Aryloxyethyl thiocyanates are potent growth inhibitors of Trypanosoma cruzi and Toxoplasma gondii

Article abstract of DOI:10.1002/cmdc.201500100

Abstract As a part of our project aimed at searching for new safe chemotherapeutic agents against parasitic diseases, several compounds structurally related to the antiparasitic agent WC-9 (4-phenoxyphenoxyethyl thiocyanate), which were modified at the te

Full text of DOI:10.1002/cmdc.201500100

DOI: 10.1002/cmdc.201500100
Full Papers
Aryloxyethyl Thiocyanates Are Potent Growth Inhibitors of
Trypanosoma cruzi and Toxoplasma gondii
Marꢀa N. Chao,[a] Carolina Exeni Matiuzzi,[a] Melissa Storey,[b] Catherine Li,[b]
Sergio H. Szajnman,[a] Roberto Docampo,[b] Silvia N. J. Moreno,[b] and Juan B. Rodriguez*[a]
As a part of our project aimed at searching for new safe che-
motherapeutic agents against parasitic diseases, several com-
pounds structurally related to the antiparasitic agent WC-9
(4-phenoxyphenoxyethyl thiocyanate), which were modified at
the terminal phenyl ring, were designed, synthesized, and eval-
uated as growth inhibitors against Trypanosoma cruzi, the etio-
logical agent of Chagas disease, and Toxoplasma gondii, the
parasite responsible of toxoplasmosis. Most of the synthetic
analogues exhibited similar antiparasitic activity and were
slightly more potent than our lead WC-9. For example, two
trifluoromethylated derivatives exhibited ED50 values of 10.0
and 9.2 mm against intracellular T. cruzi, whereas they showed
potent action against tachyzoites of T. gondii (ED50 values of
1.6 and 1.9 mm against T. gondii). In addition, analogues of
WC-9 in which the terminal aryl group is in the meta position
with respect to the alkyl chain bearing the thiocyanate group
showed potent inhibitory action against both T. cruzi and
T. gondii at the very low micromolar range, which suggests
that a para-phenyl substitution pattern is not necessary for
biological activity.
Introduction
Trypanosomatids have a strict requirement for specific endoge-
nous sterols for survival and cannot use the abundant supply
of cholesterol present in their mammalian hosts.[1–5] For that
reason, ergosterol biosynthesis has become a valid target to
control parasitic diseases caused by pathogenic trypanosoma-
tids. It has been reported that ergosterol biosynthesis inhibi-
tors with potent in vitro activity and special pharmacokinetic
properties in mammals can induce radical parasitological cure
in animal models of both acute and chronic experimental
Chagas disease.[6,7] 4-Phenoxyphenoxyethyl thiocyanate (1;
WC-9) is an interesting drug that presents ED50 values at the
low nanomolar range against the clinically more relevant repli-
cative form (amastigotes) of Trypanosoma cruzi,[8–10] the etiolog-
ical agent of Chagas disease or American trypanosomiasis
(Figure 1). WC-9 induces a dose-dependent effect of growth of
the epimastigotes (EP strain).[11] Furthermore, the growth inhib-
itory effects of WC-9 are associated with depletion of parasitic
endogenous sterols, in addition to ergosterol and its 24-ethyl
analogue with no accumulation of sterol intermediates or
Figure 1. Chemical structure of WC-9 (1) and other closely related ana-
logues.
precursors; this is indicative of obstruction of the biosynthetic
pathway at the presqualene level.[11]
Squalene synthase (SQS) is a crucial enzyme in isoprenoid
biosynthesis that catalyzes the first committed step in ergo-
sterol biosynthesis, for which reductive dimerization of two
molecules of farnesyl pyrophosphate takes place to form squa-
lene. It has been determined that the precise mode of action
of WC-9 is as an inhibitor of the enzymatic activity of T. cruzi
SQS[11] by employing highly purified glycosomes and mito-
chondrial membrane vesicles obtained from T. cruzi epimasti-
gotes as the enzyme source.[12] WC-9 is a potent inhibitor of
both glycosomal and mitochondrial T. cruzi SQS, with IC50
values of 88 and 129 nm. The dose–response curves for the ac-
tivity of WC-9 against TcSQS are consistent with noncompeti-
tive inhibition with Ki =IC50; these Ki values are two to three
orders of magnitude lower than the KM values of the
substrates.[11]
[a] M. N. Chao, C. E. Matiuzzi, Dr. S. H. Szajnman, Prof. Dr. J. B. Rodriguez
Departamento de Quꢀmica Orgꢁnica and UMYMFOR (CONICET-FCEyN)
Facultad de Ciencias Exactas y Naturales
Universidad de Buenos Aires
Pabellꢂn 2, Ciudad Universitaria, C1428EHA, Buenos Aires (Argentina)
E-mail: jbr@qo.fcen.uba.ar
[b] M. Storey, C. Li, Prof. Dr. R. Docampo, Prof. Dr. S. N. J. Moreno
Center for Tropical and Emerging Global Diseases and
Department of Cellular Biology
An Apicompexan parasite such as Toxoplasma gondii, the
agent responsible for toxoplasmosis, lacks the mevalonate
pathway and uses a prokaryotic-type 1-deoxy-d-xylulose-5-
phosphate (DOXP) pathway instead to make isopentenyl pyro-
phosphate (IPP) and dimethylallyl pyrophosphate (DMAPP).
University of Georgia, Athens, GA, 30602 (USA)
Supporting Information for this article is available on the WWW under
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the target molecules and corresponding intermediates.
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The DOXP pathway is localized to the apicoplast and is essen-
tial.[13] It has been demonstrated that T. gondii does not synthe-
size cholesterol but imports it from the host,[14] which suggests
that inhibitors of the host SQS could potentially inhibit
T. gondii growth. The fact that WC-9 and closely related ana-
logues are growth inhibitors of T. gondii is in agreement with
other work that has shown that mevalonate pathway inhibitors
are active against Apicomplexan parasites such as Babesia
divergens,[15] Plasmodium falciparum,[15,16] Cryptosporidium
parvum,[17] and T. gondii;[18] this indicates that these parasites,
which lack the mevalonate pathway, are dependent on the
biosynthesis of the precursors of the isoprenoid pathway by
the host. In this regard, it has recently been demonstrated that
T. gondii acquires isoprenoid intermediates such as farnesyl di-
phosphate and/or geranylgeranyl diphosphate from the host
cell produced by the mevalonate pathway.[19]
diaryl amines.[26] Certainly, a variety of WC-9 analogues bearing
different substituents at either the A ring or the B ring have
been prepared by employing this protocol,[24] which is a reliable
alternative to obtain these types of compounds by avoiding
the use of expensive and not always commercially available
phenylboronic acids as starting materials.[27]
Results and Discussion
Therefore, following a classical approach, the structural varia-
tions considered were those that involved different substitu-
tions on the B ring as well as the relative position of the B ring
to the aliphatic chain. The introduction of an electron-with-
drawing moiety into the B ring such as the trifluoromethyl
group was the first structural modification considered. Then,
by employing commercially available 4-(benzyloxy)phenol (6),
this compound was converted into tetrahydropyranyl (THP)
ether derivative 7 in 96% yield by treatment with 2-bromoeth-
yl tetrahydro-2H-pyran-2-yl ether in a suspension of potassium
hydroxide in dimethyl sulfoxide by following a slightly modi-
fied Williamson reaction.[28] Removal of the protecting benzyl
(Bn) group was performed by treatment with hydrogen gas
(0.3 MPa) at room temperature in the presence of palladium
on charcoal to afford phenol 8 in 73% yield. Upon treatment
with 1-iodo-3-(trifluoromethyl)benzene in the presence of 5%
cuprous iodide, 10% picolinic acid, and potassium phosphate
according to the Buchwald protocol, 8 was transformed into
conveniently functionalized diaryl ether 9 in 86% yield. Buch-
wald coupling of 8 with 1-iodo-4-(trifluoromethyl)benzene
gave 10 in 32% yield. Compound 9 was deprotected by treat-
ment with pyridinium 4-toluenesulfonate (PPTS) in methanol
to afford corresponding free alcohol 11 in 62% yield. Treat-
ment of 11 with tosyl chloride (TsCl) in pyridine (py) gave tosy-
late 13 in 86% yield. Compound 13 was further transformed
into thiocyanate 15 by treatment with potassium thiocyanate
in DMF at 1008C in 36% yield (Scheme 1). In a similar strategy,
10 was transformed into alcohol 12, which was treated with
tosyl chloride to give 14. Compound 14 was finally trans-
formed into 16 by treatment with potassium thiocyanate, as
illustrated in Scheme 1.
Rationale
To date, the crystal structure of TcSQS with WC-9 is not avail-
able. However, the X-ray crystallographic structure of WC-9
bound to dehydrosqualene synthase from Staphylococcus
aureus has been recently published.[20] This enzyme catalyzes
dehydrosqualene formation, a metabolite that is further trans-
formed into staphyloxanthin. It has been postulated that WC-9
might bind into the same hydrophobic S2 pocket in TcSQS as
it does in dehydrosqualene synthase and keeps the same polar
interactions with the thiocyanate group.[20] Furthermore, it was
recently shown that is possible to obtain crystals of WC-9
bound to human SQS, but all attempts to do so with TcSQS
were unsuccessful.[21]
On the basis of the chemical structure of WC-9, we conduct-
ed meticulous structure activity/biological activity relationship
studies that led to the assumption that the phenoxyethyl thio-
cyanate moiety (colored in red in Figure 1) should be consid-
ered as the structure of the pharmacophore.[8–10,22–24] Although
WC-9 is able to impair parasitemia in murine models of Chagas
disease, the level of protection is not as efficient as that shown
by ketoconazole, which is used as a positive control.[25] This
lack of in vivo efficacy of WC-9 may be attributed to poor phar-
macokinetic properties, which indeed should be improved. In
this respect, the finding that structural variations in the B ring
of WC-9 have a marked influence on biological activity encour-
aged us to follow this approach. As a matter of fact, the intro-
duction of a fluorine atom in the B ring of WC-9 gives rise to
compounds 2 and 3, which have estimated logP values of 4.71
compared with a logP value of 4.51 for WC-9; this is indicative
of better distribution between water/octanol. In fact, com-
pounds 2 and 3 are both significantly more potent than WC-9
in in vitro assays (Figure 1).[23]
To study the influence of the polarity of the terminal phenyl
group, this ring was replaced by a naphthyl group to give
compounds 20 and 24, the estimated logP values of which
were both 5.2 compared to 4.2 for the WC-9 molecule. Buch-
wald coupling of 8 with either 2-bromonaphthalene or 1-bro-
monaphthalene afforded diaryl ether derivative 17 or 21 in
a low but reproducible yield of 18 or 32%, respectively. Follow-
ing the general strategy, each tetrahydropyranyl protecting
group present in 17 and 21 was cleaved by treatment with
pyridinium 4-toluenesulfonate to afford corresponding free al-
cohols 18 and 22 in good yields. These alcohols were tosylated
to give 19 and 23. Upon treatment with potassium thiocya-
nate, in separate experiments, these compounds were convert-
ed into target molecules 20 and 24, respectively, as illustrated
in Scheme 2.
The question that arises is how is it possible to optimize the
chemical structure of WC-9 without knowing the binding site
at the target enzyme? The availability of this information
would be very important for the rational design of more effec-
tive noncompetitive inhibitors structurally related to WC-9.
The Buchwald coupling reaction has proven to be a reliable
method to prepare asymmetric substituted diaryl ethers and
We recently described a pyridyl analogue of WC-9 in which
the nitrogen atom occupies the 3’’-position.[24] To complete the
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cacy as those compounds bear-
ing this group at the C-4’ posi-
tion.[24] Therefore, compounds
46–50, which are regioisomers
of WC-9 bearing either a chlorine
atom or a methoxy group at di-
verse positions of the terminal
ring, were prepared. The syn-
thetic strategy to obtain these
compounds is presented in
Scheme 4 and starts with already
described
3-iodophenoxyethyl
tetrahydro-2H-pyran-2-yl ether
(30) as the common starting ma-
terial.[24] This compound was
treated separately with 2-chloro-
phenol, 3-chlorophenol, 4-chlor-
ophenol, 2-methoxyphenol, and
3-methoxyphenol under the
usual Buchwald coupling proce-
dure to give expected asymmet-
ric diaryl ethers 31–35 in moder-
ate to good yields. Then, follow-
ing the general method in indi-
vidual experiments, each of
these compounds underwent
cleavage of the tetrahydropyran-
yl ring to give 36–40. Tosylation
afforded 41–45, and nucleophilic
displacement of the tosylate
group by treatment with potas-
sium thiocyanate afforded the
expected regioisomers of WC-9,
that is, compounds 46–50
(Scheme 4).
Scheme 1. Reagents and conditions: a) Br(CH2)2OTHP, KOH, DMSO, RT, 24 h, 96%; b) H2, Pd/C, EtOAc, RT, 4 h, 73%;
c) 1-iodo-3-(trifluoromethyl)benzene or 1-iodo-4-(trifluoromethyl)benzene, 5% CuI, 10% picolinic acid, K3PO4,
DMSO, 908C, 36 h; d) PPTS, MeOH, RT, 24 h; e) TsCl, py, 08C, 4 h; f) KSCN, DMF, 808C, 48 h.
Scheme 2. Reagents and conditions: a) 2-Bromonaphthalene, 5% CuI, 10% picolinic acid, K3PO4, DMSO, 908C, 24 h,
18%; b) PPTS, MeOH, RT, 4 h, 97%; c) TsCl, py, RT, 4 h, 67%; d) KSCN, DMF, 1008C, 3 h, 43%; e) 1-bromonaphtha-
lene, 5% CuI, 10% picolinic acid, K3PO4, DMSO, 908C, 24 h, 29%; f) PPTS, MeOH, RT, 4 h, 92%;. g) TsCl, py, RT, 4 h,
91%; h) KSCN, DMF, 1008C, 3 h, 43%.
Pyridyl regioisomer analogues
structure/activity analysis, it was decided to prepare the corre-
sponding pyridyl derivative in which the nitrogen atom was
placed at the C-2’’ position to give target molecule 29. Incor-
poration of the pyridyl unit was performed through Buchwald
coupling between the already depicted 4-iodophenoxyethyl
tetrahydro-2H-pyran-2-yl ether (25) and 2-hydroxypyridine to
produce tetrahydropyranyl derivative 26 in 48% yield. Once
this adduct was at hand, similarly to the preparation of 16 and
17, cleavage of the tetrahydropyranyl protecting group of 26
gave free alcohol 27 in 60% yield. Tosylation of 27 produced
28 in 90% yield, and further substitution of the tosylate group
by the thiocyanate ion afforded
of WC-9 such as 60–62 were other interesting structural varia-
tions considered as polar compounds (estimated logP=2.82)
with the pharmacophore in the molecules intact. In this case,
the synthesis of the compounds was not straightforward, par-
ticularly, for the preparation of 62, as discussed below. Then,
compound 30 was used as a committed starting material,
which was separately treated with 2-hydroxypyridine, 3-hy-
droxypyridine, and 4-hydroxypyridine under Buchwald cou-
pling reaction conditions to give rise to coupled products 51–
53 in moderate yields. These compounds were easily depro-
tected by treatment with pyridinium 4-toluenesulfonate to
29 in 61% yield (Scheme 3).
At the present time, the opti-
mal relative position of the ter-
minal phenyl group of WC-9 is
not conclusive. We recently
demonstrated that analogues for
which the phenyl group is in the
C-3’ position exhibit antiparasitic
Scheme 3. Reagents and conditions: a) 2-Hydroxypyridine (1.2 equiv) 5% CuI, 10% picolinic acid, K3PO4, DMSO,
activity almost of the same effi- 808C, 24 h, 48%; b) PPTS, MeOH, RT, 16 h, 60%; c) TsCl, py, 08C, then RT, 90%; d) KSCN, DMF, 1008C, 61%.
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lar to that of our lead compound WC-9.[9] Then, it
would seem of interest to evaluate corresponding
bromine analogue 68. Thus, the reaction of 2,4-dibro-
mophenol with bromoethyl tetrahydropyranyl ether
afforded 65, which after hydrolysis of the tetrahydro-
pyranyl group followed by treatment with tosyl chlo-
ride and further nucleophilic attack of potassium thi-
ocyanate led to compound 68 (Scheme 7).
Finally, as a part of the strategy to evaluate a very
simple structure, pyridyl derivative 72 was considered
as a polar and very simple structure having an esti-
mated logP value of 1.32. This compound was pre-
pared straightforwardly from 3-hydroxypyridine fol-
lowing the general method, as described in
Scheme 8.
Scheme 4. Reagents and conditions: a) 5% CuI, 10% picolinic acid, K3PO4, DMSO, 808C,
24 h; b) PPTS, MeOH, RT, 16 h; c) TsCl, py, 08C, 6 h; d) KSCN, DMF, 1008C, 6 h.
Biological evaluation of these new WC-9 analogues
was very encouraging. Title compounds 15 and 16
were potent growth inhibitors of the intracellular
yield corresponding free alcohols 54–56. Upon treatment with
an excess amount of tosyl chloride, 54 and 55 were converted
into tosylates 57 and 58, respectively, whereas the correspond-
ing tosylate of alcohol 56 could not be obtain owing to forma-
tion of a tosylpyridinium ion, which not only consumes the re-
Scheme 6. Reagents and conditions: a) NaN3, DMF, 1008C, 6 h, 35%.
agent but also forms an extremely polar species that hinders
the reaction.[29] This problem was circumvented by
the preparation of bromide 59. Then, upon treatment
with N-bromosuccinimide (NBS) and triphenylphos-
phine, 56 was converted into 69.[30] Compounds 60–
62 were obtained in good yields by treatment of to-
sylates 57 and 58 or bromide 59 with potassium thi-
ocyanate (Scheme 5).
The group in WC-9 and other closely related ana-
Scheme 7. Reagents and conditions: a) KOH, BrCH2CH2OTHP, DMSO, RT, 16 h, 46%;
b) PPTS, MeOH, RT, 16 h, 70%; c) TsCl, py, 08C, 6 h, 84%; d) KSCN, DMF, 1008C, 6 h, 75%.
logues seems to be essential for biological activity. To
study the influence of this group on biological
action, its replacement with another electrophilic
group such as the azido moiety was considered.
Thus, treatment of tosylate 63 with sodium azide in DMF af-
forded compound 64 (Scheme 6).
