Chiral monofluorobenzyl carbanions: Synthesis of enantiopure β-fluorinated β-phenylethylamines

Article abstract of DOI:10.1002/chem.201100455

The preparation of a stabilized monofluorobenzyl carbanion by means of a remote homochiral sulfinyl group and its completely stereoselective reactions with N-p-tolylsulfinylimines are described. The use of these reactions followed by the simultaneous remo

Full text of DOI:10.1002/chem.201100455

DOI: 10.1002/chem.201100455
Chiral Monofluorobenzyl Carbanions: Synthesis of Enantiopure
b-Fluorinated b-Phenylethylamines
Josꢀ L. Garcꢁa Ruano,*[a] Alejandro Parra,[a] Inꢀs Alonso,[a] Santos Fustero,*[b, c]
Carlos del Pozo,[b] Yolanda Arroyo,[d] and Ascensiꢂn Sanz-Tejedor[d]
Abstract: The preparation of a stabilized monofluorobenzyl carbanion by means
of a remote homochiral sulfinyl group and its completely stereoselective reactions
with N-p-tolylsulfinylimines are described. The use of these reactions followed by
the simultaneous removal of both chiral auxiliaries with tBuLi, which occurs with-
out epimerization at the benzylic position, provides the quickest entry to enantio-
merically pure b-fluorinated b-phenylethylamines.
Keywords: asymmetric synthesis ·
fluorinated carbanions · ionic liq-
uids · stereoselectivity · sulfinyl-
AHCTUNGTRENGNiUN mines
Introduction
these reactions is rather limited due to their moderated
scope and the disadvantages associated with the use of com-
plex, tedious, and even sometimes toxic reagents. Thus, al-
ternative routes using nucleophilic monofluorinated carban-
ions as reagents have gained interest in the last years, with
the most important contributions coming from the groups of
Prakash and Olah,[7] Hu,[8] and Shibata and Toru.[9] The
main limitation of these reagents arises from the usually low
thermal stability of fluorinated carbanions,[7a] which undergo
side reactions, for example, a-fluoride elimination. The
strategies used so far to avoid this problem involved increas-
ing the stability of the anions by incorporating electron-
withdrawing groups (usually sulfonyl functionality) to the
carbanionic center,[7–9] the elimination of which, which is not
stereoselective, is frequently required at the final steps of
the process. In consequence, monofluoromethylations[10] are
the processes usually performed with these strategies, which
never allow for the synthesis of compounds containing
chiral fluorinated carbons.[11] To overcome these limitations,
we reasoned that the use of chiral groups able to stabilize
carbanionic centers without being directly connected to
them (long-distance stabilization) could offer new opportu-
nities for stereoselective alkylfluorination. As we have re-
cently demonstrated, the ortho-sulfinyl group provides sta-
bility to lithiated benzyl carbanions, which is traduced in
highly stereoselective reactions with different electro-
philes.[12] Hence, we decided to evaluate the potential of (S)-
2-p-tolylsulfinylbenzyl fluoride (S)-1 as a precursor of stabi-
lized monofluorinated benzyl carbanion (Scheme 1). We fo-
cused our attention on reactions with N-sulfinylimines (the
best electrophiles in reactions with other sulfinyl benzyl
The ability of fluorine atoms to modulate molecular proper-
ties, such as metabolic stabilities or binding affinities, has
converted fluorine substitution in a powerful tool in medici-
nal chemistry and chemical biology.[1] Since fluorinated com-
pounds occur extremely rarely in nature,[2] the strategic in-
corporation of fluorine into biologically active small mole-
cules has attracted considerable attention in drug-discovery
research.[3] To this end several methodologies have been de-
vised in recent years.[4] While the chemistry of trifluoro- and
difluoroalkyl derivatives has been studied in some detail,[5]
the synthesis and reactivity of the corresponding mono-
ACHTUNGTRENNUNGfluoroalkyl derivatives is only recently emerging and still re-
mains as a challenging task nowadays. The most often ap-
plied approach for preparing optically pure monofluorinated
compounds is the reaction of nucleophiles with electrophilic
fluorinated reagents.[6] However, the synthetic usefulness of
[a] Prof. Dr. J. L. Garcꢀa Ruano, Dr. A. Parra, Dr. I. Alonso
Departamento de Quꢀmica Orgꢁnica
Universidad Autꢂnoma de Madrid
Cantoblanco, 28049-Madrid (Spain)
Fax : (+34) 914973966
E-mail: joseluis.garcia.ruano@uam.es
[b] Prof. Dr. S. Fustero, Dr. C. del Pozo
Departamento de Quꢀmica Orgꢁnica
Universidad de Valencia, 46100 Burjassot (Spain)
Fax : (+34)963544939
E-mail: santos.fustero@uv.es
[c] Prof. Dr. S. Fustero
Laboratorio de Molꢃculas Orgꢁnicas
Centro de Investigaciꢂn Prꢀncipe Felipe
46012 Valencia (Spain)
carbACHTNUGRTNEUNG
anions)[13] due to the significant biological and pharma-
ceutical activities[3a,14] of the resulting b-fluoroamines and
the low number of methods reported for their preparation
in optically pure form.[15] 2-Fluoro-2-phenethylamines are
important chiral derivatizing agents and efficient inhibitors
of monoamine oxidases.[16] Additionally, these reactions
would open a new route for the synthesis of the enantiomer-
[d] Dr. Y. Arroyo, Dr. A. Sanz-Tejedor
Departamento de Quꢀmica Orgꢁnica (ETSII)
Universidad de Valladolid
47011-Valladolid (Spain)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100455.
