Radical Cyclization of Epoxy Vinyl- and Allylsulfones Promoted by Titanocene Chloride

Article abstract of DOI:10.1021/acs.joc.5b00206

A titanocene-mediated intramolecular radical addition of different epoxy vinyl- and allylsulfones has been achieved. Five- and six-membered ring products were obtained in good to excellent yields in the presence of both 2.2 and 0.2 equiv of Cp₂TiCl. A novel double-activation strategy allowed us to achieve small-size rings such as cyclobutanes and cyclopropanes. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.joc.5b00206

Article
pubs.acs.org/joc
Radical Cyclization of Epoxy Vinyl- and Allylsulfones Promoted by
Titanocene Chloride
A. Fernandez-Mateos,* S. Encinas Madrazo, P. Herrero Teijon, and R. Rubio Gonzalez
́
́
́
Departamento de Química Organ
Salamanca, Spain
́
ica, Facultad de CC, Químicas, Universidad de Salamanca, Plaza de los Caídos 1-5, 37008
S
* Supporting Information
ABSTRACT: A titanocene-mediated intramolecular radical
addition of different epoxy vinyl- and allylsulfones has been
achieved. Five- and six-membered ring products were obtained
in good to excellent yields in the presence of both 2.2 and 0.2
equiv of Cp2TiCl. A novel double-activation strategy allowed
us to achieve small-size rings such as cyclobutanes and
cyclopropanes.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
Intramolecular additions of carbon radicals onto alkenes are
very important reactions in organic synthesis. The efficiency of
these reactions depends on their rate, which in turn is subject to
the type of substituents on the radical and on the alkene. Thus,
Michael-type radical conjugate additions, in which a nucleo-
philic radical is added to an alkene or an alkyne attached to an
electron-withdrawing group (EWG), are among the most
efficient radical cyclizations (Scheme 1).1
Here, we designed a study of the above-mentioned titanocene-
promoted intramolecular addition, employing a series of
epoxyvinyl- and allylsulfones as substrates, with the aim of
developing a straightforward procedure for the synthesis of
functionalized cyclic compounds. The results are discussed in
different sections depending on the size of the cycle obtained.
5-Exo-Trig Cyclizations. First, we performed the titano-
cene-promoted cyclization of epoxysulfones 1 and 3a/b (see
Table 1), which have similar structures, in order to achieve a 5-
exo-trig cyclization. All reactions were performed using either
overstoichiometric or catalytic quantities of Cp2TiCl. The
results are summarized in Table 1.
Scheme 1. Michael-Type Radical Conjugate Addition
All reactions provided the expected cyclization products in
good to excellent yields, and for both sulfones better yields
were achieved when the experiments were performed with an
excess of the TiIII reagent. All intramolecular additions afforded
the cyclic products as an approximately 50% mixture of two
diastereoisomers. A mechanism for the cyclization reaction of
sulfone 1 is proposed in Scheme 3.
The reaction starts with the well-known homolytic cleavage
of the C−O bond of the oxirane as a result of the TiIII σ-
coordination to the oxygen.7 This epoxide opening regiose-
lectively affords the β-alkoxy radical A, which further proceeds
through the addition to the activated double bond to provide
radical B. The radical cyclization proceeds with a higher rate
than radical A reduction. In the next step, radical B reduces to
the corresponding anion by a second equivalent of titanocene,
yielding intermediate C, which after workup provides the
isolated cyclization products 2a and 2b. In the catalytic
reaction, titanocene is regenerated by the 2,4,6-trimethylsilyl-
pyridinium chloride present in the reaction media.8
In the early 1980s, several authors explored the synthetic
utility of intramolecular free radical conjugate additions, and
many novel ring systems and natural products have been
obtained using this methodology.1 However, very few examples
of Michael-type radical cyclizations with a vinylsulfone as
acceptor can be found in the literature.2 Among these very few
examples, it is worth mentioning the earlier work of Clive et
al.,2a,b that introduced a new methodology for the synthesis of
spiro-polycyclic compounds based on the intramolecular
addition of a radical, generated with Bu3SnH, to a vinylsulfone.
Further examples of radical cyclization reactions onto vinyl-
sulfones can be found in the review published by Srikanth and
Castle.3
A few examples of titanocene-promoted radical cyclization
reactions have been described in recent years,4 but none of
them involved a vinylsulfone as an acceptor group (Scheme 2).
Therefore, as a complement to our previous work addressing
the intermolecular radical addition of epoxides to vinylsulfones
promoted by titanocene,5 it would be interesting to study the
intramolecular radical coupling of epoxyvinyl- and allylsulfones
mediated by TiIII species.
Received: January 29, 2015
Published: April 6, 2015
© 2015 American Chemical Society
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Scheme 2. Titanocene-Promoted Radical Cyclizations
Table 1. Titanocene-Promoted 5-Exo-Trig cyclizations
a
The ratio of diastereoisomers was determined in all cases by integration of signals in 1H NMR spectra. Diastereoisomer assignation was achieved by
comparison of the spectroscopic data of products with that of similar compounds previously described in the literature.6
For epoxy sulfones 4a/b, however, the formation of 5-exo-trig
cyclization products may not be so straightforward. Previously
reported experimental data9 show that the rate constant for
cyclization reactions of 5-hexenyl radicals with an 5-alkyl
substituent is much lower than the rate constant of those
lacking this substitution. This kind of radical actually prefers the
6-endo-trig cyclization to the 5-exo-trig type, and although
mixtures of both are usually obtained, in most cases the ratio
favors the first one by 65 to 35.9 The fact that we obtained the
5-exo cyclization products, 4c/d, not only in high yields but also
as the only products clearly shows that the sulfonyl group
attached to the double bond induces a very strong activating
effect, completely overcoming the presence of the 5-methyl
substituent.
In the reactions performed with epoxyvinylsulfone 5 (entries
1 and 2 of Table 2), the desired 6-endo cyclization products
were obtained in good yields when the reaction was performed
with both 2.2 and 0.2 equiv of titanocene (III). As occurred in
the reactions performed with sulfones 1 and 3a/b, the products
were obtained as a mixture of diastereoisomers, although in this
case the trans product was clearly the major product isolated. A
stereochemical model for formation of 6a versus 6b and
assignation based on 13C NMR methyl displacements is given
in scheme below.
6-Exo-Trig/6-Endo-Trig Cyclizations. We continued our
research by studying the performance of two new epox-
ysulfones, 5 and 7 (see Table 2), which would provide six-
membered cyclic products after 6-exo and 6-endo cyclizations,
respectively. The reaction conditions and results are
summarized in Table 2.
The intramolecular addition reaction with sulfone 7 was only
performed in the presence of an overstoichiometric amount of
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Scheme 3. Cyclization Mechanism
Table 2. Titanocene-Promoted 6-Exo and 6-Endo Cyclizations
a
1
The ratio of diastereoisomers (determined by integration of signals in H NMR spectra) was 53:47, favoring the cis diastereroisomer 4a.
Scheme 4. Possible Pathways for the Transformation of 7 into 4a/4b
titanocene dichloride reagent (2.2 equiv), and the reaction
afforded as many as three cyclization products: the six-
membered ring 8 and the five-membered rings 4a and 4b
(Scheme 4). The unsaturated alcohol 8 was undoubtedly
formed through a 6-endo-trig cyclization followed by the
elimination of a sulfone group. However, two different
pathways must be considered for the formation of hydrox-
ysulfones 4a and 4b (Scheme 4): a direct 5-exo-trig cyclization
or a two-step process in which an initial double-bond
conjugation yields a vinylsulfone intermediate, which further
proceeds through a 5-exo-trig cyclization.
substituted 5-hexenyl radical is involved show a preference for
6-endo cyclization.4f The two-step process more convincingly
explains the formation of 4a/4b, in which the more activated
vinylsulfone intermediate could be formed readily, and quite
rapidly, by any of the Lewis acids (i.e., titanocene chloride or
zinc chloride) present in the reaction medium. Once this
intermediate has been formed, the reaction proceeds through a
5-exo cyclization process that leads to 4a/4b.
4-Exo-Trig Cyclization. Encouraged by the good results
obtained, we decided to apply our method to the synthesis of
four-membered cyclic hydroxy sulfones. Thus, epoxyvinylsul-
fone 9 was made to react with both 2.2 and 0.2 equiv of
titanocene chloride. However, instead of the desired cyclic
The direct 5-exo-trig cyclization must be excluded. As we
have reported previously,9 cycling processes in which a 5-alkyl-
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Scheme 5. Reaction of Epoxysulfone 9 with TiIII
products, a mixture of the open-chained saturated (10a) and
unsaturated (10b) hydroxyvinylsulfones was isolated in both
reactions (see Scheme 5). Lowering the reaction temperature
does not prevent elimination.
From this result it may concluded that for these model
compounds the 4-exo-trig cyclization is slower than the
hydrogen elimination process10 and therefore does not occur.
Activation of the sulfonyl group is insufficient for this to
happen.
the radical and the radical acceptor, therefore favoring ring
closure (Scheme 7).13
Based on the previous results described above for five- and
six-membered rings, we decided to circumvent our cyclization
rate problems through a novel strategy: the double activation of
the β-carbon to the sulfone by the attachment of an ester
moiety as an extra activating group. Accordingly, we performed
the reactions on the double activated epoxysulfone 11a/b with
two different amoung of titanocene reagent: catalytic and
overstoichiometric. Much to our surprise, different products
were isolated, depending on the reaction procedure applied
(see Scheme 8).
The synthesis of small-size rings, such as cyclopropanes or
cyclobutanes, has always been a difficult task for chemists.
Synthesizing these compounds using radical procedures
involves the problem of reversibility. That is, the homolytic
opening of the intermediate cyclic radicals (i.e., cyclo-
propylcarbinyl and cyclobutylcarbinyl) is in both cases faster
than the cyclization of the initial radicals.11 Several strategies
have been applied in titanocene radical chemistry in order to
achieve the synthesis of three- and four-membered ring
cyclization products successfully.12,4a,f,10a In the past, both our
Scheme 8. Reaction of Epoxy Sulfone 11a/b with 2.2 and 0.2
equiv of TiIII
group4a and that of Gansauer4f have described the synthesis of
̈
cyclopropanes through a titanocene-mediated Michael-type
intramolecular addition on α,β-unsaturated carbonyl com-
pounds (see Scheme 6). In these examples, the reversibility
of the cyclization reaction can be avoided by trapping the enolic
intermediate radical with TiIII complexes.
The experiment in which an excess of titanocene chloride
was added (Scheme 8, first row) afforded the desired
cyclobutane as a mixture of isomers, 12a/b, in 66% yield,
meaning that our double-activation strategy had been
successful. However, the experiment performed with a catalytic
20% of titanocene reagent (Scheme 8, second row) provided
only the cyclopropane 13, in a 36% yield. A likely mechanism
to explain the formation of 13 requires double-bond isomer-
ization toward the unconjugated position. The force respon-
sible for preventing reversibility in the formation of cyclo-
propylcarbinyl radical 12B from radical 12A is the elimination
of the sulfonyl radical, as depicted in Scheme 9.
