General and facile synthesis of indoles with oxygen-bearing substituents at the benzene moiety

Article abstract of DOI:10.1021/jo970377w

Indoles with oxygen-bearing substituents such as a methoxy or (triisopropylsilyl)oxy group at all of the positions of the benzene moiety were synthesized by cyclization of tert-butyl methoxy(or (triisopropylsilyl)oxy)-2-((trimethylsilyl)ethynyl)phenyl)carbamates with potassium tert-butoxide in tert-butyl alcohol. The (ethynylphenyl)carbamates were synthesized by the palladium-catalyzed reaction of (trimethylsilyl)acetylene and the corresponding (iodophenyl)carbamates, which were selectively synthesized by directed lithiation of the phenylcarbamates and subsequent iodination.

Full text of DOI:10.1021/jo970377w

J . Org. Chem. 1997, 62, 6507-6511
6507
Gen er a l a n d F a cile Syn th esis of In d oles w ith Oxygen -Bea r in g
Su bstitu en ts a t th e Ben zen e Moiety
Yoshinori Kondo,* Satoshi Kojima, and Takao Sakamoto*
Faculty of Pharmaceutical Sciences, Tohoku University, Aramaki-aza Aoba,
Aoba-ku, Sendai 980-77, J apan
Received February 27, 1997X
Indoles with oxygen-bearing substituents such as a methoxy or (triisopropylsilyl)oxy group at all
of the positions of the benzene moiety were synthesized by cyclization of tert-butyl methoxy(or
(triisopropylsilyl)oxy)-2-((trimethylsilyl)ethynyl)phenyl)carbamates with potassium tert-butoxide in
tert-butyl alcohol. The (ethynylphenyl)carbamates were synthesized by the palladium-catalyzed
reaction of (trimethylsilyl)acetylene and the corresponding (iodophenyl)carbamates, which were
selectively synthesized by directed lithiation of the phenylcarbamates and subsequent iodination.
Sch em e 1
In tr od u ction
Many indole derivatives with oxygen-bearing substit-
uents, such as a hydroxy, alkoxy, or acyloxy group, at
the benzene moiety are known to be synthetic medicines
(e.g., pindolol), physiologically active substances (e.g.,
serotonin), and alkaloids (e.g., reserpine). Many methods
have been developed to synthesize indoles with oxygen-
bearing functional groups at the benzene moiety. Among
these methods, synthesis by cyclization is more widely
used than the introduction of an oxygen-bearing func-
tional group into indole rings.
However, cyclization reactions to synthesize oxygen-
functionalized indoles at all of the positions of the
benzene moiety have not been well developed.1 The most
commonly known indole cyclization reactions are limited
and inadequate for the synthesis of oxygen-functionalized
indoles. For example, Nenitzescu cyclization reactions
have only been used to synthesize 5-hydroxyindoles,2 and
Fischer cyclization reactions of alkoxyphenylhydrazones
sometimes give indoles with rearranged alkoxy groups.3
Reissert, Leimgruber-Batcho, and related cyclization
reactions have been widely used for the synthesis of
oxygen-functionalized indoles;4 however the synthesis of
some of the starting compounds can be difficult.
conditions were applied to the synthesis of 7-substituted
indoles from tert-butyl 6-substituted (2-ethynylphenyl)-
carbamates.6 On the other hand, the directed ortho-
lithiation of substituted benzene derivatives followed by
reaction with various electrophiles has been used as a
powerful synthetic method to introduce substituents
regioselectively.7
We developed a strategy for synthesizing indole de-
rivatives with an oxygen-bearing substituent at all of the
positions of the benzene moiety by combining directed
ortho-lithiation and our indole cyclization reaction, as
shown in Scheme 1.
Resu lts a n d Discu ssion
P r ep a r a tion of ter t-Bu tyl (2-Iod op h en yl)ca r ba m -
a tes. It has been reported that tert-butyl phenylcarbam-
ates are ortho-lithiated with 2 equiv of tert-butyllithium8,9
and that methoxyanilines are also lithiated at the ortho-
position to the methoxy group with butyllithium in the
presence of N,N,N′,N′-tetramethylethylenediamine in
diethyl ether at 0 °C.10 These findings show that (tert-
butoxycarbonyl)amino and methoxy groups also serve as
directed metalation groups for the lithiation of a benzene
ring.
In a previous report, we described the cyclization of
ethyl (2-ethynylphenyl)carbamates into indoles in the
presence of sodium ethoxide in ethanol.5 Recently, the
reaction conditions for indole cyclization were improved,
and reflux conditions using potassium tert-butoxide in
tert-butyl alcohol were found to be superior to the
previously reported conditions.6 These improved reaction
The ortho-lithiation reaction of benzene derivatives
with two directed metalation groups, (tert-butoxycarbo-
nyl)amino and methoxy groups, has been reported,11,12
i.e., tert-butyl (4-methoxyphenyl)carbamate was regiose-
X Abstract published in Advance ACS Abstracts, August 15, 1997.
(1) For recent review articles of the indole cyclization reaction, see:
(a) Pindur, U.; Adam, R. J . Heterocycl. Chem. 1988, 25, 1-8. (b)
Gribble, G. W. Contemp. Org. Synth. 1994, 145-172.
(2) (a) Brown, R. K. Chemistry of Heterocyclic Compounds, Vol. 25,
Part 1; Houlithan, W. J ., Ed.; Wiley: New York, 1972; pp 413-436.
(b) Allen, G. R., J r. Org. React. 1973, 20, 337-454.
(5) (a) Sakamoto, T.; Kondo, Y.; Yamanaka, H. Heterocycles 1986,
24, 31-32. (b) Sakamoto, T.; Kondo, Y.; Iwashita, S.; Yamanaka, H.
