Domino synthesis of pyrimido and imidazoquinazolinones

Article abstract of DOI:10.1002/jhet.3864

A simple method for the synthesis of N-alkyl-2-arylquinazolin-4-amines, methyl 4-((2-arylquinazolin-4-yl)amino) butanoates, 6-aryl-2,3-dihydro-4H-pyrimido[1,2-c]quinazolin-4-ones, and 5-arylimidazo[1,2-c]quinazolin-3(2H)-ones has been described. It involves a simple reaction of N-(2-cyanophenyl)-substitutedbenzimidoyl chlorides with alkylamine, γ-aminobutyric acid, β-alanine, l-alanine, and glycine methyl esters hydrochloride in acetonitrile to afford the desired compounds after a series of instantaneous reactions that include Dimroth rearrangement. The reaction involves reflux for 12 hours, simple addition of reagents to an in situ generated benzimidoyl chloride, and simple workup, to form 21 examples of pure compounds in high yields. The active intermediate N-(2-cyanophenyl)-substitutedbenzimidoyl chlorides were formed by the reaction of N-(2-cyanophenyl)-substitutedbenzamides with thionyl chloride in a one-pot strategy. The alternative method described for this preparation deals with an exhausting multistep reactions starting from anthranilic acid.

Full text of DOI:10.1002/jhet.3864

Received: 16 October 2019
DOI: 10.1002/jhet.3864
Revised: 3 December 2019
Accepted: 9 December 2019
A R T I C L E
Domino synthesis of pyrimido and imidazoquinazolinones
Walid Fathalla1
| Eman Y. Nofal1 | Mohamed Abd El-Moneim2
1Physics and Mathematical Engineering
Department, Faculty of Engineering, Port
Said University, Port Said, Egypt
2Chemistry Department, Faculty of
Science, Port Said University, Port Said,
Egypt
Abstract
A simple method for the synthesis of N-alkyl-2-arylquinazolin-4-amines,
methyl 4-((2-arylquinazolin-4-yl)amino) butanoates, 6-aryl-2,3-dihydro-4
H-pyrimido[1,2-c]quinazolin-4-ones, and 5-arylimidazo[1,2-c]quinazolin-3(2H)-
ones has been described. It involves a simple reaction of N-(2-cyanophenyl)-
substitutedbenzimidoyl chlorides with alkylamine, γ-aminobutyric acid,
β-alanine, L-alanine, and glycine methyl esters hydrochloride in acetonitrile to
afford the desired compounds after a series of instantaneous reactions that
include Dimroth rearrangement. The reaction involves reflux for 12 hours, sim-
ple addition of reagents to an in situ generated benzimidoyl chloride, and sim-
ple workup, to form 21 examples of pure compounds in high yields. The active
intermediate N-(2-cyanophenyl)-substitutedbenzimidoyl chlorides were formed
by the reaction of N-(2-cyanophenyl)-substitutedbenzamides with thionyl
chloride in a one-pot strategy. The alternative method described for
this preparation deals with an exhausting multistep reactions starting from
anthranilic acid.
Correspondence
Walid Fathalla, Physics and Mathematical
Engineering Department, Faculty, Port
Said University, Port Said, Egypt.
Email: walid3369@yahoo.com
1 | INTRODUCTION
used in peptide synthesis via amidine intermediates.[10]
The undo-use of imidoyl chorides could be due to the fol-
Domino synthesis is a growing field in organic chemistry
that execute the principles of sustainability (green chem-
istry). It involves the synthesis of complex structures by
the addition of two or more active substrates and the for-
mation or cleavage of two or more bonds in a single oper-
ation without isolation of intermediates, minimal time,
maximum selectivity, and high atom economy.[1]
lowing obstacles: imidoyl chloride derivatives are pre-
pared by the reaction of amides with chlorinating agents
suffers from the formation of inactive iminium salts.
Imidoyl chloride is very reactive and reacts easily with
moisture. The chlorine atom of imidoyl chloride could be
easily eliminated and leave it in the form of nitrile.
Imidoyl chlorides having α-hydrogens could be easily
isomerized. These complications make the attempts to
isolate and store imidoyl chlorides for long period diffi-
cult; therefore, these compounds are prepared in situ
without further purifications.
In continuation of our interest in the preparation of
complex structures by Domino strategy, we found it inter-
esting to prepare benzimidoyl chlorides as active intermedi-
ates and directly use these to prepare a series of N-alkyl
2-aryl quinazolin-4-amines, methyl 4-((2-arylquinazolin-
4-yl)amino) butanoates, 6-aryl-2,3-dihydro-4H-pyrimido
[1,2-c]quinazolin-4-ones, and 5-arylimidazo[1,2-c]quinazo-
lin-3(2H)-ones.
Imidoyl chloride[2] intermediates are used extensively
in organic synthesis because of its increased reactivity.
This reactivity is centered around the electrophilic and
nucleophilic displacement and elimination of the chlo-
ride group. Imidoyl chloride is used in the synthesis of
imidates, thioimidates, imidoyl cyanides, and imidoyl
isothiocyanates by the reaction of imidoyl chloride
with alcohols, thiols, amines, and thiocyanates.[2–6] Sev-
eral named reactions Gattermann,[7] Vilsmeier-Haack
reaction,[8] and Houben-Hoesch reaction[9] use imidoyl
chloride to attack arenes and form aryl ketones by
Freidal Craft acylation reaction. Also, imidoyl chloride is
J Heterocycl Chem. 2019;1–9.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

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FATHALLA ET AL.
2 | DISCUSSION
benzyl amine, and allyl amine in acetonitrile (ACN) under
reflux condition for 12 hours to afford the desired product in
51% to 70% yield, Scheme 2. The major advantages of this
protocol are short reaction time, mild condition, simple work
up, high yields, pure products based on one-pot domino reac-
tion. We should note that the presence of unsubstituted
benzamides or chloro-substituted benzamides 8a-d were
selected carefully to facilitate the Dimroth rearrangement
and will be explained later.
