Thiocyanation on n-benzene rings of 1,3,5-trisubstituted pyrazolines with oxone

Article abstract of DOI:10.1080/00397910902957415

An efficient aromatic thiocyanation of 1,3,5-trisubstituted pyrazolines occurred regioselectively at the para position of N-benzene rings using ammonium thiocyanate as a thiocyanation reagent and oxone as an oxidant.

Full text of DOI:10.1080/00397910902957415

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Thiocyanation on N-Benzene Rings of
1,3,5-Trisubstituted Pyrazolines with
Oxone
Guaili Wu a b , Ruirui Liang a b , Yongjiang Chen b & Longmin Wu a
a State Key Laboratory of Applied Organic Chemistry, Lanzhou
University , Lanzhou , Gansu , China
b JiangSu HengRui Medicine Co. Ltd. , Jiangsu , China
Published online: 09 Dec 2009.
To cite this article: Guaili Wu , Ruirui Liang , Yongjiang Chen & Longmin Wu (2009) Thiocyanation
on N-Benzene Rings of 1,3,5-Trisubstituted Pyrazolines with Oxone, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:1, 129-134, DOI:
10.1080/00397910902957415
To link to this article: http://dx.doi.org/10.1080/00397910902957415
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Synthetic Communications1, 40: 129–134, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902957415
THIOCYANATION ON N-BENZENE RINGS OF
1,3,5-TRISUBSTITUTED PYRAZOLINES WITH OXONE
Guaili Wu,1,2 Ruirui Liang,1,2 Yongjiang Chen,2
and Longmin Wu1
1State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou, Gansu, China
2JiangSu HengRui Medicine Co. Ltd., Jiangsu, China
An efficient aromatic thiocyanation of 1,3,5-trisubstituted pyrazolines occurred regioselec-
tively at the para position of N-benzene rings using ammonium thiocyanate as a thiocyanation
reagent and oxone as an oxidant.
Keywords: Ammonium thiocyanate; oxone; pyrazolines; thiocyanation
Because of the current interest in the application of oxone in organic
synthesis,[1] we have explored some of its applications in forming carbon–heteroatom
bonds. These reactions were involved in oxone-mediated addition of thiocyanate to
aromatic=heteroaromatic compounds and 1,1-disubstituted olefins.[2] Afterward,
further study was carried out to extend the substrate scope for 1,3,5-trisubstituted
pyrazolines (1). Pyrazolines 1 not only are a kind of important structural unit present
in biologically active natural products but also are a kind of building block for the
synthesis of medicinally interesting compounds.[3] As such, the introduction of a
thiocyano group to the framework of 1 will be of significance. The thiocyanato
group is available for further chemical manipulations, including transformation of
various sulfur functional groups and sulfur-containing heterocycles.[4,5] The thiocya-
nato group also plays a special role in several biologically active natural products.[6,7]
In the present work, we disclose the results of aromatic thiocyanation of 1,3,5-trisub-
stituted pyrazolines (Scheme 1).
We started with 1,3,5-triphenyl pyrazoline 1a. The treatment of 1a with
ammonium thiocyanate and oxone in methanol gave a monothiocyanated product,
1-(para-thiocyano)phenyl-3,5-diphenyl pyrazoline 2a (Scheme 1) in 97% yield. The
thiocyanation occurred at the para position of N-benzene ring of 1a rather than at
the pyrazoline ring. No side product was detected. Extension to other 1,3,5-trisubsti-
tuted pyrazolines also gave encouraging results (Table 1).
Received January 16, 2009.
Address correspondence to Longmin Wu, State Key Laboratory of Applied Organic Chemistry,
Lanzhou University, Lanzhou 730000, China. E-mail: nlaoc@lzu.edu.cn
129

130
G. WU ET AL.
Scheme 1. Thiocyanation of 1,3,5-trisubstituted pyrazolines with oxone.
Table 1 clearly indicates that the thiocyanation regioselectively occurred at
the para position of N-benzene rings. No reaction occurred within 1 h, on
1-(20,40-dinitro)phenyl-3,5-diphenyl pyrazoline where the para position on N-benzene
ring was occupied, and no reaction took place at the ortho position. This might prove
that the reaction regiospecifically occurred at the para position of benzene rings.
