1,4-Dihydropicolinic acid derivatives: Novel NADH analogues with an altered connectivity pattern

Article abstract of DOI:10.1016/j.tetlet.2005.03.069

Sodium dithionite reduction of α-substituted N-alkylpyridinium salts (derived from picolinic acid derivatives) afforded the corresponding 1,4-dihydropyridines with a new substitution pattern, in which the electron-withdrawing group is at the α-position. These compounds promote biomimetic reductions and are hence considered functional NADH analogues.

Full text of DOI:10.1016/j.tetlet.2005.03.069

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3513–3516
1,4-Dihydropicolinic acid derivatives: novel NADH analogues
with an altered connectivity pattern
a
Elena G o´ mez, Miriam Miguel, Oscar Jim e´ nez,
a
a
a
Guillermo de la Rosa and Rodolfo Lavilla
a,b,
*
a
Parc Cient ı´ fic de Barcelona, Institut de recerca Biomedica de Barcelona, University of Barcelona, Josep Samitier 1–5,
8028 Barcelona, Spain
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Avda Joan XXIII sn, 08028 Barcelona, Spain
0
b
Received 17 February 2005; revised 10 March 2005; accepted 14 March 2005
Available online 1 April 2005
Abstract—Sodium dithionite reduction of a-substituted N-alkylpyridinium salts (derived from picolinic acid derivatives) afforded
the corresponding 1,4-dihydropyridines with a new substitution pattern, in which the electron-withdrawing group is at the a-posi-
tion. These compounds promote biomimetic reductions and are hence considered functional NADH analogues.
Ó 2005 Elsevier Ltd. All rights reserved.
4
NADH is the cofactor used by many reductases in
metabolism, and its reactive moiety is a 1,4-dihydropyr-
idine (DHP) unit. Compounds based on this heterocycle
play key roles in medicinal chemistry (as calcium chan-
nel blockers), organic synthesis (versatile intermediates)
and bioorganic chemistry (NADH analogues), and have
gation of the nitrogen atom and the b-substituent.
However, this situation may not be a sine qua non
requirement, and results of the reduction of pyridinium
salts with stabilizing electron-withdrawing groups at the
a-position are herein reported (Fig. 1). Albeit simple, the
variation strongly affects the electronic properties of
the heterocyclic system, consequently changing the
1
inspired several lines of research. Considerable efforts
5
have been devoted to the preparation of diversely substi-
tuted DHP derivatives, yet some substitution patterns
with potential applications in the aforementioned fields
remain elusive or simply unknown. This fact probably
reflects the complexity of the factors that control the sta-
bility and the reactivity of these heterocyclic systems.
The classic sodium dithionite reduction of N-alkylpyrid-
inium salts is perhaps the most simple and reliable meth-
structural and reactivity parameters of the new DHPs.
The first experiments involved the reactivity of the
N-methyl-2-methoxycarbonylpyridinium iodide (1a),
which was readily prepared by interaction of MeI with
methyl picolinate. The reduction of this compound
under standard conditions (excess of Na S O and Na-
2
2
4
HCO , CH Cl –H O, room temperature, 12h) afforded
3
2
2
2
od for the regioselective formation of the corresponding
2
a mixture of the DHP 2a together with the piperidine
derivative 3a and unreacted salt. Modifications of
stoichiometry and reaction time ultimately provided
optimized protocols for the clean partial and total
reductions of the heterocyclic system. Thus, upon
1
,4-DHP derivatives. These reactions are often con-
ducted in basic medium, whereby the key step involves
the nucleophilic attack of the sulfinic species upon the
3
c-position of the activated pyridinium salt. For this rea-
son, the process is restricted almost entirely to pyrid-
inium salts bearing electron-withdrawing substituents
at the b-position, as these salts are more electrophilic
at C-4, and the resulting DHPs benefit from the conju-
Keywords: Dihydropyridines; Piperidines; NADH; Reduction; Sodium
dithionite.
*
Corresponding author. Tel.: +34 93 403 7106; fax: +34 93 403
104; e-mail: rlavilla@pcb.ub.es
7
Figure 1.
0
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.069

