HETEROCYCLES

Paper | Regular issue | Vol. 85, No. 2, 2012, pp. 383-401
Received, 21st November, 2011, Accepted, 27th December, 2011, Published online, 29th December, 2011.
DOI: 10.3987/COM-11-12396

■ Investigation on Amino-Heck Cyclization of 1-(2-Vinylcyclohexyl)ketone Diethyl Phosphinyloximes

Sheng-Wei Tsao and Jia-Liang Zhu*

Department of Chemistry, National Dong Hwa University, 1, Sec. 2, Hsueh Rd., Shou-Feng, Hualien 974, Taiwan, R.O.C.

Abstract

Upon the treatment with Pd(PPh3)4 and Et3N in DMF at 80 °C, a range of trans-1-(2-vinylcyclohexyl)-substituted ketone diethylphosphinyloximes underwent the cyclization in a 6-endo pathway to afford 1-substituted tetrahydroisoquinolines in varying yields. Among which, the reactions of the substrates bearing the saturated alkyl groups were severely competed by hydrolysis and/or Beckmann rearrangement, while these undesired side reactions could be suppressed by introducing a β-aryl moiety possibly due to the stabilizing π-π stacking interactions between the phosphoryl and/or vinyl group and the aryl rings.

INTRODUCTION
The palladium-catalyzed intramolecular cyclization of unsaturated acyloxime derivatives (amino-Heck reaction) has emerged as a powerful means for preparing aza-heterocyclic compounds.1,2 The well-accepted mechanism for this process involves the oxidative insertion of Pd(0) to N-O bond, followed by the reaction of the resulting aminopalladium(II) complex with an internal olefin to form a cyclic product. To ensure an efficient annulation, the selection of the leaving groups on the oxime nitrogen has proven to be an important issue. First, this group should possess enough stability to minimize the competitive side reactions, mostly as Beckmann rearrangement and hydrolysis. On the other hand, it should also be sufficiently reactive towards the initial oxidative addition by Pd(0) catalyst. In term of achieving a subtle balance between the two demands, pioneering work by Narasaka and co-workers has established that O-pentafluorobenzoyl oximes are more useful in practice than many other types of oximes,2a and from which, the preparation of a large range of valuable heterocycles such as pyrroles,4 pyridines,6 imidazoles7 and pyrrolines8 have been realized.
Recently we reported the application of O-diethylphosphinyloximes as the new precursors into amino-Heck reaction.10 Under the catalysis of Pd(PPh3)4, the cyclization of a range of acyclic γ,δ-, or δ,ε-unsaturated phosphinyloximes occurred smoothly to provide the substituted pyrroles or pyridines in moderate to excellent yields. More interestingly, it was observed that the regioselectivity of the cyclization (5-exo versus 6-endo) of the γ,δ-unsaturated substrates could be controlled by the adjustment of catalytic conditions, to thus allow the selective generation of pyrroles10a or pyridines10b with the same precursors. Following this investigation, we have further extended the reaction to the 2-vinylcyclohexyl-substituted phosphinyloxime derivatives. To our knowledge, it is the first time that the amino-Heck reaction has been applied to the oximes bearing such structural motif. In addition to documenting the utility of the protocol in the construction of azabicyclic molecules, our research program is also aimed at investigating the substituting and steric factors playing on the cyclization. Herein we wish to disclose our preliminary experimental results.

RESULTS AND DISCUSSION
To access the 2-vinylcyclohexyl-substituted precursors, we first carried out the 1,4-addition reaction of 1-acetylcyclohexene with vinylmagnesium bromide in the established protocol11 to produce the known ketone 2a11 along with its trans-isomer 2b (2a/2b = 81:19) (Scheme 1). The mixture was then allowed to react with hydroxylamine hydrochloride (NH2OH·HCl) in the presence of sodium acetate (NaOAc)10a to yield four oxime intermediates (cis-E/cis-Z/trans-E/trans-Z = 72:8.7:13.8:5.5). After chromatographic separation, the major cis-E-isomer12 was treated with diethyl chlorophosphate [(EtO)2POCl] and sodium hydride (NaH) in THF to give the cis-substrate 3a (E/Z = 100:0) (Scheme 1). Moreover, compound 2a was further transformed into 2b through the base-promoted isomerization,13 which was similarly converted into the trans-substrate 3b as a mixture of two isomers (E/Z = 56:44).14
With 3a and 3b in hand, we submitted them to the amino-Heck reaction. We first examined the cyclization of 3a under the catalysis of Pd(PPh3)4 (0.2 equiv) in N,N-dimethylformamide (DMF) with the different bases10 including triethylamine, 1,8-diazabicycloundec-7-ene (DBU), N,N-diisopropylethylamine (DIPEA), and K2CO3 (Table 1). At 80 ºC,15 the cyclization reactions with triethylamine, DBU, and DIPEA all proceeded in a 6-endo pathway and were followed by the in situ oxidative dehydrogenation mediated by palladium species10b to provide 1-methyl-5,6,7,8-tetrahydroisoquinoline (4a)16 in 12-38% yields, and the best conversion was obtained with triethylamine (entry 3). Besides, large amounts of recovered 2a (10-40%) were isolated from these reactions (Table 1, entries 1-3). On the other hand, the use of K2CO3 did not afford any cyclization product but rather gave 2a solely (entry 4). By using triethylamine as a base, we further screened the catalytic conditions of Pd(OAc)2/PPh3/DMF/80 ºC and Pd(PPh3)4/CH3CN/reflux, but did not receive any improvement on the yield (entries 5 and 6). The application of the catalytic conditions in entry 3 to 3b led to the formation of 4a in a slightly higher yield (40%, entry 7). Moreover, the time for the cyclization of 3b (30 min) was found to be much shorter than that of 3a (3 h), suggesting that trans-oxime precursors should be more suited for the cyclization than the cis-isomers due to the favorable proximity of the equatorial-equatorial steric relationship (Figure 1). As such, we utilized the trans-oximes throughout the following investigations.

After the optimization of the catalytic conditions, we subsequently carried out the alkylation on 2b with iodomethane, iodoethane and benzyl bromide, respectively, to prepare ketones 2c-e (Scheme 2).17 Their oximination afforded the hydroxyloxime intermediates uniformly as the separable E- and Z-isomers. During the phosphinylation, it was observed that partial phosphinyloximes derived from 2c and 2d (3c and 3d) underwent the in situ rearrangement to yield amides 5a/5b (from E-isomers) and 6a/6b (from Z-isomers), which could be attributed to the increased steric hindrance as compared with 3b. Interestingly, no rearrangement was seen for the phosphinylation of 3e18 bearing an even larger 2-phenylethyl group. The Pd(PPh3)4-catalyzed cyclization of 3c and 3d afforded isoquinolines 4b and 4c only in 14-34% yields (Table 2, entries 1-4), and the reactions were all severely competed by the rearrangement or the hydrolysis to give the corresponding amides or ketone. Markedly different from this, the cyclization of 3e in E-form took place efficiently to furnish 4d in 70% yield without giving any detectable by-products (entry 5). Besides, a synthetically useful yield of 4d (53%) was also obtained from the Z-isomer (entry 6). For 3c-e, it was noticed that the E-oximes (entries 1, 3 and 5) are more favored for the cyclization than the corresponding Z-isomers (entries 2, 4 and 6). Furthermore, we envision that the relatively high yields of 4d should be due to a stabilizing π-π interaction between the vinyl and the β-phenyl groups of 3e to suppress the competitive side reactions. In addition, the reaction of the E-isomer may further benefit from an additional orbital interaction between the P=O bond and the benzene ring (Figure 2).

To verify the effect of the π-π interactions, we further synthesized the aromatic precursors 3f and 3g through the alkylation of 2b with α-bromo-p-xylene and 2-(bromomethyl)naphthalene, followed by the oximination and phosphinylation (Scheme 3, 2b → 2f/2g→ 3f/3g). In the sequence, the formation of trace amounts of amides 5c and 5d were also observed. Under the standard catalytic conditions, the cyclization of both substrates proceeded smoothly to provide 4e and 4f in good to acceptable yields without accompanying by hydrolysis and rearrangement, thus again confirming the positive role that the aryl moieties played on the cyclization.

