Rh/Cu-Catalyzed Cascade [4+2] Vinylic C?H O-Annulation and Ring Contraction of α-Aryl Enones with Alkynes in Air

Article abstract of DOI:10.1002/anie.201612147

An unprecedented Rh-catalyzed ketone-directed vinylic C?H activation/[4+2] O-annulation of α-aryl enones with internal alkynes followed by a Cu-catalyzed ring contraction in air to provide multiaryl-substituted furan derivatives has been developed. The preliminary mechanism study identifies the active pyrylium salt as the key intermediate.

Full text of DOI:10.1002/anie.201612147

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201612147
German Edition: DOI: 10.1002/ange.201612147
Homogeneous Catalysis
À
Rh/Cu-Catalyzed Cascade [4+2] Vinylic C H O-Annulation and Ring
Contraction of a-Aryl Enones with Alkynes in Air
Yinsong Zhao, Shiqing Li, Xuesong Zheng, Junbin Tang, Zhijie She, Ge Gao,* and
Jingsong You*
Abstract: An unprecedented Rh-catalyzed ketone-directed
pyrylium salts, which are important intermediates for various
transformations,[8] probably because the more electronegative
carbonyl oxygen atom renders the direct reductive elimina-
À
vinylic C H activation/[4+2] O-annulation of a-aryl enones
with internal alkynes followed by a Cu-catalyzed ring con-
traction in air to provide multiaryl-substituted furan derivatives
has been developed. The preliminary mechanism study
identifies the active pyrylium salt as the key intermediate.
À
tion of metallacyles to form an oxonium C O bond difficult.
Alternatively, [3+2] C-annulation usually occurs and five-
membered carbocyclic indenols are formed (Scheme 1b).[9,10]
Moreover, compared to aryl ketones, the ketone-directed
À
À
T
ransition-metal catalyzed chelation directed C H bond
vinylic C H bond functionalization of a,b-enones is more
activation followed by annulation with 2p components (such
as alkenes, alkynes) has recently emerged as an efficient and
attractive strategy to construct N-heterocycles and carbo-
cycles.[1,2] In this context, imines, oximes, and hydrazones, etc.
challenging and the examples are rare.[11,12] The majority to
date is the low-valent [Ru]- or [Rh]-catalyzed addition of
[13]
À
a vinylic C H bond to alkenes and alkynes. The reason is
probably due to their high tendency towards other compet-
itive transformations such as conjugate addition[14] as well as
polymerization.[15] To the best of our knowledge, a,b-enones
have not been involved in any oxidative annulation reaction
À
having strong N-directing groups are known to undergo C H
activation/[4+2] N-annulation to give six-membered N-het-
erocycles such as isoquinolines,[3] pyridines,[4] and isoquinoli-
nium[5] and pyridinium salts[6] (Scheme 1a). However, the
parent ketone compounds with a weakly coordinating car-
bonyl group[7] are not known to annulate similarly to deliver
O-heterocyclic structures such as isochromenylium and
À
via vinylic C H bond activation. Herein, we present the first
example of a Rh-catalyzed ketone-directed vinylic C H
activation and [4+2] O-annulation of a-aryl enones with
alkynes to form pyrylium salts, which sequentially undergo
a Cu-catalyzed ring contraction in air to provide multiaryl-
substituted furans[16] (Scheme 1c).
À
During our study on the ketone-directed [3+2] C-
annulation of 2-arylcyclo-2-enones with alkynes to access
spiro carbocyclic indenes,[17] we found that the reaction of 2-
(4-methoxyphenyl)-1-phenylprop-2-en-1-one (1aPh) with
diphenylacetylene (2a) in the presence of a [Rh]/[Cu] cata-
lytic system gave 2,3,5-trisubstituted furan 3aa and isochro-
menone 4 in 23% and 17% yield, respectively [Eq. (1)]. It
À
seemed that the C C single bond of the enone was cleaved to
À
Scheme 1. Annulation of ketones and their N-derivatives via C H
activation.
generate a vinyl fragment and a benzoyl fragment, which
annulated with the alkyne with an inserted oxygen atom to
form furan and isochromenone skeletons, respectively.
