Radical mechanism in the elimination of 2-arylsulfinyl esters

Article abstract of DOI:10.1021/jo300699w

The mechanism of the dehydrosulfenylation of 2-arylsulfinyl esters was investigated. The reaction was found to follow a homolytic cleavage mechanism as verified by electrospray ionization tandem mass spectrometry and experimental work. Rearranged sulfoxides are obtained as byproduct during the elimination reaction.

Full text of DOI:10.1021/jo300699w

Note
pubs.acs.org/joc
Radical Mechanism in the Elimination of 2-Arylsulfinyl Esters
Antonio Latorre,† Irakusne Lopez,† Victoria Ramírez,† Santiago Rodríguez,† Javier Izquierdo,†
́
Florenci V. Gonzalez,*,† and Cristian Vicent*,†,‡
́
†Departament de Química Inorgan
̀
ica i Organ
̀
ica and Serveis Centrals dInstrumentacio
́
Científica, Universitat Jaume I, 12080
‡
́
Castello,
́
Spain
S
* Supporting Information
ABSTRACT: The mechanism of the dehydrosulfenylation of 2-
arylsulfinyl esters was investigated. The reaction was found to follow a
homolytic cleavage mechanism as verified by electrospray ionization
tandem mass spectrometry and experimental work. Rearranged
sulfoxides are obtained as byproduct during the elimination reaction.
limination reactions of sulfoxides and sulfones are well-
known reactions in synthetic organic chemistry.1 In
stereoisomers (Scheme 2).11 Then compounds 2a−f were
submitted to elimination by heating to reflux in toluene for 5 h,
affording the corresponding E-enoates.12 2-Arylsulfinyl esters
2a−c gave rise to ethyl acrylate 5 and compounds 2d, 2e, and
2f afforded enoates 6, 7, and 8, respectively, as dominant
products.13
Careful isolation of all the products obtained during the
elimination reaction of compound 2a gave the phenyl-
thiosulfonate 9 (that partly converts to diphenyl disulfide and
sulfonic acid, see below) and rearranged sulfoxide 10 as a minor
product (15%) (Scheme 3).14
E
particular, the transformation of 2-arylsulfinyl esters to afford
unsaturated carbonyl compounds by elimination is a common
synthetic transformation.2−5 The elimination reaction of
sulfoxides follows an Ei (elimination internal) mechanism, as
demonstrated by the seminal work by Cram and Kingsbury,6
who also suggested the existence of a competing homolytic
mechanism for some sulfoxides having a group to stabilize a
radical intermediate. Although extensive work has been
reported for the elimination of sulfoxides through an Ei
mechanism,7,8 no convincing evidence has appeared for a
radical mechanism involving any sulfinyl substrate.
It is also noteworthy that the unprecedented rearrangement
of 2-arylsulfinyl ester 2a to yield 10 provided an alternative
synthetic entry to 3-arylsulfinyl ester. To determine whether
the formation of minor compound 10 was an inter- or an
intramolecular process, we conducted a crossover experiment
between 2b and compound 2f (see Scheme 4).
In the context of our investigations with sulfoxides,9,10 we
became interested in determining the nature of the mechanism
during the elimination reaction of 2-arylsulfinyl esters. We
considered two plausible mechanistic routes for the elimination
of a 2-arylsulfinyl ester to afford the corresponding enoate
(Scheme 1): (a) the concerted elimination reaction (Ei) or (b)
a radical process involving the homolytic scission of the C−S
bond to furnish free radical 4 and aryl sulfinyl radical 3.
1
After heating of both sulfoxides 2b and 2f, the H NMR or
13C NMR spectra were highly crowded due to the presence of
numerous species, making it difficult to identify the newly
formed species. However, after removal of volatile acrylates and
chromatographic separation of the fraction containing the 3-
arylsulfinyl esters and the thiolsulfonate esters, electrospray
ionization mass spectrometry (ESI−MS) analysis, operated in
positive ion mode (ESI(+)), unravelled a rapid and direct
snapshot of the formed species in the reaction mixture (see
Figures S1 and S2, Supporting Information) and demonstrated
that the rearrangement was an intermolecular rather than an
intramolecular process.15 A similar result was observed when
sulfoxides 2b and 2e were heated at 80 °C for 2 h as judged by
ESI−MS analysis.
Scheme 1. Possible Mechanistic Routes
The corresponding 2-arylsulfonyl esters were also prepared.
When 2-arylsulfonyl esters or 2-arylthioethers (1a−f) under-
went the same experimental conditions for elimination as the
sulfoxides, only starting material was recovered, thus illustrating
We undertook the study of the elimination reaction of 2-
arylsulfinyl esters with a range of R alkyl groups and Ar aryl
groups attached to the sulfur atom. 2-Arylsulfinyl esters 2a−f
were prepared from the corresponding 2-bromo esters by
treatment with the corresponding sodium thiophenolates,
which furnished the expected thioethers 1a−f. Upon oxidation
of the thioethers, sulfoxides 2a−f were obtained as a mixture of
Received: April 10, 2012
Published: May 14, 2012
© 2012 American Chemical Society
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Note
Scheme 2. Preparation and Elimination of 2-Arylsulfinyl Esters 2a−f
Scheme 3. Elimination Reaction of Compound 2a
Scheme 5. Trapping of the Radical Intermediates Using
Tempo
that eliminations are a characteristic feature of only the
sulfoxides.
Since the photolytic homolysis of C−S bonds has been
described,16 the elimination reactions were also performed in
the absence of light. When 2-arylsulfinyl esters 2a−f were
submitted to elimination by heating in the absence of light the
products were the same as in the presence of light, thus ruling
out a photolytic homolysis.
