Reformatsky-type aldol reactions of 4-bromo-4,4-difluoroacetoacetate with aldehydes and ketones

Article abstract of DOI:10.1016/S0040-4039(01)01106-6

In the presence of zinc and a catalytic amount of copper(I) chloride, 4-bromo-4,4-difluoroacetoacetate 4 reacted with a series of aromatic aldehydes and aryl alkyl ketones to give the corresponding δ-hydroxyl-γ,γ-difluoro-β-ketoesters 6 in good to excellent yields under mild conditions.

Full text of DOI:10.1016/S0040-4039(01)01106-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5741–5744
Reformatsky-type aldol reactions of
4-bromo-4,4-difluoroacetoacetate with aldehydes and ketones
Yanli Wang and Shizheng Zhu*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 21 March 2001; revised 11 June 2001; accepted 21 June 2001
Abstract—In the presence of zinc and a catalytic amount of copper(I) chloride, 4-bromo-4,4-difluoroacetoacetate 4 reacted with
a series of aromatic aldehydes and aryl alkyl ketones to give the corresponding d-hydroxyl-g,g-difluoro-b-ketoesters 6 in good to
excellent yields under mild conditions. © 2001 Published by Elsevier Science Ltd.
The preparation of gem-difluoromethylene substituted
The selective introduction of fluorine into organic com-
molecules falls broadly into two classes. The first involves
pounds has been receiving increasing attention in
research on biological chemistry and in the development
direct gem-difluorination,5 and the second draws from
the construction of molecules derived from CF2-syn-
thons. The Reformatsky reaction of halodifluoroacetates
of medicines due to fluorine’s unique biological and
physical
properties.1
Particularly,
the
gem-
and halodifluoroketones is by far the most common of
all the CF2-synthon approaches.6 Its products are ver-
satile intermediates which have found significant use in
the synthesis of peptidase inhibitors designed around
a,a-difluoro ketones,7 difluoromethylene analogues of
carbohydrates,8 nucleosides,9 and natural products.10
However, the Reformatsky reaction of 4-bromo-4,4-
difluoroacetoacetate with aldehydes and ketones has not
been examined. In this work, we report the preparation
of a series of d-hydroxy-g,g-difluoro-b-ketoesters by
zinc-mediated Reformatsky-type aldol reactions of 4-
bromo-4,4-difluoroacetoacetate 4 with a series of aro-
matic aldehydes and aryl alkyl ketones. The resulting
aldol-addition products are anticipated to contribute to
the construction of fluorinated intermediates by further
transformation.
difluoromethylene group, with the CF2-carbon at both
the sp3 and sp2 hybridization level is a key structural unit
in many fluorinated compounds of biological and phar-
maceutical significance.2 a,a-Difluorination of ketones
imparts increased electrophilicity to the carbonyl and
contributes to the formation of stable hydrates and
hemiketals which are purported to mimic the tetrahedral
transition states involved in the hydrolytic action of
proteases and estereases, and enzyme inhibition can
occur when the nucleophilic hydroxyl is part of the active
site.3 In addition, since difluoromethylene-containing
compounds often exhibit biological stability, the
difluoromethylene functionality may prove particularly
significant as a replacement for a CH2 or CHOH linkage
at a biochemically labile position.4
Scheme 1.
Keywords: Reformatsky reaction; zinc; gem-difluoromethylen; aldehydes; ketones.
* Corresponding author. Fax: +86(21)64166128; e-mail: zhusz@pub.sioc.ac.cn
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)01106-6

