronic acids and aryl
halides:
A resealable 2–5 mL Pyrex reaction vessel was charged with
the solid reactant(s): Pd(OAc)2 (5.0 mol%), bipyridine
(7.5 mol%), quinoxalinone 1 (1 equiv) and boronic acid (1.5
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Scheme 3. Scope of boronic acids coupling with quinoxalin-2(1H)-one 1a and phenyl halides under tandem Pd(II) and Pd(0)
catalysis[a]
or 2 equiv). After argon flushing, water (2 mL) was added
and the reaction vessel was sealed with a Teflon screwcap.
The reaction was stirred at 808C for 14 h. Then the ligand
Xphos or P(tBu)3·HBF4 (10 mol%), KOH (4 equiv) and aryl
halide (2 equiv) were added in the reaction mixture and the
reaction was stirred at 1108C for 5 h. The resulting suspen-
sion was cooled to room temperature. Dichloromethane was
added. The organic layer was filtered through celite and
evaporated under reduced pressure. The residue was puri-
fied by flash chromatography over silica gel to afford the de-
sired product.
(91.5 mg, 0.75 mmol) and then phenyl halide (2 equiv) were
mixed (ligand Xphos was added when bromobenzene was
used and P(tBu)3·HBF4 was added when iodo or chloroben-
zene was used in the second half of the tandem procedure).
The residue was purified by flash chromatography over
silica gel (cyclohexane/ethyl acetate 95:5) to afford the de-
sired product 4a (132 mg, 0.42 mmol, 84%) as a pale yellow
solid. Rf 0.37 (cyclohexane/ethyl acetate 90:10); mp 1198C
(recrystallised from isopropyl ether to give white crystals);
1H NMR (300 MHz, CDCl3) d 7.47–7.40 (m, 3H), 7.31–7.26
(m, 5H), 7.18 (d, J=8.1 Hz, 2H), 7.07–6.96 (m, 4H), 5.67 (s,
1H), 3.43 (s, 3H); 13C NMR (75 MHz, CDCl3) d 165.5,
145.3, 136.9, 132.6, 130.9, 129.4 (2C), 128.8 (2C), 128.0, 126.4
(2C), 123.7, 123.0, 121.6, 120.3 (2C), 118.3, 115.9, 65.9, 29.7;
IR (film) n (cmÀ1) 1673, 1590, 1503, 1387; HRMS (ESI+): m/
z calculated for C21H18N2ONa [M+Na]+ 337.1317; found
337.1312.
Analytical Data for substituted quinolin-2(1H)-ones 4
1-Methyl-3,4-diphenyl-3,4-dihydroquinoxalin-2(1H)-one
(4a): Following the general procedure, 1-methylquinoxalin-
2(1H)-one 1a (80 mg, 0.5 mmol), phenylboronic acid
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Scheme 4. Scope of aryl halides coupling with quinoxalin-
2(1H)-one 1a and phenylboronic acid under tandem Pd(II)
and Pd(0) catalysis[a]
3-(4-Methoxyphenyl)-1-methyl-4-phenyl-3,4-dihydroqui-
noxalin-2(1H)-one (4b): Following the general procedure,
1-methylquinoxalin-2(1H)-one 1a (80 mg, 0.5 mmol), 4-me-
thoxyphenylboronic acid (114 mg, 0.75 mmol) and then bro-
mobenzene (110 mL, 2 equiv) were mixed (Xphos ligand was
used). The residue was purified by flash chromatography
over silica gel (cyclohexane/ethyl acetate 90:10 to 80:20) to
afford the desired product 4b (162 mg, 0.47 mmol, 94%) as
a white solid. Rf 0.24 (cyclohexane/ethyl acetate 90:10); mp
1158C (recrystallised from isopropyl ether to give white
Scheme 5. Scope of quinoxalin-2(1H)-ones coupling with
boronic acids and aryl/alkenyl halides under tandem Pd(II)
and Pd(0) catalysis[a]
mixed. The residue was purified by flash chromatography
over silica gel (cyclohexane/ethyl acetate 95:5) to afford the
desired product 4c (123 mg, 0.36 mmol, 71%) as a white
solid. Rf 0.23 (cyclohexane/ethyl acetate 90:10); mp 126–
1278C (recrystallised from isopropyl ether to give white
1
1
crystals); H NMR (300 MHz, CDCl3) d 7.37 (m, 5H), 7.15
crystals); H NMR (300 MHz, CDCl3) d 7.38 (d, J=7.2 Hz,
(d, J=7.8 Hz, 2H), 7.04–6.93 (m, 4H), 6.78 (d, J=8.7 Hz,
2H), 5.57 (s, 1H), 3.72 (s, 3H), 3.41 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 165.8, 159.4, 145.3, 132.7, 130.9, 129.4
(2C), 128.9, 127.6 (2C), 123.7, 123.0, 121.5, 120.3 (2C), 118.2,
115.8, 114.2 (2C), 65.4, 55.3, 29.6; IR (film) n(cmÀ1) 1669,
1505, 1386, 1249; HRMS (ESI+): m/z calculated for
C22H20N2O2Na [M+Na]+ 367.1422; found 367.1434.
3-(3-Methoxyphenyl)-1-methyl-4-phenyl-3,4-dihydroqui-
noxalin-2(1H)-one (4c): Following the general procedure
(Xphos ligand was used), 1-methylquinoxalin-2(1H)-one 1a
(80 mg, 0.5 mmol), 3-methoxyphenylboronic acid (114 mg,
0.75 mmol) and then bromobenzene (110 mL, 2 equiv) were
1H), 7.30–7.25 (m, 2H), 7.17 (d, J=8.1 Hz, 2H), 7.06–6.96
(m, 6H), 6.77 (dd, J=2.7–8.4 Hz, 1H), 5.60 (s, 1H), 3.69 (s,
3H), 3.42 (s, 3H); 13C NMR (75 MHz, CDCl3) d 165.5,
160.0, 145.3, 138.6, 132.8, 131.0, 129.9, 129.5 (2C), 123.8,
123.1, 121.7, 120.4 (2C), 118.7, 118.3, 115.9, 113.8, 111.8,
65.9, 55.3, 29.8; IR (film) n(cmÀ1) 1671, 1584, 1503, 1386;
HRMS (ESI+): m/z calculated for C22H20N2O2Na [M+Na]+
367.1422; found 367.1424.
