A new approach for fused isoindolines via hexadehydro-Diels–Alder reaction (HDDA) by Fe(0) catalysis

Abstract

A simple method has been developed for the synthesis of fused isoindolines via a cascade HDDA approach catalyzed by Fe₂(CO)₉. In this work, a 1,3-diyne was involved in a [4 + 2] cycloisomerization with a diynophile to give an aryne intermediate, which was subsequently trapped with –OH nucleophile to beget the fused isoindolines in high yields.

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Introduction

Fused heterocycles are an important class of compounds mostly in pharmaceutical and natural products. Among them, nitrogen and oxygen containing molecules have a potent role in medicinal chemistry. In particular, isoindolines, which are nitrogen heterocycles, exhibit a number of biological functions such as diuretic, antitumor, selective serotonin uptake inhibitors, herbicidal activities,^1,2 antipsychotic agents I (Fig. 1)³ and Alzheimer’s disease II.⁴ On the other hand, the dihydrobenzofuran structural motif from oxygen heterocycles also plays a pivotal role in many bio-active natural products III & IV (Fig. 1), as well as synthetic drugs used in the treatment of hypertension, central nervous system trauma, pulmonary, and atherosclerotic peripheral arterial disease.^5,6 Hence, the study of isoindolines and 2,3-dihydrobenzofurans continues to be an interesting research field.

Fig. 1 Pharmaceutical and natural compounds.

In general, syntheses of isoindolines and 2,3-dihydrobenzofurans have been described by several approaches.^7,8 The most common methods include the utilization of transition metal catalysts⁹ and bases.¹⁰ By knowing the biological importance of these two cores, we hereby designed a new synthetic protocol to create both the cores in one molecule as shown in Scheme 1E.

Scheme 1 Synthetic approaches with triyne molecule.

The synthesis of complex heterocyclic compounds via a cascade process has been a captivating area in organic chemistry. In this view, many researchers have focused on triynes A (Scheme 1) as potential precursors for building fused ring systems. For representative examples, the combined use of enyne metathesis and the metallotropic [1,3]-shift of alkynyl ruthenium carbenes is used to construct enediynes and oligoenynes (Scheme 1B).¹¹ In a similar way, the construction of fused yne-substituted aryl halides was developed with Pd and Ag (Scheme 1C and D).^12,13 Very recently, Hoye and Lee individually developed HDDA for constructing fused ring systems by using triynes.^14–16 In this context, and following our ongoing interest in the synthesis of bicyclic[1,2,3]-triazoles from alkynols,¹⁷ we envisioned the possibility of exploring new reagents and the development of a catalytic cascade reaction with alkynols to undergo the HDDA reaction. Herein, we have developed a new synthetic pathway to afford fused isoindolines through generation of o-arynes via Fe(0) catalysis for the first time with broad substrate scope in high yields (Scheme 1E).

Results and discussion

To optimize the reaction conditions, compound 1a was synthesized and used as a model substrate. The initial investigation of 1a with AgOTf failed to produce the desired compound 2a (Table 1, entry 1). We next evaluated the feasibility of the reaction with various metal salts (entries 2–12). Among them Fe salts showed good results compared with other metal salts (entries 10–12). In particular, Fe₂(CO)₉ underwent a smooth reaction to give compound 2a in the best yield 92% (entry 11). Further, the reaction was carried out with lower catalyst loading and there was no substantial change in the reaction yield (entry 13). According to the observations from the optimizing studies, the best conditions were found to be with 5 mol% of Fe₂(CO)₉ in toluene at 80 °C for 2 h to afford the compound 2a in 92% yield (entry 13).

