Synthesis of α-trifluoromethyl-β-keto phosphonates by electrophilic trifluoromethylation with Togni reagent

Article abstract of DOI:10.1080/00397911.2016.1139724

A new synthetic method of trifluoromethylated phosphonates was developed via electrophilic trifluoromethylation with Togni reagent. A variety of β-keto phosphonates were converted into the corresponding α-trifluoromethyl-β-keto phosphonates in moderate to good yields. This protocol could also be extended to other fluoroalkylation reactions, such as pentafluoroethylation.

Full text of DOI:10.1080/00397911.2016.1139724

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Synthesis of α-trifluoromethyl-β-
keto phosphonates by electrophilic
trifluoromethylation with Togni reagent
Wen-Zhi Fu, Yangen Huang, Xiu-Hua Xu & Feng-Ling Qing
To cite this article: Wen-Zhi Fu, Yangen Huang, Xiu-Hua Xu & Feng-Ling Qing (2016): Synthesis
of α-trifluoromethyl-β-keto phosphonates by electrophilic trifluoromethylation with Togni
reagent, Synthetic Communications
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Date: 21 March 2016, At: 03:10

SYNTHETIC COMMUNICATIONS®
http://dx.doi.org/10.1080/00397911.2016.1139724
Synthesis of α-trifluoromethyl-β-keto phosphonates by
electrophilic trifluoromethylation with Togni reagent
Wen-Zhi Fua, Yangen Huanga, Xiu-Hua Xub, and Feng-Ling Qinga,b
aCollege of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, China;
bKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Science, Shanghai, China
ABSTRACT
ARTICLE HISTORY
Received 21 November 2015
A new synthetic method of trifluoromethylated phosphonates was
developed via electrophilic trifluoromethylation with Togni reagent. A
variety of β-keto phosphonates were converted into the correspond-
ing α-trifluoromethyl-β-keto phosphonates in moderate to good
yields. This protocol could also be extended to other fluoroalkylation
reactions, such as pentafluoroethylation.
KEYWORDS
Electrophilic; β-keto
phosphonate;
pentafluoroethyl;
trifluoromethyl
GRAPHICAL ABSTRACT
Introduction
Phosphonic acids and their diesters have received increasing attention in medicinal and
synthetic chemistry.[1] Phosphonates were considered in many instances as analogs of
naturally occurring phosphates, with enhanced metabolic stability.[2] Consequently,
research interest in phosphonate analogs has grown tremendously to develop new biologi-
cal compounds. It is well known that the incorporation of fluorine atom and/or fluorine-
containing groups into an organic molecule often changes the chemical, physical, and
biological properties of the parent compound.[3] Therefore, fluorinated phosphonate ana-
logs including α-monofluorinated,[4] α,α-difluorinated,[5] and α-trifluoromethylated[6–8]
phosphonates I–III have been intensively investigated (Scheme 1).
Because of the unique properties of trifluoromethyl group, such as strong electron-
withdrawing effect, high lipophilicity, and excellent metabolic stability, trifluoromethylated
phosphonates are of particular interest. However, the synthetic methods of trifluoro-
methylated phosphonates mainly relied on phosphonylation of CF3-containing building
blocks[6] (Scheme 2a) and transformation of trifluoromethylated iminophosphonates[7]
CONTACT Feng-Ling Qing
flq@mail.sioc.ac.cn
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Science, 345 Lingling Lu, Shanghai 200032, China.
Supplemental data for this article can be accessed on the publisher’s website.
© 2016 Taylor & Francis

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W.-Z. FU ET AL.
Scheme 1. Fluorinated phosphonates.
Scheme 2. Different approaches to trifluoromethylated phosphonates.
(Scheme 2b). Compared to these indirect methods, the direct trifluoromethylation is more
attractive. To the best of our knowledge, only one example was reported of the synthesis of
trifluoromethylated phosphonates by a direct trifluoromethylation approach, in which
nucleophilic trifluoromethylation of acyl phosphonates was involved (Scheme 2c).[8] Thus,
it is highly desirable to develop other direct methods to synthesize trifluoromethylated
phosphonates. In continuation of our recent research interest in trifluoromethylation
reactions,[9] herein we report a new approach to trifluoromethylated phosphonates via
electrophilic trifluoromethylation of β-keto phosphonates (Scheme 2d). This method
provides a variety of previous unknown and potentially useful α-trifluoromethyl-β-keto
phosphonates.
Results and discussion
We began our study by examining the reaction of β-keto phosphonate 1a with different
electrophilic trifluoromethylating reagents in the presence of various bases and solvents
(Table 1). Among several electrophilic trifluoromethylating reagents, Togni reagent B
was the most effective, providing the trifluoromethylated product 2a in 32% yield (entries
1–4). To our delight, the addition of hexamethylphosphoramide (HMPA), a common
cosolvent used to accelerate otherwise slow SN2 reactions by solvating cations,[10] could
improve the yield to 53% (entry 5). To further improve the reaction yield, different organic
and inorganic bases were investigated and t-BuONa was found to be the optimal base to
afford 2a in 67% yield (entries 6–10). The subsequent solvent screening demonstrated that
CH2Cl2 was superior to tetrahydrofuran (THF), Et2O, and toluene (entries 11–13). Finally,
reducing the amounts of t-BuONa and extending the reaction time could improve the yield
to 79% (entry 14).

