Synthesis of electron-rich thiamacrocycles

Article abstract of DOI:10.1055/s-0030-1258297

The stepwise syntheses of large [4+4] electron-rich thiamacrocycles, which aim at fullerene complexation, were performed using two types of building blocks, viz. 1,4-bis(bromomethyl)benzene or its dibutoxylated analogue and 4,5-bis(2-cyanoethyl-sulfanyl)-

Full text of DOI:10.1055/s-0030-1258297

PAPER
4169
Synthesis of Electron-Rich Thiamacrocycles
S
ynthesis of
E
e
lectron-Ric
t
h
T
hia
m
r
acrocycles Holý,*a Michal Buchta,a,b Jiří Rybáček,a Jana Hodačová,a,b Ivana Císařovác
a
Institute of Organic Chemistry and Biochemistry, v.v.i., Academy of Sciences of the Czech Republic, Flemingovo n. 2., 166 10 Prague 6,
Czech Republic
Fax +420(2)20183560; E-mail: petrholy@uochb.cas.cz
Department of Organic Chemistry, Institute of Chemical Technology Prague, Technická 5, 166 28 Prague 6, Czech Republic
Department of Inorganic Chemistry, Faculty of Natural Sciences, Charles University, Prague, Hlavova 2030, 128 40 Prague 2,
Czech Republic
b
c
Received 13 August 2010; revised 17 September 2010
groups can be selectively removed by a stoichiometric
amount of base.8 Such controlled liberation of thiolate
species facilitates the preparation of proper acyclic pre-
cursors in the overall synthesis of macrocycles. Here we
Abstract: The stepwise syntheses of large [4+4] electron-rich thia-
macrocycles, which aim at fullerene complexation, were performed
using two types of building blocks, viz. 1,4-bis(bromomethyl)ben-
zene or its dibutoxylated analogue and 4,5-bis(2-cyanoethyl-
sulfanyl)-1,3-dithiole-2-thione. Alternatively, a multicomponent present a new series of electron-rich thiamacrocycles pos-
mixture of thiamacrocycles, ranging in size from [2+2] to [6+6]
sessing scalable internal cavities, which should be consid-
units, was generated by the direct reaction of bis(tetraethylammoni-
ered as prospective ligands for size-matched acceptors
um) bis(thioxo-1,3-dithiole-4,5-dithiol)zincate with 1,4-bis(bro-
starting with small guests, optionally even chiral, up to
momethyl)-2,5-dibutoxybenzene, and the individual macrocycles
spacious molecules like fullerenes.
were successfully separated.
Considering the protected dithiole 1 and 1,4-bis(bromo-
methyl)benzene (2a) as two complementary building
blocks, we have shown by simple molecular modeling
that a [4+4] cyclic arrangement of these units forms a cav-
ity large enough for a conceivable inclusion of fullerene
C60. Therefore we designed and performed9 the synthesis
of the large [4+4] thiamacrocycle 6a based on several suc-
cessive deprotection/alkylation steps illustrated in
Scheme 1. This trial procedure provided reasonable yields
in all steps, but the limited solubility of the final com-
pound 6a rendered any solution-phase complexation ex-
Key words: alkylation, arenes, atropoisomerism, macrocycles, thi-
ols
The chemistry of cyclic ligands attracts continued atten-
tion due to their preformed cavities, which facilitate inter-
actions with selected guests. 1,3-Dithiole-2-thione units
and especially the related tetrathiafulvalene derivatives
(TTFs), well-known electron-rich redox-active compo-
nents, have been widely used in macrocyclic and su-
pramolecular chemistry.1 4,5-Disulfanyl-1,3-dithiole-2-
thione units have been employed as link elements in the
formation of heteroaromatic macro-rings2 or in the struc-
ture of crown-ether-like macrocycles of different ring
size.3 Macro-rings composed of electron-rich TTF units
are known to be good ligands for various electron-poor
compounds, particularly for cyclic bipyridinium accep-
tors.4 Also, a strong monocation–p interaction has been
observed, e.g. for different ammonium ions and electron-
rich cyclophane receptors.5
periments
impossible.
Nevertheless,
a
cation
complexation study was performed in the gas phase.9 Af-
ter this we decided to repeat this synthetic scheme with a
more suited aromatic building block, namely 1,4-bis(bro-
momethyl)-2,5-dibutoxybenzene (2b). Apart from the de-
sired effect on solubility, the alkoxy groups also promote
the electron-donating character of the target macrocyclic
ligand 6b.
The macro-ring construction in 6a,b proceeded in four
steps (Scheme 1). While the monothiolate derived from 1
reacted with only one bromomethyl group of 2a,b (used in
large excess) to give the two-membered acyclic precur-
sors 3a,b, its reaction with both functional groups of 2a,b
afforded the three-sectional compounds 4a,b in very good
yields. The double attachment of the two-membered parts
3a,b onto the three-sectional block of 4a,b gave smoothly
the seven-membered precursors 5a,b. The final cycliza-
tions of acyclic components 5a,b with bis(bromomethyl)
derivatives 2a,b were performed under high-dilution con-
ditions leading to the [4+4] thiamacrocycles 6a,b in satis-
factory yields.
