Base-free O-difluoromethylation of 1,3-diones with difluorocarbene

Article abstract of DOI:10.1016/j.jfluchem.2016.10.011

The base-free O-difluoromethylation of 1,3-diones with difluorocarbene generated from difluoromethylene phosphobetaine (Ph₃P⁺CF₂CO₂^?) is described. The convenient reactions proceeded smoothly to give

Full text of DOI:10.1016/j.jfluchem.2016.10.011

Accepted Manuscript
Title: Base-Free O-Difluoromethylation of 1,3-Diones with
Difluorocarbene
Author: Can Liu Xiao-Yun Deng Xian-Liang Zeng Gang
Zhao Jin-Hong Lin Hongqing Wang Ji-Chang Xiao
PII:
S0022-1139(16)30339-6
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2016.10.011
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18-10-2016
18-10-2016
Please cite this article as: Can Liu, Xiao-Yun Deng, Xian-Liang Zeng,
Gang Zhao, Jin-Hong Lin, Hongqing Wang, Ji-Chang Xiao, Base-Free O-
Difluoromethylation of 1,3-Diones with Difluorocarbene, Journal of Fluorine
Chemistry http://dx.doi.org/10.1016/j.jfluchem.2016.10.011
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Base-Free O-Difluoromethylation of 1,3-Diones with Difluorocarbene
Can Liu, [ab] Xiao-Yun Deng, [b] Xian-Liang Zeng, [b] Gang Zhao, [b] Jin-Hong Lin,*[b] Hongqing
Wang, *[a] and Ji-Chang Xiao*[b]
a School of Chemistry and Chemical Engineering, University of South China, Hengyang 421001,
P.R.China.
Fax: +86-734-8281676; Tel: +86-734-8281676; E-mail: hqwang2015@126.com
bKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China Fax: +86-21-6416-6128; Tel: +86-21-5492-5340; Email: jlin@sioc.ac.cn ;
jchxiao@sioc.ac.cn.
Abstract Graphic
The base-free O-difluoromethylation of 1,3-diones with difluorocarbene generated from
-
difluoromethylene phosphobetaine (Ph3P+CF2CO2 ) is described to give difluoromethyl enol
ethers.

Highlights
1. Under mild conditions, O-difluoromethylation of 1,3-diones with difluorocarbene occurred
smoothly.
2. No base or additive was required for this transformation.
3. The conversion gave difluoromethyl enol ethers as products, which may act as valuable
intermediates for further transformations
Abstract: The base-free O-difluoromethylation of 1,3-diones with difluorocarbene generated from
-
difluoromethylene phosphobetaine (Ph3P+CF2CO2 ) is described. The convenient reactions
proceeded smoothly to give difluoromethyl enol ethers in moderate to good yields.
Keywords: O-Difluoromethylation, Difluorocarbene, Base-free, 1,3-diones.
1. Introduction
Since OCF2H moiety in difluoromethyl ethers has served as a valuable pharmacophore in
medicinal chemistry and drug discovery [1-6], significant efforts have been directed towards the
development of efficient methods for the construction of this functionality [3, 7-11].
O-Difluoromethylation of O-nucleophiles with difluorocarbene has proved to be one of the most
attractive strategies due to its straightforward procedures [12-20]. Difluorocarbene is a moderately
electrophilic species and therefore its reaction with O-nucleophiles would readily occur [7, 8].
Intensive studies have been focused on the O-difluoromethylation of alcohols[12, 17, 19] and
phenols[12-18] with difluorocarbene to afford difluoromethyl alkyl- and aryl-ethers, respectively.
The researches on O-difluoromethylation of 1,3-diones have been largely ignored, even though
these conversions would furnish difluoromethyl enol ethers [20], which may act as valuable
intermediates for further transformations.
Recently, Shibata et al. [21, 22], Weng et al. [23] and our group [24] have independently
disclosed the O-difluoromethylation of 1,3-diones. Shibata and coworkers reported that
S-(bromodifluoromethyl)diarylsulfoniumsalts [ArS+(CF2Br)Ar’ X-] can act as a difluorocarbene
reagent to realize O-difluroomethylation [21, 22]. In contrast to Shibata’s studies, we found that

