Radical titanocene promoted coupling of epoxides and vinyl sulfones

Article abstract of DOI:10.1002/ejoc.201403288

A radical coupling reaction of diverse vinyl sulfones and epoxides was mediated by Cp₂TiCl (Cp = cyclopentadienyl) to provide a straightforward synthetic pathway to hydroxy sulfones. The reaction was successfully achieved by using either an excess or a catalytic amount of the Ti^III reagent. The scope of the reaction was studied for several different functionalized and substituted epoxides and vinyl sulfones.

Full text of DOI:10.1002/ejoc.201403288

FULL PAPER
DOI: 10.1002/ejoc.201403288
Radical Titanocene Promoted Coupling of Epoxides and Vinyl Sulfones
Alfonso Fernández-Mateos,*[a] Soledad Encinas-Madrazo,[a] Pablo Herrero-Teijón,[a] and
Rosa Rubio González[a]
Keywords: Synthetic methods / Radicals / Titanium / Cross-coupling / Epoxides / Vinyl sulfones
A radical coupling reaction of diverse vinyl sulfones and ep- an excess or a catalytic amount of the TiIII reagent. The scope
oxides was mediated by Cp2TiCl (Cp = cyclopentadienyl) to
provide a straightforward synthetic pathway to hydroxy sulf-
ones. The reaction was successfully achieved by using either
of the reaction was studied for several different function-
alized and substituted epoxides and vinyl sulfones.
Introduction
Results and Discussion
The intermolecular reaction between epoxides and vinyl
sulfones was mediated by titanocene chloride to provide hy-
droxy sulfones in good yields (see Scheme 1). An exhaustive
study was carried out to evaluate the scope of this reaction.
One of the first examples described for a radical addition
to a vinyl sulfone was published by G. A. Russell’s group in
1984.[1] In this paper, alkyl radicals were obtained by the
homolytic cleavage of organomercury compounds, RHgX,
and those radicals underwent an addition to the C=C bond
of a vinyl sulfone, which formed a new radical that pro-
ceeded through a sulfone elimination. Many methods to
carry out a radical addition to different kinds of vinyl sulf-
ones have been subsequently described.[2] In these papers,
different alternatives to generate the radical are reported.
The more recent ones focus on a substitution to Russell’s
mercury-based approach by using greener alternatives such
as silanes[2f,2g] or boranes.[2h,2l]
Radicals that are generated by the homolytic cleavage of
epoxides with Cp2TiCl (Cp = cyclopentadienyl) have
scarcely been used in intermolecular addition reactions.
Nujent and RajanBabu introduced this method[3] for the
radical addition to acrylates and vinyl ketones.[4] Shortly
after, the catalytic coupling of epoxides and acrylates in-
duced by TiIII was described by Gänsauer’s group,[5] who
also described the addition to vinyl ketones, acrylonitriles,
and acrylic amide derivatives in further publications.[6]
However, no attention has been paid to vinyl sulfones.
Vinyl sulfones are exceptional radical acceptors, and sulf-
ones are versatile functional groups that can be transformed
into other groups through straightforward reactions. These
reasons motivated the study of the intermolecular coupling
between epoxides and vinyl sulfones, which is promoted by
titanocene chloride.
Scheme 1. Coupling of epoxides with sulfones that is mediated by
titanocene.
The coupling of cyclohexene oxide (1) and phenyl vinyl
sulfone (6; see Figure 1) was first examined by increasing
the number of equivalents of 6. Then, the influence of the
order of the addition (i.e., titanocene to a mixture of epox-
ide and sulfone or vice versa) was studied. All reactions
were performed with an excess amount of TiIII (2.2 equiv.),
and the results are summarized in Table 1.
Figure 1. Sulfone and epoxide used in preliminary studies.
The yields increased with the number of equivalents of
vinyl sulfone 6, and the reaction that used 10.0 equiv. of 6
afforded the highest yield. However, as all of the reactions
provided the products in good yield, a moderate excess
amount of sulfone (2.0 or 5.0 equiv.) was employed in fur-
ther experiments to ease the experimental work. As far as
we observed, the order of addition had no effect on the
yield.
[a] Departamento de Química Orgánica, Facultad de CC
Químicas, Universidad de Salamanca,
Plaza de los Caídos 1–5, 37008 Salamanca, Spain
E-mail: afmateos@usal.es
www.usal.es
All possible reaction pathways are depicted in Scheme 2.
The initial step of the coupling reaction is the well-known
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403288.
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Radical Titanocene Promoted Coupling of Epoxides and Vinyl Sulfones
Table 1. Preliminary studies.
stitution patterns were selected. The epoxides, sulfones, and
coupling products are depicted in Figure 2, and the reaction
conditions and results are summarized in Table 2.
Entry
1
6
Addition
method[a]
Products
Yield
[%]
[equiv.]
[equiv.]
1
2
3
4
5
1
1
1
1
1
1
A
B
A
B
B
1a/1b
(60:40)
1a/1b
(62:38)
1a/1b
(67:33)
1a/1b
(56:44)
1a/1b
(58:42)
51
53
58
60
68
2
5
5
10
[a] Addition method A: a tetrahydrofuran (THF) solution of TiIII
was added to a THF solution of the epoxide and sulfone. Addition
method B: a THF solution of the epoxide and sulfone was added
to a THF solution of TiIII
.
