6H-Benzo[c]chromen-6-ones serve as core structures of secondary metabolites and are of considerable pharmacological importance. Natural sources produce limited quantities, hence the need for synthetic procedures for 6H-benzo[c]chromen-6-ones, which are herein reviewed. The literature describes protocols such as the Suzuki coupling reactions for the synthesis of biaryl, which then undergoes lactonization, reactions of 3-formylcoumarin (chromenones) with 1,3-bis(silylenol ethers), radical mediated cyclization of arylbenzoates, metal or base catalyzed cyclization of phenyl2-halobenzoates and 2-halobenzyloxyphenols, and benzoic acid coupling with benzoquinone using electrophilic metalbased catalyst.
Turk J Chem (2016) 40: 27 ă ITAK ˙ c TUB ⃝ Turkish Journal of Chemistry http://journals.tubitak.gov.tr/chem/ doi:10.3906/kim-1504-67 Review Article Synthetic protocols on 6H -benzo[c]chromen-6-ones: a review Ofentse MAZIMBA∗ Botswana Institute for Technology, Research and Innovation, Gaborone, Botswana Received: 22.04.2015 • Accepted/Published Online: 26.07.2015 • Final Version: 05.01.2016 Abstract: H -Benzo[ c ]chromen-6-ones serve as core structures of secondary metabolites and are of considerable pharmacological importance Natural sources produce limited quantities, hence the need for synthetic procedures for H -benzo[ c ]chromen-6-ones, which are herein reviewed The literature describes protocols such as the Suzuki coupling reactions for the synthesis of biaryl, which then undergoes lactonization, reactions of 3-formylcoumarin (chromenones) with 1,3-bis(silylenol ethers), radical mediated cyclization of arylbenzoates, metal or base catalyzed cyclization of phenyl2-halobenzoates and 2-halobenzyloxyphenols, and benzoic acid coupling with benzoquinone using electrophilic metalbased catalyst The efficient and simple procedures are those involving the reactions of Michael acceptor (chromenones and chalcones) with 1,3- and 1,5-dicarbonyl compounds Key words: H -Benzo[ c ]chromen-6-ones, benzopyranone, biaryls, Suzuki coupling, Michael addition, lactonization Introduction The benzopyranone nucleus is found in natural oxygen heterocycles that consist of dibenzo[d,b]pyran-6-one or H -benzo[ c]chromen-6-one These compounds could be viewed as structurally similar to coumarin or isocoumarins Isocoumarins are secondary metabolites derived through the acetate pathway and are structurally similar to coumarins but with an inverted lactone ring The basic structures 6H -benzo[ c]chromen-6-one (1) and some naturally occurring 6H -benzo[ c]chromen-6-ones are shown in Figure Autumnariol (2) and autumnariniol (3) have been isolated from Eucomis autumnalis Greab (Liliaceae) The biosynthetic pathways of alternariol (4) in a fungus from Datura stramonium was reported to be the acetate pathway A 2014 review presented natural 6H -benzo[ c ]chromen-6-one from fungi, mycobionts, plants, and animal sources This review reported various biological activities such as toxicity on human and animals and phytotoxicity as well as antioxidant, antiallergic, antimicrobial, antinematodal, and acetylcholinesterase inhibitory properties Alternariol (4) and altertenuisol (5) are metabolites of toxin-producing Alternaria fungi, 5,6 which is a known food contaminant 7,8 The in vitro fermentation of punicalagins (an ellagitannins) produced the intestinal microbial metabolites urolithins A (6) and B (7) showing antioxidant activity Gilvocarcin M (8) represents a group of antibiotics and antitumor agents isolated from Streptomyces such as gilvocarcins, chrysomycins, and ravidomycins 10,11 TMC-264 (9) was isolated from the fungus Phoma sp and displays potent antiallergic properties 12 Ellagic acid (10) has an additional lactone bridge 13 and is a constituent of the roots of Sanguisorba officinalis showing therapeutic potential for patients with blood platelet disorders, 14 while ellagic acid obtained ∗ Correspondence: mazimbaof@yahoo.com MAZIMBA/Turk J Chem from Casearia sylvestris inhibits pathological processes’ toxic effects 15 Shilajit is a herbal medicine found around the Himalayan mountains and the 6H -benzo[c ]chromen-6-ones 11 and 12 are the important antioxidants amongst the shilajit bioactive constituents 16,17 Therefore, given the pharmacological importance of 6H benzo[c ]chromen-6-one nucleus, this current review describes a comprehensive survey relating to the synthesis of H -benzo[c ]chromen-6-ones during 2000–2015 The reaction descriptions include proposed mechanisms OH 10 10b R R1 OH OH 6a 4a O O O HO O HO R HO O O O R= OH R= H OH