Table 1 Optimizing conditions to construct fused heterocycles^a

Entry no.	Catalyst	Time	Yield^e (%)
a Reaction conditions: compound 1 (0.5 mmol), catalyst (10 mol%), toluene (3 mL), 80 °C and time (h).b Complex mixture.c 28 °C.d 5 mol%.e Isolated yields.
1	AgOTf	6 h	—^b
2	ZnCl2	4 h	82
3	Pd(OAc)2	2 h	—^b
4^c	Pd(OAc)2	24 h	80
5^c	PPh3AuCl	6 h	72
6	Cu(OTf)2	6 h	79
7	Fe(OTf)3	6 h	83
8	Sc(OTf)3	6 h	75
9	Zn(OTf)2	6 h	73
10	FeCl3	2 h	88
11	Fe2(CO)9	2 h	92
12	FeBr3	2 h	85
13^d	Fe2(CO)9	2 h	92

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With the optimal reaction conditions (Table 1, entry 13) in hand, we have conducted the HDDA reaction with various substrates as shown in Table 2. The reaction follows a [4 + 2] cycloisomerization of a 1,3-diyne with a ‘diynophile’ to give a reactive aryne intermediate which was subsequently trapped with –OH nucleophiles. We conducted reactions with EDG, –OMe/Me on the phenyl ring, and the reactions produced high yields (entries 2b and 2e). The reaction was also tested with electron withdrawing groups like Cl/Br/Ts/CF₃ and all of them progressed well to produce high yields (entries 2c–2d and 2f–2g). The synthetic strategy was extended to construct fused chromane scaffolds (entries 2h–p). The electronic effects were also studied for this reaction with various functionalities such as –OMe/Me (entries 2i–k and 2n) at o/m/p positions. In a similar way, electron withdrawing groups such as Cl/Br/Ts/CF₃ obeyed the reaction conditions to produce the desired compounds in good yields (entries 2l, 2m, 2o and 2p). It is noteworthy to mention that this method is the first example for HDDA reaction with an EDG on a phenyl ring attached to nitrogen.

Table 2 Investigation of reaction with Fe₂(CO)₉ to synthesize fused isoindolines^a

a Reaction conditions: compound 1 (0.5 mmol), Fe₂(CO)₉ (5 mol%), toluene (3 mL), 80 °C, 2 h.

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Based on the previous literature reports¹⁸ and our observed results, a plausible mechanism is outlined in Scheme 3. The initial co-ordination of Fe to compound 1 resulted in the formation of intermediate 1A. Further, the intermediate 1A underwent a [4 + 2] cycloaddition to afford the key aryne intermediate 1C via iron-complex compound 1B and Fe was regenerated for the next catalytic cycle. Finally, the compound 1C was trapped by the intramolecular –OH nucleophile followed by a [1,3]-H shift to achieve the desired fused isoindolines 2. The 1,3-shift was explored previously by using –OTBS (Scheme 2), deuterium labelling and DFT experiments.^14a,16a By these results, we also predict that our reaction followed a 1,3-shift to beget the desired compound.

Scheme 2 HDDA reaction 1,3-shift.

Scheme 3 A plausible mechanism.

Conclusions

In conclusion, we have developed a simple method for the synthesis of fused isoindolines via a cascade HDDA approach catalyzed by Fe₂(CO)₉. The key features of this reaction are easy handling, atom efficiency, time economic and good reaction yields with broad substrate scope irrespective of electronic factors. It is noteworthy to mention that this method is the first example for the HDDA reaction with an EDG on a phenyl ring attached to nitrogen. Further, extension of this method for trapping with other carbo or hetero nucleophiles is in progress.

Experimental section

General information

Melting points are uncorrected. ¹H NMR and ¹³C NMR spectra were recorded at 400 and 100 MHz, respectively, using CDCl₃ as a solvent. ¹H NMR chemical shifts are referenced to TMS or CDCl₃ (7.26 ppm). ¹³C NMR was referenced to CDCl₃ (77.0 ppm). Multiplicities were determined by the DEPT sequence as s, d, t, q. Mass spectra and high-resolution mass spectra (HRMS) were measured using the ESI-Ion trap technique by Taichung Regional Instrument Center of NSC at NCHU. Flash chromatography was carried out on silica gel 60 (E. Merck, 230–400 mesh).

General procedure to synthesize compound 2

A 50 mL round-bottomed flask was charged with compound 1 (0.5 mmol) and toluene (4 mL). To this, Fe₂(CO)₉ (5 mol%) was added. After stirring at 90 °C for 2 h under air the completion of the reaction was monitored by TLC. Removal of the solvent in vacuo and purification of the residue by silica gel column chromatography afforded the desired product 2.

