Zinc-Mediated Reductive Cyclization of [60]Fullerene with Enones and Subsequent Dehydration under Solvent-Free and Ball-Milling Conditions

Article abstract of DOI:10.1021/acs.orglett.9b00612

The zinc-mediated solvent-free reaction of [60]fullerene with enones and water and the subsequent treatment of a base afford various [60]fullerene-fused cyclopentanols using the ball-milling technique. A plausible reaction mechanism is proposed on the bas

Full text of DOI:10.1021/acs.orglett.9b00612

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Zinc-Mediated Reductive Cyclization of [60]Fullerene with Enones
and Subsequent Dehydration under Solvent-Free and Ball-Milling
Conditions
Hong-Wei Liu,† Hui Xu,† Gang Shao,† and Guan-Wu Wang*,†,‡
†CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for Physical Sciences at Microscale, iChEM
(Collaborative Innovation Center of Chemistry for Energy Materials), Center for Excellence in Molecular Synthesis of CAS, and
Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, P. R. China
‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, P. R. China
S
* Supporting Information
ABSTRACT: The zinc-mediated solvent-free reaction of [60]fullerene with enones and water and the subsequent treatment of
a base afford various [60]fullerene-fused cyclopentanols using the ball-milling technique. A plausible reaction mechanism is
proposed on the basis of control experiments. In addition, the formed [60]fullerene-fused cyclopentanols can be further
dehydrated to provide [60]fullerene-fused cyclopentenes.
dehydration to provide C60-fused cyclopentenes under ball-
eveloping efficient methods toward functionalized full-
Derene derivatives are prevalent in modern organic milling conditions.
It has been reported that zinc can reduce C60.10c−e We
synthesis due to their great potential applications in the fields
of materials, biology, and nanoscience.1 However, the chemical
functionalizations and applications of fullerenes are severely
restricted because of their poor solubility in common organic
solvents. To solve this problem, mechanochemistry has emerged
as a powerful tool for constructing various fullerene derivatives
under solvent-free conditions.2 The first mechanochemical
reaction of [60]fullerene (C60) was reported in 1996 by Wang et
al.3 After that, diverse types of reactions, including nucleophilic
additions,3,4 radical additions,5 cycloadditions,6 and oxidations,7
have been established successfully under the mechanochemical
conditions. Compared with the analogous solution-based
reactions, these reactions feature many unique advantages,
such as avoiding hazardous solvents, higher product yields,
much shorter reaction times, and even different chemical
reactivities.4a,6b
On the other hand, because of the high reactivity of fullerene
anions, various chemical reactions of fullerene anions generated
by electrochemical or chemical reduction have been re-
ported.8−10 Among these methods, the use of metals such as
Li, Na, K, and Zn is a convenient way to reduce fullerenes via
both liquid-phase and solvent-free reactions.10 In light of these
successful studies, we attempted more mechanochemical
reactions of C60 mediated by Zn.3 Herein, we report the zinc-
mediated solvent-free reaction of C60 with various enones and
water to afford C60-fused cyclopentanols and the subsequent
surmised that the formed fullerene anions could undergo
Michael addition to enones. A proton source such as an acid or
water might be required to protonate the generated carbanions.
