An efficient domino synthesis of quinoxalin-2(1H)-ones via an S NAr/coupling/demesylation reaction catalyzed by copper(I) as key step

Article abstract of DOI:10.1002/adsc.200900859

An efficient copper-catalyzed method for the synthesis of quinoxalin-2(1H)-ones derivatives via domino S_NAr/coupling/ demesylation reaction of N-(2-halophenyl)methylsulfonamides with 2-halo amides has been developed. Various quinoxalinones with

Full text of DOI:10.1002/adsc.200900859

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DOI: 10.1002/adsc.200900859
An Efficient Domino Synthesis of Quinoxalin-2(1H)-ones via an
SNAr/Coupling/Demesylation Reaction Catalyzed by Copper(I) as
Key Step
Dingben Chena,b and Weiliang Baoa,*
a
Department of Chemistry, Xixi Campus, Zhejiang University, Hangzhou 310028, Peopleꢀs Republic of China
Fax : (+86)-571-8827-3814; phone: (+86)-571-8827-3814; e-mail: wlbao@css.zju.edu.cn
College of Pharmaceutical and Chemical Engineering, Taizhou University, Linhai 317000, Zhejiang, Peopleꢀs Republic of
b
China
Received: December 14, 2009; Revised: March 18, 2010; Published online: April 7, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900859.
Abstract: An efficient copper-catalyzed method for
the synthesis of quinoxalin-2ACTHUNTGRNEUNG(1H)-ones derivatives
via domino SNAr/coupling/demesylation reaction of
N-(2-halophenyl)methylsulfonamides with 2-halo
amides has been developed. Various quinoxalinones
with diversity at three positions on their scaffold
have been obained, and the method is valuable for
the construction of this kind of molecules with bio-
logical and pharmaceutical activities.
Keywords: copper; cyclization; demesylation;
domino reaction; quinoxalin-2(1H)-ones
Figure 1. Several quinoxalin-2(1H)-one derivatives reported
as biologically active and pharmaceutical compounds.
As an important pharmacophore in numerous biologi-
cally active compounds, the quinoxalin-2(1H)-one
scaffold has attracted much attention during the past
few years.[1] Quinoxalinone derivatives exhibit various
The typical methods for assembling quinoxalin-
biological and medicinal functions. For example 2(1H)-ones are based on the condensation of a substi-
(Figure 1), a quinoxalinone containing the electron- tuted o-phenylenediamine with an a-ketone acid, a-
withdrawing group CF3 (1) showed anticancer activity aldehyde acid, a-ketone acid ester or a-aldehyde acid
in vitro against a subpanel of cell lines, such as leuke- ester.[3a–c] Although these methods are relatively
mia, non-small cell lung, melanoma cell lines and so simple and straightforward for the synthesis of quin-
on.[2a] N-Alkylqunioxalinone (2) was reported to show
ACHTUNGTRENoNGNU xalinones, multiple by-products were obtained when
potential glycogen phosphorylase-inhibitory activity unsymmetrical diamines were used, which resulted in
and 3 is a specific inhibitor of Fxa, which was expect- extremely low yields of the desired compounds.[2e] Li
ed to be therapeutically useful in the treatment of et al. and Wu et al. reported regioselective methodol-
thromboembolic disease.[2b,c] N-Arylqunioxalinones or ogies for the synthesis of substituted quinoxalin-
their hydrochloride (4) are norepinephrine reuptake
ones.[3d,e] 2-Chloro-N-(2-nitrophenyl)acet
ACHUTGTNRNEUNG AHCUTNGTRENaNGUN mide or
inhibitors for the treatment of central nervous system methyl 2-(2-nitrophenylamino)acetate were used as
disorders.[2d] Moreover, other biological activities have intermediates, followed by reduction, intramolecular
been reported, including acting as antimicrobial cyclization and oxidation steps, but these routes were
agents, kinases inhibitors, benzodiazepine receptor ag- often troublesome. N-Substituted quinACTHUNGTRENNUNG
onist, etc.[2e–g]
ACHTUNGTRENNUNG
Adv. Synth. Catal. 2010, 352, 955 – 960
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955

