Nucleophilic difluoro(phenylsulfonyl)methylation of carbonyls with PhSO2CF2H reagent in the presence of in situ generated substoichiometric amount of base Dedicated to Professor Iwao Ojima on the occasion of his receipt of the ACS Aw

Article abstract of DOI:10.1016/j.jfluchem.2013.05.015

The reactions between carbonyl compounds and PhSO₂CF ₂H using substoichiometric amount of base in situ generated from N(TMS)₃ and catalytic amount of Me₄NF have been investigated. It is found that both enolizabl

Full text of DOI:10.1016/j.jfluchem.2013.05.015

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Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Nucleophilic difluoro(phenylsulfonyl)methylation of carbonyls with
PhSO2CF2H reagent in the presence of in situ generated
substoichiometric amount of base
*
Mingyou Hu, Bing Gao, Chuanfa Ni, Laijun Zhang, Jinbo Hu
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling-Ling Road, Shanghai 200032,
China
A R T I C L E I N F O
A B S T R A C T
Article history:
The reactions between carbonyl compounds and PhSO2CF2H using substoichiometric amount of base in
situ generated from N(TMS)3 and catalytic amount of Me4NF have been investigated. It is found that both
enolizable and non-enolizable aldehydes are suitable substrates to undergo nucleophilic difluoro(phe-
nylsulfonyl)methylation. Compared to the previously reported trifluoromethylation of carbonyls with
CF3H under the similar reaction conditions, the unique reactivity of PhSO2CF2H is attributed to its higher
acidity than CF3H and the reversibility of its addition reaction with ketones under basic conditions.
ß 2013 Elsevier B.V. All rights reserved.
Received 20 April 2013
Received in revised form 10 May 2013
Accepted 14 May 2013
Available online xxx
Dedicated to Professor Iwao Ojima on the
occasion of his receipt of the ACS Award for
Creative Work in Fluorine Chemistry 2013.
Keywords:
(Phenylsulfonyl)difluoromethylation
Difluoromethylation
Nucleophilic fluoroalkylation
Hydrofluorocarbons
Aldehydes
Alcohols
1. Introduction
is involved.[1d,4] However, in cases of the thermally instable
fluoroalkyl anions, their in situ generation from RfH is usually
Nucleophilic fluoroalkylation is one of the most important
transformations in organofluorine chemistry, which not only can
required; therefore, the generality of nucleophilic fluoroalkylation
with RfH is largely influenced by the compatibility between the
electrophiles and the bases [5–7].
transfer
a fluoroalkyl group to carbon-electrophiles for the
synthesis of fluoroalkylated molecules of interest in life and
materials sciences [1], but also is a fundamental method for the
synthesis of many other nucleophilic, radical, and electrophilic
fluoroalkylation reagents such as Ruppert-Prakash reagent
(TMSCF3), PhSO2CF2I reagent, and Togni reagents [2]. Although
nucleophilic fluoroalkylation with (fluoroalkyl)silanes (R3SiRf) has
become one of the widely used methods for the synthesis of
fluorinated organic compounds [3], nucleophilic fluoroalkylation
with hydrofluorocarbons and their derivatives (RfH) is a more
atom-economical way, in which the generation of the nucleophilic
fluoroalkyl anion species RfÀ under the treatment of a proper base
As an important difluoromethylation reagent, the synthetic
application of difluoromethyl phenyl sulfone (PhSO2CF2H) has
been intensively studied [8]. In 1972, Edwards and co-workers
À
claimed in
a
patent that PhSO2CF2 anion (derived from
PhSO2CF2H and potassium tert-butoxide in diglyme/Et2O at
À78 8C) was able to undergo 1,4-addition to a cyclic
a,b-
unsaturated ketone, but the chemical yield was not reported
[9a]. In 1989, Stahly reported the nucleophilic difluoro(phenyl-
sulfonyl)methylation of carbonyls with PhSO2CF2H using sodium
hydroxide as a base, and only some aromatic aldehydes and
sterically hindered aliphatic aldehydes (such as isobutyraldehyde)
were demonstrated for the reaction [9b]. In 2005, a modified
protocol was developed by Prakash and coworkers, in which
sterically hindered base lithium hexamethyldisilazide (LiHMDS)
was used, and various ketones and non-enolizable aldehydes were
* Corresponding author. Tel.: +86 21 54925174; fax: +86 21 64166128.
