Efficient asymmetric synthesis of aryl difluoromethyl sulfoxides and their use to access enantiopure α-difluoromethyl alcohols

Article abstract of DOI:10.1016/j.tet.2019.04.037

The -CHF₂ moiety has shown a growing interest in pharmaceutical and agrochemical applications over the last few years. Its introduction is therefore a current research topic for organic chemists. Several groups have reported the synthesis of di

Full text of DOI:10.1016/j.tet.2019.04.037

Accepted Manuscript
Efficient asymmetric synthesis of aryl difluoromethyl sulfoxides and their use to
access enantiopure α-difluoromethyl alcohols
Chloé Batisse, Maria F. Céspedes Dávila, Marco Castello, Amélia Messara, Bertrand
Vivet, Gilbert Marciniak, Armen Panossian, Gilles Hanquet, Frédéric R. Leroux
PII:
S0040-4020(19)30449-1
https://doi.org/10.1016/j.tet.2019.04.037
TET 30282
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 October 2018
Revised Date: 10 April 2019
Accepted Date: 15 April 2019
Please cite this article as: Batisse Chloé, Céspedes Dávila MF, Castello M, Messara Amé, Vivet
B, Marciniak G, Panossian A, Hanquet G, Leroux FrééR, Efficient asymmetric synthesis of aryl
difluoromethyl sulfoxides and their use to access enantiopure α-difluoromethyl alcohols, Tetrahedron
(2019), doi: https://doi.org/10.1016/j.tet.2019.04.037.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Efficient asymmetric synthesis of aryl difluoromethyl
sulfoxides and their use to access enantiopure α-
Leave this area blank for abstract info.
difluoromethyl alcohols
Chloé Batisse, Maria F. Céspedes Dávila, Marco Castello, Amélia Messara, Bertrand Vivet, Gilbert Marciniak, Armen Panossian, Gilles
Hanquet * and Frédéric R. Leroux *

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Efficient asymmetric synthesis of aryl difluoromethyl sulfoxides and their use to
access enantiopure α-difluoromethyl alcohols
Chloé Batisse a, Maria F. Céspedes Dávila a, c, Marco Castello b, Amélia Messara a, Bertrand Vivet c,
Gilbert Marciniak c, Armen Panossian a, Gilles Hanquet a, * and Frédéric R. Leroux a, *
a Université de Strasbourg, Université de Haute-Alsace, CNRS, UMR 7042-LIMA, ECPM, 25 Rue Becquerel, Strasbourg 67087, France.
b Università degli Studi di Basilicata, Dipartimento di Scienze, Via Nazario Sauro, 85, 85100, Potenza, Italy.
c Sanofi Aventis R&D, 16 rue d’Ankara, 67080 Strasbourg.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The -CHF2 moiety has shown a growing interest in pharmaceutical and agrochemical
applications over the last few years. Its introduction is therefore a current research topic for
organic chemists. Several groups have reported the synthesis of difluoromethylated compounds.
However, the more challenging enantioselective introduction of the difluoromethyl group has
been scarcely described yet. We recently developed a new strategy, based on the use of an
enantiopure difluoromethyl sulfoxide used as chiral and traceless auxiliary, for the synthesis of
highly enantioenriched α-difluoromethyl alcohols.8 The first method developed in our laboratory
aims to access highly stereoenriched α,α-difluoro-β-hydroxysulfoxides through the condensation
of the enantiopure difluoromethyl sulfoxide on carbonyl derivatives. It is noteworthy that highly
diastereo- and enantioenriched α,α-difluoro-β-hydroxysulfoxides can also be accessed after the
diastereoselective reduction of highly enantioenriched α,α-difluoro-β-ketosulfoxides. Finally, the
expected difluoromethyl-substituted alcohols can be obtained after removal of the chiral
auxiliary with complete retention of stereoenrichment at carbon.
Available online
Keywords:
Fluorine chemistry, chiral sulfoxides,
enantioselective difluoromethylation,
diastereoselective reduction of α,α-difluoro β-
ketosulfoxides, desulfinylation, desulfonylation.
2009 Elsevier Ltd. All rights reserved
.
molecules bearing this CHF2 moiety.4 This is for instance the
case for the synthesis of highly enantioenriched α-difluoromethyl
alcohols. They can be accessed through bio- and organometallic
reductions of α,α-difluoro ketones,5 pallado-catalyzed reductive
coupling6 or enantioselective difluoromethylations involving
naked CHF2- anion surrogates in presence of different chiral
1. Introduction
Nowadays, fluorine plays an increasingly important role in
various areas of our daily lives. The improved physical, chemical
and biological properties of drugs or agrochemicals bearing
fluorinated moieties have indeed been widely studied and
highlighted over the past few years.1 Consequently, the
development of new methodologies for the introduction of
fluorinated substituents – F, CF3, OCF3, SCF3, CmFnHp, etc. – has
become an important subject of research for organic chemists.
Moreover, their stereoselective introduction is even more
challenging.
7
quaternary ammonium salts for instance.4a, Recently, we also
reported a new enantioselective method to access these building
blocks.8
2. Results and discussion
2.1. Description of the strategy
Recently, several groups focused their efforts on the
introduction of the CHF2 moiety. This fluorinated group, in
addition to impacting the acidity, metabolic stability, lipophilicity
or even conformational preference of biologically active
compounds, is also known to be a good hydrogen bond donor and
a bioisostere of hydroxy, thiol and amide groups.2 These
outstanding properties led chemists to develop several methods
for its non-stereoselective introduction.3 In contrast, a limited
As outlined above and in contrast to enantioselective
fluorination or even trifluoromethylation, the enantioselective
introduction of a difluoromethyl group is in its infancy. In our
willingness to contribute to the development of new
methodologies to access highly enantioenriched α-difluoromethyl
alcohols, it was chosen to use enantiopure aryl difluoromethyl
sulfoxides, their non-fluorinated analogues being known as
excellent chiral inductors employed in the synthesis of a huge
number of examples describe the enantioselective synthesis of
———
Corresponding authors. e-mail addresses: frederic.leroux@unistra.fr, ghanquet@unistra.fr.

2
Tetrahedron
ACCEPTED MANUSCRIPT
number of optically pure compounds.9 This kind of
2.2 The quest for an enantiopure aryl difluoromethyl sulfoxide
difluoromethyl group attached to an electron-withdrawing
substituent can be readily deprotonated and trapped with a variety
of electrophiles, such as aldehydes and ketones. After separation
of the diastereomers of the α,α-difluoro-β-hydroxysulfoxides and
removal of the chiral auxiliary, this strategy allows to access
highly enantioenriched α-difluoromethyl alcohols (Scheme 1).8
This investigation started focusing on the synthesis of a highly
enantiopure aryl difluoromethyl sulfoxide. To the best of our
knowledge, only two groups managed to obtain this kind of
sulfoxide. Such compound had first been serendipitously
obtained as a degradation product by Bravo and co-workers in
their attempts to synthesize enantiopure α-monofluoro-β-
ketosulfoxides (Scheme 2).18 Shortly after this work, the access
to an enantiopure aryl difluoromethyl sulfoxide was studied by
the group of Yagupolskii.19 They managed to synthesize highly
enantioenriched optically active p-chlorophenyl difluoromethyl
sulfoxide (RS)-4b with 98% e.e. Unfortunately, the strategy
consisted in a multi-step process involving a chiral resolution of
an arylsulfinyldifluoroacetic acid and the use of difficult-to-
handle intermediates. It was therefore decided to search for
another efficient method to generate highly enantioenriched aryl
difluoromethyl sulfoxides.
The presence of a sulfanyl, sulfinyl or sulfonyl group in α
position of a carbanion is known to stabilize this anionic species.
This effect has therefore been widely explored and discussed
over the last decades. It has been rationalized by different
hypotheses, such as the possibility of back-donation of the lone
pair of electrons of the carbanion into the vacant d-orbitals of the
sulfur derivative,10 polarizability of sulfur11 or more recently,
negative hyperconjugation.11b, 11d, 12
Moreover, in the case of fluorinated carbanions, their
substitution with softening groups in α position, such as
arylsulfonyl or arylsulfinyl groups, is also a useful approach to
alleviate the negative fluorine effect and enhance the
nucleophilicity of the RCF2– species.13
Scheme 2. Two existing strategies to access highly enantioenriched α-
difluoromethyl alcohols
Different enantioselective sulfoxidations of prochiral sulfides
usually employed to access enantiopure non-fluorinated
sulfoxides were first tested (Scheme 3). Oxidation of ethyl p-
chlorophenylthiodifluoroacetate 6b, by using either the modified
Sharpless reagent20 or different oxidizing systems composed of
iron or vanadium complexes with Schiff bases 8 and 921 or, as a
start, achiral salens 10 and 11,22 as ligands, were unfortunately
unsuccessful, even after several days of reaction. The
simultaneous presence of the ester group and of two fluorine
atoms might be responsible for the low reactivity of the sulfide,
rendering it more electron deficient and less prone to be oxidized.
Scheme 1. Access to highly enantioenriched α-difluoromethyl alcohols – Using
sulfoxides as chiral and traceless auxiliaries
This kind of strategy involving
a difluoromethylated
arylsulfonyl group has been extensively studied by Olah, Prakash
and Hu, amongst others.14 However, the chemistry using an
arylsulfinyl group has been rarely explored yet. For instance, the
same scientists successfully achieved non-stereoselective
nucleophilic (phenylsulfinyl) difluoromethylation of both
enolizable and non-enolizable aldehydes and ketones by using
racemic difluoromethyl phenyl sulfoxide as fluoroalkylating
agent.15 Unfortunately, even if they managed to synthesize α,α-
difluoro β-hydroxysulfoxides with good yields, the
diastereomeric excesses associated were low (diastereomeric
ratios ranging between 49:51 and 33:67). This work was
considered as the starting point of our project.
In our case, the use of an enantiopure difluoromethyl
sulfoxide was required to access highly enantioenriched α,α-
difluoro-β-hydroxysulfoxides and α-difluoromethyl alcohols
(Scheme 1).8 This strategy will be discussed in detail in this
paper. We will first present the numerous trials that were carried
out in the aim of synthesizing an enantiopure aryl difluoromethyl
sulfoxide. Then, several experiments run in order to evaluate and
improve the diastereoselectivity of the addition of the sulfoxide
anion to carbonyl derivatives will be discussed. A new way to
access diastereopure α,α-difluoro-β-hydroxysulfoxides, inspired
by the well-known diastereoselective reduction of non-
fluorinated β-ketosulfoxides, will be highlighted.16 And finally,
the different strategies that have been employed to remove the
chiral auxiliary will be presented.17
Scheme 3. Attempts of enantioselective sulfoxidations

3
It was therefore decided to test those conditions on the
corresponding difluoromethyl sulfide 12b obtained through
decarboxylation of compound 6b (Scheme 4). This species is less
electron-deficient and sterically less hindered than compound 6b
due to the absence of the ester group and should consequently be
more reactive towards oxidation.
sulfoxide 4b after saponification of diastereopure 16b followed
ACCEPTED MANUSCRIPT
by a decarboxylation step, or even by a direct Krapcho
dealkoxycarbonylation-type reaction24 on 16b.
O
O
(-)-menthol
DMAP
S
S
O
O
F
F
F
F
Toluene
111 °C, 20 h
60%
Cl
Cl
6b
15b
MeCN, 45 °C, 90 min
H5IO6 + FeCl3·6H2O
or H5IO6 + 18
Resp. 85% and 87%
O
S
O
O
S
O
O
NaOH
EtOH
OH
F
F
F
F
Cl
Cl
17b
Insoluble
16b
50:50
Diastereomers
40 °C, 17 h
91%
could not be separated
Decarboxylation
O
S
N
O
N
O
Fe
Cl
CHF2
Cl
18
4b
Scheme 5. Attempts to access highly enantioenriched sulfoxide 4b by using L-
menthol as a chiral auxiliary
Scheme 4. Preparation of a less electron-deficient sulfide and attempts for its
After these unfruitful trials, it was decided to perform
Reformatsky-type reactions using ethyl bromodifluoroacetate and
enantiopure (-)-menthyl (S)-p-toluenesulfinate 19 in presence of
zinc, previously activated with HCl (Scheme 6).25 No conversion
was obtained even by activating menthyl sulfinate 19 with
diethyl- or dimethylaluminium chloride in presence of silver
acetate. Honda’s method26 involving a solution of diethylzinc in
presence of Wilkinson’s catalyst was also tried but unfortunately,
the starting material was again totally recovered. Finally, indium
beads were tested but no conversion was obtained.27
enantioselective sulfoxidation
The expected sulfoxide could indeed be obtained through
oxidation using Kagan’s conditions involving the modified
Sharpless reagent (Scheme 4).20 However, after
a rapid
optimization, only 24% of enantiomeric excess was obtained at
best for compound 4b. Moreover, large amounts of the
corresponding sulfone 13b were obtained due to overoxidation of
sulfoxide 4b and nine days of reaction were required (See
supplementary data for optimization table). The use of the
oxidizing system composed of Schiff base 9, VO(acac)2 and
H2O2 on sulfide 12b also led to a small conversion into the
expected sulfoxide after one week of reaction at room
temperature (Scheme 4).21a Unfortunately, difluoromethyl
sulfoxide 4b was obtained with only 5% e.e. Finally, Davis’
camphorsulfonyl oxaziridine 14 was tested as a stoichiometric
chiral oxygen-transfer agent on sulfide 12b (Scheme 4).23 After a
rapid optimization (See supplementary data for details), running
the reaction in HFIP as solvent gave positive results, affording 4b
with 91% conversion and 24% e.e. after seven days of reaction.
Due to the long reaction times required and to the low
enantiomeric excesses and conversions obtained in most cases,
such methods were set aside for the benefit of other strategies.
Scheme 6. Attempts to synthesize enantiopure sulfoxide 7a by performing
Reformatsky-type reactions on enantiopure (-)-menthyl (S)-p-toluenesulfinate 19
As chiral sulfinyloxazolidinones have been described as
hundred times more reactive than menthyl sulfinate 19,28
compound (RS,R)-20 was tested as starting material for those
Reformatsky-type reactions (Table 1). To our delight, and as
previously shown by our group,8 the reaction using zinc activated
with HCl gave access to ethyl α,α-difluoro-(p-tolylsulfinyl)-
acetate (SS)-7a with a good yield and an enantiomeric excess of
up to 97% (Entry 1). The Honda-Reformatsky reaction using
diethylzinc and Wilkinson’s catalyst also allowed us to obtain
(SS)-7a with slightly lower yield and enantiomeric excess (resp.
65% and 86% e.e., Entry 2). Unfortunately, reaction with indium
only gave low conversion (< 9%, Entry 3). This reaction was
optimized and highly enantioenriched sulfinyl acetate (SS)-7a
was obtained with good yield by using diethylzinc without
catalyst (79% yield and 90% e.e., Entry 4). In this way, the pre-
activation of zinc powder is not necessary. Finally, and as
previously described,8 highly enantioenriched difluoromethyl p-
tolyl sulfoxide (SS)-4a was obtained after decarboxylation of
A diastereoselective pathway was then attempted to access the
desired enantiopure aryl difluoromethyl sulfoxide 4b (Scheme 5).
For this purpose, it was decided to introduce (-)-menthol as a
chiral auxiliary. The synthesis of enantiopure menthyl (4-
chlorophenyl)thio)-2,2-difluoroacetate 15b was performed
through transesterification of sulfinyl acetate 6b. We believed
that the oxidation of this prochiral sulfide with periodic acid and
FeCl3·H2O could be selective due to the presence of the chiral
menthyl group and/or afford
a
mixture of separable
diastereomers. It was also envisaged to use iron salen complex 18
in presence of periodic acid as a chiral oxidizing agent. However,
not only the sulfoxidation was not diastereoselective in both
attempts, certainly due to the distance between the sulfide and the
chiral auxiliary in the first case, but it was also impossible to
separate the diastereomers of 16b by usual purification methods.
Otherwise, it could have been possible to get the expected
enantioenriched
sulfinylester
(SS)-7a,
followed
by
recrystallisation from diethyl ether.

