A novel and efficient synthesis of 3-[(4,5-dihydro-1H-pyrrol-3-yl)carbonyl] -2H-chromen-2-ones (=3-[(4,5-dihydro-1H-pyrrol-3-yl)carbonyl]-2H-1-benzopyran-2- ones)

Article abstract of DOI:10.1002/hlca.201200216

An efficient one-pot synthesis of 3-[(4,5-dihydro-1H-pyrrol-3-yl)carbonyl]- 2H-chromen-2-one (=3-[(4,5-dihydro-1H-pyrrol-3yl)carbonyl]-2H-1-benzopyran-2- one) derivatives 4 by a four-component reaction of a salicylaldehyde 1, 4-hydroxy-6-methyl-2H-pyran-2-one, a benzylamine 2, and a diaroylacetylene (=1,4-diarylbut-2-yne-1,4-dione) 3 in EtOH is reported. This new protocol has the advantages of high yields (Table), and convenient operation. The structures of these coumarin (=2H-1-benzopyran-2-one) derivatives, which are important compounds in organic chemistry, were confirmed spectroscopically (IR, ¹H- and ¹³C-NMR, and EI-MS) and by elemental analyses. A plausible mechanism for this reaction is proposed (Scheme 2). Copyright

Full text of DOI:10.1002/hlca.201200216

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473
A Novel and Efficient Synthesis of 3-[(4,5-Dihydro-1H-pyrrol-3-yl)carbonyl]-
2H-chromen-2-ones (¼ 3-[(4,5-Dihydro-1H-pyrrol-3-yl)carbonyl]-2H-1-
benzopyran-2-ones)
by Abdolali Alizadeh* and Rashid Ghanbaripour
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
(phone: þ 98-21-88006631; fax: þ 98-21-88006544; e-mail: aalizadeh@modares.ac.ir,
abdol_alizad@yahoo.com)
An efficient one-pot synthesis of 3-[(4,5-dihydro-1H-pyrrol-3-yl)carbonyl]-2H-chromen-2-one (¼ 3-
[(4,5-dihydro-1H-pyrrol-3yl)carbonyl]-2H-1-benzopyran-2-one) derivatives 4 by a four-component
reaction of a salicylaldehyde 1, 4-hydroxy-6-methyl-2H-pyran-2-one, a benzylamine 2, and a diaroyl-
acetylene (¼1,4-diarylbut-2-yne-1,4-dione) 3 in EtOH is reported. This new protocol has the advantages
of high yields (Table), and convenient operation. The structures of these coumarin (¼2H-1-benzopyran-
2-one) derivatives, which are important compounds in organic chemistry, were confirmed spectroscopi-
1
cally (IR, H- and 13C-NMR, and EI-MS) and by elemental analyses. A plausible mechanism for this
reaction is proposed (Scheme 2).
Introduction. – Coumarins (¼2H-1-benzopyran-2-ones) and their derivatives form
an elite class of compounds, occupying an important place in the realm of natural
products and synthetic organic chemistry. They are widely present in higher plants such
as Rutaceae, Apiaceae, Asteraceae, Leguminosae, and Thymelaeaceae, as well as occur
as animal and microbial metabolites [1]. Coumarins have various bioactivities, for
example, inhibition of platelet aggregation [2], antibacterial [3] and anticancer activity
[4], inhibition of steroid 5a-reductase [5], and inhibition of HIV-1 protease [6].
Coumarins have also been used in the preparation of insecticides [7], optical
brighteners [8], and dispersed fluorescent and tunable laser dyes [1]. Accordingly,
many reports have described various structures and biological evaluations of numerous
coumarin analogs newly synthesized or isolated from plants [9].
N-Atom-containing heterocyclic compound are also important natural and
synthetic materials. The remarkable ability of these heterocyclic cores to serve both
as biomimetics and active pharmacophores has largely contributed to their unique
value as traditional key elements of numerous drugs and designed medicinal agents in
medicinal chemistry [10]. In particular, N-containing heterocycles are prevalent in
many drugs [11], thus synthetic chemists are increasingly motivated to discover new
methods for the rapid construction of pharmacologically important drug-like com-
pounds [12]. The development of new approaches for the efficient construction of these
heterocycles continues to be essential for accessing natural products and their
structural analogues. Accordingly, and because of their scarce occurrence in exotic
organisms, novel strategies for the synthesis of N-heterocycles have received consid-
erable attention in the past decades [13].
