Asymmetric nucleophilic monofluorobenzylation of allyl and propargyl halides mediated by a remote sulfinyl group: Synthesis of homoallylic and homopropargylic fluorides

Article abstract of DOI:10.1021/jo501096f

Fluorinated 2-(p-tolylsulfinyl)benzyl carbanions react with allyl and propargyl halides in a highly stereoselective way, providing homoallylic and homopropargylic fluorides, respectively, with high optical purity. Theoretical calculations found transition states for these transformations whose relative stabilities are consistent with the experimentally observed stereoselectivity.

Full text of DOI:10.1021/jo501096f

Article
pubs.acs.org/joc
Asymmetric Nucleophilic Monofluorobenzylation of Allyl and
Propargyl Halides Mediated by a Remote Sulfinyl Group: Synthesis of
Homoallylic and Homopropargylic Fluorides
Yolanda Arroyo,† M. Ascension Sanz-Tejedor,*,† Alejandro Parra,‡ Ines Alonso,‡
́
́
and Jose Luis García Ruano*,‡
́
†Departamento de Química Organ
́
́
ica (EII), Universidad de Valladolid, Paseo del Cauce 59, 47011 Valladolid, Spain
ica (C-I), Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid, Spain
‡Departamento de Química Organ
́
S
* Supporting Information
ABSTRACT: Fluorinated 2-(p-tolylsulfinyl)benzyl carbanions react with allyl and propargyl halides in a highly stereoselective
way, providing homoallylic and homopropargylic fluorides, respectively, with high optical purity. Theoretical calculations found
transition states for these transformations whose relative stabilities are consistent with the experimentally observed
stereoselectivity.
carbonyl compounds,8 vinyl sulfones, and α,β-unsaturated
INTRODUCTION
■
esters,9 providing benzylic fluorinated centers with almost
complete control of the stereoselectivity (Scheme 1).
Organofluorine compounds are well-recognized as strong
candidates for pharmaceutical, agrochemical, and high-perform-
ance materials because of the ability of the fluorine atom to
modulate molecular characteristics.1 However, because fluori-
nated compounds occur extremely rarely in nature,2 fluorine
substituents are generally introduced into molecules through
chemical synthesis. The two main strategies that have been
developed for preparing monofluorinated molecules are
electrophilic fluorination of active methylene compounds and
nucleophilic monofluoroalkylation reactions of electrophiles,
with their asymmetric versions being notably commendable.
The former makes possible the preparation of enantiomerically
enriched (ee) α-fluorocarbonyl derivatives and allylic fluorides,3
whereas the latter, mainly based on the contributions of Olah,4
Hu,5 and Shibata and Toru,6 provide monofluoroalkyl
derivatives by using as efficient nucleophilic monofluorome-
thylating reagents fluoromethyl carbanions stabilized by some
electron-withdrawing substituent (normally sulfonyl ones),
removal of which produces CH2F groups, thus excluding the
possibility of preparing compounds with the fluorine atom
joined to a chiral carbon. Therefore, the stereoselective
construction of a fluorinated chiral carbon center still remains
an attractive challenging task. In this regard, we have recently
reported that the Li carbanion derived from 1-(fluoromethyl)-
2-[(S)-p-tolylsulfinyl]benzene, [Li]-(S)-1, is efficiently stabi-
lized by the remote o-sulfinyl group and can be used as an
efficient chiral monofluorinated reagent in its reactions with
electrophiles such as (R)-N-sulfinyl aldimines,7 prochiral
With the aim of widening the scope of the nucleophilic
monofluorobenzylation reactions with our chiral monofluori-
Scheme 1. Synthesis of Homochiral Benzylic Fluorinated
Centers Using [Li]-(S)-1
Received: May 19, 2014
© XXXX American Chemical Society
A
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Table 1. Reactions of (S)-1 with Allyl Bromides 2a−e
a
b
entry
allyl bromide
R1
R2
R3
d.r. (3/3′)
yield (%)
c
1
2
3
4
5
(S)-2a
(S)-2b
(S)-2c
(S)-2d
(S)-2e
H
H
H
78:22
81:19
88:12
85:15
80:20
78
65
78
69
68
H
H
CH3
H
c
CH3
CH3
C6H5
H
CH3
H
H
H
a
b
1
Diastereomeric ratios determined by H NMR spectroscopy on the crude reaction mixtures. Isolated yields of the major isomers after flash
c
chromatography. Combined yield.
Table 2. Reactions of (S)-1 with Propargyl Halides 4a−i
a
b
entry
propargyl bromide
R
X
d.r. (5/5′)
yield (%)
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
H
Br
Cl
Br
Br
Br
Br
Br
Br
Br
>98:<2
96:4
74
73
75
72
75
C6H5
1-naphthyl
p-CH3C6H4
p-OMeC6H4
p-CNC6H4
Si(Me)3
96:4
96:4
95:5
c
65:35
98:2
65
4g
4h
68
62
60
CH3
88:12
85:15
4i
CH2CH3
a
b
1
Diastereomeric ratios determined by H NMR spectroscopy on the crude reaction mixtures. Isolated yields of the major isomers after flash
c
chromatography. Combined yield.
nated reagent (S)-1, we have studied its reactions with allyl and
propargyl halides as an easy entry to homoallylic and
homopropargylic monofluorides, respectively, bearing the
fluorine atom attached to a chiral center (Scheme 1). These
compounds constitute important building blocks in the
construction of a wide library of chiral fluorinated molecules,
taking advantage of the chemical versatility of the easily
modifiable double and triple bonds present in their structures.10
Despite this potential interest, the chemistry of homoallylic and
homopropargylic fluorides, in both racemic and enantioen-
riched forms, remains underexplored because of the absence of
reported methods allowing their preparation. Herein we
describe the results we have obtained in the asymmetric
nucleophilic monofluorobenzylation of allyl and propargyl
halides with the α-fluoro-γ-sulfinylbenzyl carbanion derived
from (S)-1, which allows the synthesis of enantioenriched
homoallylic and homopropargylic monofluorides with the
fluorine atom joined to a chiral benzylic carbon.
propargylic alcohol with the appropriate aryl iodide followed
by a mesylation/bromination protocol.11
We first studied the behavior of (S)-1 with allyl bromides
2a−e. The alkylation reactions were performed in THF using
1.2 equiv of LDA (generated in situ at −78 °C), to which were
added 1 equiv of (S)-1 and, after 10 min of stirring, 2 equiv of
allyl bromide 2. In all cases, the reactions were complete in less
than 1 min. As summarized in Table 1, this process provided a
mixture of two diastereomers 3 and 3′ differing in the
configuration at the newly created stereogenic center. The
reaction of Li-(S)-1 and 2a, with no substituents on the olefinic
fragment, led to a 78:22 mixture of 3a and 3′a, which are
epimers at the benzylic carbon (entry 1). A slight improvement
in the stereoselectivity was observed in the reactions with
substituted allyl bromides 2b−e. Thus, the β-methyl-
substituted allyl bromide 2b yielded an 81:19 distereoisomeric
mixture of 3b and 3′b (entry 2). The reaction with (E)-1-
bromobut-2-ene (2c) proceeded with better diatereoselectivity
(76% de; entry 3), which is very similar to that obtained in the
reaction with the γ-disubstituted allyl bromide 2d (3d/3′d =
85:15; entry 4). Alkylation of cinamyl bromide (2e) was also
tested. Once again, only moderate stereoselectivity was
achieved (3e/3′e = 80:20) but the major isomer 3e was
isolated as a pure compound in 68% isolated yield (entry 5).
These results suggest that the sulfinyl group is not able to exert
complete control over the stereoselectivity of the process,
RESULTS AND DISCUSSION
■
Optically pure (S)-1 was successfully prepared in a three-step
sequence (sulfinylation, tosylation, and fluorination with CsF)
starting from 2-bromobenzylic alcohol according to the
procedure previously reported by us.7 Allyl and propargyl
halides were commercially available except for alkynes 4d−f,
which were prepared by Sonogashira coupling of the
B
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which contrasts with the results obtained in all of the other
reactions with (S)-1 studied to date7−9 (see Scheme 1).
