Synthesis of 3-[(1-aryl)aminomethyl]indoles

Article abstract of DOI:10.1021/jo020049i

We report the novel synthesis of various highly functionalized 3-arylaminomethyl indoles. This synthetic approach makes use of the directing ability of a bulky tertbutyldimethylsilyl-protecting group, which directs the condensation of an array of aromatic tosylaldimines specifically into the 3-position of the indole nucleus. The reactions, which occur under relatively mild conditions, afford the desired products in moderate yields. Prior to selective cleavage of the protecting group, the functionalized protected indoles also serve as attractive substrates for many future organic transformations.

Full text of DOI:10.1021/jo020049i

SCHEME 1
Syn th esis of
3-[(1-Ar yl)a m in om eth yl]in d oles
J ames H. Wynne and Wayne M. Stalick*
Department of Chemistry, George Mason University,
Fairfax, Virginia 22030
wstalick@gmu.edu
Received J anuary 23, 2002
reported to generate 3-(iminyl)indoles, which can be
hydrolyzed to generate ω-aminoacyl groups.7 Recently,
there have been reports of successful acylation of the
3-position of indole employing weakly activating Lewis
acids.8 Base-promoted substitutions in the 3-position
have also been noted; however, the addition of function-
alized substrates were not reported.5,9
Various 3-aminomethylindole derivatives have been
synthesized, but those without substituents on the meth-
ylene bridge are reported to be intrinsically unstable.10
Therefore, we sought to find a method for direct synthesis
of the aromatic substituted 3-aminomethylindoles. By
employing previously synthesized functionalized substi-
tuted aromatic N-tosylaldimines,11 a class of compound
that should easily condense with the indole, we planned
to introduce the desired functionality in one simple step.
Direct treatment of indole (1) with (2a -c) in refluxing
xylene resulted in the expected 3-substituted product
(3a -c), but in only trace amounts (<8%) (Scheme 1).
Unreacted indole, hydrolyzed aldimine, and unidentifi-
able tars were found in the reaction mixtures upon
workup.
Consequently, an examination of indole protecting
groups was made. Indoles possessing a sulfonyl protect-
ing group in the 1-position are reported to direct lithiation
to the 2-position.12 Even at -78 °C, 3-lithio-1-phenylsul-
fonyl indole rearranges to the more stable 2-lithio species
as was originally observed by Gribble and Saulnier.13
This rearrangement was reported to be circumvented by
cooling the 3-lithio species to -100 °C, a result that we
were unable to reproduce after several attempts.
The use of bulky silyl protecting groups was reported
to give good yields when introducing various alkyl and
organometallic substituents into the 3-position of the
indole ring.14,15 Rearrangement, as described above, is
Abstr a ct: We report the novel synthesis of various highly
functionalized 3-arylaminomethyl indoles. This synthetic
approach makes use of the directing ability of a bulky tert-
butyldimethylsilyl-protecting group, which directs the con-
densation of an array of aromatic tosylaldimines specifically
into the 3-position of the indole nucleus. The reactions, which
occur under relatively mild conditions, afford the desired
products in moderate yields. Prior to selective cleavage of
the protecting group, the functionalized protected indoles
also serve as attractive substrates for many future organic
transformations.
There is an increasing interest in indoles possessing
substituents in the 3-position due to their numerous
biological activities.1 A variety of methods have been
reported for the preparation of 3-substituted indoles.2 Of
these, the Mannich3 and Vilsmeier-Haack4 synthesis are
used most extensively; however, transforming the result-
ing adducts into indoles containing functionalized aro-
matic substituents requires several additional steps.
Likewise, the extension of the Vilsmeier-Haack reaction
to form long acyl chain derivatives usually proceeds in
low yields.5
Other less widely used methods for the 3-substitution
of indole have also been reported. Treatment of indole
with various isocyanates is reported to afford 3-amido-
indoles, a method attempted with a limited array of
substrates.6 Reaction of indole with lactams has been
* To whom correspondence should be addressed. Tel: (703) 993-
1078. Fax: (703) 993-1055.
(1) Zhang, H.; Larock, R. C. Org. Lett. 2001, 3, 3083-3086. J iang,
B.; Yang. C.-G.; Wang, J . J . Org. Chem. 2001, 66, 4865-4869. Mori,
M.; Nakanishi, M.; Kajishima, D.; Sato, Y. Org. Lett. 2001, 3, 1913-
1916. Chataigner, I.; Hess, E.; Toupet, L.; Piettre, S. R. Org. Lett. 2001,
3, 515-518. Brady, S. F.; Chao, C. J .; Handelsman, J .; Clardy, J . Org.