ꢀ 2013 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Their properties have turned coumarin and pyrrolidine derivatives into interesting
targets for organic chemists. In the course of our research program into the design of
new routes for the synthesis of new heterocyclic compounds, we were interested in the
synthesis of heterocyclic compounds containing both the coumarin and the pyrrolidine
skeleton by a one-pot and four-component reaction sequence.
Results and Discussion. – According to the importance of coumarin and pyrrole
derivatives, we became attracted to investigate reactions of coumarin-substituted
enamines and diaroylacetylenes (¼1,4-diarylbut-2-yne-1,4-diones). Our new synthetic
route is shown in Scheme 1. The sequential four-component reaction of salicylalde-
hydes (¼2-hydroxybenzaldehydes) 1, 4-hydroxy-6-methyl-2H-pyran-2-one, diaroyl-
acetylenes 3, and benzylamines 2 was performed within 4 h in EtOH in the presence of
one drop of piperidine to produce 3-[(4,5-dihydro-1H-pyrrol-3-yl)carbonyl]-2H-chro-
men-2-ones 4 in excellent yields (Table).
Scheme 1. Synthesis of 3-[(4,5-Dihydro-1H-pyrrol-3-yl)carbonyl]-2H-chromen-2-ones. For R, Ar, and
Ar’, see the Table.
Table. Prepared 3-[(4,5-Dihydro-1H-pyrrol-3-yl)carbonyl]-2H-chromen-2-ones 4
Product
R
Ar
Ar’
Yield [%]
4a
4b
4c
4d
H
MeO
H
Ph
Ph
Ph
Ph
Ph
71
75
70
78
4-MeꢀC6H4
H
4-MeꢀC6H4
4-MeꢀC6H4
The structures of compounds 4a – 4d were deduced from their elemental analysis,
1
IR, and high-field H- and 13C-NMR spectra. The mass spectrum of 4b displayed the
molecular-ion peak at m/z 583, in agreement with the proposed structure. Its IR
spectrum showed absorption bands due to the OH-stretching frequency at 3443 cmꢀ1,
and absorption bands at 1717, 1610, 1525, 1408, and 1247 cmꢀ1 were assigned to the CO,
C¼C and CꢀO groups, respectively. The 1H-NMR spectrum of 4b showed two s for the
Me and MeO groups (d(H) 2.18 and 3.86), an AB signal for the CH2N group because
these H-atoms are diastereotopic (d(H) 4.43 and 4.62, 2J ¼ 16.8 Hz), one s, three d, and
two m for aromatic H-atoms (d(H) 7.00, 7.15 (3J ¼ 7.0 Hz), 7.70 (3J ¼ 7.3 Hz), 7.80 (3J ¼
7.3 Hz), 7.19 – 7.25, and 7.29 – 7.33), and three s for an olefinic H-atom, the CH of the
1
coumarin moiety, and an OH group, (d(H) 7.62, 8.01, and 9.05, resp.). The H-

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decoupled 13C-NMR spectrum of 4b showed 30 distinct resonances in agreement with
the suggested structure.
A possible mechanism for the reaction is proposed on the basis of known reactions
[14 – 17] (Scheme 2). At first condensation of salicylaldehyde 1 and 4-hydroxy-6-
methyl-2H-pyran-2-one gives intermediate 5 [14 – 16]. The latter reacts with a
benzylamine 2 possibly via an imine formation, and imine > enamine tautomerization
leads to enamine 6. Finally, nucleophilic addition of enamine 6 to diaroylacetylene 3
[17] and cyclization give the product 4 in good yields. To support the proposed
mechanism, the structures of intermediates 5b and 6a in the synthesis of 4b and 4a,
1
respectively, were established by H- and 13C-NMR spectroscopy.
Scheme 2. A Plausible Mechanism for the Formation of Products 4a – 4d. For R, Ar, and Ar’, see the
Table.