E-mail addresses: jinbohu@sioc.ac.cn, jinbohu2007@yahoo.com.cn (J. Hu).
0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2013.05.015
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found to be suitable substrates for the reaction [6]. However, the
difluoromethylation of eneolizable aldehydes with PhSO2CF2H still
remains a challenging task, which is mainly due to the facile
enolization of these aldehydes caused by the presence of a
stoichiometric amount of strong base (Eq. (1)) [6]. We envisioned
that the enolization of aliphatic aldehydes might be diminished by
significantly lowering the concentration of the base in the reaction
system. Herein, we report an efficient nucleophilic difluoro(phe-
nylsulfonyl)methylation of enolizable aldehydes with PhSO2CF2H
reagent in the presence of in situ generated substoichiometric
amount of base.
Scheme 1. Trifluoromethylation of carbonyls with CF3H and in situ generated base
[10].
reaction was performed at 45 8C using 2.0 equiv. of N(TMS)3.
(1)
(2)
2. Results and discussion
Encouraged by the aforementioned result, we further investi-
gated the scope of this new protocol for difluoro(phenylsulfo-
nyl)methylation. Firstly, we examined the nucleophilic
difluoro(phenylsulfonyl)methylation of primary, secondary, and
tertiary aldehydes 2 with PhSO2CF2H (1) under the optimized
reaction conditions (molar ratio, 1/2/N(TMS)3/TMAF = 1.0/1.5/2.0/
10%; 45 8C; 20 h). The results are summarized in Table 1. In all
In 2000, Langlois and coworkers developed a synthetically
useful nucleophilic trifluoromethylation of carbonyl compounds in
DMF using trifluoromethane (CF3H) and tris(trimethylsilyl)amine
[N(TMS)3] in the presence of tetramethylamonium fluoride (TMAF)
(Scheme 1) [10]. In their reaction, the N(TMS)3/FÀ system
generates bis(trimethylsilyl)amide slowly, and the base is always
in low concentration, thus facilitating the trifluoromethylation of
enolizable carbonyls (such as acetophenone) by diminishing their
enolization. Inspired by this elegant work [10a] we decided to
employ the same base system to solve the enolization problem in
the (phenylsulfonyl)difluoromethylation of aliphatic aldehydes
with PhSO2CF2H (1). At the outset, we chose cyclohexanecarbal-
dehyde (2a) as a model substrate (Eq. (2)). The initial reaction of 1
(1.0 equiv.) with 2a (1.5 equiv.) using a combination of N(TMS)3
(1.5 equiv.) and Me4NF (10 mol%) was carried out in DMF at À10 8C
cases, a-difluoro(phenylsulfonyl)methyl alcohols 4 were obtained
in moderate to excellent isolated yields after subsequent
desilylation with tetrabutylammonium fluoride trihydrate
(TBAFÁ3H2O). For the volatile aldehydes such as isobutyraldehyde
(3c), 3-methylbutanal (3f), butyraldehyde (3g), the reaction using
2.0 equiv. of aldehydes can give much higher yields of the alcohols
4c, 4f, and 4g than that under the standard conditions. In cases of
the long-chain aldehydes such as undecanal (3a) and palmitalde-
hyde (3b), a prolonged reaction time is required due to their low
solubility in DMF. In general, this protocol is highly effective for the
difluoro(phenylsulfonyl)methylation of aliphatic aldehydes, even
for the readily enolizable aldehydes.
to room temperature (RT) over 20 h, and the silylated
a-
difluoro(phenylsulfonyl)methylcarbinol 3a was obtained in 53%
yield. A brief optimization of the reaction conditions revealed that
an excellent yield (92%) of product 3a was obtained when the
Table 1
Nucleophilic difluoro(phenylsulfonyl)methylation of aliphatic aldehydes with reagent 1.a.
a
Isolated yield.
b
Aldehydes (2 equiv.) were used.
c
Reaction time was 30 h.
d
Reaction time was 48 h.