O O HO MeO HO O O O O HO O OH Me OH HO O O O H Me OH RO O OMe Cl OH O O OH OH OH HO MeO OH O OH OH MeO O OMe R = alkyl, OH, O-alkyl, Ph HO O O 11 R= Me 12 R= H 10 Figure Naturally occurring H -benzo[ c ]chromen-6-ones Retrosynthetic analysis The classical approach for the synthesis of H -benzo[ c]chromen-6-one (13) involves the reaction of o -bromobenzoic acid (16) with phenol (15) followed by acid- or base-catalyzed intramolecular cyclization 18,19 The retrosynthetic analysis of 6H -benzo[ c ]chromen-6-ones based on the classical synthetic method is shown in Figure However, the scope of this method is limited due to the requirement of an organometallic catalyst and highly activated substrates and low yields of the desired compounds X OH O 13 O Intramolecular cyclization COOH OH 14 Regio and stereoselective cross coupling Figure Retrosynthetic analysis OH + O 15 16 MAZIMBA/Turk J Chem Synthetic protocols 3.1 Metal-catalyzed reactions involving phenols Sun and coworkers treated phenol 17 with o -benzoic acids 18, catalyzed by CuSO in the presence of NaOH 19,20 as shown in Scheme 1, while in the alternative method o-benzoic acid ester (21) was coupled to aryl boronic acid using (Ph P) Pd as catalyst The cyclization was achieved after deprotecting the methyl group of the biphenyl with BBr 20 as shown in Scheme The structure–activity relationship (SAR) study revealed that substitution at positions 4, 7, and 10 was required for optimum binding (minimum inhibitory concentration (MIC) < 10 nM) and selectivity of estrogen receptor ER β over ER α , while bi -hydroxyl groups at and positions were essential for good activity 20,21 OH Br + CuSO4-NaOH OH OH 17 O 18 100 oC 10-60% O O 13 Scheme H -Benzo[ c ]chromen-6-one synthesis using the Bruggink and McKillop protocol MeO OMe OMe MeO OH OMe Br B(OH)2 i ii MeO O COOMe OMe HO O O 20 21 22 23 Reagents and conditions: i) (Ph3P)4Pd, Na2CO3, EtOH, DME, 80 oC, 2-24 h; ii) BBr3, DCM, oC-rt, 1-3 h Scheme Sun and coworkers synthesis of H -benzo[ c ]chromene-6-ones Over 49 compounds were reported by Sun and coworkers 20 The structural diversity of the most selective ERβ antagonists, that is those that exhibited binding activities less than 10 nM compared to the standard Effusol (IC 50 of 12 nM), is shown in Figure R9 R10 R1 R8 OH R7 O HO O HO R4 23 24 25 26 27 28 Effusol R1 H H H H Me H R4 R7 Me H Me Br Me Me Et Me Me Me Me Me R8 Me Me OH OH OH OH R9 H OMe H H H H R10 Vinyl Me H H H H Figure H -Benzo[ c ]chromene-6-ones reported by Sun and coworkers MAZIMBA/Turk J Chem 3.2 Cycloaddition of dicarbonyl compounds to chromones When chromones (29) were reacted with dimethyl acetonedicarboxylate (31) in the presence of 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU), 7-hydroxy-6-oxo-6H-benzo[c]chromone-8-carboxylates (30) were furnished as depicted in Scheme 22 This reaction proceeded only for unsubstituted chromones at C-2 and C-3 Methyl groups at C-2 and 3-bromochromone led to the formation of furan derivatives The reaction was proposed to be initiated by the nucleophilic acetonedicarboxylate (31) nucleophilic attack at C-2 chromone carbon, followed by chromone ring opening, which forms intermediate 33 Ring closure through the intramolecular Michael reaction leads to intermediate 34 and its tautomer 35 Transesterification forms lactone 36, which undergoes aromitazation to yield 7-hydroxy-6-oxo-6H-benzo[c]chromone-8-carboxylates 30 22 COCH2COOMe O R O OMe DBU MeO O O O COOMe O O 29 31 +H OH 32 O CH2OOMe R DBU THF, rt, 2-3 h 50-65 % O COOMe DBU R O 33 O OH COOMe O OH R R COOMe O 30 COOMe 34 aromatization O R O O O -MeOH R HO COOMe O HO COOMe R= H or Cl 36 COOMe 35 Scheme Terzidis and coworkers’ synthesis of 7-hydroxy-6-oxo-6 H -benzo[ c ]chromone-8-carboxylates Sosnovskikh and coworkers replaced dimethyl acetonedicarboxylate (31) 22 reagent with ethyl cyanoacetate and diethyl malonate in the one-pot, multistep transformation of 2-(trifluromethyl)-4H -chromen-4-ones (37) to functionalized 6H -benzo[ c]chromen-6-ones 39–45 23 as shown in Scheme On the basis of the above precedent reports, 22,23 Iaroshenko and coworkers reported the synthesis of 6H benzo[c ]chromen-6-ones utilizing the base mediated cyclocondensation of 1,3 and 1,5-dicarbonyl compounds with 4-chloro-3-formylcoumarin (46) 24 The 1,5-dicarbonyls with two acidic methylene groups follow 1:1 stoichiometry, because the two groups are involved in cyclocondensation with the coumarin aldehyde group and C-4 carbon (Scheme 5) MAZIMBA/Turk J Chem R F3C O CNCH2CO2Et CF3 R EtONa, Reflux 35-66% O NC O EtONa, Reflux