Synthesis of Chiral 1,3-Dienes through Ring-Closing Metathesis of Enantioenriched Enynes: Potential Precursors of Morphane Analogs

ABSTRACT

A simple methodology for the synthesis of enynes by indium mediated diastereoselective allylation of aromatic N-tert-butanesulfinylimines bearing alkenyl groups at ortho-position with allyl bromide has been developed. The addition of the allyl indium intermediate to the chiral imine took place with excellent diastereoselectivity. Ruthenium-catalyzed ring-closing metathesis of the resulting enynes provided the expected cyclic 1,3-dienes in good to moderate yields. These chiral dienes are potential precursors of biologically and pharmacologically active morphane derivatives.

Key words:
allylation; imines; dienes; enynes; metathesis; alkaloids

INTRODUCTION

Ring closing metathesis (Schmalz 1995) is an important tool in organic synthesis because cyclic unsaturated compounds could be accessed from linear hydrocarbons with double or triple bonds at the terminal positions. When the ring closing metathesis is performed on an enyne system, the resulting cyclic 1,3-dienes with one exocyclic double bond are of special interest (Kaliappan 2005). These dienes are versatile synthetic intermediates and could be involved in a wide variety of process, such as cycloaddition reactions, electrophilic additions, etc. The first ring closing metathesis of enynes was performed by Katz and Sivavec in 1985 by means of a tungsten Fischer carbene complex (Katz and Sivavec 1985). More recently, Grubbs developed more efficient catalysts of ruthenium to perform olefin metathesis in different types of solvents (Vougioukalakis and Grubbs 2010). In addition, these catalysts were air-tolerant, avoiding the tedious work under inert atmospheres, and also compatible with a wide range of functional groups (Hoveyda et al. 2004). In 2010, Tan and co-workers studied the ring-closing metathesis of chiral propargyl amines bearing allyl and tert-butanesulfinyl groups bonded to the nitrogen atom, using a second generation ruthenium catalyst (Bauer et al. 2010). In this way, vinylpyrrolines were obtained as reaction products in high yields (Figure 1a). The group of Fustero reported the synthesis of enantiopure cyclic dienes through the ring-closing metathesis of homoallylic benzylic alcohols with an alkenyl group at ortho-position of the aromatic ring (Rodriguez et al. 2016), using Grubbs second generation catalyst in the presence of 1,7-octadiene as additive (Figure 1b). More recently, the same group performed the ring-closing metathesis of structural related N-tert-butanesulfinyl amino derivatives under similar reaction conditions (Lazaro et al. 2017), producing the expected dienes in high yields (Figure 1c). On the other hand, our research group reported the stereoselective allylation (Foubelo and Yus 2004) and propargylation (Garcia-Muñoz et al. 2013) of N-tert-butanesulfinyl aldimines and ketimines (Sirvent et al. 2012) with brominated precursors by means of indium metal, leading to homoallylic and homopropargylic amine derivatives, respectively, with high diastereoselectivity. These compounds were used as precursors in the synthesis of natural products (Foubelo and Yus 2014) and other structurally diverse nitrogen-containing compounds (Garcia-Muñoz et al. 2016). Continuing our interest in this topic, and prompted by the latest results from the group of Fustero, we report herein our approach to the synthesis enantioenriched 1,3-dienes with a N-tert-butanesulfinamide group through an enyne ring-closing metathesis.

Figure 1
Examples of ring-closing metathesis in N-tert-butasulfinamides bearing enyne moiety.

EXPERIMENTAL

GENERAL EXPERIMENTAL PROCEDURES

(R _S)-tert-Butanesulfinamide was a gift of Medalchemy (> 99% ee by chiral HPLC on a Chiracel AS column, 90:10 n-hexane/i-PrOH, 1.2 mL/min, l = 222 nm). TLC was performed on silica gel 60 F₂₅₄, using aluminium plates and visualized with phosphomolybdic acid (PMA) stain. Flash chromatography was carried out on handpacked columns of silica gel 60 (230- 400 mesh). Melting points are uncorrected. Optical rotations were measured using a polarimeter with a thermally jacketed 5 cm cell at approximately 20 ºC and concentrations (c) are given in g/100 mL. Infrared analyses were performed with a spectrophotometer equipped with an ATR component; wave numbers are given in cm^-1. Low-resolution mass spectra (EI) were obtained at 70 eV, and fragment ions in m/z with relative intensities (%) in parentheses. High-resolution mass spectra (HRMS) were also carried out in the electron impact mode (EI) at 70 eV and on an apparatus equipped with a time of flight (TOF) analyzer and the samples were ionized by ESI techniques and introduced through an ultra-high pressure liquid chromatography (UPLC) model. ¹H NMR spectra were recorded at 300 or 400 MHz for ¹H NMR and 75 or 100 MHz for ¹³C NMR, using CDCl₃ as the solvent and TMS as internal standard (0.00 ppm). The data are being reported as: s = singlet, d = doublet, t = triplet, q = quadruplet, m = multiplet or unresolved, br s = broad signal, coupling constant(s) in Hz, integration. ¹³C NMR spectra were recorded with ¹H-decoupling at 100 MHz and referenced to CDCl₃ at 77.16 ppm. DEPT-135 experiments were performed to assign CH, CH₂ and CH₃.

SYNTHESIS OF 2-VINYLBENZALDEHYDE (3A)

To a solution of o-bromostyrene (2a, 0.915 g, 0.626 mL, 5.0 mmol) in anhydrous THF (15 mL) was added drop wise a 2.5 M solution of n-BuLi in hexane (2.2 mL, 5.5 mmol) at -78 ºC. The reaction mixture was stirred at this temperature for 1 h, and after that, dry dimethylformamide (DMF, 0.456 g, 0.483 mL, 6.25 mmol) was also added dropwise. Stirring was continued for 20 min at the same temperature and the reaction was hydrolyzed with a saturated aqueous NH₄Cl solution (6 mL), and extracted with diethyl ether (3×10 mL). The organic layer was washed with brine (2×10 mL), dried over anhydrous magnesium sulfate and evaporated (15 Torr) to yield almost pure 2-vinylbenzaldehyde (3a) as a pale yellow oil (0.587 g, 4.45 mmol, 89%): R _F 0.50 (hexane/AcOEt 10:1); IR (film) ν 2917, 2858, 2750, 1691, 1595, 1565, 1479, 1205, 1186, 922, 861, 770, 741 cm^-1; ¹H-NMR (400 MHz, CDCl₃) δ 10.28 (1H, s, COH), 7.82 (1H, dt, J = 7.5, 1.0 Hz, ArH), 7.59-7.49 (3H, m, ArH), 7.45-7.38 (1H, m, CH=CH₂), 5.70 (1H, dd, J = 17.4, 1.2 Hz, CH=CHH), 5.51 (1H, dd, J = 11.0, 1.2 Hz, CH=CHH); ¹³C-NMR (101 MHz, CDCl₃) δ 192.3 (CH), 140.4 (C), 133.7, 133.3 (CH), 132.8 (C), 131.1, 127.8, 127.4 (CH), 119.3 (CH₂); LRMS (EI) m/z 132 (M⁺, 31%), 131 (14), 104 (21), 103 (24), 91 (17), 77 (15), 71 (24), 70 (21), 69 (18), 57 (28), 55 (20), 45 (19), 43 (100).

