Synthesis of functionalized tetrahydro-β-carboline derivatives by modified Pictet-Spengler reaction

Article abstract of DOI:10.3987/com-05-10336

Instead of iminium salt in Pictet-Spengler reaction, a series of indole-bearing secondary enamines were synthesized through one-carbon unit transfer reactions of a tetrahydrofolate coenzyme models with tryptamine, and applied to Pictet-Spengler reaction.

Full text of DOI:10.3987/com-05-10336

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HETEROCYCLES, Vol. 65, No. 5, 2005, pp. 1063 - 1069
Received, 14th January, 2005, Accepted, 22nd March, 2005, Published online, 24th March, 2005
SYNTHESIS OF FUNCTIONALIZED TETRAHYDRO-β-CARBOLINE
DERIVATIVES BY MODIFIED PICTET-SPENGLER REACTION
Donghong Li, Yongbin Zhang, Wei Guo,* and Chizhong Xia*
School of Chemistry and Chemical Engineering, Shanxi University, Taiyuan
030006, China; Email: guowsxu@yahoo.com.cn; Fax: 0086-351-7017424
Abstract–Instead of iminium salt in Pictet-Spengler reaction, a series of
indole-bearing secondary enamines were synthesized through one-carbon unit
transfer reactions of a tetrahydrofolate coenzyme models with tryptamine, and
applied to Pictet-Spengler reaction. Reaction of the secondary enamines in acid
conditions produced a series of functionalized tetrahydro-β-carboline derivatives
in good to excellent yields.
INTRODUCTION
The tetrahydro-β-carboline ring system is an important structural unit that is commonly encountered in
indole alkaloids and synthetic analogues with interesting biological activities.1,2 The isolation and
synthesis of naturally occurring tetrahydro-β-carboline derivatives and the synthesis of
tetrahydro-β-carboline derivatives have received considerable attention in the literature.3-7 The
Pictet-Spengler reaction is one of the most powerful methods for the formation of these ring systems.8-12
In general, this reaction can be characterized by the formation of an “iminium salt” after an acid-catalyzed
reaction of tryptamine and aldehyde (Scheme 1). Then, the “iminium ion” is attacked intramolecularly by
electrons of the pyrrole ring to provide C-1 substituted β-carboline derivatives. Although Pictet-Spengler
reaction has been widely investigated, the substrates were generally restricted to “iminium salt”.
Therefore, the approach still has limitations with regards to functionalization of the indole scaffolds,
especially in the 1-position, and in most cases, only alkyl groups coming from aldehydes were introduced
into 1-position.
Scheme 1
O
R
H
NH2
N
H+
NH
N
N
H
N
H
H
H
R
R

