An expeditious copper-catalyzed access to 3-aminoquinolinones, 3-aminocoumarins and anilines using sodium azide

Article abstract of DOI:10.1002/adsc.201000149

An efficient copper-catalyzedin in situ C-(sp²)-NH₂ bond formation to provide a range of 3-aminoquinolin-2(1H)-ones and 3-aminocoumarins from 3-bromoquinolinones and 3-bromocoumarins, respectively, has been achieved. The reaction conditions involve the use of copper powder as the catalyst, eco-friendly ethanol as the solvent in the pres ence of pipecolinic acid as the ligand and ascorbic acid as the additive. The efficiency of this practical method was demonstrated in the synthesis of various anilines.

Full text of DOI:10.1002/adsc.201000149

FULL PAPERS
DOI: 10.1002/adsc.201000149
An Expeditious Copper-Catalyzed Access to 3-Aminoquinoli-
nones, 3-Aminocoumarins and Anilines using Sodium Azide
Samir Messaoudi,a,* Jean-Daniel Brion,a and Mouꢀd Alamia,*
a
Universitꢁ Paris-Sud, CNRS, BioCIS-UMR 8076 Laboratoire de Chimie Thꢁrapeutique, Facultꢁ de Pharmacie, 5 rue J.-B.
Clꢁment, 92296 Chꢀtenay-Malabry, France
Fax : (+33)-146-83-58-28; e-mail: mouad.alami@u-psud.fr or samir.messaoudi@u-psud.fr
Received: February 26, 2010; Revised: May 27, 2010; Published online: July 7, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000149.
Abstract: An efficient copper-catalyzed in situ C- ence of pipecolinic acid as the ligand and ascorbic
2
À
G
aminoquinolin-2(1H)-ones and 3-aminocoumarins method was demonstrated in the synthesis of various
from 3-bromoquinolinones and 3-bromocoumarins, anilines.
respectively, has been achieved. The reaction condi-
tions involve the use of copper powder as the cata- Keywords: aminoheterocycles; anilines; C N bond
lyst, eco-friendly ethanol as the solvent in the pres- formation; copper catalysis; sodium azide
À
Introduction
In an ongoing medicinal chemistry program[8] di-
rected towards hsp90, an exciting new target in cancer
3-Substituted quinolin-2(1H)-ones are an important drug discovery,[9] we were interested in developing
class of heteroaromatic compounds, which have at- new approaches for the synthesis of a combinatorial
tracted considerable attention because of their phar- library of 3-N-substitued quinolinones or coumarins
macological properties.[1] One of the most important as analogues of novobiocin.[10] To this end, we have
À
subfamilies of quinolin-2(1H)-ones is the 3-aminoqui- studied the palladium-catalyzed C N bond coupling
nolin-2(1H)-one class, whose derivatives show promis- reaction of 3-bromoquinolinones[11] and related heter-
ing biological activities, including KCNQ2 channel ocyclic 3-bromocoumarins[12] with various nitrogen
openers,[2] neuronal maxi-K channel activators,[3] can- nucleophiles, including amines, amides, sulfonamides,
nabinoid CB2 receptor inverse agonists[4] or AMPA/ carbamates and ureas. During our search for new cou-
kainate and glycine antagonists.[5] While these deriva- pling partners for such processes, we decided to ex-
tives clearly hold great potential in organic synthesis, plore the ability of the azide anion to participate in a
a careful examination of the literature reveals a lack copper-catalyzed cross-coupling reaction. We expect-
of methods for their preparation. The conventional ed that the coupling of an azide with a 3-bromoquino-
route to prepare 3-aminoquinolinones is the sequen- linone 1a would lead to the corresponding 3-azidoqui-
tial nitration/reduction of 4-hydroxyquinolinones into nolinone that can be used further for generating 1,2,3-
3-amino-4-hydroxyquinolinones.[6] However, the pro- triazole derivatives. However, under the reaction con-
tocol is limited to substrates having a C-4 hydroxy ditions reported by Liang for aryl bromides,[13] 3-azi-
substituent. Alternative routes consist of the Hof- doquinolin-one was never detected and instead, 3-
mann rearrangement of quinolinone-3-carboxylic acid aminoquinolin-2(1H)-one 2a was isolated in 76%
derivatives,[4] or cyclization of a suitable N-chloroace- yield (Table 1, entry 1). On the basis of this unexpect-
tyl-ortho-aminobenzophenone precursor to form an ed result, we have explored this novel method which
a-pyridinium salt followed by hydrazinolysis.[7] All allows an expeditious and easy access to 3-aminoqui-
these multi-step procedures however, are often mod- nolin-2(1H)-ones 2 using copper as the catalyst and
erate to low yielding, and the variety of substrates is sodium azide as the amine source. More interestingly,
limited. Therefore, the search for new selective and we found that the procedure is general and was suc-
simple procedures presents an interesting challenge.
cessfully extended to the synthesis of various 3-ami-
nocoumarins and (hetero)aromatic amines. Although
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Table 1. Optimization coupling reaction of 1a with sodium azide under various conditions.[a]
Entry
[Cu]
[L]
Time [h]
Solvent
Conversion[b] [%]
Yield[c] [%]
1
2
3
4
5
6
7
8
CuI
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L6
L6[e]
9
9
9
9
9
9
9
9
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
EtOH:H2O
H2O
100
41
71
76
nd
nd
45
70
79
78
83
85
55
61
59
69
87
nd
45
25
98
CuBr
CuCN
CuCl2
Cu2O
CuSO4
81
100
100
100
100
100
79
Cu
N
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu[e]
9
3[d]
3[d]
3[d]
3[d]
3[d]
3[d]
3[d]
3[d]
3[d]
3[d]
10
11
12
13
14
15
16
17
18
90
89
100
100
60
100
100
100
EtOH
[a]
Reaction conditions: 1a (1.0 equiv.), sodium azide (2.0 equiv.), [Cu] (10 mol%), ligand (30 mol%) in solvent were heated
in a sealed Schlenk tube at 1008C.
Conversion was determined by H NMR on the crude reaction mixture and is based on remaining 1a.
Isolated yields of 2a.
20 mol% of ascorbic acid was added as the additive.
[b]
[c]
[d]
[e]
1
For control experiments, no conversion at all was observed in the absence of ligand or Cu(0) and in the absence of Cu(0)
and ligand.
the copper-catalyzed azidation of aryl halides to pro- gating the effects of various copper sources, ligands,
vide aryl azides has been reported,[13,14] to the best of additives and solvents.
our knowledge, there is no report describing an in situ
In a preliminary set of experiments, the influence
direct formation of (hetero)aromatic amines from of different sources of copper catalyst (10 mol%) was
(hetero)aryl halides and sodium azide.[15]
studied when 1a was reacted with sodium azide
(2 equiv.) in the presence of l-proline (30 mol%) in a
mixture of EtOH/H2O (7:3) at 1008C.[13]
Results and Discussion
As shown in Table 1, CuBr CuCN or CuCl2 were
less effective (entries 2–4), whereas Cu2O, CuSO4 and
To optimize conditions for the preparation of 2a, the CuACTHNUGTRENUNG(OAc)2 (entries 5–7) gave similar results to that of
coupling of 3-bromoquinolinone 1a with sodium azide CuI (entry 1). To our delight, the air-stable and inex-
was initially selected as a model reaction for investi- pensive Cu(0) powder gave the best result under
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An Expeditious Copper-Catalyzed Access to 3-Aminoquinolinones, 3-Aminocoumarins and Anilines
Table 2. Cu(0)-catalyzed amination of 3-haloquinolin-2-ones
these conditions and afforded 2a in 83% yield
(entry 8). Moreover, when running the reaction in the
presence of ascorbic acid as the additive
(20 mol%),[16] a higher rate was observed, and 1a pro-
vided 2a in 85% yield within only 3 h (entry 9).
1.[a]
Since the more successful systems employed pro-
line-type ligands, we sought to evaluate the effect of
other ligands (Table 1). The amino acid ligands L5
and L6 showed total conversion and provided better
yields than 1,2-diamine-based ligands (L2, L3 and L4,
entries 10–12). In particular, L6[17] was superior
among the ligands examined at 1008C, providing 2a
À
in 87% yield (entry 14). It seems that both the N H
and carboxylate functional groups of this ligand are
important to the activity of the catalysts derived from
it. Phenanthroline ligand L8 also showed total conver-
sion, however, the yield does not exceed 50%
(entry 16).
The screening was continued with respect to addi-
tives, solvents and temperature. After a series of
assays (not shown in Table 1), the use of ascorbic acid
(20 mol%) in EtOH at 1008C was found to be the
best combination. In summary, the best conditions
were found to require 1a (1 equiv.), sodium azide
(2 equiv.), Cu powder (10 mol%), L6 (30 mol%), as-
corbic acid (20 mol%), EtOH in a sealed tube at
1008C[18] for 3 h. Accordingly, 3-aminoquinolone 2a
was obtained in quantitative yield (98%, entry 18).