3514
E. G o´ mez et al. / Tetrahedron Letters 46 (2005) 3513–3516
In some experiments of the previous series, the form-
ation of small amounts of the corresponding piperidines
was observed when extended reaction times were
3
9
used. The full reduction of the starting heterocyclic
systems was found to proceed more efficiently in the
absence of NaHCO . In this way, piperidines 3a (96%)
3
1
0
and 3b (45%) were prepared and positively identified.
We may consider, as a reasonable mechanistic hypothe-
sis, that under these conditions, the initially formed
DHPs (2) may undergo protonation from the increas-
ingly acidic reaction medium to generate iminium ions,
which would be reduced by the dithionite, to yield the
reactive tetrahydropyridine intermediates, for instance
A. These species, which could not be detected or iso-
lated, would in turn undergo further reduction via
conjugate dithionite addition to the activated double
bond and subsequent protonolysis (see Scheme 2).
Scheme 1. Sodium dithionite reduction of pyridinium salt 1a.
treatment with reduced amounts of sodium dithionite
(2equiv) for 24 h, the dihydropyridine 2a (44%) was
selectively obtained, whereas with a larger excess of
the reducing agent, in the absence of NaHCO , piper-
3
The reduction of the cyanopyridinium salt 1e under
these conditions surprisingly afforded the 2,6-dicyanopi-
peridine 4 (35%), as a 7:1 mixture of cis/trans stereo-
idine 3a (96%) was isolated as the only product (Scheme
1
).
11
isomers (see Fig. 2). Although no rigorous mechanistic
studies were performed, a plausible explanation for this
result might involve the formation of the expected
a-cyanopiperidine, which, being an iminium ion precur-
The a-substituted DHP 2a was characterized spectro-
scopically. This compound is more prone to oxidation
and acid-catalyzed decomposition than the well known
b-substituted NADH analogues, nevertheless it could
be conveniently stored under inert atmosphere at low
12
sor, could expel a cyanide anion capable of adding to
the protonated form of a DHP intermediate (type 2,
Scheme 2). Reduction of the resulting species would
yield the dicyano structure 4.
6
temperature. Although the reduction works well with
different N-alkyl (methyl and benzyl) substituents at
the nitrogen, it seems to be highly dependent on the nat-
ure of the substituent at the a-position of the pyridine
ring. Thus, reduction under the usual conditions works
with a-CO Me and CONH groups (Table 1, entries 1
Interestingly, water acts as the hydrogen source in these
reductive processes, which apart from environmental
2
2
13
considerations, enables the deuteration of the DHPs
2
and 2), but not with a-H, Cl or alkyl groups. This is
in agreement with the known requirements for the
Na S O of b-substituted pyridinium salts, however a
and the piperidines 3, simply by using D O. In this
2
2
2
4
CHO group fails to yield detectable amounts of DHP
(Table 1, entry 3), probably due to its extended hydr-
7
ation under the reaction conditions. Pralidoxime (1d,
R1
N +
R1
N
X -
R2
Na S O
2 2 4
R2
Table 1, entry 4) did not react under the same
8
conditions.
H
O - CH
Cl
2 2
2
2
4 h, rt
1
a,b
3a,b
The transformation of salt 1e under the usual conditions
afforded a more complex mixture, hence the correspond-
ing DHP (2e) was isolated in moderate yield (entry 5).
The reactivity of the cyano derivatives merits separate
commentary (vide infra).
R1
R1
N
R2
N
R2
2a,b
A
Table 1. Reduction of a-substituted pyridinium salts 1
a: R1 = Me, R2 = CO Me
2
b: R1 = Bn, R2 = CONH2
R1
R1
N
X - Na
S
O
2
2
4
3
+
R2
N
NaHCO
R2
Scheme 2. Pyridinium salt reduction to piperidines 3.
H O - CH Cl
2
2
2
rt. 24h
1
2
1
2
R
a
Product Yield (%)
Entry Pyridinium salt
R
1
2
3
4
5
1a
1b
1c
1d
1e
Me CO
2
Me
2a
2b
—
—
2e
44
97
—
—
58
Bn CONH
Me CHO
2
Me CH@NOH
Me CN
a
Isolated yield.
Figure 2.

