Stereoselective synthesis of enantiomerically pure β-fluoroalkyl γ- butyrolactones by sulfoxide-directed lactonization

Article abstract of DOI:10.1002/(sici)1099-0690(199901)1999:1<111::aid-ejoc111>3.0.co;2-5

Enantiomerically pure α,α-dichloro β-fluoroalkyl γ-p-tolylthio γ- butyrolactones trans-6a-c have been obtained with excellent stereocontrol (> 98:2) and enantiomeric purity (> 98:2) by sulfoxide-directed lactonization (Marino's annulation reaction) of β-f

Full text of DOI:10.1002/(sici)1099-0690(199901)1999:1<111::aid-ejoc111>3.0.co;2-5

FULL PAPER
Stereoselective Synthesis of Enantiomerically Pure β-Fluoroalkyl
γ-Butyrolactones by Sulfoxide-Directed Lactonization
[a]
[b]
[a]
[a]
[c]
´
Pierfrancesco Bravo,* Alberto Arnone, Paola Bandiera, Luca Bruche, Yuji Ohashi,
Taizo Ono,[d] Akiko Sekine,[c] and Matteo Zanda[a]
Keywords: Fluorine / Lactones / Annulation / Ketene / Sulfoxides
Enantiomerically pure α,α-dichloro β-fluoroalkyl γ-p-
tolylthio γ-butyrolactones trans-6a–c have been obtained
with excellent stereocontrol (Ͼ 98:2) and enantiomeric purity
(Ͼ 98:2) by sulfoxide-directed lactonization (Marino’s annu-
lation reaction) of β-fluoroalkyl vinyl sulfoxides (R)-(E)-5a–
c with dichloroketene. Highly chemoselective dechlorination
and desulfurization reactions performed on trans-6c
efficiently provided the β-chlorodifluoromethyl γ-buty-
rolactone (S)-8c, the absolute stereochemistry of which was
determined by X-ray diffraction analysis of its γ-p-tolylthio
precursor (2R,3S)-7c.
Chiral γ-butyrolactone frameworks are widespread in na- with the appropriate fluoroacetic acid ester in THF at
ture, and are associated with a plethora of biological activi- Ϫ60°C.[5] Starting from these readily available materials,
ties. For example, several insect species use functionalized γ- the corresponding β-fluoroalkyl vinyl sulfoxides (R)-5a؊c
butyrolactones as sex attractant pheromones, whereas some were prepared in one-pot processes, in moderate to good
other γ-butyrolactones are industrially used as flavouring yields (55Ϫ83%), according to the following procedure[6]
:
components. On the other hand, it is well known that both (1) Reduction of (R)-2a؊c with NaBH4 to give a dia-
enantiomeric purity and absolute configuration are key fac- stereomeric mixture of β-hydroxy sulfoxides 3a؊c, which
tors in determining the physiological activities of these mol- was used without purification; (2) dehydration under phase-
ecules.
transfer conditions (30Ϫ90 min., CH2Cl2, NaOH 30%,
In conjunction with a program aimed at the synthesis of Bu4NHSO4) via the corresponding transient mesylates
new chemical agents for selective use against insect species, 4a؊c. In all cases, the vinyl sulfoxides (R)-5a؊c were ob-
we became interested in the development of an efficient tained almost exclusively in the (E) form, with the sulfinyl
strategy for the synthesis of chiral, non-racemic β-fluoro- and the fluoroalkyl groups in a trans arrangement, as indi-
alkyl γ-butyrolactones. An overview of relevant literature cated by J values of ca. 15 Hz for the vinylic protons. This
revealed that only a few examples of β-fluoroalkyl γ-butyro- point is of great importance for obtaining high stereocon-
lactones have been reported to date.[1] In the light of our trol in the subsequent annulation step, since the sulfoxide-
experience gained in the field of chiral sulfoxide chemis- directed lactonization is known to be a stereoconservative
try,[2] we envisaged the enantioselective sulfoxide-directed process, reflecting the stereochemistry of the starting vinyl
lactonization, first reported by Marino in 1984,[3] as a vi- sulfoxides.
able strategy for achieving our target. To the best of our
knowledge, fluorinated vinyl sulfoxides have not previously
been reacted with ketenes. Considering the dramatic change
of reactivity often brought about by the introduction of flu-
orine,[4] the outcome of these reactions was certainly not
predictable, and therefore worthy of investigation.
