The Journal of Organic Chemistry
Article
1
2
Progress of the hydrogenation was followed by TLC (2:5 EtOAc/
bromide (R,R)-6 (500 mg, 0.932 mmol) in anhydrous CH Cl (15
2 2
hexanes, starting indole 13 R = 0.33; product 14 R = 0.13). Usually, it
mL). The reaction mixture was stirred at 0 °C for 15−20 min, and the
color of the solution turned bright yellow. The reaction was complete
at that point. The solution was poured into a 1:1:2 mixture of water,
saturated aqueous NaHCO , and saturated aqueous Na CO (50 mL).
f
f
required 4−6 h for the hydrogenation to go to completion. In case of
incomplete conversion after 6 h, it is recommended to add an
additional amount of 10% Pd−C (182 mg, 0.171 mmol, 4 mol %) and
continue the hydrogenation. Once the reaction is completed, it was
filtered through a plug of Celite. The filter cake was washed with
3
2
3
Layers were separated, and the aqueous layer was extracted with Et O
2
(3 × 80 mL). The organic extracts were combined, washed with water
EtOH (120 mL), EtOAc (200 mL), and Et O (120 mL). All filtrates
(100 mL) and brine, and dried over Na SO . Column chromatography
2
2
4
were combined and solvents were concentrated (aspirator) to afford
(50 mL silica gel, column i.d. 30 mm) using gradient elution from 10%
EtOAc in hexanes to 30% EtOAc in hexanes afforded (R,R)-8 as
colorless solid (405 mg, 96% yield): analytical TLC on silica gel, 2:5
EtOAc/hexanes, Rf = 0.58; pure material was obtained by
crystallization from CH Cl /hexanes, mp 183−184 °C; IR (film,
1
4 as a grayish amorphous material (1.4 g, 88% yield): analytical TLC
−1
on silica gel, 1:1 EtOAc/hexanes, R = 0.41; IR (film, cm ) 3143 (O−
H); H NMR (400 MHz, CDCl , ppm) δ 7.38 (1H, s), 7.18 (1H, s),
f
1
3
7
(
.07−7.05 (2H, m), 6.69 (1H, br s), 6.63 (1H, m), 2.54 (3H, s), 1.70
2
2
3H, septet, J = 7.5 Hz), 1.15 (18H, d, J = 7.5 Hz); 13C{ H} NMR
1
cm ) 1734 (CO), 1487; H NMR (400 MHz, CDCl , ppm) δ
−1
1
3
(
101 MHz, CDCl , ppm) δ 159.3, 149.6, 147.4, 143.5, 128.6, 123.5,
7.44−7.30 (6H, m), 7.26 (1H, dd, J = 8.0, 1.0 Hz), 7.22 (1H, d, J = 2.7
Hz), 6.85 (1H, d, J = 2.7 Hz), 6.81 (1H, dd, J = 8.7, 2.7 Hz), 6.75 (1H,
d, J = 8.7 Hz), 6.67 (1H, t, J = 7.8 Hz), 5.27 (1H, d, J = 2.4 Hz), 5.01
3
1
21.3, 116.4, 106.9, 106.3, 105.4, 18.0, 14.1, 12.7; HRMS-ESI (m/z)
+
calcd for C H N O Si [M + H] 371.2149, found 371.2153.
21
31
2
2
(2H, s), 3.82 (3H, s); 13C{ H} NMR (101 MHz, CDCl , ppm) δ
1
3
-(2-Methyloxazol-5-yl)-1-(triisopropylsilyl)-1H-indol-4-yltri-
fluoromethanesulfonate (15). A dispersion of NaH in mineral oil
60%, 290 mg, 1.23 mmol) was added portionwise to a solution of 4-
hydroxyindole 14 (1.30 g, 3.51 mmol) in anhydrous THF (40 mL) at
°C under atmosphere of nitrogen. The resulting suspension was
3
169.7, 154.0, 152.7, 146.2, 137.1, 132.0, 128.7, 128.1, 128.1, 127.8,
127.2, 123.3, 121.1, 116.1, 111.9, 110.5, 102.8, 99.2, 71.3, 67.3, 53.4;
(
+
HRMS-ESI (m/z) calcd for C H BrNO [M + H] 452.0492, found
23
19
4
20
0
452.0495; optical rotation [α]D −176 (c 0.1, benzene). Anal. Calcd
for C H BrNO : C, 61.08; H, 4. 01; N, 3.10. Found: C, 60.61; H,
stirred at ambient temperature for 2 h until gas evolution ceased. Then
a solution of N-phenyl-bis(trifluoromethanesulfonimide) (2.19 g, 6.14
mmol) in anhydrous THF (10 mL) was added in one portion, and the
reaction mixture was stirred for 1 h at room temperature, whereupon it
was poured into aqueous NaHCO3 solution (100 mL; aqueous
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18
4
3.96; N, 2.99.
Methyl (5aR,10bR)-2-(Benzyloxy)-7-bromo-6-(methoxy-
methyl)-5a,6-dihydro-10bH-benzofuro[2,3-b]indole-10b-car-
boxylate (R,R-5). An oven-dried pressure tube was charged with
hemiaminal bromide (R,R)-8 (390 mg, 0.86 mmol) and paraformal-
dehyde (129 mg, 4.30 mmol) and flushed with nitrogen. Anhydrous
DCM (25 mL) was added, and to the resulting suspension was added
TMSCl (275 μL, 2.15 mmol). The pressure tube was closed, and the
pale yellow suspension was heated for 24 h at 35 °C. After being
cooled to ambient temperature, the suspension was transferred
dropwise to precooled (0 °C) anhydrous MeOH (15 mL) using a
metal cannula. Stirring was continued at room temperature for 15 min,
saturated NaHCO solution was diluted 1:1 with water). Aqueous
3
layer was extracted with Et O (2 × 100 mL), and combined organic
2
extracts were washed with H O (130 mL) and brine (150 mL) and
2
dried over Na SO . Column chromatography (100 mL silica gel,
2
4
column i.d. 30 mm) using gradient elution from 10% EtOAc in
hexanes to 20% EtOAc in hexanes afforded 15 as a yellowish
amorphous solid (1.61 g, 92% yield): analytical TLC on silica gel, 2:5
−
1
EtOAc/hexanes, R = 0.52; IR (film, cm ) 1221 (SO), 1213 (S
f
1
O); H NMR (400 MHz, CDCl , ppm) δ 7.51 (1H, d, J = 8.2 Hz),
then the reaction mixture was poured into saturated aqueous NaHCO
(50 mL) and extracted with Et O (3 × 50 mL). The organic extracts
were combined, washed with brine, and dried on Na SO . Column
3
3
7.43 (1H, s), 7.19 (1H, t, J = 8.1 Hz), 7.13 (1H, d, J = 8.1 Hz), 7.04
2
(
1H, s), 2.52 (3H, s), 1.70 (3H, septet, J = 7.5 Hz), 1.15 (18 H, d, J =
2
4
1
7
1
1
.5 Hz); 13C{ H} NMR (101 MHz, CDCl , ppm) δ 161.1, 145.0,
chromatography on silica gel using 10% EtOAc in hexanes as a mobile
phase afforded (R,R)-5 as an amorphous colorless solid (410 mg, 96%
3
43.8, 142.7, 132.6, 123.9, 122.2, 121.0, 120.2, 114.3, 112.8, 105.4,
8.0, 14.0, 12.7; HRMS-ESI (m/z) calcd for C H F N O SSi [M +
yield): analytical TLC on silica gel, 2:5 EtOAc/hexanes, R = 0.50; IR
f
22
30
3
2
4
+
−1
1
H] 503.1642, found 503.1651.
-Methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
-(triisopropylsilyl)-1H-indol-3-yl)oxazole (4). To a mixture of
Pd(OAc) (13.0 mg, 0.057 mmol, 1.5 mol %), DPE-Phos (61 mg,
(CHCl
3
, cm ) 1738 (CO), 1488; H NMR (400 MHz, C
D ,
6 6
2
ppm) δ 7.48 (1 H, dd, J = 7.5, 1.2 Hz), 7.43 (1 H, d, J = 2.7 Hz),
7.25−7.21 (2 H, m), 7.16−7.05 (4 H, m), 7.01 (1 H, s), 6.67 (1 H, d, J
= 8.7 Hz), 6.57 (1 H, dd, J = 8.7, 2.7 Hz), 6.39 (1 H, t, J = 7.8 Hz),
5.42 (1 H, d, J = 10.6 Hz), 4.76 (1 H, d, J = 10.6 Hz), 4.65 (2 H, s),
3.13 (3 H, s), 3.11 (3 H, s); 13C{ H} NMR (101 MHz, C D , ppm) δ
1
2
0
.114 mmol, 3 mol %), and triflate 15 (1.70 g, 3.38 mmol) in
1
anhydrous dioxane (30 mL) under nitrogen atmosphere was added
6
6
NEt (1.6 mL, 11.43 mmol), followed by pinacolborane (830 μL, 5.72
169.4, 154.4, 153.1, 144.7, 137.7, 134.90, 132.7, 128.6, 128.2, 128.0,
127.8, 123.9, 122.5, 116.2, 112.5, 110.8, 105.1, 104.3, 79.4, 71.0, 64.5,
55.0, 52.6; HRMS-ESI (m/z) calcd for C H BrNO [M + H]+
496.0754, found 496.0764; optical rotation [α]D −235 (c 0.33,
benzene).
