Facile and efficient one-pot synthesis of β-carbolines

Article abstract of DOI:10.1080/00397910903097245

Initial formation of tetrahydrocarboline 3 from tryptophan methyl ester 1 and aldehyde 2 by Pictet-Spengler reaction, followed by treatment with trichlorocyanuric acid, provides a facile and efficient route for a one-pot synthesis of-carbolines with excellent yields. Copyright Taylor & Francis Group, LLC.

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Facile and Efficient One-Pot Synthesis of
β-Carbolines
Jian-Guo Tang a b , Han Liu a , Zhong-Yu Zhou b & Ji-Kai Liu b
a Research and Development Center of Hongta Tobacco Group Co.,
Ltd., Yuxi, Yunnan, China
b State Key Laboratory of Phytochemistry and Plant Resources
in West China, Kunming Institute of Botany, Chinese Academy of
Sciences, Kunming, China
Version of record first published: 23 Apr 2010
To cite this article: Jian-Guo Tang, Han Liu, Zhong-Yu Zhou & Ji-Kai Liu (2010): Facile and Efficient
One-Pot Synthesis of β-Carbolines, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:10, 1411-1417
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Synthetic Communications1, 40: 1411–1417, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903097245
FACILE AND EFFICIENT ONE-POT SYNTHESIS
OF b-CARBOLINES
Jian-Guo Tang,1,2 Han Liu,1 Zhong-Yu Zhou,2 and Ji-Kai Liu2
1Research and Development Center of Hongta Tobacco Group Co., Ltd.,
Yuxi, Yunnan, China
2State Key Laboratory of Phytochemistry and Plant Resources in
West China, Kunming Institute of Botany, Chinese Academy of Sciences,
Kunming, China
Initial formation of tetrahydrocarboline 3 from tryptophan methyl ester 1 and aldehyde 2 by
Pictet–Spengler reaction, followed by treatment with trichlorocyanuric acid, provides a
facile and efficient route for a one-pot synthesis of b-carbolines with excellent yields.
Keywords: b-Carboline; one pot; synthesis
INTRODUCTION
b-Carbolines are a large class of natural indole alkaloids widely distributed in
nature, including in various plants,[1] fungi,[2] marine creatures,[3] and animal as well
as human tissues and body fluids.[4] These compounds have been afforded a great
deal of attention recently because of their wide range of biological activities, such
as hypnotic, anxiolytic, antimicrobial,[5] antiviral,[6] antitumor,[7] anticonvulsant,[8]
and parasiticidal[9] activities. Base on their simple structure features, some
b-carbolines were synthesized, and many synthetic methods have also been
developed.[10] The classical methods are mainly based on two strategies: (1)
Bischler–Napieralski route,[11] which involves the conversion of dihydro-b-carboline,
generated from carboxylic acids (anhydride) and tryptophan (tryptamine), to
b-carboline by oxidation using 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ),
KMnO4, SeO2, and so on, and (2) the Pictet–Spengler route,[12] wherein the tetrahydro-
b-carboline produced by the condensation reaction of tryptophan (tryptamine)
with aldehyde is treated with oxidative reagents, leading to the formation of b-car-
boline. Other methods are also used for the synthesis of b-carboline, such as the
Fisher indolization reaction and aromatization reactions of aryl hydrazine and
cyclohexanone;[13] oxime formation, electrocyclization, and aromatization reactions
of 3-vinyl indole;[14] palladium-catalyzed cross-coupling reaction of tert-butylimines
of N-substituted 3-iodoindole-2-carboxaldehydes;[15] aza-Wittig reaction and
Received February 8, 2009.
Address correspondence to Dr. Jian-Guo Tang, Research and Development Center of Hongta
Tobacco Group Co., Ltd., Yuxi 653100, Yunnan, China. E-mail: tjg111@163.com
1411

1412
J.-G. TANG ET AL.
electrocyclic ring closure of 3-azidoindole;[16] and Friedel–Crafts acylations and
cyclization of 3-substituted indole.[17] Most of the available methods have poor
yields, require special material, or utilize expensive reagents to achieve the reported
yield. Therefore, the need for large quantities of b-carboline prompted us to
develop a facile and effective method. In this article, we report a synthetic method
of b-carboline that can be carried out in one step under mild conditions.
RESULTS AND DISCUSSION
In our study, the Pictet–Spengler route was selected from among two classical
methods. As we know, the tetrahydro-b-carboline can be easily obtained by the reaction
of tryptophan with aldehydes in good yield, but the subsequent aromatizing step
is always troublesome. It is the key issue in the synthesis of carboline in good yield.
