Unexpected steric effects of "remote" alkyl groups on the rate of conjugate additions to alkyl α,β-ethylenic sulfones, sulfoxides, and esters

Article abstract of DOI:10.1021/jo062155g

Examination of conjugated ethylenic sulfones, sulfoxides, and esters in Michael-type addition reactions reveals, for the first time, that the size of the heteroatom-attached alkyl group affects the rate of conjugate addition. Molecular modeling strongly suggests that what are generally considered to be "remote" alkyl groups in -C^βH=C^αHS(O) _n,-alkyl systems and -CH₂C^βH=C ^αHCOO-alkyl systems are actually not remote from the β-carbon atom of the Michael accepting unit. Molecular modeling clearly shows that the alkyl groups in these Michael acceptors shield the β-carbons in the following order: Et < i-Pr < t-Bu. Competition experiments establish the relative rates of Michael additions to be in the following order: Et > i-Pr > t-Bu.

Full text of DOI:10.1021/jo062155g

Unexpected Steric Effects of “Remote” Alkyl Groups on the
Rate of Conjugate Additions to Alkyl r,â-Ethylenic Sulfones,
Sulfoxides, and Esters
Aimee R. Usera and Gary H. Posner*
Department of Chemistry, School of Arts and Sciences, The Johns Hopkins UniVersity,
Baltimore, Maryland 21218
ghp@jhu.edu
ReceiVed October 17, 2006
Examination of conjugated ethylenic sulfones, sulfoxides, and esters in Michael-type addition reactions
reveals, for the first time, that the size of the heteroatom-attached alkyl group affects the rate of conjugate
addition. Molecular modeling strongly suggests that what are generally considered to be “remote” alkyl
groups in -CâHdCRHS(O)nsalkyl systems and -CH2CâHdCRHCOOsalkyl systems are actually not
remote from the â-carbon atom of the Michael accepting unit. Molecular modeling clearly shows that
the alkyl groups in these Michael acceptors shield the â-carbons in the following order: Et < i-Pr <
t-Bu. Competition experiments establish the relative rates of Michael additions to be in the following
order: Et > i-Pr > t-Bu.
Introduction
Conjugate (1,4) additions to R,â-ethylenic compounds are
reliable and popular bond-forming reactions and are oftentimes
essential to the assembly of complex organic molecules. There
are, however, many factors that affect the nature of the reaction
and the formation of product during this process. The structure
of both the nucleophile and the electrophilic olefin, specifically
bulky groups at the R, â, or â′ positions and the E/Z
configuration of the double bond, can significantly affect the
stereochemistry of the conjugate addition product (Figure 1).1-3
The stereochemistry of the product can be affected by the size
of the alkyl groups attached directly to X in ethylenic systems
(Figure 1).4-6
FIGURE 1.
Substituents on the olefin not only affect the stereochemistry
of the reaction, but also influence the rate of reaction. Olefinic
R- or â-substituents on a phenyl ethylenic sulfone are shown
to greatly reduce the rate of addition.7 In addition, the use of
sterically hindered reactants requires increased reaction times
and/or temperature compared to reactions with less bulky
substrates.8
(1) Carey, F. A.; Sundberg, R. J. AdVanced Organic Chemistry. Part B:
Reactions and Synthesis, 4th ed.; Kluwer Academic/Plenum Publishers. New
York, 2001.
(2) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon Press: New York, 1992; p 106.
(3) Oare, D.; Heathcock, C. H. J. Org. Chem. 1990, 55, 157. Oare, D.
A.; Heathcock, C. H. Top. Stereochem. 1989, 19, 227.
(4) Porter, N. A.; Scott, D. M.; Lacher, B. J. Am. Chem. Soc. 1989, 111,
8311.
(5) Cousins, G.; Falshaw, A.; Hoberg, J. O. Org. Biomol. Chem. 2004,
2, 2272.
(6) Ballini, R.; Bosica, G.; Florini, D.; Palmieri, A.; Petrini, M. Chem.
ReV. 2005, 105, 933
(7) Simpkins, N. S. Sulfones in Organic Synthesis; Pergamon Press:
Oxford, 1993; Vol. 10.
(8) Chu, C.; Huang, W.; Lu, C.; Wu, P.; Liu, J.; Yao, C. Tetrahedron
Lett. 2006, 47, 7375.
10.1021/jo062155g CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/07/2007
J. Org. Chem. 2007, 72, 2329-2334
2329

Usera and Posner
FIGURE 4.
FIGURE 2.
the reaction upon addition of the nucleophile to the olefin. To
confirm the irreversibility of the reaction under these conditions,
an isolated conjugate addition product was stirred in methanol
for 16 h, and no reversibility was observed. The ratios of
reactants consumed or products formed were measured by GC,
which indicated the rate difference of conjugate addition.