Previous biological data indicates that a simplified analogue
of WC-9 (i.e., 2,4-dichlorophenoxyethyl thiocyanate), in which
the aromatic skeleton is a 2,4-dichlorophenyl group instead of
a 4-phenoxyphenyl moiety, exhibits anti-Chagasic activity simi-
form of T. cruzi, which is the clinically more relevant replicative
form of the parasite. Certainly, both of these compounds bear-
ing an electron-withdrawing group at the C-3’’ and C-4’’ posi-
tions exhibited ED50 values quite similar to that of WC-9, used
as a positive control, under the same assay conditions. Com-
pounds 15 and 16 were also potent inhibitors of T. gondii (ta-
chyzoites) growth, and possess ED50 values at the
very low micromolar level (1.6 and 2.0 mm, respective-
ly). The introduction of a naphthyl group as a terminal
B ring of WC-9 to give 20 and 24 was not beneficial,
as they were devoid of action against amastigotes of
T. cruzi. Interestingly, 20 and 24 exhibited potent in-
hibitory action against tachyzoites of T. gondii with
ED50 values of 2.3 and 2.9 mm, respectively. Surprising-
ly, in spite of having the pharmacophore moiety in
the structure, pyridyl derivative 29 was devoid of an-
tiparasitic activity against both T. cruzi and T. gondii.
With the exception of 47, which presented vanishing
biological activity, regioisomers 46–50 bearing elec-
Scheme 5. Reagents and conditions: a) 5% CuI, 10% picolinic acid, K3PO4, DMSO, 808C,
24 h; b) PPTS, MeOH, RT, 16 h; c) NBS, Ph3P, CH2Cl2, 08C, 24%; d) TsCl, py, 08C, 6 h;
e) KSCN, DMF, 1008C, 6 h.
tron-donating groups at the terminal ring showed
potent inhibitory action against T. cruzi and T. gondii;
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to access these compounds was the Buchwald coupling reac-
tion, which has proven to be reliable not only to obtain WC-9
derivatives modified at the B ring but also to synthesize deriva-
tives substituted at the A ring in the future. The promising bio-
logical activity observed for the target molecules together with
the drug-like character of these compounds motivate new
studies to find an optimized chemical structure with a known
and precise mode of action. Efforts in this direction are
currently being pursued in our laboratory.
Scheme 8. Reagents and conditions: a) KOH, BrCH2CH2OTHP, DMSO, RT, 16 h,
31%; b) PPTS, MeOH, RT, 16 h, 46%; c) TsCl, py, 08C, 6 h, 69%; d) KSCN, DMF,
1008C, 6 h, 42%.
Experimental Section
compounds 48 and 50 showed efficacy similar to that of WC-9.
Interestingly, regioisomers 46–50 were all very potent growth
inhibitors of tachyzoites of T. gondii and showed ED50 values of
2.1, 3.9, 2.8, and 4.0 mm, respectively, as shown in Table 1. Only
pyridyl analogue 61 showed potent antiparasitic action with
ED50 values of 7.5 and 3.7 mm against T. cruzi and T. gondii, re-
spectively. The rest of the pyridyl derivatives, that is, 60 and
62, were free of antiparasitic activity. Evidently, the relative po-
sition of the nitrogen atom in the B ring plays a key role in
modulating the biological activity. Unexpectedly, dibromo de-
rivative 68 was inactive as an antiparasitic agent on the basis
of the results previously exhibited by the parent dichloro ana-
logue.[9] Finally, simple pyridyl derivative 72 was also devoid of
antiparasitic activity. These data are in agreement with our pre-
vious results[24] and confirm that the para-aryl substitution pat-
tern of WC-9 is not necessary for effective biological activity.
The results are presented in Table 1.
General methods
The glassware used in air- and/or moisture-sensitive reactions was
flame dried, and the reactions were performed under a dry argon
atmosphere. Unless otherwise noted, chemicals were commercially
available and were used without further purification. Anhydrous
DMF and anhydrous dimethyl sulfoxide were used as supplied
from Aldrich. Nuclear magnetic resonance spectra were obtained
by using a Bruker AM-500 MHz spectrometer. Chemical shifts are
reported in parts per million (d) relative to tetramethylsilane.
13C NMR spectra were fully decoupled. High-resolution mass spec-
tra were recorded by using a Bruker micrOTOF-Q II spectrometer,
which is a hybrid quadrupole time of flight mass spectrometer
with MS–MS capability. Melting points were determined by using
a Fisher–Johns apparatus. Column chromatography was performed
with E. Merck silica gel plates (Kieselgel 60, 230–400 mesh). Analyti-
cal thin-layer chromatography was performed by employing
0.2 mm coated commercial silica gel plates (E. Merck, DC-Alumi-
num sheets, Kieselgel 60 F254).
Conclusions
Syntheses
It can be concluded that most of the compounds studied
behave as anti-T. cruzi agents as well as anti-Toxoplasma
agents favoring the activity against T. gondii. The key reaction
4-Benzyloxyphenoxyethyl tetrahydro-2H-pyran-2-yl ether (7): A
solution of 4-(benzyloxy)phenol (6; 5.00 g, 25.0 mmol) in DMSO
(25 mL) was treated with KOH (2.81 g, 50.0 mmol). The mix-
ture was stirred at room temperature for 5 min. Then, bro-
moethyl tetrahydropyranyl ether (6.27 g, 30.0 mmol) was
added, and the mixture was stirred at room temperature
overnight. The mixture was partitioned between H2O
Table 1. Biological activity of WC-9 analogues against T. cruzi (amastigotes),
T. gondii (tachyzoites), and Vero cells.
Compound
ED50 [mm][a]
SI[b]
T. cruzi
T. gondii
Cytotoxicity
T. cruzi T. gondii
(70 mL) and CH2Cl2 (70 mL). The aqueous phase was extract-
ed with CH2Cl2 (2ꢂ40 mL). The combined organic layer was
washed with a saturated solution of NaCl (5ꢂ50 mL), dried
(MgSO4), and concentrated. The product was purified by
column chromatography (hexane/EtOAc 19:1) to yield pure
7 (7.89 g, 96%) as a colorless oil: Rf =0.63 (hexane/EtOAc
15
16
20
24
29
46
47
48
49
50
60
61
62
64
68
71
10.0Æ2.5
9.2Æ1.8
1.66Æ0.35
1.86Æ0.38
2.25Æ0.84
2.87Æ0.19
>50.0
>50.0
104.7Æ7.8
70.1Æ7.6
>200.0
>50.0
>200.0
98.4Æ5.8
115.7Æ39.8
96.2Æ37.5
>200.0
124.0Æ12.0
>200.0
>200.0
>50.0
>5.0 >31.1
5.4 >26.7
>10.0
>10.4
>7
46.5
24.4
>10.0
>10.0
11.94Æ0.38
>20.0
>10.0
1
2.13Æ0.38
>10.0
4.2
23.4
7:3); H NMR (200 MHz, CDCl3): d=1.46–1.88 (m, 6H, H-3’’’,
H-4’’’, H-5’’’), 3.45–3.61 (m, 1H, H-6’’’a), 3.70–4.05 (m, 3H, H-
1, H-6’’’b), 4.05–4.18 (m, 2H, H-2), 4.72 (distorted (dist.) t, J=
3.2 Hz, 1H, H-2’’’), 5.02 (s, 2H, PhCH2O-), 6.87 (d, J=9.3 Hz,
2H, H-3’), 6.92 (d, J=9.3 Hz, 2H, H-2’), 7.24–7.47 ppm (m,
5H, aromatic H); 13C NMR (125.77 MHz, CDCl3): d=19.4 (C-
4’’’), 25.4 (C-5’’’), 30.5 (C-3’’’), 62.2 (C-6’’’), 65.9 (C-1), 68.1 (C-
2), 70.7 (PhCH2O-), 99.0 (C-2’’’), 115.7 (C-3’), 115.8 (C-2’, C-3’),
127.5 (C-2’’), 127.9 (C-4’’), 128.5 (C-3’’), 137.3 (C-1’’), 153.1 (C-
1’), 153.3 ppm (C-4’); HRMS (ESI): m/z: calcd for C20H24O4Na:
351.1572 [M+Na]+; found: 351.1574.
6.27Æ0.75
3.86Æ0.28
2.79Æ0.42
4.02Æ0.27
15.7
9.9
11.0
25.2
41.5
23.9
11.7Æ2.52
8.75Æ0.33
>10.0
>10.0
7.49Æ1.39
>10.0
>10.0
>20.0
>10.0
3.71Æ0.92
>10.0
>10.0
>10.0
>10.0
16.6
33.5
>200
WC-9
benznidazole
atovaquone
5.0Æ1.1
4.8Æ0.41
82.6Æ7.3
–
–
16.5
–
20.7
–
1.92Æ0.55
–
–
0.032Æ0.019
–
–
4-Hydroxyphenoxyethyl tetrahydro-2H-pyran-2-yl ether
(8): A solution of 7 (8.150 g, 24.8 mmol) in EtOAc (40 mL) in
the presence of 5% Pd/C (40 mg) was treated with H2
[a] Data are the meanÆSD of one experiment carried out in triplicate. [b] Selec-
tivity index: (ED50cytotox.)/(ED50parasite).
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(0.3 MPa). The mixture was stirred at room temperature for 4 h.
The mixture was filtered off and concentrated. The residue was
purified by column chromatography (silica gel, hexane/EtOAc 4:1)
to produce pure 8 (4.301 g, 73%) as a colorless oil: Rf =0.27
4-[(3-Trifluoro)phenoxy]phenoxyethanol (11): A solution of 9
(1.96 g, 5.13 mmol) in MeOH (50 mL) was treated with PPTS
(30 mg). The mixture was stirred at room temperature overnight.
Then, H2O (70 mL) was added, and the mixture was extracted with
CH2Cl2 (3ꢂ50 mL). The combined organic layer was washed with
brine (3ꢂ50 mL), dried (MgSO4), and concentrated. The residue
was purified by column chromatography (silica gel, hexane/EtOAc
17:1) to give pure alcohol 11 (944.0 mg, 62%) as a colorless oil:
1
(hexane/EtOAc 7:3); H NMR (500.13 MHz, CDCl3): d=1.51–1.68 (m,
4H, H-4’’, H-5’’), 1.72–1.77 (m, 1H, H-3’’a), 1.81–1.88 (m, 1H, H-
3’’b), 3.51–3.56 (m, 1H, H-6’’a), 3.79 (ddd, J=11.1, 6.4, 4.1 Hz, 1H,
H-6’’’b), 3.92 (m, 1H, H-1a), 4.03 (m, 1H, H-1b), 4.11 (m, 2H, H-2),
4.71 (t, J=3.7 Hz, 1H, H-2’’), 6.75 (d, J=9.1 Hz, 2H, H-3’), 6.81 ppm
(d, J=8.9 Hz, 2H, H-2’); 13C NMR (125.77 MHz, CDCl3): d=19.3 (C-
4’’), 25.4 (C-5’’), 30.5 (C-3’’), 62.2 (C-6’’), 66.0 (C-1), 68.1 (C-2), 99.0
(C-2’’), 115.9 (C-2’), 116.0 (C-3’), 149.7 (C-4’), 153.0 ppm (C-1’);
HRMS (ESI): m/z: calcd for C13H18O4Na: 261.1103 [M+Na]+; found:
261.1088.
1
Rf =0.30 (hexane/EtOAc 7:3); H NMR (500.13 MHz, CDCl3): d=2.03
(t, J=5.5 Hz, 1H, -OH), 3.99 (m, 2H, H-1), 4.01 (t, J=4.5 Hz, 2H, H-
2), 6.94 (d, J=9.1 Hz, 2H, H-2’), 7.00 (d, J=9.1 Hz, 2H, H-3’), 7.10
(dd, J=8.3, 2.4 Hz, 1H, H-6’’), 7.17 (t, J=1.9 Hz, 1H, H-2’’), 7.29 (d,
J=7.7 Hz, 2H, H-4’’), 7.40 ppm (t, J=8.0 Hz, 2H, H-5’’); 13C NMR
(125.77 MHz, CDCl3): d=61.5 (C-1), 69.7 (C-2), 114.1 (q, J=3.9 Hz,
C-2’’), 115.9 (C-2’), 119.0 (q, J=3.8 Hz, C-4’’), 120.5 (C-5’’), 130.2 (C-
6’’), 149.5 (C-4’), 155.5 (C-1’), 158.8 ppm (C-1’’); HRMS (ESI): m/z:
calcd for C15H13O3F3Na: 321.0714 [M+Na]+; found: 321.0703.
4-[(3-Trifluoro)phenoxy]phenoxyethyl tetrahydro-2H-pyran-2-yl
ether (9): A mixture of 8 (1.50 g, 6.29 mmol), 1-iodo-3-(trifluorome-
thyl)benzene (2.06 g, 7.56 mmol), CuI (120 mg, 0.63 mmol), 2-pico-
linic acid (155 mg, 1.26 mmol), and K3PO4 (2.68 g, 12.6 mmol)
under anhydrous conditions was evacuated and backfilled with
argon (2ꢂ). Then, DMSO was added (15.0 mL), and the mixture was
stirred vigorously at 808C for 36 h. The mixture was cooled to
room temperature and partitioned between EtOAc (20 mL) and
H2O (20 mL). The aqueous layer was extracted with EtOAc (2ꢂ
20 mL). The combined organic phase was washed with brine (5ꢂ
50 mL), dried (MgSO4), and concentrated. The product was purified
by column chromatography (silica gel, hexane/EtOAc 19:1) to
afford pure 9 (2.06 g, 86%) as a colorless oil: Rf =0.64 (hexane/
4-[(4-Trifluoro)phenoxy]phenoxyethanol (12): A solution of 10
(229 mg, 0.60 mmol) in MeOH (10 mL) was treated with PPTS
(30 mg) as described in the method for the preparation of 11. Pu-
rification by column chromatography (silica gel, hexane/EtOAc
17:1) afforded pure alcohol 12 (174 mg, 97%) as a white solid: Rf =
1
0.20 (hexane/EtOAc 7:3); H NMR (500.13 MHz, CDCl3): d=3.99 (m,
2H, H-1), 4.10 (t, J=4.5 Hz, 2H, H-2), 6.94 (d, J=9.1 Hz, 2H, H-2’),
6.98 (d, J=8.5 Hz, 2H, H-2’’), 7.01 (d, J=9.1 Hz, 2H, H-3’), 7.54 ppm
(d, J=8.6 Hz, 2H, H-3’’); 13C NMR (125.77 MHz, CDCl3): d=61.5 (C-
1), 69.7 (C-2), 115.8 (C-2’), 116.9 (C-3’), 121.6 (C-2’’), 127.0 (q, J=
3.7 Hz, C-3’’), 149.1 (C-4’), 155.7 (C-1’), 161.4 ppm (C-1’’); 19F NMR
(470.54 MHz, CDCl3): d=À61.68 ppm; HRMS (ESI): m/z: calcd for
C15H13F3NaO3 321.0714 [M+Na]+; found: 321.0719.
1
EtOAc 7:3); H NMR (500.13 MHz, CDCl3): d=1.53–1.68 (m, 4H, H-
4’’’, H-5’’’), 1.72–1.78 (m, 1H, H-3’’’a), 1.81–1.87 (m, 1H, H-3’’’b), 3.53
(m, 1H, H-6’’’a), 3.82 (ddd, J=11.2, 6.3, 4.2 Hz, 1H, H-6’’’b), 3.91
(ddd, J=11.3, 8.2, 3.1 Hz, 1H, H-1a), 4.07 (ddd, J=11.1, 4.9, 4.3 Hz,
1H, H-1b), 4.16 (m, 2H, H-2), 4.72 (t, J=3.6 Hz, 1H, H-2’’’), 6.94 (d,
J=9.3 Hz, 2H, H-2’), 7.98 (d, J=9.3 Hz, 2H, H-3’), 7.09 (dd, J=8.2,
2.1 Hz, 1H, H-6’’), 7.16 (t, J=1.9 Hz, 1H, H-2’’), 7.28 (dt, J=7.8,
0.7 Hz, 2H, H-4’’), 7.39 ppm (t, J=8.0 Hz, 2H, H-5’’); 13C NMR
(125.77 MHz, CDCl3): d=19.4 (C-4’’’), 25.4 (C-5’’’), 30.5 (C-3’’’), 62.2
(C-6’’’), 65.9 (C-1), 67.9 (C-2), 99.0 (C-2’’’), 114.0 (q, J=3.9 Hz, C-2’’),
116.0 (C-2’), 118.9 (q, J=3.8 Hz, C-4’’), 120.4 (C-5’’), 130.1 (C-6’’),
149.1 (C-4’), 155.8 (C-1’), 160.0 ppm (C-1’’); 19F NMR (470.54 MHz,
CDCl3): d=À62.71 ppm; HRMS (ESI): m/z: calcd for C20H21O4F3Na:
405.129 [M+Na]+; found: 405.1285.
4-[(3-Trifluoro)phenoxy]phenoxyethyl 4-toluenesulfonate (13):
TsCl (1.72 g, 9.02 mmol) was added to a solution of alcohol 11
(922 mg, 3.09 mmol) in pyridine (5.0 mL) at 08C. The mixture was
stirred at room temperature for 4 h. Then, 5% HCl (50 mL) was
added, and the mixture was stirred for an additional 1 h. The mix-
ture was extracted with CH2Cl2 (50 mL), and the organic layer was
washed with 5% HCl (3ꢂ50 mL) and H2O (3ꢂ50 mL). The organic
phase was dried (MgSO4) and concentrated. The product was puri-
fied by column chromatography (silica gel, hexane/EtOAc 19:1) to
afford tosylate 13 (1.29 g, 86%) as a colorless oil: Rf =0.50 (hexane/
EtOAc 7:3); 1H NMR (500.13 MHz, CDCl3): d=2.45 (s, 3H, PhCH3),
4.16 (m, 2H, H-1), 4.38 (m, 2H, H-2), 6.81 (d, J=9.1 Hz, 2H, H-2’),
6.96 (d, J=9.1 Hz, 2H, H-3’), 7.08 (dd, J=8.2, 2.3 Hz, 1H, H-6’’), 7.15
(t, J=1.9 Hz, 1H, H-2’’), 7.29 (d, J=7.7 Hz, 2H, H-4’’), 7.35 (d, J=
8.0 Hz, 2H, H-3’’’), 7.40 (t, J=8.0 Hz, 2H, H-5’’), 7.83 ppm (d, J=
8.3 Hz, 2H, H-2’’’); 13C NMR (125.77 MHz, CDCl3): d=21.6 (CH3), 66.0
(C-1), 68.0 (C-2), 114.2 (q, J=3.9 Hz, C-2’’), 116.0 (C-2’), 119.1 (q, J=
3.9 Hz, C-4’’), 120.6 (C-6’’), 121.1 (C-3’), 128.0 (C-2’’’), 129.9 (C-3’’’),
130.2 (C-5’’), 132.1 (q, J=32.6 Hz, C-3’’), 132.9 (C-4’’’), 145.0 (C-1’’’),
149.7 (C-4’), 154.8 (C-1’), 158.7 ppm (C-1’’); 19F NMR (470.59 MHz,
CDCl3): d=À62.71 ppm (s); HRMS (ESI): m/z: calcd for
C22H19F3NaO5S 475.0803 [M+Na]+; found: 475.0775.
