Pd/Cu-catalyzed direct alkenylation of azole heterocycles with alkenyl halides

Article abstract of DOI:10.1002/ejoc.201000959

Direct alkenylation of azole heterocycles through Pd-Cu-catalyzed C-H bond activation has been reported using alkenyl bromides as the coupling partners. The reaction enables the introduction of various mono-, di-, or trisubstituted alkenyl bromides as wel

Full text of DOI:10.1002/ejoc.201000959

FULL PAPER
DOI: 10.1002/ejoc.201000959
Pd/Cu-Catalyzed Direct Alkenylation of Azole Heterocycles with Alkenyl
Halides
Sophian Sahnoun,[a] Samir Messaoudi,[a] Jean-Daniel Brion,[a] and Mouâd Alami*[a]
Dedicated to the memory of Dr. Keith Fagnou
Keywords: C-H activation / Palladium / Copper / Nitrogen heterocycles / Alkenes
Direct alkenylation of azole heterocycles through Pd–Cu-cat-
alyzed C–H bond activation has been reported using alkenyl
bromides as the coupling partners. The reaction enables the
introduction of various mono-, di-, or trisubstituted alkenyl
bromides as well as a benzyl chloride to the caffeine core.
ficiencies. First, most methods allow the alkenylation of
only a few types of heterocycles, thus limiting the scope
and generality of the methodologies. Second, in most cases
studied, specific conditions are often required for every het-
erocycle to be successfully alkenylated. Thus, the develop-
ment of new and general catalyst systems for this type of
transformation is strongly desired.
Introduction
Direct transition-metal-catalyzed functionalization of C–
H bonds in heterocycles has received significant attention
in modern organic chemistry due to its atom economy, high
functional group tolerance, and the possibilities for trans-
formation of the unreactive C–H bonds into diverse func-
tions in one operation. In particular, direct arylation of het-
erocycles has already gained widespread acceptance within
the synthetic community, because of its capacity to utilize
simpler and cheaper precursors for the construction of com-
plex frameworks.[1] In contrast to the much more developed
palladium-catalyzed C–H arylation reaction of various het-
erocycles, direct alkenylations of heteroaromatics with vinyl
halides have received much less attention. In these instances,
a very few number of heterocycles were studied. Grierson
et al.[2] reported direct alkenylation of 5-phenyloxazoles
with (E)-β-bromostyrenes under copper catalysis. Other
groups have extended this methodology to the palladium-
catalyzed alkenylation of other oxazoles, including 5-aryl-
oxazoles[3] and ethyl oxazole-4-carboxylate.[4] In 2008,
Doucet et al.[5] successfully accomplished the palladium-
catalyzed direct C–H bond activation of benzoxazole and
benzothiazole[2] with alkenyl bromides. More recently, other
groups demonstrated that the palladium-catalyzed direct
C–H alkenylation of imidazopyridines,[6] sydnones,[7] and
N-iminopyridinium ylides[8] can be successfully achieved.
Although these processes can compensate for the conven-
tional coupling processes, they still suffer from some de-
During our recent studies on the metal-catalyzed direct
arylation reaction of free-(NH2) adenines,[9] we reported a
preliminary result where the newly developed catalytic sys-
tem also enabled, for the first time, efficient Pd–Cu-cata-
lyzed direct vinylation of free-(NH2) adenine with β-(E)-
bromostyrene in a satisfactory 55% yield under ligandless
conditions. It should be noted that both palladium and cop-
per catalysts are necessary to achieve this transformation.
In pursuit of our efforts to further extend the scope of the
functionalization of heteroaromatics via C–H bond acti-
vation, combined with our interest to discover news
hsp90[10] inhibitors,[11] we herein report a novel method for
the direct Pd–Cu-catalyzed alkenylation of various hetero-
cycles, including xanthines, free-(NH2) adenines, benzimid-
azoles, benzoxazoles, benzothiazoles, and thiazoles with
various alkenyl bromides. This new approach provides
straightforward and general access to a wide variety of alk-
enyl heterocycles, which would be useful due to their signifi-
cant biological importance.[12]
Results and Discussion
Initial investigations were performed by coupling caffeine
(1a) with 1-bromo-2-methylpropene (2a) as model sub-
strates by using Pd(OAc)2 (10 mol-%) and P(o-tolyl)3
(20 mol-%); tBuOLi (2 equiv.) was added as a base in diox-
ane, and the mixture was heated in a sealed tube at 110 °C
for 16 h. Satisfyingly, these preliminary conditions appeared
[a] Univ Paris-Sud, CNRS, BioCIS UMR 8076,
Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie,
5 rue J.-B. Clément, Châtenay-Malabry, 92296, France
Fax: +33-1-46835828
E-mail: mouad.alami@u-psud.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000959.
