A facile one-pot synthesis of α-fluoro-α,β-unsaturated esters from alkoxycarbonylmethyltriphenylphosphonium bromides

Article abstract of DOI:10.1016/j.tetlet.2003.12.103

A convenient one-pot synthesis of α-fluoro-α, β-unsaturated esters from ethoxy- and tert- butoxycarbonylmethyltriphenylphosphonium bromide was developed. The fluorinated phosphoranes, generated in situ from alkoxycarbonylmethyltriphenylphosphonium bromides and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor), undergo a Wittig reaction with aldehydes to yield α-fluoro-α,β-unsaturated esters with (Z)-selectivity.

Full text of DOI:10.1016/j.tetlet.2003.12.103

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:
suzuyumi@smail.u-shizuoka-ken.ac.jp
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.103

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Y. Suzuki, M. Sato / Tetrahedron Letters 45 (2004) 1679–1681
Scheme 1. Reagents and conditions: (i) NaH, CH3CN, rt; (ii) 6–8, rt; (iii) NaH, rt; (iv) 4-chlorobenzaldehyde (10a), rt.
The generality of this one-pot reaction is demonstrated
by the reactions of 1 or the tert-butyl analogue 11 with
aldehydes 10a–j. The results are shown in Table 1. The
reactions of 1 and 11 with 10a–j afforded the corre-
sponding ester 5a–j and 12a,i with (Z)-selectivity. The
reaction time of fluorination was shortened to 1–3 h
(conditions B and C). Triethylamine was used for the
reaction of fluorinated phosphorane with aliphatic
aldehyde 10i to avoid the considerable side reaction, the
aldol reaction. Although the yields are moderate, the
reagents are easy to access and to handle. The ease of
the tandem four-step procedure is advantageous
(Scheme 2, Table 1).
Scheme 2. Reagents and conditions: (i) NaH, CH3CN, rt; (ii) 6, rt; (iii)
NaH, rt; (iv) R2CHO 10a–j, rt.
With triphenylphosphine 13 and ethyl bromoacetate 14
as the starting materials, the one-pot synthesis of 5 was
carried out (Scheme 3). Phosphonium bromide 1 was
prepared from 13 and 14 in refluxing acetonitrile.
Without isolation, the routine fluorination–Wittig
Scheme 3. Reagents and conditions: (i) CH3CN, reflux, 2–4 h; (ii) NaH
(1.5 equiv), rt, 1 h; (iii) 6 (2 equiv), rt, 1 h; (iv) NaH (2 equiv), rt; (v)
RCHO 10a,i (1 equiv), rt, overnight.
Table 1. One-pot synthesis of a-fluoro-a,b-unsaturated esters 5a–j and 12a,i
Entry
R2
Phosphonium
bromide
R2
Aldehyde
Conditions
Product
Yield (%)
Ratio E/Zd
1
Et
Et
1
4-Chlorophenyl
4-Chlorophenyl
2-Chlorophenyl
Phenyl
10a
10a
10b
10c
10d
10e
10f
10g
10h
10i
Aa
Bb
Bb
Bb
Bb
Bb
Bb
Bb
Bb
Cc
Bb
Bb
Cc
5a
5a
5b
5c
5d
5e
5f
42
53
31
40
29
29
38
33
30
42
26
57
50
1:3
1:3
2
1
3
Et
Et
1
1:4
4
1
1:11
1:3
5
Et
Et
1
4-Anisyl
3-Anisyl
2-Furyl
6
1
1:2.6
7
Et
Et
1
8
1
1-Naphthyl
Styryl
Nonyl
5g
5h
5i
1:3
1:6
9
Et
Et
1
10
11
12
13
1
8:25
9:20
2:5
Et
1
Cyclohexyl
4-Chlorophenyl
Nonyl
10j
5j
t-Bu
t-Bu
11
11
10a
10i
12a
12i
2:5
a (i) NaH (1.5 equiv), rt, 4 h; (ii) 6 (2 equiv), rt, 48 h; (iii) NaH (2 equiv), rt; (iv) 10a (1 equiv), rt, 15 h.
b (i) NaH (1.5 equiv), rt, 1–3 h; (ii) 6 (2 equiv), rt, 1–3 h; (iii) NaH (2 equiv), rt; (iv) 10 (1 equiv), rt, 12–15 h.
c (i) NaH (1.5 equiv), rt, 1–3 h; (ii) 6 (2 equiv), rt, 1–3 h; (iii) triethylamine (2 equiv), rt; (iv) 10 (1 equiv), rt, 12–15 h.
d Determined by 1H NMR (500 MHz, CDCl3) spectroscopy. Vinylic hydrogen–fluorine coupling constants, JH–F ¼ 21:5 Hz for E-5a, JH–F ¼ 34 Hz for
Z-5a.

Y. Suzuki, M. Sato / Tetrahedron Letters 45 (2004) 1679–1681
1681
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reaction procedure gave 5a,i in satisfactory overall yields
from 14.
In conclusion, we have succeeded in developing a facile
one-pot synthesis of a-fluoro-a,b-unsaturated esters 5a–j
and 12a,i by the reaction of fluorinated phosphoranes,
generated in situ from phosphonium salts and Select-
fluorâ, with aldehydes. The (Z)-isomers were the major
products. This one-pot synthesis is a convenient method
for the preparation of a-fluoro-a,b-unsaturated esters. It
is not necessary to use expensive bromofluoroacetates as
the starting materials for the synthesis of fluorinated
phosphoranes. This method can be applied to synthe-
sizing various fluorinated vinyl compounds having
electron withdrawing group.
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References and notes
10. Xu and DesMarteau reported one-pot synthesis of
a-fluoro-a,b-unsaturated nitriles starting from cyano-
methylphosphonate. They used N-fluoro-bis(trifluo-
romethanesulfonyl)imide as the fluorinating reagent and
obtained a-fluoro-a,b-unsaturated nitriles in 30–58%
overall yields.7
1. Welch, J. T.; Eswarakrishnan, S. Fluorine in Bioorganic
Chemistry; John Wiley: New York, 1991.
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