Lithium triethylborohydride-promoted generation of α,α-difluoroenolates from 2-iodo-2,2-difluoroacetophenones: An unprecedented utilization of lithium triethylborohydride

Article abstract of DOI:10.1039/c7ra12130j

Lithium triethylborohydride was found to promote the generation of α,α-difluoroenolates from 2-iodo-2,2-difluoroacetophenones, and applied to the synthesis of polyfluorinated β-hydroxy ketones via self-condensation or aldol reaction. The reaction indicate

Full text of DOI:10.1039/c7ra12130j

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Lithium triethylborohydride-promoted generation
of a,a-difluoroenolates from 2-iodo-2,2-
difluoroacetophenones: an unprecedented
utilization of lithium triethylborohydride†
Cite this: RSC Adv., 2017, 7, 56034
Peng Peng, Jing-jing Wu, *ab Jun-qing Liang, Tian-yu Zhang, Jin-wen Huang
a
a
a
ab
and Fan-hong Wu*a
Received 4th November 2017
Accepted 4th December 2017
Lithium triethylborohydride was found to promote the generation of a,a-difluoroenolates from 2-iodo-2,2-
difluoroacetophenones, and applied to the synthesis of polyfluorinated b-hydroxy ketones via self-
condensation or aldol reaction. The reaction indicates an unprecedented utilization of lithium
triethylborohydride and provides novel access to the generation of a,a-difluoroenolates.
DOI: 10.1039/c7ra12130j
rsc.li/rsc-advances
3
Diuoroenolates are useful uorinated synthons for preparing LiEt BH-promoted in situ generation of diuoroenolates from 2-
1
diuoromethylene compounds, with signicant application in iodo-2,2-diuoroacetophenones and their application in aldol-
2
medicinal chemistry. Accordingly, the protocols to generate type self-condensation and aldol reactions to give various a,a-
diuoroenolates have attracted much attention. Colby rstly diuoro-b-hydroxy ketones (Scheme 1).
reported that compounds triuoromethyl-a,a-diuoro-b-keto
Initially, we chose LiEt BH as one of the reducing agents to
3
gem-diols could be used to give diuoroenolates by the release selectively reduce the carbonyl group or iodine atom of 2-iodo-
3
of triuoroacetate.
Additionally, more diuorinated 2,2-diuoroacetophenones. Surprisingly, our initial attempt to
compounds have been developed as valuable precursors of perform
diuoroenolates, such as a,a-diuoroketones, a,a-diuoro-a- phenylethanone 1a and LiEt
the
reaction
between
2,2-diuoro-2-iodo-1-
4
BH at À78 ꢀC did not furnish
3
5
6
(
trimethylsilylacet)amides, a,a-diuoro-b-ketoesters, a,a,a- any reduction product, instead leading to a self-adduct a,a,g,g-
7
8
triuoroketones, and 2,2-diuoro-1,3-diketones. Furthermore, tetrauoro-b-hydroxy ketone 2a with high yield (Table 1, entry
diuoroenoxysilanes or diuoroenol O-Boc esters were oen 1). Raising the temperature of LiEt BH only led to a little
served as diuoroenolates in different diuoromethylenation increasing of the yield of reduction product 3a and 4a (entries 2
3
9
10
reactions, as well as transition-metal diuoroenolates.
and 3). It was speculated that a diuoroenolate 5 was generated
2
-Iodo-2,2-diuoroacetophenones are one of the important from 2,2-diuoro-2-iodo-1-phenylethanone with LiEt BH, then
3
building blocks to introduce a,a-diuoromethyl ketone frag- the diuoroenolate 5 went through protonation process to form
11
ment into molecules. Our group has reported several reactions a,a-diuoroacetophenone 6. The aldol reaction between 5 and 6
with 2-iodo-2,2-diuoroacetophenones to construct structurally gave the a,a,g,g-tetrauoro-b-hydroxy ketone 2a (Scheme 2).
11d–f
diverse diuoromethylene compounds.
continued research, further structure modication of 2-iodo- diuoroacetophenone play an important role in the fortuitous
,2-diuoroacetophenones was investigated. Lithium trie- reaction. Therefore, the reaction of 2-halo-acetophenone or 2-
As part of our
We wonder that whether the uorine atom in 2-iodo-2,2-
2
thylborohydride (LiEt BH, a superhydride, 1 M in THF) is chloro(bromo, uoro)-2,2-diuoroacetophenone or 2,2-
3
a powerful reducing agent and can efficiently reduce a wide
12
range of functional groups, especially halogen atoms.
However, the reaction with 2-iodo-2,2-diuoroacetophenones
and LiEt BH result in the generation of diuoroenolates
3
instead of reduction products. Herein, we disclosed the
a
School of Chemical and Environmental Engineering, Shanghai Institute of
Technology, Shanghai 201418, China. E-mail: w@sit.edu.cn
b
Key Laboratory of Organouorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c7ra12130j
3
Scheme 1 The novel utilization of LiEt BH for the generation of a,a-
difluoroenolates from 2-iodo-2,2-difluoroacetophenones.
