Mild preparation of functionalized [2.2]paracyclophanes via the Pummerer rearrangement

Article abstract of DOI:10.1039/c1ob05319a

[2.2]Paracyclophanes, incorporating functional groups in the aliphatic bridges, suitable for elimination to give [2.2]paracyclophanedienes, are synthesized through a novel approach. It relies on a double Pummerer rearrangement on dithiacyclophane precursors, followed by ring contraction through a photochemical sulfur extrusion, and it is compatible with aryl moieties possessing very different electronic properties. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob05319a

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Montanari et al.
Mild preparation of functionalized
[2.2]paracyclophanes via the
Pummerer rearrangement
1477-0520(2011)9:14;1-U

Organic &
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Mild preparation of functionalized [2.2]paracyclophanes via the Pummerer
rearrangement†
Matteo Montanari, Alberto Bugana, Arvind K. Sharma and Dario Pasini*
Received 27th February 2011, Accepted 31st March 2011
DOI: 10.1039/c1ob05319a
[2.2]Paracyclophanes, incorporating functional groups in
the aliphatic bridges, suitable for elimination to give
[2.2]paracyclophanedienes, are synthesized through a novel
approach. It relies on a double Pummerer rearrangement on
dithiacyclophane precursors, followed by ring contraction
through a photochemical sulfur extrusion, and it is com-
patible with aryl moieties possessing very different electronic
properties.
copolymers, useful for controlling film morphology for functional
device applications, and to prevent batch-to-batch reproducibility
issues. Efficient syntheses of cyclophanediene monomers, allowing
structural and electronic variability in the molecular skeleton, are
therefore highly desirable.
Although [2.2]paracyclophane-1,9-diene 1 has been known for
more than 50 years,4 less than a handful synthetic procedures for 1
and related aryl substituted derivatives have been reported to date.5
Boekelheide and coworkers have approached the ring contraction
of [3.3]dithiacyclophane skeletons by means of Wittig6 or Stevens7
rearrangements, to obtain thioether functionalized [2.2]meta
and paracyclophanes, able to undergo oxidation/methylation
and subsequent elimination to give the carbon–carbon double
bonds (Scheme 1, left). In order to target the synthesis of
[2.2]cyclophanedienes bearing electron withdrawing and electron
rich aryl moieties, as potential precursors for innovative PPV
derivatives to be obtained through ROMP, we have synthesized
a variety of [3.3]dithiacyclophanes (Scheme 2). The synthesis
followed an established procedure7a involving nucleophilic sub-
stitution of benzylic dithiols 2–4 (thiolates in the presence of
stoichiometric amounts of KOH in the reaction mixture) on
benzylic dibromides 5–8, to give cyclization, under high dilution
conditions, affording [3.3]dithiacyclophanes in good to excellent
yields after purification by chromatography.
[2.2]Cyclophanedienes are [2.2]cyclophanes containing two
strained carbon–carbon double bonds directly joining the two
aromatic rings. Although initially produced to study formally
conjugated but orbitally unconjugated compounds, the interest in
this class of molecules has recently reemerged, following reports
by the groups of Grubbs1 and Turner,2 which have successfully
explored the ring opening metathesis polymerization (ROMP) of
the strained alkene groups embedded in [2.2]cyclophanedienes to
afford functionalized p-phenylenevinylene (PPV) polymers. These
polymers are important components for a series of functional
devices, but their conventional syntheses are not controlled.3
“Living” polymerization procedures, such as ROMP, have demon-
strated the possibility to address efficiently the synthesis of block
By applying the Boekelheide protocol7a (where the Stevens
rearrangement is induced by benzyne, generated in situ using
anthranilic acid and isoamyl nitrite) on [3.3]dithiacyclophane 9,
we were successful in isolating 1 in moderate yields (57% for step
a in Scheme 1, and 22% for steps b and c); methylation of phenyl
Department of Chemistry and INSTM Research Unit, University of Pavia,
Viale Taramelli 10, 27100, Pavia, Italy. E-mail: dario.pasini@unipv.it;
Fax: +39 0382 987323; Tel: +39 0382 987835
† Electronic supplementary information (ESI) available: detailed experi-
mental procedures, NMR characterization, GC-MS characterization, and
stereochemical analysis. See DOI: 10.1039/c1ob05319a
Scheme 1 Comparison between approaches for the ring contraction of [3.3]dithiacyclophanes to [2.2]paracyclophanes and related dienes.
5018 | Org. Biomol. Chem., 2011, 9, 5018–5020 This journal is The Royal Society of Chemistry 2011
©

