Alkyllithium-Aldehyde Condensations
J . Org. Chem., Vol. 63, No. 23, 1998 8271
toluene); 1H NMR δ 7.81-7.71 (m, 4H), 7.48-7.39 (m, 3H),
4.35-4.26 (m, 1H), 2.92-2.81 (m, 1H), 2.62 (AB, 2H, J ) 10.1,
5.3, 1.9), 2.66 (s, OH), 2.38-2.26 (m, 1H), 2.26-2.09 (m, 1H),
1.78-1.64 (m, 1H); 13C NMR δ 135.9, 133.1, 132.4, 127.6, 127.5,
127.4, 127.1, 127.0, 125.7, 125.4, 70.7, 62.7, 60.2, 52.3, 34.6;
IR (KBr) 3144, 2844, 1947, 1598, 1504, 1346 cm-1; EIMS m/z
(relative intensity) 227 (M+•, 38), 141 (100). Anal. Calcd for
(S)-1-(2-Na p h th ylm eth yl)-3-a zid op yr r olid in e (5d ): with
(R)-1-(2-naphthylmethyl)-3-hydroxypyrrolidine (4d ) being
weakly soluble in toluene, it was necessary to add THF (15-
20 mL) before PPh3: yield 86% (green oil; flash 99.5-99.0/
0.5-1.0 CH2Cl2/MeOH); [R]D +8.6, [R]578 +8.9, [R]546 +9.8, [R]436
1
+13.7 (c 4.31, CH2Cl2, T ) 25 °C); H NMR δ 7.82-7.73 (m,
4H), 7.50-7.40 (m, 3H), 3.99-3.89 (m, 1H), 3.78 (AB, 2H, J )
12.6), 2.86-2.75 (m, 1H), 2.71 (AB, 2H, J ) 10.3, 6.0, 4.1),
2.50 (td, 1H, J ) 8.5, 6.0), 2.31-2.13 (m, 1H, J ) 8.2), 1.97-
1.82 (m, 1H); 13C NMR δ 136.1, 133.2, 132.6, 127.8, 127.5,
126.8, 125.8, 125.4, 59.8, 59.7, 59.4, 52.5, 31.0; IR (film) 2960,
2796, 2100 cm-1; EIMS m/z (relative intensity) 252 (M+•., 12),
196 (16), 141 (100), 115 (17), 83 (11).
C
15H17NO: C, 79.29; H, 7.49; N, 6.17. Found: C, 78.92; H,
7.60; N, 6.10.
(R )-1-(o-Me t h oxyp h e n ylm e t h yl)-3-h yd r oxyp yr r oli-
25
d in e (4e): yield 80% (yellow oil); [R]D -3.5 (c 4.39, toluene);
1H NMR δ 7.30-7.16 (m, 2H), 6.93-6.81 (m, 2H), 4.30-4.21
(m, 1H), 3.78 (s, 3H), 3.70 (s, OH), 3.64 (s, 2H), 2.83 (td, 1H,
J ) 8.6, 5.2), 2.60 (AB, 2H, J ) 10.3, 5.0, 3.1), 2.36 (td, 1H, J
) 8.7, 6.5), 2.22-2.05 (m, 1H), 1.74-1.59 (m, 1H); 13C NMR δ
157.4, 130.4, 128.0, 120.1, 110.1, 126.2, 70.8, 62.7, 55.1, 53.2,
52.3, 34.7; IR (neat) 3380, 2942, 2834, 1600 cm-1; EIMS m/z
(relative intensity) 207 (M+•., 42), 121 (100), 91 (71).
(S)-1-((o-Met h oxyp h en yl)m et h yl)-3-a zid op yr r olid in e
(5e): yield 81% (yellow oil; flash 99/1 CH2Cl2/MeOH); 1H NMR
δ 7.36-7.18 (m, 2H), 6.97-6.83 (m, 2H), 4.02-3.88 (m, 1H),
3.80 (s, 3H), 3.69 (“AB”, 2H, J ) 14.1), 2.85-2.73 (m, 1H), 2.79
(1/2AB, 1H, J ) 10.3, 6.1), 2.66 (1/2AB, 1H, J ) 10.1, 4.0),
2.54 (td, 1H, J ) 8.6, 5.9), 2.28-2.10 (m, 1H), 1.94-1.78 (m,
1H); 13C NMR δ 157.2, 130.0, 127.8, 120.1, 110.1, 126.2, 59.7,
Gen er a l P r oced u r e for th e P r ep a r a tion of (S)-1-Alk yl-
3-a zid op yr r olid in es 5. P r ep a r a tion of Hyd r a zoic Acid
Solu tion s. WARNING! Hydrazoic acid is a highly toxic and
volatile compound.7c These operations must be carried out
under a well-ventilated hood.
59.2, 52.7, 52.3, 55.1, 30.8; IR (film) 2954, 2796, 2100 cm-1
;
EIMS m/z (relative intensity) 232 (M+•, 10), 146 (61), 121 (100),
91 (69).
