Organocatalytic enantioselective synthesis of pyrazolidines, pyrazolines and pyrazolidinones

Article abstract of DOI:10.1002/adsc.201100722

Enantiopure pyrazolidines, pyrazolines and pyrazolidinones have been accessed in a direct and efficient manner through an organocatalytic, enantioselective aza-Michael/hemiaminal formation cascade process from enals and N,N′-disubstituted hydrazides. The process takes place with high regio- and stereoselectivities and furnishes the target compounds in high overall yields by means of an operationally very simple methodology. Copyright

Full text of DOI:10.1002/adsc.201100722

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DOI: 10.1002/adsc.201100722
Organocatalytic Enantioselective Synthesis of Pyrazolidines,
Pyrazolines and Pyrazolidinones
Maitane Fernꢀndez,a Efraꢁm Reyes,a Jose L. Vicario,a,* Dolores Badꢁa,a
and Luisa Carrilloa
a
Departamento de Quꢁmica Orgꢀnica II, Facultad de Ciencia y Tecnologꢁa, Universidad del Paꢁs Vasco/Euskal Herriko
Unibertsitatea, P.O. Box 644, 48080 Bilbao, Spain
Fax : (+34)-94-6012748; phone: (+34)-94-601-5454; e-mail: joseluis.vicario@ehu.es
Received: September 16, 2011; Published online: January 19, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100722.
Abstract: Enantiopure pyrazolidines, pyrazolines
and pyrazolidinones have been accessed in a direct
and efficient manner through an organocatalytic,
enantioselective aza-Michael/hemiaminal formation
cascade process from enals and N,N’-disubstituted
hydrazides. The process takes place with high regio-
and stereoselectivities and furnishes the target com-
pounds in high overall yields by means of an opera-
tionally very simple methodology.
In this context, organocatalysis has emerged as a
useful alternative tool for the development of enan-
tioselective versions of certain transformations which
do not proceed efficiently with metal catalysis. The
enantioselective synthesis of pyrazolines is a represen-
tative example of the complementary natures of these
two different methodological approaches, with a
couple of reports describing the access to these het-
erocycles under metal-free conditions. On the one
hand, List and co-workers developed an enantioselec-
tive version of the Fischer reaction that proceeds
through a 6p-electrocyclization mechanism in the
presence of a chiral Brønsted acid catalyst, generating
5-substituted 3-methylpyrazolines by reacting methyl
alkenyl ketones with primary hydrazines.[9] Excellent
results were obtained for b-aryl-substituted enones,
Keywords: asymmetric catalysis; domino reaction;
heterocycles; hydrazines; organocatalysis
Pyrazolidines are privileged heterocyclic structures in but the use of b-alkyl-substituted substrates led to an
medicinal chemistry, principally due to their presence, important reduction of both yield and enantioselectiv-
as important subunits, in many natural and synthetic ity. Alternatively, cyclocondensation of enones with
bioactive compounds.[1,2] Pyrazolidines can be easily primary monosubstituted hydrazides has been report-
oxidized to afford pyrazolines, which are also motifs ed by Briꢂre and co-workers using chiral phase-trans-
of high relevance because of their presence in a wide fer catalysis.[10] Although very efficient and straight-
range of biologically active molecules.[3] However, de- forward, this later methodology was limited to the use
spite their interest and potential as promising candi- of chalcones. It should also be highlighted that these
dates in drug discovery programs, the number of two approaches rely on the use of enones as starting
available synthetic procedures for the stereoselective materials, thus generating pyrazolines containing an
preparation of pyrazolidines and/or pyrazolines is still aryl or a methyl substituent at the 3-position. How-
very limited. Most of the methodologies reported rely
ACHTUNGTRENeNUNG ver, the use of a,b-unsaturated aldehydes in this
on the use of chiral Lewis acids, involving typically transformation which would lead to enantioenriched
[3+2]cycloaddition chemistry using dipoles such as pyrazolines without any substitution at this 3-position
diazoalkanes,[4] nitrile imines[5] or hydrazones,[6] or by still remains elusive.
means of metal-catalyzed amination of allenes.[7] Al-
With these precedents in mind, we envisaged that
ternatively, one report addressed the access to these pyrazolidin-3-ols could be accessible by the reaction
heterocycles in a stereocontrolled manner by cyclo- between a,b-unsaturated aldehydes and N,N’-disubsti-
condensation of chalcones with a primary hydrazine, tuted hydrazines, by means of a cascade process con-
also in the presence of chiral transition metal com- sisting of an aza-Michael/hemiaminal formation se-
plexes as catalysts, although only moderate levels of quence (Scheme 1). Moreover, this proposal presents
enantioselectivity were obtained.[8]
a possibility for the development of an enantioselec-
Adv. Synth. Catal. 2012, 354, 371 – 376
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
371

Maitane Fernꢀndez et al.