There are many methods for dehydrogenation of tetrahydro-b-carboline to b-
carboline using MnO2, DDQ, SeO2, and Pd=C,[18] but none is satisfactory because of
either harsh reaction conditions or poor yield. During the course of our study, TCCA
(trichlorocyanuric acid) was reported as a mild dehydrogenating reagent of indoline and
tetrahydro-b-carboline.[18] TCCA is a mild dehydrogenating reagent and has many
advantages, such as low cost, easy accessibility (even on a large scale), high solubility,
and environmental friendliness. Because of its high solubility in organic solvent, we
successfully applied this agent to synthesis of b-carboline in one pot from tryptophan
methyl ester and aldehyde. The synthetic route is shown in Scheme 1.
In this article, the one-pot method involved the preparation of tetrahydro-b-
carboline 3 from substituted tryptophan methyl ester 1 and substituted aldehyde 2
by the Pictet–Spengler reaction. In the Pictet–Spengler reaction, methylene dichlor-
ide and trifluoroacetic acid (TFA) as solvent and catalyst, respectively, and in most
cases the reaction was completed within 2 days at room temperature. Then dichloro-
methane (DCM) was moved away under a pressure reduction, and tetrahydro-
b-carboline 3 obtained was directly added dropwise to the reagent TCCA (dissolved
in DMF) at less than 0 ꢀC. The aromatizing reaction was carried out at room
temperature, and in most cases the reaction was completed within 2 h. The respective
b-carbolines can be precipitated by pouring crushed ice. The yields and melting
points of various substituted b-carbolines prepared are summarized in Table 1.
Scheme 1. Synthetic route to b-carboline.

FACILE AND EFFICIENT ONE-POT SYNTHESIS OF b-CARBOLINES
Table 1. Yields and melting points of various b-carbolines
1413
Compound
R1
R2
R3
Yield (%)
Mp (ꢀC)
4a
4b
4c
4d
4e
4f
H
H
H
H
H
H
H
H
H
H
H
H
F
H
80
84
80
82
81
82
84
91
87
85
88
86
87
87
88
90
143–146
152–154
161–162
169–171
149–152
171–172
173–175
192–194
172–174
169–172
165–169
171–173
180–181
173–175
181–183
178–180
Methyl
Ethyl
H
H
n-Propyl
Isoropyl
Cyclopentyl
H
H
4g
4h
4i
H
Trans-1-butenyl
40-Trifuoromethylphenyl
2-Pyridyl
CH3
H
4j
F
2-Furyl
4k
4l
H
5-Acetoxymethyl-2-furyl
2-Thioyl
2-Indoly
CH3O
H
H
H
H
H
H
4m
4n
4o
4p
H
2-Benzo[b]furyl
2-Quinolyl
2-Naphthyl
CH3O
H
In conclusion, the method described in this article is a mild, facile, and efficient
process for a one-pot synthesis of b-carbolines. A large-scale production of b-
carbolines has been afforded, which confirms the simplicity of the method. Appli-
cation of this strategy to other biologically b-carboline alkaloids is in progress.
EXPERIMENTAL
Instruments and Materials
Thin-layer chromatography (TLC) was conducted on silica-gel F254 plates and
detected under ultraviolet (UV) light. The melting points were measured using an
1
X-type micro-melting-point apparatus and are uncorrected. H NMR spectra were
recorded in CDCl3 with a Bruker AM-400 or Bruker DRX-500 instrument using
tetramethylsilane (TMS) as an internal standard (chemical shifts in d ppm). Mass
spectra (MS) were taken on VG Auto Spec-3000. All reagents and solvents were
commercially obtained and of analytical grade.
General Procedure for Synthesis of Compound 4
Compounds 1 (10 mmol) and 2 (10 mmol) were added to dry dichloromethane
(DCM, 20 mL) under N2, and later TFA (0.18 mL, 2.5 mmol) was added slowly over
10 min. After stirring for 2 days at room temperature, the DCM was removed under
reduced pressure, and the mixture was taken up in 20 mL of DMF and neutralized
with triethylamine (TEA). Another 4.5 mL of TEA and 10 mmol TCCA (dissolved
in 10 mL of DMF) were added slowly, keeping the temperature at less than 0 ꢀC. When
addition was completed, the mixture was allowed to slowly warm up to room tempera-
ture and stirred for 2 h at this temperature to complete the reaction. Later, crushed
ice was added, and the resulting product was precipitated from ice water, filtered,
washed with water, dried, and recrystallized from methanol to give compound 4.

