2013 Volume 61 Issue 7 Pages 768-775
We examined In(OTf)3-catalyzed enolization and intramolecular Alder–Rickert reactions of cyclohexenone derivatives. The 3-aryl substituted cyclohexenone derivatives bearing an ethoxycarbonyl-substituted alkyne moiety could be converted into the corresponding phenols in comparatively good yield.
Phenol derivatives are an important class of molecules which are present in a variety of materials including natural products and compounds of interest in medicinal chemistry and medicines. The Alder–Rickert reaction, a cascade reaction comprising a Diels–Alder reaction of siloxy-1,3-cyclohexadienes with alkynes and a retro Diels–Alder reaction accompanied by extrusion of ethylene gas, is one powerful method utilized to prepare substituted phenol derivatives.1–3) This method relies on the preparation of starting dienes from 1,3-cyclohexanedione in several steps. We have recently succeeded in performing a one-pot synthesis of phenol derivatives 4 from cyclohexenones 1 having an activated alkyne moiety through a novel type of Alder-Rickert reaction4) (Eq. 1). The reaction might proceed through Lewis acid-catalyzed enolization of 1 to generate cyclohexadienol 2 in situ followed by an intramolecular Alder–Rickert reaction via diene 3, and avoids the cumbersome purification of highly reactive dienols by employing appropriate precursors. It has been shown that the Rh(I) complex and In(OTf)3 are effective as Lewis acids. In an effort to expand the scope of this method, we have directed our attention towards the reactivity of cyclohexenone derivatives bearing a substituent at the 3-position as substrates. It was anticipated that introducing an aryl group at the 3-position of cyclohexenone derivative 5 would facilitate formation of the relatively stable dienol intermediate 6 due to the resonance effect, which would be beneficial in promoting the subsequent Diels–Alder reaction (Eq. 2). Moreover, products 8 in this sequence would possess a 4-phenylindane unit which is utilized as a privileged platform in medicinal chemistry5–8) and observed in several natural products.9–11) Based upon the aforementioned working hypothesis, we examined the consecutive Lewis acid-catalyzed enolization and intramolecular Alder–Rickert reactions employing 3-aryl cyclohexenone derivatives. In this paper, we wish to describe the experimental results.
 | (1) |
 | (2) |
Preparation of reaction substrates 5b–i which have 3-substituted cyclohexenone moieties are shown in Chart 1. The 3-methyl, 3-phenyl, 3-(4-methoxyphenyl), 3-(3-methoxyphenyl) and 3-(4-fluorophenyl) substituted cyclohexenone derivatives 5b, 5d, 5e, 5f and 5h were synthesized from the known enone 9.12) Briefly, treatment of 9 with the corresponding Grignard reagent followed by work-up with 5% HCl solution gave cyclohexenones 10b–f, 10h and 10i. The carbonyl group in 10b, 10d, 10e, 10f and 10h were protected to give acetals 11b, 11d, 11e, 11f and 11h. The reaction substrates 5b, 5d, 5e, 5f and 5h were provided by incorporation of an ethoxycarbonyl group into the terminal alkyne moiety in 11b, 11d, 11e, 11f and 11h, followed by deacetalization. The 3-(4-ethoxycarbonylphenyl) substituted cyclohexenone derivatives 5g were prepared as follows. Treatment of ketone 9 with 4-iodophenylmagnesium chloride13) in situ generated from 1,4-diiodobenzene with i-PrMgCl, followed by work-up with 10% HCl solution gave cyclohexenone 12. Luche reduction of 12 and subsequent protection of the resulting alcohol with tetrahydropyranyl (THP) afforded THP ether 13. Following generation of both aryl magnesium and magnesium acetylide by treatment of 13 with i-PrMgCl, reaction with ClCO2Et followed by deprotection of the secondary alcohol afforded allyl alcohol 14. Oxidation of allyl alcohol 14 with Dess–Martin periodinane afforded the desired reaction substrate 5f. The 3-vinyl, 3-(1-naphtyl) substituted cyclohexenone derivatives 5c and 5i were prepared through an analogous pathway as utilized for 5i.
a Overall yield of two steps.
Having achieved the preparation of the starting materials, consecutive enolization and intramolecular Alder–Rickert reactions were next examined (Table 1). Upon treatment of 5a4) having no substituent at the 3-position with In(OTf)3 (20 mol%) in toluene at 100°C, the desired reaction proceeded to give phenol 8a,4) albeit only in 15% yield (Entry 1). A control experiment using 5b having a methyl group resulted in quite a poor yield of product 8b (Entry 2). Utilizing 5c bearing a vinyl group in the reaction failed to produce the phenol product 8c (Entry 3). When a similar reaction was performed employing 5d having a phenyl group, the chemical yield increased up to 40% (Entry 4). The improvement in chemical yield in the reaction of 5d might be attributed to the relative high stability of the dienol intermediate by the phenyl group, as we anticipated. When the similar reaction of 5d was performed using Rh(I) complex as other Lewis acid, generated from 10 mol% of [RhCl(CO)2]2, 40 mol% of P(C6H5)3 and 80 mol% of Ag(OTf), a slight improvement of chemical yield (50%) was observed. However, applying the condition using In(OTf)3 to next examinations was settled, because it was inexpensive, easy to handle, and no need to utilize phosphine ligand.
| Entry | Reaction substrates | Time | Product | Yieldc) |
|---|---|---|---|---|
| 1a) | ;%0A%09%09%09newWindow.document.open();%0A%09%09%09newWindow.document.write('<img src=%22./Graphics/FT15a.png%22>');%0A%09%09%09newWindow.document.close();%0A%09%09) | 12 h | ;%0A%09%09%09newWindow.document.open();%0A%09%09%09newWindow.document.write('<img src=%22./Graphics/FT18a.png%22>');%0A%09%09%09newWindow.document.close();%0A%09%09) | 15% |
| 2a) | ;%0A%09%09%09newWindow.document.open();%0A%09%09%09newWindow.document.write('<img src=%22./Graphics/FT15b.png%22>');%0A%09%09%09newWindow.document.close();%0A%09%09) | 20 h | ;%0A%09%09%09newWindow.document.open();%0A%09%09%09newWindow.document.write('<img src=%22./Graphics/FT18b.png%22>');%0A%09%09%09newWindow.document.close();%0A%09%09) | Trace |
| 3a) | ;%0A%09%09%09newWindow.document.open();%0A%09%09%09newWindow.document.write('<img src=%22./Graphics/FT15c.png%22>');%0A%09%09%09newWindow.document.close();%0A%09%09) | 40 h | ;%0A%09%09%09newWindow.document.open();%0A%09%09%09newWindow.document.write('<img src=%22./Graphics/FT18c.png%22>');%0A%09%09%09newWindow.document.close();%0A%09%09) | 0% |
| 4a) | ;%0A%09%09%09newWindow.document.open();%0A%09%09%09newWindow.document.write('<img src=%22./Graphics/FT15d.png%22>');%0A%09%09%09newWindow.document.close();%0A%09%09) | 63 h | ;%0A%09%09%09newWindow.document.open();%0A%09%09%09newWindow.document.write('<img src=%22./Graphics/FT18d.png%22>');%0A%09%09%09newWindow.document.close();%0A%09%09) | 40% |
| 5b) | 5d | 18 h | 8d | 50% |
a) The reaction was carried out in the presence of 20 mol% In(OTf)3 in toluene at 100°C under an Ar atmosphere. b) The reaction was carried out in the presence of 10 mol% [RhCl(CO)2]2, 40 mol% P(C6F5)3 and 80 mol% Ag(OTf) in toluene at 100°C under an Ar atmosphere. c) Isolated yields.
