Synthesis, reactions and applications of naphthofurans: A review European Journal of Chemistry 12 (3) (2021) 340-359 European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2021 The Authors – Atlanta Publishing House LLC – Printed in the USA. This work is published and licensed by Atlanta Publishing House LLC – CC BY NC – Some Rights Reserved. https://dx.doi.org/10.5155/eurjchem.12.3.340-359.2126 European Journal of Chemistry View Journal Online View Article Online Synthesis, reactions and applications of naphthofurans: A review Ashraf Hassan Fekry Abdelwahab 1,* and Salma Ashraf Hassan Fekry 2 1 Chemistry Department, Faculty of Science, Jazan University, 2097, Jazan, Saudi Arabia ahabdelwahab@jazanu.edu.sa (A.H.F.A.) 2 Faculty of pharmacy, German university, in Cairo (GUC), Cairo, Egypt salmaashraf1380@gmail.com (S.A.H.F.) * Corresponding author at: Chemistry Department, Faculty of Science, Jazan University, 2097, Jazan, Saudi Arabia. e-mail: ahabdelwahab@jazanu.edu.sa (A.H.F. Abdelwahab). 10.5155/eurjchem.12.3.340-359.2126 Received: 11 May 2021 Received in revised form: 27 May 2021 Accepted: 17 June 2021 Published online: 30 September 2021 Printed: 30 September 2021 Considering the highly important biological and medicinal properties of naphthofurans, the synthesis of these heterocycles has attracted the interest of medicinal and organic chemists. This review aims to describe the different strategies developed so far for the synthesis of naphthofurans and their applications and the literature reports for the period of 2000 to early 2020. After a brief introduction of the types of naphthofurans and their biological activities, the different synthetic approaches such as chemical and photochemical, methods are described and organized on the basis of the catalysts and the other reagents employed in the syntheses. Some of the reactions have been applied successfully to the synthesis of biologically important compounds. Synthesis Naphthol Naphthofuran Salicylaldehyde Biological activity 2-Hydroxy-1-naphthaldehyde Cite this: Eur. J. Chem. 2021, 12(3), 340-359 Journal website: www.eurjchem.com 1. Introduction Naphthofuran is a bicyclic organic compound that results from the fusion of a naphthalene ring to a heterocyclic furan ring [1]. Naphthofuran nuclei are key structural moieties found in a large number of biologically important natural products [2,3]. Therefore, the synthesis of various derivatives of naphtho [2,1-b]furan was taken up in our laboratory [1-4] in search of new biologically and pharmacologically active heterocyclic compounds. Many of the natural naphthofurans, such as (±)- Laevigatin [5,6] (1), (+)-Heritol [7-9] (2) and Balsaminone A, [10] (3), (Figure 1) possess interesting pharmacological and cytotoxic properties. Several synthetic compounds containing this ring skeleton are associated with diverse biological activi- ties such as antifungal, antibacterial [11,12], antiviral [13], antitumor [14], anthelmintic [15], anti-trypanosomal and cytotoxicity [16]. The nitro derivatives of naphtho[2,1-b]furans have been extensively studied for their mutagenic activities, for example, 7-methoxy-2-nitronaphtho[2,1-b]furan (4), the geno- toxicity of (R7000) as well as that of other nitrofurans, is due to the presence of the nitro group, actively reduced in bacteria by endogenous nitroreductases, (R7000) is one of the strongest mutagens described for mammalians. Naphthofuran derivatives have been isolated from various natural sources like Fusarium Oxysporum [16] and Gossypium barbadense [17]. The Maturin and maturing were isolated from the roots of Cacalia decomposition [18]. Later, another group of authors [19-21] isolated the natural analogs of the naphthofurans from the roots of Senecio Canescens, one was identified as naphtho[1,2-b]furan-4,5-dione (5), and the other two tentatively as 3-hydroxynaphtho[1,2-b]furan-4,5-dione (6) and 2-(2-hydroxypropan-2-yl)naphtho[1,2-b]furan-4,5-dione (7) (Figure 2). Dehydrocacalohastine (8a) was isolated from wild-growing Cacalia Hastata in 1973 [22,23]. This compound is also found in young green leaves or roots of plants of the Senecio genus of the daisy family such as Senecio Canescens [24,25], Senecio Macrospermus [26], Senecio Lydenburgensi [27], and Senecio Crispus [28]. In addition to dehydrocacalohastine (8a), hydroxy- (8b) and acetoxydehydrocacalohastines (8c) [25], dehydrocacalohastinol (8d) [28], methoxydehydro-cacalo- hastine (8e) [26], and naphtho[2,3-b]furans 8f-9a,b [27] were also isolated from these plants (Figure 3). Recently, naphtho[2,3-b]furan (10) [29] was isolated from the roots of Ligularia Veitchiana found in China, and Avicenol B (11) was isolated from the bark of Avicennia alba Blume [30] (Figure 4). ABSTRACT REVIEW ARTICLE KEYWORDS https://dx.doi.org/10.5155/eurjchem.12.3.340-359.2126 https://www.eurjchem.com/ https://dx.doi.org/10.5155/eurjchem.12.3.340-359.2126 mailto:ahabdelwahab@jazanu.edu.sa mailto:salmaashraf1380@gmail.com mailto:ahabdelwahab@jazanu.edu.sa http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.12.3.340-359.2126&domain=pdf&date_stamp=2021-09-30 Abdelwahab and Fekry / European Journal of Chemistry 12 (3) (2021) 340-359 341 