Alkoxyl radical addition to acceptor-substituted carbon-carbon double bonds

Article abstract of DOI:10.1016/j.tet.2012.08.083

Alkoxyl radicals add 5-exo-trig selectively to cyano- and methoxycarbonyl-substituted carbon-carbon double bonds, to afford α-acceptor-α-tetrahydrofuryl-2-methyl radicals. Trapping of cyclized radicals by Bu₃SnD furnishes products of site-speci

Full text of DOI:10.1016/j.tet.2012.08.083

Tetrahedron 68 (2012) 10378e10390
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Alkoxyl radical addition to acceptor-substituted carbonecarbon double bonds
*
Irina Kempter, Andreas Groß, Jens Hartung
€
€
Fachbereich Chemie, Organische Chemie, Technische Universitat Kaiserslautern, Erwin-Schrodinger-Straße, D-67663 Kaiserslautern, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 June 2012
Received in revised form 24 August 2012
Accepted 27 August 2012
Available online 1 September 2012
Alkoxyl radicals add 5-exo-trig selectively to cyano- and methoxycarbonyl-substituted carbonecarbon
double bonds, to afford
a
-acceptor-
a-tetrahydrofuryl-2-methyl radicals. Trapping of cyclized radicals by
Bu3SnD furnishes products of site-specific deuterium-labeling in
a-position to the acceptor group. In
intramolecular competition experiments, alkoxyl radicals add similarly fast to a cyano-substituted
double bond than to a terminal alkene, but by a factor >25 faster to an enol ether. The nucleophilic
component of alkoxyl radical reactivity opens an interesting new access to tetrahydrofuryl amino acids
via C,O-cyclization, as shown by synthesis of a N,O-protected 5-phenyltetrahydrofuryl-2-methyl glycine.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Acrylate
Acrylonitrile
Addition
Alkoxyl radical
Amino acid
Bromo-cyclization
Borderline reactivity
Radicals
Stereoselective synthesis
Thiazolethione
1. Introduction
oxidatively activated alkenes. Additions of oxygen radicals that are
too slow to compete with other radical consuming processes, such
The oxygen nucleus attracts an unpaired valence electron in
alkoxyl radicals stronger than the carbon nucleus in alkyl radicals.
Oxygen radicals therefore attack higher in energy s- and p-bonds
as b
-fragmentation9e11 or homolytic substitution,12 generally are
accelerated by substituting the carbon double bond with typical
donor groups, such as methyl, phenyl, or silyloxy.13e16 A drawback
for pursuing new reactions in alkoxyl radical chemistry in synthe-
sis, however, is the inherent electrophilicity, restricting selectivity
control by the polar effect so far exclusively to donor substituents.
The scope of alkoxyl radical chemistry extends, if the in-
termediates add to Michael-type acceptors. In a communication on
alkenoxyl radical generation from O-phenylsulfenates for studying
with a reactivity/selectivity profile that is characteristic for many
electrophiles.1,2 Since oxygen forms strong bonds to hydrogen and
carbon, the odd electron in alkoxyl radicals gives rise to chemical
reactivity that is by orders of magnitude higher than carbon radical
reactivity. Typical examples for reactions that take profit from
unique alkoxyl radical reactivity are found in metabolic pathways,3
and in oxidative hydrocarbon degradation, which clear the atmo-
sphere from volatile organic compounds.4,5
In spite of enormous reactivity, alkoxyl radicals generally react
selectively, following guidelines that allow to apply the in-
termediates in organic synthesis.1 A method that has received
growing attention for stereoselective synthesis within the past
decade is the alkoxyl radical addition to carbonecarbon double
bonds.6e8 The current mechanistic picture shows that alkoxyl
stereochemical aspects of 4-pentenoxyl radical cyclization,17
a-
methacrylate-type double bonds were used as O-radical acceptors,
however, without addressing the role of the polar effect.18 In view
of the potential arising from a nucleophilic component in alkoxyl
radical reactivity, we decided to explore in a systematic manner
addition to acrylate- and acrylonitrile-type
p-bonds, lacking in an
activating -methyl group (Fig. 1). The major results from the study
a
show that 4-pentenoxyl radicals add to the cyano-substituted car-
bonecarbon double in a rate that compares to the rate of addition
to a terminal double bond. The fastest reaction in the series of
competition experiments, however, is addition to an enol ether
radicals add to constitutionally dissymmetric
tivity that often complements additions of alcohols or alkoxides to
p-bonds with selec-
p
-bond. From this dichotomic behavior we concluded that alkoxyl
radicals are both, electrophiles and nucleophiles, depending on
substitution at the -bond. We used the nucleophilic component of
* Corresponding author. Tel.: þ49 631 205 2431; fax: þ49 631 205 3921; e-mail
address: hartung@chemie.uni-kl.de (J. Hartung).
p
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.08.083

I. Kempter et al. / Tetrahedron 68 (2012) 10378e10390
10379
For synthesis of alkenyl thiohydroxamates 1aej, cyclic thiohy-
droxamic acid 6 was esterified by alkenols using the Mitsunobu-
method, or a procedure that we refer to as the salt-method
(Scheme 2, Supplementary data, and Experimental). Selectivity in
the salt-method follows Pearson’s principle of hard soft acids and
bases. O-Alkylation at the hard oxygen instead of soft sulfur is at-
tainable with a hard carbon electrophile, reacting with a thiohy-
droxamate anion experiencing no contact from a hard, strongly
polarizing cation. This approach is put into practice by converting
acid 6 into tetraethylammonium salt 7, which subsequently is
treated in a strongly polar aprotic solvent, such as dimethyl form-
amide, with an alkenyl chloride (for 1aee) or a tosylate (for 1i)
(Table 1). In the Mitsunobu-method, the electrophile is generated
in situ from an alkenol and the combination of diethyl azodi-
carboxylate (DEAD) and triphenylphosphine in a solution of ben-
zene, to furnish O-alkenyl thiohydroxamates 1feh and 1j in yields
between 31 and 67% (Fig. 2). After chromatographic purification,
the target compounds were received as colorless (1gei) to yellow
(1aee, 1j) compounds, which are stable for months if stored in
a refrigerator. O-Alkenyl thiohydroxamates of the type 1 show
characteristic electronic spectra having a broad band located at
electrophilic
nucleophilic
D
A
•
O
A = CO2CH3, CN
D = CH3, OCH3
Fig. 1. Structure, substituent effects, and proposed chemical reactivity of alkoxyl
radicals used in this study to explore the polar effect in additions to carbonecarbon
double bonds.
alkoxyl radical reactivity to develop a new route to synthesis of
a N,O-protected tetrahydrofuryl-2-methyl amino acid via C,O-
cyclization.
2. Results and interpretation
l
¼332e338 nm (lg ε w3.00e3.28 m2 molꢁ1, in EtOH for 1aec, and
2.1. Alkoxyl radical generation and synthesis of radical
precursors
CHCl3 for 1d), which allows to photoexcite the molecules for
homolytically breaking the nitrogeneoxygen bond (vide supra).
We applied O-alkenyl thiohydroxamates of the type 1 in this
study as alkoxyl radical progenitors. The compounds add electro-
philic radicals Yꢀ at the thione sulfur, which causes the nitro-
geneoxygen bond to homolytically break. Radicals used for
inducing alkoxyl radical liberation from 1 generally originate from
Mitsunobu-method
An
An
ROH
an initiator, such as
a,a-azobisisobutyronitrile (AIBN), or from
S
S
DEAD / PPh3
a mediator XeY in a propagating step of a chain reaction (Scheme 1).
Typical mediators XeY used in this chemistry are tributylstannane,
the deuterium derivative Bu3SnD for isotope labeling, and bromo-
trichloromethane. An alternative approach to oxygen radical gen-
eration from 1 is photochemistry. Excitation of electronic transitions
in the molecule, by shining light into the broad electronic band at
w335 nm, selectively induces homolysis of the nitrogeneoxygen
bond. The reaction between chain propagating radical Yꢀ and
O-alkenyl thiohydroxamate 1 thus provides alkenoxyl radical 2 and
substituted thiazole 3.5,19 For synthesis of tetrahydrofurans (e.g. 5),
bimolecular trapping of alkenoxyl radical 2 by the mediator XeY
must be slower than the cyclization 2/4.20e23 Trapping of carbon
radical 4 by the mediator provides target product 5 and supplies the
chain with propagating radical Yꢀ.5
S
S
N
N
C6H6
OH
OR
6
1 (MAnTTOR)
NEt4OH
MeOH
An
S
RX
DMF
S
N
–
+
NEt4
O
7
salt-method
Scheme 2. Methods for synthesis of alkoxyl radical precursors of the type 1 [for yields,
see Table
1
and Fig. 2; X¼Cl, OTs; R¼alkenyl; all reactions were performed at
20e25 ꢂC].
An
S
S
N
Table 1
A
Yields of ester- and cyano-substituted N-alkenoxythiazolethiones 1aee prepared
O
5
O
from alkenyl chlorides via the salt-methoda
R
X
R
OMAnTT
R2
A
Y•
1
R1
A
An
X–Y
S
1a–e
A
•
SY
N
3
O•
O
Entry
1
R1
R2
A
Yield/%
(E)/(Z)
1
2
3
4
5
a
b
c
d
e
CH3
C6H5
CH3
C6H5
C6H5
H
H
H
H
CN
CN
CO2CH3
CO2CH3
CN
36
49
49
70
73
77:23
76:24
>98:2
>98:2
62:38
R
R
A
2
4
cyclo-C3H5
Scheme 1. Steps for alkoxyl radical generation in a chain reaction between N-alkoxy-
thiazole-2(3H)-thione
(R¼e.g. CH3 or Ph; A¼e.g. CN, CO2CH3; An¼p-anisyl, i.e.
p-methoxyphenyl) and a mediator XeY (Bu3SnH, Bu3SnD, or BrCCl3).
a
1
(RX¼RCl, cf. Scheme 2; MAnTT¼5-(4-methoxyphenyl)-4-methyl-2-thiooxo-2,3-
dihydrothiazol-3-yl).

10380
I. Kempter et al. / Tetrahedron 68 (2012) 10378e10390
H
OMAnTT R1
Ph
OMAnTT
(S)
R2
CO2Et
1f–i
NHAc
(S)-1j (31%)
(E):(Z) >98:2
1
R1
R2 yield / % (E):(Z)
–
f
CH3
H
CH3
OCH3 67
CN 63
CO2Et 49
60
g
h
i
80:20
72:28
>98:2
H
H
Fig. 2. Structure formulas, indexing of compounds, and yields of N-alkenoxythiazolethiones 1fej (Mitsunobu-method for 1feh and 1j, and salt-method for 1i from the alkenyltosylate).
2.2. Alkoxyl radical addition to acceptor-substituted
possibly from b-carbonecarbon fragmentation of alkoxyl radicals
carbonecarbon double bonds
or O-alkenyl thiohydroxamates 1aed. Authentic references of the
assumed products were available from the synthetic part of the
study. None of the assumed products, however, had formed in
sufficient amounts for being detected, under conditions applied to
prepare 5aed.
In the standard approach to tetrahydrofuran synthesis we pho-
tolyzed cyano-substituted alkenoxythiazolethiones 1aeb and ester
derivatives 1ced with near UV-light (350 nm) in solutions of ben-
zene containing 3.7 equiv of tributylstannane (c0¼185 mM). From
the solutions, we isolated 2,5-disubstituted tetrahydrofurans 5aed,
as mixtures of cis/trans-stereoisomers in yields between 67 and 71%
(Table 2, entries 1e2 and 4e5). The trans-stereoisomer of hetero-
cycles 5aed, in all instances, is the major product, as derived from
stereochemical analysis by proton NMR, carbon-13 NMR, and
NOESY-spectroscopy. For supplementing the mass balance and
supporting the mechanistic interpretation, we quantified in all in-
stances tributylstannylsulfanylthiazole 3a. This compound forms in
99% to quantitative yield, but decomposes upon contact with silica
gel used for separating tetrahydrofurans 5aed, particularly from
residual organotin compounds. Since we had fully characterized
stannylated thiazole 3a in a previous study, we restricted ourselves
at this point to identifying heterocycle 3a by proton NMR-spec-
troscopy.5 A supplementary photoreaction performed with Bu3SnD
as mediator, provides tetrahydrofuran 5bd1 in 74%, bearing
In controls to investigate whether tetrahydrofuran 5b possibly
had formed from an alkoxide-mediated cyclization, we treated 1-
phenyl-6-hydroxyhex-2-enenitrile, the underlying alcohol of 1b,
with tributylstannane in benzene. Also, we stirred 50/50-mixtures
of this alcohol and the derived ketone in a solution containing
tributylstannane for 90 min in the dark, and in a photoreactor
shining 350 nm-light into the sample. From the controls, we ex-
clusively recovered the starting materials. The only chemical
change we noticed was a photoisomerization at the double bond of
6-phenyl-6-hydroxyhex-2-enenitrile from (E)/(Z)¼87:13 to 51:49.
From a boiling solution of O-alkenyl thiohydroxamate 1d in
benzene, containing 0.5 M concentration of bromotrichloromethane
and minor amounts of azobisisobutyronitrile (AIBN) to initiate the
reaction, we isolated 62% of
a-thiazylsulfanyl ester 8d in a cis/trans-
ratio of 43:57, 21% of -bromoester 9d as 44/56-mixture of cis/trans-
a
isomers, and 30% of trichloromethylsulfanylthiazole 3b (Scheme 3).
From this result we concluded that regio- and stereoselectivity of
intramolecular carboneoxygen bond formation are independent
the deuterium label exclusively in
(Table 2, entry 3).
a-position to the cyano group
Table 2
Products of reductive 3-alkenoxythiazole-2(3H)-thione (MAnTTOR) conversion
Bu3SnX
An
A
R
OMAnTT
O
S
25 °C / h
R
5
2
X
+
SSnBu3
A
C6H6
N
1
3a
5
Entry
1/5
R
A
X
5/% (cis/trans)a
3a/%b
1
2
3
4
5
ab
b
CH3
CN
CN
CN
CO2CH3
CO2CH3
H
H
D
H
H
69 (38:62)
67 (44:56)
74 (46:54)
68 (37:63)
71 (41:59)
99
C6H5
C6H5
CH3
quant.
bc
cc
dd
dd
99
quant.
C6H5
a
Relative tetrahydrofuran configuration at C2 and C5; 50/50-ratio of stereoisomers with respect to Ca.
b
c
From reaction mixtures via 1H NMR-spectroscopy (pentachlorobenzene as internal standard).
Compound indexing for 5: bd1
.
d
Not determined.
In routine analysis of product mixtures obtained from reactions
from the chemical nature of the mediator, as predicted on the basis
of the general mechanistic scheme for O-alkenyoxythiazolethione
conversion under conditions that favor homolytic reactions
(Scheme 1). The preference for thioether- over alkyl bromide for-
mation in this experiment arises from the low affinity of the
between tributylstannane and O-alkenyl thiohydroxamates 1aed,
we searched via GCeMS and NMR-spectroscopy for additional
products that could have been formed, for example, alcohols from
alkoxyl radical reduction by tributylstannane, aldehydes or ketones