4
Tetrahedron
ACCEPTED MANUSCRIPT
Previous work - Hu, Prakash et al.
O
O
S
OH
R2
t-BuOK (2 equiv.)
O
Table 1. Synthesis of highly enantioenriched sulfoxide (SS)-4a by performing
Reformatsky-type reactions on enantiopure sulfinyloxazolidinone8 (RS,R)-20
S
CHF2
(Eq. 1)
+
R1
R1 R2
DMF
F
F
-30 °C, 30 min
4c
up to 99% yield
R1, R2 = H, Alk, Ar
2 equiv.
1 equiv.
up to
33:67
Starting conditions for this study
O
O
S
OH
t-BuOK (2 equiv.)
O
S
R2
(Eq. 2)
CHF2
+
R1
F
R1 R2
THF
-30 °C, 40 min
F
4a
1 equiv.
21a
R1, R2 = H, Alk, Ar, HetAr
2 equiv.
O
S
OH
O
S
OH
O
S
OH
F
F
F
F
F F
Entry
BrCF2CO2Et
(equiv.)
Metal
(equiv.)
T
(°C)
t
(h)
Yield of e.e. of
Br
7a (%)
7a (%)
21a-2
90%, 39:61
21a-3
99%, 47:53
21a-1
> 99%, 41:59
1
2
2.4
3.0
Zn (2.4)
66
-20
20
66
20
41
1
72
97
O
S
OH OMe
O
S
OH
OMe
a
ZnEt2
65
86
F
F
F F
(2.0)
4
21a-4
90%, 47:53
21a-5
> 99%, 43:57
3b
4
2.0
3.0
In (2.0)
48
4
< 9c
79
-
O
S
OH
O
S
OH
O
S
OH
ZnEt2
(2.0)
90
S
O
F
F
F
F
F F
N
a
3 mol% of Wilkinson’s catalyst were added to the reaction mixture – b The
reaction was tested on the achiral non-substituted sulfinyloxazolidinone –
Conversions were determined by 19F NMR spectroscopy.
21a-7
21a-8
85%, 42:58
21a-6
63%, 44:56
> 99%, 38:62
O
S
O
S
HO
HO
F
F
F F
2.2. Evaluation of the diastereoselectivity of the synthesis of
α,α-difluoro-β-hydroxysulfoxides under different conditions
21a-9
Conversion ~ 48%, 46:54
21a-10
88%, 50:50
Scheme 7. First screening of different carbonyl derivatives
Once an efficient pathway to access to enantiopure
difluoromethyl sulfoxide (SS)-4a was found, further efforts were
focused on its deprotonation, followed by its addition to different
carbonyl derivatives. In contrast to the group of Hu and Prakash
(Eq. 1, Scheme 7),15 it was decided to use THF, a safer and eco-
friendlier solvent than DMF. First, a quick screening of several
alkyl, aryl and even heteroaryl aldehydes and ketones was
successfully performed. Yields were mostly high, but as expected
from the work of Hu and Prakash, the diastereoselectivities were
still low (yields up to > 99%, d.r. up to 38:62, Eq. 2, Scheme 7).
A study to improve this diastereoselectivity had therefore to be
carried out. This was a challenge, since precedents in literature
Table 2. Attempts to improve the diastereomeric ratio of 21a-5 by using different
reagents (carbonyl derivative = 1-naphthaldehyde)
Entry
Additive
Conversion
of 4a (%)a
d.r.
21a-5
1
2
3
4
5
6
-
100
0
43:57
-
BF3·OEt2
Sc(OTf)3
0
-
TiCl4
47
100
35
44:56
43:57
44:56
ZnCl2
on
non-fluorinated
analogues
showed
that
the
diastereoselectivity of the addition of non-fluorinated sulfoxides
on carbonyl derivatives is generally very poor, whatever the
conditions used, the nature of the sulfoxide substituents or the
chelating metal employed.29b,30
(+)-2,3,11,12-(CO2H)4-18-C-6b
a Conversions and d.r. were determined by 19F NMR spectroscopy – b See
experimental part for details.
Different aryl sulfoxide derivatives were then tested to see if
some improved diastereoselectivities could be observed
(Scheme 8). Five different sulfoxides were synthesized according
to the procedure that was developed in our group (see
experimental section for their synthesis).8 Slightly better
diastereomeric ratios were observed when the phenyl 21c-1, p-
tolyl 21a-1 and 1-naphthyl 21e-1 derivatives were used (resp.
37:63, 40:60 and 40:60) in comparison to the p-chloro 21b-1 and
p-methoxy 21d-1 derivatives (resp. 45:55 and 43:57).
Nevertheless, starting from our previous results, the
investigation began with the addition of different reagents,
among which chelating or complexing agents for instance, into
the reaction mixture (Eq. 2, Scheme 7, Table 2). Unfortunately,
using BF3.OEt2 or Sc(OTf)3 did not give any conversion (Entries
2 and 3). It was possible to get the desired α,α-difluoro-β-
hydroxysulfoxides with TiCl4 or ZnCl2 (Entries 4 and 5).
However, the diastereoselectivities obtained were as low as those
observed without chelating agent (Entry 1). A crown ether
(2,3,11,12-tetracarboxylate-substituted 18-crown-6, Entry 6) able
to complex the potassium cation coming from the inorganic
base,31 was also tested. This complexation would generate an
almost ‘naked anion’, more nucleophilic than the non-complexed
species.32 This increased reactivity might have had an impact on
the reaction rate as well as on the organization of the transition
state, and therefore on the diastereoselectivity. Unfortunately,
when using this macrocycle, the conversion was low and the
diastereomeric ratio was unchanged.

5
Scheme 8. Attempts to improve the diastereoselectivity by changing the aromatic
our recent paper,8 Schwesinger’s superbase, P4t-Bu was tested
ACCEPTED MANUSCRIPT
ring of the sulfoxide (Base:sulfoxide:electrophile = 2:1:2)
and gave good results (Entries 12 and 13). In both cases, total
conversions of 4a were observed and diastereomeric excesses up
to 96% were reached in DMF (Entry 12).
This investigation continued with the screening of different
bases in order to evaluate their impact on the diastereoselectivity
of the synthesis of α,α-difluoro-β-hydroxysulfoxides (Table 3).
This base had been involved in the deprotonation of
fluoroform33 and difluoro(phenylsulfanyl)methane34 to generate
stabilized ‘naked’ carbanions with increased reactivity towards
electrophiles. In our case, and in contrast to other cations such as
Li+, K+ or Mg2+, having the non-coordinating counterion [P4t-
Bu/H]+ was thought to increase the nucleophilicity of the anion of
difluoromethyl p-tolyl sulfoxide 4a, thus generating an earlier
transition state for the attack on the carbonyl derivatives. The
attack of the sulfoxide carbanion being fastened, the carbonyl
derivatives would keep a close-to-planar C-sp2 geometry in the
transition state, rather than a generally more favored C-sp3-like
tetrahedral geometry. In this way, by using P4t-Bu, a more
efficient relay of the chirality from the sulfoxide to the α,α-
difluoro-β-hydroxysulfoxide was first expected.
As explained in our previous work,8 some problems of
reproducibility were encountered for the reaction performed in
DMF (d.r. varying between 55:45 and 99:1, Entry 1, Table 4).
This would mainly be due to the formation of aggregates in the
reaction mixture, probably coming from the non-miscibility of
hexane –solvent in which P4t-Bu is commercially available– and
DMF, or by the fact that the superbase is not soluble in DMF.35
Table 3. Results obtained for the screening of different bases
Base
(2 equiv.)
T
(°C)
T
Conversiona
(h) (%)
d.r.
Entry
Solvent
21a-1b
1
2
3
4
DMF
THF
DMF
THF
-30
-30
-30
-30
-30
20
2
100
54:46
41:59
53:47
40:60
t-BuOK
0.5 100
1
100
96
KHMDS
1
24
72
24
72
3
5
6
DMF
THF
90 (45)
-
-
KHMDS
+ 18-C-6
-30
20
100 (traces)
-30
20
7
8
9
DMF
THF
45 (37)
98 (92)
33 (18)
45:55
38:62
60:40
A screening of different solvents was performed (Table 4).
Practically, hexane from the commercially available solution was
removed under vacuum from the desired amount of P4t-Bu. The
superbase was then solubilized in the desired solvent, solvent A,
at –30 °C. This solution was then added dropwise onto the
mixture composed of sulfoxide 4a and benzaldehyde, previously
dissolved in solvent B at –30 °C. In each case, the conversions of
4a were excellent (Entries 2 to 7). The highest ratios were
nevertheless observed when THF was involved as solvent A
(Entry 5), solvent B (Entry 2) or both of them (Entry 7). The best
reproducible diastereomeric ratio being obtained when only THF
was used (Entry 7), this combination was therefore chosen for the
following experiments of this study.
LiHMDS
12
3
-30
-30
20
24
72
24
72
2
DMF
LiHMDS
+ 12-C-4
-30
20
10
11
THF
THF
80 (69)
36:64
59:41
-78
20
NaH
100
1
12
13
DMF
THF
-30
-30
2
100
100
98:2
P4t-Buc
2
84:16
Table 4. Screening of different solvents to evaluate their impact on the
a
Conversions were determined by 19F NMR spectroscopy; in italics, the
diastereoselectivity and reproducibility of the reaction
percentage of sulfoxide 4a converted, in bold, the conversion into 21a-1 –
b Diastereomeric ratios were determined by 19F NMR spectroscopy – c P4t-Bu
stands for [(Me2N)3P=N]3P=N-tBu and was used as a commercially available
solution in hexane.
By using potassium tert-butoxide the conversion into the
desired α,α-difluoro-β-hydroxysulfoxide was high in either DMF
or THF after 40 minutes of reaction at –30 °C (Entries 1 and 2).
Unfortunately, the observed diastereoselectivities were low
(41:59 in THF and 54:46 in DMF). The same kind of results were
observed with KHMDS after one hour at –30 °C (53:47 in DMF
vs. 40:60 in THF, Entries 3 and 4). KHMDS was also tested in
presence of 18-crown-6 (18-C-6), to generate a more nucleophilic
carbanion such as in Table 2 , but unfortunately after several days
of reaction a lot of side-products were obtained (Entries 5 and 6).
Reactions using LiHMDS as a base were then carried out and
monitored by TLC. Almost full conversion was obtained in THF
(Entry 8), but the reaction reached only 45% conversion in DMF
(Entry 7). Concerning the diastereomeric ratios, they were similar
to the ones that were usually obtained (45:55 in DMF vs. 38:62 in
THF). By using 12-crown-4 (12-C-4) to complex the lithium
cation, conversions were less interesting and the diastereomeric
excesses still low (Entries 9 and 10). A trial carried out in THF
with 2 equivalents of sodium hydride showed full conversion but
poor diastereoselectivity (Entry 11). Finally, and as described in
d.r.
Conversion of
Entry
Solvent A
Solvent B
4aa (%)
21a-1b
1c
2c
3
Hexaned
Hexaned
DMFf
Et2Of
DMF
THF
100e
100
55:45 to 99:1
84:16
DMFg
DMF
DMF
Et2O
THF
100
61:39
4
100
56:44
THFf
>99e
>99
>99d
93:7
5
Et2Of
60:40
6
THFf
> 98:2
7
Conversions were determined by 19F NMR spectroscopy – b Diastereomeric
ratios were determined by 19F NMR spectroscopy – c Results taken from ref. 8
a
d
e
–
P4t-Bu was used as a commercially available solution in hexane –
Presence of α-monofluoro-β-ketosulfoxide in small quantities was observed –
f
Hexane from the commercially available solution of P4t-Bu was removed
under reduced pressure and the superbase was solubilized in the desired

6
Tetrahedron
solvent at –30 °C – g P4t-Bu not being soluble in DMF, the reaction mixture
Figure 2. Evolution of the diastereomeric excess over time at different
ACCEPTED MANUSCRIPT
was poured onto the superbase suspension in DMF.
temperatures for 2 equivalents of P4t-Bu (19F NMR study)
A
19F NMR monitoring of the conversion of sulfoxide 4a over
time was conducted with 1 and 2 equivalents of superbase
(Figure 1). These two trials were expected to provide information
on the quantity of superbase required and on the reaction time
needed to achieve full conversion. A total conversion was
observed after 5 minutes in both cases. The diastereomeric
excesses were also measured on 19F NMR spectra after 5, 15, 45
and 120 minutes. Interestingly, the NMR spectra analyses
showed increasing diastereoselectivities over time. When 2
equivalents were used, after 5 minutes, the diastereomeric excess
was low (24%). However, a perfect diastereoselectivity was
observed after 2 hours of stirring at –30 °C. When one equivalent
was used, the diastereoselectivity was much lower after 2 hours
(52%).
Figure 3. Evolution of the percentage of side products 22a formed over time at
different temperatures for 2 equivalents of P4t-Bu (19F NMR study)
It is noteworthy that under these optimized conditions, the
corresponding non-fluorinated β-hydroxysulfoxide 23a was
obtained with low diastereoselectivity (Scheme 9). This suggests
that the two fluorine atoms play an important role in the
stereoselectivity of the reaction, for instance by affecting the pKa
of the neighbouring protons.
O
S
O
O
S
OH
P4t-Bu (2 equiv. / THF)
+
CH3
THF
- 30 °C, 2 h
23a
Figure 1. Evolution of the d.e. over time for 1 equivalent (blue curve) or 2
equivalents (pink curve) of P4t-Bu (19F NMR study)
1 equiv.
1 equiv.
100% conversion, 45:55 d.r.
No side product
Scheme 9. Access to β-hydroxysulfoxide 23a with low diastereoselectivity
The evolution of the diastereomeric ratio was then studied at
different temperatures in the reaction of 4a with benzaldehyde,
yielding 21a-1 (Figure 2). It was observed that with higher
reaction temperatures, perfect diastereoselectivities (d.r. > 99:1)
were obtained faster (after 15 minutes at 20 °C and after 2 hours
at 0 °C and –30 °C). However, it was also noticed that at a given
time, the highest the temperature, the highest the quantity of a
side product (Figure 3). For instance, by carrying out the reaction
at 20 °C for 15 minutes or at –30 °C for 2 hours, perfect
diastereoselectivities were obtained in both cases. However, at
20 °C after 15 minutes, 12% of side product had appeared, while
only 5% were measured after 2 hours for the reaction carried out
at –30 °C. It was therefore concluded that it is preferable to
perform the reaction at low temperature (–30 °C) to minimize the
amount of side product (ca. 5%), even if the reaction time
required to get full diastereoselectivity is longer (2 hours). This
side product was isolated and characterized as the corresponding
α-monofluoro-β-ketosulfoxide 22a-1 (see Table 5).
A screening of different carbonyl derivatives was further
performed employing these optimized conditions (Table 5).
Several observations already led us to assume that the
mechanism of the reaction would involve a kinetic resolution.8
The first equivalent of the superbase was suspected to
deprotonate the difluoromethyl sulfoxide, generating the
corresponding carbanion that will further react with the aldehyde.
To explain the good diastereoselectivities obtained in some cases,
we then assumed that, due to the acidifying effect of the two
fluorine atoms, the second equivalent of P4t-Bu would abstract
the proton in α position of the deprotonated alcohol and that only
one of the two diastereomers of the newly generated α,α-
difluoro-β-hydroxysulfoxide 21 would undergo this process,
leading to fluoride elimination. After work up, this would afford
the corresponding α-monofluoro-β-ketosulfoxide 22 along with
the remaining untouched diastereomer of the α,α-difluoro-β-
hydroxysulfoxide 21.8
This mechanism can be supported by several observations.
First, the diastereomeric ratio has been shown to evolve over
time (Figures 1 and 2), which is in agreement with the potential
preferential consumption of one diastereomer with regard to the
other. In other words, the enrichment could effectively be
explained by the attack undergone by only one of the
diastereomeric deprotonated α,α-difluoro-β-hydroxysulfoxides.
As observed during the screening of different carbonyl
derivatives (Table 5), when diastereomeric ratios are largely in
favor of one diastereomer, yields remain moderate (Entries 1 and
9 for instance). In the case of excellent diastereoselectivities, one
diastereomer is assumed to be converted into the corresponding
α-monofluoro-β-ketosulfoxide. The yields are therefore
obviously dependent on the initial proportion of the untouched

