Activated carbon-promoted oxidative aromatization of hantzsch 1,4-dihydropyridines and 1,3,5-trisubstituted pyrazolines using molecular oxygen

Article abstract of DOI:10.1055/s-2004-822343

In the presence of activated carbon, Hantzsch 1,4-dihydropyridines and 1,3,5-trisubstituted pyrazolines were aromatized with molecular oxygen to the corresponding pyridines and pyrazoles in excellent yields.

Full text of DOI:10.1055/s-2004-822343

PAPER
1015
Activated Carbon-Promoted Oxidative Aromatization of Hantzsch 1,4-Dihy-
dropyridines and 1,3,5-Trisubstituted Pyrazolines Using Molecular Oxygen
Aromatization of
1
a
,4-Dihydro
t
pyridin
s
es and Py
u
razolines
U
s
k
ing Molecula
i
r
O
xygen Nakamichi, Yuka Kawashita, Masahiko Hayashi*
Department of Chemistry, Faculty of Science, Kobe University, Kobe 657-8501, Japan
Fax +81(78)8035688; E-mail: mhayashi@kobe-u.ac.jp
Received 8 December 2003; revised 20 February 2004
Abstract: In the presence of activated carbon, Hantzsch 1,4-dihy-
dropyridines and 1,3,5-trisubstituted pyrazolines were aromatized
with molecular oxygen to the corresponding pyridines and pyra-
zoles in excellent yields.
Key words: activated carbon, aromatization, oxidations, pyridines,
pyrazolines, heterocycles
Six- and five-membered heterocycles such as pyridine
and pyrazole moieties are important constituents that exist
in various bioactive compounds.1 The oxidation of Hantz-
sch 1,4-dihydropyridines, which can be easily synthesized
by the reaction of aldehydes, b-keto esters, and ammonia,
provides an efficient access to the corresponding pyridine
derivatives. In fact, dihydropyridines have been aroma-
tized to pyridines by various reagents such as HNO3,2
Scheme 1
advantageous when acid-labile substituents exist in the
substrate.
During the course of a further investigation, we discov-
ered that activated carbon itself promoted the above oxi-
dative aromatization. To promote the aromatization of
Hantzsch 1,4-dihydropyridine to pyridine, the presence of
activated carbon is crucial but palladium is not neces-
sary.19 That is, the reaction proceeded by using only acti-
vated carbon without the palladium source. Treatment of
diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxy-
late (1) with 50% of activated carbon (Darco® KB) under
an oxygen atmosphere at 120 °C in acetic acid for 30 min
afforded the corresponding pyridine 7 in 84% yield (entry
1 in Table 1). The reaction proved to take place even at
50 °C (entry 4). This transformation proceeds smoothly in
xylene20 as well as in acetic acid (120 °C, 3.5 h, 85%;
50 °C, 6 h, 88%; entries 2 and 6). Table 1 exemplifies the
conversion of Hantzsch 1,4-dihydropyridines 1–6 pos-
sessing a variety of substituents such as H, Me, i-Pr, Ph,
p-OH-C6H4, and p-NO2C6H4 at the 4-position to the cor-
responding pyridine derivatives 7–11. Two types of acti-
vated carbon were used in these transformations. One is
Darco® KB, and the other is Shirasagi KL. When Hantz-
sch 1,4-dihydropyridines 1–6 were treated with 50
weight% of activated carbon under an oxygen atmosphere
in acetic acid or xylene, the desired pyridines 7–11 were
produced in excellent yields. The reactivity of Darco® KB
and Shirasagi KL proved to be almost the same. It should
be mentioned that among the 1,4-dihydropyridines we ex-
amined, substrates 1 and 3 exhibited high reactivity in par-
ticular. In each case, the reaction proceeded even without
activated carbon (entries 3 and 15). It took less time using
acetic acid compared to xylene as a solvent, nevertheless
the yields were almost the same in both cases. The reac-
tion of the Hantzsch 1,4-dihydropyridine 3 bearing an iso-
propyl group at the 4-position provided the de-alkylated
DDQ,3
NaNO2,4
(NH4)2Ce(NO3)6,5
Cu(NO3)2,6
Bi(NO3)⋅5H2O,7 Mn(OAc)3,8 and Zr(NO3)4.9 On the oth-
er hand, 1,3,5-trisubstituted pyrazolines have been readily
prepared from chalcone derivatives and phenylhydrazine.