The identity of N-benzyl-2-arylquinazolin-4-amines
7a-d is based on 1H and 13C NMR spectroscopy and phys-
icochemical analysis beside equivocal synthesis using
a classical method from 4-chloro-2-phenylquinazolines
6a-d. Thus, the 1H NMR spectrum of 7a exhibits doublet,
and broad singlet signals at δ 5.03 and 6.13 ppm are typi-
cally associated with CH2 and NH groups. The doublet
signal of CH2 group confirms the Dimroth protocol and
the location of benzyl substituent at position 4 of the
quinazoline ring. The 1H NMR spectrum of 7a also
exhibits doublet, doublet, multiplet, multiplet, and multi-
plet signals at δ 8.63, 7.99, 7.75 to 7.70, 7.54 to 7.48, and
7.42 to 7.34 ppm for 14 aromatic protons. The 13C NMR
spectrum of 7a reveals signals at δ 159.3, 159.0, 150.1,
138.6, 135.7, 113.9, and 45.7 ppm associated with two
C N groups, four quaternary aromatic carbons, and CH2
group, respectively.
The target compound N-alkyl 2-aryl quinazolin-4-amines
could be easily prepared by the reaction of benzyl amine
with chloroquinazoline in DMF for at 100ꢀC for 12 hours.
This is the most reliable classical method for this prepara-
tion; however, this method suffers from two aspects: first,
amines used for this reaction should be of high boiling
points such as benzyl amine (other amines normally of
low boiling point did not give the desired product); sec-
ond, we realize in Scheme 1 that this reliable method of
preparation of chloroquinazoline from anthranilic acid
occurs in a five-step sequential reactions and sixth step
for the reaction with benzyl amines, Scheme 1.[11,12]
Following the main definition of domino reaction reveals
synthesis of complex structures by the addition of two or
more active substrates and the formation or cleavage of two
or more bonds in a single operation without isolation of
intermediates, minimal time, maximum selectivity, and
high atom economy.[1] We found it interesting to prepare
N-alkyl-2-arylquinazolin-4-amines 7a-d and 10b from
the corresponding N-(2-cyanophenyl)-substitutedbenzamides
8a-d. The reaction of N-(2-cyanophenyl)-substitutedben-
zamides 8a-d with thionyl chloride at 70ꢀC for 8 hours
afforded the in situ generated free benzimidoyl chlorides 9a-
d that was reacted in a one pot strategy with alkyl amines,
SCHEME 1 Classical preparation of N-benzyl-2-aryl-quinazolin-4-amines 7a-d

FATHALLA ET AL.
3
SCHEME 2 Preparation of
N-alkyl-2-aryl-quinazolin-4-amines
7a-d and 10b from N-(2-cyanophenyl)-
substitutedbenzamides 8a-d and 8b,
respectively
SCHEME 3 Preparation of methyl 4-((2-arylquinazolin-4-yl)amino) butanoates 11a-d
Similarly, the reaction of the in situ generated
benzimidoyl chlorides 9a-d with γ-amino butyric acid
methyl ester hydrochloride in the presence of triethyl
amine in acetonitrile under reflux condition and gave
methyl 4-((2-arylquinazolin-4-yl)amino) butanoates 11a-
d in high yields, Scheme 3.
NMR spectroscopy and physicochemical analysis. Thus,
the H NMR spectrum of 12a reveals two triplet signals
1
at δ 4.21 and 2.71 ppm corresponding to two CH2 groups.
The 1H NMR spectrum also exhibits doublet, triplet, dou-
blet, and multiplet signals at δ 8.68, 7.85, 7.77, and
1
7.68-7.53 ppm for nine aromatic protons. The H NMR
Our next target was the application of this domino
protocol to prepare a number of more complex struc-
tures; 6-aryl-2,3-dihydro-4H-pyrimido[1,2-c]quinazolin-
4-ones 12a-d and 5-arylimidazo[1,2-c]quinazolin-3
(2H)-ones 13-14(a-d). Thus, the reaction of benzimidoyl
chlorides 9a-d with β-alanine methyl ester hydrochloride
in the presence of triethylamine in acetonitrile under
reflux condition and gave 6-aryl-2,3-dihydro-4H-pyrimido
[1,2-c]quinazolin-4-ones 12a-d (Scheme 4), while the
reaction of benzimidoyl chlorides 9a-d with glycine or L-
alanine methyl ester hydrochloride in the presence of
triethyl amine in acetonitrile under reflux condition gave
5-arylimidazo[1,2-c]quinazolin-3(2H)-one 13a-d and
5-aryl-2-methylimidazo[1,2-c]quinazolin-3(2H)-one 14a-d
in excellent yields (Scheme 4).
spectrum of 12a shows the absence of both: the ester
methyl group and NH group that suggests the cyclization
occurrence. The 13C NMR spectrum of 12a reveals signals
at δ 175.4, 157.7153.1, 146.1, 133.8, 119.6, 46.7, and
29.7 ppm associated with C O, 2C N, three quaternary
aromatic carbons, NCH2 and CH2CO, respectively.
The one pot domino reaction for the preparation of
5-phenylimidazo[1,2-c]quinazolin-3(2H)-one (13a) could
be explained as follows: a first step addition of free
glycine methyl ester to imidoyl group carbon and gave
the methyl 2-[N-(2-cyanophenyl)benzimidamido] acetate
I. Next, an intramolecular N-addition of the glycine
residue NH at the nitrile group to produce methyl
2-(4-imino-2-phenylquinazolin-3(4H)-yl) acetate II. The
subsequent Dimroth rearrangement via ring opening–
ring closing type of mechanisms proceeds by free amino
acid nucleophilic attack at C2 of the quinazoline ring and
the consequent ring opening giving intermediate III. The
aryl group at position 2 of intermediate II (phenyl group
The identity of 6-aryl-2,3-dihydro-4H-pyrimido[1,2-c]
quinazolin-4-ones 12a-d, 5-arylimidazo[1,2-c]quinazolin-
3(2H)-ones 13a-d, and 5-aryl-2-methylimidazo[1,2-c]
quinazolin-3(2H)-ones 14a-d is based on 1H and 13C

4
FATHALLA ET AL.
