Synthetic approaches, functionalization and therapeutic potential of quinazoline and quinazolinone skeletons: The advances continue

Article abstract of DOI:10.1016/j.ejmech.2014.10.084

The presence of N-heterocycles as an essential structural motif in a variety of biologically active substances has stimulated the development of new strategies and technologies for their synthesis. Among the various N-heterocyclic scaffolds, quinazolines and quinazolinones form a privileged class of compounds with their diverse spectrum of therapeutic potential. The easy generation of complex molecular diversity through broadly applicable, cost-effective, practical and sustainable synthetic methods in a straightforward fashion along with the importance of these motifs in medicinal chemistry, received significant attention from researchers engaged in drug design and heterocyclic methodology development. In this perspective, the current review article is an effort to recapitulate recent developments in the eco-friendly and green procedures for the construction of highly challenging and potentially bioactive quinazoline and quinazolinone compounds in order to help medicinal chemists in designing and synthesizing novel and potent compounds for the treatment of different disorders. The key mechanistic insights for the synthesis of these heterocycles along with potential applications and manipulations of the products have also been conferred. This article also aims to highlight the promising future directions for the easy access to these frameworks in addition to the identification of more potent and specific products for numerous biological targets.

Full text of DOI:10.1016/j.ejmech.2014.10.084

Accepted Manuscript
Synthetic approaches, functionalization and therapeutic potential of quinazoline and
quinazolinone skeletons: The advances continue…
Imtiaz Khan, Aliya Ibrar, Waqas Ahmed, Aamer Saeed
PII:
S0223-5234(14)01021-6
10.1016/j.ejmech.2014.10.084
EJMECH 7492
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 13 August 2014
Revised Date: 10 October 2014
Accepted Date: 31 October 2014
Please cite this article as: I. Khan, A. Ibrar, W. Ahmed, A. Saeed, Synthetic approaches,
functionalization and therapeutic potential of quinazoline and quinazolinone skeletons: The advances
continue…, European Journal of Medicinal Chemistry (2014), doi: 10.1016/j.ejmech.2014.10.084.
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Graphical Abstract
Synthetic approaches, functionalization and therapeutic potential of quinazoline and
quinazolinone skeletons: The advances continue…
a,‡
b,‡
c
b,*
Imtiaz Khan , Aliya Ibrar , Waqas Ahmed , Aamer Saeed
a
School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD,
United Kingdom
b
Department of Chemistry, Quaid-i-Azam University, Islamabad-45320, Pakistan
c
Office of Research, Innovation and Commercialization, University of Gujrat, Gujrat-50700,
Pakistan
The current review article summarizes the recent developments in synthetic methodologies for
the construction of quinazoline and quinazolinone heterocycles. Mechanistic investigations,
applications, product manipulations and biological potential have also been discussed.
1

ACCEPTED MANUSCRIPT
Synthetic approaches, functionalization and therapeutic potential of quinazoline and
quinazolinone skeletons: The advances continue…
a,‡
b,‡
c
b,*
Imtiaz Khan , Aliya Ibrar , Waqas Ahmed , Aamer Saeed
a
School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD,
United Kingdom
b
Department of Chemistry, Quaid-i-Azam University, Islamabad-45320, Pakistan
c
Office of Research, Innovation and Commercialization, University of Gujrat, Gujrat-50700,
Pakistan
_
_____________________________________________________________________________
To whom correspondence should be addressed:
Prof. Dr. Aamer Saeed
Department of Chemistry
Quaid-i-Azam University
Islamabad-45320
Pakistan
E-mail: aamersaeed@yahoo.com
Tel.: +92-51-9064-2128
Fax: +92-51-9064-2241
‡
I.K and A.I contributed equally to this manuscript.
2

ACCEPTED MANUSCRIPT
Abstract
The presence of N-heterocycles as an essential structural motif in a variety of biologically active
substances has stimulated the development of new strategies and technologies for their synthesis.
Among the various N-heterocyclic scaffolds, quinazolines and quinazolinones form a privileged
class of compounds with their diverse spectrum of therapeutic potential. The easy generation of
complex molecular diversity through broadly applicable, cost-effective, practical and sustainable
synthetic methods in a straightforward fashion along with the importance of these motifs in
medicinal chemistry, received significant attention from researchers engaged in drug design and
heterocyclic methodology development. In this perspective, the current review article is an effort
to recapitulate recent developments in the eco-friendly and green procedures for the construction
of highly challenging and potentially bioactive quinazoline and quinazolinone compounds in
order to help medicinal chemists in designing and synthesizing novel and potent compounds for
the treatment of different disorders. The key mechanistic insights for the synthesis of these
heterocycles along with potential applications and manipulations of the products have also been
conferred. This article also aims to highlight the promising future directions for the easy access
to these frameworks in addition to the identification of more potent and specific products for
numerous biological targets.
Keywords: Bioactive heterocycles, Synthetic methods, Cross-coupling reactions, Inhibitors,
Enzymes, Biological potential
3

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1
. Introduction
Nitrogen-containing heterocyclic compounds are the most abundant and integral scaffolds that
occur ubiquitously in a variety of synthetic drugs, bioactive natural products, pharmaceuticals
and agrochemicals. Owing to their widespread applications, these skeletons have long been a
subject of immense interest, and substantial efforts have been made to the development of
synthetic strategies which could lead to the discovery of new bioactive compounds in medicinal
chemistry [1]. Indeed, with particular reference to the pharmaceutical industry, heterocyclic
motifs are especially prevalent with over 60% of the top retailing drugs containing at least one
heterocyclic nucleus as part of the overall topography of the compound [2].
Quinazoline and quinazolinone derivatives have attracted significant attention due to their
diverse pharmacological activities such as antimicrobial [3], antimalarial [4], anti-inflammatory
[
5], antihypertensive [6], anticonvulsant [7], anti-diabetic [8], anticancer [9], cholinesterase
inhibition [10], dihydrofolate reductase inhibition [11], and kinase inhibitory activity [12].
Quinazolines also exhibit a wide variety of biological functions like cellular phosphorylation
inhibition [13], ligands for benzodiazepine and GABA receptors in the central nervous system
[
14], and some of them have acted as DNA binding agents [15]. They also act as effective α-
adrenergic blocker, prazosin [16], bunazosin [17], and doxazosin [18], are useful medicines for
antihypertensives, proquazone and fluproquazone as non-steroidal anti-inflammatory drugs,
afloqualone as muscle relaxant, and diproqualone with sedative analgesic effects. KF31327 was
developed as a heart disease remedy and an impotence medicine [19]. In a recent report, 3,4-
dihydroquinazoline derivatives have been found to perform excellent T-type calcium channel
blocking activity [20]. Some representative examples are displayed in Fig. 1.
<
Figure 1>
4