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Y. Wang, S. Zhu / Tetrahedron Letters 42 (2001) 5741–5744
and a catalytic amount of copper(I) chloride (0.3
equiv.) in ether from 0°C to ambient temperature
occurred smoothly and were completed within 2 h,
affording the aldol products 6 in good to excellent
yields (Table 2, entry 1). Various substituents on the
phenyl ring, either electron-withdrawing or electron-
donating, such as methyl, chloro, bromo, and methoxy,
could be tolerated and had little effect on the yields
except for p-nitrobenzaldehyde which gave no aldol-
addition product under various conditions.14 The aldol-
addition reaction also proceeded with alkyl and
heteroaromatic aldehydes giving moderate and good
yields, respectively, under similar conditions (Table 2,
entry 7, 8). However, the zinc-mediated addition of 4 to
a,b-unsaturated aldehydes, such as acrylaldehyde and
cinnamaldehyde did not occur at all. Although the
products 6 could be obtained through trimethylsilyl
protection of the Reformatsky adducts of ethyl bro-
modifluoroacetate with aldehydes followed by conden-
sation with lithio ethylacetate,15 we provide here a more
direct and convenient method for this transformation.
4-Bromo-4,4-difluoroacetoacetate 4 was prepared in
four steps in about 50% yield as shown in Scheme 1.11
In the first step, fluorohaloalkanes reacted with ethyl
vinyl ether in absolute ethanol initiated by sodium
dithionite and sodium bicarbonate to give the fluoro-
haloalkyl diethyl acetals 2, which were oxidized with
Caro’s acid to give the corresponding esters 3 in a 75%
yield over two steps.12 Dehydrohalogenation of the
ester 3, followed by substitution of fluorine with pyrro-
lidine and hydrolysis gave the 4-bromo-4,4-difluoroace-
toacetate 4.13
We conducted the reaction of 4-bromo-4,4-difluoroace-
toacetate 4 with zinc dust and benzaldehyde in refluxing
THF, as recommended for Reformatsky reactions using
bromodifluoroacetates,6a but no reaction occurred. We
then noticed that literature Reformatsky reactions of
chlorodifluoromethyl ketones with aldehydes and
ketones in the presence of 3 equiv. of zinc dust acti-
vated in situ by 0.3 equiv. of copper(I) chloride in
refluxing THF gave a,a-difluoro-b-ketones in good to
excellent yields6f (Scheme 2). Accordingly, the aldol-
addition product 6a (R1=Ph, R2=H) was obtained in
good yield when 4 was reacted with benzaldehyde
under these conditions. In order to establish the opti-
mal conditions for this reaction, we screened various
reaction conditions. Some typical reaction conditions
and the results obtained are summarized in Table 1. We
found that both copper(I) halides and silver acetate
could activate the reaction, and that diethyl ether was
the best solvent.
Aromatic ketones also proved to be efficacious sub-
strates, little or no qualitative difference being observed
amongst the reactions of 4 with aldehydes and ketones.
Ketones containing electron-withdrawing groups gave
higher yields of addition products, presumably due to
the enhanced electrophility of the carbonyl carbon
(Table 2, entry 10). Unfortunately, the reaction of
2-butanone with 4 under the Zn-CuCl conditions failed.
The reaction system became complex as shown by 19F
NMR and only a trace of Reformatsky product was
detected which could not be isolated from the other
unidentified materials. All products exhibited satisfac-
tory spectroscopic data in accord with the assigned
structures.16
With the optimized conditions (Table 1, entry 7) in
hand, we next carried out the Reformatsky reaction of
4 with a variety of aromatic aldehydes. Thus, the
reactions of 4 with a variety of aromatic aldehydes in
the presence of both acid-washed zinc dust (3 equiv.)
Scheme 2.
Table 1. Optimized conditions for the Reformatsky reaction using benzaldehyde
Entrya
MX /0.3 equiv.
Solvent
T (°C)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
CuCl
CuCl
CuCl
CuBr
CuI
AgOAc
CuCl
CuCl
CuCl
THF
THF
THF
THF
THF
THF
Ether
DMF
CH3CN
−78
−20
0“rt
0“rt
0“rt
0“rt
0“rt
0“rt
0“rt
20
8
2
2
2
6
2
2
2
–
–
90c
86c
85c
50
92
80
d
–
a The reaction was conducted on a scale of 0.3 mmol 4 with 0.33 mmol benzaldehyde and 0.9 mmol zinc dust in 0.6 mL solvent.
b Yield determined by 19F NMR.
c 5–10 mol% of HCF2COCH2CO2Et was detected by 19F NMR.
d The reaction mixture became a gel.