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.3.340-359.2126 O O O O OHH3CO O O 1 2 3 4 O MeO NO2 Figure 1. Examples of biological, pharmacological of naphthofurans. O O O O O O OH O O O C(OH)Me2 5 6 7 Figure 2. Naphtho[1,2-b]furan-4,5-dione derivatives. Figure 3. Cacalohastine derivatives. O Me O OMe MeO OMe Me OMe 10 11 Figure 4. Naphtho[2,3-b]furan derivatives. O O O OMe MeO OH O OAc MeO O 12 13 14 O OH O HO O MeO O OH H Figure 5. Structures of naphthofuroquinones 12-14. O O OH O O O O OH O O OH 15 16 Figure 6. Structure of naphtho[2,3-d]furan-5,10-diones. Various natural naphthofuroquinones are present in Tabebuia Ochace [31,32]. Derivatives of naphthofuroquinones (12 and 13) exhibit higher inhibitory activity [33,34] and compound 14, which contains naphthofuran as one of the constituents [35,36] found in the Chinese medicinal plant Rubiacordifolia (Figure 5). 342 Abdelwahab and Fekry / European Journal of Chemistry 12 (3) (2021) 340-359 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.3.340-359.2126 Scheme 1. Synthesis of aminonaphthofuran derivatives. CHO OH HC OH N OH NH2-OH. HCl AcONa/ EtOH Ac2O OAc CN HCOOH OH CN 17 18 21 19 Scheme 2. Synthesis of 1-cyano-2-naphthol. Scheme 3. Synthesis of 3-aminonaphthofurans. During an investigation into potentially useful anticancer agents from the wood of Crescentia Cujete, Kingston and co- workers isolated a series of nine related furofuranonaphtho- quinone derivatives [37,38]. Of particular interest are two tetracyclic naphthoquinones, which were isolated as red pig- ments and assigned structures 3-hydroxy-methylfuro[3,2-b] naphtho[2,3-d]furan-5,10-dione (15) and 9-hydroxy-3-hyd roxymethylfuro[3,2-b]naphtho[2,3-d]furan-5,10-dione (16) on the basis of extensive spectroscopic analysis [39,40] (Figure 6). 2. Synthesis of naphthofurans 2.1. From 2-hydroxy-1- naphthaldehyde Conversion of 2-hydroxy-1-naphthaldehyde (17) [41-43] into its oxime (18) [44] followed by dehydration using acetic anhydride, to obtain 2-hydroxy-1-naphthonitrile (19) [44]. The compounds 18 and 19 on reaction with bromoacetone/ phenacyl bromide or ethyl bromoacetate in presence of K2CO3 produced 1-(1-aminonaphtho[2,1-b]furan-2-yl)ethan-1-one (20a) or (1-aminonaphtho[2,1-b]furan-2-yl)(phenyl)metha-none (20b) and 1-(1-aminonaphtho[2,1-b]furan-2-yl)propan-1-one (20c) (Scheme 1). Also, 2-hydroxynaphthalene-1-carbaldehyde (17) when allowed to react with hydroxylamine hydrochloride in the presence of fused sodium acetate yielded the corresponding oxime (18) which was acetylated using acetic anhydride to give 2-acetyloxynaphthalene-1-carbonitrile (21) [45]. Treatment of compound 21 with formic acid yielded 1-cyano-2-naphthol (19), Scheme 2. Alkylation of 1-cyano-2-naphthol (19) using different activated halogenated compounds, namely chloroacetonitrile, chloroacetone, phenacyl bromide and its derivatives in acetone and the presence of potassium carbonate, o-alkylated products (22-24) were produced, that underwent ring closure by sodium ethoxide to afford the corresponding naphthofurans 25-27 (Scheme 3). In addition, thus, treatment of 2-hydroxy-1-naph- thaldehyde (17) with chloroacetone in refluxing acetone in the presence of anhydrous potassium carbonate gave the 2- acetylnaphtho[2,1-b]furan (28) and ethyl naphtho-[2,1-b] furan-2-carboxylate (29) was prepared by treating 2-hydroxy- 1-naphthaldehyde (17) with ethyl chloroacetate in presence of potassium carbonate in dimethylformamide (Scheme 4). 2.2. From various substituted salicylaldehyde The preparation of novel 2-(1-benzofuran-2-yl)quinoline- 3-carboxylic acid derivatives (32), involving the in situ formation of ether by Williamson reaction between ethyl 2- (bromomethyl)quinoline-3-carboxylate (30) and various substituted salicylaldehyde (31) followed by the hydrolysis and Abdelwahab and Fekry / European Journal of Chemistry 12 (3) (2021) 340-359 343 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.3.340-359.2126 CHO OH O COCH3 K2CO3 Acetone17 ClCH2COCH3 O COOC2H5 28 ClCH2COOEt DMF 29 Scheme 4. Synthesis of 2-acetyl or ethyl carboxylate naphtho[2,1-b]furan. Scheme 5. Synthesis of 2-(1-benzofuran-2-yl)quinoline-3-carboxylic acid derivatives. OH K2CO3, Aceton, KI O Ph Heat N,N-DEA O Ph OH K2CO3, Aceton, KI O Ph Heat N,N-DEA O Ph Cl-CH2-CH=CH-C6H5 Cl-CH2-CH=CH-C6H5 33 34 35 36 37 38 Scheme 6. Synthesis of 3-phenyl naphthofurans. OH + RCHO + CO Pd(PPh3)4 O O R OH O OR CF3COOH 33 34 39X X X = H, OCH3 + RCHO + CO Pd(PPh3)4 CF3COOH 40 Scheme 7. Synthesis of alkyl naphthofuran-2(3H)-one. intramolecular cyclization reactions. This novel procedure provides quick and easy access to the incorporation of the benzo[b]furan core to the quinoline nucleus at 2-position (Scheme 5) [46]. 2.3. From 1-naphthol or 2-naphthol Treatment of 1-naphthol or 2-naphthol (33 and 34) with alkenyl or propargyl halide gave the corresponding naphthyl ether 35 and 36 by the known methods [47,48], heating in N,N- diethyl aniline afforded naphthofurans 37 and 38 (Scheme 6). The present three-components reaction may involve the initial nucleophilic addition of naphthol (33 and 34) to aldehyde, which may be promoted by CF3COOH in C6H6 (5 mL) under CO (5 atm) at 120 °C for 18 h to give naphthofuran-2(3H)- one (39 and 40) (Scheme 7) [49]. 