Site-selective Suzuki-Miyaura reactions of 2,6-dichlorobenzoxazole

Article abstract of DOI:10.1016/j.tet.2012.11.021

Suzuki-Miyaura reactions of 2,6-dichlorobenzoxazole provide a convenient access to arylated benzoxazoles. The reactions proceed with excellent site-selectivity in favour of position 2, due to electronic reasons.

Full text of DOI:10.1016/j.tet.2012.11.021

Tetrahedron 69 (2013) 2081e2086
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Site-selective SuzukieMiyaura reactions of 2,6-dichlorobenzoxazole
,
b
c
Aws M. Hamdya, Nadi Eleya a, Hamid H. Mohammed a , Tamas Patonay ,
ꢀ
,d,
Anke Spannenberg d, Peter Langer a
*
a
€
€
Institut fur Chemie, Universitat Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b Department of Organic Chemistry, University of Al-Mustansiriyah, Baghdad, Iraq
c
ꢀ
Department of Organic Chemistry, University of Debrecen, H-4032 Debrecen, Egyetem ter 1, Hungary
Leibniz-Institut fur Katalyse e.V. an der Universitat Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
d
€
€
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 August 2012
Received in revised form 25 October 2012
Accepted 6 November 2012
Available online 13 November 2012
SuzukieMiyaura reactions of 2,6-dichlorobenzoxazole provide a convenient access to arylated benzox-
azoles. The reactions proceed with excellent site-selectivity in favour of position 2, due to electronic
reasons.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Benzoxazole
Site-selectivity
Palladium
Catalysis
SuzukieMiyaura reaction
1. Introduction
OH
O
The benzoxazole moiety is an important structural motif in
many biologically active natural products and pharmaceutical
compounds. Examples include pseudopteroxazole and salvianen
(Scheme 1).1,2 Benzoxazoles also represent important molecules
in medicinal chemistry.3 Previous reports revealed that substituted
benzoxazoles, such as the herbicide fenoxaprop, possess
diverse chemotherapeutic activities, including antibiotic,4 anti-
microbial,5e8 antivirial9 and antitumour activities.10,11 The 2-aryl-6-
hydroxybenzoxazole ERB-041 represents an oestrogen receptor-
O
F
N
O
O
N
O
OH
Cl
HO
Fenoxaprop
ERB-041
O
O
O
N
N
b
agonist.12
H
Traditional methods for the synthesis of substituted benzox-
azoles include the oxidation of aromatic amines with persulfate
and condensation of ortho-aminophenols with aldehydes.13,14 Re-
cently, general methods for the copper-catalyzed intramolecular
CeO coupling reaction of 2-haloanilides were reported.15 Nagasawa
et al. reported that 2-arylbenzoxazoles and 2,6-diarylbenzoxazoles
can be prepared by copper-catalyzed intramolecular oxidative CeO
coupling of benzanilides.16 Palladium catalyzed multi-component
reactions of aryl halides, isocyanides and aminoalcohols have also
been used for the synthesis of benzoxazoles.17
Salvianen
Pseudopteroxazole
Scheme 1. Benzoxazoles in biologically active compounds.
In recent years, site-selective Pd catalyzed cross-coupling re-
actions have attracted considerable attention.18,19 Herein, we report
a new approach to arylated benzoxazoles by site-selective Suzu-
kieMiyaura cross-coupling reactions of commercially available 2,6-
dichlorobenzoxazole (1) with arylboronic acids.
* Corresponding author. Fax: þ49 381 4986412; e-mail address: peter.langer@
uni-rostock.de (P. Langer).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.021

2082
A.M. Hamdy et al. / Tetrahedron 69 (2013) 2081e2086
Table 2
Synthesis of 4aee
The SuzukieMiayura reaction of commercially available 2,6-
dichlorobenzoxazole (1) with 1.2 equiv of arylboronic acids 2aej
afforded the 2-aryl-6-chlorobenzoxazoles 3aej in 72e90% yields
with very good site-selectivity (Scheme 2, Table 1). The reactions
2
4
Ar
% (4)a
a
b
c
a
b
c
d
e
3,5-Me2C6H3
4-EtC6H4
4-(MeO)C6H4
3-FC6H4
89
88
88
75
75
d
e
ArB(OH)2
2a-j
4-ClC6H4
N
O
N
O
a
Cl
Ar
Yields of isolated products.
i
Cl
Cl
1
3a-j
The one-pot reaction of 1 with two different arylboronic acids
was next studied. The reaction of 1 with 1.2 equiv of an arylboronic
Scheme 2. Synthesis of 3aej. Reagents and conditions: i, 1 (1.0 equiv), 2aej (1.2 equiv),
Pd(PPh3)4 (3 mol %), K2CO3 (aqueous solution, 2 M), 1,4-dioxane, 80 ꢀC, 6 h.
acid and subsequent addition of
a second arylboronic acid
(1.2 equiv) afforded the 2,6-diarylbenzoxazoles 5a,b containing two
different aryl groups in good yields (Scheme 5, Table 3). During the
optimization, it proved to be important to carry out the first step at
80 ꢀC and the second step at 120 ꢀC. It also proved to be important
to add a fresh portion of catalyst together with the second aryl-
boronic acid. The structure of 5b was independently confirmed by
X-ray crystal structure analysis (Fig. 1).20
Table 1
Synthesis of 3aej
2,3
Ar
% (3)a
a
b
c
d
e
f
g
h
i
3,5-Me2C6H3
4-EtC6H4
4-(MeO)C6H4
3-FC6H4
4-ClC6H4
Ph
2,3,4-(MeO)3C6H2
3-MeC6H4
4-tBuC6H4
4-(F3C)C6H4
90
81
90
83
88
90
80
87
72
83
1) Ar1B(OH)2
2) Ar2B(OH)2
2a,c,e,i
N
O
N
Ar1
j
Cl
Ar2
a
O
i,ii
Yields of isolated products.
Cl
2
5a,b
Scheme 5. Synthesis of 5a,b. Reagents and conditions: i, 1) 1 (1.0 equiv), Ar1B(OH)2)
1.2 equiv), Pd(PPh3)4 (3 mol %), K2CO3 (aqueous solution, 2 M), 1,4-dioxane, 80 ꢀC, 6 h;
2) Ar2B(OH)2 (1.2 equiv), Pd(PPh3)4 (3 mol %), K2CO3 (aqueous solution, 2 M), 120 ꢀC,
8 h.
were carried out under standard conditions for SuzukieMiyaura
reactions: Pd(PPh3)4 (3.0 mol %) was employed as the catalyst and
an aqueous solution of K2CO3 was used as the base (dioxane, 80 ꢀC,
6 h). Very good yields were obtained for both electron rich and poor
arylboronic acids. During the optimization, it proved to be impor-
tant to carry out the reactions at 80 ꢀC. A higher temperature
resulted in the formation of significant amounts of diarylated
products.
Table 3
Synthesis of 5a,b
2
5
Ar1
Ar2
% (5)a
The structure of product 3c was unambiguously confirmed by
HMBC correlation between carbon atom C-2 of the benzoxazole
moiety with the ortho hydrogens of the attached p-methoxyphenyl
group (Scheme 3).
e,a
i,c
a
b
4-ClC6H4
3,5-Me2C6H3
4-(MeO)C6H4
84
72
4-tBuC6H4
a
Yields of isolated products.