I. Kempter et al. / Tetrahedron 68 (2012) 10378e10390
10381
Scheme 3. Selectivity of product formation from ester-substituted thiazolethione 1d and BrCCl3 (R¼CH3). a Relative configuration at C2 and C5; 50/50-ratio of stereoisomers at Ca.
a b-fragmentation pathway, to furnish, in extension to argu-
intermediate electrophilic
a-alkoxycarbonyl alkyl radical, for
abstracting a bromine atom from bromotrichloromethane.24e26
From a photolyzed solution of benzene containing bromotri-
chloromethane and 2-cyano-2-cyclopropyl-substituted thiazole-
ments provided in the previous paragraph, a carbon radical
that is trapped by bromotrichloromethane. The mechanism
that combines adequate reactivity with selectivity to explain
formation of (d-bromo-a-cyanobutenyl)tetrahydrofuran 5ε
thione 1e, we isolated 64% of a-substituted pentenonitrile 5ε, 16% of
under such conditions is the cyclopropylmethyl to butenyl
radical ring opening,29 which in turn points to an alkoxyl
radical addition mechanism to the cyano-substituted double
bond in 2e.
ketone 10, and 41% of trichloromethylsulfanylthiazole 3b (Scheme 4).
The appearance of ketone 10 in this experiment surprised us, although
ketone formation from secondary benzylic N-alkenoxythiazolethiones
is not an entirely new reaction. Benzylic N-alkenoxythiazolethiones
tend to dissociate into a thiolactam and a carbonyl compound in a non-
radical reaction, if stored, heated, or photolyzed.27
(iii) Stereoselectivity for tetrahydrofuran formation from 1aee
leaves a fingerprint-type 60/40-selectivity in favor of the 2,5-
BrCCl3
CN
Ph
O
Ph
OMAnTT
CN
O
25 °C / h
Ph
3b(41%)
+
+
CN
Br
C6H6
5 (64%)a
1e
cis:trans = 34:66b
10 (16%)
a
Scheme 4. Formation of a-(phenyltetrahydrofuryl)-d-bromopentenonitrile 5ε from 2-cyclopropyl-2-cyano-substituted thiazolethione 1e [62:38-mixture of (E)/(Z)-isomers]. (E)/
b
(Z)-Isomers not assigned. Relative tetrahydrofuran configuration at C2 and C5.
trans-stereoisomer. This value is close to the 65/35-cis/trans-
selectivity for 5-exo-trig-cyclization of the (E)-1-phenyl-4-
penten-1-yl radical.30 Alkoxide-based cyclization of 6-
hydroxy-6-phenyl-2-pentenenitrile, catalyzed by potassium
tert-butoxide in a solution of ethanol, furnishes a mixture of
stereoisomers for tetrahydrofuran 5b, which is by 52/48
slightly in favor for the cis-isomer.
Regarding the general mechanism, we think for the following
four reasons that synthesis of side chain acceptor-substituted
tetrahydrofurans from N-alkenoxythiazolethiones 1aee having
Michael-type carbonecarbon double bonds, follows the general
alkoxyl radical pathway (Scheme 1):
(i) The concluding step of the tetrahydrofuran synthesis is hy-
drogen atom transfer from Bu3SnH to
a
reactive in-
(iv) The yields of thiazole- and alkoxyl radical-derived products 3
and 5 are in many experiments similar, as predicted from an
underlying chain mechanism. In instances of diverging mass
balances, we find explanations from the literature that are
consistent with homolytic reactions starting from 1aed. For
example, 2-trichloromethylsulfanyl thiazole 3b is a photo-
labile compound, which gradually decomposes as substrate
conversion in a photochemical experiment progresses, thus
explaining the low yield of this product.5 In other instances
(cf. Scheme 4), additional thiazole-derived products
appeared. We had described the existence of such products
in a previous study dealing with alkoxyl radical generation
from tert-O-alkyl thiohydroxamates. Since the new thiazole
derivatives now and then remained unidentified we could
not use this information for improving the thiazole mass
balance.7
termediate, deuterium-labeling by Bu3SnD, or bromination
by BrCCl3. The three reagents have in common to favor ho-
molytic substitution by carbon radicals to reactions with
cations or anions.28 The position of site specific labeling,
deuteration for synthesis of tetrahydrofuran 5bd1 and bro-
mination for synthesis of
a-bromoester 9d, correlates with
the proposed position of a carbon radical in the intermediate
(Schemes 1 and 5).
(ii) The fact that
thiazolethione 1e furnishes exclusively (
butenyl)tetrahydrofuran 5ε, and not
a
-cyano-
a
-cyclopropyl-substituted N-alkenoxy-
-bromo- -cyano-
-bromo-a-
d
a
(
a
cyclopropyltetrahydrofuryl)acetonitrile 5e, shows that the
underlying intermediate is able to induce rapid cyclopropyl
ring opening (Scheme 5). From the site of bromine
labeling, we also knew that the ring opening occurs in

10382
I. Kempter et al. / Tetrahedron 68 (2012) 10378e10390
Scheme 5. Mechanistic interpretation of (cyanobutenyl)tetrahydrofuran formation from cyano-substituted cyclopropylmethyl radical 2e ([Br] symbolizes
a homolytically
transferable bromine atom, for example, from BrCCl3).
2.3. Reactivity in intramolecular additions
Alkoxyl radical 5-exo-trig cyclization to terminal- and donor-
substituted double bonds, unlike the oxygen radical -fragmenta-
b
The affinity for alkoxyl radicals to add to Michael-type carbone
carbon double caused us to address the question on alkoxyl radical
polarity in additions by a competition kinetic study. In our
approach, we used N-dienoxythiazolethiones 1fei for determining
the polar effect of substituents on relative rates in cyclizations.
In the general experimental set-up, solutions of O-alkylthiohy-
tion,32,33 proceed irreversibly,34 and terminal substitution by a po-
lar substituent is not expected to change this situation.35 In this
mechanistic interpretation, the ratio of products 5 and 11 directly
reflects relative reactivity of the two double bonds for accepting the
alkoxyl radical. For the discussion on relative reactivity by com-
paring results from competition experiments performed under
identical conditions, we propose to use the term relative rate factor
instead of relative rate constant. A relative rate constant is the re-
droxamates 1fei (c0 ¼55 mM) containing tributylstannane
1fei
(c0¼205 mM; Table 3, entries 1e3) or Bu3SnD (Table 3, entries 4e5)
were photolyzed with 350 nm-light until the starting material is
entirely consumed.31 Methoxy- and dimethyl-substituted thiazo-
lethiones 1feg provided exclusively products 5f and 5g from ad-
dition to the donor-substituted double bond (GC, NMR). Acceptor-
substituted thiazolethiones 1hei furnished 52/48- (for R1¼CN,
R2¼H) and 42/58-mixtures (for R1¼CO2CH3, R2¼H) of products 5
versus 11 (GC, NMR; 3 independent runs). All cyclizations afforded
the trans-tetrahydrofuran as major stereoisomer (Table 3).
sult of
a reaction series performed by parameter variation,
providing from numeric analysis the desired kinetic information.
Relative rate factors for alkoxyl radical 5-exo-cyclization in-
crease along the series of alkene-substituents R from OCH3 (from
1g) and methyl (from 1f) via H (from 1h and 1i) and CN (from 1h) to
CO2CH3 (from 1i; Scheme 6). The fastest (R¼OCH3) and the slowest
(R¼CO2CH3) reaction differ by an approximated factor of 35. This
value considers a rate factor of 25 for addition to the enol ether
Table 3
Effect of terminal substituents on regioselectivity in 5-exo-trig alkenoxyl radical cyclization
R2
R1
Bu3SnX
OMAnTT R2
X
X
25 °C / h
O
O
R2
R1
+
C6H6
R1
1f–i
5f–i
11f–i
Entry
1/5/11
R1
R2
Xa
5/% (cis/trans)b
11/% (cis/trans)b
1
2
3
4
5
f
CH3
OCH3
CNe
CH3
H
H
H
H
H
H
H
D
D
93 (32:68)
93 (35:65)
46 (38:62)
48 (34:66)
29 (35:65)
dc
dc
d
g
h
hg
i
45 (45:55)f
43 (45:55)h
55 (39:61)i
CNe
i
CO2CH3
a
Bu3SnH for X¼H, Bu3SnD for X¼D.
b
c
d
e
f
cis/trans-Ratios determined via GC, stereochemical assignment via NOESY.
Not detected (1H NMR).
(E)/(Z)¼80:20.
(E)/(Z)¼72:28.
(E)/(Z)¼46:54.
g
h
i
Compound indexing for 5 and 11: hd1
.
(E)/(Z)¼53:47.
(E)/(Z) >98:2.

I. Kempter et al. / Tetrahedron 68 (2012) 10378e10390
10383
additions shows this typical dichotomic behavior of borderline
cases, being an electrophile if the alkene bears a donor group, or
H
O
•
O
•
C
a nucleophile if the attacked
p-bond is substituted by a cyano- or an
R
R
ester-group (Fig. 3).39e41
2
4
2.4. Application in synthesis
R: CO2CH3 H, CN
CH3 OCH3
The propensity of alkoxyl radicals for adding to acceptor-
substituted double bonds opens new perspectives for synthesis,
since substrates now become accessible for homolytic carbone
oxygen bond formation that so far were not attainable by this
approach. Tetrahydrofurylamino acids have not yet been prepared
via C,O-cyclization. Some tetrahydrofuryl amino acids, such as the
furanomycin derivatives, show antibiotic activity.42 We therefore
considered synthesis of a N,O-protected tetrahydrofuryl glycine an
attractive target for documenting the scope of our findings.
0.5
1.0
5.0
krel
Scheme 6. Summary of substituent effects on relative rate factors in alkenoxyl radical
cyclization (the open circle symbolizes a phenyl, methyl or a 3-buten-1-yl group).
group in 1g, based on selectivity for formation of 5g of larger than
96/4, according results from proton NMR-spectroscopy. From pre-
vious work we knew that one methyl group increases the rate of 5-
exo-trig alkenoxyl radical cyclization by a factor of 5e7, and two
methyl groups by a factor of 12e15.30,36 We therefore assigned the
methoxy group a larger activating effect than the methyl group
(Scheme 6).
A gradual increase in relative rate factor in going from sub-
stituents R¼H via CH3 to OCH3 points to an electrophilic behavior
of the radical oxygen.37 The progression of the rate factor as R
changes from methoxycarbonyl via hydrogen to cyano points to an
accelerating contribution of the cyano group, although the effect
is small. Since the cyano is the strongest acceptor in the series
of investigated substituents, known to activate a conjugated
carbonecarbon double bond for addition of nucleophiles to the
We put our strategy into practice by photolyzing N-alkenoxy-
thiazolethione (S)-1j and tributylstannane in a solution of benzene
at room temperature. From the reaction mixture, we isolated
N,O-protected
a-(5-phenyltetrahydrofuran-2-yl)methyl glycine 5j
in a yield of 73%, thus proofing the proposed concept (Scheme 7).
b
-carbon in a reaction known as Micheal-addition, we attribute
the driving force of alkoxyl addition to acrylonitrile-type double
bonds to nucleophilic behavior of the O-radical.
The underlying theory to explain reactivity and selectivity in
alkoxyl radical additions is frontier molecular orbital theory, be-
cause the reactions are fast and exothermic and therefore proceed
via transition states located early on a reaction coordinate.6,38
According to FMO-theory, the major bonding contribution, as the
Scheme 7. Synthesis of N,O-protected 2-(5-phenyltetrahydrofuran-2-yl)methyl glycine
5j from N-alkenoxythiazolethione (S)-1j and Bu3SnH (50/50-mixtures of isomers at Ca).
3. Concluding remarks
radical approaches the
p-bond of the alkene, arises from in-
teractions between the singly occupied molecular orbital (SOMO)
and either the highest occupied molecular orbital (HOMO) or the
lowest unoccupied molecular orbital (LUMO). As the alkene is
substituted by donor groups, such as methoxy or methyl, orbital
energies rise and the HOMOeSOMO-interaction becomes more
prominent (Fig. 3, right; D¼OCH3, CH3).6,38 Acceptor groups, such
as a cyano- or an ester-group, lower orbital energies of the alkene,
causing attractive LUMOeSOMO interactions to become more
significant (Fig. 3, left; A¼CN, CO2CH3). Electrophilic radicals
(e.g. ꢀCCl3) have low and nucleophilic radicals [e.g. ꢀC(CH3)3]
high SOMO-energies. Radicals that interact by their SOMO to
a similar extent with the LUMO and the HOMO of an alkene are
on the borderline between nucleophilic and electrophilic. The
responsivity of substituent effects on rates in alkoxyl radical
The affinity for adding to cyano- and ester-substituted double
bonds in rates that compare to reactivity of terminal alkenes, adds
a new component to synthesis with oxygen radicals. From the ki-
netic information provided in this work it seems that further
accepting groups, for example halogens, nitro, or arylsulfonyl, will
sufficiently activate alkenes to construct carboneoxygen bonds
via an alkoxyl radical mechanism. The argument, to consider in fu-
ture syntheses radical and not ionic reactions for addition of oxygen
compounds to Michael-type acceptors, possibly arises from stereo-
selectivity of the ring closure, and diversity of methods available for
functionalizing carbon radicals. Alkoxide-based additions to
Michael-type acceptors have the disadvantage of being reversible
and often difficult to terminate with other reagents than the proton.
Nucleophilic properties of alkoxyl radicals could have been
predicted from the day, additions were explained by frontier mo-
lecular orbital (FMO)-theory, based on kinetic36 and theoretical
data.6 In FMO-theory nucleophilicity of an alkoxyl radical is a logi-
cal consequence of the LUMO-energy of an accepting entity, for
E
LUMO
LUMO
example a
p*-type orbital predominantly located at an alkene
subunit, falling below the SOMO energy of the unpaired electron.
We have not yet performed experiments to explore whether
borderline reactivity extends to other alkoxyl radical elementary
reactions, such as homolytic substitution, rearrangements, or
HOMO
SOMO
HOMO
b
-fragmentation. Bond formation and bond breaking in all such
A
D
RO•
processes is explicable by FMO-theory. According to FMO-theory,
orbital energies of reactants are controlled by substituents in
a systematic and predictable manner. We therefore expect bor-
derline reactivity to be a general phenomenon in alkoxyl radical
Fig. 3. FMO-correlation diagram for explaining borderline reactivity of alkoxyl radicals
in additions to substituted alkenes, on the basis of stabilizing interactions in transition
states (A¼CN, CO2CH3; D¼CH3, OCH3).