2.4. From 5-hydroxy-1,4-naphthoquinone 5-Hydroxy-1,4-naphthoquinone (41) was reacted with ethyl-N,N-dimethyaminocrylate (42), which afforded novel diethyl-7-hydroxynaphtho[1, 2-b:4, 3-b`]difuran-3,4-dicarboxy late (43). Hydrolysis of compound 43 of lead to formation of two novel derivatives viz. 4-ethoxycarbonyl-7-hydroxynaph- tho[1, 2-b:4, 3-b`]difuran-3-carboxylic acid (44) and 7-hydroxy naphtho[1, 2-b:4, 3-b`]difuran-3,4-dicarboxylic (45) due to partial and complete hydrolysis of both the ester (Scheme 8) [50]. 2.5. From 2-styrylfuran Loader and Timmons [51] synthesized naphtho[2,1-b]furan (47) by photo cyclodehydrogenation of 2-styrylfuran in pure form 46 (Scheme 9). 344 Abdelwahab and Fekry / European Journal of Chemistry 12 (3) (2021) 340-359 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.3.340-359.2126 OH O O + N OC2H5 O O O COOC2H5 COOC2H5 OH CH3COOH RT, 12 h O O COOH COOH OH O O COOC2H5 COOH OH + 25% aq. NaOH C2H5OH, Reflux, 8h 41 42 43 44 45 Scheme 8. Synthesis of naphtho[1,2-b:4,3-b`]difurans. O O hv 46 47 Scheme 9. Synthesis of naphtho[2,1-b]furan. Scheme 10. Condensation of 2-acetylnaphtho[2,1-b]furan. 3. Reaction of naphtha[2,1-b]furan Condensation of 2-acetylnaphtho[2,1-b]furan (28) [52] with malononitrile in boiling benzene containing ammonium acetate and acetic acid afforded 2-(2,2-dicyano-1-methyl vinyl) naphtho[2,1-b]furan (48) In contrast to the anticipated forma- tion of pyrazoline derivatives 49, the reaction of compound 28 with phenyl hydrazine in boiling ethanol gave the imino compound 50 and is assumed to proceed via elimination of malononitrile (Scheme 10). Interaction of compound 48 with sulfur via Gewald reaction [53] produced 2-(5-amino-4-cyano-3-thienyl)naphtho[2,1-b] furan (51) while with benzene diazonium chloride afforded the open-chain product 52a instead of the closed product 2,3- dihydro-3-imino-5-(naphtho[2, 1-b]furan-2-yl)-2-phenylhyd- razine-4-carbonitrile (52c). Treatment of compound 51 with triethyl orthoformate in acetic anhydride at reflux afforded the N-acetylamino derivative 53 instead of the 2-(5-ethoxy methyleneamino-4-cyano-3-thienyl)naphtho[2,1-b]furan (54) [52], while with formic acid gave the N-formyl amino derivative 55 instead of the pyrimidine derivative 56 (Scheme 11). Interaction of compound 48 with various substituted α- cyanocinnamonitriles (57a-f) in boiling ethanol containing a few drops of piperidine, afforded 2-(3-amino-2,4-dicyano-5- arylphenyl)naphtho[2,1-b]furan (60a-c) (Scheme 12). The formation of compound 60 from the reaction of compounds 48 and 60a-c is assumed to proceed via a Michael type addition of the methyl function in compound 28 to the activated double bond to yield a cyclic Michael adduct 58a which then cyclizes into compound 59a. The latter readily loses HCN to yield the final isolable thermodynamically stable compounds (60a-c) (Scheme 12). In contrast to the anticipated formation of the esters 61, the reaction of compound 34 with various substi- tuted ethyl α-cyanocinnamates (59d-f), afforded compounds 60a-c and are assumed to proceed via elimination of ethyl formate from the intermediate (60b) [52] (Scheme 12). Thus, chalcone 62 was prepared by condensation of compound 28 with p-anisaldehyde in the presence of dry HCl gas in ethanol, while bromination of compound 62 afforded 3- [(3-bromo-4-methoxyphenyl)naphtho[2, 1-b]furan-2-yl]prop- 2-en-1-one (63) (Scheme 13). The bromine was introduced in the active aryl moiety rather than the α, β-unsaturated double bond. Treatment of the chalcone 63 with hydrazine hydrate and phenyl hydrazine in refluxing ethanol afforded 5-(4-methoxy phenyl)-3-(naphtho[2, 1-b]furan-2-yl)-4, 5-di-hydro-1H-pyra- zole (64a) and 5-(4-methoxyphenyl)-3-(naphtho[2,1-b]furan- 2-yl)-1-phenyl-4,5-dihydro-1H-pyrazole (64b), respectively (Scheme 12), while with thiourea or cyanothioacetamide gave 4-(4-methoxyphenyl)-6-(naphtho[2, 1-b]furan-2-yl)pyramidi- ne-2(1H)-thione (65) and 1,2-dihydro-4-(4-methoxyphenyl)-6- (naphtho[2, 1-b]furan-2-yl)-2-thioxopyridine-3-carbonitrile (66), respectively (Scheme 13) [52]. Abdelwahab and Fekry / European Journal of Chemistry 12 (3) (2021) 340-359 345 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.3.340-359.2126 48 H2SPhN2Cl 51 H N N Ph CN NC CH(OEt)3 54 S N CN OEt 53 52b 52a N N Ph CN NC N N H Ph CN NC N N PhNC NH 52c HCO2H S N 56 NH O 55 O S N O OH S N H CHOO S NH2 CN O O O S NHCOMe CN O O O O Scheme 11. Reaction of 2-acetylnaphtho[2,1-b]furan with sulfur via Gewald reaction, benzene diazonium chloride, and triethyl orthoformate. Scheme 12. Reaction of 2-acetylnaphtho[2,1-b]furan with various substituted α-cyanocinnamonitriles. 