Fullerenes represent another kind of weak electron-accep-
tor that are the center of attention for their unique proper-
ties. Many ligands, both cyclic and noncyclic, were
synthesized and the formation of their inclusion complex-
es with fullerenes was studied,6 but only a few of them
feature the dithiolethione or TTF units.7
An obvious obstacle in any preparation of macrocycles is
the inevitable formation of linear oligomers as byprod-
ucts. In this regard, 4,5-bis(2-cyanoethylsulfanyl)-1,3-
dithiole-2-thione (1) is a very profitable building block
because either one or both of its cyanoethyl protective
The 1H and 13C NMR spectra confirmed the symmetry of
the final [4+4] macrocycles and their elemental composi-
tions were unambiguously confirmed by HRMS measure-
ments.
SYNTHESIS 2010, No. 24, pp 4169–4176
Advanced online publication: 14.10.2010
DOI: 10.1055/s-0030-1258297; Art ID: T15910SS
© Georg Thieme Verlag Stuttgart · New York
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x.
x
x
.
2
0
1
0

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P. Holý et al.
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S
S
S
S
R
R
S
S
S
S
S
S
a
S
S
b
Br
NC
S
S
NC
S
S
CN
S
S
CN
NC
S
S
R
R
3a,b
1
4a,b
c
R
S
S
S
S
S
S
R
S
S
S
S
S
S
S
S
S
S
R
S
S
S
S
R
R
R
R
R
d
R
S
R
R
R
CN
NC
S
S
S
S
S
S
S
S
R
S
S
S
S
S
S
S
S
a R = H
b R = OBu
S
S
S
R
5a,b
6a,b
Scheme 1 Four-step synthesis of [4+4] macrocycles. Reaction conditions: (a) (i) CsOH (1 equiv), MeOH, r.t., 45 min; (ii) 2a or 2b (12 equiv),
DMF, r.t., 5 h, 42% (3a), 67% (3b); (b) (i) CsOH (1 equiv), MeOH, r.t., 45 min; (ii) 2a or 2b (0.5 equiv), DMF, r.t., 5 h, 69% (4a), 91% (4b);
(c) (i) CsOH (2 equiv), MeOH, r.t., 45 min; (ii) 3a or 3b (2 equiv), DMF, r.t., 4 h, 79% (5a), 72% (5b); (d) (i) CsOH (2 equiv), MeOH, r.t., 30
min; (ii) 2a or 2b (1 equiv), DMF, 8 h, dual-syringe pump, then 20 h, r.t., 26% (6a), 48% (6b).
The crystal structure of the [4+4] macrocycle 6b We also attempted the reaction of dithiolates derived from
(Figure 1) served as independent proof of the constitution 4a or 4b with two equivalents of bis(bromomethyl) deriv-
of the target compound. Strong p-p interactions between atives 2a or 2b. However, regardless of the structure of the
the aromatic segments were found to play an important bis(bromomethyl) unit, the small [2+2] macrocycles 8a,b
role in the conformation of the macrocycle [Figure 1 (a)] were formed as the dominant products instead of the de-
as well as in the crystal packing [Figure 1 (b)].
sired five-sectional precursors 7a,b (Scheme 2). Higher
isolated yields of 8a,b were obtained using an equimolar
ratio of the components (4a + 2a) or (4b + 2b). In the latter
case we have also proved by thorough chromatography of
the crude product the formation of the even-numbered
The solubility of the macrocycle 6b in toluene or chloro-
form is quite sufficient for a complexation study with
fullerene C60, but a preliminary measurement by UV-vis
spectroscopy did not provide distinct proof of an interac-
tion of the ligand 6b with C60.
Figure 1 The crystal structure of the [4+4] macrocycle 6b: (a) This shows the conformation of the macro-ring directed by intramolecular p-p
interactions. Only one position of disordered butyl moiety was drawn for clarity. (b) This shows molecular stacks (outlined in different colors)
are governed by intermolecular p-p stacking.
Synthesis 2010, No. 24, 4169–4176 © Thieme Stuttgart · New York

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Synthesis of Electron-Rich Thiamacrocycles
4171
S
S
R
S
S
S
S
S
S
S
S
R
R
R
R
R
S
S
R
Br
Br
S
S
a
b
S
S
7a,b
S
S
CN
NC
S
S
R
R
4a,b
S
S
S
S
S
S
S
S
R
S
S
a R = H
b R = OBu
R
R
R
R
S
S
S
S
8a,b : n = 0
6b : n = 2
9b : n = 4
n
S
Scheme 2 Formation of the [2+2] macrocycles. Reaction conditions: (a) (i) CsOH (2 equiv), MeOH, r.t., 15 min; (ii) 2a or 2b (2.2 equiv),
DMF, r.t., 5 h; (b) (i) CsOH (2 equiv), MeOH, r.t., 15 min; (ii) 2a or 2b (1.0 equiv), DMF, r.t., 5 h, 54% (8a), 39% (8b), 16% (6b), 5% (9b).
