ⁿBu₄NPF₆ promoted regioselective cascade synthesis of functionally embellished naphthofurans under acid, metal & solvent free conditions

Abstract

ⁿBu₄NPF₆ mediated highly regioselective synthesis of functionally embellished naphthofurans has been achieved from easily available naphthols and propargyl alcohols through a cascade benzylation, oxacyclisation (5-exo dig) and isomerization under solvent free conditions. The reaction works in a short time through dibenzyl ether formation followed by the decomposition to the carbocation to furnish the high yielding products with large substrate scope. The synthetic utility of the products is demonstrated through C(sp³)–H functionalization. In addition, we investigated selected naphthofurans for their anti-amyloidogenic properties. Preliminary studies suggest that these are excellent inhibitors for amyloid formation, a hallmark for several neurodegenerative diseases.

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Naphthofurans and benzofurans belong to the important class of oxygen containing heterocyclic compounds that possess a spectrum of biological and pharmacological properties.^1–3 They are an integral part of several natural & synthetic molecules (for example furomollugin, viniferifuran, anigopreissin A & 7-methoxy-2-nitronaphtho[2,1-b]furan (R7000) etc.) and serve as building blocks in organic synthesis.² The naphthofuran moiety is proven to be a “privileged structure”⁴ in the design of potential anticancer agents^1a and regulators of the nuclear receptors HNFa7.⁵ Owing to these important features several synthetic approaches have emerged for the synthesis of naphthofurans.^1h,6–10 Most of the methods were involved in two to three step syntheses starting from suitable propargyl alcohols and naphthols such as a metal/acid catalyzed benzylation followed by the base mediated oxacyclization and isomerization (Fig. 1, eqn (1) & (2)).^1h,6 It is also reported that arenols react with Morita–Baylis–Hillman (MBH) acetates in presence of a base and toluene as the reaction medium to form naphthofurans (Fig. 1, eqn (3) & (4)) though the method goes through a single step, the use of MBH acetates makes this method less amenable.⁷ In(OTf)₃ catalyzed coupling of naphthols with nitroalkenes in DCE has also been reported.⁸ Organometallic cross coupling reactions also used to synthesize the benzo/naphthofuran derivatives.⁹ A base promoted naphthofuran synthesis was reported in chloroform starting from naphthols and nitroallylic acetates.¹⁰ Although there are a number of methods reported for the synthesis of 2,3-disubstituted benzofurans, only a limited number of methods are available for the synthesis of 2,3-disubstituted naphthofurans. Some of them suffer from the drawbacks such as multistep procedures, inert conditions, longer reaction times, poor substrate scope, use of chlorinated solvents, transition metal catalysts, acid catalysts and the use of starting materials which are not easily available. Hence it is highly desired to develop a regioselective, metal, acid and solvent free, one-pot (single step) synthesis of functionally embellished naphthofurans starting from easily available materials under simple reaction procedures.

Fig. 1 Previous reports on the synthesis of 2-alkyl, 3-aryl naphthofurans.

Naphthofuran derivatives are well known as imaging agents for β-amyloid plaques in the brain.⁵ Amyloid formation is related to several devastating diseases including the most common neurodegenerative disease, Alzheimer's disease (AD).¹² AD is characterized by deposits of amyloid β-peptide (Aβ) in the brain and the disease still lacks a specific treatment.¹³ In fact, there is a great demand for compounds that can interact with early stage oligomers or amyloid plaques and/or either inhibit their formation or cause their dissolution into monomeric peptide.¹⁴ Only a few of the polyphenolic compounds, benzothiazole based small molecules are known to inhibit the amyloid formation.¹⁵ Interestingly, our preliminary analysis suggest that these naphthofuran derivatives exhibit excellent anti-amyloidogenic properties as they very efficiently inhibit fibrilization of lysozyme from chicken egg white, a readily available protein that undergo fibrilization. The detailed investigation is still in progress and the results will be published elsewhere.

On the other side the alarming calls of the global warming emphasize “the role of chemistry in investigating a sustainable future.”¹⁶ In response to the global demand to develop the green synthetic protocols,¹⁷ we are working towards the development of novel green synthetic procedures for various biologically relevant molecules¹⁸ (privileged structures) including our recent work towards the synthesis of fused benzofurans using an alkaline earth catalyst.^1f In continuation, here in we report a Bu₄NPF₆ catalysed, highly regioselective, acid, metal & solvent free synthesis of 2-alkyl-3-aryl-naphthofurans using a cascade benzylation/oxacyclisation/isomerization strategy.

The schematic representation of our concept for the regioselectivity has been described in the Fig. 2. The benzyl intermediate (I) will have two possible pathways of cyclization, either a nucleophilic (phenolic oxygen) addition at β-carbon through a 5-exo dig fashion to furnish the naphthofuran, or the nucleophilic addition at α-carbon through a 6-endo dig fashion to furnish the naphthopyran. We believe that the R group will play a critical role to differentiate α & β carbons and thus the regioselectivity could be achieved.

Fig. 2 Conceptualization for the regioselective synthesis of 2-alkyl, 3-aryl naphthofurans.

Our investigations began by treating the stoichiometric amount of 2-naphthol (1a) and 4-hydroxy-4-phenylbut-2-ynoate (2a) with 10 mol% of Ca(OTf)₂/Bu₄NPF₆ under solvent free conditions at 120 °C (entry 1, Table 1).¹⁹ As expected the reaction gave the desired ethyl 2-(3-phenylnaphtho[1,2-b]furan-2-yl)acetate (3a) in 70% after 4.5 h. When the same reaction was repeated with 10 mol% of Ca(OTf)₂ & 5 mol% of Bu₄NPF₆ only 62% of 3a was isolated. This indicated that Bu₄NPF₆ has an important role in increasing the yield of 3a. Further to confirm this, we performed the reaction in the absence of Bu₄NPF₆ (entry 3, Table 1) and were surprised to note that only 24% of 3a was formed after 5 h. The absence of catalyst/additive could not proceed even after 10 h at 120 °C under neat conditions (entry 15). Considering the importance of Bu₄NPF₆ we carried out the reaction with 10 mol% of Bu₄NPF₆ (without Ca(OTf)₂) and were delighted to see the formation of 3a in 72% after 7 h (entry 4, Table 1). Increase in the catalyst (Bu₄NPF₆) loading from 10–15 and 15–20 mol% has showed the remarkable effect on the reaction time and yield (entries 4–6). The reaction gave 90% of 3a with in 2.5 h with 20 mol% of Bu₄NPF₆ at 120 °C (entry 6).²⁰

Table 1 Optimization of reaction condition for the one-pot cascade synthesis of 2-alkyl-3-aryl naphthofuran^a

Entry	Catalyst (mol%)	Temperature^b (°C)	Solvent	Yield^c (%)	Time (h)
a 1a (1.1 eq.), 2a (1 eq.).b Oil bath temperature.c Isolated yields.d Combined yield for the mixture of furan/pyran.
1	Ca(OTf)2/Bu4NPF6 (10/10)	120 °C	Neat	70	4.5 h
2	Ca(OTf)2/Bu4NPF6 (10/5)	120 °C	Neat	62	4.5 h
3	Ca(OTf)2 (10)	120 °C	Neat	24	5 h
4	Bu4NPF6 (10)	120 °C	Neat	72	7 h
5	Bu4NPF6 (15)	120 °C	Neat	81	4 h
6	Bu4NPF6 (20)	120 °C	Neat	90	2.5 h
7	Bu4NPF6 (20)	rt	Neat	Trace	24 h
8	Bu4NPF6 (20)	60 °C	Neat	15	24 h
9	Bu4NPF6 (20)	80 °C	Neat	21	24 h
10	Bu4NPF6 (20)	100 °C	Neat	71	12 h
11	Bu4NPF6 (20)	90 °C	EtOH	<5	10 h
12	Bu4NPF6 (20)	50 °C	DCM	56	10 h
13	Bu4NPF6 (20)	70 °C	MeOH	Trace	10 h
14	Bu4NPF6 (20)	90 °C	Benzene	12	10 h
15	—	120 °C	Neat	nr	10 h
16	NH4Cl (20%)	120 °C	Neat	<5	8 h
17	Bu4NF (20%)	120 °C	Neat	15	8 h
18	KPF6 (20%)	120 °C	Neat	Trace	8 h
19	Proline 10%	120 °C	Neat	8	8 h
20	PTSA 10%	120 °C	Neat	45^d	8 h
21	NbCl5 10%	120 °C	Neat	60	8 h

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To check the temperature effect we performed the same reaction at various temperatures such as rt, 60 °C, 80 °C, 100 °C & 120 °C and found that 120 °C is the optimum temperature (Table 1, entries 6–10). The role of solvents in this reaction has been studied using ethanol, dichloromethane, methanol and benzene under the reflux conditions (entries 11–14) and found that the reaction works better under solvent free conditions. The catalytic activity of the other ammonium derivatives such as NH₄Cl (20 mol%) & ⁿBu₄NF was studied and found that none of them proved to be useful (entries 16, 17). A phosphorous salt, KPF₆ was tried but only traces of 3a could be detected (entry 18). Proline (an organocatalyst) could not produce more that 8% of 3a (entry 19). PTSA (a Bronsted acid) gave the mixture of furan/pyran (45%, no regioselectivity) after 8 h (entry 20). NbCl₅ (an oxophilic transition metal catalyst) could yield maximum of 60% of 3a at 120 °C (entry 21).