346 Abdelwahab and Fekry / European Journal of Chemistry 12 (3) (2021) 340-359 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.3.340-359.2126 Scheme 13. Synthesis of naphtho[2,1-b]furan-2-yl)-pyrazole and naphtho[2,1-b]furan-2-yl)-thioxopyridine. Scheme 14. Condensation reaction of 2-acetylnaphtho[2,1-b]furan. Condensation of 2-acetylnaphtho[2,1-b]furan (28) [52] with phenylhydrazine afforded 2-(1-phenylhydrazonoethyl) naphtho[2,1-b]furan (50). Vilsmeier formylation of the latter afforded 3-(naphtho-[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazole- 4-carboxaldehyde (67) [54]. Condensation of compound 67 with C-nucleophiles, namely, malononitrile, cyanoacetamide, cyanothioacetamide, barbaturic acid and 2-acetylnaphtho[2,1- b]furan (28) give the condensation products 68, 69 and 70 while with N-nucleophiles namely; hydrazine derivatives or amines afforded the condensation products 71 and 72 (Scheme 14) [55]. Compounds 68a and 70d were used as key intermediates in the synthesis of pyran, pyrazole, and thiazole derivatives via their interaction with different reagents. Thus, the reaction of compound 68a with 3-methyl-1-phenyl-2-pyrazolin-5-one in the presence of triethylamine did not give the expected pyrazolopyran 73. Instead, only one compound was isolated, which was identified as 4-[3-(naphtho[2,1-b]furan-2-yl)-1- phenyl-1H-pyrazol-4-yl]methylene-3-methyl-1-phenyl-2-pyra zoline-5-one (74). Condensation of compound 67 with methyl- 1-phenyl-2-pyrazolin-5-one in the presence of triethylamine to give compound 74 (Scheme 15) [55]. Abdelwahab and Fekry / European Journal of Chemistry 12 (3) (2021) 340-359 347 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.3.340-359.2126 N N Ph CN CN O 68a N N O Ph EtOH/ Et3N, reflux N N Ph O 73 N N Ph O O N N Ph NC H2N N NO Ph74 N N CHO Ph O 67 N N O Ph EtOH/ Et3N, reflux N N O Ph EtOH/ Et3N, reflux Scheme 15. Synthesis of naphthofuranopyrazole derivatives. N N Ph CN CN O 68a EtOH/ Et3N, reflux N N Ph O 75 N NPh O O EtO2C CN NH2 N NOHC Ph O 67 EtOH/ Pip., reflux CH3COCH2COOC2H5 O OH O O O O O OH O CH2(CN)2 76 Scheme 16. Synthesis of pyrazolo pyran derivatives. Scheme 17. Synthesis of 1-((3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl)methylene)hydrazone. The reaction of compound 68a with ethyl acetoacetate in dry methylene chloride containing triethylamine gave the pyrazolopyran derivative 75, while with 4-hydroxycoumarin under Michael reaction conditions afforded the 4H-pyran derivative 76. Structure 76 was further confirmed by independent synthesis via direct condensation of compound 67 348 Abdelwahab and Fekry / European Journal of Chemistry 12 (3) (2021) 340-359 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.3.340-359.2126 Scheme 18. Synthesis of thiazolidinone, thiazoline, and thiadiazole derivatives. Scheme 19. Synthesis of thiosemicarbazone, thiazole and arylidene derivatives. with 4-hydroxycoumarin in the presence of malononitrile and drops of piperidine as a base (one-pot reaction) (Scheme 16) [55]. The reaction of compound 68a with hydrazine hydrate in refluxing ethanol afforded 1-((3-(naphtho[2,1-b]furan-2-yl)-1- phenyl-1H-pyrazol-4-yl)methylene)hydrazone 77 instead of the pyrazole derivative 78. The same product was prepared by condensation of compound 67 with hydrazine hydrate (Scheme 17). When thiosemicarbazone derivative 70d was allowed to react with ethyl bromoacetate or chloroacetone in the presence of fused sodium acetate, gave the corresponding thiazolidinone and thiazoline derivatives 79 and 80, respectively, while with acetic anhydride by reflux afforded the thiadiazole derivative 81 (Scheme 18) [55]. Abdelwahab and Fekry / European Journal of Chemistry 12 (3) (2021) 340-359 349 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.3.340-359.2126 Scheme 20. Synthesis of acetohydrazide, chromene, and pyridine derivatives. O COOEt O COOEt O COOEt BrO2N Br2 AcOH HNO3 H2SO4 29 9495 Scheme 21. Bromination and nitration of naphthofuran. Condensation of 2-acetylnaphtho[2,1-b]furan (28) with thiosemicarbazide or thiocarbohydrazide (82a,b) afforded the thiosemicarbazone or thiocarbohydrazone 83a,b, respectively. The thiosemicarbazone 83a was used as a key intermediate in the synthesis of the desired thiazoles via their interaction with different α-halo carbonyl derivatives. Thus, the reaction of compound 83a with phenacyl bromide and/or chloroacetone in refluxing ethanol in the presence of sodium acetate afforded the thiazole derivatives (84a,b), respectively, while with ethyl bromoacetate afforded thiazolidin-4-one (85). Condensation of thiazolidin-4-one (85) with p-methoxybenzaldehyde and/or p- chlorobenzaldehyde in ethanol containing piperidine as a base gave arylidene derivatives (86a,b), respectively (Scheme 19) [55]. Condensation of compound 28 with cyanoacetohydrazide (87) afforded 2-cyano-N-[1-(naphtho[2,1-b]furan-2-yl)ethyli dene]acetohydrazide (88). Interaction of compound 88 with salicyaldehyde or 2-hydroxy-1-naphthaldehyde afforded the chromene derivatives 89 and 90, while with acetylacetone gave the pyridine derivative 92. Condensation of compound 89 with p-methoxy benzaldehyde afforded the arylidene derivatives 92. Reaction of arylidene 92 with malononitrile afforded the pyranone derivative 93. The structure 93 was further confir- med by independent synthesis via direct condensation of compound 88 with p-methoxy α-cyano-cinnamonitrile in refluxing ethanol/piperidine (Scheme 20) [56]. Bromination of compound 29 to give ethyl 5-bromo- naphtho[2,1-b]furan-2-carboxylate (94) and nitration of compound 26 afforded 5-nitronaphtho[2,1-b]furan-2-carboxy- late (95) (Scheme 21) [57]. These esters (29, 94, and 95) were hydrolyzed in an alkaline medium