N
OCH3
Cl
O
Scheme 3. Important HMBC correlation of compound 3c.
The SuzukieMiyaura reaction of 1 with 2.2 equiv of various
arylboronic acids 2aee afforded the 2,6-diarylbenzoxazoles 4aee
in 75e89% yields (Scheme 4, Table 2). The reactions had to be
carried out at a higher temperature (120 ꢀC) as compared to the
synthesis of products 3. Very good yields were obtained for prod-
ucts derived from both electron rich and poor arylboronic acids.
Fig. 1. Crystal structure of 5b.
The site-selectivity in favour of position 2 can be explained by
the fact that carbon C2 is more electron deficient than carbon C6
(Scheme 6). Palladium catalyzed cross-coupling reactions usually
occur at the electronically more deficient position.18,19
We have reported a new approach to arylated benzoxazoles by
site-selective SuzukieMiyaura cross-coupling reactions of com-
mercially available 2,6-dichlorobenzoxazole with arylboronic acids.
The reactions proceed with excellent site-selectivity in favour of
position C-2, which is more electron deficient than position C-6.
ArB(OH)2
2a-e
N
O
N
O
Cl
Ar
Cl
i
Ar
1
4a-e
Scheme 4. Synthesis of 4aee. Reagents and conditions: i,
(2.2 equiv), Pd(PPh3)4 (26 mg, 6 mol %), K2CO3 (aqueous solution, 2 M), 1,4-dioxane,
1 (1.0 equiv), 2aee
120 ꢀC, 8 h.

A.M. Hamdy et al. / Tetrahedron 69 (2013) 2081e2086
2083
NMR (300 MHz, CDCl3):
d
¼3.80 (s, 3H, OCH3), 6.94 (d, J¼9.1 Hz, 2H,
More electron deficient
N
O
ArH), 7.22 (dd, J¼1.9, 8.4 Hz, 1H, ArH), 7.46 (d, J¼2.0 Hz, 1H, ArH),
7.54 (d, J¼8.4 Hz, 1H, ArH), 8.07 (d, J¼9.0 Hz, 2H, ArH). 13C NMR
Cl
Cl
(62.9 MHz, CDCl3):
d
¼55.4 (OCH3), 111.0, 114.4 (CH), 119.1 (C), 120.0,
125.0, 129.4 (CH), 130.0, 141.0, 150.8, 162.5, 163.8 (C). IR (KBr, cmꢂ1):
¼3073.4, 3042.6, 3004.7, 2978.0, 2946.9, 2902.8, 2840.9, 2038.2,
n
Less electron deficient
1917.1, 1866.6 (w), 1616.8, 1601.9 (m), 1580.7 (w), 1502.1 (m), 1467.2
(w), 1452.6, 1439.5, 1428.3, 1420.4 (m), 1347.7 (w), 1332.6 (s), 1319.7,
1305.9 (m), 1283.7 (w), 1255.0, 1235.5 (m), 1283.7 (w), 1255.0 (s),
1235.5 (m), 1186.9 (w), 1174.9, 1118.4 (m), 1054.4, 1022.0 (s), 1005.9,
919.9, 864.3, 842.7 (m), 831.3, 807.7 (s), 789.4, 738.7, 698.5, 641.1,
634.4, 594.1 (m), 552.7, 531.3 (w). GCeMS (EI, 70 eV): m/z (%)¼261
Scheme 6. Possible explanation for the site-selectivity of reactions of 1.
2. Experimental section
([M]þ 37Cl, 30), 259 ([M]þ, 35Cl, 100), 244 (32), 216 (27). HRMS (ESI-
,
TOF/MS) calcd for C14H1035ClNO2 ([MþH]þ, 35Cl): 260.4780, found
2.1. General procedure for the synthesis of 3aej
260.4600.
A 1,4-dioxane solution (3 mL) of 1, arylboronic acid (1.2 equiv),
aqueous K2CO3 (2.0 M, 1.0 mL) and Pd(PPh3)4 (3 mol %) was heated
at 80 ꢀC for 6 h under argon atmosphere. After cooling to 20 ꢀC, H2O
was added and the reaction mixture was extracted with CH2Cl2
(3ꢁ25 mL). The organic layers were dried (Na2SO4), filtered and
concentrated in vacuo. The residue was purified by column chro-
matography (silica gel, heptane/EtOAc).
2.1.4. 6-Chloro-2-(3-fluorophenyl)benzo[d]oxazole
(3d). Starting
with 1 (70 mg, 0.372 mmol), 2d (61 mg, 0.446 mmol), Pd(PPh3)4
(6 mg, 3 mol %), K2CO3 (2 M, 1.0 mL) and 1,4-dioxane (3 mL), 4d was
isolated as a white solid (77 mg, 83%), mp 122e124 ꢀC. 1H NMR
(300 MHz, CDCl3):
d
¼7.14e7.21 (m, 1H, ArH), 7.28 (dd, J¼2.11,
8.23 Hz, 1H, ArH), 7.39e7.47 (m, 1H, ArH), 7.53 (d, J¼2.11 Hz, 1H,
ArH), 7.60 (d, J¼8.45 Hz, 1H, ArH), 7.82e7.86 (m, 1H, ArH),
7.93e7.96 (m, 1H, ArH). 13C NMR (75.5 MHz, CDCl3):
d
¼111.3 (CH),
2.1.1. 6-Chloro-2-(3,5-dimethyl)benzo[d]oxazole (3a). Starting with
1 (70 mg, 0.372 mmol), 2a (66 mg, 0.446 mmol), Pd(PPh3)4 (13 mg,
3 mol %), K2CO3 (2 M, 1.0 mL) and 1,4-dioxane (3 mL), 3a was iso-
lated as a white solid (86 mg, 90%), mp 98e100 ꢀC. 1H NMR
114.55 (d, JC,F¼2.0 Hz, CH), 118.70 (d, JC,F¼21.8 Hz, CH), 120.7 (CH),
123.3 (d, JC,F¼3 Hz, CH), 125.5 (CH), 128.6 (C), 130.7 (d, JC,F¼8.0 Hz,
CH), 131.1, 140.7, 150.9, 161.2 (C), 163.0 (d, JC,F¼245 Hz, CF). 19F NMR
(282.40 MHz, CDCl3):
d
¼ꢂ111.52. IR (KBr, cmꢂ1):
¼3078.2, 3065.8,
n
(300 MHz, CDCl3):
d
¼3.80 (s, 6H, 2CH3), 7.09 (br s, 1H, ArH), 7.24
(dd, J¼1.9, 8.4 Hz, 1H, ArH), 7.48 (d, J¼2.0 Hz, 1H, ArH), 7.56 (d,
3041.1, 2953.0, 2921.3, 2851.9, 1953.8, 1937.5, 1872.5, 1607.7, 1589.5
(w), 1555.8 (m), 1519.7, 1504.4 (w), 1486.2, 1469.9, 1450.9, 1435.0,
1427.7, 1327.7, 1305.7, 1294.5, 1274.3, 1261.3, 1240.3, 1209.8, 1178.0,
1154.7 (m), 1121.5, 1079.5 (w), 1057.1, 1044.9 (m), 1003.3, 969.7,
942.7, 929.6, 919.1 (w), 882.8, 862.0 (m), 808.0, 784.6 (s), 759.3,
745.9 (w), 720.8, 704.5, 673.0, 595.8 (s), 562.1, 553.1, 541.1 (w).
