One-Pot Catalytic Enantioselective Synthesis of 2-Pyrazolines

Article abstract of DOI:10.1002/anie.201811471

A scalable, one-pot, enantioselective catalytic synthesis of 2-pyrazolines from beta-substituted enones and hydrazines is described. Pivoting on a two-stage catalytic Michael addition/condensation strategy, the use of an aldehyde to generate a suitable hydrazone derivative of the hydrazine was found to be key for curtailing background reactivity and tuning the catalyst-controlled enantioselectivity. The new synthetic method is easy to perform, uses a new and readily prepared cinchona-derived bifunctional catalyst, is broad in scope, and tolerates a range of functionalities with high enantioselectivity (up to >99:1 e.r.). The significant scalability of this methodology was demonstrated with the synthesis of more than 80 grams of a pyrazoline product with 89 % catalyst recovery.

Full text of DOI:10.1002/anie.201811471

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Accepted Article
Title: One-Pot Catalytic Enantioselective Synthesis of 2-Pyrazolines
Authors: Connor Jack Thomson, David M Barber, and Darren James
Dixon
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One-Pot Catalytic Enantioselective Synthesis of 2-Pyrazolines
Connor J. Thomson[a], David M. Barber[b] and Darren J. Dixon[*][a]
Abstract: A scalable, one-pot, enantioselective catalytic synthesis of
2-pyrazolines from beta-substituted enones and hydrazines is
described. Pivoting on a two stage catalytic Michael addition /
condensation strategy, the use of an aldehyde to generate a suitable
hydrazone derivative of the hydrazine was found to be key for
curtailing background reactivity and tuning the catalyst-controlled
enantioselectivity. The new synthetic protocol is easy to perform,
uses a new and readily prepared cinchona-derived bifunctional
catalyst, is broad in scope, and tolerates a range of functionalities
with high enantioselectivity (up to >99:1 er). The significant
scalability of this methodology has been demonstrated with the
synthesis of >80 grams of a pyrazoline product with 89% catalyst
recovery.
Heterocycles containing an N-N bond are abundant in natural
products, synthetic therapeutics, and agrochemicals.[1] In
particular, optically active pyrazolines and their derivatives are in
high demand for their intrinsic biological properties.[2] 2-
Pyrazolines specifically find widespread use in small-molecule
drugs, agrochemicals, and have been noted for their valuable
properties in material science (Scheme 1).[3] Furthermore, the
use of 2-pyrazolines as valuable intermediates in the synthesis
of cyclopropanes and pyrazoles is well-documented.[4]
Although there are many examples describing the
synthesis of 2-pyrazolines as racemates, methods for the
efficient preparation of enantiomerically enriched 2-pyrazolines
Scheme 1. (A) Bioactive pyrazolines and their uses; (B) Rationale for use of
protected hydrazines and previous work with carbazates; (C) Platform for aza-
Michael addition of the hydrazine sython enabled by a cleavable hydrazone.
remain limited.[5] In 2000, Kanai reported the first
enantioselective synthesis of 2-pyrazolines, using a Lewis acid
catalyzed 1,3-dipolar cycloaddition.[6] This was subsequently
with chalcone 2a was chosen as a model system and we
hypothesized that bifunctional Brønsted base/H-bond donor
catalysts could affect the desired enantioselective aza-Michael
followed by the acid catalyzed electrocyclization methodology of
List, and independent reports from Cordova and Carillo on the
synthesis of 2-pyrazolines via pyrazolidines.[7] Brière also
addition. [12] A screen of potential catalysts revealed the cinchona
disclosed the elegant phase-transfer catalyzed addition of
family to be effective, with quinidine (Figure 1, catalyst A)
offering promising selectivity; aza-Michael adduct 3a was
obtained in 71:29 er. Encouraged by the early success with
quinidine as catalyst, other cinchona-derived systems were
investigated (Table 1A, entries 1-6). Use of the O-benzyl catalyst
B resulted in a selectivity decrease, while bifunctional urea C
showed an enhancement to 80:20 er. Interestingly, the formation
of Michael adduct 4 was observed as a competitive side-product
carbazates to chalcones.[8] Deng later reported the use of
benzyl-protected carbazates in the enantioselective synthesis of
2-pyrazolines (Scheme 1B).[9]
Despite these elegant examples, we were attracted to the
challenge of developing a broadly applicable platform for the
metal-free, expeditious synthesis of enantioenriched 2-
pyrazolines. Whilst the use of hydrazine nucleophiles in the
synthesis of racemic pyrazolines is well-established, the high
in some cases.[13] Despite this, selectivity for 3a was improved
reactivity of these reagents has, to date, restricted the
with the use of catalyst D. Enantioselectivity was further
improved with amide E, suggesting the need for a single H-bond
donor for appropriate organization of the hydrazone-chalcone
transition state. A screen of various amide groups revealed 3,5-
dichlorobenzoylamide catalyst F to be optimal (see ESI).