4-[(4-Trifluoro)phenoxy]phenoxyethyl tetrahydro-2H-pyran-2-yl
ether (10): A mixture of 8 (433 mg, 1.82 mmol), 1-iodo-4-(trifluoro-
methyl)benzene (594 mg, 2.18 mmol), CuI (34.6 mg, 0.36 mmol), 2-
picolinic acid (44.8 mg, 0.36 mmol), and K3PO4 (773 g, 3.64 mmol)
in DMSO (6.0 mL) was treated as described in the method for the
preparation of 9 for 13 days. The residue was purified by column
chromatography (silica gel, hexane/EtOAc 19:1) to give pure 10
(225 g, 32%) as a colorless oil: Rf =0.60 (hexane/EtOAc 7:3);
1H NMR (500.13 MHz, CDCl3): d=1.53–1.67 (m, 4H, H-4’’’, H-5’’’),
1.73–1.79 (m, 1H, H-3’’’a), 1.82–1.88 (m, 1H, H-3’’’b), 3.54 (m, 1H, H-
6’’’a), 3.82 (ddd, J=11.2, 6.4, 4.4 Hz, 1H, H-6’’’b), 3.91 (ddd, J=11.3,
8.2, 3.1 Hz, 1H, H-1a), 4.07 (m, 1H, H-1b), 4.16 (m, 2H, H-2), 4.72 (t,
J=3.6 Hz, 1H, H-2’’’), 6.95 (d, J=9.3 Hz, 2H, H-2’), 6.97 (m, 2H, H-
2’’), 6.99 (d, J=9.3 Hz, 2H, H-3’), 7.56 ppm (d, J=8.9 Hz, 2H, H-3’’);
13C NMR (125.77 MHz, CDCl3): d=19.4 (C-4’’’), 25.4 (C-5’’’), 30.5 (C-
3’’’), 62.2 (C-6’’’), 65.8 (C-1), 67.9 (C-2), 99.0 (C-2’’’), 116.0 (C-2’),
116.8 (C-3’), 121.5 (C-2’’), 127.0 (q, J=3.8 Hz, C-3’’), 148.8 (C-4’),
156.0 (C-1’), 161.5 ppm (C-1’’); 19F NMR (470.59 MHz, CDCl3): d=
À61.66 ppm; HRMS (ESI): m/z: calcd for C20H21F3NaO4 405.1290
[M+Na]+; found: 405.1286.
4-[(4-Trifluoro)phenoxy]phenoxyethyl 4-toluenesulfonate (14):
TsCl (352 mg, 1.84 mmol) was added to a solution of alcohol 12
(176 mg, 0.59 mmol) in pyridine (3.0 mL) at 08C. The mixture was
treated as detailed in the method for the preparation of 13 to
afford pure tosylate 14 (249 mg, 93%) as a colorless oil: Rf =0.50
(hexane/EtOAc 7:3); 1H NMR (500.13 MHz, CDCl3): d=2.45 (s, 3H,
PhCH3), 4.16 (m, 2H, H-1), 4.38 (m, 2H, H-2), 6.81 (d, J=9.1 Hz, 2H,
H-2’), 6.966 (d, J=8.5 Hz, 2H, H-2’’), 6.970 (d, J=9.1 Hz, 2H, H-3’),
&
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7.36 (d, J=8.0 Hz, 2H, H-3’’’), 7.54 (d, J=8.6 Hz, 2H, H-3’’),
7.83 ppm (d, J=8.3 Hz, 2H, H-2’’’); 13C NMR (125.77 MHz, CDCl3):
d=21.7 (PhCH3) 66.0 (C-1), 68.0 (C-2), 116.0 (C-2’), 116.9 (C-3’),
121.5 (C-2’’), 127.0 (q, J=3.8 Hz, C-3’’), 128.0 (C-2’’’), 129.9 (C-3’’’),
132.9 (C-4’’’), 145.0 (C-1’’’), 149.4 (C-4’), 155.0 (C-1’), 161.3 ppm (C-
1’’); 19F NMR (470.54 MHz, CDCl3): d=À61.69 ppm; HRMS (ESI):
m/z: calcd for C22H19O5F3SNa: 475.0803 [M+Na]+; found: 475.0809.
115.9 (C-2’), 119.3 (C-3’’), 121.0 (C-3’), 124.3 (C-6’’), 126.5 (C-8’’),
127.0 (C-7’’), 127.7 (C-5’’), 129.8 (C-4’’), 129.8 (C-10’’), 134.3 (C-9’’),
150.2 (C-4’), 155.4 (C-1’), 156.4 ppm (C-2’’); HRMS (ESI): m/z: calcd
for C23H24NaO4 387.1572 [M+Na]+; found: 387.1558.
b-Naphthyloxyphenoxyethanol (18): A solution of 17 (358 mg,
0.98 mmol) in MeOH (10 mL) was treated with PPTS (20 mg) as de-
scribed in the method for the preparation of 11. The residue was
purified by column chromatography (silica gel, hexane/EtOAc 17:1)
to yield alcohol 18 (266 mg, 97%) as a white solid: Rf =0.22
(hexane/EtOAc); 1H NMR (500.13 MHz, CDCl3): d=3.99 (dist.t, J=
4.2 Hz, 2H, H-1), 4.10 (dist.t, J=4.5 Hz, 2H, H-2), 6.95 (d, J=9.0 Hz,
2H, H-2’), 7.05 (d, J=9.2 Hz, 2H, H-3’), 7.18 (d, J=2.4 Hz, 1H, H-1’’),
7.25 (dd, J=9.0, 2.6 Hz, H-3’’), 7.40 (ddd, J=8.1, 6.8, 1.3 Hz, 1H, H-
6’’), 7.43 (ddd, J=8.2, 6.8, 1.3 Hz, 1H, H-7’’), 7.66 (dd, J=8.1, 0.7 Hz,
1H, H-8’’), 7.80 (d, J=8.2 Hz, 1H, H-4’’), 7.81 ppm (d, J=9.0 Hz, 1H,
H-5’’); 13C NMR (125.77 MHz, CDCl3): d=61.6 (C-1), 69.7 (C-2), 112.4
(C-1’’), 115.7 (C-2’), 119.4 (C-3’’), 121.0 (C-3’), 124.4 (C-6’’), 126.5 (C-
8’’), 127.0 (C-7’’), 127.7 (C-5’’), 129.8 (C-4’’), 129.8 (C-10’’), 134.3 (C-
9’’), 150.5 (C-4’), 155.1 (C-1’), 156.3 ppm (C-2’’); HRMS (ESI): m/z:
calcd for C18H17O3 281.1178 [M+H]+; found: 281.1166.
4-[(3-Trifluoro)phenoxy]phenoxyethyl thiocyanate (15): A solu-
tion of tosylate 13 (1.290 g, 2.85 mmol) in anhydrous DMF (10 mL)
was treated with KSCN (1.390 g, 14.3 mmol). The mixture was
heated at 1008C for 48 h. The mixture was allowed to cool to
room temperature and H2O (20 mL) was added. The aqueous
phase was extracted with CH2Cl2 (2ꢂ30 mL), and the combined or-
ganic layer was washed with brine (5ꢂ30 mL) and H2O (2ꢂ30 mL),
dried (MgSO4), and concentrated. The residue was purified by
column chromatography (silica gel, hexane/EtOAc 19:1) to give
pure 15 (346 mg, 36%) as a colorless oil: Rf =0.51 (hexane/EtOAc
7:3); 1H NMR (500.13 MHz, CDCl3): d=3.35 (t, J=5.8 Hz, 2H, H-1),
4.33 (t, J=5.8 Hz, 2H, H-2), 6.95 (d, J=9.1 Hz, 2H, H-2’), 7.01 (d, J=
9.1 Hz, 2H, H-3’), 7.11 (dd, J=8.2, 2.3 Hz, 1H, H-6’’), 7.18 (t, J=
2.0 Hz, 1H, H-2’’), 7.30 (d, J=7.7 Hz, 2H, H-4’’), 7.41 ppm (t, J=
8.0 Hz, 2H, H-5’’); 13C NMR (125.77 MHz, CDCl3): d=33.2 (C-1), 66.4
(C-2), 111.6 (SCN), 114.3 (q, J=3.9 Hz, C-2’’), 116.1 (C-2’), 119.2 (q,
J=3.8 Hz, C-4’’), 120.6 (C-5’’), 123.7 (q, J=272.4 Hz, CF3), 130.2 (C-
6’’), 132.1 (q, J=32.6 Hz, C-3’’), 150.1 (C-4’), 154.6 (C-1’), 158.6 ppm
(C-1’’); 19F NMR (470.54 MHz, CDCl3): d=À62.70 ppm; HRMS (ESI):
m/z: calcd for C16H12O2NSF3Na: 362.0439 [M+Na]+; found:
362.0428.
b-Naphthyloxyphenoxyethyl 4-toluenesulfonate (19): A solution
of alcohol 18 (286 mg, 1.02 mmol) in pyridine (5 mL) was treated
with TsCl (547 mg, 2.87 mmol) at 08C as described in the method
for the preparation of 13.Purification of the crude compound by
column chromatography afforded tosylate 19 (295 mg, 67%) as
a white solid: Rf =0.50 (hexane/EtOAc 7:3); 1H NMR (500.13 MHz,
CDCl3): d=2.45 (s, 3H, CH3), 4.16 (m, 2H, H-1), 4.38 m, 2H, H-2),
6.81 (d, J=9.1 Hz, 2H, H-2’), 7.00 (d, J=9.1 Hz, 2H, H-3’), 7.17 (d,
J=2.5 Hz, 1H, H-1’’), 7.23 (dd, J=8.8, 2.6 Hz, 1H, H-3’’), 7.36 (d, J=
8.0 Hz, 2H, H-3’’’), 7.38 (ddd, J=8.0, 6.8, 1.2 Hz, 1H, H-6’’), 7.44
(ddd, J=8.1, 6.9, 1.3 Hz, 1H, H-7’’), 7.66 (dd, J=8.2, 0.5 Hz, 1H, H-
8’’), 7.80 (d, J=8.1 Hz, 1H, H-4’’), 7.81 (d, J=9.0 Hz, 1H, H-5’’),
7.84 ppm (d, J=8.3 Hz, 2H, H-2’’’); 13C NMR (125.77 MHz, CDCl3):
d=21.7 (CH3), 66.1 (C-1), 68.1 (C-2), 112.5 (C-1’’), 115.8 (C-2’), 119.4
(C-3’’), 120.9 (C-3’), 124.5 (C-6’’), 126.5 (C-8’’), 127.0 (C-7’’), 127.7 (C-
5’’), 128.1 (C-2’’’), 129.8 (C-4’’), 129.9 (C-10’’), 129.9 (C-3’’’), 132.9 (C-
4’’’), 134.3 (C-9’’), 145.0 (C-1’’’), 150.8 (C-4’), 154.4 (C-1’), 158.9 ppm
(C-2’’); HRMS (ESI): m/z: calcd for C25H22O5SNa: 457.1086 [M+Na]+;
found: 457.1077.
4-[(4-Trifluoro)phenoxy]phenoxyethyl thiocyanate (16): A solu-
tion of tosylate 14 (249 mg, 0.55 mmol) in anhydrous DMF (4 mL)
was treated with KSCN (266 mg, 2.73 mmol). The mixture was
heated at 1008C for 48 h. The reaction was worked up as detailed
in the method for the preparation of 15. The residue was purified
by column chromatography (silica gel, hexane/EtOAc 19:1) to give
pure 16 (76 mg, 41%) as a colorless oil: Rf =0.53 (hexane/EtOAc
7:3); 1H NMR (500.13 MHz, CDCl3): d=3.35 (t, J=5.8 Hz, 2H, H-1),
4.33 (t, J=5.8 Hz, 2H, H-2), 6.95 (d, J=9.2 Hz, 2H, H-2’), 6.99 (d, J=
8.4 Hz, 2H, H-2’’), 7.03 (d, J=9.2 Hz, 2H, H-3’), 7.55 ppm (d, J=
8.4 Hz, 2H, H-3’’); 13C NMR (125.77 MHz, CDCl3): d=33.2 (C-1), 66.4
(C-2), 111.6 (SCN), 116.1 (C-2’), 117.0 (C-3’), 121.6 (C-2’’), 127.1 (q, J=
3.8 Hz, C-3’’), 149.7 (C-4’), 154.8 (C-1’), 161.2 ppm (C-1’’); 19F NMR
(470.54 MHz, CDCl3): d=À61.70 ppm; HRMS (ESI): m/z: calcd for
C16H12O2NSF3Na: 362.0439 [M+Na]+; found: 362.0419.
b-Naphthyloxyphenoxyethyl thiocyanate (20): A solution of 19
(295 mg, 0.68 mmol) in anhydrous DMF (5 mL) was treated with
KSCN (350 mg, 3.60 mmol) as detailed in the method for the prep-
aration of 15. The residue was purified by column chromatography
(silica gel, hexane/EtOAc 9:1) to give pure 20 (93.3 mg, 43%) as
b-Naphthyloxyphenoxyethyl tetrahydro-2H-pyran-2-yl ether
(17): A mixture of 8 (889 mg, 3.73 mmol), 2-bromonaphthalene
(111 mg, 0.54 mmol), CuI (79 mg, 0.42 mmol), 2-picolinic acid
(91.5 mg, 0.74 mmol), and K3PO4 (1.53 g, 7.22 mmol) in DMSO
(6 mL) was treated as detailed in the method for the preparation
of 9. The residue was purified by column chromatography (silica
gel, hexane/EtOAc 9:1) to afford pure 17 (244 mg, 18%) as a color-
1
a white solid: Rf =0.52 (hexane/EtOAc 7:3); m.p. 81–828C; H NMR
(500.13 MHz, CDCl3): d=3.35 (t, J=5.8 Hz, 2H, H-1), 4.32 (t, J=
5.8 Hz, 2H, H-2), 6.95 (d, J=9.1 Hz, 2H, H-2’), 7.06 (d, J=9.1 Hz,
2H, H-3’), 7.20 (d, J=2.4 Hz, 1H, H-1’’), 7.24 (dd, J=8.9, 2.5 Hz, 1H,
H-3’’), 7.38 (ddd, J=8.1, 6.9, 1.3 Hz, 1H, H-6’’), 7.43 (ddd, J=8.1,
6.9, 1.3 Hz, 1H, H-7’’), 7.67 (d, J=8.2 Hz, 1H, H-8’’), 7.81 (d, J=
7.7 Hz, 1H, H-4’’), 7.82 ppm (d, J=8.9 Hz, 1H, H-5’’); 13C NMR
(125.77 MHz, CDCl3): d=33.4 (C-1), 66.4 (C-2), 111.8 (SCN), 112.6 (C-
1’’), 115.9 (C-2’), 121.0 (C-3’), 124.5 (C-6’’), 126.5 (C-8’’), 127.0 (C-7’’),
127.7 (C-5’’), 129.83 (C-4’’), 129.87 (C-5’’a), 134.3 (C-8’’a), 151.1 (C-
4’), 154.1 (C-1’), 156.0 ppm (C-2’’); HRMS (ESI): m/z: calcd for
C19H15O2NSNa: 344.0721 [M+Na]+; found: 344.0711.
1
less oil: Rf =0.55 (hexane/EtOAc 7:3); H NMR (500.13 MHz, CDCl3):
d=1.53–1.68 (m, 4H, H-4’’’, H-5’’’), 1.73–1.79 (m, 1H, H-3’’’a), 1.85
(m, 1H, H-3’’’b), 3.55 (m, 1H, H-6’’’a), 3.83 (ddd, J=11.1, 6.4, 4.3 Hz,
1H, H-6’’’b), 3.92 (ddd, J=10.5, 8.9, 2.2 Hz, 1H, H-1a), 4.07 (m, 1H,
H-1b), 4.17 (m, 2H, H-2), 4.73 (t, J=3.5 Hz, 1H, H-2’’’), 6.96 (d, J=
9.1 Hz, 2H, H-2’), 7.04 (d, J=9.0 Hz, 2H, H-3’), 7.18 (d, J=1.9 Hz,
1H, H-1’’), 7.24 (dd, J=9.0, 2.5 Hz, 1H, H-3’’), 7.37 (m, 1H, H-6’’),
7.43 (ddd, J=7.9, 7.1, 0.8 Hz, 1H, H-7’’), 7.66 (d, J=8.2 Hz, 1H, H-
8’’), 7.799 (d, J=8.2 Hz, 1H, H-4’’), 7.804 ppm (d, J=9.1 Hz, 1H, H-
5’’); 13C NMR (125.77 MHz, CDCl3): d=19.4 (C-4’’’), 25.4 (C-5’’’), 30.5
(C-3’’’), 62.2 (C-6’’’), 65.9 (C-1), 68.0 (C-2), 99.0 (C-2’’’), 112.2 (C-1’’),
a-Naphthyloxyphenylethyl tetrahydro-2H-pyran-2-yl ether (21):
A mixture of 8 (724 mg, 3.04 mmol), 1-bromonaphthalene (840 mg,
4.08 mmol), CuI (60.7 mg, 0.32 mmol), 2-picolinic acid (75.8 mg,
0.62 mmol), and K3PO4 (1.33 g, 6.24 mmol) in DMSO (6 mL) was
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treated as described in the method for the preparation of 9 for
48 h. The residue was purified by column chromatography (silica
gel, hexane/EtOAc 9:1) to give pure 21 (322 mg, 29%) as a colorless
(ESI): m/z: calcd for C19H15O2NSNa: 344.0721 [M+Na]+; found:
344.0702.
1
oil: Rf =0.56 (hexane/EtOAc 7:3); H NMR (500.13 MHz, CDCl3): d=
4-(Pyridin-2-yloxy)phenoxyethyl tetrahydro-2H-pyran-2-yl ether
1.51–1.68 (m, 4H, H-4’’’, H-5’’’), 1.72–1.78 (m, 1H, H-3’’’a), 1.81–1.89
(m, 1H, H-3’’’b), 3.55 (m, 1H, H-6’’’a), 3.83 (ddd, J=11.1, 6.4, 4.3 Hz,
1H, H-6’’’b), 3.90 (m, 1H, H-1a), 4.02 (ddd, J=11.1, 5.0, 4.3 Hz, 1H,
H-1b), 4.16 (m, 2H, H-2), 4.70 (t, J=3.8 Hz, 1H, H-2’’’), 6.79 (dd, J=
7.6, 0.8 Hz, 1H, H-2’’), 6.94 (d, J=9.2 Hz, 2H, H-2’), 7.02 (d, J=
9.2 Hz, 2H, H-3’), 7.33 (t, J=7.8 Hz, 1H, H-3’’), 7.52 (m, 2H, H-6’’, H-
7’’), 7.58 (d, J=8.6 Hz, 1H, H-4’’), 7.85 (dd, J=7.4, 1.9 Hz, 1H, H-5’’),
8.24 ppm (d, J=8.5 Hz, 1H, H-8’’); 13C NMR (125.77 MHz, CDCl3):
d=19.4 (C-4’’’), 25.4 (C-5’’’), 30.5 (C-3’’’), 62.2 (C-6’’’), 65.9 (C-1), 68.1
(C-2), 99.0 (C-2’’’), 111.3 (C-2’’), 116.0 (C-2’), 120.5 (C-3’), 122.0 (C-4’’),
122.4 (C-8’’), 125.7 (C-3’’), 126.2 (C-7’’), 126.5 (C-9’’), 126.7 (C-6’’),
127.6 (C-5’’), 134.7 (C-10’’), 149.7 (C-4’), 153.1 (C-1’’), 155.2 ppm (C-
1’); HRMS (ESI): m/z: calcd for C23H24O4Na: 387.1572 [M+Na]+;
found: 387.1563.
(26): A mixture of 25 (1.40 g, 4.02 mmol), 2-hydroxypyridine
(450 mg, 4.73 mmol), CuI (73.3 mg, 0.38 mmol), 2-picolinic acid
(91.0 mg, 0.74 mmol), and K3PO4 (1.74 g, 8.20 mmol) in DMSO
(6 mL) was treated as described in the method for the preparation
of 9 for 8 days. The product was purified by column chromatogra-
phy (silica gel, hexane/EtOAc 3:7) to give pure 26 (607 mg, 48%)
as
a
colorless oil: Rf =0.09 (hexane/EtOAc 1:1); 1H NMR
(500.13 MHz, CDCl3): d=1.52–1.65 (m, 4H, H-4’’’, H-5’’’), 1.72–1.78
(m, 1H, H-3’’’a), 1.81–1.86 (m, 1H, H-3’’’b), 3.54 (m, 1H, H-6’’’a), 3.84
(ddd, J=11.2, 6.4, 4.4 Hz, 1H, H-6’’’b), 3.91 (ddd, J=11.2, 8.2, 3.0 Hz,
1H, H-1a), 4.07 (ddd, J=11.2, 4.8, 4.2 Hz, 1H, H-1b), 4.18 (m, 2H, H-
2), 4.72 (t, J=3.6 Hz, 1H, H-2’’’), 6.22 (dt, J=6.7, 0.9 Hz, 1H, H-4’’),
6.64 (d, J=9.2 Hz, 1H, H-6’’), 7.02 (d, J=9.0 Hz, 2H, H-2’), 7.28 (d,
J=9.0 Hz, 2H, H-3’), 7.32 (dd, J=6.8, 2.1 Hz, 1H, H-3’’), 7.39 ppm
(ddd, J=9.2, 6.6, 2.1 Hz, 1H, H-5’’); 13C NMR (125.77 MHz, CDCl3):
d=19.2 (C-4’’’), 25.3 (C-5’’’), 30.4 (C-3’’’), 62.1 (C-6’’’), 65.6 (C-1), 67.7
(C-2), 98.9 (C-2’’’), 105.7 (C-6’’), 115.1 (C-2’), 121.6 (C-4’’), 127.4 (C-
3’), 133.7 (C-4’), 138.2 (C-5’’), 139.8 (C-3’’), 158.6 (C-1’), 162.6 ppm
(C-1’’); HRMS (ESI): m/z: calcd for C18H21NO4Na: 338.1368 [M+Na]+;
found: 338.1365.
a-Naphthyloxyphenylethanol (22): A solution of 21 (322 mg,
0.89 mmol) in MeOH (10 mL) was treated with PPTS (20 mg) as de-
scribed in the method for the preparation of 11 to afford 22
(229 mg, 92%) as a colorless oil: Rf =0.24 (hexane/EtOAc 7:3);
1H NMR (500.13 MHz, CDCl3): d=3.98 (dist.t, J=4.3 Hz, 2H, H-1),
4.09 (dist.t, J=4.1 Hz, 2H, H-2), 6.80 (d, J=7.5 Hz, 1H, H-2’’), 6.93
(d, J=9.0 Hz, 2H, H-2’), 7.03 (d, J=9.0 Hz, 2H, H-3’), 7.34 (t, J=
7.9 Hz, 1H, H-3’’), 7.52 (m, 2H, H-6’’, H-7’’), 7.56 (d, J=8.3 Hz, 1H,
H-4’’), 7.86 (dd, J=7.3, 1.6 Hz, 1H, H-5’’), 8.28 ppm (dd, J=8.0,
1.5 Hz, 1H, H-8’’); 13C NMR (125.77 MHz, CDCl3): d=61.5 (C-1), 69.7
(C-2), 111.5 (C-2’’), 115.7 (C-2’), 120.6 (C-3’), 122.0 (C-4’’), 122.5 (C-
8’’), 125.7 (C-3’’), 125.8 (C-7’’), 126.4 (C-9’’), 126.6 (C-6’’), 127.7 (C-
5’’), 134.8 (C-10’’), 151.1 (C-4’), 154.3 (C-1’’), 154.9 ppm (C-1’); HRMS
(ESI): m/z: calcd for C18H16O3Na: 303.0997 [M+Na]+; found:
303.1005.
4-(Pyridin-2-yloxy)phenoxyethanol (27): A solution of 26 (607 mg,
1.92 mmol) in MeOH (10 mL) was treated with PPTS (20 mg), and
the mixture was stirred at room temperature for 4 h. The mixture
was worked up as described in the method for the preparation of
11. The product was purified by column chromatography (silica
gel, EtOAc) to afford pure alcohol 27 (266 mg, 60%) as a white
solid: Rf =0.09 (EtOAc); m.p. 1508C; 1H NMR (500.13 MHz, CDCl3):
d=3.99 (m, 2H, H-1), 4.13 (dist.t, J=4.6 Hz, 2H, H-2), 6.22 (dt, J=
6.7, 1.4 Hz, 1H, H-4’’), 6.65 (dq, J=9.3, 0.7 Hz, 1H, H-6’’), 7.02 (d,
J=9.0 Hz, 2H, H-2’), 7.31 (d, J=8.9 Hz, 2H, H-3’), 7.32 (ddd, J=6.5,
2.2, 0.6 Hz, 1H, H-3’’), 7.39 ppm (ddd, J=9.2, 6.6, 2.2 Hz, 1H, H-5’’);
13C NMR (125.77 MHz, CDCl3): d=61.4 (C-1), 69.5 (C-2), 105.8 (C-6’’),
115.2 (C-2’), 121.9 (C-4’’), 127.7 (C-3’), 138.2 (C-5’’), 139.8 (C-3’’),
158.4 (C-1’), 163.8 (C-1’’), 105.7 (C-6’’), 115.1 (C-2’), 121.6 (C-4’’),
127.4 (C-3’), 133.7 (C-4’), 138.2 (C-5’’), 139.8 (C-3’’), 158.6 (C-1’),
162.6 ppm (C-1’’); HRMS (ESI): m/z: calcd for C13H14NO3 232.0974
[M+H]+; found: 232.0978.
a-Naphthyloxyphenylethyl 4-toluenesulfonate (23): TsCl (517 mg,
2.71 mmol) was added to a solution of alcohol 22 (229 mg,
0.82 mmol) in pyridine (5 mL) at 08C. The mixture was treated as
detailed in the method for the preparation of 13. Purification of
the product afforded tosylate 23 (323 mg, 91%) as a white solid:
1
Rf =0.48 (hexane/EtOAc 7:3); H NMR (500.13 MHz, CDCl3): d=2.45
(s, 3H, CH3), 4.15 (m, 2H, H-1), 4.37 (m, 2H, H-2), 6.788 (d, J=
6.8 Hz, 1H, H-2’’), 6.790 (d, J=9.1 Hz, 2H, H-2’), 6.98 (d, J=9.1 Hz,
2H, H-3’), 7.33 (t, J=8.2 Hz, 1H, H-3’’), 7.35 (d, J=8.0 Hz, 2H, H-
3’’’), 7.52 (m, 2H, H-6’’, H-7’’), 7.57 (d, J=8.3 Hz, 1H, H-4’’), 7.83 (d,
J=8.4 Hz, 2H, H-2’’’), 7.86 (dd, J=7.3, 1.8 Hz, 1H, H-5’’), 8.26 ppm
(dd, J=7.7, 1.3 Hz, 1H, H-8’’); HRMS (ESI): m/z: calcd for
C25H22O5SNa: 457.1086 [M+Na]+; found: 457.1082.
4-(Pyridin-2-yloxy)phenoxyethyl 4-toluenesulfonate (28): A solu-
tion of alcohol 27 (122 mg, 0.53 mmol) in pyridine (2 mL) was
treated with TsCl (352 mg, 1.85 mmol) at 08C. The reaction was
quenched as detailed in the method for the preparation of 13 to
afford pure 28 (183 mg, 90%) as a white solid: Rf =0.39 (EtOAc);
1H NMR (500.13 MHz, CDCl3): d=2.46 (s, 3H, CH3), 4.18 (m, 2H, H-
1), 4.39 (m, 2H, H-2), 6.22 (dt, J=6.7, 1.3 Hz, 1H, H-4’’), 6.64 (dq,
J=9.3, 0.6 Hz, 1H, H-6’’), 6.88 (d, J=8.9 Hz, 2H, H-2’), 7.27 (d, J=
8.9 Hz, 2H, H-3’), 7.30 (ddd, J=6.9, 2.0, 0.5 Hz, 1H, H-3’’), 7.36 (d,
J=7.9 Hz, 2H, H-3’’’), 7.39 (ddd, J=9.0, 6.6, 2.3 Hz, 1H, H-5’’),
7.83 ppm (d, J=8.4 Hz, 2H, H-2’’’); 13C NMR (125.77 MHz, CDCl3):
d=21.7 (CH3), 65.8 (C-1), 67.9 (C-2), 105.8 (C-6’’), 115.2 (C-2’), 121.8
(C-4’’), 127.7 (C-3’), 128.0 (C-2’’’), 129.9 (C-3’’’), 134.5 (C-4’), 132.8 (C-
4’’’), 138.1 (C-5’’), 139.8 (C-3’’), 145.1 (C-1’’’), 157.8 (C-1’), 162.6 ppm
(C-1’’); HRMS (ESI): m/z: calcd for C20H20N2O5S 386.1062 [M+H]+;
found: 386.1055.
a-Naphthyloxyphenylethyl thiocyanate (24): A solution of tosy-
late 23 (323 mg, 1.03 mmol) in DMF (6 mL) was treated with KSCN
(581 mg, 5.98 mmol) as described in the method for the prepara-
tion of 15. The residue was purified by column chromatography
(silica gel, hexane/EtOAc 19:1) to afford pure 24 (140 mg, 43%) as
1
a white solid: Rf =0.54 (hexane/EtOAc 7:3); m.p. 95–968C; H NMR
(500.13 MHz, CDCl3): d=3.35 (t, J=5.8 Hz, 2H, H-1), 4.32 (t, J=
5.8 Hz, 2H, H-2), 6.83 (d, J=7.6 Hz, 1H, H-2’’), 6.93 (d, J=9.1 Hz,
2H, H-2’), 7.04 (d, J=9.1 Hz, 2H, H-3’), 7.35 (t, J=7.9 Hz, 1H, H-3’’),
7.52 (m, 2H, H-6’’, H-7’’), 7.58 (d, J=8.2 Hz, 1H, H-4’’), 7.87 (dd, J=
7.4, 1.9 Hz, 1H, H-5’’), 8.26 ppm (dd, J=8.0, 1.5 Hz, 1H, H-8’’);
13C NMR (125.77 MHz, CDCl3): d=33.3 (C-1), 66.4 (C-2), 111.7 (SCN),
111.8 (C-2’’), 116.0 (C-2’), 120.5 (C-3’), 122.0 (C-4’’), 122.8 (C-8’’),
125.7 (C-3’’), 125.9 (C-7’’), 126.4 (C-9’’), 126.6 (C-6’’), 127.7 (C-5’’),
134.9 (C-10’’), 151.8 (C-4’), 153.9 (C-1’’), 154.0 ppm (C-1’); HRMS
4-(Pyridin-2-yloxy)phenoxyethyl thiocyanate (29): A solution of
28 (136 mg, 0.35 mmol) in anhydrous DMF (2 mL) was treated with
KSCN (200 mg, 2.06 mmol) as described in the method for the
preparation of 15. The product was purified by column chromatog-
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raphy (silica gel, hexane/EtOAc 1:1) to yield thiocyanate 29
(56.9 mg, 61%) as
white solid: Rf =0.38 (EtOAc); 1H NMR
110.6 (C-4’), 121.2 (C-6’’), 125.0 (C-4’’), 127.99 (C-5’’), 128.02 (C-2’’’),
129.8 (C-3’’’), 130.2 (C-3’’), 130.9 (C-5’), 132.9 145.0 (C-1’’’), 152.0 (C-
1’’), 158.2 (C-3’), 159.3 ppm (C-1’); HRMS (ESI): m/z: calcd for
C21H19O5SClNa: 441.0539 [M+Na]+; found: 441.0547.
a
(500.13 MHz, CDCl3): d=3.36 (t, J=5.8 Hz, 2H, H-1), 4.36 (t, J=
5.8 Hz, 2H, H-2), 6.23 (dt, J=6.7, 1.3 Hz, 1H, H-4’’), 6.65 (dq, J=9.3,
0.7 Hz, 1H, H-6’’), 7.02 (d, J=9.0 Hz, 2H, H-2’), 7.33 (d, J=9.0 Hz,
2H, H-3’), 7.31 (ddd, J=7.0, 1.8, 0.7 Hz, 1H, H-3’’), 7.39 ppm (ddd,
J=9.2, 6.6, 2.1 Hz, 1H, H-5’’); 13C NMR (125.77 MHz, CDCl3): d=33.1
(C-1), 66.2 (C-2), 105.9 (C-6’’), 111.6 (SCN), 115.3 (C-2’), 121.9 (C-4’’),
127.9 (C-3’), 134.8 (C-4’), 138.1 (C-5’’), 139.9 (C-3’’), 157.6 (C-1’),
162.6 ppm (C-1’’); HRMS (ESI): m/z: calcd for C14H13N2O2S 273.0698
[M+H]+; found: 273.0703.
3-(2-Chlorophenoxy)phenoxyethyl thiocyanate (46): A solution of
tosylate 41 (226 mg, 0.54 mmol) in anhydrous DMF (3 mL) was
treated with KSCN (262 mg, 2.7 mmol). The mixture was heated at
1008C for 3 h. The reaction was worked up as detailed in the
method for the preparation of 15. The residue was purified by
column chromatography (silica gel, hexane/EtOAc 19:1) to give
pure 46 (15.8 mg, 10%) as a colorless oil: Rf =0.38 (hexane/EtOAc
4:1); 1H NMR (500.13 MHz, CDCl3): d=3.32 (t, J=5.8 Hz, 2H, H-1),
4.29 (t, J=5.8 Hz, 2H, H-2), 6.55 (t, J=2.3 Hz, 1H, H-3’), 6.57 (ddd,
J=8.2, 2.1, 0.8 Hz, 1H, H-4’), 6.67 (ddd, J=8.3, 2.4, 0.7 Hz, 1H, H-
6’), 7.03 (dd, J=8.2, 1.5 Hz, 1H, H-6’’), 7.11 (dt, J=7.7, 1.4 Hz, 1H,
H-4’’), 7.24 (t, J=8.2 Hz, 1H, H- H-5’), 7.24 (m, 1H, H-5’’), 7.47 ppm
(dd, J=8.0, 1.6 Hz, 1H, H-3’’); 13C NMR (125.77 MHz, CDCl3): d=
33.2 (C-1), 65.9 (C-2), 104.6 (C-2’), 109.3 (C-6’), 110.8 (C-4’), 111.6
(SCN), 121.4 (C-6’’), 125.1 (C-4’’), 126.2 (C-2’’), 128.0 (C-5’’), 130.4 (C-
5’), 130.9 (C-5’), 151.9 (C-1’’), 158.4 (C-3’), 159.1 ppm (C-1’); HRMS
(ESI): m/z: calcd for C15H12O2NSClNa: 328.0175 [M+Na]+; found:
328.0169.
