O-Nitrophenyl sulfoxides: Efficient precursors for the mild preparation of alkenes

Article abstract of DOI:10.1021/jo902248z

(Chemical Equation Presented) o-Nitrophenyl sulfoxides were found to be efficient synthetic precursors of various alkene types. The elimination occurs in toluene and NaOAc to generate substituted and terminal alkenes. Alkene products were easily obtained in high purity due to the simultaneous precipitation of the o-nitrophenyl sulfenic acid byproduct. The methods described have practical applications for the preparation of unsaturated compounds under mild, thermolytic conditions. 2009 American Chemical Society.

Full text of DOI:10.1021/jo902248z

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sulfoxides for generating alkenes under mild, thermolytic
conditions.
o-Nitrophenyl Sulfoxides: Efficient Precursors for the
Mild Preparation of Alkenes
The ONP sulfoxides (4) used for the study were synthesized
from alkyl halides and o-nitrothiophenol (2) under conven-
tional alkaline Finkelstein9 conditions by the general route
depicted in Scheme 1. Subsequent oxidation of sulfides 3 with
m-CPBA afforded sulfoxides 4 in good overall yields. The
β-elimination reactions were then performed under toluene
reflux with an inorganic base to neutralize the ONP sulfenic
acid 6 byproduct. Although not required, the base supplement
prevented decomposition of the acid into toluene-soluble
impurities thereby yielding the alkenes in high purity based
on NMR analysis. K2CO3, Na2CO3, and NaHCO3 were
each found to be effective sulfenic acid scavengers; however,
NaOAc was preferred as it did not induce isomerization of the
double bond in sensitive molecules.
Xiao Lu† and Timothy E. Long*,†,‡
†Department of Pharmaceutical and Biomedical Sciences and
‡Center for Drug Discovery, University of Georgia, Athens,
Georgia 30602-2352
tlong@rx.uga.edu
Received October 19, 2009
SCHEME 1. Synthesis of Alkenes from Alkyl Halides via ONP
Sulfoxides 4 by Thermal β-Elimination
o-Nitrophenyl sulfoxides were found to be efficient syn-
thetic precursors of various alkene types. The elimination
occurs in toluene and NaOAc to generate substituted and
terminal alkenes. Alkene products were easily obtained in
high purity due to the simultaneous precipitation of the
o-nitrophenyl sulfenic acid byproduct. The methods de-
scribed have practical applications for the preparation of
unsaturated compounds under mild, thermolytic condi-
tions.
A common method to introduce double bonds into mo-
lecules is by thermal β-elimination. Although a range of
precursors (i.e., amine oxides,1 4° ammonium iodides,2
tosylhydrazones,3 xanthate esters,4 selenoxides,5,6 sul-
foxides7) may be employed, the reaction can have limited
utility for compounds sensitive to harsh temperatures or
bases. A recent survey evaluating the efficacy of conversion
of sulfoxides to vinylglycines discovered that o-nitrophenyl
(ONP) analogues underwent synperiplanar β-elimination
at temperatures as low as 100 °C.8 Their unique reactivity
gave a reason to explore the practical application of ONP
Upon reflux over NaOAc, the toluene solutions of the
sulfoxides faded slowly from bright yellow due to precipita-
tion of sulfenic acid 6. As thermolysis of this byproduct
continued, the solvent turned pale or colorless and the solid
NaOAc darkened by the acid being absorbed. After the
reactions were complete, the salt impurities were removed
by simple vacuum filtration through Celite. Concentration
of the filtrate yielded the alkenes in high purity as illustrated
by the crude 1H NMR in Figure 1 of ester 5a.
The practical use of ONP sulfoxides was first evaluated for
the synthesis of terminal alkenes 5a and 5b (Scheme 2a).
Under the thermolytic conditions described, the alkenes were
successfully generated with no detectable side products such
as deoxygenated sulfoxide (e.g., sulfides 3a and 3b; not
shown) and isomerized alkene.
(1) (a) Cope, A. C.; Foster, T. T.; Towle, P. H. J. Am. Chem. Soc. 1949, 71,
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A. C.; Trumbell, E. R. Org. React. 1960, 11, 317–493.
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(5) Grieco, P. A.; Sydney, G.; Mugio, N. J. Org. Chem. 1976, 41, 1485–
1486.
Obtained likewise in high yield and purity were substituted
alkenes 5c and 5d demonstrating the ONP sulfoxides as
capable precursors of R,β-unsaturated esters in hindered
(6) Sharpless, K. B.; Young, M. W. J. Org. Chem. 1975, 40, 947–949.