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S. Sahnoun, S. Messaoudi, J.-D. Brion, M. Alami
FULL PAPER
to be efficient for the direct alkenylation of 1a; however, much slower or did not proceed (not shown in Table 1). A
only moderate conversion was observed (68%; Table 1, En- brief survey of solvents was therefore undertaken in which
try 1). By adding a catalytic amount of CuI (20 mol-%), the ethereal solvents (1,4-dioxane and THF) were found to be
conversion of 1a dramatically increased, and 3a was ob- the most effective (Table 1, Entries 3 and 16). THF was cho-
tained in a good 67% yield (Table 1, Entry 2). It should be sen to evaluate the effect of other parameters on the reac-
noted that both palladium and copper catalysts are neces- tion, including the amount of catalysts, temperature, and
sary to achieve this transformation, as no reaction occurred reaction time. After a series of assays (not shown in
when carrying out the C–H alkenylation in the presence of Table 1), the best result was obtained at 130 °C for 2 h by
CuI but without a palladium catalyst. The catalytic activity using Pd(acac)2 (2.5 mol-%) and CuI (5 mol-%) as catalysts,
of Pd(acac)2 proved to be similar to that of Pd(OAc)2, lead- P(o-tolyl)3 (5 mol-%) as the ligand, and tBuOLi (2 equiv.)
ing to 3a in a slightly better yield (72%; Table 1, Entry 3). as the base in THF. Under these conditions, 3a was formed
The use of other palladium sources, however, did not pro- in 87% yield (Table 1, Entry 18). It should be noted that
mote the C–H alkenylation reaction or induced a lowering both palladium and copper catalysts are necessary to
of the conversion rate (Table 1, Entries 4–7). As summa- achieve successfully this transformation.
rized in Table 1, evaluation of ligand sources revealed that
With a viable coupling procedure in hand, attention was
P(o-tolyl)3 was superior to all other choices (Table 1, En- turned to the generality of the process, and the coupling of
try 3 vs. Entries 8–13).
alkenyl halides with structurally diverse heterocycles 1a–h
was studied (Figure 1). Remarkably, this direct alkenylation
reaction appeared to be quite general with respect to dif-
ferent heterocyclic cores (Tables 2 and 3). First, we investi-
gated the scope of the alkenylation reaction of 1a,b with
various vinyl bromides. As summarized in Table 2, various
8-alkenyl caffeine derivatives were obtained with mono-,
di-, or trisubstituted alkenyl bromides 2. Although alkenyl
bromides are sterically bulky, all of them afforded moderate
to good yields. (Z)-Bromopropene (2b) gave coupling prod-
uct 3c in a moderate 42% yield as a single (E) isomer
(Table 2, Entry 3). Reaction with α-substituted or α,β-di-
substituted alkenyl bromides 2c or 2d gave 3d or 3e in 53
or 85% yield, respectively, revealing a low influence of the
substituent position on alkenyl bromides on the outcome of
the coupling process (Table 2, Entries 4 and 5). In addition,
the reactivity of various α/β-substituted bromostyrenes 2f–
i was evaluated in the direct alkenylation with 1a to give
compounds 3g–j in moderate to good yields (Table 2, En-
tries 7–10). One can note that compound 3i may be re-
garded as an analog of isocombretastatin A-4 (isoCA-4), a
highly promising cytotoxic and antitubulin agent developed
in our group.[13]
Table 1. Optimization of C-alkenylation of 1a with 1-bromo-2-
methylpropene.[a]
Entry
[Pd]
Ligand
Solvent
T [°C]/ Conv.[b] Yield[c]
Time [h]
[%]
[%]
1
2
3
Pd(OAc)2
Pd(OAc)2
Pd(acac)2
P(o-tolyl)3 dioxane
P(o-tolyl)3 dioxane
P(o-tolyl)3 dioxane
110/16
110/16
110/16
110/16
110/16
110/16
110/16
110/16
110/16
110/16
110/16
110/16
110/16
110/16
68[d]
100
100
0
59
35
Ͻ5
69
16
62
49
–
67
72
–
–
–
–
–
–
–
–
–
–
64
–
4
Pd(OH)2/C P(o-tolyl)3 dioxane
5
6
7
8
PdCl2
Pd2(dba)3
Pd/C
P(o-tolyl)3 dioxane
P(o-tolyl)3 dioxane
P(o-tolyl)3 dioxane
P(2-furyl)3 dioxane
P(mesityl)3 dioxane
binap
DPEphos
X-phos
xantphos
P(o-tolyl)3
P(o-tolyl)3 CH3CN 110/16
P(o-tolyl)3
P(o-tolyl)3
P(o-tolyl)3
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
9
10
11
12
13
14
15
16
17
18
dioxane
dioxane
dioxane
dioxane
toluene
36
65
100
42
THF
THF
110/16
130/16
130/2
88
69
86
87[g,h]
100
THF[e]
100[f]
[a] Substrate 1a (1 equiv.), 2a (1.2 equiv.), and tBuOLi (2 equiv.)
