Regioselective synthesis and zone selective deprotection of [60]fullerene tris-adducts with an e,e,e addition pattern

Article abstract of DOI:10.1039/b504748j

D_3h-symmetrical tripodal tris(malonate) tethers have been used for the synthesis of [60]fullerene tris-adducts with an e,e,e addition pattern bearing topologically distinct polar and equatorial addend zones that can selectively be deprotected. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b504748j

View Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Regioselective synthesis and zone selective deprotection of [60]fullerene
tris-adducts with an e,e,e addition pattern{
Florian Beuerle, Nikos Chronakis and Andreas Hirsch*
Received (in Cambridge, UK) 6th April 2005, Accepted 25th May 2005
First published as an Advance Article on the web 16th June 2005
DOI: 10.1039/b504748j
reactive groups are connected via alkyl spacers with a benzene
core, described as the focal point of the tether. The second ester
moiety of each malonate is terminated by another protecting
group. The concept of the newly designed tethers is demonstrated
in Fig. 1. The tris-adducts derived from the Bingel cyclopropana-
tion of C60 with this family of tethers possess two distinct addend
zones namely, polar zone A and equatorial zone B. Zone A
represents the focal point of the tether where the hydroxyl terminal
groups of the alkyl spacers located in the pole of C60 are
connected/protected with a benzene core. Zone B includes the tert-
butyl ester functional groups terminating the alkyl substituents of
the malonic ester moieties around the equator of C60. The selective
deprotection of the addends in zone A or B is expected to provide
facile access to the direct synthesis of the C60 tris-adducts I and II,
respectively. As was mentioned before, these structurally novel tris-
adducts are not accessible starting from the e,e,e tris(malonic acid)
of C60. Finally, the fullerene cage can also be regarded as a reactive
zone, taking into account the possibility of further functionaliza-
tion in targeting hexa-adducts, as well as the fact that, to a certain
extent, it retains the unique electronic properties of a fullerene
molecule.
D3h-symmetrical tripodal tris(malonate) tethers have been used
for the synthesis of [60]fullerene tris-adducts with an e,e,e
addition pattern bearing topologically distinct polar and
equatorial addend zones that can selectively be deprotected.
The cyclopropanation of the [60]fullerene cage via the Bingel
reaction can theoretically lead to the formation of eight
regioisomeric bis-adducts1 whereas, in the case of tris-adducts this
number increases to 46.2 In 1994,1 we reported the synthesis and
characterization of [60]fullerene tris-adducts via the stepwise
nucleophilic cyclopropanation of the [6,6] bonds of the fullerene
sphere. Tris-adducts with three-fold rotational symmetry like
trans-3,trans-3,trans-3 and e,e,e were isolated, but this method
required tedious chromatographic separations and purifications.
The concept of tethered systems3 connecting the reactive
malonate groups has been proved a powerful tool to control the
regioselectivity of tris-additions on C60. In 1999, Diederich4
reported the regioselective synthesis of C3-symmetrical tris-adducts
by using a cyclotriveratrylene (CTV) tether connecting the
malonate reactive groups. In this work, the all-trans-3 and all-e
tris-adducts were isolated in 11% and 9% yields respectively, while
the regioselective synthesis of C60 tris-adducts with rotational
symmetry in good yields was demonstrated in an elegant way by
utilizing cyclo-[n]-alkylmalonate5 tethers with variable alkyl spacers
connecting the malonate groups. Despite the improvements in the
regioselective synthesis of C60 tris-adducts, the tether approaches
mentioned showed two disadvantages that should be taken into
consideration. In contrast to the cyclo-[n]-alkylmalonates, the CTV
tether required multiple synthetic steps whereas, in both cases the
tethers do not offer the possibility of further structural tuning.
Specifically, the tethered functionalized tris-adducts of C60 can be
only subjected to hydrolytic removal of the tether to afford the
water soluble hexaacids of C60. Further functionalization of the
hexaacids was not possible due to decarboxylation phenomena.
