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Synthesis 2014; 46(02): 258-262
DOI: 10.1055/s-0033-1340085
paper
© Georg Thieme Verlag Stuttgart · New York

Multicomponent Synthesis of Novel Penta-Heterocyclic Ring Systems Incorporating a Benzopyranopyridine Scaffold

Sobhi M. Gomha
Department of Chemistry, Faculty of Science, University of Cairo, Giza, 12613, Egypt   Fax: 20(2)35676501   Email: riyadh1993@hotmail.com
,
Sayed M. Riyadh*
Department of Chemistry, Faculty of Science, University of Cairo, Giza, 12613, Egypt   Fax: 20(2)35676501   Email: riyadh1993@hotmail.com
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Publication History

Received: 02 September 2013

Accepted after revision: 10 October 2013

Publication Date:
07 November 2013 (online)

 
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Abstract

A simple one-pot method is reported for the synthesis of several novel series of chromeno[4′,3′:4,5]pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-6,14-diones, chromeno[4′,3′:4,5]pyr­ido[2,3-d]thiazolo[3,2-a]pyrimidine-6,14-diones, and chrom-­eno[4′′,3′′:4′,5′]pyrido[2′,3′:4,5]pyrimido[2,1-b][1,3]thiazine-6,15-dione by a multicomponent reaction of salicylaldehyde, ethyl acetoacetate, and the appropriate fused heterocyclic amines in refluxing glacial acetic acid. The structures of the newly synthesized compounds were established by spectroscopy and elemental analyses. The mechanism of the single-step reaction was elucidated.


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Key words

multicomponent reactions - heterocycles - polycycles

Multicomponent reactions are among the best tools for combinatorial chemistry.[1] In these reactions, three or more starting materials react to form a single product. Among the advantages of multicomponent reactions are higher productivities, simple procedures, and time saving. Recent examples of multicomponent reactions include the Biginelli reaction for rapid synthesis of dihydropyrimidines,[2] [3] the Gewald reaction for the synthesis of aminothiophenes,[4,5] and the Hantzsch dihydropyridine synthesis.[6,7]

Benzopyranopyridines are regarded as important bioactive heterocycles because they have diverse biological activities, including antiinflammatory,[8] antibacterial,[9] antifungal,[9] antiproliferative,[10] and anticancer activities.[11] Consequently, many synthetic pathways to such scaffold have been reported. These include the thermal reaction of 4-amino-3-formylcoumarins with various active methylene compounds under solvent-free conditions,[12] Michael additions of various naphthols to iminocoumarin derivatives;[13] and multicomponent reactions of aminopyrazoles, ethyl acetoacetate, and salicylaldehyde.[14] [15] On the basis of these precedents, we attempted to synthesize penta-heterocyclic ring systems incorporating the benzopyranopyridine scaffold by a single-step multicomponent reaction.

We began by studying the three-component reaction of salicylaldehyde (1), ethyl acetoacetate (2; ethyl 3-oxobutanoate), and various 1,3-disubstituted 7-amino[1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-ones 3a–g [16] [17] in refluxing acetic acid containing a few drops of piperidine. This reaction gave the corresponding novel penta-heterocyclic 6H-chromeno[4′,3′:4,5]pyrido[2,3-d][1,2,4]triazolo-[4,3-a]pyrimidine-6,14-diones 4a–g (Scheme [1]).

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Scheme 1

The structures of the products were confirmed by elemental analyses and spectroscopy. The IR spectra showed, in each case, a single absorption band at 1713–1747 cm–1 which was assigned to the carbonyl group of the δ-lactone and another band at 1640–1658 cm–1 corresponding to the amide carbonyl. 1H NMR revealed a singlet at δ = 2.91–2.98 ppm, assignable to the methyl group on the fused pyridine ring[14] and another multiplet at δ = 7.40–7.68 ppm, with a four-proton intensity, assignable to the coumarin ring system.[18] The 13C NMR spectra of compounds 4a–g confirmed the presence of the [1,2,4]triazolo[4,3-a] pyrimidine ring system by exhibiting a peak at δ = 160.5–161.5 ppm corresponding to the carbonyl group attached to the sp3 nitrogen atom.[19]

We propose the following mechanism to account for the formation of products 4a–g (Scheme [2]). The three-component reaction begins with condensation of salicylaldehyde (1) with ethyl acetoacetate (2). This is followed by elimination of ethanol under basic condition to give 3-acetyl-2H-chromen-2-one (5). Condensation of chromenone 5 with a 1,3-disubstituted 7-amino-[1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-one 3a–g gives the corresponding nonisolable intermediate 6a–g. Subsequent autoxidation of intermediates 6a–g gives the corresponding chromeno[4′,3′:4,5]pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-6,14-dione 4a–g as the final product.