To further explore this unexpected reaction, a systematical
screening of the reaction conditions was conducted using 3-(4-
methoxyphenyl)-but-3-en-2-one (1a) and 2a as the model
substrates. The best yield for 3aa was 72% in the presence of
[Cp*RhCl2]2 (5 mol%), AgSbF6 (20 mol%), Cu(OAc)2·H2O
(2 equiv) and butylated hydroxytoluene (BHT, 10 mol%) in
DME in air at 908C for 5 hours (Table 1, entry 1).[18] The
control experiments showed that the [Rh], [Ag], and [Cu]
[*] Y. Zhao, S. Li, X. Zheng, J. Tang, Z. She, Prof. Dr. G. Gao,
Prof. Dr. J. You
Key Laboratory of Green Chemistry and Technology of Ministry of
Education, College of Chemistry, Sichuan University
29 Wangjiang Road, Chengdu 610064 (P.R. China)
E-mail: gg2b@scu.edu.cn
jsyou@scu.edu.cn
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201612147.
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Table 1: Optimization of the reaction conditions.[a,b]
Table 2: Scope of a-aryl enones.[a,b]
Entry
Variation from the standard conditions
Yield [%][c]
1
2
3
4
none
72
ND
ND
ND
24
without Cu(OAc)2·H2O
without [Cp*RhCl2]2 or AgSbF6
in a N2 atmosphere
5
1,2-DCE as solvent
6
7
8
1,4-dioxane as solvent
AgBF4 instead of AgSbF6
AgClO4 instead of AgSbF6
other [M] instead of [Cp*RhCl2]2
1aEt (R0 =Et) instead of 1a
1aPr (R0 =i-Pr) instead of 1a
1aBu (R0 =t-Bu) instead of 1a
43
40
57
<15
67
9[d]
10
11
12
35
ND
[a] Reaction conditions: 1a (0.3 mmol), 2a (0.2 mmol), [Cp*RhCl2]2
(5 mol%), AgSbF6 (20 mol%) and Cu(OAc)2·H2O (0.4 mmol) in DME
(2 mL) at 908C for 5 h. [b] BHT (10 mol%) was added. [c] Isolated yield.
ND=not determined. [d] Other [M]: [Cp*IrCl2]2, Cp*Co(CO)l2 and [(p-
cymene)RuCl2]2. DME=1,2-dimethoxyethane, DCE=1,2-dichloro-
ethane.
[a] Reaction conditions: 1 (0.3 mmol), 2a (0.2 mmol), [Cp*RhCl2]2
(5 mol%), AgSbF6 (20 mol%) and Cu(OAc)2·H2O (0.4 mmol) in DME
(2 mL) at 908C in air for 5–24 h. [b] 10 mol% BHT was used for the
reaction of terminal enones. [c] See Ref [25]. TMP=3,4,5-trimethoxy-
phenyl.
salts were indispensable, and the reaction ceased in a N2
atmosphere (Table 1, entries 2–4). Using common solvents
À
for Rh-catalyzed C H annulations with alkynes such as DCE
Table 3: Scope of alkynes.[a,b]
and dioxane resulted in only 24% and 43% yields, respec-
tively (Table 1, entries 5 and 6).[2a,b] Other silver salts and
metal complexes showed much inferior efficiency (Table 1,
entries 7–9). The influence of the acyl group in 1a (R0) was
also studied (Table 1, entries 10–12). The yields of 3aa were
gradually decreased as increasing the steric hindrance (1aEt–
1aBu). 1aBu having a pivaloyl group could not give any 3aa. It
should also be pointed out that an a-aryl substituent is
necessary for the enone substrates, otherwise only a trace
amount of product could be detected for a-alkyl and a-H
enones.
The scope of a-aryl enones was firstly investigated under
the optimal conditions (Table 2). A range of 3-arylbut-3-en-2-
ones 1a–1i and (E)-3,4-diarylbut-3-en-2-ones 1j–1u could
successfully annulated with 2a to yield the desired 2,4,5-
triarylfurans 3aa–3ia and 2,3,4,5-tetraarylfurans 3ja–3ua in
moderate to good yields. Various substituents at different
positions on the aryl rings were well tolerated. Notably,
heteroaryl substituents were compatible, affording hetero-
aryl-substituted furan derivatives 3va–3za in moderate yields.
The generality of the alkynes was then studied (Table 3).
A variety of diaryl alkynes containing common functional
groups could smoothly reacted with 1a and 1k to afford the
corresponding multisubstituted furans 3ab–3ak and 3kl in
satisfactory yields. It is noteworthy that unsymmetrical
alkynes 2m–2o exclusively yielded 3nm–3wo in a completely
regioselective manner with the aryl group installed adjacent
to the oxygen atom of the furan products.
