Efficient and convenient method for the synthesis of poly functionalised 4H-pyrans

Article abstract of DOI:10.1081/SCC-200039502

An efficient single-pot method for the synthesis of polyfunctionalized 4H-pyrans using alkaline metal fluoride as a catalyst is described.

Full text of DOI:10.1081/SCC-200039502

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Efficient and Convenient
Method for the Synthesis of
Poly Functionalised 4H‐Pyrans
B. P. V. Lingaiah a , G. Venkat Reddy a , T. Yakaiah
a , B. Narsaiah a , S. N. Reddy a , R. Yadla a & P.
Shanthan Rao a
a Fluoroorganics Division, Indian Institute of
Chemical Technology, Hyderabad, 500007, India
Published online: 10 Jan 2011.
To cite this article: B. P. V. Lingaiah , G. Venkat Reddy , T. Yakaiah , B. Narsaiah ,
S. N. Reddy , R. Yadla & P. Shanthan Rao (2004): Efficient and Convenient Method
for the Synthesis of Poly Functionalised 4H‐Pyrans, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry,
34:23, 4431-4437
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 23, pp. 4431–4437, 2004
Efficient and Convenient Method for the
Synthesis of Poly Functionalised 4H-Pyrans#
B. P. V. Lingaiah, G. Venkat Reddy, T. Yakaiah, B. Narsaiah,
*
S. N. Reddy, R. Yadla, and P. Shanthan Rao
Fluoroorganics Division, Indian Institute of Chemical Technology,
Hyderabad, India
ABSTRACT
An efficient single-pot method for the synthesis of polyfunctionalized
4H-pyrans using alkaline metal fluoride as a catalyst is described.
Key Words: Aldehydes; Active methylene compound; Diethyl
1,3-acetone dicarboxylate; Michael addition; Polyfunctionalized
4H-pyran.
The chemistry of polyfunctionalized 4H-pyrans is an ongoing area of
interest because of their wide range of applications.[1,2] These 4H-pyrans
#IICT Communication No. 040105.
*
Correspondence: P. Shanthan Rao, Fluoroorganics Division, Indian Institute of
Chemical Technology, Hyderabad 500007, India; Fax: þ91-040-27160387; E-mail:
psrao@iict.res.in.
4431
DOI: 10.1081/SCC-200039502
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

4432
Lingaiah et al.
are isosters of 1,4-dihydro pyridine[3] with potential pharmacological interest
and active synthons that have been extensively used in heterocyclic
synthesis.[2] The 4H-pyrans are synthesized mainly by a three-component
coupling reaction of aromatic aldehydes, malononitrile, and ß-ketones/
ß-diketones[4] catalyzed by bases like triethylamine,[5] piperidine,[6] etc.
Alkali metal fluorides are also used in solid–liquid reactions more specifically
for halogen exchange reactions,[7,8] and the reactivity increases from sodium
fluoride to cesium fluoride. Alkaline metal fluorides or metal salts are also
used in amination process[9] and Michael addition reactions.[10,11] In con-
tinuation of our interest in the development of new procedures[12,13] by
using suitable catalysts from simple available starting materials, we wish to
report here for the first time a novel methodology for the synthesis of
polyfunctionalized 4H-pyrans in the shortest time using rubidium fluoride
as a catalyst.
The methodology involves an aldehyde 1, active methylene compound 2,
and a third component 1,3-diethyl acetone dicarboxylate/ethylacetoacetate/
1,3-diketones/diethyl malonate 3 in presence of a catalytic amount of
rubidium fluoride under thermal conditions to give the desired pyrans. The
rubidium fluoride acts as a base and promotes reaction by abstracting a
proton from active methylenes sequentially in twofold. As a result, the
Knoevenagel condensation with aromatic/aliphatic aldehydes and malononi-
trile form an alkene intermediate that, in situ, reacts with 1,3-diethyl acetone
dicarboxylate/ethylacetoacetate/1,3-diketones/diethyl malonate by Michael
addition to give polyfunctionalized 4H-pyrans 4 in good yields. The most
probable mechanism is depicted in Scheme 1. The mode of formation of 4
is further confirmed by the initial preparation of dicyanoalkenes 5 from aro-
matic aldehyde and malononitrile in the presence of rubidium fluoride. The
compound 5 further reacted with 1,3-diethylacetone dicarboxylate in the pre-
sence of rubidium fluoride resulted the desired pyran 4. However, in the
absence of rubidium fluoride, the initial Knoevenagel condensation reaction
did not proceed.
Different aldehydes containing electron-withdrawing and electron-
releasing substituents and ß-diketoesters are used for universal applicability
of the method for the preparation of pyrans. It is found that in all cases, the
yields are in the range 68–89%, irrespective of the substituent present
in the phenyl ring of aromatic aldehyde. The main advantage of the
method is its easy workup procedure with good yields of product. The substi-
tuent pattern and yields are given in Table 1, and spectral data are given in
Table 2.
In conclusion, a methodology has been developed for the synthesis of
polyfunctionalized 4H-pyrans using rubidium fluoride catalyst for the first
time by an efficient three-component coupling reaction.