S-(difluoromethyl)diarylsulfonium salt [ArS+(CF2H)Ar’ X-] is not only a difluorocarbene reagent,
but also a difluoromethylation reagent which can directly transfer the CF2H group to
O-nucleophiles [24]. The group of Weng discovered that ethyl chlorodifluoroacetate
(ClCF2CO2Et) is also very effective for the O-difluoromethylation of 1,3-diones [23]. Although
these methods are quite efficient, they suffer from the use of basic reaction conditions. In some
cases, low reaction temperature [21, 22] or strong basic conditions [23] are even required.
-
Difluoromethylene phosphobetaine (Ph3P+CF2CO2 , PDFA), a difluorocarbene reagent which was
developed by us recently [18, 25-28] and was applied by other groups [29-33], was previously
found to be able to realize X-difluoromethylation via the insertion of difluorocarbene into X-H
bond (X = N, O and S) without the presence of base [18]. Interestingly, the base-free
O-difluoromethylation of 1,3-diones with PDFA can also proceed smoothly simply by heating.
The preliminary results are described herein.
2. Results and discussion
Since we have shown that low-polarity solvent such as p-xylene would favour for the
generation of difluorocarbene from PDFA [26], p-xylene was firstly used as the reaction solvent
for the O-difluoromethylation of substrate 1a with PDFA. To our surprise, our initial attempts
were successful to give the desired product 2a in a good yield (Table 1, entry 1). A comparable
yield was obtained by using toluene instead of p-xylene (Table 1, entry 2). More-polar solvent led
to the decrease in the yield (Table 1, entries 3-6), and the yield was dramatically decreased in
DMF (entry 6 vs. entry 1). The reaction temperature can also affect the yield of the product (Table
1, entries 7-9). Lowering the temperature decreased the yield slightly (Table 1, entry 7 vs. entry 1),
but the yield was not increased with the elevation of the temperature (Table 1, entries 8-9 vs. entry
1). 2 equiv of PDFA seems to be a suitable loading, as evidenced by the results that lowering the
loading decreased the yield (Table 1, entry 10 vs. entry 1) and increasing the loading did not
obviously led to the rise in the yield (Table 1, entries 11-12 vs. entry 1). The yield was not
increased by prolonging reaction time, meaning that the starting materials were fully converted in
3 h (Table 1, entry 13 vs. entry 1).
With the optimized reaction conditions in hand (Table 1, entry 1), we then explored the
substrate scope for this base-free O-difluoromethylation of 1,3-diones with PDFA (Scheme 1). A
variety of 1,3-cyclohexanediones (2a-2h) and 1,3-cyclopentanediones (2i-2m) were converted
smoothly into the corresponding products in moderate to high yields. The transformation is not
quite sensitive to steric effects, as evidenced by the good yields obtained for the conversions of
substrates containing 2-position substituents (2b, 2d, 2j-2m). Surprisingly, in contrast to the high
yield for the difluoromethylation of 2-phenyl 1,3-cyclopentanedione (2l), a low yield was obtained
for the reaction of 2-phenyl 1,3-cyclohexanedione (2c). This O-difluoromethylation protocol
cannot be well applied to 1,3-cycloheptanedione (2n) or acyclic 1,3-dione (2o).

