An aerobic oxidation/homolytic substitution-cascade for stereoselective methylsulfanyl-cyclization of 4-pentenols

Article abstract of DOI:10.1039/c3ob26590k

4-Pentenols (dihomoallylic alcohols) are oxidized by cobalt(ii)-activated dioxygen in solutions of dimethyl disulfide and cyclohexa-1,4-diene to afford methylsulfanyl (CH₃S)-functionalized tetrahydrofurans in up to 74% yield. The reaction is a cascade, composed of oxidative alkenol cyclization providing tetrahydrofuryl-2-methyl radicals, which are trapped in dimethyl disulfide. Homolytic methylsulfanyl substitution by carbon radicals is a slow reaction, as exemplified by the rate constant of k^SCH3 = 3 × 10⁴ M^-1 s^-1 (70 °C) derived from competition kinetics for the reaction between dimethyl disulfide and the trans-2-phenyltetrahydrofuryl-5-methyl radical. Methylsulfanyl-cyclizations therefore are experimentally performed in neat dimethyl disulfide, containing the minimum amount of cyclohexa-1,4-diene necessary for attaining almost quantitative alkenol conversion. The oxidative tetrahydrofuran synthesis occurs with noteworthy (>99%) 2,5-trans-stereoselectivity, as shown by the synthesis of diastereomerically pure 2,3- and 2,3,3-substituted 5-(methylsulfanyl) methyltetrahydrofurans from stereodefined 1,2-di- and 1,2,2-trisubstituted 4-pentenols. Changing the chemical nature of the disulfide reagent or the alkenol extends the scope of alkylsulfanyl-cyclization to ethylsulfanyl- cyclization, allylsulfanyl-transfer, or tetrahydropyran synthesis.

Full text of DOI:10.1039/c3ob26590k

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An Aerobic Oxidation/Homolytic SubstitutionꢀCascade for
†
Stereoselective MethylsulfanylꢀCyclization of 4ꢀPentenols
a
a
a
Patrick Fries , Melanie Kim Müller , and Jens Hartung*
a
Fachbereich Chemie, Organische Chemie, Technische Universität Kaiserslautern,
ErwinꢀSchrödingerꢀStraße, Dꢀ67663 Kaiserslautern, Germany
Fax: +49ꢀ631ꢀ205ꢀ3921,
Eꢀmail: hartung@chemie.uniꢀkl.de
Graphical contents entry:
S
H
OH
Ph
H
H
O
O / CoL
2
2
Ph
S
+
S
HO
Ph
CHD / 70 °C HO
Ph
H
O
O
=
CH3
HL =
F
CHD = cyclohexaꢀ1,4ꢀdiene
Keywords: Aerobic oxidation, Catalysis, Dimethyl disulfide, Dioxygen, Cobalt(II) complexes,
Radicals, Stereoselective Synthesis, Tetrahydrofurans, Thioethers, Alkenes
1

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Summary: 4ꢀPentenols (dihomoallylic alcohols) are oxidized by cobalt(II)ꢀactivated dioxygen
in solutions of dimethyl disulfide and cyclohexaꢀ1,4ꢀdiene to afford methylsulfanyl (CH S)ꢀ
3
functionalized tetrahydrofurans in up to 74% yield. The reaction is a cascade, composed of
oxidative alkenol cyclization providing tetrahydrofurylꢀ2ꢀmethyl radicals, which are trapped
dimethyl disulfide. Homolytic methylsulfanyl substitution by carbon radicals is a slow
SCH
= 3 ×10 M–1 s (70 °C) derived from
4
–1
3
reaction, as exemplified by the rate constant of k
competition kinetics for the reaction between dimethyl disulfide and the transꢀ2ꢀ
phenyltetrahydrofurylꢀ5ꢀmethyl radical. Methylsulfanylꢀcyclizations therefore are
experimentally performed in dimethyl disulfide, containing the minimum amount of
cyclohexaꢀ1,4ꢀdiene necessary for attaining up to quantitative alkenol conversion. The
oxidative tetrahydrofuran synthesis occurs with outstanding (> 99%) 2,5ꢀtransꢀ
stereoselectivity, as shown by synthesis of diastereomerically pure 2,3ꢀ and 2,3,3ꢀsubstituted 2ꢀ
(methylsulfanyl)methyltetrahydrofurans from stereodefined 1,2ꢀdiꢀ and 1,2,2ꢀtrisubstituted 4ꢀ
pentenols. Changing the chemical nature of the disulfide reagent or the alkenol extends the
scope of alkylsulfanylꢀcyclization to ethylsulfanylꢀcyclization, allylsulfanylꢀtransfer, or
tetrahydropyran synthesis.
Introduction
The methylsulfanyl group (SCH ) is a soft and strongly nucleophilic group, which
3
1
,2
enhances response to receptor binding of bioactive compounds and opens in sulfoxidized
form pathways for selective functional group interconversion or carbonꢀskeleton
2

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3
,4
rearrangement.
Standard approaches to synthesis of methyl thioethers are nucleophilic substitution and
5
,6
addition. In substitutions, methylthioethers are formed in a Williamsonꢀtype approach from
organic thiols and methyl electrophiles, or alternatively from carbon electrophiles and
methanethiol. The standard reagent for introducing the methylsulfanyl group by addition is
methanethiol, which adds to Michaelꢀtype acceptors in polar or in homolytic reactions.
Methanethiol is at room temperature a toxic malodorous gas that for many is unpleasant
7
to use. An alternative reagent to methanethiol in thioetherꢀsynthesis is dimethyl disulfide.
Dimethyl disulfide is a liquid, which boils under standard conditions at 112 °C. The compound
has a cabbageꢀlike smell that many experience significantly less disturbing than the offensive
8
odor of methanethiol.
The use of dialkylꢀ and diaryl disulfides for sulfur functionalization, particularly of
th
9,10,11
carbon radicals, was mechanistically explored by the end of the 20 century.
The kinetic
data summarized from this era show that thiyl radicals rapidly add to alkenes, or homolytically
1
2
abstract hydrogens from aliphatic C,Hꢀbonds. Thiyl radicals, on the other hand, react
comparatively slowly with monovalent heteroatom functional groups, such as halogens,
arylthioethers or –selenoethers, which are customarily used for carbon radical generation in
1
3,14
chain reactions.
With the advent of thiohydroxamateꢀbased carbon radical progenitors,
researchers started to use the potential of this method for developing homolytic
1
1,15,16
phenylsulfanylations,
however, leaving the field of methylsulfanylation and the use of
more atomꢀeconomic radical progenitors largely unexplored.
In a project on atomꢀeconomic tetrahydrofuran synthesis we recently found that 4ꢀ
3

