TBD-organocatalysed synthesis of pyrazolines

Article abstract of DOI:10.1039/b911577c

It was found that TBD, a cheap and commercially available guanidine, easily catalysed the synthesis of biologically important 3,5-diarylpyrazolines from chalcones and acylhydrazines via a selective secondary amine alkylation.

Full text of DOI:10.1039/b911577c

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COMMUNICATION
www.rsc.org/obc | Organic & Biomolecular Chemistry
TBD-organocatalysed synthesis of pyrazolines†
Olivier Mahe´,a Denis Frath,a Isabelle Dez,c Francis Marsais,a Vincent Levachera,b and Jean-Franc¸ois Brie`re*a,b
Received 12th June 2009, Accepted 7th July 2009
First published as an Advance Article on the web 17th July 2009
DOI: 10.1039/b911577c
It was found that TBD, a cheap and commercially avail-
able guanidine, easily catalysed the synthesis of biologically
important 3,5-diarylpyrazolines from chalcones and acylhy-
drazines via a selective secondary amine alkylation.
The 3,5-diarylpyrazoline scaffold 4 (Scheme 1) is displayed within
an increasing number of bioactive compounds acting as inhibitors
of the mitotic kinesin KSP,1a mycobacterium tuberculosis1b and
West Nile viruses,1c and those with insecticidal activities,1d etc.2–3
The D2-pyrazoline ring is usually synthesised via [2+3] cycloaddi-
tions of diazoalkane or nitrilimine dipoles,2–3 although alternative
methodologies are emerging.4 On the other hand, the construction
of 3,5-diarylpyrazolines chiefly relies on the cyclocondensation
Scheme 1 Regioselective alkylation of hydrazines.
of hydrazines, having electron-rich aryl or alkyl groups, with
chalcones 2 under acidic conditions.3,5 Nevertheless, in medicinal
chemistry, the presence of an electron-withdrawing polar func-
amine moiety to form product 3.11 Therefore, we would have
tional group on N1 (4) markedly impacts on both the selectivities
and affinities of pyrazoline ligands through hydrogen bonding
or electrostatic interactions.1 The method of choice for their
synthesis consists of using an excess of hydrazine hydrate, giving
1H-pyrazolines, followed by the condensation of acyl chloride,
isocyanate and sulfonyl chloride derivatives.1,3,6 The isolation of
the rather instable 1H-pyrazolines6 was avoided by performing
the reaction in a refluxing acetic acid solution, giving rise to the
formation of the more robust acetyl diazoles 4 (EWG1 = Ac)
and,1,5b in some cases, to higher acetyl homologues (EWG1 =
EtCO, Bz).5b,7 The (thio)-semicarbazides were also successfully
added to chalcones in the presence of strong sodium hydroxide
base or HCl.8 In this context, the development of alternative
and less drastic reaction conditions would be helpful for the
elaboration of a larger array of 3,5-diarylpyrazolines 4.
With regard to the usefulness of mono-substituted hydrazines
in organic synthesis,9 the regioselective catalytic functionalisation
of only one nitrogen atom constitutes an attractive synthetic
challenge toward heterocylic compound elaboration. Aiming at
exploiting the base-catalysed aza-Michael process (Scheme 1),10
we sought an amine suitably enabled to selectively ‘activate’
the N1–H bond of hydrazine nucleophiles 1 toward chalcones.
Accordingly, a cyclocondensation into pyrazolines 4 would take
place instead of the expected conjugate addition of the primary
in our hands a straightforward and organocatalytic12 synthesis
of 3,5-diarylpyrazolines, simply releasing water and without
the possibility of any metal contamination, making products
suitable for further pharmaceutical evaluation.10b–c In fact, ele-
gant precedents described the N1 selective alkylation of mono-
substituted hydrazines but made use of an excess of inorganic
bases,13 and employed transition metals.14 Also worthy of note
is the asymmetric conjugate addition of electron-rich hydrazines
promoted by Lewis acids, developed respectively by Sibi and
Kanemasa,15 who thereby achieved pyrazolidinone and pyridyl-
substituted pyrazoline syntheses.