Dingben Chen and Weiliang Bao
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N- and O-substituted products were obtainACTHNUTRGNEUNG
ed.[3f–h]
Table 1. Optimization of the reaction conditions for the syn-
thesis of 7-methyl-1-phenylquinoxalin-2(1H)-one.[a]
Therefore, it is still highly desirable to develop more
convenient and efficient approaches for these hetero-
cycles.
À
In the past few years, the formation of aryl C X
bonds (X=N, O, S, etc.) via copper-catalyzed Ull-
mann-type coupling between aryl halides and hetero-
ACHTUNGTRENNUNGatom-centered nucleophiles has made great prog-
ress.[4] More recently, the Ullmann coupling has been
applied to construct various heterocyclic compounds
by one-pot strategies. Most of these heterocyclic com-
pounds were N-heterocycles, including pyrrole,
indole,
dihydrobenz
1(2H)-one, quninazoline, quinazolinone, 3,4-dihydro-
2H-1,4-benzoxazine, 1,4-benzodiazepin-3-one rings
benzimidazole,
ACHTUNGTRENNUNG
benzothiazole,
1,3-
Entry
R
Cat.
L
Base
Solvent Yield [%][b]
ACHTUNGTRENNUNG
etc.[5] However, to the best of our knowledge, there is
no report about the formation of quinoxalin-2(1H)-
ones via a one-pot copper-catalyzed coupling process.
Our research group is interested in the cascade syn-
thesis of heterocycles and has developed Cu-catalyzed
tandem addition/coupling, ring-open/coupling, SNAr/
coupling cyclization reactions.[6] Herein, we report a
domino SNAr/coupling/demesylation reaction, an effi-
cient copper-catalyzed one-pot reaction of N-(2-halo-
phenyl)methylsulfonamides with 2-halo amides to
synthesize quinoxalin-2(1H)-ones with diversity at
three positions on the scaffold.
1
2
3
4
5
6
7
8
Ms
Ms
Ms
Ms
Ms
Ms
Ms
Ms
Ms
Ms
Ms
Ms
Ms
Ms
Ts (1b)
CuI
CuI
CuI
CuI
CuI
CuI
CuI
L1 Cs2CO3 dioxane trace
L1 K2CO3 dioxane 87
L1 K3PO4 dioxane 68
L1 K2CO3 toluene 26
L1 K2CO3 DMF
L1 K2CO3 DMSO 62
L1 K2CO3 NMP 48
72
CuBr L1 K2CO3 dioxane 42
Cu2O L1 K2CO3 dioxane 53
9
10
11
12
13
14
CuI
CuI
CuI
CuI
CuI
CuI
L2 K2CO3 dioxane 15
L3 K2CO3 dioxane 34
L4 K2CO3 dioxane 30
L5 K2CO3 dioxane 21
As shown in Table 1 N-(2-iodo-4-methylphenyl)me-
thylsulfonamide (1a) and 2-chloro-N-phenylacetamide 15
–
K2CO3 dioxane 19
L1 K2CO3 dioxane 46
L1 K2CO3 dioxane trace
L1 Cs2CO3 dioxane 30
L1 Cs2CO3 dioxane trace
16
17
18
Tfac (1c) CuI
Tfac CuI
Ac (1d) CuI
(2a) were chosen as the model substrates to optimize
the reaction conditions including bases, solvents, cata-
lysts, and ligands. We began our study under the simi-
lar reaction conditions (10 mol% CuI, 20 mol% 1, 10-
phenanthroline, Cs2CO3 in dioxane) as for our previ-
ously reported Cu-catalyzed cascade synthesis of 2H-
[a]
Reaction conditions:
N-(2-iodophenyl)amides
1a
(0.75 mmol), 2-chloro-N-phenylacetamide 2a (0.5 mmol),
copper source (0.05 mmol), ligand (0.1 mmol) and base
(2.0 mmol) in solvent (2.0 mL) under N2 at 1008C for
13 h.
1,4-benzoxazin-3-(4H)-ones,[6d] but only
a
trace
amount of product was observed. The yield of product
was greatly improved when the bases K2CO3 and
K3PO4 were selected (87% and 68% yield, respective-
ly, entries 2 and 3). The effect of solvent was investi-
[b]
Isolated yield. Tfac=trifluoroacyl .
gated (entries 4–7). Toluene, DMF, DMSO, NMP pro- 30% yield could be obtained when the base K2CO3
vided lower yields than dioxane did. Toluene showed was replaced by Cs2CO3.
the lowest yield (only 26%). Among the Cu catalysts
The scope of copper-catalyzed one-pot synthesis of
examined (CuI, CuBr, Cu2O), CuI acted as the opti- quinoxalin-2(1H)-ones from substituted N-(2-halo-
mal catalyst (entries 2, 8 and 9). Several ligands, in- phenyl)methylsulfonamides and 2-halo amides was in-
cluding 1,10-phenanthroline, ethyl 2-oxocyclohexane- vestigated. As shown in Table 2, most of the sub-
carboxylate, DABCO, l-proline and DMEDA (L1– strates examined provided good yields. The majority
L5), were screened. 1,10-Phenanthroline was the best of the N-arylquinoxalin-2(1H)-ones could be prepared
one (entries 2, 10–13). The product could also be ob- under the optimized conditions (10 mol% CuI,
tained without ligand in 19% yield (entry 14). Varia- 4 equiv. of K2CO3, dioxane as the solvent at 1008C
tion of the N-protecting group proved to be crucial. under a nitrogen atmosphere). The substrates 2-halo-
Switching from N-(2-iodophenyl)methylsulfonamide N-phenylacetamides with an electron-donating group
(1a) to N-tosyl- or N-trifluoroacyl- or N-acyl-o-iodo- on the phenyl ring showed a higher reactivity than
ACHTUNGTRENNUNGanilines (1b–d) resulted in the formation of the de- the others with no substituted group and electron-
sired product 3a in decreased yields (entries 15–18). withdrawing groups (entries 1–3, 8 and 9). The sub-
Almost no product was observed from 1c, although a strates N-(2-iodophenyl)methylsulfonamide or those
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Adv. Synth. Catal. 2010, 352, 955 – 960

