Ferrocene-Initiated Oxidative Cyclization of Benzaldehyde with Alkyne: New Strategy to Substituted Indenones

Article abstract of DOI:10.1002/ejoc.201900281

A ferrocene-initiated oxidative cyclization of benzaldehyde with alkyne was successfully developed as a novel strategy for direct access to substituted indenones in high yields. The commercially available and cheap ferrocene was employed as an initiator. This transformation could proceed smoothly with a low initiator loading (0.5 mol-%) and provide the titled products up to 90 % yield with atom-, step-economy and good substrates tolerance. The indenones obtained would be important building blocks in organic synthesis.

Full text of DOI:10.1002/ejoc.201900281

DOI: 10.1002/ejoc.201900281
Communication
Radical C–H Activation
Ferrocene-Initiated Oxidative Cyclization of Benzaldehyde with
Alkyne: New Strategy to Substituted Indenones
Yadong Feng,[a,b] Hong Zhang,[a] Yunliang Yu,[a] Lei Yang,[a] and Xiuling Cui*[a]
Abstract: A ferrocene-initiated oxidative cyclization of benz- smoothly with a low initiator loading (0.5 mol-%) and provide
aldehyde with alkyne was successfully developed as a novel the titled products up to 90 % yield with atom-, step-economy
strategy for direct access to substituted indenones in high and good substrates tolerance. The indenones obtained would
yields. The commercially available and cheap ferrocene was em- be important building blocks in organic synthesis.
ployed as an initiator. This transformation could proceed
Introduction
attractiveness of green and atom economical features of C–H
bond activation, our focus is currently shifting towards the
redox process of ferrocene in C–H functionalization.[8]
Great success of transition-metal-catalyzed functionalization of
C–H bond has been achieved in the past decade. The main
breakthrough relies on noble metals, such as Pd, Rh, Ru or Ir.[1]
Recently, more and more attention has focused on the first-row
transition metals due to their natural abundance, low cost, low
toxicity, and recently disclosed promising catalytic activities.[2]
Among them, iron has become a rapidly growing topic in the
field of C–H bond functionalization, in which single-electron
transfer (SET) processes usually dominate. For example, in 2009,
Wunderlich and Knochel reported that an iron(II) complex of
amine promoted the alkylation of aromatic C–H bond through
an organoiron intermediate.[3] Subsequently, Li and co-workers
developed a practical protocol involving iron-catalyzed carbon-
ylation-peroxidation of alkenes via radical activation of alde-
hydes in 2011.[4] In 2013, Studer and co-workers developed an
easy method to afford 6-aroylated phenanthridines via base-
promoted homolytic aromatic substitutions using FeCl3
(0.4 mol-%) as a single-electron transfer (SET) reagent.[5] At the
same time, a noteworthy work from the same group is an effec-
tive direct synthesis of fluorenones initiated by ferrocene
(0.1 mol-%).[6] As a result, ferrocene has appeared as an effec-
tive initiator in single-electron transfer processes, in which a
low loading of initiator is enough to run the reaction. Compared
with the iron salts, the special physical and chemical properties
of ferrocene clearly result from its unique “sandwich structure”,
and reversible redox properties.[7] Driven by the synthetic
On the other hand, indenone framework is ubiquitous in
pharmaceutical and material sciences. The substituted inde-
nones have been previously explored in a wide range of drug
development and play key roles as important intermediates in
the synthesis of diverse natural products.[9] As a result, the es-
tablishment of robust synthetic approaches for indenones start-
ing from readily available materials has been continuously de-
sired. However, the literature procedures are far from step- and
atom-economy, because ortho bifunctionalized arenes are not
always commercially or readily available, and the introduction
or removal of the directing groups are not trivial (Scheme 1, eq
A and B).[10] Undoubtedly, the direct annulation of aryl alde-
hyde as commercially available starting material with alkynes is
[a] Engineering Research Center of Molecular Medicine of Ministry of
Education, Key Laboratory of Fujian Molecular Medicine, Key Laboratory of
Xiamen Marine and Gene Drugs, School of Biomedical Sciences, Huaqiao
University,
Xiamen 361021, P. R. China
E-mail: cuixl@hqu.edu.cn
[b] College of Environment and Public Health, Department of Science and
Technology for Inspection, Xiamen Huaxia University,
Xiamen 361024, China
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201900281.
