[60]Fullerenoacetyl chloride as a versatile precursor for fullerene derivatives: Efficient ester formation with various alcohols

Article abstract of DOI:10.1021/ol034793g

(Matrix presented) [60]Fullerenoacetyl chloride, one of the reactive derivatives of [60]fullerenoacetic acid, was isolated and identified for the first time. This acid chloride was easily synthesized in good yield from tert-butyl [60]fullerenoacetate through two steps. In the presence of 4-(dimethylamino)-pyridine as a base, the acid chloride smoothly reacted with various alcohols under mild conditions to give the corresponding esters including [60]fullerene-biomolecule hybrids in moderate to high yields.

Full text of DOI:10.1021/ol034793g

ORGANIC
LETTERS
2003
Vol. 5, No. 15
2643-2645
[60]Fullerenoacetyl Chloride as a
Versatile Precursor for Fullerene
Derivatives: Efficient Ester Formation
with Various Alcohols
Hiroshi Ito,† Tomoyuki Tada,† Masafumi Sudo,‡ Yasuhiro Ishida,†
,†,‡
Tetsuo Hino,§ and Kazuhiko Saigo*
Department of Chemistry and Biotechnology, Graduate School of Engineering,
The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
saigo@chiral.t.u-tokyo.ac.jp
Received May 8, 2003
ABSTRACT
[60]Fullerenoacetyl chloride, one of the reactive derivatives of [60]fullerenoacetic acid, was isolated and identified for the first time. This acid
chloride was easily synthesized in good yield from tert-butyl [60]fullerenoacetate through two steps. In the presence of 4-(dimethylamino)-
pyridine as a base, the acid chloride smoothly reacted with various alcohols under mild conditions to give the corresponding esters including
[60]fullerene−biomolecule hybrids in moderate to high yields.
Methano[60]fullerenes are a class of the most extensively
studied fullerene derivatives because of their synthetic avail-
ability while maintaining the characteristic properties of
[60]fullerene.1 Although several methods have been devel-
oped for the preparation of methano[60]fullerenes,2-4 most
of them have some limitations for further facile molecular
design. The Bingel reaction,2 the most general reaction for
the synthesis of methano[60]fullerenes, requires strong basic
reaction conditions, and only robust functional groups can
be introduced. In addition, two carbonyl units are inevitably
introduced to the resultant products; such a drawback is
unfavorable for the synthesis of monofunctionalized com-
pounds. As alternative methods, addition-elimination of sul-
fonium ylides3 and addition-thermal decomposition of diazo
compounds4 have been developed. Although these methods
have also been widely used, they are not convenient, due to
possible side reactions such as the formation of bis-adducts
† Department of Chemistry and Biotechnology, Graduate School of
Engineering, The University of Tokyo
‡ Department of Integrated Biosciences, Graduate School of Frontier
Sciences, The University of Tokyo
§ Department of Polymer Science and Engineering, Faculty of Engineer-
ing, Yamagata University
(1) Diederich, F.; Isaacs, L.; Philip, D. Chem. Soc. ReV. 1994, 23, 243.
(4) (a) Suzuki, T.; Li, Q.; Khemani, K. C.; Wudl, F.; Almarsson, O.
Science 1991, 254, 1186. (b) Isaacs, L.; Wehrsig, A.; Diederich, F. HelV.
Chim. Acta 1993, 76, 1231. (c)Isaacs, L.; Diederich, F. HelV. Chim. Acta
1993, 76, 2454. (d) Eiermann, M.; Wudl, F.; Prato, M.; Maggini, M. J.
Am. Chem. Soc. 1994, 116, 8364.
(2) Bingel C. Chem. Ber. 1993, 126, 1957.
(3) (a) Wang, Y.; Cao, J.; Schuster, D. I.; Wilson, S. R. Tetrahedron
Lett. 1995, 36, 6843. (b) Hamada, M.; Hino, T.; Kinbara, K.; Saigo, K.
Tetrahedron Lett. 2001, 42, 5069.
10.1021/ol034793g CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/25/2003

