A simple method for the synthesis of 1-substituted β-carboline derivatives from tryptamine and carboxylic acids in polyphosphoric acid

Article abstract of DOI:10.3987/COM-05-10484

A number of 1-substituted 3,4-dihydro-9H-β-carboline derivatives (4) with high purity and yields have been synthesized by treating of tryptamine (1) with carboxylic acids (2) in polyphosphoric acid. 3,4-Dihydro-9H-β-carbolines (4) were successfully transformed to 1,2,3,4-tetrahydro-9H-β-carbolines (5) and 9H-β-carbolines (6).{A figure is presented}.

Full text of DOI:10.3987/COM-05-10484

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HETEROCYCLES, Vol. 65, No. 10, 2005, pp. 2483 - 2492
Received, 17th June, 2005, Accepted, 10th August, 2005, Published online, 12th August, 2005
A SIMPLE METHOD FOR THE SYNTHESIS OF 1-SUBSTITUTED β-
CARBOLINE DERIVATIVES FROM TRYPTAMINE AND
CARBOXYLIC ACIDS IN POLYPHOSPHORIC ACID
Iliyan Ivanov,* Stoyanka Nikolova, and Stela Statkova-Abeghe
University of Plovdiv, Department of Organic Chemistry, 4000 Plovdiv, Bulgaria
E-mail: ivanov@argon.acad.bg
Abstract – A number of 1-substituted 3,4-dihydro-9H-β-carboline derivatives (4)
with high purity and yields have been synthesized by treating of tryptamine (1)
with carboxylic acids (2) in polyphosphoric acid. 3,4-Dihydro-9H-β-carbolines
(4) were successfully transformed to 1,2,3,4-tetrahydro-9H-β-carbolines (5) and
9H-β-carbolines (6).
INTRODUCTION
The use of chemotherapeutic agents in cancer has advanced from the treatment of late diseases to the
early use of effective agents in patients with relatively small tumors. Among the various
chemotherapeutic agents, 1-substituted β-carboline derivatives have attracted the attention of organic
chemists because of their biological1 and potential antitumor activity.2 New β-carbolines are continually
being isolated from natural sources,3 like Eudistoma alkaloids and bengacarbolines,4 and these
compounds subsequently become targets for total synthesis.5 Recently, endogenously formed β-
carbolines, “mammalian alkaloids”, have come under increasing scrutiny in connection with Parkinson’s
disease.6 In addition, the antiviral eudistomines C, H, I, V and E exhibit potent inhibitory activity toward
DNA viruses HSV-1, HSV-2, the Vaccinia virus and RNA viruses.7 Recently, the novel structures of
manzamines, like A-D and H, possess potent antitumor,8 antibacterial, antifungal, anti-HIV9 and
cytotoxic activity.10
However, the synthesis of these compounds involves problems. The Pictet-Spengler reaction is the most
commonly employed synthethic route towards β-carbolines, but in this method, the reaction products are

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HETEROCYCLES, Vol. 65, No. 10, 2005
the tetrahydro-β-carboline, which requires subsequent oxidation. The Bischler-Napieralski reaction is not
satisfactorily efficient and may afford products of insufficient purity,11 yields12 or lead to negative
results,13 particularly in the case of dihydro-β-carbolines containing 1-heterocycling12 and 5- or 7-
methoxy substituent. The applicability of other synthetic methods such as cyclization of 2-
acyltryptamine14 or dehydrogenation of appropriate 1,2,3,4-tetrahydro-9H-β-carboline derivatives11,15
also is very limited. As a result of microwave assisted Bischler-Napieralski reaction, 1-substituted β-
carbolines are obtained from the corresponding tryptamine derivatives with higher yields.16
RESULTS AND DISCUSSION
Since the interest for the preparation of functionalized 3,4-dihydro-9H- and 1,2,3,4-tetrahydro-9H-β-
carbolines keeps growing, we considered of the possibility of cyclizing of tryptamine (1) with various
carboxylic acids (2). As cyclization agent we used polyphosphoric acid (PPA), which is a permanent
interest in synthetic applications for us.17
In our previous report17 the reaction of equimolar amounts of 2-phenylethylamines with carboxylic acids
in PPA afforded very conveniently the corresponding 3,4-dihydroisoquinolines in very good yields and
purity. The successful application of this way to the synthesis of 3,4-dihydroisoquinolines indicated to
enlarge applications opportunities. In this paper, we continue our research with the application of this
reaction with other primary amines. There are number of publications regarding the synthesis of 1-
substituted 3,4-dihydro-9H-β-carboline derivatives. So far there are no reports for condensation of
tryptamine with carboxylic acids in PPA for the preparation of β-carboline derivatives. We applied this
approach for the synthesis of 1-methyl- and 1-phenyl-3,4-dihydro-9H-β-carbolines at first.
