untitled European Journal of Chemistry 4 (4) (2013) 467‐483 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2013 EURJCHEM DOI:10.5155/eurjchem.4.4.467‐483.775 European Journal of Chemistry Journal homepage: www.eurjchem.com The chemical reactivity of naphthols and their derivatives toward α‐cyanocinnamonitriles and ethyl α‐cyanocinnamates: A review of synthesis, reactions and applications of naphthopyrano derivatives Ashraf Hassan Fekry Abd El‐Wahab a,b,*, Hany Mostafa Mohamed b,c, Ahmed Mohamed El‐Agrody b and Ahmed Hammam Bedair b a Chemistry Department, Faculty of Science, Jazan University, 2097, Jazan, Saudi Arabia b Chemistry Department, Faculty of Science, Al‐Azhar University, 11884, Nasr City, Cairo, Egypt c Chemistry Department, Faculty of Medicine, Jazan University, 82621, Jazan, Saudi Arabia *Corresponding author at: Chemistry Department, Faculty of Science, Jazan University, 2097, Jazan, Saudi Arabia. Tel.: +2.0100.8199893; fax: +2.02.22629358. E‐mail address: ash_abdelwahab@yahoo.com (A.H.F.A. El‐Wahab). REVIEW INFORMATION ABSTRACT Received: 18 March 2013 Received in revised form: 17 April 2013 Accepted: 23 April 2013 Online: 31 December 2013 KEYWORDS This review deals with synthesis and reactions of some naphthopyrano derivatives and their applications. The main purpose of this review is to present a survey of literatures on the reactivity of naphthols and their derivatives toward α‐cyanocinnamonitrile or ethyl α‐ cyanocinnamate derivatives and the reactions of β‐enaminonitriles and β‐enaminoesters with different electrophiles followed by nucleophilic reagents. Some of these reactions have been applied successfully to the synthesis of biologically important compounds. Naphthols Naphthopyran Nucleophilic reagents α‐Cyanocinnamonitrile Naphthopyranopyrimidine Naphthopyranotriazolopyrimidine 1. Introduction Naturally occurring naphthopyrans have a variety of interesting biological activities and physiological properties [1,2]. Among these, mollugin (I) and 3,4‐dihydromollugin (II) were isolated from the medicinal plant Rubia cordifolia in China and India (Figure 1) [3]. The dried roots and rhizomes of this plant are used officially as herbal medicine in the Chinese Pharmacopeia for treating arthritis, dysmenorrhea hemostasis, and other diseases [4]. In India, this plant has been used for treatment of rheumatism, menstrual pain, and urinary disorders [5]. Mollugin (I) was also isolated from rhizome of Galium mollugo, which is found in many rubiaceous herbs in Europe and Africa [6]. Mollugin (I) and its analogue, 3,4‐ dihydromollugin (II), have biologically interesting properties such as antitumor [7], antimutagenic [8], antileukemia [9], anti‐ inflammatory [10], and antiallergic activities [10]. Figure 1. Structures of mollugin (I) and 3,4‐dihydromollgin (II). 2. Synthesis of 4H‐naphtho[2,1‐b]pyrans 2.1. Synthesis from 6‐methoxy‐2‐naphthol Condensation of 6‐methoxy‐2‐naphthol (1) with α‐cyano cinnamonitriles, 2a‐f and/or ethyl α‐cyanocinnamates, 2g‐l, afforded the corresponding 2‐amino‐4‐aryl‐7‐methoxy‐4H‐ naphtho[2,1‐b]pyran‐3‐carbonitriles, 3a‐f, and ethyl‐2‐amino‐ 4‐aryl‐7‐methoxy‐4H‐naphtho[2,1‐b]pyran‐3‐carboxy‐lates, 3g‐l, respectively [11,12] (Scheme 1). A mechanism for the piperidine catalyzed formation of the naphtho[2,1‐b]pyran derivatives 3 is outlined in Scheme 2. Scheme 1 468 El‐Wahab et al. / European Journal of Chemistry 4 (4 (2013) 467‐483 Scheme 2 2.2. Synthesis from 2‐naphthol a) Condensation of α‐cyano‐p‐methylcinnamonitrile (2e) or ethyl α‐cyano‐p‐methylcinnamate (2h), with 2‐naphthol (4) in ethanolic piperidine afforded 2‐amino‐4‐(p‐tolyl)‐4H‐ naphtho[2,1‐b]pyran‐3‐carbonitrile (5a) and ethyl 2‐amino‐4‐ (p‐tolyl)‐4H‐naphtho[2,1‐b]pyran‐3‐carboxylate (5b) (Scheme 3) [13]. Scheme 3 b) An efficient bifunctional thiourea catalyzed addition‐ cyclization reaction of arylidenemalononitriles 2 with 2‐naph‐ thol (4) is realized under mild conditions to afford the corresponding 2‐amino‐3‐cyano‐4‐aryl‐4H‐naphtho[2,1‐b] pyrans (5), in high yields and moderate enantioselectivities (Scheme 4 ) [14]. Scheme 4 c) A novel bifunctional thiourea–tertiary‐amine‐catalyzed enantioselective Friedel‐Craft‐type addition reaction of 2‐naph‐ thol (4) with β,γ‐unsaturated α‐keto ester, 6, was developed. Subsequent dehydration of the reaction adducts with a catalytic amount of concentrated H2SO4 in a one‐pot fashion readily afforded a series of new optically active