Synthesis of 4(3H)quinazolinimines by reaction of (E)-N-(aryl)-acetimidoyl or -benzimidoyl chloride with amines

Article abstract of DOI:10.1039/c5ob00444f

An efficient one-step method to access 4(3H)quinazolinimines by reaction of phenylchloroimines with 2-aminobenzonitrile is described. The reaction of (E)-N-(2-cyanophenyl)benzimidoyl chloride with substituted anilines that yields a number of their corresp

Full text of DOI:10.1039/c5ob00444f

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Synthesis of 4(3H)Quinazolinimines by Reaction of (E)‐N‐(Aryl)‐Acetimidoyl
or ‐benzimidoyl chloride with Amines
Celso Quintero,† Mauricio Valderrama,† Alexandra Becerra,† Constantin G. Daniliuc,§ Rene S.
Rojas.*, †
† Departamento de Química Inorgánica, Facultad de Química, Pontificia Universidad Católica de
Chile, Casilla 306, Santiago‐22, Chile, § Organisch‐chemisches Insꢀtut der Universitat Münster,
Corrensstrasse 40, 48149 Münster, Germany
ABSTRACT
An efficient one‐step access to 4(3H)quinazolinimines by reaction of phenylchloroimines with 2‐
aminobenzonitrile is described. The reaction of (E)‐N‐(2‐cyanophenyl)benzimidoyl chloride with
substituted anilines that yields a number of their corresponding C2, N3‐substituted
quinazoliniminium chloride or the neutral products is also reported. These methods provide a
direct and flexible access to diverse substituted iminoquinazolines substituted at the C2, N3‐
positions. All new compounds are fully characterized and six examples are given with their single‐
crystal X‐ray structure.
INTRODUCTION
Fused heterocyclic compounds are of particular interest and significant importance in the search
for new bioactive scaffolds in the agrochemical and pharmaceutical industries. In particular,
nitrogen‐containing heterocycles exhibit diverse biological and pharmacological activities due in
part to their structural relationship with many natural and synthetic compounds with known
biological activities.1 Among these kinds of molecules, the quinazolinimines2‐7 (Figure 1a) have
been studied due to their extensive therapeutic potential2 and also because of the possibility of
using them as starting materials in the synthesis of quinazolinone (Figure 1b).7a, 8 Another class of
1

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9, 10
N‐heterocyclic compounds of interest are the imidazoquinazolines
(Figure 1c), because they
introduce in their framework biologically valuable moieties like imidazole and quinazoline.9
Figure 1. General structures of (a) quinazolinimines, (b) quinazolinone, and (c)
imidazoquinazolines.
Several methods for synthesizing the class of compounds shown in Figure 1 have been reported.2 ‐
10
However, only a few of them have been optimized in terms of their scope to construct
functionalized quinazolinimines in a general way.3 For example, quinazolinimines are commonly
synthesized by reaction of anthranylonitriles with isocyanates, to give the corresponding ureas
which further undergo cyclization under basic catalytic conditions.4 To avoid the use of isocyanate,
a modification of the amino group in anthranylonitrile has been carried out with different reagents
such as diaryliodonium salts,3a triphenylphosphine bromide,3b phenyl chloroformate,4a
orthoester,5a formic acid5c and lactams.2c‐g,6 In general, some of the existing protocols require long
reaction times,5c high temperature,6 special setup and workup conditions,2f, g and they have low
yields.2e
At present, the goals in this area are directed towards the synthesis of new quinazolinimines
structurally related to bioactive products, by means of new and effective synthetic routes, which
may be quicker, more efficient and more versatile than the current methods. Based on this
background, we designed
a serie of substituted 2‐(phenyl or methyl)‐3‐aryl‐4(3H)‐
quinazoliniminium chlorides containing diverse substituents around the heterocycle through two
alternative pathways. The first procedure is based on the reaction of (E)‐N‐(2,6‐
diisopropylphenyl)benzimidoyl chloride or (E)‐N‐(2,6‐diisopropylphenyl)acetimidoyl chloride with
2

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2‐aminobenzonitrile, while the second one used the reaction of (E)‐N‐(2‐cyanophenyl)benzimidoyl
chloride with substituted anilines, chiral amines, or ethylenediamine, getting fused
quinazoliniminium heterocyclic compounds under mild reaction conditions.
This synthetic routes were proposed considering that searching new methods to synthesize
different diimine species,11 we observe that a cyclization reaction takes place forming a 4(3H)‐
quinazolinimine framework. Due to the interest of these types of heterocycles, we focused our
efforts on finding a new easy and efficient route to get these types of compounds.
RESULTS AND DISCUSSION
The compounds 3‐(2,6‐diisopropylphenyl)‐2‐methylquinazolin‐4(3H)‐imine (1) and 3‐(2,6‐
diisopropylphenyl)‐2‐phenylquinazolin‐4(3H)‐imine (2) were synthesized by reacting (E)‐N‐(2,6‐
diisopropylphenyl)acetimidoyl chloride12 and (E)‐N‐(2,6‐diisopropylphenyl)benzimidoyl chloride13
with stoichiometric amounts of 2‐aminobenzonitrile in toluene under reflux. Work up of the
reaction mixture produced compounds 1 and 2 in 66 and 68% yields, respectively (Scheme 1).
Scheme 1. Preparation of 3‐(2,6‐diisopropylphenyl)‐2‐methylquinazolin‐4(3H)‐imines (1) and 3‐
(2,6‐diisopropylphenyl)‐2‐phenylquinazolin‐4(3H)‐imines (2).
It seems possible that the formation of 2‐methyl or phenylquinazolinimines 1 and 2 proceeds via a
two step sequence which involves first the nucleophilic substitution of a chlorine atom in the
precursor induced by the arylamine to give an azaenamine intermediate, which by a subsequent 6‐
exo‐dig ring‐closure reaction14 provides the N‐heterocycles 4(3H)‐quinazolinimines.
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The FT‐IR, 1H and 13C NMR spectra, and HRMS (ESI) analyses are consistent with the formation of a
single isomer of the compounds. The NMR diagnostic peaks (in ppm) are shown in Table 1.
Table 1. Selected spectroscopic parameters of the quinazolinimine
compounds 1 and 2.
13C
1H


Compound
C4=N
RC2=N
C4N‐H
6.10
HCiPr
2.69
2.86
MeiPr
1
2
154.42 153.59
154.95 154.87
1.17, 1.11
1.14, 1.00
6.33
Compounds 1 and 2 were isolated in good yields as pure materials by crystallization, and the C4N‐H
resonances are indicative of the molecular imine moiety.
As an additional confirmation of the structure assignment of both compounds, single crystals of 1
and 2 suitable for X‐ray diffraction studies were obtained by slow evaporation of methanol (1) and
ethyl acetate (2), and the resulting structures are shown in Figures 2. The crystallographic
parameters are including in the supporting information.
Figure 2. Molecular structure of compound 1 (Left) and compound 2 (Right).
4

