Prenylation reaction performed with catalytically generated potassium prenal dienolate

Article abstract of DOI:10.1055/s-1998-1955

A new prenylation method based on the reaction of catalytically generated potassium dienolate of prenal with α,β-unsaturated aldehydes is described. The reaction is highly regioselective, via a γ-1,2-addition, and provides an efficient route to retinal.

Full text of DOI:10.1055/s-1998-1955

December 1998
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Prenylation Reaction Performed with Catalytically Generated Potassium Prenal Dienolate
*
Dominique Cahard, Lucette Duhamel, Sandrine Lecomte, Jean-Marie Poirier†
UPRES A 6014 CNRS et Institut de Recherche en Chimie Organique Fine (IRCOF), Université de Rouen, Faculté des Sciences
F-76821 Mont-Saint-Aignan Cedex, France.
Fax : 02 35 52 29 71; e-mail: Lucette.Duhamel@univ-rouen.fr
† Deceased on May 7th, 1997
Received 12 September 1998
Abstract: A new prenylation method based on the reaction of
catalytically generated potassium dienolate of prenal with α,β-
unsaturated aldehydes is described. The reaction is highly
regioselective, via a γ-1,2-addition, and provides an efficient route to
retinal.
Continuing our interest in the application of alkali enolates in synthetic
organic chemistry, we developed a new methodology providing an easy
1
access to potassium enolates. The regioselectivity, γ-1,2- versus γ-1,4-
addition, in the addition of potassium prenal dienolate to α,β-
2
unsaturated aldehydes was investigated, and was found to be highly
selective for a γ-1,2-addition. However, in some cases, the γ-1,4-
2
addition product cannot be avoided. During our investigation, we noted
that catalytically generated potassium dienolate of prenal, by means of a
Scheme 1
catalytic amount of potassium tert-butoxide on the corresponding silyl
1
enol ether 1, accomplished the aldol reaction with benzaldehyde. The
oxygen-silicon bond, which is cleaved by t-BuOK is also broken by the
hydroxy dihydropyran anion 2a, that is generated in situ. This leads to
the silyl-protected product 2b which could be isolated or transformed
into hydroxy dihydropyran 2c during the work-up (Scheme 1).
method is the formation of an O-silylated hydroxy dihydropyran
intermediate which prevents the retroaldol reaction that causes the γ-
1,4-addition.
3
Silyl enol ether 1 can be partially cleaved by 1 to 10% molar t-BuOK,
Herein, we report the outcome of the prenylation reaction of
enaldehydes performed with the dienolate of prenal generated by a
catalytic amount of alkali alkoxide. The significant advantage of this
to produce the equivalent amount of potassium dienolate and
t-butoxytrimethylsilane. The addition of a polyenaldehyde to the
mixture 1 / potassium dienolate produced only the hydroxy enaldehyde

