Microwave activation of an asymmetric Michael reaction: Unexpected behaviour of chiral α-alkoxy imines

Article abstract of DOI:10.1016/S0957-4166(03)00573-1

While it has been previously established that chiral α-alkoxy imines undergo thermal rearrangement at temperatures above 50°C, the microwave activation of the Michael addition between chiral imine 3b and methyl acrylate at 100°C led cleanly to the corresp

Full text of DOI:10.1016/S0957-4166(03)00573-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3263–3266
Microwave activation of an asymmetric Michael reaction:
unexpected behaviour of chiral a-alkoxy imines
Cheikhou Camara, Laurent Keller and Franc¸oise Dumas*
BIOCIS, Unite´ associe´e au CNRS, Centre d’Etudes Pharmaceutiques, Universite´ Paris Sud, 5, rue J.-B. Cle´ment, 92290,
Chaˆtenay-Malabry Cedex, France
Received 26 June 2003; accepted 3 July 2003
Abstract—While it has been previously established that chiral a-alkoxy imines undergo thermal rearrangement at temperatures
above 50°C, the microwave activation of the Michael addition between chiral imine 3b and methyl acrylate at 100°C led cleanly
to the corresponding Michael adduct 5b without the formation of any rearranged product and with the same regio- and
stereoselectivity as the corresponding thermal condensation at 40°C (ee 95%).
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
methyl acrylate 4. This thereby allows the more substi-
tuted Michael adducts 5 to be obtained with a high
degree of regio- and stereocontrol (Scheme 1).1 Such
adducts featuring a stereogenic tetrasubstituted carbon
center are useful synthons for the asymmetric synthesis
of a variety of bioactive compounds.2 For example, we
have recently developed the use of a-acetoxyacryloni-
trile 6 as an electrophilic equivalent to acetaldehyde in
the Michael condensation of imine 3b,3 allowing the
first asymmetric synthesis of enantiopure (R)-8 methyl
Construction of CꢀC bonds plays a fundamental role in
organic synthesis and in particular, elaboration of
stereodefined, fully substituted carbon centers remains a
major challenge. Recently, Desmae¨le et al. showed that
replacement of the alkyl substituent by an alkoxy one a
to the carbonyl group in ketone 1, does not modify the
outcome of the asymmetric Michael reaction of the
corresponding imine 3 with electrophilic alkenes such as
Scheme 1. Reagents and conditions: i: (R)-2, catalyst, cyclohexane, 20°C, 24 h. ii: excess methyl acrylate, neat, 40°C, 4 days then
,
AcOH 20%, 20°C, 75%. iii: (R)-2, SiO2, Al2O3, 5 A MS, cyclohexane, 20°C, 3 h. iv: 2 equiv. 6, 20°C, 36 h then AcOH 20%, 20°C,
4 h, 72%.
* Corresponding author. Fax: 33 1 46 83 57 52; e-mail: francoise.dumas@cep.u-psud.fr
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00573-1

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C. Camara et al. / Tetrahedron: Asymmetry 14 (2003) 3263–3266
ester of the side chain of homoharringtonine (HHT),4 a
potent antileukemic alkaloid (Scheme 1).5 In this con-
text, we were interested in the synthesis of HHT side
chain analogues starting for instance from the known
Michael adduct (R)-5b. Herein, we report on the suc-
cessful microwave activation of the Michael addition of
the chiral imine 3b and methyl acrylate leading regio-
and stereoselectively, to this adduct 5b in a very short
time.6
molecular sieves1 since, above 50°C, such imines
undergo a thermal rearrangement.13 Indeed, Frahm
reported that imine 3b was not obtained when a mix-
ture of ketone 1b and 1-phenylethylamine (R)-2 was
refluxed in toluene. Instead the a-aminoketone 9 was
formed in a non stereoselective manner, from which the
enantiopure hydrochloride 10 could be separated by
fractional crystallization. Compound 10 led in turn to
the formation of a-hydroxyketone 12 upon heating in
aqueous ethanol for one day, via hydrolysis of the
corresponding a-hydroxyimine 11 (Scheme 2).14 Such
thermal rearrangements could be a major drawback in
the case of microwave-assisted asymmetric Michael
reaction. Nevertheless, this flash heating could be
beneficial if the expected Michael reaction of imine 3b is
faster than its undesired rearrangement pathway.
We were encouraged to exploit the potential of
microwave irradiation as a non-conventional energy
source known for the promotion of organic reactions
associated with slow reaction rates such as the Michael
reaction leading to 5b. Microwave (mW) flash heating
has become a popular and efficient way of promoting
organic transformations, mainly in solvent-free systems,
giving rise to significant increases in reaction rates,
along with cleaner reactions that are easier to work up
together with improvements in yields, when compared
to the corresponding conventional thermal reactions.7
Concerning most of the studied reactions, the chemical
reactivity is unchanged and no variation in the isomeric
distribution is observed. However, the temperature
profiles achieved under microwave irradiation are not
accessible by conventional heating and can allow some
differentiation in reaction pathways.8 Consequently,
interest in microwave assisted organic reactions has
increased considerably in recent years. Since 1986,9 the
importance of mW in organic synthesis has been amply
demonstrated by more than 1000 publications in this
field, although few examples of microwave-promoted
asymmetric Michael reactions have been reported to
date.10 Due to the slow rate of the asymmetric Michael
reaction under consideration (3b+4“5b), and to the
fact that both the regio- and the stereoselectivity of the
process are unchanged at high reaction temperatures,
coupled with the asynchronous nature of the transition
state of this concerted reaction11 leading to its polariza-
tion, microwave activation of this reaction seemed
promising, provided that the remarkable regio- and
stereocontrol of the process could be maintained.12
2. Results
A first set of experiments was conducted using mixtures
of imine 3b and excess methyl acrylate 4 under conven-
tional heating, at temperatures below 50°C (Scheme 3).
This condensation did not go to completion at 20°C
even after 1 week, and at 30°C for the same time the
yield of 5b was only 61%. The best result was obtained
at 40°C for 5 days after which the keto ester (2R)-5b1
was obtained regioselectively in 85% yield without any
trace of the hydroxyketone 12. In order to compare the
stereoselectivities of the microwave and the conven-
tional processes, a method for the accurate determina-
tion of enantiomeric excess in Michael adduct 5b was
desirable. In contrast to the keto ester 5a1,15 and the
Michael adduct 7,3 however, the determination of the
ee of ketone 5b was not possible using NMR experi-
ments in the presence of the chiral shift reagent
Eu(hfc)3. Fortunately, this ee could be determined as
95% by using chiral HPLC, in comparison to ( )-5b
obtained similarly from imine 3b prepared from
racemic 1-phenylethylamine 2.
We next turned our attention to the focused-microwave
experiments. Since we were looking for rapid reactions,
high temperatures were selected, typically between 100
and 200°C, far above the rearrangement temperature
limit (50°C). Mixtures of imine 3b and 2 equivalents of
At this point, it should be noted that these chiral
a-alkoxy imines 3 have to be prepared at room temper-
ature in the presence of an acid–base catalyst and
Scheme 2. Reagents and conditions: i: (R)-2, PhCH3, 110°C, 3 h, 100%. ii: HCl, Et2O, 33%. iii: EtOH–H2O, 100°C, 24 h, 66%.

