A new and efficient approach to pyrazolines. First synthesis of 3-aryl-5-dichloromethyl-2-pyrazolines

Article abstract of DOI:10.1016/j.tet.2009.05.084

An efficient synthetic method for dichloromethylated pyrazolines has been established. 1-Aryl-4,4-dichlorobut-3-en-1-ones 4 were efficiently prepared by treatment of acetophenones with anhydrous chloral, followed by dehydration and reductive dechlorinatio

Full text of DOI:10.1016/j.tet.2009.05.084

Tetrahedron 65 (2009) 5958–5963
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A new and efficient approach to pyrazolines. First synthesis of 3-aryl-5-
dichloromethyl-2-pyrazolines
*
Antonio Guirado , Bruno Martiz, Raquel Andreu, Delia Bautista
´
´
Departamento de Qu´ımica Organica, Facultad de Quımica, Universidad de Murcia, Campus de Espinardo, 30071 Murcia, Apartado 4021, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthetic method for dichloromethylated pyrazolines has been established. 1-Aryl-4,4-di-
chlorobut-3-en-1-ones 4 were efficiently prepared by treatment of acetophenones with anhydrous
chloral, followed by dehydration and reductive dechlorination. Compounds 4 reacted with hydrazine
hydrate and methylhydrazine to give the respective 5-dichloromethyl-2-pyrazolines in high to quanti-
tative yields. The molecular structure of 5-dichoromethyl-1-methyl-3-(2-naphthyl)-2-pyrazoline has
been determined by X-ray crystallography.
Received 30 March 2009
Received in revised form 26 May 2009
Accepted 28 May 2009
Available online 6 June 2009
Keywords:
Pyrazolines
Ó 2009 Elsevier Ltd. All rights reserved.
Chloral
Acetophenones
Trichloromethyl
Dichloromethyl derivatives
1. Introduction
synthetic intermediates for preparing cyclopropane28–30 and pyr-
azole12,31–34 derivatives. 2-Pyrazolines have usually been prepared
Chloral is an inexpensive, multipurpose starting material for or-
ganic synthesis.1 It is able to react with a range of functional groups to
provide trichloromethylated derivatives of a high electrosynthetic
potential, which has attracted our research work for some years.
Chloral reacts with amides to yield chloralamides. From these pri-
mary derivatives we developed a number of significant synthetic
processes on the basis of a conjunction of chemical and key electro-
chemical reactions.2–10 The main advantages of this synthetic
methodology are the high selectivity of the electrochemical re-
ductions and the utilization of pre-chlorinated derivatives from
chloral to avoid the frequently observed lack of selectivity of the usual
chlorinating reagents. Chloral 1 also reacts with acetophenones
by starting from aldehydes or ketones, which have either actual or
potential
a,b
-unsaturation.12,35–49 1,3-Dipolar cycloadditions be-
tween diazoalkanes and different types of molecules containing ac-
tivated double bonds are also exploitable reactions.12,28,29,50,51 In our
case, the synthesis of compounds 6 and 7 was achieved by following
anunprecedentedreactionsequencesuchasthatshowninScheme1,
which involves: (a) dehydration of chloralacetophenones 2 to obtain
the corresponding 2,2,2-trichloroethylideneacetophenones 3,(b)
selective electrochemical reduction to give dichlorovinylaceto-
phenones 4 (1-aryl-4,4-dichlorobut-3-en-1-ones) and (c) treatment
with commercial hydrazines to provide the final dichloromethylated
pyrazoline derivatives 6 and 7. Our first results were communicated
preliminarily.11 We later studied the formation and properties of
synthetic intermediates 3 and 4 and drew conclusions concerning
the total selectivity of the reductive electrochemical reactions of
to give 1-aryl-4,4,4-trichloro-3-hydroxybutan-1-ones
2 (chlor-
alacetophenones). In this reaction we recognized an initial point to
develop an exclusive approach11 to a new type of pyrazoline com-
pounds: 3-aryl-5-dichloromethyl-2-pyrazolines 6 and 7.
compounds 3 yielding unconjugated
b,g-unsaturated ketones 4, in-
Over the years, the chemistry of 2-pyrazolines12,13 has received
considerable attention. It is worthy of note that substances con-
taining a 2-pyrazoline moiety have been described as having po-
tential therapeutic utility, such as anti-inflammatory,14–16
antidepressant,17,18 antipyretic,19 antibacterial,20–25 antifungal20,23,26
and antitumoral.27 Of particular interest is the use of pyrazolines as
stead of the conjugated
a,b
-unsaturated enone isomers52,53 5. In this
paper, wereportfulldetailsof thesynthesis, spectroscopic properties
and X-ray crystallographic molecular structure of one of the novel
3-aryl-5-dichloromethyl-2-pyrazolines.
2. Results and discussion
In the search for a good approach to prepare still unavailable
compounds 6 and 7 on the basis of our synthetic methodology, one
would expect that compounds 4 might be of utility, since they
* Corresponding author. Tel.: þ34 968367490; fax: þ34 968364148.
E-mail address: anguir@um.es (A. Guirado).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.084

A. Guirado et al. / Tetrahedron 65 (2009) 5958–5963
5959
O
O
O
OH
Cl3CCHO
- H2O
Ar
Ar
CCl3
(75-95%)
Ar
CCl3
1
2 (70-89%)
3
H
2e, - Cl
H
N
N
H2NNH2
Ar
CHCl2
O
O
(80-96%)
6
Ar
CHCl2
Ar
CCl2
Me
(72-98%)
5
4
N
N
MeNHNH2
Ar
CHCl2
entry
Ar
(78-95%)
7
a
b
c
d
e
f
g
h
i
C6H5
H
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
N
N
H2NNH2
Ar
Ar
CCl3
4-CH3-C6H4
8 (82-95%)
4-CH3O-C6H4
4-NO2-C6H4
4-Ph-C6H4
2-C10H7
3
Me
N
N
MeNHNH2
CCl3
(80-86%)
j
2,4-(CH3)2C6H3
9
Scheme 1.
contain two electrophilic active centres with potential ability to
react with hydrazines, leading to the compounds sought. In-
termediates 2,3 and 4 were efficiently prepared starting from an-
hydrous chloral and acetophenones according to the reaction route
shown in Scheme 1. Detailed protocols for each implied reaction
were previously reported.11,52 Yields ranged from high to
quantitative.
Reactions of compounds 4 with anhydrous methylhydrazine led
to the novel 3-aryl-5-dichloromethyl-1-methyl-2-pyrazolines 7,
whose formation, isolation and characterization were carried out in
the same way as hydrazine hydrate reactions. However, analogous
syntheses using phenylhydrazine could not be achieved, since the
formation of a complex mixture of unidentified products was
observed.
Compounds 4 were treated with commercial hydrazine hydrate
in ethanol under reflux temperature. The progress of these re-
actions could be well checked by TLC showing a complete trans-
formation of starting materials to single products, which were
easily isolated by cooling at ꢀ18 ꢁC and filtration of the precipitated
solid. Highly pure products were isolated in this manner and were
crystallized and identified by IR, MS, high field NMR spectroscopy
and elemental analyses as 3-aryl-5-dichloromethyl-2-pyrazolines
6. Yields ranged from high to almost quantitative. No synthesis of
this type of pyrazolines had been previously reported. This seems to
be attributable to incompatibility of pyrazolines with the reagents
mostly used to generate dichloromethyl groups.54 However, the
aim of this approach is to circumvent such synthetic problems by
utilization of a pre-chlorinated intermediate derived from chloral
with the advantageous result of the development of a general, facile
and highly efficient synthetic method.
Geometrical characteristics of the new class of pyrazoline
compounds were determined by single crystal X-ray crystallogra-
phy of 7i. The molecular structure found is illustrated in Figure 1.
Selected intramolecular distances and bond angles are given in
Table 1. Figure 2 corresponds to a perspective of the crystal packing,
showing hydrogen interactions of molecules with
arrangement.
a helical
The possibility of preparing compounds 6 and 7 via an alter-
native procedure was also investigated without participation of
intermediates 4, involving a prior formation of the pyrazoline ring
system from intermediates 3 and subsequent electrochemical de-
chlorination. Thus, compounds 3 were treated with hydrazine
hydrate or methylhydrazine leading to the corresponding
Regarding the formation of products 6, and considering our
observation that unconjugated enones 4 undergo base catalyzed
isomerization52 to conjugated enones 5, the participation of these
isomers seems plausible. A further fact that provides support to this
suggestion is the much greater reactivity showed by isomers 5 with
respect to that of compounds 4. This was evidenced by a competi-
tive experiment between compounds 4f and 5e, which was
obtained by base isomerization52 of 4e. When an equimolar mix-
ture of 4f and 5e was treated with a half molar amount of hydrazine
hydrate, the only pyrazoline product was 6e (total conversion)
whereas 4f remained fully unaltered.
Figure 1. ORTEP of 7i, with thermal ellipsoids shown at 50% probability.

5960
A. Guirado et al. / Tetrahedron 65 (2009) 5958–5963
Table 1
3.2. Preparation of 3-aryl-5-dichloromethyl-2-pyrazolines
(6) and (7)
Selected bond lengths and bond angles in crystal structure of 7i
Bond lengths (Å)
To a suspension of 4 (7 mmol) in EtOH (15 ml) a solution of
hydrazine hydrate or methylhydrazine (8.4 mmol) in EtOH (7 ml)
was added dropwise. The mixture was refluxed for 10 min. Then
the solution was concentrated under reduced pressure (half of
volume) and was kept at ꢀ18 ꢁC until the precipitation of a pale
yellow solid, which was collected by filtration and crystallized from
the appropriate solvent.
Cl(1)–C(1)
Cl(2)–C(1)
N(1)–N(2)
N(1)–C(15)
N(1)–C(2)
1.7839(14)
1.7818(14)
1.4078(16)
1.4580(17)
1.4750(17)
N(2)–C(4)
C(1)–C(2)
C(2)–C(3)
C(3)–C(4)
C(4)–C(5)
1.2907(17)
1.5213(18)
1.5301(18)
1.5096(18)
1.4655(18)
Bond angles (ꢁ)
N(2)–N(1)–C(15)
N(2)–N(1)–C(2)
C(15)–N(1)–C(2)
C(4)–N(2)–N(1)
C(2)–C(1)–Cl(2)
C(2)–C(1)–Cl(1)
112.06(10)
107.71(10)
116.01(11)
109.13(11)
113.02(10)
111.29(10)
Cl(2)–C(1)–Cl(1)
N(1)–C(2)–C(1)
N(1)–C(2)–C(3)
C(1)–C(2)–C(3)
C(4)–C(3)–C(2)
N(2)–C(4)–C(3)
109.66(7)
111.29(10)
102.77(10)
116.54(11)
99.87(10)
113.22(11)
3.2.1. 5-Dichloromethyl-3-phenyl-2-pyrazoline (6a)
Yield 92%; crystallization from ethanol gave pale yellow nee-
dles; mp 129–131 ꢁC (dec).(Found C, 52.35; H, 4.39; N, 12.18.
C10H10Cl2N2 requires C, 52.42; H, 4.40; N, 12.23.) 1H NMR
d (CDCl3,
400 MHz) 3.11 (dd, 1H, J¼17.1, 7.4 Hz), 3.30 (dd, 1H, J¼17.1, 10.4 Hz),
4.32 (dt, 1H, J¼10.4, 7.4 Hz), 5.06 (br s, 1H), 5.62 (d, 1H, J¼7.4 Hz),
7.32–7.40 (m, 3H), 7.61–7.65 (m, 2H); 13C NMR
d (CDCl3, 100.8 MHz)
36.44, 68.17, 73.94,126.05,128.66,129.32,132.01,151.52; MS m/z (%)
230 (Mþþ2, 9), 228 (Mþ, 14), 145 (100), 118 (34), 104 (9), 91 (23), 77
(36); IR (Nujol) 3280, 1591, 1566, 1420, 1249, 1206, 1158, 1062, 907,
864, 815, 761, 688 cmꢀ1
.
3.2.2. 5-Dichloromethyl-3-(4-fluorophenyl)-2-pyrazoline (6b)
Yield 85%; crystallization from ethanol gave yellow prisms; mp
87–91 ꢁC (dec).(Found C, 48.58; H, 3.65; N, 11.36. C10H9Cl2FN2 re-
quires C, 48.61; H, 3.67; N, 11.34.) 1H NMR
d (CDCl3, 400 MHz) 3.10
(dd, 1H, J¼17.0, 7.3 Hz), 3.29 (dd, 1H, J¼17.0, 10.4 Hz), 4.34 (dt, 1H,
J¼10.4, 7.3 Hz), 5.64 (d,1H, J¼7.3 Hz), 7.07 (t, 2H, J¼8.6 Hz), 7.62 (dd,
2H, J¼8.6, 5.4 Hz); 13C NMR
d (CDCl3, 100.8 MHz) 36.55, 68.21,
73.85, 115.76 (d, J¼21.8 Hz), 127.93 (d, J¼8.4 Hz), 128.33 (d,
J¼3.2 Hz), 150.73, 163.40 (d, J¼249.8 Hz); MS m/z (%) 248 (Mþþ2,
4), 246 (Mþ, 6), 163 (100), 146 (10), 136 (15), 120 (11), 109 (12), 95
(11), 75 (9); IR (Nujol) 3278, 1599, 1512, 1419, 1240,1207, 1152, 1065,
910, 837, 771, 745, 676 cmꢀ1
.
3.2.3. 5-Dichloromethyl-3-(4-chlorophenyl)-2-pyrazoline (6c)
Yield 93%; crystallization from ethanol gave yellow needles; mp
126–128 ꢁC.(Found C, 45.65; H, 3.41; N, 10.60. C10H9Cl3N2 requires
Figure 2. A perspective of the crystal packing of 7i, showing the hydrogen interactions.
C, 45.57; H, 3.44; N,10.63.) 1H NMR
d (CDCl3, 400 MHz) 3.09 (dd,1H,
J¼17.1, 7.3 Hz), 3.28 (dd, 1H, J¼17.1, 10.5 Hz), 4.35 (dt, 1H, J¼10.5,
trichloromethylpyrazolines 8 and 9 in high yields. However, at-
tempts to promote a selective cathodic dehalogenation of these
compounds to generate the final products 6 and 7 gave mediocre or
bad results. For example, reductions of 8e and 9a led to the re-
spective dichloromethylpyrazolines in low yields: 6e (25%) and 7a
(48%).
7.3 Hz), 5.13 (br s, 1H), 5.63 (d, 1H, J¼7.3 Hz), 7.54 (d, 2H, J¼8.7 Hz),
7.56 (d, 2H, J¼8.7 Hz); 13C NMR
d (CDCl3, 100.8 MHz) 36.34, 68.26,
73.79, 127.28, 128.91, 130.53, 135.17, 150.48; MS m/z (%) 266 (Mþþ4,
24), 264 (Mþþ2, 64), 262 (Mþ, 64), 227 (8), 181 (100), 179 (50), 152
(33), 117 (29), 144 (24); IR (Nujol) 3278, 1636, 1598, 1495, 1430,
1206, 1092, 1068, 1009, 907, 828, 745 cmꢀ1
.
To conclude, a high yield new method for the synthesis of 3-
aryl-5-dichloromethyl-2-pyrazolines,
a previously unattainable
3.2.4. 3-(4-Bromophenyl)-5-dichloromethyl-2-pyrazoline (6d)
Yield 89%; crystallization from EtOH gave yellow needles; mp
124–125 ꢁC (dec).(Found C, 38.98; H, 2.92; N, 8.98. C10H9BrCl2N2
class of compounds, is reported. Easy availability of starting mate-
rials and simple experimental procedure are noteworthy advan-
tages of this approach.
requires C, 39.00; H, 2.95; N, 9.10.) 1H NMR
d (CDCl3, 300 MHz) 3.09
(dd, 1H, J¼17, 7.3 Hz), 3.82 (dd, 1H, J¼17, 10.5 Hz), 4.35 (dt, 1H,
3. Experimental
3.1. General
J¼10.5, 7.3 Hz), 5.63 (d,1H, J¼7.3 Hz), 7.50 (s, 4H); 13C NMR
d (CDCl3,
75.4 MHz) 36.26, 68.25, 73.77, 123.42, 127.49, 130.94, 131.84,
150.45; MS m/z (%) 310 (Mþþ4, 30), 308 (Mþþ2, 63), 306 (Mþ, 39),
223 (100), 225 (100), 144 (98), 128 (22), 117 (26), 102 (25), 75 (31);
IR (Nujol) 3279, 1636, 1399, 1252, 1203, 1064, 1005, 904, 822,
NMR spectra were determined on Bruker AV-200, Bruker AV-
300 or Bruker AV-400 with tetramethylsilane as internal reference.
Electron-impact mass spectra were obtained on Thermoquest trace
MS spectrometer under an ionizing voltage of 70 eV. IR spectra
(Nujol emulsions) were recorded on a Nicolet Impact 400 Spec-
trometer. Microanalyses were performed on a Carlo Erba EA-1108
analyzer. Melting points were determined on a Bu¨chi Melting point
B-540, and are uncorrected. Compounds 2–4 were prepared as
previously described.11,52
746 cmꢀ1
.
3.2.5. 5-Dichloromethyl-3-(4-methylphenyl)-2-pyrazoline (6e)
Yield 85%; crystallization from ethanol gave pale yellow nee-
dles; mp 160–161 ꢁC (dec).(Found C, 54.14; H, 5.03; N, 11.58.
C11H12Cl2N2 requires C, 54.34; H, 4.97; N, 11.52.) 1H NMR
d (CDCl3,
400 MHz) 2.36 (s, 3H), 3.10 (dd, 1H, J¼17.1, 7.3 Hz), 3.29 (dd, 1H,
J¼17.1, 10.3 Hz), 4.31 (dt, 1H, J¼10.3, 7.3 Hz), 5.32 (br s, 1H), 5.62 (d,

A. Guirado et al. / Tetrahedron 65 (2009) 5958–5963
5961
1H, J¼7.3 Hz), 7.17 (d, 2H, J¼8.1 Hz), 7.53 (d, 2H, J¼8.1 Hz); 13C NMR
(13), 91 (13), 77 (19); IR 3061, 2966, 2870, 2795, 1636, 1594, 1448,
1362, 1136, 1043, 930, 760, 695, 669 cmꢀ1
d
(CDCl3, 100.8 MHz) 21.45, 36.58, 68.09, 73.97, 126.06, 129.19,
.
129.38,139.55,151.92; MS m/z (%) 244 (Mþþ2,17), 242 (Mþ, 27),160
(30), 159 (100), 132 (13), 117 (16), 91 (25), 79 (14); IR (Nujol) 3279,
3.2.11. 3-(4-Chlorophenyl)-5-dichloromethyl-1-methyl-2-
pyrazoline (7c)
1636, 1515, 1227, 1066, 908, 817, 761, 740, 674 cmꢀ1
.
Yield 90%; column chromatography (silica gel–AcOEt–Hexane,
1:2) gave yellow powder; mp 72–73 ꢁC.(Found C, 47.66; H, 4.01; N,
10.05. C11H11Cl3N2 requires C, 47.60; H, 3.99; N, 10.09.) 1H NMR
3.2.6. 5-Dichloromethyl-3-(4-methoxyphenyl)-2-pyrazoline (6f)
Yield 95%; crystallization from ethanol gave yellow prisms; mp
107–109 ꢁC (dec).(Found C, 51.01; H, 4.76; N, 10.81. C11H12Cl2N2O
d
(CDCl3, 300 MHz) 3.04 (s, 3H), 3.25 (dd, 1H, J¼17.1, 10.8 Hz), 3.41
requires C, 50.98; H, 4.67; N, 10.81.) 1H NMR
d
(CDCl3, 300 MHz)
(dd, 1H, J¼17.1, 10.8 Hz), 3.83 (td, 1H, J¼10.8, 4.5 Hz), 5.86 (d, 1H,
3.08 (dd, 1H, J¼17.1, 7.2 Hz), 3.27 (dd, 1H, J¼17.1, 10.2 Hz), 3.82 (s,
3H), 4.30 (dt, 1H, J¼10.2, 7.2 Hz), 5.23 (br s, 1H), 5.62 (d, 1H,
J¼7.2 Hz), 6.90 (d, 2H, J¼9.0 Hz), 7.57 (d, 2H, J¼9.0 Hz); 13C NMR
J¼4.5 Hz), 7.32 (d, 2H, J¼11.4 Hz), 7.56 (d, 2H, J¼11.4 Hz); 13C NMR
d
(CDCl3, 75.4 MHz) 36.59, 42.91, 72.88, 74.74, 127.21, 128.81, 130.58,
134.88, 148.33; MS m/z (%) 280 (Mþþ4, 2), 278 (Mþþ2, 7), 276 (Mþ,
7), 195 (33), 193 (100), 158 (4), 128 (4), 75 (4); IR 3056, 2958, 2916,
2868, 2846, 2796, 1639, 1589, 1495, 1447, 1405, 1363, 1138, 1093,
d
(CDCl3, 75.4 MHz) 36.67, 55.39, 68.10, 74.05, 114.08, 124.77, 127.57,
151.55, 160.59; MS m/z (%) 260 (Mþþ2, 13), 258 (Mþ, 19), 223 (3),
187 (8), 175 (100), 160 (49), 132 (24), 115 (15), 77 (19); IR (Nujol)
3281, 1600, 1512, 1415, 1308, 1245, 1168, 1061, 1033, 906, 837, 757,
1037, 926, 829, 762 cmꢀ1
.
672 cmꢀ1
.
3.2.12. 5-Dichloromethyl-1-methyl-3-(4-methylphenyl)-2-
pyrazoline (7e)
3.2.7. 5-Dichloromethyl-3-(4-nitrophenyl)-2-pyrazoline (6g)
Yield 87%; crystallization from ethanol gave orange powder; mp
110–112 ꢁC.(Found C, 43.91; H, 3.40; N,15.16. C10H9Cl2N3O2 requires
Yield 86%; crystallization from MeOH–H2O gave yellow needles,
mp 72–73 ꢁC.(Found C, 55.89; H, 5.44; N, 10.78. C12H14Cl2N2 re-
quires C, 56.05; H, 5.49; N, 10.89.) 1H NMR
d (CDCl3, 400 MHz) 2.36
C, 43.82; H, 3.31; N, 15.33.) 1H NMR
d
(CDCl3, 300 MHz) 3.16 (dd, 1H,
(s, 3H), 3.02 (s, 3H), 3.25 (dd, 1H, J¼17.1, 10.6 Hz), 3.58 (dd, 1H,
J¼17.1, 7.3 Hz), 3.35 (dd, 1H, J¼17.1, 10.5 Hz), 4.45 (dtd, 1H, J¼10.5,
J¼17.1, 10.6 Hz), 3.77 (td, 1H, J¼10.6, 4.6 Hz), 5.84 (d, 1H, J¼4.6 Hz),
7.3, 2.4 Hz), 5.66 (d, 1H, J¼7.3 Hz), 6.40 (br s, 1H), 7.77 (d, 2H,
7.20 (d, 2H, J¼8.2 Hz), 7.53 (d, 2H, J¼8.2 Hz); 13C NMR
d (CDCl3,
J¼8.7 Hz), 8.23 (d, 2H, J¼8.7 Hz); 13C NMR
d
(CDCl3, 75.4 MHz)
100.8 MHz) 21.44, 37.02, 43.25, 73.17, 74.73, 126.02, 129.25, 129.31,
139.27, 149.80; MS m/z (%) 260 (Mþþ4, 15), 258 (Mþþ2, 71), 256
(Mþ, 81), 221 (9), 173 (100), 174 (43), 128 (10), 115 (8), 91 (13); IR
(Nujol) 2784, 1585, 1517, 1138, 1039, 935, 925, 870, 817, 753,
35.83, 68.48, 73.49,124.01,126.42,138.16,147.67,148.58; MS m/z (%)
277 (Mþþ4, 7), 275 (Mþþ2, 25), 273 (Mþ, 35), 238 (6),190 (100),191
(37), 144 (85), 117 (20), 76 (17); IR (Nujol) 3364, 1595, 1561, 1505,
1334, 1109, 1075, 851, 754, 692 cmꢀ1
.
713 cmꢀ1
.
3.2.8. 3-(4-Biphenylyl)-5-dichloromethyl-2-pyrazoline (6h)
Yield 80%; crystallization from ethanol gave yellow needles; mp
157 ꢁC.(Found C, 62.60; H, 4.69; N, 8.98. C16H14Cl2N2 requires C,
3.2.13. 5-Dichloromethyl-3-(4-methoxyphenyl)-1-methyl-2-
pyrazoline (7f)
Yield 83%; column chromatography (AcOEt–Hexane, 1:2) gave
yellow powder; mp 62–64 ꢁC.(Found C, 52.73; H, 5.22; N, 10.30.
62.97; H, 4.62; N, 9.21.) 1H NMR
d (CDCl3, 400 MHz) 3.14 (dd, 1H,
J¼17, 7.5 Hz), 3.33 (d, 1H, J¼17, 10.4 Hz), 4.34 (dt, 1H, J¼10.4, 7.5 Hz),
5.63 (d, 1H, J¼7.5 Hz), 6.13 (br s, 1H), 7.36 (t, 1H, J¼5.4 Hz), 7.44 (t,
2H, J¼7.2 Hz), 7.62–7.60 (m, 4H), 7.40 (d, 2H, J¼8.4 Hz); 13C NMR
C12H14Cl2N2O requires C, 52.76; H, 5.17; N, 10.26.) 1H NMR
d (CDCl3,
300 MHz) 3.01 (s, 3H), 3.24 (dd, 1H, J¼17.1, 10.8 Hz), 3.43 (dd, 1H,
J¼17.1,10.8 Hz), 3.76 (td, 1H, J¼10.8, 4.5 Hz), 3.83 (s, 3H), 5.85 (d,1H,
J¼4.5 Hz), 6.89 (d, 2H, J¼8.8 Hz), 7.58 (d, 2H, J¼8.8 Hz); 13C NMR
d
(CDCl3, 100.8 MHz) 36.47, 68.24, 73.95, 126.51, 127.06, 127.32,
127.72,128.93,130.95,140.36,141.97,151.18; MS m/z (%) 306 (Mþþ2,
15), 304 (Mþ, 23), 221 (100), 222 (32), 194 (8), 178 (9), 152 (20), 111
(11); IR (Nujol) 3297, 3258, 1641, 1412, 1342, 1219, 1065, 907, 843,
d (CDCl3, 75.4 MHz) 37.10, 43.41, 55.39, 73.19, 74.77, 114.01, 124.79,
127.57, 149.72,160.47; MS m/z (%) 274 (Mþþ2,14), 272 (Mþ, 22), 237
(4), 190 (31), 189 (100), 174 (42), 146 (14), 115 (9), 77 (6); IR 3045,
3003, 2957, 2916, 2837, 2794, 2039, 1608, 1515, 1455, 1363, 1308,
768, 754, 724, 696 cmꢀ1
.
1250, 1043, 922, 831, 762, 608 cmꢀ1
.
3.2.9. 5-Dichloromethyl-3-(2-naphthyl)-2-pyrazoline (6i)
Yield 86%; crystallization from ethanol gave yellow needles; mp
131–132 ꢁC.(Found C, 59.62; H, 4.32; N, 9.97. C14H12Cl2N2 requires C,
3.2.14. 5-Dichloromethyl-1-methyl-3-(4-nitrophenyl)-2-
pyrazoline (7g)
Yield 78%; crystallization from ethanol gave orange micro
needles; mp 117–118 ꢁC. (Found C, 45.79; H, 3.83; N, 14.59.
C11H11Cl2N3O2 requires C, 45.85; H, 3.85; N, 14.58.) 1H NMR
60.23; H, 4.33; N, 10.03.) 1H NMR
d
(CDCl3, 400 MHz) 3.22 (dd, 1H,
J¼16.9, 7.3 Hz), 3.40 (dd, 1H, J¼16.9, 10.4 Hz), 4.36 (dt, 1H, J¼10.4,
7.3 Hz), 5.65 (d, 1H, J¼7.3 Hz), 7.50–7.46 (m, 2H), 7.84–7.79 (m, 4H),
7.95 (dd, 1H, J¼8.7, 1.7 Hz); 13C NMR
d
(CDCl3, 100.8 MHz) 36.42,
d
(CDCl3, 300 MHz) 3.13 (s, 3H), 3.34 (dd, 1H, J¼17.4, 10.9 Hz), 3.46
68.30, 73.98, 123.27, 125.91, 126.64, 126.78, 127.87, 128.30, 128.43,
129.64, 133.15, 133.69, 151.56; MS m/z (%) 280 (Mþþ2, 7), 278 (Mþ,
53), 196 (50), 195 (100), 178 (20), 168 (25), 153 (22), 127 (40); IR
(Nujol) 3320, 3260, 1638, 1339, 1319, 1205, 1162, 1062, 860, 821,
(dd, 1H, J¼17.4, 10.9 Hz), 4.00 (td, 1H, J¼10.9, 4.2 Hz), 5.90 (d, 1H,
J¼4.2 Hz), 7.75 (d, 2H, J¼9 Hz), 8.22 (d, 2H, J¼9 Hz); 13C NMR
d
(CDCl3, 75.4 MHz) 36.03, 42.05, 72.44, 74.47, 124.01, 126.22,
138.29, 146.11, 147.46; MS m/z (%) 289 (Mþþ2, 12), 287 (Mþ, 18), 252
(6), 205 (36), 204 (100), 158 (84), 128 (11), 102 (8), 89 (7), 76 (10); IR
(Nujol) 1640, 1601, 1545, 1507, 1343, 1137, 1109, 1039, 941, 853, 763,
754 cmꢀ1
.
3.2.10. 5-Dichloromethyl-1-methyl-3-phenyl-2-pyrazoline (7a)
Yield 85%; column chromatography (silica gel–AcOEt–Hexane,
1:2) gave red oil; (Found C, 54.30; H, 5.01; N, 11.50. C11H12Cl2N2
753, 700 cmꢀ1
.
3.2.15. 3-(4-Biphenylyl)-5-dichloromethyl-1-methyl-2-
pyrazoline (7h)
requires C, 54.34; H, 4.97; N, 11.52.) 1H NMR
d (CDCl3, 300 MHz)
3.05 (s, 3H), 3.28 (dd, 1H, J¼17.1, 10.5 Hz), 3.46 (dd, 1H, J¼17.1,
Yield 80%; crystallization from ethanol–H2O gave pale yellow
prisms; mp 119–124 ꢁC (dec). (Found C, 60.76; H, 4.88; N, 8.64.
10.5 Hz), 3.82 (td, 1H, J¼10.5, 4.5 Hz), 5.86 (d, 1H, J¼4.5 Hz), 7.32–
7.40 (m, 3H), 7.63–7.66 (m, 2H); 13C NMR
d
(CDCl3, 75.4 MHz) 36.85,
C17H16Cl2N2 requires C, 63.96; H, 5.05; N, 8.78.) 1H NMR
d (CDCl3,
43.12, 73.07, 74.69, 126.03, 128.60, 129.14, 132.02, 149.60; MS m/z
(%) 244 (Mþþ2, 11), 242 (Mþ, 18), 207 (4), 160 (30), 159 (100), 117
300 MHz) 3.06 (s, 3H), 3.30 (dd, 1H, J¼17.2, 10.8 Hz), 3.48 (dd, 1H,
J¼17.2, 10.8 Hz), 3.83 (td, 1H, J¼10.8, 4.5 Hz), 5.86 (d, 1H, J¼4.5 Hz),

5962
A. Guirado et al. / Tetrahedron 65 (2009) 5958–5963
7.35 (t, 1H, J¼7.2 Hz), 7.44 (t, 2H, J¼8.1 Hz), 7.59–7.62 (m, 4H), 7.70
3.12 (ddd, 1H, J¼18.2, 7.6, 1.2 Hz), 3.52 (dd, 1H, J¼18.2, 11.8 Hz), 4.82
(ddd, 1H, J¼11.8, 7.6, 4.1 Hz), 7.42 (d, 2H, J¼8.6 Hz), 7.63 (d, 2H,
(d, 2H, J¼8.4 Hz); 13C NMR
d (CDCl3, 75.4 MHz) 36.88, 43.11, 73.08,
74.72, 126.49, 127.06, 127.25, 127.67, 128.91, 130.99, 140.43, 141.77,
149.26; MS m/z (%) 320 (Mþþ2, 29), 318 (Mþ, 42), 283 (6), 236 (71),
235 (100), 179 (15), 152 (30), 118 (4); IR (Nujol) 1636, 1577, 1413,
J¼8.6 Hz), 8.22 (d, 1H, J¼4.1 Hz); 13C NMR
d (DMSO-d6, 50.4 MHz)
36.79, 74.56, 102.64, 127.17, 128.57, 131.05, 132.97, 147.52; MS m/z
(%) 298 (Mþþ2, 5), 296 (Mþ, 4), 261 (3), 226 (5), 179 (100), 117 (7),
75 (8); IR (Nujol) 3295, 1604, 1498, 1416, 1403, 1377, 1362, 1292,
1336, 1319, 1135, 1043, 933, 842, 762, 722, 689 cmꢀ1
.
1091, 1076, 1009, 900, 828, 786, 727 cmꢀ1
.
