Hexasulfanyl analogues of cyclotriveratrylene

Article abstract of DOI:10.1016/j.tetlet.2014.03.025

The synthesis of four 3,4-di(alkylsulfanyl)benzyl alcohol derivatives is described, in five steps from methyl 3,4-di(hydroxy)benzoate via a Newman-Kwart rearrangement. Incubation of these derivatives in formic acid affords 2,3,7,8,12,13-hexakis(alkylsulfanyl)-10,15-dihydro-5H-tribenzo[a,d,g] cyclononene products, which are hexa-sulfanyl analogues of the well-known supramolecular cavitand host, cyclotriveratrylene (CTV). The yield of this cyclization depends strongly on the alkylsulfanyl substituents present, in the order SMe > SEt ≈ SiPr ? SBn. A crystal structure determination of one of the cyclotrimers shows a mode of self-association that is commonly exhibited by CTV itself.

Full text of DOI:10.1016/j.tetlet.2014.03.025

Tetrahedron Letters 55 (2014) 2530–2533
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Tetrahedron Letters
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Hexasulfanyl analogues of cyclotriveratrylene
à
⇑
⇑
Marc A. Little , Jonathan J. Loughrey , Amedeo Santoro, Malcolm A. Halcrow , Michaele J. Hardie
School of Chemistry, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of four 3,4-di(alkylsulfanyl)benzyl alcohol derivatives is described, in five steps from
methyl 3,4-di(hydroxy)benzoate via a Newman–Kwart rearrangement. Incubation of these derivatives
in formic acid affords 2,3,7,8,12,13-hexakis(alkylsulfanyl)-10,15-dihydro-5H-tribenzo[a,d,g]cyclononene
products, which are hexa-sulfanyl analogues of the well-known supramolecular cavitand host, cyclotriv-
eratrylene (CTV). The yield of this cyclization depends strongly on the alkylsulfanyl substituents present,
in the order SMe > SEt ꢀ SiPr ꢁ SBn. A crystal structure determination of one of the cyclotrimers shows a
mode of self-association that is commonly exhibited by CTV itself.
Received 22 January 2014
Revised 17 February 2014
Accepted 5 March 2014
Available online 14 March 2014
Keywords:
Cyclotriveratrylene
Thioether
Ó 2014 Elsevier Ltd. All rights reserved.
Newman–Kwart rearrangement
Cavitand
Cyclotriveratrylene
(2,3,7,8,12,13-hexamethoxy-10,15-dihy-
We first attempted to access hexa-sulfanyl analogues of CTV by
dro-5H-tribenzo[a,d,g]cyclononene, CTV; Scheme 1) is a rigid
bowl-shaped molecule that is an important synthon in supramo-
lecular chemistry.1–3 CTV itself can complex fullerenes or other
globular molecular guests within its hydrophobic cavity. Moreover,
other functionalities can be appended onto the CTV scaffold by
derivatization of its methoxy groups, allowing organic2–5 and me-
tal-organic2,6,7 cage compounds, frameworks and other supramo-
lecular assemblies8 based on the CTV moiety to be constructed.
Recently, we9,10 and others11,12 have extended the chemistry of
CTV by preparing thiolated analogues 1 and 2 (Scheme 1). Oxida-
tive dimerization of 1 under high-dilution conditions affords the
cryptophane-0.0.0 capsule 3, one of the smallest organic capsules
yet reported, which binds methane in solution.9 A larger capsule
molecule was similarly achieved by oxidatively coupling 1 with a
trimercapto-cyclodextrin.12 As a continuation of this work, we
were keen to obtain hexa-sulfanyl analogues of CTV, bearing
purely thiyl or sulfanyl substituents at the upper rim. We report
here the synthesis of several new 3,4-disulfanylbenzyl alcohol
derivatives, and their cyclotrimerization into 2,3,7,8,12,13-hexa-
k i s -(alkylsulfanyl)-10,15-dihydro-5H-tribenzo[a,d,g]cyclononene
cavitands 4a–4d.
the same method we successfully used for 1 and 2. That is, by a
⇑
Corresponding authors. Tel.: +44 113 343 6506; fax: +44 113 343 6565
(M.A.H.); tel.: +44 113 343 6458; fax: +44 113 343 6565 (M.J.H.).
E-mail addresses: m.a.halcrow@leeds.ac.uk (M.A. Halcrow), m.j.hardie@leeds.
ac.uk (M.J. Hardie).
Current address: Department of Chemistry, University of Liverpool, Crown Street,
Liverpool L69 7ZD, UK.
à
Current address: Department of Chemistry and Biochemistry, University of
Scheme 1. Cyclotriveratrylene (CTV), and its sulfur-containing analogues referred
Arizona, PO Box 210041, 1306 East University Blvd., Tucson, AZ 85721, USA.
to in this work.
http://dx.doi.org/10.1016/j.tetlet.2014.03.025
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

