Palladium-catalyzed cascade reactions of 3-iodochromones with aryl iodides and norbornadiene leading to annulated xanthones

Article abstract of DOI:10.1039/c2sc21335d

An efficient, palladium-catalyzed cascade reaction, which leads to formation of annulated xanthones, was devised. The process, which uses readily available 3-iodochromones, aryl iodides and norbornadiene as starting materials, takes place via a tandem Heck reaction/double C-H activation/retro-Diels-Alder pathway. The high chemoselectivity of the process is mechanistically unique and it serves as a new approach to achieve regioselective control of C-H activation in Pd/norbornene or norbornadiene systems. Its broad substrate scope, including heteroaryl coupling partners, enables access to diverse annulated xanthones.

Full text of DOI:10.1039/c2sc21335d

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EDGE ARTICLE
Palladium-catalyzed cascade reactions of 3-iodochromones with aryl iodides
and norbornadiene leading to annulated xanthones†
*
Ming Cheng, Jianwei Yan, Feng Hu, Hong Chen and Youhong Hu
Received 24th August 2012, Accepted 13th September 2012
DOI: 10.1039/c2sc21335d
An efficient, palladium-catalyzed cascade reaction, which leads to formation of annulated xanthones,
was devised. The process, which uses readily available 3-iodochromones, aryl iodides and
norbornadiene as starting materials, takes place via a tandem Heck reaction/double C–H activation/
retro-Diels–Alder pathway. The high chemoselectivity of the process is mechanistically unique and it
serves as a new approach to achieve regioselective control of C–H activation in Pd/norbornene or
norbornadiene systems. Its broad substrate scope, including heteroaryl coupling partners, enables
access to diverse annulated xanthones.
The chromone ring system is an important structural motif
Introduction
frequently found in natural products, pharmaceuticals and other
important synthetic substances.6 The results of recent investiga-
tions have shown that C–H functionalization reactions could
occur at the C-2 and C-3 position of chromones.7 In a continua-
tion of an effort aimed at the development of strategies for the
preparation of diverse natural-product-like scaffolds,8 we specu-
lated that regioselective C–H activation at the C-2 position of
chromones might take place in the course of the Catellani reaction
and that this pathway would serve as a facile method for forming
flavones and/or xanthones (Scheme 1).
Amongthe importantgroupofC–Hactivation/C–C bondforming
processes, the Pd-catalyzed/norbornene-mediated reaction (Cat-
ellani reaction) is widely recognized as being a powerful method to
formdiverselyfunctionalizedaromaticcompoundsandcondensed
heterocycles. The Catellani reaction follows a cascade pathway in
which C–C bonds and C–O or C–N bonds form sequentially.1
Generally, the‘‘orthoeffect’’ ofaryliodidesensures thatCsp2–Csp2
rather than Csp2–Csp3 coupling of Pd(IV) intermediates occurs
regioselectively to generate biaryl linkages and an active Pd(II)
species, which participates in a variety of coupling reactions.2
A large effort has been devoted to improving the efficiency and
practicality of this Csp2–Csp2 coupling process.3 In contrast, the
development of techniques to selectively promote Csp2–Csp3
reductive elimination of the key aryl Pd intermediate in the reac-
tion pathway still presents a distinct challenge. In an early report,
Catellani suggested that it might be possible to facilitate aryl–
norbornyl bond formation by Csp2–Csp3 coupling when an ortho
group is absent.4 Recently, Catellani and Malacria discovered that
certain chelating functional groups on the second ortho substituent
can guide alternate reactivity, thus offsetting the normal ortho
effect.5 In the study described below, we have uncovered a new,
palladium-catalyzed cascade reaction of 3-iodochromones with
aryl iodides and norbornadiene that forms annulated xanthones
via a Heck coupling/double C–H activation/retro-Diels–Alder
sequence and that involves an unexpected Csp2–Csp3 reductive
elimination reaction of the key aryl Pd intermediate even though
no ortho chelating functional groups are present.
Results and discussion
Initial studies aimed at exploring this proposal focused on the
Pd-catalyzed reaction of 3-iodochromone (1a) with iodobenzene
State Key Laboratory of Drug Research, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, 201203,
Shanghai, China. E-mail: yhhu@mail.shcnc.ac.cn; Fax: +86 21-5080-5896
† Electronic supplementary information (ESI) available. CCDC 884029
(4b). For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2sc21335d
Scheme 1 A proposed sp2–sp3 coupling process in the palladium-cata-
lyzed reaction of 3-iodochromone with iodobenzene and norbornadiene
or norbornene.
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Table 2 Scope of aryl iodidesa
Scheme 2 Pd-catalyzed tandem formation of compound 3a.
