Copper-catalyzed direct cross-coupling of 1,3,4-oxadiazoles with N-tosylhydrazones: Efficient synthesis of benzylated 1,3,4-oxadiazoles

Article abstract of DOI:10.1039/c3ra42791a

The first copper catalyzed direct C-H benzylation of 1,3,4-oxadiazoles using N-tosylhydrazones has efficiently been accomplished. Several substituted oxadiazoles have been prepared in high yields (80-89%) in 3 h. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ra42791a

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Copper-catalyzed direct cross-coupling of 1,3,4-
oxadiazoles with N-tosylhydrazones: efficient synthesis
of benzylated 1,3,4-oxadiazoles†‡
Cite this: DOI: 10.1039/c3ra42791a
*
N. Salvanna, Gandolla Chinna Reddy, Bethapudi Rama Rao and Biswanath Das
Received 6th June 2013
Accepted 21st August 2013
The first copper catalyzed direct C–H benzylation of 1,3,4-oxadiazoles using N-tosylhydrazones has
efficiently been accomplished. Several substituted oxadiazoles have been prepared in high yields (80–
89%) in 3 h.
DOI: 10.1039/c3ra42791a
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Introduction
The oxadiazole system is an important structural motif for the
development of various useful drugs. Compounds containing
an oxadiazole moiety are known to possess a broad spectrum of
biological activities including antimicrobial, anticancer, anti-
viral and antihypertensive properties.1 They are also useful in
medicinal chemistry as bioisosters for carbocyclic acids, esters
and carboxyamides.2 Some of the oxadiazole derivatives have
been applied in the eld of organic electronics3 and multi-
photon absorbing properties.4 Because of such wide application
of the substituted oxadiazoles in pharmacology and material
science, the preparation of these compounds is an important
task in organic synthesis. Here, we report an efficient copper
catalyzed method for the synthesis of substituted 1,3,4-oxadi-
azole derivatives.
The metal mediated direct functionalization of C–H bonds of
arenes and heteroarenes is highly useful for preparation of their
derivatives.5 Different metal catalysts such as palladium,
rhodium and ruthenium have been applied for this trans-
formation. In comparison to these catalysts copper catalysts
have not yet been explored so much.6 However, their activity is
signicant as well as they are easily available and less expensive.
For all these reasons copper catalysts are of current interest for
C–H activation of different arenes and heteroarenes.6
Scheme 1 Copper-catalyzed C–C cross coupling.
In spite of all these efforts, the copper catalyzed cross-
coupling reactions of heteroarene C–H bonds with sp3 carbon
are still limited. Recently, N-tosylhydrazones, prepared from
carbonyl compounds have been found to be new type of
coupling partner in transition metal catalyzed reactions.7 In
2011 Wang et al. discovered the coupling reactions of N-tosyl-
hydrazones with 1,3-azoles using copper as a catalyst.7b Similar
reactions have been conducted by applying nickel and cobalt
catalysts.7e However to our knowledge, the copper catalyzed C–H
activation of 1,3,4-oxadiazoles by using N-tosylhydrazones has
not yet been reported. Here, we disclose this reaction for direct
benzylation of these heterocycles.
In continuation of our work8 on the development of metal-
mediated useful synthetic methodologies we observed that
1,3,4-oxadiazoles, when treated with N-tosylhydrazones in the
ꢀ
presence of CuI and Cs2CO3 in toluene under reux (110 C),
yielded the corresponding 2-benzylated derivatives in 3 h
(Scheme 1).
Recently, Daugulis and Do discovered the copper catalyzed
alkenylation of polyuoroarenes with alkenyl bromides.6a
Copper catalyst has also been applied by Grierson et al. for
alkenylation of oxazoles with vinyl bromides.6b Monguchi and
his co-workers have utilized copper catalyst for arylation of 1,3-
azoles.6d
Results and discussion
Initially, 2-phenyl 1,3,4-oxadiazole (1a) was treated with N-
tosylhydrazone (2a) for optimization of the reaction conditions.
The reaction was carried out with various metal compounds and
different bases (Table 1).
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500 607, India. E-mail: biswanathdas@yahoo.com; Fax:
+91-40-27193198
† Electronic supplementary information (ESI) available: Copies of 1H and 13C
The transformation was found to the most effective when
CuI (0.05 equiv.) and Cs2CO3 (2.5 equiv.) were utilized in toluene
ꢀ
at 110 C (Table 1, entry 6). The reaction was completed in 3 h
NMR spectrum of products. See DOI: 10.1039/c3ra42791a
‡ Part 235 in the series “studies on novel synthetic methodologies”.
with a 82% yield. When the temperature was lowered the yield
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Table 1 Optimization for cross-coupling of 2-phenyl 1,3,4-oxadiazole (1a) with
N-tosylhydrazone (2a) using different metal catalysts and various basesa
Table 2 Copper-catalyzed direct cross coupling of 2-phenyl 1,3,4-oxadiazole
(1a) with different N-tosylhydrazones (2)a
Entry
1
2
R
Product 3
Yieldb [%]
82
Entry
Catalyst (0.05 equiv.)
