Efficient one-pot double Buchwald-Hartwig coupling reaction on 5-phenyl-4-phenylsulfonyl-2,3-dihydrofuran derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.02.049

We report a new and efficient method of conducting a one-pot double Buchwald-Hartwig coupling reaction on 2,3-dihydrofuran derivatives bearing two bromine atoms. This rapid and convenient synthesis allows us to access a great variety of original mixed dic

Full text of DOI:10.1016/j.tetlet.2011.02.049

Tetrahedron Letters 52 (2011) 1919–1923
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient one-pot double Buchwald–Hartwig coupling reaction
on 5-phenyl-4-phenylsulfonyl-2,3-dihydrofuran derivatives
⇑
Ahlem Bouhlel, Christophe Curti, Omar Khoumeri, Patrice Vanelle
Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Universités d0Aix-Marseille I, II, III-CNRS, UMR 6264, Laboratoire Chimie Provence, 27 Bd J.
Moulin, 13385 Marseille Cedex 05, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a new and efficient method of conducting a one-pot double Buchwald–Hartwig coupling reac-
tion on 2,3-dihydrofuran derivatives bearing two bromine atoms. This rapid and convenient synthesis
allows us to access a great variety of original mixed dicoupled compounds. The strategy appears prom-
ising for combinatorial chemistry and pharmacomodulation studies.
Received 26 November 2010
Revised 8 February 2011
Accepted 9 February 2011
Available online 13 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
One-pot
Double Buchwald–Hartwig coupling
Manganese(III) acetate
Microwave
In view of our interest in anti-infectious drug discovery,1 we
have recently explored the antileishmaniasis potential of some
diamidoximes. Several diamidoximes presenting a 2,3-dihydrofu-
ran heterocyclic scaffold and obtained via a single Buchwald–Har-
twig coupling reaction (Scheme 1) showed interesting antiparasitic
activities.2
These promising results encouraged us to synthesize a series of
dicyano-derivatives using various aminobenzonitriles so as to per-
form a double Buchwald–Hartwig reaction. Our earlier results had
shown that Buchwald–Hartwig amination realized on the sulfone
moiety led to better yields.2 Thus, we were able to use this differ-
ence in reactivity to carry out a one-pot double Buchwald–Hartwig
reaction.
Since Buchwald–Hartwig0s discovery, the amination reaction
has successfully been applied to heteroaryl substrates, such as pyr-
idines, quinolines, thiophenes, thiazoles, indoles, 1,3,5-triazines, or
pyrimidines.3 Moreover, C–N cross-coupling reaction on dihalo-
genated compounds has been fairly thoroughly investigated, as re-
ported in the literature.4
However, there have been few examples of efficiently modulat-
ing simple aryl scaffolds, particularly with products containing a
sulfone moiety.5
HON
NH2
CN
H
H
N
N
Br
O
R1
R2
O
O
R1
R2
R1
NH2OH.HCl
KOtBu
Buchwald-Hartwig
O
O
O
reaction
R2
S
S
S
NH2
O
O
O
CN
H2N
NC
NC
R1 = Me, Ph
R2 = Bn, Ph
NOH
Scheme 1. Synthesis of amidoximes.
⇑
Corresponding author.
E-mail address: patrice.vanelle@pharmacie.univ-mrs.fr (P. Vanelle).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.049

1920
A. Bouhlel et al. / Tetrahedron Letters 52 (2011) 1919–1923
1) Na2SO3, NaHCO3,
water, 100 °C
200 W, 20 min.
O
O
O
+
O
S
Br
S
Cl
Br
Br
2) water, 100 °C
200 W, 45 min.
Br
Br
O
O
72%
1
Mn(OAc)3, Cu(OAc)2
AcOH, 80 °C
200 W, 60 min.
H2C
Br
O
O
S
O
52%
2
Br
Scheme 2. Synthesis of 5-(4-bromophenyl)-4-(4-bromophenylsulfonyl)-2,2-diphenyl-2,3-dihydrofuran 2.
To our knowledge, very few one-pot Buchwad–Hartwig cou-
pling reactions have been conducted. One of these is reported as
a tandem inter- and intra-molecular Buchwald–Hartwig amina-
tion;6 while others include an intramolecular domino process,7 or
a double amination on the same aryl halide followed by an inter-
molecular Heck reaction.8
Herein, we report a study allowing a convenient one-pot double
Buchwald–Hartwig coupling reaction using three aminobenzonitr-
iles differing from the cyano position (ortho, meta, or para) and a
2,3-dihydrofuran derivative bearing two bromine atoms. The com-
bination of these aminobenzonitriles involved in C–N cross coupling
reactions allowed us to access several dissymmetric dicoupled
products.
