Synthesis of 4 H-Pyran derivatives under solvent-free and grinding conditions

Article abstract of DOI:10.1080/00397911.2012.716484

Based on X-ray diffraction analysis, we have proved that the recently published results for ethyl 6-amino-5-cyano-4-aryl-1,4-dihydropyridine-3- carboxylate synthesis is in fact an environmentally friendly synthesis of 6-amino-5-cyano-4-aryl-4H-pyran derivatives using a multicomponent room-temperature grinding procedure of ethyl acetoacetate, [(2-aryl)methylene] malononitriles, and ammonium acetate.

Full text of DOI:10.1080/00397911.2012.716484

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Synthesis of 4H-Pyran Derivatives Under
Solvent-Free and Grinding Conditions
Rufus Smits a , Sergey Belyakov a , Aiva Plotniece a & Gunars Duburs
a
a Latvian Institute of Organic Synthesis, Riga, Latvia
Accepted author version posted online: 22 Aug 2012.Version of
record first published: 08 Nov 2012.
To cite this article: Rufus Smits, Sergey Belyakov, Aiva Plotniece & Gunars Duburs (2013): Synthesis
of 4H-Pyran Derivatives Under Solvent-Free and Grinding Conditions, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 43:4, 465-475
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Synthetic Communications1, 43: 465–475, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.716484
SYNTHESIS OF 4H-PYRAN DERIVATIVES UNDER
SOLVENT-FREE AND GRINDING CONDITIONS
Rufus Smits, Sergey Belyakov, Aiva Plotniece, and
Gunars Duburs
Latvian Institute of Organic Synthesis, Riga, Latvia
GRAPHICAL ABSTRACT
Abstract Based on x-ray diffraction analysis, we have proved that the recently published
results for ethyl 6-amino-5-cyano-4-aryl-1,4-dihydropyridine-3-carboxylate synthesis is in
fact an environmentally friendly synthesis of 6-amino-5-cyano-4-aryl-4H-pyran derivatives
using a multicomponent room-temperature grinding procedure of ethyl acetoacetate,
[(2-aryl)methylene]malononitriles, and ammonium acetate.
Keywords Green synthesis; grinding; 4H-pyran derivatives; multicomponent reactions;
solvent-free; x-ray diffraction
INTRODUCTION
The work presented here is a correction of A. M. Zonouz et al., which was recently
published in this journal[1] under the incorrect title of ‘‘Synthesis of 1,4-
Dihydropyridine Derivatives Under Solvent-Free and Grinding Conditions.’’ We have
corrected the products from ‘‘1,4-dihydropyridine (1,4-DHP) derivatives’’ to 4H-pyran
derivatives and included some additional synthesis and x-ray crystallographic proof.
On repeating the reported multicomponent grinding procedure with
thiophene-2-carbaldehyde, malononitrile, and ammonium acetate to give the thiophe-
nemalononitrile and subsequent addition of methyl acetoacetate to generate the
expected methyl 6-amino-5-cyano-2-methyl-4-(thiophen-2-yl)-1,4-dihydropyridine-
3-carboxylate, we were surprised that the x-ray single-crystal structure analysis of
the recrystallized crystals (Fig. 1) proved that the compound was nota 1,4-DHP deriva-
tive, but a 4H-pyran derivative or methyl 6-amino-5-cyano-2-methyl-4-(thiophen-2-
yl)-4H-pyran-3-carboxylate (Scheme 1).
Received April 11, 2012.
Address correspondence to Rufus Smits, Latvian Institute of Organic Synthesis, Aizkraukles 21,
Riga, Latvia. E-mail: rusmits@gmail.com
465

466
R. SMITS ET AL.
Figure 1. ORTEP representation of the molecular structure 1. (Figure is provided in color online.)
We then carefully repeated the exact procedure with 3-nitrobenzaldehyde and
ethyl acetoacetate according to the publication and again the product, which had the
1
identical melting point of 187–188 ꢀC and H NMR spectrum when subjected to an
x-ray single-crystal structure analysis, proved to be a 4H-pyran derivative. Further,
the literature melting points for 1,4-DHP derivatives differ significantly from the 4H-
pyran derivatives, in particular for this particular compound, by more than 30 ꢀC.
