Efficient one-pot synthesis of tryptamines and tryptamine homologues by amination of chloroalkynes

Article abstract of DOI:10.1016/j.tetlet.2004.02.085

A new method was developed for the one-pot synthesis of substituted 3-(2-aminoethyl)- and 3-(3-aminopropyl)indoles from commercially available aryl hydrazines and chloroalkylalkynes. Various tryptamine derivatives were prepared directly in good yield with excellent regioselectivity. The method involves a new domino reaction sequence consisting of a titanium-catalyzed amination of the chloroalkylalkyne, [3+3]-rearrangement of the resulting aryl hydrazone, and nucleophilic substitution of the chloride by ammonia.

Full text of DOI:10.1016/j.tetlet.2004.02.085

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3123–3126
Efficient one-pot synthesis of tryptamines and tryptamine
homologues by amination of chloroalkynes
Vivek Khedkar, Annegret Tillack, Manfred Michalik and Matthias Beller*
Leibniz-Institut f€ur Organische Katalyse (IfOK) an der Universit€at Rostock e.V.,Buchbinderstr. 5-6,D-18055 Rostock,Germany
Received 30 January 2004;revised 12 February 2004;accepted 17 February 2004
Abstract—A new method was developed for the one-pot synthesis of substituted 3-(2-aminoethyl)- and 3-(3-aminopropyl)indoles
from commercially available aryl hydrazines and chloroalkylalkynes. Various tryptamine derivatives were prepared directly in good
yield with excellent regioselectivity. The method involves a new domino reaction sequence consisting of a titanium-catalyzed
amination of the chloroalkylalkyne, [3þ3]-rearrangement of the resulting aryl hydrazone, and nucleophilic substitution of the
chloride by ammonia.
Ó 2004 Elsevier Ltd. All rights reserved.
There is a continuing interest in the development of new
methods for the synthesis of indoles due to their
importance as building blocks for pharmaceuticals and
natural products.1 Among the numerous indole deriva-
tives with biological activity tryptamine and its deriva-
tives such as the neurotransmitter serotonin, and the
tissue hormone melatonin constitute especially impor-
tant examples (Scheme 1).2
with aldehydes constitutes a two-step procedure, which
sometimes proceeds in low yield. For example, the direct
synthesis of tryptamine-like compounds4 is sometimes
troublesome due to side reactions of the free amino
group with the aldehyde or ketone. Recently, Odom and
co-workers described an interesting new titanium amide-
catalyzed reaction of aryl hydrazines with alkynes.5 The
obtained aryl hydrazones have been further used in the
Fischer indole reaction, which allows for an elegant two-
step (one-pot) synthesis of substituted indoles. Based on
our long standing interest in catalytic hydroamination
reactions of olefins6 and alkynes7 we studied the regio-
selective attack of aryl hydrazines on terminal alkynes
with respect to the catalyst. During these investigations
we discovered a new domino process using 1-chloro-4-
pentyne and N-methyl-N-phenylhydrazine as substrates.
As shown in Scheme 2 and Table 1 the titanium-cata-
lyzed hydroamination of 1-chloro-4-pentyne leads
directly to the hydrochloride salt of N-methyl-2-
methyltryptamine (2-(1,2-dimethyl-1H-indol-3-yl)ethyl-
amine hydrochloride) in good yield. This unusual
one-pot conversion involves first a titanium-catalyzed
Although many synthetic approaches have been devel-
oped, the Fischer indole reaction remains the most
important method to substituted indoles.3 In this
benchmark reaction aldehydes or ketones react with aryl
hydrazines to give the corresponding hydrazones, which
subsequently undergo a [3,3]-sigmatropic rearrangement
to yield indoles in the presence of a Brønstedt or Lewis
acid. Despite its versatility the Fischer indole reaction
HN
NH2
NH2
O
O
HO
N
H
N
H
N
H
NMe2
NMe2
NH3+Cl-
NaOH
NH2
Ti
O
melatonin
serotonin
tryptamine
2
Cl
1
2
Scheme 1. Examples of biologically active indoles.