SCHEME 4 Preparation of 6-aryl-2,3-dihydro-4H-pyrimido[1,2-c]quinazolin-4-ones 12a-d, 5-arylimidazo[1,2-c]quinazolin-3(2H)-ones
13a-d, and 5-aryl-2-methylimidazo[1,2-c]quinazolin-3(2H)-ones 14a-d
or chlorophenyl groups) has the advantage to facilitate the
previous Dimroth rearrangement; however, the presence of
phenyl ring attached with electron donating group (MeO)
specially at position 4 will decrease the electrophilicity of
C2 of the quinazoline ring in intermediate II and prohibit
the dimroth rearrangement. The following step is
tautomerization together with amino-imino groups flipping
and gave IV. Next, an amino group attacks at the amidine
function group to give methyl [(2-phenylquinazolin-4-yl)
amino] acetate V; this structure is formed in the case of
benzyl amine and γ-amino butyric acid methyl ester hydro-
chloride reaction with benzimidoyl chlorides 9a-d to afford
7a-d and 11a-d, respectively. The reaction continues and
the intermediate V reveals NH group at position 3 of the
quinazoline ring capable of attacking the amino acid ester
group to finally give the expected product 13a (Scheme 5).
Similar Dimroth rearrangement results were obtained as
reported in literature.[13–17]
60 F254 plastic plates (E. Merck, layer thickness, 0.2 mm)
were used, detected by UV absorption. The solvent system
used was ethyl acetate- pet ether 3:1. Elemental analyses
were performed on a Flash EA-1112 instrument at the
Microanalytical Laboratory, Faculty of Science, Suez Canal
University, Ismailia, Egypt. Melting points were deter-
mined on a Buchi 510 melting-point apparatus, and the
1
values are uncorrected. H and 13C NMR spectra were
recorded at 400 and 75.5 MHz, respectively, on a Bruker
AC 400 in CDCl3 and DMSO-d6 solution with tetra-
methylsilane as an internal standard. The NMR analyses
were performed at the Chemistry Department, Sohag
University, Sohag, Egypt. The starting substituted
N-(2-cyanophenyl)benzamides 8a-d were prepared according
to the reported method.[18] Also, starting compounds 1-6
were prepared according to reported literature.[11,12]
3.1.1 | General procedures for
preparation of 4-chloro-2-aryl-3,4-dihydro-
quinazolines 6a-d
3 | EXPERIMENTAL SECTION
3.1 | General procedures
Phosphoryl chloride (30 mL) was added to quinazolin-
4-one derivatives 5a-d (20 mmol); the reaction mixture
was stirred at 5ꢀC for 0.5 hour and then refluxed for
6 hours. The reaction mixture was evaporated under
reduced pressure, cooled, and dissolved in 20 mL of
Solvents were purified and dried by standard procedures.
The boiling range of the petroleum ether used was 40ꢀC to
60ꢀC for thin-layer chromatography (TLC) silica gel

FATHALLA ET AL.
5
SCHEME 5 Rational preparation of 5-phenylimidazo[1,2-c]quinazolin-3(2H)-one 13a
methylene chloride. The methylene chloride solution was
washed several times with ice-cold ammonia solution 5%
(20 mL) then dried over sodium sulfate. The methylene
chloride solution was filtered, evaporated, and gave
chloroquinazoline derivatives 6a-d in a pure state and
was used without further purification.[11,12]
amine or allyl amine, were dissolved in DMF and were
heated at 100ꢀC for 12 hours. The reaction mixture was
cooled and poured over H2O to give thick white precipi-
tate from the crude product. The reaction mixture was fil-
tered and was crystallized from ethanol to give N-alkyl-
2-arylquinazolin-4-amine 7a-d in good yield.
Method B
3.1.2 | General procedure for the
preparation of N-alkyl-2-arylquinazolin-
4-amines 7a-d and 10b
A mixture of substituted N-(2-cyanophenyl) benzamides
8a-d (1.0 mmol) and thionyl chloride (10 mL) was heated
at 70ꢀC for 8 hours. The thionyl chloride was removed
under reduced pressure, and the residue was heated
at 120ꢀC under reduced pressure (50 mmHg) for
4 extra hours to give a yellowish oil of substituted
N-(2-cyanophenyl) benzimidoyl chlorides 9a-d, which
Method A
A mixture of 4-chloro-2-aryl-3,4-dihydro-quinazolines
6a-d (1.0 mmol) and the appropriate amine, benzyl

6
FATHALLA ET AL.
was not further purified. The crude oil was cooled and
dissolved in dry acetonitrile; to this, acetonitrile solution
was added to the appropriate amine (2.0 mmol), benzyl
amine or allyl amine. The reaction mixture was refluxed
for 12 hours, and the acetonitrile solvent was evaporated
under reduced pressure. The crude product was crystal-
lized from ethanol to give the pure product 7a-d and 10b
in excellent yields.
N-Benzyl-2-(2-chlorophenyl)quinazolin-4-amine (7d)
Method A: 0.13 g, yield 39%; Method B: 0.18 g, yield 51%.
White crystals, mp 116-117ꢀC. 1H NMR spectrum,
(400 MHz, CDCl3), δ, ppm (J, Hz): 8.51 (1H, s, ArH); 7.97
(1H, d, J = 8.0, ArH); 7.78 (1H, t, J = 8.0, ArH); 7.71 (1H,
d, J = 8.0, ArH); 7.51-7.30 (9H, m, ArH); 6.03 (1H, bs,
NH); 5.02 (2H, d, J = 6.0, NHCH2). 13C NMR spectrum,
(75.0 MHz, CDCl3), δ, ppm: 160.8 (C N); 159.5 (C N);
147.6 (Cq); 138.2 (Cq); 133.3 (Cq); 132.9 (CHAr); 131.6
(CHAr); 130.5 (CHAr); 130.3 (CHAr); 128.7 (CHAr); 128.3
(CHAr); 127.6 (CHAr); 126.9 (CHAr); 126.6 (CHAr); 121.6
(CHAr); 113.0 (Cq); 45.4 (NHCH2). Anal. calcd. for
C21H16ClN3 (345.8): C, 72.93; H, 4.66; N, 12.15. Found: C,
72.88; H, 4.62; N, 12.02.
