Direct synthesis of substituted naphthalenes from 1,3-dicarbonyl compounds and 1,2-bis(halomethyl)benzenes including a novel rearrangement aromatization of benzo[ c ]oxepine

Article abstract of DOI:10.1021/ol302950w

An unexpected rearrangement aromatization of benzo[c]oxepine has been revealed to synthesize substituted naphthalenes. This observation was further exploited to develop an efficient approach for the construction of naphthalenes from simple and commercially available 1,3-dicarbonyl compounds and 1,2-bis(halomethyl)benzene compounds via a new domino reaction sequence.

Full text of DOI:10.1021/ol302950w

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Direct Synthesis of Substituted Naphthalenes
from 1,3-Dicarbonyl Compounds and
1,2-Bis(halomethyl)benzenes Including a
Novel Rearrangement Aromatization of
Benzo[c]oxepine
Jun-gang Wang, Meng Wang, Jia-chen Xiang, Yan-ping Zhu, Wei-jian Xue, and An-xin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education,
College of Chemistry, Central China Normal University, Hubei, Wuhan 430079,
P. R. China
chwuax@mail.ccnu.edu.cn
Received October 26, 2012
ABSTRACT
An unexpected rearrangement aromatization of benzo[c]oxepine has been revealed to synthesize substituted naphthalenes. This observation was
further exploited to develop an efficient approach for the construction of naphthalenes from simple and commercially available 1,3-dicarbonyl
compounds and 1,2-bis(halomethyl)benzene compounds via a new domino reaction sequence.
reactions,3a,4 annulation via Fischer carbenes (the Dotz
reaction),5 cyclization of aromatic enynes or enediynes,6
ring-closing metathesis,7 annulations using alkynes,8 re-
arrangements of strainedrings,9 Lewis acid catalyzed cycli-
zation,10 and many others.11 In this paper, we report an
effective route for the synthesis of substituded naphthalenes
from simple and commercially available 1,3-dicarbonyl
€
Substituted naphthalenes have attracted considerable
attention asimportant basic building blocks for the synthe-
sis of pharmaceuticals1 and polycyclic aromatic electronic
materials.2 Therefore, substantial effort has been devoted
to the development of synthetic methodologies for the
construction of these privileged structural motifs.3 A vari-
ety of methods have been reported, including DielsÀAlder
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r
10.1021/ol302950w
XXXX American Chemical Society

compounds and 1,2-bis(halomethyl)benzene compounds.
In addition, we report a novel rearrangement pro-
cess that transforms benzo[c]oxepines into napthalene
derivatives.
Initially, our investigation focused on the reactivity of
the benzo[c]oxepine skeleton. To our surprise, a naphtha-
lene-based product 3a was obtained when ethyl 6,9-dibro-
mo-3-methyl-1,5-dihydrobenzo[c]oxepine-4-carboxylate
(4a) mixed with 2 equiv of Cs2CO3 in DMSO at 80 °C
(Scheme 1, 3a). Other substituted naphthalenes were also
obtained from corresponding benzo[c]oxepine compounds
(Scheme 1, 3d, 3m, and 3q). The reaction process of 4a was
Scheme 1. Rearrangement of Benzo[c]oxepinea
Scheme 2. Merger of Two Fundamental Reactions
a Reaction conditions: 4 (1.0 mmol), Cs2CO3 (2.0 mmol) in DMSO at
80 °C for 2 h. Isolated yields.
monitored by 1H NMR spectroscopy (Figure 1). The
formation of product 3a was clearly observed after 30
min and the concentration subsequently increased over
time, which was directly related to the consumption of 4a.
This conversion continued for about 2.5 h until starting
material 4a was consumed. We did not observe the forma-
tion of intermediates in this transformation. Moreover, the
structures of product 3a and 3q were determined by X-ray
crystallographic analysis.12 These results established a fas-
cinating rearrangementÀaromatization of benzo[c]oxepine,
which could lead to an efficient approach toward substituted
naphthalenes under mild conditions.
The efficient formation of substituted naphthalenes
prompted us to study the reaction further. Based on the
previously reported synthesis of benzo[c]oxepines under
basic conditions (Scheme 2a)13 and this novel rearrange-
ment aromatization (Scheme 2b) also under basic condi-
tions, we considered whether it would be possible to con-
struct naphthalenes directly via a one-pot domino reaction
that merges these two fundamental reactions (Scheme 2c).
To our delight, the reaction of 1,4-dibromo-2,3-bis-
(bromomethyl)benzene (1a) with ethyl 3-oxobutanoate
(2a) performed smoothly to give the desired product 3a
in the presence of Cs2CO3 (2 equiv) at 20À140 °C in
DMSO (Table1, entries 1À3). Other bases, such as
K3PO4, t-BuOK, KOH, Na2CO3, Et3N, and DBU pro-
vided lower yields (Table 1, entries 6À11). Interestingly,
acids such as CH3COOH and Lewis acid ZnCl2 also pro-
moted the conversion in low yields (Table 1, entries 13À14).
The desired product was also obtained in DMF, EtOH,
and toluene in moderate yields (Table S1, Supporting
Figure 1. Reaction process of 4a (0.1 mmol) in the presence of
Cs2CO3 (0.2 mmol) at 80 °C was monitored by 1H NMR
spectroscopy (600 MHz, DMSO-d6, 298 ( 0.5 K).
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Selby, T. M.; Amberger, B. K.; McMahon, R. J.; Zwier, T. S. J. Am.
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(12) Crystal data of 3a, 3g, 3l, 3q, 4d, 4q, 5q. See SI for details.
(13) (a) Singh, P.; Paul, K. J. Heterocycl. Chem. 2006, 43, 607. (b)
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B
Org. Lett., Vol. XX, No. XX, XXXX

