Synthesis of pyrazolines by a site isolated resin-bound reagents methodology

Article abstract of DOI:10.1039/c004704j

The elaboration of biologically important 3,4-substituted pyrazolines was achieved by an organocatalysed aza-Michael/transimination domino sequence between hydrazones and enones making use of a mixture of heterogeneous resin-bound acid/base reagents. This methodology nicely illustrates the site isolation concept of supported reagents allowing the simultaneous use of otherwise destructive reactive functionalities. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c004704j

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of pyrazolines by a site isolated resin-bound reagents methodology†
Vincent Gembus,a Jean-Jacques Bonnet,b Franc¸ois Janin,b Pierre Bohn,b Vincent Levachera and
Jean-Franc¸ois Brie`re*a
Received 29th March 2010, Accepted 10th May 2010
First published as an Advance Article on the web 26th May 2010
DOI: 10.1039/c004704j
The elaboration of biologically important 3,4-substituted pyrazolines was achieved by an
organocatalysed aza-Michael/transimination domino sequence between hydrazones and enones
making use of a mixture of heterogeneous resin-bound acid/base reagents. This methodology nicely
illustrates the site isolation concept of supported reagents allowing the simultaneous use of otherwise
destructive reactive functionalities.
In this paper, we are delighted to report on an acid–base site
isolation strategy providing an innovative and practical means
to rapidly construct 3,4-substituted pyrazoline derivatives 4
Introduction
Supported heterogeneous reagents have been emerging as useful
(Scheme 1). This heterocyclic platform,9 having a polar functional
group on nitrogen such as acyl COR1,10 has shown promises
in current drug development with insecticidal properties,11a
as an inhibitor of parasitic trypanosomal infections,11b as
progesterone receptor ligands,11c and finally as cannabinoid
CB1 receptor antagonists.11d–e We envisaged a base-catalysed
aza-Michael addition of hydrazones 1 to terminal enones 2,
followed by an acid-catalysed transimination reaction (3 to 4).12
The use of readily available hydrazones to eventually deliver
monosubstituted hydrazines within the pyrazoline framework
offers several advantages: (1) protection of the hydrazine primary
amine to achieve a selective alkylation on NH1; (2) modulation of
the nucleophilic character of the amide moiety with respect to R2;
(3) masking the hydrazine as a less basic hydrazone preventing the
immobilisation of the nucleophile 1 or product 3 onto the acidic
polymer and allowing the diffusion of compounds between the
two resins to perform the multistep acid/base catalysis. Thereby,
a straightforward organocatalytic13 domino methodology was
conveniently carried out in a one-pot fashion by means of a
mixture of commercially available supported heterogeneous
tools in parallel solution-phase synthesis of chemical libraries in
medicinal chemistry, facilitating work-up and scavenging of side-
products by simple filtration, and, last but not least, allowing
continuous flow synthetic transformations.1
At the beginning of the seventies, another unique capability
of resin-bound reagents was pioneered by Cohen, Kraus and
Patchornik.2 They carried out multistep reactions by means of two
supported reagents in the same pot having incompatible functional
groups e.g. an acid and a base being, however, isolated to each other
by their surrounding polymeric matrix.3 Thereby, the different
reactants diffuse from one resin to the other to undergo successive
chemical transformations. At the same period of time, the potential
of the so-called “site isolation concept” was also highlighted for
anchoring two metal catalysts by Pittman or for the detection
of reactive intermediates by Rebek and co-workers.4 Stowell and
Hauck made use of mixed ion-exchange resins allowing concurrent
acid/base catalysis in the same flask affording an improved
synthesis of cyclopentenones by driving an otherwise unfavorable
equilibrium.5 Subsequently, many research groups focused on the
ingenious construction of multifunctional polymeric architectures
and they exemplified their use on simple model domino reactions
as proof-of-principal.6 Interestingly, Kudo and co-workers re-
ported an asymmetric sequential acid/base promoted aldolisation
by means of a chiral supported peptide.7 Recently, Dixon and co-
workers elevated this strategy to construct rather advanced aza-
heterocyclic frameworks by elegant one-pot acid–base catalysed
cyclization cascades promoted by a mixture of isolated reagents
on polystyrene (PS) beads.8 In the line of these elegant precedents,
the prospects for the development of domino transformations by
means of simultaneous use of antagonist resin-bound reagents
afford unprecedented opportunities in organic synthetic chemistry.
R
tosic acid (PS-TsOH, Amberlystꢀ A15) and PS-TBD
aCNRS UMR COBRA, INSA et Universite´ de Rouen, FR 3038, IRCOF
(Research Institute in Fine Organic Chemistry), rue Tesnie`re, BP 08, 76131
Mont Saint Aignan, France. E-mail: jean-francois.briere@insa-rouen.fr;
Fax: +33 (0)235522962; Tel: +33 (0)235522464
bFaculte´ de pharmacie de Rouen, Laboratoire de neuropsychopharmacologie
experimentale FRE, 2735
† Electronic supplementary information (ESI) available: Copy of NMR
spectra for all newly formed products and experimental data for the
synthesis of enones 2. See DOI: 10.1039/c004704j
Scheme 1 Working strategy for domino synthesis of pyrazolines.
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(1,5,7-triazabicyclo[4.4.0]dec-5-ene) providing the isolated
product by simple filtration, thus facilitating the construction of
chemical libraries.8,14
such as DBU (entry 4 vs. entries 1–3) or TBD guanidine (entry 5)
were required to achieve the conjugated addition reaction of
N-benzoyl hydrazone 1a to compounds 3a. A maximum of 64%
conversion into the aza-Michael product 3a was obtained (entry 5)
irrespective to the reaction time (entry 6) or excesses of hydrazone
1a (entry 7). Making use of the more nucleophilic or less acidic
N-acetyl hydrazone 1b (entry 8) or 1c (entry 9) an almost complete
transformation into adduct 3b was achieved. As a matter of fact,
the equilibrium between enone 2a and aza-Michael products 3 is
finely balanced with respect to the hydrazone structure (COR1 =
COMe 1a vs. COPh 1b), likely related to the thermodynamic
stability of the corresponding anions. This phenomenon engenders
the decomposition of the aza-Michael products 3 over time
limiting the scope of the reaction. Moreover, the overall yields of
pyrazolines 4 (entries 7–9), obtained by cyclization of the precursor
3 under acidic conditions, are limited to the conversion of enone
1 during the equilibrated aza-Michael process. Accordingly, we
anticipated that the use of a mixture of polymer supported reagents
isolating antagonist acid and base functional groups would afford
a unique opportunity to drive the reactions to completion by
achieving both the aza-Michael and the cyclization steps in the
same pot.16
Results and discussion
Context and preliminary results in homogeneous phase
The preparation of 3,4-substituted pyrazolines 4 (Scheme 2) is
usually carried out in two steps via the condensation of hydrazine
onto terminal enones 2 to form intermediate 1H-pyrazolines
followed by the addition of acyl chlorides, isocyanates, etc.11 First
of all, the low stability of enone precursors 2 and the sensitivity of
the 1H-pyrazoline intermediates toward oxidative events requires
the rapid execution of these steps, together with the use of an
excess of chemicals.
