1,4-Dihydropyridine/BF3OEt2 for the reduction of imines: Influences of the amount of added BF3OEt2 and the substitution at N-1 and C-4 of the dihydropyridine ring

Article abstract of DOI:10.1016/j.tetlet.2019.151129

We have evaluated four 1,4-dihydropyridines (DHPs 1a, 1b, 1c and 1d) as reducing agents, which presented free (hydrogenated) or phenyl-substituted N-1 and C-4 positions of the DHP ring. Reactions combining each of the DHP and different amounts of BF₃OEt₂ were evaluated for the reduction of imine 2a (N-benzylideneaniline). DHP simultaneously substituted at N-1 and C-4 (1a), and DHP substituted at C-4 (1b) gave lower yields for reduction of 2a in comparison with DHPs 1c and 1d (both unsubstituted at the C-4 position). By evaluating the amount of added BF₃OEt₂ to the reaction mixture, we have found that DHP 1c (substituted at N-1) provided its best yield for amine 3a (82%) when associated with stoichiometric amounts BF₃OEt₂, while DHP 1d (N-1- and C-4-unsubstituted derivative) was more effective (90% yield) with catalytic quantities of the Lewis acid. The reaction system using DHP 1c under stoichiometric BF₃OEt₂ could also be successfully applied with additional imine examples and under reductive amination conditions.

Full text of DOI:10.1016/j.tetlet.2019.151129

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
1,4-Dihydropyridine/BF3OEt2 for the reduction of imines: Influences of
the amount of added BF3OEt2 and the substitution at N-1 and C-4 of the
dihydropyridine ring
Ingrid F. Zattoni a, Lais D. Guanaes a, Letícia B. Cerqueira a, Roberto Pontarolo a, Diogo R.B. Ducatti b,
M. Eugênia R. Duarte b, Miguel D. Noseda b, Angela C.L.B. Trindade a, Alan G. Gonçalves a,
⇑
a Departamento de Farmácia, Universidade Federal do Paraná, Av. Lothario Meissner, 3400, Jardim Botânico, Curitiba, Paraná, Brazil
b Departamento de Bioquímica e Biologia Molecular, Universidade Federal do Paraná, PO Box 19046, Curitiba, Paraná, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
We have evaluated four 1,4-dihydropyridines (DHPs 1a, 1b, 1c and 1d) as reducing agents, which
presented free (hydrogenated) or phenyl-substituted N-1 and C-4 positions of the DHP ring. Reactions
combining each of the DHP and different amounts of BF3OEt2 were evaluated for the reduction of imine
2a (N-benzylideneaniline). DHP simultaneously substituted at N-1 and C-4 (1a), and DHP substituted at
C-4 (1b) gave lower yields for reduction of 2a in comparison with DHPs 1c and 1d (both unsubstituted at
the C-4 position). By evaluating the amount of added BF3OEt2 to the reaction mixture, we have found that
DHP 1c (substituted at N-1) provided its best yield for amine 3a (82%) when associated with stoichiomet-
ric amounts BF3OEt2, while DHP 1d (N-1- and C-4-unsubstituted derivative) was more effective
(90% yield) with catalytic quantities of the Lewis acid. The reaction system using DHP 1c under stoichio-
metric BF3OEt2 could also be successfully applied with additional imine examples and under reductive
amination conditions.
Received 19 August 2019
Revised 3 September 2019
Accepted 8 September 2019
Available online xxxx
Keywords:
Dihydropyridines
Reduction
Imines
Hydride transfer
Ó 2019 Published by Elsevier Ltd.
1,4-Dihydropyridines (DHPs) has long been used as reducing
agents in organic reactions [1]. They were first recognized as the
synthetic models of the naturally occurring Nicotinamide Adenine
Dinucleotide system (NADH/NAD+) [2–5]. In reduction reactions,
DHPs act mainly as hydride (or electron) donors, by promoting
the hydrogen transfer to an adequate substrate, with the concomi-
tant formation of the oxidized version of the DHP, a pyridine or
pyridinium salt [6–8]. DHPs have been utilized to reduce different
organic functions, such as ketones [9], aromatic azides [10], alke-
nes [11], reductive amination/imine [12–14] enones [15], among
others.
An important aspect factoring on the ability of DHPs to promote
reduction reactions is related to the substitution pattern of the
DHP ring, mainly in terms of the presence or absence of sub-
stituents located at the N-1 and C-4 positions [16]. These positions
appear to be key in the reduction process, which is in accordance
with the current accepted mechanisms for the hydrogen transfer
involving DHPs. Studies involving the measuring of DHP activation
energy for hydride donation indicate those lacking both N-1 and
C-4 substituents as having superior capabilities in promoting
reduction reactions [16–18]. It is worth mentioning that such com-
parative studies were performed based on electrochemical oxida-
tion and theoretical evaluations of the DHPs studied, and they
did not evaluate the comparison of the reaction output in terms
of isolated yield of a reduced product. In fact, most of the published
synthesis involving DHP-promoted reductions employs the
Hantzsch ester (Fig. 1), which presents no substituents for either
N-1 or C-4 position. The Hantzsch ester has been widely utilized
in combination with Lewis acids [12–15], Bronsted acids [19,20]
and phosphonic acid derivatives [21] to promote the reduction of
diverse chemical functions. Even though the aforementioned state-
ments lead to a general impression that the N-1 or C-4 substitution
of the DHP ring reflects into inferior reducing agents, the fact that
an N-substituted DHP (NADH/NAD+ system) was evolutively
elected in living organisms to promote metabolic reductions
should be took into consideration.
Due to the scarceness of utilization of substituted N-1- and C-4-
DHPs as reducing agents in the literature, as well as the lack of
comparative synthesis using them, we herein investigated the
reduction of imines promoted by examples of such DHPs, where
a Hantzsch ester analogue was used for comparison purposes.
The execution of the present work was also encouraged by a
⇑
Corresponding author.
E-mail address: alan.goncalves@ufpr.br (A.G. Gonçalves).
https://doi.org/10.1016/j.tetlet.2019.151129
0040-4039/Ó 2019 Published by Elsevier Ltd.
Please cite this article as: I. F. Zattoni, L. D. Guanaes, L. B. Cerqueira et al., 1,4-Dihydropyridine/BF3OEt2 for the reduction of imines: Influences of the
amount of added BF3OEt2 and the substitution at N-1 and C-4 of the dihydropyridine ring, Tetrahedron Letters, https://doi.org/10.1016/j.
tetlet.2019.151129

2
I.F. Zattoni et al. / Tetrahedron Letters xxx (xxxx) xxx
Fig. 1. Hantzsch ester and DHPs 1a–1d.
previous study [22], where some of the present authors have
demonstrated the facile aromatization of DHPs with BF3OEt2, in
the absence of added oxidizing agents. On that research, DHPs hav-
ing unsubstituted or substituted N-1 and C-4 positions could all be
successfully converted in their respective pyridines or pyridinium
salts.
In this way, the first step of the present work was the prepara-
tion of DHPs 1a–1d, which were meant to serve as the reducing
agents to be evaluated. For all cases, the substituent located at
N-1 or C-4 positions was the phenyl group, which translated into
the readily available starting materials, aniline and benzaldehyde.
DHP 1a [22] and 1c [23] were synthesized stepwise, from the
appropriate enamine and enone. DHPs 1b and 1d were prepared
through adaptations of the classic multicomponent Hantzsch syn-
thesis [22,24–27]. As shown in Fig. 1, DHP 1a was substituted at N-
1 and C-4 positions, 1b was substituted at C-4, while 1c at N-1.
Compound 1d, the dimethoxyl analogue of the Hantzsch ester,
was unsubstituted at both positions.
in Table 1). This preference was based on the fact that (a) imines
are known to be well reduced by DHPs, being sensitive probes
for such reactions, even considering presumably weak reducing
agents and (b) the pair 2a/3a could be promptly isolated by chro-
matography and differentiated by TLC or NMR analysis.
The reaction setup herein initially tested (Table 1) was based on
the previous conditions utilized for the aromatization of DHP 1a
[22]. The cited study employed a mixture of 1a and three equiva-
lents of BF3OEt2 in dichloromethane, at 0 °C for 5 h, under atmo-
spheric air. In order to take full advantage from 1a reducing
potential, we first assumed that the use of inert atmosphere would
help to direct the hydride transfer to the substrate to be reduced.
