Silver-catalyzed radical tandem cyclization for the synthesis of 3,4-disubstituted dihydroquinolin-2(1 H)-ones

Article abstract of DOI:10.1021/ol403196h

A silver-catalyzed tandem decarboxylative radical addition/cyclization of N-arylcinnamamides with aliphatic carboxylic acids is reported. This method affords a novel and straightforward route to various 3,4-disubstituted dihydroquinolin-2(1H)-ones in aque

Full text of DOI:10.1021/ol403196h

Letter
pubs.acs.org/OrgLett
Silver-Catalyzed Radical Tandem Cyclization for the Synthesis of 3,4-
Disubstituted Dihydroquinolin-2(1H)‑ones
Wen-Peng Mai,* Ji-Tao Wang, Liang-Ru Yang, Jin-Wei Yuan, Yong-Mei Xiao,* Pu Mao, and Ling-Bo Qu
Chemistry and Chemical Engineering School, Henan University of Technology, Zhengzhou, Henan 450001, P. R. China
S
* Supporting Information
ABSTRACT: A silver-catalyzed tandem decarboxylative radical addition/cyclization of N-arylcinnamamides with aliphatic
carboxylic acids is reported. This method affords a novel and straightforward route to various 3,4-disubstituted dihydroquinolin-
2(1H)-ones in aqueous solution.
any substituted 3,4-dihydroquinolin-2(1H)-ones have
attracted considerable attention in view of their
in aqueous solution which provides a novel and simple protocol
for valuable 3,4-disubstituted dihydroquinolin-2(1H)-ones
(Scheme 1).
M
cardiovascular, anti-inflammatory, and phosphodiesterase in-
hibitory activities.1 Moreover, 3,4-dihydroquinolin-2(1H)-ones
are a versatile structural unit for the preparation of other
important pharmaceuticals and natural products such as 1,2,3,4-
tetrahydroquinolines and quinolin-2(1H)-ones.2 Thus, the
development of a straightforward and highly efficient method
for the construction of 3,4-dihydroquinolin-2(1H)-one is highly
desirable. A general method for the preparation of a 3,4-
dihydroquinolin-2(1H)-one system is the Friedel−Crafts
cyclization requiring superacidity or stoichiometric amounts
of metals.3 Recently, several alternative methods such as Pd-
catalyzed sequential Heck reduction−cyclization reactions, Pd-
catalyzed cyclopropane ring expansions, Rh-mediated 1,4-
additions of the boronic acid to enone, sequential Ugi/
acrylanilide [6π]-photocyclizations, intermolecular tandem
reactions, Mn-mediated intramolecular cyclizations, and Pd-
catalyzed cyclocarbonylations reactions have been developed.4
However, for 3,4-disubstituted dihydroquinolin-2(1H)-one,
these processes still suffer from such drawbacks as the need
for complicated starting materials4g or multistep synthesis.4a,b,d,f
So far, radical reactions have widespread applications in organic
synthesis, especially in cyclization reactions for the prepration
of valuable heterocycles.5 Recently, the synthesis of substituted
oxindoles6 and construction of multiple C−C/N bonds
through radical cyclization to access 3,3-disubstituted oxindoles
have attracted special attention.7 These methods demonstrated
that this kind of radical cyclization is a very powerful tool to
construct oxindole’s framework. Recent significant progress in
radical cyclization inspired us to extend this highly efficient
method to another prominent structural motif, 3,4-dihydroqui-
nolin-2(1H)-one, because a general and tandem approach for
the construction of its six-membered ring remains rare,4f,g in
contrast to oxindole’s synthesis. Herein we disclose the silver-
catalyzed tandem decarboxylation and C−H functionalization
Scheme 1. Ring Closure for 3,4-Dihydroquinolin-2(1H)-one
We started our model reaction by investigating N-methyl-N-
phenylcinnamamide 1a and pivalic acid 2a for the optimization
of reaction conditions (Table 1). With 20 mol % AgNO3 as the
catalyst, the reaction of 1a with pivalic acid (2.0 equiv) in
aqueous solution (CH3CN/H2O) failed to provide the desired
product at room temperature (Table 1, entry 1). To our
delight, a 37% product yield was obtained when the
temperature was increased to 70 °C (Table 1, entry 2). The
expected product was obtained in 69% yield when the
temperature was further improved to 100 °C with a 20%
catalyst loading (Table 1, entry 4). The product yield decreased
when the catalyst loading was reduced (Table 1, entries 5−7).
However, no more conversion of 1a to 3a was observed with 30
mol % AgNO3 as the catalyst at 110 °C (Table 1, entry 8).
Other Ag(I) salts such as AgBF4, Ag2O, and Ag2CO3 showed
similar catalytic activity under the same conditions (Table 1,
entries 9−11). Investigation of other oxidants such as
(NH4)2S2O8, TBHP, oxone, DTBP, and O2 for this trans-
formation showed that K2S2O8 was the best choice (Table 1,
entries 12−16). The transformation did not proceed in such
aqueous solutions as DCE/H2O, CH2Cl2/H2O, EtOH/H2O,
Received: November 5, 2013
Published: December 11, 2013
© 2013 American Chemical Society
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dx.doi.org/10.1021/ol403196h | Org. Lett. 2014, 16, 204−207