N-Benzyl-2-phenylquinazolin-4-amine (7a)
Method A: 0.24 g, yield 78%; Method B: 0.20 g, yield 65%.
1
White crystals, mp 156ꢀC to 157ꢀC. H NMR spectrum,
(400 MHz, CDCl3), δ, ppm (J, Hz): 8.63 (2H, d, J = 8.0,
ArH); 7.99 (1H, d, J = 8.0, ArH); 7.75-7.70 (2H, m, ArH);
7.54-7.48 (5H, m, ArH); 7.42-7.34 (4H, m, ArH); 6.13 (1H,
bs, NH); 5.03 (2H, d, J = 6.0, NHCH2). 13C NMR spec-
trum, (75.0 MHz, CDCl3), δ, ppm: 159.3 (C N); 159.0
(C N); 150.1 (Cq); 138.6 (Cq); 135.7 (Cq); 132.7 (CHAr);
131.5 (CHAr); 129.6 (CHAr); 128.5 (CHAr); 128.2
(CHAr); 128.1 (CHAr); 127.9 (CHAr); 127.4 (CHAr); 125.6
(CHAr); 120.4 (CHAr); 113.9 (Cq); 45.7 (NHCH2). Anal.
calcd. for C21H17N3 (311.4): C, 81.00; H, 5.50; N, 13.49.
Found: C, 80.85; H, 5.47; N, 13.32.
N-Allyl-2-(4-chlorophenyl)quinazolin-4-amine (10b)
Method A: 0.25 g, yield 72%; Method B: 0.23 g, yield 69%.
1
White crystals, mp 101ꢀC to 102ꢀC. H NMR spectrum,
(400 MHz, CDCl3), δ, ppm (J, Hz): 8.60 (1H, d, J = 8.0,
ArH); 8.56 (1H, d, J = 8.0, ArH); 7.91 (1H, d, J = 8.0,
ArH); 7.72 (1H, d, J = 8.0, ArH); 7.67 (1H, t, J = 8.0, ArH);
7.53 (1H, d, J = 8.0, ArH); 7.45 (1H, d, J = 8.0, ArH); 7.40
(1H, t, J = 8.0, ArH); 7.25 (1H, bs, NH); 6.15-6.07 (1H, m,
CH); 5.39 (1H, d, J = 16.0, CH2); 5.28 (1H, d, J = 12.0,
CH2); 4.48-4.46 (2H, m, NHCH2). 13C NMR spectrum,
(75.0 MHz, CDCl3), δ, ppm: 164.4 (C N); 159.6 (C N);
140.5 (Cq); 139.1 (Cq); 134.9 (CH); 132.2 (CHAr); 130.4
(Cq); 129.4 (CHAr); 128.9 (CHAr); 128.6 (CHAr); 124.5
(CHAr); 121.2 (CHAr); 117.7 (CH2); 116.4 (Cq); 44.2
(NHCH2). Anal. calcd. for C17H14ClN3 (295.8): C,
69.04; H, 4.77; N, 14.21. Found: C, 68.86; H, 4.53; N, 14.18.
N-Benzyl-2-(4-chlorophenyl)quinazolin-4-amine (7b)
Method A: 0.24 g, yield 69%; Method B: 0.19 g, yield 56%.
1
White crystals, mp 150ꢀC to 152ꢀC. H NMR spectrum,
(400 MHz, CDCl3), δ, ppm (J, Hz): 8.55 (2H, d, J = 8.0,
ArH); 7.95 (1H, d, J = 8.0, ArH); 7.76 (1H, t, J = 8.0,
ArH); 7.70 (1H, d, J = 8.0, ArH); 7.49-7.33 (8H, m, ArH);
5.99 (1H, bs, NH); 5.02 (2H, d, J = 6.0, NHCH2). 13C
NMR spectrum, (75.0 MHz, CDCl3), δ, ppm: 159.4
(C N); 159.2 (C N); 150.6 (Cq); 138.6 (Cq); 136.2 (Cq);
132.7 (CHAr); 129.8 (CHAr); 129.0 (CHAr); 128.9 (CHAr);
128.4 (CHAr); 128.0 (CHAr); 127.4 (CHAr); 125.6 (CHAr);
120.4 (CHAr); 113.6 (Cq); 45.4 (NHCH2). Anal. calcd. for
C21H16ClN3 (345.8): C, 72.93; H, 4.66; N, 12.15. Found: C,
72.81; H, 4.62; N, 12.13.
3.1.3 | General procedure for the
preparation of methyl 4-((2-arylquinazolin-
4-yl)amino) butanoates 11a-d
A mixture of substituted N-(2-cyanophenyl) benzamides
8a-d (1.0 mmol) and thionyl chloride (10 mL) was heated
at 70ꢀC for 8 hours. The thionyl chloride was removed
under reduced pressure, and the residue was heated
at 120ꢀC under reduced pressure (50 mmHg) for
4 extra hours to give a yellowish oil of substituted
N-(2-cyanophenyl) benzimidoyl chlorides 9a-d. The crude
oil was cooled and dissolved in dry acetonitrile; to
this, acetonitrile solution was added to a solution of
γ-aminobutyric acid methyl ester hydrochloride (1.0 mmol)
and triethyl ethylamine (2.0 mmol) in acetonirile. The
reaction mixture was refluxed for 12 hours, and the aceto-
nitrile solvent was evaporated under reduced pressure. The
crude product was crystalized from ethanol to give the
pure methyl 4-((2-arylquinazolin-4-yl)amino) butanoates
11a-d.
N-Benzyl-2-(3-chlorophenyl)quinazolin-4-amine (7c)
Method A: 0.17 g, yield 49%; Method B: 0.24 g, yield 70%.