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Scheme 2

The assigned structure and the proposed mechanism were confirmed by an alternative synthesis of 4a as a typical example of the series prepared in the multistep reaction. Thus treatment of 3-acetyl-2H-chromen-2-one (5) with 6-amino-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (7)[20] in refluxing acetic acid gave 7-methyl-10-thioxo-10,11-dihydro-6H-chromeno[4′,3′:4,5]pyrido[2,3-d]pyrimidine-6,12(9H)-dione (8). Heating of dione 8 with N -phenylbenzenecarbohydrazonoyl chloride (9)[21] in 1,4-dioxane containing triethylamine gave dione 4a as an authentic product (Scheme [3]). The conversion of 8 into product 4a proceeded through S-alkylation[22] to give S-alkylated product (intermediate 10), which underwent a Smiles rearrangement[23] to give intermediate 11. This eliminated hydrogen sulfide gas to give the desired product 4a.

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Scheme 3

To investigate the scope of these reactions with respect to other amino fused-heterocyclic compounds we attempted to react salicylaldehyde (1), ethyl acetoacetate (2) with 3-aryl-7-amino-5H-thiazolo[3,2-a]pyrimidin-5-ones 12a–c [24] and with 7-amino-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (14a)[25] or 8-amino-3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one (14b)[25] under the same conditions. These reactions gave the expected products 13a–c, 15a, and 15b, respectively (Scheme [4]).

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Scheme 4

In summary, we prepared several novel series of chrom­eno[4′,3′:4,5]pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-6,14-diones, chromeno[4′,3′:4,5]pyrido[2,3-d]thiazolo[3,2-a]pyrimidine-6,14-diones, and chrom­eno[4′′,3′′:4′,5′]pyrido[2′,3′:4,5]pyrimido[2,1-b][1,3]thiazine-6,15-diones by a one-pot multicomponent reaction.

All melting points were determined on an electrothermal Gallenkamp­ apparatus and are uncorrected. Solvents were generally distilled and dried by standard procedures before use. The IR spectra were recorded on KBr discs with a Pye Unicam SP300 instrument. The 1H and 13C NMR spectra were recorded on a Varian Mercury VXR-300 spectrometer (300 MHz for 1H NMR and 75 MHz for 13C NMR), and the chemical shifts were referenced to the solvent DMSO-d 6. The mass spectra were recorded on GCMS-Q1000-EX Shimadzu and GCMS 5988-A HP spectrometers with an ionizing voltage of 70 eV. Elemental analyses were carried out by the Microanalytical Center of Cairo University, Giza, Egypt.


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Penta-Heterocyclic Compounds 4a–g, 13a–c, and 15a,b; General­ Procedure

Two drops of piperidine were added to a mixture of salicylaldehyde (1; 0.122 g, 1mmol), MeCOCH2CO2Et (2; 0.130 g, 1mmol), and the appropriate fused heterocyclic amine 3a–g, 12a–c, 14a, or 14b (1 mmol), and the mixture was stirred for 15 min. AcOH (10 mL) was added and the mixture was refluxed for 12 h. The mixture was then cooled and the product was collected by filtration, washed with EtOH, and crystallized from an appropriate solvent.


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7-Methyl-10,12-diphenyl-6H-chromeno[4′,3′:4,5]pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-6,14(10H)-dione (4a)

White microcrystals; yield: 0.32 g (67%); mp 322–324 °C (AcOH).

IR (KBr): 1739 (δ-lactone), 1658 (CO amide) cm–1.

1H NMR (DMSO-d6 ): δ = 2.97 (s, 3 H, CH3), 7.31–8.31 (m, 14 H, Ar-H).

13C NMR (DMSO-d6 ): δ = 22.4, 114.6, 119.2, 120.4, 121.5, 122.7, 123.4, 124.6, 126.8, 128.6, 130.2, 130.7, 133.9, 134.7, 136.2, 138.9, 140.3, 140.9, 143.3, 148.0, 148.9, 151.6, 161.3 (C=O), 166.5 (C=O).

MS (EI, 70 eV): m/z (%) = 472 (14) [M + 1]+, 471 (86) [M+], 193 (27), 103 (26), 78 (100).

Anal. Calcd for C28H17N5O3 (471.13): C, 71.33; H, 3.63; N, 14.85. Found: C, 71.31; H, 3.43; N, 14.59.