The required starting material, 5-(4-bromophenyl)-4-(4-bro-
mophenylsulfonyl)-2,2-diphenyl-2,3-dihydrofuran (2), was syn-
thesized in two steps (see Scheme 2). Firstly, the b-ketosulfone 1
was obtained by using a previously reported microwave irradiated
method.9 In the second step, the b-ketosulfone 1 was converted
into the desired 2,3-dihydrofuran derivative 2 under microwave
irradiation, via a manganese(III) acetate-based oxidative cycliza-
tion between compound 1 and 1,1-diphenylethene.10
Thus, we obtained our key-substrate, a double aryl halide (2), to
be used in conducting the Buchwald–Hartwig coupling reaction.
First of all, the reaction of 5-(4-bromophenyl)-4-(4-bromophenyl-
sulfonyl)-2,2-diphenyl-2,3-dihydrofuran (2) with 2-aminobenzo-
nitrile was conducted with only one equivalent of amine. We
obtained a mixture of monocoupled 3,11 dicoupled 4aa,11 and
unreacted 2 products (Scheme 3).
Figure 1. ORTEP view of compound 3.
reaction took place was confirmed by X-ray diffraction analysis
of compound 3 (2-{4-[2-(4-bromophenyl)-5,5-diphenyl-4,5-dihy-
drofuran-3-ylsulfonyl]phenylamino}-benzonitrile, Fig. 1).13
In order to optimize the one-pot double Buchwald–Hartwig
reaction, we started by investigating the conditions most likely
to lead to a majority of monocoupled product in the first step.
The study, realized with 2-aminobenzonitrile, examined various
parameters (Table 1).
We began with two catalyst systems and different bases (en-
tries 1–6). We noted that the combined use of Pd(OAc)2/BINAP
and Cs2CO3 appeared to be the best reactive combination.14
Then, studies to optimize the temperature were undertaken
(entries 1, 7–10). We noted that yields of monocoupled product
3 increased from rt to 70 °C, but decreased on reaching 100 °C,
favoring the dicoupled product.
The presence of one monocoupling product (3) revealed a dif-
ference in reactivity between the two brominated positions. This
difference can be attributed to the electron-attracting effect of
the sulfonyl group. Indeed, in the oxidative addition step, Pd(0)
acts as a nucleophile and preferentially attacks the most elec-
tron-deficient position.12 The position on which the first coupling
NH2
CN
H
N
Br
Br
O
O
O
, Toluene
Pd-catalyst,
base,
T°C.
+
CN
O
O
O
S
S
S
O
O
O
2
4aa
3
NH
NH
Br
CN
CN
Scheme 3. Reaction of 2 in a Buchwald–Hartwig reaction with 2-aminobenzonitrile.

A. Bouhlel et al. / Tetrahedron Letters 52 (2011) 1919–1923
1921
Table 1
Survey of Buchwald–Hartwig reaction conditions
Entry
Amine nbr equiv
Catalysta
Baseb
Temperature
Yieldc 2 (%)
Yieldc 3 (%)
Yieldc 4aa (%)
1
2
3
4
5
6
7
8
9
10
11
12d
13e
14
15e
16
17e
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
1
1
1
1.4
1.4
3
Pd(OAc)2/BINAP
Pd(PPh3)4
Cs2CO3
Cs2CO3
K2CO3
Na2CO3
K3PO4
KOtBu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
70
70
70
70
70
70
rt
40
50
100
70
70
70
70
70
70
70
41
82
100
100
100
60
100
83
50
10
40
35
25
28
5
26
7
0
0
0
10
0
8
25
32
29
23
37
41
42
18
16
13
0
0
0
0
0
0
8
8
Pd(OAc)2/INAP
Pd(OAc)2/INAP
Pd(OAc)2/ INAP
Pd(OAc)2/BINAP
Pd(OAc)2/BINAP
Pd(OAc)2/BINAP
Pd(OAc)2/BINAP
Pd(OAc)2/BINAP
Pd(OAc)2/BINAP
Pd(OAc)2/BINAP
Pd(OAc)2/BINAP
Pd(OAc)2/BINAP
Pd(OAc)2/BINAP
Pd(OAc)2/BINAP
Pd(OAc)2/BINAP
19
8
12
20
17
31
67
71
5
0
3
a
b
c
4 mol %.
1.2 equiv base for 1 equiv amine.
Reaction in dry toluene, under argon atmosphere, during 12 h, yields for isolated products based on compound 2.
Crown ether in catalytic amount.
d
e
Crown ether in stoichiometric amount.
NH2
1)
2)
NC
NC
CN
CN
H
N
Pd(OAc)2, BINAP,
Cs2CO3,
H
H
Br
N
N
O
O
O
O
O
1.4 equiv.
NH2
Toluene, 70 °C, 12 h.
+
+
O
O
O
O
S
S
S
S
O
O
Pd(OAc)2, BINAP,
Cs2CO3,
Crown ether
O
2
4bb
4aa
4ab
NH
Br
NH
CN
NH
CN
Toluene, 100 °C, 3 h.
CN
3 equiv.
NC
Scheme 4. Reaction of 2 in the one-pot double sequential Buchwald–Hartwig coupling reaction with 2-aminobenzonitrile and 3-aminobenzonitrile.