When the dichloromethane solution of tryptamine (1) and acetic or benzoic acid was mixed in PPA at
80°C for 2 h, the 1-substituted 3,4-dihydro-9H-β-carbolines were obtained with low purity and yield. The
same products with higher yields and purity, were also obtained, when the mixture was permanently
stirred at room temperature or at 50°C for 2 h. These results prompted us to continue our researches with
other alkyl- and arylcarboxylic acids.
We assumed that the reaction first formed ammonium salt and then the acylation occurred on the 2-
position in the indole ring. This afforded the intermediate (3), which spontaneously cyclizing to 4 at the
reaction condition (Scheme 1).
This convenient route to preparation of 3,4-dihydro-9H-β-carbolines showed to enlarge applications
possibility. The newly synthesized 3,4-dihydro-9H-β-carbolines (4) easily were transformed to 1,2,3,4-
tetrahydro-9H-β-carbolines or to 9H-β-carbolines, which are known as alkaloids (harman,
tetrahydroharman, etc.).1 First we hydrogenated the obtained 1-methyl-3,4-dihydro-9H-β-carboline (4a)

HETEROCYCLES, Vol. 65, No. 10, 2005
2485
with NaBH4 in methanol. We investigated that reduction afforded the 1-methyl-1,2,3,4-tetrahydro-9H-β-
carboline (5a). By analogy we obtained the corresponding 1,2,3,4-tetrahydro-9H-β-carbolines (5b-i) in
very good yields (88-92 %) and purity.
+
NH2
NH3
O
PPA
N
N
1
3
H
H
+
R
RCOOH (2)
PPA-
H2O/OH-
NaBH4
KMnO4
NH
N
N
N
N
N
H
5
6
4
H
H
R
R
R
Scheme 1
Table 1
Yield, Entry
[%]
R
Yield,
[%]
92
90
88
92
90
88
90
92
90
90
92
Entry
R
4a
4b
4c
4d
4e
4f
4g
4h
4i
CH3
77
60
65
55
77
70
70
67
70
90
89
5c
5d
5e
5f
5g
5h
5i
6a
6b
6c
6d
CH2CH(CH3)2
C6H5
C2H5
C3H7
C6H5
4-Cl-C6H4
3,4-(MeO)2-C6H3
3,4,5-(MeO)3-C6H2
C6H5CH2
2-naphthyl
CH3
4-Cl-C6H4
2,4-Cl2-C6H3
3,4-(MeO)2-C6H3
3,4,5-(MeO)3-C6H2
2-naphthyl
CH3
C2H5
C3H7
C6H5
5a
5b
C2H5
Finally the fully aromatic 9H-β-carbolines (6) were prepared. It is well known that fully aromatic β-
carbolines are more potent in vitro, than their corresponding tetrahydro-β-carboline derivatives. A
number of authors tried to oxidize 3,4-dihydro-9H-β-carbolines (some of them were unsuccessful) for
preparation of fully aromatic products.1 S. Misztal et al.12 unsuccessfully overoxidized these derivatives
to fully aromatic byproducts by solid potassium permanganate in tetrahydrofuran at 0°C. B. Love and P.
