Stereocontrolled fluorobenzylation of vinyl sulfones and α,β-unsaturated esters mediated by a remote sulfinyl group. Synthesis of functionalized enantiomerically pure benzylic fluorides

Article abstract of DOI:10.1021/jo300174k

A sulfinyl group in an ortho position confers enough chemical and configurational stability to monofluorobenzylcarbanions to evolve in a completely stereoselective way in their reactions with β-substituted vinyl sulfones and α,β-unsaturated esters. Reactions afford easily separable mixtures of two epimers differing in the configuration of the center derived from the Michael acceptor (up to 98% de). They can be easily converted into enantiomerically pure γ-fluorinated γ-phenylsulfones and γ-phenylesters bearing two chiral centers.

Full text of DOI:10.1021/jo300174k

Article
pubs.acs.org/joc
Stereocontrolled Fluorobenzylation of Vinyl Sulfones and
α,β-Unsaturated Esters Mediated by a Remote Sulfinyl Group.
Synthesis of Functionalized Enantiomerically Pure Benzylic Fluorides
Jose Luis García Ruano,* Jose Antonio Fernandez-Salas, and M. Carmen Maestro*
́
́
́
Departamento de Química Organ
́
ica, Universidad Auton
́
oma de Madrid, Cantoblanco, 28049 Madrid, Spain
S
* Supporting Information
ABSTRACT: A sulfinyl group in an ortho position confers
enough chemical and configurational stability to monofluor-
obenzylcarbanions to evolve in a completely stereoselective
way in their reactions with β-substituted vinyl sulfones and
α,β-unsaturated esters. Reactions afford easily separable
mixtures of two epimers differing in the configuration of the
center derived from the Michael acceptor (up to 98% de). They can be easily converted into enantiomerically pure γ-fluorinated
γ-phenylsulfones and γ-phenylesters bearing two chiral centers.
We have recently described that an ortho-sulfinyl group at (S)-
115 is able to provide enough chemical and configurational stability
to the fluorinated benzylcarbanion obtained with LDA to react
with homochiral N-sulfinylimines in an almost complete stereo-
selective manner, thus providing the first monofluorobenzyla-
tion reagent for the creation of chiral monofluorinated carbons.
These reactions are a typical example of double asymmetric
synthesis,16 and the use of reagents with the same configuration at
the sulfur atom (matched pair) allowed the synthesis of enantiopure
anti-β-fluorinated β-phenylethylamines (Scheme 1).
INTRODUCTION
■
A fluorine atom, because of its high electronegativity and small
size, is capable of conferring exceptional chemical and biological
properties to the organic molecules to which it is bonded.1 As a
consequence, even though fluorinated compounds occur rarely
in nature, the presence of fluorine atoms in biologically active
molecules2 confers them important roles in pharmaceutical3
and agrochemical research.4 Moreover, fluorine-containing
compounds have been employed as liquid crystals, dyes,
surfactants, plastics, elastomers, membranes, and many other
materials5 and as tracers for positron emission tomography.6 All
of these applications have required the development of
synthetic methodologies able to introduce fluorinated moieties,
many times in an asymmetric manner.7
Scheme 1. Synthesis of Substituted 1,2-Fluoroethylamines by
Reaction of [Li]-(S)-1 with Homochiral N-Sulfinylimines
Whereas the chemistry of trifluoro- and difluoroalkyl
derivatives has been studied in some detail,7a,8 the synthesis
and reactivity of the corresponding monofluoroalkyl derivatives
are only recently emerging and still remain a challenging task
nowadays. Two main strategies have been developed for
preparing monofluoroalkyl derivatives. The first one, involving
the creation of the C−F bonds from C−H or C−Y bonds by
using electrophilic fluorination reagents,7d,9 has some disadvan-
tages associated with the use of complex and potentially toxic
reagents. The second strategy, based on the use of mono-
fluorinated carbanions as nucleophiles, has emerged as the
preferred one in past years, especially from the contributions of
Prakash and Olah,10 Hu,11 and Shibata and Toru.12 However,
the low thermal stability of fluorinated carbanions determines
that these strategies need to incorporate electron-withdrawing
groups (usually a sulfonyl functionality) to the carbanionic
center,10−12 the elimination of which usually produces
monofluoromethyl derivatives.13 As this strategy precludes the
preparation of compounds with the fluorine atom directly bonded
to stereogenic carbons,14 the synthesis of stereogenic mono-
fluorinated benzyl carbons remained a subject for improvement in
fluorocompound chemistry.
With this precedent, and taking into account the difficulties
associated with the preparation of homochiral fluorobenzylic
centers,17 we decided to check the synthetic potential of the new
chiral monofluorinated reagent in reactions with achiral electro-
philes. Michael additions of [Li]-(S)-1 (Scheme 2) to activated
alkenes such as α-substituted vinyl sulfones or α,β-unsaturated
esters were chosen for this study because they would provide
information about the ability of the stabilized monofluorocarban-
ion to simultaneously control the configuration of the benzylic
carbon as well as that of the second chiral center created in the
reaction.18 Moreover, these reactions would expand the range of
the monofluorinated compounds with the halogen atom bonded
to a homochiral carbon, and in the case of reactions with
Received: January 23, 2012
Published: February 21, 2012
© 2012 American Chemical Society
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in THF solution with lithium diisopropylamide (LDA) at −78 °C
produced a instantaneous color change to deep red (suggesting
the formation of [Li]-(S)-1), which quickly vanished and changed
to green-blue upon addition of (E)-styryl phenylsulfone (2a)
(4 equiv), affording an easily separable 92:8 mixture of diastereo-
isomers 3a and 3′a, from which the major adduct 3a was obtained
in 86% isolated yield (Table 1, entry 1). Other β-arylvinyl
sulfones bearing 2-naphthyl (2b, entry 2, Table 1) or phenyl rings
with electron-donating groups at the para position (2c,d, entries
3 and 4, Table 1) afforded similar results. Contrarily, the sulfones
with electron-withdrawing groups on the benzene ring in β-position
provided less homogeneous results. Thus, the presence of a fluorine
atom (2e) has no significant influence neither in the diastereo-
selectivity nor in the yield (Table 1, entry 5); however, a chlorine
atom (2f) or a cyano group (2h) determined important erosion
in the yield, though the same high stereoselectivity remained
(Table 1, entries 6 and 8). The change of behavior was more
dramatic with bromo- (2g) and trifluoromethyl (2i) substituents
because these reactions afforded complex mixtures where the
expected adducts were not easily detected (Table 1, entries 7
and 9). These results suggest that the electronic factors play a
significant role on the reactivity but are much less important on
the stereoselectivity, which remains similarly high in all cases.
To broaden the scope of these reactions, we treated the
fluorinated benzylcarbanion with other vinyl sulfones (2j−m).
The dienylsulfone (2j) evolved in a stereoselective manner
even higher than the studied arylvinyl sulfones, giving a 94:6
diastereoisomeric ratio of adducts 3j/3′j (Table 1, entry 10).
The poorest results were obtained with alkyl-substituted vinyl
sulfones. Thus, the stereoselectivity falls to a ca. 4:1 ratio for
n-alkyl-substituted (2k and 2l, Table 1, entries 11 and 12),
whereas the reaction does not take place with secondary alkyl-
substituted (2m) (Table 1, entry 13), probably due to its higher
steric hindrance.23
Scheme 2. Synthesis of Homochiral Benzylic Fluorinated
Centers by Reaction of (S)-1 with Sulfonyl and
Alkoxycarbonyl Ethylenes
β-substituted acrylates, the ratio of 1,2- and 1,4-addition pro-
ducts would give some information about the hard/soft
character of [Li]-(S)-1.19
In this paper, we describe that the ortho-sulfinyl group is able to
get complete control of the configuration at the benzylic carbon,
providing an efficient method of chiral monofluorobenzylation,20
which makes possible the generation of enantiomerically pure
benzylic fluorides by reaction of [Li]-(S)-1 with β-substituted
alkoxycarbonyl and sulfonyl ethylenes. The control exerted by the
sulfinyl group in the configuration of the second chiral center
created in these reactions is also very high, and it allows the prep-
aration of enantiomerically pure γ-phenyl-γ-fluorinated β-substituted
sulfones and esters containing two vicinal chiral centers, which had
never been reported previously21 (Scheme 2).