Base (2.5 equiv.)
Yieldb [%]
1
2
3
4
CuO (nano)
Cu2O
CuFe2O4 (nano)
CuI
LiOtBu
Cs2CO3
LiOtBu
K3PO4
28
15
32
48
2a
Ph
5
6
7
8
CuI
CuI
CuI
CuI
Ni(OAc)2
Ni(COD)2
NiCl2$H2O
CuBr
Pd(PPh3)4
Pd(OAc)2
CuBr
LiOtBu
Cs2CO3
Cs2CO3
K2CO3
Cs2CO3
LiOtBu
Cs2CO3
Cs2CO3
LiOtBu
Cs2CO3
Cs2CO3
LiOtBu
Cs2CO3
68
2
3
2b
2c
4-FC6H4
86
83
82
45c
12
9
NRd
NRd
NRd
25
10
11
12
13
14
15
16
17
4-ClC6H4
NRd
NRd
25
4
5
2d
2e
2f
4-BrC6H4
4-OMeC6H4
C2H5
87
89
Cu(PPh3)Br
Cu(PPh3)Br
34
42
a
Reaction conditions: 2-phenyl 1,3,4-oxadiazole 1a (1.0 mmol), N-
tosylhydrazone 2a (1.3 mmol), catalyst (0.05 equiv.), base (2.5 equiv.)
b
at 110 ꢀC over 3 h in toluene (3 mL). Isolated yield of 3 aer column
c
chromatography. Reaction was carried out at room temperature (27
ꢀC). d No reaction.
6
80
was decreased and at the room temperature the yield was low
(Table 1, entry 7). Instead of Cs2CO3, when the bases LiOtBu and
K3PO4 were used the conversion became less efficient (Table 1,
entry 5 and 8). The catalytic activities of other copper catalysts
such as CuO (nanoparticles), CuFe2O4 (nanoparticles), CuBr,
Cu2O and Cu(PPh3)Br were signicantly weaker. Nickel and
palladium based catalysts were completely inefficient to
a
Reaction conditions: 2-aryl 1,3,4-oxadiazole
1
(1.0 mmol), N-
tosylhydrazone 2 (1.3 mmol), catalyst (0.05 equiv.), base (2.5 equiv.) at
b
110 ꢀC over 3 h in toluene (3 mL). Isolated yield of 3 aer column
chromatography.
conduct the conversion. In absence of any catalyst the reaction conversion with different substituents (electronic withdrawing
did not proceed. and electronic donating) on the 1,3,4-oxadiazoles as well as on
Following the standardization of the above reaction, direct N-tosylhydrazones. The yields of the products were not affected
benzylation and alkylation of 2-phenyl 1,3,4-oxadiazoles were signicantly with the electronic character of the substituent
carried out using various N-tosylhydrazones (Table 2). The (Tables 2 and 3). However, the 1,3,4-oxadiazoles containing a
N-tosylhydrazones used in the present conversion were derived non-aromatic substituent did not undergo the conversion
from both aromatic as well as aliphatic ketones. 1,3,4-Oxadi- under present reaction conditions, possibly due to the less
azole having a non-aromatic substituent was also tested with reactivity of such oxadiazole compounds. The structures of
aromatic N-tosylhadrazone. The reaction did not proceed and the prepared oxadiazole derivatives were established from
1
the starting material was recovered. Moreover, we tested the their spectral (IR, H and 13C NMR and ESIMS) and analytical
reaction of 1,3,4-oxadiazoles with N-tosylhydrazones derived data.
from aldehydes but the conversion did not take place. The Further, N-tosylhydrazone prepared from benzophenone
present reaction was completed in 3 h and the yields of the also reacted with 2-aryl-1,3,4-oxadiazoles and afforded the
products were high (80–89%).
benzylated products in excellent yields (84–88%) (Scheme 2).