Scheme 2. Possible reaction pathways.
titanocene-mediated ring-opening of epoxides, which re-
gioselectively affords the more substituted β-alkoxy radical
A. This initial radical undergoes a further reaction with the
corresponding vinyl sulfone to afford a new radical, which
after reduction and hydrolysis provides coupling product B.
β-Alkoxy radical A could follow alternative pathways,
which are also depicted in Scheme 2. Thus, when R = Me,
A could undergo a hydrogen abstraction by using another
equivalent of Cp2TiCl to afford C. A different option would
be the direct coupling with Cp2TiCl when R = H to give D,
and either the further elimination of (Cp2TiO)2 would af-
ford E or a hydrolysis by hydrogen interchange would give
F. As a result, in cases when R = H and addition method
B is used with an excess amount of TiIII, the coupling prod-
uct will only be obtained if the addition to the vinyl sulfone
is faster than that to TiIII. However, coupling product B is
the only product observed in the experiments so far de-
scribed.
Figure 2. Epoxides, sulfones, and coupling products.
Table 2. Coupling reactions with an excess amount of Cp2TiCl.
Entry Epoxide Sulfone Addition
method[a]
Product(s)
Yield
[%]
1
2
3
4
5
6
7
8
9
1
2
3
4
5
1
2
3
4
5
6
6
6
6
6
7
7
7
7
7
A
A
A
B
B
B
B
A
B
A
1a/1b (67:33)
2a/2b (72:28)
3a/3b (88:12)
4a
58
77
68
69
72
40
63
54
29
31
5a
1ca/1cb (67:33)
2ca/2cb (85:15)
3ca/3cb (85:15)
4c, 4d
10
5c
[a] Addition method A: a THF solution of TiIII was added to a
THF solution of the epoxide and sulfone. Addition method B: a
THF solution of the epoxide and sulfone was added to a THF
In a next step, a series of oxiranes and two different vinyl
sulfones were studied. To evaluate the scope of the reaction,
a selection of cyclic and acyclic epoxides with different sub- solution of TiIII
.
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All reactions afforded the products in good yields. Never- volved aryl and alkyl sulfones, and therefore the use of these
theless, better results were obtained by using the sterically β-substituted acceptors were abandoned.
less hindered sulfone 6. In all cases, the cyclic epoxides af-
To evaluate the effects of steric hindrance, the coupling
forded coupling compounds as a mixture of cis/trans dia- reactions of sulfones 6 and 7 with epoxide 10 were then
stereoisomers with the trans hydroxy sulfone as the major investigated. The results in Scheme 4 show that steric hin-
isolated product. This result is in agreement with previous drance disfavored the coupling reaction and favored the
intermolecular additions of cyclohexyl radicals to activated side reactions that are shown in Scheme 2.
alkenes[5c] and nitriles,[7] in which the reaction took place
preferentially at the less hindered site to give the trans prod-
uct. The coupling reactions with the highest diastereoselec-
tivity took place between sulfones 6 and 7 and cyclopentene
oxide (3), respectively.
The coupling reactions were also performed with a cata-
lytic amount of Cp2TiCl (0.2 equiv.), according to the
method described by Oltra and co-workers.[8] The results
are summarized in Table 3.
Table 3. Coupling reactions with a catalytic amount of Cp2TiCl.
Entry
Epoxide
Sulfone
Product(s)
Yield [%]
1
2
3
4
5
6
7
8
9
1
2
3
4
5
1
2
3
4
5
6
6
6
6
6
7
7
7
7
7
1a/1b (55:45)
2a/2b (75:25)
3a/3b (85:15)
4a
43
61
41
32
49
30
48
40
41
54
5a
1ca/1cb (70:30)
2ca/2cb (78:22)
3ca/3cb (95:5)
4c, 4d
Scheme 4. Study of influence of steric hindrance.
10
5c
To finalize the study, reactions were carried out with a
new series of functionalized epoxides to evaluate to what
extent side reactions could compete with the coupling reac-
tion. The epoxides, products, and yields are summarized in
Table 4. All reactions were carried out with an excess
amount of Cp2TiCl.
The coupling attempt with isophorone oxide (14) and
sulfone 6 was unsuccessful, as only deoxygenation product
15 was isolated. From this result, we concluded that the
stabilized radical that formed immediately after the homo-
lytic ring-opening of the epoxide is trapped faster by the
TiIII species than by the sulfone.
The behavior of 2,3-epoxy alcohols in the presence of
Cp2TiCl has been studied previously.[9] As reported, in the
absence of H-atom donors, these epoxides can undergo a
reaction with titanocene to give the corresponding allylic
alcohols regioselectively through a TiIV four-membered cy-
clic intermediate (see Scheme 5). However, in the presence
of some H-atom donors such as 1,4-cyclohexadiene,[3,10] ac-
rylates,[4] acrylonitrile,[4] and nitriles,[11] the trapping of the
radical intermediate has been described, and the coupling
products have been obtained. In these cases, the acceptor
trapping is faster than the dehydroxylation step.