Lett. 2001, 3, 1981-1984. Wang, T.; Cook, J . M. Org. Lett. 2000, 2,
2057-2059. Rajeswaran, W. G.; Labroo, R. B.; Cohen, L. A.; King, M.
M. J . Org. Chem. 1999, 64, 1369-1371. Doll, M. K.-H. J . Org. Chem.
1999, 64, 1372-1374 and references cited within. Saxton, J . E. In The
Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1998; Vol.
51, Chapter 1. Saxton, J . E. Nat. Prod. Rep. 1997, 559-590.
(2) Sundberg, R. J . Indoles; Academic Press: New York, 1996;
Chapter 11, pp 105-118.
(3) Smith, A. B., III; Kanoh, N.; Minakawa, N.; Rainier, J . D.; Blase´,
F. R.; Hartz, R. A. Org. Lett. 1999, 1, 1263-1266. Mahboobi, S.;
Grothus, G.; Meindl, W. Arch. Pharm, 1994, 327, 105-114. Kuhn, H.;
Stein, O. Chem. Ber. 1937, 70, 567-569.
(4) J oule, J . A.; Mills, K.; Smith, G. F. Heterocyclic Chemistry, 3rd
ed.; Chapman & Hall: New York, 1995; Chapter 17, pp 305-340.
Iwama, T.; Birman, V. B.; Kozmin, S. A.; Rawal, V. H. Org. Lett. 1999,
1, 673-676.
(7) Powers, J . C. J . Org. Chem. 1965, 30, 2534-2540. van Tambelen,
E. E.; Knapp, G. G. J . Am. Chem. Soc. 1955, 77, 1860-1862. Thesing,
J .; Klussendorf, S.; Ballach, P.; Mayer, H. Chem. Ber. 1955, 88, 1295-
1306.
(8) Ottoni, O.; Neder, A. V. F.; Bias, A. K. B.; Cruz, R. P. A. Aquino,
L. B. Org. Lett. 2001, 3, 1005-1007. Okauchi, T.; Itonaga, M.; Minami,
T.; Owa, T.; Kitoh, K.; Yoshino, H. Org. Lett. 2000, 2, 14851487.
(9) Wynne, J . H.; Mushrush, G. W.; Stalick, W. M. Org. Prep. Proced.
Int. 1999, 31, 447-450. Bocchi, V.; Palla, G. Synthesis 1982, 1096-
1097.
(10) Yamada, F.; Kobayashi, K.; Shimizu, A.; Aoki, N.; Somei, M.
Heterocycles 1993, 36, 2783-2804.
(11) Wynne, J . H.; Price, S. E.; Rorer, J . R.; Stalick, W. M. Synth.
Commun. 2003, in press.
(5) Abel, E.; DeWall, S. L.; Edwards, W. B.; Lalitha, S.; Covey, D.
F.; Gokel, G. W. J . Org. Chem. 2000, 65, 5901-5909.
(6) Vorbruggen H.; Krolikiewicz, K. Tetrahedron 1994, 50, 6549-
6558; Moody, C. J .; Swann, E. J . Chem. Soc., Perkin Trans. 1 1993,
2561-2565.
(12) Smith M. B., March J . Advanced Organic Chemistry, 5th ed.;
Wiley & Sons: New York, 2001; p 792. Zhang, H.-C.; Ye, H.; Moretto,
A. F.; Brumfield, K. K.; Maryanoff, B. E. Org. Lett. 2000, 2, 89-92.
(13) Saulnier, M. G.; Gribble, G. W. J . Org. Chem. 1982, 47, 757-
761.
10.1021/jo020049i CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/04/2002
5850
J . Org. Chem. 2002, 67, 5850-5853

SCHEME 2
SCHEME 3a
TABLE 1. Yield s of Com p ou n d 6
a
Key: (a) 1 equiv of NaOH, THF, cat. Bu4NBr, rt; (b) 1 equiv
of TBAF, THF, rt, 0.5 h; (c) excess NaOH, cat. Bu4NBr, THF,
reflux, 4 h; (d) 6 equiv of TBAF, THF, 100 °C, 6 h.
entries 1-2 and 4-7 afforded moderate yields. The low
yield obtained for entry 3 was ascribed to partial lithium
halogen exchange, which occurred in competition with
the condensation. When 2c was increased 2-fold, product
formation remained constant. Likewise, for entries 8-10,
neither increasing the amount of 2h -j nor heating the
reaction mixture to reflux for 2 h had a positive effect on
product formation.
Since aldimines with acidic protons such as 2k (R )
H) are not expected to react employing this method, a
TMS-protected phenol was envisioned 2k (R ) TMS).
However, this aldimine was unobtainable because silyl
cleavage resulted during its formation. Reaction of the
already formed 2k (R ) H) with TMSCl also resulted in
no product formation. When other silyl protecting groups
were employed, alternative problems resulted that in-
terfered with the selective removal of the silyl-protecting
functionalities later in the synthetic scheme.
Selective deprotection methods for compound 6, which
possesses protecting groups on both nitrogens, were
developed. Selective cleavage of the protecting groups as
shown for 6b was found to be possible (Scheme 3). The
silyl-protecting group was selectively cleaved in quantita-
tive yields using an equimolar solution of TBAF at room
temperature to afford 3b. Selective detosylation of 6b was
achieved through treatment with 1 equiv of NaOH and
a catalytic amount of phase-transfer catalyst. Refluxing
of 6b with an excess of sodium hydroxide, under phase-
transfer conditions, afforded quantitative cleavage of both
the silyl group and the tosyl group to form 8b. Depro-
tection of 6b to afford 8b also can be achieved by
treatment with 6 equiv of TBAF at 100 °C.
In summary, this novel synthetic approach allows for
the easy introduction of a variety of aryl-functionalized
substituents into the 3-position of indole while allowing
one to easily vary the aromatic functionality by a
pathway that would normally be attainable only with
additional steps. The overall three-step synthesis, as
described, generally produces the 3-aminomethyl indoles
in approximately 50% yields.
reported to be circumvented through the use of either a
tert-butyldimethylsilyl (TBDMS) or diisopropylsilyl (TIPS)
protecting group. In our laboratory, the 3-bromo-1-
TBDMS-indole (4) was prepared in an 83% yield using a
procedure described by Bosch and co-workers.15 The
3-lithio-1-TBDMS-indole (5) was prepared from 4 (Scheme
2).
Treatment of 5 with a variety of aromatic tosylaldi-
mines (2a -j), afforded the corresponding 3-substituted
1-TBDMS-indoles (6a -j), respectively (Table 1). No rear-
rangement during product formation, to the undesired
2-substituted isomer, was detected. The majority of the
Exp er im en ta l Section
(14) Matsuzono, M.; Fukuda, T.; Iwao, M. Tetrahedron Lett. 2001,
42, 7621-7623.
(15) Amat, M.; Hadida, S.; Sathyanaryana, S.; Bosch, J . J . Org.
Chem. 1994, 59, 10-11.
Gen er a l Meth od s. THF was distilled from Na/benzophenone
immediately prior to use. CH2Cl2 was distilled from calcium
hydride under nitrogen. Moisture-sensitive reactions were con-
J . Org. Chem, Vol. 67, No. 16, 2002 5851

ducted in oven-dried glassware under a nitrogen atmosphere.
Analytical thin-layer chromatography was performed on pre-
coated silica gel sheets, and flash column chromatography was
accomplished using silica gel, 60 Å (200-400 mesh). External
elemental analyses were performed by Atlantic Microlab, Inc.,
Norcross, GA 30091. All melting points are uncorrected. Unless
N-[[1-(ter t-Bu tyld im eth ylsila n yl)-1H-in d ol-3-yl]-(4-ch lo-
r op h en yl)m et h yl]-4-m et h ylb en zen esu lfon a m id e (6c):
mp ) 135-137 °C; IR (neat) 3269, 3051, 2954, 2928, 2853, 1597,
1493, 1451, 1321, 1259, 1160, 1093, 1041, 1016, 969, 927, 839,
1
813, 740, 667 cm-1; H NMR δ 7.56 (d, J ) 6, 2H), 7.41 (d, J )
9, 1H), 7.21 (d, J ) 9, 2H), 7.17-7.14 (m, 4H), 7.11 (d, J ) 6,
2H), 6.61 (s, 1H), 5.79 (d, J ) 9, 1H), 5.08 (d, J ) 9, N-H), 2.05
(s, 3H), 0.88 (s, 9H), 0.47 (s, 6H); 13C NMR δ 143.35, 142.02,
139.20, 137.65, 133.36, 130.24, 129.52, 128.89, 128.63, 128.59,
127.36, 122.29, 120.27, 119.33, 117.60, 114.37, 54.67, 26.39,
26.53, 21.68, 19.53. Anal. Calcd for C28H33ClN2O2SSi: C, 64.04;
H, 6.33; N, 5.33. Found: C, 63.81; H, 6.13; N, 5.71.