3-(2-Methoxyphenyl)-1-methyl-4-phenyl-3,4-dihydroqui-
noxalin-2(1H)-one (4d): Following the general procedure, 1-
methylquinoxalin-2(1H)-one 1a (80 mg, 0.5 mmol), 2-me-
thoxyphenylboronic acid (114 mg, 0.75 mmol) and then bro-
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mobenzene (110 mL, 2 equiv) were mixed (Xphos ligand was
used). The residue was purified by flash chromatography
over silica gel (cyclohexane/ethyl acetate 90:10) to afford
the desired product 4d (123 mg, 0.36 mmol, 71%) as a white
solid. Rf 0.16 (cyclohexane/ethyl acetate 90:10); mp 1068C
(recrystallised from isopropyl ether to give white crystals);
1H NMR (300 MHz, CDCl3) d 7.27–7.19 (m, 3H), 7.13–6.89
(m, 9H), 6.72 (t, J=7.5 Hz, 1H), 6.00 (s, 1H), 3.84 (s, 3H),
3.47 (s, 3H); 13C NMR (75 MHz, CDCl3) d 166.2, 156.8,
145.5, 134.0, 131.1, 129.7, 129.3 (2C), 128.0, 127.7, 123.6
(2C), 122.3 (2C), 121.0 (2C), 118.1, 115.2, 111.7, 60.3, 56.0,
29.5; IR (film) n(cmÀ1) 1669, 1586, 1503, 1385, 1249; HRMS
(ESI+): m/z calculated for C22H20N2O2Na [M+Na]+
367.1422; found 367.1420.
3-(Benzo[d][1,3]dioxol-5-yl)-1-methyl-4-phenyl-3,4-dihy-
droquinoxalin-2(1H)-one (4e): Following the general proce-
dure, 1-methylquinoxalin-2(1H)-one 1a (80 mg, 0.5 mmol),
benzo[d][1,3]dioxol-5-ylboronic acid (124.5 mg, 0.75 mmol)
and then bromobenzene (110 mL, 2 equiv) were mixed
(Xphos ligand was used). The residue was purified by flash
chromatography over silica gel (cyclohexane/ethyl acetate
95:5 to 90:10) to afford the desired product 4e (154 mg,
0.43 mmol, 86%) as a white solid. Rf 0.27 (cyclohexane/
ethyl acetate 90:10); mp 1388C (recrystallised from isopro-
pyl ether to give white crystals); 1H NMR (300 MHz,
CDCl3) d 7.36–7.25 (m, 3H), 7.15 (d, J=8.1 Hz, 2H), 7.06–
6.96 (m, 4H), 6.91–6.86 (m, 2H), 6.68 (d, J=8.1 Hz, 1H),
5.89 (s, 2H), 5.52 (s, 1H), 3.43 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 165.5, 148.1, 147.5, 145.3, 132.6, 130.8 (2C), 129.5
(2C), 123.8, 123.1, 121.7, 120.4 (2C), 119.8, 118.3, 115.9,
108.5, 107.1, 101.2, 65.7, 29.7; IR (film) n(cmÀ1) 1669, 1589,
1503, 1388, 1236; HRMS (ESI+): m/z calculated for
C22H19N2O3 [M+H]+ 359.1396; found 359.1400.
1H NMR (300 MHz, CDCl3) d 7.84–7.76 (m, 3H), 7.72–7.69
(m, 1H), 7.61 (dd, J=1.8–8.7 Hz, 1H), 7.48 (d, J=7.8 Hz,
1H), 7.44–7.41 (m, 2H), 7.29 (t, J=8.4 Hz, 2H), 7.21 (d, J=
7.8 Hz, 2H), 7.07–7.02 (m, 2H), 6.98–6.96 (m, 2H), 5.81 (s,
1H), 3.44 (s, 3H); 13C NMR (75 MHz, CDCl3) d 165.5,
145.4, 134.4, 133.3, 133.1, 132.7, 130.9, 129.5 (2C), 128.7,
128.3, 127.7, 126.3, 126.3, 125.5, 124.3, 123.9, 123.1, 121.7,
120.4 (2C), 118.4, 116.0, 66.1, 29.8; IR (film) n(cmÀ1) 1717,
1672, 1504, 1396; HRMS (ESI+): m/z calculated for
C25H20N2ONa [M+Na]+ 387.1473; found 387.1470.
3-(4-Fluorophenyl)-1-methyl-4-phenyl-3,4-dihydroquinox-
alin-2(1H)-one (4h): Following the general procedure, 1-
methylquinoxalin-2(1H)-one 1a (80 mg, 0.5 mmol), 4-fluo-
rophenylboronic acid (140 mg, 1.0 mmol) and then bromo-
benzene (110 mL, 2 equiv) were mixed (Xphos ligand was
used). The residue was purified by flash chromatography
over silica gel (cyclohexane/ethyl acetate 95:5) to afford the
desired product 4h (79.5 mg, 0.24 mmol, 48%) as a white
solid. Rf 0.37 (cyclohexane/ethyl acetate 90:10); mp 1338C
(recrystallised from isopropyl ether to give white crystals);
1H NMR (300 MHz, acetone d-6) d 7.46–7.42 (m, 2H), 7.35–
7.28 (m, 3H), 7.18–7.12 (m, 3H), 7.08–6.98 (m, 5H), 5.61 (s,
1H), 3.40 (s, 3H); 13C NMR (75 MHz, acetone d-6) d 165.6,
163.3 (d, J=243 Hz), 146.3, 134.1 (d, J=3.0 Hz), 132.9,
132.2, 130.3 (2C), 129.2 (2C, d, J=8.3 Hz), 124.3, 123.8,
122.9, 120.8 (2C), 119.4, 116.8, 116.3 (2C, d, J=21 Hz), 66.0,
29.6; IR (film) n(cmÀ1) 1666, 1588, 1503, 1386, 1223; HRMS
(ESI+): m/z calculated for C21H18N2OF [M+H]+ 333.1403;
found 333.1399.
