Organocatalytic Hantzsch Type Reaction Using Aryl Hydrazines, Propiolic Acid Esters and Enals: Enantioselective Synthesis of Paroxetine

Article abstract of DOI:10.1002/adsc.202000779

Aryl hydrazines, propiolic acid esters and enals serve as a viable substrate combination for an organocatalytic enantioselective Hantzsch type reaction. The method converts readily available starting materials into important chiral heterocycles with good to excellent yields and enantioselectivities, and has addressed the longstanding scope limitation of the classic Hantzsch reaction in the asymmetric synthesis of 2,6-unsubstituted hydropyridines. The synthetic utility has been demonstrated by the concise enantioselective synthesis of paroxetine. (Figure presented.).

Full text of DOI:10.1002/adsc.202000779

Title: Organocatalytic Hantzsch Type Reaction Using Aryl Hydrazines,
Propiolic Acid Esters and Enals: Enantioselective Synthesis of
Paroxetine
Authors: Lu Chen, Zhi Zhang, and Liansuo Zu
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000779
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10.1002/adsc.202000779
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Organocatalytic Hantzsch Type Reaction Using Aryl
Hydrazines, Propiolic Acid Esters and Enals: Enantioselective
Synthesis of Paroxetine
Lu Chen,+a Zhi Zhang,+a and Liansuo Zua,*
a
School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology
(Ministry of Education), Beijing Advanced Innovation Center for Structural Biology & Frontier Research Center for
Biological Structure, Tsinghua University, Beijing 100084 (China)
Tel: 010-62798972
E-mail: zuliansuo@tsinghua.edu.cn
These authors contributed equally to this work.
+
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
for asymmetric catalysis. In this context,
Abstract. Aryl hydrazines, propiolic acid esters and enals
serve as
a
viable substrate combination for an organocatalytic reactions of pre-formed enamines (A:
R1 = H, Scheme 1) with enals represent an appealing
approach to address the above mentioned problem.[5]
Among the scattered known examples, high
enantioselectivities have been elegantly achieved by
the groups of Kanger[5c] and Enders[5d] using pre-
formed enaminones D (Scheme 1), however, the
organocatalytic enantioselective Hantzsch type reaction.
The method converts readily available starting materials
into important chiral heterocycles with good to excellent
yields and enantioselectivities, and has addressed the
longstanding scope limitation of the classic Hantzsch
reaction in the asymmetric synthesis of 2,6-unsubstituted
hydropyridines. The synthetic utility has been demonstrated
by the concise enantioselective synthesis of paroxetine.
preparations
of
such
substrates
are
not
straightforward, which have limited the overall
synthetic efficiency and utility. Thus, it is highly
desirable to develop other viable substrates
particularly for the one-pot asymmetric Hantzsch
type synthesis to generally address this scope
limitation.
Keywords: Organocatalysis; Hantzsch; Hydropyridine;
Paroxetine; Enhydrazine
The Hantzsch dihydropyridine synthesis, first
reported in 1880s,[1a,1b] refers to the one-pot
condensation of -keto esters or 1,3-dicarbonyl
compounds with aldehydes and ammonia/amines,
involving enamines A and ,-unsaturated carbonyls
B
as the reactive species, to afford 1,4-
dihydropyridines (Scheme 1).[1c] Since the discovery,
the Hantzsch type synthesis, either the original
multicomponent protocol or modifications using pre-
formed enamines or ,-unsaturated carbonyls, has
become a powerful strategy for the rapid synthesis of
hydropyridines, pyridines (upon oxidation) and
piperidines (upon reduction), which are the core
structures of a diverse range of biologically important
molecules.[2] Significant progresses in the catalytic
enantioselective Hantzsch synthesis have also been
achieved recently, which have further improved the
synthetic utility of this traditional reaction.[3,4] Despite
of the notable achievements in this area, the
asymmetric
synthesis
of
2,6-unsubstituted
hydropyridines has been challenging mechanistically
due to the difficulties in using -formyl
carbonyls/esters (Scheme 1, R1 = H) as the substrates
1
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10.1002/adsc.202000779
Advanced Synthesis & Catalysis
Scheme 1. The organocatalytic enantioselective Hantzsch
type reactions.
