Synthesis of [60]Fullerene-Fused tetrahydroazepinones and azepinonimines via cu(oac)2-promoted n -heteroannulation reaction

Article abstract of DOI:10.1021/ol500028w

A convenient and efficient Cu(OAc)₂-mediated N-heteroannulation reaction of [60]fullerene with N-sulfonylated o-amino-aromatic methyl ketones or O-alkyl oximes has been reported for the synthesis of novel and scarce [60]fullerene-fused tetrahydroazepinones and -azepinonimines in a highly selective manner. Moreover, a possible mechanism involving two pathways is proposed on the basis of the experimental observations.

Full text of DOI:10.1021/ol500028w

Letter
pubs.acs.org/OrgLett
Synthesis of [60]Fullerene-Fused Tetrahydroazepinones and
Azepinonimines via Cu(OAc)2‑Promoted N‑Heteroannulation
Reaction
Tong-Xin Liu,* Zhenbei Zhang, Qingfeng Liu, Pengling Zhang, Penghao Jia, Zhiguo Zhang,
and Guisheng Zhang*
Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical
Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang,
Henan 453007, P. R. China
S
* Supporting Information
ABSTRACT: A convenient and efficient Cu(OAc)2-mediated
N-heteroannulation reaction of [60]fullerene with N-sulfony-
lated o-amino-aromatic methyl ketones or O-alkyl oximes has
been reported for the synthesis of novel and scarce
[60]fullerene-fused tetrahydroazepinones and -azepinonimines
in a highly selective manner. Moreover, a possible mechanism
involving two pathways is proposed on the basis of the
experimental observations.
hemical functionalization of fullerenes is an important
subject in fullerene chemistry for the creation of novel
Cu(OAc)2-promoted C−C/C−N bond forming annulation
reaction under aerobic conditions.
C
diversified fullerene-based materials with potential applications
in nanoscience, electronic devices, and biomedicine.1 During
the past two decades, a large number of chemical reactions of
fullerenes have been developed, and a great diversity of
fullerene derivatives with different functional and structural
units have been prepared.2 Among these reactions, free radical
reactions have been proven to be an efficient and important
tool for the synthesis of various fullerene derivatives.3 Especially
in recent years, increasing attention has been focused on the
transition-metal-catalyzed/mediated radical reactions for their
excellent ability to create novel functional fullerenes and
remarkable advantages over the traditional peroxide- or light-
initiated processes, such as high selectivity and efficiency, mild
reaction conditions, and high compatibility with a wide range of
functional groups.2i,3b,4
To the best of our knowledge, among numerous [60]-
fullerene derivatives with various fused rings, there are only a
few reports on the construction of more challenging seven-
membered ring systems up to now. These examples include the
photochemical cycloaddition of C60 with dienyl cyclopropanes,5
Pd(OAc)2-catalyzed annulation of C60 with N-sulfonyl-2-
aminobiaryls via directed C(sp2)−H bond activation,6 and
Co-catalyzed radical cycloaddition of C60 with 1,8-bis(bromo-
methyl)naphthalene.7 Despite these advances, the development
of new approaches to construct diversified seven-membered
[60]fullerene adducts in an efficient way with a broad substrate
scope still remains largely unrealized. Herein, we present a
flexible and efficient synthetic method for the highly selective
preparation of novel [60]fullerene-fused tetrahydroazepinones
and -azepinonimines from C60 with N-sulfonylated o-amino-
aromatic methyl ketones or O-alkyl oximes through a
Our investigations began by choosing the Cu(OAc)2-
mediated reaction of C60 with N-tosyl-o-aminoacetophenone
1a as the model reaction for the optimization of the reaction
conditions. The effect of the different bases, including organic
and inorganic bases, was first examined (Table 1, entries 1−6).
To our delight, when organic base DMAP was employed, the
reaction selectively afforded the desired seven-membered ring
C60-fused tetrahydroazepinone 2a in 8% yield at 80 °C after 2 h
(Table 1, entry 1), instead of corresponding methanofullerene
derivative, C60-fused dihydrofuran adduct, or their mixtures
generated from C60 with aromatic methyl ketone 1a under
similar conditions.8 With this preliminary and intriguing result
in hand, we turned to extensively screen various bases, such as
organic base DABCO (1,4-diazabicyclo[2.2.2]octane) and
inorganic bases Na2CO3, K2CO3, K3PO4, and Cs2CO3, to
improve the product yield (Table 1, entries 1−6). Compared to
the other bases, it was found that Cs2CO3 showed the highest
reactivity, with the formation of 2a in 40% yield (69% based on
consumed C60). Further conditions screening revealed that
lowering the reaction temperature or shortening the reaction
time gave inferior yields (Table 1, entries 7 and 9). By contrast,
raising the reaction temperature or prolonging the reaction
time also proved to be nonbeneficial to achieve a higher yield,
and it led to more byproducts and a significant consumption of
C60 (Table 1, entries 8 and 10). When decreasing the amount
of Cu(OAc)2 from 2 to 1 equiv, an obvious decrease in the
yield of 2a was observed (40% to 29%, Table 1, entry 11 vs 6).