At the outset, a mixture of C60 (0.05 mmol), chalcone 1a (0.10
mmol), zinc dust (0.10 mmol), and p-toluenesulfonic acid (p-
TSA, 0.25 mmol) was introduced into a stainless steel jar (5 mL)
together with 4 stainless steel balls (5 mm in diameter) and
milled vigorously (41.7 Hz) in a Spex SamplePrep 5100 mixer
mill at room temperature for 60 min, but only trace amounts of
products were detected (Table 1, entry 1). Then, p-TSA was
replaced with camphorsulfonic acid (D-CSA), acetic acid
(AcOH), and water. Although the former two were fruitless,
water was effective in promoting this reaction and provided
products 2a and 3a in yields of 4% and 11%, respectively (Table
1, entries 2−4). The spectral characterization showed that 2a
was a C60-fused cyclopentanol derivative and 3a was a
hydrofullerene derivative. However, we were more interested
in the C60-fused cyclopentanol instead of the hydrofullerene
derivative. We envisaged that 3a might be converted to 2a with
the assistance of a base, as deduced from their molecular
structures. Accordingly, after milling for 60 min in step 1, 5 equiv
of Et3N was then added and milled for 15 min. To our
satisfaction, almost all 3a disappeared, and 2a could be isolated
Received: February 18, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00612
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
respectively (Table 1, entries 15 and 16). Consequently, the
optimal amount of Et3N was 4 equiv. Furthermore, the zinc dust
preactivated by HCl was found to provide nearly the same yield
as that for the commercial zinc dust (Table 1, entry 17 vs entry
15). Finally, several bases, including Na2CO3, KOAc, and 4-
dimethylaminopyridine (DMAP), were screened in a bid to
improve the yield, yet all of these bases failed to afford higher
yields (Table 1, entries 18−20). On the basis of the success of
the one-pot two-step protocol described above, we further
investigated this reaction by a one-pot, one-step process. As a
result, a good yield of 36% was obtained, yet it was slightly lower
than that for the one-pot, two-step procedure (Table 1, entry 21
vs entry 15). To compare the mechanochemical reaction with its
liquid-phase counterpart, the reaction was performed in several
solvents (6 mL), including chlorobenzene, o-dichlorobenzene,
and 1,1,2,2-tetrachloroethane at 80 °C for 12 h (step 1), and
then 4 equiv of Et3N was added. The reaction mixture was
allowed to react for 2 h (step 2), but no desired product could be
isolated (Table 1, entries 22−24). On the basis of the results
presented above, the optimized reaction conditions were
established as follows: step 1, C60 (0.05 mmol), 1a (0.10
mmol), zinc dust (0.10 mmol), water (0.50 mmol), mixer mill,
41.7 Hz, 90 min; step 2, Et3N (0.20 mmol), mixer mill, 41.7 Hz,
15 min.
With the optimized conditions in hand, we then investigated
the scope of this reaction by employing various chalcones under
the optimal reaction conditions, and the results are summarized
in Scheme 1. Chalcones with an electron-donating group,
including methyl and methoxy groups at the para position on the
phenyl ring of R1, afforded 2b and 2c in yields of 30% and 33%,
respectively. Satisfyingly, the chloro and bromo substituents
were well tolerated in this reaction; products 2d and 2e could be
isolated in 36% and 32% yields, respectively. Furthermore,
reactions of chalcones containing the meta- and ortho-
substituted methyl group also proceeded smoothly and afforded
the corresponding products 2f and 2g in 37% and 34% yields,
respectively. Then, the chalcone with a methyl group on the
phenyl ring in R2 at the para position reacted fluently and
provided product 2h in 33% yield. However, the chalcone
bearing a para-substituted methoxy group retarded the reaction
obviously, giving product 2i in a lower yield of 25%. The
substrate with a meta-substituted methyl group also worked well
under our optimal conditions, providing product 2j in 38% yield.
