A synthetic entry to 3,5-disubstituted pyridines

Article abstract of DOI:10.1016/S0040-4039(03)01055-4

A straightforward entry to 3,5-disubstituted pyridines from 3-substituted pyridines, based on the acylation of N-alkyl-1,4-dihydropyridine derivatives followed by a tandem N-dealkylation-oxidation sequence is reported.

Full text of DOI:10.1016/S0040-4039(03)01055-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4711–4714
A synthetic entry to 3,5-disubstituted pyridines
M.-Llu¨ısa Bennasar,* Ester Zulaica, Toma`s Roca, Yolanda Alonso and Manuel Monerris
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona 08028, Spain
Received 5 March 2003; revised 22 April 2003; accepted 24 April 2003
Abstract—A straightforward entry to 3,5-disubstituted pyridines from 3-substituted pyridines, based on the acylation of
N-alkyl-1,4-dihydropyridine derivatives followed by a tandem N-dealkylation–oxidation sequence is reported. © 2003 Elsevier
Science Ltd. All rights reserved.
Pyridines are useful intermediates in natural product
synthesis as well as common building blocks found in
many biologically active molecules.1 Recently, we
required an efficient synthesis of 3,5-disubstituted
pyridines of general formula 1 (Scheme 1), as potential
intermediates in the synthesis of some dihydropyridine
alkaloids (lyaline, lyadine).2 An inspection of the litera-
ture data revealed that, apart from condensation reac-
tions leading to the dihydropyridine ring,1,3,4 the
reported strategies rely on the suitable manipulation of
pre-existing annular substituents, in particular through
transition metal catalyzed cross-coupling reactions.5
valuable 3,5-diacyl-4-aryl-1,4-dihydropyridines. The
acylation conditions would now have to be adapted to
4-unsubstituted 1,4-dihydropyridines,7 which would be
generated by the classical sodium dithionite reduction8
of the starting pyridinium substrates. Moreover, we
would have to be able to efficiently promote the final
N-dealkylation with subsequent oxidation.
To test the feasibility of this proposal, we first decided
to study the introduction of a methoxycarbonyl sub-
stituent at the 5-position of commercially available
3-substituted
pyridines:
methyl
nicotinate,
3-
acetylpyridine and 3-bromopyridine (Scheme 2, Table
1). The benzhydryl group was selected as the nitrogen
substituent for the required pyridinium salts 2 since it is
easily installed in a 3-acylpyridine and can be removed
from the dihydropyridine nitrogen in relatively mild
conditions.6b,9 As expected, sodium dithionite reduction
of 2a gave the corresponding 1,4-dihydropyridine (3,
R1=CO2Me), which was directly treated with
trichloroacetic anhydride in the presence of triethyl-
amine. The resulting (trichloroacetyl)dihydropyridine
4a smoothly underwent a haloform reaction with
sodium methoxide to give diester 5a in 50% overall
With the final aim of developing a common synthetic
entry to 3,5-disubstituted pyridines from readily avail-
able b-monosubstituted pyridine starting materials, we
decided to take advantage of the nucleophilic character
of the unsubstituted enaminic side of 1,4-dihydro
derivatives of N-alkyl-3-acylpyridinium salts to intro-
duce an additional acyl substituent at the 5-position.
This would represent an extension of our previous
work,6 in which the intermediate 1,4-dihydropyridine
adducts were generated by the chemo- and regioselec-
tive addition of arylcopper reagents, giving access to
Scheme 1.
Keywords: dihydropyridines; pyridines; acylation; oxidation.
* Corresponding author. Tel.: 34-934024540; fax: 34-934024539; e-mail: bennasar@farmacia.far.ub.es
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01055-4

