Diastereodirected synthesis of 1-aryl-4-phenyl-β-carbolines

Article abstract of DOI:10.1007/s10593-005-0313-2

A diastereodirected Pictet-Spengler reaction has been carried out to give the previously unknown 1-aryl(alkyl)-4-phenyl-β-carbolines and it has been found that all of the β-carbolines diastereomers obtained have predominantly the R*,R*-configuration. The

Full text of DOI:10.1007/s10593-005-0313-2

Chemistry of Heterocyclic Compounds, Vol. 41, No. 10, 2005
DIASTEREODIRECTED SYNTHESIS
OF 1-ARYL-4-PHENYL-β-CARBOLINES
1
1
1
2
3
B. B. Semenov , K. A. Novikov , Yu. I. Smushkevich , V. N. Azev , and V. V. Kachala
A diastereodirected Pictet–Spengler reaction has been carried out to give the previously unknown
-aryl(alkyl)-4-phenyl-β-carbolines and it has been found that all of the β-carbolines diastereomers
obtained have predominantly the R*,R*-configuration. The diastereoselectivity of the given reaction is
4-70%.
1
4
Keywords: β-carbolines, β-phenyltryptamine, diastereoselective synthesis, Pictet–Spengler reaction.
We have demonstrated a high diastereoselectivity of α-phenyl-nor-gramine in the Michael reaction with
cyclic ketones and acetoacetic ester [1, 2]. The present work is concerned with a study of the diastereoselectivity
of the reaction of β-phenyltryptamine (1) with aromatic and aliphatic aldehydes (the Pictet–Spengler reaction
[3]).
Two routes are possible for the reaction studied, i.e. at the phenyl ring to give a tetrahydroquinoline [3]
or at the pyrrole ring of the indole to give a β-carboline [4, 5]. We propose that the reaction will involve the
participation of the indole ring as a result of its π-excessive nature. In [4], the synthesis of 1-unsubstituted
4
-phenyl-β-carbolines was described and it was shown that they possess marked biological activity.
The previously proposed mechanism for the Pictet–Spengler reaction includes a stage of formation of a
spiro[3H-indole-3,2'-pyrrolidine] derivative which subsequently rearranges to a β-carboline [6-8]. On this basis
we propose that the reaction in our case using differently structured aldehydes and β-phenyltryptamine as
starting materials occurs via the formation of intermediate 2. It is known that the diastereoselectivity is
determined by stereoelectronic or spatial factors [9]. In this connection, in the intermediate the substituents in
position 2 and 4 of the pyrrolidine ring must be maximally removed from one another, i.e. they have a trans
arrangement. The rearrangement of compound 2 to the β-carboline system is evidently influenced by the same
steric factors to form mainly the (R*,R*)-1-aryl(alkyl)-4-phenyl-β-carbolines 3 (here, and subsequently, the *
indicates the relative configuration).
The structures of the compounds prepared were investigated using one- and two-dimensional NMR
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13
spectroscopy. The H and C NMR one- dimensional spectra show two sets of signals of differing intensity
which correspond to two diastereomers (the signals were assigned by analysing two-dimensional COSY, HSQC,
and HMBC spectra). The spatial structure of each of the diastereomers was revealed using two-dimensional H-H
NOE (NOESY) spectroscopy which allows one to identify the close positioned protons.
We have studied the configuration of both diastereomers in the case of compounds 3a,b. In all of the
compounds studied the H-3 protons have a clear equatorial or axial nature as shown by the shape of the H-3 and
1
H-3a proton signals in the H NMR spectra. This makes easier the identification of the configuration of the
_
_________________________________________________________________________________________
1
D. I. Mendeleev Chemico-Technological University, Moscow 125190; e-mail: semenovb@mail.ru,
2
3
smu@muctr.edu.ru. Tuft University, 02155 Medford, USA. N. D. Zelinsky Institute of Organic Chemistry,
Russian Academy of Sciences, Moscow 119991. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No.
1
0, pp. 1521-1528, October, 2005. Original article submitted March 1, 2004.
0
009-3122/05/4110-1273©2005 Springer Science+Business Media, Inc.
1273

NH2
RCOH
2
H SO4
NH
N
N
R
H
1
2
m
p
–HSO4
–
o
HSO4
4
2
H
3
H
4
''
3'' + N
3a''
+
N
+
2
''
1
H
5
''
H
1
''
6
''
N
R
N
H
7
''
H
R
R*,R*
a–8a
R*,S*
3
3
b–8b
1
'
2'
for R = Ar
3
'
4
'
3
R = Me, 4 R = Ph, 5 R = p-ClС
6
Н
4
, 6 R = p-MeOС
6 4
Н ,
7
R = p-O NС , 8 R = m-O
2
6
Н
4
2
6 4
NС Н
diastereomers. The NOESY spectrum of the minor 1S*,4R*-isomer shows correlations between the 1-CH group
3
protons, (H-1'), and the axial H-3a proton (see Fig. 1).
ppm
2
2
3
3
4
4
5
.0
.5
.0
.5
.0
.5
.0
ppm
Fig. 1. Part of the NOESY spectrum of compounds 3a,b (bold type for the 1R*,4R*-isomer).
1
274

Correlations were also revealed between the phenyl ortho protons, H-4, and both H-3 and H-3a protons.
This supports an equatorial positioning of the phenyl group in the six-membered ring and an axial position for
the methyl group in this ring and is supported by the presence of a correlation between the methyl group protons
and H-3a. Different correlations are found in the main isomer. Hence the ortho protons of the phenyl group have
the same cross peak with the H-3 and H-3a protons but proton H-1 interacts with the axial H-3a proton thus
pointing to an axial positioning in this ring. This fact, and the absence of a correlation between the methyl group
protons and the axial H-3a proton lead us to infer a trans arrangement for the phenyl and methyl groups in the
six-membered ring. In both cases a correlation is observed between the H-4 proton and equatorial H-3e proton. It
should be noted that the signals for the protons on the N-2 atom are strongly broadened hence the correlation of
peaks could not be made and structural information not deduced. Hence the configuration of the pair of
compounds 3a and 3b were established; the first being the 1R*,4R*- and the second the 1S*,4R*-isomer (Fig. 2).
The structure of the remaining compounds was established similarly. In the case of the predominant
1
R*,4R*-isomers the NOESY spectra showed a correlation of the axial H-3a proton with the ortho protons of the
phenyl ring, H-4, and the H-1 proton and this unambiguously points of to a trans arrangement for the
substituents at positions 1 and 4. In the example of the minor 1S*,4R*-diastereomers a characteristic correlation
is seen between H-3a and the ortho protons of the phenyl ring, H-4, and also with the ortho protons (H-1') of the
aryl substituent at C-1. This proves a cis positioning of the substituents at positions 1 and 4. Fig. 3 shows a part
of the NOESY spectrum for compounds 5a,b.
The method proposed by us leads to the preparation of compounds 3-8 with a known diastereomeric
excess of R*,R*-diastereomers and with different substituents in the position 1 of the β-carboline ring.
TABLE 1. Diastereomers Ratio for Compounds 3-8
Diastereomers
de, %*
Diastereomers
de, %*
3
4
5
a (1R*,4R*) : 3b (1S*,4R*)
a (1R*,4R*) : 4b (1S*,4R*)
a (1R*,4R*) : 5b (1S*,4R*)
44
70
62
6a (1R*,4R*) : 6b (1S*,4R*)
7a (1R*,4R*) : 7b (1S*,4R*)
8a (1R*,4R*) : 8b (1S*,4R*)
64
62
56
_
*
______
de denotes the diastereoselectivity of the reaction
Fig. 2. Correlation interactions in compounds 3a,b.
1
275