Me
Me
+
N
Me
N
H2N N
Me
Me
4
5
3
* Corresponding author. Tel.: +49-381-4669313;fax: +49-381-4669-
324;e-mail: matthias.beller@ifok.uni-rostock.de
Scheme 2. A new domino process to tryptamines.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.085

3124
V. Khedkar et al. / Tetrahedron Letters 45 (2004) 3123–3126
Table 1. Reaction of 1-chloro-4-pentyne with N-methyl-N-phenylhydrazinea
Entry
Catalyst
Catalyst (mol %)
Time (h)
Temperature (°C)
Yield (%)b
4
5
1
2
3
4
5
6
7c
8
9
1
2.5
2.5
2.5
2.5
5
52
16
4
60
80
<5
61
79
77
84
86
62
33
64
<5
1
59
78
67
80
82
58
24
54
1
100
120
100
100
100
100
100
1
1.5
4
1
1
5
24
24
24
24
1
Ti(NMe2)4
(g5-Cp)2Ti(g2-Me3SiC2SiMe3)
5
5
10
a Reaction conditions: 1.1 mmol 1-chloro-4-pentyne, 1.4 mmol N-methyl-N-phenylhydrazine, 2 mL toluene.
b Isolated yield based on 1-chloro-4-pentyne.
c 2 mL Tetrahydrofuran.
hydroamination of the alkyne to give the N-aryl-N-
chloro-alkylhydrazone, then a [3,3]-sigmatropic rear-
rangement to the corresponding indole takes place and
finally nucleophilic substitution of the halide by the
liberated ammonia occurs.8 Advantageously, the in situ
generated hydrochloride acid acts as an efficient catalyst
for the Fischer indole reaction.
indole is produced. As shown in Table 1 the model
reaction proceeds in good yield in toluene in the pres-
ence of 2.5–5 mol % of catalyst at 80–120 °C (Table 1,
entries 2–6). Below 80 °C basically no conversion is
observed. Interestingly, in the amination step in all
reactions using 1 as catalyst excellent regioselectivities
(>99%) toward the Markovnikov product (internal
regioisomer) are obtained. The importance of the aryl-
oxo ligand is clearly shown by comparing reactions in
the presence of 1 and Ti(NMe2)4 as catalysts (Table 1,
entry 6 vs 8). Also, a well-known titanocene-type cata-
lyst (g5-Cp)2Ti(g2-Me3SiC2SiMe3)11 leads to a signifi-
cant lower yield of the indole.
As catalyst for the amination reaction bis(2,6-di-tert-
butyl-4-methylphenoxo)-bisdimethylamide titanium 1
was used. 1 is easily synthesized from commercially
available
2,6-di-tert-butyl-4-methylphenol
and
Ti(NMe2)4 in one step in good yield (72%),9 and has
been introduced by us very recently as a highly chemo-
and regioselective hydroamination catalyst for terminal
and internal alkynes with primary and secondary ali-
phatic amines, benzylamines, and anilines.10
Next, we were interested in the compatibility of our new
procedure with different aryl hydrazones (Table 2).12
Apart from N-methyl-N-phenylhydrazine seven different
aryl hydrazines with Me-, Cl-, F-, and MeO-substituents
were reacted with 1-chloro-4-pentyne and 1-chloro-5-
hexyne.