Table 2
Synthesis of dicoupled products16
Entrya
First amine
Second amine
Total coupling
yield (%)
Dicoupled of 1st amine
product/yieldb (%)
Dissymmetric
Dicoupled of 2nd amine
product/yieldb (%)
product/yieldb (%)
NC
CN
1
2
3
4
5
6
83
86
71
47
72
47
4aa (31)
4aa (20)
4bb (14)
4bb (11)
4cc (16)
4cc (7)
4ab (35)
4ac (32)
4ba (36)
4bc (21)
4ca (21)
4cb (34)
4bb (17)
4cc(34)
4aa (21)
4cc (15)
4aa (37)
4bb (6)
H2N
NC
H2N
CN
CN
H2N
H2N
CN
CN
NC
H2N
H2N
H2N
NC
H2N
H2N
CN
CN
H2N
CN
H2N
H2N
a
4 mol % Pd (OAc)2, 4 mol % BINAP, 2.86 mmol Cs2CO3, 2.35 mmol of first aminobenzonitrile in dry toluene under argon atmosphere at 70 °C for 12 h; then, 4 mol %
Pd(OAc)2, 4 mol % BINAP, 6.05 mmol Cs2CO3, 5.04 mmol of second aminobenzonitrile, 5.04 mmol crown ether are added at 100 °C.
b
Yields for isolated products based on compound 2.
Concerning the equivalent number of amine (entries 1, 11, 14,
and 16), it appeared that 1.4 equiv of amine led to the best yield
of monocoupled product. Indeed, we observed some selectivity of
monosubstituted product (41% of monocoupled vs 17% of dicou-
pled product).
Moreover, as shown in Table 1, the use of three equivalents of
amine led to complete consumption of the starting material, and
we obtained, as expected, a majority of double-coupled product 4
(67%). This last result (entry 16) is considered at the time when the
second amine was added.

1922
A. Bouhlel et al. / Tetrahedron Letters 52 (2011) 1919–1923
5. (a) Cao, J.; Fine, R.; Gritzen, C.; Hood, J.; Kang, X.; Klebansky, B.; Lohse, D.; Mak,
Next, we explored the compound produced by the sequential
C. C.; McPherson, A.; Noronha, G.; Palanki, M. S. S.; Pathak, V. P.; Renick, J.; Soll,
R.; Zeng, B.; Zhu, H. Bioorg. Med. Chem. Lett. 2007, 17, 5812–5818; (b) Cao, J.;
Soll, R. M.; Noronha, G.; Barrett, K.; Gritzen, C.; Hood, J.; Mak, C. C.; Mc Pherson,
A.; Pathak, V. P.; Renick, J.; Splittgerber, U.; Zeng, B. 2006101977, 2006; PCT Int.
Appl. 2006.
double Buchwald–Hartwig coupling reaction. First, we kept the
same catalyst system and the same base, which were the most effi-
cient. Then, in order to maximize double coupling product, we in-
creased the amount of amine and the temperature. The first
attempt was performed at 100 °C, using 3 equiv of the second
aminobenzonitrile.
6. Loones, K. T. J.; Maes, B. U. W.; Dommisse, R. A.; Lemière, G. L. F. Chem. Commun.
2004, 2466–2467.
7. Cuny, G.; Bois-Choussy, M.; Zhu, J. Angew. Chem., Int. Ed. 2003, 42, 4774–4777.
8. Nandakumar, M. N.; Verkade, J. G. Angew. Chem., Int. Ed. 2005, 44, 3115–3118.
9. For procedure see: (a) Cohen, A.; Crozet, M. D.; Rathelot, P.; Vanelle, P. Green
Chem. 2009, 11, 1736–1742; (b) Curti, C.; Laget, M.; Ortiz Carle, A.; Gellis, A.;
Vanelle, P. Eur. J. Med. Chem. 2007, 42, 880–884. 1-(4-Bromophenyl)-2-(4-
bromophenylsulfonyl)ethanone (1) (with 200 W, and 45 min. in the 2nd step):
white solid, mp 162 °C. 1H NMR (DMSO-d6, 200 MHz): d 5.42 (s, 2H, CH2), 7.74
(d, 2H, CH2, J = 8.6 Hz), 7.84–7.91 (m, 6H, CH2). 13C NMR (DMSO-d6, 50 MHz): d
62.3 (CH2), 128.5 (C), 128.8 (C), 130.3 (2CH), 131.1 (2CH), 132.1 (2CH), 132.5
(2CH), 134.8 (C), 138.8 (C), 188.6 (C). Anal. Calcd for C14H10Br2O3S: C, 40.22; H,
2.41. Found: C, 40.45; H, 2.37..
10. For procedure see: Tetrahedron 2009, 65, 200–205. 5-(4-Bromophenyl)-4-(4-
bromophenylsulfonyl)-2,2-diphenyl-2,3-dihydrofuran (2): white solid, mp 166 °C.