GCeMS (EI, 70 eV): m/z (%)¼249 ([M]þ, 37Cl, 30), 247 ([M]þ, 35Cl,
100), 219 (10), 184 (10). HRMS (ESI-TOF/MS): calcd for
C13H737ClFNO ([MþH]þ, 37Cl): 250.02467, found 250.02516; calcd
for C13H735ClFNO ([MþH]þ, 35Cl): 248.0273, found 248.02771.
J¼8.4 Hz, 1H, ArH), 8.07 (br s, 2H, ArH). 13C NMR (62.9 MHz, CDCl3):
d
¼20.1 (2CH3), 110.1, 116.6, 119.2 (C), 123.3, 124.1, 124.3 (CH), 125.3
(C), 127.3 (CH), 129.4 (C), 132.5 (CH), 139.8, 149.8 (C). IR (KBr, cmꢂ1):
¼1865.4, 1732.1, 1616.6, 1600.1 (w), 1556.0, 1451.8, 1425.8 (m),
n
1370.1 (w), 1331.2, 1258.8, 1227.5, 1182.4 (m), 1124.1, 1092.7, 1057.8
(w), 927.2, 915.6 (m), 864.7, 851.5, 804.8, 725.3, 702.8, 679.2 (s),
637.8 (w), 604.6, 594.8 (m), 563.6, 541.1, 509.6, 442.8 (w), 426.8 (s),
406.3 (w). GCeMS (EI, 70 eV): m/z (%)¼GCeMS (EI, 70 eV): m/z (%)¼
259 ([M]þ, 37Cl, 33), 257 ([M]þ, 35Cl, 100). sHRMS (ESI-TOF/MS):
calcd for C15H1237ClNO ([MþH]þ, 37Cl): 259.05724, found
259.057595, calcd for C15H1235ClNO ([MþH]þ, 35Cl): 257.06019,
found 257.060137.
2.1.5. 6-Chloro-2-(4-chlorophenyl)benzo[d]oxazole
(3e). Starting
with 1 (70 mg, 0.372 mmol), 2e (66 mg, 0.446 mmol), Pd(PPh3)4
(13 mg, 3 mol %), K2CO3 (2 M, 1.0 mL) and 1,4-dioxane (3 mL), 3e
was isolated as a white solid (86 mg, 88%), mp 197e200 ꢀC. 1H NMR
2.1.2. 6-Chloro-2-(4-ethylphenyl)benzo[d]oxazole (3b). Starting with
1 (70 mg, 0.372 mmol), 2b (53 mg, 0.446 mmol), Pd(PPh3)4 (13 mg,
3 mol %), K2CO3 (2 M, 1.0 mL) and 1,4-dioxane (3 mL), 3b was iso-
lated as a white solid (78 mg, 81%), mp 90e92 ꢀC. 1H NMR
(300 MHz, CDCl3):
d
¼7.27 (dd, J¼1.9, 8.5 Hz, 1H, ArH), 7.35e7.39 (m,
1H, ArH), 7.49e7.53 (m, 2H, ArH), 7.63 (d, J¼8.5 Hz, 2H, ArH), 8.22
(d, J¼8.36 Hz, 1H, ArH). 13C NMR (62.9 MHz, CDCl3):
¼111.2, 120.4,
d
(300 MHz, CDCl3):
d
¼1.21 (t, J¼7.3 Hz, 3H, CH3), 2.65 (q, J¼7.5 Hz,
125.3, 125.7, 129.1 (CH), 130.7, 134.3, 138.2, 140.9, 143.1, 150.9 (C). IR
(KBr, cmꢂ1):
n
¼3091.3, 3065.9, 3043.6, 3027.7, 2922.6, 2851.7,
2H, CH2), 7.25 (m, 3H, ArH), 7.49 (d, J¼1.8 Hz, 1H, ArH), 7.57 (d,
J¼8.4 Hz, 1H, ArH), 8.05 (d, J¼8.2 Hz, 2H, ArH). 13C NMR (75.4 MHz,
1926.0, 1909.2, 1879.0, 1615.2, 1601.6, 1579.6, 1563.6, 1550.2, 1512.7
(w), 1479.2, 1452.2, 1428.7, 1418.1, 1393.1 (m), 1356.6, 1331.3, 1318.5,
1296.1, 1280.0, 1260.0, 1233.5, 1195.3, 1178.0, 1124.1, 1105.1, 1091.2
(w), 1054.4 (m), 1017.7, 1003.8, 971.5, 962.2, 940.8, 923.7, 917.3,
866.2, 854.4 (w), 820.3, 811.4 (s), 767.2 (w), 744.3, 704.2, 697.0 (m),
666.8, 641.3, 626.7 (w), 598.3, 546.0 (m). GCeMS (EI, 70 eV): m/z
CDCl3):
d
¼15.2 (CH3), 29.7 (CH2), 111.1, 120.2 (CH), 124.1 (C), 125.1,
127.7, 128.5 (CH), 130.4, 141.0, 148.6, 150.8, 163.9 (C). IR (KBr, cmꢂ1
)
n
¼3028.5, 2961.4, 2927.7, 2869.9, 2852.8, 1939.0, 1864.3, 1741.0,
1682.9 (w), 1615.9 (s), 1602.5, 1575.1, 1555.5, 1496.9, 1487.0 (w),
1459.8, 1442.5, 1427.0, 1412.1, 1373.2, 1328.8 (m), 1310.5, 1282.7 (w),
1254.8 (s), 1231.4, 1182.2, 1169.5, 1120.6 (m), 1081.9, 1065.7 (w),
1044.1, 1010.9 (s), 964.5, 933.7 (w), 917.8, 846.1, 836.6, 829.5, 808.3
(s), 736.9, 721.2 (w), 700.9 (s), 641.9, 631.8 (w), 597.0, 576.2, 541.6
(%)¼267 [M]þ
(
37Cl ꢁ2, 34), 265 (37Cl ꢁ1, 35Cl ꢁ1, 40), 263 (35Cl ꢁ2,
,
100), 242 (19), 63 (13). HRMS (EI, 70 eV) calcd for C13H737Cl2NO
([M]þ, 37Cl ꢁ2): 267.04159, found 267.04216; calcd for
C13H735Cl2NO ([M]þ, 35Cl ꢁ2): 263.04454, found 263.04216.
(m). GCeMS (EI, 70 eV): m/z (%)¼259 ([M]þ 37Cl, 33), 257 ([M]þ,
,
35Cl, 100), 244 (33), 243 (18). HRMS (EI, 70 eV) calcd for
C15H1237ClNO ([M]þ, 37Cl): 259.05724, found 259.057607; calcd for
C15H1235ClNO ([M]þ, 35Cl): 259.05724 found 259.057607.