1
White crystals, mp 115ꢀC to 116ꢀC. H NMR spectrum,
(400 MHz, CDCl3), δ, ppm (J, Hz): 8.60 (1H, s, ArH); 8.49
(1H, d, J = 8.0, ArH); 7.98 (1H, d, J = 8.0, ArH); 7.77-7.71
(2H, m, ArH); 7.49-7.35 (8H, m, ArH); 6.16 (1H, bs, NH);
4.99 (2H, d, J = 6.0, NHCH2). 13C NMR spectrum,
(75.0 MHz, CDCl3), δ, ppm: 159.5 (C N); 159.1 (C N);
149.9 (Cq); 140.4 (Cq); 138.4 (Cq); 134.4 (Cq); 132.8
(CHAr); 130.2 (CHAr); 129.5 (CHAr); 128.9 (CHAr); 128.6
(CHAr); 128.1 (CHAr); 127.7 (CHAr); 126.6 (CHAr); 125.9
(CHAr); 120.7 (CHAr); 113.6 (Cq); 45.5 (NHCH2). Anal.
calcd. for C21H16ClN3 (345.8): C, 72.93; H, 4.66; N, 12.15.
Found: C, 72.71; H, 4.54; N, 12.01.

FATHALLA ET AL.
7
Methyl 4-((2-phenylquinazolin-4-yl)amino)
butanoate (11a)
(1H, d, J = 8.0, ArH); 7.96 (1H, d, J = 8.0, ArH); 7.75 (1H,
d, J = 8.0, ArH); 7.71 (1H, t, J = 8.0, ArH); 7.49-7.39 (4H,
m, ArH); 6.61 (1H, bs, NH); 3.89 (2H, q, J = 6.0, NHCH2);
3.61 (3H, s, OCH3); 2.54 (2H, t, J = 6.0, CH2CO); 2.16-2.09
(2H, m, CH2). Anal. calcd. for C19H18ClN3O2 (355.8): C,
64.14; H, 5.10; N, 11.81. Found: C, 64.03; H, 5.07; N, 11.63.
0.20 g, yield 63%. Whitish oil. 1H NMR spectrum, (400 MHz,
CDCl3), δ, ppm (J, Hz): 8.60 (2H, d, J = 8.0, ArH); 8.03 (1H,
d, J = 8.0, ArH); 7.85 (1H, d, J = 8.0, ArH); 7.72 (1H, t,
J = 8.0, ArH); 7.57-7.49 (3H, m, ArH); 7.42 (1H, t, J = 8.0,
ArH); 6.77 (1H, bs, NH); 3.90 (2H, q, J = 6.0, NHCH2); 3.68
(3H, s, OCH3); 2.56 (2H, t, J = 6.0, CH2CO); 2.21-2.14 (2H,
m, CH2). 13C NMR spectrum, (75.0 MHz, CDCl3), δ, ppm:
174.4 (C O); 159.9 (C N); 159.7 (C N); 147.7 (Cq); 137.0
(Cq); 133.1 (CHAr); 130.9 (CHAr); 128.7 (CHAr); 128.4
(CHAr); 126.7 (CHAr); 126.0 (CHAr); 121.6 (CHAr); 113.4
(Cq); 51.8 (OCH3); 41.2 (NHCH2); 31.9 (CH2CO); 24.1
(CH2). Anal. calcd. for C19H19N3O2 (321.4): C, 71.01; H,
5.96; N, 13.08. Found: C, 70.83; H, 5.87; N, 13.01.
3.1.4 | General procedure for the
preparation of 6-aryl-2,3-dihydro-4H-
pyrimido[1,2-c]quinazolin-4-ones 12a-d
Compounds 6-aryl-2,3-dihydro-4H-pyrimido[1,2-c]quinazo-
lin-4-ones 12a-d were prepared according to the prescribed
method for the preparation of methyl 4-((2-arylquinazolin-
4-yl)amino) butanoates 11a-d using β-alanine methyl ester
hydrochloride instead of γ-aminobutyric acid methyl ester
hydrochloride.
Methyl 4-((2-(4-chlorophenyl)quinazolin-4-yl)amino)
butanoate (11b)
0.27 g, yield 75%. White crystals, mp 110ꢀC to 112ꢀC. H
1
NMR spectrum, (400 MHz, CDCl3), δ, ppm (J, Hz): 8.57
(2H, d, J = 8.0, ArH); 7.98 (1H, d, J = 8.0, ArH); 7.81-7.63
(2H, m, ArH); 7.58-7.50 (3H, m, ArH); 6.56 (1H, bs, NH);
3.82 (2H, q, J = 6.0, NHCH2); 3.66 (3H, s, OCH3); 2.51
(2H, t, J = 6.0, CH2CO); 2.16-2.08 (2H, m, CH2). 13C
NMR spectrum, (75.0 MHz, CDCl3), δ, ppm: 174.4
(C O); 159.6 (C N); 159.2 (C N); 149.0 (Cq); 134.4 (Cq);
132.9 (CHAr); 130.3 (CHAr); 129.5 (CHAr); 128.6 (CHAr);
127.9 (CHAr); 126.7 (CHAr); 126.0 (CHAr); 114.1 (Cq); 52.0
(OCH3); 43.3 (NHCH2); 30.5 (CH2CO); 22.5 (CH2). Anal.
calcd. for C19H18ClN3O2 (355.8): C, 64.14; H, 5.10; N,
11.81. Found: C, 63.93; H, 4.92; N, 11.76.
6-Phenyl-2,3-dihydro-4H-pyrimido[1,2-c]quinazolin-
4-one (12a)
1
0.16 g, yield 58%. White crystals, mp 230ꢀC to 231ꢀC. H
NMR spectrum, (400 MHz, CDCl3), δ, ppm (J, Hz): 8.68
(1H, d, J = 8.0, ArH); 7.85 (1H, t, J = 8.0, ArH); 7.77 (1H,
d, J = 8.0, ArH); 7.68-7.53 (6H, m, ArH); 4.21 (2H, q,
J = 6.0, NCH2); 2.71 (2H, q, J = 6.0, CH2CO). 13C NMR
spectrum, (75.0 MHz, CDCl3), δ, ppm: 175.4 (C O);
157.7 (C N); 153.1 (C N); 146.1 (Cq); 135.5 (CHAr);
133.8 (Cq); 130.7 (CHAr); 129.2 (CHAr); 128.3 (CHAr);
128.1 (CHAr); 127.5 (CHAr); 127.3 (CHAr); 119.6 (Cq); 46.7
(NCH2); 29.7 (CH2CO). Anal. calcd. for C17H13N3O
(275.3): C, 74.17; H, 4.76; N, 15.26. Found: C, 74.05; H,
4.76; N, 15.18.
