Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1679–1681
A facile one-pot synthesis of a-fluoro-a,b-unsaturated esters from
alkoxycarbonylmethyltriphenylphosphonium bromides
Yumiko Suzuki* and Masayuki Sato
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan
Received 29 September 2003; revised 17 December 2003; accepted 18 December 2003
Abstract—A convenient one-pot synthesis of a-fluoro-a,b-unsaturated esters from ethoxy- and tert-butoxycarbonylmethyltriphe-
nylphosphonium bromide was developed. The fluorinated phosphoranes, generated in situ from alkoxycarbonylmethyltriphenyl-
phosphonium bromides and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluorâ), undergo
a Wittig reaction with aldehydes to yield a-fluoro-a,b-unsaturated esters with (Z)-selectivity.
Ó 2003 Elsevier Ltd. All rights reserved.
Although the van der Waal radius of the fluorine atom is
comparable to that of hydrogen, the replacement of a
hydrogen atom in a molecule by a fluorine atom can
significantly change the properties of a molecular sys-
tem, as the fluorine substituent often enhances an
organic compoundÕs biological activities.1 Thus, syn-
theses of fluorine-containing compounds are of special
interest to organic chemists.2
ethoxylcarbonylfluoromethylenephosphoranes. How-
ever, there has been no paper concerning the reaction of
the phosphorane with aldehydes.
In this context, we report the first example of the reac-
tion of alkoxycarbonylfluoromethylenephosphoranes
with aldehydes to give a-fluoro-a,b-unsaturated esters.
We used ethyl bromoacetate as the starting compound,
because the a-bromo-a-fluoroacetate is expensive. Thus,
we studied the synthesis of alkoxycarbonylfluoromethyl-
enephosphorane 4 by electrophilic fluorination of the
parent phosphorane 2 readily prepared from inexpensive
ethyl bromoacetate. We also studied the one-pot syn-
thesis of a-fluoro-a,b-unsaturated esters from ethyl
bromoacetate and stereoselectivity in this Wittig reac-
tion.
a-Fluoro-a,b-unsaturated esters are versatile fluorinated
building blocks for the preparation of biologically active
compounds. Though other methods are available,3–6 the
main synthetic methods for the preparation of a-fluoro-
a,b-unsaturated esters and related compounds are the
Wittig and the Horner–Wadsworth–Emmons (HWE)
reactions.3 For the latter, Xu andDesMarteau7 developed
a convenient one-pot synthesis of a-fluoro-a,b-unsatu-
rated nitriles using diethyl cyanofluoromethanephosph-
onate. The HWE reaction usually gives good
(E)-selectivity at low temperatures (e.g., )78 °C). Nagao
and co-workers recently reported a (Z)-selective HWE
reaction for the preparation of (Z)-a-fluoro-a,b-unsatu-
rated esters.8 For the Wittig reaction, ethoxycarbonyl-
fluorophosphoranes were synthesized by Thenappan and
Burton.9 They used ethyl a-bromo-a-fluoroacetate as the
starting compound and studied alkylation of the
Selectfluorâ 6 (1.5 equiv) reacted with phosphorane 2,
generated in situ by the treatment of phosphonium
bromide 1 with sodium hydride (1.5 equiv), in acetoni-
trile at room temperature for 48 h. Sodium hydride was
then added, followed by the addition of 4-chlorobenz-
aldehyde 10a (1 equiv). After stirring at room tempera-
ture for 20 h, 15% yield of a-fluoro-a,b-unsaturated ester
5a (E/Z ¼ 1:3) was obtained along with 23% yield of
nonfluorinated ester 9 (E/Z ¼ 12:1). Under the same
conditions, N-fluorobenzenesulfonimide 7 was used
instead of 1 to give 5a (E/Z ¼ 1:4) and 9 (E/Z ¼ 11:3) in
5% and 11% yields, respectively. The reaction using
1-fluoropyridinium triflate 8 as a fluorinating agent
afforded only 9 (E/Z ¼ 10:1) in 55% yield. When 2 equiv
of 6 were used, 42% yield of 5a (E/Z ¼ 1:3) was obtained
without yielding 910 (Scheme 1).
Keywords: Electrophilic fluorination; One-pot synthesis; Wittig reac-
tion; Selectfluorâ.
* Corresponding author. Tel./fax: +81-54-264-5755; e-mail:
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.103