naphthopyran derivatives 7 (Scheme 5), with moderate to good yields (up to 91%) and enantio selectivities (up to 90%) [15]. A mechanism for the bifunctional thiourea‐tertiary‐amino‐catalyzed forma‐ tion of the naphthopyran derivatives 7 is outlined in Scheme 6. Scheme 5 Scheme 6 2.3. Synthesis from multicomponent reactions a) Methanesulfonic acid efficiently catalyzes the one‐pot, three component reaction of an 2‐naphthol (4), aromatic aldehyde and malononitrile to yield 2‐amino‐3‐cyano‐4‐aryl‐ 4H‐naphtho[2,1‐b]pyrans (5) in good yields (Scheme 7) [16]. A mechanism for the methanesulfonic acid catalyzed formation of the naphtho[2,1‐b]pyran derivatives 5 is outlined in Scheme 8. Scheme 7 Scheme 8 b) Naphtho[2,1‐b]pyran derivatives, 5, have been synthesized involving a one pot three‐component reaction of an aldehyde, malononitrile and 2‐naphthol (4) using catalytic amounts tetra‐butyl ammonium bromide (TBABr) under aqueous conditions (Scheme 9) [17]. El‐Wahab et al. / European Journal of Chemistry 4 (4) (2013) 467‐483 469 Scheme 9 c) Diazabicyclo[2.2.2]octane (DABCO) has been used as a mild and efficient catalyst for synthesis of 2‐amino‐3‐cyano‐4‐ aryl‐4H‐naphtho[2,1‐b]pyrans (5) via a one‐pot three‐compo‐ nent reaction of aromatic aldehydes, 2‐naphthol (4), and malononitrile at room temperature [18]. The short reaction times, easy workup, good to excellent yields, and mild reaction conditions make this domino Knoevenagel‐Michael reaction both practical and attractive (Scheme 10). A mechanism for the DABCO catalyzed formation of the naphtho[2,1‐b]pyran derivatives 5 is outlined in Scheme 11 Scheme 10 N NH CNH CN N N CN CN Ar H O NC NC O Ar H H HN N NC NC OH Ar H H NC NC Ar H HN N N N O O Ar CN H N N N O Ar NH CNH O Ar NH2 CN N N OH 4 5 - H2O Scheme 11 d) A basic functionalized ionic liquid, 1‐butyl‐3‐methyl imidazolium hydroxide ([bmim]OH), catalyzed three‐ component condensation reaction of aromatic aldehydes, malononitrile and 2‐naphthol (4) proceeded rapidly in water at reflux to afford corresponding 2‐amino‐3‐cyano‐4‐aryl‐4H‐ naphtho[2,1‐b]pyrans (5) in high yields [19]. The greener protocol was found to be fairly general and the aqueous reaction media was reused in subsequent reactions with consistent activity (Scheme 12). Scheme 12 e) The model reaction was carried out simply by mixing of 4‐chlorobenzaldehyde, malononitrile and 2‐naphthol (4) using Na2CO3 as catalyst afforded 2‐amino‐3‐cyano‐4‐(p‐chloro phenyl)‐4H‐naphtho[2,1‐b]pyran (5). In the absence of catalyst no reaction was observed at room temperature (Scheme 13) [20]. A mechanism for the Na2CO3 catalyzed formation of the naphtho[2,1‐b]pyrans 5 is outlined in Scheme 14. Scheme 13 Scheme 14 f) An aqueous solution of thiourea dioxide (TUD) was used to catalyze a one‐pot three‐component coupling reaction of an aromatic aldehyde, malononitrile, and 2‐naphthol (4) for the synthesis of various naphthopyran derivatives 5 in excellent yields (Scheme 15) [21]. A mechanism for the TUD catalyzed formation of the pyran derivatives 5 is outlined in Scheme 16. Scheme 15 g) Naphthopyran derivatives 9 have been synthesized involving a one pot three‐component reaction of an aldehyde, active methylene substrate 8, and 2‐naphthol (4) catalyzed by Bronsted acid molybdophosphoric acid [phosphomolybdic acid (PMA)] (Scheme 17) [22]. A mechanism for PMA catalyzed the formation of the pyran derivatives 9 is outlined in Scheme 18. 470 El‐Wahab et al. / European Journal of Chemistry 4 (4 (2013) 467‐483 Scheme 16 Scheme 17 OH PMA Ar HO HO O Ar R O HO CH3 OH CH3 R O Ar OO Ar R O CH3 OH O Ar R O CH3 - H2O - H2O 9 Ar-CHO Scheme 18 h) The condensation of 2‐naphthol (4), aromatic aldehde and 5,5‐dimethyl‐1,3‐cyclohexanedione (10), the presence of a catalytic amount of tungstophosphoric acid [phosphotungstic acid (PWA)] (5 mol%) at 60 °C under solvent‐free condition afforded 12‐(4‐chlorophenyl)‐9,9‐dimethyl‐8,9,10,12‐tetra‐ hydrobenzo‐[a]xanthen‐11‐one (12) (Scheme 19) [23]. A mechanism for the PWA catalyzed formation of the pyran derivatives 12 is outlined in Scheme 20. Scheme 19 Scheme 20 i) Treatment of 2‐naphthol (4), triethyl orthobenzoate (12) and acetophenone derivatives 13 and, in the presence of a catalytic amount of bis(2‐anilinotropone) Ti complex afforded naphtho[2,1‐b]pyrans 14 (Scheme 21) [24]. A mechanism for the bis(2‐anilinotropone)Ti complex catalyzed formation of the naphthopyran derivatives 14 is outlined in Scheme 22. Scheme 