Scheme 2 Synthesis of [3.3]dithiacyclophanes used in this study.
sulfide intermediate after step a and base-induced elimination
(tBuOK), as an alternative to steps b and c, did not improve the
yield of 1 (21%). Furthermore, using either of the two methods
with dithiacyclophane 12, the corresponding cyclophanediene was
obtained in low yield, it was detected by GC-MS but could not be
separated from byproducts. Using fluorinated dithiacyclophanes
10, 11 and 14, instead, the products of the Stevens rearrangement
after step a could not be obtained.
Scheme 3 Synthesis of functionalized [2.2]paracyclophanes.
As there is reported evidence that this rearrangement proceeds
through a radical pathway,8 its effectiveness could be greatly
influenced by the reactivity of the benzylic positions towards
radical species, and therefore on the nature of the aryl substituents.
The Stevens rearrangement effectively does two things: it
effects the ring contraction in [3.3]dithiacyclophanes, and at
the same time it installs into the resulting ethane bridges two
functionalities amenable to be transformed into leaving groups for
subsequent elimination and double bond formation. In focusing
on alternative synthetic pathways, we realized that the Pummerer
rearrangement,9 in its classical form, is a mild, efficient way to
install an acetate ester functionality (a good leaving group) in
the a-position of an aliphatic thioether moiety. Furthermore,
single and multilayered [2.2]cyclophanes are readily prepared
via an efficient photochemical ring contraction, through sulfur
extrusion from [3.3]dithiacyclophanes, to afford the two carbon
atom saturated bridge between the two aromatic rings.10 The
combined use of these two methodologies could overcome the
use of the Stevens rearrangement (Scheme 1, right, steps d, e and
f ). [3.3]Dithiacyclophanes 9, 11 and 13, containing aryl moieties
with differing electronic character, were subjected to the protocol
described in Scheme 3. They were oxidized to sulfoxides with m-
CPBA (2.2 eq), and then treated with an excess of Ac2O at reflux
in the presence of a catalytic amount of NaOAc.
The products 15–17 were purified by collecting the chro-
matographically homogeneous materials, and obtained in good,
unoptimized yields, as a mixture of regio and stereoisomers, as the
double Pummerer rearrangement can occur on both sides of each
of the thioether bridges.
The mixtures were analyzed by NMR spectroscopy. Although
1
complex sets of signals were observed in the H NMR spectra
of 15–17, their relative ratios were consistent with the proposed
structures, confirming that a double Pummerer rearrangement
had occurred in all cases.‡ The compounds were then subjected
Fig. 1 1H NMR (200 MHz, CDCl3) of compounds: a) 9; b) 15; c) 18; d)
1, obtained from 18.
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to a photochemical sulfur extrusion method previously used
for bridge unsubstituted [3.3]thiacyclophanes;10c essentially
quantitative conversions for 15–17 could be observed. The
relative ratios of the different sets of signals were consistent with
the proposed structures, and the diagnostic resonances for the
benzylic protons in 15–17 were shifted, as expected, to higher
fields in 18–20 as a consequence of the removal of the sulfur
atoms from the molecular skeleton, efficiently occurring on both
sides of the modified thiacyclophanes (Fig. 1b vs. 1c, and Fig
S1 and S2). The purity and identity of the mixtures of regio and
stereoisomers 18–20 were confirmed by GC-MS.
The elimination of the acetate groups to generate the strained
carbon–carbon double bonds has been attempted using acid
catalysis (PTSA, refluxing toluene), affording essentially starting
material; base-induced elimination, instead, required a strong, non
nucleophilic base (LDA, THF, room temperature) and afforded 1
in 58% yield.§
In conclusion, we have disclosed a new, mild and high-
yielding strategy for the synthesis of bridge-functionalized
[2.2]paracyclophanes; this strategy relies on a combination of a
Pummerer rearrangement on the precursor [3.3]dithiacyclophanes
and a photochemical ring contraction through sulfur extrusion,
which is here reported for the first time for bridge functionalized
[3.3]dithiacyclophanes. The synthetic methodology is compat-
ible with aryl functionalities with either an electron-rich or
electron-withdrawing nature. This strategy could lead to a milder,
more general and more efficient pathway for the synthesis of
[2.2]paracyclophanedienes, as successfully demonstrated in the
case of 1. Together with the before mentioned applications in
materials science, uses of this methodology for the synthesis of