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Quinazolinone and their derivatives [21] are also building block for approximately 150 naturally
occurring alkaloids isolated from a number of families of the plant kingdom, from
microorganisms and animals. Some of the compounds incorporating quinazolinone motif like
raltitrexed and thymitaq possess antitumor activities [22].
A vast number of quinazoline derivatives have been synthesized to provide synthetic drugs and
to design more effective medicines. There are a number of reviews [23] and monographs [24] on
quinazoline and quinazoline alkaloids. Recently, we have documented a formal collection of
significant developments (2013) [25] on the synthetic methods through which these heterocycles
(
quinazolines and quinazolinones) could be accessed, along with diverse biological profile which
they possess. Some other groups also published independently the synthesis of quinazolinones
26] and bioactive quinazolines [27], respectively. There has been no discussion on the
[
mechanistic aspects of key transformations. So, in corollary of these fascinating findings as well
as part of a programme aimed at discovering heterocyclic structures with various
pharmacological properties, in general [28], and in continuation of our previous work [25] on
these skeletons, we report here the very recent developments (2014) in the environmentally
benign, green, and efficient synthetic protocols (in most cases) to access quinazoline and
quinazolinone derivatives from cheap and readily available commercial feedstocks. This review
also focuses on the mechanistic insights for the synthesis of these cores for key reactions, while
presenting successful synthetic applications and product manipulations along with an array of
pharmaceutical and agrochemical applications.
2
. Progress in Synthetic Methods
The number of new methodologies regarding the synthesis of quinazoline and quinazolinone
cores has dramatically increased from year to year. All these transformations provide rapid
5

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access to new and original quinazoline and quinazolinone compounds, affording the possibility
of increasing structural diversity in a straightforward fashion starting from simple and common
substrates. The subject matter of current review is aimed at providing a comprehensive overview
of recent (2014) developments.
2
.1. Synthesis of Quinazolines
In this part, we outline examples dealing with the synthesis of quinazoline skeleton from readily
available feedstock.
Long and co-workers [29] developed a simple, fast and efficient divergent synthesis of a broad
range of multisubstituted quinazolines 2 by utilizing readily available amidines 1 through
3
2
2
iodine(III)-promoted oxidative C(sp )−C(sp ) and C(sp )−N bond formation in nonpolar solvents
(Scheme 1). Under a fixed set of optimized conditions, the scope of this annulation reaction was
explored delivering a range of quinazoline products in excellent yields. Various aromatic groups
with electron-withdrawing and electron-donating substituents at various positions were well
tolerated, affording the corresponding quinazolines in good to excellent yields. However, the
bulky naphthyl group gave quinazoline with lower yield. A significant extension in scope of the
reaction was also highlighted by tolerating several other groups like bromo, chloro, or fluoro on
the aniline ring.
<
Scheme 1>
Vanelle and co-workers [30] unfolded a practical and efficient synthesis of 2,4,6,8-
tetrasubstituted quinazolines 9 through one-pot chemoselective sequential bis-S Ar/bis-Suzuki–
N
Miyaura reactions under microwave irradiation (Scheme 2). This approach allows rapid and
efficient access to desired products in high yields.
6

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<
Scheme 2>
Prajapati and co-workers [31] succeeded to develop an efficient aza-Diels–Alder protocol for the
construction of 2,4-diaryltetrahydroquinazoline derivatives 13 (Scheme 3). The reaction
proceeded well under both microwave and thermal conditions and can be tuned by varying the
time to obtain dihydroquinazoline derivatives under thermal heating. The cascade nature of the
transformation as well as in situ generation of both the diene and dienophile and their subsequent
cycloaddition makes this methodology, atom and step economic. The strategy allowed exploring
the scope of reaction with a range of substituted aldehydes and the results revealed that the
nature of the substituent present in the aromatic ring of the aldehydes does not have any
significant impact on the yield of the reaction. Aryl aldehydes with both electron-donating as
well as -withdrawing substituents participated in the reaction smoothly with comparable yields.
Overall, this one-pot method is simple, rapid and efficient, and provides an alternative for the
construction of tetrahydroquinazolines in the absence of harmful organic solvents and additives.
<
Scheme 3>
Baghbanian and Farhang [32] described an attractive synthesis of quinazoline derivatives 14
using magnetically separable and reusable CuFe O nanoparticles in aqueous media (Scheme 4).
2
4
Nano sized CuFe O was prepared by the thermal decomposition of Cu(NO ) and Fe(NO ) in
2
4
3 2
3 3
water in the presence of sodium hydroxide. Under optimized reaction conditions, various
aromatic aldehydes afforded the corresponding products in high yields. The effect of the
substituent on 2-aminobenzophenone and aldehyde derivatives with regard to the reaction time
and yield has also been examined. In the presence of electron-withdrawing groups at the 5th
7