M. A. Little et al. / Tetrahedron Letters 55 (2014) 2530–2533
2531
prepared by exhaustive demethylation of CTV with BBr3.14 The
hexakis-N,N-dimethylthiocarbamoyl Newman–Kwart precursor 5
was obtained in good yield by treatment of CTC with Me2NC(S)Cl
in the presence of excess Cs2CO3. However, heating 5 in diphenyl
ether led to its decomposition above 180 °C, with no rearrange-
ment product being observed. This is an insufficiently high temper-
ature for a Newman–Kwart rearrangement to proceed in this
system. For comparison, the corresponding rearrangement reac-
tions in the syntheses of 1 and 2 from preformed CTV-type precur-
sors proceed at 255 °C and 305 °C, respectively.9 Palladium
catalysis can reduce the temperature required for the Newman–
Kwart rearrangement.15 That was not attempted in this study,
however, because that protocol did not give useful yields in the
synthesis of 1 and 2.9
CTV is prepared by the acid-catalysed trimerization of 3,4-
dimethoxybenzyl alcohol.1 We therefore pursued (previously un-
known) 3,4-disulfanylbenzyl alcohol derivatives, that could be
similarly cyclotrimerized to form 4a–4d. Since 3,4-di(hydroxy)-
benzyl derivatives are readily available, a Newman–Kwart route
to these products was also employed (Scheme 3).
Scheme 2. Attempted Newman–Kwart rearrangement from pre-formed cyclotri-
catechylene. Reagents and conditions: (i) Me2NC(S)Cl, Cs2CO3, DMF; (ii) Ph2O,
180 °C.
Newman–Kwart rearrangement13 from the tris-catechol cyclo-
tricatechylene (2,3,7,8,12,13-hexahydroxy-10,15-dihydro-
5H-tribenzo[a,d,g]cyclononene, CTC; Scheme 2), which is readily
Scheme 3. Synthesis of 3,4-di(alkylsulfanyl)benzyl alcohol derivatives, and their conversion into the desired cyclic trimer cavitand compounds 4a–4d. Reagents and
conditions: (i) Me2NC(S)Cl, DABCO, DMF; (ii) Ph2O, 160–280 °C; (iii) NaBH4, THF; (iv) Ph2O, 240 °C, 1 h; (v) NaOH (aq), 70 °C, 6 h then 1 M HCl; (vi) LiAlH4, THF, 0 °C ? rt, 18 h;
(vii) HCO2H, 70 °C or Sc(CF3SO3)3, MeCN, 60 °C; (viii) NaOH, MeOH then RBr or RI, acetone, reflux, 4 h; (ix) HCO2H, 70 °C, 48 h.

