Mild and efficient synthesis of polyfunctionalized 4H-pyran-3-carboxamide derivatives

Full text of DOI:10.1080/00304948.2014.903144

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Organic Preparations and Procedures
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Mild and Efficient Synthesis of
Polyfunctionalized 4H-Pyran-3-
carboxamide Derivatives
Ramakanth Pagadalaa, Suresh Maddilaa & Sreekanth B.
Jonnalagaddaa
a School of Chemistry & Physics, University of KwaZulu-Natal,
Westville Campus, Chiltern Hills Durban–4000, South Africa
Published online: 27 May 2014.
To cite this article: Ramakanth Pagadala, Suresh Maddila & Sreekanth B. Jonnalagadda (2014)
Mild and Efficient Synthesis of Polyfunctionalized 4H-Pyran-3-carboxamide Derivatives, Organic
Preparations and Procedures International: The New Journal for Organic Synthesis, 46:3, 261-266,
DOI: 10.1080/00304948.2014.903144
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Organic Preparations and Procedures International, 46:261–266, 2014
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2014.903144
OPPI BRIEF
Mild and Efficient Synthesis of Polyfunctionalized
4H-Pyran-3-carboxamide Derivatives
Ramakanth Pagadala, Suresh Maddila, and
Sreekanth B. Jonnalagadda
School of Chemistry & Physics, University of KwaZulu-Natal, Westville
Campus, Chiltern Hills Durban-4000, South Africa
Simple and green synthetic approaches to valuable six-membered oxygen heterocyclic com-
pounds are significant challenges in organic chemistry. Over the years, many attempts have
been made to develop multi-component reactions for the synthesis of 4H-pyrans.1–8 4H-
Pyran derivatives constitute a promising and versatile class of heterocycles with wide scope
as natural and synthetic biologically active compounds,9–11 viz., anti-cancer agents, anti-
anaphylactics, and anti-coagulants.12 A literature search indicates that amide-containing
4H-pyrans exhibit useful biological activities13 and a number of 2-amino-4H-pyrans are
valuable photo-active materials.14
Most of the synthetic methods15–20 require expensive reagents, acidic conditions, long
reaction times, excess of reagents or toxic organic solvents, and tedious work-up and in
many of the methods, the yields are not impressive. Radiative and non-radiative techniques,
such as microwave and ultrasonic irradiation have also been used.21,22 The present com-
munication describes an environment-friendly method for the preparation of 4H-pyrans in
good yields under mild conditions using water as a solvent. To our knowledge, there are no
similar reports in the literature on the synthesis of tetra-substituted 4H-pyrans. The optimal
conditions for synthesis of 4H-pyrans were determined to be K2CO3 as catalyst using one
equiv. of acetoacetanilide (1), benzaldehyde (2a), and malononitrile 3 at room temperature
(Scheme 1). The procedure was extended to a range of substituted benzaldehydes.
1
All the compounds synthesized were characterized using IR, H NMR, 13CNMR,
correct combustion analysis, and mass spectra. Compound 4a was further identified by
15N NMR (GHSQC) to confirm the presence of the amino group. All the 4H-pyran-3-
carboxamide derivatives were obtained in excellent yields (85%–98%).
Submitted September 2, 2013.
Address correspondence to Sreekanth B. Jonnalagadda, School of Chemistry & Physics, Uni-
versity of KwaZulu-Natal, Westville Campus, Chiltern Hills, Durban-4000, South Africa. E-mail:
jonnalagaddas@ukzn.ac.za
261

262
Jonnalagadda et al.
R
O
CHO
Ph
CN
K2CO3
HOH, rt
O
O
CN
CN
3
N
H
Ph
Me
N
H
Me
O
NH2
R
4a-j
2
1
a) R = H, b) R = 4-MeO, c) R = 4-Br, d) R = 4-Cl, e) R = 4-OH, f) R = 4-NO2, g) R = 4-Me2N, h) R = 2-Cl,
i) R = 2-Br, j) R = 2-CH3
Scheme 1
Synthesis of Substituted 4H-Pyran-3-carboxamides.
