Construction of naphtho-fused oxindoles via the aryne diels-alder reaction with methyleneindolinones

Article abstract of DOI:10.1021/ol3018787

Unprecedented aryne Diels-Alder reactions by using methyleneindolinones as dienes have been disclosed, thus providing a quick access to unusual naphtho-fused oxindoles. A wide range of methyleneindolinones proceed readily with arynes to afford the functionalized oxindoles in good yields.

Full text of DOI:10.1021/ol3018787

ORGANIC
LETTERS
2012
Vol. 14, No. 19
4994–4997
Construction of Naphtho-Fused Oxindoles
via the Aryne DielsꢀAlder Reaction with
Methyleneindolinones
Jian Li,*,† Ning Wang,† Chunju Li,† and Xueshun Jia*,‡
Department of Chemistry, Shanghai University, Shanghai, 200444, P. R. China, and
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou,
730000, P. R. China
lijian@shu.edu.cn; xsjia@mail.shu.edu.cn
Received July 10, 2012
ABSTRACT
Unprecedented aryne DielsꢀAlder reactions by using methyleneindolinones as dienes have been disclosed, thus providing a quick access to unusual
naphtho-fused oxindoles. A wide range of methyleneindolinones proceed readily with arynes to afford the functionalized oxindoles in good yields.
Arynes have proven to be versatile building blocks in
organic synthesis because of the inherent high strain
created by the formal triple bond.1 Accordingly, recent
decades have witnessed rapid progress in various carbonꢀ
carbon and carbonꢀheteroatom bond-forming reactions
using arynes.2 As such, arynes have been extensively inves-
tigated in transition-metal-catalyzed reactions.3 More re-
cently, much effort has also been focused on transition-
metal-free reactions, which mainly involve the addition of
nucleophiles to arynes followed by trapping the in situ
formed anion intermediates with electrophiles.4 Most im-
portantly, the generation of aryne from ortho-(trimethylsilyl)-
aryl triflate under mild conditions appears to be the key to the
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† Shanghai University.
‡ Lanzhou University.
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Santelli, M. Tetrahedron 2003, 59, 701–730.
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r
10.1021/ol3018787
Published on Web 09/14/2012
2012 American Chemical Society