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M. A. Little et al. / Tetrahedron Letters 55 (2014) 2530–2533
Attempted Newman–Kwart rearrangements employing 3,4-
formic acid17 or in MeCN with a Sc(CF3SO3)3 catalyst,18 did not
go to completion and gave mixture of bis-(di{alkylsulfa-
di(N,N-dimethylthiocarbamoyloxy)benzaldehyde (6) or 3,4-
di(N,N-dimethylthiocarbamoyloxy)benzyl alcohol (7) were also
unsuccessful, with decomposition being observed near 160 °C be-
fore a sufficiently high temperature could be reached (see above).15
However, methyl 3,4-di(N,N-dimethylthiocarbamoyl-oxy)benzoate
(8) is more thermally robust, affording the dithione 9 in moderate
yield after heating at 240 °C in Ph2O. Heating 9 with aqueous NaOH
leads to simultaneous removal of the thione protecting group and
hydrolysis of the ester function, affording 3,4-dimercaptobenzoic
acid (10) almost quantitatively.16 Reduction of 10 with LiAlH4
afforded 3,4-dimercaptobenzyl alcohol (11) in good yield. Alterna-
tively, alkylation of 10 with the appropriate alkyl bromide or alkyl
iodide in the presence of NaOH gave the 3,4-di(alkylsulfanyl)ben-
zoic acid derivatives 13a–13d, which were then reduced to the
equivalent benzyl alcohols 14a–14d with LiAlH4. Although 13a–
13d all contained 15–20% of mono-alkylated impurities, this did
not interfere with their use in the reduction step and 14a–14d
were subsequently purified by chromatography. Attempts to short-
en this reaction sequence, by reducing 9 to the corresponding alco-
hol with NaBH4 or LiAlH4, led to preferential removal of the thione
moiety with little reduction of the ester group being observed.
Cyclotrimerization of 14a–14d to the desired 2,3,7,8,12,13-
hexakis(alkylsulfanyl)-10,15-dihydro-5H-tribenzo[a,d,g]cyclo-
nonenes 4a–4d was achieved by heating in formic acid
(Scheme 3).17 The yields of the reaction depended significantly
on the alkylsulfanyl substituents present, in the order 4a
(R = Me) > 4b (R = Et) ꢀ 4c (R = iPr) ꢁ 4d (R = Bn). The trace yield
of 4d is consistent with the mechanism of the reaction, which cou-
ples the benzyl alcohol monomers by a sequence of electrophilic
aromatic substitution steps. These will be disfavored by the more
inductively withdrawing sulfanyl substituents on the benzyl alco-
hol precursors. Formation of the macrocyclic products was con-
firmed by the 1H NMR signature of their chemically equivalent
CH2 groups, which are diastereotopic in the rigid bowl-shaped con-
formation adopted by the molecules. These groups are observed as
two geminally coupled doublets near 3.7 and 4.7 ppm, assignable
to the Hexo and Hendo environments, respectively. Attempted cyclo-
trimerization of dithiol 11 to the hexa-mercapto derivative 12, in
a
nyl}phenyl)methane-containing species by mass spectrometry.
The identity of 4c was confirmed by a crystal structure determi-
nation, which showed it to adopt the expected bowl-shaped con-
formation (Fig. 1). While four of the six SiPr substituents are
approximately coplanar with their bound phenylene group, the
other two project into the molecular bowl. Molecular models imply
that this should reflect steric congestion between iso-propyl
groups around the rim of the molecule. Interconversion between
the SiPr group conformations in 4c is slow in solution by 1H
NMR spectroscopy, since the iPr methyl groups are observed as
at least three overlapping doublets whose integrals sum to the ex-
pected 36H (see the Supplementary information). There is no com-
parable splitting of the substituent resonances in the 1H NMR
spectra of the other cyclotrimers with smaller, less hindered sulfa-
nyl groups.
Molecules of 4c associate into centrosymmetric dimers in the
crystal, by inclusion of one ‘out-of-plane’ iso-propyl group from
each molecule into the hydrophobic cavity of its neighbour
(Fig. 2). This ‘handshake’ dimerization is common in crystalline
CTV derivatives, which associate by intermolecular inclusion of
their methyl groups.19 The observation of the same motif in 4c,
Figure 1. View of the molecule of 4c in its crystal structure, showing the atom
numbering scheme employed. Displacement ellipsoids are at the 50% probability
level, and H atoms have been omitted.
Figure 2. Top: the ‘handshake’ dimerization of 4c in the crystal. The C and H atoms
in the two molecules have pale and dark colouration. Bottom: the same view as a
space-filling plot.

M. A. Little et al. / Tetrahedron Letters 55 (2014) 2530–2533
2533
2. Hardie, M. J. Chem. Soc. Rev. 2010, 39, 516.
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cates that the host:guest chemistry of 4a–4d should be comparable
to CTV derivatives.
3. Hardie, M. J. In Supramolecular Chemistry: From Molecules to Nanomaterials;
Gale, P. A., Steed, J. W., Eds.; ; John Wiley & Sons: Chichester, UK, 2012; Vol. 3,
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In conclusion, we have reported here a general synthesis of 3,4-
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di(alkylsulfanyl)benzyl alcohols, employing
a Newman–Kwart
rearrangement procedure. These can be converted into cyclic,
bowl-shaped molecules that are hexa-sulfanyl analogues of the
well-known supramolecular cavitand CTV. Preliminary attempts
to obtain the hexa-mercapto derivative 12 by a Pummerer rear-
rangement from 4a,11 and by deprotection of 4b with Na/HMPA,20
have been unsuccessful. While the benzyl groups in 4d should be
easier to remove, the low yield of that compound precludes its
use as a precursor to 12. Nonetheless, as well as being of interest
in their own right, 4a–4d could also be used as components in me-
tal/organic supramolecular assemblies, through chelation of transi-
tion ions by their 1,2-di(alkylsulfanyl) moieties.21 Our synthetic
route to 4a–4d could also be adapted to yield larger hexasulfanyl
assemblies or cage compounds based on thioether linkers. Current
work is aimed at investigating these possibilities.
Acknowledgements
9. Little, M. A.; Donkin, J.; Fisher, J.; Halcrow, M. A.; Loder, J.; Hardie, M. J. Angew.
Chem., Int. Ed. 2012, 51, 764.
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This work was funded by the EPSRC. The authors thank
Dr Helena Shepherd for help with the crystal structure
determination.
Supplementary data
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Synthetic procedures and characterization, and experimental
data for the crystal structure determination. Supplementary data
associated with this article can be found, in the online version,
at http://dx.doi.org/10.1016/j.tetlet.2014.03.025. Crystallographic
data (excluding structure factors) for the structure of 4c have been
deposited with the Cambridge Crystallographic Data Centre as sup-
plementary publication no. CCDC 979574. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK, (fax: +44 (0)1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk).
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References and notes
1. Collet, A. Tetrahedron 1987, 43, 5725.