We next examined the present reactions with several substrates each possessing a different aryl group at the 3-position (Table 2). When the reaction with 5e having a 4-methoxyphenyl group at the 3-position was performed, the corresponding phenol 8e was generated in low yield (8%, Entry 1). The reaction of 5f having a 3-methoxyphenyl group in place of 5e led to the increased chemical yield of phenol 8f from 8% to 39% (Entry 2). When 5g having a 4-ethoxycarbonylphenyl group at the 3-position was employed in the present reaction, the chemical yield of phenol 8g improved to 55% (Entry 2). The reaction of 5h having a 4-fluorophenyl group at the 3-position gave phenol 8h in 24% yield (Entry 3). The reaction of 5i having a 1-naphthyl group provided the desired phenol 8i in good yield (74%, Entry 4).
| Entrya) | Reaction substrates | Time | Products | Yieldb) |
|---|---|---|---|---|
| 1 | ;%0A%09%09%09newWindow.document.open();%0A%09%09%09newWindow.document.write('<img src=%22./Graphics/FT25e.png%22>');%0A%09%09%09newWindow.document.close();%0A%09%09) | 40 h | ;%0A%09%09%09newWindow.document.open();%0A%09%09%09newWindow.document.write('<img src=%22./Graphics/FT28e.png%22>');%0A%09%09%09newWindow.document.close();%0A%09%09) | 8% |
| 2 | ;%0A%09%09%09newWindow.document.open();%0A%09%09%09newWindow.document.write('<img src=%22./Graphics/FT25f.png%22>');%0A%09%09%09newWindow.document.close();%0A%09%09) | 40 h | ;%0A%09%09%09newWindow.document.open();%0A%09%09%09newWindow.document.write('<img src=%22./Graphics/FT28f.png%22>');%0A%09%09%09newWindow.document.close();%0A%09%09) | 39% |
| 3 | ;%0A%09%09%09newWindow.document.open();%0A%09%09%09newWindow.document.write('<img src=%22./Graphics/FT25g.png%22>');%0A%09%09%09newWindow.document.close();%0A%09%09) | 40 h | ;%0A%09%09%09newWindow.document.open();%0A%09%09%09newWindow.document.write('<img src=%22./Graphics/FT28g.png%22>');%0A%09%09%09newWindow.document.close();%0A%09%09) | 55% |
| 4 | ;%0A%09%09%09newWindow.document.open();%0A%09%09%09newWindow.document.write('<img src=%22./Graphics/FT25h.png%22>');%0A%09%09%09newWindow.document.close();%0A%09%09) | 40 h | ;%0A%09%09%09newWindow.document.open();%0A%09%09%09newWindow.document.write('<img src=%22./Graphics/FT28h.png%22>');%0A%09%09%09newWindow.document.close();%0A%09%09) | 24% |
| 5 | ;%0A%09%09%09newWindow.document.open();%0A%09%09%09newWindow.document.write('<img src=%22./Graphics/FT25i.png%22>');%0A%09%09%09newWindow.document.close();%0A%09%09) | 40 h | ;%0A%09%09%09newWindow.document.open();%0A%09%09%09newWindow.document.write('<img src=%22./Graphics/FT28i.png%22>');%0A%09%09%09newWindow.document.close();%0A%09%09) | 74% |
a) All reactions were performed in the presence of 20 mol% of In(OTf)3 in toluene at 100°C under an Ar atmosphere. b) Isolated yields.
These results suggested that reactivity of substrates would be dependent upon the electronic nature of the aryl group, wherein the 1-naphtyl and phenyl bearing electron-withdrawing groups were found to be optimal in our examination. Although the precise reason remains unclear, the observed reactivity might be associated with the stability of the dienol intermediate formed as a result of the presence of an aryl group possessing a longer conjugated system.
In conclusion, it was shown that the In(OTf)3-catalyzed enolization and subsequent intramolecular Alder–Rickert reaction of 3-aryl substituted cyclohexenone derivatives gave phenol derivatives in better chemical yield compared with those substrates without possessing an aryl group at the 3-position. This may have occurred due to stabilization of the dienol intermediate due to the resonance of the aryl group. Since it was shown that the 4-phenylindane skeleton could be constructed by the present reaction, we plan on applying this method to the synthesis of bioactive compounds.
Melting points (mp) were measured using a Yanagimoto micro-melting point apparatus and are uncorrected. IR spectra were recorded using a JASCO FTIR-4100 instrument. 1H- and 13C-NMR spectra were recorded on a JEOL JNM-AL300 instrument. Chemical shifts are given on the δ (ppm) scale using tetramethylsilane (TMS) as the internal standard (s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; m, multiplet; br, broad). Mass spectra were measured on a JEOL JMS-MS700 V instrument by FAB+. Flash column chromatography was performed using Kanto Chemical Silica Gel 60N (spherical, neutral) 40–50 µm.
Typical Procedure for Preparation of 3-Methyl-4-pent-4-ynylcyclohex-2-enone (10b) Using Grignard ReagentsTo a solution of 9 (415 mg, 2.01 mmol) in tetrahydrofuran (THF) (2.0 mL) was added MeMgBr (1.06 M THF solution, 2.80 mL, 3.00 mmol) at 0°C under an Ar atmosphere and the mixture was stirred at the room temperature for 2.5 h. To the mixture was added 5% HCl solution (2.0 mL) at 0°C and the mixture was stirred at the same temperature for 10 min. The reaction mixture was extracted with Et2O. The organic layer was washed with saturated aqueous NaHCO3 solution, H2O and brine, and dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (hexane–AcOEt=6 : 1) to give 10b (254 mg, 72% yield, two steps) as a colorless oil. IR (neat) cm−1: 3290, 2116, 1663. 1H-NMR (300 MHz, CDCl3) δ: 5.84 (1H, s), 2.44 (1H, m), 2.19–2.33 (4H, m), 1.84–2.12 (6H, m), 1.53–1.80 (4H, m). 13C-NMR (75 MHz, CDCl3) δ: 199.5, 165.7, 126.9, 83.7, 68.8, 38.9, 33.7, 29.6, 26.3, 26.0, 22.8, 18.3. FAB-MS m/z: 177. High resolution (HR)-FAB-MS m/z: 177.1261 (Calcd for C12H17O: M++H, 177.1279).
4-Pent-4-ynyl-3-vinylcyclohex-2-enone (10c)This compound (301 mg, 80%) was prepared from 9 (413 mg, 2.00 mmol) with vinylmagnesium bromide (1.0 M hexane solution, 3.00 mL, 3.00 mmol) in two steps. Pale yellow oil. IR (neat) cm−1: 3292, 2115, 1660. 1H-NMR (300 MHz, CDCl3) δ: 6.40 (1H, dd, J=10.8, 17.6 Hz), 5.89 (1H, s), 5.72 (1H, d, J=17.6 Hz), 5.49 (1H, d, J=10.8 Hz), 2.69 (1H, m), 2.19–2.58 (4H, m), 1.96–2.11 (3H, m), 1.60–1.78 (4H, m). 13C-NMR (75 MHz, CDCl3) δ: 200.1, 161.3, 136.9, 127.2, 120.9, 83.7, 68.9, 32.7, 32.7, 30.0, 26.9, 25.0, 18.1. FAB-MS m/z: 189. HR-FAB-MS m/z: 189.1292 (Calcd for C13H17O: M++H, 189.1279).