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Table 2
Nucleophilic difluoro(phenylsulfonyl)methylation of aromatic aldehydes with reagent 1.a.
a
Isolated yield.
It is worthwhile to note that this reaction represents the first
example of (TMS)3N/FÀ mediated nucleophilic reaction between
an enolizable aldehyde and a pronucleophile RfH. In the reported
reaction between carbonyls and CF3H, this (TMS)3N/FÀ system only
works for the trifluoromethylation of ketones and formylamides
(Scheme 1) [10]. In a recent report using this base system for the
deprotonative functionalization of heteroaromatic C(sp2)–H and
activated C(sp3)–H bonds with carbonyls, only the reaction of
ketones and non-enolizable aldehydes was demonstrated [11]. We
believe that both the low concentration of the in situ generated
base and the high acidity of PhSO2CF2H play important roles in this
deprotonative difluoromethylation of enolizable aldehydes.
Subsequently, we extended this protocol to aromatic aldehydes,
and the results are summarized in Table 2. The reaction proved to
be general and amenable to a range of aromatic aldehydes 5, and
the desired products 6a–k were produced in moderate to excellent
yields. The reactivity of aromatic aldehydes in this reaction is
different from that of CF3H in the trifluoromethylations. In the
trifluoromethylation with CF3H, the amide anion (TMS)2NÀ was
reported to undergo imination with the benzaldehyde to give N-
trimethylsilyl imine (Scheme 2) [10a,12]; however, in the present
difluoro(phenylsulfonyl)methylation, due to the higher acidity of
PhSO2CF2H (than CF3H), the amide anion (TMS)2NÀ can readily
remove the proton of PhSO2CF2H to promote the difluoro(phe-
nylsulfonyl)methylation of aldehydes.
[14] and the slower silylation of the alcoholate intermediate by
N(TMS)3 than by TMSCF2SO2Ph. Consequently, the decomposition
of PhSO2CF2À would lead to the formation of PhSSPh, which further
reacted with PhSO2CF2 to afford the byproduct PhSO2CF2SPh
(Scheme 3) [9b]. Based on this rationalization, we also tried the
À
reaction between ketones and PhSCF2H (9), assuming that the
À
relatively lower nucleofuge of PhSCF2 (than PhSO2CF2–) would
improve the difluoromethylation reaction. As expected, the
reaction with benzophenone (7a) at room temperature afforded
the desired product 10a in 77% yield (Eq. (3)).
(3)
Finally, encouraged by the unique reactivity of PhSO2CF2H
toward various aldehydes, we investigated its reaction with
ketones by using the aforementioned base system. To our surprise,
among all the ketones that were tested, the reactions were found to
be very sluggish, and PhSO2CF2SPh was detected as the major
product in all cases (Table 3). These results are in distinct contrast
to the trifluoromethylation of ketones with CF3H (Scheme 1) [10]
and our previously reported difluoro(phenylsulfonyl)methylation
of ketones with TMSCF2SO2Ph [13]. We attributed these differ-
À
Scheme 2. Imination of aromatic aldehydes.
ences to the reversibility of the addition of PhSO2CF2 to ketones
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Table 3
available chemicals were used without further purification.
Column chromatography was performed on silica gel 300–400
(0.038–0.048 mm). 1H, 13C, and 19F NMR spectra were recorded in
Investigation on nucleophilic difluoro(phenylsulfonyl)methylation of various
ketones with reagent 1.a.
CDCl3, chemical shifts (
constants (J) are given in Hz. 1H NMR chemical shifts were
determined relative to internal (CH3)4Si (TMS) at 0.0 or to the
signal of a residual protonated solvent: CDCl3
7.26. 13C NMR
d) are given in ppm and spin–spin coupling
d
d
chemical shifts were determined relative to internal TMS at
19F NMR chemical shifts were determined relative to CFCl3 at
d
d
0.0.
0.0.
Mass spectra were obtained on a mass spectrometer. High-
resolution mass data were recorded on a high-resolution mass
spectrometer in the EI or ESI mode. Melting points are
uncorrected.
