A palladium-catalyzed coupling of 3-chloroquinoxalinones with various nitrogen-containing nucleophiles

Article abstract of DOI:10.1039/c3ob40338f

An efficient and general palladium-catalyzed coupling of 3-chloro-quinoxalinones with a variety of nitrogen-containing nucleophiles such as (hetero)aromatic and aliphatic amides as well as some challenging weakly nucleophilic nitrogen compounds including lactams, carbamates and NH-containing azoles is described. In all cases, the reactions take place rapidly and cleanly in dioxane using Pd(OAc)₂ as a catalyst, Xantphos as a ligand and K₂CO₃ as a base furnishing the coupling 3-N-substituted quinoxalinone products in good to excellent yields. This journal is The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40338f

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BiomolecularChemistry
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Volume 11 | Number 23 | 21 June 2013 | Pages 3763–3926
ISSN 1477-0520
PAPER
Samir Messaoudi, Mouâd Alami et al.
A palladium-catalyzed coupling of 3-chloroquinoxalinones with various nitrogen-
containing nucleophiles

Organic &
Biomolecular Chemistry
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PAPER
A palladium-catalyzed coupling of 3-chloroquinoxalinones
with various nitrogen-containing nucleophiles†
Cite this: Org. Biomol. Chem., 2013, 11,
3808
Etienne Brachet, Jean-François Peyrat, Jean-Daniel Brion, Samir Messaoudi* and
Mouâd Alami*
An efficient and general palladium-catalyzed coupling of 3-chloro-quinoxalinones with a variety of nitro-
gen-containing nucleophiles such as (hetero)aromatic and aliphatic amides as well as some challenging
weakly nucleophilic nitrogen compounds including lactams, carbamates and NH-containing azoles is
described. In all cases, the reactions take place rapidly and cleanly in dioxane using Pd(OAc)2 as a catalyst,
Xantphos as a ligand and K2CO3 as a base furnishing the coupling 3-N-substituted quinoxalinone pro-
ducts in good to excellent yields.
Received 15th February 2013,
Accepted 22nd March 2013
DOI: 10.1039/c3ob40338f
www.rsc.org/obc
Introduction
Substituted quinoxalinones represent an important class of
fused heterocyclic compounds regarding their various pharma-
cological properties,1,2 and some of these quinoxalinones have
been tested in clinical trials.3 One of the most important sub-
families of quinoxalinones is 3-N-substituted quinoxalinones,
whose derivatives show promising biological activities,
including antimicrobial,4 antiviral,5 anti-inflamatory,6 and
anticancer7 properties. Examples of biologically active agents
containing this structural motif include 3-amidoquinoxali-
nones (A),8 a modulator of the nociceptin opioid-receptor like Fig. 1 Chemical structures of some bioactive 3-N-substituted quinoxalinones.
1 (ORL-1), and (B),9 a cannabinoid CB2 receptor agonist,
as well as the 3-anilino-quinoxalinone (C),10 an antidiabetic
glycogen phosphorylase inhibitor (Fig. 1).
In contrast to the numerous applications of 3-N-substituted
quinoxalinone derivatives, there are very few synthetic
approaches to these compounds. To introduce a nitrogen atom
at the C-3 position of the quinoxalinone moiety, the most
common route is undoubtedly the N-functionalization of
3-chloroquinoxalinones via nucleophilic heteroaromatic sub-
stitution (SNHetAr)6,10 (Scheme 1, path 1). However, this pro-
cedure is generally restricted in substrate scope with respect to
nucleophiles, and only anilines and aliphatic amines can
undergo this type of transformation. To introduce an amide
moiety at the C-3 position of the quinoxalinone nucleus, an
Scheme 1
alternative route involves, from quinoxalinone-3-carboxylic
acid derivatives, a Curtius reaction using diphenylphosphoryl-
azide followed by further N-functionalization (path 2).8,9 This
multi-step procedure, however, is often moderate to low yield-
ing, difficult to handle for large-scale operations, the variety of
substrates is narrow, and thus finds limited application in
Université Paris-Sud, CNRS, BioCIS UMR 8076, Laboratoire de Chimie
Thérapeutique, Faculté de Pharmacie, 5 rue J.-B. Clément, Châtenay-Malabry,
F-92296, France. E-mail: Samir.messaoudi@u-psud.fr, mouad.alami@u-psud.fr;
Fax: +(33) 0146835828; Tel: +(33) 0146835887
†Electronic supplementary information (ESI) available: General, experimental
procedures for starting materials and 1H and 13C spectra for all new compounds.
See DOI: 10.1039/c3ob40338f
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library synthesis. Therefore, the search for new selective and linone 1a (1 equiv.) with 4-methoxybenzamide 2a (1.2 equiv.)
simple procedures, as well as diversity oriented reactions such under our previously reported conditions11a,b [Pd(OAc)2 (5 mol
as metal-catalyzed couplings, presents an interesting challenge %), Xantphos (5 mol%), Cs2CO3 (2 equiv.), 1,4-dioxane, 90 °C].
(Scheme 1, path 3).