4-(6-Phenyl-3,5,6,7-tetrahydro-2H-furo[2,3-f]isoindol-4-yl)but-3-yn-1-ol (2a). According to the general procedure, the title compound was synthesized (2a). The product was purified by silica gel flash column chromatography (hexane → hexane–AcOEt = 5 : 1) to afford 2a as an off-white solid (140.3 mg, 92% yield). Melting point: 105–107 °C. ¹H NMR (400 MHz, CDCl₃): δ 7.29 (t, J = 7.8 Hz, 2H), 6.75–6.65 (m, 4H), 4.61 (t, J = 8.8 Hz, 2H), 4.56 (s, 4H), 3.86 (t, 6.4 Hz, 2H), 3.23 (t, 8.8 Hz, 2H), 2.77 (t, 6.4 Hz, 2H), 1.83 (brs, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 159.5, 147.0, 137.6, 131.8, 129.3, 128.7, 116.0, 114.7, 111.4, 103.7, 92.9, 78.0, 71.6, 61.2, 54.2, 53.1, 29.4, 24.0. HRMS (ESI): calculated for [C₂₀H₂₀NO₂]⁺ requires 306.14886, found 306.14884.

4-(6-(3-Methoxyphenyl)-3,5,6,7-tetrahydro-2H-furo[2,3-f]isoindol-4-yl)but-3-yn-1-ol (2b). According to the general procedure, the title compound was synthesized (2b). The product was purified by silica gel flash column chromatography (hexane → hexane–AcOEt = 5 : 1) to afford 2b as a light yellow sticky mass (142.3 mg, 85% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.18 (t, J = 8.4 Hz, 1H), 6.64 (s, 1H), 6.284 (dddd, J = 2.4 Hz, 2H), 6.17 (t, J = 2.4 Hz, 1H), 4.57 (t, J = 8.4 Hz, 2H), 4.50 (s, 4H), 3.84 (t, J = 6.4 Hz, 2H), 3.82 (s, 3H), 3.18 (t, J = 8.4 Hz, 2H), 2.76 (t, J = 6.4 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃): δ 160.8, 159.5, 148.4, 137.5, 131.6, 130.0, 128.6, 114.7, 104.6, 103.5, 101.0, 97.8, 93.0, 77.9, 71.6, 61.2, 55.1, 54.2, 53.1, 29.3, 23.9. HRMS (ESI): calculated for [C₂₁H₂₂NO₃]⁺ requires 336.15942, found 336.15941.

4-(6-(4-Chlorophenyl)-3,5,6,7-tetrahydro-2H-furo[2,3-f]isoindol-4-yl)but-3-yn-1-ol (2c). According to the general procedure, the title compound was synthesized (2c). The product was purified by silica gel flash column chromatography (hexane → hexane–AcOEt = 5 : 1) to afford 2c as a white solid (149.1 mg, 88% yield). Melting point: 116–118 °C. ¹H NMR (400 MHz, CDCl₃): δ 7.21 (d, J = 8.8 Hz, 2H), 6.65 (s, 1H), 6.53 (d, J = 9.2 Hz, 2H), 4.60 (t, J = 8.8 Hz, 2H), 4.49 (s, 4H), 3.85 (t, J = 6.4 Hz, 2H), 3.21 (t, J = 8.8 Hz, 2H), 2.77 (t, J = 6.4 Hz, 2H), 1.90 (brs, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 159.6, 145.6, 137.3, 131.4, 129.0, 128.8, 120.9, 114.7, 112.3, 103.6, 93.0, 77.9, 71.6, 61.2, 54.3, 53.2, 29.3, 23.9. HRMS (ESI): calculated for [C₂₀H₁₈NO₂Cl]⁺ requires 339.1026, found 339.1025.