4-Pent-4-ynyl-3-phenylcyclohex-2-enone (10d)This compound (397 mg, 84%) was prepared from 9 (413 mg, 2.00 mmol) with phenylmagnesium bromide (1.09 M THF solution, 2.75 mL, 3.00 mmol) in two steps. Colorless oil. IR (neat) cm−1: 3294, 2116, 1662, 1601, 1493, 1444. 1H-NMR (300 MHz, CDCl3) δ: 7.40–7.51 (5H, m), 6.26 (1H, s), 3.01 (1H, m), 2.57 (1H, m), 2.43 (1H, m), 2.06–2.30 (4H, m), 1.91 (1H, t, J=2.6 Hz). 13C-NMR (75 MHz, CDCl3) δ: 199.7, 164.6, 138.4, 129.9, 128.9, 128.9, 126.6, 126.6, 125.5, 83.6, 68.8, 35.7, 32.7, 30.4, 26.7, 25.5, 18.1. FAB-MS m/z: 77, 239. HR-FAB-MS m/z: 239.1461 (Calcd for C17H19O: M++H, 239.1436).
3-(4-Methoxyphenyl)-4-pent-4-ynylcyclohex-2-enone (10e)This compound (588 mg, 85%) was prepared from 9 (539 mg, 2.61 mmol) with 4-methoxyphenylmagnesium bromide14) which was generated in situ from 4-bromoanisole (1.30 mL, 10.5 mmol) with Mg turnings (306 mg, 12.6 mmol) in THF (5.0 mL) in two steps. White solid. mp 63–64°C. IR (neat) cm−1: 3236, 2051, 1643, 1511, 1456. 1H-NMR (300 MHz, CDCl3) δ: 7.49 (2H, d, J=8.8 Hz), 6.94 (2H, d, J=8.8 Hz), 6.26 (1H, s), 3.85 (3H, s), 2.99 (1H, m), 2.55 (1H, m), 2.40 (1H, m), 2.04–2.25 (4H, m), 1.92 (1H, t, J=2.6 Hz), 1.51–1.72 (4H, m). 13C-NMR (75 MHz, CDCl3) δ: 199.5, 163.8, 161.1, 130.0, 128.0, 128.0, 123.5, 114.1, 114.1, 83.6, 68.7, 55.2, 35.2, 32.3, 30.2, 26.7, 25.1, 18.1. FAB-MS m/z: 107, 269. HR-FAB-MS m/z: 269.1520 (Calcd for C18H21O2: M++H, 269.1542).
3-(3-Methoxy-phenyl)-4-pent-4-ynyl-cyclohex-2-enone (10f)This compound (236 mg, 88%) was prepared from 9 (206 mg, 1.00 mmol) with 3-methoxyphenylmagnesium bromide15) which was generated in situ from 4-bromoanisole (0.5 mL, 4.00 mmol) with Mg turnings (146 mg, 6.00 mmol) in THF (20.0 mL) in two steps. Colorless oil. IR (neat) cm−1: 3289, 2116, 1661, 1597, 1575, 1488, 1456. 1H-NMR (300 MHz, CDCl3) δ: 7.33 (1H, t, J=7.9 Hz), 7.08 (1H, d, J=7.9 Hz), 6.94–7.01 (2H, m), 6.25 (1H, s), 3.84 (3H, s), 2.98 (1H, m), 2.55 (1H, m), 2.37 (1H, m), 2.04–2.29 (4H, m), 1.91 (1H, t, J=2.6 Hz), 1.48–1.69 (4H, m). 13C-NMR (75 MHz, CDCl3) δ: 199.7, 164.5, 159.9, 140.0, 129.9, 125.6, 119.0, 115.3, 112.3, 83.7, 68.8, 55.3, 35.9, 32.7, 30.4, 26.8, 25.5, 18.2. FAB-MS m/z: 269. HR-FAB-MS m/z: 269.1543 (Calcd for C18H21O2: M++H, 269.1542).
3-(4-Fluorophenyl)-4-pent-4-ynylcyclohex-2-enone (10h)This compound (426 mg, 83%) was prepared from 9 (413 mg, 2.00 mmol) with 4-fluorophenylmagnesium bromide16) which was generated in situ from 4-bromofluorobenzene (0.330 mL, 3.00 mmol) with Mg turnings (73.1 mg, 3.01 mmol) in THF (6.0 mL) in two steps. White solid. mp 62–63°C. IR (neat) cm−1: 3305, 2111, 1598, 1509, 1446. 1H-NMR (300 MHz, CDCl3) δ: 7.47–7.51 (2H, m), 7.08–7.13 (2H, m), 6.22 (1H, s), 2.96 (1H, m), 2.56 (1H, m), 2.42 (1H, m), 2.10–2.28 (4H, m), 1.91 (1H, t, J=2.6 Hz), 1.50–1.71 (4H, m). 13C-NMR (75 MHz, CDCl3) δ: 199.3, 165.3, 163.1, 162.0, 134.3, 128.5, 128.4, 125.3, 115.9, 115.7, 83.5, 68.8, 35.6, 32.5, 30.1, 26.5, 25.2, 18.0. FAB-MS m/z: 257. HR-FAB-MS m/z: 257.1349 (Calcd for C17H18FO: M++H, 257.1342).
3-Naphthalen-1-yl-4-pent-4-ynylcyclohex-2-enone (10i)This compound (674 mg, 93%) was prepared from 9 (516 mg, 2.50 mmol) with 1-naphthylmagnesium bromide17) which was generated in situ from 1-bromonaphthalene (0.520 mL, 3.75 mmol) with Mg turnings (109 mg, 4.48 mmol) in THF (7.5 mL) in two steps. Colorless oil. IR (neat) cm−1: 3297, 2116, 1666, 1608, 1506, 1456. 1H-NMR (300 MHz, CDCl3) δ: 7.82–7.90 (3H, m), 7.46–7.54 (3H, m), 7.30 (1H, d, J=6.8 Hz), 6.10 (1H, s), 2.91 (1H, m), 2.39–2.75 (3H, m), 1.91–2.20 (3H, m), 1.80 (1H, t, J=2.6 Hz), 1.25–1.67 (4H, m). 13C-NMR (75 MHz, CDCl3) δ: 199.2, 165.9, 137.9, 133.7, 130.3, 129.5, 128.8, 128.6, 126.6, 126.1, 125.0, 125.0, 124.7, 83.5, 68.6, 39.5, 33.6, 30.1, 26.4, 26.2, 18.0. FAB-MS m/z: 127, 289. HR-FAB-MS m/z: 289.1558 (Calcd for C21H21O: M++H, 289.1592).
