Synthesis of a novel series of 1,6-disubstituted-3-(cyclohexylmethoxy)- β-carboline derivatives via Minisci reaction

Article abstract of DOI:10.1080/00397911.2010.546552

A facile and efficient route for the synthesis of 1,6-disubstituted-3- cyclohexylmethoxy-β-carboline derivatives via the Minisci reaction has been described with good yields and selectivity. A novel series of β-carboline derivatives with various substitue

Full text of DOI:10.1080/00397911.2010.546552

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Synthesis of a Novel Series of 1,6-
Disubstituted-3-(cyclohexylmethoxy)-β-
carboline Derivatives via Minisci
Reaction
Guowu Lin a b , Yue Wang a , Qingfa Zhou a , Jian Wang a , Taotao
Yang a , Zhanwei Wang a & Tao Lu c
a College of Basic Science, China Pharmaceutical University, Nanjing,
China
b Department of Structural Biology, University of Pittsburgh School of
Medicine, Pittsburgh, Pennsylvania, USA
c Key Laboratory of Drug Quality Control and Pharmacovigilance,
China Pharmaceutical University, Ministry of Education, Nanjing,
China
Accepted author version posted online: 07 Dec 2011.Version of
record first published: 26 Mar 2012.
To cite this article: Guowu Lin , Yue Wang , Qingfa Zhou , Jian Wang , Taotao Yang , Zhanwei Wang
& Tao Lu (2012): Synthesis of a Novel Series of 1,6-Disubstituted-3-(cyclohexylmethoxy)-β-carboline
Derivatives via Minisci Reaction, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 42:13, 1895-1910
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Synthetic Communications1, 42: 1895–1910, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.546552
SYNTHESIS OF A NOVEL SERIES OF 1,6-
DISUBSTITUTED-3-(CYCLOHEXYLMETHOXY)-b-
CARBOLINE DERIVATIVES VIA MINISCI REACTION
Guowu Lin,1,2 Yue Wang,1 Qingfa Zhou,1 Jian Wang,1
Taotao Yang,1 Zhanwei Wang,1 and Tao Lu3
1College of Basic Science, China Pharmaceutical University, Nanjing, China
2Department of Structural Biology, University of Pittsburgh School of
Medicine, Pittsburgh, Pennsylvania, USA
3Key Laboratory of Drug Quality Control and Pharmacovigilance, China
Pharmaceutical University, Ministry of Education, Nanjing, China
GRAPHICAL ABSTRACT
Abstract A facile and efficient route for the synthesis of 1,6-disubstituted-3-cyclohexyl-
methoxy-b-carboline derivatives via the Minisci reaction has been described with good
yields and selectivity. A novel series of b-carboline derivatives with various substituents
at 1-, 3-, and 6-positions were designed and synthesized from the starting material
(ꢀ)-tryptophan on the basis of harmine chemical structure. The mechanism of the
1-substituted b-carboline derivatives by means of a nucleophilic radical was also described,
and the x-ray analysis confirmed the structures of 11-7.
Keywords b-Carboline; electron-withdrawing; harmine; synthesis; x-ray
INTRODUCTION
Malignant tumors have long threatened human health. Thus, the discovery and
development of novel therapeutic agents are of great importance for the treatment of
Received October 29, 2010.
Address correspondence to Tao Lu and Yue Wang, State Key Laboratory of Natural Medicines,
College of Basic Science, China Pharmaceutical University, Nanjing 210009, China. E-mail: lut163@
163.com; zwy_1115@126.com
1895

1896
G. LIN ET AL.
Figure 1. Structure of harmine.
maligancy. One of the successful and effective approaches in the search for new anti-
tumor agents from natural products is to synthesize novel compounds by simple
chemical modification of natural leading compounds.
The b-carboline alkaloids, containing a planar tricyclic system, are a large
group of naturally occurring and synthetic alkaloids,[1] which have a broad spectrum
of biochemical effects and pharmaceutical properties. These compounds have been
shown to intercalate into DNA; to inhibit CDK, topisomerase, and monoamine oxi-
dase; and to interact with benzodiazepine receptors (BZ), 5-hydroxy serotonin recep-
tors (5-HT), and dopamine (DA) and imidazoline receptors.[2] The harmine (Fig. 1)
is one of the most representative b-carboline alkaloids, originally isolated from seeds
of Pegannum harmala L. Research[3] over the past few decades demonstrated that
harmine and its derivatives were highly cytotoxic against human tumor cell lines,
while they had remarkable neurotoxic effects including tremors, twitching, and
jumping in experimental animal models.[4] To enhance antitumor activities and
decrease acute toxicity, we tried to introduce appropriate substituents into the 1-,
3-, and 6-positions in b-carboline nucleus on the basis of the structure–activity
relationship research and the combination principle of drug molecular design.
In this study, we designed and synthesized numerous b-carboline derivatives with
various substituents at 1-, 3-, and 6-positions in the b-carboline scaffold on the basis of
harmine chemical structure. It is possible to discover and obtain new compounds with
comparable activity and less toxicity than harmine. Moreover, this study will further
elucidate the structure–activity relationships (SARs) of these compounds with regard
to antitumor activity and neurotoxicity=acute toxicity in future research. Herein, we
report a facile synthesis of a novel series of derivatives derived from harmine for the
purpose of investigating their possible antineoplastic and kinase inhibition activity.
RESULTS AND DISCUSSION
The new 1,6-disubstituted-3-cyclohexylmethoxy-b-carboline derivatives were
prepared following the reaction sequences depicted in Schemes 1–3. Herein,
(ꢀ)-tryptophan was chosen as the starting material for the study, which was converted
into 1,2,3,4-tetrahydro-b-carboline-3-carboxylic acid (1) according to the Pictet–
Spengler[5] reaction in good yield. The treatment of 1 with excess thionyl chloride in
anhydrous EtOH at reflux for 6 h gave ethyl 1,2,3,4-tetrahydro-b-carboline-3-
carboxylate (2) as a white solid. Then, ethyl b-carboline-3-carboxylate (3) was dehy-
drogenated with KMnO4 in dimethylformamide (DMF) at room temperature for
24 h. 3-Amino-b-carboline (6) was prepared by a Curtius rearrangement reaction start-
ing with ethyl b-carboline-3-carboxylate (3). Refluxing of 3 with 85% hydrazine
hydrate in MeOH gave the hydrazide (4), which after treatment with sodium nitrite
yielded the azide (5). When 5 was refluxed for several minutes in HCl solution,