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position of 2-aminobenzophenone, the reaction time increased compared with electron-donating
groups.
<
Scheme 4>
The possible mechanism for the synthesis of quinazolines using CuFe O NPs as the clean
2
4
catalyst is depicted in Fig. 2. The coordination of CuFe O NPs with the carbonyl groups of 2-
2
4
aminoaryl ketones and aldehydes could increase the electrophilicity of carbonyl carbons and
enhance the subsequent nucleophilic attack of the amine group and NH OAc. Afterwards, the
4
condensation of aldehyde with the amine leads to aldimine 16 and then this intermediate, by the
attack of NH OAc to the keto group of benzophenone, gives ketimine 17. Thereafter,
4
intermediate 17, via the ring closure forms intermediate 18, which is followed by aromatization
through dehydration in conjunction with oxygen from the air to give the quinazoline derivatives
in good to excellent yields.
<
Figure 2>
Zhang and co-workers [33] demonstrated an elegant synthesis of quinazoline derivatives 20 in
good to excellent yields via reaction of N-arylamidine 19 and aromatic aldehyde 11 in air using
CuO nanoparticles as a recyclable catalyst (Scheme 5). With the best reaction conditions, N-
arylamidines with a range of substituents were exploited affording desired products with no
significant effect on the yield, either with electron-donating or electron-withdrawing groups.
However, the position of substituents has an obvious influence on the reaction. Furthermore,
CuO nanoparticles can be recycled without significant decrease in catalytic activity.
<
Scheme 5>
8

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Kobayashi and Ezaki [34] developed an interesting synthetic procedure for the synthesis of
quinazoline derivatives 26 by treating 2-(1-azidoalkyl)-phenyl isocyanides 22 with NaH in DMF
at 0 °C via cyclization of 1-(2-isocyanophenyl)alkylideneamine intermediates (Scheme 6).
<
Scheme 6>
Beifuss and co-workers [35] developed a facile and efficient CuI-catalyzed domino approach for
the synthesis of quinazoline 29 by the reaction of 1-(2-bromophenyl)methanamines 27 and
amidines 28 in a single step using K PO as the base, pivalic acid as the additive, and aerial
3
4
oxygen as the oxidant (Scheme 7). This method offers a new access to the desired products in
3-90% yield. Under optimized set of reaction conditions, the potential scope of this annulation
4
was explored using a diverse range of amidinium salts as well as substituted bromophenyl
methanamines.
<
Scheme 7>
With regard to the mechanism of the CuI-catalyzed domino reaction between 1-(2-
halophenyl)methanamines 27 and amidines 28, it is assumed that either an intermolecular N-
arylation/intramolecular nucleophilic substitution/aromatization sequence (Fig. 3, path A) or a
domino intermolecular nucleophilic substitution/intramolecular N-arylation/aromatization is
possible (Fig. 3, path B). However, after conducting control experiments, it is assumed that the
reaction proceeds via pathway A.
<
Figure 3>
Boulcina and co-workers [36] described an elegant, effective and simple one-pot methodology
for the synthesis of 1,2-dihydroquinazolines 30 catalyzed by 4-(N,N-dimethylamino) pyridine
9

ACCEPTED MANUSCRIPT
(DMAP) from readily available aromatic or heteroaromatic aldehydes 11, 2-aminobenzophenone
1
4, and ammonium acetate 12 under mild conditions (Scheme 8). Under the optimal reaction
conditions, the generality of this one-pot transformation was investigated by employing several
aromatic aldehydes. The results revealed that the electronic nature of the substituents on the
benzene ring had no significant influence on the reactivity. An unsubstituted phenyl group or
aryl groups with electron-donating substituents afforded high yields, as did those with electron-
withdrawing groups. However, the presence of 2-chloro-, 4-N,N-dimethylamino-, or 4-hydroxy-
groups on the aromatic ring produced slightly diminished yields of the products. Also, a variety
of more challenging heterocyclic aldehydes were reacted in a similar manner with 2-
aminobenzophenone and ammonium acetate.
<
Scheme 8>
Based on the above observations, two plausible mechanistic pathways were proposed for the
present protocol which involve DMAP as a base [37] (Fig. 4). The first reaction mechanism
(path a) is proposed to proceed via the condensation of the aldehyde 11 with 2-
aminobenzophenone 14 to furnish the corresponding aldimine 31 which on further condensation
with ammonium acetate gives diimine 32. Deprotonation of 32 with the catalyst produces
carbanion intermediate 33, which undergoes intramolecular cyclization to form the target 1,2-
dihydroquinazoline 30. In another possible mechanism (path b), the condensation of aldehyde 11
with NH OAc 12 results in the formation of aldimine 34, which on further reaction with 2-
4
aminobenzophenone 14 leads to the desired product 30, after dehydration.
<
Figure 4>
10

ACCEPTED MANUSCRIPT
Trivedi and co-workers [38] developed an efficient green protocol for the synthesis of
quinazolines 36 in the absence of solvent and catalyst. 2,4-Disubstituted quinazolines have been
synthesized from three-component one-pot reactions of 2-aminoaryl ketones 14, orthoesters 35,
and ammonium acetate 12 (Scheme 9). The scope and limitations of the present protocol were
investigated using a variety of substituted 2-aminoaryl ketones and trialkyl orthoesters. The
present method has several advantages including operational simplicity, substrate generality,
clean reaction, and high yields (76–94%) of products with moderate reaction time.
<
Scheme 9>
2
.2. Synthesis of Quinazolinones
This section highlights the different processes used to establish quinazolinone structures from
simple and readily available starting precursors in a straightforward fashion.
+
-
Liu and co-workers [39] designed a bifunctional IL catalyst, [HDBU ][TFE ], by neutralization
of a superbase (DBU) and a weak proton donor (trifluoroethanol), and found to activate CO and
2
2
-aminobenzonitriles 37 simultaneously to produce quinazoline-2,4(1H,3H)-diones 38 in
excellent yields under atmospheric pressure at room temperature (Scheme 10). Several
substituents were tolerated on the aminobenzonitrile substrate which afforded desired products in
pleasing yields. In addition, this IL could be easily recovered and reused without loss in its
activity and could act as a highly efficient, greener, and stable bifunctional IL catalytic system.
<
Scheme 10>
+
-
A possible mechanism for the [HDBU ][TFE ]-catalyzed reaction of CO with 2-
2
aminobenzonitrile 37 to give quinazoline-2,4(1H,3H)-dione 38 is proposed (Fig. 5). In
+
-
[
HDBU ][TFE ], 2-aminobenzonitrile is activated by hydrogen bonding with both the cation and
11