7
diastereomer of α,α-difluoro-β-hydroxysulfoxide obtained first
with low diastereoselectivities. Second, the diastereoselectivities
reached starting with ketones are low (Entries 10 and 11). This
corroborates with the lack of proton α to oxygen on the generated
carbinol, which prevents any stereoenrichment by the assumed
deprotonation/fluoride elimination mechanism. Last, high
stereoselectivities were observed when P4t-Bu was used as the
base, but not with LiHMDS, KHMDS or t-BuOK, which is
consistent with the higher basicity of the phosphazene superbase.
always equal to 0); (4) JH-F = JBX of Dmaj is always inferior to JH-
ACCEPTED MANUSCRIPT
F = JAX of Dmin.8 On the other hand, 19F NMR clearly shows that
the reversed stereoselectivity is obtained with t-BuOK as the base
(see ESI). These trends, especially the clearly visible one for
∆νAB, are reminiscent of those observed in the case of the parent
non-fluorinated β-hydroxysulfoxide,16b,f for which the anti
diastereomer (with regard to the oxygens of the sulfoxide and of
the alcohol) has always a larger ∆νAB than the syn diastereomer.
Accordingly, the method involving the phosphazene superbase
would be producing the anti isomer as major product, i.e. the
(SS,S) diastereomer when starting from the (SS)-sulfoxide. In fact,
this information is infirmed by a crystallographic structure
(Figure 4) obtained for the anti diastereomer of 21a-1 (vide
infra), whose ∆νAB corresponds to the one of the minor
diastereomer obtained in the superbase method. In other words,
the major isomer obtained with the P4t-Bu superbase is the syn
diastereomer. This suggests that, in terms of NMR, the two
diastereomers behave differently in presence or in absence of the
two fluorines atoms, leading to a reversal of the AB(X) system
patterns.
Table 5. Screening of different carbonyl derivatives by using P4t-Bu
Hanquet, Leroux et al., Chem. Commun. 2018
O
S
O
O
S
O
S
OH
R2
P4t-Bu
(2 equiv.) in THF
O
CHF2
+
R2
+
R1
R1 R2
F
F
F
THF
22a
4a
1 equiv.
21a
- 30 °C, 3 h
1 equiv.
R1 = H, Me
R2 = Ar, HetAr, Alk
Side
21a
Entry
R1
R2
product
Yield – d.r.b
22a (%)c
2.3. Diastereoselective reduction of α,α-difluoro-β-ketosulfoxides
21a-1
22a-1
20
1a
2
Solladié and coworkers developed a useful strategy to access
highly enantioenriched non-fluorinated alcohols by performing
the diastereoselective reduction of enantiopure β-ketosulfoxides
in presence of DIBAL-H or by using a combination DIBAL-
H/ZnCl2, followed by removal of the chiral auxiliary by
desulfinylation with Raney nickel.16b-g
Phenyl
H
H
H
H
H
H
H
H
H
53% - 99:1
21a-5
22a-5
1
1-Naphthyl
2-Naphthyl
2-Pyridinyl
3-Pyridinyl
2-Thiophenyl
3-Thiophenyl
2-Furyl
90% - 56:44
21a-11
22a-11
3
3
33% - 73:27
21a-12
With the aim of developing new procedures to synthesize
highly enantioenriched α-difluoromethyl alcohols, the former
methodology was applied to α,α-difluoro-β-ketosulfoxides (SS)-
3a-1,6,16 (Scheme 10). These compounds were accessed through
oxidation of the previously synthesized α,α-difluoro-β-
hydroxysulfoxides (SS)-21a-1,6,16 with PDC or DMP.
Enantiopure α,α-difluoro-β-ketosulfoxides (SS)- 3a-1,6,16 were
then reduced with DIBAL-H and allowed us to obtain the
expected α,α-difluoro-β-hydroxysulfoxides (SS,S)-21a-1,6,16
with high diastereoselectivity (93:7 to 98:2) and an excellent e.e.
(96–98%) of the major diastereomer.16h
22a-12
8
4
32% - 88:12
21a-6
22a-6
2
5
77% - 69:31
21a-7
22a-7
3
6
62% - 70:30
21a-13
22a-13
0
7
52% - 55:45
21a-8
22a-8
0
8
96% - 57:43
21a-14
22a-14
21
9
3-Furyl
31% - 98:2
21a-10
22a-10
0
10
11
12
-(CH2)2-Phenyl
Phenyl
Methyl
Methyl
H
89% - 60:40
21a-9
22a-9
0
57% - 56:44
21a-16
22a-16
4
4-Methoxyphenyl
73% - 79:21
a Reaction was carried out for 2 hours – b Diastereomeric ratios were determined
c
by 19F NMR spectroscopy – The percentages of α-monofluoro-β-ketosulfoxide
22a were measured by 19F NMR spectroscopy and confirmed by 1H NMR
Scheme 10. Diastereoselective reduction of a α,α-difluoro-β-ketosulfoxides (SS)-
21a-1,6,16 using DIBAL-H
spectroscopy.
Interestingly, concerning the relative configuration of the α,α-
difluoro-β-hydroxysulfoxide 21a, it appears that for most
compounds 21a, the same trends are observed in terms of 19F
NMR signals, where typical data is obtained for the ABX or AB
systems. Indeed, when P4t-Bu is used as the base, (1) the major
diastereomer produced (Dmaj) always shows a much larger ∆νAB
than the minor diastereomer (Dmin); (2) JF-F = JAB of Dmaj is
always (slightly) inferior to JF-F = JAB of Dmin; (3) JH-F = JAX of
Dmaj is always superior to JH-F = JAX of Dmin (which is almost
A X-ray crystallographic structure of the crystallized major
diastereomer (SS,S)-21a-1 was obtained and confirmed that the
product of the diastereoselective reduction is the anti isomer, as
observed in the diastereoselective reduction of non-fluorinated β-
ketosulfoxides (Figure 4).16b, 16f
This strategy represents an efficient pathway to access to
highly enantioenriched α,α-difluoro-β-hydroxysulfoxides of

8
Tetrahedron
opposite relative configuration and α-difluoromethyl alcohols
Na/Hg gave good yields but were nevertheless poorly
ACCEPTED MANUSCRIPT
and it is a good alternative to the one previously described.8
reproducible.17e The same conclusions were made in the case of
the desulfonylation by using 15 equivalents of magnesium in an
acetate buffer.36a
Major diastereomers with DIBAL-H
Starting with
Starting with
non-fluorinated ketosulfoxide
difluoromethylated ketosulfoxide
O
S
OH
O
S
OH
F
F
(SS,S)-21a-1
(RS,R)-23a
Figure 4. X-ray crystallographic structure of α,α-difluoro-β-hydroxysulfoxide
(SS,S)-21a-1 comparable to the corresponding non-fluorinated β-hydroxysulfoxide
(RS,R)-23a obtained through reduction of β-ketosulfoxide with DIBAL-H. Both
have anti relative configuration. CCDC 1871933 contains the supplementary
crystallographic data for this paper. These data are provided free of charge by The
Cambridge Crystallographic Data Centre.
Scheme 12. Access to highly enantioenriched α,α-difluoromethylated alcohols (S)-
25-1,16 by desulfonylation or desulfinylation
Eventually, the expected highly enantioenriched α,α-
2.4. Removal of the chiral auxiliary to access highly
enantioenriched α-difluoromethyl alcohols
difluoromethylated alcohols (S)-25 could
be nevertheless
obtained by three different routes (Scheme 12). First, after
oxidation of a 97:3 d.r. sample of (SS,S)-21a-1 to sulfone (S)-24a-
1, the latter was desulfonylated by means of magnesium turnings
with catalytic iodine in methanol, yielding (S)-25-1 with perfect
retention of the stereoenrichment at carbon all along the process
(i.e. from 97:3 d.r. to 95% e.e.). Second, a direct desulfinylation
of (SS,S)-21a-1 could be carried out by means of
poly(methylhydrosiloxane) in the presence of t-BuOK,36c
following a strategy by Midura et al.,36b modified by using
PMHS instead of triphenylsilane. Again, perfect retention of
configuration at carbon was obtained (from 93:7 d.r. to 88% e.e.).
Third, the direct desulfinylation could also be performed with the
magnesium method, as shown with the stereoretentive
transformation of (SS,S)-21a-16 into (S)-25-16 (from 93:7 d.r. to
86% e.e.). On the other hand, the 3-pyridinyl-substituted
compound (SS,S)-21a-6 only led to degradation under the two
sets of reaction conditions, with generation of numerous
unidentified byproducts.
Different approaches, among which single electron transfer
desulfinylations and well known desulfonylations, that have
already been successfully used for the removal of sulfinyl or
sulfonyl moieties on non-fluorinated β-hydroxysulfoxides or β-
hydroxysulfones have been tested on the previously synthesized
fluorinated analogues (Scheme 11).
Difluoromethylated alcohol
Difluoromethylated alcohol
Na/Hg
Na/Hg
or Al/Hg
NaPO2H2
Mg
AcOH
AcONa
Mg
AcOH
AcONa
NaPO2H2
up to > 99%
conversion
OH
O
O
S
OH
Ar
O
m-CPBA
(1.5 equiv.)
S
Ar
F
F
F
F
CH2Cl2
25 °C, 24 h
Quantitative
yield
21a
24a
i-PrMgCl.LiCl,
MeMgBr
MeLi,
t-BuLi,
n-BuLi
Raney
Ni
Bu3SnH
AIBN
Raney
Ni
Conclusions
Ar = Ph, 3-furyl.
After this study, we managed to address the issue of the
synthesis of a highly enantioenriched aryl difluoromethyl
sulfoxide and to find a strategy to access to α,α-difluoro-β-
hydroxysulfoxides with high diastereoselectivities. The latter can
also be synthesized through diastereoselective reduction of the
PhLi
Difluoromethylated alcohol
Difluoromethylated alcohol
Scheme 11. Attempts carried out to remove the chiral auxiliary
Unfortunately, Raney nickel gave no conversion of the
sulfinyl derivatives nor of the sulfonyl one.17a-c,
As we
corresponding
α,α-difluoro-β-ketosulfoxides.
Highly
17f, 17g
noticed that the reaction involving arenesulfinyl acetate 7b in
presence of organomagnesium (MeMgBr or iPrMgCl.LiCl) or
organolithiated reagents (MeLi) gave access to the corresponding
alkyl aryl sulfoxide by departure of ethyl difluoroacetate anion, it
was decided to assess such bases in the desulfinylation of α,α-
difluoro-β-hydroxysulfoxide 21a. Sadly, the chiral auxiliary was
not removed in presence of these reagents. Similar results were
observed with PhLi or tert-BuLi for instance. Reactions of
desulfinylation or desulfonylation involving freshly prepared
Al/Hg amalgam were not successful on either sulfinyl alcohol
21a or sulfonyl alcohol 24a while those carried out in presence of
enantioenriched α,α-difluoromethylated alcohols can finally be
obtained by desulfonylation of the corresponding α,α-difluoro-β-
hydroxysulfones, or simple desulfinylation of highly diastereo-
and enantio-enriched α,α-difluoro-β-hydroxysulfoxides by using
iodine-activated magnesium or PMHS/t-BuOK. Notably, the
stereoenrichment at the carbinol carbon atom is perfectly
preserved during the whole process.
3. Experimental section
4.0. General experimental methods and equipment

9
Starting materials, if commercially available, were purchased
resulting organic phase was dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure.
ACCEPTED MANUSCRIPT
from standard suppliers (Sigma-Aldrich, Fluorochem, ABCR,
Acros, Alfa Aesar or Apollo scientific) and used as such,
provided that adequate checks by NMR analysis had confirmed
the claimed purity. When needed, solvents were purified and
dried following standard procedures. THF was dried by
distillation over sodium/benzophenone prior to use. Toluene,
when used anhydrous, was either dried over 4 Å molecular sieves
previously activated overnight at 300 °C under vacuum or dried
by distillation over sodium. Anhydrous DMF purchased from
Sigma Aldrich was used as received. Air- and moisture- sensitive
materials were stored and handled under an atmosphere of argon.
Reactions were carried out under an atmosphere of argon when
needed. Reactions were monitored by using thin-layer
chromatography with precoated silica on aluminum foils (0.25
mm, Merck silica-gel (60-F254)). Flash column chromatography
was performed on VWR silica gel (40–63 ꢀm) using the
indicated solvents, the solvent systems being indicated in v/v.
When needed, demetalled silica was used. It was prepared by
adding an aqueous solution of 2M HCl in silica followed by
several washings with water.37 Butyllithium (1.6 M in hexanes,
Aldrich) was used as a solution in hexanes and its concentration
was determined following the Wittig-Harborth double titration
method ((total base) - (residual base after reaction with 1,2-
dibromoethane)).38 Spectroscopic NMR and MS data were
Ethyl 2,2-difluoro-2-(p-tolylthio)acetate 6a and ethyl 2,2-
difluoro-2-(4-chlorophenylthio)acetate 6b were described in our
previous paper8 and in the literature.39
Ethyl 2,2-difluoro-2-(phenylthio)acetate 6c
The reaction mixture was stirred for 21 hours at 40 °C. The
crude was purified by chromatography on silica gel with
cyclohexane/AcOEt (100/0 to 95/5). Light-yellow oil. 95% yield.
1H NMR (400 MHz, CDCl3) δ (ppm) 7.62 (d, J = 7.0 Hz, 2H),
7.47 (t, J = 7.3 Hz, 1H), 7.43-7.37 (m, 2H), 4.25 (q, J = 7.2 Hz,
2H), 1.26 (t, J = 7.1 Hz, 3H). 19F NMR (376 MHz, CDCl3)
δ (ppm) –82.2 (s, 2F). These data are consistent with those
already reported in the literature.40
Ethyl 2,2-difluoro-2-((4-methoxyphenyl)thio)acetate 6d
The reaction mixture was stirred for 43 hours at 40 °C. The
crude was purified by chromatography on silica gel with
cyclohexane/AcOEt (100/0 to 95/5). Light-yellow oil. 97% yield.
1H NMR (400 MHz, CDCl3) δ (ppm) 7.53 (d, J = 8.8 Hz, 2H),
6.91 (d, J = 8.8 Hz, 2H), 4.26 (q, J = 7.2 Hz, 2H), 3.82 (s, 3H),
1.28 (t, J = 7.2 Hz, 3H). 19F NMR (376 MHz, CDCl3) δ (ppm) –
83.2 (s, 2F). These data are consistent with those already reported
in the literature.39
1
obtained using chromatographically homogeneous samples. H
NMR (400 or 500 MHz), 19F NMR (376 or 471 MHz) and 13C
NMR (101 or 126 MHz) spectra were recorded in CDCl3 on
Bruker Avance III HD 400 and 500 MHz instruments
respectively. Chemical shifts are reported in parts per million
(ppm) and are referred to partially deuterated chloroform (δ[1H]
= 7.26 ppm and δ[13C] = 77.16 ppm). Multiplicities were
abbreviated as br s (broad singlet), s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet), td (triplet of doublets), dd
(doublet of doublets) and their corresponding combinations.
Coupling constants J were given in Hz. Spectra were processed
with the program NMR notebook (Version 2.80, NMRtec). IR
Ethyl 2,2-difluoro-2-(naphthalen-1-ylthio)acetate 6e
The reaction mixture was stirred for 24 hours at 40 °C. The crude
1
mixture was not purified. Orange oil. 88% yield. H NMR (400
MHz, CDCl3) δ (ppm) 8.55 (d, J = 8.6 Hz, 1H), 8.03-7.85 (m,
3H), 7.64 (ddd, J = 1.3 Hz, 6.8 Hz, 8.4 Hz, 1H), 7.56 (ddd, J =
1.2 Hz, 6.8 Hz, 8.1 Hz, 1H), 7.50 (dd, J = 7.3 Hz, 8.2 Hz, 1H),
4.05 (q, J = 7.2 Hz, 2H), 1.07 (t, J = 7.2 Hz, 3H). 19F NMR
(376 MHz, CDCl3) δ (ppm) –82.2 (s, 2F). 13C NMR (126 MHz,
CDCl3) δ (ppm) 161.7 (t, J = 32.7 Hz), 138.0, 135.9, 134.3,
132.1, 128.6, 127.6, 126.8, 126.1, 125.7, 122.3, 120.2 (t,
J = 288.1 Hz), 63.6, 13.6. IR ν (cm-1) 3058, 2985, 2927, 2855,
1763, 1504, 1371, 1290, 1124, 1099, 1015, 984, 965, 835, 800,
772, 721. HRMS (ESI) calcd for C14H13F2O2S: 283.0599, found:
283.0619.
spectra were recorded on
a Perkin Elmer UATR Two
spectrometer coupled to a diamond window ATR. Only the more
representative frequencies are reported in cm-1. Specific rotations
[α]D were determined at 20 °C on an Anton Paar MCP 200
polarimeter. The concentration (c) is indicated in decagram per
liter (dag/L). Chiral HPLC analyses were performed on a
Shimadzu Prominence chromatograph. High-resolution mass
spectra (HRMS) were recorded with a Bruker MicroTOF mass
analyser under ESI in positive ionization mode detection
(measurement accuracy ≤ 15 ppm) by the analytical facility at the
Université de Strasbourg. The X-ray crystallographic structure
analysis was performed by the radio-crystallographic facility at
the Université de Strasbourg. The analysis was carried out on a
Nonius Kappa-CCD diffractometer equipped with an Oxford
Cryosystem liquid N2 device, using Mo-Kα radiation
(λ = 0.71073 Å).
4.2. General procedures for the obtention of racemic α,α-
difluoro-β-sulfinylacetates 7a-e
Procedure A – Oxidation by using periodic acid and FeCl3
The corresponding sulfide 6 (1 equiv.) and FeCl3 (3 mol%)
were dissolved in acetonitrile (3.7x10-1 mol/L). After 10 minutes
of stirring, periodic acid (1 equiv.) was added to the mixture
which was mechanically stirred at 25 °C. If necessary, and after
1
controlling the conversion by H NMR, periodic acid was added
to the reaction mixture according to the proportions required to
reach full conversion. After full conversion was obtained, the
reaction was slowly quenched with a saturated solution of
Na2S2O3. The aqueous phase was extracted several times with
CH2Cl2. The combined organic layers were washed with water
and with a saturated solution of NaCl, dried over anhydrous
sodium sulfate and concentrated under reduced pressure.
4.1. General procedure for the obtention of racemic α,α-
difluoro-β-sulfanylacetates 6a-e
A solution of the corresponding thiophenol (1 equiv.)
dissolved in anhydrous DMF (2.3 mol/L) was cannulated
dropwise onto a suspension of sodium hydride (60% dispersion
in mineral oil; 1.1 equiv.) in anhydrous DMF (3 mol/L) at 0 °C
under argon. Ethyl bromodifluoroacetate (1 equiv.) was then
syringed dropwise into the previous solution. The reaction
mixture was heated at 40 °C for the desired time, then cooled to
0 °C, quenched with water and extracted three times with
CH2Cl2. The combined organic layers were washed with large
amounts of water and with a saturated solution of NaCl. The
Procedure
B – Oxidation by using freshly prepared
trifluoroperoxyacetic acid
To a solution of trifluoroperoxyacetic acid (TFPAA) at 0 °C
(1 equiv., freshly prepared by mixing 1 equiv. of H2O2, 30% w/w
in water, with 1 equiv. of trifluoroacetic acid (TFA) at 0 °C) was
added dropwise sulfide
6 (1 equiv.) dissolved in TFA
(0.6 mol/L). The solution was warmed to 25 °C and stirred at this

