One-step synthesis of 2-indolylalkylamines

Article abstract of DOI:10.1007/s11172-008-0307-1

An efficient one-step synthesis of 2-indolylalkylamines was proposed. The synthesis involves the Fischer reaction of phenylhydrazine with cyclic imines containing a CH₂ group in the α-position or with amino ketones containing two CH₂ groups in the α-position with respect to the C=O group.

Full text of DOI:10.1007/s11172-008-0307-1

Russian Chemical Bulletin, International Edition, Vol. 57, No. 10, pp. 2220—2222, October, 2008
2220
Oneꢀstep synthesis of 2ꢀindolylalkylamines*
E. S. Balenkova, E. P. Zakurdaev, and V. G. Nenajdenko
Department of Chemistry, M. V. Lomonosov Moscow State University,
1 Leninskie Gory, 119992 Moscow, Russian Federation.
Fax: +7 (495) 932 8846. Eꢀmail: nen@acylium.chem.msu.ru
An efficient oneꢀstep synthesis of 2ꢀindolylalkylamines was proposed. The synthesis
involves the Fischer reaction of phenylhydrazine with cyclic imines containing a CH2 group in
the αꢀposition or with amino ketones containing two CH2 groups in the αꢀposition with respect
to the C=O group.
Key words: indole, the Fischer reaction, cyclic imines, regiochemistry, indolylalkylamines.
the indolization pathway, we employed cyclic imine 1
and amino ketones 2a and 2b. A reaction of imine 1 with
phenylhydrazine afforded compound 3, which is a first
representative of a novel class of 3ꢀarylisohomotryptamines.
A thorough examination of the reaction products revealed
no formation of the second isomer.
Heterocyclic compounds containing an aminoalkyl
fragment occupy a special place among aromatic comꢀ
pounds because of a variety of their biological activity.
Indolylalkylamines are the most striking examples. They
are an essential part of most known indole alkaloids and
are components of many biologically active substances
and drugs.1,2 Among these compounds, 2ꢀsubstituted
3ꢀindolylalkylamines (tryptamines) attract much attenꢀ
tion because they are highly selective toward serotonin
and melatonin receptors and receptors controlling the
secretion of gonadotropin.3—5 The most convenient routes
to indolylalkylamines include the Fischer,6 Grandberg,7
and Japp—Klingemann reactions.8 In recent years, the
synthetic scope of the Fischer reaction for five—sevenꢀ
membered cyclic imines and their synthetic acyclic
analogs (amino ketones) has been extensively studied.
This approach can be effected in one step without using
protecting groups.9—11
In contrast to 3ꢀindolylalkylamines, which can be synꢀ
thesized in wellꢀdeveloped ways, 2ꢀindolylalkylamines
(isotryptamines) are studied much more poorly for lack of
accessible synthetic methods. Acylamides of 2ꢀindolylꢀ
alkylamines (isomelatonins) have been obtained in many
steps by acylation of prepared isotryptamines.12 For the
synthesis of these compounds, we successfully used the
Fischer reaction of arylhydrazines with amido ketones.13
Here we proposed a oneꢀstep synthesis of 3ꢀsubstiꢀ
tuted 2ꢀindolylalkylamines from cyclic imines containing
a CH2 group bound to the N atom or from amino ketones
containing two CH2 groups in the αꢀposition with respect
to the carbonyl group.13 According to the concept of the
mechanism of the Fischer rearrangement, cyclization of
the above compounds can follow two pathways. To study
As with cyclic imine 1, reactions of aminohexanones
2a and 2b with phenylhydrazine mainly involve the shorter
aliphatic chain, so we obtained for the first time isoꢀ
homotryptamines 4a and 4b. A 1H NMR study of the
reaction mixture revealed the formation of isomeric
dihomotryptamines 5a and 5b as minor products. The
ratios of the products 4a : 5a and 4b : 5b are 17 : 1 and
5 : 1, respectively. The higher selectivity of the Fischer
reaction in the former case can be attributed to conjugaꢀ
tion of the double bond of intermediate ene hydrazine
with the aromatic ring in the context of the Fischer reacꢀ
tion mechanism.
To sum up, we developed an efficient oneꢀstep method
for the synthesis of not easily accessible 2ꢀindolylꢀ
alkylamines via the Fischer reaction of cyclic imines (or
amino ketones) containing a CH2 group in the αꢀposition
with respect to the imino (or carbonyl) group.
* Dedicated to Academician B. A. Trofimov on the occasion of
his 70th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2178—2180, October, 2008.
