Palladium-catalyzed one-pot synthesis of 2-substituted quinazolin-4(3H)-ones fromo-nitrobenzamide and alcohols

Article abstract of DOI:10.1039/d1ra01755a

Palladium-catalyzed 2-substituted quinazolin-4(3H)-one formation from readily availableo-nitrobenzamides and alcohols using hydrogen transfer is described. Various quinazolin-4(3H)-ones were obtained in good to high yields. The cascade reaction including

Full text of DOI:10.1039/d1ra01755a

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Palladium-catalyzed one-pot synthesis of 2-
substituted quinazolin-4(3H)-ones from o-
nitrobenzamide and alcohols†
Cite this: RSC Adv., 2021, 11, 13119
*
Hao Chen, Xinyan Dai, Xupeng Huang and Zhiqiang Feng
Ke Wang,
Received 5th March 2021
Accepted 31st March 2021
Palladium-catalyzed 2-substituted quinazolin-4(3H)-one formation from readily available o-
nitrobenzamides and alcohols using hydrogen transfer is described. Various quinazolin-4(3H)-ones were
obtained in good to high yields. The cascade reaction including alcohol oxidation, nitro reduction,
condensation, and dehydrogenation occurs without any added reducing or oxidizing agent.
DOI: 10.1039/d1ra01755a
rsc.li/rsc-advances
The quinazolinones and their derivatives are a family of privi- sources for quinazolinone synthesis features their atom-
leged heterocyclic structures commonly found in a wide variety economic advantage over anilines. However, methodologies
of natural products, biologically active molecules, and func- for the synthesis quinazolinone derivatives via the acceptorless
tional organic materials.1 Due to quinazolinone's important
Table 1 Optimization of the reaction conditionsa
value, various conventional methods have been developed for
the synthesis of these molecules in both academic and indus-
trial settings.2 The most common approaches utilize 2-amino-
benzoic acid and its derivatives as the starting materials along
with aldehydes,3 acyl chlorides or their analogues4 to obtain the
corresponding structural motifs. These methods usually have
the disadvantages of multistep reactions,5 low yields,6 long
reaction times,7 and the use of stoichiometric amounts of
strong or toxic oxidants.8
t
In the past decade, direct coupling methods of C–N bonds9
through which o-aminobenzamides react with benzylic alcohols
by metal-catalyzed cascade reactions have been recognized as
an attractive methods for the synthesis of 2-substituted quina-
zolinone derivatives. For example, Yokoyama and coworkers
reported the synthesis of quinazolin-4(3H)-ones via a palla-
dium-catalyzed domino reaction of o-aminobenzamides with
benzylic alcohols.10 Wang et al. also reported the one-pot
oxidative cyclization of o-aminobenzamide with alcohols to
quinazolin-4(3H)-ones catalyzed by MnO2 under hydrogen
transfer conditions.11 The groups of Watson,12 Paul,13 and some
others14 also independently reported the Ru-, Ni-, and Cu-
catalyzed synthesis of quinazolin-4(3H)-ones via the accept-
orless dehydrogenative coupling of o-aminobenzamides with
alcohols. Considering that aniline is prepared from the corre-
sponding nitroarenes,15 and that nitroarenes are cheaper and
commercially available, the direct use of nitroarenes as amino
Entry
Catalyst
Solvent
(h)
Yield (%)
1
2
3
4
5
6
7
8
CuCl
CuCl2
dppf
FeCl3
Cu(OAc)2
CuBr2
CuBr
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMF
DMSO
PhCl
PhCl
PhCl
PhCl
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
5
8
8
8
0
0
28
22
0
Trace
Trace
14
42
59
77
56
80
87
80
79
78
87
80
PdCl2
9
Pd(OAc)2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
10
11
12
13
14
15
16
17
18
19
b
c
d
e
f
PhCl
PhCl
PhCl
g
a
Reaction conditions: 1 mmol of 1a, 2.5 equiv. of 2a, catalyst and 1 mL
Beijing Key Laboratory of Active Substance Discovery and Drugability Evaluation,
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union
Medical College, No. 1 Xiannongtan Street, Beijing 100050, P R China. E-mail:
fengzhq@imm.ac.cn
of solvent in a 10 mL sealed tube at 150 ꢀC under Ar for 8 h. Yield of the
b
c
isolated product based on 1a. At 140 ꢀC under Ar for 8 h. At 130 ꢀC
d
e
under Ar for 8 h. At 140 ꢀC under Ar for 5 h. Pd (dppf) Cl2, 5%.
f
g
Pd (dppf) Cl2, 15%. At 140 ꢀC under air for 8 h.
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d1ra01755a
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Table 2 Reaction of 1a with various alcoholsa,b
a
Reaction conditions: 1 mmol of 1a, 2.5 equiv. of 2a, catalyst and 1 mL of solvent in a 10 mL sealed tube at 140 ꢀC under Ar for 8 h. b Isolated yield.
13120 | RSC Adv., 2021, 11, 13119–13123
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Table 3 Reaction of 2a with substituted amidesa,b
a
Reaction conditions: 1 mmol of 1, 2.5 equiv. of 2a, catalyst and 1 mL of solvent in a 10 mL sealed tube at 140 ꢀC under Ar for 8 h. b Isolated yield.
Table 4 Reaction of 2t with substituted amidesa,b
Initially, a model reaction of o-nitrobenzamide (1a) and
benzyl alcohol (2a) was chosen to optimize the reaction condi-
tions (Table 1). We carried out the reaction of o-nitrobenzamide
ꢀ
with 2.5 equivalents alcohol in toluene at 150 C and an argon
atmosphere for 8 h. As shown in Table 1, various catalysts were
screened for the reaction. No or poor yield was observed in the
presence of either a copper or an iron catalyst (Table 1, entries
1–7). With regard to the palladium catalyst (Table 1, entries 8–
10), Pd(dppf)Cl2 showed the best activity, and 3a was obtained