10384
I. Kempter et al. / Tetrahedron 68 (2012) 10378e10390
chemistry. Since alkoxyl radicals play an important role in com-
bustion processes, atmospheric chemistry, biochemistry, and syn-
thesis, we think that the findings summarized in this article have
the potential to double the scope of alkoxyl radical chemistry.
2H, J 8.8, AreH), 7.24 (d, 2H, J 8.5, AreH). 13C NMR (CDCl3, 150 MHz)
d
(C50), 100.1 (C10), 114.5 (AreC), 115.9 (CN), 119.5 (C5), 122.5 (AreC),
129.8 (AreC), 133.3 (C4), 154.2 (C20), 159.9 (AreC), 179.1 (C2).
12.7 (4-CH3), 18.4 (C60), 27.6 (CH2), 33.3 (CH2), 55.4 (OCH3), 80.3
4. Experimental
4.1. General
4.2.3. 3-(10-Cyano-50-phenylpent-10-en-50-oxy)-5-(p-methoxy-
phenyl)-4-methylthiazole-2(3H)-thione (1b). 6-Chloro-6-phenylhex-
2-enenitrile: According to 4.2.1 from 6-hydroxy-6-phenylhex-2-
enenitrile (1.00 g, 5.34 mmol), PPh3 (1.82 g, 6.94 mmol) and CCl4
(6 mL). Reaction time: 4 h. Eluent used forchromatography: pentane/
Et2O¼2:1 (v/v). Yield: 896 mg [4.36 mmol, 82%, (E)/(Z)¼88:12], col-
orless oil, Rf 0.52 [SiO2, pentane/Et2O¼2:1 (v/v)]. (E)-isomer: 1H NMR
For general laboratory practice and instrumentation see Ref. 7
and the Supplementary data.
4.2. 3-Alkoxythiazole-2(3H)-thiones 1aee from alkenyl
chlorides
(CDCl3, 400 MHz)
5.36 (d,1H, J 16.2, 2-H), 6.68 (dt,1H, Jd 16.2, Jt 6.8, 3-H), 7.31e7.37 (m,
5H, PheH). 13C NMR (CDCl3, 100 MHz)
30.7 (CH2), 37.6 (CH2), 62.2
(C6), 101.0 (C2), 117.1 (CN), 126.8, 128.6, 128.8, 140.7 (PheC), 153.6
(C3). (Z)-isomer: 1H NMR (CDCl3, 400 MHz)
2.10e2.48 (m, 4H, CH2),
4.80e4.84 (m,1H, 6-H), 5.42 (d,1H, J 16.5, 2-H), 6.82 (dt,1H, Jd 16.2, Jt
6.4, 3-H), 7.31e7.37 (m, 5H, PheH). 13C NMR (CDCl3, 100 MHz)
30.7
d 2.10e2.48 (m, 4H, CH2), 4.80e4.84 (m, 1H, 6-H),
d
4.2.1. General procedure. An alkenol was dissolved in CCl4 and
treated with PPh3. The reaction mixture was stirred at 80 ꢂC for 2e4 h.
The precipitate was filtered off by suction and the filtrate was con-
centrated under reduced pressure. The residue was purified by
chromatography (SiO2)to afford an alkenyl chloride, which was added
to a solution of 3-hydroxy-5-(p-methoxyphenyl)-4-methylthiazole-
2(3H)-thione tetraethylammonium salt43 in dry DMF. The resulting
mixture was stirred at 22 ꢂC for 6e13 days in the dark. The solution
was treated at 22 ꢂC with Et2O or CH2Cl2 and H2O. The aqueous layer
was extracted with Et2O or CH2Cl2 and the combined layers were
dried (MgSO4). The solvent was removed under reduced pressure to
leave a crude product, which was purified by chromatography (SiO2).
d
d
(CH2), 36.0 (CH2), 62.2 (C6),100.7 (C2),117.3 (CN),126.8,128.6,128.8,
140.7 (PheC),153.3 (C3). 3-(10-Cyano-50-phenylpent-10-en-50-oxy)-5-
(p-methoxyphenyl)-4-methylthiazole-2(3H)-thione (1b): According to
4.2.1 from 6-chloro-6-phenylhex-2-enenitrile (519 mg, 2.52 mmol),
3-hydroxy-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-thione
tetraethylammonium salt (1.20 g, 3.14 mmol) and DMF (6 mL). Re-
action time: 10 days. The reaction mixture was treated with Et2O
(15 mL) and H2O (20 mL). The layers were separated and the organic
layer was kept. The aqueous layer was extracted with Et2O
(4ꢃ50 mL). Eluent used for chromatography: pentane/Et2O¼1:1
(v/v). Yield: 519 mg [1.23 mmol, 49%, (E)/(Z)¼76:24], pale yellow
solid, Rf 0.26 [SiO2, pentane/Et2O¼1:1 (v/v)]. UV (MeOH) lmax
(lg ε/m2 molꢁ1)¼336 nm (3.28). Anal. calcd. for C23H22N2O2S2
(422.56): C, 65.38; H, 5.25; N, 6.93; S, 15.17; found: C, 65.27; H, 5.12;
4.2.2. 3-(10-Cyanohex-10-en-50-oxy)-5-(p-methoxyphenyl)-4-
methylthiazole-2(3H)-thione (1a). 6-Chlorohept-2-enenitrile: Accord-
ing to 4.2.1 from 6-hydroxyhept-2-enenitrile (1.06 g, 8.47 mmol),
PPh3 (2.89 g,11.01 mmol) and CCl4 (10 mL). Reaction time: 3 h. Eluent
used for chromatography: pentane/Et2O¼1:1 (v/v). Yield: 879 mg
[6.12 mmol, 72%, (E)/(Z)¼83:17], yellow oil, Rf 0.63 [SiO2, pentane/
N, 6.69; S,15.04. (E)-isomer: 1H NMR (CDCl3, 600 MHz)
d 1.50 (s, 3H,
Et2O¼1:1 (v/v)]. (E)-isomer: 1H NMR (CDCl3, 600 MHz)
d
1.53 (d, 3H, J
4-CH3), 2.15e2.20 (m, 1H, CH2), 2.54e2.70 (m, 3H, CH2), 3.79 (s, 3H,
OCH3), 5.44 (d, 1H, J 16.4, 10-H), 6.19 (t,1H, J 6.7, 50-H), 6.79e6.84 (m,
1H, 20-H), 6.86 (d, 2H, J 8.7, AreH), 6.99 (d, 2H, J 8.7, AreH), 7.35e7.45
6.4, 7-H), 1.78e1.89 (m, 2H, CH2), 2.35e2.41 (m, 1H, CH2), 2.45e2.51
(m, 1H, CH2), 3.96e4.05 (m, 1H, 6-H), 5.37e5.41 (m, 1H, 2-H), 6.70
(dt,1H, Jd 16.2, Jt 7.0, 3-H). 13C NMR (CDCl3,150 MHz)
d
25.3 (C7), 30.4
(CH2), 37.8 (CH2), 57.2 (C6), 100.8 (C2), 117.2 (CN), 154.1 (C3). (Z)-
isomer: 1H NMR (CDCl3, 600 MHz)
2.53 (d, 3H, J 6.4, 7-H),1.78e1.89
(m, 5H, PheH). 13C NMR (CDCl3,150 MHz)
d 12.1 (4-CH3), 29.8 (CH2),
30.4 (CH2), 55.4 (OCH3), 84.9 (C50), 100.7 (C10), 114.4 (AreC), 117.4
(CN), 118.5 (C5), 122.5 (AreC), 128.9, 129.0, 129.8, 130.2 (PheC and
AreC),133.7 (C4),136.2 (PheC),154.5 (C20),159.8 (AreC),178.5 (C2).
d
(m, 2H, CH2), 2.55e2.67 (m, 2H, CH2), 3.96e4.05 (m, 1H, 6-H),
5.37e5.41 (m, 1H, 2-H), 6.49 (dt, 1H, Jd 10.9, Jt 7.6, 3-H). 13C NMR
(Z)-isomer: 1H NMR (CDCl3, 600 MHz)
d 1.52 (s, 3H, 4-CH3),
(CDCl3, 150 MHz)
d
25.2 (C7), 29.1 (CH2), 38.4 (CH2), 57.2 (C6), 100.5
2.15e2.20 (m, 1H, CH2), 2.54e2.70 (m, 3H, CH2), 3.79 (s, 3H, OCH3),
5.36 (d, 1H, J 10.7, 10-H), 6.19 (t, 1H, J 6.7, 50-H), 6.79e6.84 (m, 1H, 20-
H), 6.86 (d, 2H, J 8.7, AreH), 6.99 (d, 2H, J 8.7, AreH), 7.35e7.45 (5H,
(C2), 115.7 (CN), 153.3 (C3). 3-(10-Cyanohex-10-en-50-oxy)-5-(p-
methoxyphenyl)-4-methylthiazole-2(3H)-thione (1a): According to
4.2.1 from 6-chlorohept-2-enenitrile (879 mg, 6.12 mmol), 3-
hydroxy-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-thione tet-
raethylammonium salt (2.34 g, 6.12 mmol) and DMF (12 mL). Re-
action time: 13 days. The reaction mixture was treated with Et2O
(50 mL) and H2O (50 mL). The layers were separated and the organic
layer was kept. The aqueous layer was extracted with CH2Cl2
(3ꢃ50 mL). Eluent used for chromatography: pentane/Et2O¼1:2
(v/v). Yield: 798 mg [2.21 mmol, 36%, (E)/(Z)¼77:23], yellow oil,
Rf 0.30 [SiO2, pentane/Et2O¼1:2 (v/v)]. UV (MeOH) lmax
(lg ε/m2 molꢁ1)¼335 nm (3.25). (E)-isomer: 1H NMR (CDCl3,
m, PheH). 13C NMR (CDCl3,150 MHz)
d 12.1 (4-CH3), 29.8 (CH2), 30.4
(CH2), 55.4 (OCH3), 84.9 (C50), 100.7 (C10), 114.4 (AreC), 117.4 (CN),
118.5 (C5), 122.5 (AreC), 128.9, 129.0, 129.8, 130.2 (PheC and AreC),
133.7 (C4), 136.2 (PheC), 154.5 (C20), 159.8 (AreC), 178.5 (C2).
4.2.4. 3-[10-(Methoxycarbonyl)hex-10-en-50-oxy]-5-(p-methoxy-
phenyl)-4-methylthiazole-2(3H)-thione (1c). Methyl 6-chlorohept-2-
enoate: According to 4.2.1 from methyl 6-hydroxyhept-2-enoate
(1.11 g, 6.95 mmol), PPh3 (2.37 g, 9.03 mmol) and CCl4 (8 mL). Re-
action time: 3 h. Eluent used for chromatography: pentane/
Et2O¼1:1 (v/v). Yield: 731 mg (4.14 mmol, 60%), pale yellow oil, Rf
0.58 [SiO2, pentane/Et2O¼1:1 (v/v)]. 1H NMR (CDCl3, 200 MHz)
600 MHz) d
1.31 (d, 3H, J 6.2, 60-H), 1.79e1.84 (m, 1H, CH2), 1.86e1.96
(m, 1H, CH2), 2.28 (s, 3H, 4-CH3), 2.58e2.62 (m, 2H, CH2), 3.83 (s, 3H,
OCH3), 5.42e5.45 (m, 1H, 10-H), 5.46e5.52 (m, 1H, 50-H), 6.79e6.84
(m, 1H, 20-H), 6.95 (d, 2H, J 8.8, AreH), 7.24 (d, 2H, J 8.5, AreH). 13C
d
1.52 (d, 3H, J 6.6, 7-H), 1.79e1.90 (m, 2H, CH2), 2.25e2.55 (m, 2H,
CH2), 3.72 (s, 3H, OCH3), 3.92e4.09 (m,1H, 6-H), 5.87 (d,1H, J 15.6, 2-
H), 6.94 (dt, 1H, Jd 15.6, Jt 7.0, 3-H). 13C NMR (CDCl3, 150 MHz)
25.3
NMR (CDCl3, 150 MHz)
d
12.7 (4-CH3), 18.7 (C60), 29.2 (CH2), 33.2
d
(CH2), 55.4 (OCH3), 80.2 (C50), 100.5 (C10), 114.5 (AreC), 117.4 (CN),
(C7), 29.2 (CH2), 38.3 (CH2), 51.5 (OCH3), 57.5 (C6), 12.8 (C2), 147.6
(C3), 166.9 (C]O). 3-[10-(Methoxycarbonyl)hex-10-en-50-oxy]-5-(p-
methoxyphenyl)-4-methylthiazole-2(3H)-thione (1c): According
to 4.2.1 from methyl 6-chlorohept-2-enoate (731 mg, 4.14 mmol),
3-hydroxy-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-thione
tetraethylammonium salt (1.58 g, 4.14 mmol) and DMF (8.5 mL).
119.5 (C5), 122.5 (AreC), 129.8 (AreC), 133.2 (C4), 154.8 (C20), 159.9
(AreC), 179.1 (C2). (Z)-isomer: 1H NMR (CDCl3, 600 MHz)
d 1.34 (d,
3H, J 6.5, 60-H), 1.86e1.96 (m, 1H, CH2), 1.98e2.04 (m, 1H, CH2), 2.29
(s, 3H, 4-CH3), 2.66e2.77 (m, 2H, CH2), 3.83 (s, 3H, OCH3), 5.37 (d, 1H,
J 10.9, 10-H), 5.46e5.52 (m,1H, 50-H), 6.70e6.74 (m,1H, 20-H), 6.95 (d,

I. Kempter et al. / Tetrahedron 68 (2012) 10378e10390
10385
Reaction time: 6 days. The reaction mixture was treated with CH2Cl2
(40 mL) and H2O (40 mL). The layers were separated and the organic
layer was kept. The aqueous layer was extracted with CH2Cl2
(3ꢃ40 mL). Eluent used for chromatography: pentane/EtOAc¼1:1
(v/v). Yield: 452 mg (1.15 mmol, 49%), pale yellow oil, Rf 0.62 [SiO2,
pentane/EtOAc¼1:1 (v/v)]. UV (MeOH) lmax (lg ε/m2 molꢁ1)¼
cyclopropyl), 2.11e2.32 (m, 2H, CH2), 2.38e2.55 (m, 2H, CH2),
4.83e4.86 (m, 1H, 6-H), 6.17 (t, 1H, J 7.7, 3-H), 7.31e7.38 (m, 5H,
PheH). 13C NMR (CDCl3, 150 MHz)
d 5.9, 6.4, 14.1 (cyclopropyl), 29.1
(CH2), 38.8 (CH2), 62.5 (C6), 115.5 (CN), 118.8 (C2), 126.8, 128.5,
128.8, 141.0 (PheC), 143.1 (C3). (Z)-isomer: 1H NMR (CDCl3,
400 MHz)
d 0.65e0.69 (m, 1H, cyclopropyl), 0.72e0.80 (m, 2H,
332 nm (3.00). 1H NMR (CDCl3, 200 MHz)
d
1.32 (d, 3H, J 6.3, 60-H),
cyclopropyl), 0.85e0.89 (m, 1H, cyclopropyl), 1.48e1.56 (m, 1H,
cyclopropyl), 2.11e2.32 (m, 2H, CH2), 2.38e2.55 (m, 2H, CH2),
4.83e4.86 (m, 1H, 6-H), 6.28 (t, 1H, J 7.7, 3-H), 7.31e7.38 (m, 5H,
1.72e2.02 (m, 1H, CH2), 2.28 (s, 3H, 4-CH3), 2.45e2.56 (m, 2H CH2),
3.72 (s, 3H, COOCH3), 3.83 (s, 3H, OCH3), 5.39e5.55 (m, 1H, 50-H),
5.89 (d,1H, J 15.7,10-H), 6.94 (d, 2H, J 8.7, AreH), 6.94e7.09 (m,1H, 20-
PheH). 13C NMR (CDCl3, 150 MHz)
d 5.9, 6.4, 9.4 (cyclopropyl), 26.0
H), 7.24 (d, 2H, J 7.6, AreH).13C NMR (CDCl3,150 MHz)
d
12.7 (4-CH3),
(CH2), 38.4 (CH2), 62.5 (C6), 117.5 (CN), 119.3 (C2), 126.9, 128.6,
128.7, 140.9 (PheC), 144.4 (C3). 3-(10-Cyano-10-cyclopropyl-50-phe-
nylpent-10-en-50-oxy)-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-
thione (1e): According to 4.2.1 from 2-cyclopropyl-6-chloro-6-
phenylhex-2-enenitrile (623 mg, 2.53 mmol), 3-hydroxy-5-(p-
methoxyphenyl)-4-methylthiazole-2(3H)-thione tetraethylammo-
nium salt (968 mg, 2.53 mmol) and DMF (5 mL). Reaction time: 7
days. The reaction mixture was treated with Et2O (20 mL) and H2O
(25 mL). The layers were separated and the organic layer was
kept. The aqueous layer was extracted with Et2O (3ꢃ25 mL).
Eluent used for chromatography: pentane/Et2O¼1:2 (v/v). Yield:
858 mg [1.85 mmol, 73%, (E)/(Z)¼62:38], yellow oil, Rf 0.41 [SiO2,
pentane/Et2O¼1:2 (v/v)]. (E)-isomer: 1H NMR (CDCl3, 400 MHz)
18.4 (C60), 28.0 (CH2), 33.3 (CH2), 51.4 (OCH3), 55.4 (OCH3), 80.7 (C50),
114.5 (AreC),119.4 (C5),121.4 (C10),122.5 (AreC),129.8 (AreC),133.3
(C4), 148.1 (C20), 159.9 (AreC), 166.9 (C]O), 179.1 (C2).
4.2.5. 3-(10-Methoxycarbonyl-50-phenylpent-10-en-50-oxy)-5-(p-
methoxyphenyl)-4-methylthiazole-2(3H)-thione (1d). Methyl 6-
chloro-6-phenylhex-2-enoate: According to 4.2.1 from methyl 6-
hydroxy-6-phenylhex-2-enoate (2.91 g, 13.21 mmol), PPh3 (4.50 g,
17.17 mmol) and CCl4 (15 mL). Reaction time: 3 h. Eluent used for
chromatography: pentane/Et2O¼1:1 (v/v). Yield: 2.53 g [10.60 mmol,
80%, (E)/(Z)¼91:9], pale yellow oil, Rf 0.92 [SiO2, pentane/Et2O¼1:1
(v/v)]. UV (CHCl3) lmax (lg ε/m2 molꢁ1)¼338 nm (3.17), 240 nm (3.12).
(E)-isomer: 1H NMR (CDCl3, 600 MHz)
d
2.14e2.42 (m, 4H, CH2), 3.73
d 0.66e0.69 (m, 1H, cyclopropyl), 0.74e0.88 (m, 3H, cyclopropyl),
(s, 3H, OCH3), 4.83e4.85 (m,1H, 6-H), 5.86 (d,1H, J 15.5, 2-H), 6.94 (dt,
1H, Jd 15.7, Jt 6.8, 3-H), 7.30e7.33 (m, 1H, PheH), 7.35e7.37 (m, 4H,
1.24e1.27 (m,1H, cyclopropyl),1.52 (s, 3H, 4-CH3), 2.17e2.25 (m,1H,
CH2), 2.52e2.65 (m, 3H, CH2), 3.79 (s, 3H, OCH3), 6.18e6.24 (m, 1H,
50-H), 6.38e6.46 (m, 1H, 20-H), 6.86 (d, 2H, J 8.5, AreH), 7.00 (d, 2H, J
PheH). 13C NMR (CDCl3, 150 MHz)
d
29.5 (CH2), 38.0 (CH2), 51.5
(OCH3), 62.5 (C6), 122.0 (C2), 126.8, 128.4, 128.7, 141.1 (PheC), 147.1
(C3),166.8 (C]O). (Z)-isomer: 1H NMR (CDCl3, 600 MHz)
2.14e2.42
8.8, AreH), 7.38e7.42 (m, 5H, PheH).13C NMR (CDCl3,100 MHz)
d 5.9,
d
6.3 (cyclopropyl), 12.1 (4-CH3), 14.1 (cyclopropyl), 27.6 (CH2), 31.1
(CH2), 55.3 (OCH3), 85.1 (C50), 114.4 (AreC), 118.3 (CN), 118.4 (C5),
122.6 (C10), 128.8, 129.1, 129.7, 130.0, 133.7 (PheC and AreC), 136.1
(C4),144.0 (C20),159.7 (AreC),178.5(C2). (Z)-isomer: 1H NMR(CDCl3,
(m, 4H, CH2), 3.74 (s, 3H, OCH3), 4.83e4.85 (m, 1H, 6-H), 5.91 (d, 1H, J
15.8, 2-H), 7.05 (dt, 1H, Jd 15.7, Jt 6.5, 3-H), 7.30e7.33 (m, 1H, PheH),
7.35e7.37 (m, 4H, PheH).13C NMR (CDCl3,150 MHz)
d 29.5 (CH2), 35.2
(CH2), 51.5 (OCH3), 62.5 (C6), 121.8 (C2), 126.8, 128.4, 128.7, 141.1
(PheC), 146.8 (C3), 166.8 (C]O). 3-(10-Methoxycarbonyl-50-phenyl-
pent-10-en-50-oxy)-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-thi-
one (1d): According to 4.2.1 from methyl 6-chloro-6-phenylhex-2-
enoate (2.53 g, 10.60 mmol), 3-hydroxy-5-(p-methoxyphenyl)-4-
methylthiazole-2(3H)-thione tetraethylammonium salt (4.06 g,
10.60 mmol) and DMF (21 mL). Reaction time: 10 days. The reaction
mixture was treated with CH2Cl2 (100 mL) and H2O (100 mL). The
layers were separated and the organic layer was kept. The aqueous
layer was extracted with CH2Cl2 (3ꢃ50 mL). The product was crys-
tallized from Et2O/pentane. Yield: 3.38 g (7.42 mmol, 70%), pale
yellow solid, Rf 0.42 [SiO2, pentane/Et2O¼1:1 (v/v)]. 1H NMR (CDCl3,
400 MHz) d 0.66e0.69 (m, 1H, cyclopropyl), 0.74e0.88 (m, 3H,
cyclopropyl), 1.24e1.27 (m, 1H, cyclopropyl), 1.53 (s, 3H, 4-CH3),
2.17e2.25 (m, 1H, CH2), 2.52e2.65 (m, 3H, CH2), 3.79 (s, 3H, OCH3),
6.18e6.24 (m, 1H, 50-H), 6.38e6.46 (m, 1H, 20-H), 6.86 (d, 2H, J 8.5,
AreH), 7.00 (d, 2H, J 8.8, AreH), 7.38e7.42 (m, 5H, PheH). 13C NMR
(CDCl3,100 MHz) d 5.9, 6.3, 9.4 (cyclopropyl),12.1 (4-CH3), 25.1 (CH2),
31.1 (CH2), 55.3 (OCH3), 85.3 (C50), 114.4 (AreC), 115.7 (CN), 118.7
(C5), 122.5 (C10), 128.8, 129.0, 129.7, 130.1, 133.7 (PheC and AreC),
136.4 (C4), 145.3 (C20), 159.7 (AreC), 178.5 (C2).
4.3. 3-Alkoxythiazole-2(3H)-thiones 1feh and 1j from
alcohols
600 MHz) d 1.53 (s, 3H, 4-CH3), 2.17e2.23 (m,1H, CH2), 2.40e2.46 (m,
1H, CH2), 2.51e2.63 (m, 2H, CH2), 3.73 (s, 3H, COOCH3), 3.79 (s, 3H,
OCH3), 5.89 (d, 1H, J 15.6, 10-H), 6.21 (t, 1H, J 7.0, 50-H), 6.86 (d, 2H, J
8.7, AreH), 7.00 (d, 2H, J 8.7, AreH), 7.01e7.05 (m, 1H, 20-H),
7.36e7.39 (m, 4H, PheH), 7.40e7.43 (m, 1H, PheH). 13C NMR (CDCl3,
4.3.1. General procedure. In an atmosphere of nitrogen (5.0-quality,
purged through a tube filled with CaCl2), a solution of PPh3
(3.0 equiv), 3-hydroxy-5-(p-methoxyphenyl)-4-methylthiazole-
2(3H)-thione (1.5 equiv) and a dienol (1 equiv) in dry benzene
(10 mL/mmol) was treated at 0 ꢂC in a dropwise manner with diethyl
azodicarboxylate (3.0 equiv). The solution was stirred for 48 h in the
dark at 22 ꢂC. The reaction mixture was treated with a 2 M aqueous
solution of NaOH (20 mL/mmol). The layers were separated and the
organic layer was kept. The aqueous layer was extracted with Et2O
(2ꢃ20 mL/mmol) and CH2Cl2 (2ꢃ20 mL/mmol). Combined organic
solutions were washed with H2O (20 mL/mmol) and dried (MgSO4).
The solvent was removed under reduced pressure and the residue
purified by chromatography (SiO2).
150 MHz) d 12.1 (4-CH3), 28.5 (CH2), 30.5 (CH2), 51.5 (COOCH3), 55.3
(OCH3), 85.3 (C50), 114.3 (AreC), 118.3 (C5), 121.5 (C10), 122.6 (AreC),
128.8, 129.0, 129.7, 129.9, 133.7 (PheC and AreC), 136.4 (C4), 147.9
(C20), 159.7 (AreC), 166.9 (C]O), 178.5 (C2). Anal. calcd. for
C24H25NO4S2 (455.59): C, 63.27; H, 5.53; N, 3.07; S, 14.07; found: C,
63.20; H, 5.55; N, 3.12; S, 13.94.
4.2.6. 3-(10-Cyano-10-cyclopropyl-50-phenylpent-10-en-50-oxy)-5-(p-
methoxyphenyl)-4-methylthiazole-2(3H)-thione (1e). 2-Cyclopropyl-
6-chloro-6-phenylhex-2-enenitrile: According to 4.2.1 from 2-
cyclopropyl-6-hydroxy-6-phenylhex-2-enenitrile (2.48 g, 10.91
mmol), PPh3 (3.72 g, 14.18 mmol) and CCl4 (12 mL). Reaction time:
2 h. Eluent used for chromatography: pentane/Et2O¼1:3 (v/v).
Yield: 2.26 g [9.20 mmol, 84%, (E)/(Z)¼63:37], yellow oil, Rf 0.53
[SiO2, pentane/Et2O¼1:3 (v/v)]. (E)-isomer: 1H NMR (CDCl3,
4.3.2. 3-(90-Methyldeca-10,80-dien-50-oxy)-5-(p-methoxyphenyl)-4-
methylthiazole-2(3H)-thione
(1f). According to 4.3.1 from
9-methyldeca-1,8-dien-5-ol (500 mg, 2.97 mmol) and 3-hydroxy-5-(p-
methoxyphenyl)-4-methylthiazole-2(3H)-thione (1.13 g, 4.46 mmol).
Eluent used for chromatography: pentane/Et2O¼4:1 (v/v). Yield:
718 mg (1.78 mmol, 60%), pale yellow oil, Rf 0.50 [SiO2, pentane/
400 MHz)
d 0.65e0.69 (m, 1H, cyclopropyl), 0.72e0.80 (m, 2H,
cyclopropyl), 0.85e0.89 (m, 1H, cyclopropyl), 1.22e1.23 (m, 1H,
Et2O¼4:1 (v/v)]. 1H NMR (CDCl3, 400 MHz)
d 1.61 (s, 3H, CH3), 1.69 (s,

10386
I. Kempter et al. / Tetrahedron 68 (2012) 10378e10390
3H, CH3),1.69e1.86 (m, 4H, CH2), 2.07e2.32 (m, 4H, CH2), 2.28 (s, 3H, 4-
CH3), 3.83 (s, 3H, OCH3), 4.98e5.13 (m, 3H, 10-H and 80-H), 5.31e5.37
(m, 1H, 50-H), 5.80e5.90 (m, 1H, 20-H), 6.93e6.96 (m, 2H, AreH),
an atmosphere of nitrogen (5.0-quality, purged through a tube fil-
led with CaCl2), methyl (6S)-2-(acetylamino)-6-hydroxy-6-
phenylhex-2-enoate (496 mg, 1.79 mmol), diethylphosphino-
ethane (713 mg, 1.79 mmol) and 3-hydroxy-5-(p-methoxyphenyl)-
4-methylthiazole-2(3H)-thione (681 mg, 2.69 mmol) were dis-
solved in dry benzene (10 mL). Diethyl azodicarboxylate (655 mg,
3.76 mmol) was added to this solution at 0 ꢂC in a dropwise
manner. The resulting mixture was stirred for 18.5 h in the dark at
22 ꢂC. The solution was treated with 2 M aqueous NaOH (20 mL)
and CH2Cl2 (20 mL). The layers were separated and the organic
layer was kept. The aqueous layer was extracted with CH2Cl2
(2ꢃ20 mL). Combined organic layers were washed with brine
(2ꢃ20 mL) and concentrated under reduced pressure. The residue
was purified by chromatography [SiO2, pentane/EtOAc¼1:3 (v/v)].
Yield: 291 mg (0.55 mmol, 31%), pale yellow solid, Rf 0.33 [SiO2,
7.23e7.26 (m, 2H, AreH).13C NMR(CDCl3,100MHz)
d 12.9 (4-CH3),17.9
(CH3), 23.9 (CH2), 25.8 (CH3), 29.4 (CH2), 31.6 (CH2), 32.3 (CH2), 55.6
(OCH3), 84.7 (C50), 114.7 (AreC), 115.2 (C10), 119.3 (C5), 123.0 (AreC),
123.5 (C80),130.0,131.7,132.6 (C90),138.0 (C20),160.1 (AreC),179.4 (C2).
4.3.3. 3-(10-Methoxynona-10,80-dien-50-oxy)-5-(p-methoxyphenyl)-
4-methylthiazole-2(3H)-thione (1g). According to 4.3.1 from 1-
methoxynona-1,8-dien-5-ol [580 mg, 3.40 mmol, (E)/(Z)¼72:28]
and 3-hydroxy-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-thi-
one (1.29 g, 5.10 mmol). Eluent used for chromatography: pentane/
Et2O¼1:1 (v/v). The product was crystallized from pentane/Et2O.
Yield: 921 mg [2.28 mmol, 67%, (E)/(Z)¼80:20], colorless solid, Rf
0.35 [SiO2, pentane/Et2O¼1:1 (v/v)]. Anal. calcd. for C21H27NO3S2
(405.58): C, 62.19; H, 6.71; N, 3.45; found: C, 62.13; H, 6.86; N, 3.44.
pentane/EtOAc¼1:3 (v/v)]. 1H NMR (CDCl3, 400 MHz)
d 1.55 (s, 3H,
CH3), 2.09 (s, 3H, 4-CH3), 2.22e2.30 (m, 1H, CH2), 2.42e2.53 (m, 2H,
CH2), 2.59e2.66 (m, 1H, CH2), 3.78 (s, 3H, COOCH3), 3.79 (s, 3H,
OCH3), 6.24 (t, 1H, J 7.0, 50-H), 6.75 (t, 1H, J 7.4, 20-H), 6.86 (d, 2H, J
8.6, AreH), 6.98 (d, 2H, J 8.6, AreH), 7.20 (br s, 1H, NH), 7.34e7.39
(E)-isomer: 1H NMR (CDCl3, 600 MHz)
d 1.69e1.82 (m, 4H, CH2),
2.05e2.27 (m, 4H, CH2), 2.28 (s, 3H, 4-CH3), 3.51 (s, 3H, OCH3), 3.83
(s, 3H, OCH3), 4.72e4.77 (m, 1H, 20-H), 4.98e5.01 (m, 1H, 90-H),
5.04e5.07 (m, 1H, 90-H), 5.32e5.39 (m, 1H, 50-H), 5.80e5.88 (m, 1H,
80-H), 6.34 (d, 1H, J 12.6, 10-H), 6.93e6.96 (m, 2H, AreH), 7.23e7.25
(m, 5H, PheH). 13C NMR (CDCl3, 100 MHz)
d 12.2 (4-CH3), 23.3
(CH3), 25.2 (CH2), 30.4 (CH2), 52.4 (COOCH3), 55.4 (OCH3), 85.2
(C50), 114.4 (AreC), 118.6 (C5), 122.5 (C10), 126.1, 128.7, 129.2, 129.3,
130.0, 133.9 (PheC and AreC), 136.2 (C4), 137.3 (C20), 159.3 (AreC),
165.0 (C]O), 168.9 (C]O), 178.3 (C2).
(m, 2H, AreH). 13C NMR (CDCl3,150 MHz)
d 12.9 (4-CH3), 23.6 (CH2),
29.3 (CH2), 31.4 (CH2), 33.5 (CH2), 55.5 (OCH3), 56.1 (10-OCH3), 84.2
(C50), 101.9 (C20), 115.3 (C90), 114.6 (AreC), 119.4, 122.8, 130.0, 133.6,
137.8 (C80), 147.8 (C10), 160.0 (AreC), 179.2 (C2). (Z)-isomer: 1H NMR
(CDCl3, 600 MHz)
d
1.69e1.82 (m, 4H, CH2), 2.05e2.27 (m, 4H, CH2),
4.4. 3-Alkoxythiazole-2(3H)-thione 1i from alkenyl tosylates
2.28 (s, 3H, 4-CH3), 3.57 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 4.33e4.37
(m, 1H, 20-H), 4.98e5.01 (m, 1H, 90-H), 5.04e5.07 (m, 1H, 90-H),
5.32e5.39 (m, 1H, 50-H), 5.80e5.88 (m, 1H, 80-H), 5.89e5.90 (m, 1H,
10-H), 6.93e6.96 (m, 2H, AreH), 7.23e7.25 (m, 2H, AreH). 13C NMR
4.4.1. 3-[10-(Methoxycarbonyl)nona-10,80-dien-50-oxy]-5-(p-methoxy-
phenyl)-4-methylthiazole-2(3H)-thione
(1i). A
solution
of
3-hydroxy-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-thione
tetraethylammonium salt (4.00 mmol) in dry DMF was treated in an
atmosphere of nitrogen (5.0-quality, purged through a tube filled
with CaCl2) with (E)-1-(methoxycarbonyl)nona-1,8-dien-5-yl p-
toluene sulfonate (1.41 g, 4.00 mmol) and stirred for 3 days in the
dark at 22 ꢂC. The reaction mixture was treated with H2O (50 mL)
and Et2O (30 mL). The layers were separated and the organic layer
was kept. The aqueous layer was extracted with Et2O (2ꢃ30 mL).
Combined organic layers were washed with a 2 M aqueous solution
of NaOH (2ꢃ20 mL) and with brine (20 mL). The organic solution
was dried (MgSO4) and the solvent was removed under reduced
pressure. The residue was purified by chromatography [SiO2, pen-
tane/Et2O¼1:1 (v/v)] and then crystallized from pentane/Et2O.
Yield: 844 mg (1.95 mmol, 49%), colorless solid, Rf 0.24 [SiO2, pen-
(CDCl3, 150 MHz)
d 12.9 (4-CH3), 19.6 (CH2), 29.3 (CH2), 31.3 (CH2),
32.0 (CH2), 55.5 (OCH3), 56.7 (10-OCH3), 84.7 (C50), 105.3 (C20), 115.1
(C90), 114.6 (AreC), 119.3, 122.9, 130.0, 133.8, 138.0 (C80), 147.0 (C10),
160.0 (AreC), 179.2 (C2).
4.3.4. 3-(10-Cyanonona-10,80-dien-50-oxy)-5-(p-methoxyphenyl)-4-
methylthiazole-2(3H)-thione (1h). According to 4.3.1 from 6-
hydroxydeca-2,9-dienenitrile [1.01 g, 6.09 mmol, (E)/(Z)¼71:29]
and 3-hydroxy-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-thi-
one (2.31 g, 9.14 mmol). Eluent used for chromatography: pen-
tane/Et2O¼1:1 (v/v). The product was crystallized from pentane/
Et2O. Yield: 1.53 g [3.82 mmol, 63%, (E)/(Z)¼72:28], colorless solid,
Rf 0.43 [SiO2, pentane/Et2O¼1:1 (v/v)]. Anal. calcd. for
C21H24N2O2S2 (400.56): C, 62.97; H, 6.04; N, 6.99; found: C, 62.81;
tane/Et2O¼1:1 (v/v)]. 1H NMR (CDCl3, 600 MHz)
d 1.73e1.93 (m, 4H,
H, 6.08; N, 6.89. (E)-isomer: 1H NMR (CDCl3, 400 MHz)
d
1.57e1.87
CH2), 2.16e2.33 (m, 5H, 4-CH3 and CH2), 2.47e2.50 (m, 2H, CH2),
3.73 (s, 3H, COOCH3), 3.84 (s, 3H, OCH3), 5.00e5.07 (m, 2H, 90-H),
5.38e5.40 (m,1H, 50-H), 5.78e5.89 (m, 2H,10-H and 80-H), 6.94e7.02
(m, 3H, 20-H and AreH), 7.24e7.25 (m, 2H, AreH). 13C NMR (CDCl3,
(m, 4H, CH2), 2.05e2.09 (m, 2H, CH2), 2.27 (s, 3H, 4-CH3),
2.58e2.79 (m, 2H, CH2), 3.84 (s, 3H, OCH3), 4.99e5.01 (m, 2H, 90-
H), 5.36e5.45 (m, 2H, 10-H and 50-H), 5.74e5.84 (m, 1H, 80-H),
6.76e6.83 (m, 1H, 20-H), 6.93e6.97 (m, 2H, AreH), 7.23e7.26 (m,
150 MHz)
d 12.8 (4-CH3), 27.9 (CH2), 29.3 (CH2), 30.7 (CH2), 31.3
2H, AreH). 13C NMR (CDCl3, 150 MHz)
d
12.8 (4-CH3), 29.1 (CH2),
(CH2), 51.5 (COOCH3), 55.4 (OCH3), 83.8 (C50),114.6,115.6 (C90),119.3,
121.5 (C10), 122.6, 129.9, 133.3, 137.3 (C80), 148.2 (C20), 156.0 (AreC),
167.0 (C]O), 179.2 (C2). Anal. calcd. for C22H27NO4S2 (433.58): C,
60.94; H, 6.28; N, 3.23; found: C, 60.52; H, 6.14; N 3.60.
29.2 (CH2), 30.5 (CH2), 31.4 (CH2), 55.4 (OCH3), 83.4 (C50), 100.6
(C10), 114.5 (AreC), 115.8 (C90), 117.3 (CN), 119.6, 122.4, 129.9
(AreC), 133.2, 136.9 (C80), 154.9 (C20), 159.6 (AreC), 179.2 (C2). (Z)-
isomer: 1H NMR (CDCl3, 400 MHz)
d 1.57e1.87 (m, 4H, CH2),
2.05e2.09 (m, 2H, CH2), 2.27 (s, 3H, 4-CH3), 2.58e2.79 (m, 2H,
CH2), 3.84 (s, 3H, OCH3), 4.99e5.01 (m, 2H, 90-H), 5.36e5.45 (m,
2H, 10-H and 50-H), 5.74e5.84 (m, 1H, 80-H), 6.65e6.74 (m, 1H, 20-
H), 6.93e6.97 (m, 2H, AreH), 7.23e7.26 (m, 2H, AreH). 13C NMR
4.5. Conversion of 3-alkoxythiazolethiones 1aee and 1j with
Bu3SnH or Bu3SnD
4.5.1. General procedure. To a solution of 3-alkoxylthiazole-2(3H)-
thione 1 (1 equiv, c0¼50 mM) in deaerated benzene was added
Bu3SnH or Bu3SnD (3.7 equiv, c0¼185 mM). The solution was pho-
tolyzed for 1.5 h. The solvent was removed under reduced pressure
and the residue was purified by chromatography (SiO2).
(CDCl3, 150 MHz)
d 12.8 (4-CH3), 27.3 (CH2), 29.3 (CH2), 30.7 (CH2),
31.1 (CH2), 55.4 (OCH3), 83.4 (C50), 100.2 (C10), 114.5 (AreC), 115.8
(C90), 117.3 (CN), 119.6, 122.4, 129.9 (AreC), 133.2, 137.0 (C80), 154.2
(C20), 159.6 (AreC), 179.2 (C2).
4.3.5. 3-(10-Methoxycarbonyl-10-acetylamino-50-phenylpent-10-en-
50-oxy)-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-thione (1j). In
4.5.2. Conversion of 1a with Bu3SnH. According to 4.5.1 from 3-(10-
cyanohex-10-en-50-oxy)-5-(p-methoxyphenyl)-4-methylthiazole-

I. Kempter et al. / Tetrahedron 68 (2012) 10378e10390
10387
2(3H)-thione (1a) (252 mg, 0.70 mmol) and Bu3SnH (754 mg,
0.69 mL, 2.59 mmol) in benzene (14 mL). Eluent used for chroma-
tography: CH2Cl2. (5-Methyltetrahydrofuran-2-yl)acetonitrile (5a):
Yield: 61 mg (0.48 mmol, 69%, cis/trans¼38:62), pale yellow oil, Rf
0.20 (SiO2, CH2Cl2). HRMS: calcd. for C7H10NO [MþꢁH]: 124.0762;
found: 124.0780. cis-isomer: MS (EI, 70 eV) m/z 124 (2), 110 (27), 85
(100), 82 (42), 80 (7), 67 (22), 57 (22), 55 (40). 1H NMR (CDCl3,
Et2O¼2:1 (v/v)]. cis-isomer: MS (EI, 70 eV) m/z 157 (1), 143 (9), 127
(4), 116 (63), 111 (15), 85 (89), 83 (30), 67 (22), 59 (37), 55 (100).
HRMS: calcd. for C8H14O3 [Mþ]: 158.0943; Found: 158.0950. 1H
NMR (CDCl3, 400 MHz)
d 1.19e1.23 (m, 3H, 5-CH3), 1.42e1.53 (m,
1H, CH2), 1.55e1.64 (m, 1H, CH2), 1.94e2.08 (m, 2H, CH2), 2.41e2.50
(m, 1H, CH2COOCH3), 2.57e2.66 (m, 1H, CH2COOCH3), 3.68 (s, 3H,
OCH3), 3.93e4.01 (m, 1H, 2-H), 4.19e4.26 (m, 1H, 5-H). 13C NMR
600 MHz)
d
1.26 (d, 3H, J 6.2, CH3), 1.51e1.62 (m, 1H, CH2), 1.75e1.82
(CDCl3, 100 MHz) d 21.4 (5-CH3), 31.2 (CH2), 32.6 (CH2), 41.0
(m, 1H, CH2), 2.00e2.05 (m, 1H, CH2), 2.10e2.16 (m, 1H, CH2),
2.51e2.61 (m, 2H, CH2CN), 4.00e4.05 (m, 1H, 2-H), 4.09e4.13 (m,
(CH2COOCH3), 51.6 (OCH3), 75.3 (C5), 75.7 (C2). trans-isomer: MS
(EI, 70 eV) m/z 157 (2), 143 (6), 127 (6), 116 (56), 111 (14), 101 (14), 85
(82), 83 (30), 67 (23), 59 (41), 55 (100). HRMS: calcd. for C8H14O3
[Mþ]: 158.0943; Found: 158.0947. 1H NMR (CDCl3, 400 MHz)
1H, 5-H). 13C NMR (CDCl3, 150 MHz)
d 21.0 (CH3), 24.6 (CH2CN), 30.8
(CH2), 32.6 (CH2), 74.0 (C5), 76.6 (C2), 117.5 (CN). trans-isomer: MS
(EI, 70 eV) m/z 124 (3),110 (25), 85 (100), 82 (49), 80 (10), 67 (28), 57
d 1.19e1.23 (m, 3H, 5-CH3), 1.42e1.53 (m, 1H, CH2), 1.55e1.64 (m,
(28), 55 (49). 1H NMR (CDCl3, 600 MHz)
d
1.22 (d, 3H, J 6.1, CH3),
1H, CH2), 1.94e2.08 (m, 1H, CH2), 2.10e2.19 (m, 1H, CH2), 2.41e2.50
(m, 1H, CH2COOCH3), 2.57e2.66 (m, 1H, CH2COOCH3), 3.86 (s, 3H,
OCH3), 4.07e4.15 (m, 1H, 2-H), 4.37e4.44 (m, 1H, 5-H). 13C NMR
1.51e1.62 (m, 1H, CH2), 1.75e1.82 (m, 1H, CH2), 2.10e2.16 (m, 1H,
CH2), 2.19e2.24 (m, 2H, CH2), 2.51e2.61 (m, 2H, CH2CN), 4.20e4.28
(m, 2H, 2-H and 5-H). 13C NMR (CDCl3, 150 MHz)
d
20.9 (CH3), 24.3
(CDCl3, 100 MHz) d 21.2 (5-CH3), 32.1 (CH2), 33.6 (CH2), 40.8
(CH2CN), 31.7 (CH2), 33.6 (CH2), 73.6 (C5), 76.1 (C2), 117.6 (CN).
(CH2COOCH3), 51.6 (OCH3), 74.8 (C5), 75.0 (C2).
4.5.3. Conversion of 1b with Bu3SnH. According to 4.5.1 from 3-(10-
cyano-50-phenylpent-10-en-50-oxy)-5-(p-methoxylphenyl)-4-methyl-
thiazole-2(3H)-thione (1b) (212 mg, 0.50 mmol) and Bu3SnH (538 mg,
0.49 mL, 1.85 mmol) in benzene (10 mL). Eluent used for chroma-
tography: CH2Cl2. (5-Phenyltetrahydrofuran-2-yl)acetonitrile (5b):
Yield: 63 mg (0.34 mmol, 67%, cis/trans¼44:56), pale yellow oil, Rf 0.30
(SiO2, CH2Cl2). HRMS: calcd. for C12H13NO (Mþ): 187.0997; found:
187.0989. cis-isomer: MS (EI, 70 eV) m/z 186 (36), 147 (9), 144 (42), 129
(9), 120 (32), 117 (27), 115 (16), 105 (100), 91 (36), 77 (42), 51 (21). 1H
4.5.6. Conversion of 1d with Bu3SnH. According to 4.5.1 from 3-(10-
methoxycarbonyl-50-phenylpent-10-en-50-oxy)-5-(p-methoxyphenyl)-
4-methylthiazole-2(3H)-thione (1d) (319 mg, 0.70 mmol) and Bu3SnH
(754 mg, 0.69 mL, 2.59 mmol) in benzene (14 mL). Eluent used
for chromatography: pentane/Et2O¼2:1 (v/v). Methyl (5-phenyl-
tetrahydrofuran-2-yl)acetate (5d): Yield: 111 mg (0.50 mmol, 71%, cis/
trans¼41:59), colorless oil, Rf 0.24 [SiO2, pentane/Et2O¼2:1 (v/v)].
HRMS: calcd. for C13H16O3 [Mþ]: 220.1099; found: 220.1105. cis-
isomer: MS (EI, 70 eV) m/z 220 (Mþ, 7), 219 (5), 147 (28), 129 (12),
120 (100), 117 (26), 105 (46), 91 (37), 77 (28), 55 (22). 1H NMR (CDCl3,
NMR (CDCl3, 600 MHz)
CH2), 2.63e2.76 (m, 2H, CH2CN), 4.30e4.34 (m, 1H, 2-H), 4.92 (t, 1H, J
7.3, 5-H), 7.27e7.39 (m, 5H, PheH). 13C NMR (CDCl3, 150 MHz)
24.4
d 1.92e2.00 (m, 2H, CH2), 2.25e2.38 (m, 2H,
400 MHz) d 1.71e1.80 (m, 1H, CH2), 1.82e1.94 (m, 1H, CH2), 2.16e2.43
d
(m, 2H, CH2), 2.53e2.64 (m, 1H, CH2COOCH3), 2.71e2.82 (m, 1H,
CH2COOCH3), 3.71 (s, 3H, OCH3), 4.43e4.50 (m, 1H, 2-H), 4.91 (t, 1H, J
7.1, 5-H), 7.23e7.27 (m, 1H, PheH), 7.32e7.33 (m, 4H, PheH). 13C NMR
(CH2CN), 30.9 (CH2), 34.0 (CH2), 74.2 (C5), 81.5 (C2), 117.4 (CN), 125.8,
127.6, 128.4, 141.5 (PheC). trans-isomer: MS (EI, 70 eV) m/z 186 (35),
147 (8), 144 (41), 129 (11), 120 (32), 117 (27), 115 (17), 105 (100), 91
(CDCl3, 100 MHz)
d 31.2 (CH2), 34.3 (CH2), 40.8 (CH2COOCH3), 51.7
(36), 77 (39), 51 (21). 1H NMR (CDCl3, 600 MHz)
d
1.92e2.00 (m, 2H,
(OCH3), 75.8 (C5), 81.2 (C2), 125.7, 127.2, 128.3, 142.8 (PheC), 171.6 (C]
O). trans-isomer: MS (EI, 70 eV) m/z 220 (Mþ, 6), 219 (3), 147 (24), 129
(12), 120 (100), 117 (22), 105 (43), 91 (32), 77 (22), 55 (16). 1H NMR
CH2), 2.25e2.38 (m, 1H, CH2), 2.45e2.49 (m, 1H, CH2), 2.63e2.76 (m,
2H, CH2CN), 4.46e4.50 (m, 1H, 2-H), 5.15 (t, 1H, J 7.2, 5-H), 7.27e7.39
(m, 5H, PheH). 13C NMR (CDCl3, 150 MHz)
d
24.4 (CH2CN), 31.7 (CH2),
(CDCl3, 400 MHz) d 1.71e1.80 (m, 1H, CH2), 1.82e1.94 (m, 1H, CH2),
35.0 (CH2), 74.6 (C5), 82.0 (C2), 117.4 (CN), 125.5, 127.5, 128.4, 142.2
(PheC).
2.16e2.43 (m, 2H, CH2), 2.53e2.64 (m, 1H, CH2COOCH3), 2.71e2.82
(m, 1H, CH2COOCH3), 3.72 (s, 3H, OCH3), 4.60e4.66 (m, 1H, 2-H), 5.04
(t, 1H, J 7.1, 5-H), 7.23e7.27 (m, 1H, PheH), 7.32e7.33 (m, 4H, PheH).
4.5.4. Conversion of 1b with Bu3SnD. According to 4.5.1 from 3-(10-
cyano-50-phenylpent-10-en-50-oxy)-5-(p-methoxylphenyl)-4-methyl-
thiazole-2(3H)-thione (1b) (211 mg, 0.50 mmol) and Bu3SnD
(540 mg, 0.49 mL, 1.85 mmol) in benzene (10 mL). Eluent used for
chromatography: CH2Cl2. (5-Phenyltetrahydrofuran-2-yl)-2-d1-aceto-
nitrile (5bd1): Yield: 69 mg (0.37 mmol, 74%, cis/trans¼46:54), pale
yellow oil, Rf 0.41 (SiO2, CH2Cl2). cis-isomer: 1H NMR (CDCl3, 600 MHz)
13C NMR (CDCl3, 100 MHz)
d 32.1 (CH2), 35.1 (CH2), 40.7 (CH2COOCH3),
51.7 (OCH3), 75.9 (C5), 80.5 (C2), 125.5, 127.1, 128.3, 143.3 (PheC), 171.7
(C]O).
4.5.7. Conversion of 1j with Bu3SnH. According to 4.5.1 from 3-(10-
methoxycarbonyl-10-acetylamino-50-phenylpent-10-en-50-oxy)-5-
(p-methoxyphenyl)-4-methylthiazole-2(3H)-thione (1j) (179 mg,
0.35 mmol) and Bu3SnH (378 mg, 0.34 mL, 1.30 mmol) in benzene
(7 mL). Eluent used for chromatography: pentane/EtOAc¼1:3 (v/v).
rel-(2R,6R)-Methyl N-acetylamino-(5-phenyltetrahydrofuran-2-yl)
d
1.92e1.99 (m, 2H, CH2), 2.25e2.38 (m, 2H, CH2), 2.63e2.73 (m, 1H,
CHCN), 4.30e4.33 (m,1H, 2-H), 4.91 (t,1H, J 7.3, 5-H), 7.27e7.39 (m, 5H,
PheH). 13C NMR (CDCl3, 100 MHz) 24.13 (t, 1JC,D 20.34, CHDCN), 30.8
(CH2), 34.0 (CH2), 74.2 (C50), 82.0 (C20), 117.4 (CN), 125.8, 127.6, 128.4,
141.6 (PheC). trans-isomer: 1H NMR (CDCl3, 600 MHz)
1.92e1.99 (m,
d
acetate rel-(2R,6R)-(5j): Yield: 18 mg (65.0
mmol, 19%, cis/
d
trans¼32:68), pale yellow oil, Rf 0.45 [SiO2, pentane/EtOAc¼1:3 (v/
2H, CH2), 2.25e2.38 (m, 1H, CH2), 2.44e2.50 (m, 1H, CH2), 2.63e2.73
v)]. rel-(2R,5S,6R)-(5j) (cis-isomer): 1H NMR (CDCl3, 400 MHz)
(m,1H, CHCN), 4.46e4.50 (m,1H, 2-H), 5.14 (t,1H, J 7.2, 5-H), 7.27e7.39
d 1.76e1.87 (m, 2H, CH2), 1.91 (s, 3H, CH3), 2.06e2.08 (m, 1H, CH2),
1
(m, 5H, PheH). 13C NMR (CDCl3, 100 MHz)
d
24.13 (t, JC,D 20.34,
2.25e2.31 (m, 1H, CH2), 3.72 (s, 3H, OCH3), 4.50 (td, 1H, Jt 7.1, Jd 2.6,
2-H), 4.75 (dd,1H, J 9.0, 2.6, 6-H), 4.83 (t, 1H, J 7.0, 5-H), 6.08 (d,1H, J
CHDCN), 31.7 (CH2), 35.0 (CH2), 74.5 (C50), 81.4 (C20), 117.4 (CN), 125.4,
127.5, 128.4, 142.2 (PheC).
8.8, NH), 7.16e7.32 (m, 5H, PheH). 13C NMR (CDCl3, 100 MHz)
d 23.1
(CH3), 28.2 (CH2), 33.5 (CH2), 52.6 (OCH3), 54.7 (C6), 79.2 (C5), 81.0
(C2),125.6,127.6,128.5,141.9 (PheC),170.4 (C]O),171.0 (C]O). rel-
(2R,5R,6R)-(5j) (trans-isomer): 1H NMR (CDCl3, 400 MHz)
4.5.5. Conversion of 1c with Bu3SnH. According to 4.5.1 from 3-[(10-
(methoxycarbonyl)hex-10-en-50-oxy)-5-(p-methoxyphenyl)-4-
methylthiazole-2(3H)-thione (1c) (249 mg, 0.63 mmol) and
Bu3SnH (678 mg, 0.62 mL, 2.33 mmol) in benzene (12.5 mL). Eluent
used for chromatography: pentane/Et2O¼2:1 (v/v). Methyl (5-
methyltetrahydrofuran-2-yl)acetate (5c): Yield: 68 mg (0.43 mmol,
68%, cis/trans¼37:63), pale yellow oil, Rf 0.43 [SiO2, pentane/
d
1.76e1.87 (m, 2H, CH2), 2.05 (s, 3H, CH3), 2.06e2.08 (m, 1H, CH2),
2.25e2.31 (m, 1H, CH2), 3.73 (s, 3H, OCH3), 4.62 (td, 1H, Jt 7.3, Jd 2.5,
2-H), 4.71 (dd, 1H, J 8.8, 2.7, 6-H), 4.95 (t, 1H, J 7.0, 5-H), 6.31 (d, 1H, J
8.7, NH), 7.16e7.32 (m, 5H, PheH). 13C NMR (CDCl3, 100 MHz)
d
23.2
(CH3), 29.0 (CH2), 35.1 (CH2), 52.6 (OCH3), 54.8 (C6), 79.4 (C5), 81.8

10388
I. Kempter et al. / Tetrahedron 68 (2012) 10378e10390
(C2), 125.4, 127.4, 128.4, 142.7 (PheC), 170.6 (C]O), 171.1 (C]O).
rel-(2R,6S)-Methyl N-acetylamino-(5-phenyltetrahydrofuran-2-yl)
acetate rel-(2R,6S)-(5j): Yield: 53 mg (0.19 mmol, 54%, cis/
trans¼28:72), pale yellow oil, Rf 0.37 [SiO2, pentane/EtOAc¼1:3
(v/v)]. rel-(2R,5S,6S)-(5j) (cis-isomer): 1H NMR (CDCl3, 400 MHz)
100 MHz) d 15.9, 15.92, 16.1 (CH3), 29.36, 29.43, 29.8, 30.0 (CH2),
34.2, 34.4, 34.6, 34.9 (CH2), 52.4, 52.5, 52.6 (CHS), 54.55, 54.6, 55.1,
55.2, 55.4, 55.6 (2ꢃ OCH3), 78.5, 78.8, 79.2, 79.3 (C20), 81.1, 81.5, 81.8,
82.1 (C50),113.97,113.99,114.2 (AreC),121.2,121.5,123.5,123.6 (C500),
125.35, 125.4, 125.5, 125.6, 127.08, 127.09, 127.1, 127.2, 127.8, 128.07,
128.1,128.2,128.5 (PheC),130.1,130.3 (AreC),133.02,133.06,134.05,
134.1 (AreC), 141.6, 142.0, 142.4, 142.6 (AreC), 147.1, 147.2, 147.57,
147.6 (C400), 155.87, 155.89, 157.4, 157.6 (C200), 159.16, 159.2, 159.8
(AreC), 170.1, 170.2 (C]O).
d
1.60e1.70 (m, 1H, CH2), 1.97 (s, 3H, CH3), 2.08e2.14 (m, 1H, CH2),
2.16e2.22 (m, 2H, CH2), 3.70 (s, 3H, OCH3), 4.22e4.26 (m, 1H, 2-
H), 4.75e4.78 (m, 2H, 5-H and 6-H), 6.55 (br s, 1H, NH), 7.17e7.28
(m, 5H, PheH). 13C NMR (CDCl3, 100 MHz)
d 23.1 (CH3), 28.3
(CH2), 34.3 (CH2), 52.4 (OCH3), 55.5 (C6), 80.0 (C5), 81.8 (C2),
125.6, 127.5, 128.3, 141.6 (PheC), 169.8 (C]O), 170.5 (C]O). rel-
(2R,5R,6S)-(5j) (trans-isomer): 1H NMR (CDCl3, 400 MHz)
4.6.2. Conversion of 1e. To a solution of 3-(10-cyano-10-cyclopro-
pyl-50-phenylpent-10-en-50-oxy)-5-(p-methoxyphenyl)-4-methyl-
thiazole-2(3H)-thione (1e) (467 mg, 1.01 mmol) in deaerated ben-
zene (20 mL) was added BrCCl3 (2.00 g, 1.00 mL, 10.10 mmol). The
solution was photolyzed for 1.5 h. The solvent was removed under
reduced pressure and the residue was purified by chromatography.
Rf 0.31 [SiO2, pentane/Et2O¼3:1 (v/v)]: 5-bromo-2-(trans-50-phe-
d
1.76e1.85 (m, 1H, CH2), 1.98 (s, 3H, CH3), 2.08e2.14 (m, 2H,
CH2), 2.24e2.32 (m, 1H, CH2), 3.72 (s, 3H, OCH3), 4.38 (td, 1H, Jt
7.1, Jd 4.6, 2-H), 4.70 (dd, 1H, J 8.6, 4.6, 6-H), 4.90 (t, 1H, J 7.1, 5-H),
6.55 (br s, 1H, NH), 7.17e7.28 (m, 5H, PheH). 13C NMR (CDCl3,
100 MHz)
d 23.1 (CH3), 28.6 (CH2), 34.5 (CH2), 52.4 (OCH3), 55.5
(C6), 80.6 (C5), 81.4 (C2), 125.5, 127.4, 128.3, 142.5 (PheC), 169.8
(C]O), 170.8 (C]O).
nyltetrahydrofuran-20-yl)-pent-2-enenitrile trans-(5
) [Yield: 43 mg
3
(0.14 mmol,17% with respect of converted 1e)], 2-cyclopropyl-6-oxo-
6-phenylhex-2-enenitrile (10) [Yield: 14 mg (0.06 mmol, 7% with
respect of converted 1e)] and 5-(p-methoxyphenyl)-4-methyl-2-
(trichloromethylsulfanyl)-thiazole (3b) [Yield: 124 mg (0.35 mmol,
41% with respect of converted 1e)], yellow oil. 5-Bromo-2-(trans-50-
4.6. Conversion of 3-alkoxythiazolethiones 1d and 1e with
BrCCl3
4.6.1. Conversion of 1d. To a solution of 3-(10-methoxycarbonyl-50-
phenylpent-10-en-50-oxy)-5-(p-methoxyphenyl)-4-methylthiazole-
2(3H)-thione (1d) (456 mg, 1.00 mmol) in deaerated benzene
(12 mL) was added BrCCl3 (1.98 g, 1.00 mL, 10.00 mmol) and AIBN
(41 mg, 0.25 mmol). The reaction mixture was stirred for 3 h at
80 ꢂC. The solvent was removed under reduced pressure and the
residue was purified by chromatography. Rf 0.49 [SiO2, pentane/
Et2O¼1:1 (v/v)]: Methyl 2-bromo-2-(50-phenyltetrahydrofuran-20-yl)
acetate (9d)24 [Yield: 62 mg (0.21 mmol, 21%, cis/trans¼44:56) as
a mixture of diastereomers Acis/trans and Bcis/trans] and 5-(p-methoxy-
phenyl)-4-methyl-2-(trichloromethylsulfanyl)thiazole (3b) [Yield:
106 mg (0.23 mmol, 30%)], yellow oil. Methyl 2-bromo-2-(50-phe-
nyltetrahydrofuran-20-yl)acetate (9d): cis-isomer (diastereomer A
phenyltetrahydrofuran-20-yl)-pent-2-enenitrile trans-(5
(CDCl3, 400 MHz) 1.91e2.00 (m, 1H, CH2), 2.06e2.16 (m, 1H, CH2),
3
): 1H NMR
d
2.33e2.42 (m, 1H, CH2), 2.43e2.50 (m, 1H, CH2), 2.96e3.00 (m, 2H,
CH2), 3.47 (t, 2H, J 6.5, CH2Br), 4.78 (t, 1H, J 7.0, 20-H), 5.16e5.19 (m,
1H, 50-H), 6.54 (t, 1H, J 7.2, 3-H), 7.27e7.43 (m, 5H, PheH). 13C NMR
(CDCl3, 100 MHz) d
30.0, 32.1, 33.7, 34.7 (CH2), 79.3 (C20), 81.8 (C50),
115.7 (CN),120.1 (C2),125.5,127.6,128.4,142.1 (PheC),143.5 (C3). 2-
Cyclopropyl-6-oxo-6-phenylhex-2-enenitrile (10): 1H NMR (CDCl3,
400 MHz)
d 0.69e0.90 (m, 4H, cyclopropyl), 1.50e1.57 (m, 1H,
cyclopropyl), 2.74e2.80 (m, 2H, CH2), 3.15 (t, 2H, J 6.9, CH2), 6.37 (t,
1H, J 7.6, 3-H), 7.45e7.49 (m, 2H, PheH), 7.56e7.60 (m, 1H, PheH),
7.95e7.97 (m, 2H, PheH). 13C NMR (CDCl3, 100 MHz)
d 5.9, 14.1
and B): 1H NMR (CDCl3, 200 MHz)
d 1.82e2.09 (m, 2H, CH2),
(cyclopropyl), 25.7, 37.3 (CH2), 115.7 (CN), 118.5 (C2), 128.0, 128.7,
133.3, 136.5 (PheC), 143.9 (C3), 198.2 (C]O). 5-(p-Methoxyphenyl)-
4-methyl-2-(trichloromethylsulfanyl)-thiazole (3b): NMR data agreed
with published values.5 Rf 0.28ꢁ0.15 [SiO2, pentane/Et2O¼3:1 (v/
v)]: 5-bromo-2-(50-phenyltetrahydrofuran-20-yl)-pent-2-enenitrile
2.18e2.47 (m, 2H, CH2), 3.79 and 3.82 (s, 3H, OCH3), 4.23 (d, 1H, J 8.6,
CHBr), 4.47e4.61 (m, 1H, 20-H), 4.94e5.02 (m, 1H, 50-H), 7.26e7.36
(m, 5H, PheH). 13C NMR (CDCl3, 150 MHz)
d 29.6, 29.8 (CH2), 34.1,
35.0 (CH2), 47.3, 48.6 (CHBr), 53.0 (OCH3), 79.4, 79.5 (C20), 82.0, 82.7
(C50), 125.6, 125.7, 128.3 (2C), 129.0, 129.7, 141.79, 141.83 (PheC),
168.6, 168.9 (C]O). trans-isomer (diastereomer A and B): 1H NMR
(5 ) [Yield: 73 mg (0.24 mmol, 29% with respect of converted 1e, cis/
3
trans¼18:82) and 2-cyclopropyl-6-oxo-6-phenylhex-2-enenitrile (10)
[Yield: 16 mg (0.13 mmol, 9% with respect of converted 1e, (E)/(Z)¼
58:42)], yellow oil. 5-Bromo-2-(50-phenyltetrahydrofuran-20-yl)-
(CDCl3, 200 MHz) d 1.82e2.09 (m, 2H, CH2), 2.18e2.47 (m, 2H, CH2),
3.80 and 3.81 (s, 3H, OCH3), 4.22 (d, 0.3H, J 8.7, A-CHBr), 4.38 (d,
0.7H, J 6.9, B-CHBr), 4.64e4.75 (m, 1H, 20-H), 5.05e5.12 (m, 1H, 50-
pent-2-enenitrile (5
3
H), 7.26e7.36 (m, 5H, PheH). 13C NMR (CDCl3, 150 MHz)
d 30.0, 30.4
d
1.90e2.00 (m, 1H, CH2), 2.07e2.16 (m, 1H, CH2), 2.32e2.41 (m, 1H,
CH2), 2.43e2.52 (m, 1H, CH2), 2.96e3.01 (m, 2H, CH2), 3.48 (t, 2H, J
6.5, CH2Br), 4.61 (t, 1H, J 6.4, 20-H), 4.92e4.96 (m, 1H, 50-H), 6.54 (t,
1H, J 7.4, 3-H), 7.27e7.43 (m, 5H, PheH). 13C NMR (CDCl3, 100 MHz)
30.0, 31.6, 33.8, 34.7 (CH2), 79.0 (C20), 82.3 (C50), 117.4 (CN), 119.8
(C2), 126.1, 127.8, 128.5, 141.2 (PheC), 145.1 (C3). trans-isomer: NMR
data agreed with values from an authentic sample. 2-Cyclopropyl-6-
oxo-6-phenylhex-2-enenitrile (10): 1H NMR data agreed with values
from an authentic sample. 13C NMR (CDCl3, 100 MHz) 5.8, 6.4, 9.3,
14.1 (cyclopropyl), 22.9, 25.7 (CH2), 36.9, 37.3 (CH2),115.7,155.8 (CN),
118.5, 118.9 (C2), 127.95, 128.0, 128.68, 128.7, 133.3, 133.4, 136.48,
136.5 (PheC), 143.9, 144.3 (C3), 198.1, 198.2 (C]O). Rf 0.13 [SiO2,
pentane/Et2O¼3:1 (v/v)]: 5-bromo-2-(cis-50-phenyltetrahydrofuran-
(CH2), 34.9, 35.3 (CH2), 47.6, 48.2 (CHBr), 53.0, 53.1 (OCH3), 79.5, 79.7
(C20), 81.7, 81.8 (C50), 125.5, 125.6, 127.4, 127.5, 128.3 (2C), 142.22,
142.23 (PheC), 168.7, 169.0 (C]O). 5-(p-methoxyphenyl)-4-methyl-
2-(trichloromethylsulfanyl)thiazole (3b): NMR data agreed with
published values.5 Rf 0.33 [SiO2, pentane/Et2O¼1:1 (v/v)]: Methyl 2-
[500-(p-methoxyphenyl)-400-methyl-200-(methylsulfanyl)-thiazole]-
2-(50-phenyltetrahydrofuran-20-yl)acetate (8d): Yield: 282 mg
(0.62 mmol, 62%, cis/trans¼43:57) as a mixture of diastereomers
Acis/trans and Bcis/trans, yellow oil. cis-isomer (diastereomer A and B):
1H NMR (CDCl3, 200 MHz)
d 1.85e2.00 (m, 1H, CH2), 2.09e2.33 (m,
3H, CH2), 2.41 (s, 3H, 400-CH3), 3.79 (s, 3H, OCH3), 3.84 (s, 3H, OCH3),
4.36e4.40 (m, 1H, CHS), 4.63e4.87 (m, 1H, 20-H), 4.90e5.01 (m, 1H,
50-H), 6.91e6.91 (m, 2H, AreH), 7.26e7.32 (m, 7H, PheH and AreH).
trans-isomer (diastereomer A and B): 1H NMR (CDCl3, 200 MHz)
20-yl)-pent-2-enenitrile (5
) [Yield: 41 mg (0.13 mmol, 16%
3
with respect of converted 1e)] and 3-(10-cyano-10-cyclopropyl-50-
phenylpent-10-en-50-oxy)-5-(4-methoxyphenyl)-4-methylthiazole
-2(3H)-thione (1e) [Yield: 76 mg (0.16 mmol, 16%)], yellow oil. 5-
Bromo-2-(cis-50-phenyltetrahydrofuran-20-yl)-pent-2-enenitrile cis-
d
1.85e2.00 (m, 1H, CH2), 2.09e2.33 (m, 3H, CH2), 2.41 (s, 3H, 400-
CH3), 3.79 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 4.36e4.40 and
4.63e4.66 (m, 1H, CHS), 4.63e4.87 (m, 1H, 20-H), 5.05e5.16 (m, 1H,
50-H), 6.91e6.91 (m, 2H, AreH), 7.26e7.32 (m, 7H, PheH and AreH).
cis- and trans-isomer (diastereomer A and B): 13C NMR (CDCl3,
(5
): NMR data agreed with values from an authentic sample. 3-(10-