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The X‐ray crystal structure of compound 1 (Figure 2, Left) shows that the heterocyclic fragment is
orthogonal to the 2,6‐iPrPh (aryl) fragment, similar to the previously reported 4(3H)‐
quinazolinimine.3, 7b In the hetero‐atomic ring and the imine the C2‐N1, C2‐N3 and C4‐N4, C4‐N3
bond lengths are 1.290(2), 1.389(2) and 1.276(2), 1.408(2) Å, respectively, showing the double
bond character of the cyclic and exocyclic imine fragment and the tertiary amine nitrogen (N3). In
the heterocyclic ring, the C4‐C5 bond length is the only one that fits a single bond (1.468(2) Å)
indicating that the conjugation extends along the side of N3, probably associated with an sp2
instead of sp3 character of nitrogen. This is consistent with the planarity of the ring and the N3
bond angles (range 117.7(1)‐122.5(1)°), very close to a perfect trigonal planar geometry (See Table
S1 (Supporting Information)).
The crystal lattice of compound 1 presents hydrogen bond interactions involving the exocyclic
imine moieties (N4A‐‐‐H23B‐C23B 2.552 Å; N4B‐‐‐H23A‐C23A 2.568 Å). These interactions lead to
the formation of a “zig‐zag” chain structure along the c‐axis.
X‐ray diffraction studies also confirm unequivocally the structure of compound 2 (Figure 2, right).
The structures show the same rearranged to compound 1, with the aryl group orthogonal to the
fused ring. The bond lengths in the heterocyclic ring and the angles over the amine nitrogen atoms
(N3) are equivalent to those shown above for compound 1, See Figure 2. (For further detail see,
Figure S2 and Table S1, Supporting Information).
The satisfactory results arising from the reaction of (E)‐N‐(2,6‐diisopropylphenyl)acetimidoyl
chloride and (E)‐N‐(2,6‐diisopropylphenyl)benzimidoyl chloride with 2‐aminobenzonitrile to get
the quinazolinimine derivatives encourage us to study a convenient access to quinazolinimine
derivatives by reaction of (E)‐N‐(2‐cyanophenyl)benzimidoyl chloride15 with anilines.
From benzimidoyl chloride, which contains a nitrile group in the ortho position, together with the
wide range of commercially available primary amines (aliphatic and aromatic) it is possible to
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prepare a large variety of quinazolinimines, Scheme 2. Furthermore, the preparation of (E)‐N‐(2‐
cyanophenyl)benzimidoyl chloride is optimized using excess thionyl chloride instead of PCl5 for the
chlorination of N‐(2‐cyanophenyl)benzamide. Two important advantages are associated with this
chlorinating agent. First, it is cheaper, and second, the purification of the chlorinated product is
achieved, since the excess of thionyl chloride is recovered by distillation, reducing the generation
of waste pollutants, and allowing isolation of the (E)‐N‐(2‐cyanophenyl)benzimidoyl chloride in
high purity. This new strategy is highly versatile and allows the building of quinazolinimine and/or
its salt with rings and a variety of possibilities at "N3", which can be very important in the
development of new drugs that would also be accessible by simple methods and in good yield.
Scheme 2 (I) and (II) shows the two‐step synthesis and the corresponding quinazolinimine salt with
a 4‐methoxy phenyl group as an option at N3.
Following similar procedure of 1 and 2, the reaction of (E)‐N‐(2‐cyanophenyl)benzimidoyl chloride
with 4‐methoxyaniline yields target compound 3 and 4 as colorless solids in 80% and 75% yields,
respectively (Scheme 2 (I) and (II)).
1
The H and 13C NMR spectra of compound 3 in CD3Cl/CD3OD (97:3) feature C‐H5 signals as a
doublet at δ 8.65 (13C: 124.65 ppm) and a MeO singlet resonance at δ 3.83 (13C: 55.6 ppm). The
signal associated with the NH2Cl proton was not seen, while the iminium carbon (C4) appears at 
158.19 ppm. For further details see the Supporting Information. The IR (ν C=NH2Cl) band of
compound 3 was found at 3288 cm‐1 and the HRMS analysis supports these results (C21H18N3O+:
m/z calcd: 328.144, found: 328.144).
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Scheme 2. Synthesis of 4(3H)Quinazolinimines by Reaction of (E)‐N‐(2‐cyanophenyl)benzimidoyl
chloride with Amines.
ClNH2
3
N
*
4
8 : 75%
2
1
N
Ph
H2N
Toluene, 48h
(III)
R1
R1
N
Cl
ClNH2
NH
NH2
H2N
R1
3
4
3
3
4
R
4
NH2-R
N
N
2
N
2
2
1
N
1
1
N
25% NH3
DCM
(II)
Toluene, 18-96h
(I)
Toluene, 24-26h
(V)
N
Ph
N
Ph
Ph
Ph
Cl
H2N
11: R = CH2-2-C5H4N
12: R = CH2-C7H5O2
13: R = 2,5-MeO-C6H3
3: R1 = OMe, 80%
5: R1 = H, 70%
6: R1 = NH2, 69%
7: R1 = CN, 65%
4: R1 = OMe, 75%
n
NH2
Toluene, 48h
(IV)
N
n = 1 o 2
3
N
9: n=1 75%
10: n=2 60%
4
2
1
N
R
In this method of synthesis, neutralization of the salt with an ammonia solution (25% aqueous
NH3) allows isolation of the 3‐(4‐methoxyphenyl)‐2‐phenylquinazolin‐4(3H)‐imine 4, Scheme 2 (II).
The 1H and 13C NMR spectra in CD2Cl2 are consistent with the formation of a single isomer of 4. The
1H NMR spectrum features the imine‐H signal (–C4N‐H) as a broad singlet at δ 6.66 (13C: 155.37
ppm) and a singlet resonance of MeO at δ 3.76 (13C: 56.0 ppm). For further details see Table S6
and additional data in Supporting Information. The IR ( C=NH) band of compound 4 was found at
3311 cm‐1 and the HRMS analysis supports these results (C21H18N3O [M+H]+: m/z calcd: 328.144,
found: 328.144).
Single crystals of 4 suitable for solid‐state characterization were obtained by slow evaporation
from ethyl acetate. Similarly to what was seen in compounds 1 and 2 (Figures 2), the imine
presents a planar environment, while the N3 substituent is orthogonal to the fused heterocyclic
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ring. The bond lengths and angles around N3 follow the same trends seen for 1 and 2. (For further
details see Figure S3 and Table S1, Supporting Information).
The potential of (E)‐N‐(2‐cyanophenyl)benzimidoyl chloride as a starting material in the synthesis
of quinazoliminium chlorides, with alternatives at N3, was studied by direct reaction at position 3
with monosubstituted and disubstituted aromatic amines, chiral amines, and aliphatic diamines as
outlined in Scheme 2 and Table 2.
Table 2. Synthesis of 4(3H)Quinazolinimines (1‐13) by Reaction of Imidoyl
chloride with various Amines.
Imidoyl chloride
Amine
Compound
Yield
(%)
2‐aminobenzonitrile
66
1
2‐aminobenzonitrile
68
2
p‐anisidine
p‐anisidine
80
75
3
O
NH
3
4
N
2
1
N
Ph
4*
aniline
70
5
6
p‐phenylenediamine
4‐aminobenzonitrile
69
65
7
8
(R)‐(+)‐α‐methyl
benzilamine
75
8

