Pictet-spengler reaction using ion-exchange resin as a catalyst and support for 'catch and release' purification

Article abstract of DOI:10.1271/bbb.100770

The Pictet-Spengler reaction between tryptamine and aldehydes was catalyzed by Dowex 50W-X4 acidic ion-exchange resin. The products were obtained from the resin in high purity by 'catch and release' without the need for separate chromatographic purification.

Full text of DOI:10.1271/bbb.100770

Biosci. Biotechnol. Biochem., 75 (2), 391–392, 2011
Note
Pictet-Spengler Reaction Using Ion-Exchange Resin as a Catalyst
and Support for ‘Catch and Release’ Purification
y
2
Minoru IZUMI,1; Takeshi KIDO,1 Miyu MURAKAMI,1 Shuhei NAKAJIMA,1 and A GANESAN
1Graduate School of Natural Science and Technology, Okayama University,
1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan
2School of Chemistry, University of Southampton, Southampton SO17 1BJ, United Kingdom
Received October 28, 2010; Accepted November 17, 2010; Online Publication, February 7, 2011
[doi:10.1271/bbb.100770]
Table 1. Pictet-Spengler Reactions Promoted by Dowex 50W-X4
Resin
The Pictet-Spengler reaction between tryptamine and
aldehydes was catalyzed by Dowex 50W-X4 acidic ion-
exchange resin. The products were obtained from the
resin in high purity by ‘catch and release’ without the
need for separate chromatographic purification.
O
H
NH2
NH
Dowex 50W-X4
Solvent, 90 °C
2 h
N
H
N
Key words: Pictet-Spengler reaction; ion-exchange
resin; parallel synthesis; alkaloid; catch
and release
H
(0.5 mmol)
Aldehyde
(eq.)
Catalyst
(g)
Solvent
(5 mL)
Yielda)
(%)
Entry
The Pictet-Spengler reaction is a major means for
heterocyclic synthesis that is used by organic chemists
and also in nature for alkaloid biosynthesis. An acidic
catalyst activates the imine intermediate before cycliza-
tion to the tetrahydroisoquinoline or tetrahydro-ꢀ-carbo-
line in this reaction.1–4) However, classic Lewis acids
usually have high reactivity, and hence promote such a
secondary reaction as the polymerization of indoles or
phenols. We therefore attempted to discover an acidic
catalyst that was much milder and more effective.
The isolation of products is often a tiresome and time-
consuming procedure in organic synthesis, and various
techniques have therefore been developed to achieve a
high throughput.5–8) For example, we have previously
found basic ion-exchange resins to be suitable dual-
purpose reagents that can act as catalysts and aid
purification in carbanion-mediated cyclization.9–11) We
report in this paper that the acidic ion-exchange resin,
Dowex 50W-X4, is similarly powerful as an acidic
catalyst for the Pictet-Spengler reaction as well as a
polymer support for ‘catch and release’ purification of
heterocyclic products. A Nautilus 2400 automated
synthesizer was used to examine various combinations
of amines and aldehydes, and their reactivity was
surveyed with our protocol.
1
2
5
5
1
3
5
3
3
3
3
3
3
3
3
3
3
DMF
DMF
DMF
18
34
23
14
40
11
18
39
16
16
32
26
22
3
5
4
5
H2O
5
5
Toluene
BuOH
HFIPb)
DCE
6
5
7
5
8
5
9
1
DCE
DCE
10
11
12
13
1.5
3
DCE
DCE
DCE-HFIPb)
10
5
(1:1)
a)The product did not need purification by silica-gel column chromatog-
raphy, because no by-product was detected by 1H-NMR and TLC for each
reaction.
b)1,1,1,3,3,3-hexafluoropropan-2-ol
amines, so they may not be separable by this strategy.
Instead, we used an excess amount of aldehyde to drive
the Pictet-Spengler reaction to completion and minimize
the amount of remaining tryptamine.
Among the ion-exchange resins investigated, Dowex
50W-X4 gave the best results for the Pictet-Spengler
reaction. Such other ion-exchange resins as Dowex
2-X8, Diaion WK10, and Amberlyst 15Dry did not
undergo the Pictet-Spengler reaction. The effects of
loading the Dowex 50W-X4 catalyst on the yield of the
product (Table 1, entries 1–3) suggested that 3 g gave
the best results. Screening of various solvents showed
that 1,2-dichloroethane (DCE) was suitable for the
Pictet-Spengler reaction (Table 1, entries 4–8). The
importance of using excess aldehyde is shown by entry
9, where 1 or 1.5 equivalents gave a very poor yield of
We first investigated the effects of the solvent and
reagent stoichiometry by using the Pictet-Spengler
reaction of tryptamine and benzaldehyde as a model
case. All reactions were performed at 90 ꢀC for 2 h with
the Nautilus 2400 automated synthesizer. The excess
reagents were removed after 2 h by simply rinsing with
CHCl3. The product on the Dowex resin was then
treated with a solution of 10% triethylamine (TEA) in
CHCl3 to release the compound from the resin. Both the
tryptamine starting material and the product are basic
y
To whom correspondence should be addressed. Fax: +81-86-251-8388; E-mail: mizumi@cc.okayama-u.ac.jp
Abbreviations: DCE, 1,2-dichloroethane; DMF, N,N-dimethylformamide; NAADP, nicotinic acid adenine dinucleotide phosphate; TEA,
triethylamine; TLC, thin-layer chromatography

