Kinetic study of microwave-assisted Wittig reaction of stabilised ylides with aromatic aldehydes

Article abstract of DOI:10.1016/S0040-4039(01)01384-3

The Wittig reaction of a pool of stabilised ylides and aromatic aldehydes was carried out in a microwave oven. Only a few minutes were needed for high conversion rates under microwave heating in comparison to hour time with traditional methods.

Full text of DOI:10.1016/S0040-4039(01)01384-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6827–6829
Kinetic study of microwave-assisted Wittig reaction of stabilised
ylides with aromatic aldehydes
Sara Frattini, Monica Quai and Enzo Cereda*
Chemistry Centre, Boehringer Ingelheim Italia, Via Lorenzini 8, 20139 Milan, Italy
Received 13 January 2001; revised 26 July 2001; accepted 27 July 2001
Abstract—The Wittig reaction of a pool of stabilised ylides and aromatic aldehydes was carried out in a microwave oven. Only
a few minutes were needed for high conversion rates under microwave heating in comparison to hour time with traditional
methods. © 2001 Elsevier Science Ltd. All rights reserved.
The initial and empirical observation that some organic
reactions proceed faster and with higher yields under
microwave irradiation in comparison to conventional
heating has resulted in intense and broad research in
the field. Microwave-assisted synthesis is a new and
quickly growing area in synthetic organic chemistry.1 In
most cases reactions that normally require many hours
at reflux temperature under classical conditions can be
completed within a few minutes or even seconds in a
microwave oven, even at comparable reaction
temperatures.
Anyway, under conventional conditions the reaction
time of stabilised ylides with aromatic aldehydes is
normally long and it is strongly affected by the aro-
matic substitution pattern.
Our work describes the synthesis of a pool of olefins
from stabilised ylides and aromatic aldehydes via a
microwave accelerated Wittig reaction and the kinetic
study of these reactions in different conditions at differ-
ent times, with different reactive substrates. We have
compared all the results in order to demonstrate that
moving from traditional to microwave conditions, times
are shorter and yields are better.
Although more recent methods have been made avail-
able in the last decades, the Wittig reaction remains one
of the most robust and reliable tool for the formation
of the carbonꢀcarbon double bond in synthetic organic
chemistry.2
We have also compared the behaviour of two different
solvents, one more commonly used for Wittig reactions
(THF) and a more suitable one for microwave condi-
tions (DMSO).
Very recently, a method based on the microwave heat-
ing in a simple domestic oven for the rapid preparation
of phosphonium salts, precursor intermediates in the
Wittig reaction, was described.3 There are also some
reports dealing with the formation of the double bond
in the Wittig reaction from organophosphorus reagents
under microwave conditions. These papers have mainly
synthetic purposes as they describe different synthetic
approaches of Wittig reactions with ketons and
aldehydes.4
Here we report the results of our investigation on this
reaction when carried out under microwave and normal
conditions (see Scheme 1).
Four benzaldehydes substituted both with electron
releasing or withdrawing groups and one heteroaro-
matic aldehyde were reacted in a domestic oven with
five ylides stabilised by the traditional carbonyloxy,
Scheme 1. Wittig reaction of stabilised ylides with aromatic aldehydes.
Keywords: microwave heating; Wittig reaction; stabilised ylides.
* Corresponding author. Tel.: +39025355433; fax: +39025355457; e-mail: ecereda@mil.boehringer-ingelheim.com
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01384-3

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S. Frattini et al. / Tetrahedron Letters 42 (2001) 6827–6829
cyano and carbonylmethyl groups and by the less com-
extent being this effect limited to coupling to ylide 5 (5,
b–c). Under traditional conditions in THF the conver-
sion rate of the aldehydes a, b, c, d with all ylides never
equals that observed with the microwave oven even
after one hour reflux. The only case in which both
methods are similar as far as the reaction time is
concerned (5 minutes), refers to p-nitro benzaldehyde
(1–5, e; methods A and D). The conversion rates are
mostly affected by the substitution pattern of alde-
hydes; the ylides seem to play a minor role, even if
considering the lower conversion for compounds 5, a–c
one could speculate on a lower reactivity for ylide 5. It
is worthwhile noting that when method C is applied
(THF as a solvent, times lasting up to 15 minutes, 280
W potency), the results with microwave chemistry are
closely similar to that obtained under conventional
conditions (1–5, a–c). This confirms the crucial and
pivotal role played by the solvent used to carry out the
microwave reactions.
mon N-methyl-N-methoxy carbonylamino group.5
Along with a standard microwave protocol (DMSO, 5
min, 280 W potency), as a comparison different tradi-
tional conditions were tested (THF, 5–60 min, room
temperature or reflux). An additional method bridging
the gap between traditional and microwave conditions
was investigated as well (THF/DMSO drops, 15 min,
280 W potency). The conversion rate of the aldehydes
into the expected olefins was determined by monitoring
the reactions at a fixed time with HPLC chromatogra-
phy.6 In 20 cases, out of the 25 investigated, a substan-
tial and positive effect was always observed both in
terms of reaction time and conversion percentage
(Table 1).
Aldehydes b–e are fully converted (100%) into the
expected olefins after just 5 minutes microwave heating
(1–4, b–e). p-Methoxy benzaldehyde under similar con-
ditions shows a reduced reactivity (51–70%) with all five
ylides (1–5,a). Analogously, p-chloro and 3,4,5
trimethoxy benzaldehyde react to only about 50%
In conclusion we have set up a rapid and general
method for the Wittig reaction between aromatic alde-
hydes and stabilised ylides taking advantage of
Table 1. Wittig reaction of stabilised ylide and aromatic aldehyde (% of conversion of aldehyde into products)
Cpd
A
B
C
D
Cpd
A
B
C
D
Cpd A%f
D
Cpd A%f
D
Cpd A%f
D
1a
19
28 18 54 1b
67
84 93 100
1c
79
100
1d
56
100 1e
100
100
2a
3a
36
36
55 33 65 2b
81
73
92 82 100
2c
90
100
100
2d
65
100 2e
100
100
100
60 33 70 3b
87 79 100
3c7
60
3d7
50
100 3e
100
4a
5a
27
31 14 51 4b
50
60 65 100
4c
5c
67
10
100
46
4d
5d
64
35
100 4e
100 5e
100
100
100
100
n.r.
16 30 56 5b
n.r.
23 25
50
(a), (b), (c), (d), (e): The same results were obtained in classical conditions under refluxing for 24 hours.
(f): in these cases the reaction rate is high even in classical conditions, so we have to compare the reactions at shorter times.
Method A, A%, B, C, D: see Ref. 5.

S. Frattini et al. / Tetrahedron Letters 42 (2001) 6827–6829
6829
microwave chemistry. Carrying out these reactions
under this unconventional heating in the presence of an
appropriate solvent (DMSO) has the major advantage
of very shortened reaction times (5 minutes in most
cases) coupled with high yields.
aldehyde, 1 equiv. ylide, 2 ml THF, magnetic stirring,
room temperature, 5 min; (B) 60 mg aldehydes, 1 equiv.
ylide, 2 ml THF, magnetic stirring, reflux, 1 h; (C) 20 mg
aldehyde, 1 equiv. ylide, 500 ml THF/10 ml DMSO, 15 min
in a domestic microwave oven at 280 W potency; (D) 20
mg aldehyde, 1 equiv. ylide, 200 ml DMSO, 5 min in a
domestic microwave oven at 280 W potency.
References
6. HPLC method: eluent CH3CN:H2O=50:50 (plus HCOOH
10%); flux: 1 ml/min; analysis and integration of the
chromatographic peaks at 254 nm; instrument: HP series
1100.
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literature. Their structure was identified and confirmed by
LC–MS and NMR analysis. LC–MS analysis: LC: C8
reverse phase column (Symmetry Waters 4.6×15 cm) gradi-
ent method (from H2O/0.2% formic acid:CH3CN=80:20
to H2O/0.2% formic acid:CH3CN=20:80 in 20 min) 1
ml/min for 20 min; mass spectrometry was performed on a
Finnigan SSQ7000 in APCI+mode, Heater temp.=450°C.
1H NMR (Varian 200 MHz, CDCl3). Compound 3c: 3.31
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ppm (2H, d); 7.50 ppm (2H, d); 7.68 ppm (1H, d). Com-
pound 3d: 3.33 ppm (3H, s); 3.78 ppm (3H, s); 7.13 ppm
(1H, d); 7.38 ppm (1H, m); 7.72 ppm (1H, d); 7.93 ppm
(1H, m); 8.60 ppm (1H, m); 8.82 ppm (1H, d).
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5. Methods: (A) 60 mg aldehyde, 1 equiv. ylide, 2 ml THF,
magnetic stirring, room temperature, 1 h; (A%) 60 mg