Fluoride-promoted reactions of unsaturated carbonyl compounds. Dimerization by a non-Baylis-Hillman pathway

Article abstract of DOI:10.1016/S0040-4039(01)00454-3

Fluoride ion acts as a base toward α,β-unsaturated esters and cyclohexenone to induce self-condensation and/or double-bond isomerization.

Full text of DOI:10.1016/S0040-4039(01)00454-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3275–3277
Fluoride-promoted reactions of unsaturated carbonyl compounds.
Dimerization by a non-Baylis–Hillman pathway
Judy X. Xuan and Albert J. Fry*
Department of Chemistry, Wesleyan University, Middletown, CT 06459, USA
Received 23 February 2001; revised 13 March 2001; accepted 14 March 2001
Abstract—Fluoride ion acts as a base toward a,b-unsaturated esters and cyclohexenone to induce self-condensation and/or
double-bond isomerization. © 2001 Elsevier Science Ltd. All rights reserved.
the activated alkene.5,6 However, conversion of 2 must
We previously found that fluoride anion can convert
take place by a different mechanism than that by which
acrylates dimerize, for the following reasons: (a) acry-
late esters such as 1 bearing alkyl groups at the b-posi-
tion do not undergo dimerization at all under typical
Baylis–Hillman conditions; even under forcing condi-
tions (10 kbar pressure) 1 affords a dimer in only very
low yield in contrast to the relative ease with which it is
converted into 2; (b) as noted above, no fluoride-
induced dimerization took place with several more elec-
trophilic unsaturated esters not bearing such b-alkyl
groups.1,2 Conversion of 1 to 2 is very likely initiated by
g-proton abstraction from 1 by fluoride ion to produce
the resonance-stabilized anion 3. Nucleophilic attack of
3 upon 1, followed by a series of prototropic shifts,
would then lead ultimately to 2 (Scheme 1).
benzylic silanes to the corresponding benzylic carban-
ions in the presence of an unactivated silyl group and
that such carbanions can be trapped in good yield by a
variety of electrophiles.1,2 The electrophiles included the
esters dimethyl maleate, dimethyl fumarate, and methyl
cinnamate. Conjugate addition took place in good
yields with all of these esters. We report here, however,
that esters bearing g-protons follow a different reaction
course. When a dry THF solution containing methyl
crotonate (1) was refluxed in the presence of tetra-
butylammonium triphenyldifluorosilicate (TBAT)3,4 for
4 h, dimer 2 was formed in 74% yield. This reaction is
We were interested in the possibility of an intramolecu-
lar version of this dimerization. We therefore prepared
the doubly unsaturated ester 49 by double Horner–
Emmons condensation10,11 of methyl triphenylphospho-
ranylideneacetate with succindialdehyde. Treatment of
4 with TBAT in dry THF at 40°C for 40 min resulted
in complete conversion into an isomeric diester (5) as a
ca. 6:1 mixture of geometric isomers. No further reac-
tion was observed when the reaction mixture was
heated at 40°C for a further 12 h. We assign structure
5 to this isomeric diester on the basis of its 1H
superficially reminiscent of the well-studied Baylis–Hill-
man condensation of acrylate esters with aldehydes in
the presence of DABCO or related catalysts.5,6 Acrylate
esters, alkyl and aryl vinyl ketones, and acrylonitrile do
afford such dimers under Baylis–Hillman conditions.7,8
The mechanism of Baylis–Hillman dimerization
appears to be of addition–elimination type, in which
the first step is addition of DABCO at the b-position of
Scheme 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00454-3

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J. X. Xuan, A. J. Fry / Tetrahedron Letters 42 (2001) 3275–3277
and COSY NMR spectra and its ultraviolet spectrum
(umax 260 nm, log m=4.2 in EtOH), which closely
resembles that of roridin D, a naturally occurring
a,b,g,d-bis-unsaturated lactone.12 The 1D and 2D
proton NMR spectra of 5 in fact closely resemble
those of methyl sorbate and other a,b,g,d-unsaturated
esters13 and are considerably different from those of
the remaining double-bond positional isomers
dimethyl 3,5-octadienoate (6)9,14 and dimethyl 2,5-
octadienoate (7).15
pounds. Indeed, we have found that cyclohexe-
none undergoes a similar condensation in the pres-
ence of fluoride to afford dimer 8.20 Finally, it should
be noted that the fluoride-induced dimerization of
ethyl crotonate involves considerably milder condi-
tions than the literature procedure involving a sub-
stantial excess of very strong base such as potassium
or benzylpotassium.21–26 Fluoride has recently been
reported to be an efficient basic catalyst in another
context.27
We believe that fluoride again acts as a base to effect
this isomerization by a series of prototropic shifts
involving the unconjugated ester 7 as an intermediate.
The alternate Baylis–Hillman-type mechanism involv-
ing nucleophilic addition of fluoride ion to the b-posi-
tion of one of the unsaturated ester units of 4 seems
even more unlikely than for the dimerization of 1,
since it provides little driving force for conversion of
4 to 7.
Acknowledgements
Financial support was provided by the National Sci-
ence Foundation (grant c CHE-97-13306).
References
It is particularly interesting to note, in contrast to
this result, that 2,4-alkadienoic esters are deconju-
gated to the corresponding 3,5-dienoic esters under
the influence of strong bases such as lithium
dialkylamides14,16,17 and that a,b-unsaturated esters
are converted to b,g-unsaturated esters under these
same conditions.18,19 Such isomerization reactions are
typically effected by conversion of the unsaturated
ester to a conjugated anion, followed by rapid addi-
tion of a proton donor. The final step in this
sequence presumably involves kinetic protonation of
the respective pentadienyl or allyl anion. Isomeriza-
tion of 4 to 5, on the other hand, apparently pro-
ceeds under thermodynamic conditions, presumably
because of the weaker basicity of fluoride ion and the
presence of starting ester as a proton source to medi-
ate equilibration. The importance of the latter point
is demonstrated by the fact that deconjugation of a,b-
unsaturated esters does not take place if less than a
full equivalent of LDA is employed.19
1. Fry, A. J.; Xuan, J. X. Presented at the 216th American
Chemical Society National Meeting: Boston, MA,
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2. Xuan, J. X.; Fry, A. J., manuscript in preparation.
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Reactions such as these might be expected to take
place with other a,b-unsaturated carbonyl com-

