Metal-free general procedure for oxidation of secondary amines to nitrones

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1 S1 Supporting information Metal-free general procedure for oxidation of secondary amines to nitrones Carolina Gella, Èric Ferrer, Ramon Alibés, Félix Busqué,* Pedro de March, Marta Figueredo,* and Josep Font Departament de Química, Universitat Autònoma de Barcelona Bellaterra, Spain Index General procedures -tert-butyldiphenylsilyloxymethyl-1-pyrroline -oxide 3b Benzy1 1-pyrroline--carboxylate -oxide 13 (S)-3-tert-Butyldiphenylsilyloxypyrrolidine 14 (S)-3-tert-Butyldiphenylsilyloxyl-1-pyrroline -oxide 1 (S)-4-tert-Butyldiphenylsilyloxy-1-pyrroline -oxide 16 S S S3 S3 S4 S4 1 H-MR spectrum of,3,4,-tetrahydropyridine -oxide 6 S 1 H-MR spectrum of 1-pyrroline -oxide 7 S 1 H-MR spectrum of -octylideneoctylamine -oxide 8 S6 1 H-MR spectrum of -benzylidenebenzylamine -oxide 9 S6 1 H-MR spectrum of butylidenebenzyl -oxide 10 S7 1 H-MR spectrum of benzylidenebutyl -oxide 11 S7 1 H-MR spectrum of 3,4-Dihydroisoquinoline -oxide 1 S8 1 H-MR spectrum of nitrones b and 3b (reaction mixture) S8 1 H-MR spectrum of nitrone b S9 1 H and 13 C-MR spectra of -tert-butyldiphenylsilyloxymethyl-1-pyrroline -oxide 3b S10 1 H and 13 C-MR spectra of benzy1 pyrroline--carboxylate -oxide 13 S11 1 H and 13 C-MR spectra of (S)-3-tert-butyldiphenylsilyloxypyrrolidine 14 S1 1 H and 13 C-MR spectra of (S)-3-tert-butyldiphenylsilyloxy-1-pyrroline -oxide 1 S13 1 H and 13 C-MR spectra of (S)-4-tert-butyldiphenylsilyloxy-1-pyrroline -oxide 16 S14 Chiral HPLC chromatograms of endo cycloadducts 17 and ent-17 S1

2 S General Procedures. Commercially available reagents were used as received. The solvents were dried by distillation over the appropriate drying agents. All reactions were performed avoiding moisture by standard procedures and under nitrogen atmosphere and monitored by analytical thin-layer chromatography (TLC) using silica gel 60 F 4 pre-coated aluminum plates (0. mm thickness). Flash column chromatography was performed using silica gel ( mesh) or Florisil ( mesh). 1 H-MR spectra were recorded on several spectrometers. Proton chemical shifts are reported in ppm ( ) (CDCl 3, 7.6 or DMS-d 6,.0). 13 C-MR spectra were recorded on several spectrometers with complete proton decoupling. Carbon chemical shifts are reported in ppm ) (CDCl 3, 77.). MR signals were assigned with the help of CSYgpqf, and HSQC experiments. Infrared peaks are reported in cm 1. High resolution mass spectra (HRMS) were recorded using (ESI+). -tert-butyldiphenylsilyloxymethyl-1-pyrroline -oxide 3b TBDPS 3b Following the general procedure, ahc 3 (.70 g, 67.9 mmol) was added to a stirred solution of (S)--tert-Butyldiphenylsilyloxymethylpyrrolidine 1 (4.60 g, 13.6 mmol) in a mixture of acetonitrile-thf (4:1, ml) and a EDTA (0.01 M, 19 ml). The mixture was then cooled in an ice bath and xone (8.76 g, 14.3 mmol) was added portionwise over h. The mixture was stirred at ºC for 0 min and then diluted with EtAc (70 ml). The two phases were separated and the aqueous one was extracted with CH Cl (3x40 ml). The combined organic extracts were dried over anhydrous MgS 4 and concentrated under reduced pressure to afford an oil identified as a 1.3:1 mixture of nitrones (S)--tert-butyldiphenylsilyloxymethyl-1- pyrroline -oxide b and -tert-butyldiphenylsilyloxymethyl-1-pyrroline -oxide 3b (4.30 g, 1. mmol, 88% yield). The ratio b:3b was determined by 1 H-MR. Pure samples of both nitrones 3b (first eluted) and b (second eluted) can be obtained by flash chromatography (CHCl 3 /MeH 40:1). b: Previously described. 3b: IR (ATR): υ 3069, 99, 167, 188, 146, 1106, 81, 699 (cm -1 ); 1 H-MR (400 MHz, CDCl 3 ): δ 7.63 (dd, J = 7.4, 1.7 Hz, 4H, H-Ar), 7.40 (m, 6H, H-Ar), 4.68 (m, H, H-1 ), 3.9 (tt, J = 8.0,.3 Hz, H, H-),.86 (tt, J = 7.1,.3 Hz, H, H-3),.09 (tt, J = 8.0, 7.1 Hz, H, H-4), 1 Yuan, Z.-Q.; Kihlberg, J. Tetrahedron 00, 61, Sánchez-Izquierdo, F.; Blanco, P.; Busqué, F.; Alibés, R.; de March, P.; Figueredo, M.; Font, J.; Parella, T. rg. Lett. 007, 9,

3 S (s, 9H, tbu). 13 C-MR (100 MHz, CDCl 3 ): δ 148., 13.4, 13., 19.9, 17.7, 6.7, 9.7, 9.6, 6.8, 19., HRMS (ESI+) calcd for C 1 H 7 Sia: [M+a] + ; found Benzy1 pyrroline--carboxylate -oxide Bn Following the general procedure, benzy1 pyrroline--carboxylate -oxide 13 was obtained in a 8% yield starting from L-proline benzyl ester. 13: IR (ATR): υ 3366, 90, 173, 1, 118, 116, 1009, 699 (cm -1 ); 1 H-MR (400 MHz, CDCl 3 ): δ (m, H, H-Ar),.8 (s, H, CH-Ph), 4.13 (tt, J =8.1,.1 Hz, H, H-), 3.01 (tt, J = 7.3,.1 Hz, H, H-3),.13 (tt, J =8.1, 7.3 Hz, H, H-4). 13 C-MR (100 MHz, CDCl 3 ): δ 19., 13.3, 133.8, 18., 18.3, 16.8, 66.7, 66.6, 9.6, HRMS (ESI+): calcd for C 1 H 13 3 a [M+a] + ; found (S)-3-tert-Butyldiphenylsilyloxypyrrolidine 14 TBDPS 3 4 H 1 14 To a stirred solution of (S)-3-hydroxypyrrolidine (0.30 g, 3.4 mmol), imidazole (0.87 g, 8.63 mmol) and DMAP (1 mg, mmol) in CH Cl (1 ml) at 0 ºC, tertbutyldiphenylsilyl chloride (.8 g, 0.17 mmol) was slowly added over min and the mixture was allowed to warm up to room temperature and stirred for 16 h. At this time, the resulting precipitate was filtered off and brine (10 ml) was added. The phases were separated and the aqueous was then extracted with CH Cl ( x 1 ml). The whole organic phases were concentrated under reduced pressure to yield an oil which was dissolved in a mixture of CH Cl (10 ml) and H 3 1% ( ml). The mixture was stirred for 1 h, the phases were separated and the aqueous phase was then extracted with CH Cl ( x 10 ml). The whole organic phases were dried (a S 4 ), concentrated under reduced pressure and purified by flash chromatography (CH 3 Cl-MeH, 0:1) to provide (S)-3-tert-butyldiphenylsilyloxypyrrolidine 14 (0.9 g,.83 mmol, 8 % yield). 14: [α] 0 D = (c.0, CHCl 3 ); IR (ATR): υ 3069, 930, 86, 147, 1417, 1107, 8, 70 (cm -1 ); 1 H-MR (400 MHz, CDCl 3 ): δ 7.66 (t, J =.7 Hz, 4H, H-Ar), 7.4 (m, 6H, H-Ar), 4.40