6142
ꢄ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 6142 – 6147

FULL PAPER
they are not involved as intermediates in the reactions of
[Li]-(S)-1 with electrophiles (see the Supporting Informa-
tion). This preliminary study indicates that the remote
ortho-sulfinyl group might provide enough chemical stability
to the monofluor carbanion [Li]-(S)-1, thus making it a
promising chiral nucleophilic reagent.
We tried different approaches to synthesize (S)-1
(Scheme 3).[19] Reactions of (S)-4 with fluorinating electro-
philic reagents (NFSI and Selectfluor, among others)[6] and
those of the bromoderivative (S)-5 with different fluoride
sources, when using ionic liquids,[20] were unsuccessful. How-
ever, tosylate (S)-6 reacts with CsF in dry acetonitrile and
Scheme 1. Synthesis of 1,2-fluoroethylamines by using novel prochiral
fluoride synthon [Li]-(S)-1.
ically pure benzyl fluorides, underutilized in drug discovery
because of the absence of general methods for their prepa-
ration.[15a,17]
[min-tOH]ACTHNUTRGNEUNG
[OMs] as ionic liquid[21] affording ortho-sulfinyl-
benzyl fluoride (S)-1 in 88% yield. This reaction is easily
scalable to obtain up to 4 g of (S)-1.
Results and Discussion
Before initiating the synthetic study, we performed a theo-
retical calculation at the DFT (B3LYP)[18] level of theory for
establishing the relative stability of the possible species re-
sulting in the deprotonation of (S)-1 (Scheme 2). According
Scheme 3. Strategies for the synthesis of (S)-1: a) LDA; b) fluorine elec-
trophilic sources; c) [F]À, ionic liquid; d) CsF, [min-tOH]
808C.
ACHTUNGTRNEUN[NG OMs], CH3CN,
When lithium diisopropylamide (LDA) was added to a
THF solution of (S)-1 cooled to À788C, the solution turned
immediately deep red, which suggested the formation of
[Li]-(S)-1. The addition of the N-p-tolylsulfinyl benzyl-
AHCTUNGTREGiNNUN denesimine (R)-2a provided a 40:60 mixture of anti-7’a/syn-
8’a in rather low yield (Table 1, entry 1). However, the addi-
tion of the imine of the opposite configuration, (S)-2a, af-
forded the 2-fluoro-2-phenethylamine anti-7a (differing
from anti-7’a in the configuration at the sulfinamide sulfur
atom) in 81% isolated yield and with almost complete dia-
stereoselectivity (entry 2). These results indicate that the
Scheme 2. Molecular structures, representative distances (ꢅ) and ener-
gies (kcalmolÀ1) of the most stable species generated by deprotonation.
The first value indicates the relative energy, with the ZPE correction in-
cluded, of B, C, and D with respect to A. Free-energy correction is indi-
cated in brackets, first in vacuo, second “in THF” (mimicked by
IEFPCM).
Table 1. Reactions of [Li]-(S)-1 with N-sulfinylimines.
to these calculations this is a very favorable process that
yields quite stable species, such as those shown in Scheme 2.
Dimethylether and dimethylamine were used as solvent and
base, respectively, in the simplified model, and therefore in-
cluded as ligands for the lithium atom in the calculations.