4-(4-Methoxyphenyl)-1-methyl-3-phenyl-3,4-dihydroqui-
noxalin-2(1H)-one (4j): Following the general procedure, 1-
methylquinoxalin-2(1H)-one 1a (80 mg, 0.5 mmol), phenyl-
boronic acid (91.5 mg, 0.75 mmol) and then 1-bromo-4-me-
thoxybenzene (125 mL, 2 equiv) were mixed (P(tBu)3·HBF4
was used as the ligand). The residue was purified by flash
chromatography over silica gel (cyclohexane/ethyl acetate
95:5 to 90:10) to afford the desired product 4j (144 mg,
0.42 mmol, 84%) as a white solid. Rf 0.26 (cyclohexane/
ethyl acetate 90:10); mp 1158C (recrystallised from isopro-
pyl ether to give white crystals); 1H NMR (300 MHz,
CDCl3) d 7.42–7.39 (m, 2H), 7.28–7.25 (m, 3H), 7.16 (d, J=
7.8 Hz, 1H), 7.09 (d, J=8.7 Hz, 2H), 7.02–6.91 (m, 3H),
6.84 (d, J=9.0 Hz, 2H), 5.52 (s, 1H), 3.80 (s, 3H), 3.44 (s,
3H); 13C NMR (75 MHz, CDCl3) d 165.3, 156.2, 138.4,
137.7, 133.9, 130.0, 128.8 (2C), 128.0, 126.6 (2C), 123.8, 123.4
(2C), 120.5, 116.9, 115.6, 114.8 (2C), 66.6, 55.6, 29.7; IR
(film) n(cmÀ1) 1669, 1505, 1388, 1245; HRMS (ESI+): m/z
calculated for C22H20N2O2Na [M+Na]+ 367.1422; found
367.1419.
3-(4-tert-Butylphenyl)-1-methyl-4-phenyl-3,4-dihydroqui-
noxalin-2(1H)-one (4 f): Following the general procedure, 1-
methylquinoxalin-2(1H)-one 1a (80 mg, 0.5 mmol), 4-tert-
butylphenylboronic acid (178 mg, 1.0 mmol) and then bro-
mobenzene (110 mL, 2 equiv) were mixed (Xphos ligand was
used). The residue was purified by flash chromatography
over silica gel (cyclohexane/ethyl acetate 95:5 to 90:10) to
afford the desired product 4 f (155 mg, 0.42 mmol, 84%) as
a white solid. Rf 0.45 (cyclohexane/ethyl acetate 90:10); mp
2138C (recrystallised from isopropyl ether to give white
1
crystals); H NMR (300 MHz, CDCl3) d 7.39 (d, J=7.8 Hz,
1H), 7.33 (d, J=8.7 Hz, 2H), 7.30–7.25 (m, 4H), 7.16 (d, J=
7.8 Hz, 2H), 7.05–6.96 (m, 4H), 5.60 (s, 1H), 3.42 (s, 3H),
1.26 (s, 9H); 13C NMR (75 MHz, CDCl3) d 165.7, 150.9,
145.5, 133.9, 132.8, 131.0, 129.4 (2C), 126.0 (2C), 125.8 (2C),
123.7, 122.9, 121.5, 120.3 (2C), 118.3, 115.9, 65.7, 34.6, 31.4
(3C), 29.7; IR (film) n(cmÀ1) 1676, 1589, 1503, 1386; HRMS
(ESI+): m/z calculated for C25H26N2ONa [M+Na]+
393.1943; found 393.1930.
1-Methyl-3-(naphthalen-2-yl)-4-phenyl-3,4-dihydroquinox-
alin-2(1H)-one (4g): Following the general procedure, 1-
methylquinoxalin-2(1H)-one 1a (80 mg, 0.5 mmol), 2-naph-
tylboronic acid (129 mg, 0.75 mmol) and then bromoben-
zene (110 mL, 2 equiv) were mixed (Xphos ligand was used).
The residue was purified by flash chromatography over
silica gel (cyclohexane/ethyl acetate 95:5) to afford the de-
sired product 4g (141 mg, 0.39 mmol, 77%) as a white solid.
Rf 0.35 (cyclohexane/ethyl acetate 90:10); mp 120–1218C
(recrystallised from isopropyl ether to give white crystals);
4-(3-Methoxyphenyl)-1-methyl-3-phenyl-3,4-dihydroqui-
noxalin-2(1H)-one (4k): Following the general procedure,
1-methylquinoxalin-2(1H)-one 1a (80 mg, 0.5 mmol), phe-
nylboronic acid (91.5 mg, 0.75 mmol) and then 1-chloro-3-
methoxybenzene
(123 mL,
2 equiv)
were
mixed
(P(tBu)3·HBF4 was used as the ligand). The residue was pu-
rified by flash chromatography over silica gel (cyclohexane/
ethyl acetate 95:5 to 90:10) to afford the desired product 4k
(137 mg, 0.40 mmol, 80%) as a white solid. Rf 0.26 (cyclo-
hexane/ethyl acetate 90:10); mp 105–1068C (recrystallised
from isopropyl ether to give white crystals); 1H NMR
(300 MHz, CDCl3) d 7.42–7.37 (m, 3H), 7.31–7.23 (m, 4H),
7.14 (dd, J=2.1–7.2 HZ, 1H), 7.01–6.97 (m, 2H), 6.79–6.71
6
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ÝÝ
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FULL PAPERS
Assisted Tandem Pd(II)/Pd(0)-Catalyzed C- and N-Arylations
(m, 2H), 6.64 (dd, J=2.4–8.4 Hz, 1H), 5.61 (s, 1H), 3.73 (s,
3H), 3.42 (s, 3H); 13C NMR (75 MHz, acetone d-6) d 165.7,
161.6, 147.6, 138.0, 132.9, 132.2, 131.0, 129.4 (2C), 128.7,
127.1 (2C), 124.2, 122.8, 119.7, 116.7, 113.0, 108.9, 106.8,
66.5, 55.5, 29.6; IR (film) n(cmÀ1) 1673, 1591, 1504, 1386,
1208; HRMS (ESI+): m/z calculated for C22H20N2O2Na [M+
Na]+ 367.1422; found 367.1421.
124.4, 124.3, 121.1, 118.6 (2C), 117.1, 65.9, 29.7, 26.4; IR
(film) n(cmÀ1) 1674, 1587, 1510, 1386, 1266; HRMS (ESI+):
m/z calculated for C23H21N2O2 [M+H]+ 357.1603; found
357.1599.
