Copper-catalysed domino reaction of 2-bromobenzylidenemalonates and 1,3-dicarbonyls for the synthesis of chromenes

Article abstract of DOI:10.1016/j.tetlet.2016.12.006

4H-Chromenes were synthesized from 2-bromobenzylidenemalonates and 1,3-dicarbonyls under mild and simple reaction conditions via copper-catalysed domino reactions involving Michael addition and intramolecular Ullmann-type C(aryl)–O bond formation. Althoug

Full text of DOI:10.1016/j.tetlet.2016.12.006

Accepted Manuscript
Copper-Catalysed Domino Reaction of 2-Bromobenzylidenemalonates and 1,3-
Dicarbonyls for the Synthesis of Chromenes
Yotsakorn Saebang, Vatcharin Rukachaisirikul, Juthanat Kaeobamrung
PII:
S0040-4039(16)31632-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.006
TETL 48418
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 October 2016
30 November 2016
2 December 2016
Please cite this article as: Saebang, Y., Rukachaisirikul, V., Kaeobamrung, J., Copper-Catalysed Domino Reaction
of 2-Bromobenzylidenemalonates and 1,3-Dicarbonyls for the Synthesis of Chromenes, Tetrahedron Letters (2016),
doi: http://dx.doi.org/10.1016/j.tetlet.2016.12.006
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Copper-Catalysed Domino Reaction of 2-
Bromobenzylidenemalonates and 1,3-
Dicarbonyls for the Synthesis of Chromenes
Yotsakorn Saebang, Vatcharin Rukachaisirikul and Juthanat Kaeobamrung
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1
Tetrahedron Letters
Copper-Catalysed Domino Reaction of 2-Bromobenzylidenemalonates and 1,3-
Dicarbonyls for the Synthesis of Chromenes
Yotsakorn Saebang, Vatcharin Rukachaisirikul and Juthanat Kaeobamrung
Department of Chemistry and Center of Excellence for Innovation in Chemistry, Prince of Songkla University, 15 Kanjanavanit Road, Kohong, Hat-Yai,
Songkhla 90112, Thailand.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
4H-Chromenes were synthesized from 2-bromobenzylidenemalonates and 1,3-dicarbonyls under
mild and simple reaction conditions via copper-catalysed domino reactions involving Michael
addition and intramolecular Ullmann-type C(aryl)-O bond formation. Although a competitive
elimination affected these reactions, this catalytic system readily provided chromenes with
functionality at the C-4 position.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
copper-catalysed domino reaction
Ullmann-type coupling
C(aryl)-O bond formation
Michael addition
chromenes
———
 Corresponding author. Tel.: +66-74288401-2; fax: +66-7458841; e-mail: juthanat.k@psu.ac.th