EtO2C 37-62% O OH NH 38 R = H 39 R = 2-Me 40 R= 3-MeO 41 R= 1,3-diMe R F3C CH2(CO2Et)2 OH O 42 R= H 43 R= Me 44 R= Cl 37 Scheme Transformation of chromones to H -benzo[ c ]chromen-6-ones O O RO O 46 OR RO OR 45 + Cl O OH O O O K2CO3 THF, 50 oC, h 79-81% O O 47 R= Me 48 R= Et O Scheme Cyclocondensation of 4-chloro-3-formylcoumarin with 1,5-dicarbonyls O R 49 + Cl O O R O O R1 R1 R1 K2CO3 THF, 50 oC, 4-8 h 45-76 % O O 50 O 51 O Aromatization 2K2CO3 KOH KOH, CO2 O + K O R1 O O R OH R O R1 O HO O R COR1 R 2K+ R1 O O O KOH 52 55 56 59 R Me Me Ph O 53 R1 Me OMe/OEt OEt O R COR1 R1 RCO-K+ O O 54 R R1 57 Et OMe 58 CH2Cl OMe/OEt Scheme Cyclocondensation of 4-chloro-3-formylcoumarin with 1,3-dicarbonyls MAZIMBA/Turk J Chem The 1,3-dicarbonyls follow a 2:1 stoichiometry with the first 1,3-dicarbonyl undergoing a Knoevenagel condensation with the aldehyde, while the second molecule replaces the chlorine atom in a nucleophilllic substitution reaction 25 The base-catalyzed cyclization of 53 affords intermediate 54, which loses the ester/carbonyl group and aromatizes to the desired compound 50 in Scheme 24 3.3 Cycloaddition of dicarbonyl compounds to chalcones Masesane and Mazimba outlined a protocol for the synthesis of 9-aryl-6H -benzo[ c ]chromen-6-ones (62, 66–70) from the reaction of ′ -hydroxychalcones (60) and ethyl acetoacetate (61) 26 The reaction key steps were transesterification, intra-molecular Michael addition, Aldol condensation, and oxidative aromatization as outlined in Scheme This synthetic protocol was applied to the synthesis of thiophen-2-yl-6H -benzo[ c]chromen-6-one (72, 73) shown in Scheme 27 R O R O Et3N CO2Et + MeOH, 60 oC, 0.5 h 51-59% OH OH O 60 61 O 62 Aromatization Trans-esterification R R R Michael addition O O O O O 63 Intramolecular Aldol condensation O R 66 o-OMe 67 m-OMe 68 p-OMe O O O 64 R 69 p-Br 70 m,p-diOMe O 65 Scheme Reaction of ethyl acetoacetate and 2’-hydroxychalcones S O S OH O R CO2Et + K2CO3, EtOH OH 60 oC, 0.5 h, 52-60% O O R 71 61 72 R= H 73 R= OMe Scheme Synthesis of thiophen-2-yl-6 H -benzo[ c ]chromen-6-one O MAZIMBA/Turk J Chem 3.4 Cycloadditions involving silyl enol ethers Langer and coworkers reported the synthesis of 6H -benzo[ c]chromen-6-ones (77) by domino retro-Michael– Aldol–lactonization reactions of 2,3-dihydropyrans (4H -chromen-4-one) 74 with silyl enol ethers (75) as outlined in Scheme 28,29 O Me3SiO OSiMe3 O OEt R1 O O 75 i, 56-75% R1 OEt O O OH ii 72-88% O O R1 74 76 77 R1= H, Me, Et, OMe, OBn Reagents and conditions: i) Me3SiOTf, DCM, oC, h; ii) Et3N, EtOH, 20 oC, 12 h Scheme Synthesis of 7-hydroxydibenzo[ c , d ]chromen-6-one from H -chromen-4-one Chromone (78) reacted with 1,3-bis-silyl enol ether 79 in the presence of trimethylsilyl trifluoromethanesulfonate (Me SiOTf) to afford 2,3-dihydrobenzopyran (82) with very good regioselectivity Benzopyran (82) was transformed to 7-hydroxy-6H -benzo[ c]chromen-6-one (80) using Et N as shown in Scheme 10 30 Me SiOTf was necessary for the in situ generation of benzopyrylium triflate 81, 31 while refluxing the reaction mixture shortened the reaction time but decreased the yield A decrease in the yield was also reported when the base or solvent (LDA/THF, Et N/THF, KO t Bu/EtOH, or K CO /EtOH) was used 30 Compounds 85 and 89 exhibited blue fluorescence at 489 and 457 nm, respectively, with 65 nm Stokes shift The 7-hydroxy group of 7-hydroxy-6H -benzo[c ]chromen-6-ones (85) was substituted by aryl groups to afford 7-aryl-6 H -benzo[c ]chromen-6-ones (105) by Suzuki cross-coupling reaction of triflate 104 as shown in Scheme 11 30 Langer and coworkers also applied benzo[h ]chromone (106) to the synthesis of 7-hydroxydibenzo[c ,d ] chromen-6-one (108) and 3,4-dihydro-2H -1,13-dioxapicen-14-one (112) 30 7-Hydroxydibenzo[ c, d]chromen-6one (108) was synthesized by the condensation of benzo[ h]chromone (106) with 1,3-bis-silyl enol ether (79), followed by the domino retro-Michael–Aldol–lactonization The condensation of benzo[h]chromone (106) with 1,3bis-silyl enol ether (109) afforded 2,3-dihydronaphthopyran (110), which gave 7-hydroxydibenzo[ c ,d]chromen6-one (111) after treatment with Et N The latter reacted with NaH/TBAI (tetra-n -butylammonium iodide) to afford 3,4-dihydro-2H -1,13-dioxapicen-14-one (112) (Scheme 12) The synthesis of autumnariol (2) was first reported based on the condensation of orcinol (116) with 2-bromo-6-methoxybenzoic acid, but produced the product in low yields (19%) 32,33 An efficient synthesis utilized the reaction of [3,4-dimethoxy-2-diisopropylcarbamoyl)phenyl]-boronic acid (113) with 2,4-dimethoxy6-methylbromobenzene (114) in the presence of palladium catalyst 34 (Scheme 13) The Langer group 30 used orcinol (116) to synthesize chromone 118, which was condensed with 1,3-bis-silyl enol ether (75) to afford autumnariol (122) as described in Scheme 14 MAZIMBA/Turk J Chem R1 O R2 OSiMe3 Me3SiO R1 OR5 R3 R4 O 78 i i R2 b 20-87% R3 OH 80 R3 O R5OH R5 = Me or Et Lactonization activation R2 O O 79 OSiMe3 R1 R4 R2 OH R3 OR5 O OH 84 OTf 81 H2O Aldol O OSiMe3 Me3SiO OR5 R4 79 O R2 R3 Michael reaction R2 OR5 O O O 82 ii Retro- R3 Michael OH O O 83 OR5 R1 R2 R3 R4 R1 R2 R3 R4 85 H H H H 95 H Cl H Me 86 H H H Me 96 H Cl H nHex 87 H H H Alkyl (C2-8) 97 H Br H H 88 H H H Allyl 98 H Cl Me H 89 H H H OMe 99 H H OMe H 90 H H H OH 100 H H OH H 91 H Me H H 101 Me H H H 92 H Me H H 102 CN H H Me 93 H OH H H 103 CN H H Alkyl (C2-4) 94 H Cl H H Reagents and conditions: i) Me3SiOTf, 20 oC, h; ii) Et3N, EtOH, 20 oC, 12 h Scheme 10 Transformation of chromone with 1,3-bis-silyl enol ether to 7-hydroxy-6 H -benzo[ c ]chromen-6-one OH O O i OTf O O ii Ar 66-92% 85 104 Ar = Ph, pMePh, pMeOPh, pClPh, o,p,m-triMeOPh, 2-Thienyl O 105 O Reagents and conditions: i) Tf2O, pyridine, DCM, -78-20 oC, 10 h; ii) K3PO4, ArB(OH)2, Pd-(PPh3)4, 4-12 h, 100 oC Scheme 11 Synthesis of 7-aryl-6 H -benzo[ c ]chromen-6-ones by Suzuki cross coupling MAZIMBA/Turk J Chem O O OEt O OEt 79 O O OSiMe3 Me3SiO OSiMe3 Me3SiO OEt O Cl 109 i 107 ii 61% 106 i O OEt O O OH O O Cl O 110 ii 108 iii O O OH Cl 57% O O 112 O 111 o o Reagents and conditions: i) Me3SiOTf, 0-20 C, h; ii) Et3N, EtOH, 20 C, 12 h; iii) NaH, TBAI, THF, 20 oC, 20 h Scheme 12 Synthesis of 7-hydroxydibenzo[c,d]chromen-6-one and 3,4-dihydro-2 H -1,13-dioxapicen-14-one OMe O MeO OMe N MeO O OMe OMe N i MeO MeO O OMe Br 57% OMe B(OH)2 113 O ii OMe 19 114 115 + Reagents and conditions: i) PdCl2(PPh3)2, THF, K2CO3, rt, h; ii) BBr3, DCM, then H3O Scheme 13 Pd catalyst condensation of boronic acid and bromobenzene In continuation of their studies on the synthesis of 6H -benzo[c ]chromen-6-ones, the Langer group reacted 1,3-bis-silyl enol ether (79) with 4-chloro-2-oxo-2H -chromene-3-carbaldehyde (123) 35 instead of simple chromones 78, 106, and 118 28−30 This cycloaddition [3+3] formed new bonds for benzo[c]chromen-6-one ring C (124) and were formed between carbon atoms C7 and C8 and between C10 and C10a as shown in Scheme 15 Having previously managed to accomplish the synthesis of benzophenones from the domino ‘Michael– retro-Michael–Aldol’ reactions of 1,3-bis-silyl enol ethers (75) with 3-formylchromones, 36 the first molecule of MAZIMBA/Turk J Chem O HO OH O O i iii ii 41 % HO 56% HO OH 116 76% O 117 O 118 119 O OSiMe3 Me3SiO OH BnO BnO OEt O iv 67% 75 122 92% vi O v OH BnO O OEt O 81 % O BnO O O 121 120 Reagents and conditions: i) MeCN, ZnCl2, Et2O, h, 20 oC; ii) HC(OEt)3, HClO4, 12 h, 0-20 o C; iii) BnCl, K2CO3, EtOH, h, reflux; iv) Me3SiOTf, DCM, h, 0-20 oC; then HCl; v) Et3N, EtOH, 12 h, 20 oC; then 12 h, reflux; vi) BBr3, DCM, h, oC Scheme 14 Synthesis of autumnariol from orcinol OSiMe3 Me3SiO OH O OR1 Cl O R2 H O R2 OR1 i, ii O O 43-53% 123 79 O HCl TiCl3OH 124 O R2 TiCl4 OTiCl3 OR2 R2 Cl MeSi 79 O R2 O TiCl4 O 125 O O O 127 O OR1 CHOTiCl4 Me3SiCl H O OR1 OSiMe3 Me3SiO O Me3SiCl O 126 128 129 130 131 R1 Me Me Et Me R2 H C-2-C10 alkyl Cl MeO R1 132 tBu 133 (CH2)2OMe 134 Me 135 Me R2 H H CH2Ph CH2CH2Ph Reagents and conditions: i) TiCl4, DCM, -78-20 oC, 16 h; ii) HCl Scheme 15 [3+3] Cycloaddition of 1,3-bis-silyl enol ether with 4-chloro-2-oxo-2 H -chromene-3-carbaldehyde 10 MAZIMBA/Turk J Chem O OSiMe3 + R3 Me Me3SiO R2 R1 OH R1 R2 163 137 R3 R3 OSiMe3 O 168 i 20-51% 40-60% R3 R2 OH R1 164 ii 69-84% R3 O OH O 167 iv OSiMe3 Me3SiO O R2 R3 O O 79 R1 169 Et 170 Me R2 Cl Me R3 Et Me O OR4 R1 iii, 61-77% 165 O OR4 R2 OR4 R1 O R2 O R1 O O 166 R4 R1 Me 171 Me Et 172 Me R2 R3 R4 H Me Et OAc Me Me Reagents and conditions: i) TiCl4, DCM, ı -78 oC; ii) HC(OEt)3, HClO4, reflux, 12 h; iii) Me3SiOTf, 20 oC, h; then 79, DCM, 0-20 oC, 12 h and HCl; iv) NEt3, EtOH, 20 oC, 12 h Scheme 18 Synthesis of 7-hydroxy-6 H -benzo[ c ]chromen-6-ones from silyl ethers and enones O O O O2N OMe Br HO O2N OH B R OMe i O iv R 73-76% MeO 77-87% MeO 173 174 175 R= Me R= CHO 89% O H2N O2N ii 53% iii R 176 CH2OH O O iv H2N OMe R 60-80% R= Me or CH2Br MeO R 178 177 Reagents and conditions: i) PdCl2, dppf, KOAc, dioxane, reflux, 15 h; ii) BH3/DMS, THF, rt, h; iii) H2/Pd/C, THF, rt, 1h; iv) BBr3, DCM, -78 oC, h then MeOH Scheme 19 Synthesis of 2-bromomethyl-8-nitro (or amine)-benzo-[c]chromen-6-one 