Ring-closure reactions through intramolecular substitution of thiophenoxide by oxygen and nitrogen nucleophiles: Simple stereospecific synthesis of 4,5-dihydroisoxazoles and 4,5-dihydropyrazoles

Article abstract of DOI:10.1016/j.tet.2005.03.085

A new and simple method for the stereospecific synthesis of 3,5-disubstituted-4,5-dihydro-isoxazoles (chiral isoxazolines) from readily available oximes of chiral Michael adducts of thiophenol to chalcones is reported. An analogous reaction with the N-arylhydrazones of the Michael adduct gave nonracemic 1-(aryl)-3,5-diphenyl-4,5-dihydro-1H-pyrazoles (chiral pyrazolines), but these products are configurationally unstable. The key step of the synthesis is the ring-closure reaction, which occurs by a stereospecific intramoleculer nucleophilic substitution of thiophenoxide.

Full text of DOI:10.1016/j.tet.2005.03.085

Tetrahedron 61 (2005) 5235–5240
Ring-closure reactions through intramolecular substitution of
thiophenoxide by oxygen and nitrogen nucleophiles: simple
stereospecific synthesis of 4,5-dihydroisoxazoles and
4,5-dihydropyrazoles
*
Mariola Zielinska-Błajet, Rafał Kowalczyk and Jacek Skarz˙ewski
Institute of Organic Chemistry, Biochemistry and Biotechnology, Wrocław University of Technology, 50-370 Wrocław, Poland
Received 7 January 2005; revised 8 March 2005; accepted 23 March 2005
Available online 16 April 2005
Abstract—A new and simple method for the stereospecific synthesis of 3,5-disubstituted-4,5-dihydro-isoxazoles (chiral isoxazolines) from
readily available oximes of chiral Michael adducts of thiophenol to chalcones is reported. An analogous reaction with the N-arylhydrazones
of the Michael adduct gave nonracemic 1-(aryl)-3,5-diphenyl-4,5-dihydro-1H-pyrazoles (chiral pyrazolines), but these products are
configurationally unstable. The key step of the synthesis is the ring-closure reaction, which occurs by a stereospecific intramoleculer
nucleophilic substitution of thiophenoxide.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
N, S-ligands prepared from the enantiomerically enriched
adduct of thiophenol to chalcone. The respective Michael
addition was catalyzed by (C)-cinchonine and after
crystallization gave almost optically pure adducts 1 (91/
95% ee) in multi-gram quantities.2 The obtained ketone
(C)-1a was then converted into the oxime (C)-2a and its
R-configuration was proved by X-ray analysis of the
corresponding Beckmann rearrangement product.2 For
further derivatization of the nitrogen-containing function-
ality, we attempted to O-methylate (C)-2a (NaH in DMF
The stereocontrolling ability of the ligand in a metal-
catalyzed asymmetric reaction is determined mainly by the
type of donor atoms present and by the overall ligand
structure. Accordingly, heterodonating N, S-ligands have
been applied successfully in the Pd-catalyzed allylic
substitutions and their stereoelectronic trans-effects were
considered as the main cause of enantioselectivity.1 These
results turned our attention to the catalytic application of the
Scheme 1.
Keywords: Cyclization; Nucleophilic substitution of thiophenoxide; Chiral isoxazolines; Pyrazolines.
*
Corresponding author. Tel.: C4871 3203224; fax: C4871 3284064; e-mail: jacek.skarzewski@pwr.wroc.pl
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.085

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M. Zielinska-Błajet et al. / Tetrahedron 61 (2005) 5235–5240
followed by MeI). However, besides the expected methyl
oxime ether 4, we isolated isoxazoline (4,5-dihydro-
isoxazol) 3a together with thioaniosole (Scheme 1).
The desired E-(C)-4 was simply prepared by treatment of
ketone (C)-1a with O-methylhydroxylamine hydrochloride
in buffered solution. At this stage, we decided to examine
the unexpectedly observed ring-closure and the results
obtained are reported herein.
Scheme 3.