Motivated by this result, we next explored the
scope of the reaction with various 3-haloquinolinones
1. Results from these studies are shown in Table 2.
We were pleased to observe that N-alkyl-, N-benzyl-
and N-aryl-substituted 3-haloquinolinones could be
aminated in good to excellent yields. The presence of
an ethoxycarbonyl function on substrate 1e was toler-
ated under our catalytic systems (entry 5). Interesting-
ly, the reaction is quite effective with quinolone 1f in
which the nitrogen atom is non-substituted, providing
2f in 50% yield (entry 6). This system could also be
successfully applied to 3-bromoquinolone 1h bearing
a phenyl substituent on the C-4 position, indicating
that the reaction does not seem to be sensitive to
steric hindrance. In this way, an excellent yield of 3-
aminoquinolone 2h was obtained (96%, entry 8).
[a]
1 (1.0 equiv.), sodium azide (2.0 equiv.), Cu(0) powder
(10 mol%), L6 (30 mol%) and ascorbic acid (20 mol%)
in EtOH were heated in a sealed Schlenk tube at 1008C.
Isolated yields of 2.
[b]
Under our optimal conditions, the reaction selectivity tives show interesting therapeutic effects.[10,20] Overall,
was investigated with substrates 1i and 1j containing the method works well and tolerates a large variety of
two carbon-bromine bonds. The amination proceeded electron-rich and electron-deficient groups on the
at the more activated C-3 position and yielded the aromatic ring (Table 3), although the yields were
mono-aminated products 2i and 2j in satisfactory slighly lower[21] compared to 3-aminoquinolinones 2
yields (entries 9 and 10). The selectivity of this proce- (Table 2). Coumarins having electron-donating groups
dure in the case of other heterocycles must be espe- on the aromatic nucleus, such as 3b–3f led to the for-
cially underlined since the reaction of 3,5-dibromopyr- mation of the corresponding 3-aminocoumarins 4b–4f
idinone 1k give only 3-amino-5-bromopyridinone 2k in yields ranging from 52–72% (Table 3, entries 2–6).
in 67% yield (entry 11).
The protocol is also quite effective with substrate 3g
In the next step, we decided to examine the scope and was used to synthesize tricyclic 3-aminobenzocou-
of this reaction with various 3-bromocoumarins[19] marin 4g in a satisfactory yield (entry 7). Further-
that would furnish 3-aminocoumarins, whose deriva- more, the scope of this reaction was applied to sub-
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Samir Messaoudi et al.
Table 4. Cu-catalyzed amination of aryl halides 5.[a]
FULL PAPERS
Table 3. Cu(0)-catalyzed amination of 3-bromocoumarins
3.[a]
[a]
[b]
[a]
5 (1.0 equiv.), sodium azide (2.0 equiv.), Cu(0) powder
(10 mol%), L6 (30 mol%) and ascorbic acid (20 mol%)
in EtOH were heated in a sealed Schlenk tube at 1008C.
Isolated yields of 6.
3 (1.0 equiv.), sodium azide (2.0 equiv.), Cu(0) powder
(10 mol%), L6 (30 mol%) and ascorbic acid (20 mol%)
in EtOH were heated in a sealed Schlenk tube at 1008C.
[b]
Isolated yields of 4.
strates 3h and 3i containing a carbon-fluorine or a stituents on the aryl halides had no impact on the out-
carbon-chlorine bond on the aromatic nucleus. 3- come of the present reaction since the aminated prod-
Amino-6-fluorocoumarin 4h and 3-amino-6-chloro- ucts were formed in good yields, regardless of the
coumarin 4i were isolated in 43% and 42% yields, re- electronic nature of the substituents (entries 1–5). Fi-
spectively (entries 8 and 9).
nally, we were successful in extending the procedure
Encouraging by these results we next explored the to heteroaryl halides, including 3-bromoquinoline 5h
scope of this method with aryl halides to form ani- and 3-iodopyridine 5i (entries 8 and 9).
lines[22] (Table 4). Under our optimized reaction con-
Although there is no clear experimental evidence,
ditions aryl bromides and iodides with either elec- we suppose that the reaction proceeds by a nitrene
tron-donating or electron-withdrawing substituents thermolysis mechanism (Scheme 1). Initially, the
worked well providing the corresponding anilines in azide intermediate 5a is probably formed, then the ni-
good yields (Table 4, entries 1–8). As shown in en- trene species I, produced from 5a by the thermo-initi-
tries 5 and 6, the procedure is compatible with com- ated N2 liberation, was presumably converted to 2a by
pounds containing base-sensitive functional groups. hydrogen abstraction.[23] To support this mechanism,
Reactions of ethyl 2-iodobenzoate[22c] (5e) and ethyl in which the azide may be an intermediate in the cat-
4-iodobenzoate (5f) with sodium azide gave the corre- alytic process, several experiments were performed.
sponding anilines in 91% and 87% yields, respective-
First of all, we attempted to transform the pre-
ly. More interestingly, the steric effect of ortho-sub- formed 3-azidoquinolinone 5a into 3-aminoquinoli-
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An Expeditious Copper-Catalyzed Access to 3-Aminoquinolinones, 3-Aminocoumarins and Anilines
Scheme 1. Proposed mechanism for the Cu-catalyzed amination of quinolone 1a using sodium azide as the amine source.
none 2a (Scheme 2). To this end, pre-formed 5a was Cu(I)] in EtOH at 1008C. Despite extensive experi-
generated in 80% yield following a Sandmeyer-type mentation, the triazole 7a was never detected and
reaction procedure, in which 2a was reacted under only 2a was isolated. Although we were not successful
acidic medium with NaNO2 and NaN3.[24] To investi- in trapping the azide intermediate 5a, our results sug-
gate the role played by reactants [Cu(0), ascorbic gest that the transformation of the azide intermediate
acid, L6, temperature] in promoting the conversion of 5a into 2a is faster than the Huisgen cycloaddition. To
5a into 2a, several assays were carried out. From support this hypothesis, we carried out the Huisgen
these experimental studies, we found that upon heat- cycloaddition of the pre-formed azide 5a with 4-me-
ing in EtOH at 1008C, as expected 2a was formed in thoxyphenylacetylene under the above conditions
90% yield (Scheme 2). On the basis of this result, it is (Scheme 3). At 1008C only 2a was formed in 69%
reasonable to assume that 2a may arise from the yield, whereas at lower temperature (408C) the tri-
azide intermediate 5a.
ACHTUNGTRNEaNUNG zole 7a was isolated in 80% yield.
On the other hand, we tried an in situ trapping[15] of
the azide intermediate 5a by an alkyne to obtain the
corresponding triazole. To this end, 1a was stirred Conclusions
with 4-methoxyphenylacetylene in the presence of
sodium azide (2 equiv.), L6 (30 mol%), ascorbic acid In conclusion, we have developed a general and
(20 mol%) and several copper catalysts [Cu(0) or direct method for the preparation of various 3-amino-
quinolin-2(1H)-ones and 3 aminocoumarins from 3-
bromoquinolinones and 3-bromocoumarins, respec-
2
À
tively. For the first time, the in situ C
N
was formed directly by using sodium azide as a amine
source in the presence of inexpensive copper powder
as the catalyst and environmentally benign EtOH as
the solvent. More interestingly, the generality of this
practical protocol was further demonstrated in the
case of functionalized (hetero)aryl halides including,
sterically hindered substrates, and those containing
base-sensitive functional groups, to provide efficiently
the corresponding primary (hetero)arylamines. Owing
Scheme 2. Thermolysis of the pre-formed azide 5a into 3-
aminoquinolinone 2a.
Scheme 3. Synthesis of the triazole 7a via Huisgen cycloaddition.
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Samir Messaoudi et al.
FULL PAPERS
(neat): n=2925, 1653, 1515, 1507, 1470, 1456, 1250, 1243,
to the practical advantages and low environmental
impact, we believe that the reaction described here
could be an attractive alternative for the preparation
of potentially bioactive compounds.
1220, 1103, 1044, 1019, 839, 800, 755 cmÀ1
;
1H NMR
(300 MHz, CDCl3): d=8.23 (s, 1H), 7.54 (d, J=7.7 Hz, 1H),
7.37 (dd, J=8.5, 7.3 Hz, 1H), 7.25 (d, J=6.1 Hz, 1H), 7.30–
7.14 (m, 2H), 7.13–7.04 (m, 2H); 6.71 (d, J=8.6 Hz, 1H),
3.89 (s, 3H);13 C NMR (75 MHz, CDCl3): d=159.8, 158.6
(CO), 140.9, 130.1, 120.3, 117.9, 141.2, 130.3, 129.5 (2C),
127.5, 122.8, 116.3, 115.4 (2C), 55.5 (CH3); MS (APCI):
m/z=331.0 (M+H)+; anal. calcd. for C16H12BrNO2 (329.01):
C 58.20, H 3.66, N 4.24; found: 58.53, H 3.82, N 4.61.