Results and Discussion
β-Ketosulfoxides (R)-2a؊c (Scheme 1) were obtained by
fluoroacylation of lithiated (R)-methyl p-tolylsulfoxide 1
Scheme 1
[a]
Dipartimento di Chimica del Politecnico,
Via Mancinelli 7, I-20131 Milano, Italy
E-mail: bravo@dept.chem.polimi.it
The key lactonization step (Scheme 2) was performed by
adding an excess of dichloroketene (ca. 5 equiv.), generated
from trichloroacetyl chloride and zinc/copper couple in re-
fluxing diethyl ether, to the vinyl sulfoxides (R)-(E)-5a؊c
and allowing reaction to proceed for 10 min. at 0°C. In all
cases, irrespective of the nature of the fluoroalkyl residue,
[b]
[c]
[d]
C.N.R., Centro di Studio sulle Sostanze Organiche Naturali,
Via Mancinelli 7, I-20131 Milano, Italy
Department of Chemistry, Tokyo Institute of Technology,
Ookayama, Meguro-ku, Tokyo 152-8551, Japan
National Industrial Research Institute of Nagoya,
Hirate-cho 1-1, Kita-ku, Nagoya City, Aichi Prefecture 462,
Japan
Eur. J. Org. Chem. 1999, 111Ϫ115
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/0101Ϫ0111 $ 17.50ϩ.50/0
111

P. Bravo et al.
FULL PAPER
the reactions occurred with excellent stereocontrol, only the
corresponding β-fluoroalkyl γ-p-tolylthio γ-butyrolactones
trans-6a؊c being formed, in fair yields and in enantiomer-
ically pure form (vide infra).
Scheme 3
Structural Assignments: γ-p-Tolylthio γ-butyrolactone
(2R,3S)-7c was crystallized from n-hexane, which allowed
us to obtain single crystals suitable for X-ray diffraction
analysis. The ORTEP[9] representation of the molecular
structure is shown in Figure 1. Bond distances and angles
are not significantly different from those in the related 4-
Scheme 2
This excellent stereocontrol can be explained in terms of methylthio-2-phthalimido-γ-butyrolactones.[10,11] The car-
the mechanism proposed by Marino.[3] The process, belong- bonyl moieties of O1, O2, C3 and C4 of the γ-butyrolactone
ing to the family of vinylogous Pummerer reactions,[7] ring are planar within ±0.002 A, while C2 and C5 reside
˚
˚
˚
should be triggered by acylation of the sulfinyl oxygen by above (0.239 A) and below (Ϫ0.150 A) this plane, respec-
dichloroketene, thereby producing the chiral vinyl oxysul- tively. At the C2ϪC5 bond of the lactone ring, the chlorodi-
fonium enolate A (Scheme 2). This intermediate is believed fluoromethyl group is trans to the p-tolylthio group. The
to undergo a [3,3]-sigmatropic rearrangement, proceeding conformation about the C2ϪC1 bond is staggered, with the
from a single, thermodynamically preferred conformation C1ϪCl1 bond situated over the lactone ring. The dihedral
with both the sterically demanding fluoroalkyl and p-tolyl- angle between the mean plane of the benzene ring and that
thio groups in pseudoequatorial positions. This gives rise of the carbonyl moiety of the γ-butyrolactone ring is
to the zwitterionic species B with absolute enantiocontrol. 16.3(3)°. There are no unusually short contacts between
Stereoselective ring-closure of B by intramolecular nucleo- the molecules.
philic attack of the carboxylate residue on the stabilized
carbocation at C-2, attached to the sulfenyl group, rep-
resents the final step of the reaction. The overall process
can be viewed as a highly enantioselective tandem Michael
addition of the enolate of dichloroacetic acid to the vinyl
sulfoxide, followed by a Pummerer reaction involving the
sulfinyl and the carboxylate groups.
