The Two-Faced Reactivity of Alkenes - Semantic Scholar
Supporting Information
The Two-Faced Reactivity of Alkenes: Cis- Versus Trans-Aminopalladation in Aerobic PdCatalyzed Intramolecular Aza-Wacker Reactions Guosheng Liu and Shannon S. Stahl* Department of Chemistry, University of Wisconsin-Madison 1101 University Avenue, Madison, WI, 53706
General Considerations. All commercially available compounds were used as received, and were purchased from Aldrich or Acros. 1H and 13C NMR spectra were recorded on Bruker AC-300 MHz spectrometers. 2H NMR spectra was recorded on the Varian 500 MHz spectrometers. The chemical shifts (δ) are given in part per million relative to CDCl3 (7.27 ppm for 1H, and 77.23 ppm for 13C). Flash chromatography was performed on silica gel 60 (particle size 0.040-0.063 mm, 230-400 mesh ASTM, purchased from Sorbent Technology) with hexanes/ethyl acetate. Typical procedure for palladium-catalyzed aerobic oxidative cyclization. Pd(OAc)2 (5 µmol) was placed in 13x100 mm disposable culture tubes. The reaction tubes were placed into a custom 48-well parallel reactor mounted on a Large Capacity Mixer (GlasCol) and the headspace was purged with molecular oxygen for ca. 15 min. Solutions of pyridine (10 µmol) in toluene (0.5 mL) and (E)-10 (0.1 mmol) in toluene (0.5 mL) were added to tubes. The reactions were carried out for 24 h under an oxygen atmosphere (1 atm) at 80 °C. Following removal of the solvent under vacuum, the crude oxidative amination product yield was evaluated by 1H NMR spectroscopy and integrated relative to the internal standard (1,3,5-tri-t-butylbenzene). Procedure for Pd-catalyzed oxidative amination of trans-3-d-13 using stoichiometric benzoquinone as the oxidant. A mixture of PdCl2(CH3CN)2 (10 µmol), benzoquinone (0.1 mmol), LiCl (0.2 mmol), Na2CO3 (0.2 mmol) and trans-3-d-13 (0.1 mmol) in THF (2 mL) was refluxed for 24 hours. The oxidative amination product yield was evaluated by 1H NMR spectroscopy and integrated relative to the internal standard (1,3,5-trimethoxybenzene).
S1
Compound Characterization Data.
1
N Ts
Ph
(Z)-12
H NMR (CDCl3) δ 7.67 (m, 4H), 7.32-7.15 (m, 5H), 6.09 (s, 1H), 3.66 (t, J = 7.2 Hz, 2H), 2.42 (s, 3H), 2.09 (m, 2H), 1.56 (m, 2H); 13C NMR (CDCl3) δ 144.0, 138.4, 136.5, 135.2, 129.7, 129.0, 128.0, 127.9, 127.0, 119.5, 51.2, 32.3, 21.7, 21.3; HRMS: m/z (ESI) calculated [MNa]+ 336.1034, measured 336.1024. Ph
1
(E)-12
N Ts
H NMR (CDCl3) δ 7.76 (dt, J = 1.8, 8.4 Hz, 2H), 7.32-7.26 (m, 4H), 7.16 (m, 3H), 6.87 (t, J = 2.1 Hz, 1H), 3.66 (t, J = 6.9 Hz, 2H), 2.49 (dt, J = 2.1, 7.2 Hz, 2H), 2.42 (s, 3H), 1.80 (m, 2H); 13C NMR (CDCl3) δ 144.2, 140.3, 137.8, 134.8, 129.8, 128.5, 128.4, 127.7, 126.1, 110.7, 50.7, 30.4, 22.6, 21.8; HRMS: m/z (ESI) calculated [M]+ 313.1137, measured 313.1136. Ts N
14
1
H NMR (CDCl3) δ 7.73 (m, 2H), 7.33 (m, 2H), 5.81 (m, 1H), 5.75 (m, 1H), 4.55 (dq, J = 2.1, 8.1 Hz, 1H), 3.37 (ddd,, J = 4.5, 6.9, 9.9 Hz, 1H), 3.06 (ddd, J = 6.6, 8.7, 9.9 Hz, 1H), 2.61 (m, 1H), 2.47 (m, 1H), 2.43 (s, 3H), 2.11 (dq, J = 2.1, 17.1Hz, 1H), 1.83 (m, 1H), 1.51 (m, 1H); Ts N
D
3-d-14
1
H NMR (CDCl3) δ 7.73 (m, 2H), 7.33 (m, 2H), 5.81 (q, J = 2.1 Hz, 1H), 4.55 (dq, J = 2.1, 8.1 Hz, 1H), 3.37 (ddd,, J = 4.5, 6.9, 9.9 Hz, 1H), 3.06 (ddd, J = 6.6, 8.7, 9.9 Hz, 1H), 2.61 (m, 1H), 2.47 (m, 1H), 2.43 (s, 3H), 2.10 (dq, J = 2.1, 17.1 Hz, 1H), 1.83 (m, 1H), 1.51 (m, 1H); 2H NMR (CHCl3) δ 5.72 (s, 1D); 13C NMR (CDCl3) δ 143.5, 135.0, 131.9 (t, J = 25.0 Hz), 131.3, 129.8, 127.8, 70.2, 48.4, 40.0, 38.0, 32.5, 21.7; HRMS: m/z (EI) calculated [M]+ 264.1043, measured 264.1034. Ts N
D
3-d-15
1
H NMR (CDCl3) δ 7.73 (m, 2H), 7.33 (m, 2H), 5.45 (q, J = 2.1 Hz, 1H), 4.18 (dt, J = 6.9, 4.2 Hz, 1H), 3.40-3.20 (m, 2H), 2.71 (m, 2H), 2.43 (s, 3H), 2.22 (m, 1H), 1.68-1.48 (m, 2H); 2H NMR (CHCl3) δ 5.72 (s, 1D). D
Ts N
trans-2-d-15
S2
1
H NMR (CDCl3) δ 7.73 (m, 2H), 7.33 (m, 2H), 5.72 (m, 1H), 5.45 (m, 1H), 4.18 (dt, J = 6.9, 4.2 Hz, 1H), 3.40-3.20 (m, 3H), 2.71 (m, 1H), 2.43 (s, 3H), 1.68-1.48 (m, 2H); 2H NMR (CHCl3) δ 2.68 (s, 1D). D
Ts N
2-d-14
1
H NMR (CDCl3) δ 7.73 (m, 2H), 7.33 (m, 2H), 5.75 (m, 1H), 4.55 (dq, J = 2.1, 8.1 Hz, 1H), 3.37 (ddd,, J = 4.5, 6.9, 9.9 Hz, 1H), 3.06 (ddd, J = 6.6, 8.7, 9.9 Hz, 1H), 2.61 (m, 1H), 2.47 (m, 1H), 2.43 (s, 3H), 2.10 (dq, J = 2.1, 17.1 Hz, 1H), 1.83 (m, 1H), 1.51 (m, 1H); 2H NMR (CHCl3) δ 5.81 (s, 1D). Ns N
D
3-d-18
1
H NMR (CDCl3) δ 8.37 (dt, J = 2.1, 9.0 Hz, 2H), 8.03 (dt, J = 2.1, 9.0 Hz, 2H), 5.79 (q, J = 2.1 Hz, 1H), 4.62 (dq, J = 1.8, 7.8 Hz, 1H), 3.40 (ddd,, J = 4.8, 6.9, 9.9 Hz, 1H), 3.15 (ddd, J = 6.6, 8.4, 9.9 Hz, 1H), 2.71 (ddq, J = 2.1, 8.1, 8.1Hz, 1H), 2.55 (ddq, J = 1.5, 2.7, 8.4Hz, 1H), 2.13 (dq, J = 2.1, 17.1 Hz, 1H), 1.94 (m, 1H), 1.61 (m, 1H); 2H NMR (CHCl3) δ 5.68 (s, 1D); 13C NMR (CDCl3) δ 150.2, 144.2, 132.8 (t, J = 24.5 Hz), 130.4, 128.8, 124.5, 70.5, 48.4, 40.2, 38.0, 32.5; HRMS: m/z (EI) calculated [M]+ 296.0815, measured 296.0823. Ns N
D
3-d-19
1
H NMR (CDCl3) δ 8.37 (dt, J = 2.1, 9.0 Hz, 2H), 8.03 (dt, J = 2.1, 9.0 Hz, 2H), 5.49 (m, 1H), 4.25 (m, 1H), 3.22 (m, 2H), 2.73 (m, 2H), 2.24 (m, 1H), 1.75 (m, 2H); 2H NMR (CHCl3) δ 5.67 (s, 1D). Ts N O
21
1
H NMR (CDCl3) δ 7.94 (dt, J = 1.8, 8.1 Hz, 2H), 7.33 (dt, J = 1.8, 8.1 Hz,, 2H), 6.09 (m, 1H), 5.97 (m, 1H), 5.21 (ddq, J = 1.8, 1.5, 8.4 Hz, 1H), 2.99 (m, 1H), 2.71 (m, 2H), 2.43 (s, 3H), 2.22 (m, 2H); 13C NMR (CDCl3) δ 173.1, 145.2, 136.0, 134.7, 130.0, 129.7, 128.4, 69.9, 39.3, 39.2, 32.6, 21.8; HRMS: m/z (ESI) calculated [MNa]+ 300.0670, measured 300.0679. Ts N O
22
1
H NMR (CDCl3) δ 7.94 (dt, J = 1.8, 8.1 Hz, 2H), 7.33 (dt, J = 1.8, 8.1 Hz,, 2H), 5.74 (m, 1H), 5.58 (m, 1H), 4.89 (ddd, J = 3.0, 3.6, 4.8 Hz, 1H), 3.42 (m, 1H), 2.89 (m, 2H), 2.43 (s, 3H), 2.34 (d, J = 3.6 Hz, 2H).