Having the conditions set for the Bu₄NPF₆ catalysed regioselective cascade synthesis of naphthofurans, we further studied the scope of the various naphthols (1, 4) and benzylic propargylic alcohols (2) in the methodology. The benzylic alcohol bearing 4-methyl substitution on the phenyl ring (2b) was reacted with 2-naphthol for 3 h to yield the naphthofuran 3b in 81% yield. Similarly 4-methoxy, 4-bromo and 4-fluoro derivatives (2c, 2d and 2e) furnished the respective naphthofurans 3c, 3d and 3e in 84, 92 & 80% respective yields (Table 2, first row). The second row of the Table 2 shows that naphthofuran derivatives 3f, 3g and 3h with methyl esters were synthesized in 86, 81 & 80% yields.

Table 2 Substrate scope of Bu₄NPF₆ catalyzed one-pot cascade synthesis of 2-alkyl, 3-aryl naphtho[2,1-b]furans^a

a Reaction conditions: 1 (1.1 eq.), 2 (1 eq.) Bu₄NPF₆ (0.2 eq.), 120 °C.b Oil bath temperature.

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6-Bromo-2-naphthol reacted with both the propargyl alcohols bearing ethyl & methyl esters to yield the corresponding naphtho[2,1-b]furans 3i–3n in good yields (Table 2, entries 3i–3n).

Encouraged by the reactivity of 2-naphthol derivatives towards the synthesis of naphtho[2,1-b]furans, we looked forward to make the complimentary class of furans i.e. naphtho[1,2-b]furans for which we used the 1-naphthol (4) against benzylic-propargylic alcohols (2). The initial product ethyl 2-(3-phenylnaphtho[1,2-b]furan-2-yl)acetate (5a) was realized in 92% yield after 2.5 h when 2a was treated with 1-naphthol under the optimum conditions (Table 3). In the similar fashion other benzylic-propargylic alcohols (2) bearing 4-methyl, 4-methoxy, 4-bromo, 4-chloro and 4-fluoro substitutions on the phenyl ring smoothly reacted with 1-naphthol to provide the corresponding naphtho[1,2-b]furans in good yields (Table 3, products 5b–5f). Methyl ester derivatives of 2 also reacted with 1-naphthol to furnish the 2-alkyl-3-arylnaphthofurans 5g–5i in 84%, 93, 81% yields. Similarly 6-methoxy-1-naphthol furnished the naphthofurans 5j & 5k in 75, 77% yields (Table 3).

Table 3 Substrate scope of Bu₄NPF₆ catalyzed one-pot cascade synthesis of 2-alkyl, 3-aryl naphthol[2,1-b]furans^a

a Reaction conditions: 1 (1.1 eq.), 2 (1 eq.) Bu₄NPF₆ (0.2 eq.), 120 °C.b Oil bath temperature.

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Further alkynol 10a (R = TMS) reacted with 2-naphthol under same conditions and yielded the 2-methyl, 3-phenyl naphthofuran 11 in 65% after 5 h (Scheme 1). Probably due to the presence of fluorine in the reaction (in the form of catalyst) the silyl group could have deprotected.^1f 1-Phenylprop-2-yn-1-ol (10b, a terminal alkyne) gave the same 2-methyl, 3-phenyl naphthofuran 11 in 69% yield.

Scheme 1 Regioselective studies of 1-naphthol with trimethylsilyl & terminal alkynes.

The scope of various phenols also has been investigated under the same reaction conditions (Scheme 2). When the reaction of alkynol 2a was performed with simple phenol, it could not yield the expected benzofuran but the corresponding benzyl ether was obtained. But in case of m-hydroxyanisole (which has two ortho-nucleophilic sites) and benzylic alcohol 2a, the reaction gave the regioisomeric benzofurans 6a & 6b in 33%, 39% isolated yields respectively after 4 h (Scheme 1). p-Cresol and o-cresol reacted with 2a and yielded benzofurans 6c and 6d in 83%, 81% yields. p-Cresol was also furnished the benzofuran 6e in 85% yield after 2 h (Scheme 2).

Scheme 2 Scope of various substituted phenols.

The plausible mechanism for this cascade regioselective synthesis has been demonstrated in the Scheme 3. Initially benzylic alcohol 2 will undergo heat induced dehydration in presence of Bu₄NPF₆ to afford the dibenzyl ether 7 (isolated and characterized). At this temperature ether 7 will collapse to form the benzyl carbocation 7a and alcohol in a reversible pathway. Once the carbocation is available in the reaction mixture it will undergo nucleophilic substitution with naphthol (1a) to form the benzyl intermediate 7a1 (which was isolated and characterized).

Scheme 3 The plausible mechanism for the Bu₄NPF₆ mediated regioselective synthesis of functionally embellished naphthofurans.

Further 7a1 undergoes 5-exo dig oxa-cyclisation (7a2), as the β-carbon is more electrophilic to be attacked by phenolic oxygen and the resultant α-carbanion is stabilized by the ester group. Protonation of 7a2 will lead to the formation of naphthofuran with exo cyclic double bond 7a3 (isolated and characterized), which further isomerizes to the final compound 3a.

To authenticate the mechanism proposed in the Scheme 3, ether 7 was isolated and separately treated with 2-naphthol under the same reaction conditions to obtain the naphthofuran 3a in 88% yield after 1.5 h (Fig. 3).

Fig. 3 Reaction of dibenzyl ether (7) with 2-naphthol to obtain the naphthofuran 3a.

As we proposed in our regioselective conceptualization in Fig. 2, if ester group is replaced by a phenyl group the reaction should yield naphthopyrans instead of naphthofurans. This could be explained based on the mechanism proposed in the Scheme 3, the benzylated intermediate 7a1 (–CO₂Et=Ph) will undergo a 6-endo dig cyclisation as the benzylic position (α-carbon) is more electrophilic to be cyclised by the phenolic oxygen. In this case the 5 exo dig cyclisation is not preferred as the benzylic anion is less stable (7a2, –CO₂Et=Ph). To experimentally validate this, we performed a reaction with 2-naphthol and 1,3-diphenylprop-2-yn-1-ol derivatives (Scheme 3, 8a–8c) at 120 °C using 20 mol% of Bu₄NPF₆ under neat conditions. Interestingly, all three alkynols 8a–8c gave the naphthopyrans 9a–9c (Scheme 4) in moderate yields after 4 h.²¹ Yields could not increase even after continuing the reactions till 12 h.

Scheme 4 Bu₄NPF₆ regioselective synthesis of 2,3-diaryl naphthopyrans.

The utility of the 2-alkyl-3-aryl naphthofurans as the useful building blocks in the organic synthesis has been successfully delineated by functionalizing the sp³ C–H bond which is α to the ester functionality. Naphthofuran 3a was subjected to the DDQ mediated oxidative etherification²² (Scheme 5) with propargyl alcohol at room temperature for 12 h to yield the respective propargyl ether 12a in 72% yield. Naphthofuran 3c was also reacted with propargyl alcohol under same conditions and yielded the ether 12b in 70% yield. The resultant propargyl ethers (12a and 12b) were further subjected to the “click reaction” conditions with benzyl azides under standard conditions²³ (CuI, NEt₃, DMSO, rt) to isolate the triazole derivatives 13a–13d in 81–86% yields (Scheme 5).

Scheme 5 Oxidative etherification followed by the triazole formation of 2-alkyl, 3-aryl naphthofurans through sp³ C–H functionalization.