4.1. General procedures for the reaction of aldehydes with PhSO2CF2H
(1)
Under a nitrogen atmosphere, into a 20-mL Schlenk flask
containing N(TMS)3 (233 mg, 1.0 mmol) and Me4NF (4 mg,
0.05 mmol) were added PhSO2CF2H (96 mg, 0.5 mmol), aldehyde
2 or 5 (0.75 mmol), and DMF (3 mL) at RT. Then the flask
was connected with a condenser and heated at 45 8C for 20 h.
After the reaction mixture was cooled to RT, TBAFÁ3H2O
(1.5 mmol) was added and the mixture was stirred at RT for
30 min followed by adding saturated brine (10 mL). The
whole mixture was extracted with Et2O (3Â 20 mL). The
combined organic phase was washed with water (2Â 30 mL),
dried over anhydrous MgSO4, concentrated under reduced
pressure, and purified by flash column chromatography (silica
gel; petroleum ether/ethyl acetate, 10/1) to give the desired
products 4 or 6.
a
Yields of 8 were determined by 19F NMR.
b
CsF was used.
c
Me4NF was used.
4.1.1. 1-Cyclohexyl-2,2-difluoro-2-(phenylsulfonyl)ethanol (4a) [13]
White solid. 1H NMR (CDCl3, 300 MHz):
7.56–7.84 (m, 3H), 4.31 (m, 1H), 2.78 (d, J = 6.5 Hz, 1H), 1.04–1.98
(m, 11H). 19F NMR (CDCl3, 282 MHz):
d 7.99 (d, J = 7.2 Hz, 2H),
d
À106.0 (d, J = 236.0 Hz, 1F),
À114.2 (dd, J = 236.0 Hz, J = 22.0 Hz, 1F).
Scheme 3. Nucleophilic difluoro(phenylsulfonyl)methylation of ketones with
4.1.2. 1,1-Difluoro-4,8-dimethyl-1-(phenylsulfonyl)non-7-en-2-ol
PhSO2CF2H and the reversibility of the addition reaction.
(4b)
3. Conclusion
We have investigated the reaction between carbonyls and
PhSO2CF2H using substoichiometric amount of base in situ
generated from tris(trimethylsilyl)amine and catalytic tetra-
methylamonium fluoride. This research has led to the discovery
of an efficient nucleophilic difluoro(phenylsulfonyl)methylation
of both enolizable and non-enolizable aldehydes. Moreover, the
reactivity difference of PhSO2CF2H and CF3H toward carbonyls
has been rationalized, and the difluoromethylation of ketones
with PhSCF2H using the in situ generated base has been
developed.
A mixture of diastereomers (dr = 1/1). White solid. IR (film):
3516, 2962, 2921, 2854, 1584, 1449, 1335, 1162, 1104, 717, 686,
600 cmÀ1. 1H NMR (CDCl3, 300 MHz):
d 7.99 (d, J = 7.3 Hz, 2H), 7.77
(t, J = 7.3 Hz, 1H), 7.63 (t, J = 7.3 Hz, 2H), 5.09 (s, 1H), 4.55 (m, 1H),
2.67 (t, J = 5.7 Hz, 1H), 2.01–0.96 (m, 16H). 19F NMR (CDCl3,
282 MHz):
d
À107.8 (d, J = 265.0 Hz, 0.5F)/À108.2 (d, J = 265.0 Hz,
0.5F), À117.0 (d, J = 265.0 Hz, 0.5F, for one isomer)/À117.0 (dd,
J = 265.0 Hz, J = 18.4 Hz, 0.5F, for the other isomer). 13C NMR
(CDCl3, 100 MHz):
d 135.5, 133.1, 131.5 (d, J = 5 Hz), 130.6, 129.3,
124.4, 121.5 (m), 68.1 (t, J = 24.0 Hz)/67.7 (t, J = 24.0 Hz), 37.7/36.6/
36.1/35.6 (C-3 and C-5), 28.8/28.1, 25.7, 25.4/25.2, 20.3/18.4, 17.6.
MS (EI, m/z, %): 205 ([MÀPhSO2]+, 3.22), 69 (100.00). HRMS (EI):
Calcd. for C17H24F2O3S: 346.1414; Found: 346.1411.