Received: January 5, 2014
Published: January 29, 2014
© 2014 American Chemical Society
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a
Table 1. Optimization of the Reaction Conditions
Table 2. Cu(OAc)2-Mediated Synthesis of [60]Fullerene-
Fused Tetrahydroazepinones
a
b
c
entry
Cu(II)
base
molar ratio
time (h) yield (%)
1
2
3
4
5
6
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OTf)2
Cu(NO3)2
CuCl2
DMAP
1:4:2:1
1:4:2:1
1:4:2:1
1:4:2:1
1:4:2:1
1:4:2:1
1:4:2:1
1:4:2:1
1:4:2:1
1:4:2:1
1:4:1:1
1:4:3:1
1:4:2:2
1:3:2:1
1:5:2:1
1:4:2:1
1:4:2:1
1:4:2:1
1:4:2:1
2
2
2
2
2
2
2
2
1
3
2
2
2
2
2
2
2
2
2
8 (80)
trace
DABCO
Na2CO3
K2CO3
trace
trace
K3PO4
trace
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
40 (69)
32 (74)
36 (50)
34 (68)
35 (56)
29 (60)
37 (71)
32 (51)
34 (70)
40 (73)
trace
d
7
e
8
9
10
11
12
13
14
15
16
17
18
trace
trace
f
19
CuSO4
trace
a
All reactions were carried out with C60/1a/Cu(II)/base in a
designated molar ratio in cosolvent of anhydrous ODCB (7 mL)
and CH3CN (1 mL) at 80 °C under air unless specified otherwise.
b
c
Molar ratio refers to C60/1a/Cu(II)/base. Isolated yield; that in
d
parentheses was based on consumed C60. Reaction at 70 °C.
e
f
Reaction at 90 °C. Methanofullerene derivative 3a was obtained in
16% yield.
If the loading of Cu(OAc)2 was increased to 3 equiv, the
reaction only gave a comparable yield (Table 1, entry 12). An
attempt in increasing the quantity of Cs2CO3 to 2 equiv led to
an obvious decrease in the yield of 2a (40% to 32%), as well as
the formation of a small amount of byproduct methano-
fullerene derivative 3a (Table 1, entry 13). Achieving a higher
yield by changing the ratio of C60/1a was unsuccessful (Table
1, entries 14 and 15). In addition, other copper salts such as
Cu(OTf)2, Cu(NO3)2, and CuCl2 were ineffective in providing
expected product 2a (Table 1, entries 16−18). Intriguingly,
when the reaction was carried out in the presence of CuSO4,
methanofullerene derivative 3a was selectively obtained in 16%
isolated yield instead of 2a (Table 1, entry 19).
With the optimized reaction conditions in hand, the substrate
scope of the annulation was investigated for the synthesis of
[60]fullerene-fused tetrahydroazepinones, and the results are
shown in Table 2. Notably, a wide variety of N-sulfonyl-o-
aminoacetophenones 1 could effectively react with C60 to
selectively afford the corresponding products 2a−g. Aryl-
substituted substrates 1b−e bearing electron-donating and
-withdrawing groups on the aromatic ring all underwent
reaction smoothly under the optimized conditions to give the
expected products 2b−e in good yields (33−39%), indicating
that the electronic effect of the substituent group on the
aromatic ring has no significant influence on the reaction
(Table 2, entries 2−5). In addition, N-heteroaryl sulfonylated
2-aminoacetophenone 1f was also a suitable substrate for this
reaction and gave a slightly higher yield (Table 2, entry 6).