C. Camara et al. / Tetrahedron: Asymmetry 14 (2003) 3263–3266
3265
Scheme 3.
methyl acrylate 4 were placed in sealed,16 10 mL heavy-
walled Pyrex tubes17 and introduced into the cavity of a
single-mode18 device allowing control of the irradiation
power, temperature and pressure.19 Although it has
been established that microwave heating induces local-
ized enhancements of reaction rates, thus providing
non-isothermal and heterogeneous kinetics,20 the exper-
iments were conducted with continuous magnetic stir-
ring in order to achieve as much as possible
homogeneous temperature of the reaction medium. The
mW power was adjusted to reach the desired reaction
temperature in less than 2 min (100 W for experiments
at 100°C and 250 W for reactions at 200°C). Maximum
observed reaction pressures were 1.7 bars at 100°C and
4.2 bars at 200°C. The reactions were run for 15 or 30
min, and analyzed after hydrolysis of the crude reaction
mixtures (AcOH 20%: THF 1:2, 17 h, 20°C). All of the
starting imine 3b was consumed in 15 min. No inci-
dence of the reaction time on either yields (72–85%) or
regio- and stereoselectivities (>95%) was observed. At
100°C, the only reaction product was the expected
Michael adduct 5b.21 Measurement of the optical activ-
ity of Michael adduct 5b showed that both the sense
and the extent of the asymmetric induction of the
microwave experiment correlated with that obtained
with conventional heating. This was further demon-
strated by chiral HPLC analysis of adduct 5b (ee 96%).
In contrast, under forcing conditions (mW, 200°C) the
rearranged compound, 2-hydroxy-2-benzylcyclohex-
anone 12 was formed as the major product (12:5b=2:1,
combined yield 72%).
use of microwave for this asymmetric Michael reaction
of chiral imines in neutral media. Work is currently in
progress to expand the scope of this mW-promoted
asymmetric Michael addition.
Acknowledgements
We warmly thank Dr. Andre´ Loupy (Orsay, CNRS and
Universite´ Paris XI, France) for microwave facilities
and stimulating discussions, CEM Corp. for their tech-
nical assistance and Thomas Romero for performing
preliminary experiments.
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already reported,1 [h]D20=+32 (c 10, EtOHabs), lit.:1 [h]2D0=
1
+32.5 (c 10, EtOH), H NMR (200 MHz, CDCl3) l ppm:
7.4–7.2 (m, 5H), 4.47 (d, J=11.2 Hz, 1H), 4.14 (d,
J=11.2 Hz, 1H), 3.63 (s, 3H); 2.74 (m, 1H), 2.39–1.39
(m, 11H); 13C NMR (50 MHz, CDCl3) l ppm: 211.9 (C);
173.5 (C); 137.8 (C); 128 (2CH); 127.2 (2CH); 126.9
(CH); 81.8 (C); 64 (CH2); 51.2 (CH3); 39.2 (CH2); 36.7
(CH2); 27.4 (CH2); 27.2 (CH2); 26.6 (CH2); 20.5 (CH2).
IR (neat, w cm−1): 2944, 2864, 1735, 1716.