Access to indenones by rhodium(III)-catalyzed C-H annulation of arylnitrones with internal alkynes

Article abstract of DOI:10.1021/ol4025309

Under redox-neutral conditions, rhodium(III)-catalyzed C-H annulation of N-tert-butyl-α-arylnitrones with internal alkynes has been realized for the synthesis of indenones under mild conditions. This reaction proceeded in moderate to high yields and with

Full text of DOI:10.1021/ol4025309

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Access to Indenones by Rhodium(III)-
Catalyzed CÀH Annulation of Arylnitrones
with Internal Alkynes
Zisong Qi,†,‡ Mei Wang,‡ and Xingwei Li*,†
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023,
China, and State Key Laboratory of Fine Chemicals, Dalian University of Technology,
Dalian 116024, China
xwli@dicp.ac.cn
Received September 3, 2013
ABSTRACT
Under redox-neutral conditions, rhodium(III)-catalyzed CÀH annulation of N-tert-butyl-R-arylnitrones with internal alkynes has been realized for
the synthesis of indenones under mild conditions. This reaction proceeded in moderate to high yields and with good functional group tolerance.
Indenones are important carbocycles that are useful
skeletons in synthetic chemistry, biology, and material
science.1 Consequently, different metal-catalyzed routes
for efficient preparation of indenones have been developed
in the past decades.2 A well-studied strategy of catalytic
synthesis of indenones utilized ortho-functionalized
esters,3 amides,3 aldehydes,4 nitriles,5 or halides6 as the
starting material. Wender and co-workers took advantage
of the strained cyclopropenones and achieved a coupling
with in situ generated benzyne to give this type of product.7
On the other hand, metal-catalyzed CÀH bond activation
has proven to be a powerful strategyfor the construction of
CÀC bonds and has received increasing attention in the
past decade.8 Thus under rhodium(I) catalysis, the cou-
pling of aroyl chlorides with internal alkynes gave
(8) (a) Yan, G.; Wu, X.; Yang, M. Org. Biomol. Chem. 2013, 11, 5558.
(b) Ackermann, L. Acc. Chem. Res. 201310.1021/ar3002798. (c) Song, G.;
Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651. (d) Kuhl, N.; Hopkinson,
M. N.; Wencel-Delord, J.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51,
10236. (e) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev.
2012, 112, 5879. (f) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111,
1215. (g) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res.
2011, 45, 788. (h) Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A.
Acc. Chem. Res. 2011, 45, 814. (i) Cho, S. H.; Kim, J. Y.; Kwak, J.;
Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (j) Ackermann, L. Chem. Rev.
2011, 111, 1315. (k) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111,
1293. (l) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (m)
Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624.
(n) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731. (o)
Giri, R.; Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu, J.-Q. Chem. Soc. Rev.
2009, 38, 3242.
† Chinese Academy of Sciences.
‡ Dalian University of Technology.
(1) (a) Anstead, G. M.; Wilson, S. R.; Katzenellenbogen, J. A.
J. Med. Chem. 1989, 32, 2163. (b) McDevitt, R. E.; Malamas, M. S.;
Manas, E. S.; Unwalla, R. J.; Xu, Z. B.; Miller, C. P.; Harris, H. A.
Bioorg. Med. Chem. Lett. 2005, 15, 3137. (c) Jeffrey, J. L.; Sarpong, R.
Org. Lett. 2009, 11, 5450. (d) Clark, W. M.; Tickner-Eldridge, A. M.;
Huang, G. K.; Pridgen, L. N.; Olsen, M. A.; Mills, R. J.; Lantos, I.;
Baine, N. H. J. Am. Chem. Soc. 1998, 120, 4550.
(2) (a) Galatsis, P.; Manwell, J. J.; Blackwell, J. M. Can. J. Chem.
1994, 72, 1656. (b) Martens, H.; Hoornaert, G. Tetrahedron 1974, 30,
3641. (c) Floyd, M. B.; Allen, G. R. J. Org. Chem. 1970, 35, 2647. (d)
Marvel, C. S.; Hinman, C. W. J. Am. Chem. Soc. 1954, 76, 5435.