1,3,5-Trisubstituted pyrazole 1i was examined accordingly. It took much time and
gave a poor yield. Phenylhydrazine 1j was overoxidized, and no desired thiocyanated
product was obtained.
The effects of solvent were examined in various solvents, such as CCl4, CH2Cl2
(DCM), ethyl ether, and acetonitrile. Methanol was found to be highly favorable for
the thiocyanation under consideration.
It can be concluded that (a) the thiocyanation on N-benzene rings of both
1,3,5-trisubstituted pyrazolines and pyrazoles is achieved using oxone and ammonium
thiocyanate, (b) the thiocyanation of 1,3,5-trisubstituted pyrazolines is more rapid and
favorable than that of 1,3,5-trisubstituted pyrazoles under the same reaction con-
ditions, (c) this approach provides an alternate way to introduce a thiocyanato group
to these substrates,[8] and (d) this entry offers several advantages such as commercially
available reagents, mild reaction conditions, and good yields of products.
Table 1. Thiocyanation of 1,3,5-trisubstituted pyrazolines using oxone and ammonium thiocyanate in
methanol
Substrate
Entry
R1
R2
R3
Time (h)
Yield of 2 (%)
1a
1b
1c
1d
1e
1f
Ph
(p)–OCH3–Ph
(p)–Cl–Ph
(p)–Me–Ph
(p)–Br–Ph
(p)–OCH3-Ph
Ph
Ph
Ph
H
0.50
0.67
0.42
0.50
0.83
0.50
0.67
24
97
93
98
97
96
93
95
NR
35
—
H
Ph
Ph
H
H
Ph
H
(p)–Cl–Ph
(p)–MeO–Ph
Ph
H
1g
1h
1ia
1jb
H
2,4-Dinitro
H
Ph
Ph
(p)–MeO–Ph
PhNH2NH2
24
24
a1,3,5-Trisubstituted pyrazoles.
bOveroxidized by oxone; no product was formed.

THIOCYANATION OF PYRAZOLINES
131
EXPERIMENTAL
Melting points were measured on a Yanagimoto melting-point apparatus and
are uncorrected. IR spectra (KBr) were recorded on a Nicolet Nexus 670 Fourier
1
transform (FT)–IR spectrophotometer. H and 13C NMR spectra were recorded
on a Varian Mercury Plus 300=400 NMR spectrometer. Chemical shifts (d) are
reported relative to tetramethylsilane (TMS) (1H) or CDCl3 (13C) as internal
standards. Mass spectrometry–electron impact (MS-EI) (70 eV) determinations were
conducted on an HP 5985A spectrometer. High-resolution mass spectrometry–
electrospray ionization (HRMS-ESI) detections were run on a Bruker Daltonics
Apex II 47e spectrometer with ESI. Chemicals were the highest grade commercially
available and used as received. All reagents were weighed and handled in air at room
temperature.
Typical Procedure for the Preparation of 1a
A mixture of 5 mmol of chalcone and 10 mmol of phenylhydrazine in 30 mL of
glacial acetic acid was refluxed on an oil bath at 110–120ꢀC until completion of the
reaction, monitored by thin-layer chromatography (TLC). It was then cooled and
poured in ice water. The resulting solid was washed with water and recrystallized
from 95% ethanol, giving 1a.
Typical Procedure for the Reaction of 2a with Oxone and
Ammonium Thiocyanate
A solution of 1.0 mmol of 1a and 1.5 mmol of ammonium thiocyanate in 10 mL
of methanol was treated with 1.5 mmol of oxone and allowed to stir at room
temperature until completion of the reaction, monitored by TLC. Consequently, it
was diluted with water and extracted with 4 ꢁ 15 mL of DCM. The DCM solution
was dried over Na2SO4, and DCM was evaporated. The residue was purified by col-
umn chromatography on aluminium oxide neutral gel (200–300 mesh, ethyl acetate=
hexane) to afford the product as colorless crystal. It was recrystallized from
DCM=hexane or ethyl acetate=hexane, providing pure 2a. All products were ident-
1
ified by H and 13C NMR, MS, IR, and HRMS-ESI.