success of these reactions.5 Owing to their high electrophi-
licity, arynes can serve as reactive dienophiles in pericyclic
reactions.1b,c Of note is the aryne DielsꢀAlder reaction,
which has attracted significant attention since its first report
by Wittig.6 Yet, as shown in Scheme 1, whereas cyclic
dienes are frequently employed,7 acyclic dienes are less
common.8
Table 1. Reaction Optimization with Benzyne Precursor 1a and
Oxindolylideneacetate 2a
Scheme 1. Representative Aryne DielsꢀAlder Reactions
temp
yield
(%)b
entry
reagenta
solvent
(°C)
1
KF
CH3CN
THF
60
60
60
60
60
60
60
40
rt
46
2
KF
31
3
LiF
CH3CN
CH3CN
CH3CN
THF
trace
trace
trace
4
NaF
ZnF2
TBAF
CsF
CsF
CsF
CsF
CsF
CsF
5
c
6
ꢀ
7
CH3CN
CH3CN
CH3CN
THF
68
8
51
9
40
10
11
12
60
60
60
35
toluene
DCM
15
trace
On the other hand, oxindoles are important synthetic
targets owing to their significant biological activities includ-
ing insecticidal, antitumor, anthelmintic, and antibacterial
properties.9 As a result, numerous successful strategies have
emerged for the construction of these scaffolds.10,11 In spite
of these considerable advances, however, the application
of aryne in oxindole chemistry has not been reported
yet. Recently, we have paid much attention to the construc-
tion of carbocycles and heterocycles.12 Thus, several effi-
cient methods for the syntheses of functionalized oxindoles
are also disclosed.12cꢀe As a continuation, herein we wish
to report the reaction of methyleneindolinones with in situ
formed arynes, which allows the efficient construction of
structurally unusual naphtho-fused oxindoles.
a 3.0 equiv of the fluoride ion source were employed. b Isolated yield
of product. c A complex mixture was observed.
Our initial experiments began with the investigation of
benzyne precursor 1a and oxindolylideneacetate 2a. In the
presence of KF, cycloadduct 3a was isolated in 46% yield
when CH3CN was used as solvent (Table 1, entry 1),
whereas a lower yield was observed with THF (Table 1,
entry 2). However, the replacement of KF with LiF, NaF,
or ZnF2 as a fluoride source only led to the formation of a
trace amount of compound 3a (Table 1, entries 3ꢀ5). To
our delight, the employment of CsF gave the best results
and subsequent experiments also showed that lower tem-
peratures were unfavorable (Table 1, entries 7ꢀ9). Finally,
the screening of solvents further indicated that the reaction
took place most efficiently with CH3CN as solvent
(Table 1, entries 10ꢀ12).
(9) For reviews, see: (a) Marti, C.; Carreira, E. M. Eur. J. Org. Chem.
2003, 2209–2218. (b) Williams, R. M.; Cox, R. J. Acc. Chem. Res. 2003,
36, 127–139. (c) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed.
2007, 46, 8748–8758. (d) Trost, B. M.; Jiang, C. Synthesis 2006, 369–396.
(e) Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth. Catal. 2010, 352, 1381–
1407.
(10) For selected examples of total syntheses, see: (a) Greshock, T. J.;
Grubbs, A. W.; Tsukamoto, S.; Williams, R. M. Angew. Chem., Int. Ed.
2007, 46, 2262–2265. (b) Grubbs, A. W.; Artman, G. D., III; Tsukamoto,
S.; Williams, R. M. Angew. Chem., Int. Ed. 2007, 46, 2257–2261.
(c) Greshock, T. J.; Grubbs, A. W.; Jiao, P.; Wicklow, D. T.; Gloer,
J. B.; Williams, R. M. Angew. Chem., Int. Ed. 2008, 47, 3573–3577. (d)
Trost, B. M.; Cramer, N.; Bernsmann, H. J. Am. Chem. Soc. 2007, 129,
3086–3087.
(11) (a) Jaegli, S.; Erb, W.; Retailleau, P.; Vors, J.-P.; Neuville, L.;
Zhu, J. Chem.;Eur. J. 2010, 16, 5863–5867. (b) Jaegli, S.; Dufour, J.;
Wei, H.-L.; Piou, T.; Duan, X.-H.; Vors, J. P.; Neuville, L.; Zhu, J. Org.
Lett. 2010, 12, 4498–4501. (c) Ruck, R. T.; Huffman, M. A.; Kim,
M. M.; Shevlin, M.; Kandur, W. V.; Davies, I. W. Angew. Chem., Int. Ed.
2008, 47, 4711–4714. (d) Jiang, X. X.; Cao, Y. M.; Wang, Y. Q.; Liu,
L. P.; Shen, F. F.; Wang, R. J. Am. Chem. Soc. 2010, 132, 15328–15333.
(e) Pesciaioli, F.; Righi, P.; Mazzanti, A.; Bartoli, G.; Bencivenni, G.
Chem.;Eur. J. 2011, 17, 2842–2845.
With these optimized reaction conditions in hand, we
attempted to briefly establish the reaction scope. As shown
in Table 2, various substituted oxindolylideneacetates 2
with both electron-withdrawing (Table 2, entries 2ꢀ4 and
entries 8ꢀ10) and -donating substituents (Table 2, entries
5ꢀ6 and entry 11) on the aryl ring at position 5, 6, and 7
(Table 2, entry 10) all performed well to produce the
cycloadducts 3 in satisfactory yields, and all new com-
pounds were characterized by 1H, 13C NMR and HRMS
spectra.13 Moreover, the structures of compound 3g and
3k (Figure 1) were unambiguously confirmed by single
crystal X-ray analysis.14 Experiments with different pro-
tecting groups at the N-atom of 2 were also conducted
(12) (a) Li, J.; Li, S. Y.; Li, C. J.; Liu, Y. J.; Jia, X. S. Adv. Synth.
Catal. 2010, 352, 336–340. (b) Li, J.; Liu, Y. J.; Li, C. J.; Jia, X. S.
Chem.;Eur. J. 2011, 17, 7409–7413. (c) Li, J.; Liu, Y. J.; Li, C. J.; Jia,
X. S. Adv. Synth. Catal. 2011, 353, 913–917. (d) Li, J.; Liu, Y. J.; Li, C. J.;
Jia, X. S. Green Chem. 2012, 14, 1314–1321. (e) Li, J.; Wang, N.; Li, C. J.;
Jia, X. S. Chem.;Eur. J. 2012, 18, 9645–9650.
(13) See the Supporting Information for details.
(14) CCDC 887797, CCDC887796 for compounds 3g, 3k contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Center via www.ccdc.cam.ac.uk/data_request/cif.
Org. Lett., Vol. 14, No. 19, 2012
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Table 2. Cycloaddition Reaction Using Benzyne Precursor 1a
and Oxindolylideneacetates 2a
Table 3. Cycloaddition Reaction Using Benzyne Precursor 1a
and Arenacylideneoxindoles 4a
entry
R1
PGb
product
yield (%)c
1
H
Me
Me
Me
Me
Me
Me
Bnd
Bnd
Bnd
Bnd
Bnd
Me
3a
3b
3c
3d
3e
3f
68
64
76
53
65
70
77
60
80
75
55
2
5-fluoro
5-chloro
6-bromo
5-methyl
5-methoxy
H
3
4
5
6
7
3g
3h
3i
8
5-chloro
5-bromo
7-bromo
5-methyl
4-chloro
9
10
11
12
3j
3k
NR
a The reaction of 1a (1.0 mmol) and 2 (1.0 mmol) was carried out in
the presence of CsF (3.0 equiv) in 10 mL of CH3CN at 60 °C for 12 h
unless otherwise noted. b PG = protecting group. c Yield of product
after silica gel chromatography. d Bn = benzyl.
Figure 1. Single crystal X-ray structure for 3k.
a The reaction of 1a (1.0 mmol) and 4 (1.0 mmol) was carried out in
the presence of CsF (3.0 equiv) in CH3CN at 60 °C for 8 h unless
otherwise noted. b Yield of product after silica gel chromatography.
(Table 2, entries 7ꢀ11). In such cases, the benzyl group was
another good choice. As expected, no reaction occurred
when substrate 2 with a substituent at position 4 was used
(Table 2, entry 12). Pleasingly, halide and methoxy group
substitutions on the aromatic ring were tolerated, which
were potentially useful for further functionalization. Most
importantly, the present cycloaddition strategy represents
an unprecedented example of synthesizing functionalized
naphtho-fused oxindoles by using methyleneindolinones
as dienes, which provides a convergent and powerful
method for the construction of polycyclic skeletons that
cannot be otherwise accessed.
Table 3, changing the substituent at the aromatic ring
bearing the carbonyl group of 4 was first carried out
(Table 3, entries 2ꢀ7). Notably, the presence of substitu-
ents at the meta-position of substrate 4 usually gave low
yields, whereas no formation of 5 was detected when sub-
strate 4 with ortho-substitution was used (Table 3, entry 8).
In such cases, good yields of products 5 were observed
using substrate-containing para-substitution. Gratify-
ingly, substituted arenacylideneoxindoles 4 with electron-
deficient and -rich substituents on the oxindole ring pro-
ceeded readily under optimal conditions, furnishing the
To further demonstrate the utility of this annulation
procedure, cycloaddition reactions using arenacylideneox-
indoles 4 as dienes were also investigated. As shown in
4996
Org. Lett., Vol. 14, No. 19, 2012

