Organocatalyzed regioselective and enantioselective synthesis of 1,4- and 1,2-dihydropyridines

Article abstract of DOI:10.1080/00397911.2020.1778034

Herein, we introduce one of the first examples of asymmetric organocatalyzed synthesis of 1,2-dihydropyridines, affording enantioselective access to and partially solving regioselectivity challenges in the synthesis of dihydropyridines. We demonstrate that through modification of organocatalysts both 1,2- and 1,4-dihydropyridines (1,2- and 1,4-DHPs) can be obtained with high regioselectivity (ratio of 1,2-DHP/1,4-DHP from 95/5 to 0/100) and enantioselectivity (33% ee for 1,2-DHPs and up to 98% ee for 1,4-DHPs) in good yields (up to 87%).

Full text of DOI:10.1080/00397911.2020.1778034

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Organocatalyzed regioselective and
enantioselective synthesis of 1,4- and 1,2-
dihydropyridines
Truong-Giang Le , Hoai-Thu Pham , James P. Martin , Isabelle Chataigner &
Jean-Luc Renaud
To cite this article: Truong-Giang Le , Hoai-Thu Pham , James P. Martin , Isabelle Chataigner &
Jean-Luc Renaud (2020): Organocatalyzed regioselective and enantioselective synthesis of 1,4-
and 1,2-dihydropyridines, Synthetic Communications, DOI: 10.1080/00397911.2020.1778034
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https://doi.org/10.1080/00397911.2020.1778034
Organocatalyzed regioselective and enantioselective
synthesis of 1,4- and 1,2-dihydropyridines
a
a
a
b
ꢀ
Truong-Giang Le , Hoai-Thu Pham , James P. Martin , Isabelle Chataigner , and
Jean-Luc Renaudc
b
aInstitute of Chemistry, Vietnam Academy of Science and Technology, Hanoi, Vietnam; Department of
Chemistry Laboratoire COBRA – UMR CNRS 6014, University of Rouen Normandie, Rouen, France;
c
ꢀ
Laboratoire de Chimie Moleculaire et Thio-organique, ENSICAEN, Caen, France
ABSTRACT
ARTICLE HISTORY
Received 31 March 2020
Herein, we introduce one of the first examples of asymmetric orga-
nocatalyzed synthesis of 1,2-dihydropyridines, affording enantioselec-
tive access to and partially solving regioselectivity challenges in the
synthesis of dihydropyridines. We demonstrate that through modifi-
cation of organocatalysts both 1,2- and 1,4-dihydropyridines (1,2-
and 1,4-DHPs) can be obtained with high regioselectivity (ratio of
1,2-DHP/1,4-DHP from 95/5 to 0/100) and enantioselectivity (33% ee
for 1,2-DHPs and up to 98% ee for 1,4-DHPs) in good yields (up to
87%).
KEYWORDS
Asymmetric synthesis; chiral
secondary amine;
dihydropyridine; enantiose-
lective organocatalysis
GRAPHICAL ABSTRACT
Introduction
Dihydropyridines (DHPs) are an interesting structural motif in organic chemistry due
to their biological activity.[1–3] A perusal of the literature reveals that 1,4 dihydropyri-
dines (1,4-DHPs) exhibit interesting pharmacological and biological properties. They
can be active against calcium channels[4,5] find application in the treatment of cardio-
vascular disorders,[6] and present vasodilating activity.[7] Moreover, 1,4-dihydropyridines
are NADH mimics[8,9] and can be used as hydride donors in a broad range of asymmet-
ric transformations.[10–12] Different methods leading to enantiomerically enriched 1,4-
CONTACT Hoai-Thu Pham
phamht145@gmail.com
Institute of Chemistry, Vietnam Academy of Science and
Technology, Hanoi, Vietnam.
Supplemental data for this article can be accessed on the publisher’s website.
Graduate University of Science and Technology, Hanoi, Vietnam
ß 2020 Taylor & Francis Group, LLC
ꢀ

