New macrocyclic bistriazolophanes with thioindigo chromophore

Article abstract of DOI:10.1016/j.tet.2012.10.107

Bi(4-methoxycarbonyl-3-oxothiolan-2-ylidene) derivatives are prepared by oxidative dimerization of 4- oxotetrahydrothiophene-3-carboxylates with either TPAPeNMO or K₃[Fe(CN)₆]. The products are obtained as mixtures of four diastereoi

Full text of DOI:10.1016/j.tet.2012.10.107

Tetrahedron 69 (2013) 802e809
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New macrocyclic bistriazolophanes with thioindigo chromophore
*
Marvin Schulz, Jens Christoffers
€
€
Institut fur Chemie, Carl von Ossietzky-Universitat Oldenburg, D-26111 Oldenburg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Bi(4-methoxycarbonyl-3-oxothiolan-2-ylidene) derivatives are prepared by oxidative dimerization of 4-
oxotetrahydrothiophene-3-carboxylates with either TPAPeNMO or K3[Fe(CN)6]. The products are ob-
tained as mixtures of four diastereoisomers due to (E)- or (Z)-configuration of the CeC double bond and
relative syn- or anti-configuration of two stereocenters. The red compounds contain the prototype of the
thioindigo chromophore. Their double bond configuration can be switched from (E) to (Z) by visible light.
Two propargyl-functionalized thiolane monomers were clicked together by para-bis(azidoalkyl)benzene
derivatives with [Cu(m-OH)(tmeda)]2Cl2 as the catalyst, thus, the subsequent oxidative dimerization
yielded macrocyclic triazolophane products with the bi(thiolan-2-ylidene) unit only in relative syn-
configuration.
Received 18 September 2012
Received in revised form 16 October 2012
Accepted 19 October 2012
Available online 15 November 2012
Keywords:
Macrocycles
Thioindigo
Sulfur compounds
1,2,3-Triazoles
Cyclophanes
Ó 2012 Elsevier Ltd. All rights reserved.
[3þ2]-Cycloaddition
Click chemistry
1. Introduction
materials, like cation13 or anion14 receptors or materials for opto-
electronic applications.15
Thioindigo and its derivatives1 are interesting materials, whose
photochromic properties can be attributed to light-induced (E/Z)-
isomerization.2 Interestingly, the double benzo-annulation is not
necessarily required in order to achieve colored compounds. For
example, if only one benzothiophene ring is retained, so called
hemithioindigo compounds are obtained, which are also in-
teresting and well investigated photoswitchable dyes.3 Moreover,
compounds without any benzene ring, e.g., the bi(3-oxo-2-ylidene)
motif itself, define a red chromophore with absorption maxima
dependent on the double bond configuration.1d,4
In the course of our investigations on 3-oxotetrahydrothi-
ophenecarboxylates as starting materials for the preparation of
tetrahydro-1,4-thiazocin-3-ones16 we have observed the formation
of colored, dimeric oxidation products with the thioindigo chro-
mophore, which were usually formed as mixtures of several di-
astereoisomers. In order to reduce the number of possible
stereoisomers, we have formed macrocycles by applying the
copper-catalyzed Huisgen 1,3-dipolar cycloaddition. In view of the
recent focus17 of triazolophanes as functional materials, as outlined
above, we wish to report herein on our recent results and experi-
ences with this class of hetero-macrocyclic compounds.
Since the discovery of copper(I)-catalysis5 of the Huisgen 1,3-
dipolar cycloaddition of azides with alkynes,6 this so called ‘Click
reaction’7 has found widespread applications also for the forma-
tions of macrocyclic compounds. Since the 1,2,3-triazole moiety can
be regarded as a steric and electronic mimic of a peptide bond,8 it
has, for example, been used for the preparation of macrocyclic
peptidomimetics.9 Triazoles have also been incorporated into
macrocyclic oligosaccharides10 or macrocyclic drugs like epothi-
lone11 and other macrocyclic ‘drug-like’ structures.12 Apart from
potentially biologically active compounds, triazole containing
macrocycles have also found applications in several functional
2. Results and discussion
Since quite a while we are interested in the enantioselective
formation of quaternary stereocenters by conjugate addition re-
actions.18 During these studies we have prepared racemic compound
2a by iron-catalyzed reaction19 of -oxoester 120 with methyl vinyl
b
ketone (Scheme 1, Table 1). Since product 2a gave no sufficient
baseline resolution upon GLC on a chiral phase, we were looking for
a fast and reliable derivatization of this compound for analytical
purposes, which could be the oxidation of the cyclic thioether
moiety to a sulfoxide or sulfone. After some experimentation with
hydrogen peroxide and mCPBA, we have chosen the Ley-oxidation
with TPAPeNMO21 and isolated dimerization product 3a in 39%
yield as a red material. Compound 3a was obtained as a mixture of
* Corresponding author. Tel.: þ49 441 798 4744; fax: þ49 441 798 3873; e-mail
address: jens.christoffers@uni-oldenburg.de (J. Christoffers).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.107

M. Schulz, J. Christoffers / Tetrahedron 69 (2013) 802e809
803
four unseparable diastereoisomers (dr 2.5:2.5:1:1) originating from
three stereogenic elements: one CeC double bond being (E)- or (Z)-
configurated [in Scheme 1 only the (E)-isomer is shown for sim-
plicity] and two stereocenters being either in relative meso- or rac-
configuration. The meso-diastereoisomer is the anti-compound with
the (E)-double bond and the syn-isomer with the (Z)-configuration.
The racemic diastereoisomers are syn for the (E)-double bond and
anti for the (Z)-configuration. The two major diastereoisomers were
assigned (vide infra) to be the (E)-configurated meso- and rac-
compounds (dr 2.5:2.5), whereas the two minor isomers have the
double bond in (Z)-configuration (meso/rac 1:1).
was activated with TosCl and the intermediate product 5 then
-brominated to give the 1,4-dielectrophile 6, which was sub-
a
sequently cyclized with Na2S to give oxotetrahydrothiophene 8.
Oxidative dimerization to thioindigo-analog 7 was again achieved
with K3[Fe(CN)6] [41% yield, (E/Z)¼2.2:1]. The UV/vis-spectrum of
compound 7 showed a dominant absorption at 457 nm (see Table
2), which was assigned in agreement with the literature4c to be
the (E)-isomer and a shoulder, which originated from the (Z)-iso-
mer. Exposure to sunlight for six days shifted the (E/Z)-ratio to
1:7.2, which was followed by 13C NMR (C6D6) and UV/vis (CH2Cl2).
O
O
(a)
O
Me
OH
Me
OTos
O
O
O
Me
Me Me
4
Me Me
CO2Me
Me
5
(91%)
CO2Me
(88%)
(a)
S
S
1
2a
(b)
(b) + R-X
(c)
O
O
Br
OTos
R
O
Me Me
(c) or (d)
S
R
CO2Me
6
(61%)
MeO2C
CO2Me
S
S
2b
R
O
(c)
(R = Me, 56%),
(R = Bn, 61%),
3a 3e
-
2c
2d (R = allyl, 63%),
O
Me
Me
O
2e (R = propargyl, 49%)
(d)
S
Me
Me
Scheme 1. Preparation of racemic starting materials 2 and dimers 3. For compounds 3
only the (E)-isomers are shown for simplicity. For yields and residues R of products 3
see Table 1. Reagents and conditions: (a) 0.1 equiv FeCl3$6H2O, CH2Cl2, 23 ꢀC, 2 d; (b)
2 equiv MeI (for 2b) or 1.1 equiv RBr (for 2ce2e), 2 equiv K2CO3, acetone, reflux, 1 h; (c)
Me
Me
S
S
O
7 (41%)
8 (56%)
3 equiv NMO, 0.05 equiv TPAP, mol. sieves 4 A, MeCN, 16 h, 40 ꢀC; (d) 4 equiv
K3[Fe(CN)6], 4 equiv piperidine, EtOHeH2O, 60 ꢀC, 0.5 h, then 23 ꢀC, 0.5 h.
ꢀ
Scheme 2. Preparation of tetramethyl congener 7 [(E/Z)¼2.2:1, only the (E)-isomer is
shown for simplicity]. Reagents, conditions, and yields: (a) 1.2 equiv TosCl, pyridine,
23 ꢀC, 16 h, 91%; (b) 1 equiv Br2, CHCl3, 61 ꢀC, 1 h, 61%; (c) 2 equiv Na2S aq, DMF, 80 ꢀC,
1 h, 56%; (d) 4 equiv K3[Fe(CN)6], 4 equiv piperidine, EtOHeH2O, 60 ꢀC, 0.5 h, then
23 ꢀC, 0.5 h, 41%.
Despite the large number of investigations on the thioindigo
chromophore1d,4 no compounds like 3a with two
b-oxoester motifs
were reported so far. Since we found switching the double bond
configuration by visible light being an interesting issue, we have
prepared four more congeners by alkylation of oxoester 1 with the
respective halides. All compounds 2ae2e have, by the way, been
reported in the literature before,22 but without full characterization
data. Dimerization of compounds 2be2e was again achieved using
TPAPeNMO (Table 1), but it turned out that application of
The same spectroscopic features were observed for compounds
3ae3e (Table 2). The spectra are dominated by an absorption be-
tween 460 and 480 nm, respectively, which can be assigned to the
major (E)-isomer, and a shoulder between 414 and 434 nm attrib-
uted to the (Z)-isomer. Exposure to sunlight for six days led to
equilibrium mixtures, e.g., with (E/Z)¼1:1.7 (for 3b), (E/Z)¼1:1.3
(for 3c), or (E/Z)¼1:1 (for 3e), respectively. This equilibration
was again followed by 13C NMR (C6D6) and UV/vis (CH2Cl2). Each
(E)- and (Z)-isomer showed a double signal set with dr 1:1 in the
13C NMR spectra, which did not change upon irradiation and can
therefore be attributed to the rac- and meso-diastereoisomers.