[4+4] macrocycle 6b and [6+6] macrocycle 9 as minor of the first-eluted isomer 8b-anti confirmed its chiral na-
components.
ture [Figure 3 (b)]; the meso configuration belongs to the
second isomer 8b-syn [Figure 3 (a)].
Notably, the [2+2] macrocycle 8b was in some respect
different from its 8a analogue. 1H and 13C NMR spectra of Additional proof of this assignment came from the suc-
the isolated product revealed two cognate sets of signals. cessful analytical resolution of the isomer 8b-anti by
By subsequent chromatography we were able to separate HPLC using a chiral stationary phase.
the mass of [2+2] macrocycle 8b into two distinct compo-
nents, 8b-syn and 8b-anti (Figure 2). The bulky butoxy
After thermal equilibration, the ratio of 8b-anti/8b-syn
reached 55:45. Thus it can be concluded that the energy
groups attached to the aromatic units prevent their free ro-
difference between the two isomers is rather small. On the
tation and thus give rise to atropoisomerism. The structure
other hand, the energy barrier for the syn-to-anti intercon-
version is sufficiently high for customary separation of the
two rotamers at room temperature. A preliminary kinetic
measurement at 50 °C in deuterochloroform showed the
of the isomer 8b-syn corresponds to the meso form,
whereas the 8b-anti isomer represents the racemic mix-
ture of two enantiomers.
The assignment of the appropriate structures to the partic- Gibbs activation energy for the thermal interconversion to
ular isomers 8b-anti/8b-syn was based primarily on two be higher than 100 kJ mol–1.
independent single crystal X-ray analyses. The structure
OBu
BuO
OBu
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
BuO
OBu
BuO
S
S
S
S
S
S
OBu
OBu
BuO
BuO
BuO
OBu
8b-syn
8b-anti
Figure 2 Representation of the 8b-syn and 8b-anti isomers
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P. Holý et al.
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Figure 3 Crystal structures of the both isomers of [2+2] macrocycle 8b: (a) 8b-syn isomer; (b) 8b-anti isomer (only one enantiomer was
shown). Also only one position of disordered butyl moiety was drawn for clarity. Ellipsoids on 50% probability level.
Though we have proved that the multistep preparation of methyl) derivatives. Therefore, we decided to study the
the [4+4] macrocycles outlined in Scheme 1 is in principle direct alkylation of the stable dithiole–zincate10 10. Of
applicable to various bis(bromomethyl) blocks, the requi- course, a complex mixture was anticipated in the reaction
site large excess of the reagent in an early step makes this with a bifunctional alkylation reagent. Indeed, as conclud-
approach less favorable for more advanced bis(bromo- ed from the GPC analysis (Figure 4), the reaction of the
Figure 4 Gel-permeation chromatogram of the crude reaction mixture of the reaction in Scheme 3. The peaks of ascending elution times cor-
respond to the cyclic compounds with descending numbers of involved building blocks (for detailed chromatographic conditions see the expe-
rimental part).
OBu
OBu
S
S
S
S
S
S
S
S
BuO
OBu
2
Br
Br
S
8b : n = 0
11 : n = 1
6b : n = 2
12 : n = 3
9b : n = 4
S
S
S
S
S
S
S
S
S
2b
BuO
BuO
2 Et4N
S
Zn
S
10
n > 4
oligomers
+
+
OBu
BuO
S
S
S
S
n
S
Scheme 3 Direct reaction of the zincate salt 10 with 1,4-bis(bromomethyl)-2,5-dibutoxybenzene (2b). Reaction conditions: 10/2b (1:2),
DMF, r.t., 24 h.
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Synthesis of Electron-Rich Thiamacrocycles
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stability prevents long-term vacuum drying at elevated tempera-
tures.
salt 10 with 1,4-bis(bromomethyl)-2,5-dibutoxybenzene
(2b) gave a mixture composed of lower-mass cyclic and
higher-mass linear oligomeric compounds (Scheme 3).
X-ray Crystallography13
The peaks in the GPC chromatogram corresponding to
[2+2] macrocycle 8b, [4+4] macrocycle 6b, and [6+6]
macrocycle 9b were identified by comparison with au-
thentic samples obtained by the stepwise procedures (vide
supra). We were able to separate the crude mixture by pre-
parative column chromatography on silica gel to the indi-
vidual cyclic products (Table 1).