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Scheme 1. Direct organocatalytic enantioselective pyrazolidine synthesis through iminium activation.
tive version of the transformation, using organocataly- enantioselectivity was improved when the bulkier cat-
sis as the methodological approach, via iminium acti- alysts 3c and 3d were employed, although the yield
vation.
was diminished (entries 3 and 4). Imidazolidinone 3e
These pyrazolidin-3-ols have the potential to be fur- developed by MacMillan was also tested, providing 4a
ther elaborated in order to obtain an array of chemi- in good yield but low enantioselectivity (entry 5).
cally related heterocyclic structures of interest, such Next, the effect of the solvent was studied in conjunc-
as 3-unsubstituted pyrazolines. What is more, simple tion with optimal catalyst 3c (entries 6–9), but it was
transformations of these adducts can also provide a observed that the use of more polar solvents resulted
direct access to chiral pyrazolidin-3-ones and 1,3-di- in a less efficient reaction. In an attempt to improve
ACHTUNGTRENNUNG
We thought that the design of the proposed reac- thought to activate the hydrazide by forming the cor-
tion could show some selectivity issues due to the sim- responding anion. However, no reaction was observed
ilar nucleophilic characters of both the catalyst and when employing DABCO (entry 9) and, although
the hydrazine. The idea of using monosubstituted hy- DBU gave an improved yield of the pyrazolidin-3-ol,
drazines was discarded from the beginning, since enantiocontrol was lost (entry 10).
these would probably undergo either a condensation
Using the conditions shown in entry 3 of Table 1,
with the enal furnishing a highly stable hydrazone we decided to investigate the influence that the sub-
side product or, alternatively, they could undergo un- stitution pattern of the hydrazide reagent would have
catalyzed cyclocondensation reactions, affording race- on the reaction. In this context, a family of different
mic pyrazoline adducts. In order to avoid these per- N,N’-disubstituted hydrazides was tested in the reac-
ceived condensation issues, N,N’-disubstituted hydra- tion (Table 2). Initially, no reaction was observed
zines were selected for the transformation, although when the less acidic hydrazide 2b was used (entry 2),
issues regarding selectivity towards 1,4-addition vs. and low yields of the pyrazolidinol adduct were ob-
undesired 1,2-addition to the enal have still to be con- served when phthalohydrazide 2c was employed
sidered. Moreover, for the cases in which the two sub- (entry 3). The need for two strongly electron-with-
stituents of the hydrazine are different, an additional drawing substituents like the tosyl group was con-
regioselectivity issue appears. In addition, it is known firmed when hydrazides 2d and 2e were tested, for
that aza-Michael transformations are reversible in which no reaction was observed (entries 4 and 5). In
nature, which in turn results in the conjugate addition contrast, the reaction between the enal 1a and the un-
products very often being configurationally unstable. symmetrically substituted N-Boc-N’-(p-nitrobenzene-
However, this reversibility problem was thought to be sulfonyl) hydrazide 2f proceeded smoothly, providing
irrelevant to our case, since the subsequent intramo- the desired pyrazolidin-3-ol 4f in excellent yield,
lecular hemiaminal formation step would presumably enantioselectivity and remarkably as a single regioiso-
make the overall process irreversible.
mer (entry 6). The high reactivity and complete regio-
In an initial approach and in order to avoid the selectivity observed may be understood in terms of
À
aforementioned regioselectivity problem related to the higher acidity of the N H group attached to the
the use of hydrazines with two different substituents, nosyl (Ns) substituent, which presumably makes this
N,N’-bis(p-toluenesulfonyl)hydrazide (2a) was select- nitrogen group more nucleophilic for the initial aza-
ed as model substrate, also considering that the high Michael process.
À
acidity of the N H protons would favourably assist
We next proceeded to extend the reaction to the
the first conjugate addition step (Table 1). The viabili- use of a,b-unsaturated aldehydes with different sub-
ty of the reaction was initially tested for different cat- stitution patterns in order to survey the scope of the
alysts using toluene as solvent and working at room reaction and its performance for the preparation of
temperature. In this context, diphenylprolinol deriva- differently substituted pyrazolidin-3-ols (Table 3).
tives 3a and 3b delivered the desired product 4a in
From the results summarized in Table 3 we ob-
high isolated yield and diastereoselectivity, although served that hydrazide 2f reacted efficiently with a,b-
with low enantiocontrol (entries 1 and 2). In contrast, unsaturated aldehydes containing linear alkyl chains
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Organocatalytic Enantioselective Synthesis of Pyrazolidines, Pyrazolines and Pyrazolidinones
Table 1. Screening for the best reaction conditions.[a]
Entry
Solvent
3
Additive[b]
Yield of 4a [%][c]
dr[d]
ee [%][e]
1
2
3
4
5
6
7
8
9
10
toluene
toluene
toluene
toluene
toluene
CH2Cl2
CH3CN
EtOH
3a
3b
3c
3d
3e
3c
3c
3c
3c
3c
PhCO2H
PhCO2H
PhCO2H
PhCO2H
TFA
PhCO2H
PhCO2H
PhCO2H
DABCO
DBU
83
80
54
30
67
24
38
32
<10
61
>10:1
>10:1
>10:1
>10:1
10:1
>10:1
>10:1
>10:1
n.d.[f]
20
11
97
92
45
38
36
39
n.d.[f]
0
toluene
toluene
>10:1
[a]
Reactions performed on a 0.2-mmol scale of 1a and 2a using 10 mol% of catalyst 3 in 2.0 mL of the corresponding sol-
vent.
10 mol% used.
Isolated yield.
[b]
[c]
[d]
[e]
[f]
1
Determined by H NMR analysis of the crude reaction mixture.
Determined by HPLC on a chiral stationary phase.
n.d.: not determined.
Table 2. Effect of hydrazide substitution.[a]
Entry
2
R1
R2
4
Yield [%][b]
dr[c]
ee [%][e]
1
2
2a
2b
Ts
Boc
Ts
Boc
4a
4b
54
<5%
>10:1
–
97
–
3
2c
4c
23
n.d.[f]
n.d.[f]
4
5
6
2d
2e
2f
p-MeO-C6H4
p-NO2-C6H4
Boc
Ts
Ts
Ns
4d
4e
4f
<5%
<5%
87
–
–
–
–
93
>10:1
[a]
Reactions performed on a 0.2-mmol scale of 1a and 2.
[b]
[c]
[e]
[f]
Isolated yield.
1
Determined by H NMR analysis of the crude reaction mixture.
Determined by HPLC on a chiral stationary phase.
n.d.: not determined.
Adv. Synth. Catal. 2012, 354, 371 – 376
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373

Maitane Fernꢀndez et al.
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Table 3. Scope of the reaction.[a]
Entry
1 (R)
4
Yield [%][b]
dr[c]
ee [%][d]
1
1a (Et)
1b (Me)
1c (n-Pr)
1d (n-Bu)
1e (n-C5H11)
1f (n-C6H13)
1g (n-C7H15)
1h (n-C8H17)
1i (Z-EtCH=CHCH2CH2-)
1j (i-Pr)
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4a
4r
87
93
99
91
95
78
78
99
68
50
65
95
54
21
>10:1
>10:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
20:1
93
85
92
94
93
93
92
94
90
97
89
>99
97
96
2[e]
3
4
5
6
7
8
9
10
11
12
13[f]
14[f]
1k (CO2Et)
1l (CH
1a (Et)
1d (n-Bu)
A
>20:1
>10:1
>20:1
[a]
Reactions performed on a 0.2-mmol scale of 1 and 2f using 10 mol% of catalyst 3c in 2.0 mL of toluene.
[b]
[c]
[d]
[e]
[f]
Isolated yield.
1
Determined by H NMR spectroscopy of the reaction mixture.
Determined by HPLC on a chiral stationary phase.
Reaction carried out at 48C.
Hydrazide 2a was used.
of different length and size, whilst maintaining both though these types of heterocycles have been found
high yield and high levels of stereoselectivity (en- to be rather configurationally unstable.[13] Additional-
tries 1–8).[11] Furthermore, branched and unsaturated ly, pyrazolidin-3-ones 6 were also obtained in excel-
b-alkyl substituents were tested with success in the re- lent yields and as highly enantiopure materials by oxi-
action (entries 9 and 10). Functionalized a,b-unsatu- dation of pyrazolidin-3-ols.
rated aldehydes, such as 1k or 1l also performed well,
Another potential synthetic application of this type
furnishing the final adducts in high yield and stereo- of heterocycle relies on the possibility to cleave the
À
control (entries 11 and 12). Again, all these cases N N bond, giving access to highly important enan-
showed the formation of a single regioisomer, regard- tioenriched 1,3-diamines.[6,14] In particular, enantio-
less the substitution pattern at the enal reagent. It is pure 1,3-diamine 7h could be obtained after treating
interesting to note that when hydrazide 2a was em- pyrazolidin-3-ol 4h with H2 in the presence of Raney-
ployed, a very significant dependence of the yield on Ni, which occurred concomitant with the reduction of
the length of the b-alkyl substituent was observed, ob- the nitro group present at the nosyl substituent
taining very poor yields when longer substituents (Scheme 2).
were incorporated, although enantioselectivity re-
In conclusion, we have developed the first asym-
mained high (entries 13 and 14). The absolute config- metric aminocatalytic direct synthesis of pyrazolidines
uration of products 4 was assigned by analogy after a based on the aza-Michael/hemiaminalization reaction
single-crystal X-ray analysis of a pyrazolidine product of a,b-unsaturated aldehydes and hydrazides under
obtained from the reduction of the pyrazolidin-3-ol 4a iminium activation. The reaction was catalyzed by the
(see the Supporting Information).[12]
Having established a robust route to the pyrazoli-
dine motif, we proceeded to run a series of simple
transformations in order to synthesize other pyrazoli-
dine-related heterocyclic structures of interest
(Table 4). Treating compounds 4 with TFA led to se-
quential deprotection/dehydration, obtaining a series
of pyrazolines 5 in excellent yields whilst maintaining
Scheme 2. Synthesis of 1,3-diamine 7h from pyrazolin-3-ol
the stereochemical integrity of the stereocenter, al- 4h.
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Organocatalytic Enantioselective Synthesis of Pyrazolidines, Pyrazolines and Pyrazolidinones
Table 4. Synthesis of pyrazolines 5 and pyrazolidinones 6.
Entry
4 (R)
Yield of 5 [%][a]
ee of 5 [%][b]
Yield of 6 [%][a]
ee of 6 [%][b]
1
4f (Et)
4g (Me)
4h (n-Pr)
4i (n-Bu)
4j (n-C5H11)
4k (n-C6H13)
4l (n-C7H15)
4m (n-C8H17)
97
85
99
99
87
86
99
99
92
85
92
91
91
90
92
90
95
94
97
90
97
93
96
94
93
84
92
90
91
91
91
90
2[c]
3
4
5
6
7
8
[a]
Isolated yield.
[b]
[c]
Determined by HPLC on a chiral stationary phase (see Supporting Information).
Reaction carried out at 48C.
Analytical grade solvents and commercially available re-
agents were used without further purification. For flash
chromatography (FC) silica gel (Silica gel 60, 230–400 mesh,
Merck) was employed.
commercially available diarylprolinol silyl ether 3c
and took place in very high yields and excellent ste-
reoselectivities, allowing the synthesis of a wide array
of nitrogen-containing heterocycles of relevance in
medicinal chemistry. Furthermore, a series of simple
transformations of adducts has been presented, which
easily allows the formation of some pyrazolidine de-
rivatives, increasing the utility of the presented meth-
odology.
General Procedure for the Preparation of
Pyrazolidinols 4
An ordinary vial equipped with a magnetic stirring bar was
charged with catalyst 3c (0.02 mmol, 10 mol%), PhCOOH
(0.05 mmol, 25 mol%) and toluene (2 mL). Then, hydrazine
2
(0.20 mmol) and the a,b-unsatured aldehyde
1
(0.20 mmol) were added. The stirring was maintained at
room temperature until the reaction was complete (24–72 h)
and the crude reaction mixture was concentrated and direct-
ly charged onto silica gel and subjected to FC. The racemic
standards for HPLC separation conditions were prepared
using d,l-proline (0.02 mmol, 10 mol%) instead of catalyst
3c, without PhCOOH and in CH2Cl2 (2 mL) at room tem-
perature.
Experimental Section
General Methods and Materials
NMR spectra were acquired on a Bruker 300 spectrometer,
running at 300 and 75 MHz for 1H and 13C, respectively.
Chemical shifts (d) are reported in ppm relative to residual
solvent signals (CHCl3, d=7.26 ppm for 1H NMR, CDCl3,
d=77.0 ppm for 13C NMR). IR spectra were measured in a
Perkin–Elmer 1600 and a Perkin–Elmer Spectrum BX appa-
ratus. Mass spectra (MS) were recorded on an Agilent
7890 A gas chromatograph coupled to an Agilent 5975 mass
spectrometer. High-resolution mass spectra (HR-MS) were
recorded on a micromass GCT spectrometer using chemical
ionization (CI) or Acquity UPLC coupled to a QTOF mass
spectrometer (SYNAPT G2 HDMS) using the electrospray
(ESI) technique. Analytical thin layer chromatography
(TLC) was performed using precoated aluminium-backed
plates (Merck Kieselgel 60 F254) and visualized by ultravio-
let irradiation or p-anisaldehyde dip. Melting points were
measured in a Bꢄchi B-540 apparatus and are uncorrected.
Optical rotations were measured on Perkin–Elmer 241 and
Jasco P-2000 polarimeters. The enantiomeric excess (ee) of
the products was determined by chiral stationary phase
HPLC in a Waters 2695 with a Waters 2998 photodiode
array detector (Daicel Chiralpak IA, IC, AS-H and AD-H
columns).
General Procedure for the Deprotection of
Pyrazolidinols 4: Synthesis of Pyrazolines 5
A vial equipped with a magnetic stirring bar was charged
with the pyrazolidinol 4 (0.2 mmol) in 2 mL of CH2Cl2.
Then TFA (2 mmol) was added. The reaction mixture was
stirred at rrom temperature until completion of the reaction
(5 h). The reaction mixture was washed with water, dried
over Na2SO4 and concentrated under vacuum. The crude
was charged onto silica gel and subjected to FC.
General Procedure for the Oxidation of
Pyrazolidinols 4: Synthesis of Pyrazolidin-3-ones 6
A vial equipped with a magnetic stirring bar was charged
with the pyrazolidinol 4 (0.18 mmol) in CH2Cl2 (5 mL).
Then PCC (0.91 mmol) and molecular sieves (4 ꢅ) were
added. The reaction mixture was stirred at room tempera-
ture until completion (16 h) and the crude mixture was con-
Adv. Synth. Catal. 2012, 354, 371 – 376
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375

Maitane Fernꢀndez et al.
COMMUNICATIONS
centrated and directly charged onto silica gel and subjected
to FC.
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General methods and materials, experimental procedures,
characterization data, and determination of the absolute
configuration as well as copies of the NMR spectra and
HPLC traces are available in the Supporting Information.
[5] a) M. P. Sibi, L. M. Stanley, C. P. Jasperse, J. Am.
Chem. Soc. 2005, 127, 8276; b) M. P. Sibi, L. M. Stand-
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[6] a) S. Shirakawa, P. J. Lombardi, J. L. Leighton, J. Am.
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Acknowledgements
This work was supported by the University of the Basque
Country UPV/EHU (fellowship to E.R.), the Spanish
MICINN (CTQ2008-00136/BQU), and the Basque Govern-
ment (fellowship to M.F.) and subvenciꢀn a Grupos IT-328-
10.
[7] a) S. Ma, N. Jiao, Z. Zheng, Z. Ma, Z. Lu, L. Ye, Y.
Deng, G. Chen, Org. Lett. 2004, 6, 2193; b) W. Shu, G.
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2010, 49, 598.
[8] a) H. Yanagita, S. Kanemasa, Heterocycles 2007, 71,
699. For an example of a catalytic asymmetric aza-Mi-
chael/lactamization reaction of hydrazines with a,b-un-
saturated imides to afford pyrazolidinones, see: M. P.
Sibi, T. Soeta, J. Am. Chem. Soc. 2007, 129, 4522.
[9] S. Mꢄller, B. List, Angew. Chem. 2009, 121, 10160;
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[10] O. Mahꢆ, I. Dez, V. Levacher, J.-F. Briꢂre, Angew.
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[11] b-Aryl-substituted enals reacted very slowly, providing
in all cases yields below 15% yield.
[12] CCDC 844059 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[13] Compounds 5 and 6 were found to slowly racemize
upon standing at room temperature as CHCl3 solutions.
[14] a) J. J. Van Veldhuizen, D. G. Gillingham, S. B. Garber,
O. Kataoka, A. H. Hoveyda, J. Am. Chem. Soc. 2003,
125, 12502.
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Adv. Synth. Catal. 2012, 354, 371 – 376