Synthesis of (2-Aminophenyl)(naphthalen-2-yl)methanones via Intramolecular Rearrangement of (E)-3-Styrylquinolin-4(1 H)-ones under Irradiation with 365 nm UV Light

Article abstract of DOI:10.1055/s-0037-1610176

A highly efficient and environmentally friendly synthesis of (2-aminophenyl)(naphthalen-2-yl)methanones was developed. The (2-aminophenyl)(naphthalen-2-yl)methanone derivatives were obtained in high yields (up to 96%) by the irradiation of (E)-3-styrylquinolin-4(1 H)-ones in EtOH-H ₂ O (7:1) with UV light (365 nm) at room temperature under Ar atmosphere. The demonstrated photoinduced intramolecular rearrangement has advantages over other transition-metal-catalyzed reactions, e.g. no requirement of additives, green solvent, broad substrate scope, and high atom efficiency.

Full text of DOI:10.1055/s-0037-1610176

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
letter
A
en
S. Jing et al.
Letter
Synlett
Synthesis of (2-Aminophenyl)(naphthalen-2-yl)methanones via
Intramolecular Rearrangement of (E)-3-Styrylquinolin-4(1H)-ones
under Irradiation with 365 nm UV Light
R2
Sisi Jing
R3
N
Yun He
R1
Tao Wang
Jin Zhang
R1
EtOH–H2O = 7:1, Ar
Anqi Cheng
Yong Liang1
Zunting Zhang*
O
NH
O
R3
R2
1
2a–u
yields up to 96%
R1 = H, Br, F, Me R2 = H, Me, OEt, F, Cl R3 = H, Me
21 examples
Key Laboratory of the Ministry of Education for Medicinal Resources and
Natural Pharmaceutical Chemistry, National Engineering Laboratory for
Resource Development of Endangered Crude Drugs in Northwest of
China, School of Chemistry and Chemical Engineering, Shaanxi Normal
University, Xi’an 710119, P. R. of China
zhangzunting@sina.com
Received: 21.04.2018
Accepted after revision: 13.05.2018
Published online: 19.06.2018
aminobenzophenones, it could have potential application
values, such as antitumor, anti-inflammatory, analgesic,
precursors of nitrogen-containing heterocyclic compounds.
A careful review of the literature reports appraised that
all the substrates employed in the synthesis of (2-amino-
phenyl)(naphthalen-2-yl)methanone (E) contain a naph-
thalene moiety.12–16 For instance, the palladium-catalyzed
cross-coupling of naphthalen-2-ylboronic acid or sodium
naphthalene-2-sulfinate (B) with 2-aminobenzonitrile (A)
in the presence of ligands at 80 °C for 36–48 hours gave E in
81% or 91% yield (Scheme 1a).12,13 Alternatively, analogue E
could be also obtained from the reduction of 3-(naphtha-
len-2-yl)benzo[c]isoxazole (C) with hydrogen gas in the
presence of Pd/C (Scheme 1b).14 Interestingly, instead of re-
duction, the synthesis of analogue E was also reported by
the oxidative cleavage of 2-(naphthalen-2-yl)-1H-indole (D)
at 120 °C for 16 hours in the presence of Cs2CO3/O2 along
with the generation of CO2 (Scheme 1c).15 The reported
method successfully eliminates the requirement of transi-
tion metals. However, it has to be performed in the pres-
ence of oxygen at elevated temperature for a long time (120
°C/16 h), which is risky and might destroy certain sensitive
functional groups. A stepwise Friedel–Crafts acylation of N-
(3,5-dimethoxyphenyl)acetamide (G) with 6-bromo-3-me-
thoxy-2-naphthoyl chloride (F) in the presence of SnCl4 at
45 °C for 3.5 hours followed by the acidic hydrolysis in
methanol for additional four hours gave the desired aro-
matic ketone analogues H in good yields (Scheme 1d).16
Photochemical reactions are a significant technology for
green chemistry, which is highly atom efficient in some re-
actions.17,18 The light itself, as a clean energy, does not pro-
duce any chemical by-product and the required energy
could be easily adjusted with various wavelengths.19 Since
we have been focusing on the photoinduced intramolecular
DOI: 10.1055/s-0037-1610176; Art ID: st-2018-w0249-l
Abstract A highly efficient and environmentally friendly synthesis of
(2-aminophenyl)(naphthalen-2-yl)methanones was developed. The (2-
aminophenyl)(naphthalen-2-yl)methanone derivatives were obtained
in high yields (up to 96%) by the irradiation of (E)-3-styrylquinolin-
4(1H)-ones in EtOH–H2O (7:1) with UV light (365 nm) at room tem-