In conclusion, we have developed a new approach for the synthesis of 4H-pyrans in
the presence of K2CO3 in water as solvent. The major advantages of this procedure are
its operational simplicity, cost-effectiveness, high yields, and the ease of isolation of the
products, which were obtained in excellent yields and significantly shorter reaction times
than previously available methods.
Experimental Section
All chemicals used were reagent grade and used as received without further purification.1H
NMR and 13C NMR spectra were recorded at 25◦C at 400 MHz and 100 MHz (Bruker
Avance) instrument, respectively, using TMS as internal standard. Chemical shifts are given
in δ (ppm). The FT-IR spectra were obtained as KBr pellets on a Perkin-Elmer Precisely 100
FT-IR spectrometer in the 400–4000 cm−1 region. Liquid chromatography-mass spectrom-
etry (LC-MS) was determined on a MASPEC low-resolution mass spectrometer operating
at 70 eV. Elemental analyses were carried out using a Perkin-Elmer CHNS Elemental An-
alyzer model 2400. The progress of the reactions was monitored and the purity of products
was checked on thin layer chromatography (TLC) on aluminum-backed plates coated with
Merck Kieselgel 60 F254 silica gel, visualizing the spots under ultraviolet light and in an
iodine chamber. Melting points are uncorrected and were recorded on a hot stage melting
point apparatus (Ernst Leitz Wetzlar, Germany).
Typical Experimental Procedure for the Synthesis of 4H-Pyran
A mixture of freshly distilled benzaldehyde (0.1 g, 1.0 mmol) in water (5 ml), malononitrile
(0.07 g, 1.0 mmol), and acetoacetanilide (0.18 g, 1.0 mmol) was stirred at room temperature.
After 10 min of stirring, a solution of K2CO3 (0.28 g) in 15 ml of H2O was added and
the reaction mixture was stirred at room temperature for 5 h. After the starting material
had been consumed [monitored by TLC (EtOAc/hexane = 4:6)], a saturated aqueous NaCl
solution (10 ml) was added to the reaction mixture. The reaction mixture was stirred for

Synthesis of 4H-Pyran-3-carboxamide Derivatives
263
30 min and set aside for 30 min. The solid that separated was collected and washed with
water to give a pure product 4a (98% yield) as an off-white solid.
6-Amino-5-cyano-2-methyl-N,4-diphenyl-4H-pyran-3-carboxamide (4a)
Off-white solid (98%): mp 210◦C; 1H NMR (DMSO-d6) δ 2.19 (3H, s), 5.89 (1H, s), 6.78
(2H, s), 7.20–7.36 (10H, m), 8.12 (1H, s); 13C NMR (DMSO-d6): δ 20.3, 71.2, 104.9,
117.1, 119.5, 120.8, 123.7, 128.7, 129.3, 130.0, 134.6, 134.6, 151.6, 155.8, 160.5, 164.6;
IR (KBr, cm−1): 3411, 3254, 3149, 2197; HRMS of [C20H17N3O2 + K] (m/z): 370.4689
(100%); Calcd. Mass: 370.4683.
Anal. Calcd for C20H17N3O2: C, 72.49; H, 5.17; N, 12.68. Found: C, 72.53; H, 5.28;
N, 12.74.
6-Amino-5-cyano-4-(4-methoxyphenyl)-2-methyl-N-phenyl-4H-pyran-3-carboxamide
(4b)
Off-white solid (95%): mp 176◦C; 1H NMR (DMSO-d6) δ 2.13 (3H, s), 3.71 (3H, s), 5.62
(1H, s), 6.68 (2H, s), 7.18–7.55 (9H, m), 8.49 (1H, s); 13C NMR (DMSO-d6): δ 20.4, 58.6,
71.2, 104.9, 117.1, 120.5, 123.3, 128.7, 129.3, 130.0, 134.6, 138.1, 138.9, 151.6, 155.8,
160.5, 163.8; IR (KBr, cm−1): 3408, 3240, 3142, 2193; LCMS of [C21H19N3O3 + H+]
(m/z): 362 (100%).
