Synthesis and decarboxylative Wittig reaction of difluoromethylene phosphobetaine

Article abstract of DOI:10.1039/c3cc44271c

A key intermediate, difluoromethylene phosphobetaine, in the Wittig reaction of ClCF₂CO₂Na-Ph₃P with aldehydes was synthesized and characterized, which confirmed the reaction mechanism. The decarboxylation of this stable intermediate was a convenient approach for Wittig difluroolefination. Its reactivity could be adjusted by the modification of the substituent on the phosphorus.

Full text of DOI:10.1039/c3cc44271c

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Synthesis and decarboxylative Wittig reaction of
difluoromethylene phosphobetaine†‡
Cite this: Chem. Commun., 2013,
49, 7513
Jian Zheng,y Ji Cai,y Jin-Hong Lin, Yong Guo and Ji-Chang Xiao*
Received 6th June 2013,
Accepted 26th June 2013
DOI: 10.1039/c3cc44271c
www.rsc.org/chemcomm
A key intermediate, difluoromethylene phosphobetaine, in the Wittig
reaction of ClCF2CO2Na–Ph3P with aldehydes was synthesized and
characterized, which confirmed the reaction mechanism. The
decarboxylation of this stable intermediate was a convenient approach
for Wittig difluroolefination. Its reactivity could be adjusted by the
modification of the substituent on the phosphorus.
gem-Difluoroolefins constitute a distinct class of fluorine-
containing compounds.1 They have attracted much interest in
various fields such as medical and agricultural chemistry and
materials science because the gem-difluorovinyl moiety greatly
affects the biological functions and physical properties of
Scheme 1 Mechanisms for the Wittig reaction of ClCF2CO2Na.
organic molecules.2 Consequently, considerable effort has been reaction involving ClCF2CO2Na, there was a debate on the process
made to develop efficient methods for their preparation. Basically, of the reaction. Three mechanisms were proposed to explain
there are three approaches to construct the gem-difluoroolefin the formation of difluoromethylene(triphenyl)phosphorane
framework.3 b-Elimination is a general method but it requires (Ph3PQCF2) (Scheme 1).9a ClCF2CO2Na had already been
tedious multi-step synthesis of the fluorinated precursors.4 known to be an efficient difluorocarbene (:CF2) precursor.10
A second approach to construction of gem-difluoroalkenes Therefore, Fuqua tended to think that Ph3PQCF2 was gener-
utilizes organometallic reagents such as gem-difluorovinyl ated through the capture of :CF2 from ClCF2CO2Na by tri-
lithium or borane, which need careful handling due to their phenylphosphine (mechanism A).9a However, a later study
sensitivity to moisture.3a,5 A third method employs Julia, showed that the thermal decomposition of ClCF2CO2Na could
Horner–Wadsworth–Emmons (HWE) or Wittig reaction for be greatly accelerated by triphenylphosphine.9d And the trap
the difluoroolefination of aldehydes and ketones.6 Of these of :CF2 with tetramethylethylene or isopropyl alcohol was not
approaches, the Wittig type reaction is one of the most observed in the Wittig reaction of ClCF2CO2Na.9d So Herkes
straightforward methods to achieve difluoroalkenes.
and Burton proposed that (triphenylphosphonio)difluoroacetate
As part of our continuing interest in fluorinated olefins,7 we (Ph3P+CF2CO2ꢀ, PDFA, 1a) was first generated and its sub-
investigated the Wittig difluoroolefination of carbonyl com- sequent decarboxylation led to the formation of Ph3PQCF2
pounds. In this reaction, the difluoromethylene unit was mostly (mechanism B). However, their attempts to prepare Ph3P+CF2CO2
ꢀ
derived from dibromodifluoromethane (CF2Br2)8 or sodium failed.9d
chlorodifluoroacetate (ClCF2CO2Na).9 Due to the high ozone-
To gain more insight into the mechanism of this Wittig
depleting potential of CF2Br2, its use is prohibited. For the Wittig reaction, we explored the reaction of 4-phenylbenzaldehyde,
triphenylphosphine and ClCF2CO2Na under the same reaction
conditions as described by Fuqua and Burton.9a,c,d However,
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
ꢀ
Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
E-mail: jchxiao@sioc.ac.cn; Fax: +86-21-6416-6128; Tel: +86-21-5492-5430
† Dedicated to Professor Jean’ne M. Shreeve on the occasion of her 80th birthday.