Therefore, the aromatization of pyrazolines provides an
easy access to pyrazole derivatives that also exhibit bio-
logical activities, including antipyretic, anticonvulsant,
and analgesic properties.10 To oxidize 1,3,5-trisubstituted
pyrazolines to the corresponding pyrazoles, several oxi-
dants such as Pb(OAc)4,11 MnO2,12 HgO,13 KMnO4,14
9
AgNO3,15 PhI(OAc)2,16 and Zr(NO3)4 have been em-
ployed.
Herein, we report a practical and environmentally friendly
method for the preparation of pyridines and pyrazoles,
which includes the oxidation of dihydropyridines and
pyrazolines, respectively, with molecular oxygen in the
presence of activated carbon (Darco® KB, Aldrich, Inc. or
Shirasagi KL, Japan EnviroChemicals, Ltd.) in acetic acid
or xylene (Scheme 1).
In the previous paper, we reported the Pd/C-promoted aer-
obic oxidative aromatization of Hantzsch 1,4-dihydropy-
ridines and 1,3,5-trisubstituted pyrazolines which led to
the formation of pyridines and pyrazoles, respectively.17
After that report, we found that the use of xylene as a sol-
vent instead of acetic acid also exhibited high perfor-
mance.18 The use of xylene as a solvent should be
SYNTHESIS 2004, No. 7, pp 1015–1020
x
x
.
x
x
.2
0
0
4
Advanced online publication: 14.04.2004
DOI: 10.1055/s-2004-822343; Art ID: F12203SS
© Georg Thieme Verlag Stuttgart · New York

1016
N. Nakamichi et al.
PAPER
pyridine 7 (entries 5, 6, 7, and 8). This phenomenon is This simple process is not only environmentally friendly
consistent with that described in the previous reports.2,6,17
but also economical and operationally simple. Only oxy-
gen and readily available and inexpensive activated car-
bon are used. Neither metal oxides nor organic oxidizing
agents are necessary. The synthetic application and mech-
anistic study of the present oxidations are now in progress
in our laboratory.
Next, we applied the activated carbon–O2 system to the
aromatization of 1,3,5-trisubstituted pyrazolines to the
corresponding pyrazoles (Table 2). This system also ex-
hibited high performance in this transformation. That is,
1,3,5-trisubstituted pyrazolines 12–17 bearing a variety of
substituents were treated with 50% of activated carbon
(Darco® KB or Shirasagi KL) at 120 °C or 50 °C in acetic
acid for 2–12 h to afford the corresponding pyrazoles 18–
23 in high yields (77–91% yield).21 It is clear that activat-
ed carbon promotes the conversion of pyrazolines to pyra-
zoles from the results of entries 2 and 3. At present, we
assume that activated carbon would adsorb oxygen to ac-
celerate the oxidation.
All mps were measured on a Yanaco MP-500D and are uncorrected.
1H and 13C NMR spectra (400 and 100.6 MHz, respectively), were
recorded on a Jeol JNM-LA 400 or a Varian Unity Inova 400 instru-
ment using Me4Si as the internal standard in CDCl3. IR spectra were
measured on a Horiba FT-710 instrument. Elemental analyses were
performed on a Yanaco CHN Corder MT-5. Mass spectra were
measured on a Shimazu GCMS-QP 2000A instrument. Preparative
column chromatography was carried out on foil plates with silica
gel 60 F254 (E. Merck; layer thickness 0.2 mm).
