Synthesis of 3-substituted quinolin-2(1H)-ones via the cyclization of o-alkynylisocyanobenzenes

Article abstract of DOI:10.1039/c8ob01882k

A facile synthesis of various functionalized 3-substituted quinolin-2(1H)-ones through Ag(i) nitrate-catalyzed cyclization of o-alkynylisocyanobenzenes is described. The reaction allows rapid and convenient access to 3-substituted quinolin-2(1H)-one scaffolds in moderate to good yields.

Full text of DOI:10.1039/c8ob01882k

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Synthesis of 3-substituted quinolin-2(1H)‑ones via cyclization of o-
alkynylisocyanobenzenes
Received 00th January 20xx,
Accepted 00th January 20xx
Ailada Charoenpol, Jatuporn Meesin, Onnicha Khaikate, Vichai Reutrakul, Manat Pohmakotr,
Pawaret Leowanawat, Darunee Soorukram and Chutima Kuhakarn*
DOI: 10.1039/x0xx00000x
A facile synthesis of various functionalized 3-substituted quinolin-2(1H)‑ones through Ag(I) nitrate catalyzed cyclization of
o-alkynylisocyanobenzenes is described. The reaction allows rapid and convenient access to 3-substituted quinolin-
www.rsc.org/
2(1H)‑ones
scaffolds
in
moderate
to
good
yields.
Introduction
Isocyanobenzenes or arylisonitriles are one of the important
Quinolin-2(1H)‑ones have proven to be an important class of
attractive scaffold being found in biologically active natural
products and pharmaceutically important compounds as well as
valuable intermediates in organic synthesis.1-2 In particular,
quinolin-2(1H)‑one core is present in anti-tumor agents,3
endothelin receptor antagoists,4 angiotensin II receptor
antagonists,5 antiplatelet agents,6 and antibiotics.7 Highlights on
biologically active compounds bearing quinolin-2(1H)‑one core are
shown in Fig. 1. In addition, quinolin-2(1H)‑ones were found being
used as versatile synthetic intermediates in organic synthesis.8
Consequently, the synthetic routes to access quinolin-2(1H)‑one
derivatives have drawn enormous attention and a number of
approaches were addressed.9
synthetic synthons for the synthesis of nitrogen-containing
heterocyclic compounds via anionic cyclization in the presence of
nucleophiles, Lewis acid mediated cyclization reactions and radical
mediated cyclization reactions.10 In recent years, there have been
numerous studies on cascade cyclization reaction on to o-
arylisocyanobenzenes, leading to the rapid assembly of
functionalized phenanthridines.11-12 On the other hands, fewer
reports were addressed on ring formation with o-
alkynylisocyanobenzenes.13
Results and discussion
In continuation of our interest in the synthesis of functionalized
nitrogen-containing heterocycles,14 we report herein the synthesis
of 3-substituted quinolin-2(1H)‑ones through cyclization of o-
alkynylisocyanobenzenes catalyzed by AgNO3. We began our study
by screening the optimized reaction conditions employing o-
(phenylethynyl)isocyanobenzene (2a) as a model substrate (Table
1). The unstable o-(phenylethynyl)isocyanobenzene (2a) was readily
prepared
from
its
corresponding
N-(2-
(phenylethynyl)phenyl)formamide (1a) by following the previously
reported procedure with slight modification in the aqueous work-
up step.13 Thus, after aqueous work-up (washed with saturated
NaHCO3 solution and evaporated to dryness), the crude mixture of
2a was diluted with EtOAc and the solution was passed through a
short path alumina (type E) column eluted with EtOAc. After
removal of the solvent, the crude compound 2a (1H NMR analysis)
was used for screening of the reaction conditions for its conversion
to the corresponding 3-phenylquinolin-2(1H)-one (3a). It is worth to
mention here that significant amount of 2-chloro-3-phenylquinoline
was observed and lower yields of 3-substituted quinolin-2(1H)‑ones
were obtained if the crude mixture of 2a was not filtered through
an alumina column prior to the reaction. Initially, upon treatment of
Fig. 1. Examples of biologically active compounds bearing quinolin-
2(1H)‑one core.