10
Tetrahedron
ACCEPTED MANUSCRIPT
temperature for one day. The reaction mixture was carefully
times with AcOEt. The combined organic layers were washed
poured onto a saturated solution of NaHCO3. The aqueous phase
was extracted three times with AcOEt. The combined organic
phases were washed with water and with a saturated solution of
NaCl, dried over anhydrous sodium sulfate and concentrated
under reduced pressure.
three times with ice-cold water and with a cold saturated solution
of NaCl, dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure.
Compounds 4a,b were synthesized following procedure C and
were described in our previous paper8 and/or in the literature.19b
Compounds 7a,b were synthesized following procedure A and
((Difluoromethyl)sulfinyl)benzene 4c
were described in our previous paper8 and in the literature.19b,39
Following procedure C, the reaction mixture was stirred for
24 hours at 110 °C. The crude was purified by chromatography
on silica gel with cyclohexane/AcOEt (100/0 to 80/20). White
solid. 43% yield. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.71 (d,
J = 7.3 Hz, 2H), 7.63-7.55 (m, 3H), 6.04 (t, J = 53.3 Hz, 1H).
19F NMR (376 MHz, CDCl3) δ (ppm) –119.2 (ABX system,
JAB = JF-F = 261.6 Hz, JAX = JBX = JH-F = 55.2 Hz, ꢁνAB = 97.3 Hz,
2F). These data are consistent with those already reported in the
literature.15
Ethyl 2,2-difluoro-2-(phenylsulfinyl)acetate 7c
Following procedure A, the reaction mixture was stirred for
16 hours at 25 °C. The crude was purified by chromatography on
demetalated silica gel with cyclohexane/AcOEt (100/0 to 80/20).
Yellow oil. 96% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.73
(d, J = 7.6 Hz, 2H), 7.67-55 (m, 3H), 4.25 (q, J = 7.2 Hz, 2H),
1.26 (t, J = 7.2 Hz, 3H). 19F NMR (376 MHz, CDCl3) δ (ppm)
−110.2 (AB system, JAB = 227.5 Hz, ꢁνAB = 810.6 Hz, 2F). These
data are consistent with those already reported in the literature.19b
1-((Difluoromethyl)sulfinyl)-4-methoxybenzene 4d
Ethyl 2,2-difluoro-2-((4-methoxyphenyl)sulfinyl)acetate 7d
Following procedure C, the reaction mixture was stirred for
15 hours at 110 °C. The crude was purified by chromatography
on silica gel with cyclohexane/AcOEt (100/0 to 80/20). White
solid. 68% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.64 (d,
J = 8.8 Hz, 2H), 7.07 (d, J = 8.9 Hz, 2H), 6.00 (t, J = 55.5 Hz,
1H), 3.86 (s, 3H). 19F NMR (376 MHz, CDCl3) δ (ppm) –119.7
(ABX system, JAB = JF-F = 261.6 Hz, JAX = JBX = JH-F = 55.2 Hz,
ꢁνAB = 73.7 Hz, 2F). 13C NMR (126 MHz, CDCl3) δ (ppm) 163.4,
127.5, 127.1, 120.8 (t, J = 288.4 Hz), 115.1, 55.5. IR ν (cm-1)
3371, 3029, 2974, 2955, 1592, 1572, 1468, 1455, 1438, 1411,
1341, 1310, 1281, 1255, 1175, 1100, 1083, 1037, 1023, 970, 841,
821, 797, 779.
Following procedure A, the reaction mixture was stirred for
2 days at 25 °C. The crude was clean enough not to be purified.
Yellow oil. Quantitative yield. 1H NMR (400 MHz, CDCl3)
δ (ppm) 7.65 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.9 Hz, 2H), 4.30
(qd, J = 1.3 Hz, 7.2 Hz, 2H), 3.87 (s, 3H), 1.28 (t, J = 7.2 Hz,
3H). 19F NMR (376 MHz, CDCl3) δ (ppm) −111.0 (AB system,
JAB = 227.5 Hz, ꢁνAB = 749.7 Hz, 2F). These data are consistent
with those already reported in the literature.19b
Ethyl 2,2-difluoro-2-(naphthalen-1-ylsulfinyl)acetate 7e
Following procedure B, the reaction mixture was stirred for
1 day at 20 °C. The crude was clean enough not to be purified.
Brown oil. 98% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.20
(d, J = 7.3 Hz, 1H), 8.13 (d, J = 7.8 Hz, 1H), 8.07 (d, J = 8.2 Hz,
1H), 7.96-7.88 (m, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.59 (m, 2H),
4.05 (qd, J = 2.0 Hz, 7.1 Hz, 2H), 1.10 (t, J = 7.2 Hz, 3H).
19F NMR (376 MHz, CDCl3) δ (ppm) −108.6 (AB system,
JAB = 221.4 Hz, ꢁνAB = 498.7 Hz, 2F). 13C NMR (126 MHz,
CDCl3) δ (ppm) 159.4 (t, J = 28.2 Hz), 133.7, 133.5, 132.1,
130.6, 128.9, 127.9, 127.1, 126.2, 125.3, 122.2, 118.9 (t,
J = 304.2 Hz), 64.1, 13.6. IR ν (cm-1) 3060, 2925, 2855, 1758,
1506, 1371, 1300, 1161, 1142, 1127, 1082, 1011, 966, 956, 855,
802, 769, 711. HRMS (ESI) calcd for C14H12F2KO3S: 337.0107,
found: 337.0103.
1-((Difluoromethyl)sulfinyl)naphthalene 4e
Following procedure D, the reaction mixture was stirred for
15 minutes at 100 °C under microwave irradiations. The crude
was purified by chromatography on silica gel with
cyclohexane/AcOEt (100/0 to 70/30). White solid. 61% yield.
1H NMR (400 MHz, CDCl3) δ (ppm) 8.18 (d, J = 7.2 Hz, 1H),
8.14-8.01 (m, 2H), 7.99-7.91 (m, 1H), 7.68 (t, J = 7.7 Hz, 1H),
7.65-7.56 (m, 2H), 6.20 (t, J = 55.0 Hz). 19F NMR (376 MHz,
CDCl3) δ (ppm) –116.8 (ABX system, JAB = JF-F = 258.2 Hz,
JAX = JBX = JH-F = 55.9 Hz, ꢁνAB = 749.7 Hz, 2F). 13C NMR
(126 MHz, CDCl3) δ (ppm) 133.6, 133.2, 132.7, 130.3, 129.1,
128.1, 127.2, 125.5, 125.2, 124.1, 121.9, 121.7 (t, J = 290.8 Hz).
IR ν (cm-1) 3059, 2976, 2926, 1505, 1262, 1143, 10,91, 1064,
1053, 1024, 802, 767, 690. HRMS (ESI) calcd for C11H9F2OS:
227.0337, found: 227.0339.
4.3. General procedures for the obtention of racemic
difluoromethyl sulfoxides 4a-e
Procedure C – Under thermal conditions
4.4. Access to sulfide 12b
The corresponding sulfinylacetate 7 (1 equiv.), LiCl (2 equiv.)
and H2O (2 equiv.) were dissolved in DMSO (1.2x10-1 mol/L).
The reaction mixture was stirred at 110 °C for the desired time,
cooled to room temperature and then poured onto ice-cold water.
The aqueous layer was saturated with NaCl and then extracted
three times with AcOEt. The combined organic layers were
washed with water, dried over anhydrous sodium sulfate, filtered
and concentrated under reduced pressure.
(4-Chlorophenyl)(difluoromethyl)sulfane 12b
To a suspension of LiCl (2 equiv., 32.8 mg, 750 µmol) and
ethyl 2-(4-chlorophenylthio)-2,2-difluoroacetate 6b (1 equiv.,
100 mg, 375 µmol) in 3 mL of NMP was added H2O (2 equiv.,
13.5 µL, 0.75 mmol). The reaction mixture was heated at 200°C
under microwave irradiations for 30 minutes, cooled to 25 °C and
quenched with a solution of 1M HCl. It was then extracted three
times with AcOEt. The combined organic layers were washed
with water and a with a saturated solution of NaCl, dried over
anhydrous sodium sulfate, filtered and concentrated under
reduced pressure. The crude was purified by chromatography on
silica gel with pentane. 69% yield. 1H NMR (400 MHz, CDCl3) δ
(ppm) 7.52 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 6.81 (t,
J = 56.7 Hz, 1H). 19F NMR (376 MHz, CDCl3) δ (ppm) –91.7 (d,
Procedure D – Under microwave irradiations
To a suspension of LiCl (2 equiv.) and sulfinylacetate
7 (1 equiv.) in NMP (5.9 x 10-2 mol/L) was added H2O (2 equiv.).
The reaction mixture was heated to 100 °C under microwave
irradiation for 15 minutes. The dark brown reaction mixture was
cooled to room temperature. An aqueous solution of 1M HCl was
added to the mixture. The aqueous layer was extracted three

11
J = 56.5 Hz, 2F). These data are consistent with those already
16.2, 16.1. IR ν (cm-1) 2957, 2922, 2872, 1772, 1751, 1576,
ACCEPTED MANUSCRIPT
reported in the literature.41
1476, 1457, 1392, 1370, 1294, 1169, 1132, 1096, 1083, 1068,
1013, 978, 944, 905, 825, 744, 712. HRMS (ESI) calcd for
C18H23ClF2KO3S: 431.0656, found: 431.0635.
4.5. Attempts of enantioselective oxidation on sulfide 12b
See supplementary data for more details concerning
procedures and optimization.
2-[(4-Chlorophenyl)sulfinyl]-2,2-difluoroacetic acid 17b
To a solution of sulfinylester 16b (1 equiv., 87.4 mg,
223 µmol) in 0.5 mL of EtOH was added NaOH (1 equiv.,
8.9 mg, 223 µmol). The reaction mixture was heated at 40 °C for
17 hours and then cooled to room temperature. Ethanol was
removed under reduced pressure. The residue was then dissolved
in a minimum amount of water (1 mL) and acidified at 0 °C until
pH = 1 by using an aqueous solution of 2M HCl. The aqueous
phase was saturated with NaCl and extracted four times with
THF. The organic layer was dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure. 91%
1-Chloro-4-((difluoromethyl)sulfonyl)benzene 13b
1H NMR (400 MHz, CDCl3) δ (ppm) 7.93 (d, J = 8.6 Hz, 2H),
7.64 (d, J = 8.5 Hz, 2H), 6.19 (t, J = 53.4 Hz, 1H). 19F NMR
(376 MHz, CDCl3) δ (ppm) –121.3 (d, J = 53.1 Hz, 2F). These
data are consistent with those already reported in the literature.42
4.6. Attempted oxidations of L-menthyl sulfanylacetates
(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl 2-[(4-chloro
phenyl)sulfanyl]-2,2-difluoroacetate 15b
1
yield. White solid. H NMR (400 MHz, THF-d8) δ (ppm) 9.46-
To a solution of ethyl 2-(4-chlorophenylthio)-2,2-difluoro
acetate 6b (1 equiv., 1 g, 3.75 mmol) in 8 mL of anhydrous
toluene were added L-menthol (5 equiv., 2.93 g, 18.8 mmol),
DMAP (2.6 equiv., 1.19 g, 9.75 mmol) and 4 Å molecular sieves
(500 mg). The reaction mixture was then heated under reflux for
24 hours, then cooled to 25 °C and filtered. The filtrate was
concentrated under reduced pressure. The crude was purified by
chromatography on silica gel with n-hexane/CH2Cl2 (80/20) and
15b was obtained as a transparent oil. 60% yield. 1H NMR (400
MHz, CDCl3) δ (ppm) 7.55 (d, J = 7.6 Hz, 2H), 7.37 (d, J = 7.6
Hz, 2H), 4.77 (td, J = 4.4 Hz, 11.1 Hz, 1H), 1.93 (d, J = 12.0 Hz,
1H), 1.81 (quin, J = 7.0 Hz, 1H), 1.70 (d, J = 12.2 Hz, 2H), 1.47
(t, J = 11.6 Hz, 2H), 1.13-0.94 (m, 2H), 0.91 (dd, J = 7.2 Hz, 9.3
Hz, 6H), 0.89-0.81 (m, 1H), 0.75 (d, J = 6.8 Hz, 3H). 19F NMR
(376 MHz, CDCl3) δ (ppm) –81.5 (AB system, JAB = JF-F = 215.9
Hz, ꢁνAB = 118.8 Hz, 2F). 13C NMR (126 MHz, CDCl3) δ (ppm)
161.2 (t, J = 31.9 Hz), 137.9, 137.4, 129.7, 123.5, 119.9 (dd,
J = 228.3 Hz), 78.8, 46.9, 40.3, 34.1, 31.5, 26.3, 23.5, 22.0, 20.8,
16.3. IR ν (cm-1) 2957, 2928, 2872, 1760, 1575, 1477, 1456,
1390, 1371, 1291, 1283, 1111, 1092, 1006, 980, 947, 908, 845,
823, 747, 724,701. HRMS (ESI) calcd for C18H23ClF2O2S
8.33 (br s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H).
19F NMR (376 MHz, THF-d8) δ (ppm) –111.9 (AB system, JAB
=
JF-F = 224.8 Hz, ꢁνAB = 717.0 Hz, 2F). 13C NMR (101 MHz,
THF-d8) δ (ppm) 161.0 (t, J = 27.0 Hz), 139.6, 137.0, 130.1,
128.5, 119.2 (t, J = 302.5 Hz). IR ν (cm-1) 3096, 2919, 2851,
2646, 2508, 1768, 1572, 1478, 1426, 1395, 1275, 1175, 1139,
1114, 1079, 1035,1010, 947, 887, 827, 772, 745, 702. HRMS
(ESI) calcd for C8H5ClF2NaO3S: 276.9508, found: 276.9484.
4.7. Access to highly enantioenriched difluoromethyl p-tolyl
sulfoxide 4a
For more details concerning its synthesis and analyses (NMR,
chiral HPLC, IR, HRMS, etc.), see our previous paper.8
4.8. Access to α,α-difluoro-β-hydroxysulfoxides – Starting
conditions
Procedure E – Prakash and Hu’s optimized conditions
In a vial under argon were dissolved difluoromethyl p-tolyl
sulfoxide 4a (1 equiv., 50 mg, 263 µmol) and the carbonyl
derivative (2 equiv., 526 µmol) in 1 mL of freshly distilled THF.
The mixture was stirred at –30 °C for 5 minutes. Potassium tert-
butoxide (2 equiv., 60 mg, 526 µmol), previously solubilised in
1 mL of freshly distilled THF, was added dropwise to the
previous solution. The reaction mixture was stirred at –30 °C for
40 minutes, then quenched with water at –30 °C. The aqueous
layer was extracted three times with Et2O. The combined organic
layers were washed with a saturated solution of NH4Cl and with a
saturated solution of NaCl, dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure.
20
(MNa+): 399.0968, found (MNa+): 399.0966. [α]D = –36.2 °
(c 0.1, EtOH).
(1R,2S,5R)-5-Methyl-2-(propan-2-yl)cyclohexyl 2-[(4-chloro
phenyl)sulfinyl]-2,2-difluoroacetate 16b
Sulfanylester 15b (1 equiv., 100 mg, 265 µmol) and
FeCl3·6H2O or 18 (resp. 3 or 5 mol%) were dissolved in 0.7 mL
of MeCN and stirred at 25 °C for 5 minutes. To this solution was
added H5IO6 (1.43 equiv., 88.3 mg, 379 µmol). The reaction was
then heated at 45 °C for 90 minutes., then quenched with an
aqueous saturated solution of Na2S2O3 and extracted four times
with CH2Cl2. The combined organic layers were dried over
anhydrous sodium sulfate, filtered and concentrated under
reduced pressure. The crude mixture was clean enough not to be
purified. 87% yield. Transparent oil. 1H NMR (400 MHz, CDCl3)
1:1 mixture of two diastereomers δ (ppm) 7.68 (d, J = 8.3 Hz,
2H), 7.56 (d, J = 8.5 Hz, 2H), 4.81 (qd, J = 4.5 Hz, 11.0 Hz, 1H),
1.95 (d, J = 11.7 Hz, 0.5H), 1.87 (d, J = 12.2 Hz, 0.5H), 1.84-
1.75 (m, 1H), 1.75-1.65 (m, 2H), 1.53-1.41 (m, 2H), 1.09-0.97
(m, 2H), 0.95-0.85 (m, 7H), 0.75 (d, J = 7.0 Hz, 1.5H), 0.72 (d, J
= 7.0 Hz, 1.5H). 19F NMR (376 MHz, CDCl3) First diastereomer
δ (ppm) −109.8 (AB system, JAB = 227.5 Hz, ꢁνAB = 1268 Hz,
Compounds 21a-1,5–16 were synthesized following
procedure E and were described in our previous paper.8
2,2-Difluoro-1-(p-tolyl)-2-(p-tolylsulfinyl)ethan-1-ol 21a-2
The crude was purified by chromatography on silica gel with
cyclohexane/AcOEt (100/0 to 50/50). 90% yield. 1H NMR
(400 MHz, CDCl3) Two diastereomers
δ (ppm) 7.60 (d,
J = 7.5 Hz, 2H), 7.40 (d, J = 8.0 Hz, 0.8H), 7.38-7.32 (m, 3.2H),
7.20 (d, J = 8.0 Hz, 0.8H), 7.17 (d, J = 8.0 Hz, 1.2H), 5.39 (dd,
J = 3.1 Hz, 22.8 Hz, 0.6H), 5.30 (ddd, J = 2.8 Hz, 3.7 Hz,
10.3 Hz, 0.4H), 4.79 (d, J = 5.3 Hz, 0.6H), 3.92 (d, J = 3.8 Hz,
0.4H), 2.43 (s, 1.2H), 2.42 (s, 1.8H), 2.36 (s, 1.2H), 2.34 (s,
1.8H). 19F NMR (376 MHz, CDCl3) First diastereomer δ (ppm)
–115.0 (ABX system, JAB = JF-F = 218.0 Hz, JAX = JH-F = 10.2 Hz,
1F); Second diastereomer δ (ppm) −109.4 (AB system, JAB
=
228.9 Hz, ꢁνAB = 829 Hz, 1F). 13C NMR (126 MHz, CDCl3) Two
diastereomers δ (ppm) 159.2 (dd, J = 26.8 Hz, 29.1 Hz), 159.1 (t,
J = 27.8 Hz), 140.0, 139.9, 134.7, 129.9, 129.8, 127.8, 117.9 (dd,
J = 302.5 Hz, 305.6 Hz), 117.8 (t, J = 304.3 Hz), 79.8, 79.8, 46.7,
40.4, 40.4, 34.0, 33.9, 31.6, 26.2, 26.0, 23.4, 23.3, 22.0, 20.7,
JBX = JH-F
=
15.0 Hz, ꢁνAB = 3498 Hz, 0.6F); Second
diastereomer
δ
(ppm) –114.1 (ABX system, JAB = JF-
F = 224.8 Hz, JBX = JH-F = 22.5 Hz, ꢁνAB = 2288 Hz, 0.4F). 13C
NMR (126 MHz, CDCl3) Two diastereomers δ (ppm) 143.6,