Our interest in the Hantzsch reaction was partially
inspired by the structure of paroxetine, a blockbuster
serotonin inhibitor for the treatment of depression and
anxiety related disorders.[6] We envisioned that the
Hantzsch product, generated by the condensation of
an enamino ester C and an enal, could serve as a
viable intermediate for the efficient preparation of
this therapeutic agent (Scheme 1). While many
creative methods have been developed in the context
of asymmetric synthesis of paroxetine,[7,8] the
Hantzsch reaction, though straightforward from a
retrosynthetic view, has not been used before
presumably due to the difficulties of handling
enamino esters C as the substrates for asymmetric
catalysis. Using propiolic acid esters as surrogates of
-formyl esters represents an appealing and practical
way for the generation of such enamino esters via
simple conjugate addition with amines.[9] In 2010, the
group of Takemoto reported a single substrate,
generated by the addition of 4-methoxyl aniline to
ethyl propiolate, for the bifunctional thiourea
catalyzed Hantzsch reaction with enals.[5a,5b] Though
conceptually feasible, the stepwise process suffers
from low yielding in the substrate synthesis and
moderate enantioselectivities in the Hantzsch reaction.
The application of such enamino esters in a
secondary-amine catalyzed process would be more
challenging, as even a small amount release of the
amines from the enamino esters (by reversible
process or hydrolysis) would compete with the
catalyst. Inspired by the relatively higher stability of
the corresponding enhydrazines (Scheme 1, C: R =
NHAr)[10] and the recent utilizations of hydrazones[11]
in the Hantzsch reaction, we surmised that readily
available aryl hydrazines, propiolic acid esters and
enals could serve as a new substrate combination for
the one-pot Hantzsch type synthesis. Specifically, the
telescoped process involving the generation of the
enhydrazines C by the addition of aryl hydrazines to
propiolic acid esters and their subsequent annulation
with enals under organocatalysis would enable the
efficient asymmetric synthesis of tetrahydropyridines
2.[12] Of note, the easy of the cleavage of the N-N
bond for deprotection is another advantage of using
aryl hydrazines in the Hantzsch reaction. Herein, we
report the realization of a secondary-amine catalyzed
one-pot Hantzsch type synthesis employing aryl
hydrazines, propiolic acid esters and enals with good
to excellent yields and enantioselectivities, and
demonstrate the synthetic utility of the method by the
concise asymmetric synthesis of the anti-depressive
drug paroxetine.
entry catalyst
solvent
yield[b]
ee[c] dr[d]
1
I
EtOH
DCM
DCE
EtOAc
Toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
79
77
73
78
81
96
76
65
70
56
97
98
97
99
99
98
99
97
97
45
3.0:1
3.0:1
2.5:1
2.5:1
2.5:1
4.0:1
6.5:1
4.0:1
4.0:1
4.0:1
2
I
3
I
4
I
5
I
6
I
I
I
I
7[e]
8[f]
9[g]
10
II
[a] Phenyl hydrazine (0.1 mmol) and methyl propiolate (0.1
mmol) was stirred in EtOH (0.3 mL) at RT for 3 h; EtOH
was removed by concentration, and the specified solvent
(0.3 mL) was added to the same vial followed by the
addition of 1a (0.12 mmol), the additive (10 mol%) and the
catalyst (10 mol%). The reaction was stirred at RT for 24 h.
[b]
[d]
[c]
Isolated yield. Determined by Chiral HPLC analysis.
Determined by H NMR.
1
[e]
[f]
Without benzoic acid.
[g]
Using 5 mol% catalyst I. Using acetonitrile as the sole
solvent for the enhydrazine generation and subsequent
annulation.
