Synthetic Routes to Coumarin(Benzopyrone)-Fused Five-Membered Aromatic Heterocycles Built on the α-Pyrone Moiety. Part 1: Five-Membered Aromatic Rings with One Heteroatom

Abstract

This review gives an up-to-date overview of the different ways (routes) to the synthesis of coumarin (benzopyrone)-fused, five-membered aromatic heterocycles with one heteroatom, built on the pyrone moiety. Covering 1966 to 2020.

Keywords: benzopyrones; coumarins; five-membered aromatic heterocycles; furan; pyrrole; selenophen; thiophene.

Figure 1

The three most common isomers of a furan ring fused to the α-pyrone moiety of coumarin.

Scheme 1

The Nef reaction to synthesize furo[2,3-c]benzopyran-4-ones 3a,b and 4. Reagents and conditions: MeOH, piperidine, reflux, five outputs in 55%–61% yield.

Scheme 2

Rhodium(III)-catalyzed sequential ortho-C–H oxidative arylation/cyclization of sulfoxonium ylide to afford 4H-furo[2,3-c]benzopyran-4-one (7). Reagents and conditions: [Cp*RhCl₂]₂ (5 mol %), AgBF₄ (20 mol %), Zn(OAc)₂ (0.225 mmol), AcOH (0.3 mmol), and acetone (2 mL), 12 h, in a sealed Schlenk tube under N₂ at 100 °C, 25% yield.

Scheme 3

Demethylation and in situ lactonization steps to prepare the first 4H-furo[3,4-c]benzopyran-4-one 10. Reagents and conditions: (a) ethyl acetoacetate or ethyl benzoylacetate, piperidine, and MeOH (the Nef reaction condition); (b) HBr, AcOH concentration, 130 °C, 4 h, 16 outputs with 50%–65% yield.

Scheme 4

Synthesis of 2-methyl-3-phenylfuro[3,2-c]benzopyran-4-one (13). Reagents and conditions: AcOH, conc. H₂SO₄, 110 °C, 1 h, 70% yield.

Scheme 5

Atom-efficient multicomponent reactions (MCRs) and step-efficient, one-pot synthesis of 4H-furo[3,2-c]benzopyran-4-one (16). Reagents and conditions: DMF or toluene, µw, 80 °C, 20 min, 97% yield.

Scheme 6

A facile synthesis of 4H-furo[3,2-c]benzopyran-4-ones 19 by silver(I)/celite promoted an oxidative cycloaddition reaction. Reagents and conditions: (a) CH₂=CHSPh and/or CH₃CH=CHSPh, Ag₂CO₃/celite, acetonitrile, reflux, 3 h; (b) NaIO₄, MeOH, CCl₄, pyridine, Al₂O₃, four outputs with 71%–82% yield.

Scheme 7

Transition metal Cu catalyzed/mediated methodologies for synthesis of the 4H-furo[3,2-c]benzopyran-4-ones 22 and 23. Reagents and conditions: (a) CH₃SO₃H, H₂O, DMF, 90 °C, 1–3 h; (b) CuCl₂, 90 °C, 20 h; (c) CuCl, O₂, DMF, H₂O, 90 °C, 10–20 h, 10 outputs with 37%–88% yield; (d) CuBr, CuCl₂, DMF, H₂O, 75 °C, 10 h, 13 outputs with 45%–81% yield.

Scheme 8

One-pot synthesis of 4H-furo[3,2-c]chromen-4-one (25) using a Yb(OTf)₃-catalyzed propargylation and allenylation reaction. Reagents and conditions: (a) 5 mol % Yb(OTf)₃, CH₃NO₂, dioxane, 50 °C; (b) K₂CO₃, 70 °C, 37% yield.

Scheme 9

The 16-electron allyl–ruthenium(II) complex in preparation of 4H-furo[3,2-c]benzopyran-4-one (27). Reagents and conditions: 16-electron allyl–ruthenium(II) complex [Ru(η3-2-C₃H₄Me)(CO)(dppf)][SbF₆] (5 mol %), trifluoroacetic acid (TFA) (50 mol %), THF, 75 °C, 5 h, 72% yield.

Scheme 10

Et₃N-induced demethylation–annulation of an aryl alkynyl ether in the synthesis of 4H-furo[3,2-c]benzopyran-4-one (30). Reagents and conditions: (a) alkyne (3 equiv.), 8 mol % PdCl₂(PPh₃)₂, 8 mol % CuI, Et₃N/DMF, 80 °C, 48 h, 82% yield; (b) alkyne (3 equiv.), 8 mol % PdCl₂(PPh₃)₂, 8 mol % CuI, Et₃N/MeCN, 60 °C, 15 h, 70% yield.