(3) Tsukamoto, H.; Kondo, Y. Org. Lett. 2007, 9, 4227.
(4) Larock, R. C.; Doty, M. J.; Cacchi, S. J. Org. Chem. 1993, 58,
4579.
(5) (a) Larock, R. C.; Tian, Q.; Pletnev, A. A. J. Am. Chem. Soc. 1999,
121, 3238. (b) Miura, T.; Murakami, M. Org. Lett. 2005, 7, 3339.
(6) Harada, Y.; Nakanishi, J.; Fujihara, H.; Tobisu, M.; Fukumoto,
Y.; Chatani, N. J. Am. Chem. Soc. 2007, 129, 5766.
(7) Wender, P. A.; Paxton, T. J.; Williams, T. J. J. Am. Chem. Soc.
2006, 128, 14814.
(9) Kokubo, K.; Matsumasa, K.; Miura, M.; Nomura, M. J. Org.
Chem. 1996, 61, 6941.
(10) Kuninobu, Y.; Matsuki, T.; Takai, K. Org. Lett. 2010, 12, 2948.
(11) Zhao, P.; Wang, F.; Han, K.; Li, X. Org. Lett. 2012, 14, 5506.
(12) (a) Wang, C.; Sun, H.; Fang, Y.; Huang, Y. Angew. Chem., Int.
Ed. 2013, 52, 5795. (b) Patureau, F. W.; Besset, T.; Kuhl, N.; Glorius, F.
J. Am. Chem. Soc. 2011, 133, 2154. (c) Unoh, Y.; Hashimoto, Y.;
Takeda, D.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2013, 15,
3258. (d) Seo, J.; Park, Y.; Jeon, I.; Ryu, T.; Park, S.; Lee, P. H. Org.
Lett. 2013, 15, 3358. (e) Zhang, G.; Yang, L.; Wang, Y.; Xie, Y.; Huang,
H. J. Am. Chem. Soc. 2013, 135, 8850. (f) Pham, M. V.; Ye, B.; Cramer,
N. Angew. Chem., Int. Ed. 2012, 51, 10610. (g) Huang, J.-R.; Zhang,
Q.-R.; Qu, C.-H.; Sun, X.-H.; Dong, L.; Chen, Y.-C. Org. Lett. 2013, 15,
1878. (h) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc.
2010, 132, 6908. (i) Guimond, N.; Gorelsky, S. I.; Fagnou, K. J. Am.
Chem. Soc. 2011, 133, 6449. (j) Liu, G.; Shen, Y.; Zhou, Z.; Lu, X.
Angew. Chem., Int. Ed. 2013, 52, 6033. (k) Wang, D.; Wang, F.; Song, G.;
Li, X. Angew. Chem., Int. Ed. 2012, 51, 12348. (l) Sun, Z.-M.; Chen,
S.-P.; Zhao, P. Chem.;Eur. J. 2010, 16, 2619.
r
10.1021/ol4025309
XXXX American Chemical Society

indenones (Scheme 1a).9 Takai and co-workers reported
indenone synthesis via rhenium- and amide-catalyzed
three-component cycloaddition with CÀH bond activa-
tion to produce indinones.10
Scheme 1. Rhodium-Catalyzed Synthesis of Indenones via
CÀH Activation
Recently, we reported indenamine synthesis via ruthe-
nium and sulfonamide-cocatalyzed cyclization between N-
sulfonyl imines and alkynes, and subsequent aerobic oxi-
dation gaveindenones.11 Rhodium(III)-catalyzed addition
of CÀH bonds to alkyne derivatives has been extensively
investigated12 along with alkenes,13 imines,14 aldehydes,15
isocyanates,16 allenes,17 carbenes,18 azides,19 aziridines,20
and otherstrainedrings,21 where a wide variety of directing
groups have also been extensively explored.12f,j,13b,15b,22
Very recently, Shi and co-workers developed a rhodium-
(III)-catalyzed CÀH activation and annulation of benzi-
mides, in which a catalytic amount of copper acetate
additive is necessary (Scheme 1b).23 However, these routes
of indenone synthesis suffer from multiple steps, high
temperature, or prior activation of substrates. We recently
reported rhodium-catalyzed CÀH activation of azo-
methines and subsequent oxidative olefination13c and re-
dox-neutral annulation with alkynes (Scheme 1c),24
whereas theazomethine actsasanefficientdirecting group.
