Bisthioxanthylidene biscrown ethers as potential stereodivergent chiral ligands

Article abstract of DOI:10.1039/b609271c

The concept of bisthioxanthylidene biscrown ethers as potential stereodivergent chiral ligands in asymmetric synthesis is introduced. Substituted bisthioxanthylidenes may be chiral and can exist as stable enantiomers due to their folded structure. As a result, both a right-handed helix (P) and left-handed helix (M) are present in this type of molecule. This offers the unique possibility to construct two crown ether moieties, attached to the same molecule, of which one exhibits (P)-helicity and the other (M)-helicity. When the crown ether moieties differ in size they can be complexed selectively with a base containing a cation of appropriate diameter. In this manner the (P)-helix and the (M)-helix can be activated selectively to serve as a chiral environment for base catalyzed asymmetric synthesis. Thus, we envisioned the new concept of a single chiral ligand to separately synthesize two enantiomers of a chiral product just by varying the added base. For this purpose, four new bisthioxanthylidene monocrown ethers and two new bisthioxanthylidene biscrown ethers were synthesized. Two biscrowns and two monocrowns were separated into their respective enantiomers (HPLC) and optical data (UV and CD) were collected to ensure stability of enantiomers at ambient temperatures. Ion complexation of one mono- and two biscrown ethers with potassium and sodium cations was investigated. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b609271c

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Bisthioxanthylidene biscrown ethers as potential stereodivergent chiral
ligands†
Edzard M. Geertsema, Anne Marie Schoevaars, Auke Meetsma and Ben L. Feringa*
Received 29th June 2006, Accepted 15th September 2006
First published as an Advance Article on the web 9th October 2006
DOI: 10.1039/b609271c
The concept of bisthioxanthylidene biscrown ethers as potential stereodivergent chiral ligands in
asymmetric synthesis is introduced. Substituted bisthioxanthylidenes may be chiral and can exist as
stable enantiomers due to their folded structure. As a result, both a right-handed helix (P) and
left-handed helix (M) are present in this type of molecule. This offers the unique possibility to construct
two crown ether moieties, attached to the same molecule, of which one exhibits (P)-helicity and the
other (M)-helicity. When the crown ether moieties differ in size they can be complexed selectively with a
base containing a cation of appropriate diameter. In this manner the (P)-helix and the (M)-helix can be
activated selectively to serve as a chiral environment for base catalyzed asymmetric synthesis. Thus, we
envisioned the new concept of a single chiral ligand to separately synthesize two enantiomers of a chiral
product just by varying the added base. For this purpose, four new bisthioxanthylidene monocrown
ethers and two new bisthioxanthylidene biscrown ethers were synthesized. Two biscrowns and two
monocrowns were separated into their respective enantiomers (HPLC) and optical data (UV and CD)
were collected to ensure stability of enantiomers at ambient temperatures. Ion complexation of one
mono- and two biscrown ethers with potassium and sodium cations was investigated.
KOtBu, which initiated the Michael addition of methyl acrylate
2 to methyl phenylacetate 1. In this way a chiral environment
was created around the reaction center which led to formation of
product 3 in 90% yield, with an ee of 62%.
Introduction
Following the seminal discovery by C. J. Pedersen1 in 1967
numerous applications of crown ethers, and derivatives, have been
developed. These compounds have been the basis for host–guest
chemistry and are at the dawn of supramolecular chemistry.2 Cram
et al. employed chiral crown ethers as ligands for potassium
ions in base catalyzed asymmetric Michael addition reactions
(Scheme 1).3 Chiral ligand (R)-4 consists of a six oxygen crown
Concept
This methodology inspired us to construct chiral crown ethers
with bisthioxanthylidene as a chiral template (Fig. 1).
ether attached to an optically pure binaphthol moiety. The size of
the crown ether was perfectly suited for 1 : 1 complexation with
We envisioned that the combination of the unique three
dimensional shape of bisthioxanthylidene4–6 and ion complexation
capabilities of crown ethers1,2 would provide an interesting new
class of chiral bifunctional structures. Bisthioxanthylidenes are
proven to exhibit a folded structure due to the severe steric
hindrance around the central double bond (Fig. 1, structures A
and B). Unequal substituents at either side of the molecule lead to
a chiral compound with both a right (P) and a left handed helix
(M) in the same molecule (Fig. 1, structure A).7 Equal substituents
would lead to an achiral meso compound (Fig. 1, structure B).
Rebek et al. synthesized a biphenyl which was functionalized with
equally sized crown ether moieties at both sides (Fig. 1, structure
C).8 Cooperative binding affinity of this biscrown system8 and
related structures9 with cations was investigated. Since biphenyls
have a twisted conformation, two helices of same configuration
(two (P)-helices or two (M)-helices) are present in this type
of molecule. Note that, despite having equal substituents, the
presence of two helices of the same configuration makes this type of
structure chiral anyway, independent from its substitution pattern.
Bisthioxanthylidenes have racemization barriers (DG‡) around
27.0 kcal mol−1 which ensure sufficient stability to preserve optical
activity at ambient temperatures.4–6 We aimed at four bisthiox-
anthylidene monocrown ethers 5–8 and two bisthioxanthylidene
Scheme 1 Asymmetric Michael addition using crown ether (R)-4 as chiral
ligand.
Department of Organic and Molecular Inorganic Chemistry, Stratingh
Institute, University of Groningen, Nijenborgh 4, 9747, AG Groningen, The
Netherlands. E-mail: b.l.feringa@rug.nl
† Electronic supplementary information (ESI) available: Atom numbering
schemes for compounds 5, 6, 24, 25, 28, 29, 32, 33, 9, and 10; X-ray analysis
of 9; chiroptical data of 7 and 8; procedures for complexation experiments
of compounds 5, 9, and 10; 1H and 13C NMR-spectra of 5–10. See DOI:
10.1039/b609271c
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All new bisthioxanthylidene crown ethers 5–10 are chiral since
they have different substituents attached at either side of the
molecule. Bisthioxanthylidene monocrowns 5–8 were intended to
examine the complexation behavior of this class of compounds
with metal cations. The differently sized crown ether moieties of
two biscrown ethers 9 and 10 were anticipated to selectively bind
a metal ion of appropriate size. In this manner the (P)-helix and
(M)-helix can be complexed selectively by varying the size of the
added metal ion. The (P)-helix and (M)-helix can serve as a chiral
environment for base mediated asymmetric catalysis. Thus, we
envisioned the new concept of a single chiral ligand which is able
to control the formation of either enantiomers of a chiral product
in a distinct way simply by varying the added achiral base (Fig. 3).
Fig. 3 Selective activation of the (M)-helix or (P)-helix of a bisthiox-
anthylidene biscrown ether by ion binding. Left: bisthioxanthylidene
biscrown ligand. Right: schematic drawing viewed from top along central
double bond.
Fig. 1 Schematic presentation of: (A) bisthioxanthylidene with unequal
crown ether moieties; (B) bisthioxanthylidene with equal crown ether
moieties, (C) biphenyl with equal crown ether moieties. Right: projection
viewed from top along the central double bond.
Synthesis
Monocrown 5, with methylene groups between the bisthioxan-
thylidene backbone and oligoether segment, was synthesized from
thiophenol 11a and 4-bromoisophthalic acid 11b (Scheme 2).
Ketone 13 was conveniently synthesized from substrates 11a
and 11b via an aromatic substitution yielding 12 followed by
an intramolecular Friedel–Crafts reaction. The carboxylic acid
moiety of 13 was protected by esterification with cyclohexanol
to provide adduct 14. Thioxanthone ester 14 was converted into
unstable gem-dichloride 15 by refluxing in oxalyl dichloride to
facilitate subsequent intermolecular coupling by the action of
activated Cu-bronze11 in refluxing p-xylene.12 Bisthioxanthylidene
16 was obtained in 51% yield after purification by column
chromatography. A mixture of cis and trans-16, in a 1 : 1 ratio,
was obtained and separation of the two isomers was achieved
by column chromatography. However, the cis–trans mixture was
applied in the following step. The ester groups of 16 were readily
converted into dichlorides cis-18 and trans-18 (1 : 1 ratio) by a
LiAlH4 reduction and subsequent reaction with SOCl2. The crown
ether moiety was constructed by coupling pentaethylene glycol
with cis–trans-18 through a twofold Williamson ether synthesis. A
rather low yield of 15% was found due to extensive formation of
oligomers. The trans isomer of 5 was not observed.
biscrown ethers 9 & 10 bearing crown ether moieties comprising
four, five, and six oxygen atoms, connected by ethylene moieties
(Fig. 2). Crown ethers of this composition are known to have a
distinct preference for selective 1 : 1 complexation with lithium,
sodium, and potassium cations, respectively, according to the
‘optimal spatial concept’.2,10
The synthesis route towards monocrown 6 is depicted in
Scheme 3. Two 2-hydroxy-thioxanthylidene moieties 1913,14 were
coupled with triethylene glycol ditosylate using K2CO3 in refluxing
DMF providing diketone 20 in 50% yield. An intramolecular
Fig. 2 New bisthioxanthylidene monocrown ethers 5–8 and bisthioxan-
thylidene biscrown ethers 9 and 10.