When the N-protecting group of the substrates was changed to
a
All reactions were performed with a molar ratio of C60/1/Cu(OAc)2/
Cs2CO3 = 1:4:2:1 in a solvent mixture of anhydrous ODCB (7 mL)
and CH3CN (1 mL) at 80 °C. Isolated yield; that in parentheses was
based on consumed C60. Reaction at 90 °C. Ns = 4-nitrobenzene-
sulfonyl, Ms = methanesulfonyl.
b
c
alkylsulfonyl from arylsulfonyl as in the case of N-mesyl-o-
aminoacetophenone 1g, the cyclization reaction also performed
well, providing the corresponding product 2g in 28% yield,
although a higher reaction temperature (90 °C) was required
(Table 2, entry 7). To our disappointment, when other N-
substituted substrates such as N-acetyl-o-aminoacetophenone
and ethyl (2-acetylphenyl)carbamate were employed under the
same reaction conditions, no or trace expected products were
detected.
Next, we further explored the possibility of extending the
substrates from N-sulfonyl-o-aminoacetophenones to N-sulfon-
yl-o-aminoacetophenone O-alkyl oximes for the synthesis of
another novel type of fullerenyl cycloaddition products, namely,
[60]fullerene-fused tetrahydroazepinonimines. It was pleasing
to find that a range of N-sulfonyl-o-aminoacetophenone O-alkyl
oximes 4 containing different substitution patterns could also
successfully react with C60 under similar conditions to afford
the expected derivatives in 15−33% yields, as illustrated in
Table 3. Compared with N-sulfonyl-o-aminoacetophenones 1,
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15%) (Table 3, entries 2 and 4 vs entries 3 and 5). N-(2-
Thenoyl)-o-aminoacetophenone O-methyl oxime 4f exhibited a
similar reactivity to the aryl-substituted substrates featuring
electron-withdrawing groups on both phenyl rings and gave the
target product 5f in 32% yield (Table 3, entry 6). To our
satisfaction, N-methyl sulfonylated substrate 4g was also
compatible, furnishing the desired adduct efficiently (Table 3,
entry 7). In addition, upon changing the substrate from O-
methyl oxime 4c to O-benzyl oxime 4h, C60-tetrahydroaze-
pinonimine derivative 5h was also obtained, albeit in relatively
low yield, possibly due to the steric hindrance of the benzyl
group (Table 3, entry 8).
Table 3. Cu(OAc)2-Mediated Synthesis of [60]Fullerene-
Fused Tetrahydroazepinonimines
a
C60-fused tetrahydroazepinonimines 5 were also obtained
through the condensation of C60-fused tetrahydroazepinones 2
with methoxyamine hydrochloride in the presence of a base.
However, compared with the above synthesis of derivatives 5,
this indirect transformation was not a practical synthetic route.
For example, when 2a was treated with excess methoxyamine
hydrochloride and NaOAc, the reaction only afforded 5a in
27% isolated yield (11% overall yield in two steps; see
Supporting Information (SI)).
The identification of novel C60-fused tetrahydroazepinones
2a−g and C60-fused tetrahydroazepinonimines 5a−h were
unambiguously confirmed by their HRMS, 1H NMR, 13C
NMR, FT-IR, and UV−vis spectroscopy, except for the 13C
NMR data of 5e and 5g due to their poor solubility (see SI).
To obtain further insights into the mechanism, the reaction
of C60 with 1a in the presence of radical inhibitors was
conducted, as illustrated in Scheme 1. Adding TEMPO
Scheme 1. Evidence in Support of a Radical Pathway
(2,2,6,6-tetramethylpiperidine-1-oxy) or Galvinoxyl (2,6-di-
tert-butyl-α-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadiene-1-yli-
dene)-p-tolyloxy) severely retarded the heteroannulation
reaction, thus strongly suggesting that this transformation
may involve a free radical process.
a
All reactions were performed with a molar ratio of C60/4/Cu(OAc)2/
Cs2CO3 = 1:4:2:2 in a solvent mixture of anhydrous ODCB (7 mL)
and CH3CN (1 mL) at 120 °C. Isolated yield; that in parentheses
was based on consumed C60. Reaction at 130 °C. Ns = 4-
nitrobenzenesulfonyl, Ms = methanesulfonyl.