S3
Ts N
D
O
3-d-21
1
H NMR (CDCl3) δ 7.94 (dt, J = 1.8, 8.1 Hz, 2H), 7.33 (dt, J = 1.8, 8.1 Hz,, 2H), 6.09 (q, J = 2.1 Hz, 1H), 5.21 (ddq, J = 1.8, 1.5, 8.4 Hz, 1H), 2.99 (m, 1H), 2.71 (m, 2H), 2.43 (s, 3H), 2.22 (m, 2H); 2H NMR (CHCl3) δ 5.94 (s, 1D). Ts N
D
O
3-d-22
1
H NMR (CDCl3) δ 7.94 (dt, J = 1.8, 8.1 Hz, 2H), 7.33 (dt, J = 1.8, 8.1 Hz,, 2H), 5.58 (m, 1H), 4.89 (ddd, J = 3.0, 3.6, 4.8 Hz, 1H), 3.42 (m, 1H), 2.89 (m, 2H), 2.43 (s, 3H), 2.34 (d, J = 3.6 Hz, 2H); 2H NMR (CHCl3) δ 5.71 (s, 1D). D
Ts N O
trans-2-d-22
1
H NMR (CDCl3) δ 7.94 (dt, J = 1.8, 8.1 Hz, 2H), 7.33 (dt, J = 1.8, 8.1 Hz,, 2H), 5.74 (m, 1H), 5.58 (m, 1H), 4.89 (ddd, J = 3.0, 3.6, 4.8 Hz, 1H), 3.42 (m, 1H), 2.89 (m, 2H), 2.43 (s, 3H), 2.34 (d, J = 3.6 Hz, 2H); 2H NMR (CHCl3) δ 2.88 (s, 1D). Scheme S1. Synthetic Procedure for (E)-10. PhI
OH
+
a
Ph OH S-1
c
Ph
b
Ph
OH S-2
NHTs (E)-10
Reaction conditions: (a) Pd(PPh3)4, CuI, Et3N 98%. (b) LiAlH4, THF, 88%. (c) i) MeSO2Cl, Et3N, CH2Cl2. ii) p-MeC6H4SO2Cl, K2CO3, DMF. 81%.
Synthesis of S-1.1 Pd(PPh3)4 (21 mg, 0.022 mmol) and CuI (7 mg, 0.045 mmol) were added to the solution of iodobenzene (0.48 mL, 4.3 mmol) and 5-hydroxy pentyne (0.2 mL, 2.15 mmol) in triethylamine (6.2 mL, 45 mmol) and THF (1 mL) under N2. The reaction mixture was stirred at rt for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The product was purified by column chromatography to yield the desired alcohol S-1 in 98% yield (340 mg). 1H NMR (300 MHz, CDCl3) δ 7.30 (m, 5H), 3.77 (t, J = 6.0 Hz, 2H), 2.50 (t, J = 6.9 Hz, 2H), 2.23 (s, 1H), 1.82 (p, J = 7.1 Hz, 2H). Synthesis of S-2. To a THF (20 mL) solution of LiAlH4 (0.204 g, 5.4 mmol), the alcohol S-1 (340 mg, 2.13 mmol) was added at 0 °C under N2. The reaction mixture was stirred at 0 °C overnight. The reaction was quenched with wet THF. The product was extracted with diethyl ether (3 times), and the combined organic layers were washed with
S4
brine and dried over anhydrous Na2SO4. The concentrated crude product was further purified by column chromatography to yield the desired alcohol S-2 in 88% yield (303 mg). 1H-NMR (300 MHz, CDCl3) δ 7.30 (m, 5H), 6.42 (d, J = 15.7 Hz, 1H), 6.23 (dt, J = 15.9, 6.9 Hz, 1H), 3.68 (t, J = 6.6 Hz, 2H), 2.31 (s, 1H), 2.31 (q, J = 6.9 Hz, 2H), 1.74 (p, J = 6.9 Hz, 2H). Synthesis of (E)-10. Under a nitrogen atmosphere, to a solution of S-2 (300 mg, 1.9 mmol) and Et3N (1 mL, 7 mmol) in dichloromethane (20 mL), was added MsCl (0.28 mL, 3 mmol) at 0 °C. The mixture was stirred overnight at room temperature. After the reaction was completed, water (20 mL) was added. The mixture was extracted with dichloromethane. The dichloromethane solution was dried with MgSO4. After the solvent was removed under reduced pressure, the crude oil was obtained. After the crude oil was dissolved in DMF (20 mL), p-toluenesulfonamide (TsNH2) (2.8 g, 14 mmol) and K2CO3 (1.9 g, 14 mmol) were added to the DMF solution, and the mixture was stirred overnight at 80 °C. The mixture was cooled to 0 °C and neutralized with 2N HCl. The solution was extracted with diethyl ether and dried with MgSO4. After the solvent was removed, the crude oil was purified by silica gel chromatography to provide (E)-10 (484 mg, 81% yield). 1H NMR (CDCl3) δ 7.74 (dt, J = 2.1, 8.4 Hz, 2H), 7.31-7.20 (m, 7H), 6.33 (dt, J = 1.5, 15.9 Hz, 1H), 6.08 (dt, J = 6.9, 15.9 Hz, 1H), 4.48 (t, J = ? Hz, 1H), 2.99 (dt, J = 6.9, 6.3 Hz, 2H), 2.41 (s, 3H), 2.22 (m, 2H), 1.66 (m, 2H); 13C NMR (CDCl3) δ 143.6, 137.6, 137.2, 131.2, 129.9, 129.1, 128.7, 127.3, 126.2, 42.8, 30.1, 29.4, 21.7; HRMS: m/z (ESI) calculated [MNa]+ 338.1191, measured 338.1201. Scheme S2. Synthetic Procedure for (Z)-10. d
O +
Ph
c
PhMgBr
Ph NHTs
OH S-3
(Z)-10
Reaction conditions: (d) (Ph3P)2NiCl2, Toluene, 89%. (c) i) MeSO2Cl, Et3N, CH2Cl2. ii) pMeC6H4SO2Cl, K2CO3, DMF, 81%.
Synthesis of S-3.2 An ether solution of PhMgBr (1 mL, 1.0 M) was added to a stirring suspension of (Ph3P)2NiCl2 (623 mg, 1.0 mmol) in 100 mL dry toluene under N2. The stirring was continued at room temperature for 15 min. At the end of this period, additional PhMgBr (10 mL, 1.0 M) was added, followed by addition of dihydropyran (3 mL, 33 mmol). The solution was refluxed under N2 overnight. The cooled reaction mixture was poured into a saturated ammonium chloride solution and extracted with ether. The extract was dried with Na2SO4 and evaporated, and the residue was purified by silica gel chromatography to give the alcohol S-3 in 88% yield (1.58 g). 1H NMR (300 MHz, CDCl3) δ 1.71 (p, J = 6.9 Hz, 2H), 2.44 (m, 3H), 3.62 (t, J = 6.6 Hz, 2H), 5.68 (dt, J = 11.8, 7.4 Hz, 1H), 4.47 (d, J = 11.5 Hz, 1H), 7.30 (m, 5H). Synthesis of (Z)-10. The same protocol used in the preparation of (E)-10 was employed (see above) (81% yield). 1H NMR (CDCl3) δ 7.70 (dt, J = 1.8, 8.4 Hz, 2H), 7.35-7.19 (m, 7H), 6.43 (d, J = 11.7 Hz, 1H), 5.54 (dt, J = 7.5, 11.7 Hz, 1H), 4.33 (t, J = ?, 1H), 2.95 (q, J = 6.9 Hz, 2H), 2.42 (s, 3H), 2.31 (m, 2H), 1.60 (m, 2H); 13C NMR (CDCl3)
S5
δ 143.6, 137.4, 137.2, 131.2, 130.3, 129.9, 128.9, 128.5, 127.3, 127.0, 43.0, 30.0, 25.7, 21.7; HRMS: m/z (ESI) calculated [MNa]+ 338.1191, measured 338.1195. Scheme S3. Synthetic Procedure for trans-3-d-13. a
b
OTs
3
c
OTs
2
OAc
OTBDMS
S-4
S-5
4 5 1
3
d
D
2
OTBDMS
4 5 1
D
OAc
trans-5-d-S-6
trans-5-d-S-7
HOOC e
3 1 2
trans-3-d-S-8
D
f
HO
3 1 2
trans-3-d-S-9
D
g
TsHN
3 1
D
2
trans-3-d-13
Reaction condition: (a) i) Pb(OAc)4, HOAc/H2O. ii) p-MeC6H4SO2Cl, Et3N, Me3NHCl, CH2Cl2. two step 39%. (b) i) K2CO3, MeOH. ii) t-BuMe2SiCl, Imidazole. two step 85%. (c) LiBEt3D, THF, 88%. (d) i) Tetrabutylammonium fluorode, THF. ii) Acetic anhydride, Pyridine. two step 70%. (e) Lithium Diisopropylamine, t-BuMe2SiCl, THF. 73%. (f) LiAlH4, Et2O. 91%. (g) i) MeSO2Cl, Et3N, CH2Cl2. ii) K2CO3, p-MeC6H4SO2NH2, DMF, two step 81%.
Synthesis of S-4.3,4Freshly cracked cyclopentadiene (22 g) was slowly added to a magnetically stirred and chilled (ice water bath) mixture of Pb(OAc)4 (100g), acetate acid (200 mL) and water (9 mL) maintained under a nitrogen atmosphere. Shortly after completion of the addition of cyclopentadiene, the reaction mixture became homogenous, after which point the ice-water bath was removed. Stirring was continued for 1 h, then the reaction mixture was poured into diethyl ether (500 mL), and the supernatant was decanted and filtered through a pad of TLC-grade silica gel. The filtrate was treated with Na2CO3 (100 g) and the resulting mixture was stirred vigorously at room temperature overnight. The resulting precipitate was removed by filtration and washed with diethyl ether. Then the combined filtrates were concentrated under reduced pressure to give a light-yellow oil. Distillation of this oil afforded a ca. 1:0.8 mixture of regioisomeric mono-acetates of cis-cyclopent-3-ene-1,2-diol (23g, 67% yield) as a clear colorless oil. To a stirred solution of the mixture of regioisomerIC mono-acetates (19 g), Et3N (27 g) and Me3NHCl (9.5g) in 300 mL of dry dichloromethane, p-toluenesulfonyl chloride (TsCl) (29 g) was added at 0 °C. The mixture was stirred at the same temperature for 5 h. The reaction was poured into water, and it was extracted with dichloromethane. The organic layers were dried with MgSO4. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography to give S-4 (21 g, yield 52 %). 1 H NMR (CDCl3) δ 7.80 (dd, J = 6.3, 1.8 Hz, 2H), 7.35 (dd, J = 6.3, 1.8 Hz, 2H), 5.99 (m, 1H), 5.78 (m, 1H), 5.50 (m, 1H), 5.01 (q, J = 5.7 Hz, 1H), 2.64 (m, 2H), 2.45 (s, 3H), 1.98 (s, 3H); 13C NMR (CDCl3) δ 170.4, 145.1, 134.1, 133.9, 130.0, 128.3, 128.1, 112.4, 75.3, 37.3, 21.9, 21.0; HRMS: m/z (ESI) calculated [MNa]+ 319.0616, measured 319.0621. Synthesis of S-5. K2CO3 (13.8 g, 100 mmol) was added to a solution of S-4 (21g, 71 mmol) in MeOH (300 mL). The reaction was monitored by TLC. After the reaction S6
finished, a mixture of diethyl ether and hexane (600 mL, v/v 1:1) was added and the solution was filtered through a pad of TLC-grade silica gel. The solvent was removed under reduced pressure to give a colorless oil (15 g). Under a nitrogen atmosphere, the oil was dissolved in dry THF (250 mL), after which imidazole (6.8 g, 100 mmol) and tertbutyldimethylsilyl chloride (TBDMSCl) (10.5g, 70 mmol) were added. The mixture was stirred at room temperature overnight. The reaction was quenched with 50 mL 2N HCl. The mixture was extracted by diethyl ether, and the combined organic layers were dried with MgSO4. After removal of the solvent, the crude product was purified by silica gel chromatography to give S-5 (20.4 g, 85% yield). 1H NMR (CDCl3) δ 7.82 (dd, J = 6.3, 1.8 Hz, 2H), 7.33 (dd, J = 6.3, 1.8 Hz, 2H), 5.78 (m, 2H), 4.82 (dt, J = 5.4, 6.6 Hz, 1H), 4.64 (m, 1H), 2.57-2.34 (m, 2H), 2.45 (s, 3H), 0.87 (s, 9H) 0.07 (s, 6H); 13C NMR (CDCl3) δ 144.7, 134.6, 132.2, 131.4, 129.9, 128.1, 79.5, 74.9, 36.1, 26.0, 21.8, 18.6, -4.4, -4.6; HRMS: m/z (ESI) calculated [MNa]+ 391.1375, measured 391.1384. Synthesis of trans-5-d-S-6. Lithium triethylborodeuteride (super-deuteride) (60 mmol, 60 mL, 1.0 M) in THF was added to a solution of S-5 (7.7 g, 21 mmol) in dry THF (70 mL) at -20 °C. The mixture was heated to 45 °C and stirred at the same temperature for 24 hrs. The reaction was monitored by TLC. After the reaction was almost complete, 1 mL water, followed by 40 mL 15% NaOH and 40 mL 30% H2O2 were added to quench excess super-deuteride. The mixture was extracted with diethyl ether. The organic layer was washed with brine and dried with MgSO4. The solvent was removed under vacuum and the residue was purified by silica gel chromatography to give trans-5-d-S-6 (3.6 g, 88% yield). 1H NMR (CDCl3) δ 5.91 (m, 1H), 5.72 (m, 1H), 4.92 (m, 1H), 2.48 (m, 1H), 2.21 (m, 1H), 1.64 (m, 1H), 0.91 (s, 9H), 0.09 (s, 6H); 2H NMR (CHCl3) δ 2.290 (s, 1D); 13 C NMR (CDCl3) δ 134.1, 133.7, 78.3, 33.4 (t, J = 20.2 Hz), 31.1, 26.2, 18.5, -4.30, 4.33; HRMS: m/z (ESI) calculated [M]+ 199.1503, measured 199.1473. Synthesis of trans-5-d-S-7. To a solution of trans-5-d-S-6 (5.1 g, 26 mmol) in 60 mL dry THF, 40 mL tetrabutylammonium fluoride (TBAF; 1.0 M in hexane) was added at room temperature. The mixture was stirred overnight. Brine (30 mL) was added, and the mixture was extracted with diethyl ether. The organic layer was washed with brine and dried with MgSO4. The solvent was removed by distillation at ambient pressure. After the residue was dissolved in pyridine (20 mL), acetic anhydride (7 mL) and DMAP (200 mg) were added at room temperature. The mixture was stirred overnight. After the reaction was complete, the mixture was poured into 200 mL diethyl ether and washed by 2N HCl (about 50 mL). The organic layer was washed with water, brine and dried with MgSO4. After removal of the solvent, the residue was purified by silica gel chromatography (pentane/diethyl ether, 4/1) to give trans-5-d-S-7 (2.3 g, 70% yield). 1H NMR (CDCl3) δ 6.10 (m, 1H), 5.82 (m, 1H), 5.68 (m, 1H), 2.48 (m, 1H), 2.34 (m, 1H), 2.03 (s, 3H), 1.80 (m, 1H); 2H NMR (CHCl3) δ 2.36 (s, 1D); 13C NMR (CDCl3) δ 171.2, 137.7, 129.5, 80.6, 31.1, 29.7 (t, J = 20.2 Hz), 21.5. Synthesis of trans-3-d-S-8.5 To a solution of iPr2NH (3.0 g, 30 mmol) in dry THF (40 mL) at -78 °C was added nBuLi (12 mL, 2.5 M in hexane). The solution was warmed to 0 °C and stirred for an additional 30 min, then recooled to -78 °C. tert-Butyldimethylsilyl chloride (TBDMSCl) (5.2 g, 35 mmol) was added followed by trans-5-d-S-7 (2.3 g, 19 mmol) in 20 mL dry THF over a 20 min period. The mixture was stirred at -78 °C for 20 min, warmed to room temperature, and stirred for an additional 2 h. The solution was then heated at reflux overnight, cooled to 0 °C and treated with 10 mL of conc. HCl. The
S7
mixture was stirred at 0 °C for 1 h, then diluted with diethyl ether. The aqueous layer was extracted with diethyl ether. The combined organic layers were dried with MgSO4. The solvent was removed under vacuum and the residue was purified by silica gel chromatography to give trans-3-d-S-8 (1.6 g, 73% yield). 1H NMR (CDCl3) δ 5.79 (m, 1H), 5.70 (m, 1H), 3.11 (m, 1H), 2.48-2.30 (m, 3H), 2.15 (m, 1H), 1.49 (m, 1H); 2H NMR (CHCl3) δ 2.39 (s, 1D); 13C NMR (CDCl3) δ 179.3, 133.7, 131.9, 42.0, 40.4, 31.7 (t, J = 20.2 Hz), 29.7; HRMS: m/z (ESI) calculated [MNa]+ 253.1409, measured 253.1400. Synthesis of trans-3-d-S-9. To a solution of LiAlH4 (1.2g, 34 mmol) suspended in dry THF (30 mL) was added trans-3-d-S-8 (1.6 g, 12.7 mmol) slowly at 0 °C under a nitrogen atmosphere. The mixture was stirred overnight at room temperature. Water (0.5 mL) was added slowly to quench excess LiAlH4 at 0 °C. Then 5 mL 40% NaOH(aq) was added. The mixture was stirred for 30 min and filtered. The solid was washed with diethyl ether (3X). The combined diethyl ether solutions were dried with MgSO4. The solvent was removed under vacuum and the residue was purified by silica gel chromatography to give trans-3-d-S-9 (1.3 g, 11.6 mmol, 91% yield). 1H NMR (CDCl3) δ 5.74 (m, 1H), 5.69 (m, 1H), 3.69 (m, 2H), 2.77 (m, 1H), 2.34 (m, 1H), 2.06 (m, 1H), 1.73-1.53 (m, 3H), 1.45(m, 1H); 2H NMR (CHCl3) δ 2.36 (s, 1D); 13C NMR (CDCl3) δ 134.9, 130.8, 62.0, 42.4, 39.1, 31.8 (t, J = 19.9 Hz), 29.9. Synthesis of trans-3-d-13. MsCl (1.4 mL, 15 mmol) was added to a solution of trans-3d-S-9 (1.1g, 10mmol) and Et3N (5 mL, 37 mmol) in dichloromethane (50 mL) under a nitrogen atmosphere at 0 °C. The mixture was stirred overnight at room temperature. After the reaction was complete, water (20 mL) was added. The mixture was extracted with dichloromethane. The dichloromethane solution was dried with MgSO4. After the solvent was removed under reduced pressure, a crude oil was obtained. The crude oil was dissolved in DMF (100 mL). Then p-toluenesulfonamide (TsNH2) (14 g, 70 mmol) and K2CO3 were added to the DMF solution, and the mixture was stirred overnight at 80 °C. The mixture was cooled to 0 °C and neutralized with 2N HCl. The solution was extracted with diethyl ether and dried with MgSO4. After the solvent was removed, the crude oil was purified by silica gel chromatography to give trans-3-d-13 (2.1 g, 81% yield). 1H NMR (CDCl3) δ 7.76 (dt, J = 2.1, 9.0 Hz, 2H), 7.31 (dt, J = 2.1, 9.0 Hz, 2H), 5.71 (m, 1H), 5.56 (m, 1H), 4.58 (t, J = 6.0 Hz, 1H), 2.98 (dt, J = 6.6, 6.6 Hz, 2H), 2.65 (m, 1H), 2.44 (s, 3H), 2.28 (m, 1H), 1.98 (m, 1H), 1.63-1.38 (m, 2H), 1.32(m, 1H); 2H NMR (CHCl3) δ 2.31 (s, 1D); 13C NMR (CDCl3) δ 143.6, 137.2, 134.0, 131.4, 129.9, 127.3, 43.0, 42.1, 35.9, 31.7 (t, J = 19.8 Hz), 29.6, 21.7; HRMS: m/z (EI) calculated [M]+ 266.1199, measured 266.1198. Synthesis of trans-3-d-17. The same protocol used in the preparation of trans-3-d-13 was employed (see above) (85% yield). 1H NMR (CDCl3) δ 8.38 (dt, J = 2.1, 8.7 Hz, 2H), 8.07 (dt, J = 2.1, 8.7 Hz, 2H), 5.73 (m, 1H), 5.56 (m, 1H), 4.91 (t, J = 6.0 Hz, 1H), 3.06 (dt, J = 7.2, 6.3 Hz, 2H), 2.66 (m, 1H), 2.28 (m, 1H), 1.98 (m, 1H), 1.64-1.45 (m, 2H), 1.32(m, 1H); 2H NMR (CHCl3) δ 2.33 (s, 1D); 13C NMR (CDCl3) δ 150.3, 146.2, 133.6, 131.8, 128.5, 124.6, 42.8, 42.3, 35.9, 31.7 (t, J = 20.2 Hz), 29.5; HRMS: m/z (EI) calculated [M-H]+ 296.0815, measured 296.0805. Synthesis of trans-3-d-20. To a solution of trans-3-d-S-8 (0.7 g, 5.5 mmol) in dry THF (10 mL), TsNCO (1.2g, 6 mmol) was added under nitrogen. The mixture was stirred for 30 min, then Et3N (1 mL) was added. The mixture was stirred overnight, and a 2N HCl solution (10 mL) was added. The mixture was extracted with diethyl ether. The combined
S8
organic layer was washed with brine and dried over MgSO4. The solvent was removed under vacuum, and the residue was purified by silica gel chromatography to give a white solid (1.3 g, 91% yield). 1H NMR (CDCl3) δ 8.7 (br s, 1H), 7.95 (d, J = 8.1 Hz, 2H), 7.35 (dt, J = 8.1 Hz, 2H), 5.74 (m, 1H), 5.54 (m, 1H), 3.02 (m, 1H), 2.45 (s, 3H), 2.36-2.20 (m, 3H), 2.03 (m, 1H), 1.35(m, 1H); 2H NMR (CHCl3) δ 2.19; 13C NMR (CDCl3) δ 170.3, 145.3, 135.8, 133.1, 132.5, 129.8, 128.5, 42.5, 41.8, 31.6 (t, J = 20.2 Hz), 29.4, 21.9; HRMS: m/z (EI) calculated [M]+ 280.0992, measured 280.0981. Scheme S4. Synthetic Procedure for cis-3-d-13. 3 2
4 5 1
D
OTBDMS trans-5-d-S-6
d(i)
3 2
4
4 5
1
D
h
H (11% D)
3 2
5 1
D
H (16% D) e,f,g
(89% D)
OH
OAc
trans-5-d-S-10
cis-5-d-S-7
TsHN
3 1 2
D (84% D)
cis-3-d-13
Reactions condition: (d) i) Tetrabutylammonium fluorode, THF. (h) PPh3, Diisopropyl azodicarboxylate, HOAc, Et2O, 59%. (e) Lithium Diisopropylamine, t-BuMe2SiCl, THF. (f) LiAlH4, Et2O. (g) i) MeSO2Cl, Et3N, CH2Cl2. ii) K2CO3, p-MeC6H4SO2NH2, DMF, three steps 25%.
Synthesis of trans-5-d-S-7. Diisopropyl azodicarboxylate (2.3 mL, 11.8 mmol, 2eq) was added dropwise to a stirred solution of trans-5-d-cyclopent-2-en-1-ol (500mg, 5.9 mmol, 1eq), PPh3 (3.1g, 11.8 mmol, 2eq), and acetic acid (0.7 mL, 11.8 mmol, 2eq) in diethyl ether (50 mL) at -85 °C under a nitrogen atmosphere. The reaction mixture was stirred for 6 h and 10% NaHCO3 (20 mL) was added. The mixture was warmed to room temperature and extracted with diethyl ether (3x50 mL). The combined organic layer was dried with MgSO4, filtered and concentrated under vacuum. Purification by flash chromatography (silica gel, diethyl ether/pentane) gave the mixture of cis-5-d-S-7 and cis-4-d-S-7 in ratio 89/11 with 59% yield. cis-5-d-S-7: 1H NMR (CDCl3) δ 6.11 (m, 1H), 5.82 (m, 1H), 5.69 (m, 1H), 2.50 (m, 1H), 2.29 (m, 2H), 2.03 (s, 3H); 2H NMR (CHCl3) δ 1.75 (s, 1D); 13C NMR (CDCl3) δ 171.2, 137.7, 129.5, 80.7, 31.1, 29.7 (t, J = 20.2 Hz), 21.5; cis-4-d- S-7: 1H NMR (CDCl3) δ 6.11 (m, 1H), 5.82 (m, 1H), 5.69 (m, 1H), 2.29 (m, 2H), 2.03 (s, 3H), 1.82 (m, 1H); 2H NMR (CHCl3) δ 2.45 (s, 1D). Synthesis of cis-3-d-13. The procedure is the same as that for trans-3-d-13. cis-3-d-13: 1 H NMR (CDCl3) δ 7.76 (dt, J = 2.1, 9.0 Hz, 2H), 7.31 (dt, J = 2.1, 9.0 Hz, 2H), 5.71 (m, 1H), 5.56 (m, 1H), 4.75 (t, J = 6.0 Hz, 1H), 2.97 (dt, J = 6.6, 6.6 Hz, 2H), 2.64 (m, 1H), 2.43 (s, 3H), 2.22 (m, 1H), 1.98 (m, 1H), 1.63-1.38 (m, 2H), 1.32(m, 1H); 2H NMR (CHCl3) δ 2.20 (s, 1D); 13C NMR (CDCl3) δ 143.5, 137.0, 134.0, 131.3, 129.9, 127.3, 42.8, 42.1, 35.8, 31.7 (t, J = 20.1 Hz), 29.5, 21.7; HRMS: m/z (ESI) calculated [MNa]+ 289.1097, measured 289.1106. Oxidative Cyclization of cis-3-d-13. The general procedure outlined above for oxidative cyclization reactions was followed for both the Pd(OAc)2/DMSO and Pd(OAc)2/py catalyst systems (eqs S1 and S2). Use of both catalyst systems results in formation of the unlabeled product 14, consistent with a cis-aminopalladation pathway.
S9
2 3
D (84% D)
1
TsHN
4
H (16% D)
5% Pd(OAc)2 2 equiv NaOAc DMSO, O2 (1 atm) 80 oC
3
D (84% D)
1
TsHN
4
H (16% D)
cis-3-d-13
(S1) H (13% D) 14 (81% yield)
cis-3-d-13
2
Ts N
5% Pd(OAc)2 10% pyridine toluene, O2 (1 atm) 80 oC
Ts N
(S2)
H (12% D) 14 (88% yield)
(S1) Carson, J. R.; Almond, H. R.; Brannan, M. D.; Carmosin, R. J.; Flaim, S. F.; Gill, A.; Gleason, M. M.; Keely, S. L.; Ludovici, D. W.; Pitis, P. M.; Rebarchak, M. C.; Villani, F. J. J. Med. Chem. 1988, 31, 630-636. (S2) Wenkert, E.; Michelotti, E. L.; Swindell, C. S.; Tingoli, M. J. Org. Chem. 1984, 49, 4894-4899. (S3) Banwell, M. G.; Ebenbeck, W.; Edwards, A. J. J. Chem. Soc., Perkin Trans. 1, 2001, 114-117. (S4) Yoshida, Y.; Sakakura, Y.; Aso, N.; Okada, S.; Tanabe, Y. Tetrahedron 1999, 55, 2183-2185. (S5) Hu, Q.-Y.; Rege, P. D.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 5984-5986.
S10
Representative NMR Spectra obtained in the aerobic oxidative amination of all-protio substrate 13 and mono-deuterated substrate trans-3-d-13 (cf. Table 4 of the manuscript):
S11
S12
S13
The Two-Faced Reactivity of Alkenes: Cis- Versus Trans-Aminopalladation in Aerobic PdCatalyzed Intramolecular Aza-Wacker Reactions Guosheng Liu and Shannon S. Stahl* Department of Chemistry, University of Wisconsin-Madison 1101 University Avenue, Madison, WI, 53706
General Considerations. All commercially available compounds were used as received, and were purchased from Aldrich or Acros. 1H and 13C NMR spectra were recorded on Bruker AC-300 MHz spectrometers. 2H NMR spectra was recorded on the Varian 500 MHz spectrometers. The chemical shifts (δ) are given in part per million relative to CDCl3 (7.27 ppm for 1H, and 77.23 ppm for 13C). Flash chromatography was performed on silica gel 60 (particle size 0.040-0.063 mm, 230-400 mesh ASTM, purchased from Sorbent Technology) with hexanes/ethyl acetate. Typical procedure for palladium-catalyzed aerobic oxidative cyclization. Pd(OAc)2 (5 µmol) was placed in 13x100 mm disposable culture tubes. The reaction tubes were placed into a custom 48-well parallel reactor mounted on a Large Capacity Mixer (GlasCol) and the headspace was purged with molecular oxygen for ca. 15 min. Solutions of pyridine (10 µmol) in toluene (0.5 mL) and (E)-10 (0.1 mmol) in toluene (0.5 mL) were added to tubes. The reactions were carried out for 24 h under an oxygen atmosphere (1 atm) at 80 °C. Following removal of the solvent under vacuum, the crude oxidative amination product yield was evaluated by 1H NMR spectroscopy and integrated relative to the internal standard (1,3,5-tri-t-butylbenzene). Procedure for Pd-catalyzed oxidative amination of trans-3-d-13 using stoichiometric benzoquinone as the oxidant. A mixture of PdCl2(CH3CN)2 (10 µmol), benzoquinone (0.1 mmol), LiCl (0.2 mmol), Na2CO3 (0.2 mmol) and trans-3-d-13 (0.1 mmol) in THF (2 mL) was refluxed for 24 hours. The oxidative amination product yield was evaluated by 1H NMR spectroscopy and integrated relative to the internal standard (1,3,5-trimethoxybenzene).
S1
Compound Characterization Data.
1
N Ts
Ph
(Z)-12
H NMR (CDCl3) δ 7.67 (m, 4H), 7.32-7.15 (m, 5H), 6.09 (s, 1H), 3.66 (t, J = 7.2 Hz, 2H), 2.42 (s, 3H), 2.09 (m, 2H), 1.56 (m, 2H); 13C NMR (CDCl3) δ 144.0, 138.4, 136.5, 135.2, 129.7, 129.0, 128.0, 127.9, 127.0, 119.5, 51.2, 32.3, 21.7, 21.3; HRMS: m/z (ESI) calculated [MNa]+ 336.1034, measured 336.1024. Ph
1
(E)-12
N Ts
H NMR (CDCl3) δ 7.76 (dt, J = 1.8, 8.4 Hz, 2H), 7.32-7.26 (m, 4H), 7.16 (m, 3H), 6.87 (t, J = 2.1 Hz, 1H), 3.66 (t, J = 6.9 Hz, 2H), 2.49 (dt, J = 2.1, 7.2 Hz, 2H), 2.42 (s, 3H), 1.80 (m, 2H); 13C NMR (CDCl3) δ 144.2, 140.3, 137.8, 134.8, 129.8, 128.5, 128.4, 127.7, 126.1, 110.7, 50.7, 30.4, 22.6, 21.8; HRMS: m/z (ESI) calculated [M]+ 313.1137, measured 313.1136. Ts N
14
1
H NMR (CDCl3) δ 7.73 (m, 2H), 7.33 (m, 2H), 5.81 (m, 1H), 5.75 (m, 1H), 4.55 (dq, J = 2.1, 8.1 Hz, 1H), 3.37 (ddd,, J = 4.5, 6.9, 9.9 Hz, 1H), 3.06 (ddd, J = 6.6, 8.7, 9.9 Hz, 1H), 2.61 (m, 1H), 2.47 (m, 1H), 2.43 (s, 3H), 2.11 (dq, J = 2.1, 17.1Hz, 1H), 1.83 (m, 1H), 1.51 (m, 1H); Ts N
D
3-d-14
1
H NMR (CDCl3) δ 7.73 (m, 2H), 7.33 (m, 2H), 5.81 (q, J = 2.1 Hz, 1H), 4.55 (dq, J = 2.1, 8.1 Hz, 1H), 3.37 (ddd,, J = 4.5, 6.9, 9.9 Hz, 1H), 3.06 (ddd, J = 6.6, 8.7, 9.9 Hz, 1H), 2.61 (m, 1H), 2.47 (m, 1H), 2.43 (s, 3H), 2.10 (dq, J = 2.1, 17.1 Hz, 1H), 1.83 (m, 1H), 1.51 (m, 1H); 2H NMR (CHCl3) δ 5.72 (s, 1D); 13C NMR (CDCl3) δ 143.5, 135.0, 131.9 (t, J = 25.0 Hz), 131.3, 129.8, 127.8, 70.2, 48.4, 40.0, 38.0, 32.5, 21.7; HRMS: m/z (EI) calculated [M]+ 264.1043, measured 264.1034. Ts N
D
3-d-15
1
H NMR (CDCl3) δ 7.73 (m, 2H), 7.33 (m, 2H), 5.45 (q, J = 2.1 Hz, 1H), 4.18 (dt, J = 6.9, 4.2 Hz, 1H), 3.40-3.20 (m, 2H), 2.71 (m, 2H), 2.43 (s, 3H), 2.22 (m, 1H), 1.68-1.48 (m, 2H); 2H NMR (CHCl3) δ 5.72 (s, 1D). D
Ts N
trans-2-d-15
S2
1
H NMR (CDCl3) δ 7.73 (m, 2H), 7.33 (m, 2H), 5.72 (m, 1H), 5.45 (m, 1H), 4.18 (dt, J = 6.9, 4.2 Hz, 1H), 3.40-3.20 (m, 3H), 2.71 (m, 1H), 2.43 (s, 3H), 1.68-1.48 (m, 2H); 2H NMR (CHCl3) δ 2.68 (s, 1D). D
Ts N
2-d-14
1
H NMR (CDCl3) δ 7.73 (m, 2H), 7.33 (m, 2H), 5.75 (m, 1H), 4.55 (dq, J = 2.1, 8.1 Hz, 1H), 3.37 (ddd,, J = 4.5, 6.9, 9.9 Hz, 1H), 3.06 (ddd, J = 6.6, 8.7, 9.9 Hz, 1H), 2.61 (m, 1H), 2.47 (m, 1H), 2.43 (s, 3H), 2.10 (dq, J = 2.1, 17.1 Hz, 1H), 1.83 (m, 1H), 1.51 (m, 1H); 2H NMR (CHCl3) δ 5.81 (s, 1D). Ns N
D
3-d-18
1
H NMR (CDCl3) δ 8.37 (dt, J = 2.1, 9.0 Hz, 2H), 8.03 (dt, J = 2.1, 9.0 Hz, 2H), 5.79 (q, J = 2.1 Hz, 1H), 4.62 (dq, J = 1.8, 7.8 Hz, 1H), 3.40 (ddd,, J = 4.8, 6.9, 9.9 Hz, 1H), 3.15 (ddd, J = 6.6, 8.4, 9.9 Hz, 1H), 2.71 (ddq, J = 2.1, 8.1, 8.1Hz, 1H), 2.55 (ddq, J = 1.5, 2.7, 8.4Hz, 1H), 2.13 (dq, J = 2.1, 17.1 Hz, 1H), 1.94 (m, 1H), 1.61 (m, 1H); 2H NMR (CHCl3) δ 5.68 (s, 1D); 13C NMR (CDCl3) δ 150.2, 144.2, 132.8 (t, J = 24.5 Hz), 130.4, 128.8, 124.5, 70.5, 48.4, 40.2, 38.0, 32.5; HRMS: m/z (EI) calculated [M]+ 296.0815, measured 296.0823. Ns N
D
3-d-19
1
H NMR (CDCl3) δ 8.37 (dt, J = 2.1, 9.0 Hz, 2H), 8.03 (dt, J = 2.1, 9.0 Hz, 2H), 5.49 (m, 1H), 4.25 (m, 1H), 3.22 (m, 2H), 2.73 (m, 2H), 2.24 (m, 1H), 1.75 (m, 2H); 2H NMR (CHCl3) δ 5.67 (s, 1D). Ts N O
21
1
H NMR (CDCl3) δ 7.94 (dt, J = 1.8, 8.1 Hz, 2H), 7.33 (dt, J = 1.8, 8.1 Hz,, 2H), 6.09 (m, 1H), 5.97 (m, 1H), 5.21 (ddq, J = 1.8, 1.5, 8.4 Hz, 1H), 2.99 (m, 1H), 2.71 (m, 2H), 2.43 (s, 3H), 2.22 (m, 2H); 13C NMR (CDCl3) δ 173.1, 145.2, 136.0, 134.7, 130.0, 129.7, 128.4, 69.9, 39.3, 39.2, 32.6, 21.8; HRMS: m/z (ESI) calculated [MNa]+ 300.0670, measured 300.0679. Ts N O
22
1
H NMR (CDCl3) δ 7.94 (dt, J = 1.8, 8.1 Hz, 2H), 7.33 (dt, J = 1.8, 8.1 Hz,, 2H), 5.74 (m, 1H), 5.58 (m, 1H), 4.89 (ddd, J = 3.0, 3.6, 4.8 Hz, 1H), 3.42 (m, 1H), 2.89 (m, 2H), 2.43 (s, 3H), 2.34 (d, J = 3.6 Hz, 2H).
S3
Ts N
D
O
3-d-21
1
H NMR (CDCl3) δ 7.94 (dt, J = 1.8, 8.1 Hz, 2H), 7.33 (dt, J = 1.8, 8.1 Hz,, 2H), 6.09 (q, J = 2.1 Hz, 1H), 5.21 (ddq, J = 1.8, 1.5, 8.4 Hz, 1H), 2.99 (m, 1H), 2.71 (m, 2H), 2.43 (s, 3H), 2.22 (m, 2H); 2H NMR (CHCl3) δ 5.94 (s, 1D). Ts N
D
O
3-d-22
1
H NMR (CDCl3) δ 7.94 (dt, J = 1.8, 8.1 Hz, 2H), 7.33 (dt, J = 1.8, 8.1 Hz,, 2H), 5.58 (m, 1H), 4.89 (ddd, J = 3.0, 3.6, 4.8 Hz, 1H), 3.42 (m, 1H), 2.89 (m, 2H), 2.43 (s, 3H), 2.34 (d, J = 3.6 Hz, 2H); 2H NMR (CHCl3) δ 5.71 (s, 1D). D
Ts N O
trans-2-d-22
1
H NMR (CDCl3) δ 7.94 (dt, J = 1.8, 8.1 Hz, 2H), 7.33 (dt, J = 1.8, 8.1 Hz,, 2H), 5.74 (m, 1H), 5.58 (m, 1H), 4.89 (ddd, J = 3.0, 3.6, 4.8 Hz, 1H), 3.42 (m, 1H), 2.89 (m, 2H), 2.43 (s, 3H), 2.34 (d, J = 3.6 Hz, 2H); 2H NMR (CHCl3) δ 2.88 (s, 1D). Scheme S1. Synthetic Procedure for (E)-10. PhI
OH
+
a
Ph OH S-1
c
Ph
b
Ph
OH S-2
NHTs (E)-10
Reaction conditions: (a) Pd(PPh3)4, CuI, Et3N 98%. (b) LiAlH4, THF, 88%. (c) i) MeSO2Cl, Et3N, CH2Cl2. ii) p-MeC6H4SO2Cl, K2CO3, DMF. 81%.
Synthesis of S-1.1 Pd(PPh3)4 (21 mg, 0.022 mmol) and CuI (7 mg, 0.045 mmol) were added to the solution of iodobenzene (0.48 mL, 4.3 mmol) and 5-hydroxy pentyne (0.2 mL, 2.15 mmol) in triethylamine (6.2 mL, 45 mmol) and THF (1 mL) under N2. The reaction mixture was stirred at rt for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The product was purified by column chromatography to yield the desired alcohol S-1 in 98% yield (340 mg). 1H NMR (300 MHz, CDCl3) δ 7.30 (m, 5H), 3.77 (t, J = 6.0 Hz, 2H), 2.50 (t, J = 6.9 Hz, 2H), 2.23 (s, 1H), 1.82 (p, J = 7.1 Hz, 2H). Synthesis of S-2. To a THF (20 mL) solution of LiAlH4 (0.204 g, 5.4 mmol), the alcohol S-1 (340 mg, 2.13 mmol) was added at 0 °C under N2. The reaction mixture was stirred at 0 °C overnight. The reaction was quenched with wet THF. The product was extracted with diethyl ether (3 times), and the combined organic layers were washed with
S4
brine and dried over anhydrous Na2SO4. The concentrated crude product was further purified by column chromatography to yield the desired alcohol S-2 in 88% yield (303 mg). 1H-NMR (300 MHz, CDCl3) δ 7.30 (m, 5H), 6.42 (d, J = 15.7 Hz, 1H), 6.23 (dt, J = 15.9, 6.9 Hz, 1H), 3.68 (t, J = 6.6 Hz, 2H), 2.31 (s, 1H), 2.31 (q, J = 6.9 Hz, 2H), 1.74 (p, J = 6.9 Hz, 2H). Synthesis of (E)-10. Under a nitrogen atmosphere, to a solution of S-2 (300 mg, 1.9 mmol) and Et3N (1 mL, 7 mmol) in dichloromethane (20 mL), was added MsCl (0.28 mL, 3 mmol) at 0 °C. The mixture was stirred overnight at room temperature. After the reaction was completed, water (20 mL) was added. The mixture was extracted with dichloromethane. The dichloromethane solution was dried with MgSO4. After the solvent was removed under reduced pressure, the crude oil was obtained. After the crude oil was dissolved in DMF (20 mL), p-toluenesulfonamide (TsNH2) (2.8 g, 14 mmol) and K2CO3 (1.9 g, 14 mmol) were added to the DMF solution, and the mixture was stirred overnight at 80 °C. The mixture was cooled to 0 °C and neutralized with 2N HCl. The solution was extracted with diethyl ether and dried with MgSO4. After the solvent was removed, the crude oil was purified by silica gel chromatography to provide (E)-10 (484 mg, 81% yield). 1H NMR (CDCl3) δ 7.74 (dt, J = 2.1, 8.4 Hz, 2H), 7.31-7.20 (m, 7H), 6.33 (dt, J = 1.5, 15.9 Hz, 1H), 6.08 (dt, J = 6.9, 15.9 Hz, 1H), 4.48 (t, J = ? Hz, 1H), 2.99 (dt, J = 6.9, 6.3 Hz, 2H), 2.41 (s, 3H), 2.22 (m, 2H), 1.66 (m, 2H); 13C NMR (CDCl3) δ 143.6, 137.6, 137.2, 131.2, 129.9, 129.1, 128.7, 127.3, 126.2, 42.8, 30.1, 29.4, 21.7; HRMS: m/z (ESI) calculated [MNa]+ 338.1191, measured 338.1201. Scheme S2. Synthetic Procedure for (Z)-10. d
O +
Ph
c
PhMgBr
Ph NHTs
OH S-3
(Z)-10
Reaction conditions: (d) (Ph3P)2NiCl2, Toluene, 89%. (c) i) MeSO2Cl, Et3N, CH2Cl2. ii) pMeC6H4SO2Cl, K2CO3, DMF, 81%.
Synthesis of S-3.2 An ether solution of PhMgBr (1 mL, 1.0 M) was added to a stirring suspension of (Ph3P)2NiCl2 (623 mg, 1.0 mmol) in 100 mL dry toluene under N2. The stirring was continued at room temperature for 15 min. At the end of this period, additional PhMgBr (10 mL, 1.0 M) was added, followed by addition of dihydropyran (3 mL, 33 mmol). The solution was refluxed under N2 overnight. The cooled reaction mixture was poured into a saturated ammonium chloride solution and extracted with ether. The extract was dried with Na2SO4 and evaporated, and the residue was purified by silica gel chromatography to give the alcohol S-3 in 88% yield (1.58 g). 1H NMR (300 MHz, CDCl3) δ 1.71 (p, J = 6.9 Hz, 2H), 2.44 (m, 3H), 3.62 (t, J = 6.6 Hz, 2H), 5.68 (dt, J = 11.8, 7.4 Hz, 1H), 4.47 (d, J = 11.5 Hz, 1H), 7.30 (m, 5H). Synthesis of (Z)-10. The same protocol used in the preparation of (E)-10 was employed (see above) (81% yield). 1H NMR (CDCl3) δ 7.70 (dt, J = 1.8, 8.4 Hz, 2H), 7.35-7.19 (m, 7H), 6.43 (d, J = 11.7 Hz, 1H), 5.54 (dt, J = 7.5, 11.7 Hz, 1H), 4.33 (t, J = ?, 1H), 2.95 (q, J = 6.9 Hz, 2H), 2.42 (s, 3H), 2.31 (m, 2H), 1.60 (m, 2H); 13C NMR (CDCl3)
S5
δ 143.6, 137.4, 137.2, 131.2, 130.3, 129.9, 128.9, 128.5, 127.3, 127.0, 43.0, 30.0, 25.7, 21.7; HRMS: m/z (ESI) calculated [MNa]+ 338.1191, measured 338.1195. Scheme S3. Synthetic Procedure for trans-3-d-13. a
b
OTs
3
c
OTs
2
OAc
OTBDMS
S-4
S-5
4 5 1
3
d
D
2
OTBDMS
4 5 1
D
OAc
trans-5-d-S-6
trans-5-d-S-7
HOOC e
3 1 2
trans-3-d-S-8
D
f
HO
3 1 2
trans-3-d-S-9
D
g
TsHN
3 1
D
2
trans-3-d-13
Reaction condition: (a) i) Pb(OAc)4, HOAc/H2O. ii) p-MeC6H4SO2Cl, Et3N, Me3NHCl, CH2Cl2. two step 39%. (b) i) K2CO3, MeOH. ii) t-BuMe2SiCl, Imidazole. two step 85%. (c) LiBEt3D, THF, 88%. (d) i) Tetrabutylammonium fluorode, THF. ii) Acetic anhydride, Pyridine. two step 70%. (e) Lithium Diisopropylamine, t-BuMe2SiCl, THF. 73%. (f) LiAlH4, Et2O. 91%. (g) i) MeSO2Cl, Et3N, CH2Cl2. ii) K2CO3, p-MeC6H4SO2NH2, DMF, two step 81%.
Synthesis of S-4.3,4Freshly cracked cyclopentadiene (22 g) was slowly added to a magnetically stirred and chilled (ice water bath) mixture of Pb(OAc)4 (100g), acetate acid (200 mL) and water (9 mL) maintained under a nitrogen atmosphere. Shortly after completion of the addition of cyclopentadiene, the reaction mixture became homogenous, after which point the ice-water bath was removed. Stirring was continued for 1 h, then the reaction mixture was poured into diethyl ether (500 mL), and the supernatant was decanted and filtered through a pad of TLC-grade silica gel. The filtrate was treated with Na2CO3 (100 g) and the resulting mixture was stirred vigorously at room temperature overnight. The resulting precipitate was removed by filtration and washed with diethyl ether. Then the combined filtrates were concentrated under reduced pressure to give a light-yellow oil. Distillation of this oil afforded a ca. 1:0.8 mixture of regioisomeric mono-acetates of cis-cyclopent-3-ene-1,2-diol (23g, 67% yield) as a clear colorless oil. To a stirred solution of the mixture of regioisomerIC mono-acetates (19 g), Et3N (27 g) and Me3NHCl (9.5g) in 300 mL of dry dichloromethane, p-toluenesulfonyl chloride (TsCl) (29 g) was added at 0 °C. The mixture was stirred at the same temperature for 5 h. The reaction was poured into water, and it was extracted with dichloromethane. The organic layers were dried with MgSO4. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography to give S-4 (21 g, yield 52 %). 1 H NMR (CDCl3) δ 7.80 (dd, J = 6.3, 1.8 Hz, 2H), 7.35 (dd, J = 6.3, 1.8 Hz, 2H), 5.99 (m, 1H), 5.78 (m, 1H), 5.50 (m, 1H), 5.01 (q, J = 5.7 Hz, 1H), 2.64 (m, 2H), 2.45 (s, 3H), 1.98 (s, 3H); 13C NMR (CDCl3) δ 170.4, 145.1, 134.1, 133.9, 130.0, 128.3, 128.1, 112.4, 75.3, 37.3, 21.9, 21.0; HRMS: m/z (ESI) calculated [MNa]+ 319.0616, measured 319.0621. Synthesis of S-5. K2CO3 (13.8 g, 100 mmol) was added to a solution of S-4 (21g, 71 mmol) in MeOH (300 mL). The reaction was monitored by TLC. After the reaction S6
finished, a mixture of diethyl ether and hexane (600 mL, v/v 1:1) was added and the solution was filtered through a pad of TLC-grade silica gel. The solvent was removed under reduced pressure to give a colorless oil (15 g). Under a nitrogen atmosphere, the oil was dissolved in dry THF (250 mL), after which imidazole (6.8 g, 100 mmol) and tertbutyldimethylsilyl chloride (TBDMSCl) (10.5g, 70 mmol) were added. The mixture was stirred at room temperature overnight. The reaction was quenched with 50 mL 2N HCl. The mixture was extracted by diethyl ether, and the combined organic layers were dried with MgSO4. After removal of the solvent, the crude product was purified by silica gel chromatography to give S-5 (20.4 g, 85% yield). 1H NMR (CDCl3) δ 7.82 (dd, J = 6.3, 1.8 Hz, 2H), 7.33 (dd, J = 6.3, 1.8 Hz, 2H), 5.78 (m, 2H), 4.82 (dt, J = 5.4, 6.6 Hz, 1H), 4.64 (m, 1H), 2.57-2.34 (m, 2H), 2.45 (s, 3H), 0.87 (s, 9H) 0.07 (s, 6H); 13C NMR (CDCl3) δ 144.7, 134.6, 132.2, 131.4, 129.9, 128.1, 79.5, 74.9, 36.1, 26.0, 21.8, 18.6, -4.4, -4.6; HRMS: m/z (ESI) calculated [MNa]+ 391.1375, measured 391.1384. Synthesis of trans-5-d-S-6. Lithium triethylborodeuteride (super-deuteride) (60 mmol, 60 mL, 1.0 M) in THF was added to a solution of S-5 (7.7 g, 21 mmol) in dry THF (70 mL) at -20 °C. The mixture was heated to 45 °C and stirred at the same temperature for 24 hrs. The reaction was monitored by TLC. After the reaction was almost complete, 1 mL water, followed by 40 mL 15% NaOH and 40 mL 30% H2O2 were added to quench excess super-deuteride. The mixture was extracted with diethyl ether. The organic layer was washed with brine and dried with MgSO4. The solvent was removed under vacuum and the residue was purified by silica gel chromatography to give trans-5-d-S-6 (3.6 g, 88% yield). 1H NMR (CDCl3) δ 5.91 (m, 1H), 5.72 (m, 1H), 4.92 (m, 1H), 2.48 (m, 1H), 2.21 (m, 1H), 1.64 (m, 1H), 0.91 (s, 9H), 0.09 (s, 6H); 2H NMR (CHCl3) δ 2.290 (s, 1D); 13 C NMR (CDCl3) δ 134.1, 133.7, 78.3, 33.4 (t, J = 20.2 Hz), 31.1, 26.2, 18.5, -4.30, 4.33; HRMS: m/z (ESI) calculated [M]+ 199.1503, measured 199.1473. Synthesis of trans-5-d-S-7. To a solution of trans-5-d-S-6 (5.1 g, 26 mmol) in 60 mL dry THF, 40 mL tetrabutylammonium fluoride (TBAF; 1.0 M in hexane) was added at room temperature. The mixture was stirred overnight. Brine (30 mL) was added, and the mixture was extracted with diethyl ether. The organic layer was washed with brine and dried with MgSO4. The solvent was removed by distillation at ambient pressure. After the residue was dissolved in pyridine (20 mL), acetic anhydride (7 mL) and DMAP (200 mg) were added at room temperature. The mixture was stirred overnight. After the reaction was complete, the mixture was poured into 200 mL diethyl ether and washed by 2N HCl (about 50 mL). The organic layer was washed with water, brine and dried with MgSO4. After removal of the solvent, the residue was purified by silica gel chromatography (pentane/diethyl ether, 4/1) to give trans-5-d-S-7 (2.3 g, 70% yield). 1H NMR (CDCl3) δ 6.10 (m, 1H), 5.82 (m, 1H), 5.68 (m, 1H), 2.48 (m, 1H), 2.34 (m, 1H), 2.03 (s, 3H), 1.80 (m, 1H); 2H NMR (CHCl3) δ 2.36 (s, 1D); 13C NMR (CDCl3) δ 171.2, 137.7, 129.5, 80.6, 31.1, 29.7 (t, J = 20.2 Hz), 21.5. Synthesis of trans-3-d-S-8.5 To a solution of iPr2NH (3.0 g, 30 mmol) in dry THF (40 mL) at -78 °C was added nBuLi (12 mL, 2.5 M in hexane). The solution was warmed to 0 °C and stirred for an additional 30 min, then recooled to -78 °C. tert-Butyldimethylsilyl chloride (TBDMSCl) (5.2 g, 35 mmol) was added followed by trans-5-d-S-7 (2.3 g, 19 mmol) in 20 mL dry THF over a 20 min period. The mixture was stirred at -78 °C for 20 min, warmed to room temperature, and stirred for an additional 2 h. The solution was then heated at reflux overnight, cooled to 0 °C and treated with 10 mL of conc. HCl. The
S7
