Synthesis of quinazolines and imidazo[1,2-c]quinazolines with the aid of a low-valent titanium reagent

Article abstract of DOI:10.1055/s-2004-822893

A short and facile synthesis of a series of quinazolines and imidazo[1,2-c]quinazolines was accomplished in good yields via the novel reductive cyclization of 2-nitrobenzyl amines or 2-(2-nitrophenyl)imidazoles with ortho-ester, aldehydes or ketones promoted by TiCl₄/Zn system. The structures were established by spectroscopic data and confirmed by X-ray analysis.

Full text of DOI:10.1055/s-2004-822893

1098
LETTER
Synthesis of Quinazolines and Imidazo[1,2-c]quinazolines with the Aid of a
Low-Valent Titanium Reagent
Synthesis of
Q
uina
a
zolines
a
nd
q
Imidazo[1,2
i
-c]quin
n
azolines g Shi,*a–c Juxian Wang,b Chunling Shi,b Liangce Rong,b Qiya Zhuang,a,b Hongwen Huc
a
b
c
Department of Chemistry, Xuzhou Normal University, Xuzhou 221116, P. R. China
Key Laboratory of Biotechnology on Medical Plant , Jiangsu Previne, Xuzhou 221116, P. R. China
Department of Chemistry, Nanjing University, Nanjing 210093, P. R. China
Fax +86(516)3403164; E-mail: dqshi@263.net
Received 20 February 2004
X
CH2NHAr
X
Abstract: A short and facile synthesis of a series of quinazolines
and imidazo[1,2-c]quinazolines was accomplished in good yields
via the novel reductive cyclization of 2-nitrobenzyl amines or 2-(2-
nitrophenyl)imidazoles with ortho-ester, aldehydes or ketones
promoted by TiCl4/Zn system. The structures were established by
spectroscopic data and confirmed by X-ray analysis.
TiCl4-Zn
N Ar
CH(OEt)3
+
THF, reflux
NO2
N
1
2
3
Scheme 1
Key words: low-valent titanium, quinazoline, imidazo[1,2-
c]quinazoline, 2-nitrobenzyl amine, 2-(2-nitrophenyl)imidazole
Table 1 The Synthesis of 3-Arylquinazolines Promoted by
TiCl4/Zn
Entry
3a
X
Ar
Yield (%)a
In recent years, the low-valent reagent system has been
extensively used in organic synthesis. It has exceeding
efficiency in the reductive coupling of carbonyl
compounds1 and in a variety of other functional
groups.2–5 Recently, we have reported the low-valent
titanium-induced intermolecular reductive coupling reac-
tion of carboxylic derivatives with aromatic ketones,6 the
intramolecular reductive coupling reaction of 4,4-di-
cyano-1,3-diaryl-1-butanone7 and the cyclodimerization
of a,b-unsaturated ketones.8
H
4-ClC6H4
C6H5
73
71
83
82
84
79
79
91
3b
3c
Cl
Cl
Cl
H
4-CH3C6H4
4-BrC6H4
4-BrC6H4
3-Cl-4-FC6H3
4-ClC6H4
3-Cl-4-FC6H3
3d
3e
3f
H
Quinazoline derivatives have attracted a great deal of in-
terest, mainly concerning their synthesis, reactions and
biological properties, as this structural motif appears in a
large number of pharmaceutical agents and natural
products.9,10
3g
Cl
Cl
3h
a The ratio of low-valent titanium reagent, 1 and 2 is 4:1:2, in THF,
reflux for 5 h.14
Our interest in recent years has been focused on the use of
the low-valent reagent in synthesis. We have previously
reported the synthesis of bioactive molecules such as: in-
doles,11 2-aminoquinolines12 and 2-arylquinolines13 with
the aid of this reagent.
Moreover, treatment of 2-(2-nitrophenyl)imidazoles 4
and ortho-ester 5 with TiCl4/Zn in anhydrous THF under
the same reaction conditions afforded imidazo[1,2-
c]quinazolines 6 in moderate yields (Scheme 2). Table 2
summarizes our results.
Here we wish to describe a method induced by the TiCl4/
Zn system for the preparation of quinazolines and imida-
zo[1,2-c]quinazolines using 2-nitrobenzyl amines and 2-
(2-nitrophenyl)imidazoles as the starting materials.
X
When 2-nitrobenzyl amines 1 and triethyl orthoformate
(2) were treated with low-valent titanium prepared from
titanium tetrachloride and zinc powder in anhydrous THF,
the reductive cyclization products 3-arylquinazolines 3
were obtained in good yields (Scheme 1). The results are
summarized in Table 1.
X
Ph
O
Ph
Ph
N
N
N
TiCl4-Zn
R1 C R2
Y
Y
+
THF, reflux
N
H
Ph
O2N
NH
R1
R2
4
7
8
Scheme 2
SYNLETT 2004, No. 6, pp 1098–1100
0
6.
0
5.
2
0
0
4
Advanced online publication: 25.03.2004
DOI: 10.1055/s-2004-822893; Art ID: U0504ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Quinazolines and Imidazo[1,2-c]quinazolines
1099
Table 2 The Synthesis of Imidazo[1,2-c]quinazolines Promoted by
TiCl4/Zn
Entry
6a
X
Y
R
Yield (%)a
H
H
H
68
74
62
67
65
61
6b
6c
Cl
H
H
CH3O
H
CH3O
H
H
6d
6e
CH3
CH3
CH3
Cl
H
6f
CH3O
CH3O
a The ratio of low-valent titanium reagent, 4 and 5 is 5:1:2, in THF, r.t.
for 6 h 15
Figure 1 ORTEP diagram of 6a
X
X
Ph
O
Ph
Ph
N
N
N
TiCl4-Zn
+ R1 C R2
Y
Y
THF, reflux
N
H
Ph
O2N
NH
R1
R2
4
7
8
Scheme 3
However, treatment of 2-(2-nitrophenyl)imidazoles 4 and
acetone or aromatic aldehydes 7 with TiCl4/Zn in an-
hydrous THF under the same reaction conditions, the
cross-coupling
products
1,2-dihydroimidazo[1,2-
c]quinazolines 8 were obtained in moderated yields
(Scheme 3).
Figure 2 ORTEP diagram of 8b
Table 3 summarizes our results. All reactions could be
carried out under mild conditions. However, 2-(2-nitro-
phenyl)imidazoles failed to react with butanone, 3-pen- Table 3 The Synthesis of 1,2-Dihydroimidazo[1,2-c]quinazolines
Promoted by TiCl4/Zn
tanone, cyclohexanone, acetophenone under the same
conditions.
Entry X
Y
H
H
R1
R2
Yield (%)a
The structures 3, 6 and 8 were confirmed by IR, 1H NMR
and elemental analysis.16 The structures of 6a and 8b were
further confirmed by X-ray analysis (Figure 1 and
Figure 2) 17.
8a
8b
8c
8d
8e
8f
H
CH3 CH3
CH3 CH3
CH3 CH3
71
74
62
65
65
77
78
68
76
64
Cl
OCH2O
In summary, a series of 3-arylquinazolines, imidazo[1,2-
c]quinazolines and 1,2-dihydroimidazo [1,2-c]quinazo-
lines were synthesized via reductive cyclization of 2-ni-
trobenzyl amines or 2-(2-nitrophenyl)imidazoles with
ortho-ester, aldehydes or ketones induced by the TiCl4/Zn
system. The advantages of our method are the easily
accessible starting materials, convenient manipulation
and moderate to high yields.
H
H
H
H
H
H
H
H
H
4-CH3C6H4
H
H
4-ClC6H4
Cl
H
4-CH3C6H4
8g
8h
8i
Cl
H
3,4-(CH3O)2C6H3
3,4-(CH3O)2C6H3
4-CH3C6H4
H
H
CH3O
CH3O
CH3O
CH3O
8j
4-CH3OC6H4
a The ratio of low-valent titanium reagent, 4 and 7 is 3.3:1:1, in THF,
r.t. for 5 h
Synlett 2004, No. 6, 1098–1100 © Thieme Stuttgart · New York

