Received: 13 October 2019 Revised: 4 December 2019 Accepted: 19 December 2019

DOI: 10.1002/jhet.3883

REVIEW

Synthesis of heterocyclic compounds via Michael and

Hantzsch reactions

Amna M. Abdella | Amr M. Abdelmoniem | Ismail A. Abdelhamid |

Ahmed H. M. Elwahy

Chemistry Department, Faculty of

Science, Cairo University, Giza, Egypt
Correspondence
Ismail A. Abdelhamid and Ahmed H. M.
Elwahy, Chemistry Department, Faculty
of Science, Cairo University, Giza, Egypt.
Email: ismail_shafy@yahoo.com;
aelwahy@hotmail.com
Abstract
Heterocycles represent the largest diversity of organic compounds with
signifcant chemical, biomedical, and industrial applications. They exist in
numerous natural products, dyes, and as scaffolds in diverse drugs and related
pharmaceutically active substances. Substantial attention has been paid to
develop various elegant methods to synthesize heterocycles. Among different
strategies, Michael and Hantzsch reactions are considered as effective
approaches for construction of heterocycles and their corresponding fused
derivatives. This review covers this area especially in the last 10 years. The het-
erocyclic systems reported in this review are classified according to the kind of
the heterocyclic systems.

1 | INTRODUCTION The Hantzsch synthesis is a one-pot multi-component

Heterocycles are an important class of compounds that
exist in nature as a part of vitamins, hormones, alkaloids,
and many natural products. They are also present in a
wide variety of drugs as well as biologically active com-
pounds. Most of the heterocycles also find applications in
medicine, agriculture, industry, and in combinatorial and
supramolecular chemistry. Some heterocyclic compounds
have important applications in materials science such as
fluorescent, dyestuff, sensors, and molecular devices. Fur-
thermore, ionic liquids which are composed of heterocy-
clic compounds can act both as green solvents and
catalysts.[1–7]
The development of new and more efficient and selec-
tive synthetic routes to heterocyclic systems constitutes
an important issue in organic synthesis. Among a variety
of synthetic protocols, both Hantzch and Michael reac-
tions have attracted much attention in the last decades as
effective strategies for the synthesis of heterocycles and
their corresponding fused derivatives from easily accessi-
ble precursors under mild reaction conditions.
reaction that led to the formation of dihydropyridines via
the reaction of aldehyde, two equivalents of a β-keto
ester, and source of nitrogen such as ammonium acetate
or ammonia (Scheme 1). The reaction was reported for
the first time in 1881 by Arthur Rudolf Hantzsch and led
to the formation of dihydropyridine.[8] The reaction was
accomplished in acetic acid, water, or in ethanol.
Recently, some improvements have been reported on
Hantzsch reaction including performing the reaction in
the presence of Lewis acid, base, biocatalysts,
organocatalysts, and ionic liquids as catalysts.[9–16] The
reaction was also done under solvent and/or catalyst-free
conditions using conventional heating as well as micro-
wave irradiation.[17]
A modified three-component Hantzch protocol utiliz-
ing 1,3-dicarbonyl compounds, aldehydes, and enamines
has been reported affording divese regioselective 1,
4-dihydropyridine derivatives (Scheme 2).[18–21]
Michael addition is a very classical reaction in the
field of organic synthesis defined by Arthur Michael as
one of the most beneficial methods for the mild C─C

J Heterocyclic Chem. 2020;1–48. wileyonlinelibrary.com/journal/jhet © 2020 Wiley Periodicals, Inc. 1

2 ABDELLA ET AL.
bond formation,[22,23] This reaction includes a nucleo-
philic addition of a carbanion or another nucleophile to
an α,β-unsaturated carbonyl compound. The Michael
reaction requires basic conditions or acidic catalysts
(Scheme 3).
The definition of the Michael addition has been
expanded to especially refer to any 1,4-addition reaction
of α,β-unsaturated carbonyl compounds. The terms aza-
Michael reaction and oxa-Michael reaction have been
used to refer to the 1,4-addition of nitrogen and oxygen
nucleophiles, respectively. The aza-Michael reaction
(aza-MR) is one of the most important synthetic tools for
the formation of a C─N bond.[24]
The applications of Michael addition reaction in the
synthesis of natural products and heterocyclic com-
pounds have extensively been investigated.[25–29]
In continuation of our interest in reviewing different
approaches for the synthesis of heterocyclic systems,[30–35]
we report here on the utility of Michael and Hantzsch
reactions as effective tools for construction of
SCHEME 1 Hantzsch synthesis of 1,4-dihydropyridines
S C H E M E 2 Synthesis of 1,4-dihydropyridine dervatives by
three-component Hantzch-like reaction
SCHEME 3 Michael reaction as a tool for C─C bond
formation
heterocycles. Heterocyclic compounds reported in this
review are organized on the basis of the size of the het-
erocyclic ring and the nature and number of the
heteroatoms.
Yields of the target molecules reported in the review
are those given in the last step in the reaction except
when an overall yield was given.
2 | S Y N T H ES I S O F SI X -
MEMBERED HETEROCYCLES
2.1 | Synthesis of 4H-pyrans
The synthesis of 4H-pyrans 4 was achieved via a three-
components condensation of aldehydes 1, malononitrile
2, and 1,3-diketone under reaction conditions (Methods
A-H, Scheme 4, Table 1).[36–43]
Maghsoodlou et al[44] and Mohamadpour et al[45]
reported the synthesis of spiro 4H-pyran 7 and 8 by a
three-component reaction of isatin 5 or
acenaphthequinone 6 with malononitrile 2 and diketone
3 in different media (Methods A and B, Scheme 5).
2.2 | Synthesis of dihydropyridines
1,4-Dihyropyridines 9 were prepared by a three-
component reaction of aldehydes 1, 1,3-diketone or
β-diketoester 3, and ammonium acetate or ammonium
carbonate in different media (Methods A-V, Scheme 6,
Table 2).[12,46–66]
Jaismy-Jacob et al[68] reported the synthesis of 4-aryl-
2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxamide 11
in 71% to 94% via the reaction of N-arylacetoacetamides
10, arylaldehydes 1, and ammonia in methanol at reflux
(Scheme 7).
S C H E M E 4 Synthesis of pyran derivatives 4 via a three-
components reaction
ABDELLA ET AL. 3

TABLE 1 Percent yields of compounds 4

Method R1/R3 Yield Reference

3 1
A (R = OEt, R = C6H5, 4-Cl-C6H4, 4-MeO-C6H4, 3-O2N-C6H4, 2,4-Cl2-C6H3, 88%-95% Ebrahimipour et al[36]
4-Me-C6H4)
B (R3 = OEt, R1 = C6H5, 4-Cl-C6H4, 4-Br-C6H4, 2-Cl-C6H4, 3-O2N-C6H4, 4-O2N- 92%-96% Sojoudi et al[37]
C6H4, 3-Cl-C6H4, 3-Br-C6H4), (R3 = CH2Ph, R1 = C6H5, 3-Br-C6H4, 4-Br-C6H4,
3-Cl-C6H4, 3-O2N-C6H4, 4-O2N-C6H4)
C (R3 = OEt, R1 = C6H5, 4-F-C6H4, 3-HO-C6H4, 3-O2N-C6H4, 4-Cl-C6H4, 4-O2N- 86%-95% Nadu and Iran[38]
C6H4, 4-[Me]2N-C6H4, 4-Br-C6H4, 4-Me-C6H4, 4-MeO-C6H4)
D (R3 = OEt, R1 = 3-O2N-C6H4, C6H5, 2,4-Cl2-C6H3, 4-O2N-C6H4, 4-MeO-C6H4, 80%-94% Amani et al[39]
4-Cl-C6H4, 4-Me-C6H4, 4-F-C6H4, 2-Br-C6H4, 2-Cl-C6H4), (R3 = Me,
R1 = C6H5, 3-O2N-C6H4, 4-Cl-C6H4, 4-F-C6H4, 2-Br-C6H4, 4-Me-C6H4, 2-Cl-
C6H4)
E (R3 = OEt, R1 = C6H5, 3-F-C6H4, 2-F-C6H4, 4-(Me)2N-C6H4, 4-F-C6H4, 2-Cl- 67%-97% Pham et al[40]
C6H4, 3-Cl-C6H4, 4-Cl-C6H4, 3-Br-C6H4, 4-Br-C6H4, 2-O2N-C6H4, 4-O2N-C6H4,
3-HO-C6H4, 4-Me-C6H4, 4-(Me)2C-C6H4)
F (R3 = Me, R1 = 4-Cl-C6H4, 4-F-C6H4, 4-Me-C6H4, C6H5, 3-O2N-C6H4, 4-MeO- 78%-94% Tiwari et al[41]
C6H4, 2-Furyl), (R3 = OMe, R1 = 4-O2N-C6H4, 4-Cl-C6H4, 4-Me-C6H4),
(R3 = OEt, R1 = C6H5, 4-O2N-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 4-Me-C6H4, 4-HO-
C6H4, 3-O2N-C6H4, 4-MeO-C6H4, 2-Furyl)
G (R3 = OEt, R1 = C6H5, 3-O2N-C6H4, 4-O2N-C6H4, 4-Cl-C6H4, 4-Me-C6H4, 4-HO- 87%-92% Kiyani et al[42]
C6H4,4-MeO-C6H4)
H (R3 = OEt, R1 = C6H5, 3-O2N-C6H4, 4-O2N-C6H4, 3-Cl-C6H4,4-Br-C6H4, 4-Me- 83%-91% Jamshidi et al[43]
C6H4)