In conclusion, we have developed an extremely practical
and facile method for the aromatization of Hantzsch 1,4-
dihydropyridines and 1,3,5-trisubstituted pyrazolines
with molecular oxygen promoted by activated carbon.
Table 1 Oxidative Aromatization of Hantzsch 1,4-Dihydropyridines with Molecular Oxygen Promoted by Activated Carbona
Entry
1
Substrate
Activated
carbon
Solvent
HOAc
Temp (°C) Time (h)
Product
Yield (%)b
Darco® KB
120
0.5
84
O
H
O
O
H
O
EtO
OEt
EtO
OEt
N
N
H
7
1
2
3
4
5
6
7
8
Darco® KB
none
xylene
xylene
HOAc
HOAc
xylene
xylene
HOAc
120
120
50
3.5
4
85
83
Darco® KB
none
0.5
0.5
6
87
50
57 (42)c
88
Darco® KB
none
50
50
6
2 (95)c
93
Darco® KB
120
1
O
O
O
O
EtO
OEt
EtO
OEt
N
H
N
8
2
9
10
11
12
Darco® KB
none
xylene
xylene
xylene
HOAc
120
120
50
4
99
24
56 (27)
65 (34)c
93
Darco® KB
Darco® KB
36
2
120
O
H
O
O
O
EtO
OEt
EtO
OEt
N
N
H
7
3
13
Shirasagi KL HOAc
120
2
96
Synthesis 2004, No. 7, 1015–1020 © Thieme Stuttgart · New York

PAPER
Aromatization of 1,4-Dihydropyridines and Pyrazolines Using Molecular Oxygen
1017
Table 1 Oxidative Aromatization of Hantzsch 1,4-Dihydropyridines with Molecular Oxygen Promoted by Activated Carbona (continued)
Entry
Substrate
Activated
carbon
Solvent
Temp (°C) Time (h)
Product
Yield (%)b
14
15
16
Darco® KB
none
xylene
xylene
HOAc
120
120
120
6
91
96
95
6
Darco® KB
0.5
O
Ph
O
O
Ph
O
EtO
OEt
EtO
OEt
N
H
N
9
4
17
18
19
20
21
22
23
Shirasagi KL HOAc
Darco® KB
xylene
Shirasagi KL xylene
none xylene
120
120
120
120
50
1
5
4
5
5
96
98
96
21 (78)c
98
Shirasagi KL HOAc
Shirasagi KL xylene
50
24
38 (61)c
95
Darco® KB
HOAc
120
1
C6H4-p-OH
C6H4-p-OH
O
O
O
O
EtO
OEt
EtO
OEt
N
H
N
10
5
24
25
26
27
28
29
Darco® KB
xylene
120
120
50
4.5
5.5
3
97
95
96
95
96
89
Shirasagi KL xylene
Darco® KB
Darco® KB
HOAc
xylene
50
11
Shirasagi KL xylene
50
12
4
Darco® KB
HOAc
120
C6H4-p-NO2
C6H4-p-NO2
O
O
O
O
EtO
OEt
EtO
OEt
N
H
N
11
6
30
31
Darco® KB
Darco® KB
xylene
xylene
120
50
8
89
24
45 (43)c
a Reactions were carried out using 50% of activated carbon under an oxygen atmosphere.
b Isolated yield by column chromatography.
c 1H NMR analysis. Values in parentheses indicate the yield of recovered starting material.
Aromatization of Hantzsch 1,4-Dihydropyridine in Acetic Acid
(Entry 1 in Table 1); Typical Procedure
Yield: 225 mg (84%); pale yellow solid.
A mixture of 1,4-dihydropyridine 1 (270 mg, 1.07 mmol) and Dar-
co® KB (135 mg) in HOAc (3.5 mL) was placed in a 100 mL three-
necked flask under an oxygen atmosphere and stirred at 120 °C for
30 min. The reaction mixture was then filtered using Celite. The fil-
trate was then poured into sat. aq NaHCO3 and extracted with
EtOAc. After usual work-up, the obtained residue was column chro-
matographed (silica gel) to afford the corresponding pyridine 7.
