3660 J . Org. Chem., Vol. 66, No. 11, 2001
Venkatesan et al.
Cl2/MeOH). The reaction was cooled, and the volatiles were
evaporated in vacuo. The remaining thick brown oil was
dissolved in 25 mL of acetonitrile, and triethylamine (6.4 mL,
46 mmol) was added. To this mixture at room temperature
was added dropwise methanesulfonyl azide (7.05 g, 58 mmol)
dissolved in 20 mL of acetonitrile over 1 h. After stirring for
12 h, the volatiles were evaporated in vacuo and the remaining
residue was partitioned between H2O and Et2O. The organic
phase was separated, dried (MgSO4), and evaporated in vacuo.
The remaining oil was subjected to chromatography to obtain
the title compound as a yellow oil (13.75 g, 93%) that slowly
crystallized on standing: mp 54-6 °C (hexanes/Et2O); 1H NMR
(CDCl3, 400 MHz) δ 7.3-7.1 (m, 5H), 6.92 (d, J ) 9.2 Hz, 2H),
6.81 (d, J ) 8.9 Hz, 2H), 4.92 (s, 2H), 3.95 (q, J ) 7 Hz, 2H),
2.55 (s, 3H), 1.41 (t, J ) 7 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
δ 192.32, 161.21, 159.07, 137.06, 133.75, 129.16, 128.98, 128.7,
127.83, 115.83, 63.99, 54.25, 28.98, 14.87. Anal. Calcd for
acetone was refluxed for 20 h, after which time no ketal
remained by TLC (CH2Cl2/MeOH). The mixture was cooled,
evaporated in vacuo, and subjected to chromatography to
obtain the title compound (3.7 g, 90%) as a pale brown oil that
1
slowly crystallized: mp 125-8 °C (hexanes/EtOAc); H NMR
(CDCl3, 400 MHz) δ 7.35-7.2 (m, 5H), 6.85 (d, J ) 2.5 Hz,
1H), 6.69 (d, J ) 8.6 Hz, 2H), 6.64 (d, J ) 8.6 Hz, 1H), 4.9 (s,
2H), 3.95 (q, J ) 7 Hz, 2H), 3.26-3.18 (m, 2H), 2.95-2.55 (m,
2H), 2.25-2.12 (m, 4H), 1.4 (t, J ) 7 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ 210.92, 179.2, 155.55, 136.1, 135.38, 134.67,
129.06, 127.87, 127.32, 112.79, 111.34, 109.84, 64.31, 46.08,
43.75, 37.13, 33.99, 15.08. Anal. Calcd for C22H23NO3: C, 75.64;
H, 6.59; N, 4.01. Found: C, 75.36; H, 6.63; N, 3.95.
1′-Ben zyl-5′-eth oxy-4-h yd r oxysp ir o[cycloh exa n e-1,3′-
in d olin ]-2′-on e (24). To a magnetically stirred solution of 19
(415 mg, 1.2 mmol) dissolved in 5 mL of THF at -78 °C was
added dropwise 1 M L-Selectride (1.78 mL, 1.8 mmol) in THF
over 1 h. The reaction was stirred at -78 °C for an additional
2 h and then 0.2 mL of H2O was added. The volatiles were
removed in vacuo, and the residue partitioned between H2O
and CH2Cl2. The organic layer was separated, dried (Na2SO4),
and evaporated in vacuo. 1H NMR analysis demonstrated a
66:1 ratio of syn and anti alcohols. Chromatography afforded
the title compound as a colorless oil (0.38 g, 90%) that slowly
crystallized: mp 125-7 °C (hexanes/EtOAc); 1H NMR (CDCl3,
400 MHz) δ 7.2-7.3 (m, 5H), 6.85 (d, J ) 2.4 Hz, 1H), 6.65
(dd, J ) 2.4 Hz, 8.4 Hz, 1H), 6.55 (d, J ) 8.4 Hz, 1H), 4.85 (s,
2H), 3.95 (q, J ) 6.8 Hz, 2H), 3.9 (m, 1H), 2.3-2.1 (m, 3H),
2.1-1.9 (m, 3H), 1.8-1.6 (m, 2H), 1.4 (t, J ) 6.8 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) δ 179.72, 155.04, 135.89, 128.96,
127.69, 127.32, 112.27, 111.42, 109.38, 69.28, 64.26, 46.33,
43.58, 31.52, 29.96, 15.12. Anal. Calcd for C22H25NO3: C, 75.21;
H, 7.12; N, 3.99. Found: C, 75.35; H, 7.25; N, 3.98.