On the basis of above results, we propose that the reaction mechanism shown in Scheme 2 is
plausible. The decarboxylation of PDFA followed by the dissociation of P-CF2 bond would
readily generate difluorocarbene [18]. Substrate 1,3-dione is in equilibrium with its enolate form
1’. Both 1,3-dione 1 and enolate 1’ can easily trap difluorocarbene to produce intermediates Int
and Int’, respectively. The subsequent proton migration in Int and Int’ affords the final product 2.
3. Conclusions
In summary, we have described the base-free O-difluoromethylation of 1,3-diones with
-
difluorocarbene generated from difluoromethylene phosphobetaine (Ph3P+CF2CO2 ) to give
difluoromethyl enol ethers in moderate to high yields. This work represents a mild and efficient
protocol for the construction of OCF2H moiety since simply heating the mixture of 1,3-diones
with difluorocarbene reagent can furnish the desired products.
4. Experimental section
4.1. General Information
1H, 13C and 19F NMR spectra were detected on a 500 MHz, 400 MHz or 300 MHz NMR
spectrometer. Data for 1H NMR, 13C NMR and 19F NMR were recorded as follows: chemical shift
(δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, q = quartet, coupling
constant (s) in Hz). Mass spectra were obtained on GC-MS. High resolution mass data were
recorded on a high resolution mass spectrometer in the EI. All starting materials were
commercially available except 1c [34] and 1d [34], 1l [35] and 1m [35], which were prepared
according to literature. PDFA was prepared according to our previous work [25].
4.2 General procedure for O-difluoromethylation of 1,3-diones:
Into a mixture of substrate 1 (0.2 mmol, 1.0 equiv.) and PDFA (0.4 mmol, 142 mg, 2.0 equiv.)
in a dry 10 mL Schlenk tube, dry p-xylene (2 mL) was added under N2 atmosphere. The reaction
mixture was stirred at 60 oC for 3 hours. After being cooled to room temperature, the mixture was
directly subjected to flash column chromatography (PE/EA = 5:1 to 3:1 as eluent) to afford the
desired product.
1
3-(Difluoromethoxy)cyclohex-2-en-1-one (2a) [37]: 84%. Colourless oil. H NMR (400 MHz,
CDCl3) δ 6.50 (t, J = 72.0 Hz, 1H), 5.51 (s, 1H), 2.49 (t, J = 6.2 Hz, 2H), 2.39 - 2.33 (m, 2H), 2.07
- 1.98 (m, 2H). 19F NMR (376 MHz, CDCl3) δ -85.29 (d, J = 72.0 Hz, 2F).
3-(Difluoromethoxy)-2-methylcyclohex-2-en-1-one (2b) [37]: 87%. Colourless oil. 1H NMR (400
MHz, CDCl3) δ 6.52 (t, J = 73.4 Hz, 1H), 2.64 - 2.56 (m, 2H), 2.43 - 2.31 (m, 2H), 2.07 - 1.91 (m,
2H), 1.73 (s, 3H).19F NMR (376 MHz, CDCl3) δ -80.20 (d, J = 73.4 Hz, 2F).
1
6-(Difluoromethoxy)-4,5-dihydro-[1,1'-biphenyl]-2(3H)-one (2c): 30%. Colourless oil. H NMR

(400 MHz, CDCl3) δ 7.43 - 7.31 (m, 3H), 7.21 - 7.17 (m, 2H), 6.35 (t, J = 73.4 Hz, 1H), 2.80 (t, J
= 6.2 Hz, 2H), 2.59 - 2.55 (m, 2H), 2.20 - 2.11 (m, 2H). 19F NMR (376 MHz, CDCl3) δ -80.71 (d,
J = 73.4 Hz, 2F). 13C NMR (101 MHz, CDCl3) δ 197.51 (s), 163.70 (s), 131.34 (s), 130.17 (s),
128.00 (s), 127.76 (s), 127.08 (s), 114.36 (t, J = 264.3 Hz), 37.15 (s), 28.10 (s), 20.57 (s). IR (neat)
ν = 3057, 2956, 1670, 1634, 1599, 1495, 1428, 1352, 1334, 1301, 1211, 1190, 1104, 1057, 1003,
985, 965, 761, 699 cm-1. HRMS (EI): calcd. for C13H12F2O2 [M]+: 238.0805, Found: 238.0799.
1
2-Benzyl-3-(difluoromethoxy)cyclohex-2-en-1-one (2d) [37]: 74%. Colourless oil. H NMR (400
MHz, CDCl3) δ 7.37 - 7.01 (m, 5H), 6.53 (t, J = 73.3 Hz, 1H), 3.64 (s, 2H), 2.66 (t, J = 6.2 Hz,
2H), 2.40 (t, J = 6.2 Hz, 2H), 2.07 - 1.97 (m, 2H). 19F NMR (376 MHz, CDCl3) δ -80.34 (d, J =
73.3 Hz, 2F).
1
3-(Difluoromethoxy)-5-methylcyclohex-2-en-1-one (2e) [37]: 59%. Colourless oil. H NMR (400
MHz, CDCl3) δ 6.50 (t, J = 72.0 Hz, 1H), 5.50 (s, 1H), 2.52 - 2.41 (m, 2H), 2.30 - 2.18 (m, 2H),
2.09 - 2.00 (m, 1H), 1.09 (d, J = 6.2 Hz, 3H). 19F NMR (376 MHz, CDCl3) δ -84.71 (dd, J = 173.7,
72.0 Hz, 1F), -85.98 (dd, J = 173.7, 72.0 Hz, 1F).
1
3-(Difluoromethoxy)-5,5-dimethylcyclohex-2-en-1-one (2f) [36]: 58%. Colourless oil. H NMR
(400 MHz, CDCl3) δ 6.51 (t, J = 72.1 Hz, 1H), 5.52 - 5.48 (m, 1H), 2.34 (s, 2H), 2.21 (s, 2H), 1.07
(s, 6H). 19F NMR (376 MHz, CDCl3) δ -85.33 (d, J = 72.1 Hz, 2F).
1
5-(Difluoromethoxy)-1,6-dihydro-[1,1'-biphenyl]-3(2H)-one (2g) [37]: 85%. Colourless oil. H
NMR (400 MHz, CDCl3) δ 7.35 - 7.21 (m, 5H), 6.55 (dd, J = 72.6, 71.2 Hz, 1H), 5.63 (s, 1H),
3.48 - 3.33 (m, 1H), 2.83 - 2.49 (m, 4H). 19F NMR (376 MHz, CDCl3) δ -84.56 (dd, J = 173.5,
72.6 Hz, 1F), -86.12 (dd, J = 173.3, 71.2 Hz, 1F).
3-(Difluoromethoxy)-5-isopropylcyclohex-2-en-1-one (2h) [37]: 79%. Colourless oil.1H NMR
(400 MHz, CDCl3) δ 6.54 (dd, J = 72.9, 71.2 Hz, 1H), 5.53 (s, 1H), 2.54 - 2.44 (m, 2H), 2.38 -
2.28 (m, 1H), 2.15 - 2.04 (m, 1H), 2.00 - 1.88 (m, 1H), 1.69 - 1.59 (m, 1H), 0.96 (d, J = 6.8 Hz,
3H), 0.95 (d, J = 6.8 Hz, 3H).19F NMR (376 MHz, CDCl3) δ -84.57 (ddd, J = 173.8, 72.9, 0.8 Hz,
1F), -86.20 (dd, J = 173.8, 71.2 Hz, 1F).
3-(Difluoromethoxy)cyclopent-2-en-1-one (2i) [37]: 81%. Colourless oil.1H NMR (400 MHz,
CDCl3) δ 6.56 (t, J = 71.7 Hz, 1H), 5.54 (s, 1H), 2.75 - 2.71 (m, 2H), 2.51 - 2.46 (m, 2H). 19F
NMR (376 MHz, CDCl3) δ -86.85 (d, J = 71.7 Hz, 2F).
3-(Difluoromethoxy)-2-methylcyclopent-2-en-1-one (2j) [37]: 85%. Colourless oil. 1H NMR (400
MHz, CDCl3) δ 6.66 (t, J = 72.2, 1H), 2.81 - 2.75 (m, 2H), 2.65 - 2.42 (m, 2H), 1.68 (s, 3H). 19F
NMR (376 MHz, CDCl3) δ -81.30 (d, J = 72.2 Hz, 2F).
3-(Difluoromethoxy)-2-ethylcyclopent-2-en-1-one (2k) [37]: 67%. Colourless oil.1H NMR (400
MHz, CDCl3) δ 6.65 (t, J = 72.3 Hz, 1H), 2.78 - 2.73 (m, 2H), 2.50 - 2.46 (m, 2H), 2.15 (q, J = 7.6