Scheme 6. Titanocene-Promoted Synthesis of
Cyclopropanes
However, when attempting to synthesize cyclobutanes using
this strategy, successful results were only obtained when
additional strategies were also applied, such as the Thorpe−
Ingold effect12b or the use of a template catalyst that binds both
Some authors have stated that allylsulfones are more
thermodynamically stable than vinylsulfones.14 In the late
1980s, Inomata et al.15 performed a fairly exhaustive study of
Scheme 7. Gansauer’s Strategies for the Synthesis of Cyclobutanes with TiIII
̈
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Scheme 9. Mechanism for the Formation of 13
the diazabicycloundecene-mediated conversion of vinylsulfones
into allylsulfones, and isomerization to the allyl position proved
to be general.
To confirm the above proposed mechanism we synthesized
the corresponding alkene, 14a/b, and proceeded to place it
under the conditions in which the catalytic reaction had been
performed. As shown in Scheme 10, this reaction afforded total
epoxysulfone, as occurred with epoxy sulfone 9, hydrogen
elimination is faster than cyclization.
Nevertheless, as can be seen in Scheme 11, the second-
activating-group strategy proved once more to be successful for
the achievement of the desired intramolecular addition,
providing the cyclopropane 13 in a more than satisfying 97%
yield when catalytic conditions were applied. The low yield
obtained in the reaction using overstoichiometric Ti(III)
quantities could be explained by competitive hydrogen
elimination, undertaken by Ti(III) in excess, from the methyl
group of the radical initial to afford byproducts as complex
mixtures of allyl alcohol−sulfonyl esters, which we have not
been able to resolve.
Scheme 10. Study of the Double-Bond Isomerization
Tamdem Reaction. As a final point to our cyclization
experiments, we decided to slightly modify the patterns
followed by designing a two-molecule tandem cyclization
experiment.
isomerization of the double bond toward the β−γ position.
Further experiments revealed that among all species present in
the reaction vessel 2,4,6-collidine was the only one responsible
for this total isomerization, and hence, the mechanism
proposed in Scheme 9 was confirmed. In addition, DBU also
provided 15 in good yield, as described by Inomata.
3-Exo-Trig Cyclization. The above reaction, although not
initially intended for that purpose, provided us with a three-
membered ring product through a three-step process: double-
bond isomerization, 3-exo-trig cyclization, and sulfone elimi-
nation. Very few examples of the use of a process of fast
elimination of a leaving group placed in the β-position of a
cyclopropylcarbinyl radical for the synthesis of cyclopropanes
can be found in the literature. To our knowledge, in the only
examples described the authors used bromide or phenylthio
leaving groups.16 Therefore, the example described here
presents a hitherto unprecedented successful 3-exo radical
cyclization procedure.
As a next step, we decided to further study the scope of this
cyclopropanation reaction for our usual epoxy monoactivated
vinylsulfones. With this aim, we made epoxysulfone 16 react
with Cp2TiCl under the usual reaction conditions (see Scheme
11).
Unfortunately, the reaction of 16 with either 0.2 or 2.2 equiv
of TiIII provided only a mixture of the saturated and
unsaturated alcohols 17a/b, instead of the desired cyclization
product. It may therefore be concluded that, for this
Based on the information acquired in the previously studied
intra- and intermolecular addition experiments to vinyl- and
allylsulfones, we believed that it might be interesting to perform
a tandem reaction that combined both inter- and intramolecular
consecutive additions, providing a cyclic extrafunctionalized
product. To accomplish this, two molecules were selected. On
one hand, we chose epoxy sulfone 16, which provided us with
the epoxide (radical precursor) and the allylsulfone, intended to
be the secondary acceptor. On the other, phenyl vinylsulfone
19, which afforded the best results in the intermolecular study,5
was selected as the primary acceptor. The reaction was
performed in the presence of 0.2 equiv of TiIII reagent, and
the results are depicted in Scheme 12.
Reaction of sulfones 16 and 19 promoted by titanocene
chloride afforded cyclic hydroxy sulfone 20a/b as a mixture of
diastereoisomers in 51% yield. The reaction mechanism is
depicted in Scheme 13.
The tertiary radical 16A, formed after homolytic epoxide
opening promoted by TiIII, was added to the conjugated double
bond of sulfone 19, providing a new radical, 16B, which after
intramolecular addition to the allylic double bond afforded the
five-membered ring followed by the elimination of a tosyl
radical. The precise coordination of two addition processes with
accurate kinetics (a fast intermolecular addition to the
vinylsulfone and a slower intramolecular addition to the
Scheme 11. 3-Exo-Trig Cyclization Reactions
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Scheme 12. Tandem Reaction
use. 1,2-Dimethoxyethane (DME) was purified by refluxing in sodium
for 2 h before use. Sodium used for desiccation was renewed twice
during this 2 h period and once more just before final distillation
before use. All titanocene reactions were conducted under a positive
pressure of argon by using standard benchtop techniques for the
handling of air-sensitive materials. Chromatographic separations were
carried out under pressure on silica gel using flash column techniques
on Merck silica gel 60 (0.040−0.063 mm). Unless otherwise
mentioned, yields reported are for chromatographically pure isolated
products.
Scheme 13. Tandem Reaction Mechanism
Titanocene Procedures. General Procedure A (GPA). A mixture
of Cp2TiCl2 (2.20 mmol) and Zn (6.60 mmol) in strictly
deoxygenated THF (11.0 mL) was stirred at room temperature until
the red solution turned green. In a separate flask, the epoxy compound
(1.00 mmol) and the sulfone (1, 2, 5, or 10 mmol) were dissolved in
strictly deoxygenated THF (10.0 mL). The green TiIII solution was
slowly added by cannula to the epoxide solution. After 30 min, an
excess amount of saturated NaH2PO4 was added, and the mixture was
stirred for 2 h. The mixture was filtered to remove insoluble titanium
salts. The product was extracted with diethyl ether (Et2O), and the
combined organic layers were washed with water and brine and dried
over anhydrous Na2SO4. After removal of the solvent, the crude
product was purified by flash chromatography.
General Procedure B (GPB). A mixture of Cp2TiCl2 (2.20 mmol)
and Zn (6.60 mmol) in strictly deoxygenated THF (11.0 mL) was
stirred at room temperature until the red solution turned green. In a
separate flask, the epoxy compound (1.00 mmol) and the sulfone (1, 2,
5, or 10 mmol) were dissolved in strictly deoxygenated THF (10.0
mL). The epoxide solution was slowly added by cannula to the green
TiIII solution. After 1 h, an excess amount of saturated NaH2PO4 was
added, and the mixture was stirred for 2 h. The mixture was filtered to
remove insoluble titanium salts. The product was extracted with Et2O,
and the combined organic layers were washed with water and brine
and dried over anhydrous Na2SO4. After removal of the solvent, the
crude product was purified by flash chromatography.
Catalytic Procedure (CP). A mixture of Cp2TiCl2 (0.20 mmol) and
Zn (8.00 mmol) in strictly deoxygenated THF (8.0 mL) was stirred at
room temperature until the red solution turned green. In a separate
flask, the epoxy compound (1.00 mmol), 2,4,6-collidine (8.00 mmol),
and the sulfone (1, 2, 5, or 10 mmol) were dissolved in strictly
deoxygenated THF (0.8 mL). In a separate flask, chlorotrimethylsilane
(TMSCl) (2.5 mmol) was strictly deoxygenated. Next, the epoxide
solution and the TMSCl were slowly added at the same time by
different cannulas to the green TiIII solution. After 8 h, an excess
amount of HCl 2 M was added, and the mixture was stirred for 30
min. The layers were separated, and the aqueous phase was extracted
with Et2O. The combined organic layers were washed with water and
brine and dried over anhydrous Na2SO4. After removal of the solvent,
the crude product was purified by flash chromatography.
Compounds 2a and 2b. Application of GPB to 100 mg of 1
followed by flash chromatography (Hex/AcOEt 65:35) afforded a
1:0.9 mixture of 2a and 2b in 100% yield (101 mg). Application of CP
to 100 mg of 1 followed by flash chromatography (Hex/AcOEt 7:3)
provided a 1:0.9 mixture of 2a* and 2b† in 72% yield (73 mg). IR: ν =
3520, 2955, 2877, 1723, 1599, 1456, 1301, 1152, 1048, 1087 cm−1. 1H
NMR (200 MHz, CDCl3): δ = 0.74† (s, 3H), 0.94* (s, 3H), 1.2−2.4
(m, 16H), 2.41 (s, 6H), 2.85† (d, J = 9.8 Hz, 1H), 2.92* (d, J = 9.7 Hz,
1H), 3.04† (d, J = 10.6 Hz, 1H), 3.11* (d, J = 10.6 Hz, 1H), 3.34 (m,
4H), 7.32 (d, J = 7.8 Hz, 4H), 7.74 (d, J = 8.2 Hz, 4H. 13C NMR (50
MHz, CDCl3): δ = 18.2† (CH3), 21.8* (CH3), 21.9† (CH3), 22.3
(2CH2), 23.2* (CH3), 31.5† (CH2), 31.7* (CH2), 35.9† (CH2), 36.1*
(CH2), 39.2† (CH), 43.3* (CH), 46.3 (2C), 58.1* (CH2), 58.6†
(CH2), 67.1† (CH2), 70.0* (CH2), 128.1 (4CH), 130.0* (2CH),
allylsulfone, both processes faster than the reduction of the
radicals by TiIII) provided us with a five-membered ring with as
many as three different functions in good yield.
CONCLUSIONS
■
A satisfying procedure for the achievement of several cyclic
hydroxysulfones has been described. The titanocene-mediated
intramolecular addition of different epoxy vinyl- and
allylsulfones provided several 3- to 5-membered ring cyclic
products in good to excellent yields. The reaction of 6,7-
epoxyvinylsulfones with titanocene afforded the corresponding
5-exo cyclization products in very good yields as a result of the
very strong activating effect exerted by the sulfone group on the
β-carbon of the double bond. In turn, 7,8-epoxyvinylsulfones
proceed through the desired 6-exo addition, affording the 6-
membered ring products. An example of a 6-endo process
favored by the elimination of a tosyl radical from an epoxy
allylsulfone is described. This result once more confirms the
strong activation effect performed by the sulfone. Also, a novel
double activation procedure has been developed in order to
achieve the synthesis of small-size rings, such as cyclobutanes
and cyclopropanes, from the corresponding 5,6-epoxyvinylsul-
fonyl esters and 5,6-epoxy allylsulfonyl esters. Almost all
reactions described here afforded products in good yields in the
presence of both 2.2 and 0.2 equiv of Cp2TiCl, although
unfortunately, no remarkable diastereoselectivity was observed
in any of the procedures. Finally, an accurate combination of
two reactions with different addition rates allowed us to
perform a two-molecule tandem addition which afforded a
highly functionalized five-membered ring in good yield. The
epoxy vinyl- and allylsulfones reported in this work were
synthesized according to the multistep sequences depicted in
Scheme 14.