Scheme 6. Radical Mechanism in the Elimination of 2-
Arylsulfinyl Esters
The interception of the radical intermediates would provide
evidence for presence of a single-electron transfer mechanism
in the elimination reaction. A nitroxyl radical (2,2,6,6-
tetramethyl-1-piperidinyloxy) (Tempo) succeeded in intercept-
ing the radical intermediates derived from 2-arylsulfinyl esters
2b, 2d, and 2e. The reactions were investigated by electrospray
ionization mass spectrometry (ESI−MS).17 Compounds 2b,
2d, and 2e afforded adducts 11 and 15, 12 and 14, and 13 and
14, respectively. In case of the reaction using 2e as starting
material, both resulting reaction compounds 13 and 14 were
isolated and fully characterized (see the Supporting Informa-
tion) (Scheme 5).18
These results denote the occurrence of a radical process
during the elimination of 2-arylsulfinyl esters into enoates. A
possible mechanism is proposed in Scheme 6. Sulfoxide 2
would give rise to radical 4 and aryl sulfinyl radical 3. Sulfinyl
radicals combine to give vicinal disulfoxides (vic-disulfoxides)
which isomerize to give phenyl thiosulfonate 9. Thiosulfonate 9
partly converts into the corresponding diaryl sulfide 16 and
sulfonic acid as it is known.19 Radical 4 would furnish the
enoate. The formation of the subproduct 10 can be explained
by addition of in situ formed phenyl sulfenic acid to the enoate.
The addition of sulfenic acids to unsaturated esters have been
demonstrated previously.20−22 Compound 10 would be formed
in a low yield due to the high tendency of sulfinyl radicals (or
sulfenic acids) to afford thiosulphonates, although final reaction
yields would depend on the subtle interplay between kinetics
and thermodynamics of each elementary step depicted in
Scheme 6.
In studies to determine the reaction mechanism of a
multistep reaction, the identification of the intermediates is
an essential process.23 In this context, ESI−MS is a useful
technique for analyzing chemical intermediates or products in
diverse chemical and biochemical processes,24−26 as illustrated
above for the identification of the products formed in the
crossover experiment. Although the detection of free radicals is
sometimes difficult, ESI−-MS has been recently employed for
observing radical intermediates in some processes.27−32 For a
better understanding of the mechanism of the arylsulfinyl esters
elimination depicted in Scheme 6, attempts to intercept and
characterize the formed species were carried out on the basis of
online ESI mass spectrometry and ESI tandem mass
spectrometry. Closely related thermally driven homolytic
reactions have been successfully investigated by Metzgers
́
group by means of ESI mass spectrometry using modified ESI
sources.28 To investigate the elimination reaction, toluene
Scheme 4. Crossover Experiment between 2b and 2f
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Note
solutions of 2a were heated to 100 °C and at different time
intervals, aliquots were extracted, immediately diluted with hot
acetonitrile, and analyzed by ESI(+) mass spectrometry. The
obtained ESI mass spectra recorded at different intervals were
nearly identical (Figure 1), with the most significant difference
homolytic C−S bond cleavage affording the radical species
[CH3CH·CO2CH2CH3 + Na]+ (m/z = 124) whereas species
[10 + Na]+ (m/z = 249) dissociated via formation of the
closed-shell [CH2CH·CO2CH2CH3 + Na]+ (m/z = 123)
product ion. Moreover, at identical collision energies, it is
clear that species [2a + Na]+ is significantly easier to dissociate
than [10 + Na]+ as evidenced by the relative intensity of the
formed product ions. The gas-phase behavior of 2a is
reminiscent of that observed for heated solutions for which
this compound is more prone to homolytically dissociate via S−
C bond cleavage.
The same conditions were also used for monitoring the
evolution of the reaction of 2-arylsulfinyl esters 2b−f. It is
remarkable that species [2a−f + Na]+ unvariably dissociated
predominantly via homolytic C−S bond cleavage affording the
respective radical species [RCH2CH·CO2X + Na]+ respectively,
as illustrated in Figure 3 for 2b−f. Fragmentation studies were
also performed for the 2-arylsulfide esters and 2-arylsulfonyl
esters but no radical intermediates were detected in their
respective CID spectra. It is known that sulfides and sulfones
do not eliminate as easily as sulfoxides.33
The formation of rearrangement products during the
elimination of a 2-arylsulfinyl ester was also observed during
the synthesis of the natural product 18 starting from sulfoxide
17.9 In this case, 3-arylsulfonyl lactone 19 was obtained as a
minor product along with the expected α-methylene γ-
butyrolactone 18 (Scheme 7) when the reaction was performed
in open air. Sulfone 19 was formed in a highly stereoselective
fashion as judged by single-crystal X-ray diffraction methods
(see Figure S4, Supporting Information).34 In this case, sulfone
19 was formed instead of the expected sulfoxide, following the
well-known tendency of γ-hydroxy sulfides to be oxidized to
sulfones instead of sulfoxides under photooxidation condi-
tions.35
In summary, the mechanism of the dehydrosulfenylation of
2-arylsulfinyl esters for furnishing enoates has been determined
to be a homolytic process. The interception of the radical
intermediate using a nitroxyl radical and ESI−-MS and ESI
tandem MS techniques were useful for drawing a compre-
hensive picture of the intermediates involved in the
dehydrosulfenylation of 2-arylsulfinyl esters and suggest that a
radical-mediated process is operative. An unprecedented
transformation of 2-arylsulfinyl esters to 3-arylsulfinyl esters is
also observed as a side reaction whose intimate mechanism is
proposed.