Characterization Data for Products
1-(40-Thiocyano)phenyl-3,5-diphenyl Pyrazoline (2a). Yellow solid, mp
142–143ꢀC. IR (KBr, cmꢂ1) v: 3061, 3031, 2152, 589, 1496, 1398, 1330, 1132, 759.
1H NMR (300 MHz, CDCl3, ppm) d: 7.74 (dd, 2H, J ¼ 1.2 Hz, J ¼ 6.6 Hz, arom),
7.25 (m, 10H, arom), 6.80 (dd, 2H, J ¼ 3.0 Hz, J ¼ 6.9 Hz, arom), 5.28 (dd, 1H,
J ¼ 6.9 Hz, J ¼ 12.3 Hz, CH), 3.85 and 3.16 (dd, 2H, J ¼ 12.3 Hz, J ¼ 17.1 Hz,
CH2). 13C NMR (75 MHz, CDCl3, ppm) d: 148.7, 145.8, 141.3, 133.8, 131.9,
129.3, 129.2, 128.6, 127.9, 125.9, 125.6, 114.4, 112.2, 109.9, 63.7, 43.6. MS-EI m=z:
355 (Mþ), 355, 297, 278, 148, 104; HRMS-ESI m=z: calcd. for C22H17N3S þ H:
356.1216; found: 356.1219.

132
G. WU ET AL.
1-(40-Thiocyano)phenyl-3(40-methoxyl)phenyl-5-phenyl Pyrazoline
(2b). Yellow solid, mp 153–154ꢀC. IR (KBr, cmꢁ1) v: 3033, 2922, 2152, 1590,
1
1497, 1396, 1252, 1178, 831, 701. H NMR (300 MHz, CDCl3, ppm) d: 7.67 (d,
2H, J ¼ 8.7 Hz, arom), 7.31 (m, 7H, J ¼ 3.3 Hz, J ¼ 4.8 Hz, J ¼ 6.9 Hz, arom), 7.04
(d, 2H, J ¼ 9.3 Hz, arom), 6.93 (d, 2H, J ¼ 9.0 Hz, arom), 5.25 (dd, 1H, J ¼ 5.7 Hz,
J ¼ 6.3 Hz, J ¼ 12 Hz, CH), 3.84 (s, 3H, OCH3), 3.83 and 3.15 (dd, 2H, J ¼ 6.3 Hz,
J ¼ 6.6 Hz, J ¼ 16.9 Hz, CH2). 13C NMR (75 MHz, CDCl3, ppm) d: 160.5, 148.7,
146.1, 141.5, 133.9, 129.3, 127.9, 127.5, 125.6, 124.7, 114.2, 114.0, 112.3, 109.3,
63.5, 55.3, 43.8. MS-EI m=z: 385 (Mþ), 385, 328, 251, 148, 77. HRMS-ESI m=z:
calcd. for C23H19N3SO þ H: 386.1322; found: 386.1327.
1-(40-Thiocyano)phenyl-3(40-chloro)phenyl-5-phenyl Pyrazoline (2c). Yellow
solid, mp 160–161ꢀC. IR (KBr, cmꢁ1) v: 3059, 2923, 2153, 1589, 1493, 1389, 1331,
1
1131, 1092, 824, 732. H NMR (300 MHz, CDCl3, ppm) d: 7.73 (m, 2H, arom),
7.38 (m, 7H, arom), 7.19 (dd, 2H, J ¼ 1.8 Hz, J ¼ 2.1 Hz, J ¼ 5.3 Hz, arom), 7.05
(dd, 2H, J ¼ 6.6 Hz, J ¼ 6.9 Hz, J ¼ 8.0 Hz, arom), 5.27 (dd, 1H, J ¼ 5.7 Hz,
J ¼ 6.3 Hz, J ¼ 12 Hz, CH), 3.87 and 3.15 (dd, 2H, J ¼ 1.2 Hz, J ¼ 1.8 Hz J ¼ 5.4 Hz,
J ¼ 6.6 Hz, J ¼ 16.2 Hz, CH2). 13C NMR (75 MHz, CDCl3, ppm) d: 148.6, 145.6,
139.8, 133.9, 133.7, 131.7, 129.5, 129.4, 128.7, 127.0, 125.9, 114.4, 112.1, 110.3,
62.9, 43.5. MS-EI m=z: 389 (Mþ), 389, 330, 278, 148, 77. HRMS-ESI m=z: calcd.