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ethylenediamine
75
60
9
1,3‐diaminopropane
10
2‐picolinamina
45
55
11
12
piperonylamine
2,5‐dimethoxyaniline
65
13
*Neutralization of the corresponding salt (3).
The reaction of (E)‐N‐(2‐cyanophenyl)benzimidoyl chloride with one molar equivalent of aniline, p‐
phenylendiamine and 4‐aminobenzonitrile (toluene, reflux) gave the quinazoliniminium products
2,3‐diphenylquinazolin‐4(3H)‐iminium chloride 5; 3‐(4‐aminophenyl)‐2‐phenylquinazolin‐4(3H)‐
iminium chloride 6; and 3‐(4‐cyanophenyl)‐2‐phenylquinazolin‐4(3H)‐iminium chloride 7, isolated
as light yellow to light brown solids in 70, 69 and 65% yields, respectively, Scheme 2 (I) and Table
1
2. The H and 13C NMR spectra feature the C5‐H signals as doublets at δ 9.17, 8.77 and 8.43 (13C:
127.66, 126.67 and 125.90 ppm) for 5, 6 and 7, respectively. The resonances from the “exocyclic”
and cyclic imine carbon (C4 and C2) at δ 157.37 and 152.13 ppm for 5, 159.06 and 154.03 ppm for
6, and 158.87 and 153.78 ppm for 7, support the formation of the compounds. For further details
see the Supporting Information. The IR bands for (ν, C=NH2Cl) of 5, (NH2, ‐C=NH2Cl) of 6, and (‐
C=NH2Cl, CN) of 7 were found at 3378 cm‐1, [3411, 3328] cm‐1 and [3396, 2237] cm‐1, respectively,
+
and the HRMS analysis of compound 7 supports the formation of the salts (C21H15N4 : m/z; calcd:
323.129, found: 323.129).
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Single crystals of 5 suitable for X‐ray crystal structure analysis were grown by slow evaporation of
the solvent mixture (chloroform/methanol). As expected, the molecular structure corroborates
the proposed structure of the salt (see Figure S4, Supporting Information).
The use of (E)‐N‐(2‐cyanophenyl)benzimidoyl chloride as starting material in the synthesis of
quinazolinimine or its salts may extend to heterocycles with alternatives on aliphatic N3. Scheme 2
(III‐V) and Table 2 (Compounds 8‐12) shows five examples with this type of amines that illustrate
the versatility and synthetic power of the suggested route. The reaction of (E)‐N‐(2‐
cyanophenyl)benzimidoyl chloride with one molar equivalent of (R)‐(+)‐α‐methyl benzylamine in
toluene at room temperature gave the quinazoliniminium product 2‐phenyl‐3‐(1‐phenyl‐ethyl)‐
(3H)‐quinazolin‐4‐ylidene‐iminium chloride, 8. This compound was isolated and purified by silica
gel column chromatography using ethyl acetate/chloroform as eluent. Compound 8 was recovered
as a light yellow oil in 75% yield, Scheme 2 (III) and Table 2.
The 1H, 13C and 2D NMR spectroscopic characterization of compound 8 supports the formation of a
single isomer. The resonances at δ, 7.80 ppm, (d, J = 8.0 Hz, 1H, H5), 5.57 (q, J = 6.8 Hz, 1H, H15),
and 1.82 (d, J = 7.2 Hz, 3H, H16) are consistent with the proposed structure and purity of
compound 8. Because the resonances of the NH2 and the ‐NH2Cl functionalities are not seen by 1H
NMR, and although the full analysis by 2D NMR supports the proposed structure, efforts to detect
their presence in the compound were focused on getting high quality monocrystals to resolve the
structure, but they were not successful; however, the MS analysis supports the formation of the
salt, compound 8.
An interesting result was obtained from the reaction of (E)‐N‐(2‐cyanophenyl)benzimidoyl chloride
with ethylenediamine. At room temperature, and after 48 h followed by chromatographic
1
purification, a light yellow oil was isolated. The H NMR analysis of the product shows C5‐H
hydrogen atoms as a doublet at δ 8.04, (1H), and the resonance associated with the aliphatic ‐CH2‐
10

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of the ethylene fragment (multiplet) at 4.12‐3.99 ppm (4H). The resonances associated with ‐NH2
and –NH2Cl were not seen in the spectra. The IR (NH2 and –NH2Cl) bands were not seen (NMR and
IR details are available in the Supporting Information). The absence of the stretching bands of the
primary amine as well as of the C=NH2Cl group in the IR spectrum made us redouble our efforts to
complete the structural resolution of the product. Fortunately, the effort to grow a crystal was
successful; single crystals of 9 suitable for the X‐ray crystal structure analysis were obtained by
slow evaporation (ethyl acetate/chloroform). The X‐ray crystal structure of the product (see Figure
S5, Supporting Information) shows that the ethyl fragment is part of a second cycle in this
compound. The product of this reaction corresponds to the previously reported compound 5‐
9 10e

