Convenient preparation of α-bromo-α-fluoro-β-hydroxyesters building blocks from aldehydes, ketones and lactones

Article abstract of DOI:10.1016/j.tetlet.2011.03.014

A Reformatsky-type addition of ethyl dibromofluoroacetate associated with diethylzinc to various carbonyl compounds is described. Aldehydes, ketones and lactones were converted into the corresponding α-bromo-α-fluoro- β-hydroxyesters in good yields.

Full text of DOI:10.1016/j.tetlet.2011.03.014

Tetrahedron Letters 52 (2011) 2473–2475
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Tetrahedron Letters
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Convenient preparation of a-bromo-a-fluoro-b-hydroxyesters building
blocks from aldehydes, ketones and lactones
⇑
Ludivine Zoute, Gérald Lemonnier, Tanh Mai Nguyen, Jean-Charles Quirion, Philippe Jubault
INSA de Rouen et Université de Rouen, CNRS UMR 6014 C.O.B.R.A. & FR 3038, IRCOF, 1 rue Tesnière, 76821 Mont-Saint-Aignan Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A Reformatsky-type addition of ethyl dibromofluoroacetate associated with diethylzinc to various car-
bonyl compounds is described. Aldehydes, ketones and lactones were converted into the corresponding
Received 15 November 2010
Revised 24 February 2011
Accepted 2 March 2011
Available online 8 March 2011
a-bromo-a-fluoro-b-hydroxyesters in good yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Reformatsky addition
Ethyldibromofluoroacetate
Diethylzinc
Carbonyl compounds
Lactones
Despite fluorine containing compounds are barely found in nat-
ure, organofluorinated compounds occupy a major position in the
area of biologically active molecules.1 Because of its unique phys-
ico-chemical properties, the fluorine element became a useful tool
in drug development and crop protection.2 One convenient access
to organofluorinated compounds is based on the use of fluorinated
scaffolds easily prepared from commercially available fluorinated
precursors. In that context, our team developed rapid and atom
economical syntheses of fluoroalkenes (from tribromofluorome-
thane and aldehydes),3a and either fluorinated acrylates3b,c 2 or
fluorinated glycidic esters3d 3 by Reformatsky-type addition of
ethyl dibromofluoroacetate 1 to aldehydes or ketones (Scheme 1).
Recently, Ando’s group applied this system to the diastereose-
lective synthesis of monofluorinated lactams from imines in good
yields.4 This group also showed that replacing Et2Zn by unactivated
Zn powder led to the formation of monofluorinated aziridines.5
R2
Et2Zn
CO2Et
R1
excess
F
2
R1COR2
Et2Zn
CFBr2CO2Et
R2
1
O
F
CO2Et
R1
N
,
N
-dimethyl-
aminoethanol
3
Scheme 1.
Functionally-wise,
a-bromo-a-fluoro-b-hydroxy esters are
showed that
duced to
a-bromo-a-fluoro-b-hydroxy esters could be either re-
promising building-blocks for monofluorinated organic compounds
synthesis. However, only two groups have previously reported the
synthesis of such products. The first method was published by Ishi-
hara etal. andconsistsin theReformatskyaddition ofethyldibromo-
fluoroacetate to various aldehydes in moderate to good yields, using
Zn/Et2AlCl system as a halogen–metal exchange agent.6 A few years
later, Iseki et al. reported an enantioselective two-step procedure
involving a Mukaiyama-aldol addition of a bromofluoroketene silyl
acetal prepared from ethyl dibromofluoroacetate.7 The same group
a
-fluoro-b-hydroxy esters8 or converted to
a-allylated a-
fluoro-b-hydroxy esters9 through diastereoselective radical pro-
cesses. We describe herein a novel one-step efficient synthesis of
a-bromo-a-fluoro-b-hydroxy esters by Reformatsky-like addition
of ethyldibromofluoroacetate. It is noteworthythatforthefirsttime,
ketones and lactones are tolerated as carbonyl partner in such a
process.
While our efforts were turned toward the synthesis of fluori-
nated acrylates from aldehydes, we observed in some cases the
formation of the corresponding
a-bromo-a-fluoro-b-hydroxy
esters. After a short optimization process, it turned out that
addition of 2 equiv of Et2Zn to a mixture of 2 equiv of ethyl
⇑
Corresponding author. Tel.: + 33 2 35 52 24 26; fax: +33 2 35 52 29 59.
E-mail address: philippe.jubault@insa-rouen.fr (P. Jubault).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.014