However, this transformation was inefficient and resulted in
As part of our continuing effort at the functionalization of only degradation of the starting material 1a due presumably to
heterocycles via transition metal-catalyzed reactions,11 com- alkaline conditions.14 To circumvent this drawback, we
bined with our interest in discovering new hsp90 inhibitors,12 decided to investigate this coupling reaction by fine-tuning the
we decided to explore the ability of 3-chloroquinoxalinones to base, solvent, ligand and palladium source. Representative
participate in metal-catalyzed C–N13 cross-coupling reactions results from this study are summarized in Table 1.
with weakly nucleophilic nitrogen compounds including
At first, the influence of the base on the outcome of the
amides, lactames, carbamates as well as azoles (Scheme 1, reaction was examined and we were delighted to find that the
path 3). From a synthetic viewpoint, this coupling should be use of K2CO3 leads to an improvement of performance of the
the shortest and most efficient route to 3-N-substituted quinoxa- coupling reaction with yield up to 62% (entries 2–4). Upon
linones for the purpose of medicinal chemistry screening pro- adjusting the Pd(OAc)2/Xantphos ratio from 1 : 1 to 1 : 2 (5 mol
grams. To the best of our knowledge, there is no report % of Pd and 10 mol% of ligand), a complete conversion of 1a
describing the formation of these compounds using this idea.
was observed, producing exclusively the desired 3-amido qui-
noxalinone product 3a in an 87% yield (entry 5). The screening
reaction was continued with respect to the palladium source.
The catalytic activity of Pd(OAc)2 proved to be optimal since
reactions with Pd/C, Pd2dba3 and PdCl2(MeCN)2 were less
Results and discussion
To determine the feasibility of this C–N bond formation efficient or did not proceed at all (compare entries 5 and 6–8).
process, we initially examined the coupling of 3-chloroquinoxa- As summarized in Table 1, evaluation of a ligand revealed that
Table 1 Optimization of the Buchwald–Hartwig coupling reaction of 1a with 4-methoxybenzamide 2aa
Entry
[Pd]
Ligand
Pd/L ratio
Base
Solvent
Conv.b (%)
Yieldc (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd/C
Pd2dba3
PdCl2(MeCN)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L1
L1
L1
L1
L1
L1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
Cs2CO3
Li2CO3
Na2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Toluene
DMF
0
0
0
0
0
0
92
62
87
63
51
—
81
—
—
—
91d,e, f
50
—
—
—
75h
100
100
100
10
100
50
10
0
100
100
10
9
10
11
12
13
14
15
16
17
18
THF
Dioxane
Dioxane
20
85g
90
a 1a (1 equiv.), 2a (1.2 equiv.) and base (2 equiv.) were heated in a sealed Schlenk tube in the presence of [Pd] (5 mol%), ligand (5 or 10 mol%) in
dioxane at 90 °C. b The conversion was determined by 1H NMR in the crude product and was based on the remaining 1a. c Yield of the isolated
product. d K2CO3 (1.5 equiv.) was used. e Compound 3a was formed in 70% yield when the reaction was carried out with Pd(OAc)2 (2.5 mol%),
L1 (5 mol%). f For control experiments, no conversion at all was observed in the absence of Pd(OAc)2 or L1 and in the absence of Pd(OAc)2 and
L1. g K2CO3 (1.0 equiv.) was used. h The reaction was carried out at 75 °C for 3 h.
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excellent regioselectivity for the N-1 arylation product 3l was
observed.18
To expand the scope of our method further, a series of
3-chloro quinoxalinones 1a–e (Fig. 2) were subjected to the coup-
ling protocol with various nitrogen nucleophiles (Table 3). We
were pleased to observe that N-benzyl quinoxalinones led to
the formation of the corresponding product 3m in 86% yield
(entry 1). Moreover, the presence of an ethoxycarbonyl func-
tion on substrates 3n–p was tolerated under our catalytic
system (entries 2–4). Noteworthy, the reaction is not effective
with quinoxalinone 1d in which the nitrogen atom is non-sub-
stituted (entry 5). This system could also be successfully
applied to 3-chloroquinoxalinone 1e bearing methyl substitu-
ents on the aromatic nucleus, leading to 3-N-substituted quino-
xalinones 3r–u in yields ranging from 80 to 93%, regardless
of the nature of the nucleophile partner (entries 6–9). Notably,
compound 3r (entry 6), which was obtained in a 80% yield,
may be regarded as a direct analogue of 6BrCaQ, a potent
hsp90 inhibitor developed in our laboratory.19
Fig. 2 3-Chloroquinoxalinones 1a–f used in this study.
Xantphos is superior to all other choices (compare entries 5
and 9–12). Of note, the bidentate ligand phosphine DPEphos
also led to total conversion, although the yield of 3a was
slightly lower (entry 9). Finally, after screening other para-
meters (solvent and the amount of base, entries 14–18),
optimal conditions were found to require 1a (1 equiv.), 2a (1.2
equiv.), Pd(OAc)2 (5 mol%), Xantphos (10 mol%), K2CO3 (1.5
equiv.), dioxane in a sealed Schlenk tube at 90 °C for 30 min
(entry 13). Accordingly, 3a was isolated with a 91% yield.
A control experiment revealed that both a palladium catalyst
and a ligand were necessary for the coupling to occur as no
product could be formed in the absence of Pd(OAc)2 or L1.
With a viable coupling procedure in hand, attention was
turned to the generality of the process, and the couplings of
structurally diverse nitrogen nucleophiles with some 3-chloro-
quinoxalinones 1a–f were studied (Fig. 2). Results summarized
in Table 2, show that the optimized conditions described
above proved to be general for the coupling of 1a with a large
variety of nitrogen nucleophiles.
Finally, the synthetic potential of this protocol was well-
illustrated by the preparation of quinoxalinone derivative B, a
cannabinoid CB2 receptor agonist.9 The key step was the coup-
ling of 3-chloroquinoxalinone 1f with 1-naphthamide 2m
under our optimized conditions to give compound B in an
excellent 82% yield (Scheme 2).