EXPERIMENTAL SECTION
■
General Experimental Methods. IR spectra were recorded for
neat samples on NaCl plates, unless otherwise noted. 1H NMR spectra
were measured at either 200 or 400 MHz, and 13C NMR spectra were
measured at 50 or 100 MHz in CDCl3 and referenced to solvent,
except where otherwise indicated. HRMS mass spectrometry data were
acquired in a hybrid quadrupole time-of-flight mass spectromer.
Samples were dissolved in methanol, and electrospray was used for
ionization. When required, all solvents and reagents were purified by
standard techniques. Tetrahydrofuran (THF) was purified by
distillation from sodium and benzophenone and degassed before
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Scheme 14. Synthesis of Epoxy Vinyl- and Allylsulfones 1, 3a/b, 5, 7, 9, 11a/b, 16, and 18a/b
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Scheme 14. continued
130.1† (2CH), 137.1† (C), 137.2* (C), 144.7* (C), 144.9† (C).
HRMS (ESI) calcd for C15H22O3NaS 305.1182, found 305.1186.
Compounds 4a and 4b. Application of GPB to 100 mg of 3a/b
followed by flash chromatography (Hex/AcOEt 6:4) afforded a 1:0.9
mixture of 4a and 4b in 78% yield (79 mg). Application of CP to 100
mg of 3a/b followed by flash chromatography (Hex/AcOEt 6:4)
provided a 1:1 mixture of 4a* and 4b† in 62% yield (63 mg). 1H NMR
(200 MHz, CDCl3): δ = 0.73* (s, 3H), 0.74† (s, 3H), 0.84† (s, 3H),
0.88* (s, 3H), 1.23* (s, 3H), 1.32† (s, 3H), 1.4−2.2 (m, 10H), 3.01
(m, 3H), 3.34* (d, J = 14.2 Hz, 1H), 3.77* (dd, J1 = 4.6 Hz, J2 = 8.2
Hz, 1H), 3.94† (m, 1H), 7.55 (m, 6H), 7.89 (m, 4H. 13C NMR (50
MHz, CDCl3): δ = 17.1† (CH3), 17.4* (CH3), 21.5† (CH3), 21.8*
(CH3), 22.1† (CH3), 23.6* (CH3), 30.4† (CH2), 31.6* (CH2), 33.7†
(CH2), 34.4* (CH2), 45.7† (C), 46.1* (C), 48.2† (C), 49.1* (C),
63.7† (CH2), 64.2* (CH2), 79.3† (CH), 80.9* (CH), 127.7 (4CH),
129.5 (4CH), 133.6 (2CH), 142.2 (2C). HRMS (ESI): calcd for
C15H22O3NaS 305.1182, found 305.1174.
(CH2), 32.2 (CH2), 37.0 (C), 46.4 (CH2), 76.6 (CH), 109.5 (CH2),
146.2 (C).
Compounds 10a and 10b. Application of GPA to 113 mg of 9
followed by flash chromatography (Hex/AcOEt 6:4) afforded a 1:0.95
mixture of 10a† and 10b* (60 mg, 53%). Application of CP to 120 mg
of 9 followed by flash chromatography (Hex/AcOEt 6:4) provided a
1:1 mixture of 10a† and 10b* (44 mg, 37%). IR: ν = 3500, 3046, 2922,
1
2877, 1729, 1599, 1456, 1320, 1300, 1145, 1047, 814 cm−1. H NMR
(200 MHz, CDCl3): δ = 0.87† (d, J = 6.6 Hz, 3H), 1.0−2.2 (m, 11H),
2.41 (s, 6H), 3.42† (d, J = 5.8 Hz, 2H), 4.01* (s, 2H), 4.82* (s, 1H),
5.04* (s, 1H), 6.30 (m, 2H), 6.94 (m, 2H), 7.31 (d, J = 8.2 Hz, 4H),
7.72 (d, J = 8.2 Hz, 4H. 13C NMR (50 MHz, CDCl3): δ = 16.5†
(CH3), 21.8 (2CH3), 29.2* (CH2), 29.7† (CH2), 30.9* (CH2), 31.2†
(CH2), 35.4† (CH), 65.9* (CH2), 67.8† (CH2), 111.2* (CH2), 127.8
(4CH), 130.1 (4CH, C), 130.8† (CH), 131.3* (CH), 137.7† (C),
137.8* (C), 144.6† (C), 145.9* (CH), 146.7† (CH), 146.9* (C). 10a.
HRMS (ESI): calcd for C14H20O3NaS 291.1025, found 291.1016. 10b.
HRMS (ESI): calcd for C14H18O3NaS 289.0869, found 289.0870.
Compounds 12a and 12b. Application of GPB to 100 mg of 11a/
b followed by flash chromatography (Hex/AcOEt 7:3) afforded a 12a
(34 mg, 33%) followed by 12b (34 mg, 33%). 12a (less polar isomer).
1H NMR (200 MHz, CDCl3): δ = 1.0−2.0 (m, 5H), 1.23 (s, 3H), 3.15
(m, 1H), 3.51 (s, 3H), 3.56 (d, J = 2.8 Hz, 2H), 4.17 (d, J = 10.6 Hz,
1H), 7.63 (m, 3H), 7.87 (m, 2H. 13C NMR (50 MHz, CDCl3): δ =
17.9 (CH3), 20.9 (CH2), 26.8 (CH2), 35.7 (CH), 43.8 (C), 52.9
(CH3), 70.1 (CH2), 71.9 (CH), 129.3 (4CH), 134.6 (CH), 137.5 (C),
165.6 (C). 12b (more polar isomer). 1H NMR (200 MHz, CDCl3): δ
= 1.02 (s, 3H), 1.2−2.2 (m, 5H), 2.84 (m, 1H), 3.16 (d, J = 11.2 Hz,
1H), 3.31 (d, J = 11.6 Hz, 1H), 3.58 (s, 3H), 4.08 (d, J = 12.0 Hz, 1H),
7.61 (m, 3H), 7.84 (m, 2H. 13C NMR (50 MHz, CDCl3): δ = 17.7
(CH3), 21.9 (CH2), 28.1 (CH2), 36.9 (CH), 44.2 (C), 53.3 (CH3),
70.7 (CH2), 72.9 (CH), 129.3 (4CH), 134.6 (CH), 137.9 (C), 167.7
(C). HRMS (ESI): calcd for C15H20O5NaS 335.0924, found 335.0918.
Compound 13. Application of CP to 150 mg of 11a/b followed by
flash chromatography (Hex/AcOEt 8:2) provided 13 (30 mg, 36%).
Application of GPB to 100 mg of 18a/b followed by flash
chromatography (Hex/AcOEt 7:3) afforded 13 (23 mg, 42%).
Application of CP to 130 mg of 18a/b followed by flash
chromatography (Hex/AcOEt 7:3) provided 13 (67 mg, 97%). IR:
ν = 3454, 2955, 2864, 1754, 1716, 1644, 1450, 1313, 1281, 1151, 1073
cm−1. 1H NMR (200 MHz, CDCl3): δ = 0.67 (t, J = 5.2 Hz, 1H), 0.83
(m, 1H), 1.04 (m, 1H), 1.19 (s, 3H), 2.36 (br s, 1H), 3.40 (d, J = 4.8
Hz, 2H), 3.68 (s, 3H), 5.90 (m, 1H), 6.68 (m, 1H). 13C NMR (50
MHz, CDCl3): δ = 16.5 (CH3), 20.6 (CH2), 25.1 (CH), 27.9 (C),
51.6 (CH3), 70.7 (CH2), 120.4 (CH), 150.2 (CH), 167.2 (C). HRMS
(ESI): calcd for C9H14O3Na 193.0835, found 193.0840.
Compounds 6a and 6b. Application of GPB to 100 mg of 5
followed by flash chromatography (Hex/AcOEt 7:3) afforded 6a (50
mg, 49%) followed by 6b (25 mg, 24%). Application of CP to 100 mg
of 5 followed by flash chromatography (Hex/AcOEt7:3) provided 6a
(47 mg, 46%) and 6b (23 mg, 22%). 6a. IR: ν = 3524, 2929, 2854,
1589, 1465, 1288, 1146 cm−1. 1H NMR (200 MHz, CDCl3): δ = 0.67
(s, 3H), 1.1−1.7 (m, 9H), 2.10 (m, 1H), 2.45 (s, 3H), 2.62 (dd, J1 =
6.6 Hz, J2 = 14.4 Hz, 1H), 3.12 (d, J = 12.0 Hz, 1H), 3.29 (dd, J1 = 2.4
Hz, J2 = 14.4 Hz, 1H), 3.47 (d, J = 11.2 Hz, 1H), 7.36 (d, J = 8.2 Hz,
2H), 7.79 (d, J = 8.2 Hz, 2H). 13C NMR (50 MHz, CDCl3): δ = 15.4
(CH3), 21.4 (CH2), 21.9 (CH3), 26.3 (CH2), 30.3 (CH2), 34.9 (CH2),
35.1 (CH), 38.4 (C), 58.2 (CH2), 70.5 (CH2), 128.2 (2CH), 130.2
(2CH), 136.4 (C), 145.2 (C). 6b. IR: ν = 3526, 2929, 2858, 1599,
1
1463, 1288, 1145 cm−1. H NMR (200 MHz, CDCl3): δ = 0.86 (s,
3H), 1.0−2.1 (m, 10H), 2.45 (s, 3H), 2.89 (dd, J1 = 8.2 Hz, J2 = 14.8
Hz, 1H), 3.35 (d, J = 11.4 Hz, 1H), 3.38 (dd, J1 = 2.2 Hz, J2 = 16.8 Hz,
1H), 3.54 (d, J = 11.4 Hz, 1H), 7.36 (d, J = 8.2 Hz, 2H), 7.78 (d, J =
8.2 Hz, 2H. 13C NMR (50 MHz, CDCl3): δ = 21.3 (CH2), 21.9
(CH3), 23.5 (CH3), 24.5 (CH2), 28.4 (CH2), 34.4 (CH2), 37.7 (C),
38.4 (CH), 57.6 (CH2), 66.9 (CH2), 128.2 (2CH), 130.1 (2CH),
136.8 (C), 144.9 (C). HRMS (ESI): calcd for C16H24O3NaS 319.1338,
found 319.1349.