I. Kempter et al. / Tetrahedron 68 (2012) 10378e10390
10389
phenyl)-4-methylthiazole-2(3H)-thione (1e): NMR data agreed
with values from 4.2.6.
5-H), 4.20e4.26 (m, 1H, 2-H and 5-H), 4.94e5.05 (m, 2H, 40-H-5h),
5.29e5.36 (m,1H, 20-H-11h), 5.76e5.86 (m,1H, 30-H-5h), 6.50e6.57
[m, 0.46H, 30-H-(Z)-11h], 6.71e6.78 [m, 0.54H, 30-H-(E)-11h]. 13C
4.7. Conversion of 3-alkoxythiazolethiones 1fei with Bu3SnH
NMR (CDCl3,100 MHz) d 21.29 (CH3-trans-11h), 21.41 (CH3-cis-11h),
or Bu3SnD
24.4 (CH2CN-trans-5h), 24.6 (CH2CN-cis-5h), 28.78, 28.81, 30.2, 30.3,
30.7, 30.8, 31.2, 31.3, 31.6, 31.8, 32.2, 32.3, 32.8, 33.88, 33.93, 34.03,
34.07, 34.47, 34.52, 34.8, 34.9 (CH2), 73.7 (C2-trans-5h), 73.9 (C2-cis-
5h), 74.75, 74.77, 75.5 (2C), 77.5, 77.8, 78.2, 78.4 [C2- and C5-cis/
trans-(E)/(Z)-11h], 79.6 (C5-trans-5h), 80.0 (C5-cis-5h), 99.5 [C20-
(E)/(Z)-11h], 99.9 [C20-(E)/(Z)-11h],114.8 (C40-5h),116.0 [CN-(E)/(Z)-
11h], 117.6 [CN-(E)/(Z)-11h], 117.64 (CN-5h), 138.16 (C30-trans-5h),
138.23 (C30-cis-5h), 154.8, 155.0, 155.81, 155.83 [C30-cis/trans-(E)/
4.7.1. General procedure. To a solution of 3-alkoxythiazole-2(3H)-
thione 1 (1 equiv, c0¼55 mM) in deaerated benzene was added
Bu3SnH or Bu3SnD (3.7 equiv, c0¼205 mM). The solution was
photolyzed for 45 min. The solvent was removed under reduced
pressure and the residue was purified by chromatography (SiO2).
4.7.2. Conversion of 1f with Bu3SnH. According to 4.7.1 from 3-(90-
methyldeca-10,80-dien-50-oxy)-5-(p-methoxyphenyl)-4-methyl-
thiazole-2(3H)-thione (1f) (202 mg, 500 mmol), Bu3SnH (540 mg,
(Z)-11h]. n
(NaCl)/cmꢁ11087,1375,1447,1641,1733, 2222, 2251, 2931.
cis/trans-(E)/(Z)-11h: MS (EI, 70 eV) m/z 165 (Mþ, 0.3), 164 (1), 150
(3), 136 (5), 120 (5), 108 (6), 85 (100). cis-5h: MS (EI, 70 eV) m/z 165
(Mþ, 0.2), 164 (1), 136 (13), 123 (26), 110 (100), 82 (43). trans-5h: MS
(EI, 70 eV) m/z 165 (Mþ, 0.2),164 (1),136 (22),123 (47),110 (100), 82
(59). cis/trans-(E)/(Z)-11h: MS (EI, 70 eV) m/z 165 (Mþ, 0.2), 164 (1),
150 (3), 136 (2), 120 (3), 108 (5), 85 (100).
0.49 mL, 1.85 mmol) and benzene (9 mL). Eluent used for chro-
matography: pentane/Et2O¼3:1 (v/v). 2-(But-30-en-10-yl)-5-(100-
methylethyl)-tetrahydrofuran (5f): Yield: 79 mg (466 mmol, 93%, cis/
trans¼32:68), colorless oil, Rf 0.69 [SiO2, pentane/Et2O¼3:1 (v/v)].
cis-isomer: MS (EI, 70 eV) m/z 168 (Mþ, 0.4), 125 (92), 113 (14), 97
(33), 95 (78), 81 (84), 55 (100). 1H NMR (CDCl3, 400 MHz)
d
0.84 (d,
4.7.5. Conversion of 1h with Bu3SnD. According to 4.7.1 from 3-(10-
cyanonona-10,80-dien-50-oxy)-5-(p-methoxyphenyl)-4-methylthi-
3H, J 6.6, CH3), 0.95 (d, 3H, J 6.6, CH3), 1.42e2.17 (m, 9H, CH and
CH2), 3.48e3.54 (m, 1H, 5-H), 3.78e3.93 (m, 1H, 2-H), 4.92e5.04
(m, 2H, 40-H), 5.78e5.89 (m, 1H, 30-H). 13C NMR (CDCl3, 100 MHz)
azole-2(3H)-thione (1h) (111 mg, 277
mmol), Bu3SnD (297 mg,
0.27 mL, 1.02 mmol) and benzene (5 mL). Eluent used for chroma-
d
18.5 (CH3), 19.5 (CH3), 28.5 (CH2), 30.6 (CH2), 31.3 (CH2), 33.4 (CH),
tography: pentane/Et2O¼1:1 (v/v). [5-(But-30-en-10-yl)-tetrahydro-
35.4 (CH2), 78.8 (C2), 84.9 (C5), 114.4 (C40), 138.9 (C30). trans-
furan-2-yl]-2-d1-acetonitrile
(5hd1
)
and
50-[5-methyl-d1-
isomer: MS (EI, 70 eV) m/z 168 (Mþ, 3), 125 (90), 113 (14), 97 (34),
tetrahydrofuran-2-yl]-pent-20-enenitrile (11hd1): Yield: 42 mg
95 (77), 81 (88), 55 (100). 1H NMR (CDCl3, 400 MHz)
d
0.84 (d,
[253
m
mol, 91%, 5hd1 (cis/trans¼34:66):11hd1 (cis/trans¼45:55)¼
3H, J 6.6, CH3), 0.95 (d, 3H, J 6.6, CH3), 1.42e2.17 (m, 9H, CH and
CH2), 3.58e3.64 (m, 1H, 5-H), 3.78e3.93 (m, 1H, 2-H), 4.92e5.04
(m, 2H, 40-H), 5.78e5.89 (m, 1H, 30-H). 13C NMR (CDCl3, 100 MHz)
53:47], colorless oil, Rf 0.28 [SiO2, pentane/Et2O¼1:1 (v/v)]. 1H NMR
(CDCl3, 400 MHz)
d 1.19e1.24 (m, 2H, CH2D-11hd1), 1.42e1.82 (m,
8H, CH2), 1.95e2.53 (m, 8H, CH2), 2.54e2.58 (m, 1H, CHDCN-5hd1),
3.77e4.15 (m, 3H, 2-H and 5-H), 4.20e4.26 (m, 1H, 2-H or 5-H),
4.94e5.04 (m, 2H, 40-H-5hd1), 5.29e5.36 (m, 1H, 20-H-11hd1),
5.75e5.87 (m, 1H, 30-H-5hd1), 6.50e6.57 [m, 0.47H, 30-H-(Z)-11hd1],
6.71e6.78 [m, 0.53H, 30-H-(E)-11hd1]. 13C NMR (CDCl3, 100 MHz)
d
18.4 (CH3),19.5 (CH3), 29.6 (CH2), 30.6 (CH2), 32.5 (CH2), 33.4 (CH),
35.3 (CH2), 78.5 (C2), 84.2 (C5), 114.5 (C40), 138.8 (C30).
4.7.3. Conversion of 1g with Bu3SnH. According to 4.7.1 from 3-(10-
methoxynona-10,80-dien-50-oxy)-5-(p-methoxyphenyl)-4-methyl-
thiazole-2(3H)-thione (1g) (292 mg, 719
d
20.90 (t, 1JC,D 18.96, CH2D-trans-(E)/(Z)-11hd1), 20.92 (t, 1JC,D 18.96,
1
m
mol), Bu3SnH (774 mg,
CH2D-trans-(E)/(Z)-11hd1), 21.02 (t, JC,D 18.96, CH2D-cis-11hd1),
1
1
0.70 mL, 2.66 mmol) and benzene (13 mL). Eluent used for chro-
24.18 (t, JC,D 21.13, CHCDCN-trans-5hd1), 24.39 (t, JC,D 21.13,
CHCDCN-cis-5hd1), 28.79, 28.84, 30.2, 30.3, 30.7, 30.9, 31.3, 31.4, 31.6,
31.9, 32.5, 32.3, 32.9, 33.89, 33.94, 34.1, 34.2, 34.5, 34.6, 34.9, 35.0
(CH2), 73.7 (C2-trans-5hd1), 74.0 (C2-cis-5hd1), 74.74, 74.76, 75.5
(2C), 77.6, 77.8, 78.3, 78.5 [C2- and C5-cis/trans-(E)/(Z)-11hd1], 79.7
(C5-trans-5hd1), 80.1 (C5-cis-5hd1), 99.6 [C20-(E)/(Z)-11hd1], 100.0
[C20-(E)/(Z)-11hd1],114.8 (C40-5hd1), 116.0 [CN-(E)/(Z)-11hd1], 117.48
[CN-(E)/(Z)-11hd1], 117.5 (CN-5hd1), 138.2 (C30-trans-5hd1), 138.3
(C30-cis-5hd1), 154.95, 155.0, 155.76, 155.8 [C30-cis/trans-(E)/(Z)-
matography: pentane/Et2O¼2:1 (v/v). 2-(But-30-en-10-yl)-5-
(methoxymethyl)-tetrahydrofuran (5g): Yield: 114 mg (670
mmol,
93%, cis/trans¼35:65), colorless oil, Rf 0.44 [SiO2, pentane/Et2O¼2:1
(v/v)]. MS (EI, 70 eV) m/z 170 (Mþ, 0.04),125 (58),115 (7), 97 (15), 81
(64), 55 (100). cis-isomer: 1H NMR (CDCl3, 400 MHz)
d 1.46e1.79
(m, 4H, CH2), 1.89e2.18 (m, 4H, CH2), 3.37e3.40 (m, 5H, OCH3 and
CH2OCH3), 3.82e3.89 (m, 1H, 5-H), 3.92e4.06 (m, 1H, 2-H),
4.92e5.04 (m, 2H, 40-H), 5.77e5.88 (m, 1H, 30-H). 13C NMR (CDCl3,
100 MHz)
(OCH3), 75.8 (CH2OCH3), 77.8 (C5), 79.4 (C2), 114.3 (C40), 138.5 (C30).
trans-isomer: 1H NMR (CDCl3, 400 MHz)
1.46e1.79 (m, 4H, CH2),
d
28.0 (CH2), 30.3 (CH2), 30.6 (CH2), 35.0 (CH2), 59.2
11hd1]. n
(NaCl)/cmꢁ1 1081, 1368, 1447, 1641, 2222, 2250, 2935.
cis/trans-(E)/(Z)-11hd1: MS (EI, 70 eV) m/z 166 (Mþ, 0.4), 165 (1), 164
(0.3), 150 (3), 137 (5), 120 (5), 108 (6), 86 (100). cis-5hd1: MS (EI,
70 eV) m/z 166 (Mþ, 0.3),165 (1),137 (12),124 (26),111 (100), 83 (53).
trans-5hd1: MS (EI, 70 eV) m/z 166 (Mþ, 0.2), 165 (1), 137 (21), 124
(45),111 (100), 83 (65). cis/trans-(E)/(Z)-11hd1: MS (EI, 70 eV) m/z 166
(Mþ, 0.3),165 (1),164 (0.3),150 (3),137 (2),120 (5),108 (3), 86 (100).
d
1.89e2.18 (m, 4H, CH2), 3.37e3.40 (m, 5H, OCH3 and CH2OCH3),
3.92e4.06 (m, 1H, 2-H), 4.12e4.19 (m, 1H, 5-H), 4.92e5.04 (m, 1H,
40-H), 5.77e5.88 (m, 1H, 30-H). 13C NMR (CDCl3, 100 MHz)
d 28.5
(CH2), 30.2 (CH2), 31.6 (CH2), 34.8 (CH2), 59.2 (OCH3), 75.6
(CH2OCH3), 77.2 (C5), 78.8 (C2), 114.3 (C40), 138.5 (C30).
4.7.6. Conversion of 1i with Bu3SnD. According to 4.7.1 from 3-[10-
(methoxycarbonyl)nona-10,80-dien-50-oxy]-5-(p-methoxyphenyl)-
4.7.4. Conversion of 1h with Bu3SnH. According to 4.7.1 from 3-(10-
cyanonona-10,80-dien-50-oxy)-5-(p-methoxyphenyl)-4-methylthi-
4-methylthiazole-2(3H)-thione (1i) (86 mg, 198
mmol), Bu3SnD
azole-2(3H)-thione (1h) (181 mg, 499
mmol), Bu3SnH (540 mg,
(214 mg, 0.19 mL, 733 mol) and benzene (3.6 mL). Eluent used for
m
0.49 mL, 1.85 mmol) and benzene (9 mL). Eluent used for chroma-
tography: pentane/Et2O¼1:1 (v/v). [5-(But-30-en-10-yl)-tetrahydro-
furan-2-yl]acetonitrile (5h) and 50-[5-methyltetrahydrofuran-2-yl]-
chromatography: [SiO2, pentane/Et2O¼1:1 (v/v)]. Methyl [5-(but-
30-en-10-yl)-tetrahydrofuran-2-yl)-2-d1-acetate (5i): Yield: 11 mg
(57
Et2O¼1:1 (v/v)].
MS (EI, 70 eV) m/z 168 (2), 167 (1), 112 (6), 100 (13), 85 (100). cis-
isomer: 1H NMR (CDCl3, 400 MHz)
1.20e1.73 (m, 4H, CH2),
m
mol, 29%, cis/trans¼35:65), colorless oil, Rf 0.28 [SiO2, pentane/
pent-20-enenitrile (11h): Yield: 75 mg [453
mmol, 91%, 5h (cis/
n
(NaCl)/cmꢁ1 1081, 1272, 1437, 1657, 1726, 2935.
trans¼38:62):11h (cis/trans¼45:55)¼51:49], colorless oil, Rf 0.28
[SiO2, pentane/Et2O¼1:1 (v/v)]. 1H NMR (CDCl3, 400 MHz)
d
d
1.20e1.24 (m, 3H, CH3-11h),1.42e1.80 (m,10H, CH2),1.95e2.51 (m,
1.92e2.17 (m, 4H, CH2), 2.41e2.46 (m, 1H, CHD), 3.68 (s, 3H, OCH3),
3.82e3.88 (m,1H, 5-H), 4.23 (q,1H, J 6.6, 2-H), 4.92e5.03 (m, 2H, 40-
6H, CH2), 2.55e2.58 (m, 2H, CH2CN-5h), 3.77e4.15 (m, 3H, 2-H and