phenyl‐2,3‐dihydroimidazo[1,2‐c] quinazoline 9,
in our case obtained as a product of the
reaction of (E)‐N‐(2‐cyanophenyl)benzimidoyl chloride with ethylenediamine, Scheme 2 (IV) and
Table 2.
Confirming the versatility of this new synthetic method the compound 10, Scheme 2 (IV) and Table
2, which had been previously synthesized from thiazines and corresponding diamine was
prepared.16 (For more details see supporting Information). Additionally following this new
synthesis protocols, an equimolar amount of (E)‐N‐(2‐cyanophenyl)benzimidoyl chloride was
reacted with 2‐picolinamine and piperonylamine (toluene, reflux) generating the
quinazoliniminium products 2‐phenyl‐3‐(pyridin‐2‐ylmethyl)quinazolin‐4(3H)‐iminium chloride 11
and 3‐(benzo[d][1,3]dioxol‐5‐ylmethyl)‐2‐phenylquinazolin‐4(3H)‐iminium chloride 12, isolated as
white and pale yellow solids in 45 and 55% yields, respectively, Scheme 2 (V) and Table 2. The 1H
and 13C NMR spectra feature the C5‐H signals as doublets at δ 8.81 and 9.44 (13C: 121.72 and
127.70 ppm) and the resonance of carbon (C4) at δ 160.07 and 157.16 ppm for 11 and 12,
respectively, support the formation of the compounds. Additionally, the resonance corresponding
to the C15‐H of each compound appear as a singlet at δ 5.15 y 5.84 (13C: 46.41 and 53.40 ppm)
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respectively, confirming the presence of an aliphatic group on the fragment bonded to the N3
atoms of the quinazolinimine. For further details see the Supporting Information. The IR bands for
(‐C=NH2Cl) of 11 and 12 were found at 3302 cm‐1 and 3425 cm‐1, respectively. Efforts to obtain
single crystals of these compounds suitable for X‐ray analysis were unsuccessful, however the MS
+
analysis supports the purity of the compounds; for compound 11 (for C20H17N4 : m/z calcd: 313.15,
+
found: 313) and for compound 12 (for C22H18N3O2 : m/z calcd: 356.14, found: 356).
Finally, to prove the efficiency of this method with larger size aniline, was reacted (E)‐N‐(2‐
cyanophenyl)benzimidoyl chloride with 2,5‐dimethoxyaniline (toluene, reflux) yielding the desired
product 3‐(2,5‐dimethoxyphenyl)‐2‐phenylquinazolin‐4(3H)‐iminium chloride 13 isolated as a gray
solid in 65% yield, Scheme 2 (V) and Table 2. The 1H and 13C NMR spectra feature the C5‐H signals
as doublets at δ 9.54 (13C: 128.54 ppm). The resonances from the carbon (C4) at δ 157.03 ppm and
two singlet signals corresponding to methoxy groups C21,22‐H at δ 3.74 and 3.72 ppm (13C: 56.13
and 56.12 ppm) supporting the formation of the compound. For further details see the Supporting
Information. The IR bands for (‐C=NH2Cl) of 13 was found at 3393 cm‐1. The MS analysis confirm
+
the proposed structure and purity of the compound 13 [C22H20N3O2 : m/z calcd: 358.16 , found:
359].
Figure 3. Molecular structure of compound 13.
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Single crystals of 13 suitable for X‐ray crystal structure analysis were grown by slow diffusion of
solvent (dichloromethane/pentane). As expected, the molecular structure corroborates the
proposed structure of the salt (see Figure 3). The structural parameters were consistent with the
other ones shown. (For further details see Supporting Information).
Cytotoxicity studies of these compounds and other derivatives are in progress.
CONCLUSIONS
In summary, we have presented results on a novel and efficient route for the synthesis of
functionalized 4(3H)quinazolinimines and C2,N3‐substituted quinazoliniminium chlorides, starting
from phenylchloroimines and (E)‐N‐(2‐cyanophenyl)benzimidoyl chloride, respectively. The
synthetic method provides an easy new route and flexible access to iminoquinazolines with
different substituents at the C2, N3 positions with good yields (45‐80%).
EXPERIMENTAL SECTION
General
All manipulations were performed in air. Reagent‐grade solvents were obtained from E. Merck.
Toluene was distilled from benzophenone ketyl. The compounds 2‐aminobenzonitrile, aniline, p‐
phenylendiamine, 4‐aminobenzonitrile and p‐anisidine were purchased from Aldrich and used as
received. The imidoyl chlorides (E)‐N‐(2,6‐diisopropylphenyl)acetimidoyl chloride12 and (E)‐N‐(2,6‐
diisopropylphenyl)benzimidoyl chloride13 were prepared according to published procedures. The
compound (E)‐N‐(2‐cyanophenyl)benzimidoyl chloride was prepared according to a modified
literature procedure.15a The following instruments were used for the physical characterization of
1
the compounds. H and 13C NMR spectra were recorded on a Bruker Avance‐400 spectrometer.
Chemical shifts and the coupling constants are reported in parts per million (SiMe4 as standard)
and Hertz, respectively. Most of the NMR assignments were supported by additional 2D
experiments and the numbers of scans used for 13C NMR were ranged from 0.5–8K depending on
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the sample concentration. FT‐IR spectra were recorded on a Bruker Vector‐22 spectrophometer
using KBr pellets and the infrared frequencies are reported in cm‐1. Mass spectra were acquired
using a Micro Tof (Bruker) or a Clarus SQ 8T GC/MS (PerkinElmer). The structures and their labels
assignments are described on the supporting informations.
Preparation
of
(E)‐N‐(2‐cyanophenyl)benzimidoyl
chloride:
A
mixture
of
N‐
(cyanophenyl)benzamide15a (1.20 g, 5.40 mmol) and an excess of thionyl chloride (2 mL, 27 mmol)
was stirred for 8 hour under reflux. The remainder thionyl chloride was distilled off raising
temperature to 120 °C. The residues were removed under vacuum to give yellow solid (1.17 g,
90%). 1H NMR (400 MHz, CDCl3, 298 K) δ/ppm = 8.21 (d, J = 7.8 Hz, 2H, H3), 7.69 (d, J = 7.8 Hz, 1H,
H8), 7.66 – 7.55 (m, 2H, H10, 5), 7.49 (t, J = 7.8 Hz, 2H, H4), 7.27 (t, J = 7.7 Hz, 1H, H9), 7.11 (d, J = 8.1
Hz, 1H, H11). 13C NMR (100 MHz, CDCl3, 298 K) δ/ppm = 150.6 (C6), 147.6 (C1), 134.6 (C2), 133.5
(C10), 133.0 (C5), 133.0 (C8), 129.9 (C3), 128.7 (C4), 125.2 (C9), 120.9 (C11), 116.7 (C12), 104.9 (C7). FT‐
IR (KBr):  / cm‐1 = 3055, 3052, 2230 (CN), 1681, 1666, 1590, 1579, 1567, 1547, 1518, 1488, 1478,
1446, 1336, 1315, 1301, 1281, 1254, 1211, 1191, 1172, 1095, 1076, 1041, 1028, 1000, 979, 956,
925, 890, 869, 838, 764, 749, 734, 703, 682, 653, 633, 617, 604, 588, 561, 540, 504. MS (ESI) for
C14H9ClN2 [M]+: m/z calcd: 240, found: 240.
Synthesis of 3‐(2,6)‐diisopropylphenyl)‐2‐methylquinazolin‐4(3H)‐imine (1): (E)‐N‐(2,6‐
diisopropylphenyl)acetimidoyl chloride (0.48 g, 2.03 mmol) was added to a solution of 2‐
aminobenzonitrile (0.24 g, 2.03 mmol) and trietylamine (0.31 mL, 2.23 mmol) in 30 mL of toluene
and the reaction mixture was stirred for 6 hours under reflux. All volatiles were removed under
vacuum. The solid residue was dissolved in 30 mL of CH2Cl2 and washed twice with 15 mL of water.
The solution was evaporated to dryness and the crude product was crystallized from methanol to
1
give colorless crystals (0.43 g, 66%). H NMR (400 MHz, CDCl3, 298 K) δ/ppm = 8.30 (br. s, 1H, H5),
7.58 (t, J = 7.6 Hz, 1H, H7), 7.48 (m, 2H, H8,15), 7.32 (m, 3H, H6,14), 6.10 (br. s, 1H, NH), 2.69 (hept, J =
6.8 Hz, 2H, H16), 1.99 (s, 3H, H11), 1.17 (d, J = 6.9 Hz, 6H, H17), 1.11 (d, J = 6.9 Hz, 6H, H18). 13C NMR
(100 MHz, CDCl3, 298 K) δ/ppm = 154.4 (C4), 153.6 (C2), 146.6 (C13), 144.6 (C9), 132.8 (C7), 131.4
(C12), 130.6 (C15), 126.4 (C8), 126.4 (C5 Not Clear), 126.2 (C6), 125.4 (C14), 120.6 (C10), 28.4 (C16),
25.0(C18), 24.0 (C11), 23.5 (C17). FT‐IR (KBr):  / cm‐1 = 3442, 3288, 3078, 3061, 3034, 3009, 2963,
2929, 2870, 1630, 1594, 1582, 1466, 1379, 1364, 1352, 1306, 1276, 1249, 1230, 1207, 1178, 1144,
14

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1058, 1030, 870, 838, 8.15, 766, 662, 643, 627, 615, 560, 544. HRMS (ESI) for C21H26N3 [M+H]+: m/z
calcd: 320.212, found: 320.212.
Synthesis of 3‐(2,6‐diisopropylphenyl)‐2‐phenylquinazolin‐4(3H)‐imine (2): (E)‐N‐(2,6‐
diisopropylphenyl)benzimidoyl chloride (0.84 g, 2.80 mmol) was added to a solution of 2‐
aminobenzonitrile (0.33 g, 2.80 mmol) and trietylamine (0.43 mL, 3.08 mmol) in 30 mL of toluene
and the reaction mixture was stirred for 36 hours under reflux. All volatiles were removed under
vacuum and the residue was dissolved in 30 mL CH2Cl2 and washed twice with 15 mL of water.
After removal of solvent and drying, the crude product was crystallized from ethyl acetate to give
colorless crystals (0.73 g, 68 %). 1H NMR (400 MHz, CD2Cl2, 298 K) δ/ppm = 8.36 (br. s, 1H, H5), 7.67
(m, 2H, H7,8), 7.44 (m, 2H, H6,18), 7.34 ‐ 7.12 (m, 7H, H17,12,13,14), 6.33 (br. s, 1H, NH), 2.86 (hept, J =
6.7 Hz, 2H, H19), 1.14 (d, J = 6.7 Hz, 6H, H20), 1.00 (d, J = 6.8 Hz, 6H, H21). 13C NMR (100 MHz, CD2Cl2,
298 K) δ/ppm = 155.0 (C4, Not Clear), 154.9 (C2), 147.7 (C16), 145.5 (C9), 136.2 (C11), 133.2 (C7),
132.4 (C15), 131.0 (C18), 129.78 (C14), 129.7 (C13), 127.9 (C12), 127.9 (C8), 127.2 (C6), 126.5 (C5), 125.6
(C17), 121.8 (C10), 29.2 (C19), 25.8 (C20), 23.1 (C21). FT‐IR (KBr):  / cm‐1 = 3448, 3301, 3258, 3064,
2960, 2927, 2865, 1744, 1625, 1608, 1557, 1494, 1474, 1444, 1384, 1360, 1322, 1297, 1248, 1235,
1205, 1177, 1154, 1142, 1050, 1031, 1020, 900, 873, 819, 800, 768, 757, 730, 704, 696, 671, 637.
HRMS (ESI) for C26H28N3 [M+H]+: m/z calcd: 382.228, found: 382,228.
Synthesis of 3‐(4‐methoxyphenyl)‐2‐phenylquinazolin‐4(3H)‐iminium chloride (3): (E)‐N‐(2‐
cyanophenyl)benzimidoyl chloride (0.12 g, 0.49 mmol) was added to a solution of p‐anisidine (0.06
g, 0.49 mmol) in 30 mL of toluene and the reaction mixture was stirred for 36 hours under reflux.
All volatiles were removed under vacuum and the crude product was washed with acetone and
dried to give yellow solid (0.14 g, 80 %). 1H NMR (400 MHz, CDCl3/CD3OD (97:3), 298 K) δ/ppm =
8.65 (d, J = 7.8 Hz, 1H, H5), 8.36 (d, J = 7.6 Hz, 2H, H12), 8.29 (d, J = 8.0 Hz, 1H, H8), 7.77 (d, J = 8.4
Hz, 2H, H16), 7.58 (t, J = 7.2 Hz, 1H, H14), 7.54 – 7.45 (m, 3H, H13,7), 7.32 (t, J = 7.3 Hz, 1H, H6), 6.93
(d, J = 8.5 Hz, 2H, H17), 3.83 (s, 3H, H19). 13C NMR (100 MHz, CDCl3/CD3OD (97:3), 298 K) δ/ppm =
158.3 (C18), 158.2 (C4), 157.2 (C2), 138.8 (C9), 135.4 (C7), 134.0 (C13), 130.2 (C11), 129.5 (C12), 129.4
(C14), 129.3 (C15), 128.2 (C6), 125.7 (C16), 124.6 (C5), 119.8 (C8), 114.0 (C17), 112.0 (C10), 55.6 (C19).
FT‐IR (KBr): / cm‐1 = 3288, 3066, 3048, 3004, 2955, 2934, 2910, 2836, 1734, 1634, 1600, 1561,
1508, 1458, 1431, 1416, 1380, 1366, 1331, 1296, 1252, 1236, 1175, 1156, 1109, 1081, 1032, 1002,
15

