2
Table 1
Optimization of conditionsa
Entry
1
2
3
4
5
6
7
8
Metal salt
ZnBr2
ZnBr2
ZnBr2
ZnBr2
ZnI2
Zn(OTf)2
ZnCl2
InBr3
Equiv
3.0
2.0
1.0
0.1
0.1
0.1
2.0
2.0
2.0
2.0
0.1
0.1
Time (h)
16
Yieldb (%)
87
85
53
35
40
43
50
72
<5
<5
<5
17
16
16
72
72
72
16
16
16
9
FeCl3
AlCl3
CuI
10
11
12
16
16
16
PdCl2
aThe reaction was performed in toluene at 110 oC and the concentration is
0.125 M.
bIsolated yield.
efficiency under the promotion of indium bromide, while only a
trace amount of indolo[1,2-c]quinazoline was detected in the
presence of ferric chloride and aluminium chloride. To exclude
the possible trace effect of transition metals,21 a catalytic amount
of Cu(I) or Pd(II) salt was tested (Table 1, entries 11-12). The
results revealed that neither of them can catalyze the domino
sequence efficiently. In addition, even though the ZnBr2-
promoted domino hydroamination-cyclization was run on a 10
mmol scale, the tetracyclic product was still obtained without
comprising yield.
Scheme 1. Indolo[1,2-c]quinazoline assembly from alkyne
substrates
Zinc-promoted/catalyzed hydroamination of alkyne has
emerged as an attractive protocol for the assembly of nitrogen-
containing heterocycles. For instance, indole skeleton could be
elaborated
hydroamination of 2-alkynylaniline derivatives as described by
Zhao15 Okuma16,
and or using Zn(II)-promoted
either
by
Zn(II)-mediated
intramolecular
With the optimized condition in hand, the scope of the
transformation was investigated.22 Analogously, propionamide
1b and isobutyramide 1c underwent the domino hydroamination-
cyclization conveniently to afford 6-ethyl, isopropyl indolo[1,2-
c]quinazolines 2b-c (Table 2, entries 1-2). The bulky isopropyl
substitutent does not impede the conversion. In contrast, when
the formamide 1d and trifluoroacetamide 1e were employed, the
6-unsubstituted indolo[1,2-c]quinazoline and 6-trifluoromethyl
indolo[1,2-c]quinazoline were obtained in decreased yields
(Table 2, entries 3-4). A variety of benzamides were screened to
detect the effect of substitutents on the phenyl moiety (entries 5-
7). It is demonstrated that the electronwithdrawing group (NO2)
facilitates the conversion, providing the 6-(4-nitrophenyl)-
indolo[1,2-c]quinazoline 2g in 93% yield, while the
electrondonating group (OMe) is disadvantageous and the 6-(4-
methoxyphenyl)indolo[1,2-c]quinazoline 2h was obtained in
68% yield. The simple benzamide 1f was converted to 6-phenyl-
indolo[1,2-c]quinazoline in 80% yield. It is worth mentioning
that the 6-styryl-indolo[1,2-c]quinazoline can be generated from
the cinnamamide 1i according to the standard condition (Table 2,
entry 8). In addition, the substituent effect on the benzene moiety
of N-phenyl acetamides 1j-l was probed. It looks like that the
electronic property of the substitutents such as 4-chloro, 4-
methyl, 3,4-methylenedioxy give little impact on the
transformation and the corresponding 2-chloro, 2-methyl, 2,3-
methylenedioxy indolo[1,2-c]quinazolines 2j-l were achieved in
an average yield up to 90% (Table 2, entries 9-11). Furthermore,
the substitutents on the aniline moiety were also screened, the 10-
chloro, 10-methyl, 9,10-methenedioxy indolo[1,2-c]quinazolines
2m-o were obtained in excellent efficiency (Table 2, entries 12-
14).
hydrohydrazination-Fisher indole cyclization cascade starting
from phenylhydrazine and terminal alkynes.17 When 3-butynol or
enyne was employed instead of common terminal alkynes, a
divergent formation of pyrazoline occurred under the similar
intermolecular hydrohydrazination condition.18 Besides, di and
tri-substituted imidazoles can be accessed by employing a Zn(II)-
catalyzed
hydroamination
of
propargylamides.19
The
dichotomous properties of zinc salts in the domino reactions
attracted us, which involve -coordination with alkyne
functionality and -complexation with nitrogen and oxygen
containing functional groups.20
We initiated the study by choosing acetamide 1a as substrate,
which was prepared by a Sonogashira coupling reaction between
2-ethynylaniline and N-(2-iodophenyl)acetamide. As expected,
the domino cyclization took place when 3 equiv amount of zinc
bromide was employed, delivering 6-methyl indolo[1,2-
c]quinazoline 2a in 87% yield (Table 1, entry 1). Reducing the
amount of ZnBr2 from 3 to 2 equiv shows little negative effect
(Table 1, entry 2). When a stoichiometric amount of ZnBr2 was
used, the yield was dropped to 53% (Table 1, entry 3). Attempt to
use a catalytic amount of ZnBr2 resulted in inferior result. The
reaction was strongly slowed down and the indolo[1,2-
c]qunazoline was obtained in 35% yield even under a prolonged
heating (Table 1, entry 4). The yield was kept low when catalytic
zinc catalysts such as ZnI2 and Zn(OTf)2 were utilized (Table 1,
entries 5-6). To probe the effect of counteranion, zinc chloride
was examined and a decline in yield was observed (Table 1, entry
7). For comparison, a variety of other lewis acids including InBr3,
FeCl3, AlCl3 were screened (Table 1, entries 8-10). It was
demonstrated that the transformation can be carried out in lower
Xu, Min
