Cyclocondensation of 2-iodobenzaldehyde with benzamidines catalyzed by copper(I) iodide: A route to 2-arylquinazolines

Article abstract of DOI:10.1007/s10593-011-0696-1

The reaction of benzamidines with 2-bromo- and 2-iodobenzaldehydes catalyzed by the CuI/L-proline system has been studied. Reaction with 2-iodobenzaldehyde leads to the formation of quinazolines in good yield. 2-Bromobenzaldehyde forms 2-arylquinazolines

Full text of DOI:10.1007/s10593-011-0696-1

Chemistry of Heterocyclic Compounds, Vol. 46, No. 12, March, 2011 (Russian Original Vol. 46, No. 12, December, 2010)
CYCLOCONDENSATION OF 2-IODOBENZALDEHYDE
WITH BENZAMIDINES CATALYZED BY COPPER(I)
IODIDE: A ROUTE TO 2-ARYLQUINAZOLINES
A. V. Vypolzov1, D. V. Dar'in1, S. G. Ryazanov1, and P. S. Lobanov1*
The reaction of benzamidines with 2-bromo- and 2-iodobenzaldehydes catalyzed by the CuI/L-proline
system has been studied. Reaction with 2-iodobenzaldehyde leads to the formation of quinazolines in
good yield. 2-Bromobenzaldehyde forms 2-arylquinazolines in low yield due to the competing reaction
involving two molecules of amidine leading to a dihydrotriazine.
Keywords: benzamidine, 2-iodobenzaldehyde, quinazoline, catalysis by copper(I).
Up to the present many efficient methods have been developed for the N-arylation of various nitrogen
nucleophiles with aryl bromides and iodides using the Cu(I)/ligand system as catalyst [1-11]. Intramolecular
reactions of such type lead to benzo-condensed heterocycles [12-15], which broaden significantly the possibility
of synthesizing many difficultly available compounds of this family. These methods are attractive from the
availability and cheapness of reactants, simplicity of use, and frequent high yields.
The aim of the present work was the involvement of benzamidines in cyclocondensation with
o-halobenzaldehydes in the presence of a catalyst (CuI) and the development based on it of a new method of
synthesis of 4-unsubstituted quinazolines, which are usually obtained in several stages and not always in good
yield [16, 17]. There was no information in the literature at the beginning of our investigation on such reactions.
However, in the course of our work a report appeared from Chinese authors [18], which described the
interaction of amidines with various aromatic aldehydes, ketones, and esters containing an atom of chlorine or
bromine in the ortho position. In particular, 2-bromobenzaldehyde gives 2-substituted quinazolines in yields of
55-82% with amidines on catalysis with the CuI/L-proline system.
In our experiments the reaction of 2-bromobenzaldehyde with amidines proceeded esentially by other
route. We tested various conditions. The temperature regime, reaction time, solvent, and base were varied. The
most characteristic experiments are given in Table 1. The yield of 2-phenylquinazoline 3a in the reaction with
benzamidine did not exceed 32%. On carrying out the reaction with other ligands (N,N'-dimethyl-
ethylenediamine, ethylene glycol, 8-hydroxyquinoline) the target compound was formed in only trace amounts
or was not formed at all. Variation of the reactant/catalyst ratio and the use of 4 Å molecular sieve did not affect
the yield of quinazoline. Precise reproduction of the conditions of [18] also did not lead to the formation of
quinazoline in satisfactory yield.
_______
* To whom correspondence should be addressed, e-mail: pslob@mail.ru.
1Saint Petersburg State University, Saint Petersburg 198504, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, 1833-1837, December, 2010.
Original article submitted April 7, 2010.
0009-3122/11/4612-1481©2011 Springer Science+Business Media, Inc.
1481

The reason for the low yield of quinazoline was that the main direction of the reaction proved to be the
formation of dihydrotriazine 4, obtained from two molecules of amidine and one molecule of benzaldehyde as a
result of nucleophilic attack of two molecules of amidine at the formyl group. Such a pathway for the reaction of
aldehydes with amidines is characteristic of any aromatic aldehyde, including those having no halogen atom in
the ortho position [19, 20]. Triazines are of course formed without catalysis by copper(I) salts. Gradual addition
of benzamidine to the reaction mixture did not lead to a reduction of the fraction of dihydrotriazine 4 formed or
an increase in the yield of quinazoline.