1414
J.-G. TANG ET AL.
Selected Data
Compound 4a. b-Carboline-3-carboxylic þmethyl ester, yellow solid, 1.80 g.
1
Yield: 80%, mp: 143–146 ꢀC, C13H10N2O2, FAB -MS m=z: 227 (M þ 1); H NMR
(400 MHz, CDCl3) d (ppm): 9.91 (1H, s), 8.77 (1H, s), 8.13 (1H, d, J ¼ 8.0 Hz),
7.58 (1H, d, J ¼ 8.0 Hz), 7.52 (1H, t, J ¼ 7.2 Hz), 7.31 (1H, t, J ¼ 7.2 Hz), 3.99 (3H, s).
Compound 4b. 1-Methyl-b-carboline-3-carboxylic methyl ester, C14H12N2O2,
1
yellow solid, 2.01g. Yield: 84%, mp: 152–154 ꢀC; FABþ-MS m=z: 241 (M þ 1)þ; H
NMR (400MHz, CDCl3) d (ppm): 10.50 (1H, s), 8.78 (1H, s), 8.16 (1H, d, J ¼ 8.0 Hz),
7.59 (1H, d, J ¼ 8.0 Hz), 7.54 (1H, t, J ¼ 7.2 Hz), 7.32 (1H, t, J ¼ 7.2 Hz), 4.01 (3H, s),
2.38 (3H, s).
Compound 4c. 1-Ethyl-b-carboline-3-carboxylic methyl ester, yellow soliþd,
2.03 g. Yield: 80%, mp: 161–162 ꢀC, C15H14N2O2, FABþ-MS m=z: 255 (M þ 1) ;
1H NMR (400 MHz, CDCl3) d (ppm): 9.91 (1H, s), 8.77 (1H, s), 8.13 (1H, d,
J ¼ 8.0 Hz), 7.58 (1H, d, J ¼ 8.0 Hz), 7.52 (1H, t, J ¼ 7.2 Hz), 7.31 (1H, t, J ¼ 7.2 Hz),
3.99 (3H, s), 3.13 (2H, q, J ¼ 7.2 Hz), 1.29 (3H, t, J ¼ 7.2 Hz).
Compound 4d. 1-n-Propyl-b-carboline-3-carboxylic methyl ester, yellow
solid, 2.19 g. Yield: 82%, mp: 169–171 ꢀC, C16H16N2O2, FABþ-MS m=z: 269
1
(M þ 1)þ; H NMR (400 MHz, CDCl3) d (ppm): 10.52 (1H, s), 8.78 (1H, s), 8.13
(1H, d, J ¼ 7.6 Hz), 7.82 (1H, d, J ¼ 7.6 Hz), 7.52 (1H, t, J ¼ 7.2 Hz), 7.30 (1H, t,
J ¼ 7.2 Hz), 3.97 (3H, s), 1.67 (2H, t, J ¼ 7.2 Hz), 1.36–1.32 (2H, m), 0.67 (3H, t,
J ¼ 6.4 Hz).
Compound 4e. 1-Isopropyl-b-carboline-3-carboxylic methþyl ester, yellow
solid, 2.17 g. Yield: 81%, mp: 149–152 ꢀC, C16H16N2O2, FAB -MS m=z: 269
(M þ 1)þ; 1H NMR (400 MHz, CDCl3) d (ppm): 8.80 (1H, s), 8.22 (1H, d,
J ¼ 7.5 Hz), 7.67 (1H, d, J ¼ 8.0 Hz), 7.47 (1H, t, J ¼ 7.5 Hz), 7.37 (1H, t, J ¼ 7.5 Hz),
4.09 (3H, s), 3.68 (1H, m), 1.56 (6H, d, J ¼ 7.0 Hz).
Compound 4f. 1-Cyclopentyl-b-carboline-3-carboxylic methyl ester, yellow
solid, 2.41 g. Yield: 82%, mp: 171–172 ꢀC, C18H18N2O2, FABþ-MS m=z: 295
1
(M þ 1)þ; H NMR (400 MHz, CDCl3) d (ppm): 11.20 (1H, s), 8.72 (1H, s), 8.15
(1H, d, J ¼ 7.6 Hz), 7.64 (1H, d, J ¼ 8.0 Hz), 7.55 (1H, t, J ¼ 7.2 Hz), 7.29 (1H, t,
J ¼ 7.2 Hz), 4.01 (3H, s), 3.73 (1H, m), 2.15 (4H, m), 1.92 (2H, m), 1.76 (2H, m).