Figure 1. ESI(+) mass spectra of toluene/acetonitrile solutions of
compound 2a. Samples of the initial solution of 2a (upper panel) and
of compound 2a after heating for 60 min (lower panel). Note that
species at m/z 227, 249, and 265 in the lower panel correspond to 2a
and its rearranged isomer 10.
being the appearance of new signals corresponding to the
PhSSO2Ph product as evidenced for the peaks assigned to
[PhSSO2Ph + Na]+ (m/z = 273) and [PhSSO2Ph + K]+ (m/z
= 289). Negative ESI mass spectrum revealed the presence of
sulfonic acid as [M − H]− adduct. Diphenyl disulfide was not
observed in the ESI mass spectrum because it is not readily
ionized upon ESI conditions.
T h e t r a n s i e n t r a d i c a l c a t i o n s P h S O • a n d
CH3CH·CO2CH2CH3 (not as H+, Na+, or K+ adducts) could
not be identified in the ESI mass spectrum directly. However,
monitoring the advance of the 2a conversion to methylacrylate
and the rearranged product 10 was possible by ESI−MS,
provided that both 2a and 10 isomers at m/z = 249 displayed
distinctive unimolecular dissociation upon collision-induced
dissociation (CID) conditions. CID spectra of the sodium
adducts of 2a and 10 are shown in Figure 2 which allowed us to
monitor the temporal evolution of the species.
Also helpful is the use of the MS/MS technique, where the
fragment spectrum gives direct information about structural
aspects of the investigated ion and can provide efficient
information about mechanistic properties. It is remarkable that
species [2a + Na]+ (m/z = 249) dissociated predominantly via
Figure 2. CID spectra of mass-selected species at (a) m/z = 249 [2a + Na]+ and (b) m/z = 249 [10 + Na]+ (Elaboratory = 15 eV).
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Note
Figure 3. CID spectra of mass-selected species [2b−f + Na]+ using a collision energy (Elaboratory) = 15 eV. Radical species detected are m/z = 124 for
2b and 2c, m/z = 138 for 2d, m/z = 152 for 2e and m/z = 186 for 2f.
selected using the first quadrupole (Q1) and interacted with argon in
Scheme 7. Synthesis of Compounds 18 and 19
the hexapole collision cell at variable collision energies (typically in the
Elaboratory = 3−10 eV range) while mass analyzing the products with the
second analyzer. The isolation width was ca. 1 Da and argon was used
as a collision gas to produce a pressure of 8 × 10−4 mbar.
For accurate m/z determinations (for all the compounds except for
16) and CID experiments, an ESI tandem mass spectrometer
(quadrupole-Twave-time-of-flight) was used. The drying gas was
nitrogen. The temperature of the source block was set to 120 °C and
EXPERIMENTAL SECTION
■
the desolvation temperature to 150 °C. A capillary voltage of 3.5 kV
General Experimental Methods. All solvents used in reactions
was used in the positive scan mode, and the cone voltage was set to a
1
were freshly distilled from appropriate drying agents before use. H
low value to control the extent of fragmentation (typically 15 V).
NMR spectra and 13C NMR spectra were measured in CDCl3 (1H,
Methanol sample solutions were infused via syringe pump directly
7.24 ppm; 13C 77.0 ppm) solution at 30 °C on a 300 MHz or a 500
MHz NMR spectrometer. IR spectra were recorded as oil films or KBr
discs or NaCl pellets on a FT-IR spectrometer. Silica gel 60 was used
connected to the ESI source at a flow rate of 10 μL/min. Mass
calibration was performed using a mixture of NaOH 0.05 M/formic
acid 10% (50:50) from m/z 50 to 900. For accurate mass
for column chromatography, while TLC was performed with
measurements, a solution of leucine enkephalin (m/z = 556.2771)
precoated plates (Kieselgel 60, F254, 0.25 mm). Unless otherwise
was introduced via the lock spray needle at a flow rate of 30 μL/min.
specified, all reactions were carried out under argon atmosphere with
For an accurate m/z determination of compound 16, a GC−EIMS
magnetic stirring.
was used. The GC instrumentation used was equipped with an
Electrospray Ionization Mass Spectrometry (ESI−MS) and
autosampler coupled to a TOF mass spectrometer operating in
Electron Impact Mass Spectrometry (EI−MS). For the online
reaction monitoring, ESI mass spectra were recorded using an ESI
electron ionization (EI) mode. The GC separation was performed
using a fused silica column (30 m × 0.25 mm i.d., 0.25 mm film
thickness). The oven temperature was programmed as follows: 90 °C
(hold 1 min); 10 °C/min to 300 °C (hold 2 min). The total running
time was 24 min. Splitless injections of 1 mL of sample extracts were
carried out with an injector temperature of 300 °C and with a splitless
time of 1 min. Helium 99.999% was used as carrier gas at a constant
flow of 1 mL/min. The interface and ion source temperatures were set
to 260 and 250 °C, respectively. A solvent delay of 3 min was used to
prevent damage in the ion source filament. TOF MS was operated at
tandem mass spectrometer (quadrupole-hexapole-quadrupole). The
drying gas was nitrogen. The temperature of the source block was set
to 120 °C and the desolvation temperature to 150 °C. A capillary
voltage of 3.5 kV was used in the positive scan mode, and the cone
voltage (Uc) was set to 15 V to control the extent of fragmentation of
the identified ions. Toluene solutions of 2a−f were heated at 100 °C in
an open vial, a drop of the solution was immediately extracted and
diluted in hot CH3CN, and a positive-ion mass spectrum was
collected. For CID experiments, the cations of interest were mass-
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Note
an scan time of 0.95 s in the mass range m/z 60−300 and using a
multichannel plate voltage of 2700 V. TOF MS resolution was about
8500 (fwhm) at m/z 614. Pure PFTBA (Perfluorotri-n-butylamine),
used for the daily mass calibration/verification as well as for lock mass,
was injected via syringe (∼ 1 mL) in the reference reservoir at 30 °C.