Compound 8. Application of GPB to 211 mg of 7 followed by flash
chromatography (Hex/AcOEt 9:1 to Hex/AcOEt 7:3) afforded 8 (19
1
mg, 18%) followed by a 1:0.9 mixture of 2a/2b (35 mg, 34%). 8. H
NMR (200 MHz, CDCl3): δ = 0.84 (s, 3H), 0.96 (s, 3H), 1.2−2.4 (m,
7H), 3.45 (dd, J1 = 3.8 Hz, J2 = 9.0 Hz, 1H), 4.59 (s, 1H), 4.68 (s,
1H). 13C NMR (50 MHz, CDCl3): δ = 20.4 (CH3), 27.7 (CH3), 31.3
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Article
Compound 15. Application of CP to 100 mg of 14a/b provided a
crude product identified as 15 (100 mg, 100%). H NMR (200 MHz,
in AcOEt, and subsequently washed several times with water and brine
and dried over anhydrous Na2SO4. Solvent was then removed under
reduced pressure to yield the monoester 22 (5.2 g, 57%). IR: ν = 2981,
1
CDCl3): δ = 1.74 (s, 3H), 2.72 (d, J = 6.6 Hz, 2H), 3.72 (s, 3H), 4.52
(d, J = 9.4 Hz, 1H), 4.61 (s, 1H), 4.72 (s, 1H), 5.53 (s, 1H), 5.75 (m,
1H), 7.57 (m, 3H), 7.82 (m, 2H. 13C NMR (50 MHz, CDCl3): δ =
22.7 (CH3), 41.2 (CH2), 53.4 (CH3), 74.3 (CH), 112.1 (CH2), 118.7
(CH), 129.1 (2CH), 129.8 (2CH), 134.5 (CH), 137.1 (C), 139.9
(CH), 142.9 (C), 165.5 (C). HRMS (ESI): calcd for C15H18O4NaS
317.0818, found 317.0827.
1
2942, 1742, 1651, 1456, 1385, 1164, 1048, 898 cm−1. H NMR (200
MHz, CDCl3): δ = 1.22 (t, J = 7.0 Hz, 3H), 1.68 (s, 3H), 1.74 (m,
2H), 2.01 (t, J = 5.8 Hz, 2H), 2.26 (t, J = 7.4 Hz, 2H), 4.09 (q, J = 7.4
Hz, 2H), 4.65 (s, 1H), 4.69 (s, 1H). 13C NMR (50 MHz, CDCl3): δ =
14.4 (CH3), 22.4 (CH3), 22.9 (CH2), 33.9 (CH2), 37.2 (CH2), 60.4
(CH2), 110.8 (CH2), 144.9 (C), 173.8 (C). A 2 M solution of BuLi in
cyclohexane (6.4 mL, 12.82 mmol) was added dropwise to a 0 °C
solution of 4-(methylsulfonyl)toluene (1.09 g, 6.41 mmol) in
anhydrous THF (23.0 mL), and the new mixture was stirred at this
temperature for 30 min. After this time, it was cooled to −78 °C and a
solution of ester 22 (1.00 g, 6.41 mmol) in DMPU (15.0 mL) was
slowly added. This new mixture was stirred at −78 for 6 h, quenched
with a saturated aqueous solution of NH4Cl, and slowly allowed to
reach rt. The aqueous phase was extracted with AcOEt, and the
combined organic layers were subsequently washed with a 2 M
aqueous solution of HCl, a saturated aqueous solution of NaHCO3,
and brine and dried over anhydrous Na2SO4. Finally, solvent was
removed under reduced pressure and the residue was purified by flash
chromatography over silica gel (Hex/AcOEt 9:1) to afford 22 (191
mg) followed by 23 (1.5 g, 82%). IR: ν = 2929, 1723, 1599, 1333,
Compounds 17a and 17b. Application of GPB to 100 mg of 16
followed by flash chromatography (Hex/AcOEt 7:3) afforded a 0.95:1
mixture of 17a† and 17b* (62 mg, 62%). Application of CP to 100 mg
of 16 followed by flash chromatography (Hex/AcOEt 7:3) provided a
1
1:1 mixture of 17a† and 17b* (53 mg, 53%). H NMR (200 MHz,
CDCl3): δ = 0.78* (d, J = 6.6 Hz, 3H), 1.6−2.4 (m, 5H), 2.42 (s, 6H),
2.75† (d, J = 6.2 Hz, 2H), 3.35 (d, J = 6.2 Hz, 4H), 3.73* (m, 2H),
3.94† (s, 2H), 4.71† (s, 1H), 4.99† (s, 1H), 5.52 (m, 4H), 7.31 (d, J =
8.2 Hz, 4H), 7.70 (d, J = 8.2 Hz, 4H. 13C NMR (50 MHz, CDCl3): δ =
16.5* (CH3), 21.8 (2CH3), 35.7* (CH), 36.4* (CH2), 36.6† (CH2),
60.2* (CH2), 60.4† (CH2), 65.6* (CH2), 67.6† (CH2), 111.3† (CH2),
117.7† (CH), 118.3* (CH), 128.6 (4CH), 129.92* (2CH), 129.96†
(2CH), 135.7 (2C), 138.5* (CH), 139.9† (CH), 144.91† (C), 144.97*
(C), 146.5† (C).
Compounds 20a and 20b. Application of CP to a mixture of 110
mg of 16 and 139 mg of 19 followed by flash chromatography (Hex/
AcOEt 1:1) provided 20a (10 mg, 9%) followed by an overall 33:67
mixture of 20a/b (49 mg, 42%) (split in several fractions with different
isomer ratios). 20a (less polar isomer). 1H NMR (400 MHz, CDCl3):
δ = 1.04 (s, 3H), 1.38 (dd, J1 = 9.7 Hz, J2 = 13.2 Hz, 1H), 1.72 (dd, J1
= 9.5 Hz, J2 = 14.0 Hz, 1H), 1.75 (br s, 1H), 1.99 (dd, J1 = 8.3 Hz, J2 =
13.2 Hz, 1H), 2.19 (dd, J1 = 7.8 Hz, J2 = 13.8 Hz, 1H), 2.43 (br s, 1H),
3.13 (m, 1H), 3.45 (s, 2H), 4.82 (m, 2H), 5.56 (m, 1H), 7.53 (m, 2H),
7.62 (m, 1H), 7.87 (m, 2H. 13C NMR (100 MHz, CDCl3): δ = 24.8
(CH3), 36.8 (CH2), 43.1 (CH2), 43.3 (C), 44.1 (CH), 68.7 (CH),
70.0 (CH2), 115.2 (CH2), 128.6 (2CH), 129.1 (2CH), 133.6 (CH),
138.7 (C), 139.1 (CH). HRMS (ESI): calcd for C15H21O3S 281.1206,
found 281.1208. 20b (more polar isomer). 1H NMR (200 MHz,
CDCl3): δ = 1.01 (s, 3H), 1.0−2.3 (m, 6H), 3.44 (m, 1H), 3.49 (s,
2H), 5.04 (m, 2H), 6.21 (m, 1H), 7.55 (m, 3H), 7.86 (m, 2H. 13C
NMR (50 MHz, CDCl3): δ = 25.1 (CH3), 37.1 (CH2), 42.5 (CH2),
43.3 (C), 45.8 (CH), 66.8 (CH), 71.1 (CH2), 116.1 (CH2), 128.6
(2CH), 129.2 (2CH), 133.7 (CH), 136.9 (CH), 140.1 (C).
Synthetic Procedures. Compound 1. To a 0 °C solution of 3-
methyl-3-butenol (5.0 g, 58.0 mmol) in CH2Cl2 (20 mL) were added
pyridine (9.4 mL, 116.1 mmol), and methanesulfonyl chloride (7.2
mL, 92.9 mmol). The resultant reaction mixture was stirred at 0 °C
under an argon atmosphere for 1.5 h. After that time, water was added
and the resultant mixture extracted with CH2Cl2. The combined
organic layers were subsequently washed with a 2 M aqueous solution
of HCl, a saturated aqueous solution of NaHCO3, and brine and dried
over anhydrous Na2SO4. Elimination of the solvent by careful
distillation of the mixture with a Vigreux column afforded mesylate
21 (9.5 g, 100%). 1H NMR (200 MHz, CDCl3): δ = 1.78 (s, 3H), 2.46
(t, J = 7.2 Hz, 2H), 3.01 (s, 3H), 4.33 (t, J = 6.6 Hz, 2H), 4.79 (s, 1H),
4.88 (s, 1H). Diethyl malonate (13.2 mL, 86.9 mmol) was slowly
added to a suspension of 50% NaH (3.9 g, 81.0 mmol) in THF (124.0
mL), under argon atmosphere and at 0 °C, and the mixture was stirred
at room temperature until the complete formation of the anion (ca. 30
min). A solution of mesylate 21 (9.5 g, 57.9 mmol) in THF (19.0 mL)
was then added dropwise and the new mixture refluxed for 12 h, when
it was cooled to rt, quenched with a 2 M aqueous solution of HCl, and
stirred for 10 min. The aqueous layer was extracted with Et2O, the
mixture of organic extracts was washed with brine and dried over
anhydrous Na2SO4, and the solvent was removed under reduced
pressure, yielding 23.0 g of a mixture of diethyl malonate and the
diester intermediate, which was used without further purification in the
next step. In that, the mixture (23.0 g) was dissolved in DMSO (150.0
mL), and anhydrous NaCl (17.7 g, 302.7 mmol) and water (5.4 mL,
302.7 mmol) were added. The reaction vessel was next stirred at 180−
200 °C for 12 h. After this time, the mixture was cooled to rt, diluted
1
1152 cm−1. H NMR (200 MHz, CDCl3): δ = 1.66 (s, 3H), 1.68 (m,
2H), 1.97 (t, J = 7.4 Hz, 2H), 2.43 (s, 3H), 2.66 (t, J = 7.4 Hz, 2H),
4.12 (s, 2H), 4.63 (s, 1H), 4.69 (s, 1H), 7.34 (d, J = 8.6 Hz, 2H), 7.73
(d, J = 8.6 Hz, 2H. 13C NMR (50 MHz, CDCl3): δ = 21.1 (CH2), 21.9
(CH3), 22.4 (CH3), 36.8 (CH2), 43.9 (CH2), 67.2 (CH2), 11.0 (CH2),
128.5 (2CH), 130.2 (2CH), 136.0 (C), 144.9 (C), 145.7 (C), 198.5
(C). HRMS (ESI): calcd for C15H20O3NaS 303.1025, found 303.1020.