Experimental Section
General Experimental Methods
The compounds were all identified by usual physical meth-
Compounds 1g and 1j: To a solution of 1-methyl-6-me-
thoxyquinolin-2(1H)-one (1.4 g, 7.4 mmol) in CH2Cl2
(20 mL) was added N-bromosuccinimide (1.6 g, 8.9 mmol).
The mixture was stirred at room temperature for 60 h. The
resulting mixture was and extracted with CH2Cl2 three
times. The combined extract was dried over Na2SO4. The
drying agent was filtered off, and the solution was concen-
trated to dryness. The crude product was subjected to flash
column chromatography on silica gel eluted with cyclohex-
ane/AcOEt, 1:1, to afford compound 1g and compound 1j.
Compound 1g: Yield: 1.13 g (4.21 mmol, 57%); mp: 143–
1458C; TLC: Rf 0.68 (cyclohexane:AcOEt, 5:5); IR (neat):
n=2934, 1639, 1562, 1501, 1421, 1278, 1233, 1189, 1159,
1
1
ods, that is, H NMR, 13C NMR (J-MOD), IR, MS (ESI). H
and 13C NMR spectra were measured in CDCl3 or DMSO-d6
1
with a Bruker Avance-300. H chemical shifts are reported
in ppm from an internal standard TMS or of residual chloro-
form (7.27 ppm). The following abreviations 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 deuter-
iochloroform (77.14). IR spectra were measured 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 chromatography.
Melting points were recorded on a Bꢃchi B-450 apparatus
and are uncorrected.
1
1070, 1034, 952, 906, 830, 810, 751 cmÀ1; H NMR (300 MHz,
CDCl3): d=8.07 (s, 1H), 7.29 (d, 1H, J1 =9.2 Hz), 7.21 (dd,
1H, J1 =9.2 Hz, J2 =2.7 Hz), 6.94 (d, 1H, J1 =2.5 Hz), 3.86
13
(s, 3H), 3.78 (s, 3H);
C NMR (75 MHz, CDCl3): d=
157.4, 154.8 (CO), 133.9, 121.1, 118.4 (Carom), 140.0, 119.7,
115.7, 109.5 (CHarom), 55.7, 31.2 (CH3); MS (ESI+): m/z=
268.0 (M+H+, 79Br), 270.0 (M+H+, 81Br); anal. calcd. for
C11H10BrNO2 (266.99): C 49.28, H 3.76, N 5.22; found: C
49.53, H 3.86, N 5.41.
Synthetic Details for 3-Bromoquinolin-2(1H)-one
Compounds 1c, 1d, 1g, 1j and 3,5-Dibromopyridinone
1k
Compound 1c: To a solution of 3-bromo-1-quinolin-2-one
(0.5 g, 2.23 mmol) in DMF (2 mL) were added NaH (99 mg
of a 65% oil dispersion, 2.76 mmol) and iodoethane (357 mL,
4.46 mmol). The reaction mixture was stirred for 3 h at
room temperature before being diluted with water and ex-
tracted with ethyl acetate. The combined organic layers
were washed with brine, dried over sodium sulphate and
concentrated under vacuum. Purification of the residue by
silica gel column chromatography (CH2Cl2) afforded the de-
sired product 1c as a light yellow solid; yield: 505 mg
(90%); mp 112–1158C; TLC: Rf 0.5 (CH2Cl2); IR (neat): n=
1637, 1591, 1444, 1356, 1205, 1147, 1088, 1064, 907, 808, 762,
Compound 1j: Yield: 375.0 mg (1.08 mmol, 14%); mp
>2508C; TLC: Rf 0.4 (cyclohexane:AcOEt, 5:5); IR (neat):
n=3319, 1638, 1588, 1561,1558, 1487, 1455, 1447, 1421, 1338,
1
1294, 1263, 1229, 1186, 1065, 964, 903, 851 cmÀ1; H NMR
(300 MHz, CDCl3): d=8.63 (s, 1H), 7.31 (d, 1H, J=9.3 Hz),
7.23 (d, 1H, J=9.3 Hz), 3.97 (s, 3H), 3.80 (s, 3H); 13C NMR
(75 MHz, CDCl3): d=157.6, 151.8, 139.1, 134.7, 120.8, 120.3,
115.2, 114.2, 110.70, 57.1, 31.5; MS (APCI+): m/z=346.0
([M+H]+, 79Br), 348.0 ([M+H]+, 81Br), 350.0 ([M+H]+, 2ꢅ
81Br); anal. calcd. for C11H9Br2NO2 (344.9): C 38.07, H 2.66,
N 4.04; found: C 38.37, H 2.97, N 4.51.
1
750, 622 cmÀ1; H NMR (300 MHz, CDCl3): d=8.08 (s, 1H),
Compound 1k: To a solution of a commercial N-methyl
pyridinone (5 g, 45.8 mmol) in acetic acid (40 mL) was
added a solution of bromine (15 mL, 91.6 mmol) in acetic
acid (40 mL) and the resulting solution was stirred at room
temperature for 20 h. A white precipitate was filtered off,
and the filtrate was concentrated. Purification of the residue
by silica gel column chromatography (Et2O) afforded com-
pound 1k as a white solid; yield: 9.9 g (72%); mp 182–
1848C; TLC: Rf 0.48 (Et2O); IR (neat): n=3068, 1648, 1586,
1516, 1418, 1355, 1301, 1209, 1127, 1042, 893, 850, 753,
7.57 (t, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.35 (d, J=
8.5 Hz, 1H), 7.22 (t, J=7.5 Hz, 1H), 4.39 (q, J=7.0 Hz,
2H), 1.35 (t, J=7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=157.9, 140.5, 138.3, 130.8, 128.3, 122.5, 120.8, 117.6, 114.2,
39.0, 12.6; MS (ES+): m/z=252.0 (M+H+, 79Br), 254.0
(M+H+, 81Br); anal. calcd. for C11H10BrNO (250.99): C
52.41, H 4.00, N 5.56; found: C 52.67, H 4.12, N 6.01.
Compound 1d: A mixture of 3-bromo-1-quinolin-2(1H)-
one (200 mg, 0.9 mmol), 4-methoxyphenylboronic acid
(206 mg, 1.3 mmol), anhydrous cupric acetate (355 mg,
1.8 mmol), pyridine (144 mL), triethylamine (248 mL) and ac-
tivated 4 ꢄ molecular sieves in 20 mL CH2Cl2 was treated at
room temperature for 4 h. The reaction was filtered through
Celite, washed with AcOEt and was purified by flash chro-
matography on silica gel with cyclohexane/AcOEt, 9:1 then
8:2, to provide 1d; yield: 172.7 mg (0.5 mmol, 58%); mp
205–2078C; TLC: Rf 0.5 (cyclohexane:AcOEt, 8:2); IR
1
716 cmÀ1; H NMR (300 MHz, CDCl3): d=7.78 (d, 1H, J=
3.0 Hz), 7.435 (d, 1H, J=3.0 Hz), 3.59 (s, 3H); 13C NMR
(75 MHz, DMSO-d6): d=158.0 (CO), 143.8, 137.5, 117.4,
96.5, 39.0; MS (ES+): m/z=266.0 (M+H+, 79Br), 268.0
(M+H+, 81Br), 270.0 (M+H+, 2ꢅ 81Br); anal. calcd for
C6H5Br2NO (264.87): C 27.00, H 1.89, N 5.25; found: C
27.26, H 2.06, N 5.49.
1682
asc.wiley-vch.de
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1677 – 1687

An Expeditious Copper-Catalyzed Access to 3-Aminoquinolinones, 3-Aminocoumarins and Anilines
(s, 3H); 13C NMR (CDCl3, 75 MHz): d=159.7, 159.0, 136.3,
General Procedure for Cu-Catalyzed Amination of
(Hetero)Aryl halides with Sodium Azide
135.9, 130.4, 129.6 (2C), 125.3, 125.1, 122.6, 122.0, 115.7,
115.3 (2C), 109.5, 55.5; MS (ES+): m/z=67 (M+H)+; anal.
calcd. for C16H14N2O2 (266.11): C 72.16, H 5.30, N 10.52;
found: C 72.61, H 5.58, N 10.91.
A flame-dried resealable Schlenk tube was charged with Cu
powder (5 mg, 10 mol%), ascorbic acid (30 mg, 20 mol%),
pipecolinic acid (32 mg, 30 mol%), sodium azide (110 mg,
1.68 mmol), (hetero)aryl halide (0.84 mmol), The Schlenk
tube was capped with a rubber septum, evacuated and back-
filled with argon; then, EtOH (2 mL) was added through
the septum. The septum was replaced with a Teflon screw-
cap. The Schlenk tube was sealed, and the mixture was
stirred at 1008C. The resulting suspension was cooled to
room temperature and filtered through celite eluting with
ethyl acetate. The filtrate was concentrated and purification
of the residue by silica gel column chromatography gave the
desired product.