Aromatization of Hantzsch 1,4-Dihydropyridine in Xylene (En-
try 18 in Table 1); Typical Procedure
A mixture of 1,4-dihydropyridine 4 (240 mg, 0.80 mmol) and Dar-
co® KB (120 mg) in xylene (3.5 mL) was placed in a 100 mL three-
necked flask under an oxygen atmosphere and stirred at 120 °C for
5 h. The reaction mixture was then filtered using Celite. After the
filtrate was concentrated, the product was isolated by column chro-
matography (silica gel) to afford the corresponding pyridine 9.
Synthesis 2004, No. 7, 1015–1020 © Thieme Stuttgart · New York

1018
N. Nakamichi et al.
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Table 2 Oxidative Aromatization of 1,3,5-Trisubstituted Pyrazolines with Molecular Oxygen Promoted by Activated Carbona
Entry
1
Substrate
Activated carbon Temp (°C)
Time (h)
2.5
Product
Yield (%)b
Darco® KB
120
91
Ph
Ph
Ph
Ph
N
N
N
N
Ph
Ph
18
12
2
3
4
50
50
3.5
3.5
2
85
none
42 (38)c
86
Shirasagi KL
120
5
6
50
5
2
84
77
Darco® KB
Shirasagi KL
Darco® KB
120
7
8
50
5
2
78
85
120
9
50
6
85
80
10
120
2.5
O
O
C6H4-p-Me
C6H4-p-Me
N
N
N
N
Ph
16
Ph
22
11
12
50
9
2
81
83
Shirasagi KL
120
S
S
C6H4-p-Cl
C6H4-p-Cl
N
N
N
N
Ph
17
Ph
23
13
50
12
82
a All reactions were carried out using 50% of activated carbon in acetic acid under an oxygen atmosphere.
b Isolated yield by column chromatography.
c 1H NMR analysis. Value in parenthesis indicates the yield of recovered starting material.
Yield: 235 mg (98%); pale yellow solid.
Anal. Calcd for C13H17NO4: C, 62.14; H, 6.82; N, 5.57. Found: C,
62.04; H, 6.92; N, 5.54.
Diethyl 2,6-Dimethyl-3,5-pyridinedicarboxylate (7)
Rf = 0.35 (hexane–EtOAc, 8:1); mp 71–72 °C (Lit.8 71 °C).
Diethyl 2,4,6-Trimethyl-3,5-pyridinedicarboxylate (8)
Rf = 0.24 (hexane–EtOAc, 6:1).
IR (KBr): 2986, 2978, 2930, 2912, 1718, 1591, 1555, 1548, 1444,
1380, 1368, 1297, 1254, 1223, 1205, 1123, 1109, 1044, 1025, 771
cm–1.
IR (KBr): 2982, 2936, 2907, 2875, 1723, 1571, 1447, 1411, 1378,
1285, 1241, 1221, 1173, 1107, 1042, 938, 858, 837, 778, 569 cm–1.
1H NMR: d = 1.41 (t, 6 H, J = 7.3 Hz), 2.84 (s, 6 H), 4.40 (q, 4 H,
J = 7.3 Hz), 8.67 (s, 1 H).
1H NMR: d = 1.39 (t, 6 H, J = 7.3 Hz), 2.27 (s, 3 H), 2.52 (s, 6 H),
4.41 (q, 4 H, J = 7.3 Hz).
13C NMR: d = 14.3, 25.0, 61.4, 123.0, 140.9, 162.2, 165.9.
13C NMR: d = 14.0, 16.8, 22.8, 61.4, 127.4, 141.9, 154.7, 168.2.
MS: m/z (relative intensity, %) = 251 (39.8), 206 (100), 195 (19.6),
MS: m/z (relative intensity, %) = 265 (31.4), 236 (45.9), 220 (100),
178 (53.8), 150 (29.0), 106 (21.6).