[2.2]paracyclophanes with substituents at specific positions, to be
used in the field of catalysis,11 can be foreseen.
be tuned for each of 19 and 20, and related structurally and electronically
variable paracyclophanes to be prepared. It is also possible that optimal
conditions will have to take into account the substitution of the acetate
functionalities with a better leaving group. It is our aim to address these
themes in the near future.
1 V. P. Conticello, D. L. Gin and R. H. Grubbs, J. Am. Chem. Soc., 1992,
114, 9708–9710.
2 (a) C. Y. Yu, M. Horie, A. M. Spring, K. Tremel and M. L. Turner,
Macromolecules, 2010, 43, 222–232; (b) C. Y. Yu, J. W. Kingsley, D. G.
Lidzey and M. L. Turner, Macromol. Rapid Commun., 2009, 30, 1889–
1892; (c) A. M. Spring, C. Y. Yu, M. Horie and M. L. Turner, Chem.
Commun., 2009, 2676–2678; (d) C. Y. Yu and M. L. Turner, Angew.
Chem., Int. Ed., 2006, 45, 7797–7800.
3 A. C. Grimsdale, K. L. Chan, R. E. Martin, P. G. Jokisz and A. B.
Holmes, Chem. Rev., 2009, 109, 897–1091.
4 K. C. Dewhirst and D. J. Cram, J. Am. Chem. Soc., 1958, 80, 3115–
3125 1 was obtained in this paper in low yields by benzylic bromi-
nation on the parent [2.2]paracyclophane, following by elaborated
purification protocols and base-induced elimination to afford the target
compound.
5 A literature search for [2.2]paracyclophanedienes other than 1 afforded
only 7 aryl-substituted molecular structures. Three are described in
ref. 7b. The synthesis of dialkoxy aryl substituted derivatives has been
reported in: M. Staebbe, O. Reiser, T. Thiemann, R. G. Daniels and A.
de Meijere, Tetrahedron Lett., 1986, 27, 2353–2356.
6 This approach has been applied for the synthesis of
[2.2]metaparacyclophanedienes in good yields: (a) V. Boekelheide, P. H.
Anderson and T. A. Hylton, J. Am. Chem. Soc., 1974, 96, 1558–1564;
(b) R. H. Mitchell, T. Otsubo and V. Boekelheide, Tetrahedron Lett.,
1975, 16, 219–222; It fails to give efficiently [2.2]paracyclophanediene
1, as 1,6-elimination becomes an issue. Papers in ref. 2, for the
preparation of [2.2]para and [2.2]metaparacyclophanedienes with
alkoxy substituents on the aryl rings, refer to these procedures, giving
no further experimental details.
7 1 has been obtained in good yields via
a benzyne-induced
Stevens rearrangement: (a) T. Otsubo and V. Boekelheide, Tetra-
hedron Lett., 1975, 16, 3881–3884; Deuterated and permethylated
[2.2]paracyclophanedienes have also been synthesized using this route.
See: (b) J. Bruhin, F. Gerson, R. Moeckel and G. Plattner, Helv. Chim.
Acta, 1985, 68, 377–390; For vinyl-substituted derivatives, obtained
from 1, see: (c) H. A. Buchholz, J. Ho¨fer, M. Noltemeyer and A. de
Meijere, Eur. J. Org. Chem., 1998, 1763–1770; (d) M. Stoebbe, O. Reiser,
R. Naeder and A. de Meijere, Chem. Ber., 1987, 120, 1667–1674.
8 (a) J. A. Vanecko, H. Wan and F. G. West, Tetrahedron, 2006, 62, 1043–
1062; For recent work with cyclophanes, see: (b) K. K. Ellis-Holder,
B. P. Peppers, A. Y. Kovalevsky and S. T. Diver, Org. Lett., 2006, 8,
2511–2514.
We thank the University of Pavia, CARIPLO Foundation and
INSTM-Regione Lombardia for partial support of this work.
We acknowledge Dr A. Porta for experimental assistance, Prof.
A. Albini for assistance with the photochemical experiments, and
Prof. M. Mella for GC-MS and NMR assistance.
9 A. Padwa, S. K. Bur, M. D. Danca, J. D. Ginn and S. M. Lynch, Synlett,
2002, 851–862.
Notes and references
10 (a) ed. R. Gleiter and H. Hopf, Modern Cyclophane Chemistry, Wiley-
VCH: Weinheim, 2004; (b) A. de Meijere and B. Koenig, Synlett, 1997,
11, 1221–1232; (c) H. Machida, H. Tatemitsu, T. Otsubo, Y. Sakata and
S. Misumi, Bull. Chem. Soc. Jpn., 1980, 53, 2943–2952.
11 For two recent examples of the use of [2.2]paracyplophanes in catalysis,
see: (a) S. Ay, R. E. Ziegert, H. Zhang, M. Nieger, K. Rissanen, K. Fink,
A. R. Kubas, M. Gschwind and S. Bra¨se, J. Am. Chem. Soc., 2010, 132,
12899–12905; (b) J. F. Schneider, F. C. Falk, R. Fro¨hlich and J. Paradies,
Eur. J. Org. Chem., 2010, 2265–2269.
‡ In the case of 15, two spots could be separated, showing essentially
superimposable 1H NMR spectra. In the case of 17, 1H NMR spectra
were further complicated as the 2,5-dialkoxy substituted aryl ring is
a stereogenic element of planar chirality, thus effectively multiplying
the number of stereoisomers which in principle can be obtained. See
Supporting Information.
§ In the case of 19 and 20, the mentioned conditions did not afford cleanly
the corresponding cyclophanedienes. It is likely that conditions will have to
5020 | Org. Biomol. Chem., 2011, 9, 5018–5020
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The Royal Society of Chemistry 2011
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