were heated in a sealed Schlenk tube in the presence of [Pd]
(10 mol-%), CuI (20 mol-%), ligand (20 mol-%). [b] The conversion
was determined by 1H NMR spectroscopic analysis of the crude
reaction mixture and was based on remaining 1a. [c] Isolated yield.
[d] Conversion when the reaction was performed without CuI as
co-catalyst. [e] The use of dioxane instead of THF resulted in 83%
conversion. [f] A conversion of 47% was obtained when the reac-
tion was performed without CuI as co-catalyst. [g] Yield of 3a when
carrying out the reaction in the presence of Pd(acac)2 (2.5 mol-%),
CuI (5 mol-%), and P(o-tolyl)3 (5 mol-%). [h] No reaction occurred
without palladium catalyst and/or without P(o-tolyl)3 ligand.
Figure 1. Heterocycles used in this study.
Subsequently, to further expand the scope of our meth-
odology, we used this new catalytic system in the direct C–
H alkenylation of other azole heterocycles (Table 3). Over-
The screening reaction was continued with respect to the all, we were pleased with the generality of our methodology.
base. The use of tBuOLi was found to be optimal, as reac- The reaction proceeded regioselectively in satisfactory
tions with Cs2CO3, tBuOK, K3PO4, and Na2CO3 were yields with adenine 1c to afford the corresponding 8-alken-
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Pd/Cu-Catalyzed Direct Alkenylation of Azole Heterocycles
Table 2. Direct alkenylation of caffeine (1a) with alkenyl halides.[a] and provided the desired coupling products 4c and 4d in
excellent yields (Table 3, Entries 3 and 4). 1,3-Benzoxazole
(1e; Table 3, Entries 5 and 6) and 1,3-benzothiazole (1f;
Table 3, Entry 7) were found to be suitable substrates, al-
though in the last case a stoichiometric amount of copper
iodide and a higher reaction temperature (160 °C) were re-
quired to obtain total conversion.
Table 3. Direct alkenylation of heterocycles 1c–i with alkenyl bro-
mides.[a]
[a] Substrate 1 (1 equiv.), vinyl halide 2 (1.2 equiv.), Pd(acac)2
(2.5 mol-%), CuI (5 mol-%), P(o-tolyl)3 (5 mol-%), tBuOLi
[a] Substrate 1 (1 equiv.), vinyl halide 2 (1.2 equiv.), Pd(acac)2
(2 equiv.), THF (0.2 ), 130 °C, (time: see Experimental Section).
(2.5 mol-%), CuI (5 mol-%), P(o-tolyl)3 (5 mol-%), tBuOLi
[b] Isolated yield. [c] Used as a 85:15 E/Z ratio. [d] Reaction was
(2 equiv.), THF (0.2 ), 130 °C, (time: see Experimental Section).
performed in dioxane at 160 °C for 4 h. [e] Isolated as a pure (E)
[b] Isolated yield. [c] Reaction was performed in NMP using CuI
isomer.
(1 equiv.). [d] Reaction was performed without CuI. [e] Reaction
was performed in dioxane at 160 °C using CuI (1 equiv.). [f] Used
as a 85:15 E/Z ratio.
yladenines 4a and 4b (Table 3, Entries 1 and 2). Noteworthy
for this substrate, the reaction was performed in NMP by
Remarkably, 4-methylthiazole (1g) was regioselectively
using a stoichiometric amount of copper iodide for total vinylated at the C2 position to furnish 4h in a good yield
completion. It was found that the presence of a free NH2 (Table 3, Entry 8). However, compounds with higher pKa
group at the C6 position was tolerated and may be useful value (Ն30)[15] such as imidazole 1h failed and the starting
for selective C–N bond-forming reactions to access 6,8,9- material was recovered unchanged (Table 3, Entry 9).
