Copper-mediated synthesis of quinazolin-4(3: H)-ones from N-(quinolin-8-yl)benzamide and amidine hydrochlorides

Article abstract of DOI:10.1039/c9nj02311a

An efficient copper-mediated tandem C(sp²)-H amination to provide quinazolinones from N-(quinolin-8-yl)benzamide and amidine hydrochlorides has been developed. It can afford rather complex products in a single step synthesis from easily availab

Full text of DOI:10.1039/c9nj02311a

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DOI: 10.1039/C9NJ02311A
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Copper-mediated synthesis of quinazolin-4(3H)-ones from N-
(quinolin-8-yl)benzamide and amidine hydrochlorides
Zihui Ban,a Xinfeng Cui,a Fangpeng Hu,a Guoqiang Lu,a Nan Luoa and Guosheng Huang*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient copper-mediated tandem C(sp2)-H amination to under
provide quinazolinones from N-(quinolin-8-yl)benzamide and dehydrogenative coupling of o-amino benzamides with benzyl
amidine hydrochlorides has been developed. It can afford rather alcohols catalyzed by square planar Ni(II) complex
oxidant-
and
ligand-free
conditions.17
(iii)
a
complex products in a single synthesis step from easily available ([Ni(MeTAA)]) featuring a tetraaza macrocyclic ligand.18 (iv)
starting materials using 8-aminoquinoline as a removable reaction between amides and methyl anthranilate mediated by
bidentate directing group. The features of this reaction is simple the Ph3P−I2 system.19 (v) employing copper-catalyzed
to operate and avoide sensitive and expensive metals, which intramolecular decarboxylative coupling to develop new
provides an approach for the construction of polycyclic domino reaction involving isatin and benzamidine
molecules in the area of organic chemistry.
hydrochloride.20 (vi) constructing N-heterocycles under ligand-
free copper catalysis at room temperature coupling of 2-
Quinazolinone is widely found in natural alkaloids and bromobenzoic acid with acetamidine hydrochloride.21 (vii)
pharmaceuticals.1 In addition, there are useful biological and synthesis of 3-(2-aminoethylamino)-propyl-functionalized
medicinal activities to be proved among quinazolinone derivatives
,
MCM-41-immobilized copper(I) complex for the homo- and
which can be used as antituberculosis,2 antimalarial,3 anticancer,4 heterocoupling of terminal alkynes and Buchwald N-arylation
antibacterial,5 anticonvulsants6 and antihypertensive7 agents, such as reaction of indoles with aryl halides.22
bouchardatine from Bouchardatia neurococca,8 2-methyl-4(3H)-
Rencently, our group proposed a copper-mediated tandem-
quinazolinone from Bacillus cereus,9 2-(4-hydroxybutyl) quinazolin- annulation reaction for the synthesis of quinazolin-4(1H)-ones
4-one from Dichroa febrifuga,10 and luotonin A from Peganum from amidines and benzamides23b and successfully achieved it.
nigellastrum11 (Scheme 1). As a result, the quinazolinone skeleton is Analogously, synthesis of quinazolin-4(3H) ones from N-
considered to be a privileged structure.12 Therapeutic agents (quinolin-8-yl)benzamide and amidine hydrochlorides is also a
containing the quinazolinone core structure have been on the market convenient access, which is a simple and readily accessible
or used in clinical trials for the treatment of cancer.13
precursors. We displayed a copper-mediated ortho C-H
The C−N bond of quinazolinone can be formed in a good manner amination assisted by a removable 8-aminoquinoline directing
with high regioselectivity and stereoselectivity14 has attracted group followed by the intramolecular nucleophilic addition
considerable attention in the field of chemistry.15 Great progress has toward various quinazolinones. Copper salts are used as
been made toward construction of quinazolinone derivatives. transition-metal catalysts for the C−N coupling reaction, and
Representative examples of synthesis of quinazolinones include: (i) specific base is required for reductive elimination to construct
constructing quinazolinones from easily available 2-arylindoles and C−N bonds. The combination of cyclization reactions through
amines or ammoniums via Baeyer−Villiger16 oxidation expansion C−N bond activation has presented an attractive and powerful
using O2 as oxidant, followed by dehydration condensation.1 (ii)
Cu(OAc)2-mediated nucleophilic addition of 2-halobenzamides
to nitriles followed by intramolecular SNAr reaction proceeded
O
NH
O
N
N
CH3
F
Br
N
2-(4-bromophenyl)-8-methylquinazolin-4(3H)-one
2-(fluoromethyl)-3-phenylquinazolin-4(3H)-one
O
O
aState Key Laboratory of Applied Organic Chemistry, Key Laboratory of
Nonferrous Metal Chemistry and Resources Utilization of Gansu Province,
Department of Chemistry, Lanzhou University, Lanzhou 730000, China. E-mail:
hgs@lzu.edu.cn
COOH
NH
NH
N
N
N
NH
H
OH
2-((2-hydroxyphenyl)amino)quinazolin-4(3H)-one
4-((4-oxo-3,4-dihydroquinazolin-2-yl)amino)benzoic acid
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Scheme 1 Application of quinazolinones on natural alkaloids.