mixture was stirred at 0 °C for 1 h, then diluted with diethyl ether. The aqueous layer was extracted with diethyl ether. The combined organic layers were dried with MgSO4. The solvent was removed under vacuum and the residue was purified by silica gel chromatography to give trans-3-d-S-8 (1.6 g, 73% yield). 1H NMR (CDCl3) δ 5.79 (m, 1H), 5.70 (m, 1H), 3.11 (m, 1H), 2.48-2.30 (m, 3H), 2.15 (m, 1H), 1.49 (m, 1H); 2H NMR (CHCl3) δ 2.39 (s, 1D); 13C NMR (CDCl3) δ 179.3, 133.7, 131.9, 42.0, 40.4, 31.7 (t, J = 20.2 Hz), 29.7; HRMS: m/z (ESI) calculated [MNa]+ 253.1409, measured 253.1400. Synthesis of trans-3-d-S-9. To a solution of LiAlH4 (1.2g, 34 mmol) suspended in dry THF (30 mL) was added trans-3-d-S-8 (1.6 g, 12.7 mmol) slowly at 0 °C under a nitrogen atmosphere. The mixture was stirred overnight at room temperature. Water (0.5 mL) was added slowly to quench excess LiAlH4 at 0 °C. Then 5 mL 40% NaOH(aq) was added. The mixture was stirred for 30 min and filtered. The solid was washed with diethyl ether (3X). The combined diethyl ether solutions were dried with MgSO4. The solvent was removed under vacuum and the residue was purified by silica gel chromatography to give trans-3-d-S-9 (1.3 g, 11.6 mmol, 91% yield). 1H NMR (CDCl3) δ 5.74 (m, 1H), 5.69 (m, 1H), 3.69 (m, 2H), 2.77 (m, 1H), 2.34 (m, 1H), 2.06 (m, 1H), 1.73-1.53 (m, 3H), 1.45(m, 1H); 2H NMR (CHCl3) δ 2.36 (s, 1D); 13C NMR (CDCl3) δ 134.9, 130.8, 62.0, 42.4, 39.1, 31.8 (t, J = 19.9 Hz), 29.9. Synthesis of trans-3-d-13. MsCl (1.4 mL, 15 mmol) was added to a solution of trans-3d-S-9 (1.1g, 10mmol) and Et3N (5 mL, 37 mmol) in dichloromethane (50 mL) under a nitrogen atmosphere at 0 °C. The mixture was stirred overnight at room temperature. After the reaction was complete, water (20 mL) was added. The mixture was extracted with dichloromethane. The dichloromethane solution was dried with MgSO4. After the solvent was removed under reduced pressure, a crude oil was obtained. The crude oil was dissolved in DMF (100 mL). Then p-toluenesulfonamide (TsNH2) (14 g, 70 mmol) and K2CO3 were added to the DMF solution, and the mixture was stirred overnight at 80 °C. The mixture was cooled to 0 °C and neutralized with 2N HCl. The solution was extracted with diethyl ether and dried with MgSO4. After the solvent was removed, the crude oil was purified by silica gel chromatography to give trans-3-d-13 (2.1 g, 81% yield). 1H NMR (CDCl3) δ 7.76 (dt, J = 2.1, 9.0 Hz, 2H), 7.31 (dt, J = 2.1, 9.0 Hz, 2H), 5.71 (m, 1H), 5.56 (m, 1H), 4.58 (t, J = 6.0 Hz, 1H), 2.98 (dt, J = 6.6, 6.6 Hz, 2H), 2.65 (m, 1H), 2.44 (s, 3H), 2.28 (m, 1H), 1.98 (m, 1H), 1.63-1.38 (m, 2H), 1.32(m, 1H); 2H NMR (CHCl3) δ 2.31 (s, 1D); 13C NMR (CDCl3) δ 143.6, 137.2, 134.0, 131.4, 129.9, 127.3, 43.0, 42.1, 35.9, 31.7 (t, J = 19.8 Hz), 29.6, 21.7; HRMS: m/z (EI) calculated [M]+ 266.1199, measured 266.1198. Synthesis of trans-3-d-17. The same protocol used in the preparation of trans-3-d-13 was employed (see above) (85% yield). 1H NMR (CDCl3) δ 8.38 (dt, J = 2.1, 8.7 Hz, 2H), 8.07 (dt, J = 2.1, 8.7 Hz, 2H), 5.73 (m, 1H), 5.56 (m, 1H), 4.91 (t, J = 6.0 Hz, 1H), 3.06 (dt, J = 7.2, 6.3 Hz, 2H), 2.66 (m, 1H), 2.28 (m, 1H), 1.98 (m, 1H), 1.64-1.45 (m, 2H), 1.32(m, 1H); 2H NMR (CHCl3) δ 2.33 (s, 1D); 13C NMR (CDCl3) δ 150.3, 146.2, 133.6, 131.8, 128.5, 124.6, 42.8, 42.3, 35.9, 31.7 (t, J = 20.2 Hz), 29.5; HRMS: m/z (EI) calculated [M-H]+ 296.0815, measured 296.0805. Synthesis of trans-3-d-20. To a solution of trans-3-d-S-8 (0.7 g, 5.5 mmol) in dry THF (10 mL), TsNCO (1.2g, 6 mmol) was added under nitrogen. The mixture was stirred for 30 min, then Et3N (1 mL) was added. The mixture was stirred overnight, and a 2N HCl solution (10 mL) was added. The mixture was extracted with diethyl ether. The combined
S8
organic layer was washed with brine and dried over MgSO4. The solvent was removed under vacuum, and the residue was purified by silica gel chromatography to give a white solid (1.3 g, 91% yield). 1H NMR (CDCl3) δ 8.7 (br s, 1H), 7.95 (d, J = 8.1 Hz, 2H), 7.35 (dt, J = 8.1 Hz, 2H), 5.74 (m, 1H), 5.54 (m, 1H), 3.02 (m, 1H), 2.45 (s, 3H), 2.36-2.20 (m, 3H), 2.03 (m, 1H), 1.35(m, 1H); 2H NMR (CHCl3) δ 2.19; 13C NMR (CDCl3) δ 170.3, 145.3, 135.8, 133.1, 132.5, 129.8, 128.5, 42.5, 41.8, 31.6 (t, J = 20.2 Hz), 29.4, 21.9; HRMS: m/z (EI) calculated [M]+ 280.0992, measured 280.0981. Scheme S4. Synthetic Procedure for cis-3-d-13. 3 2
4 5 1
D
OTBDMS trans-5-d-S-6
d(i)
3 2
4
4 5
1
D
h
H (11% D)
3 2
5 1
D
H (16% D) e,f,g
(89% D)
OH
OAc
trans-5-d-S-10
cis-5-d-S-7
TsHN
3 1 2
D (84% D)
cis-3-d-13
Reactions condition: (d) i) Tetrabutylammonium fluorode, THF. (h) PPh3, Diisopropyl azodicarboxylate, HOAc, Et2O, 59%. (e) Lithium Diisopropylamine, t-BuMe2SiCl, THF. (f) LiAlH4, Et2O. (g) i) MeSO2Cl, Et3N, CH2Cl2. ii) K2CO3, p-MeC6H4SO2NH2, DMF, three steps 25%.
Synthesis of trans-5-d-S-7. Diisopropyl azodicarboxylate (2.3 mL, 11.8 mmol, 2eq) was added dropwise to a stirred solution of trans-5-d-cyclopent-2-en-1-ol (500mg, 5.9 mmol, 1eq), PPh3 (3.1g, 11.8 mmol, 2eq), and acetic acid (0.7 mL, 11.8 mmol, 2eq) in diethyl ether (50 mL) at -85 °C under a nitrogen atmosphere. The reaction mixture was stirred for 6 h and 10% NaHCO3 (20 mL) was added. The mixture was warmed to room temperature and extracted with diethyl ether (3x50 mL). The combined organic layer was dried with MgSO4, filtered and concentrated under vacuum. Purification by flash chromatography (silica gel, diethyl ether/pentane) gave the mixture of cis-5-d-S-7 and cis-4-d-S-7 in ratio 89/11 with 59% yield. cis-5-d-S-7: 1H NMR (CDCl3) δ 6.11 (m, 1H), 5.82 (m, 1H), 5.69 (m, 1H), 2.50 (m, 1H), 2.29 (m, 2H), 2.03 (s, 3H); 2H NMR (CHCl3) δ 1.75 (s, 1D); 13C NMR (CDCl3) δ 171.2, 137.7, 129.5, 80.7, 31.1, 29.7 (t, J = 20.2 Hz), 21.5; cis-4-d- S-7: 1H NMR (CDCl3) δ 6.11 (m, 1H), 5.82 (m, 1H), 5.69 (m, 1H), 2.29 (m, 2H), 2.03 (s, 3H), 1.82 (m, 1H); 2H NMR (CHCl3) δ 2.45 (s, 1D). Synthesis of cis-3-d-13. The procedure is the same as that for trans-3-d-13. cis-3-d-13: 1 H NMR (CDCl3) δ 7.76 (dt, J = 2.1, 9.0 Hz, 2H), 7.31 (dt, J = 2.1, 9.0 Hz, 2H), 5.71 (m, 1H), 5.56 (m, 1H), 4.75 (t, J = 6.0 Hz, 1H), 2.97 (dt, J = 6.6, 6.6 Hz, 2H), 2.64 (m, 1H), 2.43 (s, 3H), 2.22 (m, 1H), 1.98 (m, 1H), 1.63-1.38 (m, 2H), 1.32(m, 1H); 2H NMR (CHCl3) δ 2.20 (s, 1D); 13C NMR (CDCl3) δ 143.5, 137.0, 134.0, 131.3, 129.9, 127.3, 42.8, 42.1, 35.8, 31.7 (t, J = 20.1 Hz), 29.5, 21.7; HRMS: m/z (ESI) calculated [MNa]+ 289.1097, measured 289.1106. Oxidative Cyclization of cis-3-d-13. The general procedure outlined above for oxidative cyclization reactions was followed for both the Pd(OAc)2/DMSO and Pd(OAc)2/py catalyst systems (eqs S1 and S2). Use of both catalyst systems results in formation of the unlabeled product 14, consistent with a cis-aminopalladation pathway.
S9
2 3
D (84% D)
1
TsHN
4
H (16% D)
5% Pd(OAc)2 2 equiv NaOAc DMSO, O2 (1 atm) 80 oC
3
D (84% D)
1
TsHN
4
H (16% D)
cis-3-d-13
(S1) H (13% D) 14 (81% yield)
cis-3-d-13
2
Ts N
5% Pd(OAc)2 10% pyridine toluene, O2 (1 atm) 80 oC
Ts N
(S2)
H (12% D) 14 (88% yield)
(S1) Carson, J. R.; Almond, H. R.; Brannan, M. D.; Carmosin, R. J.; Flaim, S. F.; Gill, A.; Gleason, M. M.; Keely, S. L.; Ludovici, D. W.; Pitis, P. M.; Rebarchak, M. C.; Villani, F. J. J. Med. Chem. 1988, 31, 630-636. (S2) Wenkert, E.; Michelotti, E. L.; Swindell, C. S.; Tingoli, M. J. Org. Chem. 1984, 49, 4894-4899. (S3) Banwell, M. G.; Ebenbeck, W.; Edwards, A. J. J. Chem. Soc., Perkin Trans. 1, 2001, 114-117. (S4) Yoshida, Y.; Sakakura, Y.; Aso, N.; Okada, S.; Tanabe, Y. Tetrahedron 1999, 55, 2183-2185. (S5) Hu, Q.-Y.; Rege, P. D.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 5984-5986.
S10
Representative NMR Spectra obtained in the aerobic oxidative amination of all-protio substrate 13 and mono-deuterated substrate trans-3-d-13 (cf. Table 4 of the manuscript):
S11
S12
S13