J. X. Xuan, A. J. Fry / Tetrahedron Letters 42 (2001) 3275–3277
3277
18. Alcock, S. G.; Baldwin, J. E.; Bohlmann, R.; Harwood,
L. M.; Seeman, J. I. J. Org. Chem. 1985, 50, 3526.
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and dried over MgSO4. Concentration afforded a brown
oil, which was purified by flash chromatography over
silica gel. Elution with 20% ethyl acetate–hexane afforded
0.97 g (8%) of 49 as a colorless oil.
26. Dimethyl octa-2,4-dienoate (5). Dimethyl octa-2,6-
dienoate (4) (0.15 g, 0.75 mmol) and tetra-
butylammonium triphenyldifluorosilicate (0.2 g, 0.34
mmol) were dissolved in 20 mL of dry THF containing 1
g of activated molecular sieves. A trace of 5 was pro-
duced upon standing at room temperature overnight.
Heating for 40 min at 40°C under N2 resulted in complete
conversion of dimethyl octa-2,4-dienoate (5), as deter-
mined by GC–mass spectral analysis. After removal of
the molecular sieves by filtration, the THF was removed
by an aspirator and the residue redissolved in ether. It
was washed with 1 M HCl, water, and 5% NaHCO3 and
concentrated. Flash chromatography (hexane/ethyl ace-
tate) afforded 7 (0.145 g, 97%) as a clear colorless oil
whose properties suggested it to be a ca. 6:1 mixture of
23. Shabtai, J.; Ney-Igner, E.; Pines, H. J. Org. Chem. 1981,
46, 3795.
24. Ethyl 3-methyl-4-carboethoxy-D4,5-hexenoate (2). Ethyl
trans-crotonate (1.7 mL, 13.7 mmol) and tetratetra-
butylammonium triphenyldifluorosilicate (0.16 g,
3
mmol) were dissolved in dry THF containing 0.5 g of
activated molecular sieves. The clear colorless solution
was heated to 75°C for 4 h under N2. Flash chromatogra-
phy (hexane/ethyl acetate) afforded 4 (1.15 g, 74%) as a
7:1 E:Z mixture [deduced from the relative heights of the
vinyl proton quartets at l 6.83 (E) and 5.96 (Z)].
25. Dimethyl octa-2,6-dienoate (4). Dimethylsulfoxide (19.6
mL, 277 mmol) was added over 5 min to a solution of
oxalyl chloride (12.4 mL, 139.4 mmol) in 50 mL of dry
dichloromethane at −70°C. The solution was stirred for
15 min and then to it was added over 5 min a suspension
of 1,4-dihydroxybutane (5.23 g, 58 mmol) in 30 mL of
dichloromethane. After stirring for 2.5 h at −10°C, tri-
ethylamine (80.3 mL, 576 mmol) was added slowly and
the reaction mixture was allowed to warm to 0°C. Meth-
ylene chloride (400 mL) was added and to the dark
yellow suspension methyl triphenylphosphoranylideneac-
etate was added in one portion. After 21 h reflux, the
clear yellow solution was concentrated in vacuo to a
volume of 600 mL. It was then poured into 500 mL of
satd NaCl, extracted with methylene chloride (5×200 mL)
1
double-bond isomers: H NMR (CDCl3) (major isomer):
l 6.0–6.1 (m, 1H), 4.0 (s, 3H), 3.9 (s, 3H), 2.7 (m, 4H);
the COSY spectrum showed one cross-peak between l
6.0 and the 7.5 multiplet, another cross-peak between the
7.5 and 6.3–6.5 multiplets, and another within the latter
multiplet, as well as a cross-peak between the l 2.7 and l
6.3–6.5 resonances; 13C NMR (CDCl3) (major isomer): l
29, 36, 51.8, 51.9, 120.5, 130.5, 142.3, 146.5, 168.2, 173.6;
MS (EI): m/z 167, 138, 107, 99, 79, 68, 59; UV (EtOH):
umax 260 nm (log m=4.2); HRMS calcd for C10H14O4:
198.0892. Found: 198.0891.
27. Gangloff, A. R.; Litvak, J.; Shelton, E. J.; Sperandio, D.;
Wang, V. R.; Rice, K. D. Tetrahedron Lett. 2001, 42,
1441.
.
.