Generation of cyclopenta[c]chromenes via a palladium-catalyzed reaction of 2-alkynylphenol with 2-alkynylvinyl bromide

Article abstract of DOI:10.1039/c2cc32077k

A palladium-catalyzed tandem reaction of 2-alkynylphenol with 2-alkynylvinyl bromide gives rise to cyclopenta[c]chromenes in good yields. Three bonds are formed during the process and a double insertion of triple bonds is believed to be the key step.

Full text of DOI:10.1039/c2cc32077k

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COMMUNICATION
Generation of cyclopenta[c]chromenes via a palladium-catalyzed reaction
of 2-alkynylphenol with 2-alkynylvinyl bromidew
Huanhuan Wang,a Yong Luo,a Biao Zhu*b and Jie Wu*ac
Received 22nd March 2012, Accepted 12th April 2012
DOI: 10.1039/c2cc32077k
A palladium-catalyzed tandem reaction of 2-alkynylphenol with
2-alkynylvinyl bromide gives rise to cyclopenta[c]chromenes in
good yields. Three bonds are formed during the process and a
double insertion of triple bonds is believed to be the key step.
It is well known that heterocyclic compounds hold a special
and essential place among pharmaceutically important natural
products.1 Currently, heterocyclic compounds with a core of
Scheme 1 A proposed palladium-catalyzed tandem reaction for the
generation of cyclopenta[c]chromenes.
natural products are in great demand in the field of chemical
and it is easily available.9 We envisioned that the reaction
of 2-alkynylphenol 1 with 2-alkynylvinyl bromide 2 might
proceed through a double insertion of triple bonds and C–O
coupling in the presence of a palladium catalyst. We anticipated
that the three bonds would be formed in a tandem one-pot
procedure. Recently, the use of the strategy of intramolecular or
intermolecular double insertion of triple bonds for the formation of
heterocyclic or carbocyclic compounds has been demonstrated.10,11
For example, Lu et al. described the synthesis of 8H-acenaphtho-
genetics.2 So far, diversity-oriented synthesis has been utilized
successfully for the preparation of such molecules. The
cyclopenta[c]chromene system is the subunit of natural products
(iridoids).3 Compounds with the core of cyclopenta[c]chromene
have attracted considerable attention due to their important
biological activities.3,4 For instance, they were found to exhibit
a potent cytotoxicity in vitro against HTC hepatoma cells and
anti-tumor activity in vivo against KREBS II ascitic tumor.4
However, researchers seldom manage to find efficient ways to the
cyclopenta[c]chromene structural skeletons.5 For example, Hong
and co-workers reported a hetero [6+3] cycloaddition of
6-dimethylaminofulvene to benzoquinone leading to cyclopenta[c]-
chromene derivatives.5a,b The existing methods usually suffer from
scope limitation. Thus, it is highly desirable to develop an efficient
and novel pathway for rapid access to cyclopenta[c]chromenes,
especially in a combinatorial format.
[1,2-c]pyrroles via
a palladium-catalyzed bicyclization of
1,8-diarenynyl naphthalenes and primary amines using the
intramolecular double insertion of triple bonds as the key
step.10b Prompted by these results, we conceived that the
hypothesis presented in Scheme 1 seemed feasible although
there are several possible competitive pathways (such as direct
C–O coupling12 and benzofuran formation8) existing theoretically
during the transformation.
In conjunction with our continuing efforts for accessing
natural product-like compounds,6 we are interested in
cyclopenta[c]chromene derivatives. Retrosynthetically, we hypo-
thesized that the scaffold of compound 3 could be generated via a
tandem process7 from the reaction of 2-alkynylphenol 1 with
2-alkynylvinyl bromide 2 (Scheme 1). 2-Alkynylphenol 1 has
been demonstrated as a versatile building block in organic
synthesis.8 2-Alkynylvinyl bromide 2 is a useful synthon as well
At the outset, we studied the model reaction of 2-alkynyl-
phenol 1a with 2-alkynylvinyl bromide 2a in the presence of a
palladium catalyst (5 mol%) (Table 1). Initially, the reaction
was catalyzed by Pd(OAc)2 (5 mol%) and PCy3 (10 mol%) in
the presence of K2CO3 (2.0 equiv.) in 1,4-dioxane at 90 1C
(Table 1, entry 1). Gratifyingly, the expected cyclopenta-
[c]chromene 3a was obtained and isolated in 54% yield. This
product could not be formed in a control experiment without
the addition of a phosphine ligand (data not shown in
Table 1). In light of this result, we further screened different
bases (Table 1, entries 2–6). When NaOMe was employed in
the reaction, the reaction afforded the corresponding product
3a in 85% yield. The yield increased to 92% when the reaction
occurred at 95 1C (Table 1, entry 8). The result could not be
improved when the temperature was lower or higher (Table 1,
entries 7 and 9). No better yields were obtained by evaluation
of phosphine ligands (Table 1, entries 10–14). The efficiency was
retarded when the amount of palladium catalyst was reduced to
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 The Affiliated Zhongshan Hospital of Fudan University,
180 Fenglin Road, Shanghai 200032, China
c State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
w Electronic supplementary information (ESI) available: Experimental
procedure, characterization data, 1H and 13C NMR spectra of
compounds 3. CCDC 872666. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c2cc32077k
c
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Chem. Commun., 2012, 48, 5581–5583 5581