4-(6-(4-Bromophenyl)-3,5,6,7-tetrahydro-2H-furo[2,3-f]isoindol-4-yl)but-3-yn-1-ol (2d). According to the general procedure, the title compound was synthesized (2d). The product was purified by silica gel flash column chromatography (hexane → hexane–AcOEt = 5 : 1) to afford 2d as an off-white solid (160.8 mg, 84% yield). Melting point: 85–87 °C. ¹H NMR (400 MHz, CDCl₃): δ 7.33 (d, J = 9.2 Hz, 2H), 6.64 (s, 1H), 6.48 (d, J = 9.2 Hz, 2H), 4.59 (t, J = 8.8 Hz, 2H), 4.47 (s, 4H), 3.85 (t, J = 6.4 Hz, 2H), 3.20 (t, J = 8.8 Hz, 2H), 2.76 (t, J = 6.4 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃): δ 159.6, 145.9, 137.2, 131.8, 131.3, 128.8, 114.7, 112.9, 107.9, 103.5, 93.1, 77.8, 71.6, 61.2, 54.2, 53.1, 29.3, 23.9. HRMS (ESI): calculated for [C₂₀H₁₈BrNO₂ + Na]⁺ requires 406.0413, found 406.0411.

4-(6-(p-Tolyl)-3,5,6,7-tetrahydro-2H-furo[2,3-f]isoindol-4-yl)but-3-yn-1-ol (2e). According to the general procedure, the title compound was synthesized (2e). The product was purified by silica gel flash column chromatography (hexane → hexane–AcOEt = 5 : 1) to afford 2e as a light yellow sticky mass (135 mg, 85% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.10 (d, J = 8.4 Hz, 2H), 6.67 (s, 1H), 6.57 (d, J = 8.8 Hz, 2H), 4.60 (t, J = 8.8 Hz, 2H), 4.53 (s, 4H), 3.85 (t, J = 6.4 Hz, 2H), 3.22 (t, J = 8.8 Hz, 2H), 2.77 (t, J = 6.4 Hz, 2H), 2.28 (s, 3H), 1.81 (brs, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 159.4, 145.0, 137.8, 132.0, 129.8, 128.5, 125.1, 114.6, 111.4, 103.7, 92.8, 78.1, 71.6, 61.2, 54.4, 53.2, 29.4, 24.0, 20.2. HRMS (ESI): calculated for [C₂₁H₂₂NO₂]⁺ requires 320.1645, found 320.1644.

4-(6-Tosyl-3,5,6,7-tetrahydro-2H-furo[2,3-f]isoindol-4-yl)but-3-yn-1-ol (2f). According to the general procedure, the title compound was synthesized (2f). The product was purified by silica gel flash column chromatography (hexane → hexane–AcOEt = 5 : 1) to afford 2f as a light yellow sticky mass (178 mg, 93% yield). Spectral data are in agreement with the literature. ¹H NMR (400 MHz, CDCl₃): δ 7.76 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 6.47 (s, 1H), 4.58–4.52 (m, 6H), 3.82 (t, J = 6.4 Hz, 2H), 3.16 (t, J = 8.4 Hz, 2H), 2.72 (t, J = 6.4 Hz, 2H), 2.40 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 159.9, 143.6, 135.7, 133.7, 129.8, 129.4, 127.5, 115.0, 103.4, 93.8, 71.7, 61.1, 54.1, 53.2, 29.6, 29.2, 23.8, 21.4. HRMS (ESI): calculated for [C₂₁H₂₁NO₄S + Na]⁺ requires 406.10835, found 406.10837.

4-(6-(4-(Trifluoromethyl)phenyl)-3,5,6,7-tetrahydro-2H-furo[2,3-f]isoindol-4-yl)but-3-yn-1-ol (2g). According to the general procedure, the title compound was synthesized (2g). The product was purified by silica gel flash column chromatography (hexane → hexane–AcOEt = 5 : 1) to afford 2g as an off-white solid (152.9 mg, 82% yield). Melting point: 156–158 °C. ¹H NMR (400 MHz, CDCl₃): 7.50 (d, J = 8.8 Hz, 2H), 6.68 (s, 1H), 6.64 (D, J = 8.8 Hz, 2H), 4.64–4.59 (m, 6H), 3.87 (t, J = 6.4 Hz, 2H), 3.23 (t, J = 8.4 Hz, 2H), 2.78 (J = 6.4 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃): 159.8, 149.0, 136.9, 130.9, 129.1, 126.5 (q, J = 3.8 Hz), 117.7, 117.4, 114.8, 110.7, 103.6, 93.3, 77.8, 71.7, 61.2, 54.2, 53.1, 29.4, 24.0. HRMS (ESI): calculated for [C₂₁H₁₉NO₂F₃]⁺ requires 374.1290, found 374.1292.