Next, we considered the addition of our fluorinated
benzyllithium derivative [Li]-(S)-1 to propargyl halides 4 to
get the corresponding homopropargylic fluorides. Two main
complications in the preparation of these compounds are the
lower reactivities of propargylic substrates in comparison with
allylic ones [determining incomplete conversions of (S)-1] and
the difficulties associated with control of the regioselectivity
(SN2 vs SN2′). We found that the optimal conditions involved
the addition of 4 molar equiv of propargyl bromides 4 to [Li]-
(S)-1. Under these conditions, quantitative conversions and
completely regioselective processes were obtained, giving the
SN2 products, in most cases as mixtures of two diastereomers, 5
and 5′ (epimers at the benzylic position), which were readily
separated by flash chromatography.
homopropargylic fluorides or their sulfonyl derivatives
prevented us from unequivocally assigning their absolute
configurations by X-ray analysis. However, a detailed study of
the NMR spectra of the diastereomers 5 and 5′ revealed that
there were systematic differences in their chemical shifts,
allowing the unequivocal differentiation of the epimers at the
benzylic carbon (see the Supporting Information). Focusing
our attention on protons Ha, Hb, and Hx (Table 3), we
observed that the major isomers 5 always showed δH values
lower (by ∼0.1−0.2 ppm) than those of the corresponding
minor isomers 5′ (Table 3).
Table 3. Chemical Shifts (in ppm) of Compounds 5 and 5′
That Are Significant for Their Configurational Assignment
The reaction starting from propargyl bromide (4a) gave the
desired homopropargylic fluoride 5a in 74% yield with
complete diastereoselectivity (>98% de; Table 2, entry 1).
This result proves that the sulfinyl group completely controls
the configuration at the newly created stereogenic fluorinated
carbon. The reaction with γ-phenylpropargyl chloride (4b)
evolved with high diastereoselectivity, furnishing a 96:4 mixture
of 5b and 5′b. Other γ-arylpropargyl bromides bearing a 1-
naphthyl group (4c) or a phenyl ring with an electron-donating
group such as p-Me (4d) or p-MeO (4e) afforded similar
results (about 92% de; entries 3−5). In contrast, the presence
of an electron-withdrawing group on the benzene ring of the
propargyl bromide, such as p-CN (4f), strongly decreased the
stereoselectivity (entry 6).12 These results suggested a
significant role of electronic factors in the stereochemical
course of the reaction. We also studied the reaction with TMS-
propargyl bromide (4g), which proceeded with almost
complete diastereoselectivity (96% de; entry 7). Finally,
reactions of γ-alkylpropargyl bromides (4h and 4i) evolved
with high but incomplete stereoselectivity, giving easily
separable 7:1 mixtures of diastereomers 5 and 5′ in good
isolated yields (entries 8 and 9).
5
5′
R
δH
δH
δH
δH
δH
δH
x
a
b
x
a
b
C6H5
2.90
3.17
2.87
2.94
2.99
2.82
2.99
2.71
2.78
2.88
6.06
6.18
5.97
6.03
6.09
5.93
5.90
6.02
3.13
3.07
6.23
6.23
6.13
6.20
6.29
6.09
6.06
6.33
1-naphthyl
p-MeC6H4
p-OMeC6H4
p-CNC6H4
Me
3.17 (2H)
3.03
3.10
2.98
3.05
3.12 (2H)
2.47−2.70 (2H)
2.71−2.90 (2H)
2.76−2.87 (2H)
Et
2.68
2.50
a
Me
2.49
2.43
3.05
2.89
a
Estimated by theoretical calculations of model compounds in which a
phenyl group was used as a simplified model for tolyl one.
1
Aditionally, H chemical shifts of model compounds for 5h
and 5′h (R = Me; Ph instead of Tol) were estimated by means
of DFT calculations.15 The calculated chemical shifts
correspond to conformationally averaged values from the
most relevant conformers (eight structures in each case)
according to a Boltzmann analysis.16 The most stable structures
showed a favored anti arrangement of the S−O and C−F
bonds, minimizing the dipole moments. In the case of 5h, this
arrangement locates Ha, Hb, and Hx under the shielding effect
of the p-tolylsulfinyl group, which could explain the slightly
lower chemical shifts calculated for these protons, in good
agreement with experimentally observed values, thus support-
ing the configurational assignment.
Removal of the chiral auxiliary from the major monofluori-
nated homopropargyl derivatives could be successfully
performed with Raney Ni.13 We checked the efficiency of this
procedure in the cases of 5d and 5i (Scheme 2). The
corresponding monofluorinated homopropargylic compounds
6d and 6i were obtained in good yields as pure compounds.
Scheme 2. Desulfinylation of 5d and 5i with Raney Ni
On the other hand, we were interested in understanding the
origin of the diastereoselectivity observed in these processes as
well as its dependence on electronic factors. To this end, we
carried out a theoretical study of the possible transition states
that would afford compounds 5b, 5f, and 5h and their
corresponding diastereomers 5′b, 5′f, and 5′h. The different
configurations of these compounds are determined during the
C−C bond formation by the approach of the electrophile to
either the Re or Si face of the benzylic position of carbanion 1.
Since our previous theoretical studies on the structure of this
carbanion7 indicated similar contributions of conformations
with the fluorine and sulfinyl groups in syn or anti
arrangements, which would afford different configurations for
the approach of the electrophile to the same face of the
carbanion plane, several transition states varying the approach
Initially, the configurational assignments of diastereomers 3
and 3′ (Table 1) as well as 5 and 5′ (Table 2) were based on
the assumption that these reactions would follow the same
stereochemical course that has been demonstrated for all of the
other previously studied reactions of electrophiles with (S)-
17−9 and other γ-sulfinylbenzyl carbanions.14 According to this,
we tentatively assigned the R configuration at the fluorinated
carbon atom for the major compounds 3 and 5 and the S
configuration for the minor ones 3′ and 5′. The impossibility of
obtaining good crystals from any of the synthesized allylic and
C
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Figure 1. Calculated structures [CPCM(THF)/wB97xd/6-311G(d,p) (C,H,N,O,F) and SDB-cc-pVTZ (Br)//6-31G(d) (C,H,N,O,F) and
LANL2DZ* (Br)] of some possible transition states involved in the reaction of propargyl bromides 4 with [Li]-(S)-1.18 Values of the relative
Gibbs free energy (ΔGrelat, kcal·mol−1), representative distances (d1 and d2, in Å), and the F−C1−C2−C3 torsion angle (τ, in deg) are indicated.
of the electrophile to both faces of the benzylic position as well
as to both faces of the carbanion plane were studied. The most
relevant results are summarized in Figure 1.17
the p-CN group is observed, indicating a stronger interaction in
this case.
The results provided by the theoretical calculations are in
perfect concordance with the experimental ones. Thus, in the
reaction of 4b (R = Ph), TS-Re,syn is more stable than TS-
Si,syn (2.3 kcal/mol) and TS-Si,anti (2.4 kcal/mol), allowing
the prediction of a 98:2 diastereomeric ratio (96:4 was
determined by NMR analysis; Table 2, entry 2). However,
TS-Si,syn becomes much more stable for 4f (R = p-CNC6H4,
ΔGrelat = 0.7 kcal/mol), and the model predicts a 77:23 ratio of
5f and 5′f, very similar to the 65:35 ratio obtained
experimentally (Table 2, entry 6). Finally, in the case of 4h
(R = Me), TS-Si,anti is only 1.3 kcal/mol less stable than TS-
Re,syn, affording a calculated distereomeric ratio of 90:10, in
good agreement with the experimentally observed selectivity of
88:12 (Table 2, entry 8).