To further demonstrate, present copper-catalyzed direct
With an understanding of copper catalyzed cross-coupling
cross-coupling reaction was carried out by using various 2-aryl- reactions7b,9 a plausible mechanism of the present trans-
1,3,4-oxadiazoles and different N-tosylhydrazones (Table 3). formation is shown in Scheme 3. Initially in the presence of
The oxadiazoles contained both aromatic and heteroaromatic base and the copper catalyst oxadiazole (1) form the heteroaryl
moieties at the C-2 position. We have observed the reaction copper species A (Scheme 3). This species reacted with the diazo
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Table 3 Copper-catalyzed direct cross coupling of 2-aryl 1,3,4-oxadiazole (1) with different N-tosylhydrazones (2)a
Entry
1
R1(1)
R2(2)
Product 3
Yieldb [%]
83
4-MeC6H4 (1b)
Ph (2a)
2
3
4-MeC6H4 (1b)
4-MeC6H4 (1b)
4-BrC6H4 (2d)
89
85
4-OMeC6H4 (2e)
4
5
6
4-OMeC6H4 (1c)
4-ClC6H4 (1d)
4-BrC6H4 (1e)
Ph (2a)
Ph (2a)
Ph (2a)
86
82
84
7
8
4-CF3C6H4 (1f)
2-Thienyl (1g)
Ph (2a)
Ph (2a)
87
80
9
2-Furyl (1h)
2-Furyl (1h)
Ph (2a)
83
85
10
4-FC6H4 (2b)
11
2-Furyl (1h)
4-BrC6H4 (2d)
88
a
Reaction conditions: 2-aryl 1,3,4-oxadiazole 1 (1.0 mmol), N-tosylhydrazone 2 (1.3 mmol), catalyst (0.05 equiv.), base (2.5 equiv.) at 110 ꢀC over 3 h in
toluene (3 mL). b Isolated yield of 3 aer column chromatography.
compound derived from the N-tosylhydrazone (2) by treatment
with the base to produce the intermediate B. The latter was
Conclusions
In conclusion, we have developed for the rst time an efficient
copper catalyzed method for direct benzylation of aryl
substituted 1,3,4-oxadiazoles using N-tosylhydrazones derived
from ketones. The application of an easily available and less
subsequently converted into C by 1,2-migration of the hetero-
aryl group from Cu to the a-carbon centre. Finally by interaction
with proton or the starting oxadiazole (1) the intermediate C
was converted into the product 3.
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2-(1-(4-Fluorophenyl)ethyl)-5-phenyl-1,3,4-oxadiazole (3ab)
(Table 2, entry 2)
Yellow liquid, Rf 0.50 (20% EtOAc/hexane); IR (KBr): 1555, 1510,
1227, 1067 cmꢂ1; 1H NMR (200 MHz, CDCl3): d 7.99 (2H, d, J ¼
8.0 Hz), 7.51–7.42 (3H, m), 7.37–7.31 (2H, m), 7.08–7.01 (2H, m),
4.42 (1H, q, J ¼ 7.0 Hz), 1.79 (3H, d, J ¼ 7.0 Hz); 13C NMR (50
MHz, CDCl3): d 168.5, 164.9, 162.0 (d, J ¼ 280.0 Hz), 136.0,
131.2, 128.9, 126.8, 123.8, 115.9 (d, J ¼ 30.0 Hz), 36.6, 19.2;
ESIMS: m/z 269 [M + H]+; anal. calcd for C16H13FN2O: C, 71.63;
H, 4.88; N, 10.44. Found: C, 71.59; H, 4.85; N, 10.46%.
Scheme 2 Copper-catalyzed direct cross-coupling of 2-aryl 1,3,4-oxadiazoles
with N-tosylhydrazone derived from benzophenone.
2-(1-(4-Chlorophenyl)ethyl)-5-phenyl-1,3,4-oxadiazole (3ac)
(Table 2, entry 3)
Light yellow solid, mp: 70–73 ꢀC, Rf 0.55 (20% EtOAc/hexane); IR
(KBr): 1492, 1315, 1145, 1089 cmꢂ1; 1H NMR (200 MHz, CDCl3):
d 8.00 (2H, d, J ¼ 8.0 Hz), 7.52–7.43 (3H, m), 7.32–7.28 (4H, m),
4.40 (1H, q, J ¼ 7.0 Hz), 1.82 (3H, d, J ¼ 7.0 Hz); 13C NMR (50
MHz, CDCl3): d 164.8, 138.9, 132.0, 130.4, 129.2, 129.0, 128.8,
128.7, 126.9, 124.0, 36.9, 19.2; ESIMS: m/z 285, 287 [M + H]+;
anal. calcd for C16H13ClN2O: C, 67.49; H, 4.60; N, 9.84. Found:
C, 67.52; H, 4.63; N, 9.78%.
Scheme 3 Plausible mechanism of copper-catalyzed benzylation of 2-aryl 1,3,4-
oxadiazoles.
2-(1-(4-Bromophenyl)ethyl)-5-phenyl-1,3,4-oxadiazole (3ad)
(Table 2, entry 4)
costly catalyst, high yields and rapid conversion are the
advantages of the method. The method is a convenient access to
various 1,3,4-oxadiazole derivatives.
