A new and convenient one-pot solid supported synthesis of 2,4,6-triarylpyridines

Article abstract of DOI:10.1016/j.tetlet.2005.11.043

A new, convenient, efficient and cost-effective one-pot solid supported synthesis of 2,4,6-triarylpyridines from benzylideneacetophenones and urea, thiourea or their derivatives, using Bi(III) nitrate-Al₂O₃ is described. The reaction seems to proceed via β-oxygenation of Bi(III)-enolized benzylideneacetophenone followed by Michael addition, heteroannulation with simultaneous retro aldol disproportionation and subsequent catalytic oxidation and dehydration.

Full text of DOI:10.1016/j.tetlet.2005.11.043

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 837–842
A new and convenient one-pot solid supported synthesis
of 2,4,6-triarylpyridines
Anil Kumar, Summon Koul, Tej K. Razdan* and Kamal K. Kapoor
Department of Chemistry, University of Jammu, Ambedkar Road, Jammu 180 006, India
Received 25 April 2005; revised 26 October 2005; accepted 4 November 2005
Available online 28 November 2005
Abstract—A new, convenient, efficient and cost-effective one-pot solid supported synthesis of 2,4,6-triarylpyridines from benzyli-
deneacetophenones and urea, thiourea or their derivatives, using Bi(III) nitrate–Al2O3 is described. The reaction seems to proceed
via b-oxygenation of Bi(III)-enolized benzylideneacetophenone followed by Michael addition, heteroannulation with simultaneous
retro aldol disproportionation and subsequent catalytic oxidation and dehydration.
Ó 2005 Published by Elsevier Ltd.
2,4,6-Triarylpyridines are structurally related to
symmetrical triaryl-thiopyrylium, -selenopyrylium and
-telluropyrylium photosensitizers, which have been
recommended for photodynamic cell-specific cancer
therapy.1 The compounds are highly stable yet sterically
hindered bases and are capable of undergoing facile
elimination, as pyridinium ions,2 during a chemical reac-
tion. Such bases serve as useful substrates in the prepa-
ration of stereoselective reagents3 for the transformation
of organic compounds. 2,4,6-Triarylpyridinium deriva-
tives have been used in bringing about nucleophilic dis-
placement,4 C-alkylation of b-diketones5 via a chain
radical mechanism, electrophilic amination6 and synthe-
sis of azepines.7
a simple, efficient and cost-effective one-pot solid-
supported synthetic method for the synthesis of these
compounds from benzylideneacetophenones and urea,
thiourea or their derivatives, using the hitherto unex-
plored Bi(III) nitrate–Al2O3 catalyst.
Although Bi(III) nitrate is easily available in pure form
and has low toxicity12 and high stability in air and mois-
ture, its catalytic efficacy has not been thoroughly ex-
plored. This led us to evaluate the possible catalytic
potential of Bi(III) nitrate immobilized on neutral alu-
mina for the synthesis of nitrogen heterocycles. The cat-
alyst was chosen on the assumption that Bi(III) ions,
being on the borderline of hard and soft acids,13 could
bind efficiently to the surface of neutral alumina, prevent
its restructuring,14 synergize its catalytic activity15,17c
and initiate a reaction under mild conditions. The catal-
yst was prepared by adsorbing Bi(III) nitrate (5% w/w)
on neutral alumina and activation of the air-dried mix-
ture in a hot air oven, at 110 5 °C for 6 h. The catalyst
was reactivated, each time, before use.
Most of the known syntheses8 of 2,4,6-triarylpyridines
are multistage, low to moderately yielding laborious
processes and involve harsh or environmentally hazard-
ous reaction conditions. A few syntheses have been
accomplished employing heterocyclic compounds,7,9
sometimes complex ones,10 while other syntheses10,11
involve the use of triarylpyridinium substrates. We
therefore felt that there was a need to develop an
improved straightforward solid supported method for
the synthesis of 2,4,6-triarylpyridines. Herein, we report
The substrate benzylideneacetophenones 1a–k were
prepared from the appropriate benzaldehyde and ace-
tophenone by the well known Claisen–Schmidt conden-
sation.16 Subsequent reactions of 1a–k with urea 2a,
(2:1 M) and a stoichiometric amount of Bi(III) nitrate–
Al2O3, were carried out in a thermostatically controlled
hot air oven, at 130 5 °C, for 3–3.5 h. The resulting
products 3a–k (65–80% yield) were isolated with chloro-
form, purified by column chromatography and analyzed
by spectral methods, HREIMS, IR, 1H NMR and
Keywords: Bi(III) Nitrate–alumina; Benzylideneacetophenones; Urea,
thiourea and their derivatives; Solid-supported synthesis; 2,4,6-
Triarylpyridines.
*
Corresponding author. Tel.: +91 94191 91253; fax: +91 191
2565009; e-mail: tk_razdan@rediffmail.com
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.11.043