5-(7-Phenyl-2,3,4,6,7,8-hexahydropyrano[2,3-f]isoindol-5-yl)pent-4-yn-1-ol (2h). According to the general procedure, the title compound was synthesized (2h). The product was purified by silica gel flash column chromatography (hexane → hexane–AcOEt = 5 : 1) to afford 2h as an off-white solid (148 mg, 89% yield). Melting point: 124–126 °C. ¹H NMR (400 MHz, CDCl₃): δ 7.29 (t, J = 8.0 Hz, 2H), 6.75–6.72 (m, 2H), 6.66 (d, J = 8.0 Hz, 2H), 4.56 (s, 4H), 4.15 (t, J = 5.2 Hz, 2H), 3.87 (t, J = 6.0 Hz, 2H), 2.85 (t, J = 6.8 Hz, 2H), 2.65 (t, J = 7.2 Hz, 2H), 2.05–1.99 (m, 2H), 1.92 (quint, J = 6.8 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃): δ 154.4, 147.1, 136.3, 132.4, 129.3, 122.8, 118.4, 115.9, 111.4, 110.5, 97.8, 76.8, 66.2, 61.7, 54.0, 53.4, 31.6, 23.8, 22.1, 16.2. HRMS (ESI): calculated for [C₂₂H₂₃NO₂]⁺ requires 333.1729, found 333.1727.

5-(7-(4-Methoxyphenyl)-2,3,4,6,7,8-hexahydropyrano[2,3-f]isoindol-5-yl)pent-4-yn-1-ol (2i). According to the general procedure, the title compound was synthesized (2i). The product was purified by silica gel flash column chromatography (hexane → hexane–AcOEt = 5 : 1) to afford 2i as a light yellow sticky mass (157.9 mg, 87% yield). ¹H NMR (400 MHz, CDCl₃): δ 6.91 (d, J = 9.2 Hz, 2H), 6.71 (s, 1H), 6.61 (d, J = 9.2 Hz, 2H), 4.52 (s, 4H), 4.15 (t, J = 5.2 Hz, 2H), 3.87 (t, J = 6.4 Hz, 2H), 3.78 (s, 3H), 2.85 (t, J = 6.8 Hz, 2H), 2.64 (t, J = 6.8 Hz, 2H), 2.04–1.98 (m, 2H), 1.91 (quint, J = 6.4 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃): δ 154.3, 151.0, 142.1, 136.6, 132.7, 122.7, 118.3, 115.1, 112.2, 110.5, 97.7, 66.1, 61.7, 55.9, 54.5, 53.9, 31.6, 23.7, 22.1, 16.2. HRMS (ESI): calculated for [C₂₃H₂₆NO₃]⁺ requires 364.1834, found 364.1831.

5-(7-(3-Methoxyphenyl)-2,3,4,6,7,8-hexahydropyrano[2,3-f]isoindol-5-yl)pent-4-yn-1-ol (2j). According to the general procedure, the title compound was synthesized (2j). The product was purified by silica gel flash column chromatography (hexane → hexane–AcOEt = 5 : 1) to afford 2j as an off-white solid (156 mg, 86% yield). Melting point: 123–125 °C. ¹H NMR (400 MHz, CDCl₃): δ 7.19 (t, J = 8.4 Hz, 1H), 6.70 (s, 1H), 6.32–6.27 (m, 2H), 6.19 (t, J = 2.4 Hz, 1H), 4.53 (s, 4H), 4.14 (t, J = 5.2 Hz, 2H), 3.86 (t, J = 6.4 Hz, 2H), 3.83 (s, 3H), 2.83 (t, J = 6.4 Hz, 2H), 2.64 (t, J = 6.8 Hz, 2H), 2.03–1.98 (m, 2H), 1.91 (quint, J = 6.4 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃): δ 160.8, 154.3, 148.4, 136.1, 132.3, 130.0, 122.8, 118.4, 110.4, 104.6, 100.9, 97.8, 66.1, 61.6, 55.1, 54.0, 53.4, 31.6, 23.7, 22.1, 16.2. HRMS (ESI): calculated for [C₂₃H₂₅NO₃]⁺ requires 363.1834, found 363.1831.