Under catalytic conditions, all of the coupling reactions
took place successfully, but slightly lower yields were ob-
tained compared with those obtained by using an excess
amount of Cp2TiCl. The stereochemical outcomes were
also similar to those obtained by using 2.2 equiv. of
Cp2TiCl. The trans product was the major isolated product,
and the highest stereoselectivity was obtained by the reac-
tions of sulfones 6 and 7 with epoxide 3.
The coupling reactions with β-alkyl-substituted sulfones
did not provide any satisfactory results. Slightly better re-
sults were obtained when the β-aryl sulfone 8 was employed
(see Scheme 3). The reaction of cyclohexene oxide (1) and
styryl sulfone 8 in the presence of 2.2 equiv. of titanocene
provided coupling product 9 in 16% as the best yield. The
phenyl ring that is attached to the double bond of the sulf-
one directed the addition of the alkoxy radical to the α-
position of the sulfone, and the resulting radical evolved by
the elimination of the sulfone group. This behavior is in
accordance with former results for radical additions to this
sulfone.[1a] Throughout this part of the study, there was evi-
dence of slower kinetics for the coupling reactions that in-
In our experiments, epoxy alcohols 16 and 18 in the pres-
ence of sulfone 6 provided the corresponding coupling
products 17 and 21a/21b. Despite the number of times that
the coupling reaction between 16 and 6 was carefully re-
peated, a yield better than 6% could not be achieved. We
believe that this is, because both 17 and the corresponding
dehydration product obtained from 16, (i.e., 1,3-propane-
Scheme 3. Titanocene-mediated coupling reaction of epoxide 1 and
aryl sulfone 8.
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Radical Titanocene Promoted Coupling of Epoxides and Vinyl Sulfones
Table 4. Cp2TiCl-mediated coupling reactions with functionalized epoxides.
[a] Addition method B. [b] Addition method A.
diol) are both very small polar molecules. They are water-
soluble and, thus, are unfortunately lost during the extrac-
tion process.
In the reaction performed with epoxide 18, coupling
products 21a/21b were isolated along with dehydroxylation
and dehydrogenation products 19 and 20. The ratio of the
products shows that the addition reaction of the initial terti-
ary radical to vinyl sulfone 6 is faster than either its dehy-
droxylation or dehydrogenation reaction.
Similar products were obtained by the titanocene-medi-
ated coupling of 22 and 6 (see Table 4, Entry 4). The major
product, allylic alcohol 19, was formed by elimination of
the CN group, and the minor product (i.e., sulfone amine
Scheme 5. Mechanistic development of 2,3-epoxy alcohols in the
presence of Cp2TiCl.
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A. Fernández-Mateos et al.
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23) was obtained by addition of the tertiary radical to 6
according to the mechanism depicted in Scheme 6. The ra-
tio of the products suggests that the elimination of CN is
faster than the addition process, which led us to conclude
that for these functionalized epoxides, the CN group is a
better leaving group than the OH group.
Scheme 7. Mechanism for the formation of 29.
ferent radicals are formed when 32 is treated with Cp2TiCl,
that is, the benzyl and the tertiary radical. The former one
does not undergo a reaction with 6, and thus only homo-
coupling product 34 is formed. However, the tertiary radical
does undergo a reaction to yield hydroxy sulfone 33. The
ratio of the isolated products (22:78) favors 34, which shows
that the ring-opening of epoxide 32 to give the benzyl radi-
cal is faster than to give the tertiary radical.
Conclusions
The titanocene-promoted intermolecular coupling of ep-
oxides and sulfones was successfully achieved to provide
easy access to hydroxy sulfones from several different sub-
stituted epoxides and vinyl sulfones. A complete study was
carried out by using either an excess or a catalytic amount
of Cp2TiCl in the reactions. All coupling products were af-
forded in good yields, which proved that the reaction was
quite general but sensitive to steric hindrance factors. α-
Functionalized epoxides were studied too. Interesting cou-
pling results were realized when the epoxides were function-
alized by a hydroxy or cyano group. In general, aryl epox-
ides and vinyl epoxides did not provide the addition prod-
uct when treated with the vinyl sulfone as a result of the
alternative faster radical homocoupling reaction.
Scheme 6. Mechanism for the formation of 23. R = C6H13.
Radicals that are formed by the reaction between vinyl
epoxides and titanocene have been described to undergo
three different reactions, that is, homocoupling,[11,12] deoxy-
genation,[9b,13] and reduction.[9b,13] Homocoupling has been
observed under catalytic conditions[12] and seems to be a
general route, whereas deoxygenation has been reported
when terminal alkenes undergo a reaction with 2 equiv. of
Cp2TiCl.[9b,13] Reduction has been described to occur when
internal alkenes are subjected to the same conditions.[9b,13]
The reaction of vinyl epoxide 24 with phenyl vinyl sulfone
(6) in the presence of titanocene quantitatively afforded
homocoupling product 25 (see Table 4, Entry 5). This result
is consistent with the previously reported studies that were
conducted with acrylonitrile,[12] methyl acrylate,[12] and
acetonitrile[11] as trapping agents and, therefore, confirms
the allylic radical homocoupling as a very fast reaction.
To complete the study, a series of aryl epoxides were
studied (see Table 4, Entries 6–8). The main benzyl radical
formed from the homolytic regioselective ring-opening of
aryl epoxides 26, 28, and 32 is less reactive than the allylic
one and was expected to provide the coupling product.
