HETEROCYCLES

Note | Special issue | Vol. 80, No. 1, 2010, pp. 679-687
Received, 23rd July, 2009, Accepted, 25th August, 2009, Published online, 25th August, 2009.
DOI: 10.3987/COM-09-S(S)70

■ Synthesis of 3-Substituted 3-(Trimethylsiloxy)pyrrolidines from β-Aminoketones and Lithium Trimethylsilyldiazomethane

Yoshiyuki Hari, Takuya Yokoyama, and Toyohiko Aoyama*

Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan

Abstract

Lithium trimethylsilyldiazomethane reacted with N-benzyl-β-aminoketones at -78 °C in THF to give 3-substituted 1-benzyl-3-(trimethylsiloxy)pyrrolidines in moderate to good yields.

INTRODUCTION
We have previously reported that lithium trimethylsilyldiazomethane [TMSC(Li)N2] readily reacts with aliphatic β-aminoketones to give the corresponding 2-pyrrolines (intramolecular N-H insertion products)

in moderate to good yields via alkylidenecarbene intermediates (Scheme 1).1 Furthermore, we have demonstrated that the reaction of TMSC(Li)N2 with aryl ketones efficiently produces the corresponding aryl acetylenes (1,2-aryl rearrangement products) also via alkylidenecarbene intermediates.2 Due to our continued interest in the use of TMSCHN2 in organic synthesis,3 the reaction of TMSC(Li)N2 with N-benzyl-β-aminoketones 1 was reexamined in detail. Interestingly, we found that when the reaction was carried out at low temperature, -78 °C, intramolecular N-alkylation via initially formed diazoalkoxides preferentially occurred and the 3-substituted 1-benzyl-3-(trimethylsiloxy)pyrrolidines 2 were obtained as major products (Scheme 1). In this paper, we describe the details of our results.

RESULTS AND DISCUSSION
All N-benzyl-β-aminoketones 1 used in this study were synthesized from the corresponding N-methoxy-N-methylamides, vinylmagnesium bromide and benzylamine according to the procedure reported by Gomtsyan and co-workers (Figure 1).4 Initially, the N-benzyl-β-aminoketone 1a was employed as a model substrate to optimize reaction conditions. The results are summarized in Table 1. In analogy with the reaction with aryl ketones,2 the reaction of TMSC(Li)N2 with 1a at -78 °C for 2 h followed by reflux for 2 h smoothly proceeded to give the alkyne 3a (50% yield) as a major product, but an unexpected product, the pyrrolidine 2a, was also obtained in 29% yield (entry 1). Interestingly, lowering the reaction temperature remarkably affected the reaction mode and 2a was obtained as a major product (entries 2, 3 and 6-8). The change of the reaction mode at low temperature is most likely due to suppression of the elimination of lithium trimethylsiloxide (TMSOLi) and N2 gas, which generates an alkylidenecarbene intermediate, and consequently, intramolecular alkylation of the initially formed diazoalkoxide preferentially occurs with evolution of N2 to give 2a as shown in Scheme 1. THF was the reaction solvent of choice to efficiently produce 2a (entries 3 and 4). Replacement of TMSC(Li)N2 by the magnesium bromide salt [TMSC(MgBr)N2]5 was less effective (entries 3 and 5). The reaction at -78 °C in THF for 12 h was found to give the best result (entry 7). The structure of 2a was confirmed by alternative

synthesis from N-benzyl-3-pyrrolidinone, namely the reaction of N-benzyl-3-pyrrolidinone with phenylmagnesium bromide followed by trimethylsilylation by TMSCl (Scheme 2).
Next, the generality of the substrate was investigated (Table 2). When the substitutent on the benzene ring was an electron-donating group like a methoxy group (1b), the ratio of the alkyne 3b to the pyrrolidine 2b increased compared to that of 1a. Conversely, an electron-withdrawing group such as a chloro group (1c) preferentially furnished the desired pyrrolidine 2c though the yields of 2c and 3c were somewhat low due to the inherent lability of 1c.6 In the case of the naphthyl derivative 1d, the reaction proceeded smoothly to give 2d in 47% yield with 33% yield of 3d (entry 4). This reaction was also applicable to the substrate 1e bearing heteroaromatics like thiophene for R and the desired 2e was obtained in moderate yield (entry 5). The aliphatic β-aminoketone 1f also underwent the reaction to give the desired 2f in good yield (60%) though the pyrroline 4f was formed as by-product (entry 6). Similarly, phenethyl derivative 1g gave 2g in 72% yield (entry 7).