Scheme 1. Synthesis of methyl 6-amino-5-cyano-2-methyl-4-(thiophen-2-yl)-4H-pyran-3-carboxylate (1).

SYNTHESIS OF 4H-PYRAN DERIVATIVES
467
Scheme 2. Synthesis of 6-amino-5-cyano-4-aryl-4H-pyrans 3a–f.
The 4H-pyrans exhibit an extensive range of biological and pharmacological
activities, such as spasmolytic, diuretic, anticoagulant, anticancer, and antianaphy-
lactic properties. They are useful in treatment of neurodegenerative disorders,
including Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s
disease, and Parkinson’s disease.[2] Polyfunctionalized 4H-pyrans also constitute a
structural unit of many natural products,[3,4] having antiallergic,[5] antitumor,[6]
and antibacterial[7–9] activities. 4H-Pyran derivatives are also potential calcium
channel antagonists, which are structurally similar to the biologically active
1,4-dihydropyridines.[10]
Recent publications that have reported on the multicomponet synthesis of 4H-
pyrans have used aryl aldehyde, malononitrile, ethyl acetoacetate, and magnesium
oxide as a basic catalyst with grinding and without solvent,[9] the same ingredients
but with silica nanoparticles as a catalyst and ethanol as solvent,[11] and Cu(II) oxy-
metasilicate as a reusable catalyst in methanol as solvent.[12] In these reactions the
catalyst had to be separated from the reaction medium. In the present work
ammonium acetate was used instead of any catalyst, and after completion of the
reaction the ammonium acetate was simply washed away with ethanol and recrystal-
lized to give good yields of the 4H-pyran derivatives.

468
R. SMITS ET AL.
Table 1. Synthesis of 6-amino-5-cyano-4-aryl-4H-pyrans 3a–g by grinding
Entry
1
Aldehyde
Product
Yield (%)
Mp (ꢀC)
3a
78
190–192 (lit.[9] 195–196)
2
3
3b
3c
57
81
178–179
187–188 (lit.[9] 182–183)
4
5
3d
3e
76
59
175–176 (lit.[9] 180–183)
196–197
6
7
3f
68
68
176–177
204–205
3g
RESULTS AND DISCUSSION
Treatment of an aryl aldehyde (1 equiv.) with malononitrile (1 equiv.) in the
presence of ammonium acetate (1.5 equiv.) under solvent-free conditions at room
temperature on grinding gave benzylidene malononitrile derivatives 2 via the Knove-
nagel condensation without any purification. Ethyl acetoacetate (1 equiv.) was added
to the same reaction vessel, followed by grinding (Scheme 2). After workup and puri-
fication, the 6-amino-5-cyano-4-aryl-4H-pyrans 3a–f were obtained in good yields.
The results with different aldehydes are depicted in Table 1.
The reaction products were characterized by their melting points, infrared (IR)
(KBr), 1H NMR, and 13C NMR. The compound 3c has been additionally character-
ized by single-crystal x-ray diffraction (XRD) study (Fig. 2).
In both structures the geometrical parameters of pyran systems are usual for
4H-pyran heterocycles with the envelope conformation. The deviations of C(4)
˚
atom from the O(1), C(2), C(3), C(5), and C(6) plane are equal 0.271(4) A for

SYNTHESIS OF 4H-PYRAN DERIVATIVES
469
Figure 2. ORTEP representation of the molecular structure of 3c. (Figure is provided in color online.)
methyl 6-amino-5-cyano-2-methyl-4-(thiophen-2-yl)-4H-pyran-3-carboxylate (1) and
˚
0.359(3) A for 3c. Both crystal structures are characterized by intermolecular hydro-
gen bonds of NHꢁꢁꢁO and NHꢁꢁꢁN types. The hydrogen bond lengths in 1 are 2.904(4)
˚
˚
A [N(7)–H(7A)ꢁꢁꢁO(16) bond] and 3.051(4) A [N(7)–H(7B)ꢁꢁꢁN(9) bond]. In 3c these
˚
bonds are stronger and the lengths are 2.820(3) A [N(7)–H(7A)ꢁꢁꢁO(20) bond] and
˚
2.987(3) A [N(7)–H(7B)ꢁꢁꢁN(9) bond].