corresponding cycloadducts 5in satisfactory yields (Table 3,
entries 9ꢀ12).
Subsequently, a fluoride anion also behaves as a base to
abstract hydrogen from intermediate A, which leads to the
formation of anion B. Further aromatization yields highly
unusual naphtho-fused oxindole 3or 5.8b,c It is interesting to
note that no intermediate A or B was ever detected in the
reaction mixtures,15 presumably due to the rapid oxidative
aromatization following the previous [4 þ 2] cycloaddition.
Substituted aryne precursors were next examined
(Scheme 3). Reactions of triflate 1b with oxindolylidenea-
cetate 2 worked well with good yields to afford products 3l
and 3m. Furthermore, the impact on regioselectivity was
also observed when an aryne bearing a substituent was
employed. In such a case, regioisomers 3n and 3n0 were
isolated in a ratio of 55:45 (based on 1H NMR). Remark-
ably, the employment of 3-methoxy substituted triflate 1d
led toexcellent regioselectivity. The structure of product 3o
was confirmed by single X-ray analysis.16
Scheme 2. Proposed Mechanism
In conclusion, we have described the cycloaddition
reactions of methyleneindolinones and arynes to generate
structurally unusual naphtho-fused oxindoles,17 which are
difficult to access by other methods. The present strategy
also opens a convergent and powerful pathway for the
construction of polycyclic skeletons. Furthermore, this
method is also distinguished by its convenient experimen-
tal setup and broad substrate scope. A plausible mechan-
ism is proposed to account for the formation of products 3
and 5, which proceeds through an unusual [4 þ 2] cycload-
dition followed by isomerization and dehydrogenation
processes. Further experiments with a broader substrate
scope are currently underway in our laboratory.
Scheme 3. Controlled Experiments with Substituted Arynes 1
Acknowledgment. Wethank theNational Natural Science
Foundation of China (Nos. 21002061, 21142012, 20902057),
the State Key Laboratory of Applied Organic Chemistry,
Lanzhou University, Leading Academic Discipline Project of
Shanghai Municipal Education Commission (No. J50101)
for financial support. We also thank Dr. Hongmei Deng and
Min Shao of Laboratory for Microstructures, Shanghai
University for the NMR and single crystal X-ray analyses.
Supporting Information Available. Experimental proce-
dures and spectral data for all new compounds; crystallo-
graphic data in CIF format for 3g and 3k. This material is
available free of charge via the Internet at http://pubs.acs.org.
The mechanism of the above cycloaddition reaction has
not been unequivocally established, but one reasonable
possibility is outlined in Scheme 2. The methyleneindoli-
none 2 or 4 can act as a diene to react with the in situ
generated benzyne 1, affording the [4 þ 2] cycloadduct A.
(16) CCDC900344 for compound 3o contains the supplementary
crystallographic data for this paper.
(17) (a) Abramovitch, R. A.; Hey, D. H. J. Chem. Soc. 1954, 1697–
1703. (b) Daisley, R. W.; Walker, J. J. Chem. Soc. (C) 1971, 3357–3363.
ꢀ
ꢀ
(c) Gomez, B.; Guitian, E.; Castedo, L. Synlett 1992, 903–904. (d)
Nassar-Hardy, L.; Deraedt, C.; Fouquet, E.; Felpin, F.-X. Eur. J.
Org. Chem. 2011, 4616–4622.
(15) See the Supporting Information for details on the controlled
experiments. During the investigation, the excessive amount of CsF was
also found to play a significant role in the whole transformation.
The authors declare no competing financial interest.
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