to obtain their respective carboxylic acids (96). The resulting carboxylic acids were then warmed with 4- substituted aromatic amines, employing phosphorus oxychlo- ride on a water bath maintained at 40-45 °C to yield 5-substi- tuted-nahtho[2,1-b] furanoy1-4- substituted aromatic amines (97) (Scheme 22) [57]. Ethyl 3-aminonaphtho[2,1-b]furan-2-carboxylate 26 was reacted with formamide to afford naphtho[1',2':4,5]furo[3,2-d] pyrimidin-4(3H)-one (98) [58]. Later, the compound was obtai- ned by an alternative route through the condensation of 3- aminonaphtho[2,1-b]furan-2-carboxamide (27) with triethyl orthoformate in the presence of catalytic amount of acetic acid (Scheme 23). Compound 98 can be converted into 4-chloropyrimidine derivative (99) by refluxing with phosphorus oxychloride. Naphtho[1',2':4,5]furo[3,2-d]pyrimidin-4(3H)-thione (100) was prepared by two methods, either by thionation of compound 98 using phosphorus pentasulfide in pyridine or by the reaction of chloropyrimidine derivative 100 with thiourea in ethanol. 350 Abdelwahab and Fekry / European Journal of Chemistry 12 (3) (2021) 340-359 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.3.340-359.2126 O COOEt R R= H, Br, NO2 O COOH R R= H, Br, NO2 1) H2O, OH 2) H R`H2N O CONH R R= H, Br, NO2 R` R` = H, CH3 POCl3, Heat, 1 h 60-70 oC 29, 94, 95 96 97 Scheme 22. Synthesis of nahtho[2,1-b] furanoy1-4-substituted aromatic amines. O NH2 COOEt O NH2 CONH2 O NH N O CH(OEt)3 HCONH2 26 98 27 Scheme 23. Synthesis of naphtho[1',2':4,5]furo[3,2-d] pyrimidin-4(3H)-one. Scheme 24. Synthesis of naphtho[1',2':4,5]furo[3,2-d]pyrimidine derivatives. Scheme 25. Synthesis of naphthofuroriazolopyrimidine and pyrazolylnapthofuropyrimidine. The produced naphthofuropyrimidinthione was S-alkyla- ted using different halo compounds in ethanol in the presence of sodium acetate to afford S-alkylated derivative 101. Reaction of compounds 99 and 100 with hydrazine hydrate to give 8- hydrazineylnaphtho[1', 2':4, 5]furo[3, 2-d]pyrimidine 102 (Scheme 24). 4-Hydrazinonaphthofuropyrimidine (102) was used as a versatile precursor to synthesis other heterocyclic compounds. It reacts with CS2/Pyridine or triethyl orthoformate in the presence of catalytic drops of acetic acid to afford naphtho [1', 2':4, 5]furo[2, 3-e][1, 2, 4]triazolo[4, 3-c]pyrimidine-3(2H)- thione (103) and naphthofurotriazolopyrimidine 104. On the other hand, when compound 102 was allowed to react with acetylacetone in ethanol, pyrazolylnapthofuropyrimidine 105 was produced (Scheme 25). Thus, treatment of ethyl 3-aminonaphtho[2,1-b]furan-2- carboxylate (26) [59] with carbon disulphide and aqueous sodium hydroxide in dimethyl sulphoxide yielded a naphtho [2,1-b]furan-2-carboxylate (106) as a salt, which (without isolating) was then methylated with dimethyl sulphate to afford naphtho[2,1-b]furan-2-carboxylate (107). Compound 107 on reaction with hydrazine hydrate yielded the desired 3-amino- 2-mercaptonaphthofuro[3,2-d]pyrimidin-4(3H)-one (108) [60- 63] in excellent yield (Scheme 26). Abdelwahab and Fekry / European Journal of Chemistry 12 (3) (2021) 340-359 351 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.3.340-359.2126 Scheme 26. Synthesis of 3-amino-2-mercaptonaphthofuro[3,2-d]pyrimidin-4(3H)-one. O N N HS O H2N ON N O N S RNCS N H R ON N O N S R1 R1COOH POCl3R1 a) C6H5 b) 4-NO2-C6H4 c) 4-Cl-C6H4 d) 4-NH2-C6H4 R a) C6H5 b) 3-Cl-C6H4 c) 4-Cl-C6H4 d) 3-OCH3-C6H4 e) 4-OCH3-C6H4 f) 4-CH3-C6H4 g) 3-NO2-C6H4 h) 4-NO2-C6H4 108 109a-h 100a-d Scheme 27. Synthesis of 2-arylaminonaphthofurothiadiazolopyrimidin-5-ones. Scheme 28. Naphtho[2,1-b]furan-2-yl-pyrimidine-5-carboxylate. Compound 108 on reaction with various aryl isothio- cyanates yielded 2-arylaminonaphtho[2,1-b]furo-5H-[3, 2-d][1, 3, 4]thiadiazolo[3, 2-a]pyrimidin-5-ones (109a-h). Thus, reaction of compound 108, having similar functionality, on treatment with different aromatic acids in phosphrusoxy chloride led to the formation of 2-aryl naphtho[2, 1-b]furo-5H- [3, 2-d][1, 3, 4]thiadiazolo[3,2-a]pyrimidin-5-ones (100a-d) (Scheme 27). Reduction of compound 29 [64] with lithium aluminum hydride in tetrahydrofuran gave the corresponding reduction product alcohol (111) and, further the obtained compound 111 was oxidized with 2-iodoxybenzoic acid (IBX) in ethyl acetate 352 Abdelwahab and Fekry / European Journal of Chemistry 12 (3) (2021) 340-359 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.3.340-359.2126 Scheme 29. Synthesis of naphthofurobenzotriazepine. Scheme 30. Synthesis of azetidine-1-yl-naphth [2,1-b]furan-2-carboxamides. to get naphthofuran-2-carbaldehyde (112). Finally, compound 112 was subjected to bromination and nitration reaction to get compounds 113a-b. Finally, compounds 112 and 113a-b underwent acid catalyzed three-component condensation reaction with ethyl acetoacetate and urea/thiourea to give corresponding condensation products (114a-d) (Scheme 28). The compound 29 was made to react with hydrazine hydrate at an acidic condition in ethanol under microwave produce naphtho[2,1-b]furan2-carbohydrazide (115) [62,65]. To prepare N'-(2-aminobenzylidene)naphtho[2,1-b]furan-2- carbohydrazides (117a-l), the compound 115 was treated with substituted 