This journal is © The Royal Society of Chemistry 20xx
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protocol to generate quinazolinone derivatives, which involves the
departure of large groups and the the formation of C-N bonds.
Using the optimized reaction conditions, the scope of the
DOI: 10.1039/C9NJ02311A
substrates were investigated (Table 2), excellent yields were
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Initially, N-(quinolin-8-yl)benzamide (1a) with benzamidine obtained for (1a) with different electronic properties effectively and
hydrochloride (2a) was chosen as a model reaction to examine the benzamidine hydrochloride (2a) with its derivatives to provide the
reaction, conditions that containing base, catalyst, reaction corresponding products in moderate to good yields (45−93%, 3a−v).
temperature and reaction time. The results were disclosed in Table 1. In addition, N-(quinolin-8-yl)benzamide with electron-withdrawing
Firstly, we selected Cu(OAc)2 as the catalyst and K2CO3 as the base groups (fluoro- and chloro-) reacted well and furnished the desired
for the blank control experiment, and found that both the catalyst and products 3b, 3c in 52% and 49% yield, respectively. However, o-
the base were indispensable. Next we concentrated attention on the substituted substrates bearing electron-donating groups proceeded
effect of base in rank. It is obvious that excellent yields were badly and we failed to find the target product (3d). Meanwhile, m-
obtained when Na2CO3, K2CO3 ,Cs2CO3 ,NaOH and t-BuOK were substituted substrates reacted smoothly and resulted in the desired
used as the base and K2CO3 was the most effective (Table 1, entries quinazolinones in moderate yields (3e, 3f). The greater reactivity of
1-5) base. In the presence of DMAP, the desired product 3a could the substrates containing both electron-withdrawing groups and
not be detected (Table 1, entry 6), so K2CO3 was finally selected as electron-donating groups at the 4-position of the aryl ring could lead
the base for the reaction. Moreover, the effect of the catalyst on the to formation of the corresponding quinazolin-4(3H)-ones in higher
model reaction was also investigated (Table 1, entries 7-12). The yields (3g-3m). We were pleased to find that the N-(quinolin-8-yl）
yield increased significantly when CuI, CuCl, Cu(OTf)2 and Cu2O benzamide, 4-methyl, 4-ethyl, 4-methoxyl, 4-fluoro, 4-chloro , 4-
were used as the reaction media whereas Cu(acac)2 and CuBr2 bromo and 4-trifluoromethyl groups worked well and provided
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afforded low yields. As shown in Table 1, Cu(OAc)2 still gave the Table 2. Scope of N-（quinolin-8-yl）benzamides and Amidine Hydrochloridesa
O
highest yield . Among the solvents examined, DMSO was found to
NH
NH2
O
conditions
NH
be the best choice (Table 1, entries 13-16), EtOH also afforded good
yield (Table 1, entry 16). While other solvents such as DCE, 1, 4-
dioxane and DMF were substantially less effective (Table 1, entries
13-15). The temperature influence was also examined by using
K2CO3 (2.0 equiv.) as the base in DMSO (Table 1, entries 17-18).
The reaction at 110 oC gave the best result and other temperatures
were distinctly less effective. In the end, the yield of 3a decreased
with the reaction time increasing or decreasing (Table 1, entries 19-
20) .The results revealed that 2-phenylquinazolin-4(3H)-one(3a) was
obtained as a main product in 91% yield in DMSO at 110 °C when
Cu(OAc)2 (20 mol %) was used as catalyst and K2CO3 (2 equiv.)
was used as base .
N
H
HCl
N
N
2a
3a
1a
O
N
F
O
N
Cl
O
N
NH
NH
NH
3c, 49%
3a, 91%
3b, 52%
O
O
OMe O
Cl
NH
NH
NH
N
N
N
3f, trace
3e, 61%
3d, nr
O
O
O
Table 1. Optimization of the reaction conditionsa
NH
NH
NH
N
MeO
N
N
Entry
1
2
3
4
5
6
7
8
Catalyst
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuI
Base
Na2CO3
K2CO3
Cs2CO3
NaOH
t-BuOK
DMAP
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DCE
DMF
1,4-dioxane
EtOH
DMSO
DMSO
DMSO
DMSO
Yield(%)b
59
3i, 68%
3h, 81%
3g, 76%
O
91
72
63
50
nr
59
86
54
23
23
72
14
nr
14
54
41
O
O
NH
NH
NH
F
N
N
Cl
N
Br
3l, 84%
3j, 82%
3k, 92%
O
O
O
CuCl
NH
S
NH
N
NH
N
9
Cu(OTf)2
Cu(acac)2
CuBr2
F3C
N
N
10
11
12
13
14
15
16
17d
18e
19f
20g
3o, nr
3m, 67%
3n, 78%
Cu2O
O
O
O
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
NH Cl
NH
N
NH
N
N
3p, nr
3r, 61%
3q, 45%
O
59
65
86
O
O
O
N
NH
NH
NH
N
NH
N
N
F
Cl
Br
3t, 93%
3s, 86%
3u, 89%
3v, nr
aReaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), catalyst (20 mol %), base (0.2
mmol) in solvent (2.0 mL) at 110 oC for 16 h. bIsolated yield. cnr=no reaction. d 100 oC.