The m/z monitored was 218.9856.
ppm; IR (oil) δ 3079, 2970, 2936, 2877, 1959, 1884, 1735, 1583, 1480,
1443, 1368, 1343, 1300, 1234, 1209, 1160, 1091, 1026, 941, 864, 811
cm−1; HRMS m/z calcd for C12H17O2S [M + H+] 225.0949, found
225.0953; calcd for C12H16O2SNa [M + Na+] 247.0769, found
247.0772.
1
Ethyl 2-(phenylthio)pentanoate (1e). yield = 19.35 g, 88%; H
X-ray Crystallography. Crystals of compound 19 are air stable
and were mounted on the tip of a glass fiber with the use of epoxi
cement. X-ray diffraction experiments were carried out on a
diffractometer using Mo Kα radiation (λ = 0.71073 Å) at room
temperature. The data were collected with a frame width of 0.3° in ω
and a counting time of 60 s per frame at a crystal to detector distance
of 4 cm. The diffraction frames were integrated using the SAINT
package and corrected for absorption with SADABS. The structures
were solved by direct methods and refined by the full-matrix method
based on F2 using the SHELXTL software package. All non-hydrogen
atoms were refined anisotropically. Hydrogen atoms were generated
geometrically, assigned isotropic thermal parameters and allowed to
ride on their respective parent carbon atoms. Crystal data and
structure refinement for 19: empirical formula C12H14O5S; crystal
system monoclinic; space group P2(1); unit cell dimensions a =
4.8321(7) Å, b = 21.157(3) Å, c = 6.4661(9) Å, β = 95.816(3)°; Z = 2;
θ range for data collection 1.93−30.49°; reflections collected 5373;
independent reflections 3114 [R(int) = 0.0247]; goodness-of-fit on F2
= 1.030; final R indices [I > 2σ(I)] R1 = 0.0424, wR2 = 0.0928; R
indices (all data) R1 = 0.0685, wR2 = 0.1034; absolute structure
parameter −0.03(8); largest diff peak and hole 0.268 and −0.180 e·Å−3
General Experimental Procedure for the Preparation of
Thioethers 1a−f. To an ice-bath solution of sodium hydride (1.85 g,
46.2 mmol) (60% in mineral oil) in tetrahydrofuran (110 mL) was
added dropwise the corresponding thiophenol (92.4 mmol). The
resulting mixture was stirred in an ice bath for 30 min. TThe
bromoester (92.4 mmol) was added, and the resulting mixture was
stirred at room temperature for 72 h. The mixture was quenched with
brine and extracted with ethyl ether (3 × 15 mL), and then the organic
layers were washed with a saturated aqueous solution of sodium
bicarbonate and water, dried (Na2SO4), and concentrated. The crude
was purified through chromatography (silica gel, hexanes/ethyl acetate
(95:5)) to afford the desired compound.
NMR (300 MHz, CDCl3) δ 7.43−7.47 (2H, m), 7.24−7.31 (3H, m),
4.10 (2H, q, J = 7.2 Hz), 3.65 (1H, dd, J = 6.6, 8.1 Hz), 1.67−1.94 (m,
2H), 1.38−1.52 (m, 2H), 1.15 (3H, t, J = 6.6 Hz), 0.92 (3H, t, J = 7.2
Hz); 13C NMR (75 MHz, CDCl3) δ 172.0, 133.7, 132.7, 128.7, 127.6,
60.7, 50.5, 33.7, 20.5, 14.0, 13.6 ppm; IR (oil) δ 3066, 2968, 2936,
2876, 1958, 1884, 1733, 1585, 1483, 1444, 1374, 1335, 1303, 1279,
1243, 1163, 1106, 1033, 934, 860, 808 cm−1; HRMS m/z calcd for
C13H19O2S [M + H+] 239.1106, found 239.1115; calcd for
C13H18O2SNa [M + Na+] 261.0925, found 261.0923.
1
Benzyl 2-(phenylthio)propanoate (1f): yield = 17.59 g, 70%; H
NMR (300 MHz, CDCl3) δ 7.24−7.44 (10H, m), 5.11 (2H, s), 3.85
(1H, d, J = 7.2 Hz), 1.52 (3H, d, J = 7.2 Hz); 13C NMR (75 MHz,
CDCl3) δ 172.5, 135.5, 133.2, 133.0, 128.9, 128.5, 128.2, 128.0, 66.7,
45.3, 17.3 ppm; IR (oil) δ 3061, 2986, 2936, 1959, 1888, 1735, 1586,
1480, 1443, 1380, 1324, 1268, 1162, 1063, 1029, 1004, 954, 898, 780
cm−1; HRMS m/z calcd for C16H17O2S [M + H+] 273.0949, found
273.0946; calcd for C16H16O2SNa [M + Na+] 295.0769, found
295.0770.
General Experimental Procedure for the Preparation of
Sulfoxides 2a−f. To a −10 °C cold solution of thioether (0.95
mmol) in CH2Cl2 (5 mL) was added a solution of m-CPBA (77%
pure) (177 mg, 0.79 mmol) in CH2Cl2 (4 mL). The resulting mixture
was stirred at −10 °C for 30 min, quenched with saturated aqueous
solution of sodium bicarbonate, and extracted with CH2Cl2 (3 × 15
mL), and then the organic layers were sequently washed with brine
and saturated aqueous solution of sodium bicarbonate and water, dried
(Na2SO4), and concentrated. The crude was purified through
chromatography (silica gel, hexanes/ethyl acetate (7:3)) to afford
the desired sulfoxide.