However, neither 26 nor 28 provided the corresponding
coupling product when treated with 6 in the presence of
titanocene chloride. Styrene oxide (26) afforded the homo-
coupling product, and epoxy arene 28 showed very similar
behavior. No addition product was isolated, and the major
product was homocoupling compound 31 along with 29
and 30. The proposed mechanism for the formation of 29
is an asymmetric self-coupling of the initial benzyl radical,
which can be explained by steric hindrance arguments (see
Scheme 7).
Experimental Section
General Methods: IR spectra were recorded by using neat samples
on NaCl plates, unless otherwise noted. The 1H NMR spectro-
scopic data were recorded at either 200 or 400 MHz, and the 13C
NMR spectroscopic data were recorded at 50 or 100 MHz. The
samples were dissolved in CDCl3, and the chemical shifts were ref-
erenced to the solvent, except where otherwise indicated. Standard
mass spectrometry data were acquired by using a GC–MS system
in the EI mode with a maximum m/z range of 600. When required,
all solvents and reagents were purified by standard techniques.
Tetrahydrofuran was purified by distillation from sodium/benzo-
phenone and then degassed before use. All reactions were con-
ducted 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
Merck silica gel 60 (0.040–0.063 mm) by using flash column tech-
niques. Unless otherwise mentioned, the reported yields are for
chromatographically pure isolated products.
Of the three examined aryl epoxides, only 32 provided
the coupling product between the epoxide and vinyl sulfone
Addition Method A: A mixture of Cp2TiCl2 (2.20 mmol) and Zn
(6.60 mmol.) in strictly deoxygenated THF (11.0 mL) was stirred
6. From the obtained results, we can conclude that two dif- at room temperature until the red solution had turned green. In a
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Radical Titanocene Promoted Coupling of Epoxides and Vinyl Sulfones
separate flask, the epoxide (1.00 mmol) and 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 the insoluble titanium salts. The filtrate was ex-
tracted with diethyl ether, and the organic layer was washed with
H2O and brine and then dried with anhydrous Na2SO4. After re-
moval of the solvent, the crude product was purified by flash
chromatography.
Compound 3a: IR: ν = 3519, 3059, 2955, 2870, 1735, 1450, 1307,
˜
1
1151, 1093 cm–1. H NMR (200 MHz, CDCl3): δ = 1.0–2.2 (m, 9
H), 2.2 (br. s, 1 H), 3.19 (m, 2 H), 3.73 (dd, J1 = 5.6 Hz, J2
=
11.4 Hz), 7.58 (m, 3 H), 7.88 (m, 2 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 21.7 (CH2), 26.7 (CH2), 30.1 (CH2), 34.9 (CH2), 46.6
(CH), 55.3 (CH2), 78.9 (CH), 128.2 (2 CH), 129.5 (2 CH), 133.9
(CH), 139.3 (C) ppm. HRMS (ESI): calcd. for C13H18O3NaS
277.0869; found 277.0886.
Compound 3b: IR: ν = 3522, 3049, 2973, 2850, 1728, 1453, 1310,
˜
1
1151, 1090 cm–1. H NMR (200 MHz, CDCl3): δ = 1.2–2.0 (m, 10
Addition Method B: 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 had turned green. In a
separate flask, the epoxide (1.00 mmol) and 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 the insoluble titanium salts. The filtrate was ex-
tracted with diethyl ether, and the organic layer was washed with
H2O and brine and then dried with anhydrous Na2SO4. After re-
moval of the solvent, the crude product was purified by flash
chromatography.
H), 3.18 (m, 2 H), 4.12 (br. s, 1 H), 7.59 (m, 3 H), 7.91 (m, 2 H)
ppm. 13C NMR (50 MHz, CDCl3): δ = 21.9 (CH2), 22.7 (CH2),
28.9 (CH2), 35.4 (CH2), 44.4 (CH), 55.6 (CH2), 74.1 (CH), 128.3
(2 CH), 129.5 (2 CH), 133.8 (CH), 139.4 (C) ppm. HRMS (ESI):
calcd. for C13H18O3NaS 277.0869; found 277.0886.
Compound 4a: IR: ν = 3487, 2929, 2851, 1729, 1450, 1307,
˜
1
1145 cm–1. H NMR (200 MHz, CDCl3): δ = 0.85 (t, J = 6.6 Hz,
3 H), 1.21 (br. s, 10 H), 1.2–1.8 (m, 4 H), 3.17 (m, 2 H), 3.43 (dd,
J1 = 6.2 Hz, J2 = 10.6 Hz, 1 H), 3.56 (dd, J1 = 4.8 Hz, J2 = 11.0 Hz,
1 H), 7.58 (m, 3 H), 7.90 (m, 2 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 14.3 (CH3), 22.8 (CH2), 24.4 (CH2), 26.9 (CH2), 29.7
(CH2), 30.0 (CH2), 31.9 (CH2), 39.5 (CH), 54.4 (CH2), 65.2 (CH2),
128.3 (2 CH), 129.5 (2 CH), 133.9 (CH), 139.3 (C) ppm. HRMS
(ESI): calcd. for C16H26O3NaS 321.1495; found 321.1486.
