A facile route to acyclic substituted α,β-unsaturated aldehydes: The allene claisen rearrangement

Article abstract of DOI:10.1021/ol990305m

(equation presented) Sigmatropic rearrangement of allenyl ethers furnishes α,β-unsaturated aldehydes in good yield.

Full text of DOI:10.1021/ol990305m

ORGANIC
LETTERS
2000
Vol. 2, No. 5
571-572
A Facile Route to Acyclic Substituted
r,â-Unsaturated Aldehydes: The Allene
Claisen Rearrangement
,†
Philip J. Parsons,* Peter Thomson,† Andrew Taylor,‡ and Timothy Sparks†
The Chemical Laboratories, CPES, The UniVersity of Sussex, Falmer,
Brighton BN1 9QJ, and SmithKline Beecham Pharmaceuticals, New Frontier Park,
Cold Harbor Lane, Harlow, Essex CM19 5AD, U.K.
p.j.parsons@sussex.ac.uk
Received September 30, 1999
ABSTRACT
Sigmatropic rearrangement of allenyl ethers furnishes r,â-unsaturated aldehydes in good yield.
In our synthetic approach to the antifungal agent galbonolide
B1 (1) we required the highly substituted unsaturated
aldehyde 2. Retrosynthetic analysis of 2 revealed that an
substrates for chorismate mutase enzymes. Dulce`re et al have
reported a cyclic variant of the allene Claisen rearrangement,4
but to our knowledge no work has appeared on the rear-
rangement of acyclic allenyl ethers such as 3 for the
formation of R,â-unsaturated aldehydes. In this paper we
describe a convenient route to R,â-unsaturated aldehydes
from a range of aldehydes selected as part of our model study
work.
The allenyl ethers5 were synthesized according to the
general route outlined in Scheme 2. A range of aldehydes
(4) were reacted with propenylmagnesium bromide (5) to
form, after aqueous workup, the expected allylic alcohols
allene variant of the Claisen rearrangement2 should provide
the unsaturated aldehyde moiety in one synthetic operation
(Scheme 1).
Scheme 2a
Scheme 1
The literature revealed that Sleeman3 and co-workers had
synthesized highly substituted allenyl ethers as suicide
a (i) vinyl/propenylmagnesium bromide/THF/-78 °C. (ii) NaH/
propargyl bromide/THF/reflux. (iii) KOtBu/THF; (iv) ∆.
† The University of Sussex.
‡ SmithKline Beecham Pharmaceuticals.
10.1021/ol990305m CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/16/2000

of sodium hydride. Reaction of the ethers (7) with potassium
tert-butoxide gave the allenes (8) in high yield.6 Thermolysis
of the allenes (8) in dry dimethylformamide at 120 °C (9a-
f, method A) or in dry benzene at 80 °C (9g,h, method B),
gave the desired aldehydes in good yield (Table 1).7
Although the di- and trisubstituted double bonds in 9a and
9e-h were formed predominantly (97%) as the E isomers,
9c and 9d were isolated as mixtures of geometric isomers
(60:40 E/Z).
Table 1. Transformation from Propargyl Ethers to
R,â-Unsaturated Aldehydes via the Allenyl Ether
This simple rearrangement sequence offers a one-step
alternative to the Mannich reaction and a useful route to
allylic alcohols for further iterative elaboration by allene
Claisen rearrangements.
Acknowledgment. We thank SmithKline Beecham, Ya-
manouchi Pharmaceuticals, and the EPSRC for generous
support (to Peter Thomson).
OL990305M
(1) Achenbach, H.; Muhlenfeld, A.; Fauth, V.; Zahner, H. Ann. N.Y. Acad.
Sci. 1988, 544, 128.
(2) Wipf, P. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Paquette, L. A., Eds.; Pergamon Press: New York, 1991; p 827.
(3) Sleeman, M. J.; Meehan, G. V. Tetrahedron Lett. 1989, 30, 3345.
(4) Dulce`re, J.-P.; Crandall, J.; Faure, R.; Santelli, M.; Agati, V.; Mihoubi,
M. N. J. Org. Chem. 1993, 58, 5702.
(5) Hoff, S.; Brandsma, L.; Arens, J. F. Recl. TraV. Chim. Pays-Bas 1968,
87, 916.
(6) Krirdin, L. B.; Shcherbakor, V. V.; Proidakor, A. G.; Kalabin, G.
A.; Trofimov, B. A. J. Org. Chem., USSR 1988, 24, 924.
(7) A typical experimental procedure is as follows: (ii) Formation of
propargyl ether; sodium hydride 95% (0.061 g, 2.4 mmol) was added to
alcohol 7h (0.540 g, 2.0 mmol) with stirring in THF (15 cm3), and the
reaction mixture was then refluxed for 1 h under nitrogen to give a yellow
solution. Propargyl bromide was added (0279 g, 2.1 mmol), and the reaction
mixture was refluxed for a further 8 h, allowed to cool, and then partitioned
between diethyl ether (20 mL) and water (30 mL). The aqueous phase was
then extracted with diethyl ether (2 × 20 mL), and the organic phases were
combined, washed with brine, dried (MgSO4), and concentrated in vacuo.
Flash silica chromatography, eluting with 5% diethyl ether in petroleum
ether, afforded the product as a colorless oil (0.585 g, 95% yield). (iii)
Isomerization to the allenyl ether; potassium tert-butoxide (0.181 g, 162
mmol) was added in one portion to a stirred solution of the propargyl ether
8h (0.500 g, 1.62 mmol) in dry THF (30 mL) to give immediately a dark
brown solution. The reaction mixture was stirred for 4 h at room temperature
before being passed through a silica plug to remove the color impurity,
yielding the allenyl ether as a colorless oil (0.491 g, 98%). (iv) Claisen
rearrangement Method A: to the allenyl ether (typically around 1-2 mmol)
was added dry dimethylformamide (30 mL), and the reaction mixture was
heated to 120 °C for 1 h and then cooled to room temperature. The reaction
mixture was partitioned between diethyl ether (100 mL) and water (300
mL), and the aqueous phase was extracted with diethyl ether (3 × 20 mL).
The combined extracts were washed with brine (2 × 20 mL), dried (MgSO4),
and concentrated in vacuo to afford the desired aldehydes as amber oils.
Method B: to the allenyl ether (typically around 1-2 mmol) was added
dry benzene (30 mL). The reaction mixture was heated to reflux for 10 h,
cooled to room temperature, and concentrated in vacuo to afford the desired
aldehydes as amber oils.
(6). Conversion of the alcohols (6) into the propargyl ethers
(7) was achieved using propargyl bromide in the presence
572
Org. Lett., Vol. 2, No. 5, 2000