Use of supported reagents
Scheme 2 Regular strategy.
In order to probe the requirement of a hydrazone in this strategy
(Table 2), we performed test reactions with acetylhydrazine (entries
1 and 2) and enone 2a. No significant formation of pyrazoline
4b took place in the presence of a base or an acid although the
enone 2a was completely consumed.17 Next, it was shown that
neither the polystyrene supported base (PS-TBD) in the presence
of TsOH (entry 3), nor the mixture of PS-TsOH and TBD base
(entry 4) effected the domino transformations into pyrazoline 4b.
In both cases, the acid and base cancelled out each other thus
hampering any acido-basic catalysis to occur. On the contrary,
the mixture of supported reagents (entry 5), smoothly furnished
the corresponding N-acetylpyrazoline in 55% yield demonstrating
Alternatively (Table 1), Shi and co-workers disclosed a se-
quential one-pot formation of N-benzoyl-4,5-dihydropyrazoles
4 from readily available hydrazones 1 and a limited array of
unsubstituted simple enones 2 (R4 = H, R3 = Me, Ph).12 This
elegant organocatalytic sequence proceeded under the influence of
a catalytic amount of DABCO (2 to 3) followed by an acidic work-
up (3 to 4) but required several days for completion.15 Seeking
an expeditious strategy for the elaboration of bioactive 3,4-
substituted pyrazolines (Table 1), we evaluated this methodology
on the more substituted enone 2a (R4 = Ph, R3 = Ph). In our
hands, DABCO performed poorly (entry 1) and stronger bases
Table 1 Initial attempts in homogeneous conditions
Entry
1 R1, R2
Base (20 mol%)
Time/h
Conversion to 3 a(NMR Yield, %)b
4 c(%)
1
2
3
4
5
6
7
8
9
Ph, Ph (1a)
Ph, Ph (1a)
Ph, Ph (1a)
Ph, Ph (1a)
Ph, Ph (1a)
Ph, Ph (1a)
Ph, Ph (1a)e
Me, Ph (1b)e
Me, Me (1c)e
DABCO
Quinuclidine
DMAP
DBU
48
48
48
48
48
3
3
3
3
1 (3a)
—
—
—
—
—
—
42 (4a)
67 (4b)
55 (4b)
10 (3a)
4 (3a)
60 (3a)
TBDd
64 (3a)
TBDd
62 (3a)
TBDd
58 (43, 3a)
95% (83, 3b)f
95% (61, 3b)
TBDd
TBDd
a Determined by NMR. b NMR yield with an internal standard. c Isolated yield by column chromatography from 1. d 1,5,7-triazabicyclo[4.4.0]dec-5-ene.
e 1.5 equiv. f 81% of isolated yield by column chromatography from 0.5 mmol of enone 2a.
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Table 2 Optimisation of the addition reaction of acetylhydrazone 1 to enone 2aa
Entry
Hydrazone 1 (R2,R2)
Base (20 mol%)
Acid (1 equiv.)
Pyrazoline 4b (%)b
1
2
3
4
5
6
7
8
(AcNHNH2)c
(AcNHNH2)c
Me,H (1c)
PS-TBD
—
PS-TBD
TBD
PS-TBD
PS-TBD
PS-TBD
PS-TBD
PS-TBD
PS-TBD
PS-TBD
PS-TBDf
PS-TBDg
—
<10
0
0
PS-TsOH
TsOH,H2O
PS-TsOH
PS-TsOH
PS-TsOHd
PS-TsOHe
PS-TsOH
PS-TsOH
PS-TsOH
PS-TsOH
PS-TsOH
PS-TsOH
Me,H (1c)
0
Me,H (1c)
55
33
25
62
52
73
78
51
77
Me,H (1c)
Me,H (1c)
Et,H (1d)
9
Me,Me (1e)
10
11
12
13
Ph,H (1f)
4-MeOC6H4,H (1g)
4-MeOC6H4,H (1g)
4-MeOC6H4,H (1g)
a All reactions were performed with 0.5 mmol of freshly prepared enone 2a (1 M), acetylhydrazone (1.5 equiv.) and a mixture of polystyrene resin reagents
in anhydrous acetonitrile at 50 ◦C for 24 h. b NMR yield with an internal standard. c AcNHNH2 (1.5 equiv.) d 0.4 equiv. of PS-TsOH, 27% of aza-Michael
product 3a is obtained. e 25 ◦C. f 1 equiv. H2O, 26% of enone not transformed. g 10 mol% of PS-TBD.
an acid–base site isolation catalysis in action while allowing a
convenient work-up by filtration. The overall process was retarded
by decreasing the amount of acid to 0.4 equivalents (entry 6) or
by working at room temperature (entry 7). The use of hydrazones
diversely substituted at the imine moiety affords opportunities to
tune the nucleophilic character of these acylhydrazine analogues
which are eventually delivered to enones. Hydrazones derived
from an aliphatic aldehyde (entry 8) or ketone (entry 9) were
evaluated but only in the former case the yield of 4b was slightly
improved. Eventually, the best results were obtained by means
of more robust hydrazones 1f formed with aromatic aldehydes
(entry10), andelectron-rich para-anisaldehyde derived hydrazones
1g affording up to 78% yield (entry 11). The catalytic amount of
PS-TBD could be reduced to 0.1 equivalents without affecting
the outcome of the reaction over 24 h (entry 13). However, the
addition of one equivalent of water, with the hope to accelerate the
hydrolysis of the hydrazone moiety after the aza-Michael addition,
slowed down the transformation into pyrazoline (entry 12). At this
stage, the exact mechanism of the cyclization events, i.e. either a
hydrolysis of the hydrazone 3 moiety into hydrazine followed by a
cyclocondensation step or the direct cyclization of the hydrazone
to the ketone function, is not clear.