To test the viability of this synthetic route for preparing
sulfur-free β-fluoroalkyl γ-butyrolactones of biological
interest, we next addressed dechlorination and desulfuri-
zation of the chlorodifluoro derivative trans-(2R,3S)-6c,
chosen as a reference compound (Scheme 3). Dechlori-
nation at C-4 of trans-(2R,3S)-6c was achieved in a highly
Figure 1. ORTEP view of (2R,3S)-7c showing the atomic label-
ling scheme
chemoselective manner (60% isolated yield) by treatment
with Raney Ni/H2 at pH 5.2 in the presence of aqueous
NaH2PO2 (60 min., room temp.),[8] without concomitant
desulfurization at C-2, and without further dechlorination
of the chlorodifluoromethyl group at C-3. The enantiomeric
purity of the resulting γ-p-tolylthio γ-butyrolactone
(2R,3S)-7c was determined to be > 98% by NMR analysis
in the presence of the chiral shift reagent (ϩ)-Eu(hfc)3.
Desulfurization of (2R,3S)-7c was smoothly achieved by
further treatment with Raney Ni/H2 for 50 min. (methanol,
room temp.), which produced the rather volatile β-chlorodi-
fluoromethyl γ-butyrolactone (S)-8c. This was isolated (ca.
With the absolute stereochemistry of compound 7c estab-
lished, the stereochemistry of the precursor compound 6c
could be unequivocally assigned as trans-(2R,3S), while the
trans relationship between 2-H and 3-H in compounds 6a,b
followed from the close similarity of the magnitudes of the
coupling constants exhibited by these protons compared to
those of compound 6c (3J ϭ 9.5 and 9.6 vs. 8.7 Hz).
Concluding Remarks
A convenient access to biologically interesting, selectively
65% yield) by filtering off the Raney Ni and then carefully fluorinated, enantiomerically pure, chiral lactones is pro-
evaporating the solvent, and was characterized without vided by a highly stereoselective approach to enantiomer-
further purification.
ically pure β-fluoroalkyl γ-butyrolactones by sulfoxide-di-
112
Eur. J. Org. Chem. 1999, 111Ϫ115

Stereoselective Synthesis of Enantiomerically Pure β-Fluoroalkyl γ-Butyrolactones
FULL PAPER
1-Chloro-1,1-difluoro-3-(p-tolylsulfinyl)propan-2-ol (3c): Major dia-
stereoisomer: 1H NMR (CDCl3): δ ϭ 7.57 and 7.38 (m, 4 H, ArH),
4.63 (ddt, J ϭ 6.8, 5.5 and 7.1 Hz, 1 H, CHOH), 3.40 (br s, 1 H,
OH), 3.14 (dd, J ϭ 13.3 and 6.8 Hz, 1 H, CHHS), 3.10 (dd, J ϭ
13.3 and 5.5 Hz, 1 H, CHHS), 2.43 (br s, 3 H, ArCH3). Ϫ 19F
NMR (CDCl3): δ ϭ Ϫ65.22 and Ϫ67.11 (dd, J ϭ 167.4 and 7.1
rected lactonization of β-fluoroalkyl vinyl sulfoxides with
dichloroketene. Features of this protocol are excellent en-
antiocontrol, high chemoselectivity, mild conditions, and
reasonable overall yields.