In addition to the ketone oximes, we also attempted the protocol on a phosphinylaldoxime. As outlined in Scheme 4, the synthesis of the precursor began with the 1,4-addition of 1-cyclohexene-1-carboxaldehyde followed by the isomerization19 to afford aldehyde 2h, which was subsequently transformed into 3h as the sole E-isomer.20 Herein, we used CH2Cl2 as the solvent instead of previously employed CH3OH in the oximination step to avoid the formation of the acetal. Based on the previous experience,21 we predicted that the cyclization of 3h would be inevitably competed by the cyanation under the basic reaction conditions, and consequently utilized a duplicated catalytic loading (0.4 equiv) to minimize this. Under the catalysis, the reaction afforded 34% of isoquinoline (4g)10b,22 together with 30% of cyanide 7 as the side product. Therefore the utility of the strategy has been further underscored by the generation of 4g possessing the significant biological23 and synthetic values.

In summary, we have disclosed that a range of 2-vinylcyclohexyl O-diethylphosphinyloximes underwent a 6-endo cyclization under the catalysis of Pd(PPh3)4 to furnish tetrahydroisoquinoline derivatives in varying yields. As we know, it is the first time that this type of compounds has been prepared through the amino-Heck approach.24 More importantly, we discovered that the undesired side reactions competing with the cyclization could be suppressed by introducing a β-aryl moiety, and the π-π stacking interactions between the phosphoryl and/or vinyl group and aryl ring are proposed to account for this. Therefore, this method should be of particular use for preparing the tetrahydroisoquinolines bearing an 2-arylethyl appendage.

EXPERIMENTAL
All of starting materials were obtained from commercial suppliers and used without further purification. Tetrahydrofurane was distilled from sodium and benzophenone, N,N-dimethylformamide, triethylamine, diisopropylamine and dichloromethane were distilled from calcium hydride before use. TLC analysis and preparation were carried out on Merck 25 DC-Alufolien Kieselgel 60F254 glass-backed plates visualised by using UV light, or by means of ethanolic solution of vanillin (5%) with sulphuric acid (5%), iodine or aqueous KMnO4 solution (10%). The flash chromatographic purifications were performed on Merck Art.9385 Kiesegel 60 silica gel (230–400 mesh) or Brockmann I basic aluminum oxide (~150 mesh). NMR spectra (1H, 13C-NMR, DEPT, 2D-NOESY) were recorded on a Bruker 400 or Varian 600 MHz spectrometer using deuteriochloroform (CDCl3) as solvent. Chemical shifts measurements are reported in delta (δ) units. Splitting patterns are described as singlet (s), doublet (d), triplet (t), quartet (q) or multiplet (m). Coupling constants (J) are reported in Hertz (Hz). Infrared (IR) spectra were recorded on an IR-FT JASCO 410 spectrophotometer (neat) and resonances are reported in wave numbers (cm-1). High resolution mass spectra (HRMS) were determined by a Finnigan/Thermo Quest MAT 95XL spectrometer in electron impact (EI) or electrospray ionization (ESI) modes.
Typical Procedure for the Preparation of o–Diethylphosphinyloximes from Ketones; cis-(E)-Diethyl 1-(2-vinylcyclohexyl)ethylideneaminooxyphosphonate (3a): To a stirred solution of 1-(2-vinylcyclohexyl)ethanone (2a) (cis/trans = 81:19, 354 mg, 2.33 mmol) in MeOH (6.4 mL), sodium acetate (289 mg, 3.50 mmol) and NH2OH·HCl (253 mg, 3.50 mmol) were successively added. The resulting suspension was stirred at 20 ºC for 3.5 h, then diluted with CH2Cl2 (200 mL) and washed with water (40 mL x 2) and brine (40 mL). After concentration, the crude residue was purified by flash chromatography on silica gel (hexane-EtOAc 30:1, 5:1) to give the cis-E-oxime (213 mg) as the major isomer followed by the mixture of cis-Z- and the trans-E, Z-oximes (82.6 mg, cis-Z/trans-E/trans-Z = 31:49:20). cis-E-oxime: 1H NMR (400 MHz, CDCl3) δ 8.10 (broad s, 1H), 5.97 (m, 1H), 5.03 (dm, J = 10.8 Hz, 1H), 5.02 (dm, J = 16.3 Hz, 1H), 2.67 (ddd, J = 8.2, 7.8, 3.3 Hz, 1H), 2.34 (ddd, J = 11.3, 3.9, 3.9 Hz, 1H), 1.85–1.77 (m, 2H), 1.83 (s, 3H), 1.73–1.55 (m, 3H), 1.51–1.43 (m, 2H), 1.33–1.23 (m, 1H). cis-Z-oxime: 1H NMR (400 MHz, CDCl3) δ 6.12 (ddd, J = 17.2, 10.2, 9.5 Hz, 1H), 5.08–4.86 (m, 2H), 3.30 (ddd, J = 12.8, 3.9, 3.8 Hz, 1H), 2.87 (ddd, J = 9.1, 8.2, 3.4 Hz, 1H), 1.74 (s, 3H), 1.72–1.67 (m, 2H), 1.52 (m, 4H), 1.42-1.26 (m, 2H). Under a nitrogen atmosphere, NaH (60%, 183 mg, 4.58 mmol) and diethyl chlorophosphate (95%, 1.55 mL, 10.2 mmol) were successively added to a stirred solution of cis-E-oxime (213 mg, 1.27 mmol) in dry THF (7.7 mL) pre-cooled at 0 ºC. The reaction mixture was continued to stir for 24 h at room temperature, then cooled at 0 ºC and carefully quenched with saturated aqueous NH4Cl solution (20 mL). The resulting mixture was diluted with EtOAc (100 mL), washed with water (20 mL x 2) and brine (20 mL), and concentrated under vacuo. The crude mixture was subjected to chromatographic purification on silica gel (hexane-EtOAc 15:1, 5:1, 3:1, 1:1) to afford 3a as a pale yellow oil (248 mg, 35% over two steps).
IR (neat) 3050, 2982, 2932, 1637, 1448, 1276, 1033, 978, 916 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.95 (ddd, J = 17.0, 9.2, 8.8 Hz, 1H), 4.98 (br d, J = 17.6 Hz, 1H), 4.97 (br d, J = 9.2 Hz, 1H), 4.23–4.10 (m, 4H), 2.61 (ddd, J = 8.4, 8.2, 3.8 Hz, 1H), 2.47–2.43 (m, 1H), 1.86 (s, 3H), 1.81–1.71 (m, 2H), 1.70–1.57 (m, 3H), 1.48–1.41 (m, 2H), 1.31 (t, J = 7.0, 3H), 1.30 (t, J = 7.1, 3H), 1.27–1.19 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 168.9 (d, J = 12.4 Hz), 137.7, 115.8, 64.4 (d, J = 5.9 Hz), 64.2 (d, J = 5.8 Hz), 47.4, 41.5, 32.1, 25.4, 24.1, 21.3, 16.2 (d, J = 6.5 Hz), 14.8; HRMS-EI: m/z [M]+ calcd. for C14H26NO4P: 303.1599; found: 303.1594.
trans-(E,Z)-Diethyl 1-(2-vinylcyclohexyl)ethylideneaminooxyphosphonate (3b): The typical procedure for the preparation of 3a was followed; 2b (211 mg, 1.39 mmol) was used as the starting material. Flash chromatography on silica gel (hexane-EtOAc 8:1, 5:1, 3:1, 2:1) gave 3b as a mixture of two isomers (E/Z = 56:44) in 57% (236 mg) yield over two steps.
The E- and Z-oxime intermediates were isolated as a inseperable mixture (hexane-EtOAc 30:1, 5:1): 1H NMR (400 MHz, CDCl3) E-isomer: δ 8.19 (br s, 1H), 5.61 (ddd, J = 17.2, 10.2, 7.8 Hz, 1H), 4.95 (dd, J = 17.3, 1.8 Hz, 1H), 4.90 (dd, J = 10.3, 1.8 Hz, 1H), 2.11–2.06 (m, 2H), 1.82–1.73 (m, 3H), 1.78 (s, 3H), 1.70 (m, 1H), 1.42–1.15 (m, 4H); Z-isomer: δ 8.36 (br s, 1H), 5.70–5.56 (m, 1H), 5.03–4.88 (m, 2H), 2.14–2.02 (m, 2H), 1.82–1.73 (m, 3H), 1.77 (s, 3H), 1.70 (m, 1H), 1.42–1.15 (m, 4H).
3b: IR (neat) 3050, 2982, 2928, 1639, 1278, 1033, 973, 916 cm-1; 1H NMR (400 MHz, CDCl3): E-isomer δ 5.64–5.52 (m, 1H), 5.00–4.84 (m, 2H), 4.25-4.10 (m, 4H), 2.29 (ddd, J = 11.3, 11.3, 3.2 Hz, 1H), 2.12–1.98 (m, 1H), 1.85 (s, 3H), 1.82-1.67 (m, 5H), 1.37–1.27 (m, 8H), 1.24–1.15 (m, 1H); Z-isomer: δ 5.64–5.52 (m, 1H), 5.00–4.84 (m, 2H), 4.25–4.10 (m, 4H), 3.18 (m, 1H), 2.12-1.98 (m, 1H), 1.86 (s, 3H), 1.82–1.67 (m, 5H), 1.37–1.27 (m, 8H), 1.24–1.15 (m, 1H); 13C NMR (100 MHz, CDCl3): E-isomer δ 169.8 (d, J = 12.3 Hz), 141.5, 114.3, 64.3 (d, J = 5.8 Hz), 64.1 (d, J = 5.5 Hz), 48.4, 44.5, 32.7, 29.8, 25.5, 25.3, 16.1 (d, J = 6.4 Hz), 11.9; Z-isomer: δ 169.9 (d, J = 13.2 Hz), 141.2, 114.3, 64.3 (d, J = 5.2 Hz), 64.2 (d, J = 6.6 Hz), 43.7, 32.6, 28.6, 25.6, 25.2, 16.1 (d, J = 6.4 Hz); HRMS-EI m/z [M]+ cacld. for C14H26NPO4 303.1599; found 303.1608.
Typical Procedure for Amino-Heck Cyclization of trans-2-Vinylcyclohexyl-substituted Phosphinyloximes; 1-Methyl-5,6,7,8-tetrahydroisoquinoline (4a): To a solution of 3b (186 mg, 0.61 mmol) in dry DMF (30.7 mL, 0.02 M) was added Pd(PPh3)4 (143 mg, 0.12 mmol) under N2. The mixture was stirred at room temperature for 5 min before the addition of Et3N (0.43 mL, 3.07 mmol). The reaction mixture was heated at 80 ºC for 30 min, cooled to rt and diluted with water (30 mL). The solution was extracted with Et2O (100 mL x 2). The combined organic layers were washed with water (40 mL x 2) and brine (40 mL). After concentration, the crude residue was subjected to chromatographic purification on aluminum oxide (hexane-EtOAc 50:1, 20:1, 10:1) to afford recovered 2b (9.3 mg, 10%) followed by the known 4a16 (36 mg, 40%).
4a: IR (neat) 3051, 2929, 1643, 1567, 1589, 835, 808 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 5.0 Hz, 1H), 6.82 (d, J = 5.0 Hz, 1H), 2.71 (t, J = 6.2 Hz, 2H), 2.61 (d, J = 6.2 Hz, 2H), 2.42 (s, 3H), 1.88–1.80 (m, 2H), 1.79–1.72 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 156.9, 146.0, 145.1, 130.9, 122.1, 29.4, 25.9, 23.0, 22.1; HRMS-EI m/z [M]+ cacld. for C10H13N 147.1048; found 147.1042.

