Enantioselective synthesis of bio-relevant 3,5-diaryl pyrazolines

Article abstract of DOI:10.1039/c2ob25227a

The straightforward asymmetric construction of bio-relevant Δ²-pyrazolines having either N-(thio)amide or N-acetyl functional groups and flanked by aryl substituents such as phenol at C3 and C5 has been achieved through an enantioselective phase transfer organocatalytic addition of N-Boc hydrazine to chalcones followed by a transprotection sequence allowing N-Boc transformation into N-CXNHR (X = S, O) or N-Ac functional groups. This approach was applied to a straightforward elaboration of chiral monoamine oxidase inhibitor derivatives.

Full text of DOI:10.1039/c2ob25227a

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PAPER
Enantioselective synthesis of bio-relevant 3,5-diaryl pyrazolines†
Olivier Mahé,a,b Isabelle Dez,c Vincent Levachera,b,d and Jean-François Brière*a,b,d
Received 31st January 2012, Accepted 15th March 2012
DOI: 10.1039/c2ob25227a
The straightforward asymmetric construction of bio-relevant Δ2-pyrazolines having either N-(thio)amide
or N-acetyl functional groups and flanked by aryl substituents such as phenol at C3 and C5 has been
achieved through an enantioselective phase transfer organocatalytic addition of N-Boc hydrazine to
chalcones followed by a transprotection sequence allowing N-Boc transformation into N-CXNHR
(X = S, O) or N-Ac functional groups. This approach was applied to a straightforward elaboration of
chiral monoamine oxidase inhibitor derivatives.
Although it has been shown that enantiopure pyrazolines
Introduction
could lead to more potent or selective ligands for given bio-
receptors, these investigations required the use of adapted
chiral-HPLC separation5 or virtual docking based on theoretical
calculations for obtaining this information.10 Furthermore, the
absolute configuration of these derivatives has been determined
in few cases.5,11 Unfortunately, the existing diastereoselective,9
metal-catalyzed,12 or the more advanced organo-catalyzed
enantioselective synthesis of pyrazolines13 does not allow the
elaboration of such 3,5-diaryl pyrazolines featuring a polar
group on N1.
Chiral aza-heterocycle derivatives have been becoming ubiqui-
tous in medicinal chemistry. For instance, architectures derived
from the Δ2-pyrazoline platform have revealed a large array of
biological activities with respect to their five-membered ring
substitution pattern.1 Pharmaceutical investigations highlighted
several 1,4-dihydropyrazole compounds (Fig. 1) such as 1 and
3–4 as potent monoamine oxidase (MAO) inhibitors. These bio-
active derivatives possess a thioamide group (12 and 33) or, to a
lesser extent, an acetyl functional group (4)4,5 on N1 that is
flanked by phenol moieties at C3 and C5 allowing interesting
structure–selectivity relationships for subtype MAO-A or
MAO-B isoforms.2–6 In fact, MAO-A inhibitors have been
useful for the treatment of psychiatric disorders whereas MAO-B
inhibitors were used to treat Parkinson’s disease. N-Thioamide
3,5-diaryl pyrazoline 2 was also capable of selective inhibition
of other type of enzymes such as cyclooxygenase COX-2, an
important target for anti-inflammatory drug development.7 More-
over, the primary thioamide functional group on the pyrazolinyl
framework turned out to be a useful building block for the con-
struction of an extra-heterocyclic pendant such as thiazolone 5,
providing a compound possessing anticancer activity.8,9
aINSA de Rouen, Avenue de l’Université, 76800 St Etienne du Rouvray,
France
bUniversité de Rouen, Laboratoire COBRA UMR CNRS 6014 & FR
3038, IRCOF, 1 Rue Tesnière, 76821 Mont Saint Aignan cedex, France.
E-mail: jean-francois.briere@insa-rouen.fr; Fax: +33 (0)2 3552 2962;
Tel: +33 (0)2 3552 2464
cLCMT (Laboratoire de Chimie Moléculaire et Thio-organique), UMR
CNRS 6507, FR INC3M 3038, ENSICaen-Université de Caen, 14050
Caen, France
dCNRS Délégation Normandie, 14 Rue Alfred Kastler, 14052 Caen
Cedex, France
†Electronic supplementary information (ESI) available: copies of NMR
spectra and HPLC chromatograms for all newly formed products. See
DOI: 10.1039/c2ob25227a
Fig. 1 Bioactive pyrazolines.
3946 | Org. Biomol. Chem., 2012, 10, 3946–3954
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Table 1 Addition of (thio)semicarbazidesa
Entry
R/X
Solvent
Yieldb (%)
Eec (%)
1
2
3
4
5
PhNH/O (10a)
PhNH/O (10a)
PhNH/O (10a)
NH2/S (10b)
OtBu/O (8)
Toluene
THF
THF–CH2Cl2
THF
50 (11a)
54 (11a)d
55 (11a)
5 (11b)
7
11
7
nd
>99
THF
53 (9)e
Scheme 1 Synthetic strategy.
a Chalcone 7a (1 equiv), hydrazine 8 or 10 (1.1 equiv), Cs2CO3 (1.3
equiv), ammonium salt 12 (10 mol%) for 24 h at 0 °C. b Isolated yield
after column chromatography. c Determined by chiral HPLC. d K3PO4
instead of Cs2CO3. e Yield after one recrystallization.
To fill the gap, we envisaged the construction of these bio-
relevant pyrazolines by exploiting our recently developed enan-
tioselective addition of N-Boc hydrazine 8 to chalcones 7
(Scheme 1), through an aza-Michael–cyclocondensation cascade
of an hydrazide anion intermediate, under phase transfer organo-
catalytic (PTC) conditions.14 The dihydropyrazoles were
obtained with high ee, for instance 92% ee and 77% yield from
chalcone 7a (Ar1 = Ar2 = Ph), but this procedure was limited to
the formation of N-Boc derivatives such as 9. Thereby, two
novel developments were tackled. First of all, the asymmetric
addition of (thio)semicarbazide 10 was investigated (path A) to
afford directly the diazoles 11. Next, we considered a two step
sequence (path B) based on the asymmetric addition of N-Boc
hydrazine 8 followed by innovative transprotection reactions
of the obtained N-Boc pyrazolines 9 into N-thioamides 11 or
N-acetyl homologues. Either of these strategies will have to be
compatible with phenol moieties in order to expect any appli-
cation towards MAO inhibitors’ elaboration.
11b (entry 4). In order to circumvent the limitations of this PTC
catalyzed aza-Michael methodology, we developed an improved
procedure for the elaboration of N-tert-butyloxycarbonyl 3,5-
diphenyl pyrazoline 9 (entry 5).14 Accordingly, the dihydropyra-
zole 9 was easily obtained in virtually enantiopure fashion
(>99% ee), without purification on column chromatography,
through the asymmetric addition process of N-Boc hydrazine 8
to chalcone 7 (4.8 mmol) followed by one recrystallization of
the obtained crude product with an overall yield of 53%.
Enantiopure pyrazoline 9 is thereby ready for the alternative
transprotection investigation towards N-(thio)amide pyrazolines
as depicted in Scheme 1 (path B).
Synthesis of N-(thio)amide pyrazolines through a
transprotection approach (path B)
We will disclose hereby the enantioselective synthesis of these
type of pyrazolines and an application to the elaboration of
MAO-A inhibitor 4 and derivatives as depicted in Fig. 1.
Next, we tackled the elaboration of N-amide pyrazolines 11 by
performing a functional group transformation ‘transprotection’
of the enantiopure N-tert-butyloxycarbonyl 3,5-diphenyl pyrazo-
line 9 in the presence of isocyanate reagents (Table 2). At the
outset, we mastered the acidic N-Boc deprotection of 9 by means
of an excess of HCl in dioxane to afford the 1H-pyrazolinium
salt 13 in situ as a stable ammonium salt. This protonated form
prevents the facile oxidation of the corresponding conjugated
base 1H-pyrazoline into pyrazole 14. The subsequent one-pot
addition of an excess of phenylisocyanate and triethylamine to
13 achieved a smooth transformation into the desired N-amide
pyrazoline 11a (entry 1). Despite many efforts, the purification
of product 11a turned out to be unsuccessful, due to the
decomposition/oligomerization of the isocyanate reagent. Pre-
viously, this strategy was successful to form N-acetyl or N-sulfo-
nyl pyrazoline derivatives but the extrapolation to N-(thio)amide
analogues required indeed a complete reinvestigation.14 Then,
we tried the sterically more encumbered Hünig’s base in place of
Results and discussion
Synthesis of N-(thio)amide pyrazolines by PTC (path A)
We recently discovered the capability of N-benzyl quininium salt
1215,16 (Table 1) to act as an efficient organocatalyst for the
enantioselective synthesis of 3,5-diarylpyrazolines of type 9
from N-Boc hydrazine under PTC.17 Unfortunately, this method-
ology turned out to be inefficient with N-phenyl semicarbazide
10a (entries 1–2) ruling out the direct asymmetric elaboration of
the corresponding pyrazoline 11a of interest. A mixture of THF
and CH2Cl2 as solvents was employed to facilitate the solubil-
isation of the hydrazine component but no improvement was
observed (entry 3). Other quininium salts were tested but led
also to a strong background reaction. The use of thiosemicarba-
zide 10b instead furnished traces of the corresponding diazole
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Table 2 Isocyanate transprotectiona
Entry
R
X (equiv) Base (equiv) Yieldb (%) Eec (%)
1
2
3
4
5
6
Ph
Ph
Ph
Ph
O (3.0)
O (1.5)
O (1.1)
O (1.1)
Et3N (9.0)
DIEA (9.0)
Et3N (6.2)
Et3N (1.1)
Et3N (6.2)
Et3N (6.2)
98 (11a)d
0 (11a)
97 (11a)
90 (11a)e
83 (11c)
98 (11d)
nd
—
>99
>99
>99
>99
Scheme 2 Synthesis of N-thioamide pyrazoline.
Ph(CH2)2 O (1.1)
Ph S (1.1)
a N-Boc pyrazoline 9 (1 equiv in CH2Cl2), HCl in dioxane (6 equiv, 4
M) for 2 h at rt, then, in one-pot, isocyanate or isothiocyanate and a base
at rt, 18 h. b Isolated yield after column chromatography. c Determined
1
by chiral HPLC. d Yield estimated on the H NMR of the crude product
by an internal standard. e The pyrazolinium salt 13 was isolated by
evaporation under vacuum and used subsequently as a crude product.
Scheme 3 Synthesis of N-thioamide pyrazoline through ion
metathesis.
Et3N (entry 2) but no pyrazoline 11a was formed. The formation
of pyrazole 14 was observed instead (oxidative pathway) among
other unidentified compounds from the 1H NMR spectrum of
the crude product. The activation of isocyanate reagents by ter-
tiary amines acting as a Lewis base so that a faster subsequent
nucleophilic addition reaction occurs was already mentioned in
the literature.18 Due to its size, one can assume that N,N-diiso-
propylethylamine is a less efficient Lewis base than Et3N to
accelerate the addition step of the 1H-pyrazoline derived from 13
over the oxidative decomposition pathway. Eventually, after
some optimization, it was found that 1.1 equivalent of phenyliso-
cyanate (vs. pyrazoline) and a quasi-stoichiometric amount of
Et3N (vs. 6 equiv HCl) afforded the N-phenylamide pyrazoline
11a in 97% isolated yield after an easy column chromatography
with up to 99% ee (entry 3). It was also found that the crude pyr-
azolinium salt 13 could be isolated, without decomposition, after
a simple evaporation to remove the excess of solvent and acid.
Thereby the subsequent use of only 1.1 equivalent of Et3N vs.
pyrazoline (entry 4) in the same pot was allowed. These opti-
mized conditions have been applied to the construction of ali-
phatic amide 11c (entry 5) or thioamide 11d (entry 6) with very
good yields without erosion of the enantiomeric excesses.
+
intermediate NH2NH3 SCN− in equilibrium with a mixture of
hydrazine and isothiocyanic acid which undergoes a rearrange-
ment to yield NH2C(S)NHNH2. We attempted to obtain a similar
system (Scheme 2) by generating an equivalent of 1H-pyrazoline
15 by mixing the pyrazolinium salt 13 (isolated after evapor-
+
ation) and 1 equivalent of Et3N in the presence of NH4 SCN−
under different conditions (from rt to 60 °C in water or MeOH),
but only traces of the desired product 11b could be observed
along with many side products. This shows that the slow
addition step of the moderately reactive isothiocyanic acid leads
to side oxidation reaction of the 1H-pyrazoline intermediate 15.
After some trials, we eventually found that a simple mixing
between pre-isolated salt 13 and ammonium thiocyanate (3
equiv) gave rise to a smooth formation of N-thioamide pyrazo-
line 11b in 75% yield and >99% ee (Scheme 3). In that case, a
facile counterion exchange took place (ion metathesis process),
by liberating a soft acid NH4Cl,21 driving the equilibrium toward
the formation of intermediate 16 which underwent the rearrange-
ment to construct the C–N bond of 11b. This in situ trapping
process prevents the formation of the unstable 1H-pyrazoline
intermediate 15 in too high concentration.
As matter of fact, the intermediate 16 could also be considered
as a mixture of 3,5-diphenyl 1H-pyrazoline 15 and thiocyanic
acid (HSCN). Therefore, we were curious to see whether a
mixture HSCN + NH4Cl, easily formed in situ from an HCl–
dioxane solution and NH4SCN, was sufficiently acidic at 60 °C
to achieve the N-Boc deprotection followed by the nucleophilic
addition of transient 1H-pyrazoline 15 to isothiocyanic acid
(Scheme 4). Pleasingly, as depicted in Scheme 4, this improved
one-pot one-operation procedure furnished the desired pyrazoline
With the aim of completing this successful enantioselective
synthesis of N-(thio)amide pyrazolines, we tackled the construc-
tion of valuable primary thioamide dihydropyrazoles such as
11b (Scheme 2). In order to circumvent the use of the sensitive
isothiocyanic acid (HNCS) for the transprotection sequence,19
we made use of the thiosemicarbazide (NH2C(S)NHNH2) syn-
thesis of Scott et al. from a mixture of hydrazine and commer-
+
cially available ammonium thiocyanate (NH4 SCN−) reagent in
refluxing water.20 In this process, a molecule of ammonia is dis-
placed to furnish the corresponding hydrazinium thiocyanate
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11b with a good 78% yield and >99% ee. Taking into account
that the absolute configuration of precursor N-Boc 3,5-diaryl
pyrazoline 9 is known, this study brings new information regard-
ing the chiral data of the corresponding N-(thio)amide pyrazo-
lines of type 11, for which few details have been given in the
literature thus far. Indeed they are all levo-(−) isomers in our
cases.
position, nor by the sterically encumbered and chiral OTHP pro-
tecting group. Then, a smooth one-pot N-Boc and OTHP depro-
tection was orchestrated upon acidic conditions to furnish
diazole 20 after an in situ di-acetylation reaction. Eventually, a
selective acetyl deprotection of the phenol moiety was performed
to give rise to the formation of the bio-relevant pyrazoline 4 with
no racemization (93% ee). Compound 4 featured the S absolute
configuration with respect to the analytical Cirilli et al.’s studies
on HPLC and optical rotation.5 This outcome corroborates our
asymmetric model besides providing, overall, a straightforward
enantioselective synthesis of such bioactive pyrazolines.
Enantioselective synthesis of MAO-A inhibitor derivatives
Then, we moved to the synthesis of the aforementioned N-acetyl
pyrazoline 4, a potent MAO-A inhibitor discovered by Bolasco
and co-workers (Scheme 5).4 We sought to challenge the asym-
metric preparation of such a 1,4-dihydropyrazole 4 having both a
phenol substituent and an N-acetyl functional group (requiring a
N-Boc transprotection). Besides this objective, compound 4 is
one of the rare 3,5-diaryl pyrazolines whose absolute configur-
ation has been determined,5 which would allow us to validate
our model predicting the sense of stereoinduction (quininium
derived catalyst 12 giving a S pyrazoline).14 At the outset, it was
established that the known chalcone 1722 was incompatible with
our basic PTC conditions, by precipitating out of the solution.
Therefore, the corresponding tetrahydropyran (THP) protected
derivative 18 was employed in order to facilitate further acidic
deprotection (vide infra).4 Applying the asymmetric aza-
Michael–cyclocondensation cascade sequence to this chalcone
18 afforded the pyrazoline 19 with a good 87% yield and high
93% ee for both diastereoisomers resulting from the presence of
the THP protecting group. It is noteworthy that this methodology
was affected neither by the ring substituents at the ortho or para
At this stage it was appealing to test our N-Boc to N-CSNH2
transprotection from the more elaborated N-Boc pyrazoline 19 in
order to provide 22 (Scheme 6). However, whether the two step
(see Scheme 3) or the one-pot procedure (see Scheme 4) was
carried out, we were not able to purify the obtained compound
1
22 due to side products formation, although the H NMR spec-
trum of the crude product revealed a complete conversion into
22. Thus we undertook to remove firstly and selectively the THP
protective group by means of the soft pyridinium para-toluene-
sulfonate acid to give phenol 21 which was used further without
purification. To our delight, despite the poor solubility of 21, the
one-pot transprotection conditions turned out to be successful,
chemoselective and non-racemising to furnish the N-thioamide
pyrazoline 22 with 53% yield over three chemical steps from 19.
Therefore, this procedure provides MAO inhibitor derivatives
such as 22 displaying further chemical diversity on N1.
Conclusions
In conclusion, we have shown that an enantioselective addition
of N-Boc hydrazine to chalcones under organocatalytic PTC
conditions followed by a one-pot N-Boc transprotection is a
competent and practical synthetic sequence for the construction
of bio-relevant pyrazolines having phenol substituent at C3 and
C5 and N-(thio)amide or N-acetyl pendant on N1, as illustrated
by the enantioselective construction of MAO inhibitor deriva-
tives. Moreover, these data bring useful information concerning
the absolute configuration of this family of pyrazolines for
which only a handful data are provided in literature.
Scheme 4 One-pot one-step process to N-thioamide pyrazoline.
Scheme 5 First enantioselective synthesis of the MAO-A inhibitor 4.
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Scheme 6 Enantioselective synthesis of MAO inhibitor derivatives.
Found: C, 74.50; H; 6.67; N, 8.80. The analytical data match the
previously reported ones.14
Experimental
General
Representative procedure for the synthesis of N-3,5-triphenyl-
4,5-dihydro-1H-pyrazole-1-carboxamide (11a). To a solution of
enantioenriched tert-butyl 3,5-diphenyl-4,5-dihydro-1H-pyra-
zole-1-carboxylate 9 (40 mg, 0.124 mmol, >99% ee) in anhy-
drous CH2Cl2 (0.5 mL) at 0 °C under nitrogen atmosphere was
added dropwise a HCl–dioxane 4 M solution (186 μL,
0.744 mmol, 6 equiv). The reaction mixture was stirred at room
temperature for 3 h. Phenyl isocyanate (14.9 μL, 0.137 mmol,
1.1 equiv) and, subsequently, triethylamine (107.2 μL,
0.769 mmol, 6.2 equiv) were added dropwise at 0 °C. The
mixture was vigorously stirred at room temperature for 18 hours.
An HCl aqueous solution (0.5 M) was poured into the flask. The
aqueous phase was extracted with CH2Cl2 and the combined
organic layers were washed with a NaOH aqueous solution (0.25
M), brine and dried over Na2SO4. After filtration, the solvent
was removed under vacuum and the residue was purified by
column chromatography on silica gel (dichloromethane, Rf =
0.32) to give the enantioenriched N-phenylamide pyrazoline 11a
in 97% yield (41 mg, >99% ee) as a white powder. m.p. =
140–142 °C (litt.23 164–166 °C for a racemic). [α]2D0 = −132°
cm3 g−1 dm−1 (c = 0.0054 g cm−3 in CHCl3). HRMS m/z calcd
for C22H20N3O [M + H]+: 342.1606, found: 342.1592. The
NMR analytical data match the previously reported NMR ana-
lyses.23 HPLC using a Chiralpack IA Daicel chiral column,
iPrOH–heptane (50 : 50) eluent at a flow rate of 1 mL min−1 at
20 °C, λ = 230 nm. The major enantiomer eluted at 24.9 min
(the levo (−) isomer) and the minor enantiomer at 9.1 min (the
dextro (+) isomer) giving >99% ee.
Two step procedure: To a solution of enantioenriched (>99%
ee) tert-butyl 3,5-diphenyl-4,5-dihydro-1H-pyrazole-1-carboxy-
late 9 (40 mg, 0.124 mmol) in anhydrous CH2Cl2 (0.5 mL) at
0 °C under nitrogen atmosphere was added dropwise a HCl–
dioxane 4 M solution (186 μL, 6 equiv). The reaction mixture
was stirred at room temperature for 3 h. Then solvents were
evaporated and the crude residue was dissolved in dichloro-
methane (0.5 mL). Phenyl isocyanate (14.9 μL, 0.137 mmol, 1.1
equiv) and, subsequently, triethylamine (20.7 μL, 0.148 mmol,
1.2 equiv) were added dropwise at 0 °C. The mixture was vigor-
ously stirred at room temperature for 18 hours. An HCl aqueous
solution (0.5 M) was poured into the flask. The aqueous phase
was extracted with CH2Cl2 and the combined organic layers
were washed with a NaOH aqueous solution (0.25 M), brine and
dried over Na2SO4. After filtration, the solvent was removed
under vacuum and the residue was purified by column chromato-
graphy on silica gel (dichloromethane, Rf = 0.32) to give the
Chromatographic purification of compounds was achieved with
60 silica gel (40–63 μm). Thin layer chromatography was carried
out on silica gel 60 F254 (1.1 mm) with spot detection under UV
1
light or phosphomolybdic acid or KMnO4 oxidation. H NMR
spectra were recorded at 300 MHz on a Bruker AVANCE 300.
Data appear in the following order: chemical shifts in ppm,
number of protons, multiplicity (s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet), coupling constant J in Hz. 13C NMR
spectra were acquired at 75.4 MHz operating with broad band 1H
decoupling. The hydrogen multiplicity was obtained by
DEPT135 or Attached Proton Test (APT) using JMOD pulse
program. IR spectra were recorded on a Perkin Elmer IRTF 1650
spectrometer with solid dispersed on KBr pastille. Mp’s stand
uncorrected. HPLC analyses were performed with Daicel Chiral-
pack® columns (4.6 mm × 25 cm) and a mixture of heptane–
isopropanol solvents. A spectrosystem UV detector and a chiral
detector (polarimeter) were used. Optical rotations were
measured at 20 °C in CHCl3 with a micropolarimeter. Racemic
samples as references were prepared by means of either previous
methodologies23 or using n-tetrabutylammonium bromide
instead of chiral cinchona alkaloids. 3,5-Diphenyl pyrazole 14
and pyrazolinium salt 13 are known compounds.14,24
tert-Butyl 3,5-diphenyl-4,5-dihydro-1H-pyrazole-1-carboxylate
(9). This is an improved procedure on a bigger scale of the pre-
viously reported enantioselective synthesis of this pyrazoline
which prevented the use of any purification on column chrom-
atography.14 trans-Benzylidenacetophenone 7a (Ar1 = Ar2 = H,
1 g, 4.8 mmol), tert-butyl carbazate 8 (712 mg, 5.4 mmol, 1.1
equiv), N-2-methoxybenzyl quininium chloride 12 (231 mg,
0.48 mmol, 0.1 equiv) and caesium carbonate (2 g, 6.24 mmol,
1.3 equiv) were introduced into a Schlenk flask. Anhydrous THF
(9 mL) was added under nitrogen atmosphere and a vigorous
stirring was achieved for 24 h at 0 °C. Then, AcOEt (5 mL) and
a saturated aqueous solution of ammonium chloride (5 mL) were
poured into the reaction mixture. The phases were separated and
the organic layer was washed with water and brine. After evapor-
ation of the solvent under vacuum, the crude residue was dis-
solved in a small volume of dichloromethane and passed through
a plug of silica gel (AcOEt). After evaporation of the solvent
under vacuum, the solid was recrystallized in a refluxing solution
of AcOEt–petroleum ether (1 : 3, 40 mL) to give 823 mg (53%,
ee >99%) of the enantioenriched N-Boc pyrazoline 9. Anal.
calcd for C20H22N2O2 (322.40): C, 74.51; H, 6.88; N, 8.69.
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enantiopure N-phenylamide pyrazoline 11a (38 mg, >99% ee) in
90% yield.
mixture was vigorously stirred at 60 °C temperature for
72 hours. At the end of the reaction, the solvent was removed
under vacuum. The residue was dissolved in AcOEt (5 mL),
washed 2 times with water, brine, and dried over Na2SO4. After
filtration, the solvent was removed under vacuum and the residue
was purified by column chromatography on silica gel (dichloro-
methane, Rf = 0.39) to give the enantiopure pyrazoline 11b in
75% (26 mg, >99% ee) yield as yellow solid. m.p. =
183–185 °C (litt.23 196–199 °C for a racemic). [α]2D0 = −275°
cm3 g−1 dm−1 (c = 0.0051 g cm−3 in CHCl3). HRMS m/z calcd
for C16H16N3S [M + H]+: 282.1065, found: 282.1062. The
NMR analytical data matched the previously reported NMR ana-
lyses.23 HPLC using a Chiralpack IA Daicel chiral column,
iPrOH–heptane (50 : 50) eluent at a flow rate of 1 mL min−1 at
20 °C, λ = 230 nm. The major enantiomer eluted at 7.7 min (the
levo (−) isomer) and the minor enantiomer at 11.2 min (the
dextro (+) isomer) giving >99% ee.
One-pot one-step procedure (Scheme 4). Ammonium thiocya-
nate (118 mg, 1.55 mmol, 10 equiv) was dissolved in anhydrous
degassed THF (0.6 mL) in a tube under nitrogen. Hydrochloric
acid (4 N solution in dioxane, 387.7 μL, 1.55 mmol, 10 equiv)
was added dropwise, forming a pink precipitate which instan-
taneously turned to white at the end of addition. The mixture
was stirred at room temperature for 10 min and tert-butyl 3,5-
N-Phenethyl-3,5-diphenyl-4,5-dihydro-1H-pyrazole-1-carbox-
amide (11c). Prepared from phenethylisocyanate according to
the procedure used for compound 11a. 11c was obtained as an
enantioenriched mixture (38 mg, >99% ee) in 83% yield after
purification by two column chromatographies on silica gel (Rf =
0.23 – petroleum ether–EtOAc: 7 : 3, 0.62 – dichloromethane–
diethyl ether: 9 : 1). White solid, m.p. = 114–116 °C. [α]D20
=
1
−72° cm3 g−1 dm−1 (c = 0.00575 g cm−3 in CHCl3). H NMR
(CDCl3, 300 MHz) δ 2.78–2.96 (m, 2H), 3.16 (dd, J = 17.6, J =
5.8 Hz, 1H), 3.43–3.65 (m, 2H), 3.77 (dd, J = 17.6, J = 12.1 Hz,
1H), 5.52 (dd, J = 12.1, J = 5.7 Hz, 1H), 6.12–6.25 (m, 1H),
7.19–7.38 (m, 10H), 7.38–7.46 (m, 3H), 7.61–7.70 (m, 2H). 13
C
NMR (CDCl3, 75 MHz) δ 36.8 (CH2), 41.5 (CH2), 42.9 (CH2),
60.7 (CH), 125.7 (CH), 126.4 (CH), 126.5 (CH), 127.7 (CH),
128.6 (CH), 128.8 (CH), 129.0 (CH), 129.1 (CH), 130.2 (CH),
131.6 (C), 139.4 (C), 143.0 (C), 151.0 (C), 154.7 (C). IR (ATR)
ν (cm−1): 3416, 2927, 1675, 1518, 1383, 700, 689. HRMS m/z
calcd for C24H24N3O [M + H]+: 370.1919, found: 370.1904.
HPLC using a Chiralpack IA Daicel chiral column, iPrOH–
heptane (20 : 80) eluent at a flow rate of 0.8 mL min−1 at 20 °C,
λ = 230 nm. The major enantiomer eluted at 21.1 min (the levo
(−) isomer) and the minor enantiomer at 15.4 min (the dextro (+)
isomer) giving >99% ee.
diphenyl-4,5-dihydro-1H-pyrazole-1-carboxylate
9
(50 mg,
0.155 mmol, 1 equiv, 99% ee) was poured into the solution.
Then, the tube was sealed and heated at 60 °C for 30 hours with
vigorous stirring. After evaporation of solvent under vacuum,
dichloromethane (5 mL) and water (5 mL) was added, and the
aqueous phase was neutralized till pH 7 with an aqueous NaOH
solution (1 M) added dropwise. Then the mixture was extracted
with dichloromethane and the combined organic phases were
washed with brine, dried over Na2SO4 and evaporated under
vacuum after filtration. The residue was purified by column
chromatography on silica gel (dichloromethane, Rf = 0.39) to
give the enantiopure pyrazoline 11b (34 mg, >99% ee) in 78%
yield as a yellow solid.
N-3,5-Triphenyl-4,5-dihydro-1H-pyrazole-1-carbothioamide
(11d). Prepared from phenyl thioisocyanate according to the
procedure used for compound 11a. 11d was obtained as an enan-
tioenriched mixture (44 mg, >99% ee) in 98% yield, after purifi-
cation by column chromatography on silica gel (Rf = 0.75 –
dichloromethane). White solid, m.p. = 205–207 °C (litt.25
105 °C for a racemic). [α]2D0 = −266° cm3 g−1 dm−1 (c =
1
0.00555 g cm−3 in CHCl3). H NMR (CDCl3, 300 MHz) δ 3.25
(dd, J = 17.7, J = 3.7 Hz, 1H), 3.88 (dd, J = 17.7, J = 11.6 Hz,
1H), 6.20 (dd, J = 11.6, J = 3.7 Hz, 1H), 7.14–7.22 (m, 1H),
7.23–7.40 (m, 7H), 7.41–7.51 (m, 3H), 7.62–7.69 (m, 2H),
7.74–7.82 (m, 2H), 9.29 (brs, 1H). 13C NMR (CDCl3, 75 MHz)
δ 42.8 (CH2), 63.4 (CH), 124.4 (CH), 125.6 (CH), 125.6 (CH),
127.0 (CH), 127.7 (CH), 128.7 (CH), 129.0 (CH), 129.0 (CH),
130.8 (C), 131.0 (CH), 138.8 (C), 142.1 (C), 155.2 (C), 174.1
(C). IR (ATR) ν (cm−1): 3337, 1512, 1444, 1400, 1324, 754,
690, 534. HRMS m/z calcd for C22H20N3S [M + H]+: 358.1378,
found: 358.1361. HPLC using a Chiralpack IA Daicel chiral
column, iPrOH–heptane (40 : 60) eluent at a flow rate of 1 mL
min−1 at 20 °C, λ = 230 nm. The major enantiomer eluted at
10.4 min (the levo (−) isomer) and the minor enantiomer at
18.8 min (the dextro (+) isomer) giving >99% ee.
(E)-3-(2-Chlorophenyl)-1-(4-(tetrahydro-2H-pyran-2-yloxy)-
phenyl)prop-2-enone (18). Chalcone 17 (150 mg, 0.58 mmol)
and pyridinium p-toluenesulfonate (3.5 mg, 0.014 mmol, 0.024
equiv) were stirred under nitrogen in anhydrous dichloromethane
(3 mL) at room temperature for 15 min. Then dihydropyran
(225 μL, 2.4 mmol, 4.2 equiv) was added dropwise and the reac-
tion mixture was vigorously stirred at room temperature until the
total disappearance of the starting chalcone (checked by NMR)
i.e. 24 hours. After evaporation of solvent under vacuum, the
crude yellow oil was dissolved in diethyl ether (5 mL) and the
solution was washed 5 times with water, then brine and finally
dried over MgSO4. After filtration, the solvent was removed
under vacuum. The obtained yellow oil was ground in pentane
with a spatula giving a solid which was isolated by filtration and
washed with pentane. Chalcone 18 was obtained as a pale
3,5-Diphenyl-4,5-dihydro-1H-pyrazole-1-carbothioamide (11b).
One-pot two step procedure (Scheme 3). To a solution of enan-
tiopure tert-butyl 3,5-diphenyl-4,5-dihydro-1H-pyrazole-1-car-
boxylate 9 (40 mg, 0.124 mmol, 99% ee) in anhydrous CH2Cl2
(0.5 mL) at 0 °C under nitrogen atmosphere was added dropwise
a HCl–dioxane 4 M solution (186 μL, 0.744 mmol, 6 equiv).
The reaction mixture was stirred at room temperature for 2 h.
After evaporation of solvents, ammonium thiocyanate (28.3 mg,
0.372 mmol, 3 equiv) was added under nitrogen followed by
degassed anhydrous THF (0.6 mL). Tube was sealed and the
1
yellow powder in 85% yield (171 mg). m.p. = 81–83 °C. H
NMR (300 MHz, CDCl3) δ 1.59–1.79 (m, 3H), 1.86–1.93 (m,
2H), 1.95–2.09 (m, 1H), 3.59–3.69 (m, 1H), 3.80–3.93 (m, 1H),
7.10–7.18 (m, 2H), 7.27–7.37 (m, 2H), 7.39–7.46 (m, 1H), 7.49
(d, J = 15.7 Hz, 1H), 7.70–7.79 (m, 1H), 7.97–8.06 (m, 2H),
8.16 (d, J = 15.7 Hz, 1H). 13C NMR (CDCl3, 75 MHz) δ 18.6
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3946–3954 | 3951

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(CH2), 25.1 (CH2), 30.2 (CH2), 62.1 (CH2), 96.2 (CH), 116.2
(CH), 124.8 (CH), 127.1 (CH), 127.8 (CH), 130.3 (CH), 130.9
(CH), 131.0 (CH), 131.5 (C), 133.5 (C), 135.5 (C), 139.8 (CH),
161.2 (C), 188.8 (C). IR (KBr) ν (cm−1) 2940, 1654, 1606,
1508, 1334, 1242, 1177, 1114, 1022, 952, 917, 762. HRMS m/z
calcd for C20H20O3Cl [M + H]+: 343.1101, found: 343.1114.
Remark: this product is unstable and should be stored under
nitrogen at −20 °C.
at 0 °C. The mixture was vigorously stirred at room temperature
for 2 hours. An HCl aqueous solution (0.5 M) was poured into
the flask. The aqueous phase was extracted with CH2Cl2 and the
combined organic layers were washed with brine and dried over
MgSO4. After filtration, the solvent was removed under vacuum
and the residue was purified by column chromatography on
silica gel (petroleum ether–EtOAc = 3 : 2, Rf = 0.31) to give the
diacetylated pyrazoline 20 in 90% yield (67 mg) as an off-white
1
solid. m.p. = 162–164 °C. H NMR (300 MHz, CDCl3) δ 2.30
tert-Butyl-3-(4-(tetrahydropyran-2-yloxy)phenyl)-5-(2-chloro-
phenyl)-4,5-dihydro-1H-pyrazole-1-carboxylate (19). Chalcone
18 (117.3 mg, 0.342 mmol), tert-butyl carbazate 8 (98%,
50.8 mg, 0.376 mmol, 1.1 equiv), N-2-methoxybenzyl quini-
nium chloride 12 (16.4 mg, 0.034 mmol, 0.1 equiv) and caesium
carbonate (145 mg, 0.445 mmol, 1.3 equiv) were introduced in a
Schlenk flask. Anhydrous THF (1 mL) was added under nitrogen
atmosphere and a vigorous stirring was achieved for 24 h at
0 °C. Then, AcOEt (3 mL) was poured into the reaction mixture
and caesium carbonate was removed by filtration. The filtrate
was evaporated under reduced pressure and the residue was
purified by column chromatography on silica gel (petroleum
ether–EtOAc = 4 : 1, Rf = 0.24) to afford tert-butyl-3-(4-(tetrahy-
dropyran-2-yloxy)phenyl)-5-(2-chlorophenyl)-4,5dihydro-1H-
pyrazole-1-carboxylate 19 as a white powder (136 mg, 87%
yield, 93% ee). m.p. = 79–81 °C. 1H NMR (300 MHz, CDCl3) δ
1.33 (brs, 9H), 1.58–1.76 (m, 3H), 1.80–1.90 (m, 2H),
1.91–2.08 (m, 1H), 3.02 (dd, J = 17.5; 5.1 Hz, 1H), 3.53–3.66
(m, 1H), 3.80 (dd, J = 17.6; 12.2 Hz, 1H), 3.81–3.92 (m, 1H),
5.42–5.49 (m, 1H), 5.76 (dd, J = 12.0; 5.3 Hz, 1H), 6.99–7.08
(m, 2H), 7.16–7.24 (m, 3H), 7.33–7.40 (m, 1H), 7.64–7.73 (m,
2H). 13C NMR (CDCl3, 75 MHz) δ 18.7 (CH2), 25.2 (CH2),
28.2 (CH3), 30.3 (CH2), 41.8 (CH2), 58.8 (CH), 62.1 (CH2),
81.3 (C), 96.3 (CH), 116.4 (CH), 116.5 (CH), 125.0 (C), 126.3
(C), 127.5 (CH), 128.3 (CH), 128.7 (CH), 129.7 (CH), 131.6
(C), 151.8 (C), 152.6 (C), 158.7 (C). IR (KBr) ν (cm−1) 2941,
2868, 1724, 1696, 1607, 1395, 1242, 1147, 1123, 1037, 960,
920. HRMS m/z calcd for C25H30N2O4Cl [M + H]+: 457.1894,
found: 457.1892. HPLC using a Chiralpack AD-H Daicel chiral
column, iPrOH–heptane (20 : 80) eluent at a flow rate of 1 mL
min−1 at 20 °C, λ = 298 nm. HPLC using a Chiralpack AD-H
Daicel chiral column, iPrOH–heptane (20 : 80) eluent at a flow
rate of 1 mL min−1 at 20 °C, λ = 298 nm. The major S enantio-
mer (with respect to the absolute configuration of C5 of the pyra-
zoline ring, the levo (−) isomer) eluted at 12.9 min and 15.3 min
(two peaks because of THP protecting group) and the minor
enantiomer at 31.5 min and 38.5 min (the dextro (+) isomer)
giving 93% ee.
(s, 3H), 2.48 (s, 3H), 3.04 (dd, J = 17.7; 4.9 Hz, 1H), 3.83 (dd, J
= 17.7; 11.9 Hz, 1H), 5.92 (dd, J = 11.9; 4.8 Hz, 1H), 6.99–7.08
(m, 1H), 7.10–7.17 (m, 2H), 7.17–7.24 (m, 2H), 7.36–7.43 (m,
1H), 7.70–7.79 (m, 2H). 13C NMR (CDCl3, 75 MHz) δ 21.2
(CH3), 22.0 (CH3), 41.6 (CH2), 57.9 (CH), 122.1 (CH), 126.0
(CH), 127.4 (CH), 127.9 (CH), 128.9 (CH), 129.1 (C), 130.2
(CH), 131.8 (C), 138.5 (C), 152.3 (C), 153.5 (C), 169.0 (C),
169.2 (C). IR (KBr) ν (cm−1) 2922, 1755, 1655, 1424, 1361,
1191, 911, 763. HRMS m/z calcd for C19H18N2O3Cl [M + H]+:
357.1006, found: 357.1007.
1-Acetyl-3-(4-hydroxyphenyl)-5-(2-chlorophenyl)-4,5-dihydro-
1H-pyrazole (4). The diacetylated pyrazoline 20 (58 mg,
0.162 mmol, 1 equiv) and potassium carbonate (34 mg,
0.246 mmol, 1.5 equiv) were stirred in a ethanol–THF (2.6 mL :
2.6 mL) mixture for 16 hours. Then the solvents were evaporated
under vacuum and dichloromethane (5 mL) with a few drops of
methanol were added to the residue. After addition of a 0.5 M
HCl solution, the aqueous phase was extracted with dichloro-
methane. The organic phase was washed with brine, dried over
MgSO4 and concentrated under vacuum. The residue was
purified by column chromatography on silica gel (petroleum
ether–EtOAc = 3 : 2, Rf = 0.25) to give the enantioenriched 1-
acetyl-3-(4-hydroxyphenyl)-5-(2-chlorophenyl)-4,5-dihydro-1H-
pyrazole 4 as a white powder (49 mg, 95%, 93% ee). m.p. =
194–196 °C (litt.4 214–215 °C for a racemic). 1H NMR
(300 MHz, MeOD) δ 2.43 (s, 3H), 3.02 (dd, J = 17.8; 4.7 Hz,
1H), 3.91 (dd, J = 17.8; 11.7 Hz, 1H), 5.87 (dd, J = 11.6; 4.6
Hz, 1H), 6.77–6.87 (m, 2H), 7.02–7.12 (m, 1H), 7.21–7.31 (m,
2H), 7.40–7.47 (m, 1H), 7.60–7.68 (m, 2H). 13C NMR (MeOD,
75 MHz) δ 21.8 (CH3), 42.6 (CH2), 58.9 (CH), 116.6 (CH),
123.6 (C), 127.1 (CH), 128.5 (CH), 129.7 (CH), 130.0 (CH),
131.0 (CH), 132.8 (C), 140.1 (C), 157.3 (C), 161.3 (C), 170.6
(C). IR (KBr) ν (cm−1) 2927, 1593, 1473, 1440, 1364, 1287,
1238, 1173, 836, 755. HRMS m/z calcd for C17H16N2O2Cl [M +
H]+: 315.0900, found: 315.0907. HPLC using a Chiralpack
OJ-H Daicel chiral column, iPrOH–heptane (20 : 80) eluent at a
flow rate of 1 mL min−1 at 20 °C, λ = 298 nm. The minor enan-
tiomer eluted at 20.7 min (the dextro (+)-R isomer) and the
major enantiomer at 33.5 min (the levo (−)-S isomer) giving
93% ee; or HPLC using a Chiralpack AD-H Daicel chiral
column, iPrOH–heptane (20 : 80) eluent at a flow rate of 1 mL
min−1 at 20 °C, λ = 298 nm. The minor enantiomer eluted at
26.3 min (the dextro (+)-R isomer) and the major enantiomer at
35.0 min (the levo (−)-S isomer) giving 93% ee. Absolute
configurations were determined in accordance with literature
data.5
1-Acetyl-3-(4-acetoxyphenyl)-5-(2-chlorophenyl)-4,5-dihydro-1H-
pyrazole (20)
To a solution of enantioenriched tert-butyl-3-(4-(tetrahydro-
pyran-2-yloxy)phenyl)-5-(2-chlorophenyl)-4,5dihydro-1H-pyra-
zole-1-carboxylate 19 (100 mg, 0.219 mmol) in anhydrous
CH2Cl2 (0.9 mL) at 0 °C under nitrogen atmosphere was added
dropwise a HCl–dioxane 4 M solution (436 μL, 8 equiv). The
reaction mixture was stirred at room temperature for 2 h. Acetyl
chloride (62 μL, 0.872 mmol, 4 equiv) and, subsequently, tri-
ethylamine (395 μL, 2.83 mmol, 13 equiv) were added dropwise
tert-Butyl 5-(2-chlorophenyl)-3-(4-hydroxyphenyl)-4,5-dihydro-
1H-pyrazole-1-carboxylate (21). tert-Butyl-3-(4-(tetrahydropyran-
3952 | Org. Biomol. Chem., 2012, 10, 3946–3954
This journal is © The Royal Society of Chemistry 2012

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2-yloxy)phenyl)-5-(2-chlorophenyl)-4,5dihydro-1H-pyrazole-1-
carboxylate 19 (50 mg, 0.109 mmol) and pyridinium p-toluene-
sulfonate (3 mg, 0.012 mmol, 0.1 equiv) were stirred overnight
(18 h) in EtOH (0.9 mL) at 55 °C. The obtained white precipi-
tate was isolated by filtration, washed with cold ethanol,
pentane, and was used for the next step without further purifi-
Recherche Universitaire Normand de Chimie), the “Ministère de
la Recherche” and CNRS (Centre National de la Recherche
Scientifique). We also warmly thank Tyburn Agnes for her con-
tribution to the preparation of starting MAO material.
1
cation. H NMR (300 MHz, DMSO) δ 1.23 (s, 9H), 2.94–3.00
Notes and references
(m, 1H, broad dd), 3.84 (dd, J = 17.6; 12.0 Hz, 1H), 5.62 (dd, J
= 11.9; 5.1 Hz, 1H), 6.78–6.81 (m, 2H), 7.06–7.11 (m, 1H),
7.27–7.36 (m, 2H), 7.46–7.50 (m, 1H), 7.53–7.56 (m, 2H). 13C
NMR (DMSO, 75 MHz) δ 27.8 (CH3), 41.1 (CH2), 58.3 (CH),
79.9 (C), 115.5 (CH), 122.2 (C), 126.3 (C, broad signal), 127.8
(CH), 128.3 (CH), 129.0 (CH), 129.5 (CH), 130.8 (C), 140.3
(C, broad signal), 152.8 (C), 159.3 (C). Two CH are overlaps.
MS (ESI) [M + Na]+: 395.1.
1 (a) Reviews on pyrazolines: A. Lévai, J. Heterocycl. Chem., 2002, 39, 1;
(b) S. Kumar, S. Bawa, S. Drahu, R. Kumar and H. Gupta, Recent Pat.
Anti-Infect. Drug Discovery, 2009, 4, 154; (c) M. A. Rahman and A.
A. Siddiqui, Int. J. Pharm. Sciences Drug Res., 2010, 2, 165.
2 R. Fioravanti, A. Bolasco, F. Manna, F. Rossi, F. Orallo, M. Yanez,
A. Vitali, F. Ortuso and S. Alcaro, Bioorg. Med. Chem. Lett., 2010, 20,
6479.
3 V. Jayaprakash, B. N. Sinha, G. Ucar and A. Ercan, Bioorg. Med. Chem.
Lett., 2008, 18, 6362.
4 F. Chimenti, A. Bolasco, F. Manna, D. Secci, P. Chimenti, O. Befani,
P. Turini, V. Giovannini, B. Mondovi, R. Cirilli and F. La Torre, J. Med.
Chem., 2004, 47, 2071.
5 R. Cirilli, R. Ferretti, B. Gallinella, L. Turchetto, A. Bolasco, D. Secci,
P. Chimenti, M. Pierini, V. Fares, O. Befani and F. La Torre, Chirality,
2004, 16, 625.
6 (a) K. Boppana, P. K. Dubey, S. A. R. P. Jagarlapudi, S. Vadivelan and
G. Rambabu, Eur. J. Med. Chem., 2009, 44, 3584; (b) N. Gokhan-
Kelekci, S. Koyunoglu, S. Yabanoglu, K. Yelekci, O. Ozgen, G. Ucar,
K. Erol, E. Kendi and A. Yesilada, Bioorg. Med. Chem., 2009, 17, 675;
(c) M. Karuppasamy, M. Mahapatra, S. Yabanoglu, G. Ucar, N. Sinha
Barij, A. Basu, N. Mishra, A. Sharon, U. Kulandaivelu and
V. Jayaprakash, Bioorg. Med. Chem., 2010, 18, 1875; (d) A. Sahoo,
S. Yabanoglu, N. Sinha Barij, G. Ucar, A. Basu and V. Jayaprakash,
Bioorg. Med. Chem. Lett., 2010, 20, 132; (e) M. Jagrat, J. Behera,
S. Yabanoglu, A. Ercan, G. Ucar, B. N. Sinha, V. Sankaran, A. Basu and
V. Jayaprakash, Bioorg. Med. Chem. Lett., 2011, 21, 4296.
7 R. Fioravanti, A. Bolasco, F. Manna, F. Rossi, F. Orallo, F. Ortuso,
S. Alcaro and R. Cirilli, Eur. J. Med. Chem., 2010, 45, 6135.
8 D. Havrylyuk, B. Zimenkovsky, O. Vasylenko, L. Zaprutko, A. Gzella
and R. Lesyk, Eur. J. Med. Chem., 2009, 44, 1396.
9 Selected representative examples: (a) M. R. Mish, F. M. Guerra and E.
M. Carreira, J. Am. Chem. Soc., 1997, 119, 8379; (b) J. Barluenga,
F. Fernández-Marí, A. L. Viado, E. Aguilar, B. Olano, S. García-Granda
and C. Moya-Rubiera, Chem.–Eur. J., 1999, 5, 883; (c) G. Broggini,
L. Garanti, G. Molteni and G. Zecchi, Tetrahedron: Asymmetry, 1999, 10,
487; (d) D. Simovic, M. Di, V. Marks, D. C. Chatfield and K. S. Rein, J.
Org. Chem., 2007, 72, 650.
5-(2-Chlorophenyl)-3-(4-hydroxyphenyl)-4,5-dihydro-1H-pyr-
azole-1-carbothioamide (22). Ammonium thiocyanate (64.3 mg,
0.845 mmol, 10 equiv) was dissolved in anhydrous degassed
THF (0.6 mL) in a tube under nitrogen. Hydrochloric acid (4 N
solution in dioxane, 212 μL, 1.55 mmol, 10 equiv) was added
dropwise, forming a pink precipitate which instantaneously
turned into a white precipitate at the end of the addition.
The mixture was stirred at room temperature for 10 min and
enantioenriched 5-(2-chlorophenyl)-3-(4-hydroxyphenyl)-4,5-
dihydro-1H-pyrazole-1-carboxylate 21 (31.5 mg, 0.0845 mmol,
1 equiv, 93% ee) was poured into the solution. Then, the tube
was sealed and heated at 60 °C for 72 hours under vigorous stir-
ring. After evaporation of solvent under vacuum, ethyl acetate
(5 mL) was added. The solution was washed with water till
neutral pH was reached, then it was washed with an aqueous
NaHCO3 solution (10% m/m) and brine. It was finally dried over
Na2SO4 and evaporated under vacuum after filtration. The
residue was purified by column chromatography on silica gel
(petroleum ether–EtOAc = 2 : 3, Rf = 0.22) to give the enan-
tioenriched pyrazoline 22 (19.2 mg, 53% from product 19, 93%
1
ee) as a yellow solid. m.p. = 125–127 °C. H NMR (300 MHz,
MeOD) δ 1H NMR (300 MHz, MeOD) δ 3.03 (dd, J = 17.8, 3.7
Hz, 1H), 3.93 (dd, J = 17.8, 11.4 Hz, 1H), 6.26 (dd, J = 11.3,
3.7 Hz, 1H), 6.98–7.06 (m, 1H), 6.78–6.85 (m, 2H), 7.38–7.45
(m, 1H), 7.19–7.26 (m, 2H), 7.63–7.71 (m, 2H). 13C NMR
(MeOD, 75 MHz) δ 42.8 (CH2), 62.4 (CH), 116.6 (CH), 123.3
(C), 127.1 (CH), 128.4 (CH), 129.7 (CH), 130.1 (CH), 130.8
(CH), 132.4 (C), 141.0 (C), 158.0 (C), 161.6 (C), 177.4 (C). IR
(KBr) ν (cm−1) 3435, 1605, 1470, 1331, 1170, 830, 758. HRMS
m/z calcd for C16H15ClN3OS [M + H]+: 332.0624, found:
332.0622. HPLC using a Chiralpack IA Daicel chiral column,
iPrOH–heptane (50 : 50) eluent at a flow rate of 1 mL min−1 at
20 °C, λ = 254 nm. The major enantiomer eluted at 5.4 min (the
levo (−) isomer) and the minor enantiomer at 7.1 min (the dextro
(+) isomer) giving >93% ee. Remark: this powder featured
various solubility properties with respect to different batches,
likely due to polymorphism issues. The addition of methanol
was often required to solubilize the solid.
10 F. Chimenti, R. Fioravanti, A. Bolasco, F. Manna, P. Chimenti, D. Secci,
F. Rossi, P. Turini, F. Ortuso, S. Alcaro and M. C. Cardia, Eur. J. Med.
Chem., 2008, 43, 2262.
11 N. Vanthuyne, C. Roussel, J.-V. Naubron, N. Jagerovic, P. M. Lázaro,
I. Alkorta and J. Elguero, Tetrahedron: Asymmetry, 2011, 22, 1120.
12 (a) S. Kanemasa and T. Kanai, J. Am. Chem. Soc., 2000, 122, 10710;
(b) Y. Yamashita and S. Kobayashi, J. Am. Chem. Soc., 2004, 126,
11279; (c) M. P. Sibi, L. M. Stanley and C. P. Jasperse, J. Am. Chem.
Soc., 2005, 127, 8276; (d) T. Kano, T. Hashimoto and K. Maruoka, J.
Am. Chem. Soc., 2006, 128, 2174; (e) M. P. Sibi, L. M. Standley and
T. Soeta, Adv. Synth. Catal., 2006, 348, 2371; (f) M. P. Sibi, L.
M. Standley and T. Soeta, Org. Lett., 2007, 9, 1553; (g) H. Yanagita and
S. Kanesama, Heterocycles, 2007, 71, 699; (h) L. Gao, G.-S. Hwang,
M. Y. Lee and D. H. Ryu, Chem. Commun., 2009, 5460; (i) T.-T. Dang,
I. Abdellah, Y. Canac and R. Chauvin, ChemCatChem, 2011, 3, 1491.
13 (a) S. Müller and B. List, Angew. Chem., Int. Ed., 2009, 48, 9975;
(b) S. Müller and B. List, Synthesis, 2009, 2171; (c) N. R. Campbell,
B. Sun, R. P. Singh and L. Deng, Adv. Synth. Catal., 2011, 353, 3123;
(d) M. Fernández, E. Reyes, J. L. Vicario, D. Badía and L. Carrillo, Adv.
Synth. Catal., 2012, 354, 371.
14 O. Mahé, I. Dez, V. Levacher and J.-F. Brière, Angew. Chem., Int. Ed.,
2010, 39, 7072 and references cited therein.
15 For the pioneer use of ortho-substituted N-benzyl cinchona PTC:
M.-S. Yoo, B.-S. Jeong, J.-H. Lee, H.-g. Park and S.-s. Jew, Org. Lett.,
2005, 7, 1129.
Acknowledgements
16 For previous use of this catalyst: O. Marianacci, G. Micheletti,
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We gratefully acknowledge financial support from the “Région
Haute-Normandie” and the CRUNCH network (Centre de
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3954 | Org. Biomol. Chem., 2012, 10, 3946–3954
This journal is © The Royal Society of Chemistry 2012