RESULTS AND DISCUSSION
■
(S)-2-p-Tolylsulfinylbenzyl fluoride (S)-1 was successfully
prepared in excellent yield (88%) by nucleophilic substitution
with CsF from the corresponding OTs derivative in dry
acetonitrile and using [mim-tOH][OMs] as ionic liquid. The
process is easily scalable to obtain up to 4 g of fluorinated
compound (S)-1.22 Initially, we tested its reaction with
β-substituted vinyl sulfones (Table 1). The treatment of (S)-1
Removal of the chiral auxiliary from the major fluorinated
sulfone adducts is interesting because it would provide com-
pounds with two vicinal stereocenters. It can be easily
performed by treatment with 3.3 equiv of tert-butyllithium in
THF at −78 °C, as it was illustrated starting from 3a (aryl
substituted, R1 = Ph) and 3k + 3′k (alkyl-substituted, R1 =
CH2CH2Ph), affording their respective desulfinylated products
in 70 and 75% yields (Scheme 3). Better yields were obtained
Table 1. Reactions of [Li]-(S)-1 with β-Substituted α,β-
Unsaturated Phenylsulfones 2
a
b
c
Scheme 3. Desulfinylation with t-BuLi or Raney-Ni
entry
sulfone
R1
dr 3:3′
yield (%)
d
1
2a
2b
2c
2d
2e
2f
C6H5
92:8
92:8
92:8
92:8
92:8
92:8
f
86
86
89
80
81
2
2-naphthyl
p-MeOC6H4
p-MeC6H4
p-FC6H4
3
4
5
e
6
p-ClC6H4
45
7
2g
2h
2i
p-BrC6H4
8
p-CNC6H4
p-CF3C6H4
(E)-C6H5CHCH
C6H5CH2CH2
n-Pr
92:8
f
41
70
9
10
11
12
13
2j
94:6
80:20
76:24
h
g
2k
2l
70
68
2m
i-Pr
a
b
1
0.2 mmol of (S)-1 has been used. Determined by H NMR of the
c
crude mixture. Isolated yield of the major adduct after flash
chromatography. The reaction was also carried out with 1 mmol of
using Raney-Ni as desulfinylation reagent24 (84% from 3a and
83% from 3k + 3′k). None of these procedures produces
epimerization of the chiral centers present in the sulfinylated
starting products, and therefore, starting from the unseparable
d
e
(S)-1. Major adduct could not be isolated as pure compound.
f
g
Complex mixture. Isolated yield of both adducts after flash
h
chromatography. Starting material was recovered.
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4:1 mixture of 3k and 3′k (Table 1, entry 11), a new 4:1
mixture of epimers, 4k and 4′k, was obtained, which could be
separated by chromatography affording major 4k in 65% yield.
This is an interesting result to establish the relative
configuration of the minor diastereoisomers obtained in
Table 1 as we will see later.
Table 2. Reactions of [Li]-(S)-1 with β-Substituted α,
β-Unsaturated tert-Butyl Esters
The presence of the sulfone group in substrates 4 confers
them an interesting reactivity that can be used for introducing
different substituents before its removal (Scheme 4). This is an
a
b
c
entry
ester
R1
products (ratio)
yield (%)
d
d
1
2
8a
C6H5
C6H5
9a/9′a (82:18)
20
Scheme 4. Transformations of 4a
11a
11b
11c
11d
11e
11f
11g
11h
11i
12a/12′a (92:8)
12b/12′b (92:8)
12c/12′c (92:8)
12d/12′d (92:8)
12e/12′e (92:8)
12f/12′f (92:8)
12g/12′g (92:8)
g
82
e
3
p-MeOC6H4
p-MeC6H4
p-FC6H4
84
e
4
85
e
5
89
6
p-ClC6H4
p-BrC6H4
p-CNC6H4
p-CF3C6H4
(E)-C6H5CHCH
n-Pr
55
38
7
f
8
30
9
10
11
12
13
14
12i/12′i (>98:<2)
12j/12′j (>98:<2)
12k/12′k (>98:<2)
no reaction
76
77
79
11j
11k
11l
C6H5CH2CH2
Bn
important task due to the difficulties inherent to the
preparation of fluorinated compounds with two connected
stereogenic centers in an enantiomerically pure form. Sulfone
removal can be performed from 4a with Mg/MeOH,25 yielding
5a in 63% yield (Scheme 4). The methylation of 4a (n-BuLi
and then MeI) followed by the in situ desulfonylation, yielding
compound 6a (53%), illustrates the way to perform alkylation
reactions. In turn, the alkoxycarbonylation is also possible using
a similar one-pot sequence with ClCO2Me26 as the electrophile
(7a, Scheme 4).
11m
iPr
no reaction
a
b
1
0.2 mmol of (S)-1 has been used. Determined by H NMR of the
c
crude mixture. Isolated yields of the major isomer after flash
d
chromatography. 10a was obtained as major compound (see text).
e
f
Combined yield. Major adduct could not be isolated as pure
g
compound. Complex mixture.
tert-butyl ester 11a as electrophilic partner, which allows the
complete regiocontrol, only yielding the Michael products 12a
and 12′a, and a substantial increase of the stereoselectivity
(92:8) (Table 2, compare entries 1 and 2).
Configuration indicated in Table 1 for the major diastereo-
isomers (3) was established from the unequivocal assignment
of 3e performed by X-ray studies27 (see Supporting
Information), whereas that of the minor ones (3′) was deduced
from indirect proofs. Two explanations can account for the
exclusive formation of two diastereoisomers (out of the four
possible ones) in the reactions of Table 1. The first one would
involve the sulfinyl group completely controlling the config-
uration at the benzylic fluorinated carbon. Then, 3 and 3′ would
be epimers in the second chiral center created in the reaction.
Alternatively, the formation of a mixture of carbanions able to
react in a completely stereoselective way (only yielding syn or
anti products) would yield a mixture of two diastereoisomers, 3
and 3′, now differing in the configuration of the two created
chiral centers (only the configuration at the sulfur atom would
be identical). Desulfinylation of the mixture 3k + 3′k in Scheme
3 excludes the second explanation because 4k and 4′k are
diastereoisomers but not enantiomers. Then, we can conclude
that the absolute configurations of the epimers 3 and 3′ are
those indicated in Table 1 and Schemes 3 and 4.
Then we investigated the scope of the reaction with other
unsaturated aromatic tert-butyl esters containing electron-
withdrawing and electron-donating groups on the aromatic
ring (11b−g). All of them evolved into 92:8 mixtures of the
1,4-adducts 12 and 12′, regardless of the electronic character of
the substituents at the phenyl ring (Table 2, entries 3−8). As in
the case of sulfones, the lowest yields are obtained with
electron-withdrawing groups (11e−11g, entries 6−8). Separa-
tion of the mixtures could be performed only in the later cases,
which allowed the isolation of the major isomers (12e and 12f)
with higher than 98% de. The p-trifluoromethylphenyl
derivative 11h afforded a complex mixture where the conjugate
addition products could not be detected (Table 2, entry 9).
The reactions with alkenyl (11i) and alkyl-substituted (11j and
11k) acrylates evolved with a complete control of the stereo-
selectivity, only yielding one diastereoisomer (12i−k, Table 2,
entries 10−12). The failure of the reaction of 11l (R1 = Bn)
and 11m (R1 = i-Pr) is noteworthy. The easy deprotona-
tion of 11l and the steric hindrance of 11m could be responsible
for their lack of reactivity.
