Synthesis of novel serotonergics and other N-alkylamines using simple reductive amination using catalytic hydrogenation with Pd/C

Article abstract of DOI:10.1016/j.tetlet.2011.07.058

Formation of N-alkylated α-methyltryptamine derivatives (2) was accomplished by simple reductive amination of amine (1) with ketones using catalytic hydrogenation conditions (3 atm H₂ and 10% Pd on carbon). This method was also applied to other

Full text of DOI:10.1016/j.tetlet.2011.07.058

Tetrahedron Letters 52 (2011) 5117–5119
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of novel serotonergics and other N-alkylamines using simple
reductive amination using catalytic hydrogenation with Pd/C
⇑
George N. Karageorge, John E. Macor
Bristol-Myers Squibb R&D, Neuroscience Discovery Chemistry, 5 Research Parkway, Wallingford, CT 06492, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 June 2011
Revised 7 July 2011
Accepted 12 July 2011
Available online 5 August 2011
Formation of N-alkylated
a-methyltryptamine derivatives (2) was accomplished by simple reductive
amination of amine (1) with ketones using catalytic hydrogenation conditions (3 atm H2 and 10% Pd
on carbon). This method was also applied to other primary and secondary amines using ketones and
aldehydes.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Reductive amination
Catalytic hydrogenation
Tryptamine derivatives
Amine alkylation
As the field of organic synthesis continues to evolve and mature,
one of the areas for reaction optimization is the simplification of
functional group transformations. This was our goal as we were
reductive amination of 2 would be limited, if not excluded, by
the less sterically favorable formation of an imine of 2. We hoped
that a competing Pictet–Spengler reaction would be slower than
direct hydrogenation of the imine 3.
looking to prepare a series of N-alkyl analogs 2 of the
a-methyl-
tryptamine derivative 1 (Scheme 1). This serotonin (5-HT, 5-
hydroxytryptamine) analog was a known, potent 5-HT2 receptor
agonist which did not demonstrate selectivity within the 5-HT2
receptor family subtypes (i.e., 5-HT2A, 5-HT2B, and 5-HT2C).1 Our
goal was to examine the effect of N-alkyl substitution of 1 (forming
2, Scheme 1) on 5-HT2 receptor agonist subtype specificity. Given
that our approach was empirical, we desired a synthetic method
that was as simple as possible for the formation of 2, so as to allow
for a rapid examination of the effects of N-alkylation on 5-HT2
receptor subtype selectivity.
Direct alkylation was excluded as a pathway, given the likeli-
hood of the formation of tertiary amines as a side reaction. Reduc-
tive amination was seen as the best approach, but the reaction
work-ups of reductive aminations using metal hydride reagents
(a standard approach) can sometimes be tedious and require a
number of separation manipulations. We desired a simpler process
and thought that simple hydrogenation may provide a one-pot,
minimal work-up approach to gaining rapid access to our N-alkyl-
ated analogs of 1. We rationalized that a mixture of amine 1 and
aldehyde or ketone, subjected to simple palladium on carbon
(Pd/C) and hydrogen, should result in a direct reductive amination
as any imine formed in situ, however transiently, would be rapidly
reduced to the desired N-alkylated amine 2 (Scheme 2). Further
While this type of reductive amination (H2, Pd/C) was known,2
we could find only a few examples in the literature of reductive
aminations which were carried out under simple palladium on car-
bon mediated hydrogenation of an in situ formed imine. In this re-
port, we wish to describe the simple reductive amination of 1 and
other amines using simply an aldehyde or ketone, hydrogen, and
catalytic palladium on carbon.
While the synthesis of tryptamine 1 has been previously re-
ported,1 we used a more efficient methodology to make multi-
gram quantities of 1. As shown in Scheme 3, we utilized the direct
Claison rearrangement of an appropriately substituted 5-propa-
rgyloxyindole derivative3 in
a more direct synthesis of 1
(Scheme 3). Alkylation of 5-hydroxyindole using propargyl bro-
mide and cesium carbonate as base afforded 5-propargyloxyindole
4 in high yield. Vilsmeier–Haack reaction of 4 afforded the indole-
3-carboxaldehyde 5. Henry reaction with 5 using nitroethane
R2
NH2
CH3
1
2
HN
H
R1
O
CH3
O
N
H
N
H
⇑
Corresponding author. Tel.: +1 203 677 7092.
E-mail address: john.macor@bms.com (J.E. Macor).
Scheme 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.058

5118
G. N. Karageorge, J. E. Macor / Tetrahedron Letters 52 (2011) 5117–5119
CR1R2
CH3
3
N
NH2
CH3
1
NHCHR1R2
CH3
2
H2
O
O
O
Pd on C
N
H
N
H
N
H
Scheme 2.
NO2
CH3
4
6
5
CHO
HO
O
O
O
a
d
b, c
N
H
N
H
N
H
N
H
NH2
CH3
NO2
NO2
CH3
7
1
8
O
O
CH3
O
e
g
f
N
H
N
H
N
H
Scheme 3. Reagents and conditions: (a) proparyloxy bromide, Cs2CO3, acetone, rt (95%);3d (b) POCl3, DMF, rt (98%); c) K2CO3 in water, pH 10;3d (d) ammonium acetate
(2 equiv), acetic acid/nitroethane [1:10], sonication, (85%); (e) NaBH4 (6 equiv), silica gel (10Â w:w), chloroform/i-PrOH [13:3] (42%); (f) bromobenzene reflux (70%); (g) H2
(3 atm), 10% Pd/C, EtOH, rt (60%).
Table 1
Reductive aminations using hydrogenation
Starting amine
Starting carbonyl
Product
Yield (time)
56% (18 h)
NH2
CH3
CH2CH2Ph
N
O
N
CH2CH2Ph
HN
O
a
b
c
CH3
O
2a
N
H
N
H
NH2
CH3
O
N
N
HN
HN
HN
O
78% (18 h)
N
H
CH3
CH3
CH3
O
O
O
2b
2c
N
H
NH2
CH3
O
O
O
32%4 (18 h)
N
H
N
H
NH2
CH3
NBOC
2d
NBOC
O
d
52% (18 h)
N
H
N
H
NH2
CH3
O
H
O
e
No desired product
(18 h)
N
H