838
A. Kumar et al. / Tetrahedron Letters 47 (2006) 837–842
13C NMR. The spectra established the structures of
afforded products 3a–d in percentage yields comparable
to the yields obtained by the reaction of benzylideneace-
tophenones 1a–d with urea. One of the minor constitu-
ents in the product mixture obtained from the reaction
of 1a–d with benzamide was identified as benzoic acid.
In addition to product 3, all reactions afforded minor
quantities of the original aldehyde from which com-
pounds 1a–k were prepared. On repeating, the reactions
of 1a–d with semicarbazide 2e, and thiosemicarbazide
2f, 2,4,6-triarylpyridines were recovered in moderate
yields (50–68%) (Table 1). The reactions of 1a–d with
2e also yielded minor quantities of 5,7-diaryl-1,2,4-tri-
azepin-2,4-dien-3-ols 4a–d (Scheme 3), in addition to
3a–d and the original aldehydes.
3a–k as 2,4,6-triarylpyridine derivatives (Scheme 1).
1
The expanded peak segregated H NMR spectra of the
products showed characteristic two proton singlets near
d 7.20, due to the protons of the pyridine nucleus.8c 13C
NMR signals were assigned on the basis of DEPT 135
experiments. The mass fragmentation of the compounds
was characteristic of pyridines with a molecular ion peak
as the base peak, except for compound 3a whose MS
showed the base peak at m/z 77 ðC6Hþ5 Þ. Except for
compounds 3f and 3k, which possessed two monosubsti-
tuted phenyl rings at positions 2 and 6 of the pyridine
nucleus, and compound 3a, which possessed unsubsti-
tuted phenyl rings at positions 2, 4 and 6 of the nucleus,
all products had a lone substituted phenyl ring at posi-
tion 4 of the pyridine nucleus.
Since alumina chemisorbs water readily17 and retains it
even after activation at 110 5 °C, the mechanism of
the reaction may be rationalized as involving b-oxygen-
ation of the Bi(III) activated benzylideneacetophenone
enolate, which may then undergo a Michael addition
to a second a,b-unsaturated ketone (Scheme 3) to form
a 1,5-diketone enolate adduct. Subsequent heteroannu-
lation with urea or its derivatives via condensation and
retro aldol disproportionation18 may lead to the forma-
tion of 2-hydroxy-2,4,6-triaryltetrahydropyridine deriv-
atives, which on dehydration and oxidation may yield
X-ray crystallography of 3b (Fig. 1), as a representative
product, confirmed the structure and proved the pres-
ence of only one 4-methoxyphenyl ring at position 4 of
the pyridine nucleus.
To generalize this reaction, benzylideneacetophenones
1a–d were reacted, separately but under identical condi-
tions, with thiourea 2b, acetamide 2c, benzamide 2d, and
biuret 2g, using Bi(III) nitrate–Al2O3. These reactions
O
X
+
R3
1
R5
R
NH2
R4
R2
1a. R1 = R2 = R3 = R4 = H
2a. R5 = NH2; X = O
2b. R5 = NH2; X = S
2c. R5 = CH3; X = O
2d. R5 = Ph; X = O
1b. R1 = OCH3 = R2 = R3 = R4 = H
1c. R1 = F; R2 = R3 = R4 = H
1d. R1 = Cl; R2 = R3 = R4 = H
1e. R1 = R2 = Cl; R3 = R4 = H
1f. R1 = R2 = R4 = H; R3 = Cl
1g. R1 = Br, R2 = R3 = R4 = H
1h. R1, R2 = OCH2, R3 = R4 = H
1i. R1 = OH, R2 = R3 = R4 = H
1j. R1 = I, R2 = R3= R4 = H
1k. R1 = R2 = R4 = H, R3 = Br
2e. R5 = NHNH2; X = O
2f. R5 = NHNH2; X = S
2g. R5 = NHCONH2; X = O
2h. NH4OAc
Bi(NO3)3 -Al2O3
(5% w/w), ∆,130 5 OC
R1
R2
N
R3
R3
R4
R4
3a-3k
Scheme 1. Triarylpyridines from benzylideneacetophenones.