It becomes obvious, that a new approach should be addressed
for the synthesis of derivatized [60]fullerene tris-adducts that fulfils
the following requirements: a) facile synthesis of tris(malonate)
tethers, b) tunability of their structure by means of topologically
distinct addend zones bearing protected functional groups, and c)
subsequent selective chemical transformations i.e., deprotection of
the functional groups. For this purpose, we have developed the
synthesis of tripodal tris(malonate) tethers where, the malonate
Institut fu¨r Organische Chemie der Universita¨t Erlangen, Henkestrasse
42, D-91054 Erlangen, Germany. E-mail: andreas.hirsch@chemie.uni-
erlangen.de; Fax: (+49 ) 9131 8526864; Tel: (+49) 9131 8522537
{ Electronic supplementary information (ESI) available: synthesis and
characterization details. See http://www.rsc.org/suppdata/cc/b5/b504748j/
index.sht
Fig. 1 Topologically distinct polar (A) and equatorial (B) addend zones
and selective deprotection of the remote sites.
3676 | Chem. Commun., 2005, 3676–3678
This journal is ß The Royal Society of Chemistry 2005

View Online
The synthesis of the first example of such a tripodal tether (5) is
shown in Scheme 1. Triol 4 was synthesized starting from benzene-
1,3,5-tricarboxylic acid according to a literature procedure.6
Treatment of 4 with methyl 3-chloro-3-oxopropionate in the
presence of pyridine in CH2Cl2, followed by flash column
chromatographic purification, afforded pure 5 in 72% yield.
Targeting tripodal tethers bearing easily removable protective
groups in the side chains, we performed the synthesis of tether 10
(Scheme 2), where the malonic ester moieties are further elongated
with C3 alkyl chains terminated by tert-butyl ester groups. In this
case, selective hydrolysis of the ester moieties or focal deprotection
(debenzylation) of the formed tris-adducts of C60 can give a facile
access to structurally different derivatives. For this purpose, tert-
butyl 4-hydroxybutyrate7 (8) was prepared (Scheme 2) and then
subjected to a DCC monoesterification reaction with malonic acid
to yield the mono-protected diacid 9. Three-fold esterification of
triol 4 with acid 9 by using DCC and DMAP in CH2Cl2, afforded
the tether 10 in 95% isolated yield.
Molecular modelling studies showed that replacement of the
focal benzyl site by a phenyl group favors the regioselective
formation of the e,e,e fullerene tris-adduct. It is postulated that the
reduction of the tether length is responsible for the increased
calculated thermodynamic stability of the e,e,e regioisomer over
other isomers such as, for example, the trans-3,trans-3,trans-3.
Consequently, tether 10 was modified by replacing the benzyloxy
protective group with phenoxy, thus shortening each spacer by one
carbon atom. For this purpose, triol 11 was synthesized in one
step8 followed by a DCC esterification reaction with acid 9
(Scheme 3). The reaction was performed in THF, as 11 was
insoluble in CH2Cl2 and, after chromatographic purification,
tether 12 was obtained in pure form in 85% yield.