Compound 2e: Following the general procedure on a
0.84 mmol scale of 1e, the desired product was isolated as a
light yellow solid by flash chromatography using 10% ethyl
acetate/CH2Cl2; yield: 167 mg (81%); TLC: Rf 0.30 (CH2Cl2/
EtOAc, 9:1); mp 124–1268C; IR (neat): n=3340, 1730,
1
cmÀ1; H NMR (DMSO-d6, 300 MHz): d=7.44 (d, 1H, J=
6.0 Hz), 7.20–7.25 (m, 3H), 6.83 (s, 1H), 5.50 (bs, 2H), 5.14
(s, 2H), 4.16 (q, 2H, J=6.0 Hz), 1.21 (t, 3H, J=6.0 Hz);
13C NMR (DMSO-d6, 75 MHz): d=168.3, 158.3, 137.2,
133.2, 125.7, 125.0, 122.9 (2C), 114.3, 107.4, 61.0, 44.1, 14.0;
MS (ES+): m/z=269 (M+Na)+; anal. calcd. for
C13H14N2O3 (246.1): C 63.40, H 5.73, N 11.38; found: C
63.62, H 5.86, N 11.43.
Analytical Data for 3-Aminoquinolinone Products
Compound 2f: Following the general procedure on a
0.84 mmol scale of 1f, the desired product was isolated as a
brown solid by flash chromatography using 10% cyclohex-
ane/ethyl acetate; yield: 67 mg (50%); TLC: Rf 0.47
(EtOAc/cyclohexane, 9:1); mp 210–2128C; IR (neat): n=
Compound 2a: Following the general procedure on a
0.84 mmol scale of 1a, the desired product was isolated as a
yellow solid by flash chromatography using 10% ethyl ace-
tate/CH2Cl2; yield: 143 mg (98%); TLC: Rf 0.27 (CH2Cl2/
EtOAc, 9:1); mp 130–1328C; IR (neat): n=3388, 3301,
1
3333 ; 2874, 166, 1577 cmÀ1; H NMR (DMSO-d6, 300 MHz):
1
1582 cmÀ1; H NMR (CDCl3, 300 MHz): d=7.30 (d, 1H, J=
d=11.77 (se, 1H), 7.34 (dd, 1H, J1 =8.0 Hz, J2 =1.0 Hz),
7,13 (m, 3H), 6.74 (s, 1H), 5.42 (s, 2H); 13C NMR (DMSO-
d6, 75 MHz): d=158.1, 137.9, 132.1, 124.1, 124.0, 121.8 (2C),
114.5, 106.5; MS (ES+): m/z=161 (M+H)+; anal. calcd.
for C9H8N2O (160.06): C 67.49, H 5.03, N 17.49; found: C
67.92, H 5.21, N 17.68.
9.0 Hz), 7.12–7.26 (m, 2H), 7.10 (t, 1H, J=6.0 Hz), 6.73 (s,
1H), 4.35 (bs, 2H), 3.71 (s, 3H); 13C NMR (CDCl3,
75 MHz): d=158.6, 136.0, 134.3, 127.7, 125.5, 122.5, 122.3,
113.8, 109.0, 30.0; MS (ES+): m/z=175 (M+H)+; anal.
calcd. for C10H10N2O (174.08): C 68.95, H 5.79, N 16.08;
found: C 69.05, H 5.97, N 16.23.
Compound 2g: Following the general procedure on a
0.84 mmol scale of 1g, the desired product was isolated by
flash chromatography using 10% ethyl acetate/CH2Cl2 as an
orange solid; yield: 168 mg (98%); TLC: Rf 0.33 (CH2Cl2/
EtOAc, 9:1); mp 95–97; IR (neat): n=3456, 3334, 1730,
1647, 1613, 1587, 1504, 1463, 1300, 1240, 1175, 1032, 877,
Compound 2b: Following the general procedure on a
0.84 mmol scale of 1b, the desired product was isolated as a
yellow solid by flash chromatography using 10% ethyl ace-
tate/CH2Cl2; yield: 115 mg (73%); TLC: Rf 0.22 (CH2Cl2/
EtOAc, 9:1); mp 130- 1328C; IR (neat): n=3396, 3312,
1
1582 cmÀ1; H NMR (CDCl3, 300 MHz): d=7.31 (d, 1H, J=
1
791, 776, 681 cmÀ1; H NMR (CDCl3, 300 MHz): d=7.21 (d,
8.0 Hz), 7.15 (m, 3H), 6.74 (s, 1H), 4,35 (q, 2H, J=7.0 Hz),
4.00 (bs, 2H), 1.30 (t, 3H, J=7.0 Hz); 13NMR C (CDCl3,
75 MHz): d=157.4, 135.3, 132.6, 125.4, 124.9, 121.9, 121.7,
113.1, 108.7, 37.3, 12.1; MS (ES+): m/z=189 (M+H)+;
anal. calcd. for C11H12N2O (188.09): C 70.19, H 6.43, N
14.88; found: C 70.56, H 6.61, N 14.96.
1H, J=9.0 Hz), 6.92 (dd, 1H, J1 =9.0 Hz, J2 =3.0 Hz), 6.82
(d, 1H, J=3.0 Hz), 6.75 (s, 1H); 4.45 (s, 2H), 3.84 (s, 3H),
3.77ACHTNUGRTNEUNG
(s, 3H); 13C NMR (CDCl3, 75 MHz): d 158.0, 155.1,
136.6, 128.8, 123.2, 115.0, 113.7, 108.6, 108.0, 55.6, 30.1; MS
(ES+): m/z=205 (M+H)+; anal. calcd. for C11H12N2O2
(204.09): C 64.69, H 5.92, N 13.72; found: C 64.96, H 6.09, N
13.89.
Compound 2c: Following the general procedure on a
0.84 mmol scale of 1c, the desired product was isolated as a
light yellow solid by flash chromatography using 10% ethyl
acetate/CH2Cl2; yield: 191 mg (91%); TLC: Rf 0.50 (CH2Cl2/
EtOAc, 9:1) mp: 189–1918C; IR (neat): n=3327, 1614,
Compound 2h: Following the general procedure on a
0.84 mmol scale of 1h, the desired product was isolated by
flash chromatography using CH2Cl2. as a brown-yellow
amorphous solid; yield: 201 mg (96%); TLC: Rf 0.50
(CH2Cl2); IR (neat): n=3483, 3347, 1640, 1574, 1545, 1461,
1
1550 cmÀ1; H NMR (CDCl3, 300 MHz): d=7.30 (d, 1H, J=
9.0 Hz), 7.25–7.20 (m, 8H), 6.81 (s, 1H), 5.53 (s, 2H), 4.08
(bs, 2H); 13C NMR (CDCl3, 75 MHz): d=158.4, 135.8,
135.4, 133.3, 128.3 (2C), 126.8, 126.1 (2C), 125.5, 125.2,
122.2, 122.0, 114.3, 109.5, 46.2; MS (ES+): m/z=251 (M+
H)+; anal. calcd. for C16H14N2O (250.11): C 76.78, H 5.64, N
11.19; found: C 76.91, H 5.84, N 11.23.
1
1342, 1293, 1166, 909, 728, 702 cmÀ1; H NMR (acetone-d6,
300 MHz): d=7.65–7.45 (m, 7H), 7.19–6.95 (2H, m), 4,70
(bs, 2H), 3.82 (s, 3H); 13C NMR (CDCl3, 75 MHz): d=
158.2, 135.0, 134.0, 133.2, 129.9 (2C), 129.4 (2C), 128.2,
125.5, 124.6, 122.7, 122.4, 120.1, 113.9, 30.2; MS (ES+): m/
z=251 (M+H)+; anal. calcd. for C16H14N2O (250.11): C
76.78, H 5.64, N 11.19; found: C 77.32, H 5.98, N 11.41.
Compound 2i: Following the general procedure on a
0.84 mmol scale of 1i, the desired product was isolated by
TLC preparative chromatography (CH2Cl2) as a red brown
solid; yield: 121 mg (57%); TLC: Rf 0.3 (CH2Cl2); mp 113–
1158C; IR (neat): n=3416, 3344, 1610, 1578, 1547, 1493,
1459, 1418, 1334, 1292, 1245, 1120, 906, 880, 795, 777,
Compound 2d: Following the general procedure on a
0.84 mmol scale of 1d, the desired product was isolated as a
yellow white solid by flash chromatography using 10% ethyl
acetate/CH2Cl2; yield: 201 mg (90%); TLC: Rf 0.30 (CH2Cl2/
EtOAc, 9:1); mp 196–1988C; IR (neat): n=3429, 3316,
1615, 1588, 1558, 1507, 1458, 1247, 1025, 830, 748 cmÀ1
;
1H NMR (CDCl3, 300 MHz): d=7.40 (d, 1H, J=9.0 Hz),
7.30–7.00 (6H, m), 6.90 (bs, 1H), 6.65 (d, 1H, J=9.0), 3.90
Adv. Synth. Catal. 2010, 352, 1677 – 1687
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1683

Samir Messaoudi et al.