Scheme 11

A one-pot sequential coupling/cyclization strategy in the synthesis of 4H-furo[3,2-c]- benzopyran-4-ones 33. Reagents and conditions: (a) Pd(PPh₃)₂, CuI, THF, 60 °C; (b) K₂CO₃, H₂O, 13 outputs with 51%–96% yield.

Scheme 12

Metal-free synthesis of 4-H-furo[3,2-c]benzopyran-4-ones 36. Reagents and conditions: I₂, NH₄OAc, PhCl, 120 °C, 18 outputs with 28%–90% yield.

Scheme 13

Regioselective synthesis of 4H-furo[3,2-c]chromen-4-one (41). Reagents and conditions: (a) ClCH₂COCl, dry pyridine, 40 min, reflux, 85% yield; (b) AlCl₃, 140–150 °C, 60% yield; (c) AlCl₃, 140–150 °C, 30–40 min or K₂CO₃, acetone, 10 min, stirring, r.t., 50% yield; (d) NaBH₄, 85% yield; (e) H₂SO₄ (30%), EtOH, heat, 30 min, 80% yield; (f) COCH₂Cl, K₂CO₃, 73% yield; (g) HCl, 72% yield.

Scheme 14

Rhodium(II)-catalyzed aryl C–H carboxylation with CO₂ in the synthesis of 4H-furo[3,2-c] benzopyran-4-ones 43. Reagents and conditions: (a) Rh₂(OAc)₄ (1 mol %), tricyclohexylphosphine PCy₃ (2 mol %), t-BuOK (4.5 equiv.), diglyme, 100 °C, 48 h, six outputs with 70%–86% yield.

Figure 2

The three common isomers of the pyrrole ring fused to the α-pyrone moiety of coumarin.

Scheme 15

Different pathways to synthesize 3H,4H[1]benzo- pyrano[3,4-b]pyrrol-4-ones 45, 47, 49, and 50 via 3-aminocoumarin. Reagents and conditions: (a) i: NaNO₂, HCl, −30 °C, ii: SnCl₂, −10 °C, HCl, 2 h, iii: carbonyl compounds, polyphosphoric acid, 1 h, 130 °C, seven outputs with 33%–51% yield; (b) anhydride ethyl methyl ketone, K₂CO₃, NaI, reflux, 24–30 h, five outputs with 51%–63% yield; (c) N,N-dimethylaniline, reflux, 6–9 h, five outputs with 90%–94% yield; (d) KI (cat.), reflux, 5 h; (e) TFA (cat.), AcOH, 12 h, reflux, four outputs with 28%–86% yield; (f) MeOH, piperidine, reflux, five outputs with 55%–61% yield.

Scheme 16

Synthesis of 1,3-diphenyl[l]benzopyrano[3,4-e]pyrrol-4-one (55). Reagents and conditions: DMF, stirring, 120 °C, 24 h, 51% yield.

Scheme 17

Synthesis of [1]benzopyrano[3,4-e]pyrrol-4-ones 59 by a FeCl₃-promoted, three-component reaction. Reagents and conditions: FeCl₃, toluene, 110 °C, 6 h, 17 outputs with 62%–92% yield.

Scheme 18

A sequential three-component reaction to synthesize [1]benzopyrano[3,4-e]pyrrol-4-ones 63. Reagents and conditions: TEA, piperidine, DMF, r.t., 8 h, 10 outputs with 62%–95% yield.

Scheme 19

The Van Leusen protocol for the synthesis of [1]benzopyrano[3,4-e]pyrrol-4-ones 65. Reagents and conditions: K₂CO₃, EtOH, 15 min, r.t, three outputs with 72%–86% yield.

Scheme 20

Synthetic protocol to synthesize [l]benzopyrano[4,3-b]pyrrole-4(1H)-ones 68. Reagents and conditions: TsOH.H₂O, solvent-free, 24 outputs with 6%–77% yield.

Scheme 21

Synthetic protocol to synthesize [l]benzopyrano[4,3-b]pyrrole-4(1H)-ones 72. Reagents and conditions: CuFe₂O₄, H₂O, 70 °C, 25 outputs with 68%–94% yield; or KHSO₄, toluene, reflux, 23 outputs with 37%–93% yield.

Scheme 22

Synthesis of [l]benzopyrano[4,3-b]pyrrol-4-ones 76 from 4-chlorocoumarin. Reagents and conditions: (a) i: EtOH, TEA, HCl.N(Me)OMe, ii: CH₂Cl₂, TEA, DCC; (b) i: organometallic compounds (R₃M), THF, N₂, -H₂O, ii: NaOEt, EtOH, r.t., 2 h, reflux, 1 h, nine outputs with 27%–92% yield.

Scheme 23

The scope of 4-aminocoumarins in the preparation of [l]benzopyrano[4,3-b]pyrrol-4-ones 79. Reagents and conditions: Pd(OAc)₂, oxidant, DMSO, 100 °C, 12 outputs with 72%–99% yield.