2-aminobenzaldehyde (116a-l) in presence of the catalytic amount of acetic acid in ethanol under microwave irradiation. Reaction of compound 117a-l with triethyl ortho formate and was irradiated in a microwave oven afforded benzotriazepine (118a-l) (Scheme 29). Nitration of compound 29 [66] afforded ethyl 3-nitro naphtho[2,1-b]furan-2-carboxylate (119) and reaction of compound 119, with hydrazine hydrate to give 3-nitro- naphtho[2,1-b]furan-2-carbohydrazide (120). The carbohyd- razide 120 was treated with various substituted aromatic aldehydes in refluxing ethanol to obtain the corresponding Schiff’s base, 3-nitro-N'(aryl-methylene)-substituted-naphtho [2, 1-b]furan-2-carbohydrazides (121a-g) in good yield. Synthesis of 3-nitro-N-(3-chloro-2-oxo-substituted-phenyl- azetidine-1-yl)naphtho[2,1-b]furan-2-carboxamides (122a-g) was accomplished by the reaction between 3-nitro-N´(aryl- methylene)-substituted-naphtho[2,1-b]furan-2-carbohydrazi- des (121a-g) with chloroacetyl chloride in presence of triethyl amine in dioxane (Scheme 30). Nitration of 3’,5’-dinitrobenzoyl-3-nitronaphtho[2,1-b] furan (123) [67]. The reaction of compound 124 with hydra- zine hydrate in ethanol was straightforward and produced corresponding hydrazone (125), with excellent yield. However, in this case, the reaction of 2-(3’,5’-dinitrobenzoyl)-3-nitro- naphtho[2,1-b]furanhydrazone (125) with various aldehydes at reflux temperature in ethanol, in the presence of acid to give Schiff’s base (126a-g) (Scheme 31). The compound 28 [68] was converted into 2- bromo- acetylnaphtho[2,1-b]furan (127) by bromination in the presence of acetic acid at 20 °C, which served as an excellent intermediate for the synthesis of various naphtho[2,1-b]furan derivatives. The compound 128 was refluxed with thiourea and the product obtained was identified as 2-(2-aminothiazol-4- yl)naphtho[2,1-b]furan (129), based on spectral studies. The compound 129 was made to undergo condensation with various aromatic aldehydes to obtain the corresponding Schiff bases, 2-(2-arylideneaminothiazol-4-yl)naphtho[2, 1-b]furans (130a-j). On refluxing Schiff bases (130a-j), with thioglycolic acid in dimethyl formamide in the presence of a catalytic amount of anhydrous zinc chloride, cyclo-condensation occurred very smoothly and resulted in the formation of new Abdelwahab and Fekry / European Journal of Chemistry 12 (3) (2021) 340-359 353 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.3.340-359.2126 Scheme 31. Synthesis of Schiff’s base. Scheme 32. Thiazol-4-ylnaphtho[2,1-b]furan derivatives. tri-heterocyclic compounds, 2-[2-(2-aryl-4-thiazolidinono) thiazol-4-yl]naphtho[2,1-b]furans (131a-i). The compound 127 on reaction with various aromatic amines in ethanol produced 2-(N-aryl-2-amino)acetylnaphtho[2,1-b]furans (131a- k). Various substituted thiourea were prepared by the reaction between potassium thiocyanate and appropriate amines, these substituted thiourea on refluxing with compound (127), produced 2-(2-N-arylaminothiazol-4-yl)naphtho[2,1-b]furans (132a-k) in good yield (Scheme 32). Reduction of compound 27 [69] by lithium aluminum hydride in THF was added slowly with continuous stirring at 0 °C. Stirring was continued for 2 hrs afforded naphtho[2,1- b]furan-2-ylmethanol (111), and the Dess-Martin oxidation of compound 111 to corresponding 3-substituted-naphthofuran- 2-carboxaldehyde (112). condensation of compound 112 with substituted acetophenones (133) in the presence of sodium hydroxide afforded aryl-3-[(3-substituted)-2-naphthofuryl]-2- propen-1-ones (134a-f). Compounds 134a-f were then treated with hydrazine hydrate to afford 3-substituted aryl-5-(3- substituted-2-naphthofuryl)-2-pyrazolines(135a-f) (Scheme 33). 1-Substituted-naphtho[2,1-b]furan-2-carbohydrazide [70] 115a-c were cyclized with carbon disulfide in presence of potassium hydroxide to get mercaptoxadiazoles 136a-c which were then stirred with ethyl iodide to obtain 2-(ethylsulfanyl)- 5-(1-substitutednaphtho[2, 1-b]furan-2-yl)-1, 3, 4-oxadiazoles (137a-c). Compounds 137a-c were refluxed with different substituted piperazines like N-methylpiperazine, N-benzyl- piperazine, and N-phenylpiperazine to afford 1-methyl-4-[5-(1- substituted-naphtho[2, 1-b]furan-2-yl)-1, 3, 4-oxadiazol-2-yl] piperazines (138a-c), 1-benzyl-4-(5-(1-substitutednaphtho [2,1-b]furan-2-yl)-1,3,4-oxadiazole-2-yl)piperazines (139a-c) and 1-(5-(1-substituted-naphtho[2,1-b]furan-2-yl)-1,3,4-oxa diazol-2-yl)-4-phenylpiperazines (140a-c), respectively (Scheme 34). It was observed that naphtho[2,1-b]furan-2-carbohyd- razide (115) [71], on condensation with aromatic aldehydes, yields N-arylidene-naphtho[2,1-b]furan-2-carbohydrazide (141a- i). N-arylidene-naphtho[2,1-b]furan-2-carbohydrazide (141a- i) in THF and thioglycolic acid with a pinch of anhydrous ZnCl2 was refluxed for 11-12 hrs to give N-(4-oxo-2-arylthiazolidin-3- yl)naphtho[2,1-b]furan-2-carboxamide (142a-i) (Scheme 35). 