ACCEPTED MANUSCRIPT
-
anion of the IL to form the intermediate 39, while CO is activated by the anion [TFE ] to form
2
the intermediate 40. The nucleophilic nitrogen atom of 39 attacks the carbon atom of 40 to form
the intermediate 41, with subsequent nucleophilic cyclization of 41 to produced 42, which is
+
-
subsequently converted into 38 after regeneration of [HDBU ][TFE ] 43.
<
Figure 5>
Work by Zhang et al. [40] led to the development of a simple, versatile, efficient one-pot
methodology for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones 47, 48 and quinazolin-
4
(3H)-ones 50, 51 employing CuO nanoparticles as the catalyst (Scheme 11). In the case of
amine as the substrates, the reactions afford 2,3-dihydroquinazolin-4(1H)-ones in good yields.
However, when inorganic ammonium salts as the nitrogen source, the substrates undergo
intramolecular electron transfer and rearrangement yielding quinazolin-4(3H)-ones (Scheme 12).
The easy generation of molecular diversity along with the importance of quinazolinones in
medicinal chemistry makes this process an appropriate alternative for the synthesis of potentially
bioactive compounds. The important features of this protocol include inexpensive, recyclable,
efficient CuO nanoparticles, ultrasonic irradiation and water as a medium to accelerate the
reaction rate, and broad functional group tolerance.
<
<
Scheme 11>
Scheme 12>
Zhang and co-workers [41] investigated and developed an efficient cyclocondesation reaction of
o-aminobenzonitriles 37 with cycloketones 52 catalyzed by a novel, convenient, more economic,
and environmentally benign SrCl modified SSA catalyst, in water to afford quinazolin-4-ones
2
12

ACCEPTED MANUSCRIPT
5
3 (Scheme 13). The results revealed that electron-withdrawing substituents, such as nitro group,
seems beneficial to the reaction and gives a higher product yield. It has also indicated that
cycloketones with six membered ring are more active to react with enaminocarbonitriles.
<
Scheme 13>
Cheon and Kim [42] developed an efficient, user-friendly and highly environmentally benign
protocol for the synthesis of 2-substituted and 2,3-disubstituted quinazolinones 55 from
anthranilamides 54 and aldehydes 11 via aerobic oxidative cyclization in wet DMSO without any
additives (Scheme 14). Under the optimized reaction conditions, various aromatic aldehydes
were readily applied to this protocol to investigate the substrate scope which afforded the desired
products in high to excellent yields. Stereoelectronic nature of the aldehydes had a little effect on
the product formation. Heteroaromatic aldehydes were also applied to this aerobic oxidation
protocol without any sacrifice of its efficiency. In addition, this protocol could be extended to
α,β-unsaturated aldehydes, such as cinnamaldehyde. Aliphatic aldehydes including formaldehyde
were also tested in this protocol and the desired products were obtained in good to high yields. In
general, this new protocol features operational simplicity, high atom economy, and broad
substrate scope.
<
Scheme 14>
Hajra and co-workers [43] demonstrated a remarkable and efficient Nano-In O -catalyzed one-
2
3
pot three-component condensation of isatoic anhydride 44, primary amine 45 or ammonium salts
2/49 and aromatic aldehydes 11 for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones 56, 57 in
1
aqueous media (Scheme 15). Having established reaction conditions, the scope of this cascade
approach was explored by using a range of substituted aromatic aldehydes and amines.
13

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Aldehydes as well as amines containing electron-donating (-OMe) group on the aromatic ring
have shown good efficiency. On the other hand, In O nanoparticles are easily recyclable without
2
3
the significant loss of catalytic activities. In general, this one-pot protocol is also applicable on
gram-scale synthesis. The significant advantages offered by this method include: (i) use of
greener solvent, (ii) good yields, (iii) benign byproducts, (iv) low catalyst loading, and (v) simple
operation.
<
Scheme 15>
Han and co-workers [44] introduced a simple and novel synthetic route to quinazoline-
2
2
,4(1H,3H)-diones 58 under atmospheric pressure in high yields from the reaction of CO with
2
-aminobenzonitriles 37 in the presence of [Bmim]Ac which acts as a dual solvent–catalyst
(Scheme 16). To demonstrate the generality of this approach to the synthesis of quinazoline-
2
,4(1H,3H)-diones, a range of 2-aminobenzonitrile derivatives were employed. The presence of
an electron-donating group had a slight influence on the reaction. This highly-efficient, greener,
inexpensive, active and stable catalytic system could potentially find wide applications in the
generation of a library of quinazoline-2,4(1H,3H)-diones from CO and 2-aminobenzonitriles
2
under mild conditions.
<
Scheme 16>
A plausible mechanism for the [Bmim]Ac-catalyzed formation of quinazoline-2,4(1H,3H)-dione
8 from the reaction of 2-aminobenzonitrile 37 and CO is proposed as depicted in Fig. 6.
5
2
Initially, the acetate anion attacks the amino group, captures a proton, and activates the reactant
7 to produce an intermediate 59 which on reaction with CO rapidly leads to the formation of a
3
2
carbamate ester 60. An intramolecular nucleophilic cyclization of 60 affords intermediate 61
14

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which on subsequent rearrangement forms the isocyanate intermediate 62, and then 63. Finally,
the title product 58 is obtained from the stabilization of 63. In addition, the formation of the
isocyanate intermediate 62 assisted by the o-cyano group appears to be important in the whole
catalytic cycle [45].
<
Figure 6>
Tajbakhsh and co-workers [46] developed an important and straightforward protocol for the
synthesis of dihydroquinazolinones 65 and quinazolinones 66 using H PW O as a recyclable
3
12 40
catalyst in aqueous medium (Scheme 17). This procedure tolerates a range of aldehydes
affording title products in ample yields. Sterically encumbered aldehydes are also found as
effective coupling partners providing desired products in good yield. On the other hand, this
catalyst system possess several advantages including high yields, short reaction times, easy
work‐up, green procedure avoiding toxic organic solvents, and the use of a readily available,
inexpensive and relatively non‐toxic catalyst.
<
Scheme 17>
Wu and co-workers [47] developed an interesting and straightforward one-pot cascade procedure
for the carbonylative synthesis of quinazolinones 68 from commercially available 2-
aminobenzonitriles 37 and bromobenzenes 67 (Scheme 18). With the best reaction conditions in
hand [Pd(OAc) (2 mol%), BuPAd (6 mol%), K CO (2.5 mmol), DMSO–H O (v/v = 1 : 1; 2
2
2
2
3
2
mL), CO (10 bar), 120 °C, 16 h], the generality and scope of this convenient methodology was
investigated. In the first stage, substituents on 2-aminobenzonitriles were studied. Methyl-,
methoxy-, fluoro-, chloro-substituted quinazolinones were produced in good yields from their
parent substrates under identical conditions in 55-87% yields. Also, a number of aryl bromides
15