Chem. Pharm. Bull. 1987, 35, 1823-1828. (c) Sakamoto, T.; Kondo,
Y.; Iwashita, S.; Nagano, T.; Yamanaka, H. Chem. Pharm. Bull. 1988,
36, 1305-1308.
(6) Kondo, Y.; Kojima, S.; Sakamoto, T. Heterocycles 1996, 43, 2741-
2746.
(7) Snieckus, V. Chem. Rev. 1990, 90, 879-933.
(8) Muchowski, J . M.; Venuti, M. C. J . Org. Chem. 1980, 45, 4798.
(9) Stanetty, P.; Koller, H.; Mihovilovic, M. J . Org. Chem. 1992, 57,
6833.
(3) (a) Brown, R. K. Chemistry of Heterocyclic Compounds, Vol. 25,
Part 1; Houlithan, W. J ., Ed.; Wiley: New York, 1972; pp 290-297.
(b) Murakami, Y.; Takahashi, H.; Nakazawa, Y.; Koshimizu, M.;
Watanabe, T.; Yokoyama, Y. Tetrahedron Lett. 1989, 30, 2099-2100.
(4) For representative articles for synthesis of oxygen-functionalized
indoles by Reissert, Leimgruber-Batcho, and related cyclization
reactions, see: (a) Lloyd, D. H.; Nichols, D. E. Tetrahedron Lett. 1983,
24, 4561-4562. (b) Kawase, M.; Sinhababu, A. K.; Borcharot, R. T. J .
Heterocycl. Chem. 1987, 24, 1499-1501. (c) Makosza, M.; Danikiewicz,
W.; Wojciechowski, K. Liebigs Ann. Chem. 1988, 203-208. (d)
Rajeswari, S.; Drost, K. J .; Cava, M. P. Heterocycles 1989, 29, 415-
418. (e) Ezquerra, J .; Pedregal, C.; Lamas, C.; Barluenga, J .; Pe´rez,
M.; Garcia-Martin, M. A.; Gonza´lez, J . M. J . Org. Chem. 1996, 61,
5804-5812.
(10) Crowther, G. P.; Sundberg, R. J .; Sarpeshkar, A. M. J . Org.
Chem. 1984, 49, 4657.
(11) Cho, I.-S.; Gong, L.; Muchowski, J . M. J . Org. Chem. 1991, 56,
7288-7291.
S0022-3263(97)00377-0 CCC: $14.00 © 1997 American Chemical Society

6508 J . Org. Chem., Vol. 62, No. 19, 1997
Kondo et al.
Sch em e 2
Sch em e 3
Sch em e 4
lectively lithiated at the ortho-position to the (tert-
butoxycarbonyl)amino group and tert-butoxy (3-methoxy-
phenyl)carbamate was also lithiated at the ortho-position
between the (tert-butoxycarbonyl)amino group and the
methoxy group.11,12
On the basis of these findings, the starting iodobenzene
derivatives for the synthesis 4-, 5-, and 7-methoxyindoles
were easily prepared. tert-Butyl (3-methoxyphenyl)-
carbamate (1a ) was lithiated with 2.2 equiv of tert-
butyllithium in diethyl ether followed by iodination with
molecular iodine to give tert-butyl (2-iodo-3-methoxyphen-
yl)carbamate (2a ) in 55% yield (Scheme 2). Analogously,
tert-butyl (2-iodo-6-methoxy- and (2-iodo-4-methoxyphen-
yl)carbamate (2b and 2c) were prepared from tert-butyl
(2-methoxy- and 4-methoxyphenyl)carbamate (1b and 1c)
in yields of 61 and 55%, respectively.
carbamates (4a -c) were allowed to react with (trimeth-
ylsilyl)acetylene in the presence of dichlorobis(triphen-
ylphosphine)palladium and cuprous iodide in triethyl-
amine to give the corresponding (trimethylsilyl)ethynyl
phenylcarbamates (5a -c and 6a -c) in yields of 85-100%
(Scheme 4).
Using this method, the starting materials for the
synthesis of indoles with an oxygen-bearing functional
group at the 4-, 5-, and 7-positions were obtained.
However, this method is not applicable to the synthesis
of tert-butyl 2-iodo-5-substituted phenylcarbamates, which
could be starting materials for the synthesis of 6-substi-
tuted indoles using our method.
Cyclization of the (ethynylphenyl)carbamates (5a -c)
in the presence of potassium tert-butoxide in tert-butyl
alcohol proceeded smoothly to give methoxyindoles (7a -
c) in yields of 70-79%. Analogous cyclization of (((tri-
isopropylsilyl)oxy)phenyl)carbamates (6a -c) gave ((tri-
isopropylsilyl)oxy)indoles (8a ,c), except for 8b. The
cyclization of 6b under reflux conditions for 96 h gave a
complex mixture, and the desired product was obtained
in only 10% yield. This low yield is believed to be due to
the prolonged reflux conditions and decomposition of the
product (8b). With a shorter reaction time (1 h), 1-(tert-
butoxycarbonyl)-7-((triisopropylsilyl)oxy)indole was ob-
tained in 62% yield. This result suggests that indole
cyclization proceeds via 1-(tert-butoxycarbonyl)indole as
an intermediate to give 1-unsubstituted indoles.
This problem was solved by using tert-butyl (3-((tri-
isopropylsilyl)oxy)phenyl)carbamate (3a ) instead of 1a
(Scheme 3). As described above,11,12 the (tert-butoxycar-
bonyl)amino group is more effective than the methoxy
group as a directed metalation group, and the (triisoprop-
ylsilyl)oxy group is bulkier than the methoxy group.