CONCLUSION
We found that reaction of TMSC(Li)N2 with β-aminoketones at -78 °C mainly proceeded in an intramolecular N-alkylation mode, and 3-substituted 3-(trimethylsiloxy)pyrrolidines were obtained in moderate to good yields. The present method is a new application of TMSC(Li)N2 as a reagent in organic synthesis.

EXPERIMENTAL
All melting points were measured on a Yanagimoto micro melting points apparatus and are uncorrected. IR spectra were recorded on a SHIMADZU FTIR-8400S spectrophotometer. 1H and 13C NMR spectra were recorded on a JEOL JNM-EX-270 spectrometer (1H, 270 MHz; 13C, 67.8 MHz). MS spectra were recorded on a JEOL JMS-SX-102A spectrometer. Silica gel used for column chromatography is Fuji Sylisia BW-820MH.
General procedure for the synthesis of N-benzyl-β-aminoketone (1).4 Under an argon atmosphere, vinylmagnesium bromide (1.0 M in THF, 11 mL, 11 mmol) was added dropwise to a solution of N-methoxy-N-methylamide derivative (10 mmol) in THF (100 mL) at 0 °C and the mixture was stirred for 10 min, then stirred at room temperature for 1 h. A solution of BnNH2 (1.0 M in water, 15 mL, 15 mmol) was added and the mixture was stirred at room temperature for 20 min-2 h. The mixture was extracted with EtOAc. The organic extracts were washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the following product.
3-(Benzylamino)-1-phenylpropan-1-one (1a).4 Prepared from N-methoxy-N-methylbenzamide. EtOAc was used as eluent for column chromatography. 70% yield.
3-(Benzylamino)-1-(4-methoxyphenyl)propan-1-one (1b). Prepared from 4-methoxy-N-methoxy-N- methylbenzamide.7 EtOAc was used as eluent for column chromatography. 88% yield. Yellow oil. IR (neat): 3319, 1672, 1258 cm-1. 1H-NMR (CDCl3) δ: 1.72 (brs, 1H), 3.03 (t, J = 5.9 Hz, 2H), 3.16 (t, J = 5.9 Hz, 2H), 3.83 (s, 2H), 3.86 (s, 3H), 6.91-6.94 (d, J = 8.9 Hz, 2H), 7.31-7.33 (m, 5H), 7.91-7.95 (d, J = 8.9 Hz, 2H). 13C-NMR (CDCl3) δ: 38.43, 44.37, 54.15, 55.48, 113.66, 126.83, 126.96, 128.02, 128.31, 128.44, 130.18, 140.02, 197.94. EI-MS m/z: 269 (M+), 135 (bp).
3-(Benzylamino)-1-(4-chlorophenyl)propan-1-one (1c). Prepared from 4-chloro-N-methoxy-N- methylbenzamide.8 EtOAc was used as eluent for column chromatography. 41% yield. Yellow oil. IR (neat): 1682 cm-1. 1H-NMR (CDCl3) δ: 1.83 (brs, 1H), 3.03 (t, J = 5.9 Hz, 2H), 3.16 (t, J = 5.9 Hz, 2H), 3.83 (s, 2H), 7.23-7.33 (m, 5H), 7.42 (d, J = 8.6 Hz, 2H), 7.88 (d, J = 8.6 Hz, 2H). 13C-NMR (CDCl3) δ: 38.92, 44.07, 54.15, 126.85, 127.97, 128.31, 128.81, 129.30, 135.09, 139.46, 140.01, 198.14. EI-MS m/z: 275 (M+), 273 (M+), 139 (bp). HR-MS calcd for C16H1635ClNO: 273.0920, found: 273.0910. HR-MS calcd for C16H1637ClNO: 275.0891, found: 275.0867.