The molecular modeling program Spartan ’02 calculated the
lowest energy conformation from which we measured the â to
â′ distance.13 On the basis of Spartan ’02 and literature,14 the
sulfones are held in a conformation such that the â-hydrogen
atom of the olefin eclipses one of the sulfonyl oxygen atoms
(Figure 5).14 This desired conformation may create more steric
hindrance around the olefin than initially expected. This same
oxygen-hydrogen eclipsing interaction may also control the
low-energy conformation of the sulfoxide and crotonate series,
leading to a more hindered olefin than would be predicted. Since
the molecular modeling distances were measured in vacuo, the
calculations were also carried out with a molecule of methanol
bound to an oxygen atom of the sulfone unit to investigate
solvent effects. In comparing the â to â′ distance of the in vacuo
model (3.573 Å) to that of the methanol-bound structure (3.591
Å), there is a difference of less than 0.02 Å, which demonstrates
that the reaction solvent has little effect on the conformation of
the reactant (Table 1).
FIGURE 3.
Substituents at the R or â positions can also produce profound
rate effects, accelerating or slowing the reaction process
depending on electron-withdrawing or -donating ability.1 Roush
recently showed that phenyl vinyl sulfonate esters are 3000-
fold more reactive than corresponding phenyl vinyl sulfona-
mides.9
Although there are many known factors contributing to the
outcome of a conjugate addition reaction, there are only two
relevant reports addressing the steric effects of the “remote”
R′,â′-substituent on the rate of conjugate addition. Tanaka
showed that the yields of products via intramolecular conjugate
addition to alkyl crotonate esters decreased in the series Et >
i-Pr > t-Bu.10 In another study, the yield of products or success
of a Pauson-Khand reaction with CH2dCHS(O)R sulfoxides
was lowest with bulky R groups.11
In examining the ethylenic sulfones, the distance of â to â′
increases by approximately 0.5 Å as the size of the remote
substituent decreases from tert-butyl (1c) to isopropyl (1b) and
approximately 0.8 Å as the size decreases from isopropyl (1b)
to ethyl (1a) (Table 1). As this distance increases between the
â-carbon atom and the â′-carbon atom, the Michael addition
rate also increases. When an isopropyl terminus (1b) at a â to
â′ distance of 4.025 Å is compared to a tert-butyl terminus (1c)
at a â to â′ distance of 3.573 Å, the rate of reaction increases
by a factor of 3. As the terminus becomes even more remote at
a â to â′ distance of 4.806 Å, the ethyl sulfone (1a) displays a
significant rate increase by a factor of greater than 10 when
compared to the tert-butyl sulfone (1c). In comparing ethyl (1a),
isopropyl (1b), and tert-butyl (1c) remote substituents, it is
obvious that the steric hindrance of the remote substituent
inversely affects the rate of conjugate addition.
Similar to the sulfones, the alkyl vinyl sulfoxides 2a-c show
an inverse correlation between the distance between the â-carbon
atom and the â′-carbon atom and the rate of conjugate addition
(Table 2). The sulfoxide Michael addition products coeluted
using gas chromatography, and for this reason, the rate of
reaction was measured by disappearance of reactant. The rates
of reaction were too difficult to detect using 1H NMR
Recently, during the synthesis of vitamin D3 R,â-unsaturated
sulfone analogues, we discovered that the success of the critical
Horner-Wadsworth coupling is strongly affected by the size
of the terminus (R) of the conjugated ethylenic sulfone C,D-
ring side chain (Figure 2).12 The anion of the A-ring phosphine
oxide may be participating not only in the desired Horner-
Wittig coupling with the C-8 ketone, but also may be adding
in a Michael fashion to the conjugated sulfone system. The less
sterically hindered methyl or isopropyl terminus may facilitate
this competing conjugate addition and thereby lower the yield
of the desired product. To investigate this hypothesis, conjugated
sulfones, sulfoxides, and esters with various R,R′-alkyl substit-
uents were studied (Figure 3).
Results and Discussion
During competition experiments, two unsaturated compounds
(1 equiv each) with different remote substituents were treated
with 1 equiv of benzyl mercaptan in the presence of triethy-
lamine (1.1 equiv) (Figure 4). Due to the general reversibility
of conjugate additions, methanol was used as a solvent to quench
(9) Reddick, J. J.; Cheng, J.; Roush, W. R. Org. Lett. 2003, 11, 1967.
(10) Maezaki, N.; Sawamoto, H.; Yuyama, S.; Yoshigami, R.; Suzuki,
T.; Izumi, M.; Ohishi, H.; Tanaka, T. J. Org. Chem. 2004, 69, 6335.