An Efficient Domino Synthesis of Quinoxalin-2(1H)-ones
Adv. Synth. Catal. 2010, 352, 955 – 960
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
957

Dingben Chen and Weiliang Bao
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bearing electron-donating groups could react with 2-
ACHTUNGTRENaNGNU cetamide, the reactions could also be completed, but
chloro-N-phenylacetamides to afford products in ex- the the base Cs2CO3 must be used and a low yield
cellent yield (entries 1, 2, 5 and 7), while those bear- was obtained (Table 2, entry 4 and Table 3, entry 4). It
ing electron-withdrawing groups reacted slowly and was obvious that the R2 group showed a little steric
gave lower yields (entries 8–11), for example, prod- hindrance effect. 7-Methylquinoxalin-2ACTHNUTRGNEU(GN 1H)-one 3n
ucts 3j and 3k were obtained in only 61% and 55% could also be obtained in 52% yield, when the ratio
yields, respectively, even after the reaction time was of 1a to 2-chloroacetamide 2h was changed to 1:1.5.
prolonged to 36 h. Reaction of N-(2-bromophenyl)-
methylsulfonamide with 2-halo-N-p-tolylacetamide
The following pathway for the construction of quin-
AHCTUNGTREGoNNUN xalin-2(1H)-ones is proposed, which has three steps
also provided the target product 3f in moderate yield (Scheme 1). The reaction might proceed through an
(58%) under the conditions (DMF as the solvent at intermolecular nucleophilic substitution between N-
1158C).
(2-halophenyl)methylsulfonamide 1 and 2-halo amide
N-Alkylquinoxalin-2(1H)-ones could also be syn- 2 in the presence of a base (step a, the plausible inter-
thesized, but the base must be Cs2CO3 instead of mediate I would be formed), followed by the forma-
K2CO3, and the reaction time was shortened, only 9 h tion of 3,4-dihydroquinoxalin-2-(1H)-one intermedi-
À
were needed. The yield of N-benzylquinoxalin-2(1H)- ate II via an intramolecular C N coupling (step b).
one was higher than that of N-butyl- or N-propyl- This is converted into the target product 3 through an
ACHTUNGTRENNUNGquinoxalinones (Table 3, entries 1, 2, and 5–8). The elimination reaction (step c). The intermediate I has
electronic effect of the substituent group on substrates been monitored by TLC and isolated, its structure
was the consistent with the above discussed observa- was determined by spectral data (see Supporting In-
tions. In addition, when there were both R2 and R3 formation). However the intermediate II has not been
(R3 =aryl or alkl) substituted groups in the 2-halo- found by TLC and GC-MS. According to our previ-
Table 3. CuI-catalyzed one-pot synthesis of quinoxalin-2(1H)-ones from N-(2-halophenyl)methylsulfonamides and 2-halo-N-
alkylacetamides.[a]
Entry 1
2
Product
Yield
[%][b]
Entry 1
2
Product
Yield
[%][b]
1
2
3
1a 2f
1a 2g
1a 2h
1a 2i
3l
88
5
6
7
8
1e 2e
1e 2j
1g 2e
1g 2f
3p
80
62
70
60
3m