trisubstitued purines of biological interest.[14] N-Benzyl
This optimized protocol was subsequently used to exam-
benzimidazole (1d) also underwent clean C2 alkenylation ine the direct coupling reaction of caffeine (1a) with p-
Eur. J. Org. Chem. 2010, 6097–6102
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S. Sahnoun, S. Messaoudi, J.-D. Brion, M. Alami
FULL PAPER
1076, 1038, 978, 845, 758, 745 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 6.02 (br. s, 1 H), 3.90 (s, 3 H), 3.57 (s, 3 H), 3.39 (s, 3 H), 2.22
(s, 3 H), 2.01 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 155.3,
151.7, 150.0, 149.1, 148.0, 109.6, 106.3, 31.5, 29.6, 27.8, 27.6,
20.6 ppm. MS (ES+): m/z = 249 [M + H]+. C12H16N4O2 (248.13):
calcd. C 58.05, H 6.50, N 22.57; found C 57.89, H 6.33, N 22.32.
methoxybenzyl chloride.[4,16] A preliminary experiment, de-
picted below, showed that p-methoxybenzyl chloride re-
acted with 1a under our optimized conditions to give cou-
pling product 5a. It should be mentioned that it was not
necessary to add copper iodide as a co-catalyst to obtain a
satisfactory 56% yield (Scheme 1), despite the fact that the
reaction conditions had never been optimized. To the best
of our knowledge, this is the first example of the palladium-
catalyzed direct benzylation of caffeine, which provides
novel access to a library of C8 benzylcaffeines related to
PU3 as hsp90 inhibitors.[17]
Compound 3b: Reaction time: 2 h. Yield: 82% (266 mg); white solid;
m.p. 173–175 °C. TLC: Rf = 0.55 (c-hexane/EtOAc, 5:5). IR (neat):
ν = 2972, 2911, 2877, 2359, 1696, 1654, 1603, 1543, 1479, 1433,
˜
1397, 1342, 1225, 1122, 1073, 922, 831, 758, 748, 700 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 7.48 (m, 2 H), 7.28 (m, 3 H), 6.02
(s, 1 H), 5.20 (s, 2 H), 3.91 (s, 3 H), 3.57 (s, 3 H), 2.22 (s, 3 H),
2.02 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 155.3, 151.8,
150.4, 149.4, 148.4, 137.7, 128.9 (2 C), 128.5 (2 C), 127.5, 109.8,
106.6, 44.5, 31.8, 29.8, 27.7, 20.8 ppm. MS (ES+): m/z = 325 [M +
H]+. C18H20N4O2 (324.16): calcd. C 66.65, H 6.21, N 17.27; found
C 66.39, H 6.02, N 17.06.
Compound 3c: Reaction time: 2 h. Yield: 42% (98 mg); beige solid;
m.p. 190–192 °C. TLC: Rf = 0.34 (c-hexane/EtOAc, 5:5). IR (neat):
ν = 2951, 2920, 1695, 1648, 1544, 1488, 1426, 1394, 1315, 1294,
˜
1
1222, 1040, 969, 933, 743 cm–1. H NMR (300 MHz, CDCl3): δ =
Scheme 1. Pd-catalyzed direct benzylation of caffeine (1a) with p-
methoxybenzyl chloride.
6.99 (dq, J = 15.3, 7.0 Hz, 1 H), 6.31 (dq, J = 15.4, 1.6 Hz, 1 H),
3.94 (s, 3 H), 3.56 (s, 3 H), 3.38 (s, 3 H), 1.99 (dd, J = 6.9, 1.6 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 155.3, 151.7, 150.0,
148.4, 138.0, 115.5, 107.3, 31.4, 29.6, 27.8, 18.9 ppm. MS (ES+):
m/z = 235 [M + H]+. C11H14N4O2 (234.11): calcd. C 56.40, H 6.02,
N 23.92; found C 56.22, H 5.87, N 23.84.
Conclusions
In summary, we have developed a highly efficient and
versatile Pd/Cu-catalyzed C–H alkenylation reaction of a
wide range of heterocycles, including caffeine, adenine,
benzimidazole, benzoxazole, benzothiazole and thiazole.
The substrate scope of the reaction turned out to be very
broad to include not only azoles but also a variety of mono-,
di- or trisubstituted alkenyl bromides. This procedure offers
an important advance in the direct C–H alkenylation to
provide various alkenylheterocycles. In addition, the first re-
ported example of Pd-catalyzed direct benzylation of caf-
feine has been described. We believe that this methodology
should find broad applications in synthetic organic chemis-
try and pharmaceutical sciences.