€
K3[Fe(CN)6] and piperidine, as originally suggested by Luttke and
co-workers,4b was much more efficient and often gave superior
yields. Products 3be3e are again obtained as four diastereoisomers
with (E)- and (Z)-ratios as given in Table 1 and with equal amounts
of rac- and meso-isomers, respectively. An exception is compound
3e, which is obtained with dr¼13:6:2:1 [(E), (E), (Z), (Z)].
For comparison and assignment of (E)- and (Z)-isomers, we have
prepared tetramethyl-derivative 7, which was so far the standard
Table 2
Spectroscopic properties of compounds 3ae3e, 7, 11a, and 11b (CH2Cl2)
compound in investigations of the thioindigo chromophore,4 in
Compound lmax/nm lmax/nm log
lem/nm
lex/nm)
F
23
€
four steps following a strategy suggested by Luttke and De
(E/Z)
(E)
(Z)
(
3
/dm3
(
Kimpe24 (Scheme 2). The alcohol-function of aldol-compound 4
molꢁ1 cmꢁ1
)
3a
3b
3c
3d
3e
7
464
465
475
468
479
457
(458)b
479
479
414
414
434
425
439
400
(408)b
440
440
3.47
3.89
3.88
3.85
3.87
3.81
(4.07)b
3.89
3.91
533 (414), 543 (464) 0.001
a
Table 1
536 (414 or 465)
558 (434 or 475)
a
Oxidative dimerization of compound 2. Conditions and yields
546 (425), 539 (468) 0.001
Product
R
Yield (E/Z)
(TPAPeNMO)
Yield (E/Z)
(K3[Fe(CN)6])
a
541 (439 or 479)
534 (400 or 457)
0.003
3a
3b
3c
3d
3e
CH2CH2COMe
Me
Bn
Allyl
Propargyl
40% (2.5:1)
13% (2.1:1)
26% (9.5:1)
31% (2.5:1)
30% (5.7:1)
18% (20:1)
25% (5:1)
46% (8:1)
31% (5.9:1)
59% (6.3:1)
11a
11b
542 (440 or 479)
543 (440 or 479)
0.001
0.001
a
Not determined.
b
Literature value4c (CHCl3).

804
M. Schulz, J. Christoffers / Tetrahedron 69 (2013) 802e809
Compounds 3ae3e as well as 7 showed fluorescence, therefore,
Whenthedimer3easa mixtureof syn-andanti-diastereoisomers
(dr 1:1) was reacted with diazides 10, yields of compounds 11 were
significantly lower, because only half of the materials could be con-
verted to a cyclic product 11. The respective anti-diastereoisomers of
3e could however not be reisolated from the reaction mixture, pre-
sumably because of unspecified oligomer formation.
emission spectra were recorded for each compound, respectively.
Data are collected in Table 2. For spectra, see Supplementary data.
Actually, emission wavelengths were more or less independent
from excitation of the (E)- or (Z)-isomer, respectively, therefore,
a (E/Z)-isomerization process during the recordings can be as-
sumed. For compounds 3a, 3d, 7 as well as 11a and 11b quantum
yields were estimated by comparison with fluoresceine as a stan-
dard according to the ParkereRees method.25 However, all quan-
tum yields were very low.
In order to simplify the stereochemical features of compounds 3
we decided to fix the two stereocenters into relative syn-configu-
ration by ring formation between the two propargyl groups of
compound 3e. For this purpose, the two para-(azidoalkyl)benzenes
10 were prepared from the respective dihalides 9. Whereas
dichloroxylene 9a was commercially available, dibromo compound
9b had to be prepared from the respective bis(hydroxyethyl)ben-
zene.26 As reported for the bis(azidomethyl) compound 10a,27 SN2-
reaction with NaN3 proceeded smoothly at ambient temperature in
DMSO as solvent and products 10a and 10b28 were obtained in
good yields (Scheme 3).
3. Conclusion
Thiolane derivatives 2ae2e were prepared from oxoester 1 by
either Michael reaction or alkylation. Oxidative dimerization of
these compounds was achieved with either TPAPeNMO or
K3[Fe(CN)6] yielding bi(thiolane-2-ylide) derivatives 3 as products,
which are red materials, since they possess the prototype of the
thioindigo chromophore. Compounds 3 hold three stereogenic
elements and are therefore obtained as mixtures of four di-
astereoisomers: The CeC double bond can be either (E)- or (Z)-
configurated; the two stereocenters are in relative rac- or meso-
configuration. The double bond geometry can be switched from (E)
to (Z), a process, which could be followed by UV/vis- and 13C NMR-
spectroscopy. In order to simplify stereochemical issues, two enti-
ties of the alkynyl-functionalized thiolane 2e were clicked onto
para-bis(azidoalkyl)benzenes 10a and 10b. Use of [Cu(m-OH)(tme-
X
X
N3
N3
da)]2Cl2 as the catalyst turned out to be much more efficient than
using CuSO4esodium ascorbate. Subsequently, an intramolecular
oxidative dimerization of compounds 12a and 12b gave the mac-
rocyclic triazolophanes 11a and 11b holding the thioindigo chro-
mophore. Only two diastereomers are obtained now, because the
stereocenters of the bithiolanylidene moiety are fixed in relative
syn-configuration, which is the rac-diastereoisomer for the (E)-
isomer and the meso-compound with the (Z)-double bond.
(a)
n
n
n
n
9a (n = 1, X = Cl)
10a (n = 1, 88%),
9b
10b
(n = 2, X = Br)
(n = 2, 91%)
O
(b)
MeO2C
2e
S
N
N
N
S
S
4. Experimental section
n
MeO2C
N
CO2Me
MeO2C
(c)
4.1. General methods
O
O
N
N
O
N
N
S
N
n
N
N
N
Preparative column chromatography was carried out using
Merck SiO2 (35e70 mm, type 60 A) with hexane, tert-butyl methyl
CO2Me
O
n
n
ether (MTBE), CH2Cl2, ethyl acetate (EtOAc), and MeOH as eluents.
TLC was performed on Merck SiO2 F254 plates on aluminum sheets.
1H and 13C NMR spectra were recorded on a Bruker Avance DRX 500.
Multiplicities of carbon signals were determined with DEPT exper-
iments. MS and HRMS spectrawere obtainedwith a Finnigan MAT 95
(EI and CI) and a Waters Q-TOF Premier (ESI) spectrometer. IR
spectra were recorded on a Bruker Tensor 27 spectrometer equipped
with a ‘GoldenGate’ diamond ATR unit. Elemental analysis was
measured with a Euro EA-CHNS from HEKAtech. UV/vis-spectra
were recorded with a PerkineElmer LS 50. Fluorescence spectra
were recorded with a Shimadzu RF-5301PC. Compound 120 and
bisbromoethylbenzene26 were prepared according to literature
procedures. Allother startingmaterialswere commerciallyavailable.
S
11a (n = 1, 52%, E/Z = 1.6 : 1),
12a (n = 1, 72%),
11b
12b
(n = 2, 59%, E/Z = 1.4 : 1)
(n = 2, 80%)
Scheme 3. Preparation of diazides 10, dipolar cycloaddition, and oxidative di-
merization [only the (Z)-isomers are shown for simplicity]. Reagents, conditions, and
yields: (a) 2.2 equiv NaN3, DMSO, 23 ꢀC, 1 h; (b) 0.02 equiv [Cu(
m-OH)(tmeda)]2Cl2,
CH2Cl2, 23 ꢀC, 1 h; (c) 4 equiv K3[Fe(CN)6], 4 equiv piperidine, EtOHeH2O, 60 ꢀC, 0.5 h,
then 23 ꢀC, 0.5 h.
Attempts of dipolar cycloaddition of alkyne 2e with diazide 10a
under standard conditions (CuSO4, sodium ascorbate)29 led to
a 1:1-adduct. After some experimentation it turned out, that
a commercially available ‘CueTMEDA’ complex [Cu(m-OH)(tme-
da)]2Cl2 recently recommended by Mizuno et al.30 is much more
active and therefore gave superior results. The 1:2-adducts 12a and
12b were obtained in 72% and 80% yields, respectively. Oxidative
intramolecular dimerization under previously applied reaction
conditions gave the macrocyclic products 11a and 11b in 52% and
59% yield, respectively. No other materials, e.g., intermolecular di-
merization or oligomerization products, were detectable, although
such processes could be responsible for the moderate yields.
Compounds 11a and 11b are obtained as partially separable mix-
tures of two diastereoisomers, which must now be the rac-(E)- and
the meso-(Z)-isomers, because both stereocenters must be in rela-
tive syn-configuration. And indeed, the isomeric ratio cannot
be shifted by exposure to visible light, because the double
bond geometry is fixed. Moreover, two diagnostic absorptions at
lmax¼479 nm (E) and 440 nm (Z) are observed in the UV/vis-spectra
(see Table 2).
4.2. Methyl 4-oxo-3-(3-oxobutyl)tetrahydrothiophene-3-
carboxylate (2a)
A mixture of FeCl3$6H2O (223 mg, 0.824 mmol), oxoester 1
(1.32 g, 8.24 mmol), and CH2Cl2 (3 ml) was stirred for 5 min at 23 ꢀC.
Subsequently, methyl vinyl ketone (1.73 g, 24.7 mmol) was added
and the resulting mixture was further stirred for 2 d at ambient
temperature. After removal of all volatile materials in vacuum, the
residue was chromatographed (SiO2, hexane/MTBE 2:3, Rf¼0.34) to
yield the title compound 2a as a colorless solid (1.66 g, 7.22 mmol,
88%), mp 45 ꢀC (lit. 42e43 ꢀC).22b 1H NMR (CDCl3, 500 MHz):
d
¼2.00e2.09 (m, 1H), 2.15 (s, 3H), 2.22e2.31 (m, 1H), 2.44e2.53
(m, 1H), 2.67e2.75 (m, 1H), 2.88 (d, J¼11.9 Hz, 1H), 3.32 (B-part of
an AB-system, J¼17.7 Hz, 1H), 3.47 (A-part of an AB-system,

M. Schulz, J. Christoffers / Tetrahedron 69 (2013) 802e809
805
J¼18.1 Hz, 1H), 3.48 (d, J¼11.3 Hz, 1H), 3.76 (s, 3H) ppm. 13C{1H}
(w), 2955 (w),1729 (s), 1641 (w), 1436 (m), 1222 (m), 1200 (m), 1120
(m), 999 (m), 925 (m) cmꢁ1. HRMS (ESI): calcd 223.0405 (for
C9H12NaO3S); found 223.0403 [MþNaþ]. C9H12O3S (200.25).
NMR (CDCl3, 125 MHz):
d
¼29.7 (CH2), 29.8 (CH3), 35.3 (CH2), 37.2
(CH2), 38.3 (CH2), 53.0 (CH3), 60.0 (C), 170.2 (C), 206.8 (C), 207.5
~
(C) ppm. IR (ATR):
n
¼2955 (w), 1713 (s), 1433 (w), 1369 (w), 1246
(m), 1203 (m), 1167 (m), 1110 (w), 1013 (w) cmꢁ1. MS (EI, 70 eV): m/z
(%)¼230 (7) [Mþ], 160 (100), 128 (12), 127 (25),125 (50),113 (41), 81
(20), 71 (11). HRMS (EI, 70 eV): calcd 230.0613 (for C10H14O4S),
found 230.0610 [Mþ]. C10H14O4S (230.28): calcd C 52.16, H 6.13;
found C 52.33, H 6.38.
4.6. Methyl 4-oxo-3-propargyltetrahydrothiophene-3-
carboxylate (2e)
Following the procedure reported above for product 2b,
oxoester 1 (1.87 g, 11.7 mmol), K2CO3 (4.84 g, 35.0 mmol), and
propargyl bromide (1.6 ml, 2.1 g, 14 mmol) were reacted in acetone
(10 ml) to yield the title compound 2e (1.13 g, 5.70 mmol, 49%) as
a colorless liquid after chromatography (SiO2, hexane/MTBE 5:1,
4.3. Methyl 3-methyl-4-oxotetrahydrothiophene-3-
carboxylate (2b)
Rf¼0.25). 1H NMR (CDCl3, 500 MHz):
¼2.06 (t, J¼2.6 Hz, 1H), 2.71
d
A suspension of oxoester 1 (1.40 g, 8.74 mmol) and K2CO3
(3.62 g, 26.2 mmol) in acetone (10 ml) was stirred for 10 min at
23 ꢀC. MeI (1.1 ml, 2.5 g,17 mmol) was then dropwise added and the
resulting mixture heated to reflux for 1 h. After cooling to ambient
temperature, the volatiles were removed in vacuum and water
(20 ml) was added to the residue. The mixture was twice extracted
with CH2Cl2 (2ꢂ20 ml). The combined organic layers were dried
(MgSO4) and, after filtration, the solvent was removed in vacuum.
The residue was chromatographed (SiO2, hexane/MTBE 5:1,
Rf¼0.28) to yield the title compound 2b (857 mg, 4.92 mmol, 56%)
(dd, J¼2.6 Hz, J¼16.9 Hz,1H), 2.76 (dd, J¼2.6 Hz, J¼16.9 Hz,1H), 3.31
(d, J¼12.2 Hz, 1H), 3.33 (d, J¼17.6 Hz, 1H), 3.49 (d, J¼17.6 Hz, 1H),
3.54 (d, J¼12.2 Hz, 1H), 3.78 (s, 3H) ppm. 13C{1H} NMR (CDCl3,
125 MHz):
d
¼23.3 (CH2), 34.1 (CH2), 37.7 (CH2), 53.4 (CH3), 57.2 (C),
~
71.8 (CH), 78.5 (C), 169.1 (C), 205.9 (C) ppm. IR (ATR):
n
¼3284 (m),
2954 (m), 1729 (s), 1435 (s), 1282 (m), 1198 (s), 1106 (m), 1042 (w),
999 (w) cmꢁ1. MS (EI, 70 eV): m/z (%)¼198 (18) [Mþ], 159 (100), 139
(8), 127 (37), 93 (13), 65 (16), 59 (10). HRMS (EI, 70 eV): calcd
198.0351 (for C9H10O3S); found 198.0347 [Mþ]. C9H10O3S (198.24).
as a colorless liquid. 1H NMR (CDCl3, 500 MHz):
d¼1.46 (s, 3H), 2.83
4.7. Bi[4-methoxycarbonyl-3-oxo-4-(3-oxobutyl)tetrahy-
drothiophene-2-ylidene] (3a)
(d, J¼11.9 Hz, 1H), 3.30 (d, J¼17.6 Hz, 1H), 3.50 (d, J¼17.6 Hz, 1H),
3.53 (d, J¼11.9 Hz, 1H), 3.75 (s, 3H) ppm. 13C{1H} NMR (CDCl3,
ꢀ
125 MHz):
171.4 (C), 208.3 (C) ppm. IR (ATR):
d
¼19.3 (CH3), 37.2 (CH2), 37.3 (CH2), 53.1 (CH3), 57.2 (C),
Mol. sieves (4 A, ca. 1 g), TPAP (18 mg, 50
mmol), and NMO$H2O
~
n
¼2984 (w), 2954 (w), 1748 (s),
(405 mg, 3.00 mmol) were successively added to a solution of
diketone 2a (230 mg, 1.00 mmol) in MeCN (5 ml). After stirring the
suspension for 16 h at 40 ꢀC, all volatiles were removed in vacuum
and the residue elutriated in EtOAc (20 ml) and filtered through
some SiO2. The filtrate was evaporated and the residue chromato-
graphed [SiO2, hexane/EtOAc 1:1 with gradient to EtOAc, Rf (hex-
ane/EtOAc 1:1)¼0.14 and 0.11] to yield compound 3a (90 mg,
0.20 mmol, 40%) as a red oil consisting of four hardly separable
diastereoisomers (four signal sets in the 13C NMR-spectrum, dr
1726 (s), 1453 (m),1434 (m), 1276 (m), 1251 (m),1200 (m), 1132 (m),
1052 (m), 981 (m) cmꢁ1
. HRMS (ESI): calcd 197.0248 (for
C7H10NaO3S); found 197.0245 [MþNaþ]. C7H10O3S (174.22).
4.4. Methyl 3-benzyl-4-oxotetrahydrothiophene-3-
carboxylate (2c)
Following the procedure reported above for product 2b,
oxoester 1 (1.17 g, 7.30 mmol), K2CO3 (3.03 g, 21.9 mmol), and BnBr
(1.7 ml, 2.5 g, 14 mmol) were reacted in acetone (10 ml) to yield the
title compound 2c (1.11 g, 4.43 mmol, 61%) as a yellow solid after
chromatography (SiO2, hexane/MTBE 5:1, Rf¼0.33), mp 63 ꢀC. 1H
2.5:2.5:1:1). UV/vis (CH2Cl2): lmax (log
3
)¼414 (Z), 464 (3.47) nm
(E); fluorescence (CH2Cl2): lex¼414 nm, lem¼533 nm [(Z)-isomer];
lex¼464 nm, lem¼543 nm [(E)-isomer]. 1H NMR (CDCl3, 500 MHz):
d
¼2.05e2.21 (m, 32H), 2.23e2.36 (m, 8H), 2.47e2.73 (m, 16H),
NMR (CDCl3, 500 MHz):
d
¼2.92 (d, J¼12.1 Hz, 1H), 3.17 (d,
3.05e3.12 (m, 8H), 3.71e3.80 (m, 32H) ppm. 13C{1H} NMR (CDCl3,
125 MHz), rac- and meso-(E)-isomers (major):
J¼13.8 Hz, 1H), 3.23 (d, J¼17.9 Hz, 1H), 3.28 (d, J¼13.8 Hz, 1H), 3.42
(d, J¼12.1 Hz, 1H), 3.44 (d, J¼17.9 Hz, 1H), 3.75 (s, 3H), 7.14e7.17 (m,
2H), 7.23e7.30 (m, 3H) ppm. 13C{1H} NMR (CDCl3, 125 MHz):
d
¼27.7 (CH2), 27.8
(CH2), 29.73 (2CH3), 36.0 (CH2), 36.1 (CH2), 38.26 (CH2), 38.30 (CH2),
53.1 (CH3), 53.19 (CH3), 59.7 (C), 59.8 (C),131.56 (C), 131.61 (C),169.4
(C), 169.52 (C), 198.8 (C), 199.0 (C), 206.3 (C), 206.4 (C); rac- and
d
¼33.6 (CH2), 37.4 (CH2), 38.7 (CH2), 53.1 (CH3), 62.9 (C), 127.3 (CH),
128.5 (2CH), 130.1 (2CH), 135.4 (C), 169.7 (C), 206.7 (C) ppm. IR
meso-(Z)-isomers (minor):
(2CH3), 33.7 (CH2), 33.9 (CH2), 38.21 (CH2), 38.26 (CH2), 53.0 (CH3),
d
¼27.26 (CH2), 27.30 (CH2), 29.73
~
(ATR):
n
¼3028 (w), 2954 (w), 2907 (w), 1720 (vs), 1495 (m), 1441
(m), 1273 (m), 1209 (s), 1185 (s), 1103 (s), 814 (m), 746 (s), 697
(vs) cmꢁ1. HRMS (ESI): calcd 273.0561 (for C13H14NaO3S); found
273.0569 [MþNaþ]. C13H14O3S (250.31).
53.18 (CH3), 60.9 (C), 61.0 (C), 132.7 (C), 132.8 (C), 169.4 (C), 169.49
~
(C), 188.8 (C), 189.1 (C), 206.5 (C), 206.6 (C) ppm. IR (ATR):
n
¼3003
(w), 2955 (w), 1736 (s), 1716 (s), 1681 (m), 1524 (w), 1433 (m), 1370
(m), 1251 (m), 1216 (m), 1149 (s), 907 (m) cmꢁ1. HRMS (ESI): calcd
479.0810 (for C20H24NaO8S2), found 479.0813 [MþNaþ].
C20H24O8S2 (456.53).
4.5. Methyl 3-allyl-4-oxotetrahydrothiophene-3-carboxylate
(2d)
Following the procedure reported above for product 2b,
oxoester 1 (1.65 g, 10.3 mmol), K2CO3 (4.27 g, 30.9 mmol), and allyl
bromide (1.3 ml, 1.9 g, 15 mmol) were reacted in acetone (10 ml) to
yield the title compound 2d (1.30 g, 6.49 mmol, 63%) as a colorless
liquid after chromatography (SiO2, hexane/MTBE 5:1, Rf¼0.34). 1H
4.8. Bi(4-methoxycarbonyl-4-methyl-3-oxotetrahydro-
thiophene-2-ylidene) (3b)
A solution of K3[Fe(CN)6] (2.5 g, 7.6 mmol) and piperidine
(0.8 ml, 0.7 g, 7.6 mmol) in water (20 ml) was added at 40 ꢀC to
a solution of thiolane 2b (107 mg, 0.82 mmol) in 20 ml EtOH. The
resulting suspension was stirred for 0.5 h at 60 ꢀC, then for 0.5 h at
ambient temperature, subsequently diluted with water (10 ml) and
extracted with CH2Cl2 (4ꢂ10 ml). The combined organic layers
were dried (MgSO4) and, after filtration, the solvent was removed
in vacuum. The residue was chromatographed (SiO2, hexane/EtOAc
2:1, Rf¼0.41) to yield the title compound 3b (106 mg, 0.31 mmol,
NMR (CDCl3, 500 MHz):
d
¼2.54 (dd, J¼7.4 Hz, J¼14.0 Hz, 1H), 2.70
(dd, J¼7.4 Hz, J¼14.0 Hz, 1H), 2.98 (d, J¼12.1 Hz, 1H), 3.28 (d,
J¼17.7 Hz, 1H), 3.46 (d, J¼17.7 Hz, 1H), 3.47 (d, J¼12.0 Hz, 1H), 3.76
(s, 3H), 5.14 (d, J¼10.8 Hz, 1H), 5.15 (d, J¼16.3 Hz, 1H), 5.72 (ddt,
J¼16.3 Hz, J¼10.9 Hz, J¼7.3 Hz, 1H) ppm. 13C{1H} NMR (CDCl3,
125 MHz):
d
¼33.9 (CH2), 37.4 (CH2), 37.5 (CH2), 53.1 (CH3), 61.1 (C),
~
119.9 (CH2), 132.0 (CH), 169.9 (C), 207.1 (C) ppm. IR (ATR):
n
¼3081

806
M. Schulz, J. Christoffers / Tetrahedron 69 (2013) 802e809
25%) as a bright orange solid, mp 129 ꢀC. According to 13C NMR, the
material consisted of four diastereomers (four signal sets, dr
(2C), 131.86 (2CH2), 131.89 (2CH2), 131.92 (2C), 174.1 (2C), 174.2 (2C),
~
188.3 (2C), 188.7 (2C) ppm. IR (ATR):
n
¼3079 (w), 2954 (m), 2850
5:5:1:1). UV/vis (CH2Cl2): lmax (log
3
)¼414 (Z), 465 (3.89) nm (E);
(w), 1734 (vs), 1678 (s), 1433 (s), 1219 (s), 1135 (vs), 1088 (m), 1049
(m), 994 (s), 925 (m), 905 (m) cmꢁ1. HRMS (ESI): calcd 419.0599 (for
C18H20NaO6S2); found 419.0605 [MþNaþ]. C18H20O6S2 (396.48).
fluorescence (CH2Cl2): lex¼414 or 465 nm; lem¼536 nm. 1H NMR
(CDCl3, 500 MHz):
d
¼1.48e1.53 (m, 6H), 3.01e3.07 (m, 2H),
3.72e3.73 (m, 6H), 3.78e3.82 (m, 2H) ppm. 13C{1H} NMR (CDCl3,
125 MHz), rac- and meso-(E)-isomers (major):
d¼20.5 (2CH3), 20.6
4.11. Bi(4-methoxycarbonyl-3-oxo-4-propargyltetrahydro-
thiophene-2-ylidene) (3e)
(2CH3), 38.01 (2CH2), 38.04 (2CH2), 53.19 (2CH3), 53.24 (2CH3),
56.76 (2C), 56.82 (2C),131.4 (2C),131.5 (2C),170.61 (2C),170.63 (2C),
199.0 (2C), 200.1 (2C) ppm; rac- and meso-(Z)-isomers (minor):
Following the procedure given above for product 3b,
K3[Fe(CN)6] (7.7 g, 23 mmol), piperidine (2.3 ml, 2.0 g, 23 mmol),
and thiolane 2e (1.16 g, 5.86 mmol) were converted in water (60 ml)
and EtOH (60 ml) to give the title compound 3e (1.36 g, 3.45 mmol,
59%) as a bright orange solid after chromatography (SiO2, hexane/
EtOAc 1:1, Rf¼0.43), mp 136 ꢀC. According to 13C NMR, the material
consisted of four diastereomers (four signal sets, dr 13:6:2:1). UV/
d
¼20.0 (2CH3), 20.1 (2CH3), 35.5 (2CH2), 35.6 (2CH2), 53.17 (2CH3),
53.20 (2CH3), 58.1 (2C), 58.3 (2C), 132.7 (2C), 132.9 (2C), 171.00 (2C),
~
171.04 (2C), 189.4 (2C), 189.8 (2C) ppm. IR (ATR):
n
¼2952 (w), 2858
(w), 1731 (vs), 1681 (m), 1639 (w), 1447 (m), 1434 (m), 1273 (s), 1249
(s), 1145 (s), 1077 (vs), 904 (s) cmꢁ1. HRMS (ESI): calcd 367.0286 (for
C14H16NaO6S2); found 367.0286 [MþNaþ]. C14H16O6S2 (344.40).
vis (CH2Cl2): lmax (log
3
)¼439 (Z), 479 (3.87) nm (E); fluorescence
4.9. Bi(4-benzyl-4-methoxycarbonyl-3-oxotetrahydro-
thiophene-2-ylidene) (3c)
(CH2Cl2): lex¼479 or 439 nm; lem¼541 nm. 1H NMR (CDCl3,
500 MHz):
d
¼1.98e2.02 (m, 2H), 2.59e2.74 (m, 2H), 2.87e2.94 (m,
2H), 3.34e3.45 (m, 2H), 3.68e3.71 (m, 6H), 3.77e3.84 (m, 2H) ppm.
Following the procedure given above for product 3b,
K3[Fe(CN)6] (2.2 g, 6.7 mmol), piperidine (0.7 ml, 0.6 g, 6.7 mmol),
and thiolane 2c (418 mg,1.7 mmol) were converted in water (20 ml)
and EtOH (20 ml) to give the title compound 3c (207 mg, 0.4 mmol,
46%) as a bright orange solid after chromatography (SiO2, hexane/
EtOAc 5:1, Rf¼0.55), mp 169 ꢀC. According to 13C NMR, the material
consisted of three diastereomers (three signal sets, A/B/C 5:3:1).
13C{1H} NMR (CDCl3, 125 MHz), rac- and meso-(E)-isomers (major):
d
¼24.1 (2CH2), 24.2 (2CH2), 34.8 (2CH2), 34.9 (2CH2), 53.5 (2CH3),
53.6 (2CH3), 59.8 (2C), 59.9 (2C), 72.1 (2CH), 72.2 (2CH), 77.9 (2C),
78.0 (2C), 131.8 (2C), 131.9 (2C), 168.0 (2C), 168.1 (2C), 197.2 (2C),
197.5 (2C) ppm; rac- and meso-(Z)-isomers (minor):
d
¼23.9 (2CH2),
24.0 (2CH2), 32.9 (2CH2), 33.0 (2CH2), 53.5 (2CH3), 53.6 (2CH3), 61.1
(2C), 61.5 (2C), 72.0 (2CH), 72.1 (2CH), 77.97 (2C), 78.02 (2C), 132.8
(2C), 133.1 (2C), 167.8 (2C), 168.0 (2C), 187.2 (2C), 187.7 (2C) ppm. IR
~
UV/vis (CH2Cl2): lmax (log
3
)¼434 (Z), 475 (3.88) nm (E); fluores-
cence (CH2Cl2): lex¼475 or 434 nm; lem¼558 nm. 1H NMR (CDCl3,
(ATR):
n
¼3284 (m), 3003 (w), 2953 (m), 1737 (s), 1671 (s), 1428 (m),
500 MHz):
d
¼3.09e3.15 (m, 4H), 3.40e3.46 (m, 2H), 3.64e3.75 (m,
1286 (s), 1233 (s), 1155 (vs), 1123 (s), 1058 (m), 972 (m), 908
(s) cmꢁ1. MS (EI, 70 eV): m/z (%)¼392 (100) [Mþ], 353 (4), 333 (23),
321 (38), 240 (28), 201 (25), 169 (21), 88 (26). HRMS (EI, 70 eV):
calcd 392.0388 (for C18H16O6S2); found 392.0378 [Mþ]. C18H16O6S2
(392.45).
8H), 7.08e7.13 (m, 4H), 7.20e7.27 (m, 6H) ppm. 13C{1H} NMR
(CDCl3, 125 MHz), signal set A:
¼34.3 (2CH2), 39.6 (2CH2), 53.3
(2CH3), 62.6 (2C), 127.4 (2CH), 128.6 (4CH), 130.0 (4CH), 131.9 (2C),
135.2 (2C), 169.0 (2C), 198.5 (2C) ppm; signal set B:
d
d¼34.5 (2CH2),
39.9 (2CH2), 53.3 (2CH3), 62.8 (2C), 127.4 (2CH), 128.6 (4CH), 130.0
(4CH), 131.9 (2C), 135.2 (2C), 168.8 (2C), 198.2 (2C) ppm; signal set
4.12. 2,2-Dimethyl-3-oxobutyl para-toluenesulfonate (5)
C:
d
¼32.6 (2CH2), 39.5 (2CH2), 53.3 (2CH3), 63.8 (2C), 127.3 (2CH),
128.5 (4CH), 129.9 (4CH), 133.0 (2C), 135.3 (2C), 168.9 (2C), 188.1
p-Toluenesulfonyl chloride (4.06 g, 21.2 mmol) was added in
four portions over 10 min to a solution of alcohol 4 (2.06 g,
17.7 mmol) in pyridine (20 ml). The solution was stirred for 18 h at
ambient temperature and then poured into hydrochloric acid (10%,
40 ml). The aqueous phase was extracted with CH2Cl2 (3ꢂ20 ml).
The combined organic layers were dried (MgSO4) and, after filtra-
tion, the solvent was removed in vacuum to yield the title com-
pound 5 (3.34 g, 12.3 mmol, 70%) as a colorless liquid, that was used
~
(2C) ppm. IR (ATR):
n
¼3029 (w), 2955 (w), 2931 (w), 1737 (s), 1686
(s), 1494 (m), 1433 (m), 1269 (m), 1250 (m), 1187 (s), 1107 (m), 1078
(m), 906 (s), 753 (s), 702 (s) cmꢁ1. MS (EI, 70 eV): m/z (%)¼496 (100)
[Mþ], 373 (38), 292 (13), 201 (12), 169 (11), 91 (84). HRMS (EI,
70 eV): calcd 496.1014 (for C26H24O6S2); found 496.1001 [Mþ].
C26H24O6S2 (496.60).
4.10. Bi(4-allyl-4-methoxycarbonyl-3-oxotetrahydro-
thiophene-2-ylidene) (3d)
without further purification. 1H NMR (CDCl3, 500 MHz):
d¼1.15 (s,
6H), 2.11 (s, 3H), 2.45 (s, 3H), 4.00 (s, 2H), 7.35 (d, J¼7.9 Hz, 2H), 7.77
(d, J¼7.9 Hz, 2H) ppm. 13C{1H} NMR (CDCl3, 125 MHz):
¼21.5
d
Following the procedure reported above for product 3a, TPAP
(57 mg, 0.19 mmol), NMO$H2O (1.3 g, 9.7 mmol), and oxoester 2d
(647 mg, 3.23 mmol) were converted in MeCN (10 ml). Chroma-
tography (SiO2, hexane/EtOAc 2:1, Rf¼0.32) yielded the title com-
pound 3d (198 mg, 0.50 mmol, 31%) as a red liquid. According to 13C
NMR, the material consisted of four diastereomers (four signal sets,
(2CH3), 21.6 (CH3), 25.4 (CH3), 47.7 (C), 74.9 (CH2), 128.0 (2CH),
~
129.9 (2CH), 132.7 (C), 144.9 (C), 210.1 (C) ppm. IR (ATR):
n
¼3068
(w), 2976 (m), 2937 (w), 2878 (w), 1709 (s), 1598 (m), 1473 (m),
1355 (s), 1174 (s), 1097 (m), 967 (s), 830 (s) cmꢁ1. HRMS (ESI): calcd
293.0824 (for C13H18NaO4S), found 293.0822 [MþNaþ]. C13H18O4S
(270.34).
dr 2.7:2.3:1:1). UV/vis (CH2Cl2): lmax (log
3
)¼425 (Z), 468 (3.85) nm
(E); fluorescence (CH2Cl2): lex¼425 nm, lem¼546 nm [(Z)-isomer];
4.13. 4-Bromo-2,2-dimethyl-3-oxobutyl para-toluenesulfo-
nate (6)
lex¼468 nm, lem¼539 nm [(E)-isomer]. 1H NMR (CDCl3, 500 MHz):
d
¼2.49e2.62 (m, 2H), 2.79e2.88 (m, 2H), 3.14e3.23 (m, 2H),
3.73e3.79 (m, 8H), 5.11e5.19 (m, 4H), 5.65e5.76 (m, 2H) ppm. 13C
A solution of bromine (0.5 ml,1.5 g, 10 mmol) in CHCl3 (5 ml) was
dropwise added to a solution of ketone 5 (2.6 g, 10 mmol) in CHCl3
(10 ml). The resulting solutionwas stirred for 1 h under reflux, diluted
with CH2Cl2 (10 ml), and washed with 15% aq NaHCO3 solution
(50 ml). The organic phase was dried (MgSO4) and, after filtration, the
solvent was removed in vacuum. The residue was chromatographed
(SiO2, hexane/EtOAc 2:1, Rf¼0.33) to yield the title compound 6
(2.10 g, 6.01 mmol, 61%) as yellow liquid. 1H NMR (CDCl3, 500 MHz):
{1H} NMR (CDCl3, 125 MHz), rac- and meso-(E)-isomers (major):
d
¼34.6 (2CH2), 34.8 (2CH2), 38.7 (2CH2), 38.8 (2CH2), 53.29 (2CH3),
53.31 (2CH3), 60.9 (2C), 61.0 (2C), 120.3 (2CH), 120.4 (2CH), 131.69
(2CH2),131.70 (2C),131.76 (2CH2),131.81 (2C),169.2 (2C),169.3 (2C),
198.7 (2C), 198.9 (2C) ppm; rac- and meso-(Z)-isomers (minor):
d
¼32.7 (2CH2), 32.8 (2CH2), 38.2 (2CH2), 38.7 (2CH2), 53.29 (2CH3),
53.33 (2CH3), 61.1 (2C), 62.3 (2C), 120.0 (2CH), 120.2 (2CH), 131.8

M. Schulz, J. Christoffers / Tetrahedron 69 (2013) 802e809
807
d
¼1.22 (s, 6H), 2.46 (s, 3H), 4.00 (s, 2H), 4.30 (s, 2H), 7.36 (d, J¼8.1 Hz,
4.17. 1,4-Bis(2-azidoethyl)benzene (10b)
2H), 7.75 (d, J¼8.1 Hz, 2H) ppm. 13C{1H} NMR (CDCl3, 125 MHz):
d
¼21.7 (2CH3), 21.7 (CH3), 46.3 (CH2), 47.3 (C), 74.7 (CH2),128.0 (2CH),
Following the procedure given above for the preparation of
compound 10a, NaN3 (0.70 g, 10.8 mmol) and bis(bromoethyl)ben-
zene 9b (1.50 g, 5.15 mmol) were converted in DMSO (15 ml) to
furnish the title compound 10b (1.01 g, 4.69 mmol, 91%) as a yellow
liquid that was used without further purification. 1H NMR (CDCl3,
~
130.0 (2CH),132.2 (C),145.2 (C), 202.7 (C) ppm. IR (ATR):
n
¼2979 (w),
2943 (w), 1728 (s), 1598 (w), 1473 (m), 1356 (s), 1174 (vs), 1097 (m),
1052 (m), 967 (vs), 812 (s), 666 (s) cmꢁ1. MS (CI, isobutane): m/z (%)¼
349 (17) [MþHþ], 305 (12), 271 (100), 239 (2), 99 (7). HRMS (CI, iso-
butane): calcd 349.0109 (for C13H18BrSO4); found 349.0100 [MþHþ].
