Solid-Phase Synthesis of Benzofurans and Indoles
2-(2′-Am in op h en yl)-1,3-d ith ia n e (47a ).92 THF (150 mL)
was added to a three-necked flask containing thioacetal 46a
(20.7 g, 86.0 mmol) charged with argon, and the reaction
mixture was cooled using an ice bath. Pd/C (5% loading/50%
water, 13.8 g), followed by NaBH4 (11.13 g, 294 mmol) in three
equal portions over 10 min, was added, and the reaction
mixture was allowed to stir at rt for 18 h. The reaction mixture
was acidified to pH 6 with 2 M HCl, and then chloroform (150
mL) was added and the mixture was stirred for 10 min. The
solution was then filtered, and the organic layer was washed
with water (2×), dried over Na2SO4, and concentrated to leave
a yellow solid. Recrystallization from propan-2-ol gave amine92
47a as needles (15.42 g, 73.0 mmol, 85%). Rf (SiO2, DCM):
0.14. Mp: 112-115 °C. Literature mp:92 114-115 °C. IR
(KBr): 3434, 3340, 1623 cm-1. δH (400 MHz, CDCl3): 1.88-
1.99 (m, 1H), 2.15-2.22 (m, 1H), 2.90-2.95 (m, 2H), 3.06-
3.13 (m, 2H), 4.15 (s, 2H), 5.30 (s, 1H), 6.68 (dd, J ) 1.0, 7.9,
1H), 6.75 (dt, J ) 1.1, 7.5, 1H), 7.09 (dt, J ) 1.5, 7.5, 1H), 7.30
(dd, J ) 1.4, 7.7, 1H). δC (100 MHz, CDCl3): 25.3, 32.0, 48.7,
117.0, 119.1, 123.1, 128.5, 129.3, 144.4. LRMS (EI): 211.0
(M•+), 178.0 (M•+ - SH). HRMS: calcd for C10H13NS2, 211.0489;
found, 211.0490. Anal. Calcd for C10H13NS2: C, 66.89; H, 5.92;
N, 4.88. Found: C, 66.79; H, 5.82; N, 4.73.
435.0693. Anal. Calcd for C20H22N2OS4: C, 55.14; H, 5.09; N,
6.43. Found: C, 55.21; H, 5.05; N, 6.43. Structure confirmed
by X-ray crystallography.
2-[2′-(N-Boc-a m in o)p h en yl]-1,3-d ith ia n e (49a ). Adapting
a known procedure,44 we heated a solution of amine 47a (3.18
g, 15.0 mmol) and (Boc)2O (3.60 g, 16.5 mmol) in THF (25 mL)
under reflux and under nitrogen for 5 h. After this time, the
mixture was poured into water, extracted into DCM (2×),
washed with water (2×), dried over Na2SO4, and concentrated
to yield a pale yellow solid. Recrystallization from propan-2-
ol gave carbamate 49a as golden plates (4.00 g, 12.8 mmol,
86%). Rf (SiO2, DCM): 0.32. Mp: 142-144 °C. IR (KBr): 3400,
1737 cm-1. δH (400 MHz, CDCl3): 1.54 (s, 9H), 1.88-1.99 (m,
1H), 2.17-2.23 (m, 1H), 2.91-2.95 (m, 2H), 3.07-3.14 (m, 2H),
4.75 (s, 1H), 5.30 (s, 1H), 7.05 (dt, J ) 1.0, 7.6, 1H), 7.27 (dt,
J ) 1.5, 8.6, 1H), 7.40 (dd, J ) 1.2, 7.7, 1H), 7.82 (d, J ) 7.1,
1H). δC (100 MHz, CDCl3): 25.1, 28.4, 31.9, 48.3, 80.5, 122.9,
124.1, 128.3, 129.1, 136.1, 138.1, 153.2. LRMS (EI): 311.0
(M•+), 255.0 (M•+ - C4H10); HRMS: calcd for C15H21NO2S2,
311.1014; found, 311.1014. Anal. Calcd for C15H21NO2S2: C,
57.84; H, 6.80; N, 4.50. Found: C, 57.95; H, 6.80; N 4.40.
