Electronic Effects on Functional Reactivity
J . Org. Chem., Vol. 61, No. 15, 1996 4909
THF (112 µL) at 0 °C was treated with NaH (1.6 mg, 39 µmol,
60% oil dispersion), and the mixture was stirred for 30 min.
The solvent was removed under a stream of N2 and vacuum.
PTLC (SiO2, 0.25 mm × 10 × 15 cm, 30% EtOAc-hexane)
afforded 25 (1.20 mg, 1.26 mg theoretical, 95%) as a white
solid: 1H NMR (CDCl3, 400 MHz) δ 8.29 (d, 1H, J ) 8.1 Hz,
C5-H), 7.64 (dd, 1H, J ) 1.5, 8.1 Hz, C6-H), 7.14 (d, 1H, J )
1.1 Hz, C8-H), 6.87 (br s, 1H, C3-H), 4.03 (m, 2H, C1-H2), 2.81
(dt, 1H, J ) 4.9, 7.5 Hz, C9a-H), 1.65 (dd, 1H, J ) 4.7, 7.9 Hz,
C9-H), 1.55 (s, 10H, C9-H and C(CH3)3); 13C NMR (CDCl3, 100
MHz) δ 180.4, 159.8, 151.4, 140.9, 135.8, 129.6, 127.7, 125.3,
118.2, 115.0, 108.8, 83.9, 52.9, 33.2, 29.4, 28.1, 23.8; IR (film)
νmax 2977, 2230, 1727, 1634, 1608, 1396, 1369, 1295, 1277,
1250, 1159, 1131, 843 cm-1; UV (THF) λmax 259 (ꢀ ) 22 200),
267 (ꢀ ) 24 000), 300 nm (ꢀ ) 12 000); UV (CH3OH) λmax 260
(ꢀ ) 24 700), 266 (ꢀ ) 25 200), 317 nm (ꢀ ) 13 400); FABHRMS
(NBA) m/z 323.1383 (M+ + H, C19H18N2O3 requires 323.1396).
N-(ter t-Bu tyloxycar bon yl)-N-(2-pr open yl)-4-(ben zyloxy)-
7-cya n o-1-iod o-2-n a p h th yla m in e (28). A solution of 27 (160
mg, 0.31 mmol) in anhydrous DMF (5 mL) under Ar was
treated with NaH (19 mg, 0.47 mmol, 1.5 equiv, 60% oil
dispersion), and the reaction mixture was stirred for 30 min
at 0 °C. Allyl bromide (194 mg, 139 µL, 1.55 mmol, 5 equiv)
was added dropwise over 5 min, and the solution was allowed
to warm to 25 °C and stirred for 2 h. Saturated aqueous
NaHCO3 (10 mL) was added, and the aqueous phase was
extracted with EtOAc (4 × 10 mL), dried (Na2SO4), and
concentrated. Chromatography (SiO2, 2 × 15 cm, 10% EtOAc-
hexane) afforded 28 (155 mg, 168 mg theoretical, 92%) as a
clear oil that crystallized under vacuum: 1H NMR (CDCl3, 400
MHz) δ 8.60 (s, 1H), 8.38 (d, 1H, J ) 8.6 Hz), 7.63 (d, 1H, J )
8.4 Hz), 7.47-7.34 (m, 5H), 6.90 and 6.79 (two s, 1H), 5.94-
5.84 (m, 1H), 5.27 and 5.22 (two d, 2H, J ) 12.3 Hz), 5.00 (m,
2H), 4.50 (dd, 1H, J ) 5.3, 14.4 Hz), 3.81 (dd, J ) 7.0, 14.4
Hz), 1.57 and 1.29 (two s, 9H); 13C NMR (CDCl3, 100 MHz) δ
154.8, 144.9, 138.7, 135.7, 134.8, 133.2, 128.8, 128.3, 127.3,
126.9, 126.8, 124.2, 118.8, 118.4, 117.2, 112.2, 110.7, 80.8, 70.7,
53.3, 52.0, 28.4; IR (film) νmax 2977, 2228, 1703, 1593, 1503,
1410, 1368, 1324, 1250, 1223, 1150, 1108, 931, 830, 735, 696
(+)-N-BOC-CCBI (25): [R]23 +124 (c 0.04, THF).
D
en t-(-)-N-BOC-CCBI (25): [R]23 -121 (c 0.03, THF).
D
Meth od B. A solution of 23 (8.6 mg, 24.0 µmol) was
dissolved in 1:1 THF-5% aqueous NaHCO3 (2 mL), and the
mixture was stirred at 25 °C for 9 h. The THF was removed
by evaporation, and the product was extracted with EtOAc (4
× 1 mL). Chromatography (SiO2, 0.8 × 5 cm, 0-25% EtOAc-
hexane gradient) afforded 25 (7.7 mg, 7.7 mg theoretical, 100%)
as a white solid identical to that described above.
cm-1; FABHRMS (NBA-CsI) m/z 672.9948 (M+ + Cs, C26H25
-
IN2O3, requires 672.9964).