Table 1 Optimization of the cascade reaction
Entry
1
Substrate 2
Product
Yield (%)
78
2
3
78
40
Entry Solvent Pd cat.
Base
T/ꢀC t/h Yieldd (%)
1a
DMF
DMF
DMF
DMA
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
K2CO3 90
Cs2CO3 90
12
12
12
12
12
12
12
3
3
3
3
3
10
2a
Messy
45
40
31
18
50
57
78
56
47
45
38
33
3a
CsPiv
CsPiv
CsPiv
CsPiv
CsPiv
CsPiv
CsPiv
CsPiv
CsPiv
90
90
90
90
4a
5a
DMSO Pd(OAc)2
6a
DMFb
DMFc
DMFc
DMFc
DMFc
DMFc
DMFc
DMFc
DMFc
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
7a
90
8a
130
130
130
130
130
130
130
9e
4
5
6
83
63
58
10e
11e
12e
13e
14e
Pd2(dba)3
PdCl2(PPh3)2 CsPiv
Pd(PPh3)4 CsPiv
PdCl2(PPh3)2 CsPiv
3
3
a
All reactions were carried out using the following molar ratio of the
b
reagents: 1a : 2a : norbornadiene ¼ 1 : 1 : 2. Freshly distilled DMF.
c
d
Freshly distilled DMF with 1.5 equiv. of water. Isolated yield. The
e
reaction was run with molar ratio of the reagents:
1a : 2a : norbornadiene ¼ 1 : 2 : 6.
(2a) in the presence of norbornene. Under the reaction condi-
tions described by Catellani (see procedure A), the unexpected
product 3a is produced in 82% yield (Scheme 2). We hypothe-
sized that this catalytic reaction proceeds via a pathway involving
7b
67
51
8b
9b
44/22c
39/21c
13/40c
10b
11b
12
13
62
65
Scheme 3 Proposed catalytic cycle.
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Table 2 (Contd.)
represent the most direct and functionally tolerant method for
forming these targets (Table 1).
Indeed, reaction of 1a and 2a in the presence of norborna-
diene, promoted by Pd(OAc)2 in the presence of K2CO3 (see
procedure A), was observed to generate the desired benzox-
anthone 4a in only 10% yield (entry 1). The low yield of the
reaction might be a consequence of the high reactivity of nor-
bornadiene.5a,11 When the softer base Cs2CO3 was utilized (entry
2), this reaction produces an inseparable mixture of products.
Since the use of pivalate anion as a ligand is known to improve
the efficiency of many C–H activation processes.12 Me3CCO2Cs
(entry 3) was employed as a base in the reaction. Significantly,
benzoxanthone 4a is produced in 45% yield under these condi-
tions. Moreover, other higher boiling solvents, such as DMSO
and DMA, could also be used to facilitate the final retro-Diels–
Alder step (entries 4–6). However, freshly distilled DMF (entry
6) was not an effective solvent, indicating that water is required
to promote the reaction.3g,k,13 The results of a brief examination
showed that 1.5 equiv. of water is ideal. As expected, the reaction
occurs more rapidly at higher temperatures (entry 8). Impor-
tantly, increasing the amounts of both iodobenzene and nor-
bornadiene leads to a dramatically improved 78% yield (entry 9).
Finally, although other common Pd sources can be utilized to
promote this reaction, Pd(OAc)2 is the most efficient catalyst
(entries 10–14). The combined studies demonstrate that DMF
containing 1.5 equiv. H2O as the solvent at 130 ꢀC, Me3CCO2Cs
as the base, 5 mol% Pd(OAc)2 as the catalyst, 2 equiv. of PhI, 6
equiv. of norbornadiene, and 3 h reaction time are the optimal
conditions for the new reaction.
Entry
Substrate 2
Product
Yield (%)
14
40
a
All reactions were run under optimized conditions, unless otherwise
b
c
noted. Reactions were run at 90 ꢀC for 12 h. The ratios were
determined by using 1H NMR analysis.