1
Hz, 2 F, CF2). Ϫ Minor diastereoisomer: H NMR (CDCl3): δ ϭ
7.55 and 7.38 (m, 4 H, ArH), 4.56 (ddt, J ϭ 10.5, 2.3 and 7.1 Hz,
1 H, CHOH), 3.40 (br s, 1 H, OH), 3.12 (dd, J ϭ 13.3 and 10.5
Hz, 1 H, CHHS), 2.99 (dd, J ϭ 13.3 and 2.3 Hz, 1 H, CHHS),
2.43 (br s, 3 H, ArCH3). Ϫ 19F NMR (CDCl3): δ ϭ Ϫ65.08 and
Ϫ66.52 (dd, J ϭ 167.4 and 7.1 Hz, 2 F, CF2). Ϫ MS (EI); m/z: 268
[Mϩ]. Ϫ C10H11ClF2O2S: calcd. C 44.70, H 4.13; found C 44.86,
H 4.01.
Experimental Section
General: Samples for 1H-, 19F- and 13C-NMR were prepared as
dilute solutions in CDCl3 and spectra were recorded on Bruker
ARX 400 and AC 250L spectrometers. Chemical shifts (δ) are re-
ported in parts per million (ppm) of the applied field. Me4Si was
used as an internal standard (δH and δC ϭ 0.00) for 1H and 13C
nuclei, while C6F6 was used as an external standard (δF ϭ Ϫ162.90)
for the 19F nucleus. Peak multiplicities are abbreviated as: singlet,
s; doublet, d; triplet, t; quartet, q; multiplet, m. In the 13C-NMR
signal assignments, capital letters refer to the patterns resulting
from directly bonded (C,H) couplings and lower-case letters to
Synthesis of Vinyl Sulfoxides 5b,c: To a solution of the β-hydroxy
sulfoxide 3b,c (0.65 mmol) in dichloromethane (5 mL), the phase-
transfer catalyst (Bu4NHSO4) and 30% aqueous NaOH (5 mL)
were added at room temperature. The mixture was cooled to 0°C,
and then methanesulfonyl chloride (75 µL) was slowly added under
vigorous stirring. After 30 min. at 0°C followed by 1 h at room
temperature, the reaction mixture was extracted with ethyl acetate
(2 ϫ 10 mL). After drying of the combined extracts over sodium
sulfate, the solvent was evaporated under reduced pressure and the
residue was flash chromatographed on a silica gel column using
a 40:60 n-hexane/ethyl acetate mixture as eluent, affording vinyl
sulfoxides (E)-5b (65%) and (E)-5c (72%), respectively.
20
those from (C,F) couplings. Ϫ [α]D values were measured on
Jasco-Dip or W. Kernchen Propol polarimeters. Ϫ IR spectra were
recorded on a Perkin-Elmer System 2000 FT-IR spectrophoto-
meter. Ϫ Mass spectra were recorded on a Hitachi-Perkin-Elmer
ZAB 2F instrument. Ϫ Anhydrous THF was distilled from sodium
and benzophenone. In all other cases, commercially available re-
agent-grade solvents were employed without purification. Reac-
tions performed in dry solvents were carried out under nitrogen
atmosphere. Ϫ Melting points were obtained on a capillary appa-
ratus and are uncorrected. Ϫ Analytical thin-layer chromatography
(TLC) was routinely used to monitor reactions. Plates precoated
with Merck silica gel 60 F254 of 0.25 mm thickness were used.
Merck silica gel 60 (230Ϫ400 ASTM mesh) was employed for col-
umn chromatography. Ϫ Combustion microanalyses were per-
20
(E)-3,3-Difluoro-1-(p-tolylsulfinyl)but-1-ene (5b): [α]D ϭ ϩ436
1
(c ϭ 1.0, CHCl3). Ϫ H NMR (CDCl3): δ ϭ 7.51 and 7.34 (m, 4
H, ArH), 6.77 (dt, J ϭ 15.1 and 1.9 Hz, 1 H, CHSO), 6.61 (dt,
J ϭ 15.1 and 10.7 Hz, 1 H, CHCF2), 2.42 (br s, 3 H, ArCH3), 1.75
(t, J ϭ 18.0 Hz, 3 H, CF2CH3). Ϫ 13C NMR (CDCl3): δ ϭ 142.56
(S), 139.86 (S), 130.42 (D), 125.04 (D) (ArC); 139.74 (Dt, JCF
formed by Redox SNC, Cologno M. (Milano). Compounds 2a,c,[5] 7.4 Hz), 130.11 (Dt, JCF ϭ 28.7 Hz) (CHϭCH); 119.57 (St, JCF
ϭ
ϭ
2b,[12] 3a,[6] and 5a[6] were prepared according to the literature.