2
H.-T. PHAM ET AL.
DHPs, including diastereoselective cyclizations,[13,14] reductions of pyridines,[15–18] and
a chemoenzymatic approach,[19] have been described.
1,2-DHPs are less studied compared to 1,4-DHPs; however, they are an important
scaffold for the preparation of 2-azabicyclo[2.2.2]octanes (isoquinuclidines)[20] and can
be used as synthetic intermediates for the synthesis of oseltamivir phosphate
(Tamiflu).[21–23] A well-established route to the chiral ring system of oseltamivir that
can be found currently in the literature is the Diels–Alder reaction of 1,2-dihydropyri-
dines with dienophiles.[21–23] The majority of the published research into the synthesis
of 1,2-DHPs focuses on one of three approaches: condensation reactions,[24] nucleo-
philic addition to pyridines and pyridinium salts,[25–38] or pericyclic reactions.[39–51]
While organometallic compounds are common catalysts for these syntheses, organocata-
lysts have not been studied. Herein we report the asymmetric organocatalyzed synthesis
of both 1,2-DHPs and 1,4-DHPs in good yields and in moderate to high enantio-
meric excess.
Results and discussion
The investigation began with the reaction of methyl-3-(benzyl amino) acrylate 1 and
(E)-cinnamaldehyde 2 in the presence of a simple chiral secondary amine, L-proline 5.
A mixture of 1,4-DHP and 1,2-DHP was formed in moderate yield (58%) with a regioi-
someric ratio of nearly 1:1, in stark contrast to previous research in which only 1,4-
DHPs were observed,[39,52,53] necessitating an expansion of the scope of the investiga-
tion to include regioselectivity as well as enantioselectivity.
Continuing the study, catalysts 8–12 were prepared according to procedures outlined
by Chan and coworkers[34] and a screening of a modest library of catalysts was
embarked upon. Catalyst screening was carried out in the presence of 3Å molecular
sieve under an argon atmosphere using toluene or dichloromethane as the solvent. The
addition of benzoic acid (BA) as a co-catalytic additive was also investigated.
It was found that the reaction was highly dependent on the identity of the catalyst
used. The influence of the catalyst was then examined in the same model reaction
between (Z)-methyl-3-(benzyl amino) acrylate 1 and (E)-cinnamaldehyde 2 (Scheme 1).
1
The 1,2-DHP/1,4-DHP ratios were determined from H NMR spectra of the crude reac-
tion mixtures. The results are shown in Table 1.
The amino acids 5 and 6 led to undesirable regioisomeric ratios with low enantiose-
lectivity (Table 1, entries 1–2). Amino acid-derived catalysts bearing alcohol functional-
ity such as 8, 9, and 10 favored the 1,2-DHP with good regioselectivity. Of the catalysts
that provide the 1,2-DHP as the major product, 10 gave the best result in terms of
enantioselectivity with 33% ee for the 1,2-DHP and 16% ee for the 1,4-DHP (Table 1,
entry 5) (Figure 1).
Catalysts 8, 9, and 10 led to the formation of solely the 1,2-DHP regioisomer; such rever-
sal of the selectivity could result from the iminium intermediate. To further investigate this
notion the iminium ion 9b was synthesized (Scheme 2) from the ammonium tetrafluorobo-
rate salt 9a and cinnamaldehyde following procedures described by Seebach et al.[54–56]
Crystals of 9b suitable for X-ray analysis were grown by vapor diffusion crystalliza-
tion in acetonitrile/diethyl ether mixtures. As shown in Figure 2, the þN¼C bond

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Scheme 1. The synthesis of 1,2-dihydropyridines and 1,4-dihydropyridines.
Table 1. Catalyst screening in the synthesis of 1,2-dihydropyridines and 1,4-dihydropyridines.
Entry
Catalyst
Solvent
Temp.
Yield, %
4/3 ratio
ee 4, %
ee 3, %
1
2
3
4
5
6
7
8
5
6
Tol
Tol
Tol
Tol
Tol
Tol
r.t.
58
42
57
79
73
56
53
87
73
21
37
43
81
70
56
34
39/61
50/50
90/10
90/10
95/5
37/63
50/50
49/51
50/50
61/39
50/50
67/34
90/10
96/4
1
2
5
8
33
4
20
6
6
15
2
9
5
11
0
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
8a
9a
10a
11a
12a
12a
12a
12
16
85
94
79
95
93
49
75
27
0
Tolb
Et2Oc
DCMc
DCMc
DMFd
Tole
DCM
THF
CH3CN
Tol
9
10
11
12
13
14
15
16b
12a
12a
10
0
oC
3
3
0
0
rt
rt
rt
10
10
10
98/2
70/30
0
25
ꢂ20 oC
8
a10 mol% benzoic acid (BA) was used as co-catalyst (entries 5, 6, 7, 8, 9);
breaction time: 5 days;
creaction time: 2 days;
dreaction time: 3 days;
ereaction time: 8 days.
adopts a (Z)-configuration. The predominance of the (Z)-isomer might be explained by
the minimization of steric interactions between the alkenyl and aryl hydrogens, which
are more pronounced in the case of the (E)–isomer (Scheme 3).[57]
The X-ray structure of 9b reveals a clear gauche orientation, which places the
hydroxyl group synclinal endo over the pyrrolidine ring (N–C–C–O torsion angle of
–57ꢁ). This preferential conformation might be attributed to a stabilizing hyperconjuga-
tion interaction or simply a minimization of steric interactions with the phenyl groups.
A consequence of this interaction is to direct the phenyl group over one face of the