3.2.16. 5-Dichloromethyl-1-methyl-3-(2-naphthyl)-2-
pyrazoline (7i)
3.3.2. 3-(4-Methylphenyl)-5-trichloromethyl-2pyrazoline (8e)
Yield 94%; crystallization from ethanol gave white needles; mp
166–168 ꢁC (dec).(Found C, 47.49; H, 4.02; N, 10.11. C11H11Cl3N2
Yield 80%; crystallization from ethanol gave pale yellow prisms,
mp 156–157 ꢁC.(Found C, 61.36; H, 4.83; N, 9.49. C15H14Cl2N2 re-
quires C, 61.45; H, 4.81; N, 9.55.) 1H NMR
d
(CDCl3, 400 MHz) 3.08
requires C, 47.60; H, 3.99; N, 10.09.) 1H NMR
d (CDCl3, 400 MHz)
(s, 3H), 3.39 (dd, 1H, J¼17, 10.7 Hz), 3.56 (dd, 1H, J¼17, 10.7 Hz), 3.86
2.37 (s, 3H), 3.34 (dd, 1H, J¼17.7, 7.0 Hz), 3.40 (dd, 1H, J¼17.7,
(td, 1H, J¼10.7, 4.5 Hz), 5.89 (d, 1H, J¼4.5 Hz), 7.46–7.50 (m, 2H),
10.5 Hz), 4.70 (dd, 1H, J¼10.5, 7.0 Hz), 5.12 (br s, 1H), 7.19 (d, 2H,
7.79–7.84 (m, 4H), 7.96 (dd, 1H, J¼8.6, 1.7 Hz); 13C NMR
d
(CDCl3,
J¼8.2 Hz), 7.55 (d, 2H, J¼8.2 Hz); 13C NMR
d (CDCl3, 100.8 MHz)
100.8 MHz) 36.84, 43.05, 73.07, 74.75, 123.41, 125.77, 126.57, 126.66,
127.85, 128.30, 128.31, 129.67, 133.23, 133.65, 149.63; MS m/z (%)
294 (Mþþ2, 17), 292 (Mþ, 26), 210 (42), 209 (100), 178 (14), 153 (18),
127 (33), 105 (13); IR (Nujol) 2798, 1598, 1250, 1202, 1136, 932, 861,
21.46, 37.26, 75.20, 101.58, 126.10, 129.01, 129.40, 139.59, 151.23; MS
m/z (%) 280 (Mþþ4), 278 (Mþþ2, 11), 276 (Mþ, 12), 241 (3), 205 (8),
159 (100), 132 (17), 117 (20), 91 (29), 65 (16); IR (Nujol) 3278, 1603,
1516, 1424, 1354, 1075, 902, 818, 799, 776, 676 cmꢀ1
.
825, 478, 703 cmꢀ1
.
Crystal data. C15H14Cl2N2, Mr¼293.18, monoclinic, space group
3.3.3. 3-(4-Methoxyphenyl)-5-trichloromethyl-2-pyrazoline (8f)
Yield 95%; crystallization from ethanol gave white needles; mp
146–147 ꢁC (dec).(Found C, 44.92; H, 3.78; N, 9.51. C11H11Cl3N2O
P2(1)/c,
b
a¼9.5009(10),
b¼9.3486(10),
c¼15.3811(17) Å,
¼99.616(2)ꢁ, V¼1347.0(3) Å3 at ꢀ100 K; Z¼4, Dx¼1.446 g/cm3,
F(000)¼608,
m
¼0.479/mm. Data collection. A colourless block
requires C, 45.00; H, 3.78; N, 9.54.) 1H NMR
d (CDCl3, 400 MHz) 3.33
0.25ꢂ0.24ꢂ0.18 mm was mounted in inert oil on a glass fibre and
transferred to the cold gas stream of the diffractometer (Bruker
SMART APEX CCD). Of 15,090 measured reflections, 3120 were in-
dependent (Rint¼0.0516) and were used for all calculations. Struc-
ture refinement. The structures were refined anisotropically against
F2 (program SHELXL-97, G.M. Sheldrick, University of Go¨ttingen).
The methyl group was refined as a rigid group, other H with a riding
model. The final wR2 value was 0.0876 for all reflections, 173 pa-
rameters and 6 restraints, with R1 0.0339 for reflections with
(dd, 1H, J¼17.6, 6.9 Hz), 3.40 (dd, 1H, J¼17.6, 10.6 Hz), 3.83 (s, 3H),
4.70 (dd, 1H, J¼10.6, 6.9 Hz), 4.92 (br s, 1H), 6.91 (d, 2H, J¼8.8 Hz),
7.60 (d, 2H, J¼8.8 Hz); 13C NMR
d (CDCl3, 100.8 MHz) 37.38, 55.43,
75.18, 101.60, 114.12, 124.51, 127.66, 151.09, 160.68; MS m/z (%) 296
(Mþþ4), 294 (Mþþ2, 17), 292 (Mþ, 18), 221 (7), 175 (100), 160 (33),
132 (15), 117 (7), 77 (18); IR (Nujol) 3270, 1607, 1515, 1363, 1258,
1178, 1068, 1032, 1017, 914, 835, 775, 695 cmꢀ1
.
3.3.4. 3-(2,4-Dimethylphenyl)-5-trichloromethyl-2-pyrazoline (8j)
Yield 88%; crystallization from ethanol gave yellow needles; mp
89–91 ꢁC.(Found C, 49.40; H, 4.54; N, 9.60. C12H13Cl3N2 requires C,
I>2s
(I); max Dr 0.370 e/Å3, S 1.08.
Tables of fractional atomic coordinates, thermal parameters,
bond lengths and angles have been deposited at the Cambridge
Crystallographic Center (CCDC 724981).