1H NMR (CDCl3, 200 MHz): 3.76 (s, 2H, CH2), 7.29 (s, 10H, 10CH), 7.50 (s, 4H,
4CH), 7.57 (d, 2H, CH2, J = 8.7 Hz), 7.67 (d, 2H, CH2, J = 8.7 Hz). 13C NMR (CDCl3,
50 MHz): 45.3 (CH2), 92.1 (C), 110.4 (C), 115.6 (C), 125.5 (4CH), 126.1 (C), 126.9
(C), 128.1 (2CH), 128.4 (2CH), 128.6 (4CH), 131.3 (4CH), 132.3 (2CH), 140.5 (C),
143.4 (2C), 161.7 (C). Anal. Calcd for C28H20Br2O3S: C, 56.39; H, 3.38. Found: C,
56.36; H, 3.43..
This second coupling reaction was improved by the use of
crown ether. When we tested the influence of crown ether on cou-
pling reactions with the optimized parameters, we observed a sig-
nificant rate enhancement when stoichiometric amount 18-
Crown-6 was added to the reaction mixture (entris 13, 15, and
17). As reported in the literature, crown ether can facilitate the ex-
change of the halide with amine in the intermediate palladium
complex, resulting in the overall reaction rate acceleration.15
These optimizations enabled us to carry out the one-pot double
sequential Buchwald–Hartwig coupling reaction. We used a com-
bination of three aminobenzonitriles on compound 2, which per-
mitted us to obtain several dissymmetric dicoupled products
(4ab, 4ac, 4ba, 4bc, 4ca, and 4cb) (Scheme 4, Table 2).
Moreover, we were able here to synthesize three compounds
per reaction at the same time. The method, therefore, offers great
promise for future pharmacomodulation studies.
11. General procedure for the first step optimization: into
containing 25 mL of dry and degazed toluene, under inert atmosphere were
added compound (0.5 g, 0.84 mmol), 2-aminobenzonitrile (0.139 g,
a two-necked flask
2
1.18 mmol), palladium acetate (0.007 g, 0.03 mmol), BINAP (0.021 g,
0.03 mmol), and cesium carbonate (0.275 g, 1.43 mmol). The reaction
mixture was stirred at 70 °C from 12 h, and monitored by TLC. Solvent
evaporation gave a crude mixture which was solubilized in dichloromethane
and filtered through Celite in order to remove inorganic salts. The mixture was
purified by column chromatography (Chloroform/Petrolum Ether/DiethyEther:
5:4.5:0.5) and products obtained were recrystallized from isopropanol.
2-{4-[2-(4-Bromophenyl)-5,5-diphenyl-4,5-dihydro-furan-3-ylsulfonyl]-
phenylamino}benzonitrile (3): white solid, mp 171 °C. 1H NMR (CDCl3,
200 MHz): d 3.81 (s, 2H, CH2), 6.46 (brs, 1H, 1NH), 7.02–7.09 (m, 3H, 3CH),
7.21–7.35 (m, 10H, 10CH), 7.37 (s, 1H, CH), 7.47–7.51 (m, 1H, CH), 7.55–7.62
(m, 5H, 5CH), 7.67–7.71 (m, 2H, 2CH). 13C NMR (CDCl3, 50 MHz): d 45.6 (CH2),
91.8 (C), 102.2 (C), 111.4 (C), 116.8 (C), 117.5 (CH), 117.7 (2CH), 122.2 (CH),
125.5 (4CH), 125.8 (C), 127.2 (C), 128.0 (2CH), 128.5 (4CH), 129.0 (2CH), 131.2
(2CH), 131.3 (2CH), 133.5 (CH), 134.0 (CH), 134.5 (C), 143.7 (2C), 144.2 (C),
145.2 (C), 160.5 (C). Anal. Calcd for C35H25BrN2O3S: C, 66.35; H, 3.98; N, 4.42.
Found: C, 66.27; H, 4.16; N, 4.32.
In summary, we have developed a novel and efficient method
for a one-pot sequential double Buchwald–Hartwig coupling reac-
tion on 2,3-dihydrofuran derivatives. We show that by controlling
the amount of amine and the temperature, it is possible to synthe-
size dissymmetric dicoupled products in rather good global cou-
pling yields.
This strategy can now be exploited with various amines, allow-
ing access to a wide range of dihydrofuran derivatives. It should
contribute to a combinatorial chemistry approach, of value in phar-
macomodulation studies.