238.0 Hz, CF2); 24.29 (Qt, JCF ϭ 28.5 Hz, CF2CH3); 21.47 (Q,
ArCH3). Ϫ 19F NMR (CDCl3): δ ϭ Ϫ90.70 and Ϫ91.10 (dddq,
J ϭ 256.0, 10.7, 1.9 and 18.0 Hz, 2 F, CF2). Ϫ MS (EI); m/z:
230 [Mϩ]. Ϫ C11H12F2OS: calcd. C 57.38, H 5.25; found C 57.43,
H 5.12.
(E)-3-Chloro-3,3-difluoro-1-(p-tolylsulfinyl)prop-1-ene (5c): 1H
NMR (CDCl3): δ ϭ 7.52 and 7.36 (m, 4 H, ArH), 6.95 (dt, J ϭ
14.8 and 1.5 Hz, 1 H, CHSO), 6.75 (dt, J ϭ 14.8 and 8.9 Hz, 1 H,
CHClF2), 2.43 (br s, 3 H, ArCH3). Ϫ 19F NMR (CDCl3): δ ϭ
Ϫ52.20 and Ϫ52.50 (m, 2 F, CF2). Ϫ MS (EI); m/z: 250 [Mϩ]. Ϫ
C10H9ClF2OS: calcd. C 47.91, H 3.62; found C 48.04, H 3.51.
Synthesis of β-Hydroxy Sulfoxides 3b,c: To a stirred solution of the
β-ketosulfoxide 2b,c (2.5 mmol) in ethanol (6.5 mL), NaBH4 (3.3
mmol) was added at 0°C. After 30 min. stirring at the same tem-
perature, the reaction mixture was quenched with a saturated aque-
ous NH4Cl solution (15 mL). After extraction with ethyl acetate (3
ϫ 15 mL) and drying of the combined extracts over sodium sulfate,
the solvent was removed under reduced pressure. The residue was
flash chromatographed on a silica gel column using a n-hexane/
ethyl acetate mixture (50:50) as eluent, affording β-hydroxy sulfox-
ides 3b (92%) and 3c (95%), respectively, as mixtures of dia-
stereoisomers.
Synthesis of β-Fluoroalkyl γ-Butyrolactones 6a؊c. General Pro-
cedure: A suspension of zinc dust (605 mg, 9.25 mmol) and anhy-
drous CuCl (1663 mg, 16.8 mmol) in anhydrous THF (11 mL) was
refluxed for 1 h. After cooling to 0°C, a solution of the vinyl sulfox-
ide 5a؊c (0.84 mmol) in anhydrous THF (17 mL) was slowly added
under nitrogen. Trichloroacetyl chloride (4.2 mmol) was then ad-
ded over a period of 30 min. with stirring. After a further 15 min. at
0°C, the mixture was filtered through a Celite pad into a saturated
aqueous NaHCO3 solution (20 mL), kept at 0°C. The resulting
suspension was stirred for 5 min., and then extracted with diethyl
ether (3 ϫ 30 mL). The combined organic phases were washed with
a saturated aqueous solution of ammonium chloride, dried over
sodium sulfate, and concentrated to dryness under reduced pres-
sure. The residue was flash chromatographed on a silica gel column
using a 96:4 n-hexane/ethyl acetate mixture as eluent, giving γ-bu-
tyrolactones 6a (51%), 6b (53%), and 6c (60%), respectively.