Encouraged by the successful functionalization of sp³ C–H bond of 2-alkyl, 3-aryl naphthofurans to prepare propargyl ethers and triazoles, we decided to further look into the preparation of α-bromoesters which are well known building blocks & feed stock materials in the organic synthesis.²⁴ α-Bromination of 3c was achieved by refluxing with N-bromosuccinimide (NBS) in CCl₄ for 10 h to furnish the α-bromoester 14 in 71% yield (Scheme 6).

Scheme 6 Synthesis of α-bromoester derivative of naphthofuran 3c.

Anti-amyloid activity

Since naphthofuran derivatives and related compounds have been shown to interact with amyloid plaques,¹¹ we were curious to explore their effect on amyloid formation. Selected three compounds were investigated for their anti-amyloidogenic properties. Compound 3f from 2-alkyl, 3-aryl naphtho[2,1-b]furans series and 5j, 5k from 2-alkyl, 3-aryl naphtho[1,2-b]furans series were selected as representatives of the two categories of compounds reported in this work. Compound 5k was also selected to see if fluoro-substitution brings any additional change in these studies. Amyloid binding compounds having a fluoro-substitution can be of potential application for positron emitting tomography (PET).²⁵

We performed the inhibition assays using lysozyme enzyme from chicken egg white as it is a readily available amyloid forming protein.²⁶ Thioflavin-T (ThT) assay were used to monitor the progress of aggregation.²⁷ Interestingly, these three compounds inhibit lysozyme aggregation by 85, 92 and 90%, respectively (Fig. 4). The results suggest that naphthofuran framework is a good inhibitor of amyloid formation and minor substitution may not bring any big change. Although we anticipated some inhibition by these compounds given previous reports, a complete inhibition of lysozyme fibrilization is unprecedented and deserves more investigation in future.

Fig. 4 (Top) Normalized ThT fluorescence intensities for lysozyme fibrils without inhibitors and with inhibitors 3f, 5j and 5k, respectively; (bottom) thioflavin-T (ThT) fluorescence spectra with lysozyme fibrils without inhibitors and lysozyme fibrils containing inhibitors 3f, 5j, and 5k, respectively.

Experimental section

General information

Unless otherwise noted, all reagents were used as received from commercial suppliers. Bu₄NPF₆ catalyst were obtained from Sigma-Aldrich and used without further purification. THF was dried in the presence of sodium metal using benzophenone as indicator and distilled prior to use. Reactions were monitored using thin-layer chromatography (TLC) with aluminium sheets silica gel 60 F254 from Merck. TLC plates were visualized with UV light (254 nm), iodine treatment or using p-anisaldehyde or KMNO₄ stain. Column chromatography was carried out using silica gel 60–120 mesh as stationary phase. NMR spectra were recorded at 500 MHz (H) and at 125 MHz (C), respectively on Avance Bruker spectrometer. Chemical shifts (δ) are reported in ppm, using the residual solvent peak in CDCl₃ (H: δ = 7.26 and C: δ = 77.0 ppm) as internal standard, and coupling constants (J) are given in Hz. HRMS was recorded using ESI-TOF techniques. Melting points were measured with Büchi Melting Point B-540 apparatus.

General experimental procedure for the synthesis of propargylic alcohol derivatives (2, 8 & 10)^1h. LHMDS (1.2 mmol) was added to a stirred solution of alkyl propiolate or phenyl acetylene (1.1 mmol) in dry THF (15 ml) at −78 °C and stirred for 30 minutes at the same temperature. Aryl aldehyde (1 mmol) was added slowly to the reaction mixture at −78 °C and the reaction progress was monitored by TLC. After completion, the reaction was brought to rt, quenched with aq-saturated NH₄Cl and extracted into EtOAc thrice. The combined organic layers were washed with brine solution and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (8–10% EtOAc in pet-ether) to obtain the desired products 2, 8 or 10.

General procedure for the Bu₄NPF₆ catalyzed synthesis of 2-alkyl, -aryl naphthofurans (3, 5, 9, & 11). A mixer of suitable propargylic alcohol (2, 8 or 10, 1.0 mmol) and naphthol 1 or 4 (1.1 mmol) was heated at 120 °C in presence of Bu₄NPF₆ (20 mol%) for 1.5–5 h. After completion of reaction (monitored by TLC), the reaction mixture was diluted with water, extracted with EtOAc thrice, the combined organic layers were washed with brine solution and dried over anhydrous Na₂SO₄. Solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (3–5%, EtOAc in pet ether) to obtain the desired product 3, 5, 9 & 11.

Ethyl 2-(1-phenylnaphtho[2,1-b]furan-2-yl)acetate (3a)^10a. Light yellow solid; (76.6 mg, 72%); mp 79–80.5 °C; δ ¹H NMR (500 MHz, CDCl₃): δ 7.95 (d, J = 8 Hz, 1H), 7.79–7.76 (m, 2H), 7.71 (d, J = 9 Hz, 1H), 7.59–7.52 (m, 5H), 7.43 (t, J = 7.5 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 4.23–4.12 (m, 2H), 3.78 (s, 2H), 1.29 (t, J = 7 Hz, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 169.3, 151.9, 146.9, 133.2, 130.8, 130.4, 128.9, 128.8, 128.5, 128.3, 128.0, 125.9, 125.5, 124.2, 123.1, 121.9, 112.4, 61.4, 33.0, 14.2 ppm; IR (KBr): ν 3063, 2974, 2915, 1738, 1572, 1447, 1395, 1318, 1189 cm⁻¹, HRMS (ESI) m/z calcd for C₂₂H₁₈O₃ [M + Na]⁺ 353.1157; found 353.1165.

Ethyl 2-(1-(p-tolyl)naphtho[2,1-b]furan-2-yl)acetate (3b)⁷. Light orange solid; (64.1 mg, 81%); mp 70.5–72.5 °C; ¹H NMR (500 MHz, CDCl₃): δ 7.95 (d, J = 8 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 8 Hz, 1H), 7.7 (d, J = 9 Hz, 1H), 7.42–7.47 (m, 3H), 7.38–7.32 (m, 3H), 4.24–4.20 (m, 2H), 3.79 (s, 2H), 2.52 (s, 3H), 1.29 (t, J = 7 Hz, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 169.4, 151.8, 146.8, 137.7, 130.8, 130.3, 130.1, 129.5, 128.8, 128.1, 125.9, 125.4, 124.2, 123.2, 121.6, 118.0, 112.4, 61.4, 33.0, 21.4, 14.2 ppm; IR (KBr): ν 3020, 2925, 1735, 1216, 759, 669 cm⁻¹, HRMS (ESI) m/z calcd for C₂₃H₂₀O₃ [M + H]⁺ 345.1490; found 345.1494.

Ethyl 2-(1-(4-methoxyphenyl)naphtho[2,1-b]furan-2-yl)acetate (3c)^10a. Light orange viscous liquid; (64.8 mg, 84%); δ ¹H NMR (500 MHz, CDCl₃): δ 7.90 (d, J = 8 Hz, 1H), 7.79 (d, J = 8 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.65 (d, J = 9 Hz, 1H), 7.46–7.44 (m, 2H), 7.37–7.41 (m, 1H), 7.39–7.31 (m, 1H), 7.05 (d, J = 8.5 Hz, 2H), 4.16–4.20 (m, 2H), 3.90 (s, 3H), 3.75 (s, 2H), 1.25 (t, J = 7 Hz, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 169.4, 159.4, 151.8, 146.9, 131.6, 130.8, 128.9, 128.2, 125.9, 125.4, 125.2, 124.2, 123.1, 122.2, 121.3, 114.2, 112.4, 61.4, 55.4, 33.0, 14.2 ppm; IR (KBr): ν 3048, 2923, 2834, 1735, 1598, 1576, 1510, 1462, 1392, 1248, 1179, 1027, 806 cm⁻¹, HRMS (ESI) m/z calcd for C₂₃H₂₀O₄ [M + Na]⁺ 383.1259; found 383.1255.

Ethyl 2-(1-(4-bromophenyl)naphtho[2,1-b]furan-2-yl)acetate (3d)^10a. Sticky white solid; (71.0 mg, 92%); ¹H NMR (500 MHz, CDCl₃): δ 7.96 (d, J = 8 Hz, 1H), 7.76 (t, J = 9.5 Hz, 2H), 7.7 (d, J = 8 Hz, 3H), 7.46 (d, J = 8.5 Hz, 3H), 7.37 (d, J = 8 Hz, 1H), 4.24–4.20 (m, 2H), 3.77 (s, 2H), 1.29 (t, J = 7.5 Hz, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 169.1, 151.9, 146.9, 132.3, 132.1, 132.0, 130.8, 129, 127.8, 126.1, 125.8, 124.4, 122.9, 122.3, 121.6, 120.6, 112.3, 61.5, 33.0, 14.2 ppm; IR (KBr): ν 3055, 2982, 2923, 1735, 1576, 1488, 1388, 1362 cm⁻¹, HRMS (ESI) m/z calcd for C₂₂H₁₇BrO₃ [M + Na]⁺ 431.0258; found 431.0250.

