Copper-Catalyzed Aza-Diels-Alder Reaction and Halogenation: An Approach to Synthesize 7-Halogenated Chromenoquinolines

Article abstract of DOI:10.1021/acs.orglett.6b01065

A new halogenation method to construct halogen-substituted quinoline moieties is described. The Cu-catalyzed intramolecular aza-Diels-Alder reaction and halogenation reaction proceeded smoothly under mild conditions to produce the corresponding 7-chloro-6H-chromeno[4,3-b]quinolines and 7-chloro-6H-thiochromeno[4,3-b]quinolines in satisfactory yields.

Full text of DOI:10.1021/acs.orglett.6b01065

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Aza-Diels−Alder Reaction and Halogenation: An
Approach To Synthesize 7‑Halogenated Chromenoquinolines
Xiaoqiang Yu,*,† Jiao Wang,† Zhanwei Xu,† Yoshinori Yamamoto,†,‡ and Ming Bao*,†
†State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116023, China
‡WPI-AIMR (WPI-Advanced Institute for Materials Research), Tohoku University, Sendai 980-8577, Japan
S
* Supporting Information
ABSTRACT: A new halogenation method to construct
halogen-substituted quinoline moieties is described. The Cu-
catalyzed intramolecular aza-Diels−Alder reaction and halo-
genation reaction proceeded smoothly under mild conditions
to produce the corresponding 7-chloro-6H-chromeno[4,3-
b]quinolines and 7-chloro-6H-thiochromeno[4,3-b]quinolines
in satisfactory yields.
Scheme 1. Synthesis of 7-Halogenated Chromenoquinolines
hromenoquinoline structural motifs are frequently found
1
Cin biologically active compounds.
As pharmaceuticals,
substituted chromenoquinolines exhibit remarkable properties,
such as anti-inflammatory activities and serotonin and estrogen
receptor functions.2 7-Chloro-6H-chromenoquinolines and 7-
bromo-6H-chromenoquinolines have attracted considerable
attention because of their transcriptional activity in the
human progesterone receptor, which plays an important role
in medicine.2c Moreover, 7-chloro-6H-chromenoquinolines and
7-bromo-6H-chromenoquinolines are utilized as intermediates
to synthesize various substituted chromenoquinolines through
transition-metal-catalyzed cross-coupling reactions. Although
chromenoquinolines can be easily synthesized through aza-
Diels−Alder reaction,3−8 the synthesis of 7-halogenated
chromenoquinolines, such as 7-chloro-6H-chromeno[4,3-b]-
quinoline and 7-bromo-6H-chromeno[4,3-b]quinoline, is diffi-
cult. In 2007, Vu et al.2c synthesized 7-chloro-6H-chromeno-
[4,3-b]quinolines and 7-bromo-6H-chromeno[4,3-b]quinolines
for the first time (Scheme 1). However, this process presents
some limitations such as multiple steps (five steps), harsh
reaction conditions (>200 °C), and low yields (12% total
yield). Therefore, the development of a convenient and
efficient method for the synthesis of 7-halogenated chromeno-
quinolines is an important requirement.
catalyst (entry 1). No reaction was also observed when ZnCl2
and FeCl2 were used as catalysts (entries 2 and 3). Several
copper salts including CuCl, CuI, CuOTf, CuOAc, and Cu2O
were then tested as catalysts (entries 4−8). As expected, the
desired product 7-chloro-6H-chromeno[4,3-b]quinoline (2a)
was obtained as a major product along with the byproduct 6H-
chromeno[4,3-b]quinoline (3a). Among the copper salts tested,
Cu2O proved to be the best catalyst; the chlorinated product 2a
was obtained with relatively high yield (entry 8 vs entries 4−7).
To improve the yield of product 2a, we examined 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ) and N-chlorosuccini-
mide (NCS) as chlorine sources instead of chloranil. Although
the target reaction occurred in the presence of DDQ or NCS,
Conducting research on new strategies of Cu-catalyzed
nitrogen-containing heterocycle synthesis and chlorination
reaction,9,10 we found that 7-chloro-6H-chromeno[4,3-b]-
quinolines and 7-bromo-6H-chromeno[4,3-b]quinolines can
be directly obtained through Cu-catalyzed cascade reactions
(aza-Diels−Alder reaction of Schiff base, followed by
chlorination or bromination using chloranil and bromanil as
halogen sources; Scheme 1).
In our initial studies, the cascade reaction of Schiff base
substrate 1a was selected as a model reaction to optimize the
reaction conditions. The results are summarized in Table 1. No
reaction was observed when 1a was treated with chloranil in
1,2-dimethoxyethane (DME) at 80 °C in the absence of a
Received: April 14, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01065
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Letter
a
Table 1. Optimization of the Reaction Conditions
Table 2. Synthesis of 7-Chloro-6H-chromeno[4,3-
b]quinolines via Cu-Catalyzed Cascade Reaction
a
b,c
yield (%)
entry
cat.
Cl source
additive
solvent
2a
3a
1
none
chloranil
chloranil
chloranil
chloranil
chloranil
chloranil
chloranil
chloranil
DDQ
none
none
none
none
none
none
none
none
none
none
CaCl2
Na2SO4
KCl
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
dioxane
toluene
DMF
IPA
0
0
0
0
2
ZnCl2
FeCl2
CuCl
CuI
3
0
0
4
33
38
32
28
43
27
33
59
54
54
63
48
37
0
16
18
17
14
17
5
5
6
CuOTf
CuOAc
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
7
8
9
10
11
12
13
14
15
16
17
18
NCS
18
23
21
22
21
29
29
0
chloranil
chloranil
chloranil
chloranil
chloranil
chloranil
chloranil
chloranil
NaCl
NaCl
NaCl
NaCl
NaCl
22
51
a
Reaction conditions: N-(2-(prop-2-yn-1-yloxy)benzylidene) aniline
(3a, 0.2 mmol, 47 mg), chlorine source (2.0 equiv), and additive (1.5
b
c
equiv) in 2.0 mL of solvent at 80 °C for 8 h. Isolated yield. Entries
containing zeroes indicate no reaction.
the yield of product 2a remained low (entries 9 and 10). The
yield of 2a was remarkably increased when the inorganic salts
CaCl2, Na2SO4, KCl, and NaCl were individually added to the
model reaction (59%−63%, entries 11−14). It was considered
that NaCl might activate the aromatic ring by the cation−π
interaction.11
The solvent was finally screened using NaCl as an additive
(entries 14−18). Among DME, dioxane, toluene, N,N-
dimethylformamide (DMF), and isopropyl alcohol (IPA),
DME was identified as the best solvent. Therefore, the
subsequent cascade reactions of Schiff base substrates 1 were
performed using Cu2O, chloranil, and NaCl as catalyst, chlorine
source, and additive, respectively, in DME at 80 °C.
The reactions of the Schiff base substrates 1a−i were allowed
to proceed under optimized conditions; the results are
summarized in Table 2. The 7-chloro-6H-chromeno[4,3-
b]quinolines 2a−c, along with the byproducts 6H-chromeno-
[4,3-b]quinolines 3a−c with approximately 20% yields, were
obtained as major products in moderate yields (entries 1−3,
54−65%). The desired chlorination product 2d was isolated as
the sole product from the reaction of substrate 1d (entry 4,
62%). The reaction of substrate 1e containing a strong
electron-withdrawing group (CF3) on the benzene ring
produced the desired product 2e in low yield (entry 5). The
Cl and Br atoms linked to the benzene ring were notably
maintained in the structures of products 2f−h under the
specified reaction conditions. This observation suggests that
further manipulation may produce more useful compounds. To
further explore the reaction scope, we examined the fused
aromatic ring-containing substrate 1i under the optimized
a
Reaction conditions: Schiff bases 1a−i (0.2 mmol), Cu2O (10 mol %,
3.0 mg), chloranil (2.0 equiv, 98 mg), and NaCl (1.5 equiv, 18 mg) in
DME (2.0 mL) under a nitrogen atmosphere at 80 °C for 8 h.
b
Isolated yield.
reaction conditions. The desired product 2i was obtained in
42% yield (entry 9).
On the basis of our good preliminary results, we used the
present method to synthesize 7-chloro-6H-thiochromeno[4,3-
b]quinolines under the same reaction conditions. The results
are summarized in Table 3. The reactions of Schiff base
substrates 4a−e proceeded smoothly to produce 5a−e in
satisfactory yields (entries 1−5, 51%−57%). By contrast,
relatively low yields were observed in the reactions of 4f−i
containing an electron-withdrawing group on the benzene rings
(CF3, Cl, I, or Br). The desired chlorination products 5g−i
were separated in 39−53% yields (entries 6−9). Likewise, the
B
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products 7-bromo-6H-chromeno[4,3-b]quinoline (2j) and 7-
bromo-6H-thiochromeno[4,3-b]quinoline (5k) were obtained
in 56% and 45% yields, respectively (Scheme 2).