3-(Benzylamino)-1-(naphthalen-2-yl)propan-1-one (1d). Prepared from N-methoxy-N-methyl-2- naphthamide [Yellow oil. IR (neat): 1643 cm-1. 1H-NMR (CDCl3) δ: 3.42 (s, 3H), 3.57 (s, 3H), 7.52-7.58 (m, 2H), 7.74-7.77 (m, 1H), 7.85-7.92 (m, 3H), 8.22 (s, 1H). 13C-NMR (CDCl3) δ: 33.87, 61.06, 124.90, 126.31, 127.21, 127.45, 127.53, 128.51, 128.66, 131.25, 132.32, 134.05, 169.66. EI-MS m/z: 215 (M+), 155 (bp). HR-MS calcd for C13H13NO2: 215.0946, found: 215.0945.].9 Hexane-EtOAc (2:1 to 0:1) was used as eluent for column chromatography. 55% yield. Yellow solid, mp 66-69 °C. IR (neat): 3303, 1672 cm-1. 1H-NMR (CDCl3) δ: 1.91 (brs, 1H), 3.13 (t, J = 6.2 Hz, 2H), 3.38 (t, J = 6.2 Hz, 2H), 3.90 (s, 2H), 7.28-7.38 (m, 5H), 7.55-7.66 (m, 2H), 7.89-8.07 (m, 4H), 8.49 (s, 1H). 13C-NMR (CDCl3) δ: 38.92, 44.28, 54.17, 123.57, 126.65, 126.81, 127.63, 127.99, 128.29, 128.33, 128.36, 129.44, 129.64, 132.31, 134.03, 135.44, 140.04, 199.35. EI-MS m/z: 289 (M+), 155 (bp). HR-MS calcd for C20H19NO: 289.1467, found: 289.1462.
3-(Benzylamino)-1-(thiophen-2-yl)propan-1-one (1e). Prepared from N-methoxy-N-methylthiophene-2- carboxamide.10 Hexane-EtOAc (2:1) was used as eluent for column chromatography. 55% yield. Yellow oil. IR (neat): 3315, 1658 cm-1. 1H-NMR (CDCl3) δ: 1.76 (brs, 1H), 3.03 (t, J = 5.8 Hz, 2H), 3.15 (t, J = 5.8 Hz, 2H), 3.83 (s, 2H), 7.12 (m, 1H), 7.23-7.33 (m, 5H), 7.62-7.64 (m, 1H), 7.70-7.71 (m, 1H). 13C-NMR (CDCl3) δ: 39.54, 44.30, 54.07, 126.84, 127.99, 128.02, 128.31, 131.90, 133.61, 139.96, 144.07, 192.29. EI-MS m/z: 245 (M+), 111 (bp). HR-MS calcd for C14H15NOS: 245.0874, found: 245.0860.
1-(Benzylamino)-4,4-dimethylpentan-3-one (1f). Prepared from N-methoxy-N-methyl-2,2,2- trimethylacetamide.11 Hexane-EtOAc (1:1) was used as eluent for column chromatography. 69% yield. Yellow oil. IR (neat): 2966, 1699 cm-1. 1H-NMR (CDCl3) δ: 1.14 (s, 9H), 1.77 (brs, 1H), 2.73 (t, J = 5.8 Hz, 2H), 2.84 (t, J = 5.8 Hz, 2H), 3.78 (s, 2H), 7.20-7.32 (m, 5H). 13C-NMR (CDCl3) δ:26.37, 26.49, 36.84, 44.16, 54.21, 126.79, 127.97, 128.28, 140.10, 215.53. EI-MS m/z: 219 (M+), 91 (bp).