Scheme 1. Syntheses of indenones.
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Communication
the most straightforward and atom-economical pathway to-
ward indenones, and the sole by-product would only be
2 equiv. of H+ (Scheme 1, eq C). For example, Cheng and Adhik-
ary groups reported the direct annulation of aryl aldehydes
with alkynes towards synthesis of 2,3-diarylindenones in 2013
and 2018, respectively.[11] Herein, we disclose an efficient ferro-
cene-initiated oxidative cyclization of aryl aldehyde with alk-
ynes as a novel strategy to substituted indenones, which pro-
ceed through radical process followed by oxidative cyclization
(Scheme 1). In contrast to the known processes to indenones,
not only cheap and commercially available ferrocene and
tBuOOH were used as an initiator and an oxidant, but also the
introduction or removal of the directing groups was avoided.
At the same time, a low loading of ferrocene (0.5 mol-%) is
enough to obtain the products in high yields. Due to the modu-
larity of the present synthetic method, it could be useful for the
preparation of indenones libraries. This novel protocol features
easy operation, high efficiency, environmental friendliness, and
tolerance of broad functional groups.
Table 1. Optimization of the reaction conditions.[a]
entry
initiator
[mol-%]
tBuOOH
[equiv.]
solvent
temp
[°C]
t
[h]
yield
[%][b]
1
2
3
4
FeBr3 (0.5)
–
FeCl2 (0.5)
Fe2(SO4)3
(0.5)
3.0
3.0
3.0
3.0
CH3CN
CH3CN
CH3CN
CH3CN
120
120
120
120
30
30
30
30
69
21
40
51
5
6
7
8
FeCl3 (0.5)
Fc (0.5)
Fc (1.0)
Fc (0.2)
Fc (0.5)
Fc (0.5)
Fc (0.5)
Fc (0.5)
Fc (0.5)
Fc (0.5)
Fc (0.5)
Fc (0.5)
Fc (0.5)
Fc (0.5)
Fc (0.5)
Fc (0.5)
3.0
3.0
3.0
3.0
–
2.5
2.0
3.5
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
120
120
120
120
120
120
120
120
120
120
120
120
130
110
80
30
30
30
30
30
30
30
30
30
30
30
30
30
30
32
28
48
86
84
57
nd
80
71
83
trace
72
trace
63
9
10
11
12
13
14
15
16
17
18
19
20
DMSO
NMP
Results and Discussion
toluene
CH3CN
CH3CN
CH3CN
CH3CN
81
66
85
79
Initially, the reaction of benzaldehyde (1a) with 1,2-diphenyl-
ethyne (2a) was chosen as a model reaction to examine various
parameters (Table 1). The results revealed that 2,3-diphenyl-1H-
inden-1-one (3a) was obtained as the main product in 69 %
yield in CH3CN at 120 °C when FeBr3 (0.5 mol-%) was used as
an initiator and tBuOOH (3.0 equiv.) was used as an oxidant
(Table 1, entry 1). Only 21 % yield of the target product 3a was
achieved when the reaction was carried out in the absence of
an initiator (Table 1, entry 2). Iron salts, such as FeCl2, Fe2(SO4)3,
FeCl3, and ferrocene (Fc) were screened. Ferrocene gave the
highest yield (86 %) (Table 1, entry 1 vs. entries 3–6). Better
results were achieved with 0.5 mol-% of ferrocene (Table 1, en-
tries 6–8). Moreover, 3.0 equiv. of tBuOOH favor this reaction
than other conditions (Table 1, entry 6 vs. entries 9–12). CH3CN
was demonstrated to be better than other solvents, such as
DMF, DMSO, NMP and toluene (Table 1, entry 6 vs. entries 13–
16). The yield of 3a decreased when the reaction temperature
80
[a] Reaction conditions: 1a (0.20 mmol), 2a (0.3 mmol), solvent (2.0 mL).