[a] Reaction conditions: 1 (0.3 mmol), alkynes 2 (0.2 mmol), [Cp*RhCl2]2
(5 mol%), AgSbF6 (20 mol%) and Cu(OAc)2·H2O (0.4 mmol) in DME
(2 mL) at 908C in air for 5 h. [b] 10 mol% BHT was used for the reaction
of terminal enones. [c] at 1008C for 24 h. [d] at 1008C for 10 h. [e] See
Ref [25].
Information, Figures S1–S4). The reaction of 18O-1r (88%
18O) with 2a gave 3ra containing 64% 18O-3ra (Scheme 2a).
The control experiments showed that 3ra did not undergo
oxygen exchange with 18O-water, while 40% of 1r was labeled
(Scheme 2b and c). Furthermore, when 1r and 2a reacted in
the presence of 18O-water, 3ra was obtained with 24% 18O-
3ra (Scheme 2d). These results imply that the oxygen atom in
the furan products comes from a-aryl-enones, and the oxygen
atom in water may also transfer into the products through the
oxygen exchange with the a-aryl-enones.
To gain insight into the reaction mechanism, a series of
18O-labeling experiments were conducted to clarify the
oxygen source in the furan products (Scheme 2; Supporting
2
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and 2a gave a peak at m/z 399.1751, in good accordance with
2-methyl-3,4,5,6-tetraphenylpyrylium cation (M+, MW
399.1743; Supporting Information, Figure S5).
On the basis of the above experimental results and
previous reports,[5a,20] a tentative mechanism is proposed in
Scheme 4. The reaction initiates with an irreversible vinylic
Scheme 2. 18O-labeling experiments. Standard conditions: [Cp*RhCl2]2
(5 mol%), AgSbF6 (20 mol%) and Cu(OAc)2 (2.0 equiv) in DME
(2 mL) in air at 908C for 10 h.
Given that the [3+2] C-annulation usually occurs between
aromatic ketones and alkynes to form indenols, the cyclo-
pentadienol 5 was tested under the optimal conditions to
clarify whether it could be the intermediate. No furan product
was detected, excluding the [3+2] C-annulation pathway
(Scheme 3, path a). Based on the fact that the oxygen atom in
Scheme 4. Proposed mechanism (anion is omitted for clarity).
Scheme 3. Probing the possible intermediate under the optimal con-
ditions.
[21]
À
C H activation of 1 to give a five-membered rhodacycle A.
The alkyne insertion forms the seven-membered intermediate
B. The direct reductive elimination generates the pyrylium
salt C and releases the RhI species, which is oxidized by CuII
or O2 to regenerate the RhIII catalyst. C is nucleophilically
attacked at the a-position by the superoxide radical generated
by the single electron transfer from CuI to oxygen,[22] forming
a-hydroperoxide D after protonation. Further protonation
the furan products come from the carbonyl group of a-aryl
enones, we rationally proposed a pyrylium intermediate from
the [4+2] O-annulation of an a-aryl enone with an alkyne. To
verify this hypothesis, a pyrylium salt 6 was subjected to the
optimal conditions and product 3ja was indeed isolated in
67% yield (Scheme 3, path b). The control experiments
showed that 3ja could also be fomed in 69% yield in the
presence of only Cu(OAc)2·H2O (0.2 equiv) in air within
0.5 hour, but no reaction occurred without either the copper
salt or air. Upon addition of 2 equivalents of TEMPO, the
reaction did not proceed, indicating radical intermediates
were probably involved (see the Supporting Information).
The pyrylium salt 7 also yielded 3ja in 75% yield, but in
a longer time of 24 hours. Furthermore, benzoic acid was
detected by the GC-MS analysis [Eq. (2)], which could be
annulated with 2a to afford 4 under our optimal conditions.[19]
The above results clearly suggested a cascade pathway
À
triggers heterolysis of the O O bond, generating a 4-acetoxy-
1,3-diene cation F. It should be pointed out that this vinyl
cation F must be stabilized by a aryl substituent (R1 = aryl),[23]
as evidenced herein by the only validity of a-aryl enones. The
intramolecular cyclization gives O-acylated furanium G,
which is hydrolyzed to release the final furan product 3.[24]
In summary, we have developed the first Rh-catalyzed
À
ketone-directed vinylic C H activation/[4+2] O-annulaton of
a-aryl enones with internal alkynes to form pyrylium salts,
which immediately undergo a Cu-catalyzed ring contraction
in air to provide multiaryl-substituted furan derivatives. This
cascade process shows broad substrate scopes and excellent
regioselectivities. Further investigation on controlled access
to active pyrylium salts as well as new transformations are
ongoing in our laboratory.