5-(7-(2-Methoxyphenyl)-2,3,4,6,7,8-hexahydropyrano[2,3-f]isoindol-5-yl)pent-4-yn-1-ol (2k). According to the general procedure, the title compound was synthesized (2k). The product was purified by silica gel flash column chromatography (hexane → hexane–AcOEt = 5 : 1) to afford 2k as a light yellow sticky mass (161.5 mg, 89% yield). ¹H NMR (400 MHz, CDCl₃): δ 6.96–6.80 (m, 4H), 6.68 (s, 1H), 4.71 (s, 2H), 4.67 (s, 2H), 4.14 (t, J = 5.2 Hz, 2H), 3.86–3.84 (m, 5H), 2.84 (t, J = 6.8 Hz, 2H), 2.62 (t, J = 6.8 Hz, 2H), 2.04–1.98 (m, 2H), 1.89 (quint, J = 6.4 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃): δ 154.0, 149.8, 138.6, 137.2, 133.1, 122.3, 121.6, 119.0, 117.9, 115.3, 112.7, 110.1, 97.3, 77.0, 66.1, 61.6, 56.5, 56.0, 55.6, 31.5, 23.7, 22.1, 16.2. HRMS (ESI): calculated for [C₂₃H₂₅NO₃]⁺ requires 363.1834, found 363.1833.

5-(7-(4-Chlorophenyl)-2,3,4,6,7,8-hexahydropyrano[2,3-f]isoindol-5-yl)pent-4-yn-1-ol (2l). According to the general procedure, the title compound was synthesized (2l). The product was purified by silica gel flash column chromatography (hexane → hexane–AcOEt = 5 : 1) to afford 2l as a light yellow solid (157.8 mg, 86% yield). Melting point: 144–146 °C. ¹H NMR (400 MHz, CDCl₃): 7.22 (d, J = 8.8 Hz, 2H), 6.71 (s, 1H), 6.56 (d, J = 9.6 Hz, 2H), 4.53 (s, 4H), 4.15 (t, J = 5.2 Hz, 2H), 3.86 (t, J = 6.4 Hz, 2H), 2.85 (t, J = 6.8 Hz, 2H), 2.65 (t, J = 6.8 Hz, 2H), 2.053–1.99 (m, 2H), 1.92 (quint, J = 6.4 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃): 154.4, 145.6, 136.0, 132.0, 129.0, 123.0, 120.8, 118.4, 112.4, 110.5, 97.9, 76.7, 66.2, 61.7, 54.1, 53.5, 31.6, 29.6, 23.7, 22.0, 16.2. HRMS (ESI): calculated for [C₂₂H₂₃ClNO₂]⁺ requires 368.1411, found 368.1411.

5-(7-(4-Bromophenyl)-2,3,4,6,7,8-hexahydropyrano[2,3-f]isoindol-5-yl)pent-4-yn-1-ol (2m). According to the general procedure, the title compound was synthesized (2m). The product was purified by silica gel flash column chromatography (hexane → hexane–AcOEt = 5 : 1) to afford 2m as an off-white solid (172.6 mg, 84% yield). Melting point: 142–144 °C. ¹H NMR (400 MHz, CDCl₃): 7.35 (d, J = 8.8 Hz, 2H), 6.17 (s, 1H), 6.52 (d, J = 8.8 Hz, 2H), 4.52 (s, 4H), 4.15 (t, J = 5.2 Hz, 2H), 3.86 (t, J = 6.4 Hz, 2H), 2.85 (t, J = 6.4 Hz, 2H), 2.65 (t, J = 7.2 Hz, 2H), 2.05–1.99 (m, 2H), 1.92 (quint, J = 6.4 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃): 154.5, 146.0, 135.9, 132.0, 131.9, 123.0, 118.5, 113.0, 110.5, 107.9, 97.9, 76.7, 66.2, 61.7, 54.1, 53.5, 31.6, 23.8, 22.0, 16.2. HRMS (ESI): calculated for [C₂₂H₂₂NO₂Br]⁺ requires 411.0834 found 411.0837.