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Letter
a
a b
,
Table 1. Screening of Reaction Conditions
Table 2. Tandem Radical Addition/Cyclization of 1 and 2
b
entry
catalyst (mol %)
oxidant
K2S2O8
t (°C)
yield
N.R.
1
AgNO3 (20)
AgNO3 (20)
AgNO3 (20)
AgNO3 (20)
AgNO3 (5)
AgNO3 (10)
AgNO3 (15)
AgNO3 (30)
AgBF4 (20)
Ag2O (20)
Ag2CO3 (20)
AgNO3 (20)
AgNO3 (20)
AgNO3 (20)
AgNO3 (20)
AgNO3 (20)
AgNO3 (20)
−
rt (18)
70
2
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
(NH4)2S2O8
oxone
37
65
3
90
c
4
100
100
100
100
110
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
69 (35 )
22
5
6
29
7
47
8
66
9
57
10
11
12
13
14
15
16
48
60
c
55 (42 )
N.R.
N.R.
N.R.
N.R.
N.R.
N.R.
TBHP
DTBP
O2
d
17
−
e
18
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
f
h
19
g
AgNO3 (20)
AgNO3 (20)
AgNO3 (20)
Cu (20)
N.R. (N.R )
i
20
trace (N.R )
j
21
trace
N.R.
N.R.
N.R.
N.R.
N.R.
22
23
24
25
26
CuCl (20)
Cu(OAc)2 (20)
FeSO4 (20)
FeCl3 (20)
a
Reaction conditions: 1a (1.0 mmol), 2a (2.0 mmol), CH3CN/H2O
b
c
(3/3 mL), under air atmosphere, 12 h, 100 °C. Isolated yield. DMF/
H2O as solvent. Without catalyst. Without oxidant. CH2Cl2/H2O as
solvent. DCE/H2O as solvent. Dioxane/H2O as solvent. EtOH/
H2O as solvent. Acetone/H2O as solvent. N.R. = No Reaction.
d
e
f
h
g
i
j
a
Reaction conditions: 1 (1.0 mmol), 2 (2.0 mmol), AgNO3 (20 mol
%), K2S2O8 (2.0 mmol), CH3CN/H2O (3/3 mL), 100 °C, 12 h.
dioxane/H2O, and acetone/H2O (Table 1, entries 19−21). We
further explored other metals, such as copper powder, CuCl,
Cu(OAc)2, FeSO4, and FeCl3, as catalysts, but no reaction
proceeded (Table 1, entries 22−26).
b
c
Isolated yield. Crystal structure in Supporting Information.
With the optimized conditions in hand, we then set out to
explore the scope and limitations of the 6-endo radical
cyclization, and the results are summarized in Table 2. In
general, electron-donating or -withdrawing groups on aniline at
the ortho, meta, and para positions did not affect the efficiency
of the reaction, affording the desired products in moderate
yields (Table 2, 3i−m). Substituents such as Cl, Br, Me, and
OMe at the ortho, meta, and para positions on the other
aromatic ring of the substrate 1 were well tolerated in the
process of ring closure under the optimal conditions and the
corresponding products were obtained in moderate yields
(Table 2, 3b−f). The reaction still proceeded well when
different N-protected groups (e.g., Me, Et, Bz, and
CH3CH2CN) of substrate 1 were used (Table 2, 3m, 3n−o,
3v, and 3x). After investigating R1, R2, and R3 of substrate 1,
aliphatic carboxylic acids were further tested under the optimal
conditions. Various primary, secondary, and tertiary aliphatic
carboxylic acids underwent efficient intermolecular ring closure
to provide the expected products 3a−z and 3aa−3ab in
moderate to good yields. With this method, methyl or ethyl
could be introduced into the 3-position of 3,4-dihydroquinolin-
2(1H)-one in one step only using cheap AcOH or propionic
acid instead of MeLi or EtLi as substrates (Table 2, 3g−h and
3v−x).8 Primary carboxylic acids containing aromatic ringlike
3-phenylpropanoic acid and 2-(4-chlorophenyl)-acetic acid
showed different reactivity; products 3p and 3aa were obtained
in 83% and 30% yields respectively. In addition, primary
carboxylic acids containing heteroatoms (O, N) at adjacent
positions of the carboxyl group also displayed high reactivity in
this transformation (Table 2, 3n−o and 3ab). As for secondary
alkyl acids, 4-ethylcyclohexanecarboxylic acid worked well in
the same fashion and gave the corresponding product in 71%
yield (Table 2, 3u). Moreover, cyclopropanecarboxylic acid and