À
consisting of a rhodium-catalyzed ketone-directed vinylic C
H [4+2] O-annulation of 1j with 2a to form pyrylium salt 6
and a subsequent Cu-catalyzed ring contraction in air to give
3ja.[20] Although attempts to isolate the pyrylium salts were
futile, the HRMS analysis of the crude reaction mixture of 1j
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Chem. Rev. 2017, DOI: 10.1021/acs.chemrev.6b00661, and refer-
ences therein.
Acknowledgements
À
[11] For reviews on ketone-directed C H functionalization reactions,
We thank the financial supports from the National NSF of
China (Nos 21472127 and 21432005) and the NCET-13-0384.
see: a) Q.-Z. Zheng, N. Jiao, Tetrahedron Lett. 2014, 55, 1121;
b) Z. Huang, H. N. Lim, F. Mo, M. C. Young, G. Dong, Chem.
Soc. Rev. 2015, 44, 7764.
À
[12] For reviews on transition-metal-catalyzed vinylic C H function-
alization reactions, see: a) D. A. Colby, R. G. Bergman, J. A.
Ellman, Chem. Rev. 2010, 110, 624; b) K. Wang, F. Hu, Y. Zhang,
J. Wang, Sci. China Chem. 2015, 58, 1252.
Conflict of interest
The authors declare no conflict of interest.
[13] For a review, see: F. Kakiuchi, S. Murai, Acc. Chem. Res. 2002,
35, 826; For recent examples, see: a) K. Tsuchikama, Y. Kuwata,
Y.-k. Tahara, Y. Yoshinami, T. Shibata, Org. Lett. 2007, 9, 3097;
b) M.-O. Simon, R. Martinez, J.-P. GenÞt, S. Darses, Adv. Synth.
Catal. 2009, 351, 153; c) N. M. Neisius, B. Plietker, Angew. Chem.
Int. Ed. 2009, 48, 5752; Angew. Chem. 2009, 121, 5863.
[14] For a recent review, see: L. Yang, H. Huang, Chem. Rev. 2015,
115, 3468.
À
Keywords: furans · O-annulation · pyrylium · vinylic C
H activation · a-aryl enone
[15] “Dimerization and Polymerization of Enones in the Fluid and
Solid States”: C. R. Theocharis in The Chemistry of Enones
(Eds.: S. Patai, Z. Rappoport), Wiley, New York, 1989, p. 1133.
[16] For a review on transition-metal-mediated synthesis of furans,
see: A. V. Gulevich, A. S. Dudnik, N. Chernyak, V. Gevorgyan,
Chem. Rev. 2013, 113, 3084.
[17] Y. Zhao, Z. He, S. Li, J. Tang, G. Gao, J. Lan, J. You, Chem.
Commun. 2016, 52, 4613.
[18] Without BHT, 3aa was obtained in 62% yield. BHT could
suppress the polymerization of terminal enones. See: M.
Murakami, T. Itahashi, Y. Ito, J. Am. Chem. Soc. 2002, 124,
13976.
À
[1] a) Transition Metal-Catalyzed Heterocycle Synthesis via C H
À
Activation (Eds.: X.-F. Wu), Wiley-VCH, Weinheim, 2016; b) C
H Bond Activation and Catalytic Functionalization I (Eds.: P. H.
Dixneuf, H. Doucet), Springer International Publishing, Cham,
2016.
[2] For selected reviews, see: a) T. Satoh, M. Miura, Chem. Eur. J.
2010, 16, 11212; b) G. Song, F. Wang, X. Li, Chem. Soc. Rev.
2012, 41, 3651; c) L. Ackermann, Acc. Chem. Res. 2014, 47, 281;
d) M. Gulꢀas, J. L. MascareÇas, Angew. Chem. Int. Ed. 2016, 55,
11000; Angew. Chem. 2016, 128, 11164.
[3] For a review, see: R. He, Z.-T. Huang, Q.-Y. Zheng, C. Wang,
Tetrahedron Lett. 2014, 55, 5795.
[19] K. Ueura, T. Satoh, M. Miura, Org. Lett. 2007, 9, 1407.
[20] Pyrylium salts were previously used to prepare 2-acylfurans via
ring contraction in the presence of a stoichiometric amount of
various oxidants. For selected representative examples, see:
a) I2: C. L. Pedersen, Acta Chem. Scand. Ser. B 1975, 29, 791;
b) KO2: S. Kobayashi, W. Ando, Chem. Lett. 1978, 1159;
c) H2O2: T. S. Balaban, M. Hiegemann, Tetrahedron 1992, 48,
9827; d) Pb(OAc)4: B. I. Drevko, M. I. Smushkin, V. G. Kharch-
enko, Chem. Heterocycl. Compd. 1996, 32, 777; e) NaNO2: A.