for C22H16N3SCl þ Na: 412.0646; found: 412.0640.
1-(40-Thiocyano)phenyl-3(40-methyl)phenyl-5-phenyl Pyrazoline (2d). Yellow
solid, mp 143–144ꢀC. IR (KBr, cmꢁ1) v: 3061, 3031, 2918, 2153, 1590, 1497,
1
1394, 1327, 1131, 1094, 819, 701. H NMR (300 MHz, CDCl3, ppm) d: 7.62 (d,
2H, J ¼ 1.2 Hz, J ¼ 8.1 Hz, arom), 7.28 (m, 9H, arom), 7.06 (dd, 2H, J ¼ 1.8 Hz,
J ¼ 2.4 Hz, J ¼ 7.5 Hz, arom), 5.28 (dd, 1H, J ¼ 6.3 Hz, J ¼ 18.3 Hz, CH), 3.87
and 3.18 (dd, 2H, J ¼ 1.5 Hz, J ¼ 1.8 Hz, J ¼ 6.9 Hz, J ¼ 7.5 Hz, CH2), 2.39 (s,
3H, CH3). 13C NMR (75 MHz, CDCl3, ppm) d: 148.9, 145.9, 141.4, 139.4, 133.8,
129.3, 129.2, 129.1, 127.9, 125.9, 125.6, 114.3, 112.2, 109.5, 63.5, 43.7, 21.4. MS-EI
m=z: 369 (Mþ), 369, 292, 220, 148, 90, 77. HRMS-ESI m=z: calcd. for
C23H19N3S þ H: 370.1372; found: 370.1367.
1-(40-Thiocyano)phenyl-3(40-bromo)phenyl-5-phenyl Pyrazoline (2e). Yellow
solid, mp 163–164ꢀC. IR (KBr, cmꢁ1) v: 3063, 3032, 2921, 2153, 1590, 1496, 1387,
1
1325, 1133, 1072, 823, 701. H NMR (300 MHz, CDCl3, ppm) d: 7.55 (m, 4H,
J ¼ 7.9 Hz, J ¼ 8.7 Hz, J ¼ 18.3 Hz, arom), 7.35 (m, 7H, arom), 7.06 (d, 2H,
J ¼ 9.0 Hz, arom), 5.29 (dd, 1H, J ¼ 6.0 Hz, J ¼ 12.3 Hz, CH), 3.83 and 3.14 (dd,
2H, J ¼ 6.3 Hz, J ¼ 6.6 Hz, J ¼ 17.6 Hz, CH2). 13C NMR (75 MHz, CDCl3, ppm)