Single-crystal diffraction data for compounds 6b, 8b-syn, and 8b-
anti were collected on a Nonius KappaCCD diffractometer using
MoKa radiation (l = 0.71073 Å, graphite monochromator) via j
and w scans. The structures were solved by direct methods (SIR-
9214) and refined by full-matrix least squares based on F2
(SHELXL-9715). The hydrogen atoms were found on difference
Fourier maps and recalculated into idealized positions, all hydro-
gens were fixed into their positions (riding model) with assigned
temperature factors Hiso(H) = 1.2 Ueq (pivot atom) or Hiso(H) = 1.2
Ueq (pivot atom) for the methyl moiety.
Table 1 Individual Cyclic Compounds Formed in the Direct Reac-
tion of the Zincate Salt 10 with Bis(bromomethyl) Derivative 2b
3-[(5-{[4-(Bromomethyl)-2,5-dibutoxybenzyl]sulfanyl}-2-
thioxo-1,3-dithiol-4-yl)sulfanyl]propanenitrile (3b)
Compound
Elution time (min)
Isolated yield (%)
CsOH·H2O (72.1 mg, 0.493 mmol) was dissolved in MeOH (3 mL)
and added dropwise under argon to the soln of 1 (150 mg, 0.493
mmol) in degassed anhyd DMF (6 mL) at r.t. over 30 min. After
stirring for an additional 45 min, 1,4-bis(bromomethyl) derivative
2b (2.32 g, 5.68 mmol) in degassed anhyd DMF (36 mL) was added
over 30 min and the mixture was stirred at r.t. for 5 h. Then, the mix-
ture was diluted with H2O (250 mL). The precipitate was filtered
off, washed with H2O, and dried. Column chromatography (silica
gel, 50 × 400 mm, hexanes–Et2O–acetone, 60:25:15) initially eluted
excess of 2b, followed by 3b; yield: 191 mg (67%); mp 91–92 °C.
8ba
11
6b
12
9b
27.8
26.3
25.3
24.6
23.9
18.0
10.1
7.2
3.6
1.4
a The sum of syn- and anti-isomers.
IR (CHCl3): 2958, 2929, 2856, 2255, 1602, 1512, 1464, 1422, 1067,
1035, 618, 515 cm–1.
Although the total yield of the isolated cyclic compounds
reached only about 40%, the straightforward approach,
apart from its simplicity, seems to be effective for the
preparation of a wider family of multi-sized macrocycles.
For example, the [4+4] macrocycle 6b was obtained in
this manner as a pure compound in 7.2% yield, which is
comparable to the overall yield of the multistep synthesis.
1H NMR (400 MHz, CDCl3): d = 0.98 (t, J = 7.2 Hz, 3 H), 0.99 (t,
J = 7.2 Hz, 3 H), 1.48–1.54 (m, 4 H), 1.74–1.84 (m, 4 H), 2.49 (t,
J = 7.2 Hz, 2 H), 2.83 (t, J = 7.2 Hz, 2 H), 3.95 (t, J = 6.2 Hz, 2 H),
3.97 (t, J = 6.2 Hz, 2 H), 4.06 (s, 2 H), 4.54 (s, 2 H), 6.71 (s, 1 H),
6.86 (s, 1 H).
13C NMR (101 MHz, CDCl3): d = 13.9, 13.9, 18.4, 19.3, 19.4, 28.9,
31.3, 31.4, 31.9, 36.3, 68.6, 68.9, 114.2, 114.4, 117.1, 125.8, 127.0,
134.6, 140.6, 150.4, 150.5, 210.4.
MS (EI+): m/z (%) = 577 (0.2, [M]+), 327 (75), 271 (30), 215 (20),
57 (70), 41 (100).
HRMS (EI): m/z [M]+ calcd for C22H28NO2S5Br: 576.9916; found:
576.9907.
Melting points were determined on a Mikro-Heiztisch Polytherm A
apparatus (Hund Wetzlar, Germany) and are uncorrected. NMR
spectra were measured on Bruker Avance 400 (1H at 400 MHz and
13C at 101 MHz) and Bruker Avance 600 (1H at 600 MHz and 13
C
at 151 MHz) spectrometers referenced to TMS or solvent peaks as
internal standards. Mass spectra were recorded on a ZAB-EQ (VG-
Analytical/Waters, EI, 70 eV) spectrometer, and LCQ Classic
(Thermo Finnigan) and Q-Tof micro (Waters) spectrometers with
ES or APC ionization. IR spectra were measured on a Bruker Equi-
nox 55 FT-IR spectrophotometer in CHCl3 solns. Gel permeation
chromatography (GPC) was performed on a Knauer chromatograph
with UV detection at 254 nm equipped with a tandem array of col-
umns Eurogel SEG100 (8 × 300 mm) and TSK gel G2000 (8 × 300
mm), eluent THF, flow rate 0.5 mL min–1. The reaction progress
was monitored by TLC on aluminum sheets pre-coated with silica
gel 60 F254 (Merck) and column chromatography was carried out us-
ing silica gel 60 (Merck). Commercially available reagent grade
chemicals and anhyd solvents were used as received. Hexanes = a
mixture of aliphatic hydrocarbons bp 60–80 °C.