perature under Ar atmosphere. The demonstrated photoinduced intra-
molecular rearrangement has advantages over other transition-metal-
catalyzed reactions, e.g. no requirement of additives, green solvent,
broad substrate scope, and high atom efficiency.
Key words (2-aminophenyl)(naphthalen-2-yl)methanones, (E)-3-sty-
rylquinolin-4(1H)-ones, photo rearrangement reaction, photochemical
reaction, synthesis
2-Aminobenzophenone and its derivatives arouse wide
attention due to their various applications in pharmaceuti-
cal chemistry and heterocyclic synthesis.2–11 Structure-ac-
tivity relationship showed that the amino group introduced
at the ortho-position of the benzophenone ring could inhib-
it the polymerization of tubulin.2 A series of 2-aminobenzo-
phenone derivatives containing nitrogen mustard substitu-
ent were known to possess antitumor activity as well.3
Moreover, the sodium 2-(2-amino-3-benzoylphenyl)acetate
has revealed anti-inflammatory and analgesic activity.4 Last
but not least, the 2-aminobenzophenones were also used as
precursors for further transformations to various nitrogen-
containing heterocyclic compounds, including the deriva-
tives of quinolines,5,6 quinazolines,7–9 dibenzo[b,f][1,5]diaz-
ocines10 and
a
hole-blocking material 1,3,5-tris(4-
phenylquinolin-2-yl)benzene.11 Since the structure of (2-
aminophenyl)(naphthalen-2-yl)methanones is similar to 2-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
S. Jing et al.
Letter
Synlett
CN
R
[Pd], ligand, acid
+
NH2
80 °C, 36–48 h
(a)
B
A
R = B(OH)2, SO2Na
Pd/C, NEt3, H2
N
O
THF, 25 °C, 12 h
(b)
NH2
O
E
C
Cs2CO3, O2/air
N
H
D
DMSO, 120 °C, 16 h
(c)
Br
OMe
O
MeO
OMe
1. SnCl4, DCE, 45 °C, 3.5 h
Cl
+
HN
OMe
2. HClaq, MeOH, reflux 4 h
(d)
Br
OMe
NH2
O
H
OMe
O
G
F
Scheme 1 Alternative routes to (2-aminophenyl)(naphthalen-2-yl)methanones
Table 1 Optimization of the Reaction Conditionsa
dehydrogenation/dehydration for the synthesis of polyhet-
erocyclic componds,20–26 we would like to follow our inter-
est and demonstrate the intramolecular rearrangement of
(E)-3-arylvinyl-4H-chromen-4-ones under UV light (365
nm/Ar) at room temperature for the synthesis of (2-amino-
phenyl)(naphthalen-2-yl)methanones analogues (Scheme
2), which avoids a) high temperature, b) usage of transition
metals and c) directly constructed the naphthalene ring
during rearrangement rather than inherited from substrates.
Recently, the synthesis of benzoaryl-5-yl(2-hydroxy-
phenyl)methanones via the photoinduced rearrangement
of (E)-3-arylvinyl-4H-chromen-4-ones in high yields was
reported.27
H
N
hν, Ar
solvent
O
NH2
O
1a
2a
Entry Solvent (v/v)
λ (nm) Time (h) Conversion (%)b Yield (%)b
1
2
EtOH
405
376
365
365
365
365
365
365
365
365
365
365
365
365
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
7.0
9.0
11.0
88
73
87
96
56
85
92
87
88
85
79
91
91
92
15
EtOH
38
3
EtOH
65 (52)
61 (46)
5
4
MeOH
R3
N
R2
5
CH2Cl2
R1
6
MeCN
17
R1
365 nm hν , Ar
7
acetone
27
EtOH–H2O = 7:1
O
8
EtOH–H2O (9:1)
EtOH–H2O (7:1)
EtOH–H2O (5:1)
EtOH–H2O (7:1)
EtOH–H2O (7:1)
EtOH–H2O (7:1)
EtOH–H2O (7:1)
66 (57)
70 (59)
66 (58)
52
R2
NH
O
R
9
R1 = H, Br, F, Me R2 = H, Me, OEt, F, Cl R3 = H, Me
10
11c
12
13
14
Scheme 2 Synthesis of (2-aminophenyl)(naphthalen-2-yl)methanones
via the photoinduced rearrangement of (E)-3-styrylquinolin-4(1H)-ones
75 (66)
84 (75)
85 (75)
The (E)-3-styrylquinolin-4(1H)-one analogues 1 were
synthesized according to literature reports.28–30 The pho-
toinduced rearrangement of (E)-3-styrylquinolin-4(1H)-
one (1a) under various conditions was screened and the
corresponding results are presented in Table 1. Initially, the
irradiation of 1a in EtOH with a 405-nm lamp (10 W) at
a Reaction conditions: Compound 1a (0.2 mmol, 5 mM) in various solvents
(4 × 10 mL) was irradiated at a certain wavelength (10 W) at r.t. under argon
atmosphere.
b Conversion percentage and yield were determined by 1H NMR with 1,3,5-
trimethoxybenzene as internal standard. Isolated yield is displayed in the
parentheses.
c The concentration of 1a was 1 × 10–2 mol/L.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

