Synthesis of 1-aryl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indoles (1,2,3,4-tetrahydro-β-carbolines) under high pressures

Article abstract of DOI:10.1023/A:1011306517653

The reactions of aromatic aldehydes with tryptamine (1) in solvents of different polarity were studied. The yields of carbolines in the chosen media decrease with an increase in the donating properties of the aryl substituent, but they markedly increase a

Full text of DOI:10.1023/A:1011306517653

560
Russian Chemical Bulletin, International Edition, Vol. 50, No. 3, pp. 560—562, March, 2001
Synthesis of 1-aryl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indoles
(1,2,3,4-tetrahydro-β-carbolines) under high pressures
N. E. Agafonov,« A. V. Dudin, A. A. Preobrazhenskii, and V. M. Zhulin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119992 Moscow, Russian Federation.
Fax: +7 (095) 135 5328
The reactions of aromatic aldehydes with tryptamine (1) in solvents of different polarity
were studied. The yields of carbolines in the chosen media decrease with an increase in the
donating properties of the aryl substituent, but they markedly increase at a high pressure
(5 kbar), especially for compounds with electron-donating aryl groups. The phase transition of
dioxane at 5 kbar also sharply increases the yields of the target products.
Key words: carbolines, tryptamine, aromatic aldehydes, Pictet—Spengler reaction, high
pressure.
Scheme 1
1,2,3,4-Tetrahydro-β-carboline is a structural frag-
ment of many biologically active alkaloids1 such as
reserpine, tetrahydroharmine, and yohimbine. Its 1-alkyl
derivatives are usually obtained by the Pictet—Spengler
reaction,2 i.e., by condensation of tryptamine (1) with
aliphatic aldehydes in an acidic media to form interme-
diate Schiff bases that undergo in situ cyclization into
carbolines. This reaction is widely dealt with in the
literature.1 However, the behavior of aromatic aldehydes
in the Pictet—Spengler reaction has been discussed only
in a single work.3 It was shown that the yields of
carboline derivatives are high only for ArCHO with
electron-withdrawing substituents (NO2 and Cl) and
rather low in the case of electron-donating groups (Me,
OMe, and NMe2).
CH2CH2NH2
[H+]
+
ArCHO
N
H
2a—k
1
CH2CH2N CHAr
[H+]
N
H
3
The goal of our work is to carry out the reactions of
tryptamine (1) with aromatic aldehydes 2a—k (Scheme 1,
Table 1) both at ambient and high pressure (5 kbar) and
study how the phase transition of a solvent influences
the yield of carbolines. It is known1 that an intramolecu-
lar electrophilic cyclization of protonated intermediate 4
is the key stage in the synthesis, and hence this process
can be significantly accelerated at elevated pressure (en-
tropic factor).
Aldehydes with different electronic properties were
studied (in Table 1, the aldehydes appear in the order of
decreasing electron-withdrawing and increasing elec-
tron-donating properties of an aromatic substituent). All
syntheses were carried out in MeOH (a standard solvent
for the Pictet—Spengler reaction), CH2Cl2, and diox-
ane. The reaction mixtures were refluxed at ambient
pressure for 10 h and kept at ∼20 °C at a pressure of
5 kbar for 1 h (see Table 1). Hydrogen chloride was used
as an acid catalyst in the ratios close to those in Ref. 3.
At ambient pressure, the yields of carbolines 5 gradu-
ally decreased with an increase in the donating proper-
+
N
H
NH•HCl
N
H
N
H
Ar
Ar
4
5a—k
ties of the aryl substituent, being for alkyl- and alkoxy
derivatives ∼30% in MeOH and <1% in CH2Cl2 and
dioxane. Such a result was also noted earlier3 and is
probably due to a decreased electrophilicity of interme-
diate 4 with an electron-donating Ar group.
As expected, the yields of carbolines 5 at 5 kbar in all
of the solvents were much higher than those at ambient
pressure, the products from any aldehydes being ob-
tained (see Table 1).
It was also found that the course of the reaction
under study is largely affected by the solvent. In low-
polarity media (CH2Cl2 and dioxane), the yields of
compounds 5 at ambient pressure were appreciably lower
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 535—537, March, 2001.
1066-5285/01/5003-560 $25.00 © 2001 Plenum Publishing Corporation

Synthesis of 1-aryl-1,2,3,4-tetrahydro-β-carbolines Russ.Chem.Bull., Int.Ed., Vol. 50, No. 3, March, 2001
Table 1. Yields of 1-aryl-1,2,3,4-tetrahydro-β-carbolines (5a—k) in the Pictet—Spengler reaction under different conditions
561
Compound, Ar
Yields of 5a—k•HCl (%)
Ambient pressure, 10 h 5 kbar, 20 °C, 1 h
M.p. of 5•HCl/°C
M+
m/z
Our
data
Literature
data3
MeOH,
CH2Cl2, Dioxane,
MeOH
CH2Cl2
Dioxane
65 °C
40 °C
101 °C
5a, 4-CF3C6H4
5b, 4-O2NC6H4
91
88
40
36
47
35
97
91
72
60
94
90
283—285a
242—245
—
316
293
240—250
(decomp.)
5c, 3-O2N-4-ClC6H3
5d, 3-O2NC6H4
5e, 4-ClC6H4
5f, Ph
5g, m-Tol
5h, p-Tol
69
65
62
35
33
34
28
15
16
3
<1
<1
29
21
17
2
<1
<1
85
88
85
87
89
81
62
63
70
60
69
57
88
89
87
91
90
85
268—270 270 (decomp.) 327
271—273b
282—284
268—270
250—251
285—287
—
293
282
248
262
262
280—281
267—270
248—251
283—286
O
5i,
30
<1
<1
78
50
87
272—275
270—273
292
O
5j, 4-MeOC6H4
5k, 4-EtOC6H4
33
27
<1
<1
<1
<1
80
78
51
49
90
78
283—285
271—274c
283—285
—
278
292
a Found (%): C, 61.49; H, 4.30; N, 7.59. C18H16ClF3N2. Calculated (%): C, 61.28; H, 4.57; N, 7.94.
b Found (%): C, 61.82; H, 5.11; N, 13.09. C17H16ClN3O2. Calculated (%): C, 61.92; H, 4.89; N, 12.74.
c Found (%): C, 69.75; H, 6.10; N, 8.55. C19H21ClN2O. Calculated (%): C, 69.40; H, 6.44; N, 8.52.
cooling, hydrochloride (5a•HCl) was filtered off and recrystal-
lized from MeOH. The filtrates were concentrated to give an
additional amount of crystals. The total yield was 91%. 1H NMR,
δ: 3.00—3.50 (m, 4 H, CH2CH2); 6.00 (s, 1 H, CH—N+H2);
7.00—7.85 (m, 8 H, Harom); 10.40 (br.s, 2 H, N+H2); 10.80 (s,
1 H, NH).
B. Experiment in CH2Cl2 at P = 1 bar. A mixture of
compound 1 (10 mmol) and aldehyde 2a (10 mmol) in 3 mL of
CH2Cl2 was treated with a solution of HCl (10.5 mmol) in
CH2Cl2. The volume of CH2Cl2 was brought to 10 mL, and the
reaction mixture was refluxed for 10 h and evaporated to
dryness. After MeOH (5 mL) was added, hydrochloride 5a•HCl
was filtered off. An additional amount of the hydrochloride was
isolated from the filtrate. The total yield of 5a•HCl was 40%.
C. Experiment in dioxane at P = 1 bar was carried out as
described for CH2Cl2, using a solution of HCl in dioxane. The
yield of 5a•HCl was 47%.
than in MeOH, and carbolines 5g—k from aldehydes
with electron-donating substituents were formed in very
small amounts.
Of interest is also the solvent effect on the reaction at
5 kbar. Although the use of high pressure markedly
increased the yields of carbolines 5 in CH2Cl2, they were
lower than in MeOH (5 kbar). In most cases, the yields in
dioxane (5 kbar) are even higher than in MeOH (5 kbar),
as opposed to the reactions at ambient pressure. Such an
unusual jump in the yields of compounds 5 in dioxane
can be explained by its phase transition at a pressure of
5 kbar. The crystallization of the solvent increases the
concentration of the reagents and can also cause a spe-
cific "cell effect" which lowers the transition state energy,
thus facilitating the reaction (entropic factor).4
D. Experiments at P = 5 kbar. Amine 1 (1 mmol), aldehyde
2a (1 mmol), and a solvent (MeOH, CH2Cl2, or dioxane,
0.3 mL) were placed in a 1-mL Teflon tube. The reaction
mixture was treated with a solution of HCl (1.05 mmol) in the
corresponding solvent. The volume of the solvent was brought
to 1 mL, and the reaction mixture was kept at 5 kbar for 1 h and
worked up as described above for P = 1 bar.
The reactions with aldehydes 2b—k were carried out in a
similar manner. The yields and melting points of hydrochlorides
5a—5k•HCl and the molecular ions of bases 5a—k are given in
Table 1.
The 1H NMR spectra of hydrochlorides 5b•HCl—5k•HCl.
5b•HCl, δ: 3.00—3.50 (m, 4 H, CH2CH2); 6.15 (s, 1 H,
CH—N+H2); 7.00—8.40 (m, 8 H, Harom); 10.30 (br.s, 2 H,
N+H2); 10.90 (s, 1 H, NH).
5c•HCl, δ: 2.90—3.60 (m, 4 H, CH2CH2); 6.15 (s, 1 H,
CH—N+H2); 7.10 and 7.90 (both m, 4 H, H(5), H(6), H(7),
H(8)); 7.35 and 7.55 (both d, 2 H, C6H2NO2ClH, J = 7 Hz);
8.25 (s, 1 H, C6H2NO2ClH); 10.50 (br.s, 2 H, N+H2); 11.00
(s, 1 H, NH).
Experimental
1
H NMR spectra were recorded on a Bruker AC-200 spec-
trometer in DMSO-d6. The chemical shifts are referred to the δ
scale with Me4Si as the standard. Mass spectra were recorded
on a Finnigan MAT INCOS-50 instrument (EI, 70 eV). Melt-
ing points of hydrochlorides 5a—k were determined on a Boetius
hot stage. The notation "<1%" in Table 1 means that hydrochlo-
rides 5 were not isolated, but their presence (in trace amounts)
in the reaction mixtures was proved by mass spectrometry (M+).
All reagents and solvents (Aldrich) were used without addi-
tional purification.
1-(4-Trifluoromethylphenyl)-1,2,3,4-tetrahydro-β-carboline
hydrochloride (5a•HCl). A. Experiment in MeOH at P = 1 bar.
A mixture of tryptamine 1 (10 mmol) and aldehyde 2a (10 mmol)
in 3 mL of MeOH was treated with a solution of HCl
(10.5 mmol) in MeOH. The volume of MeOH was brought to
10 mL, and the reaction mixture was refluxed for 10 h. After

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Russ.Chem.Bull., Int.Ed., Vol. 50, No. 3, March, 2001
Agafonov et al.
5d•HCl, δ: 3.00—3.50 (m, 4 H, CH2CH2); 6.10 (s, 1 H,
5k•HCl, δ: 1.35 (t, 3 H, OCH2CH3); 3.00—3.50 (m, 4 H,
CH2CH2); 4.10 (q, 2 H, OCH2CH3); 5.85 (s, 1 H, CH—N+H2);
7.00—7.60 (m, 8 H, Harom); 10.00 (br.s, 2 H, N+H2); 10.85
(s, 1 H, NH).
CH—N+H2); 7.00—8.40 (m, 8 H, Harom); 10.20 (br.s, 2 H,
N+H2); 10.80 (s, 1 H, NH).
5e•HCl, δ: 3.00—3.50 (m, 4 H, CH2CH2); 5.90 (s, 1 H,
CH—N+H2); 7.00—7.60 (m, 8 H, Harom); 10.40 (br.s, 2 H,
N+H2); 10.80 (s, 1 H, NH).
5f•HCl, δ: 3.00—3.50 (m, 4 H, CH2CH2); 5.90 (s, 1 H,
CH—N+H2); 7.00—7.50 (m, 9 H, Harom); 10.30 (br.s, 2 H,
N+H2); 10.90 (s, 1 H, NH).
References
1. Organicheskie reaktsii [Organic Reactions], Eds. K. A.
Kocheshkov and I. F. Lutsenko, V. 6, p. 177 (in Russian).
2. A. Pictet and T. Spengler, Chem. Ber., 1911, 44, 2030.
3. W. A. Skinner and R. M. Parkhurst, Can. J. Chem., 1965,
43, 2251.
4. V. M. Zhulin, Z. G. Makarova, E. M. Klimov, N. N.
Malysheva, and N. K. Kochetkov, Dokl. Akad. Nauk SSSR,
1989, 309, 641 [Dokl. Chem.].
5g•HCl, δ: 2.35 (s, 3 H, CH3); 3.00—3.50 (m, 4 H,
CH2CH2); 5.80 (s, 1 H, CH—N+H2); 7.00—7.55 (m, 8 H,
Harom); 10.20 (br.s, 2 H, N+H2); 10.80 (s, 1 H, NH).
5h•HCl, δ: 2.40 (s, 3 H, CH3); 3.00—3.50 (m, 4 H,
CH2CH2); 5.80 (s, 1 H, CH—N+H2); 7.00—7.50 (m, 8 H,
H
arom); 10.00 (br.s, 2 H, N+H2); 10.75 (s, 1 H, NH).
5i•HCl, δ: 3.00—3.50 (m, 4 H, CH2CH2); 5.90 (s, 1 H,
CH—N+H2); 6.10 (s, 2 H, OCH2O); 7.00—7.50 (m, 7 H,
Harom); 10.20 (br.s, 2 H, N+H2); 10.80 (s, 1 H, NH).
5j•HCl, δ: 3.00—3.50 (m, 4 H, CH2CH2); 3.90 (s, 3 H,
OCH3); 5.90 (s, 1 H, CH—N+H2); 7.00—7.60 (m, 8 H, Harom);
10.10 (br.s, 2 H, N+H2); 10.90 (s, 1 H, NH).
Received September 29, 2000;
in revised form November 16, 2000