3,3¢-{(2,5-Dibutoxybenzene-1,4-diyl)bis[methanediylsulfane-
diyl(2-thioxo-1,3-dithiole-5,4-diyl)sulfanediyl]}dipropane-
nitrile (4b)
CsOH·H2O (352 mg, 2.01 mmol) was dissolved in MeOH (7 mL)
and added dropwise under argon to the soln of 1 (609 mg, 2.00
mmol) in degassed anhyd DMF (30 mL) at r.t. over 30 min. After
stirring for an additional 45 min, the bis(bromomethyl) derivative
2b (408 mg, 1.00 mmol) in degassed anhyd DMF (20 mL) was add-
ed over 30 min and the mixture was stirred at r.t. for 4 h, then H2O
(250 mL) was added. The precipitate was collected by filtration,
washed with H2O, dried, and crystallized (acetone); yield: 685 mg
(91%); mp 148–150 °C.
IR (CHCl3): 2961, 2935, 2874, 2255, 1612, 1507, 1467, 1420, 1234,
1069, 1028, 869, 515 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.99 (t, J = 7.2 Hz, 6 H), 1.47–
1.54 (m, 4 H), 1.76–1.84 (m, 4 H), 2.57 (t, J = 6.8 Hz, 4 H), 2.94 (t,
J = 6.8 Hz, 4 H), 3.93 (t, J = 6.8 Hz, 4 H), 4.09 (s, 4 H), 6.84 (s, 2
H).
13C NMR (101 MHz, CDCl3): d = 13.9, 18.6, 19.4, 31.5, 32.0, 36.2,
68.9, 114.2, 117.1, 125.2, 133.8, 141.1, 150.6, 210.4.
MS (ESI+): m/z = 771 ([M + Na]+), 748 ([M]+).
Bis(bromomethyl) derivative 2b was prepared as described in the
literature.11 Syntheses of compounds 3a, 5a, 6a are described
elsewhere9 and the synthesis of compound 4a is described in the lit-
erature.12 Zincate salt 10 was prepared according the published, im-
proved, large-scale procedure.10
Notably, the character of the new compounds in this study ham-
pered the determination of elemental composition with satisfactory
precision. We found that the substances in general bind solvent mol-
ecules very tightly in non-stoichiometric ratios and their thermal
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P. Holý et al.
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HRMS (ESI+): m/z [M + H]+ calcd for C28H33N2O2S10: 748.9744;
found: 748.9748; m/z [M + Na]+ calcd for C28H32N2O2S10Na:
770.9563; found: 770.9567.
(qmax = 25°), 7720 independent (Rint = 0.040) and 5680 observed [I
> 2s(I)]. One of the three symmetrically independent butyl moieties
is disordered into 2 positions with equal occupancy, disordered at-
oms were refined isotropically; 468 refined parameters, GOF 1.022,
final R indices R[F2 > 2s(F2)] = 0.0499, wR(F2) = 0.1422, maxi-
mal/minimal residual electron density Drmax = 0.72 e Å–3, Drmin
–0.71 e Å–3.
3,3¢-{(2,5-Dibutoxybenzene-1,4-diyl)bis[methanediylsulfane-
diyl(2,5-dibutoxybenzene-4,1-diyl)methanediylsulfanediyl(2-
thioxo-1,3-dithiole-5,4-diyl)sulfanediyl]}dipropanenitrile (5b)
CsOH·H2O (53.7 mg, 0.319 mmol) was dissolved in MeOH (3 mL)
and added dropwise under argon to the soln of compound 4b (120
mg, 0.160 mmol) in degassed anhyd DMF (15 mL) at r.t. over 30
min. After stirring for an additional 45 min, the dark red soln was
added dropwise into the stirred soln of compound 3b (185 mg,
0.319 mmol) in degassed anhyd DMF (20 mL) over 30 min. The
mixture was stirred for 4 h, then H2O (400 mL) was added. The mix-
ture was extracted with CHCl3 (3 × 100 mL), and the combined or-
ganic phases were washed with H2O (3 × 100 mL) and dried
(Na2SO4). Solvents were removed in vacuo and a yellow deposit
crystallized (acetone–n-hexane) to give a yellow powder; yield: 190
mg (72%); mp 80–82 °C.
[2+2] Macrocycle 8a
CsOH·H2O (144 mg, 0.986 mmol) was dissolved in MeOH (3 mL)
and added dropwise under argon to the soln of 4a (298 mg, 0.493
mmol) in degassed anhyd DMF (20 mL) at r.t. over 15 min. After
stirring for an additional 15 min, 1,4-bis(bromomethyl)benzene (2a,
131 mg, 0.496 mmol) in degassed anhyd DMF (15 mL) was added
over 2 h and the mixture was stirred at r.t. for 5 h. Then, the mixture
was diluted with H2O (250 mL), and the precipitate was filtered off,
washed with H2O, and dried. Column chromatography (silica gel,
column 30 × 250 mm, hexanes–CH2Cl2, 40:60) eluted the [2+2]
macrocycle 8a; yield: 160 mg (54%); mp 240–244 °C (n-hexane–
CHCl3).