The p-tolyl group has also been simplified as a phenyl
moiety. Species A and B, resulting from deprotonation with
the nitrogen amide, are free carbanions stabilized by hydro-
Entry
Imine
R1
R2
Product anti/syn
Yield [%][a]
1
2
3
4
5
6
7
8
(R)-2a
(S)-2a
(S)-2b
(S)-2c
(S)-2d
(S)-2e
(S)-3 f
(R)-3 f
C6H5
C6H5
H
H
H
H
H
H
Me
Me
7’a/8’a (40:60)
7a/8a (>99:1)
7b/8b (>99:1)
7c/8c (>99:1)
7d/8d (>99:1)
7e/8e (>99:1)
9 f/10 f (>99:1)
9’f/10’f (1:>99)
42[b]
81
79
74
79
71
62
66
o-Br-C6H4
p-MeO-C6H4
iPr
CH=CHPh
C6H5
À
gen bonds with the N H. C and D are benzyl lithiums stabi-
lized by chelation with the sulfinyl oxygen atom. Other spe-
cies lacking the interaction O···Li are much less stable, espe-
cially those exhibiting the carbene structure, which suggests
C6H5
[a] Isolated yields after flash column chromatography. [b] Combined
yields.
Chem. Eur. J. 2011, 17, 6142 – 6147
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www.chemeurj.org
6143

J. L. Garcꢀa Ruano, S. Fustero et al.
matched pair is formed by reagents with the same configura-
tion at the sulfur atom.
ACHTUNGTRENNUNG
We then investigated the scope of the reaction with other
N-sulfinyl aryl aldimines, such as (S)-2b and (S)-2c, contain-
ing electron-withdrawing and -donating groups. They also
evolved into only one stereoisomer, anti-7b and anti-7c
(Table 1, entries 3 and 4). In a similar way, total stereoselec-
tivity control was observed in reactions from N-sulfinyl de-
rivatives of alkyl, (S)-2d, and alkenyl aldimines, (S)-2e, re-
spectively, affording anti-7d and anti-7e (entries 5 and 6, re-
spectively). The absolute configuration of anti-7d was as-
signed as (1R,2S,SS) by X-ray diffraction studies[22] (see the
Supporting Information). The same configuration was as-
signed to all the anti compounds in Table 1.
To explain the experimental results, we must take into ac-
count that, according to the theoretical calculations, the sim-
ilar stability of species A, B, and C suggests they should be
in equilibrium, as the proportion of all of them is significant.
These species only exhibit one face accessible to the electro-
philes, because the other one is blocked by the amine, in A
and B, or the metal, in C and D (see Scheme 2). In
Scheme 4 we have represented the evolution of species A
anti-11b (Scheme 5), retain the
diastereomeric excess of the
starting products, thus demon-
strating the absence of epimeri-
zation at the benzylic position
under the conditions used.
Conclusion
We have demonstrated that
monoflourobenzyl carbanions
can be stabilized by remote
chiral auxiliaries and thus are
able to participate in reactions
with electrophiles as chiral
monofluorinated reagents. By
using the sulfinyl group as
remote stabilizer we have
Scheme 4. Favored approaches of the (R)- and (S)-imines to the only accessible face of the carbanionic species
A and B.
and B (similar to that of C and D, respectively) by assuming
as favored the anti-approach of the reagents (thus minimiz-
checked that their reactions with N-sulfinylimines are com-
pletely stereoselective and provide a new entry for the syn-
thesis of the anti-1,2-fluoroethylamines, after the removal of
the sulfinyl groups with tBuLi. Moreover, these reactions
open a new route for the preparation of enantiomerically
À
ing the strong dipolar repulsion of the C=N and C F bonds,
see Newman projections) to the less hindered face of the
(S)-N-sulfinylimines, in their presumably most stable (s)-cis
conformation. Steric interactions (Ar/Ar) relatively destabi-
lize the evolution of B, which would explain the exclusive
formation of the (S,R)-anti-7 diastereoisomers resulting in
the evolution of A (or C). This stereochemical course would
also explain that the matched pair is formed by the reagents
with the same S configuration, because the approach of the
(R)-imines to (S)-1 (the mismatched pair) will be strongly
destabilized by steric repulsions of the p-tolyl group at the
imine and the aromatic ring at the species A.
We have also studied the reactions of (S)-1 with sulfinyl-
ketimines (R)-3 f and (S)-3 f affording b-fluorinated t-alkyl-
Scheme 5. Desulfinylation with tBuLi.
6144
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Chem. Eur. J. 2011, 17, 6142 – 6147

Chiral Monofluorobenzyl Carbanions
FULL PAPER
pounds were purified by means of flash silica-gel column chromatography
(the eluent used in each case is indicated below). Yields are given below.
pure benzyl fluorides. Further applications of this methodol-
ogy are currently being studied in our laboratories.