Catalytic Procedure: 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 had turned green. In a
separate flask, the epoxide (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, chloro-
trimethylsilane (TMSCl, 2.5 mmol) was strictly deoxygenated.
Next, the epoxide solution and the TMSCl were slowly added
through different cannulas at the same time to the green TiIII solu-
tion. After 8 h, an excess amount of HCl (2 m solution) was added,
and the mixture was stirred for 30 min. The layers were separated,
and the aqueous phase was extracted with diethyl ether. The or-
ganic layer was washed with H2O and brine and then dried with
anhydrous Na2SO4. After removal of the solvent, the crude product
was purified by flash chromatography.
Compound 5a: IR: ν = 3526, 3065, 2935, 2870, 1735, 1456, 1307,
˜
1151, 1093 cm–1. 1H NMR (200 MHz, CDCl3): δ = 0.84 (t, J =
7.4 Hz, 6 H), 1.0–1.2 (m, 12 H), 1.63 (m, 2 H), 3.10 (m, 2 H), 3.29
(br. s, 2 H), 7.60 (m, 3 H), 7.90 (m, 2 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 14.2 (2 CH3), 23.6 (2 CH2), 25.2 (2 CH2), 27.2 (CH2),
33.5 (2 CH2), 39.6 (C), 51.9 (CH2), 66.9 (CH2), 128.3 (2 CH), 129.5
(2 CH), 133.9 (CH), 139.2 (C) ppm. HRMS (ESI): calcd. for
C18H30O3NaS 349.1808; found 349.1811.
Compound 1ca: IR: ν = 3439, 3067, 2929, 1720, 1644, 1455, 1298,
˜
1147, 1071 cm–1. 1H NMR (200 MHz, CDCl3): δ = 1.25 (d, J =
6.6 Hz, 3 H), 1.1–2.3 (m, 12 H), 3.17 (m, 1 H), 3.58 (m, 1 H), 7.58
(m, 3 H), 7.88 (m, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ =
14.1 (CH3), 24.8 (CH2), 25.7 (CH2), 32.5 (CH2), 35.1 (CH2), 36.3
(CH2), 42.3 (CH), 59.1 (CH), 76.3 (CH), 129.2 (2 CH), 129.3 (2
CH), 133.7 (CH), 137.4 (C) ppm. HRMS (ESI): calcd. for
C15H22O3NaS 305.1182; found 305.1188.
Compound 1a: IR: ν = 3496, 2929, 2350, 1609, 1449, 1304,
˜
1147 cm–1. 1H NMR (200 MHz, CDCl3): δ = 0.8–2.1 (m, 12 H),
3.22 (m, 3 H), 7.60 (m, 3 H), 7.91 (m, 2 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 24.9 (CH2), 25.5 (CH2), 26.3 (CH2), 30.9
(CH2), 36.3 (CH2), 44.0 (CH), 54.7 (CH2), 74.9 (CH), 128.3 (2CH),
129.5 (2 CH), 133.8 (CH), 139.4 (C) ppm. HRMS (ESI): calcd. for
C16H26O3NaS 291.1025; found 291.1009.
Compound 1cb: 1H NMR (400 MHz, CDCl3): δ = 1.23 (d, J =
6.8 Hz, 3 H), 0.8–2.0 (m, 12 H), 3.20 (m, 2 H), 7.59 (m, 3 H), 7.87
(m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.8 (CH3), 24.6
(CH2), 25.2 (CH2), 29.7 (CH2), 32.2 (CH2), 35.7 (CH2), 42.0 (CH),
57.8 (CH), 74.4 (CH), 129.0 (2 CH), 129.1 (2 CH), 133.5 (CH),
137.1 (C) ppm. HRMS (ESI): calcd. for C15H22O3NaS 305.1182;
found 305.1188.
Compound 1da: 1H NMR (200 MHz, CDCl3): δ = 1.25 (d, 3 H),
1.1–2.0 (m, 12 H), 3.17 (m, 1 H), 3.76 (m, 1 H), 7.58 (m, 3 H), 7.88
(m, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 14.1 (CH3), 20.8
(CH2), 25.8 (CH2), 27.9 (CH2), 31.6 (CH2), 32.9 (CH2), 38.3 (CH),
58.0 (CH), 69.9 (CH), 129.2 (2 CH), 129.3 (2 CH), 133.7 (CH),
137.4 (C) ppm. HRMS (ESI): calcd. for C15H22O3NaS 305.1182;
found 305.1188.
Compound 1b: IR: ν = 3499, 3005, 2352, 1611, 1452, 1304,
˜
1145 cm–1. 1H NMR (200 MHz, CDCl3): δ = 1.2–1.9 (m, 12 H),
3.16 (t, J = 8.4 Hz, 2 H), 3.82 (br. s 1 H), 7.58 (m, 3 H), 7.91 (m,
2 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 20.4 (CH2), 25.0
(CH2), 26.7 (CH2), 33.2 (2 CH2), 40.3 (CH), 54.5 (CH2), 68.8 (CH),
128.2 (2 CH), 129.5 (2 CH), 133.8 (CH), 139.4 (C) ppm. HRMS
(ESI): calcd. for C16H26O3NaS 291.1025; found 291.1009.