A. Kumar et al. / Tetrahedron Letters 47 (2006) 837–842
839
2,4,6-triarylpyridines after hydrolysis. This mechanism
is supported by the fact that the products obtained from
4-substituted benzylideneacetophenones, like 3b, pos-
sessed only one substituted phenyl group, at position 4
of the pyridine nucleus. To substantiate the proposed
mechanism, cross-reactions of benzylideneacetophe-
nones with equimolar amounts of urea and stoichiome-
tric quantities of Bi(III) nitrate–Al2O3 were carried out
at 130 5 °C (Scheme 4). The reaction of 1b, 1f and
2a yielded 3b (30%), 3f (28%) and 3l (35%), and the reac-
tion involving 1b, 2a and p-chloroacetophenone (1:1:1)
gave 3b and 3l, in nearly equal proportions.
We attempted the reaction of equimolar quantities of
1b, p-chloroacetophenone and a stoichiometric amount
of the Bi(III) nitrate–Al2O3 in the absence of urea or
its derivatives, at 130 5 °C (Scheme 5). The reaction
afforded two products, 5a and 5b, which were separated
by column chromatography and identified, by spectral
methods, as 2-(4-methoxyphenyl)-hydroxymethyl-3-(4-
methoxy)phenyl-1,5-diphenylpentan-4-en-5-ol-1-one 5a
and 1-(4-chloro phenyl)-3-(4-methoxy)phenyl-5-phen-
ylpentan-4-en-5-ol-1-one 5b (Scheme 5). The 1H
NMR, 13C NMR and DEPT 135 spectra of 5a and 5b
showed the presence of a carbonyl group, dC 197.3,
and an enol hydroxyl, d 12.9 (s br, exch. D2O, 1H).
The spectra of 5a revealed the absence of a methylene
carbon whose presence in 5b was evident from the
Figure 1. ORTEP representation of compound 3b.
Table 1. Percent yield of products 3a–k using different amino derivatives (2a–d) and enones (1a–k)
Product
% Yield with different amino compounds
2a
2b
2c
2d
2e
2f
2g
2h
MW
Time (MW) (min)
3a
3b
3c
3d
3e
3f
80
79
78
72
70
66
69
76
65
73
72
78
80
71
72
—
—
—
—
—
—
70
82
80
76
68
—
—
—
—
—
—
60
78
70
62
60
—
—
—
—
—
—
—
50
52
68
66
—
—
—
—
—
—
—
65
60
55
60
—
—
—
—
—
—
—
79
80
76
74
—
—
—
—
—
—
—
32
34
30
31
31
28
25
32
29
41
38
78
80
78
70
—
—
—
—
—
—
—
15
10
12
12
—
—
—
—
—
—
—
3g
3h
3i
3j
3k
X
R
H
1
N
O
NH2. NH. C . NH2
N
7
(2e, X = O; 2f, X = S)
OH
N
4
Bi(NO3)3 - Al2O3 ∆
, 130oC
R
4a; R = H (26%)
4b; R = OCH3 (20%)
4c; R = F (16%)
4d; R = Cl (18%)
Scheme 2. 5,7-Diaryl-1,2,4-triazepin-3-ol from benzylideneacetophenone.