5-(7-(p-Tolyl)-2,3,4,6,7,8-hexahydropyrano[2,3-f]isoindol-5-yl)pent-4-yn-1-ol (2n). According to the general procedure, the title compound was synthesized (2n). The product was purified by silica gel flash column chromatography (hexane → hexane–AcOEt = 5 : 1) to afford 2n as an off-white solid (150.9 mg, 87% yield). Melting point: 128–130 °C. ¹H NMR (400 MHz, CDCl₃): 7.09 (d, J = 8.4 Hz, 2H), 6.70 (s, 1H), 6.57 (d, J = 8.4 Hz, 2H), 4.52 (s, 4H), 4.14 (t, J = 5.2 Hz, 2H), 3.85 (t, J = 6.4 Hz, 2H), 2.83 (t, J = 6.8 Hz, 2H), 2.63 (t, J = 6.8 Hz, 2H), 2.27 (s, 3H), 2.03–1.98 (m, 2H), 1.90 (quint, J = 6.4 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃): 154.3, 145.0, 136.4, 132.6, 129.8, 124.9, 122.7, 118.3, 111.4, 110.5, 97.7, 76.8, 66.1, 61.6, 54.1, 53.5, 31.6, 29.6, 23.7, 22.1, 20.2, 16.2. HRMS (ESI): calculated for [C₂₃H₂₅NO₂]⁺ requires 347.1885, found 347.1885.

5-(7-Tosyl-2,3,4,6,7,8-hexahydropyrano[2,3-f]isoindol-5-yl)pent-4-yn-1-ol (2o). According to the general procedure, the title compound was synthesized (2o). The product was purified by silica gel flash column chromatography (hexane → hexane–AcOEt = 5 : 1) to afford 2o as a light yellow sticky mass (184.9 mg, 90% yield). 1H NMR (400 MHz, CDCl₃): 7.76 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 6.52 (s, 1H), 4.54 (d, J = 8.0 Hz, 4H), 4.10–4.07 (m, 2H), 3.82 (t, J = 6.4 Hz, 2H), 2.77 (t, J = 6.4 Hz, 2H), 2.59 (t, J = 6.8 Hz, 2H), 2.40 (s, 3H), 1.98–1.93 (m, 2H), 1.87 (quint, 2H). ¹³C NMR (100 MHz, CDCl₃): 154.8, 143.5, 134.4, 133.7, 130.4, 129.8, 127.5, 123.5, 118.7, 110.3, 98.6, 76.1, 66.2, 61.6, 54.0, 53.6, 31.5, 29.6, 23.7, 21.9, 21.4, 16.1. HRMS (ESI): calculated for [C₂₃H₂₅NO₄S + Na]⁺ requires 434.1396, found 434.1397.

5-(7-(4-(Trifluoromethyl)phenyl)-2,3,4,6,7,8-hexahydropyrano[2,3-f]isoindol-5-yl)pent-4-yn-1-ol (2p). According to the general procedure, the title compound was synthesized (2p). The product was purified by silica gel flash column chromatography (hexane → hexane–AcOEt = 5 : 1) to afford 2p as an off-white solid (174.4 mg, 87% yield). Melting point: 150–152 °C. ¹H NMR (400 MHz, CDCl₃): 7.50 (d, J = 8.4 Hz, 2H), 6.72 (s, 1H), 6.65 (d, J = 8.8 Hz, 2H), 4.60 (s, 4H), 4.17–4.14 (m, 2H), 3.87 (t, J = 6.4 Hz, 2H), 2.85 (t, J = 6.8 Hz, 2H), 2.66 (t, J = 7.2 Hz, 2H), 2.05–1.99 (m, 2H), 1.92 (quint, J = 6.8 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃): 154.6, 149.1, 135.5, 131.6, 126.5 (d, J = 3.8 Hz), 123.2, 118.6, 110.8, 110.5, 98.2, 66.2, 61.7, 54.0, 53.4, 31.6, 23.8, 22.0, 16.3. HRMS (ESI): calculated for [C₂₃H₂₃NO₂F₃]⁺ requires 402.1603, found 402.1605.

Acknowledgements

The authors gratefully acknowledge the Ministry of Science and Technology (MOST), Taiwan for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra12376j

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