4. Experimental
All reactions were carried out in oven-dried glassware under a
nitrogen atmosphere. DMF was distilled from CaH2. Commercially
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4.1.3. 1,1-Difluoro-3-methyl-1-(phenylsulfonyl)butan-2-ol (4c) [9]
4.1.8. 1,1-Difluoro-1-(phenylsulfonyl)nonan-2-ol (4h) [13]
White solid. 1H NMR (CDCl3, 300 MHz):
7.59–7.83 (m, 3H), 4.43 (m, 1H), 2.57 (d, J = 5.6 Hz, 1H), 1.88–1.20
(m, 12H),0.88(t, J = 7.0 Hz,3H).19FNMR(CDCl3, 282 MHz):
(dd, J = 237.0 Hz, 6.0 Hz, 1F), À117.4 (dd, J = 237.0 Hz, 18.0 Hz, 1F).
d 8.00 (d, J = 7.8 Hz, 2H),
White solid. 1H NMR (CDCl3, 300 MHz):
d 7.99 (d, J = 7.7 Hz, 2H),
7.58–7.82 (m, 3H), 4.36(m, 1H), 2.21 (m, 1H), 1.09 (d, J = 6.8 Hz,
3H), 1.02 (dd, J = 6.7 Hz, J = 0.8 Hz, 3H). 19F NMR (CDCl3, 282 MHz):
À106.8 (d, J = 235.0 Hz, 1F), À115.5 (dd, J = 235.0 Hz, J = 22.0 Hz).
d
À108.6
d
4.1.9. 1,1-Difluoro-1-(phenylsulfonyl)dodecan-2-ol (4i)
4.1.4. 1,1-Difluoro-3,3-dimethyl-1-(phenylsulfonyl)butan-2-ol (4d)
[9]
White solid. IR (film): 3508, 3069, 2925, 2855, 1584, 1467, 1336,
1162, 1097, 717,686, 599 cmÀ1. 1HNMR(CDCl3, 300 MHz):
J = 8.1 Hz, 2H), 7.78–7.63 (m, 3H), 4.43 (m, 1H), 2.69 (s, 1H), 1.75–
d
7.99(d,
White solid. 1H NMR (CDCl3, 300 MHz):
7.71 (t, J = 7.7 Hz, 1H), 7.63 (t, J = 7.9 Hz, 2H), 4.22 (m, 1H), 2.83 (d,
J = 6.0 Hz, 1H), 1.08 (m, 9H). 19F NMR (CDCl3, 282 MHz):
(d, J = 237.0 Hz, 1F), À114.2 (ddd, J = 237.0 Hz, J = 17.6 Hz,
J = 7.2 Hz, 1F).
d 7.99 (d, J = 8.0 Hz, 2H),
0.86 (m, 21H). 19F NMR (CDCl3, 282 MHz):
d
À108.4 (d, J = 237.3 Hz,
d
À108.2
1F), À116.9 (ddd, J = 237.3 Hz, J = 17.9 Hz, J = 8.5 Hz, 1F). 13C NMR
(CDCl3, 100 MHz):d135.5, 133.1,130.6, 129.3, 121.3(t,J = 296.2 Hz),
69.5 (t, J = 23.6 Hz), 31.9, 29.56, 29.53, 29.41, 29.31, 29.21, 25.1, 22.7,
14.1 MS (EI, m/z, %): 345 ([MÀOH]+, 1.10), 143 (100.00). HRMS (EI):
Calcd. for C18H28F2O3S–OH: 345.1700; Found: 345.1697.
4.1.5. 1,1-Difluoro-4-phenyl-1-(phenylsulfonyl)butan-2-ol (4e) [6]
4.1.10. 1,1-Difluoro-1-(phenylsulfonyl)heptadecan-2-ol (4j)
White solid. 1H NMR (CDCl3, 300 MHz):
d 7.98 (d, J = 8.2 Hz, 2H),
7.77 (t, J = 7.4 Hz, 1H), 7.62 (t, J = 8.2 Hz, 2H), 7.32–7.21 (m, 5H),
White solid. IR (film): 3550, 3406, 2963, 2918, 2848, 1471, 1449,
4.45 (m, 1H), 2.97 (m, 1H), 2.81–2.71 (m, 2H), 2.12–2.03 (m, 2H).