1100
D. Shi et al.
LETTER
r.t. When the reaction was completed (at refluxing for 5 h
under N2), most of the solvent was removed in vacuo. The
residue was poured into 10% HCl (100 mL), and extracted
with CHCl3 (3 × 50 mL). The combined organic layers were
washed with water (3 × 50 mL), dried (Na2SO4), and the
solvent was removed in vacuo to give the crude product to
give the pure product 3.
Acknowledgment
We are grateful to the Natural Science Foundation of Jiangsu
Education Committee (03KJB150136) for financial support.
References
(15) The general procedure is represented as follow: A solution of
2-(2-nitrophenyl) imindazole 4 (2 mmol) and ortho-ester 5
(4mmol) in anhyd THF (10 mL) was added carefully at r.t.
to a suspension of low-valent titanium reagent (10 mmol)
prepared as mentioned above. When the reaction was
completed (at r.t. under N2), the reaction mixture was poured
into 10% HCl, and extracted with CHCl3. The combined
organic layers were washed with water, dried (Na2SO4), and
the solvent was removed in vacuo to give the crude product.
The crude product was purified by column chromatography
on silica gel (200–300 mesh) using petroleum ether (bp 60–
90 °C)–acetone (5:1) as eluent.
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stirred suspention of zinc dust (2.6 g, 40 mmol) in freshly
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Synlett 2004, No. 6, 1098–1100 © Thieme Stuttgart · New York