Subsequently, we evaluated the scope of this straightfor-
ward one-pot pyrazoline synthesis with hydrazones 1 derived
from para-anisaldehyde and commercially available hydrazines
(Table 3). The rather unstable enones 2 were freshly prepared in
quantitative crude yield by a standard Mannich type methyle-
nation/elimination sequence of the corresponding ketones 5.18
Being used subsequently without further purification, the reported
yields correspond therefore to a three steps process from ketone
5. First of all, it was demonstrated that the domino reaction
performed well with various N-acyl (entries 1–3), carbamate
(entry 4) and semicarbazide (entry 5) type hydrazones affording
the corresponding pyrazolines 4 in 74 to 82% yields. Importantly,
the reaction furnishing the pyrazoline flanked by a Cbz group
(entry 4) could be performed on 4 mmol scale without affecting
the yield. The N-tosylhydrazone 1j furnished the corresponding
pyrazoline (entry 6) along with an inseparable aza-Michael
product arising from the conjugated addition of the TsNHNH2.
One can suppose that the cyclization step into pyrazoline is
hampered by the strong electron-withdrawing character of the
tosyl group, releasing meanwhile the tosylhydrazine through
hydrolysis of the corresponding hydrazone. A limitation of this
process was shown with 4-acylpyridinehydrazones 1k. This failure
might be due to the protonation/immobilization of 1k by the
acidic PS-TsOH resin which led to a complete decomposition of
substrates (entry 7). The different N-substituted hydrazones were
successfully added to enones bearing various substituted electron-
poor or electron-rich aromatic phenyl or heterocyclic rings to
afford the corresponding 3,4-diarylpyrazolines in more than 71%
yield (entries 8–15). The aza-Michael/transimination sequence
performed well with a-alkyl substituted enones extending the
scope of this methodology (entries 16). Furthermore, enones
whose carbonyl moiety is flanked by a pendant alkyl group
underwent a smooth transformation into N-Bz pyrazoline 4q
(entry 17) and N-CONHPh pyrazoline 4r (entry 18) with 75%
and 80% yields respectively. Taken all together, this methodology
provide an easy access to 3,4-substituted-D2-pyrazoline derivatives
having one or two aromatic groups and various polar func-
tional groups on nitrogen. Thanks to the site isolation concept
allowing the presence of both basic and acidic functionality
in the same pot driving the equilibrated aza-Michael reaction
towards the subsequent pyrazolines formation regardless to the
nature of hydrazones or enones. Consequently, this domino
process avoids tedious and time-consuming optimization for each
substrate.
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Table 3 Addition of various hydrazones 1 to enone 2a
Entry
Hydrazone (COR1)
Enone 2 (R3)
Enone 2 (R4)
Pyrazoline 4 (%)b
1
2
3
4
5
6
7
8
COPh (1f)
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
74 (4a)
77 (4b)
73 (4c)
82 (4d)c
82 (4e)
56 (4f)d
0 (4g)
72 (4h)
75 (4i)
77 (4j)
74 (4k)
78 (4l)
70 (4m)
71 (4n)
75 (4o)
65 (4p)
75 (4q)
80 (4r)
COMe (1e)
CO-2-furanyl (1g)
COOBn (1h)
CONHPh (1i)
(Ts) (1j)
CO-4-Pyr (1k)
COMe (1e)
CONHPh (1i)
COOBn (1h)
COMe (1e)
COOBn (1h)
COMe (1e)
COMe (1e)
CONHPh (1i)
COMe (1e)
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-FC6H4
4-FC6H4
4-MeOC6H4
2-thienyl
2-thienyl
Ph
9
10
11
12
13
14
15
16
17
18
4-MeOC6H4
Ph
Ph
Me
Ph
Ph
COPh (1f)
CONHPh (1i)
i-Pr
i-Pr
a All reactions were performed with 0.5 mmol of freshly prepared enones 2 (1 M), para-ani◦saldehyde derived hydrazone 1 (1.5 equiv.) and a mixture of
polystyrene resin PS-TBD (20 mol%) and PS-TsOH (1 equiv.) in anhydrous acetonitrile at 50 C for 16–22 h. b Isolated yield after column chromatography.
c Performed on 4 mmol scale. d NMR yield with an internal standard.
One-pot transprotection
protective group preventing, thereby, the isolation of the unstable
1H-pyrazoline 6. In the same manner, the addition reaction of an
isocyanate proceeded smoothly to afford the corresponding amide
4t. Therefore, more elaborate functionality could be introduced
lately on nitrogen N1 to elaborate more complex pyrazolines.
As demonstrated in the previous scope and limitation study, the
addition/cyclization reaction sequence of N-tosylhydrazone 1j did
not perform well. Nevertheless, we developed a straightforward
one-pot transprotection protocol (Scheme 3) from readily available
and stable N-benzyloxycarbonyl pyrazoline 4d (Table 3, entry
4). The introduction of various tosyl or mesyl pendants was
achieved after palladium catalysed hydrogenolysis of the Cbz
Conclusions
In summary, we achieved a straightforward site isolated base (0.2
equiv. PS-TBD) and acid (1 equiv. PS-TsOH) protocol yielding
a wide variety of 3,4-substituted pyrazolines making use of the
modified Shi’s masked hydrazine methodology.12 This metal free
domino process promoted by commercially available supported
reagents not only facilitates the work-up by means of a simple
filtration protocol but allows the facile formation of chemical
libraries of these biologically relevant nitrogen-containing hete-
rocycles.
Experimental
General
Chromatographic purification of compounds was achieved with
60 silica gel (40–63 mm).‡ 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
Scheme 3 One-pot transprotection.
‡ Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
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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. Mps stand uncorrected. The hydrazones
were synthesized with respect to known procedures and used with-
out further purification.19 TBD bound to polystyrene crosslinked
with 2% DVB (2.5 mmol g-1) provided by Fluka and Amberlyst
(CH), 140.2 (C), 130.7 (C), 130.3 (CH), 129.5 (CH), 128.7 (CH),
127.8 (CH), 127.5 (CH), 127.4 (CH), 119.1 (CH), 111.7 (CH), 55.3
(CH2), 49.8 (CH); HRMS (ESI+): Calcd for C20H17N2O2 [M+H]+:
317.1290; Found: 317.1300.