G. N. Karageorge, J. E. Macor / Tetrahedron Letters 52 (2011) 5117–5119
5119
Table 1 (continued)
Starting amine
Starting carbonyl
Product
Yield (time)
NH2
CH3
O
N
H
O
f
No desired product
(18 h)
N
H
O
H
N
HN
g
58% (18 h)
8a
8b
NH2
O
H
h
i
86% (18 h)
77% (18 h)
N
H
NH2
O
O
N
N
N
8c
8d
O
HN
HN
N
j
67% (18 h)
59% (18 h)
H
8e
k
H3CN
N
N
followed by reduction of the resulting nitroolefin 6 afforded indole
7. The key step in the synthesis was the thermal electrocyclic rear-
rangement of the propargyloxy group in 7 to form the pyrano func-
tionality in 8.3d Hydrogenation of 8 reduced both the olefin and the
with
methylene
chloride/methanol/ammonium
hydroxide
[9:1:0.1] to afford purified alkylated amine (2 or 8). Table 1 out-
lines the amines and carbonyl compounds used, the hydrogenation
times and yields. Reactions were typically run on 1 g scale of the
amine.
nitro group to afford gram quantities of racemic
a-methyltrypta-
mine 1 (Scheme 3).
The alkylated a-methyltryptamines (2a–d) prepared were
Treatment of 1 with excess ketone (a, b, c, and d, Table 1) under
Parr hydrogenation conditions (3 atm H2, 10% w/w of 10% Pd on
carbon in EtOH) afforded the desired alkylated amine 2 in moder-
ate yields (Table 1). Work-up typically was simple filtration, wash-
ing the Pd/C with ammonia in methanol, and, if necessary,
chromatography of the residue. Treatment of 1 with an excess of
aldehyde (e or f, Table 1) yielded complex mixtures, likely due to
interception of the in situ imine by C2 of the electron-rich indole
ring in a Pictet–Spengler reaction. Identification of the products
of these reactions was not pursued. In only one instance using ke-
tones (entry c) was the product of the Pictet–Spengler reaction ob-
tained/isolated.4
To expand the scope of this simple reductive amination, we
examined another primary amine (Table 1, entries h and i) and sec-
ondary amine (Table 1, entries g, j and k) using aldehydes (Table 1,
entries g, h, and j) and a ketone (i and k, Table 1). In all cases, Parr
hydrogenation conditions directly afforded the desired alkylated
amine, and the work-up involved simple filtration, washing with
1 N ammonia in methanol, removal of solvent to afford the desired
alkylated amine directly or after column chromatography.
A general Parr hydrogenation reductive amination procedure was
as follows: A mixture of amine (1 equiv), ketone or aldehyde (1–
2 equiv) was shaken under an atmosphere of hydrogen (3 atm)
with 10% by weight of 10% Pd/C in ethanol (20 mL/gram of 1) for
12–48 h, depending on the carbonyl compound used. After the
reaction was deemed to be complete (TLC or HPLC), the reaction
mixture was filtered through Celite Ò, washed with 1 N ammonia
in methanol, and the resulting filtrate was evaporated under re-
duced pressure. If the filtrate residue was not sufficiently pure
alkylated amine, then further purification was achieved by column
chromatography using silica gel (50 g/gram residue) and elution
tested for affinity across 5-HT2A, 5-HT2B, and 5-HT2C receptors to
see if some selectivity could be achieved. Unfortunately, no selec-
tivity within the 5-HT2 receptor family subtypes was seen and this
approach was not pursued further.
In conclusion, reductive amination of primary and secondary
amines can be simply accomplished using Parr hydrogenation con-
ditions (3 atm H2 and 10% Pd on carbon) with reaction work-up of-
ten entailing only filtration and removal of solvent to afford the
desired alkylated amine in high yield and purity.
References and notes
1. May, J. A.; Chen, H.-H.; Rusinko, A.; Lynch, V. M.; Sharif, N. A.; McLaughlin, M. A.
J. Med. Chem. 2003, 46, 4188.
2. Paul Rylander, L. Catalytic Hydrogenation in Organic Syntheses; Academic Press:
New York, NY, 1979. pp.165-174.
3. (a) Macor, J. E.; Blank, D. H.; Post, R. J. Tetrahedron Lett. 1994, 35, 45; (b) Macor, J.
E. Tetrahedron Lett. 1995, 36, 7019; (c) Macor, J. E.; Langer, O. D.; Gougoutas, J. Z.;
Malley, M. F.; Cornelius, L. A. M. Tetrahedron Lett. 2000, 41, 3541; (d) Karageorge,
G. N.; Macor, J. E. Tetrahedron Lett. 2011, 52, 1011.
4. The Pictet–Spengler cyclization product (9) was also obtained in 23% yield from
the reaction of 1 and cyclohexanone under the hydrogenation conditions.
CH3
O
NH
9
N
H