Typical Procedure for Alkylation of 2b; trans-1-(2-vinylcyclohexyl)propan-1-one (2c): Under a N2 atmosphere, a solution of n-BuLi (2.25 mL, 1.6 M in hexane, 3.60 mmol) was slowly added to a stirred solution of diisopropylamine (0.5 mL, 3.60 mmol) in dry THF (4.7 mL) pre-cooled to 0 ºC via a syringe in 5 min. The resulting pale-yellow solution was then cooled at -78 ºC and stirred for 30 min. After this, a solution of 2b (498 mg, 3.27 mmol) in dry THF (3.7 mL) was added dropwise to the mixture via a syringe within 18 min, and stirring was continued for an additional 30 min at -78 ºC before the quick addition of iodomethane (0.19 mL, 2.94 mmol). The mixture was allowed to stir at room temperature for 42 h, then diluted with saturated aqueous NH4Cl solution (15 mL) and extracted with Et2O (100 mL). The organic layer was separated and washed with water (40 mL x 2) and brine (40 mL). The combined aqueous layers were re-extracted with another portion of Et2O (100 mL) and the organic layer was washed with water and brine. The combined organic layers were concentrated under reduced pressure, and the crude reside was purified by flash chromatography on silica gel (hexane-EtOAc 300:1, 150:1) to give 2c in 65% yield (355.4 mg,) along with recovered 2b (54 mg).
2c: IR (neat) 3078, 2974, 2931, 1711, 1640, 917, 622 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.65 (ddd, J = 17.2, 10.2, 7.6 Hz, 1H), 4.94 (dm, J = 17.1 Hz, 1H), 4.89 (dd, J = 10.3, 1.8 Hz, 1H), 2.51–2.26 (m, 4H), 1.80–1.71 (m, 4H), 1.38–1.15 (m, 4H), 0.99 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 214.6, 141.6, 114.4, 55.8, 43.7, 35.9, 31.9, 29.1, 25.4, 25.4, 7.4; HRMS-EI: m/z [M]+ calcd. for C11H18O: 166.1358; found: 166.1365.
trans-1-(2-Vinylcyclohexyl)butan-1-one (2d): 2d was similarly prepared as 2c from 2b (200 mg, 1.31 mmol) by using 1.5 equiv of iodoethane (0.16 mL, 1.97 mmol) and 1.16 equiv of LDA (n-BuLi: 1.6 M in hexane, 1.15 mL, 1.84 mmol; diisopropylamine: 0.21 mL, 1.52 mmol). After chromatographic purification on silica gel (hexane-EtOAc 400:1, 300:1, 200:1, 100:1), 73.5 mg of 2d was obtained (40% yield based on recovered 2b).
IR (neat) 3077, 2955, 1727, 1601, 1462, 1122, 723, 700 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.61 (ddd, J = 17.3, 10.2, 7.5 Hz, 1H), 4.95 (dm, J = 17.0 Hz, 1H), 4.89 (dd, J = 10.3, 1.6 Hz, 1H), 2.44–2.24 (m, 4H), 1.82–1.71 (m, 4H), 1.59–1.49 (m, 2H), 1.38–1.10 (m, 4H), 0.88 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 214.0, 141.6, 114.4, 55.9, 44.6, 43.5, 31.9, 29.1, 25.4, 25.4, 16.7, 13.8; HRMS-EI: m/z [M]+ calcd. for C12H20O: 180.1514; found: 180.1506.
trans-3-Phenyl-1-(2-vinylcyclohexyl)propan-1-one (2e): 2e was similarly prepared as 2c from 2b (278.3 mg, 1.83 mmol) by using 2 equiv of benzyl bromide (0.45 mL, 3.66 mmol) and 1.16 equiv of LDA (n-BuLi: 1.6 M in hexane, 1.6 mL, 2.56 mmol; diisopropylamine: 0.30 mL, 2.12 mmol). After chromatographic purification on silica gel (hexane-EtOAc 100:0, 200:1), 98.7 mg of 2e was obtained (30% yield based on recovered 2b).
IR (neat) 3097, 3064, 2928, 2855, 1710, 1639, 1604, 916, 748, 700 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.31–7.24 (m, 2H), 7.21–7.15 (m, 3H), 5.59 (ddd, J = 17.2, 10.2, 7.5 Hz, 1H), 4.94 (dm, J = 17.5 Hz, 1H), 4.89 (dm, J = 10.3, Hz, 1H), 2.85 (t, J = 7.2 Hz, 2H), 2.77–2.61 (m, 2H), 2.34–2.21 (m, 2H), 1.80 (m, 4H), 1.34–1.27 (m, 2H), 1.23–1.09 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 213.0, 141.5, 141.4, 128.4, 128.3, 126.0, 114.5, 56.1, 44.3, 43.7, 31.9, 29.3, 28.9, 25.3; HRMS-EI m/z [M]+ cacld. for C17H22O 242.1671; found 242.1664.
trans-3-p-Tolyl-1-(2-vinylcyclohexyl)propan-1-one (2f): 2f was similarly prepared as 2c from 2b (493.3 mg, 3.24 mmol) by using 0.9 equiv of α-bromo-p-xylene (551 mg, 2.92 mmol, dissolved in 2.0 mL of THF before the addition) and 1.1 equiv of LDA (n-BuLi: 1.6 M in hexane, 2.2 mL, 3.56 mmol; diisopropylamine: 0.5 mL, 3.56 mmol). After chromatographic purification on silica gel (hexane-EtOAc 100:0, 200:1), 211.8 mg of 2f was obtained (41% yield based on recovered 2b).
IR (neat) 3088, 3030, 2927, 1711, 1639, 1516, 992, 809 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.08 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 8.3 Hz, 2H), 5.59 (ddd, J = 17.2, 10.2, 7.4 Hz, 1H), 4.94 (dm, J = 17.0 Hz, 1H), 4.89 (dm, J = 10.3, 1H), 2.81 (br d, J = 7.0 Hz, 2H), 2.77 (dd, J = 9.4, 4.2 Hz, 1H), 2.74–2.58 (m, 2H), 2.34–2.24 (m, 2H), 2.31 (s, 3H), 1.80–1.70 (m, 4H), 1.37–1.29 (m, 2H), 1.23–1.12 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 213.0, 141.5, 138.3, 135.4, 129.1, 128.2, 114.5, 56.1, 44.4, 43.7, 31.9, 28.9, 28.8, 25.4, 21.0; HRMS-EI m/z [M]+ cacld. for C18H24O 256.1827; found 256.1823.