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pentenols furnish tetrahydrofurylꢀ2ꢀmethyl radicals, if oxidized by cobaltꢀactivated molecular
1
7,18,19,20
oxygen.
The convincing selectivity of this method prompted us to address the question
of sulfur functionalization of carbon radicals again, with the aim to combine stereoselective 4ꢀ
2
1
pentenol ring closure and homolytic alkylsulfanylꢀtransfer to a new cascade (Scheme 1).
(i) aerobic alkenol oxidation
OH
•
O
CH
2
R
/
2 H O
II
2
R
L2Co O2
2
1
3
[ H ] / O2
III
III
L Co O H
L2Co O •
2
2
2
•
O
CH
O
H
2
R
R
(ii) carbon radical functionalization
SR'
•
O
O
CH
2
+
R'2S2
+ R'S•
R
R
2
3
Scheme 1 Mechanistic model of a aerobic oxidation/homolytic substitutionꢀcascade for
alkylsulfanylꢀcyclization of 4ꢀpentenol 1 {[H] = hydrogen atom from e.g. cyclohexaꢀ1,4ꢀdiene
–
(
CHD); R = e.g. phenyl or alkyl; R’ = e.g. methyl, ethyl, or allyl, L = 1ꢀarylbutaneꢀ1,3ꢀdione
monoanion (cf. Table 1)}.
The major results from the study show that 4ꢀpentenols undergo rapid and
chemoselective methylsulfanylꢀcyclizations, if oxidized by molecular oxygen in solutions of
dimethyl disulfide and cyclohexaꢀ1,4ꢀdiene (CHD). The 4ꢀpentenol ring closure proceeds with
4

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noteworthy 5ꢀexoꢀ and 2,5ꢀtransꢀselectivity, allowing to prepare diastereomerically pure 2,3ꢀ
and 2,3,3ꢀsubstituted 2ꢀ(methylsulfanyl)methyltetrahydrofurans. Replacing dimethyl disulfide
by other disulfides, or the 4ꢀpentenol by a 5ꢀhexenol, extends the scope of alkylsulfanylꢀ
cyclization to ethylsulfanylꢀcyclization, allylsulfanylꢀtransfer, and to tetrahydropyran synthesis.
Results and Discussion
1
Cobalt(II) complexes
From a screening of catalysts for mediating oxidative alkenol ring closure by molecular
oxygen, we selected fluoroꢀsubstituted cobalt(II)ꢀbis(βꢀdiketonate)ꢀcomplexes 4–7 of the
n
22
general formula Co(L ) (Table 1) for the pursuit of the alkylsulfanyl project. One of the
2
1
candidates, 4,4,4ꢀtrifluoroꢀ1ꢀphenylbutaneꢀ1,3ꢀdioneꢀderived complex Co(L ) (4), was
2
2
3
available from a previous project, whereas compounds 5–7 were newly prepared by mixing
n
cobalt(II)ꢀacetate tetrahydrate and two aliquots of the underlying 1ꢀarylbutaneꢀ1,3ꢀdione HL
(n = 2–4) in aqueous solutions of ethanol. Cobalt(II) bisꢀ(βꢀdiketonate) complexes 4–7 were
characterized on a routine basis by infraredꢀspectroscopy, combustion analysis, and ESIꢀmass
2
4,25
spectrometry. In fluorineꢀ19 NMR spectra,
we noticed a strong deshielding of alkylꢀbound
1
fluorines in Co(L ) (4) (
δ
= 6.4), if referenced to fluorineꢀNMR chemical shifts of the enol
2
1
1
2
HL (–77.5 ppm) and the lithium enolate Li(L ) (–76.9 ppm). For arylꢀbound fluorine in HL
(
–108.3 ppm), cobalt(II)ꢀbinding induces a slight shielding (–112.0 ppm for 5; Table 1).
Although the quantum chemical origin of these shift dispersions remained unclear, this
information offered on a qualitative basis a guideline for characterizing cobalt(II) compounds
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4
–7.
Cobalt complexes prepared according to the general method (Table 1) contain waterꢀ (4
and 5) or ethanol molecules (6 and 7). Solvateꢀfree cobalt complexes can be obtained by
–
1
drying, for example, compounds 6 and 7 at 90 °C under reduced pressure (2ꢁ10 mbar). If
tested for catalytic reactivity and selectivity in aerobic alkenol oxidations, solvated and
solvateꢀfree complexes performed similarly. For practical reasons, we used the solvate
complexes as oxidation catalysts.
Table 1 Preparation of cobalt(II) chelates from fluorinated 1,3ꢀdiketones
Co(OAc) ꢁ 4 H O
2
2
HLn
Co(Ln)
2
2
EtOH / H O / 20 °C
2
4–7
O
O
n
HL =
Ar
R
n
19
entry
HL
Ar
Ph
R
4–7
δ
F
νC=O
a
–1 b
/
%
/ ppm
+6.4
/ cm
1
c
1
2
3
4
HL
CF3
4: 99
5: 84
6: 89
7: 70
1609
1603
1616
1600
2
c
d
d
HL
pꢀFC H
CH3
CF3
–112.0
–110.3 / +7.6
–110.9
6
4
3
HL
pꢀFC H
6
4
4
HL
pꢀFC H
pꢀFC H
6 4
6
4
a
b
In acetone/CDCl [50:50 (v/v)], versus α,α,αꢀtrifluorotoluene as internal standard.
3
c
d
Pelletized in KBr. Dihydrate. Bisethanolꢀadduct.
2
Alkylsulfanyl-cyclization of 4-pentenols
6