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Scheme 2 Synthesis route towards monocrown 5.
Bisthioxanthylidene biscrown ethers 9 and 10 were synthe-
sized in eight steps from 7-methoxy-9-oxo-9H-thioxanthene-2-
carboxylic acid 216 (Scheme 4). A building block with two
different substituents was chosen to be able to selectively construct
two unequally sized crown ether moieties. First the methoxy
substituent of 21 was deprotected by BBr3 yielding 22 after which
the carboxylic acid moiety was esterified with cyclohexanol to
give 23. Two equivalents of 23 were coupled with one equivalent
of ditosylate by the action of Cs2CO3 to give compounds 24 (n =
2, 63%) and 25 (n = 3, 68%). The reaction temperature was kept
at 65 ◦C to prevent hydrolysis of the esters which, however, caused
prolonged reaction times of up to 80 h.
A crucial intramolecular coupling reaction followed which
simultaneously resulted in construction of the central double
bond of the bisthioxanthylidene backbone and the first crown
ether moiety. Diketones 24 and 25 were converted into their
respective bis-gem-dichlorides 26 and 27 by heating at reflux
in oxalyl dichloride for 24 h.12 The bis-gem-dichlorides were
unstable and therefore treated in situ with activated Cu-bronze11
in refluxing p-xylene to furnish ring closed adducts 28 (n = 2)
and 29 (n = 3) in 60% and 71% yield respectively. These were
satisfactory yields given that sterically demanding overcrowded
alkenes were prepared during intramolecular coupling reactions
which could give oligomers. Only cis-isomers were found. The
conversion of the two ester groups into methylene chlorides
and subsequent attachment of the second crown ether moiety
Scheme 3 Synthesis route towards monocrown 6.
coupling reaction of 20 by oxalyl dichloride12 and activated
Cu-bronze11 furnished bisthioxanthylidene monocrown ether 6.
Synthesis of monocrown ether compounds 7 and 8 (Fig. 2) was
reported previously.14 Allfour monocrowns5–8 werecharacterized
by 1H and 13C NMR as well as HRMS analysis.
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Scheme 4 Synthesis route towards biscrown ethers 9 and 10.
proceeded in a similar fashion as employed for monocrown 5
Chiroptical data
(Scheme 2). KOtBu was applied as base in an attempt to exploit a
template effect15 during intramolecular crown ether formation.
Thus, bisthioxanthylidene biscrown ethers 9 (n = 2) and 10
(n = 3) were obtained in gratifying yields of 28 and 34% after
purification by column chromatography. These yields are doubled
in comparison with the 15% yield found for intramolecular crown
ether formation of dichloride cis–trans-18 leading to 5 (Scheme 2).
This is in line with the fact that dichlorides 32 and 33 are
only present in the cis-configuration promoting intramolecular
coupling. Biscrown ethers 9 and 10 were characterized by mass
spectrometry, 1H NMR, 13C NMR, NOESY, and COSY NMR.
Optical resolution of monocrown ethers 7 and 8 (n = 3, 4)
and both biscrown ethers 9 and 10 was pursued to confirm the
anticipated chirality and optical stability. Separation into their
respective enantiomers was readily achieved by chiral HPLC and
specifications are summarized in Table 1. CD-spectra of 7–10
were recorded and displayed a pair of mirror images in all cases.
Data of the (M) enantiomers are given in Table 2 and UV and
CD-spectra of the (P) and (M) enantiomer of biscrown 9 are
depicted in Fig. 4. CD-spectra of the four bisthioxanthylidene
(bis) crown ethers 7–10 show similar features except for the
Table 1 Enantioresolution by chiral HPLC of crown ether compounds 7–10
Crown ether
Chiral column
Eluent
Retention times/min
Configuration first fraction
7
AD
AD
OD
AD
n-Hexane–i-propanol 120 : 1
n-Hexane–i-propanol 60 : 1
64, 72
44, 56
13, 19
15, 23
(P)
(M)
(P)
(P)
8
9
10
n-Hexane–i-propanol 9 : 1
n-Hexane–i-propanol–chloroform 8 : 1 : 1
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Table 2 CD data of (M) enantiomers of crown ethers 7–10a
Crown ether
Configurationb
k/nm, e/1000 cm2 mol−1
7
(M)
(M)
(M)
(M)
218 (+27.5)
218 (+22.8)
219 (+42.6)
220 (+14.6)
227 (−3.6)
247 (−14.7)
248 (−23.7)
252 (−28.5)
252 (−15.9)
268 (+12.1)
268 (+9.5)
270 (+19.3)
271 (+12.4)
287 (−28.0)
287 (−40.0)
289 (−44.9)
290 (−23.9)
308 (+14.1)
310 (+21.8)
312 (+23.9)
312 (+10.3)
8
228 (−18.4)
229 (−21.4)
230 (−12.5)
9
10
a all recordings in n-hexane b based on ref. 6.
caesium triflates in CDCl3 revealed that 7 has a preference for
1 : 1 complexation with lithium cations.14 Cation : 7 1 : 2
sandwich complexes were observed with potassium, rubidium, and
caesium. Monocrown 8 was found to favor 1 : 1 complexation with
potassium and rubidium cations.14 Monocrown 5 and biscrowns 9
and 10 were examined with respect to their complexation behavior
with potassium and sodium cations in acetone-d6.9,17,18 Potassium
and sodium thiocyanate were used as salts. Changes in chemical
shift (Dd (Hz)) of seven different protons [HI (X and Y), HII (A and
B), HIII, HIV, and HV) of 5, 9, and 10 upon addition of metal cation
was monitored with 1H NMR spectroscopy (Fig. 5, Table 3). The
change in chemical shift (Dd (Hz)) was screened during stepwise
increase of salt concentration up to 5 equivalents with respect to
a constant concentration of crown ether. The changes in chemical
shifts of protons HI–HV after addition of five equivalents of salt
are given in Table 3. Protons HI (XY part of ABXY system) and
HII (AB system) are aliphatic protons which are part of the large
six oxygen ring. HIII and HIV are aromatic protons attached to the
bisthioxanthylidene backbone. HV are aliphatic protons belonging
to the small four and five oxygen crown ether moieties of 9 and
10, respectively. Two of the four protons HV were detected as clear
and separate signals in 1H NMR spectra of 9 and 10 recorded in
acetone-d6. Protons at either side of the molecules were examined
which allowed distinction between cation complexation with the
large (HI–HIII) and small crown ether ring (HIV and HV).
Fig. 4 UV (n-hexane–i-propanol 9 : 1) of biscrown ether (P)-9 and CD
(n-hexane) spectra of (P) (straight) and (M) (dashed) enantiomers of 9.
sign which is dependent on the enantiomer. This led to the
conclusion that the folded16 bisthioxanthylidene backbone largely
governed the shape and sign of the CD-spectra. Maxima, or
minima, were found around 219, 228, 249, 269, 288 and 310 nm,
respectively. The absolute configurations of crown ethers 7–
10 were determined by comparison of CD-data with those of
a similarly substituted bisthioxanthylidene backbone of which
the absolute configuration was established unambiguously.6 The
collected optical data confirmed that bisthioxanthylidene crown
ethers 7–10 preserve their optical activity and can exist as stable
enantiomers at ambient temperatures.
Fig. 5 Crown ethers 5, 9, and 10 with relevant protons HI–HV.
Monocrown 5 showed preference for 1 : 1 complexation with
both potassium and sodium ions (entries 1 and 4, Table 3).
The equilibrium constants (K) for the favored 1 : 1 complexes
were determined straightforwardly18,19 although other dynamic
processes upon addition of potassium ions to 5 cannot be excluded.
As anticipated complexation of potassium ions (K = 5.9 × 103
M) with the six oxygen crown ether of 5 is favored over sodium
ions (K = 1.4 × 103 M). These equilibrium constants are of
identical magnitude compared to values found for complexation
of 15-crown-5 with sodium and potassium ions respectively.2b,20
However, they are much smaller than values found for complex-
ation of sodium and potassium with 18-crown-6.2b,20 This can
Complexation studies
Previous 1H NMR longitudinal relaxation time studies of
monocrown 7 with lithium, sodium, potassium, rubidium, and
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be explained by the observation that increased rigidity in the
crown ether ring system, for example by replacing ethylene by
benzo moieties, reduces equilibrium constants for complexation
with metal cations.2b,21 The folded bisxanthylidene backbone4,5,6,16
features severe rigidity indeed and diminishes complexation ability.
Upon stepwise addition of 5 equivalents of salt the AB system of
protons HII(AB) gradually changed into an AM system22 while the
chemical environment of HI(X) changed considerably more than
that of HI(Y) (Table 3). The downfield shift of HII(A) of 67.7 (entry 1)
and 31.0 Hz (entry 4) versus an upfield shift of HII(B) of 5.5 (entry 1)
and 6.0 Hz (entry 4) is especially notable. These observations are
an evident sign of increasing rigidity of the six oxygen crown ether
moiety as a result of potassium and sodium complexation.
