Cascade aza-Wittig/6π-Electrocyclization in the Synthesis of 1,6-Dihydropyridines

Article abstract of DOI:10.1021/acs.orglett.1c02099

A metal-free protocol for the synthesis of substituted 1,6-dihydropyridines with quaternary stereogenic centers via a cascade aza-Wittig/6π-electrocyclization process has been developed. The high functional group compatibility and broad scope of this method were demonstrated by using a wide range of easily available vinyliminophosphoranes and ketones, with yields up to 97%. A modification of the obtained products allowed for an increase in complexity and chemical diversity. Finally, attempts for asymmetric synthesis of 1,6-dihydropyridines are demonstrated.

Full text of DOI:10.1021/acs.orglett.1c02099

pubs.acs.org/OrgLett
Letter
Cascade aza-Wittig/6π-Electrocyclization in the Synthesis of 1,6-
Dihydropyridines
Vasiliki Polychronidou, Anna Krupp, Carsten Strohmann, and Andrey P. Antonchick*
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ABSTRACT: A metal-free protocol for the synthesis of substituted 1,6-dihydropyridines with quaternary stereogenic centers via a
cascade aza-Wittig/6π-electrocyclization process has been developed. The high functional group compatibility and broad scope of
this method were demonstrated by using a wide range of easily available vinyliminophosphoranes and ketones, with yields up to 97%.
A modification of the obtained products allowed for an increase in complexity and chemical diversity. Finally, attempts for
asymmetric synthesis of 1,6-dihydropyridines are demonstrated.
Scheme 1. Synthesis of 1,2-Dihydropyridines
ihydropyridines (DHPs) are a valuable chemical
structure that can be found as the core scaffold in
D
numerous compounds with varied biological and pharmaco-
logical activities.1,2 DHPs are also versatile synthetic
intermediates due to their ability to undergo further chemical
transformations, providing access to a variety of aza-hetero-
cycles.3 Regarding the scaffold of dihydropyridines, 1,4- and
1,2- or 1,6-DHPs represent the most populated group whereas
the latter has only recently gained significant attention.4
Several synthetic methods have been reported for the
construction of 1,2-dihydropyridines by means of nucleophilic
addition onto N-alkyl or N-acylpyridinium salts,3a,5 dearoma-
tization of pyridines,6 transition-metal catalyzed reactions,3c,7
and the establishment of both Lewis acid8 and Brønsted acid
catalyzed approaches9 (Scheme 1a). Furthermore, a pericyclic
fashion was employed as an additional strategy to access these
scaffolds. Palacios and co-workers have reported the synthesis
of 1,2-dihydropyridines through a [4 + 2] cycloaddition
reaction of 2-azadienes (readily prepared by aza-Wittig
reactions) and enamines (Scheme 1b).10 Tejedor et al. has
developed a convenient domino access to substituted alkyl 1,2-
dihydropyridine-3-carboxylates from propargyl enol ethers and
primary amines by means of a Claisen rearrangement/
isomerization/amine condensation/6π-aza-electrocyclization
process (Scheme 1c).11 Very recently, Yu, Zhou et al. reported
the enantioselective synthesis of 1,2-dihydropyridines, using a
chiral amine catalyst.12 Metal-free protocols that allow rapid
access to substituted DHPs and their derivatives are in high
demand.
organofluorides, the trifluoromethyl group is considered one of
the most important motifs. In particular, pyridinyl motifs with
Received: June 22, 2021
Published: July 22, 2021
On the other hand, the incorporation of fluorine-containing
derivatives into organic compounds is of high importance in
pharmaceutical, agricultural, and material science. Introducing
a C−F instead of a C−H bond in a molecule can modify its
physical, chemical, and biological properties.13 Within these
© 2021 The Authors. Published by
American Chemical Society
https://doi.org/10.1021/acs.orglett.1c02099
Org. Lett. 2021, 23, 6024−6029
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a b
,
trifluoromethyl-substituents proved to have wide applications
in different fields.14 To the best of our knowledge, there is no
synthetic method that enables the construction of multi-
substituted 1,2-dihydropyridines bearing mainly fluorinated all-
carbon quaternary centers. Having interest in developing new
methods for the synthesis and functionalization of hetero-
cycles,15 herein we report a metal-free 6π-electrocyclic
transformation of in situ generated aza-hexatrienes (Scheme
1d). The aza-hexatrienes are derived from an aza-Wittig
reaction of phosphazenes with the corresponding carbonyl
compounds.