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with various functional groups were tested subsequently. Methyl-, methoxy-, tert-butyl-,
methylsulfanyl-, and N,N-dimethylamino- as typical electron-donating functional groups were
checked and the corresponding quinazolinones were produced in 74–91% yields. The use of base
like Na CO or K PO instead of K CO gave inferior yields [48]. Remarkably, two
2
3
3
4
2
3
representative examples of heteroaryl bromides were also successfully applied in this
transformation.
<
Scheme 18>
A plausible reaction mechanism for this transformation has been proposed in Fig. 7. The reaction
started with the reduction of Pd(II) to Pd(0) 69, followed by the oxidative addition of
bromobenzene to Pd(0) affording the organopalladium species 70. After the coordination and
insertion of CO, the key intermediate acylpalladium complex 71 was formed. N-(2-
Cyanophenyl)benzamide 72 was eliminated after nucleophilic attack of 2-aminobenzonitrile 37
to the acylpalladium complex 71. Pd(0) can be regenerated under the assistance of base, ready to
enter a catalytic cycle. In the presence of water and base, N-(2-cyanophenyl)benzamide 72 was
hydrolysed into the corresponding N-(2-carbamoylphenyl)benzamide 73 which goes to the
terminal quinazolinone 68 after intramolecular condensation and thermal 1,3-proton shift. The
hydration of the cyano-group is a base induced transformation, and the palladium in this system
might behave as a Lewis acid to further assistant K CO in achieving the nitrile hydration. In
2
3
addition, palladium may promote the condensation to give the final product as well.
<
Figure 7>
In another study, Wu et al. [49] developed an impressive environmentally friendly and mild
protocol to obtain 2,3-dihydroquinazolin-4(1H)-ones 74 from 2-aminobenzonitriles 37 and
16

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aromatic aldehydes 11 using water as a cheap, green and harmless reaction medium with
inorganic base (K PO ) as the only promoter (Scheme 19). Various functional groups were
3
4
tolerated under these conditions affording the desired products in variable yields. In general,
electron-withdrawing groups on the aldehyde or the 2-aminobenzonitrile, respectively, led to the
decrease of the yields. Also, methyl-substituents neighboring the cyano-group or the aldehyde
function did not give the quinazolinone due to the steric hindrance. The electronic effect may be
responsible for the results as well, as the ortho-methyl substituent decreases the activity of the
nitrile group. This methodology can also be applied to non-α-protic aldehydes such as
cyclohexane carboxaldehyde and isobutanal.
<
Scheme 19>
Li and co-workers [50] successfully reported their findings that an iron-catalyzed one-pot single-
step oxidative system could be easily applied for the conversion of primary alcohols 75 into
quinazolinone derivatives 76 (Scheme 20). With various primary alcohols in hand, the scope of
this annulation was investigated under standard reaction conditions. For different substituted
benzyl alcohols with electron-donating and electron-withdrawing groups gave moderate to good
yields. Notably, heteroaryl substrate like 2-furylmethanol was also examined and the
corresponding product was obtained in 76% yield. In order to demonstrate the broad synthetic
utility of this system, the investigation was extended to more challenging alkyl primary alcohols
such as ethanol and octanol, and fortunately, the desired products were also afforded with
moderate yields.
<
Scheme 20>
17

ACCEPTED MANUSCRIPT
Safari and Gandomi-Ravandi [51] synthesized a series of 2-aryl-2,3-dihydroquinazolin-4(1H)-
ones 77 from sonication of anthranilamide 64 and an aldehyde 11 as precursors in the presence
of Ag–CNTs as a novel catalyst (Scheme 21). This work consistently has the advantages of
excellent yields, short reaction times, and simple experimental and work-up procedures. The
heterogeneous catalyst could be recovered and recycled several times without any loss of its
activity.
<
Scheme 21>
In another study, Li and co-workers [52] produced a novel metal-free synthesis of
3
quinazolinones 80 via dual amination of sp C–H bonds (Scheme 22). A wide range of 2-amino
benzamides 78 were employed for annulation with methylarenes 79 under the optimized
conditions. Most of the toluenes with electron-donating and electron-withdrawing substituents
could be converted to the desired products in moderate to good yields. On the other hand, the
substituents at the phenyl ring of 2-amino benzamides did not affect the efficiency of this
transformation.
<
Scheme 22>
A possible mechanism is proposed as shown in Fig. 8. Initially, the homolysis of DTBP gave
tert-butoxy radicals [53]. The benzyl radical was then generated by abstraction of H from
toluene, and subsequent coupling of these two radicals produced the intermediate 82. Then, 83
was generated from 82 via nucleophilic attack by 78 in the presence of TsOH, followed by
oxidation to give 84. Subsequently, 84 was converted to annulation product 80 via the second
amination followed by oxidation.
18