(11) Rivero, M. R.; Adrio, J.; Carretero, J. C. Synlett 2005, 1, 26.
(12) Posner, G. H.; Wang, Q.; Han, G.; Lee, J.K.; Crawford, K.; Zand,
S.; Brem, H.; Peleg, S.; Dolan, P.; Kensler, T.W. J. Med. Chem. 1999, 18,
3425.
(13) The lowest energy conformation was calculated using equilibrium
mechanics at the ground state and the MMFF force field.
(14) Lee, P. S.; Du, W.; Boger, D. L.; Jorgensen, W. L. J. Org. Chem.
2004, 69, 5448.
2330 J. Org. Chem., Vol. 72, No. 7, 2007

Conjugate Additions to R,â-Ethylenic Compounds
FIGURE 5. Ph(CH2)2CHdCHS(O)2CHnCH3RR′ (n ) 0-2; R ) H, CH3; R′ ) H, CH3).
TABLE 1
TABLE 3
rel rate of formation
of product
distance from
â to â′ (Å)
rel rate of consumption
of starting material
distance from
â to â′ (Å)
sulfone
ester
1a
1b
1c
10.3
3
1
4.806
4.025
3.573
3a
3b
3c
4.3
2.2
1
5.944
5.395
5.338
of the alkyl group becomes smaller (Table 3). The distance of
â to â′ increases by approximately 0.05 Å as the alkyl group
decreases in size from tert-butyl (3c) to isopropyl (3b). This
small difference still creates a 2.2-fold increase in the rate of
conjugate addition to the isopropyl (3b) compared to the tert-
butyl (3c) crotonate. As the size of the remote substituent
decreases from isopropyl (3b) to ethyl (3a), a â to â′ distance
increase of approximately 0.55 Å and a rate increase of
approximately 2 are observed. The crotonate systems 3a-c are
compared by disappearance of starting materials due to coelution
of products. Although the crotonates exhibit increased remote-
ness and less pronounced rate differences, in comparing ethyl
(3a), isopropyl (3b), and tert-butyl (3c) crotonates, it is clear
that steric hindrance of the alkyl substituent still inversely affects
the rate of conjugate addition.
In attempts to enhance the difference in rates, the competition
experiments were performed at both 0 and -78 °C, but no
difference in rate ratio was observed compared to reactions
carried out at room temperature. Temperature has no effect on
the rate ratio of conjugate addition. The differences in rates of
conjugate addition were also measured at 2% and 20% comple-
tion of the reaction to ensure that the rate difference was not
changing as the more reactive unsaturated system was being
consumed. The competition of benzyl mercaptan conjugate
addition to isopropyl and tert-butyl unsaturated sulfones gave
a 3:1 ratio of products at 2%, 20%, and 100% reaction
completion.
TABLE 2
rel rate of consumption
of starting material
distance from
â to â′ (Å)
sulfoxide
2a
2b
2c
15
3
1
5.244
4.654
4.094
spectroscopy. The distance of â to â′ increases by approximately
0.6 Å as the size of the remote substituent decreases from tert-
butyl (2c) to isopropyl (2b) and from isopropyl (2b) to ethyl
(2a). This increased remoteness of the â′-carbon atom to the
â-carbon atom directly correlates with an increase in the rate
of consumption of starting material. When the isopropyl
sulfoxide (2b) with the â′-carbon 4.654 Å away from the
â-carbon is compared to the tert-butyl (2c) â′-carbon, only 4.094
Å away from the â-carbon, the rate increases by a factor of 3.
The significantly smaller ethyl terminus of sulfoxide 2a exhibits
even less shielding of the olefin with a â to â′ distance of 5.244
Å. This increased remoteness results in a significant increase
in reaction rate of 15 times that of the tert-butyl sulfoxide (2c).
Both the sulfones 1a-c and the sulfoxides 2a-c exhibit a
clear inverse correlation between steric hindrance and rate of
conjugate addition. However, would a conjugated ester system
that has a more remote â′-substituent exhibit the same trend in
steric effects on the rate of conjugate addition?