[b] Isolated yields. nd = not detected.
be well tolerated and gave the corresponding products in satis-
factory yields (3d–3i, 60–90 %), which indicated that the elec-
tron density of the benzaldehyde had a slight effect. Halogen
groups, such as F, Cl, Br, and I at the para-position of benzalde-
hyde provided the corresponding products 3j–3m in 87 %,
72 %, 78 %, and 63 % yields, respectively. No product was ob-
tained when other aldehydes were introduced into the reaction,
such as furan-2-carbaldehyde, 2-pyridinecarboxaldehyde, N-
phenylformamide, 2-phenylacetaldehyde, 3-phenylpropanal, or
2-oxo-2-phenylacetaldehyde.
Moreover, benzaldehyde (1a) reacted smoothly with substi-
and reaction time were changed (Table 1, entries 17–20). Based tuted alkynes (2b–2g) to give the desired products 3n–3s in
on the results, the optimal reaction conditions were identified 42 %-64 % yields. A methyl group at the meta- and para-posi-
as follows: CH3CN as solvent, at 120 °C, ferrocene (0.5 mol-%) tion of diarylacetylenes provided the corresponding products
as an initiator and tBuOOH (3.0 equiv.) as an oxidant (Table 1, 3n and 3o in 55 % and 52 % yields, which indicated that steric
entry 6).
effect of substituted groups did not obviously affect this trans-
formation. Electron-rich diarylacetylenes (2c, 52 %) exhibited
the lower reactivity than electron-deficient diarylacetylenes (2d,
64 %). Halogen groups at the para-position of diarylacetylenes
could also provide the corresponding products 3q–3s in 58 %,
46 %, and 42 % yields, respectively. This protocol is limited to
symmetrical aromatic alkynes and is not effective for alkyl alk-
ynes, unsymmetrical alkynes and olefins.
With the optimized reaction conditions in hand, the scope
of the substrates was examined (Table 2). 1,2-Diphenylethyne
(2a) reacted smoothly with benzaldehyde (1a) and its deriva-
tives (1b–1m) to give the desired products (3a–3m) in moder-
ate to excellent yields (52 %-90 %). A methyl group at the ortho-
and para-position of benzaldehyde provided the corresponding
products 3b–3c in 69 % and 75 % yields, which indicated that
the steric effect of substituted groups did not significantly af-
To clarify the reaction mechanism, a control experiment was
fect this transformation. However, when 3-methylbenzaldehyde carried out (Scheme 2). When a radical scavenger, TEMPO, was
was introduced into the reaction, a mixture of 2- and 6- position introduced into the reaction, the yield of 3a was largely de-
products was obtained at a ratio of 1:1.5 (Supporting Informa- creased. The by-product 4 was generated and detected by
tion, Figure S1). Other groups, such as (CH3)2CH, tBu, CH3O, CF3, HRMS (Supporting Information, Figure S2), which suggested
(CH3)2N, and CH3S at the para-position of benzaldehyde could that a radical pathway might be involved in this reaction.
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Communication
Table 2. Optimization of the reaction conditions.[a,b]
[a] Reaction conditions: 1 (0.20 mmol), 2 (0.3 mmol), Fc (0.5 mol-%), tBuOOH (3.0 equiv.), solvent (2.0 mL). [b] Isolated yields.
erated from the dissociation of tBuOOH with Fe as an initiator.
Then the tert-butoxyl radical could abstract the H atom from
the aldehyde to yield the acyl radical A,[12] which attached the
alkyne to give the alkenyl radical B. Subsequently, this radical
would cyclize to the arene to form the cyclohexadienyl radical
C, which was further aromatized to yield the product 3a. It is
important to note that decarbonylation of an aromatic acyl rad-
ical is slow, which allows the reaction to take place. Besides, we
believe that the cyclohexadienyl radical C can reduce the FeIII
complex, in which the active FeII was regenerated to finish the
catalytic cycle.