1
otherwise noted, H and 13C NMR spectra were taken in CDCl3
at 300 and 75 MHz respectively, with a TMS internal standard.
Chemical shifts are reported in units downfield from TMS.
Coupling constants, J , are reported in hertz (Hz).
3-Br om o-1-(ter t-bu tyldim eth ylsilan yl)-1H-in dole (4). Syn-
thesis was performed according to a modified literature report
of Bosch and co-workers.15 To a solution of indole (4.00 g, 34.00
mmol) in 140 mL of freshly distilled THF at -78 °C was added
dropwise a solution of n-BuLi (23.4 mL, 37.00 mmol, 1.6 M
hexane solution) in a two-neck half-jacketed round-bottomed
flask equipped with a stir bar and a positive flow of nitrogen.
The temperature was raised to -10 °C over a 15 min period.
After being stirred at -10 °C for 30 min, the reaction mixture
was cooled to -50 °C and a solution of TBDMSCl (5.80 g, 38
mmol) in 30 mL of freshly distilled THF was added. After the
mixture was stirred at -10 °C for 3 h, the temperature was once
again lowered to -78 °C, and NBS (6.00 g, 34 mmol) was added
to the reaction mixture. The reaction mixture was stirred at -50
°C for 4 h before the temperature was allowed to rise slowly to
rt. Hexane (100 mL) and pyridine (1 mL) were added, and the
resulting suspension was removed by filtration through a pad
of Celite. The filtrate was evaporated in vacuo; however, extreme
caution was taken not to heat the mixture above ∼65 °C, at
which point decomposition occurred. The crude mixture was
immediately purified by flash chromatography over silica gel
using hexane/CH2Cl2 in a 6:1 ratio affording 8.71 g (28.07 mmol)
of the desired product, an 83% yield. Spectroscopic data corre-
sponds with that reported in the literature.15
Gen er a l P r oced u r e. P r ep a r a tion 6a -j fr om 4. To a
stirred solution of 3-bromo-1-(tert-butyldimethylsilyl)indole (4)
(0.5 g, 1.6 mmol) in freshly distilled THF (15 mL), cooled to -78
°C, was added a solution of t-BuLi (2.1 mL of a 1.7 M solution
in pentane, 3.6 mmol). The mixture was allowed to stir for 15
min before the rapid addition of 1.1 equiv of the corresponding
tosylaldimine (2) (1.7 mmol) in 30 mL of freshly distilled THF.
The solution was allowed to stir at rt for 12-18 h. The reaction
mixture was quenched with H2O (30 mL) and extracted with
CH2Cl2 (3 × 15 mL). The combined organic layer was washed
with H2O (2 × 15 mL) and dried over MgSO4. The resulting
organic layer was concentrated with the aid of a rotary evapora-
tor to afford a brown, viscous oil. Purification using flash column
chromatography employing silica gel and a solvent system of
EtOAc/hexanes (1:4) afforded compounds 6a -j, respectively, in
approximately 50% yields.
N-[[1-(ter t-Bu tyld im eth ylsila n yl)-1H-in d ol-3-yl]p yr id in -
2-ylm eth yl]-4-m eth ylben zen esu lfon a m id e (6d ): oil; IR (neat)
3466, 3414, 3051, 2958, 2907, 2864, 1618, 1462, 1410, 1394,
1363, 1332, 1265, 1099, 1010, 808, 735, 704 cm-1 1H NMR δ
;
8.62 (m, 1H), 7.95 (d, J ) 6, 1H), 7.74-7.71 (m, 1H), 7.64 (d,
J ) 6, 2H), 7.32 (d, J ) 6, 3H), 7.21-7.16 (m, 2H), 6.94-6.41
(m, 2H), 6.77 (t, J ) 8, 1H), 5.80 (d, J ) 4, 1H), 4.72 (bs, 1H),
2.43 (s, 3H), 0.93 (s, 9H), 0.60 (s, 6H); 13C NMR δ 174.44, 153.24,
149.10, 148.30, 144.65, 137.29, 136.95, 135.40, 128.74, 128.60,
127.08, 126.97, 126.47, 123.12, 122.57, 122.21, 119.83, 68.43,
62.04, 54.91, 47.83, 21.68. Anal. Calcd for C27H33N3O2SSi: C,
65.95; H, 6.76; N, 8.55. Found: C, 65.63; H, 6.92; N, 8.81.