2.1.6. 6-Chloro-2-phenylbenzo[d]oxazole (3f). Starting with
1
(70 mg, 0.372 mmol), 2f (60 mg, 0.446 mmol), Pd(PPh3)4 (13 mg,
3 mol %), K2CO3 (2 M, 1.0 mL) and 1,4-dioxane (3 mL), 3f was iso-
lated as a white solid (77 mg, 90%), mp 92e94 ꢀC. 1H NMR
2.1.3. 6-Chloro-2-(4-methoxyphenyl)benzo[d]oxazole (3c). Starting
with 1 (70 mg, 0.372 mmol), 2c (67 mg, 0.446 mmol) and Pd(PPh3)4
(13 mg, 3 mol %), K2CO3 (2 M, 1.0 mL), and 1,4-dioxane (3 mL), 3c
was isolated as a white solid (87 mg, 90%), mp¼140e142 ꢀC. 1H
(300 MHz, CDCl3):
d
¼7.25 (dd, J¼1.1, 8.1 Hz, 1H, ArH), 7.44e7.47 (m,
3H, ArH), 7.52 (d, J¼1.0 Hz, 1H, ArH), 7.59 (d, J¼8.1 Hz 1H, ArH), 8.14
(dd, J¼2.0, 8.6 Hz, 2H, ArH). 13C NMR (75.4 MHz, CDCl3):
¼110.6
d

2084
A.M. Hamdy et al. / Tetrahedron 69 (2013) 2081e2086
(C), 111.2 (CH), 120.0 (C), 120.4, 125.0 (CH), 126.6 (C), 127.6, 128.9
(CH), 130.0, 130.6 (C), 131.8 (CH). IR (KBr, cmꢂ1):
¼3090.0, 3059.2,
(s), 637.9, 618.6, 596.7, 550.2 (w). GCeMS (EI, 70 eV): m/z (%)¼287
([M]þ, 37Cl, 13), 285 ([M]þ, 35Cl, 100), 272 (34), 271 (19), 242 (17).
HRMS (EI, 70 eV); calcd for C17H1637ClNO ([M]þ, 37Cl): 287.08854,
found 287.08896; calcd for C17H1635ClNO ([M]þ, 35Cl): 285.09149,
found 285.98189.
n
3040.5, 2953.3, 2921.2, 2851.6, 1958.7, 1893.0, 1865.8, 1747.2, 1615.7,
1600.7, 1573.5, 1567.9 (w), 1551.9 (m), 1538.7, 1531.8, 1519.7, 1504.8,
1488.1, 1471.3 (w), 1447.3 (m), 1426.8, 1403.8, 1344.9 (w), 1330.1
(m), 1314.4, 1302.4, 1284.7, 1261.4, 1240.4, 1187.1, 1154.1, 1122.6,
1101.5, 1074.6 (w), 1050.3, 1021.7 (m), 974.8, 933.7 (w), 922.1, 915.5,
875.9 (m), 851.9, 825.8 (w), 806.1, 769.8 (s), 720.8 (w), 697.9, 680.2,
594.7 (s), 573.2, 540.0 (w). GCeMS (EI, 70 eV): m/z (%)¼231 ([M]þ,
37Cl, 44), 229 ([M]þ, 35Cl, 100), 201 (13), 166 (26). HRMS (EI, 70 eV)
calcd for C13H837ClNO ([M]þ, 37Cl): 231.02594, found 231.02641;
calcd for C13H835ClNO ([M]þ, 35Cl): 229.02889, found 229.02889.
2.1.10. 6-Chloro-2-(4-(trifluoromethyl)phenyl)benzo[d]oxazole
(3j). Starting with 1 (70 mg, 0.372 mmol), 2j (84 mg, 0.446 mmol),
Pd(PPh3)4 (6 mg, 3 mol %), K2CO3 (2 M, 1.0 mL) and 1,4-dioxane
(3 mL), 3j was isolated as a white solid (92 mg, 83%), mp
112e115 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼7.29 (dd, J¼1.72, 8.50 Hz,
1H, ArH), 7.54 (d, J¼2.37 Hz, 1H, ArH), 7.61 (d, J¼8.70 Hz, 1H, ArH),
7.72 (d, J¼8.30 Hz, 2H, ArH), 8.26 (d, J¼8.64 Hz, 2H, ArH). 13C NMR
2.1.7. 6-Chloro-2-(2,3,4-trimethoxyphenyl)benzo[d]oxazole (3g). Sta-
rting with 1 (70 mg, 0.372 mmol), 2g (80 mg, 0.446 mmol),
Pd(PPh3)4 (13 mg, 3 mol %), K2CO3 (2 M, 1.0 mL) and 1,4-dioxane
(3 mL), 3g was isolated as a white solid (95 mg, 80%), mp
(75.5 MHz, CDCl3):
d
¼111.4, 120.9 (CH), 123.4 (q, JC,F¼271 Hz, CF),
125.7, 126.0 (q, JC,F¼3.8 Hz, CH), 127.9 (CH), 130.0, 131.5 (C), 133.2 (d,
JC,F¼32.0 Hz, C), 140.6, 151.0, 162.1 (C). 19F NMR (282.40 MHz,
CDCl3):
d
¼ꢂ63.04. IR (KBr, cmꢂ1):
¼3100.0, 3080.7, 2954.2, 2922.8,
n
76e78 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼3.86 (s, 6H, 2OCH3), 3.94 (s,
2852.3, 2638.4, 1931.6, 1889.7, 1804.7, 1683.3 (w), 1614.2, 1605.7
(m), 1569.6 (w), 1557.2 (m), 1512.0, 1500.5 (w), 1461.0 (s), 1426.7,
1409.5 (m), 1344.9 (w), 1320.3 (s), 1259.3 (m), 1228.9, 1208.0 (w),
1158.2, 1130.0, 1107.2, 1064.8, 1046.1, 1009.9 (s), 970.5, 964.4, 946.4,
946.8 (w), 922.2, 916.6 (m), 843.3, 833.7 (m), 825.9, 815.2 (s), 773.7,
748.4, 725.8, 715.3 (w), 696.3 (s), 660.4, 633.3, 605.8 (w), 592.4 (s),
574.7, 541.2 (w). GCeMS (EI, 70 eV): m/z (%)¼299 ([M]þ, 37Cl, 32),
297 ([M]þ, 35Cl, 100), 269 (10), 63 (17) HRMS (EI): calcd for
C14H737ClF3NO ([M]þ, 37Cl): 299.01333, found 299.01347; calcd for
C14H735ClF3NO ([M]þ, 35Cl): 297.01628, found 297.01630.