In a 250 mL three-necked-flask equipped with a dropping
funnel, a thermometer, and a gas outlet tube, a paste was
prepared from NaN3 (13 g, 200 mmol) and 13 mL of hot water.
To this paste, benzene (80 mL) was added, and the mixture
was cooled to 0 °C. While it was vigorously stirred, concen-
trated sulfuric acid (5.4 mL, 100 mmol, 0.5 equiv) was added
dropwise, maintaining temperature below 10 °C. The reaction
mixture was stirred for 15 min, and the organic layer was
decanted and then stored at 4 °C, on sodium sulfate and under
an argon atmosphere. Its concentration, generally between
1.2 and 1.9 M, was determined with 1 M NaOH solution in
the presence of phenolphthaleine and distilled water (20 mL
for 2 mL of hydrazoic acid solution).
To a solution of (R)-1-alkyl-3-hydroxypyrrolidine (4) (10
mmol) and triphenylphosphine (3.41 g, 13 mmol, 1.3 equiv) in
anhydrous benzene or toluene (60 mL) was added, at room
temperature, hydrazoic acid solution (10 mL of 1.88 M solution,
18.8 mmol, 1.9 equiv) and then diethyl azodicarboxylate (2.26
g, 13 mmol, 1.3 equiv) dissolved in 24 mL of solvent. After 5
h at room temperature, the precipitate of diethyl hydrazodi-
carboxylate was filtered and the resulting filtrate was ex-
tracted with 1 M HCl (3 × 25 mL). The combined extracts
were washed with a mixture Et2O/AcOEt (∼70/30) and tritu-
rated with solid NaHCO3 and then with 4 M NaOH before
extraction by Et2O or CH2Cl2 (3 × 100 mL). The organic layers
were combined and dried over MgSO4, filtered, and concen-
trated to afford an oil, purified by flash chromatogaphy on
silica gel, except for (S)-1-ethyl-3-azidopyrrolidine (5a ).
(S)-1-Eth yl-3-a zid op yr r olid in e (5a ): yield 74% (oil); 1H
NMR δ 3.99-3.88 (m, 1H), 2.72-2.60 (m, 1H), 2.57 (AB, 2H,
J ) 10.3, 6.2, 3.8), 2.50-2.31 (m, 1H), 2.41 (q, 2H, J ) 7.2),
2.20-2.02 (m, 1H), 1.85-1.70 (m, 1H), 1.02 (t, 3H, J ) 7.2);
13C NMR δ 59.7, 59.2, 52.3, 49.6, 30.8, 13.6; IR (neat) 2968,
2098 cm-1; CIMS (NH3) m/z (relative intensity) 141 (M + H+,
100).
Gen er a l P r oced u r e for th e P r ep a r a tion of (S)-1-Alk yl-
3-a m in op yr r olid in es 6. An ethereal solution (50 mL) of (S)-
1-alkyl-3-azidopyrrolidine 5 (10 mmol) was added dropwise to
a suspension of LiAlH4 (1.33 g, 35 mmol, 3.5 equiv) in 30 mL
of Et2O. The mixture was stirred at room temperature for 3
h, cooled to 0 °C, and then quenched by 1.2 mL of water, 1.2
mL of 4 M NaOH, and 3.5 mL of water. The white precipitate
was removed by filtration and extracted by AcOEt or CH2Cl2
(3 × 50 mL). The crude amine was utilized without purifica-
tion.
(S)-1-Eth yl-3-a m in op yr r olid in e (6a ): yield 93% (oil); 1H
NMR δ 3.43-3.31 (m, 1H), 2.59 (dd, 1H, J ) 9.5, 6.6), 2.61-
2.49 (m, 1H), 2.41-2.24 (m, 1H), 2.33 (q, 1H, J ) 7.3), 2.32 (q,
1H, J ) 7.1), 2.15 (dd, J ) 9.6, 4.4), 2.14-1.97 (m, 1H), 1.82
(broad s, NH2), 1.42-1.26 (m, 1H), 0.96 (t, 3H, J ) 7.2); 13C
NMR δ 63.4, 52.8, 50.5, 49.9, 34.8, 13.5; IR (film) 3350, 3280,
2968, 2796 cm-1; EIMS m/z (relative intensity) 114 (M+•, 34),
99 (12), 71(100), 56 (21).
(S)-1-(2-Meth oxyeth yl)-3-a m in op yr r olid in e (6b): yield
98% (green oil); [R]D +3.6 (c 4.58, CH2Cl2); 1H NMR δ 3.50-
25
3.36 (m, 1H), 3.39 (t, 2H, J ) 5.7), 3.26 (s, 3H), 2.72 (dd, 1H,
J ) 9.3, 6.7), 2.65-2.39 (m, 4H), 2.20 (dd, 1H, J ) 9.4, 4.9),
2.14-2.01 (m, 1H), 1.45-1.29 (m, 1H + NH2); 13C NMR δ 71.0,
64.2, 58.6, 55.4, 53.5, 50.6, 34.8; IR (film) 3350, 2928, 2812
cm-1; EIMS 145 (M + H+, 1), 112 (20), 99 (100), 70 (16), 58
(19); CIMS (t-BuH) m/z (relative intensity) 145 (M + H+, 100).