1-(Benzylamino)-5-phenylpentan-3-one (1g). Prepared from N-methoxy-N-methyl-3- phenylpropanamide.12 Hexane-EtOAc (1:1) was used as eluent for column chromatography. 74% yield. Yellow oil. IR (neat): 3026, 1713 cm-1. 1H-NMR (CDCl3) δ: 1.71 (s, 1H), 2.60 (t, J = 6.2 Hz, 2H), 2.73 (t, J = 7.2 Hz, 2H), 2.84 (t, J = 6.2 Hz, 2H), 2.88 (t, J = 7.2 Hz, 2H), 3.75 (s, 2H), 7.14-7.33 (m, 10H). 13C-NMR (CDCl3) δ: 29.68, 43.11, 43.81, 44.49, 54.06, 125.99, 126.82, 127.95, 128.15, 128.27, 128.36, 140.00, 140.81. EI-MS m/z: 267 (M+), 91 (bp). HR-MS calcd for C18H21NO: 267.1623, found: 267.1624.
General procedure of reaction between TMSC(Li)N2 and N-benzyl-β-aminoketones (1). Under an argon atmosphere, a solution of 1 (1.0 mmol) in THF (3 mL) was added dropwise to a solution of TMSC(Li)N2, prepared from TMSCHN2 (2.17 M in hexane, 0.55 mL, 1.2 mmol) and n-BuLi (1.59 M in hexane, 0.75 mL, 1.2 mmol) in THF (10 mL), at -78 °C, and the mixture was stirred at -78 °C for 12 h. After being quenched with H2O, the mixture was extracted with EtOAc. The organic extracts were washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the following products.
1-Benzyl-3-phenyl-3-(trimethylsilyloxy)pyrrolidine (2a) and N-benzyl-4-phenylbut-3-yn-1-amine (3a). Hexane-EtOAc (10:1 to 2:1) was used as eluent for column chromatography. 2a: 56% yield. Yellow oil. IR (neat): 1250, 1109 cm-1. 1H-NMR (CDCl3) δ: 0.15 (s, 9H), 2.33-2.41 (m, 2H), 2.76-2.84 (m, 1H), 2.95-3.09 (m, 3H), 3.71, 3.85 (ABq, J = 12.9 Hz, 2H), 7.26-7.57 (m, 10H). 13C-NMR (CDCl3) δ: 2.14, 42.57, 53.70, 60.66, 69.23, 83.62, 125.34, 126.49, 126.80, 127.77, 128.09, 128.68, 139.01, 147.45. EI-MS m/z: 325 (M+), 133 (bp). HR-MS calcd for C20H27NOSi: 325.1859, found: 325.1862. 3a: 22% yield. Yellow oil. IR (neat): 3028, 2229 cm-1. 1H-NMR (CDCl3) δ: 2.00 (br, 1H), 2.65 (t, J = 6.6 Hz, 2H), 2.90 (t, J = 6.6 Hz, 2H), 3.87 (s, 2H), 7.27-7.43 (m, 10H). 13C-NMR (CDCl3) δ: 20.63, 47.62, 53.39, 82.04, 87.86, 126.83, 127.57, 127.95, 128.05, 128.27, 128.39, 128.44, 131.45. EI-MS m/z: 235 (M+), 91 (bp). HR-MS calcd for C17H17N: 235.1359, found: 235.1361.
