Efficient generation of indeno[1,2-c]chromenes via the Pd-catalyzed reaction of 2-alkynylhalobenzenes with 2-alkynylphenols

Article abstract of DOI:10.1039/c1cc11169h

A palladium-catalyzed reaction of 2-alkynylhalobenzenes with 2-alkynylphenols in the presence of PCy₃ is discovered, which provides an efficient and facile route to indeno[1,2-c]chromenes. This reaction works efficiently, leading to the corresp

Full text of DOI:10.1039/c1cc11169h

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2011, 47, 5298–5300
www.rsc.org/chemcomm
COMMUNICATION
Efficient generation of indeno[1,2-c]chromenes via the Pd-catalyzed
reaction of 2-alkynylhalobenzenes with 2-alkynylphenolsw
Yong Luo,a Linxiang Hongb and Jie Wu*a
Received 27th February 2011, Accepted 16th March 2011
DOI: 10.1039/c1cc11169h
A palladium-catalyzed reaction of 2-alkynylhalobenzenes with
2-alkynylphenols in the presence of PCy3 is discovered, which
provides an efficient and facile route to indeno[1,2-c]chromenes.
This reaction works efficiently, leading to the corresponding
products in good to excellent yields.
via a palladium-catalyzed reaction of 2-alkynylhalobenzene
with amine.6 Inspired by the structural similarity of
5H-cyclopenta[c]quinoline and indeno[1,2-c]chromene, we
conceived that the indeno[1,2-c]chromene scaffold could
be formed via a palladium-catalyzed reaction of 2-alkynyl-
halobenzene with 2-alkynylphenol. Herein, we wish to disclose
our recent efforts for this transformation.
Gnetuhainin S, isolated from Gnetum macrostachyum lianas,
shows antioxidant activity when subjected to an examination
of its radical scavenging against DPPH (Fig. 1).1 However,
there is lack of efficient ways to access this [6-5-6-6] tetracyclic
skeleton.2 With an expectation to generate a small library of
indeno[1,2-c]chromene (a precursor of Gnetuhainin S, Fig. 1)
for the subsequent biological screening, development of useful
and efficient synthetic methodologies for the scaffold construction
is extremely important. Recently, intense interest has been
directed toward the strategy of diversity-oriented synthesis3
for the efficient construction of structurally complex compounds.
Among the approaches, cascade reaction which uses easily
available starting materials is attractive due to its well-known
advantages.4,5 The features of cascade reaction prompt us to
design novel routes for the efficient assembly of indeno[1,2-c]-
chromene derivatives. Recently, we described a novel method
for the synthesis of 5H-cyclopenta[c]quinoline derivatives
2-Alkynylphenols are the most widely used substances for
the synthesis of benzo[b]furans.7 Among the reaction process,
nucleophilic addition of the phenolic oxide to the metal-
activated triple bond is the key step (R–PdIIX is involved in
most cases). Additionally, to the best of our knowledge, there
are no reports for the syn-insertion of R–PdX to the triple
bond against the hydroxy group. We hypothesized that the
oxidative addition would take place to afford an intermediate
A when 2-alkynylbromobenzene was employed in the reaction
(Scheme 1). The Pd(II) would selectively activate the triple
bond of 2-alkynylphenol. If the syn-insertion of R–PdIIX to
triple bond occurred first, followed by a second insertion to the
triple bond of 2-alkynylbromobenzene and intramolecular
C–O bond formation, indeno[1,2-c]chromene which contains
the [6-5-6-6] tetracyclic skeleton would be formed. This
synthetic hypothesis seems feasible. However, several factors
have to be considered in this strategy: (1) a benzo[b]furan can
be easily generated by direct cyclization of 2-alkynylphenol;7b,c
Fig. 1 Structures of Gnetuhainin S and indeno[1,2-c]chromene.