We then investigated the Bingel functionalization of C60 with the
D3h-symmetrical tether 5. The reaction was carried out at a
concentration of 0.55 mmol L21 of C60 in toluene, in the presence
of I2 and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Flash column
chromatographic separation of the crude mixture (SiO2, toluene–
EtOAc, 70:30) afforded two fractions, which were further analyzed
by FAB-MS and HPLC. The first, least polar fraction, showed the
expected 1315 m/z molecular ion in the FAB-MS spectrum, thus
confirming that the three-fold Bingel cyclopropanation occurred
successfully on C60. The HPLC elugram consisted of one peak but
1H and 13C NMR analysis revealed that this fraction was a
mixture of tris-adducts, not separable by chromatographic
methods. The second, most polar fraction consisted of a single
tris-adduct and was formed in 55% relative yield. The structure of
13 was assigned by comparison of its UV/Vis spectra with those of
previously reported e,e,e tris-adducts.1,4,5,9 The 1H and 13C NMR
spectroscopic data were in agreement with an e,e,e addition pattern
(Scheme 4). In the fullerene spectral region between 140 and
148 ppm, 17 of the 18 expected signals for the sp2 carbon atoms of
the fullerene are observed, indicating a C3 symmetry. The signal at
146.64 ppm is of double intensity. In addition, two signals for the
fullerene sp3 carbons at 69.72 and 70.65 ppm, and one signal for
the bridgehead sp3 C-atoms at 52.56 ppm are present in the
spectrum while, the carbonyl C-atoms show two absorptions at
Scheme 1 Synthesis of the tripodal tether 5; a) H2SO4, MeOH, reflux;
b) LiAlH4, THF; c) BrCH2CH2OTHP, THF, reflux, 7 days; d) HCl,
CH2Cl2–MeOH, 1:1, rt; e) ClC(O)CH2CO2CH3, C5H5N, CH2Cl2,
0 uC A rt.
1
163.20 and 163.82 ppm. The H NMR spectra (Fig. 2) shows a
singlet absorption at 7.08 ppm for the phenylic protons and two
doublets at 4.43 and 4.50 ppm for the diastereotopic benzylic
hydrogens, while it is worth noting that the two diastereotopic
methylenic protons Ha and Ha9 experience totally different
chemical environments reflected in the large difference between
their chemical shifts (0.53 ppm). These protons resonate at 4.23
Scheme 2 Synthesis of the tripodal tether 10: a) toluene, NaOH, reflux;
b) isobutene, H2SO4, CH2Cl2; c) H2, Pd/C, toluene; d) CH2(CO2H)2,
DCC, CH2Cl2, 0 uC A rt; e) DCC, DMAP, CH2Cl2, 0 uC A rt.
Scheme 3 Synthesis of the tripodal tether 12: a) NBuþ4 Br2, DMF,
150 uC, 14 h; b) DCC, DMAP, THF, 0 uC A rt.
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 3676–3678 | 3677

View Online
tris-adduct 15 (Scheme 4) which was purified by flash column
chromatography on SiO2 using a mixture of toluene–EtOAc,
80:20, as eluent. The addition pattern was unambiguously assigned
by 1H, 13C NMR, and UV/Vis spectroscopy and 15 was isolated in
pure form in 35% yield.
With the successfully synthesized and characterized e,e,e tris-
adducts 13, 14, and 15 in hand, we attempted in the next step
the selective deprotection of the distinct addend zones. The
deprotection of the benzyloxy moiety10 of tris-adduct 13 (focal
deprotection) was carried out in the present of a Lewis acid as it
had been reported that removal of the O-benzyl groups of sugar
fullerene derivatives by palladium catalyzed hydrogenolysis,
afforded a complex mixture due to decomposition of C60.11
A
rapid reaction was observed on the addition of BBr3 to a solution
of 13 in CH2Cl2 at 270 uC, and the formed e,e,e triol 16 (Scheme 4)
was isolated by flash column chromatography (SiO2, CH2Cl2–
CH3OH, 95:5). The FAB-MS showed the expected M+ molecular
ion at m/z 1201, whereas the UV/Vis spectrum was in full
agreement with the e,e,e addition pattern. Furthermore, the
treatment of tris-adducts 14, 15 with formic acid led to the
hydrolysis of the tert-butyl ester groups to form the corresponding
tris-acids 17 and 18 respectively, as demonstrated by FAB-MS and
UV/Vis spectroscopy.
Scheme 4 Tether directed remote functionalization of C60 with the
tripodal tris(malonate) tethers and subsequent selective deprotection of the
polar and equatorial addend zones.
In conclusion, we have synthesized a new family of tripodal
D3h-symmetrical tris(malonate) tethers and investigated their
regioselectivity in the Bingel cyclopropanation of C60. Tuning of
the spacer length allows for a significant improvement in selectivity
for e,e,e regioisomer formation whereas selective deprotection of
the topologically distinct polar and equatorial addend zones
provides facile synthetic access to appealing building blocks for
further selective functionalization.