1-Benzyl-3-(4-methoxyphenyl)-3-(trimethylsilyloxy)pyrrolidine (2b) and N-benzyl-4-(4- methoxyphenyl)but-3-yn-1-amine (3b). Hexane-EtOAc (5:1 to 2:1) was used as eluent for column chromatography. 2b: 42% yield. Yellow oil. IR (neat): 1248, 1103 cm-1. 1H-NMR (CDCl3) δ: 0.03 (s, 9H), 2.19-2.26 (m, 2H), 2.65-2.73 (m, 1H), 2.83-2.96 (m, 3H), 3.67 (ABq, J = 12.4 Hz, 2H), 3.76 (s, 3H), 6.79-6.83 (m, 2H), 7.18-7.35 (m, 7H). 13C-NMR (CDCl3) δ: 2.11, 42.12, 53.26, 55.25, 60.77, 68.94, 83.29, 113.11, 126.61, 126.81, 128.09, 128.69, 130.92, 138.95, 158.17. EI-MS m/z: 355 (M+), 263 (bp). HR-MS calcd for C21H29O2NSi: 355.1968, found: 355.1959. 3b: 43% yield. Yellow oil. IR (neat): 2928, 2046, 1246 cm-1. 1H-NMR (CDCl3) δ: 1.26 (br, 1H), 2.58 (t, J = 7.3 Hz, 2H), 2.88 (t, J = 7.3 Hz, 2H), 3.75 (s, 2H), 3.79 (s, 3H), 6.78-6.98 (m, 3H), 7.23-7.98 (m, 6H). 13C-NMR (CDCl3) δ: 20.68, 47.77, 53.46, 55.30, 81.54, 86.26, 113.78, 115.74, 126.86, 128.02, 128.33, 132.84, 140.13, 159.04. EI-MS m/z: 265 (M+), 91 (bp). HR-MS calcd for C18H19NO: 265.1467, found: 265.1470.
1-Benzyl-3-(4-chlorophenyl)-3-(trimethylsilyloxy)pyrrolidine (2c) and N-benzyl-4-(4- chlorophenyl)but-3-yn-1-amine (3c). Hexane-EtOAc (20:1 to 2:1) was used as eluent for column chromatography. 2c: 31% yield. Yellow oil. IR (neat): 1250, 1094 cm-1. 1H-NMR (CDCl3) δ: 0.07 (s, 9H), 2.24 (t, J = 7.1 Hz, 2H), 2.72-2.75 (m, 1H), 2.84-2.90 (m, 3H), 3.61, 3.76 (ABq, J = 12.9 Hz, 2H), 7.24-7.42 (m, 9H). 13C-NMR (CDCl3) δ: 2.16, 42.68, 53.24, 60.50, 69.13, 83.14, 126.73, 126.89, 127.85, 128.14, 128.66, 132.15, 138.77, 146.43. EI-MS m/z: 361 (M+), 359 (M+), 133 (bp). HR-MS calcd for C20H2635ClNOSi: 359.1472, found: 359.1466. HR-MS calcd for C20H2637ClNOSi: 361.1443, found: 361.1434. 3c: 7% yield. Yellow oil. IR (neat): 2924, 2228 cm-1. 1H-NMR (CDCl3) δ: 2.35 (brs, 1H), 2.63 (t, J = 6.6 Hz, 2H), 2.87 (t, J = 6.6 Hz, 2H), 3.85 (s, 2H), 7.23-7.34 (m, 9H). 13C-NMR (CDCl3) δ: 20.61, 47.43, 53.35, 80.77, 88.91, 122.02, 126.99, 128.04, 128.37, 128.43, 132.73, 133.61, 139.78. EI-MS m/z: 271 (M+), 269 (M+), 91 (bp). HR-MS calcd for C17H1635ClN: 269.0971, found: 269.0959.
1-Benzyl-3-(naphthalen-2-yl)-3-(trimethylsilyloxy)pyrrolidine (2d) and N-benzyl-4-(naphthalen-2- yl)but-3-yn-1-amine (3d). Hexane-EtOAc (15:1 to 1:1) was used as eluent for column chromatography. 2d: 47% yield. Yellow oil. IR (neat): 1250, 1040 cm-1. 1H-NMR (CDCl3) δ: 0.07 (s, 9H), 2.26-2.47 (m, 2H), 2.74-2.82 (m, 1H), 2.89-3.08 (m, 3H), 3.65, 3.81 (ABq, J = 13.0 Hz, 2H), 7.21-7.48 (m, 7H), 7.59-7.63 (m, 1H), 7.77-7.88 (m, 4H). 13C-NMR (CDCl3) δ: 2.19, 42.51, 53.42, 60.63, 69.01, 83.67, 123.24, 124.52, 125.49, 125.80, 126.83, 127.32, 127.56, 128.05, 128.11, 128.67, 132.18, 132.78, 138.96, 144.80. EI-MS m/z: 375 (M+), 91 (bp). HR-MS calcd for C24H29ONSi: 375.2019, found: 375.2018. 