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2
.1 Parameters for selective methylsulfanyl-cyclization
By systematically adapting reaction temperature, dimethyl disulfide concentration,
chemical nature and concentration of the reducing agent (see Scheme 1), and the
catalyst/substrateꢀratio we found that 2ꢀphenylꢀ5ꢀ[(methylsulfanyl)methyl]tetrahydrofuran 3a
is available in up to 59% yield from a solution of 1ꢀphenylꢀ4ꢀpentenꢀ1ꢀol (1a), containing 9.5
molar concentration of dimethyl disulfide, 2.0 molar concentration of cyclohexaꢀ1,4ꢀdiene
(CHD), and 5 mol% of cobalt(II) complex 5. This solution is kept for three hours at 70 °C in a
flask connected to a reflux condenser left open at the top for saturating the reaction mixture
with air. The alkenol conversion under such conditions varied from catalyst to catalyst, leading
to values of 66–94%, with the highest degree of conversion consistently found for oxidations
catalyzed by pꢀfluorophenylbutanedionatoꢀderived cobalt complex 5. Oxidation of 1a under
such conditions furnishes 2ꢀphenylꢀ5ꢀmethyltetrahydrofuran 8a as byꢀproduct, supplementing
the mass balance for alkenolꢀderived compounds to 88% (Table 2, entry 2). According to
protonꢀNMRꢀ, NOESYꢀ, and GCꢀMS data, tetrahydrofurans 3a and 8a are formed exclusively
2
6
as 2,5ꢀtransꢀstereoisomers. A control conducted in an atmosphere of dry nitrogen under
conditions otherwise identical conditions (cf. Table 2, entry 2) did not provide
tetrahydrofurans 3a and 8a (GC). From this information we concluded that molecular oxygen
is a key reagent for the oxidative alkenol conversion into cyclic ethers 3a and 8a.
Table 2 Reactivity and selectivity in aerobic methylsulfanylꢀcyclization of alkenols 1a–c
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(
H C) S
3 2 2
SCH3
R
H
H
H
H
Ph
OH
1
O / CHD
O
O
2
Ph
Ph
+
R
R
n
Co(L ) (4–7)
2
70 °C
(±)ꢀ3
(±)ꢀ8
cis:trans < 1:99
cis:trans < 1:99
n
a
b,c
b
entry
Co(L )
1 / R
conv. /%
3 /%
8 /%
2
1
2
3
4
5
6
7
8
4
5
6
7
4
5
4
5
1a / H
1a / H
1a / H
1a / H
75
94
66
75
55
78
74
82
3a / 47
3a / 59
3a / 41
3a / 46
3b / 15
3b / 18
3c / 44
3c / 50
b
8a / 22
8a / 29
8a / 20
8a / 22
8b / 38
8b / 50
8c / 23
8c / 24
1b / CO CH
2
3
1b / CO CH
2
3
1c / CH3
1c / CH3
n
a
3
h reaction time, 5 mol% of Co(L ) (see text), c
= 2.0 M, cDMDS = 8.5 M; yields
2
CHD
c
determined via GC; 50/50ꢀmixture of stereoisomers with respect to the stereocenter in the
tetrahydrofurylmethyl side chain for 3b and 3c.
The second important reagent for attaining catalytic oxidative alkenol turnover is
cyclohexaꢀ1,4ꢀdiene (CHD). The diene delivers reducing equivalents for converting dioxygen
into water and for reducing cobalt(III) to cobalt(II), which is the active form of the catalyst for
1
7
dioxygen activation (Scheme 1). In some applications, we tested γꢀterpinene as substitute for
CHD. Some of the γꢀterpineneꢀderived oxidation products were difficult to separate from
methylsulfanylꢀcyclized products, which let us to adhere to CHD as reductant. In controls we
noticed that methylsulfanylꢀcyclization also occurs in the absence of CHD, although at slower
8

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rate and less selectively. If stirred, for example, for twenty four hours at 70 °C in a solution of
dimethyl disulfide, a fraction of 28 % of phenylpentenol 1a remains unchanged. The rest of the
alkenol is converted into products, from which we were only able to separate and to
characterize thioether 3a (44%), being formed exclusively as 2,5ꢀtransꢀisomer, and transꢀ5ꢀ
phenyltetrahydrofurylꢀ2ꢀmethanol (4%), which is not produced in solutions containing
2
3,27
CHD.
As we raised the dimethyl disulfide concentration from 0.6 to 5.7
concentration of 1.4 , the yield of thioether 3a gradually increased, whereas the fraction of
M
at fixed CHDꢀ
M
reduction product 8a became smaller (Figure 1). From this responsivity we concluded that
dimethyl disulfide and CHD compete for the same reactive intermediate, which, according to
the mechanistic model outlined in Scheme 1, is the transꢀ2ꢀphenyltetrahydrofurylꢀ5ꢀmethyl
1
7
radical (2a). The unknown rate constant for methylsulfanylꢀtransfer from dimethyl disulfide
to primary carbon radical 2a became available from competition kinetics performed under
pseudoꢀfirst order conditions (Scheme 2). From a primary plot of product ratios 3a/8a versus
the dimethyl disulfide concentration in the range between 0.5–5.5
to eq. 1 partial rate factors f for thiomethyl substitution versus hydrogen atom abstraction by
primary radical 2a, at fixed CHDꢀconcentrations of 1.4 , 3.2 and 5.1 (Figure 2). The
slope of a linear correlation of f versus reciprocal cyclohexaꢀ1,4ꢀdiene concentration, in a
M, we calculated according
M
M
M
rel
SCH
H
3
secondary plot according to eq. 2, provides the relative rate constant k = k
/k , having a
H
value of 0.5 at a temperature of 70 °C (Figure 3). If referenced toward k for Hꢀatom transfer
from CHD to the ethyl radical at 27 °C, and assuming similar temperature dependence of the
two homolytic substitutions, the rate of homolytic methylsulfanylꢀradical substitution
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SCH
= 3 × 10 M–1 s (70 °C).
4
–1
3
translates into k
Figure 1 Relationship between product selectivity in methylsulfanylꢀcyclization of
CHD
1a
phenylpentenol 1a and dimethyl disulfide (DMDS)ꢀconcentration (c0
= 1.4 M; c0 = 0.11
4
M
, c = 5.7 ꢂ
M
, T = 70 °C).
0
k SCH3
3
a
+
+
•SCH3
H
H
(H C) S
•
3
2
2
O
Ph
CH
2
k H
8
a
(
±)ꢀ2a
CHD
•
3
[
[
3a ]
8a ]
k SCH [(H C) S ]
3 2 2
(
eq. 1)
=
k H
[CHD]
k SCH
1
3
f =
ꢁ
(eq. 2)
k H
[CHD]
Scheme 2 Elementary reactions (top) and equations for numeric analysis of rate constant
bottom) of homolytic SCH ꢀsubstitution (kSCH3) from dimethyl disulfide (DMDS) by the
(
3
10

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transꢀ2ꢀphenyltetrahydrofurylꢀ2ꢀmethyl radical (2a).
Figure 2 Primary plot – correlation of product ratios 3a/8a versus reactant concentration for
oxidation of alkenol 1a at fixed CHDꢀconcentrations (▲= 1.4
M
, ○ = 3.2
M
, ● = 5.1
M
) for
1
a
4
determining partial rate factors f, according to equation 1 (cf. Scheme 2; c0 = 0.12
M
, c =
0
5
.9 ꢂM, T = 70 °C).
Figure 3 Secondary plot – correlation of partial rate factor f versus reciprocal CHDꢀ
11

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SCH
3
concentration for determining relative rate constant k
according to equation 2.
The information gained from competition kinetics suggest that the largest split for
thioether synthesis is attainable in solutions containing a maximum concentration of dimethyl
disulfide and the minimum amount of CHD, necessary for maintaining a reasonable rate of
oxidative alkenol turn over. In synthesis, we used a 9.5 molar concentration of dimethyl
disulfide and 0.95 molar concentration of CHD. For turning over alkenols of unknown
reactivity, such as substrates 1b–c, we almost doubled the concentration of CHD to obtain
reasonable yields of products, particular from reactions catalyzed by less reactive cobalt
complexes. Oxidations of alkenols 1b having an acrylate type double bonds, for example,
furnishe more reduced than methylsufanylꢀcyclized product (Table 2, entries 5 and 6). From
the yields of thioether 3b and methyltetrahydrofuran 8b, and the concentration of the trapping
reagents dimethyl disulfide and CHD, we estimated a relative rate constant for methylsulfanylꢀ
SCH
H
3
versus hydrogen atom transfer leading to a value of k
/k ≈ 0.1 for an esterꢀsubstituted
tetrahydrofurylꢀ2ꢀmethyl radical, derived from 1b (Table 2, entry 6). The same analysis
applied for alkenol 1c, having an internal dialkylꢀsubstituted πꢀbond, furnishes a value of
SCH
H
3
k
/k ≈ 0.5 for trapping of a methylꢀsubstituted tetrahydrofurylꢀ2ꢀmethyl radical (Table 2,
entry 8). Selectivity and yields of products 3c and 8c are identical to data obtained for
oxidative conversion of alkenol 1a under identical conditions.
In GCꢀmass spectra recorded from reaction mixtures, after having separated cobaltꢀ
residues by adsorptive filtration, we never found experimental evidence for sulfoxideꢀ or
sulfoneꢀformation. We independently prepared sulfoxide 9 and sulfone 10 (Scheme 3), to use
12