Raje also tried to converse tetrahydro-β-carbolines to the aromatic system.2 They initiated this reaction by
treatment with p-toluensulfonic acid in toluene, butyllithium in THF or KOH in DMSO and oxidize
dihydro-β-carbolines in moderate yields. We also used potassium permanganate. It is known that 3,4-

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dihydro-9H-β-carbolines are stable to oxidizing agents under nonacidic conditions and the oxidation of 1-
methyl-1,2,3,4-tetrahydro-9H-β-carboline (5a) with KMnO4 in acetone afforded 1-methyl-3,4-dihydro-
9H-β-carboline, while the oxidation of 1-phenyl-1,2,3,4-tetrahydro-9H-β-carboline (5e) in
tetrahydrofuran led to a mixture of 1-phenyl-9H-β-carboline and 1-phenyl-3,4-dihydro-9H-β-carboline
(4e).11 We carried out the oxidation of the obtained 1-phenyl-3,4-dihydro-9H-β-carboline (4e) with
KMnO4 in acetone by stirring overnight at room temperature and found that the corresponding 1-phenyl-
9H-β-carboline could be obtained in good yield (92 %). By analogy we obtained 1-methyl-, 1-ethyl- and
1-propyl-9H-β-carbolines (6a-d) in high purity and good yields. The synthesized 9H-β-carbolines are
compounds with known antitumor and anti-HIV activity.7,10 The compounds were successfully oxidized
to their aromatic derivatives, but we investigated that 9H-β-carbolines were obtained more difficult than
isoquinolines in the same reaction conditions.
In conclusion, we report for the first time the application of this method for the preparation of 1-
substituted β-carboline derivatives. This represents a convenient route to obtain some biologically
important antitumor and anti-HIV active β-carboline alkaloids. The synthesized compounds were used for
the synthesis of fully aromatic 9H-β-carbolines with known in vitro neurochemical and pharmacological
activity.19,20
EXPERIMENTAL
Melting points were determined on a Boetius hostage apparatus and were uncorrected. 1H-NMR and 13C-
NMR spectra were measured in Bruker-250 devise by using CDCl3 or DMSO-d6 as solvent. Chemical
shifts (δ, ppm) were referenced to the chemical shifts of either TMS (δ=0.00ppm) as an internal standard
and coupling constants are indicated in Hz. Unless otherwise noted, all the NMR spectra were taken at
room temperature (ac. 295 K). MS spectra were recorded on a JEOL JMS-D300 spectrometer (70 eV).
All new compounds had correct parent ion peaks by MS spectrometry.
Polyphosphoric acid was obtained from 85% phosphoric acid and P2O5 (1:1 w/w).
1-Substituted 3,4-dihydro-9H-β-carbolines (4a-i); Typical procedure: Tryptamine (0.320 g, 2 mmol)
and the corresponding carboxylic acid (3 mmol) were dissolved in CH2Cl2 (3-5 mL) in an open flask and
polyphosphoric acid (10 g) was added. The mixture was stirred on a mechanical stirrer carefully at rt or
50°C for 2-3 h, then poured on crushed ice. The solution was carefully alkalized with 25% ammonia, then
extracted with CH2Cl2 (3x20 mL) and combined extracts were dried (Na2SO4) and filtrated on short
column with basic Al2O3. The products, after evaporation of the solvent, were purified by
recrystallization from ether.
1-Methyl-3,4-dihydro-9H-β-carboline (harmalan) (4a): yellow solid, mp 178-180°C (lit.,21 mp 182-

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2487
1
183). H-NMR (CDCl3): 2.38 (3H, s, CH3), 2.87 (2H, t, CH2, J=8.0 Hz), 3.87 (2H, t, CH2N, J=8.0 Hz),
13
7.15-7.73 (4H, m, Ar), 8.56 (1H, s, NH-9). C-NMR (CDCl3): 158.3, 137.1, 129.3, 125.5, 124.3, 120.1,
120.0, 116.3, 112.1, 38.0, 21.8, 19.4. MS m/z 184 (M+). Anal. Calcd for C12H12N2: C 78.23, H 6.57, N
15.20. Found: C 78.36, H 6.70, N 15.26.
1
1-Ethyl-3,4-dihydro-9H-β-carboline (4b): yellow solid, mp 165-167°C (lit.,21 mp 164-166). H-NMR
(DMSO-d6, 323K): 1.15 (3H, t, CH3, J=7.3 Hz), 2.67 (2H, q, CH2, J=7.3 Hz), 2.74 (2H, t, H-4, J=8.1 Hz),
3.72 (2H, t, H-3, J=8.1 Hz), 3.87 (2H, t, CH2N, J=7.5 Hz), 7.04-7.54 (4H, m, Ar), 11.26 (1H, br s, NH-9).
13C-NMR (DMSO-d6): 160.8, 136.4, 128.7, 125.0, 123.3, 119.4, 119.3, 114.1, 112.3, 47.6, 27.7, 18.9,
10.5. MS m/z: 198 (M+). Anal. Calcd for C13H14N2: C 78.75, H 7.12, N 14.13. Found: C 78.83, H 7.20, N
14.28.