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Table 1. Optimization of reaction conditionsa.
Entry
CF3 reagent
Additive
Base
Solvent
Yield (%)b
1
2
A
B
C
—
NaH
THF
THF
0
—
NaH
32
14
20
53
0
3
—
—
NaH
THF
4
D
B
B
B
B
B
B
B
B
B
B
NaH
THF
5
HMPA
HMPA
HMPA
HMPA
HMPA
HMPA
HMPA
HMPA
HMPA
HMPA
NaH
THF
6
DBU
THF
7
LDA
THF
32
16
67
0
40
72
29
79
8
t-BuOLi
t-BuONa
t-BuOK
t-BuONa
t-BuONa
t-BuONa
t-BuONa
THF
9
THF
10
11
12
13
14c
THF
Et2O
CH2Cl2
Toluene
CH2Cl2
aReactions were carried out using 1a (0.2 mmol), CF3 reagent (0.3 mmol), base (0.6 mmol), and additive (1.2 mmol) in solvent
(2.0 mL) for 12 h.
bYields were determined by 19 F NMR spectroscopy of the crude reaction mixture using benzotrifluoride as an internal
standard.
ct-BuONa (0.3 mmol), 18 h.
With the optimized reaction conditions in hand (Table 1, entry 14), we next investigated
the substrate scope of this reaction. As summarized in Scheme 3, the electrophilic trifluor-
omethylation of various β-keto phosphonates 1 proceeded well, affording the correspond-
ing products 2 in moderate to good yields. Several tetralone derivatives 1a–d were
successfully converted to the trifluoromethylated products 2a–d. The reaction of acyclic
β-keto phosphonates 1e–1 showed comparable yields to cyclic ones. Substrates 1e and 1f
bearing α-methyl and α-ethyl groups were both compatible with the reaction conditions.
This protocol allowed the direct trifluoromethylation of substrates 1g–i bearing different
substitutents including methyl, chloro, and acetoxyl on the arene rings. It was noteworthy
that different ester groups in 1j–l had no obvious influence to the yield. In the cases of non-
aromatic β-keto phosphonates, the desired trifluoromethylated products were isolated in
poor yields.
Furthermore, this method can be further extended to the synthesis of pentafluoroethy-
lated phosphonates (Scheme 4). Cyclic and acyclic β-keto phosphonates 1a and 1e reacted
with electrophilic pentafluoroethylating reagent E to give the corresponding products 3a
and 3e, respectively. These results showed that this protocol should be extended to other
perfluoroalkylation reactions.

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W.-Z. FU ET AL.
Scheme 3. Substrate scope of electrophilic trifluoromethylation of various β-keto phosphonates.
Scheme 4. Electrophilic pentafluoroethylation of β-keto phosphonates.
Conclusions
In conclusion, we have developed a new method for the preparation of trifluoromethylated
phosphonates. The reaction of cyclic and acyclic β-keto phosphonates with Togni reagent in
the presence of t-BuONa and HMPA provided various α-trifluoromethyl-β-keto phospho-
nates in moderate to good yields. This protocol could also be extended for the preparation

SYNTHETIC COMMUNICATIONS®
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of pentafluoroethylated phosphonates. All these fluorinated products are previously
unknown and might be used as building blocks in organic synthesis and drug development.
Experimental
A 25-mL Schlenk tube was charged with a stir bar and t-BuONa (28.8 mg, 0.3 mmol) under
N2 atmosphere. Phosphonate (0.2 mmol), HMPA (215.0 mg, 1.2 mmol), and CH2Cl2
(2.0 mL) were added to the tube. The reaction mixture was cooled 0 °C and stirred for
30 min. Then, Togni reagent B (94.8 mg, 0.3 mmol) was added to the reaction mixture.
After stirring at room temperature for 18 h, the reaction mixture was quenched with
10% NH4Cl aqueous solution and extracted with CH2Cl2 three times. The combined
organic layer was dried over Na2SO4, and the organic solvent was removed under reduced
pressure. The residue was purified by flash column chromatography on silica gel to afford
the desired product.
Funding
The authors are grateful for the financial support from the National Natural Science Foundation of
China (21421002, 21332010, 21272036), the National Basic Research Program of China
(2012CB21600), and Shanghai City (15PJ1410300).
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