1002
A. Ros et al. / Tetrahedron: Asymmetry 19 (2008) 998–1004
Eluents, yields and spectral and analytical data for com-
pounds 3a, 3b and 3d are as follows.
4.2.2.1. (R)-2-[(2S,5S)-2,5-Diphenylpyrrolidin-1-ylamino]-
4-phenylbutanenitrile (R)-6a. From hydrazone 3a
(170 mg, 0.48 mmol), flash chromatography on silica gel
4.2.1.1.
(2S,5S)-1-[(3-Phenyl)propylideneamine]-2,5-
(0.020–0.045 mm) (3:1 toluene–hexane) gave 150 mg
20
diphenylpyrrolidine 3a. From dihydrocinnamaldehyde
(0.32 mL, 2.2 mmol), flash chromatography (1:16 Et2O–
(82%) of (R)-6a as an oil: ½aꢃD ¼ ꢀ138:0 (c 1.0, CH2Cl2).
1H NMR (400 MHz, CDCl3) d 1.45–1.61 (m, 2H), 1.92–
2.09 (m, 2H), 2.21–2.40 (m, 2H), 2.41–2.52 (m, 2H), 2.85
(d, J = 10.0 Hz, 1H), 3.28–3.34 (m, 1H), 4.55 (br s, 2H),
6.76–7.42 (m, 15H). 13C NMR (100 MHz, CDCl3) d 30.7,
31.1, 33.0, 51.8, 67.1, 122.3, 126.1, 127.6, 128.3, 128.4,
128.7, 140.1, 141.8. IR (cmꢀ1) 2925, 1726, 1454, 754, 701.
MS (EI) m/z (%) 381 [M+] (4), 355 (9), 354 (34), 263
(89), 237 (76), 117 (75), 105 (29), 104 (73), 91 (100), 77
(27). HRMS calcd for C26H27N3 381.2205, found 381.2189.
hexane) gave 461 mg (65%) of hydrazone 3a as an oil:
20
½aꢃD ¼ ꢀ163:9 (c 1.4, CHCl3). 1H NMR (300 MHz,
CDCl3) d 1.70–1.80 (m, 2H), 2.32–2.67 (m, 6H), 4.98 (d,
J = 7.0 Hz, 2H), 6.17 (t, J = 5.4 Hz, 1H), 6.95–7.39 (m,
15H). 13C NMR (125 MHz, CDCl3) d 31.5, 34.5, 34.6,
65.1, 125.7, 126.5, 126.7, 126.9, 128.3, 128.5, 128.6, 128.8,
134.8, 141.7, 144.1. IR (cmꢀ1) 3025, 2942, 1602, 1493,
1450, 1225, 1029, 749, 699. MS (EI) m/z (%) 355 [M++1]
(12), 354 [M+] (40), 263 (100), 117 (60), 105 (67), 91 (71),
77 (18). HRMS calcd for C25H26N2 354.2096, found
354.2099.
4.2.2.2. (R)-2-[(2S,5S)-2,5-Diphenylpyrrolidin-1-ylamino]-
3-methylbutanenitrile (R)-6b. From hydrazone 3b
(138 mg, 0.47 mmol), flash chromatography on silica gel
4.2.1.2.
(2S,5S)-1-[(2-Methyl)propylideneamine]-2,5-
(0.020–0.045 mm) (toluene) gave 119 mg (80%) of (R)-6b
20
diphenylpyrrolidine 3b. From isobutyraldehyde (0.2 mL,
2.2 mmol), flash chromatography (1:16 Et2O–hexane) gave
as an oil: ½aꢃD ¼ ꢀ125:3 (c 1.1, CHCl3). 1H NMR
(500 MHz, CDCl3) d 0.61 (d, J = 6.9 Hz, 3H), 0.62 (d,
J = 6.9 Hz, 3H), 1.42–1.51 (m, 1H), 1.98–2.09 (m, 2H),
2.43–2.52 (m, 2H), 2.85 (d, J = 9.3 Hz, 1H), 3.15 (dd,
J = 9.3, 5.9 Hz, 1H), 4.53 (br s, 2H), 7.28–7.47 (m, 10H).
13C NMR (125 MHz, CDCl3) d 17.9, 19.0, 29.8, 30.7,
20
444 mg (76%) of hydrazone 3b as an oil: ½aꢃD ¼ ꢀ149:7 (c
1.0, CHCl3). 1H NMR (300 MHz, CDCl3) d 0.77 (d,
J = 6.9 Hz, 3H), 0.86 (d, J = 6.9 Hz, 3H), 1.75–1.78 (m,
2H), 2.23–2.35 (m, 1H), 2.45–2.52 (m, 2H), 4.97 (d,
J = 6.9 Hz, 2H), 6.02 (d, J = 6.3 Hz, 1H), 7.18–7.30 (m,
10H). 13C NMR (75 MHz, CDCl3) d 21.3, 21.5, 31.7,
32.0, 65.2, 126.7, 126.9, 128.5, 128.7, 142.2, 144.3. MS
(EI) m/z (%) 293 [M++1] (19), 292 [M+] (69), 104 (100),
91 (22), 77 (14). HRMS calcd for C20H24N2 292.1939,
found 292.1943.
59.4, 67.1, 121.5, 127.6, 128.6, 128.9, 141.8. IR (cmꢀ1
)
3031, 2962, 2919, 1455, 754, 701. MS (CI) m/z (%) 320
[M++1] (6), 319 [M+] (11), 293 (98), 237 (100), 117 (30),
105 (35), 104 (50), 91 (25), 77 (6). HRMS calcd for
C21H25N3 319.2048, found 319.2040.