Due to the highly selective Markovnikov reaction of the
alkyne with the hydrazine, only the 2,3-disubstituted
Table 2. Reaction of chloroalkylalkynes with various aryl hydrazinesa
R3
R3
R3
NH3+Cl-
n NH2
R2
R2
R2
n
Cl
NMe2
NMe2
1
NaOH
Ti
O
2
=
1
n
+
Me
Me
H2N N
R1
N
N
R1
R1
7
6
Entry
Alkyne (n)
Aryl hydrazine
R2
Catalyst
(mol %)
Time (h)
Product 7
Yield (%)b
R1
R3
H
6
7
(CH2)2NH2
CH3
1
2
3
4
2
2
2
2
CH3
CH3
CH3
CH3
H
5.0
24
24
24
24
86
65
70
71
82
60
68
69
N
CH3
(CH2)2NH2
H3C
Cl
CH3
Cl
H
H
H
5.0
5.0
5.0
CH3
N
CH3
(CH2)2NH2
CH3
N
CH3
(CH2)2NH2
CH3
H3CO
OCH3
N
CH3

V. Khedkar et al. / Tetrahedron Letters 45 (2004) 3123–3126
3125
Table 2 (continued)
Entry
Alkyne (n)
Aryl hydrazine
R2
Catalyst
(mol %)
Time (h)
Product 7
Yield (%)b
R1
Ph
R3
H
6
7
(CH2)2NH2
CH3
5
2
2
2
H
H
F
5.0
5.0
2.5
24
24
4
50
49
89
80
N
Ph
(CH2)2NH2
6
Bn
Bn
H
CH3
N
90
84
Bn
(CH2)2NH2
F
7c
Cl
CH3
N
Cl
Bn
(CH2)2NH2
Cl
8c
2
Bn
Cl
Cl
2.5
4
85
82
CH3
N
Cl
Bn
(CH2)3NH2
CH3
N
9
3
3
CH3
CH3
H
H
H
5.0
5.0
24
24
63
78
60
67
CH3
(CH2)3NH2
H3C
Cl
10
CH3
CH3
N
CH3
(CH2)3NH2
11
12
3
3
CH3
CH3
Cl
H
H
5.0
5.0
24
24
CH3
N
64
81
60
68
CH3
(CH2)3NH2
H3CO
OCH3
CH3
N
CH3
(CH2)3NH2
13
3
3
3
3
Ph
Bn
Bn
Bn
H
H
F
H
5.0
5.0
5.0
5.0
24
24
24
24
57
64
65
61
50
55
52
55
CH3
N
Ph
(CH2)3NH2
14
H
CH3
N
Bn
(CH2)3NH2
F
15c
16c
Cl
Cl
CH3
N
Cl
Bn
(CH2)3NH2
Cl
Cl
Cl
CH3
N
Bn
a Reaction conditions: 1.1 mmol chloroalkylalkyne, 1.4 mmol aryl hydrazine, 100 °C, 2 mL toluene.
b Isolated yield.
c Two isomers (4-Cl:6-Cl) were obtained in a 2:1 ratio.
In all cases the conversion was >95% and the yield of
the corresponding indole hydrochloride salt was good
(50–90%). In general, the indole was isolated as the sole
product in excellent regioselectivity.
In conclusion, a new, one-pot method for the synthesis
of functionalized tryptamines and tryptamine homo-
logues has been developed. Starting from commercially
available aryl hydrazines and chloroalkylalkynes a
variety of potentially active indoles are obtained highly
selectively in the presence of a catalytic amount of 1. We
believe that the presented approach constitutes the most
efficient access for the here shown substituted trypt-
amines and tryptamine homologues. Further investiga-
tions of this method using other titanium catalysts are
However, by using disubstituted aryl hydrazines
(Table 2, entries 7–8 and 15–16) cyclization to the
indole nucleus gave a mixture of two regioisomers,
which is well known for other Fischer indole reactions,
too.

3126
V. Khedkar et al. / Tetrahedron Letters 45 (2004) 3123–3126
4105–4108; Angew. Chem.,Int. Ed. 2001, 40, 3983–3985;
(d) Brunet, J.-J.;Neibecker, D. In Catalytic Heterofunc-
currently under way in order to allow the synthesis of
indoles, which are not substituted at the 2-position.
€
tionalization;Togni, A., Gr utzmacher, H., Eds.;Wiley–
VCH: Weinheim, 2001;(e) For a personal account see:
Beller, M.;Breindl, C.;Eichberger, M.;Hartung, C. G.;
Seayad, J.;Thiel, O. R.;Tillack, A.;Trauthwein, H.
Synlett 2002, 1579–1594.
Acknowledgements
7. (a) Hartung, C. G.;Tillack, A.;Trauthwein, H.;Beller, M.