Based on these two points, we predicted that the lithia-
tion of 3a would occur at the ortho-position to the (tert-
butoxycarbonyl)amino group and at the para-position to
the (triisopropylsilyl)oxy group. Thus, the lithiation
reaction of 3a with tert-butyllithium in diethyl ether
followed by iodination with molecular iodine gave tert-
butyl (2-iodo-5-((triisopropylsilyl)oxy)phenyl)carbamates
(4a ) in 66% yield. Similarly, directed lithiation and
iodination of tert-butyl (2-((triisopropylsilyl)oxy)- and (4-
((triisopropylsilyl)oxy)phenyl)carbamate (3b and 3c) gave
tert-butyl (2-iodo-6-((triisopropylsilyl)oxy)- and (2-iodo-
4-((triisopropylsilyl)oxy)phenyl)carbamate (4b and 4c) in
yields of 47 and 48%, respectively.
Con clu sion
Three methoxyindoles (7a -c) and three ((triisopropyl-
silyl)oxy)indoles (8a -c) were synthesized easily and in
good yields. As a result, the synthesis of indoles with
oxygen-bearing substituents at all of the positions of the
benzene moiety was achieved. Since alkoxy- and ((tri-
isopropylsilyl)oxy)indoles can be converted to (((trifluo-
romethyl)sulfonyl)oxy)indoles via hydroxyindoles and
(((trifluoromethyl)sulfonyl)oxy)indoles can be trans-
formed into various carbon-substituted indoles by a
palladium-catalyzed reaction,13 the present synthesis of
methoxyindoles and ((triisopropylsilyl)oxy)indoles can be
used for the synthesis of many indole derivatives.
P r ep a r a tion of ter t-Bu tyl(2-((Tr im eth ylsilyl)eth -
yn yl)p h en yl)ca r ba m a tes a n d Th eir Cycliza tion to
In d oles. According to the reported reaction conditions
for the standard palladium-catalyzed cross-coupling of
aryl iodides and (trimethylsilyl)acetylene,5 tert-butyl
methoxy (2a -c) and (triisopropylsilyl)oxy (2-iodophenyl)-
(13) (a) Arcadi, A.; Cacchi, S.; Marinelli, F.; Morera, E.; Ortar, G.
Tetrahedron 1990, 46, 7151-7164. (b) Arcadi, A.; Burini, A.; Cacchi,
S.; Delmastro, M.; Marinelli, F.; Pietroni, B. Synlett 1990, 47-48.
(12) Reuter, D. C.; Flippin, L. A.; McIntosh, J .; Caroon, J . M.;
Hammaker, J . Tetrahedron Lett. 1994, 35, 4899-4902.

Indoles with Oxygen-Bearing Substituents
J . Org. Chem., Vol. 62, No. 19, 1997 6509
reduced pressure. The residue was purified by silica gel (54
g) column chromatography using AcOEt-hexane (1:200) as
eluent to give a colorless liquid which was distilled under
reduced pressure: yield 446 mg (84%); bp 110 °C/3 mmHg;
Exp er im en ta l Section
Gen er a l Com m en ts. THF and Et2O were distilled from
sodium/benzophenone ketyl before use. t-BuOH was distilled
from CaH before use. n-BuLi and t-BuLi were titrated using
2,5-dimethoxybenzyl alcohol before use. All melting points and
boiling points are uncorrected. IR spectra were taken on a
J ASCO IR-810 spectrophotometer. 1H NMR spectra were
recorded on Varian Gemini 2000 (300M Hz) and Hitachi
R-3000 (300 MHz) spectrometers. Chemical shifts are ex-
pressed in δ (ppm) values with tetramethylsilane (TMS) as
the internal reference, and coupling constants are expressed
in hertz (Hz). The following abbreviations are used: s )
singlet, d ) doublet, t ) triplet, m ) multiplet, dd ) doublet
of doublet, and br ) broad. Mass spectra (MS) and high-
resolution mass spectra (HRMS) were recorded on J MS-DX303
and J MS-AX500 instruments.
ter t-Bu tyl (3-Meth oxyp h en yl)ca r ba m a te (1a ). A solu-
tion of 3-methoxyaniline (2.463 g, 20 mmol) and di-tert-butyl
dicarbonate (5.1 mL, 22 mmol) in dry THF (30 mL) was
refluxed for 5 h. The solvent was evaporated under reduced
pressure. To the residue was added H2O (20 mL), and the
mixture was extracted with Et2O (30 mL × 3). The Et2O
extract was washed with a saturated aqueous NaCl solution
(20 mL) and dried over MgSO4. The residue was purified by
silica gel (88 g) column chromatography using AcOEt-hexane
(1:10) as eluent to give colorless prisms which were recrystal-
lized from Et2O-hexane: yield 4.049 g (91%); mp 57-58 °C;
300 MHz 1H NMR (CDCl3/TMS) δ (ppm) 1.52 (9H, s), 3.80 (3H,
s), 6.46 (1H, br), 6.58 (1H, dd, J ) 2.6, 8.2 Hz), 6.83 (1H, dd,
J ) 1.5, 8.1 Hz), 7.10 (1H, s), 7.17 (1H, t, J ) 8.1 Hz); IR ν
(CHCl3) cm-1 3440, 1725; MS m/z 223 (M+); HRMS calcd for
1
300 MHz H NMR (CDCl3/TMS) δ (ppm) 1.12 (18H, d, J ) 7.3
Hz), 1.38-1.21 (3H, m), 3.86 (2H, br), 6.63-6.57 (1H, m), 6.79-
6.69 (3H, m); IR ν (CHCl3) cm-1 3450, 3390; MS m/z 265 (M+);
HRMS calcd for C15H27NOSi 265.1860, found 265.1887.