Furthermore, substrates with other aryl, heteroaryl, and alkyl
groups were also explored. The results revealed that 2-naphthyl-,
2-thienyl-, methyl-, and dimethyl-substituted enones were
compatible with our protocol, and products 2k−n were isolated
in 19−32% yields. The assigned structures of products were
unambiguously confirmed by the single-crystal X-ray diffraction
analysis of 2a as an example.11
Table 1. Optimization of the Reaction Conditions
C60:1a:Zn
molar ratio
additive 1
(equiv)
additive 2
(equiv)
yield of 2a
b
entry
t (h)
(%)
c
1
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:1:2
1:3:2
1:2:1
1:2:3
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
p-TSA (5)
D-CSA (5)
AcOH (5)
H2O (5)
H2O (5)
H2O (8)
−
−
−
−
1
1
1
1
1
1
1
1
1
1
1
1
1.5
2
1.5
1.5
1.5
trace
trace
trace
c
2
c
3
c
d
4
4 (23)
5
6
7
8
Et3N (5)
Et3N (5)
Et3N (5)
Et3N (5)
Et3N (5)
Et3N (5)
Et3N (5)
Et3N (5)
Et3N (5)
Et3N (5)
Et3N (4)
Et3N (3)
Et3N (4)
14 (68)
30 (77)
34 (69)
32 (66)
11 (73)
33 (65)
16 (53)
34 (72)
41 (67)
38 (59)
42 (66)
39 (65)
43 (65)
H2O (10)
H2O (12)
H2O (10)
H2O (10)
H2O (10)
H2O (10)
H2O (10)
H2O (10)
H2O (10)
H2O (10)
H2O (10)
H2O (10)
H2O (10)
H2O (10)
H2O (10)
H2O (10)
H2O (10)
H2O (10)
9
10
11
12
13
14
15
16
f
17
e
18
19
20
21
22
Na2CO3 (4) 1.5
20 (37)
KOAc (4)
DMAP (4)
Et3N (4)
Et3N (4)
Et3N (4)
Et3N (4)
1.5
1.5
1.75
12
12
12
38 (59)
37 (57)
36 (56)
0
0
0
g
h
i
23
24
j
a
Unless otherwise noted, reactions were performed in a Spex
SamplePrep 5100 mixer mill with 0.05 mmol of C60. Isolated yields
b
based on C60. Values in parentheses were based on the amount of C60
c
d
consumed. Only step 1 of this reaction was carried out. Product 3a
e
was isolated in 11% yield. Product 3a was isolated in 21% yield.
Preactivated zinc dust was used. The Et3N was added together with
C60, 1a, Zn, and water. The reaction time was 105 min. The reaction
was performed in chlorobenzene at 80 °C. The reaction was
performed in o-dichlorobenzene at 80 °C. The reaction was
f
g
h
i
j
performed in 1,1,2,2-tetrachloroethane at 80 °C.
in 14% yield (Table 1, entry 5). The amount of water was
subsequently screened. When the dosage of water was increased
to 8 equiv, an improved yield of 30% was obtained (Table 1,
entry 6). Further increasing the amount of water to 10 equiv led
to a slightly increased yield of 34% (Table 1, entry 7). However,
a slightly decreased yield was attained when 12 equiv of water
was employed (Table 1, entry 8), indicating that 10 equiv of
water was the optimal choice. Afterward, the C60:1a:Zn molar
ratio was investigated. It was found that decreasing or increasing
the dosage of 1a or Zn did not produce better results (Table 1,
entries 9−12). Next, with the optimal C60:1a:Zn:water molar
ratio (1:2:2:10), the reaction time of step 1 was examined. As the
reaction time was extended to 1.5 h, the yield of product 2a was
increased to 41%, yet a reduced yield of 38% was obtained when
the reaction time was further prolonged to 2 h (Table 1, entries
13 and 14). In addition, the employed base should play a crucial
role in promoting the intermediate to the cyclized product; thus,
the amount of Et3N was examined. The reaction was carried out
with an amount of Et3N decreased from 5 equiv to 4 equiv and 3
equiv, and product 2a was delivered in yields of 42% and 39%,
A scale-up solvent-free mechanochemical reaction of 100 mg
of C60 (0.14 mmol) with chalcone 1a (0.28 mmol) was
conducted under the optimal reaction conditions. Product 2a
was obtained in 33% yield, indicating that this protocol could be
performed for a larger-scale preparation.
A set of control experiments were conducted to shed light on
the reaction mechanism. Without step 2, we performed the
reaction under the step 1 conditions. Intermediate 3a was
isolated in 27% yield, along with product 2a in 15% yield
(Scheme 2a). When pre-prepared intermediate 3a was allowed
to be milled for 15 min with Et3N, product 2a was isolated in
87% yield (Scheme 2b). These results inferred that 3a was a key
intermediate in this reaction. Subsequently, when H2O was
B
DOI: 10.1021/acs.orglett.9b00612
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Results for the Reaction of C60 with Enones 2a−n
Scheme 2. Control Experiments
a
All reactions were performed in a Spex SamplePrep 5100 mixer mill
with 0.05 mmol of C60. Isolated yields based on C60. Values in
parentheses were based on the amount of C60 consumed.