21 Scheme 22 j) A facile method for the synthesis of naphthopyran derivatives 14 is reported. The procedure involves a novel three‐component reaction of 2‐naphthol (4), triethyl ortho‐ benzoate (12) and acetophenone derivatives 13 in the presence of silica supported ionic liquid [pmim]HSO4SiO2 [silica supported 1‐methyl‐3‐(triethoxysilyl‐propyl)imidazolium hydrogensulfate] as an efficient catalyst (Scheme 23) [25]. O- S O OHO O H EtO OEtEtO O X H H H CH3CN, 65 oC O OEt X 14 X = H, Br, Cl, Me, MeO, NO2, OH H 4 12 13 NH N Si + O OO SiSi OO O SiSi OH OH Scheme 23 k) A mixture of 2‐naphthol (4), aromatic aldehyde, active methylene compound, (malononitrile or ethyl cyanoacetate), activated and TiCl4 (10 mol %) was stirred at room temperature afforded naphthopyrans 5 (Scheme 24) [26]. Scheme 24 l) A three component condensation aromatic aldehyde, malononitrile and 2,7‐naphthalenediol (15), afforded only naphthopyran 17, regardless of the reagent ratio (1:1:1), whereas three‐component condensation with the use of 2,2‐ naphthalenediol (16), gave pyranonaphthopyran 18 regardless of the reagent ratio (2:2:1), respectively, (Scheme 25) [27]. El‐Wahab et al. / European Journal of Chemistry 4 (4) (2013) 467‐483 471 Scheme 25 m) A wide variety of 2‐amino‐4H‐naphthopyran derivatives 5 prepared via one‐pot, three‐component reaction of an aromatic aldehyde, malononitrile (or ethyl cyanoacetate), and 2‐naphthol (4), diverse enolizable C‐H activated acidic compounds in the presence of low loading of potassium phthalimide‐N‐oxyl (POPINO), as a new organocatalyst (Scheme 26) [28]. A mechanism for the POPINO catalyzed formation of the naphthopyran derivatives 5 is outlined in Scheme 27. Scheme 26 Scheme 27 n) A green chemistry method for synthesis of naphtho[2,1‐ b]pyran derivatives 5 is reported. The procedure involves three‐component reaction of 2‐naphthol (4), aromatic aldehyde, malononitrile in the presence of copper (II) sulfate pentahydrate, (Scheme 28) [29]. A mechanism for the CuSO4.5H2O catalyzed formation of the naphtho[2,1‐b]pyrans 5 is outlined in Scheme 29. Scheme 28 5 OH O CN NH2 O Ar H CuSO4 CH2(CN)2 CNHO Ar CN CNH Ar CN CNH Ar CN OH Ar CN N O Ar CN NHH H - H2O Scheme 29 2.4. Synthesis from 7‐substituted‐2‐naphthols Thus, condensation of 2,7‐naphthalenediol (15) or 7‐meth‐ oxy‐2‐naphthol (19) with α‐cyano‐4‐methoxycinnamo nitrile (2f) in ethanolic piperidine afforded the 1:1 adducts 17,20a along with 2‐(imino‐piperidin‐1‐yl‐methyl)‐3‐(4‐methoxy phenyl)‐acrylonitrile (21), while condensation of 15 and 19 with ethyl α‐cyano‐4‐methoxycinnamate (2i) afforded 20b,c as the only isolable products (Scheme 30) [30]. Scheme 30 2.5. Synthesis from 6‐bromo‐2‐naphthol Condensation of various substituted α‐cyanocinnamo nitriles (2a‐e) ethyl 3‐aryl 2‐cyano acrylates (2f‐j) with 6‐ bromo‐2‐naphthol (22) in ethanolic piperidine afforded naphthopyrano derivatives (23a‐j) (Scheme 31) [31,32]. 472 El‐Wahab et al. / European Journal of Chemistry 4 (4 (2013) 467‐483 Scheme 31 2.6. Synthesis from 2‐(4‐hydroxy‐3‐methoxybenzylidene) malononitrile The 2‐(4‐hydroxy‐3‐methoxybenzylidene)malononitrile (25) [33] was prepared by reaction of molononitrile with 4‐ hydroxy‐3‐methoxy benzaldehyde (24), which upon condensation with 2‐naphthol (4) to 2‐amino‐3‐cyano‐4‐(4‐ hydroxy‐3‐methoxyphenyl)‐4H‐naphtho[2,1‐b]pyran (26), respectively (Scheme 32) [34]. Scheme 32 2.7. Synthesis from 1‐phenyl‐3‐aryl‐pyrazole‐4‐ carbaldehyde Naphthopyran derivatives 28 have been synthesized by one‐pot three‐component cyclocondensation reaction of 1‐ phenyl‐3‐aryl‐pyrazole‐4‐carbaldehyde (27), malononitrile and 2‐naphthol (4), respectively [35], in the presence of piperidine as catalyst. The mixture refluxing under ethanol or acetonitrile gives moderate to good yield (50‐76%) (Scheme 33). A mechanism for the piperidine catalyzed formation of the naphthopyran derivatives 28 is outlined in Scheme 34. Scheme 33 Scheme 34 2.8. Synthesis from 2‐naphthol by [Fe(HSO4)3] 2,4‐Diaryl‐4H‐naphtho[2,1‐b]pyran (29) was synthesized by one‐pot reaction from 2‐naphthol (4), aromatic aldehydes and acetophenones (13) in acetonitrile in the presence of ferric hydrogensulfate. In the present study, the target products have been synthesized through new approach in good to excellent yields (Scheme 35) [36]. A mechanism for the Fe(HSO4)3 catalyzed formation of the naphthopyran derivatives 31 is outlined in Scheme 36. Scheme 35 Scheme 36 2.9. Synthesis