One-pot synthesis of homotryptamines from indoles

Article abstract of DOI:10.1016/j.tetlet.2004.03.070

A method is presented for the one-pot synthesis of homotryptamines by the MacMillan reaction of indoles with acrolein followed by reductive amination.

Full text of DOI:10.1016/j.tetlet.2004.03.070

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3803–3805
One-pot synthesis of homotryptamines from indoles
Derek J. Denhart,* Ronald J. Mattson, Jonathan L. Ditta and John E. Macor
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492-7660, USA
Received 23 January 2004; revised 10 March 2004; accepted 12 March 2004
Abstract—A method is presented for the one-pot synthesis of homotryptamines by the MacMillan reaction of indoles with acrolein
followed by reductive amination.
Ó 2004 Elsevier Ltd. All rights reserved.
The indole heterocycle is ubiquitous to both natural and
unnatural products. Consequently, indole containing
compounds have been the target of many synthetic
investigations over many years. Of special interest is the
indole neurotransmitter serotonin 1 (5-hydroxytrypt-
amine or 5-HT), which is an important component of
the central nervous system. Molecules that mimic sero-
tonin have been used effectively as treatments for a
variety of psychiatric illnesses including depression,
anxiety, and migraine.1 While extensive synthetic and
medicinal chemistry studies have been done on trypta-
mines, significantly less work has been done examining
the synthesis and biological activity of homotrypta-
mines. Homotryptamines 2 can be constructed from
indoles2 or indole precursors1b in a number of ways by
multistep routes. Driven by our interest to further study
the neuropharmacology of this series of indole deriva-
tives, we believed a shorter route to homotryptamines
could be realized by the conversion of indoles directly to
indole propionaldehydes, followed by reductive amina-
tion to the desired target.
There is a dearth of reports of indole propionaldehydes,
specifically those lacking additional substituents on the
propionaldehyde chain. When they do appear in litera-
ture reports, they are generally made and used imme-
diately for subsequent transformations.3;4 This is likely
due to the observed instability of the indole propional-
dehyde moiety. Accordingly, our goal was to find a
direct and simple method to generate the desired
aldehydes in situ, followed immediately by reductive
amination to afford the desired homotryptamines.
One reaction, which has been used to form 3-substituted
indole propionaldehydes is the amine-catalyzed Michael
addition of a–b unsaturated aldehydes developed by
Austin and MacMillan.5 To our knowledge, this has not
yet been applied to the unsubstituted acrolein. Herein,
we describe the reaction of indoles with acrolein in the
presence of the MacMillan amine catalysts, and the
subsequent transformation of the resulting indole
propionaldehydes to homotryptamines.
O
O
Me
Me
N
N
R2
O
Ph
Ph
NH2
N
N
N
R3
H
H
HO
4
3
R1
N
H
N
H
1
2
We have found two catalysts to be efficacious in this
sequence: t-butyl catalyst 3 and methylfuryl catalyst 4.6
It should be noted that simpler secondary amines such
as pyrrolidine and diisopropylamine were ineffective in
catalyzing the desired Michael reaction. In a typical
reaction, acrolein7 and the desired indole were stirred at
low temperature in the presence of the amine catalyst
Keywords: Homotryptamine; Indole; Serotonin; Organic catalysis.
* Corresponding author. Tel.: +1-203-677-7117; fax: +1-203-677-7702;
e-mail: derek.denhart@bms.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.070