Benzyl 3,4-diphenyl-4,5-dihydro-1H-pyrazole-1-carboxylate
(4d). Reaction time: 16 h; white solid (146.4 mg, 82%); Rf
0.24 (Petroleum ether/EtOAc: 3/1); mp 132–133 ◦C; IR (KBr)
n
max/cm-1 1714, 1446, 1408, 1373, 1299, 1164, 1127, 980, 844, 754,
686; dH(300 MHz; CDCl3) 7.61–7.58 (2 H, m), 7.36–7.09 (13 H,
m), 5.23 (2 H, br s), 4.61 (1 H, dd, J 11.5 and J 5.2), 4.29 (1 H, dd,
J 11.3 and J 11.2), 3.88 (1 H, dd, J 11.2 and J 5.1); dC(75.4 MHz;
CDCl3) 156.7 (C), 152.0 (C), 140.1 (C), 136.1 (C), 130.5 (C),
129.8 (CH), 129.2 (CH), 128.5 (CH), 128.3 (CH), 128.2 (CH),
127.6 (CH), 127.4 (CH), 127.3 (CH), 67.7 (CH2), 55.6 (CH2), 51.0
(CH); HRMS (ESI+): Calcd for C23H21N2O2 [M+H]+: 357.1603;
Found: 357.1613.
R
ꢀ 15 (dry, ≥ 4.7 eq/kg) were used as received.
Representative procedure for the synthesis of (3,4-diphenyl-
4,5-dihydro-1H-pyrazol-1-yl)(phenyl)methanone 4a. To a stirred
solution of freshly prepared 1,2-diphenylprop-2-en-1-one 2a
(104.1 mg, 0.50 mmol) and hydrazone 1f (0.75 mmol) in anhydrous
acetonitrile (0.5 mL) was added PS-TBD (40.0 mg, 0.10 mmol),
N,3,4-Triphenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (4e).
Reaction time: 16 h; white solid (140.3 mg, 82%); Rf 0.48
R
and Amberlystꢀ A-15 (106.0 mg, 0.50 mmol). The resulting
◦
◦
(Petroleum ether/EtOAc: 2/1); mp 185–187 C; (lit.,18a 185 C);
IR (KBr) nmax/cm-1 3283, 1636, 1591, 1560, 1515, 1471, 1444, 1386,
1323, 1296, 1228, 1159, 1109, 741, 693; dH(300 MHz; CDCl3) 8.18
(1 H, s), 7.65–7.56 (4 H, m), 7.37–7.04 (11 H, m), 4.76 (1 H, dd,
J 11.7 and J 5.2), 4.43 (1 H, dd, J 11.6 and J 11.3), 4.09 (1 H,
dd, J 11.3 and J 5.1); dC(75.4 MHz; CDCl3) 155.0 (C), 152.1 (C),
140.3 (C), 138.6 (C), 130.7 (C), 129.9 (CH), 129.4 (CH), 129.1
(CH), 128.7 (CH), 127.8 (CH), 127.4 (CH), 127.1 (CH), 123.1
(CH), 119.1 (CH), 54.6 (CH2), 51.4 (CH); HRMS (ESI+): Calcd
for C22H20N3O [M+H]+: 342.1606; Found: 342.1604.
mixture was smoothly magnetically stirred and heated at 50 ◦C
until the disappearance of starting material on TLC. After cooling,
the polymers were removed by filtration and the resin was washed
with dichloromethane. The filtrate was concentrated in vacuo and
purified by flash column chromatography to furnish pyrazoline
4a as described in the following characterizations. Remark: the
obtained solids tend to retain solvents such as AcOEt or CH2Cl2,
so they have to be dried for a long period of time under vacuum.
(3,4-Diphenyl-4,5-dihydro-1H-pyrazol-1-yl)(phenyl)methanone
(4a). Reaction time: 18 h; white solid (120.6 mg, 74%); Rf
0.61 (Petroleum ether/EtOAc: 1/1); mp 50–52 ◦C; IR (KBr)
1-(3-(4-Chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-
ethanone (4h). Reaction time: 21 h; white solid (107.7 mg, 72%);
Rf 0.14 (Petroleum ether/EtOAc: 3/1); mp < 50 ◦C; IR (KBr)
n
max/cm-1 1636, 1575, 1492, 1450, 1420, 1317, 1144, 825, 758,
690; dH(300 MHz; CDCl3) 8.07–8.05 (2 H, m), 7.63–7.22 (13 H,
m), 4.74 (1 H, dd, J 11.5 and J 4.9), 4.60 (1 H, dd, J 12.0 and J
11.6), 4.24 (1 H, dd, J 12.0 and J 4.9); dC(75.4 MHz; CDCl3) 167.0
(C), 157.8 (C), 140.4 (C), 134.2 (C), 131.1 (CH), 130.7 (C), 130.2
(CH), 130.1 (CH), 129.4 (CH), 128.6 (CH), 127.8 (CH), 127.5
(CH), 127.4 (CH), 55.7 (CH2), 50.0 (CH); HRMS (EI+) calcd for
C22H18N2O: 326.1419; Found: 326.1417.
n
max/cm-1 1667, 1585, 1557, 1495, 1444, 1400, 1359, 1309, 1227,
1170, 1091, 1011, 953, 834, 761, 710; dH(300 MHz; CDCl3) 7.51–
7.47 (2 H, m), 7.26–7.14 (5 H, m), 7.08–7.05 (2 H, m); 4.59
(1 H, dd, J 11.9 and J 5.4), 4.31 (1 H, dd, J 11.9 and J 12.1), 3.94
(1 H, dd, J 12.2 and J 5.4), 2.39 (3 H, s); dC(75.4 MHz; CDCl3)
169.5 (C), 155.7 (C), 140.1 (C), 135.9 (C), 129.5 (CH), 129.3 (C),
128.9 (CH), 128.5 (CH), 127.9 (CH), 127.3 (CH), 54.4 (CH2),
50.8 (CH), 21.7 (CH3); HRMS (ESI+): Calcd for C17H16N2OCl
[M+H]+: 299.0951; Found: 299.0948.
1-(3,4-Diphenyl-4,5-dihydro-1H-pyrazol-1-yl)ethanone
(4b).