13 MAZIMBA/Turk J Chem The Thasana group utilized the synthesis and lactonization of properly substituted biaryls 44 in their synthesis of benzopyrane/6H -benzo[ c]chromen-6-one Hence this group pursued a green protocol that would form C–O bonds from 2-halobiarylcarboxylates (178) using Cu(I) catalyst and microwave radiation in the presence of a bidentate ligand and basic subcritical water medium 45 Copper(I) thiophene-2-carboxylate (CuTC) efficiently catalyzed the reaction with N,N,N’,N’-tetramethylethylenediamine (TMEDA) as the best bidentate ligand over phenanthroline bipyridine and 2-oxocyclohexane derivatives; CsCO was a better base than K CO , which decreased yields in subcritical water An array of 6H -benzo[ c ]chromen-6-ones (180–189) was reported as depicted in Scheme 20 and Figure 45 N X N R CuTC, CS2CO3, H2O o COOMe 300 W, 300 C, 250 psi, 10 COOH X X = Br, Cl 178 30-99% O O 179 180 Scheme 20 Cu(i) H -benzo[ c ]chromen-6-one C–O bond formation OMe MeO OMe OMe N OMe MeO O O 181 O O MeO O 182 183 R N O O O 184 O N N R O O O O O R= H, Me O O O R= H, Me 185 186 187 188 Figure H -Benzo[ c ]chromen-6-ones reported by Nealmongkol and coworkers The above protocol was used to synthesize natural 6H -benzo[c ]chromen-6-one, urolithins A–C, as shown in Scheme 21 Their preparation was achieved in four steps starting from available boronic acid (190) in overall yields of 15%, 9%, and 7%, respectively Urolithins A–C (196–198) inhibited aromatase activity (IC 50 = 11–21 µ M) and expressed potent antioxidant activity in an oxygen radical absorbance capacity assay Urolithin C (198) showed inhibition of human leukemia cells (HL-60), with an IC 50 of 86.8 µ M 45 Singha and coworkers reported a one-pot Suzuki–Miyaura cross coupling reaction of 2-bromobenzaldehyde (201) derivative and 2-hydroxyphenylboronic acid (202) to construct the nucleus of H -benzo[c ]chromen-6one (206–215) in Figure 46,47 The initial coupling affords 2-(2-hydroxyphenyl)benzaldehyde (203), which 14 MAZIMBA/Turk J Chem equilibrates to form a hemi-acetal (204) that yields the benzo[c ]chromen-6-one (205) in the palladium-catalyzed oxidative lactonization as shown in Scheme 22 O O R1 R1 I H R2 R2 B(OH)2 Br 190 K2CO3, rt, h 62-71% OMe 191 O O R1 O R2 H PdCl2(PPh3)2, THF, i) BBr3, DCM ii) H3O 29-67% OH 195 196 R1= OH, R2= H 197 R1= R2= H 198 R1= R2= OH R1 O R2 Br OMe 192 i) KMnO4, Py, H2O, reflux 45-60% ii) (COCl2)2, DMF, DCM, then MeOH O R CuTC, TMEDA, OMe CS2CO3, H2O, MW R2 300W, 300 oC, Br OMe OMe 250 psi, 10 64-79% 194 199 R1= OMe, R2= H 200 R1, R2= OCH2O 195 Scheme 21 Synthesis of urolithins A–C by Cu(I) assisted lactonization O O O O O F O MeO O MeO 205 MeO 206 MeO 207 O O 208 O MeO O O O O O O MeO OMe 209 210 211 212 Figure H -Benzo[ c ]chromen-6-one reported by Singha and coworkers 3.6 Radical reaction in the synthesis of benzo[c]chromen-6-one The Singha group recently reported CuCl catalyzed intramolecular aryl C–H oxidative lactonization of 2arylbenzaldehyde (213) in the presence of tert-butyl hydroperoxide (TBHP) as the oxidant to accomplish the synthesis of benzo[ c]chromen-6-one (205) as shown in Scheme 23 and Figure 48 TBHP generates tert-butoxyl and tert-butylperoxy radicals in the presence of CuCl The tert-butoxyl radical abstracts the 2-arylbenzaldehyde 15 MAZIMBA/Turk J Chem aldehydic proton to generate the intermediate radical 214 that couples with the tert-butylperoxy radical to give the perester intermediate 215 or combines with the adjacent phenyl ring to form the reaction byproduct, fluorenone (218) Intermediate 215 decomposes to give intermediate 216 and tert-butoxyl radical in the presence of Cu(I) catalyst 48,49 The intermediate 216 then undergoes intramolecular lactonization to accomplish the formation of the desired benzo[ c]chromen-6-one (205) 3-Acetyl-2-fluoro-6H-benzo[c]chromen6-one, a derivative of compound 220, was reported to have been prepared in a one-pot reaction by the Suzuki– Miyaura cross-coupling and nucleophilic substitution reaction of 4′ -chloro-2′,5 ′-difluoroacetophenone with o(methoxycarbonyl)phenylboronic acid 50 O OH CHO R OH HO CHO O O i 68-91% R (HO)2B HO 202 203 204 Reagents and conditions: i) Pd(OAc)2, PPh3, K2CO3, DMF, 90 °C, h 201 205 Scheme 22 Singha and coworkers’ synthesis of H -benzo[ c ]chromen-6-one O O O H O t-BuO t-BuOH O OBu-t O [Cu]I t-BuOO CuII t-BuO 213 214 215 216 25% [Cu]I O O O t-BuOH O O 60-87% 218 205 217 Scheme 23 2-Arylbenzaldehyde CuCl assisted C–H oxidative lactonization The tri -n -butyltin hydride (Bu SnH) cyclization of aryl radicals yielded 6H -benzo[ c]chromenes, which were subsequently oxidized to 6H -benzo[c ]chromen-6-ones using pyridinium chlorochromate (PCC) 51 Aryl benzoates such as 4-methylphenyl 2-iodobenzoate failed to achieve radical cyclization in the synthesis of 6H benzo[c ]chromenes, but rather gave biphenyls 51,52 Thus aryl benzyl ethers (236) were used as substrates for the synthetic protocol shown in Scheme 24 The spirodienyl intermediate (237) rearrangement was controlled by generating the aryl radical on the substituted ring and cyclized onto the unsubstituted ring, so that the ‘neophyl rearrangement’ afforded the same product 51 The shilajit herbal medicine H -benzo[ c]chromen-6-one 11 was synthesized in 54% overall yield over three steps 16 MAZIMBA/Turk J Chem O O F O MeO O O O MeO O O O O MeO Cl 219 220 221 O O O MeO 222 O O O O 223 O O O MeO MeO OMe OMe 224 225 O 226 O O MeO F MeO 228 O MeO O O O O 227 O O O MeO 229 OMe OMe Cl OMe 230 OMe 231 232 233 Figure Dibenzopyranones derived via 2-arylbenzaldehyde oxidative lactonization R1 R2 Br R3 R1 R1 i O R2 ii R3 236 R2 H R3 O O 237 241 242 11 243 244 R1 R2 H Me H OMe H H OBn H H Cl R3 H H OMe H H 238 25-54% R1 R1 R2 R3 iv O O 240 28-100% iii R2 R3 O 239 Reagents and conditions: i) Bu3SnH, AMBN, C6H12, reflux, N2, h; ii) neophyl rearrangement; iii) -H or -H+, -e-; iv) PCC, DCM, reflux, 24 h Scheme 24 Bu SnH radical application on the synthesis of H -benzo[ c ]chromen-6-ones 3.7 Synthesis and cyclization of enyne and allyl compounds Chen and coworkers synthesized conjugated enynes via the Sonogashira coupling of alkynes and vinyl iodides using Pd catalyst The Et N mediated intramolecular [4+2] cycloaddition and aromatization of conjugated enynes accomplished the synthesis of 6H -benzo[ c]chromenes (251–258) as shown in Scheme 25 53,54 17 MAZIMBA/Turk J Chem O R1 R1 R2 Br R3 R2 i O OH 245 251 252 253 254 255 256 257 258 R1 C4H9 C4H9 TMS TMS PhSCH Ph Ph Ph 246 R2 H H H H H H Cl Me R3 Me H Me H H Me Me Me I R3 247 248 ii R3 O R1 O R1 R3 R2 iii R3 R2 O 33-66% R3 O 250 249 Reagents and conditions: i) K2CO3, Me2CO, rt; ii) PdCl2(PPh3)2-CUI, Et3N, THF, rt, 24 h, N2; iii) Et3N, EtOH, 80 oC, 24 h, N2 Scheme 25 Synthesis of H -benzo[ c ]chromenes via intramolecular [4+2] cycloaddition of enynes He and coworkers reported the synthesis of 6H -benzo[ c ]chromenes, which were then oxidized to benzo[c] chromen-6-ones 55 The synthesis of H -benzo[ c]chromenes was offset by the preparation of 2-(2-(allyloxy)phenyl) furan (262) via the Suzuki–Miyaura cross-coupling reaction 56 The intramolecular cycloaddition of 2-(2(allyloxy)phenyl)furan (262) was carried out in water under microwave irradiation to give 6H -benzo[ c ]chromenes (261: Scheme 26), while 2-(2-(prop-2-ynyloxy)phenyl)furan (265) afforded 8-hydroxy-6H -benzo[ c]chromenol (266) shown in Scheme 27 55 The H -benzo[ c]chromenes (267) were oxidized into the corresponding benzo[c ] chromen-6-one (268) using H O under microwave irradiations (Scheme 28; Figure 7) I i O OH 45-85% OH 259 O 260 261 aromatization ii 62% OH O iii O cycloaddition O O 262 263 ring opening O 264 Reagents and conditions: i) Furan-2-ylboronic acid, Pd(OAc)2, PPh3, K2CO3, EtOH, Ar, 80 o C, 16 h; ii) 3-bromoprop-1-ene, K2CO3, CH3CN, rt 48 h; iii) MW, water, 150 oC, 20 min, sealed vessel Scheme 26 Synthesis of H -benzo[ c ]chromenes from 2-(2-(allyloxy)phenyl)furan 18 MAZIMBA/Turk J Chem OH O MW, water, 150 °C, 20 min, sealed vessel 53-82% O O 265 266 Scheme 27 Synthesis of H -benzo[ c ]chromenes from 2-(2-(prop-2-ynyloxy)phenyl)furan R R H2O2, EtOH 80 oC, 24 h O O O R= H, OH 268 267 Scheme 28 H O oxidation H -benzo[ c ]chromenes R Cl Me O X MeO O 269 O X 270 O X X 273 R O O R O R X 274 X 272 R O2N O Me Me 271 R Br R R R X O X 275 276 X 277 Figure H -Benzo[ c ]chromenes and H -benzo[ c ]-chromen-6-ones reported by He and coworkers 3.8 Cyclization of aryl-2-halobenzyl ethers/ester H -Benzo[c ]chromenes (279, 280), which are oxidizable to benzo[ c]chromen-6-ones, were also synthesized through the intramolecular cyclization of 3-(2-halobenzyloxy)phenols (278) in the presence of t-BuOK instead of metal catalyst 57 as shown in Scheme 29 58 OH OH Br O t-BuOK dioxane, 140 °C, 16 h 96 (3:1) % 278 + O HO 279 O 280 Scheme 29 Intramolecular arylation of phenols 19 MAZIMBA/Turk J Chem Phenyl-2-iodobenzoates, which previously failed to cyclize under Bu SnH mediated radical cyclization, 51 were adopted by Taylor and coworkers 59 Phenyl-2-iodobenzoates (281) when treated with (Ph P) PdCl in the presence of sodium acetate in a sealed tube yielded benzo[c]chromen-6-ones (285–287) as