1808 J . Org. Chem., Vol. 62, No. 6, 1997
Zhang and Maryanoff
sodium triacetoxyborohydride (25 mg, 0.12 mmol) in one
portion. The resulting mixture was stirred at room temper-
ature for 3 h, at which time TLC showed that the reaction
was complete. Acetone (1 mL) was added to the reaction
mixture. After being stirred for another hour, the mixture was
diluted with ethyl acetate (20 mL), and the solution was
washed with water (5 mL) and brine (5 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. The resulting
crude product was purified by preparative TLC using hexane:
ethyl acetate (5:1) to afford 11.5 mg (79%) of 3.
128.8, 129.4, 129.7, 138.2, 139.5, 177.7; MS m/z 265 (MH+);
FAB-HRMS calcd for C17H16N2O + H+ 265.1341, found
265.1325.
Solid -P h a se Syn th esis of In d ole Der iva tives 15 via
P a lla d iu m -Med ia ted Cycliza tion . A. 2-[1-[4-(Tr iflu o-
r om eth yl)ben zyl]-1H-in dol-3-yl]acetam ide (15c). The pro-
cedure described here for 15c is representative. Rink amide
resin (7.5 g, 0.48 mmol/g, 3.6 mmol) was deprotected with 20%
piperidine in DMF (100 mL) at room temperature for 1.5 h
and then filtered and washed with DMF, MeOH, and CH2Cl2.
The deprotected resin was suspended in DMF (36 mL) and
treated with DIC (2.73 g, 21.6 mmol), followed by γ-bromo-
crotonic acid (9a , 3.56 g, 21.6 mmol). The mixture was stirred
at room temperature for 30 min, and then filtered, washed
with CH2Cl2 and DMF. The resulting resin was retreated with
DMF (36 mL), DIC (21.6 mmol), and 9a (21.6 mmol) at room
temperature for 30 min and then washed with DMF, MeOH,
CH2Cl2, and Et2O and dried in vacuo to give 7.41 g of resin
10a with a loading level of 0.32 mmol/g, which was determined
by cleaving an aliquot with 30% TFA in CH2Cl2 at room
temperature for 80 min. Resin 10a (1.2 g, 0.38 mmol) was
suspended in DMF (10 mL) and treated with N,N-diisopropyl-
ethylamine (387 mg, 3.0 mmol) followed by 2-iodoaniline (420
mg, 1.9 mmol). The reaction mixture was stirred at 80 °C for
18 h and then filtered, washed with CH2Cl2, MeOH, and CH2-
Cl2, and dried in vacuo to give 1.25 g of 12a . A mixture of
resin 12a (230 mg, 0.070 mmol), N,N-diisopropylethylamine
(90 mg, 0.70 mmol), and R′-bromo-R,R,R-trifluoro-p-xylene (167
mg, 0.70 mmol) in DMF (2.5 mL) was stirred at 80 °C for 22
h and then filtered, washed sequentially with MeOH and CH2-
Cl2, and dried in vacuo to give 14 (R1 ) H, R2 ) 4′-CF3).
(Note: For the alkylation of 12c, double treatments with
alkylating agents were required for the complete conversion.)
The resulting resin was then suspended in DMF-H2O (9:1, 4
mL) and treated with tetrabutylammonium chloride (29 mg,
0.11 mmol), triethylamine (21 mg, 0.21 mmol), and bis-
(triphenylphosphine)palladium(II) chloride (4.9 mg, 0.007
mmol). The suspension was stirred at 80 °C for 8 h, at which
time TLC indicated that the reaction was complete. The dark
brown reaction mixture was filtered, washed sequentially with
CH2Cl2, MeOH, and CH2Cl2, and then dried in vacuo. The
resulting resin was cleaved with 30% TFA in CH2Cl2 (8 mL)
at room temperature for 1.5 h. The crude cleaved product
obtained was dissolved in ethyl acetate (25 mL), and the
solution was washed with water (5 mL), to remove contami-
nated Et3N-TFA salt, and then brine (5 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. The resulting
product showed 85% purity by reversed-phase HPLC (2 mL/
min, 7:3 H2O/CH3CN (0.2% TFA), linear gradient to 5:95 in
30 min; Rf ) 18.5 min). After purification by preparative TLC
using ethyl acetate-methanol (95:5), 17.2 mg (74% yield for
four steps, based on the loading level of 10a ) of 15c was
obtained as a colorless solid: 1H NMR (CD3OD) δ 3.67 (s, 2
H), 5.46 (s, 2 H), 7.06 (t, J ) 7.0 Hz, 1 H), 7.13 (t, J ) 7.2 Hz,
1 H), 7.25-7.31 (m, 4 H), 7.56-7.61 (m, 3 H); 13C NMR (CD3-
In d ole-3-a cetic Acid Meth yl Ester (2). To a solution of
4-[(2-iodophenyl)amino]but-2-enoic acid methyl ester (3) (22
mg, 0.069 mmol), tetrabutylammonium chloride (29 mg, 0.10
mmol), and triethylamine (40 mg, 0.40 mmol) in DMF-H2O
(9:1, 2 mL) was added bis(triphenylphosphine)palladium(II)
chloride (5.0 mg, 0.007 mmol). The resulting mixture was
stirred under nitrogen at 80 °C for 2 days, and then the
volatiles were removed under vacuum. The residue was
separated by preparative TLC using hexane:ethyl acetate (2:
1) to afford 10.5 mg (80%) of 2 as a colorless viscous solid: 1H
NMR (CDCl3) was identical with an authentic sample: MS
m/z 190 (MH+).
4-[(2-Iod op h en yl)a m in o]bu t-2-en oic Acid (4). A solu-
tion of the crude 3 (1.5 g; see preparation of 3) and bis-
(tributyltin) oxide (8.46 g, 14.2 mmol) in toluene (50 mL) was
stirred at 90 °C for 2 days. The solvent was then removed in
vacuo, and the residue was partitioned between hexane (60
mL) and 1 N aqueous NaOH (40 mL). The aqueous layer was
separated, and the organic layer was extracted with 1 N
aqueous NaOH (3 × 40 mL). The combined aqueous extracts
were acidified with 3 N aqueous HCl to pH ) 4 and then
extracted with ethyl acetate (60 mL × 3). The combined
organic extracts were washed with brine (30 mL × 2), dried
over anhydrous Na2SO4, and concentrated in vacuo. The
resulting crude product was purified by flash column chroma-
tography using CH2Cl2:MeOH (9:1) to give 0.85 g of 4 (58%
for 2 steps) as a colorless solid: 1H NMR (CD3OD) δ 4.04 (dd,
J ) 1.4, 3.7 Hz, 2 H), 5.89 (d, J ) 15.8 Hz, 1 H), 6.42 (dd, J )
7.3 Hz, 1 H), 6.51 (d, J ) 8.1 Hz, 1 H), 6.99 (ddd, J ) 4.3, 15.7
Hz, 1 H), 7.17 (ddd, J ) 1.0, 7.6 Hz, 1 H), 7.64 (dd, J ) 1.0,
7.6 Hz, 1 H); 13C NMR (CD3OD) δ 45.5, 85.2, 112.1, 119.9,
122.7, 130.4, 140.4, 147.5, 148.4, 169.9; MS m/z 304 (MH+).
Anal. Calcd for C10H10INO2: C, 39.63; H, 3.33; N, 4.62.
Found: C, 39.22; H, 3.20; N, 4.43.
2-(1-Ben zyl-1H-in d ol-3-yl)a ceta m id e (8). Rink amide
AM resin (1.0 g, 0.49 mmol/g, 0.49 mmol) was treated with
20% piperidine in DMF (20 mL) at room temperature for 2.5
h and then washed with DMF (3×), MeOH (3×), and CH2Cl2
(3×) to give the deprotected resin, 0.87 g. Deprotected resin
(435 mg, 0.245 mmol) was suspended in DMF (10 mL) and
then treated with acid 4 (120 mg, 0.40 mmol) followed by HOBt
(108 mg, 0.80 mmol) and DCC (165 mg, 0.80 mmol). The
resulting mixture was stirred at room temperature for 24 h
and then filtered and washed sequentially with DMF, MeOH,
CH2Cl2, and Et2O to provide 504 mg of resin-bound indole
derivative 5. To a mixture of resin 5 (70 mg, 0.034 mmol) and
N,N-diisopropylethylamine (110 mg, 0.85 mmol) in DMF (3
mL) was added benzyl bromide (149 mg, 0.85 mmol). The
mixture was stirred at 80 °C for 20 h, at which time TLC
indicated that the benzylation reaction was complete. (An
aliquot was taken, filtered, washed, cleaved with 30% TFA in
CH2Cl2, and checked by TLC). The reaction mixture was then
filtered and washed sequentially with DMF, MeOH, and CH2-
Cl2 to give the resin-bound cyclization precursor 6. Resin 6
was suspended in DMF-H2O (9:1, 4 mL), and to the suspen-
sion were added tetrabutylammonium chloride (14 mg, 0.051
mmol), triethylamine (27 mg, 0.27 mmol), and bis(tri-
phenylphosphine)palladium(II) chloride (3.6 mg, 0.005 mmol).
After being stirred at 80 °C for 24 h, the reaction mixture was
filtered, washed with DMF, MeOH, and CH2Cl2, and cleaved
with 30% TFA in CH2Cl2 at room temperature for 2 h to afford
7.9 mg (88%, based on 5) of the cleaved product 8 as a light
yellow solid: 1H NMR (CD3OD) δ 3.66 (s, 2 H), 5.34 (s, 2 H),
7.02-7.30 (m, 9 H), 7.58 (d, J ) 7.7 Hz, 1 H); 13C NMR (CD3-
OD) δ 33.4, 50.7, 109.7, 111.0, 119.8, 120.3, 122.8, 128.0, 128.5,
OD) δ 33.4, 50.3, 110.3, 111.0, 120.1, 120.7, 123.2, 125.8 (q,
2
J CF ) 271.9 Hz), 126.7, 128.6, 128.9, 129.6, 130.8 (q, J CF
)
32.3 Hz), 138.2, 144.4, 177.7; MS m/z 333 (MH+); FAB-HRMS
calcd for C18H15F3N2O + H+ 333.1215, found 333.1165. Anal.
Calcd for C18H15F3N2O‚1.3H2O: C, 60.77; H, 4.99; N, 7.87; F,
16.02. Found: C, 60.45; H, 4.22; N, 7.79; F, 16.57.
B. 2-[1-(4-F lu or oben zyl)-1H-in d ol-3-yl]a ceta m id e (15b):
1H NMR (CD3OD) δ 3.66 (s, 2 H), 5.33 (s, 2 H), 6.97-7.20 (m,
6 H), 7.22 (s, 1 H), 7.29 (d, J ) 8.1 Hz, 1 H), 7.58 (d, J ) 7.7
Hz, 1 H); 13C NMR (CD3OD) δ 33.3, 50.0, 109.9, 110.9, 116.2,
116.4, 119.9, 120.4, 122.9, 128.7, 129.4, 129.9, 130.0, 135.5,
138.0, 163.6 (d, J CF ) 244.3 Hz), 177.7; MS m/z 283 (MH+);
FAB-HRMS calcd for C17H15FN2O + H+ 283.1247, found
283.1310.
C. 2-[1-(4-Meth ylben zyl)-1H-in dol-3-yl]acetam ide (15d):
1H NMR (CD3OD) δ 2.27 (s, 3 H), 3.65 (s, 2 H), 5.29 (s, 2 H),
7.01-7.13 (m, 6 H), 7.19 (s, 1 H), 7.29 (d, J ) 8.1 Hz, 1 H),
7.57 (d, J ) 7.8 Hz, 1 H); 13C NMR (CD3OD) δ 21.1, 33.4, 50.5,
109.6, 111.0, 119.8, 120.2, 122.8, 128.1, 128.7, 129.4, 130.2,
136.4, 138.1, 138.3, 177.7; MS m/z 279 (MH+); FAB-HRMS
calcd for C18H18N2O + H+ 279.1497, found 279.1515.