Highly efficient Lewis acid-catalysed Pictet-Spengler reactions discovered by parallel screening

Article abstract of DOI:10.1039/b212063a

High yielding Lewis acid-catalysed one-pot Pictet-Spengler reactions of tryptophan methyl ester and tryptamine with aliphatic and aromatic aldehydes were achieved in short reaction times with the aid of microwave irradiation.

Full text of DOI:10.1039/b212063a

Highly efficient Lewis acid-catalysed Pictet–Spengler reactions
discovered by parallel screening†
Natarajan Srinivasan and A. Ganesan*
Combinatorial Centre of Excellence, Department of Chemistry, University of Southampton, Southampton,
United Kingdom SO17 1BJ. E-mail: ganesan@soton.ac.uk; Fax: +44 2380 596805; Tel: +44 2380 593897
Received (in Cambridge, UK) 5th December 2002, Accepted 19th February 2003
First published as an Advance Article on the web 11th March 2003
Table 1 Lewis acid catalysis of the Pictet–Spengler reaction of imine 1a
High yielding Lewis acid-catalysed one-pot Pictet–Spengler
reactions of tryptophan methyl ester and tryptamine with
Activitya Lewis acid
aliphatic and aromatic aldehydes were achieved in short
reaction times with the aid of microwave irradiation.
High
In(OTf)3, Sm(OTf)3, YbCl3, Sc(OTf)3, YCl3, Ce(OTf)3,
Y(OTf)3, [bmim]Cl–AlCl3, N = 0.5
The tetrahydro-b-carboline ring system is present in numerous
biologically active indole alkaloids as well as synthetic
compounds. The World Drug Index, for instance, contains over
200 listings of this heterocycle, which is usually assembled by
the Pictet–Spengler reaction1 (Scheme 1). Activation of imine 1
is most commonly achieved via Brønsted acid catalysis (X =
H). An alternative involves putative N-acyliminium ions (X =
acyl group), and we have previously employed2 this method-
ology for solution and solid-phase applications. Meanwhile,
Lewis acid-catalysed Pictet–Spengler reactions yielding tetra-
hydro-b-carbolines are rare,3,4 and largely limited to iminium
species where X is a heteroatom containing coordinating
group.
Moderate InCl3, Zn(OTf)2, AlCl3, TiCl4, SiCl4, Hg(OAc)2, Cu(OTf)2,
Ho(OTf)3, Tb(OTf)3, Gd(OTf)3, Nd(OTf)3, Dy(OTf)3,
Eu(OTf)3, Pr(OTf)3, [bmim][BF4]
Ba(OTf)2, AgOTf, CuOTf, Sn(OTf)2, La(OTf)3, CoCl2, BiCl3
a High activity: complete conversion in 24 h; moderate: 2.5 days needed;
poor: incomplete reaction after 4 days.
Poor
liquid chloroaluminate salt, [bmim]Cl–AlCl3, N = 0.5,7 was a
highly active catalyst.
As the reactions needed one day or longer at room
temperature, we investigated the effects of microwave irradia-
tion.8 With metal chloride Lewis acids, imine hydrolysis was a
competing reaction, possibly due to attack of chloride on the
activated iminium species. Lewis acids with less nucleophilic
triflate counterions were superior. Of these, Yb(OTf)3 gave the
best yields when tested with other imines, and was selected for
further optimisation. Using only 5 mol% of catalyst and 30
minutes of microwave irradiation, high conversions were
obtained with both aliphatic and aromatic imines.
The above conditions were equally applicable to a one-pot
version in which the imine is formed in situ, and these
consistently gave higher yields and cleaner product mixtures
than those with preformed imines (Table 3, entries 2a–2e). To
drive the reaction forward, 120 mol% of aldehyde was used, and
the excess scavenged with amine functionalized resins. It is
noteworthy that yields are equally good with electron-poor and
electron-rich aromatic imines, as the latter are less reactive in
Pictet–Spengler cyclizations. The mechanisms9 by which
microwave irradiation influence organic reactions remain
controversial. In our case, a conventionally heated (oil bath)
reaction gave incomplete conversion, but increasing the time
and temperature (120 °C, 50 minutes) resulted in similar yields
to the microwave experiments.
Scheme 1 The Pictet–Spengler reaction.
We carried out parallel screening to discover Lewis acids that
efficiently catalyse Pictet–Spengler reactions of simple imines.