FULL PAPERS
1
728 cmÀ1; H NMR (CDCl3, 300 MHz): d=7.48 (d, 1H, J=
3350, 2834, 1693, 1629, 1565, 1491, 1452, 1433, 1402, 1328,
3.0 Hz), 7.38 (dd, 1H, J1 =9.0 Hz, J2 =3.0 Hz), 7.14 (d, 1H,
J=9.0 Hz), 6.68 (s, 1H), 4.53 (bs, 2H) ; 3.76 (s, 3H);
13C NMR (CDCl3, 75 MHz): d=158.2, 136.9, 133.0, 128.0,
127.6, 124.0, 115.5, 115.4, 107.1, 30.1; MS (ES+):
m/z=267 (M+H)+; anal. calcd. for C10H9BrN2O (215.99): C
47.46, H 3.58, N 11.07; found: C 47.81, H 3.71, N 11.21.
Compound 2j: Following the general procedure on a
0.84 mmol scale of 1j, the desired product was isolated as a
yellow solid by flash chromatography using 10% ethyl ace-
tate/CH2Cl2; yield: 154 mg (65%); TLC: Rf 0.32 (CH2Cl2/
EtOAc, 9:1); mp 173–1758C; IR (neat): n=3464, 3315,
1730, 3229, 1645, 1609, 1577, 1550, 1493, 1458, 1433, 1410,
1312, 1240, 1222, 1154, 1096, 1042, 879, 788, 768, 686 cmÀ1
;
1H NMR (CDCl3, 300 MHz): d=7.19 (d, 1H, J=9.0 Hz),
6.83 (dd, 1H, J=9.0, 3.0 Hz), 6.73 (d, 1H, J=3.0 Hz), 6.64
(s, 1H), 4.28 (bs, 2H), 3.81 (s, 3H) ppm; 13C NMR (CDCl3,
75 MHz): d=159.4, 156.3, 143.5, 132.3, 121.7, 117.0, 113.8,
110.6, 107.8, 55.7;MS (ES+): m/z=214 (M+23)+; anal.
calcd. for C10H9NO3 (191.06): C 62.82, H 4.74, N 7.33;
found: C 62.99, H 4.68, N 7.51.
Compound 4d: Following the general procedure on a
0.84 mmol scale of 3d, the desired product was isolated as a
orange solid by flash chromatography using CH2Cl2/cyclo-
hexane, 8:2; yield: 104 mg (65%); TLC: Rf 0.38 (CH2Cl2);
mp 140–1428C; IR (neat): n=3427, 3323, 2925, 1684, 1628,
1289, 1253, 1070, 1040, 839, 784, 733, 693 cmÀ1 1H NMR
;
1598, 1491, 1400, 1351, 1267, 1165, 1085, 867, 774, 717 cmÀ1
;
(CDCl3, 300 MHz): d=7.27–7.19 (m, 2H), 6.92 (d, 1H, J=
9.0 Hz), 3.75 (se, 2H), 3.93 (s, 3H), 3.77 (s, 3H); 13C NMR
(CDCl3, 75 MHz): d=157.6, 151.7, 137.5, 129.4, 122.9, 113.5,
109.4, 108.2, 106.9, 56.8, 30.4; MS (ES+): m/z=283, 285
(M+H)+; anal. calcd. for C11H11BrN2O2 (282.00): C 46.66, H
3.92, N 9.89; found: C 46.98, H 4.02, N 10.09.
1H NMR (CDCl3, 300 MHz): d=7.19 (t, J=8.3 Hz, 1H),
7.06 (s, 1H), 6.90 (d, J=8.4 Hz, 1H), 6.68 (d, J=8.2 Hz,
1H), 4.20 (bs, 2H), 3.90 (s, 3H); 13C NMR (CDCl3,
75 MHz): d=159.4, 154.1, 149.9, 130.8, 126.6, 111.6, 108.8,
106.5, 105.1, 55.7; MS (ES+): m/z=214 (M+23)+; anal.
calcd. for C10H9NO3 (191.06): C 62.82, H 4.74, N 7.33;
found: C 62.91, H 4.57, N 7.49.
Compound 2k: Following the general procedure on a
0.84 mmol scale of 1k, the desired product was isolated by
flash chromatography using Et2O as amorphous brown
solid; yield: 113 mg (67%); TLC: Rf 0.30 (Et2O); IR (neat):
Compound 4e: Following the general procedure on a
0.84 mmol scale of 3e, the desired product was isolated by
flash chromatography using CH2Cl2/cyclohexane, 8:2, as a
yellow solid; yield: 101 mg (72%); TLC: Rf 0.40 (CH2Cl2);
mp 124–1268C (Lit.[25] 124–1258C); IR (neat): n=3452,
3362, 1702, 1633, 1572, 1482, 1332, 1276, 1156, 1104, 881,
n=3318, 1639, 1568, 1412, 1295, 1061, 889, 787, 770 cmÀ1
;
1H NMR (300 MHz, acetone): d=7.04 (d, J=2.4 Hz, 1H),
6.56 (d, J=2.5 Hz, 1H), 5.15 (bs, 2H), 3.50 (s, 3H);
13C NMR (75 MHz, acetone): d=156.5, 139.3, 124.3, 111.8,
98.1, 36.2; MS (ES+): m/z=225 (M+23)+; anal. calcd. for
C6H7BrN2O (201.97): C 35.49, H 3.48, N 27.99; found: C
35.81, H 3.69, N 28.11.
1
764, 723 cmÀ1; H NMR (300 MHz, CDCl3): d=7.12 (t, J=
8.0 Hz, 1H), 6.8–6.90 (m, 2H), 6.67 (s, 1H), 4.27 (s, 2H),
3.94 (s, 3H); 13C NMR (CDCl3, 75 MHz): d=158.9, 146.9,
138.5, 132.2, 124.4, 121.9, 116.9, 110.8, 109.0, 56.1; MS (ES+
): m/z=214 (M+23)+; anal. calcd. for C10H9NO3 (191.06): C
62.82, H 4.74, N 7.33; found: C 62.99, H 4.68, N 7.51.
Analytical Data for the 3-Aminocoumarin Products
Compound 4f: Following the general procedure on a
0.84 mmol scale of 3f, the desired product was isolated as a
yellow solid by flash chromatography using CH2Cl2/cyclo-
hexane, 8:2; yield: 103 mg (70%); TLC: Rf 0.40 (CH2Cl2);
mp 80–828C; IR (neat): n=3432, 3342, 2922, 2853, 1688,
Compound 4a: Following the general procedure on a
0.84 mmol scale of 3a, the desired product was isolated as a
yellow solid by flash chromatography using CH2Cl2/cyclo-
hexane, 7:3; yield 99 mg, 73%); TLC: Rf 0.20 (CH2Cl2/cyclo-
hexane, 8:2); mp 130–1328C; IR (neat): n=3312, 1701,
1
1634, 1467, 1383, 1321, 1161, 879, 769, 735 cmÀ1; H NMR
1635, 1456, 1332 cmÀ1 1H NMR (CDCl3, 300 MHz): d=
;
7.10–7.30 (m, 4H), 6.63 (s, 1H), 3.81 (bs, 2H); 13C NMR
(CDCl3, 75 MHz): d=159.4, 149.0, 132.0, 126.5, 125.0, 124.6,
121.2, 116.0, 110.9; MS (ES+): m/z=283, 285 (M+H)+;
anal. calcd. for C9H7NO2 (161.05): C 67.07, H 4.38, N 8.69;
found: C 67.21, H 4.61, N 8.93.
(300 MHz, CDCl3): d=7.12 (m, 3H), 6.70 (s, 1H), 4.23 (bs,
2H), 2.44 (s, 3H); 13C NMR (CDCl3, 75 MHz): d=158.9,
146.9, 131.7,128.2, 125.5, 124.2, 122.9, 120.8, 111.4, 109.0,
15.4; MS (ES+): m/z=198 (M+23)+; anal. calcd. for
C10H9NO2 (175.06): C 68.56, H 5.18, N 8.00; found: C 68.97,
H 5.39, N 8.23.