This assumption was based on evidences [22] indicating that the
oxygen present in the reaction media was crucial for the aromati-
zation of 1a. However, condition shown in entry 1 of Table 1, which
used Argon atmosphere, gave no detectable reduced product from
imine 2a. By increasing the temperature from 0 °C to rt, and by
extending the reaction time, it was possible to promote the reduc-
tion of 2a to produce amine 3a with 10% yield (entry 2). Even
though the presence or absence of inert atmosphere greatly influ-
ences the aromatization of DHP 1a [22], we noted that it did not
In order to compare DHPs 1a–1d efficacies as reducing agents,
we utilized imine 2a (N-benzylideneaniline) [28] as substrate,
which would be converted into amine 3a [29] (see reaction shown
Table 1
Evaluation of DHPs 1a–1d as reducing agents for imine 2a in the presence of BF3OEt2.
Entry
DHP
BF3Et2O (mmol)
Atmosphere
Temperature
Reaction time (h)
Reduced product yield (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1c
1d
1a
1b
1c
1d
1a
1b
1c
1d
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.1
0.1
0.1
0.1
0.01
0.01
0.01
0.01
Argon
Argon
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
0 °C
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
5
–
24
24
24
24
24
24
24
24
24
24
24
24
24
24
10a
10a
14b
32b
72b
66b
27b
45b
82b
68b
–
9
10
11
12
13
14
15
7b
21b
90b
a
product isolated from silica gel column;
product isolated from preparative TLC plates.
b
Please cite this article as: I. F. Zattoni, L. D. Guanaes, L. B. Cerqueira et al., 1,4-Dihydropyridine/BF3OEt2 for the reduction of imines: Influences of the
amount of added BF3OEt2 and the substitution at N-1 and C-4 of the dihydropyridine ring, Tetrahedron Letters, https://doi.org/10.1016/j.
tetlet.2019.151129

I.F. Zattoni et al. / Tetrahedron Letters xxx (xxxx) xxx
3
make any difference, when considering the isolated yield of the 3a
from 2a (compare entries 2 and 3). Therefrom, we assumed that
our previous published reaction [22], which was simply developed
for DHP aromatization, presumably do not match the best condi-
tions to direct the hydride transfer to imine 2a.
of the Lewis acid would not match the best condition for hydrogen
transfer, probably due to the higher reactivity of 1d in comparison
to 1c. This hypothesis can be related with the lower
DG
H-D (X-H)
involved in hydride dissociation for the Hantzsch ester
(42.57 kcal.molÀ1) in comparison to its N-substituted derivative
(45.14 kcal.molÀ1) [16].
Condition outlined in entry 3 (Table 1) was repeated; however,
instead of isolating amine 3a from column chromatography, we
utilized preparative TLC plates (entry 4, Table 1). From here, we
decided to continue our evaluation by using purification with
preparative TLC, because it was considered to be more practical
and accurate for the determination of the isolated yields, at least
for the scale of the reactions herein assayed. By employing entry
4 experimental setting, we then utilized DHPs 1b–1d (see entries
5–7). As observed for 1a, the other DHPs (1b–1d) were capable
of reducing imine 2a to produce 3a. By comparing the isolated
yields shown in entries 4–7, it was also observed that the C-4-
unsubstituted DHPs (1c and 1d) provided substantially higher
yields than C-4-substituted 1a and 1b, with the simultaneously
N-1- and C-4-substituted 1a being the less effective DHP. These
results indicated that the substitution of the C-4 position impaired
hydrogen transfer to some extent [16], while the same effect could
not be surely attributed to the N-1 substitution.
The conditions utilized for our preliminary tests (entries 1–7,
Table 1) were conducted with excess of BF3OEt2 (3 equivalents),
because it was critical for the aromatization of 1a, as stated previ-
ously [22]. In order to verify if different amounts of the added
Lewis acid would influence the yield of amine 3a from imine 2a,
we repeated the conditions shown in entries 4–7 of Table 1, this
time by employing catalytic and stoichiometric amounts of BF3-
OEt2 (entries 8–15, Table 1). This evaluation generally indicated
that the use of stoichiometric amounts of BF3OEt2 was more effec-
tive than operating reactions under excess or catalytic quantities of
the Lewis acid, except for the Hantzsch ester analogue (1d), which
gave the best yield of Table 1 (90%) with a catalytic proportion of
BF3OEt2 (entry 15). On the other hand, DHP 1d was less effective
than N-substituted DHP 1c, when using excess (compare entries
6 and 7) or stoichiometric amounts of BF3OEt2 (compare entries
10 and 11).
As discussed above, as well as previously stated [16], N-1, C-4-
unsubstituted DHPs constitute more powerful reducing agents, in
comparison to their substituted counterparts. Based on the results
here exposed, it was possible to found conditions in which the less
reactive N-1-substituted derivative (1c) could approximately
match the maximum effectiveness of the Hantzsch ester analogue
(1d). Although the following matter is complex and involve diverse
factors, the present findings could provide an insight of why the
NADH/NAD+ system throve through the evolutionary barriers as
an N-substituted DHP, which is responsible to promote the meta-
bolic reductions in living cells. Perhaps, one of the reasons lies on
the fact that the reactivity of an N-substituted DHP could be more
efficiently modulated, especially considering the high complex
intracellular environment. Considering more practical matters,
reduction reactions requiring highly controlled hydride transfer
could be benefit from the use of less reactive DHPs, such as those
presenting substituents at N-1 of the DHP ring.
Based on the literature, the superiority of DHP 1c over 1d
(entries 10 and 11, Table 1), even despite of using selected condi-
tions, was somewhat unexpected. In this way, we decided to fur-
ther exploring the use of 1c under stoichiometric amounts of
BF3OEt2. First, by using the same conditions [31] of entry 10
(Table 1), DHP 1c was evaluated with imines 2b–2e [28,32–34]
(Scheme 1), which presented p-nitro or p-methyl substituents
located at the benzaldehyde- or aniline-derivative moieties, con-
sidering imine 2a scaffold. From these experiments, we noted that
the best yield (3d [35], 86%) was attained with imine 2d, which
was modified at the aniline moiety with electron-donor methyl
group. By contrast, when the imine scaffold was substituted at
the same position, but with the highly electron-withdrawing nitro
group, the expected product could not be detected. Imines 2c and
2e, both modified at the benzaldehyde moiety, gave intermediate
close yields for the corresponding amines 3c [35] and 3e [35]
(56% and 49%, respectively).
The fact that the best reduction conditions herein found con-
sisted of utilizing (a) DHP 1d added of catalytic amounts of BF3-
OEt2, or (b) DHP 1c added of stoichiometric BF3OEt2, could lead
to a number of tentative explanations. We understand that in the
case of DHP 1c, in order to perform the hydrogen transfer, the
DHP could require its own activation with boron trifluoride, plus
the transitory BF3-imine association, thus requiring larger amounts
of BF3OEt2 in the reaction mixture. This is accordance with findings
of De Kok and coworkers [30], which propose the activation of N-
substituted DHPs through the association of a Lewis acid with
the oxygen of the carbonyl groups attached to the DHP ring. Differ-
ently, for DHP 1d reaction, the catalytic amount of added BF3OEt2
would be sufficient to activate imine 2a, while any further amount
Results shown in Scheme 1 could be related to the mechanism
of the reactions herein described, where the substitution of the
aniline moiety in 2b and 2d structures interfered with the avail-
ability of the electron pair of the imine nitrogen. In the case of
2b, the interaction of the imine nitrogen with the Lewis acid could
be compromised, thus hindering the imine carbon to be the
hydride acceptor in the reaction course. Exactly the opposite effect
could be expected for imine 2d. In this way, the first step of the
reaction mechanism could be the Lewis acid-base interaction
between boron trifluoride and the imine nitrogen. This proposition
approximates with the accepted mechanism [1,8], when a DHP
Scheme 1. Reduction of imines 2b–2e using DHP 1c, under stoichiometric amounts of BF3OEt2, and the respective isolated yields of amines 3c–3e. *nd: product not detected.