3-(2-Chlorophenoxy)phenoxyethyl
tetrahydro-2H-pyran-2-yl
ether (31): A mixture of 30 (927 mg, 2.6 mmol), 2-chlorophenol
(411 mg, 3.2 mmol), CuI (50.6 mg, 0.27 mmol), 2-picolinic acid
(65.5 mg, 0.53 mmol), and K3PO4 (1.129 g, 5.3 mmol) was evacuated
and backfilled with argon as detailed in the method for the prepa-
ration of 9. The product was purified by column chromatography
(silica gel, hexane/EtOAc 24:1) to afford pure 31 (475 mg, 51%) as
1
a colorless oil: Rf =0.47 (hexane/EtOAc 4:1); H NMR (500.13 MHz,
CDCl3): d=1.50–1.65 (m, 4H, H-4’’’, H-5’’’), 1.70–1.76 (m, 1H, H-
3’’’a), 1.79–1.86 (m, 1H, H-3’’’b), 3.52 (m, 1H, H-6’’’a), 3.80 (ddd, J=
11.2, 6.4, 4.2 Hz, 1H, H-6’’’b), 3.88 (ddd, J=11.2, 8.2, 3.1 Hz, 1H, H-
1a), 4.07 (m, 1H, H-1b), 4.12 (m, 2H, H-2), 4.69 (t, J=3.6 Hz, 1H, H-
2’’’), 6.54 (m, 2H, H-4’, H-6’), 6.55 (t, J=2.3 Hz, 1H, H-2’), 7.02 (dt,
J=8.0, 1.5 Hz, 1H, H-6’’), 7.09 (dt, J=7.7, 1.5 Hz, 1H, H-4’’), 7.21 (t,
J=8.0 Hz, 1H, H-5’), 7.22 (m, 1H, H-5’’), 7.45 ppm (dd, J=8.0,
1.6 Hz, 1H, H-3’’); 13C NMR (125.77 MHz, CDCl3): d=19.4 (C-4’’’),
25.4 (C-5’’’), 30.5 (C-3’’’), 62.2 (C-6’’’), 65.7 (C-1), 67.6 (C-2), 99.0 (C-
2’’’), 104.8 (C-2’), 109.6 (C-6’), 110.2 (C-4’), 121.2 (C-6’’), 124.8 (C-4’’),
126.0 (C-2’’), 127.9 (C-5’’), 130.1 (C-3’’), 130.8 (C-5’), 152.2 (C-1’’),
158.1 (C-3’), 160.2 ppm (C-1’); HRMS (ESI): m/z: calcd for
C19H21O4ClNa: 371.1026 [M+Na]+; found: 371.1023.
3-(3-Chlorophenoxy)phenoxyethyl
tetrahydro-2H-pyran-2-yl
ether (32): A mixture of 30 (959 mg, 2.7 mmol), 3-chlorophenol
(708 mg, 5.5 mmol), CuI (52.4 mg, 0.27 mmol), 2-picolinic acid
(67.8 mg, 0.55 mmol), and K3PO4 (1.169 g, 5.5 mmol) as detailed in
the method for the preparation of 9. The mixture was stirred vigo-
rously at 908C for 21 days. The product was purified by column
chromatography (silica gel, hexane/EtOAc 24:1) to afford pure 32
(826 mg, 86%) as a colorless oil: Rf =0.76 (hexane/EtOAc 3:2);
1H NMR (500.13 MHz, CDCl3): d=1.52–1.65 (m, 4H, H-4’’’, H-5’’’),
1.72–1.76 (m, 1H, H-3’’’a), 1.81–1.84 (m, 1H, H-3’’’b), 3.55 (m, 1H, H-
6’’’a), 3.80 (ddd, J=10.7, 6.6, 3.8 Hz, 1H, H-6’’’b), 3.91 (ddd, J=11.1,
8.7, 2.4 Hz, 1H, H-1a), 4.07 (m, 1H, H-1b), 4.12 (m, 2H, H-2), 4.72 (t,
J=3.3 Hz, 1H, H-2’’’), 6.61 (t, J=2.3 Hz, 1H, H-2’), 6.72 (m, 2H, H-4’,
H-6’), 6.90 (dd, J=8.0, 1.3 Hz, 1H, H-6’’), 7.00 (t, J=2.0 Hz, 1H, H-
2’’), 7.09 (m, 1H, H-4’’), 7.25 ppm (t, J=8.2 Hz, 2H, H-5’, H-5’’);
13C NMR (125.77 MHz, CDCl3): d=19.2 (C-4’’’), 25.3 (C-5’’’), 30.4 (C-
3’’’), 62.3 (C-6’’’), 65.8 (C-1), 67.5 (C-2), 99.1 (C-2’’’), 106.1 (C-2’),
110.2 (C-6’), 111.6 (C-4’), 116.8 (C-6’’), 118.9 (C-2’’), 123.2 (C-4’’),
130.2 (C-5’’), 130.4 (C-5’), 134.6 (C-3’’), 157.4 (C-1’’), 158.0 (C-3’),
160.2 ppm (C-1’).
3-(2-Chlorophenoxy)phenoxyethanol (36):
A solution of 31
(475 mg, 1.4 mmol) in MeOH (75 mL) was treated with PPTS
(30 mg) at 08C. The mixture was treated as described in the
method for the preparation of 11. The residue was purified by
column chromatography (hexane/EtOAc 4:1) to give pure alcohol
36 (252 mg, 70%) as a colorless oil: Rf =0.05(hexane/EtOAc 4:1);
1H NMR (500.13 MHz, CDCl3): d=3.95 (dist.t, J=4.5 Hz, 2H, H-1),
4.06 (dist.t, J=4.5 Hz, 2H, H-2), 6.54 (t, J=2.2 Hz, 1H, H-4’), 6.56
(ddd, J=8.1, 2.3, 0.9 Hz, 1H, H-6’), 6.66 (ddd, J=8.2, 2.3, 0.8 Hz,
1H, H-2’), 7.03 (dd, J=8.1, 1.5 Hz, 1H, H-6’’), 7.10 (ddd, J=7.7, 7.5,
1.5 Hz, 1H, H-4’’), 7.22 (t, J=8.0 Hz, 1H, H-5’), 7.24 (m, 1H, H-5’’),
7.46 ppm (dd, J=8.0, 1.6 Hz, 1H, H-3’’); 13C NMR (125.77 MHz,
CDCl3): d=61.4 (C-1), 67.3 (C-2), 104.5 (C-2’), 109.3 (C-6’), 110.3 (C-
4’), 121.3 (C-6’’), 125.0 (C-4’’), 126.1 (C-2’’), 128.0 (C-5’’), 130.3 (C-3’’),
130.8 (C-5’), 152.2 (C-1’’), 158.1 (C-3’), 160.3 ppm (C-1’); HRMS (ESI):
m/z: calcd for C14H14O3Cl 265.0631 [M+H]+; found: 265.0633.
3-(3-Chlorophenoxy)phenoxyethanol (37):
A solution of 32
(581 mg, 1.7 mmol) in MeOH (75 mL) was treated with PPTS
(30 mg). The mixture was stirred at room temperature overnight
and was quenched as described in the method for the preparation
of 11. The product was purified by column chromatography
(hexane/EtOAc 86:14) to give pure alcohol 37 (302 mg, 55%) as
1
3-(2-Chlorophenoxy)phenoxyethyl 4-toluenesulfonate (41): A so-
lution of alcohol 36 (253 mg, 0.95 mmol) in pyridine (3 mL) was
treated with TsCl (546 mg, 2.9 mmol) as detailed in the method for
the preparation of 13. The product was purified by column chro-
matography (silica gel, hexane/EtOAc 9:1) to afford tosylate 41
(226 mg, 66%) as a colorless oil: Rf =0.25 (hexane/EtOAc 4:1);
1H NMR (500.13 MHz, CDCl3): d=2.44 (s, 3H, CH3), 4.11 (m, 2H, H-
1), 4.35 (m, 2H, H-2), 6.39 (t, J=2.3 Hz, 1H, H-2’), 6.53 (m, 2H, H-4’,
H-6’), 7.00 (dd, J=8.1, 1.5 Hz, 1H, H-6’’), 7.11 (dt, J=7.7, 1.5 Hz, 1H,
H-4’’), 7.18 (t, J=8.2 Hz, 1H, H-5’), 7.24 (ddd, J=8.1, 7.5, 1.6 Hz, 1H,
H-5’’), 7.32 (d, J=8.0 Hz, 2H, H-3’’’), 7.46 (dd, J=8.0, 1.6 Hz, 1H, H-
3’’), 7.81 ppm (d, J=8.4 Hz, 2H, H-2’’’); 13C NMR (125.77 MHz,
CDCl3): d=21.6 (CH3), 65.5 (C-1), 68.0 (C-2), 104.6 (C-2’), 109.2 (C-6’),
a colorless oil: Rf =0.14 (hexane/EtOAc 4:1); H NMR (500.13 MHz,
CDCl3): d=3.98 (m, 2H, H-1), 4.09 (t, J=4.1 Hz, 2H, H-2), 6.62 (t, J=
2.3 Hz, 1H, H-2’), 6.65 (dd, J=8.1, 1.6 Hz, 1H, H-4’), 6.74 (dd, J=8.2,
2.1 Hz, 1H, H-6’), 6.93 (dd, J=8.3, 1.6 Hz, 1H, H-6’’), 7.03 (t, J=
2.1 Hz, 1H, H-2’’), 7.11 (dd, J=7.9, 0.7 Hz, 1H, H-4’’), 7.28 ppm (dt,
J=8.2, 2.6 Hz, 2H, H-5’, H-5’’); 13C NMR (125.77 MHz, CDCl3): d=
61.4 (C-1), 69.3 (C-2), 105.9 (C-2’), 110.0 (C-6’), 111.8 (C-4’), 117.0 (C-
6’’), 119.1 (C-2’’), 123.4 (C-4’’), 130.4 (C-5’’), 130.5 (C-5’), 135.0 (C-3’’),
157.6 (C-1’’), 157.9 (C-3’), 160.0 ppm (C-1’); HRMS (ESI): m/z: calcd
for C14H13O3ClNa: 287.0451 [M+Na]+; found: 287.0441.
3-(3-Chlorophenoxy)phenoxyethyl 4-toluenesulfonate (42): TsCl
(796 mg, 4.18 mmol) was added to a solution of 37 (368 mg,
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1.39 mmol) in pyridine (3 mL) as described in the method for the
preparation of 13. The product was purified by column chromatog-
raphy (silica gel, hexane/EtOAc 97:3) to give pure 42 (290 mg,
50%) as a colorless oil: Rf =0.19 (hexane/EtOAc 4:1); 1H NMR
(500.13 MHz, CDCl3): d=2.43 (s, 3H, CH3), 4.12 (m, 2H, H-1), 4.36
(m, 2H, H-2), 6.42 (t, J=2.3 Hz, 1H, H-2’), 6.57 (ddd, J=8.3, 2.4,
0.7 Hz, 1H, H-4’), 6.61 (ddd, J=8.2, 2.3, 0.8 Hz, 1H, H-6’), 6.88 (ddd,
J=8.3, 2.4, 0.9 Hz, 1H, H-6’’), 6.97 (t, J=2.2 Hz, 1H, H-2’’), 7.08
(ddd, J=8.0, 1.9, 0.9 Hz, 1H, H-4’’), 7.24 (m, 2H, H-5’, H-5’’), 7.32 (d,
J=8.0 Hz, 2H, H-3’’’), 7.81 ppm (d, J=8.3 Hz, 2H, H-2’’’); 13C NMR
(125.77 MHz, CDCl3): d=21.6 (CH3), 65.5 (C-1), 67.9 (C-2), 106.0 (C-
2’), 109.8 (C-6’), 112.1 (C-4’), 116.9 (C-6’’), 119.0 (C-2’’), 123.5 (C-4’’),
128.0 (C-2’’’), 129.8 (C-3’’’), 130.4 (C-5’’), 130.5 (C-5’), 132.8 (C-4’’’),
135.0 (C-3’’), 145.0 (C-1’’’), 157.5 (C-1’’), 157.9 (C-3’), 159.4 ppm (C-
1’); HRMS (ESI): m/z: calcd for C21H19O5SClNa: 441.0539 [M+Na]+;
found: 441.0543.
(ddd, J=8.1, 2.2, 0.7 Hz, 1H, H-4’), 6.68 (ddd, J=8.3, 2.4, 0.7 Hz,
1H, H-6’), 6.95 (d, J=9.0 Hz, 2H, H-3’’), 7.23 (t, J=8.2 Hz, 1H, H-5’),
7.29 ppm (d, J=9.0 Hz, 2H, H-2’’); 13C NMR (125.77 MHz, CDCl3):
d=61.4 (C-1), 69.3 (C-2), 105.5 (C-2’), 109.6 (C-6’), 111.4 (C-4’), 120.4
(C-2’’), 128.5 (C-4’’), 129.7 (C-5’), 130.3 (C-3’’), 155.6 (C-1’’), 158.2 (C-
1’), 160.0 ppm (C-3’); HRMS (ESI): m/z: calcd for C14H13O3ClNa:
287.0451 [M+Na]+; found: 287.0450.
3-(4-Chlorophenoxy)phenoxyethyl 4-toluenesulfonate (43): TsCl
(474 mg, 2.48 mmol) was added to a solution of 8 (219 mg,
0.83 mmol) in pyridine (3 mL) as described in the method for the
preparation of 13. The product was purified by column chromatog-
raphy (silica gel, hexane/EtOAc 47:3) to give pure 43 (269 mg,
78%) as a colorless oil: Rf =0.25 (hexane/EtOAc 4:1); 1H NMR
(500.13 MHz, CDCl3): d=2.43 (s, 3H, CH3), 4.11 (m, 2H, H-1), 4.35
(m, 2H, H-2), 6.41 (t, J=2.3 Hz, 1H, H-2’), 6.55 (ddd, J=8.3, 2.4,
0.7 Hz, 1H, H-4’), 6.58 (ddd, J=8.2, 2.2, 0.7 Hz, 1H, H-6’), 6.93 (d,
J=9.0 Hz, 2H, H-3’’), 7.20 (t, J=8.3 Hz, 1H, H-5’), 7.30 (d, J=9.0 Hz,
2H, H-2’’), 7.33 (d, J=8.0 Hz, 2H, H-3’’’), 7.81 ppm (d, J=8.4 Hz,
2H, H-2’’’); 13C NMR (125.77 MHz, CDCl3): d=21.6 (CH3), 65.5 (C-1),
67.9 (C-2), 105.6 (C-2’), 109.5 (C-6’), 111.6 (C-4’), 120.3 (C-2’’), 128.0
(C-2’’’), 128.5 (C-4’’), 129.7 (C-5’), 129.8 (C-3’’’), 130.3 (C-3’’), 132.8
(C-4’’’), 145.0 (C-1’’’), 155.5 (C-1’’), 158.1 (C-1’), 159.3 ppm (C-3’);
HRMS (ESI): m/z: calcd for C21H20O5ClS 419.0720 [M+H]+; found:
419.0717.
3-(3-Chlorophenoxy)phenoxyethyl thiocyanate (47): KSCN
(293 mg, 3.0 mmol) was added to a solution of 12 (252 mg,
0.60 mmol) in DMF (3 mL). The mixture was treated as described in
the method for the preparation of 15. The product was purified by
column chromatography (silica gel, hexane/EtOAc 91:9) to afford
47 (92.3 mg, 50%) as a colorless oil: Rf =0.36 (hexane/EtOAc 4:1);
1H NMR (500.13 MHz, CDCl3): d=3.33 (t, J=5.8 Hz, 2H, H-1), 4.30 (t,
J=5.8 Hz, 2H, H-2), 6.59 (t, J=2.3 Hz, 1H, H-2’), 6.66 (ddd, J=8.2,
2.3, 0.8 Hz, 1H, H-4’), 6.71 (ddd, J=8.3, 2.4, 0.7 Hz, 1H, H-6’), 6.91
(ddd, J=8.3, 2.4, 0.9 Hz, 1H, H-6’’), 7.00 (t, J=2.1 Hz, 1H, H-2’’),
7.09 (ddd, J=8.0, 1.9, 0.9 Hz, 1H, H-4’’), 7.30 ppm (m, 2H, H-5’, H-
5’’); 13C NMR (125.77 MHz, CDCl3): d=33.2 (C-1), 65.9 (C-2), 106.1
(C-2’), 109.9 (C-6’), 111.6 (SCN), 112.4 (C-4’), 117.0 (C-6’’), 119.1 (C-2’’)
123.6 (C-4’’), 130.5 (C-5’’), 130.6 (C-5’), 135.1 (C-3’’), 157.7 (C-1’’),
157.8 (C-3’), 159.2 ppm (C-1’); HRMS (ESI): m/z: calcd for
C15H12O2SNClNa: 328.0175 [M+Na]+; found: 328.0177.
3-(4-Chlorophenoxy)phenoxyethyl thiocyanate (48): KSCN
(319 mg, 3.2 mmol) was added to a solution of 43 (269 mg,
0.64 mmol) in DMF (3 mL). The mixture was treated as detailed in
the method for the preparation of 15. The product was purified by
column chromatography (silica gel, hexane/EtOAc 24:1) to afford
48 (104 mg, 53%) as a colorless oil: Rf =0.18 (hexane/EtOAc 4:1);
1H NMR (500.13 MHz, CDCl3): d=3.32 (t, J=5.8 Hz, 2H, H-1), 4.29 (t,
J=5.8 Hz, 2H, H-2), 6.56 (t, J=2.3 Hz, 1H, H-2’), 6.62 (dd, J=7.9,
2.0 Hz, 1H, H-4’), 6.68 (dd, J=8.3, 2.4 Hz, 1H, H-6’), 6.96 (d, J=
9.0 Hz, 2H, H-3’’), 7.25 (t, J=8.3 Hz, 1H, H-5’), 7.30 ppm (d, J=
9.0 Hz, 2H, H-2’’); 13C NMR (125.77 MHz, CDCl3): d=33.2 (C-1), 65.9
(C-2), 105.6 (C-2’), 109.6 (C-6’), 111.6 (SCN), 111.9 (C-4’), 120.4 (C-2’’),
128.6 (C-4’’), 129.8 (C-5’), 130.5 (C-3’’), 155.4 (C-1’’), 158.3 (C-1’),
159.2 ppm (C-3’); HRMS (ESI): m/z: calcd for C15H13O2NSCl 306.0356
[M+H]+; found: 306.0365.
3-(4-Chlorophenoxy)phenoxyethyl
tetrahydro-2H-pyran-2-yl
ether (33): A mixture of 30 (810 mg, 2.3 mmol), 4-chlorophenol
(598 mg, 4.6 mmol), CuI (44.4 mg, 0.23 mmol), 2-picolinic acid
(57.4 mg, 0.47 mmol), and K3PO4 (987 mg, 4.6 mmol) was treated as
described in the method for the preparation of 9 and was stirred
at 908C for 19 days. The product was purified by column chroma-
tography (silica gel, hexane/EtOAc 24:1) to afford pure 33 (417 mg,
51%) as a colorless oil: Rf =0.34 (hexane/EtOAc 3:2); 1H NMR
(500.13 MHz, CDCl3): d=1.52–1.69 (m, 4H, H-4’’’, H-5’’’), 1.73–1.79
(m, 1H, H-3’’’a), 1.82–1.88 (m, 1H, H-3’’’b), 3.55 (m, 1H, H-6’’’a), 3.82
(ddd, J=11.2, 6.4, 4.1 Hz, 1H, H-6’’’b), 3.91 (ddd, J=11.2, 8.3, 3.0 Hz,
1H, H-1a), 4.06 (m, 1H, H-1b), 4.14 (m, 2H, H-2), 4.72 (t, J=3.6 Hz,
1H, H-2’’’), 6.60 (m, 2H, H-2’, H-4’), 6.79 (d, J=9.0 Hz, 1H, H-6’),
6.97 (d, J=9.0 Hz, 2H, H-3’’), 7.21 (d, J=8.9 Hz, 1H, H-6’), 7.22 (t,
J=8.5 Hz, 1H, H-5’), 7.31 ppm (d, J=9.1 Hz, 2H, H-2’’); 13C NMR
(125.77 MHz, CDCl3): d=19.4 (C-4’’’), 25.4 (C-5’’’), 30.5 (C-3’’’), 62.2
(C-6’’’), 65.7 (C-1), 67.6 (C-2), 99.0 (C-2’’’), 105.7 (C-2’), 109.9 (C-6’),
111.2 (C-4’), 120.2 (C-2’’), 128.3 (C-4’’), 129.5 (C-5’), 129.7 (C-3’’),
155.7 (C-1’’), 158.0 (C-1’), 160.3 ppm (C-3’); HRMS (ESI): m/z: calcd
for C19H21O4ClNa: 371.1026 [M+Na]+; found: 371.1002.