GENERAL PROCEDURE FOR THE PREPARATION OF ALDEHYDES 9

To a solution of the corresponding o-bromobenzaldehyde 3 (7.0 mmol) in freshly distilled Et₃N (28 mL) was successively added the corresponding terminal alkyne 8 (8.4 mmol), CuI (0.0133 g, 0.07 mmol) and Pd(PPh₃)₄ (0.161 g, 0.14 mmol). The resulting mixture was stirred at 50 ºC for 5 h and after that, a white solid was filtered off through a short plug of celite, washed with ethyl acetate (3×10 mL) and concentrated (15 Torr). The residue was purified by column chromatography (hexane/ethyl acetate) to yield pure compounds 9. Yields for these compounds 9 are given on Table I. Physical and spectroscopic data follow.

TABLE I
Synthesis of enynes 11.

Entry	R1	R2	Aldehyde 9			Enyne 11
			No.	Yield (%)a		No.	Yield (%)a
1	Me3Si	H	9ª	50		11a	55
2	Me(CH2)5	H	9b	88		11b	51
3	Ph	H	9c	98		11c	82
4	Ph	OMe	9d	85		11d	30
5	4-MeOC6H4	H	9e	93		11e	64
6	H	H				11f	>98b

• ^a
  Isolated yield after column chromatography purification. ^b Compound 11f was obtained by desilylation of 11a under basis conditions.

2-(Trimethylsilylethynyl)benzaldehyde (9a): yellow solid; mp 42-43 ºC (hexane/CH₂Cl₂); R _F 0.58 (hexane/AcOEt 20:1); IR (KBr) ν 2957, 2854, 2761, 2151, 1697, 1592, 1247, 866, 845, 763 cm^-1; ¹H-NMR (400 MHz, CDCl₃) δ 10.56 (1H, d, J = 0.9 Hz, COH), 7.93-7.89 (1H, m, ArH), 7.60-7.51 (1H, m, ArH), 7.46-7.41 (1H, m, ArH), 0.28 [9H, s, Si(CH₃)₃]; ¹³C-NMR (101 MHz, CDCl₃) δ 192.0 (CH), 136.3 (C), 133.8 (CH), 133.6 (CH), 129.0 (C), 127.0 (C), 126.9 (CH), 102.5 (C), 100.2 (C), 0.1 (CH₃); LRMS (EI) m/z 202 (M⁺, 4%), 201 (18), 188 (18), 187(100), 161 (11), 128 (27).

2-(Oct-1-yn-1-yl)benzaldehyde (9b): colourless oil; R _F 0.62 (hexane/AcOEt 10:1); IR (film) ν 2957, 2929, 2856, 1697, 1594, 1192, 823, 761, 726 637 cm^-1; ¹H-NMR (400 MHz, CDCl₃) δ 10.54 (1H, d, J = 0.8 Hz, COH), 7.88 (1H, dt, J = 7.9, 1.0 Hz, ArH), 7.55-7.45 (2H, m, ArH), 7.37 (1H, dddd, J = 7.8, 5.8, 2.8, 0.9 Hz, ArH), 2.48 (2H, t, J = 7.1 Hz, CH₂), 1.71-1.54 (2H, m, CH₂), 1.52-1.38 (2H, m, CH₂), 1.39-1.26 (4H, m, 2 × CH₂), 0.91 (3H, t, J = 7.0 Hz, CH₃); ¹³C-NMR (101 MHz, CDCl₃) δ 192.2 (CH), 135.9 (C), 133.6, 133.2 (CH), 127.9 (C), 127.8, 126.8 (CH), 98.2, 76.3 (C), 31.3, 28.6, 28.5, 22.5, 19.6 (CH₂), 14.0 (CH₃); LRMS (EI) m/z 214 (M⁺, 8%), 185 (12), 167 (11), 157 (40), 145 (25), 144 (100), 143 (15), 131 (13), 129 (18), 128 (27), 116 (28), 115 (63).

2-(Phenylethynyl)benzaldehyde (9c): yellow oil; R _F 0.47 (hexane/AcOEt 10:1); IR (film) ν 3060, 2843, 1695, 1591, 1492, 1264, 1192, 817, 753, 688, 637 cm^-1; ¹H-NMR (400 MHz, CDCl₃) δ 10.65 (1H, d, J = 0.8 Hz, COH), 7.94 (1H, ddd, J = 7.8, 1.4, 0.6 Hz, ArH), 7.65-7.61 (1H, m, ArH), 7.60-7.52 (3H, m, ArH), 7.47-7.41 (1H, m, ArH), 7.40-7.34 (3H, m, ArH); ¹³C-NMR (101 MHz, CDCl₃) δ 191.6 (CH), 135.8 (C), 133.7, 133.2, 131.6, 129.0, 128.5, 128.4, 127.2 (CH), 126.8, 122.3, 96.3, 84.8 (C); LRMS (EI) m/z 206 (M⁺, 60%), 205 (27), 180 (11), 178 (30), 177 (26), 176 (26), 167 (16), 165 (12), 152 (18), 151 (18), 150 (14), 149 (50), 137 (11), 135 (10), 127 (13), 125 (16), 123 (17), 111 (27), 109 (25), 83 (36), 77 (14), 71 (49), 57 (68), 44 (44), 43 (100).

5-Methoxy-2-(phenylethynyl)benzaldehyde (9d): yellow solid; mp 77-79 ºC (hexane/CH₂Cl₂); R _F 0.38 (hexane/AcOEt 10:1); IR (KBr) ν 2848, 1685, 1604, 1594, 1499, 1323, 1226, 1164, 1023, 830, 753, 746, 684, 619 cm^-1; ¹H-NMR (400 MHz, CDCl₃) δ 10.61 (1H, s, COH), 7.58-7.50 (3H, m, ArH), 7.42 (1H, d, J = 2.8 Hz, ArH), 7.38-7.33 (3H, m, ArH), 7.13 (1H, dd, J = 8.6, 2.8 Hz, ArH), 3.87 (3H, s, CH₃); ¹³C-NMR (101 MHz, CDCl₃) δ 191.5 (CH), 159.7, 137.1 (C), 134.5, 131.4, 128.7, 128.4 (CH), 122.6 (C), 121.7 (CH), 119.6 (C), 109.8 (CH), 94.8, 84.8 (C), 55.6 (CH₃); LRMS (EI) m/z 236 (M⁺, 100%), 222 (13), 221 (67), 193 (27), 165 (63), 164 (17), 163 (19), 149 (24), 139 (11), 70 (15), 43 (65).

2-[(4-Methoxyphenyl)ethynyl]benzaldehyde (9e): yellow solid; mp 44-46 ºC (hexane/CH₂Cl₂); R _F 0.32 (hexane/AcOEt 10:1); IR (KBr) ν 2843, 1695, 1603, 1591, 1507, 1248, 1018, 839, 766, 635 cm^-1; ¹H-NMR (400 MHz, CDCl₃) δ 10.64 (1H, d, J = 0.8 Hz, COH), 7.93 (1H, ddd, J = 7.8, 1.5, 0.6 Hz, ArH), 7.61 (1H, ddd, J = 7.8, 1.4 0.6 Hz, ArH), 7.56 (1H, td, J = 7.5, 1.4 Hz, ArH), 7.50 (2H, d, J = 8.9 Hz, ArH), 7.46-7.37 (1H, m, ArH), 6.90 (2H, d, J = 8.8 Hz, ArH), 3.83 (3H, s, CH₃); ¹³C-NMR (101 MHz, CDCl₃) δ 191.8 (CH), 160.2, 135.6 (C), 133.7, 133.2, 133.0, 128.2 (CH), 127.3 (C), 127.2 (CH), 114.3 (C), 114.2 (CH), 96.5, 83.7 (C), 55.3 (CH₃); LRMS (EI) m/z 236 (M⁺, 100%), 221 (61), 193 (19), 165 (57), 164 (15), 163 (17).