3H, OCH3), 6.73 (d, J¼8.8 Hz, 1H, ArH), 7.22 (dd, J¼1.6, 8.0 Hz, 1H,
ArH), 7.49 (d, J¼1.8 Hz, 1H, ArH), 7.59 (d, J¼8.8 Hz, 1H, ArH), 7.77 (d,
J¼8.8 Hz, 1H, ArH). 13C NMR (75.4 MHz, CDCl3):
¼56.1, 61.1, 61.7
d
(3OCH3), 107.7, 111.0 (CH), 114.0 (C), 120.4, 124.9, 125.8 (CH), 130.2,
140.9, 143.2, 150.5, 153.6, 156.7, 161.9 (C). IR (KBr, cmꢂ1):
n¼3091.4,
3068.5, 2994.6, 2962.8, 2935.6, 2874.5, 2849.4, 2838.7, 1862.9,
1609.3 (w), 1592.3 (m), 1573.9, 1555.2 (w), 1487.5, 1454.7, 1441.4,
1428.7, 1408.6 (s), 1332.5, 1310.5 (m), 1286.8, 1253.3, 1237.4, 1229.2,
1214.8 (s), 1201.7, 1174.9, 1150.0, 1126.6 (w), 1111.2, 1085.5, 1052.5,
1000.3 (s), 947.4 (w), 918.3, 906.5, 862.8, 848.7 (m), 807.0, 791.4 (s),
718.4, 705.8, 694.5 (m), 667.6, 657.5, 628.4, 614.7, 595.1, 564.3, 542.2
(w). GCeMS (EI, 70 eV): m/z (%)¼321 ([M]þ, 37Cl, 32), 319 ([M]þ, 35Cl,
100), 304 (19), 290 (26), 230 (25). HRMS (EI, 70 eV) calcd for
C16H1435ClNO4 ([M]þ, 35Cl): 319.06059, found 319.06103.
2.2. General procedure for the synthesis of 4aee
A 1,4-dioxane solution (3 mL) of 1, arylboronic acid (2.2 equiv),
aqueous K2CO3 (2.0 M, 1.0 mL) and Pd(PPh3)4 (6 mol %) was heated
at 120 ꢀC for 8 h under argon atmosphere. After cooling to 20 ꢀC,
H2O was added and the reaction mixture was extracted with CH2Cl2
(3ꢁ25 mL). The organic layers were dried (Na2SO4), filtered and
concentrated in vacuo. The residue was purified by column chro-
matography (silica gel, heptane/EtAOc).
2.1.8. 6-Chloro-2-m-tolylbenzo[d]oxazole (3h). Starting with
1
(70 mg, 0.372 mmol), 2h (60 mg, 0.446 mmol), Pd(PPh3)4 (13 mg,
3 mol %), K2CO3 (2 M, 1.0 mL) and 1,4-dioxane (3 mL), 3h was iso-
lated as a white solid (79 mg, 87%), mp 99e101 ꢀC. 1H NMR
(300 MHz, CDCl3):
d
¼2.36 (s, 3H, CH3), 7.23 (dd, J¼2.0, 8.7 Hz, 1H,
ArH), 7.27 (d, J¼6.3 Hz, 1H, ArH), 7.32 (d, J¼8.0 Hz, 1H, ArH), 7.47 (d,
2.2.1. 2,6-Bis(3,5-dimethylphenyl)benzo[d]oxazole(4a). Starting with
1 (70 mg, 0.372 mmol), 2a (122 mg, 0.818 mmol), Pd(PPh3)4 (26 mg,
6 mol %), K2CO3 (2 M,1.0 mL) and 1,4-dioxane (3 mL), 4a was isolated
as a white solid (109 mg, 89%), mp 169e170 ꢀC. 1H NMR (300 MHz,
J¼2.1 Hz, 1H, ArH), 7.56 (d, J¼8.62 Hz, 1H, ArH), 7.91 (t, J¼7.3 Hz, 2H,
ArH), 13C NMR (62.9 MHz, CDCl3):
d
¼21.3 (CH3), 111.1, 120.3, 124.7,
125.2 (CH), 126.5 (C), 128.1, 128.8, 130.5 (CH), 132.6, 138.8, 140.8,
150.8, 163.8 (C). IR (KBr, cmꢂ1):
¼3085.5, 3063.2, 3040.3, 3023.2,
n
CDCl3):
d
¼2.32 (s, 6H, 2CH3), 2.34 (s, 6H, 2CH3), 6.94 (br s, 1H, ArH),
2953.0, 2922.0, 2855.7, 1955.8, 1865.6, 1828.0, 1789.9, 1731.3, 1619.7,
1602.9 (w), 1552.4 (m), 1504.6 (w), 1485.0 (m), 1470.1 (w), 1452.3,
1427.2 (m), 1375.0, 1345.3 (w), 1330.8 (s), 1307.7, 1282.2 (w), 930.8,
917.3 (m), 864.1, 806.5, 788.8, 716.0, 703.3, 682.5, 596.0 (s), 550.5,
529.5 (w). GCeMS (EI, 70 eV): m/z (%)¼245 ([M]þ, 37Cl, 34), 243
([M]þ, 35Cl, 100), 63 (13). HRMS (EI, 70 eV) calcd for C14H1037ClNO
([M]þ, 37Cl): 245.04159, found 245.04216; calcd for C14H1035ClNO
([M]þ, 35Cl): 243.04454, found 245.04216.
7.09 (br s, 1H, ArH), 7.17 (br s, 2H, ArH), 7.48 (dd, J¼1.8, 8.0 Hz, 1H,
ArH), 7.67e7.70 (m, 2H, ArH), 7.82 (br s, 2H, ArH). 13C NMR
(75.4 MHz, CDCl3):
125.3, 125.41 (CH), 126.9 (C), 129.0, 133.3 (CH), 133.3, 138.4, 138.6,
139.1, 140.9, 141.3, 151.3, 125.3, 129.0 (C). IR (KBr, cmꢂ1):
¼3008.6,
d
¼21.25 (2CH3), 22.70 (2CH3), 109.0, 119.6, 124.1,
n
2951.0, 2916.3, 2855.5, 2732.6, 1888.1, 1760.6, 1737.6, 1619.7 (w),
1592.9, 1551.9, 1459.6, 1410.1 (m), 1376.2, 1363.6, 1332.5, 1310.7,
1274.1 (w), 1258.7, 1230.9 (m), 1200.6, 1185.6, 1155.7, 1127.1, 1091.7,
1081.3, 1053.3, 1037.7, 993.7, 965.5, 939.5, 927.0, 919.4, 909.0, 872.1
(w), 847.1, 828.8, 815.8 (s), 776.2, 759.8, 746.7 (w), 729.3, 702.0,
682.5, 648.7 (s), 598.3, 544.0 (w). GCeMS (EI, 70 eV): m/z (%)¼328
([MþH]þ, 23), 327 ([M]þ, 100), 311 (10). HRMS (EI, 70 eV) calcd for
C23H21NO [M]þ: 327.16177; found: 327.16159.
