Organic Letters
Letter
interest in C−H activation reactions,13 we herein report the
ruthenium(II)-catalyzed annulation coupling of 2-arylquinazo-
linones with vinylene carbonate as unstable ethynol equivalents
(Scheme 1e). In this work, the C−C bond formation occurs
first via C−H formylmethylation followed by intramolecular
C−N formation.
Having established the optimized reaction conditions, we
next examined the substrate scope and limitations of the
reactions between 2-arylquinazolin-4(3H)-ones and 1,3-dioxol-
2-one. As depicted in Scheme 2, a variety of functional groups,
a b
,
Scheme 2. Scope of 2-Arylquinazolin-4(3H)-ones
Initially, 2-phenylquinazolin-4(3H)-one (1a) and 1,3-dioxol-
2-one (2) were selected as substrates to explore the feasibility
of our design. Using Li2CO3 as the base, the reaction catalyzed
by [Ru(p-cymene)Cl2]2/AgSbF6 proceeded in 1,2-dichloro-
ethane (DCE) at 80 °C for 12 h, and the desired product 3a
was obtained with a 64% yield (Table 1, entry 1). The
a
Table 1. Optimization of Reaction Conditions
b
entry
additive
solvent
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DMF
DMSO
toluene
1,4-dioxane
EtOH
DCE
DCE
DCE
DCE
DCE
T (°C)
yield (%)
1
2
3
4
5
6
7
8
Li2CO3
LiOAc
80
80
80
80
80
80
80
80
80
80
80
80
100
60
80
80
80
80
64
56
70
71
82
38
trace
28
NR
44
28
37
77
72
63
50
NR
58
Na2CO3
NaHCO3
NaOAc
NaOH
DBU
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
9
10
11
12
13
14
15
16
17
18
a
Conditions: 1a (0.2 mmol), 2a (0.3 mmol), [Ru(p-cymene)Cl2]2 (5
mol %), NaOAc (0.4 mmol), and AgSbF6 (20 mol %) in the solvent
b
c
(1 mL) under an Ar atmosphere. Isolated yield. Reaction at 60 °C.
d
e
Reaction for 8 h. Reaction at 100 °C.
c
d
such as methyl, ethyl, isopropyl, tert-butyl, methoxy, trifluor-
omethyl, and chloro, were introduced into the para position of
the phenyl ring relative to the aryl moiety of the substrates 1.
Furthermore, in all the cases, the desired products 3b−3i were
obtained in acceptable yields. Similarly, ortho- and meta-
substituted 2-arylquinazolin-4(3H)-ones were also compatible
with the reaction conditions, forming the target products 3j−
3m in moderate yields. The disubstituted substrates were also
well tolerated, forming the target compound 3n with a good
yield. The furan-heterocycle reacted smoothly, providing a
product with a slightly decreased reaction yield. Moreover,
substrates with electron-donating groups (e.g., methyl and
methoxyl groups) and electron-withdrawing groups (e.g., nitro
and halo groups) in the different positions of the quinazolin-
4(3H)-one moiety were all compatible for this transformation,
giving the products 3p−3ab with 57−92% yields.
To examine the potential of this method, the reaction using
phthalazinone or pyridazinone was also explored. In the case of
phthalazinone 4a, the reaction delivered product 5a in 64%
yield (Scheme 3f). When pyridazinone 6a was utilized as the
substrate, product 7a was afforded in 94% yield (Scheme 3g).
To further demonstrate the synthetic applicability of this
catalytic system, 3a was synthesized on a 5 mmol scale,
affording a 65% isolated yield under a reduced loading of
[Ru(p-cymene)Cl2]2 (2.5 mol %) and AgSbF6 (10 mol %)
(Scheme 3h). Furthermore, the intermolecular or intra-
molecular dehydration of 3a provided convenient access to
the corresponding ether 8a or olefin 9a with 68% and 52%
e
f
DCE
a
Conditions: 1a (0.2 mmol), 2a (0.3 mmol), [Ru(p-cymene) Cl2]2 (5
mol %), NaOAc (0.4 mmol), and AgSbF6 (20 mol %) in the solvent
b
c
(1 mL) for 12 h under Ar atmosphere. Isolated yield. 2a (0.4
mmol). Without AgSbF6. Without [Ru(p-cymene)Cl2]2. Under air.
d
e
f
molecular structure of 3a was unambiguously confirmed using
X-ray crystallography (CCDC 2048469). Through further
optimization of the bases, it was demonstrated that NaOAc as
base was more effective for this transformation upon the
formation of product 3a in 82% yield (entries 2−7). Next, a
series of solvents (DMF, DMSO, toluene, 1,4-dioxane, and
EtOH) were evaluated, and DCE was found to be the optimal
one (entries 8−12). The effect of the reaction temperature was
investigated, and it was shown that both elevating and lowering
the temperature was detrimental to the reaction efficiency
(entries 13 and 14). Control experiments indicated that base
and additive were essential in the reaction, as the yield dropped
in the absence of either of them. Moreover, the reaction did
not take place without [Ru(p-cymene)Cl2]2, thus revealing that
the ruthenium catalyst was essential in the reaction (entry 17).
Finally, when the reaction proceeded in an air atmosphere
rather than nitrogen, under the optimal conditions, a
significant decrease in yield (58%) was observed (entry 18).
996
Org. Lett. 2021, 23, 995−999