e120 oC. f12 h. g20 h.
aReaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), catalyst (20 mol %), base
(0.2mmol) in solvent (2.0 mL). bIsolated yield. cnr=no reaction.
2 | J. Name., 2012, 00, 1-3
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quinazolin-4(3H)-one derivatives in 67%–92% yields. Interestingly,
View Article Online
DOI: 10.1039/C9NJ02311A
thiophene ring (3n) could be a suitable substrate. Nevertheless,
pyridine ring (3o) was examined no target product. Notably, the
quinazoline scaffolds which formed with a diverse range of halogen
atoms, providing enormous possibilities for further modification.
The reactions were also attempted with a range of amidine
hydrochlorides under the optimal conditions. It was found that the
reaction conditions were suitable for both electron-rich (4- methyl
and 3-methyl) and halogenic (4-F, Cl, Br) substituents on the phenyl
rings of the benzamidine hydrochloride, which obtained the
corresponding products in good yields (45−93%, 3q−3u). However,
alkyl and 2-chloro (3v, 3p) substituents were not found to be
compatible with this transformation. Steric hindrance had an obvious
effect on this transformation, indicating that at the para-position was
easily available target in this reaction.
A series of control experiments were conducted to gain more
insight into the reaction mechanism of this tandem reaction. First,
when a stoichiometric amount of a radical inhibitor 2,2,6,6-
tetramethylpiperidine-N-oxyl (TEMPO) was employed in the
standard reaction, the yield of the desired product 3a was only
slightly decreased, which indicated that a free radical pathway might
be ruled out in this transformation. So the ethene-1,1-diyldibenzene
was reacted as a radical inhibitor. Meanwhile, we used benzoyl
chloride instead of N-(quinolin-8-yl)benzamide to participate in the
reaction, with the results of no target 3a (Scheme 2) appeared. Based
on the experiments and other supporting information, a mechanism23
for the formation of quinazolinones has been proposed in Scheme 3.
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Scheme 3. Plausible mechanistic pathway.
In summary, a method for copper-catalyzed reaction of N-
(quinolin-8-yl)benzamide and amidine hydrochlorides has been
developed for assembling quinazolinone framework ,which provided
an approach for the construction of polycyclic molecules in organic
synthesis. The wide availability of the starting materials, and the
simplicity of the procedure enabled a convenient access to diverse
quinazolin-4(3H)-ones from simple and readily accessible materials.
Moreover, we used cheap copper catalysts, avoiding sensitive and
expensive metals. It is worthwhile to explore experiments on the
formation of quinazolinones.
O
NH
NH2
O
NH
standard conditions
N
H
HCl
N
TEMPO(2 equiv)
N
84%
O
O
NH
NH2
NH
standard conditions
N
H
HCl
Conflicts of interest
N
ethene-1,1-diyldibenzene
(2 equiv)
N
86%
There are no conflicts to declare.
O
NH
NH2
O
standard conditions
NH
HCl
Cl
N
Notes and references
nr
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Scheme 2 Control Experiments
The distinct catalytic cycle of C−H coupling with aryl nitrogen
proceeding through a transmetalation step supported the formation of
an aryl cupperate intermediate. First, intermediate A was generated
via coordination of N, N-bidentate substrate 1a with Cu(OAc)2
followed by ligand exchange, which underwent intramolecular C-H
activation. Next, the disproportionation gave CuOAc (CuⅠ) and B
(Cu Ⅲ ). Benzamidine hydrochloride (2a) then interacted with
intermediate B, which subsequently led to the formation of
intermediate C. The intermediate C then experienced a reductive
elimination and produced the important intermediate D. Finally, the
target product 3a was generated by protonolysis reaction.
5. Yi, Y.; Fu, Y.; Wang, K.; Shui, Y.; Cai, J.; Jia, Z.; Niu, B.;
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New Journal of Chemistry
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View Article Online
DOI: 10.1039/C9NJ02311A
O
NH
NH2
O
Cu(OAc)2
K2CO3
NH
R1
N
H
HCl
R2
R1
N
6
N
R2
7
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9
simple operation
economical
a wide range of substrate scopes up to 93% yield
easily available starting materials
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