mg, 0.2 mmol, 1.0 equiv.) in DCM was added cyclohexylamine (69 μL, 0.6 mmol, 3.0 equiv.)
and DIPEA (105 μL, 0.6 mmol, 3.0 equiv.). The reaction mixture was cooled to 0 °C and EDC (153 mg, 0.8 mmol, 4.0 equiv.) was added. The reaction mixture was warmed to rt over 30
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minutes and was stirred overnight. The reaction mixture was transferred to a separatory funnel and diluted with DCM. The organic phase was extracted with DCM and was washed with 1% aqueous HCl, sat. aq. sodium bicarbonate, and brine. The combined organic phases were dried
over Na2SO4 and were concentrated in vacuo. Column chromatography on silica gel (0-30%
ethyl acetate in hexanes) afforded the product I-12 (67.8 mg, 54% yield).
A round-bottomed flask was charged with Pd/C (140 mg, 200 wt % with respect to I-12),
which was slurried with EtOAc. MeOH (2.2 mL) was slowly added to the slurry, and I-12 (68
mg, 0.11 mmol, 1.0 equiv.) was transferred to the flask using MeOH (1 mL). The flask was submerged in a rt water bath and 1,4-cyclohexadiene (0.42 mL, 2.2 mmol, 40 equiv.) was added. The reaction was stirred and monitored by MS until no starting material remained (~12–24 h). The reaction mixture was filtered through Celite and rinsed with MeOH, and was concentrated via rotary evaporation in vacuo. The residue was suspended in Et2O and HBArF24·Et2O (206 mg, 0.22 mmol, 2.0 equiv.) was added. The suspension was stirred for 15 min and the reaction mixture was then filtered through Celite. The filtrate was concentrated via rotary evaporation in vacuo to afford 11 as a colorless oil that formed a foamy solid under vacuum (153 mg, 67% yield). 1H NMR (500 MHz, Acetone-d 6) 7.97 (s, 4 H), 7.80 (s, 16 H), 7.70 (s, 8 H), 3.88–3.87 (m, 2 H), 3.65–3.64 (m, 2 H), 2.23–2.20 (m, 2H), 2.09–2.05 (m, 8 H), 1.75 (m, 4 H), 1.58–1.56 (m, 4 H), 1.42–1.31 (m, 8 H), 1.18–1.15 (m, 2 H); 13C NMR{1H} (125 MHz, Acetone-d 6) δ161.7 (q, J = 49.6 Hz), 154.8, 142.0, 134.6, 132.9, 131.6 (q, J = 33.3), 129.1 (q, J = 32.6), 124.5 (q, J = 271.8 Hz), 55.6, 51.1, 32.5, 29.3, 24.7, 24.3, 23.9; IR(film) νmax 2944, 2866, 1686, 1609, 1454, 1354, 1274, 1161, 1117, 1028, 887, 839, 745, 712, 670, 482;
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MS (ESI-TOF) calcd. for C20H39N6 [M – H+ – 2BArF24] 363.3236, found 363.3295.
A round-bottomed flask was charged with the primary aminourea50(116 mg, 0.29 mmol,
1.0equiv.), and DCM (2 mL) was added. Triethylamine (45 μL, 0.32 mmol, 1.1 equiv.) was
added, followed by benzyloxyisothiocyanate (62 mg, 0.32 mmol, 1.1 equiv.) as a solution in DCM (0.9 mL). After stirring for 12 h, the reaction mixture was transferred to a separatory funnel. The organic phase was washed with 1M HCl (aq.) (3 x 10 mL) and brine. The organic
phase was dried over Na2SO4 and was concentrated via rotary evaporation in vacuo. Column
chromatography on silica gel (0-20% ethyl acetate in hexanes) afforded the product as a white solid (111 mg, 68% yield). 1H NMR (500 MHz, Acetone-d 6) δ 9.92 (br. s, 1 H), 9.74 (s, 1 H), 8.61 (s, 1 H), 8.17 (s, 2 H), 7.52 (s, 1 H), 7.38–7.31 (m, 5 H), 6.13 (d, 1 H, J = 8.4), 5.20 (d, 1 H, J = 12.5), 5.12 (d, 1 H, J = 12.0), 4.34–4.27 (m, 1 H), 3.93–3.87 (m, 1 H), 2.92–2.27 (m, 1 H), 2.12–2.09 (m, 1 H), 1.78– 1.76 (m, 2 H), 1.45–1.34 (m, 4 H); 13C NMR{1H} (125 MHz, Acetone-d 6) δ 179.8, 154.4, 153.1, 142.7, 135.5, 131.5, 131.3, 128.4, 128.3, 128.1, 117.7, 113.9, 67.3, 58.7, 52.9, 32.8, 31.0, 24.5, 24.4;
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IR (film) νmax 2937, 2860, 1721, 1657, 1531, 1475, 1449, 1386, 1277, 1228, 1176, 1130, 1026, 882, 732, 701, 682;
MS (ESI-TOF) calcd. for C24H24F6N4O3S [M + H+] 563.1552, found 563.1585.