In order to validate our working hypothesis, we evaluated the
ability of several amines (with increased pKa values) to catalyse the
reaction between acetylhydrazine 1a and chalcone 2a at 60 ◦C in
toluene (Table 1). At the onset, it was shown that the aza-Michael
product 3a was formed via a background reaction (entry 1), but,
DABCO, quinuclidine and DMAP (entries 2–4) increased, to some
extent, the formation rate of 3a without giving any acetylpyra-
zoline 4a. By means of the more basic DBU base (entry 5),
traces of 4a were formed. Therefore, we turned our attention to
stronger guanidine bases.16 Although TMG and MTBD (entries
6–7) mainly furnished 3a, pleasingly, TBD (entry 8) achieved an
86% yield of pyrazoline 4a. Increasing the catalyst loading from
10 to 20% secured a complete transformation into 4a in 93%
yield (entry 9). Importantly, this reaction is smoothly performed
without using any large excess of reactants and all partners are
cheap and commercially available. The catalytic activity of TBD
vs MTBD or TMG is remarkable and may be ascribed to both its
high pKa and its Brønsted acid–base properties (vide infra).17
Further optimisation revealed that the reaction was slightly
faster in acetonitrile but decreasing the temperature to 40 ◦C
slowed down the process (see ESI†). Therefore, we evaluated
various EWG-substituted hydrazines 1a–1h with 10% of TBD in
acetonitrile at 60 ◦C (Table 2)‡. Thus, the formation of pyrazolines
aINSA et Universite´ de Rouen, UMR CNRS COBRA, rue Tesnie`re,
BP 08, 76131, Mont-Saint-Aignan, France. E-mail: jean-francois.briere@
insa-rouen.fr
bCNRS, IRCOF (Research Institute in Fine Organic Chemistry), UMR
COBRA, rue Tesnie`re, BP 08, 76131, Mont-Saint-Aignan, France
cLCMT (Laboratoire de Chimie Mole´culaire et Thio-organique), UMR
CNRS 6507, ENSICaen-Universite´ de Caen, 14050, Caen, France
† Electronic supplementary information (ESI) available: Experimental
procedures, mechanistic investigation details and analytical data for all
newly formed products, as well as details for the ReactIR study. See DOI:
10.1039/b911577c
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Table 3 Addition of acetylhydrazine 1a to various chalcones 2a
Table 1 Addition of acetylhydrazine 1a to chalcone 2a (EWG1 = Ac;
Ar = Ph)a
Entry
Chalcones 2
Ar3
Ar5
Pyrazolines 4b
Amine base
(0.1 equiv.)
Aza-Michael
Pyrazoline
Entry
3a (%)b
4a (%)b
1
2
3
4
5
6
7
8
9
2i
4-MeOC6H4
2-MeOC6H4
4-FC6H4
2-Thienyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
81% (4i)
78% (4j)
84% (4k)
69% (4l)
68% (4m)
81% (4n)
77% (4o)
<20% (4p)c,d
83% (4q)
2j
1
2
3
4
5
6
7
8
9
—
41
72
69
68
68
75
54
9
0
0
0
0
5
2k
2l
2m
2n
2o
2p
2q
DABCO
DMAP
Quinuclidine
DBU
4-ClC6H4
4-MeOC6H4
2-Thienyl
4-NO2C6H4
2-MeC6H4
TMGc
MTBDd
TBDe
3
11
86
93
a 1 mmol of chalcone 2 (1 M) with acetylhydrazine 1a (1.2 equiv.), TBD
(0.1 equiv.) in anhydrous acetonitrile at 60 ◦C for 24 h. b Isolated yield
after column chromatography. c 48 h with 0.2 equiv of TBD. d 10% of
aza-Michael product 3p was isolated.
TBDf
0
a All reactions were performed with 0.25 mmol of chalcone 2a (0.5 M)
with acetylhydrazine 1a (1.1 equiv.), amine base (0.1 equiv.) in anhy-
drous toluene at 60 ◦C for 17 h. b NMR yield with an internal stan-
dard. c N,N,N¢,N¢-tetramethylguanidine. d 7-methyl-1,5,7-triazabicyclo-
[4.4.0]dec-5-ene. e 1,5,7-triazabicyclo[4.4.0]dec-5-ene. f 0.2 equiv. of TBD
for 23 h.
Table 2 Addition of hydrazines 1 to chalcone 2a (Ar = Ph)a
Entry
EWG1 (1.2 equiv.)
Pyrazolines 4 (%)b
Scheme 2 Mechanistic investigations.
1
2
3
4
5
6
7
8
COMe (1a)
COPh (1b)
82 (4a)
80 (4b)
88 (4c)
79 (4d)
66 (4e)c,d
97 (4f)
81 (4g)
20 (4h)e
COOt-Bu (1c)
CO-2-furyl (1d)
CO-4-Pyr (1e)
CONHPh (1f)
CSNH2 (1g)
Ts (1h)
led to traces of pyrazoline 4a, ruling out the condensation of
hydrazine 1a to chalcone 2a before cyclisation.19 However, the
aza-Michael derivative 3a was quantitatively transformed into
4a. In fact, a cross-over experiment conducted in the presence
of 1-(4-fluorophenyl)-3-phenylprop-2-en-1-one 2k led to 33% of
fluoropyrazoline 4k besides pyrazoline 4a, which suggested an
equilibrated process between 3a and starting materials 1a and 2a
(see ESI† for further details).
This led us to perform an in situ infrared spectroscopy study
(ReactIR technology) in order to follow up the formation of
both 3a and 4a versus time in the presence of 20% of TBD
in acetonitrile at 60 ◦C (full details in the ESI†). As depicted
a 1 mmol of chalcone 2a (1 M) with hydrazine derivative 1 (1.2 equiv.),
TBD (0.1 equiv.) in anhydrous acetonitrile at 60 ◦C for 24 h. b Isolated yield
after column chromatography. c 0.2 equiv. of TBD was used. d Conversion
of 75% after 24 h with 0.1 equiv. of TBD. e NMR yield with an internal
standard.
having acetyl (entry 1), benzoyl (entry 2), acid sensitive Boc
(entry 3) and carboxy-2-furyl (entry 4) functional groups on the
nitrogen was achieved with 79 to 88% yields. The reaction of
4-pyridinecarboxylic acid hydrazide turned out to be more slug-
gish and required 20% of TBD to reach a complete transformation
in 24 hours (entry 5). Semicarbazide and thiosemicarbazide
(entries 6–7) smoothly added to chalcone with 97 and 81%
yields respectively. Despite the large scope of the methodology,
tosylhydrazine (entry 8) gave 4h in low yield along with an
inseparable mixture of products. It is assumed that an elimination
of sulfinate took place, affording diimide (gas evolution was
observed) followed by some reduction events.18
in Fig. 1, the rapid disappearance of chalcone 2a was easily
-1
=
monitored with the n(C C) vibrations at 1609 cm . Although the
absorption at 1683 cm-1 corresponds to the overlapping of both
acetylhydrazine 1a and aza-Michael 3a vibrations, the increase
Subsequently, we performed the addition of acetylhydrazine
1a to various chalcone derivatives 2 (Table 3). These conditions
were tolerant to para- (entries 1, 3 and 5–6), ortho-substituted aryl
(entries 2 and 9) and heteroaromatic groups (entries 4 and 7) at
pyrazoline C3 and C5. On the other hand, the reaction was less
fruitful with electron-poor aryl groups at C5 and the limit was
observed with a para-nitroaryl moiety (entry 8). In this case, the
reaction was not clean and the pyrazoline 4p turned out to be
unstable on silica gel.
Fig. 1 (Only spectra from 1750 to 1580 cm-1 over the first 18 minutes
are shown for clarity). 1683 cm-1: aza-Michael 3a and acetylhydrazine 1a.
(*) A sample analyzed by NMR after 3 min giving 2a/3a/4a = 51/40/9.
1667 cm-1: chalcone 2a and pyrazoline 4a. 1609 cm-1: chalcone 2a.
In order to get an insight into the mechanism of this trans-
formation, we performed two test reactions (Scheme 2). In
the presence of TBD, the known unsaturated hydrazone11
5
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in intensity during the first minutes might account for the rapid
electron-withdrawing functional group on the N1 nitrogen. This
study highlights the ability of the TBD guanidine to promote
the regioselective alkylation of the secondary amine moiety of
hydrazines 1, while the other amine bases tested promote an
aza-Michael reaction (via the primary amine addition). This
straightforward metal-free methodology would be useful for the
rapid synthesis of pyrazolines in medicinal chemistry.
transformation of 1a to 3a, which parallels the chalcone peak
1
shrinking at 1609 cm-1. Indeed, a sample was analysed by H
NMR after 3 minutes (roughly the intensity maximum) revealing
the presence of 2a/3a/4a in a ratio of 51/40/9 respectively (see
the ESI† for further experiments). One can notice that both
-1
=
n(C O) of 4a and 2a are concomitantly detected at 1667 cm .
This vibration profile versus time shows a decrease in intensity at
the beginning, corresponding to the consumption of 2a, followed
by an increasing intensity owing to the formation of 4a. The
complementary shapes of the vibration waves at 1683 cm-1 (1a+3a)
and 1667 cm-1 (2a+4a) suggest that pyrazoline 4a originates from
a pre-equilibrated mixture of 3a, 2a and 1a derivatives.