White solid, mp: 150–152 ꢀC, Rf 0.50 (20% EtOAc/hexane); IR
(KBr): 1557, 1487, 1213, 1071 cmꢂ1; 1H NMR (200 MHz, CDCl3):
d 7.99 (2H, d, J ¼ 8.0 Hz), 7.54–7.43 (5H, m), 7.24 (2H, d, J ¼ 8.0
Hz), 4.40 (1H, q, J ¼ 7.0 Hz), 1.81 (3H, d, J ¼ 7.0 Hz); 13C NMR
(50 MHz, CDCl3): d 165.0, 139.3, 132.1, 132.0, 129.0, 128.9,
126.9, 126.8, 123.8, 121.5, 36.9, 19.2; ESIMS: m/z 329, 331 [M +
H]+; anal. calcd for C16H13BrN2O: C, 58.38; H, 3.98; N, 8.51.
Found: C, 58.41; H, 4.01; N, 8.47%.
Experimental section
General experimental procedure for benzylation of 1,3,4-
oxadiazoles with N-tosylhydrazones
In a 10 mL round bottom ask CuI (9 mg, 0.05 equiv.), Cs2CO3
(812 mg, 2.5 equiv.), N-tosylhydrazone 2 (1.3 mmol) and 2-aryl
1,3,4-oxadiazole 1 (1.0 mmol) in toluene (3.0 mL) were taken.
The reaction mixture was stirred at 110 ꢀC for 3 h. The progress
of the reaction was monitored by TLC. Aer the consumption of
the starting materials, the reaction mixture was allowed to cool,
and subsequently extracted with EtOAc (2 ꢁ 10 mL). The
combined organic extracts were dried over anhydrous Na2SO4.
Concentration of the material in vacuo followed by ash chro-
matography on silica gel column afforded benzylated oxadi-
azole derivatives 3 in good yield.
2-(1-(4-Methoxyphenyl)ethyl)-5-phenyl-1,3,4-oxadiazole (3ae)
(Table 2, entry 5)
White solid, mp: 99–101 ꢀC, Rf 0.35 (20% EtOAc/hexane); IR
(KBr): 1553, 1458, 1080 cmꢂ1; 1H NMR (200 MHz, CDCl3): d 7.99
(2H, d, J ¼ 8.0 Hz), 7.51–7.39 (3H, m), 7.29 (2H, d, J ¼ 8.0 Hz),
6.90 (2H, d, J ¼ 8.0 Hz), 4.39 (1H, q, J ¼ 7.0 Hz), 3.79 (3H, s), 1.80
(3H, d, J ¼ 7.0 Hz); 13C NMR (50 MHz, CDCl3): d 164.5, 158.8,
145.1, 133.9, 132.0, 131.7, 128.9, 128.2, 126.2, 123.9, 114.0, 55.1,
36.5, 19.9; ESIMS: m/z 281 [M + H]+; anal. calcd for C17H16N2O2:
C, 72.84; H, 5.75; N, 9.99. Found: C, 72.87; H, 5.73; N, 9.98%.
2-Phenyl-5-(1-phenylethyl)-1,3,4-oxadiazole (3aa) (Table 2,
entry 1)
2-(sec-Butyl)-5-phenyl-1,3,4-oxadiazole (3af) (Table 2, entry 6)
Light yellow solid, mp: 71–74 ꢀC, Rf 0.45 (20% EtOAc/hexane); IR
(KBr): 1606, 1560, 1450, 1203 cmꢂ1; 1H NMR (200 MHz, CDCl3): Light green liquid, Rf 0.30 (20% EtOAc/hexane); IR (KBr): 1553,
d 8.00 (2H, d, J ¼ 8.0 Hz), 7.51–7.42 (3H, m), 7.36–7.24 (5H, m), 1458, 1080 cmꢂ1; 1H NMR (200 MHz, CDCl3): d 8.08 (2H, d, J ¼
4.42 (1H, q, J ¼ 7.0 Hz), 1.82 (3H, d, J ¼ 7.0 Hz); 13C NMR (50 8.0 Hz), 7.60–7.47 (3H, m), 3.10 (1H, m), 1.99–1.70 (2H, m), 1.42
MHz, CDCl3): d 164.8, 140.5, 131.8, 129.0, 127.8, 127.7, 127.3, (3H, d, J ¼ 7.0 Hz), 0.99 (3H, t, J ¼ 7.0 Hz); 13C NMR (50 MHz,
126.8, 124.0, 37.8, 19.7; ESIMS: m/z 251 [M + H]+; anal. calcd for CDCl3): d 164.7, 148.4, 131.8, 129.0, 127.0, 124.1, 33.5, 27.9,
C
16H14N2O: C, 76.78; H, 5.64; N, 11.19. Found: C, 76.81; H, 5.61; 18.0, 11.6; ESIMS: m/z 203 [M + H]+; anal. calcd for C12H14N2O:
N, 11.23%.
C, 71.26; H, 6.98; N, 13.85. Found: C, 71.23; H, 6.97; N, 13.89%.
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anal. calcd for C16H13ClN2O: C, 67.49; H, 4.60; N, 9.84. Found:
C, 67.51; H, 4.58; N, 9.81%.