The difference in â-â′ distance among the alkyl crotonates
3a-c follows the same trend of increasing distance as the size
J. Org. Chem, Vol. 72, No. 7, 2007 2331

Usera and Posner
Sulfones. (i) Ethyl 4-Phenyl-1(E)-butenyl Sulfone (1a). Ethyl
methyl sulfide (0.500 g, 6.60 mmol) was dissolved in dichlo-
romethane (66.0 mL) in a 100 mL round-bottom flask. 3-Chlorop-
eroxybenzoic acid (m-CPBA; 70% in H2O, 3.90 g, 15.8 mmol) and
sodium bicarbonate (0.550 g, 6.60 mmol) were added. The reaction
was stirred for 16 h, at which time the starting material was
consumed. The reaction was quenched with saturated sodium
bicarbonate (50 mL) and extracted with methylene chloride (3 ×
50 mL). The organic layers were combined and washed with
concentrated sodium bicarbonate (3 × 50 mL), dried over mag-
nesium sulfate, filtered, and concentrated in vacuo to give a pure
white solid in 75% yield (0.540 g).
2,6-Dimethylpyridine (DMP; 0.110 g, 0.940 mmol) was dissolved
in tetrahydrofuran (6 mL) in a 25 mL oven-dried round-bottom
flask charged with argon and a magnetic stir bar. The reaction
mixture was cooled to -78 °C, and 1.6 M n-BuLi (0.588 mL,
0.940 mmol) was added dropwise. The reaction mixture was stirred
for 30 min, at which time ethyl methyl sulfone (0.090 g, 0.832
mmol) was added in tetrahydrofuran (2.5 mL) via cannula. The
reaction was stirred for 30 min, at which time hydrocinnamaldehyde
(0.110 g, 0.820 mmol) was added by syringe. The reaction was
stirred overnight at -60 °C. Upon consumption of starting material,
the reaction was quenched with H2O (10 mL), extracted with ethyl
acetate (3 × 20 mL), and washed with brine. The combined organic
layers were dried over magnesium sulfate, filtered, and concentrated
in vacuo to give the crude product. The crude mixture was purified
by flash silica chromatography (50% hexanes/50% ethyl acetate)
to give 0.107 g of the desired â-hydroxy sulfone as an oil in 52%
yield.
Conclusion
In conclusion, we show here that what are widely considered
to be remote alkyl groups in -CHdCHS(O)nsalkyl systems
and in -CH2CHdCHCOOsalkyl systems are actually not
remote from the â-carbon of these Michael acceptors. Molecular
modeling shows clearly that the alkyl groups in these conjugated
systems shield the â-carbons in the following order: t-Bu >
i-Pr > Et. Although the termini differ by only one carbon, using
competition experiments, we show for the first time that a
compound with a bulkier tert-butyl terminus has a slower
conjugate addition reaction rate than the corresponding com-
pound having an isopropyl terminus. This isopropyl compound,
in turn, has a slower rate than the corresponding molecule with
a less sterically hindering ethyl terminus.
Experimental Section
All air- and moisture-sensitive reactions were carried out in
flame-dried or oven dried (at 120 °C) glassware under an inert
atmosphere of argon. All reactive liquids were transferred by syringe
or cannula and were added to the flask through a rubber septum.
All other solvents and reagents were used as received unless
otherwise stated. Melting points were obtained on a metal block
apparatus and are not corrected. 1H and 13C spectra were obtained
on a 300 or 400 MHz spectrometer. All NMR spectra were obtained
in a solution in CDCl3. Chemical shifts (δ) are reported in parts
1
per million (ppm). Multiplicities of signals in the H spectra are
reported as follows: s (singlet), d (doublet), t (triplet), q (quartet),
m (multiplet), dd (doublet of doublets), etc. Infrared spectra were
obtained on an FR-IR spectrometer as liquid films or as a thin layer
with NaCl cells. Intensities were reported as s (strong, 67-100%),
m (medium, 34-66%), and w (weak, 0-33%) with the following
notations: br (broadened), sh (shoulder), etc. Analytical thin layer
chromatography (TLC) was performed on silica gel plates
(0.25 mm thickness) with F254 indicator. Compounds were visual-
ized under a UV lamp and/or by developing with iodine, vanillin,
p-anisaldehyde, KMnO4, or phosphomolybdic acid followed by
heating on a hot plate. FAB mass spectra were obtained using a
double focusing magnetic sector mass spectrometer equipped with
a Xe gas FAB gun (8 kV at 1.2 mA), an off-axis electron multiplier,
and a data system at Johns Hopkins University. The resolution of
the instrument was set at 10000 (100 ppm peak width). Samples
were mixed with m-nitrobenzyl alcohol matrix deposited on the
target of a direct insertion probe for introduction into the source.
Nominal mass scan spectra were acquired with a mass scan range
of 10-950 amu using a magnet scan rate of 25 s/decade. For
accurate mass measurements, a narrower mass scan range was
employed, with the matrix containing 10% PEG mass calibrant.