3d: 33% yield. Yellow oil. IR (neat): 2945, 2230 cm-1. 1H-NMR (CDCl3) δ: 2.13 (br, 1H), 2.68 (t, J = 6.6 Hz, 2H), 2.90 (t, J = 6.6 Hz, 2H), 3.85 (s, 2H), 7.21-7.46 (m, 8H), 7.72-7.91 (m, 4H). 13C-NMR (CDCl3) δ: 20.64, 47.50, 53.31, 82.04, 88.21, 120.71, 126.18, 126.81, 127.39, 127.49, 127.66, 127.94, 128.25, 128.42, 131.01, 132.29, 132.74, 139.88. EI-MS m/z: 285 (M+), 91 (bp). HR-MS calcd for C21H19N: 285.1518, found: 285.1521.
1-Benzyl-3-(thiophen-2-yl)-3-(trimethylsilyloxy)pyrrolidine (2e) and N-benzyl-4-(thiophen-2-yl)but- 3-yn-1-amine (3e). Hexane-EtOAc (10:1 to 2:1) was used as eluent for column chromatography. 2e: 36% yield. Yellow oil. IR (neat): 1250, 1030 cm-1. 1H-NMR (CDCl3) δ: 0.07 (s, 9H), 2.30-2.37 (m, 2H), 2.68-2.73 (m, 1H), 2.71-3.03 (m, 3H), 3.63, 3.75 (ABq, J = 13.0 Hz, 2H), 6.91-6.93 (m, 2H), 7.14-7.33 (m, 6H). 13C-NMR (CDCl3) δ: 1.89, 43.02, 52.75, 60.43, 69.32, 81.68, 122.01, 123.63, 126.32, 126.83, 128.09, 128.64, 138.78, 153.03. EI-MS m/z: 331 (M+), 133 (bp). HR-MS calcd for C18H25NOSSi: 331.1426, found: 331.1434. 3e: 19% yield. Yellow oil. IR (neat): 3026, 2226 cm-1. 1H-NMR (CDCl3) δ: 1.25 (s, 1H), 2.65 (t, J = 6.6 Hz, 2H), 2.86 (t, J = 6.6 Hz, 2H), 3.84 (s, 2H), 6.91-6.94 (m, 1H), 7.12-7.34 (m, 7H). 13C-NMR (CDCl3) δ: 20.81, 47.27, 53.29, 74.89, 91.90, 123.49, 126.07, 126.65, 126.88, 127.99, 128.30, 131.14, 139.75. EI-MS m/z: 241 (M+), 91 (bp). HR-MS calcd for C15H15NS: 241.0925, found: 249.0916.
1-Benzyl-3-tert-butyl-3-(trimethylsilyloxy)pyrrolidine (2f) and 1-benzyl-4-tert-butyl-2,3-dihydro- 1H-pyrrole (4f). Hexane-EtOAc (50:1 to 5:1) was used as eluent for column chromatography. 2f: 60% yield. Yellow oil. IR (neat): 1248, 1036 cm-1. 1H-NMR (CDCl3) δ: 0.11 (s, 9H), 0.89 (s, 9H), 1.65 (m, 1H), 2.08 (m, 2H), 2.43, 2.63 (ABq, J = 10.0 Hz, 2H), 2.82 (m, 1H), 3.34, 3.74 (ABq, J = 12.7 Hz, 2H), 7.26-7.32 (m, 5H). 13C-NMR (CDCl3) δ: 2.26, 25.69, 35.25, 37.57, 53.57, 60.70, 62.67, 88.26, 126.72, 128.00, 128.80, 139.16. EI-MS m/z: 305 (M+), 91 (bp). HR-MS calcd for C18H31ONSi: 305.2175, found: 305.2170. 4f: 23% yield. Yellow oil. IR (neat): 1678 cm-1. 1H-NMR (270 MHz, CDCl3) δ: 1.04 (s, 9H), 2.39 (td, J = 8.7, 1.5 Hz, 2H), 2.90 (t, J = 8.7 Hz, 2H), 3.77 (s, 2H), 5.61 (d, J = 1.5 Hz, 1H), 7.26-7.34 (m, 5H). 13C-NMR (CDCl3) δ: 29.47, 29.77, 31.20, 54.43, 59.53, 126.90, 128.18, 128.44, 128.60, 132.27, 138.72. EI-MS m/z: 215 (M+), 91 (bp). HR-MS calcd for C15H21N: 215.1674, found: 215.1684.