Scheme 2. Control experiment.
Based on the experimental observation and literature re-
ports,[5–7] a plausible reaction mechanism was proposed and
depicted in Scheme 3. Initially, the tert-butoxyl radical was gen-
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Communication
[1]
a) L. Ackermann, R. Vicente, A. R. Kapdi, Angew. Chem. Int. Ed. 2009, 48,
9792–9826; Angew. Chem. 2009, 121, 9976; b) D. Alberico, M. E. Scott, M.
Lautens, Chem. Rev. 2007, 107, 174–238; c) T. W. Lyons, M. S. Sanford,
Chem. Rev. 2010, 110, 1147–1169; d) R. Giri, B. Shi, K. M. Engle, N. Maugel,
J. Yu, Chem. Soc. Rev. 2009, 38, 3242–3272; e) L. McMurray, F. O′Hara,
M. J. Gaunt, Chem. Soc. Rev. 2011, 40, 1885–1898; f) T. Yuan, C. Pi, C. You,
X. Cui, S. Du, T. Wang, Y. Wu, Chem. Commun. 2019, 55, 163–166; g) H.
Butenschön, Angew. Chem. Int. Ed. 2008, 47, 5287–5290; Angew. Chem.
2008, 120, 5367; h) K. E. O. Ylijoki, J. M. Stryker, Chem. Rev. 2013, 113,
2244–2266; i) M. Harmata, Chem. Commun. 2010, 46, 8886–8903; j) Z.
Wang, P. Xie, X. Xia, Chin. Chem. Lett. 2018, 29, 47–53; k) N. Lv, Z. Chen,
Y. Liu, Z. Liu, Y. Zhang, Org. Lett. 2017, 19, 2588–2591; l) W. Yu, W. Zhang,
Z. Liu, Y. Zhang, Chem. Commun. 2016, 52, 6837–6840; m) L. Kong, X.
Yang, X. Zhou, S. Yu, X. Li, Org. Chem. Front. 2016, 3, 813–816; n) L. Xu,
T. Li, L. Wang, X. Cui, J. Org. Chem. 2019, 84, 560–567; o) Z. Yang, L. Jie,
Z. Yao, Z. Yang, X. Cui, Adv. Synth. Catal. 2019, 361, 214–218; p) P. Zhang,
Y. GAO, L. Zhang, Z. Li, Y. Liu, G. Tang, Y. Zhao, Adv. Synth. Catal. 2016,
358, 138–142; q) L. Xu, S. Zhang, P. Li, Org. Chem. Front. 2015, 2, 459–
463.
Scheme 3. Proposed reaction mechanism.
Conclusions
[2]
a) R. Braslau, M. O. Anderson, F. Rivera, A. Jimenez, T. Haddad, J. R. Axon,
Tetrahedron 2002, 58, 5513–5523; b) L. Benati, G. Calestani, R. Leardini,
M. Minozzi, D. Nanni, P. Spagnolo, S. Strazzari, Org. Lett. 2003, 5, 1313–
1316; c) S. Esposti, D. Dondi, M. Fagnoni, A. Albini, Angew. Chem. Int. Ed.
2007, 46, 2531–2586; Angew. Chem. 2007, 119, 2583; d) S. Selvakumar,
R. Sakamoto, K. Maruoka, Chem. Eur. J. 2016, 22, 6552–6555; e) D. Ravelli,
M. Zema, M. Mella, M. Fagnoni, A. Albini, Org. Biomol. Chem. 2010, 8,
4158–4164; f) P. J. Fagan, P. J. Krusic, C. N. McEwen, J. PLazar, D. H. Park-
ert, N. Herron, E. Wasserman, Science 1993, 262, 404–407; g) M. D. Tzi-
rakis, M. Orfanopoulos, J. Am. Chem. Soc. 2009, 131, 4063–4069; h) D.
Ravelli, A. Albini, M. Fagnoni, Chem. Eur. J. 2011, 17, 572–579; i) I. Ryu,
A. Tani, T. Fukuyama, D. Ravelli, M. Fagnoni, A. Albini, Angew. Chem. Int.
Ed. 2011, 50, 1869–1872; Angew. Chem. 2011, 123, 1909; j) H. Yi, G.