In summary, we described a novel approach to the synthesis of 3-[(4,5-dihydro-1H-
pyrrol-3-yl)carbonyl]-2H-chromen-2-ones by a one-pot and sequential four-component
reaction between salicylaldehydes, 4-hydroxy-6-methyl-2H-pyran-2-one, benzylamines,
and diaroylacetylenes. Characteristics of this method are good yields of the products, a
simple procedure, inexpensive starting materials, and the synthesis of new coumarin
derivatives.
Experimental Part
General. All starting materials were obtained from Merck (Germany) and Fluka (Switzerland) and
were used without further purification. Diaroylacetylenes 3 were prepared according to published
procedures [18][19]. M.p.: Electrothermal-9100 apparatus. IR Spectra: Shimadzu-IR-460 spectrometer;
in KBr; ˜n in cmꢀ1. 1H- and 13C-NMR Spectra: Bruker-DRX-500-Avance FT-NMR instrument; at 500 and
125 MHz, resp.; in CDCl3; d in ppm rel. to Me4Si as internal standard, J in Hz. EI-MS: Finnigan-MAT-
8430 mass spectrometer, ionization potential 70 eV; in m/z (rel.%). Elemental analyses for C, H, and N:
Heraeus CHN-O-Rapid analyzer.
General Procedure (exemplified for 4a). A soln. of salicylaldeyde (1a; 0.122 g, 1 mmol) and 4-
hydroxy-6-methyl-2H-pyran-2-one (0.126 g, 1 mmol) in EtOH (5 ml) and one drop of piperidine were
magnetically stirred for 1 h under reflux. Then benzenemethanamine (2a; 0.107 g, 1 mmol) was added
and the soln. was stirred for 1 h under reflux. After this time, 1,4-diphenylbut-2-yne-1,4-dione (3a;

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Helvetica Chimica Acta – Vol. 96 (2013)
0.234 g, 1 mmol) was slowly added to the mixture at r.t. and stirred for 2 h. After completion of the
reaction, the mixture was filtered and the precipitate washed with cold EtOH: pure 4a.
3-{[(4Z)-4,5-Dihydro-5-hydroxy-2-methyl-4-(2-oxo-2-phenylethylidene)-5-phenyl-1-(phenyl-
methyl)-1H-pyrrol-3-yl]carbonyl}-2H-1-benzopyran-2-one (4a): Yield 392 mg (71%). Yellow powder.
M.p. 201 – 2038. IR: 3427 (OH), 1719 (br., 3 C¼O), 1608 (C¼C), 1524 and 1460 (Ar), 1240 (CꢀO).
1H-NMR: 2.14 (s, 3 H); 4.52 (d, 2J ¼ 15.5, 1 H); 4.65 (d, 2J ¼ 15.5, 1 H); 7.10 (s, 2 H); 7.23 – 7.31 (m, 8 H);
7.42 – 7.49 (m, 3 H); 7.59 – 7.66 (m, 6 H); 7.86 (s, 1 H); 8.37 (s, 1 H); 8.91 (s, 1 H). 13C-NMR: 15.42; 45.41;
95.90; 106.45; 110.22; 116.34; 118.56; 125.07; 125.68; 126.69; 127.16; 127.69; 128.00; 128.37; 128.60; 128.74;
129.66; 129.87; 132.72; 133.27; 136.21; 138.33; 138.92; 143.63; 153.76; 158.36; 166.43; 172.08; 182.83;
190.27. EI-MS: 553 (47, Mþ), 535 (10), 448 (37), 380 (80), 291 (100), 263 (56), 236 (16), 173 (27), 106
(41), 91 (43). Anal. calc. for C36H27NO5 (553.61): C 78.10, H 4.92, N 2.53; found: C 77.24, H 4.82, N 2.55.