1
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Table 1 The influence of temperature to reaction of 2,2-difluoro-2-
a
3
iodo-1-phenylethanone with LiEt BH
b
Yield (%)
Entry
Temp.
2a
3a
4a
ꢀ
1
2
3
À78 C
98.9
43.9
42.3
0.8
6.9
7.9
0.3
49.2 Scheme
49.8 oacetophenone 1a. Yield based on GC.
ꢀ
0 C
3
The reduction reactions of 2-iodo-2,2-difluor-
a
rt
a
3
Reaction conditions: 1a (1 mmol), LiEt BH (1.2 mmol, 1.2 equiv.), THF
b
2
(dry), N , 4 h. Yield based on GC.
3
through the reaction with LiEt BH, which provided a novel and
efficient access to diuoromethylenation reactions.
diuoroacetophenone with LiEt
3
BH were also performed in
a,a-Diuoro-b-hydroxy ketones are an important class of
THF at À78 ꢀC. The results showed that all these reduction substructure in medicinal chemistry, which could be obtained
13
14
reactions proceeded well leading to the formation of different via aldol reaction with diuoroenolates. Accordingly, to
reduction products (see Scheme 1 in ESI†), which demonstrates further demonstrate the utility of LiEt
the specic characteristic of substrate
2-iodo-2,2- iodo-2,2-diuoroacetophenones with aldehydes promoted by
diuoroacetophenone owing to the adjacent uorine atoms of LiEt BH were conducted. 2-Iodo-2,2-diuoro-1-phenylethanone
carbonyl group.
1a and benzaldehyde 7 was selected as model reaction
3
BH, aldol reaction of 2-
3
Then, other reducing agents were also investigated using 2,2- substrates to optimize the reaction condition (Table 3). The
diuoro-2-iodo-1-phenylethanone 1a as substrate, only led to corresponding aldol produce 8 was produced in the presence of
ꢀ
the formation of different reduction products (Scheme 3). It was LiEt
BH (1.2 equiv. to compound 1a) at À78 C in THF (entry 1).
3
noteworthy that the reducing agents sodium borohydride and The results showed that raising the temperature led to an
Zn power show high selectivity, affording 2,2-diuoro-2-iodo-1- increased yield of reduction product 4a (entries 2–4) and the
phenylethan-1-ol 3a and 2,2-diuoro-1-phenylethanone 6 as conversation decreased with the decreasing of the amount of
major products separately.
3
LiEt BH (entry 5).
Next, the scope of 2,2-diuoro-2-iodo-1-phenylethanone 1
Hence, more aldol reactions were carried out under the
was explored through the LiEt
Table 2). The 2-iodo-2,2-diuoroacetophenones 1b–f bearing products polyuorinated b-hydroxy ketones were obtained in
3
BH promoted self-condensation optimized condition (Scheme 4). To our delight, the aldol
(
electron-donating groups, electron-withdrawing group or high yields by employing the uorinated aldehydes such as 2,2-
halogen atoms, 2,2-diuoro-2-iodo-1-(thiophen-2-yl)ethanone
1
g
and 2,2-diuoro-2-iodo-1-(naphthalen-2-yl)ethanone 1h
Table
3
2 LiEt BH-promoted self-condensation of 2,2-difluoro-2-
were subjected to the self-condensation reaction and all were
found applicable to the reaction, giving the corresponding
a,a,g,g-tetrauoro-b-hydroxy ketones 2a–h in good yields. Few
of the reduction products 4d, 4f, 4g were still observed in low
a
iodo-1-phenylethanones
yields.
The
results
indicated
that
2-iodo-2,2-
diuoroacetophenone derivatives bearing different aryl or
heterocyclic ring could be served as diuoroenolates precursors
a
Yield (%)
Entry
R
2
4
1
2
3
4
5
6
7
8
Ph
4-MeC H
6 4
2a, 86
2b, 83
2c, 85
2d, 72
2e, 87
2f, 71
2g, 70
2h, 84
4a, —
4b, —
4c, —
4d, 20
4e, —
4f, 14
4g, 15
4h, —
4-BrC
3-FC
4-ClC
4-CF
Thienyl
Naphthyl
6
H
H
4
4
6
6
H
4
3
C
6
H
4
3
Scheme 2 Proposed mechanism of LiEt BH-promotd aldol-type self-
condensation.
a
Isolated yields.
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Table 3 The optimization of aldol reaction of 2-iodo-2,2-difluor- the specic property of 2-iodo-2,2-diuoroacetophenones,
a
oacetophenone 1a and benzaldehyde 7
which might due to that the uorine atoms of 2-iodo-2,2-
diuoroacetophenones have signicant impact and change
the property of the adjacent C–I bond. Further study to apply the
protocol for the preparation of diverse diuoromethylene
compounds are in progress in our laboratory.
b
Yield (%)
Conflicts of interest
3
LiEt BH
(equiv.)
b
Entry
Temp.
Conv.(1a) (%)
8
4a
There are no conicts to declare.
ꢀ
1
2
3
4
5
1.2
1.2
1.2
1.2
1.0
À78 C
100
100
100
100
91.6
95.2
85.2
79.6
74.7
90.1
4.8
ꢀ
À40 C
14.8 Acknowledgements
ꢀ
0 C
20.4
rt
25.3 We are grateful for nancial supports from the National Natural
9.9 Science Foundation of China (No. 21472126, 21672151).
ꢀ
À78 C
a
Reaction conditions: 1a (1.0 mmol), 7 (1.0 mmol), THF (dry), N
2
, 4 h.
b
Yield based on GC.
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