General Procedure for Optimization of the Suzuki Cross-
Coupling (Table 1). The hemiaminal bromide (R,R)-5 (30 mg,
0.0604 mmol), the indolyl boronate 4 (29 mg, 0.0604 mmol), an oven-
3
mmol). The resulting yellow solution was heated at 80 °C for 1 h in a
sealed vessel under nitrogen atmosphere, cooled to ambient
temperature, poured into water (150 mL), and extracted with
EtOAc (2 × 150 mL). The organic extracts were combined and
washed with brine, dried on Na SO , filtered, and concentrated.
25
23
5
20
2
4
Column chromatography (200 mL of silica gel, column i.d. 45 mm)
using gradient elution from 10% EtOAc in hexanes to 50% EtOAc in
hexanes afforded 4 as a yellowish oil (1.48 g, 91%) that crystallized
upon standing: analytical TLC on silica gel, 1:1 Et O/hexanes, R =
dried K PO (51 mg, 0.242 mmol), Pd catalyst (20 mol %), and
3 4
phosphine ligand (if indicated in Table 1) were weighted into an oven-
dried pressure vial in a glovebox (argon atmosphere). A solution of 4-
cyanotoluene as an internal standard (0.0604 mmol, 1 equiv with
respect to the hemiaminal bromide (R,R)-5) in dry degassed dioxane
or toluene (2 mL) was added, and the pressure vial was closed. The
reaction mixture was heated in an oil bath (for appropriate time and
temperature, see Table 1), and progress of the reaction was monitored
by reversed-phase HPLC (an aliqot of the reaction mixture was diluted
with MeCN, filtered trough a plug of Celite, and submitted to HPLC
analysis). Conversion of the starting bromide (R,R)-5 and yield of the
biaryl product (R,R)-3 were determined based on a calibration curve
using the internal standard.
2
f
0
.20; pure material was obtained by crystallization from CH Cl /
2 2
−1
1
hexanes, mp 97−98 °C; IR (film, cm ) 1363 (B−O); H NMR (400
MHz, CDCl , ppm) δ 7.61 (2H, dt, J = 8.5, 0.8 Hz), 7.34 (1H, s), 7.17
3
(
(
1H, m), 6.92 (1H, s), 2.50 (3H, s), 1.68 (3H, septet, J = 7.6 Hz), 1.21
12H, s), 1.13 (18H, d, J = 7.7 Hz); C{ H} NMR (101 MHz,
13
1
CDCl , ppm) δ 160.1, 147.1, 140.7, 134.2, 133.1, 129.1, 124.3, 121.4,
3
1
16.8, 107.7, 83.3, 29.8, 24.7, 18.0, 14.5, 12.8. Anal. Calcd for
C H N O SiB: C, 67.49; H, 8.60; N, 5.83. Found: C, 67.23; H, 8.79;
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2
3
N, 5.65.
Methyl (5aR,10bR)-2-(benzyloxy)-7-bromo-5a,6-dihydro-
0bH-benzofuro[2,3-b]indole-10b-carboxylate (R,R-8). 1,3-Di-
1
2
methylbarbituric acid (7) (437 mg, 2.80 mmol) and Pd(PPh ) (54
Preparation of (PCy ) Pd(η -O ) (16). A freshly prepared solid
3
4
3 2
2
2
2a
mg, 0.047 mmol, 5 mol %) were added to a cooled (0 °C) solution of
Pd(PCy ) complex (294 mg, 0.44 mmol) was weighted into a
3 2
F
J. Org. Chem. XXXX, XXX, XXX−XXX