from 2‐hydroxy naphthaldehyde a) Phenylsulfonylacetonitrile (30) reacts with 2‐hydroxy naphthaldehyde (31) in refluxing ethanol in the presence of triethylamine TEA gave 2‐imino‐3‐phenylsulfonyl‐naphtho[2,1‐ b]pyran (32), which by acid hydrolysis gave 3‐phenylsulfonyl‐ naphtho[2,1‐b]pyran‐2‐one (33) (Scheme 37) [37]. Scheme 37 b) 2‐Substituted naphtho[2,1‐b]pyran‐2‐ones (35) have been synthesized by a novel one‐pot method which involves cyclocondensation of 2‐hydroxy‐1‐naphthaldehyde (31) with 5‐methyl‐1,3,4‐thiadiazol‐2‐ylsulfanyl‐, 1H‐1,2,3,4‐tetrazol‐1‐ yl‐, 1H‐indol‐3‐yl‐, quinolin‐8‐yloxy‐ and 4‐methylquinolin‐2‐ yloxy‐acetic acids (34) in the presence of DCC–DMSO using microwaves as well as conventional heating (Scheme 38) [38]. Scheme 38 El‐Wahab et al. / European Journal of Chemistry 4 (4) (2013) 467‐483 473 2.10. Synthesis from of dimethyl acetylenedicarboxylate (DMAD) or dibenzoylacetylene The reaction of dimethyl acetylene‐dicarboxylate DMAD or dibenzoylacetylene (36) with tert‐butyl isocyanide (37) in the presence of naphthols, proceeded spontaneously at room temperature in dichloromethane, and produced 2‐tert‐ butylamino‐4H‐ naphtho[2,1‐b]pyrans 38‐40 (Scheme 39) [39]. A mechanism for the formation of the pyran derivatives, 39‐41, is outlined in Scheme 40. NC + R-C C C O C O R + O 37 36 4 38 38 R % Yield a OMe 93 b Ph 75 OH N R O O R H NC + R-C C C O C O R + O 37 36 15 39 39 R % Yield a OMe 85 b Ph 65 OH N R O O R H HO HO NC + R-C C C O C O R + O 37 36 16 40 40 R % Yield a OMe 90 b Ph 57 OH N R O O R H OH OH Scheme 39 O N R O OR H R O R O N C R O R O C N OH O O CC N O R H OH CC N O R R O 4 37 36 38 R O Scheme 40 3. Synthesis of 4H‐naphtho[1,2‐b]pyrans 3.1. Synthesis from 4‐chloro‐1‐naphthol Thus, condensation of various substituted benzyliden malonitrile (2a‐e) and ethyl 3‐aryl 2‐cyano acrylates (2f‐j) with 4‐chloro‐1‐naphthol (41) in the ethanolic piperidine afforded naphthopyran derivatives 42a‐j (Scheme 41) [40,41]. Scheme 41 3.2. Synthesis from 4‐methoxy‐1‐naphthol Reaction of 4‐methoxy‐1‐naphthol (43) with α‐cyano‐p‐ chlorocinnamonitrile (2e) or ethyl α‐cyano‐p‐chlorocinnamate (2j) in ethanolic piperidine afforded naphthopyrano deriva‐ tives 44a,b (Scheme 42) [42]. Scheme 42 3.3. Synthesis from multicomponent reactions a) Naphtho[1,2‐b]pyrans (46) have been synthesized through the three‐component reaction of aromatic aldehydes, malononitrile, and 1‐naphthol (45) using a catalytic amount of N,N‐dimethylaminoethylbenzyldimethylammonium chloride as catalyst under solvent‐free condition (Scheme 43) [43]. Scheme 43 b) Using the reaction of 1‐naphthol (45), malononitrile and aromatic aldehydes in the presence of 10% mol of potassium phosphate tribasic trihydrate under solvent‐free conditions, afforded naphtho[1,2‐b]pyrans 46 (Scheme 44) [44]. A mechanism for the K3PO4.3H2O catalyzed formation of the pyran derivatives 46 is outlined in Scheme 45. Scheme 44 c) 1,8‐Diazabicyclo[5.4.0]undec‐7‐ene (DBU) has been used as a catalyst for synthesis of naphtho[1,2‐b]pyran derivatives 46 via a one‐pot three‐component reaction of 1‐naphthol (45), aromatic aldehydes and malononitrile/ethyl cyanocacetate in water under reflux (Scheme 46) [45]. A mechanism for the DBU catalyzed formation of the 4H‐naphtho[1,2‐b]pyrans 46 is outlined in Scheme 47. d) Condensation of aromatic aldehyde, malononitrile and 1‐naphthol (45) or 4‐chloro‐1‐naphthol (41) using Na2CO3 as catalyst afforded naphtho[1,2‐b]pyrans 46 and 42 (Scheme 48) [20]. e) One‐pot, three components reaction of 1‐naphthol (45), aromatic aldehyde and malonitrile in presences of methanesulfonic acid to yield 4H‐naphtho[1,2‐b]pyrans 46 in good yields (Scheme 49) [16] . 474 El‐Wahab et al. / European Journal of Chemistry 4 (4 (2013) 467‐483 Scheme 45 Scheme 46 f) A basic functionalized ionic liquid, 1‐butyl‐3‐methyl‐ imidazolium hydroxide ([bmim]OH), catalyzed three component condensation of aromatic aldehydes, malononitrile and 1‐naphthol (45), proceeded rapidly in water at reflux to afford corresponding naphtho[1,2‐b]pyrans 46 in high yields. (Scheme 50) [19]. g) An aqueous solution of thiourea dioxide was used to catalyze a one‐pot three‐component coupling reaction of an aromatic aldehyde, malononitrile, and 1‐naphthol (45), for the synthesis of various naphthopyran derivatives 46 in excellent yields (Scheme 51) [21]. h) Diazabicyclo[2.2.2]octane (DABCO) has been used as a mild and efficient catalyst for synthesis of 