The most stable transition state in all cases was TS-Re,syn,
which would afford products showing the R configuration at the
benzylic position. In this transition state, the F−C1−C2−C3
dihedral angle (τ) is almost 180°, indicating that the triple bond
adopts an antiperiplanar arrangement with respect to the
fluorine atom, thus minimizing the steric interactions and the
electronic repulsion of the lone electron pairs on fluorine with
the π electrons of the triple bond. The other two TSs (TS-
Si,syn and TS-Si,anti) would afford the S diastereomer. They
are sterically less stable because the triple bond adopts an
almost eclipsed arrangement with respect to one of the benzylic
hydrogens (τ close to 120°). In the case of TS-Si,anti, this
arrangement minimizes the interactions of the R−CC and
SOPh moieties (strongly repulsive for the antiperiplanar
arrangement between F and R−CC) and is less destabilizing
when R = Me (ΔGrelat = 1.3 kcal/mol). By contrast, deviations
of the antiperiplanar arrangement between F and R−CC in
TS-Si,syn must be attributed to a stabilizing π−π-stacking
interaction between the aryl group and the triple bond. As the
relative Gibbs free energy (ΔGrelat) varies in the order p-
CNC6H4 < C6H5 < Me (Figure 1), we conclude that the
presence of the aryl ring on the triple bond reinforce this π−π-
stacking interaction, mainly for deactivated rings. These
electronic effects translate into certain structure parameters of
TS-Si,syn that are shown in Figure 2. Thus, the C1−C2−C3
CONCLUSION
■
We have studied the asymmetric nucleophilic monofluoroben-
zylation of allyl and propargyl halides with 2-(p-tolylsulfinyl)-
benzyl fluorides in the presence of LDA. The evolution of the
fluorinated benzylcarbanions stabilized by a remote sulfinyl
group is highly stereoselective, which allows the synthesis of
homoallylic and homopropargylic fluorides with high optical
purity. The course of the reaction has been studied by
theoretical calculations, which provide results that are in an
excellent agreement with the experimental data.
EXPERIMENTAL SECTION
■
General Methods. Dry solvents and liquid reagents were distilled
under argon just prior to use; THF and CH2Cl2 were dried over
activated 4 Å molecular sieves, and diisopropylamine was dried over
KOH. n-BuLi (2.5 M solution in hexane) was purchased from a
commercial supplier and used as received. Reactions were carried out
in flame- or oven-dried glassware under an inert Ar atmosphere. NMR
spectra were acquired on a 400 MHz spectrometer running at 400,
Figure 2. Calculated structures [CPCM(THF)/wB97xd/6-311G(d,p)
(C,H,N,O,F) and SDB-cc-pVTZ (Br)//6-31G(d) (C,H,N,O,F) and
LANL2DZ* (Br)] of TS-Si,syn. Values of the relative Gibbs free
energy (ΔGrelat, kcal·mol−1), representative distances (d3, d4, and d5, in
Å), and the C1−C2−C3 bond angle (α in deg) are indicated.
1
100, and 375 MHz for H, 13C, and 19F, respectively. Chemical shifts
(δ) are reported in parts per million relative to residual solvent signals
1
(CDCl3, 7.26 ppm for H NMR spectra and 77.0 ppm for 13C NMR
spectra), and coupling constants (J) are given in hertz. 13C NMR
spectra were acquired in broadband-decoupled mode. Mass spectra
were measured by electron impact (EI, 70 eV) or fast atom
bombardment (FAB). Analytical thin-layer chromatography (TLC)
was performed using precoated aluminum-backed plates and visualized
by UV irradiation or phosphomolybdic acid solution. Purification of
reaction products was carried out by flash chromatography (FC) using
silica gel and an SCX column. Diastereoisomeric ratios were
determined from integration of well-separated signals in the 1H
NMR and 19F spectra of the crude reaction mixtures (H−C1 for
angle (α) and the C1′−C3 distance (d3) decrease as π−π-
stacking interactions increase. The distances between the
centroid of the aromatic ring on the nucleophile and the triple
bond of the electrophile (d4) are the same for aromatic R
groups, but d4 is slightly longer for R = Me.19 Moreover, a
shorter distance between the aromatic rings (d5) in the case of
D
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compounds 3/3′ and 5/5′). Melting points were measured in open
capillary tubes and are uncorrected. The optical rotation was measured
at room temperature using a polarimeter (concentration c given in g/
100 mL).
system, 4H), 7.39−7.56 (m, 3H), 8.02 (dd, 1H, J = 1.2, 8.0 Hz); 13C
NMR (100 MHz, CDCl3) δ 18.0, 21.4, 40.1 (d, JC−F = 24.3 Hz), 90.6
(d, JC−F = 174.7 Hz), 124.7 (d, JC−F = 3.8 Hz), 125.3, 126.1, 127.0,
127.9, 129.5 (d, JC−F = 7.6 Hz), 130.1, 131.2, 138.3 (d, JC−F = 21.0
Hz), 142.0, 142.5 (d, JC−F = 2.6 Hz); 19F NMR (375 MHz, CDCl3) δ
Allyl bromides 2a−e and propargyl bromides 4a−c and 4g−i were
commercially available. Propargyl bromides 4d−f were prepared by
Sonogashira coupling of the propargylic alcohol with the appropriate
aryl iodide followed by a mesylation/bromination protocol.11
General Procedure for the Reactions Summarized in Table
1. A solution of n-BuLi (0.6 mmol, 2.3 M in hexane) was added to
iPr2NH (0.9 mmol) in THF (3 mL) at 0 °C. After 10 min of stirring,
the mixture was cooled to −78 °C, and then a solution of the
compound (S)-1 (0.5 mmol) in THF (2 mL) was added. After 30 min
of stirring, the corresponding allyl halide 2a−e, (1 mmol) in THF (2
mL) was added at −78 °C. When the reaction was completed (15
min), the mixture was hydrolyzed at that temperature with saturated
aqueous NH4Cl solution (2 mL) and extracted with CH2Cl2 (3 × 10
mL). The combined organic layers were dried over MgSO4, and the
solvent was removed under reduced pressure. The residue was purified
by flash column chromatography.
1
−169.8 (ddd, 1F, J = 17.3, 31.0, 47.3 Hz). Minor diastereomer: H
NMR δ 1.45 (d, 3H, J = 6.8 Hz), 2.23−2.40 (m, 1H), 2.34 (s, 3H),
2.56−2.70 (m, 1H), 5.72 (ddd, 1H, J = 7.0, 8.5, 46.7 Hz), 5.79−6.03
(m, 2H), 7.21−7.46 (AA′BB′ system, 4H), 7.39−7.56 (m, 3H), 7.87−
7.92 (m, 1H); 19F NMR (375 MHz, CDCl3) δ −174.0 (ddd, 1F, J =
17.8, 28.2, 46.7 Hz). HRMS calcd for C18H19FOSNa (TOF/ESI+)
([M + Na]+) 325.1032, found 325.1045.
1-[(R)-1-Fluoro-4-methylpent-3-enyl]-2-[(S)-p-tolylsulfinyl]-
benzene (3d). Compound 3d was obtained as the major diastereomer
from allyl bromide 2d and (S)-1. Eluent for chromatography hexane/
CH2Cl2/AcOEt 3:2:1; yield 69% (108 mg); white syrup; [α]D20
=
1
−57.8 (c 0.5, CHCl3); H NMR (400 MHz, CDCl3) δ 1.45 (s, 3H),
1.67 (s, 3H), 2.15−2.31 (m, 1H), 2.34 (s, 3H), 2.58 (qd, 1H, J = 8.2,
15.8 Hz), 5.03−5.13 (m, 1H), 5.77 (ddd, 1H, J = 4.6, 8.2, 46.8 Hz),
7.21 and 7.46 (AA′BB′ system, 4H), 7.37−7.56 (m, 3H), 8.01 (d, 1H,
J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 17.8, 21.4, 25.7, 35.8 (d,
JC−F = 24.4 Hz), 90.9 (d, JC−F = 174.7 Hz), 117.6 (d, 4.0 Hz), 125.4,
125.9, 126.9 (d, JC−F = 7.5 Hz), 129.5, 130.0, 131.1, 135.8, 138.8 (d,
JC−F = 20.6 Hz), 141.6, 142.0, 142.6 (d, JC−F = 2.3 Hz); 19F NMR (375
MHz, CDCl3) δ −168.8 (ddd, 1F, J = 15.8, 29.0, 46.8 Hz); HRMS
calcd for C19H21FOSNa (TOF/ESI+) ([M + Na]+) 339.1189, found
339.1178.
1-[(R/S)-1-Fluorobut-3-enyl]-2-[(S)-p-tolylsulfinyl]benzene (3a/
3′a). These compounds were obtained as an inseparable mixture of
diastereomers (78:22) from allyl bromide 2a and (S)-1. Eluent for
chromatography hexane/AcOEt 5:1; yield 78% (113 mg); colorless oil.