Hz, 2H), 0.97 (t, J = 7.6 Hz, 3H). 19F NMR (376 MHz, CDCl3) δ -81.57 (d, J = 72.3 Hz, 2F).
3-(Difluoromethoxy)-2-phenylcyclopent-2-en-1-one (2l): 83%. Colourless oil. 1H NMR (400 MHz,
CDCl3) δ 7.58 (d, J = 7.2 Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.31 (tt, J = 7.6, 1.3 Hz, 1H), 6.71 (t, J
= 71.9 Hz, 1H), 2.94 - 2.88 (m, 2H), 2.66 - 2.62 (m, 2H). 19F NMR (376 MHz, CDCl3) δ -81.84 (d,
J = 71.9 Hz, 2F). 13C NMR (101 MHz, CDCl3) δ 202.57 (s), 174.31 (s), 128.69 (s), 128.64 (s),
128.29 (s), 128.24 (s), 124.35 (s), 114.23 (t, J = 266.9 Hz), 34.25 (s), 25.73 (s). IR (neat) ν = 3058,
2926, 2854, 1701, 1647, 1600, 1497, 1446, 1437, 1365, 1334, 1303, 1280, 1220, 1104, 1057, 983,
925, 836, 765, 697, 655, 578, 478 cm-1. HRMS (EI): calcd. for C12H10F2O2 [M]+: 224.0649, Found:
224.0642.
1
2-Benzyl-3-(difluoromethoxy)cyclopent-2-en-1-one (2m) [37]: 79%. Colourless oil. H NMR
(400 MHz, CDCl3)δ 7.27 - 7.13 (m, 5H), 6.65 (t, J = 72.1 Hz, 1H), 3.50 (s, 2H), 2.87 - 2.73 (m,
2H), 2.56 - 2.42 (m, 2H). 19F NMR (376 MHz, CDCl3) δ -81.48 (d, J = 72.1 Hz, 2F).
Acknowledgements
We thank National Basic Research Program of China (2015CB931900, 2012CBA01200), the
National Natural Science Foundation (21421002, 21472222, 21502214, 11175080), the Chinese
Academy of Sciences (XDA02020105, XDA02020106), the Science and Technology Commission
of Shanghai Municipality (15DZ1200102, 14ZR1448800) and the Natural Science Foundation of
Hunan province (2016JJ5003) for financial support.
Appendix A. Supplementary data
Supplementary data associated with this article can be found in the online version.
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Scheme 1. Substrate scope for O-difluoromethylation. Isolated yields. Values in parentheses are
the yields determined by 19F NMR.

Scheme 2. The plausible reaction mechanism

Table 1 Optimization of the reaction conditions
Entry
1
Ratiob
1:2
Solvent
Temp. (oC)
Yeild (%)c
p-Xylene
Toluene
1,4-Dioxane
THF
60
60
60
60
60
60
50
70
80
60
60
60
60
74
73
69
68
53
32
68
72
71
49
72
75
74
2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:1
1:3
1:4
1:2
3
4
5
Acetonitrile
DMF
6
7
p-Xylene
p-Xylene
p-Xylene
p-Xylene
p-Xylene
p-Xylene
p-Xylene
8
9
10
11
12
13d
b
aReaction conditions: 1a (0.2 mmol) and PDFA in solvent (2 mL); Molar ratio of
1a:PDFA; cDetermined by 19F NMR; dThe reaction time was prolonged to 10 h.