tert-Butyl 3-(4-methyl-3-oxo-2-phenyl-3,4-dihydroquinoxa-
lin-1(2H)-yl)benzoate (4o): Following the general proce-
dure, 1-methylquinoxalin-2(1H)-one 1a (80 mg, 0.5 mmol),
phenylboronic acid (91.5 mg, 0.75 mmol) and then tert-butyl
4-(4-(Dimethylamino)phenyl)-1-methyl-3-phenyl-3,4-dihy-
droquinoxalin-2(1H)-one (4l): Following the general proce-
dure, 1-methylquinoxalin-2(1H)-one 1a (80 mg, 0.5 mmol),
phenylboronic acid (91.5 mg, 0.75 mmol) and then 4-bromo-
N,N-dimethylaniline (201 mg, 2 equiv) were mixed
(P(tBu)3·HBF4 was used as the ligand). The residue was pu-
rified by flash chromatography over silica gel (cyclohexane/
ethyl acetate 90:10 to 85:15) to afford the desired product
4l (108 mg, 0.30 mmol, 60%) as a pale yellow solid. Rf 0.17
(cyclohexane/ethyl acetate 90:10); mp 149–1508C (recrystal-
lised from isopropyl ether to give off-white crystals);
1H NMR (300 MHz, acetone d-6) d 7.37–7.34 (m, 2H), 7.30–
7.24 (m, 3H), 7.10–7.07 (m, 1H), 7.01–6.85 (m, 5H), 6.72 (d,
J=9.0 Hz, 2H), 5.37 (s, 1H), 3.40 (s, 3H), 2.91 (s, 6H);
13C NMR (75 MHz, acetone d-6) d 165.3, 149.0, 139.5,
135.42, 135.36, 130.8, 129.4 (2C), 128.7, 127.5 (2C), 124.8
(2C), 124.2, 120.8, 117.0, 116.3, 114.2 (2C), 67.7, 40.9 (2C),
29.5; IR (film) n(cmÀ1) 1670, 1518, 1389; HRMS (ESI+): m/z
calculated for C23H24N3O [M+H]+ 358.1919; found
358.1919.
3-chlorobenzoate
(212.5 mg,
2 equiv)
were
mixed
(P(tBu)3·HBF4 was used as the ligand). The residue was pu-
rified by flash chromatography over silica gel (cyclohexane/
ethyl acetate 95:5 to 90:10) to afford the desired product 4o
(111 mg, 0.27 mmol, 54%) as a white solid. Rf 0.29 (cyclo-
hexane/ethyl acetate 90:10); mp 1598C (recrystallised from
isopropyl ether to give off-white crystals); 1H NMR
(300 MHz, acetone d-6) d 7.79–7.78 (m, 1H), 7.64–7.61 (m,
1H), 7.45–7.35 (m, 5H), 7.33–7.26 (m, 3H), 7.18–7.15 (m,
1H), 7.07–7.03 (m, 2H), 5.64 (s, 1H), 3.42 (s, 3H), 1.52 (s,
9H); 13C NMR (75 MHz, acetone d-6) d 165.63, 165.59,
146.5, 137.8, 134.2, 132.7, 132.4, 130.3, 129.6 (2C), 128.9,
127.1 (2C), 124.7, 124.3, 124.2, 123.3, 121.2, 119.4, 116.9,
81.5, 66.5, 29.6, 28.2 (3C); IR (film) n(cmÀ1) 1712, 1674,
1504, 1388, 1303; HRMS (ESI+): m/z calculated for
C26H26N2O3Na [M+Na]+ 437.1841; found 437.1843.
1-Methyl-4-(naphthalen-2-yl)-3-phenyl-3,4-dihydroquinox-
alin-2(1H)-one (4p): Following the general procedure, 1-
methylquinoxalin-2(1H)-one 1a (80 mg, 0.5 mmol), phenyl-
boronic acid (91.5 mg, 0.75 mmol) and then 2-bromo-naph-
talene (207 mg, 2 equiv) were mixed (P(tBu)3·HBF4 was
used as the ligand). The residue was purified by flash chro-
matography over silica gel (cyclohexane/ethyl acetate 95:5
to 90:10) to afford the desired product 4p (148.5 mg,
0.41 mmol, 82%) as a white solid. Rf 0.30 (cyclohexane/
ethyl acetate 90:10); mp 1688C (recrystallised from isopro-
pyl ether to give white crystals); 1H NMR (300 MHz,
CDCl3) d 7.80–7.75 (m, 2H), 7.63 (d, J=7.5 Hz, 1H), 7.55–
7.47 (m, 3H), 7.45–7.29 (m, 7H), 7.09–7.00 (m, 3H), 5.84 (s,
1H), 3.46 (s, 3H); 13C NMR (75 MHz, CDCl3) d 165.5,
142.9, 136.7, 134.5, 132.4, 131.0, 129.0, 128.9 (2C), 128.1,
127.7, 127.1, 126.7, 126.4 (2C), 124.7, 123.8, 121.9, 121.1,
118.4, 115.9, 115.8, 66.1, 29.7; IR (film) n(cmÀ1) 1673, 1505,
1391; HRMS (ESI+): m/z calculated for C25H20N2ONa [M+
Na]+ 387.1473; found 387.1474.
4-(4-Fluorophenyl)-1-methyl-3-phenyl-3,4-dihydroquinox-
alin-2(1H)-one (4m): Following the general procedure, 1-
methylquinoxalin-2(1H)-one 1a (80 mg, 0.5 mmol), phenyl-
boronic acid (91.5 mg, 0.75 mmol) and then 1-bromo-4-fluo-
robenzene (110 mL, 2 equiv) were mixed (P(tBu)3·HBF4 was
used as the ligand). The residue was purified by flash chro-
matography over silica gel (cyclohexane/ethyl acetate 95:5)
to afford the desired product 4m (100 mg, 0.30 mmol, 60%)
as a white solid. Rf 0.33 (cyclohexane/ethyl acetate 90:10);
mp 127–1288C (recrystallised from isopropyl ether to give
1
white crystals); H NMR (300 MHz, CDCl3) d 8.42 (m, 2H),
7.89 (d, J=8.1 Hz, 1H), 7.56–7.51 (m, 1H), 7.37–7.27 (m,
2H), 7.13 (t, J=8.7 Hz, 2H), 3.72 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 164.2 (d, J=250 Hz), 154.7, 152.6, 133.3,
133.0, 132.2, 132.0, 131.9, 130.4 (2C), 123.8, 115.1 (2C, d, J=
22.8 Hz), 113.6, 29.3; 19F NMR (188 MHz, CDCl3) d À119.6;
IR (film) n(cmÀ1) 1670, 1504, 1387, 1218; HRMS (ESI+): m/
z calculated for C21H17N2OFNa [M+Na]+ 355.1223; found
355.1227.