Anal. Calcd for C21H19N3O3: C, 69.79; H, 5.30; N, 11.63. Found: C, 69.87; H, 5.48;
N, 11.71.
6-Amino-4-(4-bromophenyl)-5-cyano-2-methyl-N-phenyl-4H-pyran-3-carboxamide
(4c)
Off-white solid (97%): mp 198◦C; 1H NMR (DMSO-d6) δ 2.16 (3H, s), 5.66 (1H, s), 6.66
(2H, s), 7.21–7.52 (9H, m), 8.50 (1H, s); 13C NMR (DMSO-d6): δ 20.3, 71.2, 104.9, 117.1,
120.8, 123.7, 128.7, 129.3, 130.0, 134.6, 138.0, 138.9, 151.6, 155.8, 160.5, 163.6; IR (KBr,
cm−1): 3412, 3246, 3139, 2196; LCMS of [C20H16BrN3O2 + H+] (m/z): 411 (100%).
Anal. Calcd for C20H16BrN3O2: C, 58.55; H, 3.93; N, 10.24. Found: C, 58.72; H, 3.98;
N, 10.36.
6-Amino-4-(4-chlorophenyl)-5-cyano-2-methyl-N-phenyl-4H-pyran-3-carboxamide
(4d)
Off-white solid (98%): mp 192◦C; 1H NMR (DMSO-d6) δ 2.16 (3H, s), 5.66 (1H, s), 6.66
(2H, s), 7.22–7.54 (9H, m), 8.50 (1H, s); 13C NMR (DMSO-d6): δ 20.3, 71.2, 104.9, 117.1,
120.8, 123.8, 128.7, 129.3, 130.0, 134.6, 137.9, 138.7, 151.6, 155.8, 160.5, 163.1; IR (KBr,
cm−1): 3410, 3243, 3142, 2193; LCMS of [C20H16ClN3O2 + H+] (m/z): 366 (100%).
Anal. Calcd for C20H16ClN3O2: C, 65.67; H, 4.41; N, 11.49. Found: C, 65.72; H, 4.58;
N, 11.62.

264
Jonnalagadda et al.
6-Amino-5-cyano-4-(4-hydroxyphenyl)-2-methyl-N-phenyl-4H-pyran-3-carboxamide
(4e)
Off-white solid (94%): mp 170◦C; 1H NMR (DMSO-d6) δ 2.16 (3H, s), 5.66 (1H, s), 6.66
(2H, s), 7.22–7.56 (9H, m), 8.43 (1H, s), 9.8 (1H, s); 13C NMR (DMSO-d6): δ 20.3, 71.2,
104.9, 117.1, 120.5, 123.9, 128.7, 129.3, 130.0, 134.6, 137.9, 138.7, 151.6, 155.8, 160.5,
163.4; IR (KBr, cm−1): 3465, 3304, 3064, 3084, 2206; LCMS of [C20H17N3O3 + K] (m/z):
386 (100%).
Anal. Calcd for C20H17N3O3: C, 69.15; H, 4.93; N, 12.10. Found: C, 69.28; H, 4.99;
N, 12.18.
6-Amino-5-cyano-2-methyl-4-(4-nitrophenyl)-N-phenyl-4H-pyran-3-carboxamide (4f)
Off-white solid (92%): mp 188◦C; 1H NMR (DMSO-d6) δ 2.16 (3H, s), 5.66 (1H, s), 6.66
(2H, s), 7.23–7.55 (9H, m), 8.50 (1H, s); 13C NMR (DMSO-d6): δ 20.3, 71.2, 104.9, 117.1,
120.5, 123.5, 128.7, 129.3, 130.0, 134.6, 137.5, 138.7, 151.6, 155.8, 160.5, 163.4; IR (KBr,
cm−1): 3417, 3230, 3126, 2190; LCMS of [C20H16N4O4 + H+] (m/z): 377 (100%).
Anal. Calcd for C20H16N4O4: C, 63.82; H, 4.28; N, 14.89. Found: C, 63.97; H, 4.42;
N, 14.98.