The coupling was found to be compatible with primary sub-
stituted (hetero)aromatic and aliphatic amides 2a–e providing
the corresponding coupling products 3a–e in good to excellent
yields (entries 1–5). Interestingly, product 3c revealed excellent
chemical selectivity preserving the C–Cl bond on the benz-
amide moiety, which could undergo further metal-catalyzed
functionalization processes (entry 3).15 The selectivity of this
reaction must be also underlined with respect to nucleophile
coupling partners. With 2-hydroxypropanamide 2e, the amida-
tion reaction of 3-chloro-quinoxalinone 1a occurred rather
than the etherification process, giving exclusively the amide 3e
in 78% yield (entry 5) without any significant side product
resulting from O-arylation under Pd-catalysis.16 The reaction
was also effective with cyclic amides 2f–h providing the corre-
sponding lactames N-containing quinoxalin ones 3f–h in
yields ranging from 58 to 74% (entries 6–8). Moreover, the C–N
bond forming reaction was studied with the less nucleophilic
benzyl carbamate 2i, which was found to be a suitable nucleo-
phile for the coupling reaction, although a longer reaction
time was required to obtain a total conversion, and satisfactory
yield of coupling product 3i (63%, entry 9). Since the mole-
cules containing heteroaryl–azole linkages are prevalent in bio-
logical and pharmaceutical sciences,17 azoles nuclei (e.g.,
indole 2j and imidazole 2k) were next evaluated as coupling
partners with 3-chloroquinoxalinone 1a. The coupling pro-
ducts 3j and 3k were isolated in 75% and 62% yields, respecti-
vely (entries 10 and 11). Extending this chemistry to include
indazoles as substrates proved to be quite successful. Thus,
reaction of 1a with indazole 2l was readily accomplished, and
Scheme 2 Synthesis of cannabinoid CB2 receptor agonist B.
Conclusion
In summary, we demonstrated that the use of Pd(OAc)2/Xant-
phos as the catalytic system and K2CO3 as the base constitute a
versatile and efficient protocol for the coupling of a wide range
of weak nitrogen nucleophiles with 3-chloroquinoxalinones.
Various amide, lactam, carbamate and azole derivatives were
successfully employed, providing the corresponding coupling
products in good yields. Owing to their practical advantages
and low environmental impact, we believe that the reaction
described here could be an attractive alternative for the prepa-
ration of a library of N-substituted quinoxalinones as potent
inhibitors of hsp90.
Experimental details
General experimental
General procedure for the synthesis of 3-N-substituted qui-
noxalinones 3a–u. A flame-dried resealable Schlenk tube was
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Table 2 Pd-catalyzed coupling of 3-chloroquinoxalinone 1a with various nitrogen nucleophilesa
Entry
1
1
NuH 2
Product 3
Yieldb (%)
91
1a
2
3
1a
1a
88
93
4
5
1a
1a
71
78
6
7
1a
1a
58
74
8
9
1a
1a
59
63c
10
11
1a
1a
75d
62d
12
1a
65d
a 1a (1 equiv.), 2a–l (1.2 equiv.) and K2CO3 (1.5 equiv.) were heated in a sealed Schlenk tube in dioxane at 90 °C for 30 min in the presence of Pd
(OAc)2 (5 mol%) and Xantphos (10 mol%). b Yield of the isolated product. c Reaction time: 2 h. d No reaction occurred in the absence of Pd(OAc)2
or L1.
charged with Pd(OAc)2 (0.05 mmol, 5 mol%), Xantphos and the mixture was stirred at 90 °C for 30 min. The resulting
(0.10 mmol, 10 mol%), 1a–e (1.0 mmol), nitrogen nucleophile suspension was cooled to room temperature and filtered
2 (1.2 mmol) and K2CO3 (1.5 mmol). The Schlenk tube was through a pad of celite eluting with ethyl acetate, and the in-
capped with a rubber septum, evacuated and backfilled with organic salts were removed. The filtrate was concentrated and
argon; this evacuation/backfill sequence was repeated one purification of the residue by silica gel column chromato-
additional time. The liquid reactant(s) and 1,4-dioxane (2 mL graphy gave the desired product.
mmol−1) were added through the septum. The septum was
4-Methoxy-N-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)benz-
replaced with a Teflon screw cap. The Schlenk tube was sealed, amide (3a). Yield 91% (72 mg) white-yellow solid, m.p.:
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Table 3 Pd-catalyzed coupling of substituted 3-chloroquinoxalinones 1 with various nitrogen nucleophilesa
Entry
1
1
NuH 2
Product 3
Yieldb (%)
86
1c
2
1b
84
3
4
1b
1e
70
75
5
6
1d
1e
0
80
7
1e
85
8
9
1e
1e
93c
87
a 1b–e (1 equiv.), 2 (1.2 equiv.) and K2CO3 (1.5 equiv.) were heated in a sealed Schlenk tube in dioxane at 90 °C for 30 min in the presence of Pd
(OAc)2 (5 mol%) and Xantphos (10 mol%). b Yield of the isolated product. c No reaction occurred in the absence of Pd(OAc)2 or L1.