Methyl 4-((2-(3-chlorophenyl)quinazolin-4-yl)amino)
butanoate (11c)
1
0.30 g, yield 84%. White crystals, mp 95ꢀC to 96ꢀC. H
6-(3-Chlorophenyl)-2,3-dihydro-4H-pyrimido[1,2-c]
NMR spectrum, (400 MHz, CDCl3), δ, ppm (J, Hz): 8.57
(1H, s, ArH); 8.48 (1H, d, J = 8.0, ArH); 7.95 (1H, d,
J = 8.0, ArH); 7.78 (1H, d, J = 8.0, ArH); 7.73 (1H, t,
J = 8.0, ArH); 7.46-7.40 (3H, m, ArH); 6.52 (1H, bs, NH);
3.85 (2H, q, J = 6.0, NHCH2); 3.69 (3H, s, OCH3); 2.56
(2H, t, J = 6.0, CH2CO); 2.17-2.12 (2H, m, CH2). 13C NMR
spectrum, (75.0 MHz, CDCl3), δ, ppm: 174.6 (C O); 159.8
(C N); 158.8 (C N); 149.0 (Cq); 140.0 (Cq); 134.4.0 (Cq);
132.9 (CHAr); 130.3 (CHAr); 129.5 (CHAr); 128.6 (CHAr);
127.9 (CHAr); 126.7 (CHAr); 126.0 (CHAr); 121.1 (CHAr);
113.7 (Cq); 51.8 (OCH3); 41.3 (NHCH2); 32.0 (CH2CO);
24.0 (CH2). Anal. calcd. for C19H18ClN3O2 (355.8): C,
64.14; H, 5.10; N, 11.81. Found: C, 63.95; H, 4.84; N, 11.63.
quinazolin-4-one (12b)
1
0.23 g, yield 74%. White crystals, mp 178ꢀC to 179ꢀC. H
NMR spectrum, (400 MHz, CDCl3), δ, ppm (J, Hz): 8.65
(1H, d, J = 8.0, ArH); 7.84 (1H, t, J = 8.0, ArH); 7.74 (1H,
d, J = 8.0, ArH); 7.60-7.52 (5H, m, ArH); 4.21 (2H, q,
J = 6.0, NCH2); 2.71 (2H, q, J = 6.0, CH2CO). 13C NMR
spectrum, (75.0 MHz, CDCl3), δ, ppm: 175.2 (C O); 157.6
(C N); 152.1 (Cq); 145.9 (Cq); 137.2 (Cq); 135.5 (CHAr);
132.1 (Cq); 129.6 (CHAr); 129.5 (CHAr); 128.5 (CHAr); 127.5
(CHAr); 127.3 (CHAr); 119.6 (Cq); 46.7 (NCH2); 29.7
(CH2CO). Anal. calcd. for C17H12ClN3O (309.8): C,
65.92; H, 3.91; N, 13.57. Found: C, 65.83; H, 3.87; N, 13.46.
6-(3-Chlorophenyl)-2,3-dihydro-4H-pyrimido[1,2-c]
Methyl 4-((2-(2-chlorophenyl)quinazolin-4-yl)amino)
butanoate (11d)
quinazolin-4-one (12c)
1
0.22 g, yield 70%. White crystals, mp 210ꢀC to 211ꢀC. H
1
0.22 g, yield 62%. White crystals, mp 150ꢀC to 151ꢀC. H
NMR spectrum, (400 MHz, CDCl3), δ, ppm (J, Hz): 8.64
(1H, d, J = 8.0, ArH); 7.84 (1H, t, J = 8.0, ArH); 7.74 (1H, d,
NMR spectrum, (400 MHz, CDCl3), δ, ppm (J, Hz): 8.54

8
FATHALLA ET AL.
J = 8.0, ArH); 7.64 (1H, s, J = 8.0, ArH); 7.60-7.46 (4H, m,
ArH); 4.21 (2H, q, J = 6.0, NCH2); 2.72 (2H, q, J = 6.0,
CH2CO). Anal. calcd. for C17H12ClN3O (309.8): C, 65.92; H,
3.91; N, 13.57. Found: C, 65.78; H, 3.83; N, 13.45.
(CHAr); 129.5 (CHAr); 128.6 (CHAr); 127.5 (CHAr); 125.5
(CHAr); 115.2 (Cq); 53.5 (CH2). Anal. calcd. for C16H10
ClN3O (295.7): C, 64.98; H, 3.41; N, 14.21. Found: C,
64.82; H, 3.38; N, 14.04.
6-(2-Chlorophenyl)-2,3-dihydro-4H-pyrimido[1,2-c]
quinazolin-4-one (12d)
5-(3-Chlorophenyl)imidazo[1,2-c]quinazolin-3(2H)-
one (13c)
1
1
0.17 g, yield 56%. White crystals, mp 178ꢀC to 179ꢀC. H
0.18 g, yield 62%. White crystals, mp 214ꢀC to 215ꢀC. H
NMR spectrum, (400 MHz, CDCl3), δ, ppm (J, Hz): 8.66
(1H, d, J = 8.0, ArH); 7.85 (1H, t, J = 8.0, ArH); 7.72 (1H,
d, J = 8.0, ArH); 7.61 (1H, d, J = 8.0, ArH); 7.63-7.52 (4H,
m, ArH); 4.21 (2H, q, J = 6.0, NCH2); 2.73 (2H, q, J = 6.0,
CH2CO). Anal. calcd. for C17H12ClN3O (309.8): C,
65.92; H, 3.91; N, 13.57. Found: C, 65.79; H, 3.83; N, 13.41.