49.43; H, 4.49; N, 9.61.) 1H NMR
d (CDCl3, 300 MHz) 2.33 (s, 3H),
2.52 (s, 3H), 3.36 (dd, 1H, J¼17.7, 6.9 Hz), 3.45 (dd, 1H, J¼17.7,
10.5 Hz), 4.63 (dd, 1H, J¼10.5, 6.9 Hz), 5.11 (br s, 1H), 7.03 (d, 1H,
3.2.17. 5-Dichloromethyl-1-methyl-3-(2,4-dimethylphenyl)-2-
pyrazoline (7j)
J¼7.8 Hz), 7.06 (s, 1H), 7.23 (d, 1H, J¼7.8 Hz); 13C NMR
d (CDCl3,
75.4 MHz) 21.20, 22.81, 39.55, 74.53, 101.75, 126.44, 128.00, 128.46,
132.54, 137.53, 138.71, 151.96; MS m/z (%) 292 (Mþþ2, 11), 290 (Mþ,
12), 219 (11), 173 (100), 146 (19), 131 (30), 117 (12), 77 (27); IR
(Nujol) 3286, 1612, 1588, 1341, 1061, 1007, 908, 791, 769, 721,
Yield 92%; column chromatography (AcOEt–Hexane, 1:2) gave
orange powder; mp 42–44 ꢁC.(Found C, 57.55; H, 6.00; N, 10.31.
C13H16Cl2N2 requires C, 57.58; H, 5.95; N, 10.33.) 1H NMR
d (CDCl3,
400 MHz) 2.32 (s, 3H), 2.51 (s, 3H), 3.02 (s, 3H), 3.26 (dd, 1H, J¼17,
10.6 Hz), 3.43 (dd, 1H, J¼17, 10.6 Hz), 3.72 (td, 1H, J¼10.6, 4.6 Hz),
5.85 (d, 1H, J¼4.6 Hz), 7.02–7.04 (m, 2H), 7.21 (d, 1H, J¼7.8 Hz); 13C
666 cmꢀ1
.
3.3.5. 1-Methyl-3-phenyl-5-trichloromethyl-2-pyrazoline (9a)
Yield 80%; crystallization from ethanol gave white needles; mp
104–105 ꢁC.(Found C, 47.75; H, 3.97; N, 10.13. C11H11Cl3N2 requires
NMR
d (CDCl3, 100.8 MHz) 21.20, 22.89, 39.46, 43.54, 73.30, 74.23,
126.38, 128.17, 128.44, 132.45, 137.49,138.41, 150.85; MS m/z (%) 272
(Mþþ2, 17), 270 (Mþ, 26), 235 (5), 188 (53), 187 (100), 172 (10), 145
(12), 131 (20), 115 (12), 86 (14); IR 2963, 2922, 2867, 2843, 2794,
C, 47.60; H, 3.99; N, 10.09.) 1H NMR
d (CDCl3, 400 MHz) 3.23 (s, 3H),
3.36 (dd, 1H, J¼18.0, 7.4 Hz), 3.64 (dd, 1H, J¼18.0, 11.7 Hz), 4.17 (dd,
1614, 1588, 1505, 1447, 1351, 1209, 1136, 935, 918, 814, 759 cmꢀ1
.
1H, J¼11.7, 7.4 Hz), 7.33–7.40 (m, 3H), 7.64–7.67 (m, 2H); 13C NMR
d
(CDCl3, 100.8 MHz) 39.58, 44.97, 81.36, 102.28, 126.20, 128.65,
3.3. Preparation of 3-aryl-5-trichloromethyl-2-pyrazolines
(8) and (9)
129.36, 131.70, 149.37; MS m/z (%) 278 (Mþþ2, 9), 276 (Mþ, 10), 205
(3), 241 (5), 159 (100), 117 (18), 91 (21), 77 (33); IR (Nujol) 1595,
1321, 1143, 1064, 1038, 1013, 927, 786, 758, 693 cmꢀ1
.
To a suspension of 3 (11 mmol) in EtOH (45 ml) a solution of
hydrazine hydrate or methylhydrazine (13 mmol) in EtOH (40 ml)
was added dropwise. The mixture was refluxed for 10 min. Then
the solution was concentrated under reduced pressure (half of
volume) and was kept at ꢀ18 ꢁC until the precipitation of a white
solid, which was collected by filtration and crystallized from EtOH.
3.3.6. 1-Methyl-3-(4-nitrophenyl)-5-trichloromethyl-2-
pyrazoline (9g)
Yield 86%; crystallization from ethanol gave yellow needles; mp
169–171 ꢁC.(Found C, 41.02; H, 3.17; N, 12.98. C11H10Cl3N3O2 re-
quires C, 40.96; H, 3.12; N, 13.03.) 1H NMR
d (CDCl3, 300 MHz) 3.33
(s, 3H), 3.40 (dd, 1H, J¼18.0, 7.6 Hz), 3.66 (dd, 1H, J¼18.0, 11.8 Hz),
3.3.1. 3-(4-Chlorophenyl)-5-trichloromethyl-2-pyrazoline (8c)
Yield 82%; crystallization from ethanol gave white needles; mp
176–180 ꢁC (dec).(Found C, 40.09; H, 2.75; N, 9.37. C10H8Cl4N2 re-
4.33 (dd, 1H, J¼11.8, 7.6 Hz), 7.77 (d, 2H, J¼8.8 Hz), 8.22 (d, 2H,
J¼8.8 Hz); 13C NMR
d (CDCl3, 75.4 MHz) 39.10, 44.30, 81.41, 101.70,
123.98, 126.43, 137.80, 145.94, 147.63; MS m/z (%) 323 (Mþþ2, 5),
quires C, 40.30; H, 2.71; N, 9.40.) 1H NMR
d
(DMSO-d6, 200 MHz)
321 (Mþ, 5), 286 (7), 250 (3), 204 (100), 158 (72), 117 (9), 76 (13); IR

A. Guirado et al. / Tetrahedron 65 (2009) 5958–5963
5963
19. Souza, F. R.; Souza, V. T.; Ratzlaff, V.; Borges, L. P.; Oliveira, M. R.; Bonacorso, H.
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Acknowledgements
We gratefully acknowledge the financial support of the Funda-
´
´
´
´
cion Seneca of the Comunidad Autonoma de la Region de Murcia
(project 08755/PI/08).
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Supplementary data
X-ray structural data of compound 7i; NMR spectra of com-
pounds 6–9. Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2009.05.084.
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