Typical Procedure for Preparation of 7-Methyl-8-pent-4-ynyl-1,4-dioxaspiro[4.5]dec-6-ene (11b)To a solution of 10b (254 mg, 1.44 mmol) in CH2Cl2 (6.5 mL) was added 1,2-bis(trimethylsilyloxy)ethane (3.20 mL, 13.1 mmol) at −78°C under an Ar atmosphere. To the mixture was added TMSOTf (0.05 mL, 0.276 mmol) dropwise at the same temperature, and the mixture was stirred at −60°C for 70 h. The reaction mixture was treated with addition of pyridine (0.52 mL). After concentration of the solvent under reduced pressure, the residue was purified by a silica gel column chromatography (hexane/AcOEt=6: 1) to give acetal 11b (221 mg, 69% yield) as a pale yellow oil. IR (neat) cm−1: 3288, 2116, 1079, 1101. 1H-NMR (300 MHz, CDCl3) δ: 5.35 (1H, s), 3.91–4.01 (4H, m), 2.13–2.26 (2H, m), 1.35–1.98 (13H, m). 13C-NMR (75 MHz, CDCl3) δ: 144.4, 123.4, 106.4, 84.3, 68.4, 64.4, 64.4, 38.0, 30.9, 30.4, 25.9, 25.2, 21.6, 18.5. FAB-MS m/z: 221. HR-FAB-MS m/z: 221.1528 (Calcd for C14H21O2: M++H, 221.1542).
8-Pent-4-ynyl-7-phenyl-1,4-dioxaspiro[4.5]dec-6-ene (11d)This compound (313 mg, 67%) was prepared by the reaction of 10d (397 mg, 1.67 mmol) at −78°C for 5 d. Colorless oil. IR (neat) cm−1: 3289, 2116, 1662, 1599, 1491, 1444, 1112, 1099. 1H-NMR (300 MHz, CDCl3) δ: 7.28–7.32 (5H, m), 5.70 (1H, s), 3.94–4.09 (4H, m), 2.71 (1H, m), 1.75–2.10 (7H, m), 1.25–1.59 (4H, m). 13C-NMR (75 MHz, CDCl3) δ: 147.7, 141.0, 128.3, 128.3, 127.5, 126.7, 126.7, 125.4, 106.2, 84.2, 68.3, 64.6, 64.4, 35.4, 31.1, 30.1, 26.3, 24.8, 18.3. FAB-MS m/z: 215, 283. HR-FAB-MS m/z: 283.1715 (Calcd for C19H23O2: M++H, 283.1698).
7-(4-Methoxyphenyl)-8-pent-4-ynyl-1,4-dioxaspiro[4.5]dec-6-ene (11e)This compound (260 mg, 41%) was prepared by the reaction of 10e (542 mg, 2.02 mmol) at −30°C for 4 d. Colorless oil. IR (neat) cm−1: 3290, 2116, 1607, 1510, 1456, 1243, 1110. 1H-NMR (300 MHz, CDCl3) δ: 7.26 (2H, d, J=8.8 Hz), 6.85 (2H, d, J=8.8 Hz), 5.65 (1H, s), 3.95–4.06 (4H, m), 3.81 (3H, s), 2.67 (1H, m), 1.75–2.10 (6H, m), 1.25–1.60 (5H, m). 13C-NMR (75 MHz, CDCl3) δ: 159.2, 147.1, 133.2, 127.7, 127.7, 124.0, 113.6, 113.6, 106.4, 84.3, 68.3, 64.6, 64.4, 55.2, 35.3, 31.0, 29.9, 26.4, 24.7, 18.3. FAB-MS m/z: 245, 313. HR-FAB-MS m/z: 313.1795 (Calcd for C20H25O3: M++H, 313.1804).
7-(3-Methoxy-phenyl)-8-pent-4-ynyl-1,4-dioxa-spiro[4.5]dec-6-ene (11f)This compound (177 mg, 65%) was prepared by the reaction of 10f (236 mg, 0.881 mmol) at −70°C for 2 d. Colorless oil. IR (neat) cm−1: 3289, 2116, 1607, 1597, 1577, 1488, 1457, 1285, 1111. 1H-NMR (300 MHz, CDCl3) δ: 7.22 (1H, t, J=7.9 Hz), 6.90 (1H, d, J=7.9 Hz), 6.80–6.85 (2H, m), 5.70 (1H, s), 3.93–4.08 (4H, m), 3.81 (3H, s), 2.66 (1H, m), 1.74–2.23 (6H, m), 1.33–1.64 (5H, m). 13C-NMR (75 MHz, CDCl3) δ: 159.6, 147.6, 142.5, 129.2, 125.4, 119.2, 113.0, 112.4, 106.2, 84.2, 68.3, 64.6, 64.4, 55.2, 35.6, 31.1, 30.1, 26.3, 24.8, 18.3. FAB-MS m/z: 245, 313. HR-FAB-MS m/z: 313.1807 (Calcd for C20H25O3: M++H, 313.1804).
7-(4-Fluorphenyl)-8-pent-4-ynyl-1,4-dioxaspiro[4.5]dec-6-ene (11h)This compound (358 mg, 72%) was prepared by the reaction of 10h (426 mg, 1.66 mmol) at −70°C for 2 d. Colorless oil. IR (neat) cm−1: 3302, 2116, 1603, 1508, 1456, 1224, 1112. 1H-NMR (300 MHz, CDCl3) δ: 7.28–7.31 (2H, m), 6.97–7.03 (2H, m), 5.66 (1H, s), 3.95–4.06 (4H, m), 2.64 (1H, m), 1.74–2.10 (7H, m), 1.32–1.58 (4H, m). 13C-NMR (75 MHz, CDCl3) δ: 164.0, 160.8, 146.7, 136.9, 136.9, 128.3, 128.2, 125.6, 115.3, 115.0, 106.1, 84.1, 68.4, 64.4, 64.4, 35.5, 30.9, 30.0, 26.2, 24.7, 18.2. FAB-MS m/z: 233, 301. HR-FAB-MS m/z: 301.1592 (Calcd for C19H22FO2: M++H, 301.1604).
Typical Procedure for Preparation of Ethyl 6-(2-Methyl-4-oxocyclohex-2-enyl)hex-2-ynoate (5b)To a solution of 11b (221 mg, 1.00 mmol) in THF (5.0 mL) was added n-BuLi (1.67 M hexane solution, 0.720 mL, 1.20 mmol) at −78°C under an Ar atmosphere and the mixture was stirred at the same temperature for 1 h. To the mixture was added ethyl chloroformate (0.200 mL, 2.09 mmol) at −78°C and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by addition of saturated aqueous NH4Cl solution at 0°C, and the mixture was extracted with AcOEt. The organic layer was washed with H2O and brine, and dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was used for the next reaction without further purification.
To a solution of the above crude product in acetone (4.0 mL) and water (0.7 mL) was added pyridinium-p-toluenesulfonate (PPTS) (50.3 mg, 0.200 mmol) at 0°C, and the mixture was stirred at room temperature for 12 h. The reaction mixture was quenched by addition of saturated aqueous NaHCO3 solution, and the mixture was extracted with AcOEt. The organic layer was washed with H2O and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (hexane–AcOEt=3 : 1) to give 5b (155 mg, 63% yield, two steps) as a colorless oil. IR (neat) cm−1: 2233, 1704, 1665. 1H-NMR (300 MHz, CDCl3) δ: 5.85 (1H, s), 4.22 (2H, q, J=7.2 Hz), 2.24–2.48 (5H, m), 1.51–2.13 (9H, m), 1.30 (3H, t, J=7.2 Hz). 13C-NMR (75 MHz, CDCl3) δ: 199.3, 165.2, 153.7, 127.0, 100.6, 88.1, 73.8, 61.8, 38.8, 33.7, 29.8, 26.0, 25.5, 22.8, 18.6, 13.9. FAB-MS m/z: 175, 249. HR-FAB-MS m/z: 249.1523 (Calcd for C15H21O3: M++H, 249.1491).