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933, 827, 801, 768, 704, 675, 581, 529, 513. HRMS (ESI) for C21H18N3O+: m/z calcd: 328.144, found:
328.144.
Synthesis
of
3‐(4‐methoxyphenyl)‐2‐phenylquinazolin‐4(3H)‐imine
(4):
(E)‐N‐(2‐
cyanophenyl)benzimidoyl chloride (0.12 g, 0.49 mmol) was added to a solution of p‐anisidine (0.06
g, 0.49 mmol) in 30 mL of toluene and the reaction mixture was stirred for 36 hours under reflux.
All volatiles were removed under vacuum and the residue was dissolved in 30 mL CH2Cl2 and
washed twice with 15 mL of 25% aqueous NH3 solution. After removal of solvent and drying, the
crude product was crystallized from ethyl acetate to give colorless crystals (0.12 g, 75 %). 1H NMR
(400 MHz, CD2Cl2, 298 K) δ/ppm = 8.30 (br. s, 1H, H5), 7.64 (t, J = 7.4 Hz, 1H, H7), 7.57 (d, J = 7.9 Hz,
1H, H8), 7.41 (t, J = 7.5 Hz, 1H, H6), 7.32 – 7.18 (m, 5H, H12,13,14), 7.07 (d, J = 8.8 Hz, 2H, H16), 6.87 (d,
J = 8.7 Hz, 2H, H17), 6.66 (br. s, 1H, NH), 3.76 (s, 3H, H19). 13C NMR (100 MHz, CD2Cl2, 298 K) δ/ppm
= 160.2 (C18), 155.4 (C4 Not Clear), 155.4 (C2), 145.2 (C9), 137.1 (C11), 133.2 (C7), 131.6 (C16), 130.8
(C15), 129.2 (C14), 129.2 (C13), 128.3 (C12), 127.8 (C8), 127.2 (C6), 126.1 (C5), 122.0 (C10), 115.5 (C17),
56.0 (C19). FT‐IR (KBr):  / cm‐1 = 3311, 3297, 3060, 3033, 3002, 2859, 2936, 2909, 2835, 1678,
1632, 1606, 1584, 1565, 1508, 1473, 1463, 1442, 1362, 1317, 1298, 1251, 1176, 1152, 1136, 1108,
1075, 1053, 1029, 949, 916, 887, 875, 839, 821, 806, 766, 725, 698, 673, 656, 631, 583, 543, 481.
HRMS (ESI) for C21H18N3O [M+H]+: m/z calcd: 328.144, found: 328.144.
Synthesis
of
2,3‐Diphenylquinazolin‐4(3H)‐iminium
chloride
(5):
(E)‐N‐(2‐
cyanophenyl)benzimidoyl chloride (0.21 g, 0.86 mmol) was added to a solution of aniline (0.08 g,
0.86 mmol) in 30 mL of toluene and the reaction mixture was stirred for 36 hours under reflux. All
volatiles were removed under vacuum and the light yellow solid was washed with acetone and
1
crystallized from chloroform/methanol to give light yellow crystals (0.20 g, 70 %). H NMR (400
MHz, CDCl3/MeOH*, 298 K) δ/ppm = 9.17 (d, J = 8.2 Hz, 1H, H5), 7.98 (t, J = 7.6 Hz, 1H, H7), 7.89 (d,
J = 8.0 Hz, 1H, H8), 7.76 (t, J = 7.5 Hz, 1H, H6), 7.48 (m, 3H, H17,18), 7.34 – 7.19 (m,7H, H16,12,13,14). 13C
NMR (100 MHz, CDCl3/MeOH*, 298 K) δ/ppm = 157.4 (C4), 152.1 (C2), 145.7 (C9), 137.6 (C7), 134.4
(C15), 133.2 (C11), 131.4 (C18), 131.2 (C17), 130.2 (C14), 120.0 (C6), 129.0 (C16), 128.6 (C8), 128.5 (C13),
128.2 (C12), 127.7 (C5), 113.2 (C10). Note: A drop of methanol HPLC (MeOH*) was added to the RMN
sample (CDCl3) to increase the solubility of the product. FT‐IR (KBr): / cm‐1 = 3378, 3201, 3052,
3027, 2940, 2780, 1654, 1606, 1595, 1570, 1536, 1489, 1472, 1458, 1444, 1338, 1308, 1291, 1280,
16