Compounds 2a† and 2b*: IR: ν = 3519, 3065, 2929, 2851, 1450,
˜
1
1294, 1151, 1093 cm–1. H NMR (200 MHz, CDCl3): δ = 0.80† (s,
3 H), 0.85* (s, 3 H), 1.2–2.0 (m, 20 H), 2.48 (br. s, 2 H), 3.0–3.3
(m, 6 H), 7.55 (m, 6 H), 7.89 (m, 4 H) ppm. 13C NMR (50 MHz, Compound 1db: 1H NMR (200 MHz, CDCl3): δ = 1.25 (d, 3 H),
CDCl3): δ = 16.4† (CH3), 21.1* (CH2), 21.2† (CH2), 23.1* (CH2), 1.1–2.0 (m, 12 H), 3.17 (m, 1 H), 3.74 (m, 1 H), 7.58 (m, 3 H), 7.88
23.8* (CH3), 24.5† (CH2), 29.9* (CH2), 30.0* (CH2), 31.1† (CH2), (m, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 14.9 (CH3), 20.4
33.8† (CH2), 35.0* (CH2), 36.1† (CH2), 37.2* (C), 37.9† (C), 52.9*
(CH2), 52.4† (CH2), 75.8† (CH), 75.9* (CH), 128.2 (4 CH), 129.5
(4 CH), 133.8 (2 CH), 139.4 (2 C) ppm. HRMS (ESI): calcd. for
C15H22O3NaS 305.1182; found 305.1191.
(CH2), 24.4 (CH2), 25.3 (CH2), 31.3 (CH2), 33.1 (CH2), 38.6 (CH),
57.8 (CH), 67.1 (CH), 129.2 (2 CH), 129.3 (2 CH), 133.7 (CH),
137.4 (C) ppm. HRMS (ESI): calcd. for C15H22O3NaS 305.1182;
found 305.1188.
Eur. J. Org. Chem. 2015, 548–555
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A. Fernández-Mateos et al.
FULL PAPER
Compounds 2ca, 2cb, 2da, and 2db: IR: ν = 3508, 3061, 2935, 1632,
128.5 (2 CH), 129.4 (2 CH), 134.0 (CH), 138.7 (C) ppm. HRMS
(ESI): calcd. for C19H32O3NaS 363.1964; found 363.1948.
˜
1462, 1298, 1153, 1071 cm–1. 1H NMR (200 MHz, CDCl3): δ =
0.79 (s, 6 H), 0.86 (s, 6 H), 1.26 (m, 12 H), 1.1–1.7 (m, 32 H), 2.1–
2.6 (m, 8 H), 2.99 (br. s, 4 H), 3.0–3.5 (m, 8 H), 7.56 (m, 12 H),
7.85 (m, 8 H) ppm. 13C NMR (50 MHz, CDCl3, isomer 2ca): δ =
17.9 (CH3), 18.4 (CH3), 21.3 (CH2), 25.1 (CH2), 30.0 (CH2), 35.2
(CH2), 39.2 (C), 39.7 (CH2), 55.9 (CH), 73.1 (CH), 129.2 (2 CH),
129.4 (2 CH), 133.9 (CH), 137.1 (C) ppm. 13C NMR (50 MHz,
CDCl3, isomer 2cb): δ = 16.1 (CH3), 17.5 (CH3), 21.2 (CH2), 24.8
(CH2), 31.1 (CH2), 37.1 (CH2), 38.6 (C), 41.2 (CH2), 56.5 (CH),
76.1 (CH), 128.5 (2 CH), 130.2 (2 CH), 134.0 (CH), 137.6 (C) ppm.
13C NMR (50 MHz, CDCl3, isomer 2da): δ = 18.2 (CH3), 21.3
(CH2), 22.2 (CH2), 22.8 (CH3), 29.4 (CH2), 35.5 (CH2), 35.8 (CH2),
38.1 (C), 56.3 (CH), 74.0 (CH), 128.3 (2 CH), 130.2 (2 CH), 133.3
(CH), 137.6 (C) ppm. 13C NMR (50 MHz, CDCl3, isomer 2db): δ
= 17.0 (CH3), 20.9 (CH2), 23.1 (CH2), 24.9 (CH3), 30.1 (CH2), 34.4
(CH2), 35.5 (CH2), 37.9 (C), 56.8 (CH), 76.7 (CH), 129.3 (2 CH),
129.5 (2 CH), 133.8 (CH), 137.5 (C) ppm. HRMS (ESI): calcd. for
C16H24O3NaS 319.1338; found 319.1348.
1
Compound 9: H NMR (200 MHz, CDCl3): δ = 1.2–1.9 (m, 8 H),
2.06 (m, 2 H), 3.33 (dt, J1 = 4.4 Hz, J2 = 9.6 Hz, 1 H), 6.07 (dd,
J1 = 8.8 Hz, J2 = 15.8 Hz, 1 H), 6.53 (d, J = 15.8 Hz, 1 H), 7.32
(m, 5 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 25.0 (CH2), 25.4
(CH2), 31.7 (CH2), 34.1 (CH2), 50.9 (CH), 73.4 (CH), 126.4 (2 CH),
127.6 (CH), 128.8 (2 CH), 132.2 (CH), 132.3 (CH), 137.2 (C) ppm.
HRMS (ESI): calcd. for C14H18ONa 225.1249; found 225.1267.