Ethyl 2-(1-(4-fluorophenyl)naphtho[2,1-b]furan-2-yl)acetate (3e). Pale green viscous; (62.6 mg, 80%); ¹H NMR (500 MHz, CDCl₃): δ 7.95 (d, J = 8 Hz, 1H), 7.77 (d, J = 9 Hz, 1H), 7.78–7.71 (m, 2H), 7.57–7.54 (m, 2H), 7.46–7.43 (m, 1H), 7.37–7.35 (m, 1H), 7.25 (dd, J = 1.5 Hz, J = 6.5 Hz, 2H), 4.24–4.21 (m, 2H), 3.77 (s, 2H), 1.29 (t, J = 7 Hz, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 169.2, 163.7, 161.7, 151.8, 147.0, 132.2, 132.1, 130.8, 129.0, 128.0, 126.0, 125.7, 124.3, 122.9, 115.9, 115.8, 112.4, 61.5, 33.0, 14.2 ppm; IR (KBr): ν 3063, 2974, 2915, 1738, 1572, 1447, 1395, 1318, 1189 cm⁻¹; HRMS (ESI) m/z calcd for C₂₂H₁₇FO₃ [M + Na]⁺ 371.1059; found 371.1062.

Methyl 2-(1-(p-tolyl)naphtho[2,1-b]furan-2-yl)acetate (3f). Light yellow viscous liquid; (69.6 mg, 86%); ¹H NMR (500 MHz, CDCl₃): δ 7.94 (d, J = 8 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 9 Hz, 1H), 7.70 (d, J = 9 Hz, 1H), 7.47–7.42 (m, 2H), 7.36 (t, J = 9.5 Hz, 1H), 7.28 (s, 3H), 3.81 (s, 2H), 3.76 (s, 3H), 2.52 (s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 169.9, 151.9, 146.6, 137.8, 130.8, 130.3, 130.0, 129.5, 128.9, 128.2, 125.9, 125.5, 124.2, 123.2, 122.0, 121.7, 112.3, 52.5, 32.8, 21.4 ppm; IR (KBr): ν 3060, 2974, 2915, 1738, 1572, 1447, 1395, 1318, 1180 cm⁻¹; HRMS (ESI) m/z calcd for C₂₂H₁₈O₃ [M + Na]⁺ 353.1157; found 353.1165.

Methyl 2-(1-(4-methoxyphenyl)naphtho[2,1-b]furan-2-yl)acetate (3g). Pale orange viscous liquid; (63.7 mg, 81%); ¹H NMR (500 MHz, CDCl₃): δ 7.94 (d, J = 8 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 9 Hz, 1H), 7.69 (d, J = 8.5 Hz, 2H), 7.48 (dd, J = 2 Hz, J = 6.5 Hz, 1H), 7.10–7.08 (m, 2H), 7.08–7.02 (m, 1H), 3.94 (s, 3H), 3.8 (s, 2H), 3.76 (s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 169.7, 159.4, 151.9, 146.7, 132.0, 131.5, 130.8, 128.9, 128.2, 125.9, 125.5, 125.1, 124.2, 123.1, 121.3, 114.3, 112.3, 55.4, 52.5, 32.7 ppm; IR (KBr): ν 3063, 2974, 2915, 1738, 1572, 1447, 1395, 1318, 1189 cm⁻¹; HRMS (ESI) m/z calcd for C₂₂H₁₈O₄ [M + H]⁺ 347.1283; found 347.1282.

Methyl 2-(1-phenylnaphtho[2,1-b]furan-2-yl)acetate (3h). Yellow viscous liquid; (66.3 mg, 80%); ¹H NMR (500 MHz, CDCl₃): δ 7.93 (d, J = 8.5 Hz, 1H), 7.77–7.68 (m, 3H), 7.56–7.51 (m, 5H), 7.43–7.33 (m, 2H), 1.99 (s, 2H), 3.75 (s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 168.5, 150.6, 145.4, 131.9, 129.5, 129.1, 127.6, 127.5, 126.8, 124.7, 124.3, 123.0, 121.9, 121.6, 120.6, 120.5, 111.1, 51.2, 31.5 ppm; IR (KBr): ν 3063, 2974, 2915, 1738, 1572, 1447, 1395, 1318, 1180 cm⁻¹; HRMS (ESI) m/z calcd for C₂₁H₁₆O₃ [M + H]⁺ 317.1177; found 317.1179.

Ethyl 2-(7-bromo-1-phenylnaphtho[2,1-b]furan-2-yl)acetate (3i). Orange viscous liquid; (61.0 mg, 79%); ¹H NMR (500 MHz, CDCl₃): δ 8.09 (d, J = 2 Hz, 1H), 7.72 (d, J = 9 Hz, 1H), 7.67–7.63 (m, 2H), 7.55 (d, J = 9 Hz, 5H), 7.40–7.38 (m, 1H), 4.24–4.20 (m, 2H), 3.79 (s, 2H), 1.30 (t, J = 14 Hz, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 169.2, 151.9, 147.4, 132.8, 132.1, 130.8, 130.3, 129.1, 128.9, 128.2, 126.5, 124.8, 124.5, 122.1, 121.5, 118.0, 113.4, 61.5, 33.0, 14.2 ppm; HRMS (ESI) m/z calcd for C₂₂H₁₇BrO₃ [M + Na]⁺ 431.0258; found 431.0237.

Ethyl 2-(7-bromo-1-(4-fluorophenyl)naphtho[2,1-b]furan-2-yl)acetate (3j). Orange viscous liquid; (61.9 mg, 82%); ¹H NMR (500 MHz, CDCl₃): δ 8.09 (d, J = 2 Hz, 1H), 7.71 (d, J = 9 Hz, 2H), 7.67 (s, 1H), 7.50–7.53 (m, 2H), 7.42 (s, 1H), 7.26 (t, J = 9 Hz, 2H), 4.20–4.24 (m, 2H), 3.77 (s, 2H), 1.29 (t, J = 7 Hz, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 169.1, 163.8, 161.8, 151.8, 147.6, 132.1, 132.0, 130.9, 129.2, 126.4, 124.6, 124.5, 120.5, 118.1, 116.1, 115.9, 113.4, 61.5, 32.9, 14.1 ppm; HRMS (ESI) m/z calcd for C₂₂H₁₆BrFO₃ [M + Na]⁺ 449.0164; found 449.0145.

Ethyl 2-(7-bromo-1-(4-methoxyphenyl)naphtho[2,1-b]furan-2-yl)acetate (3k). Light orange viscous liquid; (62.8 mg, 84%); ¹H NMR (500 MHz, CDCl₃): δ 8.06 (d, J = 2 Hz, 1H), 7.69–7.62 (m, 3H), 7.43 (d, J = 8.5 Hz, 2H), 7.38 (dd, J = 2 Hz, J = 7 Hz, 1H), 7.06 (d, J = 8.5 Hz, 2H), 4.43–4.19 (m, 2H), 3.94 (s, 2H), 3.77 (s, 3H), 1.29 (t, J = 7 Hz, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 169.3, 159.5, 151.8, 147.4, 132.1, 131.5, 130.8, 129.1, 126.6, 124.8, 124.4, 122.4, 121.1, 117.9, 114.3, 113.8, 113.4, 61.4, 55.4, 33.0, 14.2 ppm; HRMS (ESI) m/z calcd for C₂₃H₁₉BrO₄ [M + H]⁺ 439.0544; found 439.0540.