(7) (a) Field, L. Synthesis 1972, 101–133. (b) Field, L. Synthesis 1978, 713–
740. (c) Trost, B. M.; Salzman, T. N.; Hiroi, K. J. Am. Chem. Soc. 1976, 98,
4887–4902. (d) Trost, B. M. Acc. Chem. Res. 1978, 11, 453–461. (e) Trost,
B. M. Chem. Rev. 1978, 78, 363–382.
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J. Org. Chem. 2010, 75, 249–252 249
DOI: 10.1021/jo902248z
r
Published on Web 12/04/2009
2009 American Chemical Society

Lu and Long
SCHEME 3. Terminal vs. Substituted Alkene Generation
JOCNote
detected by a transient blue tinting of the aqueous layer.
This further revealed that the pKa of the β-hydrogen atom
was perhaps more influential on the sulfoxides’ ability to
convert to alkenes.11a
FIGURE 1. 1H NMR of filtered reaction product 5a prior to
chromatographic purification.
Correspondingly, the eliminations were effected in the
absence of heat for esters positioned β to the ONP sulfoxide.
The conversion of ester 4f occurred within minutes under reflux
giving ester (E)-5c exclusively, and when performed at rt using
biphasic alkaline conditions, the trans alkene was the only
isomer isolated from the organic layer (Scheme 3). The rele-
vance of β-hydrogen acidities was further probed by evaluating
directional preferences in ONP sulfoxide 4g, which possessed
negligible differences in the pKa values. The reaction afforded a
mixture of alkenes 5g, (E)-5g, and (Z)-5g, thus revealing a lack
of influence in the degree of carbon substitution and the
significance of β-proton acidity on product outcome.
SCHEME 2. Preparation of Terminal and Substituted Alkenes
from ONP Sulfoxides
Attention was next turned to evaluating the relative
efficiency of ONP sulfoxides in comparison with aryl
sulfoxide groups (Scheme 4) that were employed in reported
preparations11-14 of alkenes. The study was performed by
screening disulfoxides 4h-m under the mild thermolysis
conditions established for the ONP sulfoxides. Phenyl sulfo-
xides7 which are often used as alkene precursors was found to
be an ineffective substrate in disulfoxides 4h and 4i as only
ONP eliminated products 5h and 5i were generated after 18 h
of reflux. This was not unexpected as temperatures g140 °C
are typically needed to effectively catalyze the elimination
of phenyl sulfoxides bound to n-alkyl chains in molecules.12
p-Tolyl13 and p-chlorophenyl14 sulfoxides 5j and 5k, respec-
tively, were similarly obtained in high yield thereby demon-
strating that harsher conditions are also required to prompt
their reaction.
aCalculated from isolated crude yield.
substrates (Scheme 2b). In the case of sulfoxide 4c, only trans
product 5c was observed,10 and surprisingly, a trace amount
of the alkene was isolated during the preceding
S-oxidation reaction. This suggested that the activation
energy to generate terminal alkenes is higher and the reaction
temperature could be reduced for substituted alkene synthe-
ses. Phenyl was shortly after identified as a substituent that
prompted expulsion of acid 6 during the oxidation of sulfide
3e, providing (E)-benzyl cinnamate (E)-5e in situ at rt. In
addition, workup with 5% NaHCO3 was found to catalyze
the elimination of other branched ONP sulfoxides as
A final comparison was performed to establish the effect
of nitro group positioning (Scheme 4d). It was discovered
with p-nitrophenyl sulfoxides that partial thermolysis under
toluene reflux can occur. Although a minor amount of
bis-eliminated alkene was generated during the reaction,
(11) (a) Yoshimura, T.; Tsukurimichi, E.; Iizuka, K.; Mizuno, H.; Isaji,
H.; Shimasaki, C. Bull. Chem. Soc. Jpn. 1989, 62, 1891–1899. (b) Emerson,
D. W.; Korniski, T. J. J. Org. Chem. 1969, 34, 4115–4118.
(12) (a) Catozzi, N.; Edwards, M. G.; Raw, S. A.; Wasnaire, P.; Taylor,
R. J. K. J. Org. Chem. 2009, 74, 8343–8354. (b) Matsuo, J.; Kawano, M.;
Takeuchi, K.; Tanaka, H.; Ishibashi, H. Tetrahedron Lett. 2009, 50, 1917–
1919. (c) Simila, S. T. M.; Martin, S. F. Tetrahedron Lett. 2008, 49, 4501–
4504. (d) Ishibashi, H.; Kato, I.; Takeda, Y.; Kogure, M.; Tamura, O. Chem.
Commun. 2000, 16, 1527–1528. (e) Mash, E. A.; Gregg, T. M. J. Org. Chem.
1995, 60, 6180–6182. (f) Zonjee, J. N.; De Koning, H.; Speckamp, W.
Tetrahedron 1989, 45, 7553–7564.