a Department of Chemistry, Fudan University, 220 Handan Road,
Shanghai 200433, China. E-mail: jie_wu@fudan.edu.cn;
Fax: +86 21 6564 1740; Tel: +86 21 6510 2412
b Department of Macromolecular Science, Fudan University,
220 Handan Road, Shanghai 200433, China
w Electronic supplementary information (ESI) available: Experimental
procedure, characterization data, 1H and 13C NMR spectra of
compounds 3, and X-ray crystal data of compound 3a. CCDC
815061. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c1cc11169h
Scheme 1 Possible mechanism for indeno[1,2-c]chromenes generation
via a Pd-catalyzed reaction of 2-alkynylhalobenzene with 2-alkynylphenol.
c
5298 Chem. Commun., 2011, 47, 5298–5300
This journal is The Royal Society of Chemistry 2011

View Article Online
(2) aryl halide reacts with 2-alkynylphenol in the presence of a
palladium catalyst leading to 2,3-diarylbenzo[b]furan;7c (3) the
direct C–O bond formation of aryl halide and phenol which is
established8 cannot be excluded in our protocol. However, as
mentioned above for the 5H-cyclopenta[c]quinoline generation
through a palladium-catalyzed reaction of o-alkynylhalobenzene
with amine,6 the double triple bond insertion and subsequent
C–N bond formation would occur under suitable conditions in
the reaction process. Encouraged by this result, we conceived
that the proposed synthetic route showed in Scheme 1 was
possible. Thus, we started to investigate the practicability for
the synthesis of indeno[1,2-c]chromenes via a palladium-
catalyzed cascade reaction of 2-alkynylhalobenzene with
2-alkynylphenol.
illustrated by X-ray diffraction analysis in the meantime
(see the ESIw). With these results in hand, we next screened
different bases. Sodium methanolate (NaOCH3) was demon-
strated as the best choice (95% yield, Table 1, entry 14).
Further screening of solvents discovered that the reaction
worked efficiently in 1,4-dioxane, which furnished the corres-
ponding product in 96% yield (Table 1, entry 16). The
reactivity was diminished when the reaction occurred at a
lower temperature (data not shown in Table 1).
Under the optimized conditions [Pd(OAc)2 (5 mol%), PCy3
(10 mol%), NaOCH3, 1,4-dioxane, 105 1C], the palladium-
catalyzed cascade reactions of 2-alkynylbromobenzenes with
2-alkynylphenols were then carried out to define the protocol
generality (Table 2). In all cases, the reactions produced the
desired indeno[1,2-c]chromenes in 63–96% yield. Substituents
on the aromatic ring of the substrates or attached on the triple
bond did not obviously affect formation of the expected
products. For instance, 1-bromo-2-(phenylethynyl)benzene
1a reacted with 2-alkynylphenols 2a–2d leading to the
corresponding indeno[1,2-c]chromenes in good yields
(Table 2, entries 1–4). When 2-alkynylbromobenzene 1b was
utilized in the reaction, excellent results were obtained as well
(Table 2, entries 5 and 6). Additionally, 4-methyl or 4-chloro
substituted 2-alkynylbromobenzene and 2-alkynylphenol were
examined. These reactions worked efficiently as well to afford
the corresponding indeno[1,2-c]chromenes in good yields.
Moreover, the reaction of 1-chloro-2-(2-phenylethynyl)-
benzene 4 with 2-(2-phenylethynyl)phenol 2a was explored
under the standard conditions in the meantime (Scheme 2).
From the result (78% yield), it showed that aryl chloride was a
The preliminary screening was performed for the reaction of
1-bromo-2-(phenylethynyl)benzene 1a with 2-(2-phenylethynyl)-
phenol 2a catalyzed by palladium acetate (5 mol%) at 105 1C
(Table 1). Only a trace amount of product was detected when
the reaction occurred in the presence of ligand L1 (10 mol%)
and K3PO4 in toluene (Table 1, entry 1). Similar results were
t
observed when the ligand was changed to L2–L4 and Bu3P
(Table 1, entries 2–5). The reaction was complex when DPPF
was utilized as a replacement of the ligand (Table 1, entry 6).