Please cite this article as: I. F. Zattoni, L. D. Guanaes, L. B. Cerqueira et al., 1,4-Dihydropyridine/BF3OEt2 for the reduction of imines: Influences of the
amount of added BF3OEt2 and the substitution at N-1 and C-4 of the dihydropyridine ring, Tetrahedron Letters, https://doi.org/10.1016/j.
tetlet.2019.151129

4
I.F. Zattoni et al. / Tetrahedron Letters xxx (xxxx) xxx
Scheme 2. A. Reductive amination of benzaldehyde and aniline using DHP 1c under stoichiometric amounts of BF3OEt2 to produce amine 3a. *one-pot, two-step procedure:
under rt, benzaldehyde and aniline were mixed with 1 mL of CH2Cl2. The mixture was kept under stirring for 24 h. DHP 1c and BF3OEt2 were then added. The resulting
mixture was kept for further 24 h. **one-step procedure: under room temperature, benzaldehyde, aniline, DHP 1c and BF3OEt2 were mixed in 1 mL and kept for 24 h. B.
Attempted reduction of benzaldehyde to produce benzyl alcohol.
reacts with a mild oxidizing agent, namely, a catalyzed one-step
hydride transfer.
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amination conditions, specifically through one-pot, two-step and
one-step procedures (Scheme 2A), which gave 3a with 72% and
60% yield, respectively. A reaction conducted in the absence of ani-
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N1, C4-unsubstituted Hantzsch ester analogue (1d) was more
effective with catalytic quantities of the Lewis acid. The reaction
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reductive amination conditions.
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CDCl3) d (ppm) 168.8, 148.6, 141.0, 130.7, 129.50, 128.6, 125.1, 124.6, 101.6,
51.3, 25.0, 18.5. ESI-Q-TOF m/z calc, for [M+Na]+ C17H19NNaO4+ 324.1206;
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Acknowledgments
This study was financed in part by the Coordenação de Aper-
feiçoamento de Pessoal de Nível superior – Brasil (CAPES) –
Finance Code 0001. Grants from Fundação Araucária (15152) and
PRONEX-Carboidratos (14669) also supported the present work.
I.F.Z. thanks the scholarship from CAPES. R.P, D.R.B.D, M.E.D and
M.D.N are research members of CNPq (National Research Council
of Brazil). The authors are thankful to Professor Anderson Barison
from UFPR NRM Center for NMR experiments and to CEB UFPR
for HRMS experiments.
Appendix A. Supplementary data
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Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.151129.
Please cite this article as: I. F. Zattoni, L. D. Guanaes, L. B. Cerqueira et al., 1,4-Dihydropyridine/BF3OEt2 for the reduction of imines: Influences of the
amount of added BF3OEt2 and the substitution at N-1 and C-4 of the dihydropyridine ring, Tetrahedron Letters, https://doi.org/10.1016/j.
tetlet.2019.151129

I.F. Zattoni et al. / Tetrahedron Letters xxx (xxxx) xxx
5
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were observed under ultraviolet light and the region with the product was
marked and collected. The product was extracted washing the collected silica
with 50 mL of methanol. Finally, the solvent was removed under reduced
pressure, isolating the corresponding product.
[31] In an appropriate flask imine was added (0.1 mmol), as well as the
dihydropyridine 1c (30.1 mg, 0.1 mmol) and BF3Et2O (12 mL, 0.1 mmol). The
reaction was stirred for 24 hours in room temperature. Afterwards, 5 mL of
dichloromethane and 5 mL of NH4OH 10% were added and stirred. The organic
phase was collected and filtered in anhydrous sodium sulfate. The solvent was
completely removed under reduced pressure. The product was isolated using
chromatographic plates with hexane/ethyl acetate 9:1 as eluent. The plates
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Please cite this article as: I. F. Zattoni, L. D. Guanaes, L. B. Cerqueira et al., 1,4-Dihydropyridine/BF3OEt2 for the reduction of imines: Influences of the
amount of added BF3OEt2 and the substitution at N-1 and C-4 of the dihydropyridine ring, Tetrahedron Letters, https://doi.org/10.1016/j.
tetlet.2019.151129