Zhang, H. Wang, Z. Huang, J. Wang, A. K. Singh, A. Lei, Chem. Rev. 2017,
117, 9016–9085.
In summary, we have demonstrated an efficient ferrocene-initi-
ated an annulation of aryl aldehyde with alkynes as a new strat-
egy towards substituted indenones. In contrast to the known
processes, not only cheap and commercially available ferrocene
and tBuOOH were used as an initiator and an oxidant, but also
the prefunctionalization of the reacting partners is avoided in
this transformation. At the same time, a low loading of initiator
(0.5 mol-%) is enough to run the reaction. This protocol features
easy operation, high efficiency, environmental friendliness, and
tolerance of a broad range of functional groups. Due to the
modularity of the present method, the ferrocene-initiated acyl
radical addition to alkynes provides a novel strategy for atom/
step economical syntheses of useful pharmaceutical molecules.
[3]
S. H. Wunderlich, P. Knochel, Angew. Chem. Int. Ed. 2009, 48, 9717–9720;
Angew. Chem. 2009, 121, 9897.
[4]
[5]
[6]
[7]
W. Liu, Y. Li, K. Liu, Z. Li, J. Am. Chem. Soc. 2011, 133, 10756–10759.
D. Leifert, C. G. Daniliuc, A. Studer, Org. Lett. 2013, 15, 6286–6289.
S. Wertz, D. Leifert, A. Studer, Org. Lett. 2013, 15, 928–931.
Experimental Section
a) E. M. Schustorovich, M. E. Dyatkina, Dokl. Akad. Nauk SSSR 1959, 128,
1234–1237; b) N. G. Connelly, W. E. Geiger, Chem. Rev. 1996, 96, 877–
910; c) J. D. Dunitz, L. E. Orgel, Nature 1953, 171, 121; d) P. Seiler, J. D.
Dunitz, Acta Crystallogr., Sect. B 1979, 35, 1068–1074; e) M. Chen, B. Yang,
C. Chen, Angew. Chem. Int. Ed. 2015, 54, 15520–15524; f) Q. Zhang, X.
Cui, L. Zhang, S. Luo, H. Wang, Y. Wu, Angew. Chem. Int. Ed. 2015, 54,
5210–5213; Angew. Chem. 2015, 127, 5299; g) J. B. Thomson, Tetrahedron
Lett. 1959, 1, 26–27; h) D. H. R. Barton, V. N. Le Gloahec, H. Patin, F.
Launay, New J. Chem. 1998, 22, 559–563.
General Procedure for the Synthesis of Products 2: To a 20 mL
tube were added 1 (0.20 mmol), 2 (0.30 mmol), Fc (0.001 mmol),
tBuOOH (0.60 mmol) and followed by addition of CH3CN (2.0 mL).
The formed mixture was stirred in 120 °C oil bath for 30 h. The
reaction was monitored by TLC. The solution was then quenched
with H2O (10 mL), extracted with ethyl acetate (3 × 10 mL). The
combined organic phases were washed with saturated sodium
bicarbonate solution, dried with sodium sulfate, filtered, and
the solvents evaporated under vacuum. The crude product was pu-
rified by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 200:1 to 100:1) to afford the desired products
3.
[8]
[9]
a) C. Pi, Y. Li, X. Cui, H. Zhang, Y. Han, Y. Wu, Chem. Sci. 2013, 4, 2675–
2679; b) H. Zhang, X. Cui, X. Yao, H. Wang, J. Zhang, Y. Wu, Org. Lett.
2012, 14, 3012–3015.
a) C. F. Huebner, E. M. Donoghue, A. J. Plummer, D. A. Furness, J. Med.
Chem. 1966, 9, 830–832; b) J. L. Jeffrey, R. Sarpong, Org. Lett. 2009, 11,
5450–5453; c) J. Barbera, O. A. Rakitin, M. B. Ros, T. Torroba, Angew. Chem.