Table 3. Synthesis of 7-Chloro-6H-thiochromeno[4,3-
b]quinolines via Cu-Catalyzed Cascade Reaction
a
Scheme 2. Synthesis of 7-Bromo-6H-chromeno[4,3-
b]quinoline and 7-Bromo-6H-thiochromeno[4,3-
b]quinoline
Control experiments were conducted to gain insights into the
mechanism of this type of cascade reaction. No reaction was
observed when chloroacetylene 7 was treated in the absence of
chloranil (Scheme 3, eq 1). This result reveals that the
Scheme 3. Control Experiments
chlorinated product 2a was not formed via a chloroacetylene
intermediate. No reaction was also observed when the
byproduct 3a was treated under the optimized reaction
conditions (Scheme 3, eq 2). This phenomenon indicates
that the chlorinated product 2a was not formed through the
chlorination reaction of the byproduct 3a. The reaction of 1a
was conducted by adding 2.0 equiv of 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) under the optimized reaction
conditions (Scheme 3, eq 3). The target reaction was
completely inhibited; this result suggests that the target
reaction may involve radical intermediates.12
A plausible reaction mechanism is depicted in Scheme 4 on
the basis of the mechanistic studies described above. The Schiff
base substrate 1a reacts with a Cu(I) species in the presence of
chloranil to produce Cu(II) acetylide A,13 which subsequently
undergoes intramolecular aza-Diels−Alder reaction to form
intermediate B. The Cl radical derived from chloranil14 reacts
with intermediate B to generate intermediate C. Intermediate C
undergoes reductive elimination reaction to form a chlorinated
intermediate D and regenerate Cu(I) species.15 The dehydro-
genation of intermediate D with chloranil occurs to produce the
desired product 2a. Byproduct 3a is generated through the
hydrolysis reaction of intermediate B with 2,3,5,6-tetrachlor-
obenzene-1,4-diol, followed by dehydrogenation reaction.
2,3,5,6-Tetrachlorobenzene-1,4-diol is generated in the dehy-
drogenation reaction step. Therefore, the side reaction can not
be completely avoided.
a
Reaction conditions: Schiff base substrates 4a−j (0.2 mmol), Cu2O
(10 mol %, 3.0 mg), chloranil (2.0 equiv, 98 mg), and NaCl (1.5 equiv,
18 mg) in DME (2.0 mL) under a nitrogen atmosphere at 80 °C for 8
h. Isolated yield.
b
fused aromatic ring-containing substrate formed the desired
product in low yield (entry 10, 21%).
The Cu-catalyzed cascade reactions of the Schiff base
substrates 1a and 4a with bromanil were also evaluated under
the same reaction conditions. As expected, the bromination
In summary, a new method was developed to synthesize 7-
halogenated chromenoquinolines and 7-halogenated thiochro-
menoquinolines. The Cu-catalyzed cascade reaction, namely,
C
DOI: 10.1021/acs.orglett.6b01065
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Scheme 4. Proposed Mechanism
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aza-Diels−Alder reaction and halogenation (chlorination or
bromination), proceeded smoothly in the presence of chloranil
or bromanil to give the desired halogenated products in
moderate yields. Cu2O functioned as a Lewis acid catalyst and
transition-metal catalyst in the aza-Diels−Alder reaction and
halogenation reaction, respectively. Chloranil and bromanil also
performed dual functions, that is, as a halogen source and
oxidant. Although the halogenated products were obtained in
moderate yields, the present method is highly useful in organic
synthesis because of mild reaction conditions and experimental
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01065.
Experimental procedures, characterization, and NMR
spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: yuxiaoqiang@dlut.edu.cn.
*E-mail: mingbao@dlut.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Nos. 21273026 and 21572028) for their financial
support. This work was also supported by the Fundamental
Research Funds for the Central Universities (DUT15LK37)
and the Outstanding Young Scholars Development Growth
Plan of universities in Liaoning Province (LJQ2015027).
REFERENCES
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DOI: 10.1021/acs.orglett.6b01065
Org. Lett. XXXX, XXX, XXX−XXX