10390
I. Kempter et al. / Tetrahedron 68 (2012) 10378e10390
H), 5.78e5.86 (m, 1H, 30-H). 13C NMR (CDCl3, 100 MHz)
31.0 (CH2), 31.8 (CH2), 35.3 (CH2), 40.73 (t, JC,D 20.34, CHD), 51.5
(OCH3), 75.1 (C2), 79.2 (C5), 114.4 (C40), 138.4 (C30), 171.7 (C]O).
NOESY (cross peaks) 2-H45-H. trans-isomer: 1H NMR (CDCl3,
d
30.3 (CH2),
3. Halliwell, B.; Gutteridge, J. M. C. Free Radicals in Biology and Medicine, 3rd ed.;
Oxford Universtiy: Oxford, 1999, Chapter 2, pp 36e104.
4. Atkinson, R. Atmos. Environ. 2007, 41, 8468e8485.
5. Hartung, J.; Schur, C.; Kempter, I.; Gottwald, T. Tetrahedron 2010, 66,
1365e1374.
1
6. Hartung, J.; Kneuer, R.; Rummey, C.; Bringmann, G. J. Am. Chem. Soc. 2004, 126,
12121e12129.
400 MHz)
d 1.20e1.73 (m, 4H, CH2), 1.92e2.17 (m, 4H, CH2),
2.41e2.46 (m, 1H, CHD), 3.68 (s, 3H, OCH3), 3.92e4.00 (m, 1H, 5-H),
€
7. Schur, C.; Becker, N.; Bergstraßer, U.; Gottwald, T.; Hartung, J. Tetrahedron 2011,
4.25 (q, 1H, J 6.5, 2-H), 4.92e5.03 (m, 2H, 40-H), 5.78e5.86 (m, 1H,
67, 2338e2347.
30-H). 13C NMR (CDCl3,100 MHz)
d 30.3 (CH2), 30.8 (CH2), 31.6 (CH2),
8. Beckwith, A. L. J.; Hay, B. P. J. Am. Chem. Soc. 1988, 110, 4415e4416.
9. Bietti, M.; Lanzalunga, O.; Salamone, M. J. Org. Chem. 2005, 70,
1417e1422.
34.9 (CH2), 40.45 (t, 1JC,D 20.34, CHD), 51.5 (OCH3), 74.7 (C2), 78.5
(C5), 114.4 (C40), 138.4 (C30), 171.7 (C]O). NOESY (cross peaks) 5-
H410-H. Methyl 5-[50-methyl-d1-tetrahydrofuran-20-yl]-pent-2-
ꢁ
10. Suarez, E. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-
VCH: Weinheim, 2001; Vol. 2, pp 440e454.
11. Wilsey, S.; Dowd, P.; Houk, K. N. J. Org. Chem. 1999, 64, 8801e8811.
12. Boto, A.; Gallardo, J. A.; Hernandez, D.; Hernandez, R. J. Org. Chem. 2007, 72,
7260e7269.
13. Hartung, J.; Gottwald, T. Tetrahedron Lett. 2004, 45, 5619e5621.
14. Schneiders, N.; Gottwald, T.; Hartung, J. Eur. J. Org. Chem. 2009, 797e800.
15. Schur, C.; Kempter, I.; Hartung, J. Org. Synth. 2012, 89, in press.
16. Rueda-Becerril, M.; Leung, J. C. T.; Dunbar, C. R.; Sammis, G. M. J. Org. Chem.
2011, 76, 7720e7729.
enoate (11i): Yield: 22 mg (108
m
mol, 55%, cis/trans¼39:61), color-
less oil, Rf 0.22 [SiO2, pentane/Et2O¼1:1 (v/v)]. v (NaCl)/cmꢁ1 1081,
1272,1437, 1657, 1726, 2935. MS (EI, 70 eV) m/z 170 (8), 157 (14),144
(88), 125 (30), 117 (52), 112 (89), 55 (100). cis-isomer: 1H NMR
(CDCl3, 400 MHz) d 1.17e1.25 (m, 2H, CH2D),1.47e1.77 (m, 4H, CH2),
1.91e2.09 (m, 2H, CH2), 2.21e2.38 (m, 2H, CH2), 3.71 (s, 3H, OCH3),
17. Beckwith, A. L. J.; Hay, B. P.; Williams, G. M. J. Chem. Soc., Chem. Commun. 1989,
1202e1203.
3.77e3.85 (m, 1H, 20-H), 3.89e4.01 (m, 1H, 50-H), 5.84 (m, 1H, 3-H),
6.95e7.02 (m, 1H, 4-H). 13C NMR (CDCl3, 100 MHz)
d
21.09 (t, 1JC,D
18. Guindon, Y.; Denis, R. C. Tetrahedron Lett. 1998, 39, 339e342.
19. Arnone, M.; Hartung, J.; Engels, B. J. Phys. Chem. A 2005, 109, 5943e5950.
20. Giese, B. Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds;
Pergamon: Oxford, 1986; Vol. 5.
19.43, CH2D), 28.9 (CH2), 31.2 (CH2), 32.8 (CH2), 34.5 (CH2), 51.3
(OCH3), 75.3 (C5), 78.5 (C2), 121.0 (C40), 149.1 (C30), 167.1 (C]O).
trans-isomer: 1H NMR (CDCl3, 400 MHz)
d 1.17e1.25 (m, 2H, CH2D),
ꢁ
21. Bertrand, M. P.; Surzur, J. M.; Boyer, M.; Mihailovic, M. L. Tetrahedron 1979, 35,
1365e1372.
1.47e1.77 (m, 4H, CH2), 1.91e2.09 (m, 2H, CH2), 2.21e2.38 (m, 2H,
CH2), 3.71 (s, 3H, OCH3), 3.89e4.01 (m, 1H, 2-H), 4.04e4.10 (m, 1H,
5-H), 5.84 (m, 1H, 30-H), 6.95e7.02 (m, 1H, 40-H). 13C NMR (CDCl3,
22. Rieke, R. D.; Moore, N. A. Tetrahedron Lett. 1969, 10, 2035e2038.
23. Hartung, J.; Daniel, K.; Rummey, C.; Bringmann, G. Org. Biomol. Chem. 2006, 4,
4089e4100.
d
20.8e21.3 (t, 1JC,D 19.43, CH2D), 29.0 (CH2), 32.2 (CH2),
€
100 MHz)
24. Schuch, D.; Fries, P.; Donges, M.; Hartung, J. J. Am. Chem. Soc. 2009, 131,
33.8 (CH2), 34.4 (CH2), 51.3 (OCH3), 74.5 (C5), 77.8 (C2), 121.0 (C40),
12918e12920.
25. Tanner, D. D.; Arhart, R. J.; Blackburn, E. V.; Das, N. C.; Wada, N. J. Am. Chem. Soc.
1974, 96, 829e834.
26. Herwig, K.; Lorenz, P.; Ruchardt, C. Chem. Ber. 1975, 108, 1421e1436.
149.1 (C30), 167.1 (C]O).
€
€
27. Hartung, J.; Daniel, K.; Bergstraßer, U.; Kempter, I.; Schneiders, N.; Danner, S.;
Acknowledgements
Schmidt, P.; Svoboda, I.; Fuess, H. Eur. J. Org. Chem. 2009, 4135e4142.
28. Rajan-Babu, T. V. In Handbook of Reagents for Organic Synthesis e Reagents for
Radical and Radical Ion Chemistry; Crich, D., Ed.; Wiley: Chichester, UK, 2008;
pp 575e579.
This work was supported by the State of Rheinland-Pfalz (Gra-
duiertenstipendium for A.G.) and is part of the Ph.D. theses of I.K.
and A.G
29. Newcomb, M. Tetrahedron 1993, 49, 1151e1176.
30. Hartung, J.; Hiller, M.; Schmidt, P. Liebigs Ann. 1996, 1425e1436.
31. Groß, A. Dissertation, TU Kaiserslautern, 2009, pp. 63e76.
32. Beckwith, A. L. J.; O’Shea, D. M.; Westwood, S. W. J. Am. Chem. Soc. 1988, 110,
2565e2575.
Supplementary data
33. Dowd, P.; Zhang, W. Chem. Rev. 1993, 93, 2091e2115.
34. Hartung, J.; Hiller, M.; Schmidt, P. Chem.dEur. J. 1996, 2, 1014e1023.
35. Winkler, J. D.; Sridar, V. J. Am. Chem. Soc. 1986, 108, 1708e1709.
36. Hartung, J.; Gallou, F. J. Org. Chem. 1995, 60, 6706e6716.
37. Houk, K. N.; Munchausen, L. L. J. Am. Chem. Soc. 1976, 98, 937e946.
38. Anh, N. G. Frontier Orbitals; Wiley: Chichester, UK, 2007.
39. Giese, B.; He, J.; Mehl, W. Chem. Ber. 1988, 121, 2063e2066.
40. Heberger, K.; Fischer, H. Int. J. Chem. Kinet. 1993, 25, 249e263.
Instrumentation, reagent specification, preparation of alkenols,
carbon-13 NMR-spectra of N-alkenoxythiazolethiones and tetra-
hydrofurans. Supplementary data related to this article can be
found at http://dx.doi.org/10.1016/j.tet.2012.08.083.
References and notes
€
41. Knuhl, B.; Marque, S.; Fischer, H. Helv. Chim. Acta 2001, 84, 2290e2300.
€
€
42. Kazmaier, U.; Pahler, S.; Endermann, R.; Habich, D.; Kroll, H.-P.; Riedl, B. Bioorg.
ꢀ
Med. Chem. 2002, 10, 3905e3913.
1. Hartung, J.; Gottwald, T.; Spehar, K. Synthesis 2002, 1469e1498.
43. Hartung, J.; Schwarz, M.; Svoboda, I.; Fuess, H.; Duarte, M. T. Eur. J. Org. Chem.
1999, 1275e1293.
2. Jones, M. J.; Moad, G.; Rizzardo, E.; Solomon, D. H. J. Org. Chem. 1989, 54,
1607e1611.