1
276

1
277

ppm
2
3
4
4
5
5
.8
.4
.0
.6
.2
.8
ppm
Fig. 3. Part of the NOESY spectrum of compounds 5a,b (bold type for the 1R*,4R*-isomer).
EXPERIMENTAL
1
13
H and C NMR spectra were taken on a Bruker DRX-500 instrument (500 and 125 MHz respectively)
using DMSO-d solvent at 30°C using Bruker standard methods. Two-dimensional HSQC and HMBC spectra
6
were obtained using a gradient method. The internal standard was TMS. Mass spectra were recorded on a
Finnigan MAT SSQ-710 spectrometer with an electron ionizing energy of 70 eV.
β-Phenyltryptamine (1). Hydrazine hydrate (75 ml) was added dropwise over 60 h to a mixture of 3-(2-
nitro-1-phenylethyl)indole [10] (26.6 g, 0.1 mol) in 94% alcohol (100 ml) and freshly prepared Raney nickel (1
g) at the temperature of reflux of the mixture. If the reflux stops a further portion of catalyst is added. The
product was filtered and the filtered catalyst was washed with hot alcohol (3 × 10 ml). The filtrate was
evaporated. The residue was dissolved in anhydrous ether and a saturated solution of HCl in ether was added.
The hydrochloride formed was filtered off, suspended in ether, and shaked with an aqueous solution of alkali.
The ether solution was dried over MgSO and evaporated to give 21 g of product (90%) with mp 131-132°C
4
(
mp 131-132°C (ethyl acetate) [10]).
Preparation of Compounds 3-8 (General Method). Conc. H SO (0.5 g) was added to a mixture of
2
4
β-phenyltryptamine (1.18 g, 0.005 mol) and 5% acetaldehyde (37.5 ml, 0.04 mol). The product was refluxed to
the solution of compound 1, cooled, and the precipitated carboline sulphates were filtered off.
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13
H and C NMR spectra are given in Tables 2 and 3.
-Methyl-4-phenyl-2,3,4,9-tetrahydro-β-carboline Sulfate (3). Yield 50%; mp 218°C (sulfate). Mass
1
+
spectrum, m/z (I , %): 262 [M] (10). Found, %: C 82.53; H 7.02; N 10.45 (base). C H N . Calculated, %:
rel
18 18
2
C 82.41; H 6.92; N 10.68 (base).
1
278

1
,4-Diphenyl-2,3,4,9-tetrahydro-β-carboline sulphate (4). Yield 60%; mp 228°C (sulfate). Mass
spectrum, m/z (I , %): 234 [M] (14). Found, %: C 86.13; H 6.72; N 7.15 (base). C H N . Calculated, %:
rel
23 20
2
C 85.15; H 6.21; N 8.63 (base).
1
-(4-Chlorophenyl)-4-phenyl-2,3,4,9-tetrahydro-β-carboline Sulphate (5). Yield 63%; mp 255°C
+
(
sulfate). Mass spectrum, m/z (I , %): 358 [M] (14). Found, %: C 77.33; H 5.81; N 7.75 (base). C H ClN .
rel 23 19 2
Calculated, %: C 76.98; H 5.34; N 7.81 (base).
-(4-Methoxyphenyl)-4-phenyl-2,3,4,9-tetrahydro-β-carboline Sulfate (6). Yield 55%; mp 225°C
1
+
(
sulfate). Mass spectrum, m/z (I , %): 354 [M] (20). Found, %: C 81.83; H 6.81; N 8.00 (base). C H N O.
rel 24 22 2
Calculated, %: C 81.33; H 6.26; N 7.90 (base).
-(4-Nitrophenyl)-4-phenyl-2,3,4,9-tetrahydro-β-carboline Sulfate (7). Yield 80%; mp >260°C
1
+
(
sulfate). Mass spectrum, m/z (I , %): 369 [M] (30). Found, %: C 74.33; H 5.05; N 11.40 (base). C H N O .
rel 23 19 3 2
Calculated, %: C 74.78; H 5.18; N 11.37 (base).
-(3-Nitrophenyl)-4-phenyl-2,3,4,9-tetrahydro-β-carboline Sulfate (8). Yield 76%; mp >260°C
1
+
(
sulfate). Mass spectrum, m/z (I , %): 369 [M] (27). Found, %: C 74.43; H 4.95; N 11.40 (base). C H N O .
rel 23 19 3 2
Calculated, %: C 74.78; H 5.18; N 11.37 (base).
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2
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.
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