Phthalan (1,3-dihydrobenzofuran) represents an important class of heterocycles,which are frequently found in many biologically active natural products and pharmacologically important agents (Fig. 1) ^{[1, 2]}. For example,pestacin (I) was isolated from the microorganism pestalotiopsis microspore,and has been found to display potent antioxidant activity and moderate antifungal properties ^[3]. Citalopram (II) is a widely used antidepressant drug of the selective serotonin reuptake inhibitor (SSRI) class ^[4]. Phthalans have also received considerable interest in organic synthesisdue to theirunique andinteresting reactivity ^[5].Typically, the five-membered oxy-ring of phthalan can be opened reductively byan excess of lithiumin thepresence of a substoichometricamount of naphthalene to give dianionic intermediates,which have a wide use in organic synthesis ^[6].Moreover,through the activation of C-O bond of the heterocyclic unit by Lewis acids with subsequent C-N and C-C bond formation reactions,recent studies have demonstrated phthalans as good synthons for obtaining important unsaturated linear or arene compounds ^[7].

Fig. 1

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Fig. 1. The structures of phthalan and two pharmaceutically important molecules.

On contrary to the importance in medicinal chemistry and organic synthesis,synthetic methods for phthalans are rather limited ^{[1, 8, 9, 10, 11]}. The most frequently employed strategy for their preparation is based on an intramolecular cyclization of the performed o-phthalyl alcohol or o-phthalyl halides,via either an electrophilic cyclization or a nucleophilic substitution ^[8]. It is apparent that these methods suffer from long procedure,troublesome preparation of the precursors and a lack of generality. The recent development of Ni,Co and Rh catalyzed [2 + 2 + 2] cyclotrimerization of oxy-tethered alkynes with carbon-carbon triple bonds have provided an attractive alternative ^[9]. However, the high-cost catalysts and specifically designed ligands were usually required,and mixtures of 1,3-dihydrobenzofuran isomers were often produced when asymmetric alkynes were used as substrates ^[9]. Other methods including the modified oxa-Pictet- Spengler reaction and hydrodeoxygenation or hydrodesulfurization of the performed phthalides were also reported,but only limited to the preparation of some phthalans such as hydroxyphthalans ^[10].

In this regard,we reported a highly efficient synthesis of fused phthalan derivatives from electron-deficient vinyl iodides and bispropargyl ethers in 2008,based on a cascade Sonogashira coupling,propargyl-allenyl isomerization and Diels-Alder cycloaddition reaction (CIRs) ^[11]. The methodology was also successfully extended to construct a variety of more complex phthalan derivatives via a two-fold coupling-isomerization sequence. However,the lack of efficient methods to generate the starting stereo-defined vinyl halides restricted the scope of the reaction and further applications. As a continued interest,quite recently we have realized a new atom-economic Pd-catalyzed addition- isomerization reaction sequence (AIRs) which employed very easily accessible (or commercially available) linear ynoates as the starting materials,leading to an easy access to a variety of 1,6,7,7atetrahydro- isobenzofurans in moderate to good yields ^[12]. In this paper,we wish to report the utility of AIRs to provide a facile synthesis of substituted phthalans directly from ynoate and bispropargyl ethers. 2. Experimental

All reactions were carried out under nitrogen atmosphere in Schlenk flask. Dry solvents were distilled prior to use: dioxane,THF and toluene were distilled from sodium-benzophenone; Et₃N were distilled from CaH₂. Petroleum ether (PE) refers to the fraction with boiling point in the range 60-90 °C. All ¹H NMR and ¹³C NMR spectra were measured in CDCl₃ with TMS as the internal standard. Chemical shifts were expressed in ppm and J values in Hz. Starting materials 1 were commercially available or prepared via a known procedure in literature ^[13]. Starting materials 2 were prepared according to known methods from the corresponding 1-aryl prop- 2-yn-1-ols and propargyl bromides ^[14].