Compound 4b: Following the general procedure on a
0.84 mmol scale of 3b, the desired product was isolated by
flash chromatography using CH2Cl2/cyclohexane, 8:2, as a
white solid; yield: 96 mg (52%); TLC: Rf 0.10 (CH2Cl2/cy-
clohexane, 8:2); mp 136–1388C; IR (neat): n=3357,
Compound 4g: Following the general procedure on a
0.84 mmol scale of 3g, the desired product was isolated by
flash chromatography using CH2Cl2/cyclohexane, 8:2, as a
red solid; yield: 113 mg (64%); TLC: Rf 0.50 (CH2Cl2); mp
155–1568C (Lit.[25] 150–1528C); IR (neat): n=3354, 1689,
1
1700 cmÀ1; H NMR (CDCl3, 300 MHz): d=7.27 (d, 1H, J=
1618, 1562, 1516, 1160, 991, 856, 734, 611 cmÀ1 1H NMR
;
9.0 Hz), 6.84 (d, 1H, J=9.0 Hz), 3.88 (s, 3H), 2.31 (s, 3H),
2.21 (s, 3H); 13C NMR (CDCl3, 75 MHz): d=159.5, 157.0,
147.7, 126.5, 120.5, 120.0, 115.3, 113.9, 107.2, 55.9, 11.9, 8.2;
MS (ES+): m/z=220 (M+H)+; anal. calcd. for C12H13NO3
(219.09): C 65.74, H 5.98, N 6.39; found: C 66.08, H 6.12, N
6.69.
Compound 4c: Following the general procedure on a
0.84 mmol scale of 3c, the desired product was isolated as a
yellow solid by flash chromatography using CH2Cl2/cyclo-
hexane, 8:2; yield: 115 mg (72%); TLC: Rf 0.50 (CH2Cl2);
mp 117–1188C (Lit.[25] 119–1218C); IR (neat): n=3450,
(300 MHz, CDCl3): d=8.47 (d, J=8.3 Hz, 1H), 8.22 (d, J=
8.0 Hz, 1H), 8.07 (d, J=9.0 Hz, 1H), 8.01–7.84 (m, 2H),
7.81 (s, 1H), 7.76 (d, J=9.0 Hz, 1H), 4.78 (bs, 2H);
13C NMR (75 MHz, CDCl3): d=159.6, 147.4, 132.4, 131.0,
129.1, 128.4, 127.7, 127.3, 126.0, 122.2, 116.9, 115.71, 107.8;
MS (ES+): m/z=234 (M+23)+; anal. calcd. for C13H9NO2
(211.06): C 73.92, H 4.29, N 6.63; found: C 74.12, H 4.62, N
6.74.
Compound 4h: Following the general procedure on a
0.84 mmol scale of 3h, the desired product was isolated as a
1684
asc.wiley-vch.de
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1677 – 1687

An Expeditious Copper-Catalyzed Access to 3-Aminoquinolinones, 3-Aminocoumarins and Anilines
light yellow solid by flash chromatography using CH2Cl2/cy-
clohexane, 8:2; yield: 65 mg (43%); TLC: Rf 0.50 (CH2Cl2);
mp 208–2108C; IR (neat): n=3425, 3316, 1699, 1643, 1562,
Compound 6c: Following the general procedure on a
0.84 mmol scale of 5c, the desired product was isolated as a
purple amorphous solid by flash chromatography using
CH2Cl2/cyclohexane, 5:5; yield: 100 mg (69%); TLC: Rf 0.40
(CH2Cl2/cyclohexane, 5:5); IR (neat): n=3460, 3373, 2934,
2836, 1603, 1511, 1474, 1459, 1376, 1266, 1229, 1207, 1094,
1488, 1444, 1292, 1219, 1174, 1144, 895, 805, 685 cmÀ1
;
1H NMR (300 MHz, acetone): d=7.27 (dd, J=9.0, 4.7 Hz,
1H), 7.15 (dd, J=9.2, 3.0 Hz, 1H), 7.09–6.93 (m, 1H), 5.40
(bs, 2H); 13C NMR (75 MHz, acetone): d=160.8, 157.6,
144.8, 134.0, 123.3(d, JC,F=9.0 Hz), 117.1 (d, JC,F =9.0 Hz),
112.3 (d, JC,F =24.7 Hz), 110.0 (d, JC,F =24.7 Hz), 107.0 (d,
790, 742, 698 cmÀ1 1H NMR (300 MHz, CDCl3): d=7.77
;
(dd, J=8.1, 2.3 Hz, 2H), 7.44 (td, J=8.3, 1.2 Hz, 1H), 7.30–
740 (m, 2H), 7.25 (d, J=8.9 Hz, 1H), 3.98 (s, 3H), 3.74 (bs,
2H); 13C NMR (75 MHz, CDCl3): d=142.5, 129.4, 129.4,
128.4, 125.01, 123.9, 123.5, 120.3, 118.5, 113.5, 56.7; MS
(ES+): m/z=196 (M+23)+; anal. calcd. for C11H11NO
(173.08): C 76.28, H 6.40, N 8.09; found: C 76.74, H 6.76, N
8.39.
J
C,F =2.2 Hz); MS (ES+): m/z=180 (M+H)+; anal. calcd.
for C9H6FNO2 (179.04): C 60.34, H 3.38, N 7.82; found: C
60.95, H 3.67, N 7.91.
Compound 4i: Following the general procedure on a
0.84 mmol scale of 3i, the desired product was isolated as a
yellow solid by flash chromatography using CH2Cl2/cyclo-
hexane, 8:2; yield: 69 mg (42%); TLC: Rf 0.50 (CH2Cl2); mp
204–2068C; IR (neat): n=3325, 1709, 1634, 1483, 1425,
Compound 6d:[22e] Following the general procedure on a
0.42 mmol scale of 5d, the desired product was isolated as a
yellow amorphous solid by flash chromatography using cy-
clohexane/CH2Cl2, 7:3; yield: 30 mg (52%); TLC: Rf 0.25
1
1165, 1079, 889, 809, 652 cmÀ1; H NMR (300 MHz, CDCl3):
1
d=7.29 (d, J=1.9 Hz, 1H), 7.21 (d, J=1.9 Hz, 1H), 7.21ACTHNUTRGNEUNG(s,
(cyclohexane/CH2Cl2, 7:3); H NMR (300 MHz, CDCl3): d=
1H), 6.95 (s, 1H), 4.46 (bs, 2H); 13C NMR (75 MHz, ace-
tone): d=158.5, 147.4, 134.3, 129.5, 125.5, 124.2, 123.9, 117.4,
106.9; MS (ES+): m/z=196 (M+H)+ ; anal. calcd. for
C9H6ClNO2 (195.01): C 55.26, H 3.09, N 7.16; found: C
55.69, H 3.38, N 7.47.
8.90 (d, J=8.6 Hz, 1H), 8.15 (dd, J=8.3, 7.0 Hz, 1H), 7.60
(d, J=8.4 Hz, 1H), 7.49 (dd, J=8.4, 7.2 Hz, 1H), 6.84 (s,
2H); 13C NMR (75 MHz, CDCl3): d=144.61, 135.60, 132.31,
126.17, 118.72, 116.94, 77.43, 77.00, 76.58.
Compound 6e: Following the general procedure on a
0.42 mmol scale of 5e, the desired product was isolated as a
purple amorphous solid by flash chromatography using
CH2Cl2/cyclohexane, 5:5; yield: 63 mg (91%); TLC: Rf 0.22
Synthesis of 3-Azidoquinolin-2(1H)-one 5a
1
(cyclohexane/CH2Cl2, 7:3); H NMR (300 MHz, CDCl3): d=
A round-bottomed flask was charged with 2a (106 mg,
0.61 mmol) in 310 mL of concentrated HCl and 310 mL of
H2O. At 0 8C, nitrite sodium (84 mg, 1.22 mmol) was added
dropwise. After stirring at 08C within 30 min, sodium azide
(119 mg, 1.83 mmol) was added dropwise. The red brown
precipitate was collected by filtration and abundantly
washed with H2O and cyclohexane.;yield: 92 mg (75%);
TLC: Rf 0.65 (CH2Cl2); mp 120–1228C; IR (neat): n=2108,
7.89 (d, J=8.2 Hz, 1H), 7.26 (t, J=7.6 Hz, 1H), 6.66 (d, J=
7.6 Hz, 2H), 5.56 (s, 2H), 4.34 (q, J=6.7 Hz, 2H), 1.39 (t,
J=6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=168.14,
150.43, 133.93, 131.19, 116.66, 116.19, 111.06, 60.26, 14.34.
Compound 6f:[22d] Following the general procedure on a
0.42 mmol scale of 5f, the desired product was isolated as a
purple amorphous solid by flash chromatography using
CH2Cl2; yield: 60 mg (87%); TLC: Rf 0.50 (CH2Cl2);
1H NMR (300 MHz, CDCl3): d=7.85 (d, J=8.3 Hz, 2H),
6.63 (d, J=8.3 Hz, 2H), 4.31 (q, J=7.1 Hz, 2H), 3.97 (s,
2H), 1.35 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=166.71, 150.78, 131.51, 119.99, 113.76, 60.28, 14.39.