Scheme 3. Proposed Reaction Mechanism
replaced by D2O under the identical reaction conditions, we
found the H/D scrambling on product 2a and intermediate 3a,
which confirmed that water could act as a hydrogen donor
(Scheme 2c). However, it was found that the hydroxyl group of
compound d1-2a was undeuterated because of the facile
hydrogen−deuterium exchange with water during the workup
process, consistent with the literature.12 Because the single
electron transfer (SET) from Zn to α,β-unsaturated ketones
would generate the corresponding radical enolates,13 we
investigated whether this process was involved under our
reaction conditions. The reaction in the absence of C60 under
the optimized reaction conditions afforded polysubstituted
cyclopentanol derivative 4a in 30% yield (Scheme 2d).
Compound 4a was produced by the radical coupling of radical
enolates formed by SET and subsequent intramolecular aldol
cyclization.13 In addition, 4a could also be isolated in the same
yield without the addition of Et3N. However, 4a could not be
isolated when C60 was present. Therefore, the enolate radical
anion was unlikely involved, and Zn preferentially reduced C60
rather than the enones.
molecular cyclization and protonation to deliver cyclized
product 2. In the absence of a base, part of anionic 5 is
protonated to afford hydrofullerene 3, which can be converted
back to 5 by the added base.
Further dehydration to provide C60-fused cyclopentenes 6
was investigated by employing 2a and 2b as representative
examples (Scheme 4). As desired, C60-fused cyclopentene 6a
was obtained in 73% yield when 2a was treated with 4 equiv of
trifluoromethanesulfonic acid (TfOH) for 30 min under ball-
milling conditions. Although MgSO4 alone could not promote
the dehydration of 2a, the combination of 4 equiv of TfOH with
4 equiv of MgSO4 afforded a higher yield of 91%. Similarly, 6b
On the basis of the control experiments and the literature,8,10
a plausible reaction mechanism is proposed (Scheme 3). At first,
the C60 dianion is readily produced through the acceptance of
two electrons from Zn. Subsequently, the Michael addition of
the C60 dianion to substrate 1 followed by protonation generates
fullerenyl anion 5. Finally, anionic 5 undergoes an intra-
C
DOI: 10.1021/acs.orglett.9b00612
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Nanoscience and Nanotechnology; Nalwa, H. S., Ed.; American Scientific
Publishers: Stevenson Ranch, CA, 2004; p 557. (c) Komatsu, K. Top.
Curr. Chem. 2005, 254, 185. (d) Zhu, S.-E; Li, F.; Wang, G.-W. Chem.
Soc. Rev. 2013, 42, 7535.
Scheme 4. Dehydration Reaction
(3) Wang, G.-W.; Murata, Y.; Komatsu, K.; Wan, T. S. M. Chem.
Commun. 1996, 2059.
(4) (a) Wang, G.-W.; Komatsu, K.; Murata, Y.; Shiro, M. Nature 1997,
387, 583. (b) Komatsu, K.; Wang, G.-W.; Murata, Y.; Tanaka, T.;
Fujiwara, K.; Yamamoto, K.; Saunders, M. J. Org. Chem. 1998, 63, 9358.
(c) Tanaka, T.; Komatsu, K. Synth. Commun. 1999, 29, 4397. (d) Wang,
G.-W.; Zhang, T.-H.; Li, Y.-J.; Lu, P.; Zhan, H.; Liu, Y.-C.; Murata, Y.;
Komatsu, K. Tetrahedron Lett. 2003, 44, 4407. (e) Zhang, T.-H.; Wang,
G.-W.; Lu, P.; Li, Y.-J.; Peng, R.-F.; Liu, Y.-C.; Murata, Y.; Komatsu, K.
Org. Biomol. Chem. 2004, 2, 1698. (f) Peng, R.-F.; Wang, G.-W.; Shen,
Y.-B.; Li, Y.-J.; Zhang, T.-H.; Liu, Y.-C.; Murata, Y.; Komatsu, K. Synth.
Commun. 2004, 34, 2117.
(5) (a) Cheng, X.; Wang, G.-W.; Murata, Y.; Komatsu, K. Chin. Chem.
Lett. 2005, 16, 1327. (b) Chen, Z.-X.; Zhu, B.; Wang, G.-W. Lett. Org.
Chem. 2008, 5, 65. (c) Su, Y.-T.; Wang, G.-W. Org. Lett. 2013, 15, 3408.
(6) (a) Murata, Y.; Kato, N.; Fujiwara, K.; Komatsu, K. J. Org. Chem.
1999, 64, 3483. (b) Murata, Y.; Kato, N.; Komatsu, K. J. Org. Chem.
2001, 66, 7235. (c) Murata, Y.; Suzuki, M.; Komatsu, K. Chem.
Commun. 2001, 2338. (d) Wang, G.-W.; Zhang, T.-H.; Hao, E.-H.; Jiao,
L.-J.; Murata, Y.; Komatsu, K. Tetrahedron 2003, 59, 55. (e) Wang, G.-
W.; Li, Y.-J.; Peng, R.-F.; Liang, Z.-H.; Liu, Y.-C. Tetrahedron 2004, 60,
3921. (f) Wang, G.-W.; Chen, Z.-X.; Murata, Y.; Komatsu, K.
Tetrahedron 2005, 61, 4851. (g) Nakamura, Y.; Inamura, K.;
Oomuro, R.; Laurenco, R.; Tidwell, T. T.; Nishimura, J. Org. Biomol.
Chem. 2005, 3, 3032.
could be successfully isolated in 84% yield under the same
reaction conditions.
In summary, we have developed a solvent-free reductive
cyclization reaction of C60 with enones mediated by zinc in the
presence of water and triethylamine under ball-milling
conditions, affording a series of C60-fused cyclopentanols. On
the basis of the control experiments, a plausible reaction
mechanism has been proposed. In addition, the formed C60-
fused cyclopentanols can be efficiently transformed into C60-
fused cyclopentene derivatives via dehydration reaction with
TfOH and MgSO4. Our protocol features solvent-free
conditions and easily available and cheap reagents.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b00612.
(7) (a) Zhang, P.; Pan, H.; Liu, D.; Guo, Z.-X.; Zhang, F.; Zhu, D.
Synth. Commun. 2003, 33, 2469. (b) Watanabe, H.; Matsui, E.;
Ishiyama, Y.; Senna, M. Tetrahedron Lett. 2007, 48, 8132. (c) Muradyan,
V. E.; Arbuzov, A. A.; Smirnov, Y. N.; Lesnichaya, V. A. Russ. J. Gen.
Chem. 2011, 81, 1671.
Detailed experimental procedures and characterization
data, NMR spectra of 2a−n, d1-2a, 3a, d2-3a, 4a, 6a, and
6b, and crystal data of 2a (PDF)
(8) (a) For selected examples, see: Caron, C.; Subramanian, R.;
D’Souza, F.; Kim, J.; Kutner, W.; Jones, M. T.; Kadish, K. M. J. Am.
Chem. Soc. 1993, 115, 8505. (b) Fukuzumi, S.; Suenobu, T.; Hirasaka,
T.; Arakawa, R.; Kadish, K. M. J. Am. Chem. Soc. 1998, 120, 9220.