Department of Chemistry and Center of Excellence for Innovation in Chemistry
(PERCH-CIC), Faculty of Science, Mahidol University, Rama 6 Road, Bangkok
10400, Thailand. Email: chutima.kon@mahidol.ac.th
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
o
2a with AgNO3 (5 mol%) using water as the solvent at 80 C for 2 h,
the desired product 3a was isolated in 15% yield after
chromatographic purification (Table 1, entry 1). Next, a few solvents
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(THF, CH3CN, ClCH2CH2Cl and DMF) were screened (Table 1, entries Table 1. Optimization of reaction conditionsa
2‒5). Delightfully, when the reaction was performed in DMF, 3a was
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DOI: 10.1039/C8OB01882K
obtained in the moderate yield (53% yield). Efforts to use water as a
co-solvent was next evaluated. While the use of DMF:H2O (2:1 v/v)
deteriorated the reaction efficiency, the yield of 3a was increased
to 80% yield when the reaction of 2a was carried out in DMF:H2O
(2:0.1 v/v) (Table 1, entries 6‒7). Attempts to optimize the yield of
Entry Additive
(5 mol%)
Solvent (mL)
Temp Time Yield
3a by extending the reaction time or performing the reaction at
higher temperature did not give satisfactory results (Table 1, entries
8‒9). Other Ag(I) salts, including Ag2CO3, AgF, AgOAc, Ag2O and
AgClO4, were also evaluated; all of those gave comparable results to
those obtained from AgNO3 (Table 1, entries 8‒14). The use of
other metal salts, i.e. CuCl2, Cu(OAc)2, CuBr , ZnCl2, FeCl3 as well as
Brønsted acids (pTolSO3H) in place of Ag(I) gave inferior results
(Table 1, entries 15‒20). In the absence of AgNO3, although the
reaction readily proceeded, the results obtained were less
satisfactory (Table 1, entry 21). Attempts to perform the reaction
under forcing conditions either by extended the reaction time (from
(oC)
80
80
80
80
80
80
(h)
2
2
2
2
2
2
2
6
2
2
2
2
2
2
2
2
2
2
2
2
2
4
2
2
(%)b
15
-
1
2
3
4
5
6
7
8
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
Ag2CO3
AgF
AgOAc
Ag2O
AgClO4
CuCl2
Cu(OAc)2
CuBr
H2O (2)
THF (2)
CH3CN (2)
ClCH2CH2Cl (2)
DMF (2)
Trace
17
53
35
80
79
78
78
79
77
73
80
54
67
31
59
28
38
54
62
42
33
DMF:H2O (2:1)
DMF:H2O (2:0.1) 80
DMF:H2O (2:0.1) 80
DMF:H2O (2:0.1) 100
DMF:H2O (2:0.1) 80
DMF:H2O (2:0.1) 80
DMF:H2O (2:0.1) 80
DMF:H2O (2:0.1) 80
DMF:H2O (2:0.1) 80
DMF:H2O (2:0.1) 80
DMF:H2O (2:0.1) 80
DMF:H2O (2:0.1) 80
DMF:H2O (2:0.1) 80
DMF:H2O (2:0.1) 80
DMF:H2O (2:0.1) 80
DMF:H2O (2:0.1) 80
DMF:H2O (2:0.1) 80
DMF:H2O (2:0.1) 100
DMF:H2O (2:0.1) 120
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
o
2 h to 4 h) or at elevated reaction temperature (from 80 C to 100
o
oC and 120 C) resulted in poorer yields of 3a (Table 1, entries 22‒
24). After extensive experimentation, AgNO3 was chosen to be used
in the present work due to reduced cost of AgNO3. Thus, the
optimum reactions were to use AgNO3 (5 mol%) in DMF:H2O (2:0.1
v/v) at 80 oC for 2 h (Table 1, entry 7).
ZnCl2
FeCl3
pTsOH
-
-
-
-
a Reaction conditions: Step A: A mixture of 1a (0.5 mmol), iPr2NEt
(8 equiv.) in CH2Cl2 (4 mL) was added dropwise POCl3 (1.5 equiv)
under Ar balloon at 0 oC; after conventional aqueous work-up,
the crude mixture of 2a was diluted with EtOAc and the solution
was passed through a short path alumina (type E) column eluted
with EtOAc; Step B: A crude mixture of 2a from Step A, and
metal salts, were stirred in solvent under indicated reaction
b
conditions. Isolated yields after chromatographic purification
(SiO2, column chromatography).