Acknowledgements
We gratefully acknowledge financial support from the “Ministe`re
de la Recherche”, CNRS (Centre National de la Recherche
Scientifique), the “Re´gion Haute-Normandie” and the CRUNCH
network (Centre de Recherche Universitaire Normand de Chimie).
Accordingly, we propose the following mechanism (Scheme 3).
The aza-Michael adduct 3a is rapidly formed as the kinetic product
in equilibrium with the starting materials 1a and 2a via 6.20
Meanwhile, upon the selective N1–H bond activation by TBD, the
conjugate addition of the secondary amine moiety of 1a occurs,
giving rise to the formation of 7 which subsequently cyclises into
pyrazoline 4a. The superior efficiency of the guanidine TBD at
promoting the overall process may be attributed to its higher
pKa in comparison with the other bases.21 However, it is difficult
to find clear-cut information as to whether TBD catalyses the
reaction by deprotonating the N1–H of hydrazine 1a or simply
by assisting the aza-Michael step through transient N–H bond
coordination.22 Furthermore, the difference between the TBD and
MTBD reactivity underlines a likely bifunctional catalysis.17 One
might envisage that TBD acts as a proton shuttle by facilitating the
transport of a hydrogen atom (Scheme 3) in the carbon–nitrogen
bond formation (2a to 7 and 8) up to the dehydrating event. This
last irreversible step secures the end of the process. On the other
hand, the action of TBD in the retro-aza-Michael step (3a to 6
and 2a) cannot be ruled out. Moreover, the a-effect of hydrazine
might also help to promote the aza-Michael reaction.23 Further
investigations are required to probe all the mechanistic aspects
but the use of chiral guanidines could be envisaged for developing
an original asymmetric organocatalysed synthesis of pyrazoline
derivatives.
Notes and references
‡ Representative procedure for the synthesis of 1-acetyl-3,5-diphenyl-
4,5-dihydro-1H-pyrazole 4a. Chalcone (214.5 mg, 1.0 mmol, 1 equiv.),
acetylhydrazine (98.8 mg, 1.2 mmol, 1.2 equiv.) and triazabicyclo[4.4.0]dec-
5-ene (TBD, 13.9 mg, 0.1 mmol, 0.1 equiv.) were introduced into a Schlenk
tube under nitrogen. Then, 1 mL of anhydrous acetonitrile was added
at room temperature and the solution was heated at 60 ◦C (oil bath
temperature) for 24 h. The reaction mixture was allowed to stand at room
temperature and concentrated in vacuo. The residue was purified by flash
column chromatography (AcOEt/petroleum ether 2:3, Rf = 0.33) to afford
the desired pyrazoline 4a as a white powder (216.4 mg, 82%). m.p. 124–
126 ◦C (lit.,24 125–125.5 ◦C). 1H NMR (CDCl3, 300 MHz) d 2.44 (s, 3H),
3.14–3.22 (dd, J = 4.5 Hz and 17.7 Hz, 1H), 3.72–3.82 (dd, J = 11.8 Hz
and 17.7 Hz, 1H), 5.58–5.63 (dd, J = 4.5 Hz and 11.8 Hz, 1H), 7.23–
7.36 (m, 5H), 7.42–7.46 (m, 3H), 7.74–7.77 (m, 2H). 13C NMR (CDCl3,
63 MHz) d 22.1 (CH3), 42.4 (CH), 60.0 (CH2), 125.6 (CH), 126.6 (CH),
127.67 (CH), 128.8 (CH), 128.9 (CH), 130.4 (CH), 131.5 (C), 141.9 (C),
153.9 (C), 168.9 (C). IR (KBr) n (cm-1) 1656, 1645, 1596, 1455, 1443, 1410,
1360, 1327, 762, 691. HRMS m/z calcd for C17H17N2O1 [M+H]+: 265.1341,
found: 265.1349. Remark: the obtained solids tend to retain solvents such
as AcOEt or CH2Cl2, so they have to be dried for long period of time under
vacuum.
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Scheme 3 Mechanistic proposal.
In summary, it was found that TBD base efficiently catalyses
the cyclocondensation of N-acylhydrazine derivatives 1 with
chalcones to yield various 3,5-diarylpyrazolines 4 possessing an
3650 | Org. Biomol. Chem., 2009, 7, 3648–3651
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