SYNTHESIS OF 2-[2-(OCT-1-YL)PHENYL]ACETALDEHYDE (13)

A 1 M solution of potassium hexamethyldisilazide (KHMDS, 2.0 mL, 2.0 mmol) was added to a suspension of (methoxymethyl) triphenylphosphonium chloride (0.684 g, 2.0 mmol) in THF (4 mL) at -78 ºC. The reaction mixture was stirred at the same temperature for 1 h. After that, a solution of aldehyde 9b (0.214 g, 1.0 mmol) in THF (8 mL) and stirring was maintained for 3 h allowing the system to reach 0 ºC. The resulting mixture was filtered through a short plug of celite, washed with hexane (3×15 mL) and concentrated (15 Torr). The residue was dissolved in THF (1.5 mL), treated with a 3 M solution of HCl (0.25 mL, 0.75 mmol) and the resulting solution was stirred at 78 ºC for 18 h. After that, the reaction mixture was cooled down to room temperature, basified with a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (3×15 mL). The organic layer was washed with brine (2×10 mL), dried over anhydrous magnesium sulfate and evaporated (15 Torr) to yield aldehyde 16 which was used in the next step without purification.

GENERAL PROCEDURE FOR THE PREPARATION OF N-TERT-BUTANESULFINYL ALDIMINES 4A AND 14

To a solution of (R)-tert-butanesulfinamide (1, 0.601 g, 5.0 mmol) and the corresponding aldehyde (5.5 mmol) in THF (20 mL) was added Ti(OEt)₄ (2.28 g, 2.08 mL, 10.0 mmol) at room temperature under argon. The resulting mixture was stirred for 5 h at the same temperature, and after that, quenched with brine (3.0 mL), and diluted with ethyl acetate (50.0 mL). The resulting suspension was filtered through a short plug of Celite and concentrated Then, the reaction mixture was filtered through a short plug of Celite and the solvent was evaporated (15 Torr). The residue was purified by column chromatography (hexane/EtOAc) to yield pure compounds 4a and 14. Yields for compounds 4a and 14 are given in Figures 2 and 4, respectively. Physical and spectroscopic data follow.

Figure 2
Synthesis of enyne 6b.

Figure 3
Attempt to perform ring-closing metathesis of enynes 6.

Figure 4
Synthesis of diene 16.

(R_S )-N-(tert-Butanesulfinyl)-N-(2-vinylbenzyliden)amine (4a): yellow oil; R _F 0.32 (hexane/AcOEt 9:1); = -166.5 (c 1.05, CH₂Cl₂); IR (film) ν 3060, 2981, 2962, 2932, 2864, 1602, 1584, 1474, 1363, 1221, 1183, 1082, 983, 920, 769, 715 cm^-1; ¹H-NMR (400 MHz, CDCl₃) δ 8.93 (1H, s, CNH), 7.95 (1H, dd, J = 7.8, 1.5 Hz, ArH), 7.55 (1H, dd, J = 7.7, 1.4 Hz, ArH), 7.48 (1H, td, J = 7.6, 1.5 Hz, ArH), 7.43-7.32 (2H, m, ArH, CH=CH₂), 5.67 (1H, dd, J = 17.3, 1.2 Hz, CH=CHH), 5.47 (1H, dd, J = 11.0, 1.2 Hz, CH=CHH), 1.28 [9H, s, C(CH₃)₃]; ¹³C-NMR 161.3 (CH), 139.7 (C), 133.6, 132.1 (CH), 131.0 (C), 129.1, 127.9, 127.3 (CH), 118.9 (CH₂), 57.7 (C), 22.6 (CH₃); LRMS (EI) m/z 235 (M⁺, 1%), 179 (21), 149 (16), 132 (12), 131 (18), 130 (51), 116 (30), 115 (10), 77 (11), 70 (19), 61 (16), 57 (52), 45 (17), 43 (100), 41 (16).

(R_S )-N-(tert-Butanesulfinyl)-N-{2-[2-(1-octynyl)phenyl]ethyliden}amine (14): yellow oil; R _F 0.31 (hexane/AcOEt 9:1); = -186.0 (c 1.05, CH₂Cl₂); IR (film) ν 2955, 2928, 2858, 1697, 1619, 1457, 1087, 756 cm^-1; ¹H-NMR (400 MHz, CDCl₃) δ 8.14 (1H, t, J = 4.9 Hz, CNH), 7.45-7.39 (1H, m, ArH), 7.26-7.15 (3H, m, ArH), 4.00 (2H, t, J = 4.8 Hz, CH₂), 2.42 (2H, t, J = 7.1 Hz, CH₂), 1.67-1.53 (2H, m, CH₂), 1.51-1.41 (2H, m, CH₂), 1.37-1.27 (4H, m, 2 × CH₂), 1.17 [9H, s, C(CH₃)], 0.95-0.84 (3H, m, CH₃); ¹³C-NMR 167.3 (CH), 136.7 (C), 132.4, 129.4, 127.8, 127.0 (CH), 124.3, 95.4, 78.8, 56.8 (C), 41.3, 31.3, 28.7, 28.6 22.5 (CH₂), 22.4 (CH₃), 19.5 (CH₂), 14.0 (CH₃); LRMS (EI) m/z 275 (M⁺C₄H₈, 5%), 230 (11), 229 (62), 227 (11), 226 (37), 170 (15), 169 (16), 168 (13), 167 (15), 157 (22), 156 (27), 155 (22), 154 (14), 143 (19), 142 (14), 141 (22), 131 (14), 130 (20), 129 (29), 128 (37), 127 (18), 116 (12), 115 (30), 113 (22), 85 (16), 57 (100), 55 (20), 43 (51), 41 (30).

SYNTHESIS OF (1 S , R _S )-N-(TERT-BUTANESULFINYL)-1-(2-VINYLPHENYL)-4-(TRIMETHYLSILYL)BUT-3-YN-1-AMINE (6A)

A mixture of imine 4a (0.118 g, 0.5 mmol), 3-bromo-1-trimethylsilyl-1-propyne (5; 313 mg, 0.275 mL, 1.65 mmol), and indium (189 mg, 1.65 mmol) was sonicated in dry THF (2 mL) for 7 h. Then the resulting mixture was hydrolyzed with H₂O (5 mL) and extracted with ethyl acetate (3×15 mL). The organic phase was washed with brine (3×10 mL), dried with anhydrous magnesium sulfate, and the solvent evaporated (15 Torr). The residue was purified by column chromatography (silica gel, hexane/EtOAc) to yield pure compound 6a as a pale yellow oil (0.082 g, 0.35 mmol, 70%): R _F 0.50 (hexane/AcOEt 2:1); = -78.3 (c 2.24, CH₂Cl₂); IR (film) ν 3193, 2958, 2897, 2868, 2174, 1474, 1411, 1363, 1249, 1053, 840, 759 cm^-1; ¹H-NMR (300 MHz, CDCl₃) δ 7.48-7.43 (1H, m, ArH), 7.42-7.37 (1H, m, ArH), 7.31-7.25 (2H, m, ArH), 7.13 (1H, dd, J = 17.2, 10.9 Hz, CH=CH₂), 5.61 (1H, dd, J = 17.2, 1.5 Hz, CH=CHH), 5.36 (1H, dd, J = 10.9, 1.5 Hz, CH=CHH), 4.89 (1H, ddd, J = 8.2, 5.1, 3.0 Hz, CH), 4.23 (1H, d, J = 3.0 Hz, NH), 2.73 (1H, dd, J = 16.9, 5.1 Hz, CHH), 2.63 (1H, dd, J = 16.9, 8.4 Hz, CHH), 1.24 [9H, s, C(CH₃)₃], 0.16 [9H, s, Si(CH₃)₃]; ¹³C-NMR (75 MHz, CDCl₃) δ 137.3, 137.2 (C), 134.1, 128.0, 127.7, 127.2, 126.8 (CH), 117.5 (CH₂), 102.1, 86.2, 55.8 (C), 52.4 (CH), 29.2 (CH₂), 22.6, -0.08 (CH₃); LRMS (EI) m/z 243 (M⁺C₄H₈OS, 4%), 228 (11), 207 (13), 180 (25), 179 (19), 167 (16), 165 (12), 164 (100), 132 (37), 131 (25), 130 (66), 128 (15), 117 (23), 116 (39), 115 (26), 77 (15), 73(76).