354 Abdelwahab and Fekry / European Journal of Chemistry 12 (3) (2021) 340-359 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.3.340-359.2126 Scheme 33. Synthesis of 2-naphthofuryl pyrazolines. O NHNH2 O O R CS2 KOH O NN SH O O NN SC2H5 C2H5I K2CHO3 O O NN SC2H5 O O NN S N N O O NN S N N O O NN S N N N N H C6H5 CH2C6H5 N N HC6H5 N N H R R R R R R R a) H b) OCH3 c) NH2 115a-c 136a-c 137a-c 137a-c 138a-c 139a-c 140a-c Scheme 34. Synthesis of naphtho[2,1-b]furan-2-yl-oxadiazol derivatives. Scheme 35. Synthesis of naphtho[2,1-b]furan-2-carboxamide derivatives. Reaction of 2-acetylnaphtho[2,1-b]furan (28) with various substituted aromatic aldehydes in the presence of aq. KOH in ethanol to give substituted Chalcones (143). These chalcones on reaction with 2-[(quinoline-8-yl)oxy]acetohydrazide (144) [72] in presence of glacial acetic acid gave the naphtho[2,1- b]furo-2-y1)pyrazol-1-y1)-2-(quinolin-8-yloxy)ethanone derivatives (145) (Scheme 36). 4. Biologically active naphthofurans Naphthofurans fused or coupled with oxygen and nitrogen heterocycles do not occur in nature. Even synthetic naphtho- furans coupled or fused with oxygen and nitrogen heterocycle are not reported so far, except for some reports of such compounds from this literature method [73-78]. Abdelwahab and Fekry / European Journal of Chemistry 12 (3) (2021) 340-359 355 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.3.340-359.2126 O O + Ar-CHO O O Ar N OCH2CONHNH2 O N N Ar O N O aq. KOH EtOH Ar = C6H5, p-OCH3-C6H4, p-OH-C6H4, p-Cl-C6H4 28 143 144 145 Scheme 36. Synthesis of chalcones and naphtho[2,1-b]furo-2y1pyrazol. O O N 146 Figure 7. Structure 2-phenyl-3-p-(β-pyrrolidinoethoxy)-phenyl [2,1-b] naphthofuran. O NO2 O 147 148 O NO2 O Figure 8. Structure of 2-nitronaphtho[2,1-b]furans. O N O Ar O N NR Ar O NH O N Ar H O 149 150 151 Figure 9. Naphtho[2,1-b]furans exhibit antimicrobial and fungi. These observations prompted us to undertake the investi- gation of naphthofuran with oxadiazole and indole as second heterocyclic components. Some of the derivatives of naphtho- furans which show biological and pharmacological activities are given below the biologic properties of a new oral antifertility agent, 2-phenyl-3-p-(β-pyrrolidinoethoxy)-phenyl [2,1-b]naphthofuran (146) (Figure 7) [79] have been investi- gated in detail on rodent species and rhesus monkeys the rhesus macaque (Macaca mulatta) is native throughout Asia and is considered to have the largest native range of any non-human primate by Kamboj et al. [80]. The influence of the uvr gene-dependent excision repair system on the lethal action, mutagenic specificity. The Save Our Souls (SOS) response inhibits septum formation until bacterial DNA can be repaired and is observable as filamentation when cells are examined by microscopy and DNA adducts formation of 7-methoxy-2-nitronaphtho[2,1-b]furan (147) and 2-nitro-8- methoxynaphtho[2, 1-b]furan (148) (R6998) (Figure 8), a potent genotoxic nitrofuran, were examined on Escherichia coli by Touati et al. [81]. Vagdevi et al. [82] and co-workers have reported that the derivatives of naphtho[2, 1-b] furan (149-151) (Figure 9) exhibit antimicrobial activity against Staphylococcus aureus, Klebsiella pneumoniae and fungi Aspergillus niger. Lee et al. [83] and Bor-Ruey Huang, reported the tricyclic naphtho[2, 1-b]furan derivatives (152) and these compounds exhibit a unique cytotoxicity profile (Figure 10). They are highly cytostatic for leukemia cancer cells but are not cytocidal. However, they are both cytostatic and cytocidal for almost all the solid tumors tested. 356 Abdelwahab and Fekry / European Journal of Chemistry 12 (3) (2021) 340-359 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.3.340-359.2126 O R CH2CONHCHR`-COOCH3 R = H, OH, OCH3 R` = CH3, CH2Ph, CH(CH3)2 152 Figure 10. Structure of naphtho[2,1-b]furan derivatives. O N H N RHOOC N Cl NH R = R = R = N Cl H2N N Cl NH N O R = H 153 Figure 11. Naphtho[2,1-b]furan-carboxylates. ORHN HN COOCH3 HCl OHN HN COOCH2CH3 HCl H N NH HCl 154 155 Figure 12. Naphthofurans are inhibition of tumor cell growth in vitro. O HN NH NH O S R = Cl, Br 156 R Figure 13. Structure of 2-(naphtho[2,1-b]furan-2-carbonyl)-N-phenylhydrazine-1-carbothioamide derivatives. O OCH3H3CO H3CO 157 Figure 14. Structure of 1-(3’,4’,5’-trimethoxy)phenylnaphtho[2,1-b]furan. Hranjec et al. [84], reported substituted naphtho[2,1- b]furan compounds (153) were tested for cytostatic activities against malignant cell lines like, pancreatic carcinoma (MiaPaCa2), breast carcinoma (MCF7), cervical carcinoma (HeLa), laryngeal carcinoma (Hep2), colon carcinoma (HT 29), melanoma (HBL), and human fibroblasts cell line (WI38). All compounds inhibited the proliferation of tumor cell lines (Figure 11). Starcevic et al. [85], report details about their synthesis of naphthofurans (154,155) characterization in respect to their potential of photoinduced cyclization, interactions with DNA, and inhibition of tumor cell growth in vitro (Figure 12). Naphtho[2,1-b]furans and their complexes (156) have been screened for their fungicidal and bactericidal activities [86]. Complex was derived from reaction between naphthofuran-2- carboxyhydrazide and p-chlorophenylisothiocynate (NCClPT)/ p-bromophenylisothiocynate (NCBrPT) (Figure 13). Srivastava et al. [87] reported 1-(3’,4’,5’-trimethoxy)phenyl naphtho[2,1-b]furan (Figure 14) and other derivatives as a novel anticancer agent an anti-cancer agent. Base catalyzed intramolecular condensation