We reason that a ylidic nitrone could also function as a
directing group, although it is a relatively weaker ligating
group. Indeed, stoichiometric CÀH activation of nitrone
has been recently reported by Yao and us.25 However, no
catalytic CÀH activation of nitrone has been reported. We
now report a relatively mild approach to access indenones
Table 1. Optimization Studiesa
yieldb
(%)
entry
catalyst
[RhCp*Cl2]2
additive (equiv) solvent
Cu(OAc)2 (2.1) DCE
1
2
3
4
5
6
7
8
9
nd
[RhCp*Cl2]2
AgOAc (2.1)
DCE
DCE
DCE
DCE
DCE
nd
39
62
46
70
[RhCp*Cl2] 2/AgSbF6
[RhCp*Cl2]2/AgSbF6
[RhCp*Cl2]2/AgSbF6
€
(13) (a) Wang, H.; Schroder, N.; Glorius, F. Angew. Chem., Int. Ed.
PivOH (1.0)
AcOH (1.0)
2013, 52, 5386. (b) Liu, B.; Fan, Y.; Gao, Y.; Sun, C.; Xu, C.; Zhu, J.
J. Am. Chem. Soc. 2012, 135, 468. (c) Zhen, W.; Wang, F.; Zhao, M.; Du,
Z.; Li, X. Angew. Chem., Int. Ed. 2012, 51, 11819.
(14) (a) Li, Y.; Zhang, X.-S.; Li, H.; Wang, W.-H.; Chen, K.; Li, B.-J.;
Shi, Z.-J. Chem. Sci. 2012, 3, 1634. (b) Li, Y.; Li, B.-J.; Wang, W.-H.;
Huang, W.-P.; Zhang, X.-S.; Chen, K.; Shi, Z.-J. Angew. Chem., Int. Ed.
2011, 50, 2115. (c) Tsai, A. S.; Tauchert, M. E.; Bergman, R. G.; Ellman,
J. A. J. Am. Chem. Soc. 2011, 133, 1248.
[RhCp*(MeCN)3](SbF6)2 PivOH (1.0)
[RhCp*(MeCN)3](SbF6)2 PivOH (1.0)
[RhCp*(MeCN)3](SbF6)2 PivOH (1.0)
[RhCp*(MeCN)3](SbF6)2 PivOH (1.0)
dioxane trace
t-AmOH trace
DCM
DCE
43
58
10c [RhCp*(MeCN)3](SbF6)2 PivOH (1.0)
a Reaction conditions: [RhCp*Cl2]2 (4 mol %), AgSbF6 (16 mol %)
or [RhCp*(MeCN)3](SbF6)2 (6 mol %), additive, 1a (0.36 mmol), and 2a
(0.25 mmol) in solvent (2 mL) at 80 °C for 15 h. b Yield of isolated
product. c The reaction was carried out at 50 °C.
(15) (a) Li, Y.; Zhang, X.-S.; Chen, K.; He, K.-H.; Pan, F.; Li, B.-J.;
Shi, Z.-J. Org. Lett. 2012, 14, 636. (b) Lian, Y.; Bergman, R. G.; Lavis,
L. D.; Ellman, J. A. J. Am. Chem. Soc. 2013, 135, 7122.
(16) (a) Hou, W.; Zhou, B.; Yang, Y.; Feng, H.; Li, Y. Org. Lett.
2013, 15, 1814. (b) Zhou, B.; Hou, W.; Yang, Y.; Li, Y. Chem.;Eur. J.
2013, 19, 4701. (c) Hesp, K. D.; Bergman, R. G.; Ellman, J. A. J. Am.
Chem. Soc. 2011, 133, 11430.
(17) (a) Wang, H.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 7318.
(b) Zeng, R.; Fu, C.; Ma, S. J. Am. Chem. Soc. 2012, 134, 9597.