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12-Acetyl-7-methyl-10-phenyl-6H­-chromeno[4′,3′:4,5] pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-6,14-(10H)-dione (4b)

Pale-yellow crystals; yield: 0.32 g (73%); mp 262–264 °C (AcOH).

IR (KBr): 1728 (δ-lactone), 1680 (COCH3), 1648 (CO amide) cm–1.

1H NMR (DMSO-d6 ): δ = 2.12 (s, 3 H, COCH3), 2.91 (s, 3 H, CH3), 7.05–8.29 (m, 9 H, Ar-H).

13C NMR (DMSO-d6 ): δ = 22.6, 119.2, 120.4, 121.2, 121.8, 123.7, 124.6, 125.9, 128.6, 130.2, 130.7, 133.9, 136.2, 138.9, 140.3, 140.9, 143.3, 148.9, 151.6, 161.3 (C=O), 165.3 (C=O), 189.6 (COCH3).

MS (EI, 70 eV): m/z (%) = 438 (7) [M + 1]+, 437 (69) [M+], 395 (41), 278 (16), 223 (10), 153 (7), 78 (36), 43 (100).

Anal. Calcd for C24H15N5O4 (437.11): C, 65.90; H, 3.46; N, 16.01. Found: C, 65.68; H, 3.49; N, 15.81.


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12-Acetyl-7-methyl-10-(4-tolyl)-6H-chromeno [4′,3′:4,5]pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-6,14(10H)-dione (4c)

Pale-yellow crystals; yield: 0.33 g (74%); mp 232–234 °C (AcOH).

IR (KBr): 1736 (δ-lactone), 1683 (COCH3), 1642 (CO amide) cm–1.

1H NMR (DMSO-d6 ): δ = 2.08 (s, 3 H, Ar-CH3), 2.20 (s, 3 H, COCH3), 2.93 (s, 3 H, CH3), 7.12–8.23 (m, 8 H, Ar-H).

MS (EI, 70 eV): m/z (%) = 451 (100) [M+], 278 (89), 223 (16), 122 (21), 43 (91).

Anal. Calcd for C25H17N5O4 (451.13): C, 66.51; H, 3.80; N, 15.51. Found: C, 66.48; H, 3.88; N, 15.31.


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Ethyl 7-Methyl-6,14-dioxo-10-phenyl-10,14-dihydro-6H-chromeno[4′,3′:4,5]pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-12-carboxylate (4d)

White crystals; yield: 0.31 g (67%); mp 214–216 °C (AcOH).

IR (KBr): 1747 (δ-lactone), 1701 (COOEt), 1640 (CO amide) cm–1.

1H NMR (DMSO-d6 ): δ = 1.44 (t, J = 7 Hz, 3 H, CH2CH3), 2.97 (s, 3 H, CH3), 4.56 (q, J = 7 Hz, 2 H, CH2CH3), 7.03–8.19 (m, 9 H, Ar-H).

13C NMR (DMSO-d6 ): δ = 16.3, 23.4, 48.4, 118.4, 120.8, 122.2, 122.9, 123.6, 124.1, 127.3, 130.0, 130.7, 133.4, 136.6, 137.9, 140.3, 141.9, 143.3, 146.6, 150.6, 161.5 (C=O), 164.3 (C=O), 169.6 (C=O).

MS (EI, 70 eV): m/z (%) = 468 (6) [M + 1]+, 467 (100) [M+], 395 (31), 278 (7), 92 (34), 78 (33), 44 (18).

Anal. Calcd for C25H17N5O5 (467.43): C, 64.24; H, 3.67; N, 14.98. Found: C, 64.13; H, 3.69; N, 14.66.


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7-Methyl-6,14-dioxo-N,10-diphenyl-10,14-dihydro-6H-chromeno[4′,3′:4,5]pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-12-carboxamide (4e)

White crystals; yield: 0.34 g (66%); mp 256–258 °C (DMF).

IR (KBr): 3460 (NH), 1732 (δ-lactone), 1643, 1631 (2 CO amide) cm–1.

1H NMR (DMSO-d6 ): δ = 2.98 (s, 3 H, CH3), 7.07–8.00 (m, 14 H, Ar-H), 11.97 (br s, 1 H, NH).

13C NMR (DMSO-d6 ): δ = 22.8, 114.8, 118.4, 121.6, 121.8, 123.6, 123.9, 124.3, 125.2, 125.9, 126.6, 130.2, 130.3, 133.4, 134.7, 137.2, 138.8, 140.6, 141.2, 143.9, 145.6, 151.4, 160.5 (C=O), 165.2 (C=O), 167.2 (C=O).