The capability of accommodating potassium did not increase
upon offering an extra four oxygen crown ether moiety (compound
9, entry 2). Addition of potassium to biscrown 9 resulted in a 1 : 1
crown : salt complex. Final shifts of protons HI–HIII were similar
compared to monocrown 5 indicating complexation of potassium
with the large crown ether moiety. Complexation with the small
crown was not favored since small additional shifts of only 2.9 Hz
were observed for protons HIV and HV. The equilibrium constant
of 6.3 × 103 M for this 1 : 1 complex is in line with the constant of
5.9 × 103 M found for 1 : 1 complexation of 5 with potassium
(entry 1). The situation changed significantly when the small
crown ether moiety was enlarged with an ethoxy unit (biscrown
10, entry 3). Compared to entry 2, shifts of protons HIV and HV
increased by 4.9 and 10.3 Hz, respectively, upon addition of 5
equivalents of salt indicating that the small crown ether moiety
now has reasonable capacity of binding potassium as well. The
titration curves suggest initial formation of a 2 : 3 crown–salt
complex. A complex comprising two biscrown compounds 10
which both accommodate one potassium ion in their large crown
rings and sandwich a third between their small crown moieties
is proposed here. The chemical shifts of protons HI–HIII moved
downfield up to addition of 2.5 equivalents of salt and remained
constant beyond this point. However, shifts of protons HIV and HV
moved downfield up to addition of 5 equivalents This observation
suggests that complexation of potassium with the small crown
ether ring is weaker than with the large one and that the 2 : 3 crown :
salt complex slowly tended towards a 1 : 2 crown–salt complex.
A different picture was seen for addition of sodium to biscrowns
9 and 10 (entries 5 and 6). In both cases a 1 : 1 crown–salt complex
was found with equilibrium constants (K) of 2.0 (9) and 1.1 ×
103 M (10), respectively. The downfield shifts of protons HI–HIII
of 9 and 10 are of identical magnitude compared to monocrown
5 (entry 4). Moreover, the equilibrium constants found for 9
and 10 are of similar dimension compared to the value found
for complexation of sodium with monocrown 5. These findings
indicate that sodium strongly favors complexation with the large,
six oxygen containing, crown ether ring over the smaller four and
five oxygen crown systems.
In all cases, potassium and sodium ions favor complexation with
the large six oxygen crown ether ring of compounds 5, 9, and 10 as
can be concluded from equal downfield shifts of protons HI (∼77
and 56 Hz), HII (∼68 and −5 Hz), and HIII (∼10 Hz) in entries 1–3
and in entries 4–6 (HI: ∼60 and ∼9 Hz; HII: ∼26 and −2 Hz; HIII:
∼6.5 Hz) upon addition of 5 equivalents of salt. The increasing
change in downfield shift of proton HIV in entry series 1–3 (4.2 →
12.0 Hz) and 4–6 (2.7 → 9.9 Hz) and of proton HV in entries
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2 & 3 (2.9 → 13.1 Hz) and 5 & 6 (2.1 → 3.9 Hz) is in line with
the increasing ability of cation accommodation at this side of the
bisthioxanthylidene backbone going from crown ether 5 to 10. In
conclusion, sodium and potassium ions selectively bind to the large
crown ether moiety of biscrown ether adduct 9 whereas sodium se-
lectively complexes with the large crown ether ring of biscrown 10.
was concentrated in vacuo and the residue was stripped twice
with dichloroethane (50 mL). The residue was dissolved in
dichloroethane (100 mL) and cooled to −5 ◦C after which AlCl3
(15.0 g, 112.5 mmol) was added carefully. The resulting black
mixture was stirred for 90 min at −5 ◦C. The reaction was
quenched by careful addition of water (100 mL). The product
was extracted with CH2Cl2 (twice 150 mL). The combined organic
layers were thoroughly washed with water, dried (Na2SO4), and
concentrated in vacuo to yield pure 13 (6.82 g, 26.61 mmol, 91%)
as a white powder. 1H NMR (200 MHz, DMSO-d6, 25 ◦C) d 9.32
(d, J = 2.2 Hz, 1H, 1-H), 8.60 (d, J = 8.4 Hz, 1H, 4-H), 8.20 (dd,
J = 8.4, 2.2 Hz, 1H, 3-H), 7.70–7.65 (m, 2H, 7-,8-H), 7.59–7.51
(m, 2H, 5-,6-H); 13C NMR (50 MHz, DMSO-d6, 25 ◦C) d 172.44
(s), 161.21 (s), 138.72 (s), 129.58 (s), 127.82 (d), 126.86 (d), 126.09
(d), 124.73 (s), 123.81 (d), 122.85 (s), 122.62 (s), 121.14 (d), 120.64
(d), 119.94 (d).
Conclusions
Two new bisthioxanthylidene monocrown 5 and 6 and two new
bisthioxanthylidene biscrown ethers 9 and 10 were synthesized.
Biscrowns 9 and 10 both contain two crown ether moieties of
different size of which one exhibits (M)- and the other exhibits
(P)-helicity. Enantioresolution of monocrown ether compounds 7
and 8 and biscrowns 9 and 10 was achieved by chiral HPLC. UV
and CD spectroscopy confirmed stability of enantiomers at
ambient temperatures and absolute configurations were estab-
lished. Potassium and sodium complexes with monocrown 5 and
biscrowns 9 and 10 were observed. Favored crown : salt ratios and
equilibrium constants were determined. It was found that sodium
and potassium prefer complexation with the large six oxygen over
the small four and five oxygen crown ether moieties of biscrowns
9 and 10.
Cyclohexyl 9-oxo-9H-thioxanthene-2-carboxylate 14
Substrate 13 (5.70 g, 22.27 mmol) was refluxed for 24 h in
cyclohexanol (80 mL) and concentrated H2SO4 (0.75 mL). After
cooling, a precipitate began to form. n-Hexane (80 mL) was added
and the mixture was s◦tirred for 5 min after which it was set aside
for one night at −12 C. A white precipitate was collected on a
glass filter and the product was washed thoroughly with hot n-
hexane to get rid of remaining cyclohexanol. Product 14 (5.84 g,
Experimental
1H (200, 400 MHz) and 13C (50 or 125 MHz) NMR spectra
were recorded in CDCl3 or DMSO-d6. Chemical shifts are
denoted in d (ppm) referenced to the residual protic solvents.
Column chromatography was performed on silica gel 60 PF254
under pressure. Procedures for synthesis of compounds 7,14 8,14
19,13,14 21.6 Supplementary information contains atom numbering
Schemes for compounds 5, 6, 24, 25, 28, 29, 32, 33, 9, and 10;
X-ray analysis of 9; chiroptical data of 7 and 8; procedures for
1
17.28 mmol, 78%) was obtained as a white powder. H NMR
(200 MHz, CDCl3, 25 ◦C) d 8.92 (s, 1H, 1-H), 8.31 (d, J = 7.7 Hz,
1H, 4-H), 7.96 (d, J = 7.7 Hz, 1H, 3-H), 7.39 (m, 3H, 5-,6-,7-H),
7.27 (dd, J = 6.6, 1.5 Hz, 1H, 5-H), 4.78 (m, 1H, OCH(CH2)2),
1.69–1.07 (m, 10H, c-hexyl); 13C NMR (50 MHz, CDCl3, 25 ◦C)
d 177.96 (s), 163.48 (s), 140.36 (s), 135.01 (s), 131.15 (d), 130.80
(d), 129.84 (d), 128.46 (d), 127.62 (s), 127.36 (s), 125.33 (d), 124.66
(d), 124.55 (d), 124.36 (s), 72.31 (d), 30.17 (t), 23.92 (t), 22.28 (t);
HRMS calcd for C20H18O3S: 338.0977; found: 338.0980.
complexation experiments of compounds 5, 9, and 10; 1H and 13
NMR-spectra of 5–10.
C
9,9-Dichloro-9H-thioxanthene-2-carboxylic acid cyclohexyl ester
15 and cis–trans-cyclohexyl 9-{2-[(cyclohexyloxy)-carbonyl]-9H-
thioxanthen-9-ylidene}-9H-thioxanthene-2-carboxylate 16
4-(Phenylsulfanyl)isophthalic acid 12
Under nitrogen, 4-bromoisophthalic acid 11b (8.00 g,
32.65 mmol), thiophenol 11a (3.59 g, 32.64 mmol), Cu-bronze
100 mg (1.57 mmol), and K2CO3 (14.00 g, 101.27 mmol) were
refluxed overnight in DMF (300 mL). After cooling, the mixture
was filtered and the residue was dissolved in water (250 mL). The
solution was carefully acidified with concentrated HCl (aq.) to
pH < 1. The product precipitated and was collected on a glass
filter. The product was thoroughly washed with water after which
it was dried at 100 ◦C in air to yield pure 12 (8.43 g, 30.76 mmol,
94%) as a white powder. 1H NMR (200 MHz, DMSO-d6, 25 ◦C)
d 13.28 (br, 2H, OH), 8.45 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H),
7.54 (m, 5H), 6.76 (d, J = 8.5 Hz, 1H); 13C NMR (50 MHz,
DMSO-d6, 25 ◦C) d 166.34, 165.98, 147.53, 135.13, 132.30, 131.82,
131.44, 130.10, 129.60, 127.74, 127.31, 126.77; HRMS calcd for
C14H10O4S: 274.0230; found: 274.0306.
Under nitrogen, 14 (4.00 g, 11.83 mmol) was refluxed overnight
in oxalyl dichloride (40 mL). After cooling, the excess of oxalyl
dichloride was removed under reduced pressure. The residue (15)
was dissolved in freshly distilled p-xylene (100 mL, from sodium).
Activated Cu-bronze11 (4.50 g, 70.82 mmol) was added and this
mixture was refluxed overnight. After cooling, the mixture was
filtered and the filtrate concentrated in vacuo to yield a brownish
residue. Purification by column chromatography (SiO2, CH2Cl2–
n-hexane 1 : 1) yielded 16 (1.95 g, 3.03 mmol, 51%) as a light
yellow powder. Product 16 was obtained in a cis : trans ratio of 1 :
1. A small fraction of 16 was purified by column chromatography
(SiO2, CH2Cl2–n-hexane 1 : 1) to separate the cis and trans isomer
(Rf = 0.28 and Rf = 0.37). The two isomers were readily separated,
however, no cis : trans assignment was performed. 1H NMR
(200 MHz, CDCl3, 25 ◦C) (Rf = 0.28) d 7.81 (dd, J = 8.1, 1.7 Hz,
2H, 3-H), 7.60 (d, J = 8.1 Hz, 2H, 4-H), 7.54 (dd, J = 7.8, 1.5 Hz,
2H, 5-H), 7.42 (d, J = 1.7 Hz, 2H, 1-H), 7.17 (ddd, J = 7.8,
7.3, 1.5 Hz, 2H, 6-H), 6.93 (ddd, J = 7.8, 7.3, 1.2 Hz, 2H, 7-H),
6.84 (dd, J = 7.8, 1.2 Hz, 2H, 8-H), 4.81 (m, 2H, OCH(CH2)2),
9-Oxo-9H-thioxanthene-2-carboxylic acid 13
Under nitrogen, 12 (8.00 g, 29.20 mmol) was refluxed in
dichloroethane (75 mL) and SOCl2 (50 mL) until the evolu-
tion of HCl gas had ceased (approximately 2 h). The mixture
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1.72–0.84 (m, 20H, c-hexyl); 13C NMR (50 MHz, CDCl3, 25 ◦C)
d 163.46 (s), 139.62 (s), 133.66 (s), 133.32 (s), 133.32 (s), 131.93
(s), 129.14 (d), 128.43 (d), 126.93 (s), 126.42 (d), 125.68 (d), 125.59
(d), 125.39 (d), 71.26 (d), 29.86 (t), 29.71 (t), 23.94 (t), 21.86 (t); 1H
NMR (200 MHz, CDCl3, 25 ◦C) (Rf = 0.37) d 7.83 (dd, J = 8.0,
1.7 Hz, 2H, 3-H), 7.59 (d, J = 8.0 Hz, 2H, 4-H), 7.52 (dd, J = 7.8,
1.5 Hz, 2H, 5-H), 7.50 (d, J = 1.7 Hz, 2H, 1-H), 7.14 (ddd, J = 7.8,
7.3, 1.5 Hz, 2H, 6-H), 6.91 (ddd, J = 1.2, 7.3, 7.8 Hz, 2H, 7-H),
6.78 (dd, J = 7.8, 1.2 Hz, 2H, 8-H), 4.86 (m, 2H, OCH(CH2)2),
1.73–1.27 (m, 20H, c-hexyl); 13C NMR (50 MHz, CDCl3, 25 ◦C)
d 163.63 (s), 139.67 (s), 133.84 (s), 133.35 (s), 133.20 (s), 131.94
(s), 129.42 (d), 128.10 (d), 126.96 (s), 126.25 (d), 125.79 (d), 125.55
(d), 125.46 (d), 124.66 (d), 71.12 (d), 29.81 (t), 29.66 (t), 23.95 (t),
21.68 (t).
of 18 (300 mg, 0.61 mmol) and pentaethylene glycol (146 mg,
0.61 mmol) in toluene (100 mL) was added very slowly (3 drops
per min). After addition, the reaction mixture was stirred for 90 h
◦
at 90 C. After cooling, the solvent was removed under reduced
pressure and the residue was dissolved in CH2Cl2 (15 mL) and
2 M HCl (aq.) (15 mL). After separation of the two layers the
water layer was extracted with CH2Cl2 (15 mL) and the combined
organic layers were washed with of 2 M HCl (aq.) (10 mL), dried
(Na2SO4), and concentrated in vacuo to yield a brown residue.
Purification by column chromatography (Al2O3, CH2Cl2–acetone
40 : 1 changing to CH2Cl2–acetone 8 : 1, Rf = 0.60 with CH2Cl2–
acetone 40 : 1 as eluent) gave pure racemic 5 (58 mg, 8.9 ×
10−2 mmol, 15%). H NMR (200 MHz, CDCl3, 25 ◦C) d 7.51
1
(d, J = 7.7 Hz, 2H, 7-,38-H), 7.50 (d, J = 8.1 Hz, 2H, 34-,46-H),
7.15 (d, J = 8.1 Hz, 2H, 33-,45-H), 7.10 (dd, J = 7.7, 7.3 Hz,
2H, 6-,39-H), 6.89 (dd, J = 7.7, 7.3 Hz, 2H, 5-,40-H), 6.79 (d,
cis–trans-{9-[2-(Hydroxymethyl)-9H-thioxanthen-9-ylidene]-9H-
thioxanthen-2-yl}-methanol 17 and cis–trans-2-(chloromethyl)-9-
[2-(chloromethyl)-9H-thioxanthen-9-ylidene]-9H-thioxanthene 18
J = 7.7 Hz, 2H, 4-,41-H), 6.73 (s, 2H, 12-,44-H), 4.23 (AB, JAB
=
12.5 Hz, Dm = 19.4 Hz, 4H, 14-,31-H), 3.70–3.58 (m, 12H, 19–
26-H), 3.54 (AB part of ABXY system, apparent as ddd, J =
22.7, 10.3, 5.5 Hz, 4H, OCH2, 17-,28-H), 3.31 (XY part of ABXY
system, apparent as ddd, J = 22.7, 10.3, 5.5 Hz, 4H, OCH2, 16-
Under nitrogen, LiAlH4 (0.60 g, 15.81 mmol) was suspended in
diethyl ether (20 mL). Substrate 16 (1.50 g of cis–trans mixture,
2.33 mmol) was added and this mixture was stirred overnight at
room temperature. To quench the reaction 2 M HCl (aq.) (20 mL)
was added and the two layers were transferred to a separatory
funnel. CH2Cl2 (100 mL) was added and the water and organic
layer were separated. The water layer was extracted twice with
CH2Cl2 (75 mL) and the combined organic layers were washed
three times with 2 M HCl (aq.), dried (Na2SO4), and concentrated
in vacuo to yield cis–trans-17 as a yellow powder. The product was
obtained as a cis–trans 1 : 1 mixture and the NMR data of one of
the isomers are given here. 1H NMR (200 MHz, DMSO-d6, 25 ◦C)
d 7.65 (dd, J = 7.7, 1.1 Hz, 2H, 5-H), 7.60 (d, J = 8.1 Hz, 2H,
4-H), 7.27–7.18 (m, 4H, 3-,6-H), 6.98 (ddd, J = 7.7, 7.3, 1.1 Hz,
2H, 7-H), 6.69 (d, J = 7.7 Hz, 2H, 8-H), 6.63 (d, 2H, J = 1.5 Hz,
1-H), 5.00 (t, J = 5.5 Hz, 2H, OH), 4.14 (d, J = 5.5 Hz, 4H,
PhCH2OH). Without further purification 17 was added to pure
SOCl2 (15 mL). After 3 h of stirring at room temperature, water
was added carefully to quench the reaction. The water layer was
extracted twice with CH2Cl2 (50 mL) and the combined organic
layers were washed twice with water (50 mL), dried (Na2SO4),
and concentrated in vacuo to yield an orange residue. Purification
by column chromatography (SiO2, n-hexane–CH2Cl2 1 : 1, Rf =
0.65) gave 18 (0.80 g, 1.64 mmol, 70%) as a cis–trans 1 : 1 mixture.
NMR data of one of the isomers is given here. 1H NMR (200 MHz,
CDCl3, 25 ◦C) d 7.52 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H),
7.14 (d, J = 8.1 Hz, 2H), 7.13 (dd, J = 8.1, 7.7 Hz, 2H), 6.92 (dd,
J = 7.7, 7.7 Hz, 2H), 6.81–6.74 (m, 4H), 4.21 (AB, JAB = 11.7 Hz,
Dm = 9.4 Hz, 4H, PhCH2Cl); 13C NMR (50 MHz, CDCl3, 25 ◦C)
d 134.47 (s), 134.16 (s), 133.91 (s), 133.82 (s), 133.76 (s), 131.87
(s), 128.55 (d), 128.3 (d), 125.98 (d), 125.68 (d), 125.61 (d), 125.49
(d), 124.43 (d), 44.27 (t); HRMS calcd for C28H18Cl2S2: 488.0227;
found: 488.0213.