Compound 6g:[22d] Following the general procedure on a
0.42 mmol scale of 5g, the desired product was isolated as a
yellow amorphous solid by flash chromatography using
CH2Cl2; yield: 51 mg (88%); TLC: Rf 0.16 (CH2Cl2);
1H NMR (300 MHz, DMSO): d=7.98 (d, J=9.0 Hz, 2H),
6.73 (s, 2H), 6.64 (d, J=9.0 Hz, 2H); 13C NMR (75 MHz,
DMSO): d=156.13, 136.11, 126.82, 112.82, 40.27, 39.99,
39.71.
1633, 1593 cmÀ1 1H NMR (CDCl3, 300 MHz): d=7.49 (d,
;
2H, J=8 Hz), 7.33 (d, 1H, J=8 Hz), 7.20–7.28 (m, 3H),
3.76 (s, 3H); 13C NMR (CDCl3, 75 MHz): d=30.0, 114.1,
120.3, 122.8, 122.9, 128.1, 129.3, 130.0, 137.2, 158.7; MS
(ES+): m/z=223 (M+23)+; anal. calcd. for C10H8N4O
(200.07): C 59.99, H 4.03, N 27.99; found: C 60.03, H 4.26, N
28.16.
Analytical Data for Aniline Products
Compound 6a:[22c] Following the general procedure on a
0.42 mmol scale of 5a, the desired product was isolated as a
purple amorphous solid by flash chromatography using
CH2Cl2/cyclohexane, 5:5; yield: 37 mg (73%); TLC: Rf 0.40
Compound 6h:[22d] Following the general procedure on a
0.84 mmol scale of 5h, the desired product was isolated as
an amorphous brown solid by flash chromatography using
Et2O; yield: 99 mg (82%); TLC: Rf 0.40 (Et2O); IR (neat):
n=3321, 3155, 1607, 1497, 1470, 1435, 1379, 1346, 1289,
1
(CH2Cl2/cyclohexane, 5:5); H NMR (300 MHz, CDCl3): d=
7.17–6.17 (m, 4H), 3.86 (s, 3H), 3.55 (s, 2H); 13C NMR
(75 MHz, CDCl3): d=147.32, 136.13, 121.06, 118.45, 115.01,
110.44, 55.41.
1
1127, 980, 882, 742, 609 cmÀ1; H NMR (300 MHz, CDCl3):
Compound 6b: Following the general procedure on a
0.42 mmol scale of 5b, the desired product was isolated as a
red amorphe solid by flash chromatography using CH2Cl2/
cyclohexane, 3:7; yield: 43 mg (74%); TLC: Rf 0.30
d=8.50 (d, J=2.4 Hz, 1H), 7.96 (d, J=9.5 Hz, 1H), 7.66–
7.51 (m, 1H), 7.49–7.35 (m, 2H), 7.22 (d, J=2.5 Hz, 1H),
3.75 (bs, 2H); 13C NMR (75 MHz, CDCl3): d=143.1, 142.6,
139.7, 129.1, 128.9, 126.9, 125.9, 125.6, 115.0; MS (ES+):
m/z=167 (M+23)+; anal. calcd. for C9H8N2 (144.07): C
74.98, H 5.59, N 19.43; found: C 75.09, H 5.87, N 19.59.
Compound 6i:[22d] Following the general procedure on a
0.84 mmol scale of 5i, the desired product was isolated as a
1
(CH2Cl2/cyclohexane, 3:7); H NMR (300 MHz, CDCl3): d=
7.37 (d, J=7.2 Hz, 1H), 7.11 (t, J=7.1 Hz, 1H), 6.72 (d, J=
3.9 Hz, 2H), 4.03 (s, 2H), 2.38 (s, 3H); 13C NMR (75 MHz,
CDCl3): d=147.05, 133.39, 128.87, 125.68, 125.45, 120.32,
118.81, 115.06, 17.71.
Adv. Synth. Catal. 2010, 352, 1677 – 1687
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1685

Samir Messaoudi et al.
FULL PAPERS
yellow solid by flash chromatography using EtOAc; yield:
60 mg (76%); TLC: Rf 0.24 (EtOAc); H NMR (300 MHz,
[6] D. R. Buckle, B. C. C. Cantello, H. Smith, B. A. Spicer,
J. Med. Chem. 1975, 18, 726–732.
1
CDCl3): d=8.02 (d, J=2.7 Hz), 7.94 (d, J=4.6 Hz, 1H),
7.00 (m, 1H, H4), 6.90 (m, 1H), 3.80 (s, br, 2H); 13C NMR
(75 MHz, CDCl3): d=142.5, 139.5, 137.0, 123.5, 121.0.
[7] P. Cheng, Q. Zhang, Y.-B. Ma, Z.-Y. Jiang, X.-M.
Zhang, F.-X. Zhang, J.-J Chen, Bioorg. Med. Chem.
Lett. 2008, 18, 3787–3789.
[8] a) S. Messaoudi, B. Treguier, A. Hamze, O. Provot, J.-F.
Peyrat, J. R. Rodrigo De Losada, J.-M. Liu, J. Bignon,
J. Wdzieczak-Bakala, S. Thoret, J. Dubois, J.-D. Brion,
M. Alami, J. Med. Chem. 2009, 52, 4538–4542; b) C.
Mousset, A. Giraud, O. Provot, A. Hamze, J. Bignon,
J. M. Liu, S. Thoret, J. Dubois, J.-D. Brion, M. Alami,
Bioorg. Med. Chem. Lett. 2008, 18, 3266–3271; c) A.
Hamze, A. Giraud, S. Messaoudi, O. Provot, J.-F.
Peyrat, J. Bignon, J.-M. Liu, J. Wdzieczak-Bakala, S.
Thoret, J. Dubois, J.-D. Brion, M. Alami, ChemMed-
Chem 2009, 4, 1912–1924; d) O. Provot, A. Giraud, J.-
F. Peyrat, M. Alami, J.-D. Brion, Tetrahedron Lett.
2005, 46, 8547–8550.
Synthesis of Triazole 7a
To
a
mixture of 4-methoxyphenylacetylene (100 mg,
0.75 mmol) and 5a (50 mg, 0.25 mmol) in ethyl alcohol
(1.5 mL), sodium ascorbate (9 mg, 0.05 mmol) and pipeco-
linic acid (9.5 mg, 0.075 mmol) were added, followed by the
addition of copper iodide (5 mg, 0.025 mmol). The heteroge-
neous mixture was stirred vigorously overnight in the dark
at 408C. The precipitate was collected by filtration, washed
with cold water (10 mL) and cyclohexane, dried under
vacuum to afford the pure product as a yellow powder;
yield: 66 mg (80%); TLC: Rf 0.30 (CH2Cl2); mp 200–2028C;
IR (neat): n=1650, 1594, 1470, 1245, 1021 cmÀ1 1H NMR
;
[9] S. Messaoudi, J.-F. Peyrat, J.-D. Brion, M. Alami, Anti-
(300 MHz): d=8.93 (s, 1H), 8.54 (s, 1H), 7.79 (d, J=8.8 Hz,
2H), 7.68 (dd, J=8.0, 1.0 Hz, 1H), 7.60 (m, 1H), 7.38 (d,
J=8.5 Hz, 1H), 7.33–7.23 (m, 1H), 6.91 (d, J=8.8 Hz, 2H),
3.80 (s, 3H), 3.77 (s, 3H); 13C NMR (75 MHz, CDCl3): d=
159.6, 156.5, 147.3, 138.7, 131.5, 129.8, 127.1, 126.6 (2C),
123.3, 123.1, 120.3, 119.2, 114.3 (2C), 114.2, 55.3, 30.3;MS
(ES+): m/z=333 (M+H)+; anal. calcd. for C19H16N4O2
(332.13): C 68.66, H 4.85, N 16.86; found: C 68.59, H 4.72, N
16.66.
cancer Agents Med. Chem. 2008, 8, 761–782.
[10] a) G. Le Bras, C. Radanyi, J.-F. Peyrat, J.-D. Brion, M.
Alami, V. Marsaud, B. Stella, J.-M. Renoir, J. Med.
Chem. 2007, 50, 6189–6200; b) C. Radanyi, G. Le Bras,
S. Messaoudi, C. Bouclier, J.-F. Peyrat, J.-D. Brion, V.
Marsaud, J.-M. Renoir, M. Alami, Bioorg. Med. Chem.
Lett. 2008, 18, 2495–2498; c) C. Radanyi, G. Le Bras,
V. Marsaud, J.-F. Peyrat, S. Messaoudi, M. G. Catelli, J.-
D. Brion, M. Alami, J.-M. Renoir, Cancer Lett. 2008,
274, 88–94; d) C. Radanyi, G. Le Bras, C. Bouclier, S.
Messaoudi, J.-F. Peyrat, J.-D. Brion, M. Alami, J.-M.
Renoir, Biochem. Biophys. Res. Commun. 2009, 379,
514–518; e) D. Audisio, S. Messaoudi, I. Ijjaali, E.
Dubus, F. Petitet, J.-F. Peyrat, J.-D. Brion, M. Alami,
Eur. J. Med. Chem. 2010, 45, 2000–2009.