‡ Electronic supplementary information (ESI) available: Experimental procedures
and characterization of data for all compounds. CCDC 929401 (1a). For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c3cc44271c
§ These authors contributed equally to this work.
not any Ph3P+CF2CO2 could be observed by 19F NMR spectro-
scopy when the reaction was performed in various solvents
(DG, DMF or NMP) at different temperatures (160 1C, 100 1C or
80 1C). The result is still the same without the presence of
aldehydes. It is speculated that such a difluoromethylene
phosphobetaine (1a) might easily undergo decarboxylation at
c
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Scheme 2 Preparation of (triphenylphosphonio)difluoroacetate (PDFA, 1a).
Fig. 1 Reaction intermediate: (triphenylphosphonio)-difluoroacetate (PDFA, 1a).
Fig. 2 19F NMR analysis of the reaction mixture.
the tested temperature. When the reaction was performed in
DMF at 55 1C, a weak doublet at ꢀ94.10 ppm ( J = 100.3 Hz)
appeared in the 19F NMR spectrum, which might be the signal
of –CF2– in PDFA. Nevertheless, the reaction was too weak to be
worthy of further isolation.
Due to the easier breaking of C–Br bonds as compared with
that of C–Cl bonds, BrCF2CO2K was employed instead of
ClCF2CO2Na in the above reaction. It was found that the
reaction of BrCF2CO2K with PPh3 proceeded very well in DMF
at room temperature, giving PDFA in 67% yield (Scheme 2). Its
structure was characterized by NMR spectroscopy, mass spectro-
metry, elemental analysis, and further confirmed by single
crystal X-ray analysis (Fig. 1). Its low solubility in H2O and
DMF allows for simple work-up and easy scale-up. The
phosphobetaine is stable in air and water. Thermal analysis
(DSC-TGA) showed no decomposition below 105 1C (see the
ESI‡), demonstrating relatively good thermal stability. However,
as shown by 19F NMR spectroscopy, slow decomposition com-
menced in the presence of polar solvent such as DMF or
CH3OH even at room temperature.
Scheme 3 gem-Difluoroolefination of aldehydes and ketones. Reaction condi-
tions: 1a (1.6 mmol) and 2 (0.8 mmol) in NMP at 80 1C for 4 h. Isolated yields
obtained after column chromatography. a Determined by 19F NMR through the
quantitative addition of trifluoromethylbenzene (0.1 mmol) as the standard.
Given that the above (triphenylphosphonio)difluoroacetate
(PDFA) was produced from BrCF2CO2K, it was therefore neces-
sary to know if PDFA is the right intermediate in the Wittig
reaction of ClCF2CO2Na (mechanism B, Scheme 1). As described
above, heating a solution (SCl) of ClCF2CO2Na and Ph3P in DMF
Then a series of carbonyl compounds were tested for their
at 55 1C gave a trace amount of product showing a doublet suitability for use in this difluoroolefination under the optimal
signal at ꢀ94.10 ppm in the 19F NMR spectrum (Fig. 2A), which reaction conditions (Scheme 3). It was found that the reaction
is exactly the same as that observed in the 19F NMR spectrum of with aryl aldehydes displayed a remarkable tolerance towards
PDFA prepared from BrCF2CO2K. Furthermore, the external different electron-donating and -withdrawing groups on the
addition of the prepared PDFA to the solution (SCl) increased aryl ring, giving the desired difluoroolefinated product in
the signal intensity at ꢀ94.10 ppm (Fig. 2B). Subsequent moderate to excellent yield (3a–h). The relatively lower yield
addition of 4-phenylbenzaldehyde led to the signal disappearance for m-trifluoromethyl benzaldehyde is partially due to the high
at ꢀ94.10 ppm and the formation of the gem-difluoroolefination volatility of the product, because the yield determined by
product after keeping the resulting solution at 55 1C for 1 h 19F NMR analysis was 83% (3b). The double bond present in
(Fig. 2C). This indicated that mechanism B involving phospho- the substrate remained intact during the reaction, indicating
betaine is the most probable process for the Wittig reaction of that few or no difluorocarbene was formed under the reaction
ClCF2CO2Na (Scheme 1).