Ethyl 2-(7-bromo-1-(p-tolyl)naphtho[2,1-b]furan-2-yl)acetate (3l). Light yellow viscous liquid; (62.6 mg, 85%); ¹H NMR (500 MHz, CDCl₃): δ 8.08 (d, J = 2 Hz, 1H), 7.70 (t, J = 10 Hz, 2H), 7.64 (d, J = 9 Hz, 1H), 7.42–7.40 (m, 3H), 7.36 (d, J = 7.5 Hz, 2H), 4.24–4.20 (m, 2H), 3.79 (s, 2H), 2.51 (s, 3H), 1.29 (t, J = 7.5 Hz, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 169.2, 151.9, 147.4, 138.0, 132.1, 130.8, 130.2, 129.7, 129.6, 129, 126.6, 124.9, 124.4, 122.2, 121.4, 117.9, 113.4, 61.4, 33.0, 21.4, 14 ppm; IR (KBr): ν 3063, 2974, 2915, 1738, 1572, 1447, 1395, 1318, 1189 cm⁻¹; HRMS (ESI) m/z calcd for C₂₃H₁₉BrO₃ [M + Na]⁺ 445.0415; found 445.0395.

Methyl 2-(7-bromo-1-(p-tolyl)naphtho[2,1-b]furan-2-yl)acetate (3m). Light yellow solid; (67.9 mg, 88%); mp 139–141 °C; ¹H NMR (500 MHz, CDCl₃): δ 8.08 (d, J = 2 Hz, 1H), 7.72–7.64 (m, 3H), 7.43–7.39 (m, 3H), 7.36 (d, J = 8 Hz, 2H), 3.80 (s, 2H), 3.76 (s, 3H), 2.51 (s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 169.7, 151.9, 147.1, 138, 132.1, 130.8, 130.1, 129.7, 129.6, 129.1, 126.6, 124.9, 124.5, 122.2, 121.5, 118.0, 113.4, 52.5, 32.7, 21.4 ppm; HRMS (ESI) m/z calcd for C₂₂H₁₇BrO₃ [M + Na]⁺ 431.0258; found 431.0250.

Methyl 2-(7-bromo-1-(4-methoxyphenyl)naphtho[2,1-b]furan-2-yl)acetate (3n). Light orange viscous liquid; (63.6 mg, 84%); ¹H NMR (500 MHz, CDCl₃): δ 8.08 (d, J = 2 Hz, 1H), 7.87 (d, J = 9 Hz, 1H), 7.71–7.64 (m, 3H), 7.46–7.41 (m, 2H), 7.08 (dd, J = 2 Hz, J = 6.5 Hz, 2H), 3.94 (s, 3H), 3.8 (s, 2H), 3.75 (s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 169.7, 159.5, 151.8, 147.2, 132.1, 131.4, 130.8, 129.1, 126.6, 124.8, 124.4, 122.3, 121.2, 118, 114.3 (2C), 113.4, 55.4, 52.5, 32.7 ppm; IR (KBr): ν 3063, 2974, 2915, 1738, 1570, 1447, 1395, 1318, 1180 cm⁻¹; HRMS (ESI) m/z calcd for C₂₂H₁₇BrO₄ [M + Na]⁺ 447.0207; found 447.0193.

Ethyl 2-(3-phenylnaphtho[1,2-b]furan-2-yl)acetate (5a)^10a. Orange sticky solid; (74.4 mg, 92%); ¹H NMR (500 MHz, CDCl₃): δ 7.95 (d, J = 8 Hz, 1H), 7.81–7.78 (m, 2H), 7.7 (d, J = 9 Hz, 1H), 7.57–7.54 (m, 4H), 7.45–7.41 (m, 2H), 7.34–7.31 (m, 1H), 4.24–4.20 (m, 2H), 3.79 (s, 2H), 1.29 (t, J = 7 Hz, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 169.3, 151.9, 146.9, 130.8, 130.4, 128.9, 128.8, 128.5, 128.3, 128.1, 126.8, 125.9, 125.5, 124.2, 123.1, 118.0, 112.4, 61.4, 33.0, 14.2 ppm; IR (KBr): ν 3055, 2982, 2922, 1735, 1580, 1443, 1377, 1252, 1182, 1027, 982 cm⁻¹, HRMS (ESI) m/z calcd for C₂₂H₁₈O₃ [M + Na]⁺ 353.1157; found 353.1164.

Ethyl 2-(3-(p-tolyl)naphtho[1,2-b]furan-2-yl)acetate (5b)⁷. Light yellow viscous liquid; (69.7 mg, 88%); ¹H NMR (500 MHz, CDCl₃): δ 7.94 (d, J = 9 Hz, 1H), 7.82 (d, J = 7 Hz, 1H), 7.75 (d, J = 9 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.44 (t, J = 8 Hz, 3H), 7.34 (m, 3H), 4.24–4.20 (m, 2H), 3.78 (s, 2H), 2.51 (s, 3H), 1.28 (t, J = 7 Hz, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 169.42, 151.8, 146.8, 137.7, 130.7, 130.3, 130.1, 129.5, 128.8, 128.1, 125.8, 125.4, 124.2, 123.2, 122.0, 121.6, 112.4, 61.4, 33.0, 21.4, 14.2, ppm; IR (KBr): ν 3022, 2983, 2926, 1737, 1513, 1382, 1258, 1216, 812, 758 cm⁻¹, HRMS (ESI) m/z calcd for C₂₃H₂₀O₃ [M + Na]⁺ 367.1310; found 367.1314.

Ethyl 2-(3-(4-methoxyphenyl)naphtho[1,2-b]furan-2-yl)acetate (5c)^10a. Orange solid; (71.8 mg, 93%); mp 85–87 °C; ¹H NMR (500 MHz, CDCl₃): δ 7.95 (d, J = 8 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 9 Hz, 1H), 7.71 (d, J = 9 Hz, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.46–7.43 (m, 1H), 7.37–7.32 (t, J = 7 Hz, 1H), 7.10 (d, J = 8 Hz, 2H), 4.26–4.21 (m, 2H), 3.95 (s, 3H), 3.80 (s, 2H), 1.3 (t, J = 7 Hz, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 169.4, 159.4, 151.8, 146.9, 131.6, 130.8, 128.9, 128.2, 125.9, 125.4, 125.2, 124.2, 123.13, 122.2, 121.3, 114.2, 112.4, 61.4, 55.4, 33.0, 14.2 ppm; IR (KBr): ν 2915, 2836, 1741, 1515, 1459, 1381, 1250, 1179 cm⁻¹, HRMS (ESI) m/z calcd for C₂₃H₂₀O₄ [M + Na]⁺ 383.1259; found 383.1255.

Ethyl 2-(3-(4-bromophenyl)naphtho[1,2-b]furan-2-yl)acetate (5d)^10a. Orange solid; (65.6 mg, 85%); mp 87–89.5 °C; ¹H NMR (500 MHz, CDCl₃): δ 7.95 (d, J = 8.5 Hz, 1H), 7.77 (t, J = 9 Hz, 2H), 7.70 (dd, J = 2 Hz, J = 7.5 Hz, 3H), 7.48–7.45 (m, 3H), 7.38 (dd, J = 1.5 Hz, J = 8.5 Hz, 1H), 4.24–4.20 (m, 2H), 3.77 (s, 2H), 1.3 (t, J = 7.5 Hz, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 169.1, 151.9, 146.9, 132.3, 132.1, 132.0, 130.1, 129.0, 127.9, 126.1, 127.9, 126.1, 125.8, 124.4, 122.9, 122.3, 121.6, 120.6, 112.4, 61.5, 33.0, 14.2 ppm; IR (KBr): ν 3055, 2923, 2843, 1735, 1488, 1377, 1253, 1189 cm⁻¹; HRMS (ESI) m/z calcd for C₂₂H₁₇BrO₃ [M + Na]⁺ 431.0258; found 431.0259.

Ethyl 2-(1-(4-chlorophenyl)naphtho[2,1-b]furan-2-yl)acetate (5e)^10a. Yellow solid; (57.3 mg, 75%); mp 62–63.5 °C; ¹H NMR (500 MHz, CDCl₃): δ 7.83 (d, J = 8 Hz, 1H), 7.64 (t, J = 9 Hz, 2H), 7.58 (d, J = 8.5 Hz, 3H), 7.35–7.31 (m, 3H), 7.26–7.23 (m, 1H), 4.1 (q, J = 7 Hz, 2H), 3.65 (s, 2H), 1.17 (t, J = 7 Hz, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 169.1, 159.1, 146.6, 131.3, 130.5, 128.6, 127.9, 125.6, 125.1, 124.9, 123.9, 122.8, 121.9, 121.0, 113.9, 112.1, 61.1, 55.1, 32.7, 13.9 ppm; IR (KBr): ν 3055, 2923, 2841, 1735, 1490, 1377, 1255, 1189, 1086 cm⁻¹; HRMS (ESI) m/z calcd for C₂₂H₁₇ClO₃ [M + Na]⁺ 387.0764; found 387.0773.