cyclobutanecarboxylic acid were also successfully converted to
the desired products without ring opening (Table 2, 3c−f and
3s). Interestingly, product 3y was isolated in 72% yield as a 1:1
ratio of cis/trans isomers when 2-ethylhexanoic acid was
explored as the substrate (Table 2, 3y and 3y′). However, in
comparison with pivalic acid, 1-adamantanecarboxylic acid
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Organic Letters
Letter
which is more congested gave a low yield under the same
conditions (Table 2, 3t).
A postulated mechanism is described in Scheme 2. Initially,
Ag+ is oxidized by the persulfate anion (S2O82−) to generate the
The structure of product 3b was clearly confirmed by single-
crystal X-ray crystallographic analysis (Figure 1). Obviously,
product 3b is a trans-form which contains a six-membered ring.
Scheme 2. Postulated Mechanism for the Radical Tandem
Cyclization
Figure 1. Molecular structure of 3b.
Ag2+ cation and sulfate radical anion. Then, the Ag2+ cation
obtains a single electron from carboxylate to produce the
carboxyl radical.11 Quick decarboxylation of the carboxyl radical
provides the corresponding alkyl radical A, followed by addition
to the double bond of cinnamamide 1a, thus leading to
intermediate B. Intramolecular cyclization of B gives the
intermediate C. Finally, intermediate C can be aromatized to
the desired product D after hydrogen abstraction by the sulfate
radical anion.
In summary, we have developed an unprecedented and
highly efficient method for the preparation of biologically
interesting 3,4-disubstituted dihydroquinolin-2(1H)-one deriv-
atives by silver-catalyzed tandem decarboxylative radical
addition/cyclization of N-arylcinnamamides with aliphatic
carboxylic acids in aqueous solution. A significant feature of
the novel protocol is the formation of a six-membered ring;
meanwhile, it could be alkylated or trifluoromethylated. This
approach represents one of the most straightforward routes to
various functional 3,4-dihydroquinolin-2(1H)-one syntheses.
Encouraged by this finding, we continued to explore the
trans-selective 6-endo radical cyclization leading to 3,4-
disubstituted dihydroquinolin-2(1H)-one derivatives. Trifluor-
omethylated heteroaryl compounds represent an important
structural motif in pharmaceuticals and advanced organic
materials.9 Thus, two alkyl acids containing the CF3 group
were subjected to the reaction. Unfortunately, both TFA and
3,3,3-trifluoropropanoic acid failed to provide any of the
desired products. The reason for this is still not clear at present.
However to our delight, when CF3SO2Na (Langlois reagent)
was employed as the source of the CF3 radical,10 the reaction
took place under the slightly modified conditions, in which the
CF3 group was introduced into the 3-position of 3,4-
dihydroquinolin-2(1H)-one successfully (Table 3). An inves-
tigation into different substituents (R1−3) of substrate 1 showed
that the transformation still proceeded well, affording the
desired trifluoromethylated products 4a−4e without much
difference in yields. Products 4e and 4e′ were isolated as two
stereoisomers in a 4:3 ratio under the same reaction conditions.
ASSOCIATED CONTENT
* Supporting Information
■
S
a
Table 3. Study of Trifluoromethylation in the Cyclization
Experimental procedures, characterization of products, and
copies of 1H and 13C NMR spectra are provided. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: maiwp@yahoo.com.
*E-mail: xymxbr@aliyun.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge NSFC (Nos. 21302042 and
21172055).
■
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