Mouradzadegun, F. Abadast, S. Elahi, N. Askarikia, Res. Chem.
Intermed. 2016, 42, 3147.
[21] The deuterium-exchange and intermolecular KIE experiments
are included in the Supporting Information.
[22] a) C. Zhang, C. Tang, N. Jiao, Chem. Soc. Rev. 2012, 41, 3464;
b) S. E. Allen, R. R. Walvoord, R. Padilla-Salinas, M. C.
Kozlowski, Chem. Rev. 2013, 113, 6234.
[23] a) Z. Rappoport, Acc. Chem. Res. 1976, 9, 265; b) M. Hanack,
Acc. Chem. Res. 1976, 9, 364.
[24] The possible 1,2-alkenyl shift pathway, which generates a 1,4-
dione to afford furan 3 via the Paal–Knorr synthesis is ruled out
according to the control and 18O-labeling experiments. See the
Supporting Information.
[25] CCDC 1504272 and 1504274 contains the supplementary crys-
tallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre.
[4] For a review, see: J. M. Neely, T. Rovis, Org. Chem. Front. 2014,
1, 1010.
[5] a) G. Zhang, L. Yang, Y. Wang, Y. Xie, H. Huang, J. Am. Chem.
Soc. 2013, 135, 8850; b) N. Senthilkumar, P. Gandeepan, J.
Jayakumar, C.-H. Cheng, Chem. Commun. 2014, 50, 3106; c) S.
Prakash, K. Muralirajan, C.-H. Cheng, Angew. Chem. Int. Ed.
2016, 55, 1844; Angew. Chem. 2016, 128, 1876; d) Y.-X. Lao, S.-S.
Zhang, X.-G. Liu, C.-Yo. Jiang, J.-Q. Wu, Q. Li, Z.-S. Huang, H.
Wang, Adv. Synth. Catal. 2016, 358, 2186.
[6] a) Z. Shi, D. C. Koester, M. Boultadakis-Arapinis, F. Glorius, J.
Am. Chem. Soc. 2013, 135, 12204; b) C.-Z. Luo, J. Jayakumar, P.
Gandeepan, Y.-C. Wu, C.-H. Cheng, Org. Lett. 2015, 17, 924.
[7] For selected reviews, see: a) K. M. Engle, T.-S. Mei, M. Wasa, J.-
Q. Yu, Acc. Chem. Res. 2012, 45, 788; b) S. De Sarkar, W. Liu,
S. I. Kozhushkov, L. Ackermann, Adv. Synth. Catal. 2014, 356,
1461; c) Y. Yang, K. Li, Y. Cheng, D. Wan, M. Li, J. You, Chem.
Commun. 2016, 52, 2872.
[8] For selected reviews, see: a) S. V. Krivun, O. F. Alfꢁrova, S. V.
Sayapina, Russ. Chem. Rev. 1974, 43, 835; b) E. A. Zvezdina,
M. P. Zhadonva, G. N. Dorofeenko, Russ. Chem. Rev. 1982, 51,
469.
[9] a) F. W. Patureau, T. Besset, N. Kuhl, F. Glorius, J. Am. Chem.
Soc. 2011, 133, 2154; b) K. Muralirajan, K. Parthasarathy, C.-H.
Cheng, Angew. Chem. Int. Ed. 2011, 50, 4169; Angew. Chem.
2011, 123, 4255; c) R. K. Chinnagolla, M. Jeganmohan, Eur. J.
Org. Chem. 2012, 417.
[10] N-Containing substrates could also undergo [3+2] C-annulation
with alkynes, see: J. R. Hummel, J. A. Boerth, J. A. Ellman,
Manuscript received: December 14, 2016
Final Article published: && &&, &&&&
4
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Communications
Homogeneous Catalysis
Y. Zhao, S. Li, X. Zheng, J. Tang, Z. She,
G. Gao,* J. You*
&&&& — &&&&
Rh/Cu-Catalyzed Cascade [4+2] Vinylic
First rhodium, then copper: An unprece-
ring contraction in air to form multiaryl-
À
C H O-Annulation and Ring Contraction
of a-Aryl Enones with Alkynes in Air
dented cascade reaction consisting of
substituted furan derivatives is realized.
The pyrylium salt is identified as the key
intermediate.
À
a Rh-catalyzed ketone-directed vinylic C
H [4+2] O-annulation of a,b-enones with
alkynes and a subsequent Cu-catalyzed
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