The isopropyl and tert-butyl â-hydroxy sulfides were prepared
according to the experiment of Clive.15 The ethyl vinyl sulfoxide
(2a) and tert-butyl vinyl sulfoxide (2b) were prepared according
to Jenks.16 Ethyl 4-phenyl-2(E)-pentenoate (3a) and tert-butyl
4-phenyl-2(E)-pentenoate (3c) were synthesized according to a
procedure by Pandolfi.17 The compounds 2a,18 2c,19 3a,20 and 3c21
are all known, and their structures are consistent with their published
data.
The â-hydroxy sulfone (0.107 g, 0.442 mmol) was dissolved in
methylene chloride (8.0 mL) in a 100 mL oven-dried round-bottom
flask charged with argon and a magnetic stir bar. The reaction flask
was cooled to 0 °C, and triethylamine (0.718 g, 7.10 mmol) and
methanesulfonyl chloride (0.370 g, 3.20 mmol) were added. The
reaction was stirred for 1 h, at which time 1,8-diazabicyclo[5,4,0]-
undec-7-ene (DBU; 0.250 g, 1.60 mmol) was added. The reaction
was stirred for 1 h at 0 °C and 1 h at room temperature. The reaction
was diluted with brine and extracted with ethyl acetate (3 ×
30 mL). The combined organic layers were dried over magnesium
sulfate, filtered, and concentrated. The crude material was purified
by flash silica chromatography (50% hexanes/50% ethyl acetate)
to give 0.790 g of ethyl 4-phenyl-1-butenyl sulfone as an oil in
80% yield of 5.3:1 E/Z isomers. Data for the E-isomer: 1H NMR
(CDCl3, 400 MHz) δ 7.33-7.28 (m, 2H), 7.24-7.17 (m,3H), 6.92
(ddd, 1H, J ) 14.8, 14.0, 7.2 Hz), 6.15 (dt, 1H, J ) 15.2, 1.6 Hz),
2.91 (m, 2H), 2.85-2.79 (m, 2H), 2.64-2.59 (m, 2H), 1.14 (t, 3H,
J ) 7.6 Hz); 13C NMR (CDCl3, 100 MHz) δ 148.4, 139.8, 128.4,
128.2, 127.8, 126.3, 48.8, 33.7, 33.0, 7.0; IR (thin film, cm-1) 3054-
(m), 3034(m), 2996(m), 2928(m), 2851(m), 1625(m), 1606(m),
1496(m), 1452(m), 1423(w), 1297(s), 1287(s), 1210(m), 1123(s),
1056(w), 950(m), 921(m), 901(w), 824(m), 757(s), 689(m); HRMS
m/z calcd for C12H16O2S 225.0949, found 225.0944.
(ii) Isopropropyl 4-Phenyl-1(E)-butenyl Sulfone (1b). Diiso-
propylamine (1.00 g, 9.84 mmol) was dissolved in tetrahydrofuran
(10 mL) in an oven-dried 50 mL round-bottom flask charged with
argon and a magnetic stir bar. The solution was cooled to -78 °C,
and 1.6 M n-BuLi (6.15 mL, 9.84 mmol) was added dropwise. The
reaction was stirred for 30 min, at which time methyl isopropyl
sulfone (0.600 g, 4.90 mmol) was added in via cannula in
tetrahydrofuran (5 mL). The reaction was stirred for 30 min, at
which time diethyl chlorophosphonate (0.850 g, 4.90 mmol) was
added via syringe. After the resulting solution was stirred for 1 h,
hydrocinnamaldehyde (0.548 g, 4.08 mmol) was added and the
reaction stirred at -78 °C for 16 h. The reaction was quenched
with H2O (20 mL), extracted with diethyl ether (3 × 20 mL), and
washed with brine. The combined organic layers were dried over
magnesium sulfate, filtered, and concentrated in vacuo to give the
crude product. The crude mixture was purified by flash silica
chromatography (80% hexanes/20% ethyl acetate) to give 0.464 g
(15) Clive, D. L. J., Boivin, T. L. B. J. Org. Chem. 1989, 54, 1997-
2003.
(16) Jenks, W. S.; Cubbage, J. W.; Guo, Y.; McCulla, R. D. J. Org.
Chem. 2001, 66, 8722-8736.
(17) Pandolfi, E., Comas, H. Synthesis 2004, 15, 2493-2498.
(18) Touchkine, A.; Clennan, E. L. Tetrahedron Lett. 1999, 40, 6519.
(19) Rivero, M. R.; de la Rosa, J. C.; Carretero, J. C. J. Am. Chem. Soc.
2003, 125, 14992.
(20) Bach, J.; Blache`re, C.; Bull, S. D.; Davies, S. G.; Nicholson, R. L.;
Price, P. D.; Sanganee, H. J.; Smith, A. D. Org. Biomol. Chem. 2003, 1,
2001.