Ethyl 2-(3-(4-fluorophenyl)naphtho[1,2-b]furan-2-yl)acetate (5f). Orange viscous liquid; (66.5 mg, 85%); ¹H NMR (500 MHz, CDCl₃): 7.95 (d, J = 8 Hz, 1H), 7.77 (d, J = 9 Hz, 1H), 7.74–7.69 (m, 2H), 7.56–7.54 (m, 2H), 7.53 (s, 1H), 7.44 (t, J = 7 Hz, 1H), 7.34 (t, J = 7 Hz, 1H), 7.29–7.26 (m, 1H), 4.24–4.20 (m, 2H), 3.77 (s, 2H), 1.29 (t, J = 7 Hz, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 169.2, 163.7, 161.7, 151.8, 147.0, 132.2, 132.1, 130.8, 129.0, 128.0, 126.0, 125.7, 124.3, 122.9, 115.9, 115.8, 112.4, 61.5, 33.0, 14.2 ppm; HRMS (ESI) m/z calcd for C₂₂H₁₇FO₃ [M + Na]⁺ 371.1059; found 371.1062.

Methyl 2-(3-(4-methoxyphenyl)naphtho[1,2-b]furan-2-yl)acetate (5g). Light orange viscous liquid; (66.1 mg, 84%); ¹H NMR (500 MHz, CDCl₃): δ 7.87 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 6.5 Hz, 1H), 7.76 (d, J = 9 Hz, 1H), 7.69 (d, J = 9 Hz, 1H), 7.48 (d, J = 2 Hz, 2H), 7.45–7.41 (m, 1H), 7.36–7.32 (m, 1H), 7.11–7.03 (m, 2H), 3.95 (s, 3H), 3.80 (s, 2H), 3.76 (s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 169.9, 159.4, 151.8, 146.6, 131.5, 130.8, 128.9, 128.2, 125.9, 125.5, 125.1, 124.2, 123.1, 122.1, 114.3, 114.2, 112.3, 55.4, 52.5, 32.8 ppm; HRMS (ESI) m/z calcd for C₂₂H₁₈O₄ [M + H]⁺ 347.1283; found 347.1281.

Methyl 2-(3-(p-tolyl)naphtho[1,2-b]furan-2-yl)acetate (5h). Light yellow viscous liquid; (75.2 mg, 93%); ¹H NMR (500 MHz, CDCl₃): δ 7.95 (d, J = 8 Hz, 1H), 7.84 (d, J = 8 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.7 (d, J = 8.5 Hz, 1H), 7.47–7.42 (m, 2H), 7.38 (s, 1H), 7.37–7.33 (m, 3H), 3.82 (s, 2H), 3.77 (s, 3H), 2.52 (s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): 169.9, 151.9, 146.6, 137.8, 130.8, 130.3, 130.0, 129.5, 128.9, 128.2, 125.9, 125.5, 124.2, 123.2, 122.0, 121.7, 112.4, 52.5, 32.8, 21.4 ppm; HRMS (ESI) m/z calcd for C₂₂H₁₈O₃ [M + Na]⁺ 353.1153; found 353.1138.

Methyl 2-(3-phenylnaphtho[1,2-b]furan-2-yl)acetate (5i). Light yellow viscous liquid; (67.1 mg, 81%); ¹H NMR (500 MHz, CDCl₃): δ 7.95 (d, J = 8.5 Hz, 1H), 7.78 (dd, J = 6 Hz, J = 9 Hz, 3H), 7.57–7.56 (m, 4H), 7.55–7.52 (m, 1H), 7.44–7.41 (m, 1H), 7.34–7.31 (m, 1H), 3.81 (s, 2H), 3.76 (s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 169.8, 151.9, 146.3, 135.8, 133.2, 130.8, 130.4, 128.9, 128.8, 128.1, 125.9, 125.6, 124.3, 123.1, 121.9, 121.7, 112.3, 52.5, 32.8 ppm; HRMS (ESI) m/z calcd for C₂₁H₁₆O₃ [M + H]⁺ 317.1177; found 317.1176.

Ethyl 2-(5-methoxy-3-phenylnaphtho[1,2-b]furan-2-yl)acetate (5j). Pale green gummy; (59 mg, 75%); ¹H NMR (500 MHz, CDCl₃): δ 8.33 (d, J = 8 Hz, 1H), 8.29 (dd, J = 1 Hz, J = 7.5 Hz, 1H), 7.63–7.61 (m, 3H), 7.57 (d, J = 7.5 Hz, 2H), 7.54–7.45 (m, 3H), 4.24–4.28 (m, 2H), 4.01 (s, 3H), 3.96 (s, 2H), 1.31 (t, J = 7 Hz, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 169.5, 152.4, 146.0, 132.4, 129.1, 128.6, 127.5, 126.9, 125.2, 124.6, 124.1, 123.0, 122.9, 121.6, 121.2, 119.9, 95.6, 61.4, 55.9, 33.6, 14.2 ppm; HRMS (ESI) m/z calcd for C₂₃H₂₀O₄ [M + Na]⁺ 383.1259; found 383.1255.

Ethyl 2-(3-(4-fluorophenyl)-5-methoxynaphtho[1,2-b]furan-2-yl)acetate (5k). Brown solid; (58.8 mg, 77%); mp 100–102 °C; ¹H NMR (500 MHz, CDCl₃): δ 8.30 (dd, J = 1.5 Hz, J = 8.5 Hz, 2H), 7.66–7.64 (m, 1H), 7.63–7.58 (m, 2H), 7.54–7.51 (m, 1H), 7.27–7.24 (m, 2H), 6.88 (s, 1H), 4.28–4.24 (m, 2H), 4.01 (s, 3H), 3.92 (s, 2H), 1.32 (t, J = 7 Hz, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 169.4, 152.5, 146.0, 144.8, 130.8, 130.7, 127.0, 124.7, 124.1, 123.0, 122.9, 121.6, 120.3, 119.9, 116.1, 115.9, 95.3, 61.5, 55.9, 33.5, 14.2 ppm; HRMS (ESI) m/z calcd for C₂₃H₁₉FO₄ [M + H]⁺ 379.1345; found 379.1345.

Ethyl 2-(6-methoxy-3-phenylbenzofuran-2-yl)acetate (6b). Light yellow viscous liquid; (26.9 mg, 39%); ¹H NMR (500 MHz, CDCl₃): δ 7.48–7.44 (m, 3H), 7.31 (t, J = 8 Hz, 2H), 7.76 (d, J = 2.5 Hz, 1H), 6.91–6.89 (m, 1H), 4.24–4.22 (m, 2H), 3.88 (s, 3H), 3.85 (s, 2H), 2.44 (s, 3H), 1.30 (t, J = 7 Hz, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 169.5, 158.1, 155.3, 145.4, 137.3, 129.6, 129.0, 128.8, 121.8, 120.1, 119.5, 111.7, 95.9, 61.4, 55.8, 33.4, 21.3, 14.2 ppm; HRMS (ESI) m/z calcd for C₂₀H₂₀O₄ [M + Na]⁺ 347.1259; found 347.1243.

Diethyl 4,4′-oxybis(4-phenylbut-2-ynoate) (7). Colourless liquid; (37 mg, 88%); ¹H NMR (500 MHz, CDCl₃): δ 7.49–7.48 (m, 2H), 7.43–7.42 (m, 2H), 7.37–7.32 (m, 6H), 5.64 (s, 1H), 5.29 (s, 1H), 4.24–4.18 (m, 4H), 1.3–1.25 (m, 6H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 153.1, 153, 135.9, 135.6, 129.5, 129.2, 129, 128.8, 127.9, 127.7, 83.5, 83.2, 79.9, 79.3, 69.6, 69, 62.4, 62.3, 14.05, 14.03 ppm. HRMS (ESI) m/z calcd for C₂₄H₂₂O₅ [M + Na]⁺ 413.1364; found 413.1360.

Ethyl 4-(2-hydroxynaphthalen-1-yl)-4-phenylbut-2-ynoate (7a1). Pale yellow liquid; ¹H NMR (500 MHz, CDCl₃): δ 7.77 (s, 1H), 7.73 (d, J = 9.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 7.5 Hz, 3H), 7.38–7.30 (m, 3H), 7.12 (d, J = 7.5 Hz, 2H), 5.41 (s, 1H), 5.27 (s, 1H), 4.31–4.27 (m, 2H), 1.35 (d, J = 7.5 Hz, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 153.8, 139.4, 134.4, 133.8, 129.9, 128, 128.7, 128, 127.6, 127.5, 127.2, 126.6, 126.4, 118.3, 109.4, 88.2, 62.2, 43, 14.1 ppm. HRMS (ESI) m/z calcd for C₂₂H₁₈O₃ [M + Na]⁺ 353.1157; found 353.1165.