(18) Chan, W.-W.; Lo, S.-F.; Zhou, Z.; Yu, W.-Y. J. Am. Chem. Soc.
2012, 134, 13565.
(19) Kim, J. Y.; Park, S. H.; Ryu, J.; Cho, S. H.; Kim, S. H.; Chang, S.
J. Am. Chem. Soc. 2012, 134, 9110.
(20) Li, X.; Yu, S.; Wang, F.; Wan, B.; Yu, X. Angew. Chem., Int. Ed.
2013, 52, 2577.
(21) (a) Qi, Z.; Li, X. Angew. Chem., Int. Ed. 2013, 52, 8995. (b) Jijy,
E.; Prakash, P.; Shimi, M.; Pihko, P. M.; Joseph, N.; Radhakrishnan,
K. V. Chem. Commun. 2013, 49, 7349. (c) Cui, S.; Zhang, Y.; Wu, Q.
Chem. Sci. 2013, 4, 3421.
(22) (a) Wang, C.; Chen, H.; Wang, Z.; Chen, J.; Huang, Y. Angew.
Chem., Int. Ed. 2012, 51, 7242. (b) Villuendas, P.; Urriolabeitia, E. P.
J. Org. Chem. 2013, 78, 5254. (c) Muralirajan, K.; Cheng, C.-H. Chem.;
Eur. J. 2013, 19, 6198.
via rhodium(III)-catalyzed annulation of N-tert-butyl-R-
arylnitrones with internal alkynes.
We initiated our studies with the screening of the reaction
conditions for the coupling of N-tert-butyl-R-phenylnitrone
(PBN, 1a) with diphenylacetylene (2a) using a rhodium(III)
catalyst (Table 1). While no product was detected with
Cu(OAc)2 or AgOAc being an additive when [RhCp*Cl2]2
was used as a catalyst (Table 1, entries 1 and 2), addition of
AgSbF6 (16 mol %) improved the efficiency and the desired
indenone 3aa was isolated in 39% yield (entry 3). Further
addition of pivalic acid (PivOH) boosted the yield to 62%
(entry 4). In contrast, a lower yield was isolated when AcOH
was used as an additive (entry 5). To our delight, 3aa was
isolated in 70% yield when a cationic rhodium catalyst was
employed (entry 6). Under these conditions, changing the
solvent or lowering the reaction temperature all gave infer-
ior results (Table 1, entries 7À10). In contrast to the good
(23) Li, B.-J.; Wang, H.-Y.; Zhu, Q.-L.; Shi, Z.-J. Angew. Chem., Int.
Ed. 2012, 51, 3948.
(24) Chen, Y.; Wang, F.; Zhen, W.; Li, X. Adv. Synth. Catal. 2013,
355, 353.
(25) (a) Yao, Q.; Zabawa, M.; Woo, J.; Zheng, C. J. Am. Chem. Soc.
2007, 129, 3088. (b) Zhang, Y.; Song, G.; Ma, G.; Zhao, J.; Pan, C.-L.;
Li, X. Organometallics 2009, 28, 3233.
B
Org. Lett., Vol. XX, No. XX, XXXX

efficiency of 1a, coupling using an N-methyl analogue of
this notrone only afforded 3aa in 40% isolated yield. Thus
the following conditions were eventually chosen for subse-
quent studies: [RhCp*(MeCN)3](SbF6)2 (6 mol %) and
PivOH (1.0 equiv) in DCE under argon at 80 °C.
Scheme 3. Alkyne Substrate Scopea
Scheme 2. Scope of Nitrone Substratesa
a Reaction conditions: [RhCp*(MeCN)3](SbF6)2 (6 mol %), PivOH
(1.0 equiv), 1a (0.36 mmol), and alkyne (0.25 mmol) in DCE (2 mL) at
80 °C for 15 h.
a Reaction conditions: [RhCp*(MeCN)3](SbF6)2 (6 mol %), PivOH
(1.0 equiv), nitrone (0.36 mmol), and alkyne (0.25 mmol) in DCE (2 mL)
at 80 °C for 15 h.
