Synthesis of α-alkyl- and α,α-dialkyl-β-phenyltryptamines

Article abstract of DOI:10.1023/A:1015050806098

A new method was developed for the synthesis of α-alkyl- and α,α-dialkyl-β-phenyl-tryptamines based on alkylation of nitroalkanes with α-phenyl-nor-gramine.

Full text of DOI:10.1023/A:1015050806098

Russian Chemical Bulletin, International Edition, Vol. 51, No. 1, pp. 185—186, January, 2002
185
Synthesis of αꢀalkylꢀ and α,αꢀdialkylꢀβꢀphenyltryptamines

B. B. Semenov and Yu. I. Smushkevich
Department of Organic Chemistry, D. I. Mendeleev Russian University of Chemical Technology,
9 pl. Miusskaya, Moscow 125047, Russian Federation.
Fax: +7 (095) 200 4204. Eꢀmail: SMU@muchtr.edu.ru, semenovb@mail.ru
A new method was developed for the synthesis of αꢀalkylꢀ and α,αꢀdialkylꢀβꢀphenylꢀ
tryptamines based on alkylation of nitroalkanes with αꢀphenylꢀnorꢀgramine.
Key words: αꢀphenylꢀnorꢀgramine, nitroalkanes, tryptamines.
Scheme 1
The chemistry and pharmacology of tryptamines atꢀ
tract steady interest even within 50 year after the discovꢀ
ery of serotonine (1948).1 Tryptamines possess a broad
spectrum of physiological activities, viz., antitumor,
antiradiation, and psychotropic activities.2 The synthesis
as well as the adrenoblocking and antioxidase activities of
αꢀmethyltryptamine (indopan) have been described in the
literature.3,4 The present study was aimed at developing a
convenient procedure for the synthesis of αꢀalkylꢀ and
α,α´ꢀdialkylꢀβꢀphenyltryptamines, which is necesary for
studying these compounds in more detail.
Several methods for the synthesis of tryptamines are
presently available. These procedures can be arbitrarily
divided into two groups, viz., the formation of the indole
ring starting from compounds containing the ethylamine
chain and the formation of the ethylamine chain based on
compounds of the indole series. We chose the latter alterꢀ
native taking into account that the target compounds can
be prepared from the readily accessible starting compounds
in two steps.
2, 3: R´ = H; R″ = Me (a); R´ = R″ = Me (b);
R´ = H; R″ = Et (c)
In the present study, we describe for the first time
alkylation of nitroalkanes with αꢀphenylꢀnorꢀgramine5 (1)
followed by reduction of the resulting 3ꢀ(2ꢀnitroꢀ1ꢀpheꢀ
nylalkyl)indoles 2 to the corresponding tryptamines 3.
The reactions of compound 1 with nitroethane, 1ꢀnitꢀ
ropropane, and 2ꢀnitropropane in EtOH in the presence
of bases afforded 3ꢀ(2ꢀnitroꢀ1ꢀphenylpropyl)ꢀ1Hꢀindole
(2a), 3ꢀ(2ꢀmethylꢀ2ꢀnitroꢀ1ꢀphenylpropyl)ꢀ1Hꢀindole
(2b), and 3ꢀ(2ꢀnitroꢀ1ꢀphenylbutyl)ꢀ1Hꢀindole (2c), reꢀ
spectively, in good yields. The reactions proceeded, apꢀ
parently, through the formation of 3ꢀ[(Z)ꢀphenylmethylꢀ
idene]ꢀ3Hꢀindole (4) followed by the attack with the poꢀ
tassium salt of the aci form of nitroalkanes 5 (Scheme 1).
We prepared for the first time tryptamines 3a—c in
high yields by reducing compounds 2a—c, respectively,
with hydrazine hydrate in the presence of Raney nickel.
methyl groups in compounds 2b and 3b are magnetically
nonequivalent, their NMR spectra have signals of two
methyl groups. Interestingly, compound 3a is a structural
analog simultaneously of phenamine and indopan.
Experimental
The 1H NMR spectra were recorded on a Bruker WMꢀ250
spectrometer with Me4Si as the internal standard. The mass
spectra (EI) were measured on an SSQꢀ710 (Finnigan MAT)
spectrometer; the energy of ionizing electrons was 70 eV.
Nitroalkanes were purchased from Fluka.
3ꢀ(2ꢀNitroꢀ1ꢀphenylalkyl)indoles 2 (general procedure). A soꢀ
lution of K2CO3 (0.1 g, 0.07 mmol) in H2O (1 mL) and
nitroalkane (0.625 mmol) were added to a boiling solution of
αꢀphenylꢀnorꢀgramine (1) (1.0 g, 0.42 mmol) in 95% EtOH
(10 mL). The reaction mixture was heated at the boiling temꢀ
perature under a stream of an inert gas until the starting comꢀ
1
According to the H NMR spectroscopic data, comꢀ
pounds 2a,c and 3a,c were obtained as mixtures of diasteꢀ
reomers in a ratio of 50 : 50. Since the diastereotopic
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 174—175, January, 2002.
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Russ.Chem.Bull., Int.Ed., Vol. 51, No. 1, January, 2002
Semenov and Smushkevich
pound was consumed. The course of the reaction was monitored
by TLC (Silufol UVꢀ254, the EtOAc—CCl4 system, 1 : 4). The
reaction mixture was cooled to ∼20 °C. The precipitate that
formed was filtered off and recrystallized from 95% EtOH.
3ꢀ(2ꢀNitroꢀ1ꢀphenylpropyl)ꢀ1Hꢀindole (2a). The yield was
63%. M.p. 150.5—151 °C. 1H NMR (CDCl3), δ: 8.18 (br.s, 1 H,
NH); 7.64 (m, 1 H, H(4)Ind); 7.38 (m, 3 H, H(7)Ind, oꢀPh); 7.26
(m, 2 H, mꢀPh); 7.20 (m, 1 H, pꢀPh); 7.13—7.20 (m, 2 H,
H(5)Ind, H(6)Ind); 7.10 (d, 1 H, H(2)Ind, J = 2.1 Hz); 5.44 (dd,
1 H, CHMe, JCH—CH = 10.7 Hz, JCH—Me = 6.4 Hz); 4.77 (d,
1 H, IndCHPh); 1.62 (d, 3 H, Me). MS, m/z (Irel (%)): 280
[M]+ (14), 206 [IndCHPh]+ (100). Found (%): C, 72.64;
H, 5.65; N, 9.81. C17H16N2O2. Calculated (%): C, 72.84;
H, 5.75; N, 9.99.
3ꢀ(2ꢀMethylꢀ2ꢀnitroꢀ1ꢀphenylpropyl)ꢀ1Hꢀindole (2b). The
yield was 69%. M.p. 146—148 °C. 1H NMR (CDCl3), δ: 9.40
(br.s, 1 H, NH); 7.49 (m, 1 H, H(2)Ind); 7.47 (m, 1 H, H(4)Ind);
7.44 (m, 2 H, oꢀPh); 7.39 (m, 1 H, H(7)Ind); 7.3 (m, 3 H, pꢀ and
mꢀPh); 7.11 (m, 1 H, H(6)Ind); 7.00 (m, 1 H, H(5)Ind);
5.16 (s, 1 H, CH); 1.71 (s, 3 H, Me); 1.70 (s, 3 H, Me).
MS, m/z (Irel (%)): 294 [M]+ (34), 206 [IndCHPh]+ (100).
Found (%): C, 73.04; H, 5.94; N, 9.71. C18H18N2O2. Calcuꢀ
lated (%): C, 73.45; H, 6.16; N, 9.52.
3ꢀ(2ꢀNitroꢀ1ꢀphenylbutyl)ꢀ1Hꢀindole (2c). The yield was
60%. Viscous oil. 1H NMR (CD3CN), δ: 9.27—9.35 (m, 1 H,
NH); 7.67—7.00 (m, 10 H, Ph, Ind); 5.38—5.41 (m, 1 H,
CHNO2); 4.76—4.81 (m, 1 H, IndCHPh); 1.66 (m, 2 H, CH2);
0.89—0.91 (m, 3 H, Me, both diastereomers). MS, m/z (Irel (%)):
294 [M]+ (11), 206 [IndCHPh]+ (100). Found (%): C, 73.24;
H, 5.85; N, 10.01. C18H18N2O2. Calculated (%): C, 73.45;
H, 6.16; N, 9.52.
3ꢀ(2ꢀAminoꢀ1ꢀphenylalkyl)indoles 3 (general procedure).
Raney nickel (0.1 g) was added to a solution of compounds
2a—c (0.42 mmol) in 95% EtOH (10 mL). Then a 20% hydraꢀ
zine hydrate solution in ethanol, which was prepared by mixing
hydrazine hydrate (20 g) with 95% EtOH (80 mL), was added
portionwise with intense stirring. The reaction mixture was
heated and then refluxed with stirring under a stream of inert gas
until the starting compound was consumed. The course of
the reaction was monitored by TLC (Silufol UVꢀ254, the
EtOAc—CCl4 system, 1 : 4). The reaction mixture was cooled to
∼20 °C, an insoluble precipitate was filtered off, and the solvent
was distilled off on a rotary evaporator.
CHMe); 0.94—1.05 (both d, 3 H, Me, J = 5.85, both diastereꢀ
omers). MS, m/z (Irel (%)): 250 [M]+ (11). Found (%): C, 81.24;
H, 7.14; N, 10.83. C17H18N2. Calculated (%): C, 81.56;
H, 7.25; N, 11.19.
1ꢀ(1HꢀIndolꢀ3ꢀyl)ꢀ2ꢀmethylꢀ1ꢀphenylꢀ2ꢀpropylamine (3b).
The yield was 90%. M.p. 122—124 °C. 1H NMR (CDCl3), δ:
8.14 (br.s, 1 H, NH); 7.59 (m, 1 H, H(4)Ind); 7.52 (d, 1 H,
H(2)Ind, J = 2.14 Hz); 7.48 (m, 2 H, oꢀPh); 7.30 (m, 1 H,
H(7)Ind); 7.30 (m, 3 H, pꢀ and mꢀPh); 7.14 (m, 1 H, H(6)Ind);
7.06 (m, 1 H, H(5)Ind); 4.26 (s, 1 H, CH); 1.23 (s, 3 H, Me);
1.20 (s, 3 H, Me). 1H NMR (CD3CN), δ: 9.30 (br.s, 1 H, NH);
7.62 (d, 1 H, H(2)Ind, J = 2.1 Hz); 7.57 (m, 1 H, H(4)Ind); 7.53
(m, 2 H, oꢀPh); 7.36 (m, 1 H, H(7)Ind); 7.25 (m, 2 H, mꢀPh);
7.15 (m, 1 H, pꢀPh); 7.08 (m, 1 H, H(6)Ind); 6.99 (m, 1 H,
H(5)Ind); 4.29 (s, 1 H, CH); 1.16 (s, 3 H, Me); 1.13 (s, 3 H,
Me). MS, m/z (Irel (%)): 264 [M]+ (13), 206 [IndCHPh]+ (100).
Found (%): C, 81.54; H, 7.34; N, 10.31. C18H20N2. Calcuꢀ
lated (%): C, 81.78; H, 7.63; N, 10.60.
1ꢀ(1HꢀIndolꢀ3ꢀyl)ꢀ1ꢀphenylꢀbutꢀ2ꢀylamine (3c). The yield
was 90%, m.p. 118—120 °C. 1H NMR (DMFꢀd6), δ: 11.17 (br.s,
1 H, NH); 7.68 (m, 1 H, H(2)Ind); 7.66 (m, 1 H, H(4)Ind); 7.52
(m, 2 H, oꢀPh); 7.49 (m, 1 H, H(7)Ind); 7.29 (m, 2 H, mꢀPh);
7.16 (m, 2 H, pꢀPh); 7.08 (m, 1 H, H(6)Ind); 6.97 (m, 1 H,
H(5)Ind); 4.38 (d, 1 H, IndCHPh, J = 9.9 Hz); 3.88 (m, 1 H,
CHEt); 1.42—1.61 (m, 2 H, CH2); 1.40 (t, 3 H, Me, J = 7.3 Hz).
1H NMR (CD3CN+TFA), δ: 7.68 (m, 1 H, H(4)Ind); 7.48 (m,
1 H, H(2)Ind); 7.48 (m, 2 H, oꢀPh); 7.48 (m, 1 H, H(7)Ind); 7.35
(m, 2 H, mꢀPh); 7.23 (m, 1 H, pꢀPh); 7.19 (m, 1 H, H(6)Ind);
7.10 (m, 1 H, H(5)Ind); 4.47 (d, 1 H, IndCHPh, J = 11.6 Hz);
4.15 (m, 1 H, CHEt); 1.63—1.76 (m, 2 H, CH2); 1.40 (t, 3 H,
Me, J = 7.7 Hz). MS, m/z (Irel (%)): 264 [M]+ (13). Found (%):
C, 81.44; H, 7.27; N, 10.43. C18H20N2. Calculated (%): C, 81.78;
H, 7.63; N, 10.60.
References
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1ꢀ(1HꢀIndolꢀ3ꢀyl)ꢀ1ꢀphenylꢀ2ꢀpropylamine (3a). The yield
was 90%, the compound sublimed without melting. 1H NMR
(DMSOꢀd6), δ: 10.85—10.93 (m, 1 H, NH); 7.53 (m, 1 H,
H(2)Ind); 7.51 (m, 1 H, H(4)Ind); 7.42 (m, 2 H, oꢀPh); 7.40 (m,
1 H, H(7)Ind); 7.26 (m, 2 H, mꢀPh); 7.13 (m, 2 H, pꢀPh); 7.03
(m, 1 H, H(6)Ind); 6.92 (m, 1 H, H(5)Ind); 3.92—3.95 (both d,
1 H, PhCHCHMe, J = 8.77, both diastereomers); 3.72 (m, 1 H,
4. D. Repke and W. Ferguson, J. Heterocycl. Chem., 1976,
13, 775.
5. B. B. Semenov and Yu. I. Smushkevich, Izv. Akad. Nauk, Ser.
Khim., 2001, 521 [Russ. Chem. Bull., Int. Ed., 2001, 50, 543].
Received April 27, 2001;
in revised form July 16, 2001