2-(1-Phenylethyl)-5-(p-tolyl)-1,3,4-oxadiazole (3ba) (Table 3,
entry 1)
Colorless liquid, Rf 0.45 (20% EtOAc/hexane); IR (KBr): 1615,
1557, 1452, 1219 cmꢂ1; 1H NMR (200 MHz, CDCl3): d 7.89 (2H,
d, J ¼ 8.0 Hz), 7.40–7.35 (3H, m), 7.31–7.22 (4H, m), 4.43 (1H, q,
J ¼ 7.0 Hz), 2.40 (3H, s), 1.82 (3H, d, J ¼ 7.0 Hz); 13C NMR (50
MHz, CDCl3): d 164.0, 142.0, 138.3, 129.5, 128.8, 128.4, 127.2,
126.8, 120.9, 48.8, 21.1(2CH3); ESIMS: m/z 265 [M + H]+; anal.
calcd for C17H16N2O: C, 77.25; H, 6.10; N, 10.60. Found: C,
77.27; H, 6.08; N, 10.64%.
2-(4-Bromophenyl)-5-(1-phenylethyl)-1,3,4-oxadiazole (3ea)
(Table 3, entry 6)
Light yellow solid, mp: 88–90 ꢀC, Rf 0.55 (20% EtOAc/hexane); IR
(KBr): 1601, 1481, 1307, 1142 cmꢂ1; 1H NMR (200 MHz, CDCl3):
d 7.84 (2H, d, J ¼ 8.0 Hz), 7.59 (2H, d, J ¼ 8.0 Hz), 7.35–7.13 (5H,
m), 4.42 (1H, q, J ¼ 7.0 Hz), 1.81 (3H, d, J ¼ 7.0 Hz); 13C NMR (50
MHz, CDCl3): d 164.7, 144.3, 140.1, 132.2, 129.3, 129.1, 128.2,
127.2, 122.8, 37.5, 19.6; ESIMS: m/z 331, 329 [M + H]+; anal. calcd
for C16H13BrN2O: C, 58.38; H, 3.98; N, 8.51. Found: C, 58.41; H,
3.95; N, 8.49%.
2-(1-(4-Bromophenyl)ethyl)-5-(p-tolyl)-1,3,4-oxadiazole (3bd)
(Table 3, entry 2)
Light yellow solid mp: 78–80 ꢀC, Rf 0.50 (20% EtOAc/hexane); IR
(KBr): 1497, 1420, 1215 cmꢂ1; 1H NMR (200 MHz, CDCl3): d 7.88
(2H, d, J ¼ 8.0 Hz), 7.45 (2H, d, J ¼ 8.0 Hz), 7.25 (2H, d, J ¼ 8.0
Hz), 7.22 (2H, d, J ¼ 8.0 Hz), 4.39 (1H, q, J ¼ 7.0 Hz), 2.40 (3H, s),
1.79 (3H, d, J ¼ 7.0 Hz); 13C NMR (50 MHz, CDCl3): d 164.9,
142.0, 139.1, 132.0, 129.9, 129.7, 128.9, 127.6, 126.4, 121.2,
121.0, 36.9, 21.9, 19.4; ESIMS: m/z 345, 343 [M + H]+; anal. calcd
for C17H15BrN2O: C, 59.49; H, 4.41; N, 8.16. Found: C, 59.52; H,
4.39; N, 8.19%.
2-(1-Phenylethyl)-5-(4-(triuoromethyl) phenyl)-1,3,4-
oxadiazole (3fa) (Table 3, entry 7)
White solid, mp: 108–110 ꢀC, Rf 0.40 (20% EtOAc/hexane); IR
(KBr): 1557, 1452, 1324, 1134 cmꢂ1; 1H NMR (200 MHz, CDCl3):
d 7.43 (2H, d, J ¼ 8.0 Hz), 7.31–7.12 (7H, m), 4.21 (1H, q, J ¼ 7.0
Hz), 1.72 (3H, d, J ¼ 7.0 Hz); 13C NMR (50 MHz, CDCl3): d 168.8,
144.4, 134.0, 129.2, 129.0, 128.9, 128.6, 127.2, 127.0, 126.9 (q, J ¼
270.0 Hz), 37.6, 21.5; ESIMS: m/z 319 [M + H]+; anal. calcd for
C
17H13F3N2O: C, 64.15; H, 4.12; N, 8.80. Found: C, 64.12; H,
4.14; N, 8.78%.