General procedure for palladium-catalyzed sequential reactions of alkynoates with propargyl ethers: an oven-dried Schlenk tube containing a Teflon-coated stir bar was charged with Pd(OAc)2 (5.5 mg,5 mol%) and TDMPP (11.0 mg,5 mol%). The Schlenk tube was sealed and then evacuated and backfilled with N₂ (3 cycles). 1,4-Dioxane (1 mL) was then injected under N2. After stirring at room temperature for 15 min,a solution of ynoate 1 (0.5 mmol) and propargyl ether 2 (0.75 mmol) in 0.5 mL of 1,4-dioxane and 0.5 mL of Et₃N was subsequently injected. The reaction mixture was subjected to a preheated oil bath at 100 °C for 2 h,and further kept stirring at room temperature overnight. After the reaction was complete (monitored by TLC),removal of the solvent in vacuo left a slurry residue,which was purified by flash chromatography on silica to afford 3.

Methyl 4-ethyl-1,6-diphenyl-1,3-dihydroisobenzofuran-5-carboxylate (3a): Slurry solid (from PE/EtOAc). IR (KBr,cm^-1): v 2949, 1728,1453,1257,1160,701. ¹H NMR (CDCl₃,400 MHz): δ 7.37- 7.26 (m,10H),6.91 (s,1H),6.23 (s,1H),5.44 (d,1H,J₁,J₂ = 12.4 Hz), 5.30 (dd,1H,J₁,J₂ = 12.4 Hz),3.57 (s,3H),2.73-2.63 (m,2H),1.27 (t, 3H,J = 7.3 Hz). ¹³C NMR (CDCl₃,100 MHz): δ 170.1,143.5,141.5, 140.7,140.6,137.2,135.3,132.4,128.6,128.2,128.1,127.4,126.9, 121.3,86.5,72.3,51.9,24.9,14.7. HRMS (EI-TOF) (m/z): calcd. for C₂₄H₂₂O₃ [M⁺] 358.1569; found 358.1562.

Ethyl 6-hexyl-1,4-diphenyl-1,3-dihydroisobenzofuran-5-carboxylate (3b): Slurry solid (from PE/EtOAc). IR (KBr,cm^-1): v 2948,1729,1454,1257,1158,701. ¹H NMR (CDCl₃,400 MHz): δ 7.42-7.25 (m,10H),6.87 (s,1H),6.15 (s,1H),5.12 (d,1H,J = 2.8 Hz), 5.06 (d,1H,J = 2.8 Hz),3.98 (q,2H,J = 7.2 Hz),2.65-2.61 (m,2H), 1.57-1.53 (m,2H),1.32-1.26 (m,6H),0.91 (t,1H,J = 7.2 Hz),0.85 (t,1H,J = 6.8 Hz). ¹³C NMR (CDCl₃,100 MHz): δ 169.2,143.7,142.6, 140.8,138.2,135.8,134.5,134.0,133.3,129.9,128.4,128.3,128.2, 127.8,127.1,125.1,122.0,85.8,73.0,60.9,33.7,31.5,29.2,22.5, 14.0,13.6. HRMS (EI-TOF) (m/z): calcd. for C₂₉H₃₂O₃ [M⁺] 428.2351; found 428.2356.

Methyl 1-(2-bromophenyl)-4-ethyl-6-phenyl-1,3-dihydroisobenzofuran- 5-carboxylate (3c): Slurry solid (from PE/EtOAc). IR (KBr,cm^-1): v 2950,1728,1436,1257,1161,1026,760,701. 1H NMR (CDCl₃,400 MHz): δ 7.58 (d,J = 7.8 Hz,1H),7.37-7.26 (m, 7H),7.17-7.08 (m,2H),6.72 (s,1H),5.44 (dd,1H,J₁,J₂ = 12.4, 2.8 Hz),5.30 (dd,1H,J₁,J₂ = 12.4,1.8 Hz),3.55 (s,3H),2.73-2.58 (m,2H),1.24 (t,3H,J = 7.8 Hz). ¹³C NMR (CDCl₃,100 MHz): δ 170.1, 142.8,141.0,140.8,140.6,137.2,135.4,132.9,132.6,129.6,128.9, 128.3,128.2,127.9,127.4,122.3,121.4,85.1,72.6,52.0,25.0,14.8. HRMS (EI-TOF) (m/z): calcd. for C₂₄H₂₁BrO₃ [M⁺] 436.0674; found 436.0679.