2‐amino‐3‐cyano naphthopyran derivatives (46) [18] via a one‐pot three‐ component reaction of aromatic aldehydes, 1‐naphthol (45), and malononitrile at room temperature. The short reaction times, easy workup, good to excellent yields (Scheme 52). i) A green chemistry method for synthesis of naphtho[1,2‐ b]pyrans (46) is reported. The procedure invoves three‐ component reaction of 1‐naphthol (45), aromatic aldehyde, malononitrile in the presence of copper(II)sulfate penta hydrate, (Scheme 53) [29]. j) A wide variety of naphtho[1,2‐b]pyrans 46 prepared via one‐pot, three‐component reaction of an aromatic aldehyde, malononitrile (or ethyl cyanoacetate), and 1‐naphthol (45), in the presence of low loading of potassium phthalimide‐N‐oxyl (POPINO), as a new organocatalyst (Scheme 54) [28]. Scheme 47 Scheme 48 Scheme 49 Scheme 50 El‐Wahab et al. / European Journal of Chemistry 4 (4) (2013) 467‐483 475 Scheme 51 Scheme 52 Scheme 53 Scheme 54 k) A simple and efficient three component process for the synthesis of naphtho[1,2‐b]pyrans 46 and 47 utilizing the reaction of aryl with active methylenes (malononitrile, 2‐ cyanoethyanethioamide) and 1‐naphthol (45), in refluxing ethanol/piperidine under microwave‐heating is described (Scheme 55) [46]. Scheme 55 l) Mg/Al hydrotalcite, a heterogeneous base catalyst, was found to be highly effective for the synthesis of naphtho[1,2‐ b]pyrans 46 via a multicomponent reaction of aromatic aldehydes, malononitrile and 1‐naphthol (45) under microwaves. The reaction is rapid, clean and gives the products in high yields. The catalyst is reusable; however, there was reduction in the yield of the product (Scheme 56) [47]. Scheme 56 m) One pot multicomponent, condensation reaction of 1‐naphthol (45) aldehyde and malononitrile using catalytic amounts tetrabutyl ammonium bromide (TBABr) under microwaves aqueous conditions afforded naphthopyrans 46 (Scheme 57) [17]. Scheme 57 n) Maggi et al. [48] have described the use of basic alumina as a heterogeneous and reusable catalyst for the three‐ component synthesis of substituted naphtho[1,2‐b]pyrans 46. The reaction is highly regioselective. This process is industrially viable due to the use of water as a solvent and γ‐alumina as an inexpensive and reusable catalyst. However, one drawback of this methodology is 1‐naphthol (45) can only be used as an activated phenol. The preparation of these compounds has also been reported by Wang et al. [49] using KF‐alumina as a catalyst (Scheme 58). Scheme 58 o) A facile method for the synthesis of naphtho[1,2‐ b]pyrans 48 is reported. The procedure involves a novel three‐ component reaction of 1‐naphthol (45), triethyl ortho benzoate(12) and acetophenone derivatives 13, in the presence of silica supported ionic liquid [pmim]HSO4 SiO2 [silica supported 1‐methyl‐3‐(triethoxysilyl‐propyl)imidazo lium hydrogen‐sulfate] (Scheme 59) [25]. Scheme 59 476 El‐Wahab et al. / European Journal of Chemistry 4 (4 (2013) 467‐483 3.4. Synthesis from 1‐phenyl‐3‐aryl‐pyrazole‐4‐ carbaldehyde Naphthopyran derivatives 49a‐g has been synthesized by one‐pot three‐component cyclocondensation reaction of 1‐ phenyl‐3‐aryl‐pyrazole‐4‐carbaldehyde (27a‐g), malononitrile and 1‐naphthol (45), respectively, in the presence of piperidine as catalyst (Scheme 60) [35]. Scheme 60 3.5. Synthesis from 1‐naphthol by [Fe(HSO4)3] Synthesis of 2,4‐diaryl‐4H‐ naphtho[1,2‐b]pyrans 50 by one‐pot reaction from 1‐naphthol (45) , aromatic aldehydes and acetophenone in acetonitrile in the presence of ferric hydrogen sulfate. In the present study, the target products have been synthesized through new approach in good to excellent yields (Scheme 61) [36]. Scheme 61 3.6. Synthesis from of dimethyl acetylenedicarboxylate DMAD or dibenzoylacetylene The reaction of dimethyl acetylenedicarboxylate DMAD or dibenzoylacetylene (36) with tert‐butyl isocyanide (37) in the presence of 1‐naphthol (45), proceeded spontaneously at room temperature in dichloromethane, and produced 2‐tert‐ butylamino‐4H‐naphtho[1,2‐b]pyrans 52 (Scheme 62) [39]. Scheme 62 3.7. Synthesis from ethylacetoacetate Formation of 4‐methyl‐naphtho[1,2‐b]pyran‐2‐one (53) takes place via cyclization reaction of 1‐naphthol (45) and ethylacetoacetate (52) in presence of sulphuric acid. (Scheme 63) [50]. Scheme 63 4. Reactions of naphtho[2,1‐b]pyrans and naphtha [1,2‐b]pyrans with some electrophilic and nucleophilic reagents 4.1. Reactions of naphthopyranoaminonitriles 4.1.1. Acetic anhydride Treatment of naphtho[2,1‐b]pyran 3, 5 and 23 and or naphtho[1,2‐b]‐pyran 42 and 44 derivatives with Ac2O gave two products dependening on the reaction time; one product was identified as 2‐acetylamino‐naphthopyrans derivatives 54 and 56 (30 min), while the other was identified as naphthopyranopyrimidine derivatives 55 and 57 (6 h) (Scheme 64) [11‐13,30‐33,40‐42]. 