3-((Tr iisop r op ylsilyl)oxy)a n ilin e. Triisopropylsilyl chlo-
ride (0.47 mL, 2.4 mmol) was added to a dichloromethane
solution (5 mL) of 3-aminophenol (218 mg, 2 mmol) and
imidazole (163 mg, 2.4 mmol) at room temperature, and the
mixture was stirred for 26 h. After addition of H2O (10 mL),
the mixture was extracted with CH2Cl2 (20 mL × 3). The CH2-
Cl2 extract was washed with a saturated aqueous NaCl
solution (10 mL), dried over MgSO4, and evaporated under
reduced pressure. The residue was purified by silica gel (16
g) column chromatography using AcOEt hexane (1:10) as
eluent to give a viscous colorless liquid: yield 385 mg (73%);
1
bp 100 °C/3 mmHg; 300 MHz H NMR (CDCl3/TMS) δ (ppm)
1.09 (18H, d, J ) 7.3 Hz), 1.29-1.18 (3H, m), 3.58 (2H, br),
6.30-6.24 (3H, m), 6.97 (1H, t, J ) 7.7 Hz); IR ν (CHCl3) cm-1
3455, 3385; MS m/z 265 (M+); HRMS calcd for C15H27NOSi
265.1860, found 265.1904.
ter t-Bu tyl (3-((Tr iisopr opylsilyl)oxy)ph en yl)car bam ate
(3a ). A solution of 3-((triisopropylsilyl)oxy)aniline (265 mg, 1
mmol) and di-tert-butyl dicarbonate (0.35 mL, 1.5 mmol) in
dry THF (5 mL) was stirred at room temperature for 4 days.
The solvent was evaporated under reduced pressure. To the
residue was added H2O (10 mL), and the mixture was
extracted with CH2Cl2 (30 mL × 3). The CH2Cl2 extract was
washed with a saturated aqueous NaCl solution (20 mL) and
dried over MgSO4. The residue was purified by silica gel (10
g) column chromatography using AcOEt-hexane (1:20) as
eluent to give colorless needles which were recrystallized from
hexane: yield 313 mg (86%); mp 124-126 °C; 300 MHz 1H
NMR (CDCl3/TMS) δ (ppm) 1.09 (18H, d, J ) 7.0 Hz), 1.28-
1.18 (3H, m), 1.51 (9H, s), 6.37 (1H, br), 6.54 (1H, dd, J ) 1.1,
7.7 Hz), 6.88 (1H, s), 6.97 (1H, d, J ) 8.1 Hz), 7.10 (1H, t, J )
7.7 Hz); IR ν (CHCl3) cm-1 3455, 1735; MS m/z 365 (M+);
HRMS calcd for C20H35NO3Si 365.2384, found 365.2361. Anal.
Calcd for C20H35NO3Si: C, 65.71; H, 9.65; N, 3.83. Found: C,
65.59; H, 9.65; N, 3.89.
ter t-Bu tyl (2-((Tr iisopr opylsilyl)oxy)ph en yl)car bam ate
(3b). A solution of 2-((triisopropylsilyl)oxy)aniline (531 mg, 2
mmol) and di-tert-butyl dicarbonate (0.7 mL, 3 mmol) in dry
THF (5 mL) was stirred at room temperature for 72 h. The
solvent was evaporated under reduced pressure. To the
residue was added H2O (10 mL), and the mixture was
extracted with CH2Cl2 (30 mL × 3). The CH2Cl2 extract was
washed with a saturated aqueous NaCl solution (10 mL) and
dried over MgSO4. The residue was purified by silica gel (15
g) column chromatography using AcOEt-hexane (1:100) as
eluent to give a colorless viscous liquid: yield 683 mg (93%);
300 MHz 1H NMR (CDCl3/TMS) δ (ppm) 1.12 (18H, d, J ) 7.3
Hz), 1.37-1.26 (3H, m), 1.51 (9H, s), 6.94-6.79 (3H, m), 7.09
(1H, br), 7.97 (1H, d, J ) 7.3 Hz); IR ν (CHCl3) cm-1 3440,
1725; MS m/z 365 (M+); HRMS calcd for C20H35NO3Si 365.2384,
found 365.2369.
ter t-Bu tyl (4-((Tr iisopr opylsilyl)oxy)ph en yl)car bam ate
(3c). Triisopropylsilyl chloride (1.6 mL, 7.5 mmol) was added
to a solution of 4-aminophenol (546 mg, 5.0 mmol) and
imidazole (510 mg, 7.5 mmol) in dichloromethane (10 mL) at
room temperature, and the mixture was stirred for 2 h. After
addition of H2O (10 mL), the mixture was extracted with CH2-
Cl2 (30 mL × 3). The CH2Cl2 extract was washed with a
saturated aqueous NaCl solution (10 mL), dried over MgSO4,
and evaporated under reduced pressure. Di-tert-butyl dicar-
bonate (1.7 mL, 7.5 mmol) was added to a solution of the
residue in dry THF (15 mL), and the mixture was stirred at
room temperature for 39 h. The solvent was evaporated under
reduced pressure. To the residue was added H2O (20 mL), and
the mixture was extracted with CH2Cl2 (30 mL × 3). The CH2-
Cl2 extract was washed with a saturated aqueous NaCl
solution (10 mL), dried over MgSO4, and evaporated under
reduced pressure. The residue was purified by silica gel (100
C12H17NO3 223.1207, found 223.1221. Anal. Calcd for C12H17
NO3: C, 64.55; H, 7.67; N, 6.27. Found: C, 64.77; H, 7.69; N,
6.27.