(21) Hon, Y.; Lee, C. Tetrahedron 2000, 56, 7893.
2332 J. Org. Chem., Vol. 72, No. 7, 2007

Conjugate Additions to R,â-Ethylenic Compounds
of the desired isopropyl 4-phenyl-1(E)-butenyl sulfone as an oil in
50% yield as a 5.7:1 E/Z mixture of isomers. Data for the
E-isomer: 1H NMR (CDCl3, 400 MHz) δ 7.28-7.24 (m, 2H),
7.19-7.12 (m,3H), 6.84 (ddd, 1H, J ) 15.2, 13.6, 6.8 Hz), 6.15
(dt, 1H, J ) 15.2, 3.2 Hz), 2.91 (m, 2H), 2.97-2.88 (m, 1H), 2.83-
2.74 (m, 2H), 2.60-2.55 (m, 2H), 1.20 (d, 6H, J ) 6.8 Hz); 13C
NMR (CDCl3, 100 MHz) δ 148.8, 139.6, 128.2, 127.9, 126.0, 125.9,
55.7, 33.4, 32.7, 15.0; IR (thin film, cm-1) 3054(m), 3025(m), 2996-
(m), 2938(m), 2870(m), 1625(m), 1606(m), 1500(m), 1471(m),
1442(s), 1384(w), 1365(w), 1297(s), 1249(s), 1172(m), 1123(s),
1075(w), 1046(m), 1027(w), 969(m), 930(w), 872(m), 815(s), 747-
(s), 699 (s), 660(s), 602(w), 593(w), 573(m); HRMS m/z calcd for
C13H18O2S 239.1106, found 239.1107.
(iii) tert-Butyl 4-Phenyl-1(E)-butenyl Sulfone (1c). Oxone (8.85
g, 14.4 mmol) was dissolved in water (16.0 mL) in a 50 mL round-
bottom flask and cooled to 0 °C. tert-Butyl methyl sulfide
(0.500 g, 4.80 mmol) in methanol (8.00 mL) was added to the oxone
solution via cannula. After the resulting solution was stirred for 16
h, the oxone was filtered off to give methyl tert-butyl sulfone, which
was purified by recrystallization to give 0.520 g of a white solid in
79% yield.
tert-Butyl methyl sulfone (0.252 g, 1.85 mmol) was dissolved
in tetrahydrofuran (25 mL) in a 50 mL oven-dried round-bottom
flask charged with argon and a magnetic stir bar. The reaction
mixture was cooled to -78 °C, and 1.56 M n-BuLi (1.31 mL,
2.05 mmol) was added dropwise. The reaction was stirred for 30
min, at which time hydrocinnamaldehyde (0.125 g, 0.931 mmol)
was added by syringe. The reaction was stirred overnight at -60
°C. Upon consumption of starting material, the reaction was
quenched with H2O (10 mL), extracted with ethyl acetate (3 × 20
mL), and washed with brine. The combined organic layers were
dried over magnesium sulfate, filtered, and concentrated in vacuo
to give the crude product. The crude mixture was purified by flash
silica chromatography (70% hexanes/30% ethyl acetate) to give
0.235 g of the desired â-hydroxy sulfone as an oil in 91% yield.
The â-hydroxy sulfone (0.235 g, 0.869 mmol) was dissolved in
methylene chloride (50 mL) in a 100 mL oven-dried round-bottom
flask charged with argon and a magnetic stir bar. The reaction flask
was cooled to 0 °C, and triethylamine (1.41 g, 13.9 mmol) and
methane sulfonyl chloride (0.727 g, 6.34 mmol) were added. The
reaction was stirred for 1 h, at which time it was concentrated,
dissolved in brine (50 mL), and extracted with ethyl acetate (3 ×
30 mL). The combined organic extracts were dried over magnesium
sulfate, filtered, and concentrated in vacuo. The crude mesylate
was brought on to the next step.
