An expedient synthesis of α,α-difluoro-β-hydroxy ketones via decarboxylative aldol reaction of α,α-difluoro-β-keto acids with aldehydes

Article abstract of DOI:10.1016/j.tetlet.2017.07.060

A novel decarboxylative aldol reaction of α,α-difluoro-β-keto acids with aldehydes in the absence of any base and metal catalysts has been developed. This reaction provides a highly convenient and efficient method for the synthesis of structurally diverse α,α-difluoro-β-hydroxy ketones in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2017.07.060

Tetrahedron Letters xxx (2017) xxx–xxx
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Tetrahedron Letters
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An expedient synthesis of
a,a-difluoro-b-hydroxy ketones via
decarboxylative aldol reaction of
aldehydes
a,a-difluoro-b-keto acids with
a
a,
Da-Kang Huang a, Zhong-Liang Lei a, Yu-Jun Zhu a, Zhen-Jiang Liu a,b, , Xiao-Jun Hu , Hai-Fang Mao
⇑
⇑
a School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Haiquan Road, Shanghai 201418, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel decarboxylative aldol reaction of a,a-difluoro-b-keto acids with aldehydes in the absence of any
base and metal catalysts has been developed. This reaction provides a highly convenient and efficient
Received 22 May 2017
Revised 14 July 2017
Accepted 17 July 2017
Available online xxxx
method for the synthesis of structurally diverse
yields.
a,
a
-difluoro-b-hydroxy ketones in good to excellent
Ó 2017 Elsevier Ltd. All rights reserved.
Keywords:
Decarboxylative aldol reaction
a
a
,
,
a
-Difluoro-b-keto acid
a-Difluoro-b-hydroxy ketone
Introduction
During the past decades, fluorine-containing compounds have
attracted an increasing interest in the fields of agrochemistry,
pharmaceutical industry, and materials science.1 In part, this is
due to the introduction of a fluoroalkyl group into organic com-
pounds that may result in profound changes to physical, chemical,
and biological properties. Among various fluorine-containing com-
Fig. 1.
a,a-Difluoro-b-hydroxy ketone motifs in bioactive molecules.
pounds, a,a-difluoro-b-hydroxy ketones have been the focus of the
scientific community since this compound class represents a criti-
cal and widely found substructure unit in bioactive compounds
and pharmaceuticals (Fig. 1).2 Based on the high significance in
drug industry, a variety of synthetic methods have been developed
for this compound species, including the Mukaiyama-Aldol reac-
tion of difluoroenoxysilanes or difluoroenol O-Boc esters
(Scheme 1, eq. a),3 the metal-mediated Reformatsky reaction of
halodifluoromethyl ketones (Scheme 1, eq. b),4 the detrifluo-
the production of metal waste. Furthermore, these reactions gener-
ally lack of atomic economy. Therefore, the development of new,
simple and efficient methods for the rapid synthesis of
a,a-diflu-
oro-b-hydroxy ketones still remains a critical, albeit unmet, scien-
tific goal.
In recent years, the decarboxylative aldol reaction has emerged
as a powerful tool for the generation of carbon-carbon bonds due
to its mild reaction conditions.7 Although great progress has been
made for the development of advanced decarboxylative aldol reac-
tions of malonic acid half thioesters (MAHT) and malonic acid half
oxyesters (MAHO),8 the decarboxylative aldol reaction of b-ketoa-
cids remains far less explored.9 To the best of our knowledge, no
report on the decarboxylative aldol reaction of fluorinated b-ketoa-
cids can be found in the literature to date.10 In an effort to continue
our studies in the field of fluorinated ketones and imines,11 herein,
roacetylative aldol reaction of trifluoromethyl a,a-difluoro-b-keto
gem-diols (Scheme 1, eq. c),5 etc.6 However, most of these reactions
exhibit various practical drawbacks, including the use of pre-
formed difluoroenoxysilanes or difluoroenol O-Boc esters which
renders the reaction process more tedious and often results in
⇑
Corresponding authors at: School of Chemical and Environmental Engineering,
Shanghai Institute of Technology, 100 Haiquan Road, Shanghai 201418, China
(Z.-J. Liu).
we report the first decarboxylative aldol reaction of
a,a-difluoro-b-
keto acids with aldehydes. This reaction provides a convenient, yet
E-mail addresses: zjliu@sit.edu.cn (Z.-J. Liu), mhf@sit.edu.cn (H.-F. Mao).
http://dx.doi.org/10.1016/j.tetlet.2017.07.060
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Huang D.-K., et al. Tetrahedron Lett. (2017), http://dx.doi.org/10.1016/j.tetlet.2017.07.060

2
D.-K. Huang et al. / Tetrahedron Letters xxx (2017) xxx–xxx
rized in Table 1. In order to improve the efficacy of the
decarboxylation and to inhibit the formation of the decarboxyla-
tive protonation side product,
-difluoroacetophenone,5b–e
a,a
inorganic bases such as Na2CO3 and Cs2CO3 were used initially.
However, lower yields (9–13%) of the desired product 3a were
obtained (Table 1, entries 1–2). The decarboxylative aldol
reaction proceeded smoothly, without the need for any further
addition of base or metal catalyst (Table 1, entries 3–15). Among
the solvents tested, toluene demonstrated to be the best solvent
for this reaction, resulting in the formation of the corresponding
aldol adduct 3a in moderate to high yield (Table 1, entries 3–19).
Further screening of the reaction conditions revealed that the
reaction could be completed in 12 h at 100 °C, providing the
aldol product in 95% yield (Table 1, entry 10). Decreasing the
amount of
a,a-difluoro-b-keto acid 1a or performing the reaction
in an open flask resulted in a significant yield reduction (Table 1,
entries 14–15). Thus, the optimized reaction conditions for this
novel decarboxylative aldol reaction were as follows:
a,a-
difluoro-b-keto acid 1a (3.0 equiv.) and benzaldehyde 2a
(1.0 equiv.) in toluene at 100 °C for 12 h.
With the optimized reaction conditions in hand, the substrate
scope and generality of this decarboxylative aldol reaction was
Scheme 1. Methods for the synthesis of a,a-difluoro-b-hydroxy ketones.
investigated through variations of both
and aldehydes. As is shown in Table 2, all reactions proceeded
readily and furnished the corresponding -difluoro-b-hydroxy
a,a-difluoro-b-keto acids
efficient base- and metal-free process for the synthesis of
difluoro-b-hydroxy ketones in high yields.
a,a-
a,a
ketones in good to high yields. Aromatic aldehydes were demon-
strated to be excellent substrates for the reaction (Table 2, entries
1–8). The electronic properties and positions of the substituents on
the phenyl ring of the aromatic aldehydes exhibited a negligible
effect on the yields of the reaction (Table 2, entries 2–7). However,
worth noting in this context is the finding that in the case of
Results and discussion
The precursor
a,a-difluoro-b-keto acid 1a was selected as a
model substrate to investigate the feasibility of this decarboxyla-
tive aldol reaction with benzaldehyde 2a. The results are summa-
Table 1
The decarboxylative aldol reaction of a,a
-difluoro-b-keto acid 1a with benzaldehyde under different conditions.a
Entry
Base (equiv.)
Solvent
Temp. (°C)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
Na2CO3 (1)
Cs2CO3 (1)
–
–
–
THF
Toluene
THF
70
80
70
70
80
90
100
110
100
100
100
100
100
100
100
100
100
100
100
24
24
24
24
24
24
24
24
16
12
10
8
13
9
21
59
89
94
95
89
95
95
94
91
86
65
64
NRe
NRe
NRe
NRe
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
NMP
–
–
–
–
–
–
–
–
–
–
–
–
–
9
10
11
12
13
14c
15d
16
17
18
19
6
12
12
12
12
12
12
DMF
DMSO
Dioxane
a
b
c
Reaction conditions: a,a-difluoro-b-keto acid 1a (0.6 mmol), benzaldehyde 2a (0.2 mmol), solvent (1.5 mL).
Yields of products isolated after column chromatography.
0.4 mmol of -difluoro-b-ketoacid 1a was used.
a,a
d
e
The reaction was performed in an open flask.
NR = No reaction.
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D.-K. Huang et al. / Tetrahedron Letters xxx (2017) xxx–xxx
3
Table 2
Scope of the decarboxylative aldol reaction of
a
,
a
-difluoro-b-keto acids 1 with aldehydes 2.a
Entry
R1
R2
Product
Yield (%)b
1
2
3
4
5
6
7
8
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (2a)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
95
99
88
>99
83
>99
77
90
4-MeC6H4 (2b)
4-MeOC6H4 (2c)
4-ClC6H4 (2d)