Synthesis of Poly Functionalised 4H-Pyrans
4433
Scheme 1.
EXPERIMENTAL SECTION
Melting points were determined in open glass capillaries on a Mettler
FP51 melting point apparatus and are uncorrected. Infrared (IR) spectra
were recorded on Fourier transform infrared (FT-IR) Schimadzu Perkin-
1
Elmer 1310 infrared spectrophotometer. H NMR spectra were recorded on
Varian Gemini (200 MHz) spectrometer, and tetramethylsilane (TMS) was
Table 1. The reaction time and yields of polyfunctionalized pyrans (4).
Time
(min) Mp. (8C)
Lit. Mp. Yield
(8C)
Entry
R
R0
R00
(%)
4a
4b
4c
4d
4e
4f
C6H5
p-Cl-C6H4
COOEt CH2COOEt
COOEt CH2COOEt
20
25
25
35
20
35
30
25
30
25
50
117–118
128–129
135–136
159–160
131–132
116–117
118–119
205–206
132–133
172–173
106–107
—
—
89
80
82
81
78
78
68
72
71
87
68
p-CH3-C6H4 COOEt CH2COOEt
p-OH-C6H4 COOEt CH2COOEt
—
—
p-NO2-C6H4 COOEt CH2COOEt
m-Oph-C6H4 COOEt CH2COOEt
—
—
4g
4h
4i
C6H5 COOEt OEt
C6H5 COCH3 CH3
p-CH3-C6H4 COCH3 CH3
—
210
135
176
—
4j
4k
C6H5
C2H5
COOEt CH3
COOEt CH2COOEt

4434
Lingaiah et al.
Table 2. Spectral data of polyfunctionalized 4H-pyrans (4).
Entry
IR (cm21
)
Mass (m/z)
1H NMR (DMSO-d6). d
4a
3407, 3331,
2197, 1745,
1692, 1647
356[M]þ, 279,
205, 141
1.18 (t, 3H), 1.35 (t, 3H), 3.70
(d, 1H, J ¼ 17.2 Hz), 3.9
(d, 1H, J ¼ 17.2 Hz), 4.0
(q, 2H), 4.25 (q, 2H), 4.45
(s, 1H), 4.54 brs, 2H), 7.28
(m, 5H)
4b
4c
3440, 3302,
2200, 1693,
1647, 1604
390[M]þ, 345,
303, 279, 205
1.1 (t, 3H), 1.35 (t, 3H), 3.62
(d, 1H, J ¼ Hz), 3.98 (d, 1H,
J ¼ 17.1 Hz), 4.05 (q, 2H),
4.25 (q, 2H), 4.45 (s, 1H), 4.6
(brs, 2H), 7.3 (m, 4H)
3402, 3331,
2190, 1740,
1697, 1647
370[M]þ, 325,
297, 279
1.1 (t, 3H), 1.34 (t, 3H), 2.34
(s, 3H), 3.65 (d, 1H,
J ¼ 17.1 Hz), 3.96 (d, 1H,
J ¼ 17.1 Hz),4.05 (q, 2H),
4.2 (q, 2H), 4.42 (s, 1H), 4.48
(brs, 2H), 7.16 (m, 4H)
1.1 (t, 3H), 1.23 (t, 3H), 3.52
(d, 1H, J ¼ 17.1 Hz), 3.85
(d,1H, J ¼ 17.1 Hz), 4.0
(q, 2H), 4.15 (q, 2H), 4.22
(s, 1H), 4.40 (brs, 2H), 6.74
(d, 2H), 7.02 (d, 2H), 9.05
brs, 1H)
4d
3342, 3261,
2196, 1695,
1679, 1605
372[M]þ, 327,
279, 205, 167
4e
4f
3315, 3300,
2189, 1692,
1655, 1635
401[M]þ, 355,
328, 279, 167
1.1 (t, 3H), 1.32 (t, 3H), 3.60
(d, 1H, J ¼ 17.1 Hz), 3.78
(d, 1H, J ¼ 17.1 Hz), 4.0
(q, 2H), 4.2 (q, 2H), 4.29
(s, 1H), 4.54 (brs, 2H), 7.5
(d, 2H), 8.18 (d, 2H)
3385, 3204,
2201, 1769,
1681, 1613
448[M]þ, 375,
355, 279, 205
1.1 (t, 3H), 1.3 (t, 3H), 3.68
(d, 1H, J ¼ 17.1 Hz), 3.94
(d, 1H, J ¼ 17.1 Hz), 4.08
(q, 2H), 4.2 (q, 2H), 4.42
(s, 1H), 4.55 (brs, 2H), 7.02
(m, 5H), 7.35 (m, 4H)
4g
3404, 3295,
2196, 1754,
1729, 1704
314[M]þ, 269,
241, 223, 203
0.98 (t, 3H), 1.32 (t, 3H), 3.95
(q, 2H), 4.28 (q, 2H), 4.40
(s, 1H), 4.62 (brs, 2H), 7.59
(m, 5H)
(continued)