There was no report in [18] of the formation of dihydrotriazine in the reaction of benzamidine with
2-bromoaldehydes. According to our data, dihydrotriazine 4 as the free base in solution is a mixture of tautomers
with various dispositions of double bonds in the ring, but the hydrochloride is a single tautomer. The NMR
spectra did not permit the position of the double bonds in the tautomers to be established.
Ph
.
HCl
NH
HN
N
H2N
Ph
CHO
Br
2a
N
N
Ph
+
CuI, ligand,
base, solvent
N
Ph
Br
4
3a
1
We also introduced acetamidine 2b into reaction with 2-bromobenzaldehyde 1. However on using
conditions giving a maximum yield in the case of benzamidine 2a, 2-methylquinazoline 3b was observed by us
1
in only trace amounts (TLC and H NMR of the reaction mixture). We also reproduced the reaction conditions
described by the Chinese authors with acetamidine, for which a yield of 75% is given [18], however a result was
obtained analogous to ours, the yield of quinazoline did not exceed 5%.
TABLE 1. Reaction of 2-Bromobenzaldehyde (1) with Benzamidine 2a
Experi-
ment
Temperature,
°C
Yield 3а,
Solvent
Base
Time, h
%
1
2
3
4
5
6
7
9
DMSO
DMSO
DMSO
DMF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
t-BuOK
—
70
20
1
12
3
32
32
28
18
—
29
—
20
100
100
70
3
Toluene
DMSO
Pyridine
DMSO
2
20
12
2
70
K3PO4
100
2
TABLE 2. Reaction of 2-Iodobenzaldehyde (5) with Benzamidines 2
Amidine
R
Base
Temperature, °C
Time, h
Yield 3, %
Ph
Ph
Ph
Ph
Cs2CO3
K2CO3
K3PO4
70
20
20
20
70
70
70
70
70
1
12
12
1
75
50
50
73
62
60
52
60
63
2а
2а
2а
2а
2c
2d
2e
2f
t-BuOK
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
4-ClC6H4
1
4-MeOC6H4
3,4-(MeO)2С6H3
4-FC6H4
1
1
1
2-FC6H4
1
2g
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The use of 2-iodobenzaldehyde (5) under the same conditions led to a significant increase in the yields
of the desired compounds. On introducing a series of substituted benzamidines 2 into the reaction we obtained
2-arylquinazolines 3 in good yield (Table 2).
.
NH HCl
CHO
I
N
CuI, L-proline
base, DMSO
+
H2N
R
N
R
3a, c–g
2a, c–g
5
The reaction, in all appearances, occurs as addition of amidine to the aldehyde group with subsequent
cyclization involving the catalyst. Just the intramolecularity of the second stage of the substitution of the
halogen atom catalyzed by copper explains, in our view, the fairly mild conditions of carrying out the reaction
and its high rate in comparison with amination reactions of aryl bromides with amines, which usually occur at
temperatures above 80oC for more than 30 h [4].
We were therefore unable to reproduce the results of [18] in the part of the synthesis of quinazolines
from amidines and 2-bromobenzaldehyde, however replacement of the latter by 2-iodobenzaldehyde enabled
quinazolines to be obtained in good yield.
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on a Bruker DPX 300 instrument (300 and 75 MHz
respectively) in CDCl3. Internal standard was the residual signal of CHCl3 (δ 7.26 for 1H) and CDCl3 (δ 77.7 ppm
for 13C). Coupling constants in 1H NMR spectra were measured to a first order approximation. The mass spectra
were obtained on a Waters Micromass ZQ instrument, ionization was by electrodispersion (ESI+). Elemental
analysis was carried out on a Hewlett–Packard HP-185B CHN analyzer. The purity of preparations and the
progress of reactions was checked by TLC on Silufol UV-254 plates.
2-Iodobenzaldehyde 5 was obtained from 2-iodobenzoic acid by the known procedure of [21].