Methyl 1-(3-chlorophenyl)-4,6-diphenyl-1,3-dihydroisobenzofuran- 5-carboxylate (3d): Slurry solid (from PE/EtOAc). IR (KBr, cm^-1): v 2947,1733,1436,1284,1128,702. ¹H NMR (CDCl₃, 400 MHz): δ 7.45-7.24 (m,14H),7.03 (s,1H),6.22 (s,1H),5.22 (dd, 1H,J₁,J₂ = 12.8,2.7 Hz),5.11 (dd,1H,J₁,J₂ = 12.8,1.8 Hz),3.31 (s, 3H). ¹³C NMR (CDCl₃,100 MHz): δ 169.3,143.5,142.9,140.7,140.1, 137.6,137.3,134.6,134.3,133.2,130.0,128.5,128.4,128.33, 128.28,128.1,128.0,127.7,127.0,125.0,122.6,85.9,73.1,51.8. HRMS (EI-TOF) (m/z): calcd. for C₂₈H₂₁ClO₃ [M⁺] 440.1179; found 440.1173.

Methyl 1-(4-tert-butylphenyl)-4-ethyl-6-phenyl-1,3-dihydroisobenzofuran- 5-carboxylate (3e): Slurry solid (from PE/EtOAc). IR (KBr,cm^-1): v 2964,1730,1454,1258,703. ¹H NMR (CDCl₃, 400 MHz): δ 7.37-7.24 (m,9H),6.92 (s,1H),6.20 (s,1H),5.39 (dd, 1H,J₁,J₂ = 12.4,2.3 Hz),5.25 (dd,1H,J₁,J₂ = 12.4,1.4 Hz),3.55 (s, 3H),2.73-2.58 (m,2H),1.29-1.22 (m,12H). ¹³C NMR (CDCl₃, 100 MHz): δ 170.1,151.2,143.5,140.7,140.6,138.4,137.4,135.3, 132.3,128.22,128.17,127.4,126.7,125.5,121.4,86.4,72.1,51.9, 34.5,31.3,24.9,14.7. HRMS (EI-TOF) (m/z): calcd. for C₂₈H₃₀O₃ [M⁺] 414.2195; found 414.2189.

But-3-enyl 4-butyl-1,6-diphenyl-1,3-dihydroisobenzofuran-5- carboxylate (3f): Slurry solid (from PE/EtOAc). IR (KBr,cm^-1): v 3062,3030,2956,1732,1455,1243,699. ¹H NMR (CDCl₃, 400 MHz): δ 7.35-7.26 (m,10H),6.87 (s,1H),6.20 (s,1H),5.52- 5.39 (m,2H),5.28-5.24 (m,1H),4.96-4.92 (m,2H),4.02-3.98 (m, 2H),2.70-2.58 (m,2H),2.08-2.03 (m,2H),1.63-1.55 (m,3H), 1.46-1.37 (m,2H),0.95 (t,3H,J = 7.2 Hz). ¹³C NMR (CDCl₃, 100 MHz): δ 169.6,143.3,141.6,140.8,140.7,137.5,134.2,133.7, 132.6,128.6,128.3,128.2,127.4,127.0,121.3,117.0,86.6,72.5, 64.3,32.7,32.4,31.4,23.0,13.9. HRMS (EI-TOF) (m/z): calcd. for C₂₉H₃₀O₃ [M⁺] 426.2195; found 426.2196.

