Syntheses of functionalized 1,4-disubstituted γ-carbolines

Article abstract of DOI:10.1021/jo034290o

We report the complete synthesis of a variety of 1,4-disubstituted γ-carbolines. These compounds are of particular interest for their involvement in many biological processes and are believed to possess various medicinal activities. A large number of N-to

Full text of DOI:10.1021/jo034290o

Syn th eses of F u n ction a lized 1,4-Disu bstitu ted γ-Ca r bolin es
J ames H. Wynne†,‡ and Wayne M. Stalick*,†
Department of Chemistry, George Mason University, Fairfax, Virginia 22030, and
Chemistry Division, Naval Research Laboratory, Washington, D.C. 20375
wstalick@gmu.edu
Received March 5, 2003
We report the complete synthesis of a variety of 1,4-disubstituted γ-carbolines. These compounds
are of particular interest for their involvement in many biological processes and are believed to
possess various medicinal activities. A large number of N-tosylaldimines were condensed with
indoles affording an array of 3-aminomethyl indoles. Subsequent additions, followed by intramo-
lecular cyclization, afforded an array of 1,2-dihydro-3H-γ-carbolones in good yield. Upon subsequent
aromatization, the corresponding fully aromatic functionalized 1-aryl-4-hydroxy-γ-carbolines
resulted.
In tr od u ction
bolines, especially those that contain substituents in the
1- and 4-positions. Of the methods reported, the most
widely used for γ-carboline formation, the Fischer syn-
thesis, often fails completely, or proceeds in low yields
unless forcing thermal conditions are used or an activated
pyridine ring is employed.7,8 An alternative approach is
the Grabe-Ullman synthesis and its subsequent modi-
fications.9 This reaction involves the preparation of a
phenyl-substituted triazolopyridine followed by elimina-
tion of nitrogen gas upon thermal degradation at tem-
peratures ranging between 190 and 500 °C. Microwave
irradiation has also proven successful on several sub-
strates.10 Likewise, Bunyan and co-workers report the
formation of a small series of γ-carbolines by the ring
closure of internally generated 2-nitrosobiphenyls, which
were synthesized in situ.11,12 This reaction proceeds in
moderate yields and the products are limited to alkyl-
substituted carbolines. In summary, many of these
previously reported methods employing intramolecular
cyclization proceed in low yields, are limited to nonfunc-
tional substrates, or involve extreme thermal conditions.
The γ-carbolines formed in several cases were actually
byproducts formed while attempting to synthesize the
more notable â-carbolines. Robinson and Thornley,13 for
example, were attempting to synthesize â-carbolines
when they developed a unique three-step γ-carboline
synthesis employing 4-chloropyridine and o-phenylene-
diamine in a catalytic palladium(II) coupling reaction.
â-Carbolines, pyrido[3,4-b]indoles, are of interest to the
pharmaceutical industry due to their close relationship
with natural products such as tryptophan as well as their
numerous reported biological activities.1 Through the
years, a number of reports have shown that γ-carbolines,
pyrido[4,3-b]indoles, also possess similar biological activi-
ties.2 Several substituted γ-carbolines have been synthe-
sized and examined in a series of in vitro and in vivo
pharmacological tests and have demonstrated antipsy-
chotic,3 antibiotic,4 antitumor,5 and other related activi-
ties.6,7
There exists no general efficient synthetic route that
allows for the formation of highly functionalized γ-car-
* To whom correspondence should be addressed. Fax: (703) 993-
1055.
† George Mason University.
‡ Naval Research Laboratory.
(1) Hino, T.; Nakagawa, M. J . Heterocycl. Chem. 1994, 31, 625-
630. Baker, B. J . Alkaloids: Chem. Biol. Perspect. 1996, 10, 357-407.
Love, B. E. Org. Prep. Proced. Int. 1996, 28, 1-64. Magnier, E.;
Langlois, Y. Tetrahedron 1998, 54, 6201-6258. Nakagawa, M. J .
Heterocycl. Chem. 2000, 37, 567-581. Ohmoto, T.; Koike, K. In The
Alkaloids; Brossi, A., Ed.; Academic: San Diego, 1989; Vol. 36, pp 135-
170.
(2) Gribble, G. W. In The Alkaloids; Brossi, A., Ed.; Academic: San
Diego, CA, 1990; Vol. 39, Chapter 7. Tan, G. T.; Pezzuto, J . M. In
Chemistry and Toxicology of Diverse Classes of Alkaloids; Blum, M.
S., Ed.; Alaken, Inc.: Ft. Collins, CO, 1996; pp 1-119. Nguyen, C. H.;
Lavelle, F.; Riou, J .-F.; Bissery, M.-C.; Huel, C.; Bisagni, E. Anti-Cancer
Drug Des. 1992, 7, 235-251. Guillonneau, C.; Pierre´, A.; Charton, Y.;
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Chem. 1987, 30, 1100-1105. Harbert, C. A.; Plattner, J . J .; Welch, W.
M.; Weissman, A.; Koe, B. K. Mol. Pharmacol. 1980, 17, 38-42.
J ohnson, R. P.; Oswald, J . P. U.S. Patent 3 382 250, 1968. Welch, W.
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27, 1058-1060. Wakelin, L. P. G. Med. Res. Rev. 1986, 6, 275-340.