1-Methyl-3-phenyl-4-(4-(trifluoromethyl)phenyl)-3,4-dihy-
droquinoxalin-2(1H)-one (4q): Following the general proce-
dure, 1-methylquinoxalin-2(1H)-one 1a (80 mg, 0.5 mmol),
phenylboronic acid (91.5 mg, 0.75 mmol) and then 1-bromo-
4-(trifluoromethyl)benzene (140 mL, 2 equiv) were mixed
(P(tBu)3·HBF4 was used as the ligand). The residue was pu-
rified by flash chromatography over silica gel (cyclohexane/
ethyl acetate 95:5) to afford the desired product 4q (160 mg,
0.42 mmol, 84%) as a white solid. mp 1288C (recrystallised
from isopropyl ether to give white crystals); Rf 0.34 (cyclo-
4-(4-Acetylphenyl)-1-methyl-3-phenyl-3,4-dihydroquinox-
alin-2(1H)-one (4n): Following the general procedure, 1-
methylquinoxalin-2(1H)-one 1a (80 mg, 0.5 mmol), phenyl-
boronic acid (91.5 mg, 0.75 mmol) and then 4’-bromoaceto-
phenone (123 mL, 2 equiv) were mixed (P(tBu)3·HBF4 was
used as the ligand). The residue was purified by flash chro-
matography over silica gel (cyclohexane/ethyl acetate 95:5
to 90:10) to afford the desired product 4n (130 mg,
0.36 mmol, 73%) as a pale yellow solid. Rf 0.11 (cyclohex-
ane/ethyl acetate 90:10); mp 144–1458C (recrystallised from
1
hexane/ethyl acetate 90:10); H NMR (400 MHz, acetone d-
6) d 7.64 (d, J=8.8 Hz, 2H), 7.54–7.51 (m, 1H), 7.42 (d, J=
7.2 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.32–7.24 (m, 3H),
7.20–7.18 (m, 1H), 7.11–7.07 (m, 2H), 5.76 (s, 1H), 3.43 (s,
3H); 13C NMR (75 MHz, acetone d-6) d 165.8, 149.8, 136.9,
133.1, 131.5, 129.6 (2C), 128.9, 127.5 (q, J=3.50 Hz), 127.0
(2C), 124.4 (2C), 123.8 (q, J=32 Hz), 120.8, 119.5 (2C),
117.1, 66.0, 29.6; 19F NMR (188 MHz, acetone d-6) d À60.3;
IR (film) n(cmÀ1) 1672, 1503, 1326, 1268, 1106, 1067; HRMS
1
isopropyl ether to give white crystals); H NMR (300 MHz,
acetone d-6) d 7.95 (d, J=8.7 Hz, 2H), 7.54–7.51 (m, 1H),
7.44–7.41 (m, 2H), 7.32–7.26 (m, 5H), 7.21–7.17 (m, 1H),
7.12–7.08 (m, 2H), 5.78 (s, 1H), 3.43 (s, 3H), 2.51 (s, 3H);
13C NMR (75 MHz, acetone d-6) d 196.0, 165.8, 150.3, 136.9,
133.1, 132.0, 131.4, 130.9 (2C), 129.6 (2C), 128.9, 127.0 (2C),
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
7
ÞÞ
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FULL PAPERS
Amandine Carrꢀr et al.
(ESI+): m/z calculated for C22H18N2OF3 [M+H]+ 383.1371;
found 383.1371.
calculated for C24H21N2OF3Na [M+Na]+ 433.1504; found
433.1498.
(E)-1-Methyl-3-phenyl-4-styryl-3,4-dihydroquinoxalin-
2(1H)-one (4r): Following the general procedure, 1-methyl-
quinoxalin-2(1H)-one 1a (80 mg, 0.5 mmol), phenylboronic
acid (91.5 mg, 0.75 mmol) and then bromostyrene (129 mL,
2 equiv) were mixed (P(tBu)3·HBF4 was used as the ligand).
The residue was purified by flash chromatography over
silica gel (cyclohexane/ethyl acetate 95:5) to afford the de-
sired product 4r (138 mg, 0.41 mmol, 81%) as a pale yellow
solid. Rf 0.33 (Cyclohexane/ethyl acetate 90:10); mp 1588C
(recrystallised from isopropyl ether to give pale yellow crys-
tals); 1H NMR (300 MHz, acetone d-6) d 7.59 (d, J=
14.4 Hz, 1H), 7.40–7.34 (m, 5H), 7.31–7.05 (m, 9H), 5.97 (d,
J=14.4 Hz, 1H), 5.77 (s, 1H), 3.41 (s, 3H); 13C NMR
(75 MHz, acetone d-6) d 164.9, 138.7, 137.0, 132.4, 131.2
(2C), 130.8, 129.5 (2C), 129.3 (2C), 128.8, 127.1 (2C), 126.1,
125.8 (2C), 124.9, 122.9, 117.3, 116.2, 107.7, 63.1, 29.5; IR
(film) n(cmÀ1) 1673, 1639, 1594, 1509, 1394; HRMS (ESI+):
m/z calculated for C23H20N2ONa [M+Na]+ 363.1473; found
363.1471.
3-(Benzo[d][1,3]dioxol-5-yl)-1-methyl-4-(4-nitrophenyl)-
3,4-dihydroquinoxalin-2(1H)-one (4u): Following the gener-
al procedure, 1-methylquinoxalin-2(1H)-one 1a (80 mg,
0.5 mmol), benzo[d][1,3]dioxol-5-ylboronic acid (124.5 mg,
0.75 mmol) and then 1-bromo-4-nitrobenzene (202 mg,
2 equiv) were mixed (P(tBu)3·HBF4 was used as the ligand).
The residue was purified by flash chromatography over
silica gel (cyclohexane/ethyl acetate 90:10 to 80:20) to
afford the desired product 4u (185 mg, 0.46 mmol, 92%) as
a yellow solid. Rf 0.13 (cyclohexane/ethyl acetate 90:10); mp
211–2128C (recrystallised from ethyl acetate to give yellow
crystals); 1H NMR (300 MHz, acetone d-6) d 8.20 (d, J=
9.0 Hz, 2H), 7.60 (dd, J=1.8–7.5 Hz, 1H), 7.38 (d, J=
9.0 Hz, 2H), 7.28–7.11 (m, 3H), 6.89–6.87 (m, 2H), 6.76 (d,
J=8.7 Hz, 1H), 5.96 (s, 2H), 5.77 (s, 1H), 3.45 (s, 3H);
13C NMR (75 MHz, acetone d-6) d 165.8, 152.0, 149.2, 148.6,
142.4, 133.5, 130.4, 129.8, 126.4 (2C), 125.5, 124.5, 121.8,
120.4, 118.6 (2C), 117.3, 109.2, 107.3, 102.4, 65.6, 29.7; IR
(film) n(cmÀ1) 1675, 1584, 1503, 1325, 1240; HRMS (ESI+):
m/z calculated for C22H18N3O5 [M+H]+ 404.1246; found
404.1242.