E. G o´ mez et al. / Tetrahedron Letters 46 (2005) 3513–3516
4,15 16
3515
1
way the deuterated analogues of 2a
and 3b were
applications of these DHPs are currently under
investigation.
efficiently prepared (Fig. 2). Remarkably, the last reac-
tion allows the simultaneous incorporation of up to
seven deuterium atoms (five C–D and two N–D bonds).
Acknowledgements
Finally, the ability of the new DHPs 2 to promote bio-
mimetic reductions was preliminarily tested. Thus under
standard conditions [Mg(II), CH CN] 2b was capable
3
Financial supports from the DGICYT (Spain, project
BQU2003-00089) and from Almirall Prodesfarma
Barcelona) are gratefully acknowledged. We thank
Dr. Jos e´ Luis D ´ı az (Laboratorios. Dr. Esteve, Barce-
lona) for useful comments.
1
4a
of reducing methyl benzoylformate to form methyl man-
1
(
7
delate. Additionally, a reductive amination, (p-methyl-
aniline, ethyl glyoxalate) was carried out with DHP 2b
in the presence of Sc(OTf) (Scheme 3). Interestingly
3
these compounds seem to be comparatively more
efficient reducing agents than the classic b-susbtituted
Supplementary data
1
leading to multicomponent reactions under the afore-
,4-DHPs, as the latter behave as enamine derivatives
1
8
A supplementary data section is provided, which in-
cludes the experimental procedures and characterization
data. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2005.03.069.
mentioned conditions (see Scheme 3). These results
illustrate the dramatic influence of the substituent loca-
tion at the DHP ring on its reactivity. The overall yield
of these processes is moderate (ꢀ60%) presumably be-
cause of the fragility of the DHPs and their tendency
1
9
to spontaneously oxidize. To the best of our knowl-
edge, this is the first non-Hantzsch dihydropyridine,
which promotes the biomimetic reductive amination.
References and notes
1
. For reviews on the chemistry of dihydropyridines, see: (a)
Fowler, F. W. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford,
In conclusion, access to a novel class of stable DHPs
with an altered substitution pattern has been described.
The synthetic process is simple, employs a cheap reduc-
ing agent and uses water as the proton source. In addi-
tion, modification of the reaction conditions permits the
straightforward preparation of the corresponding
piperidines and deuterated derivatives. The DHPs thus
prepared can be considered as functional NADH ana-
logues, as they promote the same type of biomimetic
carbonyl and imine reductions as NADH. Further
1
984; Vol.2, p 365; (b) Lounasmaa, M.; Tolvanen, A. In
Comprehensive Heterocyclic Chemistry II; Katritzky, A.
R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon:
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2
3
. For instance, see: Brewster, M. E.; Simay, A.; Czako,
C.; Windwood, D.; Farag, H.; Bodor, N. J. Org. Chem.
1
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. For a recent mechanistic study, see: Carelli, V.; Libera-
tore, F.; Scipione, L.; Musio, R.; Sciacovelli, O. Tetrahe-
dron Lett. 2000, 41, 1235.
Bn
N
Bn
N
H NOC
2
H NOC
4. Some exceptions, however, are reported in the literature,
although the DHPs lacking electron-withdrawing groups
are very unstable. See MarazanoÕs approach to chiral
dihydropyridines: Wong, Y.-S.; Marazano, C.; Gnecco,
D.; G e´ nisson, Y.; Chiaroni, A.; Das, B. C. J. Org. Chem.
1997, 62, 729; For a Birch-type approach, see: De Konig,
A. J.; Budzelaar, P. H. M.; Brandsma, L.; De Bie, M. J.
A.; Boersma, J. Tetrahedron Lett. 1980, 21, 2105.
2
O
OH
CO Me
2
b
1b
CO Me
2
2
Mg(ClO4) CH CN
2,
3
rt, 48 h, Ar
60%
Bn
N
5. For instance, see: Hentall, P. L.; Flowers, N.; Bugg, T. D.
H. Chem. Commun. 2001, 2098; Also see: Pop, E.;
Brewster, M. E.; Huang, M.-J.; Bodor, N. J. Mol. Struct.
Bn
N
H NOC
H NOC
2
2
H
N
CO Et
2
(
Theochem) 1995, 337, 49.
1
b
2
b
6. DFT calculations (B3LYP; basis set 6-31G*) show that 2a
is about 8.7 kcal/mol less stable than the corresponding
b-substituted isomer. Remarkably, the steric interaction
between the N-methyl and the methoxycarbonyl groups
seems to force a nonplanar alignment of the enamine
moieties of the heterocyclic ring, resulting in a significant
Me
56%
O
Sc(OTf)3, CH CN
3
H
CO Et
2
rt, 24 h, Ar
Me
NH
+
NH2
Sc(OTf)3, CH CN
Bn
N
3
rt, 24 h, Ar
loss of conjugation.
. The H NMR spectrum in DMSO-d of the 2-formyl-1-
1
7
6
Me
Bn
N
methylpyridinium iodide shows a 1:1 equilibrium between
the carbonyl and the hydrate forms, which should
presumably be totally shifted towards the gem-diol in
water, thus deactivating the pyridinium salt.
H NOC
2
6
7% CO Et
2
H NOC
ref. 18
2
8
. Although a lenghty route for a putative 1,6-dihydropral-
idoxime has been described, the 1,4-dihydro derivative is
Scheme 3. Biomimetic reductions promoted by the new DHPs 2.

