Copper-catalyzed synthesis of quinazolines in water starting from o-bromobenzylbromides and benzamidines

Article abstract of DOI:10.1002/chem.201200583

Water makes it possible: The Cu₂O-catalyzed reaction between easily available o-bromobenzylbromides and benzamidines by using Cs ₂CO₃ as the base and N,N'-dimethylethylenediamine (DMEDA) as the additive in water as the solvent gives access to substituted quinazolines in a single step with yields ranging from 57 to 85 % (see scheme).

Full text of DOI:10.1002/chem.201200583

COMMUNICATION
DOI: 10.1002/chem.201200583
Copper-Catalyzed Synthesis of
N
ACHTUNGTRENNUNG
Chandi C. Malakar, Alevtina Baskakova, Jꢀrgen Conrad, and Uwe Beifuss*[a]
Dedicated to Professor Lutz F. Tietze on the occasion of his 70th birthday
Quinazolines and their derivatives exhibit a wide range of
biological and pharmacological activities including anticanc-
er,[1] antiviral,[2] antitubercular,[3] and antimalarial[4] proper-
ties. This is why their synthesis receives much attention. Al-
though a number of well-known protocols to synthesize qui-
nazolines are available, there is a strong ongoing interest to
develop new and more efficient methods for their prepara-
tion.[5,6] More recent approaches to quinazolines include the
reaction between 2-aminobenzophenones and benzylic
amines by using catalytic amounts of copper-oxide nanopar-
ticles,[6c] the Cu-catalyzed reaction between 2-halobenzalde-
hydes or 2-halophenylketones with amidines,[6f] the transi-
C-benzylation/O-arylation. It is clear that Cu-catalyzed
domino reactions with 2-halobenzyl halides can also be em-
ployed for the synthesis of other six-membered heterocyclic
systems, if they are reacted with suitably 1,3-difunctionalized
reaction partners. Considering the synthesis of quinazolines
F, we assumed that both a domino intermolecular N-benzy-
lation/intramolecular N-arylation (A+B!C!E) and
a domino intermolecular N-arylation/intramolecular N-ben-
zylation (A+B!D!E) between a 2-halobenzyl halide A
and an amidine B followed by aromatization of the resulting
3,4-dihydroquinazoline E to the quinazoline F could serve
this purpose (Scheme 1).
ꢀ
tion-metal-catalyzed intramolecular oxidative C H function-
alization of N-phenylbenzamidines[6d] and N-(2-iodophenyl)-
trifluoroacetimidoyl chlorides,[6b] the Bischler quinazoline
synthesis under microwave conditions,[6g] and the oxidative
synthesis of 2-aryl quinazolines by reaction of 2-aminoben-
zophenones with benzylamines.[6a,e] To date, ortho-haloben-
zyl halides have not been employed as substrates for the
preparation of quinazolines.
The level of interest in Cu-catalyzed arylations has in-
creased considerably over the last few years.[7] This trend is
at least partly due to the fact that Cu reagents are much
cheaper than their Pd counterparts, which are usually em-
ployed for this type of transformation. Originally, Cu-cata-
lyzed arylations required comparably harsh reaction condi-
tions, but meanwhile protocols that allow for much milder
conditions have been developed. Cu-catalyzed arylations are
extensively used to synthesize aromatic amines, ethers, and
thioethers, but can also be employed for the synthesis of
many heterocycles.[7]
Scheme 1. Proposal for the Cu-catalyzed synthesis of quinazolines.
Herein, we report a new method for the efficient synthesis
of quinazolines that is based on the Cu-catalyzed reaction
between 2-bromobenzyl bromides and amidines in H2O.