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HETEROCYCLES, Vol. 65, No. 5, 2005
In this paper, we hope to report a modified Pictet-Spengler reaction, that is, an acid-catalyzed cyclization
of a series of “indole-bearing secondary enamines” produced by one-carbon unit transfer reactions of a
tetrahydrofolate coenzyme models with tryptamine, for the synthesis of functionalized
tetrahydro-β-carboline derivatives.
RESULTS AND DISCUSSION
In our earlier research, a series of 1-aryl-4,5-dihydroimidazolium iodides and 1-arylsulfonyl-4,5-dihydroi-
midazolium iodides had been synthesized as the tetrahydrofolate (THF) coenzyme model for the study of
one-carbon unit transfer reactions.13-16 Recently, we synthesized a more activated THF model,
1-tosyl-3,4-dimethylimidazolinium iodide (1). It was showed that the model could easily react with a
series of aromatic or aliphatic amines to produce
a
series of N,N,N′-trisubstituted
2-methylethylenediamine derivatives.17 Furthermore, we found that the model could easily react with
carbon anions to produce the unsymmetrical trisubstituted imidazolidines (2, 3, 4),18 and the ring-opening
products, N,N,N′-trisubstituted 2-methyl-ethylenediamines (5, 6)19 (Table 1). Inspired by our published
results, we anticipated that the structural property of compound (2-6) should also assist in substituted
one-carbon unit transfer reaction with tryptamine. The observed results were found to be in agreement
with our assumption. When compound (2-6) were treated with tryptamine, the corresponding complete
transfer products, a series of secondary enamine (7-11), were produced in the yields of 58–87% (Table 1),
all of which were clearly identified as a single isomer in this case. The reaction was refluxed in
acetonitrile and easily followed by TLC. The reaction time was generally from 1 to 24 h and workout was
straightforward (see, EXPERIMENTAL).
Table 1 One-carbon unit transfer reactions of addition products (2-6) with tryptamine.
R1
R2
R1
N
R2
N
NH2
N
CH3
I
Ts
N
N
H
NaH
THF
CH3
CH3
NH
R2
or
Ts NH
N
+
CH2R1R2
Ts
N
CH3CN, Reflux
H
CH3
CH3
R1
CH3
7 - 11
1
2 - 4
5, 6
Entry
Substrate
R1
–COCH3
R2
Product
E/Z
--
Time (h)
Yield (%)
1
2
3
4
5
2
3
4
5
6
–COCH3
–COCH3
–CH3
7
8
3
1
86
86
87
68
58
–COOC2H5
–COC6H5
–CN
E
9
E
2
–CN
10
11
--
24
18
–H
–NO2
Z
The stereochemistry of compounds (8, 9) was determined to be E-type by the X-Ray diffraction (For 8,
see reference 20; For 9, see Figure 1). However, the stereochemistry of compound (11) was deduced to be

HETEROCYCLES, Vol. 65, No. 5, 2005
1065
Z-type from the coupling pattern of the adjacent two double bond protons, possibly resulting from the
intramolecular hydrogen bond between nitro O atom and the adjacent N-H group.
Figure 1 X-Ray structure of compound (9)
Compared to “iminium salt” formed by an acid-catalyzed reaction of tryptamine and aldehyde in
Pictet-Spengler condensation, the secondary enamines (7-11) were thought by us to be promising
substrates for the preparation of tetrahydro-β-carboline derivatives. In this case, the construction of the
tetrahydro-β-carboline skeleton could involve an acid-catalyzed cyclization between indole group and the
electrophilic carbon of the secondary enamine unit. The results obtained were in agreement with our
assumptions. The indole derivatives (7-9) could quickly undergo a cyclization reaction under influence of
HCl/C6H6 at room temperature, thus leading to the formation of tetrahydro-β-carboline derivatives
(12-14) (Table 2). However, compounds (10, 11) failed to provide any product at the same condition.
Interestingly, when compounds (10, 11) were refluxed in CH3CN/CH3COOH along with lengthening time,
tetrahydro-β-carboline derivatives (15, 16) were obtained with good yields (Table 2).
Table 2 Cyclization of indole derivatives for preparation of the tetrahydro-β-carboline derivatives
(12-16).
HCl/C H
6
6
12 - 14
HCl
NH
r t
N
H
NH
R
R
R
2
N
1
H
R
R
2
CH CN/CH COOH
1
3
3
15 - 16
NH
Reflux
7 - 11
N
H
R
1
2
Entry
R1
R2
Product
Time (h)
0.5
Yield(%)
1
2
3
4
5
–COCH3
–COCH3
–COCH3
–CH3
12
13
14
15
16
92
89
94a
–COOC2H5
–COC6H5
–CN
0.5
0.5
–CN
24
79
–H
–NO2
15
83
a Anti-type determined by 1H NMR analysis.