TMS-substituted phenylacetylene and ethyl phenyl-
propiolate are also viable substrates, and the indenone
products (3al and 3am) were isolated in moderate yield,
which could be further readily derivatized to other useful
structures. In contrast, alkyl-substituted internal alkynes
failed to react under the standard conditions.
We further performed several experiments to gain in-
sight into the reaction mechanism. A kinetic isotope effect
(KIE) value of 4.0 was obtained using an equimolar
mixture of 1a and 1a-d6 in the coupling with di-(2-thio-
phenyl)acetylene at a low conversion under the standard
conditions (eq 1). This result indicated that cleavage of the
CÀH bond activation is involved in the rate-limiting step.
Moreover, both 18O-labeled indenone 3aa and regular 3aa
were obtained when 18O-labeled water was introduced into
the catalytic system, indicating that the oxygen atom in
indenone could originate from water (eq 2).
With the optimized conditions in hand, we first exam-
ined the reaction scope of the N-tert-butyl-R-substrate
(Scheme 2). Nitrones bearing electron-donating and -with-
drawing substituents all underwent smooth coupling with
diphenylacetylene (2a) toaffordthe indenones in moderate
to good yields (3aaÀ3ga). The reaction efficiency is related
to the electronic effect of the para substituent. Thus a
relatively lower yield was obtained for electron-donating
groups (3ba, 3ca). In particular, functionalizable electron-
withdrawing groups such as ester, cyano, and nitro groups
are also well-tolerated, and the corresponding indenones
were isolated in 51À79% yields (3haÀ3ja). In contrast,
electronic effect seems less obvious for meta substituents
(3kaÀ3ma). Halogen groups are also well-tolerated, al-
though introduction of a fluoro group at the ortho position
tends to lower the yield of the desired product (3na).
The scope of the internal alkynes was next investigated
(Scheme 3). Symmetric diarylacetylenes bearing various
substituents such as methyl, methoxy, tert-butyl, halo, and
trifluoromethyl at different positions coupled with 1a to
afford the corresponding products in 42À82% yields
(3abÀ3ai). It is interesting to note that ortho-fluoro-sub-
stituted diarylacetylene is also tolerated (3aj). In addition,
the aryl group of the alkyne is not limited to the benzene
ring. When di(2-thiophenyl)acetylene was applied, pro-
duct 3ak was isolated in 71% yield. More importantly,
On the basis of these experimental results, a proposed
reaction mechanism is given in Scheme 4.24 Coordination
Org. Lett., Vol. XX, No. XX, XXXX
C

Protonolysis of C releases the hydroxyl amine intermediate
D, which is proposed to undergo dehydration to give an
imine E. This dehydration could be metal-catalyzed since
D can be a stable compound. Hydrolysis of this imine
eventually furnished the indenone product.
Scheme 4. Proposed Reaction Mechanism
In summary, we have developed a mild approach to
access indenones26 through cationic rhodium(III)-cata-
lyzed CÀH activation and annulation of N-tert-butyl-R-
arylnitrones with internal alkynes, where nitrone functions
as both a directing group and an electrophile. The scope of
the arylnitrone and internal alkyne substrates has been
defined, and good functional group tolerance has been
achieved. This work established nitrone as an efficient
directing group for CÀH bond activation and may find
applications in the synthesis of useful structures.
Acknowledgment. Financial support was from the
NSFC (No. 21272231) and the Dalian Institute of Chemi-
cal Physics, Chinese Academy of Sciences.
of 1a to the cationic rhodium and subsequent CÀH
activation generates rhodacycle A. Alkyne coordination
and subsequent insertion give an eight-membered rhoda-
cyclic intermediate B, which is believed to undergo migra-
tory insertion of the RhÀvinyl bond into the azomethine
imine group to form a rhodium(III) amino oxide C.
Supporting Information Available. Standard experi-
mental procedure and characterization data of products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(26) After the submission of this paper, Cheng and co-workers
reported an oxidative synthesis of indenones from benzaldehydes under
Rh(III) catalysis. See: Chen, S.; Yu, J.; Jiang, Y.; Chen, F.; Cheng, J.
Org. Lett. 2013, 15, 4754.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX