α,α-Difluoro-α-phenylsulfanyl-α- trimethylsilylmethane as a difluoromethyl building block: A general strategy to α,α-difluoromethyl aryl ketones

Article abstract of DOI:10.1016/j.jfluchem.2011.06.036

The synthetic utility of α,α-difluoro-α-phenylsulfanyl- α-trimethylsilylmethane (PhSCF₂SiMe₃; 1) as a difluoromethyl building block providing a general strategy to α,α-difluoromethyl aryl ketones was demonstrated. Oxidation, by using

Full text of DOI:10.1016/j.jfluchem.2011.06.036

Journal of Fluorine Chemistry 132 (2011) 987–990
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Short communication
a
,
a
-Difluoro-
a
-phenylsulfanyl-
a
-trimethylsilylmethane as a difluoromethyl
-difluoromethyl aryl ketones
building block: A general strategy to
a,a
Kanhokthron Boonkitpattarakul, Darunee Soorukram, Patoomratana Tuchinda, Vichai Reutrakul,
*
Manat Pohmakotr
Department of Chemistry and Center for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahidol University, Rama VI Road, Bangkok 10400, Thailand
A R T I C L E I N F O
A B S T R A C T
Article history:
The synthetic utility of
a
,
a
-difluoro-
a
-phenylsulfanyl-
a
-trimethylsilylmethane (PhSCF2SiMe3; 1) as a
-difluoromethyl aryl ketones was
Received 25 May 2011
Received in revised form 27 June 2011
Accepted 28 June 2011
Available online 14 July 2011
difluoromethyl building block providing a general strategy to
a,a
demonstrated. Oxidation, by using m-chloroperoxybenzoic acid, of the readily available 1-aryl-2,2-
difluoro-2-phenylsulfanyl-1-trimethylsiloxyethanes obtained from fluoride-catalyzed nucleophilic
addition of PhSCF2SiMe3 with aromatic aldehydes followed by flash vacuum pyrolytic elimination
provided
a
,
a
-difluoromethyl aryl ketones in moderate overall yields.
Keywords:
ß 2011 Elsevier B.V. All rights reserved.
a,
a
-Difluoro-
trimethylsilylmethane
-Difluoromethyl aryl ketones
a-phenylsulfanyl-a-
a,a
1. Introduction
-Difluoromethyl ketones are important fluorine-containing
gel [13]. Compounds of type 2 (R1 = H, alkyl, aryl; R2 = alkyl, aryl)
have been demonstrated as useful precursors for the preparation of
1,1-difluoroalkenes (Scheme 1) [14].
a,a
building blocks in organic and medicinal chemistry [1]. Numerous
synthetic methods for the preparation of these compounds, based
on direct fluorination of nonfluorinated starting materials using
various electrophilic fluorinating reagents, such as cesium
fluoroxysulfate [2], 1-chloromethyl-4-fluoro-1,4-diazoniabicy-
clo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor; F-TEDA-BF4)
[3], N-fluoro-bis[(trifluoromethyl)sulfonyl]imide [4], have been
reported. However, these methods cannot be used as general
strategies to gem-difluoromethylenated carbonyl compounds. On
Due to the readily available of the silyl ether derivatives 4,
obtained from the reaction of 1 with aromatic aldehydes, we
envisioned that they could be employed as the starting materials
for the preparation of a,a-difluoromethyl ketones 6 by pyrolysis of
their sulfoxides 5 as summarized in Scheme 2.
2. Results and discussion
The oxidation of compound 4a was first attempted using NaIO4
in aqueous methanol at 0 8C to room temperature. The reaction
proceeded incompletely, leading to a mixture of 3 (R1 = H; R2 = 4-
MeOPh), 4a and 5a as well as the corresponding sulfones. However,
the reaction employing m-CPBA (1.2 equiv.) in THF at À78 8C to
room temperature overnight provided the expected sulfoxide 5a in
quantitative yield. Since the sulfoxide 5a underwent O–SiMe3
bond cleavage rapidly, it was directly subjected to flash-vacuum
pyrolysis (FVP) to afford the expected 2,2-difluoro-1-(4-methox-
yphenyl)ethanone (6a) in 44% yield (Entry 1, Table 1). 1-Aryl-2,2-
difluoroketones 6b–6e were also be prepared in moderate yields
by using this approach (Entries 2–5, Table 1). The formation of aryl
the other hand, the preparation of a,a-difluoromethyl ketones via
the corresponding 2,2-difluoro enol derivatives, such as 2,2-
difluoro enol esters [5] and 2,2-difluoro enol silyl ethers [6] has
received more attention [7], because such compounds can be
readily prepared from, for examples, trifluoroethanol [8], halodi-
fluoromethyl ketones [9], trifluoromethylacylsilane [10], trifluor-
omethyl ketones [11], and trifluoromethyltrimethylsilane or
perfluoroalkyl organometallics [12].
We have recently reported that PhSCF2SiMe3 (1) underwent
fluoride-catalyzed nucleophilic addition to various aromatic
aldehydes to provide the mixtures of 1-aryl-2,2-difluoro-1-
hydroxy-2-phenylsulfanylethanes (2) and their silyl ether deriva-
tives 3 which were easily separated by chromatography on silica
a,a-difluoromethyl ketones 6 resulted from the sulfoxide elimi-
nation of the sulfoxides 5 to afford the corresponding gem-difluoro
silyl enol ethers, followed by hydrolysis (Scheme 2).
In conclusion, we have demonstrated the synthetic utility of
PhSCF2SiMe3 (1) as difluoromethyl building block providing a
* Corresponding author. Tel.: +66 2201 5158; fax: +66 2644 5126.
E-mail address: scmpk@mahidol.ac.th (M. Pohmakotr).
general strategy to
a,a-difluoromethyl aryl ketones.
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.06.036

988
K. Boonkitpattarakul et al. / Journal of Fluorine Chemistry 132 (2011) 987–990
O
F
F
R1
R2
F
F OH
R2
R1
PhS C SiMe3
PhS C C R1
R2
TBAF (10 mol%)
THF, −78 oC to rt,
overnight
F
1
F
2
R1, R2 = H, alkyl, aryl
+
F OSiMe3
PhS C C R1
F
R2
3
Scheme 1.
3. Experimental
pyrolysis to give a crude mixture which was purified by
chromatography to give the corresponding product 6a.
The 1H and 13C NMR spectra were recorded on either a Bruker
DPX-300 or a Bruker DPX-400 spectrometer in CDCl3 using
tetramethylsilane as an internal standard. The 19F NMR spectra
were recorded on a Bruker DPX-400 (376 MHz) spectrometer and
3.1.1. 2,2-Difluoro-1-(4-methoxyphenyl)ethanone (6a) [3c,5]
Pale yellow oil (24 mg, 44% yield); IR (CHCl3): 1690 (s), 1602 (s),
1574 (s), 1514 (s), 1303 (s), 1266 (s), 1178 (s), 1139 (s), 1062 (s),
1029 (s) cmÀ1. 1H NMR (400 MHz, CDCl3):
d
8.07 (d, J = 9.1 Hz, 2H,
ArH), 7.02–6.97 (m, 2H, ArH), 6.26 (t, J = 53.7 Hz, 1H, CHF2), 3.91 (s,
3H, OCH3). 13C NMR (100 MHz, CDCl3):
186.7 (t, J = 24.9 Hz, CO),
165.6 (C), 132.8 (2Â CH), 125.1 (C), 114.9 (2Â CH), 112.1 (t,
chemical shifts (
d) were measured with fluorotrichloromethane
(
d
= 0) as an internal standard. The IR spectra were recorded on
either a Jasco A-302 or a Perkin Elmer 683 infrared spectrometer.
The electron impact mass spectra were recorded by using Thermo
Finnigan Polaris Q mass spectrometer. The high resolution mass
spectra were recorded on HR-TOF-MS Micromass model VQ-TOF2.
Melting points were recorded on a Buchi 501 melting point
apparatus and are uncorrected.
d
J = 252.4 Hz, CF2), 56.3 (OCH3). 19F NMR (376 MHz, CDCl3/CFCl3):
d
À121.9 (d, J = 53.2 Hz, 2F, CF2). MS (EI, m/z, %): 186 [M]+ (1), 135
(100), 107 (10), 77 (39).
Tetrahydrofuran (THF) was distilled from sodium-benzophe-
none ketyl. Other common solvents (hexane and ethyl acetate)
were distilled before use. Column chromatography was performed
using Merck silica gel 60H (Art. 7736). PhSCF2SiMe3 was prepared
according to the literature procedure [15]. Compound 4 was
prepared from PhSCF2SiMe3 and aromatic aldehydes according to
the previous report [14].
3.1.2. 2,2-Difluoro-1-(2,4-dimethoxyphenyl)ethanone (6b)
According to the general procedure, compound 4b (104 mg,
0.26 mmol) was treated with 70% m-CPBA (77 mg, 0.31 mmol),
followed by FVP to give compound 6b (29 mg, 52% yield) as a white
solid; mp: 72–73 8C. IR (KBr): 1666 (s), 1603 (s), 1257 (s), 1107 (s),
1017 (s) cmÀ1. 1H NMR (400 MHz, CDCl3):
d 7.90 (d, J = 8.8 Hz, 1H,
ArH), 6.60 (dd, J = 2.3, 8.8 Hz, 1H, ArH), 6.58 (t, J = 53.9 Hz, 1H,
CHF2), 6.47 (d, J = 2.3 Hz, 1H, ArH), 3.93 (s, 3H, OCH3), 3.89 (s, 3H,
OCH3). 13C NMR (100 MHz, CDCl3):
d 187.3 (t, J = 23.9 Hz, CO),
3.1. Typical procedure for the preparation of compounds 6
167.0 (C), 162.3 (C), 134.5 (CH), 117.1 (C), 110.3 (t, J = 245.5 Hz,
CF2), 107.1 (CH), 99.0 (CH), 56.5 (OCH3), 56.4 (OCH3). 19F NMR
A solution of compound 4a (107 mg, 0.29 mmol) in dry THF
(5 mL) at À78 8C was treated with
a solution of 70% m-
(376 MHz, CDCl3/CFCl3):
d
À128.6 (d, J = 53.8 Hz, 2F, CF2). MS (EI,
m/z, %): 216 [M]+ (7), 165 (100), 122 (11), 77 (10). HRMS (EI): calcd.
chloroperbenzoic acid (m-CPBA; 86 mg, 0.35 mmol) in dry THF
(5 mL). The reaction mixture was stirred at À78 8C and slowly
warmed up to room temperature overnight (12 h). The reaction
mixture was quenched with a saturated NaHCO3 solution (5 mL).
The aqueous layer was extracted with EtOAc (3Â 20 mL) and the
combined organic phase was dried over anhydrous Na2SO4. After
removal of the solvents under reduced pressure, the crude
sulfoxide 5a (117 mg) was directly subjected to flash-vacuum
for C10H10F2O3: 216.0598; found: 216.0600.
3.1.3. 2,2-Difluoro-1-(3,4-dimethoxyphenyl)ethanone (6c)
According to the general procedure, compound 4c (110 mg,
0.28 mmol) was treated with 70% m-CPBA (81 mg, 0.33 mmol),
followed by FVP to give compound 6c (22 mg, 36% yield) as a pale
yellow oil; IR (CHCl3): 1691 (s), 1597 (s), 1518 (s), 1277 (s) cmÀ1
.
O
F OSiMe3
PhS C C
O F OSiMe3
H
PhS
F
m-CPBA
−78 oC to rt
FVP
H
PhS C C
F Ar
H
C C OSiMe3
F Ar
F Ar
4
5
O
F
F
OSiMe3
C C
Ar
H2O
Ar
CF2H
6
Scheme 2.

K. Boonkitpattarakul et al. / Journal of Fluorine Chemistry 132 (2011) 987–990
989
Table 1
Preparation of 1-aryl-2,2-difluoroketones 6 from compounds 4.
Entry
1
4
5
FVP conditions (8C, mmHg)
6
Yield (%)a
4a
600, 0.03
44
52
36
37
46
OTMS
CF2S(O)Ph
O
O
O
F
F
F
F
F
F
MeO
MeO
5a
6a
2
3
4
4b
4c
4d
4e
600, 0.03
600, 0.05
600, 0.05
600, 0.03
OMe OTMS
CF2S(O)Ph
OMe
MeO
MeO
5b
6b
6c
6d
OTMS
CF2S(O)Ph
MeO
MeO
MeO
MeO
5c
O
OTMS
CF2S(O)Ph
F
F
Me
Me
5d
5
O
OTMS
CF2S(O)Ph
F
F
Br
Br
6e
5e
a
Isolated yield.
1H NMR (400 MHz, CDCl3):
J = 2.0 Hz, 1H, ArH), 6.95 (d, J = 8.4 Hz, 1H, ArH), 6.27 (t, J = 54.0 Hz,
1H, CHF2), 3.99 (s, 3H, OCH3), 3.96 (s, 3H, OCH3). 13C NMR
d
7.78–7.73 (m, 1H, ArH), 7.58 (d,
followed by FVP to give compound 6e (26 mg, 46% yield) as a
colorless oil; IR (neat): 1715 (s), 1587 (s), 1073 (s) cmÀ1 1H NMR
(300 MHz, CDCl3): 7.90 (d, J = 8.3 Hz, 2H, ArH), 7.60 (d, J = 8.6, 2H,
ArH), 6.29 (t, J = 53.4 Hz, 1H, CHF2). 13C NMR (100 MHz, CDCl3):
.
d
(100 MHz, CDCl3):
125.7 (CH), 125.2 (C), 112.1 (t, J = 252.4 Hz, CF2), 111.8 (CH), 111.0
(CH), 52.8 (OCH3), 56.7 (OCH3). 19F NMR (376 MHz, CDCl3/CFCl3):
d
186.9 (t, J = 23.9 Hz, CO), 155.6 (C), 150.1 (C),
d
186.7 (t, J = 26.0 Hz, CO), 132.3 (2Â CH), 130.9 (t, J = 2.5 Hz, 2Â CH),
d
130.5 (C), 130.1 (t, J = 2.1 Hz, C), 111.3 (t, J = 252.7 Hz, CF2). 19F
À121.3 (d, J = 53.8 Hz, 2F, CF2). MS (EI, m/z, %): 216 [M]+ (30), 165
(100), 122 (14), 107 (11), 77 (44). HRMS (EI) calcd. for C10H10F2O3:
216.0598; found: 216.0605.
NMR (376 MHz, CDCl3/CFCl3):
(EI, m/z, %): 235 (11), 197 (14), 149 (47), 97 (52), 85 (68), 77 (34).
d
À122.0 (d, J = 53.0 Hz, 2F, CF2). MS
Acknowledgements
3.1.4. 2,2-Difluoro-1-(4-methylphenyl)ethanone (6d) [6]
According to the general procedure, compound 4d (105 mg,
0.30 mmol) was treated with 70% m-CPBA (89 mg, 0.36 mmol)
followed by FVP to give compound 6d (19 mg, 37% yield) as a
colorless oil; IR (neat): 1705 (s), 1608 (s), 1299 (m), 1138 (m), 1064
We acknowledge financial supports from the Thailand Research
Fund (BRG5380019), the Office of the Higher Education Commis-
sion and Mahidol University under the National Research
Universities Initiative, and the Center for Innovation in Chemistry
(PERCH-CIC). D.S. would like to thank Mahidol University for
financial support.
(s) cmÀ1. 1H NMR (300 MHz, CDCl3):
7.32 (d, J = 8.1 Hz, 2H, ArH), 6.27 (t, J = 53.6 Hz, 1H, CHF2), 2.45 (s, 3H,
CH3). 13C NMR (75 MHz, CDCl3):
187.2 (t, J = 25.0 Hz, CO), 146.2 (C),
d 7.97 (d, J = 8.1 Hz, 2H, ArH),
d
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129.7 (t, J = 2.3 Hz, 2Â CH), 129.7 (2Â CH), 129.0 (t, J = 1.8 Hz, C),
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CFCl3):
d
À122.3 (d, J = 54.1 Hz, 2F, CF2). MS (EI, m/z, %): 171 [M+H]+
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