Please do not adjust margins
Chinese Chemical Letters
toxic than aldehydes. The first reaction step continuously provides material for the second step, which
effectively reduces loss through volatilization, oxidation, and polymerization of the aldehyde, while avoiding
its toxicity. A variety of quinazolinones can be prepared in the presence of visible light without any additional
photocatalyst. The developed synthesis protocol proceeds with the merits of mild conditions, broad substrate
scope, operational simplicity, and high atom efficiency, with an eco-energy source under metal-free,
photocatalyst-free, and ambient conditions.
Keywords:
Visible light
Photocatalyst-free
In-situ formed acetaldehyde
One pot tandem reaction
Quinazolinones
Room temperature
Quinazolinones and their scaffolds are widely used in many
fields, especially organic, natural product, medicinal, and
agricultural chemistry. For example, the quinazolinone motif and its
derivatives are abundant in a number of synthetic compounds and
natural alkaloids with diverse biological and pharmacological
properties (Fig. 1), including antimalarial [1], antimicrobial [2],
anticancer [3], anti-inflammatory [4, 5], anticonvulsant [6],
antihypertensive [7], antitumor [8-10], anti-diabetic, dihydrofolate
reductase-inhibitory, and kinase-inhibitory activities [11-15]. The
substituents at the 2 and 3 positions of the quinazolinone nucleus
have been reported to markedly influence pharmacological activity
Fig. 1. Selected examples of biologically active quinazolines.
[
16]. In view of their importance, several reports have appeared in
the literature describing the synthesis of these heterocycles. Among
these methods, reacting o-substituted anilines with an aldehyde
appears to be the most-employed strategy, with various catalysts
used to promote this reaction, including cellulose-SO
thiamine hydrochloride (VB ) [18], p-TSA [19], β-cyclodextrin-
SO H [20], 2-morpholinoethanesulfonic acid [21], L-proline nitrate
22], SiO -H 40 [23], chiral phosphoric acids [24], ascorbic
3
H [17],
1
3
[
2
3
PW12O
acid [25], ionic liquids [26, 27], zirconium (IV) chloride [28],
scandium triflate (III) [29], and metals [30, 31] (Scheme 1A). As a
class of compound, alcohols are known to be greener, more
economical, more stable, more available, and less toxic than
aldehydes. In recent years, the use of alcohols instead of aldehydes
has also aroused interest, and various catalysts such as Ru [32], Ir
Scheme 1. Routes used to synthesize quinazolinones.
[
33,34], Pd [35], Pt [36-38], Zn [39], Cu [40,41], Fe [42-44], Ni [45],
To optimize the reaction conditions, we initially chose 2-
aminobenzamide (1a) to react with benzyl alcohol (2a) as a model
system. To achieve a green reaction outcome, we examined
KOH [46], or high temperatures [47,48] have been used to prepare
these compounds (Scheme 1B). Therefore, the development of more
practical, green, and efficient approaches to quinazolinones remains
an attractive task for organic chemists [49].
3 2
photocatalysts such as eosin Y, rose bengal, Ru(bpy) Cl , 9-
fluorenone, and benzophenone. The reaction was carried out in
DMSO under light from an 18-W blue LED in air for 24 h when 9-
fluorenone or benzophenone (5.0 mol%) was used as the photoredox
catalyst; pleasingly the reaction proceeded to afford the desired
product 3a in 21% or 24% yield, respectively (Table 1, entries 4 and
Visible light is clean, easy to handle, and an eco-friendly energy
source with excellent prospects for the development of sustainable
and eco-friendly protocols. Owing to these advantages, visible-light-
promoted chemical reactions have received considerable attention
and have emerged as a hot research topic in organic chemistry [50-
5
). To our delight, 3a was obtained in 14% yield when the model
reaction was conducted in DMSO in the absence of a photocatalyst
entry 6). A further control experiment without the photocatalyst and
6
8], water splitting [69], PCN materials [70], organic photocatalyst
[
71] or applications in medicine synthesis [72]. As a continuation of
(
our interest in visible-light photochemistry and inspired by the
reported results [73], herein we report a novel, green, and mild
protocol for the synthesis of quinazolinones by irradiating alcohols
and o-substituted anilines with visible light under photocatalyst-free
and room-temperature conditions (Scheme 1C). To the best of our
knowledge, this is the first example of quinazolinone synthesis
involving a tandem reaction promoted by visible light.
without irradiation with LED light only recovered the two starting
materials (entry 6). Subsequently, a number of solvents, oxidants,
times, and molar ratios of substrates were examined with the aim of
improving reaction efficiency. It is noteworthy that, among the
solvents screened (entries 6–13), the target product was obtained
only in DMSO as the solvent (entry 6). Furthermore, when various
oxidants were screened (entries 14–18), a slightly improved yield of
3
a was achieved when an oxygen balloon was used instead air (entry
Please do not adjust margins
Xie, Zongbo
