Novel synthesis of substituted 4′-hydroxy-2,2′:6′,2″-terpyridines

Article abstract of DOI:10.1039/a704295g

4-Substituted-2,6-diacetylpyridines 2-4 have been synthesised; by using the Kroehnke-methodology, chalcone and methylacylpyridinium salts have been reacted to yield 4′-ethoxy-2,2′:6′,2″-terpyridines 5-7. These novel 2,2′:6′,2″-terpyridines are functionali

Full text of DOI:10.1039/a704295g

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Novel synthesis of substituted 4Ј-hydroxy-2,2Ј:6Ј,2Љ-terpyridines
Reza-Ali Fallahpour * and Edwin C. Constable
Institut für Anorganische Chemie, Universität Basel, Spitalstrasse 51, CH-4056 Basel,
Switzerland
4-Substituted-2,6-diacetylpyridines 2–4 have been syn-
thesised; by using the K röhnke-methodology, chalcone
and methylacylpyridinium salts have been reacted to yield
4Ј-ethoxy-2,2Ј:6Ј,2Љ-terpyridines 5–7. These novel 2,2Ј:6Ј,2Љ-
terpyridines are functionalised at C(4Ј) and possess sub-
stituents at C(4), C(5) and C(6) of both terminal pyridines,
respectively. The ethyl ether protecting group has been
cleaved to obtain 4Ј-hydroxy-2,2Ј:6Ј,2Љ-terpyridine 8.
2,6-diacetylpyridine 2 as yellowish crystals in 30% overall yield
from 4-ethoxypyridine-2,6-dicarboxylic acid.‡
Alternatively diethyl 4-chloropyridine-2,6-dicarboxylate was
hydrolysed to 4-chloropyridine-2,6-dicarboxylic acid which
readily reacted with thionyl chloride to give 4-chloropyridine-
2,6-dicarbonyl dichloride.12 The reaction of 4-chloropyridine-
2,6-dicarbonyl dichloride with Meldrum’s acid gave, after
evaporation of solvent, brown crystals which were hydrolysed
with aqueous acetic acid to give 4-chloro-2,6-diacetylpyridine 3
as yellow crystals in 32% overall yield from 4-chloropyridine-
2,6-dicarboxylic acid.§
Chelidamic acid 1 was esterified to diethyl 4-hydroxy-
pyridine-2,6-dicarboxylate then reacted with benzyl bromide in
the presence of crown ether to give diethyl 4-benzyloxy-
pyridine-2,6-dicarboxylate.13 This ester was hydrolysed, reacted
with thionyl chloride and after treatment with Meldrum’s acid
and aqueous hydrolysis gave 4-benzyloxy-2,6-diacetylpyridine
4¶ as colorless crystals in 35% overall yield from 4-benzyl-
oxypyridine-2,6-dicarboxylic acid.
Oligopyridines have received considerable attention in supra-
molecular chemistry1 and have been incorporated into helic-
ates,2 catenanes,3 dendrimers4 and knots5 among others. An
interesting field in supramolecular chemistry relates to the
photochemical properties of homo- and hetero-metallic com-
plexes using oligopyridine metal-binding domains.6,7
The 2,2Ј:6Ј,2Љ-terpyridine metal-binding is commonly incorp-
orated into multinucleating systems using 4Ј-chloro- or 4Ј-
hydroxy-functionalised derivatives.8 To date the synthetic
approaches to these key intermediates have not permitted add-
itional functionalisation on the terminal rings. We now report
the synthesis of 4Ј-hydroxy derivatives bearing functionality at
the 4,4Љ-, 5,5Љ- or 6,6Љ-positions.
All data for the fully characterised protected 4-hydroxy-2,6-
diacetylpyridines 2–4 are in agreement with the expected prop-
erties of these compounds in comparison with the known 2,6-
diacetylpyridine.
Among the existing methods for the synthesis of pyridines
and oligopyridines the Kröhnke-methodology is the most
commonly used.14 The synthesis consists of the reaction of a
chalcone and a methacylpyridinium [N-(2-oxoalkyl)pyridinium]
salt. The same methodology was applied to 4-ethoxy-2,6-di-
acetylpyridine 2. Thus we were able to synthesise terpyridines
with substituents at C(4), C(5) and C(6) of both terminal pyri-
dines while the 4Ј-position of terpyridine is functionalised as a
protected hydroxy group.
OH
HO
OH
N
O
O
1
Chelidamic acid 1 has not, to the best of our knowledge, been
used as a starting material for the synthesis of oligopyridines.
The presence of functionality in a position destined to become
C(4Ј) of a 2,2Ј:6Ј,2Љ-terpyridine makes it an attractive starting
point.
Compound 2 was reacted with p-tolualdehyde in ethanol at
0 ЊC to obtain the chalcone which readily gave 4Ј-ethoxy-6,6Љ-
dimethyl-4,4Љ-di(p-tolyl-2,2Ј:6Ј,2Љ-terpyridine 5|| in the reaction
Chelidamic acid 1 was esterified to diethyl 4-chloropyridine-
2,6-dicarboxylate which was then reacted with sodium ethoxide
to obtain diethyl 4-ethoxypyridine-2,6-dicarboxylate.†,9 This
ester was hydrolysed and converted to 4-ethoxypyridine-2,6-
dicarbonyl dichloride on reaction with thionyl chloride. The
reaction of 4-ethoxypyridine-2,6-dicarbonyl dichloride with
2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum’s acid)10 fol-
lowed by hydrolysis with aqueous acetic acid 11 gave 4-ethoxy-
‡ Compound 2: yellow crystals; mp 103–4 ЊC (hexane); νmax(KBr)/cmϪ1
1704; δH (CDCl3; J/Hz) 7.60 (s, 2H), 4.13 (q, J 7.3, 2H), 2.70 (s, 6H), 1.41
(t, J 7.33, 3H); δC(CDCl3) 199.34 (H3CC᎐O), 166.70 [C(4)], 154.39
᎐
[C(2,6)], 110.72 [C(3,5)], 64.37 (H3CCH2O), 25.56 (H3CC᎐O), 14.24
᎐
(H3CCH2O).
§ Compound 3: yellow crystals; mp 64 ЊC (hexane); νmax(KBr)/cmϪ1
1704; δH (CDCl3) 8.17 (s, 2H), 2.77 (s, 6H); δC(CDCl3) 197.95 (H3CC᎐O),
᎐
153.73 [C(2,6)], 146.75 [C(4)], 124.78 [C(3,5)], 25.50 (H3CC᎐O).
᎐
¶ Compound 4: colorless crystals; mp 74 ЊC (hexane); νmax(KBr)/cmϪ1
1699; δH (CDCl3) 7.78 (s, 2H), 7.41–7.37 (m, 5H), 5.21 (s, 2H), 2.77 (s,
6H); δC(CDCl3) 199.26, 166.49, 154.53, 134.91, 128.72, 128.50, 127.51,
111.11, 70.41, 25.62.
† The Claisen condensation of 4-ethoxy and 4-benzyloxy9 diethyl
pyridine-2,6-dicarboxylates with sodium ethoxide and ethyl acetate to
give a β-keto ester failed, although the reaction of diethyl pyridine-2,6-
dicarboxylate to obtain 2,6-diacetylpyridine has already been
reported.16
|| Compound 5: colorless crystals; mp 116–117 ЊC (ethanol); δH (CDCl3;
J/Hz) 8.63 (m, 2H), 8.04 (s, 2H), 7.68 (d, J 7.80, 2H), 7.40 (m, 2H), 7.31
(d, J 7.80, 2H), 4.34 (q, J 7.3, 2H), 2.70 (s, 6H), 2.44 (s, 6H), 1.51 (t,
J 7.3, 3H).
J. Chem. Soc., Perkin Trans. 1, 1997
2263

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with N-(methylacetyl)pyridinium chloride [N-(2-oxopropyl)-
pyridinium chloride] in 60% yield. A bis-Mannich-base was
obtained in the reaction of 2 with paraformaldehyde and
dimethylamine in DMF which readily reacted with N-
(methylacetyl)pyridinium chloride to give 4Ј-ethoxy-6,6Љ-
dimethyl-2,2Ј:6Ј,2Љ-terpyridine 6†† in 56% yield.
The data for the new terpyridines 5–8 are in agreement with
the expected properties of the known 4Ј-hydroxy-2,2Ј:6Ј,2Љ-
1
terpyridine.8 In the H NMR spectrum of 8 the protons at
C(6,6Љ) and C(3Ј,5Ј) were each observed as singlets at 8.59 and
7.02 ppm, respectively, while protons at C(3,3Ј) were observed
as a doublet at 7.81 ppm and protons at C(4,4Ј) as a doublet of
doublets at 7.67 ppm, respectively. The methyl groups were
observed as a singlet at 2.43 ppm. Compound 8 has been fully
characterised. While terpyridines 7 and 8 react readily at
ambient temperature to give purple FeII-complexes, the FeII-
complexes of 5 and 6 are formed only at elevated temperatures,
because of the substituents at the 6,6Љ-positions.
In conclusion, we have established a methodology for prepar-
ing 8 which has the potential for undergoing regioselective reac-
tions both at C(5), C(5Љ) and, more importantly, at C(4Ј) which
possesses a hydroxy group.
R1
R1
R2
R2
R3
N
N
N
N
R3
O
O
R4
R4
5 R1 = OEt, R2 = Me, R4 = p-tolyl, R3 = H
6 R1 = OEt, R2 = Me, R3 = R4 = H
7 R1 = OEt, R3 = Me, R2 = R4 = H
2 R1 = OEt
3 R1 = Cl
4 R1 = OBn
Acknowledgements
We thank the Schweizerischer Nationalfonds zur Förderung
der wissenschaftlichen Forschung and the University of Basel.
References
OH
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N
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8
Scheme 1
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2,6-Bis(1-oxo-2-pyridinoethyl)-4-ethoxypyridinediiodidewas
obtained by the reaction of 2 with iodine in pyridine; this
reacted with methacrolein (2-methylpropenal) to give a terpyri-
dine substituted at C(5) of both terminal pyridines, namely 4Ј-
ethoxy-5,5Љ-dimethyl-2,2Ј:6Ј,2Љ-terpyridine 7‡‡ in 45% yield.
The ethyl ether protecting group was cleaved in pyridine and
hydrochloric acid at elevated temperature15 and 5,5Љ-dimethyl-
4Ј-hydroxy-2,2Ј:6Ј,2Љ-terpyridine 8 was obtained in 50% yield.§§
†† Compound 6: colorless crystals; mp 169–170 ЊC (ethanol);
δH (CDCl3; J/Hz) 8.39 (d, J 7.80, 2H), 8.01 (s, 2H), 7.72 (t, J 7.80, 2H),
7.18 (d, J 7.80, 2H), 4.31 (q, J 7.3, 2H), 2.64 (s, 6H), 1.49 (t, J 7.3, 3H).
‡‡ Compound 7: yellow needles; mp 140–141 ЊC (ethanol); δH (CDCl3;
J/Hz) 8.50 (s, 2H), 8.48 (d, J 7.3, 2H), 7.93 (s, 2H), 7.63 (d, J 7.3, 2H),
4.28 (q, J 7.3, 2H), 2.40 (s, 6H), 1.47 (t, J 7.3, 3H); δC(CDCl3) 167.21,
156.26, 152.84, 148,83, 137.88, 133.74, 121.12, 107.12, 64.02, 18.32,
14.53.
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§§ Compound 8: colorless crystals; mp 168–169 ЊC (hexane); δH (CDCl3)
8.59 (s, 2H), 7.81 (d, J 8.30, 2H), 7.67 (dd, J 8.30, J 1.95, 2H), 7.02 (s,
2H), 2.43 (s, 6H); δC(CDCl3) 149.66, 146.18, 144.59, 137.78, 135.01,
119.71, 112.65, 18.31.
Paper 7/04295G
Received 19th June 1997
Accepted 19th June 1997
2264
J. Chem. Soc., Perkin Trans. 1, 1997