1
1-Propyl-3,4-dihydro-9H-β-carboline (4c): yellow solid, mp 161-162°C (lit.,22 mp 162-165). H-NMR
(CDCl3): 1.00 (3H, t, CH3, J=7.4 Hz), 1.76 (m, 2H), 2.66 (2H, t, CH2, J=7.6 Hz), 2.86 (2H, t, H-4, J=8.3
Hz), 3.88 (2H, t, H-3, J=8.2 Hz), 6.97-7.60 (4H, m, Ar), 8.88 (1H, br s, NH-9). 13C-NMR (CDCl3): 161.0,
136.7, 128.8, 125.7, 124.4, 120.3, 120.0, 116.8, 111.9, 48.2, 37.5, 20.2, 19.3, 13.9. MS m/z: 212 (M+).
Anal. Calcd for C14H16N2: C 79.24, H 7.60, N 13.20. Found: C 79.30, H 7.68, N 13.27.
1
1-Phenyl-3,4-dihydro-9H-β-carboline (4d): yellow solid, mp 230-232°C (lit.,12 mp 232-234°C). H-
NMR (CDCl3): 3.04 (2H, t, H-4, J=8.0 Hz), 4.13 (2H, t, H-3, J=8.0 Hz), 7.23-7.89 (9H, m, Ar), 8.25 (1H,
br s, NH-9). 13C-NMR (CDCl3): 159.5, 137.1, 136.7, 130.1, 127.8, 124.7, 120.4, 118.1, 112.0, 48.4, 19.2.
MS m/z: 246 (M+). Anal. Calcd for C17H14N2: C 82.82, H 5.68, N 11.37. Found: C 82.90, H 5.75, N 11.45.
1-(4′-Chlorophenyl)-3,4-dihydro-9H-β-carboline (4e): white solid, mp 102-103°C (lit.,10 mp 102-
1
104°C). H-NMR (CDCl3): 2.99 (2H, t, H-4, J=8.3 Hz), 4.06 (2H, t, H-3, J=8.3 Hz), 7.20-7.67 (4H, m,
13
Ar), 8.04 (1H, s, NH-9). C-NMR (CDCl3): 159.9, 136.2, 126.9, 122.4, 120.8, 118.1, 111.1, 41.2, 39.9,
27.1, 25.7. MS m/z: 280 (M+). Anal. Calcd for C17H13N2Cl: C 72.66, H 4.63, N 9.97. Found: C 72.76, H
4.70, N 10.05.
1
1-(2′,4′-Dichlorophenyl)-3,4-dihydro-9H-β-carboline (4f): yellow solid, mp 193-195°C. H-NMR
(CDCl3): 3.02 (2H, t, H-4, J=8.5 Hz), 4.08 (2H, t, H-3, J=8.5 Hz), 7.17-7.66 (7H, m, Ar), 8.28 (1H, s,
NH-9). 13C-NMR (CDCl3): 157.8, 137.0, 136.0, 131.3, 127.8, 125.3, 120.5, 117.5, 112.0, 48.8, 19.2. MS
m/z: 315 (M+). Anal. Calcd for C17H12N2Cl2: C 64.72, H 3.81, N 8.88. Found: C 64.79, H 3.90, N 8.98.
1-(3′,4′-Dimethoxyphenyl)-3,4-dihydro-9H-β-carboline (4g): yellow solid, mp 285-288°C (lit.,10 mp
1
288-290°C). H-NMR (CDCl3): 2.95 (2H, t, H-4, J=8.0 Hz), 3.88 (6H, s, OMe), 4.03 (2H, t, H-3, J=8.0
Hz), 7.20-7.66 (7H, m, Ar), 8.90 (1H, br s, NH-9). 13C-NMR (CDCl3): 158.9, 136.7, 129.8, 127.7, 124.6,
120.4, 118.2, 112.1, 48.3, 19.2. MS m/z: 306 (M+). Anal. Calcd for C19H18N2O2: C 74.41, H 5.87, N 9.14.
Found: C 74.49, H 5.95, N 9.21.