N-(1R/1S,2S)-1-Fluoro-2-phenyl-1-{2-[(S)-p-tolylsulfinyl]phenyl}ethyl-
(R)-p-tolylsulfinamide (anti-7’a/syn-8’a): These compounds were ob-
tained as an inseparable mixture of diastereoisomers from the starting
imine (R)-2a and (S)-1. Chromatography: n-hexane/AcOEt 1:1; global
yield: 42%; colorless oil; 1H-RMN of the major diastereoisomer
(300 MHz): d=7.89 (d, J=6.5 Hz, 1H), 7.58–7.47 (m, 2H), 7.46–7.44 (m,
1H), 7.40 (d, J=8.3 Hz, 2H), 7.21–7.00 (m, 6H), 7.12 (d, J=8.3 Hz, 5H),
6.19 (dd, J=32.8, 7.3 Hz, 1H), 4.97 (dt, J=7.3, 2.1 Hz, 1H), 2.31 (s, 3H),
2.30 ppm (s, 3H).
Experimental Section
Method: NMR spectra were acquired on a Bruker 300 or a Varian AS
400 spectrometer, running at 300 or 400 and 75 or 100 MHz for 1H and
13C, respectively. 19F NMR spectra were acquired at 282.4 MHz. Chemi-
cal shifts (d) are reported in ppm relative to residual solvent signals
(CHCl3, 7.26 ppm for 1H NMR, CDCl3, 77.0 ppm for 13C NMR spectra).
13C NMR spectra were acquired on a broad-band decoupled mode. Opti-
cal rotations were measured on a Perkin–Elmer 241 polarimeter. All re-
actions were carried out in anhydrous solvents and under an argon at-
mosphere. THF and Et2O were distilled from sodium-benzophenone
under argon and CH2Cl2 was distilled from P2O5. Flash column chroma-
tography was performed by using silica gel Merk-60 (230–400 mesh).
nBuLi (2.5m solution in hexanes), and meta-chloroperbenzoic acid
(mCPBA) were purchased from Aldrich.
N-(1S,2R)-1-Fluoro-2-phenyl-1-{2-[(S)-p-tolylsulfinyl]phenyl}ethyl-(S)-p-
tolylsulfinamide (7a): Compound 7a was obtained as a unique diastereo-
isomer from the starting imine (S)-2a and (S)-1. Chromatography: n-
hexane/AcOEt 2:1; yield: 81%; white solid; m.p. 133–1358C; [a]D20
=
+62.2 (c=1.0 in CHCl3); 1H-RMN (300 MHz): d=7.90 (dd, J=3.5,
2.5 Hz, 1H), 7.58–7.47 (m, 2H), 7.46–7.44 (m, 1H), 7.40 (d, J=8.3 Hz,
2H), 7.21–7.00 (m, 6H), 7.12 (d, J=8.3 Hz, 5H), 6.21 (dd, J=32.8,
7.3 Hz, 1H), 6.11 (d, J=7.1 Hz, 1H), 4.42 (dt, J=7.3, 2.1 Hz, 1H), 2.33
(s, 3H), 2.30 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=141.6 (d,
Materials: Commercially available starting materials and solvents were
used without further purification. Compounds (S)-4,[23] (R)-2a,[24] (S)-2a–
e,[24] (R)-3 f,[25] and (S)-3 f[25] were previously synthesized.
J
CÀF =3.8 Hz), 141.4 141.1, 140.8, 139.3, 137.3 (d, JCÀF =21.3 Hz), 132.2,
130.1 (2C), 129.3, 128.9, 128.9 (2C), 128.0, 127.7, 127.4 (d, JCÀF =8.7 Hz),
125.9, 125.1, 90.8 (d,
JCÀF =177.1 Hz), 61.1 (d, JCÀF =28.4 Hz), 21.3,
21.2 ppm; 19F NMR (282.4 MHz): d=À180.2 ppm (s, 1F); HRMS: m/z:
Synthesis of (S)-2-(p-tolylsulfinyl)benzyl-p-toluenesulfonate ((S)-6): TsCl
(1.1 mmol) was added to a solution of (S)-[2-(p-tolylsulfinyl)phenyl]me-
thanol (5)[26] (1.0 mmol) and KOH (5.0 mmol) in dry THF (50 mL). The
reaction mixture was stirred at RT and checked with the aid of TLC until
the reaction was complete (5 h). The solid was then filtered through a
Celite pad and the solvent was removed under reduced pressure to
afford tosylate (S)-6. This compound was used without additional purifi-
cation. Yield: 95%; white solid; m.p. 124–1268C; [a]2D0 =À115.9 (c=1.0
calcd for C28H27FNO2S2: 492.1463 [M+H]+; found: 492.1461.
