Diastereoselective synthesis of 1,1-disubstituted 4-phenyl-2,3,4,9- tetrahydrospiro-β-carbolines from β-phenyltryptamine and isatin derivatives

Article abstract of DOI:10.1007/s11172-005-0345-x

The reaction of β-phenyltryptamine with isatin derivatives is diastereoselective (de 66-88%) and affords earlier unknown 1,1-disubstituted 4-phenyl-2,3,4,9-tetrahydrospiro-β-carbolines based on phenyltryptamine and isatins. The study by NMR (NOESY) spectr

Full text of DOI:10.1007/s11172-005-0345-x

988
Russian Chemical Bulletin, International Edition, Vol. 54, No. 4, pp. 988—991, April, 2005
Diastereoselective synthesis of 1,1ꢀdisubstituted
4
ꢀphenylꢀ2,3,4,9ꢀtetrahydrospiroꢀβꢀcarbolines
from βꢀphenyltryptamine and isatin derivatives
B. B. Semenov,aꢀ K. A. Novikov, V. N. Azev, and V. V. Kachala
a
b
c
aD. I. Mendeleev University of Chemical Technology,
9
Miusskaya pl., 125047 Moscow, Russian Federation.
Fax: +7 (095) 200 4204. Eꢀmail: semenovb@mail.ru
b
Tufts University,
6
2 Talbot Ave., 02155 Medford, USA.
Eꢀmail: vazev02@tufts.edu
c
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
4
7 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. Eꢀmail: kachala@ioc.ac.ru
The reaction of βꢀphenyltryptamine with isatin derivatives is diastereoselective (de 66—88%)
and affords earlier unknown 1,1ꢀdisubstituted 4ꢀphenylꢀ2,3,4,9ꢀtetrahydrospiroꢀβꢀcarbolines
based on phenyltryptamine and isatins. The study by NMR (NOESY) spectroscopy showed the
(
R*,R*)ꢀconfiguration of the predominant diastereomers of the resulting 2,3,4,9ꢀtetraꢀ
hydrospiroꢀβꢀcarbolines.
Key words: βꢀcarbolines, 2,3,4,9ꢀtetrahydrospiroꢀβꢀphenyltryptamine, Piktet—Spengler
reaction, diastereoselective synthesis, NMR spectroscopy.
1
The Piktet—Spengler reaction is widely used for the
posed that the reaction involves the indole bicycle beꢀ
cause of its πꢀexcessive character.
syntheses (including diastereoselective synthesis) of variꢀ
ous 2,3,4,9ꢀtetrahydrospiroꢀβꢀcarboline derivatives. As the
most close analogies, we should mention the synthesis of
A mechanism of the Piktet—Spengler reaction includꢀ
ing the formation of the spiro[3Hꢀindoleꢀ3.3´ꢀpyrrolidine]
followed by its rearrangement to 2,3,4,9ꢀtetrahydrospiroꢀ
2
,3,4,9ꢀtetrahydrospiroꢀβꢀcarbolines with substituents at
1
,13,14
the C(4) atom, 4ꢀphenylꢀsubstituted 2,3,4,9ꢀtetrahydroꢀ
spiroꢀβꢀcarbolines containing no substituents at the C(1)
and C(3) atoms,2 1,1,3,4ꢀtetrasubstituted βꢀcarbolines
with a phenyl group at the C(4) atom, and 4ꢀphenylꢀ
substituted 2,3,4,9ꢀtetrahydrospiroꢀβꢀcarboline derivaꢀ
βꢀcarboline has previously
been proposed. Thereꢀ
fore, we expected the interaction to involve similar interꢀ
—5
15
mediate 3 (see Scheme 1). It is known that diastereoꢀ
6
selectivity of the reaction is determined by stereoelectronic
and spatial factors. According to this, the intermediates
in the pyrrolidine ring of intermediate 3 should be reꢀ
mote from each other at a maximum distance. Similar
factors induce, most likely, the predominant formation of
(R*,R*)ꢀ1,1ꢀdisubstituted 4ꢀphenylꢀ2,3,4,9ꢀtetrahydroꢀ
spiroꢀβꢀcarbolines 4 by the rearrangement of intermediꢀ
ate 3 to the 2,3,4,9ꢀtetrahydrospiroꢀβꢀcarboline system.
The structures of the compounds were confirmed by
7
tives containing no substituents at the C(1) atom.