◦
,29-H); 13C NMR (50 MHz, CDCl3, 25 C) d 134.98 (s), 134.49
(s), 134.33 (s), 134.12 (s), 133.25 (s), 132.03 (s), 128.20 (d), 127.32
(d), 125.66 (d), 125.63 (d), 125.23 (d), 124.64 (d), 124.22 (d), 70.86
(t), 69.45 (t), 69.35 (t), 69.27 (t), 69.15 (t), 67.80 (t); HRMS calcd
for C38H38O6S2: 654.2110; found: 654.2124.
2-[2-(2-{2-[(9-Oxo-9H-thioxanthen-2-yl)oxy]ethoxy}-
ethoxy)-ethoxy]-9H-thioxanthen-9-one 20
Under a nitrogen atmosphere, 2-hydroxy-9H-thioxanthen-9-one
1913,14 (2.55 g, 11.18 mmol), K2CO3 (1.82 g, 13.18 mmol),
and triethylene glycol di-p-tosylate (2.41 g, 5.27 mmol) were
suspended/dissolved in DMF (250 mL). This mixture was refluxed
for 72 h and after cooling, the solvent was removed under reduced
pressure. The residue was dissolved in CH2Cl2 (150 mL) and 2 M
HCl (aq.) (150 mL). After separation of the two layers the water
layer was extracted with CH2Cl2 (50 mL). The combined organic
layers were washed (twice with 2 M HCl (aq.)), dried Na2SO4, and
concentrated in vacuo to yield a yellow residue. Purification by
column chromatography (Al2O3 (5% water), CHCl3–acetone 30 :
1) and subsequent recrystallization from CH2Cl2 yielded pure 20
(1.50 g, 2.63 mmol, 50%). 1H NMR (200 MHz, CDCl3, 25 ◦C) d
8.55 (dd, J = 8.4, 1.1 Hz, 2H, 8-H), 7.99 (d, J = 2.6 Hz, 2H, 1-H),
7.56–7.48 (m, 4H), 7.43–7.38 (m, 4H), 7.23 (dd, J = 8.8, 2.6 Hz,
2H, 3-H), 4.22 (t, J = 4.4 Hz, 4H, CH2CH2OPh), 3.89 (t, J =
4.4 Hz, 4H, OCH2CH2OPh), 3.75 (s, 4H, CH2OCH2CH2OPh);
13C NMR (50 MHz, CDCl3, 25 ◦C) d 178.00 (s), 156.01 (s), 135.95
(s), 130.42 (d), 128.57 (s), 128.29 (d), 127.72 (s), 127.01 (s), 125.74
(d), 124.50 (d), 124.41 (d), 121.55 (d), 109.64 (d), 69.42 (t), 68.15 (t),
66.29 (t); HRMS calcd for C32H26O6S2: 570.1171; found: 570.1172.
14,17,20,23-Tetraoxa-9,28-dithiaheptacyclo-
[22.10.2.210,13.02,11.03,8.027,35.029,34]octatriaconta-
1,3,5,7,10(38),11,13(37),24,26,29,31,33,35-tridecaene 6
15,18,21,24,27,30-Hexaoxa-9,36-dithiaheptacyclo-
[30.10.2.210,13.02,11.03,8.035,43.037,42]hexatetraconta-
1,3,5,7,10(46),11,13(45),32,34,37,39,41,43-tridecaene 5
Under nitrogen, 20 (1.40 g, 2.46 mmol) was refluxed overnight
in oxalyl dichloride (40 mL). After cooling, the excess of oxalyl
dichloride was removed under reduced pressure and the residue
Under nitrogen, KOtBu (276 mg, 2.46 mmol) was suspended in
toluene (100 mL) and this mixture was heated to 90 ◦C. A solution
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was dissolved in freshly distilled p-xylene (300 mL, from sodium).
Activated Cu-bronze11 (3.50 g, 55.00 mmol) was added and this
mixture was refluxed overnight. After cooling, the mixture was
filtered and the filtrate was concentrated in vacuo to yield a
brown residue. Purification by column chromatography (Al2O3
(3% water), CH2Cl2, Rf = 0.58) yielded pure racemic 6 (0.70 g,
1.30 mmol, 53%). 1H NMR (200 MHz, CDCl3, 25 ◦C) d 7.50 (d,
J = 7.7 Hz, 2H, 7-,30-H), 7.42 (d, J = 8.4 Hz, 2H, 26-,38-H), 7.10
(dd, J = 7.7, 1.5 Hz, 2H, 6-,31-H), 6.87 (dd, J = 7.7, 1.5 Hz, 2H,
5-,32-H), 6.81 (dd, J = 8.4, 2.9 Hz, 2H, 25-,37-H), 6.76 (d, J =
7.7 Hz, 2H, 4-,33-H), 6.44 (d, J = 2.9 Hz, 2H, 12-,36-H), 3.95–3.88
(m, 2H, 15-,22-H), 3.80–3.59 (m, 10H, CH2O, 15–22-H);13C NMR
(50 MHz, CDCl3, 25 ◦C) d 155.75 (s), 155.75 (s), 135.37 (s), 134.43
(s), 134.43 (s), 132.15 (s), 128.45 (d), 126.62 (d), 125.47 (d), 125.22
(d), 124.14 (d), 114.00 (d), 113.68 (d), 69.64 (t), 68.16 (t), 66.78 (t);
HRMS calcd for C32H26O4S2: 538.1272; found: 538.1260.
(d), 31.21 (t), 25.08 (t), 23.34 (t); HRMS calcd for C20H18O4S:
354.0926; found: 354.0945.
Cyclohexyl 7-(2-{2-[2-({7-[(cyclohexyloxy)carbonyl]-9-oxo-9H-
thioxanthen-2-yl}oxy)-ethoxy]-ethoxy}ethoxy)-9-oxo-9H-
thioxanthene-2-carboxylate 24
Under nitrogen, 23 (6.40 g, 18.07 mmol), Cs2CO3 (8.60 g,
26.39 mmol), and triethylene glycol di-p-tosylate (3.30 g,
7.20 mmol) were dissolved/suspended in DMF (250 mL). This
◦
mixture was stirred at 65 C for 80 h. After cooling, the solvent
was removed in vacuo and the residue was dissolved in CH2Cl2
(150 mL). The organic layer was washed with 2 M HCl (aq.)
(2 × 100 mL), dried (Na2SO4), and concentrated in vacuo to yield
a brown residue. Purification by column chromatography (Al2O3
(4.5% water), CH2Cl2–acetone 40 : 1, Rf = 0.72) yielded 24 (3.74 g,
4.55 mmol, 63%) as a yellow powder. 1H NMR (200 MHz, CDCl3,
25 ◦C) d 9.09 (d, J = 1.7 Hz, 2H, 1-H), 8.07 (dd, J = 8.6, 1.7 Hz,
2H, 3-H), 7.88 (d, J = 2.7 Hz, 2H, 8-H), 7.44 (d, J = 8.6 Hz, 2H,
4-H), 7.31 (d, J = 9.0 Hz, 2H, 5-H), 7.17 (dd, J = 9.0, 2.7 Hz, 2H,
6-H), 5.06–4.97 (m, 2H, OCH(CH2)2), 4.18 (t, J = 3.9 Hz, 4H,
CH2CH2OPh), 3.88 (t, J = 3.9 Hz, 4H, OCH2CH2OPh), 3.76 (s,
4H, CH2OCH2CH2OPh), 1.98–1.35 (m, 20H, CH2, c-hexyl); 13C
NMR (50 MHz, CDCl3, 25 ◦C) d 178.71 (s), 164.84 (s), 157.66 (s),
141.79 (s), 131.64 (d), 131.11 (d), 129.70 (s), 128.51 (s), 128.13 (s),
127.80 (s), 127.09 (d), 125.87 (d), 122.95 (d), 111.03 (d), 73.47 (d),
70.69 (t), 69.37 (t), 67.53 (t), 31.39 (t), 25.16 (t), 23.49 (t); HRMS
calcd for C46H46O10S2: 822.2532; found: 822.2535.
7-Hydroxy-9-oxo-9H-thioxanthene-2-carboxylic acid 22
Under nitrogen, 7-methoxy-9-oxo-9H-thioxanthene-2-carboxylic
acid 216 (16.00 g, 55.94 mmol) was suspended in CH2Cl2 (200 mL).
The mixture was cooled to 0 ◦C and BBr3 (25.0 mL, 0.26 mol) was
added carefully. The reaction temperature was allowed to raise
to room temperature and the mixture was stirred overnight. The
mixture was cooled to 0 ◦C and ice was added carefully to quench
the reaction. The suspension was filtered and the residue dissolved
in 2.5 M NaOH (aq.) (600 mL) during 1 h of vigorous stirring. The
resulting suspension was filtered and the filtrate was acidified to
pH = 1 with concentrated HCl (aq.). The product precipitated as
a yellow solid and after filtration the product was washed 4 times
with hot water. The product was dried at 100 ◦C in air to yield
Cyclohexyl 7-[2-(2-{2-[2-({7-[(cyclohexyloxy)carbonyl]-9-oxo-9H-
thioxanthen-2-yl}oxy)-ethoxy]-ethoxy}ethoxy)ethoxy]-9-oxo-9H-
thioxanthene-2-carboxylate 25
1
22 (11.20 g, 41.17 mmol, ◦74%) as a brown powder. H NMR
(200 MHz, DMSO-d6, 25 C) d 10.20 (br, 1H, COOH), 8.96 (d,
J = 1.8 Hz, 1H, 1-H), 8.14 (dd, J = 8.4, 1.8 Hz, 1H, 3-H), 7.91 (d,
J = 8.4 Hz, 1H, 4-H), 7.83 (d, J = 2.9 Hz, 1H, 8-H), 7.71 (d, J =
8.4 Hz, 1H, 5-H), 7.27 (dd, J = 8.4, 2.9 Hz, 1H, 6-H), 3.50 (br, 1H,
OH); 13C NMR (50 MHz, DMSO-d6, 25 ◦C) d 178.50 (s), 166.72
(s), 157.19 (s), 141.86 (s), 132.04 (d), 130.59 (d), 129.70 (s), 128.69
(s), 128.23 (d), 127.63 (s), 127.11 (d), 125.70 (s), 123.16 (d), 113.64
(d); HRMS calcd for C14H8O4S: 272.0143; found: 272.0157.
See procedure for 24. 23 (6.40 g, 18.07 mmol), Cs2CO3 (10.00 g,
30.69 mmol), and tetraethylene glycol di-p-tosylate (3.65 g,
7.27 mmol) yielded 25 (4.29 g, 4.95 mmol, 68%) as a yellow powder
after purification by column chromatography (Al2O3 (4.5% water),
CH2Cl2–acetone 20 : 1). H NMR (200 MHz, CDCl3, 25 ◦C) d
1
9.15 (d, J = 1.8 Hz, 2H, 1-H), 8.13 (dd, J = 8.4, 1.8 Hz, 2H,
3-H), 7.96 (d, J = 2.9 Hz, 2H, 8-H), 7.52 (d, J = 8.4 Hz, 2H,
4-H), 7.40 (d, J = 8.6 Hz, 2H, 5-H), 7.24 (dd, J = 8.6, 2.9 Hz,
2H, 6-H), 5.06–4.97 (m, 2H, OCH(CH2)2), 4.20 (t, J = 4.4 Hz, 4H,
CH2CH2OPh), 3.87 (t, J = 4.4 Hz, 4H, OCH2CH2OPh), 3.72–3.67
(m, 8H, OCH2CH2OCH2CH2OPh), 2.12–1.32 (m, 20H, CH2, c-
hexyl); 13C NMR (50 MHz, CDCl3, 25 ◦C) d 178.82 (s), 164.85 (s),
157.76 (s), 141.81 (s), 131.71 (d), 131.18 (d), 129.82 (s), 128.60 (s),
128.18 (s), 127.91 (s), 127.15 (d), 125.92 (d), 123.03 (d), 111.12 (d),
73.47 (d), 70.63 (t), 70.52 (t), 69.32 (t), 67.64 (t), 31.39 (t), 25.16 (t),
23.48 (t); HRMS calcd for C48H50O11S2: 866.2794; found: 866.2795.
Cyclohexyl 7-hydroxy-9-oxo-9H-thioxanthene-2-carboxylate 23
Substrate 22 (11.00 g, 40.44 mmol) was suspended in cyclohexanol
(100 mL). Concentrated H2SO4 (1 mL) was added and this mixture
was refluxed overnight. After cooling, n-hexane (80 mL) was added
and this mixture was stirred for 5 min at room temperature and
then allowed to stand overnight at −12 ◦C. The orange precipitate
was collected on a glass filter and thoroughly washed with hot n-
hexane to get rid of cyclohexanol. After drying, pure 23 (11.78 g,
Dicyclohexyl 14,17,20,23-tetraoxa-9,28-dithiaheptacyclo-
[22.10.2.210,13.02,11.03,8.027,35.029,34]octa-triaconta-1,3,5,7,10(38),
11,13(37),24,26,29,31,33,35-tridecaene-5,32-dicarboxylate 28
1
33.28 mmol, 82%) was obtained as a yellow powder. H NMR
(200 MHz, DMSO-d6, 25 ◦C) d 10.22 (br, 1H, OH), 8.93 (d, J =
1.8 Hz, 1H, 1-H), 8.13 (dd, J = 8.6, 1.8 Hz, 1H, 3-H), 7.91 (d,
J = 8.6 Hz, 1H, 4-H), 7.82 (d, J = 2.9 Hz, 1H, 8-H), 7.70 (d,
J = 8.8 Hz, 1H, 5-H), 7.26 (dd, J = 8.8, 2.9 Hz, 1H, 6-H), 4.98–
Under nitrogen, 24 (3.00 g, 3.65 mmol) was refluxed in oxalyl
dichloride (70 mL) for 24 h. The excess of oxalyl dichloride was re-
moved under reduced pressure and the brown residue (crude gem-
dichloride 26) was dissolved in freshly distilled p-xylene (500 mL,
from sodium). Activated Cu-bronze11 (4.50 g, 70.82 mmol) was
added and this mixture was refluxed overnight. After cooling,
4.92 (m, 1H, OCH(CH2)2), 1.87–1.32 (m, 10H, CH2, c-hexyl); 13
C
NMR (50 MHz, DMSO-d6, 25 ◦C) d 178.34 (s), 164.36 (s), 157.16
(s), 142.17 (s), 131.64 (d), 130.26 (d), 129.66 (s), 128.28 (d), 127.95
(s), 127.59 (s), 127.21 (d), 125.69 (s), 123.13 (d), 113.57 (d), 73.23
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the reaction mixture was filtered and the filtrate was concentrated
in vacuo to yield a brown residue. Purification by column chro-
matography (silica gel, CH2Cl2–n-hexane–acetone 60 : 15 : 2, Rf =
0.38) gave pure 28 (1.72 g, 2.18 mmol, 60%) as a yellowish powder.
1H NMR (200 MHz, CDCl3, 25 ◦C) d 7.76 (dd, J = 8.0, 1.5 Hz, 2H,
6-,31-H), 7.55 (d, J = 8.0 Hz, 2H, 7-,30-H), 7.39 (d, J = 8.8 Hz,
2H, 26-,38-H), 7.36 (d, J = 1.5 Hz, 2H, 4-,33-H), 6.82 (dd, J = 8.8,
2.6 Hz, 2H, 25-,37-H), 6.43 (d, J = 2.6 Hz, 2H, 12-,36-H), 4.82–
4.74 (m, 2H, OCH(CH2)2), 3.93–3.88 (m, 2H, OCH2, 15-,22-H),
3.74–3.55 (m, 10H, OCH2, 15-,22-H), 1.68–1.32 (m, 20H, CH2,
c-hexyl); 13C NMR (50 MHz, CDCl3, 25 ◦C) d 164.81 (s), 157.41
(s), 141.39 (s), 135.88 (s), 134.65 (s), 133.34 (s), 130.70 (d), 128.15
(s), 127.97 (d), 127.77 (d), 126.62 (d), 125.87 (s), 115.41 (d), 115.41
(d), 72.46 (d), 70.98 (t), 69.45 (t), 68.07 (t), 31.08 (t), 30.94 (t),
25.20 (t), 23.04 (t); HRMS calcd for C46H46O8S2: 790.2634; found:
790.2620.
to low solubility no 13C NMR was recorded. HRMS calcd for
C34H30O6S2: 598.1483; found: 598.1472.
[35-(Hydroxymethyl)-14,17,20,23,26-pentaoxa-9,31-
dithiaheptacyclo[25.10.2.210,13.02,11.03,8.030,38.032,37]hentetraconta-
1,3,5,7,10(41),11,13(40),27,29,32,34,36,38-tridecaen-5-yl]-
methanol 31
See procedure for 30. LiAlH4 (0.45 g, 11.86 mmol) and 29 (2.40 g,
2.88 mmol) yielded pure 31 (1.70 g, 2.65 mmol, 92%) as a yellow
powder. H NMR (200 MHz, DMSO-d6, 25 ◦C) d 7.59 (d, J =
1
2.6 Hz, 2H, 29-,41-H), 7.57 (d, J = 2.6 Hz, 2H, 28-,40-H), 7.20 (d,
J = 8.4 Hz, 2H, 7-,33-H), 6.95 (dd, J = 8.4, 2.6 Hz, 2H, 6-,34-H),
6.60 (s, 2H, 12-,39-H), 6.28 (d, J = 2.6 Hz, 2H, 4-,36-H), 4.97
(t, J = 5.1 Hz, 2H, OH), 4.10 (d, J = 5.1 Hz, 4H, PhCH2OH),
3.96–3.80 (m, 2H, OCH2, 15-,25-H), 3.65–3.40 (m, 14H, OCH2,
15-,25-H); 13C NMR (50 MHz, DMSO-d6, 25 ◦C) d 154.33 (s),
137.57 (s), 133.73 (s), 131.93 (s), 130.54 (s), 130.41 (s), 125.64 (d),
125.01 (d), 124.07 (d), 123.52 (s), 122.87 (d), 113.08 (d), 111.87
(d), 67.54 (t), 67.49 (t), 65.79 (t), 65.16 (t), 59.72 (t); HRMS calcd
for C36H34O7S2: 642.1746; found: 642.1748.
Dicyclohexyl 14,17,20,23,26-pentaoxa-9,31-dithiaheptacyclo-
[25.10.2.210,13.02,11.03,8.030,38.032,37]hentetraconta-1,3,5,7,10(41),
11,13(40),27,29,32,34,36,38-tridecaene-5,35-dicarboxylate 29
See procedure for 28. Oxalyl dichloride (70 mL), 25 (3.50 g,
4.04 mmol), p-xylene (650 mL, from sodium), and activated Cu-
bronze11 (6.50 g, 102.14 mmol) gave pure 29 (2.40 g, 2.88 mmol,
71%) as a yellowish powder after purification by column chro-
5,32-Bis(chloromethyl)-14,17,20,23-tetraoxa-9,28-
dithiaheptacyclo[22.10.2.210,13.02,11.03,8.027,35.029,34]octatriaconta-
1,3,5,7,10(38),11,13(37),24,26,29,31,33,35-tridecaene 32
1
matography (silica gel, CH2Cl2–acetone 30 : 1, Rf = 0.33); H
Under nitrogen, 30 (1.48 g, 2.47 mmol) was added in one portion
to pure SOCl2 (15 mL). The deep red solution was stirred for 3 h
at room temperature. Water was added carefully to quench the
reaction and subsequently CH2Cl2 (50 mL) was added. The water
layer and organic layer were separated and the water layer was once
extracted with CH2Cl2 (15 mL). The combined organic layers were
washed with water (2 × 50 mL), dried (Na2SO4), and concentrated
in vacuo to yield pure 32 (1.33 g, 2.10 mmol, 85%) as a yellow
powder. 1H NMR (200 MHz, CDCl3, 25 ◦C) d 7.50 (d, J = 8.0 Hz,
2H, 7-,30-H), 7.41 (d, J = 8.6 Hz, 2H, 26-,38-H), 7.13 (dd, J = 8.0,
1.8 Hz, 2H, 6-,31-H), 6.82 (dd, J = 8.6, 2.9 Hz, 2H, 25-,37-H),
6.69 (d, J = 1.8 Hz, 2H, 4-,33-H), 6.42 (d, J = 2.9 Hz, 2H,
12-,36-H), 4.20 (AB, JAB = 11.5 Hz, Dm = 7.4 Hz, 4H, PhCH2Cl),
3.95–3.89 (m, 2H, OCH2, 15-,22-H), 3.79–3.58 (m, 10H, OCH2,
15-,22-H);13C NMR (50 MHz, CDCl3, 25 ◦C) d 157.28 (s), 136.19
(s), 135.45 (s), 135.10 (s), 133.31 (s), 130.06 (d), 128.01 (d), 127.22
(d), 127.09 (d), 126.40 (s), 115.36 (d), 115.24 (t), 70.99 (t), 69.46
(t), 68.09 (t), 45.56 (t); HRMS calcd for C34H28O4S2Cl2: 634.0806;
found: 634.0804.
NMR (200 MHz, CDCl3, 25 ◦C) d 7.77 (dd, J = 8.0, 1.8 Hz, 2H,
6-,34-H), 7.56 (d, J = 8.4 Hz, 2H, 29-,41-H), 7.37 (d, J = 8.0 Hz,
2H, 7-,33-H), 7.36 (d, J = 1.8 Hz, 2H, 4-,36-H), 6.82 (dd, J = 8.4,
2.6 Hz, 2H, 28-,40-H), 6.40 (d, J = 2.6 Hz, 2H, 12-,39-H), 4.84–
4.74 (m, 2H, OCH(CH2)2), 3.81–3.47 (m, 16H, CH2O, 15-,25-H),
1.68–1.32 (m, 20H, CH2, c-hexyl); 13C NMR (50 MHz, CDCl3,
◦
25 C) d 164.80 (s), 157.36 (s), 141.32 (s), 135.84 (s), 134.48 (s),
133.32 (s), 130.56 (d), 128.19 (s), 127.98 (d), 127.78 (d), 126.64 (d),
126.03 (s), 116.25 (d), 114.63 (d), 72.48 (d), 70.71 (t), 70.63 (t),
68.98 (t), 67.97 (t), 31.07 (t), 30.93 (t), 25.18 (t), 23.04 (t); HRMS
calcd for C48H50O9S2: 834.2896; found: 834.2869.
[32-(Hydroxymethyl)-14,17,20,23-tetraoxa-9,28-dithiaheptacyclo-
[22.10.2.210,13.02,11.03,8.027,35.029,34]octatriaconta-1,3,5,7,10(38),
11,13(37),24,26,29,31,33,35-tridecaen-5-yl]methanol 30
Under nitrogen, LiAlH4 (0.40 g, 10.54 mmol) was suspended in
diethyl ether (100 mL). Substrate 28 (2.50 g, 3.16 mmol) was
added and this suspension was stirred at room temperature for
5 h. The solvent was removed under reduced pressure and the
residue was dissolved in CH2Cl2 (150 mL) and 2 M HCl (aq.)
(100 mL). After separation of the two layers the water layer was
extracted once with CH2Cl2 (50 mL) and the combined organic
layers were washed (2 M HCl (aq.) (100 mL)), dried (Na2SO4), and
concentrated in vacuo to yield a yellow residue. The residue was
washed with n-hexane to remove cyclohexanol. Pure 30 (1.80 g,
5,35-Bis(chloromethyl)-14,17,20,23,26-pentaoxa-9,31-
dithiaheptacyclo[25.10.2.210,13.02,11.03,8.030,38.032,37]hentetraconta-
1,3,5,7,10(41),11,13(40),27,29,32,34,36,38-tridecaene 33
See procedure for 32. SOCl2 (15 mL) and 31 (1.52 g, 2.37 mmol)
yielded pure 33 (1.44 g, 2.12 mmol, 89%) as a yellow powder. 1H
NMR (200 MHz, CDCl3, 25 ◦C) d 7.50 (d, J = 8.0 Hz, 2H, 7-,33-
H), 7.41 (d, J = 8.8 Hz, 2H, 29-,41-H), 7.13 (dd, J = 8.0, 1.8 Hz,
2H, 6-,34-H), 6.82 (dd, J = 8.8, 2.6 Hz, 2H, 28-,40-H), 6.71 (d,
J = 1.8 Hz, 2H, 4-,36-H), 6.39 (d, J = 2.6 Hz, 2H, 12-,39-H),
4.21 (AB, JAB = 11.4 Hz, Dm = 11.4 Hz, 4H, PhCH2Cl), 3.83–3.49
(m, 16H, OCH2, 15-,25-H); 13C NMR (50 MHz, CDCl3, 25 ◦C) d
157.23 (s), 136.14 (s), 136.14 (s), 135.31 (s), 135.11 (s), 133.28 (s),
129.94 (d), 128.03 (d), 127.26 (d), 127.09 (d), 126.53 (s), 116.04
1
3.01 mmol, 95%) was obt◦ained as a yellow powder. H NMR
(200 MHz, DMSO-d6, 25 C) d 7.53 (d, J = 2.6 Hz, 2H, 7-,30-
H), 7.51 (d, J = 2.6 Hz, 2H, 6-,31-H), 7.15 (d, J = 8.4 Hz, 2H,
26-,38-H), 6.88 (dd, J = 8.4, 2.6 Hz, 2H, 25-,37-H), 6.52 (s, 2H,
4-,33-H), 6.26 (d, J = 2.6 Hz, 2H, 12-,36-H), 4.91 (t, J = 5.1 Hz,
2H, OH), 4.07 (d, J = 5.1 Hz, 4H, PhCH2OH), 4.03–3.98 (m,
2H, OCH2, 15-,22-H), 3.60–3.48 (m, 10H, OCH2, 15-,22-H); Due
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(d), 114.63 (d), 70.74 (t), 70.64 (t), 69.01 (t), 68.00 (t), 45.53 (t);
HRMS calcd for C34H28O4S2Cl2: 678.1068; found: 678.1076.
(s), 136.36 (s), 135.66 (s), 134.95 (s), 133.49 (s), 128.61 (d), 127.90
(d), 127.02 (s), 126.81 (d), 125.96 (d), 115.70 (d), 114.79 (d), 72.21
(t), 70.82 (t), 70.82 (t), 70.76 (t), 70.76 (t), 70.68 (t), 70.52 (t), 69.25
(t), 69.25 (t), 68.13 (t); HRMS calcd for C46H52O12S2: 844.2950;
found: 844.2948. Chiral HPLC analysis; Daicel AD column, n-
hexane–i-propanol–chloroform 8 : 1 : 1, retention times: 15 (P)
and 23 min (M).
