YB(OTF)3-catalyzed synthesis of 2-substituted 4(3H)- quinazolinones via cleavage of a carbon-carbon bond

Article abstract of DOI:10.3987/COM-15-S(T)59

A general, selective, and practical one-pot synthesis of 2-substituted 4(3H)-quinazolinones by the Yb(OTf)3-catalyzed cyclo-condensation of 2-Aminobenzamides with acyclic or cyclic 1,3-diketones (β-diketones) under mild and neutral reaction conditions has been developed, which involves the highly selective cleavage of a C-C bond in 1,3-diketones by Yb(OTf)3 catalyst. For example, the Yb(OTf)3-catalyzed cyclo-condensation of 2-Aminobenzamide (1a) with 1-phenylbutane-1,3-dione (2c) gave 2-methyl-4(3H)-quinazolinone (3a) in 90% yield, together with acetophenone in 65% yield. Ring-opening cyclo-condensation of 2-Aminobenzamides (1a) with cyclic 1,3-diketones (2i and 2k-m), except for cyclopentane-1,3-dione (2j), gave 2-substitued 4(3H)-quinazolinones (3i and 3k-m) with one carbonyl group.

Full text of DOI:10.3987/COM-15-S(T)59

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HETEROCYCLES, Vol. 93, No. 2, 2016
HETEROCYCLES, Vol. 93, No. 2, 2016, pp. 816 - 823. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 28th September, 2015, Accepted, 30th November, 2015, Published online, 10th December, 2015
DOI: 10.3987/COM-15-S(T)59
Yb(OTf)3-CATALYZED SYNTHESIS OF 2-SUBSTITUTED 4(3H)-
QUINAZOLINONES VIA CLEAVAGE OF A CARBON-CARBON BOND
Tsutomu Yoshimura,1 Shun-ichi Naito,1 Di Yuanjun,1 Aoi Son,1 Yu
Kimura,1,2 Akio Toshimitsu,1,3 and Teruyuki Kondo1,4*
1
Department of Energy and Hydrocarbon Chemistry, Graduate School of
Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan.
2
Research and Educational Unit of Leaders for Integrated Medical System,
Center for the Promotion of Interdisciplinary Education and Research, Kyoto
3
University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan.
Division of
Multidisciplinary Chemistry, Institute for Chemical Research, Kyoto University,
4
Gokanosho, Uji, Kyoto 611-0011, Japan. Advanced Biomedical Engineering
Research Unit, Center for the Promotion of Interdisciplinary Education and
Research, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan.
Tel.:+81(75)3837055 Fax: +81(75)3832805 E-mail: teruyuki@scl.kyoto-u.ac.jp
Abstract — A general, selective, and practical one-pot synthesis of 2-substituted
4(3H)-quinazolinones by the Yb(OTf)3-catalyzed cyclo-condensation of
2-aminobenzamides with acyclic or cyclic 1,3-diketones (β-diketones) under mild
and neutral reaction conditions has been developed, which involves the highly
selective cleavage of a C-C bond in 1,3-diketones by Yb(OTf)3 catalyst. For
example, the Yb(OTf)3-catalyzed cyclo-condensation of 2-aminobenzamide (1a)
with 1-phenylbutane-1,3-dione (2c) gave 2-methyl-4(3H)-quinazolinone (3a) in
90% yield, together with acetophenone in 65% yield. Ring-opening
cyclo-condensation of 2-aminobenzamides (1a) with cyclic 1,3-diketones (2i and
2k-m), except for cyclopentane-1,3-dione (2j), gave 2-substitued
4(3H)-quinazolinones (3i and 3k-m) with one carbonyl group.
4(3H)-Quinazolinones belong to one of the most important classes of fused heterocyclic compounds and
Dedicated with respect to Professor Dr. Lutz F. Tietze on the occasion of his 75th birthday

HETEROCYCLES, Vol. 93, No. 2, 2016
817
have a wide range of biological activities.1 Various methods for the synthesis of 4(3H)-quinazolinones
have been developed and reported,2 almost all of which are based on the condensation of 2-aminobenzoic
acid (anthranilic acid) with carbonyl compounds (aldehydes or ketones) and amines, i.e., the
Niementowski synthesis.3 However, these methods suffer from multi-step and tedious procedures, costly
reagents, and often low yields. Three reactions that have attracted the interest of organic and
organometallic chemists have been reported independently. Manhas reported the pioneering synthesis of
2-methyl-3-aryl-4(3H)-quinazolinones from the reaction of 2-amino-N-arylbenzamides and
pentane-2,4-dione (acetylacetone) under acidic reaction conditions (6% ethanolic hydrogen chloride),
involving retro-Aldol reaction of pentane-2,4-dione,4 and Pihlaja reported a three-step synthesis of
2-methyl-4(3H)-quinazolinone from 2-aminobenzamide with 1-(4-substituted)phenylbutane-1,3-dione via
Z-enamine intermediates which underwent cyclization followed by elimination of aryl methyl ketones
under acidic reaction conditions (with trifluoroacetic acid for one week).5 Wang developed an
iodine-catalyzed ring-opening condensation of 5,5-dimethyl-1,3-cyclohexadienone (dimedone) with
2-aminobenzamides to give bis-quinazolin-4(3H)-ones.6 Unfortunately, the applicable substrates were
strictly limited in the above three reactions,4-6 and the reactions were generally carried out under acidic
reaction conditions4,5 or in the presence of I2.6
As a continuation of our study on the rare earth metal-catalyzed synthesis of heterocyclic compounds,7 we
succeeded in developing a general, selective, and practical one-pot synthesis of 2-substituted
4(3H)-quinazolinones 3 by the Yb(OTf)3-catalyzed cyclo-condensation of 2-aminobenzamides 1 with
1,3-diketones (β-diketones) 2 under mild and neutral reaction conditions (Scheme 1). For example, the
reaction of 1a (X = H) with pentane-2,4-dione (R1 = R2 = CH3) 2a gave 2-methyl-4(3H)-quinazolinone 3a
in high yield. The present reaction is surprising, but can be explained by assuming the formation of
1,2-dihydroquinazolone intermediates and the subsequent decomposition of 1,2-dihydroquinazolones by
the Yb(OTf)3-assisted cleavage of a C-C bond (Scheme 1, vide infra), which is a reminiscent of the
McLafferty rearrangement in mass spectroscopy.8
Scheme 1. Yb(OTf)3-catalyzed synthesis of 2-substituted 4(3H)-quinazolinones 3 from the
cyclo-condensation of 2-aminobenzamides 1 and 1,3-diketones 2 via cleavage of a C-C bond

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HETEROCYCLES, Vol. 93, No. 2, 2016
First, we examined the catalytic activities of several metal triflates and typical Lewis acids in the model
o
reaction of 2-aminobenzamide 1a with pentane-2,4-dione 2a in mesitylene at 60 C for 24 h under an
argon atmosphere. The results are summarized in Table 1. Among the catalysts examined, Yb(OTf)3 was
the best, and gave 2-methyl-4(3H)-quinazolinone (3a) in 93% yield. In addition to Yb(OTf)3, Sc(OTf)3
showed high catalytic activity (3a, 92%), and other metal triflates showed moderate catalytic activity.
.
However, YbCl3 and Yb(OAc)3 4H2O showed moderate to low catalytic activity to give 3a in respective
yields of 78% and 21%, probably due to the weak coordination ability of chloro- and acetato-ligands to
the ytterbium center. When the reaction was carried out in the presence of a catalytic amount of Brønsted
acid such as CF3SO3H in place of Yb(OTf)3 catalyst, the yield of 3a decreased to 47%.
Table 1. Catalytic activity of
several metal triflates and
typical Lewis acid for the
synthesis of 3a from 1a and 2aa
Table 2. Synthesis of 2-methyl-4(3H)-quinazolinones 3b-e
by Yb(OTf)3-catalyzed cross-condensation of 2-amino-
benzamides 1b-e with pentane-2,4-dione 2aa
a
1 (1.0 mmol), 2a (1.5 mmol), Yb(OTf)3 (0.050 mmol) in
o
mesitylene (2.0 mL) at 60 C for 24 h under an Ar
atmosphere.
a
1a (1.0 mmol), 2a (1.5
mmol), catalyst (0.050 mmol)
in mesitylene (2.0 mL) at 60
oC for 24 h under an Ar
b
atmosphere. Determined by
GLC.

HETEROCYCLES, Vol. 93, No. 2, 2016
819
The present reaction occurred smoothly in several organic solvents such as mesitylene (3a, 93%),
acetonitrile (90%), ethyl acetate (75%), THF (72%), and methanol (69%), and mesitylene was used as the
best solvent for the following reactions.
Under the optimum reaction conditions, 2-aminobenzamides bearing several electron-withdrawing and
electron-donating substituents on an aromatic ring (1b-e) were treated with 2a and Yb(OTf)3 catalyst in
mesitylene at 60 oC for 24 h under an argon atmosphere to give the corresponding
2-methyl-4(3H)-quinazolinone derivatives (3b-e) in high isolated yields (Table 2).9 All reactions of
2-aminobenzamide (1a) with various acyclic 1,3-diketones (2a-c and 2e, R1 = Me) by Yb(OTf)3 catalyst
gave 2-methyl-4(3H)-quinazolinone (3a) in high yields with high selectivity (Scheme 2). Similarly,
methyl acetoacetate (2d), a β-keto ester, can be used in the present reaction to give
2-methyl-4(3H)-quinazolinone (3a) quantitatively.
O
O
O
O
O
Yb(OTf)3 0.050 mmol
NH2
NH
R1
+
+
R1
R2
R2
mesitylene 2.0 mL
at 60 oC for 12 h
under Ar
NH2
N
1a 1.0 mmol
2a (R1 = Me, R2 = Me)
2b (R1 = Me, R2 = tBu)
2c (R1 = Me, R2 = Ph)
2d (R1 = Me, R2 = OMe)
2e (R1 = Me, R2 = CF3)
2f (R1 = Et, R2 = Et)
2g (R1 = tBu, R2 = tBu)
2h (R1 = Ph, R2 = Ph)
1.5 mmol
3a 93%
3a 96%
3a 90(87)%
3a 99%
3a 68%
3f
3g 66%
3h (53)%
(35)%
GLC yield (Figures in the parentheses are
Isolated yield.)
Scheme 2. Yb(OTf)3-catalyzed synthesis of 2-substituted 4(3H)-quinazolinones 3 from
2-aminobenzamide 1a and 1,3-diketones (or β-ketoester) 2
To obtain 4(3H)-quinazolinones bearing other alkyl substituents at the 2-position, symmetrically
substituted 1,3-diketones such as heptane-3,5-dione (2f), 2,2,6,6-tetramethylheptane-3,5-dione
(dipivaloylmethane) (2g), and 1,3-diphenylpropane-1,3-dione (2h) without an acetyl moiety (CH3CO) to
give 2-ethyl-, 2-(tert-butyl)-, and 2-phenyl-4(3H)-quinazolinone (3f-h) selectively in moderate to good
yields. In addition, the products obtained by the Yb(OTf)3-catalyzed cyclo-condensation reaction of
2-aminobenzamide (1a) with 1-phenylbutane-1,3-dione (2c) were analyzed carefully, and the formation
of 2-methyl-4(3H)-quinazolinone (3a) in 90% yield and acetophenone in 65% yield was observed. This
result is consistent with the proposed mechanism illustrated in Scheme 1 (vide supra) and Scheme 3 (vide
infra).

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HETEROCYCLES, Vol. 93, No. 2, 2016
The reactions of 2-aminobenzamide (1a) with several cyclic 1,3-diketones (2i-m) were examined under
the same optimum reaction conditions, and the results are summarized in Table 3. Except for 2j,
ring-opening and cyclo-condensation of cyclic 1,3-diketones (2i and 2k-m) with 1a gave the
corresponding
2-(oxoalkyl)-4(3H)-
Table 3. Synthesis of 2-substituted 4(3H)-quinazolinones
3i-m by the Yb(OTf)3-catalyzed condensation of
quinazolinones (3i and 3k-m) in good to
high isolated yields. On the other hand, a 2-aminobenzamide 1a with cyclic 1,3-diketones 2i-ma
five-membered cyclic 1,3-diketone,
cyclopentane-1,3-dione (2j), gave a
simple open-chain condensation product,
2-((3-cyclopent-1-en-1-yl)amino)benzam-
ide 3j, in 49% isolated yield without
ring-opening, because of the high
stability of an enol form of 2j.
Based on a consideration of all of the
results obtained above, the most
plausible mechanism is illustrated in
Scheme 3. We believe that the
dissociation of a triflate anion OTf− from
Yb(OTf)3 first occurs to generate
+
catalytically active Yb(OTf)2 , which
immediately coordinates to a carbonyl
oxygen in 1,3-diketone. Subsequent
nucleophilic attack of an amino group in
2-aminobenzamide to the activated
a
1a (1.0 mmol), 2 (1.5 mmol), Yb(OTf)3 (0.050 mmol) in
o
mesitylene (2.0 mL) at 60 C for 24 h under an Ar
atmosphere.
carbonyl carbon in 1,3-diketone proceeds
to give a hemiaminal intermediate,
+
followed by migration of H+ and dehydration to give an imine intermediate coordinated by Yb(OTf)2 .
The intramolecular nucleophilic attack of an amino group to the imine carbon gives an aminal
+
intermediate. Subsequent migration of H+ and cleavage of a C-C bond assisted by coordinated Yb(OTf)2
give 2-substituted 4(3H)-quinazolinone and an enol with the regeneration of catalytically active
+
Yb(OTf)2 . The generated enol easily tautomerizes to the stable ketone.

HETEROCYCLES, Vol. 93, No. 2, 2016
821
Scheme 3. The most plausible mechanism
In conclusion, we have succeeded in developing a general, selective, and practical one-pot synthesis of
2-substituted 4(3H)-quinazolinones by the Yb(OTf)3-catalyzed cyclo-condensation of
3
2-aminobenzamides 1 with both acyclic and cyclic 1,3-diketones (β-diketones) 2 via the selective
cleavage of a C-C bond in 1,3-diketones. A wide range of starting materials can be used in the present
4(3H)-quinazolinone synthesis, since the reaction proceeds smoothly under mild and neutral reaction
conditions. Future studies on the use of Yb(OTf)3 and other rare earth metal catalysts to construct
valuable nitrogen-, oxygen-, and sulfur-containing heterocyclic compounds are in progress in our
laboratory.

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HETEROCYCLES, Vol. 93, No. 2, 2016
ACKNOWLEDGEMENTS
T.K. acknowledges financial support from the Asahi Glass Foundation and the Yazaki Memorial
Foundation for Science and Technology. This research was conducted in part at the Katsura-Int’tech
Center, Graduate School of Engineering, Kyoto University.
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9. General procedure for the synthesis of 2-substituted 4(3H)-quinazolinones 3: A mixture of
2-aminobenzamide (1, 1.0 mmol), 1,3-diketone (2, 1.5 mmol), Yb(OTf)3 (0.050 mmol, 5.0 mol%),
and mesitylene (2.0 mL) was placed in a 20-mL Pyrex flask equipped with a magnetic stirring bar
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recrystallization from MeOH/hexane. The products 3l and 3m were isolated by recrystallization
1
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previously. The products 3i,15 and 3m16 were characterized below.

HETEROCYCLES, Vol. 93, No. 2, 2016
823
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1
15. 3i: a pale yellow solid. H NMR (DMSO-d6, 400 MHz) δ: 1.03 (6H, d, J = 6.56 Hz), 1.51 (6H, s),
2.94-3.01 (m, 1H), 7.49 (1H, t, J = 7.34 Hz), 7.57 (1H, d, J = 7.80 Hz), 7.78 (1H, t, J = 8.30 Hz),
8.10 (1H, dd, J = 7.94 and 1.44 Hz), 12.04 (1H, br s); 13C NMR (DMSO-d6, 100 MHz) δ: 20.6, 22.2,
35.8, 54.8, 120.9, 125.7, 126.6, 127.0, 134.5, 147.8, 158.8, 162.1, 213.5. MS (ESI):
259.4188(M+H)+. Anal. Calcd for C15H18N2O2: C, 69.74; H, 7.02; N, 10.84. Found: C, 69.62; H,
7.26; N, 10.71.
1
16. 3m: a white solid. H NMR (DMSO-d6, 400 MHz) δ: 1.46-1.54 (2H, m), 1.64-1.71 (2H, m), 2.06
(3H, s), 2.46 (2H, t, J = 7.04 Hz), 2.57 (2H, t, J = 7.56 Hz), 7.44 (1H, t, J = 7.08 Hz), 7.57 (1H, d, J
13
= 8.28 Hz), 7.75 (1H, t, J = 7.80 Hz), 8.06 (1H, dd, J = 7.80 and 1.48 Hz), 12.15 (1H, br s); C
NMR (DMSO-d6, 100 MHz) δ: 22.6, 26.2, 29.6, 34.2, 42.3, 120.7, 125.6, 125.9, 126.7, 134.2, 148.9,
157.2, 161.7, 208.3. MS (ESI): 245.1342(M+H)+. Anal. Calcd for C14H16N2O2: C, 68.83; H, 6.60; N,
11.47. Found: C, 59.93; H, 6.16; N, 9.54.