Access to 6H-naphtho[2,3-c]chromenes by a palladium-catalyzed reaction of 2-haloaryl allene with 2-alkynylphenol

Article abstract of DOI:10.1039/c4cc00374h

A palladium-catalyzed reaction of 2-haloaryl allene with 2-alkynylphenol is described, leading to 6H-naphtho[2,3-c]chromenes in good to excellent yields. This transformation proceeds efficiently with excellent chemoselectivity and regioselectivity. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc00374h

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Access to 6H-naphtho[2,3-c]chromenes by a
palladium-catalyzed reaction of 2-haloaryl allene
with 2-alkynylphenol†‡
Xiaolin Pan,§a Mo Chen,§b Liangqing Yao*b and Jie Wu*ac
Cite this: Chem. Commun., 2014,
50, 5891
Received 16th January 2014,
Accepted 6th March 2014
DOI: 10.1039/c4cc00374h
www.rsc.org/chemcomm
A palladium-catalyzed reaction of 2-haloaryl allene with 2-alkynylphenol
is described, leading to 6H-naphtho[2,3-c]chromenes in good to
excellent yields. This transformation proceeds efficiently with
excellent chemoselectivity and regioselectivity.
Heterocyclic compounds1 are always in great demand in
organic synthesis, especially in medicinal chemistry, chemical
biology, and the drug discovery process. Among the approaches
developed for the generation of heterocycles with complexity
and diversity,2 the domino reaction3 is an attractive pathway to
efficiently synthesize natural product-like compounds with
privileged skeletons. In the past decade, this strategy has been
applied broadly for the formation of complex small molecules.
Recently, we have been interested in 6H-naphtho[2,3-c]chromenes
and their related derivatives, which show broad and remarkable
biological activities. An example is displayed in Scheme 1, which
is a kind of natural product containing the core of naphtho[2,3-c]-
chromene. Additionally, this skeleton has been widely employed
as a critical structural intermediate to synthesize some natural
products and pharmaceuticals in total synthesis.4 Among the
methods available for the generation of complex polycycles,
double carbometallation of alkynes is a powerful and efficient
strategy.5 For instance, 5H-cyclopenta[c]quinolines were produced
Scheme 1 A proposed synthetic route for the generation of naphtho-
[2,3-c]chromenes.
via a palladium-catalyzed reaction of 2-alkynylhalobenzene with However, only [6-5-6-6] or [6-5-7-6] tetracyclic skeletons could be
an amine.5e This reaction process involved double insertion generated through this approach. Encouraged by these results, we
into the triple bond with the formation of four new bonds. envisioned that the core of naphtho[2,3-c]chromene could also be
constructed via a similar double carbometallation. The proposed
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 Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Road,
Shanghai 200011, China. E-mail: yaoliangqingcn@126.com
c State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032,
China
synthetic route is illustrated in Scheme 1. We conceived that the
allene substrate 1 could be taken into consideration as a building
block instead of an alkyne for the formation of [6-6-6-6] tetracyclic
polycycles.
Retrosynthetically, the core structure of naphtho[2,3-c]chromene
can be traced back to 2-bromoaryl allene 1 with 2-alkynylphenol 2.
In the presence of palladium(0) generated in situ with a phosphine
ligand,6 an oxidative addition occurred to afford Pd(II) species a.
After the insertion of Pd(II) species a into the triple bond
of 2-alkynylphenol 2, a vinyl palladium(II) b was afforded.
The regioselectively intramolecular coordination and insertion
† Dedicated to Prof. Li-Xin Dai on the occasion of his 90th birthday.
‡ Electronic supplementary information (ESI) available. CCDC 977123. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4cc00374h
§ X. Pan and M. Chen contributed equally.
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of Pd(II) into the double bond of the allene generated intermediate c. The reaction did not occur when t-BuOK was employed as the
In the presence of a base, a C–O bond was formed with the release base (Table 1, entry 1). A trace amount of product was detected
of Pd(0), which re-entered the catalytic cycle. Although this route using KOH as a replacement (Table 1, entry 2). The outcome
seemed feasible, we had to face several competitive reaction path- improved slightly when the base was changed to Cs2CO3,
ways. For example, benzofuran compounds were easily produced via NaOMe or Na2CO3 (Table 1, entries 3–5, respectively). Compared
the direct cyclization of 2-alkynylphenols. Moreover, after the to K3PO4, potassium carbonate seemed to be a better choice for
oxidative addition of Pd(0) with aryl bromide 1, the in situ generated this transformation, giving rise to the desired product 3a in 54%
Pd(II) species a activated the triple bond of 2-alkynylphenol 2 to yield (Table 1, entries 6 and 7, respectively). Encouraged by this
furnish 3-aryl substituted benzofurans.7
result, we then examined different ligands, but no higher yields
Among various allenes, those substituted by phosphine were obtained (Table 1, entries 8–13). Further investigation
oxide which are relatively stable and easily prepared have drawn showed that the conversion was sensitive to palladium sources.