Ethyl 2-(phenylsulfinyl)propanoate (2a): yield = 178 mg, 83%);
1H NMR (500 MHz, CDCl3) δ 7.25−7.45 (5H, m) (major and
minor), 4.12 (2H, m) (major and minor), 3.81 (1H, q, J = 6.5 Hz)
(major), 3.49 (1H, q, J = 7.0 Hz) (minor), 1.49 (3H, d, J = 7.0 Hz)
(major), 1.32 (3H, d, J = 7.5 Hz) (minor), 1.21 (3H, t, J = 6.5 Hz)
(minor), 1.18 (3H, t, J = 7.0 Hz) (major); 13C NMR (125 MHz,
CDCl3) δ 168.9, 168.1, 142.6, 140.9, 134.5, 132.1, 131.9, 129.7, 129.5,
129.3, 125.5, 125.1, 66.2, 64.1, 62.1, 62.0, 14.3, 14.2, 10.0, 9.1 ppm; IR
(NaCl) δ 3051, 2988, 2926, 1968, 1895, 1724, 1577, 1472, 1445, 1371,
1316, 1254, 1215, 1165, 1083, 1045, 1017, 920, 889, 858, 749, 691
cm−1; HRMS m/z calcd for C11H14O3SNa [M + Na+] 249.0556, found
249.0557.
1
Ethyl 2-(phenylthio)propanoate (1a): yield = 12.61 g, 65%; H
NMR (300 MHz, CDCl3) δ 7.46−7.48 (2H, m), 7.26−7.32 (3H, m),
4.11 (2H, q, J = 7.2 Hz), 3.78 (1H, q, J = 6.9 Hz), 1.48 (3H, d, J = 6.9
Hz), 1.17 (3H, t, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 173.0,
133.4, 129.2, 128.3, 61.5, 45.6, 17.7, 14.3 ppm; IR (NaCl) δ 3060,
2981, 2933, 2872, 1955, 1883, 1732, 1583, 1476, 1440, 1375, 1323,
1256, 1225, 1159, 1068, 1025, 897, 859, 776, 748, 691, 596 cm−1;
HRMS m/z calcd for C11H14O2SNa [M + Na+] 233.0612, found
233.0611.
Ethyl 2-((4-methoxyphenyl)sulfinyl)propanoate (2b): yield = 124
1
Ethyl 2-((4-methoxyphenyl)thio)propanoate (1b): yield = 13.3 g,
mg, 51%; H NMR (500 MHz, CDCl3) δ 7.56 (2H, d, J = 8.5 Hz)
1
60%; H NMR (500 MHz, CDCl3) δ 7.36 (2H, d, J = 8.0 Hz), 6.79
(major), 7.52 (2H, d, J = 8.5 Hz) (minor), 7.00 (2H, d, J = 8.5 Hz)
(major and minor), 4.04−4.20 (2H, m) (major and minor), 3.85 (3H,
s) (major and minor), 3.78 (1H, q, J = 7.0 Hz) (major), 3.47 (1H, q, J
= 8.0 Hz) (minor), 1.50 (3H, d, J = 7.0 Hz) (major), 1.27 (3H, d, J =
7.0 Hz) (minor), 1.23 (3H, t, J = 7.0 Hz) (minor), 1.15 (3H, t, J = 7.0
Hz) (major); 13C NMR (125 MHz, CDCl3) δ 169.1, 168.3, 162.7,
133.2, 131.5, 127.3, 126.9, 114.9, 114.8, 66.3, 64.3, 61.9, 55.8, 14.3,
14.3, 10.4, 8.9 ppm; IR (KBr) δ 3096, 3069, 2981, 2940, 2842, 1727,
1598, 1500, 1459, 1306, 1258, 1173, 1092, 1024, 834, 793, 626 cm−1;
HRMS m/z calcd for C12H17O4S [M + H+] 257.0848, found 257.0849;
calcd for C12H16O4SNa [M + Na+] 279.0667, found 279.0656.
Ethyl 2-((4-nitrophenyl)sulfinyl)propanoate (2c): yield = 160 mg,
62%; 1H NMR (500 MHz, CDCl3) δ 8.31 (2H, d, J = 8.5 Hz) (major),
8.30 (2H, d, J = 9.0 Hz) (minor), 7.82 (2H, d, J = 9.0 Hz) (major),
7.77 (2H, d, J = 9.0 Hz) (minor), 4.04−4.15 (2H, m) (major and
minor), 3.84 (1H, q, J = 7.0 Hz) (major), 3.48 (1H, q, J = 7.0 Hz)
(minor), 1.41 (3H, d, J = 7.5 Hz) (major), 1.30 (3H, d, J = 7.0 Hz)
(minor), 1.17 (3H, t, J = 7.5 Hz) (minor), 1.15 (3H, t, J = 7.5 Hz)
(major); 13C NMR (125 MHz, CDCl3) δ 169.6, 168.3, 149.7, 147.9,
126.6, 126.2, 127.3, 125.6, 125.0, 65.6, 63.7, 62.5, 62.3, 14.2, 9.4, 9.0
ppm; IR (NaCl) δ 3101, 2985, 1732, 1603, 1579, 1527, 1475, 1450,
(2H, d, J = 8.5 Hz), 4.06 (2H, q, J = 7.0 Hz), 3.75 (3H, s), 3.57 (1H, q,
J = 7.0 Hz), 1.37 (3H, d, J = 7.0 Hz), 1.14 (3H, t, J = 7.5 Hz); 13C
NMR (75 MHz, CDCl3) δ 172.9, 160.5, 136.7, 123.4, 114.7, 61.2, 55.5,
46.2, 17.4, 14.3 ppm; IR (NaCl) δ 2927, 1727, 1591, 1493, 1461, 1286,
1247, 1172, 1029, 827 cm−1; HRMS m/z calcd for C12H16O3SNa [M +
Na+] 263.0718, found 263.0712.