12
Tetrahedron
ACCEPTED MANUSCRIPT
143.5, 139.4, 139.0, 132.8 (d, J = 3.2 Hz), 132.2 (d, J = 3.2
of argon. Titanium(IV) chloride (2 equiv., 35 µL, 315 µmol) was
Hz), 131.9, 131.5 (d, J = 1.8 Hz), 130.0, 129.9, 129.3, 129.1,
128.1, 127.9, 126.5, 124.7 (dd, J = 297.0 Hz, 305.2 Hz), 124.0
(dd, J = 293.8 Hz, 309.3 Hz), 73.0 (t, J = 21.8 Hz), 70.4 (dd, J =
19.5 Hz, 29.1 Hz), 21.7, 21.7, 21.4, 21.3. IR ν (cm-1) 3325, 2923,
2855, 1597, 1515, 1494, 1449, 1181, 1112, 1085, 1041, 1015,
975, 835, 810, 780, 747, 703. HRMS (ESI) calcd for
C16H17F2O2S: 311.0912, found: 311.0901.
then added to the reaction mixture. It became dark red. The
reaction was stirred at –20 °C for 35 minutes. It was quenched
with water and the aqueous phase was extracted three times with
Et2O. The combined organic layers were washed with a saturated
solution of NH4Cl, dried over anhydrous sodium sulfate, filtered
and concentrated under reduced pressure.
Procedure G – Use of ZnCl2
1-(4-Bromophenyl)-2,2-difluoro-2-(p-tolylsulfinyl)ethan-1-ol
21-a3
Pre-drying of zinc(II) chloride – ZnCl2 (2 equiv., 71.7 mg,
526 µmol), a highly hygroscopic compound, was previously
dried using the following method: in a Schlenk tube, zinc
dichloride was heated to 140 °C under vacuum. After 6 hours of
stirring under such conditions, the tube was cooled to room
temperature and 1 mL of freshly distilled THF was added under
an atmosphere of argon. The mixture was stirred until total
dissolution of ZnCl2.
The crude was purified by chromatography on silica gel with
cyclohexane/AcOEt (100/0 to 50/50). 99% yield. 1H NMR
(400 MHz, CDCl3) Two diastereomers δ (ppm) 7.62-7.64 (m,
4H), 7.51 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 7.42-7.30
(m, 8H), 5.47-5.29 (m, 2H), 5.26 (d, J = 5.1 Hz, 1H), 4.25 (d,
J = 3.0 Hz, 1H), 2.44 (s, 3H), 2.43 (s, 3H). 19F NMR (376 MHz,
CDCl3) First diastereomer δ (ppm) –114.5 (ABX system,
Difluoromethyl p-tolyl sulfoxide 4a (1 equiv., 50 mg, 263
µmol) and 1-naphthaldehyde (2 equiv., 71.4 µL, 526 µmol) were
introduced in another Schlenk tube. The mixture was cooled to –
30 °C and a solution of potassium tert-butoxide (2 equiv.,
60.2 mg, 526 µmol) dissolved in 1.5 mL of freshly distilled THF
was added dropwise, under an atmosphere of argon. The reaction
mixture turned dark yellow/orange. The freshly prepared solution
of ZnCl2 in THF was then cannulated onto this mixture, which
became immediately light-yellow. The reaction was stirred at –
30 °C for 35 minutes. It was quenched with water and the
aqueous phase was extracted three times with Et2O. The
combined organic layers were washed with a saturated solution
of NH4Cl, dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure.
J
AB = JF-F = 219.3 Hz, JAX = JH-F = 8.9 Hz, JBX = JH-F = 15.0 Hz,
ꢁνAB = 4081 Hz, 0.5F); Second diastereomer δ (ppm) –114.1
(ABX system, JAB = JF-F = 224.8 Hz, JBX = JH-F = 23.2 Hz,
ꢁνAB = 2318 Hz, 0.5F). 13C NMR (126 MHz, CDCl3) Two
diastereomers δ (ppm) 144.0, 143.8, 133.9, 133.3, 133.3, 132.3,
132.3, 131.8, 131.6, 130.1, 129.9, 129.6, 126.5, 126.5, 124.3 (dd,
J = 297.0 Hz, 304.7 Hz), 123.8, 123.4, 123.1 (dd, J = 293.4 Hz,
312.0 Hz), 73.0 (t, J = 22.3 Hz), 70.2 (dd, J = 20 Hz, 28.6 Hz),
21.8, 21.7. IR ν (cm-1) 3309, 2921, 1595, 1489, 1403, 1192,
1111, 1084, 1042, 1012, 979, 847, 809, 771, 703. HRMS (ESI)
calcd for C15H14BrF2O2S: 374.9860, found: 374.9853.
1-(2,3-Dimethoxyphenyl)-2,2-difluoro-2-(p-
tolylsulfinyl)ethan-1-ol 21a-4
The crude was purified by chromatography on silica gel with
cyclohexane/AcOEt (100/0 to 50/50). 99% yield. 1H NMR
Procedure H – Use of a tetra-substituted 18-crown-6 crown
ether
(400 MHz, CDCl3) Two diastereomers
δ (ppm) 7.68 (d,
Difluoromethyl p-tolyl sulfoxide 4a (1 equiv., 30 mg,
J = 8.1 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1.1H), 7.39-7.30 (m, 2H),
7.11 (d, J = 7.9 Hz, 0.54H), 7.07-7.01 (m, 1H), 6.98 (d,
J = 7.4 Hz, 0.46H), 6.93-6.86 (m, 1H), 5.79 (dd, J = 6.0 Hz, 24.6
Hz, 0.54H), 5.36 (dt, J = 6.1 Hz, 19.5 Hz, 0.46H), 4.98 (d,
J = 6.6 Hz, 0.54H), 4.63 (d, J = 6.6 Hz, 0.46H), 3.85 (s, 1.4H),
3.83 (s, 1.4H), 3.81 (s, 1.6H), 3.77 (s, 1.6H), 2.42 (s, 1.4H), 2.41
(s, 1.6H). 19F NMR (376 MHz, CDCl3) First diastereomer
δ (ppm) –114.7 (ABX system, JAB = JF-F = 217.3 Hz, JAX = JH-
F = 6.1 Hz, JBX = JH-F = 19.8 Hz, ꢁνAB = 3764 Hz, 0.46F); Second
diastereomer δ (ppm) –114.2 (ABX system, JAB =JF-F = 223.4 Hz,
JBX = JH-F = 24.5 Hz, ꢁνAB = 2481 Hz, 0.54F). 13C NMR (126
MHz, CDCl3) Two diastereomers δ (ppm) 152.5, 152.4, 147.9,
147.8, 143.6, 143.4, 133.6 (d, J = 3.2 Hz), 133.0 (d, J = 2.3 Hz),
130.0, 129.9, 127.7, 127.2, 126.6, 126.5, 124.7 (dd, J = 297.0 Hz,
306.1 Hz), 124.5 (dd, J = 297.0 Hz, 305.2 Hz), 124.2, 124.1,
121.3, 121.2, 113.5, 113.3, 70.1 (dd, J = 20.9 Hz, 25.0 Hz), 67.1
(dd, J = 19.5 Hz, 28.6 Hz), 61.3, 61.1, 55.9, 55.9, 21.7, 21.7. IR ν
(cm-1) 3333, 2941, 1589, 1483, 1432, 1266, 1224,1171, 1116,
1086, 1050, 1005, 977, 898, 810,774, 751, 722. HRMS (ESI)
calcd for C17H19F2O4S: 357.0967, found: 357.0970.
158 µmol), 1-naphthaldehyde (2 equiv., 45.1 µL, 315 µmol) and
crown
ether
(+)-(2R,3R,11R,12R)-1,4,7,10,13,16-
acid
Hexaoxacyclooctadecane-2,3,11,12-tetracarboxylic
(10 mol%, 7.1 mg, 15.8 µmol) were dissolved in 1 mL of freshly
distilled THF. The mixture was cooled to –30 °C and potassium
tert-butoxide (2 equiv., 35.4 mg, 315 µmol) dissolved in 1.5 mL
of freshly distilled THF was added dropwise. The reaction
mixture was stirred at –30 °C for 35 minutes. It was quenched
with water and the aqueous phase was extracted three times with
Et2O. The combined organic layers were washed with a saturated
solution of NH4Cl, dried over anhydrous sodium sulfate, filtered
and concentrated under reduced pressure.
4.9.2. Varying the aromatic ring of the sulfoxide
Procedure
E
was used to access α,α-difluoro-β-
hydroxysulfoxides 21b-1 to 21e-1.
2-((4-Chlorophenyl)sulfinyl)-2,2-difluoro-1-phenylethan-1-ol
21b-1
The crude was purified by chromatography on silica gel with
cyclohexane/AcOEt (100/0 to 80/20). 90% yield. 1H NMR
4.9. Optimization attempts for the diastereoselective access to
α,α-difluoro-β-hydroxysulfoxides
(500 MHz, CDCl3) Two diastereomers
δ (ppm) 7.61 (d,
J = 8.1 Hz, 2H), 7.53-7.49 (m, 4H), 7.43-7.33 (m, 3H), 5.45 (d,
J = 23.0 Hz, 0.5H), 5.33-5.19 (m, 1H), 4.41 (s, 0.5H). 19F NMR
(471 MHz, CDCl3) First diastereomer δ (ppm) –114.2 (ABX
system, JAB = JF-F = 217.3 Hz, JAX = JH-F = 10.9 Hz, JBX = JH-F
= 14.3 Hz, ꢁνAB = 2764 Hz, 0.48F); Second diastereomer δ (ppm)
–113.9 (ABX system, JAB = JF-F = 222.1 Hz, JBX = JH-F = 22.5 Hz,
ꢁνAB = 2018 Hz, 0.52F). 13C NMR (101 MHz, CDCl3) Two
diastereomers δ (ppm) 139.3, 139.2, 134.6, 134.5 (d, J = 2.6 Hz),
4.9.1. Addition of chelating agents
Procedure F – Use of TiCl4
To a solution of difluoromethyl p-tolyl sulfoxide 4a (1 equiv.,
30 mg, 158 µmol) and 1-naphthaldehyde (2 equiv., 45.1 µL, 315
µmol) in 1 mL of freshly distilled THF at –30 °C was added
potassium tert-butoxide (2 equiv., 36.1 mg, 315 µmol) previously
dissolved in 1 mL of freshly distilled THF, under an atmosphere