Ethyl-2-(1-(p-tolyl)naphtho[2,1-b]furan-2(1H)-ylidene)acetate (7a3). Yellow viscous liquid; (48.5 mg, 68%); ¹H NMR (500 MHz, CDCl₃): δ 7.85–7.83 (m, 2H), 7.65 (d, J = 8 Hz, 1H), 7.39 (d, J = 9 Hz, 2H), 7.34 (t, J = 8 Hz, 1H), 7.27 (d, J = 8 Hz, 2H), 7.08 (d, J = 8 Hz, 2H), 6.07 (s, 1H), 5.85 (d, J = 2 Hz, 1H), 4.13 (q, J = 7.5 Hz, 2H), 2.28 (s, 3H), 1.26 (t, J = 7 Hz, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 177.3, 166.4, 153.1, 137.1, 136.5, 130.8, 130.3, 130.2, 129.5, 129.3, 129.1, 129, 128.5, 127.4, 124.2, 123.2, 122.9, 111.2, 95.7, 59.8, 51.1, 21.1, 14.4 ppm; HRMS (ESI) m/z calcd for C₂₃H₂₀O₃ [M + H]⁺ 345.1490; found 345.1494.

2,4-Diphenyl-4H-benzo[h]chromene (9a)²⁸. Yellow solid; (48.8 mg, 60%); mp 200–203 °C; ¹H NMR (500 MHz, CDCl₃): δ 7.83 (d, J = 8.5 Hz, 2H), 7.78 (t, J = 1.5 Hz, 3H), 7.46–7.38 (m, 4H), 7.39–7.37 (m, 2H), 7.33–7.31 (m, 3H), 7.29 (d, J = 2.5 Hz, 2H), 5.85 (d, J = 5 Hz, 1H), 5.4 (d, J = 5 Hz, 1H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 149.6, 146.6, 146.3, 133.9, 131.7, 131, 130.6, 129, 128.8, 128.4, 128.3, 127.7, 125.5, 125, 124.7, 124.1, 123.7, 118.1, 114.3, 102.2, 39.2 ppm.

1-(4-Methoxyphenyl)-3-phenyl-1H-benzo[f]chromene (9b)²⁸. White solid; (46.7 mg, 61%); mp 198–200 °C; ¹H NMR (500 MHz, CDCl₃): δ 7.8 (t, J = 1.5 Hz, 1H), 7.72–7.70 (m, 2H), 7.64 (s, 1H), 7.56 (d, J = 8 Hz, 1H), 7.36 (s, 1H), 7.32–7.26 (m, 3H), 7.16 (t, J = 8 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 6.71 (d, J = 8.5 Hz, 2H), 5.71 (d, J = 5 Hz, 1H), 5.22 (d, J = 5 Hz, 1H), 3.65 (s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 158.1, 149.2, 145.1, 138.3, 136.1, 131.6, 131.3, 129.8, 129, 128.7, 127.7, 126.6, 124.2, 123.6, 123.2, 122.6, 118, 114.4, 114.2, 103.5, 55.2, 38.2 ppm.

1-(4-Bromophenyl)-3-phenyl-1H-benzo[f]chromene (9c). Light yellow solid; (41.8 mg, 60%); mp 176–178 °C ¹H NMR (500 MHz, CDCl₃): δ 7.73 (d, J = 3 Hz, 2H), 7.58–7.56 (m, t, J = 10 Hz, 1H), 7.52–7.51 (m, 2H), 7.45–7.43 (m, 2H), 7.32–7.29 (m, J = 6H), 7.02–7.05 (m, 2H), 5.67 (d, J = 5 Hz, 1H), 5.24 (d, J = 10 Hz, 1H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 149.4, 146.1, 145.1, 132.7, 132, 131.5, 131.4, 131.1, 129.4, 129.3, 128.5, 126.8, 126.3, 124.4, 123.4, 122.7, 120.4, 117.9, 113.5, 102, 38 ppm; (ESI) m/z for C₂₅H₁₇BrO [M + H]⁺ 413.0540; found 413.0526.

2-Methyl-1-phenylnaphtho[2,1-b]furan (11)⁸. Brown liquid; (40.3 mg, 65%); ¹H NMR (500 MHz, CDCl₃): δ 7.95 (d, J = 8 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.55 (t, J = 8 Hz, 4H), 7.51 (d, J = 2 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 2.47 (s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 150.2, 134.3, 130.7, 130.5, 129.2, 128.8, 128, 127.9, 127.6, 125.6, 124.5, 124, 123.2, 122.3, 119, 112, 12.3 ppm.

General procedure for the oxidative C(sp³)–H functionalization of 2,3-disubstituted naphthofurans (12)⁵. To a stirred solution of propargyl alcohol 2 (2 ml) and naphthofuran 3a or 3c (1 mmol) in dichloromethane was added DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) (2 mmol) at rt. The mixture was continued for 12 h. After completion of reaction (monitored by TLC), reaction mixture was diluted with water, neutralized with Na₂CO₃ and extracted with dichloromethane thrice. The combined organic layers were washed with brine solution and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (12–14%, EtOAc in pet ether) to obtain desired product 12.

Ethyl 2-(1-phenylnaphtho[2,1-b]furan-2-yl)-2-(prop-2-yn-1-yloxy)acetate (12a). Pink oily liquid; (45.5 mg, 72%); ¹H NMR (500 MHz, CDCl₃): δ 7.96 (d, J = 8 Hz, 1H), 7.84–7.78 (m, 2H), 7.73 (d, J = 9 Hz, 1H), 7.66 (t, J = 8 Hz, 2H), 7.6–7.56 (m, 3H), 7.48–7.44 (m, 1H), 7.38–7.35 (m, 1H), 5.39 (s, 1H), 4.36–4.2 (m, 4H), 2.23 (s, 1H), 1.23 (t, J = 7 Hz, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 168.1, 152.4, 146.3, 132.1, 130.8, 130.7, 130.6, 129, 128.8, 128.7, 128.4, 128.2, 127, 126.3, 125.1, 124.6, 123.1, 121.3, 112.7, 78, 75.8, 70.3, 62, 56.4, 14.1 ppm; HRMS (ESI) m/z calcd for C₂₅H₂₀O₄ [M + Na]⁺ 407.1259; found 407.1231.

Ethyl 2-(1-(4-methoxyphenyl)naphtho[2,1-b]furan-2-yl)-2-(prop-2-yn-1-yloxy)acetate (12b). Pink viscous liquid; (43.1 mg, 70%); ¹H NMR (500 MHz, CDCl₃): δ 7.95 (d, J = 8 Hz, 1H), 7.82 (t, J = 9.5 Hz, 2H), 7.71 (d, J = 9 Hz, 1H), 7.56 (t, J = 7 Hz, 2H), 7.46 (t, J = 8 Hz, 1H), 7.36 (t, J = 8 Hz, 1H), 7.56 (m, 2H), 5.38 (s, 1H), 4.35–4.23 (m, 4H), 3.96 (s, 3H), 2.27 (s, 1H), 1.28 (t, J = 7 Hz, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 168.1, 159.7, 152.3, 146.2, 131.9, 131.7, 130.8, 129, 128.3, 126.8, 126.3, 124.7, 124.5, 124.1, 123.1, 121.6, 114.3, 113.9, 112.7, 78.1, 75.8, 70.4, 62, 56.4, 55.4, 14.1 ppm. (ESI) m/z for C₂₆H₂₂O₅ [M + H]⁺ 415.1545; found 415.1534.

General procedure for the synthesis of triazole formation from 12 (13). To a stirred solution of terminal alkyne 12a or 12b (1 mmol) and benzyl azide (1.5 mmol) in DMSO (1.5 ml) was added Et₃N (0.4 mmol) and CuI (10 mol%) at rt. After completion (monitored by TLC) of the reaction, the reaction mixture was diluted with cold water and extracted with EtOAc thrice. The combined organic layers were washed with brine solution and dried over anhydrous Na₂SO₄. Solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (30–40%, EtOAc in pet ether) to obtain desired triazole products 13.