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1-(3′,4′,5′-Trimethoxylphenyl)-3,4-dihydro-9H-β-carboline (4h): yellow solid, mp 250-252°C (lit.,10
1
mp 251°C). H-NMR (CDCl3): 2.96 (2H, t, H-4, J=7.5 Hz), 3.85 (9H, s, OMe), 4.01 (2H, t, H-3, J=7.5
Hz), 7.21-7.68 (6H, m, Ar), 9.12 (1H, br s, NH-9). 13C-NMR(CDCl3): 159.4, 153.0, 139.0, 136.7, 133.2,
127.9, 125.4, 120.2, 119.9, 117.9, 112.1, 105.0, 48.8, 19.2. MS m/z: 336 (M+). Anal. Calcd for
C20H20N2O3: C 71.35, H 5.95, N 8.32. Found: C 71.43, H 6.01, N 8.40.
1
1-(2′-Naphthyl)-3,4-dihydro-9H-β-carboline (4i): white solid, mp 145-150°C. H-NMR(CDCl3): 2.95
(2H, t, H-4, J=8.0 Hz), 4.01 (2H, t, H-3, J=8.0 Hz), 7.18-7.65 (11H, m, Ar), 8.76 (1H, s, NH-9). 13C-NMR
(CDCl3): 159.5, 136.7, 134.4, 127.8, 126.5, 120.3, 118.1, 112.1, 48.5, 19.2. MS m/z: 296 (M+). Anal.
Calcd for C21H16N2: C 85.03, H 5.40, N 9.45. Found: C 85.13, H 5.48, N 9.54.
1-Substituted 1,2,3,4-tetrahydro-9H-β-carboline (5a-i); Typical procedure: To solution of 1 mmol of
the corresponding 3,4-dihydro-9H-β-carboline (4) in 15 mL of methanol, NaBH4 (2 mmol, 0,1 g) was
added portionwise. The solution was stirred 30 min at rt, than the solvent was removed under vacuum.
Water (30 mL) was added to the residue and the solution was extracted with CH2Cl2 (3x20 mL), then the
combined extracts were dried (Na2SO4) and filtered on short column with basic Al2O3. The products, after
evaporation of the solvent, were purified by recrystallization from n-hexane or ether.
1-Methyl-1,2,3,4-tetrahydro-9H-β-carboline (tetrahydroharman) (5a): semi-solid.23 1H-NMR
(CDCl3): 1.46 (d, 3H, J=6.8 Hz), 1.58 (s,1H, NH), 2.72 (m, 1H, H-4), 3.06 (m, 1H, H-3), 4.20 (q, 1H, H-1,
J=6.8 Hz), 7.1-7.48 (m, 4H, Ar), 7.75 (1H, s, NH). MS m/z: 187 (M+H+). Anal. Calcd for C12H14N2: C
77.32, H 7.52, N 15.03. Found: C 77.40, H 7.60, N 15.10.
1-Ethyl-1,2,3,4-tetrahydro-9H-β-carboline (5b): yellow solid, mp 223-225°C (lit.,20 mp 225-228°C).
1H-NMR (DMSO-d6,323K): 1.08 (t, 3H, CH2CH3, J=7.6 Hz), 1.93, 2.20 (each 1H, m, CH2CH3), 2.96 (m,
2H, H-4), 3.35, 3.58 (each 1H, m, H-3), 4.58 (1H, br s, H-1), 7.02-7.45 (m, 4H, Ar), 9.12 (1H, s, NH).
MS m/z: 201 (M+H+). Anal. Calcd for C13H16N2: C 77.89, H 7.99, N 13.98. Found: C 77.98, H 8.08, N
14.04.
1-i-Buthyl-1,2,3,4-tetrahydro-9H-β-carboline (5c): oil.23 1H-NMR (CDCl3): 1.00 (6H, d, 2xCH3, J=6.3
Hz), 1.63 (1H, m), 1.82 (1H, s, NH), 1.98 (2H, m), 2.80 (2H, t, CH2, J=5.8 Hz), 3.18 (2H, t, CH2, J=5.8
Hz), 4.12 (1H, dd, J=5.6, 13.8 Hz), 7.49-7.14 (m, 4H, Ar), 7.78 (1H, s, NH). MS m/z: 229 (M+H+). Anal.
Calcd for C15H20N2: C 78.83, H 8.76, N 12.26. Found: C 78.92, H 8.83, N 12.34.
1-Phenyl-1,2,3,4-tetrahydro-9H-β-carboline (5d): white solid, mp 257-258°C (lit.,24 mp 258-259°C).