4
H.-T. PHAM ET AL.
Figure 1. Catalysts 8, 9, and 10.
Scheme 2. Synthesis of the iminium ion 9b.
Figure 2. X-ray structure of the iminium ion 9b.
Scheme 3. Steric interactions in the selective (Z)-iminium ion formation.
p–system, thus directing an incoming nucleophile to the opposite Si face. NMR spec-
troscopy showed that the conformations of 9b observed in the crystals also dominate in
CDCl3 solution. Similar conformational effects have previously been observed during
studies of the iminium ion derived from cinnamaldehyde and 2-(fluorodiphenylmethyl)-
pyrrolidine, as reported by Gilmour et al.[58,59]
The reaction catalyzed by the silyl ether pyrrolidine 11 led to moderate regioselectiv-
ity (63/37) favoring the formation of the 1,4-isomer with good enantioselectivity (85%

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5
Table 2. The screening of enaminoester in the synthesis of 1,2- and 1,4-dihydropyridines.
Entry
Enaminoester
Yield, %
1,2-/1,4- ratio
ee 1,2-,%
ee 1,4-,%
1
2
3
4
1a
1b
1c
1d
63
53
73
75
0/100
0/100
49/51
0/100
–
–
6
–
38
15
95
0
ee). The best result in terms of enantioselectivity was obtained with catalyst 12 provid-
ing the 1,4-DHP in an excellent 94% ee, with the caveat of no regioselectivity (Table 1,
entry 7).
Prolinol type catalysts all favored the formation of the 1,2-DHP, but the enantioselec-
tivities remained low. Diphenylprolinols 8 and 9 provided good regioselectivity but
were inefficient as enantioselective catalysts in the screening reaction. Although (S)-
diphenylprolinol-TMS ether 12 gave the 1,4-DHP as the major product with 93% ee in
21% yield after 5 days of reaction (Table 1, entry 10), the selectivity (up to 95%) and
yield (up to 73% in 2 days) were improved when benzoic acid (BA) was introduced as a
co-catalyst (Table 1, entry 9). Attempts to further optimize the reaction were made by
screening solvents and reducing temperature. The use of dichloromethane as a solvent
improved the selectivity further, affording the desired 1,4-DHP in 73% yield and 95%
ee in shorter reaction time. Lowering the reaction temperature 0 ꢁC decreased the yield
(43% in 8 days) and reduced the enantiomeric excess of the 1,4-DHP to 72% ee (Table
1, entry 12).
Catalyst 10 (Table 1, entries 13–16), which led to good regioselectivity in favor of the 1,2-
DHP isomer and promising ee’s, was first selected as the catalyst with which to evaluate the
influence of the solvent and temperature for condition optimization. Increasing the polarity
of the solvent led to higher regioselectivity (Table 1, entries 13–15). The reaction in aceto-
nitrile led to the quasi-exclusive formation of the 1,2-regioisomer; however, with no enantio-
selectivity (Table 1, entry 15). The reaction in toluene at room temperature remained the
best in terms of enantioselectivity (entry 6). Disappointingly, reducing the temperature to
ꢂ20ꢁC (entry 16) decreased both the regio- and enantio-selectivity.
With optimized reaction conditions in hand (Table 1, entry 9) the scope of the meth-
odology was explored by testing a library of a,b-unsaturated aldehydes, and enaminoest-
ers in the reaction (Table 2). The reaction smoothly undergoes a cascade cyclization or
6p-electrocyclizaton to afford dihydropyridines in good yields and regioselectivities and
modest to high enantioselectivities (up to 98% ee for 1,4-DHP and 16% ee for
1,2-DHP).
The steric hindrance of the enaminoester appears to play an important role in the
regioselectivity of the process. Substrates bearing an isopropyl or a tert-butyl group led
to the formation of the 1,4-DHP exclusively. The enantioselectivity is also highly influ-
enced by the substituent on the nitrogen atom, substrates bearing N-tert-butyl substitu-
tion led to better enantiomeric excess than the sister compound bearing N-isopropyl
substitution (38% ee vs. 15% ee, Table 2, entries 1–2). The identity of the R1 group
(Scheme 4) also has a strong influence on the course of the reaction, with the enami-
noester 1c, bearing a benzyl group, leading to lower regioselectivity but much higher
enantioselectivity (entry 3). Introducing b-methyl substitution, 1d (Scheme 4), resulted
in the restoration of 1,4-DHP exclusive regioselectivity at the cost of providing the

6
H.-T. PHAM ET AL.
Scheme 4. The screening of enaminoesters in the synthesis of 1,2- and 1,4-dihydropyridines.
Table 3. The screening of aldehydes in the synthesis of dihydropyridines.
Entry
Aldehyde
Catalyst
Co-catalyst
Yield,%
1,2-/1,4- ratio
ee 1,2-, %
ee 1,4-, %
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
12
12
12
12
12
12
12
12
12
12
BA
BA
BA
BA
BA
BA
BA
BA
BA
Sal
73
21
79
84
81
70
57
44
NR
NR
49/51
54/46
7/93
5/95
10/90
0/100
0/100
0/100
–
6
16
–
1
4
–
–
–
–
95
98
83
80
97
86
55
18
–
10
2k
–
–
–
NR: no reaction (entry 7, 8); AB: benzoic acid (10 mol%); Sal: salicylic acid (10 mol%).
product as a racemate (Table 2, entry 4); the steric influence of the methyl group may
be an influential factor leading to this observation.
To further explore the scope of the method various a,b-unsaturated aldehydes were
investigated (Table 3). Both aromatic and aliphatic aldehydes reacted smoothly, afford-
ing 1,4-DHPs with good yields and enantioselectivities (up to 98% ee).
Electron donating substitutions at the aryl ring of the enal had little effect on the
yields and enantioselectivities but provided high regioselectivity favoring the formation
of 1,4-DHPs (Table, entries 2–4). Aliphatic aldehydes (Table 3, entries 6–8) led to the
exclusive formation of 1,4-DHPs at high enantiomeric excess (up to 86% ee), similarly
to the results published by Kanger et al.[39](Scheme 5).
The aldehydes bearing aryl substituents generally preferred formation of the 1,4-
regioisomer with good to excellent enantioselectivities of up to 98% ee (entries 1–5).
With aldehydes bearing substituents at the a-position no reaction occurred (entries
9–10), this might be explained by the steric hindrance exerted by the substituent. In
most cases, the 1,4-DHPs were the major compounds and obtained with high enantio-
meric excesses, while the 1,2-DHPs were the minor compounds obtained with low
enantiomeric excesses (up to 16% ee).
Conclusion
The development of atom efficient and metal-free asymmetric syntheses is an important
goal in the green chemistry century. Progress toward an organocatalyzed enantioselec-
tive synthetic methodology that expands the synthetic space available for

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7
Scheme 5. The screening of aldehydes in the synthesis of dihydropyridines.
enantiomerically enriched dihydropyridines to include both 1,2- and 1,4-dihydropyri-
dine regioisomers provides the potential for new and green synthetic routes to both
prospective and known pharmacologically and biologically active compounds. We have
developed the first organocatalyzed synthesis of 1,2-dihydropyridines with high regiose-
lectivity and up to 33% ee and the organocatalytic synthesis of 1,4-dihydropyridines
with high regioselectivity and high enantioselectivity (up to 98%). These reactions pro-
ceeded in mild condition and products were obtained in very good yields as mixtures of
regioisomers.
Experimental part
General information
All reactions were carried out under an argon atmosphere with dried, freshly distilled
solvents under anhydrous conditions unless otherwise noted. Merck silica gel plates
(60 F-254) using UV light as visualizing agent and phosphomolybdic acid and heat as
developing agents. Merck silica gel (60, particle size 0.040–0.063 mm) was used for flash
chromatography.
General procedure A for the preparation of b-enaminoesters
The amine (1.3 mmol, 1.3 eq.) in water (2.6 ml) was added to methyl propiolate
(1.0 mmol, 1.0 eq.) and the reaction mixture was stirred at room temperature for
15 minutes. EtOAc (2.0 mL) was then added to the reaction mixture and the organic
phase was extracted with EtOAc (2.0 mL ꢃ 3). The combined organic layers were dried
over MgSO4 and the solvent was removed under vacuum. The crude residue was puri-
fied by column chromatography on silica (cyclohexane/EtOAc).