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1222, 1156, 1076, 1037, 1017, 999, 972, 953, 923, 891, 873, 850, 773, 698, 677, 630, 614, 581,
+
560, 537, 522, 487. HRMS (ESI) for C20H16N3 : m/z calcd: 298.134, found: 298.134.
Synthesis of 3‐(4‐aminophenyl)‐2‐phenylquinazolin‐4(3H)‐iminium chloride (6): (E)‐N‐(2‐
cyanophenyl)benzimidoyl chloride (0.11g, 0.46 mmol) was added to a solution of p‐
phenylenediamine (0.05 g, 0.46 mmol) in 30 mL of toluene and the reaction mixture was stirred
for 18 hours under reflux. Light brown solid was formed, which were filtered and dried under
vacuum (0.11 g, 69 %). 1H NMR (400 MHz, CD2Cl2/CD3OD (97:3), 298 K) δ/ppm = 8.77 (d, J = 8.2 Hz,
1H, H5), 8.08 (t, J = 7.6 Hz, 1H, H7), 7.96 (d, J = 8.3 Hz, 1H, H8), 7.83 (t, J = 7.6 Hz, 1H, H6), 7.37 – 7.25
(m, 5H, H12,13,14), 6.96 (d, J = 8.0 Hz, 2H, H17), 6.70 (d, J = 8.0 Hz, 2H, H16), 3.74 (br. s, 2H, H19, Not
clear). 13C NMR (100 MHz, CD2Cl2/CD3OD (97:3), 298 K) δ/ppm = 159.1 (C4), 154.0 (C2), 150.8 (C15),
146.6 (C9), 138.4 (C7), 134.2 (C11), 130.6 (C14), 130.5 (C6), 129.7 (C13), 129.5 (C17), 129.5 (C8), 128.7
(C12), 126.7 (C5), 123.5 (C18) , 116.5 (C16), 113.5 (C10). FT‐IR (KBr): / cm‐1 = 3411, 3328, 3224, 3181,
3026, 2950, 2881, 2675, 2603, 2563, 1649, 1628, 1613, 1577, 1506, 1445, 1338, 1311, 1292, 1198,
1178,1159, 1113, 1031, 954, 825, 769, 708, 696, 677, 623, 593, 584, 540, 511. HRMS (ESI) for
+
C20H17N4 : m/z calcd: 313.145, found: 313.145.
Synthesis of 3‐(4‐cyanophenyl)‐2‐phenylquinazolin‐4‐(3H)‐iminium chloride (7): (E)‐N‐(2‐
cyanophenyl)benzimidoyl chloride (0.12g, 0.51mmol) was added to a solution of 4‐
aminobenzonitrile (0.06g, 0.51mmol) in 30 mL of toluene and the reaction mixture was stirred for
96 hours under reflux. All volatiles were removed under vacuum and the crude product was
1
washed with acetone and dried to give light yellow solid (0.12 g, 65 %). H NMR (400 MHz,
D2O/CD3OD (97:3), 298 K) δ/ppm = 8.43 (d, J = 8.4 Hz, 1H, H5), 8.19 (t, J = 7.7 Hz, 1H, H7), 7.96 (d, J
= 8.3 Hz, 1H, H8), 7.90 (m, 3H, H6,17), 7.68 (d, J = 8.4 Hz, 2H, H16), 7.43 – 7.28 (m, 5H, H12,13,14). 13C
NMR (100 MHz, D2O/CD3OD (97:3), 298 K) δ/ppm = 158.9 (C4), 153.8 (C2), 145.9 (C9), 139.4 (C15),
139.3 (C7), 136.1 (C17), 133.0 (C11), 131.5 (C14), 131.1 (C6), 130.8 (C16), 129.9 (C13), 129.4 (C12), 128.9
(C8), 125.9 (C5), 118.7 (C19), 115.5 (C18), 113.8 (C10). FT‐IR (KBr):  / cm‐1 = 3396, 3213, 3091, 3031,
2963, 2237 (CN), 1632, 1604, 1578, 1549, 1506, 1480, 1459, 1444, 1432, 1411, 1383, 1338, 1318,
1292, 1261, 1160, 1097, 1021, 956, 928, 864, 800, 734, 699, 673, 627, 583, 564, 546, 521. HRMS
+
(ESI) for C21H15N4 : m/z calcd: 323.129, found: 323.129.
Synthesis of 2‐Phenyl‐3‐(1‐phenyl‐ethyl)‐(3H)‐quinazolin‐4‐ylidene‐iminium chloride (8):
Compound 8 was prepared by reaction of (E)‐N‐(2‐cyanophenyl)benzimidoyl chloride (0.15 g, 0.59
17

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mmol) with (R)‐(+)‐α‐methyl benzilamine (0.08 mL, 0.59 mmol) in 20 mL of toluene. Then was
added at 0°C and stirred at this temperature for 2 hours. Then the reaction mixture was stirred for
48 hours at room temperature. The precipitate was filtrated and discarded. All volatiles were
removed under vacuum from the solution; the product was separated by a short column of silica
gel, using ethyl acetate and then chloroform. The chloroform was removed under vacuum and the
light yellow oil was obtained. Crystals of this compound were acquired from solution
chloroform/ethyl acetate to give light yellow crystals (0.16 g, 70 %). 1H NMR (400 MHz, CDCl3, 298
K) δ/ppm = 7.80 (d, J = 8.0 Hz, 1H, H5), 7.51 – 7.47 (m, 2H, H7, 14), 7.41 – 7.39 (m, 2H, H12), 7.32 –
7.31 (m, 3H, H13,8), 7.26 – 7.22 (m, 1H, H6), 7.20 – 7.19 (m, 2H, H19), 7.16 – 7.10 (m, 3H, H18, 20), 5.57
(q, J = 6.8 Hz, 1H, H15), 1.82 (d, J = 7.2 Hz, 3H, H16). 13C NMR (100 MHz, CDCl3, 298 K) δ/ppm = 156.8
(C2), 154.9 (C4), 143.7 (C10), 139.8 (C17), 136.8 (C9), 132.3 (C7), 129.4 (C8), 128.7 (C13), 128.5 (C19),
127.4 (C14), 127.2 (C12), 126.8 (C20), 126.5 (C6), 125.6 (C18), 124.0 (C5), 121.2 (C11), 57.4 (C15), 16.2
(C16). FTIR (KBr):  / cm‐1 = 3059, 3028, 2964, 2906, 2362, 2027, 1919, 1622, 1604, 1566, 1523,
1494, 1476, 1460, 1446, 1414, 1391, 1357, 1319, 1262, 1209, 1096, 1025, 875, 800, 698, 670, 642,
+
594, 539, 520, 394, 297. HRMS (ESI) for C20H20N3 : m/z calcd: 326.165, found: 326.165.
Synthesis of 5‐phenyl‐2,3‐dihydroimidazo[1,2‐c] quinazoline (9): Compound 9 was prepared by
reaction of (E)‐N‐(2‐cyanophenyl)benzimidoyl chloride (0.15 g, 0.59 mmol) with ethylenediamine
(0.04 mL, 0.59 mmol) in 20 mL of toluene. The ethylendiamine was added at 0°C and stirred at this
temperature for 2 hours. Then the reaction mixture was stirred for 48 hours at room temperature.
The precipitate was filtrated and discarded. All volatiles were removed under vacuum from the
solution; the product was separated by a short column of silica gel, using ethyl acetate and then
chloroform. The chloroform was removed under vacuum and the light yellow oil was obtained.
Crystals of this compound were acquired from a solution chloroform/ethyl acetate to give light
yellow crystals (0.09 g, 57 %). 1H NMR (400 MHz, CDCl3, 298 K) δ/ppm = 8.04 (d, J = 7.6 Hz, 1H, H5),
7.64 – 7.61 (m, 2H, H13), 7.58 (d, J = 1.2 Hz, 1H, H8), 7.56 (br. s, 1H, H7), 7.50 (d, J = 2.4 Hz, 2H, H12),
7.48 (d, J = 1.2 Hz, 1H, H14), 7.33 – 7.31 (m, 1H, H6), 4.12 – 3.99 (m, 1H, H15, 16). 13C NMR (100 MHz,
CDCl3, 298 K) δ/ppm = 155.5 (C4), 153.8 (C11), 146.7 (C9), 135.1 (C2), 133.1 (C7), 130.2 (C14), 128.7
(C12), 127.7 (C13), 127.2 (C8), 126.5 (C6), 125.2 (C5), 117.9 (C10), 53.4 (C15), 48.9 (C16). FTIR (KBr):  /
cm‐1 = 3423, 3332, 3233, 3065, 2952, 2873, 1647, 1614, 1601, 1582, 1550, 1498, 1478, 1467, 1447,
1405, 1352, 1297, 1277, 1242, 1179, 1154, 1076, 1044, 1028, 1001, 979, 919, 856, 841, 779, 712,
18