3-(2-Methoxyphenoxy)phenoxyethyl
tetrahydro-2H-pyran-2-yl
ether (34): DMSO (3.0 mL) was added to a mixture of 30 (939 mg,
2.7 mmol), 2-methoxyphenol (670 mg, 5.4 mmol), CuI (51.4 mg,
0.27 mmol), 2-picolinic acid (66.4 mg, 0.54 mmol), and K3PO4
(1.148 g, 5.4 mmol), and the mixture was stirred at 908C for 3 days
as described in the method for the preparation of 9. The product
was purified by column chromatography (silica gel, hexane/EtOAc
47:3) to afford pure 34 (628 mg, 68%) as a colorless oil: Rf =0.35
1
(hexane/EtOAc 4:1); H NMR (500.13 MHz, CDCl3): d=1.50–1.65 (m,
4H, H-4’’’, H-5’’’), 1.70–1.76 (m, 1H, H-3’’’a), 1.79–1.85 (m, 1H, H-
3’’’b), 3.51 (m, 1H, H-6’’’a), 3.79 (ddd, J=11.0, 6.5, 4.4 Hz, 1H, H-
6’’’b), 3.84 (s, 3H, OCH3), 3.88 (ddd, J=11.3, 8.2, 3.1 Hz, 1H, H-1a),
4.02 (m, 1H, H-1b), 4.10 (m, 2H, H-2), 4.69 (t, J=3.6 Hz, 1H, H-2’’’),
6.53–6.55 (m, 2H, H-2’, H-4’), 6.62 (ddd, J=8.2, 2.3, 0.6 Hz, 1H, H-
6’), 6.92 (dt, J=7.7, 1.4 Hz, 1H, H-6’’), 7.00 (ddd, J=8.1, 4.9, 1.5 Hz,
2H, H-3’’, H-5’’), 7.13 (dt, J=7.8, 1.5 Hz, 1H, H-4’’), 7.17 ppm (t, J=
8.1 Hz, 1H, H-5’); 13C NMR (125.77 MHz, CDCl3): d=19.4 (C-4’’’), 25.4
(C-5’’’), 30.5 (C-3’’’), 56.0 (OCH3), 62.2 (C-6’’’), 65.7 (C-1), 67.4 (C-2),
99.0 (C-2’’’), 104.0 (C-2’), 108.7 (C-6’), 109.6 (C-4’), 112.8 (C-3’’), 121.1
(C-6’’), 121.3 (C-5’’), 124.9 (C-4’’), 129.8 (C-5’), 144.8 (C-1’’), 151.5 (C-
2’’), 159.1 (C-1’), 160.1 ppm (C-3’); HRMS (ESI): m/z: calcd for
C20H24O5Na: 367.1521 [M+Na]+; found: 367.1515.
3-(4-Chlorophenoxy)phenoxyethanol (38):
A solution of 33
(417 mg, 1.2 mmol) in MeOH (75 mL) was treated with PPTS
(30 mg). The mixture was stirred at room temperature overnight
and was quenched as described in the method for the preparation
of 11. The product was purified by column chromatography
(hexane/EtOAc 9:1) to give pure alcohol 38 (219 mg, 69%) as a col-
orless oil: Rf =0.11 (hexane/EtOAc 8:2); 1H NMR (500.13 MHz,
CDCl3): d=1.98 (t, J=6.3, 1H, -OH), 3.95 (dt, J=6.0, 4.6 Hz, 2H, H-
1), 4.05 (dist.t, J=4.5 Hz, 2H, H-2), 6.56 (t, J=2.3 Hz, 1H, H-2’), 6.60
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3’’’b), 3.55 (m, 1H, H-6’’’a), 3.81 (s, 3H, OCH3), 3.82 (ddd, J=11.0, 6.5,
4.2 Hz, 1H, H-6’’’b), 3.91 (ddd, J=11.3, 8.2, 3.1 Hz, 1H, H-1a), 4.06
(m, 1H, H-1b), 4.14 (m, 2H, H-2), 4.72 (t, J=3.6 Hz, 1H, H-2’’’), 6.60–
6.64 (m, 4H, aromatic H), 6.68 (ddd, J=8.3, 2.3, 0.8 Hz, 1H, H-6’),
6.71 (ddd, J=8.3, 2.2, 0.9 Hz, 1H, H-6’’), 7.24 (t, J=8.5 Hz, 1H, H-5’),
7.25 ppm (t, J=8.1 Hz, 1H, H-5’’); 13C NMR (125.77 MHz, CDCl3): d=
19.3 (C-4’’’), 25.4 (C-5’’’), 30.5 (C-3’’’), 55.3 (OCH3), 62.2 (C-6’’’), 65.7
(C-1), 67.5 (C-2), 99.0 (C-2’’’), 105.0 (C-2’), 105.8 (C-2’’), 109.0 (C-6’),
109.7 (C-4’), 111.1 (C-4’’), 111.3 (C-6’’), 130.0 (C-5’), 130.1 (C-5’’),
158.1 (C-1’’), 158.2 (C-3’’), 160.2 (C-1’), 160.9 ppm (C-3’); HRMS (ESI):
m/z: calcd for C20H24O5Na: 367.1521 [M+Na]+; found: 367.1516.
3-(2-Methoxyphenoxy)phenoxyethanol (39): A solution of 34
(611 mg, 1.8 mmol) in MeOH (10 mL) was treated with PPTS
(30 mg). The mixture was stirred at room temperature overnight
and was quenched as described in the method for the preparation
of 11. The product was purified by column chromatography
(hexane/EtOAc 87:13) to give pure alcohol 39 (349 mg, 76%) as
1
a colorless oil: Rf =0.08 (hexane/EtOAc 4:1); H NMR (500.13 MHz,
CDCl3): d=2.00 (t, J=6.2, 1H, -OH), 3.84 (s, 3H, OCH3), 3.94 (m, 2H,
H-1), 4.04 (t, J=4.5 Hz, 2H, H-2), 6.52–6.55 (m, 2H, H-2’, H-4’), 6.61
(ddd, J=8.3, 2.3, 0.7 Hz, 1H, H-6’), 6.93 (dt, J=7.7, 1.4 Hz, 1H, H-
6’’), 7.00 (td, J=8.1, 1.4 Hz, 2H, H-3’’, H-5’’), 7.15 (dt, J=7.8, 1.4 Hz,
1H, H-4’’), 7.18 ppm (t, J=8.1 Hz, 1H, H-5’); 13C NMR (125.77 MHz,
CDCl3): d=56.0 (OCH3), 61.4 (C-1), 69.2 (C-2), 103.8 (C-2’), 108.5 (C-
6’), 109.7 (C-4’), 112.8 (C-3’’), 121.1 (C-6’’), 121.4 (C-5’’), 125.1 (C-4’’),
130.0 (C-5’), 144.6 (C-1’’), 151.5 (C-2’’), 159.3 (C-1’), 160.0 ppm (C-3’).
3-(3-Methoxyphenoxy)phenoxyethanol (40):
A solution of 5
(852 mg, 2.5 mmol) in MeOH (10 mL) was treated with PPTS
(30 mg). The mixture was stirred at room temperature overnight
and was quenched as described in the method for the preparation
of 11. The product was purified by column chromatography
(hexane/EtOAc 23:2) to give pure alcohol 40 (582 mg, 90%) as
3-(2-Methoxyphenoxy)phenoxyethyl 4-toluenesulfonate (44):
TsCl (767 mg, 4.02 mmol) was added to a solution of 39 (349 mg,
1.34 mmol) in pyridine (3 mL) as described in the method for the
preparation of 13. The product was purified by column chromatog-
raphy (silica gel, hexane/EtOAc 9:1) to give pure 44 (456 mg, 82%)
1
a colorless oil: Rf =0.10 (hexane/EtOAc 4:1); H NMR (500.13 MHz,
CDCl3): d=2.01 (brs, 1H, OH), 3.94 (dist.t, J=4.4 Hz, 2H, H-1), 3.78
(s, 3H, OCH3), 4.04 (t, J=4.5 Hz, 2H, H-2), 6.59 (m, 2H, aromatic H),
6.62 (m, 2H, aromatic H), 6.67 (dd, J=8.1, 2.2 Hz, 2H, H-6’, H-6’’),
7.22 ppm (t, J=8.1 Hz, 2H, H-5’, H-5’’); 13C NMR (125.77 MHz,
CDCl3): d=55.4 (OCH3), 61.4 (C-1), 69.2 (C-2), 105.1 (C-2’), 105.5 (C-
2’’), 109.1 (C-6’), 109.4 (C-4’), 111.2 (C-4’’), 111.5 (C-6’’), 130.1 (C-5’),
130.2 (C-5’’), 158.1 (C-1’’), 158.3 (C-3’’), 159.9 (C-1’), 160.9 ppm (C-
3’); HRMS (ESI): m/z: calcd for C15H17O4Na: 283.0946 [M+Na]+;
found: 283.0941.
1
as a white solid: Rf =0.13 (hexane/EtOAc 4:1); m.p. 928C; H NMR
(500.13 MHz, CDCl3): d=2.44 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 4.09
(m, 2H, H-1), 4.33 (m, 2H, H-2), 6.38 (t, J=2.4 Hz, 1H, H-2’), 6.47
(ddd, J=8.3, 2.4, 0.8 Hz, 1H, H-4’), 6.52 (ddd, J=8.2, 2.3, 0.8 Hz,
1H, H-6’), 6.93 (ddd, J=7.8, 7.4, 1.4 Hz, 1H, H-6’’), 6.98 (dd, J=7.9,
1.8 Hz, 1H, H-3’’), 7.01 (dd, J=8.2, 1.4 Hz, 1H, H-5’’), 7.14 (t, J=
8.2 Hz, 1H, H-4’’), 7.15 (ddd, J=8.1, 7.1, 2.0 Hz, 1H, H-5’), 7.32 (d,
J=8.0 Hz, 2H, H-3’’’), 7.80 ppm (d, J=8.3 Hz, 2H, H-2’’’); 13C NMR
(125.77 MHz, CDCl3): d=21.6 (PhCH3), 56.0 (OCH3), 65.4 (C-1), 68.0
(C-2), 103.9 (C-2’), 108.3 (C-6’), 110.0 (C-4’), 112.8 (C-3’’), 121.1 (C-
6’’), 121.4 (C-5’’), 125.1 (C-4’’), 128.0 (C-2’’’), 129.8 (C-3’’’), 130.0 (C-
5’), 132.8 (C-4’’’), 144.6 (C-1’’), 144.9 (C-1’’’), 151.5 (C-2’’), 159.3 (C-
1’), 160.0 ppm (C-3’); HRMS (ESI): m/z: calcd for C22H23O6S 415.1215
[M+H]+; found: 415.1219.
3-(3-Methoxyphenoxy)phenoxyethyl 4-toluenesulfonate (45):
TsCl (1.28 g, 6.71 mmol) was added to a solution of 36 (582 mg,
2.24 mmol) in pyridine (3 mL) following the method for the prepa-
ration of 13. The product was purified by column chromatography
(silica gel, hexane/EtOAc 4:1) to give pure 45 (209 mg, 59%) as
1
a colorless oil: Rf =0.22 (hexane/EtOAc 4:1); H NMR (500.13 MHz,
CDCl3): d=2.43 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 4.10 (m, 2H, H-1),
4.35 (m, 2H, H-2), 6.43 (t, J=2.4 Hz, 1H, H-2’), 6.53 (ddd, J=8.2,
2.4, 0.6 Hz, 1H, aromatic H), 6.57 (m, 2H, aromatic H), 6.61 (ddd,
J=8.2, 2.2, 0.7 Hz, 1H, H-6’), 6.67 (dd, J=8.1, 2.2 Hz, 1H, H-6’’), 7.19
(t, J=8.2 Hz, 1H, H-5’), 7.23 (t, J=8.1 Hz, 1H, H-5’’), 7.32 (d, J=
8.0 Hz, 2H, H-3’’’), 7.81 ppm (d, J=8.3 Hz, 2H, H-2’’’); 13C NMR
(125.77 MHz, CDCl3): d=21.6 (PhCH3), 55.4 (OCH3), 65.5 (C-1), 68.0
(C-2), 105.1 (C-2’), 105.6 (C-2’’), 109.1 (C-6’), 109.2 (C-4’), 111.2 (C-
4’’), 111.8 (C-6’’), 128.0 (C-2’’’), 129.8 (C-3’’’), 130.15 (C-5’), 130.18 (C-
5’’), 132.8 (C-4’’’), 145.0 (C-1’’’), 158.1 (C-1’’), 158.2 (C-3’’), 159.2 (C-
1’), 160.9 ppm (C-3’); HRMS (ESI): m/z: calcd for C22H23O6SNa:
437.1035 [M+Na]+; found: 437.1031.
3-(2-Methoxyphenoxy)phenoxyethyl thiocyanate (49): KSCN
(526 mg, 5.4 mmol) was added to a solution of 44 (449 mg,
1.08 mmol) in DMF (3 mL). The mixture was treated as described in
the method for the preparation of 15. The product was purified by
column chromatography (silica gel, hexane/EtOAc 93:7) to afford
49 (156 mg, 48%) as a colorless oil: Rf =0.22 (hexane/EtOAc 4:1);
1H NMR (500.13 MHz, CDCl3): d=3.31 (t, J=5.9 Hz, 2H, H-1), 3.84 (s,
3H, OCH3), 4.27 (t, J=5.9 Hz, 2H, H-2), 6.53 (t, J=2.3 Hz, 1H, H-2’),
6.56 (ddd, J=8.2, 2.3, 0.8 Hz, 1H, H-4’), 6.61 (ddd, J=8.2, 2.4,
0.7 Hz, 1H, H-6’), 6.94 (dt, J=7.7, 1.4 Hz, 1H, H-6’’), 7.00 (m, 2H, H-
3’’, H-5’’), 7.15 (ddd, J=8.1, 7.4, 1.7 Hz, 1H, H-4’’), 7.19 ppm (t, J=
8.2 Hz, 1H, H-5’); 13C NMR (125.77 MHz, CDCl3): d=33.3 (C-1), 56.0
(OCH3), 65.8 (C-2), 103.9 (C-2’), 108.5 (C-6’), 110.2 (C-4’), 111.7 (SCN),
112.9 (C-3’’), 121.1 (C-6’’), 121.5 (C-5’’), 125.2 (C-4’’), 130.1 (C-5’),
144.4 (C-1’’), 151.5 (C-2’’), 158.9 (C-1’), 159.4 ppm (C-3’); HRMS (ESI):
m/z: calcd for C16H15O3NS 324.0670 [M+Na]+; found: 324.0660.
3-(3-Methoxyphenoxy)phenoxyethyl thiocyanate (50): KSCN
(397 mg, 4.1 mmol) was added to a solution of 15 (339 mg,
0.82 mmol) in DMF (3 mL). The mixture was treated as detailed in
the method for the preparation of 15. The product was purified
by column chromatography (silica gel, hexane/EtOAc 19:1) to
afford 50 (112 mg, 45%) as a colorless oil: Rf =0.31 (hexane/EtOAc
3-(3-Methoxyphenoxy)phenoxyethyl
tetrahydro-2H-pyran-2-yl
1
ether (35): DMSO (3.0 mL) was added to a mixture of 30 (800 mg,
2.3 mmol), 3-methoxyphenol (570 mg, 4.6 mmol), CuI (43.8 mg,
0.23 mmol), 2-picolinic acid (56.6 mg, 0.46 mmol), and K3PO4
(978 mg, 4.6 mmol), and the mixture was stirred at 908C for 5 days
as described in the method for the preparation of 9. The product
was purified by column chromatography (silica gel, hexane/EtOAc
49:1) to afford pure 35 (505 mg, 64%) as a colorless oil: Rf =0.46
4:1); H NMR (500.13 MHz, CDCl3): d=3.32 (t, J=5.8 Hz, 2H, H-1),
3.79 (s, 3H, OCH3), 4.28 (t, J=5.8 Hz, 2H, H-2), 6.58–6.62 (m, 3H,
aromatic H), 6.65–6.69 (m, 3H, aromatic H), 7.24 ppm (dt, J=8.2,
3.5 Hz, 2H, H-5’, H-5’’); 13C NMR (125.77 MHz, CDCl3): d=33.2 (C-1),
55.4 (OCH3), 65.8 (C-2), 105.2 (C-2’), 105.6 (C-2’’), 109.2 (C-6’), 109.4
(C-4’), 111.3 (C-4’’), 111.7 (SCN), 112.1 (C-6’’), 130.2 (C-5’), 130.4 (C-
5’’), 157.9 (C-1’’), 158.4 (C-3’’), 159.0 (C-1’), 161.0 ppm (C-3’); HRMS
(ESI): m/z: calcd for C16H15O3NSNa: 324.0670 [M+Na]+; found:
324.0661.