13
134.2 (d, J = 2.2 Hz), 133.8, 129.6, 129.6, 129.5, 129.2, 128.7,
4.9.3. Screening of different bases
ACCEPTED MANUSCRIPT
128.5, 128.1, 127.9, 127.9, 127.9, 127.1, 125.2 (dd, J = 300.0 Hz,
306.6 Hz), 124.3 (dd, J = 295.5 Hz, 309.2 Hz), 72.9 (t, J = 22.0
Hz), 70.1 (dd, J = 19.4 Hz, 29.3 Hz). IR ν (cm-1) 3325, 2920,
2851, 1576, 1494, 1476, 1456, 1393, 1191, 1110, 1093,1079,
1046, 1011, 973, 821, 800, 743, 726, 697. HRMS (ESI) calcd for
C14H12ClF2O2S: 317.0209, found: 317.0192.
Procedure I – Use of KHMDS/crown ether 18-crown-6
Pre-drying of crown ether 18-crown-6 – Each time it was
used, crown ether 18-crown-6 was previously dried. It was
solubilized in anhydrous toluene and the potential traces of water
were removed by evaporation of the toluene/water azeotrope
under reduced pressure. This procedure was repeated several
times and the solid obtained was maintained under vacuum
overnight. It is also possible to recrystallize it from acetonitrile.
2,2-Difluoro-1-phenyl-2-(phenylsulfinyl)ethan-1-ol 21c-1
The crude was purified by chromatography on silica gel with
cyclohexane/AcOEt (100/0 to 50/50). Quantitative yield.
1H NMR (400 MHz, CDCl3) Two diastereomers δ (ppm) 7.77-
7.70 (m, 2H), 7.64-7.50 (m, 3.8H), 7.49-7.44 (m, 1.2H), 7.43-
7.34 (m, 3H), 5.48-5.35 (m, 1H), 4.40 (d, J = 5.3 Hz, 0.6H), 3.69
(d, J = 3.9 Hz, 0.4H). 19F NMR (376 MHz, CDCl3) First
In a reaction tube under argon were dissolved difluoromethyl
p-tolyl sulfoxide 4a (1 equiv., 30 mg, 158 µmmol), benzaldehyde
(1 equiv., 16.3 µL, 158 µmol) and, when required, crown ether
18-crown-6 (1 equiv., 41.7 mg, 158 µmol) in 2 mL of the desired
anhydrous solvent. The mixture was stirred at –30 °C for
10 minutes. A solution of KHMDS (2 equiv., 0.5 M in toluene,
631 µL, 315 µmol) was then added dropwise to the previous
solution at –30 °C. The reaction was stirred at this temperature
for the desired time, possibly followed by a period of stirring at
room temperature, depending on the result of the TLC control. It
was quenched with water and the aqueous phase was extracted
three times with Et2O. The combined organic layers were washed
with a saturated solution of NH4Cl, dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure.
diastereomer
δ
(ppm) –114.2 (ABX system,
JAB = JF-
F = 219.3 Hz, JAX = JH-F = 8.9 Hz, JBX = JH-F = 15.7 Hz,
ꢁνAB = 3961 Hz, 0.36F); Second diastereomer δ (ppm) –113.5
(ABX system,
JAB = JF-F = 224.8 Hz, JBX = JH-F = 22.5 Hz,
ꢁνAB = 2495 Hz, 0.64F). These data are consistent with those
already reported in the literature.15
2,2-Difluoro-2-((4-methoxyphenyl)sulfinyl)-1-phenylethan-1-
ol 21d-1
The crude was purified by chromatography on silica gel with
cyclohexane/AcOEt (100/0 to 50/50). 90% yield. 1H NMR
Procedure J – Use of LiHMDS/crown ether 12-crown-4
(500 MHz, CDCl3) Two diastereomers
δ (ppm) 7.65 (d,
In a reaction tube under argon were dissolved difluoromethyl
p-tolyl sulfoxide 4a (1 equiv., 30 mg, 158 µmol), benzaldehyde
(1 equiv., 16.3 µL, 158 µmol) and, when required, 12-crown-4
(1 equiv., 27.8 mg, 158 µmol) in 1 mL of the chosen anhydrous
solvent. The mixture was stirred at –30 °C for 10 minutes. In the
meanwhile, to a solution of distilled HMDS (2 equiv., 67 µL,
315 µmol) in 1.5 mL of the chosen anhydrous solvent at –78 °C
was added dropwise n-butyllithium (2 equiv., 1.54 M in hexanes,
205 µL, 315 µmol). This solution was stirred at –30 °C for
20 minutes. The mixture was added dropwise to the previous
solution. The reaction mixture was stirred at –30 °C for the
desired time, possibly followed by a period of stirring at room
temperature, depending on the result of the TLC control. It was
quenched with water and the aqueous phase was extracted three
times with Et2O. The combined organic layers were washed with
a saturated solution of NH4Cl, dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure.
J = 7.8 Hz, 2H), 7.53-7.45 (m, 2H), 7.41-7.33 (m, 3H), 7.06-7.01
(m, 2H), 5.44 (dd, J = 1.4 Hz, 22.6 Hz, 0.55H), 5.32 (dd,
J = 9.6 Hz, 15.3 Hz, 0.45H), 3.86 (s, 1.45H), 3.85 (s, 1.55H).
19F NMR (471 MHz, CDCl3) First diastereomer δ (ppm) –115.2
(ABX system, JAB = JF-F = 219.3 Hz, JAX = JH-F = 9.5 Hz,
JBX = JH-F
diastereomer
=
15.6 Hz, ꢁνAB = 4746 Hz, 0.45F); Second
(ppm) –114.4 (ABX system, JAB = JF-
δ
F = 224.5 Hz, JBX = JH-F = 22.5 Hz, ꢁνAB = 2486 Hz, 0.55F). 13C
NMR (126 MHz, CDCl3) Two diastereomers δ (ppm) 163.5,
163.5, 134.9, 134.5 (d, J = 1.4 Hz), 129.5, 129.1, 128.6, 128.6,
128.6, 128.4, 128.2, 128.1, 126.6 (d, J = 3.2 Hz), 126.0 (d, J =
2.3 Hz), 124.5 (dd, J = 296.6 Hz, 304.7 Hz), 123.6 (dd, J = 292.9
Hz, 309.7 Hz), 114.9, 114.9, 73.4 (t, J = 22.3 Hz), 70.6 (dd, J =
20.0 Hz, 29.1 Hz), 55.7, 55.7. IR ν (cm-1) 3324, 2921, 2817,
1594, 1577, 1496, 1456, 1443, 1308, 1258, 1175, 1108, 1087,
1062, 1027, 978, 831, 798, 729, 699. HRMS (ESI) calcd for
C15H14F2NaO3S: 335.0524, found: 335.0519.
Procedure K – Use of NaH
2,2-Difluoro-2-(naphthalen-1-ylsulfinyl)-1-phenylethan-1-ol
21e-1
In a reaction tube under argon were dissolved difluoromethyl
p-tolyl sulfoxide 4a (1 equiv., 50 mg, 260 µmol) and
benzaldehyde (1 equiv., 50 µL, 260 µmol) in freshly distilled
THF. After some minutes of stirring at –78 °C, NaH (2 equiv.,
21 mg, 530 µmol, 60% dispersion in oil) was added portionwise.
The solution turned yellow then orange. This solution was stirred
at this temperature for 2 h and was then allowed to warm to room
temperature. It was stirred at this temperature for 1 h. The
reaction mixture was quenched with a saturated solution of
NH4Cl. The aqueous layer was extracted three times with Et2O.
The combined organic layers were washed with brine, dried over
anhydrous sodium sulfate, filtered and concentrated under
reduced pressure.
The crude was purified by chromatography on silica gel with
cyclohexane/AcOEt (100/0 to 50/50). Quantitative yield.
1H NMR (400 MHz, CDCl3) Two diastereomers δ (ppm) 8.21 (d,
J = 6.5 Hz, 1H), 8.13 (d, J = 4.3 Hz, 0.6H), 8.04 (t, J = 7.8 Hz,
1H), 7.97 (d, J = 7.1 Hz, 0.4H), 7.94-7.88 (m, 1H), 7.70-7.63 (m,
1H), 7.59-7.58 (m, 4H), 7.43-7.31 (m, 3H), 5.61 (d, J = 19.3 Hz,
0.6H), 5.44 (dd, J = 9.5 Hz, 13.3 Hz, 0.4H), 5.28 (br s, 0.6H),
4.33 (br s, 0.4H). 19F NMR (471 MHz, CDCl3) First diastereomer
δ (ppm) −112.0 (ABX system, JAB = 215.9 Hz, JBX = JH-
F = 14.3 Hz, ꢁνAB = 4236 Hz, 0.4F). Second diastereomer δ (ppm)
–111.9 (AB system, JAB = 220.7 Hz, ꢁνAB = 1588 Hz, 0.6F).
13C NMR (126 MHz, CDCl3) Two diastereomers δ (ppm) 134.8,
134.4, 133.6, 133.5, 133.2, 133.1, 132.3, 131.2, 130.9, 129.5,
129.1, 128.8, 128.7 128.6, 128.4, 128.2, 128.0, 127.7, 127.6,
127.1, 126.9, 126.8, 126.6, 126.5, 125.5, 125.3, 122.6, 122.5,
73.7 (t, J = 22.3 Hz), 70.7 (dd, J = 19.1 Hz, 28.2 Hz). IR ν (cm-1)
3339, 3063, 2927, 1505, 1455, 1193, 1115, 1064, 1049, 973, 800,
769, 729, 698. HRMS (ESI) calcd for C18H15F2O2S: 333.0755,
found: 333.0748.
Procedure L-1 – Use of P4t-Bu
Non-reproducible results
In a reaction tube under argon were dissolved difluoromethyl
p-tolyl sulfoxide 4a (1 equiv., 15 mg, 78.9 ꢀmol) and
benzaldehyde (1 equiv., 8.13 ꢀL, 78.9 ꢀmol) in 1 mL of the

14
Tetrahedron
ACCEPTED MANUSCRIPT
appropriate anhydrous solvent. P4t-Bu (0.8 M solution in
stirred at room temperature for 48 h. Et2O and water were added
hexane, 2 equiv., 197 µL, 158 µmol) was added dropwise to this
solution cooled to –30 °C. The reaction mixture was stirred at –
30 °C for 2 hours, then quenched with water at this temperature.
The aqueous layer was extracted three times with Et2O. The
combined organic layers were washed with a saturated solution
of NaCl, dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure.
to the reaction mixture, which was then filtered. The aqueous
phase was extracted three times with Et2O. The combined
organic layers were washed with a saturated solution of NaCl,
dried over anhydrous sodium sulfate, filtered and concentrated
under reduced pressure.
(S)-2,2-Difluoro-1-phenyl-2-(p-toluenesulfinyl)ethan-1-one
(SS)-3a-1
Procedure L-2 – Use of P4t-Bu
The crude was purified by chromatography on silica gel with
cyclohexane/AcOEt (100/0 to 50/50). Quantitative yield.
1H NMR (500 MHz, CDCl3) δ (ppm) 8.01 (dd, J = 1.1 Hz, 8.6
Hz, 2H), 7.67 (tt, J = 1.2 Hz, 7.5 Hz, 1H), 7.56-7.48 (m, 4H),
7.31 (d, J = 7.9 Hz, 2H), 2.42 (s, 3H). 19F NMR (471 MHz,
Reproducible results
Hexane was removed under vacuum from 197 ꢀL of the
commercially available solution of P4t-Bu superbase (0.8 M in
hexane, 2 equiv., 197 ꢀL, 158 ꢀmol). The solid obtained was
dissolved in 0.7 mL of freshly distilled THF (or another solvent
for tests) previously cooled to –30 °C. To a solution of
difluoromethyl p-tolyl sulfoxide 4a (1 equiv., 15 mg, 78.9 ꢀmol)
and carbonyl derivative (1 equiv., 78.9 ꢀmol) dissolved in
1.8 mL of freshly distilled THF (or another solvent for tests) at
–30 °C was added dropwise the previous solution of P4t-Bu in
THF (or another solvent for tests). The reaction mixture was
stirred at –30 °C for 2 hours, then quenched with water at this
temperature. The aqueous layer was extracted three times with
Et2O. The combined organic layers were washed with a saturated
solution of NaCl, dried over anhydrous sodium sulfate, filtered
and concentrated under reduced pressure.
CDCl3) –103.7 (AB system, JAB
=
JF-F
=
237.7 Hz,
ꢁνAB = 1223.8 Hz, 2F). 13C NMR (126 MHz, CDCl3) δ (ppm)
185.5 (t, J = 22.7 Hz), 144.1, 135.3, 132.8, 132.5, 130.7, 130.2,
129.0, 126.4, 21.8. IR (cm-1) 2924, 1694, 1597, 1493, 1450,
1274, 1142, 1090, 1067, 974, 810. HRMS (ESI) calcd for
C15H13F2O2S: 295.0598, found: 295.0584.
(S)-2,2-Difluoro-1-(4-methoxyphenyl)-2-(p-toluenesulfinyl)-
ethan-1-one (SS)-3a-16
The crude was purified by chromatography on silica gel with
1
cyclohexane/AcOEt (100/0 to 80/20). 89% yield. H NMR (500
MHz, CDCl3) δ (ppm) 8.02 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.0
Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 3.90
(s, 3H), 2.42 (s, 3H). 19F NMR (471 MHz, CDCl3) –104.9 (AB
system, JAB = JF-F = 235.8 Hz, ꢁνAB = 1385 Hz, 2F). 13C NMR
(126 MHz, CDCl3) δ (ppm) 183.3, 165.4, 143.9, 133.4, 132.9,
130.1, 126.3, 114.2, 55.8, 21.8. IR (cm-1) 2924, 1694, 1597,
1493, 1450, 1274, 1142, 1090, 1067, 974, 810. HRMS (ESI)
calcd for C15H13F2O2S: 295.0598, found: 295.0584. IR (cm-1)
1684, 1598, 1269, 1147, 603. HRMS (ESI) calcd for
C16H14F2O3SK: 363.0263, found: 363.0253.
4.10. Study with P4t-Bu
4.10.1. Evolution of the d.r. depending on the stoichiometry in
P4t-Bu
Procedure L-2 was used, varying the stoichiometry in P4t-Bu
(1 or 2 equiv.). After 5, 15, 45 and 120 minutes, 0.5 mL of the
reaction mixture were sampled and directly quenched with a
saturated solution of NH4Cl. The aqueous layer was extracted
with Et2O and 19F NMR analyses of the different crude mixtures
were carried out to determine the conversions and the
diastereomeric ratios.
Procedure N – Use of DMP as oxidizing agent
DMP (1.2 equiv., 685 mg, 0.50 mL, 1.61 mmol) was added to
a solution of …(1 equiv., 400 mg, 1.35 mmol) 21a-6 and
NaHCO3 (4 equiv., 452.1 mg, 5.38 mmol) in 8 mL of anhydrous
CH2Cl2 at 25 ºC. The mixture was stirred for 30 min. A saturated
solution of NaHCO3 was added to the reaction mixture. The
aqueous phase was extracted three times with Et2O. The
combined organic layers were washed with a saturated solution
of NaCl, dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure. The crude was purified by
chromatography on silica gel with cyclohexane/AcOEt (100/0 to
30/70). 83% yield.
4.10.2. Evolution of the d.r. and of the percentage of side-
product 22a depending on the temperature
Procedure L-2 was also used, varying the temperature (–
30 °C, 0 °C or 20 °C).
4.10.3. Synthesis of β-hydroxysulfoxide 23a
The synthesis of β-hydroxysulfoxide 23a was carried out by
using procedure L-2. Methyl p-tolyl sulfoxide was employed
instead of difluoromethyl p-tolyl sulfoxide 4a.
(S)-2,2-Difluoro-1-(3-pyridinyl)-2-(p-toluenesulfinyl)-ethan-
1-one (SS)-3a-6
4.10.4. Screening of different carbonyl derivatives
Procedure L-2 was used for the screening of different
carbonyl derivatives. This study and the analyses corresponding
to the α,α-difluoro-β-hydroxysulfoxides synthesized is available
in the corpus and electronic supporting information of our
previous paper.8
The crude was purified by chromatography on demetalled
silica gel with cyclohexane/AcOEt (100/0 to 20/80). 87% yield.
1H NMR (500 MHz, CDCl3) δ (ppm) 9.12 (dd, J = 2.3, 1.0 Hz,
1H), 8.84 (dd, J = 4.9, 1.7 Hz, 1H), 8.31 (dq, J = 9.0, 1.9 Hz,
1H), 7.55 – 7.49 (m, 2H), 7.45 (ddd, J = 8.1, 4.8, 0.9 Hz, 1H),
7.36 – 7.30 (m, 2H), 2.42 (s, 3H). 19F NMR (471 MHz, CDCl3) δ
(ppm) –104.3 (AB system, JAB = JF-F = 238.4 Hz, ꢁνAB = 1907,6
Hz, 2F).13C NMR (126 MHz, CDCl3) δ (ppm) 185.1 (t, J = 24.6
Hz), 154.9, 151.5, 144.4, 138.0, 132.3, 130.3, 129.8, 128.6,
126.1, 123.6, 21.8. IR (cm-1), 2924, 1699, 1585, 1140, 1089, 810,
700, 515. HRMS (ESI) calcd for C14H11F2O2SNNa: 318.0371,
found: 318.0360.
4.11. Diastereoselective reduction of α,α-difluoro-β-
ketosulfoxides (SS)-3a–c
4.11.1. General procedures to access to enantiopure α,α-
difluoro-β-ketosulfoxides (SS)-3a-1,6,16
Procedure M – Use of PDC as oxidizing agent
4Å molecular sieves and PDC (1.5 equiv.) were added to a
solution of 2,2-difluoro-1-aryl-2-(p-tolylsulfinyl)ethan-1-ol 21a-1
or 21a-16 in anhydrous CH2Cl2. The resulting suspension was
IR (cm-1) 1699, 1585, 1140, 1089, 810, 700, 515. HRMS
(ESI) calcd for C14H11F2O2SNNa: 318.0371, found: 318.0360.