in 59% yield (Table 1, entry 10). Several solvents such as DMF,
DMSO, and chlorobenzene were screened, and chlorobenzene
a
Reaction conditions: 1 mmol of 1, 2.5 equiv. of 2t, catalyst and 1 mL of
solvent in a 10 mL sealed tube at 140 ꢀC under Ar for 8 h. b Isolated yield.
dehydrogenative coupling of nitroarenes with alcohols are
relatively scarce.16
Herein, we report a new approach for directly synthesizing 2-
substituted quinazolin-4(3H)-ones from o-nitrobenzamides
with alcohols via a hydrogen transfer methodology.17
Scheme 1 Postulated reaction pathway.
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was found to be the optimal solvent (Table 1, compared entries 3bg). The yield of the product was not affected by the o-nitro-
11–13), the yield of 3a increased to 80% (Table 1, entry 13). The benzamide with substituents at the 3 or 6 positions (Table 3,
impact of reaction temperatures was also investigated. The 3be–3bf). In addition to benzylic alcohols, long-chain aliphatic
ꢀ
reaction conducted at 140 C resulted in a higher yield (87%) alcohols such as 1-hexanol also yielded the corresponding
than that conducted at 150 ꢀC (Table 1, entry 14). But the quinazolin-4(3H)-one in moderate to good yields (42–54%)
ꢀ
reaction performed at 130 C resulted in a lower 3a yield of to (Table 4, 3bh–3bk).
80% (Table 1, entry 15). When the reaction time was reduced to
Based on the above experimental results along with the
5 h, the yield of 3a was slightly reduced to 79% (Table 1, entry literature,17 we proposed possible mechanisms of the reaction
17), but the yield did not increase with increasing of reaction (Scheme 1). The reaction involved the oxidation of the alcohol to
time to 10 h. When the amount of catalyst was decreased from aldehyde (A) and the generation of hydrogen in the presence of
0.1 to 0.05 equiv., the yield of 3a decreased to 78% (Table 1, Pd(dppf)Cl2, and the hydrogen will reduce 2-nitrobenzamide to
entry 17). However, 0.15 equiv. of catalyst did not change the 2-aminobenzamide (B) via a hydrogen-transfer process. One
yield of the product (Table 1, entry 18). A slightly lower yield was equivalent of 2-aminobenzamide (B) condenses with the alde-
obtained when the reaction was carried out in air (80%) (Table hyde (A) and an intermediate that easily dehydrates to yield the
1, entry 19).
imine (C). Then, the nitrogen atom of the amine attacked the
Aer optimized reaction conditions (Pd(dppf)Cl2, chloro- imine to generate dehydrogenated quinazolinone (D). Finally,
benzene, 140 ꢀC, argon) were established, the reaction scope dehydrogenation of D can achieve the desired product 3a via
and generality of various primary alcohols were tested, as shown a hydrogen-transfer process.
in Table 2. The position and electronic effect of substituents on
the phenyl ring of benzyl alcohols was examined. A series of
benzyl alcohols with electron-donating groups (Me and MeO)
Conclusions
could be converted to the desired products in good yields. We have developed a strategy for Pd(dppf)Cl2-catalyzed quina-
Benzyl alcohols with methyl substituents at ortho-, meta-, or zolin-4(3H)-one formation from o-nitrobenzamides and alco-
para-positions (Table 2, 3b–d) produced the corresponding hols via the hydrogen-transfer. Functional groups such as
quinazolin-4(3H)-ones in 69%, 80% and 78% isolated yields. halogen, methoxy, methyl and hydroxyl groups were all well
The lower yield of the o-methylbenzyl alcohol may be due to the tolerated under the optimized reaction conditions. A wide
steric effect of ortho groups on the substrate. Benzyl alcohols variety of desired quinazolin-4(3H)-ones were obtained in
having methoxyl substituents at meta- or para-positions also moderate to high yields starting from inexpensive and easily
produced the corresponding quinazolin-4(3H)-ones in 76% and available nitrobenzamides and alcohols. Further studies on the
75% isolated yields. Halogen substituents on the benzylic synthetic applications of this reaction are under investigation in
alcohols were also well tolerated in the reaction. Fluorine and our laboratory.
chlorine substituted at the meta- and para-positions of
substrates were applied to the synthesis of the corresponding
quinazolin-4(3H)-ones in good yields (Table 2, 3f, 3g and 3k).
Conflicts of interest
Similarly, lower yields were observed using o-uorobenzyl There are no conicts to declare.
alcohol and o-chlorobenzyl alcohol as coupling partners (46%
and 60%) (Table 2, 3e and 3j). A strong electron-withdrawing
group such as CF3 was also found to be compatible affording
Acknowledgements
quinazolin-4(3H)-ones in good yield (76%) (Table 2, 3l). Starting This work was supported by grants from the Beijing Municipal
from 6-methyl-2-pyridinemethanol, 2-thiophenemethanol and Natural Science Foundation (7192133), the Non-prot Central
thiazole-5-methanol, the corresponding quinazolin-4(3H)-ones Research Institute Fund of Chinese Academy of Medical
were obtained in 83%, 66% and 78% isolated yields. However, Sciences (2018PT35003) and CAMS Innovation Fund for
lower yields (54% and 48%) (Table 2, 3o and 3p) were observed Medical Sciences (CIFMS) (2017-I2M-1-010).
using 3-pyridinemethanol and 4-pyridinemethanol as coupling
partners. Aliphatic alcohols were also tested, providing the
corresponding products in moderate to good yields. The reac-
Notes and references
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