NaBH4 (35 mg, 0.92 mmol) was added to a solution of keto sulfone
23 (216 mg, 077 mmol) in MeOH (3.8 mL), and the mixture was
stirred under argon atmosphere at rt for 15 min. It was then quenched
with acetone and stirred, and all solvents were removed at reduced
pressure to yield a residue that was diluted in Et2O and brine. The
aqueous phase was extracted with Et2O, the combined organic layers
washed with brine and dried over anhydrous Na2SO4, and solvent was
removed under reduced pressure, affording a residue identified as
hydroxy sulfone 24 (211 mg, 97%). IR: ν = 3500, 2923, 1651, 1599,
1
1307, 1145, 1080 cm−1. H NMR (200 MHz, CDCl3): δ = 1.42 (m,
4H), 1.61 (s, 3H), 1.91 (t, J = 6.6 Hz, 2H), 2.39 (s, 3H), 3.16 (m, 2H),
3.29 (br s, 1H), 4.09 (m, 1H), 4.55 (s, 1H), 4.61 (s, 1H), 7.32 (d, J =
7.8 Hz, 2H), 7.65 (d, J = 8.2 Hz, 2H. 13C NMR (50 MHz, CDCl3): δ =
21.9 (CH3), 22.4 (CH3), 23.0 (CH2), 36.2 (CH2), 37.5 (CH2), 62.5
(CH2), 65.9 (CH), 110.5 (CH2), 128.1 (2CH), 130.3 (2CH), 136.5
(C), 145.3 (C), 145.4 (C). HRMS (ESI): calcd for C15H22O3NaS
305.1182, found 305.1167. To a solution of 24 (211 mg, 0.75 mmol)
in CH2Cl2 (3.6 mL) at 0 °C were added Et3N (248 μL, 1.79 mmol)
and MsCl (69 μL, 0.89 mmol), and the new mixture was stirred at this
temperature under argon atmosphere for 30 min. After this time, more
Et3N (207 μL, 1.50 mmol) was added and stirring maintained at 0 °C
for 3 h, when the reaction was quenched by addition of an aqueous
saturated solution of NaHCO3 and stirred for a further 20 min. The
aqueous phase was extracted with CH2Cl2, a the combined organic
layers were washed with a 2 M aqueous solution of HCl, water, and
brine and dried over anhydrous Na2SO4, and solvent was removed
under reduced pressure to yield 25 (191 mg, 97%). IR: ν = 2974,
2929, 2858, 1638, 1592, 1450, 1320, 1145, 1093 cm−1. 1H NMR (200
MHz, CDCl3): δ = 1.59 (t, J = 7.4 Hz, 2H), 1.68 (s, 3H), 2.01 (t, J =
7.8 Hz, 2H), 2.22 (q, J = 7.4 Hz, 2H), 2.44 (s, 3H), 4.62 (s, 1H), 4.71
(s, 1H), 6.30 (d, J = 15.2 Hz, 1H), 6.94 (m, 1H), 7.33 (d, J = 7.8 Hz,
2H), 7.76 (d, J = 7.8 Hz, 2H. 13C NMR (50 MHz, CDCl3): δ = 21.8
(CH3), 22.4 (CH3), 25.6 (CH2), 31.1 (CH2), 37.1 (CH2), 110.9
(CH2), 127.8 (2CH), 130.1 (2CH), 131.1 (CH), 138.9 (C), 144.4
(C), 144.8 (C), 146.5 (CH). HRMS (ESI): calcd for C15H20O2NaS
287.1076, found 287.1085. A mixture of 25 (191 mg, 0.72 mmol),
NaHCO3 (73 mg, 0.87 mmol), and m-CPBA (137 mg, 0.79 mmol) in
CH2Cl2 (3.6 mL) was stirred at rt for 90 min and then was quenched
with a 10% aqueous solution of Na2S2O3. The new mixture was further
stirred for 30 min, the aqueous layer was extracted with CH2Cl2, the
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The Journal of Organic Chemistry
Article
combined organic extracts were washed with a saturated aqueous
solution of NaHCO3 and brine and dried over anhydrous Na2SO4, and
the solvent was removed under reduced pressure. Purification of the
residue by flash chromatography over silica gel (Hex/AcOEt 8:2)
afforded epoxyvinylsulfone 1 (184 mg, 91%). IR: ν = 3513, 3046,
acetate 28 (6.5 g, 57.0 mmol), in THF (88.0 mL) at 0 °C, were added
triphenylphosphine (1.34 g, 5.13 mmol) andPd(PPh3)4 (132 mg,
0.114 mmol), and this mixture was refluxed under argon atmosphere
for 1 h. In the meantime, diethyl malonate (30.3 mL, 199.5 mmol) was
slowly added to a suspension of 60% NaH (8.7 g, 182.4 mmol) in
anhydrous THF (250 mL), under argon atmosphere at 0 °C, and the
mixture was stirred at room temperature until complete formation of
the anion (ca. 30 min). Once both solutions (Suzuki’s reagent and
malonate anion) were prepared, the malonate anion was slowly added
over the Suzuki’s reagent solution, avoiding both air and moisture, and
the new mixture was refluxed for 24 h and then allowed to reach rt. In
that moment, a 2 M aqueous solution of HCl was added, and the
aqueous layer was extracted with AcOEt. The mixture of organic
extracts was washed with an aqueous saturated solution of Na2CO3
and brine and dried over anhydrous Na2SO4, and the solvent was
distilled away, yielding 40.5 g of a mixture of diethyl malonate and the
diester intermediate, which was used without further purification in the
next step. In that step, the mixture (40.5 g) was dissolved in DMSO
(100.0 mL), and anhydrous NaCl (40.7 g, 696 mmol) and water (12.5
mL, 696 mmol) were added. The reaction vessel was next stirred at
180−200 °C for 48 h. After this time, the mixture was cooled to rt,
diluted in AcOEt, subsequently washed several times with water and
brine, and dried over anhydrous Na2SO4. Solvent was then carefully
removed by distillation, and monoester 29 (8.1 g, 99%) was afforded.
IR: ν = 2929, 2851, 1741, 1450, 1378, 1170, 1028, 891 cm−1. 1H NMR
(200 MHz, CDCl3): δ = 1.23 (t, J = 7.4 Hz, 3H), 1.72 (s, 3H), 2.39
(m, 4H), 4.11 (q, J = 7.0 Hz, 2H), 4.66 (s, 1H), 4.72 (s, 1H). 13C
NMR (50 MHz, CDCl3): δ = 14.4 (CH3), 22.7 (CH3), 32.8 (CH2),
32.9 (CH2), 60.5 (CH2), 110.5 (CH2), 144.3 (C), 173.5 (C). A
solution of 29 (3.0 g, 21.1 mmol) in dry Et2O (21.0 mL) under argon
atmosphere was stirred at 0 °C while a LiAlH4 (1.6 g. 42.2 mmol) was
added portionwise. The reaction was vigorously stirred at rt for 1 h 30
min. Then 1.54 mL of water was added dropwise, followed by 1.54 mL
of a 15% aqueous solution of NaOH, 5 min stirring, another 2.5 mL of
water, and a final 15 min stirring. The reaction was then filtered under
reduced pressure through a fritted glass funnel, the solid washed with
Et2O, and the filtrate dried over anhydrous Na2SO4. After removal of
the solvent under reduced pressure, the residue obtained was identified
1
2936, 2877, 1716, 1632, 1599, 1463, 1320, 1152, 1087, 808 cm−1. H
NMR (200 MHz, CDCl3): δ = 1.24 (s, 3H), 1.51 (m, 4H), 2.21 (m,
2H), 2.38 (s, 3H), 2.52 (s, 2H), 6.28 (d, J = 15.8 Hz, 1H), 6.89 (dt, J1
= 6.8 Hz, J2 = 15.2 Hz, 1H), 7.28 (d, J = 7.8 Hz, 2H), 7.70 (d, J = 8.2
Hz, 2H. 13C NMR (50 MHz, CDCl3): δ = 21.0 (CH3), 21.8 (CH3),
23.4 (CH2), 31.4 (CH2), 36.0 (CH2), 53.9 (CH2), 56.7 (C), 127.8
(2CH), 130.1 (2CH), 131.3 (CH), 137.8 (C), 144.5 (C), 145.9 (CH).
HRMS (ESI): calcd for C15H20O3NaS 303.1025, found 303.1022.
Compounds 3a/b. A 2 M solution of BuLi in cyclohexane (2.4 mL,
4.75 mmol) was added dropwise to a solution of the trimethylsilyl
derivative 2617 (1.09 g, 6.41 mmol) in completely anhydrous and
deoxygenated DME (23.0 mL) at −70 °C, and the resultant mixture
was stirred under argon atmosphere at −70 °C for 30 min. At this
point, a previously prepared deoxygenated solution of 6-methyl-5-
hepten-2-one (300 mg, 2.38 mmol) in anhydrous DME (2.4 mL) was
carefully added dropwise to the mixture, and once the addition was
finished the reaction was allowed to reach rt (ca. 10 min) and then
quenched with a saturated aqueous solution of NH4Cl. The new
mixture was then stirred for a further 15 min, the layers were
separated, and the aqueous phase was extracted with CH2Cl2. The
combined organic layers were washed with brine and dried over
anhydrous Na2SO4, and solvent removed at reduced pressure. The
crude product was purified by flash chromatography (Hex/AcOEt 9:1)
1
to yield 27a*/b† (543 mg, 86%) as a mixture of E/Z isomers. H
NMR (200 MHz, CDCl3): δ = 1.50 (s, 6H), 1.60 (s, 6H), 1.64† (s,
3H), 1.86* (s, 3H), 2.11 (m, 8H), 4.93* (m, 1H), 5.03† (m, 1H), 6.15
(s, 2H), 7.54 (m, 6H), 7.89 (m, 4H. 13C NMR (50 MHz, CDCl3): δ =
17.9† (CH3), 18.1* (CH3), 25.7 (2CH2), 25.8 (4CH3), 40.6* (CH2),
48.6† (CH2), 122.3† (CH), 126.3* (CH), 126.9* (3CH), 127.2†
(2CH), 127.3† (CH), 129.3 (4CH), 133.1* (CH), 133.2† (CH), 133.4
(2C), 142.7* (C), 143.9† (C), 157.7 (2C). A mixture of 27a/b (932
mg, 3.53 mmol), NaHCO3 (415 mg, 4.94 mmol), and m-CPBA (731
mg, 4.24 mmol) in CH2Cl2 (18.0 mL) was stirred at rt for 14 h and
then was quenched with a 10% aqueous solution of Na2S2O3. The new
mixture was further stirred for 30 min, the aqueous layer was extracted
with CH2Cl2, the combined organic extracts were washed with a
saturated aqueous solution of NaHCO3 and brine and dried over
anhydrous Na2SO4, and the solvent was removed under reduced
pressure. Purification of the residue by flash chromatography over
silica gel (Hex/Et2O 8:2) afforded epoxyvinylsulfones 3a*/b† (880
mg, 89%) as a mixture of E/Z isomers in which the E isomer (3a) was
clearly favored. IR: ν = 3519, 2974, 2929, 1625, 1456, 1307, 1151,
1086 cm−1. 1H NMR (200 MHz, CDCl3): δ = 1.14* (s, 3H), 1.17* (s,
3H), 1.19† (s, 3H), 1.23† (s, 3H), 1.60 (m, 4H), 1.83† (s, 3H), 2.08*
(s, 3H), 2.24 (m, 4H), 2.54* (t, J = 6.8 Hz, 1H), 2.67† (t, J = 6.0 Hz,
1H), 6.12† (s, 1H), 6.16* (s, 1H), 7.48 (m, 6H), 7.83 (m, 4H. 13C
NMR (50 MHz, CDCl3): δ = 18.0* (CH3), 18.9 (2CH3), 24.9
(2CH3), 25.0† (CH3), 26.8* (CH2), 27.8† (CH2), 29.6† (CH2), 37.4*
(CH2), 58.7 (2C), 63.2* (CH), 63.7† (CH), 126.7* (CH), 126.9†
(CH), 127.2 (4CH), 129.4 (4CH), 133.3 (2CH), 142.4 (2C), 156.7
(2C). HRMS (ESI): calcd for C15H20O3NaS 303.1025, found
303.1026.
1
as alcohol 30 (2.0 g, 95%). IR: ν = 3396, 2929, 2851, 1352 cm−1. H
NMR (200 MHz, CDCl3): δ = 1.72 (m, 3H), 1.74 (s, 3H), 2.09 (t, J =
8.2 Hz, 2H), 3.65 (t, J = 6.2 Hz, 2H), 4.72 (s, 1H). 13C NMR (50
MHz, CDCl3): δ = 22.6 (CH3), 30.7 (CH2), 34.3 (CH2), 62.9 (CH2),
110.4 (CH2), 145.7 (C). HRMS (ESI): calcd for C6H13O 101.0961,
found 101.0955. To a 0 °C solution of 30 (1.4 g, 14.0 mmol) in
CH2Cl2 (4.7 mL) were added Et3N (3.9 mL, 28.0 mmol) and MsCl
(1.8 mL, 22.4 mmol), and the new mixture was stirred at this
temperature under argon atmosphere for 2 h 15 min when the reaction
was quenched by addition of water and stirred for further 10 min. The
aqueous phase was then extracted with Et2O, the combined organic
layers were washed with a 2 M aqueous solution of HCl, an aqueous
saturated solution of NaHCO3, and brine, and dried over anhydrous
Na2SO4, and solvent was removed under reduced pressure to yield
1
mesylate 31 (1.8 g, 74%). H NMR (200 MHz, CDCl3): δ = 1.72 (s,
3H), 1.87 (m, 2H), 2.12 (t, J = 7.8 Hz, 2H), 2.99 (s, 3H), 4.21 (t, J =
6.4 Hz, 2H), 4.70 (s, 1H), 4.76 (s, 1H). 13C NMR (50 MHz, CDCl3):
δ = 22.5 (CH3), 27.1 (CH2), 33.6 (CH2), 37.5 (CH3), 69.8 (CH2),
111.3 (CH2), 143.9 (C). HRMS (ESI): calcd for C7H14O3NaS
201.0556, found 201.0561. To a 0 °C suspension of 50% NaH (687
mg, 14.31 mmol) in THF (22.0 mL) under argon atmosphere was
slowly diethyl malonate (2.3 mL, 15.3 mmol), and the mixture was
stirred at room temperature until the complete formation of the anion
(ca. 30 min). A solution of mesylate 31 (1.8 g, 10.2 mmol) in THF
(3.4 mL) was then added dropwise and the new mixture refluxed for
12 h, when it was cooled to rt, quenched with a 2 M aqueous solution
of HCl, and stirred for 10 min. The aqueous layer was extracted with
Et2O, the mixture of organic extracts was washed with water and brine
and dried over anhydrous Na2SO4, and the solvent was removed under
reduced pressure, yielding 3.9 g of a mixture of diethyl malonate and
the diester intermediate, which was used without further purification in
the next step. In that step, the mixture (3.9 g) was dissolved in DMSO
Compound 5. To a solution of 2-methyl-2-propen-1-ol (5.0 g, 69.3
mmol) in pyridine (11.2 mL, 138.6 mmol) were added Ac2O (9.8 mL,
103.9 mmol) and a catalytic amount of DMAP. The mixture was
stirred at rt for 1 h 15 min, quenched with water, and further stirred
for another 30 min. The aqueous phase was extracted with Et2O, and
the combined organic layers were subsequently washed with a 2 M
aqueous solution of HCl, a 5% aqueous solution of NaHCO3 and
brine and and dried over anhydrous Na2SO4. Elimination of the
solvent by careful distillation of the mixture with a Vigreux column
afforded allyl acetate 28 (6.5 g, 82%). 1H NMR (200 MHz, CDCl3): δ
= 1.72 (s, 3H), 2.05 (s, 3H), 4.45 (s, 2H), 4.88 (s, 1H), 4.93 (s, 1H).
13C NMR (50 MHz, CDCl3): δ = 19.7 (CH3), 21.1 (CH3), 67.9
(CH2), 113.1 (CH2), 140.1 (C), 170.9 (C). To a flask with allyl
4387
DOI: 10.1021/acs.joc.5b00206
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The Journal of Organic Chemistry
Article
(28.7 mL) and anhydrous NaCl (3.4 g, 58.5 mmol) and water (1.0
mL, 57.96 mmol) were added. The reaction vessel was next stirred at
180−200 °C for 19 h. After this time, the mixture was cooled to rt,
diluted in AcOEt, subsequently washed several times with water and
brine, and dried over anhydrous Na2SO4. Solvent was then removed
by careful distillation, yielding the monoester 32 (1.7 g, 98%). IR: ν =
3085, 2870, 1741, 1644, 1456, 1372, 1190, 1034 cm−1. 1H NMR (200
MHz, CDCl3): δ = 1.20 (t, J = 7.0 Hz, 3H), 1.3−1.7 (m, 4H), 1.67 (s,
3H), 1.99 (t, J = 7.0 Hz, 2H), 2.27 (t, J = 7.8 Hz, 2H), 4.09 (m, 2H),
4.63 (s, 1H), 4.66 (s, 1H). 13C NMR (50 MHz, CDCl3): δ = 14.4
(CH3), 22.5 (CH3), 24.7 (CH2), 27.2 (CH2), 34.4 (CH2), 37.6 (CH2),
60.4 (CH2), 110.2 (CH2), 145.6 (C), 173.9 (C). A 2 M solution of
BuLi in cyclohexane (6.5 mL, 11.76 mmol) was added dropwise to a 0
°C solution of 4-(methylsulfonyl)toluene (1.0 g, 5.88 mmol) in
anhydrous THF (21.0 mL), and the new mixture was stirred at this
temperature for 30 min. After this time, the mixture was cooled to −78
°C, and a solution of ester 32 (1.00 mg, 5.88 mmol) in DMPU (21.0
mL) was slowly added. This new mixture was stirred at −78 °C for 14
h, quenched with a saturated aqueous solution of NH4Cl, and slowly
allowed to reach rt. The aqueous phase was extracted with AcOEt, and
the combined organic layers were subsequently washed with a 2 M
aqueous solution of HCl, a saturated aqueous solution of NaHCO3,
and brine and dried over anhydrous Na2SO4. Finally, solvent was
removed under reduced pressure, and the residue was purified by flash
chromatography over silica gel (Hex/AcOEt 8:2 to Hex/AcOEt 7:3)
to afford 32 (177 mg) followed by keto sulfone 33 (755 mg, 44%). IR:
and then was quenched with a 10% aqueous solution of Na2S2O3. The
new mixture was further stirred for 30 min, the aqueous layer was
extracted with CH2Cl2, the combined organic extracts were washed
with a saturated aqueous solution of NaHCO3 and brine and dried
over anhydrous Na2SO4, and the solvent was removed under reduced
pressure. Purification of the residue by flash chromatography over
silica gel (Hex/AcOEt 8:2 to Hex/AcOEt 1:1) afforded epoxyvinyl-
sulfone 5 (193 mg, 91%). IR: ν = 3513, 3052, 2929, 2864, 1729, 1638,
1599, 1450, 1326, 1145, 1093 cm−1. 1H NMR (200 MHz, CDCl3): δ =
1.24 (s, 3H), 1.44 (m, 6H), 2.21 (q, J = 7.0 Hz, 2H), 2.40 (s, 3H), 2.53
(s, 2H), 6.28 (d, J = 14.8 Hz, 1H), 6.91 (dt, J1 = 6.6 Hz, J2 = 14.0 Hz,
1H), 7.29 (d, J = 8.2 Hz, 2H), 7.72 (d, J = 8.2 Hz, 2H. 13C NMR (50
MHz, CDCl3): δ = 21.0 (CH3), 21.8 (CH3), 24.8 (CH2), 27.8 (CH2),
31.6 (CH2), 36.5 (CH2), 54.0 (CH2), 56.9 (C), 127.8 (2CH), 130.1
(2CH), 131.1 (CH), 137.9 (C), 144.5 (C), 146.3 (CH). HRMS (ESI):
calcd for C16H22O3NaS 317.1182; found 317.1176.
Compound 7. A 2 M solution of BuLi in cyclohexane (2.4 mL, 4.75
mmol) was added dropwise to a solution of the trimethylsilyl
derivative 2617 (1.08 g, 4.75 mmol) in completely anhydrous and
deoxygenated DME (23.7 mL) at −70 °C, and the resultant mixture
was stirred under argon atmosphere at −70 °C for 30 min. At this
point, a previously prepared deoxygenated solution of 6-methyl-5-
hepten-2-one (300 mg, 2.38 mmol) in anhydrous DME (2.4 mL) was
carefully added dropwise to the mixture, and once the addition was
finished the reaction was allowed to reach rt for 48 h and then
quenched with a saturated aqueous solution of NH4Cl. The new
mixture was then stirred for further 15 min, the layers were separated,
and the aqueous phase was extracted with CH2Cl2. The combined
organic layers were washed with brine and dried over anhydrous
Na2SO4, and solvent was removed at reduced pressure. The crude
product was purified by flash chromatography (Hex/AcOEt 9:1) to
1
ν = 2929, 2864, 1729, 1657, 1599, 1333, 1151, 1086 cm−1. H NMR
(200 MHz, CDCl3): δ = 1.2−1.4 (m, 4H), 1.67 (s, 3H), 1.97 (t, J = 7.0
Hz, 2H), 2.42 (s, 3H), 2.68 (t, J = 7.0 Hz, 2H), 4.11 (s, 2H), 4.63 (s,
1H), 4.67 (s, 1H), 7.33 (d, J = 7.8 Hz, 2H), 7.72 (d, J = 8.2 Hz, 2H.
13C NMR (50 MHz, CDCl3): δ = 21.9 (CH3), 22.5 (CH3), 22.9
(CH2), 26.8 (CH2), 37.6 (CH2), 44.4 (CH2), 67.2 (CH2), 110.4
(CH2), 128.5 (2CH), 130.2 (2CH), 135.9 (C), 145.6 (C), 145.7 (C),
198.6 (C). HRMS (ESI): calcd for C16H22O3NaS 317.1182, found
317.1178. NaBH4 (44 mg, 1.16 mmol) was added to a solution of keto
sulfone 33 (285 mg, 0.96 mmol) in MeOH (4.8 mL), and the mixture
was stirred under argon atmosphere at rt for 4 h. It was then quenched
with acetone and stirred, and all solvents were removed at reduced
pressure, yielding a residue that was diluted in Et2O and brine. The
aqueous phase was extracted with Et2O, the combined organic layers
washed with brine, dried over anhydrous Na2SO4, and solvent was
removed under reduced pressure, affording a residue identified as
hydroxy sulfone 34 (275 mg, 96%). IR: ν = 3500, 2935, 2858, 1294,
1151 cm−1. 1H NMR (200 MHz, CDCl3): δ = 1.2−1.6 (m, 7H), 1.66
(s, 3H), 2.03 (m, 2H), 2.45 (s, 3H), 3.18 (m, 2H), 4.12 (m, 1H), 4.71
(s, 1H), 4.66 (s, 1H), 7.37 (d, J = 8.6 Hz, 2H), 7.79 (d, J = 8.2 Hz, 2H.