ACCEPTED MANUSCRIPT
<
Figure 8>
Research group headed by Siddiki [54] reported an effective HBEA zeolite-supported Pt metal
nanoclusters (Pt/HBEA) catalyst for direct dehydrogenative synthesis of quinazolinones 86 from
o-aminobenzamide 64 and alcohols 75 under promoter-free conditions (Scheme 23). The general
applicability of the present catalytic system was investigated by isolating a range of the
quinazolinones in variable yields. Both electron-rich and electron-poor benzylalcohols were
tolerated to give desired products in excellent isolated yields (82–95%). The reaction of a
sterically hindered o-substituted benzylalcohol also proceeded in good yield. In addition,
heteroaromatic alcohols with thienyl, furanyl and pyridinyl groups were also tolerated with good
yields (75%, 65% and 78%, respectively). It is important to note that various aliphatic alcohols,
including linear and branched aliphatic alcohols also worked well.
<
Scheme 23>
Kaeobamrung and co-workers [55] uncovered a domino synthesis of quinazolinone derivatives
9 via a copper-catalyzed Ullmann-type coupling, an intramolecular Michael addition and a
8
retro-Mannich reaction, under mild and simple reaction conditions (Scheme 24). Having
established optimized conditions, the scope of the substrates in the copper-catalyzed domino
reactions was investigated. A variety of N-substituted benzamides 87 and enaminones 88 were
applicable for the copper-catalyzed domino reactions. As the size of the substituents on the
enaminones increased, the yields of corresponding quinazolinones were dramatically diminished,
demonstrating that steric hindrance, especially the substituents on the enaminones, played a
crucial role in determining the product yields. On the other hand, N-Phenyl substituted
benzamides gave low yields due to their low nucleophilicities for Michael additions.
19

ACCEPTED MANUSCRIPT
<
Scheme 24>
Cai and co-workers [56] developed an efficient and practical two-step protocol for the synthesis
of 2-amino-4(3H)-quinazolinones 91 via ring-opening of isatoic anhydride 44 and palladium-
catalyzed oxidative isocyanide insertion in one-pot (Scheme 25). This regioselective procedure
could construct a wide range of 2-amino-4(3H)-quinazolinones in moderate to excellent yields.
Under the optimized conditions, the reaction occurs smoothly using a variety of amines,
isocyanides and isatoic anhydrides. Various amines, including aryl and alkyl amines were also
well tolerated. Benzyl amines bearing both electron-rich and electron-deficient aromatic ring
furnished the desired products in high yields. With regard to amines bearing heterocycles, the
corresponding products were isolated in high yields. Next, scope of this process was extended to
isocyanide component which afforded desired products in appreciable yields. When cylcohexyl
isocyanide and 1,1,3,3-tetramethylbutyl isocyanide were employed instead of tert-butyl
isocyanide, the reaction worked as expected giving corresponding products in high yields. In
addition, the use of different isatoic anhydrides containing electron-donating and halogen groups
reacted efficiently, affording expected products in moderate to high yields. Overall, the
methodology also had distinct advantages of easily accessible starting materials and operational
simplicity.
<
Scheme 25>
The proposed mechanism (Fig. 9) starts with the ring-opening reaction of isatoic anhydride 44
with amine 45 generating the bis-nucleophile 90. Catalyst 92 reacts with the bisnucleophile 90 to
form the intermediate 93. Then, isocaynide insertion reaction occurs, resulting in the species 94
which on subsequent reductive elimination affords the product 91. Pd(0) species is stabilized by
20

ACCEPTED MANUSCRIPT
coordination of multiple isocyanides and then oxidized by silver carbonate to regenerate the
catalyst.
<
Figure 9>
Chen et al. [57] disclosed an efficient and convenient metal-free aerobic oxidative C–N bond
cleavage of tertiary amines 95 to construct N-heterocycles 96 using molecular oxygen as the sole
oxidant with high atom efficiency (Scheme 26). Under the optimized reaction conditions, the
substrate scope of this reaction was investigated where o-substituted anilines could readily react
with aliphatic tertiary amines to produce the corresponding quinazolinone derivatives. It should
be noted that the reactivity of the oxidative cyclocondensation was independent of the alkyl
chain length, and different aliphatic tertiary amines could efficiently undergo oxidative
cyclocondensation with o-substituted anilines, giving the quinazolinone derivatives in high
yields. On the other hand, several substituted o-aminobenzamides with various functionalities
also led to the desired products on reaction with tertiary amines.
<
Scheme 26>
Based on above results and the reported literature [58], the reaction possibly takes place as
shown in Fig. 10. Initially, in the presence of molecular oxygen, the tertiary amine 95 is oxidized
to N-oxide 97, followed by protonation to form 98 under suitable pH conditions. Dehydration of
9
8 affords the immonium ion 99, which is readily hydrolyzed to produce a secondary amine and
an aldehyde [59]. Finally, N-heterocyclic compound 96 is produced by condensation/oxidative
dehydrogenation of in situ aldehyde with o-substituted aniline.
<
Figure 10>
21

ACCEPTED MANUSCRIPT
Cheng et al. [60] successfully synthesized a series of biologically important 4(3H)-
quinazolinones 101 from readily available 2-amino-N-methoxybenzamides 100 and aldehydes 11
via a cascade reaction in good to excellent yields (Scheme 27). By this process, under optimal
reaction conditions, the title compounds were readily generated providing insights into the scope
and generality of this new one-pot protocol. The results also revealed that several substituted
aldehydes bearing electron-withdrawing groups led to the desired products. The method was
equally well tolerable of the benzaldehydes bearing electron-rich substituent. In the case of di-
substituted benzaldehydes, bearing either electron-withdrawing or electron-donating group, the
desired products were obtained in even better yields.
<
Scheme 27>
Jiang and co-workers [61] established a novel palladium-catalyzed three-component cascade
reaction for the synthesis of quinazolin-4(3H)-ones 104 from readily available 2-
aminobenzamides 64 and aryl halides 102 via a palladium-catalyzed isocyanide
insertion/cyclization sequence (Scheme 28). The scope and generality of this process was
investigated using anthranilamides and various aryl halides under optimized reaction conditions.
From results it could be concluded that most of the aryl iodides with electron-donating groups
give better results than the substrates with electron-withdrawing groups. However, substrates
with electron-donating group, p-phenyliodobenzene gave a poor yield. The suitability of
electron-poor substituents including p-fluoro, p-chloro, and p-trifluoromethyl groups was
evaluated which gave the desired products in 41−86% yield. Also, heteroaromatic substrates
were converted to the corresponding product in good yield. Overall, this methodology efficiently
constructs quinazolin-4(3H)-ones in moderate to excellent yields with the advantages of
operational simplicity.
22

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<
Scheme 28>
A plausible mechanism for this reaction is depicted in Fig. 11. Oxidative addition of aryl halides
02 to the Pd(0) catalyst 105 facilitates the formation of palladium complex 106, followed by
1
tert-butyl isocyanide 103 insertion to get palladium(II) species 107. Then, under the assistance of
t-BuONa, the addition of 2-aminobenzamide 64 gives the generation of 108, which leads to the
desired 4(3H)-quinazolinones 104 after cyclization with losing tert-butylamine.
<
Figure 11>
Sarva and co-workers [62] disclosed a simple and highly efficient synthesis of 2-substituted
quinazolin-4(3H)-ones 110 by the iron(III) chloride catalyzed reaction of isatoic anhydride 44
with various amidoxime derivatives 109 (Scheme 29). The scope of the method was evaluated by
using a variety of substituted aryl amidoximes under the optimized conditions, and the results
gratifyingly gave the desired products in high yields regardless of the nature of the substituents
on the amidoxime. Interestingly, neither electron-donating (methyl, 4-hydroxy, 4-methoxy, 4-
amino, or 4-methylsulfanyl) nor electron-withdrawing groups (4-bromo or 4-nitro) on the
amidoxime had any effect on the reaction profile and yield. Heteroaromatic aldoximes also gave
the corresponding quinazolinones in good yields. Furthermore, several alkyl amidoximes
afforded similar results.
<
Scheme 29>
Pouramini and Tamaddon [63] discovered an efficient process for the synthesis of
quinazolinones 111 via reaction of 2-aminobenzonitrile 37 with carbonyl compounds 11 using
macroporous Amberlyst A26 OH in H O–EtOH (Scheme 30). To define the scope of the A26
2
23

ACCEPTED MANUSCRIPT
OH-catalyzed synthesis of 2-substituted 2,3-dihydro-4(1H)-quinazolinones, various aldehydes
were reacted with 2-aminobenzonitrile under optimized reaction conditions. The electronic
effects of the substituents of the aldehydes had little effect on the yield, and the products were
isolated in high purity by simple filtration of the catalyst and addition of cold water.
<
Scheme 30>
The mechanistic cycle (Fig. 12) involve the initial hydration of 2-aminobenzonitrile to 112
occurred efficiently, giving a 93% yield of the corresponding amide. Condensation of the
isolated intermediate 112 with benzaldehyde under similar conditions yielded 2-(phenyl)-2,3-
dihydro-4(1H)-quinazolinone in excellent yield.
<
Figure 12>
Alizadeh and co-workers [64] developed an efficient dual-catalyst system of piperidine and
molecular iodine for the synthesis of 2-alkyl-2-(2-oxo-2H-chromen-3-yl)-2,3-dihydro-
4
(1H)quinazolinone derivatives 116 by a four-component reaction of salicylaldehydes 114, β-
keto esters 115, ammonium acetate 12, and isatoic anhydride 44 (Scheme 31). The products were
obtained in good yields under mild reaction conditions. This protocol tolerates a variety of
salicylaldehydes containing both electron-withdrawing and electron-donating substituents.
<
Scheme 31>
Li and co-workers [65] disclosed an efficient strategy to access 2-hetarylquinazolin-4(3H)-ones
3
1
18 via copper-catalyzed direct aerobic oxidative amination of sp C−H bonds using cheap and
readily available (2-azaaryl)methane 117 (Scheme 32). Having developed a set of standard
reaction conditions, a range of substrates were applied in this oxidative amination process to
24

ACCEPTED MANUSCRIPT
produce the corresponding 2-hetaryl-quinazolin-4(3H)-one products in good yields. The
heteroaryl substrates include pyridine, quinoline, pyrazine, quinoxaline, and benzothiazole with
different substituent pattern. All these substrates were well tolerated in this transformation
affording corresponding products in efficient yields. On the other hand, suitability of the
benzamide core was also assessed. Chloro- and methyl-substituted benzamides produced
oxidative
oxidation−amination−cyclization transformation represents a straightforward protocol to prepare
-hetaryl-substituted quinazolinones from simple starting materials.
Scheme 32>
condensation
products
in
ample
yields.
Overall,
this
tandem
2
<
Wu and co-workers [66] developed an efficient, novel and convenient method for the synthesis
of quinazolinones 122 from 2-bromoformanilides 119 and organo nitros 120 as substrates, under
palladium catalysis (Scheme 33). Mo(CO) 121 is used as multiple promoter in this process
6
delivering the desired products in moderate to excellent yields. Under suitable reaction
conditions, the scope and limitations of this methodology were examined using a range of
substituents like methyl-, isopropyl-, and tert-butyl- on nitrobenzene. 1-Nitronaphthalene also
gave the corresponding 3-(naphthalen-1-yl)quinazolin-4(3H)-one in 81% isolated yield.
Moreover, several electron-withdrawing groups substituted aromatic nitro compounds were
tested subsequently, which afforded moderate to excellent yields. However, this procedure seems
quite sensitive to the steric property of the substrates. On the other hand, 2'-bromoformanilides
with a variety of electron-rich and electron-poor functional groups were tolerated which provided
different quinazolinones in 63-83% yields.
<
Scheme 33>
25

ACCEPTED MANUSCRIPT
A plausible reaction pathway is proposed and given in Fig. 13. Initially, oxidative addition of 2'-
bromoformanilide 119 to Pd(0) afforded organopalladium intermediate 123 which on
coordination and insertion of CO, released from Mo(CO) , gave acylpalladium complex 124 as
6
the key intermediate. At the same time, nitro compound was reduced by Mo(CO) to form an
6
amine which acts as a nucleophile to attack on the acylpalladium complex. Finally, the
eliminated 2- formamido-N-phenylbenzamide 125 gave the final quinazolinone product 122 after
intramolecular condensation which was promoted by palladium or molybdenum salts as Lewis
acids.
<
Figure 13>
Liu and co-workers [67] demonstrated the synthesis of 2-thioxoquinazolinone derivatives 126
achieved by the condensation of isatoic anhydride 44, primary amine, and carbon disulfide under
microwave irradiation (Scheme 34). The scope was examined with regard to the amine
component where aliphatic and aromatic amines bearing electron-rich and electron-poor
substituents worked efficiently delivering desired products in good to excellent yields. Also,
amines with heterocyclic moiety were also tolerated smoothly. In general, this convenient and
efficient method affords the desired products with good to excellent yields under mild conditions
with operational simplicity.
<
Scheme 34>
Balalaie and co-workers [68] introduced a wide variety of spiroquinazolinone derivatives 129
accessed through a one-pot three-component reaction of isatoic anhydride 44, hydrazides 127
and cyclic ketones 128 in the presence of catalytic amount (20 mol%) of H PO in ethanol
3
3
(Scheme 35). A range of cyclic ketones were reacted with ISA 44 to examine the scope of this
26