Compound 12: 1H NMR (200 MHz, CDCl3): δ = 0.84 (s, 3 H), 0.85
(s, 3 H), 1.64 (s, 3 H), 1.1–2.2 (m, 9 H), 3.25 (m, 2 H), 5.24 (br. s
1 H), 7.58 (m, 3 H), 7.89 (m, 2 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 21.9 (CH3), 22.8 (CH3), 23.4 (CH3), 26.9 (CH2), 27.7
(CH2), 30.1 (CH2), 33.1 (CH2), 39.4 (C), 53.7 (CH2), 74.2 (C), 118.4
(CH), 128.2 (2 CH), 129.5 (2 CH), 133.8 (CH), 134.3 (C), 139.4
(C) ppm. HRMS (ESI): calcd. for C18H26O3NaS 345.1495; found
345.1490.
Compound 17: IR: ν = 3408, 2923, 1720, 1650, 1449, 1298,
˜
1147 cm–1. 1H NMR (200 MHz, CDCl3): δ = 1.8–2.1 (m, 5 H), 3.21
(t, J = 7.4 Hz, 2 H), 3.71 (m, 4 H), 7.62 (m, 3 H), 7.91 (m, 2 H)
ppm. 13C NMR (50 MHz, CDCl3): δ = 21.2 (CH2), 41.0 (CH), 54.4
(CH2), 64.9 (2 CH2), 128.2 (2 CH), 129.6 (2 CH), 134.0 (2 CH),
139.2 (C) ppm. HRMS (ESI): calcd. for C11H16O4NaS 267.0661;
found 267.0651.
Compound 3da (less polar cis isomer): IR: ν = 3487, 3059, 2942,
˜
2877, 1722, 1450, 1300, 1151, 1086 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 1.29 (d, J = 7.0 Hz, 3 H), 1.4–1.9 (m, 7 H), 2.21 (m,
1 H), 3.19 (m, 1 H), 4.10 (m, 1 H), 7.60 (m, 3 H), 7.89 (m, 2 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 14.5 (CH3), 21.8 (CH2),
29.0 (CH2), 29.3 (CH2), 34.8 (CH2), 43.1 (CH), 59.1 (CH), 73.2
(CH), 129.1 (4 CH), 133.5 (CH), 137.1 (C) ppm. HRMS (ESI):
calcd. for C14H20O3NaS 291.1025; found 291.1016.
Compound 21a (less polar isomer): IR: ν = 3461, 2929, 2851, 1443,
˜
1
1307, 1158, 1093 cm–1. H NMR (200 MHz, CDCl3): δ = 0.74 (s,
Compounds 3db* and 3ca†: IR: ν = 3526, 3074, 2933, 2857, 1729,
˜
3 H), 0.88 (m, 3 H), 1.27 (m, 10 H), 1.4–2.2 (m, 4 H), 3.0–3.6 (m,
6 H), 3.91 (m, 1 H), 7.60 (m, 3 H), 7.90 (m, 2 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 14.3 (CH3), 19.4 (CH3), 22.8 (CH2), 24.1
(CH2), 26.7 (CH2), 29.4 (CH2), 31.7 (CH2), 32.0 (CH2), 40.7 (C),
52.2 (CH2), 70.1 (CH2), 80.1 (CH), 128.2 (2 CH), 129.5 (2 CH),
133.9 (CH), 139.3 (C) ppm. HRMS (ESI): calcd. for C18H30O4NaS
365.1757; found 365.1754.
1449, 1307, 1147, 1095 cm–1. 1H NMR (200 MHz, CDCl3): δ =
1.24* (d, J = 6.9 Hz, 3 H), 1.25† (d, J = 6.8 Hz, 3 H), 1.1–2.2 (m,
20 H), 3.10* (m, 1 H), 3.33† (m, 1 H), 3.73† (dd, J1 = 6.0 Hz, J2 =
12.2 Hz, 1 H), 4.09* (m, 1 H), 7.58 (m, 6 H), 7.85 (m, 4 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 14.3† (CH3), 14.6* (CH3), 21.8*
(CH2), 22.0† (CH2), 28.3* (CH2), 29.2* (CH2), 31.5† (CH2), 34.0†
(CH2), 35.1* (CH2), 35.3* (CH2), 42.6* (CH2), 44.7† (CH), 59.1†
(CH), 59.5* (CH), 75.0* (CH), 79.2† (CH), 129.2 (4 CH), 129.3 (4
CH), 133.8† (CH), 133.9* (CH), 137.3 (2 C) ppm. HRMS (ESI):
calcd. for C14H20O3NaS 291.1025; found 291.1016.
Compound 21b (more polar isomer): IR: ν = 3480, 2925, 2862, 1449,
˜
1
1306, 1162, 1090 cm–1. H NMR (200 MHz, CDCl3): δ = 0.67 (s,
3 H), 0.85 (t, J = 6.6 Hz, 3 H), 1.24 (m, 10 H), 1.91 (m, 2 H), 2.94
(br. s, 2 H), 3.0–3.4 (m, 4 H), 3.67 (d, J = 11.4 Hz, 1 H), 7.59 (m,
3 H), 7.89 (m, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 14.3
(CH3), 18.2 (CH3), 22.8 (CH2), 26.9 (CH2), 27.9 (CH2), 29.5 (CH2),
31.6 (CH2), 32.0 (CH2), 40.8 (C), 52.1 (CH2), 68.0 (CH2), 77.3
(CH), 128.2 (2 CH), 129.5 (2 CH), 133.9 (CH), 139.2 (C) ppm.