8,11,14,17,30,33,36,39,42,45-Decaoxa-52,54-dithiaoctacyclo-
[45.3.1.13,7.14,50.118,22.121,25.124,28.02,23]hexapentaconta-1(51),2(23),
3(56),4,6,18,20,22(55),24(53),25,27,47,49-tridecaene 9
Under nitrogen, KOtBu (274 mg, 2.44 mmol) was suspended in
toluene (80 mL). The mixture was heated to 90 ◦C. At a very slow
rate (3 drops per min) a solution of 32 (384 mg, 0.61 mmol) and
pentaethylene glycol (144 mg, 0.60 mmol) in toluene (160 mL)
was added. After addition, the mixture was stirred for another
60 h at 90 ◦C. After cooling, the solvent was removed to yield
an orange residue which was dissolved in CH2Cl2 (40 mL). The
organic layer was washed (4 × 25 mL 1 M HCl (aq.)), dried
(Na2SO4), and concentrated in vacuo. The residue was purified
by column chromatography (Al2O3, (3% water), CH2Cl2–acetone
20 : 1, Rf = 0.30) to yield pure racemic 9 (139 mg, 0.17 mmol,
28%) as an orange solid. kmax (n-hexane–i-propanol 9 : 1)/nm 214
(e/dm3 mol−1 cm−1 68400), 236 (3◦3500), 271 (17100), 368 (7400);
1H NMR (400 MHz, CDCl3, 25 C) d 7.47 (d, J = 8.1 Hz, 2H,
26-,49-H), 7.40 (d, J = 8.8 Hz, 2H, 5-,20-H), 7.13 (dd, J = 8.1,
1.1 Hz, 2H, 27-,48-H), 6.79 (dd, J = 8.8, 2.6 Hz, 2H, 6-,19-H),
6.69 (d, J = 1.1 Hz, 2H, 51-,53-H), 6.41 (d, J = 2.6 Hz, 2H, 55-
,56-H), 4.20 (AB, JAB = 12.8 Hz, Dm = 22.2 Hz, 4H, PhCH2O,
29-,46-H), 3.90 (ddd, J = 11.6, 5.2, 2.1 Hz, 2H, OCH2, 9-,16-
H), 3.77–3.57 (m, 22H, OCH2, 9–16-H, 34–41-H), 3.54 (AB part
of ABXY system, 2 × ddd, J = 10.6, 6.0, 4.1 Hz, 4H, OCH2,
32-,43-H), 3.27 (XY part of ABXY system, 2 × ddd, J = 10.6,
6.0, 4.1 Hz, 4H, OCH2, 31-,44-H); 13C NMR (50 MHz, CDCl3,
References
1 C. J. Pedersen, J. Am. Chem. Soc., 1967, 89, 7017.
2 For reviews on crown ethers see (a) E. Weber, J. L. Toner, I. Goldberg, F.
Vo¨gtle, D. A. Laidner, J. F. Stoddart, R. A. Bartsch and C. L. Liotta, in
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Chemistry, VCH Thieme Verlag, Weinheim, 1992; (f) B. G. Cox and
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3 D. J. Cram and G. D. Y. Sogah, J. Chem. Soc., Chem. Commun., 1981,
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4 For a review with relevant references see: P. U. Biedermann, J. J.
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1966, 5, 385.
8 (a) J. Rebek, Jr., R. V. Wattley, T. Costello, R. Gadwood and L.
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◦
25 C) d 157.29 (s), 136.80 (s), 136.45 (s), 136.04 (s), 135.20 (s),
133.70 (s), 129.03 (d), 128.23 (d), 127.11 (d), 127.01 (s), 126.27
(d), 115.42 (d), 115.17 (d), 72.41 (t), 71.21 (t), 71.05 (t), 70.94 (t),
70.86 (t), 70.73 (t), 69.71 (t), 69.29 (t), 68.30 (t); HRMS calcd for
C44H48O10S2: 800.2688; found: 800.2696. Chiral HPLC analysis;
Daicel OD column, n-hexane–i-propanol 9 : 1, retention times: 13
(P) and 19 min (M).
9 J. J. H. Schlotter, I. J. A. Mertens, A. M. A. van Wageningen, F. P. J.
Mulders, J. W. Zwikker, H.-J. Buschmann and L. W. Jenneskens,
Tetrahedron Lett., 1994, 35, 7255.
10 C. J. Pedersen and H. Frensdorff, Angew. Chem., Int. Ed. Engl., 1972,
84, 16.
8,11,14,17,20,33,36,39,42,45,48-Undecaoxa-55,57-dithiaocta
cyclo[48.3.1.13,7.14,53.121,25.124,28.127,31.02,26]nonapentaconta-1(54),
2(26),3(59),4,6,21,23,25(58),27(56),28,30,50,52-tridecaene 10
11 B. S. Furniss, A. J. Hannaford, V. Rogers, P. W. G. Smith and A. R.
Tatchell, Vogel’s Textbook of Practical Organic Chemistry, Longman,
London and New York, 4th edn, 1978, pp. 285 and 611.
12 (a) A. Scho¨nberg and S. Nickel, Ber., 1934, 67, 1795; (b) A. Scho¨nberg
and W. Asker, J. Chem. Soc., 1942, 272; (c) A. Scho¨nberg, A. Mustafa
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14 A. M. Schoevaars, R. Hulst and B. L. Feringa, Tetrahedron Lett., 1994,
35, 9745.
See procedure for 9. Substrate 33 (1.44 g, 2.12 mmol), pentaethy-
lene glycol (0.51 g, 2.52 mmol), KOtBu (0.95 g, 8.47 mmol), and
toluene (150 mL) yielded pure racemic 10 (0.61 g, 0.72 mmol, 34%)
as an orange solid after purification by column chromatography
(Al2O3, (5% water), starting with CH2Cl2–acetone 20 : 1 (Rf =
0.10) changing to CH2Cl2–acetone 10 : 1) kmax (n-hexane)/nm 236
1
(e/dm3 mol−1 cm−1 36000), 271 (15700), 364 (6800); H NMR
◦
(400 MHz, CDCl3, 25 C) d 7.45 (d, J = 7.7 Hz, 2H, 29-,52-H),
7.37 (d, J = 8.4 Hz, 2H, 5-,23-H), 7.11 (dd, J = 7.7, 1.5 Hz, 2H,
30-,51-H), 6.76 (dd, J = 8.4, 2.6 Hz, 2H, 6-,22-H), 6.67 (d, J =
1.5 Hz, 2H, 54-,56-H), 6.35 (d, J = 2.6 Hz, 2H, 58-,59-H), 4.18
(AB, JAB = 12.6 Hz, Dm = 20.4 Hz, 4H, PhCH2O, 32-,49-H), 3.78
ddd, J = 10.4, 5.1, 2.9 Hz, 2H, OCH2, 9-,19-H), 3.75–3.60 (m,
26H, OCH2, 9–19-H, 44 − 37-H), 3.55 (AB part of ABXY system,
2 × ddd, J = 10.6, 6.0, 4.1 Hz, 4H, OCH2, 35-,46-H), 3.28 (XY
part of ABXY system, 2 × ddd, J = 10.6, 6.0, 4.1 Hz, 4H, OCH2,
34-,47-H); 13C NMR (125 MHz, CDCl3, 50 ◦C) d 157.14 (s), 136.65
15 (a) D. N. Reinhoudt, R. T. Gray, C. J. Smit and I. Veenstra, Tetrahedron,
1976, 32, 1161; (b) A. J. Rest and B. R. Bowsher, Inorg. Chim. Acta,
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Soc., 1981, 103, 2780; (d) O. Piepers and R. M. Kellogg, J. Chem. Soc.,
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Kellogg, J. Org. Chem., 1987, 4230; (h) J. Buter and R. M. Kellogg,
Org. Synth., 1993, Coll. Vol. VIII, 592.
16 See supplementary information for X-Ray analysis of bisthioxan-
thylidene biscrown ether (M)-9 exhibiting a folded structure. CCDC
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reference numbers 613520. For crystallographic data in CIF or other
electronic format see DOI: 10.1039/b609271c.
20 Equilibrium constants referred to were determined in methanol.
21 See reference 2b to compare equilibrium constants (in methanol) of
sodium and potassium, respectively, with 15-crown-5, benzo-15-crown-
5 and dibenzo-15-crown-5 and with 18-crown-6, benzo-18-crown-6 and
dibenzo-18-crown-6.
17 J. C. Lockhart, A. C. Robson, M. E. Thompson, P. D. Tyson and
I. H. M. Wallace, J. Chem. Soc., Dalton Trans., 1978, 611.
18 D. Live and S. I. Chan, J. Am. Chem. Soc., 1976, 98, 3769.
19 K. E. Koenig, G. M. Lein, P. Stuckler, T. Kaneda and D. J. Cram, J. Am.
Chem. Soc., 1979, 101, 3553.
22 M. Hesse, H. Meier and B. Zeeh, Spectroscopic Methods in Organic
Chemistry, VCH Thieme Verlag, Stuttgart and New York, 1997.
4112 | Org. Biomol. Chem., 2006, 4, 4101–4112
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