2.1.9. 2-(4-tert-Butylphenyl)-6-chlorobenzo[d]oxazole (3i). Starting
with 1 (70 mg, 0.372 mmol), 2i (79 mg, 0.446 mmol), Pd(PPh3)4
(13 mg, 3 mol %), K2CO3 (2 M,1.0 mL) and 1,4-dioxane (3 mL), 3i was
isolated as a white solid (77 mg, 72%), mp 98 ꢀC. 1H NMR (300 MHz,
CDCl3):
6.68e6.71 (m, 3H, ArH), 6.81 (d, J¼8.4 Hz,1H, ArH), 7.29 (d, J¼8.5 Hz
2H, ArH). 13C NMR (75.4 MHz, CDCl3):
¼31.1 (3CH3), 35.1 (C), 111.1,
120.3 (CH), 123.8 (C), 125.1, 125.9, 126.2 (CH), 130.4, 141.0, 150.8,
155.4, 163.9 (C). IR (KBr, cmꢂ1):
2924.6, 2902.2, 2860.4,1916.5,1692.8,1673.2 (w),1617.6 (m),1601.1,
1573.6, 1553.2 (w), 1495.3, 1459.2 (m), 1441.8, 1430.3, 1408.6, 1359.9
(w), 1328.1 (s), 1299.0, 1286.8 (w), 1260.6 (s), 1232.3, 1202.3, 1191.6,
1121.4, 1108.0 (w), 1048.8 (s), 1022.7, 1011.0, 969.7, 955.4 (w), 918.3
(s), 874.0, 846.9 (w), 836.1, 822.1, 812.2 (s), 749.0, 733.9 (w), 702.0
d
¼0.5 (s, 9H, 3CH3), 6.47 (dd, J¼1.9, 8.4 Hz, 1H, ArH),
2.2.2. 2,6-Bis(4-ethylphenyl)benzo[d]oxazole (4b). Starting with 1
(70 mg, 0.372 mmol), 2b (97 mg, 0.818 mmol) and Pd(PPh3)4
(26 mg, 6 mol %), K2CO3 (2 M, 1.0 mL), and 1,4-dioxane (3 mL), 4b
was isolated as a white solid (108 mg, 88%), mp 74e77 ꢀC. 1H NMR
d
n¼3093.0, 3062.7, 3041.4, 2956.6,
(300 MHz, CDCl3):
d
¼1.20 (t, J¼7.5 Hz, 6H, 2CH3), 2.68 (q, J¼7.5 Hz,
4H, 2CH2), 7.21 (d, J¼8.0 Hz, 2H, ArH), 7.26 (d, J¼8.0 Hz, 2H, ArH),
7.46e7.50 (m, 3H, ArH), 7.66e7.70 (m, 2H, ArH), 8.10 (d, J¼8.0 Hz,
2H, ArH). 13C NMR (75.4 MHz, CDCl3):
d¼15.2, 15.5 (2CH3), 28.5,
28.9 (2CH2), 108.8, 119.7, 123.9 (CH), 124.6 (C), 127.3, 127.7, 128.4,

A.M. Hamdy et al. / Tetrahedron 69 (2013) 2081e2086
2085
128.5 (CH), 138.3, 138.7, 141.3, 143.6, 148.2, 151.3, 163.6 (C). IR (KBr,
cmꢂ1):
¼3023.5 (w), 2959.0, 2926.7, 2868.8, 1617.7 (m), 1603.3,
1616.2, 1602.6, 1580.6, 1564.6, 1551.2, 1513.7 (w), 1480.2, 1453.2,
1429.7, 1419.1, 1394.1 (m), 1357.6, 1332.3, 1319.5, 1297.1, 1281.0,
1261.0, 1234.5, 1196.3, 1179.0, 1125.1, 1106.1, 1091.2 (w), 1054.4 (m),
1017.7, 1003.8, 971.5, 962.2, 940.8, 923.7, 917.3, 866.2, 854.4 (w),
820.3, 811.4 (s), 767.2 (w), 744.3, 704.2, 697.0 (m), 666.8, 641.3,
626.7 (w), 598.3, 546.0 (m). GCeMS (EI, 70 eV): m/z (%)¼341 ([M]þ,
37Cl ꢁ1, 35Cl ꢁ1, 11), 339 ([M]þ, 35Cl ꢁ2, 100), 305 (15), 98 (17).
HRMS (EI, 70 eV) calcd for C19H1135Cl2NO ([M]þ, 35Cl ꢁ2):
339.2013, found 339.0301.
n
1577.1, 1567.4, 1551.6, 1520.0 (w), 1498.4, 1472.5, 1454.5, 1434.6,
1417.5, 1408.5 (m), 1370.8, 1335.4, 1322.7, 1289.4 (w), 1262.2 (s),
1209.2, 1180.5, 1165.1, 1135.6, 1118.1, 1081.2 (w), 1057.0, 1046.7,
1016.7 (m), 962.5, 923.1, 916.0, 874.5, 864.8 (w), 833.5, 807.9 (s),
783.6, 758.8, 738.9 (w), 701.1 (s), 648.1, 642.3, 634.0, 594.2, 553.4
(w), 529.6 (m). GCeMS (EI, 70 eV): m/z (%)¼327 ([M]þ, 100), 312
(60), 297 (19), 152 (10), 148 (17). HRMS (EI, 70 eV): calcd for
C23H21NO [M]þ: 327.16177; found: 327.161480.
2.3. General procedure for the synthesis of 5a,b
2.2.3. 2,6-Bis(4-methoxyphenyl)benzo[d]oxazole (4c). Starting with
1 (70 mg, 0.372 mmol), 2c (124 mg, 0.818 mmol), Pd(PPh3)4 (26 mg,
6 mol %), K2CO3 (2 M, 1.0 mL) and 1,4-dioxane (3 mL), 4c was iso-
lated as a white solid (108 mg, 88%), mp 180e182 ꢀC. 1H NMR
The reaction was carried out in a pressure tube. To a 1,4-dioxane
suspension (3 mL) of 1, arylboronic acid Ar1B(OH)2 and Pd(PPh3)4
(3 mol %) was added an aqueous solution of K2CO3 (2 M, 1 mL) and
the resulting solution was degassed by bubbling argon through the
solution for 10 min. The mixture was heated at 80 ꢀC under an
argon atmosphere for 6 h. The mixture was cooled to 20 ꢀC. Aryl-
boronic acid Ar2B(OH)2 and Pd(PPh3)4 (3 mol %), K2CO3 (2 M,
0.5 mL), and dioxane (2 mL) were added. The reaction mixture was
heated under an argon atmosphere for 8 h at 120 ꢀC. Then it was
diluted with H2O and extracted with CH2Cl2 (3ꢁ25 mL). The com-
bined organic layers were dried (Na2SO4), filtered and the filtrate
was concentrated in vacuo. The residue was purified by flash
chromatography (silica gel, heptane/EtAOc).
(300 MHz, CDCl3):
d
¼3.79 (s, Hz, 6H, 2OCH3), 6.93 (t, J¼7.4 Hz, 4H,
ArH), 7.42e7.45 (m, 3H, ArH), 7.61e7.67 (m, 2H, ArH), 8.12 (d,
J¼8.5 Hz, 2H, ArH). 13C NMR (75.4 MHz, CDCl3):
d¼55.3, 55.4
(OCH3), 107.3, 113.3, 113.4, 118.4 (CH), 118.7 (C), 122.6, 127.3, 128.3
(CH), 132.4, 137.1, 140.1, 150.3, 158.2, 161.2, 162.3 (C). IR (KBr, cmꢂ1):
n
¼3071.7, 3038.4, 3012.1, 2955.7 (w), 2920.8, 2851.7 (s), 2548.6,
2478.6, 2418.7, 2402.9, 1892.2, 1730.6 (w), 1614.3, 1603.4, 1580.8,
1556.7, 1520.3, 1495.1, 1464.6, 1454.1, 1435.7, 1422.2, 1407.0 (m),
1378.2, 1364.8, 1335.0, 1319.2, 1303.7 (w), 1294.3, 1233.3, 1177.9,
1133.7, 1115.8, 1107.6, 1080.9, 1057.7, 1035.2, 1022.0, 968.6, 956.9,
922.7, 915.4, 864.5 (m), 836.7, 806.1, 787.0, 757.7, 738.2, 722.9,
698.9, 665.8, 650.9, 640.8, 627.1, 593.8, 557.8 (m), GCeMS (EI,
70 eV): m/z (%)¼331 ([M]þ, 100), 317 (10), 316 (46), 288 (10), 165
(14). HRMS (EI, 70 eV) calcd for C21H17NO3 [M]þ: 331.12029; found:
331.120195.