1066ꢀ5285/08/5710ꢀ2220 © 2008 Springer Science+Business Media, Inc.

Oneꢀstep synthesis of 2ꢀindolylalkylamines
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 10, October, 2008
2221
3ꢀ(3ꢀPhenylꢀ1Hꢀindolꢀ2ꢀyl)propylamine hydrochloride (3).
A twoꢀneck 250ꢀmL flask fitted with a Würtz adapter, a reflux
condenser, and a dropping funnel was charged with phenylꢀ
hydrazine hydrochloride (1.45 g, 10 mmol) and 2ꢀbenzylꢀ
4,5ꢀdihydroꢀ2Hꢀpyrrole (1.59 g, 10 mmol) in 5 M HCl (20 mL).
The reaction mixture was heated on an air bath until a puddingꢀ
like mass formed, while preventing the latter from complete
drying. Then water was added through the dropping funnel at
such a rate as to maintain the mixture equally viscous throughꢀ
out the reaction time (monitoring by TLC, CH3CN—25% NH3
(100 : 5) as an eluent). The mixture was evaporated to dryness,
diluted with water (10 mL), evaporated again, and recrystallized
from a mixture of ethanol (1 mL) and water (4 mL). On cooling,
the precipitate that formed was filtered off and washed with
methanol—ether (1 : 10, 2×5 mL). The yield of hydrochloride 3
was 2.2 g (81%), m.p. 244—245 °C. 1H NMR (DMSOꢀd6), δ:
1.96—2.04 (m, 2 H, CH2—CH2—CH2—NH3+), 2.73—2.81 (m,
2 H, CH2—CH2—CH2—NH3+), 2.88 (t, 2 H,—CH2—CH2—
CH2—NH3+, J = 7.8 Hz), 6.96—7.50 (m, 9 H, CHAr), 8.12 (br.s,
3 H, NH3+), 11.39 (br.s, 1 H, NHInd). 13C NMR (DMSOꢀd6),
δ: 23.1 (CH2—CH2—CH2—NH3+), 27.3 (CH2—CH2—CH2—
NH3+), 38.8 (CH2—CH2—CH2—NH3+), 111.0 (CInd(3)),
112.7 (CHInd(7)), 117.9 (CHInd(4)), 119.2 (CHInd(5)), 120.9
(CHInd(6)), 125.5 (CPh(1)), 127.0 (CHPh(2) and CHPh(6)), 128.6
(CHPh(4)), 128.9 (CHPh(3) and CHPh(5)), 135.1 (CInd(3a)), 135.2
(CInd(7a)), 135.4 (CInd(2)). Found (%): C, 70.88; H, 6.41.
C17H19ClN2. Calculated (%): C, 71.19; H, 6.68.
2ꢀIndolylalkylamines 4a,b. Phenylhydrazine (1.08 g, 10 mmol)
was mixed with amino ketone hydrochloride 2a,b (10 mmol)
in glacial acetic acid (15 mL) and refluxed with conc. HCl
(1.5 mL) until the reaction was completed (monitoring by TLC,
CH3CN—25% NH3 (100 : 5) as an eluent). The mixture was
evaporated to dryness, dissolved in water (15 mL), and alkalified
with 50% KOH to pH 10. The product was extracted with CH2Cl2
(2×20 mL). The combined extracts were washed with warm
water (2×40 mL), dried with Na2SO4, concentrated, and disꢀ
solved in methanol (5 mL). A solution of oxalic acid dihydrate
(1 equiv.) in hot methanol (5 mL) was added. If no precipitation
occurred in 5 min, then the solution was heated to boiling,
concentrated by half, and cooled to room temperature. After
20 min, ether (30 mL) was added. The precipitate was filtered
off and washed successively with acetone (15 mL), ether—methaꢀ
nol (9 : 1, 2×10 mL), and ether. The filter cake was dried.
R = Ph(a), R = Me(b)
Experimental
1H and 13C NMR spectra were recorded on a Varian VXRꢀ400
spectrometer (400 and 100 MHz, respectively) in DMSOꢀd6
with Me4Si as the internal standard. TLC analysis was carried
out on Silufol UVꢀ254 plates (spots were visualized with an
acidified solution of KMnO4, with a solution of ninhydrin in
butanol, with the iodine vapor, and under UV light). Comꢀ
pounds 2a,b were prepared as described earlier.10
7ꢀAminoꢀ1ꢀphenylheptanꢀ2ꢀone hydrochloride (2a). Yield
80%, m.p. 144—147 °C. 1H NMR (D2O), δ: 1.22—1.38 (m, 2 H,
O=C—CH2—CH2—CH2—CH2—CH2—NH3+), 1.53—1.67 (m,
+
4 H, O=C—CH2—CH2—CH2—CH2—CH2—NH3 ), 2.54—
2.64 (m, 2 H, O=C—CH2—CH2—CH2—CH2—CH2—NH3+),
2.92—3.0 (m, 2 H, O=C—CH2—CH2—CH2—(CH2)2—NH3+),
3.84 (s, 2 H, PhCH2), 7.21 (d, 2 H, oꢀHPh, J = 7.1 Hz),
7.32—7.40 (m, 3 H, mꢀ and pꢀHPh). 13C NMR (D2O), δ:
23.9 (O=C—CH2—CH2—CH2—CH2—CH2—NH3+), 26.3
(O=C—CH2—CH2—CH2—CH2—CH2—NH3+), 27.7 (O=C—
CH2—CH2—CH2—CH2—CH2—NH3+), 40.5 (O=C—CH2—
CH2—CH2—CH2—CH2—NH3+), 42.9 (O=C—CH2—CH2—
CH2—CH2—CH2—NH3+), 50.3 (PhCH2), 128.4 (pꢀCHPh),
130.1 (mꢀCHPh), 130.9 (oꢀCHPh), 135.5 (ipsoꢀCPh(1), 216.4
(C=O). Found (%): C, 64.25; H, 8.65. C13H20ClNO. Calcuꢀ
lated (%): C, 64.59; H, 8.34.
5ꢀ(3ꢀPhenylꢀ1Hꢀindolꢀ2ꢀyl)pentylammonium
oxalate
monohydrate (4a). Yield 83%, m.p. 124—125 °C. 1H NMR
(DMSOꢀd6), δ: 1.31—1.35 (m, 2 H, —CH2—CH2—CH2—
CH2—CH2—NH3+), 1.52—1.62 (m, 2 H, CH2—CH2—CH2—
CH2—NH3+), 1.67—1.75 (m,
2
H, CH2—CH2—CH2—
H, CH2—CH2—
8ꢀAminooctanꢀ3ꢀone hydrochloride (2b). Yield 84%, m.p. 113—
115 °C. 1H NMR (D2O), δ: 0.98 (t, 3 H, CH3—CH2—C=O,
J = 7 Hz), 1.33—1.38 (m, 2 H, O=C—CH2—CH2—CH2—CH2—
CH2—NH3+), 1.53—1.67 (m, 4 H, O=C—CH2—CH2—CH2—
CH2—CH2—NH3+), 2.52—2.58 (m, 4 H, CH3—CH2—C=O,
—CH2—CH2—CH2—CH2—CH2—NH3+), 2.98 (t, 2 H, O=C—
CH2—CH2—CH2—CH2—CH2—NH3+, J = 7.1 Hz). 13C NMR
(D2O), δ: 8.5 (CH3—CH2—C=O), 24.0 (O=C—CH2—CH2—
CH2—CH2—CH2—NH3+), 26.4 (O=C—CH2—CH2—CH2—
CH2—CH2—NH3+), 27.7 (O=C—CH2—CH2—CH2—CH2—
CH2—NH3+), 37.0 (CH3—CH2—C=O), 40.6 (O=C—CH2—
CH2—CH2—CH2—CH2—NH3+), 42.8 (O=C—CH2—CH2—
CH2—CH2—CH2—NH3+), 220.9 (C=O). Found (%): C, 53.61;
H, 10.25. C8H18ClNO. Calculated (%): C, 53.47; H, 10.10.
CH2—CH2—NH3+), 2.75—2.81 (m,
4
CH2—CH2—CH2—NH3+), 6.90—7.45 (m, 9 H, CH arom.),
7.97 (br.s, 3 H, NH3+), 11.21 (br.s, 1 H, NH indole). 13C NMR
(DMSOꢀd6), δ: 25.7 (—CH2—CH2—CH2—CH2—CH2—NH3+),
26.7
(—CH2—CH2—CH2—CH2—CH2—NH3+),
28.7
(CH2—CH2—CH2—CH2—CH2—NH3+), 38.7 (—CH2—
CH2—CH2—CH2—CH2—NH3+), 110.9 (CHInd(7)), 112.4
(CInd(3)), 117.7 (CHInd(5)), 119.0 (CHInd(4)), 120.6
(CHInd(6)), 125.4 (CHPh(4)), 127.0 (CInd(3a)), 128.5
(CHPh(2) and CHPh(6)), 128.9 (CHPh(3) and CHPh(5)),
135.4 (CHPh(1)), 135.5 (CHInd(7a)), 136.3 (CInd(2)), 164.5
(COOH). Found (%): C, 65.49; H, 6.50. C21H26N2O5.
Calculated (%): C, 65.27; H, 6.78.

2222
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 10, October, 2008
Balenkova et al.
5ꢀ(3ꢀMethylꢀ1Hꢀindolꢀ2ꢀyl)pentylammonium
oxalate
5. T. F. Walsh, R. B. Toupence, F. Ujjainwalla, J. R. Young,
M. T. Goulet, Tetrahedron, 2001, 57, 5233.
6. G. W. Gribbe, J. Chem. Soc., Perkin Trans. 1, 2000, 1045.
7. N. M. Przheval´skii, L. Yu. Kostromina, I. I. Grandberg,
Khim. Geterotsikl. Soedin., 1988, 867 [Chem. Heterocycl.
Compd., 1988 (Engl. Transl.)].
8. R. A. Abramovich, J. Chem. Soc., 1956, 4593.
9. E. P. Zakurdaev, V. G. Nenajdenko, E. S. Balenkova,
Izv. Akad. Nauk, Ser. Khim., 2005, 1186 [Russ. Chem. Bull.,
Int. Ed., 2005, 54, 1219.]
10. V. G. Nenajdenko, E. P. Zakurdaev, E. S. Balenkova,
Tetrahedron Lett., 2002, 43, 8449.
11. V. G. Nenajdenko, E. P. Zakurdaev, E. V. Prusov, E. S.
Balenkova, Tetrahedron, 2004, 60/51, 11719.
12. G. Spadoni, C. Balsamini, A. Bedini, G. Diamantini,
B. Di Giacomo, A. Tontini, G. Tarzia, M. Mor, P. V. Plazzi,
S. Rivara, R. Nonno, M. Pannacci, V. Lucini, F. Fraschini,
B. M. Stankov, J. Med. Chem., 1998, 41, 3624.
monohydrate (4b). Yield 70%, m.p. 135—137 °C. 1H NMR
(DMSOꢀd6), δ: 1.29—1.35 (m, 2 H, —CH2—CH2—CH2—
CH2—CH2—NH3+), 1.53—1.66 (m,
4 H, CH2—CH2—
CH2—CH2—CH2—NH3+), 2.15 (s, 3 H, CH3), 2.62—2.77
(m, 4 H, CH2—CH2—CH2—CH2—CH2—NH3+), 6.88—7.40
(m, 4 H, CHInd), 7.91 (br.s, 3 H, NH3+), 10.63 (br.s, 1 H, NH
indole). 13C NMR (DMSOꢀd6), δ: 8.3 (CH3), 25.2 (—CH2—
CH2—CH2—CH2—CH2—NH3+), 25.5 (—CH2—CH2—CH2—
CH2—CH2—NH3+), 26.8 (—CH2—CH2—CH2—CH2—CH2—
NH3+), 28.6 (CH2—CH2—CH2—CH2—CH2—NH3+), 38.8
(—CH2—CH2—CH2—CH2—CH2—NH3+), 104.7 (CInd(3)),
110.3 (CHInd(6)), 117.3 (CInd(3a)), 117.8 (CHInd(4)),
119.8 (CHInd(5)), 128.8 (CHInd(7)), 135.2 (CInd(7a)), 135.5
(CHInd(2)), 164.7 (COOH). Found (%): C, 58.96; H, 7.53.
C16H24N2O5. Calculated (%): C, 59.24; H, 7.46.
References
13. E. P. Zakurdaev, E. S. Balenkova, V. G. Nenajdenko,
Mendeleev Commun., 2006, 213.
1. R. A. Glennon, J. M. Jacyno, R. Young, J. D. McKenney,
D. Nelson, J. Med. Chem., 1984, 27, 41.
2. H. Person, M. D. A. Pardo, A. Founcaud, Tetrahedron Lett.,
1979, 21, 281.
3. G. I. Stevenson, A. L. Smith, S. Lewis, S. G. Michie, J. G.
Neduvelil, S. Patel, R. Marwood, S. Patel, J. L. Castro,
Bioorg. Med. Chem. Lett., 2000, 10, 2697.
4. M. Mor, G. Spadoni, B. D. Giacomo, G. Diamantini,
A. Bedini, G. Tarzia, P. V. Plazzi, S. Rivara, R. Nonno,
V. Lucini, M. Pannacci, F. Fraschini, B. M. Stankov, Bioorg.
Med. Chem., 2001, 9, 1045.
Received July 16, 2008