1H-NMR (CDCl3): 2.50-3.30 (m, 4H, 2xCH2), 5.22 (s, 1H, CH), 7.00-7.70 (m, 9H, Ar), 10.40 (1H, br s,
NH). 13C-NMR (CDCl3): 141.72, 135.86, 134.33, 128.63, 128.46, 128.05, 127.23, 121.53, 119.18, 118.07,
110.79, 109.97, 57.89, 42.51, 22.43. MS m/z: 249 (M+H+). Anal. Calcd for C17H16N2: C 82.15, H 6.44, N
11.28. Found: C 82.27, H 6.52, N 11.34.
1-(4′-Chlorophenyl)-1,2,3,4-tetrahydro-9H-β-carboline (5e): white solid plates, mp 162-163°C (lit.,10

HETEROCYCLES, Vol. 65, No. 10, 2005
2489
mp 165°C). 1H-NMR (CDCl3): 2.85 (2H, m, H-4), 3.11 (1H, m, H-3), 5.09 (1H, s, H-1), 7.17-7.57 (4H, m,
Ar), 7.87 (1H, s, NH-9). 13C-NMR (CDCl3): 140.3, 135.9, 133.9, 133.7, 129.8, 128.9, 127.2, 121.8, 119.4,
118.2, 110.8, 110.2, 57.1, 42.4, 22.3. MS m/z: 282 (M+). Anal. Calcd for C17H15N2Cl: C 72.14, H 5.30, N
9.90. Found: C 72.21, H 5.40, N 9.97.
1-(3′,4′-Dimethoxylphenyl)-1,2,3,4-tetrahydro-9H-β-carboline (5f): pale yellow solid, mp 302-305°C
(lit.,20 mp>300°C). 1H-NMR (CDCl3): 2.89 (2H, m, H-4), 3.10 (1H, m, H-3), 3.70 (3H, s, OMe), 3.84 (3H,
s, OMe), 5.04 (1H, s, H-1), 7.12-7.56 (4H, m, Ar), 8.32 (1H, s, NH-9). 13C-NMR (CDCl3): 149.0, 148.6,
135.8, 134.5, 134.2, 127.2, 121.4, 120.5, 119.0, 118.0, 111.2, 110.8, 109.7, 57.9, 55.7, 55.6, 42.9, 22.3.
MS m/z: 308 (M+). Anal. Calcd for C19H20N2O2: C 73.99, H 6.49, N 9.09. Found: C 74.08, H 6.54, N 9.18.
1-(3′,4′,5′-Trimethoxylphenyl)-1,2,3,4-tetrahydro-9H-β-carboline (5g): pale yellow solid, mp 160-
1
160.5°C. H-NMR (CDCl3): 3.29 (2H, m, H-4), 3.59 (1H, m, H-3), 3.71 (9H, s, OMe), 5.85 (1H, s, H-1),
13
7.11-7.55 (4H, m, Ar), 8.30 (1H, s, NH-9). C-NMR (CDCl3): 153.8, 153.4, 136.2, 133.3, 128.6, 126.7,
122.4, 119.7, 118.4, 111.1, 109.4, 60.7, 56.1, 51.5, 41.7. MS m/z: 338 (M+). Anal. Calcd for C20H22N2O3:
C 70.97, H 6.51, N 8.28. Found: C 71.06, H 6.60, N 8.38.
1-Benzyl-1,2,3,4-tetrahydro-9H-β-carboline (5h): yellow oil.25 1H-NMR (CDCl3): 1.80 (1H, br s, NH),
2.50-3.50 (m, 4H, 2xCH2), 3.01 (d, 2H, CH2Ar, J=7.0 Hz), 4.33 (t, 1H, H-1, J=7.0 Hz), 7.73-6.94 (m, 10H,
13
Ar and NH-9). C-NMR (CDCl3): 138.1, 135.56, 135.5, 129.3, 128.8, 127.2, 126.88, 121.5, 119.28,
118.08, 110.7, 109.28, 53.98, 42.8, 41.64, 22.6. MS m/z: 262 (M+). Anal. Calcd for C18H18N2: C 82.33, H
6.86, N 10.67. Found: C 82.42, H 6.93, N 10.73.