3 0 m in . 6 h r 30 m in . 6 h r Scheme 64 4.1.2. Formic acid or benzoyl chloride Reaction of naphtho[2,1‐b]pyrans 3, 5 and 23 and or naphtho[1,2‐b]‐pyran 42 and 44 derivatives with formic acid or benzoyl chloride to give naphthopyranopyrimidine and phenyl‐naphthopyranopyrimidine derivatives 58 and 59 (6h), respectively (Scheme 65) [11‐13,30‐33,40‐42]. Scheme 65 El‐Wahab et al. / European Journal of Chemistry 4 (4) (2013) 467‐483 477 4.1.3. Formamide Reaction of naphtho[2,1‐b]pyrans 3, 5 and 23 and or naphtho[1,2‐b]‐pyran 42 and 44 derivatives with formamide to give aminonaphtho‐pyranopyrimidine derivatives 60 and 61 (Scheme 66) [11‐13,30‐33,40‐42]. Scheme 66 4.1.4. Carbon disulfide or phenyl isothiocyanate [13] Treatment of compound 5 with carbon disulphide in alcoholic postassium hydroxide furnished 9,11‐dithione derivative 62, whereas treatment with phenyl isothiocyanate yielded the 9‐thione derivative 63 (Scheme 67) [13]. O Ar CN NH2 O Ar NH NS S H Ar = 4-CH3-C6H4 CS2 / KOH O Ar NH NHN S C6H5 PhNCS 5 62 63 Scheme 67 4.1.5. Aromatic aldehyde Condensation of compound 43 with benzaldehyde or 4‐ methyloxy‐benzaldehyde in dioxin‐ piperidine solution under reflux afforded the corresponding arylmethyleneamino derivatives 64a‐f (Scheme 68) [41]. Scheme 68 4.1.6. Triethyl orthoformate Ethoxymethylene derivatives 65 and 66 was obtained by refluxing compounds naphthopyrano derivatives 3, 5, 22, 42 and 44, with triethyl orthoformate as electrophile in the presence of acetic anhydride (Scheme 69) [11‐13,30‐33,40‐42]. Scheme 69 Treatment of 65 and 66 with hydrazine hydrate in ethanol, at room temperature furnished the novel naphthopyrano pyrimidine derivatives 67 and 69 in good yield. Also, compound 64 and 65 underwent aminolysis and cyclization with primary amine, while with dimethylamine the opene‐ chain product 68 and 70. Ammonolysis of compound 64 and 65 in methanol at room temperature afforded amino‐ naphthopyranpyrimidine derivatives 60 and 61 (Scheme 70) [11‐13,30‐33,40‐42]. Scheme 70 Reaction of naphthopyranpyrimidine derivatives 67 and 68 with formic acid or triethyl orthoformate, acetylchloride and benzoyl chloride, ethyl cyanoacetate and diethyl oxalate 478 El‐Wahab et al. / European Journal of Chemistry 4 (4 (2013) 467‐483 afforded the corresponding triazolopyrimidine derivatives 73 and 74 (Scheme 71) [11‐13,30‐33,40‐42]. Ar = C6H5, 4-CH3-C6H4, 4-OCH3-C6H4, 4-Cl-C6H4, 4-Br-C6H4 O Ar N N NH 67 O X Ar N N N N 73 R NH2 a) HCOOH b) CH(OEt)3 c) PhCOCl d) CNCH2COOEt e) (COOEt)2 X X = H, OCH3, Br a; R =H b; R = CH3 c; R = C6H5 d; R = CH2CN e; R = COOEt O 68 O N N 74 a) HCOOH b) CH(OEt)3 c) PhCOCl d) CNCH2COOEt e) (COOEt)2 a; R =H b; R = CH3 c; R = C6H5 d; R = CH2CN e; R = COOEtAr X N N NH NH2 N NX R Ar X = Cl, OCH3 Scheme 71 Treatment of 67 and 68 with ethyl chloroformate in dry benzene afforded traizolo‐2‐one derivative 75 and 76 (Scheme 72) [11‐13,30‐33,40‐42]. Scheme 72 Reaction of compound 67 and 68 with benzaldehyde gave 10‐benzalamino‐10,11‐dihydro‐11‐imino‐3‐methoxy‐12‐(aryl)‐ 12H‐naphtho‐[2,1‐b]pyrano‐[2,3‐d]pyrimidine (77 and 78) instead of the expected triazolopyrimidine derivative 72 and 73 (Scheme 73) [11,13,30‐33,40‐42]. Scheme 73 4.1.7. Active methylene reagents Compound 2‐(3‐amino‐2‐cyano‐1H‐benzo[f]chromen‐1‐yl)‐ malononitrile (79) was condensed with different active methylene reagents such as methyl 3‐oxobutanoate (80b), 2,4‐ pentanedione (80c) and 1,3‐diphenyl‐1,3‐propanedione (80d) to give the corresponding pentacyclic compounds 82b‐d (Scheme 74). According to the literature results [52,53‐55] the heterocycles obtained in the reaction between aminonitriles and β‐dicarbonyles is formed via the intermediate β‐ enaminodiones (81). These intermediates have never been isolated possibly due to their fast intramolecular cyclization to heterocyclic rings. Therefore, the structure of compounds 82a‐d is rationalized in terms of the initial formation of the intermediate 81, which on subsequent intramolecular cyclization followed by elimination of a water molecule and partial dehydrogenation