Reaction time: 18 h; white solid (101.6 mg, 77%); Rf 0.23
(Petroleum ether/EtOAc: 2/1); mp 106–107 ◦C; IR (KBr)
max/cm-1 1659, 1586, 1557, 1458, 1444, 1419, 1362, 1228, 1154,
3-(4-Chlorophenyl)-N,4-diphenyl-4,5-dihydro-1H-pyrazole-1-
carboxamide (4i). Reaction time: 17 h; white solid (141.1 mg,
75%); Rf 0.28 (Petroleum ether/EtOAc: 3/1); mp 164–166 ◦C;
(lit.,18a 157 ◦C); IR (KBr) nmax/cm-1 3387, 1686, 1593, 1526, 1445,
1381, 1309, 1225, 1149, 1091, 829, 790, 742, 695; dH(300 MHz;
CDCl3) 8.12 (1 H, s), 7.60–7.57 (4 H, m), 7.37–7.06 (10 H, m),
4.72 (1 H, dd, J 11.7 and J 5.4), 4.40 (1 H, t, J 11.5), 4.09 (1
H, dd, J 11.3 and J 5.4); dC(75.4 MHz; CDCl3) 153.9 (C), 152.0
(C), 140.0 (C), 138.5 (C), 135.9 (C), 129.5 (CH), 129.2 (C), 129.1
(CH), 129.0 (CH), 128.4 (CH), 128.0 (CH), 127.4 (CH), 123.3
(CH), 119.2 (CH), 54.7 (CH2), 51.3 (CH); HRMS (ESI+): Calcd
for C22H19N3OCl [M+H]+: 376.1217; Found: 376.1216.
n
1044, 952, 848, 762, 701, 691; dH(300 MHz; CDCl3) 7.66–7.63 (2
H, m), 7.31–7.15 (8 H, m), 4.70 (1 H, dd, J 11.5 and J 5.0), 4.37
(1 H, dd, J 12.0 and J 11.6), 4.02 (1 H, dd, J 12.0 and J 5.0), 2.47
(3 H, s); dC(75.4 MHz; CDCl3) 169.6 (C), 156.9 (C), 140.4 (C),
130.8 (C), 130.0 (CH), 129.4 (CH), 128.6 (CH), 127.7 (CH), 127.3
(CH), 126.0 (CH), 54.3 (CH2), 50.8 (CH), 21.7 (CH3); HRMS
(EI+) calcd for C17H16N2O: 264.1262; Found: 264.1249.
(3,4-Diphenyl-4,5-dihydro-1H-pyrazol-1-yl)(furan-2-yl)metha-
none (4c). Reaction time: 22 h; white solid (115.7 mg, 73%); Rf
0.25 (Petroleum ether/EtOAc: 2/1); mp 134–136 ◦C; IR (KBr)
n
max/cm-1 1635, 1557, 1473, 1436, 1318, 1226, 1155, 1082, 1017,
808, 757, 699; dH(300 MHz; CDCl3) 7.73–7.67 (4 H, m), 7.34–7.19
(8 H, m), 6.61 (1 H, dd, J 3.5 and J 1.7), 4.73 (1 H, dd, J 11.5 and
J 4.9), 4.57 (1 H, dd, J 12.2 and J 11.5), 4.23 (1 H, dd, J 12.2 and
J 4.9); dC(75.4 MHz; CDCl3) 158.4 (C), 156.4 (C), 146.3 (C), 145.6
Benzyl 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-
carboxylate (4j). Reaction time: 21 h; white solid (150.7 mg,
77%); Rf 0.37 (Petroleum ether/EtOAc: 3/1); mp <50 ◦C; IR
(KBr) nmax/cm-1 1724, 1593, 1417, 1291, 1164, 1123, 1087, 967,
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826, 758, 698; dH(300 MHz; CDCl3) 7.53–7.50 (2 H, m), 7.35–7.07
(12 H, m), 5.23 (2 H, s), 4.58 (1 H, dd, J 11.6 and J 5.4), 4.31 (1 H,
t, J 11.5), 3.89 (1 H, dd, J 11.6 and J 5.3); dC(75.4 MHz; CDCl3)
155.5 (C), 152.8 (C), 139.8 (C), 136.0 (C), 135.7 (C), 129.3 (CH),
129.0 (C), 128.6 (CH), 128.5 (CH), 128.2 (CH), 127.7 (CH), 127.2
(CH), 67.7 (CH2), 55.8 (CH2), 50.9 (CH); HRMS (ESI+): Calcd
for C23H20N2O2Cl [M+H]+: 391.1213; Found: 391.1216.
N ,4-Diphenyl-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-
carboxamide (4o). Reaction time: 19 h; white solid (130.5 mg,
75%); Rf 0.62 (Petroleum ether/EtOAc: 1/1); mp 154–155 ◦C; IR
(KBr) nmax/cm-1 3389, 1681, 1593, 1531, 1445, 1377, 1310, 1223,
1144, 1100, 1076, 845, 751, 702; dH(300 MHz; CDCl3) 8.08 (1 H,
s), 7.60–7.58 (2 H, m), 7.38–7.27 (8 H, m), 7.09 (1 H, t, J 7.3), 6.98
(1 H, dd, J 3.7 and J 1.1), 6.91 (1 H, dd, J 4.9 and J 3.7), 4.70
(1 H, dd, J 11.7 and J 6.0), 4.48 (1 H, dd, J 11.4 and J 11.7), 4.09
(1 H, dd, J 11.3 and J 6.0); dC(75.4 MHz; CDCl3) 151.9 (C), 150.8
(C), 140.1 (C), 138.5 (C), 134.3 (C), 129.4 (CH), 129.1 (CH), 129.0
(CH), 128.1 (CH), 128.0 (CH), 127.7 (CH), 127.6 (CH), 123.1
(CH), 119.1 (CH), 54.7 (CH2), 52.5 (CH); HRMS (ESI+): Calcd
for C20H18N3OS [M+H]+: 348.1171; Found: 348.1166.
1-(3-(4-Fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-
ethanone (4k). Reaction time: 18 h; white solid (104.8 mg, 74%);
Rf 0.18 (Petroleum ether/EtOAc: 3/1); mp 116–117 ◦C; IR (KBr)
n
max/cm-1 1651, 1604, 1512, 1453, 1410, 1361, 1312, 1231, 1156,
955, 841, 700, 520; dH(300 MHz; CDCl3) 7.65–7.61 (2 H, m),
7.34–7.15 (5 H, m), 7.01–6.93 (2 H, m); 4.68 (1 H, dd, J 11.6 and
J 5.2), 4.39 (1 H, dd, J 11.7 and J 12.2), 4.02 (1 H, dd, J 12.2
and J 5.1), 2.47 (3 H, s); dC(75.4 MHz; CDCl3) 169.4 (C), 163.7
(C, J 250.1), 155.8 (C), 140.2 (C), 129.5 (CH), 129.3 (CH, J 8.4),
127.8 (CH), 127.3 (CH), 127.1 (C, J 3.3), 127.0 (CH), 115.6 (CH,
J 21.8), 54.3 (CH2), 50.9 (CH), 21.7 (CH3); HRMS (ESI+): Calcd
for C17H16N2OF [M+H]+: 283.1247; Found: 283.1240.
1-(4-Methyl-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)ethanone
(4p)20. Reaction time: 20 h; pale yellow solid (66.1 mg, 65%);
◦
Rf 0.16 (Petroleum ether/EtOAc: 1/1); mp 53–54 C; IR (KBr)
n
max/cm-1 1660, 1586, 1562, 1442, 1357, 1157, 1087, 1030, 992,
953, 834, 780, 762, 702, 688; dH(300 MHz; CDCl3) 7.75–7.72 (2 H,
m), 7.43–7.41 (3 H, m), 4.11–4.04 (1 H, m), 3.81 (1 H, dd, J 11.8
and J 4.5), 3.74–3.62 (1 H, m), 2.39 (3 H, s), 1.29 (3 H, d, J 7.1);
dC(75.4 MHz; CDCl3) 169.5 (C), 159.9 (C), 130.6 (C), 130.1 (CH),
128.8 (CH), 126.9 (CH), 52.2 (CH2), 38.8 (CH), 21.4 (CH3), 19.0
(CH3); HRMS (ESI+): Calcd for C12H15N2O [M+H]+: 203.1184;
Found: 203.1176.
Benzyl 3-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-
carboxylate (4l). Reaction time: 19 h; white solid (146.4 mg,
78%); Rf 0.4 (Petroleum ether/EtOAc: 3/1); mp 122–123 ◦C; IR
(KBr) nmax/cm-1 1718, 1603, 1514, 1447, 1417, 1403, 1371, 1302,
1229, 1159, 1128, 979, 857, 695; dH(300 MHz; CDCl3) 7.66–7.64
(2 H, m), 7.44–7.16 (10 H, m), 6.98–6.90 (2 H, m), 5.3 (2 H, s),
4.67 (1 H, dd, J 11.6 and J 5.3), 4.38 (1 H, dd, J 11.3 and J 11.5),
3.97 (1 H, dd, J 11.3 and J 5.1); dC(75.4 MHz; CDCl3) 163.6.2
(C, J 249.3), 155.7 (C), 153.0 (C), 139.9 (C), 136.2 (C), 129.5
(CH, J 8.3), 129.4 (CH), 128.6 (CH), 128.38 (CH), 128.35 (CH),
127.8 (CH), 127.3 (CH), 126.9 (C, J 3.9), 115.6 (CH, J 21.8), 67.8
(CH2), 64.6 (CH), 55.8 (CH2), 51.3 (CH); HRMS (ESI+): Calcd
for C23H20N2O2F [M+H]+: 375.1509; Found: 375.1494.
(3-Isopropyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(phenyl)-
methanone (4q). Reaction time: 18 h; colorless oil (110.0 mg,
75%); Rf 0.26 (Petroleum ether/EtOAc: 1/1); IR (KBr) nmax/cm-1
2968, 1694, 1633, 1574, 1494, 1452, 1346, 1249, 1030, 897, 821,
757, 704, 669; dH(300 MHz; CDCl3) 8.03 (2 H, d, J 6.9), 7.48–7.17
(8 H, m), 4.51 (1 H, dd, J 11.4 and J 11.9), 4.28 (1 H, dd, J 11.3
and J 6.0), 4.13 (1 H, dd, J 11.9 and J 6.2), 2.46–2.37 (1 H, m),
1.10 (3 H, d, J 6.7), 1.06 (3 H, d, J 7.1); dC(75.4 MHz; CDCl3)
167.3 (C), 166.5 (C), 155.2 (C), 139.8 (C), 134.3 (C), 130.9 (CH),
130.2 (CH), 129.3 (CH), 127.8 (CH), 127.6 (CH), 54.5 (CH2), 51.1
(CH), 28.2 (CH), 20.5 (CH3), 19.5 (CH3); HRMS (ESI+): Calcd
for C19H21N2O [M+H]+: 293.1654; Found: 293.1646. Remark: this
compound tends to decompose if standing at room temperature.
1-(3,4-Bis(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)eth-
anone (4m). Reaction time: 20 h; pale yellow solid (113.8 mg,
70%); Rf 0.12 (Petroleum ether/EtOAc: 2/1); mp 58–60 ◦C; IR
(KBr) nmax/cm-1 1625, 1515, 1466, 1424, 1368, 1325, 1304, 1250,
1173, 1112, 1034, 977, 838; dH(300 MHz; CDCl3) 7.61–7.56 (2 H,
m), 7.09–7.04 (2 H, m), 6.83–6.76 (4 H, m); 4.61 (1 H, dd, J 11.5
and J 5.1), 4.31 (1 H, dd, J 11.8 and J 11.5), 3.95 (1 H, dd, J 12.0
and J 5.1), 3.76 (3 H, s); 3.75 (3 H, s); 2.44 (3 H, s); dC(75.4 MHz;
CDCl3) 169.3 (C), 160.9 (C), 158.9 (C), 156.9 (C), 132.7 (C), 128.9
(CH), 128.4 (CH), 123.4 (C), 114.7 (CH), 114.0 (CH), 55.38 (CH3),
55.34 (CH3), 54.2 (CH2), 50.2 (CH), 21.6 (CH3); HRMS (ESI+):
Calcd for C19H21N2O3 [M+H]+: 325.1552; Found: 325.1545.