Employing BINAP as a ligand in the reaction could not
improve the final outcome (Table 1, entry 7). Gratifyingly,
the desired product 3a was obtained in 59% yield when the
reaction proceeded with tricyclohexylphosphine (PCy3) as the
ligand (Table 1, entry 8). The structure of compound 3a was
Table 1 Initial studies for the palladium-catalyzed reaction of 1-bromo-
2-(phenylethynyl)benzene 1a with 2-(2-phenylethynyl)phenol 2a
Table 2 Synthesis of indeno[1,2-c]chromenes via a Pd-catalyzed
reaction of 2-alkynylbromobenzene with 2-alkynylphenola
Entry
R1, R2
R3, R4
Yieldb (%)
1
2
3
4
5
6
7
8
H, C6H5 (1a)
H, C6H5 (1a)
H, C6H5 (1a)
H, C6H5 (1a)
H, n-Bu (1b)
H, n-Bu (1b)
H, 4-MeC6H4 (1c)
H, 4-MeC6H4 (1c)
H, 4-MeC6H4 (1c)
H, 4-MeOC6H4 (1d)
H, 4-MeOC6H4 (1d)
H, 4-MeOC6H4 (1d)
H, 4-ClC6H4 (1e)
H, 4-ClC6H4 (1e)
H, 4-ClC6H4 (1e)
H, 4-ClC6H4 (1e)
H, 4-ClC6H4 (1e)
4-Me, C6H5 (1f)
4-Cl, C6H5 (1g)
H, C6H5 (2a)
96 (3a)
82 (3b)
76 (3c)
79 (3d)
95 (3e)
95 (3f)
81 (3g)
90 (3h)
94 (3i)
90 (3j)
96 (3k)
79 (3l)
95 (3m)
86 (3n)
86 (3o)
93 (3p)
70 (3q)
74 (3r)
63 (3s)
H, 4-MeC6H4 (2b)
H, 4-MeOC6H4 (2c)
H, 4-ClC6H4 (2d)
H, C6H5 (2a)
H, 4-MeC6H4 (2b)
H, C6H5 (2a)
H, 4-ClC6H4 (2d)
4-Me, C6H5 (2e)
H, C6H5 (2a)
H, 4-MeOC6H4 (2c)
4-Me, 4-ClC6H4 (2f)
H, C6H5 (2a)
H, 4-MeC6H4 (2b)
4-Me, C6H5 (2e)
4-Me, 4-ClC6H4 (2f)
4-Cl, C6H5 (2g)
H, C6H5 (2a)
Entry
Ligand
Base
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
L1
L2
L3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
NaOtBu
K2CO3
KOtBu
LiOtBu
KOH
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
1,4-Dioxane
DMF
Trace
Trace
Trace
Trace
Trace
Complex
Trace
59
87
79
67
81
55
95
72
96
Trace
nr
L4
tBu3PÁHBF4
DPPF
BINAP
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
9
10
11
12
13
14
15
16
17
18
19
9
10
11
12
13
14
15
16
17
18
NaOCH3
Cs2CO3
NaOCH3
NaOCH3
NaOCH3
H, C6H5 (2a)
a
Reaction conditions: 2-alkynylbromobenzene
2-alkynylphenol
1
2 (0.60 mmol), Pd(OAc)2 (5 mol%), PCy3
(0.40 mmol),
DMSO
b
(10 mol%), CH3ONa (0.8 mmol), 1,4-dioxane (3.0 mL), reflux. Isolated
yield based on 2-alkynylbromobenzene.
a
Isolated yield based on 1-bromo-2-(phenylethynyl)benzene 1a.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 5298–5300 5299

View Article Online
3 (a) D. P. Walsh and Y.-T. Chang, Chem. Rev., 2006, 106, 2476;
(b) P. Arya, D. T. H. Chou and M.-G. Baek, Angew. Chem., Int. Ed.,
2001, 40, 339; (c) S. L. Schreiber, Science, 2000, 287, 1964.
4 L. F. Tietze, G. Brasche and K. Gericke, Domino Reactions in
Organic Synthesis, Wiley-VCH, Weinheim, Germany, 2006.