Int. Ed. 1998, 37, 296–299; Angew. Chem. 1998, 110, 308; d) K. Morinaka,
T. Ubukata, Y. Yokoyama, Org. Lett. 2009, 11, 3890–3893; e) G. M. An-
stead, S. R. Wilson, J. A. Katzenellenbogen, J. Med. Chem. 1989, 32, 2163–
2171; f) M. Froimowitz, K. Wu, A. Moussa, R. M. Haidar, J. Jurayj, C. Ge-
orge, E. L. Gardner, J. Med. Chem. 2000, 43, 4981–4992; g) K. Gao, N.
Yoshikai, Chem. Commun. 2012, 48, 4305–4307; h) Y. Kuninobu, T. Mat-
suki, K. Takai, Org. Lett. 2010, 12, 2948–2950.
a) B. Li, H. Wang, Q. Zhu, Z. Shi, Angew. Chem. Int. Ed. 2012, 51, 3948–
3952; Angew. Chem. 2012, 124, 4014; b) L. Yang, C. A. Correia, C. Li, Adv.
Synth. Catal. 2011, 353, 1269–1273; c) H. Tsukamoto, Y. Kondo, Org. Lett.
2007, 9, 4227–4230; d) T. Miura, M. Murakami, Org. Lett. 2005, 7, 3339–
3341; e) F. W. Patureau, T. Besset, N. Kuhl, F. Glorius, J. Am. Chem. Soc.
2011, 133, 2154; f) J. Jayakumar, K. Parthasarathy, C. Cheng, Angew.
Chem. Int. Ed. 2012, 51, 197–200; Angew. Chem. 2012, 124, 201;
g) L. Ackermann, A. V. Lygin, Org. Lett. 2012, 14, 764–767; h) T. Fukutani,
N. Umeda, K. Hirano, T. Satoh, M. Miura, Chem. Commun. 2009, 5141–
Acknowledgments
This work was supported by the NSF of China (Nos. 21572072),
Xiamen Southern Oceanographic Center (15PYY052SF01), 111
project (BC2018061) and Y. F. thanks the Postgraduates Innova-
tive Fund in Scientific Research of Huaqiao University and, the
financial support of Scientific Research Foundation of Xiamen
Huaxia University (HX201807), Outstanding Youth Scientific Re-
search Cultivation Plan in Fujian Province University (2018).
[10]
Keywords: Ferrocene · Cyclization · Radical reactions ·
C–H activation · Synthetic methods
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5143; i) P. Zhao, F. Wang, K. Han, X. Li, Org. Lett. 2012, 14, 5506–5509;
j) J. Chen, G. Song, C. Pan, X. Li, Org. Lett. 2010, 12, 5426–5429; k) Y.
Kuninobu, A. Kawata, K. Takai, J. Am. Chem. Soc. 2005, 127, 13498–13499;
l) Y. Kuninobu, Y. Tokunaga, A. Kawata, K. Takai, J. Am. Chem. Soc. 2006,
128, 202–209.
[11] a) S. Chen, J. Yu, Y. Jiang, F. Chen, J. Cheng, Org. Lett. 2013, 15, 4754–
4757; b) B. Banerji, L. Majumder, S. Adhikary, ChemistrySelect 2018, 3,
1381–1384.
[12] C. Chatgilialoglu, D. Crich, M. Komatsu, I. Ryu, Chem. Rev. 1999, 99, 1991–
2070.
Received: February 20, 2019
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Communication
Radical C–H Activation
Y. Feng, H. Zhang, Y. Yu, L. Yang,
X. Cui* .................................................... 1–6
Ferrocene-Initiated Oxidative Cycli-
zation of Benzaldehyde with Alk-
yne: New Strategy to Substituted
Indenones
A ferrocene-initiated oxidative cycliza- tuted indenones in high yields. The
tion of benzaldehyde with alkyne was commercially available and cheap fer-
successfully developed as a novel rocene was employed as an initiator.
strategy for the direct access to substi-
DOI: 10.1002/ejoc.201900281
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