Our attention then turned to the structure of the hydrazone
and its influence on the stereochemical outcome of the reaction.
The presence of a methyl group at the 2, 3, or 4 positions of the
arene ring of 1 all improved enantioselectivity (see Table 1A and
ESI for details). Pleasingly, 4-tert-butyl benzaldehyde was found
to give the most substantial enantioselectivity when compared
development of a corresponding enantioselective method.[10] As
a strategy to circumvent their high inherent nucleophilicity, we
envisaged the use of an aldehyde to generate a suitable
hydrazone derivative to impart tunability and dampen reactivity
of the hydrazine moiety (Scheme 1B).[11] Such an approach
could grant stereoselective access to enantioenriched 2-
pyrazolines after in-situ cleavage of the hydrazone and
subsequent intramolecular condensation (Scheme 1C). Herein
we wish to report our findings.
The reaction of methylhydrazine-derived hydrazone 1a
with benzaldehyde (entry 9, 90:10 er). Lowering the reaction
temperature to -15 oC and extending the reaction time to 48
hours further improved the er and conversion, to 95:5 er and
93%, respectively. Furthermore, quantitative in situ cleavage of
the chiral hydrazone intermediate (thereby releasing oxime 6b)
[a]
C. J. Thomson, Prof. Dr. D. J. Dixon, Department of Chemistry,
Chemistry Research Laboratory, University of Oxford, United
Kingdom, Mansfield Road, Oxford OX1 3TA
Dr. D. M. Barber, Research & Development, Weed Control
Chemistry Bayer AG, Crop Science Division, Industriepark Höchst,
Frankfurt am Main, 65926, Germany
[b]
[*]
darren.dixon@chem.ox.ac.uk
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COMMUNICATION
Entry
1
cat.
A
B
C
D
E
F
R (1)
H (1a)
3 (%)a
4 (%)a
0
3 erb
71:29
36:64
80:20
82:18
86:14
87:13
89:11
88:12
90:10
88:12
95:5
86 (3a)
74 (3a)
69 (3a)
50 (3a)
58 (3a)
56 (3a)
87 (3b)
65 (3c)
90 (3d)
68 (3d)
93 (3d)
trace
2
H (1a)
0
3
H (1a)
9
Figure 1. Selected catalysts investigated for the aza-Michael addition of 1a-d
to chalcone 2.
4
H (1a)
29
7
could be achieved using hydroxylamine, without compromising
the enantioselectivity (see Entry 4, Table 1B).
5
H (1a)
6
H (1a)
17
2
Combining these optimized transformations delivered a
7
F
4-CH3 (1b)
2-CH3 (1c)
4-tBu (1d)
4-tBu (1d)
4-tBu (1d)
H (1a)
streamlined
one-pot
route
to
2-pyrazolines
from
methylhydrazine, which was then ready for assessment of its
scope. When substituents on both aromatic rings of the
chalcone were varied, minimal fluctuation in enantioselectivity
was observed across a range of electron-rich and electron-poor
substrates (Scheme 2A). Potentially incompatible functionalities
such as cyano, vinyl and ester groups were all well-tolerated.
Difluorocyclopropane 5l and benzodioxole 5q are particularly
appealing, with potential applications in medicinal chemistry
programs.[14] Substrates derived from alkyl aldehydes were
compatible with this chemistry, giving excellent er’s of up to
>99:1 for hexyl pyrazoline 5w (82% yield). Ynenone 5z, enynone
5x and alkenyl enone 5y were successfully employed to afford
the corresponding alkynyl and alkenyl scaffolds in moderate to
excellent er. Notably, heterocycles were competent substrates;
furnishing the pyrazine, pyridine and thiophene structures 5r-5t.
Furthermore, variation of the hydrazine moiety afforded the N-
ethyl (5ab), N-cyanoethyl (5ac) and N-benzyl (5ad) 2-
pyrazolines in good yield and er at reaction rates similar to the
methyl hydrazine system, thus demonstrating wider applicability
of this chemistry.[15]
In order to explore the scalability of this methodology, we
performed a model reaction with enone 2b on 100 gram scale.