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M.-L. Bennasar et al. / Tetrahedron Letters 44 (2003) 4711–4714
disproportionation, can account for this result. Satis-
factorily, the yield of pyridine 1a increased (75%) when,
inspired by the recent report of Hayashi,12 the dealkyla-
tion with TFA–phenol was effected in the presence of a
Pd/C catalyst. This tandem N-dealkylation–oxidation
sequence was successfully applied to dihydropyridines
5b and 5c to give pyridines 1b and 1c.
Representative experimental procedure: synthesis of pyri-
dine 1b. Na2S2O4 (17.4 g, 0.1 mol) was added under Ar
to a mixture of pyridinium bromide 2b (3.31 g, 9 mmol)
in CH2Cl2 (220 mL) and 1 M aqueous NaHCO3 (200
mL). After stirring at rt in the dark for 5 h, the mixture
was extracted with CH2Cl2 (3×200 mL) and the organic
extracts were dried and concentrated. The crude residue
was dissolved in anhydrous THF (90 mL), treated with
Et3N (3.75 mL, 27 mmol) and TCAA (4.93 mL, 27
mmol) at 0°C, and stirred at 0°C overnight. The reac-
tion mixture was poured into saturated aqueous
Na2CO3 (90 mL) and extracted with AcOEt (3×90 mL).
The organic extracts were dried and concentrated. The
resulting residue was digested with Et2O (3×100 mL)
and the ethereal extracts were concentrated to afford
4b. A solution of 4b in MeOH–THF (1:1, 50 mL) was
added dropwise to a solution of MeONa (27 mmol) in
MeOH (90 mL), and the mixture was stirred at rt for 3
min. The solvent was removed, and the resulting
residue was partitioned between CH2Cl2 (100 mL) and
H2O (100 mL), and extracted with CH2Cl2 (2×100 mL).
After removal of the solvent, the resulting residue was
digested with Et2O (3×100 mL) and the ethereal
extracts were concentrated to give dihydropyridine 5b
(1.9 g, 60%).
Scheme 2.
yield from 2a. Satisfactorily, when the above sodium
dithionite
reduction–acylation–haloform
reaction
sequence was applied to N-(benzhydryl)pyridinium
salts 2b and 2c, asymmetrically substituted dihydropy-
ridines 5b and 5c (through 4b and 4c) were obtained in
similar yields. Acetyl derivative 5b could also be
obtained by radical reduction of the trichloroacetyl
group of 4a with tributylstannane–AIBN, although the
yield was less satisfactory (50% for the single step). It is
worth noting that the best yields in the above transfor-
mations were observed when chromatographic purifica-
tions were avoided and, instead, the crude reaction
products were digested with ether. In fact, unlike 4-aryl
derivatives,6 dihydropyridines 4 and 5 were somewhat
unstable and acid sensitive and were only identified by
their NMR data.
With dihydropyridines 5 in hand, attention was turned
to the oxidative step. The oxidation of 1,4-dihydropy-
ridines to pyridines or pyridiniums has been extensively
studied, in large part due to the occurrence of the
1,4-dihydropyridine ring system in the reduced forms of
NADH and NADPH, which are responsible for a
number of biological oxidations and reductions. From
a synthetic standpoint, most of the information of the
literature deals with N-unsubstituted dihydropyridines
having electron withdrawing substituents at the b-posi-
tions (Hantzsch dihydropyridines).10,11 For our pur-
poses, by analogy with our previous experience,6b
N-(benzhydryl)dihydropyridine 5a was treated with
TFA–phenol at 50°C in order to first promote N-
dealkylation. However, under these acidic conditions
pyridine 1a was isolated in 40% yield along with highly
polar substances. Oxidation of the formed N-unsubsti-
tuted dihydropyridine, either by air (it was not
rigourously excluded from the reaction vessel) or by
A suspension of 1,4-dihydropyridine 5b (1.9 g, 5.5
mmol), phenol (1.03 g, 11 mmol) and 10% Pd/C (0.38
g) in TFA (9 mL) was stirred at 50°C for 3 h. The
reaction mixture was filtered through Celite and the
cake was washed with CH2Cl2 (30 mL). The resulting
organic solution was poured into a saturated aqueous
solution of Na2CO3 (50 mL) and extracted with CH2Cl2
(3×50 mL). The solvent was removed and the residue
was chromatographed (SiO2, 7:3 hexane–AcOEt) to
give 1b (0.78 g, 80% yield). The spectroscopic data of
1b were identical with those reported in the literature.13
To ascertain the scope of the oxidative aromatization
step we focused our attention on 4-phenyl substituted
dihydropyridine 7,14 which was easily prepared in 55%
overall yield as outlined in Scheme 3, by copper-cata-
lyzed addition of phenylmagnesium chloride to 3-
ethylpyridinium salt 6, followed by acylation with
trichloroacetic anhydride and the subsequent haloform
Table 1. Synthesis of 3,5-disubstituted pyridines
Pyridinium salt
R1
Dihydropyridines (overall yield, %)a
Pyridine (yield, %)a
2a
2b
2c
CO2Me
COMe
Br
4a, 5a (50)
4b, 5b (60)
4c, 5c (50)
1a (75)
1b (80)
1c (80)
a Isolated yields of pure material.

M.-L. Bennasar et al. / Tetrahedron Letters 44 (2003) 4711–4714
4713
In summary, we have reported a general method for the
synthesis of valuable 3,5-disubstituted pyridines. The
method is attractive due to the simplicity of the opera-
tional procedure, the mildness of the conditions, and
the applicability to a great variety of starting 3-substi-
tuted pyridine substrates.
Acknowledgements
Financial support from the ‘Ministerio de Ciencia y
Tecnolog´ıa’ (Spain, project BQU2000-0785) is grate-
fully acknowledged. We also thank the DURSI (Gener-
alitat de Catalunya) for Grant 2001SGR00084 and for
a fellowships to M.M. One of us (Y.A.) also thanks the
‘Ministerio de Educacio´n, Cultura y Deporte’ for a
Grant.
Scheme 3.
reaction. Satisfactorily, the TFA–phenol–Pd/C system
also exhibited a high performance since pyridine 815
was obtained in 65% yield from 7.
References
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Scheme 4.

4714
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(CDCl3, 300 MHz): l 15.6 (CH3), 23.6 (CH2), 51.9 (CH3),
126.4 (C), 127.6 (CH), 127.7 (CH), 127.9 (CH), 136.9 (C),
137.7 (C), 148.0 (CH), 149.0 (C), 152.5 (CH), 166.7 (C).
Anal. calcd for C15H15NO2: C, 74.67; H, 6.27; N, 5.81.
Found: C, 74.84; H, 6.31; N, 5.69.
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11. N-Alkyldihydropyridines are usually oxidized to pyri-
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18. Dihydropyridine 12a: 1H NMR (CDCl3, 300 MHz): l
1.80 (m, 4H), 3.20 (d, J=15 Hz, 1H), 3.30 (s, 3H), 3.40
(m, 5H), 3.69 (s, 3H), 4.30 (m, 1H), 4.37 (s, 2H), 6.30 (s,
1H), 7.12 (s, 1H), 7.20–7.40 (m, 5H). 13C NMR (CDCl3,
300 MHz): l 23.1 (CH2), 24.7 (CH2), 27.7 (CH2), 49.1
(CH2), 51.2 (CH3), 56.8 (CH), 57.6 (CH2), 59.0 (CH3),
72.9 (CH2), 101.3 (C), 110.9 (C), 127.0 (CH), 128.0 (CH),
128.9 (CH), 132.9 (CH), 16.5 (C), 140.0 (CH), 167.8 (C),
169.1 (C). [h]2D2=−132 (c 1, MeOH).
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1985, 23, 1707–1723. See also Refs. 3 and 5a.
1
14. Dihydropyridine 7: H NMR (CDCl3, 300 MHz): l 0.87
19. Pyridine 13: 1H NMR (CDCl3, 300 MHz): l 2.02 (m,
4H), 3.18 (m, 1H), 3.40 (s, 3H), 3.45 (m, 1H), 3.65 (m,
2H), 3.98 (s, 3H), 4.42 (br s, 1H), 8.44 (s, 1H), 8.93 (s,
1H), 9.25 (s, 1H). 13C NMR (CDCl3, 300 MHz): l 25.1
(CH2), 27.5 (CH2), 50.5 (CH2), 52.6 (CH3), 57.2 (CH),
59.2 (CH3), 72.3 (CH2), 125.5 (C), 132.7 (C), 135.8 (CH),
151.5 (CH), 151.8 (CH), 165.0 (C), 166.2 (C). [h]2D2=−96
(c 1, MeOH). HRMS calcd for C14H18N2O4: 278.1260;
found: 278.1263.
(t, J=7.5 Hz, 3H), 1.81 (q, J=7.5 Hz, 2H), 3.49 (s, 3H),
4.46 (s, 1H), 5.79 (s, 1H), 5.82 (s, 1H), 7.2–7.4 (m, 16H).
13C NMR (CDCl3, 300 MHz): l 11.5 (CH3), 25.4 (CH2),
42.3 (CH), 50.6 (CH3), 70.2 (CH), 101.5 (C), 121.5 (CH),
122.3 (C), 126.0 (CH), 127.6–128.8 (CH), 138.6 (CH),
138.9 (C), 139.0 (C), 146.4 (C), 168.2 (C).
15. Pyridine 8: 1H NMR (CDCl3, 300 MHz): l 1.05 (t, J=7.4
Hz, 3H), 2.05 (q, J=7.8 Hz, 2H), 3.60 (s, 3H), 7.17 (m,
2H), 7.41 (m, 3H), 8.65 (s, 1H), 8.91 (s, 1H). 13C NMR