Compound 4g. Trans-1-(10-butenyl)-b-carboline-3-carboxylic mþethyl ester,
yellow solid, 2.35 g. Yield: 84%, mp: 173–175 ꢀC, C17H16N2O2, FAB -MS m=z:
1
281 (M þ 1)þ; H NMR (400 MHz, CDCl3) d (ppm): 8.80 (1H, s), 8.22 (1H, d,
J ¼ 7.5 Hz), 7.67 (1H, d, J ¼ 8.0 Hz), 7.47 (1H, t, J ¼ 7.5 Hz), 7.37 (1H, t, J ¼ 7.5 Hz),
6.67 (1H, d, J ¼ 12.6 Hz), 6.62 (1H, d, J ¼ 12.6 Hz), 4.09 (3H, s), 2.00 (2H, m), 1.06
(3H, t, J ¼ 6.0 Hz).
Compound 4h. 1-(40-Trifuoromethylphenyl)-6-methyl-b-carboline-3-carboxylic
methyl ester, yellow solid, 3.49 g. Yield: 91%, mp 192–194 ꢀC, C21H15N2O2F3, FABþ-MS
1
m=z: 385 (M þ 1)þ; H NMR (500 MHz, CDCl3) d (ppm): 8.86 (1H, s), 8.20 (2H, d,
J ¼ 7.5Hz), 8.01 (1H, s), 7.85 (2H, d, J ¼ 7.5Hz), 7.54 (1H, t, J ¼ 7.0Hz), 7.42 (1H, d,
J ¼ 8.0Hz), 4.05 (3H, s), 2.56 (3H, s).

FACILE AND EFFICIENT ONE-POT SYNTHESIS OF b-CARBOLINES
1415
Compound 4i. 1-(20-Pyridyl)-b-carboline-3-carboxylic methyl ester, yellow
solid, 2.63 g. Yield: 87%, mp: 172–174 ꢀC, C18H13N3O2, FABþ-MS m=z: 304
(M þ 1)þ;1H NMR (400 MHz, CDCl3) d (ppm): 9.84 (1H, s), 8.31 (1H, d, J ¼ 8.0 Hz),
8.28 (1H, d, J ¼ 8.0 Hz), 8.12 (1H, s), 7.86 (1H, d, J ¼ 7.6 Hz), 7.68 (1H, d,
J ¼ 7.6 Hz), 7.62 (2H, t, J ¼ 7.2 Hz), 7.32 (2H, t, J ¼ 6.5 Hz), 3.76 (3H, s).
Compound 4j. 1-(20-Furyl)-6-fuoro-b-carboline-3-carboxylic methyl ester,
yellow solid, 2.48 g. Yield: 85%, mp: 168–172 ꢀC, C17H12N2O3, FABþ-MS m=z:
1
293 (M þ 1)þ; H NMR (400 MHz, CDCl3) d (ppm): 9.61 (1H, s, br), 8.79 (1H, s),
8.18 (1H, d, J ¼ 8.0 Hz), 7.63–7.59 (2H, m), 7.44 (1H, d, J ¼ 2.5 Hz), 7.36 (1H, t,
J ¼ 7.0 Hz), 6.67 (1H, d, J ¼ 1.0 Hz), 4.06 (3H, s).
Compound 4k. 1-(50-Aceoxylmethyl-20-furyl)-7-fuoro-b-carboline-3-car-
boxylic methyl ester, yellow solid, 3.36 g. Yield: 88%, mp 165–169 ꢀC,
C20H15FN2O5, FABþ-MS m=z: 383 (M þ 1)þ; 1H NMR (400 MHz, CDCl3) d
(ppm): 10.37 (1H, s, br), 8.73 (1H, s), 8.22 (1H, dd, J ¼ 1.2 Hz, 8.8 Hz), 7.71 (1H,
dd, J ¼ 2.0 Hz, 9.2 Hz), 7.31 (1H, d, J ¼ 3.6 Hz), 7.31 (1H, dt, J ¼ 2.0 Hz, 9.2 Hz),
6.63 (1H, d, J ¼ 3.6 Hz), 5.26 (2H, s), 4.02 (3H, s), 2.18 (3H, s).
Compound 4l. 1-(20-Thioyl)-6-methoxyl-b-carboline-3-carboxylic methyl
ester, yellow solid, 2.90 g. Yield: 86%, mp: 171–173 ꢀC, C18H14N2O3S, FABþ-MS
1
m=z: 339 (M þ 1)þ; H NMR (400 MHz, CDCl3) d (ppm): 8.79 (1H, s), 8.76 (1H,
s), 7.79 (1H, d, J ¼ 3.6 Hz), 7.62 (1H, d, J ¼ 2.4 Hz), 7.53 (1H, t, J ¼ 5.2 Hz), 7.49
(1H, s), 7.26 (1H, d, J ¼ 4.0 Hz), 7.24 (1H, d, J ¼ 4.0 Hz), 4.06 (3H, s), 3.95 (3H, s).
Compound 4m. 1-(20-Indoly)-b-carboline-3-carboxylic methyl ester, yellow
solid, 2.96 g. Yield: 87%, mp: 180–181 ꢀC, C21H15N3O2, FABþ-MS m=z: 342
1
(M þ 1)þ; H NMR (500 MHz, CDCl3) d (ppm): 10.02 (1H, s), 8.88 (1H, s), 8.70
(1H, d, J ¼ 8.0 Hz), 7.76 (1H, d, J ¼ 8.0 Hz), 7.68 (1H, d, J ¼ 6.5 Hz), 7.58 (2H, t,
J ¼ 7.5 Hz), 7.52 (1H, d, J ¼ 6.5 Hz), 7.48 (2H, t, J ¼ 7.5 Hz), 6.94 (1H, s), 3.94
(3H, s).
Compound 4n. 1-(20-Benzofuryl)-b-carboline-3-carboxylic mþethyl ester, yel-
low solid, 2.89 g. Yield: 87%, mp: 173–175 ꢀC, C21H14N2O3, FAB -MS m=z: 343
1
(M þ 1)þ; H NMR (500 MHz, CDCl3) d (ppm): 11.05 (1H, s), 8.36 (1H, s), 8.05
(1H, d, J ¼ 8.5 Hz), 7.98 (1H, d, J ¼ 8.0 Hz), 7.78 (2H, t, J ¼ 7.5 Hz), 7.48 (1H, d,
J ¼ 6.5 Hz), 7.32 (1H, d, J ¼ 6.5 Hz), 7.20 (2H, t, J ¼ 7.5 Hz), 6.79 (1H, s), 4.09
(3H, s).
Compound 4o. 1-(20-Quindyl)-6-methoxyl-b-carboline-3-carboxylic methyl
ester, yellow solid, 3.37 g. Yield: 88%, mp: 181–183 ꢀC, C23H17N3O3, FABþ-MS
1
m=z: 384 (M þ 1)þ; H NMR (500 MHz, CDCl3) d (ppm): 11.82 (1H, s), 9.02 (1H,
d, J ¼ 8.5 Hz), 8.39 (1H, s), 8.36 (1H, d, J ¼ 8.0 Hz), 8.28 (1H, d, J ¼ 8.5 Hz), 7.90
(1H, d, J ¼ 8.0 Hz), 7.78 (2H, t, J ¼ 7.5 Hz), 7.68 (1H, d, J ¼ 6.5 Hz), 7.32 (1H, d,
J ¼ 6.5 Hz), 4.08 (3H, s), 3.91 (3H, s).
Compound 4p. 1-(20-Naphthyl)-b-carboline-3-carboxylic meþthyl ester, yellow
solid, 3.16 g. Yield: 90%, mp: 178–180 ꢀC, C23H16N2O2, FAB -MS m=z: 353
(M þ 1)þ; 1H NMR (500 MHz, CDCl3) d (ppm): 9.89 (1H, s), 8.45 (1H, d,
J ¼ 8.5 Hz), 8.24 (1H, d, J ¼ 8.5 Hz), 8.22 (1H, s), 8.18 (1H, d, J ¼ 8.0 Hz), 7.96

1416
J.-G. TANG ET AL.
(1H, d, J ¼ 8.0 Hz), 7.78 (2H, t, J ¼ 7.5 Hz), 7.65 (1H, d, J ¼ 6.5 Hz), 7.51 (H, t,
J ¼ 7.5 Hz), 7.45 (1H, d, J ¼ 6.5 Hz), 7.32 (2H, t, J ¼ 6.5 Hz), 4.09 (3H, s).
ACKNOWLEDGMENT
This work was supported by the National Natural Science Foundation of
China (30470027 and 30225048).
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