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

Abstract

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.

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The tetrahydro-β-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 methodology for solution and solid-phase applications. Meanwhile, Lewis acid-catalysed Pictet–Spengler reactions yielding tetrahydro-β-carbolines are rare,^3,4 and largely limited to iminium species where X is a heteroatom containing coordinating group.

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-β-carboline 2a (R₁ = CO₂Me, R₂ = Ph). Remarkably, many Lewis acids tested were found to be effective catalysts, although hitherto unreported for this transformation (Table 1).

Table 1 Lewis acid catalysis of the Pictet–Spengler reaction of imine 1a

Activity^a	Lewis acid
a High activity: complete conversion in 24 h; moderate: 2.5 days needed; poor: incomplete reaction after 4 days.
High	In(OTf)3, Sm(OTf)3, YbCl3, Sc(OTf)3, YCl3, Ce(OTf)3, Y(OTf)3, [bmim]Cl–AlCl3, N = 0.5
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]
Poor	Ba(OTf)2, AgOTf, CuOTf, Sn(OTf)2, La(OTf)3, CoCl2, BiCl3

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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 liquid chloroaluminate salt, [bmim]Cl–AlCl₃, N = 0.5,⁷ was a highly active catalyst.

Table 2 Quantitative analysis of promising Lewis acid catalysts for the Pictet–Spengler reaction of imine 1a

Lewis acid	Mol%	Yield (%)^a	Cis/trans^a
a Crude yield of 2a, cis/trans ratio determined by HPLC.
In(OTf)3	15	78	1∶1.2
Sm(OTf)2	15	80	1∶1.4
YbCl3	15	80	1∶1.4
Yb(OTf)3	9	85	1∶1.6
Sc(OTf)3	10	86	1∶1.7
Ce(OTf)3	10	80	1∶1.2
YCl3	15	82	1∶1.3
Y(OTf)3	10	82	1∶1.4
[bmim]Cl–AlCl3, N = 0.5	20	80	1∶1.6
InCl3	20	69	1∶1.4
Zn(OTf)2	20	72	1∶1.2
AlCl3	45	70	1∶1.2
TiCl4	40	65	1∶1.1

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As the reactions needed one day or longer at room temperature, we investigated the effects of microwave irradiation.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.

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

	R^1	R^2	Yield (%)^c	Cis/trans^c
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 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.
2a	CO2Me	Ph	96 (90)	1∶1.2
2b	CO2Me	p-NO2–Ph	92 (90)	1∶1.1
2c	CO2Me	p-OMe–Ph	97 (92)	1∶1.4
2d	CO2Me	3,4,5(OMe)3–Ph	93 (92)	1∶1.4
2e	CO2Me	c-C6H11	92 (86)	1∶1.2
2f	H	Ph	92 (93)	–
2g	H	p-NO2–Ph	85 (84)	–
2h	H	p-OMe–Ph	90 (92)	–
2i	H	3,4,5(OMe)3–Ph	89 (85)	–
2j	H	c-C6H11	95 (82)	–

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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).

In summary, we demonstrate for the first time that the one-pot Pictet–Spengler cyclization to tetrahydro-β-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.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: full experimental procedures. See http://www.rsc.org/suppdata/cc/b2/b212063a/

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