1
Major diastereomer: H NMR (400 MHz, CDCl3) δ 2.08−2.20 (m,
1H), 2.35 (s, 3H), 2.48−2.66 (m, 1H), 4.96−5.11 (m, 2H), 5.67−5.83
(m, 1H), 5.81 (ddd, 1H, J = 3.8, 8.8, 47.7 Hz), 7.22 and 7.46 (AA′BB′
system, 4H), 7.36−7.62 (m, 3H), 8.04 (d, 1H, J = 7.6 Hz); 13C NMR
1-[(S)-1-Fluoro-4-methylpent-3-enyl]-2-[(S)-p-tolylsulfinyl]-
benzene (3′d). Compound 3′d was obtained as the minor
diastereomer from allyl bromide 2d and (S)-1, and it was characterized
from a mixture of diastereomers 3d and 3′d. Eluent for
(100 MHz, CDCl3) δ 21.4, 40.1 (d, JC−F = 24.0 Hz), 90.6 (d, JC−F
=
173.3 Hz), 124.7 (d, JC−F = 3.8 Hz), 125.9, 126.0, 127.0, 127.9, 129.5
(d, JC−F = 7.5 Hz), 130.0, 131.2, 138.3 (d, JC−F = 21.0 Hz), 141.9,
142.5 (d, JC−F = 3.5 Hz); 19F NMR (375 MHz, CDCl3) δ −170.7
1
chromatography hexane/CH2Cl2/AcOEt 3:2:1; H NMR (400 MHz,
1
(ddd, 1F, J = 17.4, 31.4, 47.7 Hz). Minor diastereomer: H NMR (400
CDCl3) δ 1.56 (s, 3H), 1.71 (s, 3H), 2.16−2.41 (m, 1H), 2.34 (s, 3H),
2.60−2.78 (m, 1H), 5.13−5.20 (m, 1H), 5.91 (ddd, 1H, J = 5.6, 7.6,
47.2 Hz), 7.22 and 7.47 (AA′BB′ system, 4H), 7.39−7.56 (m, 3H),
7.89 (dd, 1H, J = 3.6, 5.3 Hz); 19F NMR (375 MHz, CDCl3) δ −173.9
(ddd, 1F, J = 19.2, 28.4, 47.2 Hz).
1-[(R)-1-Fluoro-4-phenylbut-3-enyl]-2-[(S)-p-tolylsulfinyl]benzene
(3e). Compound 3e was obtained as the major diastereomer from allyl
bromide 2e and (S)-1. Eluent for chromatography hexane/CH2Cl2/
AcOEt 3:1:1; yield 68% (124 mg); white syrup; [α]2D0 = −85.1 (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.29−2.41 (m, 1H), 2.34 (s,
3H), 2.74 (dddd, 1H, J = 6.7, 8.4, 15.1, 19.3 Hz), 5.89 (ddd, 1H, J =
4.2, 8.5, 47.7 Hz), 6.10 (ddd, 1H, J = 6.7, 7.4, 16.6 Hz), 6.31 (d, 1H, J
= 16.6 Hz), 7.19 and 7.46 (AA′BB′ system, 4H), 7.21−7.30 (m, 4H),
7.47−7.60 (m, 4H), 8.04 (dt, 1H, J = 1.3, 7.5 Hz); 13C NMR (100
MHz, CDCl3) δ 21.4, 40.5 (d, JC−F = 24.5 Hz), 90.0 (d, JC−F = 175.1
Hz), 123.6 (d, JC−F = 4.0 Hz), 125.5, 126.1, 126.2, 127.0 (d, JC−F = 7.2
MHz, CDCl3) δ 2.20−2.27 (m, 1H), 2.35 (s, 3H), 2.66−2.79 (m, 1H),
5.12−5.20 (m, 2H), 5.67−5.83 (m, 1H), 6.00 (ddd, 1H, J = 4.7, 7.9,
46.8 Hz), 7.23 and 7.47 (AA′BB′ system, 4H), 7.36−7.62 (m, 3H),
7.90 (t, 1H, J = 4.4 Hz); 19F NMR (375 MHz, CDCl3) δ −174.6 (ddd,
1F, J = 18.1, 28.8, 46.8 Hz). HRMS calcd for C17H17FOSNa (TOF/
ESI+) ([M + Na]+) 311.0876, found 311.0862.
1-[(R)-1-Fluoro-3-methylbut-3-enyl]-2-[(S)-p-tolylsulfinyl]benzene
(3b). Compound 3b was obtained as the major diastereomer from allyl
bromide 2b and (S)-1. Eluent for chromatography hexane/CH2Cl2/
AcOEt 3:2:1; yield 65% (100 mg); white syrup; [α]2D0 = +26.0 (c 0.5,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.72 (s, 3H), 2.08 (ddd, 1H,
J = 3.2, 15.2, 36.3 Hz), 2.35 (s, 3H), 2.58 (qd, 1H, J = 9.6, 15.2 Hz),
4.76 (s, 1H), 4.86 (s, 1H), 5.93 (ddd, 1H, J = 3.2, 9.6, 47.2 Hz), 7.23
and 7.49 (AA′BB′ system, 4H), 7.46−7.57 (m, 3H), 8.03 (d, 1H, J =
7.5 Hz); 13C NMR (100 MHz, CDCl3) δ 21.4, 22.7, 45.0 (d, JC−F
=
24.3 Hz), 89.3 (d, JC−F = 175.0 Hz), 113.8, 125.6, 126.1, 126.9 (d, JC−F
= 7.2 Hz), 129.6, 130.1, 131.4, 138.6 (d, JC−F = 27.9 Hz), 138.8, 140.6,
141.8, 142.2 (d, JC−F = 3.5 Hz); 19F NMR (375 MHz, CDCl3) δ
−169.9 (ddd, 1F, J = 15.2, 36.3, 47.2 Hz); HRMS calcd for
C18H19FOSNa (TOF/ESI+) ([M + Na]+) 325.1032, found 325.1021.
1-[(S)-1-Fluoro-3-methylbut-3-enyl]-2-[(S)-p-tolylsulfinyl]benzene
(3′b). Compound 3′b was obtained as the minor diastereomer from
allyl bromide 2b and (S)-1, and it was characterized from a mixture of
diastereomers 3b and 3′b. Eluent for chromatography hexane/
Hz), 127.5, 128.5, 130.0, 130.1, 131.3, 133.7, 136.9, 138.0 (d, JC−F =
21.1 Hz), 141.7, 141.8, 142.3; 19F NMR (375 MHz, CDCl3) δ −175.2
(ddd, 1F, J = 19.3, 29.0, 47.7 Hz); HMRS calcd C23H21FS ([M − O]+)
348.1348, found 348.1332.
1-[(S)-1-Fluoro-4-phenylbut-3-enyl]-2-[(S)-p-tolylsulfinyl]benzene
(3′e). Compound 3′e was obtained as the minor diastereomer from
allyl bromide 2e and (S)-1, and it was characterized from a mixture of
diastereomers 3e and 3′e. Eluent for chromatography hexane/
CH2Cl2/AcOEt 3:1:1; 1H NMR (400 MHz, CDCl3) δ 2.30−2.42
(m, 1H), 2.35 (s, 3H), 2.78−2.92 (m, 1H), 6.07 (ddd, 1H, J = 4.4, 8.0,
47.0 Hz), 6.21 (dt, 1H, J = 7.1, 15.9 Hz), 6.48 (d, 1H, J = 15.9 Hz),
7.20−7.36 (m, 7H), 7.45−7.57 (m, 5H), 7.90 (dd, 1H, J = 3.6, 6.0
Hz); 19F NMR δ −169.8 (ddd, 1F, J = 17.0, 30.2, 47.0 Hz).