Furthermore, an analogous intermolecular substitution,
specifically the reaction between acetophenone oximate
and benzyl phenyl sulfide did not lead to the respective
nucleophilic substitution product. Thus, it seems that the
observed unusual substitution is caused by the close
proximity of the nucleophile to the reaction center
(E-configuration of oxime). The five-membered ring closure
5-exo-tet process is highly favored for the stereoelectronic
reasons.9 The reaction is clearly enantioselective and
offers a simple synthetic route to 4,5-dihydroisoxazoles in
enantioenriched forms.
2. Results and discussion
The enantiomerically enriched (C)-R-E-oximes 2a–d were
treated with sodium hydride in DMF and kept at 70 8C for
1–1.5 h. After an aqueous work-up, the corresponding
isoxazolines 3a–c were isolated in 71–76% yield. The
products were dextrorotatory (57–86% ee) and, after
recrystallization, of high enantiomeric excess of O98, 70,
and 86%, respectively, as demonstrated by 1H NMR spectra
measured in the presence of Eu(hfc)3 (Scheme 2).
In order to test the scope of ring closure we tried to prepare
various hydrazones of (C)-2a. The N-phenyl and N-2-
pyridyl derivatives 5a and b were obtained easily, and the
hydrazones were cyclized to the corresponding pyrazolines
6a and b, respectively. An attempted preparation of
N-methyl and N,N-dimethylhydrazones failed. Instead, in
both cases the same cyclized product 6c was formed. In the
last reaction, in addition to 6c thioanisole was produced,
accordingly documenting demethylation of the primary
cyclization product (Scheme 4).
Scheme 2.
One of them, (C)-3a has already been reported in the
literature as an enantioenriched (C)-S-isomer.3,4 This
assignment4 was based on chemical correlation to the
known optically active b-hydroxyketone.5 Thus, the intra-
molecular nucleophilic substitution occurred and R-2a–d
cyclized to the products 3a–c of S-configuration. Moreover,
we prepared enantioenriched S-2a using the corresponding
adduct S-1a (57% ee). This material was obtained after two-
fold crystallization of the primary 14% ee product of the
Michael addition of thiophenol to chalcone in the presence
of cinchonidine.2 Thus, the obtained (K)-S-E-2a (ca. 57%
ee) underwent cyclization giving (K)-R-3a (55% ee).
The observed inversion of configuration strongly suggests
an SN2-type mechanism, where an oximate ion with the
nucleophilicity enhanced by the a-effect expels a thio-
phenoxide ion directly. To the best of our knowledge, there
is only one precedent of the reaction of this kind that has
been reported.6 Namely, cyclopropanone dithioacetals were
formed by an intermolecular substitution of thiophenoxide
and this ring-closure was considered as an apparently
unique example of the SN2 reaction. An analogous reaction
leading to four- and five-membered rings did not work.6
On the other hand, some nucleophilic displacements of
thiophenoxide were accounted for by an elimination–
addition mechanism.7 However, the observed reaction
enantiospecifity seems to exclude this mechanism in our
case. Interestingly, when the reaction of 2a was run for over
2 h, along with the main 3a, the oxime of chalcone8 was
isolated as a side elimination product formed in 5–12%
yield. When the cyclization of this product was attempted
under the same reaction conditions in a separate experiment,
no isoxazoline 3a could be detected (Scheme 3). Thus, the
elimination–addition mechanism does not operate here.
Scheme 4.
Thus, obtained pyrazolines (4,5-dihydropyrazoles) showed
only small to medium optical activity (no ee could be
established) and quickly underwent complete racemization.
Anyhow, even this activity supports the SN2-type mecha-
nism operating here. Moreover, along with the pyrazoline
6c, its aromatization product (pyrazole) was obtained.
It seems that in spite of their easy formation via the
nucleophilic displacement of thiophenoxide, the pyrazolines
6 unlike isoxazolines 3 are configurationally unstable and
their easy aromatization, if reversible, can be responsible for
this instability.
In conclusion, an exceptional example of the intramolecular
SN2-type reaction, with thiophenoxide as a leaving group
was observed. The reaction leading to the ring-closure offers
a simple route for the stereospecific synthesis of chiral
isoxazolines and pyrazolines, but, the second products can

M. Zielinska-Błajet et al. / Tetrahedron 61 (2005) 5235–5240
5237
be prepared in racemic form only because of their
configurational instability.