Acknowledgments
2-(4-{2-[4-(2-Cyanophenylamino)phenyl]-5,5-diphenyl-4,5-dihydrofuran-3-
ylsulfonyl}phenyl-amino)benzonitrile (4aa): white solid, mp 220 °C. 1H NMR
(CDCl3, 200 MHz): d 3.82 (s, 2H, CH2), 6.45 (brs, 1H, 1NH), 6.48 (brs, 1H, 1NH),
6.94–7.07 (m, 4H, 4CH), 7.18 (d, 2H, 2CH, J = 8.6 Hz), 7.29–7.37 (m, 10H, 10CH),
7.43–7.64 (m, 8H, 8CH), 7.86 (d, 2H, 2CH, J = 8.6 Hz). 13C NMR (CDCl3, 50 MHz):
d 45.7 (CH2), 91.2 (C), 100.7 (C), 102.0 (C), 109.4 (C), 116.4 (CH), 116.9 (C),
117.2 (C), 117.4 (CH), 117.7 (2CH), 118.1 (2CH), 121.0 (CH), 122.1 (CH), 122.5
(C), 125.6 (4CH), 127.9 (2CH), 128.5 (4CH), 128.9 (2CH), 131.5 (2CH), 133.3
(CH), 133.5 (CH), 133.9 (CH), 134.0 (CH), 134.8 (C), 143.2 (C), 143.9 (2C), 144.3
(C), 145.0 (C), 145.2 (C), 161.1 (C). HMRS (ESI): m/z calcd for C42H30N4O3S
M+H+: 671.2111. Found: 671.2110.
This work was supported by the Centre National de le Recher-
che Scientifique and the Université de la Méditerranée. We would
like to express our thanks to Dr. V. Remusat for RMN spectra
recording.
References and notes
1. (a) Kabri, Y.; Azas, N.; Dumètre, A.; Hutter, S.; Laget, M.; Verhaeghe, P.; Gellis,
A.; Vanelle, P. Eur. J. Med. Chem. 2010, 45, 616–622; (b) Juspin, T.; Laget, M.;
Terme, T.; Azas, N.; Vanelle, P. Eur. J. Med. Chem. 2010, 45, 840–845; (c) Crozet,
M. D.; Botta, C.; Gasquet, M.; Curti, C.; Remusat, V.; Hutter, S.; Chapelle, O.;
Azas, N.; De Meo, M.; Vanelle, P. Eur. J. Med. Chem. 2009, 44, 653–659; (d)
Verhaeghe, P.; Azas, N.; Gasquet, M.; Hutter, S.; Ducros, C.; Laget, M.; Rault, S.;
Rathelot, P.; Vanelle, P. Bioorg. Med. Chem. Lett. 2008, 18, 396–401; (e) Upcroft,
J. A.; Dunn, L. A.; Wright, J. M.; Benakli, K.; Upcroft, P.; Vanelle, P. Antimicrob.
Agents Chemother. 2006, 50, 344–347; (f) Rathelot, P.; Azas, N.; El-Kashef, H.;
Delmas, F.; Di Giorgio, C.; Timon-David, P.; Maldonado, J.; Vanelle, P. Eur. J. Med.
Chem. 2002, 37, 671–679; (g) Vanelle, P.; Meuche, J.; Maldonado, J.; Crozet, M.
P.; Delmas, F.; Timon-David, P. Eur. J. Med. Chem. 2000, 35, 157–162; (h)
Upcroft, J. A.; Campbell, R. W.; Benakli, K.; Uocroft, P.; Vanelle, P. Antimicrob.
Agents Chemother. 1999, 43, 73–76; (i) Delmas, F.; Gasquet, M.; Timon-David,
P.; Madadi, N.; Vanelle, P.; Vaille, A.; Maldonado, J. Eur. J. Med. Chem. 1993, 28,
23–27; (j) Jentzer, O.; Vanelle, P.; Crozet, M. P.; Maldonado, J.; Barreau, M. Eur. J.
Med. Chem. 1991, 26, 687–697.
12. Schröter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245–2267.
13. Crystal data for compound 3: C35H27BrN2O4S, colorless prism (0.4 ꢀ 0.2 ꢀ 0.2
mm3), MW = 651.56, orthorhombic, space group Pna21 (T = 293 K),
a = 12.3746(2) Å, b = 9.9706(2) Å, c = 24.0578(5) Å,
V = 2968.30(10) Å3, Dcalcd = 14.58 g cmꢁ1
Z = 4,
F(0 0 0) = 1336, index ranges 0 6 h 6 15, 0 6 k 6 12, ꢁ30 6 l 6 0,
a
= 90°, b = 90°,
c = 90°,
,
l
= 1.499 mmꢁ1
,
h
range = 3.12°–27.29°, 388 variables and one restraint, were refined for 2762
reflections with l P 2 l to R = 0.05, GoF = 1.135.
Crystallographic data for the structure have been deposited with the
r
3
Cambridge Crystallographic Data Centre (CCDC) under number 798040. Copy
of the data can be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK (fax: +44 (0) 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk).
14. (a) Scholz, U.; Schlummer, B. Tetrahedron 2005, 61, 6379–6385; (b) Wolfe, J. P.;
Buchwald, S. L. J. Org. Chem. 2000, 65, 1144–1157; (c) Scholz, U.; Wolfe, J. P.;
Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 7215–7216.
15. (a) Torisawa, Y.; Nishi, T.; Minamikawa, J.-I. Bioorg. Med. Chem. Lett. 2000, 10,
2489–2491; (b) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805–818.
2. Bouhlel, A.; Curti, C.; Dumètre, A.; Laget, M.; Crozet, M. D.; Azas, N.; Vanelle, P.
Bioorg. Med. Chem. 2010, 18, 7310–7320.
3. (a) Das, A. R.; Medda, A.; Singha, R. Tetrahedron Lett. 2010, 51, 1099–1102; (b)
Patriciu, O.-I.; Fînaru, A.-L.; Massip, S.; Léger, J.-M.; Jarry, C.; Guillaumet, G. Eur.
J. Org. Chem. 2009, 22, 3753–3764; (c) Begouin, A.; Hesse, S.; Queiroz, M.-J. R. P.;
Kirsch, G. Eur. J. Org. Chem. 2007, 10, 1678–1982; (d) Queiroz, M.-J. R. P.;
Calhelha, R. C.; Kirsch, G. Tetrahedron 2007, 63, 13000–13005; (e) Hostyn, S.;
Maes, B. U. W.; Van Baelen, G.; Gulevskaya, A.; Meyers, C.; Smits, K. Tetrahedron
2006, 62, 4684; (f) Sing Li, C.; Dixon, D. D. Tetrahedron Lett. 2004, 45, 4257–
4260.
16. General procedure for one pot double sequential Buchwald–Hartwig coupling
reaction: into a two-necked flask containing 50 mL of dry and degazed toluene,
under inert atmosphere were added compound
2 (1 g, 1.68 mmol),
corresponding first aminobenzonitrile (0.278 g, 2.35 mmol), palladium
acetate (0.015 g, 0.07 mmol), BINAP (0.042 g, 0.07 mmol), and cesium
carbonate (0.552 g, 2.86 mmol). The reaction mixture was stirred at 70 °C
from 12 h. Then were added the second aminobenzonitrile (0.595 g,
5.04 mmol), crown ether (1.33 g, 5.04 mmol), palladium acetate (0.015 g,
0.07 mmol), BINAP (0.042 g, 0.07 mmol), and cesium carbonate (1.17 g,
4. (a) Koley, M.; Schnuerch, M.; Mihovilovic, M. D. Synlett 2010, 1505–1510; (b)
Romero, M.; Harrak, Y.; Basset, J.; Orue, J. A.; Pujol, M. D. Tetrahedron 2009, 65,
1951–1956; (c) Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1996, 61, 7240–7241.

A. Bouhlel et al. / Tetrahedron Letters 52 (2011) 1919–1923
1923
6.05 mmol). The reaction mixture was stirred at 100 °C for 3 h, and
monitored by TLC. Solvent evaporation gave a crude mixture which was
solubilized in dichloromethane and filtered through Celite in order to remove
inorganic salts. The mixture was purified by column chromatography
(Dichloromethane/Petrolum Ether/DiethyEther: 6.5:3:0.5) and products
obtained were recrystallized from isopropanol.
3-(4-{2-[4-(3-Cyanophenylamino)phenyl]-5,5-diphenyl-4,5-dihydrofuran-3-
ylsulfonyl}phenylamino)benzonitrile (4bb): white solid, mp 188 °C. 1H NMR
(DMSO-d6, 200 MHz): d 3.78 (s, 2H, CH2), 7.10 (d, 2H, 2CH, J = 8.8 Hz), 7.20 (d,
2H, 2CH, J = 8.7 Hz), 7.27–7.40 (m, 9H, 9CH), 7.45–7.51 (m, 9H, 9CH), 7.58 (d,
2H, 2CH, J = 8.8 Hz), 7.82 (d, 2H, 2CH, J = 8.7 Hz), 9.04 (s, 1H, 1NH), 9.13 (s, 1H,
1NH). 13C NMR (DMSO-d6, 50 MHz): d 45.3 (CH2), 90.2 (C), 108.7 (C), 112.2
(2C), 115.3 (3CH), 118.7 (C), 118.8 (C), 119.2 (C), 119.9 (CH), 120.9 (CH), 122.3
(CH), 123.2 (CH), 124.1 (CH), 125.0 (CH), 125.1 (4CH), 127.6 (2CH), 128.5 (5CH),
130.6 (2CH), 130.7 (2CH), 131.1 (2CH), 131.5 (C), 142.2 (C), 143.0 (C), 144.1
(2C), 145.1 (C), 146.8 (C), 159.7 (C). HMRS (ESI): m/z calcd for C42H30N4O3S
M+H+: 671.2111. Found: 671.2113.