N-(1R,2S)-1-(2-Bromophenyl)-2-fluoro-2-{2-[(S)-p-tolylsulfinyl]pheny-
l}ethyl-(S)-p-tolylsulfinamide (7b): Compound 7b was obtained as
a
unique diastereoisomer from the starting imine (S)-2b and (S)-1. Chro-
matography: n-hexane/AcOEt 3:1; yield: 68%; colorless oil; [a]2D0 =+
118.5 (c=0.7 in CHCl3); 1H-RMN (300 MHz): d=7.76 (d, J=7.5 Hz,
1H), 7.54–7.41 (m, 4H), 7.36 (d, J=8.3 Hz, 2H), 7.21–7.10 (m, 6H),
6.96–6.87 (m, 3H), 6.51 (d, J=7.2 Hz, 1H), 6.12 (dd, J=37.9, 7.8 Hz,
1H), 5.03–4.97 (m, 1H), 2.24 (s, 3H), 2.18 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3): d=141.6 (d, JCÀF =3.8 Hz), 141.3, 140.7, 140.6, 140.4,
138.9, 137.2 (d, JCÀF =21.3 Hz), 132.5, 131.9, 130.1 (2C), 129.8, 129.3 (d,
in CHCl3); IR (KBr): n˜ =1356, 1038, 940 cmÀ1 1H NMR: d=7.90 (d, J=
;
7.7 Hz, 1H), 7.75, 7.32 (AA’BB’ system, 4H), 7.51 (td, J=1.2, 7.3 Hz,
1H), 7.46–7.36 (m, 2H), 7.43, 7.22 (AA’BBꢆ system, 4H), 5.27, 5.14 (AB
system, J=11.6 Hz, 2H), 2.43 (s, 3H), 2.35 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3): d=145.0, 144.3, 141.5, 140.7, 132.4, 132.3, 131.2, 130.2,
129.9, 129.8 (2C), 129.7 (2C), 127.7 (2C), 125.4, 125.2 (2C), 67.1, 21.4,
21.1 ppm; MS (FAB+): m/z: 401 [M+H]+ (100), 245 (36), 229 (72);
HRMS (FAB+): m/z: calcd for C21H21O4S2: 401.0881; found: 401.0874.
Synthesis of 1-(fluoromethyl)-2-[(S)-p-tolylsulfinyl]benzene ((S)-1):[21]
CsF (3.0 mmol) was added to a solution of the tosylate 6 (1.0 mmol) in
dry CH3CN (3.0 mL) and [min-tOH]ACTHNUTRGENUGN[OMs] (0.5 mmol) under Ar. The re-
J
CÀF =6.7 Hz), 128.9 (2C), 128.8, 127.6, 127.4, 125.9, 124.9, 92.6 (d, JCÀF
=
177.4 Hz), 56.9 (d,
J
CÀF =25.7 Hz), 21.2, 21.4 ppm; 19F NMR
(282.4 MHz): d=À180.1 ppm (s, 1F); HRMS: m/z: calcd for
C28H26BrFNO2S2: 570.0585 [M+H]+; found: 570.0566.
N-(1R,2S)-2-Fluoro-1-(4-methoxyphenyl)-2-{2-[(S)-p-tolylsulfinyl]phenyl}-
ethyl-(S)-p-tolylsulfinamide (7c): Compound 7c was obtained as a unique
diastereoisomer from the starting imine (S)-2c and (S)-1. Chromatogra-
phy: n-hexane/AcOEt 4:1; yield: 74%; colorless oil; [a]2D0 =À62.3 (c=1.0
in CHCl3); 1H-RMN (300 MHz): d=7.82 (d, J=7.4 Hz, 1H), 7.49–7.39
(m, 4H), 7.33–7.26 (m, 5H), 6.97 (d, J=8.3 Hz, 2H), 6.84 (d, J=8.6 Hz,
2H), 6.63 (d, J=8.6 Hz, 2H), 6.12 (dd, J=38.9, 7.1 Hz, 1H), 5,83 (d, J=
7.7 Hz, 1H), 4.35–4.24 (m, 1H), 2.27 ppm (s, 3H); 13C NMR (75 MHz,
action mixture was stirred at reflux and checked with the aid of TLC
until the reaction was complete. The resulting reaction mixture was hy-
drolyzed (1 mL H2O), extracted (3ꢇ10 mL Et2O), washed (2ꢇ10 mL sat
NaCl), dried (MgSO4), and the solvent was removed under reduced pres-
sure. Compound (S)-1 was purified by means of flash silica-gel column
chromatography by using 2:1 hexane/ethyl acetate. Yield: 88%; white