Y. Wang, S. Zhu / Tetrahedron Letters 42 (2001) 5741–5744
5743
Table 2. The Reformatsky reactions of 4-bromo-4,4-difluoroacetoacetate 4 with aldehydes and ketones.
Carbonyl compounds
R1
Solvent
Product 6
Yielda (%)
Entry
5
R2
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
Ph
H
H
H
H
H
H
H
H
CH3
CH3
CH3
C2H5
Ether
Ether
Ether
Ether
Ether
Ether
THF
Ether
THF
THF
THF
THF
6a
6b
6c
6d
6e
6f
6g
6h
6i
90
83
80
85
2-ClC6H4
2-BrC6H4
4-MeC6H4
4-MeOC6H4
4-NO2C6H4
(CH3)2CHCH2
2-furyl
91
–
30b
80
9
Ph
50b
45b
30b
36b
10
11
12
5j
5k
5l
4-BrC6H4
4-CH3OC6H4
Ph
6j
6k
6l
a Isolated yields of pure compounds based on 4.
b 30–40 mol% HCF2COCH2CO2Et was detected by 19F NMR.
In summary, we have described the successful Refor-
matsky-type reactions of 4 with a diversity of aromatic
aldehydes, alkyl aldehydes, heteroaromatic aldehydes
and aryl alkyl ketones in the presence of zinc dust
activated in situ by catalytic amounts of copper(I)
chloride to produce d-hydroxy-g,g-difluoro-b-keto-
esters. Further transformations of these products, such
as reduction to 1,3-diol derivatives, intramolecular
cyclization to d-lactones, and diazotization of the active
methylene, are now in progress.
Rao, Y. K.; Premchandran, R. H.; Halushka, P. V.;
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Acknowledgements
The authors thank the National Natural Science Foun-
dation of China (NNSFC) (No. 20072049) and the
Innovation Foundation of Chinese Academy of Sci-
ences for financial support.
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concentration in vacuum, the residue was distilled to give
4-bromo-4,4-difluoroacetoacetate 4 as a colourless liquid.
(78–82°C/10 mmHg)
14. Altenburger, J. M.; Schirlin, D. Tetrahedron Lett. 1991,
32, 7255–7258.
12. With magnetic stirring, a mixture of sodium dithionite
(75 mmol, 13.1 g) and sodium bicarbonate (150 mmol,
12.6 g) was added to a solution of dibromotetra-
fluoroethane (75 mmol, 19.5 g) and ethyl vinyl ether (75
mmol, 8 mL) in absolute ethanol (300 mL). The mixture
was stirred at 50°C for 15 h (3 h for 1b) and was then
diluted with water (300 mL) and extracted with ether (150
mL×3). The organic layer was concentrated under vac-
uum to afford diacetal 2a as a yellowish liquid. Then the
Caro’s acid prepared from 85% sulfuric acid (765 mmol,
47.3 mL) and ammonium persulfate (37.5 mmol, 85.5 g)
was added to a vigorously stirred solution of diacetal in
absolute ethanol (150 mL). After being stirred for 24 h at
rt, the mixture was diluted with cold water (300 mL) and
extracted with ether (150 mL×4). The organic layer was
washed with brine and dried over sodium sulfate. Con-
centration under vacuum and distillation afforded ester
3a in a 75% 2-step yield (68–70°C/20 mmHg).
13. To a well-stirred solution of 3a (20 mmol, 5.3 g) in
dichloromethane (40 ml) was added triethylamine (30
mmol, 4.2 mL) and sodium bicarbonate (30 mmol, 2.5 g)
at 0°C. The mixture was refluxed for 1 h, then pyrrolidine
(20 mmol, 1.65 mL) was added to the mixture. After
further reflux for 2 h, the mixture was hydrolyzed with
3N hydrochloric acid (40 mL), neutralized with saturated
sodium carbonate, and extracted with dichloromethane
(30 mL×3). The organic layer was washed with water and
then with brine. After drying over sodium sulfate and
15. Dreyer, G. B.; Metcalf, B. W. Tetrahedron Lett. 1988, 29,
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16. Representative general procedure for the Reformatsky-
type aldol reactions of 4 with aldehydes and ketones: A
solution of 4-methylbenzaldehyde (0.132 g, 1.1 mmol)
and 4 (0.245 g, 1 mmol) in diethyl ether (1 mL) was
added dropwise to a heterogeneous solution of acid-
washed zinc dust (0.196 g, 3.0 mmol) and copper(I)
chloride (0.030 g, 0.3 mmol) in diethyl ether (2 mL),
which had been stirred at rt for 0.5 h. After the addition
was completed, the reaction mixture was warmed to rt
and stirred for another 1.5 h. Then saturated ammonium
chloride (5 mL) was added. Excess zinc was removed by
suction filtration and washed with ethyl acetate (10 mL).
The organic layer was separated. The aqueous layer was
extracted with ethyl acetate (10 mL×3), and the organic
layers were combined and washed with water and brine
and then dried over sodium sulfate. After evaporation of
the solvents, the residue was chromatographed on silica
gel eluting with petroleum ether–ethyl acetate (3:1/v:v) to
1
give 6d (0.243 g) in 85% yield. For 6d: H NMR (CDCl3,
300 MHz): l 1.29 (t, 3H, J=7.1 Hz), 2.36 (s, 3H), 2.72 (s,
0.46H), 2.93 (s, 0.54H), 3.65 (s, 1.2H), 4.19 (q, 2H, J=7.1
Hz), 5.05 (m, 1H), 5.48 (s, 0.4H), 7.17–7.35 (m, 4H),
12.10 (s, 0.4H). 19F NMR (CDCl3, 300 MHz): l −111.6
(dd, 0.56F, J=265 Hz, J=6.2 Hz), −114.8 (dd, 0.44F,
J=260 Hz, J=8.7 Hz), −121.2 (dd, 0.44F, J=260 Hz,
J=8.7 Hz), −123.6 (dd, 0.56F, J=265 Hz, J=6.2 Hz).
.