13C NMR (50 MHz, CDCl3): δ = 21.9 (CH3), 22.5 (CH3), 24.8
(CH2), 27.4 (CH2), 36.5 (CH2), 37.8 (CH2), 62.5 (CH2), 66.1 (CH),
110.2 (CH2), 128.2 (2CH), 130.3 (2CH), 136.4 (C), 145.4 (C), 145.9
(C). HRMS (ESI): calcd for C16H24O3NaS 319.1338, found 319.1339.
To a 0 °C solution of 34 (275 mg, 0.93 mmol) in CH2Cl2 (4.4 mL)
were added Et3N (180 μL, 1.30 mmol) and MsCl (86 μL, 1.11 mmol),
and the new mixture was stirred at this temperature under argon
atmosphere for 30 min. After this time, more Et3N (257 μL, 1.86
mmol) was added and stirring maintained at 0 °C for 3 h, when the
reaction was quenched by addition of an aqueous saturated solution of
NaHCO3 and stirred for further 20 min. The aqueous phase was
extracted with CH2Cl2, the combined organic layers were washed with
a 2 M aqueous solution of HCl, water and brine, and dried over
anhydrous Na2SO4, and solvent was removed under reduced pressure
to yield 35 (223 mg, 86%). 1H NMR (200 MHz, CDCl3): δ = 1.41 (m,
4H), 1.64 (s, 3H), 1.96 (t, J = 6.4 Hz, 2H), 2.21 (m, 2H), 2.39 (s, 3H),
4.60 (s, 1H), 4.66 (s, 1H), 6.28 (d, J = 14.4 Hz, 1H), 6.91 (m, 1H),
7.29 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.2 Hz, 2H. 13C NMR (50 MHz,
CDCl3): δ = 21.8 (CH3), 22.5 (CH3), 27.1 (CH2), 27.3 (CH2), 31.5
(CH2), 37.5 (CH2), 110.4 (CH2), 127.8 (2CH), 130.1 (2CH), 130.9
(CH), 137.9 (C), 144.4 (C), 145.5 (C), 146.7 (CH). HRMS (ESI):
calcd for C16H22O2NaS 301.1233, found 301.1221. A mixture of 35
(400 mg, 1.44 mmol), NaHCO3 (145 mg, 0.73 mmol), and m-CPBA
(273 mg, 1.58 mmol) in CH2Cl2 (7.2 mL) was stirred at rt for 19 h,
1
yield 36 (505 mg, 80%). H NMR (200 MHz, CDCl3): δ = 1.55 (s,
3H), 1.61 (s, 3H), 2.08 (m, 4H), 3.75 (s, 2H), 4.74 (s, 1H), 4.96 (m,
1H), 5.00 (s, 1H), 7.54 (m, 3H), 7.83 (m, 2H). A mixture of
allylsulfone 36 (505 mg, 1.91 mmol), NaHCO3 (225 mg, 2.68 mmol),
and m-CPBA (396 mg, 2.29 mmol) in CH2Cl2 (9.6 mL) was stirred at
rt for 12 h and then was quenched with a 10% aqueous solution of
Na2S2O3. The new mixture was further stirred for 30 min, the aqueous
layer was extracted with CH2Cl2, the combined organic extracts were
washed with a saturated aqueous solution of NaHCO3 and brine and
dried over anhydrous Na2SO4, and the solvent was removed under
reduced pressure. Purification of the residue by flash chromatography
over silica gel (Hex/Et2O 8:2) afforded epoxy sulfone 7 (410 mg,
1
76%). H NMR (200 MHz, CDCl3): δ = 1.21 (s, 3H); 1.25 (s, 3H),
1.67 (m, 2H), 2.30 (t, J = 7.4 Hz, 1H), 2.66 (m, 2H), 3.77 (s, 2H),
4.78 (s, 1H), 5.05 (s, 1H), 7.54 (m, 3H), 7.85 (m, 2H. 13C NMR (50
MHz, CDCl3): δ = 18.9 (CH3), 25.0 (CH3), 27.1 (CH2), 32.7 (CH2),
58.5 (C), 63.1 (CH2), 63.7 (CH), 120.4 (CH2), 128.7 (2CH), 129.3
(2CH), 133.9 (CH), 136.7 (C), 138.5 (C).
Compound 9. A 2 M solution of BuLi in cyclohexane (6.5 mL,
13.03 mmol) was added dropwise to a 0 °C solution of 4-
(methylsulfonyl)toluene (1.1 g, 7.04 mmol) in anhydrous THF
(23.2 mL), and the new mixture was stirred at this temperature for 30
min. After this time, the mixture was cooled to −78 °C, and a solution
of ester 29 (925 mg, 6.51 mmol) in DMPU (16.3 mL) was slowly
added. This new mixture was stirred at −78 °C for 17 h, quenched
with a saturated aqueous solution of NH4Cl, and slowly allowed to
reach rt. The aqueous phase was extracted with AcOEt, and the
combined organic layers were subsequently washed with a 2 M
aqueous solution of HCl, a saturated aqueous solution of NaHCO3
and brine, and dried over anhydrous Na2SO4. Finally, solvent was
removed under reduced pressure, and the residue was purified by flash
chromatography over silica gel (Hex/AcOEt 7:3 to Hex/AcOEt 1:1)
to afford 29 (108 mg) followed by 37 (1.03 g, 59%). IR: ν = 2922,
1722, 1450, 1320, 1145, 1086 cm−1. 1H NMR (200 MHz, CDCl3): δ =
1.68 (s, 3H), 2.23 (t, J = 7.4 Hz, 2H), 2.42 (s, 3H), 2.81 (t, J = 7.4 Hz,
2H), 4.14 (s, 2H), 4.62 (s, 1H), 4.71 (s, 1H), 7.33 (d, J = 8.6 Hz, 2H),
7.73 (d, J = 8.2 Hz, 2H. 13C NMR (50 MHz, CDCl3): δ = 21.9 (CH3),
22.8 (CH3), 31.0 (CH2), 42.7 (CH2), 67.2 (CH2), 110.9 (CH2), 128.5
(2CH), 130.2 (2CH), 135.9 (C), 143.8 (C), 145.7 (C), 198.0 (C).
4388
DOI: 10.1021/acs.joc.5b00206
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Article
HRMS (ESI): calcd for C14H18O3NaS 289.0869, found 289.0871.
NaBH4 (176 mg, 4.64 mmol) was added to a solution of keto sulfone
37 (1.03 g, 3.87 mmol) in MeOH (19.0 mL), and the mixture was
stirred under argon atmosphere at rt for 45 min. It was then quenched
with acetone and stirred, and all solvents were removed at reduced
pressure, yielding a residue that was diluted in Et2O and brine. The
aqueous phase was extracted with Et2O, the combined organic layers
were washed with brine and dried over anhydrous Na2SO4, and solvent
was removed under reduced pressure, affording a residue identified as
hydroxy sulfone 38 (1.01 g, 97%). IR: ν = 3506, 2916, 2858, 1605,
NMR that the reduction was successful, an aliquot of the mixture was
withdrawn and solvent carefully evaporated without heating. Once the
formation of 41 was so verified, the mixture of product and solvent
was used in the next reaction assuming a 100% yield had been reached.
All different procedures tried led either to evaporation and/or
1
decomposition of aldehyde 41. H NMR (200 MHz, CDCl3): δ =
1.75 (s, 3H), 2.34 (m, 2H), 2.58 (m, 2H), 4.69 (s, 1H), 4.77 (s, 1H),
9.78 (s, 1H). Thiophenol (324 μL, 3.15 mmol) and piperidine (31 μL,
0.315 mmol) were added to a flask containing a 0 °C stirred solution
of 41 (309 mg, 3.15 mmol) and methyl phenylsulfonyl acetate (608
mg, 2.84 mmol) in CH3CN (6.3 mL), and the new mixture was stirred
at the same temperature under argon atmosphere for 23 h. After this
time, the mixture was dried under reduced pressure, and the residue
was purified by flash chromatography over silica gel (Hex/AcOEt 9:1
to Hex/AcOEt 7:3) to afford 42a*/b† as a mixture of isomers (635
mg, 50% two steps). IR: ν = 3072, 2948, 2858, 1748, 1450, 1333, 1158,
1
1287, 1132, 1093 cm−1. H NMR (200 MHz, CDCl3): δ = 1.50 (m,
2H), 1.59 (s, 3H), 1.98 (m, 2H), 2.36 (s, 3H), 3.14 (br s, 2H), 3.50
(br s, 1H), 4.06 (br s, 1H), 4.53 (s, 1H), 4.59 (s, 1H), 7.29 (d, J = 7.4
Hz, 2H), 7.73 (d, J = 7.0 Hz, 2H. 13C NMR (50 MHz, CDCl3): δ =
21.8 (CH3), 22.6 (CH3), 33.3 (CH2), 34.6 (CH2), 62.5 (CH2), 65.9
(CH), 110.7 (CH2), 128.1 (2CH), 130.2 (2CH), 136.6 (C), 144.8
(C), 145.3 (C). HRMS (ESI): calcd for C14H20O3NaS 291.1025,
found 291.1024. To a solution of 38 (591 mg, 2.20 mmol) in CH2Cl2
(10.5 mL) at 0 °C were added Et3N (427 μL, 3.09 mmol) and MsCl
(205 μL, 2.64 mmol), and the new mixture was stirred at this
temperature under argon atmosphere for 30 min. After this time, more
Et3N (610 μL, 4.41 mmol) was added and stirring maintained at 0 °C
for 1 h 45 min, when the reaction was quenched by addition of an
aqueous saturated solution of NaHCO3 and stirred for further 20 min.