Ethyl 2-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)-2-(1-phenylnaphtho[2,1-b]furan-2-yl)acetate (13a). Yellow sticky solid; (81.2 mg, 81%); ¹H NMR (500 MHz, CDCl₃): δ 7.95 (d, J = 8 Hz, 1H), 7.81 (d, J = 9 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.7 (d, J = 8 Hz, 1H), 7.59–7.54 (m, 5H), 7.42 (t, J = 7 Hz, 1H), 7.37–7.33 (m, 5H), 7.24 (t, J = 3 Hz, 2H), 5.44 (q, J = 18.5 Hz, 2H), 5.17 (s, 1H), 4.71 (q, J = 11.5 Hz, 2H), 4.24 (q, J = 6.5 Hz, 2H), 1.26 (t, J = 7 Hz, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 168.3, 152.3, 146.7, 144.5, 134.4, 132.2, 130.8, 130.7, 130.4, 129.1, 129, 128.9, 128.8, 128.4, 128.2, 128.1, 126.9, 126.3, 124.6, 124.4, 123.1, 122.8, 121.3, 112.7, 71.8, 63.2, 61.9, 54.1, 14.1 ppm; HRMS (ESI) m/z calcd for C₃₂H₂₇N₃O₄ [M + H]⁺ 518.2079; found 518.2088.

Ethyl 2-((1-(1-phenylethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(1-phenylnaphtho[2,1-b]furan-2-yl)acetate (13b). Light yellow sticky solid; (76.8 mg, 83%); ¹H NMR (500 MHz, CDCl₃): δ 7.96 (d, J = 8 Hz, 1H), 7.82 (d, J = 9 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 6.5 Hz, 1H), 7.55 (s, 4H), 7.45 (t, J = 7.5 Hz, 1H), 7.36–7.33 (m, 5H), 7.72–7.22 (m, 2H), 5.77–5.71 (m, 1H), 5.17 (s, 1H), 4.75–4.71 (m, 2H), 4.28–4.21 (m, 2H), 1.91 (dd, J = 17 Hz, J = 17.5 Hz, 3H), 1.27 (t, J = 4.5 Hz, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): partially rotamers, δ 168.3, 152.2, 146.8, 144.1, 144.0, 139.8, 139.7, 132.1, 132.1, 130.8, 130.6, 130.3, 129, 128.9, 128.8, 128.6, 128.56, 128.55, 128.4, 128.2, 126.9, 126.6, 126.5, 126.3, 124.6, 124.43, 124.41, 123.1, 121.7, 121.5, 121.4, 112.7, 72, 71.9, 63.4, 63.3, 62, 60.3, 60.2, 21.3, 21.2, 14.1 ppm; HRMS (ESI) m/z calcd for C₃₃H₂₉N₃O₄ [M + H]⁺ 532.2236; found 532.2246.

Ethyl 2-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)-2-(1-(4-methoxyphenyl)naphtho[2,1-b]furan-2-yl)acetate (13c). Light yellow sticky solid; (93.1 mg, 88%); ¹H NMR (500 MHz, DMSO-d₆): δ 8.03 (d, J = 8.5 Hz, 2H), 7.91 (d, J = 9 Hz, 1H), 7.81 (d, J = 9 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.47–7.25 (m, 9H), 7.14–7.06 (m, 2H), 5.53 (s, 2H), 5.11 (s, 1H), 4.57 (q, J = 17.5 Hz, 2H), 4.08 (q, J = 7 Hz, 2H), 3.86 (s, 3H), 1.11 (t, J = 7 Hz, 3H) ppm; ¹³C NMR (125 MHz, DMSO-d₆): δ 173.1, 164.5, 156.6, 152.6, 148.4, 141.1, 136.8, 136.5, 135.7, 133.9, 133.4, 133.1, 132.8, 132.1, 131.7, 129.9, 128.4, 128.1, 127.4, 126, 119.6, 117.8, 76.1, 67.3, 66.6, 60.4, 57.9, 19.1 ppm; HRMS (ESI) m/z calcd for C₃₃H₂₉N₃O₅ [M + Na]⁺ 570.1999; found 570.2045.

Ethyl 2-(1-(4-methoxyphenyl)naphtho[2,1-b]furan-2-yl)-2-((1-(1-phenylethyl)-1H-1,2,3-triazol-4-yl)methoxy)acetate (13d). Yellow sticky solid; (83.9 mg, 86%); ¹H NMR (500 MHz, CDCl₃): δ 7.95 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 9 Hz, 1H), 7.51 (d, J = 8 Hz, 1H), 7.45 (t, J = 7 Hz, 2H), 7.38–7.32 (m, 5H), 7.24–7.21 (m, 2H), 7.09 (t, J = 8.5 Hz, 2H), 5.77–5.69 (m, 1H), 5.17 (s, 1H), 4.71 (s, 2H), 4.24 (q, J = 4 Hz, 2H), 3.96 (s, 3H), 1.9 (dd, J = 21 Hz, J = 21 Hz, 3H), 1.26 (t, J = 7.5 Hz, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): partially rotamers, δ 168.4, 152.2, 146.7, 144.2, 131.8, 130.8, 129, 129, 128.5, 128.5, 128.3, 126.8, 126.6, 126.5, 126.2, 124.5, 124.1, 124, 123.1, 121.6, 121.4, 114.4, 112.7, 72, 63.4, 63.3, 61.9, 60.3, 60.1, 55.4, 21.3, 21.2, 14.1 ppm; HRMS (ESI) m/z calcd for C₃₄H₃₁N₃O₅ [M + H]⁺ 562.2341; found 562.2354.

Ethyl 2-bromo-2-(1-(4-methoxyphenyl)naphtha[2,1-b]furan-2-yl)acetate (14). Light brown viscous liquid; (42.9 mg, 71%) ¹H NMR (500 MHz, CDCl₃): δ 8.28 (d, J = 7.5 Hz, 1H), 7.59–7.45 (m, 8H), 7.35 (t, J = 7 Hz, 1H), 6.13 (s, 1H), 4.07 (q, J = 4 Hz, 2H), 3.44 (s, 3H), 1.14 (t, J = 7.5 Hz, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 170.8, 167.3, 145, 131.6, 131.3, 130.3, 129.9, 129.4, 128.7, 128.3, 127.9, 127.4, 127.2, 125.2, 123.2, 122.8, 114.9, 100.8, 60.9, 50.6, 40.9, 14.1 ppm; HRMS (ESI) m/z calcd for C₂₃H₁₉BrO₄ [M + H]⁺ 439.0544; found 439.0540.

Lysozyme fibrilization experiment

Lysozyme from chicken egg white was purchased from Sigma Aldrich (catalog number L6876). Lysozyme fibrils were prepared by dissolving monomeric lysozyme films in DMSO, diluting into the PBS buffer to a final concentration of 20 μM. The resulting solutions were incubated for 72 h at 60 °C with continuous agitation (final DMSO concentration was <2%). For aggregation inhibition studies, inhibitors (20 μM final concentration using a 2 mM stock solution in DMSO) were added to lysozyme solutions and then incubated for 72 h at 60 °C with constant agitation.

Fluorescence measurements

All fluorescence measurements were performed using a Perkin Elmer fluorescence spectrometer (model no. LS55). For ThT fluorescence studies, samples were diluted to a final lysozyme concentration of 2.5 μM in PBS containing ThT (10 μM) and the fluorescence intensities were measured at 485 nm (λ_ex = 435 nm).

Conclusions

In conclusion, we have developed an Bu₄NPF₆ catalyzed, acid, metal and solvent free, regioselective one pot cascade synthesis of 2-alkyl, 3-aryl naphthofurans from the easily available reactants under simple reaction conditions. Control experiments have been performed to justify the mechanism. The utility of the synthetic compounds has also been illustrated successfully by synthesizing the α-bromo esters, ethers and triazole derivatives. Atom and step economy, large substrate scope, high yields and short reaction time make this methodology superior to the existing metal catalysed and multistep procedures. In addition, the biological relevance of these compounds has been established for selected compounds. ThT fluorescence data for the lysozyme aggregation clearly suggest that complete arrest of aggregation process occurred when these compounds were added in fibrilization conditions. This preliminary anti-amyloidogenic feature of these compounds is being explored further in our laboratories.

Acknowledgements

Science and Engineering Research Board (DST-SERB) India is acknowledged for the financial support through Fast Track Young Scientist programme (No. SB/FT/CS-149/2012). AP, RD & MR thank Central University of Rajasthan for their fellowships. AKS thank DST-INSPIRE programme for research grant IFA-13, CH-97. The authors are thankful to Dr Rambabu Chegondi for the technical support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra17411f

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