3,3-Difluoro-1-(p-tolylsulfinyl)butan-2-ol (3b): Major diastereoiso-
mer: 1H NMR (CDCl3): δ ϭ 7.56 and 7.38 (m, 4 H, ArH), 4.41
(dddd, J ϭ 15.4, 8.6, 5.1 and 3.0 Hz, 1 H, CHOH), 3.15 (br s, 1
H, OH), 3.07 (dd, J ϭ 13.6 and 3.0 Hz, 1 H, CHHS), 3.00 (dd,
J ϭ 13.6 and 8.6 Hz, 1 H, CHHS), 2.43 (br s, 3 H, ArCH3), 1.68
(t, J ϭ 19.3 Hz, 3 H, CF2CH3). Ϫ 19F NMR (CDCl3): δ ϭ Ϫ101.00
(ddq, J ϭ 247.8, 19.3 and 5.1 Hz, 1 F, CFFCH3), Ϫ108.36 (ddq,
J ϭ 247.8, 19.3 and 15.4 Hz, 1 F, CFFCH3). Ϫ Minor diastereoiso-
mer: 1H NMR (CDCl3): δ ϭ 7.54 and 7.38 (m, 4 H, ArH), 4.21
(dddd, J ϭ 15.3, 10.4, 5.3 and 2.0 Hz, 1 H, CHOH), 3.20 (dd, J ϭ
13.6 and 10.4 Hz, 1 H, CHHS), 3.15 (br s, 1 H, OH), 2.84 (dd, J ϭ
13.6 and 2.0 Hz, 1 H, CHHS), 2.43 (br s, 3 H, ArCH3), 1.63 (t,
J ϭ 19.3 Hz, 3 H, CF2CH3). Ϫ 19F NMR (CDCl3): δ ϭ Ϫ101.46
(ddq, J ϭ 247.8, 19.3 and 5.3 Hz, 1 F, CFFMe), Ϫ107.38 (ddq,
J ϭ 247.8, 19.3 and 15.3 Hz, 1 F, CFFMe). Ϫ MS (EI); m/z: 248
[Mϩ]. Ϫ C11H14F2O2S: calcd. C 53.21, H 5.68; found C 53.05, H
5.80.
(2R,3S)-4,4-Dichloro-3,4-dihydro-2-(p-tolylthio)-3-trifluoromethyl-
1
5(2H)-furanone (6a): H NMR (CDCl3): δ ϭ 7.48 and 7.23 (m, 4
Eur. J. Org. Chem. 1999, 111Ϫ115
113

P. Bravo et al.
FULL PAPER
H, ArH), 5.74 (d, J ϭ 9.5 Hz, 1 H, 2-H), 3.40 (dq, J ϭ 9.5 and 6.6 polarization effects. An empirical absorption correction[13] was
Hz, 1 H, 3-H), 2.38 (br s, 3 H, ArCH3). Ϫ 19F NMR (CDCl3): δ ϭ
Ϫ63.72 (d, J ϭ 6.6 Hz, 3 F, CF3). Ϫ MS (EI); m/z: 344 [Mϩ]. Ϫ
C12H9Cl2F3O2S: calcd. C 41.76, H 2.63; found C 41.62, H 2.71.
also applied.
Structure Analysis and Refinement: The crystal structure was solved
by direct methods using the program SIR-92[14], and refined by
full-matrix least-squares on F2 values using SHELXL-97[15]. Non-
hydrogen atoms were refined with anisotropic temperature factors.
Hydrogen atoms were included at calculated positions and refined
in the riding mode, except for H2 and H5, which were located on
a difference map and refined with isotropic temperature factors.
The final values of the residual R and wR2 [for 1230 reflections
with I > 2σ (I)] were 0.057 and 0.143, respectively, with S ϭ 1.08.