b-CARBOLINE DERIVATIVES
1897
Scheme 1. (a) HCHO, NaOH; (b) C2H5OH, SOCl2; (c) KMnO4, DMF, rt; (d) NH2NH2 ꢂ H2O, MeOH,
reflux; (e) NaNO2, HCl; (f) reflux, then NaOH; (g) NaNO2, concentrated HCl; (h) NaH, DABCO; (i)
FeSO4, H2O2, HCONH2, concentrated H2SO4, 10–15 ꢁC; (j) ClSO3H; and (k) NH3 ꢂ H2O.
rearrangement to the amine (6) occurred in good yield. 3-Chloro-b-carboline
(7) was obtained by carrying out the reaction in concentrated hydrochloric acid
saturated with dry hydrogen chloride gas under standard Sandmeyer conditions.
Compound 7 was heated with DABCO (1,4-diazabicyclo [2.2.2]octane) and NaH
in the presence of an excess of dry cyclohexylmethanol for 24 h at reflux to give
3-cyclohexylmethoxy-b-carboline (8). Subsequently, we treated 8 with FeSO4 and
H2O2 in different reagents (including formamide or N-methylformamide),
under mild conditions (10–15 ꢁC) via the Minisci reaction,[6] giving the expected
Scheme 2. (a) FeSO4, H2O2, HCONHCH3, concentrated H2SO4, 10–15 ꢁC; (b) ClSO3H; and (c)
NH3 ꢂ H2O.

1898
G. LIN ET AL.
Scheme 3. (a) ClSO3H; (b) NH3 ꢂ H2O; and (c) FeSO4, H2O2, CH3OH, concentrated H2SO4, 10–15 ꢁC.
products 1-carbamoyl-3-cyclohexylmethoxy-b-carboline (9) in 60% yield and
1-N-methylcarbamoyl-3-cyclohexylmethoxy-b-carboline (9-N) (Scheme 2) in 57%
yield according to procedure A. The key intermedates 9 and 9-N were converted into
the target molecules (11-X) in 45–80% yields (Table 1) through both the chlorosulfona-
tion in dry chlorosulfonic acid and subsequent aminolysis with different amines using
the method B. Another kind of title compound, 1-hydroxymethyl-3-cyclohexyl-
methoxy-6-aminosulfonyl-b-carboline (11-O), was achieved by chlorosulfonation
and subsequent aminolysis to give 3-cyclohexylmethoxy-6-aminosulfonyl-b-carboline
(10-O) and then the hydroxymethyl substituent to 10-O was introduced at 1-positon
using the procedure C[7] (Scheme 3).
Based on the classic Minisci reaction mechanism, according to the literature[6]
and our experimental results, the reaction mechanism of b-carboline derivatives with
a variety of nucleophilic radicals was presumed as shown in Scheme 4. The overall
process is summarized as follows: (i) Generation of the nucleophilic radical. Here.
R1 was generated from different reagents (R1-H) by FeSO4 and H2O2 redox system
(Eq. 1). (ii) Addition to the protonated b-carboline ring. In our experiment, b-carbo-
line ring was protonated by concentrated sulfuric acid (Eq. 2). (iii) Rearomatization
of the radical adducts. The mechanism illustrated by Eq. 3 has been envisaged in the
rearomatization step of the heteroaromatic substitution.
H2O2 þ Fe2þ ꢃ! Fe3þ þ OHꢃ þ HOꢄ
ð1Þ
HOꢄ þ R1 ꢃ H ꢃ! H2O þꢄ R1
At the same time, we have obtained the colorless block crystals of 11-7 from
methanol=ethyl acetate at room temperature (Fig. 2). CCDC 757533 contains the
supplementary crystallographic data of compound 11–7. These data can be obtained
free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
CONCLUSION
We described a convenient and efficient route for the synthesis of the
1,6-disubstituted-3-cyclohexylmethoxy-b-carboline derivatives in moderate to good

b-CARBOLINE DERIVATIVES
1899
Table 1. Synthesis of various 1,6-disubstituted-3-cyclohexylmethoxy-b-carboline derivatives
Compound
R1
R2
Melting point (ꢁC)a
Yield (%)b
8
-H
-H
-H
145–147
233–235
253–255
304–306
294–296
288–289
199–201
203–204
321–323
207–209
191–193
253–255
299–301
309–310
315–316
297–298
281–283
265–267
314–315
311–312
251–253
236–238
60
60
57
65
75
55
60
72
45
78
73
76
80
60
65
75
58
52
62
70
60
65
9
9-N
-CONH2
-CONHCH3
-CONH2
-CONH2
-CONH2
-CONH2
-CONH2
-CONH2
-CONH2
-CONH2
-CONH2
-CONH2
-CONHCH3
-CONHCH3
-CONHCH3
-CONHCH3
-CONHCH3
-H
-H
-SO2NH2
-SO2NHCH3
11
11-1
11-2
11-3
11-4
11-5
11-6
11-7
11-8
11-9
11-N
11-N-1
11-N-2
11-N-3
11-N-4
10-O
10-O-1
11-O
11-O-1
-SO2NHCH2CH2OH
-SO2NH(CH2)3-morpholinyl
-SO2-N-hydroxyethylpiperazine-1-yl
-SO2NH-pyridine-2-yl
-SO2-N-methylpiperazine-1-yl
-SO2NH-cyclohexyl
-SO2NHCH2CH2SO2CH3
-SO2NH-cyclopropyl
-SO2NH2
-SO2NH-cyclohexyl
-SO2NHCH3
-SO2NHCH2CH2OH
-SO2NH CH2CH(OH)CH2OH
-SO2NH2
-H
-CH2OH
-CH2OH
-SO2NH-cyclohexyl
-SO2NH2
-SO2NH-cyclohexyl
aDetermined with a digital melting-point apparatus and reported uncorrected.
bIsolated yield by column chromatography.
yields. This method offered a facile way to introduce various electron-withdrawing
substituents to the b-carboline scaffold at the 1-positon, which will broaden the
application scope of the skeleton of b-carbolines. This type of reaction for prep-
aration of 1-substituted b-carboline derivatives has been widely applied in our
laboratory.[7] In addition, the mechanism of the 1-substituted b-carboline derivatives
by means of nucleophilic radical is described. We have synthesized 22 new title
1
compounds, which were confirmed by infrared (IR), H NMR, mass spectrometry,
and elemental analysis. The data of all the compounds were given in the experi-
mental section. The compound 11-7 was confirmed by x-ray analysis.
EXPERIMENTAL
Unless otherwise specified, reagents were purchased from commercial suppliers
and used without further purification. Reaction progress was monitored using
analytical thin-layer chromatography (TLC) on precoated Merck silica-gel Kiesegel
60 F254 plates, and the spots were detected under ultraviolet light (254 nm). Melting