GENERAL PROCEDURE FOR THE AMINOALLYLATION OF ALDEHYDES 9: SYNTHESIS OF ENYNES 11

A mixture of indium powder (173 mg, 1.50 mmol), (R _S)-N-tert-butanesulfinamide (1, 0.121 g, 1.0 mmol), the corresponding aldehyde 9 (1.15 mmol), and Ti(OEt)₄ (0.456 g, 0.450 mL, 2.0 mmol) in THF (2 mL) was stirred under argon for 1 h at 23 ºC. At this time, allyl bromide (10, 0.254 g, 0.18 mL, 1.50 mmol) was added and the reaction mixture heated for 5 h at 60 ºC. The mixture was allowed to cool to room temperature, quenched with brine (2 mL), and diluted with ethyl acetate. The resulting suspension was filtered through a short plug of Celite and the solvent evaporated (15 Torr). The residue was purified by column chromatography (hexane/EtOAc) to yield pure compounds 11. Yields are given on Table I. Physical and spectroscopic data follow.

(1S,R_S )-N-(tert-Butanesulfinyl)-1-[2-(trimethylsilylethynyl)phenyl]but-3-en-1-amine (11a): colourless oil; R _F 0.38 (hexane/AcOEt 2:1); = -68.0 (c 1.10, CH₂Cl₂); IR (film) ν 3075, 2958, 2154, 1475, 1447, 1249, 1053, 862, 840, 758, 644 cm^-1; ¹H-NMR (300 MHz, CDCl₃) δ 7.46 (1H, ddd, J = 7.5, 1.4, 0.6 Hz, ArH), 7.38-7.26 (2H, m, ArH), 7.20 (1H, ddd, J = 7.6, 6.9, 2.0 Hz, ArH), 5.87-5.60 (1H, m, CH=CH₂), 5.23-5.11 (2H, m, CH=CH ₂), 5.02-4.90 (1H, m, CH), 3.80 (1H, d, J = 3.9 Hz, NH), 2.84-2.69 (1H, m, CHH), 2.63-2.46 (1H, m, CHH), 1.21 [9H, s, C(CH₃)₃], 0.27 [9H, s, Si(CH₃)₃]; ¹³C-NMR (75 MHz, CDCl₃) δ 144.2 (C), 134.3, 133.0, 128.5, 127.0, 126.8 (CH), 121.8 (C), 119.0 (CH₂), 102.8, 100.2 (C), 55.9 (CH), 41.7 (CH₂), 22.6 (CH₃), -0.08 (CH₃); LRMS (EI) m/z 291 (M⁺ -C₄H₈, 1%), 235 (17), 234 (100), 231 (17), 230 (24), 218 (54), 202 (25), 200 (21), 186 (32), 160 (20), 156 (97), 143 (23), 75 (21), 73 (75), 59 (16).

(1S,R_S )-N-(tert-Butanesulfinyl)-1-[2-(oct-1-yn-1-yl)phenyl]but-3-en-1-amine (11b): colourless oil; R _F 0.43 (hexane/AcOEt 2:1); = -59.3 (c 1.12, CH₂Cl₂); IR (film) ν 3065, 2955, 2929, 2858, 1638, 1448, 1362, 1055, 910, 757 cm^-1; ¹H-NMR (300 MHz, CDCl₃) δ 7.40 (1H, dd, J = 7.6, 1.5 Hz, ArH), 7.31 (1H, dd, J = 7.7, 1.7 Hz, ArH), 7.23 (1H, dd, J = 7.6, 1.6 Hz, ArH), 7.18 (1H, td, J = 7.3, 1.7 Hz, ArH), 5.83-5.64 (1H, m, CH=CH₂), 5.23-5.10 (2H, m, CH=CH ₂), 5.04-4.94 (1H, m, CH), 3.77 (1H, d, J = 3.9 Hz, NH), 2.82-2.66 (1H, m, CHH), 2.61-2.47 (1H, m, CHH), 2.45 (2H, t, J = 7.1 Hz, CH₂), 1.68-1.57 (3H, m, CH₂, CHH), 1.51-1.42 (1H, m, CHH), 1.38-1.28 (4H, m, 2 × CH₂), 1.20 (9H, s, C(CH₃)₃), 0.96-0.85 (3H, m, CH₃); ¹³C-NMR (75 MHz, CDCl₃) δ 143.4 (C), 134.3, 132.6, 127.5, 126.9, 126.6 (CH), 122.8 (C), 118.9 (CH₂), 96.1, 55.8 (C), 55.6 (CH), 42.0, 31.3, 28.7, 28.6 (CH₂), 22.6 (CH₃), 22.5, 19.6 (CH₂), 14.1 (CH₃); LRMS (EI) m/z 287 (M⁺ -C₅H₁₂, 3%), 262 (23), 246 (26), 243 (18), 242 (100), 227 (20), 226 (99), 214 (29), 213 (22), 212 (21), 183 (30), 172 (20), 170 (29), 168 (25), 157 (20), 156 (84), 155 (22), 154 (20), 144 (14), 143 (48), 142 (36), 141 (22), 130 (36), 129 (24), 128 (24).

(1S,R_S )-N-(tert-Butanesulfinyl)-1-[2-(phenylethynyl)phenyl]but-3-en-1-amine (11c): colourless oil; R _F 0.25 (hexane/AcOEt 2:1); = -42.9 (c 1.61, CH₂Cl₂); IR (film) ν 3214, 3061, 2960, 2922, 2867, 1638, 1492, 1473, 1261, 1053, 912, 755, 689 cm^-1; ¹H-NMR (400 MHz, CDCl₃) δ 7.57-7.51 (3H, m, ArH), 7.41-7.27 (6H, m, ArH), 5.84-5.70 (1H, m, CH=CH₂), 5.23-5.13 (2H, m, CH=CH ₂), 5.12-5.04 (1H, m, CH), 3.80 (1H, d, J = 3.7 Hz, NH), 2.81 (1H, dt, J = 14.1, 5.9 Hz, CHH), 2.62 (1H, dt, J = 14.8, 7.9 Hz, CHH), 1.21 [9H, s, C(CH₃)₃]; ¹³C-NMR (75 MHz, CDCl₃) δ 143.6 (C), 134.2, 132.6, 131.5, 128.5, 128.4, 128.3, 127.1, 126.9 (CH), 123.0, 122.1 (C), 119.1 (CH₂), 94.7, 87.1, 55.8 (C), 55.7 (CH), 42.0 (CH₂), 22.6 (CH₃); LRMS (EI) m/z 247 (M⁺ -C₄H₈SO, 6%), 237 (15), 236 (17), 235 (24), 234 (100), 219 (18), 218 (22), 207 (23), 205 (57), 204 (69), 203 (19), 202 (23), 176 (18).