ACCEPTED MANUSCRIPT
methodology. The reactions proceeded smoothly in all these cases to afford the corresponding
spiro 2,3-dihydroquinazolin-4(1H)-ones in good to high yields. It was also notable to observe the
influence of ring size on the yield of products. For example, the use of cyclopentane instead of
cyclohexane led to lower yields. The type of hydrazide has also efficient role in the yields of
products.
<
Scheme 35>
2
.3. Synthesis of hybrid skeletons
In this section, different methods for the construction of quinazoline- and quinazolinone-hybrid
structures from simple starting materials are highlighted.
Guo et al. [69] reported an efficient and facile procedure for the preparation of 5,6-
dihydropyrazolo[1,5-c]quinazolines 131 via CuCl-catalyzed tandem reaction of 5-(2-bromoaryl)-
1
3
H-pyrazoles 130 with aldehydes 11 and aqueous ammonia under nitrogen atmosphere (Scheme
6). With the optimized reaction conditions in hand, a variety of aldehydes were reacted with 5-
(2-bromoaryl)-1H-pyrazoles to investigate the scope of this protocol. The effect of substituents
on phenyl ring of aldehydes was examined and the results indicated that electron-donating (Me,
MeO, Cl, Br, and F) reacted very well with 130 and aqueous ammonia to afford the desired
products 131 in 65-86% yields. 1-Naphthaldehyde and thiophene-2-carbaldehyde also underwent
the tandem reactions smoothly, thus generating the corresponding products in 85% and 65%
yields, respectively. In addition, alkyl-substituted aldehydes were also found to be compatible
with the reaction conditions to provide corresponding conjugated products in 51 and 76% yields.
Next, pyrazoles 130 with different substitution patterns were examined, and it was found that the
1
2
electronic effect and steric hindrance of R and R groups on pyrazoles 130 did not influence the
formation of products.
27

ACCEPTED MANUSCRIPT
<
Scheme 36>
Kumar and Kumar [70] were able to develop a microwave accelerated and expedited
cyclocondensation reactions of 2-(3-aryl-1H-pyrazol-5-yl)anilines 132 with diverse aryl
aldehydes 11 in water to access quinazoline derivatives 133 (Scheme 37). In order to assess the
generality and scope of the reaction, 132 was treated with equimolar amount of various aryl
aldehydes under the optimized reactions conditions that is microwave in water for 5-15 min.
<
Scheme 37>
Chen et al. [71] developed a new and facile approach for the synthesis of fused quinazolinone
scaffolds 136, 137 through a palladium-catalyzed carbonylative coupling followed by an
intramolecular nucleophilic aromatic substitution (Scheme 38). In this process, base serves as the
key modulator. The scope and limitations of this methodology were focused by tolerating a
variety of analogues of 1-bromo-2-fluorobenzene which delivered the corresponding products in
moderate to good yields. Notably, 4- and 5-substituted substrates gave better yields than 3-
substituted substrates. Interestingly, 2-bromo-4-(difluoromethyl)-1-fluorobenzene was
successfully converted into the desired product in 60% yield. Chloride substituents and acetyl
groups remained intact under reaction conditions to provide valuable products in moderate to
good yields. Subsequently, different kinds of 2-aminopyridines were investigated. Methyl- and
fluoro-substituted products were isolated without any problem. However, halides attached to the
pyridine ring also reacted.
In the case of the angular products, steric and electronic modification of the substrates did not
influence the outcome of the reactions. Ortho-methyl- and cyano-substituted 2-aminopyridines
delivered the corresponding products in 72 and 64% yield. A methyl group at the para position as
28

ACCEPTED MANUSCRIPT
a representative example of an electron-donating group was tolerated well. Substrates with
electron-deficient p-cyano, p-fluoro, and p-chloro substituents were also converted into the
corresponding angular isomers in moderate yields.
<
Scheme 38>
A proposed catalytic cycle for this reaction is given in Fig. 14. The formation of the active
catalyst takes place by the reduction of Pd(II) to Pd(0) with CO or amines. The oxidative
addition of 1-bromo-2-fluorobenzene 134 to Pd(0) then leads to the corresponding
organopalladium species 138. By the coordination and insertion of CO, the key intermediate acyl
palladium complex 139 is formed. In the presence of DBU, 2-imino-2H-pyridin-1-ide 140
undergoes nucleophilic attack on the acyl palladium complex 139 with the elimination of 141.
On the other hand, in the presence of NEt as the base, the nucleophilic reaction of 2-
3
aminopyridine with the acyl palladium complex yields compound 142. Finally, intramolecular
nucleophilic aromatic substitution of intermediate 141 or 142 affords the terminal linear 136 or
angular product 137, respectively. The active Pd(0) catalyst is regenerated with the assistance of
the base.
<
Figure 14>
Vlaar et al. [72] have shown that azoles are suitable nucleophiles in the Pd(II)-catalyzed aerobic
oxidative coupling of bisnucleophiles and isocyanides. Various medicinally important
azolo[c]quinazolines 144 or 145 were readily obtained by oxidative coupling of a-(2-
aminophenyl)azoles 143 with isocyanides 103 using air as the stoichiometric oxidant (Scheme
3
9). A range of triazole substrates were involved in the Pd-catalyzed coupling with tert-butyl
isocyanide using the optimized reaction conditions. Pleasingly, a wide range of (hetero)-aromatic
29