15
4.11.2. General procedure to access to highly diastereo- and
enantioenriched α,α-difluoro-β-hydroxysulfoxides (SS,S)-21a-
1,6,16 by reduction with DIBAL-H
132.32, 130.00, 129.58, 129.25, 126.79, 126.52, 113.90, 70.39
ACCEPTED MANUSCRIPT
(dd, J = 28.9, 19.4 Hz), 55.39, 21.70. The diastereomeric ratio
and the enantiomeric excess of the product were determined by
chiral HPLC using a Chiracel IC column (n-hexane/i-PrOH =
80/20, flow rate: 0.5 mL/min, λ = 204 nm, τ = 13,0 min ; 15,5
min ; 31,7 min and 41,7 min.). IR (cm-1) 3326, 1611, 1513, 1250,
1085, 1034, 975, 789, 522. HRMS (ESI) calcd for
C16H16F2KO3S: 365.0420, found: 365.0432.
A solution of DIBAL-H (1.1 equiv., 1 M in THF,) was added
to a solution of enantioenriched (S)-2,2-difluoro-1-(het)aryl-2-(p-
toluenesulfinyl)ethan-1-one (SS)-3a (1 equiv.) in freshly distilled
THF (ca. 5 mL /mmol) under argon at –78°C. The resulting
mixture was stirred at –78°C for 15 minutes. It was then allowed
to warm to 22 ºC and stirred at this temperature for 3 hours. The
mixture was cooled to 0 ºC and diluted with Et2O. Water was
slowly added, followed by a 1M solution of NaOH. The cooling
bath was removed, and the mixture was stirred for 15 minutes at
22 ºC. The aqueous phase was extracted three times with Et2O.
The combined organic layers were washed with a saturated
solution of NaCl, dried over anhydrous sodium sulfate, filtered
and concentrated under reduced pressure.
4.12. Removal of the chiral auxiliary
4.12.1. Access to enantiopure α,α-difluoro-β-hydroxysulfone
(S)-24a-1
(S)-2,2-Difluoro-1-phenyl-2-tosylethan-1-ol (S)-24a-1
To a solution of 2,2-difluoro-1-phenyl-2-(p-tolylsulfinyl) ethan-
1-ol (SS,S)-21a-1 (1 equiv., 3.3 mg, 11.1 ꢀmol) in 0.2 mL of
anhydrous CH2Cl2 was added m-CPBA (78% of active oxygen,
1.5 equiv., 3.74 mg, 16.7 ꢀmol) at 25 °C. The solution was stirred
at this temperature for 24 hours. The reaction was quenched with
a saturated solution of Na2S2O3. The aqueous phase was extracted
three times with CH2Cl2. The combined organic phases were
washed with a saturated solution of NaHCO3 and with a saturated
solution of NaCl, dried over anhydrous sodium sulfate, filtered
and concentrated under reduced pressure. The crude product was
(S)-2,2-Difluoro-1-phenyl-2-((S)-p-tolylsulfinyl)ethan-1-ol
(SS,S)-21a-1
The crude was purified by chromatography on silica gel with
cyclohexane/AcOEt (100/0 to 50/50). 77% yield. 98:2 d.r., 96%
e.e. One diastereomer 1H NMR (500 MHz, CDCl3) δ (ppm) 7.62
(d, J = 7.9 Hz, 2H), 7.49-7.45 (m, 2H), 7.39-7.34 (m, 5H), 5.42
(ddd, J = 1.4 Hz, 5.0 Hz, 22.6 Hz, 1H), 4.67 (d, J = 5.5 Hz, 1H),
2.43 (s, 3H). 19F NMR (471 MHz, CDCl3) δ (ppm) –114.7 (ABX
system, JAB = JF-F = 225.4 Hz, JBX = JH-F = 22.5 Hz,
ꢁνAB = 2417 Hz, 2F). 13C NMR (126 MHz, CDCl3) δ (ppm)
143.6, 134.7, 132.3, 130.1, 129.2, 128.5, 128.0, 126.5, 124.4 (dd,
J = 297.5 Hz, 305.6 Hz), 70.9 (dd, J = 20.0 Hz, 28.6 Hz), 21.7.
The diastereomeric ratio and the enantiomeric excess of the
product were determined by HPLC using a Chiracel IC column
(n-hexane/i-PrOH= 80/20, flow rate 0.5 mL/min, λ = 205 nm,
τ = 9.4 min, 10.8 min, 20.0 min, 23.6 min). [α589] = +125.07
(20 °C, 0.895 g/100 mL, CHCl3). IR (cm-1) 3225, 2924, 1494,
1456, 1112, 1086, 1042, 809, 729, 698.
purified
by
chromatography
on
silica
gel
using
cyclohexane/AcOEt (100/0 to 80/20). Quantitative yield. 94%
e.e. White solid. H NMR (400 MHz, CDCl3) δ (ppm) 7.88 (d, J
= 8.3 Hz, 2H), 7.51-7.45 (m, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.40-
7.36 (m, 3H), 5.56 (dd, J = 21.3 Hz, 2.1 Hz, 1H), 3.44-3.17 (br s,
1H), 2.48 (s, 3H). 19F NMR (376 MHz, CDCl3) δ (ppm) –111.9
1
(ABX system, JAB = JF-F = 237.1 Hz, JBX = JH-F = 21.1 Hz, ꢁνAB
=
5850 Hz, 2F). 13C NMR (126 MHz, CDCl3) δ (ppm) 147.4,
133.8, 130.9, 130.3, 129.7, 129.7, 128.7, 128.3, 120.2 (dd, J =
288.8 Hz, 298.4 Hz), 71.5 (dd, J = 20.0 Hz, 26.3 Hz), 22.1. The
enantiomeric excess of the product was determined by chiral
HPLC using a Chiracel IC column (n-hexane/i-PrOH = 80/20,
flow rate: 0.5 mL/min, λ = 220 nm, τ = 17.8 min and 20.1 min).
See our previous paper.8
(S)-2,2-Difluoro-1-(3-pyridinyl)-2-((S)-p-tolylsulfinyl)ethan-
1-ol (SS,S)-21a-6
The crude was purified by chromatography on silica gel with
cyclohexane/AcOEt (100/0 to 30/70). 39% yield. 93:7 d.r., 96%
e.e. 1H NMR (500 MHz, CDCl3) δ (ppm) 8.66 (s, 2H), 7.89 (d, J
= 6.8 Hz, 1H), 7.60 (d, J = 7.7 Hz, 2H), 7.35 (d, J = 7.7 Hz, 3H),
5.51 (d, J = 22.9 Hz, 1H), 2.41 (s, 3H). 19F NMR (376 MHz,
CDCl3) δ (ppm) –114.4 (ABX system, JAB = JF-F = 225.4 Hz, JBX
= JH-F = 23.2 Hz, ꢁνAB = 2245 Hz, 2F). 13C NMR (101 MHz,
CDCl3) δ (ppm) 149.9, 148.9, 143.8, 136.2, 132.0 (d, J = 3.7 Hz),
131.5, 130.1, 126.6, 123.7, 68.4 (dd, J = 29.4, 19.6 Hz), 21.7.
The diastereomeric ratio and the enantiomeric excess of the
product were determined by chiral HPLC using a Chiracel IC
column (n-hexane/i-PrOH = 80/20, flow rate: 0.5 mL/min, λ =
207 nm, τ = 20.6 min ; 23.6 min ; 49.1 min and 59.5 min.).
IR (cm-1) 3056, 1699, 1585, 1420, 1280, 1140, 1065, 810, 700,
515. HRMS (ESI) calcd for C14H11F2NaNO2S: 318.0371, found:
318.0360.
4.12.2. Access to a highly enantioenriched α,α-difluoromethyl
alcohol by desulfonylation
(S)-2,2-Difluoro-1-phenylethan-1-ol (S)-25-1
Magnesium turnings (30 equiv., 68.26 mg, 2.59 mmol) were
previously placed under vacuum. 0.3 mL of methanol and a
minimal amount of iodine were added to the medium. The
mixture was cooled to 0 ºC. A solution of (S)-2,2-difluoro-1-
phenyl-2-tosylethan-1-ol (S)-24a-1 (1 equiv., 27 mg,
0.086 mmol) in 0.7 mL of methanol was added. The reaction
mixture was allowed to warm to 20 °C and stirred at this
temperature for 16 h. The reaction was quenched with a saturated
solution of ammonium chloride. The aqueous phase was
extracted three times with Et2O. The combined organic layers
were washed with a saturated solution of NaCl, dried over
anhydrous sodium sulfate, filtered and concentrated under
reduced pressure. The crude was purified by chromatography on
silica gel with cyclohexane/AcOEt (100/0 to 70/30). 66% yield.
95% e.e. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.46-7.35 (m, 5H),
5.77 (td, J = 4.8 Hz, 55.9 Hz, 1H), 4.84 (td, J = 4.6 Hz, 10.1 Hz,
1H), 2.43 (br s, 1H). 19F NMR (376 MHz, CDCl3) δ (ppm) –
127.2 (ABX system, JAB = JF-F = 284.1 Hz, JAX = JH-F = 55.9 Hz,
JBX = JH-F = 9.5 Hz, ꢁνAB = 278.5 Hz, 1F) and –128.0 (ABX
(S)-2,2-Difluoro-1-(4-anisyl)-2-((S)-p-tolylsulfinyl)ethan-1-ol
(SS,S)-21a-16
The crude was purified by chromatography on silica gel with
cyclohexane/AcOEt (100/0 to 50/50). 29% yield. 93:7 d.r., 98%
1
e.e. H NMR (500 MHz, CDCl3) δ (ppm) 7.60 (d, J = 7.8 Hz,
1H), 7.39 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H), 6.89 (d, J
= 8.3 Hz, 1H), 5.37 (d, J = 22.6 Hz, 1H), 3.79 (s, 2H), 2.43 (s,
2H). 19F NMR (471 MHz, CDCl3) δ (ppm) –114,0 (ABX system,
JAB = JF-F = 224.2 Hz, JBX = JH-F = 22.3 Hz, ꢁνAB = 3035.4 Hz,
2F). 13C NMR (126 MHz, CDCl3) δ (ppm) 160.30, 143.51,
system, JAB = JF-F = 284.1 Hz, JAX = JH-F = 55.9 Hz, JBX = JH-F
=
10.9 Hz, ꢁνAB = 278.8 Hz, 1F). The enantiomeric excess of the
product was determined by chiral HPLC using a Chiracel IC
column (n-hexane/i-PrOH = 95/5, flow rate: 0.5 mL/min, λ = 207

16
Tetrahedron
ACCEPTED MANUSCRIPT
1012; f) K. Müller, C. Faeh, F. Diederich, Science 2007, 317,
1881-1886; g) P. Shah, A. D. Westwell, J. Enzyme Inhib. Med.
nm, τ = 10.7 min and 11.7 min). These data are consistent
with those already reported in the literature.5a
Chem. 2007, 22, 527-540; h) K. L. Kirk, Org. Proc. Res. Dev.
2008, 12, 305-321; i) S. Purser, P. R. Moore, S. Swallow, V.
Gouverneur, Chem. Soc. Rev. 2008, 37, 320-330; j) D. O’Hagan,
J. Fluorine Chem. 2010, 131, 1071-1081; k) T. Liang, C. N.
Neumann, T. Ritter, Angew. Chem. Int. Ed. 2013, 52, 8214-8264;
l) J. Wang, M. Sánchez-Roselló, J. L. Aceña, C. del Pozo, A. E.
Sorochinsky, S. Fustero, V. A. Soloshonok, H. Liu, Chem. Rev.
2014, 114, 2432-2506; m) C. D. Murphy, G. Sandford, Expert
Opinion on Drug Metabolism & Toxicology 2015, 11, 589-599; n)
H. Groult, F, Leroux, A. Tressaud, Modern Synthesis Processes
and Reactivity of Fluorinated Compounds: Progress in Fluorine
Science, Elsevier Science, 2016; o) Y. Zhou, J. Wang, Z. Gu, S.
Wang, W. Zhu, J. L. Aceña, V. A. Soloshonok, K. Izawa, H. Liu,
Chem. Rev. 2016, 116, 422-518; p) G. Haufe, F. Leroux, in
Fluorine in Life Sciences: Pharmaceuticals, Medicinal
Diagnostics, and Agrochemicals, Elsevier, 2018.
a) J. A. Erickson, J. I. McLoughlin, J. Org. Chem. 1995, 60,
1626-1631; b) N. A. Meanwell, J. Med. Chem. 2011, 54, 2529-
2591; c) Q. A. Huchet, B. Kuhn, B. Wagner, H. Fischer, M.
Kansy, D. Zimmerli, E. M. Carreira, K. Müller, J. Fluorine Chem.
2013, 152, 119-128; d) K. Müller, Chimia 2014, 68, 356-362; e)
M. D. Martínez, L. Luna, A. Y. Tesio, G. E. Feresin, F. J. Durán,
G. Burton, J. Pharm. Pharmacol. 2016, 68, 233-244; f) C. D.
Sessler, M. Rahm, S. Becker, J. M. Goldberg, F. Wang, S. J.
Lippard, J. Am. Chem. Soc. 2017, 139, 9325-9332; g) Y. Zafrani,
D. Yeffet, G. Sod-Moriah, A. Berliner, D. Amir, D. Marciano, E.
Gershonov, S. Saphier, J. Med. Chem. 2017, 60, 797-804.
4.12.3. Access to highly enantioenriched α,α-difluoromethyl
alcohols by desulfinylation with Mg(0) or PMHS/t-BuOK
(S)-2,2-Difluoro-1-phenylethan-1-ol (S)-25-1 by PMHS/t-
BuOK-mediated desulfinylation
To a stirred solution of 2,2-difluoro-1-phenyl-2-(p-tolyl
sulfinyl)ethan-1-ol
(SS,S)-21a-1
(1
equiv.,
50
mg,
169 µmol) and t-BuOK (3 equiv., 56.8 mg, 506 µmol) in freshly
distilled THF was added dropwise PMHS (3 equiv., 137 µL,
506 µmol). The mixture was stirred at 20 °C for 48 h in a sealed
tube, then quenched with a solution of KOH in a H2O/methanol
(1:1, V/V) mixture and left under stirring for 2 h. The aqueous
phase was extracted three times with Et2O. The combined
organic phases were washed with a saturated solution of NaHCO3
and with a saturated solution of NaCl, dried over anhydrous
sodium sulfate, filtered over Celite® and activated charcoal and
concentrated under reduced pressure. The crude was purified by
chromatography on silica gel with cyclohexane/AcOEt (100/0 to
70/30). 52% yield. 88% e.e.
2.
(S)-2,2-Difluoro-1-(4-anisyl)-ethan-1-ol (S)-25-16 by Mg(0)-
mediated desulfinylation
3. a) C. Ni, J. Hu, Synthesis 2014, 46, 842-863; b) L. Yang, L. Chao,
C. Qing-Yun, Curr. Org. Chem. 2015, 19, 1638-1650; c) Y. D. E.,
B. V. Sebastian, P. Al, Chem. Eur. J. 2017, 23, 14676-14701; d) J.
Rong, C. Ni, J. Hu, Asian J. Org. Chem. 2017, 6, 139-152.
4. a) N. Shibata, S. Mizuta, H. Kawai, Tetrahedron: Asymmetry
2008, 19, 2633-2644; b) X. Yang, T. Wu, R. J. Phipps, F. D.
Toste, Chem. Rev. 2015, 115, 826-870.
5. a) P. V. Ramachandran, A. V. Teodorovic, B. Gong, H. C. Brown,
Tetrahedron: Asymmetry 1994, 5, 1075-1086; b) K. Nakamura, R.
Yamanaka, Tetrahedron: Asymmetry 2002, 13, 2529-2533; c) S.
Goushi, K. Funabiki, M. Ohta, K. Hatano, M. Matsui, Tetrahedron
2007, 63, 4061-4066; d) W. Borzęcka, I. Lavandera, V. Gotor, J.
Org. Chem. 2013, 78, 7312-7317; e) K. Kato, H. Nakamura, K.
Nakanishi, Appl. Surf. Sci. 2014, 293, 312-317.
The same procedure as for the desulfonylation of (S)-24a-1
was used on (SS,S)-21a-16. The crude product was purified by
chromatography on silica gel using with cyclohexane/AcOEt
1
(100/0 to 60/40) as eluent. 64% yield. 86% e.e. H NMR (500
MHz, CDCl3) δ (ppm) 7.34 (d, J= 8.7 Hz, 2H), 6.93 (d, J= 8.7
Hz, 2H), 5.74 (td, J = 5.1 Hz, 56.3 Hz, 1H), 4.77 (td, J = 4.7 Hz,
10.3 Hz, 1H), 3.81 (s, 3H). 19F NMR (376 MHz, CDCl3) δ (ppm)
–127.5 (app. dd, J = 56.2, J = 9.5 Hz, 2F). 13C NMR (126 MHz,
CDCl3) δ (ppm) 160.3, 131.8, 130.0, 129.7, 129.6, 128.6, 117.9,
116.0, 114.3, 114.0, 113.9, 73.4 (d, J =26 Hz), 55.5, 29.8.
IR (cm-1) 3414, 2924, 1515, 1250, 1068, 832, 552. HRMS (ESI)
calcd for C9H9F2O2: 187.0576, found: 187.0591. [α589] = +13.40
(20 °C, 0.7 g/100 mL, CHCl3). The enantiomeric excess of the
product was determined by chiral HPLC using a Chiracel IC
column (n-hexane/i-PrOH = 98/2, flow rate: 0.5 mL/min, λ = 224
nm, τ = 27.2 min and 30.7 min).
6. K. Aikawa, S. Yoshida, D. Kondo, Y. Asai, K. Mikami, Org. Lett.
2015, 17, 5108-5111.
7. C. Ni, F. Wang, J. Hu, Beilstein J. Org. Chem. 2008, 4, 21.
8. C. Batisse, A. Panossian, G. Hanquet, F. R. Leroux, Chem.
Commun. 2018, 54, 10423-10426.
9. a) G. Solladié, Synthesis 1981, 185-196; b) P. Pitchen, C. J.
France, I. M. McFarlane, C. G. Newton, D. M. Thompson,
Tetrahedron Lett. 1994, 35, 485-488; c) M. C. Carreno, Chem.
Rev. 1995, 95, 1717-1760; d) J. Legros, J. R. Dehli, C. Bolm, Adv.
Synth. Catal. 2005, 347, 19-31; e) H. Pellissier, Tetrahedron 2006,
62, 5559-5601; f) J. Drabowicz, P. Kiełbasiński, D. Krasowska,
M. Mikołajczyk, in Organosulfur Chemistry in Asymmetric
Synthesis, Vol. 40 (Eds.: T. Toru, C. Bolm), Wiley VCH Verlag
GmbH & Co., 2008, 31-54; g) J. L. García Ruano, J. Alemán, M.
B. Cid, M. Á. Fernández Ibáñez, M. C. Maestro, M. R. Martín,
A. M. Martín Castro, in Organosulfur Chemistry in Asymmetric
Synthesis, Vol. 40 (Eds.: T. Toru, C. Bolm), Wiley VCH Verlag
GmbH & Co., 2008, 55-159; h) M. C. Carreno, G. Hernandez-
Torres, M. Ribagorda, A. Urbano, Chem. Commun. 2009, 6129-
6144; i) J. Han, V. A. Soloshonok, K. D. Klika, J. Drabowicz, A.
Wzorek, Chem. Soc. Rev. 2018, 47, 1307-1350.
10. a) G. Cilento, Chem. Rev. 1960, 60, 147-167; b) C. C. Price, S.
Oae, Sulfur Bonding, Ronald Press Co., New York, 1962; c) S.
Oae, W. Tagaki, A. Ohno, Tetrahedron 1964, 20, 417-425; d) D.
J. Cram, in Fundamentals of Carbanion Chemistry, Academic
Press, New York, 1965, 47-84; e) D. L. Coffen, Rec. Chem. Prog.
1969, 30, 275-288; f) D. J. Peterson, Organometal. Chem. Rev.
Sect. A 1972, 7, 295.
Acknowledgments
We thank the Centre National de la Recherche Scientifique
(CNRS) and the Université de Strasbourg and are very much
grateful to the International Centre for Frontier Research in
Chemistry (IcFRC) for a project grant to C.B. We thank Sanofi-
Aventis for a PhD grant to MFCD. The French Fluorine Network
(GIS Fluor) is also acknowledged. We thank the analytical
platform and the Mass spectroscopy service of the Chemistry
Institute of Strasbourg for both microanalysis and H.R.M.S
results. We also thank the Crystallography service at the
Université de Strasbourg (UMR 7177, C. Bailly and L.
Karmazin-Brelot) for their precious help.
Appendix A. Supplementary data
Experimental details are provided in the Supporting
Information.
11. a) F. Bernardi, I. G. Csizmadia, A. Mangini, H. B. Schlegel, M.-H.
Whangbo, S. Wolfe, J. Am. Chem. Soc. 1975, 97, 2209-2218; b)
N. D. Epiotis, R. L. Yates, F. Bernardi, S. Wolfe, J. Am. Chem.
Soc. 1976, 98, 5435-5439; c) J. M. Lehn, G. Wipff, J. Am. Chem.
Soc. 1976, 98, 7498-7505; d) P. V. R. Schleyer, T. Clark, A. J.
Kos, G. W. Spitznagel, C. Rohde, D. Arad, K. N. Houk, N. G.
Rondan, J. Am. Chem. Soc. 1984, 106, 6467-6475; e) F. Bernardi,
References
1. a) I. Ojima, Bioorganic and Medicinal Chemistry of Fluorine,
Wiley, 2008; b) B. E. Smart, J. Fluorine Chem. 2001, 109, 3-11;
c) H.-J. Böhm, D. Banner, S. Bendels, M. Kansy, B. Kuhn, K.
Müller, U. Obst-Sander, M. Stahl, ChemBioChem 2004, 5, 637-
643; d) P. Maienfisch, R. G. Hall, Chimia 2004, 58, 93-99; e) J.-P.
Bégué, D. Bonnet-Delpon, J. Fluorine Chem. 2006, 127, 992-