1329, 1167, 1128, 1104, 998, 718, 682, 616, 603 cmÀ1 1H NMR
.
19F NMR (CDCl3, 282 MHz):
(ddd, J = 236.3 Hz, J = 17.8 Hz, J = 7.2 Hz, 1F).
d
À108.2 (d, J = 236.3 Hz, 1F), À116.4
(CDCl3, 300 MHz):
7.64(t, J = 7.4 Hz, 2H), 4.44 (m, 1H), 2.56(d, J = 5.7 Hz, 1H), 1.85–1.25
(m, 28H), 0.88 (t, J = 6.6 Hz, 3H). 19F NMR (CDCl3, 282 MHz):
À108.1 (d, J = 236.5 Hz, 1F), À116.9 (dd, J = 236.5 Hz, J = 17.4 Hz, 1F).
13C NMR (CDCl3, 100 MHz):
135.5, 133.1, 130.6, 129.3, 69.5 (t,
d 8.00 (d, J = 7.4 Hz, 2H), 7.78 (t, J = 7.4 Hz, 1H),
d
4.1.6. 1,1-Difluoro-4-methyl-1-(phenylsulfonyl)pentan-2-ol (4f)
d
J = 25.0 Hz), 31.9, 29.7, 29.65, 29.60, 29.5, 29.3, 29.2, 25.0, 22.7, 14.1
MS(EI, m/z, %): 414([MÀOH] +, 1.74), 143 (100.00). HRMS (EI): Calcd.
for C23H38F2O3S–OH: 415.2484; Found: 415.2487.
White solid. IR (film): 3512, 3069, 2960, 2872, 1584, 1469,
1388, 1335, 1163, 1137, 718, 685, 598 cmÀ1
.
1H NMR (CDCl3,
4.1.11. 2,2-Difluoro-1-phenyl-2-(phenylsulfonyl)ethanol (6a) [9]
300 MHz): d 8.00 (d, J = 7.8 Hz, 2H), 7.78 (t, J = 6.7 Hz, 1H), 7.63 (t,
J = 7.2 Hz, 2H), 4.51 (m, 1H), 2.76 (s, 1H), 2.43 (m, 1H), 2.04–0.89
(m, 8H). 19F NMR (CDCl3, 282 MHz):
d
À108.1 (d, J = 236.4 Hz, 1F),
À116.7 (dd, J = 236.4 Hz, J = 17.5 Hz, 1F). 13C NMR (CDCl3,
100 MHz):
d 135.5, 133.1, 130.6, 129.4, 121.4 (t, J = 294.6 Hz),
68.0 (t, J = 21.3 Hz), 37.9, 24.0, 23.5, 21.1 MS (EI, m/z, %): 278 (M+,
2.42), 77 (100.00). HRMS (EI): Calcd. for C12H16F2O3S: 278.0788;
Found: 278.0787.
White solid. 1H NMR (CDCl3, 300 MHz):
7.76 (t, J = 7.1 Hz, 1H), 7.62 (t, J = 7.5 Hz, 2H), 7.48 (s, 1H), 7.38 (m,
3H), 5.57 (m, 1H), 3.29 (m, 1H). 19F NMR (CDCl3, 282 MHz):
d 8.00 (d, J = 7.5 Hz, 2H),
d
À103.8 (d, J = 238.8 Hz, 1F), À119.2 (ddd, J = 238.8 Hz, J = 21.9 Hz,
4.1.7. 1,1-Difluoro-1-(phenylsulfonyl)pentan-2-ol (4g)
J = 6.1 Hz, 1F).
4.1.12. 1-[4-(Dimethylamino)phenyl]-2,2-difluoro-2-
(phenylsulfonyl)ethanol (6b) [15]
Colorless oil. IR (film): 3508, 2964, 2935, 2875, 1449, 1335,
1164, 1084, 717, 686, 597 cmÀ1. 1H NMR (CDCl3, 300 MHz):
d
7.95
(d, J = 7.0 Hz, 2H), 7.78 (t, J = 7.3 Hz, 1H), 7.62 (m, 2H), 4.46 (m, 1H),
3.00–0.89 (m, 9H). 19F NMR (CDCl3, 282 MHz):
d
À108.1 (d,
J = 236.9 Hz, 1F), À116.7 (dd, J = 236.9 Hz, J = 17.9 Hz, 1F). 13C NMR
(CDCl3, 100 MHz): 135.5, 133.1, 130.6, 129.3, 121.4 (t,
J = 299.1 Hz), 69.2 (t, J = 24.2 Hz), 31.4, 18.3, 13.6 MS (EI, m/z, %):
264 (M+, 1.33), 78 (100.00). HRMS (EI): Calcd. for C11H14F2O3S:
264.0632; Found: 264.0627.