Compound 3d: Reaction time: 4 h. Yield: 53% (124 mg); white solid;
m.p. 144–146 °C. TLC: Rf = 0.34 (c-hexane/EtOAc, 5:5). IR (neat):
ν = 2958, 2929, 1694, 1653, 1537, 1491, 1432, 1366, 1339, 1287,
˜
1251, 1216, 1123, 1043, 975, 937, 745 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 5.61 (br. s, 1 H), 5.39 (br. s, 1 H), 4.00 (s, 3 H), 3.55
(s, 3 H), 3.38 (s, 3 H), 2.18 (br. s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 155.5, 155.5, 151.6, 147.7, 133.5, 120.9, 108.0, 33.8,
29.6, 27.9, 22.1 ppm. MS (ES+): m/z = 235 [M + H]+. C11H14N4O2
(234.11): calcd. C 56.40, H 6.02, N 23.92; found C 56.19, H 5.69,
N 23.78.
Compound 3e: Reaction time: 2 h. Yield: 85% (223 mg); white solid;
m.p. 162–164 °C. TLC: Rf = 0.28 (c-hexane/EtOAc, 5:5). IR (neat):
ν = 2917, 1709, 1661, 1539, 1486, 1418, 1365, 1342, 1288, 1222,
˜
1132, 1076, 1038, 979, 740 cm–1. 1H NMR (300 MHz, CDCl3): δ =
3.74 (s, 3 H), 3.55 (s, 3 H), 3.37 (s, 3 H), 1.92 (s, 3 H), 1.85 (s, 3
H), 1.55 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 155.4,
154.8, 151.7, 148.1, 138.9, 117.8, 106.9, 32.2, 29.7, 27.8, 22.3, 20.1,
18.1 ppm. MS (ES+): m/z = 263 [M + H]+. C13H18N4O2 (262.14):
calcd. C 59.53, H 6.92, N 21.36; found C 59.45, H 6.81, N 21.17.
Experimental Section
General Procedure for Direct Alkenylation of Caffeine A flame-
dried resealable 2–5-mL Pyrex reaction vessel was charged with the
solid reactant(s): Pd(acac)2 (2.5 mol-%), CuI (5 mol-%), P(o-tolyl)3
(5 mol-%), heterocycle 1 (1 mmol), alkenyl bromide (1.2 mmol),
and tBuOLi (2 mmol). The reaction vessel was capped with a rub-
ber septum, evacuated, and backfilled with argon; this evacuation/
backfill sequence was repeated one additional time. The liquid reac-
tant(s) and THF (5 mL per mmol) were added through the septum.
The septum was replaced with a Teflon screw cap. The reaction
vessel was sealed, and then heated at 130 °C (time: see the Experi-
mental Section). The resulting suspension was cooled to room tem-
perature and filtered through a pad of Celite eluting with ethyl
acetate, and the inorganic salts were removed. The filtrate was con-
centrated and purification of the residue by silica gel column
chromatography gave the desired product.
Compound 3f: Reaction time: 2 h. Yield: 55% (167 mg); beige solid;
m.p. 88–90 °C. TLC: R = 0.46 (c-hexane/EtOAc, 5:5). IR (neat): ν
˜
f
= 2952, 2927, 2857, 2362, 1700, 1650, 1600, 1546, 1434, 1339, 1290,
1227, 1041, 967, 919, 744, 731 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 6.99 (dt, J = 15.3, 7.1 Hz, 1 H), 6.27 (dt, J = 15.4, 1.5 Hz, 1
H), 3.94 (s, 3 H), 3.56 (s, 3 H), 3.37 (s, 3 H), 2.30 (qd, J = 7.4,
1.4 Hz, 2 H), 1.51 (m, 2 H), 1.30 (m, 6 H), 0.88 (t, J = 6.7 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 155.4, 151.8, 150.2,
148.5, 143.3, 114.2, 107.5, 33.5, 31.8, 31.5, 29.8, 29.1, 28.7, 28.0,
22.7, 14.2 ppm. MS (ES+): m/z = 305 [M + H]+. C16H24N4O2
(304.19): calcd. C 63.13, H 7.95, N 18.41; found C 63.01, H 7.83,
N 18.26.