17
A. Mangini, G. Tonachini, P. Vivarelli, J. Chem. Soc., Perkin
Trans. 2 1985, 111-114.
W. Han, P. J. Carroll, J. Am. Chem. Soc. 1992, 114, 1428-
ACCEPTED MANUSCRIPT
1437; h) P. C. Bulman Page, J. P. Heer, D. Bethell, E. W.
Collington, D. M. Andrews, Tetrahedron: Asymmetry 1995, 6,
2911-2914.
12. a) A. C. Hopkinson, M. H. Lien, J. Org. Chem. 1981, 46, 998-
1003; b) K. B. Wiberg, H. Castejon, J. Am. Chem. Soc. 1994, 116,
10489-10497; c) G. Cuevas, E. Juaristi, J. Am. Chem. Soc. 1997,
119, 7545-7549; d) G. Ludwig, T. Rüffer, A. Hoppe, T. Walther,
H. Lang, S. G. Ebbinghaus, D. Steinborn, Dalton Trans. 2015, 44,
5323-5330.
13. a) C. Ni, Y. Li, J. Hu, J. Org. Chem. 2006, 71, 6829-6833; b) C.
Ni, J. Liu, L. Zhang, J. Hu, Angew. Chem., Int. Ed. 2007, 46, 786-
789; c) W. Zhang, C. Ni, J. Hu, in Fluorous Chemistry, Vol. 308
(Ed.: I. Horváth), Topics in Current Chemistry, 2011.
24. A.
P.
Krapcho,
E.
Ciganek,
in
The
Krapcho
Dealkoxycarbonylation Reaction of Esters with α-Electron-
Withdrawing Substituents, Organic Reactions, 2013.
25. a) S. Reformatsky, Chem. Ber. 1887, 20, 1210-1211; b) R. L.
Shriner, in Organic Reactions, Vol. 1, John Wiley & Sons, 1942,
1-37; c) M. W. Rathke, in Organic Reactions, Vol. 22, John Wiley
&
Sons, 1975, 423-460; d) R. Ocampo, W. R. Dolbier,
Tetrahedron 2004, 60, 9325-9374.
14. a) G. P. Stahly, J. Fluorine Chem. 1989, 43, 53-66; b) G. K. S.
Prakash, J. Hu, T. Mathew, G. A. Olah, Angew. Chem., Int. Ed.
2003, 42, 5216-5219; c) G. K. S. Prakash, J. Hu, Y. Wang, G. A.
Olah, Angew. Chem., Int. Ed. 2004, 43, 5203-5206; d) G. K. S.
Prakash, J. Hu, Y. Wang, G. A. Olah, Org. Lett. 2004, 6, 4315-
4317; e) Y. Li, J. Hu, Angew. Chem., Int. Ed. 2005, 44, 5882-
5886; f) G. K. Surya Prakash, J. Hu, Y. Wang, G. A. Olah, Eur. J.
Org. Chem. 2005, 2005, 2218-2223; g) J. Liu, C. Ni, F. Wang, J.
Hu, Tetrahedron Lett. 2008, 49, 1605-1608; h) C. Ni, L. Zhang, J.
Hu, J. Org. Chem. 2008, 73, 5699-5713.
26. K. Kanai, H. Wakabayashi, T. Honda, Org. Lett. 2000, 2, 2549-
2551.
27. T. Poisson, M.-C. Belhomme, X. Pannecoucke, J. Org. Chem.
2012, 77, 9277-9285.
28. D. A. Evans, M. M. Faul, L. Colombo, J. J. Bisaha, J. Clardy, D.
Cherry, J. Am. Chem. Soc. 1992, 114, 5977-5985.
29. a) M. Braun, W. Hild, Chem. Ber. 1984, 117, 413-414; b) G.
Demailly, C. Greck, G. Solladie, Tetrahedron Lett. 1984, 25,
4113-4116.
30. a) H. Sakuraba, S. Ushiki, Tetrahedron Lett. 1990, 31, 5349-5352;
b) O. De Lucchi, D. Fabri, Synlett 1990, 1990, 287-289.
31. C. L. Liotta, J. Berkner, in Encyclopedia of Reagents for Organic
Synthesis, 2001.
32. a) C. L. Liotta, E. E. Grisdale, H. P. Hopkins, Tetrahedron Lett.
1975, 16, 4205-4208; b) G. W. Gokel, H. D. Durst, Synthesis
1976, 1976, 168-184; c) C. L. Liotta, in Synthetic Multidentate
Macrocyclic Compounds (Eds.: R. M. Izatt, J. J. Christensen),
Academic Press, 1978, 111-205; d) E. V. Dehmlow, in Phase
Transfer Catalysis, 2nd ed., Verlag Chemie: Deerfield Beach, FL,
1983; e) L. Yu, I. Yoshihisa, H. Tadao, Bull. Chem. Soc. Jpn.
1990, 63, 3044-3046; f) C. M. Starks, C. L. Liotta, M. Halpern, in
Phase Transfer Catalysis, Springer Science Business Media
Dordrecht, 1994; g) J. W. Steed, J. L. Atwood, in Supramolecular
Chemistry (Ed.: J. W. S. a. J. L. Atwood), 2009.
33. a) Y. Zhang, M. Fujiu, H. Serizawa, K. Mikami, J. Fluorine
Chem. 2013, 156, 367-371; b) H. Kawai, Z. Yuan, E. Tokunaga,
N. Shibata, Org. Biomol. Chem. 2013, 11, 1446-1450; c) S.
Okusu, K. Hirano, E. Tokunaga, N. Shibata, ChemistryOpen 2015,
4, 581-585; d) N. Punna, T. Saito, M. Kosobokov, E. Tokunaga,
Y. Sumii, N. Shibata, Chem. Commun. 2018, 54, 4294-4297.
34. T. Punirun, D. Soorukram, C. Kuhakarn, V. Reutrakul, M.
Pohmakotr, Eur. J. Org. Chem. 2014, 2014, 4162-4169.
35. R. Schwesinger, Y. Kondo, in e-EROS Encyclopedia of Reagents
for Organic Synthesis, 2010.
36. a) C. Ni, J. Hu, Tetrahedron Lett. 2005, 46, 8273-8277; b) W. H.
Midura, A. Rzewnicka, J. A. Krysiak, Beilstein J. Org. Chem.
2017, 13, 1513-1517; c) K. Revunova, G. I. Nikonov, Chem. Eur.
J. 2014, 20, 839-845.
37. J. S. Hubbard, T. M. Harris, J. Org. Chem. 1981, 46, 2566-2570.
38. M. Schlosser, in Organometallics in Synthesis: A Manual, 2nd
Edition (Ed.: M. Schlosser), John Wiley & Sons, 2002, 295.
39. V. Hugenberg, G. Haufe, J. Fluorine Chem. 2010, 131, 942-950.
40. A. Konno, T. Fuchigami, J. Org. Chem. 1997, 62, 8579-8581.
41. J.-B. Han, H.-L. Qin, S.-H. Ye, L. Zhu, C.-P. Zhang, J. Org.
Chem. 2016, 81, 2506-2512.
15. L. Zhu, Y. Li, C. Ni, J. Hu, P. Beier, Y. Wang, G. K. S. Prakash,
G. A. Olah, J. Fluorine Chem. 2007, 128, 1241-1247.
16. a) R. Annunziata, M. Cinquini, F. Cozzi, J. Chem. Soc., Perkin
Trans. 1 1979, 1687-1690; b) G. Solladié, C. Greck, G. Demailly,
A. Solladié-Cavallo, Tetrahedron Lett. 1982, 23, 5047-5050; c) G.
Solladie, G. Demailly, C. Greck, J. Org. Chem. 1985, 50, 1552-
1554; d) G. Solladié, G. Demailly, C. Greck, Tetrahedron Lett.
1985, 26, 435-438; e) G. Solladie, C. Frechou, G. Demailly, C.
Greck, J. Org. Chem. 1986, 51, 1912-1914; f) M. C. Carreno, J. L.
Garcia Ruano, A. M. Martin, C. Pedregal, J. H. Rodriguez, A.
Rubio, J. Sanchez, G. Solladie, J. Org. Chem. 1990, 55, 2120-
2128; g) A. Solladié-Cavallo, J. Suffert, A. Adib, G. Solladié,
Tetrahedron Lett. 1990, 31, 6649-6652. h) Interestingly, whereas
the DIBAL-H reduction of non-fluorinated β-ketoxulfoxides leads
to a reversal of diastereoselectivity if carried out in the presence of
ZnCl2 as shown by Solladié et al., in our case, the adjunction of
ZnCl2 gave exactly the same major diastereomer (anti) of 21a-1 as
in the absence of ZnCl2, with 78% yield and 96:4 d.r.
17. a) W. A. Bonner, J. Am. Chem. Soc. 1952, 74, 5089-5090; b) H.
Hauptmann, W. F. Walter, Chem. Rev. 1962, 62, 347-404; c) W.
E. Truce, F. M. Perry, J. Org. Chem. 1965, 30, 1316-1317; d) G.
H. Posner, D. J. Brunelle, Tetrahedron Lett. 1973, 14, 935-938; e)
B. M. Trost, H. C. Arndt, P. E. Strege, T. R. Verhoeven,
Tetrahedron Lett. 1976, 17, 3477-3478; f) K. Nishide, Y. Shigeta,
K. Obata, T. Inoue, M. Node, Tetrahedron Lett. 1996, 37, 2271-
2274; g) M. Node, K. Nishide, Y. Shigeta, K. Obata, H. Shiraki,
H. Kunishige, Tetrahedron 1997, 53, 12883-12894; h) D. A.
Alonso, C. N. Ájera, in Organic Reactions, John Wiley & Sons,
Inc., 2004.
18. A. Arnone, P. Bravo, M. Frigerio, G. Salani, F. Viani, M. Zanda,
C. Zappalà, J. Fluorine Chem. 1997, 84, 79-82.
19. a) A. V. Matsnev, N. V. Kondratenko, Y. L. Yagupolskii, L. M.
Yagupolskii, Tetrahedron Lett. 2002, 43, 2949-2952; b) L. M.
Yagupolskii, A. V. Matsnev, Mendeleev Commun. 2006, 16, 132-
134.
42. B. Xing, C. Ni, J. Hu, Chin. J. Chem. 2018, 36, 206-212.
20. a) P. Pitchen, H. B. Kagan, Tetrahedron Lett. 1984, 25, 1049-
1052; b) P. Pitchen, E. Dunach, M. N. Deshmukh, H. B. Kagan, J.
Am. Chem. Soc. 1984, 106, 8188-8193.
21. a) C. Bolm, F. Bienewald, Angew. Chem., Int. Ed. 1995, 34, 2640-
2642; b) J. Legros, C. Bolm, Angew. Chem., Int. Ed. 2003, 42,
5487-5489; c) J. Legros, C. Bolm, Angew. Chem., Int. Ed. 2004,
43, 4225-4228; d) J. Legros, C. Bolm, Chem. Eur. J. 2005, 11,
1086-1092.
22. a) K. Nakajima, M. Kojima, J. Fujita, Chem. Lett. 1986, 15, 1483-
1486; b) H. Egami, T. Katsuki, J. Am. Chem. Soc. 2007, 129,
8940-8941; c) K. P. Bryliakov, E. P. Talsi, Chem. Eur. J. 2007,
13, 8045-8050;
23. a) F. A. Davis, R. Jenkins, S. Q. A. Rizvi, T. W. Panunto, J.
Chem. Soc., Chem. Commun. 1979, 0, 600-601; b) F. A. Davis, R.
H. Jenkins, S. B. Awad, O. D. Stringer, W. H. Watson, J. Galloy,
J. Am. Chem. Soc. 1982, 104, 5412-5418; c) F. A. Davis, J. M.
Billmers, J. Org. Chem. 1983, 48, 2672-2675; d) F. A. Davis, J. P.
McCauley, M. E. Harakal, J. Org. Chem. 1984, 49, 1465-1467; e)
F. A. Davis, J. P. McCauley, S. Chattopadhyay, M. E. Harakal, J.
C. Towson, W. H. Watson, I. Tavanaiepour, J. Am. Chem. Soc.
1987, 109, 3370-3377; f) F. A. Davis, A. C. Sheppard,
Tetrahedron 1989, 45, 5703-5742; g) F. A. Davis, R. T. Reddy,