Job/Unit: O21306
/KAP1
Date: 05-02-13 17:44:33
Pages: 10
H.-W. Zhao, H.-L. Li, Y.-Y. Yue, Z.-H. Sheng
FULL PAPER
30% yield). [α]2D8 = 81.0 (c = 0.2, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 9.43 (br., 2 H), 7.88 (d, J = 4.0 Hz, 2 H), 7.09 (dd, J
= 8.4, 4.4 Hz, 2 H), 7.04 (d, J = 8.4 Hz, 2 H), 3.85 (br., 2 H), 3.51–
3.53 (m, 2 H), 3.26 (s, 4 H), 3.02–3.06 (m, 2 H), 2.94–2.98 (m, 2
7.00–7.28 (m, 6 H), 4.23 (m, 1 H), 2.99–3.17 (m, 2 H), 2.14 (m, 1
H), 1.95 (s, 3 H), 1.79 (m, 3 H), 1.36–1.42 (m, 9 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 171.1, 168.5, 155.5, 154.1, 136.0, 135.9,
135.1, 130.3, 130.1, 129.8, 129.4, 125.7, 125.2, 124.8, 123.7, 123.0,
H), 1.96–2.01 (m, 2 H), 1.76–1.88 (m, 4 H), 1.53–1.58 (m, 2 122.6, 80.5, 80.3, 62.0, 60.8, 60.4, 46.8, 30.9, 28.7, 28.3, 28.2, 24.3,
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 144.6, 140.7, 133.5,
123.1, 117.6, 57.2, 47.0, 46.1, 29.4, 25.3 ppm. HRMS: calcd. for
C20H29N6 [M + H+] 353.2448; found 353.2452.
23.6, 21.0, 14.2 ppm. HRMS: calcd. for C24H30N3O4 [M + H+]
424.2231; found 424.2246.
(S)-tert-Butyl 2-[(3Ј-Acetamido-2,2Ј-bipyridin-3-yl)carbamoyl]pyr-
rolidine-1-carboxylate (5b): By following the same procedure as that
of 5a, starting from 4b (203 mg, 0.53 mmol), 5b was prepared as a
white foam (217 mg, 96% yield). [α]1D8 = –71.0 (c = 0.16, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 13.48–13.64 (br. d, 1 H), 13.19
(br. s, 1 H), 9.28 (d, J = 8.4 Hz, 1 H), 9.04 (d, J = 8.0 Hz, 1 H),
8.43–8.48 (m, 1 H), 8.33 (m, 1 H), 7.32–7.35 (m, 2 H), 4.33–4.45
(m, 1 H), 3.57–3.66 (m, 2 H), 2.22–2.30 (m, 1 H), 2.14 (s, 3 H),
2.11–2.13 (m, 1 H), 1.81–1.89 (m, 2 H), 1.25–1.43 (m, 9 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 173.3, 169.2, 154.6, 142.3, 141.5,
141.3, 140.5, 136.4, 129.8, 129.3, 123.9, 80.5, 62.7, 47.1, 31.7, 28.4,
28.1, 25.5, 23.8, 19.1 ppm. HRMS: calcd. for C22H28N5O4 [M +
H+] 426.2136; found 426.2141.
Synthesis and Characterization Data for Intermediates 4a–b
(S)-tert-Butyl 2-[(2Ј-Aminobiphenyl-2-yl)carbamoyl]pyrrolidine-1-
carboxylate (4a): Compound 3a was prepared according to a re-
1
ported procedure and the H NMR spectroscopic data was consis-
tent with the reported values.[6] 1H NMR (400 MHz, CDCl3): δ =
7.20 (d, J = 14 Hz, 2 H), 7.13 (dd, J = 19.2, J = 7.6 Hz, 2 H), 6.82
(t, J = 7.6 Hz, 2 H), 6.75 (d, J = 7.6 Hz, 2 H), 3.68 (br. s, 4 H) ppm.
To a solution of (S)-Boc-proline (237 mg, 1.1 mmol) and 3-[3-(di-
methylamino)propyl]-1-ethylcarbodiimide
(EDCI;
211 mg,
1.1 mmol) in CH2Cl2 (5 mL) was added compound 3a (184 mg,
1.0 mmol) in CH2Cl2 (5 mL) at 0 °C. The resulting mixture was
stirred at 0 °C for 0.5 h. CH2Cl2 (10 mL) was added to the reaction
mixture and the mixture was washed with saturated NaHCO3(aq.)
(20 mL) and water (20 mL) successively. The organic layer was
dried with anhydrous Na2SO4 and concentrated under reduced
pressure. The crude product was purified by flash chromatography
on silica gel (eluent: petroleum ether/EtOAc = 3:1) to afford com-
Synthesis and Characterization Data for Intermediates 6a–b
(S)-N-(2Ј-Acetamidobiphenyl-2-yl)pyrrolidine-2-carboxamide (6a):
To a solution of compound 5a (209 mg, 0.49 mmol) in CH2Cl2
(1 mL) was added TFA (1 mL) dropwise at 0 °C. The resulting mix-
ture was stirred for 3 h at room temp. CH2Cl2 (20 mL) was added
and the mixture was concentrated under reduced pressure, dis-
solved in CH2Cl2 (10 mL), and treated with 2 n NaOH(aq.) to reach
pH 9. The mixture was extracted with CH2Cl2 (20 mLϫ3). The
organic layer was dried with anhydrous Na2SO4, and concentrated
under reduced pressure. The crude product was purified by flash
chromatography on silica gel (eluent: petroleum ether/EtOAc/TEA
= 1:2:0.01) to yield 6a (155 mg, 98% yield). [α]1D8 = –35.2 (c = 0.13,
1
pound 4a (198 mg, 52% yield). [α]1D8 = 10.3 (c = 0.18, CHCl3). H
NMR (400 MHz, CDCl3): δ = 8.39–8.96 (m, 1 H), 8.06–8.15 (m, 1
H), 7.41–7.43 (m, 1 H), 7.22–7.33 (m, 3 H), 7.03–7.08 (m, 1 H),
6.81–6.90 (m, 2 H), 4.23–4.26 (m, 1 H), 3.59–3.70 (m, 2 H), 3.19–
3.29 (m, 2 H), 2.07–2.12 (m, 2 H), 1.61–1.88 (m, 2 H), 1.30–1.43
(m, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.3, 154.3,
142.6, 135.5, 135.1, 131.2, 130.7, 130.6, 130.4, 129.3, 128.9, 128.7,
125.2, 124.5, 122.8, 122.7, 120.6, 119.8, 115.9, 115.4, 80.2, 61.9,
46.7, 31.2, 28.4, 28.3, 23.1 ppm. HRMS: calcd. for C22H28N3O3 [M
+ H+] 382.2125; found 382.2132.
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 9.60–9.70 (br. d, 1 H),
8.27–8.39 (m, 1 H), 8.19 (dd, J = 8.0, 3.6 Hz, 1 H), 7.43–7.49 (m,
2 H), 7.19–7.28 (m, 4 H), 6.88–7.00 (br. d, 1 H), 3.66 (dd, J = 9.2,
4.8 Hz, 1 H), 2.77–2.80 (m, 1 H), 2.40–2.60 (m, 1 H), 2.08 (m, 1
H), 1.96 (d, J = 5.6 Hz, 3 H), 1.75–1.91 (m, 2 H), 1.40–1.63 (m, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.4, 174.1, 168.7,
168.3, 136.0, 135.7, 135.6, 135.5, 130.5, 130.4, 130.4, 130.1, 129.5,
129.5, 129.4, 129.1, 129.0, 128.4, 128.2, 127.9, 125.2, 124.7, 124.6,
124.2, 122.5, 121.7, 121.1, 60.7, 46.9, 46.9, 30.7, 30.7, 26.0, 25.9,
24.6, 24.4 ppm. HRMS: calcd. for C19H22N3O2 [M + H+] 324.1707;
found 324.1717.
(S)-tert-Butyl
2-[(3Ј-Amino-2,2Ј-bipyridin-3-yl)carbamoyl]pyrrol-
idine-1-carboxylate (4b): Compound 3b was prepared according to
a previous procedure.[5i] By following the same procedure as that
of 4a, starting from 3b (186 mg, 1.0 mmol), 4b was prepared as a
yellow foam (249 mg, 65% yield). [α]1D8 = –109.7 (c = 0.18, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 13.71–13.92 (br. d, 1 H), 9.21
(d, J = 8.0 Hz, 1 H), 8.32 (d, J = 3.2 Hz, 1 H), 8.10–8.16 (m, 1 H),
7.25 (m, 1 H), 7.11 (d, J = 12.0 Hz, 2 H), 6.48 (br. s, 2 H), 4.33–
4.48 (m, 1 H), 3.56–3.67 (m, 2 H), 2.28–2.35 (m, 1 H), 2.12–2.18
(m, 1 H), 1.88–1.91 (m, 2 H), 1.27–1.45 (m, 9 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 173.2, 154.6, 144.7, 143.8, 140.9, 138.2,
136.0, 135.4, 135.2, 128.6, 128.1, 125.1, 124.0, 123.7, 122.6, 80.3,
62.7, 62.3, 53.4, 47.5, 47.1, 31.7, 30.9, 30.7, 29.7, 28.4, 28.1, 24.6,
23.8 ppm. HRMS: calcd. for C20H26N5O3 [M + H+] 384.2030;
found 384.2061.
(S)-N-(3Ј-Acetamido-2,2Ј-bipyridin-3-yl)pyrrolidine-2-carboxamide
(6b): By following the same procedure as for 6a, starting from 5b
(203 mg, 0.48 mmol), 6b was prepared as a white foam (148 mg,
1
95% yield). [α]1D8 = 109.3 (c = 0.13, CHCl3). H NMR (400 MHz,
CDCl3): δ = 13.51 (br. s, 1 H), 12.65 (br. s, 1 H), 9.14 (d, J =
1.2 Hz, 1 H), 9.12 (d, J = 1.6 Hz, 1 H), 8.34–8.98 (m, 1 H), 8.31
(dd, J = 4.4, 1.2 Hz, 1 H), 7.33 (td, J = 8.8, 4.4 Hz, 2 H), 3.88 (dd,
J = 9.2, 5.2 Hz, 1 H), 3.05–3.09 (m, 1 H), 2.92–2.96 (m, 1 H), 2.15–
2.22 (m, 5 H), 1.94–1.97 (m, 1 H), 1.67–1.72 (m, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 176.0, 169.2, 143.4, 142.1, 141.2,
140.7, 136.0, 135.8, 130.0, 129.6, 123.9, 123.7, 61.8, 47.4, 31.2, 26.3,
25.4 ppm. HRMS: calcd. for C17H20N5O2 [M + H+] 326.1612;
found 326.1616.
Synthesis and Characterization Data for Intermediates 5a–b
(S)-tert-Butyl 2-[(2Ј-Acetamidobiphenyl-2-yl)carbamoyl]pyrrolidine-
1-carboxylate (5a): To a solution of 4a (198 mg, 0.52 mmol) in dry
pyridine (5 mL) was added acetic anhydride (1 mL, 10.0 mmol)
dropwise at room temp. The reaction mixture was stirred at room
temp. for 3 h. CH2Cl2 (50 mL) was added and the solution was
washed with water (20 mLϫ3). The organic layer was separated,
dried with anhydrous Na2SO4, and concentrated under reduced
pressure. The crude product was purified by flash chromatography
on silica gel (eluent: petroleum ether/EtOAc = 1:2) to yield 5a
(209 mg, 95% yield). [α]1D8 = –76.1 (c = 0.21, CHCl3). 1H NMR
Synthesis and Characterization Data for Catalysts 7a–b:
(S)-N2-Ethyl-N2Ј-(pyrrolidin-2-ylmethyl)biphenyl-2,2Ј-diamine (7a):
Under an N2 atmosphere to 6a (91 mg, 0.28 mmol) in a 10 mL vial
was added BH3 (1.4 mmol, 1.4 mL, 1 m in THF) dropwise at room
(400 MHz, CDCl3): δ = 8.06–8.30 (m, 2 H), 7.46–7.60 (m, 2 H), temp. The reaction mixture was heated to reflux at 66 °C for 2 h
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0