C
S. Jing et al.
Letter
Synlett
room temperature under argon atmosphere for five hours
showed a 15% 1H NMR yield of 2a and 88% conversion of 1a
(Table 1, entry 1). It is interesting that the shorter the wave-
length was (with same wattage), the better the yield of 2a
was, obtained yet with similar conversion yields (Table 1,
entries 2 and 3), which might be attributed to the higher
energy of the light source. Replacement of EtOH with
MeOH led to the formation of 2a in a slightly lower yield
(61%, Table 1, entry 4). While, employment of aprotic sol-
vent, e.g. CH2Cl2, MeCN, acetone, yielded 2a in only up to
27% yield (Table 1, entries 5–7). It is important to note that
protic solvent27 and acid31 could significantly improve the
rearrangement efficiency, which is consistent with the ref-
erences.27,31
er yield of 2a was observed with increased concentration of
1a (1 × 10–2 mol/L, 52%, Table 1, entry 11). Finally, the effect
of the irradiation time on the yield of 2a was explored
(Table 1, entries 10 and 12–14). With longer irradiation
time, a better yield of 2a was obtained. Since there was
barely any difference in the yields of 2a for 9 hours and 11
hours of irradiation time, irradiation for 9 hours was chosen
as the optimal reaction time. Thus, irradiation of 1a (5 mM)
in EtOH–H2O (7:1) with the UV light (365 nm, 10 W) at
room temperature for 9 hours under the argon atmosphere
was determined to be the optimal condition, which yielded
2a in 84% yield.
With the optimized reaction conditions in hand, the
scope and generality for the rearrangement of 1 was sub-
sequently examined (Scheme 3).32 It has been found that
the presence of electron-donating group on the C-ring
Interestingly, addition of water could slightly boost the
yield of 2a (66–70%, Table 1, entries 8–10). However, a low-
R3
N
R2
R1
C
R1
B
A
365 nm, hν, Ar
D
A
C
EtOH–H2O = 7:1
O
R2
NH
O
R3
1
2
R1 = H, Br, F, Me R2 = H, OEt, Me, F, Cl R3 = H, Me
OEt
Cl
F
Me
NH2
Br
O
NH2
Br
O
NH2
O
NH2
O
NH2
O
2a, 75%
2b, 83%
2c, 70%
2d, 72%
2e, 77%
OEt
OEt
F
F
Me
Me
NH2
O
NH2
O
NH2
O
NH2
O
NH2
O
2f, 87%
2g, 88%
2h, 92%
2i, 85%
2j, 89%
F
F
OEt
Br
Me
NH
O
NH
O
NH
O
NH2
O
NH
O
Me
Me
OEt
Me
Me
OEt
2k, 75%
2l, 80%
2m, 93%
2n, 85%
2o, 86%
F
Br
F
Me
Me
NH
Me
O
NH
O
NH
O
NH
O
Me
Me
Me
2p, 90%
2q, 96%
2r, 95%
2s, 78%
Scheme 3 Reaction scope of (E)-3-styrylquinolin-4(1H)-ones. Reaction conditions: Irradiation of 1 (0.2 mmol, 5 mM) in EtOH–H2O (4 × 10 mL, 7:1)
with a UV lamp (365 nm, 10 W) at room temperature under the argon atmosphere. The irradiation time of 1a–1k was 9 hours and 1l–1s was 4.5 hours.
Isolated yields.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