208 (43.2), 192 (25.9), 77 (34.5).
Synthesis 2004, No. 7, 1015–1020 © Thieme Stuttgart · New York

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Aromatization of 1,4-Dihydropyridines and Pyrazolines Using Molecular Oxygen
1019
Anal. Calcd for C14H19NO4: C, 63.38; H, 7.22; N, 5.28. Found: C,
63.21; H, 7.33; N, 5.19.
IR (KBr): 3119, 3060, 1624, 1596, 1546, 1496, 1482, 1456, 1434,
1415, 1362, 1311, 1284, 1214, 1173, 1066, 1020, 1000, 972, 957
cm–1.
Diethyl 4-Phenyl-2,6-dimethyl-3,5-pyridinedicarboxylate (9)
1H NMR: d = 6.83 (s, 1 H), 7.3–7.5 (m, 13 H), 7.93 (d, 2 H, J = 7.7
Hz).
Rf = 0.24 (hexane–EtOAc, 6:1); mp 60–61 °C (Lit.8 63–64 °C).
IR (KBr): 3000, 2980, 2953, 2933, 1732, 1713, 1557, 1466, 1377,
1299, 1290, 1227, 1211, 1172, 1099, 1042, 861, 771, 755, 705 cm–1.
1H NMR: d = 0.90 (t, 6 H, J = 7.3 Hz), 2.60 (s, 6 H), 4.00 (q, 4 H,
J = 7.3 Hz), 7.2–7.4 (m, 5 H).
13C NMR: d = 13.4, 22.8, 61.2, 126.8, 127.9, 128.0, 128.3, 136.4,
146.0, 155.3, 167.7.
13C NMR: d = 105.1, 125.2, 125.7, 127.3, 127.9, 128.2, 128.4,
128.6, 128.7, 128.8, 130.5, 133.0, 140.0, 144.3, 151.9.
MS: m/z (relative intensity, %) = 297 (21.8), 296 (100), 295 (61.5),
77 (48.5), 51 (27.1).
Anal. Calcd for C21H16N2: C, 85.11; H, 5.44; N, 9.45. Found: C,
85.41; H, 5.50; N, 9.20.
MS: m/z (relative intensity, %) = 327 (71.2), 282 (48.1), 254 (42.4),
236 (100), 209 (29.4), 139 (33.8).
1,3-Diphenyl-5-(4-methoxyphenyl)pyrazole (19)
Rf = 0.28 (hexane–EtOAc, 10:1); mp 79–80 °C (Lit.9 78–80 °C).
Anal. Calcd for C19H21NO4: C, 69.71; H, 6.47; N, 4.28. Found: C,
69.56; H, 6.49; N, 4.33.
IR (KBr): 2835, 1613, 1596, 1519, 1496, 1457, 1362, 1295, 1251,
1175, 1111, 1074, 1030, 971, 913, 835, 798, 767, 693, 593 cm–1.
Diethyl 4-(4-Hydroxyphenyl)-2,6-dimethyl-3,5-pyridinedicar-
boxylate (10)
1H NMR: d = 3.81 (s, 3 H, CH3O), 6.77 (s, 1 H), 6.85 (d, 2 H, J = 8.5
Hz), 7.2–7.4 (m, 10 H), 7.92 (d, 2 H, J = 7.7 Hz).
13C NMR: d = 55.2, 104.7, 113.9, 122.9, 125.3, 125.7, 127.3, 127.9,
128.6, 128.9, 130.0, 133.1, 140.2, 144.2, 151.8, 159.5.
Rf = 0.26 (hexane–EtOAc, 2:1); mp 174–176 °C (Lit.8 171 °C).
IR (KBr): 3454, 2985, 2927, 2349, 1741, 1720, 1613, 1588, 1572,
1558, 1514, 1442, 1334, 1299, 1281, 1239, 1215, 1166, 1110, 1101
cm–1.