J. Org. Chem. 2001, 66, 6339–6343;(b) Tillack, A.;Garcia
Castro, I.;Hartung, C. G.;Beller, M. Angew. Chem. 2002,
114, 2646–2648; Angew. Chem.,Int. Ed. 2002, 41, 2541–
2543;(c) Garcia Castro, I.;Tillack, A.;Hartung, C. G.;
Beller, M. Tetrahedron Lett. 2003, 44, 3217–3221;(d)
Tillack, A.;Jiao, H.;Garcia Castro, I.;Hartung, C. G.;
Beller, M. Chem. Eur. J. 2004, in press.
This work has been supported by the State of Meck-
lenburg-Vorpommern. In addition financial support
€
from the BMBF (Bundesministerium fur Bildung und
Forschung) and the VCI are gratefully acknowledged.
We thank Mrs. C. Mewes, Mrs. H. Baudisch, Mrs. A.
Lehmann, and Mrs. S. Buchholz (all IfOK) for their
excellent technical and analytical support.
8. With regard to the mechanism it is important to note that
we cannot exclude nucleophilic substitution taking partly
place at the stage of the aryl hydrazone or chloro-
alkylalkyne.
References and notes
9. Duff, A. W.;Kamarudin, R. A.;Lappert, M. F.;Norton,
R. J. J. Chem. Soc.,Dalton Trans. 1986, 489–498.
10. Khedkar, V.;Tillack, A.;Beller, M. Org. Lett. 2003, 5,
4767–4770.
1. (a) Campos, K. R.;Woo, J. C. S.;Lee, S.;Tillyer, R. D.
Org. Lett. 2004, 6, 79–82;(b) Hong, K. B.;Lee, C. W.;
Yum, E. K. Tetrahedron Lett. 2004, 45, 693–697;(c)
€
Kohling, P.;Schmidt, A. M.;Eilbracht, P. Org. Lett. 2003,
11. For reviews on the use of this complex see: (a) Rosenthal,
U.;Burlakov, V. V.;Arndt, P.;Baumann, W.;Spannen-
berg, A. Organometallics 2003, 22, 884–900;(b) Rosenthal,
U.;Burlakov, V. V. In Titanium and Zirconium in Organic
Synthesis;Marek, I., Ed.;Wiley–VCH: New York/Wein-
heim, 2002;pp 355–389. The so-called Rosenthal catalysts
are commercially available from Fluka.
5, 3213–3216;(d) Cacchi, S.;Fabrizi, G.;Parisi, L. M.
Org. Lett. 2003, 5, 3843–3846;(e) Siebeneicher, H.;
Bytschkov, I.;Doye, S. Angew. Chem. 2003, 115, 3151–
3153; Angew. Chem.,Int. Ed. 2003, 42, 3042–3044;(f)
Onitsuka, K.;Suzuki, S.;Takahashi, S. Tetrahedron Lett.
2002, 43, 6197–6199;(g) Rutherford, J. F.;Rainka, M. P.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 15168–
15169;(h) Tokunaga, M.;Ota, M.;Haga, M.;Wakatsuki,
Y. Tetrahedron Lett. 2001, 42, 3865–3868;(i) Gribble, G.
W. J. Chem. Soc.,Perkin Trans. 1 2000, 1045–1075;(j)
Verspui, G.;Elbertse, G.;Sheldon, F. A.;Hacking, M. A.
P. J.;Sheldon, R. A. Chem. Commun. 2000, 1363–1364;(k)
Beller, M.;Breindl, C.;Riermeier, T. H.;Eichberger, M.;
Trauthwein, H. Angew. Chem. 1998, 110, 3571–3573;
Angew. Chem.,Int. Ed. 1998, 37, 3389–3391.