When 1 equivalent of 2-iodobenzyl bromide (1) and 2 equiv-
alents of benzamidinium hydrochloride (3a) were reacted in
the presence of 10 mol% CuI and 2 equivalents of Cs2CO3
in DMF at 408C for 20 h under argon, 2-phenylquinazoline
(4a) could be isolated in 14% yield (Table 1, entry 1). This
result clearly demonstrated that quinazolines can be synthe-
sized by reaction between a 2-halobenzyl halide and an ami-
dine. However, it was obvious that optimization was needed
to make this an interesting synthetic method. The yield
could not be improved with 4-hydroxy-l-proline as an addi-
tive (see the Supporting Information). Further experiments
Recently, we reported the synthesis of 4H-chromenes by
Cu-catalyzed reaction between 2-halobenzyl halides and b-
ketoesters.[8] In this 4H-chromene synthesis one C C and
ꢀ
ꢀ
one C O bond are formed in a single step, and we have pro-
posed that these transformations proceed as a domino
[a] Dr. C. C. Malakar, Dr. A. Baskakova, Dr. J. Conrad,
Prof. Dr. U. Beifuss
Institut fꢀr Chemie, Universitꢁt Hohenheim
Garbenstr. 30, 70599 Stuttgart (Deutschland)
Fax : (+)(49)711-459-22951
E-mail: ubeifuss@uni-hohenheim.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200583.
Chem. Eur. J. 2012, 00, 0 – 0
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Table 1. Optimization of the Cu-catalyzed reaction of 2-halobenzyl halides 1 and 2a with benzamidinium hydrochloride (3a).
Substrate
Cu source [mol%]
Additive [mol%]
Base [equiv]
Solvent
T [8C]
t [h]
Yield [%]
1
2
3
4
5
6
7
8
1
CuI; 10
CuI; 10
CuI; 10
Cu2O; 10
Cu2O; 10
Cu2O; 10
Cu2O; 10
Cu2O; 10
CuI; 10
CuBr; 10
CuCl; 10
–
–
Cs2CO3; 2
Cs2CO3; 4
Cs2CO3; 4
Cs2CO3; 4
Cs2CO3; 4
Cs2CO3; 4
Cs2CO3; 4
Cs2CO3; 4
Cs2CO3; 4
Cs2CO3; 4
Cs2CO3; 4
Cs2CO3; 4
K2CO3; 4
Cs2CO3; 3
DMF
DMF
DMF
DMF
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
40
50
50
20
24
24
24
24
40
40
40
40
40
40
40
40
40
14[a]
29[a]
30
39
45
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
DMEDA; 20
DMEDA; 20
DMEDA; 20
DMEDA; 20
DMEDA; 20
–
DMEDA; 20
DMEDA; 20
DMEDA; 20
DMEDA; 20
DMEDA; 20
DMEDA; 20
DMEDA; 20
100
100
100
100
100
100
100
100
100
100
100
61
traces
40[a]
36
14
9
–
40
49
9
10
11
12
13
14
Cu2O; 10
Cu2O; 10
[a] The reaction was performed under Ar.
with 2-bromobenzyl bromide (2a) revealed that N,N’-dime-
thylethylenediamine (DMEDA) was a more suitable addi-
tive. The yield of 4a could be doubled to 29%, when
20 mol% DMEDA was added, and the amount of Cs2CO3
was increased to 4 equivalents. (Table 1, entry 2). Unexpect-
edly, the yield could not be improved further by running the
reaction under air (Table 1, entry 3).
solvents, such as DMF, DMSO, and MeCN, and the nonpo-
lar meta-xylene, were found to be less effective than H2O
(see the Supporting Information). To summarize, the highest
yield of 2-phenyl quinazoline (4a) was obtained when the
reaction between 1 equivalent of 2a and 2 equivalents of 3a
Experiments with different Cu sources in DMF at 1008C
revealed that the yield of 4a could be increased to 39%
with Cu2O as the catalyst (Table 1, entry 4). Further im-
provements were achieved by replacing DMF with H2O as
the solvent (Table 1, entry 5) and by extending the reaction
time from 24 h to 40 h (Table 1, entry 6). Finally, 4a could
be isolated with 61% when the reaction was performed with
10 mol% Cu2O, 20 mol% DMEDA, and 4 equivalents of
Cs2CO3 in H2O at 1008C for 40 h in a sealed vial under air
(Table 1, entry 6). A control experiment revealed the impor-
tance of DMEDA as an additive: without any DMEDA,
only traces of 4a were formed (Table 1, entry 7). Another
control showed that the yield of 4a was higher in the pres-
ence of aerial O2 than in its absence (Table 1, entry 8).