Ethyl 4-butyl-6-hexyl-1-phenyl-1,3-dihydroisobenzofuran-5- carboxylate (3g): Slurry solid (from PE/EtOAc). IR (KBr,cm^-1): v 2945,1728,1453,1255,1158,700. ¹H NMR (CDCl₃,400 MHz): d 7.38-7.30 (m,5 H),6.72 (s,1H),6.13 (s,1H),5.31 (dd,1H,J₁, J₂ = 12.0,2.4 Hz),5.17 (dd,1H,J₁,J₂ = 12.0,2.4 Hz),4.39 (q,2H, J = 7.2 Hz),2.55-2.49 (m,4H),1.58-1.47 (m,4H),1.39 (t,3H, J = 7.2 Hz),1.32-1.25 (m,8H),0.94 (t,1H,J = 7.2 Hz),0.85 (t,1H, J = 6.8 Hz). ¹³C NMR (CDCl₃,100 MHz): δ 170.1,143.0,141.8,140.1, 135.9,132.2,128.5,128.1,127.1,120.7,86.6,72.4,61.0,33.9,32.5, 31.60,31.56,31.46,29.2,23.0,22.5,14.2,14.0,13.8. HRMS (EI-TOF) (m/z): calcd. for C₂₇H₃₆O₃ [M⁺] 408.2664; found 408.2661.

Ethyl 4-butyl-1,6-diphenyl-1,3-dihydroisobenzofuran-5-carboxylate (3h): Slurry solid (from PE/EtOAc). IR (KBr,cm^-1): v 2957,2871,1732,1456,1253,700. ¹H NMR (CDCl₃,400 MHz): d 7.35-7.25 (m,10H),6.87 (s,1H),6.20 (s,1H),5.40 (dd,1H,J₁, J₂ = 12.0,2.4 Hz),5.26 (dd,1H,J₁,J₂ = 12.0,1.6 Hz),4.02 (q,2H, J = 7.2 Hz),2.69-2.60 (m,2H),1.46-1.39 (m,2H),0.97-0.91 (m, 6H). ¹³C NMR (CDCl₃,100 MHz): δ 169.5,143.3,141.6,140.8,140.7, 137.5,134.1,132.8,128.6,128.3,128.2,128.1,127.3,126.9,121.2, 86.6,72.5,61.0,32.6,31.4,23.0,13.9,13.6. HRMS (EI-TOF) (m/z): calcd. for C₂₇H₂₈O₃ [M⁺] 400.2038; found 400.2035.

3i: Slurry solid (from PE/EtOAc). IR (KBr,cm^-1): v 2953,2867, 1721,1466,1253,1162,1027,699. ¹H NMR (CDCl₃,400 MHz): d 7.27-7.19 (m,10H),6.78 (s,1H),6.12 (s,1H),5.35-5.31 (m,1H), 5.20-5.17 (m,2H),4.52-4.42 (m,1H),2.61-2.57 (m,2H),1.93-0.78 (m,47H),0.58 (s,3H). ¹³C NMR (CDCl₃,100 MHz): δ 168.9,143.2, 141.7,140.9,140.7,139.5,137.5,134.0,133.1,128.64,128.55, 128.25,128.20,127.4,127.0,122.68,122.66,121.3,86.7,75.0,72.6, 56.7,56.1,50.0,42.3,39.7,39.5,37.5,37.4,36.9,36.6,36.2,35.8, 32.7,31.9,31.8,31.4,28.2,28.0,27.3,27.2,24.3,23.8,23.1,22.9, 22.6,21.0,19.2,18.7,14.0,11.9. HRMS (EI-TOF) (m/z): calcd. for C₅₂H₆₈O₃ [M⁺] 740.5168; found 740.5161.

Ethyl 1,4,6-triphenyl-3,5-dihydroisobenzofuran-5-carboxylate (4): Slurry solid (from PE/EtOAc). IR (KBr,cm^-1): v 3060,2979, 1730,1494,1450,1271,1114,758,701. ¹H NMR (CDCl₃,400 MHz): d 7.73 (d,2H,J = 7.6 Hz),7.56 (d,2H,J = 8.0 Hz),7.45-7.26 (m,11H), 7.13 (s,1H),5.47 (dd,1H,J₁,J₂ = 16.0,3.2 Hz),5.29 (s,1H),5.14 (dd, 1H,J₁,J₂ = 16.0,3.2 Hz),3.89-3.81 (m,2H),0.80 (t,3H,J = 7.2 Hz). ¹³C NMR (CDCl₃,100 MHz): δ 171.1,156.7,139.8,139.2,138.7, 134.3,130.9,129.2,128.6,128.4,127.6,127.0,126.83,126.76, 126.1,118.2,117.9,113.7,72.4,60.8,52.3,13.7. HRMS (EI-TOF) (m/ z): calcd. for C₂₉H₂₄O₃ [M⁺] 420.1725; found 420.1721. 3. Results and discussion

The reaction of (1a) and (2a) was conducted under the conditions similar to previously reported by us ^[12],affording the desired product in 51% yield (Table 1,entry 1). The reaction also proceeds smoothly for an alkylpropiolate (e.g.,ethyl non-2- ynoate),affording the desired product 3b in 60% yield (Table 1, entry 2). The expected product 3f was also obtained in 55% yield when but-3-enyl 3-phenylpropiolate was employed (Table 1,entry 6),indicating the tolerance of the double bond appended in ynoate. For the bispropargyl ethers,R³ could be an alkyl group (e.g.,ethyl, butyl group) or a phenyl group,and R⁴ could be substituted phenyl group with either electron-donating or electron-withdrawing group (Table 1,entries 3-5). Noteworthy,a bromide functionality appended on the aryl ring is also compatible with the current palladium catalyst (Table 1,entry 3). The products 3a-3h were all characterized by spectroscopy techniques including ¹H NMR,13C NMR,IR and HRMS,and the results are summarized in Table 1.

As for the application,the present reaction could be employed as a promising approach for modification of important bioactive molecules or drug candidates. As shown in Scheme 1,when substrate 1c derived from cholesterol was employed to react with the propagyl ether 2b,a complex natural-product-like molecule 3i was obtained in 41% yield.

Table 1

Table 1 Pd-catalyzed tandem reaction of ynoates with propargyl ethers to produce 1,3- dihydroisobenofurans 3.

Table 1 Pd-catalyzed tandem reaction of ynoates with propargyl ethers to produce 1,3- dihydroisobenofurans 3.

Scheme 1

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Scheme 1. Synthetic application.

Mechanistically,two plausible reaction pathways were considered (Scheme 2). The first one starts from the intermolecular addition of a terminal alkyne 2 to the electron-deficient alkyne 1 to produce an ene-enyne species A. The combination of Pd(OAc)2 and TDMPP serves as the catalyst to implement the addition reaction ^[15]. Subsequently,the organic base Et₃N promotes a propargyl- allenyl isomerization process,yielding an ene-vinylallene intermediate B. Then an intramolecular Diels-Alder cycloaddition reaction occurs to give rise to the intermediate C. Aromatization of C via C55C bond migration finally affords the product 3 (Scheme 2, path). Alternatively,another reaction pathway involving cyclopalladation of 2 followed by insertion of 1 into the palladacycle D and subsequent reductive elimination was also possible (Scheme 2,path B). However,a control experiment revealed that the reaction of 1b and 2c at 80 °C for 1 h produced the cyclic triene compound 4,a product similar to the intermediate C (Scheme 3). The identification of compound 4 thus confirmed that path A should be the most likely mechanism.

Scheme 2

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Scheme 2. The plausible mechanism for the formation of 3.

Scheme 3

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Scheme 3. Identification of the reaction intermediate 4.

In conclusion,we have developed a tandem hydroalkynylation, alkyne-allene isomerization,Diels-Alder cycloaddition and aromatization sequence to provide a facile synthesis of phthalan derivatives in moderate yields. The reaction carries the advantages of easily available starting materials and high efficiency. A plausible mechanism was also proposed to rationalize the reaction with evidence of the determination of reaction intermediates.

The financial support from the National Natural Science Foundation of China (No. 21302095),Research Fund for the Doctoral Program of Higher Education of China (No. 20133221120003),Jiangsu Provincial NSFC (No. BK20130924) and Foundation of Jiangsu Educational Committee of China (No. 13KJB150019) is fully acknowledged. This work was also partially supported by the Project of Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). R.S. thanks Prof. L. Wu of Zhejiang University for the help on HRMS analysis.