3804
D. J. Denhart et al. / Tetrahedron Letters 45 (2004) 3803–3805
amines (Table 1). Accordingly, reaction of indole 9
CHO
with acrolein in the usual way, followed by reductive
amination in the same pot afforded homotrypt-
amines 10.9 For our initial study, we chose dimethyl-
amine as a standard amine for all reductive aminations.
This sequence represents a general and direct synthesis
of homotryptamines.
CHO
I
I
TFA / 4
N
H
N
H
-25oC
38%
5
6
Scheme 1.
As shown in Table 1, a variety of substituted indoles can
be used. The speed of the addition to acrolein is
dependent on the nucleophilicity of the indole, such that
5-methoxyindole (entry 2) is faster than indole (entry 1),
while 5-cyanoindole (entry 5) is very slow under the
same conditions. Both catalysts 3 and 4 appear to be
efficacious for these reactions. The reaction produces a
number of undesired products, which results in low (but
reproducible) yields and often challenging purifications.
Nevertheless, the directness of the procedure, only one
step from indoles, has made it more convenient than
alternative routes.
and TFA for an appropriate length of time. This reac-
tion produced a solution containing the indolepropion-
aldehyde. In most cases involving indoles without
electron withdrawing substituents, attempts to work up
and purify the product were unsuccessful. It appears,
however that some indolepropionaldehydes stabilized
by electron withdrawing groups can be isolated in rea-
sonable yield and purity. For example, reaction of
5-iodoindole 5 gave the indole propionaldehyde 68
(Scheme 1).
In conclusion, we have developed a convenient method
for the concise synthesis of homotryptamines directly
from indoles. This sequence has produced a series of
homotryptamines, whose neuropharmacology is pres-
ently under investigation. The results from this study
will be presented in due course.
OH
CHO
1)
TFA / 3
-25oC
N
N
H
H
2) NaBH4
22%
8
7
Scheme 2.
References and notes
Direct reduction of the indole propionaldehyde using
sodium borohydride in methanol afforded the corre-
sponding alcohol. For example, treatment of indole 7
under MacMillan conditions followed by borohydride
reduction gave alcohol 8 (Scheme 2).
1. (a) Wong, D. T.; Bymaster, F. P.; Engelman, E. A. Life
Sci. 1995, 57, 411–441; (b) Brodfuehrer, P. R.; Chen, B.;
Sattleberg, T. R.; Smith, P. R.; Reddy, J. P.; Stark, D. R.;
Quinlan, S. L.; Reid, J. G.; Thottathil, J. K.; Wang, S. J.
Org. Chem. 1997, 62, 9192.
2. (a) Suvarov, N. N.; Mura Sheva, V. S. Meditsinskaya
Promyshlennost SSSR 1961, 15, 6; (b) Basanagoudar, L.
D.; Siddappa, S. J. Karnatak Univ. 1972, 17, 33; (c)
Hofmann, A.; Troxler, F. Swiss Patent 380129, 1964;
(d) Hofman, A.; Troxler, F. Swiss Patent 379505,
1964.
Alternatively, directly applied reductive amination
converted the indole propionaldehydes to homotrypt-
Table 1. Conditions and yields for homotryptamine synthesis
3. Kuehne, M. E.; Cowen, S. D.; Xu, F.; Borman, L. S.
J. Org. Chem. 2001, 66, 5303.
4. Indole-3-propionaldehydes with an additional substituent
at the 3 position of the propionaldehyde appear to be more
stable than the similar molecules lacking this substitution,
based on unpublished results.
NMe2
CHO
4
7
1)
5
6
TFA / 3 or 4
-25oC
R1
R1
N
H
N
H
2) NaBH(OAc)3
Me2NH
9
10
5. Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002,
124, 1172.
6. Catalyst 3 is available from commercial sources; catalyst 4
according to: Northrup, A. B.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2002, 124, 2458.
Entry
R1
Catalyst
Time for
acrolein
addition
Yield of
product 10
7. Reactions performed using 90% acrolein from the Aldrich
Chemical Company, Inc, but the reagent should be
checked by 1H NMR before use. The use of freshly distilled
acrolein did not produce significant improvement in yield
or purity.
8. Compound 6: Acrolein (0.082 mL) and catalyst 4 (22 mg)
were stirred in CH2Cl2/iPrOH (85:15; 10 mL) at ꢀ40 °C and
TFA (0.006 mL) was added. After 15 min indole 5 (200 mg)
was added as a solution in CH2Cl2/iPrOH (3 mL). The
reaction was stirred at ꢀ30 °C for 2 h. Added aqueous
NaHCO3, extracted with CH2Cl2, and dried with MgSO4.
Purified by chromatography on SiO2 eluting with 4:1
1
H
4
4
4
4
3
3
3
3
3
3
3
3 h
3 h
10a 29%
10b 25%
10c 35%
10d 16%
10e 34%
10f 34%
10g 28%
10h 30%
10i 15%
10j 37%
10k 14%
2
5-MeO
5-BnO
5-F
3
3 h
3 h
4
5
5-CN
4-Cl
5-Cl
2 days
5 h
5 h
6
7
8
6-Cl
7-Cl
5 h
5 h
9
10
11
5-Br
5-I
5 h
5 h

D. J. Denhart et al. / Tetrahedron Letters 45 (2004) 3803–3805
3805
hexanes/ethyl acetate. Obtained 94 mg (38%) of aldehyde 6:
1H NMR (400 MHz, CDCl3) d 9.83 (t, J ¼ 1:4 Hz, 1H),
8.01 (br s, 1H), 7.91 (t, J ¼ 1:0 Hz, 1H), 7.43 (dd, J ¼ 8:4,
1.5 Hz, 1H), 7.13 (d, J ¼ 8:6 Hz, 1H), 6.95 (t, J ¼ 1:0 Hz,
1H), 3.05 (t, J ¼ 7:2 Hz, 2H), 2.82 (td, J ¼ 7:2, 1.2 Hz, 2H);
MS (EI) 256.21.
(10 mL of a 2 M solution in THF, 20 mmol) was added
followed by methanol (10 mL) and sodium triacetoxyboro-
hydride (2.1 g, 10 mmol). The reaction was stirred at room
temperature for 1 h. The solvent was removed in vacuo and
the residue was taken up in aqueous NaHCO3, extracted
with ethyl acetate, and dried with MgSO4. Purified by
careful chromatography on SiO2 eluting with 95:5 CH2Cl2/
2 M NH3 in MeOH. Obtained 329 mg (28%) of compound
10g. 1H NMR (400 MHz, CDCl3) d 8.12 (br s, 1H), 7.55 (d,
J ¼ 1:9 Hz, 1H), 7.24 (d, J ¼ 8:4 Hz, 1H), 7.11 (dd, J ¼ 8:4,
2.0 Hz, 1H), 6.99 (t, J ¼ 1:2 Hz, 1H), 2.72 (t, J ¼ 7:5 Hz,
2H), 2.35 (t, J ¼ 7:4 Hz, 2H), 2.24 (s, 6H), 1.86 (pentet,
J ¼ 7:5 Hz, 2H); MS (EI) 236.99.
9. Representative procedure for preparation of homotrypt-
amines: Acrolein (0.050 mL, 5 mmol) and catalyst
3
(135 mg, 0.5 mmol) were stirred in CH2Cl2/iPrOH (85:15;
10 mL) at ꢀ40 °C and TFA (0.039 mL, 0.5 mmol) was
added. After 15 min 5-chloroindole (758 mg, 151.6 mmol)
was added as a solution in CH2Cl2/iPrOH (5 mL). The
reaction was stirred at ꢀ25 °C for 5 h. Dimethylamine