reactions. Because of the presence of (up to) four positive
charges preorganized within a macrocyclic ring, S-
alkylated thiacalix[4]arenes could play the role of anion
receptors as an analogy with well-known polyammonium
cage-like structures.6 Hence, we decided to study this
phenomenon to gain deeper understanding of possibilities
and limitations of sulfur alkylation in a thiacalixarene
series.
Derivative 17 immobilized in the cone conformation
was selected as a representative of tetra-O-alkylated thi-
acalix[4]arenes. This compound is known to yield stereo-
selectively the rccc-isomer of tetrasulfinylcalixarene during
its oxidation;8,9 therefore, one may expect similar prefer-
ences on the sulfur atoms in the alkylation reactions
(Scheme 1). Compound 1 was treated with commercially
available alkylating reagents (12 equiv of methyl deri-
vatives were used): iodide, tosylate, brosylate, nosylate,
mesylate, triflate, and trimethyloxonium tetrafluoroborate
(Meerwein’s salt).10 The reactionswere carried out at room
temperature or at reflux for 3 days.
were obtained in acceptable yields (56% and 48%, respec-
tively, entries 14 and 15).
To review the general applicability of these reaction
conditions, reagents bearing longer alkyl groups have been
also tested. Thus, ethyl triflate in DCM at rt did not show
any alkylation reaction, while the same reaction under
reflux gave mono derivative 2b in an acceptable yield
(47%). The change of solvent to DCE and longer reaction
time enabled us to isolate bis-derivative 3b in an essen-
tially quantitative yield. Interestingly, the alkylation with
Et3OBF4 gave only monoalkyl compound 2e (87% yield)
after 10 days reflux in DCE. This indicates that the
application of Meerwein’s salts with longer alkyl chains
is limited only to the monoalkylation of 1. As the corre-
sponding agents withlonger alkyl groups are commercially
unavailable, pentyl triflate was prepared from pentan-1-ol
and was used without any purification for the subsequent
alkylation of 1. Depending on the reaction conditions,
mono-S-pentyl and bis-S-pentyl derivatives 2c and 3c were
smoothly obtained in 55 and 71% yields, respectively, thus
indicating a general applicability of alkyl triflates for the
thiacalixarene S-alkylation. It is worth mentioning that the
new derivatives, unlike starting thiacalixarene 1, are very
well soluble in polar solvents like methanol, acetone, or
ethanol. Taking into account the ionic character of S-
alkylated compounds, unexpectedly low melting tempera-
tures were measured (mp 65 °C for 2d or 95 °C for 2b),
which is surprising among thiacalixarene derivatives pos-
sessing usually very high melting points.
Scheme 1. S-Alkylation Reactions of Cone Derivative 1
Table 1. Reaction Conditions Survey for S-Alkylation of 1
Depending on the reagent used, we observed mainly no
reaction (in the case of iodide, tosylate, brosylate, nosylate,
and mesylate), and unreacted starting compound 1 was
recycled from the reaction mixture (Table 1, entries 1ꢀ5).
On the other hand, in the case of triflate, the formation of
new compounds was observed. Thus, stirring 1 with 12
equiv of MeOTf in DCM (entry 6) for 3 days gave
monoalkylated compound 2a (58% yield). While the use
of acetonitrile did not lead to better yield (entry 8), DCE as
a solvent (entry 7) gave a much higher yield of 2a after 1 h
of reflux (93%). Interestingly, the larger excess of the
alkylating agent (36 equiv) led smoothly to dialkylated
compound 3a in a very good yield (89% in DCM, 88% in
DCE, entries 9 and 10). Using the Meerwein’s salt
Me3OBF4, similar results were achieved. Again, depending
on the excess of the alkylating agents, derivatives 2d and 3d
yield of yield of
entry reagenta equiv (time) solventc/ temp 2 (%)
3 (%)
1
2
MeI
12 (3 d)
12 (3 d)
12 (3 d)
12 (3 d)
12 (3 d)
12 (3 d)
12 (1 h)
12 (3 d)
36 (2 d)
36 (18 h)
12 (2 d)
24 (3 d)
36 (5 d)
12 (5 d)
36 (10 d)
36 (10 d)
DCM/rt
DCM/rt
DCM/rt
DCM/rt
DCM/rt
DCM/rt
DCE/reflux
0b
0
MeOTs
MeOBs
MeONs
MeOMs
MeOTf
MeOTf
MeOTf
MeOTf
MeOTf
EtOTf
0b
0
3
0b
0
4
0b
0
5
0b
0
6
2a (58)
2a (93)
0
7
0
8
MeCN/reflux 2a (30)
0
9
DCM/reflux
DCE/reflux
DCM/rt
0
3a (89)
3a (88)
0
10
11
12
13
14
15
16
0
0b
EtOTf
DCM/reflux
DCE/reflux
DCE/reflux
DCE/reflux
DCE/reflux
2b (47)
0
EtOTf
0
3b (98)
Me3OBF4
Me3OBF4
Et3OBF4
2d (56) 3d (31)
2d (17) 3d (48)
2e (87)
0
a OTs = p-toluenesulfonate, OBs = 4-bromobenzenesulfonate,
ONs = 4-nitrobenzenesulfonate, OTf = triflate. b No reaction observed
(starting material recovered). c DCE = 1,2-dichloroethane.
(6) Sessler, J. L.; Gale, P. A.; Cho, W. S. Anion Receptor Chemistry;
Royal Society of Chemistry: Cambridge, 2008; pp 27ꢀ130.
(7) Himl, M.; Pojarova, M.; Stibor, I.; Sykora, J.; Lhotak, P. Tetra-
hedron Lett. 2005, 46, 461.
(8) Lhotak, P.; Moravek, J.; Smejkal, T.; Stibor, I.; Sykora, J.
Tetrahedron Lett. 2003, 44, 7333.
(9) For other modifications of sulfur bridges, see: Morohashi, N.;
Kojima, M.; Suzuki, A.; Ohba, Y. Heterocycl. Commun. 2005, 11, 249–
254.
(10) For the alkylation of diphenyl sulfide, see: Wyatt, P.; Hudson,
A.; Charmant, J.; Orpen, A. G.; Phetmung, H. Org. Biomol. Chem. 2006,
4, 2218.
The structures of alkylated products were assigned by
MS. Thus, MS ESIþ analysis of monoalkylated com-
pounds showed signals at m/z = 679.20 for S-methyl 2a
or 2d and m/z = 693.24 for S-ethyl salts 2b and 2e, which
correspond to the molecular weights of cations formed.
Org. Lett., Vol. 13, No. 15, 2011
4033