1
(hexane/EtOAc 4:1); H NMR (500.13 MHz, CDCl3): d=1.53–1.68 (m,
4H, H-4’’’, H-5’’’), 1.73–1.79 (m, 1H, H-3’’’a), 1.82–1.89 (m, 1H, H-
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3-(2-Pyridyloxy)phenoxyethyl Tetrahydro-2H-pyran-2-yl Ether
(51): mixture of 30 (1.051 g, 3.0 mmol), 2-hydroxypyridine
purified by column chromatography (CH2Cl2/MeOH 49:1) to give
pure alcohol 54 (281 mg, 67%) as a white solid: Rf =0.12 (EtOAc);
m.p. 958C; 1H NMR (500.13 MHz, CDCl3): d=2.04 (brs, 1H, OH),
3.97 (dist.t, J=4.5 Hz, 2H, H-1), 4.12 (dist.t, J=4.6 Hz, 2H, H-2),
6.24 (dt, J=6.7, 1.3 Hz, 1H, H-4’’), 6.66 (dq, J=9.2, 0.7 Hz, 1H, H-6’),
6.96–7.00 (m, 3H, aromatic H), 7.33 (ddd, J=6.9, 2.1, 0.7 Hz, 1H, H-
3’’), 7.38–7.42 ppm (m, 2H, aromatic H); 13C NMR (125.77 MHz,
CDCl3): d=61.4 (C-1), 69.5 (C-2), 105.8 (C-2’), 113.2 (C-6’), 115.0 (C-
4’), 119.1 (C-6’’), 122.0 (C-4’’), 130.2 (C-5’), 137.8 (C-5’’), 139.9 (C-3’’),
142.0 (C-1’’), 159.2 (C-3’,), 162.3 ppm (C-1’).
A
(861 mg, 9.0 mmol), CuI (57.5 mg, 0.30 mmol), 2-picolinic acid
(74.3 mg, 0.60 mmol), and K3PO4 (1.928 g, 9.0 mmol) in DMSO
(3.0 mL) was treated as described in the method for the prepara-
tion of 9. The product was purified by column chromatography
(silica gel, hexane/EtOAc 2:3) to afford 51 (625 mg, 66%) as a color-
less oil: Rf =0.49 (EtOAc); 1H NMR (500.13 MHz, CDCl3): d=1.53–
1.68 (m, 4H, H-4’’’, H-5’’’), 1.73–1.79 (m, 1H, H-3’’’a), 1.82–1.88 (m,
1H, H-3’’’b), 3.56 (m, 1H, H-6’’’a), 3.85 (ddd, J=11.3, 6.2, 4.2 Hz, 1H,
H-6’’’b), 3.92 (ddd, J=11.3, 8.3, 3.1 Hz, 1H, H-1a), 4.08 (ddd, J=11.3,
5.0, 4.2 Hz, 1H, H-1b), 4.20 (m, 2H, H-2), 4.72 (t, J=3.6 Hz, 1H, H-
2’’’), 6.25 (dt, J=6.7, 1.3 Hz, 1H, H-4’’), 6.68 (dq, J=9.3, 0.7 Hz, 1H,
H-6’), 6.97–7.03 (m, 3H, aromatic H), 7.34 (ddd, J=6.9, 2.1, 0.7 Hz,
1H, H-3’’), 7.39–7.43 ppm (m, 2H, aromatic H); 13C NMR
(125.77 MHz, CDCl3): d=19.3 (C-4’’’), 25.4 (C-5’’’), 30.5 (C-3’’’), 62.2
(C-6’’’), 65.7 (C-1), 67.7 (C-2), 99.0 (C-2’’’), 105.8 (C-2’), 113.2 (C-6’),
115.1 (C-4’), 118.8 (C-6’’), 122.0 (C-4’’), 130.1 (C-5’), 137.8 (C-5’’),
139.8 (C-3’’), 141.9 (C-1’’), 159.5 (C-3’,), 162.4 ppm (C-1’); HRMS
(ESI): m/z: calcd for C18H22O4NNa: 338.1368 [M+Na]+; found:
338.1368.
3-(3-Pyridyloxy)phenoxyethanol (55): A solution of 52 (477 mg,
1.51 mmol) in MeOH (3 mL) was treated with PPTS (30 mg). The
mixture was stirred at room temperature overnight and was
quenched as described in the method for the preparation of 13.
The product was purified by column chromatography (hexane/
EtOAc 1:1) to give pure alcohol 55 (290 mg, 83%) as a colorless
1
oil: Rf =0.14 (hexane/EtOAc 1:1); H NMR (500.13 MHz, CDCl3): d=
2.07 (brs, 1H, OH), 3.96 (m, 2H, H-1), 4.01 (t, J=4.5 Hz, 2H, H-2),
6.60 (t, J=2.3 Hz, 1H, H-2’), 6.62 (ddd, J=8.1, 2.3, 0.7 Hz, 1H, H-4’),
6.72 (ddd, J=8.3, 2.4, 0.6 Hz, 1H, H-6’), 7.24–7.33 (m, 3H, aromatic
H), 8.38 (dd, J=4.5, 1.4 Hz, 1H, H-4’’), 8.42 ppm (d, J=2.7 Hz, 1H,
H-2’’); 13C NMR (125.77 MHz, CDCl3): d=61.3 (C-1), 69.3 (C-2), 105.6
(C-2’), 110.1 (C-6’), 111.4 (C-4’), 124.1 (C-6’’), 125.8 (C-5’’), 130.5 (C-
5’), 141.6 (C-2’’), 144.6 (C-4’’), 153.6 (C-1’’), 157.6 (C-1’), 160.1 ppm
(C-3’).
3-(3-Pyridyloxy)phenoxyethyl tetrahydro-2H-pyran-2-yl ether
(52): A mixture of 30 (900 mg, 2.6 mmol), 3-hydroxypyridine
(491 mg, 5.2 mmol), CuI (49.2 mg, 0.26 mmol), 2-picolinic acid
(63.6 mg, 0.52 mmol), and K3PO4 (1.100 g, 5.2 mmol) in DMSO
(3.0 mL) was stirred at 908C for 3 days. The product was purified
by column chromatography (silica gel, hexane/EtOAc 83:17) to
afford pure 52 (484 mg, 59%) as a colorless oil: Rf =0.09 (hexane/
3-(4-Pyridyloxy)phenoxyethanol (56): A solution of 53 (617 mg,
1.96 mmol) in MeOH (3 mL) was treated with PPTS (30 mg). The
mixture was stirred at room temperature overnight and was
quenched as described in the method for the preparation of 11.
The product was purified by column chromatography (CH2Cl2/
MeOH 97:3) to give alcohol 56 (156 mg, 34%) as a white solid: Rf =
1
EtOAc 4:1); H NMR (500.13 MHz, CDCl3): d=1.50–1.65 (m, 4H, H-
4’’’, H-5’’’), 1.71–1.76 (m, 1H, H-3’’’a), 1.79–1.85 (m, 1H, H-3’’’b), 3.52
(m, 1H, H-6’’’a), 3.80 (ddd, J=11.2, 6.4, 4.1 Hz, 1H, H-6’’’b), 3.89
(ddd, J=11.2, 8.2, 3.1 Hz, 1H, H-1a), 4.04 (m, 1H, H-1b), 4.13 (m, 2H,
H-2), 4.69 (t, J=3.7 Hz, 1H, H-2’’’), 6.60 (m, 2H, aromatic H), 6.73
(ddd, J=8.3, 2.2, 0.9 Hz, 1H, H-6’), 7.23–7.32 (m, 3H, H-5’’, H-6’’),
8.37 (d, J=3.7 Hz, 1H, H-4’’), 8.41 ppm (d, J=2.4 Hz, 1H, H-2’’);
13C NMR (125.77 MHz, CDCl3): d=19.4 (C-4’’’), 25.4 (C-5’’’), 30.5 (C-
3’’’), 62.2 (C-6’’’), 65.7 (C-1), 67.6 (C-2), 99.0 (C-2’’’), 105.8 (C-2’),
110.3 (C-6’), 111.2 (C-4’), 124.1 (C-6’’), 125.6 (C-5’’), 130.4 (C-5’),
141.6 (C-2’’), 144.4 (C-4’’), 153.7 (C-1’’), 157.5 (C-1’), 160.4 ppm (C-
3’).
1
0.45 (EtOAc/MeOH 3:2); m.p. 1178C; H NMR (500.13 MHz, CDCl3):
d=2.02 (t, J=6.2 Hz, 1H, -OH), 4.02 (m, 2H, H-1), 4.15 (t, J=4.5 Hz,
2H, H-2), 6.49 (d, J=7.8 Hz, 2H, H-2’’), 6.90 (t, J=2.3 Hz, 1H, H-2’),
6.95 (ddd, J=7.9, 2.2, 0.7 Hz, 1H, H-4’), 6.99 (ddd, J=8.4, 2.4,
0.7 Hz, 1H, H-6’), 7.43 (t, J=8.2 Hz, 1H, H-5’), 7.59 ppm (d, J=
7.8 Hz, 2H, H-3’’); 13C NMR (125.77 MHz, CDCl3): d=61.3 (C-1), 69.7
(C-2), 109.7 (C-2’’), 114.2 (C-2’), 115.2 (C-6’), 119.0 (C-4’), 131.2 (C-5’),
138.9 ppm (C-3’’).
3-(4-Pyridyloxy)phenoxyethyl tetrahydro-2H-pyran-2-yl ether
(53): A mixture of 30 (795 mg, 2.3 mmol), 4-hydroxypyridine
(436 mg, 4.6 mmol), CuI (43.7 mg, 0.23 mmol), 2-picolinic acid
(56.5 mg, 0.46 mmol), and K3PO4 (976 mg, 4.6 mmol) in DMSO
(3.0 mL) was stirred at 908C for 2 days. The product was purified
by column chromatography (silica gel, CH2Cl2/MeOH 97:3) to afford
53 (508 mg, 70%) as a colorless oil: Rf =0.14 (CH2Cl2/MeOH 19:1);
1H NMR (500.13 MHz, CDCl3): d=1.51–1.65 (m, 4H, H-4’’’, H-5’’’),
1.72–1.78 (m, 1H, H-3’’’a), 1.79–1.86 (m, 1H, H-3’’’b), 3.54 (m, 1H, H-
6’’’a), 3.84 (ddd, J=11.3, 6.4, 4.0 Hz, 1H, H-6’’’b), 3.89 (ddd, J=11.3,
8.3, 3.1 Hz, 1H, H-1a), 4.10 (m, 1H, H-1b), 4.21 (m, 2H, H-2), 4.70 (t,
J=3.7 Hz, 1H, H-2’’’), 6.49 (d, J=7.7 Hz, 2H, H-2’’), 6.91 (m, 2H, H-
2’, H-4’), 7.00 (ddd, J=8.3, 2.1, 0.6 Hz, 1H, H-6’), 7.41 (t, J=8.5 Hz,
1H, H-5’), 7.59 ppm (d, J=7.8 Hz, 2H, H-3’’); 13C NMR (125.77 MHz,
CDCl3): d=19.4 (C-4’’’), 25.3 (C-5’’’), 30.5 (C-3’’’), 62.4 (C-6’’’), 65.7
(C-1), 68.0 (C-2), 99.2 (C-2’’’), 109.9 (C-2’’), 114.4 (C-2’), 114.9 (C-6’),
119.0 (C-4’), 131.0 (C-5’), 139.0 (C-3’’), 144.2 (C-3’), 159.4 (C-1’),
179.1 ppm (C-1’’).
3-(2-Pyridyloxy)phenoxyethyl 4-toluenesulfonate (57): TsCl
(702 mg, 3.68 mmol) was added to a solution of 54 (284 mg,
1.22 mmol) in pyridine (3 mL), and the mixture was stirred at room
temperature for 4 h, and quenched as described in the method for
the preparation of 13. The residue was purified by column chroma-
tography (silica gel, hexane/EtOAc 35:75) to give pure 57 (289 mg,
61%) as a white solid: Rf =0.44 (EtOAc); m.p. 1578C; 1H NMR
(500.13 MHz, CDCl3): d=2.44 (s, 3H, PhCH3), 4.17 (m, 2H, H-1), 4.37
(m, 2H, H-2), 6.24 (dt, J=6.7, 1.3 Hz, 1H, H-4’’), 6.65 (dq, J=9.3,
0.6 Hz, 1H, H-6’), 6.82 (t, J=2.2 Hz, 1H, H-2’), 6.86 (ddd, J=8.4, 2.5,
0.8 Hz, 1H, H-6’’), 6.96 (ddd, J=6.9, 2.1, 0.7 Hz, 1H, H-5’), 7.30 (ddd,
J=7.9, 2.0, 0.9 Hz, 1H, H-3’’), 7.34–7.41 (m, 2H, aromatic H), 7.36
(d, J=8.1 Hz, 2H, H-3’’’), 7.82 ppm (d, J=8.3 Hz, 2H, H-2’’’);
13C NMR (125.77 MHz, CDCl3): d=21.6 (PhCH3), 65.7 (C-1), 67.9 (C-
2), 105.9 (C-2’), 113.3 (C-6’), 114.9 (C-4’), 119.4 (C-6’’), 122.0 (C-4’’),
128.0 (C-2’’’), 129.9 (C-3’’’), 130.2 (C-5’), 137.8 (C-5’’), 139.9 (C-3’’),
142.0 (C-1’’), 145.0 (C-1’’’), 158.6 (C-3’,), 162.3 ppm (C-1’).
3-(3-Pyridyl-3-yloxy)phenoxyethyl 4-toluenesulfonate (58): TsCl
(994 mg, 5.21 mmol) was added to a solution of 55 (402 mg,
1.74 mmol) in pyridine (3 mL) as described in the method for the
preparation of 13. The product was purified by column chromatog-
3-(2-Pyridyloxy)phenoxyethanol (54): A solution of 51 (575 mg,
1.82 mmol) in MeOH (10 mL) was treated with PPTS (30 mg) as de-
scribed in the method for the preparation of 11. The residue was
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raphy (silica gel, hexane/EtOAc 3:2) to give pure 58 (305 mg, 46%)
as a colorless oil: Rf =0.69 (EtOAc); 1H NMR (500.13 MHz, CDCl3):
d=2.44 (s, 3H, PhCH3), 4.13 (m, 2H, H-1), 4.36 (m, 2H, H-2), 6.45 (t,
J=2.3 Hz, 1H, H-2’), 6.60 (m, 2H, aromatic H), 7.29 (m, 3H, aromat-
ic H), 7.33 (d, J=8.1 Hz, 2H, H-3’’’), 7.81 (d, J=8.3 Hz, 2H, H-2’’’),
8.38 (dd, J=4.1, 1.5 Hz, 1H, H-4’’), 8.40 ppm (d, J=1.9 Hz, 1H, H-
2’’); 13C NMR (125.77 MHz, CDCl3): d=21.7 (PhCH3), 65.8 (C-1), 67.9
(C-2), 105.7 (C-2’), 109.9 (C-6’), 111.7 (C-4’), 124.1 (C-6’’), 125.7 (C-
5’’), 128.0 (C-2’’’), 129.9 (C-3’’’), 130.5 (C-5’), 132.8 (C-4’’’), 141.6 (C-
2’’), 144.6 (C-4’’), 145.0 (C-1’’’), 153.5 (C-1’’), 157.5 (C-1’), 159.4 ppm
(C-3’); HRMS (ESI): m/z: calcd for C20H20O5NS 386.1062 [M+H]+;
found: 386.1055.
chromatography (silica gel, CH2Cl2/MeOH 24:1) to afford 62
(37.0 mg, 87%) as a white solid: Rf =0.67 (EtOAc/MeOH 3:2); m.p.
528C; H NMR (500.13 MHz, CDCl3): d=3.37 (t, J=5.7 Hz, 2H, H-1),
4.39 (t, J=5.7 Hz, 2H, H-2), 6.49 (d, J=7.8 Hz, 2H, H-2’’), 6.93 (t, J=
2.3 Hz, 1H, H-2’), 7.00 (m, 2H, H-4’, H-6’), 7.46 (t, J=8.2 Hz, 1H, H-
5’), 7.60 ppm (d, J=7.8 Hz, 2H, H-3’’); 13C NMR (125.77 MHz, CDCl3):
d=33.0 (C-1), 66.3 (C-2), 109.9 (C-2’’), 111.4 (SCN), 113.9 (C-2’), 115.9
(C-6’), 119.0 (C-4’), 131.3 (C-5’), 138.9 (C-3’’), 144.3 (C-3’), 159.0 (C-
1’), 179.0 ppm (C-1’’); HRMS (ESI): m/z: calcd for C14H13O2N2S
273.0698 [M+H]+; found: 273.0704.
1
4-Phenoxyphenoxyethyl azide (64): NaN3 (213 mg, 3.28 mmol)
was added to a solution of 63 (252 mg, 0.66 mmol) in DMF (3 mL).
The mixture was heated at 1008C for 3 h. The mixture was allowed
to cool to room temperature and H2O (20 mL) was added. The
aqueous phase was extracted with CH2Cl2 (2ꢂ30 mL), and the
combined organic layer was washed with brine (5ꢂ30 mL) and
H2O (2ꢂ30 mL), dried (Na2SO4), and concentrated. The residue was
purified by column chromatography (silica gel, hexane) to give
pure 64 (59.5 mg, 35%) as a colorless oil: Rf =0.44 (hexane/EtOAc
4:1); 1H NMR (500.13 MHz, CDCl3): d=3.60 (t, J=5.0 Hz, 2H, H-1),
4.14 (t, J=5.0 Hz, 2H, H-2), 6.91 (d, J=9.1 Hz, 2H, H-2’), 6.95 (m,
2H, aromatic H), 6.99 (d, J=9.2 Hz, 2H, H-3’), 7.05 (tt, J=7.4,
1.1 Hz, 1H, H-4’’), 7.30 ppm (m, 2H, aromatic H); 13C NMR
(125.77 MHz, CDCl3): d=50.2 (C-1), 67.5 (C-2), 115.7 (C-2’’), 117.7 (C-
2’), 120.8 (C-3’), 122.6 (C-4’’), 129.6 (C-3’’), 150.8 (C-4’), 154.4 (C-1’),
158.3 ppm (C-1’’); HRMS (ESI): m/z: calcd for C14H13O2N3Na:
278.0905 [M+Na]+; found: 278.0892.
3-(4-Pyridyloxy)phenoxyethyl bromide (59): Ph3P (191 mg,
0.73 mmol) and NBS (129 mg, 0.73 mmol) were added to a mixture
of alcohol 56 (153 mg, 0.62 mmol) in CH2Cl2 (10 mL) at 08C. The
mixture was stirred at room temperature for 2 h. The reaction was
quenched by the addition of H2O (25 mL). Then, the mixture was
extracted with CH2Cl2 (3ꢂ15 mL). The combined organic layer was
washed with brine (3ꢂ50 mL), dried (Na2SO4), and concentrated.