8
,9
We have previously found high diastereoselectivity in
the Michael reaction of αꢀphenylꢀnorꢀgramine with cyclic
ketones and acetoacetic ester. Continuing these studies,
we studied the diastereoselectivity of the Piktet—Spengler
reaction10 using the reactions between racemic βꢀphenylꢀ
tryptamine (1) and substituted isatins (Scheme 1) as an
example. We obtained earlier unknown 1,1ꢀdisubstituted
1
13
1D and 2D NMR spectroscopy. The H and С NMR
spectra contained two sets of signals with different intenꢀ
sities corresponding to two diastereomers 4 and 5. The
signals were assigned by an analysis of the 2D COSY,
TOCSY, HSQC, and HMBC spectra (Fig. 1). The ratio
of diastereomers was determined by a comparison of the
integral intensities of the signals of the H(3a), H(3), and
4
ꢀphenylꢀβꢀcarbolines 3 and 4.
Taking into account the structure of tryptamine 1,
only two different routes of the Piktet—Spengler reaction
can be proposed : the route involving tryptamine 1 at the
phenyl ring to form tetrahydroquinoline and the route at
the pyrrole ring of indole to form 2,3,4,9ꢀtetrahydrospiroꢀ
βꢀcarboline.7 Based on the published data, we supꢀ
1
0
,11
12
1
H(4) protons in the H NMR spectra of the resulting
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 964—967, April, 2005.
066ꢀ5285/05/5404ꢀ0988 © 2005 Springer Science+Business Media, Inc.
1

1
,1ꢀDisubstituted tetrahydrospiroꢀβꢀcarbolines
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 4, April, 2005
989
Scheme 1
2
, 3: R = H (a), 5ꢀBr (b), 5,7ꢀBr2 (c), 5ꢀNO2 (d); 4, 5: R = H (a), 9ꢀBr (b), 9,11ꢀBr2 (c), 9ꢀNO2 (d)
Table 1. Diastereoselectivity of the reactions affording pairs of
diastereomers of compounds 4a—d and 5а—d
δ
8
/3a
14/3a
ꢀ
Diastereomers of compounds 4 and 5
de (%)
3
.1
.3
.5
.7
(1R*,4R*)ꢀ4a : (1S*,4R*)ꢀ5a
88
72
72
66
3
3
3
(1R*,4R*)ꢀ4b : (1S*,4R*)ꢀ5b
(
(
1R*,4R*)ꢀ4c : (1S*,4R*)ꢀ5c
1R*,4R*)ꢀ4d : (1S*,4R*)ꢀ5d
8
/3b
ꢀ
In all cases, the (1R*,4R*)ꢀdiastereomer of 4 predominates.
1
4/3a
8
.1
7.9
7.7
7.5
δ
orthoꢀprotons of the phenyl ring (H(14)) and of the H(3b)
proton with the H(8) proton, which indicates unambiguꢀ
ously the transꢀarrangement of substituents at the C(1)
and C(4) atoms. For the minor 1R*,4S*ꢀisomers, the charꢀ
acteristic correlations of the H(3a) proton with the
orthoꢀprotons of the phenyl group (H(14)) and with
the H(8) proton were detected, which evidenced for the
cisꢀarrangement of the substituents at the C(1) and C(4)
atoms.
It should be noted that the signals of protons at
the N(2) atom are strongly broadened and, hence, they
give no correlation peaks and bear no structural inforꢀ
mation.
Fig. 1. Fragment of the NOESY spectrum of compounds 4d
and 5d (the signals of the 1R*,4R*ꢀisomer are shown in bold type
and underlined).
compounds. The corresponding diastereoselectivities of
the reactions are given in Table 1. The chemical shifts of
signals in the H and С NMR spectra of the compounds
under study are presented in Tables 2 and 3, respectively.
The spatial structure of each diastereomer was proved by
1
13
2
D NOESY spectroscopy, revealing closely arranged proꢀ
tons (the correlations are shown by arrows in Scheme 1).
In both cases, the configurations were assigned using
the correlation between the H(4) and H(3a) protons,
which indicated their cisꢀarrangement ("at one side" of
the cycle).
The method proposed in this work enables one to
obtain a diastereomeric excess of R*,R*ꢀdiastereomers of
1,1,4ꢀtrisubstituted 2,3,4,9ꢀtetrahydrospiroꢀβꢀcarbolines
by the Piktet—Spengler reaction of βꢀphenyltryptamine
with substituted isatins.