Scheme 24

Various arylglyoxals in the synthesis of [l]benzopyrano[4,3-b]pyrrol-4-ones 82, 83, and 85. Reagents and conditions: (a) i: AcOH, reflux, 40 min; ii: an appropriate alkyl p-toluenesulfonate (TsOR₂), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), toluene, reflux, 1.5 h, 14 outputs with 73%–89% yield; (b) R₁=Ph, 4-CH₃OC₆H₄, 4-CH₃C₆H₄, 4-FC₆H₄, 4-ClC₆H₄, 4-BrC₆H₄, 2-thienyl; dimedone, 2-hydroxy-1,4-naphtoquinone barbituric acid, 1,3 dimethyl barbituric acid, I₂, DMSO, stirring, 100 °C, 7 h, 15 outputs with 15%–80% yield.

Figure 3

The three common isomers of the thiophene ring fused to the α-pyrone moiety of coumarin.

Scheme 25

Synthesis of 4H-thieno[2,3-c]benzopyran-4-one (88). Reagents and conditions: 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-dioxane, 60 °C, 12 h, N₂, 95% yield.

Scheme 26

4H-thieno[3,4-c]benzopyran-4-ones 91 and 92 via a Suzuki–Miyaura cross coupling reaction. Reagents and conditions: (a) Pd(PPh₃)₄ (10 mol %), Cs₂CO₃ (4 equiv.), DME, H₂O, MW 125 °C, 15 min, 86% yield; (b) i: Pd(PPh₃)₄ (5 mol %), K₃PO₄ (1.5 equiv.), 1,4-dioxane, 90 °C, 4 h; ii: (a) BBr₃, CH₂Cl₂, (b) KOtBu, H₂O, five outputs with 75%–81% yield [83].

Scheme 27

The Gewald reaction to synthesize 4H-thieno[3,4-c]benzopyran-4-one (94). Reagents and conditions: (a) CNCH₂COOEt, base; (b) NH₃, EtOH, 48% yield [85], 37% yield [90].

Scheme 28

Synthesis of 4H-thieno[3,4-c] [1]benzopyran-4(4H)-ones 97 via [4 + 1] annulations. Reagents and conditions: NaOH, diethyl azodicarboxylate (DEAD), MeCN, r.t., 20 min, 17 outputs with 68%–95% yield.

Scheme 29

A plausible reaction mechanism proposed for the preparation of 4H-thieno[3,4-c][1] benzopyran-4(4H)-ones 99. Reagents and conditions: [Rh(COD)Cl]₂ (5 mol %), 1,1′-Ferrocenediyl-bis(diphenylphosphine) (DPPF) (12 mol %), PhCl, 130 °C, 30 min, three outputs with 75%–90% yield.

Scheme 30

The synthesis of 4H-thieno[3,2-c][1]benzopyran-4(4H)-ones 102 and 103 via the cyclization of Vilsmeier–Haack products. Reagents and conditions: (a) POCl₃, DMF, 60 °C, overnight; (b) SHCH₂COOR₁, EtOH, base, 90% yield [25], 88% yield [94]; (c) 1,4-dithiane-2,5-diole, K₂CO₃, acetone, stirring, 1 h, r.t., 45 °C, 3 h, 85% yield.

Scheme 31

One-pot synthesis of 4H-thieno[3,2-c][1]benzopyran-4(4H)-one (105) by CO insertion into phenol. Reagents and conditions: 10 mol % Pd(OAc)₂, AgOAc, CH₃CN, 80 °C, 48 h, 62% yield.

Figure 4

The two common isomers of the selenophene ring fused to the α-pyrone moiety of coumarin.

Scheme 32

Reagents and reaction conditions: a: PdCl₂ (10 mol %), Ph₃P (20 mol %), CuI (10 mol %), terminal acetylene (1.5 equiv.), NMP, Et₃N, 55 °C, 20 h; b: (Ph₃P)4Pd (5 mol %), CuI (20 mol %), terminal acetylene (1.5 equiv.), DMF, Et₃N, r.t., 20 h; c: SeO₂ (2 equiv.), conc. HBr, dioxane, r.t., 24–48 h, compounds 108, four outputs with 68%–75% yield; compounds 111, four outputs with 64%–70% yield.

Scheme 33

Synthesis of selenopheno[2,3-c]benzopyran-4-ones (115) from 4-hydroxycoumarin. Reagents and reaction conditions: a: POCl₃, DMF, 84% yield; b: NH₂OH.HCl, 80% yield; c: Se, NaBH₄, EtOH, 85% yield; d: ClCH₂CN(R), DMF, stirring, r.t., 2 h, three outputs with 80%–88% yield.