1-Benzyl-3-phenethyl-3-(trimethylsilyloxy)pyrrolidine (2g). Hexane-EtOAc (10:1) was used as eluent for column chromatography. 72% yield. Yellow oil. IR (neat): 1250, 1040 cm-1. 1H-NMR (CDCl3) δ: 0.22 (s, 9H), 1.92-2.01 (m, 4H), 2.48-2.59 (m, 2H), 2.68-2.85 (m, 4H), 3.57, 3.74 (ABq, J = 12.9 Hz, 2H), 7.23-7.38 (m, 10H). 13C-NMR (CDCl3) δ: 2.41, 30.94, 39.69, 44.61, 52.98, 60.52, 66.98, 82.60, 125.49, 126.76, 128.04, 128.20, 128.24, 128.65, 138.95, 142.73. EI-MS m/z: 353 (M+), 91 (bp). HR-MS calcd for C22H31NOSi: 353.2175, found: 353.2168.
Alternative synthesis of 2a from 1-benzylpyrrolidin-3-one. Under an argon atmosphere, phenylmagnesium bromide (1.09 M THF solution, 1.0 mL, 1.1 mmol) was added dropwise to a solution of 1-benzylpyrrolidin-3-one (0.16 mL, 1.0 mmol) in THF (10 mL) at 0 °C and the mixture was stirred for 1.5 h, then stirred for 18 h at room temperature. The mixture was extracted with EtOAc. The organic extracts were dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using hexane-EtOAc (1:1) as eluent to give 1-benzyl-3-phenylpyrrolidin-3-ol (134 mg, 53 %) [Yellow oil. IR (neat): 3414 cm-1. 1H-NMR (CDCl3) δ: 2.18-2.26 (m, 1H), 2.32-2.43 (m, 1H), 2.51-2.66 (m, 2H), 2.97-3.00 (m, 1H), 3.12-3.20 (m, 1H), 3.74 (s, 2H), 7.21-7.36 (m, 8H), 7.48-7.51 (m, 2H). 13C-NMR (CDCl3) δ: 41.86, 52.65, 59.89, 68.39, 80.65, 125.09, 126.90, 127.03, 128.06, 128.23, 128.66, 138.44, 143.92. EI-MS m/z: 253 (M+), 91 (bp). HR-MS calcd for C17H19NO: 253.1467, found: 253.1464.]. Under an argon atmosphere, 2,6-lutidine (0.23 mL, 2.0 mmol) and TMSCl (0.10 mL, 0.75 mmol) were added to a solution of 1-benzyl-3-phenylpyrrolidin-3-ol (127 mg, 0.5 mmol) in CH2Cl2 (3 mL) at 0 °C and the mixture was stirred for 7 h. After addition of brine, the mixture was extracted with EtOAc. The organic extracts were dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using hexane-EtOAc (10:1) to give 2a (106 mg, 65%).

ACKNOWLEDGEMENTS
This work was financially supported by a Grant-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science, and Special Coordination Funds for Promoting Science and Technology of the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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