Copper-catalyzed intermolecular cyclization of nitriles and 2-aminobenzylamine for 3,4-dihydroquinazolines and quinazolines synthesis via cascade coupling and aerobic oxidation

Article abstract of DOI:10.1039/c4ra09240f

A copper-catalyzed cascade coupling and aerobic oxidation of aromatic nitriles and 2-aminobenzylamine for the synthesis of 3,4-dihydroquinazolines and quinazolineshas been achieved. The catalytic system, characterized by not adding additives and using molecular oxygen as the sole oxidant, exhibited exquisite substrate specificity and operated under mild conditions through inherently green processes. This journal is

Full text of DOI:10.1039/c4ra09240f

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Copper-catalyzed intermolecular cyclization of
nitriles and 2-aminobenzylamine for 3,4-
dihydroquinazolines and quinazolines synthesis via
cascade coupling and aerobic oxidation†
Cite this: RSC Adv., 2014, 4, 49888
Received 25th August 2014
Accepted 30th September 2014
*
Cheng Li,‡ Shujuan An,‡ Yuelu Zhu, Jin Zhang, Yifan Kang, Ping Liu, Yaoyu Wang
DOI: 10.1039/c4ra09240f
*
and Jianli Li
www.rsc.org/advances
A
copper-catalyzed cascade coupling and aerobic oxidation of dihydroquinazolines that are compatible with various func-
aromatic nitriles and 2-aminobenzylamine for the synthesis of 3,4- tional groups and proceed under mild conditions remain highly
dihydroquinazolines and quinazolineshas been achieved. The catalytic desirable. Herein, we report the transformations of various
system, characterized by not adding additives and using molecular nitriles with 2-aminobenzylamine via copper-catalyzed cascade
oxygen as the sole oxidant, exhibited exquisite substrate specificity coupling to synthesize 3,4-dihydro-quinazolines and aerobic
and operated under mild conditions through inherently “green” oxidative process to produce 2-substituted quinazolines. The
processes.
catalytic system, characterized by not adding additives and
using molecular oxygen as the sole oxidant, exhibited exquisite
substrate specicity and operate under mild conditions through
inherently “green” processes. Particularly, the present method
could provide a practical route for synthesis of 3,4-dihy-
droquinazolines for the rst time.
To standardize the reaction conditions a series of experi-
ments were performed with variation of reaction parameters
such as catalyst, solvent and temperature for are presentative
coupling of benzonitrile 1a and 2-aminobenzylamine 2. As
shown in Table 1, screening of various copper catalysts (entries
1–9) revealed that CuII(L1)2 displayed greater catalytic reactivity
for the transformations (entry 6). Only a trace amount of target
Among pharmaceutical substances, the N-heterocycles
comprise an important class.1 A recent survey found that more
than 70% of the top-selling proprietary drugs contain N-
heterocycles in their structures.2 As such, 2-substituted quina-
zolines and 3,4-dihydroquinazolines have been widely used in
organic synthesis and medicinal chemistry as building blocks
because of their biological and therapeutic activities (Fig. 1).3,4
For example, quinazolines are used as ligands for benzodiaze-
pine and GABA receptors in the CNS system5 or as DNA
binders.6 There are some synthetic strategies available for the
synthesis of quinazolines7,8 involving several substrates such as
2-halophenylmethanamines9 or 2-aminobenzoketones10 or
amidines11 or 2-aminobenzaldehydes12 (Scheme 1). Despite
these advances, the reported synthetic approachs suffer from
some drawbacks that nonrenewable oxidant has to be used and
the yields are not satisfactory. Unfortunately, few methods are
reported for synthetic approaches to 3,4-dihydroquinazolines
until now,11a,13 and this transformation is considered to be a big
challenge. Therefore, novel and efficient methods for the
synthesis
of
2-substituted
quinazolines
and
3,4-
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of The
Ministry of Education and College of Chemistry & Materials Science, Northwest
University, Xi'an, Shaanxi 710069, P. R. China. E-mail: lijianli@nwu.edu.cn;
liuping@nwu.edu.cn; Fax: +86 2988308396
† Electronic supplementary information (ESI) available: Experimental procedure,
characterization data, copies of 1HNMR, 13C NMR and IR spectra. CCDC 977533
and 977534. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c4ra09240f
Fig. 1 This work and general methods for the synthesis of quinazo-
‡ Cheng Li and Shujian An contributed equally to this work.
lines and 3,4-dihydroquinazolines.
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Table
2
Copper-catalyzed cascade coupling for synthesis of 2-
substituted 3,4-dihydroquinazolinesa,b
Scheme 1 Quinazolines as core structures in drugs.
Table 1 Optimization of the reaction conditionsa
Entry
Catalyst
Solvent
Temp (ꢀC)
Yieldb (%)
1
2
3
4
6
7
8
9
10
11
12
13
14
15
16
CuCl2
CuBr2
CuI2
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
75
75
75
75
75
75
75
75
75
75
75
75
90
100
110
n.d.
n.d.
n.d.c
20
60
<5
13
38
n.d.
62
65
Cu(OAc)2
CuII(L1)2
CuII(L2)2
CuII(L3)2
CuII(L4)2
—
CuII(L1)2
CuII(L1)2
CuII(L1)2
CuII(L1)2
CuII(L1)2
CuII(L1)2
a
The reaction conditions were as follow: 1 (1 mmol), 2 (1.25 mmol),
CuII(L1)2 (0.1 mmol) in 2 mL toluene at 110 ꢀC under air. Yield of
b
the isolated pure product. c Reaction time is 6 h. d Reaction time is 8 h.
EtOH
nitriles showed better reactivity and provided higher yields than