(1S,R_S )-N-(tert-Butanesulfinyl)-1-[5-methoxy-2-(phenylethynyl)phenyl]but-3-en-1-amine (11d): colourless oil; R _F 0.23 (hexane/AcOEt 2:1); = -41.8 (c 2.08, CH₂Cl₂); IR (film) ν 3075, 2951, 2834, 1732, 1606, 1595, 1498, 1292, 1233, 1032, 914, 821, 755, 690 cm^-1; ¹H-NMR (300 MHz, CDCl₃) δ 7.54-7.45 (3H, m, ArH), 7.37-7.30 (3H, m, ArH), 6.95 (1H, d, J = 2.7 Hz, ArH), 6.79 (1H, dd, J = 8.5, 2.6 Hz, ArH), 5.90-5.68 (1H, m, CH=CH₂), 5.25-5.13 (2H, m, CH=CH ₂), 5.08-4.99 (1H, m, CH), 3.82 (3H, s, CH₃), 2.81 (1H, dt, J = 14.5, 6.0 Hz, CHH), 2.59 (1H, dt, J = 14.8, 8.0 Hz, CHH), 1.22 [9H, s, C(CH₃)₃]; ¹³C-NMR (75 MHz, CDCl₃) δ 159.7, 145.5 (C), 134.2, 134.0, 131.3, 128.3, 128.1 (CH), 123.3 (C), 119.1 (CH₂), 114.1 (C), 112.8, 112.6 (CH), 93.4, 87.1 (C), 55.9 (C), 55.7 (CH), 55.3 (CH₃), 42.0 (CH₂), 22.6 (CH₃); LRMS (EI) m/z 277 (M⁺ -C₄H₈OS, 10%), 237 (25), 236 (100), 235 (18), 215 (12), 192 (13), 191 (13), 57 (20).

(1S,R_S )-N-(tert-Butanesulfinyl)-1-{2-[(4-methoxyphenyl)ethynyl]phenyl}but-3-en-1-amine (11e): colourless oil; R _F 0.19 (hexane/AcOEt 2:1); = -22.2 (c 1.38, CH₂Cl₂); IR (film) ν 3213, 3065, 2976, 2957, 2908, 2209, 1605, 1509, 1459, 1286, 1248, 1174, 1054, 1030, 913, 831, 758 cm^-1; ¹H-NMR (400 MHz, CDCl₃) δ 7.53-7.45 (3H, m, ArH), 7.37 (1H, dd, J = 7.7, 1.5 Hz, ArH), 7.30 (1H, td, J = 7.5, 1.5 Hz, ArH), 7.26-7.21 (1H, m, ArH), 6.91-6.85 (2H, m, ArH), 5.87-5.69 (1H, m, CH=CH₂), 5.24-5.13 (2H, m, CH=CH ₂), 5.11-5.02 (1H, m, CH), 3.83 (4H, s, CH₃, NH), 2.84-2.76 (1H, m, CHH), 2.62 (1H, dt, J = 14.8, 7.9 Hz, CHH), 1.20 [9H, s, C(CH₃)₃]; ¹³C-NMR (101 MHz, CDCl₃) δ 159.7, 143.3 (C), 134.3, 133.0, 132.4, 128.0, 127.1, 126.8 (CH), 122.4 (C), 119.0 (CH₂), 115.1 (C), 114.0 (CH), 94.8, 85.8, (C), 55.8 (CH), 55.3 (CH₃), 42.0 (CH₂), 22.7 (CH₃); LRMS (EI) m/z 277 (M⁺ -C₄H₈OS, 24%), 276 (84), 246 (13), 237 (17), 236 (100), 235 (34), 215 (14), 57 (18).

ALLYLATION OF IMINE 14: SYNTHESIS OF HOMOALLYL AMINE DERIVATIVE 15

A mixture of imine 14 (0.166 g, 0.5 mmol), allyl bromide (10; 0.127 g, 0.090 mL, 0.75 mmol) and indium (0.063 g, 0.55 mmol) was stirred in THF (2 mL) for 6 h at 60 ºC. Then the resulting mixture was hydrolyzed with H₂O (5 mL) and extracted with ethyl acetate (3×15 mL). The organic phase was washed with brine (3×10 mL), dried with anhydrous magnesium sulfate, and the solvent evaporated (15 Torr). The residue was purified by column chromatography (silica gel, hexane/EtOAc) to yield pure compound 15 as a colourless oil (0.093 g, 0.25 mmol, 50%): R _F 0.41 (hexane/AcOEt 2:1); = -12.3 (c 1.10, CH₂Cl₂); IR (film) ν 2954, 2928, 2858, 1638, 1448, 1363, 1051, 914, 756 cm^-1; ¹H-RMN (400 MHz, CDCl₃) δ 7.47-7.31 (1H, m, ArH), 7.23-7.09 (3H, m, ArH), 5.69-5.75 (1H, m, CH=CH₂), 5.24-5.16 (2H, m, CH=CH ₂), 3.77-3.62 (1H, m, CH), 3.37 (1H, d, J = 7.2 Hz, NH), 2.98 (1H, dd, J = 13.5, 8.4 Hz, CHH), 2.92 (1H, dd, J = 13.5, 6.3 Hz, CHH), 2.48-2.39 (4H, m, 2 × CH₂), 1.68-1.58 (4H, m, 2 × CH₂), 1.52-1.42 (4H, m, 2 × CH₂), 1.04 [9H, s, C(CH₃)₃], 0.95-0.87 (3H, m, CH₃); ¹³C-RMN (101 MHz, CDCl₃) δ 140.4 (C), 134.1, 132.2, 129.9, 127.5, 126.2 (CH), 124.2 (C), 119.3 (CH₂), 94.6, 79.4 (C), 56.8 (CH), 55.8 (C), 40.8, 40.2, 31.4, 28.8, 28.7, 22.6 (CH₂), 22.4 (CH₃), 19.6 (CH₂), 14.1 (CH₃); LRMS (EI) m/z 317 (M⁺ -C₄H₈, 3%), 275 (23), 242 (27), 226 (23), 207 (33), 186 (13), 157 (12), 156 (12), 141 (21), 131 (14), 129 (20), 128 (34), 118 (100), 115 (18), 102 (34).

GENERAL PROCEDURE FOR THE DESILYLATION OF COMPOUNDS 6A AND 11A: SYNTHESIS OF TERMINAL ALKYNES 6B AND 11F

A suspension of potassium carbonate (0.005 g, 0.036 mmol) in methanol (4 mL) was added dropwise to a solution of compounds 6a or 11a (0.5 mmol) in THF (4 mL). The reaction mixture was stirred for 12 h at room temperature and then it was hydrolyzed with a 1 M NH₄Cl aqueous solution (8 mL) and extracted with methyl tert-butyl ether (3×15 mL). The organic layer was dried with anhydrous magnesium sulfate and the solvent evaporated (15 Torr). The residue was purified by column chromatography (silica gel, hexane/EtOAc, 2:1) to yield pure compounds 6b or 11f in 69 and >95% yield, respectively. Physical and spectroscopic data follow.