SCHEME 5 Synthesis of spiro 4H-pyran

7 and 8 by a three component reaction

Mahendra et al[69] and Navarrete-Encina et al[70] pre-
pared 3,5-dicyano-1,4-dihydro pyridine derivatives 13 by
the reaction of aldehydes 1 with ethyl 3-aminocrotonate
12a or 3-aminocrotononitrile 12b in acetic acid (Methods
A and B, Scheme 8, Table 3).
Kassab et al[71] reported the synthesis of bis(2,
6-dimethyl-1,4-dihydropyridine-3,5-dicarbonitrile) deriva-
tives 15 in 52% to 90% via the reaction of bis-aldehydes 14
containing ether linkage with 3-aminobut-2-enenitrile 12
in acetic acid at reflux (Scheme 9).
Similarly, the reaction of bis-aldehydes containing
arene or heteroarene 16 with 3-aminobut-2-enenitrile 12
in acetic acid under conventional heating as well as
under microwave irradiation afforded bis-1,4-DHPs 17 in
good to excellent yield (Scheme 10).[72]
Under similar conditions, the reaction of the bis-
aldehydes 18 linked to anthracene core with 4 mol of
12 gave a mixture of the corresponding bis-
dihydropyridines 19 and its aromatized product 20
(Scheme 11).[72]
Similary, the reaction of bis-aldehydes 21 linked to
pyridine core with 12 under microwave irradiation
afforded the bis-dihydropyridine 22. On the other hand,
under conventional heating, the reaction resulted in the
4 ABDELLA ET AL.
SCHEME 6 Synthesis of 1,4-dihydropyridines 9 by a three component reaction
formation of a mixture of bis-1,4-DHP 22 and 2,6-bis
[benzo[b]furan-2-yl]pyridine 23 (Scheme 12).[72]
Attempted synthesis of bis(dihydropyridine) 25 linked
via quinoxaline ring by the reaction of bis
(2-formylphenoxymethyl)quinoxaline 24 with 12 under
similar conditions was unsuccessful. The reaction gave
instead 2,3-bis[benzo[b]furan-2-yl]quinoxaline 26 as a
sole product (Scheme 13).[72]
Tris(2,6-dimethyl-4-phenyl-1,4-dihydropyridinyl)ben-
zenes 28 were prepared by the reaction of tris-aldehydes
27 and 3-aminobut-2-enenitrile 12 in acetic acid at reflux
(Scheme 14).[73]
Similarly, tetrakis and hexakis(2,6-dimethyl-4-phenyl-
1,4 dihydropyridinyl) benzenes 31a,b and 32a,b were pre-
pared by the reaction of tetrakis(4-formylphenoxymethyl)
benzenes 29a,b or hexakis(4-formylphenoxymethyl) ben-
zenes 30a,b, respectively, with 3-aminobut-2-enenitrile
12 in acetic acid at reflux (Scheme 15).[73]
Mohamed et al[74] reported the synthesis of tetrakis(2,
6-dimethyl-4-phenyl-1,4-dihydropyridinyl)methanes 34a-
d by condensation of tetrakis-aldehydes 33 with eight
equivalents of 3-aminobut-2-enenitrile 12 in acetic acid at
reflux (Scheme 16).
Yang et al[75] reported the synthesis of 9,10-bis
(4-((3,5-dicyano-2,6-dipyridyl)dihydropyridyl)phenyl)
anthracene 37 and 1,4-bis(4-(3,5-dicyano-2,6-dipyridyl)
dihydropyridyl)benzene 38, respectively, via the reaction
of 9,10-bis(4-formylphenyl)anthracene 35 and
terephthalaldehyde 36, respectively, with β-amino-
β-(pyrid-4-yl)acrylonitrile in acetic acid (Scheme 17).
A macromolecule 41 containing 1,4-
polyhydropyridines was prepared by the reaction of 3,
3-benzene-1,4-diylbis(3-aminoprop-2-enenitrile) 39 with
benzene-1,4-dicarbaldehyde 40a or biphenyl-4,4-
dicarbaldehyde 40b in glacial acetic acid at reflux
(Scheme 18).[76]
Abdelmoniem et al[77] has developed an effective
method for synthesis of bis (20 ,60 -dimethyl-2-oxo-10 H-
spiro[indoline-3,40 -pyridine]-30 ,50 dicarbonitrile) deriva-
tives 43 by the reaction of 3-aminocrotononitrile 12 with
a series of bis(indoline-2,3-diones) 42 in acetic acid at
reflux (Scheme 19).
Ghozlan et al[78] developed an efficient procedure for
the synthesis of dihydropyridine-3,5-dicarbonitrile deriva-
tives 46 by the reaction of arylidenemalononitrile 45 with
N-(pyrazol-5-yl)cyanoacetamide 44 in ethanol in presence
of piperidine at reflux (Scheme 20).
Compounds 46 were alternatively obtained by firstly
the reaction of N-(pyrazol-5-yl)cyanoacetamide 44 with
aldehydes 1 to give 2-cyano-N-(1H-pyrazol-5-yl)acrylam-
ide derivatives 47. Subsequent reaction of 47 with
malononitrile gave 46 (Scheme 21).[78]
Abdelmoniem et al[79] reported the synthesis of bis
(dihydropyridine-3,5-dicarbonitriles) 49 by the condensa-
tion reaction of bis-cyanoacetamides 48 with
arylidenemalononitrile derivatives 45 in the presence of
basic catalysts as piperidine, chitosan, or montmorillonite
(Methods A-C, Scheme 22, Table 4).
On the other hand, the formation of bis(pyridines) 51
linked via aromatic core was achieved by the reaction of
ABDELLA ET AL. 5

TABLE 2 Percent yields of compounds 9

Method R1/R3 Yield Reference

2 1
A (R = OEt, R = C6H5, 2-MeO-C6H4, 4-O2N-C6H4, 3-O2N-C6H4, 2-Thienyl, 23%-84% Debache et al[46]
2-Furyl)
B (R2 = OEt, R1 = H, 4-MeO-C6H4, 4-O2N-C6H4,4-Br-C6H4, 4-Me-C6H4, 4-Cl- 62%-92% Rajendraprasad et al[47]
C6H4, 2-Cl-C6H4, 4-CN-C6H4, 4-HO-C6H4, 2-Furyl)
C (R2 = OEt, R1 = C6H5, 4-Me-C6H4, 4-MeO-C6H4, 3-Cl-C6H4, 4-Cl-C6H4, 3-O2N- 72%-95% Debache et al[48]
C6H4, 4-O2N-C6H4, 4-Br-C6H4, 3,5-Cl2-C6H3, C6H5CH=CH, 2-Thienyl,
2-Furyl)
D (R2 = OEt, R1 = C6H5, 4-Cl-C6H4, C6H5CH=CH, Hexyl, 2-Furyl, 4-Me-C6H4, 95%-98% Heydari et al[49]
4-Br-C6H4, 4-HO-C6H4, 4-O2N-C6H4, Me(CH2)4)
E (R2 = OEt, R1 = C6H5, 4-Cl-C6H4, C6H5CH=CH, n-Hexyl, 2-Furyl, 4-Me-C6H4, 95%-98% Meysam et al[67]
4-Br-C6H4, 4-HO-C6H4, 4-O2N-C6H4, Me(CH2)4)
F (R2 = OEt, R1 = C6H5, 3-Cl-C6H4, 3-O2N-C6H4, 4-Cl-C6H4, 4-MeO-C6H4, 4-O2N- 90%-98% Kuraitheerthakumaran
C6H4, 4-F-C6H4, C6H5CH=CH, 3,4,5-(MeO)3C6H2, 2-Furyl, 2-Naphthyl, et al[50]
3-Indoyl)
G (R2 = OEt, R1 = Et, Me, Me(CH2)2, (Me)2CH, C6H5CH=CH, C6H5, 4-Me-C6H4, 80%-94% Lei et al[51]
4-MeO-C6H4, 2,4-Cl2-C6H3, 3-O2N-C6H4, 2-Furyl), (R2 = OMe, R1 = Me
(CH2)2, (Me)2CH, C6H5CH=CH)
H (R2 = OEt, R1 = C6H5, 4-Me-C6H4, 4-MeO-C6H4, 3,4-(MeO)2C6H3, 2,3-(O-CH2- 82%-95% Siddaiah et al[52]
O)C6H3, 4-HO-C6H4, 4-Cl-C6H4, 2-Cl-C6H4, 4-Br-C6H4, 2-Br-C6H4, 4-O2N-
C6H4, 2-O2N-C6H4, 2-Cl-5-O2N-C6H3, 2-Furyl, 2-Pyridyl), (R3 = Me,
R1 = C6H5, 2-O2N-C6H4, 4-Me-C6H4, 4-MeO-C6H4)
I (R2 = OEt, R1 = C6H5, 4-MeO-C6H4, 4-HO-C6H4, 4-Cl-C6H4, 4-CN-C6H4, 86%-96% Kiasat et al[53]
4-EtO-C6H4, 4-(Me)2N-C6H4, 4-O2N-C6H4, 2-Cl-C6H4, 2-O2N-C6H4)
J (R2 = Et, R1 = C6H5, 4-O2N-C6H4, 4-Br-C6H4, 4-F-C6H4, 4-Cl-C6H4, 2-Cl-C6H4, 69%-87% Sebagai et al[54]
2-Br-C6H4, 2-F-C6H4, 3-F-C6H4, 3-Br-C6H4, 4-(Me)2CH)
K (R2 = OEt, R1 = C6H5, 4-Br-C6H4, 4-Cl-C6H4, 4-O2N-C6H4, 4-MeO-C6H4, 76%-91% Srinivasan et al[55]
2-Furyl, 2-Thienyl)
L (R2 = OEt, R1 = C6H5, 3-O2N-C6H4, 3,4-(MeO)2C6H3, 4-MeO-C6H4, 80%-98% Safari et al[56]
C6H5CH=CH, 4-Cl-C6H4, 4-HO-C6H4, 2-Pyridyl, 3-Pyridyl, 2-Furyl, 2-thienyl)
M (R2 = C6H5, R1 = H, 4-Cl-C6H4, 4-F-C6H4, 4-O2N-C6H4, 3-O2N-C6H4, 4-Br-C6H4, 68%-98% Veisi et al[57]
2-Cl-C6H4, 4-Me-C6H4, 3-MeO-4-HO-C6H3, 2-Thienyl, 2-Furyl, 4-MeO-C6H4,
4-HO-C6H4, C6H4CH=CH)
N (R2 = OEt, R1 = H, Me, C6H5, 2-MeO-C6H4, 4-MeO-C6H4, 3,4-(MeO)2C6H3, 84%-94% Sohal et al[58]
2-O2N-C6H4, 3-O2N-C6H4, 4-O2N-C6H4, 3-Cl-C6H4, 4-Cl-C6H4, 3-HO-C6H4,
4-HO-C6H4, 4-Br-C6H4, 4-Me-C6H4, 3,4,5-(MeO)3C6H2, 2-Furyl, 2-Thienyl,
4-OHC-C6H4), (R3 = Me, R1 = Me, C6H5, 2-O2N-C6H4, 3-O2N-C6H4, 4-O2N-
C6H4, 4-Cl-C6H4, 4-HO-C6H4, 4-MeO-C6H4, 4-Me-C6H4, 2-Furyl)
O (R2 = OEt, R1 = C6H5, 4-MeO-C6H4, 4-Cl-C6H4, 4-O2N-C6H4) a
Veisi et al[59]
P (R2 = OEt, R1 = C6H5, 4-Br-C6H4, 4-O2N-C6H4, 3-Cl-C6H4, 4-NC-C6H4, 86%-92% Demirci et al[60]
4-(Me)2N-C6H4)
Q (R2 = OEt, R1 = C6H5, 2-Thienyl, 2-Furyl, 4-MeO-C6H4, 2-O2N-C6H3CH=CH), 72%-94% Nasr-Esfahani et al[61]
(R3 = Me, R1 = C6H5, C6H11, 3-EtO-4-HO-C6H3, 4-O2N-C6H4, 2,4-Cl2-C6H3,
3-O2N-C6H4, (Me)2CHCH2, 4-Br-C6H4, 3-Cl-C6H4, 4-Cl-C6H4, 4-Me-C6H4,
2-Thienyl, 2-Furyl, 4-MeO-C6H4)
R (R2 = OEt, R1 = C6H5, 2-O2N-C6H4, 4-MeO-C6H4, 4-HO-C6H4, 4-O2N-C6H4, 80%-93% Sadeghi et al[62]
2-Br-C6H4, 4-NC-C6H4, 4-Cl-3-O2N-C6H3)
S (R2 = OEt, R1 = C6H5, 4-Cl-C6H4, 4-Me-C6H4, 4-MeO-C6H4, 4-O2N-C6H4, 86%-96% Ren et al[63]
3-O2N-C6H4, 4-Br-C6H4, 4-HO-C6H4)
(Continues)
6 ABDELLA ET AL.