Ethyl 6-(4-Oxo-2-phenylcyclohex-2-enyl)hex-2-ynoate (5d)This compound (292 mg, 85%) was prepared from 11d (313 mg, 1.11 mmol) in two steps. Colorless oil. IR (neat) cm−1: 2233, 1703, 1665. 1H-NMR (300 MHz, CDCl3) δ: 7.40–7.50 (5H, m), 6.26 (1H, s), 4.20 (2H, q, J=7.2 Hz), 3.02 (1H, m), 2.07–2.62 (6H, m), 1.53–1.71 (4H, m), 1.29 (3H, t, J=7.2 Hz). 13C-NMR (75 MHz, CDCl3) δ: 199.5, 164.2, 153.7, 138.4, 130.0, 129.0, 129.0, 126.6, 126.6, 125.8, 88.1, 73.6, 61.8, 35.7, 32.8, 30.6, 25.9, 25.6, 18.4, 13.9. FAB-MS m/z: 237, 311. HR-FAB-MS m/z: 311.1632 (Calcd for C20H23O3: M++H, 311.1647).
Ethyl 6-[2-(4-Methoxyphenyl)-4-oxocyclohex-2-enyl]-hex-2-ynoate (5e)This compound (232 mg, 92%) was prepared from 11e (233 mg, 0.744 mmol) in two steps. Pale yellow oil. IR (neat) cm−1: 2233, 1704, 1656. 1H-NMR (300 MHz, CDCl3) δ: 7.48 (2H, d, J=8.8 Hz), 6.94 (2H, d, J=8.8 Hz), 6.25 (1H, s), 4.20 (2H, q, J=7.2 Hz), 3.85 (3H, s), 3.00 (1H, m), 2.08–2.60 (6H, m), 1.54–1.77 (4H, m), 1.29 (3H, t, J=7.2 Hz). 13C-NMR (75 MHz, CDCl3) δ ppm: 199.4, 163.5, 161.2, 153.6, 130.0, 128.0, 128.0, 123.8, 114.3, 114.3, 88.1, 73.6, 61.7, 55.2, 35.2, 32.4, 30.5, 25.9, 25.2, 18.4, 13.8. FAB-MS m/z: 267, 341. HR-FAB-MS m/z: 341.1777 (Calcd for C21H25O4: M++H, 341.1753).
Ethyl 6-[2-(3-Methoxyphenyl)-4-oxocyclohex-2-enyl]-hex-2-ynoate (5f)This compound (135 mg, 70%) was prepared from 11f (177 mg, 0.568 mmol) in two steps. Colorless oil. IR (neat) cm−1: 2234, 1704, 1664. 1H-NMR (300 MHz, CDCl3) δ: 7.33 (1H, t, J=7.9 Hz), 7.08 (1H, d, J=7.9 Hz), 6.93–6.98 (2H, m), 6.24 (1H, s), 4.20 (2H, q, J=7.2 Hz), 3.83 (3H, s), 2.98 (1H, m), 2.08–2.62 (6H, m), 1.59–1.70 (4H, m), 1.29 (3H, t, J=7.2 Hz). 13C-NMR (75 MHz, CDCl3) δ: 199.5, 164.2, 160.0, 153.7, 139.9, 129.9, 125.8, 119.0, 115.3, 112.2, 88.1, 73.6, 61.8, 55.2, 35.9, 32.8, 30.7, 25.9, 25.6, 18.5, 13.9. FAB-MS m/z: 267, 341. HR-FAB-MS m/z: 341.1739 (Calcd for C21H25O4: M++H, 341.1753).
Ethyl 6-[2-(4-Fluorophenyl)-4-oxocyclohex-2-enyl]hex-2-ynoate (5h)This compound (348 mg, 89%) was prepared from 11h (358 mg, 1.19 mmol) in two steps. Colorless oil. IR (neat) cm−1: 2233, 1703, 1663. 1H-NMR (300 MHz, CDCl3) δ: 7.45–7.50 (2H, m), 7.08–7.14 (2H, m), 6.22 (1H, s), 4.20 (2H, q, J=7.2 Hz), 2.98 (1H, m), 2.07–2.60 (6H, m), 1.52–1.75 (4H, m), 1.29 (3H, t, J=7.2 Hz). 13C-NMR (75 MHz, CDCl3) δ: 199.2, 165.5, 162.9, 162.1, 153.6, 134.3, 134.3, 128.6, 128.5, 125.6, 116.2, 115.9, 87.9, 73.7, 61.8, 35.7, 32.6, 30.3, 25.7, 25.4, 18.3, 13.9. FAB-MS m/z: 255, 329. HR-FAB-MS m/z: 329.1560 (Calcd for C20H22FO3: M++H, 329.1553).
3-(4-Iodophenyl)-4-pent-4-ynylcyclohex-2-enone (12)To a solution of 1,4-diiodobenzene (5.28 g, 16.0 mmol) in THF (15.0 mL) was added i-PrMgCl (1.0 M THF solution, 16.0 mL, 16.0 mmol) at 0°C under an Ar atmosphere and the mixture was stirred at the room temperature for 0.5 h. To the mixture was added a solution of 9 (825 mg, 4.00 mmol) in THF (5.0 mL) at 0°C and the mixture was stirred at 40°C for 2 h. To the mixture was added 10% HCl solution (2.0 mL) at 0°C and the mixture was stirred at same temperature for 1 h. The reaction mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous NaHCO3 solution, H2O and brine, and dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (hexane–AcOEt=5 : 1) to give 12 (1.21 g, 83% yield, two steps) as a colorless oil. IR (neat) cm−1: 3292, 2115, 1661, 1598, 1578, 1484, 1455. 1H-NMR (300 MHz, CDCl3) δ: 7.76 (2H, d, J=8.5 Hz), 7.23 (2H, d, J=8.5 Hz), 6.23 (1H, s), 2.95 (1H, m), 2.37–2.61 (2H, m), 2.08–2.28 (4H, m), 1.92 (1H, t, J=2.6 Hz), 1.46–1.70 (4H, m). 13C-NMR (75 MHz, CDCl3) δ: 199.4, 163.3, 138.1, 138.1, 137.9, 128.3, 128.3, 125.7, 96.1, 83.5, 68.9, 35.5, 32.7, 30.3, 26.6, 25.4, 18.1. FAB-MS m/z: 365. HR-FAB-MS m/z: 365.0402 (Calcd for C17H18IO: M++H, 365.0402).
Typical Procedure for Preparation of 2-[3-(4-Iodophenyl)-4-pent-4-ynylcyclohex-2-enyloxy]tetrahydropyran (13)To a solution of 12 (1.20 g, 3.31 mmol) in MeOH (33.0 mL) were added CeCl3·7H2O (1.48 g, 3.97 mmol) and NaBH4 (150 mg, 3.97 mmol) at 0°C, and the mixture was stirred at room temperature for 5 h. The reaction mixture was quenched by addition of saturated aqueous NH4Cl solution at 0°C and the mixture was extracted with AcOEt. The organic layer was washed with H2O and brine, and dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was used for the next reaction without further purification.
