Tandem reactions leading to benzo[c]chromen-6-ones and 3-substituted isocoumarins

Article abstract of DOI:10.1002/ejoc.201101559

A simple and convenient protocol for the synthesis of benzo[c]chromen-6- ones and 3-substituted isocoumarins through a Cu^I-catalyzed tandem reaction of 2-bromobenzoates withcyclohexane-1,3-diones or acyclic 1,3-diones is developed. This strategy can also be extended to the one-pot synthesis of isoquinolin-1(2H)-one and 3,4-dihydrophenanthridine-1,6(2H,5H)-dione. A simple and convenient protocol for the synthesis of benzo[c]chromen-6-ones and 3-substituted isocoumarins through a Cu^I-catalyzed tandem reaction of 2-bromobenzoates with cyclohexane-1,3-dione or acyclic 1,3-dione has been developed. This strategy can also be extended to the one-pot synthesis of isoquionlin-1(2H)-one and 3,4-dihydrophenanthridine-1,6-(2H,5H)-dione. Copyright

Full text of DOI:10.1002/ejoc.201101559

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101559
Tandem Reactions Leading to Benzo[c]chromen-6-ones and 3-Substituted
Isocoumarins
Xuesen Fan,*[a] Yan He,[a] Liangyan Cui,[a] Shenghai Guo,[a] Jianji Wang,[a] and
Xinying Zhang*[a]
Keywords: Natural products / Fused-ring systems / Copper / Domino reactions
A simple and convenient protocol for the synthesis of benzo-
[c]chromen-6-ones and 3-substituted isocoumarins through a
CuI-catalyzed tandem reaction of 2-bromobenzoates with
cyclohexane-1,3-diones or acyclic 1,3-diones is developed.
This strategy can also be extended to the one-pot synthesis
of isoquinolin-1(2H)-one and 3,4-dihydrophenanthridine-
1,6(2H,5H)-dione.
diate B. Intermediate B isomerizes to BЈ, which then un-
dergoes a retro-Favorskii reaction to afford 3a as the final
product.
Introduction
Recently, we sought to develop new synthetic strategies
by exploring the Michael addition of 1,2-allenic ketones.[1]
In this regard, we envisioned a synthetic pathway to benz-
oxocinone[2] through the copper-catalyzed tandem reaction
of 1-(2-bromophenyl)buta-2,3-dien-1-one (1) with cyclohex-
ane-1,3-dione (2a). Unexpectedly, the reaction did not give
the envisioned benzoxocinone (I); instead, 3,4-dihydro-2H-
benzo[c]chromene-1,6-dione (3a) was obtained (Scheme 1).
This result might be explained by the following mechanistic
rationale: the CuI-catalyzed C–C coupling of 1 with 2a af-
fords intermediate A.[3] Subsequent intramolecular nucleo-
philic 1,2-addition of the enol onto the carbonyl group, in-
stead of 1,4-addition onto the allene moiety, yields interme-
Even though the reaction of 1 with 2a failed to give the
proposed benzoxocinone, it still attracted our interest, as
it offered a potential pathway towards benzo[c]chromen-6-
ones. Benzo[c]chromen-6-ones constitute one of the major
classes of pharmacologically relevant natural products[4]
that display a wide range of biological activities.[5] The de-
velopment of general and practical synthetic methods for
the preparation of benzo[c]chromen-6-ones has thus been
strongly pursued.[6] On the basis of the pathway described
in Scheme 1, we speculated that commercially available
methyl 2-bromobenzoate (4a) might be a more direct and
economical substrate than 1 for the preparation of 3a
(Scheme 2).
Scheme 1. Unexpected formation of 3a from 1 and 2a.
Scheme 2. Proposed synthesis of 3a from 4a and 2a.
[a] School of Chemistry and Environmental Sciences,
Key Laboratory of Green Chemical Media and Reactions,
Ministry of Education, Henan Key Laboratory for
Environmental Pollution Control, Henan Normal University,
Xinxiang, Henan 453007, P. R. China
A literature search revealed that the CuI-catalyzed cou-
pling of o-bromobenzoic acid with 1,3-diketones has been
sporadically described,[7] but those few cases were limited
to carboxylic acid. It is believed that under basic conditions,
carboxylic acid could form a chelate with copper to activate
the bromine towards nucleophilic displacement (Scheme 3).
Fax: +86-373-3326336
E-mail: xuesen.fan@htu.cn
xinyingzhang@htu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101559.
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X. Fan, Y. He, L. Cui, S. Guo, J. Wang, X. Zhang
SHORT COMMUNICATION
On the other hand, the reaction of 2-bromobenzoate with Table 1. Scope of the reaction leading to 3 from 4 and 2.[a]
1,3-diketones under CuI catalysis still remains to be ex-
plored.
Scheme 3. CuI-catalyzed reaction of o-bromobenzoic acid.