Information (SI)). After the above experimental optimi-
zations, we found that 1a (1 mmol) could react with 2a
(1 mmol) in the presence of Cs2CO3 (2 mmol) in DMSO at
80 °C to afford the desired product in 86% yield after 2 h
(Table 1, entry 2).
Scheme 3. Scope of 1,3-Dicarbonyl Compounds and 1,2-Bis-
(halomethyl)benzene Compoundsa
Table 1. Optimization of the Reaction Conditionsa
molar
ratio
yieldb
(%)
entry
solvent
base
temp/°C
1
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
t-BuOK
KOH
20
80
140
80
80
80
80
80
80
80
80
80
80
80
1:1
1:1
1:1
1:0.5
1:2
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
84
86
86
84
86
68
64
45
26
<5
64
<5
15
25
2
3
4
5
6
7
8
9
Na2CO3
Et3N
10
11
12
13
14
DBU
HCl
CH3COOH
ZnCl2
a Isolated yields.
a Reaction conditions: 1 (1 mmol), 2 (1 mmol), base (2 mmol), solvent
(5 mL). The reaction was performed for 2 h. b Isolated yields.
To gain some insight into the mechanism of the reac-
tion process, the following experiments were perfor-
med (Scheme 4). First, we conducted the reaction of
1-(bromomethyl)-2-ethylbenzene (1q) with ethyl 3-(4-
nitrophenyl)-3-oxopropanoate (2q) withCs2CO3 in DMSO
at rt. The reaction was monitored by TLC and stopped after
20 min to obtain ethyl 3-(4-nitrophenyl)-1,5-dihydrobenzo-
[c]oxepine-4-carboxylate (4q) and ethyl 2-(4-nitrobenzoyl)-
2,3-dihydro-1H-indene-2-carboxylate (5q) (Scheme 4a),
whose structures were confirmed by X-ray diffraction.12
When benzo[c]oxepine 4q was subsequently treated with
Cs2CO3 in DMSO at 80 °C, the aromatic product 3q was
obtained in good yield after 20 min (90%, Scheme 4b).
However, when the byproduct indene 5q was treated under
the same conditions, the aromatic product 3q was not
observed in the experiment (Scheme 4c). Moreover, there
were no indications that the seven-membered ring 4q and the
five-membered ring 5q interconvert under the reaction con-
ditions (Scheme 4d).
Under the optimal conditions, a wide range of 1,3-
dicarbonyl compounds and 1,2-bis(halomethyl)benzene
compounds were investigated. As shown in Scheme 3,
different 1,3-dicarbonyl compounds reacted smoothly with
1a to afford the desired products in moderate to good yields.
For example, derivatives of ethyl benzoylacetate substituted
with electron-withdrawing or -donating groups on the
phenyl ring exhibited good reactivity (Scheme 3, entries
3cÀg, 46%À88%). Ethyl 3-(furan-2-yl)-3-oxopropanoate
also gave a satisfying result (Scheme 3, 3h, 68%). Further-
more, the reactions of methyl 3-oxobutanoate, benzyl 3-oxo-
butanoate, pentane-2,4-dione, and 1,3-diphenylpropane-
1,3-dione also took place smoothly to furnish the desired
products in moderate to good yields (Scheme 3, 3iÀ3l,
56À82%). In addition, cyclohexanedione and substituted
cyclohexanediones also delivered the corresponding aro-
matic products in good yields (Scheme 3, 3mÀp, 72À76%).
The scope of this reaction was further extended to
various 1,2-bis(halomethyl)benzene compounds. For
example, when different benzyl halides, such as 1,2-
bis(chloromethyl)benzene, 1,2-bis(bromomethyl)benzene,
or 1,2-bis(iodomethyl)benzene were used, naphthalene 3q
was isolated in 68%, 78%, and 82% yields, respectively.
When different substituents were attached to the aromatic
rings of the 1,2-bis(halomethyl)benzene starting materials,
the reaction afforded the analogous products in moderate
yields (Scheme 3, 3sÀt, 62À78%).
To further probe the reaction process, we monitored the
1
reaction of 1a and 2a by H NMR spectroscopic studies
(Figure 2). All of the signals were assigned by marked
symbols. As shown in the figure, the consumption of 1a
and 2a occurred during the first 10 min, providing the
intermediate seven-membered ring 4a (Figure 2c and 2d).
Then, the naphthalene-based product 3a began to appear
after about 1 h and the concentration subsequently in-
creased over time (Figure 2eÀ2g). The rearrangement
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Control Experiments
Scheme 5. Proposed Reaction Pathway
On the basis of the results described above and in the
literature,13a,14 a plausible mechanism of this reaction is
described in Scheme 5. Due to the presence of an active
methylene group, the first C-alkylation in 1,3-dicarbonyl
compounds gave intermediate 6, which could exist in two
tautomericforms6aand6b. Theexistenceofmonalkylated
6 in enolic forms caused a competition between C-alkyla-
tion to give the five-membered ring 5 and O-alkylation to
present the seven-membered ring 4.13a The stability of
seven-membered benzo[c]oxepine provided 4 as the major
product. Finally, rearrangement of 4 followed by aroma-
tization in the presence of Cs2CO3 afforded the desired
naphthalene-based product 3.
In summary, we have illustrated an efficient and
novel rearrangement aromatization of benzo[c]oxepine
to construct substituted naphthalenes. This process
was further developed to a route that integrates C-al-
kylation/O-alkylation/rearrangement/aromatization
sequences to directly synthesize substituted naphtha-
lene products from simple and commercially available
1,3-dicarbonyl compounds and 1,2-bis(halomethyl)-
benzenes. A variety of functional groups were toler-
ated under these reaction conditions. Investigations
into the detailed mechanism and synthetic applica-
tions of this reaction are currently underway in our
laboratory.
Acknowledgment. This work was supported by the Na-
tional Natural Science Foundation of China (Grants
21032001, 21272085). We alao thank Dr. Chuanqi Zhou,
Hebei University, for analytical support.
Figure 2. Reaction process of 1a (0.1 mmol) and 2a (0.1 mmol) in
the presence of Cs2CO3 (0.2 mmol) at 80 °C was monitored by
1H NMR spectroscopy (600 MHz, DMSO-d6, 298 ( 0.5 K).
Supporting Information Available. Experimental pro-
cedures and compound characterization data. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
aromatization of the seven-membered ring 4q in the pre-
sence of Cs2CO3 was also monitored by 1H NMR spectro-
scopic studies (Figure S2, SI).
(14) Weinheimer, A. J.; Kantor, S. W.; Hauser, C. R. J. Org. Chem.
1953, 18, 801.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX