Microwave-promoted and Lewis acid catalysed synthesis of 2,4,6-triarylpyridines using urea as benign source of ammonia

Article abstract of DOI:10.1055/s-0028-1087273

An efficient method for the synthesis of 2,4,6-triarylpyridines via microwave-promoted and BF₃·OEt₂-catalysed one-pot reaction of ω-pyrrolidinoacetophenone with chalcone is reported. This method illustrates urea as an environmentally

Full text of DOI:10.1055/s-0028-1087273

LETTER
3125
Microwave-Promoted and Lewis Acid Catalysed Synthesis of
2,4,6-Triarylpyridines Using Urea as Benign Source of Ammonia
S
ynthesis of 2,4,6-Tria
o
rylpyridines
y
Using Urea
a
u
s
B
enign
S
o
r
urce of
A
i
mmon
m
ia a Borthakur, Mandakini Dutta, Shyamalee Gogoi, Romesh C. Boruah*
Medicinal Chemistry Division, North-East Institute of Science and Technology, Jorhat 785006, India
E-mail: rc_boruah@yahoo.co.in
Received 10 July 2008
dine using aqueous ammonia17 and addition of lithiated b-
enaminophosphonates to chalcones.18 However, most of
these methodologies have the discrepancies of multistage
reactions with low to moderately yielding laborious pro-
cesses and environmentally hazardous or harsh reaction
conditions.
Abstract: An efficient method for the synthesis of 2,4,6-triaryl-
pyridines via microwave-promoted and BF3·OEt2-catalysed one-pot
reaction of w-pyrrolidinoacetophenone with chalcone is reported.
This method illustrates urea as an environmentally benign source of
ammonia for the synthesis of 2,4,6-triarylpyridines.
Key words: 2,4,6-triarylpyridine, urea, microwave, Lewis acid
The utility of unconventional microwave energy in syn-
thetic organic chemistry is increasingly recognised in
recent years.19 Microwave-promoted solid-phase hetero-
geneous reactions have turned out as environmentally be-
nign reaction methodologies having greater selectivity,
enhanced reaction rates, cleaner products and manipula-
tive simplicity.20 Microwave-mediated multicomponent
reactions constitute a specially attractive synthetic strate-
gy for rapid and efficient library generation due to the fact
that products are formed in a single step and the diversity
can be achieved simply by varying the reacting compo-
nents.21 Recently, we have demonstrated solid-phase syn-
thesis of aza heterocycles using urea as an efficient source
of ammonia under microwave irradiation.22 In continua-
tion of our interests towards development of newer strate-
gy for pyridines,23 we describe herein a BF3·OEt2-
catalysed and solventless one-pot synthesis of 2,4,6-tri-
arylpyridines from the reaction of w-pyrrolidinoacetophe-
none with chalcone using urea as an environmentally
benign source of ammonia under microwave irradiation.
2,4,6-Triarylpyridines are prominent building blocks in
supramolecular chemistry1 and are important because of
their biological activities.2 The quaternary 2,4,6-triarylpy-
ridinium derivatives have significant synthetic applica-
tions such as in nucleophilic displacement reaction,3 C-
alkylation of b-diketones,4 electrophilic amination5 and
azepine synthesis.6 The facile elimination of pyridinium
ions from these stable and sterically hindered compounds
have made them useful substrates in organic transforma-
tion reactions.7 The 2,4,6-triarylpyridine nucleus is
structurally related to symmetrical triarylthiopyrylium,
-selenopyrylium and -telluoropyrylium photosensitisers
which have been recommended for photodynamic cell-
specific cancer therapy.8
The synthesis of 2,4,6-triarylpyridines has attracted a
great deal of attention from organic chemists. Traditional-
ly, these compounds are synthesised through the reaction
of N-phenacylpyridinium9or N-phenacylisoquinolinium
salts10 with a,b-unsaturated ketones in the presence of
NH4OAc. Recently, the synthesis of triarylpyridines has
been reported from the dimerisation–heteroannulation re-
action of chalcones employing compounds possessing ter-
minal CONH2 functionality catalysed by a BiNO3-derived
heterocatalyst.11 A few more new syntheses have been ac-
complished by NH4OAc-promoted reactions, for exam-
ple, one-pot reaction of acetophenone with benz-
aldehyde,12 sodium hydroxide catalysed condensation of
heterocyclic aldehydes,13 Michael addition and solid-
phase condensation of chalcones,14 and reaction of a-ben-
zotriazolyl ketone with 1,5-diketones.15 The synthesis of
2,4,6-triarylpyridines is also reported from the reaction of
N-(diphenylphosphenyl)-1-phenylethaneimine with aro-
matic aldehydes,16 reaction of a-benzotriazolyl ketone
with 1,5-diketones in the presence of NH4OAc,16 conver-
sion of 2,4,6-triarylpyrylium salts into 2,4,6-triarylpyri-
When a finely ground mixture of w-pyrrolidinoacetophe-
none (1a), 1,3-diphenyl-2-propen-1-one (2a), urea and
BF3·OEt2 was irradiated under microwave in an open ves-
sel in a Prolabo Synthwave 402 microwave reactor24 for
three minutes at atmospheric pressure, it afforded 2,4,6-
triphenylpyridine (3a) in 90% yield (Table 1). The prod-
uct 3a was characterised by comparison of its physical
and spectral data.25 Similarly 1a reacted with chalcones
2b–g in the presence of urea and BF3·OEt2 to yield 2,4,6-
triarylpyridines 3b–g in high yields. The reaction of 1b,c
with 2a–e under identical conditions afforded 3h–p in
high yields. However, the reaction failed to proceed when
thiourea was employed in place of urea under identical
conditions. The replacement of the pyrrolidine moiety in
1a with morpholine or pyridine led to comparatively poor
yields of the product 2a.
In order to study the influence of the Lewis acid on the
azacyclisation reaction, we carried out the solid-phase re-
action of 1a and 2a independently with SmCl3, ZrCl4,
TiCl4, InCl3 and AlCl3 and obtained 3a in 33–51% yields.
SYNLETT 2008, No. 20, pp 3125–3128
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Advanced online publication: 26.11.2008
DOI: 10.1055/s-0028-1087273; Art ID: D26308ST
© Georg Thieme Verlag Stuttgart · New York