b
c
Based on the above control experiments and literature
survey, a possible mechanism involving two pathways for the
oxidative formation of C60-fused tetrahydroazepinones 2 and
azepinonimines 5 is depicted in Scheme 2. Under the basic
conditions, the formed enolate or enamine of the substrate 1 or
4 could coordinate to Cu(OAc)2 to generate Cu(II) complex
I.8,9 Next, the radical species II was generated from complex I
via one-electron oxidation by Cu(II) in the radical pathway
(Path A), which could be captured by C60 to produce the
fullerenyl radical III, after which the active species III was
further oxidized by another molecule of Cu(OAc)2 to provide
uncommon nitrogen radicals,10 leading to a C- and N-centered
biradical intermediate IV.7,11 Subsequently, intramolecular
cyclization occurred to selectively afford seven-membered
annulated azepinones 2 and azepinonimines 5 via the biradical
C−N coupling, instead of methanofullerene or C60-fused
dihydrofuran derivative. We thought species IV was a key
intermediate, which made the reaction switch the pathway and
N-sulfonyl-o-aminoacetophenone O-alkyl oximes 4 were less
reactive substrates for the present oxidative annulation,
requiring a higher reaction temperature (120 or 130 °C)
(Table 3, entries 1−8), which may be attributed to the lower
acidity of CH3 adjacent to CNOR than CO. It was
noteworthy that the electronic nature of the substituents on the
phenyl ring played an important role in the reaction, which was
not in agreement with the observations in the reaction of C60
with N-sulfonyl-o-aminoacetophenones. For example, by
employing the aryl-substituted substrates with electron-with-
drawing groups on both phenyl rings, the reactions afforded the
corresponding [60]fullerene-fused tetrahydroazepinonimines in
good yields (33% and 32%), while the aryl-substituted
substrates possessing electron-donating groups on both phenyl
rings just led to the desired products in lower yields (18% and
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Scheme 2. Proposed Mechanism of Copper-Mediated
Oxidative Cascade Formation of C60-Fused
Tetrahydroazepinones 2 and Azepinonimines 5
REFERENCES
■
(1) For reviews, see: (a) Nakamura, E.; Isobe, H. Acc. Chem. Res.
2003, 36, 807. (b) Hirsch, A.; Brettreich, M. Fullerenes: Chemistry and
Reactions; Wliey-VCH: Weinheim, Germany, 2005. (c) Fullerenes:
Principles and Applications; Langa, F., Nierengarten, J.-F., Eds.; RSC:
Cambridge, 2007. (d) Guldi, D. M.; Illescas, B. M.; Atienza, C. M.;
Wielopolski, M.; Martín, N. Chem. Soc. Rev. 2009, 38, 1587.
(e) Giacalone, F.; Martín, N. Adv. Mater. 2010, 22, 4220. (f) Li, C.-
Z.; Yip, H.-L.; Jen, A. K.-Y. J. Mater. Chem. 2012, 22, 4161.
(2) For selected reviews, see: (a) Hirsch, A. Synthesis 1995, 895.
(b) Thilgen, C.; Diederich, F. Chem. Rev. 2006, 106, 5049. (c) Matsuo,
Y.; Nakamura, E. Chem. Rev. 2008, 108, 3016. (d) Murata, M.; Murata,
Y.; Komatsu, K. Chem. Commun. 2008, 6083. (e) Vougioukalakis, G.
C.; Roubelakis, M. M.; Orfanopoulos, M. Chem. Soc. Rev. 2010, 39,
817. For recent representative examples: (f) Filippone, S.; Maroto, E.
́
E.; Martín-Domenech, A.; Suarez, M.; Martín, N. Nat. Chem. 2009, 1,
578. (g) Nambo, M.; Wakamiya, A.; Yamaguchi, S.; Itami, K. J. Am.
Chem. Soc. 2009, 131, 15112. (h) Tzirakis, M. D.; Orfanopoulos, M.
Angew. Chem., Int. Ed. 2010, 49, 5891. (i) Xiao, Z.; Matsuo, Y.;
Nakamura, E. J. Am. Chem. Soc. 2010, 132, 12234. (j) Zhang, G.; Liu,
Y.; Liang, D.; Gan, L.; Li, Y. Angew. Chem., Int. Ed. 2010, 49, 5293.
(k) Kurotobi, K.; Murata, Y. Science 2011, 333, 613. (l) Xin, N.;
Huang, H.; Zhang, J.; Dai, Z.; Gan, L. Angew. Chem., Int. Ed. 2012, 51,
6163. (m) Chang, W.-W.; Li, Z.-J.; Gao, X. Org. Lett. 2013, 15, 1642.
(3) For reviews, see: (a) Morton, J. R.; Negri, F.; Preston, K. F. Acc.
Chem. Res. 1998, 31, 63. (b) Tzirakis, M. D.; Orfanopoulos, M. Chem.
Rev. 2013, 113, 5262.