Because initially we were interested in synthesizing 1,4-DHP derivatives, we
tried a reaction where the ethyl acetoacetate in Scheme 2 was substituted with ethyl
3-aminobut-2-enoate. Analysis of the product by NMR revealed that the compound
formed was an intermediate (4) with an acyclic structure and an intramolecular
NHꢁꢁꢁO hydrogen bond (Scheme 3).
The generation of this intermediate with a strong internal NHꢁꢁꢁO bond in
a six-membered ring configuration explains why no further reaction takes place
at room temperature to produce the dihydropyridine derivative. Even when

470
R. SMITS ET AL.
Scheme 3. Formation of intermediate 4.
intermediate 4 was boiled in ethanol for 6 h with dimethylaminopyridine (DMAP) as
catalyst, the starting material only slowly reacted to form a mixture of products,
which was not further analyzed. From this reaction it is also apparent that ethyl acet-
atoacetate reacts first with compound 2c and cyclizes to the 4H-pyran before it could
form the enamine. The structure of intermediate was futher proved by single-crystal
x-ray diffraction. In the crystal structure of intermediate 4 there are two independent
molecules in the asymmetric unit. The bond lengths and valence angles in these mole-
cules are near and correspond to standard values. However, these molecules differ by
conformation: the torsion angle H7–C7–C17–H17 is equal 161ꢀ for molecule A and
ꢂ41 ꢀ for molecule B. Figure 3 illustrates a perspective view of these molecules.
Figure 3. ORTEP representation of the structure of intermediate 4. (Figure is provided in color online.)

SYNTHESIS OF 4H-PYRAN DERIVATIVES
471
Scheme 4. Arylidinemalononitrile reaction with dimedone and ammonium acetate in refluxing glacial
acetic acid to form 1,4-dihydropyridine derivative 5.
When the possibility of internal hydrogen bonding is eliminated, as in the case
of dimedone, the dihydropyridine structure is formed readily (Scheme 4).[13]
CONCLUSIONS
We have proved unequivocally using single-crystal x-diffraction analysis that
the structures which A. M. Zonouz et al. recently published in this journal[1] as
1,4-dihydropyridine derivatives are in fact 4H-pyran derivatives. Consequently
we have corrected all the incorrectly reported ‘‘1,4-dihydropyridine’’ derivatives
to the correct 4H-pyran structures. Therefore, an efficient and environmentally
friendly synthesis of 6-amino-5-cyano-4-aryl-4H-pyran and not 1,4-DHP deriva-
tives has been developed using a multicomponent room-temperature grinding
procedure of ethyl acetoacetate, [(2-aryl)methylene]malononitriles, and ammonium
acetate.
EXPERIMENTAL
Preparation of Ethyl 6-Amino-5-cyano-2-methyl-4-phenyl-4H-
pyran-3-carboxylate (3a), Typical Procedure
A mixture of benzaldehyde (10 mmol, 1 ml), malononitrile (10 mmol, 0.66 g),
and ammonium acetate (15 mmol, 1.15 g) was thoroughly mixed in a mortar by
grinding until the completion of reaction as indicated by thin-layer chromatography
(TLC) (15 min). The mixture solidified during the grinding. Then, ethyl acetoacetate
(10 mmol, 1.26 ml) was added to the same vessel. The mixture, which initially was in
a partially liquid state, solidified during the process of grinding (15 min). The pure
product (3a) was obtained by recrystallized from ethanol (2.21 g, 78%).
Mp 190–192 ꢀC; IR (KBr) n ¼ 3402 (s), 3328 (s), 3223 (m), 2966 (w), 2189 (s),
1693 (s), 1259 (s), 1060 (s) cmꢂ1
;
1H NMR (300 MHz, CDCl3): d ¼ 1.10
(t, J ¼ 7.20 Hz, 3H, CH3 ester), 2.38 (s, 3H, CH3-2), 4.05 (m, 2H, CH2 ester), 4.45
[s, 1H, C(4)-H], 4.50 (br, s, 2H, NH2), 7.17–7.35 (m, 5H, Ar-H) ppm; 13C NMR
(75 MHz, CDCl3): d ¼ 13.86 (CH3 ester), 18.37 (CH3-2), 38.75 (C-4), 60.64 (CH2
ester), 62.58 (C-5), 108.00 (C-3), 118.80 (CN), 127.17 (C-40), 127.50 (C-30,50),
128.56 (C-20,60), 143.72 (C-10), 156.76, 157.39 (C-2, 6), 165.83 (CO) ppm.