Then we considered the direct addition of our fluorinated
benzyl lithium derivative [Li]-(S)-1 on α,β-unsaturated esters.28
The addition of 4 molar equiv of (E)-ethyl cinnamate 8a
afforded a mixture of three compounds 9a, 9′a, and 10a, the
two former ones (9a and 9′a) being epimers at C-329 resulting
from the conjugated addition and 10a, the major one, the 1,2-
addition product. Both an adverse regioselectivity (9a + 9′a/
10a = 30:70) and a moderate stereoselectivity (9a/9′a = 82:18)
were attained (Table 2, entry 1). However, the formation of the
1,2-addition product can be avoided by using the corresponding
Desulfinylation of the resulting compounds can be successfully
performed with Raney-Ni30 under similar conditions to that used
with the sulfones in Scheme 3 to afford the corresponding tert-
butyl butanoates (Table 3) without affecting the enantiomeric
integrity. This protocol was applied to obtain compounds 13b,
13c, 13d (R1 aromatic), and 13k (R1 aliphatic). In the three
former cases, we used as starting compounds the unseparable
92:8 diastereomeric mixtures in Table 2, which afforded 92:8
mixtures of their corresponding 13 and 13′, which could now be
separated. Thus, reactions of (S)-1 with β-substituted acrylates
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integrity in the corresponding 1,2-diarylfluoroalkanes. On the
other hand, the same monofluorobenzyl lithium derivatives
afforded the corresponding Michael adducts, with high or
complete diastereoselectivity by addition to β-aryl or β-alkyl
α,β-unsaturated tert-butyl esters, respectively. However, with
the β-aryl esters, although the ring substituent effect is not
related to the diastereoselectivity, a strong decrease in yield
(p-Cl, p-Br, or p-CN) or no adduct (p-CF3) is observed with
electron-withdrawing groups bonded to the aromatic ring. The
importance of the Michael-type process described herein, which
takes place with high yields and excellent stereoselectivities,
lies in the preparation of enantiomerically pure fluorinated
compounds that, to the best of our knowledge, have not been
prepared so far.
Table 3. Synthesis of Enantiomerically Pure β-Substituted
γ-Fluoroesters (13) by Desulfinylation of Their Precursors
a
entry
starting ester
R1
compound (%)
1
2
3
4
12b + 12′b
12c + 12′c
12d + 12′d
12k
p-MeOC6H4
p-MeC6H4
13b (85)
13c (87)
13d (86)
13k (80)
p-FC6H4
C6H5CH2CH2
a
Isolated yield of the major epimer after flash chromatography.
EXPERIMENTAL SECTION
followed by desulfinylation gave access to β-substituted γ-fluoro-
esters bearing two connected chiral centers in only two steps, with
good yields and excellent diastereoselectivities.
■
General Procedures. 1H NMR spectra were acquired at 300 MHz,
and 13C NMR spectra were acquired at 75 MHz. 19F NMR spectra
were acquired at 282.4 MHz. Chemical shifts (δ) are reported in
parts per million relative to residual solvent signals (CHCl3, 7.26 ppm
The formation of the major isomers 12 could be explained by
assuming the approach depicted in Scheme 5. The carbanion,
stabilized by hydrogen bonds with the N−H of the amine,31
only has one accessible face for attacking the electrophile. It
would explain the R configuration observed for compounds 3
(and 3′) and 12 (and 12′) obtained, respectively, from vinyl
sulfones and acrylates. The R or S configuration at the second
chiral center depends on the electrophile’s face being attacked
by the carbanion. Approaches A and B (Scheme 5) are those
resulting from the presumably favored orientations of the
electrophilic double bond (with an antiperiplanar arrangement
with respect to the aromatic ring bonded to the carbanion).
Major compounds (3 and 12) result from the approach A,
which suggests that the (SOTol-Ar/R)gauche is larger than [(Ar/
R)gauche + (R/F)gauche] destabilizing B.
1
for H NMR, CDCl3, 77.0 ppm for 13C NMR spectra). 13C NMR
spectra were acquired on a broad-band proton decoupled mode. High-
resolution mass spectra (HRMS) were obtained with an electrospray
ion source. Melting points were determined in open capillary tubes.
All reactions were carried out in anhydrous solvents and under an
argon atmosphere. Commercial anhydrous THF was dried with
molecular sieves. iPr2NH was distilled from KOH. Analytical thin layer
chromatography (TLC) was performed using precoated aluminum-
backed plates (Kieselgel 60 F254) and visualized by ultraviolet
irradiation or KMnO4 dip. Flash column chromatography was
performed by using silica gel (230−400 mesh).
Commercially available starting materials and solvents were used
without purification. Compound (S)-115 was previously synthesized,
and vinyl sulfones and unsaturated esters were obtained according to
the literature.32
General Procedure for the Conjugate Addition of Sulfoxide
(S)-1 to Vinyl Sulfones and α,β-Unsaturated Esters. A solution
of n-BuLi (0.24 mmol, 2.5 M in hexane) was added over iPr2NH
(0.36 mmol) in THF (1.2 mL) at 0 °C. After stirring for 10 min, the
mixture was cooled at −78 °C and then a solution of (S)-1 (0.20 mmol)
in THF (1 mL) was added. After stirring for 5 min, the corresponding
vinyl sulfones 2a−m (Table 1) or unsaturated ester 11a−m (Table 2)
(0.8 mmol) in THF (0.4 mL) were added at −78 °C. Immediately, the
reaction mixture was hydrolyzed (2 mL of saturated NH4Cl), extracted
(3 × 10 mL Et2O), washed (2 × 10 mL of saturated NaCl), dried
(MgSO4), and the solvent evaporated under reduced pressure. The
residue was purified by flash column chromatography. The eluent and
CONCLUSION
■
We have demonstrated that monofluorobenzylcarbanions
stabilized by a remote homochiral sulfinyl group react with
high stereoselectivity and good yields with β-aryl-substituted
vinyl aryl sulfones (92:8 dr) if the aryl substituent bears
electron-donating groups or F in para position. The obtained
sulfonyl adducts could be transformed successfully, by succes-
sive desulfinylation and desulfonylation reactions (with or
without previous alkylation) and without loss of configurational
Scheme 5. Favored Approaches of β-Substituted Vinyl Sulfones or α,β-Unsaturated Esters to the Only Accessible Face of the
Carbanionic Species
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1
the obtained yield in each case are indicated below or in the
Supporting Information.
3.72−3.39 (m, 3H), 2.38 (s, 3H); 13C NMR δ 162.2 (d, JC‑F
=
247.0 Hz), 142.0, 142.0, 141.9, 139.6, 136.4, 136.1, 133.3, 131.3,
131.3 (d, 4JC‑F = 3.4 Hz), 130.7 (d, 3JC‑F = 8.0 Hz), 130.3, 129.5, 128.0
(2R,3R)-3-Fluoro-3-{2-[(S)-p-tolylsulfinyl]phenyl}-2-phenyl-
prop-1-yl phenyl sulfone (3a). Compound 3a was obtained as the
major diastereomer from vinyl sulfone 2a and (S)-1. Chromatography:
3
2
(d, JC‑F = 8.1 Hz), 127.7, 126.4, 125.7, 126.4, 125.7, 115.1 (d, JC‑F
=
1
3
21.4 Hz), 91.1 (d, JC‑F = 179.7 Hz), 58.2 (d, JC‑F = 4.3 Hz), 46.1
n-hexane/AcOEt, 3:1; yield 86%; colorless oil; [α]20 64 (c 0.5,
3
D
(d, JC‑F = 23.9 Hz), 21.4; 19F NMR δ −114.4, −181.5; IR (KBr)
1
CHCl3); IR (NaCl) 2965, 2922, 1447, 1305, 1141, 1085 cm−1; H
2975, 2921, 1511, 1307, 1140, 1084 cm−1; MS (ESI+) m/z (%) 533
[M + Na]+ (35), 511 [M + 1]+ (100), 491 [M − F]+ (40); HRMS m/z
calcd for C28H25O3F2S2 511.1207, found 511.1204.
NMR δ 7.95 (d, J = 7.9 Hz, 1H), 7.59−7.45 (m, 6H), 7.36−7.28 (m,
6H), 7.14−7.02 (m, 3H), 6.97−6.94 (m, 1H), 6.78 (d, J = 7.9 Hz,
2
1H), 6.32 (dd, JH−F = 45.8 and J = 4.6 Hz, 1H), 3.67−3.44 (m, 3H),
(2R,3R)-3-Fluoro-3-{2-[(S)-p-tolylsulfinyl]phenyl}-2-(4-
cyanophenyl)prop-1-yl phenyl sulfone (3h). Compound 3h was
obtained as the major diastereomer from vinyl sulfone 2h and (S)-1.