3-{[(4Z)-4,5-Dihydro-6-hydroxy-2-methyl-4-(2-oxo-2-phenylethylidene)-5-phenyl-1-(phenyl-
methyl)-1H-pyrrol-3-yl]carbonyl}-6-methoxy-2H-1-benzopyran-2-one (4b): Yield 437 mg (75%). Orange
powder. M.p. 183 – 1858. IR: 3443 (OH), 1717 (br., 3 C¼O), 1610 (C¼C), 1525 and 1408 (Ar), 1247
(CꢀO). 1H-NMR: 2.18 (s, 3 H); 3.86 (s, 3 H); 4.43 (d, 2J ¼ 16.8, 1 H); 4.62 (d, 2J ¼ 16.8, 1 H); 7.00 (s, 1 H);
7.15 (d, 3J ¼ 7.0, 2 H); 7.19 – 7.25 (m, 7 H); 7.29 – 7.33 (m, 3 H); 7.39 (t, 3J ¼ 7.0, 1 H); 7.62 (s, 1 H); 7.70 (d,
3
3J ¼ 7.3, 2 H); 7.80 (d, J ¼ 7.3, 2 H); 8.01 (s, 1 H); 9.05 (s, 1 H). 13C-NMR: 15.67; 46.47; 55.90; 96.50;
108.38; 110.56; 111.15; 117.75; 119.06; 121.20; 126.01; 126.84; 127.51; 128.16; 128.33; 128.71; 128.80;
131.23; 132.24; 135.92; 138.95; 138.98; 143.43; 148.93; 156.42; 158.91; 165.89; 171.35; 183.09; 191.84. EI-
MS: 583 (40, Mþ), 478 (23), 400 (41), 380 (54), 321 (100), 263 (27), 236 (28), 203 (22), 91 (33). Anal.
calc. for C37H29NO6 (583.64): C 76.14, H 5.01, N 2.40; found: C 75.84, H 4.99, N 2.43.
3-{{(4Z)-4,5-Dihydro-5-hydroxy-2-methyl-5-(4-methylphenyl)-4-[2-(4-methylphenyl)-2-oxoethyli-
dene]-1-(phenylmethyl)-1H-pyrrol-3-yl}carbonyl}-2H-1-benzopyran-2-one (4c): Yield 406 mg (70%).
Yellow powder. M.p. 215 – 2178. IR: 3433 (OH), 1723 (br., 3 C¼O), 1610 (C¼C), 1521 and 1408 (Ar),
1244 (CꢀO). 1H-NMR: 2.13 (s, 3 H); 2.26 (s, 3 H); 2.31 (s, 3 H); 4.38 (d, 2J ¼ 16.7, 1 H); 4.62 (d, 2J ¼ 16.7,
3
3
3
3
1 H); 7.04 (d, J ¼ 7.9, 2 H); 7.10 (d, J ¼ 7.9, 2 H); 7.17 (d, J ¼ 6.9, 2 H); 7.22 (d, J ¼ 6.9, 2 H); 7.25 (s,
3
3
1 H); 7.34 (t, J ¼ 7.5, 1 H); 7.40 (d, J ¼ 8.3, 1 H); 7.56 – 7.66 (m, 7 H); 8.05 (s, 1 H); 9.10 (br. s, 1 H).
13C-NMR: 15.67; 21.11; 21.51; 46.47; 96.50; 108.53; 111.20; 116.70; 118.75; 124.92; 125.33; 125.91; 126.89;
127.47; 128.55; 128.70; 128.81; 128.84; 128.86; 129.03; 129.28; 132.97; 136.08; 138.50; 143.03; 143.39;
154.41; 158.72; 165.46; 170.99; 182.85; 191.45. EI-MS: 581 (16, Mþ), 551 (24), 523 (20), 408 (27), 368
(83), 313 (38), 264 (42), 236 (100), 152 (41), 98 (65). Anal. calc. for C38H31NO5 (581.66): C 78.47, H 5.37,
N 2.41; found: C 78.0, H 5.31, N 2.47.