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information on their retention times (GC), chemical shifts (protonꢀ and carbonꢀ13 NMR), and
resonance fine structures to clarify this aspect in a more systematical manner. These efforts, in
summary, confirmed that sulfoxidation products are not notably formed in this new method for
thioether synthesis.
tBuOOH
V(O)LSB(OEt)cat.
O
SCH3
S
H
H
H
H
O
O
Ph
Ph
CHCl / 20 °C
3
(
±)ꢀ3a
(±)ꢀ9 (66%)
O
O
tBuOOH
V(O)LSB(OEt)cat.
S
S
H
H
H
H
O
O
O
Ph
Ph
CHCl / 20 °C
3
(
±)ꢀ9
(±)ꢀ10 (75%)
SB
Scheme 3 Sulfoxidation of thioether 3 by tertꢀbutyl hydroperoxide [V(O)L (OEt) = 2ꢀ[(2ꢀ
oxidophenyl)iminomethyl](ethanolato)oxidovanadium(V), used as EtOHꢀsolvate].
From cisꢀ2ꢀallylcyclopentanol 1d and cisꢀ2ꢀallylcyclohexanol 1e we prepared
methylsulfanylꢀfunctionalized oxabicycloalkanes 3d–e in 71–74% yield along with 10–11% of
reduction products 8d–e (Table 3, entries 1–2). The analytical data show that all bicyclic
products were formed as single diastereomers, having substituents next to the endocyclic
oxygen bound in relative transꢀconfiguration to the heterocyclic core.
Table 3 Oxidative cyclization of cisꢀ2ꢀallylcycloalkanols
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(
H C) S
3 2 2
H
H
H
H
H
H
OH
O / CHD
O H SCH
O H
2
3
+
n
n
n
2
Co(L ) (5)
2
70 °C
(
±)ꢀ1d–e
(±)ꢀ3d–e
(±)ꢀ8d–e
a
a
entry
1 / 3 / 8
n
1
2
3 /% (cis:trans)
71 (<1:99)
8 /% (cis:trans)
11 (<1:99)
1
2
d
e
74 (<1:99)
10 (<1:99)
a
Relative configuration refers to substituents next to the endocyclic oxygen atom.
2
.2 Aerobic cobalt-catalyzed oxidation in the presence of disulfides other than dimethyl
disulfide
For extending the scope of the new thioether synthesis, we replaced dimethyl disulfide
by diethyl disulfide and diallyl disulfide. Oxidation of 1ꢀphenylpentenol 1a in a 6.7
of diethyl disulfide, containing 1.7 concentration of CHD and 5 mol% of cobalt complex 5,
provided 36% of ethyl thioether 11 and about the same amount of reduction product 8a (39%)
Scheme 4).
M solution
M
(
(
H C ) S
5 2 2 2
SC H
H
H
2
5
H
H
Ph
OH
O / CHD
O
O
2
Ph
Ph
+
2
Co(L ) (5)
2
1
a
70 °C
(±)ꢀ11 (36%)
cis trans < 1:99
(±)ꢀ8a (39%)
cis trans < 1:99
:
:
Scheme 4 Termination of cobaltꢀcatalyzed oxidative alkenol cyclization by diethyl disulfide.
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From cobaltꢀcatalyzed oxidiation of phenylpentenol 1a in a solution of diallyl disulfide
) and CHD (1.7 ), we isolated allyl thioether 12 (24%), methylꢀsubstituted
tetrahydrofuran 8a (14%), 2ꢀphenylꢀ5ꢀbutenyltetrahydrofuran 13 (22%), and disulfide 14
10%) (Scheme 5). Butenylꢀsubstituted tetrahydrofuran 13 possibly originates from a sequence
(4.6
M
M
(
of carbon radical addition to the terminal alkene carbon in diallyl disulfide, followed by
allyldisulfanyl radical elmination. This sequence is mechanistically similar to the pathway
2
8,29
reported for carbon radical allylation by allylphenylsulfide,
and furthermore explains the
origin of mixed disulfide 14 as putative combination product of the allyldisulfanyl radical and
thephenyltetrahydrofurylmethyl radical 2a.
Attempts to prepare the tertꢀbutylsulfanyl derivative of 3a from phenylpentenol 1a,
cobaltꢀcatalyst 5, diꢀ(tertꢀbutyl) disulfide (4.7
M), and cyclohexaꢀ1,4ꢀdiene (0.9 M) exclusively
provided transꢀ2ꢀphenylꢀ5ꢀmethyltetrahydrofuran (8a), and therefore was not further pursued.
Considering the underlying mechanism of competitive carbon radicalꢀtrapping by CHD and an
dialkyl disulfide, we think that homolytic substitution at diꢀ(tertꢀbutyl) disulfide is too slow to
notably compete with hydrogen atom trapping from CHD.
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allyl2S2
S
H
H
H
H
Ph
OH
O / CHD
2
O
O
Ph
Ph
+
2
Co(L ) (5)
2
1
a
70 °C
(±)ꢀ12 (24%)
cis trans < 1:99
(±)ꢀ8a (14%)
:
cis:trans < 1:99
S
S
H
H
H
H
O
O
Ph
Ph
+
(
±)ꢀ13 (22%)
(±)ꢀ14 (10%)
cis trans < 1:99
cis trans < 1:99
:
:
Scheme 5 Products of aerobic cobaltꢀcatalyzed alkenol oxidation in the presence of diallyl
disulfide.
3
Application in Synthesis
To use the potential of the new oxidation/homolytic substitutionꢀcascade in synthesis, we
chose 2,3,3,5ꢀtetrasubstituted tetrahydrofuran 3f as target. The ethylsulfanyl derivative of this
3
0
product is a potent cyclooxygenase 2ꢀinhibitor, which was prepared in three steps from the
underlying alkenol via iodocyclization, separation of the 20/80ꢀmixture of cis/transꢀ
diastereomers, and substitution of ethylthiolate for iodide. Our objective in synthesis of
compound 3f was to (i) apply the outstanding 2,5ꢀtransꢀstereoselectivity for tetrahydrofuran
formation of the cobaltꢀcatalyzed alkenol cyclization, (ii) safe the iodocyclization step, and
(iii) prepare the methylsulfanylꢀfunctionalized derivative (Scheme 6), which for uncommented
3
0
reasons had not been included in the cyclooxygenase structureꢀactivity survey.
16