1
or fulleroids, and due to difficult synthetic efforts to prepare
the corresponding ylides or diazo compounds. On the other
hand, [60]fullerenoacetic acid is used for the formation of
various [60]fullerenoacetic acid esters and amides upon
treatment with alcohols and amines in the presence of a
condensing agent.4c However, the yields of the esters and
amides thus obtained are not satisfactory in general, presum-
ably due to the low solubility of the acid in common organic
solvents.4c Here, we describe a versatile and convenient
method for the preparation of [60]fullerenoacetyl chloride
and the application of the acid chloride for the synthesis of
[60]fullerenoacetic acid esters.5
from 1700 cm-1 of 1 to 1780 cm-1 for 2. The H NMR
spectrum of 2 in CDCl3/CS2 showed a singlet attributed to
the proton of the bridge head at δ ) 5.23 (for reference,
1: δ ) 5.14), and the amount of contaminated 1 was found
to be significantly small.
In the presence of triethylamine as a base, 2 readily reacted
with methanol and ethanol to give the corresponding esters
in high yields under mild conditions (in bromobenzene at
room temperature). However, in the case of the reaction with
2-propanol, which is a less-reactive alcohol, the yield was
depressed. Then, to improve the yield, various bases (1.05
equiv) were employed for the condensation of 2 with
2-propanol (8.0 equiv). The data in Table 1 indicate that
[60]Fullerenoacetyl chloride (2) was synthesized as follows
(Scheme 1). tert-Butyl [60]fullerenoacetate, prepared by
Table 1. Condensation of [60]Fullerenoacetyl Chloride with
2-Propanol
Scheme 1. Synthesis of [60]Fullerenoacetic Acid Esters from
[60]Fullerenoacetic Acid
entry
base
yield (%)
1
2
3
4
5
N,N-diisopropylethylamine
triethylamine
N-methylmorphorine
4-(dimethylamino)pyridine
pyridine
49
52
34
61
38
proton-accepting ability of the base used is an important but
not a crucial factor for the efficient ester formation. In the
cases of aliphatic tertiary amines with strong basicity,
relatively moderate yields were attained (Table 1, entries 1
and 2), compared with pyridine with low basicity (Table 1,
entry 5). Noteworthy is the fact that exceptionally good yield
was realized when 4-(dimethylamino)pyridine (DMAP) was
used as the base despite its weak basicity (Table 1, entry 4).
These observations suggest that DMAP promotes the con-
densation not only as a base possessing sufficient basicity,
but also as an activator of 2. In general, it is well-known
that DMAP catalyzed acyl-transfer reactions.9
From the viewpoint of the suppression of side reactions,
DMAP is a suitable base for the condensation, too. In the
condensation with 2-propanol, the use of triethylamine as a
base resulted in the formation of byproducts. This side
reaction is presumably the nucleophilic attack of triethyl-
amine to the carbon atoms of 2, which is not negligible when
the nucleophilicity of the alcohol is low.10 In sharp contrast,
the use of DMAP in the place of triethylamine completely
suppressed the side reaction, because of the low nucleophi-
licity of DMAP.
following the literature method with some modification,3a
was treated with p-TsOH in toluene to give [60]fullerenoace-
tic acid (1) as a brown solid.4c,6 Although the solid was
insoluble in most organic solvents, we finally found that
CH2Cl2/dioxane (1:1 v/v) dissolves 1 very well. In this mixed
solvent, 1 was efficiently converted to 2 by treatment with
thionyl chloride (81-100% yield).7 For several hours, the
acyl chloride 2 was stable at room temperature, which
allowed us spectroscopic characterization of 2. The MALDI-
TOF-MS spectrum showed a peak at m/z ) 795.79, which
is consistent with the calculated value (795.97 for C62HClO).8
IR spectroscopy also confirmed the transformation of
-COOH to -COCl, since the absorption of the CdO shifted
(5) For examples of in situ generation and subsequent reaction of
methano[60]fullerenecarboxylic acid chlorides, see: (a) Woods, C. R.;
Bourgeois, J.-P.; Seiler, P.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39,
3813. (b) Agrawal, Y. K. Fullerene Sci. Technol. 1997, 5, 275.
(6) Preparation of [60]Fullerenoacetic Acid (1). A solution of tert-
butyl [60]fullerenoacetate (214 mg, 0.26 mmol) and p-TsOH‚H2O (88 mg,
0.52 mmol) in toluene (150 mL) was refluxed for 8 h to afford a suspension.
The brown solid thus precipitated was collected by filtration, and the solid
was washed successively with toluene (100 mL) and water (30 mL). The
residual solid was dissolved in CH2Cl2/dioxane (1:1 v/v, 30 mL), and the
soluble fraction was separated by filtration. The filtrate was evaporated to
dryness to afford 1 as a brown solid (145 mg, 0.19 mmol, 72%).
(7) Preparation of [60]Fullerenoacetyl Chloride (2). A solution of 1
(50 mg, 0.064 mmol) and thionyl chloride (5.0 mL, 67 mmol) in CH2Cl2/
dioxane (1:1 v/v, 40 mL) was refluxed for 5 h, whereupon a black precipitate
was formed. The precipitate was separated by filtration and washed with
CH2Cl2/dioxane (1:1 v/v, 100 mL). The residual solid was dissolved in
CS2 (20 mL), and the soluble fraction was separated by filtration. The filtrate
was evaporated to dryness to afford 2 as a black solid (51 mg, 0.064 mmol,
quant.).
Under the optimized conditions, the condensation of 2 with
various alcohols and phenols was carried out.11 The results
are summarized in Table 2. By using DMAP (1.05 equiv)
(8) In the MALDI-TOF-MS spectrum of 2, several unidentified peaks
were observed. These peaks are probably due to the reaction of 2 with the
matrix (dithranol) and/or the fragmentation of 2 caused by the laser
irradiation. See the Supporting Information.
(9) (a) Ho¨fle, G.; Steglich, W.; Vorbru¨ggen, H. Angew. Chem., Int. Ed.
Engl. 1978, 17, 569. (b) Hassner, A.; Krepski, L. R.; Alexanian, V.
Tetrahedron 1978, 34, 2069.
(10) Lawson, G. E.; Kitaygorodskiy, A.; Sun, Y.-P. J. Org. Chem. 1999,
64, 5913.
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Org. Lett., Vol. 5, No. 15, 2003