180–182 °C, Rf = 0.50 (2/8 cyclohexane–EtOAc); IR (neat): 3084, 3462, 3431, 3370, 2921, 2488, 2423, 2360, 2332, 2276, 2207,
3067, 2601, 2370, 2314, 2246, 2190, 2170, 2151, 2126, 2047, 2049, 1960, 1649, 1612, 1524, 1505, 1416, 1277, 1130, 827, 721;
2030, 2012, 2989, 1969, 1702, 1650, 1604, 1503, 1487, 1419, 1H NMR (300 MHz, CDCl3) δ 9.76 (s, 1H), 7.93 (dd, J = 8.0,
1
1361, 1311, 1261, 1208; H NMR (300 MHz, DMSO) δ 10.14 (s, 1.5 Hz, 1H), 7.76 (dd, J = 3.8, 1.1 Hz, 1H), 7.63 (dd, J = 5.0,
1H), 7.95 (d, J = 8.9 Hz, 2H), 7.68 (d, J = 7.7 Hz, 1H), 7.59–7.52 1.1 Hz, 1H), 7.49 (ddd, J = 8.3, 7.4, 1.6 Hz, 1H), 7.40 (dd, J =
(m, 2H), 7.43–7.35 (m, 1H), 7.10 (d, J = 8.9 Hz, 2H), 3.85 (s, 7.9, 1.3 Hz, 1H), 7.32 (dd, J = 8.2, 1.2 Hz, 1H), 7.17 (dd, J = 5.0,
3H), 3.70 (s, 3H); 13C NMR (75 MHz, DMSO) δ 164.0 (CO), 3.8 Hz, 1H), 3.80 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 158.5,
163.0 (CO), 151.4 (CvN), 145.7, 131.9, 131.8, 130.0 (2CH), 151.3, 144.1, 138.9, 132.6, 132.2, 130.9, 129.6, 129.5, 128.4,
128.8, 128.3, 126.2, 124.5, 115.2, 114.5 (2CH), 55.9, 30.1; MS 128.1, 124.8, 113.7, 30.0; MS (ESI positive): m/z = 286 [M + H]+;
(ESI positive): m/z = 310 [M + H]+; HR-MS (ESI positive): m/z = HR-MS (ESI positive): m/z = 286.0632, calcd for C14H12N3O2S
310.1157, calcd for C17H16N3O3 (M + H): 310.1190.
(M + H): 286.0650.
N-(4-Methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)thiophene-2-carb-
4-Chloro-N-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)benz-
oxamide (3b). Yield 88% (65 mg) white solid, m.p.: amide (3c). Yield 93% (76 mg) orange solid, m.p.: 199–201 °C,
188–190 °C, Rf = 0.52 (2/8 cyclohexane–EtOAc); IR (neat): 3491, Rf = 0.64 (2/8 cyclohexane–EtOAc); IR (neat): 3430, 3404, 2399,
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2150, 2082, 2056, 2021, 1713, 1650, 1594, 1505, 1484, 1360, [M + H]+; HR-MS (ESI positive): m/z = 244.1071, calcd for
1
1276, 1210, 1094, 1011, 711, 618; H NMR (300 MHz, CDCl3) C13H14N3O2 (M + H): 244.1086.
δ 9.88 (s, 1H), 7.94 (d, J = 8.6 Hz, 2H), 7.93 (s, 1H), 7.50 (d, J =
1-Methyl-3-(2-oxopiperidin-1-yl)quinoxalin-2(1H)-one (3h).
8.6 Hz, 2H), 7.49 (s, 1H), 7.45–7.37 (m, 1H), 7.37–7.29 (m, 1H), Yield 59% (40 mg) yellow solid, m.p.: 197–199 °C, Rf = 0.16 (2/8
3.81 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.1, 151.3, 144.1, cyclohexane–EtOAc); IR (neat): 3485, 3378, 3349, 3313, 3263,
139.1, 132.2, 132.0, 130.8, 129.5, 129.2 (2CH), 128.9 (2CH), 2465, 2355, 2233, 2136, 2016, 1677, 1603, 1501, 1474, 1347,
128.5, 124.7, 113.6, 29.9; MS (ESI positive): m/z = 314 [M + H]+; 1306, 1241, 1040, 909, 756, 650; 1H NMR (300 MHz, CDCl3)
HR-MS (ESI positive): m/z = 314.0687, calcd for C16H13N3O2Cl δ 7.77 (dd, J = 7.9, 1.3 Hz, 1H), 7.61–7.50 (m, 1H), 7.39–7.27
(M + H): 314.0696.
(m, 2H), 3.76 (d, J = 5.6 Hz, 2H), 3.71 (s, 3H), 2.61 (t, J = 6.0 Hz,
2H), 2.10–1.93 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 171.5,
152.1, 151.7, 133.5, 131.4, 130.3, 129.5, 123.7, 113.7, 48.6, 32.8,
29.7, 23.1, 21.4; MS (ESI positive): m/z = 258 [M + H]+; HR-MS
(ESI positive): m/z = 258.1234, calcd for C14H16N3O2 (M + H):
258.1243.
N-(4-Methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)acetamide (3d).
Yield 71% (40 mg) white-yellow solid, m.p.: 210–212 °C, Rf =
0.46 (2/8 cyclohexane–EtOAc); IR (neat): 3255, 2371, 2195,
2009, 1689, 1664, 1610, 1572, 1510, 1486, 1472, 1372, 1290,
1
1210, 1126, 1020, 810, 638; H NMR (300 MHz, CDCl3) δ 9.02
Benzyl(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)carbamate
(3i). Yield 63% (60 mg) white solid, m.p.: 131–133 °C, Rf = 0.40
(5/5 cyclohexane–AcOEt); IR (neat): 2368, 2353, 2310, 2035,
1759, 1723, 1652, 1613, 1472, 1455, 1340, 1274, 1240, 1178,
1132, 1063, 753, 655; 1H NMR (300 MHz, CDCl3) δ 8.63 (brs,
1H), 7.76 (dd, J = 7.9, 1.5 Hz, 1H), 7.49–7.08 (m, 8H), 5.19 (s,
2H), 3.64 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 207.1, 150.8,
150.8, 144.0, 135.4, 132.0, 130.7, 129.0, 128.5 (2C), 128.4 (2C),
127.9, 124.5, 113.6, 67.5, 29.7; MS (ESI positive): m/z = 310
[M + H]+; HR-MS (ESI positive): m/z = 310.1178, calcd for
C17H16N3O3 (M + H): 310.1192.