d: 147.5, 145.6, 141.0, 133.8, 131.7, 130.9, 129.3, 128.0, 127.3, 125.5, 123.2,
114.5, 112.1, 110.3, 63.8, 43.4. MS-EI m=z: 433 (Mþ), 433, 375, 277, 192, 148,
90. HRMS-ESI m=z: calcd. for C22H16N3SBr þ H: 434.0321; found: 434.0328.
1-(40-Thiocyano)phenyl-3(40-methoxyl)phenyl-5(40-chloro)phenyl Pyrazo-
line (2f). Yellow solid, mp 107–108ꢀC. IR (KBr, cmꢁ1) v: 3045, 2959, 2933, 2153,
1
1591, 1496, 1396, 1252, 1091, 829, 732. H NMR (300 MHz, CDCl3, ppm) d: 7.66
(d, 2H, J ¼ 8.7 Hz, arom), 7.31 (m, 4H, J ¼ 2.7 Hz, J ¼ 10.4 Hz, J ¼ 10.5 Hz, arom),
7.19 (d, 2H, J ¼ 8.4 Hz, arom), 6.97 (m, 4H, J ¼ 9.0 Hz, J ¼ 24.0 Hz, arom), 5.21
(dd, 1H, J ¼ 6.0 Hz, J ¼ 6.6 Hz, CH), 3.82 (s, 3H, J ¼ 8.7 Hz, OCH3), 3.80

THIOCYANATION OF PYRAZOLINES
133
and 3.10 (dd, 2H, J ¼ 5.7 Hz, J ¼ 6.6 Hz, J ¼ 17.3 Hz, CH2). 13C NMR (75 MHz,
CDCl3, ppm) d: 160.9, 148.9, 146.2, 140.3, 134.2, 133.9, 129.8, 127.8, 127.4, 124.8,
114.6, 114.4, 112.5, 110.1, 63.3, 55.6, 44.0. MS-EI m=z: 419 (Mþ), 308, 271, 178,
148, 84. HRMS-ESI m=z: calcd. for C23H18N3SClO þH: 420.0932; found: 420.0924.
1-(40-Thiocyano)phenyl-3-phenyl-5(40-methoxyl)phenyl Pyrazoline
(2g). Yellow solid, mp 121–122ꢀC. IR (KBr, cmꢂ1) v: 3060, 3002, 2836, 2153, 1588,
1
1508, 1496, 1398, 1248, 1178, 827, 732, 692. H NMR (300 MHz, CDCl3, ppm) d:
7.74 (dd, 2H, J ¼ 1.8 Hz, J ¼ 7.5 Hz, arom), 7.40 (m, 5H, arom), 7.18 (d, 2H,
J ¼ 8.7 Hz, arom), 7.08 (dd, 2H, J ¼ 2.4 Hz, J ¼ 8.7 Hz, arom), 6.88 (d, 2H,
J ¼ 8.7 Hz, arom), 5.24 (dd, 1H, J ¼ 5.7 Hz, J ¼ 6.3 Hz, J ¼ 9.6 Hz, CH), 3.83 (s,
3H, J ¼ 8.7 Hz, OCH3), 3.82 and 3.16 (dd, 2H, J ¼ 6.3 Hz, J ¼ 6.6 Hz, J ¼ 17.6 Hz,
CH2). 13C NMR (75 MHz, CDCl3, ppm) d: 159.1, 148.7, 145.8, 133.8, 133.3,
132.0, 129.1, 128.6, 126.8, 125.9, 114.6, 114.4, 112.2, 109.7, 63.1, 55.2, 43.6. MS-EI
m=z: 385 (Mþ), 278, 251, 236, 193, 148, 90. HRMS-ESI m=z: calcd. for
C23H19N3SO þ H: 386.1322; found: 386.1327.
1-(40-Thiocyano)phenyl-3-phenyl-5(40-methoxyl)phenyl Pyrazole (2i). White
solid, mp 154–155ꢀC. IR (KBr, cmꢂ1) v: 2956, 2924, 2854, 2155, 1610, 1490, 1453,
1255, 1029, 836, 735, 693. 1H NMR (300 MHz, CDCl3, ppm) d: 7.98 (m, 2H,
J ¼ 1.2 Hz, J ¼ 7.5 Hz, arom), 7.51 (m, 3H, arom), 7.31 (m, 8H, arom), 6.97 (s,
1H, CH), 3.86 (s 3H, OCH3). 13C NMR (75 MHz, CDCl3, ppm) d: 160.5, 154.2,
148.5, 139.3, 131.5, 131.0, 129.1, 129.0, 128.7, 128.4, 128.1, 124.9, 119.7, 114.3,
112.0, 55.3, 29.7. MS-EI m=z: 383 (Mþ), 382, 280, 210, 149. HRMS-ESI m=z: calcd.
for C23H17N3SO þH: 384.1165; found: 384.1156.
ACKNOWLEDGMENT
Project 20572040 was supported by the National Natural Science Foundation
of China.
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