1H NMR: d = 1.00 (t, 6 H, J = 7.2 Hz), 2.63 (s, 6 H), 4.06 (q, 4 H,
J = 7.2 Hz), 5.89 (br s, 1 H, OH), 7.1–7.3 (m, 4 H).
13C NMR: d = 13.7, 22.6, 61.5, 115.2, 127.4, 128.0, 129.5, 146.0,
155.1, 156.5, 168.2.
MS: m/z (relative intensity, %) = 327 (22.4), 326 (100), 325 (23.9),
311 (18.0), 77 (33.8).
Anal. Calcd for C22H18N2O: C, 80.96; H, 5.56; N, 8.58. Found: C,
81.02; H, 5.56; N, 8.53.
5-(4-Chlorophenyl)-1,3-diphenylpyrazole (20)
Rf = 0.35 (hexane–EtOAc, 15:1); mp 114–115 °C (Lit.9 114–
115 °C).
MS: m/z (relative intensity, %) = 343 (100), 297 (17.9), 269 (56.6),
252 (87.0), 225 (21.8), 121 (21.1).
Anal. Calcd for C19H21NO5: C, 66.46; H, 6.16; N, 4.08. Found: C,
66.61; H, 6.19; N, 4.16.
IR (KBr): 3052, 1595, 1497, 1484, 1424, 1391, 1360, 1211, 1175,
1092, 1014, 970, 917, 830, 806, 767, 691, 596, 537, 502 cm–1.
1H NMR: d = 6.82 (s, 1 H), 7.2–7.5 (m, 12 H), 7.91 (d, 2 H, J = 7.7
Diethyl 4-(4-Nitrophenyl)-2,6-dimethyl-3,5-pyridinedicarboxy-
Hz).
late (11)
13C NMR: d = 105.2, 125.3, 125.8, 127.6, 128.1, 128.6, 128.7,
128.9, 129.0, 129.9, 132.8, 134.3, 139.8, 143.1, 152.0.
Rf = 0.25 (hexane–EtOAc, 5:1); mp 115–116 °C (Lit.8 114–
115 °C).
MS: m/z (relative intensity, %) = 332 (34.6), 331 (39.6), 330 (100),
329 (53.3), 77 (67.1), 51 (38.9).
IR (KBr): 3113, 2979, 2928, 1722, 1602, 1558, 1518, 1350, 1315,
1229, 1216, 1118, 1107, 1045, 865, 843, 800, 748, 703, 663 cm–1.
1H NMR: d = 0.98 (t, 6 H, J = 7.3 Hz), 2.63 (s, 6 H), 4.03 (q, 4 H,
J = 7.3 Hz), 7.4–7.5 (m, 2 H), 8.2–8.3 (m, 2 H).
Anal. Calcd for C21H15ClN2: C, 76.24; H, 4.57; N, 8.47. Found: C,
76.21; H, 4.57; N, 8.46.
13C NMR: d = 13.7, 23.1, 61.7, 123.2, 126.1, 129.3, 143.3, 143.9,
147.7, 156.1, 167.1.
1,3-Diphenyl-5-(4-nitrophenyl)pyrazole (21)
Rf = 0.31 (hexane–EtOAc, 8:1); mp 142–144 °C (lit.9 142–143 °C).
MS: m/z (relative intensity, %) = 372 (48.8), 355 (29.5), 327 (100),
299 (39.5), 281 (32.5), 139 (23.2).
IR (KBr): 3062, 1596, 1548, 1496, 1457, 1427, 1339, 1290, 1262,
1176, 1108, 972, 853, 809, 769, 753, 695, 671, 596, 491 cm–1.
Anal. Calcd for C19H20N2O6: C, 61.28; H, 5.41; N, 7.52. Found: C,
61.43; H, 5.46; N, 7.55.