2.3.1. 2-(4-Chlorophenyl)-6-(3,5-dimethylphenyl)benzo[d]-oxazole
(5a). Starting with 1 (70 mg, 0.372 mmol), 2e (66 mg, 0.446 mmol),
Pd(PPh3)4 (13 mg, 3 mol %), K2CO3 (2 M, 1.0 mL), 2a (66 mg,
0.446 mmol) and Pd(PPh3)4 (13 mg, 3 mol % mmol), K2CO3 (2 M,
0.5 mL), and 1,4-dioxane (3 mL), 5a was isolated as a white solid
2.2.4. 2,6-Bis(3-fluorophenyl)benzo[d]oxazole (4d). Starting with 1
(70 mg, 0.372 mmol), 2d (112 mg, 0.818 mmol), Pd(PPh3)4 (12 mg,
6 mol %), K2CO3 (2 M, 1.0 mL) and 1,4-dioxane (3 mL), 4d was iso-
lated as a white solid (86 mg, 75%), mp 100 ꢀC. 1H NMR (300 MHz,
(104 mg, 84%), mp 57e59 ꢀC. 1H NMR (300 MHz, CDCl3):
d¼2.31 (s,
6H, 2CH3), 6.94 (d, J¼5.2 Hz, 1H, ArH), 7.15e7.19 (m, 3H, ArH), 7.49
(dd, J¼1.9, 8.6 Hz, 1H, ArH), 7.63e7.71 (m, 3H, ArH), 8.21 (d,
J¼8.4 Hz, 2H, ArH). 13C NMR (62.9 MHz, CDCl3):
¼20.3 (2CH3),
d
CDCl3):
d
¼7.14e7.18 (m, 2H, ArH), 7.21e7.25 (m, 1H, ArH), 7.30e7.33
107.9, 118.6, 121.2 (CH), 123.2, 124.0, 124.3 (C), 124.7, 126.5, 126.9,
(m, 1H, ArH), 7.35 (d, J¼8.15 Hz, 1H, ArH), 7.38e7.40 (m, 1H, ArH),
7.48 (dd, J¼2.71, 8.15 Hz, 1H, ArH), 7.67 (d, J¼2.10 Hz, 1H, ArH), 7.72
(d, J¼8.06 Hz, 1H, ArH), 7.84e7.88 (m, 1H, ArH), 7.95e7.98 (m, 1H,
128.0 (CH), 128.6, 137.3, 137.4, 139.8, 140.4, 143.4 (C). IR (KBr, cmꢂ1):
n
¼3015.5, 2961.6, 2913.5, 2853.1, 2730.4, 1614.6, 1598.4, 1573.7,
1556.0, 1552.5, 1538.5, 1531.7, 1497.6, 1487.4, 1462.9, 1455.4, 1441.7,
1435.0, 1412.4, 1398.1, 1373.6, 1325.5 (w), 1258.3 (s), 1233.9, 1209.2,
1183.0, 1156.9, 1086.0, 1051.0, 1033.5, 1013.6, 939.6, 921.4, 896.2,
847.0 (w), 833.2, 814.7, 803.5 (s), 758.6 (w), 760.0, 694.9 (m), 666.7
(w), 647.5 (m), 647.5, 596.6, 583.0, 540.0 (w). GCeMS (EI, 70 eV):
m/z (%)¼335 ([M]þ, 37Cl, 34), 333 ([M]þ, 35Cl, 100), 331 (17), 167
(12). HRMS (EI, 70 eV) calcd for C21H1637ClNO ([M]þ, 37Cl):
335.08854, found 335.08862; calcd for C21H1635ClNO ([M]þ, 35Cl):
333.09149, found 333.09147.
ArH). 13C NMR (75.5 MHz, CDCl3):
d
¼108.1 (CH), 114.1 (d,
JC,F¼21.0 Hz, CH), 114.2 (d, JC,F¼21.0 Hz, CH), 114.4 (d, JC,F¼21.8 Hz,
CH), 117.5 (d, JC,F¼21.1 Hz, CH), 119.2 (CH), 121.9 (d, JC,F¼2.7 Hz, CH),
122.3 (d, JC,F¼2.7 Hz, CH),123.2 (CH),130.4 (d, JC,F¼8.4 Hz, CH),130.6
(d, JC,F¼8.0 Hz, CH), 136.9 (d, JC,F¼2.3 Hz, C), 140.7, 141.8, 141.9 (C),
161.4 (d, JC,F¼3.5 Hz, C), 163.5 (d, JC,F¼247.5 Hz, CF), 163.8 (d,
JC,F¼245.5 Hz, CF), 150.3 (C). 19F NMR (282.40 MHz, CDCl3):
d
¼ꢂ111.6, ꢂ112.6 (ArCF3). IR (KBr, cmꢂ1):
¼3088.9, 3069.3, 2954.1,
n
2922.3, 2852.5, 1946.2, 1873.5, 1789.0, 1731.0, 1608.6 (w), 1577.2,
1556.6 (m), 1519.7, 1466.6 (w), 1450.5, 1413.4 (m), 1331.3, 1316.8,
1289.5, 1275.8 (w), 1262.8, 1210.6, 1182.0 (m), 1160.0, 1144.8, 1133.2,
1077.7, 1059.5, 1045.9, 1035.5, 1001.1, 974.4, 944.2 (w), 928.0, 880.1,
858.4, 815.5, 784.1, 723.2, 692.0, 678.2, 648.2 (s), 634.0, 596.6,
588.6, 573.1, 540.0 (w). GCeMS (EI, 70 eV): m/z (%)¼307 ([M]þ,100),
157 (33). HRMS (EI, 70 eV): calcd for C19H11F2NO [M]þ: 307.08032;
found: 307.080780.