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HETEROCYCLES, Vol. 65, No. 5, 2005
In conclusion, the present research reported a modified Pictet-Spengler condensation by the application of
the indole-bearing secondary enamines chemistry, and provided a new method for the synthesis of a
series of functionalized tetrahydro-β-carboline derivatives, and may enable chemical and biological
studies on these derivatives. Ongoing studies are directed at providing mechanistic information, at
developing more efficient secondary enamines of the type for the condensation reaction.
EXPERIMENTAL
1
MS spectra were obtained on a JMS-D300 GC/MS spectrometer. The H NMR spectra were recorded at
300MHz with TMS as a spectra standard. Combustion analyses were performed on a Perkin-Elmer 240C
or a MOD 1106 instrument. IR spectra were obtained on a Shimadzu IR-1700 spectrophotometer. The
TLC was carried out on silica get GF-254 20*20 cm2 plate. Melting points were uncorrected. All reagents
and solvents were purified and dried as required.
General procedure for the preparation of compounds (7-11):
50% Sodium hydride suspended in oil (86.4 mg, 1.8 mmol) was added to a solution of CH2R1R2 (1.5
mmol) in 10 mL of dry tetrahydrofuran which was cooled with an ice-water bath. The reaction mixture
was stirred for 30 minutes, then the 1-tosyl-3,4-dimethylimidazolinium iodide (1) (380 mg, 1 mmol) was
added and the mixture was allowed to warm to rt for 2 h. Then the solution was extracted with
dichloromethane (3 × 30 mL), the combined organic layers were washed with water and dried over
anhydrous sodium sulfate. Evaporation of dichloromethane in vacuum gave the crude products (2-6) as
diastereomeric mixture. No effort was done to purify the diastereomeric mixture, which was directly
applied to the next step.
To the crude products (2-6) produced from the above process was added 10 mL of acetonitrile followed
by tryptamine (160 mg, 1 mmol). The obtained mixture was refluxed and monitored by TLC. Upon
completion or after the indicated reaction time, the mixture was filtrated and concentrated under reduced
pressure. The residue was purified by column chromatography (SiO2; EtOAc/hexanes, 1:2) to give the
desired products (7-11).
o
1
Compound (7): yield 86%, recrystallized from EtOAc as yellow solid, mp 150~152 C. H-NMR (300
MHz, δ ppm, CDCl3): 1.90(s, 3H), 2.45(s, 3H), 3.09(t, J = 6.18, 2H), 3.68(m, 2H), 7.03(s, 1H),
7.12-7.23(m, 2H), 7.37(m, 2H), 7.55(d, J = 7.8, 1H), 8.20(s, 1H), 11.02 (br, 1H). IR (KBr) cm-1: 3229,
2922, 1644, 1611, 1457, 1436, 1395, 1268, 1130, 1052; MS m/z: 270(M+). Anal. Calcd for C16H18N2O2:
C, 71.09; H, 6.34, N, 10.36. Found, C, 70.69; H, 6.67; N, 10.07.
Compound (8): yield 86%, recrystallized from EtOH as white crystals, mp 130oC~132 oC. 1H-NMR (300
MHz, δ ppm, CDCl3): 1.25 (m, 3H), 2.44 (s, 3H), 3.06 (t, J = 6.51, 2H), 3.64 (m, 2H), 4.14 (m, 2H), 7.03
(s, 1H), 7.18 (m, 2H), 7.35 (d, J = 8.01, 1H), 7.54 (d, J = 7.71, 1H), 7.82 (d, J = 13.65, 1H), 8.07 (br, 1H),

