Published on the web May 28, 2013
769
Cycloaddition of 1,4-Diaryl-1,3-butadiynes with Nitriles:
An Atom-economic One-pot Approach to Benzo[ f]quinazolines
Lichen Yang1 and Ruimao Hua*1,2
1Key Laboratory of Organic Optoelectronics and Molecular Engineering of Ministry of Education,
Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China
2State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P. R. China
(Received March 10, 2013; CL-130206; E-mail: ruimao@mail.tsinghua.edu.cn)
A one-pot synthesis of benzo[ f]quinazoline by a novel
R
N
cycloaddition of 1,4-diaryl-1,3-butadiynes with nitriles in the
H
presence of trifluoromethanesulfonic acid at 120 °C is devel-
oped.
R
[2+2+2]
N
+
Cycloaddition
N
R'
R'
R'
pyrimidine intermediate
Quinazoline derivatives are an important class of N-
heterocyclic compounds, which have been found as the core
structure in many natural and synthetic products showing
biological and physiological activities,1 or optoelectronic prop-
erties.2 Therefore, many methods have been developed for
the synthesis of such compounds.3 Recently, various domino
reactions based on substituted phenyl halides have also been
developed as powerful methods to construct quinazoline
skeletons.4
R
Intramolecular
hydroarylation
N
R'
N
R'
Scheme 1. Strategy for the formation of benzoquinazolines.
Table 1. The cycloaddition of 1,4-diphenyl-1,3-butadiyne (1a)
with acetonitrile (2a) under different conditionsa
TfOH
On the other hand, benzoquinazolines also exhibit interest-
ing biologic activities such as antifolate5a and antimalarial
activities5a and show inhibiting effects on many enzymes such as
thymidylate synthase5b,5c and topoisomerase.5d However, only a
few methods for the syntheses of benzoquinazolines have been
reported, including the use of naphthylamine derivatives5a,6a or
tetralone derivatives,6b which are not easily accessible, as the
starting materials or those employing simple starting compounds
but involve multiple steps and give a low total yield.7
3a
+
N
Me
temp. 12 h
2a
excess amount
1a
Entry TfOH/equiv 2a/mL
Temp/°C Yield of 3a/%
1b
2
3
4
5
6
7
8
9
2.5
2.5
2.5
2.5
2.5
2.5
2.5
4.0
0.5
1
1
4
10
4
4
4
4
4
80
80
80
5
11
25
26
33
45
39
44
0
In recent years, 1,4-disubstituted-1,3-butadiynes, which are
easily obtained from alkynes by several efficient synthetic
methods,8 have become an important class of starting materials
for the synthesis of cyclic compounds such as furans,9
pyrroles,9,10 naphthalenes,11 thiophenes,9b,12 and others.13 In-
spired by our previous work on naphthalene synthesis from
1,4-diaryl-1,3-butadiyne,11 we design a domino route for the
formation of the benzoquinazoline ring, via the [2 + 2 + 2]
cycloaddition of aryl-substituted 1,3-butadiyne with two mole-
cules of nitrile to form pyrimidine derivatives and subsequent
intramolecular hydroarylation of the other C-C triple bond to
achieve a novel cycloaddition reaction, as shown in Scheme 1.
It is well known that strong protonic acids can promote the
[2 + 2 + 2] cycloaddition of alkynes with nitriles to afford
pyrimidine derivatives14 and the intramolecular hydroarylation
of alkynes.15 Thus, we examined the reaction of 1,4-diphenyl-
1,3-butadiyne (1a) with acetonitrile (2a) in 1,2-dichloroethane
(DCE) in the presence of different acidic reagents. Lewis acids
such as CuCl2, Cu(OTf)2, AuCl3, and protonic acids such as
AcOH, TFA, methanesulfonic acid, and sulfuric acid failed
to promote the cycloaddition reaction. Fortunately, trifluoro-
methanesulfonic acid (TfOH) (2.5 equiv) could promote the
expected cycloaddition reaction at 80 °C to afford 1,3-dimethyl-
6-phenylbenzo[ f]quinazoline (3a) in low yield (Table 1,
Entry 1).
80
100
120
150
120
120
aThe reactions were carried out with 0.5 mmol of 1a,
acetonitrile (2a) in the presence of TfOH. bThe reaction is
conducted in DCE (4.0 mL).
The structure of 3a was confirmed from spectroscopic data
and X-ray crystallography (Figure 1).16 The other possible
structure of the cycloadduct 2,4-dimethyl-6-phenylbenzo[h]quin-
azoline (3a¤) could not be determined at all in the reaction
mixture, indicating that 3a was formed with high selectivity
(Scheme 2).
Encouraged by the initial results, we studied the reaction of
1a with 2a under different conditions in detail to optimize the
reaction conditions for the formation of 3a. Screening of
solvents revealed that when the reaction was carried out in
organic solvents such as DCE, DCM, DMF, toluene, THF, and
n-hexane at 80 or 120 °C in a sealed tube, 3a was formed in low
yield (<10%), while under solvent-free conditions, the forma-
Chem. Lett. 2013, 42, 769-771
© 2013 The Chemical Society of Japan
Yang, Lichen