NMR spectrum, (400 MHz, DMSO-d6), δ, ppm (J, Hz): 8.27
(1H, d, J = 8.0, ArH); 8.02 (1H, t, J = 8.0, ArH); 7.94 (1H, s,
ArH); 7.85 (2H, t, J = 8.0, ArH); 7.75-7.69 (2H, m, ArH);
7.62 (1H, t, J = 8.0, ArH); 4.71(2H, s, CH2). 13C NMR spec-
trum, (75.0 MHz, DMSO-d6), δ, ppm: 185.1 (C O); 171.3
(C N); 150.2 (C N); 147.3 (Cq); 136.8 (CHAr); 135.7 (Cq);
133.8 (Cq); 131.3 (CHAr); 131.1 (CHAr); 128.8 (CHAr); 128.3
(CHAr); 127.6 (CHAr); 127.1 (CHAr); 115.8 (Cq); 53.9
(NCH2). Anal. calcd. for C16H10ClN3O (295.7): C, 64.98; H,
3.41; N, 14.21. Found: C, 64.82; H, 3.29; N, 14.06.
3.1.5 | General procedure for
the preparation of 5-aryl-
2-substitutedimidazo[1,2-c]quinazolin-3
(2H)-ones 13a-d and 14a-d
5-(2-Chlorophenyl)imidazo[1,2-c]quinazolin-3(2H)-
one (13d)
1
Compounds
5-arylimidazo[1,2-c]quinazolin-3(2H)-ones
0.18 g, yield 60%. White crystals, mp 181ꢀC to 182ꢀC. H
13a-d and 5-aryl-2-methyl imidazo[1,2-c]quinazolin-3(2H)-
ones 14a-d were prepared according to the prescribed
method for the preparation of methyl 4-((2-arylquinazolin-
4-yl)amino) butanoates 11a-d using glycine methyl ester
hydrochloride or L-alanine methyl ester hydrochloride,
respectively instead of γ-aminobutyric acid methyl ester
hydrochloride.
NMR spectrum, (400 MHz, DMSO), δ, ppm (J, Hz): 8.32
(1H, d, J = 8.0, ArH); 8.05 (1H, t, J = 8.0, ArH); 7.86 (1H,
d, J = 8.0, ArH); 7.79-7.56 (5H, m, ArH); 4.38 (2H, s,
CH2). 13C NMR spectrum, (75.0 MHz, CDCl3), δ, ppm:
183.8 (C O); 171.1 (C N); 148.7 (Cq); 147.2 (Cq); 136.5
(CHAr);; 132.4 (CHAr); 131.9 (Cq); 130.4 (CHAr); 129.8
(CHAr); 128.8 (CHAr); 128.4 (CHAr); 128.0 (CHAr); 127.6
(CHAr); 122.8 (CHAr); 115.8 (Cq); 51.9 (NCH2). Anal.
calcd. for C16H10ClN3O (295.7): C, 64.98; H, 3.41; N,
14.21. Found: C, 64.65; H, 3.29; N, 14.03.
5-Phenylimidazo[1,2-c]quinazolin-3(2H)-one (13a)
1
0.22 g, yield 86%. White crystals, mp 236ꢀC to 237ꢀC. H
NMR spectrum, (400 MHz, CDCl3), δ, ppm (J, Hz): 8.47
(1H, d, J = 8.0, ArH); 7.93 (1H, t, J = 8.0, ArH); 7.89 (1H,
d, J = 8.0, ArH); 7.75 (2H, d, J = 8.0, ArH); 7.68-7.61
(4H, m, ArH); 4.56 (2H, s, CH2). 13C NMR spectrum,
(75.0 MHz, CDCl3), δ, ppm: 185.7 (C O); 171.2 (C N);
159.3(C N); 150.1 (Cq); 147.0 (CHAr); 136.5 (Cq); 133.8
(CHAr); 133.1 (CHAr); 131.0 (CHAr); 129.5 (CHAr); 128.0
(CHAr); 127.2 (CHAr); 125.8 (CHAr); 115.4 (Cq); 52.8
(CH2). Anal. calcd. for C16H11N3O (261.3): C, 73.55; H,
4.24; N, 16.08. Found: C, 73.44; H, 4.15; N, 15.86.
2-Methyl-5-phenylimidazo[1,2-c]quinazolin-3(2H)-
one (14a)
1
0.13 g, yield 49%. White crystals, mp 230ꢀC to 231ꢀC. H
NMR spectrum, (400 MHz, CDCl3), δ, ppm (J, Hz): 8.40
(1H, d, J = 8.0, ArH); 7.90-7.81 (2H, m, ArH); 7.75-7.73
(2H, m, ArH); 7.63-7.56 (4H, m, ArH); 4.79 (1H, q, J = 6.0,
CH); 1.17 (3H, d, J = 6.0, CH3). 13C NMR spectrum,
(75.0 MHz, CDCl3), δ, ppm: 188.0 (C O); 170.8 (C N);
159.0 (C N); 150.8 (Cq); 147.3 (CHAr); 136.5 (Cq); 134.1
(CHAr); 133.3 (CHAr); 131.3 (CHAr); 129.4 (CHAr); 128.4
(CHAr); 127.6 (CHAr); 126.4 (CHAr); 115.6 (Cq); 59.9 (CH);
16.5 (CH3). Anal. calcd. for C17H13N3O (275.3): C,
74.17; H, 4.76; N, 15.26. Found: C, 74.11; H, 4.64; N, 15.17.