A fixed amount (20 mg, corresponding to 9–45 mol%) of Lewis
acid was added to reaction vessels containing 100 mg of imine
1a (R1 = CO2Me, R2 = Ph). Qualitatively, reactions were
monitored by TLC using Dragendorff’s staining reagent, which
produces different colours for the starting imine and product
tetrahydro-b-carboline 2a (R1 = CO2Me, R2 = Ph). Re-
markably, many Lewis acids tested were found to be effective
catalysts, although hitherto unreported for this transformation
(Table 1).
Promising reactions were then analysed by HPLC analysis of
the crude product mixture (Table 2). Based on the Kobayashi
classification,5 both aldehyde (e.g. Al, Ti) and aldimine
selective (e.g. Sc, In, Cu(II), Yb, Y) Lewis acids were among
those found to promote the Pictet–Spengler reaction. While
AlCl3 and the ionic liquid6 [bmim]BF4 (bmim = 1-butyl-
3-methylimidazolium) were moderately effective, the ionic
Table 2 Quantitative analysis of promising Lewis acid catalysts for the
Pictet–Spengler reaction of imine 1a
Lewis acid
Mol%
Yield (%)a
Cis/transa
In(OTf)3
Sm(OTf)2
YbCl3
Yb(OTf)3
Sc(OTf)3
Ce(OTf)3
YCl3
Y(OTf)3
[bmim]Cl–AlCl3, N = 0.5
InCl3
Zn(OTf)2
AlCl3
15
15
15
9
10
10
15
10
20
20
20
45
40
78
80
80
85
86
80
82
82
80
69
72
70
65
1+1.2
1+1.4
1+1.4
1+1.6
1+1.7
1+1.2
1+1.3
1+1.4
1+1.6
1+1.4
1+1.2
1+1.2
1+1.1
TiCl4
† Electronic supplementary information (ESI) available: full experimental
procedures. See http://www.rsc.org/suppdata/cc/b2/b212063a/
a Crude yield of 2a, cis/trans ratio determined by HPLC.
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CHEM. COMMUN., 2003, 916–917
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Table 3 One-pot synthesis of tetrahydro-ß-carbolines from aldehydes and
tryptophan methyl ester (2a–2e)a or tryptamine (2f–2j)b using microwave
irradiation
In summary, we demonstrate for the first time that the one-pot
Pictet–Spengler cyclization to tetrahydro-b-carbolines can be
catalysed by a wide variety of Lewis acids. This should facilitate
the future evaluation of chiral Lewis acids for the development
of reagent-controlled asymmetric versions of these reactions. In
the present study, the achiral Lewis acid Yb(OTf)3 is shown to
be highly effective in catalysing the Pictet–Spengler reactions
of tryptophan and tryptamine. The latter needed the addition of
50 mol% [bmim]Cl–AlCl3, N = 0.5, and suggests that such
ionic liquids may be effective additives for other slow Lewis
acid-catalysed processes.
The Combinatorial Centre of Excellence is funded by an
industrial consortium comprising Amersham, AstraZeneca,
GlaxoSmithKline, Lilly, Merck Biosciences, Organon, Pifzer,
Roche and government funding through the JIF initiative. We
are grateful to Personal Chemistry for the donation of a Smith
Synthesizer focused microwave instrument.
R1
R2
Yield (%)c
Cis/transc
2a
2b
2c
2d
2e
2f
2g
2h
2i
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
H
H
H
H
H
Ph
96 (90)
92 (90)
97 (92)
93 (92)
92 (86)
92 (93)
85 (84)
90 (92)
89 (85)
95 (82)
1+1.2
1+1.1
1+1.4
1+1.4
1+1.2
–
–
–
–
–
p-NO2–Ph
p-OMe–Ph
3,4,5(OMe)3–Ph
c-C6H11
Ph
p-NO2–Ph
p-OMe–Ph
3,4,5(OMe)3–Ph
c-C6H11
2j
a Reactions carried out with tryptophan methyl ester (200 mg), Yb(OTf)3
(20 mg), and aldehyde (120 mol%) in dichloromethane (2.5 ml) heated at
100 °C for 30 minutes in a Smith Synthesizer microwave instrument.
b Reactions carried out with tryptamine (200 mg), Yb(OTf)3 (40mg),
[bmim]Cl–AlCl3, N
= 0.5 (200 mg), and aldehyde (120 mol%) in
Notes and references
dichloromethane (2.5 ml) heated at 120 °C for 60 minutes in a Smith
Synthesizer microwave instrument. c Isolated yields of purified product by
the one-pot method, or by using preformed imine (yield in parentheses),
with cis/trans ratio for 2a–2e determined by HPLC analysis.