3-Isopropyl-N ,4-diphenyl-4,5-dihydro-1H -pyrazole-1-carbo-
xamide (4r). Reaction time: 17 h; pale yellow solid (123.2 mg,
80%); Rf 0.31 (Petroleum ether/EtOAc: 1/1); mp 105–106 ◦C; IR
(KBr) nmax/cm-1 3391, 2973, 2879, 1681, 1590, 1526, 1447, 1388,
1333, 1210, 1139, 1116, 1076, 797, 753, 709, 691, 579; dH(300 MHz;
CDCl3) 8.04 (1 H, s), 7.54 (2 H, d, J 7.7), 7.37–7.25 (5 H, m), 7.18
(2 H, d, J 7.1), 7.04 (1 H, t, J 7.1), 4.32 (2 H, br s), 3.99 (1
H, br s), 2.46–2.37 (1 H, m), 1.15 (3 H, d, J 6.8), 1.08 (3 H, d,
J 7.0); dC(75.4 MHz; CDCl3) 164.4 (C), 152.4 (C), 139.8 (C), 138.8
(C), 129.2 (CH), 129.0 (CH), 127.8 (CH), 127.7 (CH), 122.8 (CH),
119.0 (CH), 53.5 (CH2), 52.8 (CH), 28.1 (CH), 20.6 (CH3), 19.6
(CH3); HRMS (ESI+): Calcd for C19H22N3O [M+H]+: 308.1763;
Found: 308.1758.
1-(4-Phenyl-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)eth-
anone (4n). Reaction time: 19 h; pale yellow solid (96.4 mg, 71%);
Rf 0.28 (Petroleum ether/EtOAc: 2/1); mp 164–166 ◦C; IR (KBr)
n
max/cm-1 1651, 1454, 1416, 1231, 1159, 1089, 1032, 955, 847, 734,
705; dH(300 MHz; CDCl3) 7.20–7.36 (6 H, m), 6.92 (1 H, dd, J 3.6
and J 1.1), 6.88 (1 H, dd, J 5.0 and J 3.7), 4.63 (1 H, dd, J 11.8 and
J 6.0), 4.41 (1 H, t, J 11.8), 4.00 (1 H, dd, J 11.8 and J 6.0), 2.44 (3
H, s); dC(75.4 MHz; CDCl3) 169.3 (C), 152.7 (C), 140.2 (C), 134.5
(C), 129.4 (CH), 129.3 (CH), 128.2 (CH), 128.0 (CH), 127.7 (CH),
127.6 (CH), 54.4 (CH2), 52.0 (CH), 21.6 (CH3); HRMS (ESI+):
Calcd for C15H15N2OS [M+H]+: 271.0905; Found: 271.0906.
General procedure for the transprotection reaction. A solution
of pyrazoline 4d (89.1 mg, 0.25 mmol) in THF (2 ml) was
hydrogenated in the presence of Pd/C 10% (10 mg) at 1 atm
for 1 h. Then, hydrogen was removed by bubbling the nitrogen
through the solution. Triethylamine (0.07 mL, 0.5 mmol, 2 equiv)
and para-toluenesulfonic anhydride (81.6 mg, 1 equiv) was added
at room temperature. The mixture was stirred for 1 h and the
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R
catalyst was removed by filtration (Celiteꢀ, CH2Cl2).The filtrate
4 (a) C. U. Pittman and L. R. Smith, J. Am. Chem. Soc., 1975, 97, 1749;
(b) J. Rebek and F. Gavina, J. Am. Chem. Soc., 1975, 97, 3453.
5 J. C. Stowell and H. F. Hauck, J. Org. Chem., 1981, 46, 2428.
6 For representative references in the field of metal free cascade processes,
see: (a) G. Faina, B. Jochanan and A. David, Angew. Chem., Int. Ed.,
2001, 40, 3647; (b) H. Brett, J. G. Steven, X. Yu, M. Meredith, J. H.
Craig and M. J. F. Jean, Angew. Chem., Int. Ed., 2005, 44, 6384; (c) K.
Motokura, N. Fujita, K. Mori, T. Mizugaki, K. Ebitani and K. Kaneda,
J. Am. Chem. Soc., 2005, 127, 9674; (d) T. S. P. Nam, S. G. Christopher,
V. N. Joseph, Z. J. Zhang and W. J. Christopher, Angew. Chem., Int. Ed.,
2006, 45, 2209; (e) K. Z. Ryan, H. Son-Jong and E. D. Mark, Angew.
Chem., Int. Ed., 2006, 45, 6332; (f) S. Sankaranarayanapillai, W. Alex,
S. Andreas, E. Stefan and R. T. Werner, Chem.–Eur. J., 2009, 15, 7052;
(g) K. Motokura, M. Tada and Y. Iwasawa, J. Am. Chem. Soc., 2009,
131, 7944; (h) L. Xin, D. Hui, Z. Bo, L. Jiuyuan, Z. Long, L. Sanzhong
and C. Jin-Pei, Chem.–Eur. J., 2010, 16, 450.
was concentrated. Purification by flash chromatography gave
pyrazoline 4f as described in the following characterizations data.
3,4-Diphenyl-1-tosyl-4,5-dihydro-1H-pyrazole (4f). Pale yel-
low solid (84.9 mg, 90%); Rf 0.58 (Petroleum ether/EtOAc: 1/1);
mp 168–169 ◦C; IR (KBr) nmax/cm-1 1597, 1493, 1446, 1360, 1166,
1094, 1027, 755, 671, 597, 548; dH(300 MHz; CDCl3) 7.85 (2 H, d,
J 8.1), 7.60–7.57 (2 H, m), 7.34–7.21 (8 H, m), 7.01–6.98 (2 H, m),
4.50 (1 H, dd, J 10.5 and J 4.9), 3.86 (1 H, t, J 10.3), 3.77 (1 H, dd,
J 10.0 and J 4.9), 2.43 (3 H, s); dC(75.4 MHz; CDCl3) 159.5 (C),
144.6 (C), 139.0 (C), 131.1 (C), 130.3 (CH), 130.2 (C), 129.7 (CH),
129.3 (CH), 129.0 (CH), 128.6 (CH), 127.9 (CH), 127.6 (CH),
127.5 (CH), 58.0 (CH2), 51.9 (CH), 21.7 (CH3); HRMS (ESI+):
Calcd for C22H21N2O2S [M+H]+: 377.1324; Found: 377.1312.
7 K. Akagawa, S. Sakamoto and K. Kudo, Tetrahedron Lett., 2007, 48,
985.
8 (a) W. P. Adam, B. Jutta and J. D. Darren, Angew. Chem., Int. Ed.,
2007, 46, 5428; (b) A. W. Pilling, J. Bo¨hmer and D. J. Dixon, Chem.
Commun., 2008, 832and references cited therein.