Anal. Calcd for C26H25IN2O3: C, 57.99; H, 4.66; N, 5.18.
Found: C, 57.60; H, 4.41; N, 5.27.
5-(Be n zyloxy)-3-(t er t -b u t yloxyca r b on yl)-8-cya n o-1-
[(2′,2′,6′,6′- tetr a m eth ylp ip er id in o)oxy]m eth yl-1,2-d ih y-
d r o-3H-ben z[e]in d ole (29). A solution of 28 (200 mg, 0.37
mmol) in freshly distilled benzene (12 mL) was treated
sequentially with TEMPO (3.0 equiv) and Bu3SnH (1.0 equiv).
The reaction mixture was warmed to 60 °C. After 20 min, an
additional 1 equiv of Bu3SnH was added. After 30 min,
additional TEMPO (2 equiv) and Bu3SnH (1.0 equiv) were
added. After 20 min, 2 equiv of TEMPO and Bu3SnH in two
separate portions at 15 min intervals were added. After 45
min at 60 °C, the solvent was removed by evaporation. PCTLC
(4 mm SiO2, 0-25% EtOAc-hexane gradient) afforded 29 (144
mg, 212 mg theoretical, 68%) as a semisolid: 1H NMR (CDCl3,
400 MHz) δ 8.31 (d, 1H, J ) 8.7 Hz), 8.19 (s, 1H), 8.01 (s, 1H),
7.53 (d, 2H, J ) 7.0 Hz), 7.44 (t, 2H, J ) 7.0 Hz), 7.40 (m,
2H), 5.26 (s, 2H), 4.13 (m, 2H), 3.96 (m, 1H), 3.88 (t, 1H, J )
7.0 Hz), 3.80 (m, 1H), 1.59 (s, 9H), 1.39 (m, 4H), 1.10 (s, 3H),
1.03 (s, 6H), 0.96 (s, 3H), 0.92 (t, 2H, J ) 7.3 Hz); 13C NMR
(CDCl3, 100 MHz) δ 155.2, 152.6, 143.0, 136.4, 129.8, 129.6,
128.7, 128.2, 127.7, 124.5, 123.3, 123.1, 119.5, 117.1, 110.3,
99.1, 81.1, 78.7, 70.5, 59.9, 52.8, 39.6, 39.5, 38.1, 33.0, 28.5,
26.6, 20.4, 20.2, 17.1, 13.6; IR (film) νmax 2968, 2926, 1701,
7-Cyan o-1,2,9,9a-tetr ah ydr ocyclopr opa[c]ben z[e]in dol-
4-on e (26, CCBI). A solution of 23 (2.5 mg, 7.0 µmol) in 4 M
HCl-EtOAc (400 µL) was stirred at 25 °C under Ar for 30 min.
The solvent was removed under a stream of N2. After being
dried in vacuo, the residue 3014 was dissolved in THF (200
µL) and treated with 200 µL of 5% aqueous NaHCO3. The
reaction mixture was stirred at 25 °C for 5 h before the solvent
was removed in vacuo. PTLC (SiO2, 0.25 mm × 20 × 20 cm,
70% THF-hexane) afforded 26 (1.6 mg, 1.6 mg theoretical,
100%) as a cream colored solid: 1H NMR (CDCl3, 250 MHz) δ
8.30 (d, 1H, J ) 8.1 Hz, C5-H), 7.61 (dd, 1H, J ) 1.5, 8.1 Hz,
C6-H), 7.11 (d, 1H, J ) 1.5 Hz, C8-H), 5.77 (s, 1H, C3-H), 4.88
(br s, 1H, NH) 3.87 (dd, 1H, J ) 5.2, 10.3 Hz, C1-H), 3.69 (d,
1H, J ) 10.3 Hz, C1-H), 2.92 (dt, J ) 3.6, 6.7 Hz, 1H, C9a-H),
1.63 (dd, 1H, J ) 4.3, 7.9 Hz, C9-H), 1.49 (t, 1H, J ) 4.7 Hz,
C9-H); IR (film) νmax 3097, 2851, 2227, 1622, 1583, 1519, 1328,
1241, 1092, 809 cm-1; UV (THF) λmax 337 (ꢀ ) 4400), 312 (ꢀ )
4000), 266 (ꢀ ) 6300), 246 (ꢀ ) 13 500), 222 nm (ꢀ ) 15 000);
UV (CH3OH) λmax 348 (ꢀ ) 5500), 317 (ꢀ ) 4300), 264 (ꢀ )
6500), 248 (ꢀ ) 16 300), 221 nm (ꢀ ) 12 800); FABHRMS (NBA)
m/z 223.0865 (M+ + H, C14H10N2O requires 223.0871).
(+)-CCBI (26): [R]23 +64 (c 0.05, THF).
1623, 1586, 1450, 1407, 1352, 1326, 1143, 1041, 855 cm-1
;
D
en t-(-)-CCBI (26): [R]23 -67 (c 0.05, THF).