Ethyl 2-((4-nitrophenyl)thio)propanoate (1c): yield = 12.25 g,
1
52%; H NMR (500 MHz, CDCl3) δ 8.11 (2H, d, J = 8.5 Hz), 7.46
(2H, d, J = 9.0 Hz), 4.15 (2H, m), 4.00 (2H, q, J = 7.0 Hz), 1.56 (3H,
d, J = 7.5 Hz), 1.19 (3H, t, J = 7.0 Hz); 13C NMR (125 MHz, CDCl3)
δ 172.2, 144.9, 131.5, 129.3, 124.3, 62.1, 44.1, 17.6, 14.4 ppm; IR
(NaCl) δ 2925, 1732, 1596, 1578, 1515, 1477, 1341, 1259, 1174, 1076,
1013, 853, 742, 683 cm−1; HRMS m/z calcd for C11H14NO4S [M +
H+] 256.0644, found 256.0647; calcd for C11H13NO4SNa [M + Na+]
278.0463, found 278.0464.
Ethyl 2-(phenylthio)butanoate (1d): yield = 19.25 g, 93%; 1H
NMR (300 MHz, CDCl3) δ 7.44 (2H, m), 7.25 (3H, m), 4.09 (2H,
dq, J = 1.2, 7.2 Hz), 3.56 (1H, dd, J = 6.6, 8.4 Hz), 1.70−1.95 (m, 2H),
1.15 (3H, t, J = 6.9 Hz), 1.09 (3H, t, J = 7.2 Hz); 13C NMR (75 MHz,
CDCl3) δ 172.0, 133.7, 132.7, 128.8, 127.7, 60.9, 52.4, 25.1, 14.0, 11.7
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Note
1398, 1347, 1150, 1089, 1054, 1011, 1017, 853, 743, 723, 684 cm−1;
HRMS m/z calcd for C11H14NO5S [M + H+] 272.0593, found
272.0580; calcd for C11H13NO5SNa [M + Na+] 294.0412, found
294.0405.
Experimental Procedure for Trapping the Radical. A mixture
of compound 2e (500 mg, 1.96 mmol) and 2,2,6,6-Tetramethyl-1-
piperidinyloxy (Tempo) (614 mg, 3.93 mmol) in toluene (10 mL) was
heated at 80 °C for 2 h. The resulting crude mixture was carefully
concentrated under vacuum and then purified through chromatog-
raphy (silica gel, hexanes/ethyl acetate (95:5)) to afford compound 13
(17 mg, 3%) as an oil and compound 14 (60 mg, 11%) as a white
solid. Recrystallization of 14 from CH2Cl2/hexanes gave white
prismatic crystals (mp =128−130 °C).
1
Ethyl 2-(phenylsulfinyl)butanoate (2d): yield = 187 mg, 82%; H
NMR (500 MHz, CDCl3) δ 7.49−7.66 (5H, m) (major and minor),
3.95−4.10 (2H, m) (major and minor), 3.48 (1H, dd, J = 5.0, 10.0 Hz)
(major), 3.39 (1H, dd, J = 5.0, 9.5 Hz) (minor), 2.06−2.16 (1H, m)
(major and minor), 1.76−1.90 (1H, m) (major and minor), 1.12 (3H,
t, J = 7.5 Hz) (major), 1.06 (3H, t, J = 7.5 Hz) (minor), 1.03 (3H, t, J
= 7.0 Hz) (major), 1.00 (3H, t, J = 7.5 Hz) (minor); 13C NMR (125
MHz, CDCl3) δ 167.6, 166.7, 142.2, 141.1, 131.7, 131.4, 129.9, 128.9,
124.8, 124.7, 73.5, 70.6, 61.3, 20.3, 18.7, 13.8, 11.5, 11.3 ppm; IR (oil)
δ 3066, 2975, 2940, 2880, 2088, 1972, 1894, 1726, 1638, 1581, 1476,
1448, 1374, 1335, 1258, 1202, 1163, 1089, 1039, 952, 860, 815 cm−1;
HRMS m/z calcd for C12H17O3S [M + H+] 241.0898, found 241.0900;
calcd for C12H16O3SNa [M + Na+] 263.0718, found 263.0722.
Ethyl 2-((2,2,6,6-tetramethylpiperidin-1-yl)oxy)pentanoate (13):
1H NMR (300 MHz, CDCl3) δ 4.21 (1H, dd, J = 6.6, 7.5 Hz), 4.15
(2H, q, J = 7.2 Hz), 1.74−1.85 (2H, m), 1.01−1.48 (23H, m), 0.91
(3H, t, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 173.6, 85.5, 60.1,
40.3, 34.2, 33.6, 33.0, 20.2, 17.9, 17.1, 14.2, 13.9 ppm; IR (KBr) δ
2974, 2933, 2876, 1748, 1466, 1381, 1366, 1269, 1245, 1184, 1133,
1105, 1058, 1031, 993, 976, 963, 929, 881, 857, 793, 752, 722, 681,
650 cm−1; HRMS m/z calcd for C16H32NO3 [M + H+] 286.2382,
found 286.2377.
1
Ethyl 2-(phenylsulfinyl)pentanoate (2e): yield = 222 mg, 92%; H
2,2,6,6-Tetramethylpiperidin-1-yl benzenesulfinate (14): 1H
NMR (300 MHz, CDCl3) δ 7.82−7.89 (2H, m), 7.39−7.47 (3H,
m), 1.66 (6H, s), 1.57 (12H, s); 13C NMR (75 MHz, CDCl3) δ 147.2,
131.2, 128.5, 126.0, 60.8, 43.8, 31.1, 16.7 ppm; IR (KBr) δ 3069, 3035,
2984, 2944, 2916, 2879, 1404, 1394, 1245, 1204, 1184, 1139, 1095,
1071, 980, 922, 786, 766, 715, 701, 626, 613 cm−1; HRMS m/z calcd
for C15H23NO2SNa [M + Na+] 304.1347, found 304.1348.