MS (EI, 70 eV): m/z (%) = 514 (19) [M+], 471 (37), 276 (19), 202 (33), 120 (10), 105 (63), 78 (54), 44 (100).

Anal. Calcd for C29H18N6O4 (514.14): C, 67.70; H, 3.53; N, 16.33. Found: C, 67.65; H, 3.50; N, 16.16.


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7-Methyl-6,14-dioxo-N-phenyl-10-(4-tolyl)-10,14-dihydro-6H-chromeno[4′,3′:4,5]pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-12-carboxamide (4f)

White crystals; yield: 0.4 g (75%); mp 241–243 °C (DMF).

IR (KBr): 3449 (NH), 1713 (δ-lactone), 1674, 1642 (2CO amide) cm–1.

1H NMR (DMSO-d6 ): δ = 2.43 (s, 3 H, Ar-CH3), 2.98 (s, 3 H, CH3), 7.17–8.34 (m, 13 H, Ar-H), 11.22 (br s, 1 H, NH).

MS (EI, 70 eV): m/z (%) = 528 (2) [M+], 471 (30), 278 (14), 105 (11), 78 (35), 43 (100).

Anal. Calcd for C30H20N6O4 (528.15): C, 68.18; H, 3.81; N, 15.90. Found: C, 68.13; H, 3.62; N, 15.68.


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12-Benzoyl-7-methyl-10-phenyl-6H-chromeno[4′,3′:4,5]pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-6,14(10H)-dione (4g)

Yellow crystals; yield: 0.38 (77%); mp 274–276 °C (DMF).

IR (KBr): 1737 (δ-lactone), 1680 (ArCO), 1641 (CO amide) cm–1.

1H NMR (DMSO-d6 ): δ = 2.92 (s, 3 H, CH3), 6.97–8.28 (m, 14 H, Ar-H).

MS (EI, 70 eV): m/z (%) = 499 (20) [M+], 405 (8), 105 (65), 77 (100).

Anal. Calcd for C29H17N5O4 (499.13): C, 69.74; H, 3.43; N, 14.02. Found: C, 69.79; H, 3.35; N, 13.82.


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7-Methyl-12-phenyl-6H,14H-chromeno[4′,3′:4,5]pyrido[2,3-d][1,3]thiazolo[3,2-a]pyrimidine-6,14-dione (13a)

White solid; yield: 0.31 g (75%); mp 273–275 °C (1,4-dioxane).

IR (KBr): 1736 (δ-lactone), 1643 (CO amide) cm–1.

1H NMR (DMSO-d 6): δ = 2.76 (s, 3 H, CH3), 6.89–7.72 (m, 9 H, Ar-H), 7.79 (s, 1 H, thiazole-H).

MS (EI, 70 eV): m/z (%) = 411 (15) [M+], 274 (100), 188 (51), 119 (34), 91 (23).

Anal. Calcd for C23H13N3O3S (411.07): C, 67.14; H, 3.18; N, 10.21; S, 7.79. Found: C, 67.11; H, 3.03; N, 10.13; S, 7.66.


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12-(4-Chlorophenyl)-7-methyl-6H,14H-chromeno[4′,3′:4,5]pyrido[2,3-d][1,3]thiazolo[3,2-a]pyrimidine-6,14-dione (13b)

White solid; yield: 0.37 g (84%); mp 364–366 °C (EtOH–1,4-dioxane).

IR (KBr): 1728 (δ-lactone), 1637 (CO amide) cm–1.

1H NMR (DMSO-d 6): δ = 2.78 (s, 3 H, CH3), 6.80–7.71 (m, 8 H, Ar-H), 7.86 (s, 1 H, thiazole-H).

MS (EI, 70 eV): m/z (%) = 447 (10) [M + 2]+, 445 (34) [M+], 326 (20), 259 (59), 145 (28), 114 (67), 43 (100).

Anal. Calcd for C23H12ClN3O3S (445.03): C, 61.96; H, 2.71; N, 9.42; S, 7.19. Found: C, 61.87; H, 2.69; N, 9.22; S, 7.05.


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12-(4-Bromophenyl)-7-methyl-6H,14H-chromeno[4′,3′:4,5]pyrido[2,3-d][1,3]thiazolo[3,2-a]pyrimidine-6,14-dione (13c)

White solid; yield: 0.36 g (73%); mp 287–289 °C (1,4-dioxane).

IR (KBr): 1743 (δ-lactone), 1647 (CO amide) cm–1.

1H NMR (DMSO-d 6): δ = 2.79 (s, 3 H, CH3), 6.84–7.78 (m, 8 H, Ar-H), 7.87 (s, 1 H, thiazole-H).