4 S4 (s br, 1H, H-3), 4.9 (s br, 1H, H), 3.0 (q, J=7.8 Hz, 1H, H-),.94 (d, J=11.4 Hz, 1H, H-),.88 (m, 1H, H-),.79 (dd, J = 1.4, 4.7 Hz, 1H, H-), 1.79 (m, H, H-4), 1.08 (s, 9H, H-tBu). 13 C-MR (100 MHz, CDCl 3 ): δ 13.6, 134.9, 134.0, 19.6, 17.7, 73.8,.4, 4., 3.6, 7.0, HRMS (ESI+) calcd for C 0 H 7 Si: [M+H] + ; found (S)-3-tert-Butyldiphenylsilyloxy-1-pyrroline -oxide 1 and (S)-4-tert-butyldiphenylsilyloxy- 1-pyrroline -oxide 16 TBDPS 3 4 TBDPS Following the general procedure, (S)-3-tert-butyldiphenylsilyloxypyrrolidine 14 (1.0 g, 3.08 mmol) afforded a yellow oil identified as a.:1 mixture of nitrones (S)-3-tertbutyldiphenylsilyloxy-1-pyrroline -oxide 1 and (S)-4-tert-butyldiphenylsilyloxy-1-pyrroline -oxide 16 (0.866 g,. mmol, 83% yield). The ratio 1:16 was determined by 1 H-MR. Pure samples of both nitrones 1 (first eluted) and 16 (second eluted) can be obtained by flash chromatography (CHCl 3 /MeH 30:1). 1: [α] 0 D = (c 1.7, CHCl 3 ); IR (ATR): υ 3069, 930, 86, 1719, 188, 146, 110, 81, 699 (cm -1 ); 1 H-MR (400 MHz, CDCl 3 ): δ 7.7 (d, J = 8. Hz, H, H-Ar), 7.66 (d, J = 7.1 Hz, H, H-Ar), 7.43 (m, 6H, H-Ar), 6.70 (q, J =.1 Hz, 1H, H-), 4.9 (m, 1H, H-3), 4.13 (dddt, J = 1.8, 9.,.8,.0 Hz, 1H:H-), 3.77 (dddt, J = 1.6, 9.0,.8, 1.0 Hz, 1H, H-),.41 (ddd, J = 13., 9.0,.8 Hz, 1H, H-4),.19 (dddd, J = 13., 9.,.7, 3.6 Hz, 1H, H-4), 1.09 (s, 9H, tbu). 13 C-MR (100 MHz, CDCl 3 ): δ 136.4, 13., 13.8, 19.7, 17.9, 73.0, 61.0, 30., 6.6, HRMS (ESI+) calcd for C 0 H Sia: [M+a] + ; found : [α] 0 D = (c 0.6, CHCl 3 ); IR (ATR): υ 3069, 99, 86, 1707, 189, 147, 1106, 81, 699 (cm -1 ); 1 H-MR (0 MHz, CDCl 3 ): δ 7.74 (d, J = 8. Hz, H, H-Ar), 7.63 (d, J = 7.0 Hz, H, H-Ar), 7.43 (m, 6H, H-Ar), 6.89 (m, 1H, H-), 4.6 (m, 1H, H-4), 3.91 (m, H, H-),.84 (dddt, J = 19.0, 6.6,., 1.9 Hz, 1H, H-3),.71 (dtt, J = 19.0,.9, 1.6 Hz, 1H, H-3), 1.09 (s, 9H, tbu). 13 C-MR (6. MHz, CDCl 3 ): δ 136.0, 13.3, 134.7, 133.3, 133.0, 130.6, 130.0, 18.4, 18.1, 70., 67.6, 40.0, 7., HRMS (ESI+): calcd for C 0 H Sia [M+a] + ; found

5 S ppm 1 H-MR (0 MHz, CDCl 3 ) ppm 1 H-MR (0 MHz, CDCl 3 )

6 S6 7' ' 3' 1' ' 6' 4' ' CH 3 10CH H 1 H 1 H ppm 1 H-MR (0 MHz, CDCl 3 ) Ph Ph 9 1 H-MR (0 MHz, CDCl 3 )

7 S7 10 H Ar 3H 4 H 1 H 3 H 1 H ppm 1 H-MR (0 MHz, CDCl 3 ) 11 3H 4 H Ar H 1 H Ar-orto H H ppm 1 H-MR (0 MHz, CDCl 3 )

8 S8 1 1 H-MR (0 MHz, CDCl 3 ) 1 H-MR spectrum of nitrones b and 3b (reaction mixture) a 4a 3a a H 1'a TBDPS + b 4b 3b b 1'b TBDPS b 3b 1 H-MR (0 MHz, CDCl 3 )

9 S9 1 H-MR (0 MHz, CDCl 3 )

10 S b 1 TBDPS H-1 1 H-MR (400 MHz, CDCl 3 ) Ph Ph t Bu Ph Ph C-7 C- C-1 C-3 C-4 t Bu C C-MR (100 MHz, CDCl 3 )

11 S Bn -CH -Ph 1 H-MR (400 MHz, CDCl 3 ) -CH -Ph 13 C-MR (100 MHz, CDCl 3 )

12 S1 TBDPS 3 4 H H-MR (400 MHz, CDCl 3 ) 13 C-MR (100 MHz, CDCl 3 )

13 S13 TBDPS H-MR (400 MHz, CDCl 3 ) 13 C-MR (100 MHz, CDCl 3 )

14 S14 TBDPS H-MR (0 MHz, CDCl 3 ) 13 C-MR (6. MHz, CDCl 3 )

15 S1 Chiral HPLC chromatograms of endo cycloadducts of nitrones b and ent-b with (E)-- hexenedioic acid dimethyl ester The enantiomeric purity of nitrones b and ent-b can be confirmed by chiral HPLC of the corresponding endo cycloadducts 17 and ent-17 derived from the 1,3-dipolar cycloaddition with (E)--hexenedioic acid dimethyl ester. Chromatogram A of cycloadduct 17 clearly shows the lack of a peak at 40 minutes, where compound ent-17 appears according chromatogram B. L-Prolinol D-Prolinol ref.1 SI Me C TBDPS TBDPS H H ref. SI H H Me TBDPS C TBDPS TBDPS ref. SI C Me b ent-b ref. SI C Me 17 ent-17 TBDPS AU Chromatogram A: Cycloadduct 17 derived from L-prolinol. Minutes AU Minutes Chromatogram B: Cycloadduct ent-17 derived from D-prolinol.

16 S AU Minutes Chromatogram C: Approximately 1:1 mixture of cycloadducts 17 and ent HPLC condicions: Daicel Chiralpak AD-H 4.6x0 mm column, iprh-hexane 1:99, 0.8 ml/min flow.