3.3. Preparation of oximes 2
The preparation of oximes was carried out in 2 mmol scale
as described before.2 The crude products (containing up to
9% of Z-stereoisomers by 1H NMR) were purified by
column chromatography on silica gel using as eluent tert-
BuOMe/CHCl3/hexane (2.5:2.0:14.0 for 2a,b,d and
2.5:2.0:12.0 for 2c). All the oximes were obtained as
colorless oils.
3. Experimental
3.1. General
Melting points were determined using a Boetius hot-stage
apparatus and are uncorrected. IR spectra were recorded on
a Perkin Elmer 1600 FTIR spectrophotometer. 1H NMR and
13C NMR spectra were measured on a Bruker CPX (1H,
300 MHz) or a Bruker Avance (1H, 500 MHz) spectrometer
using TMS as an internal standard. GC/MS spectra were
determined on a Hewlett–Packard 5890 II gas chromato-
graph (25 m capillary column) with a Hewlett–Packard
mass spectrometer 5971A operating on the electron impact
mode (70 eV). Optical rotations at 578 nm were measured
using an Optical Activity Ltd Model AA-5 automatic
polarimeter. Separations of products by chromatography
were performed on silica gel 60 (230–400 mesh) purchased
from Merck. TLC was performed using silica gel 60
precoated plates (Merck).
3.3.1. E-(3R)-(C)-1,3-Diphenyl-3-phenylsulfanylpro-
pan-1-one oxime (2a). Yield: 600 mg, 90%; [a]DZC105
(c 1.48, CH2Cl2). All spectral data were reported earlier in
the literature.2
3.3.2. E-(3S)-(K)-1,3-Diphenyl-3-phenylsulfanylpropan-
1-one oxime (ent-2a). Yield: 480 mg, 72%; [a]DZK71 (c
0.58, CH2Cl2). All spectral data were reported earlier in the
literature.2
3.3.3. E-(3R)-(C)-3-(4-Methoxyphenyl)-1-phenyl-3-
phenylsulfanylpropan-1-one oxime (2b). Yield: 632 mg,
87%; Rf 0.22 (tert-BuOMe/CHCl3/hexane, 2.5:2.0:14.0);
[a]DZC95 (c 1.11, CH2Cl2); nmax (liquid film) 3267, 3058,
1610, 1512, 1439, 1304, 1250, 1177, 1035, 959, 762,
693 cmK1; dH (300 MHz, CDCl3) 3.42 (d, 2H, JZ8.0 Hz,
CH2), 3.74 (s, 3H, OMe), 4.57 (t, 1H, JZ8.0 Hz, CH), 6.72
(d, 2H, JZ8.7 Hz, ArH), 7.13–7.35 (m, 12H, ArH), 8.43
(br s, 1H, OH); dC (75 MHz, CDCl3): 33.6 (C-2), 49.3 (C-3),
55.2 (OMe), 113.6, 126.7, 127.2, 128.4, 128.7, 128.9, 129.1,
132.5, 132.7, 134.8, 135.6 (Ph and Ar moiety), 157.4 (C-1),
158.8 (ArOMe). Anal. Calcd for C22H21NO2S (363.49): C,
72.70; H, 5.82; N, 3.86; S, 8.82. Found: C, 72.59; H, 5.93;
N, 3.80; S, 8.89%.
3.2. Preparation of the chiral Michael adducts 1
The addition was carried out in 2 mmol scale as reported
before.2 The products obtained as white crystals were
further enantioenriched by recrystallization from hexane/
methylene chloride. For 1a, ent-1a, and 1d the enantiomeric
forms were isolated from the mother liquors and had lower
mps than the corresponding racemic crystals. For 1b and 1c,
the enantioenriched crystals were separated and had higher
mps than the respective racemates. All spectral data for the
Michael adducts were described earlier.2
3.3.4. E-(R)-(C)-4,4-Dimethyl-1-phenyl-1-phenylsulfa-
nylpentan-3-one oxime (2c). Yield: 508 mg, 81%; Rf
0.46 (tert-BuOMe/CHCl3/hexane, 2.5:2.0:12.0); [a]DZ
C99 (c 0.88, CH2Cl2); nmax (liquid film) 3253, 2967,
1602, 1583, 1481, 1453, 1365, 1026, 956, 926, 746,
698 cmK1; dH (300 MHz, CDCl3) 0.87 (s, 9H, t-Bu), 2.72
(dd, 1H, JZ13.6, 9.7 Hz, CH2), 3.10 (dd, 1H, JZ13.6,
5.6 Hz, CH2), 5.27 (dd, 1H, JZ9.7, 5.6 Hz, CH), 7.15–7.40
(m, 10H, ArH), 8.63 (s, 1H, OH); dC (75 MHz, CDCl3) 28.0
(t-Bu), 28.8 (C-4), 35.1 (C-2), 48.1 (C-1), 126.6, 128.2,
128.4, 128.7, 131.1, 135.7, 139.2, 141.9 (each Ph), 164.0
(C-3). Anal. Calcd for C19H23NOS (313.47): C, 72.80; H,
7.40; N, 4.47; S, 10.23. Found: C, 72.62; H, 7.30; N, 4.53; S,
10.35%.