General Procedure for the Reactions Summarized in Table
2. A solution of n-BuLi (0.6 mmol, 2.3 M in hexane) was added to
iPr2NH (0.9 mmol) in THF (3 mL) at 0 °C. After 10 min of stirring,
the mixture was cooled to −78 °C, and then a solution of the
compound (S)-1 (0.5 mmol) in THF (2 mL) was added. After 30 min
of stirring, the corresponding propargyl compound 4a−j (2.0 mmol)
in THF (1 mL) was added at −78 °C. When the reaction was
completed (5 min), the mixture was hydrolyzed at that temperature
with saturated aqueous NH4Cl solution (2 mL) and extracted with
1
CH2Cl2/AcOEt 3:2:1; H NMR (400 MHz, CDCl3) δ 1.82 (s, 3H),
1.97−2.21 (m, 1H), 2.35 (s, 3H), 2.47−2.74 (m, 1H), 4.82 (s, 1H),
4.90 (s, 1H), 6.09 (ddd, 1H, J = 4.3, 8.6, 48.5 Hz), 7.24 and 7.50
(AA′BB′ system, 4H), 7.39−7.58 (m, 3H), 7.90 (dd, 1H, J = 3.6, 5.4
Hz); 19F NMR (375 MHz, CDCl3) δ −174.6 (ddd, 1F, J = 17.1, 32.9,
48.5 Hz).
1-[(R/S,E)-1-Fluoropent-3-enyl]-2-[(S)-p-tolylsulfinyl]benzene (3c/
3′c). These compounds were obtained as an inseparable mixture of
diastereomers (88:12) from allyl bromide 2c and (S)-1. Eluent for
chromatography hexane/AcOEt 5:1; yield 78% (127 mg); colorless oil.
1
Major diastereomer: H NMR (400 MHz, CDCl3) δ 1.63 (d, 3H, J =
6.0 Hz), 2.14 (dddd, 1H, J = 4.3, 6.2, 14.6, 31.0 Hz), 2.35 (s, 3H),
2.43−2.58 (m, 1H), 5.26−5.61 (m, 3H), 7.22 and 7.45 (AA′BB′
E
dx.doi.org/10.1021/jo501096f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
CH2Cl2 (3 × 10 mL). The combined organic layers were dried over
MgSO4, and the solvent was removed under reduced pressure. The
residue was purified by flash column chromatography.
and 7.42 (two AA′BB′ systems, 8H), 7.39−7.53 (m, 3H), 7.94 (dd,
1H, J = 2.0, 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 21.4, 21.5, 28.0
(d, JC−F = 27.3 Hz), 82.9, 83.4, 88.6 (d, JC−F = 177.5 Hz), 119.9, 125.5,
125.8, 127.3 (d, JC−F = 7.7 Hz), 128.9, 130.1, 131.2, 131.5, 137.0 (d,
JC−F = 20.9 Hz), 138.2, 141.5, 141.8, 142.5; 19F NMR (375 MHz,
CDCl3) δ −168.7 (ddd, 1F, J = 19.5, 22.2, 46.0 Hz); HMRS calcd for
C24H21FS ([M − O]+) 360.1348, found 360.1365.
1-[(R)-1-Fluoro-3-butynyl]-2-[(S)-p-tolylsulfinyl]benzene (5a).
Compound 5a was obtained as a unique diastereomer from propargyl
bromide 4a and (S)-1. Eluent for chromatography hexane/Et2O 1:2;
yield 74% (106 mg); colorless oil; [α]2D0 = −102.4 (c 1.0, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 2.01 (t, 1H, J = 2.6 Hz), 2.35 (s, 3H), 2.49
(dddd, 1H, J = 2.6, 4.6, 17.3, 24.4 Hz), 2.70 (dddd, 1H, J = 2.6, 7.2,
17.3, 19.2 Hz), 5.94 (ddd, 1H, J = 4.6, 7.2, 46.0 Hz), 7.23 (part of
AA′BB′ system, 2H), 7.43−7.58 (m, 5H), 8.00 (d, 1H, J = 7.6 Hz);
13C NMR (100 MHz, CDCl3) δ 21.4, 27.0 (d, JC−F = 27.0 Hz), 71.3,
1-[(S)-1-Fluoro-4-tolyl-3-butynyl]-2-[(S)-p-tolylsulfinyl]benzene
(5′d). Compound 5′d was obtained as the minor diastereomer from
propargyl bromide 4d and (S)-1, and it was characterized from a
mixture of diastereomers 5d and 5′d. Eluent for chromatography
1
hexane/CH2Cl2/AcOEt 3:1:1; H NMR (400 MHz, CDCl3) δ 2.26
78.3, 88.2 (d, JC−F = 182.0 Hz), 125.6, 125.8, 127.2 (d, JC−F = 7.9 Hz),
129.9, 130.1, 131.3, 141.5, 141.8, 142.4; 19F NMR (375 MHz, CDCl3)
δ −169.8 (ddd, 1F, J = 19.2, 24.4, 46.0 Hz); HMRS calcd for C17H15FS
([M − O]+) 270.0878, found 270.0889.
and 2.30 (two s, 6H), 2.98 (ddd, 1H, J = 6.0, 18.4, 22.2 Hz), 3.03
(ddd, 1H, J = 6.4, 20.4, 22.2 Hz), 6.13 (ddd, 1H, J = 6.0, 6.4, 46.4 Hz),
7.02 (part of AA′BB′ system, 2H), 7.11−7.22 (m, 4H), 7.41−7.52 (m,
4H), 7.57 (dd, 1H, J = 4.6, 6.4 Hz), 7.87 (dd, 1H, J = 5.0, 6.8 Hz); 19F
NMR (375 MHz, CDCl3) δ −171.9 (ddd, 1F, J = 18.4, 20.4, 46.4 Hz).
1-[(R)-1-Fluoro-4-(4-methoxyphenyl)-3-butynyl]-2-[(S)-p-
tolylsulfinyl]benzene (5e). Compound 5e was obtained as the major
diastereomer from propargyl bromide 4e and (S)-1. Eluent for
chromatography hexane/AcOEt 2:1; yield 75% (147 mg); white syrup;
1-[(R)-1-Fluoro-4-phenyl-3-butynyl]-2-[(S)-p-tolylsulfinyl]benzene
(5b). Compound 5b was obtained as the major diastereomer from
propargyl chloride 4b and (S)-1. Eluent for chromatography hexane/
Et2O 1:2; yield 73% (133 mg); white syrup; [α]2D0 = −55.2 (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.35 (s, 3H), 2.82 (ddd, 1H,
J = 5.0, 17.1, 22.0 Hz), 2.90 (ddd, 1H, J = 6.7, 17.1, 27.7 Hz), 6.06
(ddd, 1H, J = 5.0, 6.7, 45.9 Hz), 7.21−7.37 (m, 6H), 7.50−7.60 (m,
2H), 7.52 and 7.58 (AA′BB′ system, 4H), 8.03 (dd, 1H, J = 1.8, 7.1
Hz); 13C NMR (100 MHz, CDCl3) δ 21.6, 28.2 (d, JC−F = 27.2 Hz),
83.6, 83.9, 88.7 (d, JC−F = 179.4 Hz), 125.9, 126.0, 127.5 (d, JC−F = 7.8
Hz), 128.3, 128.4, 130.2, 130.3, 131.5, 131.8, 137.3 (d, JC−F = 21.0
Hz), 141.9, 142.0, 142.9; 19F NMR (375 MHz, CDCl3) δ −169.1
(ddd, 1F, J = 22.0, 27.7, 45.9 Hz); HMRS calcd for C23H20FOS (M+ +
1) 363.1213, found 363.1216.
[α]2D0 = −63.4 (c 0.3, CHCl3); H NMR (400 MHz, CDCl3) δ 2.34
1
and 3.80 (two s, 6H), 2.78 (ddd, 1H, J = 5.0, 17.3, 22.3 Hz), 2.94
(ddd, 1H, J = 6.8, 17.3, 19.4 Hz), 6.03 (ddd, 1H, J = 5.0, 6.8, 46.0 Hz),
6.81, 7.21, 7.28, and 7.50 (two AA′BB′ systems, 8H), 7.48−7.59 (m,
3H), 8.03 (d, 1H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 21.4,
28.0 (d, JC−F = 27.6 Hz), 55.2, 82.1, 83.3, 88.6 (d, JC−F = 177.0 Hz),
113.8, 115.1, 125.6, 125.7, 127.3 (d, JC−F = 7.7 Hz), 129.9, 130.0,
130.1, 131.2, 133.0, 137.1 (d, JC−F = 21.0 Hz), 141.6, 141.7, 142.6,
159.4; 19F NMR (375 MHz, CDCl3) δ −168.5 (ddd, 1F, J = 19.4, 22.3,
46.0 Hz); HMRS calcd for C24H21FOS ([M − O]+) 376.1297, found
376.1283.