3-{{(4Z)-4,5-Dihydro-5-hydroxy-2-methyl-5-(4-methylphenyl)-1-[(4-methylphenyl)methyl]-4-[2-(4-
methylphenyl)-2-oxoethylidene]-1H-pyrrol-3-yl}carbonyl}-2H-1-benzoyran-2-one (4d): Yield 464 mg
(78%). Orange powder. M.p. 198 – 2018. IR: 3438 (OH), 1721 (br., 3 C¼O), 1608 (C¼C), 1518 and
1406 (Ar), 1241 (CꢀO). 1H-NMR: 2.16 (s, 3 H); 2.29 (s, 3 H); 2.31 (s, 3 H); 2.35 (s, 3 H); 4.35 (d, 2J ¼ 16.7,
1 H); 4.57 (d, 2J ¼ 16.7, 1 H); 7.03 – 7.07 (m, 6 H); 7.11 (d, 3J ¼ 7.9, 2 H); 7.34 (t, 3J ¼ 7.5, 1 H); 7.40 (d, 3J ¼
8.3, 1 H); 7.59 – 7.67 (m, 7 H); 8.04 (s, 1 H); 9.08 (s, 1 H). 13C-NMR: 15.23; 20.53; 20.64; 21.03; 45.82;
96.06; 107.96; 110.41; 116.22; 118.28; 124.43; 125.44; 126.40; 128.07; 128.36; 128.37; 128.54; 128.89;
130.66; 132.46; 132.50; 135.68; 135.96; 136.71; 137.99; 142.52; 142.83; 153.92; 158.24; 165.06; 170.60;
182.31; 190.95. EI-MS: 595 (24, Mþ), 476 (19), 422 (35), 384 (72), 333 (27), 305 (77), 160 (64), 119 (67),
105 (100). Anal. calc. for C39H33NO5 (595.69): C 78.64, H 5.58, N 2.35; found: C 78.23, H 5.53, N 2.41.
3-[(1Z)-1-Hydroxy-3-oxobut-1-en-1-yl]-6-methoxy-2H-1-benzopyran-2-one (5b). A soln. of 2-
hydroxy-5-methoxybenzaldehyde (1b, 0.152 g, 1 mmol) and 4-hydroxy-6-methyl-2H-pyran-2-one
(0.126 g, 1 mmol) in EtOH (5 ml) and one drop of piperidine was magnetically stirred for 1 h under
reflux. After cooling of the mixture to r.t., the mixture was filtered and the precipitate washed with cold
EtOH: pure intermediate 5b (239 mg, 80%). Yellow powder. M.p. 1708 (dec.). 1H-NMR: 2.27 (s, 3 H);
4
4
3
3.86 (s, 3 H); 7.03 (d, J ¼ 3.0, 1 H); 7.03 (s, 1 H); 7.21 (dd, 3J ¼ 9.1, J ¼ 3.0, 1 H); 7.29 (d, J ¼ 9.1, 1 H);
8.60 (s, 1 H); 15.87 (s, 1 H). 13C-NMR: 27.55; 55.88; 101.65; 110.53; 117.65; 118.82; 120.78; 122.43; 145.20;
149.02; 156.37; 158.18; 171.95; 199.73.
3-{(2Z)-1-Oxo-3[(phenylmethyl)amino]but-2-en-1-yl}-2H-1-benzopyran-2-one (6a). A soln. of
salicylaldehyde (1a, 0.122 g, 1 mmol) and 4-hydroxy-6-methyl-2H-pyran-2-one (0.126 g, 1 mmol) in
EtOH (5 ml) and one drop of piperidine was magnetically stirred for 1 h under reflux. Then,

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benzenemethanamine (2a, 0.107 g, 1 mmol) was added, and the soln. was stirred for another 1 h under
reflux. After cooling of the mixture to r.t., the mixture was filtered and the precipitate washed with cold
1
EtOH: pure intermediate 6a (271 mg, 85%). Yellow crystals. M.p. 185 – 1888 (dec.). H-NMR: 2.13 (s,
3 H); 4.58 (d, 3J ¼ 6.0, 2 H); 6.40 (s, 1 H); 7.26 – 7.39 (m, 7 H); 7.57 (t, 3J ¼ 7.8, 1 H); 7.60 (d, 3J ¼ 7.8, 1 H);
8.57 (s, 1 H); 12.01 (s, 1 H). 13C-NMR: 19.11; 46.86; 95.76; 115.86; 118.72; 123.98; 125.98; 126.48; 127.26;
128.50; 128.75; 132.25; 136.69; 144.41; 154.02; 159.04; 166.53; 180.11.
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Received April 25, 2012