3516
E. G o´ mez et al. / Tetrahedron Letters 46 (2005) 3513–3516
not known. Bodor, N.; Shek, E.; Higuchi, T. J. Med.
Chem. 1976, 19, 102.
. For the only precedent of a low yielding dithionite
reduction of deactivated pyridinium salts to piperidines,
see: Minato, H.; Fujie, S.; Okuma, K.; Kobayashi, M.
Chem. Lett. 1977, 1091.
Chem. 1993, 21, 423; (b) Zhu, X.-Q.; Cao, L.; Liu, Y.;
Yang, Y.; Lu, J.-Y.; Wang, J.-S.; Cheng, J.-P. Chem. Eur.
J. 2003, 9, 3937.
9
15. Incidentally, the spontaneous (oxygen promoted) oxid-
ation of the deuterated DHP 2a (4-D), afforded a nearly
quantitative yield of the corresponding pyridinium salt,
bearing a deuterium atom at the c-position [1a (4-D)],
1
1
0. (a) Koskinen, A.; Lounasmaa, M. Tetrahedron 1983, 39,
627; (b) Crabb, T. A.; Newton, R. F. J. Chem. Soc.,
Perkin Trans. 2 1972, 1920.
+
1
which could be considered as a labeled NAD analogue.
16. Presumably as a mixture of isotopomers. For the deute-
rium transfer reduction of pyridines using deuterated
ammonium formate, see: Derkau, V. Tetrahedron Lett.
2004, 45, 8889.
17. For a recent example of reductive aminations using
Hantzsch dihydropyridines, see: Itoh, T.; Nagata, K.;
Miyazaki, M.; Ishikawa, H.; Kurihara, A.; Ohsawa, A.
Tetrahedron 2004, 60, 6649.
18. Carranco, I.; D ´ı az, J. L.; Jim e´ nez, O.; Vendrell, M.;
Albericio, F.; Royo, M.; Lavilla, R. J. Comb. Chem. 2005,
7, 33.
19. Although DHPs 2 rapidly decompose in open air, the
NMR spectrum of a DMSO-d6 solution of 2a remains
unchanged after 7 days at rt.
1. For the preparation, structure and reactivity of 2,6-
dicyanopiperidines, see: (a) Johnson, H. E.; Crosby, D.
G. J. Org. Chem. 1961, 27, 1298; (b) Bonin, M.; Chiaroni,
A.; Beloeil, J.-C.; Grierson, D.; Husson, H.-P. J. Org.
Chem. 1987, 52, 382; (c) Putkonen, T.; Valkonen, E.;
Tolvanen, A.; Jokela, R. Tetrahedron 2002, 58, 7869.
2. The dithionite reduction of this iminium ion would afford
the N-methylpiperidine, which was detected.
1
1
1
3. Catalytic (Pd, PtO , etc.) hydrogenation is the standard
2
procedure for reduction of pyridinium salts to piperidines.
4. The use of deuterated NADH analogues is useful for
studying the hydride transfer mechanism. See, for
instance: (a) He, G.-X.; Blask o´ , A.; Bruice, T. Bioorg.