Chromatography: n-hexane/AcOEt, 3:1; yield 41%; colorless oil;
[α]20D 114 (c 1.1, CHCl3); 1H NMR δ 7.87 (d, J = 7.9 Hz, 1H), 7.56−
7.46 (m, 5H), 7.43−7.33 (m, 8H), 7.28−7.26 (m, 2H), 7.01 (d, J =
8.4 Hz, 1H), 6.28 (dd, 2JH‑F = 46.0 and J = 4.9 Hz, 1H), 3.76−3.62 (m,
2H), 3.37−3.33 (m, 1H), 2.36 (s, 3H); 13C NMR δ 142.0, 141.8,
141.6, 140.8, 139.4, 136.4, 136.1, 133.5, 131.9, 131.8, 130.3, 130.0,
129.7, 129.1, 128.0, 127.9, 127.7, 127.2, 125.3, 118.4 (CN), 111.6, 90.7
(d, 1JC‑F = 179.9 Hz), 57.8 (d, 3JC‑F = 4.5 Hz), 47.0 (d, 2JC‑F = 24.4 Hz),
21.4; 19F NMR δ −180.7; IR (NaCl) 2985, 2925, 2229, 1447, 1306,
1142, 1084 cm−1; MS (ESI+) m/z (%) 540 [M + Na]+ (33), 518
[M + 1]+ (100), 498 [M − F]+ (34); HRMS m/z calcd for
C29H25NO3FS2 518.1249, found 518.1254.
2.38 (s, 3H); 13C NMR δ 142.3, 142.2, 142.0, 141.4, 139.6, 136.3,
136.1, 135.5, 133.3, 131.2. 130.3, 129.5, 129.2, 129.0, 128.2, 128.0,
1
127.9, 127.8, 127.7, 127.5, 126.0, 91.1 (d, JC−F = 176.3 Hz), 58.0 (d,
2
3JC−F = 4.5 Hz), 46.6 (d, JC−F = 23.2 Hz), 21.4; 19F NMR δ −180.8;
MS (ESI+) m/z (%) 493 [M + H]+ (100), 515 [M + Na]+ (21), 473
[M − F]+ (33); HRMS m/z calcd for C28H26O3FS2 493.1301, found
493.1299.
(2R,3R)-3-Fluoro-3-{2-[(S)-p-tolylsulfinyl]phenyl}-2(1-
naphthyl)prop-1-yl phenyl sulfone (3b). Compound 3b was
obtained as the major diastereomer from vinyl sulfone 2b and (S)-1.
Chromatography: n-hexane/AcOEt, 3:1; yield 86%; colorless oil;
[α]20D 154 (c 1.0, CHCl3); 1H NMR δ 7.87 (d, J = 7.8 Hz, 1H), 7.63−
7.60 (m, 1H), 7.47−7.32 (m, 9H), 7.5−7.11 (m, 5H), 7.02 (d, J = 7.7
Hz, 2H), 6.98−6.93 (m, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.32 (dd,
2JH‑F = 45.9 and J = 4.7 Hz, 1H), 3.74−3.40 (m, 3H), 2.32 (s, 3H); 13
C
(2R,3E)-2-((R)-Fluoro{2-[(S)-p-tolylsulfinyl]phenyl}methyl)-
4-phenylbut-3-en-1-yl phenyl sulfone (3j). Compound 3j was
obtained as the major diastereomer from vinyl sulfone 2j and (S)-1.
Chromatography: n-hexane/AcOEt, 3:1; yield 70%; colorless oil;
[α]20D 56 (c 1.6, CHCl3); 1H NMR δ 7.96 (d, J = 7.6 Hz, 1H), 7.83−
7.81 (m, 2H), 7.56−7.4 (m, 8H), 7.29−7.21 (m, 5H), 7.10−7.07 (m,
NMR δ 142.1, 141.3, 139.5, 136.5, 136.4, 133.0, 132.9, 132.9,
132.7,131.4, 130.4, 129.5, 128.8, 128.6, 128.2, 128.1, 128.0, 127.7,
1
127.6, 127.5, 126.3, 126.3, 126.1, 126.0, 90.9 (d, JC‑F = 179.2 Hz),
3
2
58.2 (d, JC‑F = 4.5 Hz), 46.9 (d, JC‑F = 24.3 Hz), 21.4; 19F NMR
δ −179.6; IR (NaCl) 2923, 1509, 1305, 1216, 1138, 1084 cm−1;
MS (ESI+) m/z (%) 565 [M + Na]+ (18), 543 [M + 1]+ (100), 523
[M − F]+ (26); HRMS m/z calcd for C32H28O3FS2 543.1456, found
543.1458.
2
2H), 6.27 (dd, JH‑F = 45.8 and J = 4.5 Hz, 1H), 5.94−5.76 (m, 2H),
3.42−3.30 (m, 2H), 3.24−3.08 (m, 1H), 2.39 (s, 3H); 13C NMR δ
142.2, 142.2, 141.9, 141.5, 139.7, 136.4, 136.1, 136.1, 135.6, 133.6,
131.1, 130.2, 129.6, 129.2, 128.4, 128.4, 128.1, 128.0, 127.9, 126.4,
(2R,3R)-3-Fluoro-3-{2-[(S)-p-tolylsulfinyl]phenyl}-2-(4-
methoxyphenyl)prop-1-yl phenyl sulfone (3c). Compound 3c
was obtained as the major diastereomer from vinyl sulfone 2c and (S)-
1. Chromatography: n-hexane/AcOEt, 3:1; yield 89%; colorless oil;
[α]20D 66 (c 1.0, CHCl3); 1H NMR δ 7.94 (d, J = 7.9 Hz, 1H), 7.61−
7.44 (m, 6H), 7.36−7.26 (m, 5H), 6.94 (d, J = 8.8 Hz, 1H), 6.68 (d,
J = 8.5 Hz, 2H), 6.56 (d, J = 8.8 Hz, 2H), 6.27 (dd, 2JH‑F = 45.8 and J =
4.5 Hz, 1H), 3.71 (s, 3H), 3.67−3.36 (m, 3H), 2.38 (s, 3H); 13C NMR
δ 159.0, 142.1, 142.1, 142.0, 141.4, 139.8, 136.5, 136.2, 133.2, 131.1,
130.3, 130.2, 129.4, 128.9, 128.0, 127.9, 127.8, 127.3, 125.9, 113.7, 91.4
1
3
126.2, 125.9, 123.2, 123.1, 91.4 (d, JC‑F = 179.3 Hz), 57.6 (d, JC‑F
=
3.2 Hz), 44.8 (d, JC‑F = 23.4 Hz), 21.4; 19F NMR δ −183.2; IR
(NaCl): 3035, 2924, 1493, 1306, 1216, 1084 cm−1; MS (ESI+) m/z
(%) 541 [M + Na]+ (23), 519 [M + 1]+ (100), 499 [M − F]+ (36);
HRMS m/z calcd for C30H28O3FS2 519.1448, found 519.1458.
(2R)-2-((R)-Fluoro{2-[(S)-p-tolylsulfinyl]phenyl}methyl)-4-
phenylbutyl phenyl sulfone (3k). Compound 3k was obtained as
the major diastereomer from vinyl sulfone 2k and (S)-1. Chromato-
2
graphy: n-hexane/AcOEt, 3:1; yield 70%; colorless oil; [α]20 −35 (c
1
3
2
D
(d, JC‑F = 176.3 Hz), 58.3 (d, JC‑F = 4.0 Hz), 55.2, 45.9 (d, JC‑F
=
1.5, CHCl3); 1H NMR δ 8.03 (d, J = 7.8 Hz, 1H), 7.82−7.74 (m, 2H),
7.68−7.61 (m, 1H), 7.57−7.39 (m, 7H), 7.25−7.15 (m, 5H), 7.02−
23.8 Hz), 21.4; 19F NMR δ −181.1; IR (NaCl) 3020, 2895, 1515,
1305, 1216, 1035 cm−1; MS (ESI+) m/z (%) 545 [M + Na]+ (18), 523
[M + 1]+ (100), 503 [M − F]+ (36); HRMS m/z calcd for
C29H28O4FS2 523.1407, found 523.1413.
2
6.94 (m, 2H), 6.14 (dd, JH‑F = 46.1 and J = 5.5 Hz, 1H), 3.12−2.92
(m, 2H), 2.60−2.51 (m, 2H), 2.37−2.33 (m, 1H), 2.36 (s, 3H), 1.95−
1.89 (m, 2H); 13C NMR δ 143.1, 141.8, 141.7, 140.9, 139.5, 136.3,
136.0, 133.8, 131.4, 130.1, 129.7, 129.4, 128.5, 128.4, 127.7, 127.3,
(2R,3R)-3-Fluoro-3-{2-[(S)-p-tolylsulfinyl]phenyl}-2-(4-tolyl)-
prop-1-yl phenyl sulfone (3d). Compound 3d was obtained as the
major diastereomer from vinyl sulfone 2d and (S)-1. Chromatography:
1
3
127.2, 126.1, 126.1, 125.9, 92.3 (d, JC‑F = 178.0 Hz), 55.7 (d, JC‑F
=
4.8 Hz), 39.1 (d, 2JC‑F = 24.4 Hz), 32.4, 30.0, 21.4; 19F NMR δ −181.4;
IR (NaCl) 3035, 2925, 2229, 1494, 1307, 1148, 1085 cm−1; MS (ESI
+) m/z (%) 543 [M + Na]+ (19), 521 [M + H]+ (100), 501 [M − F]+
(63); HRMS m/z calcd for C30H30O3FS2 521.1614, found 521.1622.
(2R)-2((R)-Fluoro{2-[(S)-p-tolylsulfinyl]phenyl}methyl)pentyl
phenyl sulfone (3l + 3l′). This compound was obtained as a 88:12
(3l + 3l′) enriched mixture from vinyl sulfone 2l and (S)-1. Chromato-
n-hexane/AcOEt, 3:1; yield 80%; colorless oil; [α]20 77 (c 1.0,
D
1
CHCl3); H NMR δ 7.94 (d, J = 7.6 Hz, 1H), 7.58−7.44 (m, 6H),
7.35−7.27 (m, 5H), 6.99 (dd, J = 7.8, 1.3 Hz, 1H), 6.85 (d, J = 7.8 Hz,
2
2H), 6.68 (d, J = 7.8 Hz, 2H), 6.29 (dd, JH‑F = 45.8 and J = 4.7 Hz,
1H), 3.64−3.39 (m, 3H), 2.37 (s, 3H), 2.23 (s, 3H); 13C NMR δ
142.3, 142.2, 142.0, 141.4, 139.7, 137.3, 136.5, 136.2, 133.1, 132.4,
131.2, 130.3, 129.5, 129.0, 128.9, 128.9, 128.0, 127.9, 127.8, 125.9, 91.2
(d, 1JC‑F = 179.3 Hz), 58.5 (d, 3JC‑F = 4.3 Hz), 46.3 (d, 2JC‑F = 24.2 Hz),
21.4, 21.0; 19F NMR δ −180.2; IR (NaCl) 3021, 2923, 1515, 1306,
1141, 1084 cm−1; MS (ESI+) m/z (%) 529 [M + Na]+ (33), 507
[M + 1]+ (100), 487 [M − F]+ (50); HRMS m/z calcd for
C29H28O3FS2 507.1458, found 507.1459.
graphy: n-hexane/AcOEt, 3:1; yield 68%; colorless oil; [α]20 −41
D
(c 1.9, CHCl3); 1H NMR δ 8.05 (d, J = 6.7 Hz, 1H), 7.84−7.81 (m, 2H),
7.55−7.44 (m, 7H), 7.38−7.33 (m, 1H), 7.22 (d, J = 8.2 Hz, 2H), 6.14
(dd, 2JH‑F = 46.0 and J = 5.2 Hz, 1H, A), 5.76 (dd, 2JH‑F = 46.0 and J =
4.9 Hz, B), 3.07 (dd, J = 14.7, 6.4 Hz, 1H), 2.92 (dd, J = 14.7, 5.2 Hz,
1H), 2.55−2.39 (m, 1H), 2.34 (s, 3H), 1.63−1.39 (m, 2H), 1.33−1.22
(m, 1H), 0.89−0.75 (m, 1H), 0.72 (t, J = 7.2 Hz, 3H); 13C NMR δ
(2R,3R)-3-Fluoro-3-{2-[(S)-p-tolylsulfinyl]phenyl}-2-(4-
fluorophenyl)prop-1-yl phenyl sulfone (3e). Compound 3e was
obtained as the major diastereomer from vinyl sulfone 2e and (S)-1.
143.1, 141.9, 141.7, 139.7, 136.3, 136.0, 133.8, 131.3, 130.2, 130.0,
1
129.7, 129.4, 127.8, 127.3, 127.1, 125.9, 125.9, 125.9, 92.3 (d, JC‑F
=
Chromatography: n-hexane/AcOEt, 3:1; yield 81%; white solid; mp
3
2
1
131−133 °C; [α]20 102 (c 0.9, CHCl3); H NMR δ 7.93 (d, J =
178.1 Hz), 55.3 (d, JC‑F = 4.7 Hz), 39.3 (d, JC‑F = 23.7 Hz), 29.8,
21.4, 19.2, 13.8; 19F NMR δ −182.6 (A), −186.82 (B); IR (NaCl)
2961, 2873, 2229, 1447, 1307, 1148, 1084 cm−1; MS (ESI+) m/z (%)
D
7.8 Hz, 1H), 7.58−7.46 (m, 6H), 7.38−7.28 (m, 5H), 6.96 (d, J = 7.8 Hz,
1H), 6.77−6.73 (m, 4H), 6.27 (dd, JH‑F = 45.9 and J = 4.6 Hz, 1H),
2
2897
dx.doi.org/10.1021/jo300174k | J. Org. Chem. 2012, 77, 2893−2900

The Journal of Organic Chemistry
Article
1
481 [M + Na]+ (100), 459 [M + 1]+ (73), 439 [M − F]+ (55); HRMS
m/z calcd for C25H28O3FS2 459.1458, found 459.1441.
131.0, 129.9, 129.6, 127.7, 127.6, 125.9, 125.9, 94.5 (d, JC‑F = 175.6
2
3
Hz), 80.7, 40.7 (d, JC‑F = 22.7 Hz), 36.0 (d, JC‑F = 5.1 Hz), 30.8 (d,
tert-Butyl (3R,4R)-4-Fluoro-{2-[(S)-p-tolylsulfinyl]phenyl}-
3-phenylbutanoate (12a). Compound 12a was obtained as the
major diastereomer from unsaturated ester 11a and (S)-1. Chromato-
3JC‑F = 2.9 Hz), 28.1, 21.3, 19.8, 14.1; 19F NMR δ −177.2; IR (NaCl)
2962, 2873, 1726, 1493, 1393, 1154 cm−1; MS (ESI+) m/z (%) 859
[2M + Na]+ (34), 441 [M + Na]+ (100), 419 [M + H]+ (33); HRMS
m/z calcd for C24H32O3FS 419.2050, found 419.2035.
graphy: n-hexane/AcOEt, 2:1; yield 82%; colorless oil; [α]20 24
D
(c 1.5, CHCl3); 1H NMR δ 8.00 (d, J = 7.9 Hz, 1H), 7.55 (d, J = 8.2 Hz,
2H), 7.50−7.45 (m, 1H), 7.34−7.28 (m, 2H), 7.23−7.17 (m, 4H),
7.01−6.97 (m, 3H), 6.11 (dd, 2JH‑F = 46.0 and J = 5.3 Hz, 1H), 3.41−
3.26 (m, 1H), 2.68−2.52 (m, 2H), 2.37 (s, 3H), 1.22 (s, 9H); 13C
NMR δ 170.3, 142.7, 142.6, 141.9, 141.8, 137.7, 136.9, 136.6, 130.8,
130.1, 129.8, 129.4, 129.1, 128.1, 128.0, 127.9, 127.3, 126.1, 125.6, 92.5
tert-Butyl (3S)-3-((R)-Fluoro{2-[(S)-p-tolylsulfinyl]phenyl}-
methyl)-5-phenylpentanoate (12k). Compound 12k was obtained
as a unique diastereomer from unsaturated ester 11k and (S)-1.