-
ter t-Bu tyl (2-Meth oxyp h en yl)ca r ba m a te (1b). A solu-
tion of 2-methoxyaniline (246 mg, 2 mmol) and di-tert-butyl
dicarbonate (0.69 mL, 3 mmol) in dry THF (5 mL) was stirred
at room temperature for 17 h. The solvent was evaporated
under reduced pressure. To the residue was added H2O (10
mL), and the mixture was extracted with CH2Cl2 (30 mL ×
3). The CH2Cl2 extract was washed with a saturated aqueous
NaCl solution (10 mL) and dried over MgSO4. The residue
was purified by silica gel (9 g) column chromatography using
AcOEt-hexane (1:20) as eluent to give a colorless viscous
liquid which was distilled under reduced pressure: yield 444
mg (99%); bp 60 °C/3 mmHg; 300 MHz 1H NMR (CDCl3/TMS)
δ (ppm) 1.53 (9H, s), 3.86 (3H, s), 6.86-6.83 (1H, m), 6.97-
6.93 (2H, m), 7.08 (1H, br), 8.07 (1H, d, J ) 6.6 Hz); IR ν
(CHCl3) cm-1 3440, 1725; MS m/z 319 (M+); HRMS calcd for
C12H17NO3 223.1207, found 223.1210.
ter t-Bu tyl (4-Meth oxyp h en yl)ca r ba m a te (1c). A solu-
tion of 4-methoxyaniline (1.847 g, 15 mmol) and di-tert-butyl
dicarbonate (5.1 mL, 22 mmol) in dry THF (15 mL) was stirred
at room temperature for 18 h. The solvent was evaporated
under reduced pressure. To the residue was added H2O (20
mL), and the mixture was extracted with CH2Cl2 (30 mL ×
3). The CH2Cl2 extract was washed with a saturated aqueous
NaCl solution (20 mL) and dried over MgSO4. The residue
was purified by silica gel (70 g) column chromatography using
AcOEt-hexane (1:5) as eluent to give colorless needles which
were recrystallized form Et2O-hexane: yield 3.072 g (92%);
mp 92-94 °C; 300 MHz 1H NMR (CDCl3/TMS) δ (ppm) 1.51
(9H, s), 3.78 (3H, s), 6.32 (1H, br), 6.83 (2H, d, J ) 9.2 Hz),
7.26 (2H, d, J ) 8.8 Hz); IR ν (CHCl3) cm-1 3450, 1730; MS
m/z 223 (M+); HRMS calcd for C12H17NO3 223.1207, found
223.1200. Anal. Calcd for C12H17NO3: C, 64.55; H, 7.67; N,
6.27. Found: C, 64.53; H, 7.66; N, 6.32.
2-((Tr iisop r op ylsilyl)oxy)a n ilin e. Triisopropylsilyl chlo-
ride (0.64 mL, 3 mmol) was added to a dichloromethane
solution (5 mL) of 2-aminophenol (218 mg, 2 mmol) and
imidazole (204 mg, 3 mmol) at room temperature, and the
mixture was stirred for 33 h. After addition of H2O (10 mL),
the mixture was extracted with CH2Cl2 (30 mL × 3). The CH2-
Cl2 extract was washed with a saturated aqueous NaCl
solution (10 mL), dried over MgSO4, and evaporated under

6510 J . Org. Chem., Vol. 62, No. 19, 1997
Kondo et al.
g) column chromatography using AcOEt-hexane (1:20) as
eluent to give a pale yellow liquid which was distilled at 70
°C under 4 mmHg. The residue was purified by silica gel (100
g) column chromatography using AcOEt-hexane (1:20) as
eluent to give a pale yellow solid. Recrystallization from
hexane at 0 °C gave colorless prisms: yield 1.494 g (82%); mp
57-58 °C; 300 MHz 1H NMR (CDCl3/TMS) δ (ppm) 1.08 (18H,
d, J ) 7.0 Hz), 1.31-1.16 (3H, m), 1.50 (9H, s), 6.31 (1H, br),
6.80 (2H, d, J ) 8.8 Hz), 7.18 (2H, d, J ) 8.4 Hz); IR ν (CHCl3)
ter t-Bu t yl
(3-Met h oxy-2-((t r im et h ylsilyl)et h yn yl)-
p h en ylca r ba m a te (5a ): Rep r esen ta tive P r oced u r e.
A
mixture of tert-butyl (2-iodo-3-methoxyphenyl)carbamate (2a )
(105 mg, 0.30 mmol), (trimethylsilyl)acetylene (0.06 mL, 0.45
mmol), Pd(PPh3)2Cl2 (11 mg, 0.02 mmol), CuI (3 mg, 0.02
mmol), and Et3N (1 mL) in a sealed tube was heated at 80 °C
for 24 h. To the reaction mixture were added H2O (10 mL)
and Et2O (20 mL), and the whole was filtered through a Celite
pad. The filtrate was extracted with Et2O (20 mL × 2). The
ethereal extract was washed with a saturated aqueous NaCl
solution (20 mL), dried over MgSO4, and evaporated under
reduced pressure. The residue was purified by silica gel (10
g) column chromatography using AcOEt-hexane (1:40) as
eluent to give a colorless viscous liquid: yield 82 mg (85%);
300 MHz 1H NMR (CDCl3/TMS) δ (ppm) 0.31 (9H, s), 1.53 (9H,
s), 3.87 (3H, s), 6.52 (1H, d, J ) 8.4 Hz), 7.23 (1H, t, J ) 8.1
Hz), 7.44 (1H, br), 7.75 (1H, d, J ) 8.4 Hz); IR ν (CHCl3) cm-1
cm-1 3440, 1730; MS m/z 365 (M+); HRMS calcd for C20H35
-
NO3Si 365.2384, found 365.2359. Anal. Calcd for C20H35NO3-
Si: C, 65.71; H, 9.65; N, 3.83. Found: C, 65.58; H, 9.64; N,
3.84.