3.2.1. (3R)-(C)-1,3-Diphenyl-3-phenylsulfanylpropan-1-
one (1a). Yield: 446 mg, 70%, mp 96–97 8C; [a]DZC136
(c 1.02, CH2Cl2), O95% ee by 1H NMR in the presence of
Eu(hfc)3.
3.2.2. (3S)-(K)-1,3-Diphenyl-3-phenylsulfanylpropan-1-
one (ent-1a). The title compound was obtained in the
addition catalyzed by cinchonidine.2 Yield: 121 mg, 19%,
mp 96–97 8C; [a]DZK72 (c 0.94, CH2Cl2), 57% ee by 1H
NMR in the presence of Eu(hfc)3.
3.2.3.
(3R)-(C)-3-(4-Methoxyphenyl)-1-phenyl-3-
phenylsulfanylpropan-1-one (1b). Yield: 502 mg, 72%,
mp 87.5–88.0 8C; [a]DZC148 (c 0.98, CH2Cl2), 93% ee by
1H NMR in the presence of Eu(hfc)3.
3.3.5. E-(3R)-(C)-3-(4-Methoxyphenylsulfanyl)-1,3-
diphenylpropan-1-one oxime (2d). Yield: 691 mg, 95%;
Rf 0.26 (tert-BuOMe/CHCl3/hexane, 2.5:2.0:14.0);
[a]DZC82 (c 1.20, CH2Cl2); nmax (liquid film) 3243,
3060, 1591, 1492, 1453, 1286, 1245, 1172, 1030, 960, 827,
755, 695 cmK1; dH (300 MHz, CDCl3) 3.42 (d, 2H, JZ
7.9 Hz, CH2), 3.75 (s, 3H, OMe), 4.39 (t, 1H, JZ7.9 Hz,
CH), 6.72 (d, 2H, JZ8.8 Hz, ArH), 7.15–7.33 (m, 12H,
ArH), 8.41 (br s, 1H, OH); dC (75 MHz, CDCl3) 33.1 (C-2),
51.1 (C-3), 55.3 (OMe), 114.3, 126.6, 127.3, 127.9, 128.2,
128.5, 129.1, 132.7, 135.6, 135.9, 140.9 (Ph and Ar moiety),
157.4 (C-1), 159.7 (ArOMe). Anal. Calcd for C22H21NO2S
3.2.4. (R)-(C)-4,4-Dimethyl-1-phenyl-1-phenylsulfanyl-
pentan-3-one (1c). Yield: 113 mg, 19%, mp 103–104 8C;
1
[a]DZC170 (c 0.94, CH2Cl2), 91% ee by H NMR in the
presence of Eu(hfc)3.
3.2.5. (3R)-(C)-3-(4-Methoxyphenylsulfanyl)-1,3-di-
phenylpropan-1-one (1d). Yield: 425 mg, 61%, mp 91.5–
92.0 8C; [a]DZC110 (c 0.98, CH2Cl2), 94% ee by 1H NMR
in the presence of Eu(hfc)3.

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(363.49): C, 72.70; H, 5.82; N, 3.86; S, 8.82. Found: C,
72.58; H, 5.61; N, 3.95; S, 8.90%.
70 eV) 253 (18, MC), 134 (100), 119 (17), 117 (9), 91 (17),
77 (16), 65 (10), 51 (12%). IR and NMR spectra are in
agreement with the literature for the racemic form.11
3.4. Heterocyclization of oximes to isoxazolines 3
3.4.4. (5S)-(C)-3-(t-Butyl)-5-phenyl-4,5-dihydro-isoxa-
zole (3c). Yield: 150 mg, 74%, a colorless oil; Rf 0.42
(tert-BuOMe/CHCl3/hexane, 2.5:2.0:16.0); [a]DZC157 (c
1.04, CH2Cl2); 86% ee; nmax (liquid film) 2967, 1603, 1458,
1366, 1248, 878, 758, 699 cmK1; dH (300 MHz, CDCl3)
1.24 (s, 9H, t-Bu), 2.94 (dd, 1H, JZ16.8, 8.1 Hz, CH2),
3.41 (dd, 1H, JZ16.8, 10.7 Hz, CH2), 5.55 (dd, 1H, JZ
10.7, 8.1 Hz, *CH), 7.27–7.41 (m, 5H, ArH); 1H NMR
(300 MHz, CCl4, Eu(hfc)3) Dd 0.351 ppm for the *CH
signal, the major dextrorotatory (S)-enantiomer shifted
upfield; GC retention time: 12.6 min (from 120 to 280 8C,
5 8C/min); m/z (EI, 70 eV) 203 (7, MC), 188 (2), 131 (6),
104 (100), 97 (20), 91 (8), 82 (12), 77 (15), 57 (32), 51
(12%). All data are in agreement with those reported earlier
for the racemic form.12
A suspension of NaH (0.072 g in mineral oil (50%), washed
twice with hexane, 1.5 mmol) in hexane (1 mL) was added
in one portion to a magnetically stirred solution of the oxime
(1.0 mmol) in dry DMF (10 mL) at rt under argon
atmosphere. The stirring was continued for 10 min. Then,
the mixture was heated at 70 8C under slightly reduced
pressure for 1–1.5 h, until most of the solvent was distilled
off. Finally, the reaction residue was dissolved in water
(10 mL) and extracted with Et2O (3!10 mL). The com-
bined extracts were washed with water, brine, dried over
Na2SO4, and the solvent was evaporated under the reduced
pressure. The crude product was purified by column
chromatography on silica gel using the tert-BuOMe/
CHCl3/hexane mixture as an eluent. The ee of the title
compound was determined by 1H NMR in CCl4 using
Eu(hfc)3 (ca. 0.5 equiv) as a chiral shift reagent. The
products 3a, 3b obtained as white solids were then
enantioenriched by crystallization from hexane/methylene
chloride and their ees were measured again.
3.5. Preparation of O-methyl-oxime 4
The Michael adduct 1a (0.637 g, 2 mmol), O-methyl-
hydroxylamine hydrochloride (0.184 g, 2.2 mmol) and
Na2CO3 (0.117 g, 1.1 mmol) were dissolved in MeOH
(8 mL). Then, AcOH (0.5 mL) was added to the stirred
solution to adjust the pH to 4.5 and the mixture was refluxed
for 3 h. The cooled mixture was diluted with water (2 mL),
extracted with CHCl3 (2!4 mL) and the combined organic
phase was washed with water (2!3 mL) and dried over
Na2SO4. The solvent was evaporated and the crude product
was purified by column chromatography on florisil (hexane/
CHCl3, 9:1). The crude product contained E/Z isomers in
4.7:1 ratio. The main E-stereoisomer (Rf 0.27) was isolated
in pure form, while the minor one (Rf 0.18) was identified by
its 1H NMR (300 MHz, CDCl3): d 3.03–3.13 (m, 2H, CH2),
3.70 (s, 3H, OMe), 4.13 (t, 1H, JZ7.9 Hz, CH), 7.07–7.31
(m, 15H, ArH).
3.4.1. (5S)-(C)-3,5-Diphenyl-4,5-dihydro-isoxazole (3a).
Yield: 170 mg, 76% (83% ee). This product was recrys-
tallized twice forming 121 mg (54% yield) of white crystals;
mp 83.7–84.2 8C; [a]DZC262 (c 0.88, CH2Cl2); O98%
ee; nmax (KBr) 3027, 2876, 1563, 1493, 1447, 1364, 1052,
895, 751, 687 cmK1; dH (300 MHz, CDCl3) 3.33 (dd, 1H,
JZ16.6, 8.3 Hz, CH2), 3.77 (dd, 1H, JZ16.6, 11.0 Hz,
CH2), 5.73 (dd, 1H, JZ11.0, 8.3 Hz, *CH), 7.34–7.41 (m,
1
8H, ArH), 7.68–7.71 (m, 2H, ArH); H NMR (300 MHz,
CCl4, Eu(hfc)3) Dd 0.094 ppm for the *CH signal, the major
dextrorotatory (S)-enantiomer shifted upfield; GC retention
time: 20.1 min (from 120 to 280 8C, 5 8C/min); m/z (EI,
70 eV) 223 (38, MC), 193 (4), 117 (18), 115 (25), 104 (100),
103 (19), 91 (21), 78 (25), 77 (43), 51 (33%). This spectral
characteristic is in agreement with the literature data for the
racemic form.10
3.5.1. E-(3R)-(C)-1,3-Diphenyl-3-phenylsulfanylpro-
pan-1-one O-methyl-oxime (4). Yield: 535 mg, 77%; a
light yellow oil; Rf 0.27 (hexane/CHCl3, 9.0:1.0); [a]DZ
C121 (c 1.0, CH2Cl2); nmax (liquid film) 3059, 2935, 1583,
1481, 1439, 1329, 1048, 895, 749, 693 cmK1; dH (500 MHz,
CDCl3) 3.29 (d, 2H, JZ8.0 Hz, CH2), 3.81 (s, 3H, OMe),
4.44 (t, 1H, JZ8.0 Hz, CH), 7.06–7.17 (m, 15H, ArH); dC
(125 MHz, CDCl3) 34.5 (C-2), 50.6 (C-3), 62.2 (OMe),
127.0, 127.6, 127.8, 128.2, 128.6, 128.7, 129.1, 129.3,
132.8, 135.2, 136.0, 141.2 (Ph moiety), 156.4 (C-1); GC
retention time: 19.8 min (from 140 to 280 8C, 8 8C/min);
m/z (EI, 70 eV) 347 (10, MC), 316 (3), 238 (55), 206 (17),
199 (44), 165 (8), 121 (100), 109 (11), 103 (14), 91 (8), 77
(15%). Anal. calcd for C22H21NOS (347.49): C, 76.04; H,
6.09; N, 4.03; S, 9.23. Found: C, 76.20; H, 6.28; N, 3.84; S,
9.23%.
3.4.2. (5R)-(K)-3,5-Diphenyl-4,5-dihydro-isoxazole (ent-
3a). Yield: 112 mg, 50%, [a]DZK141 (c 0.50, CH2Cl2);
55% ee, 1H NMR (300 MHz, CCl4, Eu(hfc)3) Dd 0.094 ppm
for the *CH signal, the major laevorotatory (R)-enantiomer
shifted downfield.
3.4.3. (5S)-(C)-5-(4-Methoxyphenyl)-3-phenyl-4,5-di-
hydro-isoxazole (3b). Yield: 180 mg, 71% (57% ee). This
product was recrystallized twice forming 117 mg (46%
yield) of the title compound as a white solid, mp 104–
104.5 8C; [a]DZC244 (c 0.92, CH2Cl2); 70% ee; nmax
(KBr) 2957, 1615, 1586, 1518, 1445, 1367, 1303, 1255,
1177, 1031, 899, 815, 754, 688 cmK1; dH (300 MHz,
CDCl3) 3.33 (dd, 1H, JZ16.7, 8.6 Hz, CH2), 3.73 (dd,
1H, JZ16.7, 10.8 Hz, CH2), 3.80 (s, 3H, OMe), 5.69 (dd,
1H, JZ10.8, 8.6 Hz, *CH), 6.90 (d, 2H, JZ8.7 Hz, ArH),
7.32 (d, 2H, JZ8.7 Hz, ArH), 7.40–7.42 (m, 3H, ArH);
7.67–7.72 (m, 2H, ArH); 1H NMR (300 MHz, CCl4,
Eu(hfc)3) Dd 0.143 ppm for the *CH signal, the major
dextrorotatory (S)-enantiomer shifted upfield; GC retention
time: 19.7 min (from 130 to 290 8C, 6 8C/min); m/z (EI,
3.6. Preparation of hydrazones 5
A solution of the Michael adduct 1a (0.479 g, 1.5 mmol)
and PhNHNH2 (0.195 g, 1.8 mmol) or 2-(H2NNH)C5H4N
(0.180 g, 1.65 mmol) in MeOH (20 mL) was placed in a
flask with a catalytic amount of KHSO4 (30 mg, 20 mol%).