HETEROCYCLES, Vol. 65, No. 5, 2005
1067
9.72 (br, 1H). IR (KBr) cm-1: 3354, 3215, 2931, 1676, 1635, 1591, 1485, 1458, 1418, 1365, 1257, 1166,
1061. MS m/z: 300 (M+). Anal. Calcd for C17H20N2O3: C, 67.98; H, 6.71; N, 9.33. Found C, 67.72; H,
6.75; N, 9.16.
Compound (9): yield 87%, recrystallized from DMF as yellow crystals, mp 233oC~235oC. 1H-NMR (300
MHz, δ ppm, CDCl3): 1.69 (s, 3H), 2.85 (br, 2H), 3.32 (m, 2H), 6.66 (d, J = 13.7, 1H), 6.90-7.50 (m,
10H), 10.89 (br, 1H). IR (KBr) cm-1: 3215, 2850, 1628, 1577, 1506, 1456, 1365, 1224, 1026. MS m/z:
304 (M+). Anal. Calcd for C20H20N2O: C, 78.92; H, 6.62; N, 9.20. Found C, 78.51; H, 6.62; N, 9.26
o
1
Compound (10): yield 68%, recrystallized from EtOH as yellow crystals, mp 234oC~236 C. H-NMR
(300 MHz, δ ppm, CDCl3): 3.07 (t, J = 5.94, 2H), 3.64 (t, J = 6.02, 2H), 6.38 (br, 1H), 7.06 (t, J = 7.53,
2H), 7.18 (m, 1H), 7.20 (m, 1H), 7.44 (d, J = 7.93, 1H), 7.52 (d, J = 7.70, 1H), 8.19 (br, 1H). IR (KBr)
cm-1: 3319, 3224, 2920, 2219, 2204, 1616, 1558, 1490, 1456, 1180. MS m/z: 236 (M+). Anal. Calcd for
C14H12N4: C, 71.17; H, 5.12; N, 23.71. Found C, 71.06; H, 5.10; N, 23.48.
Compound (11): yield 58% as an yellow oil. 1H-NMR (300 MHz, δ ppm, CDCl3): 3.09 (t, J = 6.31, 2H),
3.65 (m, 2H), 6.35 (d, J = 5.67, 1H), 6.50 (m, 1H), 7.05 (s, 1H), 7.14-7.28 (m, 2H), 7.40 (d, J = 8.01, 1H),
7.56 (d, J = 7.76, 1H), 8.31 (br, 1H), 9.23 (br, 1H). IR (KBr) cm-1: 3053, 2922, 2852, 1639, 1550, 1458,
1126. HRMS (EI) m/z calcd for C12H13N3O2 231.2536 (M+), found 231.2531.
Procedure for the preparation of compounds (12-16)
For 12-14: The indole derivative (7-9) (1 mmol) was dissolved in 10 mL of saturated HCl/benzene
o
solution and stirred for 30 min at 20 C. After evaporation of the solvent and recrystallization from ethyl
alcohol, the desired products were obtained. For 15, 16: To a solution of indole derivatives (10, 11) (1
mmol) in 10 mL of acetonitrile was added 1 mL of glacial acetic acid. The reaction mixture was refluxed
under nitrogen. Upon completion or after the indicated reaction time, the solvent was removed under
reduced pressure. The residue was purified by column chromatography (SiO2; EtOAc/hexane, 4:1) to give
the desired products.
Compound (12): yield 92%, recrystallized from EtOH as white crystals, 200oC (decomp). 1H-NMR (300
MHz, δ ppm, DMSO-d6): 2.29 (s, 3H), 3.06 (m, 2H), 3.29 (s, 3H), 3.51 (m, 2H), 3.65 (m, 1H), 5.07 (m,
1H), 7.05 (t, J = 7.32, 1H), 7.15 (t, J = 7.73, 1H), 7.33 (d, J = 8.1, 1H), 7.45 (d, J = 7.84, 1H), 9.67 (br,
2H). IR (KBr) cm-1: 3232, 3051, 2922, 2736, 1712, 1606, 1494, 1458, 1379, 1207, 1178. MS m/z: 307
(M+). Anal. Calcd for C16H19N2O2Cl: C, 62.64; H, 6.24; N, 9.13. Found C, 62.90; H, 6.20; N, 9.47.
Compound (13): yield 89%, recrystallized from EtOH as yellow crystals, 250oC (decomp). 1H-NMR (300
MHz, δ ppm, DMSO-d6): 2.93 (m, 2H), 3.13 (m, 1H), 3.43 (m, 1H), 3.56 (m, 1H), 3.75 (s, 3H), 5.05 (m,
1H), 7.04 (t, J = 7.47, 1H), 7.14 (t, J = 7.23, 1H), 7.37 (d, J = 8.01, 1H), 7.46 (d, J = 7.68, 1H), 9.53 (br,
2H), 11.08 (s, 1H). IR (KBr) cm-1: 3429, 3254, 3044, 2924, 2706, 1722, 1602, 1454, 1398, 1204, 1181.
MS m/z: 309 (M+). Anal. Calcd for C15H17N2O3Cl: C, 58.35; H, 5.55; N, 9.07. Found C, 58.69; H, 6.04;