ter t-Bu tyl (2-Iod o-3-m eth oxyp h en yl)ca r ba m a te (2a ):
Rep r esen ta tive P r oced u r e. Addition of 1.34 M tert-butyl-
lithium in pentane (8.2 mL, 11 mmol) to a solution of tert-
butyl (3-methoxyphenyl)carbamate (1a ) (1.116 g, 5 mmol) in
dry Et2O (6 mL) under an argon atmosphere at -20 °C
followed by stirring for 3 h. To the mixture was added iodine
(1.523 g, 6 mmol) in dry Et2O (14 mL) at -100 °C, and the
whole was gradually warmed up to room temperature and
stirred overnight. After addition of a saturated aqueous
Na2S2O3 solution (20 mL), the mixture was extracted with Et2O
(30 mL × 3). The Et2O extract was washed with a saturated
aqueous NaCl solution (20 mL), dried over MgSO4, and
evaporated under reduced pressure. The residue was purified
by silica gel (85 g) column chromatography using AcOEt-
hexane (1:100) as eluent to give a crude product. Recrystal-
lization from hexane gave colorless prisms: yield 0.954 g (55%);
mp 73-75 °C; 300 MHz 1H NMR (CDCl3/TMS) δ (ppm) 1.54
(9H, s), 3.88 (3H, s), 6.53 (1H, d, J ) 8.4 Hz), 7.04 (1H, br),
7.25 (1H, t, J ) 7.7 Hz), 7.73 (1H, d, J ) 8.4 Hz); IR ν (CHCl3)
3395, 2145, 1730; MS m/z 319 (M+); HRMS calcd for C17H25
NO3Si 319.1602, found 319.1582.
-
ter t-Bu tyl (6-Meth oxy-2-((tr im eth ylsilyl)eth yn yl)p h en -
yl)ca r ba m a te (5b). Reaction was carried out at room tem-
perature for 24 h. 5b: colorless prisms from Et2O-hexane:
yield 87%; mp 116-118 °C; 300 MHz 1H NMR (CDCl3/TMS) δ
(ppm): 0.24 (9H, s), 1.50 (9H, s), 3.84 (3H, s), 6.18 (1H, br),
6.88 (1H, dd, J ) 3.0, 6.5 Hz), 7.13-7.07 (2H, m); IR ν (CHCl3)
cm-1 3420, 1730; MS m/z 319 (M+); HRMS calcd for C17H25NO3
319.1602, found 319.1601. Anal. Calcd for C17H25NO3Si: C,
63.91; H, 7.89; N, 4.38. Found: C, 63.75; H, 7.73; N, 4.37.
ter t-Bu tyl (4-Meth oxy-2-((tr im eth ylsilyl)eth yn yl)p h en -
yl)ca r ba m a te (5c). Reaction was carried out at room tem-
perature for 24 h. 5c: colorless prisms from hexane; yield
1
93%; mp 70-72 °C; 300 MHz H NMR (CDCl3/TMS) δ (ppm):
cm-1 3395, 1730; MS m/z 349 (M+); HRMS for calcd C12H16
INO3 349.0173, found 349.0129. Anal. Calcd for C12H16
-
-
0.29 (9H, s), 1.52 (9H, s), 3.76 (3H, s), 6.89-6.85 (2H, m), 7.15
(1H, br), 7.98 (1H, d, J ) 8.8 Hz); IR ν (CHCl3) cm-1 3410,
2150, 1725; MS m/z 319 (M+); HRMS calcd for C17H25NO3Si
319.1602, found 319.1618. Anal. Calcd for C17H25NO3Si: C,
63.91; H, 7.89; N, 4.38. Found: C, 63.93; H, 7.81; N, 4.37.
INO3: C, 41.28; H, 4.62; N, 4.01. Found: C, 41.24; H, 4.44;
N, 3.97.
ter t-Bu tyl (2-iod o-6-m eth oxyp h en yl)ca r ba m a te (2b):
colorless scales (61%) from Et2O; mp 106-108 °C; 300 MHz
1H NMR (CDCl3/TMS) δ (ppm) 1.50 (9H, s), 3.82 (3H, s), 6.00
(1H, br), 6.95-6.85 (2H, m), 7.43 (1H, d, J ) 7.7 Hz); IR ν
(CHCl3) cm-1 3420, 1725; MS m/z 349 (M+); HRMS calcd for
C12H16INO3 349.0173, found 349.0155. Anal. Calcd for
C12H16INO3: C, 41.28; H, 4.62; N, 4.01; I, 36.34. Found: C,
41.05; H, 4.65; N, 3.99; I, 36.26.
ter t-Bu tyl (5-((Tr iisop r op ylsilyl)oxy)-2-((tr im eth ylsil-
yl)eth yn yl)p h en yl)ca r ba m a te (6a ). Reaction was carried
out at room temperature for 47 h. 6a : pale yellow viscous
liquid; yield 95%; 300 MHz 1H NMR (CDCl3/TMS) δ (ppm):
0.25 (9H, s), 1.07 (18H, d, J ) 7.1 Hz), 1.28-1.20 (3H, m),
1.50 (9H, s), 6.42 (1H, dd, J ) 2.2, 8.4 Hz), 7.20 (1H, d, J )
8.5 Hz), 7.30 (1H, br), 7.69 (1H, d, J ) 2.2 Hz); IR ν (CHCl3)
cm-1 3405, 2160, 1735; MS m/z 461 (M+); HRMS calcd for
C25H43NO3Si2 461.2779, found 461.2782.
ter t-Bu tyl (6-((Tr iisop r op ylsilyl)oxy)-2-((tr im eth ylsil-
yl)eth yn yl)p h en yl)ca r ba m a te (6b). Reaction was carried
out at room temperature for 24 h. 6b: pale yellow viscous
liquid; yield 99%; 300 MHz 1H NMR (CDCl3/TMS) δ (ppm):
0.23 (9H, s), 1.09 (18H, d, J ) 7.0 Hz), 1.33-1.19 (3H, m),
1.48 (9H, s), 6.19 (1H, br), 6.83 (1H, dd, J ) 1.1, 8.2 Hz), 6.97
(1H, t, J ) 8.1 Hz), 7.08 (1H, dd, J ) 1.1, 7.7 Hz); IR ν (CHCl3)
cm-1 3430, 2160, 1730; MS m/z 461 (M+); HRMS calcd for
C25H43NO3Si2: 461.2779, found 461.2780.
ter t-Bu tyl (2-Iod o-4-m eth oxyp h en yl)ca r ba m a te (2c).