2
Tetrahedron
Introduction
domino, Michael addition and C-O Ullmann type coupling
reactions.
Metal-catalysed domino reactions have drawn significant
O
attention from synthetic chemists for more than a century,
especially reactions catalysed by copper due to its low toxicity
and high natural abundance. Therefore, copper-catalysed domino
reactions have been developed for the formation of C(aryl)-N,
C(aryl)-C and C(aryl)-O bonds.1 Unlike C(aryl)-N bond
formation, tandem reactions for C(aryl)-O formation offer
considerably less reaction diversity due to the lower valence of
the oxygen atom.2 In continuation of our research interest in
copper-catalysed domino reactions for the synthesis of
heterocyclic molecules, we were inspired by the work of Li and
Fang for the formation of 4H-chromenes via copper-catalysed
intramolecular coupling of aryl bromides and 1,3-dicarbonyls.3
Their results suggested that C(aryl)-O Ullmann-type coupling
occurred smoothly in an intramolecular fashion. Furthermore,
Beifuss and co-workers recently took advantage of
intramolecular C(aryl)-O coupling to furnish 4H-chromene
derivatives via tandem process from 2-bromobenzyl bromides
and 1,3-ketoesters.4 These domino reactions involved substitution
of a stabilised carbanion, generated from a 1,3-ketoester, with a
bromine atom at the benzylic position, followed by
tautomerization and intramolecular Ullmann-type C-O bond
formation. In order to introduce functionality at the C-4 position
of 4H-chromenes, we alternatively envisioned that the
2-bromobenzylidenemalonates would undergo C-C bond
formation via Michael addition with 1,3-dicarbonyls, followed by
intramolecular copper-catalysed C(aryl)-O bond formation to
O
CN
O
OH
O
H
O
O
O
OH
O
O
O
HO
O
O
O
NH2
Rhodomyrtone
(a glycosidase inhibitor)
O
O
HA14-1
(apoptosis inducer)
Uvafzlefin
(antimicrobial)
Figure 2. Representative biologically active molecules
containing the chromene moiety
Our investigation initially began with optimization of the
reaction conditions. The reaction of diethyl 2-(2-
bromobenzylidene) malonate (1a) and cyclohexane-1,3-dione
(2a) was selected as a model (Table 1).
Various ligands were examined using CuI as the copper
source, K2CO3 as a base and ACN as a solvent. The reactions
were heated at 90 C for 15 hours (Entries 17). The reaction
with DMEDA as ligand gave the best yield (Entry 3), while PPh3
afforded none of the desired product (Entry 5). On the other
hand, proline and ethylenediamine were not effective in this
reaction (Entries 1 and 6) and only trace amounts of the product
o
1
were observed from the H NMR spectrum of the crude reaction
mixture. Next, various copper salts were explored. With
Cu(OAc)2, chromene 3a was obtained in 32% yield (Entry 10)
while CuBr and CuCl were not applicable to this system,
resulting in low yield and no reaction, respectively (Entries 8 and
9). Without copper there was no reaction (Entry 11).
Accordingly, the choice of copper was CuI. A variety of bases
were then examined. NEt3, an organic base, was not effective and
afford the desired 4H-chromenes (Fig. 1).
1
no reaction was observed according to the H NMR spectrum of
the crude reaction mixture (Entry 14). The reactions with weak
inorganic bases, K3PO4 or Cs2CO3 (Entries 12 and 13), gave
comparable yields to the reaction with K2CO3 (Entry 3). The
t
yield was slightly decreased when the stronger base BuOK was
used (Entry 15). We then conducted an exploration of solvents.
The yield of reaction in THF with K3PO4 as a base was 50%
(Entry 16), slightly lower than that of ACN (Entry 12). However,
upon changing the base to Cs2CO3, the yield increased to 68%
(Entry 17). These results suggested that the combination of base
and solvent affected this catalytic reaction. Upon using the less
polar solvent, toluene, or the more polar solvent, DMSO, the
yield dropped dramatically to 30% and 15%, respectively
(Entries 18 and 20). Finally, the higher boiling point solvent
dioxane was used, resulting in a much lower yield (Entry 19).
Subsequently, the optimal reaction conditions were DMEDA as a
ligand, CuI as a copper source, Cs2CO3 as a base and THF as a
solvent. Notably, the use of 20 mol% of copper and 30 mol% of
ligand was required to complete the reaction.
Figure 1. Copper-catalysed reactions for the synthesis of 4H-
chromenes
Chromenes are one of the most important O-containing
heterocyclic systems due to their common occurrence as a
structural motif in natural products5 as well as their biological
activities which include antitumor, antimicrobial, antioxidant,
anticancer and estrogenic properties6 (Fig. 2). Chromene
derivatives also play important roles in material science, for
example as fluorescent dyes, synthetic fibers, daylight fluorescent
pigments and electroluminescent devices.7 Due to their wide
range of utilities, the syntheses of chromene have been
consistently developed; most reported methods involve phenol
derivatives.8 Herein, we reported a synthesis of 4H-chromenes
containing a functionality pendent at the C-4 position via
Interestingly, the diester moiety of benzylidene was required.
Upon subjecting ethyl-3-(2-bromophenyl)acrylate, an ,-
unsaturated monoester, to the optimal conditions (Scheme 1), we
only observed both starting materials from the 1H NMR spectrum
of the crude reaction mixture.
Table 1. Reaction optimizationa