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701, 683, 670, 640, 586, 542, 435, 347, 297. HRMS (ESI) for C16H14N3 [M+H]+: m/z calcd: 248.118 ,
found: 248.118.
Synthesis of 6‐phenyl‐3,4‐dihydro‐2H‐pyrimido[1,2‐c] quinazoline (10): Compound 10 was
prepared by reaction of (E)‐N‐(2‐cyanophenyl)benzimidoyl chloride (0.15 g, 0.59 mmol) with 1,3‐
diaminopropane (0.05 mL, 0.59 mmol) in 20 mL of toluene. The reaction mixture was stirred for 48
hours under reflux. The precipitate was filtrated and discarded. All volatiles were removed under
vacuum from the solution and the crude product was crystallized from diethyl ether to give light
yellow crystals (0.09 g, 60 %). 1H NMR (400 MHz, CDCl3, 298 K) δ/ppm = 8.17 (d, J = 7.6 Hz, 1H,
H5), 7.51 – 7.45 (m, 7H, H7,8,12,13,14), 7.32 (t, J = 7.2 Hz, 1H, H6), 3.69 – 3.64 (m, 4H, H15,17), 1.92 –
1.86 (m, 2H, H16). 13C NMR (100 MHz, CDCl3, 298 K) δ/ppm = 155.5, 146.6, 144.0, 135.6, 122,66
(C2,4,9,10,11), 132.0, 129.8, 129.00, 127.9, 127.0 (C7,8,12,13,14), 126.8 (C6), 124.6 (C5), 47.7, 44.6 (C15,17),
20.8 (C16). FTIR (KBr):  / cm‐1 = 3424, 3332, 3223, 3073, 2932, 2857, 1635, 1600, 1585, 1564,
1493, 1479, 1461, 1443, 1378, 1352, 1287, 1242, 1174, 1146, 1075, 1036, 1007, 956, 772, 718,
706, 672, 594, 542, 408, 348, 297.
Synthesis of 2‐phenyl‐3‐(pyridin‐2‐ylmethyl)quinazolin‐4(3H)‐iminium chloride (11): 2‐
picolinamina (0.22 g, 2.08 mmol) was added to a solution of (E)‐N‐(2‐cyanophenyl)benzimidoyl
chloride (0.50g, 2.08 mmol) in 20 mL of toluene and the reaction mixture was stirred for 26 hours
under reflux. The precipitate was filtrated and discarded and from the solution a white solid was
1
precipited from, which were filtered and dried under vacuum (0.32 g, 45 %). H NMR (400 MHz,
CDCl3, 298 K) δ/ppm = 10.21 (br. s. 1H, NH), 8.81 (d, J = 8.4, 1H, H5), 8.60 – 8.51 (m, 4H, H6, 7, 8, 18),
7.72 – 7.69 (m, 2H, H19, 20), 7.53 – 7.44 (m, 5H, H12, 13, 14), 7.24 – 7.23 (m, 1H, H21), 5.15 (s, 2H, H15).
13C NMR (100 MHz, CDCl3, 298 K) δ/ppm = 160.07 (C4), 157.86, 155.36, 130.85, 120.30 (C2, 9, 11, 16),
148.67, 129.90, 123.69 (C6, 7, 8), 137.72, 135.49 (C19, 20), 133.65, 129.06, 122.42 (C12, 13, 14), 128.21
(C18), 123.09 (C21), 121.72 (C5), 46.41 (C15). FT‐IR (KBr): / cm‐1 = 3302, 3062, 2851, 1632, 1616,
1563, 1519, 1504, 1477, 1458, 1431, 1404, 1383, 1330, 1288, 1274, 1213, 1189, 1153, 1117, 1030,
+
1018, 995, 966, 930, 881, 821, 767, 702, 678, 628, 581. HRMS (ESI) for C20H17N4 : m/z calcd:
313.15 , found: 313.
Synthesis of 3‐(benzo[d][1,3]dioxol‐5‐ylmethyl)‐2‐phenylquinazolin‐4(3H)‐iminium chloride (12):
piperonylamine (0.31 g, 2.08 mmol) was added to a solution of (E)‐N‐(2‐cyanophenyl)benzimidoyl
chloride (0.50g, 2.08 mmol) in 20 mL of toluene and the reaction mixture was stirred for 24 hours
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under reflux. Pale yellow solid was formed, which were filtered and dried under vacuum (0.44 g,
1
55 %). H NMR (400 MHz, CDCl3, 298 K) δ/ppm = 11.49 (br. s. 1H, HCl), 10.55 (br. s. 1H, NH), 9.44
(d, J = 8.2 Hz, 1H, H5), 8.00 – 7.85 (m, 2H, H7, 8), 7.77 (t, J = 7.5 Hz, 1H, H6), 7.61 – 7.51 (m, 5H, H12, 13,
14), 6.64 – 6.61 (m, 3H, H17, 20, 21), 5.98 (s, 2H, H15), 5.84 (s, 2H, H22). 13C NMR (100 MHz, CDCl3, 298
K) δ/ppm = 157.16 (C4), 154.08 (C2), 148.30 (C19), 147.88 (C18), 145.55 (C9), 137.14, 128.53 (C7, 8),
133.72 (C15), 131.20 (C14), 129.81 (C6), 129.31, 128.74 (C12, 13), 127.70 (C5), 126.55 (C11), 120.93,
108.76, 107.42 (C17, 20, 21), 114.30 (C10), 101.30 (C22), 53.40 (C15). FT‐IR (KBr): / cm‐1 = 3425, 2995,
2875, 2782, 2560, 2057, 1854, 1695, 1613, 1599, 1585, 1500, 1486, 1467, 1445, 1388, 1358, 1322,
1275, 1249, 1206, 1189, 1154, 1132, 1118, 1105, 1089, 1043, 970, 939, 915, 892, 812, 772, 727,
+
711, 700, 675, 631, 614, 600, 585, 517, 498, 448, 425, 388, 318. HRMS (ESI) for C22H18N3O2 : m/z
calcd: 356.14 , found: 356.
Synthesis of 3‐(2,5‐dimethoxyphenyl)‐2‐phenylquinazolin‐4(3H)‐iminium chloride (13): 2,5‐
dimethoxyaniline (0.32 g, 2.08 mmol) was added to
a
solution of (E)‐N‐(2‐
cyanophenyl)benzimidoyl chloride (0.50g, 2.08 mmol) in 20 mL of toluene and the reaction
mixture was stirred for 24 hours under reflux. Gray solid was formed, which were filtered and
1
dried under vacuum (0.53 g, 65 %). H NMR (400 MHz, CDCl3, 298 K) δ/ppm = 13.01 (s, 1H, NH),
9.54 (d, J = 8.1 Hz, 1H, H5), 8.09 – 7.82 (m, 3H, H6, 7, 8), 7.39 – 7.28 (m, 5H, H12, 13, 14), 7.04 – 6.89 (m,
2H, H17, 18), 6.79 (br. s, 1H, H20 ), 3.74 (s, 3H, H21,22), 3.72 (s, 3H, H21, 22). 13C NMR (100 MHz, CDCl3,
298 K) δ/ppm = 157.03 (C4), 154.35, 152.32, 132.94, 121.98 (C2, 11, 15, 19) 147,62 (C16), 145.86 (C9),
137.78 (C7), 130.42 (C14), 130.06 (C6), 128.54 (C5), 128.50 (C8), 128.27, 128.05 (C12, 13) , 118.75,
114.10 (C17, 18), 114.45 (C20) , 112.78 (C10), 56.13 , 56.12 (C21, 22). FT‐IR (KBr): / cm‐1 = 3393, 3029,
3000, 2938, 2834, 2745, 2663, 2012, 1830, 1658, 1625, 1599, 1573, 1530, 1506, 1479, 1465, 1446,
1340, 1314, 1298, 1275, 1234, 1204, 1160, 1144, 1117, 1078, 1041, 1016, 964, 935, 904, 887, 858,
+
808, 796, 779, 737, 726, 706, 678, 642, 586, 519, 492, 397, 355. HRMS (ESI) for C22H20N3O2 : m/z
calcd: 358.16 , found: 359.
X‐ray crystal structure analyses: For compounds 1, 2, 4, 9 and 13 data sets were collected with a
Nonius KappaCCD diffractometer. Programs used: data collection, COLLECT (Nonius B.V., 1998);
data reduction Denzo‐SMN (Z. Otwinowski, W. Minor, Methods Enzymol. 1997, 276, 307‐326);
absorption correction, Denzo (Z. Otwinowski, D. Borek, W. Majewski, W. Minor, Acta Crystallogr.
2003, A59, 228‐234); structure solution SHELXS‐97 (G. M. Sheldrick, Acta Crystallogr. 1990, A46,
467‐473); structure refinement SHELXL‐97 (G. M. Sheldrick, Acta Crystallogr. 2008, A64, 112‐122)
20