N-[[1-(ter t-Bu tyld im eth ylsila n yl)-1H-in d ol-3-yl](2-tr iflu -
or om et h ylp h en yl)m et h yl]-4-m et h ylb en zen esu lfon a m id e
(6e): mp ) 199-202 °C; IR (neat) 3436, 3281, 1642, 1599, 1450,
1
1306, 1258, 1156, 1119, 1093, 1034, 965 cm-1; H NMR δ 7.82
(t, J ) 9, 1H), 6.70 (d, J ) 9, 2H), 7.61 (d, J ) 9, 1H), 7.50 (t,
J ) 9, 1H), 7.38-7.32 (m, 2H), 7.25 (d, J ) 9, 2H), 7.12 (t, J )
8.5, 1H), 6.96-6.93 (m, 2H), 6.27 (s, 1H), 6.17 (d, J ) 6, 1H),
4.97 (d, J ) 6, 1H), 2.43 (s, 3H), 0.77 (s, 9H), 0.41 (s, 6H); 13C
NMR δ 143.45, 141.64, 139.41, 136.84, 131.64, 130.83, 129.70,
129.52, 128.99, 128.33, 127.48, 127.21, 126.45, 125.99, 122.13,
120.10, 118.53, 117.85, 114.06, 50.55, 29.69, 26.09, 21.49, 19.23.
Anal. Calcd for C29H33F3N2O2SSi: C, 62.34; H, 5.95; N, 5.01.
Found: C, 62.74; H, 6.12; N, 4.78.
N-[[1-(ter t-Bu tyldim eth ylsilan yl)-1H-in dol-3-yl]th ioph en -
2-ylm eth yl]-4-m eth ylben zen esu lfon a m id e (6f): mp ) 152-
154 °C; IR 3259, 3051, 2926, 2854, 1597, 1550, 1451, 1327, 1259,
1156, 1088, 1026, 964, 922, 839, 808, 787, 741, 704, 668 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.57 (d, J ) 9, 2H), 7.41 (d, J ) 9,
2H), 7.27-7.24 (m, 1H), 7.17-7.14 (m, 1H), 7.12-7.08 (m, 2H),
7.02 (t, J ) 6, 1H), 6.86-6.84 (m, 3H), 6.09 (d, J ) 9, 1H), 5.11
(d, J ) 6, 1NH), 2.35 (s, 3H), 0.87 (s, 9H), 0.52 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ 181.76, 151.80, 145.10, 141.74, 137.53,
129.87, 129.19, 128.34, 127.12, 126.59, 125.28, 121.94, 119.97,
119.31, 117.47, 114.10, 110.97, 51.29, 26.20, 21.77, 19.35. Anal.
Calcd for C26H32N2O2S2Si: C, 62.86; H, 6.49; N, 5.64. Found:
C, 62.97; H, 6.21; N, 5.83.
N-[[1-(ter t-Bu tyld im eth ylsila n yl)-1H-in d ol-3-yl]p h en yl-
m eth yl]-4-m eth ylben zen esu lfon a m id e (6a ): mp ) 114-116
°C; IR (neat) 3341, 3240, 2947, 2854, 1451, 1306, 1156, 1093,
N-[An th r a cen -9-yl-[1-(ter t-bu tyld im eth ylsila n yl)-1H-in -
d ol-3-yl]m eth yl]-4-m eth ylben zen esu lfon a m id e (6g): mp )
158-161 °C; IR (neat) 3240, 3051, 2947, 2916, 2854, 1659, 1602,
1550, 1519, 1451, 1420, 1259, 1218, 1157, 1088, 1057, 1010, 964,
984, 907, 839, 813, 787, 741 cm-1 1H NMR δ 7.82 (d, J ) 6,
;
886, 894, 808, 730, 668 cm-1 1H NMR δ 8.84 (s, 1H), 8.78 (s,
;
2H), 7.62 (d, J ) 6, 1H), 7.52 (d, J ) 6, 1H), 7.41 (d, J ) 6, 1H),
7.34 (d, J ) 6, 2H), 7.20-7.25 (m, 2H), 7.10-7.19 (m, 3H), 6.62
(d, J ) 3, 1H), 6.58 (s, 1H), 4.73 (s, 1H), 2.44 (s, 3H), 0.93 (s,
9H), 0.60 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 143.66, 140.99,
139.05, 131.33, 130.96, 129.73, 128.29, 126.49, 124.07, 121.98,
120.60, 119.75, 113.86, 110.98, 104.74, 102.66, 52.92, 26.34,
26.27, 21.53, 19.50. Anal. Calcd for C28H34N2O2SSi: C, 68.53;
H, 6.98; N, 5.71. Found: C, 68.22; H, 7.11; N, 5.32.
1H), 8.49 (s, 1H), 8.35 (d, J ) 6, 4H), 8.03 (d, J ) 6, 4H), 7.80
(d, J ) 9, 2H), 7.57-7.48 (m, 6H), 7.31 (d, J ) 9, 2H), 7.23 (s,
1H), 7.17, (s, 1H), 6.79 (d, J ) 6, 1H), 4.69 (bs, 1H), 2.42, (s,
3H), 0.92 (s, 6H), 0.59 (s, 6H); 13C NMR δ 145.08, 142.67, 142.17,
142.16, 141.57, 137.49, 129.21, 129.04, 129.03, 128.03, 127.93,
127.59, 126.95, 125.88 (overlapping peaks), 124.60, 119.24,
117.38, 113.93, 60.79, 51.11, 26.25, 21.42, 13.53. Anal. Calcd for
C
36H38N2O2SSi: C, 73.18; H, 6.48; N, 4.74. Found: C, 72.89; H,
N-[[1-(ter t-Bu tyld im eth ylsila n yl)-1H-in d ol-3-yl](4-m eth -
oxyp h en yl)m et h yl]-4-m et h ylb en zen esu lfon a m id e (6b ):
mp ) 155-156 °C; IR (neat) 3404, 3279, 2947, 2854, 1607, 1509,
6.47; N, 4.53.
N-[[1-(ter t-Bu tyld im eth ylsila n yl)-1H-in d ol-3-yl](2-n itr o-
p h en yl)m eth yl]-4-m eth ylben zen esu lfon a m id e (6h ): mp )
219-220 °C; IR (neat) 3286, 3259, 2948, 2843, 1524, 1450, 1489,
1
1451, 1317, 1254, 1156, 1093, 1029, 965 cm-1; H NMR δ 7.56
(d, J ) 9, 2H), 7.41 (d, J ) 9, 1H), 7.18-7.08 (m, 6H), 6.96 (t,
J ) 9, 1H), 6.76 (s, 1H), 6.73 (d, J ) 9, 2H), 5.79 (d, J ) 6, 1H),
4.96 (d, J ) 6, 1H), 3.77 (s, 3H), 2.36 (s, 3H), 0.86 (s, 9H), 0.50
(s, 6H). 13C NMR δ 158.88, 141.85, 137.67, 132.60, 130.02,
129.20, 128.61, 128.46 (overlapping peak), 127.16, 121.83,
120.87, 119.83, 119.37, 118.01, 114.04, 113.69, 55.66, 55.08,
26.65, 21.87, 19.77. Anal. Calcd for C29H36N2O3SSi: C, 66.89;
H, 6.97; N, 5.38. Found: C, 66.54; H, 6.67; N, 5.01.
1348, 1260, 1157, 1090, 1039, 1024, 962, 920, 839, 813, 787 cm-1
;
1H NMR δ 8.10 (d, J ) 9, 1H), 7.83 (d, J ) 9, 1H), 7.74, (d, J )
12, 2H), 7.65 (t, J ) 6, 1H), 7.45-7.36 (m, 2H), 7.29 (d, J ) 9,
2H), 7.10 (t, J ) 6, 1H), 6.91 (t, J ) 6, 1H), 6.78 (d, J ) 6, 1H),
6.51 (d, J ) 6, 1H), 6.45 (s, 1H), 5.15 (d, J ) 6, 1H), 2.45 (s, 3H),
0.81 (s, 9H), 0.45 (s, 6H); 13C NMR δ 136.08, 132.93, 130.23,
130.22, 129.76 (overlapping peaks), 128.30, 127.83, 127.47,
5852 J . Org. Chem., Vol. 67, No. 16, 2002

125.01, 123.32, 122.15, 120.15, 118.42 (overlapping peaks), 51.25,
30.94, 26.14, 21.55, 19.27. Anal. Calcd for C28H33N3O4SSi: C,
62.77; H, 6.21; N, 7.84. Found: C, 62.54; H, 5.87; N, 8.02.