To a solution of the above crude product in CH2Cl2 (15.0 mL) were added 3,4-dihydro-2H-pyran (DHP) (1.20 mL, 13.2 mmol) and PPTS (415 mg, 1.66 mmol) at 0°C under an Ar atmosphere, and the mixture was stirred at room temperature for 18 h. The reaction mixture was quenched by addition of saturated aqueous NaHCO3 solution, and the mixture was extracted with AcOEt. The organic layer was washed with H2O and brine, and dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (hexane–AcOEt=10 : 1) to give 13 (1.26 g, 84% yield, two steps) as a colorless oil. IR (neat) cm−1: 3292, 2116, 1484, 1453, 1440, 1020. 1H-NMR (300 MHz, CDCl3) δ: 7.63 (2H, d, J=8.3 Hz), 7.02–7.11 (2H, m), 5.92 (1H, m), 4.79 (1H, m), 4.33 (1H, m), 3.93 (1H, m), 3.52 (1H, m), 2.63 (1H, m), 1.23–2.14 (17H, m). 13C-NMR (75 MHz, CDCl3) δ: 143.9, 143.5, 137.4, 137.4, 137.3, 137.3, 128.6, 128.5, 128.5, 128.3, 127.2, 98.2, 97.9, 97.1, 96.7, 92.5, 92.4, 84.2, 71.9, 71.0, 69.9, 68.3, 62.8, 62.6, 62.6, 35.2, 35.0, 35.0, 31.8, 31.7, 31.5, 31.1, 31.1, 31.0, 31.0, 26.7, 26.6, 25.9, 25.8, 25.4, 25.2, 24.1, 24.1, 23.9, 23.4, 19.8, 19.7, 19.6, 18.3. FAB-MS m/z: 349, 450. HR-FAB-MS m/z: 450.1064 (Calcd for C22H27IO2: M+, 450.1056).
2-(4-Pent-4-ynyl-3-vinylcyclohex-2-enyloxy)tetrahydropyran (15c)This compound (358 mg, 84%) was prepared from 10c (291 mg, 1.54 mmol) in two steps. Colorless oil. IR (neat) cm−1: 3298, 2117, 1020. 1H-NMR (300 MHz, CDCl3) δ: 6.22 (1H, m), 5.72 (1H, m), 5.21 (1H, m), 5.04 (1H, m), 4.76 (1H, m), 4.32 (1H, m), 3.93 (1H, m), 3.50 (1H, m), 2.17–2.32 (3H, m), 1.24–1.95 (15H, m). 13C-NMR (75 MHz, CDCl3) δ: 142.5, 142.4, 138.4, 130.7, 129.3, 112.7, 112.4, 98.2, 96.7, 84.4, 73.2, 71.9, 68.3, 62.7, 62.6, 32.3, 31.5, 31.1, 31.0, 27.3, 27.3, 25.8, 25.4, 24.2, 24.0, 23.9, 19.7, 19.6, 18.4. FAB-MS m/z: 173, 273. HR-FAB-MS m/z: 273.1865 (Calcd for C18H25O2: M+−H, 273.1855).
2-(3-Naphthalen-1-yl-4-pent-4-ynylcyclohex-2-enyloxy)tetrahydropyran (15i)This compound (859 mg, 98%) was prepared from 10i (674 mg, 2.34 mmol) in two steps. Colorless oil. IR (neat) cm−1: 3293, 2116, 1590, 1506, 1453, 1440, 1019. 1H-NMR (300 MHz, CDCl3) δ: 8.02 (1H, m), 7.74–7.85 (2H, m), 7.39–7.47 (3H, m), 7.29 (1H, m), 5.81 (1H, m), 4.80 (1H, m), 4.44 (1H, m), 3.91 (1H, m), 3.50 (1H, m), 2.58 (1H, m), 1.17–2.19 (17H, m). 13C-NMR (75 MHz, CDCl3) δ: 140.5, 140.4, 140.4, 133.7, 133.7, 131.7, 130.4, 130.1, 129.0, 128.7, 128.3, 128.2, 128.2, 127.1, 127.0, 127.0, 125.9, 125.8, 125.7, 125.7, 125.6, 125.5, 125.1, 125.1, 98.0, 97.6, 97.0, 96.5, 84.1, 71.3, 70.8, 70.7, 70.3, 68.1, 63.0, 62.8, 62.2, 62.1, 38.7, 38.4, 31.9, 31.7, 31.6, 31.5, 31.1, 31.0, 31.0, 30.9, 28.2, 26.6, 26.4, 26.2, 26.0, 25.9, 25.3, 25.1, 24.9, 24.5, 24.4, 24.2, 20.0, 19.8, 19.5, 19.3, 18.2. FAB-MS m/z: 273, 374. HR-FAB-MS m/z: 374.2224 (Calcd for C26H30O2: M+, 374.2246).
Ethyl 4-[6-(5-Ethoxycarbonylpent-4-ynyl)-3-hydroxycyclohex-1-enyl]benzoate (14)To a solution of 13 (1.26 g, 2.79 mmol) in THF (28.0 mL) was added a i-PrMgCl (1.0 M THF solution, 11.2 mL, 11.2 mmol) at 0°C under an Ar atmosphere, and the mixture was stirred at the room temperature for 1 h. To the mixture was added ethyl chloroformate (2.70 mL, 27.9 mmol) at 0°C, and the mixture was stirred at 40°C for 6 h. The reaction mixture was quenched by addition of saturated aqueous NH4Cl solution, the mixture was extracted with AcOEt, and the organic layer was washed with H2O and brine, and dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was used for the next reaction without further purification.
To a solution of the crude product in EtOH (19 mL) was added TsOH·H2O (183 mg, 0.963 mmol) at 0°C, and the mixture was stirred at room temperature for 13 h. The reaction mixture was quenched by addition of saturated aqueous NaHCO3 solution, and the mixture was extracted with AcOEt. The organic layer was washed with H2O and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (hexane–AcOEt=3 : 1) to give 14 (704 mg, 66% yield, two steps) as a colorless oil. IR (neat) cm−1: 3414, 2235, 1708, 1606, 1447. 1H-NMR (300 MHz, CDCl3) δ: 8.00 (2H, d, J=8.3 Hz), 7.34–7.39 (2H, m), 5.98 (1H, m), 4.34–4.41 (3H, m), 4.19 (2H, q, J=7.2 Hz), 2.67 (1H, m), 1.76–2.29 (5H, m), 1.18–1.72 (12H, m). 13C-NMR (75 MHz, CDCl3) δ: 166.5, 153.8, 146.2, 145.8, 144.0, 143.9, 130.4, 130.3, 130.1, 129.7, 129.7, 129.3, 126.6, 126.4, 126.4, 88.6, 77.2, 73.3, 66.7, 66.4, 66.0, 64.0, 61.7, 60.8, 35.3, 35.0, 32.0, 31.7, 29.0, 28.0, 25.5, 24.7, 23.7, 23.4, 18.6, 18.5, 17.9, 17.3, 14.2, 14.1, 13.8. FAB-MS m/z: 367, 383. HR-FAB-MS m/z: 383.1874 (Calcd for C23H27O5: M+−H, 383.1858).