IR (CHCl3): 3000, 2930, 2855, 2256, 1602, 1462, 1421, 1067, 1035,
515 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.96–1.00 (m, 18 H), 1.46–1.52
(m, 12 H), 1.72–1.78 (m, 12 H), 2.54 (t, J = 6.8 Hz, 4 H), 2.92 (t,
J = 6.8 Hz, 4 H), 3.87–3.93 (m, 12 H), 3.97 (s, 4 H), 3.98 (s, 4 H),
4.06 (s, 4 H), 6.64 (s, 2 H), 6.69 (s, 4 H).
13C NMR (101 MHz, CDCl3): d = 13.9, 13.9, 18.6, 19.4, 31.4, 31.5,
32.1, 36.1, 36.2, 36.3, 68.9, 114.2, 114.3, 117.0, 124.9, 125.2,
125.6, 138.5, 141.2, 150.5, 150.6, 210.4, 211.5.
IR (CHCl3): 3055, 3020, 3000, 2929, 2855, 1603, 1512, 1462, 1422,
1066, 1035, 1021, 829, 515 cm–1.
1H NMR (600 MHz, CDCl3): d = 3.92 (s, 8 H), 7.04 (s, 8 H).
13C NMR (151 MHz, CDCl3): d = 40.2, 129.4, 136.0, 136.2, 210.8.
MS (EI+): m/z (%) = 600 (23, [M]+), 300 (22), 166 (47), 104 (100),
76 (75), 64 (35).
HRMS (EI+): m/z [M]+ calcd for C22H16S10: 599.8459; found:
599.8449.
MS (APCI+): m/z = 1659 [M + Na]+, 1637 [M + H]+, 1636 [M]+.
HRMS (APCI+): m/z [M + H]+ calcd for C66H81N2O6S20: 1637.0477;
found: 1637.0503.
[4+4] Macrocycle 6b [2+2] Macrocycle 8b, and [6+6] Macrocy-
cle 9b
CsOH·H2O (177 mg, 1.05 mmol) was dissolved in MeOH (3 mL)
and added dropwise under argon to the soln of 4b (376 mg, 0.501
mmol) in degassed anhyd DMF (20 mL) at r.t. over 15 min. After
stirring for an additional 15 min, 1,4-bis(bromomethyl) derivative
2b (225 mg, 0.551 mmol) in degassed anhyd DMF (15 mL) was
added over 2 h and the mixture was stirred at r.t. for 8 h. Then, the
mixture was diluted with H2O (250 mL), and the precipitate was fil-
tered off, washed with H2O, and dried. Column chromatography
(silica gel, column 30 × 350 mm, hexanes–CH2Cl2, 60:40) initially
eluted the [2+2] macrocycle 8b [ratio 8b-anti/8b-syn, 55:45 (1H
NMR signal integration)]; yield: 175 mg (39%). Further elution
(hexanes–CH2Cl2, 50:50) afforded [4+4] macrocycle 6b [yield:
58 mg (13%)] and the [6+6] macrocycle 9b [yield: 22 mg (5%)].
[4+4] Macrocycle 6b
CsOH·H2O (40.8 mg, 0.243 mmol) was dissolved in MeOH (1 mL)
and added dropwise under argon to the soln of compound 5b (188
mg, 0.114 mmol) in degassed anhyd DMF (29 mL) over 10 min and
the resulting soln was stirred for 30 min. Bis(bromomethyl) deriva-
tive 2b (51.2 mg, 0.125 mmol) was dissolved in degassed anhyd
DMF (30 mL). The two solns were simultaneously added (using the
dual syringe pump) to the flask containing anhyd DMF (40 mL)
with stirring over 8 h. After stirring for an additional 20 h, the soln
was diluted with H2O (400 mL). The mixture was extracted with
CHCl3 (3 × 100 mL), and the combined organic phases were washed
with H2O (3 × 100 mL) and dried (Na2SO4). Solvents were removed
in vacuo and the yellow deposit was subjected to column chroma-
tography (silica gel, 30 × 300 mm, hexanes–CH2Cl2, 1:1). Evapora-
tion of collected fractions and crystallization (CH2Cl2–n-hexane)
gave the macrocycle 6b; yield: 97.0 mg (48%); mp 134–137 °C.
[2+2] Macrocycle 8b-anti and 8b-syn
MS (EI+): m/z (%) = 888 (20, [M]+), 691 (25), 248 (100), 215 (20),
76 (80).