With the optimized reaction conditions in hands (Table 1, entry
7), the exploration of substrate scopes and limitations of the
formation of 3-substituted quinolin-2(1H)-ones 3 via cyclization of
o-alkynylisocyanobenzenes 2 were studied and the results are
summarized in Scheme 1. First, substrates 2 with variation on
substituents R1 were evaluated. It was found that the reactions
proceeded smoothly to yield the corresponding products 3b−h in
the range of 46–72% yields. Electronically different substituents (R2)
on the arylethynyl moiety (including p-CH3, p-OCH3, p-Br, p-Cl, p-F,
p-NO2, m-CH3, m-Br, m-Cl, m-F) were well tolerated and gave the
corresponding products 3i−r in moderate to good yields (32–84%
yields). Next, sterically hindrance position of the substituents was
also highlighted. Although 3s and 3t were obtained in good yields,
3u, and 3-(naphthalen-2-yl)quinolin-2(1H)-one (3v) were isolated in
only moderate yields. The reaction can accommodate substrate
bearing 2-thienyl substituent to yield 3w in 75% yield. It is worth
2 | J. Name., 2012, 00, 1-3
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noting that aliphatic alkynyl substrates were good substrates and
afforded the corresponding products 3x‒z and 3a' in moderate
yields (54–73% yields).
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DOI: 10.1039/C8OB01882K
Scheme 2 The reaction of 2a in DMF:D2O.
To expand the synthetic utility of our developed synthetic
protocol, the synthesis of 3c', which is a synthetic precursor of
natural compounds, neocryptolepine (cryprotackieine) and
isocryptolepine (cryptosanguinolentine),15 previously isolated from
Cryptolepis sanguinolenta (Lindl.) Schlachter (Periplocaceae) was
demonstrated (Scheme 3). Under standard reaction conditions, 1c'
was employed to prepared 3c' (32% yield). Then, 3c' can be
converted to neocryptolepine and isocryptolepine by the following
previously reported protocols.16
3a, R1 = H (80%)
3b, R1 = CH3 (72%)
3c, R1 = Br (72%)
3d, R1 = Cl (61%)
3e R1 = F (46%)
3i, R2 = CH3 (77%)
3j, R2 = OCH3 (73%)
3k, R2 = Br (67%)
3l, R2 = Cl (80%)
3m, R2 = F (77%)
3n, R2 = NO2 (32%)
3h (55%)
3f, R1 = NO2 (49%)
3g, R1 = CF3 (65%)
3o, R2 = CH3 (76%)
3p, R2 = Br (71%)
3q, R2 = Cl (84%)
3r, R2 = F (73%)
3s, R2 = Cl (64%)
3t, R2 = F (73%)
3u (34%)
3x, R = cyclopropyl (73%)
3y, R = (CH2)3CH3 (68%)
3z, R2 = (CH2)2CH(CH3)2 (72%)
3a', R2 = (CH2)5CH3 (54%)
3v (45%)
3w (75%)
Scheme 3 Synthetic application.
Scheme 1 Synthesis of 3-substituted quinolin-2(1H)‑ones 3.
Conditions: 2 [Freshly prepared from 1 (0.5 mmol)], AgNO3 (5
mol%) in DMF (2 mL), H2O (0.1 mL) at 80 C, 2 h. In parentheses:
isolated yields after chromatographic purification (SiO2, column
chromatography).
On the basis of the results obtained and the previously reported
literature,13 a plausible mechanism has been proposed as depicted
in Scheme 4. Acting as an activator, Ag(I) initiates the reaction by
chelation to the alkynyl moiety of 2. At the same time, water acts as
a nucleophile by addition to the terminal carbon of the isocyanide
moiety in 2. Cycloaddition of the resulting carbanion to the Ag(I)-
chelated triple bond delivers adduct A. Subsequent protonation
yields B with the release of Ag(I) ion. Finally, B undergoes
tautomerization to give 3-substituted quinolin-2(1H)‑ones 3.
o
Although the exact reaction pathway is still not entirely clear,
some control experiments were performed in order to shed some
lights on the reaction mechanism. When D2O was employed in
1
place of water, a mixture of product 3b' and 3a (3b' : 3a = 9 : 1, H
NMR analysis) was obtained (Scheme 2). Compound 3b' was
spectroscopically characterized (See Supplementary data for 1H, 13C,
and HRMS data of 3b'). The results obtained suggested that water
served as a proton donor.
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Scheme 4 Plausible mechanism.
Conclusions
In summary, a facile method for the formation of 3-substituted
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Acknowledgements
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Franco−Thai Cooperation Program in Higher Education and
Research (PHC Siam 2017), and the Swedish Research Council (VR)
for financial support. The Institute for the Promotion of Teaching
Science and Technology and Science Achievement Scholarship of
Thailand (SAST) for financial support through student scholarships
to O.K. and J.M. are also gratefully acknowledged.
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