Chromatography: n-hexane/AcOEt, 2:1; yield 79%; colorless oil;
[α]20D −43 (c 0.5, CHCl3); 1H NMR δ 8.04 (d, J = 7.6 Hz, 1H), 7.55−
7.47 (m, 4H), 7.45−7.39 (m, 1H), 7.28−7.19 (m, 5H), 7.12−7.10 (m,
1
2
3
2
(d, JC‑F = 178.7 Hz), 80.6, 47.8 (d, JC‑F = 22.7 Hz), 38.0 (d, JC‑F
=
2H), 5.91 (dd, JH‑F = 46.5 and J = 6.5 Hz, 1H), 2.75−2.65 (m, 1H),
4.5 Hz), 27.8, 21.4; 19F NMR δ −178.1; IR (NaCl) 2978, 2868, 2229,
1727, 1393, 1258, 1150 cm−1; MS (ESI+) m/z (%) 927 [2M + Na]+
(43), 475 [M + Na]+ (100), 453 [M + H]+ (42), 397 (66); HRMS
m/z calcd for C27H30O3FS 453.1876, found 453.1894.
2.59−2.43 (m, 2H), 2.36 (s, 3H), 2.28−2.11 (m, 2H), 2.01−1.89 (m,
1H), 1.84−1.76 (m, 1H), 1.43 (s, 9H); 13C NMR δ 171.2, 143.6,
142.2, 141.8, 141.4, 137.2, 136.9, 131.1, 129.9, 129.7, 129.7, 128.4,
128.2, 127.8, 127.6, 126.1, 125.9, 125.9, 125.8, 94.3 (d, 1JC‑F = 175.8 Hz),
80.8, 40.7 (d, 2JC‑F = 22.7 Hz), 36.1 (d, 3JC‑F = 5.2 Hz), 33.0, 30.7 (d, J =
2.7 Hz), 28.1, 21.4; 19F NMR δ −176.8; IR (NaCl) 2980, 2928, 2823,
1724, 1454, 1367, 1150 cm−1; MS (ESI+) m/z (%) 503 [M + Na]+ (68),
481 [M + H]+ (83), 425 (100); HRMS m/z calcd for C29H34O3FS
481.2207, found 481.2218.
tert-Butyl (3R,4R)-4-Fluoro-4-{2-[(S)-p-tolylsulfinyl]phenyl}-
3-(4-chlorophenyl)butanoate (12e). Compound 12e was obtained
as the major diastereomer from unsaturated ester 11e and (S)-1. Chro-
matography: n-hexane/AcOEt, 3:1; yield 55%; colorless oil; [α]20D 17
1
(c 1.4, CHCl3); H NMR δ 7.98 (d, J = 8.0 Hz, 1H), 7.53−7.46 (m,
3H), 7.36−7.32 (m, 3H), 7.21−7.18 (m, 2H), 6.99−6.92 (m, 3H),
6.10 (dd, 2JH‑F = 46.1 and J = 5.2 Hz, 1H), 3.39−3.24 (m, 1H), 2.69−
2.51 (m, 2H), 2.37 (s, 3H), 1.24 (s, 9H); 13C NMR δ 170.0, 142.4,
142.4, 141.9, 141.7, 136.8, 136.6, 136.3, 133.1, 131.0, 130.5, 130.1,
General Methods for Adducts Desulfinylation. Raney-Ni:
A
solution of the corresponding adducts (0.1 mmol) in THF
(0.2 mL) was added over a solution of previously activated Raney-
Ni (450 mg) in THF (0.5 mL). The resulting reaction was stirred
for 4.5 h at rt, and then the crude was directly filtered on Celite
and the pure products were recovered with ether.
tert-BuLi: To a solution of the corresponding sulfoxide (0.12 mmol)
in dry THF (2 mL) at −78 °C was dropwise added tert-BuLi (0.4 mmol,
1.7 M in pentane). When the reaction was complete (30 min), the
resulting reaction mixture was hydrolyzed (1 mL of H2O), extracted
(3 × 10 mL AcOEt), washed (10 mL of NaCl), dried (MgSO4), and
the solvent was removed under reduced pressure.
1
129.9, 129.5, 128.2, 128.0, 127.9, 127.7, 125.9, 92.0 (d, JC‑F = 178.6
Hz), 80.8, 47.3 (d, 2JC‑F = 22.9 Hz), 38.0 (d, 3JC‑F = 4.1 Hz), 27.8, 21.4;
19F NMR δ −178.9; IR (NaCl) 2985, 2896, 2229, 1733, 1503, 1383,
1253 cm−1; MS (ESI+) m/z (%) 509 [M + Na]+ (23), 487 [M + 1]+
(63), 431 (100); HRMS m/z calcd for C27H29O3FSCl 487.1504, found
487.1518.
tert-Butyl (3R,4R)-4-Fluoro-4-{2-[(S)-p-tolylsulfinyl]phenyl}-
3-(4-bromophenyl)butanoate (12f). Compound 12f was obtained
as the major diastereomer from unsaturated ester 11f and (S)-1. Chro-
matography: n-hexane/AcOEt, 2:1; yield 38%; colorless oil; [α]20D 31
(2R,3R)-3-Fluoro-2,3-diphenylpropyl phenyl sulfone (4a).
Compound 4a was obtained as a unique diastereomer from sulfone
3a: yield 84%; colorless oil; [α]20D 9 (c 1.5, CHCl3); 1H NMR δ 7.80−
7.59 (m, 2H), 7.57−7.52 (m, 1H), 7.43−7.38 (m, 2H), 7.22−7.20 (m,
3H), 7.12−7.03 (m, 3H), 6.96−6.93 (m, 2H), 6.83 (d, J = 7.8 Hz,
1
(c 1.6, CHCl3); H NMR δ 8.06−7.86 (m, 1H), 7.53−7.50 (m, 3H),
7.37−7.30 (m, 3H), 7.29−7.27 (m, 2H), 7.00−6.97 (m, 1H), 6.88 (d,
J = 8.3 Hz, 2H), 6.10 (dd, 2JH‑F = 46.0 and J = 5.2 Hz, 1H), 3.39−3.23
(m, 1H), 2.66−2.52 (m, 2H), 2.37 (s, 3H), 1.24 (s, 9H); 13C NMR δ
170.0, 142.4, 142.4, 142.1, 141.9, 141.6, 136.9, 136.9, 136.6, 131.2,
131.0, 130.8, 130.1, 129.5, 128.0, 127.9, 126.5, 125.9, 121.2, 91.9 (d,
1JC‑F = 178.6 Hz), 80.8, 47.3 (d, 2JC‑F = 22.7 Hz), 37.9 (d, 3JC‑F = 4.1 Hz),
2
2H), 5.90 (dd, JH‑F = 46.4 and J = 3.2 Hz, 1H), 3.86−3.57 (m, 3H);
13C NMR δ 139.5, 137.2, 136.9, 135.4, 133.5, 129.6, 129.2, 129.1,
1
128.8, 128.3, 128.1, 127.9, 127.5, 127.1, 125.6, 125.5, 94.1 (d, JC‑F
=
181.1 Hz), 57.7 (d, 3JC‑F = 3.5 Hz), 47.1 (d, 2JC‑F = 22.6 Hz); 19F NMR
δ −188.8; IR (NaCl) 3026, 2905, 1504, 1304, 1152, 705 cm−1; MS
(ESI+) m/z (%) 731 [2M + Na]+ (30), 377 [M + Na]+ (12), 193
(100); HRMS m/z calcd for C21H19O2FNaS 377.0982, found
377.0994.