under the reaction conditions affords the final product (Scheme 74) [51]. In a similar manner, compound 79 condensed with benzoylacetonitrile (80e) under the previous reaction conditions to yield a product formulated as 82e (Scheme 74). Moreover, a mixture of equimolar amounts of compound 79 and malononitrile (80f) reacted in refluxing ethanol and in the presence of a catalytic amount of piperidine to yield a solid product naphthyridine 84 (route A) or pyridopyrimidine 86 (route B) (Scheme 74). Thus it appears that the dicyanomethyl anion attacks the cyano group of 79 yielding the intermediate 83 (route A) which by intra‐molecular cyclization between amino and cyano groups with partial dehydrogenation under the reaction conditions gives compound 84 (Scheme 74) [51]. Scheme 74 2‐Amino‐5‐methyl‐benzo[5,6]chromeno[4,3,2‐de]1,6]napht hyridine‐1,4‐dicarbonitrile (89) was obtained when 79 was heated under reflux with 3‐amino‐crotononitrile (87) in boiling ethanol. The formation of compound 89 can be described in terms of the initial formation of the intermediate 88 followed by its cyclization to the final product 89 (Scheme 75). Trinitriles 79 reacted with ammonium acetate in molar ratio 1:2 to afford 2,6‐diamino‐4‐(2‐hydroxy‐1‐naphthyl)‐3,5‐ pyridine‐dicarbonitrile (90). Compound 90 was converted, in the presence of hydrochloric acid, into 2,4‐diamino‐5‐oxo‐5H‐ benzo[5,6]chromeno[3,4‐c]pyridine‐1‐carbonitrile (92), presu‐ meably the imino group in the postulated intermediate 91 is hydrolysed during formation of 92 (Scheme 75). 4.1.8. Cyclohexanone The cyclocondensation of 2‐amino‐3‐cyano‐4H‐4‐aryl‐ naphthopyran derivatives 5 with cyclohexanone (93) in DMF in the presence of anhydrous zinc chloride under reflux gave two different skeletons compounds, one is quinolines 94 El‐Wahab et al. / European Journal of Chemistry 4 (4) (2013) 467‐483 479 (tacrineanalogues) from the famous Friendlander conden‐ sation, and another one is the spiro compound 95 from new annulation (Scheme 76). A plausible mechanism was proposed (Scheme 77) [56]. Scheme 75 O Ar CN NH2 a; Ar = 3-Nitro-phenyl b; Ar = 4-Nitro-phenyl O ZnCl2 O N NH2Ar 94a; 47.2% b; 50.4 O N H O NH2Ar O N H NH OAr 95a; 30.2 b; 27.6 5 93 Scheme 76 4.2. Reactions of naphthopyranoaminoester 4.2.1. Dimethyl formamide Reaction of ethyl 2‐amino‐4‐phenyl‐4H‐naphtho[2,1‐ b]pyran‐2‐carboxylate (5) with dimethyl formamide in presence of phosphorus oxychloride, afforded ethyl 2‐(dimethylaminomethyleneamino)‐4‐phenyl‐4H‐naphtho[2,1‐ b]pyran ‐3‐carboxylate (96) (Scheme 78). Thus, treatment of compound 96 with aromatic amine in refluxing ethanol afforded 2‐(phenylaminomethyleneamino)‐4‐phenyl‐4H‐naph‐ tho[2,1‐b]pyran‐3‐carboxylic acid (98). So, it was assumed that the reaction proceeded via losing N‐dimethylamine to give the intermediate 97 which underwent hydrolysis rather than cyclization via losing ethanol yielding what we expected as product 98, (Scheme 78) [57]. While repeating this reaction in pyridine at reflux for five hours afforded the expected 10,12‐ diphenyl‐12H‐ naphtho[2,1‐b]pyrano[2,3‐d]pyrimidine‐11‐one (99). Compound 96 formed via losing of N‐dimethylamine to give the intermediate 97 which cyclized through releasing of ethanol. On the other hand, compound 96 reacted with substituted hydrazine to yield the corresponding naphtho[2,1‐ b]pyrano[2,3‐d]pyrimidine derivatives 101a,b via elimination of ethanol from the corresponding intermediate 100 which cyclized via release of ethanol [57]. Scheme 77 Scheme 78 4.2.2. With carbon disulfide A solution of compound 5 in dimethyl sulfoxide was treated with carbon disulfide in presence of sodium hydroxide solution. The sodium salt of dithiocarbamic acid, 102, was obtained in situ and then methylated with dimethyl sulfate to yield ethyl 2‐(methylsulfanylthiocarbonylamino)‐4‐phenyl‐4H‐naphtho[2, 1‐b]pyran‐3‐carboxylate (104), but non‐isolable compound 103. The compound 104 when reacted with hydrazine hydrate in ethanol with stirring at room temperature yielded the open chain thiosemicarbazide derivative 105 via elimination of methylsulfane, while, under reflux in ethanol for 8 hours, it yielded the expected naphtho[2,1‐b]pyrano[2,3‐d]pyrimidine 106 via elimination of methylsulfane and ethanol. Boiling the thiosemicarbazide 105 in ethanol in presence of triethylamine yielded the same compound 106 (Scheme 79) [57]. Compound 106 was allowed to react with benzaldehyde and/or 4‐chlorobenzaldehyde