Other carbonyl reducing agents were employed as follows:
A solution of 19 (140 mg, 0.4 mmol) in 5 mL of absolute EtOH
at 0 °C was treated with solid NaBH4 (23.3 mg, 0.6 mmol).
After 1 h the reaction was warmed at room temperature and
the solvent evaporated. The residue was partitioned between
EtOAc and H2O. The aqueous layer was extracted with EtOAc
(2 × 10 mL). The combined organic layers were washed with
brine and dried with Na2SO4, and the solvent was evaporated.
The product was purified with flash chromatography using
EtOAc/hexane (2:3). A final purification with EtOAc/hexane
(3:2) gave the diastereomeric mixture of 24 (2:1 syn:anti by
NMR).
C
19H19N3O3: C, 67.66; H, 5.64; N, 12.46. Found: C, 67.72; H,
5.73; N, 12.41.
N-Ben zyl-N-(4-eth oxyp h en yl)d ia zoa ceta m id e (10). To
a
magnetically stirred solution of 9 (13.75 g, 41 mmol)
dissolved in 40 mL of acetonitrile at room temperature was
added dropwise 16% KOH (30 mL) over 1 h. Stirring was
continued for another 12 h, after which the reaction was
complete by TLC. The volatiles were evaporated in vacuo, and
the remaining residue was partitioned between Et2O and H2O.
The organic phase was separated, dried (MgSO4), and evapo-
rated in vacuo to an orange oil. Chromatography yielded the
title compound as a yellow oil (10.06 g, 84%) that slowly
1
crystallized: mp 49-52 °C (hexanes/Et2O); H NMR (CDCl3,
400 MHz) δ 7.3-7.19 (m, 5H), 6.89 (d, J ) 8.8 Hz, 2H), 6.79
(d, J ) 8.9 Hz, 2H), 4.87 (s, 2H), 4.44 (s, 1H), 3.9 (q, J ) 7 Hz,
2H), 1.4 (t, J ) 7 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 166.4,
158.75, 137.85, 134.01, 129.84, 129.0, 128.58, 127.54, 115.34,
63.88, 53.21, 47.4, 14.97. Anal. Calcd for C17H17N3O2: C, 69.15;
H, 5.76; N, 14.24. Found: C, 69.31; H, 5.87; N, 14.15.
1-Ben zyl-5-et h oxy-2-in d olin on e (8). To a magnetically
stirred solution of rhodium(II) acetate dimer (95.5 mg, 0.2
mmol) in 127 mL of CH2Cl2 at room temperature. was added
dropwise over 1 h a solution of 10 (7.5 g, 25.5 mmol) in 20 mL
of CH2Cl2. The evolution of N2 gradually occurred and the
reaction was stirred for 12 h. The reaction was filtered through
neutral Al2O3 (5 g), then solvent was evaporated in vacuo,
leaving a yellow solid. A single recrystallization (hexanes/
1
EtOAc) furnished 8 (5.96 g, 88%): mp 108-11 °C; H NMR
(CDCl3, 400 MHz) δ 7.35-7.2 (m, 5H), 6.87 (s, 1H), 6.68 (d, J
) 8.8 Hz, 1H), 6.58 (d, J ) 8.6 Hz, 1H), 4.89 (s, 2H), 3.95 (q,
J ) 7 Hz, 2H), 3.6 (s, 2H), 1.37 (t, J ) 7 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 175.00, 155.30, 137.92, 136.14, 128.93,