1,2-Diiodoethane was used as an iodinating reagent. 2c:
colorless prisms (55%) from Et2O-hexane; mp 49-50 °C; 300
1
MHz H NMR (CDCl3/TMS) δ (ppm) 1.52 (9H, s), 3.76 (3H, s),
6.53 (1H, br), 6.89 (1H, dd, J ) 2.9, 9.0 Hz), 7.29 (1H, d, J )
2.9 Hz), 7.80 (1H, d, J ) 9.1 Hz); IR ν (CHCl3) cm-1 3400, 1730;
MS m/z 349 (M+); HRMS calcd for C12H16INO3 349.0173, found
349.0197. Anal. Calcd for C12H16INO3: C, 41.28; H, 4.62; N,
4.01. Found: C, 41.46; H, 4.69; N, 4.04.
ter t-Bu t yl (2-iod o-5-((t r iisop r op ylsilyl)oxy)p h en yl)-
ca r ba m a te (4a ): colorless viscous liquid; yield 66%; 300 MHz
1H NMR (CDCl3/TMS) δ (ppm) (1.10 (18H, d, J ) 7.3 Hz),
1.19-1.35 (3H, m), 1.56 (9H, s), 6.35 (1H, dd, J ) 2.9, 8.4 Hz),
6.72 (1H, br), 7.51 (1H, d, J ) 8.8 Hz), 7.70 (1H, d, J ) 2.6
Hz); IR ν (CHCl3) cm-1 3395, 1735; MS m/z 491 (M+); HRMS
calcd for C20H34INO3Si 491.1350, found 491.1346.
ter t-Bu tyl (4-((Tr iisop r op ylsilyl)oxy)-2-((tr im eth ylsil-
yl)eth yn yl)p h en yl)ca r ba m a te (6c). Reaction was carried
out at room temperature for 24 h. 6c: pale yellow viscous
1
liquid; yield 100%; 300 MHz H NMR (CDCl3/TMS) δ (ppm):
0.29 (9H, s), 1.08 (18H, d, J ) 6.6 Hz), 1.30-1.18 (3H, m),
1.51 (9H, s), 6.87-6.81 (2H, m), 7.16 (1H, br), 7.91 (1H, d, J )
8.8 Hz); IR ν (CHCl3) cm-1 3400, 2150, 1725; MS m/z 461 (M+);
HRMS calcd for C25H43NO3Si2 461.2779, found 461.2769.
ter t-Bu t yl (2-Iod o-6-((t r iisop r op ylsilyl)oxy)p h en yl)-
ca r ba m a te (4b). 1,2-Diiodoethane was used as an iodinating
reagent. 4b: colorless prisms from Et2O-hexane; yield 47%;
mp 117-118 °C; 300 MHz 1H NMR (CDCl3/TMS) δ (ppm) 1.10
(18H, d, J ) 6.9 Hz), 1.22-1.34 (3H, m), 1.48 (9H, s), 6.08
(1H, br), 6.85-6.77 (2H, m), 7.43 (1H, dd, J ) 2.2, 7.0 Hz); IR
ν (CHCl3) cm-1 3430, 1735; MS m/z 392. Anal. Calcd for
C20H34INO3Si: C, 48.88; H, 6.97; N, 2.85; I, 25.82. Found: C,
48.75; H, 6.68; N, 2.92; I, 25.58.
ter t-Bu t yl (2-iod o-4-((t r iisop r op ylsilyl)oxy)p h en yl)-
ca r ba m a te (4c): pale yellow viscous liquid; yield 58%; 300
MHz 1H-NMR (CDCl3/TMS) δ (ppm) 1.08 (18H, d, J ) 7.0 Hz),
1.30-1.12 (3H, m), 1.52 (9H, s), 6.54 (1H, br), 6.84 (1H, dd, J
) 2.9, 9.0 Hz), 7.29 (1H, d, J ) 2.9 Hz), 7.76 (1H, d, J ) 9.2
Hz); IR ν (CHCl3) cm-1 3400, 1725; MS m/z 491 (M+); HRMS
calcd for C20H34INO3Si 491.1350; found 491.1317.
4-Meth oxyin d ole (7a ): Rep r esen ta tive P r oced u r e. tert-
Butyl (3-methoxy-2-((trimethylsilyl)ethynyl)phenyl)carbamate
(5a ) (432 mg, 1.4 mmol) in dry t-BuOH (3 mL) was added to a
dry t-BuOH solution (3 mL) of potassium tert-butoxide (561
mg, 6.8 mmol) under an argon atmosphere, and the mixture
was refluxed for 5 h. After evaporation of the solvent, H2O
(10 mL) was added to the residue, and the whole was extracted
with CH2Cl2 (20 mL × 3). The CH2Cl2 extract was washed
with a saturated aqueous NaCl solution (10 mL), dried over
MgSO4, and evaporated under reduced pressure. The residue
was purified by silica gel (6 g) column chromatography using
AcOEt-hexane (1:20) as eluent to give a crude product.