4-(4-{2-[4-(4-Cyanophenylamino)phenyl]-5,5-diphenyl-4,5-dihydrofuran-3-
ylsulfonyl}phenylamino)benzonitrile (4cc): white solid, mp 209 °C. 1H NMR
(DMSO-d6, 200 MHz): d 3.80 (s, 2H, CH2), 7.12–7.32 (m, 10H, 10CH), 7.35–7.39
(m, 3H, 3CH), 7.44–7.48 (m, 4H, 4CH), 7.59–7.71 (m, 7H, 7CH), 7.80–7.84 (m,
2H, 2CH), 9.32 (s, 1H, 1NH), 9.39 (s, 1H, 1NH). 13C NMR (DMSO-d6, 50 MHz): d
45.3 (CH2), 90.7 (C), 101.1 (C), 102.0 (C), 109.4 (C), 116.4 (2CH), 117.2 (2CH),
117.3 (4CH), 119.6 (C), 119.8 (C), 120.5 (C), 125.3 (4CH), 127.9 (2CH), 128.6
(2CH), 128.7 (4CH), 131.2 (2CH), 132.7 (C), 133.9 (4CH), 144.1 (C), 144.2 (2C),
145.9 (C), 146.1 (C), 146.9 (C), 160.0 (C). HMRS (ESI): m/z calcd for C42H30N4O3S
M+H+: 671.2111. Found: 671.2111.
(2CH), 134.3 (C), 134.5 (CH), 144.1 (C), 144.2 (C), 144.3 (2C), 146.9 (C), 147.8
(C), 159.7 (C). HMRS (ESI): m/z calcd for C42H30N4O3S M+H+: 671.2111. Found:
671.2110.
2-(4-{3-[4-(3-Cyanophenylamino)phenyl]-5,5-diphenyl-4,5-dihydrofuran-2-
ylsulfo-nyl}phenylamino)benzonitrile (4ba): yellow solid, mp 121 °C. 1H NMR
(DMSO-d6, 200 MHz): d 3.78 (s, 2H, CH2), 7.05–7.21 (m, 5H, 5CH), 7.27–7.59
(m, 18H, 18CH), 7.77–7.81 (m, 3H, 3CH), 8.98 (s, 1H, 1NH), 9.13 (s, 1H, 1NH).
13C NMR (DMSO-d6, 50 MHz): d 45.4 (CH2), 90.4 (C), 103.8 (C), 109.1 (C), 112.4
(C), 115.5 (2CH), 115.7 (CH), 115.9 (2CH), 117.7 (C), 118.9 (C), 119.7 (CH), 120.8
(CH), 121.1 (CH), 122.9 (CH), 123.5 (CH), 125.3 (4CH), 127.8 (2CH), 128.7 (4CH),
130.9 (2CH), 131.1 (2CH), 131.3 (CH), 131.7 (C), 134.3 (CH), 134.5 (C), 142.4 (C),
144.3 (2C), 145.1 (C), 145.9 (C), 147.0 (C), 159.9 (C). HMRS (ESI): m/z calcd for
C
42H30N4O3S M+H+: 671.2111. Found: 671.2115.
3-(4-{2-[4-(4-Cyanophenylamino)phenyl]-5,5-diphenyl-4,5-dihydrofuran-3-
ylsulfonyl}phenylamino)benzonitrile (4bc): yellow solid, mp 211 °C. 1H NMR
(DMSO-d6, 200 MHz): d 3.79 (s, 2H, CH2), 7.10 (d, 2H, 2CH, J = 8.7 Hz), 7.22–
7.41 (m, 11H, 11CH), 7.45–7.49 (m, 7H, 7CH), 7.58 (d, 2H, 2CH, J = 8.7 Hz), 7.67
(d, 2H, 2CH, J = 8.7 Hz), 7.82 (d, 2H, 2CH, J = 8.7 Hz), 9.14 (s, 1H, 1NH), 9.32 (s,
1H, 1NH). 13C NMR (DMSO-d6, 50 MHz): d 45.4 (CH2), 90.6 (C), 101.0 (C), 109.5
(C), 112.4 (C), 115.5 (CH), 116.4 (2CH), 117.2 (2CH), 117.3 (2CH), 117.9 (CH),
118.9 (C), 120.6 (C), 121.1 (CH), 123.5 (C), 125.3 (4CH), 127.3 (CH), 127.9 (2CH),
128.7 (4CH), 130.9 (2CH), 131.2 (2CH), 131.5 (C), 133.9 (2CH), 142.4 (C), 144.1
(C), 144.3 (2C), 145.8 (C), 146.9 (C), 159.7 (C).). HMRS (ESI): m/z calcd for
C
42H30N4O3S M+H+: 671.2111. Found: 671.2114.
2-(4-{3-[4-(4-Cyanophenylamino)phenyl]-5,5-diphenyl-4,5-dihydrofuran-2-
ylsulfonyl}phenylamino)benzonitrile (4ca): yellow solid, mp 140 °C. 1H NMR
(DMSO-d6, 200 MHz): d 3.79 (s, 2H, CH2), 7.01–7.05 (m, 1H, 1CH), 7.12–7.16
(m, 2H, 2CH), 7.20–7.27 (m, 5H, 5CH), 7.29–7.38 (m, 6H, 6CH), 7.44–7.47 (m,
5H, 5CH), 7.55–7.71 (m, 5H, 5CH), 7.76–7.84 (m, 2H, 2CH), 8.98 (s, 1H, 1NH),
9.39 (s, 1H, 1NH). 13C NMR (DMSO-d6, 50 MHz): d 45.4 (CH2), 90.6 (C), 102.0
(C), 103.9 (C), 109.0 (C), 115.7 (CH), 115.9 (2CH), 116.4 (CH), 117.2 (2CH), 117.3
(2CH), 119.7 (C), 120.8 (C), 122.9 (C), 125.3 (4CH), 127.9 (2CH), 128.6 (2CH),
128.7 (4CH), 131.2 (2CH), 132.9 (C), 133.9 (2CH), 134.3 (CH), 134.5 (CH), 144.3
(2C), 145.0 (C), 145.8 (C), 146.0 (C), 146.2 (C), 160.2 (C). HMRS (ESI): m/z calcd
for C42H30N4O3S M+H+: 671.2111. Found: 671.2108.