472
R. SMITS ET AL.
Methyl 6-Amino-5-cyano-2-methyl-4(thiophen-2-yl)-4H-
pyran-3-carboxylate (1)
This compound was synthesized by this procedure except 1.12 g (10 mmol)
thiophene-2-carbaldehyde and 1.16 g (10 mmol) methyl acetoacetate instead of ethyl
acetoacetate were used. At the end of the grinding procedure, the sticky yellow sub-
stance was recrystallized from ethanol to give white crystals (1.98 g, 72%). Mp
1
142–144 ꢀC; H NMR (400 MHz, DMSO-d6): d ¼ 2.28 (s, 3H, CH3), 3.64 (s, 3H,
CH3 ester), 4.65 [s, 1H, C(4)-H], 6.85 (d, J ¼ 3.6 Hz, 1H, Ar), 6.93 (dd, J ¼ 5.1,
3.5, 1H, Ar), 7.05 (br, s, 2H, NH2), 7.36 (d, J ¼ 5.1, 1H, Ar) ppm; 13C NMR
(100 MHz, DMSO-d6): d ¼ 18.22, 33.81, 51.69, 56.93, 107.61, 119.55, 123.55,
124.78, 126.97, 149.34, 156.90, 159.09, 165.76 ppm.
Ethyl 6-Amino-5-cyano-2-methyl-4-(2-nitrophenyl)-4H-
pyran-3-carboxylate (3b)
Mp 177.5–178.5 ꢀC; IR (KBr) n ¼ 3453 (s), 3294 (s), 3215 (s), 3185 (s), 2984 (w),
2208 (s), 1719 (s), 1684 (s), 1601 (s), 1530 (s), 1381 (s), 1225 (s), 1062 (s), 786 (s), 726
(s) cmꢂ1; 1H NMR (300 MHz, CDCl3): d ¼ 0.99 (t, J ¼ 7.20 Hz, 3H, CH3 ester), 2.41
(s, 3H, CH3-2), 3.96 (m, 2H, CH2 ester), 4.67 (br, s, NH2), 5.26 [s, 1H, C(4)-H],
7.32–7.40 (m, 2H, Ar-H40, H60), 7.58 (dt, J1 ¼ 7.50 Hz, J2 ¼ 1.20 Hz, 1H, Ar-H50),
7.82 (dd, J1 ¼ 7.70 Hz, J2 ¼ 1.20 Hz, 1H, Ar-H30) ppm; 13C NMR (75 MHz, CDCl3):
d ¼ 13.66 (CH3 ester), 18.45 (CH3-2), 32.97 (C-4), 60.95 (CH2 ester), 63.50 (C-5),
107.30 (C-3), 118.21 (CN), 124.06 (C-30), 127.91 (C-40), 130.61 (C-60), 133.23
(C-50), 139.08 (C-10), 149.09 (C-20), 158.05, 158.24 (C-2, 6), 165.04 (CO) ppm.