TABLE 2 (Continued)

Method R1/R3 Yield Reference

2 1
T (R = OEt, R = C6H5, 4-MeO-C6H4, 4-HO-C6H4, 4-Br-C6H4, 4-Cl-C6H4, 4-Me- 85%-95% Rekunge et al[64]
C6H4, 4-O2N-C6H4, 3-HO-C6H4, 3-Cl-C6H4, 3-Br-C6H4, 3-O2N-C6H4, 2-MeO-
C6H4, 2-HO-C6H4, 2-Cl-C6H4, H, CH3(CH)2, CH3CH=CH, C6H5CH=CH),
(R3 = Me, R1 = 2-O2N-C6H4)
U (R2 = OEt, OMe, R1 = 4-Br-2-Thienyl) 35%-77% Sharma et al[65]
V (R2 = OEt, R1 = C6H5, 4-HO-C6H4, 4-MeO-C6H4, 4-Br-C6H4, 2-Furyl, 64%-89% Khodja et al[66]
C6H5CH=CH)
a
Yields are not mentioned in the original paper.

SCHEME 7 Synthesis of 1,4-dihydro pyridine derivatives 11

SCHEME 8 Synthesis of 1,4-dihydro pyridine derivatives 13

TABLE 3 Percent yields of compounds 13

Method R1/R2 Yield Reference

2 1
A (R = CN, R = C6H5) 70% Mahendra et al[69]
B (R2 = CN, R1 = 5-O2N-2-Furyl), (R2 = COOEt, R1 = 3-HO-C6H4, 4-HO-C6H4, 24%-85% Navarrete-Encina
2,4-HO-C6H3, 3,4-HO-C6H3, 2,5-HO-C6H3, 3,5-HO-C6H3, 4-HO-3-MeO-C6H3, et al[70]
3-HO-4-MeO-C6H3, 5-O2N-2-Furyl)

bis-cyanoacetamide 50 with benzylidenemalononitrile 2 with one equivalent of bis-cyanoacetamides 50 in

derivatives 45 in ethanol in the presence of piperidine as
catalyst (Scheme 23).[80]
Compounds 51 were also obtained in good to
excellent yields via a three-component reaction of two
equivalents of both arylaldehyde 1 and malononitrile
ethanol in the presence of piperidine as a catalyst
(Scheme 24).[80]
Similarly, the reaction of bis-cyanoacetamide 52
linked to pyridine core with benzylidenemalononitrile
derivatives 45 in dioxane in the presence of piperidine as
ABDELLA ET AL. 7

S C H E M E 9 Synthesis of bis
(1,4-dihydropyridine-3,5-dicarbonitrile)
derivatives 15

SCHEME 10 Synthesis of bis-

1,4-DHPs 17

a catalyst gave 6,600 -diamino-2,200 -dioxo-4,400 -diaryl-2H, Sanad et al[81] reported a synthesis of bis(6-amino-1,
2”H-[1,20 :60 ,100 -terpyridine]-3,300 ,5,500 -tetracarbonitriles 53 2-dihydropyridine-3,5-dicarbonitriles) 55 containing
in good yields (Scheme 25).[80] thioether linkages by the reaction of bis-(cyanoacetamides)
8 ABDELLA ET AL.

SCHEME 11 Synthesis of bis-pyridines linked to anthracene core 19 and 20

SCHEME 12 Synthesis of bis-1,4-DHP 22 and 2,6-bis[benzo[b]furan-2-yl]pyridine 23

SCHEME 13 Synthesis of bis[benzo[b]furan-2-yl]quinoxaline 26

SCHEME 14 Synthesis of Tris

(1,4-dihydropyridinyl)benzenes 28
ABDELLA ET AL.
SCHEME 15 Synthesis of tetrakis and
hexakis(1,4 dihydropyridinyl)benzenes
31a,b and 32a,b
54 with arylidenmalononitriles 45 in ethanol at reflux in
the presence of piperidine (Scheme 26).
3 | S Y N T H E S I S O F FU S E D
BICY CLIC SYS TEM
3.1 | Fused [5-6]systems: One
heteroatom
3.1.1 | Tetrahydro-cyclopenta[b]pyran
Khan et al[82] and Khurana et al[83] developed efficient
methods for the synthesis of tetrahydro-cyclopenta[b]
pyrans 57 by the reaction of aldehydes 1, malononitrile 2,
and cyclopenta-1,3-dione 56 in different basic media
(Scheme 27, Table 5).
3.2 | Fused [5-6] systems: Two
heteroatoms
3.2.1 | Bis(pyrazolo[1,5-a]pyridine)
derivatives
Abdelmoniem et al[84] reported that the reaction of bis-
aldehydes 14 and 16 with malononitrile 2 and 3-amino-
5-(cyanomethyl)-1H-pyrazole-4-carbonitrile 58 in dioxane
in the presence of piperidine as a catalyst gave bis
(pyrazolo[1,5-a]pyridine) derivatives 59 (Scheme 28).
In a similar manner, the bis(pyrazolo[1,5-a]pyridines)
(linked to aromatic cores via ester linkage) were also suc-
cessfully prepared via a three-component reaction of the
9
bis-aldehydes 60 with of both malononitrile 2 and 58
(Scheme 29).[84]
3.3 | Fused [5-6] systems: Three
heteroatoms
3.3.1 | Pyrano[2,3-c]pyrazole derivatives
Pyrano[2,3-c]pyrazole derivatives 63 were successfully
prepared by a four-components reaction of ethyl
acetoacetate 3, malononitrile 2, hydrazine derivatives 62,
and aldehydes 1 using different catalysts and solvents
(Methods A-C, Scheme 30, Table 6).[85–87]
The synthesis of pyrano[2,3-c]pyrazole derivatives 63
has also been achieved by a three-components condensa-
tion of aldehydes 1, 3-methyl-1Hpyrazole-5(4H)-one 64
and malononitrile 2 under various catalysts and solvents
(Methods A-C, Scheme 31, Table 7).[88–90]
Bis(1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile)
derivatives 65 have been prepared by treatment of bis-
aldehydes 14 and 16 with both malononitrile 2 and
pyrazolone 64 in ethanol in the presence of piperidine at
reflux (Scheme 32).[91]
Safari et al[92] reported the synthesis of some bis-spiro
pyrano[2,3-c]pyrazoles 66 via the condensation reaction
of bis(isatins) 42 with malononitrile 2, hydrazine hydrate
and ß-ketoesters 3 in ethanol at reflux in the presence of
a catalytic amount of DABCO (Scheme 33).
3.3.2 | Pyrrolo[2,3-d]pyrimidines
Rad-Moghadam et al[93] reported the synthesis of
2-oxoindolin-3-yl-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-
10 ABDELLA ET AL.

SCHEME 16 Synthesis of tetrakis

(1,4-dihydropyridinyl)methanes 34

SCHEME 17 Synthesis of bis(2,6-dipyridyldihydropyridines) 37 and 38

ABDELLA ET AL. 11

SCHEME 18 Synthesis of macromolecules 41 containing 1,4-polyhydropyridines

SCHEME 19 Synthesis of bis(10 H-spiro[indoline-3,40 -pyridine]-30 ,50 dicarbonitriles) 43

SCHEME 20 Synthesis of dihydropyridine-3,5-dicarbonitrile derivatives 46

SCHEME 21 Alternative synthesis of dihydropyridine-3,5-dicarbonitrile derivatives 46

SCHEME 22 Synthesis of bis(dihydropyridine-3,5-dicarbonitriles) 49

12 ABDELLA ET AL.

TABLE 4 Percent yields of compounds 49

n R Yield
n=0 4-Cl-C6H4 A: 93%, B: 92%, C: 90%
4-MeO-C6H4 A: 89%, B: 87%, C: 90%
Benzo[d][1,3]dioxole-5-yl A: 90%, B: 91%, C: 89%
n=1 C6H5 A: 91%, B: 90%, C: 89%
4-Cl-C6H4 A: 89%, B: 88%, C: 90%
4-MeO-C6H4 A: 87%, B: 88%, C: 85%
Benzo[d][1,3]dioxole-5-yl A: 85%, B: 83%, C: 85%
n=2 C6H5 A: 93%, B: 90%, C: 86%
4-Cl-C6H4 A: 91%, B: 89%, C: 85%
4-MeO-C6H4 A: 88%, B: 86%, C: 87%
Benzo[d][1,3]dioxol-5-yl A: 87%, B: 88%, C: 85%

SCHEME 23 Synthesis of bis(2-pyridones) 51

SCHEME 24 Three-component synthesis

of compounds bis(2-pyridones) 51

SCHEME 25 Synthesis of bis(pyridines)

linked to pyridine core 53

SCHEME 26 Synthesis of bis(1,2-dihydropyridine-3,5-dicarbonitriles) 55

ABDELLA ET AL. 13

SCHEME 27 Synthesis of tetrahydro-cyclopenta[b]pyrans 57

TABLE 5 Percent yields of compounds 57

Method R Yield Reference

A 4-Cl-C6H4 98% Khan et al[82]
B 3-O2N-C6H4, 2-O2N-C6H4, 4-Me-C6H4, 4-HO-C6H4, 4-Cl-C6H4 60%-85% Khurana et al[83]

SCHEME 28 Synthesis of bis(pyrazolo

[1,5-a]pyridine) derivatives 59

SCHEME 29 Synthesis of bis(pyrazolo[1,5-a]pyridines) 61

SCHEME 30 Synthesis of pyrano[2,3-c]pyrazole derivatives 63 by four-components reaction

14 ABDELLA ET AL.

TABLE 6 Percent yields of compounds 63

Method R1/R2 Yield Reference

A (R2 = H, R1 = C6H5, 4-Cl-C6H4, 4-HO-C6H4, 4-(Me)2N-C6H4, 2-Cl-C6H4, 4-Me-C6H4, 85%-91% Tekale et al[85]
4-Br-C6H4, 4-O2N-C6H4, 3-O2N-C6H4, 2-Furyl)
B (R2 = H, Ph, R1 = C6H5, 4-O2N-C6H4, 3-O2N-C6H4, 2-O2N-C6H4, 4-Me-C6H4, 78%-94% Kiyani et al[86]
4-MeO-C6H4, 4-OH-C6H4, 4-(Me)2N-C6H4, 4-Cl-C6H4)
C (R2 = H, R1 = C6H5, 4-Cl-C6H4, 4-MeO-C6H4, 2-Cl-C6H4, 4-HO-C6H4, 4-Me-C6H4, 87%-91% Pawar et al[87]
4-O2N-C6H4, 4-F-C6H4, 2-HO-C6H4, 4-(Me)2N-C6H4)

SCHEME 31 Synthesis of pyrano[2,3-c]pyrazole derivatives 63 by a three-component reaction

TABLE 7 Percent yields of compounds 63

Method R1 Yield Reference

A C6H5, 4-Cl-C6H4, 2,4-Cl2-C6H3, 4-Br-C6H4, 4-F-C6H4, 3-O2N-C6H4, 4-O2N-C6H4, 88%-98% Niknam et al[88]
4-HO-C6H4, 3,4-(MeO)2-C6H3, 2-C10H7
B C6H5, 3-O2N-C6H4, 4-Cl-C6H4, 4-O2N-C6H4, 4-F-C6H4, 2,4-Cl2-C6H3, 2,6-Cl2-C6H3, 71%-97% Chimie et al[89]
4-HO-C6H4, 4-MeO-C6H4, 4-Me-C6H4
C 4-Cl-C6H4, 4-O2N-C6H4 91%-93% Taylor et al[90]

SCHEME 32 Synthesis of bis

(1,4-dihydropyrano[2,3-c]pyrazole-
5-carbonitrile) derivatives 65
ABDELLA ET AL. 15

SCHEME 33 Synthesis of bis-spiropyranpyrazoles 66

SCHEME 34 Synthesis of 2-oxoindolin-3-yl-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dione derivatives 69

SCHEME 35 Synthesis of 2-amino-4-aryl-7-hydroxy-4H-chromenes 71

TABLE 8 Percent yields of compounds 71

Method R1/R2 Yield Reference

A (R2 = H, R1 = C6H5, 3-O2N-C6H4, 4-O2N-C6H4, 4-Me-C6H4, 92-98% Kiyani et al[42]
4-HO-C6H4, 4-MeO-C6H4, 4-(Me)2N-C6H4, 2-Furyl, 2-Thienyl)
B (R2 = H, R1 = C6H4, 4-Me-C6H4, 4-CN-C6H4, 4-MeO-C6H4, 88%-94% Akocak et al[94]
4-Me2N-C6H4, 3,4-Me2-C6H3, 3,4,5-Me3-C6H2, 3,5-Me2-C6H3,
2,3,5,6-F4-C6H1)
C (R2 = H, R1 = C6H5, 4-MeO-C6H4, 4-HO-C6H4, 2-MeO-4-HO-C6H3, 54%-96% Masesane et al[95]
2-Me-C6H4, 4-Me-C6H4, 3-Me-C6H4, 4-O2N-C6H4, 4-Cl-C6H4),
(R2 = OH, R1 = 4-MeO-C6H4, 4-OH-C6H4, 3-MeO-4-HO-C6H3,
2-Me-C6H4, 4-Me-C6H4, 3-Me-C6H4, 4-O2N-C6H4, 4-Cl-C6H4)
D (R2 = H, R1 = 4-Cl-C6H4, 2-Cl-C6H4, C6H5, 4-Br-C6H4, 4-F-C6H4, 96%-98% Dekamin et al[96]
4-O2N-C6H4, 3-O2N-C6H4, 4-Me-C6H4, 4-HO-C6H4, 4-MeO-C6H4,
4-Me2N-C6H4, 2-Furyl, 2-Thienyl)
16 ABDELLA ET AL.

SCHEME 36 Synthesis of tetrahydrobenzo[b]pyrans 73

TABLE 9 Percent yields of compounds 73

Method R1/R2 Yield Reference

A (R2 = H, Me, R1 = C6H5, 4-MeO-C6H4, 3-O2N-C6H4, 4-Cl-C6H4, 2,4-Cl2-C6H4) 90%-98% Honarmand et al[97]
B (X = CN, R2 = H, R1 = 4-O2N-C6H4, 4-Cl-C6H4, 4-Me-C6H4, 4-(Me)2N-C6H4), 89%-98% Kiyani et al[42]
(X = CN, R6 = Me, R1 = C6H5, 4-O2N-C6H4, 4-Cl-C6H4, 3-O2N-C6H4, 2,4-Cl2-
C6H3, 4-Me-C6H4, 4-HO-C6H4, 4-MeO-C6H4, 3-MeO-4-HO-C6H3, 3-HO-C6H4,
4-(Me)2-C6H4, 2-Furyl, 2-Thienyl), (X = COOEt, R2 = H, R1 = 4-Cl-C6H4),
(X = COOEt, R2 = Me, R1 = C6H5, 3-O2N-C6H4, 4-Cl-C6H4, 4-(Me)2N-C6H4)
C (X = CN, R2 = H, R1 = C6H5, 4-Cl-C6H4, 4-O2N-C6H4, 2-O2N-C6H4, 3-O2N-C6H4, 80%-95% Chen et al[98]
4-Me-C6H4, 4-MeO-C6H4, 4-HO-C6H4, 2-Furyl), (X = CN, R2 = Me, R1 = 2-Cl-
C6H4, 4-O2N-C6H4, 3-O2N-C6H4, 2-O2N-C6H4, 4-HO-C6H4, 4-(Me)2N-C6H4,
2-MeO-C6H4, 3-MeO-C6H4, 4-MeO-C6H4, 2-Thienyl, 2-Furyl, 4-F-C6H4)
D (X = CN, R2 = H, R1 = C6H5, 2-O2N-C6H4, 3-O2N-C6H4, 3-Br-C6H4, 4-Br-C6H4, 81%-91% Lu et al[99]
2-Me-C6H4, 4-Me-C6H4, 2-Cl-C6H4, 3-Cl-C6H4, 4-Cl-C6H4, 2-MeO-C6H4, 4-MeO-
C6H4, 2-Furyl),
(X = CN, R2 = Me, R1 = C6H5, 2-O2N-C6H4, 4-O2N-C6H4, 3-Br-C6H4, 4-Br-C6H4,
2-Cl-C6H4, 4-Cl-C6H4, 2-F-C6H4, 2-Me-C6H4, 4-MeO-C6H4, 3-MeO-C6H4, 2-Furyl)
E (X = CN, R2 = Me, R1 = C6H5, 4-Cl-C6H4, 2-Cl-C6H4, 3-O2N-C6H4, 4-HO-C6H4) 85%-92% Sankpal et al[100]
F (X = CN, R2 = H, R1 = 4-Cl-C6H4, 2-Cl-C6H4, 3-O2N-C6H4, 4-O2N-C6H4, 4-MeO- 79%-98% Hojati et al[101]
C6H4), (X = CN, R2 = Me, R1 = C6H5, 4-Cl-C6H4, 2-Cl-C6H4, 4-Br-C6H4, 4-O2N-
C6H4, 4-NC-C6H4, 3-HO-C6H4, 4-HO-C6H4, 4-MeO-C6H4, 3,4-(MeO)2-C6H3,
2-Thienyl, 2-Furyl)
G (X = CN, R2 = H, R1 = 4-Cl-C6H4, 4-O2N-C6H4, 2-Furyl, 2-Thiophenyl), (X = CN, 85%-92% Khurana et al[83]
R2 = Me, R1 = 4-Cl-C6H4, 4-O2N-C6H4, 4-HO-C6H4, 4-Me-C6H4, 4-MeO-C6H4,
4-F-C6H4, 4-Br-C6H4, 2-Furyl, 2-Thiophenyl), (X = COOEt, R2 = Me, R1 = C6H5,
4-Me-C6H4, 3-O2N-C6H4, 4-O2N-C6H4)
H (X = COOEt, R2 = Me, R1 = C6H5, 4-Cl-C6H4, 4-Me-C6H4, 3-O2N-C6H4, 4-MeO- 98%-91% Khan et al[82]
C6H4), (X = CN, R2 = Me, R1 = 4-Cl-C6H4), (X = CN, COOEt, R2 = H, R1 = 4-Cl-
C 6H 4)
I (X = CN, R2 = Me, R1 = 2-Furyl, 2-Thienyl, 2-Pyrroyl) 84%-97% Jain et al[102]
J (X = CN, R2 = H, R1 = 2,4-Cl2-C6H3, 3-O2N-C6H4, 3,4,5-(MeO)3-C6H2, 2-Cl-C6H4), 87%-96% Taylor et al[90]
(X = CN, R2 = Me, R1 = 4-Cl-C6H4, 4-HO-C6H4, 4-O2N-C6H4, 3-Br-C6H4, 2-Furyl,
2-Naphthyl)
ABDELLA ET AL.
SCHEME 37 Synthesis of bis(4H-chromene-3-carbonitrile) derivatives 74
SCHEME 38 Synthesis of spiro tetrahydrobenzo[b]pyrans 75 and 76
TABLE 10 Percent yields of compounds 75 and 76
Method R1/R2
2 1
A (R = Me, R = H, 5-Cl)
B (R2 = Me, H, R1 = H)
C (R2 = Me, H, X = CN, COOEt, R1 = H)
dione derivatives 69 by the reaction of 6-aminouracils 67
with isatins 5 and acetophenones 68 in the presence of
piperidine and p-TSA in ethanol at reflux (Scheme 34).
3.4 | Fused [6-6]systems: One
heteroatom
3.4.1 | 2-Amino-4-aryl-7-hydroxy-4H-
chromenes
Reaction of aldehydes 1 with malononitrile 2 and resor-
cinol 70a or phloroglucinol 70b afforded 2-amino-4-aryl-
7-hydroxy-4H-chromenes 71 in good yields under
different conditions (Methods A-D, Scheme 35,
Table 8).[42,94–96]
17
Yield Reference
80%-83% Mohamadpour et al[45]
88%-94% Li et al[105]
82%-90% Saluja et al[106]
3.4.2 | Tetrahydrobenzo[b]pyrans
Tetrahydrobenzo[b]pyrans 73 were prepared by a three-
components reaction of aldehyde 1, malononitrile 2 or
ethylcyanoacetate 2a, and dimedone 72 or cyclohexa-1,
3-dione 72a in the presence of different catalysts
and various solvents (Methods A-J, Scheme 36,
Table 9).[42,82,83,97–102]
Abdella et al,[103,104] reported the synthesis of bis(4H-
chromene-3-carbonitrile) derivatives 74 via a one-pot,
multi-component reaction of bis(aldehydes) 14 or 16 with
malononitrile 2 and dimedone 72 in the presence of
piperidine in ethanol at reflux (Scheme 37).
Spiro tetrahydrobenzo[b]pyrans 75 and 76 were
prepared by a three-component reaction of isatin 5
or acenaphthequinone 6, malononitrile or ethyl
18 ABDELLA ET AL.