1-[(S)-1-Fluoro-4-phenyl-3-butynyl]-2-[(S)-p-tolylsulfinyl]benzene
(5′b). Compound 5′b was obtained as the minor diastereomer from
propargyl bromide 4b and (S)-1, and it was characterized from a
mixture of diastereomers 5b and 5′b. Eluent for chromatography
1-[(S)-1-Fluoro-4-(4-methoxyphenyl)-3-butynyl]-2-[(S)-p-
tolylsulfinyl]benzene (5′e). Compound 5′e was obtained as the minor
diastereomer from propargyl bromide 4e and (S)-1, and it was
characterized from a mixture of diastereomers 5e and 5′e. Eluent for
1
hexane/Et2O 1:2; H NMR (400 MHz, CDCl3) δ 2.38 (s, 3H), 3.07
(ddd, 1H, J = 6.4, 20.1, 21.8 Hz), 3.13 (ddd, 1H, J = 6.1, 18.6, 21.8
Hz), 6.23 (ddd, 1H, J = 6.1, 6.4, 46.0 Hz), 7.14 (part of AA′BB′
system, 2H), 7.22−7.42 (m, 4H), 7.49−7.75 (m, 6H), 7.88−7.90 (m,
1H); 19F NMR (375 MHz, CDCl3) δ −172.5 (ddd, 1F, J = 18.6, 20.1,
46.0 Hz).
1
chromatography hexane/AcOEt 2:1; H NMR (400 MHz, CDCl3) δ
2.37 and 3.79 (two s, 6H), 3.05 (ddd, 1H, J = 6.4, 20.0, 25.0 Hz), 3.10
(ddd, 1H, J = 6.0, 18.0, 25.0 Hz), 6.20 (ddd, 1H, J = 6.0, 6.4, 46.4 Hz),
6.81, 7.28, 7.32, and 7.53 (two AA′BB′ systems, 8H), 7.43−7.66 (m,
3H), 7.91−7.96 (m, 1H); 19F NMR (375 MHz, CDCl3) δ −171.9
(ddd, 1F, J = 18.0, 20.0, 46.4 Hz).
1-[(R)-1-Fluoro-4-naphthyl-3-butynyl]-2-[(S)-p-tolylsulfinyl]-
benzene (5c). Compound 5c was obtained as the major diastereomer
from propargyl bromide 4c and (S)-1. Eluent for chromatography
hexane/Et2O 1:1; yield 75% (155 mg); white syrup; [α]2D0 = −59.0 (c
2.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.36 (s, 3H), 2.99 (ddd,
1H, J = 5.2, 17.2, 22.0 Hz), 3.17 (ddd, 1H, J = 6.7, 18.5, 22.0 Hz), 6.18
(ddd, 1H, J = 5.2, 6.7, 46.0 Hz), 7.14 and 7.41 (AA′BB′ system, 4H),
7.38−7.70 (m, 8H), 7.71−7.79 (m, 2H), 8.06 (d, 1H, J = 7.7 Hz); 13C
NMR (100 MHz, CDCl3) δ 21.3, 28.1 (d, JC−F = 28.0 Hz), 81.5, 88.3,
(d, JC−F = 178.7.4 Hz), 89.4, 125.1, 125.6, 125.7, 126.0, 126.3, 126.6,
127.4 (d, JC−F = 7.5 Hz), 128.1, 128.5, 130.0, 130.1, 130.3, 131.3,
133.0, 133.3, 137.0 (d, JC−F = 20.8 Hz), 141.4, 141.7, 142.6; 19F NMR
(375 MHz, CDCl3) δ −168.5 (ddd, 1F, J = 17.2, 18.5, 46.0 Hz);
HMRS calcd for C27H21FS ([M − O]+) 396.1353, found 396.1336.
1-[(S)-1-Fluoro-4-naphthyl-3-butynyl]-2-[(S)-p-tolylsulfinyl]-
benzene (5′c). Compound 5′c was obtained as the minor
diastereomer from propargyl bromide 4c and (S)-1, and it was
characterized from a mixture of diastereomers 5c and 5′c. Eluent for
1-[(R/S)-1-Fluoro-4-(4-cyanophenyl)-3-butynyl]-2-[(S)-p-
tolylsulfinyl]benzene (5f/5′f). This compound was obtained as an
inseparable mixture of diastereomers (65:35) from propargyl bromide
5f and (S)-1. Eluent for chromatography hexane/Et2O 1:1; yield 65%
1
(126 mg); colorless syrup. Major diastereomer: H NMR (400 MHz,
CDCl3) δ 2.35 (s, 3H), 2.88 (ddd, 1H, J = 6.6, 15.0, 21.0 Hz), 2.99
(ddd, 1H, J = 6.9, 21.0, 24.0 Hz), 6.09 (ddd, 1H, J = 6.6, 6.9, 45.9 Hz),
7.23 and 7.27 (AA′BB′ system, 4H), 7.42−7.60 (m, 7H), 8.04 (d, 1H,
J = 7.1 Hz); 19F NMR (375 MHz, CDCl3) δ −170.1 (ddd, 1F, J =
15.0, 24.0, 45.9 Hz). Minor diastereomer: 1H NMR (400 MHz, CDCl3)
δ 2.37 (s, 3H), 3.12 (td, 2H, J = 6.3, 21.0 Hz), 6.29 (td, 1H, J = 6.3,
46.0 Hz), 7.33−7.62 (m, 10H), 7.68−7.72 (m, 1H), 7.88−7.92 (m,
1H); 19F NMR (375 MHz, CDCl3) δ −173.1 (ddd, 1F, J = 17.5, 20.0,
46.0 Hz). HMRS calcd for C24H18FNS ([M − O]+) 371.1144, found
371.1128.
1
1-[(R)-1-Fluoro-4-(trimethylsilyl)-3-butynyl]-2-[(S)-p-tolylsulfinyl]-
benzene (5g). Compound 5g was obtained as the major diastereomer
from propargyl bromide 4g and (S)-1. Eluent for chromatography
hexane/Et2O 1:1; yield 68% (122 mg); colorless oil; [α]2D0 = +60.0 (c
chromatography hexane/Et2O 1:1; H NMR (400 MHz, CDCl3) δ
2.28 (s, 3H), 3.19 (dd, 2H, J = 6.0, 20.0 Hz), 6.23 (td, 1H, J = 6.0, 46.0
Hz), 7.10 (part of AA′BB′ system, 2H), 7.15−7.21 (m, 2H), 7.26−
7.67 (m, 9H), 7.96−8.01 (m, 1H), 8.10−8.18 (m, 1H); 19F NMR (375
MHz, CDCl3) δ −168.1 (td, 1F, J = 20.0, 46.0 Hz).
1
2.0, CHCl3); H NMR (400 MHz, CDCl3) δ 0.14 (s, 9H), 2.38 (s,
3H), 2.59 (ddd, 1H, J = 4.8, 17.4, 22.4 Hz), 2.76 (ddd, 1H, J = 6.7,
17.4, 21.0 Hz), 5.93 (ddd, 1H, J = 4.8, 6.7, 45.7 Hz), 7.25 and 7.49
(AA′BB′ system, 4H), 7.48−7.60 (m, 3H), 8.01 (dd, 1H, J = 1.0, 7.5
Hz); 13C NMR (100 MHz, CDCl3) δ 0.1, 21.4, 28.4 (d, JC−F = 26.7
Hz), 88.3, 88.6 (d, JC−F = 178.9 Hz), 100.4, 125.5, 125.7, 127.5 (d, JC−F
= 8.1 Hz), 129.9, 130.1, 131.0, 136.7 (d, JC−F = 21.1 Hz), 141.6, 141.7,
142.3; 19F NMR (375 MHz, CDCl3) δ −170.0 (ddd, 1F, J = 21.0, 22.4,
1-[(R)-1-Fluoro-4-tolyl-3-butynyl]-2-[(S)-p-tolylsulfinyl]benzene
(5d). Compound 5d was obtained as the major diastereomer from
propargyl bromide 4d and (S)-1. Eluent for chromatography hexane/
CH2Cl2/AcOEt 3:1:1; yield 72% (136 mg); white syrup; [α]2D0 = +96.0
(c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.26 and 2.27 (two s,
6H), 2.71 (ddd, 1H, J = 5.0, 17.3, 22.2 Hz), 2.87 (ddd, 1H, J = 6.8,
17.3, 19.5 Hz), 5.97 (ddd, 1H, J = 5.0, 6.8, 46.0 Hz), 7.01, 7.14, 7.15,
F
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45.7 Hz); HMRS calcd for C20H23FSSi ([M − O]+) 342.1274, found
342.1285.