of 3’,4’,5’-trimethoxybenzoyl- naphthalene 2-o-acetic acid yield exclusively 1-(3`,4’,5’-tri- methoxy)phenylnaphtho[2,l-b]furan (157) and reported the compounds (157) that showed significant anticancer activity Abdelwahab and Fekry / European Journal of Chemistry 12 (3) (2021) 340-359 357 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.3.340-359.2126 O O N N N OH CH3 CH3 H Cu ClCl O N N NHO H3C H3C H O 158 Figure 15. Naphthofuran-2-carbohydrazide O NH N X NH2 X = S, O O N X NH2 159 160 Figure 16. Naphthofurans are antimicrobial, and anthelmintic, analgesic and anti-inflammatory. O R R` N N H ``R a) R= H, R`= COOCH3 , R``=i-pr-amidine b) R= CN, R`= COOC2H5, R``=i-pr-amidine 161 Figure 17. Structure of naphthofurans are antitumor activity. O O HO 162 Figure 18. Structure bis(naphtho[2,1-b]furan-2-yl)methanol. O OH OCH3 HO 163 Figure 19. Structure of 4-methoxydinaphtho[1,2-b:1',2'-d]furan-5,8-diol. against human cancer cell lines COLO320DM (colon), CaCo2 (colon) and WRL68 (liver) in the in-vitro MTT assay. Sumathi et al. [88], reported the compounds (158) (Figure 15) screened for their antibacterial and antifungal activities against Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans exhibited significant activity. Mahadevan et al. [89], reported the synthesized compounds (159, 160) (Figure 16) which are screened for antimicrobial against S. aureus, K. pneumoniae, A. niger, and anthelmintic, analgesic and anti-inflammatory and exhibited significant activity. Hranjec et al. [90], the tested synthesized compounds (161) (Figure 17) show very differential and strong antitumor activity without apparent difference depending on their structures. Kirilmis et al. [86], tested synthesized compounds (162) (Figure 18) were tested for anti-microbial activity against S. typhimurium, E. coli, B. subtilis, C. Globrata and C. Tropicalis. All of the selected compounds showed weak antimicrobial activity against microorganisms. Xylarianaphthol-1, a novel dinaphthofuran derivative (163) (Figure 19), was isolated from a marine sponge-derived fungus of order Xylariales on the guidance of a bioassay using transfected human osteosarcoma MG63 cells (MG63luc+) [91]. 358 Abdelwahab and Fekry / European Journal of Chemistry 12 (3) (2021) 340-359 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.3.340-359.2126 O OH O O OH Me O COOMe OH 164 Figure 20. Structure of rubicordifolin. The biomimetic (164) synthesis and full structural elucidation of rubicordifolin (Figure 20), a cytotoxic natural product isolated from Rubia cordifolia [36], was described. 5. Conclusion In this review, a wide range of synthetic strategies of naphthofurans as an important class of arene ring-fused furans has been discussed. We started with chemical and photo- chemical for the synthesis of naphthofurans, followed by presenting of their diverse biological and pharmacological activities. In general, of 2-hydroxy-1-naphthaldehyde plays an important role and works well in construction of naphtho- furans. Moreover, different types of reactions of naphthols and various substituted salicylaldehyde and etc. were demonstra- ted for synthesis of naphthofurans. We explained in this report that naphthofurans are based on the construction of new heterocyclic compounds that are used in the medical field. ORCID Ashraf Hassan Fekry Abdelwahab https://orcid.org/0000-0001-9400-9396 Salma Ashraf Hassan Fekry https://orcid.org/0000-0002-8199-9885 References [1]. Vagdevi, H. M.; Latha, K. P.; Vaidya, V. P.; Vijaya Kumar, M. L.; Pai, K. S. R. Indian J. Pharm. 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This is an open access article distributed under the terms and conditions of the CC BY NC License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited without any further permission from Atlanta Publishing House LLC (European Journal of Chemistry). No use, distribution or reproduction is permitted which does not comply with these terms. Permissions for commercial use of this work beyond the scope of the License (http://www.eurjchem.com/index.php/eurjchem/pages/view/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry). http://www.eurjchem.com/index.php/eurjchem/pages/view/terms http://creativecommons.org/licenses/by-nc/4.0 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms 1. Introduction 2. Synthesis of naphthofurans 2.1. From 2-hydroxy-1- naphthaldehyde 2.2. From various substituted salicylaldehyde 2.3. From 1-naphthol or 2-naphthol 2.4. From 5-hydroxy-1,4-naphthoquinone 2.5. From 2-styrylfuran 3. Reaction of naphtha[2,1-b]furan 4. Biologically active naphthofurans 5. Conclusion ORCID References PrintField10: PrintField11: PrintField12: PrintField13: PrintField14: PrintField15: PrintField16: PrintField17: PrintField18: PrintField19: PrintField110: PrintField111: PrintField112: PrintField113: PrintField114: PrintField115: PrintField116: PrintField117: PrintField118: PrintField119: PrintField20: PrintField21: PrintField22: PrintField23: PrintField24: PrintField25: PrintField26: PrintField27: PrintField28: PrintField29: PrintField210: PrintField211: PrintField212: PrintField213: PrintField214: PrintField215: PrintField216: PrintField217: PrintField218: PrintField219: