Tandem Horner-Wadsworth-Emmons olefination/Claisen rearrangement/hydrolysis sequence: Remarkable acceleration in water with microwave irradiation

Article abstract of DOI:10.1055/s-2005-918452

A tandem three-step, one-pot method for the conversion of aldehydes into β-substituted-2-oxohex-5-enoic acids 1 in good to excellent yield is described. The optimised sequence is carried out in water with microwave irradiation and involves sequential Horn

Full text of DOI:10.1055/s-2005-918452

SHORT PAPER
3193
Tandem Horner–Wadsworth–Emmons Olefination/Claisen Rearrangement/
Hydrolysis Sequence: Remarkable Acceleration in Water with Microwave
Irradiation
Tandem
Horner
r
–Wadsw
n
orth–Emm
o
e
ns
O
lefina
t
s
t
nRearr
o
a
ngement Quesada,*,1 Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Fax +44(1904)434523; E-mail: rjkt1@york.ac.uk
Received 21 February 2005
Dedicated to Professor Steven Ley on the occasion of his 60th birthday to acknowledge his friendship and his inspirational contributions to
synthetic organic chemistry
phosphonate 3. Compound 3 was easily obtained on a
Abstract: A tandem three-step, one-pot method for the conversion
multigram scale from diazophosphonate 67 and allyl alco-
of aldehydes into b-substituted-2-oxohex-5-enoic acids 1 in good to
excellent yield is described. The optimised sequence is carried out
hol in a ruthenium-mediated8 process (Scheme 2).
in water with microwave irradiation and involves sequential Hor-
ner–Wadsworth–Emmons (HWE) olefination, Claisen rearrange-
ment and ester hydrolysis. The outcome of this domino sequence
can be controlled by the temperature of the process.
allyl alcohol (3 equiv)
O
O
N2
Rh2(OAc)4 (1 mol%)
toluene, Ar
O
EtO
EtO
EtO
EtO
EtO
EtO
P
P
O
reflux, 3 h
83%
O
Key words: tandem reactions, rearrangements, domino reactions,
Wittig reactions, carboxylic acids
6
3
Scheme 2 Synthesis of phosphonate 3.
As part of a natural product programme, we required easy
access to a range of homoallylic a-ketoacids 1. We
thought that Horner–Wadsworth–Emmons (HWE) olefi-
nation of aldehydes 2 with phosphonate 3 bearing an allyl
group would produce 2-alkoxycarbonyl allyl vinyl ethers
4, whose rearrangement should give esters 5 and hence ac-
ids 1. Given our recent interest in tandem processes2 we
also envisaged that the sequence depicted in Scheme 1
could ultimately be carried out in a one-pot process.
With phosphonate 3 in hand, the viability of the stepwise
and tandem methodology was explored using benzalde-
hyde as the model system (Scheme 3). First, HWE olefi-
nation was carried out under heterogeneous conditions in
water, using a concentrated aqueous solution of K2CO3 as
the base under the conditions developed by Villieras and
co-workers.9 The transformation proceeded at room tem-
perature, affording 1,5-diene 4a in 96% yield (E:Z = 1:1)
after three hours. Diene 4a underwent thermal rearrange-
ment in toluene (120 °C, 6 h), affording racemic ester 5a
in 83% yield. Finally, saponification of 5a using aqueous
K2CO3 then gave acid 1a in 87% yield. Ketoacid 1a was
crystalline and X-ray crystallographic analysis10 confir-
med the proposed structure (Figure 1).
Of course, the Claisen rearrangement of allyl vinyl ethers
is a well known process3 but phosphorus-based olefina-
tion methods have not been widely used to access Claisen
rearrangement precursors.4,5 Moreover, the combination
of these methodologies in a tandem fashion has been re-
ported only rarely,5 although recent examples have dem-
onstrated the power of the methodology.6 In order to
explore the procedure for olefination/Claisen rearrange-
ment depicted in Scheme 1, we first prepared the novel
We next focused our attention on the development of a
tandem procedure. Given the success of the aqueous
HWE process, we attempted to carry out the three-step se-
Stepwise process
O
O
R
Claisen
rearrangement
O
R
O
R
O
O
HWE
O
Hydrolysis
O
O
EtO
EtO
+
EtO
HO
EtO
EtO
R
H
P
O
5
2
4
1
3
Tandem process
Scheme 1 Stepwise thermal transformation vs. tandem three-step, one-pot HWE olefination/Claisen rearrangement/hydrolysis sequence to
prepare a-ketoacids 1.
SYNTHESIS 2005, No. 19, pp 3193–3195
x
x.
x
x
.
2
0
0
5
Advanced online publication: 27.10.2005
DOI: 10.1055/s-2005-918452; Art ID: C04705SS
© Georg Thieme Verlag Stuttgart · New York

3194
E. Quesada, R. J. K. Taylor
SHORT PAPER
quence in one-pot fashion in water. Unfortunately, using
conventional heating, high temperature and prolonged re-
action times are required, which precludes a clean trans-
formation. However, we were delighted to discover that
microwave irradiation (50 W) of an equimolecular, heter-
ogeneous mixture of benzaldehyde and allyl phosphonate
3 in aqueous K2CO3 heated to 105 °C over ten minutes
produced ketoacid 1a directly in an excellent 88% overall
yield.
O
O
CHO
O
O
K2CO3/H2O
HO
EtO
EtO
EtO
+
Microwave
irradiation
50 W, 105 °C,
10 min
P
O
1a
3
2a
25 °C, 3 h (96%)
or
Microwave irradiation
50 W, 55 °C, 30 min
(100%)
K2CO3/H2O
∆, 3 h, 87%
88%
K2CO3/H2O
O
O
O
O
toluene
EtO
EtO
In addition to the simplicity and efficiency of the tandem
process, a further advantage is that the aqueous reaction
conditions ensure an extremely simple purification proce-
dure: extraction of the crude mixture with CH2Cl2 re-
moves all of the organic by-products, and acidification
with 10% HCl allows the acid 1a to be extracted into
EtOAc (leaving phosphorus by-products in the aqueous
layer). It is noteworthy that the progress of the process can
be controlled by adjustment of the reaction temperature in
the microwave reactor. The sequence stops after the HWE
olefination (quantitative) on heating to 55 °C at 50 W for
30 minutes, a significant rate enhancement compared to
the standard thermal process (Scheme 3).
∆, 120 °C
4a; E:Z = 1:1
5a
6 h, 83%
Scheme 3 Stepwise conventional vs. tandem microwave-mediated
transformation.
Thus, the sequential three-step process gave an overall
yield of 69% with a combined reaction time of 12 hours,
compared to the tandem process which gives 88% yield in
a single operation lasting ten minutes. The aqueous medi-
um employed for the tandem sequence presumably assist-
ed the sigmatropic rearrangement via the well-known
Figure 1 ORTEP plot of a-ketoacid ( )-1a (50% probability ther-
mal ellipsoids).
Table 1 Tandem Microwave-Assisted HWE–Claisen–Hydrolysis to Give Ketoacids 1
Entry Aldehyde
1
Product
Yield (%)
88
Entry Aldehyde
7
Product
Yield (%)
94
HO2C
HO2C
CHO
O
O
CHO
2
83
8
58b
HO2C
CHO
HO2C
O
OHC
Me
CHO
O
O
Me
HO2C
3
4
5
53
9
10
11
86
74
67c
HO2C
HO2C
HO2C
O
MeO
Ph
CHO
71a
O
CHO
MeO
Ph
64
93
CHO
HO2C
O
O
CHO
CHO
O
HO2C
HO2C
CHO
F3C
O
F3C
6
78
12
75c
HO2C
HO2C
O
CHO
O
CHO
Br
Br
a HWE olefination carried out for 12 h at r.t. prior to microwave irradiation.
b Phosphonate 3 (3 equiv) used and HWE olefination carried out at r.t. for 12 h prior to microwave irradiation.
c Diastereomeric (1:1) mixtures.
Synthesis 2005, No. 19, 3193–3195 © Thieme Stuttgart · New York

SHORT PAPER
Tandem Horner–Wadsworth–Emmons Olefination/Claisen Rearrangement/Hydrolysis
3195
hydrophobic acceleration effect,11 as well as effecting the
in situ hydrolysis of the intermediate a-ketoester.
CHa), 5.07 (m, 1 H, C6-CHb), 5.7 (m, 1 H, C5-CH), 7.25–7.4 (m, 5
H, Ph), 8.9 (br s, 1 H, OH).
13C NMR (100 MHz, CDCl3): d = 35.8, 51.9, 117.7, 128.1, 129.0,
129.1, 134.4, 134.8, 160.3, 194.5.
Having established an effective tandem protocol on the
model system, we investigated the scope and limitations
of the method (Table 1). The results clearly show that the
method is particularly efficient for aryl aldehydes (entries
1–8). The reaction is compatible with both electron-donat-
ing (entries 2 and 3) and electron-withdrawing (entries 4–
6) functional groups on the aromatic core. The method is
also applicable to hindered aromatic substrates (entries 6
and 7) and to bifunctional aryl aldehydes (entry 8). Ali-
phatic aldehydes are also suitable substrates (entries 9–
12), even when highly enolisable (entry 9). The method is
highly selective for aldehydes as ketones (e.g. acetophe-
none, cyclobutanone, cyclopentanone) do not react under
these conditions. It should be noted that, in certain exam-
ples (e.g. entry 3), improved yields were obtained if the
olefination reaction was allowed to reach completion pri-
or to microwave irradiation.
+
HRMS–CI: m/z [M + NH4 ] calcd for C12H16NO3: 222.11302;
found: 222.11302.
Acknowledgment
We thank A. C. Whitwood for the assistance with X-ray crystallo-
graphy.
References
(1) Present address: Instituto de Quimica Medica CSIC, Juan de
la Cierva 3, 28006 Madrid, Spain. E-mail: EQ1@iqm.csic.es.
(2) (a) Raw, S. A.; Taylor, R. J. K. J. Am. Chem. Soc. 2004, 126,
12260. (b) Oswald, M. F.; Raw, S. A.; Taylor, R. J. K. Org.
Lett. 2004, 6, 3997; and references cited therein. (c) Taylor,
R. J. K.; Reid, M.; Foot, J.; Raw, S. A. Acc. Chem. Res. in
press.
In conclusion, we have developed a technically simple
method for the synthesis of racemic 3-functionalised-2-
oxohex-5-enoic acids 1 in good to excellent yields
through a tandem three-step transformation involving
HWE olefination, Claisen rearrangement and hydrolysis
carried out in water under mild microwave-mediated con-
ditions. We are currently applying this methodology in
natural product synthesis.
(3) For recent reviews see: (a) Martín Castro, A. M. Chem. Rev.
2004, 104, 2939. (b) Ito, H.; Taguchi, T. Chem. Soc. Rev.
1999, 28, 43.
(4) (a) Kulkarni, M. G.; Pendharkar, D. S.; Rasne, R. M.
Tetrahedron Lett. 1997, 38, 1459. (b) For olefination thio-
Claisen rearrangement see: Corey, E. J.; Shulman, J. I. J.
Am. Chem. Soc. 1970, 92, 5522.
(5) (a) Schobert, R.; Gordon, G. J. Curr. Org. Chem. 2002, 6,
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(6) Schobert, R.; Gordon, G. J.; Mullen, G.; Stehle, R.
Tetrahedron Lett. 2004, 45, 1121.
(7) Tanako, S.; Tomita, S.; Takahashi, M.; Ogasawara, K.
Synthesis 1987, 1116.
One-Pot Microwave-Assisted Reaction; General Procedure
To a microwave tube containing benzaldehyde (63 mL, 0.53 mmol)
and phosphonate 3 (150 mg, 0.53 mmol), was added a 10 M aque-
ous solution of K2CO3 (12 equiv). The heterogeneous mixture was
efficiently stirred and irradiated in a CEM focused microwave (Dis-
covery model) operating at 50 W at 105 °C for 10 min. The crude
material was diluted with water and extracted with CH2Cl2 (3 × 10
mL). The aqueous layer was acidified with 10% HCl solution (20
mL) and extracted with EtOAc (5 × 10 mL). The EtOAc layer was
washed with water and brine (15 mL), dried (MgSO4), the solvent
was removed under reduced pressure, affording 1a (115 mg, 88%
yield) as a waxy viscous solid; mp 64–65 °C.
(8) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091.
(9) Villieras, J.; Rambaud, M. Synthesis 1983, 300.
(10) Crystallographic data for 1a can be obtained on request from
The Director, Cambridge Crystallographic Data Centre,
University Chemical Laboratory, Lensfield Road,
Cambridge CB2 1EW, UK. CCDC reference number:
255362. Selected crystallographic data: C12H12O3·C12H12O3
(dimer), M = 408.44, crystal system: Monoclinic, a = 16.103
(4), b = 5.4841 (12), c = 23.444 (5) Å, U = 2058.3 (8) Å3,
T = 115 (2) K, space group P2 (1)/c, Z = 8, m = 0.094 mm–1,
11027 reflections measured.
IR (film): 3430, 1725, 1519, 1258 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.59 (m, 1 H, C4-CHa), 2.85 (m,
1 H, C4-CHb), 4.68 (t, J = 7.6 Hz, 1 H, C3-CH), 5.02 (m, 1 H, C6-
(11) Gajewski, J. J. Acc. Chem. Res. 1997, 30, 219.
Synthesis 2005, No. 19, 3193–3195 © Thieme Stuttgart · New York