For the prevailing 1R*,4R*ꢀisomers, the NOESY specꢀ
tra exhibited correlations of the H(3a) proton with the

990
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 4, April, 2005
Semenov et al.
1
Table 2. Chemical shifts of the signals in the H NMR spectra (δ) of compounds 4 and 5
Proꢀ
ton
δ
(
1R*,4R*)ꢀ4a (1S*,4R*)ꢀ5a (1R*,4R*)ꢀ4b (1S*,4R*)ꢀ5b (1R*,4R*)ꢀ4c (1S*,4R*)ꢀ5c (1R*,4R*)ꢀ4d (1S*,4R*)ꢀ5d
3
3
4
5
8
9
1
1
1
1
1
1
2
2
2
2
a
b
4.13
3.79
4.80
11.31
7.45
7.13
7.52
7.16
7.41
7.40
7.33
10.97
6.58
6.77
7.03
7.25
3.44
3.98
4.68
11.28
7.43
7.15
7.46
7.20
7.40
7.40
7.34
11.08
6.70
6.82
7.08
7.28
3.88
3.97
4.57
11.14
7.47
—
7.62
7.04
7.38
7.38
7.31
10.88
6.59
6.76
7.01
7.23
3.16
3.63
4.40
11.02
7.36
—
7.54
6.98
7.38
7.38
7.31
10.91
6.83
6.83
7.04
7.23
3.63
3.37
4.37
11.08
7.33
—
3.03
4.02
4.29
10.99
7.28
—
3.71
3.41
4.45
11.41
8.06
—
8.33
7.21
7.35
7.35
7.28
10.76
6.60
6.75
6.98
7.18
3.06
4.03
4.34
11.25
7.91
—
8.29
7.18
7.35
7.35
7.26
10.81
6.95
6.85
7.03
7.20
0
1
4
5
6
7
1
2
3
4
7.75
—
7.73
—
7.33
7.32
7.25
10.76
6.62
6.73
6.97
7.20
7.33
7.32
7.25
10.81
6.93
6.82
7.03
7.21
Table 3. Chemical shifts of the signals in the 13С NMR spectra (δ) of compounds 4 and 5
Atom
C
δ
(
1R*,4R*)ꢀ4a (1S*,4R*)ꢀ5a (1R*,4R*)ꢀ4b (1S*,4R*)ꢀ5b (1R*,4R*)ꢀ4c (1S*,4R*)ꢀ5c (1R*,4R*)ꢀ4d (1S*,4R*)ꢀ5d
1
3
4
6
7
8
9
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
59.7
45.2
37.1
60.3
46.8
37.2
60.2
46.2
38.3
61.3
47.3
38.3
61.9
47.8
39.8
62.2
47.4
38.5
60.4
47.5
39.4
60.9
47.5
38.1
172.6
124.9
126.2
122.8
131.7
111.2
143.1
140.7
128.7
128.5
127.5
127.5
112.0
125.0
119.2
119.0
122.2
111.7
136.8
170.9
126.6
125.7
122.7
131.2
111.6
142.7
140.3
128.6
128.5
127.2
127.6
111.9
125.1
119.1
119.0
122.2
111.7
136.8
174.3
130.2
128.3
114.0
133.6
112.7
142.3
141.9
128.6
128.4
127.1
128.6
112.5
125.2
119.1
118.9
121.9
111.6
136.6
173.1
132.4
128.3
114.0
132.7
112.5
142.0
141.7
128.6
128.4
126.5
128.6
112.0
125.5
118.8
118.8
121.7
111.5
136.6
177.1
134.8
126.2
114.0
134.1
103.4
141.8
143.1
128.3
128.2
126.8
131.0
113.9
125.6
119.0
118.5
121.4
111.4
136.4
175.0
135.9
126.1
113.9
133.9
103.5
141.8
144.3
128.2
128.2
126.5
131.3
113.8
125.5
118.6
118.5
121.5
111.4
136.4
177.3
131.4
120.6
142.3
126.9
110.4
149.3
142.8
128.2
128.2
126.5
132.2
113.3
125.5
119.0
118.5
121.4
111.3
136.4
178.4
133.1
119.8
142.2
126.5
110.3
149.3
144.2
128.1
128.2
126.1
130.6
112.4
125.8
118.6
118.5
121.4
111.3
136.4
0
1
2
3
4
5
6
8
9
0
1
2
3
4
5
Experimental
βꢀPhenyltryptamine (1). Freshly prepared Raney nickel (1 g)
was added to a solution of 3ꢀ(2ꢀnitroꢀ1ꢀethylphenyl)indole
1
6
NMR spectra were recorded on a Bruker DRXꢀ500 specꢀ
(26.6 g, 0.1 mol) in 94% EtOH (100 mL), and then hydrazine
hydrate (50 mL, 1 mol) was added dropwise. The reaction mixꢀ
ture was refluxed for 60 h; if reflux was interrupted, a new
portion of the catalyst (1 g) was added. After the reaction mixꢀ
ture was cooled, and the catalyst was filtered off and washed
with hot EtOH (3×10 mL). The filtrate was concentrated to
1
13
trometer ( H, 500.13; C, 125.76 MHz) in DMSOꢀd at 30 °C
6
using Me Si as an internal standard. 2D HSQC and HMBC
4
spectra were obtained using a gradient procedure. Mass spectra
EI, 70 eV) were measured on a Finnigan MAT SSQꢀ710 specꢀ
trometer.
(

1
,1ꢀDisubstituted tetrahydrospiroꢀβꢀcarbolines
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 4, April, 2005
991
dryness. The residue was dissolved in anhydrous Et O, and exꢀ
C, 55.09; H, 3.27; N, 8.03 (base). Mass spectrum, m/z (I (%)):
523 [M] (15).
2
rel
+
cess saturated solution of HCl in Et O was added to the resulting
2
solution. The hydrochloride formed was filtered off, suspended
(R*,R*)ꢀ and (R*,S*)ꢀ5´ꢀNitroꢀ4ꢀphenylꢀ2,3,4,9ꢀtetraꢀ
hydrospiro[βꢀcarbolineꢀ1,3´ꢀindol]ꢀ2´(1´H )ꢀone sulfates 4d
and 5d. The yield was 0.8 g (39%), m.p. 246 °C. Found (%):
C, 70.59; H, 4.53; N, 13.55 (base). C H N O . Calculated (%):
in Et O, and shaken with excess 20% solution of KOH. The
2
ethereal extract was dried with MgSO , and the solvent was
4
evaporated. Compound 1 was obtained in 90% yield (21 g), m.p.
24
18
4
3
1
31—132 °С (cf. Ref. 16: m.p. 131—132 °С (AcOEt)).
ꢀBromoindoleꢀ2,3(1H )ꢀdione (2b) was obtained by a previꢀ
C, 70.23; H, 4.42; N, 13.65 (base). Mass spectrum, m/z (I (%)):
410 [M] (15).
rel
+
5
1
7a
ously described procedure.
,7ꢀDibromoindoleꢀ2,3(1H )ꢀdione (2c). Molecular bromine
5
References
(
(
40 g, 0.5 mol) was added dropwise to a mixture of isatin 2a
30 g, 0.2 mol) and concentrated H SO (80 mL) at a temperaꢀ
2
4
1
2
. E. D. Cox and J. M. Cook, Chem. Rev., 1995, 95, 1797.
. A. van Loevezijn, J. D. Allen, A. H. Schinkel, and G. J.
Koomen, Bioorg. Med. Chem. Lett., 2001, 11, 29.
ture below 0 °С with vigorous stirring. The reaction mixture was
stored for 1 h at this temperature. After the mixture was warmed
to room temperature, it was left to stand for 16 h. Molecular
bromine (40 g, 0.5 mol) and AcOH (300 mL) were added to the
mixture, and the solution was refluxed until the bromine color
disappeared. The mixture was poured onto ice, and the precipiꢀ
tate formed was filtered off and washed with an aqueous solution
of K CO and water to the neutral reaction in the filtrate. Comꢀ
3
4
5
6
. H. Wang and A. Ganesan, Org. Lett., 1999, 1, 1647.
. L. Yang, Tetrahedron Lett., 2000, 41, 6981.
. K. Kaljuste and A. Unden, Tetrahedron Lett., 1995, 36, 9211.
. T. Nagy, L. Jeannin, J. Sapi, J. Y. Laronze, P. Renard,
B. Pfeiffer, and J. G. BizotꢀEspiard, Eur. J. Med. Chem.,
2
3
1
995, 30, 575.
. J. Lehmann, N. Jiang, and A. Behncke, Arch. Pharm., 1993,
26, 813.
pound 2c was obtained in 95% yield (59 g), m.p. 253 °С (cf.
Ref. 17a: m.p. 252 °С).
7
3
5
ꢀNitroindoleꢀ2,3(1H )ꢀdione was synthesized by a known
procedure.1
7b
8. B. B. Semenov, Yu. I. Smushkevich, G. V. Grintselevꢀ
Knyazev, and M. Yu. Antipin, Izv. Akad. Nauk, Ser. Khim.,
Compounds 4 and 5 (general procedure). Concentrated H SO4
2
2
001, 543 [Russ. Chem. Bull., Int. Ed., 2001, 50, 570].
(
1 g) was added to a mixture of βꢀphenyltryptamine 1 (5 mmol)
9
. B. B. Semenov, Yu. I. Smushkevich, I. I. Levina, L. N.
Kurkovskaya, K. A. Lyssenko, and V. V. Kachala, Khim.
Geterotsikl. Soedin., 2005, No. 5 [Chem. Heterocycl. Compd.,
and the corresponding isatin 2 (5 mmol) in water (40 mL). The
reaction mixture was refluxed for 50 h and cooled. A precipitate
of 2,3,4,9ꢀtetrahydrospiroꢀβꢀcarboline sulfates was filtered off
and triply washed with boiling isopropyl alcohol. The bases were
obtained by suspending the corresponding sulfates in excess aqueꢀ
ous 10% solution of K CO .
2
005, No. 5 (Engl. Transl.)].
1
1
0. A. Piktet and T. Spengler, Ber., 1911, 44, 2030.
1. B. E. Maryanoff, D. F. Mccomsey, and B. A. Duhlꢀ
Emswiler, J. Org. Chem., 1983, 48, 5062.
2
3
(
R*,R*)ꢀ and (R*,S*)ꢀ4ꢀPhenylꢀ2,3,4,9ꢀtetrahydroꢀ
1
1
1
2. Organic Reaction, New York, 1951, Vol. 6.
3. T. Hino and M. Nakagawa, Heterocycles, 1997, 46, 673.
4. K. Tanaka, Y. Mori, and K. Narasaka, Chem. Lett., 2004,
spiro[βꢀcarbolineꢀ1,3´ꢀindol]ꢀ2´(1´H )ꢀone sulfates 4а and 5а.
The yield was 0.83 g (46%), m.p. >300 °C. Found (%): C, 79.23;
H, 5.40; N, 11.45 (base). C H N O. Calculated (%): C, 78.88;
H, 5.24; N, 11.50 (base). Mass spectrum, m/z (I (%)):
3
2
4
19
3
3
3, 26.
15. M.
Verlagsgesellschaft, Weinheim, 1987.
rel
+
Nogradi,
Stereoselective
Synthesis,
VCH
65 [M] (10).
(
R*,R*)ꢀ and (R*,S*)ꢀ5´ꢀBromoꢀ4ꢀphenylꢀ2,3,4,9ꢀtetraꢀ
1
6. E. P. Styngach, K. I. Kuchkova, and T. M. Efremova, Khim.
Geterotsikl. Soedin., 1973, 1523 [Chem. Heterocycl. Compd.,
hydrospiro[βꢀcarbolineꢀ1,3´ꢀindol]ꢀ2´(1´H )ꢀone sulfates 4b
and 5b. The yield was 1.33 g (60%), m.p. 263 °C (with decomp.).
Found (%): C, 64.99; H, 4.20; N, 9.30 (base). C H BrN O.
Calculated (%): C, 64.88; H, 4.08; N, 9.46 (base). Mass specꢀ
trum, m/z (Irel (%)): 444 [M]+ (15).
1
973 (Engl. Transl.)].
2
4
18
3
1
7. G. I. Zhungietu, Izatin i ego proizvodnye [Isatine and Its
Derivatives], Shtiintsa, Kishinev, 1977, (a) p. 54; (b) p. 67
(
in Russian).
(
R*,R*)ꢀ and (R*,S*)ꢀ5´,7´ꢀDibromoꢀ4ꢀphenylꢀ2,3,4,9ꢀ
tetrahydrospiro[βꢀcarbolineꢀ1,3´ꢀindol]ꢀ2´(1´H )ꢀone sulfates 4c
and 5c. The yield was 1.98 g (76%), m.p. >300 °C. Found (%):
C, 55.29; H, 3.3; N, 7.89 (base). C H Br N O. Calculated (%):
Received April 15, 2004;
in revised form March 31, 2005
24
17
2
3