White solid. 1H NMR (CDCl3, 300 MHz):
d 7.99 (d, J = 7.3 Hz, 2H),
7.75 (t, J = 6.4 Hz, 1H), 7.60 (t, J = 7.4 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H),
6.68 (d, J = 8.3 Hz, 2H), 5.44 (m, 1H), 2.96 (s, 6H). 19F NMR (CDCl3,
282 MHz):
J = 20.7 Hz, 1F).
d
À103.8 (d, J = 235.3 Hz, 1F), À119.0 (dd, J = 235.3 Hz,
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4.1.13. 2,2-Difluoro-1-(4-methoxyphenyl)-2-
3.41 (s, 1H). 19F NMR (CDCl3, 282 MHz):
1F), À118.8 (dd, J = 236.2 Hz, J = 21.0 Hz, 1F).
d
À103.6 (d, J = 236.2 Hz,
(phenylsulfonyl)ethanol (6c) [9]
4.1.18. 2,2-Difluoro-2-(phenylsulfonyl)-1-p-tolylethanol (6h) [9]
White solid. 1H NMR (CDCl3, 300 MHz):
d 7.98 (d, J = 7.5 Hz,
2H), 7.74 (t, J = 7.0 Hz, 2H), 7.59 (t, J = 7.9 Hz, 2H), 7.39 (d,
J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 5.52 (dt, J = 21.0 Hz,
J = 3.3 Hz, 1H), 3.78 (s, 1H), 3.43 (d, J = 1.7 Hz, 1H). 19F NMR
White solid. 1H NMR (CDCl3, 300 MHz):
d 8.00 (d, J = 7.9 Hz, 2H),
7.76 (t, J = 7.6 Hz, 1H), 7.62 (t, J = 7.2 Hz, 2H), 7.36 (d, J = 7.9 Hz, 2H),
7.19 (d, J = 7.9 Hz, 2H), 5.53 (m, 1H), 3.17 (d, J = 3.7 Hz, 1H), 2.35 (s,
(CDCl3, 282 MHz):
J = 239.0 Hz, J = 21.0 Hz, 1F).
d
À103.9 (d, J = 239.0 Hz, 1F), À119.0 (dd,
3H). 19F NMR (CDCl3, 282 MHz):
À119.0 (dd, J = 236.3 Hz, J = 20.0 Hz, 1F).
d
À103.8 (d, J = 236.3 Hz, 1F),
4.1.14. 1-(4-Chlorophenyl)-2,2-difluoro-2-(phenylsulfonyl)ethanol
(6d) [9]
4.1.19. 2,2-Difluoro-1-(furan-2-yl)-2-(phenylsulfonyl)ethanol (6i) [9]
White solid. 1H NMR (CDCl3, 300 MHz):
7.56–7.76 (m, 3H), 7.41 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H),
5.58 (d, J = 21.0 Hz, 1H), 3.75 (s, 1H). 19F NMR (CDCl3, 282 MHz):
d
7.96 (d, J = 7.6 Hz, 2H),
White solid. 1H NMR (CDCl3, 300 MHz):
d 8.00 (d, J = 7.9 Hz, 2H),
7.77 (t, J = 7.7 Hz, 1H), 7.63 (t, J = 7.6 Hz, 2H), 7.46 (s, 1H), 6.56 (s,
1H), 6.41 (s, 1H), 5.58 (m, 1H), 3.08 (d, J = 6.4 Hz, 1H). 19F NMR
d
À104.1 (d, J = 237.0 Hz, 1F), À119.2 (dd, J = 237.0 Hz, J = 21.0 Hz, 1F).