(1S,R_S )-N-(tert-Butanesulfinyl)-1-(2-vinylphenyl)but-3-yn-1-amine (6b): yellow oil; R _F 0.26 (hexane/AcOEt 2:1); = -80.9 (c 1.20, CH₂Cl₂); IR (film) ν 3296, 3218, 2981, 2962, 2922, 2864, 1624, 1474, 1452, 1364, 1053, 916, 762, 637 cm^-1; ¹H-NMR (300 MHz, CDCl₃) δ 7.48-7.44 (1H, m, ArH), 7.42-7.39 (1H, m, ArH), 7.32-7.27 (2H, m, ArH), 7.12 (1H, dd, J = 17.2, 10.9 Hz, CH=CH₂), 5.62 (1H, dd, J = 17.2, 1.4 Hz, CH=CHH), 5.37 (1H, dd, J = 11.0, 1.4 Hz, CH=CHH), 4.92 (1H, ddd, J = 8.4, 5.1, 3.6 Hz, CH), 4.06 (1H, d, J = 3.6 Hz, NH), 2.74 (1H, ddd, J = 16.9, 5.2, 2.6 Hz, CHH), 2.65 (1H, ddd, J = 16.9, 8.1, 2.6 Hz, CHH), 2.12 (1H, t, J = 2.6 Hz, CH), 1.24 [9H, s, C(CH₃)₃]; ¹³C-NMR (75 MHz, CDCl₃) δ 137.3, 137.1 (C), 134.0, 128.1, 127.8, 126.9, 126.8 (CH), 117.6 (CH₂), 79.9 (C), 72.2 (CH), 55.9 (C), 52.8 (CH), 27.7 (CH₂), 22.6 (CH₃); LRMS (EI) m/z 171 (M⁺-C₄H₈OS, 2%), 131 (12), 130 (100), 128 (11), 116 (19), 115 (19), 77 (10).

(1S,R_S )-N-(tert-Butanesulfinyl)-1-(2-ethynylphenyl)but-3-en-1-amine (11f): colourless oil; R _F 0.22 (hexane/AcOEt 2:1); = -94.2 (c 1.45, CH₂Cl₂); IR (film) ν 3292, 3203, 2976, 2957, 2868, 1638, 1474, 1446, 1363, 1054, 914, 759 cm^-1; ¹H-NMR (400 MHz, CDCl₃) δ 7.50 (1H, dd, J = 7.4, 1.1 Hz, ArH), 7.39-7.30 (2H, m, ArH), 7.23 (1H, ddd, J = 7.6, 6.9, 1.9 Hz, ArH), 5.82-5.68 (1H, m, CH=CH₂), 5.22-5.14 (2H, m, CH=CH ₂), 5.03 (1H, ddd, J = 8.5, 5.4, 3.4 Hz, CH), 3.77 (1H, d, J = 3.5 Hz, NH), 3.35 (1H, s, CH), 2.78-2.67 (1H, m, CHH), 2.60-2.46 (1H, m, CHH), 1.20 [9H, s, C(CH₃)₃]; ¹³C-NMR (101 MHz, CDCl₃) δ (101 MHz, CDCl₃) δ 144.4 (C), 134.1, 133.2, 128.8, 127.1, 126.8 (CH), 121.0 (C), 119.2 (CH₂), 82.6 (C), 81.3 (CH), 55.8 (C), 55.2 (CH), 42.1 (CH₂), 22.6 (CH₃); LRMS (EI) m/z 219 (M⁺ -C₄H₈, 3%), 178 (93), 177 (28), 171 (13), 170 (14), 161 (39), 160 (26), 159 (27), 158 (60), 130 (60), 129 (100), 128 (48), 115 (27), 103 (20), 102 (30), 101 (15), 77 (23).

GENERAL PROCEDURE FOR THE RING-CLOSING METATHESIS OF ENYNES 11 AND 15: SYNTHESIS OF DIENES 12 AND 16

A mixture of the corresponding enyne 11 or 15 (0.1 mmol), ruthenium Grubbs second generation catalyst (0.0085 g, 0.01 mmol) in dry toluene (10 mL) was stirred at 120 ºC under argon for 1 h. Then the solvent was evaporated (15 Torr) and the resulting residue was purified by column chromatography (silica gel, hexane/AcOEt) to yield pure compounds 12 and 16. Yields are given on Table II. Physical and spectroscopic data follow.

(1S,R_S )-N-(tert-Butanesulfinyl)-4-(oct-1-en-2-yl)-1,2-dihydronaphthalen-1-amine (12b): colourless oil; R _F 0.53 (hexane/AcOEt 1:1); = -10.3 (c 1.12, CH₂Cl₂); IR (film) ν 3208, 2954, 2926, 2856, 1451, 1362, 1052, 898, 772, 747 cm^-1; ¹H-NMR (300 MHz, CDCl₃) δ 7.40-7.36 (1H, m, ArH), 7.31-7.19 (3H, m, ArH), 5.86 (1H, t, J = 4.5 Hz, C=CH), 5.09 (1H, dt, J = 2.5, 1.3 Hz, C=CHH), 5.00 (1H, d, J = 2.4 Hz, C=CHH), 4.50-4.40 (1H, m, CH), 3.45 (1H, d, J = 8.8 Hz, NH), 2.74 (1H, ddd, J = 17.0, 5.7, 4.2 Hz, CHH), 2.58 (1H, ddd, J = 17.0, 7.1, 4.9 Hz, CHH), 2.23 (2H, t, J = 7.3 Hz, CH₂), 1.40-1.21 (8H, m, 4 × CH₂), 1.19 [9H, s, C(CH₃)₃], 0.90-0.82 (3H, m, CH₃); ¹³C-NMR (75 MHz, CDCl₃) δ 148.7, 140.8, 136.3, 133.3 (C), 127.9, 127.3, 126.6, 125.7, 122.0 (CH), 114.1 (CH₂), 56.0 (C), 54.7 (CH), 35.8, 32.4, 31.7, 28.9, 28.3 (CH₂), 22.6, 14.0 (CH₃); LRMS (EI) m/z 303 (M⁺ -C₄H₈, 4%), 240 (25), 239 (100), 238 (38), 169 (14), 168 (19), 167 (27), 155 (36), 154 (13), 153 (20), 152 (11), 142 (10), 141 (67), 129 (13), 57 (31), 43 (11), 41 (13).

(1S,R_S )-N-(tert-Butanesulfinyl)-4-(1-phenylvinyl)-1,2-dihydronaphthalen-1-amine (12c): colourless oil; R _F 0.33 (hexane/AcOEt 1:1); = -12.5 (c 1.34, CH₂Cl₂); IR (film) ν 3198, 2962, 2922, 2864, 1474, 1447, 1262, 1047, 900, 770, 696 cm^-1; ¹H-NMR (400 MHz, CDCl₃) δ 7.42-7.37 (3H, m, ArH), 7.25-7.22 (3H, m, ArH), 7.17 (1H, td, J = 7.4, 1.4 Hz, ArH), 7.10 (1H, td, J = 7.5, 1.5 Hz, ArH), 7.00 (1H, dd, J = 7.7, 1.4 Hz, ArH), 6.09 (1H, t, J = 4.5 Hz, C=CH), 5.67 (1H, d, J = 1.6 Hz, C=CHH), 5.35 (1H, d, J = 1.6 Hz, C=HH), 4.58 (1H, q, J = 7.1 Hz, CH), 3.49 (1H, d, J = 8.1 Hz, NH), 2.89 (1H, ddd, J = 17.1, 5.7, 4.1 Hz, CHH), 2.67 (1H, ddd, J = 17.2, 7.1, 4.8 Hz, CHH), 1.23 [9H, s, C(CH₃)₃]; ¹³C-NMR (101 MHz, CDCl₃) δ 147.9, 139.7, 139.6, 135.6, 133.4 (C), 128.3, 128.0, 127.7, 127.3, 126.7, 126.6, 126.3, 125.1 (CH), 115.4 (CH₂), 56.1 (C), 54.3 (CH), 32.6 (CH₂), 22.6 (CH₃); LRMS (EI) m/z 295 (M⁺ -C₄H₈, 3%), 232 (25), 231 (92), 230 (65), 229 (29), 228 (10), 215 (15), 153 (39), 152 (13), 104 (10), 103 (100), 77 (13), 71 (17), 69 (14), 57 (45), 55 (15), 43 (27), 41 (18).