trans-3-Naphthalen-2-yl-1-(2-vinylcyclohexyl)propan-1-one (2g): 2g was similarly prepared as 2c from 2b (502.9 mg, 3.30 mmol) by using 0.9 equiv of 2-(bromomethyl)naphthalene (685 mg, 2.97 mmol, dissolved in 2.0 mL of THF before the addition) and 1.2 equiv of LDA (n-BuLi: 1.6 M in hexane, 2.48 mL, 3.96 mmol; diisopropylamine: 0.56 mL, 3.96 mmol). After chromatographic purification on silica gel (hexane-EtOAc 400:1, 200:1, 100:1, 60:1), 138.5 mg of 2g (14%) was obtained mixed with the dialkylated byproduct.
IR (neat) 3054, 2927, 2855, 1707, 1640, 1509, 917, 854, 817 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.86–7.70 (m, 3H), 7.61 (s, 1H), 7.50–7.38 (m, 3H), 5.61 (ddd, J = 17.1, 10.2, 7.6 Hz, 1H), 4.95 (dm, J = 17.1 Hz, 1H), 4.89 (dm, J = 10.4, 1H), 3.02 (t, J = 7.9 Hz, 2H), 2.90–2.64 (m, 2H), 2.37–2.23 (m, 2H), 1.81–1.71 (m, 4H), 1.40–1.07 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 212.8, 141.5, 138.9, 133.6, 132.0, 128.0, 127.6, 127.4, 127.2, 126.4, 126.0, 125.2, 114.5, 56.2, 44.2, 43.7, 32.0, 29.4, 29.0, 25.4; HRMS-EI: m/z [M]+ calcd. for C21H24O: 292.1827; found: 292.1835.
trans-(E)- and (Z)-Diethyl 1-(2-vinylcyclohexy)lpropylideneaminooxyphosphonate (3c), trans-N-(2-vinylcyclohexyl)propionamide (5a) and trans-N-ethyl-2-vinylcyclo-hexanecarboxamide (6a): 3c was similarly prepared as 3a by using 2c as the starting material. Oximination of 2c (328.4 mg, 1.98 mmol) with NH2OH·HCl and NaOAc gave 181 mg of E-oxime and 98 mg of Z-oxime after the chromatographic purification on silica gel (hexane-EtOAc 80:1, 40: 1 and 10:1). E-oxime: 1H NMR (400 MHz, CDCl3) δ 8.84 (broad s, 1H), 5.64 (ddd, J = 17.2, 10.1, 7.6 Hz, 1H), 4.94 (dm, J = 17.2 Hz, 1H), 4.90 (dm, J =10.0 Hz, 1H), 2.37 (dq, J = 15.0, 7.6 Hz, 1H), 2.14 (dq, J = 15.0, 7.6 Hz, 1H), 2.20-2.11 (m, 1H), 2.05 (ddd, J = 11.3, 11.1, 3.0 Hz, 1H), 1.82-1.72 (m, 4H), 1.44-1.14 (m, 4H), 1.11 (t, J = 7.5 Hz, 3H); Z-oxime: 1H NMR (400 MHz, CDCl3) δ 9.66 (br s, 1H), 5.64 (ddd, J = 17.2, 10.2, 7.8 Hz, 1H), 4.96 (dm, J = 17.2 Hz, 1H), 4.89 (dm, J = 10.5 Hz, 1H), 3.10 (m, 1H), 2.20 (q, J = 7.3 Hz, 2H), 2.16-2.03 (m, 1H), 1.81-1.66 (m, 4H), 1.43-1.13 (m, 4H), 1.06 (t, J = 7.3 Hz, 3H).
The phosphinylation of E-oxime (61.4 mg, 0.34 mmol) was carried out with (EtO)2POCl (95%, 0.10 mL, 0.68 mmol) and NaH (60%, 16 mg, 0.41 mmol) in THF. Chromatographic purification on silica gel (hexane-EtOAc 10:1, 5:1, 3:1, 1:1) gave 3c (E-form, 49.7 mg, 23% over two steps) and 5a (22.3 mg, 18%, over two steps) as an inseparable mixture.
3c (E-form): 1H NMR (400 MHz, CDCl3): δ 5.73–5.54 (m, 1H), 5.03–4.84 (m, 2H), 4.27–4.12 (m, 4H), 2.42 (dq, J = 12.7, 7.6 Hz, 1H), 2.25 (ddd, J = 11.4, 11.3, 2.6 Hz, 1H), 2.20–2.12 (m, 2H), 1.86–1.66 (m, 4H), 1.47–1.14 (m, 4H), 1.34 (td, J = 7.1, 0.9 Hz, 6H),1.11 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) major: δ 173.5 (J = 12.2 Hz), 141.8, 114.3, 64.2 (J = 5.6 Hz), 64.1 (J = 5.6 Hz), 48.6, 44.4, 32.7, 30.4, 25.5, 25.4, 21.1, 16.1 (d, J = 6.7 Hz).
5a: IR (neat) 3307, 3074, 2975, 2933, 1642, 1543, 994, 912 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.66 (ddd, J = 17.1, 10.1, 8.6 Hz, 1H), 5.23 (br s, 1H), 4.99 (dm, J = 17.2 Hz, 1H), 4.95 (dm, J = 10.3 Hz, 1H), 3.60 (dtd, J = 15.0, 6.8, 4.0, 1H), 2.14 (q, J = 7.6 Hz, 2H), 2.05 (dm, J = 12.6 Hz, 1H), 1.85–1.65 (m, 4H), 1.42–1.28 (m, 2H), 1.27–1.18 (m, 2H), 1.11 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.1, 141.3, 115.0, 51.5, 49.4, 33.2, 32.5, 30.0, 25.3, 25.1, 10.0; HRMS-EI m/z [M]+ cacld. for C11H19NO 181.1467; found 181.1459.
The phosphinylation of Z-oxime (85.3 mg, 0.47 mmol) was carried out with (EtO)2POCl (95%, 0.29 mL, 1.88 mmol) and NaH (60%, 45 mg, 1.13 mmol) in THF. Chromatographic purification on silica gel (hexane-EtOAc 10:1, 5:1, 2:1) gave 3c (Z-form, 94.0 mg, 17% over two steps) and 6a (28 mg, 9%, over two steps) as an inseparable mixture.
3c (Z-form): 1H NMR (400 MHz, CDCl3) δ 5.69–5.52 (m, 1H), 5.04–4.85 (m, 2H), 4.26–4.10 (m, 4H), 3.14–2.91 (m, 1H), 2.25 (q, J = 7.2 Hz, 2H), 2.18–2.05 (m, 1H), 1.84–1.71 (m, 4H), 1.33 (t, J = 7.0 Hz, 6 H), 1.30–1.11 (m, 4H), 1.07 (t, J = 7.1Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.2 (J = 12.1 Hz), 141.5, 114.2, 64.4 (J = 5.9 Hz), 64.3 (J = 6.0 Hz), 43.6, 32.8, 28.8, 25.6, 25.4, 16.2 (d, J = 6.4 Hz), 10.3.
6a: IR (neat) 3295, 3081, 2975, 1639, 1556, 995, 911 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.64 (ddd, J = 17.2, 10.2, 7.7 Hz, 1H), 5.52 (br s, 1H), 5.00 (dm, J = 17.2 Hz, 1H), 4.90 (dm, J = 10.2 Hz, 1H), 3.32–3.15 (m, 2H), 2.29–2.18 (m, 1H), 1.84–1.68 (m, 5H), 1.53 (ddm, J = 19.4, 12.9 Hz, 1H), 1.34-1.10 (m, 3H), 1.08 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.9, 141.5, 114.2, 51.6, 43.8, 34.4, 31.8, 29.8, 25.4, 25.4, 14.9; HRMS-EI: m/z [M]+ calcd. for C11H19NO: 181.1467; found: 181.1470.

trans-(E) and (Z)- Diethyl 1-(2-vinylcyclohexyl)butylideneaminooxyphosphonate (3d), trans-N-(2-vinylcyclohexyl)butyramide (5b) and trans-N-propyl-2-vinylcyclo-hexanecarboxamide (6b): 3d was similarly prepared as 3a by using 2d as the starting material. Oximination of 2d (164.6 mg, 0.91 mmol) with NH2OH·HCl and NaOAc gave 99 mg of E-oxime and 41.6 mg of Z-oxime after the chromatographic purification on silica gel (hexane-EtOAc 60:1, 40:1, 10:1). E-oxime: 1H NMR (400 MHz, CDCl3) δ 8.42 (br s, 1H), 5.64 (ddd, J = 17.2, 10.2, 7.8 Hz, 1H), 4.94 (dm, J = 17.3 Hz, 1H), 4.90 (dm, J = 10.4 Hz, 1H), 2.30 (ddd, J = 12.5, 11.0, 5.5 Hz, 1H), 2.18–1.98 (m, 3H), 1.82–1.72 (m, 4H), 1.68–1.57 (m, 1H), 1.54–1.43 (m, 1H), 1.39–1.16 (m, 4H), 0.96 (t, J = 7.4 Hz, 3H); Z-oxime: 1H NMR (400 MHz, CDCl3) δ 9.23 (br s, 1H), 5.65 (ddd, J = 17.3, 10.2, 7.8 Hz, 1H), 4.96 (dm, J = 17.2 Hz, 1H), 4.90 (dm, J = 10.5 Hz, 1H), 3.10 (m, 1H), 2.11 (td, J = 7.8, 2.7 Hz, 2H), 2.13–2.09 (m, 1H), 1.81–1.66 (m, 4H), 1.61–1.46 (m, 2H), 1.45–1.12 (m, 4H), 0.92 (t, J = 7.3 Hz, 3H).
The phosphinylation of E-oxime (98 mg, 0.50 mmol) was carried out with (EtO)2POCl (95%, 0.31 mL, 2.00 mmol) and NaH (60%, 48 mg, 1.20 mmol) in THF. Chromatographic purification on silica gel (hexane-EtOAc 10:1, 5:1, 2:1) gave 3d (E-form, 60 mg, 20% over two steps) mixed with 5b (31.4 mg, 17.8%, over two steps).
3d (E-form): 1H NMR (400 MHz, CDCl3) major: δ 5.73–5.56 (m, 1H), 5.04–4.86 (m, 2H), 4.27–4.09 (m, 4H), 2.35 (ddd, J = 12.2, 11.1, 5.5 Hz, 1H), 2.26–2.14 (m, 2H), 2.14–2.03 (m, 1H), 1.86–1.67 (m, 4H), 1.55–1.43 (m, 2H), 1.43–1.14 (m, 4H), 1.34 (t, J = 7.0 Hz, 6H), 0.91 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) major: δ 172.3 (d, J = 12.1 Hz), 141.7, 114.2, 64.2 (d, J = 5.8 Hz), 64.1 (d, J = 5.8 Hz), 48.6, 44.5, 32.7, 30.6, 30.2, 25.5, 25.4, 19.6, 16.1 (d, J = 6.4 Hz), 14.6.
5b: IR (neat) 3289, 3075, 2959, 1640, 1550, 989, 909 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.66 (ddd, J = 17.3, 10.0, 8.6 Hz, 1H), 5.23 (br s, 1H), 4.99 (dm, J = 17.3 Hz, 1H), 4.95 (dm, J = 10.0 Hz, 1H), 3.61 (dtd, J = 13.1, 8.7, 4.3 Hz, 1H), 2.15–2.02 (m, 3H), 1.85–1.70 (m, 4H), 1.61 (tq, J = 7.4, 7.4 Hz, 2H), 1.42–1.14 (m, 3H), 1.12–1.01 (m, 1H), 0.91 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.3, 141.3, 115.0, 51.6, 49.3, 39.0, 33.3, 32.5, 25.3, 25.1, 19.3, 13.8; HRMS-EI: m/z [M]+ calcd. for C12H21NO: 195.1623; found: 195.1615.
The phosphinylation of Z-oxime (23.3 mg, 0.12 mmol) was carried out with (EtO)2POCl (95%, 0.07 mL, 0.48 mmol) and NaH (60%, 11 mg, 0.29 mmol) in THF. Chromatographic purification on silica gel eluting with hexane and EtOAc (15:1, 6:1, 3:1) gave 6b (5.1 mg, 5% over two steps) followed by 3d (Z-form, 15.9 mg, 9.4% over two steps).
3d (Z-form): IR (neat) 3083, 2964, 1640, 1448, 1276, 1035, 967, 914 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.59 (ddd, J = 17.2, 10.0, 8.0 Hz, 1H), 4.95 (br d, J = 17.2 Hz, 1H), 4.89 (dm, J = 9.9 Hz, 1H), 4.26–4.12 (m, 4H), 3.22–2.92 (m, 1H), 2.23–2.07 (m, 3H), 1.81–1.71 (m, 3H), 1.67 (br d, J = 13.1 Hz, 1H), 1.63–1.53 (m, 2H), 1.37-1.11 (m, 4H), 1.34 (t, J = 7.0 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H), 0.91 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.1 (d, J = 12.6 Hz), 141.5, 114.2, 64.3 (d, J = 5.9 Hz), 64.2 (d, J = 5.8 Hz), 46.5, 32.8, 28.7, 25.6, 25.4, 19.1, 16.2 (d, J = 6.5 Hz), 14.0; HRMS-EI: m/z [M]+ calcd. for C16H30NO4P: 331.1912; found: 331.1903.
6b: IR (neat) 3300, 3081, 2960, 1638, 1556, 995, 911cm-1; 1H NMR (400 MHz, CDCl3) δ 5.66 (ddd, J = 17.3, 10.2, 7.7 Hz, 1H), 5.37 (br s, 1H), 5.02 (dm, J = 17.2 Hz, 1H), 4.93 (dm, 10.3 Hz, 1H), 3.27–3.09 (m, 2H), 2.30–2.20 (m, 1H), 1.87-1.69 (m, 5H), 1.62–1.52 (m, 1H), 1.48 (qt, J = 7.3, 7.3 Hz, 2H), 1.39-1.09 (m, 3H), 0.90 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.0, 114.5, 114.3, 51.8, 43.8, 40.9, 31.8, 29.9, 25.4, 25.3, 22.9, 11.4; HRMS-EI: m/z [M]+ calcd. for C12H21NO: 195.1623; found: 195.1616.