Synthesis of Poly Functionalised 4H-Pyrans
Table 2. Continued.
Mass (m/z)
4435
Entry
IR (cm21
)
1H NMR (DMSO-d6). d
4k
3355, 3340,
2987, 2221,
1702, 1690
308[M] þ , 280,
0.81 (t, 3H), 1.23 (t, 3H), 1.30
(t, 3H), 2.82 (m, 2H), 3.38
(t, 1H), 3.58 (d, 1H,
263, 235
J ¼ 17.1 Hz), 3.70 (d, 1H,
J ¼ 17.1 Hz), 4.12 (q, 2H),
4.21 (q, 2H), 5.88 (brs, 2H)
All the compounds give satisfactory elemental data.
used as the internal standard. Mass spectra were recorded on a VG-micro mass
7070H instrument at 70 ev. Elemental analyses were performed on a Vario EL
analyzer.
General Procedure for the Preparation of 4H-Pyran (4)
A mixture of 1,3-diethyl acetone dicarboxylate 3 (1.88 mmol), aromatic/
aliphatic aldehyde 1 (1.88 mmol), malononitrile 2 (1.88 mmol), and rubidium
fluoride (0.94 mmol) in methanol (10 mL) was refluxed for a specified time.
After completion of the reaction, the solvent was distilled off and treated
with water (10 mL). The precipitated solid was filtered off and recrystallized
from methanol to give the title compound.
Benzylidene Malononitrile
Benzaldehyde (0.2 g, 1.88 mmol) and malononitrile (0.124 g, 1.88 mmol)
were dissolved in methanol (10 mL) and rubidium fluoride (0.098 g,
0.94 mmol) was added. The mixture was reacted at room temperature for
5 min. After completion of the reaction, the solvent was distilled off and
diluted with water. The precipitated solid was filtered, washed with water,
and dried. It is further used without purification.
Condensation of Benzylidene Malononitrile with
Diethylacetone Dicarboxylate
To a mixture of benzylidene malononitrile (0.2 g, 1.29 mmol) and 1,3-
diethyl acetone dicarboxylate (0.262 g, 1.29 mmol) in methanol rubidium

4436
Lingaiah et al.
fluoride (0.06 g, 0.57 mmol) was added to it. The mixture was refluxed for
20 min, cooled, solvent was removed, and the residue was treated with
water (10 mL). The precipitated solid was filtered off and recrystalized from
methanol to obtain pyran 4.
ACKNOWLEDGMENTS
The authors are thankful to Dr. J.S. Yadav, Director, II CT, Hyderabad,
for constant encouragement and financial support from an industry-sponsored
project. GVR is thankful to CSIR for award of fellowship.
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Received August 12, 2004