2-(1-(4-Methoxyphenyl)ethyl)-5-(p-tolyl)-1,3,4-oxadiazole (3be)
(Table 3, entry 3)
2-(1-Phenylethyl)-5-(thiophene-2-yl)-1,3,4-oxadiazole (3ga)
(Table 3, entry 8)
White solid, mp: 86–88 ꢀC, Rf 0.30 (20% EtOAc/hexane); IR
(KBr): 1612, 1514, 1464, 1250 cmꢂ1; 1H NMR (200 MHz, CDCl3):
d 7.89 (2H, d, J ¼ 8.0 Hz), 7.29 (2H, d, J ¼ 8.0 Hz), 7.23 (2H, d, J ¼
8.0 Hz), 6.88 (2H, d, J ¼ 8.0 Hz), 4.35 (1H, q, J ¼ 7.0 Hz), 3.78 (3H,
s), 2.37 (3H, s), 1.78 (3H, d, J ¼ 7.0 Hz); 13C NMR (50 MHz,
CDCl3): d 158.8, 142.0, 132.1, 129.6, 129.5, 128.2, 127.0, 126.8,
121.2, 114.1, 55.2, 36.7, 21.5, 19.8; ESIMS: m/z 295 [M + H]+;
anal. calcd for C18H18N2O2: C, 73.45; H, 6.16; N, 9.52. Found: C,
73.42; H, 6.17; N, 9.55%.
Light yellow solid, mp: 83–85 ꢀC, Rf 0.45 (20% EtOAc/hexane); IR
(KBr): 1599, 1558, 1427, 1238 cmꢂ1; 1H NMR (200 MHz, CDCl3):
d 7.69 (1H, m), 7.51 (1H, m), 7.39–7.27 (5H, m), 7.12 (1H, m),
4.41 (1H, q, J ¼ 7.0 Hz), 1.82 (3H, d, J ¼ 7.0 Hz); 13C NMR
(50 MHz, CDCl3): d 163.6, 140.1, 130.0, 129.9, 129.1, 127.9,
127.6, 127.5, 37.7, 19.8; ESIMS: m/z 257 [M + Na]+; anal. calcd for
C
14H12N2OS: C, 65.60; H, 4.72; N, 10.93. Found: C, 65.58; H,
4.75; N, 10.89%.
2-(4-Methoxyphenyl)-5-(1-phenylethyl)-1,3,4-oxadiazole (3ca)
(Table 3, entry 4)
2-(Furan-2-yl)-5-(1-phenylethyl)-1,3,4-Oxadiazole (3ha) (Table
3, entry 9)
White solid, mp: 113–115 ꢀC, Rf 0.28 (20% EtOAc/hexane); IR
Black solid, mp: 65–68 ꢀC, Rf 0.42 (20% EtOAc/hexane); IR (KBr):
1636, 1520, 1452, 1168 cmꢂ1; 1H NMR (200 MHz, CDCl3): d 7.60
(1H, m), 7.38–7.27 (5H, m), 7.09 (1H, m), 6.54 (1H, m), 4.40 (1H,
q, J ¼ 7.0 Hz), 1.81 (3H, d, J ¼ 7.0 Hz); 13C NMR (50 MHz, CDCl3):
d 168.0, 157.9, 145.6, 140.0, 139.0, 129.1, 127.2, 127.1, 113.9,
110.8, 37.2, 19.7; ESIMS: m/z 241[M + H]+; anal. calcd for
1
(KBr): 1609, 1562, 1511, 1446, 1243 cmꢂ1; H NMR (200 MHz,
CDCl3): d 7.91 (2H, d, J ¼ 8.0 Hz), 7.40–7.21 (5H, m), 6.94 (2H, d,
J ¼ 8.0 Hz), 4.41 (1H, q, J ¼ 7.0 Hz), 3.84 (3H, s), 1.80 (3H, d, J ¼
7.0 Hz); 13C NMR (50 MHz, CDCl3): d 158.8, 145.1, 133.9, 132.0,
131.7, 128.9, 128.2, 126.2, 123.9, 114.0, 55.1, 36.5, 19.9; ESIMS:
m/z 281 [M + H]+; anal. calcd for C17H16N2O2: C, 72.84; H, 5.75;
N, 9.99. Found: C, 72.86; H, 5.74; N, 10.02%.
C
14H12N2O2: C, 69.99; H, 5.03; N, 11.66. Found: C, 70.01; H,
4.98; N, 11.68%.
2-(4-Chlorophenyl)-5-(1-phenylethyl)-1,3,4-oxadiazole (3da)
(Table 3, entry 5)
2-(1-(4-Fluorophenyl)ethyl)-5-(furan-2-yl)-1,3,4-oxad-iazole
(3hb) (Table 3, entry 10)
White solid, mp: 98–100 ꢀC, Rf 0.50 (20% EtOAc/hexane); IR Black semi-solid, Rf 0.40 (20% EtOAc/hexane); IR (KBr): 1564,
(KBr): 1606, 1582, 1483, 1254 cmꢂ1; 1H NMR (200 MHz, CDCl3): 1512, 1228, 1162 cmꢂ1; 1H NMR (200 MHz, CDCl3): d 7.61 (1H,
d 7.93 (2H, d, J ¼ 8.0 Hz), 7.45 (2H, d, J ¼ 8.0 Hz), 7.39–7.27 (5H, m), 7.34–7.27 (2H, m), 7.11–7.00 (3H, m), 6.55 (1H, m), 4.41 (1H,
m), 4.42 (1H, q, J ¼ 7.0 Hz), 1.82 (3H, d, J ¼ 7.0 Hz); 13C NMR q, J ¼ 7.0 Hz), 1.79 (3H, d, J ¼ 7.0 Hz); 13C NMR (50 MHz, CDCl3):
(50 MHz, CDCl3): d 164.2, 140.4, 137.8, 129.2, 129.0, 128.1, d 167.9, 163.8, 160.4, 157.8, 145.9, 135.9, 129.0, 116.1, 116.0,
127.2, 127.0, 122.1, 38.6, 19.2; ESIMS: m/z 287, 285 [M + H]+; 113.0, 112.2, 36.8, 19.9; ESIMS: m/z 259 [M + H]+; anal. calcd for
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C14H11FN2O2: C, 65.11; H, 4.29; N, 10.85. Found: C, 65.09; H, 2 (a) D. Leung, W. Du, C. Hardouin, H. Cheng, I. Hwang,
4.27; N, 10.88%.
B. F. Cravatt and D. L. Boger, Bioorg. Med. Chem. Lett., 2005,
15, 1423; (b) J. Bostrom, A. Hogner, A. Llinas, E. Wellner
and A. T. Plowright, J. Med. Chem., 2012, 55, 1817.
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1471; (b) E. V. Zarudnitskii, I. I. Pervak, A. S. Merkulov,
A. A. Yurcenko and A. A. Tolmachev, Tetrahedron, 2008, 64,
10431.
2-(1-(4-Bromophenyl)ethyl)-5-(furan-2-yl)-1,3,4-oxadi-azole
(3hd) (Table 3, entry 11)
Black solid, mp: 118–120 ꢀC, Rf 0.45 (20% EtOAc/hexane); IR
(KBr): 1636, 1564, 1162, 1073 cmꢂ1; 1H NMR (200 MHz, CDCl3):
d 7.61 (1H, m), 7.49 (2H, d, J ¼ 8.0 Hz), 7.21 (2H, d, J ¼ 8.0 Hz),
7.11 (1H, m), 6.57 (1H, m), 4.38 (1H, q, J ¼ 7.0 Hz), 1.79 (3H, d, J
¼ 7.0 Hz); 13C NMR (50 MHz, CDCl3): d 167.8, 157.9, 145.8,
139.1, 139.0, 132.0, 129.1, 121.5, 114.2, 112.0, 36.9, 19.2; ESIMS:
m/z 321, 319 [M + H]+; anal. calcd for C14H11BrN2O2: C, 52.69; H,
3.47; N, 8.78. Found: C, 52.71; H, 3.45; N, 8.76%.
4 G. S. He, L. S. Tan, Q. Zheng and P. N. Prasad, Chem. Rev.,
2008, 108, 1245.
5 Some recent examples: (a) I. V. Seregin, V. Ryabova and
V. Gevorgyan, J. Am. Chem. Soc., 2007, 129, 7742; (b) J. Zhao,
Y. Zhang and K. Cheng, J. Org. Chem., 2008, 73, 7428; (c)
S. Yanagisawa, T. Sudo, R. Noyori and K. Itami, Tetrahedron,
2008, 64, 6073; (d) G. Cusati and L. Djakovitch, Tetrahedron
Lett., 2008, 49, 2499; (e) C. Verrier, C. Hoarau and
F. Marsais, Org. Biomol. Chem., 2009, 7, 647; (f) J. P. Brand,
J. Charpentier and J. Waser, Angew. Chem., Int. Ed., 2009,
48, 9346; (g) T. Kawano, N. Matsuyama, K. Hirano, T. Satoh
and M. Miura, J. Org. Chem., 2010, 75, 1764; (h)
M. Miyasaka, K. Hirano, T. Satoh and M. Miura, J. Org.
Chem., 2010, 75, 5421; (i) M. Kitahara, K. Hirano,
H. Tsurugi, T. Satoh and M. Miura, Chem.–Eur. J., 2010, 16,
1772; (j) M. Yu, Y. Xie, C. Xie and Y. Zhang, Org. Lett., 2012,
14, 2164; (k) T. Shibata, S. Takasuya, S. Yuzava and T. Otani,
Org. Lett., 2012, 14, 5106; (l) D. Yu, L. Lu and Q. Shen, Org.
Lett., 2013, 15, 940.
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1128; (b) F. Besselievre, S. Piguel, F. Mahuteau-Betzer and
D. S. Grierson, Org. Lett., 2008, 10, 4029; (c) G. Brasche and
S. L. Buchwald, Angew. Chem., Int. Ed., 2008, 47, 1932; (d)
D. Monguchi, A. Yamamura, T. Fujiwara, T. Somete and
A. Mori, Tetrahedron Lett., 2010, 51, 850; (e) J. Xu, D.-F. Luo,
B. Xiao, Z.-J. Liu, T.-J. Gong, Y. Fu and L. Liu, Chem.
Commun., 2011, 47, 4300; (f) O. A. Tomashenko,
E. C. Escudero-Adan, M. M. Belmonte and V. V. Grushin,
Angew. Chem., Int. Ed., 2011, 50, 3793.
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Nat. Chem., 2009, 1, 494; (b) X. Zhao, G. Wu, Y. Zang and
J. Wang, J. Am. Chem. Soc., 2011, 133, 3296; (c) J. Barluenga
and C. Valdes, Angew. Chem., Int. Ed., 2011, 50, 7486; (d)
A. Hamze, B. Treguier, J.-D. Brion and M. Alami, Org.
Biomol. Chem., 2011, 9, 6200; (e) T. Yao, K. Hirano, T. Sato
and M. Miura, Angew. Chem., Int. Ed., 2012, 51, 775; (f)
Z. Shao and H. Zhang, Chem. Soc. Rev., 2012, 41, 560; (g)
Q. Xiao, Y. Zhang and J. Wang, Acc. Chem. Res., 2013, 46, 236.
8 (a) B. Das, N. Salvanna, G. C. Reddy and
P. Balasubramanyam, Tetrahedron Lett., 2011, 52, 6497; (b)
B. Das, G. C. Reddy, P. Balasubramanyam and N. Salvanna,
Synthesis, 2011, 816; (c) G. C. Reddy, P. Balasubramanyam,
N. Salvanna and B. Das, Eur. J. Org. Chem., 2012, 471; (d)
B. Das, G. C. Reddy, P. Balasubramanyam and N. Salvanna,
Tetrahedron, 2012, 68, 300; (e) N. Salvanna, G. C. Reddy and
B. Das, Tetrahedron, 2013, 69, 2220.
2-Benzhydryl-5-phenyl-1,3,4-oxadiazole (3ag)
White solid, mp: 132–135 ꢀC, Rf 0.45 (20% EtOAc/hexane); IR
(KBr): 1562, 1491, 1455, 1290, 1179 cmꢂ1; H NMR (200 MHz,
1
CDCl3): d 8.02 (2H, d, J ¼ 8.0 Hz), 7.58–7.48 (4H, m), 7.40–7.27
(9H, m), 5.82 (1H, s); 13C NMR (50 MHz, CDCl3): d 165.2, 138.8,
132.0, 129.9, 128.8, 128.7, 128.3, 127.4, 127.0, 123.7, 48.5;
ESIMS: m/z 313 [M + H]+; anal. calcd for C21H16N2O: C, 80.75; H,
5.16; N, 8.97. Found: C, 80.71; H, 5.14; N, 8.99%.
2-Benzhydryl-5-(p-tolyl)-1,3,4-oxadiazole (3bg)
White solid, mp: 120–123 ꢀC, Rf 0.40 (20% EtOAc/hexane); IR
(KBr): 1555, 1497, 1453, 1179 cmꢂ1; 1H NMR (200 MHz,CDCl3): d
7.91 (2H, d, J ¼ 8.0 Hz), 7.43–7.27 (12H, m), 5.80 (1H, s), 2.40
(3H, s); 13C NMR (50 MHz, CDCl3): d 165.3, 142.2, 138.5, 129.6,
128.8, 128.6, 127.5, 126.7, 121.0, 48.6, 21.7; ESIMS: m/z 327 [M +
H]+; anal. calcd for C22H18N2O: C, 80.96; H, 5.56; N, 8.58. Found:
C, 80.94; H, 5.60; N, 8.53%.
2-Benzhydryl-5-(4-bromophenyl)-1,3,4-oxadiazole (3eg)
White solid, mp: 128–130 ꢀC, Rf 0.40 (20% EtOAc/hexane); IR
(KBr): 1602, 1554, 1483, 1275, 1082 cmꢂ1 1H NMR (200
;
MHz,CDCl3): d 7.89 (2H, d, J ¼ 8.0 Hz), 7.62 (2H, d, J ¼ 8.0 Hz),
7.41–7.28 (10H, m), 5.81 (1H, s); 13C NMR (50 MHz, CDCl3): d
164.4, 138.2, 132.2, 128.8, 128.5, 128.2, 127.6, 122.6, 48.5;
ESIMS: m/z 392, 390 [M + H]+; anal. calcd for C21H15BrN2O: C,
64.46; H, 3.86; N, 7.16. Found: C, 64.43; H, 3.87; N, 7.14%.
Acknowledgements
The authors thank Council of Scientic and Industrial Research
(CSIR) and University Grants Commission (UGC), New Delhi for
nancial assistance.
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