In the final refinement (∆/σ)max became 0.000. The maximum and
(2R,3S)-4,4-Dichloro-3,4-dihydro-2-(p-tolylthio)-3-(1,1-difluoro-
ethyl)-5(2H)-furanone (6b): [α]D20 ϭ ϩ86.7 (c ϭ 1.0, CHCl3). Ϫ 1H
NMR (CDCl3): δ ϭ 7.46 and 7.21 (m, 4 H, ArH), 5.79 (d, J ϭ 9.6
Hz, 1 H, 2-H), 3.15 (ddd, J ϭ 9.6, 13.0 and 9.0 Hz, 1 H, 3-H), 2.37
(br s, 3 H, ArCH3), 1.98 (t, J ϭ 19.5 Hz, 3 H, CF2CH3). Ϫ 13C
NMR (CDCl3): δ ϭ 164.94 (S, C-5); 140.59 (S), 135.04 (D), 130.42
(D), 124.71 (S) (ArC); 120.07 (Sdd, JCF ϭ 247.8 and 242.3 Hz,
CF2); 84.20 (D br d, JCF ϭ 6.0 Hz, C-2), 75.91 (D br d, JCF ϭ 7.0
Hz, C-4), 60.66 (Ddd, JCF ϭ 28.0 and 25.0 Hz, C-3), 23.47 (Qt,
JCF ϭ 25.9 Hz, CF2CH3), 21.26 (Q, ArCH3). Ϫ 19F NMR (CDCl3):
δ ϭ Ϫ84.44 (ddd, J ϭ 255.5, 19.5 and 9.0 Hz, 1 F, CFFMe), Ϫ92.62
(ddd, J ϭ 255.5, 19.5 and 13.0 Hz, 1 F, CFFMe). Ϫ MS (EI); m/z:
340 [Mϩ]. Ϫ C13H12Cl2F2O2S: calcd. C 45.76, H 3.54; found C
45.88, H 3.45.
minimum peaks on the final difference map were 0.28 and Ϫ0.52
˚
A
Ϫ3. The refined value of the Flack χ parameter[16], 0.10(4), clearly
indicates the absolute configuration as being (2R,3S).
Desulfurization of γ-Butyrolactone (2R,3S)-7c: A suspension of γ-
butyrolactone 7c (0.17 mmol) and Raney Ni (70 mg) in methanol
was hydrogenated at atmospheric pressure for 50 min. at room tem-
perature. After filtration through a Celite pad and extraction with
dichloromethane (3 ϫ 10 mL), the organic layer was dried over
sodium sulfate and the solvent was carefully evaporated under a
nitrogen stream with no heating. The residue contained (S)-4-chlo-
rodifluoromethyl-4,5-dihydro-2(3H)-furanone (8c) (65%), which
was characterized without further purification: [α]D20 ϭ ϩ19.4 (c ϭ
(2R,3S)-3-Chlorodifluoromethyl-4,4-dichloro-3,4-dihydro-2-(p-tolyl-
thio)-5(2H)-furanone (6c): 1H NMR (CDCl3): δ ϭ 7.48 and 7.23
(m, 4 H, ArH), 5.80 (d, J ϭ 8.7 Hz, 1 H, 2-H), 3.58 (ddd, J ϭ 9.2,
8.7 and 7.5 Hz, 1 H, 3-H), 2.38 (br s, 3 H, ArCH3). Ϫ 19F NMR
(CDCl3): δ ϭ Ϫ49.72 (dd, J ϭ 175.0 and 7.5 Hz, 1 F, CFFCl),
Ϫ50.97 (dd, J ϭ 175.0 and 9.2 Hz, 1 F, CFFCl). Ϫ MS (EI); m/z:
360 [Mϩ]. Ϫ C12H9Cl3F2O2S: calcd. C 39.86, H 2.51; found C
39.72, H 2.63.