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SCH3
H
H
H
O
Ph
Ph
OH
Ph
+
[ SCH ] – [ H ]
3
Ph
HO
HO
reactivity / stereocontrol?
relꢀ(2S,3R,5R)ꢀ3f
relꢀ(1S,2R)ꢀ1f
Scheme 6 Approach to synthesis of a methylsulfanylꢀderivative of a potent cyclooxygenase 2ꢀ
3
0
inhibitor via stereoselective methylsulfanylꢀcyclization of trisubstituted alkenol 1f.
To approach target molecule 3f, we addressed at first the effects of a phenylꢀ and a
hydroxyl group in position 2 in oxidative 4ꢀpentenol ring closures, conducted in dimethyl
disulfide. 2ꢀPhenylpentenꢀ4ꢀol (1g) provides under such conditions 2ꢀphenylꢀ4ꢀ
(methylsulfanyl)methyltetrahydrofuran (3g) as major product, along with a minor fraction of
reduction product 8g (Scheme 7, top). Both products were obtained as 88/12ꢀmixture of
cis/transꢀstereoisomers, which is in line with previous findings and a general stereochemical
1
7
guideline for this chemistry. Attempts to oxidize relꢀ(1S,2S)ꢀ1ꢀphenylꢀ4ꢀpenteneꢀ1,2ꢀdiol relꢀ
1S,2S)ꢀ(1h) under standard conditions furnished exclusively benzaldehyde (Scheme 7,
(
bottom). From this information we concluded that aerobic oxidation catalyzed by cobalt
complexes is able to selectively break the central carbonꢀcarbon bond of a glycol. This
phenomenon is under current investigation in our laboratory.
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(
H C) S
3 2 2
SCH3
H
H
OH
O / CHD
O
O
2
+
2
Co(L ) (5)
Ph
2
Ph
Ph
H
H
7
0 °C
(±)ꢀ1g
(±)ꢀ3g (68%)
(±)ꢀ8g (17%)
cis:trans = 88:12
cis:trans 87:13
(
H C) S
3 2 2
H
H
Ph
OH
O / CHD
2
PhCHO
70%
2
Co(L ) (5)
HO
2
7
0 °C
relꢀ(1S,2S)ꢀ1h
Scheme 7 Study on the effect of an alkenol substituent in position 2 on reactivity and
selectivity of cobaltꢀcatalyzed oxidation.
To explore effects of cumulative phenyl substitution on selectivity in methylsulfanyl
cyclization, we oxidized relꢀ(1R,2R)ꢀ1,2ꢀdiphenylpentenol relꢀ(1R,2R)ꢀ1i and the higher
homologue, relꢀ(1R,2R)ꢀ1,2ꢀdiphenylhexenol relꢀ(1R,2R)ꢀ15 in solutions of dimethyl disulfide
and CHD. From both reactions, we isolated substantial yields (70–72%) of diastereomerically
pure methylsulfanylꢀcyclized products 3i and 16, and minor amounts of reduced products 8i
and 17. All the cyclic ethers have substituents next to endocyclic oxygen attached in relative
transꢀconfiguration to the heterocyclic core (Scheme 8).
With an extension of the cobalt method to tetrahydropyran synthesis we encountered an
interesting stereochemical question. In tetrahydrofuran, 2,5ꢀtransꢀconfiguration of substituents
2
3
is thermochemically favored. In tetrahydropyran, 2,6ꢀtransꢀconfiguration places one of the
3
1
carbon substituents into axial position, which is thermochemically disfavored. Since
tetrahydropyrans 16 and 17 are the only examples for 6ꢀexoꢀalkenol cyclization from cobaltꢀ
18

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catalyzed aerobic oxidation so far, we have no explanation on the origin of this selectivity.
(
H C) S
3 2 2
H
H
SCH3
H
H
H
H
Ph
Ph
OH
O / CHD
O
O
2
Ph
Ph
2
5
2
5
+
3
3
2
Co(L ) (5)
2
Ph
Ph
H
H
70 °C
relꢀ(1R,2R)-1i
relꢀ(2R,3R,5R)-3i
relꢀ(2R,3R,5S)-8i (7%)
7
2%
7%
SCH3
(
H C) S
3 2 2
H
H
H
H
H
H
H
Ph
Ph
OH
Ph
Ph
O
Ph
Ph
O
O / CHD
2
2
3
6
2
3
6
+
2
Co(L ) (5)
2
H
70 °C
relꢀ(1R,2R)-15
relꢀ(2R,3R,6R)-16
0%
relꢀ(2R,3R,6S)-17
7
9%
Scheme 8. Oxidations of 1,2ꢀlikeꢀconfigured alkenols catalyzed by cobalt(II)ꢀcomplexes.
With the necessary information in hand to finalize the project, we oxidized relꢀ(1S,2R)ꢀ
1
,2ꢀdiphenylpentenꢀ1,2ꢀdiol relꢀ(1S,2R)ꢀ(1f) in a solution of dimethyl disulfide/CHD at lower
temperature, for preventing glycol cleavage as effectively as possible. From an oxidation
performed at 60 °C, we isolated by chromatography 67% of stereochemically pure 2,3,3,5ꢀ
tetrasubstituted tetrahydrofuran 3f and 10% of reduction product 8f, both showing 2,5ꢀtransꢀ
configuration (Table 4, entry 2). From the reaction mixture, we further isolated 9% of
phenylbutenyl ketone 18, which is the major product from an oxidation conducted at 70 °C
(Table 4, entry 1).
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Table 4 Products of aerobic alkenediolꢀoxidation in solutions of CHD and dimethyl disulfide
(
H C) S
3 2 2
SCH3
H
H
H
H
H
OH
O
O
O
O /CHD / T
2
Ph
Ph
Ph
2
5
2
5
+
+
3
3
HO
2
Ph
Co(L ) (5)
HO
HO
Ph
2
Ph
relꢀ(1S,2R)ꢀ1f
Ph
relꢀ(2S,3R,5R)ꢀ3f
relꢀ(2S,3R,5S)ꢀ8f
18
entry
T / °C
70
2f / %
22
7f / %
11
18 / %
1
2
40
9
60
67
10
Concluding remarks
Methylsulfanylꢀcyclization is a new approach to stereoselective synthesis of
tetrahydrofurans bearing a methylthioether functional group in the side chain next to the
endocyclic oxygen. The mechanism follows the scheme put forward to explain other oxidative
alkenol cyclizations mediated by cobaltꢀactivated dioxygen, and uses homolytic methylsulfanyl
transfer to tetrahydrofurylꢀ2ꢀmethyl radicals as new conclusive step.
The oxidation/homolytic substitutionꢀcascade is particularly useful for constructing 2,5ꢀ
transꢀconfigured tetrahydrofurans, as exemplified by synthesis of diastereomerically pure 2,5ꢀ
diꢀ, 2,3,5ꢀtriꢀ, and 2,3,3,5ꢀtetrasubstituted cyclic ethers. In view of the ease, intermediates and
products along the sequence can be oxidized, it is worth to emphasize that we never found
alkyl hydroperoxides, sulfoxides, or sulfones as side products. We relate this noteworthy
chemoselectivity to the reductant cyclohexaꢀ1,4ꢀdiene, originally added to maintain reactivity
and selectivity in the catalytic cycle by in situ reducing cobalt(III) to cobalt(II).
Cyclohexaꢀ1,4ꢀdiene, combined with a fluoroꢀsubstituted cobalt(II)ꢀcatalysts of the type
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5
, furthermore opens new aspects in this chemistry, as shown by synthesis of a trisubstituted
tetrahydropyran from a 5ꢀhexenol. We have attempted the oxidative 6ꢀexoꢀcyclization many
times before and always failed. The success described in this article possibly arises from the
ability of cyclohexaꢀ1,4ꢀdiene to balance selectivity in oxidative and reductive steps in a more
appropriate manner than previously used reductants.
The tetrahydropyran synthesis described in this article suggests that the concept of
oxidation/homolytic substitutionꢀcascade possibly extends to synthesis of larger heterocycles,
or intermolecular carbonꢀoxygen bond formation. Both questions are being addressed at the
moment in our laboratory.
Experimental
1
General
1
8
For general laboratory practice and instrumentation see ref. and the Supporting Information.
2
Cobalt Complexes
A solution of 4ꢀfluorobenzoylacetone (367 mg, 2.04 mmol) in EtOH (5 mL) was poured into
an aqueous solution (15 mL) of cobalt acetate tetrahydrate (250 mg, 1.00 mmol). The yellow
precipitate was filtrated and dried. Bis-[1-(4-fluorophenyl)-3-(oxo-κO)-but-1-en-1(olato-
κO)]cobalt(II) dihydrate (5): Yield: 381 mg (481 mmol, 84 %), yellow solid. νmax (KBr) /
–
1
cm 3391 (OH), 1603 (CO), 1572, 1523, 1499, 1417, 1388, 1297, 1233, 1157, 1163, 1110,
1
011; δ (CDCl /acetone, 377 MHz) –112.0. Found C, 53.33; H, 4.92. C H CoF O (453.30)
F
3
20 20
2
6
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2
+
requires C, 52.99; H, 4.45 %. ESIꢀMS: Found: 439.99 [CoL +Na ], C H CoF NaO
2
20 16
2
4
requires 440.02.
3
3
Aerobic Oxidation Reactions
.1 Oxidation of 1-phenylpent-4-en-1-ol (1a). A solution of alcohol 1a (163 mg, 1.01
mmol) and cobalt catalyst 5 (22.9 mg, 50.5 ꢂmol) in dimethyl disulfide (9.5 mL) and CHD
1.0 mL) was stirred at 70 °C for 6 h while being exposed to laboratory atmosphere. The
(
reaction mixture was cooled to 20 °C and concentrated under reduced pressure to afford a
residue that was purified by column chromatography [SiO , Et O/pentane = 1:10 (v/v)]. trans-
2
2
2
-methyl-5-phenyltetrahydrofuran (8a). Yield: 16.2 mg (100 ꢂmol, 10 %). Analytical data
3
2
agree with published values. trans-2-(methylsulfanyl)-methyl-5-phenyltetrahydrofuran
(
3a). Yield: 151 mg (726 ꢂmol, 72 %), R 0.50 [SiO , acetone/pentane = 1:5 (v/v)], colorless
f
2
oil. δ (600 MHz, CDCl ) 1.84–1.94 (2 H, m), 2.20–2.25 (1 H, m), 2.22 (3 H, s, Me), 2.39–
H
3
2
.43 (1 H, m), 2.70 (1 H, dd, J 13.3, 6.7), 2.82 (1 H, dd, J 13.3, 5.4), 4.45 (1 H, quint, J 6.4),
5
.07 (1 H, t, J 6.9), 7.25–7.27 (1 H, m), 7.33–7.36 (4 H, m). NOESY 2ꢀH || 5ꢀH. δ (100 MHz,
C
CDCl ) 16.5 (CH ), 31.7, 35.2, 39.6, 79.2, 80.8, 125.5, 127.1, 128.3, 143.3. GCꢀMS (EI, 70
3
3
+
eV) m/z (%) 208 (39, M ), 147 (100), 129 (63), 117 (20), 105 (31), 91 (94), 77 (25). HRMS
+
+
+
(
EI ) m/z 208.0921 (M ); calculated mass for C H OS : 208.0922.
12 16
3
.2 Oxidation of rel-(1S,2R)-1,2-diphenylpent-4-en-1,2-diol (1f). A solution of alcohol 1f
(127 mg, 500 ꢂmol) and cobalt catalyst 5 (11.5 mg, 25.4 ꢂmol) in dimethyl disulfide (5.0 mL)
and CHD (0.5 mL) was stirred at 60 °C for 5 h while being exposed to laboratory atmosphere.
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The reaction mixture was cooled to 20 °C and concentrated under reduced pressure to afford
an oily residue that was purified by column chromatography [SiO , Et O/pentane = 1:10 (v/v)].
2
2
rel-(2S,3R,5S)-5-methyl-2,3-diphenyltetrahydrofuran-3-ol (8f). Yield: 12.9 mg (50.7 ꢂmol,
0 %), R 0.42 [SiO , acetone/pentane = 1:5 (v/v)], colorless oil. δ (600 MHz, CDCl ) 1.49 (3
1
f
2
H
3
H, d, J 6.1), 1.74 (1 H, d, J 1.8, OH), 2.21–2.27 (1 H, m), 2.52 (1 H, dd, J 12.9, 5.5), 4.76–4.83
1 H, m), 5.40 (1 H, s), 7.03–7.07 (2 H, m), 7.24–7.26 (3 H, m), 7.28–7.31 (1 H, m), 7.37 (2 H,
t, J 7.7), 7.40–7.44 (2 H, m). δ (100 MHz, CDCl ) 21.5, 50.9, 75.2, 83.5, 90.0, 125.3, 126.6,
(
C
3
+
1
27.1, 128.1, 128.26, 128.29, 136.0, 142.1. GCꢀMS (EI, 70 eV) m/z (%) 254 (<1, M ), 236
(13), 193 (10), 178 (6), 165 (8), 148 (88), 133 (65), 115 (23), 105 (100), 91 (8), 77 (65).
+
+
+
HRMS (EI ) m/z 254.1312 (M ); calculated mass for C H O : 254.1307. rel-(2S,3R,5R)-5-
1
7
18
2
(methylsulfanyl)-methyl-2,3-diphenyltetrahydrofuran-3-ol (3f). Yield: 100 mg (334 ꢂmol,
6
7 %, cis:trans), R 0.37 [SiO , acetone/pentane = 1:5 (v/v)], colorless oil. δ (600 MHz,
f
2
H
CDCl ) 1.78 (1 H, s, OH), 2.26 (3 H, s, CH ), 2.56 (1 H, d, J 7.4), 2.88–2.99 (1 H, m), 4.86–
3
3
4
7
8
.94 (1 H, m), 5.45 (1 H, s), 7.05 (2 H, dd, J 6.3, 2.7 ), 7.23–7.32 (4 H, m), 7.38 (2 H, t, J 7.4),
.42–7.46 (2 H, m). NOESY 2ꢀH || 5ꢀH. δ (150 MHz, CDCl ) 16.9 (Me), 39.7, 47.9, 78.4,
C
3
3.2, 89.5, 125.3, 126.6, 127.2, 128.27, 128.34, 135.5, 141.7. GCꢀMS (EI, 70 eV) m/z (%) 300
+
+
(
<1, M ), 234 (3), 221 (8), 192 (8), 147 (17), 115 (10), 105 (100), 91 (8), 77 (33). HRMS (EI )
+
+
m/z 282.1090 (M –H O); calculated mass for C H OS : 282.1078.
2
18 18
3
.3 Oxidation of rel-(1R,2R)-1,2-diphenylhex-5-en-1-ol (15). A solution of alcohol 15
169 mg, 669 ꢂmol) and cobalt catalyst 5 (15.1 mg, 33.3 ꢂmol) in dimethyl disulfide (6.6 mL)
and CHD (0.65 mL) was stirred at 70 °C for 16 h while being exposed to laboratory
(
23

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atmosphere. Another batch of cobalt catalyst 5 (15.2 mg, 33.5) and CHD (0.65 mL) were
added and the reaction mixture was stirred another 6 h at 70 °C. The reaction mixture was
cooled to 20 °C and concentrated under reduced pressure to afford a residue that was purified
by column chromatography [SiO , Et O/pentane = 1:10 (v/v)]. rel-(2R,3R,6S)-6-methyl-2,3-
2
2
diphenyltetrahydropyran (17). Yield: 15.4 mg (61.0 ꢂmol, 9 %), R 0.56 [SiO ,
f
2
acetone/pentane = 1:5 (v/v)], colorless oil. δ (400 MHz, CDCl ) 1.21 (3 H, d, J 6.1), 1.39–
H
3
1
.49 (1 H, m), 1.58–1.68 (1 H, m), 1.85–2.00 (1 H, m), 3.92 (1 H, d, J 8.4), 4.09 (1 H, quind, J
.9, 6.1), 4.76 (td, J 8.4, J 6.2), 7.14–7.19 (2 H, m), 7.23–7.29 (6 H, m), 7.33–7.37 (1 H, m).
7
t
d
δ (100 MHz, CDCl ) 21.4, 31.6, 33.6, 57.0, 75.3, 80.4, 126.1, 126.3, 128.2, 128.4, 128.6,
C
3
+
1
28.7, 142.8, 143.1. GCꢀMS (EI, 70 eV) m/z (%) 252 (<1, M ), 178 (3), 165 (17), 152 (7), 115
+
+
(
5), 85 (100), 77 (3). HRMS (EI ) m/z 252.1515 (M ); calculated mass for C H O: 252.1514.
18 20
rel-(2R,3R,6R)-6-(methylsulfanyl)-methyl-2,3-diphenyltetrahydropyran (16). Yield: 134
mg (450 ꢂmol, 67 %), R 0.51 [SiO , acetone/pentane = 1:5 (v/v)], colorless oil. δ (400 MHz,
f
2
H
CDCl ) 1.57–1.72 (2 H, m), 1.84–1.93 (1 H, m), 1.95–2.04 (1 H, m), 2.09 (3 H, s, CH ), 2.55
3
3
(1 H, dd, J 13.3, 7.2), 2.69 (1 H, dd, J 13.3, 5.1), 3.92 (1 H, d, J 8.1), 4.16 (1 H, quin, J 6.6),
4
2
7
2
.75 (1 H, dt, J 8.1, 6.0), 7.13–7.19 (2 H, m), 7.21–7.28 (6 H, m), 7.32–7.36 (2 H, m). NOESY
ꢀH ↔ 3ꢀH, 2ꢀH || 6ꢀH, 3ꢀH || 6ꢀH. δ (100 MHz, CDCl ) 16.4 (Me), 31.2, 31.3, 39.3, 56.8,
C
3
9.1, 81.1, 126.1, 126.3, 128.1, 128.3, 128.5, 128.7, 142.4, 142.9. GCꢀMS (EI, 70 eV) m/z (%)
+
98 (<1, M ), 237 (1), 193 (5), 178 (5), 165 (21), 152 (12), 131 (100), 115 (8), 103 (20), 87
+
+
(
20). HRMS (EI ) m/z 298.1384 (M ); calculated mass for C H OS: 298.1391.
19 22
Acknowledgements. This work was supported by the ScheringꢀStiftung (Scholarship for P.F.)
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and the Stiftung für Innovation des Landes RheinlandꢀPfalz (Grant 898), and is part of the
Ph.D. thesis of P.F. We thank Dipl.ꢀChem. Fabian Menges for recording ESIꢀMSꢀspectra of
cobalt(II) complexes.
Notes and References
†
Electronic supplementary information (ESI) available: Standard instrumentation, protocol for
...... See http://www.rsc........................
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(
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(
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