5-(4-Chlorophenyl)imidazo[1,2-c]quinazolin-3(2H)-
one (13b)
1
0.22 g, yield 74%. White crystals, mp 206ꢀC to 207ꢀC. H
NMR spectrum, (400 MHz, CDCl3), δ, ppm (J, Hz): 8.46
(1H, d, J = 8.0, ArH); 7.93 (1H, t, J = 8.0, ArH); 7.87 (1H,
d, J = 8.0, ArH); 7.74 (2H, d, J = 8.0, ArH); 7.64 (1H, t,
J = 8.0, ArH); 7.59 (2H, d, J = 8.0, ArH); 4.55 (2H, s,
CH2). 13C NMR spectrum, (75.0 MHz, CDCl3), δ, ppm:
186.6 (C O); 171.0 (C N); 159.8 (C N); 150.5(Cq); 145.4
(CHAr); 136.3 (Cq); 133.4 (Cq); 133.1 (CHAr); 131.7
5-(4-Chlorophenyl)-2-methylimidazo[1,2-c]quinazolin-3
(2H)-one (14b)
1
0.22 g, yield 71%. White crystals, mp 225ꢀC to 226ꢀC. H
NMR spectrum, (400 MHz, CDCl3), δ, ppm (J, Hz): 8.57
(1H, d, J = 8.0, ArH); 7.96 (1H, t, J = 8.0, ArH); 7.89 (1H,
d, J = 8.0, ArH); 7.76 (2H, d, J = 8.0, ArH); 7.67 (1H, t,

FATHALLA ET AL.
9
J = 8.0, ArH); 7.61 (2H, d, J = 8.0, ArH); 4.92 (1H, q,
J = 6.0, CH); 1.27 (3H, d, J = 6.0, CH3). 13C NMR spec-
trum, (75.0 MHz, CDCl3), δ, ppm: 187.5 (C O); 171.6
(C N); 160.2 (C N); 150.5 (Cq); 145.1 (CHAr); 135.6 (Cq);
133.1 (Cq); 133.6 (CHAr); 130.4 (CHAr); 129.5 (CHAr);
128.2 (CHAr); 127.9 (CHAr); 125.3 (CHAr); 115.6 (Cq); 59.6
(CH); 16.2 (CH3). Anal. calcd. for C17H12ClN3O
(309.8): C, 65.92; H, 3.91; N, 13.57. Found: C, 65.87; H,
3.73; N, 13.48.
ORCID
Walid Fathalla https://orcid.org/0000-0002-7769-4042
REFERENCES
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New York 1968.
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574–87.
[4] W. Fathalla, P. Pazdera, ARKIVOC 2002, (i), 7.
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Mechanisms, and Structure (3rd ed.), New York: Wiley, ISBN
0–471–85472-7.
5-(3-Chlorophenyl)-2-methylimidazo[1,2-c]quinazolin-3
(2H)-one (14c)
1
0.27 g, yield 86%. White crystals, mp 240ꢀC to 241ꢀC. H
NMR spectrum, (400 MHz, CDCl3), δ, ppm (J, Hz): 8.52
(1H, d, J = 8.0, ArH); 7.95 (1H, t, J = 8.0, ArH); 7.88
(1H, d, J = 8.0, ArH); 7.78 (1H, s, ArH); 7.68-7.61
(3H, m, ArH); 7.56 (1H, t, J = 8.0, ArH); 4.84 (1H,
q, J = 6.0, CH); 1.25 (3H, d, J = 6.0, CH3). 13C NMR spec-
trum, (75.0 MHz, DMSO-d6), δ, ppm: 185.3 (C O); 170.9
(C N); 150.2 (C N); 147.3 (Cq); 136.7 (CHAr); 135.3 (Cq);
133.2 (Cq); 131.3 (CHAr); 131.0 (CHAr); 128.9 (CHAr); 128.6
(CHAr); 127.7 (CHAr); 126.8 (CHAr); 115.5 (Cq); 59.4 (CH);
16.9 (CH3). Anal. calcd. for C17H12ClN3O (309.8): C,
65.92; H, 3.91; N, 13.57. Found: C, 65.74; H, 3.79; N, 13.42.
[10] C. A. G. N. Montalbetti, V. Falque, Tetrahedron 2005, 61,
10827.
[11] M. Megahed, W. Fathalla, J. Heterocyclic, Chem. 2018, 55,
2799.
[12] M. Megahed, W. Fathalla, J. Heterocyclic, Chem. 2018, 55,
2809.
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C. Buquet, M. Iannelli, B. Leblond, F. Marsais, T. Besson, Tet-
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5-(2-Chlorophenyl)-2-methylimidazo[1,2-c]quinazolin-3
(2H)-one (14d)
1
0.15 g, yield 48%. White crystals, mp 150ꢀC to 151ꢀC. H
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2143.
NMR spectrum, (400 MHz, CDCl3), δ, ppm (J, Hz): 8.49
(1H, d, J = 8.0, ArH); 8.10 (1H, t, J = 8.0, ArH); 8.00-7.88
(2H, m, ArH); 7.76-7.66 (3H, m, ArH); 7.33 (1H, t,
J = 8.0, ArH); 5.03 (1H, q, J = 6.0, CH); 1.29 (3H, d,
J = 6.0, CH3). 13C NMR spectrum, (75.0 MHz, CDCl3), δ,
ppm: 184.6 (C O); 170.4 (C N); 147.3 (Cq); 147.7 (Cq);
137.0 (CHAr);; 132.9 (CHAr); 131.3 (Cq); 130.7 (CHAr);
129.6 (CHAr); 128.9 (CHAr); 128.5 (CHAr); 128.0 (CHAr);
127.2 (CHAr); 123.1 (CHAr); 115.5 (Cq); 59.0 (CH); 16.7
(CH3). Anal. calcd. for C17H12ClN3O (309.8): C, 65.92; H,
3.91; N, 13.57. Found: C, 65.82; H, 3.86; N, 13.44.
How to cite this article: Fathalla W, Nofal EY,
El-Moneim MA. Domino synthesis of pyrimido
and imidazoquinazolinones. J Heterocycl Chem.
2019;1–9. https://doi.org/10.1002/jhet.3864