HRMS (ESI): calcd. for C18H30O4NaS 365.1757; found 365.1754.
Compound 3cb (more polar trans isomer): IR: ν = 3493, 3085, 2979,
˜
2887, 1722, 1456, 1305, 1149, 1093 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 1.25 (d, J = 6.9 Hz, 3 H), 1.0–1.9 (m, 9 H), 3.13 (m,
1 H), 3.79 (dd, J1 = 5.7 Hz, J2 = 11.8 Hz, 1 H), 7.60 (m, 3 H), 7.88
(m, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 13.7 (CH3), 21.3
(CH2), 29.1 (CH2), 33.1 (CH2), 34.6 (CH2), 44.78 (CH), 58.8 (CH),
79.1 (CH), 129.0 (4 CH), 133.6 (CH), 137.1 (C) ppm. HRMS (ESI):
calcd. for C14H20O3NaS 291.1025; found 291.1016.
Compound 23: IR: ν = 3451, 3060, 2934, 2855, 1735, 1461, 1260,
˜
1
1150 cm–1. H NMR (200 MHz, CDCl3): δ = 0.87 (m, 6 H), 1.24
Compounds 4c* and 4d†: IR: ν = 3490, 3105, 2895, 1731, 1449,
(m, 10 H), 2.01 (d, J = 13.2 Hz, 1 H), 2.12 (d, J = 16.4 Hz, 1 H),
2.39 (d, J = 13.2 Hz, 1 H), 2.70 (d, J = 16.3 Hz, 1 H), 3.29 (d, J =
9 Hz, 1 H), 7.53 (m, 3 H), 7.84 (m, 2 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 14.3 (CH3), 22.0 (CH3), 22.8 (CH2), 26.8 (CH2), 29.5
(CH2), 32.0 (CH2), 32.5 (CH2), 40.7 (CH2), 43.8 (C), 46.5 (CH2),
78.3 (CH2), 96.4 (C), 126.6 (2 CH), 129.1 (2 CH), 132.5 (CH),
142.5 (C), 156.2 (C) ppm. HRMS (ESI): calcd. for C19H28O4NaS
375.1600; found 375.1603.
˜
1315, 1139 cm–1. 1H NMR (200 MHz, CDCl3): δ = 0.87 (t, J =
6.2 Hz, 6 H), 1.24 (m, 26 H), 1.64 (m, 6 H), 1.93 (m, 2 H), 3.27
(m, 2 H), 3.52 (m, 4 H), 7.60 (m, 6 H), 7.88 (m, 4 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 14.3 (2 CH3), 14.4* (CH3), 14.5†
(CH3), 22.8 (2 CH2), 26.5† (CH2), 27.1* (CH2), 29.7* (CH2), 29.8†
(CH2), 30.3† (CH2), 31.6† (CH2), 31.7† (CH2), 31.9* (2 CH2), 32.3*
(CH2), 38.0 (2 CH), 58.2† (CH), 58.6* (CH), 65.4* (CH2), 65.8†
(CH2), 129.3 (8 CH), 133.8 (2 CH), 137.4 (2 C) ppm. HRMS (ESI):
calcd. for C17H28O3NaS 335.1651; found 335.1657.
Compound 33: IR: ν = 3500, 3065, 2929, 2864, 1722, 1450, 1300,
˜
1
1151, 1093 cm–1. H NMR (200 MHz, CDCl3): δ = 0.82 (s, 3 H),
Compound 5c: IR: ν = 3496, 3160, 2925, 2850, 1729, 1449, 1305, 0.83 (s, 3 H), 1.74 (m, 2 H), 3.22 (m, 2 H), 4.37 (s, 1 H), 7.26 (m,
˜
1
1149 cm–1. H NMR (200 MHz, CDCl3): δ = 0.88 (m, 6 H), 1.0– 4 H), 7.59 (m), 7.90 (m, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ
1.4 (m, 16 H), 2.22 (dd, J1 = 5.2 Hz, J2 = 12.6 Hz, 2 H), 3.18 (m, = 22.9 (CH3), 24.0 (CH3), 31.4 (CH2), 37.9 (C), 53.0 (CH2), 81.2
1 H), 3.39 (m, 2 H), 7.59 (m, 3 H), 7.89 (m, 2 H) ppm. 13C NMR (CH), 127.8 (2 CH), 127.9 (CH), 128.0 (2 CH), 128.3 (2 CH), 129.5
(50 MHz, CDCl3): δ = 14.3 (2 CH3), 17.8 (CH3), 23.7 (2 CH2), 25.1 (2 CH), 133.8 (CH), 139.3 (C), 141.5 (C) ppm. HRMS (ESI): calcd.
(2 CH2), 34.0 (2 CH2), 34.1 (CH2), 40.7 (C), 56.2 (CH), 66.4 (CH2), for C18H22O3NaS 341.1182; found 341.1172.
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Received: October 1, 2014
Published Online: December 4, 2014
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