References
[1] a) P. R. Angibaud, G. C. Sanz, M. G. Venet, P. Muller,
Janssen Pharmaceutica NV, Patent EP 1,162,201, 2001;
b) C. A. Hicks, M. A. Ward, N. Ragumoorthy, S. J.
Ambler, C. P. Dell, D. Dobson, M. J. OꢆNeill, Brain
Res. 1999, 819, 65–74; c) W. W. K. R. Mederski, M.
Osswald, D. Dorsch, M. Christadler, C.-J. Schmitges, C.
Wilm, Bioorg. Med. Chem. Lett. 1997, 7, 1883–1886.
[2] a) P. Hewawasam, N. Chen, M. Ding, J. T. Natale, C. G.
Boissard, S. Yeola, V. K. Gribkoff, J. Starrett, S. I.
Dworetzky, Bioorg. Med. Chem. Lett. 2004, 14, 1615–
1618; b) P. Hewawasam, W. Fan, M. Ding, K. Flint, D.
Cook, G. D. Goggings, R. A. Myers, V. K. Gribkoff,
C. G. Boissard, S. I. Dworetzky, J. E. Starret, N. J.
Lodge, J. Med. Chem. 2003, 46, 2819–2822.
[3] P. Hewawasam, W. Fan, J. Knipe, S. L. Moon, V. C. G.
Boissard, K. Gribkoff, J. E. Starret, Bioorg. Med.
Chem. Lett. 2002, 12, 1779–1783.
[4] K. H. Raitio, J. R. Savinainen, J. Vepsꢇlꢇinen, J. T. Lai-
tinen, A. Poso, T. Jꢇrvinen, T. Nevalainen, J. Med.
Chem. 2006, 49, 2022–2027.
[5] a) A. A. Cordi, P. Desos, J. C. R. Randle, J. Lepagnol,
Bioorg. Med. Chem. 1995, 3, 129–141; b) P. Desos,
J. M. Lepagnol, P. Morain, P. Lestage, A. A. Cordi, J.
Med. Chem. 1996, 39, 197–206; c) R. W. Carling, P. D.
Leeson, K. W. Moore, J. D. Smith, C. R. Moyes, I. M.
Mawer, S. Thomas, T. Chan, R. Baker, A. Foster, S.
Grimwood, J. A. Kemp, G. R. Marshall, M. D. Trickle-
bank, K. L. Saywell, J. Med. Chem. 1993, 36, 3397–
3408.
[11] S. Messaoudi, D. Audisio, J.-D. Brion, M. Alami, Tetra-
hedron 2007, 63, 10202–10210.
[12] D. Audisio, S. Messaoudi, J.-F. Peyrat, J.-D. Brion, M.
Alami, Tetrahedron Lett. 2007, 48, 6928–6932.
[13] J. Anderson, U. Madsen, F. Bjçrkling, X. Liang, Synlett
2005, 2209–2213.
[14] a) W. Zhu, D. Ma, Chem. Commun. 2004, 888–889;
b) D. Ma, Q. Cai, Acc. Chem. Res. 2008, 41, 1450–1460.
[15] During reviewing of this manuscript, Qiao reported the
Cu(I)-catalyzed direct amination of ortho-functional-
ized haloarenes with sodium azide as the amino source:
H. Zhao, H. Fu, R. Qiao, J. Org. Chem. 2010, DOI:
10.1021/jo100345t.
[16] Usually, sodium ascorbate is used as an additive, for
recent examples, see: a) A. K. Feldman, B. Colasson,
V. V. Fokin, Org. Lett. 2004, 6, 3897–3899; b) P. Ap-
pukkuttan, W. Dehaen, V. Fokin, E. Van der Eycken,
Org. Lett. 2004, 6, 4223–4225; c) J. Anderson, S.
Bolvig, X. Liang, Synlett 2005, 2941–2947.
[17] X. Guo, H. Rao, H. Fu, Y. Jiang, Y. Zhao, Adv. Synth.
Catal. 2006, 348, 2197–2202.
[18] At lower temperature (40 or 608C), no reaction oc-
curred; only starting material was recovered un-
changed.
[19] D. Audisio, S. Messaoudi, J.-D. Brion, M. Alami, Eur. J.
Org. Chem. 2010, 1046–1051.
[20] a) J. A. Burlison, L. Neckers, A. B. Smith, A. Maxwell,
B. S. J. Blagg, J. Am. Chem. Soc. 2006, 128, 15529–
1686
asc.wiley-vch.de
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1677 – 1687

An Expeditious Copper-Catalyzed Access to 3-Aminoquinolinones, 3-Aminocoumarins and Anilines
15536; b) M. G. Marcu, A. Chadli, I. Bouhouche, M.
Catelli, L. M. Neckers, J. Biol. Chem. 2000, 275, 37181–
37186; c) A. Maxwell, Biochem. Soc. Trans. 1999, 27,
48–53; d) D. C. Hooper, J. S. Wolfson, G. L. McHugh,
M. B. Winters, M. N. Swartz, Antimicrob. Agents Che-
mother. 1982, 22, 662–671; e) C. Charitos, C. Tzougra-
ki, G. Kokotos, J. Peptide Res. 2000, 56, 373–381; f) A.
Dorlars, C. Schellhammer, J. Schroeder, Angew. Chem.
1975, 87, 693–707; Angew. Chem. Int. Ed. Engl. 1975,
14, 665–679; g) G. Li, D. Wang, M. Sun, G. Li, J. Hu,
Y. Zhang, Y. Yuan, H. Ji, N. Chen, G. Liu, J. Med.
Chem. 2010, 53, 1741–1754; h) M. Alami, J.-D Brion,
S. Messaoudi, A. Hamze, O. Provot, J. Bignon, J.
Bakala-Wdzieczak, J. M. Liu, PCT N8 EP2009/056885-
WO2009/147217A1, 2009.
4546; f) X.-F. Wu, C. Darcel, Eur. J. Org. Chem. 2009,
4753–4756; g) M. K. Elmkaddem, C. Fischmeister,
C. M. Thomas, J.-L. Renaud, Chem. Commun. 2010, 46,
925–927; for the palladium-catalyzed synthesis of ani-
lines, see: h) D. Y. Lee, J. F. Hartwig, Org. Lett. 2005, 7,
1169–1172; i) X. H. Huang, K. W. Anderson, D. Zim,
L. Jiang, A. Klapars, S. L. Buchwald, J. Am. Chem.
Soc. 2003, 125, 6653–6655; j) G. A. Grasa, M. S. Viciu,
J. K. Huang, S. P. Nolan, J. Org. Chem. 2001, 66, 7729–
7737; k) G. D. Vo, J. F. Hartwig, J. Am. Chem. Soc.
2009, 131, 11049–11061; l) Q. Shen, J. F Hartwig, J.
Am. Chem. Soc. 2006, 128, 10028–10029; m) S. Lee, M.
Jorgensen, J. F. Hartwig, Org. Lett. 2001, 3, 2729–2732;
n) X. Huang, S. L. Buchwald, Org. Lett. 2001, 3, 3417–
3419; o) R. J. Lundgren, A. Sappong-Kumankumah, M.
Stradiotto, Chem. Eur. J. 2010, 16, 1983–1991.
[21] In all cases studied, even those where the yields of the
amine products were moderate, the azide intermediate
was never isolated.
[23] a) V. Voskresenska, R. M. Wilson, M. Panov, A. N. Tar-
novsky, J. A. Krause, S. Vyas, A. H. Winter, C. M.
Hadad, J. Am. Chem. Soc. 2009, 131, 11535–11547;
b)Y. Itagaki, T. Iseoka, T. Iida, J. Ohshita, M. Shiotani,
A. Kunai, Chem. Phys. Lett. 2001, 348, 249–254.
[24] S. Dꢈez-Gonzꢉlez, S. P. Nolan, Angew. Chem. 2008, 120,
9013–9016; Angew. Chem. Int. Ed. 2008, 47, 8881–
8884.
[22] For the copper-catalyzed synthesis of anilines using
NH3·H2O as the amine source, see: a) J. Kim, S. Chang,
Chem. Commun. 2008, 3052–3054; b) R. Ntaganda, B.
Dhudshia, C. L. B. Macdonald and A. N. Thadani,
Chem. Commun. 2008, 6200–6202; c) N. Xia, M. Taille-
fer, Angew. Chem. 2009, 121, 343–345; Angew. Chem.
Int. Ed. 2009, 48, 337–339; d) H. Xu, C. Wolf, Chem.
Commun. 2009, 3035–3037; e) L. Jiang, X. Lu, H.
Zhang, Y. Jiang, D. Ma, J. Org. Chem. 2009, 74, 4542–
[25] A. A. Kudale, J. Kendall, C. C. Warford, N. D. Wilkins,
G. J. Bodwell, Tetrahedron Lett. 2007, 48, 5077–5080.
Adv. Synth. Catal. 2010, 352, 1677 – 1687
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1687