27.8, 21.4; 19F NMR δ −178.8; IR (NaCl) 2978, 2915, 2229, 1727,
1492, 1365, 1258 cm−1; MS (ESI+) m/z (%) 533 [M + 2]+ (57), 397
[M]+ (52), 477 (100); HRMS m/z calcd for C27H29O3FSBr 531.1006,
found 531.0999.
tert-Butyl (3R,4E)-3-((R)-Fluoro{2-[(S)-p-tolylsulfinyl]phenyl}-
methyl)-5-phenylpent-4-enoate (12i). Compound 12i was
obtained as a unique diastereomer from unsaturated ester 11i and
(2R)-2-[(R)-Fluoro(phenyl)methyl]-4-phenylbutyl phenyl sul-
fone (4k). Compound 4k was isolated from the 80:20 diastereoiso-
meric mixture (4k + 4k′) obtained from 3k + 3k′. Chromatography:
n-hexane/AcOEt, 15:1; yield 65%; colorless oil; [α]20 18 (c 1.5,
(S)-1. Chromatography: n-hexane/AcOEt, 2:1; yield 76%; colorless
D
1
oil; [α]20 33 (c 1.0, CHCl3); H NMR δ 8.04−7.99 (m, 1H), 7.53−
CHCl3); 1H NMR δ 7.92−7.80 (m, 2H), 7.72−7.63 (m, 1H), 7.57 (m,
2H), 7.34−7.29 (m, 3H), 7.23−7.13 (m, 5H), 6.97−6.92 (m, 2H),
5.86 (dd, 2JH‑F = 46.8 and J = 3.6 Hz, 1H), 3.44 (dd, J = 14.5, 7.0 Hz,
1H), 3.12 (dd, J = 14.5, 4.8 Hz, 1H), 2.68−2.33 (m, 2H), 2.47−2.33
(m, 1H), 1.86−1.74 (m, 2H); 13C NMR δ 140.8, 139.5, 137.9, 137.6,
133.8, 133.4, 129.4, 129.2, 129.1, 128.5, 128.4, 128.4, 128.3, 128.2,
D
7.37 (m, 6H), 7.27−7.19 (m, 6H), 6.15−6.13 (m, 2H), 6.00 (dd,
2JH‑F = 46.2 and J = 4.8 Hz, 1H), 3.10−2.95 (m, 1H), 2.49−2.31 (m, 2H),
2.36 (s, 3H), 1.24 (s, 9H); 13C NMR δ 170.5, 142.8, 141.9, 141.7, 137.1,
136.8, 136.8, 134.0, 131.0, 130.0, 129.6, 128.5, 127.9, 127.7, 127.6, 126.3,
126.0, 126.0, 125.9, 125.6, 125.6, 92.7 (d, 1JC‑F = 177.8 Hz), 80.8, 45.9 (d,
2JC‑F = 22.8 Hz), 37.8 (d, 3JC‑F = 3.5 Hz), 28.1, 21.4; 19F NMR δ −178.9;
127.9, 126.0, 125.1, 125.0, 94.32 (d, 1JC‑F = 177.5 Hz), 56.14 (d, 3JC‑F
=
2
3
IR (NaCl) 2980, 2806, 1726, 1493, 1368, 1151 cm−1; MS (ESI+) m/z
(%) 501 [M + Na]+ (52), 479 [M + H]+ (53), 423 (100); HRMS m/z
calcd for C29H32O3FS 479.2050, found 479.2067.
3.2 Hz), 39.16 (d, JC‑F = 22.1 Hz), 32.79, 29.04 (d, JC‑F = 4.4 Hz);
19F NMR δ −195.4; IR (NaCl) 3032, 2927, 1448, 1307, 1149, 699
cm−1; MS (ESI+) m/z (%) 787 [2M + Na]+ (13), 767 (37), 405 [M +
Na]+ (59), 363 [M − F]+ (69), 143 (100); HRMS m/z calcd for
C23H23O2FNaS 405.1295, found 405.1255.
tert-Butyl (3S)-3-((R)-Fluoro{2-[(S)-p-tolylsulfinyl]phenyl}-
methyl)hexanoate (12j). Compound 12j was obtained as a unique
diastereomer from unsaturated ester 11j and (S)-1. Chromatography:
tert-Butyl (3R,4R)-4-Fluoro-4-phenyl-3-(4-methoxyphenyl)-
butanoate (13b). Compound 13b was obtained as the major
n-hexane/AcOEt, 2:1; yield 77%; colorless oil; [α]20 −68 (c 0.5,
D
1
CHCl3); H NMR δ 8.05 (d, J = 6.9 Hz, 1H), 7.53−7.39 (m, 5H),
7.23 (d, J = 8.1 Hz, 2H), 5.85 (dd, JH‑F = 46.6 and J = 6.4 Hz, 1H),
diastereomer from the mixture 12b/12b′. Chromatography: n-hexane/
2
1
AcOEt, 20:1; yield 85%; colorless oil; [α]20 37 (c 1.5, CHCl3); H
D
2.52−2.38 (m, 1H), 2.35 (s, 3H), 2.10 (dc, J = 15.6, 6.5 Hz, 2H),
1.58−1.47 (m, 3H), 1.41 (s, 9H), 1.23−1.10 (m, 1H), 0.85 (d, J =
7.2 Hz, 3H); 13C NMR δ 171.4, 143.7, 142.4, 141.4, 137.3, 137.0,
NMR δ 7.27−7.26 (m, 2H), 7.10−7.05 (m, 2H), 7.00 (d, J = 8.7 Hz,
2
2H), 6.77 (d, J = 8.2 Hz, 2H), 5.61 (dd, JH‑F = 46.6 and J = 5.1 Hz,
1H), 3.76 (s, 3H), 3.58−3.43 (m, 1H), 2.83−2.42 (m, 2H), 1.29
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Article
(s, 9H); 13C NMR δ 169.9, 157.6, 137.4, 137.1, 129.1, 129.0, 127.1,
(1.5 equiv) was added. The mixture was stirred at −78 °C for 1 h, and
then saturated solution NH4Cl (5 mL) was added. The organic phase
was separated, and the aqueous layer was extracted with EtOAc (2 ×
10 mL). The combined organic phases were dried (MgSO4), filtered, and
concentrated. The residue was dissolved in 0.4 mL of CH2Cl2, and then
the general procedure for the desulfonylation was followed.
1
127.0, 125.0, 124.9, 112.4, 95.1 (d, JC‑F = 177.7 Hz), 79.6, 54.1, 46.7
(d, 2JC‑F = 23.0 Hz), 36.8 (d, 3JC‑F = 4.1 Hz), 26.9; 19F NMR δ −183.5;
IR (NaCl) 3026, 2994, 2924, 1731, 1152, 702 cm−1; MS (ESI+) m/z
(%) 367 [M + Na]+ (30), 263 (94), 225 (100); HRMS m/z calcd for
C21H25O3FNa 367.1679, found 367.1696.
1,1′-[(1R,2R)-1-Fluorobutane-1,2-diyl]dibenzene (6a). Com-
tert-Butyl (3R,4R)-4-Fluoro-4-phenyl-3-(4-tolyl)butanoate
(13c). Compound 13c was obtained as the major diastereomer from
the mixture 12c/12c′. Chromatography: n-hexane/AcOEt, 20:1; yield
84%; white solid; mp 45−46 °C; [α]20D 49 (c 0.9, CHCl3); 1H NMR δ
7.29−7.26 (m, 2H), 7.13−7.10 (m, 2H), 7.06−6.97 (m, 4H), 5.61 (dd,
2JH‑F = 46.6 and J = 5.5 Hz, 1H), 3.60−3.45 (m, 1H), 2.72−2.54 (m,
pound 6a was obtained as the unique diastereomer from sulfone 4a
and MeI. Chromatography: n-hexane/AcOEt, 10:1; yield 53%;
1
colorless oil; [α]20 64 (c 0.85, CHCl3); H NMR δ 7.28−7.20 (m,
D
1
6H), 7.19−7.11 (m, 4H), 5.47 (dd, JH‑F = 46.6 and J = 6.6 Hz, 1H),
2.90−2.77 (m, 1H), 1.65−1.54 (m, 2H), 0.68 (d, J = 7.3 Hz, 3H); 13C
NMR δ 139.9, 139.8, 139.2, 128.9, 128.9, 128.2, 128.2, 128.1, 128.1,
126.7, 126.3, 126.2, 97.2, (d, 1JC‑F = 175.9 Hz), 54.3 (d, 2JC‑F = 22.2 Hz),
24.5 (d, 3JC‑F = 4.6 Hz), 11.9; 19F NMR δ −177.0; IR (NaCl) 3026, 2994,
2930, 1451, 1210 cm−1; MS (EI) m/z (%) 228 [M]+ (9), 208 (61),
193 (34), 179 (35), 115 (47), 91 (100); HRMS m/z calcd for C16H17F
228.1314, found 228.1302.