Table 2. Condensation of [60]Fullerenoacetyl Chloride with
Table 3. Synthesis of [60]Fullerene-Biomolecule Hybrids
Various Alcohols
as a base, 2 smoothly reacted with primary alcohols (8 equiv),
such as methanol and ethanol, to afford the methyl and ethyl
esters in excellent yields (Table 2, entries 1 and 2). In
contrast, 2-propanol, a representative secondary alcohol, and
phenols gave the corresponding esters in moderate yields
(Table 2, entries 3, 5 and 7). However, the yields were highly
improved when an excess amount of DMAP (2.1 equiv) was
used. The improvement is consistent with our expectation
that DMAP plays a role as an activator of 2 (Table 2, entries
4, 6, and 8).
of 2 easily proceeded to give the target hybrids in moderate
to good yields.
These results strongly indicate that [60]fullerenoacetyl
chloride (2), isolated and characterized in the present study
for the first time, is highly potent as an intermediate for the
synthesis of [60]fullerene derivatives.
In summary, we developed a new method for the prepara-
tion of [60]fullerenoacetyl chloride (2) in good yield with
sufficient purity for common use in organic synthesis. Taking
the advantage of the high reactivity and solubility of 2,
[60]fullerenoacetic acid esters were synthesized in good
yields. Thus, condensation of the acyl chloride would be a
versatile and convenient method for the synthesis of hy-
brids of [60]fullerene and functional molecules, such as
[60]fullerene-biomolecule hybrids. Considering the potential
for the transformation of the acyl chloride to other functional
groups, [60]fullerenoacetyl chloride would be a key inter-
mediate of novel [60]fullerene derivatives.
The observed efficiency of the condensation motivated us
to apply the reaction for the preparation of fullerene-
biomolecule hybrids (Table 3).12 Even when natural products
and their derivatives were used as alcohols, the condensation
(11) General Procedure for the Condensation of 2 with Alcohols. To
a bromobenzene solution (15 mL) of 2 (15 mg, 0.019 mmol) was added a
bromobenzene solution of methanol (0.4 M, 0.40 mL, 0.16 mmol), and
DMAP (2.4 mg, 0.020 mmol) was added to the mixture. The reaction
mixture was stirred at room temperature for 3 h, and then evaporated to
dryness. The residue was subjected to preparative thin-layer chromatography
developed with CH2Cl2/CS2 to afford the methyl ester as a brown solid
(14.3 mg, 0.018 mmol, 96%).
(12) For examples of [60]fullerene-biomolecule hybrids, see: (a)
Murakami, H.; Watanabe, Y.; Nakashima, N. J. Am. Chem. Soc. 1996, 118,
4484. (b) Nakamura, E.; Isobe, H.; Tomita, N.; Sawamura, M.; Jinno, S.;
Okayama, H. Angew. Chem., Int. Ed. 2000, 39, 4254. (c) Ishi-i, T.; Ono,
Y.; Shinkai, S. Chem. Lett. 2000, 808.
Supporting Information Available: Spectral data of 2.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL034793G
Org. Lett., Vol. 5, No. 15, 2003
2645