6-Amino-5-cyano-4-(4-(dimethylamino)phenyl)-2-methyl-N-phenyl-4H-pyran-3-
carboxamide (4g)
Off-white solid (94%): mp 169◦C; 1H NMR (DMSO-d6) δ 2.16 (3H, s), 2.8 (6H, s), 5.66
(1H, s), 6.66 (2H, s), 7.21–7.58 (9H, m), 8.49 (1H, s); 13C NMR (DMSO-d6): δ 20.3, 46.5,
71.2, 104.9, 117.1, 120.4, 123.6, 128.7, 129.3, 130.0, 134.6, 137.3, 138.9, 151.6, 155.8,
160.4, 163.5; IR (KBr, cm−1): 3409, 3241, 3132, 2194; LCMS of [C22H22N4O2 + H+]
(m/z): 375 (100%).
Anal. Calcd for C22H22N4O2: C, 70.57; H, 5.92; N, 14.96. Found: C, 70.71; H, 6.07;
N, 15.12.
6-Amino-4-(2-chlorophenyl)-5-cyano-2-methyl-N-phenyl-4H-pyran-3-carboxamide
(4h)
1
Off-white solid (90%): mp 154◦C; H NMR (DMSO-d6) δ = 2.19 (3H, s), 5.89 (1H, s),
6.78 (2H, s), 7.20–7.36 (9H, m), 8.12 (1H, s); 13C NMR (DMSO-d6): δ 19.4, 46.5, 71.5,
105.3, 117.4, 120.6, 123.8, 128.6, 129.3, 130.4, 134.8, 137.6, 138.7, 151.8, 155.9, 160.5,
163.7; IR (KBr, cm−1): 3412, 3238, 3075, 2197; LCMS of [C20H16ClN3O2 + Na] (m/z):
388 (100%).
Anal. Calcd for C20H16ClN3O2: C, 65.67; H, 4.41; N, 11.49. Found: C, 65.63; H, 4.50;
N, 11.57.
6-Amino-4-(2-bromophenyl)-5-cyano-2-methyl-N-phenyl-4H-pyran-3-carboxamide (4i)
1
Off-white solid (85%): mp 146◦C; H NMR (DMSO-d6) δ = 2.13 (3H, s), 5.62 (1H, s),
6.96 (2H, s), 7.21–7.67 (9H, m), 8.35 (1H, s); 13C NMR (DMSO-d6): δ 19.4, 46.8, 71.8,

Synthesis of 4H-Pyran-3-carboxamide Derivatives
265
105.7, 117.1, 120.4, 123.8, 128.9, 129.6, 130.9, 134.6, 137.3, 138.8, 151.6, 155.9, 160.4,
163.5; IR (KBr, cm−1): 3407, 3256, 3032, 2193; LCMS of [C20H16BrN3O2 + H+] (m/z):
411 (100%).
Anal. Calcd for C20H16BrN3O2: C, 58.55; H, 3.93; N, 10.24. Found: C, 58.62; H, 3.84;
N, 10.38.
6-Amino-5-cyano-2-methyl-N-phenyl-4-o-tolyl-4H-pyran-3-carboxamide (4j)
Off-white solid (88%): mp 169◦C; 1H NMR (DMSO-d6) δ 2.09 (3H, s), 2.78 (3H, s), 4.96
(1H, s), 6.59 (2H, s), 6.95–7.58 (9H, m), 8.00 (1H, s); 13C NMR (DMSO-d6): δ 19.8, 41.1,
46.6, 71.3, 104.9, 117.1, 120.6, 123.4, 128.9, 129.6, 130.4, 134.8, 137.4, 140.2, 151.9,
155.8, 160.6, 163.9; IR (KBr, cm−1): 3416, 3247, 3038, 2199; LCMS of [C21H19N3O2 +
Na] (m/z): 368 (100%).
Anal. Calcd for C21H19N3O2: C, 73.03; H, 5.54; N, 12.17. Found: C, 73.01; H, 5.67;
N, 12.20.
Acknowledgment
We thank to the School of Chemistry and Physics and the College of Agriculture, Engineer-
ing and Science, University of KwaZulu-Natal, South Africa for the facilities and financial
support.
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