FABHRMS (NBA) m/z 570.3330 (M+ + H, C35H43N3O4 requires
570.3332).
D
N-(ter t-Bu tyloxycar bon yl)-4-(ben zyloxy)-7-cyan o-1-iodo-
2-n a p h th yla m in e (27). A solution of 23 (250 mg, 0.67 mmol)
in 10 mL of THF-CH3OH (1:1) at -40 °C was treated with a
catalytic amount of TsOH-H2O (20 mg) and NIS (180 mg, 0.80
mmol, 1.2 equiv) in 2 mL of THF. The reaction mixture was
stirred under Ar at -40 °C for 1 h and then warmed to 0 °C.
Additional TsOH-H2O (10 mg) and NIS (75 mg, 0.5 equiv)
were added. After the reaction mixture was stirred for 1 h at
25 °C, it was quenched with the addition of 5 mL of saturated
aqueous NaHCO3 and extracted with Et2O (4 × 15 mL). The
combined organic layer was washed with saturated aqueous
NaCl and dried (Na2SO4). PCTLC (2 mm SiO2, 0-10%
EtOAc-hexane gradient) afforded 27 (230 mg, 338 mg theo-
retical, 68%) as a solid: mp 177 °C dec (needles, EtOAc-
hexane); 1H NMR (CDCl3, 400 MHz) δ 8.38 (d, 1H, J ) 1.5
Hz), 8.26 (d, 1H, J ) 8.6 Hz), 8.21 (s, 1H), 7.52 (dd, 2H, J )
1.0, 7.8 Hz), 7.47 (dd, 1H, J ) 1.5, 8.6 Hz), 7.45-7.35 (m, 3H),
7.33 (br s, 1H), 5.26 (s, 2H), 1.59 (s, 9H); 13C NMR (CDCl3,
100 MHz) δ 155.4, 152.5, 140.2, 137.0, 135.9, 134.2, 128.7,
128.4, 127.9, 125.1, 125.0, 124.3, 119.0, 112.2, 102.2, 81.8, 78.8,
70.7, 28.3; IR (film) νmax 3383, 2978, 2228, 1732, 1600, 1563,
seco-CCBI-TMI (34). A solution of 23 (1.5 mg, 4.2 µmol)
in 150 µL of 4 M HCl-EtOAc was stirred at 25 °C for 20 min.
The solvent was removed under a stream of N2. After being
dried in vacuo, the residue, 3014 (1.0 mg, 4.2 µmol, 1 equiv),
and EDCI (2.9 mg, 12.6 µmol, 3 equiv) were dissolved in
anhydrous DMF, and the reaction mixture was stirred at 25
°C for 16 h. The solvent was removed under vacuum, and the
residue was dissolved in THF and loaded directly onto a silica
gel column. Chromatography (SiO2, 0.5 × 6 cm, 50% EtOAc-
hexane) afforded 34 (1.7 mg, 2.0 mg theoretical, 85%) as a
mustard-colored solid: 1H NMR (DMSO-d6, 250 MHz) δ11.50
(br s, 1H, NH), 10.86 (s, 1H, OH), 8.53 (s, 1H, C9-H), 8.22 (d,
1H, J ) 8.7 Hz, C6-H), 8.04 (s, 1H, C4-H), 7.59 (dd, 1H, J )
1.5, 8.7 Hz, C7-H), 7.07 (d, 1H, J ) 1.7 Hz, C4′-H), 6.95 (s,
1H, C3′-H), 4.75 (t, 1H, J ) 10.0 Hz, C2-H), 4.46 (d, 1H, J )
10.5 Hz, C2-H), 4.26 (m, C1-H), 4.04 (dd, 1H, J ) 2.8, 11.3
Hz, CHHCl), 3.92 (s, 3H), 3.88 (dd, 1H, J ) 3.9, 11.3, Hz), 3.81
(s, 3H), 3.79 (s, 3H); IR (film) νmax 3422, 3122, 2938, 2225, 1587,
1525, 1493, 1454, 1389, 1312, 1235, 1110, 1050, 997, 824, 794
cm-1; FABHRMS (NBA) m/z 492.1347 (M+ + H, C26H22ClN3O5
requires 492.1326).
1495, 1397, 1366, 1331, 1230, 1154, 987, 879, 735 cm-1
;
FABHRMS (NBA-CsI) m/z 632.9674 (M+ + Cs, C23H21IN2O3
requires 632.9651).
Anal. Calcd for C23H21IN2O3: C, 55.21; H, 4.23; N, 5.60.
Found: C, 55.28; H, 4.03; N, 5.40.
(1S)-34: [R]25 -19 (c 0.12, CHCl3).
D
en t-(1R)-34: [R]25 +19 (c 0.12, CHCl3).
D
CCBI-TMI (35). A solution of 34 (2.2 mg, 4.4 µmol) in
20% DMF-THF (0.25 mL, 0.018 M) under Ar was cooled to 0