4.2.2.3. (R)-2-[(2S,5S)-2,5-Diphenylpyrrolidin-1-ylamino]-
4-methylpentanenitrile (R)-6c. From hydrazone 3c
(135 mg, 0.44 mmol), flash chromatography on silica gel
(0.040–0.063 mm) (1:2?2:1 toluene–hexane) gave 120 mg
(83%) of (R)-6c as a white solid. X-ray quality crystals were
4.2.1.3. (2S,5S)-1-Hexylideneamine-2,5-diphenylpyrroli-
dine 3d. From hexanal (0.27 mL, 2.2 mmol), flash chro-
matography (1:16 Et2O–hexane) gave 529 mg (75%) of
20
1
hydrazone 3d as an oil: ½aꢃD ¼ ꢀ149:0 (c 1.0, CHCl3). H
NMR (300 MHz, CDCl3) d 0.78 (t, J = 6.9 Hz, 3H),
1.14–1.27 (m, 6H), 1.72–1.79 (m, 2H), 1.97–2.04 (m, 2H),
2.45–2.52 (m, 2H), 4.99 (d, J = 7.2 Hz, 2H), 6.13 (t,
J = 5.4 Hz, 1H), 7.17–7.29 (m, 10H). 13C NMR (75 MHz,
CDCl3) d 14.3, 22.7, 28.1, 31.3, 31.6, 33.0, 65.1, 126.6,
126.6, 128.8, 136.6, 144.4. MS (EI) m/z (%) 321 [M++1]
(24), 320 [M+] (100), 249 (46), 243 (34), 222 (7), 91 (34),
77 (15). HRMS calcd for C22H28N2 320.2252, found
320.2245.
grown from a solution of (R)-6c in pentane at ꢀ20 °C: mp
20
108–110 °C. ½aꢃD ¼ ꢀ142:8 (c 1.5, CHCl3). 1H NMR
(400 MHz, CDCl3) d 0.38 (d, J = 6.7 Hz, 3H), 0.58 (d,
J = 6.7 Hz, 3H), 1.01–1.14 (m, 2H), 1.29–1.39 (m, 1H),
1.97–2.03 (m, 2H), 2.40–2.50 (m, 2H), 2.71 (d, J =
10.3 Hz, 1H), 3.29 (c, J = 8.3 Hz, 1H), 4.52 (br s, 2H),
7.24–7.41 (m, 10H). 13C NMR (100 MHz, CDCl3) d 21.3,
22.1, 24.3, 30.6, 40.3, 51.2, 67.1, 123.0, 127.5, 128.6,
128.7, 141.8. IR (cmꢀ1) 2957, 2931, 2871, 1728, 1455,
754, 702. MS (EI) m/z (%) 333 [M+] (8), 307 (5), 306
(21), 237 (100), 117 (29), 105 (20), 104 (28), 91 (20), 77
(5). HRMS calcd for C22H27N3 333.2205, found 333.2194.
4.2.2. Synthesis of hydrazino nitriles 6a–d. General proce-
dure. In a Schlenk tube, Et2AlCl (0.5 mmol, 500 lL of
solution 1 M in hexane) was added to a solution of hydra-
zone 3a–d (0.5 mmol) in dry CH2Cl2 (8 mL, 0.06 M) under
an argon atmosphere. The mixture was stirred at rt for 20
minutes, cooled to ꢀ78 °C and TMSCN (1.5 mmol,
188 lL) was added. The mixture was stirred at ꢀ78 °C until
total consumption of the starting material (1–3d, TLC).
MeOH (2 mL) was added and the reaction mixture was al-
lowed to warm to rt. The mixture was then washed with
H2O (10 mL) and the aqueous layer was extracted with
CH2Cl2 (3 ꢄ 15 mL). The combined organic layers were
dried (Na2SO4), concentrated, and the residue was purified
by flash chromatography. Starting material, eluents, yields
and spectral and analytical data for compounds 6a–d are as
follows.
4.2.2.4. (R)-2-[(2S,5S)-2,5-Diphenylpyrrolidin-1-ylamino]-
heptanenitrile (R)-6d. From hydrazone 2d (130 mg,
0.41 mmol), flash chromatography on silica gel (0.020–
0.045 mm) (1:3?3:1 toluene–hexane) gave 106 mg (84%)
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of (R)-6d as an oil: ½aꢃD ¼ ꢀ152:3 (c 1.1, CHCl3). 1H
NMR (500 MHz, CDCl3) d 0.75 (t, J = 7.3 Hz, 3H),
0.83–0.99 (m, 4H), 1.00–1.12 (m, 2H), 1.17–1.26 (m, 2H),
1.97–2.06 (m, 2H), 2.43–2.52 (m, 2H), 2.81 (br s, 1H),
3.30 (t, J = 7.0 Hz, 1H), 4.54 (br s, 2H), 7.28–7.47 (m,
10H). 13C NMR (100 MHz, CDCl3) d 13.9, 22.3, 24.8,
30.7, 30.8, 31.2, 52.6, 67.1, 122.6, 127.6, 128.6, 128.7,
141.9. IR (cmꢀ1) 2927, 1455, 754, 701. MS (EI) m/z (%)
347 [M+] (4), 321 (21), 320 (85), 249 (42), 237 (86), 194