3
was postulated to undergo C(aryl)-O bond formation faster than
the more sterically hindered one. This indicated that in the
catalytic cycle, the rate determining step was possibly the
Ullmann-type coupling.
Table 2. Formation of chromenes 3a-g from 1,3-dicarbonylsa
Entry
Cu
Ligand
proline
Base
Solvent
Yield
(%)b
Tracec
10
1
2
CuI
CuI
K2CO3
ACN
ACN
1,10-phenan
throline
K2CO3
3
4
5
6
CuI
CuI
CuI
CuI
DMEDA
picolinic acid
PPh3
K2CO3
K2CO3
K2CO3
K2CO3
ACN
ACN
ACN
ACN
52
42
Entry
1
Benzylidene
malonate
Chromene
Yield
(%)b
0
1a
1a
3a
68
ethylene
Trace
diamine
7
CuI
CuBr
CuCl
Cu(OAc)2
-
2,2’-bipyridine
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
ACN
ACN
12
15
0
2
3b
66
8
9
ACN
10
11
12
13
14
15
16
17
18
19
20
ACN
32
0
ACN
3
4
1a
1b
3c
62
48
CuI
ACN
58
56
0
CuI
Cs2CO3
NEt3
ACN
CuI
ACN
3d
CuI
tBuOK
K3PO4
ACN
43
50
68
30
15
0
CuI
THF
CuI
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
THF
CuI
CuI
CuI
toluene
dioxane
DMSO
5
6
1c
3e
3f
65
56
aReaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), catalyst (20
mol %), ligand (30 mol %), solvent (0.1 M), 90 C, 15 h. Isolated
yield. cTrace amount of product observed from the 1H NMR
spectrum of the crude reaction mixture.
1d
o
b
Based on this result, the electrophilicity of the Michael
acceptor was deemed crucial in this system. Having established
the optimal reaction conditions, we explored the substrate scope
in the copper-catalysed domino reaction (Table 2).
7
1a
3g
50
Scheme 1. Reaction of ethyl-3-(2-bromophenyl)acrylate and 1,3-
cyclicdiketone
aReaction conditions: 1a-d (0.5 mmol), 2 (0.75 mmol). bIsolated yield.
We then explored the effect of electron density on the
aromatic
ring
of
the
benzylidenemalonates.
Benzylidenemalonates bearing both electron-donating and
electron-withdrawing groups on the benzene ring were applicable
to the reaction. However, dimethoxy substituents gave the desired
chromene in only 48% yield (Entry 4). On the other hand, the
reaction of benzylidenemalonates with a nitro group at the para-
position to the bromine on the benzene ring gave a slightly better
yield than that at the ortho-position (Entries 5 and 6), resulting
from a steric effect. Next, acyclic dicarbonyls were subjected to
Cyclohexane-1,3-diones, with and without the geminal-
dimethyl substituent, gave the desired chromenes in moderate
yield (Entries 13). The results showed that the presence of the
active geminal-dimethyl substituent had no effect on the reaction.
Additionally, we confirmed the location of the geminal-dimethyl
unit of chromene 3c using heteronuclear multiple bond
correlation (HMBC) spectroscopy (see ESI). Based on the
structure of 3c, the less sterically hindered oxygen nucleophile