4-(4-Acetylphenyl)-3-(4-tert-butylphenyl)-1-methyl-3,4-di-
hydroquinoxalin-2(1H)-one (4s): Following the general pro-
cedure,
0.5 mmol),
1-methylquinoxalin-2(1H)-one
1a
acid
(80 mg,
(178 mg,
2-Fluoro-4-(4-methyl-3-oxo-2-(3,4,5-trimethoxyphenyl)-
3,4-dihydroquinoxalin-1(2H)-yl)benzaldehyde (4v): Follow-
ing the general procedure, 1-methylquinoxalin-2(1H)-one
1a (80 mg, 0.5 mmol), 3,4,5-trimethoxyphenylboronic acid
(178 mg, 1.00 mmol) and then 1-bromo-4-methoxybenzene
(125 mL, 2 equiv) were mixed (P(tBu)3·HBF4 was used as the
ligand). The residue was purified by flash chromatography
over silica gel (cyclohexane/ethyl acetate 80:20) to afford
the desired product 4v (183 mg, 0.38 mmol, 77%) as a white
solid. Rf 0.10 (cyclohexane/ethyl acetate 80:20); mp 1968C
(recrystallised from ethyl acetate to give pale yellow crys-
4-tert-butylphenylboronic
1.00 mmol) and then 4’-bromoacetophenone (123 mL,
2 equiv) were mixed (P(tBu)3·HBF4 was used as the ligand).
The residue was purified by flash chromatography over
silica gel (cyclohexane/ethyl acetate 90:10 to 85:15) to
afford the desired product 4s (103 mg, 0.25 mmol, 50%) as
a yellow solid. Rf 0.16 (cyclohexane/ethyl acetate 90:10); mp
2208C (recrystallised from isopropyl ether to give pale
1
yellow crystals); H NMR (300 MHz, acetone d-6) d 7.94 (d,
J=8.7 Hz, 2H), 7.54–7.51 (m, 1H), 7.34 (s, 4H), 7.26 (d, J=
8.7 Hz, 2H), 7.20–7.17 (m, 1H), 7.11–7.08 (m, 2H), 5.73 (s,
1H), 3.42 (s, 3H), 2.51 (s, 3H), 1.25 (s, 9H); 13C NMR
(75 MHz, acetone d-6) d 196.0, 165.9, 151.7, 150.3, 133.8,
133.1, 131.9, 131.5, 130.9 (2C), 126.8 (2C), 126.5 (2C),
124.35, 124.3, 121.0, 118.6 (2C), 117.1, 65.7, 35.0, 31.5 (3C),
29.6, 26.4; IR (film) n(cmÀ1) 1672, 1586, 1504, 1419, 1264;
HRMS (ESI+): m/z calculated for C27H28N2O2Na [M+Na]+
435.2048; found 435.2047.
3-(3,5-Dimethylphenyl)-1-methyl-4-(4-(trifluoromethyl)-
phenyl)-3,4-dihydroquinoxalin-2(1H)-one (4t): Following
the general procedure, 1-methylquinoxalin-2(1H)-one 1a
(80 mg, 0.5 mmol), 3,5-dimethylphenylboronic acid (150 mg,
1.00 mmol) and then 1-bromo-4-trifluoromethylbenzene
(140 mL, 2 equiv) were mixed (P(tBu)3·HBF4 was used as the
ligand). The residue was purified by flash chromatography
over silica gel (cyclohexane/ethyl acetate 95:5 to 90:10) to
afford the desired product 4t (163 mg, 0.40 mmol, 79%) as
a white solid. Rf 0.39 (cyclohexane/ethyl acetate 90:10); mp
2098C (recrystallised from isopropyl ether to give white
crystals); 1H NMR (300 MHz, acetone d-6) d 7.63 (d, J=
8.7 Hz, 2H), 7.54–7.50 (m, 1H), 7.35 (d, J=8.7 Hz, 2H),
7.20–7.16 (m, 1H), 7.12–7.06 (m, 1H), 7.03 (s, 2H), 6.89 (s,
1H), 5.67 (s, 1H), 3.42 (s, 3H), 2.18 (s, 6H); 13C NMR
(75 MHz, acetone d-6) d 165.8, 149.8, 139.1 (2C), 136.8,
133.2, 131.6, 130.4, 127.5 (2C, q, J=3.6 Hz), 125.5 (q, J=
254 Hz), 124.7 (2C), 124.33, 124.32, 123.7 (q, J=32 Hz),
120.7, 119.4 (2C), 117.1, 65.9, 29.6, 21.4 (2C); IR (film)
n(cmÀ1) 1677, 1504, 1386, 1326, 1118; HRMS (ESI+): m/z
1
tals); H NMR (300 MHz, DMSO d-6) d 10.05 (s, 1H), 7.76
(t, J=8.4 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.28 (d, J=
7.8 Hz, 1H), 7.23–7.12 (m, 3H), 7.07–7.03 (m, 1H), 6.56 (s,
2H), 5.89 (s, 1H), 3.61 (s, 6H), 3.59 (s, 3H), 3.37 (s, 3H);
13C NMR (75 MHz, [D6]DMSO) d 185.6 (d, J=3.75 Hz),
165.0, 164.8 (d, J=255 Hz), 153.0 (2C), 151.9 (d, J=12 Hz),
137.2, 132.2, 130.7 (d, J=3 Hz), 130.1, 129.0, 124.9, 123.7,
121.3, 117.3 (d, J=9 Hz), 116.8, 113.7, 104.2 (d, J=25 Hz),
103.2 (2C), 63.8, 59.9, 55.7 (2C), 29.3; IR (film) n(cmÀ1)
1683, 1616, 1507, 1384; HRMS (ESI+): m/z calculated for
C25H23N2O5FNa [M+Na]+ 473.1489; found 473.1491.