Compound 3a: Reaction time: 2 h. Yield: 87% (216 mg); white solid;
m.p. 193–195 °C. TLC: Rf = 0.39 (c-hexane/EtOAc, 5/5). IR (neat):
Compound 3g: Reaction time: 2 h. Yield: 60% (178 mg); light-
brown solid; m.p. 219–221 °C. TLC: Rf = 0.52 (c-hexane/EtOAc,
ν = 2944, 2918, 1693, 1655, 1545, 1435, 1368, 1340, 1288, 1225, 5:5). IR (neat): ν = 2953, 2924, 2862, 2361, 1692, 1662, 1598, 1545,
˜
˜
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Pd/Cu-Catalyzed Direct Alkenylation of Azole Heterocycles
1476, 1447, 1426, 1305, 1288, 1226, 1035, 967, 908, 845, 757,
Compound 4c: Reaction time: 2 h. Yield: 83% (217 mg); beige solid;
1
741 cm–1. H NMR (300 MHz, CDCl3): δ = 7.77 (d, J = 15.8 Hz, m.p. 95–97 °C. TLC: R = 0.48 (c-hexane/EtOAc, 5:5). IR (neat): ν
˜
f
1 H), 7.55 (m, 2 H), 7.37 (m, 3 H), 6.87 (d, J = 15.8 Hz, 1 H), 4.02
(s, 3 H), 3.59 (s, 3 H), 3.37 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 155.2, 151.7, 149.9, 148.5, 138.3, 135.5, 129.6, 129.0
(2 C), 127.4 (2 C), 111.2, 107.9, 31.6, 29.8, 28.0 ppm. MS (ES+):
m/z = 297 [M + H]+. C16H16N4O2 (296.13): calcd. C 64.85, H 5.44,
N 18.91; found C 64.58, H 5.33, N 18.69.
= 2926, 2906, 1649, 1601, 1494, 1451, 1397, 1366, 1324, 1283, 1232,
1177, 1001, 922, 841, 745, 727, 693 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.79 (m, 1 H), 7.24 (m, 6 H), 7.03 (m, 2 H), 6.15 (m,
1 H), 5.32 (s, 2 H), 2.25 (s, 3 H), 1.96 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 151.3, 143.2, 136.2, 134.5 128.9 (2 C), 127.7,
126.2 (2 C), 122.4, 122.1, 119.4, 111.4, 109.4, 44.4, 48.9, 27.1,
20.8 ppm. MS (ES+): m/z = 263 [M + H]+. C18H18N2 (262.15):
calcd. C 82.41, H 6.92, N 10.68; found C 82.19, H 6.81, N 10.41.
Compound 3h: Reaction time: 2 h. Yield: 48% (142 mg); beige solid;
m.p. 139–141 °C. TLC: Rf = 0.42 (c-hexane/EtOAc, 5:5). IR (neat):
ν = 2956, 2908, 1693, 1656, 1601, 1537, 1499, 1433, 1370, 1336,
˜
Compound 4d: Reaction time: 2 h. Yield: 82% (255 mg); beige solid;
m.p. 177–179 °C. TLC: Rf = 0.55 (c-hexane/EtOAc, 7:3). IR (neat):
1286, 1252, 1218, 1033, 976, 936, 920, 743, 703 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 7.3 (m, 3 H), 7.22 (m, 2 H), 5.99 (s, 1 H),
5.73 (s, 1 H), 3.57 (s, 3 H), 3.56 (s, 3 H), 3.35 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 155.5, 151.9, 151.6, 148.0, 137.8,
137.1, 128.9 (3 C), 126.5 (2 C), 122.5, 108.3, 33.4, 29.8, 27.9 ppm.
MS (ES+): m/z = 297 [M + H]+. C16H16N4O2 (296.13): calcd. C
64.62, H 5.23, N 18.51; found C 64.85, H 5.44, N 18.91.
ν = 2357, 1630, 1493, 1447, 1409, 1368, 1329, 1207, 1071, 981, 929,
˜
1
756, 731, 700 cm–1. H NMR (300 MHz, CDCl3): δ = 8.00 (d, J =
15.8 Hz, 1 H), 7.83 (d, J = 7.8 Hz, 1 H), 7.53 (m, 2 H), 7.30 (m, 9
H), 7.13 (m, 2 H), 7.04 (d, J = 15.8 Hz, 1 H), 5.44 (s, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 151.0, 143.1, 137.5, 136.0, 135.8,
135.5, 129.0 (3 C), 128.7 (2 C), 127.9, 127.2 (2 C), 126.1 (2 C),
122.8 (2 C), 119.3, 112.9, 109.6, 46.8 ppm. MS (ES+): m/z = 311 [M
+ H]+. C22H18N2 (310.15): calcd. C 85.13, H 5.85, N 9.03; found C
84.93, H 5.78, N 8.91.
Compound 3i: Reaction time: 2 h. Yield: 40% (155 mg); beige solid;
m.p. 207–209 °C. TLC: Rf = 0.42 (c-hexane/EtOAc, 2:8). IR (neat):
ν = 3002, 2945, 2922, 2838, 1704, 1651, 1584, 1538, 1510, 1433,
˜
1413, 1370, 1323, 1287, 1251, 1230, 1185, 1124, 1036, 1006, 978,
947, 840 cm–1. 1H NMR (300 MHz, CDCl3): δ = 6.48 (s, 2 H), 5.97
(s, 1 H), 5.76 (s, 1 H), 3.85 (s, 3 H), 3.81 (s, 6 H), 3.67 (s, 3 H),
3.61 (s, 3 H), 3.41 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
155.5, 153.5 (2 C), 151.7, 151.6, 147.9, 138.8, 137.8, 132.9, 122.2
108.3, 104.0 (2 C), 60.9, 56.2 (2 C), 33.4, 29.8, 27.9 ppm. MS (ES+):
m/z = 287 [M + H]+. C19H22N4O5 (386.16): calcd. C 59.06, H 5.74,
N 14.50; found C 58.79, H 5.67, N 14.36.