The mixture was stirred for 4 h at 50 8C and then kept

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5239
overnight at 25 8C. In the case 5a of the resulting yellow
crystals were filtered off and washed with MeOH (2.5 mL).
For 5b the reaction mixture was evaporated and the products
were isolated by column chromatography on silica gel.
Finally, both title products were recrystallized from hexane/
CH2Cl2.
proper fraction was recrystallized twice forming yellow
crystals; yield: 111 mg, 37%; mp 134–136 8C; [a]DZK2.0
(c 1.6, CH2Cl2). All the optical activity was lost after 2 days.
nmax (KBr) 3027, 1588, 1473, 1442, 1086, 865, 765,
694 cmK1; dH (300 MHz, CDCl3) 3.20 (dd, 1H, JZ17.2,
5.3 Hz, CH2), 3.83 (dd, 1H, JZ17.2, 12.3 Hz, CH2), 5.82
(dd, 1H, JZ12.3, 5.3 Hz, CH), 6.62–6.66 (m, 1H, ArH),
7.22–7.54 (m, 10H, ArH), 7.76–7.79 (m, 2H, ArH), 8.05–
8.07 (m, 1H, ArH); dC (75 MHz, CDCl3) 42.6 (C-4), 61.8
(C-5), 109.1, 114.4, 125.8, 126.0, 127.1, 128.6, 128.7,
129.1, 132.6, 137.1, 143.3, 147.8, 149.3 (Ph and Ar moiety),
155.5 (C-3); GC retention time 26.5 min (120–290 8C, 6 8C/
min); m/z (EI, 70 eV) 299 (30, MC), 195 (100), 155 (12), 78
(14%). Anal. Calcd for C20H17N3 (299.36): C, 80.24; H,
5.72; N, 14.04. Found: C, 80.04; H, 6.01; N, 14.15%.
3.6.1. (3R)-(C)-1,3-Diphenyl-3-phenylsulfanylpropan-1-
one phenylhydrazone (5a). Yield: 509 mg, 83%; mp
144.5–145.5 8C, yellow crystals; [a]DZC358 (c 0.98,
CH2Cl2); nmax (KBr) 3335, 1601, 1513, 1488, 1453, 1253,
1146, 1074, 747, 692 cmK1; dH (500 MHz, CDCl3) 3.21–
3.38 (m, 2H, CH2), 4.35 (dd, 1H, JZ9.3, 4.4 Hz, CH), 6.82
(d, 3H, JZ7.7 Hz, ArH), 7.01 (s, 1H, NH), 7.15–7.52 (m,
17H, ArH); dC (125 MHz, CDCl3) 35.1 (C-2), 51.5 (C-3),
113.6, 120.6, 126.0, 127.9, 128.7, 129.4, 129.5, 133.7,
134.7, 138.2, 141.9, 142.2 (Ph moiety), 145.5 (C-1). Anal.
Calcd for C27H24N2S (408.57): C, 79.37; H, 5.92; N, 6.86;
S, 7.85. Found: C, 79.17; H, 5.69; N, 6.60; S, 7.60%.