C13H17BrO4S (349.24).
500 MHz):
d
¼2.88 (t, J¼7.2 Hz, 4H), 3.50 (t, J¼7.2 Hz, 4H), 7.18 (s,
4H) ppm. 13C{1H} NMR (CDCl3, 125 MHz):
(2CH2),129.0 (4CH),136.5 (2C) ppm. IR (ATR):
d
¼34.9 (2CH2), 52.4
~
n
¼3024 (w), 2928 (w),
4.14. 4,4-Dimethyl-3-oxotetrahydrothiophene (8)
2871 (w), 2084 (vs),1514 (m),1458 (m),1421 (m),1347 (m),1255 (s),
1113 (m), 1022 (m), 806 (m) cmꢁ1. HRMS (ESI): calcd 239.1021 (for
C10H12N6Na); found 239.1015 [MþNaþ]. C10H12N6 (216.24).
A suspension of Na2S aq (33e38%) (2.0 g, ca. 9 mmol) and bro-
moketone 6 (800 mg, 2.30 mmol) in DMF (30 ml) was stirred for 1 h
at 80 ꢀC. Water (40 ml) was added and the mixture extracted with
CH2Cl2 (4ꢂ30 ml). The combined organic layers were washed with
water (4ꢂ30 ml), dried (MgSO4), filtered, and the solvent was re-
moved in vacuum. The residue was chromatographed (SiO2, hex-
ane/MTBE 5:1, Rf¼0.61) to yield the title compound 8 (170 mg,
1.31 mmol, 56%) as a colorless liquid. 1H NMR (CDCl3, 500 MHz):
4.18. 1,4-Bis{[4-(3-methoxycarbonyl-4-oxotetrahydro-3-
thienyl)methyl-[1,2,3]triazole-1-yl]methyl}benzene (12a)
A solution of alkyne 2e (211 mg,1.06 mmol) in CH2Cl2 (5 ml) was
added under an inert atmosphere to a solution of diazide 10a
(100 mg, 0.53 mmol) and [Cu(m-OH)(tmeda)]2Cl2 (9 mg, 0.02 mmol)
d
¼1.20 (s, 6H), 2.86 (s, 2H), 3.32 (s, 2H) ppm. 13C{1H} NMR (CDCl3,
in CH2Cl2 (5 ml). The resulting mixture was stirred for 3 h at 23 ꢀC.
After removal of all volatiles, the residue was chromatographed
(SiO2, CH2Cl2/MeOH 10:1, Rf¼0.80) to yield the title compound 12a
(223 mg, 0.38 mmol, 72%) as a yellow liquid. 1H NMR (CDCl3,
125 MHz):
d
¼23.8 (2CH3), 36.5 (CH2), 40.7 (CH2), 45.8 (C), 215.8
~
(C) ppm. IR (ATR):
n
¼2968 (m), 2927 (w), 2869 (w), 1734 (vs), 1465
(w), 1380 (w), 1278 (w), 1199 (w), 1083 (m), 907 (m), 730 (s) cmꢁ1
.
MS (EI, 70 eV): m/z (%)¼130 (100) [Mþ], 102 (9), 88 (57), 56 (58), 41
(46). HRMS (EI, 70 eV): calcd 130.0452 (for C6H10OS); found
130.0449 [Mþ]. C6H10OS (130.21).
500 MHz):
d
¼3.18 (d, J¼12.0 Hz, 2H), 3.21 (d, J¼17.4 Hz, 2H), 3.22 (d,
J¼14.2 Hz, 2H), 3.29 (d, J¼14.2 Hz, 2H), 3.42 (d, J¼17.5 Hz, 2H), 3.43
(d, J¼11.9 Hz, 2H), 3.67 (s, 6H), 5.44 (s, 4H), 7.18 (s, 4H), 7.30 (s,
2H) ppm. 13C{1H} NMR (CDCl3, 125 MHz):
d
¼28.9 (2CH2), 33.7
4.15. Bi(4,4-dimethyl-3-oxothiolan-2-ylidene) (7)
(2CH2), 37.4 (2CH2), 53.0 (2CH2), 53.4 (2CH3), 61.3 (2C), 123.2 (2CH),
128.4 (4CH), 135.3 (2C), 142.6 (2CH), 169.7 (2C), 206.8 (2C) ppm. IR
~
Following the procedure given above for product 3b, K3[Fe(CN)6]
(1.1 g, 3.3 mmol), piperidine (0.3 ml, 0.3 g, 3.3 mmol), and thiolane 8
(107 mg, 0.82 mmol) were converted inwater (5 ml) and EtOH (3 ml)
to give the title compound 7 (43 mg, 0.17 mmol, 41%) as a bright
yellow solid after chromatography (SiO2, hexane/EtOAc 2:1,
Rf¼0.62), mp 205 ꢀC. According to NMR spectra, the material con-
sisted of two diastereomers [(E/Z)¼2:1]. UV/vis (CH2Cl2): lmax
(ATR):
n
¼3140 (w), 2953 (w), 2245 (w),1729 (vs),1667 (s),1434 (m),
1250 (m), 1222 (s), 1126 (m), 1095 (m), 1050 (m), 909 (s), 725
(s) cmꢁ1. MS (EI, 70 eV): m/z (%)¼584 (25) [Mþ], 553 (6), 525 (10),
510 (10), 451 (6), 426 (20), 352 (9), 323 (4), 241 (6), 182 (6), 157
(100), 104 (79), 44 (77). HRMS (EI, 70 eV): calcd 584.1512 (for
C26H28N6O6S2); found 584.1499 [Mþ]. C26H28N6O6S2 (584.67).
(log
3
)¼400 (Z), 457 (3.81) nm (E); fluorescence (CH2Cl2): lex¼457 or
4.19. 1,4-Bis{2-[4-(3-methoxycarbonyl-4-oxotetrahydro-3-
thiophenyl)methyl-[1,2,3]triazole-1-yl]ethyl}benzene (12b)
400 nm; lem¼534 nm.1H NMR (CDCl3, 500 MHz), (E)-isomer:
¼1.26
d
(s, 12H), 3.07 (s, 4H) ppm; (Z)-isomer:
d
¼0.99 (s, 12H), 2.42 (s,
4H) ppm.13C{1H} NMR (CDCl3,125 MHz), (E)-isomer:
42.1 (2CH2), 46.5 (2C),131.5 (2C), 207.8 (2C) ppm; (Z)-isomer:
d
¼24.8 (4CH3),
Following the procedure given above for the preparation of
compound 12a, alkyne 2e (316 mg, 1.60 mmol), diazide 10b
d¼24.5
(4CH3), 40.2 (2CH2), 47.7 (2C), 134.0 (2C), 197.6 (2C) ppm. IR (ATR,
(172 mg, 0.80 mmol), and [Cu(m-OH)(tmeda)]2Cl2 (15 mg,
~
mixture of diastereomers):
n
¼2968 (m), 2931 (m), 2866 (m), 1672
0.03 mmol) were reacted in CH2Cl2 (2ꢂ5 ml) for 3 h at 23 ꢀC.
Chromatography (SiO2, CH2Cl2/MeOH 10:1, Rf¼0.69) gave the title
compound 12b (392 mg, 0.64 mmol, 80%) as a yellow liquid. 1H
(s), 1468 (m), 1379 (m), 1379 (m), 1184 (m), 1102 (m), 1085 (s), 888
(s) cmꢁ1. MS (EI, 70 eV): m/z (%)¼256 (49) [Mþ], 172 (100), 116 (10),
88 (31), 41 (9). HRMS (EI, 70 eV): calcd 256.0592 (for C12H16O2S2);
found 256.0594 [Mþ]. C12H16O2S2 (256.38).
NMR (CDCl3, 500 MHz):
d
¼3.14 (t, J¼7.1 Hz, 4H), 3.15 (d, J¼11.3 Hz,
2H), 3.19 (d, J¼17.7 Hz, 2H), 3.24 (d, J¼14.7 Hz, 2H), 3.31 (d,
J¼14.7 Hz, 2H), 3.42 (d, J¼11.2 Hz, 2H), 3.44 (d, J¼17.9 Hz, 2H), 3.74
(s, 6H), 4.46e4.57 (m, 4H), 6.96 (s, 4H), 7.12 (br, 2H) ppm. 13C{1H}
4.16. 1,4-Bis(azidomethyl)benzene (10a)
NMR (CDCl3, 125 MHz):
37.5 (2CH2), 51.5 (2CH2), 53.2 (2CH3), 61.5 (2C), 123.2 (2CH), 129.1
d
¼28.8 (2CH2), 33.6 (2CH2), 36.2 (2CH2),
A
solution of NaN3 (1.48 g, 22.8 mmol) and 1,4-
bis(chloromethyl)benzene (9a) (1.82 g, 10.4 mmol) in DMSO
(15 ml) was stirred for 1 h at ambient temperature, then poured
into ice water (50 ml) and extracted with EtOAc (3ꢂ10 ml). The
combined organic layers were washed with water (2ꢂ20 ml), dried
(MgSO4), filtered, and the solvent was removed in vacuum to fur-
nish the title compound 10a (1.73 g, 9.19 mmol, 88%) as a yellow
liquid that was used without further purification. 1H NMR (CDCl3,
(4CH), 135.8 (2C), 142.5 (2C), 169.9 (2C), 207.2 (2C) ppm. IR (ATR):
~
n
¼3140 (w), 2952 (w), 1726 (vs), 1434 (m), 1274 (m), 1213 (s), 1125
(s), 1052 (s), 819 (m) cmꢁ1. HRMS (ESI): calcd 635.1722 (for
C28H32N6NaO6S2); found 635.1711 [MþNaþ]. C28H32N6O6S2
(612.72).
4.20. 7(1,4)-Benzena-3(4,40)[4,40-di(methoxycarbonyl)-3,30-di-
oxo-2,20-bithiolanylidena]-1(1,4),5(4,1)-di[1,2,3]tri-
azolacyclooctaphane (11a)
500 MHz):
125 MHz):
~
d
¼4.36 (s, 4H), 7.35 (s, 4H) ppm. 13C{1H} NMR (CDCl3,
d¼54.4 (2CH2), 128.6 (4CH), 135.6 (2C) ppm. IR (ATR):
n
¼3033 (w), 2937 (w), 2879 (w), 2089 (vs), 1446 (m), 1423 (m),
1346 (m), 1248 (s), 1204 (s), 881 (m), 806 (m) cmꢁ1. MS (EI, 70 eV):
m/z (%)¼188 (14) [Mþ], 146 (52), 118 (25), 84 (100), 49 (71). HRMS
(EI, 70 eV): calcd 188.0810 (for C8H8N6); found 188.0807 [Mþ].
C8H8N6 (188.19).
A solution of K3[Fe(CN)6] (250 mg, 0.76 mmol) and piperidine
(0.1 ml, 70 mg, 0.76 mmol) in water (3 ml) was added at 40 ꢀC to
a solution of bisthiolane 12a (1.16 g, 5.86 mmol) in EtOH/CH2Cl2
(10 ml, 3:1). The resulting suspension was stirred for 0.5 h at 60 ꢀC

808
M. Schulz, J. Christoffers / Tetrahedron 69 (2013) 802e809
and 0.5 h at 23 ꢀC, diluted with water (10 ml) and extracted with
CH2Cl2 (4ꢂ20 ml). The combined organic layers were dried
(MgSO4), filtered, and the solvent was removed in vacuum. The
residue was chromatographed (SiO2, CH2Cl2/MeOH 10:1, Rf¼0.27)
to yield the title compound 11a (57 mg, 0.10 mmol, 52%) as a bright
red solid consisting of two diastereomers [two signal sets in the 13C
NMR-spectrum, (E/Z)¼2.1:1], mp 230 ꢀC (dec). UV/vis (CH2Cl2):
€
Chem. 1976, 70, 157e169; (d) Hasenkamp, R.; Luhmann, U.; Luttke, W. Chem. Ber.
1980, 113, 1708e1722; (e) Voss, G. Color. Technol. 2006, 122, 317e323.
2. (a) Wyman, G. M.; Zarnegar, B. M. J. Phys. Chem. 1973, 77, 831e837; (b) Bauer,
H.; Kowski, K.; Kuhn, H.; Luttke, W.; Rademacher, P. J. Mol. Struct. 1998, 445,
277e286; (c) Lemieux, R. P. Chem. Record 2004, 3, 288e295; (d) Lemieux, R. P.
Soft Matter 2005, 1, 348e354; (e) Jacquemin, D.; Preat, J.; Wathelet, V.; Fon-
taine, M.; Perpete, E. A. J. Am. Chem. Soc. 2006, 128, 2072e2083.
3. (a) Steinle, W.; Ruck-Braun, K. Org. Lett. 2003, 5, 141e144; (b) Herre, S.; Steinle,
W.; Ruck-Braun, K. Synthesis 2005, 3297e3300; (c) Cordes, T.; Heinz, B.; Regner,
N.; Hoppmann, C.; Schrader, T. E.; Summerer, W.; Ruck-Braun, K.; Zinth, W.
ChemPhysChem 2007, 8, 1713e1721; (d) Cordes, T.; Schadendorf, T.; Priewisch,
B.; Ruck-Braun, K.; Zinth, W. J. Phys. Chem. A 2008, 112, 581e588.
4. (a) Luttke, W.; Hermann, H.; Klessinger, M. Angew. Chem. 1966, 78, 638e639;
Angew. Chem., Int. Ed. Engl. 1966, 5, 598e599; (b) Hermann, H.; Luttke, W. Chem.
Ber. 1968, 101, 1708e1714; (c) Hermann, H.; Luttke, W. Chem. Ber. 1968, 101,
1715e1728; (d) Hermann, H. J. A.; Ammon, H. L.; Gibson, R. E. Tetrahedron Lett.
1969, 2559e2560; (e) Fitjer, L.; Luttke, W. Chem. Ber. 1972, 105, 937e947; (f)
Luhmann, U.; Wentz, F. G.; Knieriem, B.; Luttke, W. Chem. Ber. 1978, 111,
3233e3245; (g) Ammon, H. L.; Hermann, H. J. Org. Chem. 1978, 43, 4581e4586;
€
€
€
€
lmax (log
3
)¼440 (Z), 479 (3.89) nm (E); fluorescence (CH2Cl2):
lex¼479 or 440 nm; lem¼542 nm. 1H NMR (CDCl3, 500 MHz):
€
€
d
¼3.14e3.29 (m, 4H), 3.36e3.45 (m, 4H), 3.56e3.63 (m, 6H),
5.34e5.42 (m, 4H), 6.97e7.00 (m, 2H), 7.10e7.14 (m, 4H) ppm. 13C
€
€
{1H} NMR (CDCl3, 125 MHz), (E)-isomer:
(2CH2), 53.4 (2CH3), 54.1 (2CH2), 61.2 (2C), 123.3 (2CH), 129.1 (4CH),
d¼29.9 (2CH2), 34.5
€
€
132.3 (2C), 135.3 (2C), 142.2 (2C), 169.5 (2C), 198.5 (2C) ppm; (Z)-
isomer:
d
¼20.0 (2CH2), 34.7 (2CH2), 53.4 (2CH3), 53.5 (2CH2), 61.5
€
(h) Rademacher, P.; Kowski, K.; Hermann, H.; Luttke, W. Eur. J. Org. Chem. 1999,
3191e3197; (i) Gerke, R.; Fitjer, L.; Muller, P.; Uson, I.; Kowski, K.; Rademacher,
(2C), 123.3 (2CH), 128.8 (2CH), 129.1 (2CH), 132.0 (2C), 135.3 (C),
€
~
P. Tetrahedron 1999, 55, 14429e14434.
136.9 (C), 141.5 (2C), 169.8 (2C), 198.3 (2C) ppm. IR (ATR):
n
¼3140
5. (a) Tornøe, C. W.; Christensen, C.; Medal, M. J. Org. Chem. 2002, 67, 3057e3064;
(b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem.
2002, 114, 2708e2711; Angew. Chem., Int. Ed. 2002, 41, 2596e2599.
(w), 2952 (w), 1732 (vs),1675 (s), 1509 (w), 1430 (m), 1220 (w), 1182
(s), 1048 (s), 908 (s), 797 (m), 732 (m) cmꢁ1. HRMS (ESI): calcd
603.1096 (for C26H24N6NaO6S2); found 603.1096 [MþNaþ].
C26H24N6NaO6S2 (580.64).
€
6. Huisgen, R.; Szeimies, G.; Mobius, L. Chem. Ber. 1967, 100, 2494e2507.
7. (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. 2001, 113, 2056e2075;
Angew. Chem., Int. Ed. 2001, 40, 2004e2021; (b) Block, V. D.; Hiemstra, H.; van
Maarseveen, J. H. Eur. J. Org. Chem. 2006, 51e68; (c) Moses, J. E.; Moorhouse, A.
D. Chem. Soc. Rev. 2007, 36, 1249e1262; (d) Moorhouse, A. D.; Moses, J. E.
ChemMedChem 2008, 3, 715e723; (e) Amblard, F.; Cho, J. H.; Schinazi, R. F.
Chem. Rev. 2009, 109, 4207e4220.
4.21. 8(1,4)-Benzena-3(4,40)[4,40-di(methoxycarbonyl)-3,30-di-
oxo-2,20-bithiolanylidena]-1(1,4),5(4,1)-di[1,2,3]tri-
azolacyclodecaphane (11b)
8. Angell, Y. L.; Burgess, K. Chem. Soc. Rev. 2007, 36, 1674e1689.
9. (a) Holub, J. M.; Kirshenbaum, K. Chem. Soc. Rev. 2010, 39, 1325e1337; (b)
Bogdan, A. R.; James, K. Org. Lett. 2011, 13, 4060e4063; (c) Ghorai, A.; Gayen, A.;
Kulsi, G.; Padmanaban, E.; Laskar, A.; Achari, B.; Mukhopadhyay, C.; Chatto-
padhyay, P. Org. Lett. 2011, 13, 5512e5515; (d) Empting, M.; Avrutina, O.;
Meusinger, R.; Fabritz, S.; Reinwarth, M.; Biesalski, M.; Voigt, S.; Buntkowsky,
G.; Kolmar, H. Angew. Chem. 2011, 123, 5313e5317; Angew. Chem. Int. Ed. 2011,
50, 5207e5211; (e) Isidro-Llobet, A.; Murillo, T.; Bello, P.; Cilibrizzi, A.; Hodg-
kinson, J. T.; Galloway, W. R. J. D.; Bender, A.; Welch, M.; Spring, D. R. Proc. Natl.
Acad. Sci. U.S.A. 2011, 108, 6793e6798; (f) Pedersen, D. S.; Abell, A. Eur. J. Org.
Chem. 2011, 2399e2411; (g) Davis, M. R.; Singh, E. K.; Wahyudi, H.; Alexander,
L. D.; Kunicki, J. B.; Nazarova, L. A.; Fairweather, K. A.; Giltrap, A. M.; Jolliffe, K.
A.; McAlpine, S. R. Tetrahedron 2012, 68, 1029e1051.
10. (a) Dondoni, A. Chem. Asian J. 2007, 2, 700e708; (b) Lewandowski, B.; Jarosz, S.
Synth. Commun. 2011, 41, 2161e2168; (c) Tiwari, V. K.; Kumar, A.; Schmidt, R. R.
Eur. J. Org. Chem. 2012, 2945e2956; (d) Allam, A.; Dupont, L.; Behr, J.-B.;
Plantier-Royon, R. Eur. J. Org. Chem. 2012, 817e823.
11. Duan, X.; Zhang, Y.; Ding, Y.; Lin, J.; Kong, X.; Zhang, Q.; Dong, C.; Luo, G.; Chen,
Y. Eur. J. Org. Chem. 2012, 500e508.
12. (a) Marcaurelle, L. A.; Comer, E.; Dandapani, S.; Duvall, J. R.; Gerard, B.; Kesavan,
S.; Lee, M. D., IV; Liu, H.; Lowe, J. T.; Marie, J.-C.; Mulrooney, C. A.; Pandya, B. A.;
Rowley, A.; Ryba, T. D.; Suh, B.-C.; Wei, J.; Young, D. W.; Akella, L. B.; Ross, N. T.;
Zhang, Y.-L.; Fass, D. M.; Reis, S. A.; Zhao, W.-N.; Haggarty, S. J.; Palmer, M.;
Foley, M. A. J. Am. Chem. Soc. 2010, 132, 16962e16976; (b) Bogdan, A. R.; James,
K. Chem.dEur. J 2010, 16, 14506e14512; (c) Chouhan, G.; James, K. Org. Lett.
2011, 13, 2754e2757; (d) Bogdan, A. R.; Jerome, S. V.; Houk, K. N.; James, K. J.
Am. Chem. Soc. 2012, 134, 2127e2138.
Following the procedure given above for compound 11a,
K3[Fe(CN)6] (263 mg, 0.80 mmol), piperidine (0.1 ml, 70 mg,
0.80 mmol), and bisthiolane 12b (123 mg, 0.20 mmol) were reacted
in water (3 ml) and EtOH/CH2Cl2 (10 ml, 3:1). Chromatography
(SiO2, CH2Cl2/MeOH 10:1, Rf¼0.26) furnished the title compound
11b (72 mg, 0.12 mmol, 59%) as a bright red solid consisting of two
diastereomers [two signal sets in the 13C NMR-spectrum, (E/Z)¼
1.7:1], mp 230 ꢀC (dec). UV/vis (CH2Cl2): lmax (log
3 )¼440 (Z), 479
(3.91) nm (E); fluorescence (CH2Cl2): lex¼479 or 440 nm;
lem¼542 nm. 1H NMR (CDCl3, 500 MHz):
¼3.10e3.14 (m, 4H),
d
3.39e3.43 (m, 4H), 3.44e3.50 (m, 4H), 3.63e3.73 (m, 6H),
4.46e4.53 (m, 4H), 6.97e7.00 (m, 2H), 7.10e7.14 (m, 4H) ppm. 13C
{1H} NMR (CDCl3, 125 MHz), (E)-isomer:
34.8 (CH2), 36.1 (2CH2), 51.3 (2CH2), 52.2 (CH2), 53.4 (2CH3), 61.2
(2C), 123.3 (2CH), 128.9 (4CH), 131.9 (2C), 135.7 (2C), 141.5 (2C),
d
¼29.8 (CH2), 34.4 (CH2),
169.9 (2C), 198.5 (2C) ppm; (Z)-isomer:
34.9 (2CH2), 36.2 (CH2), 51.5 (CH2), 52.3 (2CH2), 53.4 (2CH3), 61.5
d
¼29.9 (CH2), 34.6 (CH2),
(2C), 123.3 (2CH), 128.8 (2CH), 129.1 (2CH), 132.0 (2C), 135.3 (C),
~
136.9 (C), 141.5 (2C), 169.8 (2C), 198.3 (2C) ppm. IR (ATR):
n
¼3135
13. (a)Chande,M.S.;Chandran,S.K.;Mondkar,H.S.Synth.Commun.2011,41,1858e1868;
(b)Lau, Y. H.;Price,J. R.;Todd,M. H.;Rutledge,P.J.Chem.dEur. J. 2011,17, 2850e2858.
(w), 2951 (w), 1735 (vs), 1676 (s), 1509 (w), 1433 (m), 1364 (w), 1218
(s), 1144 (vs), 1051 (s), 956 (w), 907 (s), 858 (m), 819 (m) cmꢁ1. MS
(EI, 70 eV): m/z (%)¼608 (3) [Mþ], 472 (1), 414 (1), 354 (1), 340 (12),
256 (5),173 (10),152 (13),117 (26), 44 (100). HRMS (EI, 70 eV): calcd
608.1512 (for C28H28N6O6S2); found 608.1515 [Mþ]. C28H28N6O6S2
(608.69).
14. (a) Hua, Y.; Flood, A. H. Chem. Soc. Rev. 2010, 39,1262e1271; (b) Haridas, V.; Sahu,
S.; Venugopalan, P. Tetrahedron 2011, 67, 727e733; (c) Ramabhadran, R. O.; Hua,
Y.; Li, Y.-j.; Flood, A. H.; Raghavachari, K. Chem.dEur. J. 2011, 17, 9123e9129; (d)
Krause, M. R.; Goddard, R.; Kubik, S. J. Org. Chem. 2011, 76, 7084e7095; (e)
Chhatra, R. K.; Kumar, A.; Pandey, P. S. J. Org. Chem. 2011, 76, 9086e9089; (f)
McDonald, K. P.; Hua, Y.; Lee, S.; Flood, A. H. Chem. Commun. 2012, 5065e5075; (g)
White, N. G.; Beer, P. D. Beilstein J. Org. Chem. 2012, 8, 246e252.
15. Juricek, M.; Kouwer, P. H. J.; Rowan, A. E. Chem. Commun. 2011, 8740e8749.
16. Pflantz, R.; Sluiter, J.; Kricka, M.; Saak, W.; Hoenke, C.; Christoffers, J. Eur. J. Org.
Acknowledgements
ꢁ
Chem. 2009, 5431e5436.
We are grateful to M.Ed. Jonas Sluiter for preliminary experi-
ments and Dr. Herbert Frey for helpful discussions.
17. (a) Hradilova, L.; Grepl, M.; Hlavac, J.; Lycka, A.; Hradil, P. K. Synthesis 2012, 44,
1398e1404; (b) Yu, Y.; Li, Y.; Chen, S.; Liu, T.; Qin, Z.; Liu, H.; Li, Y. Eur. J. Org.
Chem. 2012, 4287e4292.
18. (a) Christoffers, J.; Sluiter, J.; Schmidt, J. Synthesis 2011, 895e900; (b) Chris-
toffers, J. Chem.dEur. J. 2003, 9, 4862e4867; (c) Christoffers, J.; Schuster, K.
Chirality 2003, 15, 777e782.
Supplementary data
19. (a) Christoffers, J.; Frey, H. Chimica Oggi/Chem. Today Suppl. 2008, 26, 26e28; (b)
Bauer, M.; Kauf, T.; Christoffers, J.; Bertagnolli, H. Phys. Chem. Chem. Phys. 2005,
7, 2664e2670; (c) Christoffers, J. Tetrahedron Lett. 1998, 39, 7083e7084.
20. (a) Woodward, R. B.; Eastman, R. H. J. Am. Chem. Soc. 1946, 68, 2229e2235; (b)
Gianturco, M. A.; Friedel, P.; Giammarino, A. S. Tetrahedron 1964, 20,
1763e1772; (c) Liu, H.-J.; Ngooi, T. K. Can. J. Chem. 1982, 60, 437e439.
21. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639e666.
22. (a) Baraldi, P. G.; Barco, A.; Benetti, S.; Moroder, F.; Pollini, G. P.; Simoni, D.;
Zanirato, V. J. Chem. Soc., Chem. Commun. 1982, 1265e1266; (b) Baraldi, P. G.;
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.10.107.
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