1 For reviews, see (a) W. M. Whaley and T. R. Govindachari in Organic
Reactions, Vol. 6 Ed. R. Adams, Wiley, New York, 1951, p. 151; (b) E.
D. Cox and J. M. Cook, Chem. Rev., 1995, 95, 1797.
2 (a) H. Wang and A. Ganesan, Tetrahedron Lett., 1997, 38, 4327; (b) H.
Wang and A. Ganesan, Org. Lett., 1999, 1, 1647; (c) H. Wang and A.
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3 (a) T. Kawate, M. Nakagawa, K. Ogata and T. Hino, Heterocycles,
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Extending these results to tryptamine (1, R1 = H) was less
straightforward. Due to the absence of the inductively electron-
withdrawing carbonyl group in tryptophan, tryptamine imines
are significantly less reactive. In the literature,10 protic acid
catalysed Pictet–Spengler reactions of tryptamine often feature
harsher conditions and poorer yields than their tryptophan
counterparts. Indeed, those Lewis acids successful in the
tryptophan cyclizations were unable to promote the analogous
conversion of 1f (R1 = H, R2 = Ph) to 2f under a number of
experimental conditions.
Various additives were tested to boost the reactivity of
Yb(OTf)3: no reaction occurred with 100 mol% of benzoic
acid11 or TMSOTf,12 HCl13 led to extensive decomposition, and
TMSCl gave low yields. Encouraged by the activity of ionic
liquids in Table 2, these were tested as well. It was found that
the combination of 10 mol% Yb(OTf)3 and 50 mol%
[bmim]Cl–AlCl3, N = 0.5, resulted in a very active catalyst
which gave uniformly high yields, either with preformed imines
1f–1j or in one-pot condensations with the aldehydes (Table 3,
entries 2f–2j). The ionic liquid is integral to the additive’s
effects, as substitution by 50 mol% AlCl3 alone resulted in
lower yields. Although ionic liquids are often employed as
solvents, and have been used as such in lanthanide triflate
catalyzed reactions,14 we believe this is the first example where
they are beneficial as a substoichiometric additive. While this
work was in progress, Nakagawa reported15 the one-pot Pictet–
Spengler reaction of tryptamine with p-nitrobenzaldehyde using
5 mol% Yb(OTf)3 and 100 mol% TMSCl. The reaction did not
proceed with benzaldehyde, whereas our ionic liquid assisted
conditions are applicable to even more electron-rich aldehydes
(2h,2i).
6 For reviews, see: (a) T. Welton, Chem. Rev., 1999, 99, 2071; (b) R.
Sheldon, Chem. Commun., 2001, 2399.
7 Prepared by the following procedure: J. S. Wilkes, J. A. Levisky, R. A.
Wilson and C. L. Hussey, Inorg. Chem., 1982, 21, 1263.
8 For a recent example of microwave accelerated Pictet–Spengler
reactions, see: C.-Y. Wu and C.-M. Sun, Synlett, 2002, 1709.
9 For a discussion, see: (a) N. Kuhnert, Angew. Chem., Int. Ed., 2002, 41,
1863; (b) C. R. Strauss, Angew. Chem., Int. Ed., 2002, 41, 3589.
10 For example: (a) W. A. Skinner and R. M. Parkhurst, Can. J. Chem.,
1965, 43, 2251; (b) R. Grigg, H. Q. N. Gunaratne and E. McNaghten, J.
Chem. Soc., Perkin Trans. 1, 1983, 185; (c) H. C. Hiemstra, H.
Bierangel, M. Wijnberg and U. K. Pandit, Tetrahedron, 1983, 39,
3981.
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39, 9283.
12 A. Kakuuchi, T. Taguchi and Y. Hanzawa, Tetrahedron Lett., 2001, 42,
1547.
13 K. Manabe and S. Kobayashi, Tetrahedron Lett., 1999, 40, 3773.
14 S. Lee, J. H. Park, J. Kang and J. K. Lee, Chem. Commun., 2001,
1698.
15 R. Tsuji, M. Yamanaka, A. Nishida and M. Nakagawa, Chem. Lett.,
2002, 428.
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