indicated in Scheme 30 59 The key intermediates were the cyclic ArPd(II)-enolate intermediates (283), formed by intramolecular C–H activation by ArPd(II) The reductive elimination of Pd(II)-palladacycle (284) afforded the H -benzo[c ]chromen-6-ones (282) R1 R R1 R2 O (Ph3P)2PdCl2, NaOAc OMe O R2 I OMe DMA, 125 °C, h, 71-85% R MeO O MeO 281 O 282 Reductive elimination Pd(0) OMe R R1 R2 R R1 R2 285 H H H 286 OMe OMe H 287 OMe OMe OMe HI O O (II) Pd I OMe OMe O OMe O Pd(II) R2 R R1 283 284 Scheme 30 Cyclization of aryl benzoates to H -benzo[ c ]chromen-6-ones 3.9 Miscellaneous reactions Hong and coworkers reported a highly stereoselective domino Michael–acetalization–Henry reaction of nitrostyrenes (292) and aldehydes (290) to afford the tetrahydro-6H -benzo[ c ]chromen-6-ones (296, 297) 60 The source of the high stereoselectivity was the transition state (293) shown in Scheme 31, where the Michael addition of the aldehyde enamine and nitrostyrene occurred and favored the cis intermediate 294 The iminium intermediate (294) underwent a Henry reaction and acetalization to produce the chromanol (295) that oxidized to tetrahydro-6H -benzo[ c ]chromen-6-ones (296, 297) in the presence of PCC 60,61 The electrophilic Ir(III) catalyst C–H functionalization of benzoic acid (298) with benzoquinone (301) produced 2-hydroxy-6H -benzo[ c]chromen-6-one (299) on attempts aimed at the synthesis of hydroxybenzoic acid 62 The catalytic cycle begun by producing the active catalyst Cp*Ir(OAc) + from bis-Pentamethylcyclopentadienyliridium(i)dichloride (Cp*IrCl )2 , followed by the iridium metallacycle (300) formation by ortho C–H bond activation 63 of the benzoic acid The C–H bond functionalization occurs as benzoquinone insert into the iridium–carbon bond, followed by intramolecular reduction of the benzoquinone ketone moieties and elimination of 2-hydroxy-6H -benzo[ c ]chromen-6-one (299) as shown in Scheme 32 62 20 MAZIMBA/Turk J Chem OH OH O O H N H i) Nitrostyrene, PhCO2H water, 24 h H 289 H H ii) PCC, DCM, ee >99% 290 O2N O2N R + H O O 296: cis 80-88% H O O 297: trans 12-20% R OH O2N N H R H H O OH 295: cis 80-88% H O R 291 NO2 HO N R O NO2 OH H Ph 292 = N H 289 N H H Ph Ph OTMS N O 293 294 Scheme 31 Tandem Michael–acetalization–Henry reactions in the synthesis of tetrahydro-6 H -benzo[ c ]chromen-6-ones R R *Cp O Cp*IrCl2)2 NaOAc OH HO HO Toluene, 120 oC 24 h 20-63% R Ir HOAc+ H+ O 298 O OH HO Cp*Ir(OAc)+ 299 O 303 + Cp*Ir(OAc) HOAc+ H+ H+ O O *Cp Ir O O 301 O O *Cp Ir R O O R 300 R = H, Me, Cl, tBu, NO2 302 Scheme 32 Reaction of benzoic acid and benzoquinone to afford 2-hydroxy-6 H -benzo[ c ]chromen-6-one 21 MAZIMBA/Turk J Chem The condensation of resorcinol (17) with 4-piperidino and pyrrolidinoethoxy-5-methoxy-2-bromo benzoic acids (304) formed H -benzo[c ]chromen-6-one (305, 306), which were demethylated using BBr to afford compounds 307 and 308 in Scheme 33 H -Benzo[ c]chromen-6-one 309 was functionalized to H benzo[c ]chromenes 313 and 314 as described in Scheme 34 64 6H -Benzo[c ]chromen-6-one 307 and 308 exhibited (dose 10 mg/kg) estrogenic activity in rats with uterine weight gain of 21% and 25% over the control, respectively 6H -Benzo[ c]chromenes 313 and 314 at the same dose displayed estrogenic activity shown by the uterine weight gain of 63% and 71%, respectively, but these compounds failed to show antiestrogenic (antagonist) activity induced by 17β -oestradiol 6H -Benzo[c ]chromenes 313 and 314 also exhibited postcoital contraceptive (anti-implantation) activity at 100% inhibition of implantation at 10 mg/kg dose, while the activity dropped to 50% and 60% when tested at mg/kg 64 NP PN OH O + i OH ii 48-50% HO Br O COOH 304 17 O OMe OMe HO NP O O 60% HO O 305 NP= pyrrolidine 306 NP= piperidine O 307 308 Reagents and conditions: i) CuSO4/NaOH, heat; ii) BBr3, DCM, -78 oC Scheme 33 Condensation of resorcinol and benzoic acids OH OTBDMS i, ii HO O 70% O OTBDMS iii TBDMSO 309 O OH 47% TBDMSO 310 O OPh 311 iv OH OTBDMS v HO O TBDMSO O O O NP NP 313 NP= pyrrolidine 312 314 NP= piperidine Reagents and conditions: i) TBDMSCl, imidazole, DMF, ii) DIBAL-H, -95 to -75 oC, iii) 4-(2piperidinoethoxy)/4-(2-pyrrolidinoethoxy)phenyl magnesium bromide, THF, v) I2, MeOH, rt Scheme 34 Functionalization of H -benzo[ c ]chromen-6-one to H -benzo[c]chromenes 22 MAZIMBA/Turk J Chem Aminoalkyl-6H -benzo[c ]chromen-6-ones (322, 323), which are biomarkers of ellagitannins present in various nutrition, were synthesized and evaluated as potential acetylcholinesterase and butyrylcholinesterase inhibitors The synthetic strategy