840
A. Kumar et al. / Tetrahedron Letters 47 (2006) 837–842
cat.
R2
O
X
R1
- cat
R2
O
NH2
R5
R1
O
R4
Bi(III) - Al 2O3
R2
o
+
∆
, 130 5 C
R3
cat.
+
R1
O
R3
R4
R4
Michael-
addition
type
R3
cat.
R2
cat.
R2
R3
R4
R3
R4
O
O
R1
X
R1
R1
R5
X
NH2
N
O
O
R5
R1
O
-H2O
cat.
R4
cat.
R2
R2
R4
R3
R3
+
H
cat.
O
R3
R2
R3
R4
H
O
R1
R1
R4
R2
.
.X
.
Heteroannul.
& retro-aldol
.
N
O
X
R5
R1
N
R2
+
R5
H
R2
R1
HO
R4
R3
R3
R3
R3
R4
R3
R4
H2O
R4
R4
R2
R2
X
R1
N
oxidation
X
..
Hydrolysis
R1
N
N
R5
+
R1
H
R5
R2
R3
R4
R4
R3
R4
R3
Scheme 3. Possible mechanism for the formation of 2,4,6-triarylpyridines.
O
CH3
Cl
1f, 2a, cat.
3b
+
+ 3f
(28%)
; 130 + 5 oC
(30%)
∆
N
(3.5 h)
1b
3l
(35%)
Cl
, 2a, cat.
O
3b
+
3l
(35%)
o
+
(38%)
; 130 5 C
∆
(4.0 h)
Scheme 4. Cross-reactions of 1b.

A. Kumar et al. / Tetrahedron Letters 47 (2006) 837–842
841
O
OH
H3CO
1
Bi(III) - Al2O3
H
o
1b +
+
∆
, 130 5 C
O
OH
+
H3CO
3
(MW : 10 min.)
5
Cl
5a (35%)
Cl
(MW : 39%)
O
H3CO
OH
5b (49%)
(MW; 52%)
Scheme 5. Reaction of 1b and p-chloroacetophenone in the absence of urea.
resonance signals at d 2.69 (d, J = 4.5 Hz, 2H), in its 1H
NMR spectrum, and dC 25.3, in its 13C NMR and
DEPT 135 spectra. The spectra of 5a showed the pres-
ence of a secondary hydroxyl displaying resonance
signals at d 2.80 (s br, exch. D2O, 1H) and 5.01 (d,
J = 3.6 Hz, 1H; –CHOH), dC 83.2. These signals were
absent in the spectra of 5b. These observations were con-
sistent with the proposed mechanism and indicated that
the retro-aldol disproportionation is probably triggered
by heteroannulation of the Michael adduct with urea
or its derivatives.
Bi(III) nitrate in organic transformations are under
investigation.
A representative procedure for the preparation of the
Bi(III) nitrate–Al2O3 and the synthesis of 2,4,6-triaryl-
pyridines and the spectral data (IR, 1H NMR, 13C
NMR, HREIMS) are available as a supplement to this
letter. X-ray crystallographic data have been deposited
at the Cambridge Crystallographic Data Centre CCDC
198750.
As most of the earlier syntheses8 of 2,4,6-triarylpyridines
employed ammonium acetate 2h, as the source of ammo-
nia, we felt it obligatory to make use of it in the present
reaction. 2,4,6-Triarylpyridines were obtained, albeit in
poor yields (Table 1), under our reaction conditions.
The minor products 4a–d, in the reaction of 1a–d and
2e (Scheme 2) may result from a direct Michael addition
to the Bi(III)-enolized benzylideneacetophenone fol-
lowed by cyclodehydration. The reaction is sensitive to
temperature; the optimum temperature being
130 5 °C. The reaction failed to proceed in solution
and also on using neat Al2O3 or Bi(III) nitrate as the
reagent. We repeated the reactions of 1a–d, 2a and
Bi(III)–Al2O3 (Scheme 1) and also the reaction of 1b,
p-chloroacetophenone and Bi(III)–Al2O3 (Scheme 5) in
a domestic microwave (2450 MHz), at 60% power using
the procedure of Mukhopadhyay et al.,19 which allows
the temperature to remain at ca. 130 °C. The reactions
were complete in 10–15 min without any appreciable
improvement in the yields of the 2,4,6-triarylpyridines.
Acknowledgements
The authors are thankful to IISC, Bangalore, for pro-
viding the X-ray structure and 300 MHz NMR spectra.
Thanks are also due to Mrs. B. Poornima Wakhlu, R.
R. L. Jammu, for spectral facilities. One of the authors
(S.K.) is thankful to CSIR, New-Delhi, for a senior
research fellowship.
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