127.75, 127.52, 125.91, 113.15, 112.70, 109.53, 64.28, 44.01,
36.37, 15.09. Anal. Calcd for C17H17NO2: C, 76.4; H, 6.37; N,
5.24. Found: C, 76.45; H, 6.41; N, 5.17.
Compound 19 (414 mg, 1.2 mmol) was dissolved in 10 mL
of absolute EtOH, and a solution of LiBr in 5 mL of absolute
EtOH (161 mg, 1.2 mmol) was added. After cooling at 0 °C,
solid NaBH4 (70 mg, 1.2 mmol) was added in portions with
vigorous stirring over 1 h. The reaction was stirred for another
2 h at room temperature and then quenched with 15 mL of
H2O. The volatiles were removed in vacuo, and the residue
was partitioned between EtOAc and H2O. The aqueous layer
was extracted with EtOAc (2 × 20 mL). The combined organic
layers were washed with brine, dried with Na2SO4, and
evaporated. The mixture was purified by flash chromatography
as for NaBH4 above to give a 3:1 syn:anti diastereomeric
mixture of 24 (by NMR).
Compound 19 (100 mg, 0.3 mmol) in 2.0 mL of THF at 0 °C
was treated with LiAlH4 (3 mg, 0.3 equiv) in THF. After 5 min,
an additional 3 mg of reducing agent was added. The reaction
was stirred at 0 °C for 1 h, followed by quenching with 3 drops
of saturated NH4Cl. The latter was extracted with CH2Cl2. The
dried organic layer was subjected to GCMS analysis to reveal
two peaks of MW 351 in a ratio of 3:1.
Compound 19 (140 mg, 0.4 mmol) in 2.5 mL of THF at -78
°C was treated with 1M N-Selectride (0.6 mL, 0.6 mmol) in
THF over 1 h. The reaction was stirred at -78 °C for an
additional 2 h, and then 0.1 mL of H2O was added. The
volatiles were removed in vacuo and the residue partitioned
between CH2Cl2 and H2O. The organic layer was separated,
dried with Na2SO4, and evaporated. Purification as above gave
a 4:1 syn:anti diastereomeric mixture of 24 (by NMR).
1′-Ben zyl-5′-et h oxy-4-[2-(4-m or p h olin o)et h oxy]sp ir o-
[cycloh exa n e-1, 3′-in d olin ]-2′-on e (25). To a magnetically
1′-Ben zyl-5′-et h oxysp ir o[cycloh exa n e-1,3′-in d olin e]-
4,2′-d ion e Cyclic 4-Eth ylen e Keta l (18). To a magnetically
stirred solution of 8 (2.67 g, 10 mmol) in DME (70 mL) at 0 °C
was added NaH (0.96 g, 40 mmol). After 15 min of stirring,
dibromide 4 (4.3 g, 15 mmol) was added at 0 °C and the
reaction allowed to warm to room temperature. After 16 h the
reaction was quenched with water (30 mL) at 0 °C and
extracted with ethyl acetate (3 × 60 mL). The combined
organics were washed with brine, dried over Na2SO4, and
concentrated in vacuo. Flash chromatography using 20%
EtOAc/methylene chloride yielded 3.5 g (90%) of 18: 1H NMR
(CDCl3, 400 MHz) δ 7.2-7.3 (m, 5H), 6.95 (d, J ) 2.4 Hz, 1H),
6.65 (dd, J ) 2.4 Hz, 8.4 Hz, 1H), 6.55 (d, J ) 8.4 Hz, 1H),
4.85 (s, 2H), 4.0 (t, J ) 2.1 Hz, 4H), 3.9 (q, J ) 6.8 Hz, 2H),
2.3 (m, 2H), 2.0 (m, 1H), 2.2 (m, 1H), 1.8-1.95 (m, 4H), 1.35
(t, J ) 6.8 Hz, 3H); 13C NMR (CDCl3, 400 MHz) δ 179.64,
155.03, 150.17, 136.15, 135.67, 135.19, 128.67, 127.38, 127.02,
112.34, 111.55, 109.14, 108.13, 64.36, 64.28, 64.05, 46.30,
43.34, 31.51, 30.17, 14.86. Anal. Calcd for C24H27NO4: C, 73.26;
H, 6.92; N, 3.56. Found: C, 73.30; H, 6.95; N, 3.58.
1′-Ben zyl-5′-et h oxysp ir o[cycloh exa n e-1,3′-in d olin e]-
4,2′-d ion e (19). A magnetically stirred solution of 18 (4.64 g,
11.8 mmol), PPTS (0.88 g), 10 mL of H2O, and 100 mL of