Communication
DOI: 10.1002/bkcs.12239
BULLETIN OF THE
J. In Lee
KOREAN CHEMICAL SOCIETY
An Efficient Synthesis of (1-Methyl)-2-phenyl-4-quinolones
from (N-Methyl)isatoic Anhydride
Jae In Lee
Department of Chemistry, College of Science and Technology, Duksung Women’s University, Seoul
01369, Republic of Korea. E-mail: jilee@duksung.ac.kr
Received August 27, 2020, Accepted January 19, 2021, Published online February 3, 2021
The acyl substitution of (N-methyl)isatoic anhydride with N,O-dimethylhydroxylamine hydrochloride in
CH3CN gave N-methoxy-N-methyl 2-(N-methyl)aminobenzamide, which was treated with ethynyllithium
reagents to afford 1-[2-(N-methyl)amino]-3-phenyl-2-propyn-1-ones. The 6-endo cyclization of 1-[2-(N-
methyl)amino]-3-phenyl-2-propyn-1-ones using NaOCH3 in CH3OH at 65 ꢀC gave various (1-methyl)-
2-phenyl-4-quinolone derivatives in high yields.
Keywords: (1-Methyl)-2-phenyl-4-quinolones, (N-Methyl)isatoic anhydride, Acyl substitution,
6-endo Cyclization
(1-Methyl)-2-phenyl-4-quinolones are found in plants of the
Rutaceae family and are regarded as a biologically relevant scaf-
fold that occurs in natural products.1 2-Phenyl-4-quinolones
exhibit cytotoxic activities against human tumor cell2 and leuke-
mia cell.3 1-Methyl-2-phenyl-4-quinolones are used to treat
Alzheimer’s disease by inhibition of acetylcholinesterase4 and
show antiplatelet activity through inhibition of cyclooxygenase.5
Several types of reactions for synthesizing (1-methyl)-
2-phenyl-4-quinolones have been described.6 Acetylation
of N-phenyl benzamides7a and benzoylation of 20-amino-
acetophenones7b commonly produced N-(2-acetylphenyl)
benzamides. These compounds were cyclized with an
excess of t-BuOK to give 2-phenyl-4-quinolones, which
could be further N-methylated to obtain 1-methyl-2-phenyl-
4-quinolones.7 The amidation of 20-haloacetophenones with
of the C C bond.12 Deprotection of the Boc group in N-Boc
alkynones and the subsequent cyclization with K2CO3 gave
2-phenyl-4-quinolones; however, it required for five steps from
2-aminobenzoic acids.13 Palladium-catalyzed carbonylative cou-
pling of 2-iodoanilines and phenylacetylenes using Mo(CO)6
and subsequent cyclization also gave 2-phenyl-4-quinolones via
2-aminophenylalkynone intermediates.14 Alternatively, the
1,4-addition of amines to o-haloaryl alkynones afforded the
corresponding enamine intermediates that underwent subsequent
substitution to give 2-phenyl-4-quinolones in the presence of
2 equiv. of Li2CO3 at 160 ꢀC.15
To date, several types of reactions for the synthesis of
2-phenyl-4-quinolones have been reported, but some
methods required excessive usage of reagents, multiple steps,
and harsh conditions. Previously, N-methylisatoic anhydride
was condensed with lithium enolate of acetophenones to give
N-methyl-2-phenyl-4-quinolones, but only few examples
were reported.6a This article describes efficient synthesis of
(1-methyl)-2-phenyl-4-quinolones by the cyclization of
1-[2-(N-methyl)amino]phenyl-3-phenyl-2-propyn-1-ones,
derived from (N-methyl)isatoic anhydride as cost-effective
starting materials, using NaOCH3.
8a
benzamides in the presence of 10 mol % CuI/K2CO3 or
8b
1 mol % Pd2(dba)3/Cs2CO3 also gave N-(2-acetylphenyl)
benzamides. It could further underwent subsequent cycliza-
tion with an excess of NaOH8a or t-BuONa8b at 100 ꢀC to
give 2-phenyl-4-quinolones.
The treatment of 2-aminochalcones with KHCO3 afforded the
corresponding 2,3-dihydro-2-phenyl-4-quinolones which under-
went elimination with 3 equiv. of tetramethyl-1-piperidinyloxy
(TEMPO) radical to give 2-phenyl-4-quinolones at 120 ꢀC.9
An oxidative reaction of 20-(N-benzylamino)acetophenones
using 2 equiv. of TEMPO and t-BuOK afforded the corres-
ponding enamine intermediates, which underwent cyclization
and dehydrogenation to give 2-phenyl-4-quinolones.10 The
reductive cyclization of 2-nitrochalcones by a low-valent
3 equiv. of TiCl4/Zn also gave 2-phenyl-4-quinolones via
2-aminochalcone intermediates.11
N-Methoxy-N-methyl 2-(N-methyl)aminobenzamide (2a, b)
was prepared by the acyl substitution of (N-methyl)isatoic
In contrast, the cyclization of 2-aminophenylalkynones
allowed convenient synthesis of 2-phenyl-4-quinolones.
The cyclization of 2-aminophenylalkynones with 5 mol %
PPh3AuNTf2 gave 2-phenyl-4-quinolones through the activation
Scheme 1. Reagents and conditions: (a) CH3(CH3O)NH2Cl, Et3N,
0.1 equiv. DMAP, CH3CN, rt, 36 h; (b) LDA, THF, −10 ꢀC,
10 min; (c) THF, −10 ꢀC, 15 min; (d) NaOCH3, CH3OH,
65 ꢀC, 3–24 h.
Bull. Korean Chem. Soc. 2021, Vol. 42, 556–558
© 2021 Korean Chemical Society, Seoul & Wiley-VCH GmbH
Wiley Online Library
556