1900
G. LIN ET AL.
Scheme 4. Mechanism for the synthesis of 1-substituted b-carboline derivatives.
points were determined with a digital melting-point apparatus and are reported uncor-
1
rected. H NMR spectra were recorded at 300 MHz on Bruker ARX 300 spectro-
meters. IR spectra were measured on a Jasco FT=IR-430 spectrophotometer. Mass
spectra were recorded on an a Quattro MicroMS Micromass UK mass spectrometer
and were recorded on an electrospray ionization (ESI) mass spectrometer as the value
m=z. Elemental analyses were carried out with a GG315-Vario EL III instrument. The
x-ray measurements were made on a Rigaku Raxis Rapid diffractometer with graphite
˚
monochromatized Mo Ka radiation (k ¼ 0.71069 A) using x scan mode.
Figure 2. ORTEP drawing of x-ray crystal structure of compound 11-7.

b-CARBOLINE DERIVATIVES
1901
1,2,3,4-Tetrahydro-b-carboline-3-carboxylic Acid (1)
The preparation of 1,2,3,4-tetrahydro-b-carboline-3-carboxylic acid was
achieved by the method of Synder et al.[8] A mixture of (ꢀ)-tryptophan (10.2 g,
0.05 mol), NaOH (2.0 g, 0.05 mol), and H2O (40 mL) was stirred until clear, and then
formalin (30%, 5 g, 0.05 mol) was added. The mixture was stirred at room tempera-
ture for 3 h and subsequently refluxed for another 3 h until there were no starting
materials left (TLC control). It was then neutralized (pH 5) with glacial acetic acid
and cooled. The precipitate formed was collected by filtration, washed with water
(2 ꢅ 15 mL), and dried in vacuo to give the product as a pale white solid 1 (9.7 g,
90%); mp 306–308 ꢁC.[9]
Ethyl 1,2,3,4-Tetrahydro-b-carboline-3-carboxylate (2)
The acid 1 (10.8 g, 0.05 mol) and dry EtOH (180 mL) were placed in a 250-ml,
three-necked, round-bottomed flask equipped with a magnetic stirrer and a drying
tube. The stirring mixture was cooled to 0 ꢁC, and then thionyl chloride (12 mL)
was added gradually for 30 min. The resulting mixture was held at reflux under nitro-
gen for 6 h until there were no starting materials left (TLC control). Exess EtOH was
removed by evaporation under reduced pressure, and the residue was triturated with
water (120 mL), followed by neutralization with saturated solution of NaOH and
extraction with ethyl acetate (3 ꢅ 100 mL). The combined organic layers were washed
with brine (1 ꢅ 100 mL) and dried with MgSO4, and the solvent was removed under
vacuum to provide an oil, which was crystallized from ethyl acetate to provide white
solid 2 (10.7 g, 88%); mp 184–186 ꢁC.[10]
Ethyl b-Carboline-3-carboxylate (3)
KMnO4 (44.5 g, 100 mmol) was added gradually for 30 min to a cooled, rap-
idly stirring solution of 2 (12.2 g, 0.05 mol) in DMF (200 mL), and then the result-
ing mixture was stirred for 24 h at room temperature. The suspension was filtered,
and the precipitate was washed with DMF (2 ꢅ 100 mL). The combined organic
solvent was removed under reduced pressure to provide a brown residue, which
was crystallized from ethyl acetate to give white powder 3 (9.0 g, 75%); mp
244–246 ꢁC.[11]
b-Carboline-3-carbohydrazide (4)
A solution of ethyl b-carboline-3-carboxylate (3) (12.0 g, 0.05 mol) in MeOH
(120 mL) containing hydrazine hydrate (85%, 20 mL) was refluxed for 6 h until there
were no starting materials left (TLC control). The resulting mixture was cooled, and
the precipitate that formed was collected by fitration, washed with MeOH
(1 ꢅ 30 mL), and dried under vacuum, yielding compound 4 (10.3 g, 85%). An ana-
lytical sample was recrystallized from 95% MeOH, giving silver solid; mp
288–290 ꢁC.[12]

1902
G. LIN ET AL.
3-(Azidocarbonyl)-b-carboline (5)
A suspension of the hydrazide 4 (12.1 g, 0.05 mol) in water (200 mL) was dis-
solved by the dropwise addition of concentrated HCl (10 mL). The pale yellow sol-
ution was cooled to 0–5 ꢁC before the addition of a solution of sodium nitrite (3.6 g,
0.053 mol) in water (10 mL). After stirring for 30 min at 0 ꢁC, the mixture was made
basic with saturated aqueous NaHCO3, and the precipitate that formed was col-
lected by filtration, washed with water, and dried in a dessicator under vacuum,
yielding crude 5 (8.8 g, 75%) as a yellow solid with a tendency to decompose. The
material was used without further purification for the following steps.
3-Amino-b-carboline (6)
A suspension of the azide 5 (11.85 g, 0.05 mol) in a mixture of water (200 mL)
and concentrated HCl (10 mL) was brought to reflux, during which carbon dioxide
was evolved and the starting material disappeared. After refluxing for 30 min, the
reaction mixture was cooled, the precipitate that formed was collected by filtration
and washed with water, and an analytical sample was recrystallized from EtOH,
yielding 6 (6.4 g, 70%) as yellow powder; mp 288–290 ꢁC.[12]
3-Chloro-b-carboline (7)
A mechanically stirred solution of 3-amino-b-carboline (6) (9.2 g, 0.05 mol) in
concentrated HCl (150 ml) was cooled to 0–5 ꢁC and saturated carefully with dry
hydrogen chloride gas for 30 min. Sodium nitrite solid (3.6 g, 0.053 mol) was added
in batches to the homogeneous solution that resulted, and the solution was allowed
to stir for 2 h at 0–5 ꢁC. The mixture was then made basic (pH 8) with concentrated
NH4OH. The aqueous layer was extracted with ethyl acetate (3 ꢅ 100 mL), and the
organic extracts were combined and dried with Mg2SO4. The solvent was removed
under reduced pressure, and the residue was purified by flash column chromato-
graphy to yield 3-chloro-b-carboline (7) as a pale yellow solid (5.05 g, 50%); mp
276–277 ꢁC.[13]
3-Cyclohexylmethoxy-b-carboline (8)
3-Chloro-b-carboline (7) (10.1 g, 0.05 mol), DABCO (0.1 equiv.[14]), NaH solid
(1.44 g, 0.06 mol), and dry cyclohexylmethanol (200 mL) were placed in a 250-ml,
single-necked, round-bottomed flask equipped with a magnetic stirrer and a drying
tube. The stirring mixture was refluxed for 24 h under nitrogen until there were no
starting materials left (TLC control). The resulted mixture was cooled to room tem-
perature, poured into ice water (100 mL), neutralized (pH 7–8) by addition of glacial
acetic acid, and extracted with ethyl acetate (3 ꢅ 30 mL). The organic solvent was
removed in vacuo. The residue was purified by flash column chromatography to
afford the adduct 3-cyclohexylmethoxy-b-carboline (8) as a pale yellow solid
(8.4 g, yield 60%); mp 145–147 ꢁC IR (KBr) 3132, 2923, 2848, 1631, 1502, 1452,
1
1375, 1251, 1224, 1186, 1041, 740, 632 cmꢃ1; MS m=z 282.22 (M þ 1)þ; H NMR
(300 MHz, DMSO-d6) d (ppm): 11.18 (s, 1H, indole), 8.49 (s, 1H, ArH), 8.17 (d,

b-CARBOLINE DERIVATIVES
1903
1H, J ¼ 7.9 Hz, ArH), 7.46–7.50 (m, 3H, ArH), 7.14 (m, 1H, ArH), 4.20 (d, 2H,
J ¼ 5.6 Hz, -CH2O), 0.8–1.9 (m, 11H, cyclohexyl). Anal. calcd. (%) for
C18H20N2O: C, 77.11; H, 7.19; N, 9.99. Found (%): C, 77.14; H, 7.22; N, 9.96.
Procedure A
Procedure A offers a facile way to introduce various electron-withdrawing
substituents (such as carbamoyl and N-methylcarbamoyl) to b-carboline derivatives
at the 1-positon.
1-Carbamoyl-3-cyclohexylmethoxy-b-carboline (9). 3-Cyclohexylmethoxy-
b-carboline (8) (1.4 g, 5 mmol), formamide (100 mL), and concentrated H2SO4
(2 mL) were placed in a 150-ml, single-necked, round-bottomed flask equipped with
a magnetic stirrer. The stirred mixture was cooled to 10–15 ꢁC. A saturated solution
of FeSO4 and H2O2 (30% solution in water) were added simultaneously over a period
of 10 min and stirring was continued. The addition of FeSO4 and H2O2 was repeated
until there was no starting material left (TLC control[15]). The reacted mixture was
poured into water (300 mL) followed by neutralization (pH 8) with saturated sol-
ution of sodium carbonate and extraction with ethyl acetate (3 ꢅ 100 mL). The com-
bined organic layers were washed with brine (1 ꢅ 100 mL) and dried with MgSO4,
and the solvent was removed under vacuum. The residue was purified by flash col-
umn chromatography to afford the corresponding compound 1-carbamoyl-3-cyclo-
hexylmethoxy-b-carboline (9) as a pale yellow solid (0.98 g, yield 60%); mp
233–235 ꢁC IR (KBr) 3320, 3125, 2933, 2850, 1675, 1621, 1600, 1590, 1559, 1448,
1
1316, 1251, 1120, 990, 760, 595, 563 cmꢃ1; MS m=z 224.23 (M þ 1)þ; H NMR
(300 MHz, DMSO-d6) d (ppm): 11.20 (1H, s, indole), 8.20 (1H, d, J ¼ 8.0 Hz,
ArH), 8.00 (1H, s, ArH), 7.75 (1H, s, ArH), 7.67-7.69 (2H, m, -CONH2), 7.51
(1H, m, ArH), 7.16 (2H, m, ArH), 4.23 (2H, d, J ¼ 5.0 Hz, -CH2O), 0.9–1.9 (11H,
m, cyclohexyl). Anal. calcd. (%) for C19H21N3O2: C, 70.57; H, 6.55; N, 12.99. Found
(%): C, 70.60; H, 6.57; N, 12.98.
1-N-Methylcarbamoyl-3-cyclohexylmethoxy-b-carboline (9-n). Prepared
from 8 according to procedure A, yield 57%; mp 253–255 ꢁC IR (KBr) 3332, 3150,
2926, 2830, 1648, 1560, 1555, 1440, 1326, 1130, 993, 732, 603, 551, 521 cmꢃ1; MS
m=z 336.11 (M ꢃ 1)–; 1H NMR (300 MHz, DMSO-d6) d (ppm): 11.41 (1H, s, indole),
8.67 (1H, m, ArH), 7.58 (1H, d, J ¼ 8.8 Hz, ArH), 7.78 (1H, d, J ¼ 9.1 Hz, ArH), 7.71
(1H, m, -CONH), 7.53 (1H, m, ArH), 7.15 (1H, m, ArH), 4.27 (2H, d, J ¼ 5.3 Hz,
-CH2O), 2.9 (3H, d, J ¼ 4.7 Hz, -CH3N), 0.9–1.9 (11H, m, cyclohexyl). Anal. calcd.
(%) for C20H23N3O2: C, 71.19; H, 6.87; N, 12.45. Found (%): C, 71.17; H, 6.90; N,
12.44.
Procedure B
Procedure B is typical procedure for the synthesis of 1-substituted-3-cyclohex-
ylmethoxy-6-aminosulfonyl-b-carboline derivatives, exemplified by the preparation
of 1-carbamoyl-3-cyclohexylmethoxy-6-aminosulfonyl-b-carboline 11.

1904
G. LIN ET AL.
To a single-necked, round-bottomed flask equipped with a drying tube and a
magnetic stir bar, 10 mL of dry chlorosulfonic acid were added. The stirring mixture
was allowed to cool at 0 ꢁC, and 1-carbamoyl-3-cyclohexylmethoxy-b-carboline (9)
(0.32 g, 1 mmol) was added to this solution in batches. The resulting mixture was
kept at 0–5 ꢁC until there were no starting materials left (TLC control). The reacted
mixture was quenched by pouring it onto ice water (50 mL); the precipitate that
formed was collected by suction filtration, washed with cold water, and dried under
vacuum, giving 0.33 g (78%) of 1-carbamoyl-3-cyclohexylmethoxy-6-chlorosulfonyl-
b-carboline (10), which was used without further purification.
Excess concentrated aqueous ammonia (5 mL) was added to a suspension of
1-carbamoyl-6-chlorosulfonyl-b-carboline (0.33 g, 0.77 mmol) in cold water (30 mL).
After the resulting mixture was stirred at room temperature until there were no start-
ing materials left (TLC control), the solvent was removed under reduced pressure,
and the residues were purified by flash chromatography using an eluent
MeOH-CHCl3 to give the title compound (11) as a pale yellow solid (0.20 g, yield
65%). Other compounds were synthesized similarly.
1-Carbamoyl-3-cyclohexylmethoxy-6-aminosulfonyl-b-carboline (11).
Prepared from 9 according to procedure B, yield 65%; mp 304–306 ꢁC, IR (KBr)
3465, 3346, 3319, 2923, 2850, 1672, 1631, 1606, 1560, 1479, 1442, 1321, 1251,
1153, 1132, 1085, 1051, 1022, 941, 746, 622, 590, 511 cmꢃ1; MS m=z 401.84 (M ꢃ
1
1)–; H NMR (300 MHz, DMSO-d6) d (ppm): 11.64 (1H, s, indole), 8.70 (1H, s,
ArH), 8.07 (1H, s, ArH), 7.97 (1H, d, J ¼ 7.9 Hz, ArH), 7.89 (1H, m, ArH),
7.69–7.81 (2H, m, -CONH2), 7.22 (2H, m, -SO2NH2), 4.23 (2H, d, J ¼ 5.2 Hz, -
CH2O), 1.0–2.0 (11H, m, cyclohexyl). Anal. calcd. (%) for C19H22N4O4S: C, 56.70;
H, 5.51; N, 13.92; S, 7.97. Found (%): C, 56.67; H, 5.55; N, 13.90; S, 7.96.
1-Carbamoyl-3-cyclohexylmethoxy-6-methylaminosulfonyl-b-carboline
(11-1). Prepared from 9 according to procedure B, yield 75%; mp 294–296 ꢁC, IR
(KBr) 3483, 3379, 3286, 2923, 2850, 1664, 1631, 1575, 1471, 1438, 1361, 1315,
1244, 1188, 1149, 1080, 1022, 825, 748, 703, 661, 619, 590, 536, 478 cmꢃ1; MS m=z
1
416.05 (M ꢃ 1)–; H NMR (300 MHz, DMSO-d6) d (ppm): 11.70 (1H, s, indole),
8.70 (1H, s, ArH), 8.09 (1H, s, ArH), 7.92 (1H, d, J ¼ 11.0 Hz, ArH), 7.88 (1H, m,
ArH), 7.78–7.84 (2H, m, -CONH2), 7.27 (1H, m, -SO2NH), 4.23 (2H, d, J ¼ 5.9 Hz,
-CH2O), 2.4 (3H, d, J ¼ 5.0 Hz, -CH3N), 1.0-2.0 (11H, m, cyclohexyl). Anal. calcd.
(%) for C19H14N6O3S: C, 56.15; H, 3.47; N, 20.68; S, 7.89. Found (%): C, 56.18;
H, 3.45; N, 20.70; S, 7.86.
1-Carbamoyl-3-cyclohexylmethoxy-6-(2-hydroxyethyl)aminosulfonyl-b-
carboline (11-2). Prepared from 9 according to procedure B, yield 55%; mp
288–289 ꢁC, IR (KBr) 3504, 3446, 3263, 2921, 2848, 1674, 1633, 1604, 1579, 1564,
1479, 1440, 1359, 1319, 1253, 1149, 1074, 1053, 950, 889, 752, 632, 586, 547,
460 cmꢃ1; MS m=z 446.14 (M ꢃ 1)–; 1H NMR (300 MHz, DMSO-d6) d (ppm):
11.69 (1H, s, indole), 8.71 (1H, s, ArH), 8.08 (1H, s, ArH), 7.93 (1H, s, ArH),
7.90 (1H, m, ArH), 7.78–7.83 (2H, m, -CONH2), 7.34 (1H, t, J ¼ 8.2 Hz, -SO2NH),
4.62 (1H, t, J ¼ 4.5 Hz, -OH), 4.24 (2H, d, J ¼ 5.4 Hz, -CH2O), 3.3 (2H, m, -CH2O),
2.8 (2H, m, -CH2N), 1.0–1.9 (11H, m, cyclohexyl). Anal. calcd. (%) for

b-CARBOLINE DERIVATIVES
1905
C21H26N4O5S: C, 56.49; H, 5.87; N, 12.55; S, 7.18. Found (%): C, 56.51; H, 5.93; N,
12.54; S, 7.17.
1-Carbamoyl-3-cyclohexylmethoxy-6-(N-(3-morpholinopropyl)amino-
sulfonyl-b-carboline (11-3). Prepared from 9 according to procedure B, yield 60%;
mp 199–201 ꢁC, IR (KBr) 3407, 3344, 3355 (N-H), 3263, 3205, 3064, 2923, 2854,
1674, 1633, 1593, 1573, 1440, 1319, 1242, 1197, 1143, 1033, 1022, 865, 756, 624,
582, 549 cmꢃ1; MS m=z 531.31 (M þ 1)þ; 1H NMR (300 MHz, DMSO-d6) d
(ppm): 11.69 (1H, s, indole), 8.7 (1H, s, ArH), 8.08 (1H, s, ArH), 7.94 (1H, m,
ArH), 7.70–7.83 (2H, m, -CONH2), 7.42 (1H, m, -SO2NH), 4.23 (2H, d, J ¼ 4.9 Hz,
-CH2O), 3.34 (4H, q, -CH2O ꢅ 2), 2.79 (2H, m, -CH2NSO2), 2.15–2.17 (6H, m,
-CH2N ꢅ 3), 1.89 (2H, m, -CH2), 1.0–1.8 (11H, m, cyclohexyl). Anal. calcd. (%)
for C26H35N5O5S: C, 58.96; H, 6.66; N, 13.22; S, 6.05. Found (%): C, 58.94; H,
6.71; N, 13.25; S, 6.00.
1-Carbamoyl-3-cyclohexylmethoxy-6-(4-(2-hydroxyethyl)piperazin-1-yl)
sulfonyl-b-carboline (11-4). Prepared from 9 according to procedure B, yield 72%;
mp 203–204 ꢁC, IR (KBr) 3460, 3348, 3419, 3278, 2923, 2850, 1674, 1633, 1568, 1475,
1438, 1352, 1323, 1247, 1155, 1134, 1081, 1056, 948, 756, 630, 584, 543 cmꢃ1; MS m=z
517.26 (M þ 1)þ; 1H NMR (300 MHz, DMSO-d6) d (ppm): 1.77 (1H, s, indole), 8.70
(1H, s, ArH), 8.09 (1H, s, ArH), 7.86 (1H, m, ArH), 7.78 (1H, m, ArH), 7.97–8.05
(2H, m, -CONH2), 4.31 (1H, t, J ¼ 5.6 Hz, -OH), 4.23 (2H, d, J ¼ 5.0 Hz, -CH2O),
3.36 (2H, q, -CH2O), 2.7-2.8 (8H, m, -CH2N ꢅ 4), 2.33 (2H, t, J ¼ 6.0 Hz, -CH2N),
1.0–2.0 (11H, m, cyclohexyl). Anal. calcd. (%) for C25H33N5O5S: C, 58.23; H,
6.45; N, 13.58; S, 6.22. Found (%): C, 58.25; H, 6.52; N, 13.56; S, 6.21.
1-Carbamoyl-3-cyclohexylmethoxy-6-(pyridin-2-yl)aminosulfonyl-b-
carboline (11-5). Prepared from 9 according to procedure B, yield 45%; mp
321–323 ꢁC, IR (KBr) 3490, 3412, 3112, 3055, 2929, 2854, 1672, 1630, 1606, 1560,
1477, 1360, 1310, 1249, 1190, 1130, 1050, 1037, 930, 745, 593, 550, 524 cmꢃ1; MS
m=z 479.19 (M ꢃ 1)–; 1H NMR (300 MHz, DMSO-d6) d (ppm): 11.65 (1H, s, indole),
8.82 (1H, s, ArH), 8.06 (1H, s, ArH), 7.9–8.0 (4H, m, ArH), 7.74–7.77 (2H, m,
-CONH2), 7.64 (1H, m, ArH), 7.20 (1H, s, -SO2NH), 6.83 (1H, m, ArH), 4.23
(2H, d, J ¼ 4.3 Hz, -CH2O), 1.0–1.9 (11H, m, cyclohexyl). Anal. calcd. (%) for
C24H25N5O4S: C, 60.11; H, 5.25; N, 14.60; S, 6.69. Found (%): C, 60.09; H, 5.20;
N, 14.63; S, 6.68.
1-Carbamoyl-3-cyclohexylmethoxy-6-(4-methylpiperazin-1-yl)sulfonyl-
b-carboline (11-6). Prepared from 9 according to procedure B, yield 78%; mp
207–209 ꢁC, IR (KBr) 3452, 3407, 2925, 2852, 2798, 1674, 1633, 1600, 1595, 1575,
1469, 1440, 1352, 1326, 1290, 1242, 1153, 1089, 1026, 948, 754, 634, 582, 543,
513 cmꢃ1; MS m=z 487.20 (M þ 1)þ; 1H NMR (300 MHz, DMSO-d6) d (ppm):
11.78 (1H, s, indole), 8.70 (1H, s, ArH), 8.11 (1H, s, ArH), 8.01 (1H, d, J ¼ 7.2 Hz,
ArH), 7.88 (1H, m, ArH), 7.80 (2H, m, -CONH2), 4.24 (2H, d, J ¼ 3.1 Hz, -CH2O),
2.90 (4H, t, -CH2N ꢅ 2), 2.35 (4H, t, -CH2N ꢅ 2), 2.11 (3H, s, -CH3), 1.0-1.9 (11H,
m, cyclohexyl). Anal. calcd. (%) for C24H31N5O4S: C, 59.36; H, 6.43; N, 14.42; S,
6.60. Found (%): C, 59.35; H, 6.47; N, 14.40; S, 6.63.

1906
G. LIN ET AL.
1-Carbamoyl-3-cyclohexylmethoxy-6-(cyclohexyl)aminosulfonyl-b-
carboline (11-7). Prepared from 9 according to procedure B, yield 73%; mp
191–193 ꢁC, IR (KBr) 3490, 3352, 3190, 2921, 2852, 1670, 1635, 1558, 1475, 1442,
1353, 1323, 1294, 1245, 1201, 1147, 1083, 1029, 991, 871, 752, 711, 601, 514,
474 cmꢃ1; MS m=z: 484.09 (M ꢃ 1)–; 1H NMR (300 MHz, DMSO-d6) d (ppm):
11.70 (s, 1H, indole), 8.70 (s, 1H, ArH), 8.10 (s, 1H, ArH), 7.96 (m, 1H, ArH),
7.92 (s, 1H, ArH), 7.82 (m, 2H, -CONH2), 7.51 (m, 1H, -SO2NH), 4.24 (d, 2H,
J ¼ 5.2 Hz, -CH2O), 2.9 (m, 1H, -CHN), 1.0–2.0 (m, 21H, cyclohexyl). Anal. calcd.
(%) for C25H32N4O4S: C, 61.96; H, 6.66; N, 11.56; S, 6.62. Found (%): C, 61.99;
H, 6.69; N, 11.54; S, 6.60.
1-Carbamoyl-3-cyclohexylmethoxy-6-(n-(2-(methylsulfonyl)ethyl))amino-
sulfonyl-b-carboline (11-8). Prepared from 9 according to procedure B, yield 76%;
mp 253–254 ꢁC, IR (KBr) 3428, 3400, 3180, 2922, 2830, 1673, 1630, 1610, 1550,
1423, 1345, 1245, 1128, 1030, 1011, 955, 905, 740, 600, 570, 534 cmꢃ1; MS m=z:
1
507.47 (M ꢃ 1)–; H NMR (300 MHz, DMSO-d6) d (ppm): 11.66 (1H, s, indole),
8.67 (1H, s, ArH), 8.08 (1H, s, ArH), 7.90 (1H, m, ArH), 7.87(1H, s, ArH), 7.82
(2H, m, -CONH2), 7.51 (1H, m, -SO2NH), 4.24 (2H, d, J ¼ 3.8 Hz, -CH2O), 3.7 (2H,
t, -CH2SO2), 3.5 (2H, t, -CH2N), 2.9 (3H, s, -CH3), 1.0–2.0 (11H, m, cyclohexyl). Anal.
calcd. (%) for C22H28N4O6S2: C, 51.95; H, 5.55; N, 11.02; S, 12.61. Found (%): C, 51.93;
H, 5.57; N, 11.00; S, 12.64.
1-Carbamoyl-3-cyclohexylmethoxy-6-(cyclopropyl)aminosulfonyl-b-
carboline (11-9). Prepared from 9 according to procedure B, yield 80%; mp
299–301 ꢁC, IR (KBr) 3494, 3409, 3251, 2925, 2848, 1674, 1637, 1569, 1475, 1444,
1363, 1319, 1240, 1190, 1147, 1026, 964, 879, 819, 754, 619, 582, 541, 503,
451 cmꢃ1; MS m=z: 442.10 (M ꢃ 1)–; 1H NMR (300 MHz, DMSO-d6) d (ppm):
11.72 (1H, s, indole), 8.72 (1H, s, ArH), 8.10 (1H, s, ArH), 7.95 (1H, s, ArH),
7.91 (1H, d, ArH), 7.82-7.85 (2H, m, -CONH2), 7.76 (1H, m, -SO2NH), 4.23 (2H,
d, J ¼ 3.9 Hz, -CH2O), 1.0-2.0 (16H, m, cyclohexyl and cyclopropyl). Anal. calcd.
(%) for C22H26N4O4S: C, 59.71; H, 5.92; N, 12.66; S, 7.25. Found (%): C, 59.73;
H, 5.96; N, 12.64; S, 7.24.
1-N-Methylcarbamoyl-3-cyclohexylmethoxy-6-aminosulfonyl-b-carboline
(11-N). Prepared from 9-N according to procedure B, yield 60%; mp 309–310 ꢁC, IR
(KBr) 3400, 3352, 3303, 3103, 2923, 2848, 1647, 1577, 1541, 1469, 1423, 1342, 1218,
1153, 1122, 1070, 1008, 921, 862, 813, 752, 665, 597, 553, 507 cmꢃ1; MS m=z: 416.07
(M ꢃ 1)–; 1H NMR (300 MHz, DMSO-d6) d (ppm): 11.85 (1H, s, indole), 8.68 (1H, d,
J ¼ 8.0 Hz, ArH), 8.57 (1H, d, J ¼ 6.9 Hz, ArH), 8.40 (1H, d, J ¼ 7.4 Hz, ArH), 7.91
(1H, m, -CONH), 7.81 (1H, m, ArH), 7.31 (2H, m, -SO2NH2), 4.28 (2H, d,
J ¼ 4.1 Hz, -CH2O), 3.0 (3H, s, -CH3N), 0.9-1.9 (11H, m, cyclohexyl). Anal. calcd.
(%) for C20H24N4O4S: C, 57.68; H, 5.81; N, 13.45; S, 7.70. Found (%): C, 57.69;
H, 5.85; N, 13.43; S, 7.71.
1-N-Methylcarbamoyl-3-cyclohexylmethoxy-6-(cyclohexyl)aminosulfo-
nyl-b-carboline (11-N-1). Prepared from 9-N according to procedure B, yield 65%;
mp 315–316 ꢁC, IR (KBr) 3379, 3357, 3240, 2929, 2854, 1656, 1539, 1440, 1413, 1348,
1315, 1222, 1155, 1122, 1070, 1002, 929, 881, 815, 657, 601, 547, 439 cmꢃ1; MS m=z:
499.20 (M ꢃ 1)–; 1H NMR (300 MHz, DMSO-d6) d (ppm): 11.89 (1H, s, indole), 8.70