Scheme 2. Substrate Scope with Different Ketones
To establish the reaction method, initial screening studies
were conducted with different easily available N-vinylic-λ5-
phosphazenes 1a and 2,2,2-trifluoroacetophenone 2a. As
shown in Table 1, when the N-vinylic- λ5-phosphazene bearing
a
Table 1. Optimization of Reaction Conditions
b
yield (%)
entry
PR3
PPh3
PPh2Me
PMe3
PMe3
PPh3
solvent [0.1 M] temp (°C) time (h)
3a
4a
1
2
3
4
5
6
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
CHCl3
PhMe
rt
rt
rt
rt
60
60
110
72
48
12
96
72
72
72
20
70
92
92
25
−
−
−
−
−
30
84
80
PMe3
PMe3
−
a
Reaction conditions: 1a (0.15 mmol) and 2a (0.15 mmol) were
b
stirred at given temperature for given time. Isolated yield.
a triphenylphosphine substituent was reacted with the
trifluoromethyl ketone 2a, in dichloromethane at ambient
temperature, only the formation of the acyclic imine 3a was
observed in low yield (entry 1). Varying the substituent on the
phosphorus atom of the N-vinylic- λ5-phosphazene, thus
inducing changes of the electronic properties of the
phosphorus, led to an increase in reactivity that resulted in
improved yields of acyclic imine 3a. However, the desired
cyclized product 4a was not observed at ambient temperature
regardless of the reaction time (entries 2−4). Remarkably,
changing the solvent to chloroform and heating the reaction to
60 °C yielded the desired product 4a, albeit in low yield and
with the acyclic imine still present (entry 5). Gratifyingly, by
changing to the more reactive λ5-phosphazene bearing a
trimethylphosphine substituent, the reaction proceeded
smoothly and resulted to the cyclized product 4a in 84%
yield (entry 6). Further attempts, using toluene as solvent and
high temperature did not improve the reaction outcome (entry
7).
With the optimized conditions in hand, we first explored the
scope and limitations of our method by using a series of readily
available ketones 2. The aryl group of the ketone was
systematically varied (Scheme 2). Both para- and meta-
substituted ketones with electron-donating or electron-with-
drawing groups were well tolerated and provided the desired
products (4a−4j) in moderate to excellent yields (43−93%).
In the case of ortho-substituted ketones, the yields were notably
decreased and afforded the product 4k in 24% yield due to the
steric hindrance. It is noteworthy that, in the case of example
a
Reaction conditions: 1a (0.15 mmol), 2 (0.15 mmol), in CHCl3 [0.1
b
c
M] were stirred at 60 °C for 72 h. Isolated yield. Reaction was
conducted by heating the corresponding isolated noncyclized product
in toluene, at 110 °C for 72 h. Isolated as inseparable mixture with
the intermediate acyclic imine in a ratio of 4:1.
d
4l, the standard conditions afforded mainly the noncyclized
imine and only traces of the cyclized one. To obtain the
desired cyclized product for this substrate, alternative
conditions were used, in which the isolated acyclic imine in
toluene was heated to 110 °C for 72 h. Strikingly, the scope
could also be extended to heteroaryl-substituted ketones
providing product 4m in 60%. To our delight, this method
was also applicable to ketones bearing difluoromethyl,
chlorodifluoromethyl, and ethoxycarbonyl groups, affording
the products (4n−4p) in moderate to excellent yields (48−
97%). Remarkably, the 7-fluoroisatin could be used in our
method, affording the valuable dihydropyridine-based spiroox-
indole 4q, albeit in moderate yield, 45%. Unfortunately, when
acetophenone and aliphatic trifluoromethyl ketones such as
1,1,1-trifluoroacetone were tested under the standard con-
ditions, the reaction did not take place, probably due to
isomerization of imine to enamine.
To rapidly expand the chemical space accessible via our
method, we further explored the transformation with a series of
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Letter
substituted vinyliminiphosphoranes 1. As illustrated in Scheme
3, a range of products 5 were obtained. Pleasingly, ortho-,
Based on the above results and the reported literature7f,16
a
putative reaction mechanism is proposed (Scheme 4). The
Scheme 3. Substrate Scope with Different
Vinyliminophosphoranes
Scheme 4. Proposed Reaction Mechanism
a b
,
reaction proceeds via an aza-Wittig reaction between the
vinyliminophospharene 1a and ketone 2a to afford the
corresponding azatriene 3a through formation of imine and
elimination of trimethyl phosphine oxide. The linear imine s-
trans, s-trans 3a (confirmed by X-ray analysis, Scheme 4) must
be converted to the “cyclization-reactive” s-cis, s-cis conformer
3a′ through bond rotations in order to undergo 1,6-
electrocyclization. This isomerization to the reactive con-
formation is thermodynamically unfavored and can therefore
be accessed under thermal conditions. The subsequent thermal
6π disrotatory electrocyclization provides the intermediate A
which, by means of a [1,5]-hydride shift, results in the final
product 4a.
Furthermore, product 4a could be converted onto its
tetrahydropyridine 6a or piperidine moiety 6b as a single
diastereomer upon reduction with hydrogen over Pd/C
catalyst by simply changing the temperature and the reaction
time (Scheme 5). Not only does this allow access to a novel
range of compounds, but it also provides an option to explore a
different dimension of chemical space.
a
Reaction conditions: 1 (0.15 mmol), 2a (0.15 mmol), in CHCl3 [0.1
b
c
M] were stirred at 60 °C for 72 h. Isolated yield. Isolated yield for
1.00 mmol scale.
meta-, and para-substituted phenyl rings were well tolerated.