Ethyl 6-Amino-5-cyano-2-methyl-4-(3-nitrophenyl)-4H-
pyran-3-carboxylate (3c)
Mp 187–188 ꢀC; IR (KBr) n ¼ 3402 (s), 3328 (s), 3221 (m), 2987 (w), 2190 (s), 1672
(s), 1531 (s), 1344 (s), 1063 (s) cmꢂ1
;
1H NMR (400 MHz, CDCl3): d ¼ 1.12
(t, J ¼ 7.20 Hz, 3H, CH3 ester), 2.41 (s, 3H, CH3-2), 4.05 (m, 2H, CH2 ester), 4.58 [s,
1H, C(4)-H], 4.69 (br, s, NH2), 7.49 (t, J ¼ 8.00 Hz, 1H, Ar-H50), 7.58 (td,
J1 ¼ 8.00 Hz, J2 ¼ 0.80 Hz, Ar-H60), 8.06 (t, J ¼ 1.60 Hz, 1H, Ar-H20), 8.11 (md,
J ¼ 8.00 Hz, 1H, Ar-H40) ppm; 1H NMR (400 MHz, DMSO-d6): d ¼ 1.01
(t, J ¼ 7.20 Hz, 3H, CH3 ester), 2.07 (s, 2H, NH2), 2.34 (s, 3H, CH3-2), 3.95 (m, 2H,
CH2 ester), 4.52 [s, 1H, C(4)-H], 7.60–7.70 (m, 2H, Ar-H50, H60), 7.98 (s, 1H, Ar-H20),
8.10 (dt, J1 ¼ 7.50 Hz, J2 ¼ 1.92 Hz, 1H, Ar-H40) ppm; 13C NMR (100 MHz, CDCl3):
d ¼ 12.90 (CH3 ester), 17.64 (CH3-2), 37.75 (C-4), 59.95 (CH2 ester), 63.50 (C-5),
105.93 (C-3), 117.33 (CN), 121.39 (C-40), 121.55 (C-20), 128.51 (C-50), 133.01 (C-60),
145.10 (C-10), 147.47 (C-30), 159.77, 156.95 (C-2, 6), 164.26 (CO) ppm.
Ethyl 6-Amino-5-cyano-2-methyl-4-(4-nitrophenyl)-4H-
pyran-3-carboxylate (3d)
Mp 175–176 ꢀC; IR (KBr) n ¼ 3404 (s), 3333 (s), 3204 (s), 2983 (w), 2200 (s),
1
1690 (s), 1650 (s), 1518 (s), 1345 (s), 1270 (s), 1060 (s) cmꢂ1; H NMR (300 MHz,
CDCl3): d ¼ 1.11 (t, J ¼ 7.20 Hz, 3H, CH3 ester), 2.42 (s, 3H, CH3-2), 4.05

SYNTHESIS OF 4H-PYRAN DERIVATIVES
473
(q, J ¼ 7.20 Hz, 2H, CH2 ester), 4.57 [s, 1H, C(4)-H], 4.67 (br, s, NH2), 7.39
(d, J ¼ 7.70 Hz, 2H, Ar-H2,60), 8.18 (d, J ¼ 7.70 Hz, 1H, Ar-H30,50) ppm; 13C
NMR (75 MHz, CDCl3): d ¼ 13.92 (CH3 ester), 18.61 (CH3-2), 38.82 (C-4), 60.86
(C-5), 60.97 (CH2 ester), 106.79 (C-3), 118.28 (CN), 123.99 (C-20,60), 128.42
(C-30,50), 147.09 (C-10), 151.09 (C-40), 157.73, 158.05 (C-2, 6), 165.26 (CO) ppm.
Ethyl 6-Amino-5-cyano-2-methyl-4-(2-methoxyphenyl)-4H-
pyran-3-carboxylate (3e)
Mp 196–197 ꢀC; IR (KBr) n ¼ 3403 (s), 3326 (s), 3220 (m), 2967 (w), 2933 (w),
1
2187 (s), 1693 (s), 1606 (m), 1256 (s), 1063 (s), 713 (s) cmꢂ1; H NMR (300MHz,
CDCl3): d ¼ 1.06 (t, J ¼ 7.20Hz, 3H, CH3 ester), 2.38 (s, 3H, CH3-2), 3.84 (s, 3H,
OCH3), 4.00 (m, 2H, CH2 ester), 4.41 (br, s, 2H, NH2), 4.88 [s, 1H, C(4)-H],
6.82–6.92 (m, 2H, Ar-H50, 30), 7.06 (dd, J1 ¼ 7.50Hz, J2 ¼ 1.50Hz, 1H, Ar-H60), 7.19
(dt, J1 ¼ 7.50Hz, J2 ¼ 1.50Hz, 1H, Ar-H40) ppm; 13C NMR (75 MHz, CDCl3):
d ¼ 13.77 (CH3 ester), 18.31 (CH3-2), 32.61 (C-4), 55.58 (OCH3), 60.42 (CH2 ester),
61.81 (C-5), 107.06 (C-3), 111.05 (C-30), 119.10 (CN), 120.65 (C-50), 128.24 (C-40),
128.68 (C-60), 131.79 (C-10), 157.07 (C-2), 157.45 (C-20), 157.94 (C-6), 166.08 (CO) ppm.