5 For recent examples, see: (a) P. Lu and Y.-G. Wang, Synlett, 2010,
165; (b) E. J. Yoo and S. Chang, Curr. Org. Chem., 2009, 13, 1766;
(c) L.-Q. Lu, Y.-J. Cao, X.-P. Liu, J. An, C.-J. Yao, Z.-H. Ming and
W.-J. Xiao, J. Am. Chem. Soc., 2008, 130, 6946; (d) X.-F. Wang,
J.-R. Chen, Y.-J. Cao, H.-G. Cheng and W.-J. Xiao, Org. Lett.,
2010, 12, 1140; (e) W. Song, W. Lu, J. Wang, P. Lu and Y. Wang,
J. Org. Chem., 2010, 75, 3481; (f) W. Hu, X. Xu, J. Zhou, W.-J. Liu,
H. Huang, J. Hu, L. Yang and L.-Z. Gong, J. Am. Chem. Soc.,
2008, 130, 7782.
Scheme 2 Palladium-catalyzed reaction of 1-chloro-2-(phenylethynyl)-
benzene 4 with 2-alkynylphenol 2a.
suitable partner in this transformation, which expands the
substrate scope of this reaction.
In summary, we have described an efficient assembly of
indeno[1,2-c]chromene derivatives via a palladium-catalyzed
cascade reaction of 2-alkynylhalobenzene with 2-alkynyl-
phenol. The reaction works efficiently with excellent selectivity,
and the reaction scope is demonstrated. The related library
construction is currently ongoing.
6 Y. Luo, X. Pan and J. Wu, Org. Lett., 2011, 13, 1150.
7 For selected examples, see: (a) A. Arcadi, S. Cacchi, G. Fabrizi and
L. Moro, Eur. J. Org. Chem., 1999, 1137; (b) Y. Hu, Y. Zhang,
Z. Yang and R. Fathi, J. Org. Chem., 2002, 67, 2365; (c) Y. Hu,
K. J. Nawoschik, Y. Liao, J. Ma, R. Fathi and Z. Yang, J. Org.
Chem., 2004, 69, 2235; (d) Y. Nan, H. Miao and Z. Yang, Org. Lett.,
2000, 2, 297; (e) H.-A. Du, X.-G. Zhang, R.-Y. Tang and J.-H. Li,
J. Org. Chem., 2009, 74, 7844; (f) Y. Liao, J. Smith, R. Fathi and
Z. Yang, Org. Lett., 2005, 7, 2707; (g) Y. Liang, S. Tang,
Financial support from National Natural Science Foundation
of China (No. 21032007) and the Science & Technology
Commission of Shanghai Municipality (No. 09JC1404902) is
gratefully acknowledged.
X.-D. Zhang, L.-Q. Mao, Y.-X. Xie and J.-H. Li, Org. Lett.,
2006, 8, 3017; (h) C. Martı
´
´
nez, R. Alvarez and
J. M. Aurrecoechea, Org. Lett., 2009, 11, 1083; (i) M. Nakamura,
L. Ilies and S. Otsubo, Angew. Chem., Int. Ed., 2006, 45, 944.
8 Selected examples for Pd-catalyzed intermolecular C–O bond
formation: (a) A. Aranyos, D. W. Old, A. Kiyomori, J. P. Wolfe,
J. P. Sadighi and S. L. Buchwald, J. Am. Chem. Soc., 1999,
121, 4369; (b) Q. Shelby, N. Kataoka, G. Mann and J. Hartwig,
J. Am. Chem. Soc., 2000, 122, 10718; (c) S. Harkal, K. Kumar,
D. Michalik, A. Zapf, R. Jackstell, F. Rataboul, T. Riermeier,
A. Monseesb and M. Beller, Tetrahedron Lett., 2005, 46, 3237.
Notes and references
1 (a) S. Saisin, S. Tip-pyang and P. Phuwapraisirisan, Nat. Prod. Res.,
2009, 23, 1472; (b) S. Zhou, Y. H. Wang and M. Lin, Chin. Chem.
Lett., 2002, 13, 549.
2 (a) R. Singh, M. K. Parai and G. Panda, Org. Biomol. Chem., 2009,
7, 1858; (b) M. Chakraborty, D. B. McConville, T. Saito, H. Meng,
P. L. Rinaldi, C. A. Tessier and W. J. Youngs, Tetrahedron Lett.,
1998, 39, 8237.
c
5300 Chem. Commun., 2011, 47, 5298–5300
This journal is The Royal Society of Chemistry 2011