trans-(E) and (Z)-Diethyl 3-phenyl-1-(2-vinylcyclohexyl)propylideneamino-oxyphosphonate (3e): 3e was similarly prepared as 3a by using 2e as the starting material. Oximination of 2e (98.7 mg, 0.43 mmol) with NH2OH·HCl and NaOAc gave 53.4 mg of E-oxime and 35.4 mg of Z-oxime after the chromatographic purification on silica gel (hexane-EtOAc 50:1, 20:1, 10:1).
The phosphinylation of E-oxime (53.4 mg, 0.21 mmol) was carried out with (EtO)2POCl (95%, 0.25 mL, 1.66 mmol) and NaH (60%, 40 mg, 1.00 mmol) in THF. Chromatographic purification on silica gel (hexane-EtOAc 10:1, 5:1, 2:1) gave 3e (E-form,18 50 mg, 29% over two steps).
IR (neat) 3027, 2982, 1640, 1604, 1276, 1033, 979, 924 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.32–7.28 (m, 2H), 7.21 (m, 1H), 7.22 (br d, J = 7.2 Hz, 2H), 5.61 (ddd, J = 17.1, 10.2, 8.2 Hz, 1H), 4.94 (dm, J = 17.1 Hz, 1H), 4.90 (dm, J = 10.2 Hz, 1H), 4.27–4.14 (m, 4H), 2.93 (ddd, J = 11.8, 11.6, 5.0 Hz, 1H), 2.75 (ddd, J = 11.6, 11.6, 4.5 Hz, 1H), 2.66 (ddd, J = 11.6, 11.6, 4.5 Hz, 1H), 2.41 (ddd, J = 11.8, 11.5, 5.1 Hz, 1H), 2.27 (ddd, J = 11.3, 11.3, 3.1 Hz, 1H), 2.20–2.11 (m, 1H), 1.81–1.72 (m, 4H), 1.46–1.18 (m, 4H), 1.36 (t, J = 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 171.7 (d, J = 12.3 Hz), 141.8, 141.1, 128.6, 128.2, 126.4, 114.5, 64.4 (d, J = 5.9 Hz), 64.2 (d, J = 5.7 Hz), 48.8, 44.7, 32.8, 32.0, 30.3, 30.2, 25.5, 25.4, 16.2(d, J = 6.5 Hz); HRMS-EI m/z [M]+ cacld. for C21H32NPO4 393.2069; found 393.2075.
The phosphinylation of Z-oxime (34 mg, 0.13 mmol) was carried out with (EtO)2POCl (95%, 0.08 mL, 0.53 mmol) and NaH (60%, 13 mg, 0.32 mmol) in THF. Chromatographic purification on silica gel (hexane-EtOAc 8:1, 2:1) gave 3e (Z-form, 37 mg, 23% over two steps).
IR (neat) 3055, 2921, 1639, 1452, 1266, 1034, 965, 916 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.34–7.26 (m, 2H), 7.23–7.16 (m, 3H), 5.60 (ddd, J = 17.2, 10.3, 8.1 Hz, 1H), 4.95 (dm, J = 17.2 Hz, 1H), 4.90 (dm, J = 10.3 Hz, 1H), 4.28–4.14 (m, 4H), 3.32–3.03 (m, 1H), 2.93–2.83 (m, 2H), 2.60–2.49 (m, 2H), 2.19–2.06 (m, 1H), 1.86–1.63 (m, 4H), 1.36 (t, J = 7.1 Hz, 6H), 1.33–1.13 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 170.7 (d, J = 12.4 Hz), 141.5, 141.4, 128.4, 128.4, 126.1, 114.4, 64.4 (d, J = 6.0 Hz), 64.3 (d, J = 5.9 Hz), 43.7, 32.7, 31.5, 28.7, 25.6, 25.3, 16.2 (d, J = 6.4 Hz); HRMS-EI m/z [M]+ cacld. C21H32NPO4 393.2069; found 393.2078.
1-Ethyl-5,6,7,8-tetrahydroisoquinoline (4b): The typical procedure for the preparation of 4a was followed; 3c (E-form) (49.3 mg, 0.16 mmol, mixed with 22.1 mg of 5a) was used as the starting material. The reaction time was 11 min. Flash chromatography on silica gel (hexane-EtOAc 30:1, 5:1, 2:1) gave 4b (8.4 mg, 34%) plus non-reacted 5a (20 mg) and 2c (3.9 mg, 15%). 4b was also prepared from the Z-form of 3c (73.3 mg, 0.23 mmol, mixed with 21.6 mg of 6a). Chromatographic purification on silica gel (hexane-EtOAc 30:1, 8:1, 1:1) gave 4b (6.6 mg, 17.7%) plus non-reacted 6a (19 mg) and 2c (11.5 mg, 30%).
4b: IR (neat) 3066, 2925, 1773, 1674, 1591, 1578, 1457, 841, 736 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 5.1 Hz, 1H), 6.82 (d, J = 5.1 Hz, 1H), 2.79–2.66 (m, 6H), 1.87-1.81 (m, 2H), 1.81–1.73 (m, 2H), 1.26 (t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.3, 146.1, 145.4, 130.2, 122.0, 29.5, 27.9, 25.3, 23.0, 22.1, 12.7; HRMS-EI: m/z [M]+ calcd. for C11H15N: 161.1204; found: 161.1197.
1-Propyl-5,6,7,8-tetrahydroisoquinoline (4c): The typical procedure for the preparation of 4a was followed; 3d (E-form) (59.6 mg, 0.18 mmol, mixed with 31.1 mg of 5b) was used as the starting material. The reaction time was 12 min. Flash chromatography on silica gel (hexane-EtOAc 20:1, 10:1, 2:1) gave 4c (6.8 mg, 22%) plus 5b (38.1 mg, 20% based on the total amount). 4c was also prepared from the Z-form of 3d (14.7 mg, 0.044 mmol). Chromatographic purification on silica gel (hexane-EtOAc 20:1, 8:1, 2:1) gave 4c (1.1 mg, 14%) plus 6b (2.2 mg, 25%).
IR (neat) 3049, 2926, 1650, 1587, 1564, 1460, 836, 812 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 5.0 Hz, 1H), 6.82 (d, J = 4.9 Hz, 1H), 2.75–2.67 (m, 6H), 1.88–1.65 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 160.4, 146.2, 145.3, 130.4, 122.0, 36.9, 29.7, 25.4, 23.1, 22.1, 22.0, 14.3; HRMS-EI: m/z [M]+ calcd. for C12H17N: 175.1361; found: 175.1366.
1-Phenethyl-5,6,7,8-tetrahydroisoquinoline (4d): The typical procedure for the preparation of 4a was followed; 3e (E-form) (39.6 mg, 0.10 mmol) was used as the starting material. The reaction time was 15 min. Flash chromatography on silica gel (hexane-EtOAc 30:1, 8:1, 4:1) provided 4d (17 mg, 70%). 4d was also prepared from the Z-form of 3e (35.9 mg, 0.09 mmol). Chromatographic purification on silica gel (hexane-EtOAc 30:1, 8:1) gave 4d (11.5 mg, 53%).
IR (neat) 3057, 3026, 2928, 1643, 1588, 1563, 840, 812 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 5.0 Hz, 1H), 7.31–7.26 (m, 2H), 7.25-7.17 (m, 3H), 6.86 (d, J = 5.0 Hz, 1H), 3.01 (s, 4H), 2.74 (dd, J = 6.2, 6.2 Hz, 2H), 2.62 (dd, J = 5.9, 5.9 Hz, 2H), 1.84–1.71 (m, 4H) ; 13C NMR (100 MHz, CDCl3) δ 159.4, 146.3, 145.5, 142.2, 130.6, 128.5, 128.4, 125.9, 122.3, 36.9, 35.0, 29.5, 25.4, 23.0, 22.0; HRMS-EI m/z [M]+ cacld. for C17H19N 237.1517; found 237.1510.