2-[2′-(N-Boc-a m in o)-4′,5′-m et h ylen ed ioxyp h en yl]-1,3-
d ith ia n e (49c). Amine 47c was prepared as a yellow solid
(7.69 g) in the same way as amine 47e, using Fe powder (4.70
g, 28.0 mmol), thioacetal 46c (8.00 g, 50.0 mmol), and NH4Cl
(7.49 g, 140 mmol) in EtOH (125 mL) and water (75 mL). The
2-(2′-Am in o-5′-h ydr oxyph en yl)-1,3-dith ian e (47e). Adapt-
ing a literature procedure,81 we added Fe powder (7.54 g, 135
mmol) to a solution of thioacetal 46e (12.87 g, 50.0 mmol) and
NH4Cl (12.04 g, 225 mmol), in EtOH (200 mL) and water (200
mL) and heated under reflux for 2 h. After cooling, the mixture
was filtered through Celite and washed with EtOAc. The dark
green solution was then concentrated in vacuo. The resulting
slurry was partitioned between EtOAc and brine, the organics
were then washed with water (2×), dried over MgSO4, and
concentrated in vacuo to give amine 47e as a yellow solid (9.87
g, 43.4 mmol, 87%), which was used in the next step. Recrys-
tallization of a 0.30 g portion, from propan-2-ol, gave amine
47e as needles (0.24 g, 70%). Rf (EtOAc, SiO2): 0.46. Mp: 156-
159 °C. IR (KBr): 3441, 1583, 1520 cm-1. δH (250 MHz, C2D6-
SO): 1.61-1.77 (m, 1H), 2.08-2.15 (m, 1H), 2.80-2.88 (m, 2H),
3.04-3.16 (m, 2H), 4.57 (s, 2H), 5.39 (s, 1H), 6.43-6.49 (m,
2H), 6.69 (d, J ) 2.5, 1H), 8.51 (s, 1H). δC (62.8 MHz, C2D6-
SO): 25.5, 31.6, 46.0, 114.8, 116.3, 117.3, 123.6, 137.5, 148.9;
LRMS (EI): 257.0 (M•+), 240 (M•+ - OH). HRMS: calcd for
1
product was one compound by both H NMR spectroscopy and
TLC analysis and was not further purified after workup due
to its instability. Rf (DCM, SiO2): 0.42. δH (400 MHz, CDCl3):
1.85-1.97 (m, 1H), 2.13-2.20 (m, 1H), 2.88-2.94 (m, 2H),
3.05-3.12 (m, 2H), 5.25 (s, 1H), 5.86 (s, 2H), 6.31 (s, 1H), 6.87
(s, 1H). LRMS (EI): 255 (M•+), 180 (M•+ - C3H7S•). HRMS:
calcd for C11H13NO2S2, 255.0388; found, 255.0385. A solution
of amine 47c (5.61 g, 22.0 mmol) and (Boc)2O (11.52 g, 52.8
mmol) in THF (75 mL) was heated under reflux for 15 h. After
this time, the reaction mixture was poured into water and
extracted into EtOAc (2×). The combined organics were
washed with brine and water, dried over Na2SO4, and con-
centrated to give the crude imide 50c as a green solid. The
solid was dissolved in DCM (250 mL), TFA (2.6 mL, 33.0 mmol)
was added dropwise, and the mixture was allowed to stir for
15 h. After this time, the reaction mixture was washed with
NaHCO3 (2×) then water, dried over Na2SO4, and concentrated
to yield a yellow solid. Recrystallization from propan-2-ol gave
carbamate 49c as yellow needles (6.53 g, 18.4 mmol, 83% over
3 steps). Rf (SiO2, DCM): 0.15. Mp: 156-158 °C. IR (KBr):
3404, 1727, 1508 cm-1. δH (400 MHz, CDCl3): 1.53 (s, 9H),
1.85-1.95 (m, 1H), 2.15-2.21 (m, 1H), 2.88 (dt, J ) 14.4, 3.3,
2H), 3.05-3.12 (m, 2H), 5.22 (s, 1H), 5.93 (s, 2H), 6.94 (s, 1H),
6.24 (s, 1H). δC (90 MHz, CDCl3): 25.1, 28.4, 32.0, 47.7, 80.5,
101.5, 105.6, 107.7, 130.1, 147.9, 153.5. LRMS (EI): 355.0
C10H13NOS2, 257.0180; found, 257.0178. Anal. Calcd for C10H13
-
NOS2: C, 52.86; H, 5.73; N, 6.17. Found: C, 52.86,; H, 5.76;
N, 6.13.