Typical Procedure for Preparation of Ethyl 4-[6-(5-Ethoxycarbonylpent-4-ynyl)-3-oxo-cyclohex-1-enyl]benzoate (5g)To a solution of 14 (704 mg, 1.83 mmol) in CH2Cl2 (18.0 mL) were added Dess–Martin periodinane (931 mg, 2.20 mmol) and NaHCO3 (769 mg, 9.15 mmol) at 0°C under an Ar atmosphere, and the mixture was stirred at room temperature for 3 h. The reaction mixture was quenched by addition of 1:1 mixture saturated aqueous Na2S2O3 solution and saturated aqueous NaHCO3 solution, and the mixture was extracted with Et2O. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (hexane–AcOEt=3 : 1) to give 5g (455 mg, 65% yield) as a colorless oil. IR (neat) cm−1: 2233, 1707, 1667, 1604, 1456, 1408. 1H-NMR (300 MHz, CDCl3) δ: 8.09 (2H, d, J=8.4 Hz), 7.53 (2H, d, J=8.4 Hz), 6.26 (1H, s), 4.40 (2H, q, J=7.2 Hz), 4.20 (2H, q, J=7.2 Hz), 3.02 (1H, m), 2.04–2.63 (6H, m), 1.52–1.71 (4H, m), 1.40 (3H, t, J=7.2 Hz), 1.29 (3H, t, J=7.2 Hz). 13C-NMR (75 MHz, CDCl3) δ: 199.1, 166.0, 163.0, 153.6, 142.8, 131.6, 130.1, 130.1, 126.9, 126.6, 126.6, 87.8, 73.7, 61.8, 61.1, 35.8, 32.9, 30.5, 25.6, 25.6, 18.3, 14.1, 13.8. FAB-MS m/z: 383. HR-FAB-MS m/z: 383.1874 (Calcd for C23H27O5: M++H, 383.1858).
Ethyl 6-(4-Oxo-2-vinylcyclohex-2-enyl)-hex-2-ynoate (5c)This compound (72.7 mg, 80%) was prepared from 16c (91.6 mg, 0.349 mmol). Colorless oil. IR (neat) cm−1: 2233, 1702, 1664. 1H-NMR (300 MHz, CDCl3) δ: 6.40 (1H, dd, J=10.8, 17.6 Hz), 5.90 (1H, s), 5.71 (1H, d, J=17.6 Hz), 5.50 (1H, d, J=10.8 Hz), 4.22 (2H, q, J=7.2 Hz), 2.68 (1H, m), 2.33–2.57 (4H, m), 2.02–2.08 (2H, m), 1.51–1.86 (4H, m), 1.30 (3H, t, J=7.2 Hz). 13C-NMR (75 MHz, CDCl3) δ: 199.9, 160.8, 153.7, 136.9, 127.4, 120.9, 88.1, 73.7, 61.8, 32.7, 32.7, 30.3, 26.1, 25.0, 18.5, 13.9. FAB-MS m/z: 187, 261. HR-FAB-MS m/z: 261.1485 (Calcd for C16H21O3: M++H, 261.1491).
Ethyl 6-(2-Naphthalen-1-yl-4-oxocyclohex-2-enyl)hex-2-ynoate (5i)This compound (259 mg, 77%) was prepared from 16i (338 mg, 0.932 mmol). Pale yellow oil. IR (neat) cm−1: 2233, 1704, 1669, 1609, 1588, 1506, 1456. 1H-NMR (300 MHz, CDCl3) δ: 7.81–7.90 (3H, m), 7.46–7.54 (3H, m), 7.30 (1H, m), 6.10 (1H, m), 4.18 (2H, q, J=7.2 Hz), 2.92 (1H, m), 2.39–2.74 (3H, m), 2.04–2.21 (3H, m), 1.34–1.66 (4H, m), 1.28 (3H, t, J=7.2 Hz). 13C-NMR (75 MHz, CDCl3) δ: 199.0, 165.4, 153.5, 137.7, 133.7, 130.2, 129.6, 128.8, 128.6, 126.6, 126.2, 125.0, 124.9, 124.6, 88.0, 73.4, 61.6, 39.4, 33.6, 30.3, 26.2, 25.6, 18.3, 13.8. FAB-MS m/z: 287, 361. HR-FAB-MS m/z: 361.1783 (Calcd for C24H25O3: M++H, 361.1804).
Typical Procedure for Preparation of Ethyl 6-(4-Hydroxy-2-vinylcyclohex-2-enyl)hex-2-ynoate (16c)To a solution of 15c (204 mg, 0.743 mmol) in THF (10.0 mL) was added a n-BuLi (1.62 M hexane solution, 0.55 mL, 0.892 mmol) at −78°C under an Ar atmosphere, and the mixture was stirred at the same temperature for 1 h. To the mixture was added ethyl chloroformate (0.140 mL, 1.49 mmol) at −78°C, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by addition of saturated aqueous NH4Cl solution, the mixture was extracted with AcOEt, and the organic layer was washed with H2O and brine, and dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was used for the next reaction without further purification.
To a solution of the above crude product in EtOH (6.0 mL) was added PPTS (28.4 mg, 0.113 mmol) at 0°C, and the mixture was stirred at room temperature for 36 h. The reaction mixture was quenched by addition of saturated aqueous NaHCO3 solution, and the mixture was extracted with AcOEt. The organic layer was washed with H2O and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (hexane–AcOEt=2 : 1) to give 16c (91.6 mg, 47% yield, two steps) as a colorless oil. IR (neat) cm−1: 3367, 2234, 1706. 1H-NMR (300 MHz, CDCl3) δ: 6.22 (1H, dd, J=11.0, 17.8 Hz), 5.67 (1H, s), 5.19 (1H, d, J=17.8 Hz), 5.07 (1H, d, J=11.0 Hz), 4.31 (1H, br), 4.21 (2H, q, J=7.2 Hz), 2.28–2.40 (3H, m), 1.95 (1H, m), 1.41–1.83 (8H, m), 1.31 (3H, t, J=7.2 Hz). 13C-NMR (75 MHz, CDCl3) δ: 153.9, 142.1, 138.1, 131.5, 113.1, 88.9, 73.4, 67.8, 61.7, 32.3, 31.7, 27.9, 26.3, 24.1, 18.7, 13.9. FAB-MS m/z: 245, 261. HR-FAB-MS m/z: 261.1508 (Calcd for C16H21O3: M+−H, 261.1491).
Ethyl 6-(4-Hydroxy-2-naphthalen-1-ylcyclohex-2-enyl)hex-2-ynoate (16i)This compound (338 mg, 40%) was prepared from 15i (859 mg, 2.29 mmol) in two steps. Colorless oil. IR (neat) cm−1: 3360, 2233, 1704, 1590, 1505, 1446. 1H-NMR (300 MHz, CDCl3) δ: 7.75–7.95 (3H, m), 7.40–7.49 (3H, m), 7.23 (1H, m), 5.81 (1H, m), 4.43 (1H, br), 4.18 (2H, q, J=7.2 Hz), 2.59 (1H, m), 1.53–2.19 (8H, m), 1.25–1.38 (6H, m). 13C-NMR (75 MHz, CDCl3) δ: 153.8, 140.1, 139.9, 133.7, 131.6, 131.0, 130.8, 128.4, 127.3, 125.9, 125.9, 125.7, 125.6, 125.5, 125.4, 125.2, 125.2, 88.9, 73.1, 66.2, 65.9, 61.7, 38.6, 38.5, 31.9, 31.7, 29.4, 28.7, 25.6, 25.2, 24.0, 23.9, 18.5, 13.9. FAB-MS m/z: 345, 362. HR-FAB-MS m/z: 362.1852 (Calcd for C24H26O3: M+, 362.1882).