NMR (500 MHz, CDCl3) δ 7.46−7.65 (5H, m) (major and minor),
3.88−4.10 (2H, m) (major and minor), 3.53 (1H, dd, J = 5.5, 10.0 Hz)
(major), 3.43 (1H, dd, J = 5.0, 9.0 Hz) (minor), 2.02−2.10 (1H, m)
(major and minor), 1.73−1.84 (1H, m) (major and minor), 1.28−1.48
(2H, m) (major and minor), 1.09 (3H, t, J = 7.0 Hz) (major), 1.03
(3H, t, J = 7.5 Hz) (minor), 0.91 (3H, t, J = 7.0 Hz) (major), 0.88
(3H, t, J = 7.5 Hz) (minor); 13C NMR (125 MHz, CDCl3) δ 167.9,
166.8, 142.3, 141.7, 131.7, 131.5, 129.0, 128.8, 124.8, 124.7, 72.1, 68.8,
61.2, 28.7, 27.0, 20.3, 13.8, 13.5 ppm; IR (oil) δ 3062, 2968, 2940,
2879, 2095, 1972, 1891, 1729, 1585, 1469, 1447, 1377, 1335, 1275,
1247, 1191, 1156, 1089, 1057, 941, 860, 825 cm−1; HRMS m/z calcd
for C13H19O3S [M + H+] 255.1055, found 255.1053; calcd for
C13H18O3SNa [M + Na+] 277.0874, found 277.0876.
(4S,5S)-Dihydro-4-hydroxy-5-methyl-3-methylenefuran-2(3H)-
one (18) and (3R,4S,5S)-Dihydro-4-hydroxy-5-methyl-3-
((phenylsulfonyl)methyl)furan-2(3H)-one (19). An oxygen-flushed
mixture of compound 17 (124 mg, 0.48 mmol) in toluene (8 mL)
was heated at 110 °C for 5 h. Then the solvent was removed under
vacuum and the resulting mixture was purified through chromatog-
raphy (silica gel, hexanes/ethyl acetate (1:1), (1:2) and ethyl acetate)
to afford 44 mg (71%) of compound 18 as a colorless oil and 16 mg
(12%) of compound 19 as a white solid. Recrystallization from
CHCl3/hexanes gave white needles (mp = 117−120 °C).
Benzyl 2-(phenylsulfinyl)propanoate( 2f): yield = 192 mg, 70%; 1H
NMR (300 MHz, CDCl3) δ 7.17−7.55 (10H, m) (major and minor),
5.10 (1H, d, J = 12.0 Hz) (major), 5.10 (1H, d, J = 12.0 Hz) (minor),
5.00 (1H, d, J = 12.0 Hz) (major), 4.99 (1H, d, J = 12.0 Hz) (minor),
3.82 (1H, q, J = 7.2 Hz) (major), 3.50 (1H, q, J = 7.2 Hz) (minor),
1.41 (3H, d, J = 6.9 Hz) (major), 1.26 (3H, d, J = 7.2 Hz) (minor);
13C NMR (75 MHz, CDCl3) δ 168.4, 167.5, 142.0, 140.2, 134.9, 131.7,
131.5, 129.1, 128.9, 128.6, 128.5, 128.4, 128.3, 125.0, 124.6, 67.4, 67.3,
65.4, 63.5, 9.4, 8.6 ppm; IR (oil) δ 3067, 3036, 2939, 1965, 1894, 1732,
1583, 1499, 1477, 1449, 1380, 1318, 1222, 1163, 1050, 998, 957, 920,
848, 820, 777 cm−1; HRMS m/z calcd for C16H17O3S [M + H+]
289.0898, found 289.0894; calcd for C16H16O3SNa [M + Na+]
311.0718, found 311.0713.
20
1
Spectroscopic data of 18: [α]D = −97.26 (c = 1.3, CHCl3); H
NMR (300 MHz, CDCl3) δ 6.41 (1H, d, J = 2.1 Hz), 5.97 (1H, d,
J=1.5 Hz), 4.83 (1H, d, J = 5.7 Hz), 4.65 (1H, dq, J = 6.0, 6.6 Hz),
1.34 (3H, d, J = 6.6 Hz); 13C NMR (75 MHz, CDCl3) δ 168.9, 138.8,
126.3, 78.4, 69.7, 14.3; IR (NaCl) δ 3439, 3015, 2930, 1756, 1672,
1387, 1263, 1186, 1103, 1045, 958, 910, 861, 821, 784 cm−1; HRMS
m/z calcd for C6H8O3Na [M + Na+] 151.0371, found 151.0354.
26
1
Spectroscopic data of 19: [α]D = −33.94 (c = 1, CHCl3); H
NMR (300 MHz, CDCl3) δ 7.95 (2H, d, J = 7.2 Hz), 7.72 (t, 1H, J =
7.5 Hz), 7.61 (t, 2H, J = 7.8 Hz), 4.72 (m, 1H), 4.63 (m, 1H), 3.56 (m,
2H), 3.26 (m, 1H), 2.93 (d, 1H, J = 4.2 Hz), 1.49 (3H, d, J = 6.6 Hz);
13C NMR (75 MHz, CDCl3) δ 174.6, 138.4, 134.5, 129.7, 127.8, 79.6,
70.1, 51.2, 42.7, 13.6 ppm; IR (NaCl) δ 3350, 2949, 2836, 1764, 1656,
1449, 1412, 1117, 1033 cm−1; HRMS m/z calcd for C12H14O5SNa [M
+ Na+] 293.0460, found 293.0429.