2H), 2.54 (s, 3H), 1.28 (s, 9H); 13C NMR δ 170.9, 138.4, 138.1, 136.5,
1
135.2, 128.8, 128.7, 128.2, 128.1, 126.1, 126.0, 96.2 (d, JC‑F = 177.6
Hz), 80.6, 48.0 (d, 2JC‑F = 23.2 Hz), 37.7 (d, 3JC‑F = 4.2 Hz), 27.9, 21.1;
19F NMR δ −182.4; IR (KBr) 3026, 2991, 2925, 1731, 1152,
699 cm−1; MS (ESI+) m/z (%) 537 (33), 519 (32), 351 [M + Na]+
(72), 253 (100); HRMS m/z calcd for C21H25O2FNa 351.1730, found
351.1736.
Methyl (3R,4R)-4-Fluoro-3,4-diphenylbutanoate (7a). Com-
pound 7a was obtained as the unique diastereomer from sulfone 4a
and ClCO2Me. Chromatography: n-hexane/AcOEt, 20:1; yield 55%;
tert-Butyl (3R,4R)-4-Fluoro-3-(4-fluorophenyl)-4-phenylbu-
tanoate (13d). Compound 13d was obtained as the major
diastereomer from the mixture 12d/12d′. Chromatography: n-hexane/
1
colorless oil; [α]20 55 (c 0.3, CHCl3); H NMR δ 7.28−7.26 (m,
D
1
AcOEt, 20:1; yield 86%; white solid; mp 82−84 °C; [α]20 49 (c 1.6,
3H), 7.24−7.15 (m, 3H), 7.15−7.09 (m, 4H), 5.68 (dd, JH‑F = 46.5
D
1
and J = 5.4 Hz, 1H), 3.71−3.60 (m, 1H), 3.56 (s, 3H), 2.89−2.69 (m,
CHCl3); H NMR δ 7.34−7.27 (m, 2H), 7.09−7.03 (m, 4H), 6.94−
2H); 13C NMR δ 172.1, 138.1, 138.1, 137.8, 128.8, 128.3, 128.2, 128.1,
2
6.89 (m, 2H), 5.64 (dd, JH‑F = 45.9 Hz and J = 1H), 3.61−3.47 (m,
1
2
1H), 2.75−2.59 (m, 2H), 1.28 (s, 9H); 13C NMR δ 170.7, 161.9 (d,
127.1, 126.0, 125.9, 95.9 (d, JC‑F = 178.0 Hz), 51.7, 48.1 (d, JC‑F
=
23.0 Hz), 36.3 (d, JC‑F = 4.7 Hz); 19F NMR δ −183.3; IR (NaCl)
3023, 2990, 2929, 1735, 1140, 695 cm−1; MS (EI) m/z (%) 295 [M +
Na]+ (35), 253 [M − F]+ (18), 221 (31), 193 (100); HRMS m/z
calcd for C17H17O2FNa 295.1104, found 295.1113.
3
1JC‑F = 245.2 Hz), 138.1, 137.9, 133.8, 129.4 (d, 3JC‑F = 8.1 Hz), 128.3,
2
1
128.1, 125.8, 125.7, 114.8, (d, JC‑F = 21.2 Hz), 95.9 (d, JC‑F = 178.0
2
3
Hz), 80.8, 47.9 (d, JC‑F = 22.9 Hz), 37.8 (d, JC‑F = 4.1 Hz), 27.9;
19F NMR δ −115.8, −185.0; IR (KBr) 3012, 2998, 2920, 1732, 1156,
704 cm−1; MS (ESI+) m/z (%) 355 [M + Na]+ (77), 257 (100), 211 (83);
HRMS m/z calcd for C20H22O2F2Na 355.1480, found 355.1488.
ASSOCIATED CONTENT
* Supporting Information
■
tert-Butyl (3S)-3-[(R)-Fluoro(phenyl)methyl]-5-phenylpenta-
S
noate (13k). Compound 13k was obtained as the unique dia-
1H and 13C NMR for compounds 3a−e, 3h, 3j, 3k, 3l + 3l′,
12a, 12e, 12f, 12i, 12k, 12j, 4a, 4k, 13b−d, 13k,(5−7)a, and X-
ray ORTEP and crystallographic data for compound 3e (CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
stereomer from ester 12k: yield 80%; colorless oil; [α]20 16 (c 2.0,
D
1
CHCl3); H NMR δ 7.30−7.19 (m, 5H), 7.17−7.14 (m, 2H), 7.10−
2
7.08 (m, 2H), 5.56 (dd, JH‑F = 47.1 and J = 4.6 Hz, 1H), 2.75−2.65
(m, 1H), 2.58−2.50 (m, 1H), 2.47−2.39 (m, 2H), 2.30−2.22 (m, 1H),
1.90−1.78 (m, 1H), 1.71−1.61 (m, 1H), 1.46 (s, 9H); 13C NMR δ
171.8, 142.0, 138.9, 138.6, 129.3, 128.4, 128.3, 128.3, 128.3, 128.1,
1
2
125.8, 125.8, 125.7, 95.9 (d, JC‑F = 174.7 Hz), 80.7, 40.9 (d, JC‑F
=
AUTHOR INFORMATION
Corresponding Author
*E-mail: joseluis.garcia.ruano@uam.es, carmen.maestro@
uam.es.
■
22.4 Hz), 36.2 (d, 3JC‑F = 4.3 Hz), 33.3, 30.3, 28.1; 19F NMR δ −187.8;
IR (NaCl) 3020, 2993, 2931, 1727, 1149, 700 cm−1; MS (ESI+) m/z
(%) 365 [M + Na]+ (15), 249 (20), 189 (80), 129 (100); HRMS m/z
calcd for C22H27O2FNa 365.1887, found 365.1886.
General Procedure for Synthesis of Compounds 5a−7a
(Scheme 4). General Procedure for the Desulfonylation. The
corresponding sulfone (0.1 mmol) was dissolved in 0.4 mL
of CH2Cl2 and added to a solution of magnesium (10 equiv,
previously flame-dried under a stream of argon) in 1 mL of
MeOH under argon atmosphere. After complete consump-
tion, 10 equiv more of magnesium was added. When the reac-
tion was finished (as monitored by TLC), the crude was directly
filtered on silica. The residue was purified by flash column
chromatography.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support of this work by the Spanish Government
(grant CTQ2009-12168) and Comunidad Auto
■
́
noma de
Madrid (AVANCAT S2009/PPQ1634) is gratefully acknowl-
edged. J.A.F.-S. thanks Comunidad Autonoma de Madrid
(AVANCAT S2009/PPQ1634) for a predoctoral contract.
́
1,1′-[(1R,2R)-1-Fluoropropane-1,2-diyl]dibenzene (5a). Com-
pound 5a was obtained as the unique diastereomer from sulfone 4a.
Chromatography: n-hexane/AcOEt, 10:1; yield 63%; colorless oil;
[α]20D 54 (c 0.45, CHCl3); 1H NMR δ 7.35−7.28 (m, 5H), 7.24−7.20
DEDICATION
Dedicated to the late Prof. Dr. Guy Solladie
contribution to asymmetric organic synthesis mediated by the
sulfinyl group.
■
́
for his valuable
2
(m, 5H), 5.46 (dd, JH‑F = 46.5 and J = 7.3 Hz, 1H), 3.32−3.71 (m,
1H), 1.20 (d, J = 7.2 Hz, 3H); 13C NMR δ 142.0, 141.9, 138.8, 138.5,
1
128.4, 128.3, 128.3, 128.2, 128.1, 126.7, 126.4, 126.4, 98.1, (d, JC‑F
=
176.0 Hz), 46.1 (d, 2JC‑F = 23.2 Hz), 17.2 (d, 3JC‑F = 5.6 Hz); 19F NMR
δ −174.2; IR (NaCl) 3029, 2995, 2926, 1452, 1216 cm−1; MS (ESI+)
m/z (%) 214 [M]+ (10), 194 (23), 179 (81), 105 (100); HRMS m/z
calcd for C15H15F 214.1158, found 214.1154.
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