7.5 Hz), 2.12 (qt, 2H, J = 2.4, 7.5 Hz), 2.67−2.95 (m, 2H), 5.96 (dt,
1H, J = 6.4, 46.4 Hz), 7.33−7.62 (m, 4H), 7.83−7.93 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 12.3, 13.5, 28.0 (d, JC−F = 9.5 Hz), 74.9,
80.0, 89.6 (d, JC−F = 164.2 Hz), 128.7, 130.4, 136.6; 19F NMR (375
MHz, CDCl3) δ −176.4 (ddd, 1F, J = 14.9, 20.3, 46.7 Hz); HMRS
calcd for C12H12 ([M − HF]+) 156.0939, found 156.0923.
1-[(R)-1-Fluoro-3-pentynyl]-2-[(S)-p-tolylsulfinyl]benzene (5h).
Compound 5h was obtained as the major diastereomer from propargyl
bromide 4h and (S)-1. Eluent for chromatography hexane/
isopropanol 10:1; yield 62% (93 mg); colorless oil; [α]2D0 = −44.4 (c
1.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.76 (t, 3H, J = 2.5 Hz),
2.37 (s, 3H), 2.47−2.70 (m, 2H), 5.93 (ddd, 1H, J = 4.8, 7.2, 46.1 Hz),
7.25 and 7.50 (AA′BB′ system, 4H), 7.49−7.59 (m, 3H), 8.03 (dd, 1H,
J = 1.5, 7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 3.5, 21.4, 27.4 (d,
JC−F = 27.1 Hz), 73.2, 78.9, 89.0 (d, JC−F = 177.7 Hz), 123.5, 125.4,
125.7, 127.0 (d, JC−F = 7.6 Hz), 130.0, 131.2, 133.4, 136.2, 137.1 (d,
JC−F = 21.2 Hz), 138.8, 142.6; 19F NMR (375 MHz, CDCl3) δ −169.0
(ddd, 1F, J = 19.9, 22.5, 46.1 Hz); HMRS calcd for C18H18FOS (M+ +
1) 301.1056, found 301.1059.
1-[(S)-1-Fluoro-3-pentynyl]-2-[(S)-p-tolylsulfinyl]benzene (5′h).
Compound 5′h was obtained as the minor diastereomer from
propargyl bromide 4h and (S)-1, and it was characterized from a
mixture of diastereomers 5h and 5′h. Eluent for chromatography
hexane/isopropanol 10:1; 1H NMR (400 MHz, CDCl3) δ 1.70 (t, 3H,
J = 2.4 Hz), 2.36 (s, 3H), 2.71−2.90 (m, 2H), 6.09 (td, 1H, J = 6.3,
45.8 Hz), 7.25 (part of AA′BB′ system, 2H), 7.49−7.65 (m, 4H),
7.85−7.97 (m, 2H); 19F NMR (375 MHz, CDCl3) δ −171.6 (dd, 1F, J
= 18.4, 45.8 Hz).
1-[(R)-1-Fluoro-3-hexynyl]-2-[(S)-p-tolylsulfinyl]benzene (5i).
Compound 5i was obtained as the major diastereomer from propargyl
bromide 4i and (S)-1. Eluent for chromatography hexane/CH2Cl2/
AcOEt 3:1:1; yield 60% (95 mg); colorless oil; [α]2D0 = −121.8 (c 0.5,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.07 (t, 3H, J = 7.5 Hz), 2.12
(qd, 2H, J = 2.4, 7.5 Hz), 2.35 (s, 3H), 2.50 (dddd, 1H, J = 2.4, 4.8,
17.1, 23.5 Hz), 2.68 (dddd, 1H, J = 2.4, 7.1, 17.1, 19.5 Hz), 5.90 (ddd,
1H, J = 4.8, 7.5, 46.1 Hz), 7.22 and 7.47 (AA′BB′ system, 4H), 7.48−
7.57 (m, 3H), 7.99 (d, 1H, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3)
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental and computational details as well as spectroscopic
and analytical data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: atejedor@eii.uva.es.
*E-mail: joseluis.garcia.ruano@uam.es.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support of this work by the Spanish Government
(CTQ2012-35957) is gratefully acknowledged. We thank the
■
́
Centro de Computacion
allocation of computer time.
́
Cientifica de la UAM for a generous
REFERENCES
■
(1) For recent reviews, see: (a) O’Hagan, D. Chem. Soc. Rev. 2008,
37, 308. (b) Beg
́
ue,
́
J.-P.; Bonnet-Delpon, D. In Bioorganic and
Medicinal Chemistry of Fluorine; John Wiley & Sons: Hoboken, NJ,
2008. (c) Kirck, K. L. Org. Process Res. Dev. 2008, 12, 305−321.
(d) Hunter, L. Beilstein J. Org. Chem. 2010, 6, No. 38. For other
references, see: (e) Sparr, C.; Schweizer, W. B.; Senn, H. M.; Gilmour,
R. Angew. Chem., Int. Ed. 2009, 48, 3065. (f) Sparr, C.; Gilmour, R.
Angew. Chem., Int. Ed. 2010, 49, 6520.
δ 12.4, 13.9, 21.4, 27.4 (d, JC−F = 27.0 Hz), 73.3, 85.0, 89.1 (d, JC−F
=
176.8 Hz), 125.3, 125.4, 125.8, 127.2 (d, JC−F = 7.6 Hz), 129.9, 130.0,
130.1, 131.2, 137.1 (d, JC−F = 21.3 Hz), 141.7; 19F NMR (375 MHz,
CDCl3) δ −168.8 (ddd, 1F, J = 19.5, 23.5, 46.1 Hz); HMRS calcd for
C19H18OS ([M − HF]+) 294.1078, found 294.1105.
1-[(S)-1-Fluoro-3-hexynyl]-2-[(S)-p-tolylsulfinyl]benzene (5′i).
Compound 5′i was obtained as the minor diastereomer from
propargyl bromide 4i and (S)-1, and it was characterized from a
mixture of diastereomers 5i and 5′I. Eluent for chromatography
hexane/Et2O 1.5:1; 1H NMR (400 MHz, CDCl3) δ 1.07 (t, 3H, J = 7.6
Hz), 2.13 (qd, 2H, J = 2.4, 7.6 Hz), 2.35 (s, 3H), 2.76−2.88 (m, 2H),
6.06 (td, 1H, J = 6.3, 46.4 Hz), 7.26 and 7.47 (AA′BB′ system, 4H),
7.46−7.55 (m, 3H), 7.88−7.91 (m, 1H); 19F NMR (375 MHz,
CDCl3) δ −171.4 (ddd, 1F, J = 16.3, 19.4, 46.4 Hz).
Representative Procedure for Desulfinylation with Raney
Ni. To a stirred solution of the corresponding compound 5d and 5i
(0.09 mmol) in THF (1 mL) was added activated Raney nickel (0.6 g)
in THF (2 mL) at room temperature. When the reaction was
completed (1.5 h), the crude was filtered and the solvent was removed
under reduced pressure. The residue was purified by flash column
chromatography.
(2) Deng, H.; O’Hagan, D. J.; Schaffrath, C. Nat. Prod. Rep. 2004, 21,
773.
(3) For reviews see: (a) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108,
1. (b) Brunet, V. A.; O’Hagan, D. Angew. Chem., Int. Ed. 2008, 47,
1179. (c) Cahard, D.; Xu, X.; Couve-Bonnaire, S.; Pannecoucke, X.
Chem. Soc. Rev. 2010, 39, 558−568. (d) Nie, J.; Guo, H.-C.; Cahard, D.