3126
M. Borthakur et al.
LETTER
Table 1 Synthesis of Unsymmetrical 2,4,6-Triphenylpyridines 3a–pa
Ar2
O
O
O
BF3⋅OEt2
+
+
Ar2
N
Ar3
H2N
NH2
Ar1
MW, 3–4 min
Ar1
Ar3
2a–g
N
1a–c
3a–p
Entry
1
1
2
Ar1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ar2
Ph
Ar3
Ph
Product
Yieldb (%) Mp (°C) (Lit.)c
135–36 (134–35)16
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
1c
1c
1c
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
90
94
88
93
95
87
90
88
92
90
87
89
92
91
88
85
2
Tol
Ph
123–24 (124.5–25)16
126–28 (129–30)16
123–24 (124–125)18
127–28 (125–27)10a
159–51 (150–52)15
105–06 (105–07)10a
127–28 (125–27)10a
154–55 (155–56)10b
139–40 (140–42)15
152–54
3
4-ClC6H4
Ph
4
Ph
Tol
5
Ph
4-ClC6H4
6
Ph
4-BrC6H4
PMP
Ph
7
2g
2a
2b
2c
2d
2e
2a
2b
2c
2d
Ph
3g
3h
3i
8
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Tol
Ph
9
Tol
Ph
10
11
12
13
14
15
16
4-ClC6H4
Ph
Ph
3j
Tol
3k
3l
Ph
4-ClC6H4
Ph
176–78 (178–79)10b
123–24 (124–125)18
133–35
Ph
3m
3n
3o
3p
Tol
Tol
Ph
Tol
4-ClC6H4
Ph
Ph
119–21 (120–22)15
156–57 (157–58)14
Tol
Tol
a Conditions: 2 (1 mmol), 1 (1.5 mmol), urea (3.0 mmol), BF3·OEt2 (cat.).
b Isolated yields.
c Values in parentheses are the melting points reported in the literature.
However, the reactions were found to be sluggish in the In conclusion, we have developed a facile and novel strat-
absence of Lewis acid and the products were obtained in egy for the preparation of 2,4,6-triarylpyridines from
very poor yields (<10%). When this reaction was carried BF3·OEt2-catalysed one-pot reaction of w-pyrrolidinoace-
out under thermal condition, it afforded products 3a–p in tophenone, chalcone and urea under microwave irradia-
very poor yields.
tion. We have successfully demonstrated the utility of
urea as an environmentally benign source of ammonia for
pyridine synthesis under microwave irradiation. The util-
ity of urea as a source of ammonia represents an alterna-
tive and novel strategy for pyridine synthesis with respect
to hitherto known methodologies using ammonium ace-
tate. The method reported herein describes a new applica-
tion of w-pyrrolidinoacetophenone and is expected to be a
general route for facile and combinatorial synthesis of a
wide range of unsymmetrical 2,4,6-triarylpyridines. Also
our strategy provides an efficient methodology for the
synthesis of easily inaccessible 1,5-diketones. Further
synthetic application of the newly developed methodolo-
gy is in progress.
A plausible mechanism is proposed via BF3·OEt2-cataly-
sed enolate addition of w-pyrrolidinoacetophenone (1a) to
chalcone (2a) to afford 1,5-dicarbonyl intermediate A fol-
lowed by elimination of pyrrolidine to form intermediate
B (Scheme 1). Under microwave irradiation urea released
ammonia22 which combined with B to facilitate diimine
intermediate C followed by enolisation and cycloconden-
sation to afford 3a with concomitant loss of ammonia. The
BF3·OEt2 presumably played a key role by enhancing the
electron deficiency on carbonyl carbon of 1a facilitating
Michael addition to afford 1,5-dicarbonyl intermediate A
and elimination of pyrrolidine from A to form intermedi-
ate B. The isolation of 1,3,5-triphenylpent-2-en-1,5-dione
(B)25 from the reaction of 1a and 2a without urea under
identical condition supported our proposed mechanism.
Synlett 2008, No. 20, 3125–3128 © Thieme Stuttgart · New York