The residue was purified by column chromatography (silica gel,
CH2Cl2/MeOH 24:1) to give pure 59 (45.9 mg, 24%) as a white
1
solid: Rf =0.34 (EtOAc/MeOH 3:2); m.p. 688C; H NMR (500.13 MHz,
CDCl3): d=3.67 (t, J=6.1 Hz, 2H, H-1), 4.35 (t, J=6.1 Hz, 2H, H-2),
6.50 (d, J=7.8 Hz, 2H, H-2’’), 6.90 (t, J=2.3 Hz, 1H, H-2’), 6.97 (m,
2H, H-4’, H-6’), 7.44 (t, J=8.2 Hz, 1H, H-5’), 7.59 ppm (d, J=7.8 Hz,
2H, H-3’’).
3-(2-Pyridyloxy)phenoxyethyl thiocyanate (60): KSCN (363 mg,
3.7 mmol) was added to a solution of 57 (288 mg, 0.75 mmol) in
DMF (3 mL). The mixture was treated as described in the method
for the preparation of 15. The product was purified by column
chromatography (silica gel, hexane/EtOAc 45:65) to afford 60
(141 mg, 69%) as a white solid: Rf =0.26 (EtOAc); m.p. 1428C;
1H NMR (500.13 MHz, CDCl3): d=3.35 (t, J=5.8 Hz, 2H, H-1), 4.35 (t,
J=5.8 Hz, 2H, H-2), 6.24 (dt, J=6.7, 1.3 Hz, 1H, H-4’’), 6.66 (dq, J=
9.2, 0.6 Hz, 1H, H-6’), 6.98–7.02 (m, 3H, aromatic H), 7.33 (ddd, J=
6.9, 2.1, 0.7 Hz, 1H, H-3’’), 7.39–7.44 ppm (m, 2H, aromatic H);
13C NMR (125.77 MHz, CDCl3): d=33.1 (C-1), 66.0 (C-2), 106.0 (C-2’),
111.6 (SCN), 113.3 (C-6’), 115.0 (C-4’), 119.8 (C-6’’), 122.0 (C-4’’), 130.4
(C-5’), 137.8 (C-5’’), 139.9 (C-3’’), 142.1 (C-1’’), 158.3 (C-3’,),
162.3 ppm (C-1’); HRMS (ESI): m/z: calcd for C14H12O2N2SNa:
295.0517 [M+Na]+; found: 295.0516.
2,4-Dibromophenoxyethyl tetrahydro-2H-pyran-2-yl ether (65): A
solution of 2,4-dibromophenol (1.5 g, 5.95 mmol) in DMSO (5 mL)
was treated with KOH (668 mg, 11.9 mmol) and bromoethyl tetra-
hydropyranyl ether (1.24 g, 5.95 mmol) as described in the method
for the preparation of 7. The residue was purified by column chro-
matography (silica gel, hexane/EtOAc 19:1) to afford pure 65
(293 mg, 46%) as a colorless oil: Rf =0.43 (hexane/EtOAc 4:1);
1H NMR (500.13 MHz, CDCl3): d=1.51–1.63 (m, 4H, H-4’’’, H-5’’’),
1.71–1.77 (m, 1H, H-3’’’a), 1.80–1.84 (m, 1H, H-3’’’b), 3.53 (m, 1H, H-
6’’’a), 3.86 (ddd, J=11.0, 5.9, 5.1 Hz, 1H, H-6’’’b), 3.92 (ddd, J=11.3,
8.5, 2.9 Hz, 1H, H-1a), 4.07 (m, 1H, H-1b), 4.19 (m, 2H, H-2), 4.77 (t,
J=3.6 Hz, 1H, H-2’’’), 6.82 (d, J=8.8 Hz, 1H, H-6’), 7.35 (dd, J=8.7,
2.4 Hz, 1H, H-5’), 7.66 ppm (d, J=2.4 Hz, 1H, H-2’); 13C NMR
(125.77 MHz, CDCl3): d=19.2 (C-4’’), 25.4 (C-5’’), 30.5 (C-3’’), 62.1 (C-
6’’), 65.4 (C-1), 69.1 (C-2), 99.0 (C-2’’), 113.1 (C-4’), 113.2 (C-2’), 114.8
(C-6’), 131.1 (C-5’), 135.5 (C-3’), 154.8 ppm (C-1’); HRMS (ESI): m/z:
calcd for C13H16O3Br2Na: 400.9364 [M+Na]+; found: 400.9370.
3-(3-Pyridyn-3-yloxy)phenoxyethyl thiocyanate (61): KSCN
(309 mg, 3.2 mmol) was added to a solution of 58 (245 mg,
0.64 mmol) in DMF (3 mL). The mixture was treated according to
the method for the preparation of 15. The product was purified by
column chromatography (silica gel, hexane/EtOAc 65:35) to afford
61 (73.5 mg, 64%) as a colorless oil: Rf =0.26 (hexane/EtOAc 1:1);
1H NMR (500.13 MHz, CDCl3): d=3.33 (t, J=5.9 Hz, 2H, H-1), 4.33 (t,
J=5.8 Hz, 2H, H-2), 6.61 (t, J=2.3 Hz, 1H, H-2’), 6.65 (ddd, J=8.2,
2.3, 0.7 Hz, 1H, H-4’), 6.72 (ddd, J=8.3, 2.3, 0.6 Hz, 1H, H-6’), 7.27–
7.34 (m, 3H, aromatic H), 8.38 (dd, J=4.6, 1.4 Hz, 1H, H-4’’),
8.42 ppm (d, J=2.7 Hz, 1H, H-2’’); 13C NMR (125.77 MHz, CDCl3):
d=33.2 (C-1), 65.9 (C-2), 105.8 (C-2’), 110.0 (C-6’), 111.6 (SCN), 112.0
(C-4’), 124.1 (C-6’’), 125.8 (C-5’’), 130.7 (C-5’), 141.7 (C-2’’), 144.7 (C-
4’’), 153.4 (C-1’’), 157.7 (C-1’), 159.2 ppm (C-3’); HRMS (ESI): m/z:
calcd for C14H13O2N2S 273.0698 [M+H]+; found: 273.0702.
2,4-Dibromophenoxyethanol (66):
A solution of 65 (1.04 g,
2.74 mmol) in MeOH (10 mL) was treated with PPTS (30 mg). The
mixture was stirred at room temperature overnight and was
quenched as described in the method for the preparation of 6.
The product was purified by column chromatography (hexane/
EtOAc 43:7) to give pure alcohol 66 (568 mg, 70%) as a white
solid: Rf =0.14 (hexane/EtOAc 4:1); m.p. 598C; 1H NMR
(500.13 MHz, CDCl3): d=2.15 (t, J=6.5 Hz, 1H, OH), 3.99 (dt, J=6.2,
4.6 Hz, 2H, H-1), 4.12 (t, J=4.5 Hz, 2H, H-2), 6.80 (d, J=8.7 Hz, 1H,
H-6’), 7.38 (dd, J=8.7, 2.4 Hz, 1H, H-5’), 7.68 ppm (d, J=2.4 Hz, 1H,
H-2’); 13C NMR (125.77 MHz, CDCl3): d=61.2 (C-1), 71.0 (C-2), 113.4
(C-4’), 113.6 (C-2’), 114.9 (C-6’), 131.3 (C-5’), 135.6 (C-3’), 154.3 ppm
(C-1’); HRMS (ESI): m/z: calcd for C8H8O2Br2Na: 316.8789 [M+Na]+;
found: 316.8773.
3-(4-Pyridyloxy)phenoxyethyl thiocyanate (62): KSCN (75.8 mg,
0.78 mmol) was added to a solution of 57 (45.9 mg, 0.16 mmol) in
DMF (3.0 mL). The mixture was treated as described in the method
for the preparation of 15. The product was purified by column
2,4-Dibromophenoxyethyl 4-toluenesulfonate (67): TsCl (1.10 g,
5.76 mmol) was added to a solution of 66 (568 mg, 1.92 mmol) in
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ꢁ 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ

Full Papers
pyridine (3 mL) as described in the method for the preparation of
13. The product was purified by column chromatography (silica
gel, hexane/EtOAc 9:1) to give pure 67 (725 mg, 84%) as a colorless
3-Pyridyloxyethyl
4-toluenesulfonate
(71):
TsCl
(1.25 g,
6.54 mmol) was added to a solution of 70 (303 mg, 2.18 mmol) in
pyridine (3 mL) as described in the method for the preparation of
13. The product was purified by column chromatography (silica
gel, hexane/EtOAc 13:7) to give pure 71 (441 mg, 69%) as a color-
1
oil: Rf =0.33 (hexane/EtOAc 4:1); H NMR (500.13 MHz, CDCl3): d=
2.44 (s, 3H, PhCH3), 4.22 (m, 2H, H-1), 4.42 (m, 2H, H-2), 6.71 (d, J=
8.8 Hz, 1H, H-6’), 7.350 (d, J=8.7, 2H, H-3’’), 7.353 (dd, J=8.5,
2.4 Hz, 1H, H-5’), 7.66 (d, J=2.4 Hz, 1H, H-2’), 7.84 ppm (d, J=8.3,
2H, H-3’’); 13C NMR (125.77 MHz, CDCl3): d=21.7 (PhCH3), 66.8 (C-
1), 67.6 (C-2), 113.4 (C-4’), 114.0 (C-2’), 114.8 (C-6’), 128.0 (C-2’’),
129.9 (C-3’’), 131.2 (C-5’), 132.6 (C-4’’), 135.7 (C-3’), 145.0 (C-1’’),
153.8 ppm (C-1’); HRMS (ESI): m/z: calcd for C15H14O4SBr2Na:
470.8877 [M+Na]+; found: 470.8864.
1
less oil: Rf =0.48 (EtOAc); H NMR (500.13 MHz, CDCl3): d=2.45 (s,
3H, PhCH3), 4.21 (m, 2H, H-1), 4.40 (m, 2H, H-2), 7.24 (m, 2H, aro-
matic H), 7.35 (d, J=8.0, 2H, H-3’’), 7.82 (d, J=8.4, 2H, H-3’’), 8.22
(d, J=3.0 Hz, 1H, H-2’), 8.25 ppm (dd, J=4.7, 1.3 Hz, 1H, H-4’);
HRMS (ESI): m/z: calcd for C14H16O4NS 294.0800 [M+H]+; found:
294.0798.
3-Pyridyloxyethyl thiocyanate (72): KSCN (683 mg, 7.04 mmol)
was added to a solution of 71 (413 mg, 1.41 mmol) in DMF (3 mL).
The mixture was treated as detailed in the method for the prepara-
tion of 15. The product was purified by column chromatography
(silica gel, hexane/EtOAc 7:3) to afford 72 (107 mg, 42%) as a color-
2,4-Dibromophenoxyethyl thiocyanate (68): KSCN (782 mg,
8.05 mmol) was added to a solution of 67 (725 mg, 1.61 mmol) in
DMF (3 mL). The mixture was treated as described in the method
for the preparation of 15. The product was purified by column
chromatography (silica gel, hexane/EtOAc 23:2) to afford 68
(405 mg, 75%) as a white solid: Rf =0.34 (hexane/EtOAc 4:1); m.p.
1
less oil: Rf =0.38 (EtOAc); H NMR (500.13 MHz, CDCl3): d=3.37 (t,
J=5.8 Hz, 2H, H-1), 4.38 (t, J=5.8 Hz, 2H, H-2), 7.25 (m, 2H, aro-
matic H), 8.30 (dd, J=4.0, 2.0 Hz, 1H, H-4’), 8.35 ppm (m, 1H, H-2’);
13C NMR (125.77 MHz, CDCl3): d=33.1 (C-1), 66.1 (C-2), 111.4 (SCN),
121.5 (C-6’), 124.0 (C-5’), 137.9 (C-2’), 143.3 (C-4’), 154.1 ppm (C-1’);
HRMS (ESI): m/z: calcd for C8H8ON2SNa: 203.0255 [M+Na]+; found:
203.0255.
1
858C; H NMR (500.13 MHz, CDCl3): d=3.39 (t, J=5.9 Hz, 2H, H-1),
4.34 (t, J=5.9 Hz, 2H, H-2), 6.81 (d, J=8.7 Hz, 1H, H-6’), 7.40 (dd,
J=8.7, 2.4 Hz, 1H, H-5’), 7.70 ppm (d, J=2.4 Hz, 1H, H-2’); 13C NMR
(125.77 MHz, CDCl3): d=33.0 (C-1), 67.3 (C-2), 111.5 (SCN), 113.5 (C-
4’), 114.5 (C-2’), 115.1 (C-6’), 131.4 (C-5’), 135.9 (C-3’), 153.6 ppm (C-
1’); HRMS (ESI): m/z: calcd for C9H7ONSBr2Na: 357.8513 [M+Na]+;
found: 357.8508.
Drug screening
3-Pyridyloxyethyl tetrahydro-2H-pyran-2-yl ether (69): A solution
of 3-hydroxypyridine (1 g, 10.5 mmol) in DMSO (5 mL) was treated
with KOH (1.18 g, 21.0 mmol). The suspension was stirred for
30 min at room temperature. Then, bromoethyl tetrahydropyranyl
ether (2.20 g, 10.5 mmol) was added, and the mixture was stirred
at room temperature overnight. The mixture was partitioned be-
tween CH2Cl2 (30 mL) and H2O (30 mL). The aqueous phase was ex-
tracted with CH2Cl2 (2ꢂ70 mL). The combined organic layer was
washed with a saturated solution of NaCl (2ꢂ100 mL), dried
(Na2SO4), and concentrated. The residue was purified by column
chromatography (silica gel, hexane/EtOAc 7:3) to afford pure 69
(736 mg, 31%) as a yellow oil: Rf =0.26 (hexane/EtOAc 1:1);
1H NMR (500.13 MHz, CDCl3): d=1H NMR (500.13 MHz, CDCl3) d=
1.52–1.65 (m, 4H, H-4’’’, H-5’’’), 1.71–1.77 (m, 1H, H-3’’’a), 1.81–1.85
(m, 1H, H-3’’’b), 3.53 (m, 1H, H-6’’’a), 3.83 (ddd, J=11.4, 6.3, 3.9 Hz,
1H, H-6’’’b), 3.89 (ddd, J=11.2, 8.1, 3.2 Hz, 1H, H-1a), 4.08 (ddd, J=
11.4, 5.2, 4.0 Hz, 1H, H-1b), 4.12 (m, 2H, H-2), 4.71 (t, J=3.6 Hz, 1H,
H-2’’’), 7.23 (m, 2H, aromatic H), 8.24 (dd, J=4.4, 1.5 Hz, 1H, H-4’),
8.34 ppm (t, J=2.7 Hz, 1H, H-2’); 13C NMR (125.77 MHz, CDCl3): d=
19.3 (C-4’’), 25.3 (C-5’’), 30.4 (C-3’’), 62.2 (C-6’’), 65.7 (C-1), 67.7 (C-2),
99.1 (C-2’’), 121.2 (C-6’), 123.9 (C-5’), 138.0 (C-2’), 142.5 (C-4’),
154.9 ppm (C-1’); HRMS (ESI): m/z: calcd for C12H18O3N 224.1287
[M+H]+; found: 224.1291.
T. cruzi amastigote assays: These experiments were done as re-
ported by using tdTomato labeled trypomastigotes[31] with the
modifications described by Recher et al.[32] ED50 values were deter-
mined by nonlinear regression analysis by using SigmaPlot.
T. gondii tachyzoites assays: Experiments on T. gondii tachyzoites
were performed as described previously[33] by using T. gondii tachy-
zoites expressing red fluorescent protein[34] with the modifications
described by Recher et al.[32] Plates were read with covered lids,
and both excitation (544 nm) and emission (590 nm) were read
from the bottom.
Cytotoxicity toward Vero cells: The cytotoxicity was tested by
using the Alamar Blue assay, as described by Recher et al.[32]
Acknowledgements
This work was supported by grants from the National Research
Council of Argentina (PIP 0797), Agencia Nacional de Promociꢂn
Cientꢀfica y Tecnolꢂgica (ANPCyT) (PICT 2012 #0457), and the Uni-
versidad de Buenos Aires (20020130100223BA) to J.B.R., the
Bunge & Born Foundation to S.H.S, and the US National Institutes
of Health to R.D. (AI-107663) and S.N.J.M. (AI-102254).
3-Pyridyloxyethanol (70): A solution of 69 (725 mg, 3.25 mmol) in
MeOH (3 mL) was treated with PTSA (30 mg). The mixture treated
as detailed in the method for the preparation of 11. The product
was purified by column chromatography (hexane/EtOAc 3:7) to
give pure alcohol 70 (304 mg, 67%) as a yellow oil: Rf =0.19
Keywords: antiparasitic agents
chemotherapeutic agents
relationships
·
biological activity
·
·
inhibitors structure–activity
·
1
(EtOAc); H NMR (500.13 MHz, CDCl3): d=2.34 (brs, 1H, OH), 4.00
(dist.t, J=4.8 Hz, 2H, H-1), 4.14 (dist.t, J=4.1 Hz, 2H, H-2), 7.23 (m,
2H, aromatic H), 8.24 (t, J=3.0 Hz, 1H, H-4’), 8.34 ppm (t, J=
1.8 Hz, 1H, H-2’); 13C NMR (125.77 MHz, CDCl3): d=61.3 (C-1), 69.6
(C-2), 121.2 (C-6’), 123.9 (C-5’), 138.0 (C-2’), 142.5 (C-4’), 154.9 ppm
(C-1’); HRMS (ESI): m/z: calcd for C7H10O2N 140.0712 [M+H]+;
found: 140.0710.
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Received: March 4, 2015
Published online on && &&, 0000
ChemMedChem 0000, 00, 0 – 0
www.chemmedchem.org
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ꢁ 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
These are not the final page numbers! ÞÞ

FULL PAPERS
M. N. Chao, C. E. Matiuzzi, M. Storey, C. Li,
S. H. Szajnman, R. Docampo,
Finding the WC: WC-9 is a well-known
antichagasic agent targeting squalene
synthase. We describe the design, syn-
thesis, and biological evaluation of WC-
9 analogues bearing the aryloxy moiety
bonded either at the C-4’ or the C-3’
position of the A ring. Some of the ana-
logues are effective growth inhibitors of
both Trypanosoma cruzi and Toxoplasma
gondii, the etiologic agents of Chagas
disease and toxoplasmosis, respectively.
S. N. J. Moreno, J. B. Rodriguez*
&& – &&
Aryloxyethyl Thiocyanates Are Potent
Growth Inhibitors of Trypanosoma
cruzi and Toxoplasma gondii
&
ChemMedChem 0000, 00, 0 – 0
www.chemmedchem.org
16
ꢁ 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!