(s, 1H), 7.76 (dd, J = 8.0, 1.4 Hz, 1H), 7.47 (ddd, J = 8.3, 7.4,
1.6 Hz, 1H), 7.37 (dd, J = 7.9, 1.3 Hz, 1H), 7.30 (dd, J = 8.3,
1.2 Hz, 1H), 3.76 (s, 3H), 2.61 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 170.5, 151.1, 144.2, 131.8, 131.0, 128.8, 128.2, 124.7,
113.8, 30.0, 25.8; MS (ESI positive): m/z = 218 [M + H]+; HR-MS
(ESI positive): m/z = 218.0938, calcd for C11H12N3O2 (M + H):
218.0930.
2-Hydroxy-N-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)propan-
amide (3e). Yield 78% (50 mg) yellow solid, m.p.: 191–193 °C,
Rf = 0.24 (2/8 cyclohexane–EtOAc); IR (neat): 3329, 2361, 2160,
2145, 2033, 1722, 1657, 1608, 1512, 1487, 1358, 1320, 1285,
3-(1H-Indol-1-yl)-1-methylquinoxalin-2(1H)-one
(3j). Yield
1
1249, 1223, 1124, 1031, 920, 750; H NMR (300 MHz, CDCl3)
75% (57 mg) yellow solid, m.p.: 157–159 °C, Rf = 0.18 (6/4
cyclohexane–DCM); IR (neat): 3392, 2419, 2339, 2172, 2056,
2027, 2000, 1979, 1962, 1659, 1603, 1590, 1448, 1336, 1313,
1073, 1128, 721; 1H NMR (300 MHz, DMSO) δ 8.49 (d, J =
9.7 Hz, 1H), 8.46 (d, J = 3.7 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H),
7.64 (m, 3H), 7.44 (m, 1H), 7.37–7.16 (m, 2H), 6.73 (d, J =
3.6 Hz, 1H), 3.75 (s, 3H); 13C NMR (75 MHz, DMSO) δ 151.7
(CO), 144.8 (CvN), 136.1, 132.7, 131.1, 130.0, 129.5, 129.1,
128.5, 124.4, 123.5, 122.6, 121.0, 116.0, 115.2, 105.6, 30.3;
MS (ESI positive): m/z = 276 [M + H]+; HR-MS (ESI positive):
m/z = 276.1134, calcd for C17H14N3O (M + H): 276.1137.
δ 9.97 (s, 1H), 7.85 (dd, J = 7.9, 1.2 Hz, 1H), 7.56–7.44 (m, 1H),
7.37 (td, J = 7.9, 1.2 Hz, 1H), 7.30 (dd, J = 8.3, 1.0 Hz, 1H), 4.67
(s, 1H), 3.75 (s, 3H), 3.67 (m, 1H), 1.56 (d, J = 6.8 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 151.0, 143.7, 131.6, 130.9, 130.0,
129.0, 128.4, 124.6, 113.6, 68.9, 29.8, 20.5; MS (ESI positive):
m/z = 248 [M + H]+; HR-MS (ESI positive): m/z = 248.1018,
calcd for C12H14N3O3 (M + H): 248.1035.
1-Methyl-3-(2-oxoazetidin-1-yl)quinoxalin-2(1H)-one (3f). Yield
58% (35 mg) white-yellow solid, m.p.: 202–204 °C, Rf = 0.21
(4/6 cyclohexane–EtOAc); IR (neat): 3401, 3366, 3345, 2390,
2348, 2297, 2059, 2004, 1987, 1768, 1659, 1476, 1378, 1315,
3-(1H-Imidazol-1-yl)-1-methylquinoxalin-2(1H)-one (3k). Yield
62% (47 mg) yellow solid, m.p.: 166–168 °C, Rf = 0.28 (2/8
cyclohexane–EtOAc); IR (neat): 2924, 2853, 2365, 1748, 1659,
1
1253, 760, 675, 622; H NMR (300 MHz, CDCl3) δ 7.78 (dd, J =
8.0, 1.5 Hz, 1H), 7.45 (ddd, J = 8.3, 7.3, 1.5 Hz, 1H), 7.31 (ddd,
J = 8.0, 7.4, 1.3 Hz, 1H), 7.25 (dd, J = 8.3, 1.1 Hz, 1H), 4.22 (t,
J = 5.1 Hz, 2H), 3.69 (s, 3H), 3.19 (t, J = 5.1 Hz, 2H); 13C NMR
(75 MHz, CDCl3) δ 165.2, 150.9, 143.5, 131.9, 131.6, 128.9,
128.5, 124.2, 113.4, 42.1, 38.1, 29.2; MS (ESI positive): m/z =
230 [M + H]+; HR-MS (ESI positive): m/z = 230.0921, calcd for
C12H12N3O2 (M + H): 230.0930.