solid; m.p. 123–1258C; [a]2D0 =À64.71 (c=1.0 in CHCl3); 1H NMR
(300 MHz): d=7.52 and 7.27 (AA’BB’ system, 4H), 7.59–7.46 (m, 4H),
5.63 (dd, J=56.0, 11.6 Hz, 1H), 5.47 (dd, J=56.0, 11.6 Hz, 1H), 2.37 ppm
(s, 3H); 13C NMR (75 MHz, CDCl3): d=144.1, 141.6, 139.6, 131.6, 131.3,
130.0, 130.6, 128.7 (d, J=8,8 Hz), 125.5 (d, J=13,1 Hz), 125.1, 80.2 (d,
J=167.8 Hz), 21.3 ppm; 19F NMR (282.4 MHz): d=À206.6 ppm (t,
CDCl3): d=141.7 (d, JCÀF =3.2 Hz), 140.9, 140.8, 140.6, 137.2 (d, JCÀF
20.3 Hz), 132.1, 130.2, 129.6, 129.3 (d, JCÀF =6.7. Hz), 127.3, 125.3, 125.8,
125.4, 125.3, 125.1, 113.7, 113.8, 113.6, 91.6 (d, JCÀF =176.4 Hz), 56.9 (d,
=
J
CÀF =24.7 Hz), 55.2, 21.4, 21.3 ppm; 19F NMR (282.4 MHz): d=
À180.1 ppm (s, 1F); HRMS: m/z: calcd for C29H29FNO3S2: 522.1552
[M+H]+; found: 522.1567.
N-(1S,2R)-1-Fluoro-3-methyl-1-{2-[(S)-p-tolylsulfinyl]phenyl}butan-2-yl-
(S)-p-tolylsulfinamide (7d): Compound 7d was obtained as a unique dia-
stereoisomer from the starting imine (S)-2d and (S)-1. Chromatography:
J
FÀH =47.5 Hz, 1F); elemental analysis calcd (%) for C14H13FOS: C
67.72, H 5.28, S 12.91; found: C 68.26, H 5.26, S 12.94.
General procedure for the addition of sulfoxide (S)-1 to imines (S/R)-
2a–e or (S/R)-3 f: Synthesis of the fluoroamines anti-7a–e, syn-8’a, anti-
9 f, and syn-10’f (Table 1). A solution of nBuLi (0.6 mmol, 2.3m in
hexane) was added to iPr2NH (0.9 mmol) in THF (3 mL) at 08C. After
stirring for 15 min, the mixture was cooled to À788C. A solution of the
corresponding (S)-1 (0.5 mmol) in THF (2 mL) was added. After stirring
for 15 min, the corresponding N-sulfinylimine 2a–e or 3 f (0.5 mmol; the
corresponding imines in each case are indicated below) in THF (1 mL)
was added at À788C. When the reaction was complete (20–30 min), the
resulting reaction mixture was hydrolyzed (1 mL H2O), extracted (3ꢇ
10 mL Et2O), washed (2ꢇ10 mL NaCl sat.), dried (MgSO4), and the sol-
vent was removed under reduced pressure. The corresponding com-
n-hexane/AcOEt 2:1; yield: 79%; white solid; m.p. 133–1358C; [a]D20
=
+13.8 (c=1.0 in CHCl3); 1H-RMN (300 MHz): d=7.82 (d, J=7.4 Hz,
1H), 7.67–7.62 (m, 3H), 7.27 (d, J=8.4 Hz, 2H), 7.10 (t, J=8.9 Hz, 4H),
6.87 (d, J=8.4 Hz, 2H), 6.91 (dd, J=37.7, 8.9 Hz, 1H), 4.77 (d, J=
10.1 Hz, 1H), 3,62–3.51 (m, 1H), 2.34 (s, 3H), 2.30 (s, 3H), 2.15–2.07 (m,
1H), 0.96 ppm (t, J=6.8 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=142.5,
142.3 (d, JCÀF =2.9 Hz), 141.3, 140.8 (d, JCÀF =4.4 Hz), 138.7 (d, JCÀF
=
20.2 Hz), 132.3, 129.9 (2C), 129.1 (2C), 128.4 (d, JCÀF =7.1. Hz), 127.6,
125.0, 124.9, 98.1 (d, JCÀF =175.5 Hz), 65.2 (d, JCÀF =27.9 Hz), 28.9, 21.2,
19.8, 16.2 ppm; 19F NMR (282.4 MHz): d=À175.3 ppm (s, 1F); HRMS:
m/z: calcd for C25H29FNO2S2: 458.1613 [M+H]+; found: 458.1618.