(1S,R_S )-N-(tert-Butanesulfinyl)-7-methoxy-4-(1-phenylvinyl)-1,2-dihydronaphthalen-1-amine (12d): colourless oil; R _F 0.38 (hexane/AcOEt 1:1); = -13.5 (c 1.34, CH₂Cl₂); IR (film) ν 3198, 3030, 2951, 2922, 2863, 2834, 1607, 1569, 1492, 1261, 1250, 1039, 897, 735, 696 cm^-1; ¹H-NMR (400 MHz, CDCl₃) δ 7.42-7.37 (2H, m, ArH), 7.25-7.20 (3H, m, ArH), 6.97 (1H, dd, J = 2.7, 0.8 Hz, ArH), 6.91 (1H, d, J = 8.5 Hz, ArH), 6.61 (1H, dd, J = 8.5, 2.7 Hz, ArH), 5.97 (1H, t, J = 4.5 Hz, C=CH), 5.64 (1H, d, J = 1.7 Hz, C=CHH), 5.34 (1H, d, J = 1.7 Hz, C=CHH), 4.54 (1H, td, J = 8.2, 5.7 Hz, CH), 3.76 (3H, s, CH₃), 3.48 (1H, d, J = 8.5 Hz, NH), 2.87 (1H, ddd, J = 16.9, 5.8, 4.5 Hz, CHH), 2.62 (1H, ddd, J = 16.9, 8.0, 4.6 Hz, CHH), 1.25 [9H, s, C(CH₃)₃]; ¹³C-NMR (101 MHz, CDCl₃) δ 158.7, 148.0, 139.8, 139.2, 137.7 (C), 128.3, 127.7, 126.6 (CH), 126.5 (C), 122.7 (CH), 115.2 (CH₂), 112.7, 112.3 (CH), 56.1 (C), 55.2 (CH), 54.9 (CH₃), 32.7 (CH₂), 22.7 (CH₃); LRMS (EI) m/z 277 (M⁺ -C₄H₈OS, 4%), 262 (45), 261 (87), 260 (100), 229 (15), 215 (12), 202 (14), 183 (27), 103 (88), 97 (18), 85 (18), 83 (16), 77 (12), 71 (24), 70 (19), 69 (19), 57 (54), 55 (22), 43 (78).

(1S,R_S )-N-(tert-Butanesulfinyl)-4-[1-(4-methoxyphenyl)vinyl]-1,2-dihydronaphthalen-1-amine (12e): colourless oil; R _F 0.30 (hexane/AcOEt 1:1); = -13.1 (c 1.53, CH₂Cl₂); IR (film) ν 3213, 2957, 2927, 2859, 1604, 1509, 1458, 1247, 1176, 1031, 897, 835, 755, 737 cm^-1; ¹H-NMR (400 MHz, CDCl₃) δ 7.40-7.37 (1H, m, ArH), 7.33 (2H, d, J = 8.9 Hz, ArH), 7.17 (1H, td, J = 7.4, 1.5 Hz, ArH), 7.11 (1H, td, J = 7.5, 1.5 Hz, ArH), 7.00 (1H, dd, J = 7.7, 1.4 Hz, ArH), 6.77 (2H, d, J = 8.8 Hz, ArH), 6.08 (1H, t, J = 4.5 Hz, C=CH), 5.57 (1H, d, J = 1.7 Hz, C=CHH), 5.24 (1H, d, J = 1.7 Hz, C=CHH), 4.58 (1H, q, J = 7.2 Hz, CH), 3.77 (3H, s, CH₃), 3.48 (1H, d, J = 8.1 Hz, NH), 2.88 (1H, ddd, J = 17.2, 5.8, 4.2 Hz, CHH), 2.66 (1H, ddd, J = 17.1, 7.3, 4.8 Hz, CHH), 1.23 [9H, s, C(CH₃)₃]; ¹³C-NMR (101 MHz, CDCl₃) δ 159.3, 147.2, 139.8, 135.6, 133.5, 132.2 (C), 127.9, 127.8, 126.6, 126.3, 124.8, 113.6 (CH), 113.5 (CH₂), 56.0 (C), 55.2 (CH), 54.4(CH₃), 32.6 (CH₂), 22.6 (CH₃); LRMS (EI) m/z 277 (M⁺ -C₄H₈OS, 8%), 263 (15), 261 (56), 260 (47), 259 (26), 153 (16), 135 (14), 133 (100), 70 (13), 57 (35), 43 (57).

(1S,R_S )-N-(tert-Butanesulfinyl)-4-vinyl-1,2-dihydronaphthalen-1-amine (12f): colourless oil; R _F 0.33 (hexane/AcOEt 1:1); = -6.9 (c 1.57, CH₂Cl₂); IR (film) ν 3208, 2955, 2864, 1736, 1474, 1450, 1362, 1241, 1046, 911, 747 cm^-1; ¹H-NMR (300 MHz, CDCl₃) δ 7.45-7.36 (2H, m, ArH), 7.37-7.19 (2H, m, ArH), 6.62 (1H, dd, J = 17.3, 10.9 Hz, CH=CH₂), 6.12 (1H, t, J = 4.8 Hz, C=CH), 5.55 (1H, dd, J = 17.3, 1.8 Hz, CH=CHH), 5.24 (1H, dd, J = 10.9, 1.7 Hz, CH=CHH), 4.45 (1H, dt, J = 8.9, 6.4 Hz, CH), 3.43 (1H, d, J = 9.1 Hz, NH), 2.77 (1H, dt, J = 17.2, 5.2 Hz, CHH), 2.63 (1H, dt, J = 17.2, 6.2 Hz, CHH), 1.19 [9H, s, C(CH₃)₃]; ¹³C-NMR (75 MHz, CDCl₃) δ 136.5, 136.1 (C), 134.7 (CH), 133.2 (C), 127.9, 127.5, 126.8, 124.4, 122.6 (CH), 116.1 (CH₂), 56.1 (C), 54.7 (CH), 32.5 (CH₂), 22.6 (CH₃); LRMS (EI) m/z 171 (M⁺ -C₄H₈OS, 1%), 168 (30), 155 (22), 154 (100), 153 (71), 152 (29), 141 (11), 115 (14).

