Assembly of fused indenes via Au(i)-catalyzed C1-C5 cyclization of enediynes bearing an internal nucleophile

Article abstract of DOI:10.1039/c2cc36245g

A tandem reaction initiated by Au(i)-catalyzed C1-C5 cyclization of enediynes bearing an internal carboxy nucleophile has been developed, providing a distinctive methodology for the assembly of fused indenes including indeno[1,2-c]isochromen-5(11H)-ones and indeno[1,2-b]pyran-2(5H)-ones. A mechanism involving the concerted formation of the five- and six-membered rings was proposed.

Full text of DOI:10.1039/c2cc36245g

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Assembly of fused indenes via Au(I)-catalyzed C1–C5
cyclization of enediynes bearing an internal
nucleophile†
Cite this: Chem. Commun., 2013,
49, 695
Received 28th August 2012,
Qiwen Hou,a Zhenhua Zhang,a Fanji Kong,a Shaozhong Wang,*a Huaqin Wangb
and Zhu-Jun Yaoa
Accepted 22nd November 2012
DOI: 10.1039/c2cc36245g
www.rsc.org/chemcomm
A tandem reaction initiated by Au(I)-catalyzed C1–C5 cyclization of
enediynes bearing an internal carboxy nucleophile has been developed,
providing a distinctive methodology for the assembly of fused
indenes including indeno[1,2-c]isochromen-5(11H)-ones and indeno-
[1,2-b]pyran-2(5H)-ones.
A mechanism involving the concerted
formation of the five- and six-membered rings was proposed.
Annelated tetracyclic and tricyclic indenes containing heteroatoms
(N, O) are basic scaffolds of natural alkaloids such as epicryp-
topirubin chloride and dielsine.1 Some tetracyclic 5H-indeno-
[1,2-c]isoquinolin-5-ones named indotecan and indimitecan
have been developed as phase I clinical candidates for the
treatment of cancers.2 However, as oxygen analogues, indeno-
[1,2-c]isochromen-5(11H)-ones have attracted less attention,3
even though they could serve as straightforward precursors for
the preparation of 5H-indeno[1,2-c]isoquinolin-5-ones.4 Aiming at
exploring novel chemical transformations based on the enediynes
functionality and establishing new methodology to construct fused
indene compounds, we envisioned a tandem reaction triggered
by Au(I)-catalyzed C1–C5 cyclization of enediynes, providing a
distinctive approach to indeno[1,2-c]isochromen-5(11H)-ones and
indeno[1,2-b]pyran-2(5H)-ones (Scheme 1, top).
C1–C5 cyclization of enediynes emerged as a divergent
reactivity pattern, which is complementary to the Bergman
cycloaromatization (C1–C6 cyclization).5 Initially, studies on the
reagent-controlled C1–C5 cyclization and the substrate-dependent
C1–C5 cyclization under thermal or UV irradiation conditions
were intensively investigated. Various 2,8-diaryl substituted
1H-methylene-indenes were generated starting from symmetrical
1,2-bis(arylethynyl)benzenes under the promotion of electro-
philes,5a–c nucleophiles5b and radical reagents.5e–f In 2007, Wu
Scheme 1 Indene assembly via Au(I)-catalyzed C1–C5 cyclization.
reported firstly a transition metal-catalyzed C1–C5 cyclization,
which involves a halopalladation of one alkyne followed by an
insertion of C–Pd to another alkyne moiety.6 Recently, Zhang7 and
Hashmi8 independently described a tandem process involving
C1–C5 cyclization of unsymmetrical enediynes, where two mole-
cules of gold catalysts work in syn en route to the formation of gold
vinylidene intermediates (Scheme 1, bottom). The formation of
gold vinylidene caused the terminal carbon to be installed in the
cyclopenta[a]indene ring.9 However, our proposed C1–C5 cycliza-
tion, by taking advantage of the presence of an internal nucleo-
phile, displays a different reactivity pattern, and the terminal
alkyne eventually is transformed into an exocyclic CQC bond.
Enediyne 1a, bearing one terminal alkyne and a carboxy group,
was initially designed as a model substrate (Table 1). It was
prepared from 1,2-diethynyl-4,5-dimethoxybenzene and methyl
2-iodobenzoate by mono Sonogashira coupling reaction and sub-
sequent hydrolysis. When 10 mol% Ph3PAuOTf was employed as
catalyst, complete conversion of enediynes 1a was observed in acetic
acid after 15 min. A yellow solid was isolated in 78% yield, which was
identified as 8,9-dimethoxy-11-methyleneindeno[1,2-c]isochromen-
5(11H)-one (Table 1, entry 1). The structure was confirmed
unambiguously by X-ray diffraction analysis (see the ESI†).10
a School of Chemistry and Chemical Engineering, State Key Laboratory of
Coordination Chemistry, Nanjing University, Nanjing 210093, P. R. China.
E-mail: wangsz@nju.edu.cn; Fax: +86 25 83317761; Tel: +86 25 83593732
b Modern Analytical Center of Nanjing University, Nanjing 210093, P. R. China
† Electronic supplementary information (ESI) available: Typical experimental
procedure, characterization of products, 1H and 13C NMR spectra. CCDC 807572
and 843665. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c2cc36245g
c
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Table 1 Optimization of conditions
Table 2 Fused indene assembly by Au(I)-catalyzed C1–C5 cyclizationa
Entry
Fused indenes
Entry
Fused indenes
1
7
Yieldb
Conditiona
2a
3
Entry
1
2
3
4
5
6
7
8
10 mol% Ph3PAuOTf, HOAc, rt, 15 min
10 mol% Ph3PAuSbF6, HOAc, rt, 15 min
10 mol% Ph3PAuNTf2, HOAc, rt, 15 min
10 mol% Ph3PAuNTf2, Toluene, rt, 15 min
10 mol% Ph3PAuNTf2, CH3CN, rt, 15 min
10 mol% Ph3PAuNTf2, THF, rt, 15 min
10 mol% Ph3PAuNTf2, CH2Cl2, rt, 15 min
5 mol% Ph3PAuNTf2, CH2Cl2, rt, 15 min
10 mol% AuCl, CH2Cl2, rt, 30 min
78
56
84
80
64
69
87
85
0
8
4
5
o1
o1
o1
5
2
8
5
3b
9
9
80
80
0
10
10 mol% AuCl3, CH2Cl2, rt, 30 min
10 mol% HNTf2, CH2Cl2, rt, 12 h
0
0
11c
a
b
The concentration is 0.05 M. Isolated yield after column chromato-
c
graphy. Decomposition of 1a happened.
4
10
11
Catalyst tuning by changing the counteranion of the gold
complex demonstrated that Ph3PAuNTf2 displayed a higher
catalytic ability while Ph3PAuSbF6 led to an inferior result. No
incorporation of acetoxy group by intermolecular nucleophilic
addition was detected (Table 1, entries 2–3). Under the catalysis
of Ph3PAuNTf2, a variety of solvents involving toluene, aceto-
nitrile, dichloromethylene, tetrahydrofuran were examined
(Table 1, entries 4–7). The best yield was obtained in the
presence of CH2Cl2. Further attempts to decrease the catalyst
loading show little detrimental effect (Table 1, entry 8). On the
contrary, when the simple gold salts such as AuCl and AuCl3
were used, a divergent 6-endo-dig hydrocarboxylation of the
internal alkyne took place preferentially without any C1–C5 cycliza-
tion. The 1H-isochromen-1-one 3 was formed predominantly as a
5
6
a
Reaction condition: 5 mol% Ph3PAuNTf2 in CH2Cl2; the concentration
b
is 0.05 M. 2,3-Dichloro-6H-dibenzo[c,h]chromen-6-one was isolated.
major product and the terminal alkyne was kept untouched substituents (OMe, OCH2O) retard the conversion. In
a
(Table 1, entries 9–10). A control experiment using Brønsted acid similar manner, enediynes 1i–l prepared from (Z)-methyl 3-iodo-
HNTf2 in the absence of gold catalyst led to substrate decomposi- phenylacrylate, (Z)-methyl 3-iodobut-2-enoate and (Z)-methyl
tion, neither 2a nor 3 was formed (entry 11). Accordingly, a 3-iodoacrylate were transformed to the tricyclic indeno[1,2-b]-
combination of Ph3PAuNTf2 and CH2Cl2 was established as the pyran-2(5H)-ones 2i–l conveniently, demonstrating the molecular
optimized condition.
diversity of the transformation (Table 2, entries 8–11). The X-ray
The scope of the transformation was then studied (Table 2). crystal structure unambiguously proved the formation of
Enediynes 1b–c derived from 1,2-diethynyl-4,5-dimethylbenzene and 4-phenylindeno[1,2-b]pyran-2(5H)-one 2i (see the ESI†).10
1,2-diethynylbenzene underwent the tandem reaction expectedly
The proposed mechanism of the transformation is shown in
albeit in somewhat decreased yields (Table 2, entries 1–2). The Scheme 2.11 Activation of the terminal alkyne by coordination
electron-withdrawing substituent on the 1,2-diethynylbenzene of the carbophilic gold complex initiates a 5-endo-dig cyclization
moiety proved to be detrimental. The dichloroenediyne 1d was followed by an intramolecular nucleophilic attack from the
converted to indeno[1,2-c]isochromen-5(11H)-one 2d only in carboxy group. After protonolysis of the C–Au bond, the
23% yield (Table 2, entry 3). To examine the substituent effect indeno[1,2-c]isochromen-5(11H)-one or indeno[1,2-b]pyran-
on the benzoic acid moiety, enediynes 1e–h generated from 2(5H)-one was formed (pathway a). Alternatively, when the gold
1,2-diethynyl-4,5-dimethoxybenzene and methyl 2-iodobenzoate catalyst activates the internal alkyne, the ortho carboxy group
containing methoxy, methylenedioxy, methyl and chlorine attacks the activated alkyne to form 1H-isochromen-1-one,
groups were subjected to the identical condition. The which can be converted to tetracyclic or tricyclic indenes
indeno[1,2-c]isochromen-5(11H)-ones 2e–h were achieved in by hydroarylation stepwisely (pathway b). However, the con-
yields ranging from 65 to 90% (Table 2, entries 4–7). It seems certed formation of the five-membered carbocycle and the six-
like that the electron-withdrawing substituent (Cl) facilitates the membered heterocycle was preferred according to the following
formation of the tetracyclic product while the electron-donating studies. When 1H-isochromen-1-one 3, separately prepared by
c
696 Chem. Commun., 2013, 49, 695--697
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Meanwhile, a novel methodology has been developed for the
assembly of tetracyclic indeno[1,2-c]isochromen-5(11H)-one or tri-
cyclic indeno[1,2-b]pyran-2(5H)-one derivatives. Further studies on
the gold catalysis of enediynes are underway.
The work was financially supported by National Science
Foundation of China (20802034, 21032002) and the Fundamental
Research Funds for the Central Universities (1117020507,
1082020502).
Notes and references
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Scheme 2 Proposed mechanism of the C1–C5 cyclization.
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6 (a) C.-Y. Lee and M.-J. Wu, Eur. J. Org. Chem., 2007, 3463; (b) for a
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7 L. Ye, Y. Wang, D. H. Aue and L. Zhang, J. Am. Chem. Soc., 2012,
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Scheme 3 Chemical modifications of 2a.
AuCl3-catalyzed 6-endo-dig hydrocarboxylation as exemplified in
Table 1, was treated with Ph3PAuOTf (10 mol%) using HOAc as
the solvent, no cyclization to the final product occurred even
after prolonging the reaction times, the addition of acetic
acid to alkyne took place instead to afford vinyl acetate as a
major product. When CH2Cl2 was employed as the solvent, the
indeno[1,2-c]isochromen-5(11H)-one was obtained only in 20%
yield after 12 hours accompanied by a more polar inseparable
mixture.
To explore the synthetic potential of the gold(I)-catalyzed
tandem reaction, the transformations including oxidative clea-
vage and reductive hydrogenation of the exocyclic CQC bond in
tetracyclic compound 2a were performed, leading to indeno-
[1,2-c]isochromene-5,11-dione 4 and 11-methylindeno[1,2-c]iso-
chromen-5(11H)-one 5 in good yields, respectively (Scheme 3).
In conclusion, a tandem reaction initiated by gold(I)-
catalyzed C1–C5 cyclization of enediynes bearing a pendant
carboxy group has been described, which involves the form-
9 For a divergent PtCl2-catalyzed C1–C6 cyclization of similar ene-
diynes, see: B. P. Taduri, Y.-F. Ran, C.-W. Huang and R.-S. Liu, Org.
Lett., 2006, 8, 883.
10 CCDC 807572 (2a) and 843665 (2i) contain the supplementary
crystallographic data for this paper.
ation of a carbon–carbon bond and a carbon–oxygen bond. 11 A. S. K. Hashmi, Angew. Chem., Int. Ed., 2010, 49, 5232.
c
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Chem. Commun., 2013, 49, 695--697 697