“All-Water” Synthesis of β-Amino α,α-Difluoro Ketones from Fluorinated Enol Silyl Ethers and Imines

Article abstract of DOI:10.1002/ejoc.201700591

A one-pot synthesis of β-amino α,α-difluoro ketones without any additives was developed. Through a series of control experiments we found that water played a crucial and indispensable role. The hydrogen bond between water and fluorinated enol silyl ether

Full text of DOI:10.1002/ejoc.201700591

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Accepted Article
Title: "All-water" synthesis of β-amino α,α-difluoro ketones from
fluorinated enol silyl ethers and imines
Authors: Yebin Wu, Wan Li, Guoping Lu, and Chun Cai
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700591
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10.1002/ejoc.201700591
European Journal of Organic Chemistry
COMMUNICATION
“All-water” synthesis of β-amino α,α-difluoro ketones from
fluorinated enol silyl ethers and imines
Ye-bin Wu, [a] Li Wan, [c] Guo-ping Lu, [a] and Chun Cai* [a], [b]
Abstract: A one-pot synthesis of β-amino α,α-difluoro ketones is
developed without any additives. Through a series of control
experiments we found that water plays a crucial and indispensable
role. The hydrogen bond between water and fluorinated enol silyl
ether has a significant impact on the addition reaction.
with the hydrogen-bonding activation of the electrophile to
facilitate on water reactions. Inspired by that result, we wonder if
aldimines, generated in situ from carbonyl compounds and amino
compounds, could react with difluoroenoxysilanes in water
offering a direct entry towards the β-amino α,α-difluoro ketones
without any additives. To this end, we report herein a novel “all-
water” synthesis of β-amino α,α-difluoro ketones from fluorinated
enol silyl ethers and imines.
Introduction
Fluorine, emerged as a magic element in pharmaceuticals,
agrochemicals and functional materials, has become more and
more significant for a large range of applications.[1] Unique
physical and chemical advantages conferred by the C-F bond
usually result in enhanced membrane permeability, elevated
electronegativity and oxidation resistance.[2] Compounds
containing-CF2R groups have been widely applied in the
preparation of pharmaceuticals, agrochemicals, and enzyme
inhibitors. Difluoroalkylation can not only introduce fluorine atoms
into a molecule, but also install a nonfluorinated moiety
simultaneously which can be further modified into various CF2
containing functional groups.[3]
Alkyl amines are common structural features in natural
products, pharmaceutical agents, and other small-molecule
probes of biological function.[4] Among them, β-amino α,α-difluoro
ketones as valuable intermediates for drug design have received
considerable attention.[5] For example, rhodopeptin derivative
which contained a β-amino-α,α-difluoro carbonyl unit exhibited
improved physical and biological properties while retaining its
antifungal activity.[6] And it has been proved that the introduction
of β-amino α,α-difluoro ketone units into peptides is successful in
designing enzyme inhibitors such as protease inhibitors.[7]
The traditional synthetic methods for preparing β-amino α,α-
difluoro ketones rely on deoxydifluorination of β-keto carbonyl
compounds with diethylaminosulfur trifluoride,[8] the Reformatsky
reaction of α-bromo α,α-difluoroacetate with aldimines [9] and the
Mannich-type reaction of difluorinated silyl enol ether with
aldimines.[10] [11] Although remarkable progress has been made,
most current methods still suffer from harsh reaction conditions.
Therefore, further developments are needed to enable the use of
cheap and abundantly available starting materials as well as mild
reaction conditions. In 2014, Zhou et.al reported an on water
reaction of the difluoroenoxysilanes with aldehydes, ketones, and
isatylidene malononitriles without catalyst.[12] That process
implied that the C-F···H-O interactions between the
difluoroenoxysilane and water at the phase boundary cooperate
Results and Discussion
Initially, we commenced our investigation by treating
benzaldehyde (1a), aniline (2a) and difluoroenoxysilane (3a) in
water without any additives. To our delight, the reaction provided
a 65% yield of the desired product 4a. The impact of various
solvents was also evaluated, and the water gave the highest yield
of 4a. When twice equivalent 3a was added, the yield was greatly
improved to 89%. To our delight, the yield had no significant effect
when the time was reduced to 6 hours. In the screening of the
solvents, we found MeCN also afforded a good result just a bit
worse than water, but it was hard to confirm if MeCN had some
special effects to promote the reaction. Therefore, control
experiments were made to reveal this phenomenon.
Table 1. optimization of reaction conditions a.
Entry
Solvent
Time [h]
Yield b [%]
1
2
H2O
EtOAc
MeCN
DMF
THF
24
24
24
24
24
24
12
6
65
15
3
60
4
19
5
11
6 c
7 c
8 c
9 c
H2O
89
H2O
87
H2O
90 (88) d
85
MeCN
6
[a]
[b]
Chemical Engineering college, Nanjing University of Science and
Technology, 200 Xiao Ling Wei Street, Nanjing, Jiangsu, People’s
Republic of China
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu,
Shanghai 20032.
a Reaction conditions: 1a (0. 25 mmol), 2a (1 equiv.), 3a (1 equiv.), solvent (1
mL), vigorous stirring under at room temperature. b Yield based on 19F NMR
c
spectroscopy using trifluoroacetophenone as an internal standard. 3a (2
equiv.). d Value in parentheses refers to the isolated yield.
[c]
*
Biotechnology and Pharmaceutical Engineering College, Nanjing
Tech University, Nanjing 211816, People’s Republic of China
Corresponding Author E-mail: c.cai@njust.edu.cn
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10.1002/ejoc.201700591
European Journal of Organic Chemistry
COMMUNICATION
Scheme 1. control experiments a.
took a significant impact.[13] Then, using D2O as solvent was
tested under standard conditions.[14] To our surprise, the almost
similar yield of 4a was obtained in D2O compared in water. Then
another substrate which contains a nitro group was tested too. In
this case, the yield of 4e was significantly reduced. Based on this
studies, we speculate that the HB effect plays an important role in
promoting the reaction. According to this mechanistic insight, a
proposed mechanism is illustrated in Figure 1.
Entry
Solvent (dry)
MeCN
DMF
Yield b [%]
1
2
3
4
19
11
5
Figure 1. a proposed mechanism.
EtOAc
THF
6
Scheme 2. scope of the Nucleophilic Addition Reaction a, b
.
a Reaction conditions: 1a’ (0. 25 mmol), 3a (1 equiv.), solvent (1 mL), vigorous
stirring under at room temperature, 6h. b Yield based on 19F NMR spectroscopy
using trifluoroacetophenone as an internal standard. c Reaction conditions: 1a
(0. 25 mmol), 2a (1 equiv.), 3e (1 equiv.), H2O (1 mL), vigorous stirring under at
room temperterature. d Reaction conditions: 1a (0. 25 mmol), 2a (1 equiv.), 3a
(1 equiv.), D2O (1 mL), vigorous stirring under at room temperature.
In this reaction, imine was generated in situ from
corresponding aldehyde and amine, and a molecule H2O was also
produced. In order to rule out the effect of water, we carried out a
series of reactions under Ar atmosphere and used imine 1a’ as
started substrate (Scheme 1). It was found that the yield of 4a was
drastically reduced when the water in the reaction was strictly
controlled. Therefore we speculate the small amount of water in
the reaction plays a key role to promote the nucleophilic addition
reaction. On the other hand, we should also figure out why only in
MeCN could get a good yield. Then the hydrolysis of 3a in
different solvents was tested. Just as expected, 3a was more
stable in MeCN than other water-soluble solvents (Scheme S1,
ESI†). It took 6 h for the complete hydrolysis of 3a in EtOAc.
