A microwave-assisted facile one-pot synthesis of annelated pyridines from β-formyl enamides via henry reaction

Article abstract of DOI:10.1055/s-2004-825595

The base-catalysed solid phase condensation of β-formyl enamides with nitromethane under microwave irradiation afforded a novel one-pot synthesis of pyridines via Henry reaction.

Full text of DOI:10.1055/s-2004-825595

LETTER
1309
A Microwave-Assisted Facile One-Pot Synthesis of Annelated Pyridines from
b-Formyl Enamides via Henry Reaction
M
icrowave-Assist
p
e
d
Facile
O
n
u
e-Pot Synthe
r
sis of
A
n
b
nelated
P
yri
a
dines Chetia, Moanochet Longchar, Kushal C. Lekhok, Romesh C. Boruah*
Medicinal Chemistry Division, Regional Research Laboratory, Jorhat-785006, India
Fax +91(376)2370011; E-mail: rc_boruah@yahoo.co.in
Received 11 January 2004
90% yield. The product was characterized by spectral and
Abstract: The base-catalysed solid phase condensation of b-formyl
enamides with nitromethane under microwave irradiation afforded
a novel one-pot synthesis of pyridines via Henry reaction.
analytical analysis.12 The 1H NMR showed a characteris-
tic singlet proton signal at d = 8.02 for the aromatic pro-
ton. Similarly, steroidal, acyclic- and aromatic b-formyl
enamides 2–9 reacted with nitromethane under micro-
wave irradiation to yield products 11–18 in high yields
(Table 1). However, the pyrrolidine-catalyzed Henry re-
action of 1–9 and nitromethane under thermal conditions
in refluxing toluene necessitated longer reaction times (8–
10 h) and led to comparatively lower yields of products
10–18 (62–74%).
Key words: pyrrolidine, b-formyl enamide, nitromethane, micro-
wave, Henry reaction
The nitroaldol or Henry reaction has attracted enormous
attention as one of the valuable fundamental synthetic
strategies for construction of carbon-carbon bonds.1 The
importance of the Henry reaction is due to the great poten-
tial of the newly formed b-nitro alcohols or nitroalkenes
for further transformations.2 The opportunity to employ
this strategy is particularly appealing as its application has
been developed extensively using sonication,3 high pres-
sure reactions,4 heterogeneous catalysts,5 microwave,6
polymer supports7 and solvent free conditions.8 On the
other hand, the widespread occurrence and biological ac-
tivity of pyridines in natural products and pharmaceuticals
make them important targets of synthetic chemists.9 Fur-
thermore, the research effort in our laboratory has afford-
ed b-formyl enamides as efficient organic synthons for
one-pot preparation of pyridines.10 In continuation of our
efforts, we report herein a facile and convenient synthesis
of annelated pyridines from b-formyl enamide under mi-
crowave irradiation,11 employing a previously unreported
Henry reaction.
In an attempt to investigate the influence of bases, the
condensation reaction of 1 and nitromethane was similar-
ly carried out in the presence of morpholine and piperi-
dine, to afford the desired products 10 in 65–68% yields.
The combination of secondary amines with basic alumina
showed a slight improvement in the yield of the product
(72–94%). However, when the reaction of 1 and ni-
tromethane was carried without base, we failed to obtain
the desired products 10.
The formation of 10 is envisaged to occur via a mecha-
nism which involves a Henry reaction of nitromethane
with the formyl group of 1 to give the 2-nitro alcohol in-
termediate A, which undergoes dehydration to nitro-ole-
fin intermediate B, followed by base-catalysed cyclisation
and aromatisation with loss of water to afford product 10
as shown in Scheme 2. However, an attempt to isolate the
unstable nitroaldol intermediate A failed in our hands.
In conclusion, we have developed a facile one-pot synthe-
sis of annelated pyridines from b-formyl enamides using
the Henry reaction under microwave irradiation. The reac-
Scheme 1
In a typical reaction, steroidal b-formyl enamide (1) and
nitromethane were mixed with pyrrolidine and irradiated
in a Synthwave Microwave Module 402 (Prolabo) at op-
erating frequency of 2450 MHz and 80% of output power
for 8–10 minutes (Scheme 1). The work up of the reaction
mixture did not afford the expected nitro-aldol or nitro-
olefin product; rather it afforded a cyclised product 5¢-
nitro-6¢-methyl-pyrido-(17,16-b)-androst-5-ene (10) in
SYNLETT 2004, No. 7, pp 1309–1311
0
3.
0
6.
2
0
0
4
Advanced online publication: 10.05.2004
DOI: 10.1055/s-2004-825595; Art ID: D00204ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