Table 3 Iodochromone scope of the process
Entry
1
Substrate 1
Product
Yield (%)
71
To gain insight into the mechanism of the process, reaction of
1a with para-iodotoluene (2b) was carried out under the opti-
mized conditions. This reaction generates the benzoxanthone 4b
in 78% yield. The structure of 4b and in particular the position of
the methyl group was assigned by using X-ray crystallographic
analysis (ESI†). Importantly, the position of methyl group in 4b
is fully consistent with the proposed catalytic cycle, where Csp2–
Csp3 rather than Csp2–Csp2 coupling takes place in the reductive
elimination step (Scheme 3). The overall route could be initiated
by oxidative addition of Pd(0) to 1a, followed by norbornadiene
insertion, and intramolecular sp2 C–H activation at the 2-posi-
tion of the chromone ring then forms the chromone fused pal-
ladacycle B. A second oxidative addition of the aryl iodide
affords the Pd(IV) complex C, which then undergoes reductive
elimination by either Csp2–Csp3 or Csp2–Csp2 coupling. The
position of the methyl group in 4b shows that Csp2–Csp3
reductive elimination regioselectively gives intermediate D,
which undergoes the second sp2 C–H activation to form F fol-
lowed by release of the Pd(0) complex. The retro-Diels–Alder
2
3
4
85
60
73
5
80
ꢀ
reaction of F, taking place at 130 C leads to formation of the
benzoxanthone product. An alternative mechanism may involve
initial oxidative addition by ArI, which reacts with norborna-
diene to generate a phenyl fused palladacycle and followed by a
second oxidative addition of 3-iodochromone to give the same
Pd(IV) complex C. Since 3-iodochromone with an electron-
withdrawing group is more reactive than iodobenzene for the
initial oxidative addition of Pd(0), the first possibility is favored.
Also, we speculate that the selective operation of Csp2–Csp3
coupling is a consequence of stabilization of intermediate D by
the electron-donating effect of the oxovinyl system.
Csp2–Csp3 reductive elimination. Intrigued by this hypothesis,
norbornadiene was utilized as a substrate in a reaction carried
out under otherwise identical conditions. We believed that retro-
Diels–Alder reaction would occur on the initially formed product
to afford a benzoxanthone derivative. Importantly, substances in
the benzoxanthone family display interesting bioactivities9 and,
as a result, various methods for their synthesis have been
described.10 However, the cascade process we envisioned would
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M. Lautens, Top. Curr. Chem., 2010, 292, 1; (f) D. Alberico,
M. E. Scott and M. Lautens, Chem. Rev., 2007, 107, 174; (g)
Next, differently substituted aryl iodides were used to explore
the scope of the new tandem reaction, conducted under optimized
conditions. The results, summarized in Table 2, show that the
electronic nature of para-substituents on the aryl iodide has a
significant effect on the reaction (entries 2–5). Specifically, elec-
tron donating group substituted aryl iodides undergo inefficient
reactions owing to a slow oxidative insertion step converting
Pd(II) to Pd(IV) (entry 3). In addition, the steric bulk of meta aryl
iodide substituents can be used to govern the regioselectivity of the
C–H activation step. As demonstrated by reactions of the meta-
tert-butyl and -methoxycarbonyl substituted aryl iodides 2g and
2h that yield the respective benzoxanthones 4g and 4h, the course
of the process is guided by steric hindrance (entries 7 and 8). As
expected, mixtures of two benzoxanthones, arising by C–H acti-
vation at either ortho-phenyl site, are generated in reactions of the
aryl iodides 2i, 2j and 2k, which contain smaller electron-donating
or electron-withdrawing meta-groups (entries 9–11). It should be
noted that reactions of aryl iodides bearing ortho-CH3, -OMe and
-CF3 substituents are low yielding, perhaps because of steric
effects that slow oxidative insertion in the Pd(II) intermediate B.
It is significant that the heteroaryl iodides, 2-iodothiophene, 4-
iodopyridine and 3-iodoindole, undergo this reaction to give the
desired products in moderate to good yields. In contrast, bro-
mobenzene can not be used in place of its iodide counterpart as the
coupling partner, presumably because it does not react with the
palladium(II) metallacycle intermediate. Lastly, different 3-iodo-
chromones containing both electron-withdrawing and -donating
substituents on the chromonering react with4-iodotoluene (Table
3) to give the corresponding benzoxanthones in good yields.
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Conclusions
In the investigation described above, we have developed a highly
efficient cascade process that involves unique C–H activation of
the 2-position of the chromone ring system. The compatibility of
this novel reaction with aryl iodides allows for an efficient method
to prepare benzoxanthones. The high selectivity of the novel Pd/
norbornene catalytic system should be applicable to reactions that
result in the construction of interesting fused ring systems. More-
over, observations made in this study suggest that slightly different
catalysts might be needed for reactions of each substrate type and
that the Pd/norbornene catalytic system may be more mechanis-
tically complicated than previously believed. We anticipate that
thenovelreactiondiscoveredinthis investigationwillbeapplicable
to other substrates and that future studies in this area will lead to
the development of more comprehensive catalytic systems.
Acknowledgements
This work was supported by grant from National Natural
Science Foundation of China (21172232) and the Ministry of
Science and Technology of China (2009CB940903)
Notes and references
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Pure Appl. Chem., 2006, 78, 351; (e) A. Martins, B. Mariampillai and
€
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13 S. Deledda, E. Motti and M. Catellani, Can. J. Chem., 2005, 83, 741.
Chem. Sci.
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