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Table 1 Initial studies of the palladium-catalyzed reaction of 2-alky-
nylphenol 1a with 2-alkynylvinyl bromide 2aa
Table 2 Synthesis of cyclopenta[c]chromenes 3 via a palladium-catalyzed
reaction of 2-alkynylphenol 1 with 2-alkynylvinyl bromide 2a
Entry [Pd]
Ligand
Base
Solvent
Yieldb (%)
1
2
3
4
Pd(OAc)2
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
K2CO3 1,4-Dioxane 54
Cs2CO3 1,4-Dioxane 40
t-BuOK 1,4-Dioxane 23
K3PO4 1,4-Dioxane 51
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
5
KOH
1,4-Dioxane 45
6
NaOMe 1,4-Dioxane 85
NaOMe 1,4-Dioxane 70
NaOMe 1,4-Dioxane 92
NaOMe 1,4-Dioxane 77
7c
8d
9e
10d
11d
12d
13d
14d
15d
16d
17d
18d
19d
Xantphos NaOMe 1,4-Dioxane Trace
X-phos
PPh3
DPPF
DPPP
PCy3
NaOMe 1,4-Dioxane 78
NaOMe 1,4-Dioxane 81
NaOMe 1,4-Dioxane 84
NaOMe 1,4-Dioxane 80
NaOMe 1,4-Dioxane 43
NaOMe 1,4-Dioxane 85
NaOMe 1,4-Dioxane 81
Pd2(dba)3
PdCl2(PPh3)2 PCy3
Pd(OAc)2
Pd(OAc)2
PCy3
PCy3
PCy3
NaOMe Toluene
NaOMe DMF
Trace
67
a
Reaction conditions: 2-alkynylphenol 1a (1.0 equiv.), 2-alkynylvinyl
bromide 2a (1.2 equiv.), palladium catalyst (5 mol%), ligand (10 mol%),
b
base (2.0 equiv.), 90 1C. Isolated yield based on 2-alkynylphenol 1a.
c
d
The reaction was performed at 70 1C. The reaction occurred at
e
95 1C. The reaction was performed at 105 1C.
2 mol% (data not shown in Table 1). Changing the palladium
sources or solvents did not result in further improvement
(Table 1, entries 15–19).
a
Isolated yield based on 2-alkynylphenol 1.
The generality of this palladium-catalyzed tandem reaction
of 2-alkynylphenols 1 with 2-alkynylvinyl bromides 2 was then
explored under the optimized conditions (5 mol% of Pd(OAc)2,
10 mol% of PCy3, 2.0 equiv. of NaOMe, 1,4-dioxane, 95 1C).
The results are exemplified in Table 2. A range of cyclopenta[c]-
chromenes 3 were obtained in good to excellent yields. Various
2-alkynylphenols 1 were demonstrated to be tolerated in the
transformation. The nature of the substituents on the aromatic
ring of 2-alkynylphenols 1 could not affect the conversion.
Reactions employing 2-alkynylphenols 1 with aryl or alkyl
groups attached on the triple bond all worked well to afford
the desired products 3. During the reaction process, only a trace
amount of benzofuran was detected under the standard conditions,
which indicated the high selectivity of this transformation.
Additionally, the substituents in 2-alkynylvinyl bromides 2 did not
affect the final outcomes. Interestingly, the chloro group in both
substrates was retained during the conversion, which indicated that
the oxidative addition of aryl chloride did not take place under the
optimized conditions. The structure of cyclopenta[c]chromene 3n
was unambiguously illustrated by X-ray diffraction analysis (Fig. 1)
(see the ESIw). For the possible mechanism (Scheme 2), we
envisioned that an oxidative addition of Pd(0) to vinyl bromide 2
would occur first, which then coordinated with the triple bond of
2-alkynylphenols 1. After insertion, a vinyl Pd(II) B was generated,
which subsequently underwent an intramolecular insertion of
another triple bond. Further C–O coupling afforded the desired
cyclopenta[c]chromene 3.
Fig. 1 X-ray ORTEP illustration of cyclopenta[c]chromene 3n
(30% probability ellipsoids).
In conclusion, we have described a novel and efficient route
for the preparation of cyclopenta[c]chromenes via a palladium-
catalyzed tandem reaction of 2-alkynylphenol with 2-alkynylvinyl
bromide. Three bonds are formed in a tandem one-pot procedure.
During the reaction process, the transformation proceeds through
a double insertion of triple bonds and C–O coupling in the
presence of a palladium catalyst. Currently, the use of the strategy
of intramolecular or intermolecular double insertion of triple
bonds for the formation of other heterocyclic compounds is
ongoing in our laboratory.
c
5582 Chem. Commun., 2012, 48, 5581–5583
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Scheme 2
A
proposed mechanism for the generation of
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Financial support from the National Natural Science
Foundation of China (Nos 21032007 and 21172038) is gratefully
acknowledged.
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Chem. Commun., 2012, 48, 5581–5583 5583