Indoles with Oxygen-Bearing Substituents
J . Org. Chem., Vol. 62, No. 19, 1997 6511
Recrystallization from Et2O-hexane gave colorless prisms.
7a : yield 139 mg (70%); mp 69-70 °C (lit.4c mp 67-68 °C;
300 MHz 1H NMR (CDCl3/TMS) δ (ppm): 3.97 (3H, s), 6.54
(1H, d, J ) 7.7 Hz), 6.68-6.65 (1H, m), 7.03 (1H, dd, J ) 0.8,
8.2 Hz), 7.15-7.10 (2H, m), 8.16 (1H, br); IR ν (CHCl3) cm-1
3485; MS m/z 147 (M+); HRMS calcd for C9H9NO 147.0684,
found 147.0694. Anal. Calcd for C9H9NO: C, 73.45; H, 6.16;
N, 9.52. Found: C, 73.54; H, 6.16; N, 9.40.
7-Meth oxyin d ole (7b). Reaction time was 3 h. 7b:
colorless viscous liquid; yield 70%; bp 130 °C/3.5 mmHg (lit.4c
bp 138-139 °C/5 Torr); 300 MHz 1H NMR (CDCl3/TMS) δ
(ppm) 3.96 (3H, s), 6.53 (1H, t, J ) 2.6 Hz), 6.64 (1H, d, J )
7.7 Hz), 7.03 (1H, t, J ) 8.1 Hz), 7.18 (1H, t, J ) 2.6 Hz), 7.25
(1H, d, J ) 8.1 Hz), 8.36 (1H, br); IR ν (CHCl3) cm-1 3495; MS
m/z 147 (M+); HRMS calcd for C9H9NO 147.0684, found
147.0666.
5-Meth oxyin d ole (7c). Reaction time was 3 h. 7c: color-
less solid; yield 79%; mp 55-56 °C (lit.4c mp 55-56 °C), bp
160 °C/4 mmHg); 300 MHz 1H-NMR (CDCl3/TMS) δ (ppm):
3.86 (3H, s), 6.50-6.48 (1H, m), 6.87 (1H, dd, J ) 2.5, 8.8 Hz),
7.11 (1H, d, J ) 2.5 Hz), 7.19 (1H, t, J ) 2.5 Hz), 7.29 (1H, d,
J ) 8.8 Hz), 8.05 (1H, br); IR ν (CHCl3) cm-1 3485; MS m/z
147 (M+); HRMS calcd for C9H9NO: 147.0684, found 147.0660.
Anal. Calcd for C9H9NO: C, 73.45; H, 6.16; N, 9.52. Found:
C, 73.33; H, 6.20; N, 9.48.
(1H, s), 7.08 (1H, t, J ) 2.6 Hz), 7.43 (1H, d, J ) 8.4 Hz), 7.93
(1H, br); IR ν (CHCl3) cm-1 3490; MS m/z 289 (M+); HRMS
calcd for C17H27NOSi 289.1860, found 289.1835.
7-((Tr iisop r op ylsilyl)oxy)in d ole (8b). Reaction time was
96 h. 8b : colorless viscous liquid; yield 10%; 300 MHz 1H
NMR (CDCl3/TMS) δ (ppm) 1.14 (18H, d, J ) 7.1 Hz), 1.41-
1.30 (3H, m), 6.52 (1H, t, J ) 3.0 Hz), 6.65 (1H, d, J ) 7.7
Hz), 6.93 (1H, t, J ) 7.7 Hz), 7.18 (1H, t, J ) 3.0 Hz), 7.24
(1H, d, J ) 7.7 Hz), 8.20 (1H, br); IR ν (CHCl3) cm-1 3500; MS
m/z 289 (M+); HRMS calcd for C17H27NOSi 289.1860, found
289.1890.
1-(ter t-Bu t oxyca r b on yl)-7-((t r iisop r op ylsilyl)oxy)in -
d ole. Reaction time was 1 h. Colorless viscous liquid: yield
62%. 300 MHz 1H NMR (CDCl3/TMS) δ (ppm) 1.11 (18H, d, J
) 7.3 Hz), 1.50-1.16 (3H, m), 1.60 (9H, s), 6.47 (1H, d, J )
3.7 Hz), 6.76 (1H, d, J ) 7.3 Hz), 7.13-7.03 (2H, m), 7.42 (1H,
d, J ) 3.7 Hz); IR ν (CHCl3) cm-1 1755; MS m/z 389 (M+);
HRMS calcd for C22H35NO3Si 389.1780, found 389.2376.
5-((Tr iisop r op ylsilyl)oxy)in d ole (8c). Reaction time was
1
18 h. 8c: pale yellow viscous liquid; yield 70%; 300 MHz H
NMR (CDCl3/TMS) δ (ppm) 1.12 (18H, d, J ) 7.0 Hz), 1.33-
1.19 (3H, m), 6.42 (1H, t, J ) 2.2 Hz), 6.81 (1H, dd, J ) 2.6,
8.6 Hz), 7.10 (1H, d, J ) 2.2 Hz), 7.15 (1H, t, J ) 2.6 Hz), 7.20
(1H, d, J ) 8.8 Hz), 7.98 (1H, br); IR ν (CHCl3) cm-1 3490; MS
m/z 289 (M+); HRMS calcd for C17H27NOSi 289.1860, found
289.1859.
6-((Tr iisop r op ylsilyl)oxy)in d ole (8a ). Reaction time was
1
17 h. 8a : pale yellow viscous liquid; yield 67%; 300 MHz H
NMR (CDCl3/TMS) δ (ppm): 1.11 (18H, d, J ) 7.0 Hz), 1.33-
1.21 (3H, m), 6.46 (1H, s), 6.74 (1H, dd, J ) 1.8, 8.4 Hz), 6.88
J O970377W