to give the corresponding expected Schiff's base 107. However, the isolated compounds proved to be the new and unexpected compounds 108a,b 480 El‐Wahab et al. / European Journal of Chemistry 4 (4 (2013) 467‐483 formed via simultaneous nucleophilic attack of the sulfur atom on the hydrazone carbon with cyclization to the new thiadiazole derivatives 108a,b, as shown in (Scheme 80) [57]. O Ph COOEt NH2 O Ph COOEt NH CS2 / NaOH O Ph NH SO S Reflux R.T. -CH3SH- CH3SH, -EtOH O Ph N NO NH2 SH O Ph CO2Et H N S NHNH2 Reflux, TEA SNa S O Ph COOEt NH SCH3 S 5 102 103 104 105 106 DMS DMSO NH2-NH2.H2O - EtOH Scheme 79 Scheme 80 Furthermore compound 5, when treated with carbon disulfide and potassium hydroxide solution, yielded the soluble potassium salt of dithiocarbamic acid, 109, which was further treated in situ with chloroacetic acid and phenacylbromide, respectively, to afford ethyl 2‐(4‐oxo‐2‐thioxothiazolidin‐3‐yl) ‐4‐phenyl‐4H‐naphtho[2,1‐b]pyran‐3‐carboxylate (111) and 4‐phenyl‐2‐(4‐phenyl‐2‐thioxothiazol‐3(2H)‐yl)‐4H‐naphtha[2, 1‐b]pyran ‐3‐carboxylate (113) via release of water from the two corresponding intermediates 110 and 112, respectively, (Scheme 81) [57]. O NH2Ph COOEt CS2 / KOH O H NPh COOEt S S K Br-CH2-COPh ClCH2-COOH O H NPh COOEt S S Ph HO O N S COOEt S Ph Ph O H NPh COOEt S S O HO O N S COOEt S O Ph 5 109 110 111 112 113 - H2O - KBr - KCl - H2O Scheme 81 4.2.3. Acetic anhydride Compound 5 was acylated with acetic anhydride yielding the acetyl derivative, 114, which easily reacted with hydrazine hydrate to afford the new substituted 10‐amino‐9‐ methyl‐12‐phenyl‐12H‐naphtho[2,1‐b]pyrano[2,3‐d]‐pyrimidi ne‐11‐one (116) via intermediate 115 which formed from 114 by displacement of ethanol rather than water as shown in (Scheme 82) [57]. 5. Applications of naphthopyrans Naphtho[2,1‐b]pyran derivatives 3, 5 and 23 and naphtho[1,2‐b]pyran derivatives 42 were found exhibited inhibition antibacterial activities (Scheme 83) [11‐13,23‐ 26,33]. 4‐Aryl‐2‐amino‐5,6‐dihydro‐4H‐naphtho[1,2‐b]pyran‐3‐ carbonitrile derivatives, 117, have antiproliferative activities (Scheme 84) [58,59]. 4‐(Piperazin‐1‐yl)‐4H‐naphtho[2,1‐b]pyran‐2‐one, 4‐ (piperazin‐1‐yl)‐4H‐naphtho[1,2‐b]pyran‐2‐one, and 4‐ (piperazin‐1‐yl)‐4H‐naphtho[2,3‐b]‐pyran‐2‐one (118‐120) have antiplatelet agents (Scheme 85) [60]. 3,3‐Dihydro‐2,2‐dimethyl‐4H‐naphtho[1,2‐b]pyran‐4‐ one (121) was hypotensive action (Scheme 86) [61]. 4‐Methyl‐7‐hydroxy‐4H‐naphtho[1,2‐b]pyran‐2‐one (122) as used fluorescence reagents (Scheme 87) [62]. El‐Wahab et al. / European Journal of Chemistry 4 (4) (2013) 467‐483 481 Scheme 82 Scheme 83 Scheme 84 Scheme 85 Scheme 86 3,4‐Dihydro‐2,2‐dimethyl‐4‐(2‐oxo‐pyrrolidin‐1‐yl)‐4H‐ naphtho[1,2‐b]pyran‐6‐carbonitrile (123) and 3,4‐dihydro‐2,2‐ dimethyl‐4‐(2‐oxo‐pyridin‐1‐yl)‐4H‐naphtho[1,2‐b]pyran‐6‐ carbonitrile(124) were promised vasorelaxant activity (Scheme 88) [63]. Scheme 87 The photochromic properties of naphthopyrans (125) have been extensively studied in the last decade due to the wide range of applications with prominence in the manufacture of ophthalmic plastic lenses and solar protection glasses (Scheme 89) [64‐67]. Scheme 88 Scheme 89 6‐Acetoxy‐3‐(4‐(2,5‐dihydro‐2,5‐dioxo‐1H‐pyrrol‐1‐yl) phenyl)‐4H‐naphtho[2,1‐b]pyran‐2‐one (126) show have cytoxicity activities (Scheme 90) [68]. Scheme 90 7‐Hydroxy‐4‐methyl‐naphtho[1,2‐b]pyran‐2‐one‐8,10‐di carbaldehyde (127) as potential antidyslipidemic and antioxidant agents (Scheme 91) [69]. Scheme 91 2‐Amino‐4a,5,6,10b‐tetrahydro‐4‐(3‐(trifluoromethyl) phenyl)‐4H‐naphtho[1,2‐b]pyran‐3‐carbonitrile (128) show have rheumatoid arthritis (Scheme 92) [70,71]. Scheme 92 2‐Amino‐4‐(pyridine‐3‐yl)‐4H‐naphtho[1,2‐b]pyran‐3‐ carbonitrile (129) show have restenosis (Scheme 93) [72‐75]. Scheme 93 2‐Amino‐4‐(3‐nitrophenyl)‐4H‐naphtho[1,2‐b]pyran‐3‐ carbonitrile (130), 4‐(3‐nitrophenyl)‐2‐(1H‐pyrrol‐1‐yl)‐4H‐ naphtho[1,2‐b]pyran‐3‐carbonitrile (131) and 4‐(3‐nitro 482 El‐Wahab et al. / European Journal of Chemistry 4 (4 (2013) 467‐483 phenyl)‐2‐(2,5‐dioxopyrrolidin‐1‐yl)‐4H‐ naphtho[1,2‐b]pyran‐ 3‐carbonitrile (132) show have diabetic complications (Scheme 94) [76,77]. Scheme 94 6. Conclusions Naphthopyran derivatives have been reported in the literatures as a result of fusion of naphthalene moiety to the pyran ring and were synthesized either starting with naphthols and arylidene in presence catalyst. 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