4
Tetrahedron
the reaction. Unfortunately, acetylacetone and 1,3-diphenyl-1,3-
acid (1g) would undergo decarboxylation after the addition of 2a,
instead of elimination to give the mono acid substituent on the
chromene. Based on our proposal, the yield of chromene would
be improved. However, the reaction of diacid 1g and 2a gave
chromene 3j in comparable yield to the reaction of diethyl ester
propanedione were unreactive in this system. However, the
reaction of methyl acetoacetate gave a moderate yield (Entry 7).
These results suggested that the nucleophilicity of the
dicarbonyls was crucial.
1
1a (Entry 3). Furthermore, the H NMR spectrum of the crude
We hypothesized that the first transformation was
intermolecular Michael addition, followed by intramolecular C-O
bond formation since an isochromene had not been observed.
Furthermore, we observed the loss of diethylmalonate from the
1H NMR spectrum of the crude reaction, resulting in the low to
moderate product yield obtained for the domino reaction. Our
findings were consistent with a report from Mayr and co-workers
regarding the reactivity of benzylidenemalonates in the Michael
addition of carbanion nucleophiles.9 We postulated that the
stabilized carbanion added to the benzylidenemalonate to form
the carbanion intermediate I which further underwent proton
transfer to generate carbanion intermediate II. Based on the loss
of diethylmalonate and reports from Mayr10 and Li4, we
rationalized that II could alternatively undergo elimination,
resulting in the elimination of diethylmalonate to give an
unidentified product or tautomerization to form the enolate III.
Subsequently, Ullmann-type C-O bond formation takes place to
give desired chromene (Scheme 2).
reaction mixture prior to being quenched with acid showed a
mixture of mono- and di-acid chromenes (see ESI).
Table 3. 4H-Chromene formation from a variety of ester
substituted benzylidenemalonatesa
Entry
1
Benzylidene
malonate
Chromene
Yield
(%)b
1e
1f
3h
3i
10
Scheme 2. Possible reaction mechanism
Me
O
Me
O
2
3
0
O
O
O
O
1g
3j
65
aReaction conditions: benzylidenemalonate (0.5 mmol),
cyclohexane-1,3-dione (0.75 mmol). bIsolated yield.
Conclusion
We have demonstrated the domino synthesis of 4H-chromene
derivatives via a copper-catalysed Michael addition and C-O
Ullmann-type coupling reaction under mild and simple reaction
conditions. The 1,3-cyclic diketones were shown to be a better
reaction partner than 1,3-acyclic diketones which were not
suitable in this domino system. Nonetheless, the reaction with
1,3-diketo ester gave satisfactory yields.
In this catalytic system, the product yields were limited by the
nature of benzylidenemalonates in the Michael addition.
Alternatively, Beifuss and co-workers elegantly designed a
domino process4 utilizing the nucleophilic substitution reactions
of benzylbromide and 1,3-ketoesters, followed by C-O Ullmann-
type coupling yielding 4H-chromene derivatives in moderate to
high yields. Based on our proposed mechanism, the yields were
diminished via an elimination step. Next, we explored the ester
substituents of benzylidenemalonates in order to possibly avoid
undesired elimination (Table 3).
Acknowledgments
This work was supported by Prince of Songkla University
(SCI580907S). Further support was generously provided by The
Science Achievement Scholarship of Thailand (SAST) for Mr.
Saebang.
Increasing the size of the ester group was initially examined.
Unfortunately, the reaction of di-tert-butyl benzylidenemalonate
(1e) gave a low yield of the desired chromene (Entry 1).
Additionally, the 1H NMR spectrum of the crude reaction
mixture showed that the ratio of 1e and 3h was 10:1. The result
suggested that the bulky ester group resulted in low reactivity.
We next considered the geometry of benzylidenemalonate. 5-(2-
Supplementary Material
Supplementary data (experimental procedures and
characterization data) for new compounds associated with this
article can be found, in the online version, at
References and notes
Bromobenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione
(1f),
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derived from Meldrum’s acid, was selected, however, the
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decomposed throughout the reaction course. In order to overcome
the undesired elimination, we speculated that benzylidenemalonic

5
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3
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Copper-Catalysed Domino Reaction of 2-
Bromobenzylidenemalonates and 1,3-
Dicarbonyls for the Synthesis of Chromenes
Leave this area blank for abstract info.
Yotsakorn Saebang, Vatcharin Rukachaisirikul and Juthanat Kaeobamrung

Tetrahedron
4
Highlights

4H-Chromenes were synthesized from
benzylidenemalonates and 1,3-dicarbonyls.

The reactions proceed under simple reaction
conditions.


Michael addition and Ullmann-type coupling are
two key features in the domino process.
The elimination of stabilized carbanion is
rationalized as the competitive reaction.