4-NO2C6H4 (2e)
3-MeC6H4 (2f)
2-MeC6H4 (2g)
2-naphthyl (2h)
PhCH@CH (2i)
Ph(CH2)2 (2j)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
9
92
10
11
12
13
14
55c
88
4-MeC6H4 (1b)
4-MeOC6H4 (1c)
4-ClC6H4 (1d)
2-Furyl (1e)
>99
>99
89
a
b
c
Reaction conditions: a,a-difluoro-b-keto acids 1 (0.9 mmol) and aldehydes 2 (0.3 mmol) in toluene (1.5 mL) at 100 °C for 12 h under N2.
Yields of products isolated after column chromatography.
The reaction was run at 110 °C for 16 h.
b-keto acid species 1b–e could also be used in this reaction and
high yields were obtained (Table 2, entries 11–14). However,
alkyl-substituted a,a-difluoro-b-keto acid was found to be unsuit-
able for this transformation and no product formation could be
observed. Furthermore, the model reaction could be scaled up to
gram quantities, and excellent yields could be obtained (Scheme 2),
indicating the potential industrial applicability of this reaction.
To gain further insights into the reaction pathway, a control
Scheme 2. Scaled-up version of the decarboxylative aldol reaction.
experiment was carried out using
a,a-difluoroacetophenone 4a
cinnamaldehyde 2i employed as the electrophilic partner, the reac-
tion proceeded regiospecifically in a 1,2-addition fashion, provid-
ing the 1,2-adduct in high yield (92%, Table 2, entry 9).
Moreover, enolizable aliphatic aldehyde 2j was also found to be
tolerated, affording the corresponding aldol product in moderate
yield (Table 2, entry 10). Heteroaromatic aldehydes such as 2-fury-
laldehyde and 2-pyridylaldehyde were also evaluated for this reac-
tion, but only traces of the desired aldol products were found. In
instead of -difluoro-b-keto acid 1a under the optimized
a,a
reaction conditions described above (Scheme 3, eq. a). However,
via 19F NMR monitoring of the crude reaction mixture, we
determined that no desired product 3a was formed. On the basis
of our research results and other published literature proce-
dures,5b–e,9a–c,f
a
preliminary reaction mechanism for this
decarboxylative aldol reaction could be proposed as shown in
Scheme 3, eq. b. Upon heating above 70 °C, the -difluoro-b-keto
acids 1 first decarboxylate to form the difluoro enol intermediate
a,a
addition, different aryl- and heteroaryl-substituted
a,a-difluoro-
Scheme 3. Plausible reaction mechanism.
Please cite this article in press as: Huang D.-K., et al. Tetrahedron Lett. (2017), http://dx.doi.org/10.1016/j.tetlet.2017.07.060

4
D.-K. Huang et al. / Tetrahedron Letters xxx (2017) xxx–xxx
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In summary, we have successfully developed the first
decarboxylative aldol reaction of
aldehydes in the absence of any base or metal catalysts. The
reaction is very mild and variety of structurally diverse
-difluoro-b-hydroxy ketones could be obtained in good to
excellent yields. These -difluoro-b-hydroxy ketones represent
a,a-difluoro-b-keto acids with
a
a,a
a,a
useful structural motifs for the synthesis of a variety of natural
products and bioactive compounds. Further studies are currently
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Acknowledgements
Financial support from the National Natural Science Foundation
of China (No. 21102093), the Science and Technology Commission
of Shanghai Municipality (Nos. 15DZ1942203, 15120503700), the
Innovation Program of Shanghai Municipal Education Commission
(No. 14YZ144), Chemical Engineering and Technology (Perfume
and Aroma Technology) of Shanghai Plateau Discipline and Shang-
hai Institute of Technology (No. XTCX2016-5) is gratefully
acknowledged.
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Supplementary data associated with this article can be found, in
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