Ethyl 2-(3-(6-methoxynaphthalen-2-yl)-4-(4-methoxyphen-
yl)-2-oxo-3,4-dihydroquinoxalin-1(2H)-yl)acetate (4w): Fol-
lowing the general procedure, ethyl 2-(2-oxoquinoxalin-
1(2H)-yl)acetate 1b (116 mg, 0.5 mmol), 6-methoxynaphtha-
len-2-ylboronic acid (151.5 mg, 0.75 mmol) and then 1-
bromo-4-methoxybenzene (125 mL, 2 equiv) were mixed
(P(tBu)3·HBF4 was used as the ligand). The residue was pu-
rified by flash chromatography over silica gel (cyclohexane/
ethyl acetate 90:10 to 85:15) to afford the desired product
4w pure at 86% (180 mg, 0.31 mmol, 61%) as a yellow
solid. Rf 0.13 (cyclohexane/ethyl acetate 90:10), 1H NMR
(300 MHz, CDCl3) d 7.79 (s, 1H), 7.73 (d, J=8.7 Hz, 1H),
7.66 (d, J=8.7 Hz, 1H), 7.51 (dd, J=1.8–8.7 Hz, 1H), 7.24
(d, J=2.7 Hz, 1H), 7.17–7.08 (m, 4H), 7.01–6.86 (m, 5H),
5.62 (s, 1H), 5.98 (d, J=17.5 Hz, 1H), 4.65 (d, J=17.5 Hz,
1H), 4.13 (q, J=7.2 Hz, 2H), 3.88 (s, 3H), 3.77 (s, 3H), 1.13
(t, J=7.2 Hz, 3H); 13C NMR (75 MHz, [D6]acetone) d
8
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Assisted Tandem Pd(II)/Pd(0)-Catalyzed C- and N-Arylations
168.9, 166.0, 159.0, 157.4, 139.6, 135.3, 134.8, 133.5, 130.9,
130.3, 129.5, 128.1, 126.7, 126.1, 124.7 (2C), 124.6, 121.8,
119.9, 118.7, 116.3, 115.6 (2C), 106.5, 67.5, 61.8, 55.8, 55.7,
44.8, 14.4; IR (film) n(cmÀ1) 1752, 1672, 1509, 1393, 1266,
1245; HRMS (ESI+): m/z calculated for C25H17N2O [M+
H]+ 497.2071; found 497.2063.
1-Benzyl-3-(4-tert-butylphenyl)-4-(4-methoxyphenyl)-3,4-
dihydroquinoxalin-2(1H)-one (4x): Following the general
procedure, 1-benzylquinoxalin-2(1H)-one 1c (118 mg,
1H NMR (300 MHz, [D6]acetone) d 7.90–7.80 (m, 4H),
7.62–7.59 (m, 1H), 7.52–7.45 (m, 2H), 7.28 (t, J=8.1 HZ,
1H), 7.19–7.11 (m, 2H), 6.87–6.70 (m, 4H), 5.78 (s, 1H),
3.73 (s, 3H), 3.44 (s, 3H); 13C NMR (75 MHz, [D6]acetone)
d 165.1, 161.5, 160.1 (d, J=259 Hz), 146.9, 135.5 (2C), 135.0
(d, J=10 Hz), 134.2, 134.0, 131.3, 129.5, 128.9, 128.5, 127.3,
127.2, 126.3, 125.1, 117.9 (d, J=10 Hz), 114.1, 110.1, 108.6
(d, J=23 Hz), 107.9, 105.9 (d, J=27 Hz), 66.8, 55.6, 30.1; IR
(film) n(cmÀ1) 1677, 1599, 1512, 1394, 1214; HRMS (ESI+):
m/z calculated for C26H21N2O2FNa [M+Na]+ 435.1485;
found 435.1490.
6-Fluoro-1-(4-methoxybenzyl)-3-phenyl-4-p-tolyl-3,4-dihy-
droquinoxalin-2(1H)-one (4ab): Following the general pro-
cedure, 6-fluoro-1-(4-methoxybenzyl)quinoxalin-2(1H)-one
1e (142 mg, 0.5 mmol), phenylboronic acid (91.5 mg,
0.75 mmol) and then 1-bromo-4-methylbenzene (123 mL,
2 equiv) were mixed (P(tBu)3·HBF4 was used as the ligand).
The residue was purified by flash chromatography over
silica gel (cyclohexane/ethyl acetate 95:5) to afford the de-
sired product 4ab (159 mg, 0.35 mmol, 70%) as a white
solid. Rf 0.35 (cyclohexane/ethyl acetate 90:10); mp 2038C
(recrystallised from isopropyl ether to give white crystals);
1H NMR (300 MHz, [D6]acetone) d 7.46–7.43 (m, 2H),
7.37–7.31 (m, 3H), 7.20 (d, J=8.4 Hz, 2H), 7.13–7.08 (m,
4H), 7.01 (dd, J=5.4–9.0 Hz, 1H), 6.91 (dd, J=2.7–10.5 Hz,
1H), 6.79 (d, J=8.4 Hz, 2H), 6.57 (td, J=3.0–8.4 Hz, 1H),
5.63 (s, 1H), 5.34 (d, J=15.9 Hz, 1H), 5.05 (d, J=15.9 Hz,
1H), 3.74 (s, 3H), 2.32 (s, 3H); 13C NMR (75 MHz,
[D6]acetone) d 165.1, 160.0 (d, J=239 Hz), 159.9, 143.1,
138.1, 135.9 (d, J=10 Hz), 134.6, 131.0 (2C), 129.6 (2C),
129.0, 128.7 (2C), 127.2 (2C), 127.1, 122.4 (2C), 118.5 (d, J=
10 Hz), 114.9 (2C), 107.9 (d, J=23 Hz), 105.1 (d, J=26 Hz),
67.0, 55.5, 45.6, 20.8; 19F NMR (188 MHz, CDCl3) d À118.3;
IR (film) n(cmÀ1) 1669, 1512, 1248; HRMS (ESI+): m/z cal-
culated for C29H25N2O2FNa [M+Na]+ 475.1798; found
475.1808.
(E)-3-(4-Methoxyphenyl)-1-methyl-4-styryl-3,4-dihydro-
benzo[g]quinoxalin-2(1H)-one 4ac: Following the general
procedure, 1-methyl-3,4-dihydrobenzo[g]quinoxalin-2(1H)-
one 1 f (105 mg, 0.5 mmol), 4-methoxyphenylboronic acid
(114 mg, 0.75 mmol) and then bromostyrene (129 mL,
2 equiv) were mixed (P(tBu)3·HBF4 was used as the ligand).