3.7.3. 1-Methyl-3,5-diphenyl-4,5-dihydro-1H-pyrazole
(6c). This product was obtained directly in the attempted
syntheses (1.5 mmol scale) of 1a N,N-dimethyl- and
N-methylhydrazone according to the procedure given
above for the hydrazones 5a and b. Yields: 184 mg, 52%
and 195 mg, 55%, respectively, oil; Rf 0.55 (tert-BuOMe/
CHCl3/hexane, 2.5:2.0:16.0); [a]DZK1.3 and K1.1,
respectively (c 0.8, CH2Cl2); nmax (liquid film) 3061,
2861, 2834, 1586, 1496, 1446, 1362, 1194, 1132, 1037,
940, 756, 694 cmK1; dH (300 MHz, CDCl3) 2.85 (s, 3H,
Me), 3.01 (dd, 1H, JZ16.1, 14.5 Hz, CH2), 3.49 (dd, 1H,
JZ16.1, 10.0 Hz, CH2), 4.13 (dd, 1H, JZ14.5, 10.0 Hz,
CH), 7.32–7.51 (m, 8H, ArH), 7.66 (dd, 2H, JZ8.1, 1.5 Hz,
ArH); GC retention time 19.8 min (120–290 8C, 5 8C/min);
m/z (EI, 70 eV) 236 (58, MC), 159 (100), 132 (9), 131 (11),
118 (11), 115 (21), 104 (24), 103 (18), 91 (21), 77 (47), 51
(33%). In both reactions leading to 6c also the correspond-
ing aromatization product (1-methyl-3,5-diphenylpyra-
zole)14 was isolated in 35% (123 mg) and 40% (141 mg)
yield, respectively; Rf 0.31 (tert-BuOMe/CHCl3/hexane,
2.5:2.0:16.0). 1H NMR and IR spectra are in agreement with
the literature data for the racemic form of 6c and for the
aromatization product.14
3.6.2. (3R)-(C)-1,3-Diphenyl-3-phenylsulfanylpropan-1-
one 2-pirydylhydrazone (5b). Yield: 233 mg, 38% (50%
of 1a recovered); yellow crystals; mp 107–109 8C;
[a]DZC118 (c 1.22, CH2Cl2); nmax (KBr) 3316, 1591,
1574, 1491, 1456, 1437, 1260, 1142, 1076, 751, 694 cmK1
;
dH (300 MHz, CDCl3) 3.33 (m†, 2H, JZ18.2, 14.7, 7.4 Hz,
CH2), 4.43 (dd, 1H, JZ8.5, 6.2 Hz, CH), 6.74–6.78 (m, 1H,
ArH), 7.16–7.35 (m, 14H, ArH), 7.52–7.56 (m, 3H, ArH),
8.05 (s, 1H, NH), 8.12–8.14 (m, 1H, ArH); dC (75 MHz,
CDCl3) 34.1 (C-2), 50.8 (C-3), 107.7, 115.9, 126.0, 127.4,
127.9, 128.1, 128.3, 128.4, 128.9, 132.8, 134.2, 137.6,
137.9, 140.9, 143.4, 147.6, 157.0 (C-1). Anal. Calcd for
C26H23N3S (409.55): C, 76.25; H, 5.66; N, 10.26; S, 7.83.
Found: C, 75.99; H, 6.00; N, 10.15; S, 7.71%.
3.7. Preparation of the pyrazolines 6
The cyclization of hydrazones was run in dry DMF/NaH in
1 mmol scale according to the procedure described above
for the cyclization of oximes.
3.7.1. 1,3,5-Triphenyl-4,5-dihydro-1H-pyrazole (6a).
Yield: 277 mg, 93% directly after chromatography,
[a]DZK26 (c 0.86, CH2Cl2). This material was recrystal-
lized twice to yield yellow crystals, 176 mg, 59%, mp 138–
139.5 8C; [a]DZK49 (c 0.84, CH2Cl2). After 6 days the
specific rotation value diminished to zero. nmax (KBr) 3022,
1596, 1504, 1394, 1325, 1125, 873, 759, 692 cmK1; dH
(300 MHz, CDCl3) 3.14 (dd, 1H, JZ17.1, 7.2 Hz, CH2),
3.84 (dd, 1H, J1Z17.1, 12.4 Hz, CH2), 5.27 (dd, 1H, JZ
12.4, 7.2 Hz, CH), 6.78 (t, 1H, JZ7.2 Hz, ArH), 7.06–7.41
(m, 12H, ArH), 7.72 (d, 2H, JZ7.4 Hz, ArH); GC retention
time: 21.0 min (from 130 to 290 8C, 8 8C/min); m/z (EI,
70 eV) 298 (100, MC), 221 (38), 194 (12), 115 (9), 104 (10),
91 (41), 77 (24), 64 (9), 51 (12%). All spectra data are in
agreement with the literature data for the racemic form.13
References and notes
´ ´ ´
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´
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