9 Review on pyrazolines: (a) A. Le´vai, 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.
10 For recent literature, see: O. Mahe´, D. Frath, I. Dez, F. Marsais,
V. Levacher and J.-F. Brie`re, Org. Biomol. Chem., 2009, 7, 3648and
references cited therein.
1-(Methylsulfonyl)-3,4-diphenyl-4,5-dihydro-1H-pyrazole (4s).
White solid (64.0 mg, 85%); Rf 0.50 (Petroleum ether/EtOAc:
1/1); mp 170–171 ◦C; IR (KBr) nmax/cm-1 1495, 1446, 1340, 1158,
1093, 1015, 961, 840, 784, 767, 753, 697, 590, 552; dH(300 MHz;
CDCl3) 7.69–7.66 (2 H, m), 7.34–7.23 (8 H, m), 4.73 (1 H, dd,
J 10.5 and J 4.3), 4.14 (1 H, dd, J 10.3 and J 10.0), 3.91 (1 H,
dd, J 10.0 and J 4.2), 3.15 (3 H, s); dC(75.4 MHz; CDCl3) 160.1
(C), 138.6 (C), 130.6 (CH), 130.0 (C), 129.4 (CH), 128.7 (CH),
128.1 (CH), 127.7 (CH), 127.6 (CH), 56.6 (CH2), 52.1 (CH), 35.9
(CH3); HRMS (ESI+): Calcd for C16H17N2O2S [M+H]+: 301.1011;
Found: 301.1000.
11 (a) J. M. Renga, K. L. McLaren and M. J. Ricks, Org. Process Res.
Dev., 2003, 7, 267; (b) X. Du, C. Guo, E. Hansell, P. S. Doyle, C. R.
Caffrey, T. P. Holler, J. H. McKerrow and F. E. Cohen, J. Med. Chem.,
2002, 45, 2695; (c) D. G. Jones, X. Liang, E. L. Stewart, R. A. Noe,
L. S. Kallander, K. P. Madauss, S. P. Williams, S. K. Thompson, D. W.
Gray and W. J. Hoekstra, Bioorg. Med. Chem. Lett., 2005, 15, 3203;
(d) H. M. L. Jos and G. K. Chris, Chem. Rec., 2008, 8, 156; (e) S. R.
Donohue, V. W. Pike, S. J. Finnema, P. Truong, J. Andersson, B. z.
Gulya´s and C. Halldin, J. Med. Chem., 2008, 51, 5608.
N-Cyclohexyl-3,4-diphenyl-4,5-dihydro-1H-pyrazole-1-carbo-
xamide (4t). Pale yellow solid (80.0 mg, 92%); Rf 0.45 (Petroleum
ether/EtOAc: 1/1); mp 160–161 ◦C; IR (KBr) nmax/cm-1 3384,
2934, 2852, 1651, 1526, 1395, 1130, 691; dH(300 MHz; CDCl3)
7.63–7.60 (2 H, m), 7.30–7.18 (8 H, m), 6.03 (1 H, d, J 8.3), 4.66
(1 H, dd, J 11.6 and J 5.3), 4.32 (1 H, dd, J 11.5 and J 11.3),
4.01 (1 H, dd, J 11.1 and J 5.0), 3.80–3.70 (1 H, m), 2.10–1.95
(2 H, m), 1.83–1.57 (3 H, m), 1.50–1.16 (5 H, m); dC(75.4 MHz;
CDCl3) 154.5 (C), 153.9 (C), 140.5 (C), 131.0 (C), 129.4 (CH),
129.2 (CH), 128.5 (CH), 127.5 (CH), 127.4 (CH), 126.9 (CH), 54.8
(CH2), 51.0 (CH), 48.9 (CH), 34.0 (CH2), 33.9 (CH2), 25.7 (CH2),
25.16 (CH2), 25.13 (CH2); HRMS (ESI+): Calcd for C22H26N3O
[M+H]+: 348.2076; Found: 348.2079.
12 G.-L. Zhao and M. Shi, Tetrahedron, 2005, 61, 7277.
13 Reviews on supported organic catalysts: (a) M. Benaglia, A. Puglisi and
F. Cozzi, Chem. Rev., 2003, 103, 3401; (b) M. Benaglia, New J. Chem.,
2006, 30, 1525; (c) F. Cozzi, Adv. Synth. Catal., 2006, 348, 1367.
14 For reviews, see: (a) L. F. Tietze, Chem. Rev., 1996, 96, 115; (b) K. J.
Nicolaou, D. J. Edmonds and P. G. Bulger, Angew. Chem., Int. Ed.,
2006, 45, 7134; (c) J. C. Chapman and C. G. Frost, Synthesis, 2007, 1
and references cited therein.
15 Selected recent review on organocatalysis: Special issue on organocatal-
ysis: (a) B. List, Chem. Rev., 2007, 107, 5413; (b) Enantioselective
Organocatalysis; ed. P. I. Dalko, Ed.; Wiley-VCH: Weinheim, Germany,
2007; (c) S. Bertelsen and K. A. Jørgensen, Chem. Soc. Rev., 2009, 38,
2178 and references cited therein.
16 For the elegant use of supported reagents methodologies for the
synthesis of 3,5-substituted pyrazolines following a sequential multistep
strategy, see: (a) F. Haunert, M. H. Bolli, B. Hinzen and S. V. Ley,
J. Chem. Soc., Perkin Trans. 1, 1998, 2235; (b) U. Bauer, B. J. Egner, I.
Nilsson and M. Berghult, Tetrahedron Lett., 2000, 41, 2713.
17 We previously reported on the synthesis of 3,5-diarylpyrazolines by
addition of N-acetylhydrazines to chalcone derivatives catalysed by
TBD guanidine. The same conditions applied to terminal enones 2 did
not furnish the corresponding 3,4-substituted pyrazolines and led to a
rapid decomposition of the unsaturated ketone. Enones 2 are indeed
markedly prone to polymerisation under basic conditions or in the
presence of strong nucleophiles such as monosubstituted hydrazines.
See reference 10.
Acknowledgements
This research was supported by the French National Research
Agency (ANR) as part of the ANR-08-JCJC-004301 project. We
also gratefully acknowledge financial support from CNRS (Centre
National de la Recherche Scientifique) and the “Ministe`re de la
Recherche”.
18 (a) A. C. Arnold, C. Grosscurt, R. van Hes and K. Wellinga, J. Agric.
Food Chem., 1979, 27, 406; (b) J. H. M. Lange, H. K. A. C. Coolen,
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