The residue was purified by flash chromatography over
silica gel (cyclohexane/ethyl acetate 95:5 to 90:10) to afford
the desired product 4ac (136 mg, 0.32 mmol, 65%) as
a yellow oil, Rf 0.17 (cyclohexane/ethyl acetate 90:10),
1H NMR (300 MHz, [D6]acetone) d 7.87–7.80 (m, 2H), 7.73
(s, 1H), 7.69 (d, J=14.1 Hz, 1H), 7.55 (s, 1H), 7.43–7.23 (m,
8H), 7.13–7.08 (m, 1H), 6.80 (d, J=8.7 Hz, 2H), 6.04 (d, J=
14.1 Hz, 1H), 5.75 (s, 1H), 3.68 (s, 3H), 3.50 (s, 3H);
13C NMR (75 MHz, [D6]acetone) d 165.9, 160.5, 138.7, 132.6,
131.9, 131.5, 131.1, 130.6, 129.4 (2C), 129.1, 128.5 (2C),
128.1, 127.3, 126.3 (2C), 126.0 (2C), 125.4, 115.0 (2C),
112.93, 112.89, 109.0, 62.8, 55.5, 29.8; IR (film) n(cmÀ1) 1678,
1599, 1511, 1481, 1250; HRMS (ESI+): m/z calculated for
C26H21N2O2FNa [M+Na]+ 421.19011; found 421.1909.
0.5 mmol),
4-tert-butylphenylboronic
acid
(178 mg,
1.00 mmol) and then 1-bromo-4-methoxybenzene (125 mL,
2 equiv) were mixed (P(tBu)3·HBF4 was used as the ligand).
The residue was purified by flash chromatography over
silica gel (cyclohexane/ethyl acetate 95:5) to afford the de-
sired product 4x (183 mg, 0.38 mmol, 77%) as a white solid.
Rf 0.40 (cyclohexane/ethyl acetate 90:10); mp 808C (recrys-
tallised from isopropyl ether to give white crystals);
1H NMR (300 MHz, CDCl3) d 7.37–7.28 (m, 4H), 7.19–7.12
(m, 6H), 7.02–6.99 (m, 2H), 6.95–6.90 (m, 1H), 6.86–6.75
(m, 4H), 5.59 (s, 1H), 5.54 (d, J=16.2 Hz, 1H), 4.90 (d, J=
16.2 Hz, 1H), 3.80 (s, 3H), 1.29 (s, 9H), 13C NMR (75 MHz,
CDCl3) d 165.3, 156.2, 151.1, 138.7, 136.7, 134.2, 134.1, 129.4,
128.8 (2C), 127.2, 126.3 (2C), 126.2 (2C), 125.8 (2C), 123.8,
123.4 (2C), 120.5, 117.1, 116.3, 114.8 (2C), 66.4, 55.7, 45.9,
34.7, 31.4 (3C); IR (film) n(cmÀ1) 1676, 1509, 1395, 1244;
HRMS (ESI+): m/z calculated for C32H32N2O2Na [M+Na]+
499.2361; found 499.2358.
3-(2,5-Dimethylphenyl)-6-fluoro-1-methyl-4-(4-(trifluoro-
methyl)phenyl)-3,4-dihydroquinoxalin-2(1H)-one (4y): Fol-
lowing the general procedure, 6-fluoro-1-methylquinoxalin-
2(1H)-one 1d (89 mg, 0.5 mmol), 2,5-dimethylphenylboronic
acid (150 mg, 1.0 mmol) and then 1-bromo-4-trifluorome-
thylbenzene (140 mL, 2 equiv) were mixed (P(tBu)3·HBF4
was used as the ligand). The residue was purified by flash
chromatography over silica gel (cyclohexane/ethyl acetate
95:5 to 90:10) to afford the desired product 4y (205 mg,
0.48 mmol, 96%) as a white solid. Rf 0.29 (cyclohexane/
ethyl acetate 90:10); mp 152–1538C (recrystallised from iso-
propyl ether to give white crystals); 1H NMR (300 MHz,
[D6]acetone) d 7.67 (d, J=8.7 Hz, 2H), 7.33–7.25 (m, 3H),
7.14 (d, J=7.8 Hz, 1H), 7.01–6.96 (m, 2H), 6.90–6.83 (m,
2H), 5.79 (s, 1H), 3.41 (s, 3H), 2.61 (s, 3H), 2.05 (s, 3H);
13C NMR (75 MHz, [D6]acetone) d 165.3, 160.0 (d, J=
239 Hz), 148.9, 137.8, 136.5, 135.0 (d, J=10 Hz), 134.2,
132.2, 129.8, 127.6 (q, J=3.6 Hz), 127.4, 125.6 (q, J=33 Hz),
125.5 (q, J=288 Hz), 122.2 (2C), 118.0 (d, J=10 Hz), 109.1
(d, J=23 Hz), 105.3 (d, J=27 Hz), 63.5, 29.8, 21.1, 19.9;
19F NMR (188 MHz, CDCl3) d À60.6, À118.1; IR (film)
n(cmÀ1) 1675, 1606, 1517, 1327, 1115; HRMS (ESI+): m/z
calculated for C24H20N2OF4Na [M+Na]+ 451.1409; found
451.1410.
6-Fluoro-4-(3-methoxyphenyl)-1-methyl-3-(naphthalen-2-
yl)-3,4-dihydroquinoxalin-2(1H)-one (4z): Following the
general procedure, 6-fluoro-1-methylquinoxalin-2(1H)-one
1d (89 mg, 0.5 mmol), naphthalen-2-ylboronic acid (129 mg,
0.75 mmol) and then 1-chloro-3-methoxybenzene (123 mL,
2 equiv) were mixed (P(tBu)3·HBF4 was used as the ligand).
The residue was purified by flash chromatography over
silica gel (cyclohexane/ethyl acetate 95:5 to 90:10) to afford Acknowledgements
the desired product 4z (172 mg, 0.42 mmol, 83%) as a white
solid. Rf 0.22 (cyclohexane/ethyl acetate 90:10); mp 2038C
(recrystallised from isopropyl ether to give white crystals);
The CNRS is gratefully acknowledged for financial support
of this research. Our laboratory BioCIS-UMR 8076 is
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FULL PAPERS
Amandine Carrꢀr et al.
a member of the laboratory of Excellence LERMIT support-
ed by a grant from ANR (ANR-10-LABX-33). The ANR is
also acknowledged for the Postdoctoral fellowship to A.C.
Int. Ed. 2012, 51, 11522–11526; b) A. Heutling, F. Pohlki,
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c) A. N. Thadani, V. H. Rawal, Org. Lett. 2002, 4, 4317–
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10
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FULL PAPERS
Assisted Tandem Palladium(II)/Palladium(0)-Catalyzed C-
11
and N-Arylations of Quinoxalin-2(1H)-ones in Water
Adv. Synth. Catal. 2014, 356, 1 – 11
Amandine Carrꢀr, Jean-Daniel Brion, Mouad Alami,*
Samir Messaoudi*
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!