2474
L. Zoute et al. / Tetrahedron Letters 52 (2011) 2473–2475
Table 1
Scope of the reaction with aldehydes and ketones
R2
R1
OH
R2 OH
O
Et2Zn
CO2Et
CO2Et
CFBr2CO2Et
R1
R1
R2
THF,rt,3h
Br
F
Br
F
1
4a-k
syn-
anti-4a-k
Entry
R1
R2
Yielda (%)
dr (syn:anti)b
1
2
3
4
5
6
7
8
Ph–
H–
H–
H–
H–
H–
H–
H–
Me–
Me–
Me–
––
4a
4b
4c
4d
4e
4f
4g
4h
4i
99
96
92
40
98
30
93
85
73
30
47
58:42
55:45
55:45
52:48
58:42
50:50
52:48
49:51
47:53
50:50
––
4-MeO-Ph–
4-CF3-Ph–
4-MeO2C-Ph–
trans-Ph-CH@CH–
PhCH2CH2–
n-Pentyl–
Ph–
9
10
11
trans-Ph-CH@CH–
PhCH2CH2–
–(C5H10)–
4j
4k
a
Combined yield.
b
Determined by 19F NMR on the crude mixture (see Ref. 7b).
Table 2
Scope of the reaction with lactones
OH
CO2Et
O
O
OH CO2Et
O
Et2Zn
O
F
CFBr2CO2Et
Br
THF,rt,3h
Br
F
1,2
1,2
1,2
5
-
anti
syn-5
1
Entry
1
Substrate
Yielda (%)
Ratiob
85:15
O
O
5a
82
O
O
2
5b
5c
86
48
>95:5
75:25
O
O
3
a
Combined yield.
b
Determined by 19F NMR on the crude mixture.
dibromofluoroacetate 1 and benzaldehyde resulted in the forma-
tion of the corresponding Refomatsky adduct 4a in quantitative
yield (Table 1, entry 1).10,11 Aromatic aldehydes bearing an elec-
tron-donating (entry 2) or an electron withdrawing (entries 3
OH
CO2Et
O
F
Br
CFBr2CO2Et
ZnEt2
and 4) group as well as
hydes (entries 6 and 7) were converted into the corresponding
bromo- -fluoro-b-hydroxy esters 4. Interestingly, for the first time,
a,b-unsaturated (entry 5) or aliphatic alde-
O
O
5c
Et2Zn
THF,rt
100%
a
-
a
OH
CO2Et
F
aromatic and aliphatic ketones are also tolerated in this process
(entries 8–11).
O
No diastereoselectivity was observed but, in most cases, syn-
and anti- diastereoisomers can be separated by silica gel chroma-
tography.12 Generally, yields are good to excellent, except for the
methyl benzoate derived aldehyde (entry 4) where addition of
the zinc carbenoid to the ester function is suspected. Also, it is still
not clear why a drop of yield is observed with 3-phenylpropyl de-
rived carbonyl compounds (entries 6 and 10) and with cyclohexa-
none (entry 11).
6
Scheme 2.
d-valerolactone (entry 2) the corresponding a-bromo-a-fluoro-b-
hydroxy esters 5a and 5b were obtained in good yields. With dihy-
drocoumarine, compound 5c was isolated in an average 48% yield.
Modifying the stoichiometry of the reagents or the reaction condi-
tions did not lead to an improvement in yield. In this particular case,
Next, we examined the reactivity of lactones under the same
conditions (Table 2). Starting from
c-butyrolactone (entry 1) or