Typical Procedure for In(OTf)3-Catalyzed Synthesis of Ethyl 5-Hydroxy-7-phenylindane-4-carboxylate (8d) (Table 1, Entry 1)To a solution of 5d (37.2 mg, 0.120 mmol) in toluene (1.5 mL) was added In(OTf)3 (13.5 mg, 0.0240 mmol) at room temperature under an Ar atmosphere, and the mixture was stirred at 100°C for 63 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane–EtOAc=20 : 1) to give 8d (13.8 mg, 40% yield) as a white solid. mp 129–130°C. IR (neat) cm−1: 1653, 1598, 1558, 1459. 1H-NMR (300 MHz, CDCl3) δ: 11.17 (1H, s), 7.35–7.44 (5H, m), 6.85 (1H, s), 4.44 (2H, q, J=7.2 Hz), 3.27 (2H, t, J=7.5 Hz), 2.85 (2H, t, J=7.5 Hz), 2.02 (2H, quint, J=7.5 Hz), 1.44 (3H, t, J=7.2 Hz). 13C-NMR (75 MHz, CDCl3) δ: 171.3, 161.3, 147.5, 144.6, 140.4, 133.6, 128.3, 128.3, 128.3, 128.3, 127.7, 115.7, 109.0, 61.2, 35.6, 31.8, 25.2, 14.1. FAB-MS m/z: 283. HR-FAB-MS m/z: 283.1341 (Calcd for C18H19O3: M++H, 283.1334).
Ethyl 5-Hydroxy-7-(4-methoxyphenyl)indane-4-carboxylate (8e)This compound (5.2 mg, 8%) was prepared from 5e (68.1 mg, 0.200 mmol). White solid. mp 93–94°C. IR (neat) cm−1: 1651, 1606, 1516, 1465, 1241, 1035. 1H-NMR (300 MHz, CDCl3) δ: 11.16 (1H, s), 7.39 (2H, d, J=8.6 Hz), 6.96 (2H, d, J=8.6 Hz), 6.83 (1H, s), 4.43 (2H, q, J=7.2 Hz), 3.85 (3H, s), 3.26 (2H, t, J=7.5 Hz), 2.86 (2H, t, J=7.5 Hz), 2.02 (2H, quint, J=7.5 Hz), 1.44 (3H, t, J=7.2 Hz). 13C-NMR (75 MHz, CDCl3) δ: 171.4, 161.3, 159.4, 147.6, 144.4, 133.6, 132.8, 129.6, 129.6, 115.4, 113.8, 113.8, 108.7, 61.3, 55.3, 35.7, 32.0, 25.4, 14.2. FAB-MS m/z: 313. HR-FAB-MS m/z: 313.1451 (Calcd for C19H21O4: M++H, 313.1440).
Ethyl 5-Hydroxy-7-(3-methoxyphenyl)indane-4-carboxylate (8f)This compound (12.4 mg, 39%) was prepared from 5f (34.0 mg, 0.100 mmol). White solid. mp 67–68°C. IR (neat) cm−1: 1658, 1599, 1561, 1472. 1H-NMR (300 MHz, CDCl3) δ: 11.16 (1H, s), 7.34 (1H, t, J=7.9 Hz), 6.89–7.02 (3H, m), 6.86 (1H, s), 4.43 (2H, q, J=7.2 Hz), 3.84 (3H, s), 3.26 (2H, t, J=7.5 Hz), 2.86 (2H, t, J=7.5 Hz), 2.02 (2H, quint, J=7.5 Hz), 1.44 (3H, t, J=7.2 Hz). 13C-NMR (75 MHz, CDCl3) δ: 171.4, 161.3, 159.6, 147.6, 144.6, 141.9, 133.7, 129.4, 120.9, 115.7, 114.0, 113.3, 109.2, 61.3, 55.3, 35.7, 31.9, 25.3, 14.2. FAB-MS m/z: 313. HR-FAB-MS m/z: 313.1451 (Calcd for C19H21O4: M++H, 313.1440).
Ethyl 7-(4-Ethoxycarbonylphenyl)-5-hydroxyindane-4-carboxylate (8g)This compound (23.0 mg, 55%) was prepared from 5g (45.3 mg, 0.118 mmol). White solid. mp 93–94°C. IR (neat) cm−1: 1715, 1660, 1604, 1556, 1474. 1H-NMR (300 MHz, CDCl3) δ: 11.18 (1H, s), 8.10 (2H, d, J=8.3 Hz), 7.49 (2H, d, J=8.3 Hz), 6.85 (1H, s), 4.37–4.48 (4H, m), 3.27 (2H, t, J=7.5 Hz), 2.83 (2H, t, J=7.5 Hz), 2.03 (2H, quint, J=7.5 Hz), 1.39–1.47 (6H, m). 13C-NMR (75 MHz, CDCl3) δ: 171.1, 166.3, 161.3, 147.7, 144.8, 143.3, 133.4, 129.6, 129.5, 129.5, 128.2, 128.2, 115.5, 109.5, 61.3, 60.8, 35.5, 31.7, 25.1, 14.1, 14.0. FAB-MS m/z: 355. HR-FAB-MS m/z: 355.1538 (Calcd for C21H23O5: M++H, 355.1545).
Ethyl 7-(4-Fluorophenyl)-5-hydroxyindane-4-carboxylate (8h)This compound (8.5 mg, 24%) was prepared from 5h (39.2 mg, 0.119 mmol). White solid. mp 135–136°C. IR (neat) cm−1: 1652, 1601, 1513, 1487. 1H-NMR (300 MHz, CDCl3) δ: 11.17 (1H, s), 7.73–7.42 (2H, m), 7.08–7.14 (2H, m), 6.81 (1H, s), 4.43 (2H, q, J=7.2 Hz), 3.26 (2H, t, J=7.5 Hz), 2.82 (2H, t, J=7.5 Hz), 2.02 (2H, quint, J=7.5 Hz), 1.44 (3H, t, J=7.2 Hz). 13C-NMR (75 MHz, CDCl3) δ: 171.3, 164.1, 161.4, 160.9, 147.7, 143.6, 136.4, 136.4, 133.6, 130.1, 130.0, 115.7, 115.4, 115.1, 109.2, 61.4, 35.6, 31.9, 25.3, 14.1. FAB-MS m/z: 301. HR-FAB-MS m/z: 301.1263 (Calcd for C18H18FO3: M++H, 301.1240).
Ethyl 5-Hydroxy-7-naphthalen-1-ylindane-4-carboxylate (8i)This compound (29.4 mg, 74%) was prepared from 5i (43.2 mg, 0.120 mmol). White solid. mp 116–117°C. IR (neat) cm−1: 1658, 1602, 1559, 1470. 1H-NMR (300 MHz, CDCl3) δ: 11.23 (1H, s), 7.86–7.92 (2H, m), 7.33–7.59 (5H, m), 6.85 (1H, s), 4.47 (2H, q, J=7.2 Hz), 3.31 (2H, dd, J=7.5, 2.9 Hz), 2.44–2.49 (2H, m), 1.97 (2H, quint, J=7.5 Hz), 1.46 (3H, t, J=7.2 Hz). 13C-NMR (75 MHz, CDCl3) δ: 171.5, 161.2, 146.9, 143.9, 138.4, 135.4, 133.6, 130.9, 128.3, 128.0, 126.2, 126.0, 125.9, 125.9, 125.3, 117.1, 109.4, 61.3, 35.8, 31.2, 24.7, 14.2. FAB-MS m/z: 333. HR-FAB-MS m/z: 333.1503 (Calcd for C22H21O3: M++H, 333.1491).