Ethyl 6-Amino-5-cyano-2-methyl-4-(3-methylphenyl)-4H-
pyran-3-carboxylate (3f)
Mp 176–177 ꢀC; IR (KBr) n ¼ 3401 (s), 3330 (m), 3222 (m), 2981 (w), 2192 (s),
1697 (s), 1675 (s), 1647 (m), 1604 (m), 1372 (m), 1266 (s), 1058 (s), 721 (m) cmꢂ1; 1H
NMR (300 MHz, CDCl3): d ¼ 1.11 (t, J ¼ 6.90 Hz, 3H, CH3 ester), 2.33 (s, 3H,
CH3-2), 2.38 (s, 3H, CH3), 4.05 (m, 2H, CH2 ester), 4.41 [s, 1H, C(4)-H], 4.45 (br,
s, NH2), 6.92–7.25 (m, 4H, Ar-H) ppm; 13C NMR (75 MHz, CDCl3): d ¼ 13.86
(CH3 ester), 18.37 (CH3-2), 21.45 (CH3), 38.68 (C-4), 60.61 (CH2 ester), 62.52
(C-5), 108.08 (C-3), 118.91 (CN), 124.62 (C-40), 127.96, 128.20, 128.40 (C-20,50,60),
138.07 (C-30), 143.64 (C-10), 156.61, 157.45 (C-2,6), 165.91 (CO) ppm.
Ethyl 6-Amino-5-cyano-2-methyl-4-(2-furyl)-4H-pyran-3-
carboxylate (3g)
Mp 204–205 ꢀC; IR (KBr) n ¼ 3393 (m), 3370 (m), 3202 (m), 2963 (m), 2193 (s),
1
1693 (s), 1685 (s), 1261 (s), 1065 (s), 802 (s) cmꢂ1; H NMR (300 MHz, CDCl3):
d ¼ 1.23 (t, J ¼ 7.20 Hz, 3H, CH3 ester), 2.37 (s, 3H, CH3-2), 4.16 (m, 2H, CH2 ester),
4.53 (br, s, 2H, NH2), 4.64 [s, 1H, C(4)-H], 6.102 (d, J ¼ 3.30 Hz, 1H, Ar-H50), 6.28
(m, 1H, Ar-H40), 7.31 (s, 1H, Ar-H30) ppm; 13C NMR (75 MHz, CDCl3): d ¼ 14.00
(CH3 ester), 18.43 (CH3-2), 32.37 (C-4), 59.53 (C-5), 60.78 (CH2 ester), 105.71 (C-3),
105.93 (C-50), 110.33 (C-40), 118.62 (CN), 141.93 (C-30), 155.13 (C-10), 157.78, 158.54
(C-2,6), 165.63 (CO) ppm.
(Z)-Ethyl 3-Amino-2-(2,2-dicyano-1-(3-nitrophenyl)ethyl)but-2-
enoate (4)
This intermediate was synthesized according to the typical grinding procedure
using 3-nitrobenzaldehyde (10 mmol) and (Z)-ethyl 3-aminobut-2-enoate (1.29 g

474
R. SMITS ET AL.
10 mmol) instead of ethyl acetoacetate. The yellow sticky mixture was washed with
ethanol and recrystallized to give light green needles (1.9 g, 58%).
1
Mp 142–144 ꢀC; H NMR (400 MHz, DMSO-d6): d ¼ 1.02 (t, J ¼ 7.0 Hz, 3H,
CH3, ester), 2.17 (s, 3H, CH3), 3.67–4.12 (m, 2H, CH2, ester), 4.75 [d, J ¼ 11.4 Hz,
1H, CH(CN)2], 5.73 (d, J ¼ 11.4 Hz, 1H, CH-Ar), 7.46 (br, s, 1H, NH), 7.58
(t, J ¼ 7.9 Hz, 1H, Ar-H5), 7.73 (d, J ¼ 7.6 Hz, 1H, Ar-H6), 8.07 (d, J ¼ 8.0 Hz,
1H, Ar-H4), 8.14 (s, 1H, Ar-H2), 8.61 (br, s, 1H, NH. . .O) ppm; 13C NMR
(100 MHz, DMSO-d6): d ¼ 13.99, 20.92, 26.69, 43.34, 58.45, 88.97, 113,79, 114.38,
121.92, 122.24, 129.47, 135.03, 141.99, 147.38, 163.10, 167.55 ppm.