N-[[1-(ter t-Bu tyld im eth ylsila n yl)-1H-in d ol-3-yl]fu r a n -2-
ylm eth yl]-4-m eth ylben zen esu lfon a m id e (6i): semisolid; IR
(neat) 3259, 2916, 2843, 1446, 1327, 1259, 1161, 1155, 1088,
1021, 964, 839, 808, 787, 741 cm-1; 1H NMR δ 7.94 (s, 1H), 7.73,
(d, J ) 9, 1H), 7.45 (d, J ) 9, 2H), 7.33-7.25 (m, 2H), 7.16-
7.08 (m, 2H), 7.00 (t, J ) 6, 2H), 6.91 (s, 1H), 6.85 (d, J ) 3,
1H), 6.27 (q, J ) 3, 1H), 6.03 (d, J ) 3, 1H), 5.91 (s, 1H), 5.33 (d,
J ) 6, 1H), 2.32 (s, 3H), 1.39 (s, 9H), 0.88 (s, 6H); 13C NMR δ
157.05, 141.22, 136.53, 129.41, 126.78, 122.99, 121.96 (overlap-
ping peaks), 119.36, 117.25, 111.07, 110.11 (overlapping peaks),
106.59, 53.92, 34.10, 29.68, 29.60, 22.68, 15.31. Anal. Calcd for
mmol) was dissolved in 30 mL of freshly distilled THF in a 50
mL round-bottomed flask. To this stirred solution were added
tetra-n-butylammonium bromide (0.02 g, 0.06 mmol) and solid
sodium hydroxide pellet (0.024 g, 0.60 mmol). The resulting
solution was allowed to stir at rt for 6 h and quenched with 15
mL of H2O. The mixture was extracted with CH2Cl2 (3 × 25 mL)
and washed with H2O (3 × 20 mL). The organic layer was dried
over MgSO4 and the solvent evaporated under reduced pressure.
The final traces of solvent were removed under vacuum over-
night. The desired selective detosylated compound was afforded
in a 62% yield (0.09 g, 0.36 mmol): mp ) 155-156 °C; IR 2947,
2854, 1607, 1509, 1451, 1317, 1254, 1156, 1093, 1029, 965 cm-1
;
1H NMR δ 7.56 (d, J ) 9, 2H), 7.41 (d, J ) 9, 1H), 7.18-7.08
(m, 4H), 6.96 (t, J ) 9, 1H), 6.76 (s, 1H), 6.73 (d, J ) 9, 2H),
5.79 (d, J ) 6, 1H), 4.96 (d, J ) 6, 1H), 3.77 (s, 3H), 0.86 (s, 9H),
0.50 (s, 6H); 13C NMR δ 158.88, 141.85, 137.67, 132.60, 130.02,
129.20, 128.61, 127.16, 121.83, 120.87, 119.83, 118.01, 113.69,
55.66, 26.65, 21.87, 19.77. Anal. Calcd for C22H30N2OSi: C, 72.08;
H, 8.25; N, 7.64. Found: C, 71.75; H, 8.09; N, 7.87.
C
26H32N2O3SSi: C, 64.96; H, 6.71; N, 5.83. Found: C, 65.21; H,
6.58; N, 5.78.
N-[[1-(ter t-Bu tyldim eth ylsilan yl)-1H-in dol-3-yl]qu in olin -
2-ylm eth yl]-4-m eth ylben zen esu lfon a m id e (6j): oil; IR (neat)
3414, 2958, 2903, 2854, 1638, 1514, 1446, 1259, 1140, 1099,
1021, 803, 741 cm-1; 1H NMR δ 8.30 (s, 1H), 7.63 (d, J ) 9, 2H),
7.44 (d, J ) 12, 1H), 7.36 (d, J ) 6, 2H), 7.23-7.08 (m, 8H),
6.62 (d, J ) 3, 1H), 6.53 (d, J ) 3, 1H), 2.38 (s, 3H), 0.93 (s, 9H),
0.59 (s, 6H); 13C NMR δ 156.20, 146.81, 136.94, 136.87, 130.40,
130.24, 129.81, 129.64, 129.40, 129.21, 128.53, 127.93, 127.74,
127.59, 126.59, 126.40, 126.24, 123.72, 122.91, 120.25, 111.24,
34.51, 31.91, 29.68, 22.68; 14.11. Anal. Calcd for C31H35N3O2-
SSi: C, 68.72; H, 6.51; N, 7.76. Found: C, 69.03; H, 6.57; N,
7.94.
N-[(1H-In d ol-3-yl)(4-m eth oxyp h en yl)m eth yl]-4-m eth yl-
ben zen esu lfon a m id e (3b) fr om (6b). Compound 6b (0.30 g,
0.58 mmol) was dissolved in 15 mL of freshly distilled THF in a
50 mL round-bottomed flask. To this stirred solution was added
TBAF (0.18 g, 0.58 mmol). The resulting solution was allowed
to stir for 20 min at rt, quenched with 15 mL of H2O, extracted
with CH2Cl2 (3 × 15 mL), and washed with H2O (2 × 10 mL).
The organic layer was dried over MgSO4 and the solvent
evaporated under reduced pressure to afford a yellow powder
as the desired product in a 92% yield (0.22 g, 0.53 mmol):
mp ) 123-125 °C; IR (HATR) 1578, 1563, 1513, 1432, 1278,
1265, 1253, 1175, 1101, 1031, 896, 858, 826, 719 cm-1; 1H NMR
δ 8.01 (bs, 1NH), 7.57 (d, J ) 9, 2H), 7.30 (t, J ) 6, 1H), 7.22-
7.13 (m, 6H), 6.99 (t, J ) 9, 1H), 6.75-6.73 (m, 3H), 5.80 (d,
J ) 6, 1H), 4.94 (d, J ) 6, 1H), 3.77 (s, 3H), 2.38 (s, 3H); 13C
NMR δ 149.90, 143.65, 142.93, 139.05, 132.49, 129.73, 129.22,
128.42, 127.22, 126.49, 123.62, 119.94, 113.71, 111.19, 77.42,
55.25, 21.51. Anal. Calcd for C23H22N2O3S: C, 67.96; H, 5.46;
N, 6.89. Found: C, 68.32; H, 5.65; N, 6.52.
C-(1H-In dol-3-yl)-C-(4-m eth oxyph en yl)m eth ylam in e (8b).
Compound 6b (0.29 g, 0.56 mmol) was dissolved in 15 mL of
CH2Cl2 in a 25 mL round-bottomed flask equipped with a
magnetic stir bar and a reflux condenser. To this were added
NaOH pellets (0.09 g, 2.22 mmol) and 0.20 g of tetra-n-
butylammonium bromide (0.06 mmol). The resulting solution
was allowed to reflux with rapid stirring for 4 h. After being
allowed to stir and cool to rt, the reaction mixture was diluted
with an additional 25 mL of CH2Cl2 and quenched with (15 mL)
water. The organic layer was removed and washed with H2O
(3 × 25 mL). The resulting organic layer was dried over MgSO4
and the solvent removed under reduced pressure. Upon removal
of the last traces of solvent under vacuum, 0.04 g of the desired
viscous oily product (0.17 mmol) in a 31% yield was isolated:
IR 3252, 1618, 1516, 1462, 1453, 1327, 1249, 1151, 1083, 1041,
951, 926 cm-1 1H NMR δ 7.93 (bs, 1NH), 7.51 (d, J ) 9, 1H),
;
7.33 (d, J ) 9, 1H), 7.21-7.15 (m, 4H), 7.07 (t, J ) 6, 1H), 6.88
(s, 1H), 6.81 (d, J ) 9, 2H), 4.05 (s, NH2), 3.77 (s, 3H); 13C NMR
δ 142.4, 140.9, 136.5, 131.6, 129.5, 128.3, 127.1, 126.5, 122.8,
121.7, 120.5, 112.1, 111.3, 56.2. Anal. Calcd for C16H16N2O: C,
76.16; H, 6.39; N, 11.10. Found: C, 75.81; H, 6.54; N, 10.83.
Ack n ow led gm en t. Financial support by the J ef-
fress Trust is gratefully acknowledged (Grant No.
J -587). We thank Dr. Robert Najarian of Georgetown
University Medical Center for invaluable medicinal
chemistry discussions.
C-[1-(ter t-Bu tyldim eth ylsilan yl)-1H-in dol-3-yl]-C-(4-m eth -
oxyp h en yl)m eth yla m in e (7b). Compound 6b (0.30 g, 0.58
J O020049I
J . Org. Chem, Vol. 67, No. 16, 2002 5853