Results and Discussion
Initially, a mixture of 4a (0.5 mmol) and 2a (1.0 mmol)
was treated with CuI (0.05 mmol) and K2CO3 (2 mmol) in
DMF at 80 °C for 12 h. To our delight, it gave 3a in 41%
yield. Optimization of the reaction conditions with regard
to Cu source, base, solvent, temperature, and molar ratio of
substrates revealed that 66% yield of 3a was obtained when
4a (0.5 mmol) and 2a (1.5 mmol) were treated with CuI
(0.05 mmol) and K2CO3 (1.5 mmol) in DMF at 90 °C for
20 h. Several ligands such as pipecolinic acid, N,N-dimeth-
ylglycine, and l-proline were also examined, but no im-
provement in the yield of 3a was observed, indicating that
the ligand may be unnecessary for this process.
With the optimized reaction conditions, the scope and
generality of this reaction were studied. For this purpose,
several alkyl-substituted cyclohexane-1,3-diones were firstly
treated with different 2-bromobenzoates. The results in
Table 1 show that the reaction is compatible with 5-meth-
yl-, 5-isopropyl-, and 5,5-dimethylcyclohexane-1,3-diones.
With 4-methyl- or 4,4-dimethylcyclohexane-1,3-dione, two
isomeric products were observed, whereas the 2-substituted
isomer was found to be dominant (Table 1, Entries 5, 6 and
11). Identification of the isomers was established on the ba-
sis of heteronuclear multiple bond correlation (HMBC)
studies.
The reaction was then studied with 5-phenylcyclohexane-
1,3-dione (5a). Surprisingly, instead of the expected 3,4-di-
hydro-3-phenyl-2H-benzo[c]chromene-1,6-dione (II), 1-hy-
droxy-3-phenyl-6H-benzo[c]chromen-6-one (6a) was ob-
tained (Scheme 4). A plausible pathway including copper-
catalyzed C–C coupling, intramolecular transesterification,
and subsequent in situ oxidative aromatization of II to ac-
count for the formation of 6a is outlined in Scheme 4.
To further investigate the unexpected formation of 6a,
several 5-arylcyclohexane-1,3-diones 5 were employed as
substrates. The results in Table 2 show that substrates with
either electron-withdrawing or electron-donating groups on
the aryl rings of 4 or 5 were tolerated. Functional groups
such as methyl, methoxy, and halides were well tolerated
under these conditions.
From the results listed in Tables 1 and 2, it was con-
cluded that unsubstituted or alkyl-substituted 3,4-dihydro-
2H-benzo[c]chromene-1,6-diones 3 are less prone to un-
[a] Reaction conditions:
(0.05 mmol), K2CO3 (1.5 mmol), DMF (3 mL), 90 °C, 20 h. [b] Iso-
lated yield.
4
(0.5 mmol),
2
(1.5 mmol), CuI
dergo oxidative aromatization than their aryl-substituted
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Benzo[c]chromen-6-ones and 3-Substituted Isocoumarins
Table 2. Scope of the reaction leading to 6.[a]
Scheme 4. Plausible pathway for the formation of 6a.
counterparts (i.e., II) and thus fail to give the corresponding
6H-benzo[c]chromen-6-ones 6 under the same conditions.
To assist the oxidative aromatization of 3, FeCl3,
FeCl3·6H2O, RuCl3, DDQ, and I2 were investigated as pos-
sible oxidants. Among them, I2 was found to be the most
efficient. With the promotion of I2, several alkyl-substituted
benzo[c]chromene-6-ones
6 were successfully obtained
(Table 3).
To further extend the scope of the above reactions and
considering that isocoumarins are ubiquitous structural
units in a plethora of natural products with biological inter-
ests,[8–10] we set out to study the reaction between 4 and
acyclic 1,3-diketones 7 with the aim to develop a new
method for the synthesis of 3,4-disubstituted isocoumarins.
To our surprise, the reaction of 4a and pentane-2,4-dione
(7a) under the promotion of CuI/K2CO3 in DMF afforded
3-methyl-1H-isochromen-1-one (8a) exclusively, rather than
the expected 4-acetyl-3-methyl-1H-isochromen-1-one (III,
Scheme 5). This result may be explained by the following
pathway: initially formed C–C coupling product C un-
dergoes retro-Claisen deacylation to give intermediate D,[11]
which then undergoes intramolecular transesterification to
give 8a as the final product.
Scheme 5. Unexpected formation of 8a from 4a and 7a.
The formation of 8a turns out to be very interesting, be-
cause the majority of the naturally occurring isocoumarins
that are of polyketide origin possess a C-3 substituent and
the development of practical and convenient synthetic pro-
tocols for 3-substituted isocoumarins has been a challenge
in the synthetic community.[8,12] On the basis of the above
[a] Reaction conditions:
(0.05 mmol), K2CO3 (1.5 mmol), DMF (3 mL), 90 °C, 20 h. [b] Iso-
lated yield.