1310
A. Chetia et al.
LETTER
Table 1 Reaction of b-Formyl Enamides with Nitromethane under Microwave Irradiationa
Entry
b-Formyl enamide
Time (min) Product
Yieldb (%) Yieldc (%)
1
2
3
4
1
8
10
10
9
10
11
12
13
90
85
80
82
74
68
64
66
R = Ac
2
R = Bz
3
R = H
4
R = Me
5
6
5
9
8
14
15
86
84
64
62
6
7
8
9
7
9
8
8
16
17
18
83
82
80
70
72
70
X = H
8
X = Cl
9
X = OMe
a Reactions were carried using 1 mmol of b-formyl enamide, 1.2 equiv of nitromethane, 1.2 equiv of base.
b Isolated yields under microwave irradiation.
c Isolated yields under thermal conditions; reaction time 8–10 h.
Tetrahedron 1990, 46, 7443. (d) Handbook of Reagents for
Organic Synthesis: Reagents, Auxiliaries and Catalysts for
C-C Bond Formation; Coates, R. M.; Denmark, S. E., Eds.;
John Wiley & Sons: New York, 2000, 542.
tion has the advantage of being carried out on solid phase
and avoiding harsh reaction conditions or multi-step syn-
thesis.13 Furthermore, we have demonstrated that the in-
corporation of an acetamido group adjacent to an
aldehyde moiety can facilitate the conversion of the in situ
generated nitro-olefins14 to pyridines, thus providing a
novel strategy for the one-pot preparation of annelated py-
ridines from steroidal, alicyclic or aromatic b-formyl ena-
mides. The methodology reported herein represents a new
application of the Henry reaction and is expected to be a
general route for facile, one-pot combinatorial synthesis
for a wide range of annelated pyridines.
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Acknowledgement
We are grateful to Department of Science and Technology, New
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interest in this work.
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Synlett 2004, No. 7, 1309–1311 © Thieme Stuttgart · New York

LETTER
Microwave-Assisted Facile One-Pot Synthesis of Annelated Pyridines
(12) All compounds gave satisfactory spectroscopic and
1311
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analytical data. Spectral data of representative compound
10: Yield: 90%; mp 208–209 °C; Rf = 0.5 (toluene–EtOAc,
95:5). IR (KBr): 2938, 1730, 1521, 1373 cm–1. 1H NMR
(CDCl3): d = 8.02 (s, 1 H), 5.24 (br s, 1 H), 4.56 (br s, 1 H),
2.50 (s, 3 H), 2.20 (s, 3 H), 1.10 (s, 3 H), 1.09 (s, 3 H), 2.34–
1.06 (m, 17 H). 13C NMR (CDCl3): d = 177.2, 173.3, 170.5,
140.3, 135.2, 134.4, 128.6, 121.7, 73.7, 55.9, 55.5, 50.4,
38.1, 36.8, 33.3, 31.3, 30.7, 29.9, 28.9, 21.4, 20.5, 19.3, 17.2,
17.0, 14.5. MS (ESI): m/z = 447.53 [M+ + 23]. Anal. Calcd
for C25H32O4N2: C, 70.73; H, 7.59; N, 6.51. Found: C, 71.26;
H, 7.86; N, 6.05. Compound 14: Yield: 86%; mp 78–79 °C;
Rf = 0.55 (toluene–EtOAc, 95:5). IR (KBr): 2945, 1525,
1360 cm–1. 1H NMR (CDCl3): d = 8.05 (s, 1 H), 3.60–3.25
(m, 4 H), 2.05 (s, 3 H), 2.00–1.78 (m, 4 H). 13C NMR
(CDCl3): d = 169.5, 168.7, 140.5, 137.2, 136.5, 55.1, 54.8,
50.3, 47.6, 16.4. MS (ESI): m/z = 215.74 [M+ + 23]. Anal.
Calcd for C10H12O2N2: C, 62.49; H, 6.29; N, 14.57. Found:
C, 62.30; H, 6.56; N, 14.35.
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Synlett 2004, No. 7, 1309–1311 © Thieme Stuttgart · New York