8
H.-T. PHAM ET AL.
General procedure B for the preparation of b-enaminoesters in the presence of
lewis acid
A dried round-bottomed flask was charged with activated molecular sieve, La(OTf)3
(5 mol%), dichloromethane (5 mL), the dicarbonyl derivative (1 mmol, 1 eq.) and the
primary amine (1.5 mmol, 1.5 eq.). The reaction mixture was stirred at room tempera-
ture until completion by TLC analysis. The solution was then filtered through celite,
and concentrated under vacuum. The crude residue was purified on silica gel by flash
chromatography (EtOAc/cyclohexane)
General procedure C for the preparation of dihydropyridines in the presence of
benzoic acid as a brønsted acid
To a dried Schlenk’s tube charged molecular sieve was added dichloromethane (5 ml),
benzoic acid (0.10 mmol, 10 mol%), a,b-unsaturated aldehyde (1.5 mmol, 1.5 eq.) and
the enaminoester (1 mmol, 1.5 eq.) under argon. The mixture was allowed to stir at
room temperature for 8–24 hours. After filtration on Celite, the solvent was removed
under reduced pressure. The residue was purified by column chromatography (cyclo-
hexane/EtOAc ¼ 10: 1 – 20:1 or pentane/EtOAc 20:1 – 30/1) to afford the 1,2-dihydro-
pyridine and the 1,4-dihydropyridine.
General procedure D for the preparation of dihydropyridines in the presence of
10 mol% of lewis acid
(D1) A Schlenk’s tube under argon was charged with sodium sulfate (150 mg), the
Lewis acid catalyst (0.05 mmol, 5 mol%), dichloromethane (10 ml), the enaminoester
(1 mmol, 1 eq.) and the unsaturated aldehyde (1.2 mmol, 1.2 eq.). The solution was
stirred at room temperature until completion by TLC analysis. The solution was then
filtered through a Celite pad, and concentrated under vacuum. The crude residue was
purified on silica gel by flash chromatography (petroleum ether/diethyl ether).
(D2) Molecular sieves (M.S.) were added to a Schlenk’s tube and dried under vac-
uum. La(OTf)3 (0.10 mmol, 10 mol%) was added, followed by dichloromethane (10 ml),
the a,b-unsaturated aldehyde (1 mmol, 1.5 eq.) and the enaminoester (1 mmol, 1.0 eq.).
The mixture was allowed to stir at room temperature for 8 to 24 hours. After filtration
on Celite, the solvent was removed under reduced pressure. The residue was purified by
column chromatography (cyclohexane/EtOAc ¼ 10: 1 – 20:1 or pentane/EtOAc 20:1 –
30/1) to afford the 1,4-dihydropyridine.
General procedure E for the preparation of enantioenriched dihydropyridines in
the presence of L-proline type derivatives as the catalyst
Molecular sieves were added into a Schlenk’s tube and dried under vacuum.
The catalyst (0.10 mmol, 10 mol %) and co-catalyst (0.010 mmol, 10 mol%) were
added, followed by dichloromethane (10 ml), the a,b-unsaturated aldehyde (1.5 mmol,
1.5 eq.) and the enaminoester (1.0 mmol, 1.0 eq.) The reaction mixture was allowed to
stir at room temperature for 1 to 2 days. After filtration on Celite, the solvent was

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SYNTHETIC COMMUNICATIONSV
9
removed under reduced pressure. The residue was purified by column chromatography
to afford a mixture of 1,2- dihydropyridine and 1,4-dihydropyridine. Both regioisomers
were isolated with column chromatography where practical.
1
Full experimental detail, including H and 13C NMR spectra of all compounds and
HPLC chromatography traces are available via the “Supplementary Content” section of
this article’s webpage.
Funding
This research is funded by the Graduate University of Science and Technology under [grant
-
number GUST.STS.DT2017-HH10] and Vietnamese National Foundation for Science and
Technology Development (NAFOSTED, code: 104.01-2017.27).
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