(6S,R_S )-N-(tert-Butanesulfinyl)-9-(oct-1-en-2-yl)-6,7-dihydro-5Hbenzo[7]anulen-7-amine (16): colourless oil; R _F 0.54 (hexane/AcOEt 1:1); = -9.5 (c 1.76, CH₂Cl₂); IR (film) ν 3208, 2954, 2926, 2858, 1449, 1362, 1055, 900, 752, 730 cm^-1; ¹H-NMR (400 MHz, CDCl₃) δ 7.28-7.21 (1H, m, ArH), 7.20-7.17 (3H, m, ArH), 6.16 (1H, t, J = 7.3 Hz, C=CH), 5.04-4.98 (1H, m, C=CHH), 4.92 (1H, d, J = 2.2 Hz, C=CHH), 4.15-4.05 (1H, m, CH), 3.16 (1H, d, J = 6.7 Hz, NH), 2.89 (1H, dd, J = 13.2, 6.2 Hz, CHH), 2.60 (1H, dd, J = 13.2, 5.3 Hz, CHH), 2.29-2.19 (3H, m, CH₂, CHH), 1.95-1.85 (1H, m, CHH), 1.43-1.34 (2H, m, CH₂), 1.32-1.24 (6H, m, 3 × CH₂), 1.23 [9H, s, C(CH₃)₃], 0.92-0.81 (3H, m, CH₃); ¹³C-NMR (101 MHz, CDCl₃) δ 148.9, 145.0, 139.1, 137.5 (C), 129.2, 129.1, 127.0, 126.2, 123.1 (CH), 114.6 (CH₂), 63.4 (CH), 55.6 (C), 39.9, 34.5, 34.1, 31.7, 28.9, 28.1 (CH₂), 22.6 (CH₃), 22.6 (CH₂), 14.1 (CH₃); LRMS (EI) m/z 269 (M⁺ -C₄H₈OS, 2%), 267 (16), 252 (29), 251 (38), 182 (32), 181 (49), 179 (13), 168 (26), 167 (100), 166 (18), 165 (33), 156 (16), 155 (26), 154 (16), 153 (28), 152 (19), 141 (36), 128 (24), 115 (21).

RESULTS AND DISCUSSION

Homopropargylamine derivatives 6a and 6b were prepared first starting from ortho-bromostyrene 2a. The reaction of 2a with n-BuLi in THF (an aromatic organolithium compound is formed through a bromine-lithium exchange), followed by reaction with N,N-dimethylformamide (DMF) and final hydrolysis with water gave ortho-vinylbenzaldehyde (3a) in 89% yield. Condensation of aldehyde 3a with (R)-N-tert-butanesulfinamide (1) in the presence of Ti(OEt)₄ led to N-tert-butanesulfinyl imine 4a in 75% yield. Further indium promoted propargylation of 4a with trimethylsilylpropargyl bromide (5) gave rise to the expected compound 6a with high diastereoselectivity (>98:2) and yield (70%). Finally, treatment of 6a with potassium carbonate in a mixture of THF and methanol for 12 hours led to the formation of terminal alkyne 6b in 89% yield (Figure 2).

Unfortunately, all the attempts to perform a ring-closing metathesis in enynes 6a and 6b, under the reaction conditions described by Bolm in the synthesis of cyclic sulfoximines with Grubbs second generation catalyst failed to produce the desired cyclic dienes 7 (Furger and Bolm 2009). Instead of that, starting compounds were recovered unaltered (Figure 3).

We decided to study the enyne ring-closing metathesis in other compounds different to 6a and 6b. These compounds were prepared in two synthetic operations starting from ortho-bromobenzaldehyde (3b, R² = H) and 2-bromo-5-methoxybenzaldehyde (3c, R² = OMe). First, the palladium catalyzed Sonogashira coupling reaction of aromatic aldehydes 3 with terminal alkynes 8 led to ortho-alkynyl aldehydes in high yields. After that, enynes 11 were obtained by aminoallylation of aldehyde 9 by successive reaction with (R)-N-tert-butanesulfinamide (1) in the presence of Ti(OEt)₄ at room temperature for 1 hour, followed by addition of indium metal and allyl bromide (10), and further reaction of the resulting mixture at 60 ºC for 6 hours, in a one-pot process. The reaction was monitorized by TLC and it was not necessary to isolate the imine intermediate. The expected enynes 11 were obtained in good to moderate yields. The aminoallylation of aldehyde 9d with an electron-donating substituent at the aromatic ring took place in only 30% yield, leading to enyne 11d. On the other hand, enyne 11f was obtained in quantitative yield by desilylation of 11a (Table I).

The treatment of compounds 11 with a catalytic amount of Grubbs second generation catalyst in toluene a 110 ºC for 1 hour led to the expected cyclic dienes 12 in variable yields, but for silylated derivative 11a (R¹ = SiMe₃) which did not undergo ring-closing metathesis and was recovered at the end of the reaction. The highest yields were obtained for enynes 11b [R¹ = (CH₂)₅Me] and 11f (R¹ = H), which derived from aliphatic alkynes 8, leading to dienes 12b and 12f, in 70 and 69% yield, respectively. On the other hand, lower yields were found for enynes 11d and 11e with electron-donating methoxy groups in one of the aromatic rings (Table II).

Ring-closing metathesis of all enynes 11 shown on Table I produced six-membered cycles. With the aim of widen the scope of this reaction, we prepared an enyne system which after ring-closing metathesis would generate a seven-membered ring. For this purpose, aromatic aldehyde 9b was transformed into aldehyde 13. This homologation process was carried out through a Wittig reaction with methoxymethyl triphenylphosphonium chloride, followed by acidic hydrolysis. After that, the imine 14 was prepared in 64% yield by condensation with (R)-N-tert-butanesulfinamide (1) in the presence of Ti(OEt)₄. Allylation of this imine with allyl bromide (10) in the presence of indium metal gave the expected enyne 15 in 50% yield. Finally, the ring-closing metathesis of 15 under the reactions conditions depicted on Table II led to diene 16 upon formation of a seven-membered ring. Surprisingly this metathesis took place in higher yield (78%) than for compounds 12, in spite of the higher stability of six-membered rings (Figure 4). Importantly, two stereogenic centers are present in dienes 12 and 16 (the carbon atom bonded to the nitrogen, and the sulfur atom), and are of potential interest in Diels-Alder reactions with different dienophiles, because high levels of regio- and stereoselectivity could be achieved in these transformations.

TABLE II
Synthesis of dienes 12. ^a

• ^a
  Isolated yield after column chromatography purification.

In conclusion, second generation Grubbs catalyst demonstrated to be effective in the ring-closing metathesis of N-tert-butanesulfinyl homoallylamine derivatives bearing ortho-alkynyl substituted aryl groups. The resulting dienes 12 and 16 are of potential interest in Diels-Alder reactions with different dienophiles, because high levels of regio- and stereoselectivity could be achieved in these transformations due to the presence of two stereogenic centers (the sulfur atom and the carbon atom bonded to the nitrogen). These chiral dienes are interesting precursors for the asymmetric synthesis of the skeleton present in some alkaloids, such as 17 (Foubelo and Yus 2014, 2016), and particularly in morphane derivatives (see, e.g. morphine; Figure 5) (Abate et al. 2012).

Figure 5
Potential synthetic applications of dienes 12.

ACKNOWLEDGMENTS

We thank the continued financial support from our Ministerio de Ciencia e Innovación (MCINN; CONSOLIDER INGENIO 2010-CDS2007-00006, CTQ2011-24165), the Ministerio de Economía y Competitividad (MINECO; projects CTQ2014-53695-P, CTQ2014-51912-REDC, CTQ2016-81797-REDC, CTQ2017-85093-P), FEDER, the Generalitat Valenciana (PROMETEO 2009/039, PROMETEOII/2014/017), and the University of Alicante.

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Publication Dates

• Publication in this collection
  2018

History

• Received
  27 Sept 2017
• Accepted
  24 Oct 2017