electron-rich ones, and the reactions were insensitive to the
steric hindrance of the substituents on the aromatic rings. The
nitriles possessing phenyl, pyridyl, and thienyl groups under-
went the desired reaction to give the corresponding dihy-
droquinazolines 3a–3e in good yields. However, 2-(pyridin-3-yl)-
3,4-dihydroquinazoline 3c was obtained in trace amounts due
to the volatility of dihydroquinazoline. Nitriles with uoro,
chloro, bromo, nitro, and triuoromethyl groups on the phenyl
ring reacted smoothly to give the corresponding dihy-
droquinazolines 3f–3o in excellent yields in the reactions. The
ability to incorporate C–Br and C–Cl bonds makes this method
appealing, since it offers an opportunity for further trans-
formation. An extensive investigation of the reaction showed
that dinitriles were converted into the respective mono-
dyhydroquinazolines with excellent chemoselectivity (3p–3s). It
is note worthy that mixtures of dinitriles (1 mmol) with double
CH3CN
Toluene
Dioxane
Toluene
Toluene
Toluene
55
72
75
81
a
The reaction conditions were as follow: a mixture of benzonitrile (1a, 1
mmol), 2-aminobenzylamine (2, 1.25 mmol), catalyst (0.1 mmol),
b
solvent (2 mL) were heated in a 10 mL ask for 12 h under air. Yield
of the isolated pure product. c n.d. ¼ not detected.
product was observed in the absence of copper catalyst (entry
10). Optimization of different solvents revealed that EtOH,
dioxane and CH3CN were inferior to toluene in the reaction
(entries 11–13). There action temperature was also varied, and
110 ꢀC gave the best result (compare entries 14–16). Accord-
ingly, the optimized reaction conditions are as follows: CuII(L1)2
ꢀ
2-aminobenzylamine
(2.5
mmol)
gave
only
2-sub-
(10 mol%), under air atmosphere in toluene at 110 C.
stitutedmonodihydroquinazolines, which is of practical signif-
icance because the remaining nitrile group can be converted
into other important functional groups. Even if sterically bulky
aromatic nitriles such as 3,4,5,6-tetrauorophthalonitrile 1s
was used, the corresponding 3s were obtained in 89% yields.
With the optimized reaction conditions established, the
scope and generality of the reaction were investigated (Table 2).
There action showed high functional group tolerance and
proved to beaquitegeneral method for the preparation of dihy-
droquinazoline 3. In general, the electron-decient aromatic
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Unfortunately, couplings of 2-aminobenzylamine with alkyl in 42% yield (Scheme 2). This result indicated that the 3,4-
nitriles did not work by using a similar procedure. dihydroquinazolines 3 was probably an intermediate in the
Next, we continued our investigation by studying the synthesis of quinazoline 4, and the copper catalyst serves a
conversion of 1 and 2 to the desired quinazolines 4 using a double catalytic function for both cascade coupling and aerobic
combination of a copper catalyst together with O2 as the sole oxidation.
oxidant (Table 3). Satisfactorily, quinazolines could be obtained
A tentative mechanism is depicted in Scheme 3. First, the
smoothly with good results. These results that showed electron- nitrile 1 is activated by CuII(L1)2 to give intermediate A.14
withdrawing groups had more favorable effects than electron- Nucleophilic addition of A with 2-aminobenzylamine 2 provides
donating groups. As is depicted in Table 3, nitriles with uoro, B. Intramolecular cycloaddition of B provides C, intermediate C
chloro, nitro, and triuoromethyl groups on the phenyl ring releases CuII(L1)2 and NH3 to afford 3. As part of our ongoing
reacted smoothly to give the corresponding products in high effort, we also calculate the Fukui function (f+) of the compound
yields. These functional groups provide ample opportunity for 3 (Fig. 2), the result proved the tentative mechanism. The
further synthetic manipulations. The introduction of uorine nitrogen atom of tertiary amines 3 coordinate to CuII(L1)2 to give
atoms or uorine-containing groups into heterocyclic rings has D by a ligand-exchange reaction. Then the intermediate D
made possible the discovery of new bioactive products. We then through deprotonation to form E. Finally, aer deprotonation
succeeded in performing the reaction to demonstrate the would liberate quinazolines 4 and the reoxidation of the Cu(I)
practicability of the developed method in a one-pot fashion, and complex to the Cu(II) complex would close the catalytic cycle.15
our oxidation reaction could provide a useful route for drug
discovery. Similarly, copper-catalyzed aerobic oxidation of 2-
aminobenzylamine with alkyl nitrile was not effective under this
set of conditions.
To gain more insight into the mechanism of the reaction,
when 3a was treated under oxygen atmosphere for 6 h, 98%
yield of aromatized quinazoline 4a could be obtained. However,
when 3a was treated in the absence of CuII(L1)2, 4a was obtained
Scheme 2 The oxidation of 3,4-dihydroquinazoline to synthesize
quinazoline.
Table
3 Copper-catalyzed aerobic oxidation for synthesis of 2-
substituted quinazolinesa,b
Scheme 3 Possible mechanism for synthesis of 3,4-dihydroquinazo-
lines and quinazolines.
a
Reaction conditions: 1 (1 mmol), 2 (1.25 mmol), CuII(L1)2 (0.1 mmol)
b
in 2 mL toluene under oxygen atmosphere at 110 ꢀC. Yield of the
isolated pure product. c Reaction time is 6 h.
Fig. 2 The Fukui function (f+) of the compound 3a.
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