our attention. Meanwhile, a growing interest has been paid to The reaction was more complex when PdCl2(PhCN)2, PdCl2, or
arylphosphonates in medicinal chemistry8 and nucleic acid PdCl2(PPh3)2 were utilized as the catalyst (Table 1, entries 14–16,
chemistry9 due to their remarkable biological activities. respectively), while the use of Pd2dba3 enhanced the reaction
Additionally, it has been found that phosphonates also have yield to 65% (Table 1, entry 17). Finally, we identified that
extensive applications in organic synthesis.10 Therefore, con- Pd(dppf)Cl2 was the most efficient palladium source, affording
sidering the easy preparation of the starting materials and the compound 3a in 93% yield (Table 1, entry 18). The reaction could
incorporation of a phosphonate fragment into the scaffold of also take place in other solvents, such as DMSO, DMF, toluene,
naphtho[2,3-c]chromene, (1-(2-bromophenyl)-3-phenylpropa-1,2-
dien-1-yl)diphenylphosphine oxide11 was selected as a model
substrate for the exploration of this transformation.
Our initial exploration focused on the reaction between
phosphonated 2-bromoaryl allene 1a12 and 2-(phenylethynyl)-
phenol 2a in the presence of Pd(OAc)2 (5 mol%) and PCy3
(10 mol%) under reflux. Several bases were initially screened.
Table
2
Synthesis of phosphonated naphtho[2,3-c]chromenes by a
palladium-catalyzed reaction of 2-bromoaryl allene 1 with 2-alkynylphenol 2a
Table 1 Initial studies for the palladium-catalyzed reaction of 2-bromoaryl
allene 1a with 2-(phenylethynyl)phenol 2a
Entry [Pd]
Ligand
Solvent Solvent
Yielda (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
DPPP
PtBu3
SPhos
t-BuOK Dioxane
nd
Trace
16
14
21
36
54
Trace
Trace
25
23
37
32
33
47
42
65
93
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(PhCN)2 PCy3
PdCl2
PdCl2(PPh3)2
Pd2(dba)3
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
KOH
Dioxane
Cs2CO3 Dioxane
NaOMe Dioxane
Na2CO3 Dioxane
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
DMSO
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25b
26c
DPE-Phos K2CO3
DPPF
PPh3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
61
44
61
68
DMF
Toluene
Diglyme
PhCF3
1-Pentanol 64
Dioxane
Dioxane
58
62
34
a
Isolated yield based on 2-(phenylethynyl)phenol 2a, nd = not detected.
The reaction was performed at 90 1C. The reaction occurred at 70 1C.
a
b
c
Isolated yield based on 2-alkynylphenol 2.
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diglyme, trifluoromethylbenzene and 1-pentanol. However, only
Financial support from the National Natural Science
moderate yields were achieved (Table 1, entries 19–24, respectively). Foundation of China (No. 21032007, 21202022, 21372046) is
The yield was reduced when the reaction temperature was decreased gratefully acknowledged.
(Table 1, entries 25 and 26). The structure of compound 3a was
determined by X-ray crystallography analysis (see ESI,‡ CCDC
977123).
Notes and references
1 For selected examples, see: (a) C. J. Ball, J. Gilmore and M. C. Willis,
Subsequently, exploration of the scope of this conversion
Angew. Chem., Int. Ed., 2012, 51, 5718; (b) J. Li, T. Mei and J. Yu,
was carried out under the optimized conditions: Pd(dppf)Cl2
(5 mol%), PCy3 (10 mol%), K2CO3 (2.0 equiv.), 1,4-dioxane,
under reflux, 12–16 hours. The results are presented in Table 2. All
of the reactions between the (1-(2-bromophenyl)-3-phenylpropa-
1,2-dien-1-yl)diphenylphosphine oxides 1 and 2-alkynylphenols 2
proceeded well with high efficiency and excellent selectivity
to generate phosphonated naphtho[2,3-c]chromenes. In addition,
2-alkynylphenols with alkyl groups (R4) also had high reactivity,
especially with the tert-butyl group, illustrating that steric hindrance
was not a barrier in the transformation. No difference was observed
for the reactions of 2-alkynylphenols with electron-donating groups
or electron-withdrawing groups attached to the aromatic ring.
Various 2-bromoaryl allenes 1 were also examined, and the corres-
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transformation, allenes with different R2 substituents were explored.
These reactions successfully provided the corresponding products
when R2 was the electron-donating group, electron-withdrawing
group, heterocycle or sterically hindered group. Furthermore,
2-chloroaryl allenes were also employed to afford the desired
products, although they showed lower activity in this reaction
(Table 3).
In conclusion, we have developed an efficient route for the
facile assembly of diverse phosphonated naphtho[2,3-c]chromenes
by a palladium-catalyzed reaction of 2-haloaryl allene 1 with
2-alkynylphenol 2. In this process, complexity could be easily
introduced with the formation of three new bonds. Under the
reaction conditions, the phosphonated naphtho[2,3-c]chromenes
were generated in good to excellent yields. Moreover, the transforma-
tion showed excellent chemoselectivity and regioselectivity, since
competitive reaction pathways for the formation of benzofurans
seem to have been inhibited completely. Further work on the
applications of double carbometallation for the construction of
other polycycles is ongoing in our laboratory.
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Isolated yield based on 2-alkynylphenol 2.
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