1
1601, 1562, 1478, 1460, 1402, 1392, 1263, 1228, 1102; H NMR
(300 MHz, CDCl3) δ 9.17 (s, 1H), 8.19 (d, J = 1.4 Hz, 1H), 7.85
(dd, J = 8.0, 1.1 Hz, 1H), 7.68–7.54 (m, 1H), 7.49–7.34 (m, 2H),
7.22 (s, 1H), 3.83 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 141.4,
138.0, 132.7, 131.0, 130.6, 129.8, 128.8, 128.2, 124.8, 118.0,
114.0, 30.0; MS (ESI positive): m/z = 227 [M + H]+; HR-MS (ESI
1-Methyl-3-(2-oxopyrrolidin-1-yl)quinoxalin-2(1H)-one (3g). Yield positive): m/z = 227.0923, calcd for C17H14N3O (M + H):
74% (45 mg) white-yellow solid, m.p.: 138–140 °C, Rf = 0.1 (2/8 227.0933.
cyclohexane–EtOAc); IR (neat): 3447, 3107, 2200, 2167, 2017,
3-(1H-Indazol-1-yl)-1-methylquinoxalin-2(1H)-one (3l). Yield
1988, 1720, 1705, 1658, 1603, 1586, 1504, 1403, 1332, 1254, 65% (45 mg) white solid, m.p.: 197–199 °C, Rf = 0.16 (2/8 cyclo-
1226, 1096, 926, 816, 642; 1H NMR (300 MHz, CDCl3) δ 7.79 hexane–EtOAc); IR (neat): 3485, 3378, 3349, 3313, 3263, 2465,
(dd, J = 8.0, 1.1 Hz, 1H), 7.61–7.48 (m, 1H), 7.34 (dd, J = 14.4, 2355, 2233, 2136, 2016, 1677, 1603, 1501, 1474, 1347, 1306,
7.7 Hz, 2H), 4.04 (t, J = 7.0 Hz, 2H), 3.74 (s, 3H), 2.64 (t, J = 1241, 1040, 909, 756, 650; 1H NMR (300 MHz, CDCl3) δ 8.34 (d,
8.0 Hz, 2H), 2.20 (tt, J = 7.0, 8.0 Hz, 2H); 13C NMR (75 MHz, J = 0.8 Hz, 1H), 8.18 (dd, J = 8.5, 0.8 Hz, 1H), 7.92 (dd, J = 7.2,
CDCl3) δ 175.0, 151.5, 147.7, 133.1, 131.4, 130.0, 129.5, 123.9, 1.4 Hz, 1H), 7.80 (dd, J = 8.0, 0.9 Hz, 1H), 7.69–7.46 (m, 2H),
113.6, 48.3, 31.8, 29.7, 19.0; MS (ESI positive): m/z = 244 7.47–7.27 (m, 3H), 3.85 (s, 3H); 13C NMR (75 MHz, CDCl3)
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δ 151.2, 145.2, 140.2, 138.4, 133.1, 131.1, 130.0, 129.5, 127.8,
125.6, 124.2, 123.0, 121.0, 114.0, 113.7, 30.0; MS (ESI positive):
m/z = 277 [M + H]+; HR-MS (ESI positive): m/z = 277.1068,
calcd for C16H13N4O (M + H): 277.1089.
4-Methoxy-N-(4,6,7-trimethyl-3-oxo-3,4-dihydroquinoxalin-2-yl)-
benzamide (3r). Yield 80% (60 mg) yellow solid, m.p.:
256–258 °C, Rf = 0.55 (2/8 cyclohexane–EtOAc); IR (neat): 3375,
2919, 2848, 2363, 1694, 1650, 1623, 1597, 1518, 1493, 1441,
1
1414, 1290, 1150, 1029; H NMR (300 MHz, CDCl3) δ 7.96 (d,
N-(4-Benzyl-3-oxo-3,4-dihydroquinoxalin-2-yl)-4-methoxybenz-
amide (3m). Yield 86% (61 mg) white-yellow solid, m.p.:
130–132 °C, Rf = 0.40 (5/5 cyclohexane–EtOAc); IR (neat): 3377,
2925, 2362, 2234, 2185, 2169, 2050, 1972, 1701, 1521, 1500,
J = 8.8 Hz, 2H), 7.70 (s, 1H), 7.06 (s, 1H), 6.99 (d, J = 8.8 Hz,
2H), 3.86 (s, 3H), 3.75 (s, 3H), 2.39 (s, 3H), 2.34 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 163.7, 163.2, 151.5, 143.9, 137.9,
133.6, 130.4, 129.7 (C), 129.7 (2C), 128.9, 126.5, 114.3 (C),
114.2 (2C), 55.6, 29.9, 20.4, 19.3; MS (ESI positive): m/z = 338
[M + H]+; HR-MS (ESI positive): m/z = 338.1472, calcd for
C19H20N3O3 (M + H): 338.1505.
1
1479, 1439, 1309, 1190, 910, 728; H NMR (300 MHz, CDCl3)
δ 9.90 (s, 1H), 7.99 (d, J = 8.9 Hz, 2H), 7.46–7.14 (m, 9H), 6.99
(d, J = 8.9 Hz, 2H), 5.57 (s, 2H), 3.88 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 163.8, 163.3, 151.8, 144.6, 134.7, 132.6, 130.2, 129.8
(2C), 129.6, 129.1 (2C), 128.3, 128.0, 126.8 (2C), 126.2, 124.8,
114.5, 114.2 (2C), 55.6, 46.8; MS (ESI positive): m/z = 386
[M + H]+; HR-MS (ESI positive): m/z = 386.1473, calcd for
C23H20N3O3 (M + H): 386.1505.
N-(4,6,7-Trimethyl-3-oxo-3,4-dihydroquinoxalin-2-yl)picolin-
amide (3s). Yield 85% (86 mg) yellow solid, m.p.: 166–168 °C,
Rf = 0.23 (5/5 cyclohexane–EtOAc); IR (neat): 3062, 2920, 2360,
1713, 1623, 1601, 1587, 1496, 1436, 1333, 1290, 1248, 1175,
1
1086, 1024, 998; H NMR (300 MHz, CDCl3) δ 11.78 (brs, 1H),
Ethyl
2-(3-(4-methoxybenzamido)-2-oxoquinoxalin-1(2H)-yl)-
8.70 (ddd, J = 4.8, 1.6, 0.9 Hz, 1H), 8.39–8.25 (m, 1H),
8.04–7.85 (m, 1H), 7.73 (s, 1H), 7.51 (ddd, J = 7.6, 4.8, 1.2 Hz,
1H), 7.07 (s, 1H), 3.77 (s, 3H), 2.40 (s, 3H), 2.34 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 161.8, 151.5, 149.6, 148.6, 143.8,
138.0, 137.7, 133.4, 130.4, 129.8, 129.2, 127.0, 123.0, 114.3,
29.8, 20.5, 19.3; MS (ESI positive): m/z = 309 [M + H]+; HR-MS
(ESI positive): m/z = 309.1341, calcd for C17H17N4O2 (M + H):
309.1352.
acetate (3n). Yield 84% (60 mg) yellow solid, m.p.: 96–98 °C, Rf
= 0.3 (5/5 cyclohexane–EtOAc); IR (neat): 3255, 2371, 2195,
2009, 1689, 1664, 1610, 1572, 1510, 1486, 1472, 1372, 1290,
1
1210, 1126, 1020, 810, 638; H NMR (300 MHz, CDCl3) δ 9.75
(s, 1H), 7.95 (d, J = 8.6 Hz, 2H), 7.95 (s, 1H), 7.52–7.30 (m, 2H),
7.08 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H), 5.07 (s, 2H),
4.25 (q, J = 7.1 Hz, 2H), 3.87 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H); 13
C
NMR (75 MHz, CDCl3) δ 166.5, 163.5, 163.2, 151.3, 144.1,
132.2, 129.9, 129.6, 129.6 (2CH), 128.3, 126.0, 124.8, 114.1
(2CH), 112.9, 62.2, 55.4, 44.2, 14.0; MS (ESI positive): m/z = 382
[M + H]+; HR-MS (ESI positive): m/z = 382.1364, calcd for
C20H20N3O5 (M + H): 382.1403.
3-(Indolin-1-yl)-1,6,7-trimethylquinoxalin-2(1H)-one (3t). Yield
93% (66 mg) white-yellow solid, m.p.: 172–174 °C, Rf = 0.30
(2/8 cyclohexane–EtOAc); IR (neat): 3255, 2371, 2195, 2009,
1689, 1664, 1610, 1572, 1510, 1486, 1472, 1372, 1290, 1210,
1
1126, 1020, 810, 638; H NMR (300 MHz, CDCl3) δ 8.20 (d, J =
Ethyl 2-(3-(1H-imidazol-1-yl)-2-oxoquinoxalin-1(2H)-yl)acetate
(3o). Yield 70% (41 mg) white solid, m.p.: 154–156 °C, Rf =
0.16 (6/4 cyclohexane–EtOAc); IR (neat): 3473, 3197, 2372,
2350, 2272, 2178, 2139, 2051, 1950, 1932, 1660, 1606, 1477,
8.3 Hz, 1H), 7.39 (s, 1H), 7.25–7.14 (m, 2H), 7.02–6.86 (m, 2H),
4.67 (t, J = 8.4 Hz, 2H), 3.68 (s, 3H), 3.16 (t, J = 8.3 Hz, 2H),
2.37 (s, 3H), 2.32 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 152.5,
147.3, 144.8, 134.6, 132.4, 132.4, 131.0, 129.0, 127.1, 126.7,
124.4, 122.1, 116.7, 113.9, 51.8, 29.3, 28.9, 20.1, 19.2; MS (ESI
positive): m/z = 306 [M + H]+; HR-MS (ESI positive): m/z =
306.1580, calcd for C19H20N3O (M + H): 306.1606.
1-(4,6,7-Trimethyl-3-oxo-3,4-dihydroquinoxalin-2-yl)-1H-indole-
3-carbonitrile (3u). Yield 87% (70 mg) yellow solid, m.p.:
225–227 °C, Rf = 0.53 (7/3 cyclohexane–EtOAc); IR (neat): 3243,
2368, 2220, 2171, 2143, 2117, 2060, 2017, 1962, 1655, 1621,
1604, 1604, 1587, 1501, 1452, 1261, 1060, 913; 1H NMR
(300 MHz, CDCl3) δ 9.05 (s, 1H), 8.50 (d, J = 7.6 Hz, 1H), 7.71
(d, J = 7.5 Hz, 1H), 7.57 (s, 1H), 7.48–7.29 (m, 2H), 7.05 (s, 1H),
3.72 (s, 3H), 2.44 (s, 3H), 2.38 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 151.0 (CvO), 142.0 (CvN), 140.5, 135.9, 135.3, 133.9,
130.3, 129.2, 128.8, 127.8, 125.1, 123.9, 119.3, 116.1, 115.0,
114.3, 90.0 (CN), 29.9, 20.6, 19.2; MS (ESI positive): m/z = 329
[M + H]+; HR-MS (ESI positive): m/z = 329.1402, calcd for
C20H17N4O (M + H): 329.1402.
1
1395, 1305, 1100, 935, 669, 619; H NMR (300 MHz, CDCl3) δ
9.05 (s, 1H), 8.16 (s, 1H), 7.92–7.76 (m, 1H), 7.56 (dd, J = 11.5,
4.3 Hz, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.21–7.06 (m, 2H), 5.12 (s,
2H), 4.28 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 166.6, 150.5, 138.2, 131.8, 131.1, 130.5,
130.0, 129.8, 128.2, 125.0, 117.8, 113.3, 62.5, 44.3, 14.2; MS
(ESI positive): m/z = 299 [M + H]+; HR-MS (ESI positive): m/z =
299.1121, calcd for C15H15N4O3 (M + H): 299.1144.
Ethyl
2-(3-(4-methoxybenzamido)-2-oxoquinoxalin-1(2H)-yl)-
acetate (3p). Yield 75% (60 mg) yellow solid, m.p.: 172–174 °C,
Rf = 0.46 (5/5 cyclohexane–EtOAc); IR (neat): 3355, 2358, 1748,
1706, 1653, 1612, 1575, 1501, 1481, 1421, 1318, 1229, 1212,
1117, 1019; 1H NMR (300 MHz, CDCl3) δ 9.62 (s, 1H), 8.54 (dd,
J = 8.0, 1.1 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.94 (dd, J = 7.9,
1.6 Hz, 1H), 7.89 (dd, J = 7.4, 2.0 Hz, 1H), 7.85 (dd, J = 7.1, 1.1
Hz, 1H), 7.63–7.56 (m, 1H), 7.56–7.52 (m, 1H), 7.50 (dd, J = 9.0,
1.8 Hz, 1H), 7.44 (dd, J = 8.1, 1.6 Hz, 1H), 7.38 (td, J = 7.7, 1.3
Hz, 1H), 7.08 (dd, J = 8.2, 1.2 Hz, 1H), 5.04 (s, 2H), 4.24 (q, J =
CB2 receptor agonist (C). Yield 82% (60 mg) yellow oil, Rf =
7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) 0.26 (5/5 cyclohexane–EtOAc); IR (neat): 2853, 1705, 1648,
1
δ 166.6, 166.4, 151.2, 144.3, 133.9, 133.0, 132.2, 132.1, 130.3, 1611, 1479, 1348, 1280, 1229, 1186, 1116, 1036, 1009, 920; H
130.2, 129.8, 128.7, 128.5, 127.7, 126.7, 126.1, 125.4, 125.0, NMR (300 MHz, CDCl3) δ 9.68 (s, 1H), 8.62–8.44 (m, 1H), 8.00
124.7, 113.1, 62.3, 44.3, 14.1; MS (ESI positive): m/z = 402 (d, J = 8.3 Hz, 1H), 7.94 (dd, J = 8.2, 1.4 Hz, 1H), 7.91–7.87 (m,
[M + H]+.
1H), 7.85 (dd, J = 7.1, 1.0 Hz, 1H), 7.63–7.57 (m, 1H), 7.57–7.53
3814 | Org. Biomol. Chem., 2013, 11, 3808–3816
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(m, 1H), 7.53–7.48 (m, 1H), 7.47 (d, J = 1.5 Hz, 1H), 7.42–7.34
(m, 2H), 4.47 (t, J = 7.1 Hz, 2H), 3.82–3.61 (m, 4H), 2.74 (t, J =
9 W. B. Cowden, D. R. March, A. Robertson and N. Jenkins,
WO 2005021547 A2 20050310, 2005.
7.1 Hz, 2H), 2.59 (s, 4H); 13C NMR (75 MHz, CDCl3) δ 166.4, 10 (a) J. Dudash Jr., Y. Zhang, J. B. Moore, R. Look, Y. Liang,
151.1, 144.4, 133.9, 133.0, 132.4, 132.1, 130.3, 130.1, 129.9,
128.5, 127.7, 126.7, 126.0, 125.3, 124.7, 124.6, 113.6, 66.9, 55.1,
53.9, 40.4; MS (ESI positive): m/z = 429 [M + H]+; HR-MS (ESI
positive): m/z = 429.1899, calcd for C25H25N4O3 (M + H):
429.1927.
M. P. Beavers, B. R. Conway, P. J. Rybczynski and
K. T. Demarest, Bioorg. Med. Chem. Lett., 2005, 15, 4790–
4793; (b) J. Fleischhauer, R. Beckert, Y. Juttke, D. Hornig,
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Chem.–Eur. J., 2009, 15, 12799–12806.
11 (a) D. Audisio, S. Messaoudi, J.-F. Peyrat, J.-D. Brion and
M. Alami, Tetrahedron Lett., 2007, 48, 6928–6932;
(b) S. Messaoudi, D. Audisio, J.-D. Brion and M. Alami,
Tetrahedron, 2007, 63, 10202–10210; (c) S. Sahnoun,
S. Messaoudi, J.-F. Peyrat, J. D. Brion and M. Alami, Tetra-
hedron Lett., 2008, 49, 7279–7283; (d) S. Sahnoun,
S. Messaoudi, J. D. Brion and M. Alami, Org. Biomol.
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Acknowledgements
The CNRS is gratefully acknowledged for financial support of
this research and Ministère (MENRT) for a doctoral fellowship
to E.B. Our laboratory BioCIS-UMR 8076 is a member of the
Laboratory of Excellence LERMIT supported by a grant from
ANR (ANR-10-LABX-33).
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