Further studies established that also in H2O as the sol-
vent, Cu2O is a more efficient catalyst than CuI, CuBr, and
CuCl (Table 1, entries 9–11). When the amount of Cu2O was
decreased, the yield of 4a dropped considerably (see the
Supporting Information). In the absence of any Cu source,
not even traces of 4a were formed (Table 1, entry 12). This
result underlines the decisive role of the Cu catalyst for this
reaction. Then we focused on the base. When Cs2CO3 was
replaced with other bases, such as K2CO3, the yield dropped
to 40% (Table 1, entry 13). Reduction of the amount of
Cs2CO3 to 3 equivalents also resulted in substantial loss in
yield (Table 1, entry 14).
Table 2. Synthesis of substituted quinazolines 4a–e.
3
4
Yield
[%]
1
2
61
71
a
b
c
a
b
c
3
4
5
57
69
66
d
e
d
e
Finally, the influence of different solvents on the outcome
of the reaction between 2a and 3a was studied. Alcohols,
such as iPrOH and ethylene glycol, as well as polar aprotic
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Copper-Catalyzed Synthesis of Quinazolines
COMMUNICATION
Table 3. Synthesis of substituted quinazolines 4 f–m.
It was also demonstrated that substituted 2-bromobenzyl
bromides 2b–d are tolerated as substrates for the new qui-
nazoline synthesis as well (Table 3). They were reacted
under standard conditions with the unsubstituted 3a as well
as with the substituted derivatives 3b,d to give the quinazo-
lines 4 f–m with yields ranging from 61 to 85%. These re-
sults suggest that the newly developed quinazoline synthesis
will find a broad range of application.
2
3
4
Yield
[%]
In conclusion, a simple to execute and efficient one-pot
synthesis of substituted quinazolines from easily accessible
ortho-bromobenzyl bromides and benzamidines as starting
materials has been developed. The new Cu2O-catalyzed re-
action delivered the products selectively and with yields
ranging from 57 to 85% by using water as the solvent under
mild reaction conditions.
1
2
3
4
81
83
79
69
b
b
a
f
b
g
Experimental Section
A
vial (10 mL) was charged with Cu2O (0.05 mmol), DMEDA
(0.1 mmol), Cs2CO3 2.0 mmol), the 2-bromobenzyl bromide 2 (0.5 mmol),
and the amidinium salt 3 (1 mmol). The vial was sealed under air, and
H2O (2 mL) was added by syringe. The reaction mixture was heated in
an oil bath at 1008C for 40 h. After cooling to RT, the reaction mixture
was partitioned between CH2Cl2 (50 mL) and brine (20 mL). The aque-
ous phase was extracted with CH2Cl2 (2ꢃ40 mL). The combined organic
layers were dried over MgSO4 and concentrated in vacuo. The residue
thus obtained was purified by flash-column chromatography over silica
gel (petrol ether (PE)/EtOAc 20:1).
b
c
d
a
h
i
5
6
7
8
80
83
61
85
c
d
a
j
Acknowledgements
d
k
We thank Ms. S. Mika for recording the NMR spectra.
Keywords: N-arylation
· copper · domino reactions ·
heterocycles · water chemistry
d
d
b
d
l
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Received: February 22, 2012
Published online: && &&, 0000
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Copper-Catalyzed Synthesis of Quinazolines
COMMUNICATION
Domino Reactions
C. C. Malakar, A. Baskakova,
J. Conrad, U. Beifuss* ....... &&&& — &&&&
Copper-Catalyzed Synthesis of
A
Water makes it possible: The Cu2O-
catalyzed reaction between easily
available o-bromobenzylbromides and
benzamidines by using Cs2CO3 as the
base and N,N’-dimethylethylene-
ACHTUNGTRNEdNUNG iamine (DMEDA) as the additive in
ACHTUNGTRENNUNGo-
water as the solvent gives access to
substituted quinazolines in a single
step with yields ranging from 57 to
85% (see scheme).
AHCTUNGTRENNUNG
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
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These are not the final page numbers!