(4) For reviews, see: (a) Wang, G.-W.; Li, F.-B. Curr. Org. Chem.
2012, 16, 1109. (b) Li, F.-B.; Wang, G.-W. Chin. Sci. Bull. 2012, 55,
2009. For recent representative examples: (c) Lu, S.; Jin, T.; Bao, M.;
Yamamoto, Y. J. Am. Chem. Soc. 2011, 133, 12842. (d) Lu, S.; Jin, T.;
Kwon, E.; Bao, M.; Yamamoto, Y. Angew. Chem., Int. Ed. 2012, 51, 802.
(5) Hatzimarinaki, M.; Orfanopoulos, M. Org. Lett. 2006, 8, 1775.
(6) Rajeshkumar, V.; Chan, F.-W.; Chuang, S.-C. Adv. Synth. Catal.
2012, 354, 2473.
thus favor the formation of these intriguing seven-membered
ring systems. An alternative pathway involving N−Cu(II) bond
formation might coexist with the above radical process in the
cyclization. In Path B, the C60−Cu(II) complex V might be
12
generated by the nucleophilic addition of carbanion I to C60
and then underwent ligand exchange to give the C60−Cu(II)
complex VI accomplished by the loss of one molecule of
HOAc,10a,13 which further converted into the final product
through reductive elimination. The exact reason for the
formation of methanofullerene 3a is not clear at the present
stage in the presence of CuSO4.
(7) Lu, S.; Si, W.; Bao, M.; Yamamoto, Y.; Jin, T. Org. Lett. 2013, 15,
In summary, we have developed a new and efficient synthetic
method for the highly selective construction of the scarce C60-
fused tetrahydroazepinones and -azepinonimines through the
Cu(OAc)2-mediated [5 + 2] oxidative cycloaddition of C60 with
N-sulfonylated o-aminoaromatic methyl ketones or O-alkyl
oximes. This methodology features a broad substrate scope,
high chemoselectivity, readily available starting materials, and
simple operation of the process.
4030.
(8) Wang, G.-W.; Li, F.-B. Org. Biomol. Chem. 2005, 3, 794.
(9) (a) Sun, Y.; Fan, R. Chem. Commun. 2010, 46, 6834.
(b) Ilangovan, A.; Satish, G. Org. Lett. 2013, 15, 5726.
(10) (a) Sherman, E. S.; Chemler, S. R.; Tan, T. B.; Gerlits, O. Org.
Lett. 2004, 6, 1573. (b) Wang, Y.-F.; Zhu, X.; Chiba, S. J. Am. Chem.
Soc. 2012, 134, 3679. (c) Wang, Y.-F.; Chen, H.; Zhu, X.; Chiba, S. J.
Am. Chem. Soc. 2012, 134, 11980. (d) Tang, D.; Wu, P.; Liu, X.; Chen,
Y.-X.; Guo, S.-B.; Chen, W.-L.; Li, J.-G.; Chen, B.-H. J. Org. Chem.
2013, 78, 2746. (e) He, C.-L.; Liu, R.; Li, D.-D.; Zhu, S.-E.; Wang, G.-
W. Org. Lett. 2013, 15, 1532. (f) Yang, H.-T.; Liang, X.-C.; Wang, Y.-
H.; Yang, Y.; Sun, X.-Q.; Miao, C.-B. Org. Lett. 2013, 15, 4650. (g) Si,
W.; Lu, S.; Bao, M.; Asao, N.; Yamamoto, Y.; Jin, T. Org. Lett. 2014,
16, 620. (h) Yang, H.-T.; Liang, X.-C.; Wang, Y.-H.; Yang, Y.; Sun, X.-
Q.; Miao, C.-B. J. Org. Chem. 2013, 78, 11992.
(11) Hatzimarinaki, M.; Roubelakis, M. M.; Orfanopoulos, M. J. Am.
Chem. Soc. 2005, 127, 14182.
(12) 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.
(13) Yu, D.-G.; Suri, M.; Glorius, F. J. Am. Chem. Soc. 2013, 135,
8802.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, spectral data, and NMR spectra of
products 2a−g, 3a and 5a−h. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: liutongxin_0912@126.com.
*E-mail: zgs6668@yahoo.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the financial support from NSFC
(21172056, 21272057, 21372065, 21302044, and U1304524),
PCSIRT (IRT1061), China Postdoctoral Science Foundation
funded project (2012M521397, 2013T60701, and
2013M530339), and Key Project of Henan Educational
Committee (13A150546).
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