2.3.2. 2-(4-tert-Butylphenyl)-6-(4-methoxyphenyl)-benzo[d]oxazole
(5b). Starting with 1 (70 mg, 0.372 mmol), 2i (79 mg, 0.446 mmol)
and Pd(PPh3)4 (2ꢁ13 mg, 2ꢁ3 mol %), K2CO3 (2 M, 1.0 mL, then
1.5 mL), 2c (67 mg, 0.446 mmol), and 1,4-dioxane (3 mL), 5b was
isolated as a white solid (96 mg, 72%), mp¼100 ꢀC. 1H NMR
(300 MHz, CDCl3):
d
¼1.27 (s, 9H, 3CH3), 3.74 (s, 3H, OCH3), 6.90 (d,
J¼8.0 Hz, 2H, ArH), 7.42e7.48 (m, 5H, ArH), 7.62 (d, J¼1.3 Hz, 1H,
ArH), 7.67 (d, J¼8.4 Hz, 1H, ArH), 8.08 (d, J¼8.4 Hz, 2H, ArH). 13C
2.2.5. 2,6-Bis(4-chlorophenyl)benzo[d]oxazole (4e). Starting with 1
(70 mg, 0.372 mmol), 2e (122 mg, 0.818 mmol), and Pd(PPh3)4
(26 mg, 6 mol %), K2CO3 (2 M, 1.0 mL), and 1,4-dioxane (3 mL), 4e
was isolated as a white solid (95 mg, 75%), mp 370e372 ꢀC. 1H NMR
NMR (75.4 MHz, CDCl3):
118.6, 122.6 (CH), 123.3 (C), 124.8, 126.3, 127.3 (CH), 132.3, 137.3,
140.0, 150.3, 154.0, 157.6, 158.2, 162.3 (C). IR (KBr, cm):
¼3064.0,
d
¼30.1 (3CH3), 54.2 (OCH3), 107.4, 113.3,
n
3032.9, 3002.4, 2961.4, 2953.5, 2927.9, 2900.6, 2865.2, 2832.5,
1617.5 (w), 1605.5 (m), 1573.1, 1552.1 (w), 1517.2, 1495.2, 1471.1,
1434.5 (m), 1408.7, 1399.1, 1363.3, 1331.0, 1302.8, 1291.9 (w), 1267.5,
1246.5, 1235.3 (s), 1194.2 (w), 1178.1 (s), 1162.7, 1131.6, 1123.1, 1110.4
(w), 1053.7, 1040.1, 1011.9 (m), 972.1, 959.1, 941.3, 923.9, 914.7, 861.3
(w), 844.8, 830.8 (m), 809.7, 797.1 (s), 755.6, 750.6, 734.4, 724.0 (w),
706.2 (s), 646.0, 629.0, 584.0 (w), 563.5, 544.0, 527.8 (m). GCeMS
(300 MHz, CDCl3):
d
¼7.37 (dd, J¼2.2, 8.2 Hz, 1H, ArH), 7.41 (d,
J¼8.6 Hz, 2H, ArH), 7.54e7.58 (m, 3H, ArH), 7.59e7.65 (m, 3H, ArH),
8.22 (d, J¼8.7 Hz, 2H, ArH). 13C NMR (62.9 MHz, CDCl3):
¼110.2,
d
119.4, 124.3 (CH), 124.7 (C), 126.4, 127.1, 127.3, 128.1 (CH), 129.7,
133.3, 137.2, 139.9, 142.1, 149.9, 162.3 (C). IR (KBr, cm):
3066.9, 3044.6, 3028.7, 2923.6, 2852.7, 1927.0, 1910.2, 1878.0,
n
¼3092.3,

2086
A.M. Hamdy et al. / Tetrahedron 69 (2013) 2081e2086
(EI, 70 eV): m/z (%)¼357 ([M]þ, 100), 342 (66), 157 (11). HRMS (EI,
11. Strotman, N. A.; Chobanian, H. ,R.; Guo, Y.; Jiafang, H.; Wilson, J. E. Org. Lett.
2010, 12, 3578.
12. Leventhal, L.; Brandt, M. R.; Cummons, T. A.; Piesla, M. J.; Rogers, K. E.; Harris,
70 eV): calcd for C24H23NO2 [M]þ: 357.17233; found: 357.17182.
H. A. Eur. J. Pharmacol. 2006, 553, 146.
13. Boyland, E.; Sims, P. J. Chem. Soc. 1954, 980.
Acknowledgements
14. For aldehydes, see: (a) Kawashita, Y.; Nakamichi, N.; Kawabata, H.; Hayashi, M.
Org. Lett. 2003, 5, 3713; (b) Chang, J.; Zhao, K.; Pan, S. Tetrahedron Lett. 2002, 43,
951; (c) Varma, R.; Kumar, D. J. Heterocycl. Chem. 1998, 35, 1539 For carboxylic
acid derivatives, see; (d) Pottorf, R.; Chadha, N.; Katkevics, M.; Ozola, V.; Suna,
E.; Ghane, H.; Regberg, T.; Player, M. Tetrahedron Lett. 2003, 44, 175; (e) Bougrin,
K.; Loupy, A.; Fiaoui, M. Tetrahedron 1998, 54, 8055; (f) Terashima, M.; Ishii, M.;
Kanaoka, Y. Synthesis 1982, 484.
15. (a) Viirre, R.; Evindar, G.; Batey, R. J. Org. Chem. 2008, 73, 3452; (b) Barbero, N.;
Carril, M.; San Martin, R.; Dominguez, E. Tetrahedron 2007, 63, 10425.
16. Ueda, S.; Nagasawa, H. Angew. Chem., Int. Ed. 2008, 47, 6411.
17. Boissarie, P. J.; Hamilton, E. Z.; Lang, S.; Murphy, J. A.; Suckling, C. J. Org. Lett.
2011, 13, 6256.
Financial support by the DAAD (scholarships for A.H. and N.E.)
and by the State of Iraq (scholarship for M.H.) is gratefully
acknowledged.
References and notes
1. (a) Rodriguez, A.; Ramirez, C.; Rodriguez, I.; Gonzalez, E. Org. Lett. 1999, 1, 527;
(b) Davidson, J.; Corey, E. J. Am. Chem. Soc. 2003, 125, 13486.
2. Don, M.; Shen, C.; Lin, Y.; Syu, W.; Ding, Y.; Sun, C. J. Nat. Prod. 2005, 68, 1066.
18. For reviews of cross-coupling reactions of polyhalogenated heterocycles, see:
3. Evindar, G.; Batey, R. J. Org. Chem. 2006, 71, 1802.
€
€
(a) Schroter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245; (b) Schnurch, M.;
Flasik, R.; Khan, A. F.; Spina, M.; Mihovilovic, M. D.; Stanetty, P. Eur. J. Org. Chem.
2006, 3283; (c) Rossi, R.; Bellina, F.; Lessi, M. Adv. Synth. Catal. 2012, 354, 1181.
19. Handy, S. T.; Zhang, Y. Chem. Commun. 2006, 299.
4. Prudhomme, M.; Guyot, J.; Jeminet, G. J. Antibiot. 1986, 39, 934.
€
5. Oren, I.; Ozlem, T.; Ismail, Y.; Esin, A.; Altanlar, N. Eur. J. Pharm. Sci. 1998, 7, 153.
€
6. Ozlem, T.;Esin, A.;Ismail, Y.;Altanlar, N. Arch. Pharm. (Weinheim, Ger.)2002, 6, 283.
€
€
7. Ozlem, T.; Ozdemir, A.; Ismail, Y.; Esin, A.; Altanlar, N. Arch. Pharm. (Weinheim,
20. CCDC-907771 contains all crystallographic details of this publication and is
available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or can be
ordered from the following address: Cambridge Crystallographic Data Centre,
12 Union Road, GB-Cambridge CB21EZ; Fax: (þ44)1223-336-033; or deposit@
ccdc.cam.ac.uk.
Ger.) 2005, 105, 338.
8. Vinsova, J.; Horak, V.; Buchta, V.; Kaustova, J. Molecules 2005, 10, 783.
9. Huang, S.; Hsei, I.; Chen, C. Bioorg. Med. Chem. 2006, 14, 6106.
€
10. Pınar, A.; Yurdakul, P.; Yildiz, I.; Ozlem, T.; Acan, N.; Esin, A.; Ismail, Y. Biochem.
Biophys. Res. Commun. 2004, 317, 670.