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16, 1081-1084. Maquestiau, A.; Flammang-Barbieux, M.; Flammang,
R.; Chen, L.-Z. Bull. Soc. Chim. Belg. 1988, 97, 245-254. Nantka-
Namirski, P. Acta Polon. Pharm. 1962, 19, 229-242.
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synthesis. In Heterocyclic Chemistry, 3rd ed.; Chapman Hall: New
York, 1996; pp 305-349.
(11) Bunyan, P. J .; Codogan, J . I. G. J . Chem. Soc. 1963, 42-49.
(12) Scheiner, P. J . Org. Chem. 1965, 30, 7-10.
(13) Robinson, R.; Thornley J . J . Chem. Soc. 1924, 125, 2169-2176.
10.1021/jo034290o CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/15/2003
J . Org. Chem. 2003, 68, 4845-4849
4845

Wynne and Stalick
Likewise, Ro¨nner and co-workers14 also produced γ-car-
bolines as byproducts using the palladium-catalyzed
condensation of tryptophan derivatives with glucose. This
route is very limited in substitution due to the starting
materials.
SCHEME 1
A couple of examples where γ-carbolines were the
object of synthesis involve the intramolecular coupling
of a boronic acid with o-fluoroiodopyridine by a Suzuki-
type reaction employing a Pd(0) species.15 Although
seemingly an efficient conversion, it does involve the
synthesis of specialty starting materials, and the authors
report that the overall three-step process is limited to
nonacid-sensitive substrates.15 Most recently, Larock and
co-workers16 developed a novel palladium-catalyzed imi-
noannulation of internal alkynes. This unique method
allows for the introduction of functionality into both the
3- and 4-positions of γ-carbolines. Additionally, Larock’s
group has shown that γ-carbolines substituted in the
3-position, some of which possess 4-annularization, are
readily available by a novel palladium/copper-catalyzed
intramolecular cyclization reaction of alkynyl indoles.17
These γ-carboline derivatives have been found to act as
cardiovascular agents or 5-HT3 receptor antagonists.18
Because of these recent advances and the importance of
this class of compounds, we report a general synthesis
and novel approach to afford the complimentary series
of γ-carbolines that are substituted in the 1- and 4-posi-
tions.
SCHEME 2 a
a
Reagents: (i) NaOEt, BrCH2CO2Et, (ii) Bentonite K-10 Clay,
(iii) NaOH.
Discu ssion
In the â-carboline series it was found that the more
saturated tetrahydro-precursors possessed multidrug
resistance.19 This led to their attempted synthesis by
many groups who mainly used the Pictet-Spengler
synthesis.20 However, much less is known about the
synthesis and biological activity of their counterparts, the
corresponding tetrahydro-γ-carbolines.21
The lack of commercially available 3-aminomethyl
indoles has impeded the development of a novel synthetic
approach to afford a large selection of functionalized
γ-carbolines. We recently reported the development of a
procedure for the facile synthesis of the 3-substituted
aminomethyl indoles.22 With this in place, we now report
the development of a methodology that allows for control
of the substituents, not only in the 1-position, but also
in the 4-position of the tetrahydro-γ-carboline if desired.
By altering the substitution in these two positions,
compounds of varying binding abilities should be obtain-
able. Therefore, this synthetic approach could be easily
manipulated to produce compounds with maximum
pharmacological/biological effect.
Our goal was to start with readily available indole and
to proceed by a method allowing for the control of
substitution of various groups into the 1- and 4-positions
in the final γ-carboline product. We reached this goal as
follows. Treatment of 3-bromo-1-tert-butyldimethyl silyl
indole (1) with tert-butyllithium followed by condensation
with a variety of freshly prepared N-tosylaldimines23 (2)
affords the corresponding 1-protected-3-arylaminomethyl
indoles (3) in good yields (Scheme 1).22 This procedure
allows for a wide variety of aryl substituents containing
both electron-withdrawing and electron-donating func-
tionalities to be introduced. Eventually the aryl substitu-
ent on 2 will become the 1-position aryl group of the final
γ-carboline molecule. Therefore, altering the tosylaldi-
mines (2) allows for direct control of the substituent in
the 1-position.
Subsequent treatment of 3, with sodium ethoxide
followed by addition of ethyl bromoacetate affords com-
pound 4 (Scheme 2). A variety of bases were employed
in an attempt to optimize yields; however, it was discov-
ered that sodium ethoxide afforded higher yields than
other bases such as sodium hydroxide, sodium hydride,
or sodium methoxide. When the 1,2-dihydro-3-H-γ-car-
bolone (5) was the target molecule, treatment of 4 with
a variety of Lewis acids readily afforded this product by
intramolecular cyclization. We elected to proceed via the
carbolone (5) rather than the tetrahydro-γ-carboline,
which could be produced by a Pictet-Spengler synthesis.
By doing so, it becomes possible to vary substituents in
the 4-position of the γ-carboline intermediate in addition
to the aforementioned 1-position. The desired carbolone
(5) was afforded in lower yields than expected, due to
(14) Ro¨nner, B.; Lerche, H.; Bergmu¨ller, W.; Freilinger, C.; Severin,
T.; Pischetsrieder, M. J . Agric. Food Chem. 2000, 48, 2111-2116.
(15) Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G. Tetrahedron
1993, 49, 49-64.
(16) Zhang, H.; Larock, R. C. Org. Lett. 2001, 3, 3083-3086.
(17) Zhang, H.; Larock, R. C. J . Org. Chem. 2002, 67, 7048-7056.
Zhang, H.; Larock, R. C. Tetrahedron Lett. 2002, 43, 1359-1362.
(18) Zhang, H.; Larock, R. C. Org. Lett. 2002, 4, 3035-3038.
(19) Madrigal, A.; Grande, M.; Avendano, C. J . Org. Chem. 1998,
63, 2724-2727.
(20) Gremmen, C. B.; Wanner, M. J .; Koomen, G.-J . Org. Lett. 2000,
2, 1955-1958. Audia, J . E.; Droste, J . J .; Nissen, J . S.; Murdoch, G.
L.; Evrard, D. A. J . Org. Chem. 1996, 61, 7937-7939. Li, X.; Zang, L.;
Zang, W.; Hall, S. E.; Tam, J . P. Org. Lett. 2000, 2, 3075-3078.
(21) Engler, T.; Wanner, J . J . Org. Chem. 2000, 65, 2444-2457.
(22) Wynne, J . H.; Stalick, W. M. J . Org. Chem. 2002, 68, 5850-
5853.
(23) Wynne, J . H.; Price, S. E.; Rorer, J . R.; Stalick, W. M. Synth.
Commun. 2003, 33, 341-352.
4846 J . Org. Chem., Vol. 68, No. 12, 2003

Functionalized 1,4-Disubstituted γ-Carbolines
TABLE 1. Str u ctu r e a n d Yield s of Com p ou n d 4
TABLE 3. Syn th esis of γ-Ca r bolin e (8) by Dir ect
Con ver sion of 4
entry
starting material
product
yield (%)
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4f
8a
8b
8c
8d
8e
8f
35
31
28
33
43
18
26
4g
8g
sodium/benzophenone ketal-pair and CH2Cl2 from P2O5, all
under nitrogen. All moisture-sensitive reactions and reagent
transfers were carried out under either nitrogen or argon.
Thin-layer chromatography (TLC) was performed on precoated
silica gel sheets with glass backing. Preparative column
chromatography was performed on an Isco-100s automated
flash column chromatograph system employing pre-packed
silica gel columns 60 Å (200-400 mesh).
Gen er a l P r oced u r e. P r ep a r a tion of 3 fr om 1. To a
stirred solution of 3-bromo-1-(tert-butyldimethylsilyl)indole25
(1; 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 room
temperature for 24 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 evaporator to afford a
brown, viscous oil. Purification with flash column chromatog-
raphy employing silica gel and a solvent system of EtOAc:
hexanes (1:4) afforded compounds 3a -g, respectively, in good
yields.22
TABLE 2. Syn th esis of 1,2-Dih yd r o-3-H-γ-ca r bolon e by
In tr a m olecu la r Cycliza tion
entry
starting material
product (yield %)
1
2
3
4a
4b
4c
5a (61); 6a (9); 7a (21)
5b (45); 6b (4); 7b (17)
5c (57); 6c (16); 7c (11)
Gen er a l P r oced u r e. P r ep a r a tion of 4 fr om 3. Into a 50-
mL RB flask was placed a sample of compound 3 (2.01 mmol)
dissolved in 30 mL of freshly distilled THF, and this mixture
was allowed to stir under a positive flow of N2 for 15 min.
Sodium ethoxide (2.21 mmol) was added to the stirred solution
and stirring was continued for an additional 30 min before
ethyl bromoacetate (2.52 mmol) was added. The resulting
solution was heated at reflux for 3.5 h and allowed to cool
slowly to room temperature before being quenched with 10 mL
of H2O. The resulting solution was extracted with CH2Cl2 (3
× 25 mL), washed with H2O (3 × 15 mL), and dried over
MgSO4 before being concentrated on a rotary evaporator. The
final traces of solvent were removed under vacuum for 12 h.
Gradient flash column chromatography (hexane:ethyl acetate)
was performed to afford the desired purified product.
[[[1-TBDMS-1H-in d ol-3-yl]-p h en yl-m eth yl]-(tolu en e-4-
su lfon yl)-a m in o]-a cetic a cid eth yl ester (4a ): A viscous
red oil, 86% yield. FTIR 3466, 3051, 2956, 2916, 2854, 1716,
1638, 1451, 1415, 1264, 1140, 1093, 1010, 969, 896, 803, 741
cm-1. 1H NMR δ 7.79 (d, J ) 9, 1H), 7.74-7.71 (m, 1H), 7.64-
7.61 (m, 1H), 7.51 (d, J ) 9, 1H), 7.36-7.26 (m, 4H), 7.24 (s,
1H), 7.30-7.10 (m, 5H), 6.62 (s, 1H), 4.19 (s, 2H), 4.10 (q, J )
6, 2H), 2.40 (s, 3H), 1.17 (t, J ) 3, 3H), 0.92 (s, 9H), 0.60 (s,
6H). 13C NMR δ 144.0, 141.9, 136.7, 130.2, 128.7, 128.1, 126.0,
124.1, 123.6, 122.0, 121.3, 120.7, 120.1, 119.2, 113.8, 111.0,
102.7, 40.3, 34.8, 31.5, 26.4, 23.8, 19.5, 14.1. Anal. Calcd for
contamination with 6 and 7. A variety of Lewis acids such
as BF3/Et2O, PPA, ZnCl2, AlCl3, TiCl4, K-10 Clay, and
P2O5 were examined as cyclizing catalysts with yields of
5 ranging from trace amounts to about 60%. The highest
yield was achieved by employing Bentonite K-10 Clay.
It has been noted that esters undergo either acylation
(ring closure) or alkylation depending upon the choice of
catalyst and it is believed that occurred in this case.24 It
was discovered that stronger Lewis acids, such as TiCl4,
frequently afforded a variety of products as noted by the
increased formation of 6 and 7. Since any of the com-
pounds 5, 6, or 7, when reacted with base, afforded the
desired carboline 8, it was unnecessary to isolate or purify
the group of compounds that resulted from the acid-
catalyzed cyclization step. Thus, a direct conversion from
4 to 8 was achieved in good yields, and when the
carbolone 5 was the desired goal, this scheme allowed
for its facile synthesis as well.
Exp er im en ta l Section
Gen er a l P r oced u r es. Reagents were obtained from com-
mercial suppliers and were used without further purification
except as noted. Melting points are uncorrected. FTIR spectra
of samples were obtained either as KBr pellets or on NaCl
C
32H40N2O4SSi: C, 66.63; H, 6.99; N, 4.86. Found: C, 66.28;
H, 7.14; N, 4.61.
1
disks. H NMR and 13C NMR were determined at 300 and 75
[[[1-TBDMS-1H-in d ol-3-yl]-(4-m eth oxy-p h en yl)-m eth -
yl]-(tolu en e-4-su lfon yl)-a m in o]-a cetic a cid eth yl ester
(4b): A yellow powder, 72% yield, mp 110-112.5 °C. FTIR
3279, 3051, 2947, 2854, 1747, 1612, 1550, 1550, 1509, 1451,
MHz, respectively, in CDCl3 unless otherwise noted, and
chemical shifts are reported downfield from TMS. Coupling
constants, J , are reported in Hz. THF was distilled from a
(24) Smith, M. B.; March, J . Advanced Organic Chemistry, 5th ed.;
Wiley-Interscience: New York, 2001; p 708.
(25) Amat, M.; Hadida, S.; Sathyanaryana, S.; Bosch, J . J . Org.
Chem. 1994, 59, 10-11.
J . Org. Chem, Vol. 68, No. 12, 2003 4847

Wynne and Stalick
1306, 1254, 1156, 1093, 1031, 969, 917, 839, 813 cm-1. 1H NMR
δ 7.82 (d, J ) 6, 2H), 7.50 (d, J ) 6, 2H), 7.40 (d, J ) 9, 1H),
7.15 (d, J ) 9, 2H), 6.93 (d, J ) 9, 1H), 6.97-6.69 (m, 2H),
6.40 (s, 1H), 5.80 (d, J ) 6, 2H), 5.47 (d, J ) 9, 1H), 4.20 (q, J
) 6, 2H), 3.75 (s, 2H), 3.72 (s, 3H), 2.31 (s, 3H), 0.99 (t, J ) 9,
3H), 0.87 (s, 9H), 0.48 (s, 6H). 13C NMR δ 169.5, 158.8, 142.6,
141.8, 137.7, 132.6, 130.0, 129.2, 128.4, 127.1, 121.5, 120.0,
119.5, 119.4, 118.0, 113.9, 113.6, 60.8, 58.5, 55.2, 54.6, 46.4,
26.2, 21.4, 19.3, 13.8. Anal. Calcd for C33H42N2O5SSi: C, 65.31;
H, 6.98; N, 4.62. Found: C, 65.67; H, 7.03; N, 4.34.
1H), 7.22 (s, 1H), 7.13 (t, J ) 9, 2H), 6.98 (t, J ) 6, 2H), 6.76
(d, J ) 6, 2H), 6.68 (s, 1H), 6.33 (d, J ) 9, 2H), 5.76 (d, J ) 6,
1H), 4.19 (q, J ) 3, 2H), 3.91 (s, 2H), 2.05 (s, 3H), 0.86 (t, J )
6, 3H), 0.79 (s, 9H), 0.42 (s, 6H). 13C NMR δ 186.7, 146.6, 142.0,
136.3, 131.5, 130.5, 130.3, 129.2, 128.1, 128.0, 126.0, 124.7,
121.9, 120.1, 120.1, 117.4, 114.0, 100.3, 96.3, 93.8, 50.7, 31.9,
29.7, 26.3, 21.2, 14.1. Anal. Calcd for C40H44N2O4SSi: C, 70.97;
H, 6.55; N, 4.14. Found: C, 71.36; H, 6.46; N, 3.83.
Gen er a l P r oced u r e. P r ep a r a tion of 5 fr om 4. Into a 50-
mL RB flask was placed a sample of compound 4 (8.42 mmol)
dissolved in 25 mL of freshly distilled THF. The solution was
allowed to stir under a positive flow of N2 for 15 min. To the
stirred solution was added 1.00 g of Bentonite K-10 clay. The
resulting solution was heated in an 80 °C oil bath for 12 h.
Upon completion, the reaction mixture was cooled, then diluted
with 20 mL of CH2Cl2 and vacuum filtered with the aid of a
Bu¨chner funnel to remove the clay from the reaction mixture.
The organic layer was dried over MgSO4 and concentrated
under reduced pressure. Final traces of solvent were removed
under vacuum for 4 h. Gradient flash column chromatography
(hexane:ethyl acetate) was performed to afford the desired
product 5.
[[[1-TBDMS-1H-in d ol-3-yl]-(4-ch lor o-p h en yl)-m eth yl]-
(tolu en e-4-su lfon yl)-a m in o]-a cetic a cid eth yl ester (4c):
A yellow oil, 63% yield. FTIR 3373, 3051, 2947, 2864, 1742,
1597, 1545, 1488, 1451, 1420, 1337, 1265, 1207, 1161, 1088,
1
1016, 969, 896, 839, 808, 740, 699 cm-1. H NMR δ 7.83 (d, J
) 9, 2H), 7.54 (d, J ) 9, 1H), 7.46-7.42 (m, 1H), 7.31 (d, J )
9, 2H), 7.24 (d, J ) 9, 2H), 7.18-6.88 (m, 4H), 6.69 (s, 1H),
6.43 (s, 1H), 5.83 (d, J ) 3, 1H), 3.82 (q, J ) 6, 2H), 2.42 (s,
3H), 2.36 (s, 2H), 1.01 (t, J ) 9, 3H), 0.88 (s, 9H), 0.50 (s, 6H).
13C NMR δ 156.2, 146.6, 142.0, 136.3, 131.5, 130.5, 130.3,
129.2, 128.2, 128.1, 128.0, 126.0, 124.7, 121.9, 120.1, 120.1,
117.4, 114.0, 50.7, 29.7, 26.2, 21.2, 19.3, 14.1. Anal. Calcd for
C
32H39ClN2O4SSi: C, 62.88; H, 6.43; N, 4.58. Found: C, 62.55;
1-P h en yl-2-(tolu en e-4-su lfon yl)-1,2,3,5-tetr a h yd r o-p y-
r id o[4,3-b]in d ol-4-on e (5a ): A brown oil, 61% yield. FTIR
3650, 3522, 3134, 3004, 3051, 2916, 1719, 1492, 1441, 1368,
H, 6.22; N, 4.88.
[[[1-TBDMS-1H-in d ol-3-yl]-p yr id in -2-yl-m eth yl]-(tolu -
en e-4-su lfon yl)-a m in o]-a cetic a cid eth yl ester (4d ):
A
1259, 1171, 1124, 1088, 989, 746, 678 cm-1 1H NMR δ
.
yellow powder, 61% yield, mp 87.5-93 °C. FTIR 3435, 3051,
8.18 (br s, 1NH), 7.78 (d, J ) 6, 2H), 7.62-7.40 (m, 2H), 7.31
(d, J ) 6, 2H), 7.17-7.02 (m, 7H), 4.97 (s, 1H), 4.32 (s, 1H),
2.35 (s, 3H). 13C NMR δ 185.6, 146.3, 141.6, 136.3, 134.6, 134.0,
133.8, 128.7 (overlapping peak), 127.8, 125.8, 124.9, 122.2,
121.8, 121.5, 119.7, 109.8, 51.7, 50.3, 22.4. Anal. Calcd for
2978, 1737, 1633, 1592, 1420, 1332, 1265, 1161, 1093, 1021,
1
896, 808, 740, 704 cm-1. H NMR δ 8.36 (d, J ) 6, 2H), 7.86
(d, J ) 6, 2H), 7.78-7.45 (m, 4H), 7.35 (d, J ) 6, 1H), 7.20-
6.78 (m, 3H), 6.78 (s, 1H), 5.78 (d, J ) 3, 1H), 4.01 (q, J ) 6,
2H), 2.43 (s, 3H), 2.32 (s, 2H), 1.13 (t, J ) 3, 3H), 0.75 (s, 9H),
0.45 (s, 6H). 13C NMR δ 169.3, 143.4, 141.5, 137.1, 133.3, 131.8,
129.4, 129.3, 128.6, 128.3, 128.0, 121.9, 119.9, 119.6, 117.3,
114.6, 113.9, 60.9, 58.3, 54.4, 54.3, 46.6, 26.1, 21.4, 19.2, 13.7.
Anal. Calcd for C31H39N3O4SSi: C, 64.44; H, 6.80; N, 7.27.
Found: C, 64.13; H, 7.12; N, 6.93.
C
24H20N2O3S: C, 69.21; H, 4.84; N, 6.73. Found: C, 68.97; H,
5.13; N, 6.49.
1-(4-Meth oxy-p h en yl)-2-(tolu en e-4-su lfon yl)-1,2,3,5-tet-
r a h yd r o-p yr id o[4,3-b]in d ol-4-on e (5b): Dark oil, 45% yield.
FTIR 3414, 3187, 3049, 2981, 2918, 1710, 1657, 1587, 1478,
1448, 1376, 1352, 1312, 1227, 1181, 1054, 1024, 1018, 998, 761
[[[1-TBDMS-1H-in d ol-3-yl]-(2-tr iflu or om eth yl-p h en yl)-
m eth yl]-(tolu en e-4-su lfon yl)-a m in o]-a cetic a cid eth yl es-
ter (4e): A yellow oil, 59% yield. FTIR 3269, 3051, 2937, 2854,
1742, 1597, 1550, 1493, 1467, 1451, 1420, 1337, 1311, 1239,
1
cm-1. H NMR δ 8.26 (br s, 1NH), 7.51 (d, J ) 6, 2H), 7.35 (d,
J ) 6, 2H), 7.21-7.15 (m, 3H), 7.07 (t, J ) 6, 1H), 7.04 (d, J
) 6, 1H), 6.89 (d, J ) 6, 1H), 6.81 (d, J ) 6, 2H), 5.07 (s, 1H),
4.05 (s, 2H), 3.77 (s, 3H), 1.55 (s, 3H). 13C NMR δ 158.9, 143.6,
142.9, 139.1, 137.6, 136.6, 132.5, 129.7, 129.2, 128.4, 127.2,
126.5, 125.4, 119.9, 119.4, 116.6, 113.7, 111.2, 55.2, 30.2, 29.7,
22.7. Anal. Calcd for C25H22N2O4S: C, 67.25; H, 4.97; N, 6.27.
Found: C, 67.04; H, 5.16; N, 6.19.
1213, 1161, 1119, 1036, 964, 927, 896, 808, 735, 709, 678 cm-1
.
1H NMR δ 7.82 (d, J ) 6, 2H), 7.75 (d, J ) 9, 2H), 7.59 (t, J )
6, 1H), 7.42 (t, J ) 6, 1H), 7.39-7.33 (m, 3H), 7.23 (d, J ) 6,
1H), 7.20-6.73 (m, 2H), 6.28 (s, 1H), 6.20 (d, J ) 3, 1H), 5.12
(d, J ) 3, 1H), 3.47 (q, J ) 6, 2H), 2.45 (s, 3H), 2.41 (s, 2H),
1.08 (t, J ) 9, 3H), 0.77 (s, 9H), 0.42 (s, 6H). 13C NMR δ 170.0,
168,7, 143.4, 141.7, 136.9, 131.7, 130.8, 129.7, 129.6, 129.5,
129.4, 129.0, 128.4, 127.4, 127.1, 122.1, 120.1, 118.6, 117.9,
114.1, 61.4, 55.1, 50.5, 48.3, 26.1, 21.5, 19.2, 14.1. Anal. Calcd
for C33H39F3N2O4SSi: C, 61.47; H, 6.10; N, 4.34. Found: C,
61.14; H, 5.86; N, 3.97.
1-(4-Ch lor o-p h en yl)-2-(t olu en e-4-su lfon yl)-1,2,3,5-t et -
r a h yd r o-p yr id o[4,3-b]in d ol-4-on e (5c): A brown oil, 57%.
FTIR 3352, 3097, 3081, 2975, 2961, 1719, 1643, 1602, 1302,
1
1156, 1093, 906, 813 cm-1. H NMR δ 8.46 (br s, 1NH), 7.79-
7.68 (m, 3H), 7.34-7.09 (m, 9H), 5.07 (s, 1H), 4.31 (s, 1H), 2.39
(s, 3H). 13C NMR δ 187.4, 146.7, 146.3, 142.3, 137.9, 135.9,
133.8, 130.3, 129.6, 129.1, 126.5, 125.2, 124.8, 122.6, 121.1,
120.8, 110.6, 52.3, 48.7, 23.1. Anal. Calcd for C24H19ClN2O3S:
C, 63.92; H, 4.25; N, 6.21. Found: C, 64.01; H, 4.52; N, 5.93.
[[[1-TBDMS-1H-in dol-3-yl]-th ioph en -2-yl-m eth yl]-(tolu -
en e-4-su lfon yl)-a m in o]-a cetic a cid eth yl ester (4f): A
brown powder, 43% yield, mp 87.5-93 °C. FTIR 3373, 3051,
2948, 2854, 2304, 1752, 1732, 1602, 1550, 1472, 1451, 1420,
1332, 1265, 1213, 1161, 1093, 1021, 964, 896, 839, 813, 740,
Gen er a l P r oced u r e. P r ep a r a tion of 8 fr om 4. Into a 50-
mL RB flask was placed a sample of compound 4 (8.42 mmol)
dissolved in 25 mL of freshly distilled THF. The solution was
allowed to stir under a positive flow of N2 for 15 min. To the
stirred solution was added 1.00 g of Bentonite K-10 clay. The
resulting solution was heated in an 80 °C oil bath for 12 h.
The reaction mixture was cooled and vacuum filtered with the
aid of a Bu¨chner funnel to remove the clay from the reaction
mixture. To the resulting combined organic layer was added
20 mL of THF, NaOH (16.84 mmol), and tetrabutylammonium
bromide (0.84 mmol). The solution was heated at reflux for 6
h, allowed to slowly cool to room temperature, diluted with
20 mL of CH2Cl2, and neutralized with 1 M HCl. The resulting
solution was washed with H2O (3 × 20 mL) and brine (1 × 15
mL). The organic layer was dried over MgSO4 and concen-
trated under reduced pressure. Final traces of solvent were
removed under vacuum for 4 h. Gradient flash column chro-
1
699, 668 cm-1. H NMR δ 7.83 (d, J ) 9, 1H), 7.55 (d, J ) 9,
2H), 7.41 (t, J ) 9, 1H), 7.26-6.98 (m, 3H), 6.97 (d, J ) 9,
2H), 6.97-6.89 (m, 2H), 6.68 (s, 1H), 6.09 (d, J ) 9, 1H), 4.11
(q, J ) 18, 2H), 2.38 (s, 2H), 2.32 (s, 3H), 0.91 (t, J ) 6, 3H),
0.86 (s, 9H), 0.54 (s, 6H). 13C NMR δ 169.3, 145.1, 142.7, 142.2,
141.6, 137.5, 129.8, 129.2, 129.0, 126.5, 125.7, 125.1, 121.8,
119.8, 119.7, 119.2, 117.4, 113.9, 60.8, 54.7, 51.1, 46.1, 26.1,
21.4, 19.2. Anal. Calcd for C30H38N2O4S2Si: C, 61.82; H, 6.57;
N, 4.81. Found: C, 61.71; H, 6.32; N, 5.18.
[[An t h r a ce n -9-yl-[1-TBDMS-1H -in d ol-3-yl]-m e t h yl]-
(tolu en e-4-su lfon yl)-a m in o]-a cetic a cid eth yl ester (4
g): A yellow oil, 61% yield. FTIR 3373, 3051, 2958, 2916, 2854,
1732, 1602, 1451, 1420, 1264, 1156, 1093, 1010, 964, 896, 839,
809, 735, 704 cm-1 1H NMR δ 8.17 (m, 2H), 7.86 (d, J ) 9,
.
2H), 7.54 (d, J ) 12, 2H), 7.43 (d, J ) 6, 1H), 7.36 (t, J ) 6,
4848 J . Org. Chem., Vol. 68, No. 12, 2003

Functionalized 1,4-Disubstituted γ-Carbolines
matography (hexane:ethyl acetate) was performed to afford the
desired product 8.
8.03 (br s, 1H), 7.92 (d, J ) 9, 1H), 7.46-7.42 (m, 2H), 7.38-
7.33 (m, 3H), 7.19 (t, J ) 6, 1H), 7.09 (t, J ) 6, 1H), 6.99 (s,
1H), 4.45 (s, 1H). 13C NMR δ 149.4, 136.3, 136.1, 132.8, 131.8,
127.3, 127.0, 124.0, 123.5, 122.2, 122.1, 119.6, 118.9, 113.0,
111.2, 110.9, 110.2. Anal. Calcd for C16H11N3O: C, 73.55; H,
4.24; N, 16.08. Found: C, 73.39; H, 4.08; N, 15.99.
Gen er a l P r oced u r e. P r ep a r a tion of 8 fr om 5. Com-
pound 5 was dissolved in 25 mL of freshly distilled THF and
allowed to stir for 15 min before the addition of NaOH (16.84
mmol) and tetrabutylammonium bromide (0.84 mmol). The
resulting solution was heated at reflux for 6 h and then allowed
to slowly cool to room temperature, diluted with 20 mL of
CH2Cl2, and neutralized with 1 M HCl. The resulting solution
was washed with H2O (3 × 20 mL) and brine (1 × 15 mL).
The organic layer was dried over MgSO4 and concentrated
under reduced pressure. Final traces of solvent were removed
under vacuum for 4 h. Gradient flash column chromatography
(hexane:ethyl acetate) was performed to afford the desired
product 8.
1-(2-Tr iflu or om eth yl-p h en yl)-5H-p yr id o[4,3-b]in d ol-4-
ol (8e): A yellow oil, 43% yield (from 4). FTIR 3360, 3256,
2956, 1640, 1600, 1524, 1490, 1450, 1415, 1374, 1305, 1259,
1155, 1091, 1028, 906, 803, 745 cm-1 1H NMR δ 8.36 (br s,
.
1H), 7.86 (d, J ) 9, 1H), 7.76 (d, J ) 9, 1H), 7.69 (d, J ) 9,
1H), 7.59-7.47 (m, 1H), 7.40-7.30 (m, 2H), 7.20-7.17 (m, 1H),
6.97 (d, J ) 9, 1H), 5.74 (s, 1H), 4.69 (s, 1H). 13C NMR δ 188.2,
144.0, 136.7, 134.7, 128.7, 128.2, 127.1, 126.1, 124.5, 123.6,
122.2, 121.9, 119.9, 119.8, 119.2, 119.2, 111.0, 70.3. Anal. Calcd
for C18H11F3N2O: C, 65.85; H, 3.38; N, 8.53. Found: C, 66.02;
H, 3.57; N, 8.46.
1-P h en yl-5H-p yr id o[4,3-b]in d ol-4-ol (8a ): A yellow oil,
35% yield (from 4). FTIR 3406, 2956, 2910, 2852, 1733, 1634,
1577, 1536, 1455, 1415, 1334, 1258, 1091, 1016, 860, 802 cm-1
.
1-Th iop h en -2-yl-5H-p yr id o[4,3-b]in d ol-4-ol (8f): A yel-
low oil, 18% yield (from 4). FTIR 3406, 2944, 1640, 1548, 1455,
1426, 1339, 1288, 1259, 1224, 1184, 1155, 1086, 1034, 970, 849,
1H NMR δ 7.91 (br s, 1H), 7.73 (d, J ) 6, 1H), 7.40-7.34 (m,
2H), 7.19-7.12 (m, 4H), 7.02-6.97 (m, 1H), 6.67 (d, J ) 6,
1H), 5.89 (s, 1H), 4.25 (s, 1H). 13C NMR δ 144.0, 136.7, 134.7,
128.7, 128.2, 127.1, 126.1, 124.5, 123.6, 122.2, 121.9, 119.9,
119.8, 119.2, 119.2. Anal. Calcd for C17H12N2O: C, 78.44; H,
4.65; N, 10.76. Found: C, 78.21; H, 4.58; N, 10.43.
1
808, 739, 623 cm-1. H NMR δ 8.03 (br s, 1H), 7.57 (d, J ) 9,
1H), 7.36 (d, J ) 9, 1H), 7.12 (t, J ) 6, 1H), 7.10-7.05 (m,
2H), 7.05 (s, 1H), 6.92 (s, 1H), 6.93-6.87 (m, 2H), 4.32 δ (s,
1H). 13C NMR δ 196.4, 145.6, 128.3, 127.1, 126.7, 124.7, 123.7,
122.2, 119.7, 119.6, 119.5, 118.6, 115.3, 111.1, 110.8. Anal.
Calcd for C15H10N2OS: C, 67.65; H, 3.78; N, 10.52. Found: C,
67.78; H, 3.69; N, 10.35.
1-(4-Meth oxy-p h en yl)-5H-p yr id o[4,3-b]in d ol-4-ol (8b):
A yellow oil, 31% yield (from 4). FTIR 3406, 2921, 2863, 1611,
1577, 1513, 1455, 1340, 1299, 1241, 1172, 1086, 1033, 849, 808,
1
739, 704 cm-1. H NMR δ 8.01 (br s, 1H), 7.79 (d, J ) 6, 2H),
1-An th r a cen -9-yl-5H-p yr id o[4,3-b]in d ol-4-ol (8 g): An
orange oil, 26% yield (from 4). FTIR 3418, 2933, 2852, 1640,
1455, 1369, 1259, 1184, 1091, 1022, 964, 802 cm-1. 1H NMR δ
8.39 (br s, 1H), 8.23 (d, J ) 9, 2H), 8.03 (d, J ) 9, 2H), 7.93-
7.87 (m, 8H), 7.46 (d, J ) 6, 4H), 7.38 (t, J ) 6, 1H), 7.14 (s,
1H), 7.06 (d, J ) 6, 2H), 6.13 (s, 1H), 5.01 (s, 1H). 13C NMR δ
147.6, 147.1, 139.1, 138.4, 134.0, 132.6, 131.7, 129.0, 127.2,
125.6, 125.0, 124.4, 124.0, 122.9, 119.9, 114.0, 109.9, 107.6,
92.4. Anal. Calcd for C25H16N2O: C, 83.31; H, 4.47; N, 7.77.
Found: C, 83.58; H, 4.63; N, 8.06.
7.55 (d, J ) 6, 2H), 7.30-7.17 (m, 1H), 7.14-7.09 (m, 1H),
6.97 (t, J ) 9, 1H), 6.73 (d, J ) 9, 1H), 6.72 (s, 1H), 4.82 (br s,
1H), 3.75 (s, 3H). 13C NMR δ 189.9, 158.9, 143.6, 142.9, 136.6,
129.7, 129.2, 128.4, 125.4, 124.0, 122.5, 119.9, 116.6, 113.7,
11.2, 54.6. Anal. Calcd for C18H14N2O2: C, 74.47; H, 4.86; N,
9.65. Found: C, 74.09; H, 4.75; N, 9.51.
1-(4-Ch lor o-p h en yl)-5H-p yr id o[4,3-b]in d ol-4-ol (8c): A
yellow oil, 28% yield (from 4). FTIR 3383, 3291, 3059, 2956,
2922, 1646, 1599, 1547, 1489, 1461, 1414, 1328, 1299, 1218,
1155, 1091, 1027, 1010, 808, 738, 716, 629 cm-1 1H NMR δ
.
8.04 (br s, 1H), 7.75 (s, 1H), 7.44 (d, J ) 9, 2H), 7.35 (d, J )
9, 2H), 7.24-6.98 (m, 3H), 6.61 (d, J ) 6, 1H), 5.80 (s, 1H).
13C NMR δ 140.4, 139.6, 136.7, 135.1, 124.0, 123.0, 122.7,
121.5, 120.1, 119.6, 119.4, 118.7, 116.9, 111.3, 110.4, 110.3,
109.1. Anal. Calcd for C17H11ClN2O: C, 69.28; H, 3.76; N, 9.50.
Found: C, 68.93; H, 3.54; N, 9.79.
Ack n ow led gm en t. Financial support by the Tho-
mas F. and Kate Miller J effress Memorial Trust is
gratefully acknowledged (Grant J -587). The authors also
wish to thank Dr. Robert Najarian of Georgetown
University Medical Center for invaluable medicinal
chemistry discussions.
1-P yr id in -2-yl-5H-p yr id o[4,3-b]in d ol-4-ol (8d ): A brown
oil, 33% yield (from 4). FTIR 3406, 2956, 1634, 1525, 1444,
1
1345, 1259, 1155, 1091, 1022, 930, 866, 803 cm-1. H NMR δ
J O034290O
J . Org. Chem, Vol. 68, No. 12, 2003 4849