Reaction of 2-Bromobenzaldehyde (1) with Benzamidine 2a. A mixture of aldehyde 1 (2 mmol),
benzamidine hydrochloride (376 mg, 2.4 mmol), copper(I) iodide (76 mg, 0.4 mmol), L-proline (100 mg,
0.8 mmol), Cs2CO3 (1.63 g, 5 mmol), and dry DMSO (5 ml) was stirred at 70oC for 1 h. Water (50 ml) and ethyl
acetate (25 ml) were added. The aqueous layer was extracted with ethyl acetate (220 ml). The combined
organic layer was dried over MgSO4, the solvent was distilled off in vacuum, and the residue chromatographed
on a column (eluent was methylene chloride). Yield of 2-phenylquinazoline 3a was 132 mg (32%); mp
1
98-100oC (hexane) (lit. mp 98-100oC [22])). H NMR spectrum, δ, ppm (J, Hz): 7.53-7.59 (3H, m, m-C6H5,
p-C6H5): 7.61 (1H, t, J = 7.6, H-6); 7.91 (1H, t, J = 7.6, H-7); 7.93 (1H, d, J = 7.6, H-5); 8.10 (1H, d, J = 7.6,
H-8); 8.65 (2H, dd, J = 8.0, J = 2.0, o-C6H5); 9.48 (1H, s, H-4). 13C NMR spectrum, δ, ppm: 123.9, 127.4, 127.6,
128.88, 128.93, 130.9, 134.4, 138.3, 151.1, 160.8, 161.3. On further elution 2-(2-bromophenyl)-4,6-diphenyl-
dihydrotriazine (4) was isolated, mp 136-138oC and was characterized as the hydrochloride, mp 193-197oC. 1H
NMR spectrum, δ, ppm, (J, Hz): 6.87 (1H, s, CH); 7.40-7.90 (10H, m, H Ar); 8.22 (2H, d, J = 8.0, o-H Ar); 8.23
(2H, d, J = 8.0, o-H Ar); 11.9 (2H, br. s, 2NH). Mass spectrum, m/z (Irel, %): 393 (23), 392 [M+1]+ (96), 391
(24), 390 [M+1]+ (100), 290 (9), 288 (8), 186 (50), 184 (44). Found, %: C 58.75; H 4.03; N 9.66.
C21H17BrClN3. Calculated, %: C 59.11; H 4.02; N 9.85.
Reaction of 2-Iodobenzaldehyde 5 with Benzamidines 2. A mixture of aldehyde 5 (2 mmol),
benzamidine hydrochloride 2 (2.4 mmol), copper(I) iodide (0.4 mmol), L-proline (0.8 mmol), cesium carbonate
(5 mmol), and dry DMSO (5 ml) was stirred at 70oC for 1 h. The reaction product was isolated as in the reaction
with 2-bromobenzaldehyde.
1483

2-Phenylquinazoline 3a. Yield was 75%.
1
2-(4-Chlorophenyl)quinazoline (3c). Yield 62%; mp 139-141oC (lit. mp 137-138oC [23]). H NMR
spectrum, δ, ppm (J, Hz): 7.51 (2H, d, J = 8.6, 3,5-(p-ClC6H4)); 7.62 (1H, t, J = 8.0, H-6); 7.91 (1H, t, J = 8.0,
H-7); 7.93 (1H, d, J = 8.0, H-5); 8.08 (1H, d, J = 8.0, H-8); 8.58 (2H, d, J = 8.6, 2,6-(p-ClC6H4)); 9.44 (1H, s, H-4).
13C NMR spectrum, δ, ppm: 123.9, 127.5, 127.7, 128.9, 129.1, 130.2, 134.5, 136.8, 137.1, 151.0, 160.3, 160.8.