392
M. IZUMI et al.
Table 2. Pictet-Spengler Reaction with Various Aldehydes Using
Dowex 50W-X4
Spengler reaction of tryptamine with various aldehydes
in DCE. The resin also efficiently sequestered the
desired product to facilitate purification by ‘catch and
release.’ We believe that the Pictet-Spengler reaction
using Dowex 50W-X4 will be widely applicable for
synthesis and provide products without the need for
separate chromatographic purification.
R-CHO
(5 eq)
NH2
NH
Dowex 50W-X4
DCE, 90 °C, 2 h
N
N
H
H
R
(0.5 mmol)
Entry
Yielda)
(%)
References and Notes
Aldehyde
R–CHO (5 eq)
1) Pictet A and Spengler T, Ber., 44, 2030–2036 (1911).
2) Whaley WM and Govindachari TR, Org. React., 6, 74–150
(1951).
1
2
3
4
R=H
R=CH3
12
28
22
20
R=C2H5
R=C5H11
3) Cox ED and Cook JM, Chem. Rev., 95, 1797–1842 (1995), and
references therein.
4) Saito A, Numaguchi J, and Hanazawa Y, Tetrahedron Lett., 48,
835–839 (2007), and references therein.
5
6
7
39
25
43
R=
R=
R=
5) Curran DP, Angew. Chem. Int. Ed., 37, 1174–1196 (1998).
6) Yoshida J and Itami K, Chem. Rev., 102, 3693–3716 (2002), and
references therein.
OMe
OH
7) Mothana S, Chahal N, Vanneste S, and Hall DG, J. Comb.
Chem., 9, 193–196 (2007), and references therein.
8) Kim CB, Cho CH, Kim CK, and Park K, J. Comb. Chem., 9,
1157–1163 (2007), and references therein.
a)The product did not need purification by silica-gel column chromatog-
raphy, because no by-product was detected by 1H-NMR and TLC for each
reaction.
9) Kulkarni BA and Ganesan A, Angew. Chem. Int. Ed., 36, 2454–
2455 (1997).
10) Kulkarni BA and Ganesan A, Chem. Commun., 785–786 (1998).
11) Kulkarni BA and Ganesan A, Tetrahedron Lett., 40, 5637–5638
(1999).
mainly unreacted starting materials by thin-layer chro-
matography (TLC; entries 9 and 10). On the other hand,
there were many by-products in the case of 10
equivalents of aldehyde (entry 12). A fairly high yield
was obtained when the temperature was 90 ꢀC, the
reaction time was 2 h, and the amount of catalyst was
3 g. More importantly, the purity of the resulting
compound was very high and further chromatography
was not required, because no by-product was detected
by 1H-NMR and TLC for each reaction.12)
Our method was then applied to various aldehydes in
order to synthesize a library of tetrahydro-ꢀ-carboline
compounds. For example, Ned-19, which was synthe-
sized from a tryptophan derivative in five steps, was a
potent cell-permeable NAADP receptor antagonist.13,14)
The reaction with aromatic aldehydes had a higher yield
than could be achieved by aliphatic aldehydes that were
vulnerable to other pathways due to enolization and
higher reactivity (Table 2, entries 5–7).
12) General Procedure for Pictet-Spengler Reactions using Auto-
mated Synthesizer Nautilus 2400: The case of 1-phenyl-1,2,3,4-
tetrahydro-ꢀ-carboline; To a mixture of tryptamine (80 mg,
0.5 mmol) and benzaldehyde (0.255 mL, 2.5 mmol) in 1,2-
dichloroethane (5 mL) was added Dowex 50W-X4 (3.0 g). The
resulting mixture was heated and mixed at 90 ꢀC in the Nautilus
2400 (Argonaut). The reaction mixture was filtered and the
supernatant discarded and the resin then washed sequentially
with CHCl3 (30 mL, 3 times). The resin was treated with 10%
TEA of CHCl3 (30 mL, 3 times) to effect product release, and
the combined solution evaporated to give the desired compound.
1-Phenyl-1,2,3,4-tetrahydro-ꢀ-carboline: 1H-NMR (300 MHz,
CDCl3) ꢁ 1.88 (br s, 1H), 2.78–2.86 (m, 1H), 2.88–2.99 (m, 1H),
3.14 (ddd, 1H, J ¼ 12:0, 9.0, 5.1 Hz), 3.38 (ddd, 1H, 12.0, 5.1,
3.9 Hz), 5.17 (s, 1H), 7.11–7.15 (m, 2H), 7.18–7.23 (m, 1H),
7.29–7.36 (m, 5H), 7.53–7.57 (m, 2H). ESI-MS calcd for
C
17H16N2 248.1 [M]þ, found 249.1 ½M þ Hꢁþ.
13) Naylor E, Arredouani A, Vasudevan SR, Lewis AM, Parkesh R,
Mizote A, Rosen D, Thomas JM, Izumi M, Ganesan A, Galione
A, and Churchill GC, Nat. Chem. Biol., 4, 220–226 (2009).
14) Rosen D, Lewis AM, Mizote A, Thomas JM, Aley PK,
Vasudevan SR, Parkesh R, Galione A, Izumi M, Ganesan A,
and Churchill GC, J. Biol. Chem., 284, 34930–34934 (2009).
In conclusion, we demonstrated that the acidic ion-
exchange resin, Dowex 50W-X4, catalyzed the Pictet-