b-CARBOLINE DERIVATIVES
1907
(1H, m, ArH), 8.60 (1H, d, J ¼ 8.8 Hz, ArH), 8.37 (1H, s, ArH), 7.93 (1H, m,
-CONH), 7.85 (1H, m, ArH), 7.60 (1H, m, -SO2NH), 4.28 (2H, d, J ¼ 4.5 Hz,
-CH2O), 2.9 (3H, m, -CH3N), 2.85 (1H, m, -CHNSO2), 0.8-1.9 (21H, m,
cyclohexyl ꢅ 2). Anal. calcd. (%) for C26H34N4O4S: C, 62.63; H, 6.87; N, 11.24; S,
6.43. Found (%): C, 62.64; H, 6.91; N, 11.23; S, 6.45.
1-N-Methylcarbamoyl-3-cyclohexylmethoxy-6-methylaminosulfonyl-b-
carboline (11-N-2). Prepared from 9-N according to procedure B, yield 75%; mp
297–298 ꢁC, IR (KBr) 3381, 3360, 3230, 2920, 2833, 1655, 1557, 1428, 1410, 1350,
1319, 1261, 1133, 1030, 999, 923, 730, 570, 533 cmꢃ1; MS m=z: 430.26 (M ꢃ 1)–;
1H NMR (300 MHz, DMSO-d6) d (ppm): 11.65 (1H, s, indole), 8.71 (1H, m,
ArH), 8.58 (1H, d, J ¼ 10.1 Hz, ArH), 8.40 (1H, s, ArH), 7.87 (1H, m, -CONH),
7.81 (1H, m, ArH), 7.50 (1H, m, -SO2NH), 4.28 (2H, d, J ¼ 3.9 Hz, -CH2O), 2.9
(3H, d, J ¼ 4.1 Hz, -CH3N), 2.4 (3H, d, J ¼ 4.7 Hz, -CH3NSO2), 0.9–1.9 (11H, m,
cyclohexyl). Anal. calcd. (%) for C21H26N4O4S: C, 58.59; H, 6.09; N, 13.01; S,
7.45. Found (%): C, 58.60; H, 6.14; N, 13.00; S, 7.43.
1-N-Methylcarbamoyl-3-cyclohexylmethoxy-6-(2-hydroxyethyl)amino-
sulfonyl-b-carboline (11-N-3). Prepared from 9-N according to procedure B, yield
58%; mp 281–283 ꢁC, IR (KBr) 3542, 4430, 3340, 3139, 2921, 2852, 1649, 1577, 1531,
1429, 1353, 1321, 1218, 1155, 1120, 1066, 929, 810, 744, 659, 613, 551,466, 435 cmꢃ1
;
MS m=z: 459.99 (M ꢃ 1)–; H NMR (300 MHz, DMSO-d6) d (ppm): 11.90 (1H, s,
indole), 8.69 (1H, m, ArH), 8.58 (1H, m, ArH), 8.35 (1H, s, ArH), 7.92 (1H, m,
-CONH), 7.83 (1H, m, ArH), 7.55 (1H, m, -SO2NH), 4.55 (1H, t, -OH), 4.28 (2H,
d, J ¼ 5.0 Hz, -CH2O), 3.35 (2H, m, -CH2O), 2.94 (2H, m, -CH2N), 2.8 (3H, d,
J ¼ 2.9 Hz, -CH3N), 1.0–1.9 (11H, m, cyclohexyl). Anal. calcd. (%) for
C22H28N4O5S: C, 57.37; H, 6.13; N, 12.17; S, 6.96. Found (%): C, 57.36; H, 6.16;
N, 12.16; S, 6.99.
1
1-N-Methylcarbamoyl-3-cyclohexylmethoxy-6-(N-(2,3-dihydroxypropy-
l))aminosulfonyl-b-carboline (11-N-4). Prepared from 9-N according to procedure
B, yield 52%; mp 265–267 ꢁC, IR (KBr) 3578, 3556, 3421, 3320, 3119, 2925, 2844, 1646,
1550, 1430, 1350, 1178, 1156, 1119, 1040, 1000, 990, 750, 571, 546, 500 cmꢃ1; MS m=z:
490.37 (M ꢃ 1)–; 1H NMR (300 MHz, DMSO-d6) d (ppm): 11.90 (1H, s, indole), 8.7
(1H, m, ArH), 8.6 (1H, m, ArH), 8.35 (1H, s, ArH), 7.93 (1H, m, -CONH), 7.86
(1H, m, ArH), 7.44 (1H, m, -SO2NH), 4.7–4.8 (2H, m, -OH ꢅ 2), 4.28 (2H, d,
J ¼ 3.3 Hz, -CH2O), 2.8–2.9 (5H, d, J ¼ 1.7 Hz, -CH2CHCH2), 0.9-1.9 (11H, m, cyclo-
hexyl). Anal. calcd. (%) for C23H30N4O6S: C, 56.31; H, 6.16; N, 11.42; S, 6.54. Found
(%): C, 56.28; H, 6.19; N, 11.40; S, 6.52.
3-Cyclohexylmethoxy-6-aminosulfonyl-b-carboline
(10-O). Prepared
from 8 according to procedure B, yield 62%; mp 314–315 ꢁC, IR (KBr) 3440,
3400, 3215, 2923, 2843, 1553, 1430, 1327, 126, 1150, 1032, 997, 813, 676, 558,
478 cmꢃ1; MS m=z 360.83 (M þ 1)þ; 1H NMR (300 MHz, DMSO-d6) d (ppm):
11.66 (1H, s, indole), 8.67 (1H, s, ArH), 8.50 (1H, s, ArH), 7.96 (1H, m, ArH),
7.62 (2H, m, -CONH2), 7.23 (2H, s, -SO2NH2), 4.10 (2H, d, J ¼ 4.6 Hz, -CH2O),
1.1-2.0 (11H, m, cyclohexyl). Anal. calcd. (%) for C18H21N3O3S: C, 60.15; H, 5.89;
N, 11.69; S, 8.92. Found (%): C, 60.14; H, 5.92; N, 11.67; S, 8.94.

1908
G. LIN ET AL.
3-Cyclohexylmethoxy-6-(cyclohexyl)aminosulfonyl-b-carboline
(10-O-1). Prepared from 8 according to procedure B, yield 70%; mp 311–312 ꢁC, IR
(KBr) 3441, 3240, 3152, 2920, 2845, 1553, 1467, 1310, 1243, 1130, 1051, 1026, 918,
1
736, 587, 545, 511 cmꢃ1; MS m=z 442.98 (M þ 1)þ; H NMR (300 MHz, DMSO-
d6) d (ppm): 11.69 (1H, s, indole), 8.67 (1H, s, ArH), 8.50 (1H, s, ArH), 7.90 (1H,
d, J ¼ 8.9 Hz, ArH), 7.62 (2H, m, -CONH2), 7.46 (1H, d, J ¼ 11.2 Hz, -SO2NH),
4.10 (2H, d, J ¼ 4.0 Hz, -CH2O), 2.92 (1H, m, -CHNSO2), 0.8-2.0 (21H, m,
cyclohexyl ꢅ 2). Anal. calcd. (%) for C24H31N3O3S: C, 65.28; H, 7.08; N, 9.52; S,
7.26. Found (%): C, 65.29; H, 7.13; N, 9.50; S, 7.24.
Procedure C
Procedure C is isgeneral procedure for the synthesis of 1-hydroxymethyl-3-
cyclohexylmethoxy-6-aminosulfonyl-b-carboline derivatives.
1-Hydroxymethyl-3-cyclohexylmethoxy-6-aminosulfonyl-b-carboline
(11-O). 3-Cyclohexylmethoxy-6-aminosulfonyl-b-carboline (1.8 g, 5 mmol), 100 mL
MeOH, and 2 mL concentrated sulfuric acid were placed in a 150-ml single-necked,
round-bottomed flask equipped with a magnetic stirrer. The stirred mixture was
cooled to 10–15 ꢁC. Then a saturated solution of FeSO4 and H2O2 (30% solution
in water) was added over a period of 10 min, and stirring was continued. The
addition of FeSO4 and H2O2 was be repeated until there is no starting material left
(TLC control). The reaction mixture was poured into water (300 mL), followed by
neutralization with a saturated solution of sodium carbonate and extraction with
ethyl acetate (3 ꢅ 100 mL). The combined organic layers were washed with brine
(1 ꢅ 100 mL) and dried with MgSO4, and the solvent was removed under vacuum.
The residue was purified by flash column chromatography to afford the correspond-
ing adduct 1-hydroxymethyl-3-(1H-benzo[d]imidazol-2-yl)-6-aminosulfonyl-b-car-
boline (11-O) as a white solid (1.2 g, yield 60%); mp 251–253 ꢁC, IR (KBr) 3456,
3410, 3215, 3156, 2920, 2843, 1601, 1533, 1434, 1330, 1290, 1191, 1155, 1032,
1000, 803, 663, 552, 503 cmꢃ1; MS m=z 390.81 (M þ 1)þ; 1H NMR (300 MHz,
DMSO-d6) d (ppm): 11.39 (1H, s, indole), 8.64 (1H, s, ArH), 7.92 (1H, d, J ¼ 12.3 Hz,
ArH), 7.69 (1H, d, J ¼ 7.9 Hz, ArH), 7.50 (1H, s, ArH), 7.19 (2H, s, -SO2NH2), 5.53
(1H, t, -OH), 4.87 (2H, d, J ¼ 2.1 Hz, -CH2), 4.09 (2H, d, J ¼ 3.9 Hz, -CH2O), 2.9
(1H, m, -CHN), 1.0-1.9 (11H, m, cyclohexyl). Anal. calcd. (%) for C19H23N3O4S:
C, 58.59; H, 5.95; N, 10.79; S, 8.23. Found (%): C, 58.61; H, 5.63; N, 10.76; S, 8.22.
1-Hydroxymethyl-3-cyclohexylmethoxy-6-(cyclohexyl)aminosulfonyl-b-
carboline (11-O-1). Prepared from 10-O-1 according to procedure C, yield 65%;
mp 236–238 ꢁC, IR (KBr) 3431, 3323, 3245, 3153, 2923, 2852, 1631, 1583, 1479,
1442, 1325, 1294, 1191, 1139, 1051, 1026, 935, 748, 607, 543, 497 cmꢃ1; MS m=z
1
473.15 (M þ 1)þ; H NMR (300 MHz, DMSO-d6) d (ppm): 11.42 (1H, s, indole),
8.64 (1H, s, ArH), 7.90 (1H, d, J ¼ 11.8 Hz, ArH), 7.70 (1H, d, J ¼ 9.7 Hz, ArH),
7.54 (1H, m, ArH), 7.41 (1H, d, J ¼ 8.9 Hz, -SO2NH), 5.53 (1H, t, -OH), 4.87
(2H, d, J ¼ 4.5 Hz, -CH2OH), 4.08 (2H, d, J ¼ 5.0 Hz, -CH2O), 2.94 (1H, m,
-CHNSO2), 0.8-1.9 (21H, m, cyclohexyl ꢅ 2). Anal. calcd. (%) for C24H31N3O3S:
C, 65.28; H, 7.08; N, 9.52; S, 7.26. Found (%): C, 65.29; H, 7.13; N, 9.50; S, 7.24.

b-CARBOLINE DERIVATIVES
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ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of China (No.
30973609), the Natural Science Foundation of Jiangsu Province (Program No.
BK2009303), the Fundamental Research Funds for the Central Universities (Pro-
gram No. 2J10004), and Specialized Research Fund for the Doctoral Program of
Higher Education (Program No. 20100096110007) for financial support. This study
was also supported by the Project Program of State Key Laboratory of Natural
Medicines, China Pharmaceutical University (No. JKGP201105).
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