D
S. Jing et al.
Letter
Synlett
could give the corresponding rearrangement products 2 in
higher yields compared to those bearing electron-with-
drawing groups (2b vs. 2d, 2e and 2j vs. 2k). Regardless of
the electron-withdrawing/-donating locations, all the rear-
rangement products 2 were obtained in good to high yields
(70–96%). It is important to note that the presence of meth-
yl group (R3 = Me) at the nitrogen atom could dramatically
shorten the irradiation time by half and give the corre-
sponding rearrangement products 2l–2s in higher yields.
To further explore the functional group tolerance, irra-
diation of (E)-3-[2-(naphthalen-1-yl)vinyl]quinolin-4(1H)-
one (1t) and (E)-1-methyl-3-[2-(naphthalen-1-yl)vi-
nyl]quinolin-4(1H)-one (1u) under the optimal condition
gave 2t and 2u in 50% and 54%, respectively (Scheme 4).32
Figure 1 UV absorption spectra of 1a in EtOH–H2O (7:1)
be accelerated/facilitated by the presence of carbonyl
group.27,38 The final rearrangement product 2a was isolated
as the only product due to the restoration of aromaticity via
proton migration as well as the opening of the heterocyclic
quinolin-4(1H)-one ring at the C10–N bond. Additionally,
the structure of 2a could be further stabilized by the forma-
tion of an intramolecular hydrogen bond between the ami-
no group and the carbonyl group, which pushes the forma-
tion of rearrangement product.
R
N
365 nm, hν, Ar
EtOH–H2O = 7:1
O
NH
O
R
1t, R = H
1u, R = Me
2t, 50%
2u, 54%
Scheme 4 Photoinduced rearrangement of 1t and 1u under the opti-
mal condition
In summary, we have developed a highly efficient and
environmentally friendly method for the synthesis of (2-
aminophenyl)(naphthalen-2-yl)methanones by irradiation
of (E)-3-styrylquinolin-4(1H)-ones in EtOH–H2O (7:1) with
365-nm UV lamps at room temperature under Ar atmo-
sphere. Compared with the previous work,12–16 the advan-
tages of the described photoinduced rearrangement are: a)
transition-metal-catalyst-free, b) additives-free, c) uses
ethanol as the solvent, d) tolerates various functional
groups, e) involves the construction of naphthalene ring
during the rearrangement, and f) exhibits high atom effi-
ciency with high yield.
The UV absorption spectra of 1a in ethanol [EtOH–H2O
(7:1)] is shown in Figure 1. The typical π → π* maximum
absorption peaks at 349 nm (ε = 21010 L·mol–1·cm–1) can be
attributed to the existence of the expanding aromatic rings
and the wavelength was basically close to the excitation at
365 nm of the reaction.
Based on the literature reports33–37 and previous work,27
a plausible mechanism for the formation of 2a has been
proposed and is depicted in Scheme 5. Upon the irradiation
of 1a-(E) with UV light (365 nm), the intermediate 1a-(Z) is
formed via photoisomerization, followed by a conrotatory
6π-electron-cyclization to give the intermediate A. A simi-
lar isomerization/cyclization has been well discussed and
reviewed.27,33 The proposed thermal suprafacial [1,9]-H
shift leads to the formation of intermediate B, which might
Funding Information
We are grateful for the financial support from the National Natural
Science Foundation of China and the Fundamental Funds Research for
the Central Universities.
N
oaitn
a
l
Natuarl
Secince
F
o
u
n
d
oaitn
of
C
h
n
i
a
2(
1
5
0
2
1
1
0)
2(
1
6
7
2
1
3
2)
3
4
5
H2
H
H
N
H
H
N
H
N
H
H
365 nm hν
1
conrotatory
10
6
7
6π-electron-cyclization
9
8
O
H
O
O
A
1a-(E)
1a-(Z)
H
N
H
H
[1,9]-H shift
rearomatization
O
O
NH2
B
2a
Scheme 5 Plausible reaction mechanism for the photoinduced rearrangement of 1a
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

E
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Letter
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Supporting Information
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Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610176.
S
u
p
p
ortioInfgrmoaitn
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p
p
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(32) General Procedure for the Synthesis of (2-Aminophe-
nyl)(naphthalen-2-yl)methanones (2a–2u): (E)-3-styrylquin-
olin-4(1H)-ones 1 (0.20 mmol, 5 mM) was dissolved or sus-
pended in EtOH–H2O (7:1, 40 mL) in four quartz tubes (4 × 10
mL). The solution/suspension was bubbled with argon (3 × 2
min) and sealed. The resulting mixture was irradiated with a
UV lamp (365 nm, 10 W) at r.t. for 9.0 h (1a–1k, 1t, 1u) or 4.5 h
(1l–1s). The reaction mixture in four quartz tubes was com-
bined and volatiles were removed under reduced pressure. The
oily residue was column chromatographed (petroleum
ether/EtOAc = 20:1) to give (2-aminophenyl)(naphthalen-2-
yl)methanones 2.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E