Moreover, the presence of electron-donating as well as
electron-withdrawing substituents still resulted in high
reactivity affording the desired products 5a−5l in moderate
to excellent yields (49−94%). Compound 5a was obtained in a
scale up experiment, and its structure was confirmed by X-ray
crystallographic analysis. A similar trend was observed with the
heterocycle-containing compounds yielding the products 5m
and 5k in 89% and 83% yield, respectively. Notably, switching
to vinyliminophosphorane bearing an aliphatic moiety, in this
case methyl, led to a dramatic decrease in reactivity, and only
traces of product 5o were obtained. We tested whether a direct
protocol which does not require the preparation of vinylimino-
phosphoranes is feasible. Unfortunately, a one-pot procedure,
using vinyl-azide (precursor of compound 1), trimethylphos-
phine, and ketone 2a did not lead to the formation of the
desired product.
Finally, asymmetric 6π-electrocyclization reactions are a
challenging task with several successful examples in literature.17
Scheme 5. Further Transformation of 4a
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In this context, we performed a preliminary investigation on
the catalytic asymmetric version of our method employing
chiral Brønsted acids. As shown in Table 2, in the presence of
synthesis of 1,6-dihydropyridines was studied using various
Brønsted acids.
ASSOCIATED CONTENT
* Supporting Information
■
sı
Table 2. Preliminary Investigation of the Asymmetric
a
Electrocyclization of Substrate 3b
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02099.
1
Experimental procedures, characterization data, and H,
19
13C, F NMR spectra (PDF)
Accession Codes
CCDC 2046566, 2046825, 2060066, and 2081540 contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Andrey P. Antonchick − Max-Planck-Institut fu
Physiologie, Abteilung Chemische Biologie, 44227 Dortmund,
Germany; Technische Universität Dortmund, Fakultät fu
Chemie und Chemische Biologie, 44227 Dortmund,
Germany; Nottingham Trent University, Department of
Chemistry and Forensics, NG11 8NS Nottingham, United
Kingdom; orcid.org/0000-0003-0435-9443;
Email: andrey.antonchick@ntu.ac.uk
̈
r Molekulare
̈
r
b
c
entry
cat.
temp (°C)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
(R)-7a
(S)-7b
(R)-7c
(R)-7d
(R)-7e
(R)-7e
(R)-7e
8
60
60
60
60
60
50
30
60
60
90
88
90
70
75
40
traces
80
85
5
3
16
13
24
34
−
3
Authors
Vasiliki Polychronidou − Max-Planck-Institut fu
Physiologie, Abteilung Chemische Biologie, 44227 Dortmund,
Germany; Technische Universität Dortmund, Fakultät fu
Chemie und Chemische Biologie, 44227 Dortmund, Germany
̈
r Molekulare
9
2
̈
r
a
Reaction conditions: 3b (0.025 mmol) in CHCl3 [0.1 M] using 20
mol % of chiral catalyst for 72 h. Isolated yield. Values of ee were
b
c
Anna Krupp − Technische Universität Dortmund, Fakultät fur
̈
Chemie und Chemische Biologie, 44227 Dortmund, Germany
determined using chiral HPLC.
Carsten Strohmann − Technische Universität Dortmund,
Fakultät fur Chemie und Chemische Biologie, 44227
̈
several representative chiral phosphoric acids (7 and 8) and
chiral disulfonimide 9, the electrocyclization of substrate 3b
was achieved in generally good yields. However, the
enantioselectivities in all cases were low (up to 34% ee).
Among these catalysts, chiral phosphoric acid 7e afforded
product 5b in comparatively lower yield but with a promising
level of enantioselectivity (24%, entry 5). When decreasing the
temperature from 60 to 50 °C, an increase in the
enantioselectivity was observed, although it resulted in a
lower yield (entry 6). A further decrease in temperature led to
traces of product (entry 7). The low enantioselectivity of the
reaction might be partly ascribed to the strong background
reaction because the electrocyclization of substrate 3b could
occur in the absence of any catalysts (Table 1, entry 6).
In summary, we have developed a metal-free and efficient
approach for the synthesis of unprecedented 1,6-dihydropyr-
idines with quaternary stereocenters via an aza-Wittig/6π-
electrocyclization process. This protocol provides an access to
a new class of pyridine frameworks under mild reaction
conditions, featuring good functional group tolerance and
operational simplicity. These novel building blocks could
access interesting bioactivities through a range of synthetic
transformations. A plausible reaction mechanism for the
developed cascade process is proposed. Finally, asymmetric
Dortmund, Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02099
Author Contributions
A.P.A. and V.P. designed experiments. A.P.A supervised the
project. V.P. performed the experiments. C.S. and A.K. carried
out the X-ray crystallographic analysis. A.P.A. and V.P.
discussed the results, commented, and wrote the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.P.A. acknowledges the support of the DFG (AN 1064/4-1)
and the Boehringer Ingelheim Foundation (Plus 3). V.P.
acknowledges the International Max Planck Research School
for Living Matter (Dortmund, Germany).
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