(S)-1-(1-Naph th ylm eth yl)-3-am in opyr r olidin e (6c): yield
25
1
96% (oil); [R]D -1.2 (c 5.06, CH2Cl2); H NMR δ 8.30-8.25
(m, 1H), 7.86-7.73 (m, 2H), 7.55-7.35 (m, 4H), 4.00 (s, 2H),
3.50-3.39 (m, 1H), 2.82-2.66 (m, 2H), 2.47 (td, 1H, J ) 8.7,
6.3), 2.36 (dd, 1H, J ) 9.2, 4.0), 2.25-2.07 (m, 1H), 1.53-1.37
(m, 1H), 1.45 (broad s, NH2); 13C NMR δ 134.8, 133.4, 132.0,
128.1, 127.4, 126.2, 125.4, 125.2, 124.9, 124.2, 63.8, 58.0, 52.9,
50.7, 34.9; IR (film) 3328, 2960, 2788 cm-1; EIMS m/z (relative
intensity) 226 (M+•, 25), 209 (12), 141 (100), 182 (33).
(S)-1-(2-Meth oxyeth yl)-3-a zid op yr r olid in e (5b): yield
75% (green oil; flash 99/1 CH2Cl2/MeOH); [R]D +18.0, [R]578
+18.7, [R]546 +21.0, [R]436 +32.4 (c 2.13, CH2Cl2, T ) 26 °C);
1H NMR δ 4.03-3.92 (m, 1H), 3.44 (t, 2H, J ) 5.6), 3.30 (s,
3H), 2.82 (dd, 1H, J ) 10.1, 6.5), 2.72-2.49 (m, 5H), 2.24-
2.06 (m, 1H), 1.87-1.71 (m, 1H); 13C NMR δ 71.1, 59.7, 59.6,
58.7, 54.9, 53.0, 30.7; IR (film) 2926, 2812, 2100 cm-1; EIMS
m/z (relative intensity) 170 (M+•, 7), 125 (100), 97 (27), 42 (66).
(S)-1-(1-Na p h th ylm eth yl)-3-a zid op yr r olid in e (5c): yield
87% (green oil; flash 99.5/0.5 CH2Cl2/MeOH); 1H NMR δ 8.32-
8.27 (m, 1H), 7.89-7.75 (m, 2H), 7.58-7.38 (m, 4H), 4.06 (AB,
2H, J ) 13.0), 3.95-3.84 (m, 1H), 2.87-2.69 (m, 3H), 2.52 (td,
1H, J ) 8.6, 6.0), 2.30-2.12 (m, 1H), 1.97-1.81 (m, 1H); 13C
NMR δ 134.4, 133.6, 132.0, 126.2, 127.8, 126.4, 125.7, 125.5,
125.0, 124.4, 59.7, 59.6, 57.8, 52.6, 31.0; IR (neat) 2798, 2094,
1596, 1508 cm-1; CIMS (t-BuH) m/z (relative intensity) 253
(M + H+, 100).
(S)-1-(2-Naph th ylm eth yl)-3-am in opyr r olidin e (6d): yield
98% (green oil); H NMR δ 7.82-7.72 (m, 4H), 7.50-7.37 (m,
1
3H), 3.71 (AB, 2H, J ) 13.1), 3.54-3.42 (m, 1H), 2.73 (dd, 1H,
J ) 9.2, 6.5), 2.77-2.65 (m, 1H), 2.48 (td, 1H, J ) 8.5, 6.1),
2.30 (dd, 1H J ) 9.5, 4.5), 2.26-2.08 (m, 1H), 1.54-1.39 (m,
1H + NH2); 13C NMR δ 136.6, 133.1, 132.5, 127.6, 127.5, 127.4,
127.0, 126.8, 125.7, 125.3, 63.8, 60.4, 53.0, 50.7, 34.9; IR (film)
3360, 3052, 2954, 2790 cm-1; EIMS m/z (relative intensity) 226
(M+•, 21), 209 (21), 141 (100).
(S )-1-((o-Me t h ox yp h e n yl)m e t h yl)-3-a m in o p y r r oli-
25
d in e (6e): yield 97% (yellow oil); [R]D +0.35 (c 5.07, CH2-
1
Cl2); H NMR δ 7.34-7.15 (m, 2H), 6.93-6.80 (m, 2H), 3.79
(s, 3H), 3.63 (s, 2H), 3.53-3.41 (m, 1H), 2.76 (dd, 1H, J ) 9.4,
6.3), 2.71 (td, 1H, J ) 8.6, 5.7), 2.51 (td, 1H, J ) 8.5, 6.1), 2.31
(dd, 1H, J ) 9.4, 4.5), 2.25-2.07 (m, 1H), 1.52-1.36 (m, 1H +
NH2); 13C NMR δ 157.2, 130.0, 127.6, 120.0, 110.0, 126.8, 63.7,