trans-(E)-Diethyl 3-p-tolyl-1-(2-vinylcyclohexyl)propylideneaminooxyphosphonate (3f) and trans-3-p-tolyl-N-(2-vinylcyclohexyl)propionamide (5c): 3f was similarly prepared as 3a by using 2f as the starting material. Oximination of 2f (176.2 mg, 0.69 mmol) with NH2OH·HCl and NaOAc gave 113 mg of E-oxime, which was then subjected to phosphinylation with (EtO)2POCl (0.51 mL, 3.32 mmol) and NaH (60%, 80 mg, 1.99 mmol) in THF. Flash chromatography on silica gel (hexane-EtOAc 8:1, 2:1) gave 97 mg of 3f (35%, over 2 steps) as a viscous oil and a trace amount of 5c.
3f: IR (neat) 3080, 1638, 1516, 1100, 1066, 980, 922 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.11 (br s, 4H), 5.61 (ddd, J = 17.2, 10.3, 8.2 Hz, 1H), 4.94 (dm, J = 17.2 Hz, 1H), 4.89 (dm, J = 10.3 Hz, 1H), 4.27–4.14 (m, 4H), 2.89 (ddd, J = 12.2, 11.0, 4.8 Hz, 1H), 2.70 (ddd, J = 12.3, 11.6, 4.8 Hz, 1H), 2.63 (ddd, J = 11.8, 11.6, 4.8 Hz, 1H), 2.39 (ddd, J = 11.6, 10.9, 4.8 Hz, 1H), 2.32 (s, 3H), 2.27 (ddd, J = 11.2, 11.4, 3.1 Hz, 1H), 2.21–2.11 (m, 1H), 1.82–1.73 (m, 4H), 1.36 (t, J = 7.0 Hz, 6H), 1.31–1.22 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 171.7 (d, J = 12.3 Hz), 141.8, 138.0, 135.9, 129.2, 128.1, 114.4, 64.3 (d, J = 5.8 Hz), 64.2 (d, J = 5.8 Hz), 48.8, 44.7, 32.8, 31.6, 30.5, 30.3, 25.5, 25.4, 21.0, 16.2 (d, J = 6.6 Hz); HRMS-EI: m/z [M]+ calcd. for C22H34NPO4: 407.2225; found: 407.2229.
5c: 1H NMR (400 MHz, CDCl3) δ 7.08 (s, 4H), 5.60 (ddd, J = 17.1, 10.1, 8.3 Hz, 1H), 5.10 (br s, 1H), 4.94 (dm, J = 17.2 Hz, 1H), 4.91 (dm, J = 10.1 Hz, 1H), 3.58 (dtd, J = 13.4, 8.4, 4.3 Hz, 1H), 2.89 (t, J = 7.6 Hz, 2H), 2.44–2.36 (m, 2H), 2.31 (s, 3H), 2.03 (dm, J = 12.8 Hz, 1H), 1.80-1.66 (m, 4H), 1.41–1.16 (m, 3H), 1.06–0.94 (m, 1H); HRMS-EI: m/z [M]+ calcd. for C18H25NO: 271.1936; found: 271.1927.
trans-(E)-Diethyl 3-(naphthalen-2-yl)-1-(2-vinylcyclohexyl)propylideneamino-oxyphosphonate (3g) and 3-naphthalen-2-yl-N-(2-vinylcyclohexyl)propionamide (5d): 3g was similarly prepared as 3a by using 2g as the starting material. Oximination of 2g (117.7 mg, 0.40 mmol) with NH2OH·HCl and NaOAc gave 91.4 mg of E-oxime, which was then subjected to phosphinylation with (EtO)2POCl (0.35 mL, 2.32 mmol) and NaH (60%, 56 mg, 1.39 mmol) in THF. Flash chromatography on silica gel (hexane-EtOAc 5:1, 2:1) afforded 64mg of 3g (37%, over 2 steps) and a trace amount of 5d.
3g: IR (neat) 3056, 1636, 1508, 1281, 1034, 973, 920 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.86–7.76 (m, 3H), 7.65 (s, 1H), 7.45 (m, 2H), 7.37 (dd, J = 8.4, 1.5 Hz, 1H), 5.63 (ddd, J = 17.2, 10.2, 8.1 Hz, 1H), 4.96 (dm, J = 17.2 Hz, 1H), 4.91 (dm, J = 10.3 Hz, 1H), 4.29–4.15 (m, 4H), 3.09 (ddd, J = 12.1, 13.5, 5.3 Hz, 1H), 2.92 (ddd, J = 12.6, 11.0, 5.3Hz, 1H), 2.76 (ddd, J = 12.0, 12.4, 5.3Hz, 1H), 2.51 (ddd, J = 12.0, 12.0, 5.2 Hz, 1H), 2.30 (ddd, J = 11.2, 11.4, 2.7 Hz, 1H), 2.26–2.14 (m, 1H), 1.85–1.74 (m, 4H), 1.51–1.42 (m, 1H), 1.37 (t, J = 7.0 Hz, 3H), 1.36 (t, J = 7.0 Hz, 3H), 1.32–1.17 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 171.6 (d, J = 11.8 Hz), 141.8, 138.5, 133.6, 132.2, 128.2, 127.6, 127.4, 126.9, 126.4, 126.1, 125.4, 114.5, 64.4 (d, J = 6.0 Hz), 64.2 (d, J = 5.7 Hz), 48.9, 44.7, 32.8, 32.2, 30.4, 30.3, 25.5, 25.4, 16.2 (d, J = 6.5 Hz); HRMS-EI: m/z [M]+ calcd. for C25H34NO4P: 443.2225; found: 443.2216.
5d: 1H NMR (400 MHz, CDCl3) δ 7.83–7.72 (m, 3H), 7.62 (s, 1H), 7.42-7.39 (m, 2H), 7.32 (dd, J = 8.5, 1.3 Hz, 1H), 5.53 (ddd, J = 17.1, 10.0, 8.4 Hz, 1H), 5.22 (br s, 1H), 4.89 (dm, J = 17.1 Hz, 1H), 4.77 (dm, J = 10.2, 1.6 Hz, 1H), 3.58 (dtd, J = 14.0, 8.1, 3.9 Hz, 1H), 3.10 (t, J = 7.6 Hz, 2H), 2.50 (t, J = 7.9 Hz, 2H), 2.01 (dm, J = 12.6 Hz, 1H), 1.79–1.62 (m, 4H), 1.40–1.23 (m, 2H), 1.20–1.10 (m, 1H), 1.03-0.90 (m, 1H); HRMS-EI: m/z [M]+ calcd. for C21H25NO: 307.1936; found: 307.1945.
1-(2-p-Tolyl-ethyl)-5,6,7,8-tetrahydroisoquinoline (4e): The typical procedure for the preparation of 4a was followed; 3f (54 mg, 0.13 mmol) was used as the starting material. The reaction time was 15 min. Flash chromatography on silica gel (hexane-EtOAc 30:1, 15:1, 4;1) provided 4e (22 mg, 65%) as a brown oil.
IR (neat) 3046, 3008, 1645, 1586, 1514, 839, 809 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 5.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 5.0 Hz, 1H), 2.98 (s, 4H), 2.74 (t, J = 6.3 Hz, 2H), 2.64 (t, J = 6.4 Hz, 2H), 2.33 (s, 3H), 1.85-1.73 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 159.5, 146.2, 145.5, 139.2, 135.3, 130.6, 129.0, 128.3, 122.2, 37.0, 34.5, 29.5, 25.4, 23.0, 22.1, 21.0; HRMS-EI: m/z [M]+ calcd. for C18H21N: 251.1674; found: 251.1680.
1-(2-Naphthalen-2-yl-ethyl)-5,6,7,8-tetrahydroisoquinoline (4f): The typical procedure for the preparation of 4a was followed; 3g (31.4 mg, 0.071 mmol) was used as the starting material. The reaction time was 8 min. Flash chromatography on silica gel (hexane-EtOAc 10:1) provided 4f (10.3 mg, 50%) as a brown oil.