Dia zin e-N-oxid e (48). THF (150 mL) was added to a three-
necked flask charged with argon and containing thioacetal 46a
(14.15 g, 58.6 mmol), and the reaction was cooled using an ice
bath. Pd/C (5% loading/ 50% water, 4.38 g), followed by NaBH4
(5.54 g, 147 mmol) in three equal portions over 15 min, was
added, and the reaction was allowed to stir at rt for 18 h. After
this time, the reaction was worked up exactly as for amine
(M•+), 298.0 (M•+ - C4H8), 282.0 (M•+ - C4H9O), 225.0 (M•+
-
-
-
1
C6H10O3), 192.0 (M•+ - C6H12NO4). HRMS: calcd for C16H21
47a above, to leave an orange oil (13.52 g). H NMR spectros-
copy confirmed that an 18:8:2 mixture of amine 47a /diazine-
N-oxide 48/starting material 46a was obtained. Column
chromatography (SiO2, CHCl3) gave pure starting material 46a
(0.50 g, 2.07 mmol), amine 47a (5.21 g, 24.7 mmol), and
diazine-N-oxide 48 (1.93 g, 4.43 mmol). The latter was
recrystallized from EtOAc, to give diazine-N-oxide 48 as
orange/yellow needles (1.59 g, 3.65 mmol). Rf (SiO2, CHCl3):
0.25. Mp: 202-204 °C. IR (KBr): 1630 cm-1. δH (400 MHz,
CDCl3): 1.86-1.97 (m, 2H), 2.09-2.15 (m, 2H), 2.81-2.85 (m,
4H), 3.04-3.12 (m, 4H), 5.75 (s, 1H), 6.00 (s, 1H), 7.41-7.47
(m, 3H), 7.53-7.7.54 (m, 1H), 7.71 (dd, J ) 1.2, 7.9, 1H), 7.81-
7.83 (m, 1H), 7.89 (dd, J ) 1.3, 7.8, 1H), 8.55-8.57 (m, 1H).
δC (100 MHz: CDCl3): 25.0, 25.1, 32.0, 32.1, 45.6, 122.0, 124.1,
128.4, 129.0, 129.1, 130.0, 130.1, 130.7, 132.1, 136.5, 138.1,
140.2, 147.8. LRMS (CI+): 435.0 [(M + H)+], 417.1 [(M + H)+
- H2O]. HRMS: calcd for C20H22N2OS4, 435.0693; found,
NO4S2, 355.0912; found, 355.0914. Anal. Calcd for C16H21
NO4S2: C, 54.08; H, 5.91; N, 3.94. Found: C, 54.23; H, 6.05;
N, 3.86.
2-[2′-(N,N-d i-ter t-bu toxyca r boxya m in o)p h en yl]-1,3-d i-
th ia n e (50a ). A solution of NaHMDS (22.0 mL, 22.0 mmol, 1
M in THF) was added to a solution of amine 47a (2.11 g, 10.0
mmol) and (Boc)2O (5.46 g, 25.0 mmol) in THF (50 mL) at 0
°C under nitrogen. The reaction was allowed to warm to rt
and stirred for 16 h. After this time, the reaction was poured
into water, extracted into DCM (2×), washed with water (2×),
dried over Na2SO4, and concentrated to yield a white/yellow
solid. Recrystalization from petroleum ether (40-60 °C) gave
imide 50a as needles (3.21 g, 7.80 mmol, 78%). Rf (hexane/
DCM 1:9, SiO2): 0.10. Mp: 106-109 °C. IR (KBr): 1789 cm-1
.
δH (400 MHz, CDCl3): 1.36 (s, 18H), 1.91-1.95 (m, 1H), 2.13-
2.17 (m, 1H), 2.84-2.89 (m, 2H), 2.98-3.05 (m, 2H), 5.22 (s,
1H), 5.30 (s, 1H), 7.06 (dd, J ) 1.2, 7.8, 1H), 7.27 (dt, J ) 1.6,
7.5, 1H), 7.31 (dt, J ) 1.2, 7.5, 1H), 7.67 (dd, J ) 1.5, 7.7, 1H).
δC (100 MHz: CDCl3): 25.1, 27.6, 32.0, 45.8, 82.8, 128.4, 128.5,
(92) Gassman, P. G.; Drews, H. R. J . Am. Chem. Soc. 1978, 100,
7600-7610.
J . Org. Chem, Vol. 68, No. 2, 2003 399