IR (CHCl3): 2961, 2934, 2874, 1604, 1507, 1466, 1429, 1405, 1390,
1314, 1235, 1066, 1030, 868, 516 cm–1.
HRMS (ESI–): m/z [M – H]– calcd for C38H47O4S10: 887.0687;
found: 887.0672.
1H NMR (400 MHz, CDCl3): d = 0.97 (t, J = 7.6 Hz, 24 H), 1.46–
1.51 (m, 16 H), 1.71–1.76 (m, 16 H), 3.84 (s, 16 H), 3.86 (t, J = 6.4
Hz, 16 H), 6.58 (s, 8 H).
13C NMR (101 MHz, CDCl3): d = 14.0, 19.4, 31.6, 36.3, 69.0,
114.3, 125.3, 138.6, 150.5, 211.4.
[4+4] Macrocycle 6b
The analytical data of [4+4] macrocycle 6b prepared in this manner
were consistent with those of the product obtained by the stepwise
procedures (vide supra).
HRMS (APCI+): m/z [M + H]+ calcd for C76H97O8S20: 1777.1592;
found: 1777.1546.
[6+6] Macrocycle 9b
Mp 87–89 °C.
IR (CHCl3): 2960, 2933, 2873, 1613, 1507, 1466, 1429, 1405, 1390,
1314, 1235, 1065, 1030, 867, 516 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.97 (t, J = 7.4 Hz, 36 H), 1.43–
1.52 (m, 24 H), 1.70–1.77 (m, 24 H), 3.87 (t, J = 6.4 Hz, 24 H), 3.92
(s, 24 H), 6.63 (s, 12 H).
X-ray Crystal Data
6b: C76H96O8S20, Mr = 1778.73, triclinic, P1 (No. 2), a = 11.1065(5)
Å, b = 14.1727(6) Å, c = 15.1553(7) Å, a = 67.256(2)°,
b = 84.538(2)°, g = 81.493(2)°, Z = 1, Dx = 1.359 g cm–3, orange
crystal of dimensions 0.30 × 0.17 × 0.17 mm, T = 150(2) K, absorp-
tion was neglected (m = 0.544 mm–1); 32458 diffractions collected
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Synthesis of Electron-Rich Thiamacrocycles
4175
13C NMR (101 MHz, CDCl3): d = 14.0, 19.4, 31.5, 36.2, 68.9,
goodness of fit 1.04, final R indices R[F2 > 2s(F2)] = 0.034,
wR(F2) = 0.081, maximal/minimal residual electron density
Drmax = 0.61 e Å–3, Drmin –0.26 e Å–3.
114.3, 125.3, 138.5, 150.6, 211.4.
HRMS (APCI+): m/z [M + H]+ calcd for C114H145O12S30: 2665.2352;
found: 2665.2379.
Direct Reaction of Bis(tetraethylammonium) Bis(2-thioxo-1,3-
dithiole-4,5-dithiol)zincate (10) with 1,4-Bis(bromomethyl)-2,5-
dibutoxybenzene (2b)
By subsequent chromatography of the mixture of 8b-anti and 8b-
syn (160 mg) (silica gel, column 30 × 300 mm, hexanes–acetone–
Et2O, 80:10:10) the pure 8b-anti isomer was eluted first [yield: 72
mg after crystallization (n-hexane–CHCl3); mp 150–152 °C], fol-
lowed by mixed fractions and finally by the pure 8b-syn isomer
[yield: 48 mg after crystallization (n-hexane–CHCl3); mp 192–194
°C].
The mixture of bis(bromomethyl) derivative 2b (408 mg, 1.00
mmol) and zincate salt 10 (360 mg, 0.500 mmol) in degassed anhyd
DMF (20 mL) was stirred at r.t. for 24 h. The mixture was diluted
with H2O (150 mL), the resulting precipitate was filtered off,
washed with H2O, dried and subjected to column chromatography
(silica gel, 50 × 450 mm, hexanes–CH2Cl2, 2:1 to 1:1). Five individ-
ual macrocycles were successively eluted in order of their increas-
ing size and identified by comparison with authentic samples
prepared previously and by their NMR and HRMS spectral data.
Yields of the pure macrocycles were as follows: [2+2] macrocycle
8b (mixture of syn- and anti-isomers): 140 mg (18%); [3+3] macro-
cycle 11: 84 mg (10%); [4+4] macrocycle 6b: 32 mg (7%); [5+5]
macrocycle 12: 18 mg (3%), [6+6] macrocycle 9b: 18 mg (1.4%).
8b-anti
IR (CHCl3): 2961, 2935, 2874, 1614, 1508, 1466, 1432, 1421, 1390,
1234, 1066, 1036, 867, 518 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.01 (t, J = 7.4 Hz, 12 H), 1.45–
1.59 (m, 8 H), 1.71–1.84 (m, 8 H), 3.52 (d, J = 11.8 Hz, 4 H), 3.86–
3.91 (m, 8 H), 4.19 (d, J = 11.8 Hz, 4 H), 6.42 (s, 4 H).