(10) The trans selectivity for ester (E)-5c was believed to be due to an
unfavorable interaction between the benzyl ester and methyl in the transition
state of the cis product.
(13) Cinquini, M.; Cozzi, F.; Raimondi, L.; Restelli, A. Gazz. Chim. Ital.
1985, 115, 347–350.
(14) (a) Ishibashi, H.; Komatsu, H.; Maruyama, K.; Ikeda, M. Tetra-
hedron Lett. 1985, 26, 5791–5794. (b) Ishibashi, H.; Komatsu, H.; Ikeda, M.
J. Chem. Res., Synop. 1987, 9, 296–297.
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Lu and Long
JOCNote
SCHEME 4. Comparisons of ONP Sulfoxide Efficacy with
degassed THF was added PPh3 (1.03 g, 3.92 mmol), 2-mercap-
toethanol (184 μL, 2.61 mmol), and 470 μL of H2O (26.1 mmol).
The solution was stirred at 50 °C for 6 h then cooled to rt,
concentrated, redissolved in DCM, washed with brine, dried
over Na2SO4, and evaporated. The resulting orange oil was
subjected to flash chromatography (9:1 hexanes:EtOAc) and
o-nitrothiophenol16 (653 mg, 4.21 mmol) was isolated in 80.5%
yield from the bright yellow band fractions: mp 40-42 °C.
Preparation of Sulfides 3: General Procedure. To a suspension
of NaI (0.4 mmol), K2CO3 (1 mmol), and bromide 1 (1 mmol) in
dry acetone (10 mL) was added 1.05 mmol equiv of o-nitrothio-
phenol (2). The mixture was refluxed with stirring until the
reaction was complete. The solution was then filtered, evapo-
rated, redissolved in DCM, washed with brine, dried over
Na2SO4, and concentrated. The sulfides were purified by flash
chromatography in accordance to product Rf values.
Reported Aryl Sulfoxide Groupsa
Benzyl 11-(2-nitrophenylthio)undecanoate (3a): yellow oil (670
mg, 88%); TLC (SiO2) Rf 0.48 (6:1 hexanes:EtOAc); 1H NMR
(500 MHz, CDCl3) δ 8.17 (dd, 1H, J = 7.0, 1.5 Hz), 7.52 (dt, 1H,
J = 8.0, 1.5 Hz), 7.38 (d, 1H, J = 8.0 Hz), 7.34-7.29 (m, 5H),
7.21 (dt, 1H, J = 8.0, 1.0 Hz), 5.09 (s, 2H), 2.92 (t, 2H, J = 7.5
Hz), 2.33 (t, 2H, J = 7.5 Hz), 1.71 (qnt, 2H, J = 7.5 Hz), 1.62
(qnt, 2H, J = 7.5 Hz), 1.45 (qnt, 2H, J = 7.5 Hz), 1.30-1.26 (m,
10H); 13C NMR (125 MHz, CDCl3) δ 173.7, 146.0, 138.4, 136.2,
133.5, 128.6, 128.2, 126.7, 126.2, 124.3, 66.1, 34.4, 32.4, 29.4,
29.3, 29.2, 27.9, 25.0; ESI-HRMS calcd for C24H31NO4S [M þ
H]þ 430.2052, found 430.2041.
S-Oxidation of Sulfides 3: General Procedure. To a stirring
solution of sulfides 3a-g (1 mmol) in DCM (10 mL) was added
m-CPBA (1.25 mmol equiv) in 5 mL of DCM or in the case of
disulfoxides 4h-m, 2.50 equiv of peroxide was used. After 2.5 h,
the reactions were quenched with 5% NaHCO3 (20 mL) and
extracted twice with DCM. The combined organic extracts were
dried over Na2SO4, filtered, and concentrated. The crude sulf-
oxides were purified by flash chromatography in accordance to
product Rf values.
Benzyl 11-(2-nitrophenylsulfinyl)undecanoate (4a): yellow so-
lid (532 mg, 74%); mp 37-38 °C; TLC (SiO2) Rf 0.43 (3:1
hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 8.31-8.28 (m,
2H), 7.93 (t, 1H, J = 7.5 Hz), 7.68 (t, 1H, J = 7.5 Hz), 7.32-7.28
(m, 5H), 5.09 (s, 2H), 3.15 (ddd, 1H, J = 13.0, 9.5, 7.0 Hz), 2.72
(ddd, 1H, J = 13.0, 9.5, 4.5 Hz), 2.32 (t, 2H, J = 7.5 Hz),
2.02-1.95 (m, 1H), 1.63-1.58 (qnt, 2H, J = 7.5 Hz), 1.51-1.46
(m, 1H), 1.41-1.35 (m, 1H), 1.30-1.24 (m, 10H); 13C NMR
(125 MHz, CDCl3) δ 173.8, 144.8, 144.0, 136.3, 135.5, 131.4,
128.7, 128.3, 126.9, 125.3, 66.2, 57.2, 34.4, 29.4, 29.4, 29.3, 29.2,
28.6, 25.2, 23.3; ESI-HRMS calcd for C24H32NO5S [M þ H]þ
446.1996, found 446.2004.
β-Elimination of ONP Sulfoxides (4): General Procedure.
Sulfoxide 4 (1 mmol equiv) and NaOAc (10 mmol equiv) were
heated with stirring in PhMe (10 mL) at 110 °C for 1-18 h. The
solution was then cooled to rt and the precipitate removed by
vacuum filtration through Celite. The flask was rinsed with
toluene then filtered, and the solvent was evaporated to provide
alkene 5. Decolorization of the concentrated product can be
achieved by vacuum filtration of the oil through a plug of silica
with 3:1 hexanes:EtOAc, or for instances when starting material
is still present, the mixture can be reheated in toluene with a fresh
10 equiv of NaOAc until the reaction is complete.
aCalculated from the theoretical yield.
the absence of ONP sulfoxide in the crude product indicated
that the ortho position maximizes the effect of the nitro
group to promote the β-elimination. Such electronic influ-
ences were similarly observed by Sharpless6 and Sayama15 in
their evaluation of aryl selenoxides. It was therefore rea-
soned that the enhanced reactivity of ONP sulfoxides is due
to an increase in β-proton acidity conferred by the electron-
withdrawing nitro group and that ortho positioning may
further accelerate the elimination at the congested pyramidal
sulfur center to relieve steric strain.
In summary, the results of this study revealed that
o-nitrophenyl sulfoxides can serve as effective precursors of
different alkene types. Their ability to convert under mild reflux
and essentially neutral conditions makes them useful substrates
for generating unsaturation in molecules. As noted, β-elimina-
tions typically require harsh conditions that may include strong
bases and prolong heating at 140 °C or above. Phenyl selenides
are often utilized in place of aryl sulfides in thermal or base
sensitive molecules; however, the higher cost and toxicity asso-
ciated with selenoxide use may limit reaction scales. The readily
available o-nitrothiophenol is price efficient and its bright yellow
sulfoxides can be easily visualized on silica gel allowing for their
simple purification. Likewise, the ONP chromophore is bene-
ficial as a colorimetric indicator providing an efficient means to
conduct and monitor β-elimination reactions.
Benzyl undec-10-enoate (5a): colorless oil (28.2 mg, 86%);
TLC (SiO2) Rf 0.40 (20:1 hexanes:EtOAc); 1H NMR (500 MHz,
CDCl3) δ 7.34-7.30 (m, 5H), 5.79 (ddt, 1H, ABM, JBM = 16.5
Hz, JAM = 10.5, 6.5 Hz), 5.10 (s, 2H), 4.98 (dd, 1H, ABM,
JBM = 16.5 Hz, JAB = 1.5 Hz), 4.92 (dd, 1H, ABM, JAM = 10.5
Hz, JAB = 1.5 Hz), 2.34 (t, 2H, J = 7.5 Hz), 2.02 (m, 2H), 1.63
Experimental Section
Preparation of o-Nitrothiophenol (2). To a suspension of
o-nitrophenyl disulfide (0.805 g, 2.61 mmol) in 20 mL of
(16) Sopchik, A. E.; Kingsbury, C. A. J. Chem. Soc., Perkin Trans. 2 1979,
8, 1058–1063.
(15) Sayama, S.; Onami, O. Tetrahedron Lett. 2000, 41, 5557–5560.
J. Org. Chem. Vol. 75, No. 1, 2010 251

Lu and Long
JOCNote
(qnt, 2H, J = 7.0 Hz), 1.36 (qnt, 2H, J = 7.0 Hz), 1.28-1.25 (m,
8H); 13C NMR (125 MHz, CDCl3) δ 173.7, 139.2, 136.2, 128.6,
128.2, 128.2, 114.2, 66.1, 34.4, 33.8, 29.3, 29.2, 29.1, 28.9, 24.0;
ESI-HRMS calcd for C18H26O2 [M þ Na]þ 297.1825, found
297.1826.
Pharmaceutical Education. Special thanks are also given to
the Department of Pharmaceutical and Biomedical Sciences
and Dr. Dennis Phillips for mass spectroscopy analyses.
Supporting Information Available: Experimental proce-
dures and analytical data for all new compounds. This ma-
terial is available free of charge via the Internet at http://pubs.
acs.org.
Acknowledgment. Generous financial support of this
research was provided by the American Foundation for
252 J. Org. Chem. Vol. 75, No. 1, 2010