L. Zoute et al. / Tetrahedron Letters 52 (2011) 2473–2475
2475
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we observed the formation of the corresponding a-fluoro-b-hydro-
xy esters 6 (dr: 60:40) as a result of the reduction of the second car-
bon–bromine bond by another equivalent of Et2Zn (Scheme 2). This
was confirmed by the quantitative preparation of 6 (dr: 60:40) by
reacting isolated bromohydrine 5c with Et2Zn in THF at rt. Interest-
ingly, with lactones, the reaction occurs with good to excellent dia-
stereoselectivity. This last phenomenon is still unclear and is
actually under study within our laboratory. Moreover, it is gener-
ally assumed that this type of reaction goes through the formation
of zinc enolate. This zinc enolate has never been observed in our
case especially by NMR spectroscopy.
3. (a) Zoute, L.; Dutheuil, G.; Quirion, J. C.; Jubault, P.; Pannecoueke, X. Synthesis
2006, 3409–3418; (b) Zoute, L.; Lacombe, C.; Quirion, J. C.; Charette, A. B.;
Jubault, P. Tetrahedron Lett. 2006, 47, 7931–7933; (c) Lemonnier, G.; Zoute,
L.; Dupas, G.; Quirion, J. C.; Jubault, P. J. Org. Chem. 2009, 74, 4124–4131; (d)
Lemonnier, G.; Zoute, L.; Quirion, J. C.; Jubault, P. Org. Lett. 2010, 12, 844–
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3493–3497.
To conclude, we have developed a one-step and versatile meth-
od to prepare
a-bromo-a-fluoro-b-hydroxy esters starting from
commercially available reagents. These highly functionalized fluo-
rinated building blocks can be prepared from aldehydes and for the
first time from ketones and lactones. Except in the case of lactones,
no diastereoselectivity was observed.
10. Typical procedure: To a dry THF solution (10 ml) of the carbonyl compound
(1 mmol, 1 equiv) and ethyl dibromofluoroacetate 1 (2 mmol., 2 equiv) was
added diethylzinc (1 M in hexane, 2 mmol, 2 equiv) under argon. The reaction
mixture was stirred for 3 hours at room temperature. The resulting solution
was then quenched with ethanol (15 ml), stirred for 15 min, and concentrated
under reduced pressure. The residue was taken up in Et2O (5 ml), filtered over
celite and purified by chromatography on silica gel (eluent/cyclohexane–
EtOAc), affording the expected product.
11. Spectroscopic data for anti- and syn- isomers of ethyl 2-bromo-2-fluoro-3-
hydroxy-3-(4-(trifluoromethyl)phenyl)propanoate (4c). anti-4c: colorless oil.
Rf = 0.25 (15% EtOAc/cyclohexane). 1H NMR (300 MHz, CDCl3) d: ppm 7.6 (m,
4H), 5.4 (dd, 1H, J = 20.7, 6.4 Hz, 1H), 4.3 (q, J = 7.2 Hz, 2H), 3.5 (d, J = 6.5 Hz,
OH), 1.4 (t, J = 7.2 Hz, 3H); 13C NMR (300 MHz, CDCl3) d: ppm 166.1 (d,
J = 27 Hz, CO), 139.5 (Cq), 131.7 (q, J = 32 Hz, Cq), 129.6 (d, J = 2 Hz, CH), 129.1
(d, J = 2 Hz, CH), 125.5 (dd, J = 8, 4 Hz, CF3), 97.8 (d, J = 276 Hz, CF), 77.8 (d,
J = 20 Hz, CH), 64.2 (CH2), 14.2 (CH3); 19F NMR (282.5 MHz, CDCl3) d: ppm
ꢀ63.2 (s, 3F), ꢀ138.1 (d, J = 20.4 Hz). syn-4c: colorless oil. Rf = 0.17 (15% EtOAc/
cyclohexane). 1H NMR (300 MHz, CDCl3) d: ppm 7.5–7.4 (m, 4H), 5.2 (dd,
J = 15.6, 3.6 Hz, 1H), 4.2 (q, J = 7.2 Hz, 2H), 3.5 (d, J = 3.7 Hz, OH), 1.2 (t,
J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) d: ppm 166.2 (d, J = 26 Hz, CF), 139.5
(Cq), 131.7 (q, J = 32 Hz, Cq), 129.6 (CH),125.5 (m, CF3), 97.8 (d, J = 275 Hz, Cq),
77.7 (d, J = 20 Hz, CH), 64.2 (CH2), 14.2 (CH3); 19F NMR (282.5 MHz, CDCl3) d:
ppm ꢀ63.2 (s, 3F), ꢀ130 .8 (d, J = 16.2 Hz). MS (EI): m/z = u359; IR (neat) 3535,
1737 cmꢀ1. Anal. calcd for C12H11BrF4O3: C, 40.14; H, 3.09. Found: C, 40.22; H,
3.24.
Acknowledgments
This work was supported by MESR (Ministère de l0Enseigne-
ment Supérieur et de la Recherche), the Région Haute-Normandie
(CRUNCH program), and INSA of Rouen. G.L. thanks MESR for a
Ph.D fellowship.
Supplementary data
Supplementary data (experimental procedures; complete spec-
troscopic data for all new compounds) associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2011.03.014.
References and notes
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320–330; Begué, J.-P.; Bonnet-Delpon, D. Chimie bioorganique et médicinale du
fluor; CNRS Editions: Paris, 2005; (c) Thomas, C. J. Curr. Top. Med. Chem. 2006, 6,
1529–1543; (d) Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013–1029.
2. For reviews on fluorine-containing organic compounds, see: (a) Hiyama, T.
Organofluorine Compounds: Chemistry Applications; Springer: Berlin, 2000; (b)
Iseki, K. Tetrahedron 1998, 54, 13887–13914; Kirsch, P. Modern Fluoorganic
12. The relative configuration of the syn- and anti-diastereoisomers have been
determined using previously reported methods.7a
a-Bromo-a-fluoro-b-
hydroxy esters could be easily reduced to diols and then converted to
acetonide derivatives.