IR (neat) 3050, 1635, 1589, 1508, 959, 890, 853, 816, 746 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 5.0 Hz, 1H), 7.86–7.74 (m, 3H), 7.66 (s, 1H), 7.47–7.37 (m, 3H), 6.87 (d, J = 5.0 Hz, 1H), 3.22–3.15 (m, 2H), 3.15–3.06 (m, 2H), 2.74 (t, J = 6.0 Hz, 2H), 2.65 (t, J = 6.0 Hz, 2H), 1.81–1.72 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 159.3, 146.3, 145.5, 139.8, 133.7, 132.0, 130.6, 127.9, 127.6, 127.5, 127.4, 126.4, 125.9, 125.1, 122.3, 36.7, 35.1, 29.5, 25.5, 23.0, 22.0; HRMS-EI: m/z [M]+ calcd. for C21H21N: 287.1674; found: 287.1678.
trans-(E)-Diethyl (2-vinylcyclohexyl)methyleneaminooxyphosphonate (3h): Vinylmagnesium bromide (0.7 M in THF, 57.4 mL, 40.17 mmol) and hexamethylphosphoramide (7.06 mL, 40.17 mmol) were successively added to a solution of Me2S·CuBr (762 mg, 3.67 mmol) in THF (20 mL) pre-cooled to -55 ºC. The resulting dark orange solution was continued to stir for 30 min and added dropwise with a mixture of 1-cyclohexene-1-carboxaldehyde (1.56 mL, 13.39 mmol) and chlorotrimethylsilane (3.4 mL, 26.78 mmol) in dry THF (10 mL) via a syringe. At -55 ºC, the reaction mixture was stirred for an additional 2 hours, then diluted with Et2O (350 mL), and successively washed with aqueous 10% HCl solution (70 mL), water (70 mL x 2) and brine (70 mL). After concentration, the crude residue was subjected to chromatographic purification on silica gel (hexane-EtOAc 200:1) to afford 1.07 g of vinyl-aldehyde as a mixture of two isomers (cis: trans = 60:40). The freshly prepared vinylaldehyde (1.07 g) was dissolved in dry CH2Cl2 (36 mL) and added with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.22 mL, 7.98 mmol). The mixture was stirred at room temperature for 2 days and concentrated under reduced pressure. Chromatography on silica gel (hexane-EtOAc 200:1) gave trans-2-vinylcyclohexanecarbaldehyde (2h) (870 mg, 61%). 1H NMR (400 MHz, CDCl3) δ 9.56 (d, J = 3.2 Hz, 1H), 5.72 (ddd, J = 17.2, 10.1, 7.8 Hz, 1H), 5.02 (dm, J = 17.2 Hz, 1H), 5.00 (dm, J = 10.0 Hz, 1H), 2.31–2.20 (m, 1H), 2.18–2.08 (m, 1H), 1.87–1.72 (m, 4H), 1.68–1.54 (m, 1H), 1.40–1.14 (m, 3H).
To a stirred solution of 2h (411.6 mg, 2.98 mmol) in CH2Cl2 (12 mL), NaOAc (737 mg, 8.93 mmol) and NH2OH·HCl (647 mg, 8.93 mmol) were successively added. The resulting suspension was stirred at room temperature for 4 h, then diluted with CH2Cl2 (200 mL) and washed with water (50 mL x 2) and brine (30 mL). After concentration, the crude residue was purified by flash chromatography on silica gel (hexane-EtOAc 20:1, 10:1) to give the oxime intermediate as a single isomer (398 mg). Under a nitrogen atmosphere, NaH (60%, 25 mg, 0.63 mmol) and diethyl chlorophosphate (95%, 0.13 mL, 0.84 mmol) were successively added to a stirred solution of the oxime (107 mg, 0.70 mmol) in dry THF (3 mL) pre-cooled at 0 ºC. The reaction mixture was continued to stir for 24 h at room temperature, then cooled at 0 ºC and carefully quenched with saturated aqueous NH4Cl solution (2 mL). The resulting mixture was diluted with EtOAc (20 mL), washed with water (5 mL x 2) and brine (5 mL), and concentrated under vacuo. The crude mixture was subjected to chromatographic purification on silica gel (hexane-EtOAc 12:1, 1:1) to afford 3h20 as a yellow oil (43.2 mg, 22% over two steps, base on the recovered starting oxime) plus 16.7 mg of recovered oxime.
IR (neat) 3057, 1737, 1642, 1037, 982, 910, 738 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 7.8 Hz, 1H), 5.61 (ddd, J = 17.2, 10.0, 8.4 Hz, 1H), 5.04–4.92 (m, 2H), 4.25–4.14 (m, 4H), 2.28–2.18 (m, 1H), 2.02–1.92 (m, 1H), 1.88–1.73 (m, 4H), 1.33 (t, J = 7.1 Hz, 6H), 1.31–1.22 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 163.6 (J = 13.9 Hz), 141.4, 115.1, 64.4 (J = 5.9 Hz), 64.3 (J = 5.6 Hz), 45.4, 42.9, 32.4, 29.8, 25.2, 24.9, 16.1 (d, J = 6.6 Hz); HRMS-ESI m/z [M]+ cacld. for C13H24O4NP: 289.1443; found: 289.1043.
Isoquinoline (4g) and trans-2-vinylcyclohexanecarbonitrile (7): To a solution of 3h (41.2 mg, 0.14 mmol) in dry DMF (7.1 mL, 0.02 M) was added Pd(PPh3)4 (66 mg, 0.057 mmol) under N2. The mixture was stirred at room temperature for 5 minutes before the addition of Et3N (0.1 mL, 0.71 mmol). The reaction mixture was heated at 80 ºC for 8 min, cooled to rt and diluted with water (7 mL). The solution was extracted with Et2O (70 mL x 2). The combined organic layers were washed with water (20 mL x 2) and brine (20 mL). After concentration, the cure residue was subjected to TLC preparation (eluting solvent: hexane-EtOAc 2:1) to afford 4g22 (6.3 mg, 34%) and 7 (5.8 mg, 30%).
4g: 1H NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 8.53 (d, J = 5.8 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.7 (td, J = 6.9, 0.8 Hz, 1H), 7.66 (d, J = 5.8 Hz, 1H), 7.61 (td, J = 7.5, 0.8 Hz, 1H) ; 13C NMR (100 MHz, CDCl3) δ 152.6, 143.0, 135.8, 130.3, 128.7, 127.6, 127.3, 126.5, 120.5.
7: IR (neat) 3081, 2936, 2238, 1642, 995, 922 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.76 (ddd, J = 17.2, 10.3, 7.2 Hz, 1H), 5.19 (dm, J = 17.2 Hz, 1H), 5.15 (dm, J = 10.3 Hz, 1H), 2.25 (ddd, J = 11.0, 10.9, 3.6 Hz, 1H), 2.21–2.10 (m, 2H), 1.90–1.84 (m, 1H), 1.83–1.73 (m, 2H), 1.65–1.56 (m, 1H), 1.38–1.12 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 139.4, 121.8, 116.3, 44.3, 34.3, 31.2, 29.7, 24.7, 24.6.

ACKNOWLEDGEMENTS
We are grateful to the National Science Council of Taiwan (R.O.C.) for financial support.

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