MS (EI, 70 eV): m/z (%) = 491 (7) [M + 2]+, 489 (8) [M+], 302 (65), 259 (46), 231 (100), 114 (67), 77 (18).

Anal. Calcd for C23H12BrN3O3S (488.98): C, 56.34; H, 2.47; N, 8.57; S, 6.54. Found: C, 56.13; H, 2.42; N, 8.56; S, 6.43.


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7-Methyl-11,12-dihydro-6H,14H-chromeno[4′,3′:4,5]pyrido[2,3-d][1,3]thiazolo[3,2-a]pyrimidine-6,14-dione (15a)

White solid; yield: 0.25 g (73%); mp 194–196 °C (EtOH).

IR (KBr): 1738 (δ-lactone), 1682 (CO amide) cm–1.

1H NMR (DMSO-d6 ): δ = 2.78 (s, 3 H, CH3), 3.67 (t, J = 7 Hz, 2 H, CH2), 4.46 (t, J = 7 Hz, 2 H, CH2), 7.12–8.01 (m, 4 H, Ar-H).

MS (EI, 70 eV): m/z (%) = 337 (13) [M+], 213 (17), 119 (97), 91 (81), 78 (100).

Anal. Calcd for C17H11N3O3S (337.05): C, 60.52; H, 3.29; N, 12.46; S, 9.50. Found: C, 60.47; H, 3.20; N, 12.35; S, 9.39.


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7-Methyl-12,13-dihydro-6H,11H,15H-chromeno[4′′,3′′:4′,5′]pyrido[2′,3′:4,5]pyrimido[2,1-b][1,3]thiazine-6,15-dione (15b)

White solid; yield: 0.27 g (78%); mp 177–179 °C (EtOH).

IR (KBr): 1740 (δ-lactone), 1674 (CO amide) cm–1.

1H NMR (DMSO-d 6): δ  =  2.03 (m, 2 H, CH2), 2.71 (s, 3 H, CH3), 2.98 (t, J = 6 Hz, 2 H, CH2), 4.27 (t, J = 7 Hz, 2 H, CH2), 7.12–8.01 (m, 4 H, Ar-H).

MS (EI, 70 eV): m/z (%) = 351 (54) [M+], 213 (34), 119 (100), 105 (87), 78 (64).

Anal. Calcd for C18H13N3O3S (351.07): C, 61.53; H, 3.73; N, 11.96; S, 9.13. Found: C, 61.53; H, 3.73; N, 11.96; S, 8.99.


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7-Methyl-10-thioxo-9,10,11,12-tetrahydrochromeno[4′,3′:4,5]pyrido[2,3-d]pyrimidine-6,12-dione (8)

AcOH (20 mL) was added to a mixture of 3-acetylcoumarin (5) (0.188 g, 1 mmol) and 6-amino-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (7; 0.143 g, 1 mmol), and the mixture was refluxed for 12 h then cooled. The product was collected by filtration, washed with EtOH, and crystallized (AcOH) to give white microcrystals; yield: 0.24 g (76%); mp 347–349 °C.

IR (KBr): 3414, 3252 (2 NH), 1743 (δ-lactone), 1689 (CO amide) cm–1.

1H NMR (DMSO-d 6): δ = 2.91 (s, 3 H, CH3), 6.91–8.36 (m, 4 H, Ar-H), 12.42 (br s, 1 H, NH), 13.36 (br s, 1 H, NH).

MS (EI, 70 eV): m/z (%) = 311 (100) [M+], 294 (9), 197 (3), 143 (20), 115 (23), 77 (18).

Anal. Calcd for C15H9N3O3S (311.04): C, 57.87; H, 2.91; N, 13.50; S, 10.30. Found: C, 57.76; H, 2.87; N, 13.38; S, 10.23.


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7-Methyl-10,12-diphenyl-6H-chromeno[4′,3′:4,5]pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-6,14(10H)-dione (4a); Alternative Synthesis

Et3N (0.14 mL, 1 mmol) was added to a mixture of equimolar amounts of dione 8 (0.311 g, 1 mmol) and PhC(Cl)=NNHPh (9; 0.23 g, 1 mmol) in 1,4-dioxane (15 mL). The mixture was refluxed until all the starting materials disappeared (TLC) and H2S gas ceased to evolve (12 h). The solvent was evaporated and the residue was treated with MeOH. The solid that formed was collected by filtration and crystallized (AcOH) to give an authentic sample of compound 4a; yield: 0.31 g (65%).


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Supporting Information

    for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synthesis.
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Scheme 1
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Scheme 2
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Scheme 3
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Scheme 4