We thank the European network programs FAMOUS (2002-
00171) and WONDERFULL (2002-00172), the Deutsche
Forschungsgemeinschaft HI 468/14-1 and the C Sixty Inc. for
financial support.
Notes and references
1 A. Hirsch, I. Lamparth and H. R. Karfunkel, Angew. Chem., Int. Ed.
Engl., 1994, 33, 437.
2 A. Hirsch and M. Brettreich, Fullerenes - Chemistry and Reactions,
Wiley-VCH, Weinheim, 2005.
Fig. 2 1H NMR (400 MHz, CDCl3) spectrum of 13.
3 (a) L. Icaacs, R. F. Haldimann and F. Diederich, Angew. Chem., Int.
Ed. Engl., 1994, 33, 2339; (b) L. Icaacs, F. Diederich and R. F.
Haldimann, Helv. Chim. Acta, 1997, 80, 317; (c) F. Diederich and
R. Kessinger, Acc. Chem. Res., 1999, 32, 537; (d) F. Diederich and
M. Gomez-Lopez, Chem. Soc. Rev., 1999, 28, 263; (e) M. Prato
and M. Maggini, Acc. Chem. Res., 1998, 31, 519.
and 4.76 ppm, correspondingly. Tris-adduct 13 was isolated in
pure form (SiO2, toluene–EtOAc, 70:30) as a cherry-red solid, in
25% yield.
4 G. Rapenne, J. Crassous, A. Collet, L. Echegoyen and F. Diederich,
Chem. Commun., 1999, 1121.
5 U. Reuther, T. Brandmu¨ller, W. Donaubauer, F. Hampel and
A. Hirsch, Chem. Eur. J., 2002, 8, 2261.
6 H. An, J. S. Bradshaw, K. E. Krakowiak, B. J. Tarbet, N. K. Dalley,
X. Kou, C. Zhu and R. M. Izatt, J. Org. Chem., 1993, 58, 7694.
7 M. Braun, S. Atalick, D. M. Guldi, H. Lanig, M. Brettreich,
S. Burghardt, M. Hatzimarinaki, E. Ravanelli, M. Prato, R. van
Eldik and A. Hirsch, Chem. Eur. J., 2003, 9, 3867.
The Bingel cyclopropanation of C60 with the D3h-symmetrical
tether 10 was carried out under the same experimental conditions
used in the reaction of C60 with tether 5. Tether 10 showed similar
regioselectivity, leading to the formation of a mixture of non-
separable tris-adducts eluted in a single fraction (SiO2, toluene–
EtOAc, 70:30) and the e,e,e regioisomer 14, which was formed in
55% relative yield (Scheme 4). Tris-adduct 14 was isolated in 25%
1
yield and characterized by H, 13C NMR and UV/Vis spectro-
8 N. Tugcu, S. K. Park, J. A. Moore and S. M. Cramer, Ind. Eng. Chem.
Res., 2002, 41, 6482.
scopy, and FAB-MS.
9 (a) F. Djojo and A. Hirsch, Chem. Eur. J., 1998, 4, 344; (b) F. Djojo,
A. Hirsch and S. Grimme, Eur. J. Org. Chem., 1999, 3027.
10 J. F. W. McOmie, M. L. Watts and D. E. West, Tetrahedron, 1968, 24,
2289.
An improved enhancement in the regioselectivity of the Bingel
tris-addition was observed when C60 was treated with the tripodal
tether 12 in toluene, in the presence of I2 and DBU. The reaction
afforded with complete regioselectivity the C3-symmetrical e,e,e
11 A. Dondoni and A. Marra, Tetrahedron Lett., 2002, 43, 1649.
3678 | Chem. Commun., 2005, 3676–3678
This journal is ß The Royal Society of Chemistry 2005