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HETEROCYCLES, Vol. 65, No. 5, 2005
N, 9.44.
Compound (14): yield 94%, recrystallized from EtOH as white crystals, 220oC (decomp). 1H-NMR (300
MHz, δ ppm, DMSO-d6): 2.09 (d, J = 7.20, 3H), 3.04 (m, 2H), 3.28 (m, 2H), 3.61 (d, J = 12.54, 1H), 5.03
(m, 1H), 6.83-7.49 (m, 9H). IR (KBr) cm-1: 3418, 3224, 3036, 2937, 1716, 1605, 1554, 1503, 1449, 1382,
1212, 1171. MS m/z: 341 (M+). Anal. Calcd for C20H21N2OCl: C, 70.48; H, 6.21; N, 8.22. Found C,
70.36; H, 6.20; N, 8.13.
Compound (15): yield 79% as an yellow oil, 1H-NMR (300 MHz, δ ppm, CDCl3): 3.10 (m, 2H), 3.61 (m,
2H), 3.81 (m, 1H), 4.11 (m, 1H), 5.64 (br, 1H), 7.06 (br, 1H), 7.12 (t, J = 7.16, 1H), 7.21 (t, J = 7.99, 1H),
7.40 (d, J = 7.97, 1H), 7.61 (d, J = 7.74, 1H). IR (KBr) cm-1: 3413, 3228, 2925, 2264, 2215, 1712, 1604,
1549, 1504, 1445, 1376, 1230. HRMS (EI) m/z calcd for C14H12N4 236.2756 (M+), found 236.2762.
Compound (16): yield 83% as a brown oil, 1H-NMR (300 MHz, δ ppm, CDCl3): 3.16 (m, 2H), 3.89 (m,
2H), 3.97 (m, 1H), 4.14 (m, 1H), 5.54 (br, 1H), 7.15 (br, 1H), 7.19 (m, 1H), 7.28 (m, 1H), 8.19 (d, J =
7.63, 1H), 8.40 (d, J = 8.02, 1H). IR (KBr) cm-1: 3258, 3115, 3069, 1607, 1559, 1504, 1425, 1218, 1126.
HRMS (EI) m/z calcd for C12H13N3O2 231.2536 (M+), found 231.2533.
Crystal data for compound (9)
Empirical formula: C20H20N2O, crystal size: 0.30×0.10×0.10, Monoclinic, a = 11.758(5)Å, b = 9.329(4)Å,
c = 15.415(6)Å, α = 90.00°, β = 103.014(7)°, γ = 90.00°, V = 1647.3(12), T = 293(2)K, space group
P2(1)/n, Z = 4, dcalc = 1.227 g/cm3, F(000) = 648, 6580 reflections measured, 2895 unique (Rint= 0.0332).
The final R1 = 0.0761(I > 2σ ), 0.1464(all data), wR2 = 0.1311(I > 2σ ), 0.1575(all data).
ACKNOWLEDGEMENTS
This work was supported by the National Natural Science Foundation of China (20272034), and the
Natural Science Foundation of Shanxi Province, China (20041006).
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