The mesylate was dissolved in benzene (40 mL) in an oven-
dried 100 mL round-bottom flask charged with argon and a
magnetic stir bar. DBU (0.489 g, 3.22 mmol) was added, and the
reaction was refluxed for 1 h. The reaction was cooled to room
temperature, diluted with brine, and extracted with ethyl acetate
(3 × 30 mL). The combined organic layers were dried over
magnesium sulfate, filtered, and concentrated. The crude material
was purified by flash silica chromatography (70% hexanes/30%
ethyl acetate) to give 0.219 g of the desired tert-butyl 4-phenyl-
1(E)-butenyl sulfone as a white solid in 94% yield as a 10:1 E/Z
mixture of isomers, mp 88-90 °C. Data for the E-isomer: 1H NMR
(CDCl3, 400 MHz) δ 7.31-7.27 (m, 2H), 7.22-7.16 (m, 3H), 6.88
(ddd, 1H, J ) 15.2, 13.6, 6.8 Hz), 6.20 (dt, 1H, J ) 15.2, 1.6 Hz),
2.85-2.81 (m, 2H), 2.67-2.61 (m, 2H), 1.25 (s, 9H); 13C NMR
(CDCl3, 100 MHz) δ 149.7, 139.7, 128.4, 128.1, 126.2, 124.3, 58.0,
33.6, 33.0, 22.9; IR (thin film, cm-1) 3044(w), 3034(w), 2967(m),
2938(m), 2870(w), 1628(m), 1606(m), 1500(m), 1461(m), 1403-
(w), 1355(w), 1278(s), 1258(s), 1191(w), 1114(s), 1027(m), 805-
(s), 786(s), 728(m), 879(m), 850(m); HRMS m/z calcd for
C14H20O2S 253.1262, found 253.1256.
absolute ethanol (65.0 mL) in a 100 mL oven-dried round-bottom
flask charged with argon and a magnetic stir bar. The solution was
stirred for 15 min, at which time 2-chloroethanol (3.33 g,
41.3 mmol) was added slowly. After the solution was refluxed for
1 h, the solvent was removed slowly by distillation. The residue
was cooled, and solid NaBr was filtered off to yield 4.5 g of the
desired 2-(1-methylethyl)thioethanol as an oil in 91% yield: 1H
NMR (CDCl3, 300 MHz) δ 3.74-3.64 (m, 2H), 2.98-2.90 (m,
1H), 2.77-2.73 (m, 2H), 1.26 (d, 6H, J ) 7.8 Hz).
(ii) Isopropyl Vinyl Sulfide. The vinyl sulfide was prepared
according to Jenks.16 A 20 mL oven-dried two-neck round-bottom
flask was equipped with two condensers. One condenser led to a
short-path distillation head. The other was used as an inlet for 2-(1-
methylethyl)thioethanol and argon. The distillation head was
equipped with a round-bottom flask used for the sulfide trap, cooled
to -78 °C. Argon was used to control the flow of sulfide gas to
the trap. KOH (0.467 g, 8.33 mmol) was added to the two-neck
round-bottom flask, which was then heated to 320 °C using a
heating mantle and sand bath. After the KOH turned to a molten
liquid, 2-(1-Methylethyl)thioethanol (1.00 g, 8.33 mmol) was added
dropwise directly onto the KOH, resulting in evolution of gas which
was collected as a liquid in the trap. The reaction was stirred until
1
the evolution of gas stopped. The product was pure by H NMR,
yielding 48% of the desired material: 1H NMR (CDCl3, 300 MHz)
δ 6.35 (dd, 1H, J ) 16.8, 9.90 Hz), 5.22 (d, 1H, J ) 2.4 Hz), 5.18
(d, 1H, J ) 8.7 Hz), 2.74-2.65 (m, 1H), 3.18-3.09 (m, 1H), 1.29
(d, 6H, J ) 10.8 Hz).
(iii) Isopropyl Vinyl Sulfoxide. The vinyl sulfoxide was
prepared according to Jenks.16 2-Propyl vinyl sulfide (0.384 g, 3.80
mmol) was placed in a 10 mL round-bottom flask charged with a
magnetic stir bar and argon. Acetic acid (1.50 mL) was added, and
the reaction was cooled to 0 °C. Hydrogen peroxide (30%,
0.430 mL, 3.80 mmol) was added, and the reaction was stirred for
2.5 h, at which time the reaction was quenched dropwise with
sodium carbonate until a pH of 7 was reached. The organics were
extracted with CH2Cl2, washed with water, dried over magnesium
sulfate, and concentrated. The concentrated product (0.21 g, 46%
yield) was pure by 1H NMR: 1H NMR (CDCl3, 100 MHz) δ 6.29
(dd, 1H, J ) 15.9, 9.90 Hz), 5.68 (d, 1H, J ) 16.2), 5.60 (d, 1H,
J ) 6.6 Hz), 2.54-2.40 (m, 1H), 0.92 (d, 3H, J ) 6.9 Hz), 0.85
(d, 3H, J ) 6.9 Hz); 13C NMR (CDCl3, 100 MHz) δ 138.2, 123.3,
51.5, 15.3, 14.2; IR (thin film, cm-1) 2938(m), 2861(m), 1702(m),
1635(m), 1587(m), 1558(m), 1461(m), 1384(w), 1316(w), 1278-
(m), 1230(s), 1181(w), 1114(m), 959(w), 853(w), 757(s), 728(m),
679(m); HRMS m/z calcd for C5H10OS 119.0531, found 119.0521.
Isopropyl 5-Phenyl-2(E)-pentenoate (3b). Diisopropylamine
(0.506 g, 5.00 mmol) was dissolved in tetrahydrofuran (26 mL) in
an oven-dried 50 mL round-bottom flask charged with argon and
a magnetic stir bar. The solution was cooled to -78 °C, and 1.5 M
n-BuLi (3.33 mL, 5.00 mmol) was added dropwise. The reaction
was stirred for 30 min, at which time isopropyl acetate (0.441 g,
5.00 mmol) was added. After the solution was stirred for 30 min
more, hydrocinnamaldehyde (0.560 g, 4.17 mmol) was added by
syringe. The reaction was stirred overnight at -60 °C. Upon
consumption of starting material, the reaction was quenched with
H2O (10 mL), extracted with ethyl acetate (3 × 20 mL), and washed
with brine. The combined organic layers were dried over magne-
sium sulfate, filtered, and concentrated in vacuo to give the crude
product. The crude mixture was purified by flash silica chroma-
tography (90% hexanes/10% ethyl acetate) to give 0.754 g of the
desired â-hydroxy ester as an oil in 82% yield.
The â-hydroxy ester (0.508 g, 2.31 mmol) was dissolved in
methylene chloride (18 mL) in a 100 mL oven-dried round-bottom
flask charged with argon and a magnetic stir bar. The reaction flask
was cooled to 0 °C, and triethylamine (3.74 g, 37.0 mmol) and
methanesulfonyl chloride (1.93 g, 16.9 mmol) were added. The
reaction was stirred for 1 h, at which time DBU (1.30 g, 8.55 mmol)
was added. After being stirred for 1 h more, the reaction was
quenched with H2O, diluted with brine, and extracted with ethyl
Isopropyl Vinyl Sulfoxide (2b). (i) 2-(1-Methylethyl)thioet-
hanol. The â-hydroxy sulfide was prepared according to the
experiment of Clive.15 1-Methylethyl thiol (3.14 g, 41.3 mmol) was
added dropwise to a solution of sodium (0.950 g, 41.3 mmol) in
J. Org. Chem, Vol. 72, No. 7, 2007 2333

Usera and Posner
acetate (3 × 30 mL). The combined organic layers were dried over
magnesium sulfate, filtered, and concentrated. The crude material
was purified by flash silica chromatography (90% hexanes/10%
ethyl acetate) to give 0.349 g of the desired isopropyl ester as an
oil in 75% yield: 1H NMR (CDCl3, 400 MHz) δ 7.35-7.31 (m,
2H), 7.26-7.21 (m, 3H), 7.04 (ddd, 1H, J ) 15.6, 13.6, 6.8 Hz),
5.88 (d, 1H, J ) 15.6 Hz), 5.14-5.08 (m, 1H), 2.81 (t, 2H, J )
7.6 Hz), 2.57-2.52 (m, 2H), 1.30 (d, 6H, J ) 6.0 Hz); 13C NMR
(CDCl3, 100 MHz) δ 165.9, 147.5, 140.7, 128.3, 128.2, 126.0,
122.2, 67.2, 34.2, 33.7, 21.7; IR (cm-1) 3025(w), 3005(m), 2967-
(m), 2947(m), 1712(s), 1654(m), 1480(m), 1471(m(, 1452(m), 1365-
(m), 1355(m), 1307(m), 1268(s), 1210(m), 1181(m), 1152(m),
1104(s), 998(m), 974(m), 930(w), 911(w), 843(w), 737(m), 689-
(m).
dropwise, and the reaction was stirred for 30 min. One equivalent
of each of two of the unsaturated compounds was dissolved in
methanol and added via cannula to the benzylmercaptan solution.
Upon consumption of benzyl mercaptan as determined by TLC,
the reaction was quenched with H2O, extracted with Et2O, dried
over magnesium sulfate, filtered, and concentrated. The crude
material was then analyzed by GC to obtain a ratio of products
formed or starting materials consumed.
Acknowledgment. We thank the NIH (Grant CA93547) for
financial support and Professor Thomas Lectka for helpful
discussions.
Supporting Information Available: 1H and 13C NMR spectra
and GC traces of the reactions. This material is available free of
charge via the Internet at http://pubs.acs.org.
General Competition Experiment. Benzyl mercaptan (1 equiv)
was dissolved in methanol (0.5 M) in an oven-dried round-bottom
flask charged with argon and equipped with a magnetic stir bar.
Triethylamine (1.1 equiv), distilled over calcium hydride, was added
JO062155G
2334 J. Org. Chem., Vol. 72, No. 7, 2007