1H NMR: d = 6.94 (s, 1 H), 7.3–7.5 (m, 10 H), 7.92 (d, 2 H, J = 7.7
Hz), 8.18 (d, 2 H, J = 8.5 Hz).
13C NMR: d = 106.1, 123.7, 125.3, 125.7, 128.1, 128.2, 128.6,
129.1, 129.2, 132.3, 136.5, 139.4, 141.8, 147.1, 152.2.
Aromatization of 1,3,5-Trisubstituted Pyrazoline in Acetic Acid
(Entry 1 in Table 2); Typical Procedure
A mixture of 1,3,5-triphenylpyrazoline (12) (300 mg, 1.01 mmol)
and Darco® KB (150 mg) in HOAc (3.5 mL) was placed in a 100
mL three-necked flask under an oxygen atmosphere and stirred at
120 °C for 2.5 h. The reaction mixture was then filtered using
Celite. The filtrate was then poured into sat. aq NaHCO3 and ex-
tracted with EtOAc. After usual work-up, the obtained residue was
column chromatographed (silica gel) to afford 1,3,5-triphenylpyra-
zole (18).
MS: m/z (relative intensity, %) = 341 (100), 340 (32.8), 294 (30.1),
77 (36.9), 51 (21.8).
Anal. Calcd for C21H15N3O2: C, 73.89; H, 4.43; N, 12.31. Found: C,
73.64; H, 4.42; N, 12.15.
5-(2-Furyl)-3-(4-methylphenyl)-1-phenylpyrazole (22)
Rf = 0.30 (hexane–EtOAc, 15:1); mp 96–98 °C (Lit.16 93–94 °C).
IR (KBr): 2918, 2387, 2349, 1596, 1503, 1474, 1450, 1352, 1179,
1152, 1114, 1064, 1015, 989, 957, 895, 845, 819, 781 cm–1.
Yield: 270 mg (91%); pale yellow solid.
1H NMR: d = 2.38 (s, 3 H, CH3), 5.97 (d, 1 H, J = 3.4 Hz), 6.33 (dd,
1 H, J = 3.4 Hz), 6.95 (s, 1 H), 7.23 (d, 2 H, J = 8.5 Hz), 7.4–7.5 (m,
4 H), 7.79 (d, 2 H, J = 8.1 Hz).
1,3,5-Triphenylpyrazole (18)
Rf = 0.28 (hexane–EtOAc, 30:1); mp 141–142 °C (Lit.9 139–
140 °C).
Synthesis 2004, No. 7, 1015–1020 © Thieme Stuttgart · New York

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N. Nakamichi et al.
PAPER
(8) Varma, R. S.; Kumar, D. Tetrahedron Lett. 1999, 40, 21.
13C NMR: d = 21.3, 103.1, 108.8, 111.2, 125.7, 128.4, 129.1, 129.9,
135.6, 137.8, 140.2, 142.5, 144.5, 152.0.
(9) (a) Sabitha, G.; Reddy, G. S. K. K.; Reddy, Ch. S.; Fatima,
N.; Yadav, J. S. Synthesis 2003, 1267. (b) See also, Pd/C or
KMnO4: Kamal, A.; Ahmad, M.; Mohd, N.; Hamid, A. M.
Bull. Chem. Soc. Jpn. 1964, 37, 610. (c) RuCl3/O2:
Mashraqui, S. H.; Karnik, M. A. Tetrahedron Lett. 1998, 39,
4895. (d) hn/high pressure: Liu, Z.-L.; Jin, M.-Z. Chem.
Commun. 1998, 2451. (e) CrO2: Ko, K.-Y.; Kim, J.-Y.
Tetrahedron Lett. 1999, 40, 3207. (f) NO: Cheng, J.-P.;
Zhu, X.-O. J. Org. Chem. 2000, 65, 8158. (g) Co-
naphthenate/O2: Chavan, S. P.; Kharul, R. K.; Kalkote, U.
R.; Shivakumar, I. Synth. Commun. 2003, 33, 1333.
