An acid-free Pictet-Spengler reaction using deep eutectic solvents (DES)

Article abstract of DOI:10.1016/j.tetlet.2014.04.077

Deep eutectic solvents (such as the combination of either urea or glycerol with choline chloride) are effective solvents/organocatalysts for Pictet-Spengler condensations to form carbolines. The reaction conditions are quite mild and do not require additi

Full text of DOI:10.1016/j.tetlet.2014.04.077

Accepted Manuscript
An Acid-Free Pictet-Spengler Reaction using Deep Eutectic Solvents (DES)
Scott Handy, Matthew Wright
PII:
S0040-4039(14)00702-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.077
TETL 44539
Reference:
Tetrahedron Letters
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Accepted Date:
3 April 2014
21 April 2014
Please cite this article as: Handy, S., Wright, M., An Acid-Free Pictet-Spengler Reaction using Deep Eutectic
Solvents (DES), Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.04.077
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An Acid-Free Pictet-Spengler Reaction using
Deep Eutectic Solvents (DES)
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Scott T. Handy* and Matthew Wright

1
Tetrahedron Letters
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An Acid-Free Pictet-Spengler Reaction using Deep Eutectic Solvents (DES)
Scott Handya ∗ and Matthew Wright
aDepartment of Chemistry, Middle Tennessee State University, Murfreesboro, TN 37132
ARTICLE INFO
ABSTRACT
Article history:
Received
Deep Eutectic solvents (such as the combination of either urea or glycerol with choline chloride)
are effective solvents/organocatalysts for Pictet-Spengler condensations to form carbolines. The
reaction conditions are quite mild and do not require additional Bronsted or Lewis acid catalyst.
Given the inexpensive, non-toxic, and recyclable nature of the DES, these reaction conditions
are simple and highly environmentally friendly.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
organocattalysis
condensation reaction
deep eutectic
carbolines
1. Introduction
our recent success in performing the Pictet-Spengler reaction in
DES.
In the ongoing effort to attain “greener” synthetic methods,
reaction solvents have attracted a great deal of attention.
Certainly this attention is well justified as reaction solvents are
generally the largest component of a reaction by volume/mass.
They are also typically volatile, flammable, and toxic. A number
of alternatives have been developed over the last two decades,
including water, supercritical fluids, and room temperature ionic
liquids.1 Each of these alternatives has its own strengths and
weaknesses. RTILs have achieved the broadest range of
interest/applications, in large part due to their tunable nature.2 At
the same time, RTILs are quite expensive as solvents (well over
$200/L for even the most common ones, such as BMIM BF4).3
2. Results
The Pictet-Spengler reaction is a well-known reaction that
enables access to tetrahydrocarbolines.10 These products are
generally quite biologically active with many natural and non-
natural examples finding great use over the years (Figure 1).
Since its discovery in 1911,11 many different sets of reaction
conditions have been reported, including: Lewis Acids,12
Bronsted acids,13 organocatalysts,14 supported Bronsted acids,15
enzymatic,16 RTILs,17 and microwave reaction conditions.18
In light of this situation, general utilization of RTILs is highly
unlikely. Fortunately, a promising alternative has recently come
to light – deep eutectic solvents (DES).4 A number of possible
DES have been reported and many more are likely to appear in
the future. The most commonly employed example to date is the
combination of choline chloride and urea in a 1:2 molar ratio.
The combination of these two inexpensive, non-toxic solids
results in a material that is a viscous liquid at room temperature
(mp 8 ºC).5 This solvent has received extensive study in the area
of electroplating and metal recovery.6 There has also been
considerable interest in the area of enzymatic synthesis as
enzymes are generally very stable and more active in DES
compared to other solvents.7 At the same time, there has been
relatively little work reported in the area of Organic synthesis.8
Due to the long-standing interest of my group in the areas of
RTILs and heteroaromatic synthesis, we have begun to explore
the application of DES in this area.9 In this paper, we describe
———
Figure 1. Representative Biologically Active Tetrahydrocarbolines.
On the basis of our previous study of the Paal-Knorr reaction in
CC/U, we felt that this solvent should be similarly capable of
catalyzing the Pictet-Spengler reaction under very mild and
neutral conditions.9 To that end, the reaction of tryptamine with
p-anisaldehyde was undertaken in CC/U at 80 ºC. After 2 hours,
all of the starting material was consumed and the product could
∗ Corresponding author. Tel.: +615-904-8114; fax: +615-xxx-xxxx; e-mail: shandy@mtsu.edu