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4 and the hydroxy dihydropyran 5 both resulting from the γ-1,2-
coupling reaction. The hydroxy enaldehyde 4 is the primary reaction
product and the 2Z isomer cyclises to form the hydroxy dihydropyran 5
(Scheme 2). The anion of the hydroxy dihydropyran 5 was the reason
for the cleavage of the silyl enol ether 1 and allowed the reaction to
methodology is of great interest in the preparation of polyene aldehydes
belonging to the vitamine A series. Therefore, aldehyde 3d served as
starting material to give the hydroxy dihydropyran 5d in 55 % yield but
together with 20 % of recyclable starting aldehyde.
Access to the polyenadehydes from both the hydroxy enaldehydes and
the hydroxy dihydropyrans was then studied. The reagents of choice
were either pyridine hydrochloride (method A in DMF/toluene at
4
proceed to completion. Prenal 3a, citral 3b, 3-methyl-5-phenyl-2,4-
5
pentadienal 3c and β-ionylidene acetaldehyde 3d served as
7
8
enaldehydes for this study (Table 1).
reflux) or hydrochloric acid 10% (method B in dichloroethane at r.t.) ,
due to a fast and clean reaction (Table 2). Methods A and B reported to
transform hydroxy dihydropyrans into polyenadehydes led respectively
to predominantly 2E and 2Z polyenadehydes 6. Applied to hydroxy
enaldehydes 4 method B led to polyenadehydes 6 via the intermediate
hydroxy dihydropyrans
5
as evidenced by TLC. The 2Z
polyenaldehydes that were obtained after a short reaction time slowly
isomerised to the 2E isomers reaching the thermodynamic equilibrium.
In conclusion, the catalytically generated dienolate of prenal is readily
available by alkoxide mediated cleavage of silyl enol ethers and it leads
to only a γ-1,2-addition with enaldehydes. We believe that the short and
efficient prenylation procedure we have demonstrated should prove a
very efficient route to polyenaldehydes.
Scheme 2
It is essential to note that none of the γ-1,4-coupled products was
1
detected by 200MHz H NMR in the crude reaction mixture. Moreover,
Acknowledgement: We are very grateful to the Ministère de la
the hydroxy enaldehyde was never obtained in experiments run with a
stoichiometric amount of t-BuOK but was present when a catalytic
Recherche et de l'Espace for supporting this research.
2
amount of t-BuOK was used. As a comparison, entries 1 and 2 of table 1
show that using a catalytic amount of t-BuOK, to generate the dienolate,
gave the γ-1,2-addition product with an improved yield. The lower yield
obtained when using a stoichiometric amount of t-BuOK (entry 1) was
due to the formation of 20% of γ-1,4-coupled product. This result
clearly shows that the use of a catalytic amount of potassium alkoxide
has a very positive impact on the outcome of the reaction. The reaction
time to achieve the prenylation took between 1 and 3 h, with 1 to 10 %
References and notes
(1) Duhamel, P.; Cahard, D.; Poirier, J.M. J. Chem. Soc. Perkin
Trans.1 1993, 2509-2511. Cahard, D.; Desmurs, J.R.; Duhamel,
L.; Duhamel, P.; Poirier, J.M. Fr. Patents 93.079.65 and 93.079.66.
(2) Cahard, D.; Poirier, J.M.; Duhamel, P. Tetrahedron Lett, 1998, 39,
7093-7096.
(3) Cazeau, P.; Duboudin, F.; Molines, F.; Laporte, O.; Dunoguès, J.
6
molar, at -78 °C (for a typical procedure see ). The stereoisomeric ratio
is in favour of the 2E isomer for the hydroxy enaldehyde 4 and the cis
diastereoisomer is predominant for the hydroxy dihydropyran 5. Our
Tetrahedron 1987, 43, 2089.
(4) In some experiments the O-silylated hydroxy dihydropyran was
inferred in the crude reaction mixture, but due to its high
propensity to hydrolyse during the work-up it was never obtained
in the expected yield.
(5) 3c was synthesised by prenylation of benzaldehyde and served as
the starting aldehyde for the new prenylation reaction.
(6) Typical procedure for the formation of 5d from 3d: A solution of
freshly sublimated potassium tert-butoxide (0.5 mmol) in
tetrahydrofuran (2 mL) was added to a stirred solution of the silyl
enol ether of prenal (5 mmol) in tetrahydrofuran (10 mL) at -78°C
and the mixture was stirred for 60 min. Then β-ionylidene
acetaldehyde (5 mmol) in tetrahydrofuran (5 mL) was added and
stirred for 60 min at -78°C. It was then quenched with water (10
mL), extracted with Et O and dried over MgSO . Concentration
2
4
and purification by flash chromatography on silica gel (Et O-light
2
petroleum ether, 15-85) gave 5d (833 mg, 55%) as a pale yellow
1
oil. Compound 5d: H NMR (CDCl ) : 0.97 (6H, s); 1.63 (3H, s);
3
1,74 (3H, s); 1.84 (3H, s); 1.35-2.10 (8H, m); 3.28 (OH, s); 4.84
(1H, m) ; 5.37 (1H, m) ; 5.45 (1H, m); 5.98 (1H, d, J=16.1); 6.11
13
(1H, d, J=16.1). C NMR (CDCl ) : 12.8, 19.1, 21.5, 22.7, 32.8,
3
39.4, 28.8, 34.1, 35.4, 63.7, 89.4, 120.0, 120.2, 127.1, 128.8,
129.2, 136.9, 137.3, 137.4. IR (neat): 3400, 2924, 1680. Anal.
C
H O (302.4): calcd C, 79.42; H, 10.00; found: C, 79.57; H,
20 30 2
10.16.
(7) Olson, G.L. Hoffmann La Roche. US Patent 1976 3,997,529.
(8) Bennani, Y.L.; Boehm, M.F. J. Org. Chem. 1995, 60, 1195-1200.

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(9) HIBAR Merck Licrosorb Si 60, 5µm column, 5% ethyl acetate-
hexane, 1.5 mL/min, 23 °C, λ = 366 nm. The mixture of
stereoisomers of retinal can be easily isomerised to the E isomer
according to Mukaiyama, T.; Ishida, T. Chem. Lett. 1975, 1201-
1203. Also U.S. Patent Eastman Kodak 1961, 3, 013, 080; Patent
AEC 1, 288, 972, C07c, Patent AEC 1, 291, 622, C07c.