Compound 4e: Reaction time: 2 h. Yield: 65% (113 mg); brown so-
lid; m.p. 58–60 °C. TLC: Rf = 0.47 (c-hexane/EtOAc, 9:1). IR
(neat): ν = 2985, 2922, 2862, 2357, 1650, 1600, 1546, 1452, 1355,
˜
1248, 1134, 1058, 1001, 948, 841, 745 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.61 (m, 1 H), 7.40 (m, 1 H), 7.21 (m, 2 H), 6.19 (m,
1 H), 2.29 (s, 3 H), 1.97 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 162.8, 150.6, 149.7, 141.9, 124.2, 124.1, 119.6, 111.9, 110.1,
27.6, 21.0 ppm. MS (ES+): m/z = 174 [M + H]+. C11H11NO
(173.08): calcd. C 76.28, H 6.40, N 8.09; found C 76.03, H 6.19, N
7.92.
Compound 3j: Reaction time: 4 h at 160 °C. Yield: 88% (395 mg);
yellow solid; m.p. 229–231 °C. TLC: Rf = 0.29 (c-hexane/EtOAc,
7:3). IR (neat): ν = 2953, 2361, 2146, 1689, 1651, 1604, 1540, 1490,
˜
Compound 4f: Reaction time: 2 h. Yield: 51% (96 mg); light-brown
solid; m.p. 58–60 °C. TLC: Rf = 0.49 (c-hexane/EtOAc, 9:1). IR
1442, 1424, 1374, 1343, 1288, 1221, 1074, 1041, 1025, 978, 750,
1
696 cm–1. H NMR (300 MHz, CDCl3): δ = 7.12 (m, 15 H), 3.56
(neat): ν = 2983, 2923, 2854, 2362, 1633, 1530, 1454, 1376, 1275,
˜
(s, 3 H), 3.47 (s, 3 H), 3.39 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 155.3, 153.4, 151.6, 149.2, 148.2, 141.9, 140.8, 138.9,
131.0 (2 C), 130.0 (2 C), 129.5 (2 C), 128.2 (5 C), 128.0 (2 C), 127.9,
127.5, 127.1, 106.7, 32.5, 29.8, 27.9 ppm. MS (ES+): m/z = 449 [M
+ H]+. C28H24N4O2 (448.19): calcd. C 74.98, H 5.39, N 12.49;
found C 74.83, H 5.11, N 12.16.
1177, 1058, 1003, 919, 847, 763 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 7.72 (m, 1 H), 7.50 (m, 1 H), 7.22 (m, 2 H), 2.26 (s, 3 H), 2.19
(s, 3 H), 1.98 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.5,
149.9, 142.8, 141.6, 124.4, 124.0, 119.6, 117.5, 110.2, 23.4, 23.0,
16.8 ppm. MS (ES+): m/z = 188 [M + H]+. C12H13NO (187.10):
calcd. C 76.98, H 7.00, N 7.48; found C 76.79, H 6.69, N 7.24.
Compound 4a: Reaction time: 2 h. Yield: 66% (184 mg); white solid;
m.p. 205–207 °C. TLC: Rf = 0.25 (CH2Cl2/MeOH, 95:5). IR (neat):
Compound 4g: Reaction time: 4 h. Yield: 52% (98 mg); brown solid;
m.p. 79–81 °C. TLC: R = 0.56 (c-hexane/EtOAc, 9:1). IR (neat): ν
˜
f
ν = 3316, 3146, 2937, 2911, 2358, 2336, 1657, 1601, 1571, 1498,
˜
= 3050, 2903, 2854, 2357, 2338, 1650, 1540, 1434, 1367, 1316, 1241,
1222, 1157, 1124, 1070, 1015, 887, 839, 756, 724, 638 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 7.99 (d, J = 7.9 Hz, 1 H), 7.84 (d,
J = 7.9 Hz, 1 H), 7.45 (t, J = 7.2 Hz, 1 H), 7.33 (t, J = 7.2 Hz, 1
H), 6.61 (s, 1 H), 2.27 (s, 3 H), 2.04 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 165.5, 153.2, 146.0, 134.7, 126.0, 124.6,
122.7, 121.2, 119.6, 27.8, 20.9 ppm. MS (ES+): m/z = 190 [M +
H]+. C11H11NS (189.06): calcd. C 69.80, H 5.86, N 7.40; found C
69.62, H 5.71, N 7.39.