Experimental Procedure for Elimination. A mixture of
compound 2 (1 mmol) in toluene (6 mL) was heated at 110 °C for
5 h (in the case of compounds 2a, 2b, 2c ,and 2f, the reaction was
performed in a sealed flask to avoid acrylate loss). Then the resulting
crude mixture was purified through chromatography (silica gel,
hexanes/ethyl acetate (1:1), (1:2) and ethyl acetate) to afford the
corresponding enoate.
S-phenyl benzenesulfonothioate (9): 1H NMR (500 MHz,
CDCl3) δ 7.13−7.51 (10H, m); 13C NMR (125 MHz, CDCl3) δ
143.0, 136.6, 133.6, 131.4, 129.4, 129.0, 128.8, 127.9, 127.6, 127.2
ppm; IR (NaCl) δ 3064, 1580, 1445, 1323, 1144, 1076, 1021, 748, 688
cm−1; HRMS m/z calcd for C12H10O2S2Na [M + Na+] 273.0020,
found 273.0026.
ASSOCIATED CONTENT
■
S
* Supporting Information
Crystallographic data (CIF), graphical NMR spectra of all
compounds, and ORTEP representations. This material is
available free of charge via the Internet at http://pubs.acs.org.
Diphenyl disulfide (16): 1H NMR (500 MHz, CDCl3) δ 7.13−7.17
(2H, m), 7.21−7.24 (4H, t, J = 8.5 Hz), 7.42 (4H, d, J = 8.5 Hz); 13C
NMR (125 MHz, CDCl3) δ 137.1, 129.0, 127.6, 127.2 ppm; IR
(NaCl) δ 3064, 1946, 1864, 1800, 1735, 1574, 1470, 1432, 1379, 1298,
1068, 1017, 896, 787, 735, 686, 605 cm−1; HRMS (EI) m/z calcd for
C12H10S2 [M] 218.0224, found 218.0210.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: fgonzale@qio.uji.es, barrera@sg.uji.es.
2-(Ethoxycarbonyl)ethyl benzenesulfenate (10): 1H NMR (500
MHz, CDCl3) δ 7.61−7.62 (2H, m), 7.49−7.54 (3H, m), 4.11 (2H, q,
J = 7.5 Hz), 3.22 (1H, m), 2.97 (1H, m), 2.84 (1H, m), 2.54 (1H, m),
1.22 (3H, d, J = 7.5 Hz); 13C NMR (125 MHz, CDCl3) δ 171.5, 143.4,
131.5, 129.6, 124.4, 61.4, 51.5, 26.5, 14.4 ppm; IR (NaCl) δ 2963,
1733, 1445, 1373, 1260, 1087, 1045, 799, 750, 691 cm−1; HRMS m/z
calcd for C11H14O3SNa [M + Na+] 249.0561, found 249.0561.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financed by Bancaixa-UJI Foundation (P1
1B2011-59 and P1 1B2011-28). We are grateful to the Serveis
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The Journal of Organic Chemistry
Note
́
(23) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry;
Kluwer Academic/Plenum Publishers: New York, 2000; Part A, pp226.
(24) Santos, L. S.; Knaack, L.; Metzger, J. O. Int. J. Mass Spectrom.
2005, 246, 84−104.
(25) Eberlin, M. N. Eur. J. Mass Spectrom. 2007, 13, 19−28.
(26) Santos, L. S. Eur. J. Org. Chem. 2008, 235−253.
(27) Meyer, S.; Koch, R.; Metzger, J. O. Angew. Chem., Int. Ed. 2003,
42, 4700−4703.
(28) Griep; Raming, J.; Metzger, J. O. Anal. Chem. 2000, 72, 5665−
5668.
Centrals d’Instrumentacio
́
Cientifica (SCIC) of the Universitat
Jaume I for providing us with mass spectrometry and NMR.
DEDICATION
■
We dedicate this work to the memory of Prof. Purificacion
́
Escribano.
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obtained in all cases (see the Supporting Information).
́
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z, J.; Vicent, C.; Peris,
(12) The elimination reactions afforded trans isomers as the reaction
product, and the corresponding cis isomers were never observed
(NMR spectra) even in trace amounts. The elimination reactions were
also performed at 80 °C, and the result was similar to that for the
reaction carried out at 110 °C: only trans enoates were obtained.
(13) Compounds 5−8 were identifed on the basis of NMR (see the
Supporting Information) comparing with prior literature. For
1
compound 5: Aldrich Library of 13C and H FT NMR spectra; Aldrich:
Milwaukee; 1993, p 973C. Forcompound 6: Nishizawa, M.; Hirakawa,
H.; Nakagawa, Y.; Yamamoto, H.; Namba, K.; Imagawa., H. Org. Lett.
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Pittelkow, M.; Christensen, J. B. Org. Lett. 2005, 7, 1295−1298.
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reactions of compounds 2b-2f have been detected as traces by NMR
and MS of the crude.
(15) Compound 10 was isolated from the crossover experiment
reaction mixture depicted in scheme 4, and compared with authentic
sample already isolated and characterized.
(16) Guo, Y.; Jenks, W. S. J. Org. Chem. 1997, 62, 857−864.
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detected but 11−13 were not. Finally, compounds 11−13 could be
detected when the reaction was carried out at 80 °C.
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Supporting Information), and phenylsulfonic acid was detected by
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into disulfides, see: Pinnick, H. W.; Reynolds, M. A.; McDonald, R. T.;
Brewster, W. D. J. Org. Chem. 1980, 45, 930−932 and cites herein.
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