2-(4-Methoxyphenyl)quinazoline (3d). Yield 60%; mp 94-96oC (lit. mp 91-93oC [24]). H NMR
1
spectrum, δ, ppm (J, Hz): 3.92 (3H, s, CH3O); 7.06 (2H, d, J = 8.6, 3,5-(p-CH3OC6H4)); 7.59 (1H, t, J = 8.0,
H-6); 7.90 (1H, t, J = 8.0, H-7); 7.91 (1H, d, J = 8.0, H-5); 8.06 (1H, d, J = 8.0, H-8); 8.59 (2H, d, J = 8.6,
2,6-(p-CH3OC6H4)); 9.44 (1H, s, H-4). 13C NMR spectrum, δ, ppm: 55.7, 114.3, 123.6, 127.1, 127.4, 128.7,
130.5, 131.1, 134.3, 151.1, 160.7, 161.1, 162.1.
1
2-(3,4-Dimethoxyphenyl)quinazoline (3e). Yield 52%; mp 112-114oC. H NMR spectrum, δ, ppm (J,
Hz): 4.00 (3H, s, CH3O); 4.09 (3H, s, CH3O); 7.04 (1H, d, J = 8.6, 5-(3,4-(CH3O)2C6H3)); 7.60 (1H, t, J = 8.0,
H-6); 7.90 (1H, t, J = 8.0, H-7); 7.91 (1H, d, J = 8.0, H-5); 8.07 (1H, d, J = 8.0, H-8); 8.22 (1H, d, J = 1.5,
2-(3,4-(CH3O)2C6H3)); 8.28 (1H, dd, J = 8.6, J = 1.5, 6-(3,4-(CH3O)2C6H3)); 9.44 (1H, s, H-4). 13C NMR
spectrum, δ, ppm ; 56.24, 56.28, 111.1, 111.3, 122.3, 123.6, 127.1, 127.4, 128.6, 131.2, 134.3, 149.3, 151.0,
151.6, 160.6, 160.9. Found, %: C 72.08; H 5.27; N 10.56. C16H14N2O2. Calculated, %: C 72.17; H 5.30;
N 10.52.
1
2-(4-Fluorophenyl)quinazoline (3f). Yield 60%; mp 135-137oC. H NMR spectrum, δ, ppm (J, Hz):
7.23 (2H, t, J = 8.6, 3,5-(p-FC6H4)); 7.63 (1H, t, J = 8.0, H-6); 7.93 (1H, t, J = 8.0, H-7); 7.94 (1H, d, J = 8.0,
13
H-5); 8.08 (1H, d, J = 8.0, H-8); 8.62-8.67 (2H, m, 2,6-(p-FC6H4)); 9.46 (1H, s, H-4). C NMR spectrum, δ,
2
3
ppm (J, Hz): 115.8 (d, JC-F = 21.0); 123.8, 127.4, 127.6, 128.8, 130.9 (d, JC-F = 8.0), 134.5, 134.6 (d,
4JC-F = 4.0); 151.0, 160.4, 160.8, 165.0 (d, JC-F = 250.0). Found, %: C 74.83; H 4.06; N 12.51. C14H9FN2.
1
Calculated, %: C 74.99; H 4.05; N 12.49.
1
2-(2-Fluorophenyl)quinazoline (3g). Yield 63%; mp 88-90oC. H NMR spectrum, δ, ppm (J, Hz):
7.22-7.34 (2H, m, 3,4-(o-FC6H4)); 7.44-7.51 (1H, m, (o-FC6H4)); 7.66 (1H, t, J = 8.0, H-6); 7.93 (1H, t, J = 8.0,
H-7); 7.95 (1H, d, J = 8.0, H-5); 8.12 (1H, d, J = 8.0, H-8); 8.17 (1H, m, 6-(o-FC6H4)); 9.52 (1H, s, 4-H).
13C NMR spectrum, δ, ppm (J, Hz): 117.2 (d, J = 23.0); 123.5, 124.5 (d, J = 4.0); 127.36 (d, 3JC-F = 10.0); 127.4,
3
2
1
128.1, 129.0, 131.9 (d, JC-F = 9.0); 132.5, 134.6 (d, JC-F = 19.0); 150.9, 160.0, 160.7, 161.6 (d, JC-F = 240).
Found, %: C 74.97; H 4.07; N 12.56. C14H9FN2. Calculated, %: C 74.99; H 4.05; N 12.49.
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