13C NMR (101 MHz, CDCl3): d = 13.9, 19.4, 31.6, 36.5, 69.0,
114.1, 125.8, 138.8, 150.7, 212.3.
[3+3] Macrocycle 11
Mp 59–62 °C.
HRMS (EI+): m/z [M]+ calcd for C38H48O4S10: 888.0760; found:
888.0754.
IR (CHCl3): 2961, 2934, 2874, 1611, 1507, 1466, 1430, 1405, 1390,
1314, 1235, 1066, 1030, 868, 516 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.00 (t, J = 7.4 Hz, 18 H), 1.46–
1.55 (m, 12 H), 1.73–1.80 (m, 12 H), 3.78 (s, 12 H), 3.88 (t, J = 6.5
Hz, 12 H), 6.56 (s, 6 H).
13C NMR (101 MHz, CDCl3): d = 14.0, 19.5, 31.6, 36.5, 69.0,
114.2, 125.5, 138.6, 150.5, 211.5.
A sample of the 8b-anti isomer was subjected to HPLC analysis on
a chiral stationary phase (column Knauer Eurocel 01, 5 mm, 250 ×
4.6 mm, n-heptane–i-PrOH, 99.5:0.5, 1 mL min–1, Knauer isocratic
instrument with UV and polarimetric detectors). Two peaks with
the same integral intensity were recorded at 16.6 min for the (+)-8b-
anti enantiomer and at 34.0 min for the (–)-8b-anti enantiomer.
HRMS (APCI+): m/z [M + H]+ calcd for C57H73O6S15: 1333.1212;
found: 1333.1188.
8b-syn
IR (CHCl3): 2961, 2934, 2874, 1613, 1508, 1467, 1432, 1422, 1406,
1390, 1233, 1066, 1036, 867, 518 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.01 (t, J = 7.4 Hz, 12 H), 1.46–
1.55 (m, 8 H), 1.73–1.79 (m, 8 H), 3.50 (d, J = 12.1 Hz, 4 H), 3.83–
3.89 (m, 8 H), 4.24 (d, J = 12.1 Hz, 4 H), 6.52 (s, 4 H).
13C NMR (101 MHz, CDCl3): d = 14.0, 19.5, 31.6, 36.6, 68.9,
114.3, 126.1, 138.2, 150.7, 212.0.
HRMS (EI+): m/z [M]+ calcd for C38H48O4S10: 888.0760; found:
888.0754.
[5+5] Macrocycle 12
Mp 66–68 °C.
IR (CHCl3): 2961, 2933, 2873, 1613, 1507, 1466, 1429, 1405, 1390,
1314, 1235, 1066, 1030, 867, 516 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.96 (t, J = 7.4 Hz, 30 H), 1.43–
1.52 (m, 20 H), 1.70–1.77 (m, 20 H), 3.86 (t, J = 6.5 Hz, 20 H), 3.90
(s, 20 H), 6.62 (s, 10 H).
13C NMR (101 MHz, CDCl3): d = 14.0, 19.4, 31.5, 36.2, 68.9,
X-ray quality single crystals of the both isomers (8b-anti and 8b-
syn) were grown by a slow evaporation of their solns (n-hexane–
CHCl3 mixtures).
114.3, 125.3, 138.6, 150.6, 211.4.
HRMS (APCI+): m/z [M + H]+ calcd for C95H121O10S25: 2221.1972;
found: 2221.2010.
X-ray Crystal Data
8b-anti: C38H48O4S10, Mr = 889.36, monoclinic, C2/c (No. 15),
a = 13.9823(3) Å, b = 21.2394(6) Å, c = 15.3770(4) Å,
b = 107.1324(12)°, Z = 4, Dx = 1.354 g cm–3, yellow crystal of di-
mensions 0.25 × 0.20 × 0.12mm, T = 230(2) K (the crystal splits
below this temperature), absorption was neglected (m = 0.54 mm–1);
30959 diffractions collected (qmax = 26°), 4455 independent
(Rint = 0.043) and 3397 observed [I > 2s(I)]. One of the two sym-
metrically independent butyl moieties is disordered into three posi-
tions with 0.5:0.3:0.2 occupancies, disordered atoms were refined
isotropically; 248 refined parameters, goodness of fit 1.02, final R
indices R[F2 > 2s(F2)] = 0.038, wR(F2) = 0.107, maximal/minimal
residual electron density Drmax = 0.52 e Å–3, Drmin –0.42 e Å–3.
Acknowledgment
This work was carried out under the research project Z4 055 0506.
The financial support provided by the Grant Agency of the Acade-
my of Sciences of the Czech Republic (grant No. IAA400550704)
is gratefully acknowledged. I.C. thanks to MSM0021620857.
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PAPER
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Synthesis 2010, No. 24, 4169–4176 © Thieme Stuttgart · New York