3n
3o
68
3q
3r
3s
52[c]
4
35[d]
[a]
Reaction conditions: N-(2-halophenyl)methylsulfonamides 1 (0.75 mmol), 2-halo amides 2 (0.5 mmol), CuI (0.05 mmol),
ligand (0.1 mmol) and Cs2CO3 (2.0 mmol) in dioxane (2.0 mL) under N2 at 1008C for 9 h.
Isolated yield.
1a (0.5 mmol), 2h (0.75 mmol).
At reflux, 36 h.
[b]
[c]
[d]
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An Efficient Domino Synthesis of Quinoxalin-2(1H)-ones
(s, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.65–7.57 (m, 3H), 7.30–
7.28 (m, 2H), 7.15 (d, J=8.0 Hz,1H), 6.48 (s, 1H), 2.32 (s,
3H); 13C NMR (100 MHz, CDCl3): d=154.9, 149.6, 141.7,
135.3, 133.8, 131.4, 130.3, 129.8, 129.5, 128.2, 125.3, 115.5,
21.9; anal. calcd. for C15H12N2O: C 76.25, H 5.12, N 11.86;
found: C 75.98, H 5.29, N 11.67; EI-MS: m/z=236 (M+).
Acknowledgements
This work was financially supported by the Specialized Re-
search Fund for the Doctoral Program of Higher Education
of China (20060335036).
Scheme 1. Proposed reaction pathway for the one-pot syn-
thesis of quinoxalin-2(1H)-ones.
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In summary, an efficient method for the assembly
of quinoxalin-2(1H)-ones has been developed, which
relied on copper-catalyzed one-pot reaction of N-(2-
halophenyl)methylsulfonamides with 2-halo amides
via a domino SNAr/coupling/demesylation process.
Most of the quinoxalin-2(1H)-one derivatives with di-
versity at three substituents on their scaffold were ob-
tained in good to excellent yields. This method should
be valuable for the construction of this kind of mole-
cule with biological and medicinal activities, so it may
find application in organic synthesis.
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Experimental Section
General Experimental Procedures for the Cu(I)-
Catalyzed One-Pot Synthesis of Quinoxalin-2(1H)-
ones
An oven-dried Schlenk tube was charged with a magnetic
stir bar, CuI (10 mg, 0.05 mmol, 10 mol%), 1,10-phenanthro-
line (20 mg, 0.1 mmol, 20 mol%), and base (2.0 mmol), N-
(2-halophenyl)methylsulfonamide
1
(0.75 mmol), 2-halo
amide 2 (0.5 mmol). The Schlenk tube was capped, and then
evacuated and backfilled with N2 (3 times). Under a coun-
ter-flow of N2, dioxane (2.0 mL) was added by syringe and
the mixture was stirred at 1008C. After the reaction was fin-
ished, the mixture was directly passed through Celite and
rinsed with an additional 30 mL of CH2Cl2. The combined
filtrate was concentrated and purified by column chromatog-
raphy on silica gel (eluting with 5:1 to 2:1 petroleum ether/
ethyl acetate) to give the corresponding product 3.
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7-Methyl-1-phenylquinoxalin-2(1H)-one (3a): Yellow
1
solid; mp 165–1678C; H NMR (400 MHz, CDCl3): d=8.33
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Adv. Synth. Catal. 2010, 352, 955 – 960