3-(4-{3-[4-(4-Cyanophenylamino)phenyl]-5,5-diphenyl-4,5-dihydrofuran-2-
ylsulfonyl}phenylamino)benzonitrile (4cb): yellow solid, mp 139 °C. 1H NMR
(DMSO-d6, 200 MHz): d 3.79 (s, 2H, CH2), 7.08–7.28 (m, 6H, 6CH), 7.32–7.39
(m, 6H, 6CH), 7.44–7.49 (m, 8H, 8CH), 7.55–7.71 (m, 4H, 4CH), 7.79–7.83 (m,
2H, 2CH), 9.13 (s, 1H, 1NH), 9.39 (s, 1H, 1NH). 13C NMR (DMSO-d6, 50 MHz): d
45.4 (CH2), 90.5 (C), 102.0 (C), 108.7 (C), 112.4 (C), 115.5 (2CH), 116.4 (CH),
117.2 (2CH), 119.0 (C), 120.1 (CH), 121.1 (C), 122.5 (C), 123.4 (CH), 124.3 (CH),
125.3 (4CH), 127.8 (2CH), 128.7 (4CH), 130.8 (2CH), 131.2 (2CH), 131.3 (2CH),
132.9 (C), 133.9 (2CH), 142.4 (C), 143.1 (C), 144.3 (2C), 145.3 (C), 146.2 (C),
160.1 (C). HMRS (ESI): m/z calcd for C42H30N4O3S M+H+: 671.2111. Found:
671.2114.
2-(4-{2-[4-(3-Cyanophenylamino)phenyl]-5,5-diphenyl-4,5-dihydrofuran-3-
ylsulfonyl}phenylamino)benzonitrile (4ab): white solid, mp 220 °C. 1H NMR
(DMSO-d6, 200 MHz): d 3.78 (s, 2H, CH2), 7.03 (d, 2H, 2CH, J = 8.7 Hz), 7.17-7.22
(m, 3H, 3CH), 7.25–7.39 (m, 8H, 8CH), 7.44–7.51 (m, 8H, 8CH), 7.57 (d, 2H, 2CH,
J = 8.8 Hz), 7.78–7.7.82 (m, 3H, 3CH), 9.04 (s, 1H, 1NH), 9.12 (s, 1H, 1NH). 13C
NMR (DMSO-d6, 50 MHz): d 45.4 (CH2), 90.4 (C), 105.0 (C), 108.9 (C), 112.3 (C),
115.5 (2CH), 115.7 (2CH), 117.4 (C), 109.0 (C), 119.4 (C), 120.1 (CH), 121.9 (CH),
122.5 (CH), 123.8 (CH), 124.3 (CH), 125.3 (4CH), 127.3 (CH), 127.8 (2CH), 128.5
(2CH), 128.7 (4CH), 130.8 (CH), 131.3 (2CH), 131.9 (C), 134.3 (CH), 143.1 (C),
144.2 (C), 144.3 (2C), 145.2 (C), 147.7 (C), 159.9 (C). HMRS (ESI): m/z calcd for
C
42H30N4O3S M+H+: 671.2111. Found: 671.2108.
2-(4-{2-[4-(4-Cyanophenylamino)phenyl]-5,5-diphenyl-4,5-dihydrofuran-3-
ylsulfonyl}phenylamino)benzonitrile (4ac): yellow solid, mp 138 °C. 1H NMR
(DMSO-d6, 200 MHz): d 3.79 (s, 2H, CH2), 7.01–7.16 (m, 3H, 3CH), 7.20–7.39
(m, 10H, 10CH), 7.44–7.47 (m, 5H, 5CH), 7.55–7.71 (m, 5H, 5CH), 7.77–7.84 (m,
3H, 3CH), 9.12 (s, 1H, 1NH), 9.31 (s, 1H, 1NH). 13C NMR (DMSO-d6, 50 MHz): d
45.4 (CH2), 90.6 (C), 101.0 (C), 105.0 (C), 109.6 (C), 115.7 (2CH), 115.9 (CH),
116.4 (2CH), 117.2 (2CH), 117.3 (2CH), 119.6 (C), 120.6 (C), 122.0 (CH), 123.8
(CH), 125.3 (4CH), 127.8 (2CH), 128.7 (4CH), 131.2 (2CH), 131.7 (C), 133.9