Chem. Rev. 2011, 111, 455.
(4) (a) Prakash, G. K. S.; Hu, J. Acc. Chem. Res. 2007, 40, 921.
(b) Prakash, G. K. S.; Chacko, S.; Alconcel, S.; Stewart, T.; Mathew,
T.; Olah, G. A. Angew. Chem. 2007, 119, 5021; Angew. Chem., Int. Ed.
2007, 46, 4933. (c) Prakash, G. K. S.; Zhao, X.; Chacko, S.; Wang, F.;
Vaghoo, H.; Olah, G. A. Beilstein J. Org. Chem. 2008, 4, No. 17.
(d) Prakash, G. K. S.; Chacko, S.; Vaghoo, H.; Shao, N.; Gurung, L.;
Mathew, T.; Olah, G. A. Org. Lett. 2009, 11, 1127.
(5) (a) Li, Y.; Ni, C.; Liu, J.; Zhang, L.; Zheng, J.; Zhu, L.; Hu, J. Org.
Lett. 2006, 8, 1693. (b) Ni, C.; Li, Y.; Hu, J. J. Org. Chem. 2006, 71,
6829. (c) Ni, C.; Zhang, L.; Hu, J. J. Org. Chem. 2008, 73, 5699.
(d) Liu, J.; Zhang, L.; Hu, J. Org. Lett. 2008, 10, 5377. (e) Ni, C.;
Zhang, L.; Hu, J. J. Org. Chem. 2009, 74, 3767. (f) Ni, C.; Hu, J. Synlett
2011, 770.
(6) (a) Fukuzumi, T.; Shibata, N.; Sugiura, M.; Yasui, H.; Nakamura,
S.; Toru, T. Angew. Chem. 2006, 118, 5095; Angew. Chem., Int. Ed.
2006, 45, 4973. (b) Mizuta, S.; Shibata, N.; Goto, Y.; Furukawa, T.;
Nakamura, S.; Toru, T. J. Am. Chem. Soc. 2007, 129, 6394.
(c) Furukawa, T.; Goto, Y.; Kawazoe, J.; Tokunaga, E.; Nakamura,
S.; Yang, Y.; Du, H.; Kakehi, A.; Shiro, M.; Shibata, N. Angew. Chem.
2010, 122, 1686; Angew. Chem., Int. Ed. 2010, 49, 1642.
(7) García Ruano, J. L.; Parra, A.; Alonso, I.; Fustero, S.; del Pozo, C.;
Arroyo, Y.; Sanz-Tejedor, M. A. Chem.Eur. J. 2011, 17, 6142.
(8) Arroyo, Y.; Sanz-Tejedor, M. A.; Parra, A.; García Ruano, J. L.
Chem.Eur. J. 2012, 18, 5314.
1-[(R)-1-Fluoro-4-tolyl-3-butynyl]benzene (6d). Compound 6d
was obtained as a unique diastereomer from 5d. Eluent for
chromatography hexane/Et2O 75:1; yield 75% (17 mg); white
1
syrup; [α]2D0 = +20.5 (c 0.4, CHCl3); H NMR (400 MHz, CDCl3)
δ 2.31 (s, 3H), 2.56−2.67 (m, 2H), 5.43 (ddd, 1H, J = 4.3, 8.0, 47.6
Hz), 7.01 and 7.08 (AA′BB′ system, 4H), 7.12−7.25 (m, 1H), 7.27−
7.39 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 21.0, 26.9 (d, JC−F
=
4.2 Hz), 79.4, 92.5, 94.5 (d, JC−F = 170.5 Hz), 125.5, 125.6, 128.1 (d,
JC−F = 2.0 Hz), 128.2, 128.4, 129.0, 130.0, 130.8, 132.7, 135.2, 138.8,
140.5; 19F NMR (375 MHz, CDCl3) δ −174.5 (ddd, 1F, J = 17.1, 28.0,
47.6 Hz); HMRS calcd for C17H14 ([M − HF]+) 218.1096, found
218.1083.
1-[(R)-1-Fluoro-3-hexynyl]benzene (6i). Compound 6i was ob-
tained as a unique diastereomer from 5i. Eluent for chromatography
hexane/AcOEt 1:2; yield 70% (12 mg); colorless syrup; [α]D20
=
+185.0 (c 0.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.06 (t, 3H, J =
G
dx.doi.org/10.1021/jo501096f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(9) García Ruano, J. L.; Fernan
Chem. 2012, 77, 2893.
́
dez-Salas, J. A.; Maestro, C. J. Org.
(10) (a) Pacheco, M. C.; Purser, S.; Gouverneur, V. Chem. Rev. 2008,
108, 1943−1981. (b) Modern Acetylene Chemistry; Stang, P. J.,
Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany, 1994.
(c) Acetylene Chemistry; Diederich, F., Stang, P. J., Tykwinski, R. R.,
Eds.; Wiley-VCH: New York, 2005.
(11) (a) Lee, H. W.; Lee, L. N.; Chan, A. S. C.; Kwong, F. Y. Eur. J.
Org. Chem. 2008, 3403. (b) Castagnolo, D.; Pagano, M.; Bernardini,
M.; Botta, M. Synlett 2009, 2093.
(12) Propargyl bromides bearing p-CF3 and p-NO2 groups gave
almost equimolecular mixtures of the two diastereomers 5 and 5′ in
very low conversion.
(13) (a) García Ruano, J. L.; Aleman
(b) García Ruano, J. L.; Aleman, J.; Soriano, J. F. Org. Lett. 2003, 5,
4513. (c) García Ruano, J. L.; Aleman, J.; Parra, A. J. Am. Chem. Soc.
2005, 127, 13048.
́
, J. Org. Lett. 2003, 5, 677.
́
́
(14) (a) García Ruano, J. L.; Carreno, M. C.; Toledo, M. A.; Aguirre,
̃
J. M.; Aranda, M. T.; Fischer, J. Angew. Chem., Int. Ed. 2000, 39, 2736.
́
(b) Arroyo, Y.; Meana, A.; Rodríguez, J. F.; Santos, M.; Sanz-Tejedor,
M. A.; García Ruano, J. L. J. Org. Chem. 2005, 70, 3914. (c) Arroyo, Y.;
́
Meana, A.; Sanz-Tejedor, M. A.; García Ruano, J. L. Org. Lett. 2008,
́
10, 2151. (d) Arroyo, Y.; Meana, A.; Sanz-Tejedor, M. A.; Alonso, I.;
García Ruano, J. L. J. Org. Chem. 2009, 74, 764. (e) Arroyo, Y.; Meana,
́
A.; Rodríguez, J. F.; Sanz-Tejedor, M. A.; Alonso, I.; García Ruano, J.
́
L. J. Org. Chem. 2009, 74, 4217. (f) Arroyo, Y.; Meana, A.; Sanz-
Tejedor, M. A.; Alonso, I.; García Ruano, J. L. Chem.Eur. J. 2010, 16,
́
9874. (g) García Ruano, J. L.; Shopping, C.; Alvarado, C.; Aleman, J.
̈
Chem.Eur. J. 2010, 16, 8968.
(15) Lodewyk, M. W.; Siebert, M. R.; Tantillo, D. J. Chem. Rev. 2012,
112, 1839. The geometries of all conformers were optimized with the
B3LYP functional in chloroform using the CPCM model and the 6-
31+G(d,p) basis set. NMR single-point calculations with the B3LYP
functional, the same solvent model, and the 6-311+G(2d,p) basis set
were carried out on selected conformers (see the Supporting
Information for details).
(16) Up to 10 conformers for 5h and 12 for 5′h were optimized, and
those with no significant contribution to the conformational
equilibrium (less than 1%) were discarded.
(17) Many other transition-state structures were studied and found
to be less stable than those collected in Figure 1 (see the Supporting
Information).
(18) Me2O, Me2NH, and Ph were used as simplified models for the
solvent, base, and p-Tol group, respectively.
(19) Distances are in the range of usual π−π interactions. See:
Krenske, E. H.; Houk, K. N. Acc. Chem. Res. 2013, 46, 979.
H
dx.doi.org/10.1021/jo501096f | J. Org. Chem. XXXX, XXX, XXX−XXX