The aqueous phase was extracted with CH2Cl2, the combined organic
layers were washed with a 2 M aqueous solution of HCl, water, and
brine, and dried over anhydrous Na2SO4, and solvent was removed
under reduced pressure to yield 39 (534 mg, 97%). IR: ν = 3078,
1
1093, 904 cm−1. H NMR (200 MHz, CDCl3): δ = 1.67 (m, 4H),
1.75* (s, 3H), 1.80† (s, 3H), 2.37 (m, 4H), 3.40* (s, 3H), 3.61† (m,
1H), 3.66* (m, 1H), 3.70† (s, 3H), 4.18 (m, 2H), 4.73* (s, 1H), 4.77
(s, 2H), 4.81† (s, 1H), 7.2−7.8 (m, 20H. 13C NMR (50 MHz, CDCl3):
δ = 22.4† (CH3), 22.7* (CH3), 27.6† (CH2), 29.3* (CH2), 34.6†
(CH2), 35.6* (CH2), 46.1† (CH), 47.5* (CH), 52.9* (CH3), 53.1†
(CH3), 72.3† (CH), 76.1* (CH), 111.5* (CH2), 111.9† (CH2), 128.9
(2CH), 129.3 (8CH), 129.41 (2CH), 129.44 (2CH), 129.6 (2CH),
131.3† (C), 132.9 (2CH), 133.1* (C), 134.8 (2CH), 138.3 (2C),
144.4* (C), 144.6† (C), 164.6† (C), 165.8* (C). HRMS (ESI): calcd
for C21H24O4NaS2 427.1008, found 427.1001. To a solution of 42a/b
(2.3 g, 5.7 mmol) in a 1:1 CH2Cl2/water biphasic mixture (20.0 mL)
were added Oxone (7.0 g, 11.4 mmol) and tetrabutylammonium
bromide (175 mg, 1.13 mmol) , and the reaction was vigorously stirred
for 5 days. The reaction was then filtered under reduced pressure
through a fritted glass funnel, the solid washed with CH2Cl2, and the
filtrate aqueous phase extracted with CH2Cl2. The mixture of organic
extracts was washed with brine and dried over anhydrous Na2SO4, the
solvent was removed under reduced pressure, and the residue was
purified by flash chromatography over silica gel (Hex/AcOEt 7:3) to
afford sulfonyl ester 14a*/b† as a mixture of isomers (1.4 g, 80%). 1H
NMR (200 MHz, CDCl3): δ = 1.69* (s, 3H), 1.74† (s, 3H), 2.24 (t, J
= 7.4 Hz, 4H), 2.76* (q, J = 7.4 Hz, 2H), 3.12† (q, J = 7.4 Hz, 2H),
3.65† (s, 3H), 3.68* (s, 3H), 4.68* (s, 1H), 4.72† (s, 1H), 4.76* (br s,
1H), 4.77† (br s, 1H), 7.49 (,m 8H), 7.92 (m, 4H. 13C NMR (50 MHz,
CDCl3): δ = 22.4* (CH3), 22.5† (CH3), 27.2† (CH2), 28.3* (CH2),
36.2* (CH2), 36.6† (CH2), 52.6* (CH), 52.9† (CH), 111.8* (CH2),
111.9† (CH2), 128.3† (2CH), 128.6* (2CH), 129.0* (2CH), 129.1†
(2CH), 133.6* (CH), 133.8† (CH), 134.9† (C), 135.8* (C), 140.3*
(C), 141.3† (C), 143.7* (C), 143.8† (C), 156,5* (CH), 158.3† (CH),
162.1* (C), 162.7† (C). HRMS (ESI): calcd for C15H18O4NaS
317.0818, found 317.0824. A mixture of alkene 14a/b (300 mg, 1.02
mmol), NaHCO3 (146 mg, 1.73 mmol), and m-CPBA (264 mg, 1.53
mmol) in CH2Cl2 (10.0 mL) was stirred at rt for 3 h and then was
quenched with a 10% aqueous solution of Na2S2O3. The new mixture
was further stirred for 30 min, the aqueous layer was extracted with
CH2Cl2, the combined organic extracts were washed with a saturated
aqueous solution of NaHCO3 and brine and dried over anhydrous
Na2SO4, and the solvent was removed under reduced pressure.
Purification of the residue by flash chromatography over silica gel
(Hex/AcOEt 7:3) afforded the mixture of isomers 11a*/b† (222 mg,
1
2929, 2864, 1651, 1599, 1456, 1320, 1151, 1086, 820 cm−1. H NMR
(200 MHz, CDCl3): δ = 1.63 (s, 3H), 2.09 (t, J = 7.6 Hz, 2H), 2.29
(m, 2H), 2.36 (s, 3H), 4.60 (s, 1H), 4.68 (s, 1H), 6.28 (s, J = 15.2 Hz,
1H), 6.89 (m, 1H), 7.26 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 8.2 Hz, 2H.
13C NMR (50 MHz, CDCl3): δ = 21.8 (CH3), 22.5 (CH3), 29.6
(CH2), 36.7 (CH2), 111.5 (CH2), 127.8 (2CH), 130.1 (2CH), 131.1
(CH), 137.9 (C), 143.7 (C), 144.4 (C), 146.1 (CH). HRMS (ESI):
calcd for C14H18O2NaS 273.0920, found 273.0917. A mixture of 39
(200 mg, 0.84 mmol), NaHCO3 (81 mg, 0.96 mmol), and m-CPBA
(152 mg, 0.88 mmol) in CH2Cl2 (4.0 mL) was stirred at rt for 2 h and
then was quenched with a 10% aqueous solution of Na2S2O3. The new
mixture was further stirred for 30 min and the aqueous layer extracted
with CH2Cl2, the combined organic extracts washed with a saturated
aqueous solution of NaHCO3 and brine, and dried over anhydrous
Na2SO4, and the solvent removed under reduced pressure. Purification
of the residue by flash chromatography over silica gel (Hex/AcOEt
8:2) afforded epoxyvinylsulfone 9 (159 mg, 75%). IR: ν = 3052, 2929,
1
2864, 1638, 1592, 1456, 1313, 1287, 1158, 1086, 820 cm−1. H NMR
(200 MHz, CDCl3): δ = 1.25 (s, 3H), 1.67 (m, 2H), 2.28 (m, 2H),
2.39 (s, 3H), 2.53 (s, 2H), 6.29 (d, J = 14.8 Hz, 1H), 6.89 (dt, J1 = 6.6
Hz, J2 = 14.8 Hz, 1H), 7.29 (d, J = 8.6 Hz, 2H), 7.71 (d, J = 8.2 Hz,
2H. 13C NMR (50 MHz, CDCl3): δ = 21.1 (CH3), 21.8 (CH3), 27.2
(CH2), 34.6 (CH2), 53.9 (CH2), 56.2 (C), 127.8 (2CH), 130.1
(2CH), 131.3 (CH), 137.7 (C), 144.6 (C), 145.5 (CH). HRMS (ESI):
calcd for C14H18O3NaS 289.0869, found 289.0863.
Compounds 11a/b. To a solution of mesylate 21 in DMSO was
added powdered NaCN, and the mixture was stirred at 50 °C for 30 h,
quenched with water, and allowed to cool down to rt. The aqueous
phase was extracted with Et2O, the combined organic layers were
washed several times with water and brine and dried over anhydrous
Na2SO4, and solvent was carefully removed by distillation, which
afforded 40 (2.0 g, 85%). IR: ν = 3084, 2940, 2247, 1651, 1441, 1384,
1
70%). IR: ν = 2968, 1741, 1456, 1326, 1151, 1086 cm−1. H NMR
(200 MHz, CDCl3): δ = 1.25* (s, 3H), 1.30† (s, 3H), 1.76† (m, 2H),
1.78* (m, 2H), 2.28† (m, 1H), 2.52† (d, J = 1.2 Hz, 2H), 2.55* (d, J =
4.2 Hz, 2H), 2.61* (d, J = 8.0 Hz, 1H), 2.69* (d, J = 7.4 Hz, 1H),
3.02† (m, 1H), 3.59† (s, 3H), 3.63* (s, 3H), 7.52 (m, 8H), 7.83 (m,
4H. 13C NMR (50 MHz, CDCl3): δ = 21.0* (CH3), 21.3† (CH3),
24.9† (CH2), 26.1* (CH2), 35.1* (CH2), 35.5† (CH2), 52.5* (CH3),
52.9† (CH3), 53.5† (CH2), 53.6* (CH2), 56.3* (C), 56.5† (C), 128.3†
(2CH), 128.6* (2CH), 129.1 (4CH), 133.7* (CH), 133.8† (CH),
135.8* (C), 136.9† (C), 140.2* (C), 141.2† (C), 155.9* (CH), 157.6†
(CH), 161.9* (C), 162.5† (C). HRMS (ESI): calcd for C15H19O5S
311.0937, found 311.0942.
1
897 cm−1. H NMR (200 MHz, CDCl3): δ = 1.77 (s, 3H), 2.40 (m,
2H), 2.50 (m, 2H), 4.79 (s, 1H), 4.88 (s, 1H). 13C NMR (50 MHz,
CDCl3): δ = 15.7 (CH3), 21.7 (CH2), 33.0 (CH2), 112.3 (CH2), 119.2
(C), 141.6 (C). To a flask containing neat 40 (300 mg, 3.16 mmol) at
−30 °C under argon atmosphere was added dropwise a 1 M solution
of DIBAH in CH2Cl2 (3.5 mL). The reaction was stirred at this
temperature for 2 h, when 3.1 mL of water was added and the stirred
mixture allowed to reach room temperature. The reaction was then
filtered through a fritted glass funnel, the solid washed with Et2O, and
1
the filtrate dried over anhydrous Na2SO4. In order to confirm by H
4389
DOI: 10.1021/acs.joc.5b00206
J. Org. Chem. 2015, 80, 4378−4391

The Journal of Organic Chemistry
Article
Compound 16. DBU (490 μL, 3.28 mmol) was added to a solution
of 39 (410 mg, 250 mmol) in CH3CN (13.0 mL), and the mixture was
stirred at rt. Reaction was followed by H NMR. When the reaction
AUTHOR INFORMATION
Corresponding Author
*Fax: (+34) 923294574. Tel: (+34) 923294481. E-mail:
afmateos@usal.es.
■
1
was complete (24 h), solvent was removed under reduced pressure
and residue diluted again with AcOEt. This new mixture was next
washed with a 2 M aqueous solution of HCl, a saturated aqueous
solution of NaHCO3 and brine, and dried over anhydrous Na2SO4 and
solvent removed under reduced pressure, affording allylsulfone 43 as a
mixture of E/Z isomers so enriched in isomer E that it is the only one
herein described. IR: ν = 2929, 2851, 1722, 1599, 1300, 1151, 1093
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the Junta deCastilla y Leon
1) is gratefully acknowledged. S.E.M. and P.H.T. thank the
Spanish Ministry of Education and the University of Salamanca
for the fellowships that allowed them to fulfill this work.
■
́
(SA200A12-
1
cm−1. H NMR (200 MHz, CDCl3): δ = 1.58 (s, 3H), 2.40 (s, 3H),
2.65 (d, J = 6.4 Hz, 2H), 3.73 (d, J = 6.2 Hz, 2H), 4.51 (s, 1H), 4.66
(s, 1H), 5.48 (m, 2H), 7.29 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 8.6 Hz,
2H. 13C NMR (50 MHz, CDCl3): δ = 21.6 (CH3), 22.6 (CH3), 41.1
(CH2), 60.3 (CH2), 111.6 (CH2), 118.0 (CH2), 128.7 (2CH), 129.9
(2CH), 135.7 (C), 138.9 (CH), 143.4 (C), 144.8 (C). HRMS (ESI):
calcd for C14H18O2NaS 273.0920, found 273.0917. A mixture of 43
(424 mg, 1.70 mmol), NaHCO3 (214 mg, 2.54 mmol), and m-CPBA
(322 mg, 1.86 mmol) in CH2Cl2 (17.0 mL) was stirred at rt for 5 h
and then was quenched with a 10% aqueous solution of Na2S2O3. The
new mixture was further stirred for 30 min, the aqueous layer was
extracted with CH2Cl2, the combined organic extracts were washed
with a saturated aqueous solution of NaHCO3 and brine and dried
over anhydrous Na2SO4, and the solvent was removed under reduced
pressure. Purification of the residue by flash chromatography over
silica gel (Hex/Et2O 8:2) afforded epoxy sulfone 16 (337 mg, 75%)
again as a mixture of E/Z isomers so enriched in isomer E that it is the
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333.0767, found 333.0778.
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