followed the reductive amination of acetophenone derivatives (315), the esterification, and finally the aryl-coupling reactions, which have been demonstrated previously as described in Schemes 35 and 36 65 In Scheme 35 only active compounds are shown but a variety of compounds were reported based on combinations of n = 2–4 and R = 1–6 (Scheme 36) O OH N O OH 315 i 61% N O O HCl O O HCl N N O O N vi 322 O 323 96% N N O OH 316 ii, iii 70% O HCl O O v 79% vi 318 81-84% O O Br O O HCl OH iv N O 320 O HCl HO O v O 317 O 72% O HCl 86% N N 319 321 Reagents and conditions: i) NaOH, DMS, 50 oC, h; ii) NaCNBH3, DMA-HCl, MeOH, reflux, 17 h; iii) 2-bromobenzoic acid, PPA, 80 oC, 15 min; iv) PdCl2(PPh3)2, NaOAc, DMA, 130 oC, 16 h; v) HBr, 130 oC, 24 h; vi) N-Ethyl-N-methylcarbamyl chloride, pyridine, rt, 20 h Scheme 35 Synthesis of amino alkyl H -benzo[ c ]chromen-6-one derivatives Compounds 328–334 exhibited good acetylcholinesterase (Ache) activity with 50% inhibitory concentration (IC 50 ) of 0.8–1.7 µ M, while good butyrylcholinesterase (BuChe) activity was shown by compounds 320, 323, and 332–334 with IC 50 of 4.2–12.1 µ M The standards used were donepezil and galantamine for the in vitro cholinesterase activities on the AChe (IC 50 = 0.0008 and 0.7 µ M) and BuChe (IC 50 = 7.1 and 21.9 µ M) assays Compounds 328–334 showed that they had better potential and selectivity to inhibit Ache; these compounds were also reported to show good activities in in vivo experiments 65,66 Mannich reactions were used for the C-aminomethylations of 7,8,9,10-tetrahydrobenzo[c]chromen-6-one (335, 336) with 1,1-diaminomethanes (339, 340) as described in Scheme 37 The preferred positions for the aminomethylations were positions ortho to 1-OH and 3-OH groups 67,68 23 MAZIMBA/Turk J Chem X n HO O O O O O X n O ii i 91% iii 50-82% O iii 80% 326 327 iv 78-88% X= Cl, Br; n= 2-4 R n N O O 47-84% 17 324 iv 60-82% O O OH 325 R n HO OH O O N N R= R= O N O OH R= O O N N O R= 328 R= n= 329 R= n= 330 R= n= 331 R= n= OH R= N 332 R= n= 333 R= n= 334 R= n= N O R= Reagents and conditions: i) ethyl 2-oxocyclohexanecarboxylate, ZrCl4, 70 oC, h; ii) 2-iodobenzoic acid, NaOH, CuSO4, H2O, reflux, 40 min; iii) alkyl halide (1,2-dichloroethane, 1-bromo-3-chloropropane, or 1bromo-4-chlorobutane), NaOEt; iv) K2CO3, NaI, Acetonitrile, amine derivative (1-6), 32 min, MW, 105 oC Scheme 36 Synthesis of amino alkoxy H -benzo[ c ]chromen-6-one derivatives R3 N HO X R4 O O R4 R3 N R3 N 340 R HO R4 ii R= H 75-88% R1 N HO O O X O N 339 R1 R2 HO N ii R= H/Me R1= H, Cl 343 R=Me R1= H X O R= H 76-91% 335 i 76-79% O O R1 341 R=Me R1= H HO R1 O O O 78-86% R4 N HO R 337 R= H/Me, R2= H/Me R1= H/Cl R3 344 O O R4 R4 N R3 OH 345 OH ii R3 N R3 N 340 O 76-86% O 338 i, 61% R=R1= H O O N X X R4 342 X N O O N 339 76-85% OH ii 74-81% N OH 336 X X= CH2, CHMe, (CH2)4, NMe, O 346 R3=R4= H, Me, CH2Me, (CH2)4, CH2CHMeCH2CH2, CH(CH2Me)CH2CH2CH2CH2 Reagents and conditions: i) EtOH, H2SO4, oC, 24 h; ii) 1,1-diaminomethane, dioxane, 100 oC, 0.5-10 h Scheme 37 Mannich reactions of 7,8,9,10-tetrahydrobenzo[ c ]chromen-6-one with 1,1-diaminomethanes 24 MAZIMBA/Turk J Chem Conclusion This literature survey has revealed that the key reactions in the synthesis of benzo[c ]chromen-6-one are as follows: i) The synthesis and lactonization of 2’-methoxy-2-acetate(or acid)biaryls, which are mostly obtained via the Suzuki coupling reactions ii) Oxidative cyclization of biphenyl-2-carboxaldehyde and aryl benzyl ethers iii) Michael addition of 1,3-, 1,5-diketones or esters and silyl 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S.; Esiringu, I.; Ercetin, T.; Sahin, Y.; Oz, D.; Sahin, M F Bioorg Med Chem 2014, 22, 5141–5154 66 Hodges, D B Jr.; Lindner, M D.; Hogan, J B.; Jones, K M.; Markus, E J Behav Pharmacol 2009, 20, 237–251 67 Garazd, Y L.; Panteleimonova, T N.; Garazd, M M.; Khilya, V P Chem Nat Compd 2002, 38, 532–538 68 Kallay, F.; Janzs, G Tetrahedron Lett 1978, 19, 1443–1446 27 ... ]chromen-6-ones (62, 66–70) from the reaction of ′ -hydroxychalcones (60) and ethyl acetoacetate (61) 26 The reaction key steps were transesterification, intra-molecular Michael addition, Aldol condensation,... 1,5-diketones or esters and silyl enol ethers to Michael acceptors such as chromones, chromenes, and chalcones followed by lactonization iv) The cycloaddition and aromatization of conjugated enynes... v) Oxidation of 6H -benzo[ c ]chromene The reactions involving 1,3- and 1,5-diketones avoid the use of metal catalyst (palladium and copper), are one-step reactions, and offer easy reaction mixture