(CDCl3, 282 MHz):
À115.9 (dd, J = 237.1 Hz, J = 18.5 Hz, 1F).
d
À105.9 (dd, J = 237.1 Hz, J = 4.1 Hz, 1F),
4.1.15. 1-(2-Bromophenyl)-2,2-difluoro-2-(phenylsulfonyl)ethanol
(6e)
4.1.20. 1-(4-tert-Butylphenyl)-2,2-difluoro-2-
(phenylsulfonyl)ethanol (6j) [17]
White solid. IR (film): 3478, 3265, 3090, 3063, 1645, 1473, 1451,
1338, 1155, 1121, 1027, 998, 761, 746, 685, 586 cmÀ1
.
1H NMR
White solid. 1H NMR (CDCl3, 300 MHz):
7.76 (t, J = 7.4 Hz, 1H), 7.61 (t, J = 7.4 Hz, 2H), 7.40 (s, 4H), 5.55
(m, 1H), 3.19 (s, 1H), 1.30 (s, 9H). 19F NMR (CDCl3, 282 MHz):
d 8.00 (d, J = 7.9 Hz, 2H),
(CDCl3, 300 MHz): d 8.05 (d, J = 7.7 Hz, 2H), 7.81–7.55 (m, 5H),
7.40–7.18 (m, 3H), 6.16 (dd, J = 19.6 Hz, J = 3.9 Hz, 1H), 3.36 (d,
d
J = 3.2 Hz, 1H). 19F NMR (CDCl3, 282 MHz):
d
À102.9 (d, J = 239.3 Hz,
À102.9 (d, J = 239.4 Hz, 1F), À118.7 (dd, J = 239.4 Hz, J = 20.3 Hz,
1F), À120.1 (dd, J = 239.3 Hz, J = 21.4 Hz, 1F). 13C NMR (CDCl3,
1F).
100 MHz):
d 135.7, 133.5, 133.4, 132.9, 132.8, 132.5, 130.9, 130.8,
130.0, 129.8, 129.5, 127.9, 127.7, 124.0, 120.2, 69.5 (t, J = 23.6 Hz).
MS (EI, m/z, %): 376 (M+, 4.87), 378 ([M+2]+, 5.83), 187 (100.00).
HRMS (EI): Calcd. for C14H11BrF2O3S: 375.9580; Found: 375.9586.
4.1.21. 1-(2,4-Dichlorophenyl)-2,2-difluoro-2-
(phenylsulfonyl)ethanol (6k) [18]
4.1.16. 1-(4-Bromophenyl)-2,2-difluoro-2-(phenylsulfonyl)ethanol
(6f) [16]
White solid. 1H NMR (CDCl3, 300 MHz):
7.79 (t, J = 7.4 Hz, 1H), 7.66–7.62 (m, 3H), 7.39 (s, 1H), 7.30 (m, 1H),
6.12 (d, J = 21.8 Hz, 1H), 3.69 (s, 1H). 19F NMR (CDCl3, 282 MHz):
d 8.02 (d, J = 7.8 Hz, 2H),
d
À103.9 (d, J = 239.3 Hz, 1F), À119.8 (dd, J = 239.3 Hz, J = 21.6 Hz, 1F).
White solid. 1H NMR (CDCl3, 300 MHz):
d 7.99 (d, J = 7.7 Hz, 2H),
7.79 (t, J = 6.6 Hz, 1H), 7.63 (t, J = 8.0 Hz, 2H), 7.53 (s, 1H), 7.51 (s,
1H), 7.36 (d, J = 8.4 Hz, 2H), 5.54 (m, 1H), 3.37 (s, 1H), 1.57 (s, 3H).
Acknowledgements
19F NMR (CDCl3, 282 MHz):
d
À104.1 (d, J = 237.9 Hz, 1F), À119.2
Support of our work by the National Basic Research Program of
China (2012CB821600, 2012CB215500), the National Natural
Science Foundation of China (20825209, 21202189), and Chinese
Academy of Sciences is gratefully acknowledged.
(dd, J = 237.9 Hz, J = 21.9 Hz, 1F).
4.1.17. 2,2-Difluoro-1-(naphthalen-2-yl)-2-(phenylsulfonyl)ethanol
(6g) [6]
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