12. Typical reaction procedure: (Table 2, entry 2): In an Ace-
pressure tube under an argon atmosphere a solution of
catalyst 1 in 2 mL toluene was added to a mixture of
110 lL (113 mg, 1.1 mmol) 1-chloro-4-pentyne and 190 lL
(191 mg, 1.4 mmol) N-methyl-N-(4-tolyl)hydrazine. The
reaction mixture was heated at 100 °C for 24 h. During
this time the corresponding 2-(1,2,5-trimethyl-1H-indol-3-
yl)ethylamine hydrochloride precipitated. The mixture was
diluted with 5 mL hexane and the precipitate was filtered
off. Yield 170 mg (65%). For isolation of the free 2-(1,2,5-
trimethyl-1H-indol-3-yl)ethylamine, the hydrochloride
was dissolved in 20 mL water and NaOH was added until
the solution reached a pH of 9. Then 20 mL CH2Cl2 were
added and the organic layer was separated. The aqueous
phase was washed twice with 10 mL CH2Cl2 and the
combined organic phases were dried over anhydrous
MgSO4. After evaporation of the solvent 2-(1,2,5-tri-
methyl-1H-indole-3-yl)ethylamine was obtained as brown
oil. Yield 133 mg (60%). 1H NMR (400 MHz, CDCl3):
d ¼ 7:29 (s, 1H), 7.10 (d, J ¼ 8:3 Hz, 1H), 6.95 (d,
J ¼ 8:3 Hz, 1H), 3.57 (s, 3H), 2.91 (t, J ¼ 6:4 Hz, 2H),
2.82 (t, J ¼ 6:4 Hz, 2H), 2.43 (s, 3H), 2.32 (s, 3H), 1.32 (bs,
2H). 13C NMR (100 MHz, CDCl3): d ¼ 134:9, 133.5,
127.9, 127.7, 121.9, 117.6, 108.1, 107.7, 42.8, 29.3, 28.5,
21.3, 10.2. MS (EI, 70 eV): m=z (rel. intensity) ¼ 202 (16,
MþÅ), 172 (100), 157 (8), 128 (3), 115 (6), 91 (3), 77 (2), 51
(2), 30 (6). IR (neat, cmꢀ1): 3340, 3250, 3161, 1577, 1462,
1373, 785. HRMS Calcd. for C13H18N2: 202.14700.
Found: 202.14733. All compounds were characterized by
1H NMR, 13C NMR, MS, and IR spectroscopy. New
compounds were further characterized by HRMS (high-
resolution mass spectrometry).
2. (a) Hibino, S.;Choshi, T. Nat. Prod. Rep. 2002, 19, 148–
180, and earlier reviews in this series;(b) Szantay, C. Pure
Appl. Chem. 1990, 62, 1299–1302.
3. For reviews see: (a) Robinson, B. The Fischer Indole
Synthesis;John Wiley & Sons: Chichester, 1982;(b)
Hughes, D. L. Org. Prep. Proced. Int. 1993, 25, 607–623.
4. (a) Street, L. J.;Baker, R.;Castro, J. L.;Chambers, M. S.;
Guiblin, A. R.;Hobbs, S. C.;Matassa, V. G.;Reeve, A. J.;
Beer, M. S.;Middlemiss, D. N. J. Med. Chem. 1993, 36,
1529–1538;(b) Castro, J. L.;Matassa, V. G. Tetrahedron
Lett. 1993, 34, 4705–4708;(c) Chen, C.;Senanayake,
C. H.;Bill, T. J.;Larsen, R. D.;Verhoeven, T. R.;Reider,
P. J. J. Org. Chem. 1994, 59, 3738–3741;(d) Simeone, J.;
Bugianesi, R. L.;Ponpipom, M. M.;Goulet, M. T.;
Levorse, M. S.;Desai, R. C. Tetrahedron Lett. 2001, 42,
6459–6461;(e) Gorohovsky, S.;Meir, S.;Shkoulev, V.;
Byk, G.;Gellerman, G. Synlett 2003, 1411–1414.
5. Cao, C.;Shi, Y.;Odom, A. L. Org. Lett. 2002, 4, 2853–
2856.
€
6. For reviews see: (a) Muller, T. E.;Beller, M. Chem. Rev.
1998, 98, 675–703;(b) Seayad, J.;Tillack, A.;Hartung, C.
G.;Beller, M. Adv. Synth. Catal. 2002, 344, 795–813;(c)
€
Nobis, M.;Drießen-H olscher, B. Angew. Chem. 2001, 113,