To ensure affordability and practicality upon scale-up, the
reaction was performed at room temperature, rather than -15 oC,
and benzaldehyde was employed as the hydrazone precursor
instead of tert-butyl benzaldehyde. Smooth reactivity and a
clean reaction profile allowed the isolation of 84.9 grams of
pyrazoline 5b in 77% yield and >99.9:0.1 er after a single
recrystallization. The mild protocol allowed 5b to be cleanly
isolated without the need for silica gel chromatography.
Importantly, 89% of catalyst F was recovered in addition to 97%
isolation of the benzaldehyde oxime by-product.[16] The
recovered catalyst was reused (on 0.5 mmol scale) with no loss
of reactivity or selectivity (see ESI).
8
F
11
0
9
F
10c
11d
12e
F
0
F
0
-
-
-
Entry
Reagent
5 (%)a (er)
4 (%)a,b
1
2
3
4
Amberlyst-15R®
aq. HCl (1.5 eq)
0 (N.D.)
0 (N.D.)
76 (N.D.)
0
0
aq. H2SO4 (0.5 eq)
30% NH2OH in MeOH
24
0
100 (90:10)
Table 1. (A) Optimization of the organocatalyzed aza-Michael addition; (B)
Optimization of conditions for hydrazone cleavage. adetermined by 1H NMR. b4
was always obtained as a racemic mixture. c10 mol% of catalyst F was
used.dperformed at -15 oC for 48 hours with 10 mol% catalyst F. eperformed
for 7 days. N.D: not determined.
functionalization (Scheme 3). Accordingly, 5b was treated with
ethyl acrylate under ruthenium catalysis to obtain the ortho-
alkenylated product 8 in 48% yield.
knowledge, this is the first example of pyrazoline-directed C-H
functionalization; this method could find use in library synthesis
for lead-optimization in medical chemistry/agrochemical
programs. Furthermore, treatment of 5b with zinc in acetic acid
[17]
To the best of our
With the aim of demonstrating the broader utility of our
platform, pyrazoline 5b was explored as a scaffold for late stage
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Scheme 2. (A) Scope of aza-Michael addition of in-situ generated 1d to enones 2a-2aa; (B) Large scale synthesis of 5b (see ESI for details). aperformed in
CH2Cl2. bperformed at -40 oC. cwith EtNHNH2.oxalate and 1.95 eq DIPEA. dwith BnNHNH2.2HCl and 3.8 eq DIPEA. Stereochemical configuration was assigned by
analogy with (R)-5b (determined by single crystal X-ray diffraction studies).
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Scheme 3. Derivatization of pyrazoline 5b.
furnished a 3:2 diastereomeric mixture of the enantioenriched
diamine 9 in 96% yield. Methods to access diamine structures
are limited and this example represents the first protocol to
obtain optically active 1,3-diamines from pyrazolines. Lastly,
Sonogashira coupling with the hormone drug mestranol readily
furnished enantiopure alkyne 10 in 88% yield.
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In summary, an efficient platform for the synthesis of
enantioenriched 2-pyrazoline scaffolds from beta-substituted
enones
and
monoalkyl-substituted
hydrazine-derived
hydrazones has been designed and developed. Deployment of a
novel cinchonidine-derived bifunctional catalyst in conjunction
with an optimized hydrazone derivative allowed good control of
reactivity and enantioselectivity in the initial Michael addition
step. A staged addition of hydroxylamine then facilitated 2-
pyrazoline formation after cleavage of the chiral hydrazone
intermediate. The new synthetic protocol was found to be
compatible with a range of functionalities including esters,
nitriles, heterocycles, alkenes and alkynes, and was amenable
to decagram scale synthesis. The scalability of this method,
coupled with a range of novel late-stage derivatizations has
highlighted the synthetic versatility of the reaction products, with
potential applications in biomedical and agrochemical contexts.
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[10] In our initial studies, a wide screen of organocatalysts failed to produce
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Acknowledgements
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DJD and CJT wish to thank Bayer AG for generous financial support and Dr.
Uwe Döller for helpful discussions. We are grateful to Dr. Jamie Leitch for help
in the preparation of this manuscript. Heyao Shi is also thanked for X-ray
structure determination of compound 5b, and Dr Amber L. Thompson and Dr
Kirsten E. Christensen (Oxford Chemical Crystallography) for X-ray mentoring.
Keywords: hydrazone, enantioselective catalysis, pyrazolines, aza-Michael
addition, bifunctional catalysis
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[2]
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Connor J. Thomson, David M. Barber
and Darren J. Dixon*
1 – 5
One-Pot Catalytic Enantioselective
Synthesis of 2-Pyrazolines
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