A model reaction of phenyl hydrazine, methyl
propiolate and 4-chlorocinnamaldehyde 1a was
carried out first to test the feasibility of our
hypothesis (Table 1). Diphenylprolinol TMS ether
I[13] was selected as the first organocatalyst for the
reaction due to its commercial availability and widely
usage in the activation of enals via iminium ion.[14]
We initially tested the reaction using ethanol as the
sole solvent. Phenyl hydrazine and methyl propiolate
were allowed to react at room temperature first, upon
completion of the generation of the enhydrazine (by
TLC), enal 1a, the organocatalyst I (10 mol%) and
benzoic acid (10 mol%) were added to the same vial
for the subsequent annulation. By such a one-pot
protocol, 2a was obtained in 79% yield and 97% ee
(Table 1, entry 1).[15] The OH-containing stereogenic
center consisted of a pair of diastereomers, with anti /
syn = 3:1. The results were very promising with
satisfactory enantioselectivity, but the yield was not
optimal. Then we tried the model reaction using
different solvents. As the enhydrazine generation was
best performed in ethanol, an operation involving
concentration and solvent switch was added to the
above one-pot protocol (see foot [a] in Table 1).
Among of the various solvents tested, acetonitrile
afforded the best results with excellent
enantioselectivity and nearly quantitative yield (entry
6). As the OH-containing stereogenic center is
epimerizable and inconsequential for the synthesis of
paroxetine, we did not go further to optimize the
Table 1. Optimization of the reaction conditions.[a]
2
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10.1002/adsc.202000779
Advanced Synthesis & Catalysis
diastereomer ratio. It should be noted that much
lower reaction yields were observed when benzoic
acid was not used as an acidic additive, or 5 mol%
catalyst I was used, or acetonitrile was used as the
sole solvent for both the enhydrazine generation and
subsequent annulation (entry 7-9). The switch of
catalyst to II gave only moderate yield and ee (entry
10). The structure of 2a and its absolute configuration
With the optimized reaction conditions identified,
the substrate scope of the organocatalytic Hantzsch
type reaction was next examined (Scheme 2). A
variety of aromatic ,-unsaturated aldehydes proved
to
be
efficient
substrates,
generating
tetrahydropyridines 2 with good to excellent yields
and enantioselectivities. When the R2 groups were
substituted benzenes, the reactions tolerated both the
electronic and steric properties of the substituents
(2a-2p). A series of functional groups, such as
halogens, nitro and hydroxy, could be thus introduced
into the products, which could serve as handles for
further elaboration. Besides methyl propiolate, ethyl
propiolate could also be suitable substrate for the
Hantzsch type reaction with similar results (2i).
Furthermore, the substrate scope of the reaction could
include heterocyclic ,-unsaturated aldehydes. Thus,
the enantioselective Hantzsch type reactions could
successfully allow for the incorporation of
heterocycles, such as furan and benzofuran, into the
products with good to excellent yields and ees (2q-r).
The structures of aryl hydrazines could also be varied,
tolerating both electron donating and withdrawing
groups at varied positions (2s-u). Of note, the less
reactive aliphatic ,-unsaturated aldehydes could
not be used as substrates for the reactions.
were
determined
by
single-crystal
X-ray
diffraction.[16]
Finally, to demonstrate the synthetic utility of the
one-pot organocatalytic Hantzsch type reaction, we
turned to the asymmetric synthesis of the anti-
depressive drug paroxetine. The structure of this
therapeutic agent has stimulated many creative
method developments for its synthesis.[8] Among
them, two organocatalytic approaches have been
reviewed by Howell to be potentially practical.[17]
The group of Jørgensen has pioneered the use of an
organocatalytic Michael addition of malonate with 4-
fluorocinnamaldehyde followed by reductive
amination–lactamization to afford the lactam
intermediate for paroxetine synthesis.[8b] The group of
Vesely / Moyano / Rios[8h-i] has further streamlined
the synthesis by using amidomalonates directly,
however, this method requires the use of
trifluoroethanol as the solvent, limiting its utility in
scale-up activities.[15] The group of Ma[8f] and Most
recently, the group of Otvos / Kappe[8v] have
elegantly made significant improvements of
Jørgensen’s approach by using water as a green
solvent and continuous flow synthesis. Though such
Michael-addition based approaches are very efficient
and concise, the use of lactams as intermediates
requires the handle of strong reducing agents, such as
LAH (lithium aluminium hydride) and BH3,
generating concerns about safety and operational
simplicity, particularly in scale-up activities.
The gram-scale organocatalytic Hantzsch reaction
of phenyl hydrazine, methyl propiolate and 4-
fluorocinnamaldehyde was carried out first using the
(S)-diphenylprolinol TMS ether catalyst (Scheme 3).
The reaction successfully afforded the key
intermediate 2b’ (8.16 g) in 87% yield and 97% ee.[18]
Of note, this one-pot reaction employed all
commercially available starting materials, catalyst
Scheme 2. Substrate scope of the organocatalytic one-pot
Hantzsch type reaction.
3
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10.1002/adsc.202000779
Advanced Synthesis & Catalysis
Phenyl hydrazine (10.8 mg, 0.1 mmol) and methyl
propiolate (8.4 mg, 0.1 mmol) was stirred in EtOH (0.3
mL) at RT for 3 h; EtOH was removed by concentration,
and CH3CN (0.3 mL) was added to the same vial followed
by the addition of 4-fluorocinnamaldehyde (18 mg, 0.12
mmol), benzoic acid (1.2 mg, 0.01 mmol) and the catalyst
(3.3 mg, 0.01 mmol). The reaction was stirred at RT for 24
h. The mixture was concentrated under reduced pressure
and purified by via silica gel column chromatography
(eluting with petroleum ether/EtOAc = 15:1 to 5:1) to
afford the desired product 2b as a mixture of two
diastereomers (92% combined yield, 97% ee, dr: anti/syn =
4:1).
and industrially friendly solvents, and proceeded at
room temperature. Subsequent diastereoselective
reduction of the hydropyridin-2-ol moiety was
achieved by the treatment with triethylsilane, a cheap
and mild reductant.[19] The reduction of the ester
group was realized using simple NaBH4, furnishing
alcohol 4 in 95% yield. The installation of the
sesamol side chain was then achieved by a two-step
sequence, involving mesylate activation and SN2
alkylation. Finally, reductive cleavage of the N-N
bond by zinc powder produced paroxetine in 96%
yield. Our asymmetric synthesis of paroxetine took
only six steps and featured the use of all readily
available starting materials, the use of asymmetric
catalysis to set up the stereogenic centers, the use of
mild and simple reagents for reduction and late stage
deprotection (via N-N bond cleavage). We believe
that the simplicity and efficiency of our synthesis
should be well suited for further scale-up activities.
Acknowledgements
This work is supported by National Natural Science Foundation
of China (Grant No. 21871161), the Drug Innovation Major
Project (Grant No. 2018ZX09711-001) and Beijing Advanced
Innovation Center for Structural Biology & Frontier Research
Center for Biological Structure.
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Scheme 3. Enantioselective synthesis of paroxetine.
In summary, we have developed an organocatalytic
enantioselective Hantzsch type reaction using aryl
hydrazines, propiolic acid esters and enals to afford
hydropyrines with excellent enantioselectivities. The
method serves as a general approach to address the
longstanding scope limitation of the Hantzsch
reaction in the asymmetric synthesis of 2,6-
unsubstituted hydropyridines. The synthetic utility of
the method has been demonstrated by the concise
asymmetric synthesis of paroxetine.
Experimental Section
4
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10.1002/adsc.202000779
Advanced Synthesis & Catalysis
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[15] The yield of 2a referred to the mixture of the two
diastereomers. The ee of 2a was obtained by the HPLC
analysis of the major (anti) isomer. As a representative
example, full characterization of both the anti and syn
diastereomers of 2b, including 1H NMR, 13C NMR and
chiral HPLC spectra, can be found in the supporting
information, indicating that the ees of both the
diastereomers were identical.
[16] CCDC 2008770 (the anti-isomer of 2a) contains the
supplementary crystallographic data. These data can be
obtained free of charge from The Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/structures.
[17] G. P. Howell, Org. Process Res. Dev. 2012, 16, 1258-
1272.
[18] For the post-functionalization of 2b’ to
dihydropyridone and 1,4-dihydropyridine, see
supporting information.
5
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10.1002/adsc.202000779
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6
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