FULL PAPER
synthesis of nitrogen-containing compounds,[14,15] here-
in we reported a PPTS-catalyzed bicyclization reaction
Results and Discussion
of 2-isocyanobenzaldehydes as 1,5-dielectrophiles with Initially, the reaction of 2-isocyanobenzaldehyde 1a
various amines for the first time (Scheme 1). The and o-phenylenediamine 2a was investigated to opti-
advantages of the current protocol can be summarized mize the reaction conditions (Table 1). We found that
as follows: (1) the reaction provides a simple and the benzo[4,5]imidazo[1,2-c]quinazoline 3aa was ob-
efficient strategy for the assembly of structurally tained in 52% yield when the reaction of 1a
diverse fused quinazoline derivatives; (2) this strategy (0.2 mmol) with 2a (0.5 mmol) was performed in the
allows the formation of two rings and three new bonds presence of pyridinium p-toluenesulfonate (PPTS,
with only water and hydrogen as the by-products in a 10 mol%) at room temperature for 1 h (Table 1,
single step; (3) this protocol is characterized by a broad entry 1). To our delight, the yield of 3aa was raised to
substrate scope, readily available starting materials, 91% by the addition of 4Å molecular sieves (100 mg)
mild reaction conditions, and high scalability.
under otherwise identical conditions (entry 2). De-
creasing the amount of PPTS led to comparatively
lower yield (entry 3). Further increasing the amount of
PPTS did not improve the yield of 3aa (entry 4). Other
acid catalysts, such as AcOH, TsOH, and TfOH were
less effective than PPTS (entries 5–7). Among the
solvents tested, DMSO turned out to be the best
choice. Other solvents, such as DMF, MeCN, THF,
1,4-dioxane, toluene and DCE gave lower yields.
With the optimized reaction conditions in hand, the
scope of the bicyclization reaction was examined and
the results are summarized in Table 2. We found that
the bicyclization showed broad tolerance to various
diamines. All selected o-phenylenediamines 2a–k
bearing either electron-withdrawing or electron-donat-
ing groups on the aromatic rings and pyridine-3,4-
diamine 2l reacted smoothly with 2-isocyanobenzalde-
hyde 1a to give the corresponding benzo[4,5]imidazo
[1,2-c]quinazolines 3aa–l in high to excellent yields.
In this transformation, symmetrical o-phenylenedi-
amines 2a–d gave single isolated products 3aa–d as
expected. Reactions of o-phenylenediamines 2f–k with
1a provided inseparable regioisomers 3af–k. In the
case of 3-methylbenzene-1,2-diamine 2e and pyridine-
3,4-diamine 2l, the bicyclization reaction showed
exclusive regioselectivity and produced the desired
products 3ae and 3al in 85% and 69% yields,
respectively. Similarly, N1-phenylbenzene-1,2-diamine
2m could react efficiently with 1a to produce desired
product 3am in 91% yield. When naphthalene-1,8-
diamine 2n was employed as reaction partner, the
dihydroquinazolino[3,4-a]perimidine 3an was pro-
duced in 93% yield. In addition, the bicyclization of 2-
(aminomethyl)aniline 2o with 1a also proceeded
efficiently in a highly regioselective manner, resulting
in the expected single product 3ao in 92% yield.[16]
Besides to aromatic amines, a range of aliphatic
diamines, such as propane-1,3-diamine 2p, N1-meth-
ylpropane-1,3-diamine 2q, and butane-1,4-diamine 2r
also proved to be efficient partners, and the desired
fused quinazoline derivatives 3ap–r were obtained in
high to excellent yields. Notably, even using 2-amino-
benzamide 2s as dinucleophile, the bicyclization also
worked well, yielding the desired product 3as in 67%
yield. More importantly, 2-(1H-benzo[d]imidazol-2-yl)
Scheme 1. Bicyclization reaction of o-formyl arylisocyanides
with amines for the synthesis of diverse fused quinazolines.
Table 1. Optimization of reaction conditions.[a]
Entry Catalyst
[mol%]
Addition
–
Solvent
DMSO
t
Yield[b]
[%]
1
PPTS (10)
1
1
1
1
1
1
1
1
1
2
2
2
2
52
91
86
90
33
45
57
74
58
46
51
38
41
2
3
PPTS (10) 4ÅMS (100 mg) DMSO
PPTS (5) 4ÅMS (100 mg) DMSO
4
5
6
7
8
9
10
11
12
13
PPTS (15) 4ÅMS (100 mg) DMSO
AcOH (10) 4ÅMS (100 mg) DMSO
TsOH (10) 4ÅMS (100 mg) DMSO
TfOH (10) 4ÅMS (100 mg) DMSO
PPTS (10) 4ÅMS (100 mg) DMF
PPTS (10) 4ÅMS (100 mg) MeCN
PPTS (10) 4ÅMS (100 mg) THF
PPTS (10) 4ÅMS (100 mg) dioxane
PPTS (10) 4ÅMS (100 mg) toluene
PPTS (10) 4ÅMS (100 mg) DCE
[a] 1a (0.2 mmol), 2a (0.2 mmol), catalyst (5–15 mol%), 4Å MS
(100 mg), solvent (0.5 mL), at room temperature for 1–2 h.
[b] Isolated yield.
Adv. Synth. Catal. 2021, 363, 1923–1929
1924
© 2021 Wiley-VCH GmbH