1-(2′-Naphtyl)-1,2,3,4-tetrahydro-9H-β-carboline (5i): yellow solid, mp 183-185°C (lit.,1 mp 184-
185°C). 1H-NMR (CDCl3): 2,37 (1H, s, NH), 2.87-2.97 (m, 2H, H-4), 3.10-3.18 (m, 1H, H-3), 3.33-3.42
(m, 1H, H-3), 5.28 (s, 1H, H-1), 7.13-7.17 (m, 3H, Ar), 7.47-7.51 (m, 4H, Ar), 7.71-8.06 (m, 5H, Ar and
13
NH-9). C-NMR (CDCl3): 139.0, 135.96, 134.3, 128.7, 127.9, 127.3, 126.3, 121.7, 119.4, 118.2, 110.9,
110.2, 58.1, 42.8, 22.4. MS m/z: 298 (M+). Anal. Calcd for C21H18N2: C 84.46, H 6.03, N 9.38. Found: C
84.54, H 6.09, N 9.46.
1-Substituted 9H-β-carbolines (6a-d). Typical procedure: To the stirred solution of 1 mmol of
corresponding 3,4-dihydro-9H-β-carboline (4) in 20 mL of acetone at rt KMnO4 (0.316 g, 2 mmol) was
added portionwise. The colour of the reaction mixture gradually turned from violet to brown from the
formed MnO2. Saturated aqueous sodium metabisulfite solution (50 mL) was added carefully. The
resulting mixture was alkalized with 25% ammonia and the solution was extracted with CH2Cl2 (3x20
mL). The combined extracts were dried (Na2SO4), the solvent evaporated and the products purified by
recrystallization from ether.
1-Methyl-9H-β-carboline (6a): colorless needles, mp 202-202.5°C (lit.,20 mp 202°C). 1H-NMR (DMSO-

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d6, 323 K): 2.76 (s, 3H, CH3), 7.23-7.92 (m, 4H), 8.19 (1H, d, H-5, J=8.2 Hz), 8.20 (1H, d, H-3, J=5.3
Hz), 11.53 (1H, br s, NH). MS m/z: 182 (M+). Anal. Calcd for C12H10N2: C 79.10, H 5.53, N 15.37.
Found: C 79.30, H 5.89, N 15.66.
1
1-Ethyl-9H-β-carboline (6b): colorless needles, mp 193-195°C (lit.,20 mp 195-197°C). H-NMR
(DMSO-d6, 323 K): 1.42 (3H, t, CH2CH3, J=7.7 Hz), 3.19 (2H, q, CH2CH3, J=7.7 Hz), 7.24-7.91 (m, 4H,
Ar), 8.18 (1H, d, H-5, J=8.1 Hz), 8.29 (1H, d, H-3, J=5.5 Hz), 11.53 (1H, br s, NH). MS m/z: 196 (M+).
Anal. Calcd for C13H12N2: C 79.49, H 6.11, N 14.27. Found: C 79.60, H 6.20, N 14.40.
1
1-Propyl-9H-β-carboline (6c): colorless needles, mp 217-219°C (lit.,20 mp 218-220°C). H-NMR
(DMSO-d6, 323 K): 1.00 (3H, t, CH2CH2CH3, J=7.3 Hz), 1.86 (2H, m, CH2CH2CH3), 3.08 (m, 2H,
CH2CH2CH3), 7.22-7.89 (m, 4H), 8.17 (1H, d, H-5, J=8.1 Hz), 8.25 (1H, d, H-3, J=5.1 Hz), 11.43 (1H, br
s, NH). MS m/z: 210 (M+). Anal. Calcd for C14H14N2: C 79.97, H 6.71, N 13.32. Found: C 79.90, H 6.84,
N 13.11.
1-Phenyl-9H-β-carboline (6d): yellow powder, mp 241-242°C (lit.,2 mp 240-243°C). 1H-NMR (CDCl3):
13
7.25 (t, 1H, J=5.3 Hz), 7.4-8.5 (m, 9H, Ar), 11.07 (1H, s, NH). C-NMR (CDCl3): 111.4, 112.6, 118.5,
120.25, 120.3, 127.1, 127.4, 127.6, 127.8, 128.6, 132.6, 137.5, 137.8, 140.4, 141.8. MS m/z: 244 (M+).
Anal. Calcd for C17H12N2: C 83.51, H 4.91, N 11.46. Found: C 83.60, H 4.99, N 11.55.
ACKNOWLEDGEMENTS
We acknowledge financial support from the Fund for scientific research of the University of Plovdiv.
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