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and graphics, XP (BrukerAXS, 2000). Thermals ellipsoids are shown with 30% probability, R‐values
are given for observed reflections, and wR2 values are given for all reflections.
Exceptions and special features: For compound 2 a half badly disordered dichloromethane
molecule was found in the asymmetrical unit and could not be satisfactorily refined. Compound 5
crystallized with one badly disordered over tree positions methanol molecule. The program
SQUEEZE (A. L. Spek J. Appl. Cryst., 2003, 36, 7‐13) was therefore used to remove mathematically
the effect of the solvents. The quoted formula and derived parameters are not included the
squeezed solvent molecules.
Crystallographic data for 1, 2, 4, 5, 9 and 13 have been deposited with Cambridge Crystallographic
Data Centre, CCDC numbers 1008256, 1008257, 1008258, 1008259, 1008260 and 1057208. These
data can be obtained free at www.ccdc.cam.ac.uk/conts/rtrieving.html [or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(1223)336‐033, e‐
mail: deposit@ccdc.cam.ac.uk].
X‐ray crystal structure analysis of 1: formula C21H25N3, M = 319.44 colourless crystal, 0.38 x 0.35 x
0.15 mm, a = 11.8867(3), b = 12.5284(6), c = 13.0514(4) Å, α = 79.096(4), β = 89.444(2), γ =
77.230(5)°, V = 1860.3(1) Å3, ρcalc = 1.141 gcm‐3, μ = 0.521 mm‐1, empirical absorption correction
(0.826 ≤ T ≤ 0.925), Z = 4, triclinic, space group P1 (No. 2), λ = 1.54178 Å, T = 223(2) K, ω and φ
scans, 21856 reflections collected (±h, ±k, ±l), [(sin)/λ] = 0.60 Å‐1, 6335 independent (Rint = 0.037)
and 5970 observed reflections [I>2σ(I)], 441 refined parameters, R = 0.045, wR2 = 0.118, max.
(min.) residual electron density 0.15 (‐0.16) e.Å‐3, the hydrogen atoms at N4A and N4B were
refined freely, but with N‐H distance restraints (SADI); others were calculated and refined as riding
atoms.
X‐ray crystal structure analysis of 2: formula C26H27N3, M = 381.51 colourless crystal, 0.23 x 0.15 x
0.03 mm, a = 16.4490(8), b = 16.4490(8), c = 8.4714(4) Å, V = 2292.1(2) Å3, ρcalc = 1.106 gcm‐3, μ =
0.502 mm‐1, empirical absorption correction (0.893 ≤ T ≤ 0.985), Z = 4, tetragonal, space group P‐4
(No. 81), λ = 1.54178 Å, T = 223(2) K, ω and φ scans, 8679 reflections collected (±h, ±k, ±l),
[(sin)/λ] = 0.60 Å‐1, 3410 independent (Rint = 0.058) and 2945 observed reflections [I>2σ(I)], 269
refined parameters, R = 0.059, wR2 = 0.162, max. (min.) residual electron density 0.19 (‐0.23) e.Å‐3,
the hydrogen at N3 atom was refined freely, but with N‐H distance restraints (DFIX and U‐fixed
value); others were calculated and refined as riding atoms.
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X‐ray crystal structure analysis of 4: formula C21H17N3O, M = 327.38 colourless crystal, 0.40 x 0.15
x 0.04 mm, a = 12.9137(5), b = 14.1902(4), c = 14.6060(6) Å, α = 107.781(2), β = 90.352(2), γ =
98.594(2)°, V = 2516.2(2) Å3, ρcalc = 1.296 gcm‐3, μ = 0.649 mm‐1, empirical absorption correction
(0.781 ≤ T ≤ 0.974), Z = 6, triclinic, space group P1 (No. 2), λ = 1.54178 Å, T = 223(2) K, ω and φ
scans, 34337 reflections collected (±h, ±k, ±l), [(sin)/λ] = 0.60 Å‐1, 8764 independent (Rint = 0.040)
and 7650 observed reflections [I>2σ(I)], 691 refined parameters, R = 0.038, wR2 = 0.104, max.
(min.) residual electron density 0.04 (‐0.10) e.Å‐3, the hydrogen atoms at N4A, N4B and N4C were
refined freely; others were calculated and refined as riding atoms.
X‐ray crystal structure analysis of 5: formula C20H16N3Cl, M = 333.81 pale yellow crystal, 0.38 x
0.28 x 0.18 mm, a = 14.6582(9), b = 17.3558(12), c = 7.0639(7) Å, β = 98.146(3) °, V = 1779.0(2) Å3,
ρ
calc = 1.246 gcm‐3, μ = 0.220 mm‐1, Z = 4, monoclinic, space group P21/c (No. 14), λ = 0.71703 Å, T =
297(2) K, ω and φ scans, 14711 reflections collected (±h, ±k, ±l), 3634 independent (Rint = 0.053)
and 2634 observed reflections [I>2σ(I)], 225 refined parameters, R = 0.041, wR2 = 0.112, max.
(min.) residual electron density 0.36 (‐0.16) e.Å‐3, the hydrogen atoms at N4 were refined freely,
but with N‐H distance restraints (SADI); others were calculated and refined as riding atoms.
X‐ray crystal structure analysis of 9: formula C16H13N3 ٠ H2O, M = 265.31 colourless crystal, 0.30 x
0.20 x 0.18 mm, a = 8.9276(2), b = 9.0785(2), c = 16.8687(3) Å, β = 96.058(2) °, V = 1359.6(1) Å3,
ρcalc = 1.296 gcm‐3, μ = 0.084 mm‐1, empirical absorption correction (0.975 ≤ T ≤ 0.985), Z = 4,
monoclinic, space group P21/n (No. 14), λ = 0.71073 Å, T = 223(2) K, ω and φ scans, 8031
reflections collected (±h, ±k, ±l), [(sin)/λ] = 0.62 Å‐1, 2695 independent (Rint = 0.033) and 2386
observed reflections [I>2σ(I)], 189 refined parameters, R = 0.044, wR2 = 0.110, max. (min.) residual
electron density 0.18 (‐0.15) e.Å‐3, the hydrogen atoms at O1 were refined freely; others were
calculated and refined as riding atoms.
٠
X‐ray crystal structure analysis of 13: formula C22H20N3Cl H2O, M= 411.87 pale yellow needle‐like
crystals, 0.020 mm x 0.080 mm x 0.200 mm, a = 7.7886(2), b = 9.9350(3), c = 13.6151(4) Å, α =
83.463(2)°, β = 84.947(2)°, γ = 73.188(2)°, volume = 1000.26(5) Å3, ρcalc = 1.368 gcm‐3, μ = 1.932
mm‐1, Z = 2, triclinic, space group P ‐1, 16418 reflections collected (±h, ±k, ±l), 3365 independent
(Rint = 0.0514) and 2859 observed reflections [I>2σ(I)], 285 refined parameters, R = 0.0443, wR2 =
0.0910, max. (min.) residual electron density 0.241 (‐0.223) e.Å‐3.
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AUTHOR INFORMATION
Corresponding Author
*René S. Rojas, Departamento de Química Inorgánica, Facultad de Química, Pontificia Universidad
Católica de Chile, Casilla 306 E‐mail: rrojasg@uc.cl
Author Contributions
All authors have approved the final version of the manuscript.
ACKOWLEDGMENTS
Financial support from FONDECYT N° 1130077 and 3140329 and Núcleo Milenio project
ICM120082. C.Q. acknowledges funding from PUC via a VRI fellowship and Ph.D. CONICYT
fellowship N° 63130173.
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