(10) (a) Kameyama, T.; Niwa, H. Chem. Abstr. 1968, 69,
106704. (b) Batulin, Yu. M. Chem. Abstr. 1969, 70, 2236.
(c) Polevoi, L. G. Chem. Abstr. 1966, 65, 19147.
(11) Gladstone, W. A. F.; Norman, R. O. C. J. Chem. Soc., Chem.
Commun. 1966, 1536.
MS: m/z (relative intensity, %) = 301 (22.6), 300 (100), 299 (20.2),
77 (38.8), 51 (22.4).
Anal. Calcd for C20H16N2O: C, 79.98; H, 5.37; N, 9.33. Found: C,
80.02; H, 5.47; N, 9.21.
3-(4-Chlorophenyl)-1-phenyl-5-(2-thienyl)pyrazole (23)
Rf = 0.28 (hexane–EtOAc, 30:1); mp 134–135 °C (Lit.9 128–
129 °C).
IR (KBr): 3095, 3070, 3052, 1951, 1810, 1753, 1677, 1597, 1561,
1520, 1494, 1437, 1402, 1351, 1292, 1225, 1206, 1155, 1091, 1065
cm–1.
1H NMR: d = 6.81 (s, 1 H), 7.2–7.5 (m, 10 H), 7.91 (d, 2 H, J = 7.7
Hz).
13C NMR: d = 105.2, 125.3, 125.3, 125.8, 127.6, 128.1, 128.7,
128.8, 129.9, 132.8, 134.3, 139.8, 143.1, 152.0.
(12) Bhatnager, I.; George, M. V. Tetrahedron 1968, 24, 1293.
(13) Auwers, K.; Heimke, P. Liebigs Ann. 1927, 458, 186.
(14) (a) Strauss, F.; Muffat, C.; Heitz, W. Ber. Dtsch. Chem. Ges.
1918, 51, 1457. (b) Smith, L. I.; Howard, K. L. J. Am. Chem.
Soc. 1943, 65, 159.
MS: m/z (relative intensity, %) = 337 (33.6), 336 (100), 335 (33.1),
77 (44.9), 51 (25.1).
Anal. Calcd for C19H13ClN2S: C, 67.75; H, 3.89; N, 8.32. Found: C,
67.78; H, 3.92; N, 8.32.
(15) Dodwadmath, R. P.; Wheeler, T. S. Proc. Ind. Acad. Sci.
1935, 2A, 438.
(16) Singh, S. P.; Kumar, D.; Prakash, O.; Kapoor, R. P. Synth.
Commun. 1997, 27, 2683.
(17) Nakamichi, N.; Kawashita, Y.; Hayashi, M. Org. Lett. 2002,
4, 3955.
Acknowledgment
This research was supported by a Grant-in-Aid for Scientific Rese-
arch from the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
(18) For example, the aromatization of pyrazoline 12 in MeCN
and EtOH produced the corresponding pyrazole 18 only in
low yield (1–33% yield). In the case of dihydropyridine, the
use of MeCN and EtOH as a solvent was also ineffective.
(19) (a) Recently, we reported that substituted 9,10-
dihydroanthracenes were aromatized to anthracenes in
xylene under oxygen in the presence of activated carbon:
Nakamichi, N.; Kawabata, H.; Hayashi, M. J. Org. Chem.
2003, 68, 8272. (b) We also reported that 2-arylbenzo-
xazoles were directly synthesized from substituted 2-amino-
phenols and aldehydes by using activated carbon in xylene
under oxygen: Kawashita, Y.; Nakamichi, N.; Kawabata,
H.; Hayashi, M. Org. Lett. 2003, 5, 3713.
References
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(20) We used a mixture of o-, m-, and p-xylene.
(21) This conversion also proceeds efficiently in xylene instead
of HOAc (for example, 81% yield for 7 h at 120 °C, for
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Synthesis 2004, No. 7, 1015–1020 © Thieme Stuttgart · New York