Chem. Eur. J. 2011, 17, 6142 – 6147
ꢄ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6145

J. L. Garcꢀa Ruano, S. Fustero et al.
N-(1S,2R,E)-1-Fluoro-4-phenyl-1-{2-[(S)-p-tolylsulfinyl]phenyl}but-3-en-
2-yl-(S)-p-tolylsulfinamide (7e): Compound 7e was obtained as a unique
diastereoisomer from the starting imines (S)-2e and (S)-1. Chromatogra-
phy: n-hexane/AcOEt 4:1; yield: 71%; colorless oil; [a]2D0 =À62.0 (c=1.0
in CHCl3); 1H-RMN (300 MHz): d=7.84 (d, J=7.4 Hz, 1H), 7.49–7.41
(m, 3H), 7.38–7.21 (m, 6H), 7.12–7.06 (m, 8H), 6.03 (s, 1H), 6.01 (dd,
J=39.9, 6.0 Hz, 1H), 5.10 (d, J=8.5 Hz, 1H), 4.16–4.05 (m, 1H), 2.26 (s,
Acknowledgements
Financial support of this work by the Spanish Government (grants
CTQ2009-12168 and CTQ2010-19744), Comunidad Autꢂnoma de Madrid
(AVANCAT S2009/PPQ1634), and Generalitat Valenciana (PROME-
TEO2010/061/GV) is gratefully acknowledged. A.P. expresses his thanks
for a pre-doctoral fellowship and C.P. for a Ramꢂn y Cajal contract. We
also thank the Centro de Computaciꢂn Cientꢀfica de la UAM for gener-
ous allocation of computer time.
3H), 2.23 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=142.1 (d, JCÀF
=
3.3 Hz), 141.5, 141.1 (d, JCÀF =5.6 Hz), 136.4 (d, JCÀF =20.8 Hz), 136.2,
133.7, 131.8, 131.2, 130.0, 129.9, 129.6, 129.8, 128.5, 128.4, 128.3, 127.8,
126.9, 126.7, 125.8, 125.1, 91.6 (d,
JCÀF =177.2 Hz), 59.3 (d, JCÀF =
26.2 Hz), 21.3, 21.1 ppm; 19F NMR (282.4 MHz): d=À182.2 ppm (s, 1F);
HRMS: m/z: calcd for C30H29FNO2S2: 518.1621 [M+H]+; found:
518.1618.
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N-(1S,2R)-1-Fluoro-2-phenyl-1-{2-[(S)-p-tolylsulfinyl]phenyl}propan-2-
yl-(S)-p-tolylsulfinamide (9 f): Compound 9 f was obtained as a unique
diastereoisomer from the starting imines (S)-3 f and (S)-1. Chromatogra-
phy: n-hexane/AcOEt 4:1; yield: 62%; colorless oil; [a]2D0 =À36.4 (c=1.0
in CHCl3); 1H NMR (300 MHz): d=7.81 (d, J=7.7 Hz, 1H), 7.53 (d, J=
8.1 Hz, 2H), 7.35–7.16 (m, 12H), 7.04 (d, J=7.4 Hz, 2H), 6.33 (d, J=
7.7 Hz, 1H), 6.04 (d, J=45.4 Hz, 1H), 2.35 (s, 6H), 2.06 ppm (s, 3H);
13C NMR (75 MHz, CDCl3): d=144.8, 143.4, 142.2, 141.1, 140.9, 138.2 (d,
J
CÀF =3.8 Hz), 133.2 (d, JCÀF =20.7 Hz), 130.0, 129.7, 129.6, 129.2, 129.1,
129.0, 128.6, 128.3, 126.1, 125.3, 125.2 (d, JCÀF =2.7 Hz), 98.4 (d, JCÀF
184.2 Hz), 65.1 (d,
CÀF =21.9 Hz), 23.5, 21.4, 21.3 ppm; 19F NMR
=
J
(282.4 MHz): d=À175.5 ppm (s, 1F); HRMS: m/z: calcd for
C30H29FNO2S2: 518.1621 [M+H]+; found: 518.1618.
N-(1S,2S)-1-Fluoro-2-phenyl-1-{2-[(S)-p-tolylsulfinyl]phenyl}propan-2-yl-
(S)-p-tolylsulfinamide (10’f): Compound 10’f was obtained as a unique
diastereoisomer from the starting imine (R)-3 f and (S)-1. Chromatogra-
phy: n-hexane/AcOEt 2:1; yield: 66%; colorless oil; [a]2D0 =À57.7 (c=0.3
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1
in CHCl3); H-RMN (300 MHz): d=7.71 (d, J=7.8 Hz, 1H), 7.51 (d, J=
8.3 Hz, 2H), 7.43–7.38 (m, 2H), 7.31–7.22 (m, 8H), 7.15 (d, J=8.3 Hz,
2H), 7.02 (d, J=8.3 Hz, 2H), 6.01 (d, J=43.9 Hz, 1H), 5.44 (s, 1H), 2.34
(s, 3H), 2.23 (s, 3H), 1.99 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=
[9] a) T. Fukuzumi, N. Shibata, M. Sugiura, H. Yasui, S. Nakamura, T.