Crystal Data
For ethyl 6-amino-5-cyano-2-methyl-4-(3-nitrophenyl)-4H-pyran-3-carboxy-
late (3c), methyl 6-amino-5-cyano-2-methyl-4-(thiophen-2-yl)-4H-pyran-3-carboxy-
late (1), and intermediate 4, diffraction data were collected at ꢂ100 ꢀC (for 3c and
1) and at room temperature for 4 on a Bruker-Nonius KappaCCD diffractometer
˚
using graphite monochromated Mo-Ka radiation (k ¼ 0.71073 A). Both crystal
structures were solved by the direct method and refined by full-matrix least squares.
All non hydrogen atoms were refined anisotropically.
Crystal Data for 1. C13H12N2O3S, triclinic, a ¼ 8.6311(2), b ¼ 9.0785(3),
3
ꢀ
˚
˚
c ¼ 9.6055(3) A, a ¼ 96.548(2), b ¼ 115.097(2), c ¼ 95.679(2) , V ¼ 668.02(3) A ,
Z ¼ 2, m ¼ 0.250 mmꢂ1, Dcalc ¼ 1.374 g cmꢂ3, space group P 1. A total of 3256 inde-
ꢀ
pendent reflection intensities were collected at room temperature. For structure
refinement, 2055 reflections with I > 3r(I) were used. The final R factor is 0.059.
Crystal Data for 3c. C16H15N3O5, triclinic, a ¼ 8.3621(2), b ¼ 8.4736(3),
3
ꢀ
˚
˚
c ¼ 12.0001(5) A, a ¼ 82.192(1), b ¼ 71.039(2), c ¼ 76.176(2) , V ¼ 779.29(5) A ,
Z ¼ 2, m ¼ 0.106 mmꢂ1, Dcalc ¼ 1.403 g cmꢂ3, space group P 1. A total of 3911 inde-
ꢀ
pendent reflection intensities were collected at room temperature. For structure
refinement, 2546 reflections with I > 3r(I) were used. The final R factor is 0.047.
Crystal Data for 4. C16H16N4O4, monoclinic, a ¼ 19.8757(7), b ¼ 8.4327(3),
3
c ¼ 20.637(1) A, b ¼ 106.330(1) ꢀ, V ¼ 3319.3(2) A , Z ¼ 8, m ¼ 0.097 mmꢂ1
,
˚
˚
Dcalc ¼ 1.314 gꢁcmꢂ3, space group P21=n. A total of 8959 independent reflection
intensities were collected at room temperature. For structure refinement, 3496 reflec-
tions with I > 3r(I) were used. The final R factor is 0.074. For further details, see
crystallographic data for these structures deposited with the Cambridge Crystallo-
graphic Data Centre as Supplementary Publication Numbers CCDC 865274 (for
1), 865275 (for 3c), and 870203 (for ‘‘intermediate’’). Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK.
ACKNOWLEDGMENT
This work was supported by ESF Project No. 2009=0197=1DP=1.1.1.2.0=09=
APIA=VIAA=014.

SYNTHESIS OF 4H-PYRAN DERIVATIVES
475
REFERENCES
1. Zonouz, A. M.; Moghani, D. Synthesis of 1,4-dihydropyridine derivatives under
solvent-free and grinding conditions. Synth. Commun. 2011, 41, 2152–2160.
2. (a) Foye, W. O. Principi di Chemico Farmaceutica; Piccin: Padora, Italy, 1991; p. 416; (b)
Andreani, L. L.; Lapi, E. On some esters of coumarin-3-carboxylic acid with balsamic
bronchodilator action. Bull. Chim. Farm. 1960, 99, 583–586; (c) Zhang, Y. L.; Chen, B.