1453, 1430, 1370, 1324, 1295, 1170, 1074, 1032, 979, 943, 889, 829,
1
727, 700 cm–1. H NMR (300 MHz, CDCl3): δ = 8.5 (br. s, 1 H),
7.24 (m, 7 H), 6.32 (s, 1 H), 5.39 (s, 2 H), 2.25 (s, 3 H), 1.93 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 149.6, 147.6, 146.2,
137.0, 128.5 (2 C), 127.3, 126.6 (2 C), 110.9, 44.4, 26.9, 20.4 ppm.
MS (ES+): m/z = 280 [M + H]+. C16H17N5 (279.15): calcd. C 68.79,
H 6.13, N 25.07; found C 68.56, H 6.03, N 24.97.
Compound 4b: Reaction time: 4 h at 160 °C). Yield: 54% (259 mg);
beige solid; m.p. 231–233 °C. TLC: Rf = 0.28 (CH2Cl2/MeOH,
Compound 4h: Reaction time: 2 h. Yield: 63% (97 mg); orange oil.
95:5). IR (neat): ν = 3310, 3140, 3061, 2364, 2218, 2176, 1638, 1596,
˜
TLC: R = 0.47 (c-hexane/EtOAc, 9:1). IR (neat): ν = 2976, 2924,
˜
f
1573, 1494, 1455, 1449, 1369, 1327, 1298, 1077, 1029, 907, 760,
727, 696 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.28 (s, 1 H), 7.10
(m, 16 H), 6.75 (d, J = 7.7 Hz, 2 H), 6.63 (d, J = 7.7 Hz, 2 H), 5.82
(s, 2 H), 4.80 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
154.95, 152.70 (2 C), 152.33, 150.78, 147.83, 141.97, 141.43, 139.52,
136.59, 131.20 (2 C), 130.44 (2 C), 129.83 (2 C), 128.87, 128.70 (2
C), 128.17 (3 C), 128.04 (4 C), 127.98 (3 C), 127.70, 127.33,
2856, 2357, 1688, 1647, 1516, 1442, 1374, 1306, 1237, 1109, 1043,
977, 863 cm–1. 1H NMR (300 MHz, CDCl3): δ = 6.77 (s, 1 H), 6.52
(s, 1 H), 2.43 (s, 3 H), 2.10 (s, 3 H), 1.96 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 165.1, 152.3, 141.7, 119.6, 112.3, 27.4, 20.5,
17.0 ppm. MS (ES+): m/z = 154 [M + H]+. C8H11NS (153.06):
calcd. C 62.70, H 7.24, N 9.14; found C 62.61, H 7.19, N 9.03.
45.92 ppm. MS (ES+): m/z = 480 [M + H]+. C32H25N5 (479.21): Compound 5a: Reaction time: 16 h. Yield: 56% (176 mg); white so-
calcd. C 80.14, H 5.25, N 14.60; found C 80.01, H 5.02, N 14.33. lid; m.p. 172–174 °C. TLC: R = 0.5 (EtOAc). IR (neat): ν = 2961,
˜
f
Eur. J. Org. Chem. 2010, 6097–6102
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6101

S. Sahnoun, S. Messaoudi, J.-D. Brion, M. Alami
FULL PAPER
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2938, 2842, 2362, 1697, 1649, 1543, 1512, 1445, 1427, 1289, 1243,
1218, 1179, 1025, 976, 855 cm–1. 1H NMR (300 MHz, CDCl3): δ =
7.08 (d, J = 8.7 Hz, 2 H), 6.82 (d, J = 8.7 Hz, 2 H), 4.07 (s, 2 H),
3.78 (s, 3 H), 3.76 (s, 3 H), 3.57 (s, 3 H), 3.36 (s, 3 H) ppm. 13C
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27.8 ppm. MS (ES+): m/z = 313 [M + H]+. C16H18N4O3 (314.14):
calcd. C 61.13, H 5.77, N 17.82; found C 61.02, H 5.69, N 17.79.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the NMR spectra for all new compounds.
Acknowledgments
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Nationale de la Recherche et de la Technologie (MENRT) for a
doctoral fellowship to S.S. Thanks also to E. Morvan for her help
in the NMR experiments and A. Solgadi for performing mass spec-
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Received: July 7, 2010
Published Online: September 15, 2010
6102
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Eur. J. Org. Chem. 2010, 6097–6102