Toru, Angew. Chem. 2006, 118, 5095; Angew. Chem. Int. Ed. 2006,
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riched compounds with quaternary fluorinated carbon atoms can be
obtained (e.g., C. Ding, K. Muruoka, Synlett 2009, 664; X. Han, J.
Luo, C. Liu, X. Lu, Chem. Commun. 2009, 2044).
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144.8, 142.9, 141.3 (d,
22.6 Hz), 130.6, 130.0, 129.5, 129.7, 129.5 (d, JCÀF =8.2 Hz), 129.4, 128.2,
JCÀF =4.9 Hz), 140.9, 140.6, 134.3 (d, JCÀF =
128.1, 127.9, 126.6, 125.4, 125.1, 96.4 (d, JCÀF =183.7 Hz), 64.3 (d, JCÀF
=
22.9 Hz), 22.7 (d, JCÀF =3.3 Hz), 21.4, 21.1 ppm; 19F NMR (282.4 MHz):
d=À175.8 ppm (s, 1F); HRMS: m/z: calcd for C29H29FNO2S2: 506.1622
[M+H]+; found: 506.1618.
General procedure for desulfinylation of sulfinamides anti-7a and anti-
7d: tBuLi (0.4 mmol, 1.7m in pentane, 3.3 equiv) was added dropwise to
a solution of the corresponding sulfonamide (0.12 mmol) in dry THF
(2 mL) at À788C. When the reaction was complete (20–30 min), the re-
sulting reaction mixture was hydrolyzed (1 mL H2O), extracted (3ꢇ
10 mL Et2O), washed (2ꢇ10 mL NaCl sat.), dried (MgSO4), and the sol-
vent was removed under reduced pressure. The corresponding com-
pounds were purified by SCX column. Yields are given below.
ACHTUNGTRENNUNG(1R,2S)-2-Fluoro-1,2-diphenylethylamine (11a): Compound 11a was iso-
lated as a colorless oil in 86% yield. [a]2D0 =+15.8 (c=1.0 in CHCl3); H-
RMN (300 MHz): d=7.24–7.13 (m, 10H), 5.40 (dd, J=40.0, 6.2 Hz, 1H),
4.23 ppm (dd, J=7.0, 6.2 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=140.6
(d, JCÀF =10.9 Hz), 136.8 (d, JCÀF =22.3 Hz), 128.6, 125.5, 128.3, 128.2,
1
128.0, 127.8, 127.5, 126.5, 97.3 (d, JCÀF =176.0 Hz), 60.2 ppm (t, JCÀF
=
25.7 Hz); 19F NMR (282.4 MHz): d=À185.1 ppm (s, 1F); HRMS: m/z:
calcd for C14H15FN: 216.1183 [M+H]+; found: 216.1183.
ACHTUNGTRENNUNG(1S,2R)-1-Fluoro-3-methyl-1-phenylbutan-2-amine (11b): Compound
11b was isolated as a colorless oil in 84% yield. [a]2D0 =+8.2 (c=0.5 in
CHCl3); 1H-RMN (300 MHz): d=7.34–7.31 (m, 5H), 5.21 (dd, J=46.7,
7.5 Hz, 1H), 2.96 (m, 1H), 2.00–1.94 (m, 1H), 0.99 (d, J=6.9 Hz, 3H),
0.92 ppm (d, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=138.0 (d,
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CÀF =19.6 Hz), 128.6 (d, JCÀF =1.6 Hz), 128.5, 126.8, 126.7, 95.7 (d, JCÀF
=
175.1 Hz), 59.9 (d,
J
CÀF =25.1 Hz), 28.3, 20.4, 15.9 ppm; 19F NMR
(282.4 MHz): d=À179.3 ppm (s, 1F); HRMS: m/z: calcd for C11H17FN:
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6146
www.chemeurj.org
ꢄ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 6142 – 6147

Chiral Monofluorobenzyl Carbanions
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Crystallographic
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via
www.ccdc.cam.ac.uk/data_request/cif.
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Received: February 10, 2011
Published online: April 13, 2011
Chem. Eur. J. 2011, 17, 6142 – 6147
ꢄ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6147