(c) Zheng, M.; Li, F.; Shi, Z.; Gao, X.; Kadish, K. M. J. Org. Chem. 2007,
72, 2538. (d) Yang, W.-W.; Li, Z.-J.; Gao, X. J. Org. Chem. 2010, 75,
4086. (e) Hou, H.-L.; Gao, X. J. Org. Chem. 2012, 77, 2553. (f) Xiao, Y.;
Zhu, S.-E.; Liu, D.-J.; Suzuki, M.; Lu, X.; Wang, G.-W. Angew. Chem.,
Int. Ed. 2014, 53, 3006. (g) Niu, C.; Zhou, D.-B.; Yang, Y.; Yin, Z.-C.;
Wang, G.-W. Chem. Sci. 2019, 10, 3012.
Accession Codes
CCDC 1859109 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
(9) (a) For selected examples, see: Cheng, F.; Murata, Y.; Komatsu, K.
Org. Lett. 2002, 4, 2541. (b) Allard, E.; Delaunay, J.; Cousseau, J. Org.
Lett. 2003, 5, 2239.
Corresponding Author
*E-mail: gwang@ustc.edu.cn.
ORCID
(10) (a) Haufler, R. E.; Conceicao, J.; Chibante, L. P. F.; Chai, Y.;
Byrne, N. E.; Flanagan, S.; Haley, M. M.; O’Brien, S. C.; Pan, C.; Xiao,
Z.; Billups, W. E.; Ciufolini, M. A.; Hauge, R. H.; Margrave, J. L.;
Wilson, L. J.; Curl, R. F.; Smalley, R. E. J. Phys. Chem. 1990, 94, 8634.
(b) Banks, M. R.; Dale, M. J.; Gosney, I.; Hodgson, P. K. G.; Jennings,
R. C. K.; Jones, A. C.; Lecoultre, J.; Langridge-Smith, P. R. R.; Maier, J.
P.; Scrivens, J. H.; Smith, M. J. C.; Smyth, C. J.; Taylor, A. T.; Thorburn,
P.; Webster, A. S. J. Chem. Soc., Chem. Commun. 1993, 1149. (c) Meier,
M. S.; Corbin, P. S.; Vance, V. K.; Clayton, M.; Mollman, M.;
Poplawska, M. Tetrahedron Lett. 1994, 35, 5789. (d) Bergosh, R. G.;
Meier, M. S.; Laske Cooke, J. A.; Spielmann, H. P.; Weedon, B. R. J. Org.
Chem. 1997, 62, 7667. (e) Spielmann, H. P.; Wang, G.-W.; Meier, M. S.;
Weedon, B. R. J. Org. Chem. 1998, 63, 9865.
Guan-Wu Wang: 0000-0001-9287-532X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful for financial support from the National
Natural Science Foundation of China (21372211) and the
Strategic Priority Research Program of the Chinese Academy of
Sciences (XDB20000000).
(11) CCDC 1859109 contains the crystallographic data for this paper.
(12) Takaki, K.; Beppu, F.; Tanaka, S.; Tsubaki, Y.; Jintoku, T.;
Fujiwara, Y. J. Chem. Soc., Chem. Commun. 1990, 516.
(13) Kapoor, K. K.; Kumar, S.; Ganai, B. A. Tetrahedron Lett. 2005, 46,
6253.
REFERENCES
■
(1) (a) For selected reviews, see: Nakamura, E.; Isobe, H. Acc. Chem.
Res. 2003, 36, 807. (b) Segura, J. L.; Martín, N.; Guldi, D. M. Chem. Soc.
Rev. 2005, 34, 31. (c) Matsuo, Y.; Nakamura, E. Chem. Rev. 2008, 108,
3016. (d) Li, C.-Z.; Yip, H.-L.; Jen, A. K.-Y. J. Mater. Chem. 2012, 22,
4161. (e) Li, Y. Acc. Chem. Res. 2012, 45, 723.
(2) (a) For reviews, see: Komatsu, K.; Murata, Y.; Wang, G.-W.;
Tanaka, T.; Kato, N.; Fujiwara, K. Fullerene Sci. Technol. 1999, 7, 609.
(b) Wang, G.-W. Fullerene Mechanochemistry. In Encyclopedia of
D
DOI: 10.1021/acs.orglett.9b00612
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