However the reaction of 1a’ and 3a gave the adduct 4a in only 5%
in EtOAc. At last, the hydrogen bond effect between C-F···H-O
was also investigated. When 3a was replaced by 3e, trace
corresponding product 5 was got. And monofluorinated analogue
3f reacted sluggishly to give 6 in 35% yield (NMR) under the same
reaction conditions. However, the reactivity of 3a, 3e and 3f is
different, so it is not enough to estimate whether the HB effect
a
Reaction conditions: 1 (0. 25 mmol), 2 (1 equiv.), 3a (2 equiv.), H2O (1 mL),
vigorous stirring under at room temperature., 6 h. b isolated yield.
With the optimized reaction conditions established, the
substrate scope of the protocol was surveyed (Scheme 2). Owing
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10.1002/ejoc.201700591
European Journal of Organic Chemistry
COMMUNICATION
to the mild reaction conditions, the reaction condition has shown
excellent tolerance to electron-donating substituents while got
somewhat lower yields for electron-withdrawing substituents,
tolerating many common functional groups such as cyano, nitro,
trifluoromethyl, methoxy, and halogen. Also, 2-substituted and 3-
substituted aldehydes or amines reacted efficiently to generate β-
amino α, α -difluoro ketones (4h-4k, 4n-4q). Fortunately,
heteroaromatic aldehydes or amines including furfural and
furylamine also underwent the nucleophilic addition successfully
(4s, 4t). Inspired by these results, we tried to expand this kind of
reaction to other silyl enol ethers. To our delight, the β-amino α,α-
difluoro ketones were generated in good yield (4u-4z). But when
we tried to expand this kind of reaction to other fluorinated TMS-
sources, such as TMSCF2Br and TMSCF2COOEt. However, trace
desired product could be observed via GC-MS analysis.
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Conclusions
In conclusion, we have developed a simple and efficent “all water”
synthesis of β-amino α,α-difluoro ketones. By experimental
studies, we found that the water environment is important to
prevent fluorinated enol silyl ethers from hydrolysis while trace of
water is enough to promote the reaction, and the hydrogen bond
between water and fluorinated enol silyl ether significantly impact
the nucleophilic addition process. Based on these findings, more
“all water” reactions are now in progress.
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Experimental Section
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To a 5 mL vial was added amines 1 (0.25 mmol) and aldehydes 2 (0.25
mmol), followed by 1 mL H2O and difluoroenoxysilane 3 (0.5 mmol). The
reaction mixture was stirred at room temperature for 6 h, and then the
mixture was extracted with EtOAc (3 * 5.0 mL). The combined organic
layer was dried over MgSO4, filtered and concentrated in vacuum. The
residue was purified by flash chromatography using petrol ether/ethyl
acetate as the eluent. The conditions for chromatography and data for
characterization of the products are given in Supporting Information.
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We gratefully acknowledge Nature Science Foundation of
Jiangsu Province (BK 20140776) for financial support. This work
was also supported by National Natural Science Foundation of
China (21402093, 21476116) and Chinese Postdoctoral Science
Foundation (2015M571761, 2016T90465) for financial support.
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Keywords: in water • one-pot synthesis • β-amino α,α-difluoro
ketones • mannich reaction • aldimines
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European Journal of Organic Chemistry
COMMUNICATION
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European Journal of Organic Chemistry
COMMUNICATION
Mannish reaction*
Ye-bin Wu, Li Wan, Guo-ping Lu, and
Chun Cai* ………………………….. 1-3
“All-water” synthesis of β-amino α,α-
difluoro ketones from fluorinated enol
silyl ethers and imines
A one-pot synthesis of β-amino α,α-difluoro ketones is developed without any
additives. Through a series of control experiments we found that water plays a crucial
and indispensable role. The hydrogen bond between water and fluorinated enol silyl
ether has a significant impact on the addition reaction.
This article is protected by copyright. All rights reserved.