Z.; Zeng, K. Q.; Xu, M. L.; Lei, X. H.; Yaoxue, X. B. Chemotherapeutic studies on
schistosomiasis XXV: Derivatives of substituted coumarin-3-carboxylic esters and amides.
Chinese Acta Pharmaceutica Sinica 1982, 17, 17; Chem. Abstr. 1982, 96, 135383e; (d)
Bonsignore, L.; Loy, G.; Secci, D.; Calignano, A. Synthesis and pharmacological activity
of 2-oxo-(2H) 1-benzopyran-3-carboxamide derivatives. Eur. J. Med. Chem. 1993, 28,
517–520.
3. Kuthan, J. Pyrans, thiopyrans, and selenopyrans. Adv. Heterocycl. Chem. 1983, 34,
145–303.
4. Hatakeyama, S.; Ochi, N.; Numata, H.; Takano, S. A new route to substituted 3-methox-
ycarbonyldihydropyrans enantioselective synthesis of (ꢂ)-methyl enolate. J. Chem. Soc.,
Chem. Commun. 1988, 1202–1204.
5. Witte, E. C.; Neubert, P.; Roesch, A. Ger. Offen. Patent DE3427985, 1986.
6. Wang, J. L.; Liu, D.; Zhang, Z. J.; Shan, S.; Han, X.; Srinivasula, S. M.; Croce, C. M.;
Alnemri, E. S.; Huang, Z. Structure-based discovery of an organic compound that binds
Bcl-2 protein and induces apoptosis of tumor cells. Proc. Natl. Acad. Sci. U. S. A. 2000,
97, 7124–7129.
7. El-Saghier, A. M. M.; Naili, M. B.; Rammash, B. K.; Saleh, N. A.; Kreddan, K. M. Syn-
thesis and antibacterial activity of some new fused chromenes. Arkivoc. 2007, 16, 83–91.
8. Kumar, R. R.; Perumal, S.; Senthilkumar, P.; Yogeeswari, P.; Sriram, D. An
atom-efficient, solvent-free, green synthesis and antimycobacterial evaluation of
2-amino-6-methyl-4-aryl-8-[(E)-arylmethylidene]-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyri
dine-3-carbonitriles. Bioorg. Med. Chem. Lett. 2007, 17, 6459–6462.
9. Kumar, D.; Reddy, V. B.; Sharad, S.; Dube, U.; Kapur, S. A facile one-pot green syn-
thesis and antibacterial activity of 2-amino-4H-pyrans and 2-amino-5-oxo-
5,6,7,8-tetrahydro-4H-chromenes. Eur. J. Med. Chem. 2009, 44, 3805–3809.
10. Suarez, M.; Slafran, E.; Verdecia, Y.; Ochoa, E.; Alba, L.; Martin, N.; Martinez, R.;
Quinteiro, M.; Seoane, C.; Novoa, H.; Blaton, N.; Peeters, O. M.; De Ranter, C. X-ray
and theoretical structural study of novel 5,6,7,8-tetrahydrobenzo-4H-pyrans. Tetrahedron.
2002, 58, 953–960.
11. Banerjee, S.; Horn, A.; Khatri, H.; Sereda, G. A green one-pot multicomponent synthesis
of 4H-pyrans and polysubstituted aniline derivatives of biological, pharmacological, and
optical applications using silica nanoparticles as reusable catalyst. Tetrahedron. Lett. 2011,
52, 1878–1881.
12. Heravi, M. M.; Beheshtiha, Y. S.; Piernia, Z.; Sadjadi, S.; Adibi, M. One-pot,
three-component synthesis of 4H-pyrans using Cu(II) oxymetasilicate. Synth. Commun.
2009, 39, 3663–3667.
13. Suarez, M.; Verdecia, Y.; Ochoa, E.; Martin, N.; Martinez, R.; Quinteiro, M.; Seoane, C.;
Soto, J. L.; Novoa, H.; Blaton, N.; Peeters, O. M.; De Ranter, C. Synthesis and structural
study of novel 1,4,5,6,7,8-hexahydroquinolones. J. Heterocycl. Chem. 2000, 37, 735–742.