LETTER
Synthesis of 2,4,6-Triarylpyridines Using Urea as Benign Source of Ammonia
3127
Ph
Ph
O
O
Ph
O
O
Ph
O
N
N
2a
BF3⋅OEt2
Ph
Ph
Ph
BF3⋅OEt2
– pyrrolidine
B
A
1a
urea
NH3
MW
Ph
Ph
Ph
H2N
HN
Ph
HN
HN
Ph
– NH3
Ph
Ph
N
Ph
Ph
3a
C
Scheme 1 Proposed mechanism for 2,4,6-triphenylpyridine synthesis
(9) (a) Krohnke, F.; Zecher, W. Angew. Chem., Int. Ed. Engl.
1962, 1, 626. (b) Krohhnke, F. Synthesis 1976, 1.
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1980, 19, 153. (b) Tewari, R. S.; Dubey, A. K. J. Chem. Eng.
Data 1980, 25, 91.
Acknowledgment
We thank the Department of Science and Technology (DST), New
Delhi for financial support and CSIR, New Delhi for the award of a
Senior Research fellowship to MB. We also thank Director, NEIST-
Jorhat for his keen interest.
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Synlett 2008, No. 20, 3125–3128 © Thieme Stuttgart · New York

3128
M. Borthakur et al.
LETTER
196.0, 190.5, 152.7, 152.0, 143.3, 141.7, 136.9, 136.2,
4767. (e) Balalaie, S.; Arabanian, A. Green Chem. 2000, 2,
274.
134.2, 132.9, 132.4, 129.1, 129.0, 128.5 (2 × C), 128.4,
128.3, 128.2, 128.2, 128.0, 126.5, 123.3, 42.7, 21.4. MS
(ESI): m/z = 341 [M+ + 1].
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Saikia, A.; Bora, U.; Chetia, A.; Boruah, R. C. Synlett 2007,
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Compound 3a: mp 135–36 °C; Rf = 0.8 (EtOAc–hexane,
10:90). IR (KBr): 3035, 2924, 1595, 1550, 1495, 1449, 1180,
756 cm–1. 1H NMR (300 MHz, CDCl3): d = 8.21 (m, 4 H),
7.89 (s, 2 H), 7.75 (d, 2 H, J = 7.0), 7.03–7.53 (m, 9 H).
13C NMR (75 MHz, CDCl3): d = 157.2 (2 × C), 149.9, 139.3
(2 × C), 138.8, 128.9 (2 × C), 128.8, 128.7 (3 × C), 128.4 (3
× C), 126.9 (3 × C), 126.9 (3 × C), 116.9 (2 × C). MS (ESI):
m/z = 308 [M+ + 1].
(24) Microwave experiments were conducted in open reaction
vessels of a Synthwave 402 reactor manufactured by M/s
Prolabo, 54 rue Roger Salengro, Cedex, France. The
temperature of the reaction mixture was set at 140 °C and
measured by a computer controlled sensor using 80% power
(maximum output 300 Watts) with an operating frequency of
2.45 GHz. The reaction time specified is the total irradiation
time. The hold time at final temperature is 25% of the total
time.
(25) Spectral and Analytical Data of Selected Compounds:
Compound B: mp 97–99 °C; Rf = 0.7 (EtOAc–hexane,
10:90). IR (KBr): 3059, 3028, 2922, 1686, 1653, 1606, 1448,
1217, 1180, 1010, 755 cm–1. 1H NMR (300 MHz, CDCl3):
d = 8.01 (d, 2 H, J = 7.4 Hz), 7.92 (d, 2 H, J = 7.4 Hz), 7.88
(d, 2 H, J = 8.0 Hz), 7.18–7.54 (m, 6 H), 5.25 (s, 1 H), 4.84
(s, 2 H), 2.40 (s, 3 H). 13C NMR (75 MHz, CDCl3): d =
Compound 3k: mp 152–54 °C; Rf = 0.8 (EtOAc–hexane,
10:90). IR (KBr): 3056, 2922, 1596, 1544, 1492, 1184 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.32–8.14 (m, 13 H), 7.82
(s, 2 H), 2.42 (s, 3 H). 13C NMR (75 MHz, CDCl3): d =
157.3, 157.1, 155.8, 150.0, 149.7, 138.9, 138.7, 137.8,
136.6, 136.3, 134.8, 129.2, 129.1, 128.9, 128.8, 128.6,
128.1, 126.9, 126.7 (2 × C), 125.6, 116.8, 116.3, 21.1.
MS (ESI): m/z = 356 [M+ + 1].
Compound 3n: mp 133–35 °C; Rf = 0.7 (EtOAc–hexane,
10:90). IR (KBr): 3034, 2924, 1597, 1546, 1496, 1417, 1185
cm–1. 1H NMR (300 MHz, CDCl3): d = 8.20 (m, 4 H), 7.87
(s, 2 H), 7.64 (d, 2 H, J = 5.8 Hz), 7.14–7.51 (m, 7 H), 2.42
(s, 3 H), 1.34 (s, 3 H). 13C NMR (75 MHz, CDCl3): d = 157.2
(2 × C), 139.4 (2 × C), 129.6 (3 × C), 128.7 (3 × C), 128.4 (3
× C), 126.9 (4 × C), 126.7 (4 × C), 116.6 (2 × C), 29.5, 21.0.
MS (ESI): m/z = 336 [M+ + 1].
Synlett 2008, No. 20, 3125–3128 © Thieme Stuttgart · New York

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