To a solution of I-12 (110 mg, 0.2 mmol, 1.0 equiv) in dichloromethane (0.1 M) was added cyclohexylamine (69 μL, 0.6 mmol, 3.0 equiv) and DIPEA (0.1 mL, 0.6 mmol, 3.0equiv). The stirred solution was cooled to 0 °C and EDC (0.12 g, 0.6 mmol, 3.0 equiv.) was added. The reaction mixture was allowed to warm to room temperature, and was stirred until the reaction was complete by mass spectrometry. The reaction mixture was transferred to a separatory funnel and was diluted with DCM. The organic phase was washed with 1% aqueous HCl (2x20 mL), and brine (1x20 mL). The organic phase was dried over Na2SO4 and was concentrated via rotary evaporation in vacuo. Column chromatography on silica gel (0-20% EtOAc in hexanes) yielded the product as a colorless oil. (MS (ESI-TOF) calcd. for C24H24F6N4O3S [M + H+] 563.1552, found 563.1585.)
A round-bottomed flask was charged with Pd/C (160 mg, 200 wt % with respect to I-13),
which was slurried with EtOAc. MeOH (1.6 mL) was slowly added to the slurry, and I-13 (79
mg, 0.13 mmol, 1.0 equiv.) was transferred to the flask using MeOH (1 mL). The flask was submerged in a rt water bath and 1,4-cyclohexadiene (0.24 mL, 2.5 mmol, 20 equiv.) was added. The reaction was stirred and monitored by MS until no starting material remained. The reaction mixture was filtered through Celite and rinsed with MeOH (~25 mL), and the filtrate was
concentrated via rotary evaporation in vacuo. The residue was taken up in Et2O and
HBArF24·Et2O (122 mg, 0.13 mmol, 1.0 equiv.) was added. The suspension was stirred for 10 min and was concentrated via rotary evaporation in vacuo. The residue was dissolved in DCM
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and filtered through Celite, and was concentrated via rotary evaporation in vacuo to afford the product a brown oil (137 mg, 78% yield).
1H NMR (500 MHz, Acetone-d 6) δ 8.68 (s, 1 H), 8.14 (s, 2 H), 7.92 (s, 1 H), 7.80 (s, 8 H), 7.68 (s, 4 H), 7.60 (s, 1 H), 7.08 (s, 2 H), 6.47 (s, 1 H), 3.79 (br. s., 1 H), 3.67–3.63 (m, 1 H), 3.59–3.56 (m, 1 H), 2.17–1.11 (m, 18 H); 13C NMR{1H} (125 MHz, Acetone-d 6) δ 161.7 (q, J = 49.6 Hz), 156.0, 154.8, 142.0, 134.6, 132.9, 131.6 (q, J = 33.3), 129.1 (q, J = 32.6), 124.6, 124.5 (q, J = 271.8 Hz), 122.4, 119.9, 118.1, 117.5, 114.6, 52.4, 50.8, 32.4, 24.8, 24.3, 23.8, 23.2; IR (film) νmax 2943, 2866, 1636, 1569, 1475, 1453, 1386, 1354, 1315, 1273, 1116, 1041, 943, 885, 839, 745, 712, 669, 579, 448;
MS (ESI-TOF) calcd. for C22H30F6N5O [M – 2 BArF2 ] 494.2354, found 494.2518.
2c.4.2 Oxidative lactonization procedures and substrate synthesis Synthesis of oxidative lactonization substrate
2-(4-Methoxybenzoyl)benzoic acid (I-15)
4-Methoxyphenylmagnesium bromide (8 mL, 0.5 M in THF, 4.0 mmol, 1.0 equiv) was added dropwise to phthalic anhydride (711 mg, 4.8 mmol, 1.2 equiv) in THF (10 mL) at 0 ºC. The reaction was warmed to rt and stirred for 12 h. The mixture was quenched with 1M HCl (aq) and extracted with Et2O. The organic phase was extracted twice with 1 M NaOH (aq) and the aqueous extracts were acidified with concentrated HCl. The resulting mixture was extracted with
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compound as a white solid (778 mg, 3.03 mmol, 76% yield). Spectral data matched that which has been previously reported.51
2-(4-Methoxybenzyl)benzoic acid (13)
Trifluoroacetic acid (3 mL) was added dropwise to 2-(4-methoxybenzoyl)benzoic acid (778 mg, 3.04mmol, 1.0 equiv) and triethylsilane (1.45 mL, 9.1 mmol, 3.0 equiv) in chloroform (3 mL) at 0 ºC. The solution was then heated at reflux for 18 h. After cooling to rt, the reaction was diluted with Et2O and washed twice with 1M HCl (aq). The organic phase was extracted twice with 1 M NaOH (aq) and the aqueous extracts were acidified with concentrated HCl. The resulting mixture was extracted with Et2O, washed with brine, dried with MgSO4, and concentrated in vacuo to yield the title compound as a white solid (619 mg, 2.56 mmol, 84% yield).Spectral data matched that which has been previously reported.52
Catalyst rate comparison
A solution of o-chloranil (16.0 mg, 0.065 mmol, 1.3 equiv) in DCM (0.1 mL) was added to a solution of (12.2 mg, 0.05 mmol, 1.0 equiv) and HBD (10 mol%) in CH2Cl2 (0.5 mL) at +4 ºC. After 24 h the reaction was quenched with a sat. aq. ascorbic acid solution and extracted with EtOAc. The organic phase was washed with brine, dried with MgSO4, and concentrated. Yields
51 Miao, J.; Ge, H. Org. Lett.2013, 15, 2930–2933.
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were determined by 1H NMR analysis of the crude reaction versus an internal NMR standard
(Bn2O). The lactone product is a known compound and spectral data matched that which has
been previously reported.53
2c.4.3 KIE experiment
Synthesis of deuterated substrate
2-((4-Methoxyphenyl)methyl-d2)benzoic acid (13-d2)
Trifluoroacetic acid (0.15 mL) was added dropwise to 2-(4-methoxybenzoyl)benzoic acid (38 mg, 0.15 mmol, 1.0 equiv) and triethyl(silane-d) (72 μL, 0.45 mmol, 3.0 equiv) in CHCl3 (0.15 mL) at 0 ºC. The solution was then heated at reflux for 18 h. After cooling to rt, the reaction was diluted with Et2O and washed twice with 1M HCl (aq). The organic phase was extracted twice with 1 M NaOH (aq) and the aqueous extracts were acidified with concentrated HCl. The resulting mixture was extracted with Et2O, washed with brine, dried over MgSO4, and
concentrated in vacuo to yield the title compound as a white solid (30 mg, 0.12 mmol, 82%
yield).
Kinetic isotope experiment Catalyzed with 10
A solution of o-chloranil (2.5 mg, 0.01 mmol, 0.1 equiv) in DCM (0.2 mL) was added to a solution of 2-((4-methoxyphenyl)methyl-d2)benzoic acid (12.2 mg, 0.05 mmol, 0.5 equiv), 2-
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((4-methoxyphenyl)methyl-H2)benzoic acid (12.2 mg, 0.05 mmol, 0.5 equiv), and bis-amidinium salt 10 (19.4 mg, 0.01 mmol, 10 mol%) in DCM (0.8 mL) at +4 ºC. After 48 h, the reaction was quenched with a sat. aq. ascorbic acid solution and extracted with EtOAc. The organic phase was washed twice with 1M NaOH (aq), washed with brine, dried over MgSO4, and concentrated
in vacuo to yield the lactone product. The average H/D product ratio for two separate runs was determined by integration of the 1H NMR spectra in CDCl3 with d1 = 10s. PdtH / PdtD = 7.7.