2
Tetrahedron
be readily isolated via extraction with ether in good yield
4
3
4
95
91
following cooling of the reaction to room temperature.19 Armed
with this promising result, we examined a number of aldehydes
including aryl, alkenyl, and alkyls (Table 1). In all cases, the
anticipated products were obtained in good yield, the one
exception being 4-nitrobenzaldehyde (Table 1, entry 2).20 In this
case, the low yield is the result of incomplete reaction. If the
reaction is allowed to run for 6 hours instead of 2, the yield
improves to 87%.
5
a. These reactions were allowed to run for 2 hours and were isolated via
extraction with ether.
It is anticipated that the catalytic properties of urea are
responsible for the activity of CC/U in the Pictet-Spengler
reaction. As has been proposed before, urea is able to doubly
activate aldehydes, rendering them more reactive with
nucleophiles. Under ordinary circumstances, this activation is
very modest, but the high concentration of urea present in the
DES serves to overcome this low activity and render them useful
organocatalysts. Interestingly, attempts to preform similar
reactions using 3,4-dimethoxyphenethylamine failed to afford the
cyclized product and only resulted in recovery of the imine
intermediate 1, indicating both the limits and the modest
activation afforded by this solvent. (Scheme 1) Further efforts
using CC/U in other reactions and attempts to explore a more
strongly activating DES employing thiourea are in progress and
will be reported in due course.
Table 1. Pictet-Spengler Reactions in Choline-Chloride/Urea.
Entrya
112a
212a
312a
413a
521
Aldehyde
Isolated Yieldb
97%
p-Anisaldehyde
4-Nitrobenzaldehyde
2-Furylaldehyde
2-Thiopehnylaldehyde
2-Pyridylaldehyde
Cinnamaldehyde
64% (87%)c
92%
79%
91%
620
97%
Scheme
dimethoxyphenethylamine.
1.
Failed
Reaction
with
3,4-
720
92%
β-cyclocitral
814
Isobutanal
99%
912a
Dihydrocinnamaldehyde 98%
References and notes
a. Reference numbers refer to source of literature data used cor comparison.
b. Isolated yields. c. This reaction was run for 6 hours instead of 2.
1
2
Adams, D.J.; Dyson, P.J.; Tavener, S.J. “Chemistry in Alternative
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Solvents for Synthesis and Catalysis. 2” Chem. Rev. 2011, 111,
3508-3576. B). Handy, S.T. “Room temperature ionic liquids:
Different classes and physical properties.” Curr. Org. Chem.
2005, 9, 959-988.
Beyond the low toxicity, biorenewable nature, and low
volatility of the DES, another potential advantage is the ability to
recycle this catalytic solvent. As seen in Table 2, the DES
solvent was recovered and recycled through five cycles of a
Pictet-Spengler reaction with little loss in activity. Recovery
simply involved evaporating any residual solvents on a rotory
evaporator for 15 minutes before reuse.
3
4
Based on prices from the 2013-2014 Aldrich catalog.
For recent reviews, see: A). Russ, C.; Koenig, B. “Low melting
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52, 3074-3085.
Table 3. Choline-Chloride/Urea Recycling.
5
6
7
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% Yield
97
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17 A). Uthukrishnan, M.; More, S.V.; Garud, D.R.; Ramana, C.V.;
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tetrahydro- β
-carbolinequinxalinones
in
1-n-butyl-2,3-
(bis)trifluoromethylsulfonylimide
1-n-butyl-2,3-dimethylimidazoium
dimethylimidazolium
([bdmim][Tf2N])
and
perfluorobutylsulfonate ([bdmim][PFBuSO3]) ionic liquids.
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19 Representative Procedure: The aldehyde (1 mmol) and tryptamine
(1 mmol) were combined in 1 mL of choline chloride/urea and
heated to 80 C with stirring for two hours. Upon completion of
the reaction, it was cooled and then extracted with diethyl ether (3
x 3 mL). The ether layer was concentrated by rotary evaporation
to afford the anticipated products in pure form. The residual DES
layer could be recycled following brief drying in vacuo. In a few
cases (such as entry 9 of Table 1), the product formed as a solid in
the reaction and could be isolated by simple filtration in pure
form. All products were characterized by 1H and 13C NMR, IR,
and melting point or Mass Spec and agreed with the data reported
in the literature.
9
10 For a recent review, see: Stoeckigt, J.; Antonchick, A.P.; Wu, F.;
Waldmann, H. “The Pictet-Spengler Reaction in Nation and
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8564.
11 Pictet, A.; Spengler, T. Ber. 1911, 44, 2030-2036.
12 A). Prajapati, D.; Gohain, M. “Iodine-Catalyzed Highly Effective
20 Spectral Data for two new compounds: Beta cyclocitral product:
1H NMR (360 MHz, CDCl3) 8.04 (br s, 1H), 7.64 (dd, J = 8.0 Hz,
1H), 7.46-7.41 (m, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.11 (t, J = 7.5
Hz, 1H), 7.02 (d, J = 7.8 Hz, 1H), 3.82 (t, J = 6.4 Hz, 1H), 3.10 (t,
J = 7.6 Hz, 2H), 2.03 (m, 2H), 1.60 (m, 2H), 1.44 (m, 2H), 1.71 (s,
3H), 0.87 (s, 3H), 0.72 (s, 3H); 13C NMR (90 MHz, CDCl3)
166.21, 161.93, 146.17, 130.98, 127.45, 121.90, 119.24, 119.20,
112.08, 111.11, 62.76, 61.71, 58.53, 56.59, 33.62, 28.49, 27.28,
22.56, 18.53, 15.35. trans-cinnamaldehyde product: 1H NMR
(360 MHz, CDCl3) 8.15 (br s, 1H), 7.92 (d, J = 15.4 Hz, 1H), 7.64
(dd, J = 7.0, 7.8 Hz, 1H), 7.45 (d, J = 7.8 Hz, 2H), 7.38-7.33 (m,
3H), 7.18 (t, J = 7.8 Hz, 1H), 7.12 (dd, J = 7.0, 7.4 Hz, 1H), 7.02
(d, J = 7.4 Hz, 1H), 6.89 (d, J = 15.4 Hz, 1H), 6.88 (s, 1H), 6.08
(br s, 1H), 3.87 (t, J = 6.8 Hz, 1H), 3.14 (t, J = 7.6 Hz, 2H), 2.94 (t,
J = 7.6 Hz, 2H); 13C NMR (90MHz, CDCl3) 162.9, 141.5, 136.4,
135.8, 129.4, 128.9, 128.7, 128.3, 127.6, 127.3, 122.1, 122.0,
119.3, 119.0, 111.2, 61.9, 42.3, 29.7.
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of
1,2,3,4,6,7,9,
10,
15b,
decahydropyrido[1”,2”:1’,2’]pyrzaino[4’,3’:1,2]pyrido[3,4-
15c-
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b]indoles.” J. Chem. Soc., Perkin Trans 1 1990, 2311-2315.
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