1
0.73, CHCl3). Ϫ H NMR (CDCl3): δ ϭ 4.48 (dd, J ϭ 10.2 and
8.2 Hz, 1 H, 5a-H), 4.42 (dd, J ϭ 10.2 and 5.5 Hz, 1 H, 5b-H),
3.01 (dddddd, J ϭ 11.0, 9.8, 9.5, 8.2, 6.5 and 5.5 Hz, 1 H, 4-H),
2.80 (dd, J ϭ 18.4 and 9.5 Hz, 1 H, 3a-H), 2.75 (dd, J ϭ 18.4 and
6.5 Hz, 1 H, 3b-H). Ϫ 13C NMR (CDCl3): δ ϭ 173.80 (S, C-2),
128.78 (St, JCF ϭ 292.5 Hz, CF2), 66.70 (Tt, JCF ϭ 3.3 Hz, C-5),
45.71 (Dt, JCF ϭ 25.8 Hz, C-4), 29.13 (Tt, JCF ϭ 2.4 Hz, C-3). Ϫ
19F NMR (CDCl3): δ ϭ Ϫ59.01 (dd, J ϭ 167.2 and 9.8 Hz, 1 F,
CFFCl), Ϫ60.16 (dd, J ϭ 167.2 and 11.0 Hz, 1 F, CFFCl). Ϫ MS
(EI); m/z: 170 [Mϩ].
Dechlorination of γ-Butyrolactone (2R,3S)-6c: To a solution of γ-
butyrolactone 6c (0.80 mmol) in ethanol (8 mL), a buffer solution
(AcOH/AcONa, pH 5.2, 3.0 mL) and Raney Ni (4 equiv.) were
added. Immediately thereafter, 5 mL of aqueous NaPH2O2 ·H2O
(8.0 mmol) solution was added. The reaction mixture was hydro-
genated at atmospheric pressure for 1 h, then filtered through a
Celite pad, which was rinsed with dichloromethane. After washing
with saturated aqueous NaCl solution, the organic layer was dried
over sodium sulfate and concentrated under reduced pressure. The
residue was flash chromatographed on a silica gel column using a
90:10 n-hexane/ethyl acetate mixture as eluent, affording (2R,3S)-
3-chlorodifluoromethyl-3,4-dihydro-2-(p-tolylthio)-5(2H)-furanone
(7c) (60%): [α]D20 ϭ ϩ106 (c ϭ 0.9, CHCl3). Ϫ 1H NMR (CDCl3):
δ ϭ 7.47 and 7.21 (m, 4 H, ArH), 5.79 (d, J ϭ 3.4 Hz, 1 H, 2-H),
3.33 (ddt, J ϭ 10.2, 4.2 and 10.3 Hz, 1 H, 3-H), 2.62 (br dd, J ϭ
18.5 and 4.2 Hz, 1 H, 4a-H), 2.43 (dd, J ϭ 18.5 and 10.2 Hz, 1 H,
4b-H), 2.38 (br s, 3 H, ArCH3). Ϫ 13C NMR (CDCl3): δ ϭ 172.35
(S, C-5); 140.39 (S), 135.11 (D), 130.50 (D), 125.30 (S) (ArC);
128.43 (St, JCF ϭ 294.5 Hz, CClF2); 84.79 (Dt, JCF ϭ 3.0 Hz, C-
2); 51.89 (Dt, JCF ϭ 26.0 Hz, C-3); 29.74 (T br d, JCF ϭ 4.0 Hz,
C-4); 21.27 (Q, ArCH3). Ϫ 19F NMR (CDCl3): δ ϭ Ϫ59.44 and
Ϫ59.65 (br dd, J ϭ 167.5 and 10.3 Hz, 2 F, CF2). Ϫ MS (EI); m/z:
292 [Mϩ]. Ϫ C12H11ClF2O2S: calcd. C 49.24, H 3.79; found C
49.28, H 3.70.
Acknowledgments
C.N.R. “Progetto Finalizzato per i Beni Culturali” is gratefully
acknowledged for financial support.
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115