conditions (3f). The steric hindrance did not significantly affect
With the stable reaction intermediate PDFA in hand, we the reaction (3h). The reaction proceeded equally well for the
then investigated its application as a ylide precursor in Wittig heteroaromatics (3i, 3j) and a,b-unsaturated aldehyde (3k).
difluoroolefination. The screening of reaction conditions showed In the case of enolizable aldehyde, relatively good yield was
that 2 : 1 of phosphobetaine to aldehyde at 80 1C for 4 h in NMP obtained (3l). Moderate yield could be obtained in the reaction of
was the optimal reaction condition (see the ESI‡).
PDFA with activated ketone (4a). But as for nonactivated ketones,
c
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which provided direct evidence for the reaction mechanism.
The generation of the ylide through decarboxylation was found
to be an efficient and simplest pathway for Wittig reaction. The
difluoromethylene phosphobetaine might reasonably be
expected to become a convenient difluoroolefination reagent
due to its stability, adjustable reactivity and ease of handling.
Further research on the application of difluoromethylene phos-
phobetaine to other reactions is currently underway.
Scheme 4 Preparation of [tris(dimethylamino)phosphonio]difluoroacetate (ADFA).
We thank the National Natural Science Foundation (21032006,
21172240), the 973 Program of China (2012CBA01200) and the
Chinese Academy of Sciences.
Notes and references
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Scheme 5 gem-Difluoroolefination of ketones. Reaction conditions: 1b (1.0 mmol)
and 2 (0.5 mmol) in NMP at 120 1C for 4 h. Isolated yields obtained after column
chromatography.
´
´
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amino)phosphonium ylide formed in situ could react well with
nonactivated ketones.8b This prompted us to synthesize [triꢀs-
(dimethylamino)phosphonio]difluoroacetate [(Me2N)3P+CF2CO2
,
ADFA, 1b]. It was found that (Me2N)3P+CF2CO2 can be similarly
obtained using the same procedure as that used for obtaining
PDFA (Scheme 4).
ꢀ
¨
and R. G. Hall, Chimia, 2004, 58, 93–99; (g) T. Pitterna, M. Boger and
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The phosphobetaine (ADFA) was then applied in the reac-
tion with nonactivated ketone, 40-phenylacetophenone. Under
the same reaction conditions as those used for PDFA, the
desired difluoroolefinated product (4b) was formed in 12%
yield. However, much of the salt (1b) remained unreacted after
being heated at 80 1C for 4 h. Further screening of the reaction
temperature showed that a yield of 72% was achieved when the
reaction was performed at 120 1C for 4 h (4b, Scheme 5). The
reaction with other nonactivated ketones also proceeded smoothly
under these reaction conditions (4c–4e). This indicated that the
reactivity of the phosphobetaine could be modified through
changing the substituents on the phosphorus.
´
´
4 (a) J.-P. Begue, D. Bonnet-Delpon and M. H. Rock, Synlett, 1995,
´
´
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It is obvious that this Wittig reaction was driven by the
decarboxylation of the phosphobetaine, giving the corresponding
difluoromethylene phosphonium ylide (R3P+–CF2ꢀ). Although
the decarboxylation of a carboxylate often generates an anion,
this strategy was seldom employed in Wittig reactions,11 prob-
ably because of the usually high decarboxylation temperature.
The relatively lower decarboxylation temperature of the phospho-
betaine made this Wittig difluoroolefination feasible and
practical. Compared with other difluoroolefination methods
using ClCF2CO2Na9 or CF2Br2,8 which suffer from high hygro-
scopicity or commercial availability of the reagents or forcing
reaction conditions, the present reaction starting from the
isolated phosphobetaine appears more simple and convenient
because no catalyst or additive is required.
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In conclusion, the reaction intermediate, difluoromethylene
phosphobetaine (PDFA), was successfully synthesized and char-
acterized as the ylide precursor of the Wittig difluoroolefination,
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 7513--7515 7515