4
(0.5 mmol),
5
(1.5 mmol), CuI
facts, we set out to develop the reaction of 4 with 7 into a substrates and all the reactions proceeded smoothly with
general method for the synthesis of 3-substituted isocouma- moderate efficiency (Table 4). It is noted that in the forma-
rins. A range of acyclic 1,3-diketones was thus studied as tion of 8, the retro-Claisen deacylation is highly regioselec-
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X. Fan, Y. He, L. Cui, S. Guo, J. Wang, X. Zhang
Table 4. Synthesis of 3-substituted isocoumarins.[a]
SHORT COMMUNICATION
Table 3. Oxidative aromatization of 3 toward 6.[a]
[a] Reaction conditions:
(0.5 mmol), DMF (5 mL), 90 °C, 16 h. [b] Isolated yield.
3 (0.5 mmol), K2CO3 (0.5 mmol), I2
tive with the unsymmetrical 1-arylbutane-1,3-dione, and
only the deacetylated product, 3-arylisocoumarin, was ob-
tained. The debenzoylation product, 3-methylisocoumarin,
was not observed. Interestingly, with 1,3-diphenylpropane-
1,3-dione (7d), debenzoylation did occur smoothly to give
3-phenylisocoumarin with good efficiency (Table 4, En-
try 9).
[a] Reaction conditions:
(0.05 mmol), K2CO3 (1.5 mmol), DMF (3 mL), 90 °C, 20 h. [b] Iso-
lated yield.
4
(0.5 mmol),
7
(1.5 mmol), CuI
Finally, we noticed that isoquinolin-1(2H)-ones are im- with 1-phenylbutane-1,3-dione in the presence of CuI and
portant structural moieties in both synthetic and medicinal K2CO3 in DMF followed by reaction with NH4OH allowed
chemistry and several procedures for their synthesis from the isolation of 3-phenylisoquinolin-1(2H)-one (9) in 53%
isocoumarins have been reported.[13] Having successfully yield (Scheme 6). This methods offers a straightforward
developed an efficient procedure for the preparation of 3- one-pot route towards isoquinolin-1(2H)-one from readily
substituted isocoumarins, we turned our attention to study available starting materials. As an extension of this pro-
the feasibility of developing a one-pot synthesis of isoquin- cedure, 3,4-dihydrophenanthridine-1,6-(2H,5H)-dione (10)
olin-1(2H)-one directly from 2-bromobenzoate and 1,3-di- was also obtained directly and conveniently from 2-bromo-
ketones. It turned out that treatment of 2-bromobenzoate benzoate and cyclohexane-1,3-dione as shown in Scheme 7.
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Benzo[c]chromen-6-ones and 3-Substituted Isocoumarins
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Scheme 7. One-pot synthesis of 3,4-dihydrophenanthridine-1,6-
(2H,5H)-dione (10).
Conclusions
In conclusion, we have developed a copper-catalyzed tan-
dem process for the assembly of benzo[c]chromen-6-ones
and 3-substituted isocoumarins from 2-bromobenzoates
and 1,3-diketones. In addition, this new process was suc-
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1(2H)-one and 3,4-dihydrophenanthridine-1,6-(2H,5H)-di-
one. With advantages such as readily available starting ma-
terials, mild reaction conditions, and simple synthetic pro-
cedures, the methods developed herein are expected to serve
as promising protocols for the construction of relevant oxy-
gen- and nitrogen-containing heterocycles.
Experimental Section
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Typical Procedure for the Preparation of Benzo[c]chromene-6-ones
3a–m and 6a–j and Isochromen-1-ones 8a–h: To a flask containing
the 2-bromobenzoate (0.5 mmol) and the dione (1.5 mmol) was
added DMF (3 mL), CuI (0.05 mmol), and K2CO3 (1.5 mmol). The
mixture was stirred at 90 °C. Upon completion of the reaction as
monitored by TLC, the reaction was quenched with aqueous
NH4Cl. Then, the mixture was filtered through Celite, and the fil-
trate was extracted with ethyl acetate (3ϫ5 mL). The combined
organic phases were dried, filtered, and concentrated under vac-
uum. The residue was purified by column chromatography on silica
gel (ethyl acetate/hexane) to give the pure product.
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Supporting Information (see footnote on the first page of this article):
1
Full experimental details, characterization data, H NMR and 13C
NMR spectra of all products, and HMBC spectra of 3g and 3l.
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (20972042, 20911140238), the Innovation Scientists and
Technicians Troop Construction Projects of Henan Province
(104100510019), and the Program for Changjiang Scholars and In-
novative Research Team in University (PCSIRT) (IRT1061) for fin-
ancial support.
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Received: October 25, 2011
Published Online: December 19, 2011
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