SCHEME 39 Synthesis of compounds 78 by four-components reaction

SCHEME 40 Synthesis of compounds 78

by a three-component reaction

SCHEME 41 Synthesis of polyhydroquinolines 78

cyanoacetate 2a,b, and dimidone or cyclohexa-1,3-dione 400) as a biodegradable polymeric solvent at room tem-
in different media (Methods A-C, Scheme 38, perature (Scheme 39).
Table 10).[45,105,106] The synthesis of 78 by a three-component reaction
Safari et al[107] developed an efficient method for the of dimidone 72, malononitrile 2, and bis(indoline-2,
synthesis of bis-spirooxindoles 78 by the reaction of isatin 3-dione) derivatives 42 in the presence of piperidine
5, dihalide 77, malononitrile 2, and dimedone 72 in the in ethanol at reflux was also reported
presence of K2CO3 and polyethylene glycol 400 (PEG- (Scheme 40).[108]
ABDELLA ET AL. 19

TABLE 11 Percent yields of compounds 79

Method R1/R3/R4 Yield Reference

A (R4 = Me, R3 = OEt, C6H5, 2-Cl-C6H4, 3-Cl-C6H4, 4-Cl-C6H4, 2-O2N-C6H4, 82%-98% Taghavi et al[109]
3-O2N-C6H4, 4-O2N-C6H4, 3-Br-C6H4, 4-Br-C6H4,4-Me-C6H4, 4-F-C6H4,
4-HO-C6H4, 4-MeO-C6H4, 2-Furyl, 2-Theinyl, 5-Br-2-theinyl, 2-Naphtal)
B (R4 = Me, R3 = OEt, R1 = H, 4-Me-C6H4, 4-MeO-C6H4, 4-Cl-C6H4, 4-O2N- 65%-94% Rao et al[110]
C6H4, 2,4-Cl2-C6H3, 2-Cl-C6H4, 3,4,5-(MeO)3-C6H2, 2-O2N-C6H4, 3-O2N-
C6H4, 4-F-C6H4, 3,4-(MeO)2C6H3, 4-(Me)2N-C6H4, 4-HO-3-MeO-C6H3,
4-HO-C6H4,4-Br-C6H4, 3-Br-C6H4, 2-Furyl, 2-Pyridyl), (R4 = Me, R3 = Me,
R1 = 3,4,5-(MeO)3-C6H2, 4-(Me)2N-C6H4)
C (R4 = Me, R3 = OEt, R1 = H, 3-MeO-C6H4, 4-Me-C6H4, 4-Br-C6H4, 4-O2N- 78%-93% Rajendraprasad et al[47]
C6H4, 4-Cl-C6H4, 2-Cl-C6H4, 2-O2N-C6H4, 4-HO-C6H4, 4-F-C6H4, 2,4-Cl2-
C6H3, 2-Furyl)
D (R4 = Me, R1 = C6H5, 4-Me-C6H4, 4-MeO-C6H4,4-HO-C6H4, 4-Br-C6H4, 65%-94% Debache et al[46]
4-O2N-C6H4, 4-O2N-C6H4, C6H5CH=CH)
E (R4 = Me, R3 = OEt, R1 = C6H5, 4-Me-C6H4, 4-HO-C6H4, 4-MeO-C6H4, 39%-96% Mondal et al[111]
3,5-(HO)2C6H3, 3,4-(MeO)2-C6H3, 3-O2N-C6H4, 4-O2N-C6H4, 4-F-C6H4,
4-Br-C6H4, 4-Cl-C6H4, Thienyl
F (R4 = Me, R3 = OEt, R1 = C6H5, 4-Cl-C6H4, C6H5CH=CH, 4-MeO-C6H4, 75%-98% Meysam et al[67]
4-HO-C6H4, 4-O2N-C6H4,4-Br-
C6H4, 3-Pyridyl, Et), (R4 = Me, R3 = Me, R1 = 4-Me-C6H4)
G (R4 = Me, R3 = OEt, Me, R1 = C6H5, 4-Cl-C6H4, 4-Me-C6H4, 4-MeO-C6H4, 85%-94% Kumar et al[112]
4-O2N-C6H4), (R4 = H, R3 = Et, Me, R1 = C6H5, 4-Cl-C6H4, 4-Me-C6H4,
4-MeO-C6H4, 4-O2N-C6H4)
H (R4 = Me, R3 = OEt, R1 = C6H5, 2-Cl-C6H4, 2-MeO-C6H4, 2-O2N-C6H5, 88%-95% Goli-jolodar et al[113]
2-Me-C6H4, 4-Cl-C6H4, 4-Br-C6H4), (R4 = H, R3 = OEt, R1 = C6H5, 4-Cl-
C6H4, 4-Br-C6H4, 4-Me-C6H4), (R4 = Me, R3 = Me, R1 = 4-Cl-C6H4, 4-NC-
C6H4, 4-MeO-C6H4)
I (R4 = Me, R3 = OEt, R1 = C6H5, 4-Me-C6H4, 4-MeO-C6H4, 4-HO-C6H4, 75%-93% Heravi et al[114]
4-O2N-C6H4, 4-Cl-C6H4, 2-Cl-C6H4, 2-Furyl), (R4 = H, R3 = OEt,
R1 = C6H5, 4-Me-C6H4, 4-MeO-C6H4, 4-O2N-C6H4)
G (R4 = Me, R3 = OEt, R1 = C6H5, 4-Br-C6H4, 4-O2N-C6H4) 92%-96% Demirci et al[60]
4 3 1
K (R = Me, R = OEt, R = C6H5, 4-Me-C6H4, 4-MeO-C6H4, 4-HO-C6H4, 4-Cl- 82%-96% Hong et al[115]
C6H4, 4-Br-C6H4, 4-O2N-C6H4, 2-Furyl, 2-Pyridyl), (R4 = H, R3 = OEt,
R1 = C6H5, 4-Cl-C6H4, 4-Me-C6H4), (R4 = Me, R3 = OMe, R1 = C6H5,
4-Me-C6H4)
L (R4 = Me, R3 = OEt, R1 = C6H5, 4-Cl-C6H4, 4-HO-C6H4, 4-Me-C6H4, 4-MeO- 82%-98% Mansoor et al[116]
C6H4, 4-Br-C6H4, 4-O2N-C6H4, 2,4-Cl2-C6H3, 3,4-Cl2-C6H4, 4-F-C6H4,
4-(Me)2N-C6H4)
M (R4 = Me, R3 = OEt, R1 = C6H5, 4-O2N-C6H4, 4-Me-C6H4, 4-MeO-C6H4, 85%-92% Veisi et al[57]
4-HO-C6H4, 4-Br-C6H4, 3-Br-C6H4, 3-HO-C6H4, 2-MeO-C6H4, 4-Cl-C6H4,
2,4-Cl2-C6H3, 2-Furyl), (R4 = Me, R3 = OEt, R1 = 4-HO-C6H4, 4-MeO-
C6H4, 3-Br-C6H4, 3-O2N-C6H4)
N (R4 = Me, H, R3 = OEt, Ome, R1 = 4-Tetrazolo[1,5-a]quinolone, 7-Me- 70%-84% Ladani et al[117]
4-tetrazolo[1,5-a]quinolone, 7-MeO-4-tetrazolo[1,5-a]quinolone)
O (R4 = Me, H, R3 = OEt, R1 = C6H5, 4-HO-C6H4, 4-Cl-C6H4, 4-Me-C6H4, 91%-95% Ren et al[63]
4-MeO-C6H4, 4-O2N-C6H4, 3-O2N-C6H4)
P (R4 = Me, R3 = OEt, R1 = C6H5, 4-F-C6H4, 4-Cl-C6H4, 4-Me-C6H4, 4-HO- 78%-95% Nia et al[118]
C6H4, 4-MeO-C6H4, 3-MeO-C6H4, 3-HO-C6H4, 2-Thienyl), (R4 = H,
R3 = OEt, R1 = C6H5, 4-Cl-C6H4, 4-Me-C6H4, 4-F-C6H4)
Q (R4 = Me, R3 = OEt, R1 = C6H5, 2-Cl-C6H4, 4-Cl-C6H4, 2-HO-C6H4, 4-HO- 82%-95% Saikia et al[119]
C6H4, 2-O2N-C6H4, 4-O2N-C6H4)
20 ABDELLA ET AL.

SCHEME 42 Synthesis of bis-4-aryl-

l,4-dihydropyridines 80

SCHEME 43 Synthesis of 1,4-dihydropyridines 81

TABLE 12 Percent yields of Compounds 81

Method R1 Yield Reference

4 1
A (R = COOEt, R = C6H5, 4-Me-C6H4, 4-MeO- 88%-94% Mohammadi et al[120]
C6H4, 4-Cl-C6H4, 4-O2N-C6H4, 4-F-C6H4),
(R4 = COOMe, R1 = C6H5, 4-Me-C6H4, 4-O2N-
C6H4, 3-MeO-C6H4)
B C6H5, 2-Cl-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 4-CN- 86%-93% Sun et al[121]
C6H4, 4-Me-C6H4, 2,3-Cl2-C6H3, 2,4-Cl2-C6H3,
3,5-(MeO)2-C6H3

SCHEME 44 Synthesis of 1,4-dihydropyridines 83

3.4.3 | Polyhydroquinolines acetate in the presence of [DMBSI]HSO4 as a catalyst

(Scheme 42).
Polyhydroquinoline derivatives 79 were prepared by treat- Mohammadi et al[120] and Sun et al[121] reported the
ment of aldehydes 1, diketone or β-ketoester 3, dimidone 72 synthesis of 1,4-dihydropyridines 81 in good yields by the
or 1,3-cyclohexanedione 72a, and ammonium acetate under reaction of aldehydes 1 with dimidone 72 and enamine
different reaction conditions (Methods A-Q, Scheme 41, 12, respectively, under different conditions (Methods A
Table 11).[12,46,47,57,60,63,109–119] and B, Scheme 43, Table 12).
Nia et al[118] synthesized bis-4-aryl-l,4-dihydropyridines Mansoor et al[122] reported the synthesis of 1,
80 by a one-pot, four-components reaction of bis- 4-dihydropyridine derivatives 83 are synthesized by a one-
aldehydes 14, dimidone 72, β-ketoester 3, and ammonium pot, three-component reaction of 5,5-dimethyl-
ABDELLA ET AL. 21

SCHEME 45 Synthesis of hexahydroquinoline-3-carbonitrile derivatives 85

TABLE 13 Percent yields of compounds 85

2
R Yield
Piperidine DABCO Chitosan
C 6H 5 88% 90% 95%
4-O2N-C6H4 90% 90% 94%
4- MeO-C6H4 85% 93% 96%
Benzo[d][1,3]dioxol-4-yl 82% 89% 94%

SCHEME 46 Synthesis of spirocyclic quinolines 87

SCHEME 47 Synthesis of spirocyclic hexahydroquinoline derivatives 89

SCHEME 48 Synthesis of 4,8-dihydropyrano[3,2-b]pyran derivatives 91

22 ABDELLA ET AL.

TABLE 14 Percent yields of compounds 91

Method R1 Yield Reference

A (X = CN, R1 = C6H5, 2-Cl-C6H4, 2-F-C6H4, 2-Furyl, 4-Pyridyl, n- 89%-95% Molaei et al[126]
Butyl, 2-HO-C6H4, 4-O2N-
C6H4, 4-Cl-2-O2N-C6H3), (X = COOEt, R1 = C6H5, 2-Cl-C6H4,
4-NC-C6H4, 4-O2N-C6H4)
B (X = CN, R1 = C6H5, 3-Me-C6H4, 4-F-C6H4, 2-Cl-C6H4, 3-Br-C6H4, 82%-96% Teimuri-Mofrad et al[127]
4-Br-C6H4, 3-O2N-C6H4, 4-MeO-C6H4, 2-Furyl, 2-Thiophenyl)
C (X = CN, R1 = C6H5, 2-F-C6H4, 2-Cl-C6H4, 2,4-Cl2-C6H3, 3-F-C6H4, 85%-98% Hossein et al[128]
3-Br-C6H4, 3-Me-C6H4, 2-Furyl, 2-Thienyl)

SCHEME 49 Synthesis of 4,5-dihydropyrano[4,3-b]pyran derivatives 93

TABLE 15 Percent yields of compounds 93

Method R1 Yield Reference

1
A (X = CN, R = C6H5, 4-Cl-C6H4, 4-Br-C6H4, 2,4-Cl2-C6H3, 2-Br-C6H4, 3-O2N- 89%-92% Abaszadeh and Seifi[129]
C6H4, 4-O2N-C6H4, 4-MeO-C6H4, 2-Furyl, 2-Thieophenyl, 4-OHC-C6H4,
3-OHC-C6H4)
B (X = CN, R1 = C6H5, 4-MeO-C6H4, 3-O2N-C6H4, 4-Cl-C6H4, 2,4-Cl2-C6H3) 82%-92% Honarmand et al[97]
C (X = CN, R1 = C6H5, 4-F-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 4-Me-C6H4, 4-MeO- 69%-88% Khaligh[130]
C6H4, 4-O2N-C6H4, 3,4-(MeO)2C6H4, 3-O2N-C6H4, 2-Furyl)

SCHEME 50 Synthesis of Pyrano[2,3-d]pyrimidine derivatives 95

1,3-cyclohexanedione 72, chalcones 82, and ammonium
acetate in the presence of silica-supported perchloric acid
(HClO4-SiO2) as a catalyst under free solvent condition
(Scheme 44).
Hexahydroquinoline-3-carbonitrile derivatives 85
were obtained via the reaction of 3-arylamino-5,
5-dimethylcyclohex-2-enone 84 with arylidenemalononitrile
45 in dioxane in the presence of piperidine,
DABCO, or chitosan as catalysts as well (Scheme 45,
Table 13).[123]
A series of spirocyclic quinolines 87 were synthesized
in good yields via the reaction of enamines 84 with
3-cyanomethylidene-2-oxindoles 86 in dioxane in the
presence of piperidine (Scheme 46).[124]
ABDELLA ET AL. 23

TABLE 16 Percent yields of pyrano[2,3-d]pyrimidines derivatives 95

Method R1 Yield Reference

A (R2 = H, R1 = 4-Br-C6H4, 4-Cl-C6H4, 3-Cl-C6H4, 2-Cl-C6H4, 4-O2N-C6H4, 3-O2N-C6H4, 6%-93% Chen et al[98]
2-O2N-C6H4, 4-Me-C6H4, 4-MeO-C6H4, 4-HO-C6H4, C6H5, 2-Furyl, 2-Thienyl)
B (R2 = Me, R1 = 4-MeO-C6H4, 4-Cl-C6H4, 3-O2N-C6H4, 2,4-Cl2-C6H3) 80%-89% Honarmand et al[97]
C (R2 = Me, R1 = C6H5, 4-Me-C6H4, 4-MeO-C6H4, 4-F-C6H4, 2-Cl-C6H4, 4-Cl-C6H4, 3-Br- 89%-95% Elinson et al[131]
C6H4, 4-O2N-C6H4), (R = Et, R1 = C6H5, 4-F-C6H4, 2-Cl-C6H4)
D (R2 = Me, R1 = C6H5, 4-Cl-C6H4, 4-O2N-C6H4, 3-Cl-C6H4, 4-Me-C6H4, 2-Cl-C6H4, 85%-95% Khurana et al[83]
3-O2N-C6H4, 4-HO-C6H4, 4-MeO-C6H4)
E (R2 = H, R1 = 2-Furyl, 2-Thienyl, 2-Pyrroyl, 3-Me-2-thienyl, 5-Me-2-furyl, 5-Me- -a Jain et al[102]
2-thienyl)
a
Yields are not mentioned in the original paper.

SCHEME 51 Synthesis of bis-

tetrahydrospiro[indoline-3,50 -pyrano[2,3-d]
pyrimidine]-60 -carbonitrile derivatives 96

SCHEME 52 Synthesis of 1,4-dihydropyrido[2,3-d]pyrimidines 97

SCHEME 53 Synthesis of hexahydropyrido[2,3-d]pyrimidines 99

24 ABDELLA ET AL.

SCHEME 54 Synthesis of 5,6-dihydropyrido[2,3-d]pyrimidinetriones 101

SCHEME 55 Synthesis of 7-Amino-pyrido[2,3-d]pyrimidines-6-carbonitrile 102

SCHEME 56 Synthesis of isoxazolo[5,4-b]oxazolo[4,5-e]pyridine 105

SCHEME 57 Synthesis of pyrazolo[3,4-b]quinolines 107

SCHEME 58 Synthesis of isoxazolo[5,4-b]quinolone 108

SCHEME 59 Synthesis of hexahydroisoxazolo[5,4-b]quinolones 110

ABDELLA ET AL. 25

SCHEME 60 Synthesis of
1,4-dihydropyrazolo[40 ,30 :5,6]pyrano
[2,3-b]pyridines 112

SCHEME 61 Synthesis of 4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidines 114

SCHEME 62 Three-component synthesis of compounds 114

SCHEME 63 Synthesis of furo[30 ,40 :5,6]pyrido[2,3-d]pyrimidine derivatives 116

26 ABDELLA ET AL.

SCHEME 64 Synthesis of [1,2,4]triazolo[5,1-b]quinazolines 118

SCHEME 65 Synthesis of pyrazolo[40 ,30 :5,6]pyrido[2,3-d]pyrimidines 119

SCHEME 66 Synthesis of spiroindoline-3,40 isoxazolo[40 ,50 :5,6]pyrido[2,3-d]pyrimidines 121

SCHEME 67 Synthesis of indeno[1,2-b]pyridine derivatives 123

Spirocyclic hexahydroquinoline derivatives 89 3-cyanomethylidene-2-oxindoles 86 in ethanol in

containing pyrazole ring were obtained by the reac- the presence of piperidine as a catalyst
tion of β-enaminones 88 incorporating pyrazole with (Scheme 47).[125]
ABDELLA ET AL. 27

TABLE 17 Percent yields of compounds 123

Method R1/R2/R3 Yield Reference

A (R2 = Me, R3 = COOEt, R1 = C6H5, 4-Br-C6H4, 4-O2N-C6H4, 4-MeO-C6H4, 87%-98% Turhan et al[141]
2-PhO-C6H4, 3,5-F3C-C6H3, 5-Br-2-Furyl, 5-I-2-Furyl)
B (R3 = H, R2 = 4-MeO-C6H4, R1 = 2-Cl-C6H4, 4-F-C6H4, 3-O2N-C6H4), 85%-95% Daryabari and Khaksar[142]
(R3 = Me, R2 = C6H4, R1 = 3-O2N- C6H4, 4-O2N-C6H4, 4-Cl-C6H4, 4-Br-
C 6H 4)

SCHEME 68 Synthesis of spiro[ideno[1,2-b]pyridine-indoline] derivatives 124

SCHEME 69 Synthesis of benzo[h]quinolines 126

3.5 | Fused [6-6]system: Two

SCHEME 70 Synthesis of 4H-benzo[g]chromene-3-carbonitrile derivatives 127

heteroatoms 91 in good yields under different conditions (Methods A-

C, Scheme 48, Table 14).[126–128]
3.5.1 | Pyrano[3,2-b]pyrans

The reaction of 5-hydroxy-2-hydroxymethyl-4H-pyran- 3.5.2 | Pyrano[4,3-b]pyrans

4-one 90 with aldehydes 1 and malononitrile or alkyl
cyanoacetate 2 afforded the respective 2-amino-4,8- 2-Amino-4,5-dihydropyrano[4,3-b]pyran-3-carbonitrile de-
dihydropyrano[3,2-b]pyran-3-carbonitrile or alkyl amino- rivatives 93 were synthesized in good yields upon treat-
4,8-dihydropyrano[3,2-b]pyran-3-carboxylate derivatives ment of 4-hydroxy-6-methylpyrone 92 with aldehydes
28 ABDELLA ET AL.

SCHEME 71 Synthesis of spiro[benzo[g]chromene-4,30 -indolines] 128

SCHEME 72 Synthesis of compounds 130 by a three-components approach

TABLE 18 Percent yields of compounds 130

Method R Y Z Yield Reference

A C6H5, 4-Cl-C6H4, 2-Cl-C6H4, 4-Br-C6H4, 3-O2N-C6H4, OH H 80%-94% Niknam et al[88]
4-O2N-C6H4, 4-Me-C6H4, 4-HO-C6H4, 3,4,5-Me3O-
C 6H 2
B 2,3-Me2O-C6H3, 2,5-Me2O-C6H3, 4-Cl-C6H4, 3-O2N- OH H 96%-99% El-Maghraby[146]
C6H4, C6H5, 4-MeO-C6H4, 3,4,5-Me3O-C6H2
2,3-Me2O-C6H3, 2,4-Me2O-C6H4, 3,4,5-Me3O-C6H2, H OH
3-O2N-C6H4, C6H5, 4-MeO-C6H4
C C6H5, 4-Cl-C6H4, 4-F-C6H4, 3-O2N-C6H4, 4-Me-C6H4, OH H 78%-94% Amani et al[39]
2-Cl-C6H4
C6H5, 4-F-C6H4, 2-Cl-C6H4, 4-Cl-C6H4, 4-Me-C6H4, H OH
4-MeO-C6H4, 3-O2N-C6H4
D 4-Cl-C6H4, 4-F-C6H4, 2-Cl-C6H4, 3-O2N-C6H4, 4-O2N- OH H 96%-99% Dekamin and
C6H4, C6H5, 4-NC-C6H4, 4-Me-C6H4, 4-MeO-C6H4, Eslami[96]
4-HO-C6H4
2-Cl-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 4-O2N-C6H4, 3-O2N- H OH
C6H4, C6H5, 4-NC-C6H4, 4-MeO-C6H4

1 and malononitrile 2 under different conditions
(Methods A-C, Scheme 49, Table 15).[97,129,130]
3.6 | Fused [6-6] systems: Three
heteroatoms
3.6.1 | Pyrano[2,3-d]pyrimidines
Pyrano[2,3-d]pyrimidine derivatives 95 were synthesized
in good yields via the reaction of aldehydes 1 with
malononitrile 2 and barbituric acid or 1,3-
dimethylbarbituric acid 94 under different conditions of
catalysts and solvents (Methods A-E, Scheme 50,
Table 16).[83,97,98,102,131]
Ghozlan et al[108] reported the synthesis of bis-tetra-
hydrospiro[indoline-3,50 -pyrano[2,3-d]pyrimidine]-60 -
carbonitrile derivatives 96 in good yields by the
reaction of bis(indoline-2,3-diones) 42 with 1,3-
dimethylbarbituric acid 94 and malononitrile in ethanol
in the presence of catalytic amount of piperidine at
reflux (Scheme 51).
ABDELLA ET AL. 29

SCHEME 73 Synthesis of 5H-Acridines 131

TABLE 19 Synthesis of compounds 131

Method R1 Yield Reference

2 1
A R = H, R = C6H5, 4-Cl-C6H4 95%-98% Heydari et al[49]
B 3-(4-MeO-C6H4)-1-C6H5-4-pyrazolyl, 3-(4-Cl- 78%-90% Fekri et al[147]
C6H4)-1-C6H5-4-pyrazolyl, 3-(3-O2N-C6H4)-
1-C6H5-4-pyrazolyl,3-(3-OH-C6H4)-1-C6H5-
4-pyrazolyl, 3-(4-Me-C6H4)-1-C6H5-4-pyrazolyl
C C6H5, 2-Me-C6H4, 4-MeO-C6H4, 4-Cl-C6H4, 67%-90% Khodja et al[66]
4-(Me)2N-C6H4, 2-Thienyl
D C6H5, 2,4-(MeO)2-C6H3, 4-Cl-C6H4, 2,4-(HO)2- 90%-98% Prajapati et al[148]
C6H4, 3-O2N-C6H4, 2-Thienyl
E (R3 = C6H5, R1 = C6H5, 4-Cl-C6H4, 4-NC-C6H4, 70%-90% Xia and Zhang[149]
4-O2N-C6H4, 3-O2N-C6H4, 3,4-Cl2-C6H3,
4-MeO-C6H4), (R3 = 4-MeO-C6H4, R1 = 4-Cl-
C6H4, 4-NC-C6H4, 4-O2N-C6H4, 3,4-Cl2-C6H3,
4-MeO-C6H4)

3.6.2 | 1,4-Dihydropyrido[2,3-d] Compounds 102 were also prepared by the reaction of

pyrimidines
The reaction of aldehydes 1 and diketone (acetylacetone,
trifloroacetylacetone, dibenzoylmethane, or benzoylacetone)
3 with 6-aminothiouracil 67 in DMF afforded the
corresponding 1,4-dihydropyrido[2,3-d]pyrimidines 97 in
good yields (Scheme 52).[132]
7-(3H-Indol-3-yl)-hexahydropyrido[2,3-d]pyrimidine
99 were synthesized via a one-pot, three-component reac-
tion of 6-aminouracil or 6-aminothiouracil 67 with alde-
hyde 1 and 3-cyanoacetyl-1H-indole 98 using InCl3 as a
catalyst (Scheme 53).[133]
6-(2-Hydroxybenzoyl)-5,6-dihydropyrido[2,3-d]pyrim-
idine-2,4,7(1H, 3H, 8H)-trione derivatives 101 were syn-
thesized via the reaction of 6-aminouracils 67 with
aldehydes 1 and 4-hydroxycoumarin 100 in acetonitrile
in the presence of a catalytic amount of sulfamic acid
(Scheme 54).[134]
7-Amino-pyrido[2,3-d]pyrimidines-6-carbonitrile
derivatives 102 have been synthesized in 82% to 95%
yields via the reaction of aldehydes 1, malononitrile, and
6-aminouracil 67 in DMF under microwave irradiation.
the same reactants in the presence of diammonium
hydrogen phosphate as a catalyst under conventional
heating condition in good yields 85% to 95%
(Scheme 55).[135]
4 | S Y N T H ES I S O F FU S E D
TRICYCLIC S YSTEM
4.1 | Fused [5-6-5] systems: Five
heteroatoms
4.1.1 | 3-Methyl-4,6-diphenyl-
4,8-dihydroisoxazolo[5,4-b]oxazolo[4,5-e]
pyridine
3-Methyl-4,6-diphenyl-4,8-dihydroisoxazolo[5,4-b]
oxazolo[4,5-e]pyridine 105 was prepared in 70% yield by
the reaction of 3-methylisoxazol-5-amine 104 with (Z)-
4-benzylidene-2-phenyloxazol-5(4H)-one 103 in ethanol/
glacial acetic acid mixture (Scheme 56).[136]
30
4.2 | Fused [5-6-6] systems: Three
heteroatoms
4.2.1 | Pyrazolo[3,4-b]quinolines
Polo et al[137] reported the synthesis of pyrazolo[3,4-b]
quinolin-5(6H)-one 107 by the reaction of formaldehyde
with 3-methyl-1-phenyl-1H-pyrazolo-5-amine 106 and
cyclohexane-1,3-diones 72 and 72a under microwave irra-
diation in aqueous media catalyzed by InCl3 (Scheme 57).
4.2.2 | Isoxazolo[5,4-b]quinolines
Hamama et al[136] reported the synthesis of 3,
7,7-trimethyl-4-phenyl-4,6,8,9-tetrahydroisoxazolo[5,4-b]
quinolin-5-one 108 in 88% yield by the reaction of benzal-
dehyde, dimedone 72, and 3-methylisoxazol-5-amine 104
in ethanol and acetic acid at reflux (Scheme 58).[136]
8-Benzylidene-3-methyl-4-phenyl-4,
5,6,7,8,9-hexahydroisoxazolo[5,4-b]quinolone 110 was
prepared by the reaction of 3-methylisoxazol-5-amine 104
with 2,6-dibenzylidenecyclohexanone 109 in DMF at
reflux (Scheme 59).[136]
ABDELLA ET AL.
SCHEME 74 Synthesis of
bis(hexahydroacridinediones) 133
SCHEME 75 Synthesis of
tris(hexahydroacridines) linked to
1,3,5-triazine core 135
4.3 | Fused [5-6-6] systems: Four
heteroatoms
0 0
4.3.1 | 1,4-Dihydropyrazolo[4 ,3 :5,6]
pyrano[2,3-b]pyridines
Salama et al[91] reported the synthesis of bis(2,1-phenylene))
0 0
bis(5,7-diamino-3-methyl-1,4-dihydropyrazolo[4 ,3 :5,6]
pyrano[2,3-b]pyridine-6-carbonitrile 112 by the reaction of
bis-aldehyde with dimer malononitrile 111 and pyrazolone
64 in refluxing ethanol at reflux in the prersence of piperi-
dine (Scheme 60).[91]
4.3.2 | Pyrazolo[1,5-a]pyrido[3,2-e]
pyrimidines
The reaction of 7-aminopyrazolo[1,5-a]pyrimidin-5
(4H)-one 113 with arylidenemalononitriles 45 in
ethanol in the presence of piperidine as a catalyst
afforded 4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]
pyrimidine-7-carbonitrile derivatives 114 in good
yields (Scheme 61).[78]
ABDELLA ET AL. 31

SCHEME 76 Synthesis of pyrano[3,2-c]chromenes 136

TABLE 20 Percent yields of compounds 136

Method R1 Yield Reference

A C6H5, 4-Cl-C6H4, 2,4-Cl2-C6H3, 4-Br-C6H4, 2-Br- 88%-93% Abaszadeh and Seifi[129]
C6H4, 4-O2N-C6H4, 3-O2N-C6H4, 4-Me-C6H4,
4-MeO-C6H4, 2-Furyl, 2-Pyridyl, 2-Pyrrol,
4-OHC-C6H4, 3-OHC-C6H4
B C6H5, 3-O2N-C6H4, 4-O2N-C6H4, 2-Br-C6H4, 3-Br- 85%-93% Lu et al[99]
C6H4, 2-Cl-C6H4, 3-Cl-C6H4, 4-Cl-C6H4, 2-Me-
C6H4, 4-Me-C6H4, 2-MeO-C6H4, 3-MeO-C6H4,
4-MeO-C6H4
C C6H5, 4-F-C6H4, 4-Br-C6H4, 4-Me-C6H4, 4-MeO- 65%-91% Paul et al[150]
C6H4, 4-O2N-CH4, 4-NC-C6H4, 2-Naphtyl,
4-OHC-C6H4, 2-Thienyl
D C6H5, 4-F-C6H4, 4-Cl-C6H4, 3-O2N-C6H4, 4-Me- 89%-95% Patel et al[151]
C6H4, 4-MeO-C6H4, 4-Me2N-C6H4, 2-Furyl,
4-O2N-C6H4, 2-Cl-C6H4, 3,4-(MeO)2-C6H3
E C6H5, 4-Cl-C6H4 89%-93% Hojati et al[101]

Compounds 114 were alternatively prepared in good tetronic acid 115 in water in the presence of manganese
yields by one-pot, three-components reaction of alde- ferrite nanoparticles (Scheme 63).[138]
hyde, malononitrile, and 7-aminopyrazolo[1,5-a]
pyrimidin-5(4H)-one 113 under the same reaction condi-
tion (Scheme 62).[78] 4.3.4 | [1,2,4]triazolo[5,1-b]quinazolines

Abd El-Fatah et al[139] developed a series of bis(tetra-

0 0
4.3.3 | Furo[3 ,4 :5,6]pyrido[2,3-d]
pyrimidines
Spirocyclic oxiindole of furo[30 ,40 :5,6]pyrido[2,3-d]pyrimi-
dine derivatives 116 were synthesized via a three-
components reaction of isatin 5, 6-aminouracil 67, and
hydro[1,2,4]triazolo[5,1-b]quinazolin-8(4H)-ones) 118 via
a three-component reaction of bis-aldehydes 14 or 16
with both 5-amino-1,2,4-triazole 117 and dimedone 72
under conventional heating as well as under microwave
irradiation in DMF in the presence of ZnO NPs as a het-
erogeneous catalyst (Scheme 64).
32
4.4 | Fused [5-6-6] systems: Five
heteroatoms
4.4.1 | Pyrazolo[40 ,30 :5,6]pyrido[2,3-d]
pyrimidines
Pyrazolo[40 ,30 :5,6]pyrido[2,3-d]pyrimidine derivatives
119 were synthesized by the reaction of formaldehyde
1, pyrazole-5-amine 106, and aminouracil or
aminothiouracil 67 in the presence of InCl3 as a catalyst
under microwave irradiation (Scheme 65).[137]
4.4.2 | Isoxazolo[40 ,50 :5,6]pyrido[2,3-d]
pyrimidines
Poomathi et al[140] reported that the reaction of isatin 5,
6-aminouracil 67 and 3-phenylisoxazol-5(4H)-one 120 in
ABDELLA ET AL.
SCHEME 77 Synthesis of bis
(dihydropyrano[3,2-c]chromenes) 137
SCHEME 78 Synthesis of spiro
(indoline-3,40 -pyrano[3,2-c]chromene)
139 and 140
the presence of p-toluenesulfonic acid as a catalyst in
water afforded spiroindoline-3,40 isoxazolo[40 ,50 :5,6]pyrido
[2,3-d]pyrimidine derivatives 121 in good yields
(Scheme 66).
4.5 | Fused [6-5-6] systems: One
heteroatom
4.5.1 | Indeno[1,2-b]pyridines
Indeno[1,2-b]pyridine derivatives 123 were prepared by
the reaction of aldehydes 1, indandione 122, and
β-diketoester or ketone 3 in the presence of different cata-
lysts and solvents (Methods A and B, Scheme 67,
Table 17).[141,142]
One-pot, three-components reactions of indandione
122, isatin 5, and enamine 12 in the presense of L-proline
ABDELLA ET AL.
SCHEME 79 Synthesis of bis-spirooxindole chromene 142
as a catalyst in 2-propanol at reflux afforded spiro(ideno
[1,2-b]pyridine-indoline) derivatives 124 in good yields
(Scheme 68).[143]
4.6 | Fused [6-6-6] systems: One
heteroatom
4.6.1 | Benzo[h]quinolines
Sun et al[121] reported the synthesis of benzo[h]quinoline
derivatives 126 in good yields by the reaction of aldehyde
1, 2-hydroxynaphthalene-1,4-dione 125, and 3-aminobut-
2-enenitrile 12 in the presence of ionic liquid [BMIm]Br
(Scheme 69).
4.6.2 | Benzo[g]chromenes
Brahmachari et al[144] reported that the reaction of alde-
hydes 1, malononitrile 2, and 2-hydroxynaphthalene-1,
4-dione 125 in the presence of urea as a catalyst in aque-
ous ethanol afforded good yields of 4H-benzo[g]
chromene-3-carbonitrile derivatives 127 at room temper-
ature (Scheme 70).
Zhang et al[145] developed an efficient one-pot proce-
dure for the synthesis of spiro[benzo[g]chromene-4,30 -
indoline]-3-carbonitrile derivatives 128 by the reaction of
isatin 5, malononitrile, and 2-hydroxynaphthalene-1,
4-dione 125 under visible-light irradiation in water-ethyl
lactate (EL) at room temperature (Scheme 71).
4.6.3 | Benzo[h]chromenes and 4H-
benzo[f]chromenes
4H-Benzo[h]chromene-3-carbonitriles 130a and 4H-
benzo[f]chromene-3-carbonitriles 130b were synthesized
by the three-components reaction of aldehydes 1,
malononitrile 2 and α- or β-naphthol 129 in different
media (Methods A-D, Scheme 72, Table 18).[39,88,96,146]
33
4.6.4 | 5H-Acridines
The reaction of aldehydes 1 with dimedone 72 and
ammonium acetate or aniline derivatives in the presence
of different catalysts and solvents afforded 5H-acridine-1,
8-dione derivatives 131 (Methods A-E, Scheme 73,
Table 19).[49,66,147–149]
Fekri et al[147] have reported that a one-pot, multi-
component reaction of bis(aldehydes) 132, dimedone 72,
and ammonium acetate in the presence of a catalytic
amount of nano particle Fe3O4 afforded bis(1-phenyl-1H-
pyrazole-4,3-diyl))bis(3,3,6,6-tetramethyl-
3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione deriva-
tives 133 in good yields (Scheme 74).
The same authors reported the synthesis of 9,90 ,900 -
(((1,3,5-triazine-2,4,6-triyl)tris(oxy))tris(benzene-3,1-diyl))
tris(3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydroacridine-
1,8(2H,5H)-dione) 135 by three-component reactions of
tris-aldehyde 134, dimidone 72, and ammonium acetate
in the presence of nanoparticles Fe3O4 (Scheme 75).[147]
4.7 | Fused [6-6-6] systems: Two
heteroatoms
4.7.1 | Pyrano[3,2-c]chromenes
The reactions of aldehyde, malononitrile, and 4-
hydroxycoumarin 100 were performed in different sol-
vents and under different reaction conditions to give
pyrano[3,2-c]chromene-3-carbonitrile derivatives 136
(Methods A-E, Scheme 76, Table 20).[99,101,129,150,151]
Abdella et al[152] reported the synthesis of bis
(dihydropyrano[3,2-c]chromenes) 137 by a three-
component reaction of bis-aldehydes 14 or 16,
malononitrile, and 4-hydroxycoumarin 100 in pyridine or
acetic acid/sodium acetate at reflux (Scheme 77).[152]
One-pot, three-components reaction of
4-hydroxycoumarin 100, malononitrile or methyl
2-cyanoacetate, and isatin 5, ninhydrin 138, or
acenaphthenequinone 6 in the presence of different
34
SCHEME 80 Synthesis of hexahydrobenzo[b][1,8]naphthyridines 143
SCHEME 82 Synthesis of pyrimido[4,5-b]quinolines 146
catalysts and solvents afforded spiro(indoline-3,40 -pyrano
[3,2-c]chromene) derivatives 139-141 (Methods A-E,
Scheme 78).[105,106,153–155]
Safari et al[107] reported a room temperature-based
synthesis of bis-spirooxindole chromene 142 via one-pot,
four-component reactions of isatin 5, dihalides 77, methyl
2-cyanoacetate 2, and 4-hydroxycoumarin 100 in the
presence of potassium carbonate (K2CO3) in polyethylene
glycol 400 (PEG-400) as a biodegradable polymeric sol-
vent (Scheme 79).
4.7.2 | Hexahydrobenzo[b][1,8]
naphthyridines
4-Amino-5-aryl-2-methoxy-6-oxo-5,6,7,8,9,10hexahy-
drobenzo[b][1,8]naphthyridine-3-carbonitriles 143 were
ABDELLA ET AL.
S C H E M E 8 1 Synthesis bis(2H-
chromeno[2,3-b]pyridine-3-carbonitriles)
144 and 145
synthesized by the reaction of aldehydes 1 and
2-aminoprop-1-ene-1,1,3-tricarbonitrile 111 with 1,
3-cyclohexanediones 72 in methanol in the
presence of sodium methylate as a catalyst
(Scheme 80).[156]
Bis(chromeno[2,3-b]pyridine) derivatives 145 and
146 were prepared by one-pot, three-component reac-
tion of bisaldehydes with 2-aminoprop-1-ene-1,
1,3-tricarbonitrile 111 and dimedone 72 in ethanol in
the presence of piperidine. The reactions were
proceeded to give either the bis(4-amino-2,6-dioxo-hexa-
hydro-2H-chromeno[2,3-b]pyridine-3-carbonitriles) 144
or bis(2,4-diamino-tetrahydro-5H-chromeno[2,3-b]pyri-
dine-3-carbonitriles) 145 depending on the length and
position of the spacer in the bisaldehyde derivatives
(Scheme 81).[157]
ABDELLA ET AL. 35

TABLE 21 Percent yields of compounds 146

Method R1/R2/R3 Yield Reference

A (R3, R3 = H, R1 = 4-Cl-C6H4, 4-O2N-C6H4), 91%-93% Khurana et al[158]
(R2 = Me, R3 = H, R1 = 4-Cl-C6H4, 4-O2N-
C6H4, 4-Br-C6H4)
B (R3, R3 = Me, R1 = 4-MeO-C6H4, 4-O2N-C6H4, 85%-92% Veisi et al[59]
4-Cl-C6H4, 2-O2N-C6H4, 3-O2N-C6H4, 3- Br-
C6H4, 2-Cl-C6H4, 2-Cl-3-F-C6H3, 4-F-C6H4,
4-Br-C6H4), (R3, R3 = H, R1 = 3-O2N-C6H4, 4-F-
C6H4, 4-Cl-C6H4, 4-O2N-C6H4, 4-Me-C6H4,
4-(Me)2N-C6H4)
C (R3, R3 = Me, R1 = 4-HO-C6H4, 4-Me-C6H4, 88%-93% Upadhyay et al[159]
4-O2N-C6H4, 4-Cl-C6H4, 4-Br-C6H4)
D (R3, R3 = Me, R1 = C6H5, 4-MeO-C6H4, 3-Br- 81%-92% Nemati and Saeedirad[160]
C6H4, 3-O2N-C6H4, 2-Cl-C6H4, 4-Cl-C6H4, 4-F-
C6H4, 2-Thienyl)
E (R3, R3 = Me, R1 = 4-O2N-C6H4, 4-Cl-C6H4, 4-Me- 86%-94% Verma et al[161]
C6H4, 4-Br-C6H4, 3-HO-C6H4, 2-O2N-C6H4,
3-O2N-C6H4), (R3, R3 = H, R1 = 4-O2N-C6H4,
3-O2N-C6H4, 2,4-Cl2-C6H3, C6H5, 2-Cl-C6H4,
2-MeO-C6H4)

SCHEME 83 Synthesis of spirooxindole derivatives 147

4.8 | Fused [6-6-6] system: Three 4.8.2 | Pyrano[20 ,30 :5,6]pyrano[2,3-b]

heteroatoms pyridines

4.8.1 | Pyrimido[4,5-b]quinolines Pyrano[20 ,30 :5,6]pyrano[2,3-b]pyridine derivatives 149

were prepared by the reaction of aldehydes 1, 5-hydroxy-
Pyrimido[4,5-b]quinoline derivatives 146 were synthe- 2-(hydroxymethyl)-4H-pyran-4-one 90 and 2-aminoprop-
sized via a three-component reaction of aldehyde, 1-ene-1,1,3-tricarbonitrile 111 in ethanol in the presence
6-amino-1,3-dimethyluracil 67, and cyclohexadione deriv- of triethylamine under microwave irradiation
[164]
atives 72 in the presence of different catalysts and sol- (Scheme 85).
vents (Methods A-E, Scheme 82, Table 21).[59,158–161]
One-pot, three-components reaction of isatin 5,
dimedone 72 and aminothiouracil or aminouracil 67 cat- 4.9 | Fused [6-6-6] systems: Four
alyzed by PTSA in water yielded a variety of heteroatoms
spirooxindole derivatives 147 (Scheme 83).[162]
Mohamed et al[163] reported a novel synthesis of bis 4.9.1 | Pyrimido[4,5-b]-
spiro-cyclic 2-oxindole derivatives of pyrimido[4,5-b] 1,8-naphthyridines
quinolone tetraone derivatives 148 by the reaction of bis-
isatin 42, dimidone 72, and 6-aminouracil 67 in acetic Naidu et al[165] reported the synthesis of pyrimido[4,5-b]-
acid (Scheme 84). 1,8-naphthyridine derivatives 151 by the reaction of
36
2-cyano-3-(1H-indol-3-yl)-pent-2-enedinitrile or ethyl-2,
4-dicyano-3-(1H-indol-3-yl)but-2-enoate derivatives
150 with aryl aldehydes and 6-aminouracil derivatives
67 in the presence of Et3N in ethanol at reflux
(Scheme 86).
4.10 | Fused [6-6-6] systems: Five
heteroatoms
4.10.1 | Pyrido[2,3-d:6,5-d0 ]dipyrimidines
Reaction of aldehyde with aminouracil or dimethyl
aminouracil 67 and barbituric acid derivatives 94 under
ABDELLA ET AL.
SCHEME 84 Synthesis of bis
spiro-cyclic 2-oxindole derivatives of
pyrimido[4,5-b]quinolone tetraone 148
SCHEME 85 Synthesis of pyrano[20 ,30 :5,6]
pyrano[2,3-b]pyridines 149
SCHEME 86 Synthesis of
pyrimido[4,5-b]-1,8-naphthyridine
derivatives 151
different conditions (Methods A and B) afforded pyrido
[2,3-d:6,5-d0 ]dipyrimidine derivatives 152 in good yields
(Methods A and B, Scheme 87, Table 22).[160,166]
Rostamizadeh et al[167] reported the synthesis of
pyrido[2,3-d:6,5-d0 ]dipyrimidine derivatives 153 in good
yields through reaction of aldehydes 1 and 6-aminouracil
67 in the presence of SBA-15-SO3H as nanocatalyst under
solvent-free condition (Scheme 88).
Spiro cyclic 2-oxindole derivatives of pyrido[2,
3-d:6,5-d0 ]dipyrimidine-2,4,6-trione 154 were synthesized
from the one-pot, three-components cyclocondensation
reaction involving isatin 5, amionuracil or thiouracil 67,
and barbituric acid 94 in water in the presence of PTSA
as catalyst (Scheme 89).[162]
ABDELLA ET AL. 37

SCHEME 87 Synthesis of pyrido[2,3-d:6,5-d0 ]dipyrimidines 152

TABLE 22 Percent yields of compounds 152

Method R1/R2/R3 Yield Reference

2 3 1
A (R = Me, R = Me, Y = O, R = 4-Me-C6H4) 95% Nemati et al[160]
B (R2 = H, R3 = H, Y = S, R1 = C6H5, 4-Me-C6H4, 4-Cl-C6H4, 72%-98% Bhat et al[166]
4-MeO-C6H4, 4-HO-C6H4, 3,4-(MeO)2-C6H3, 3-O2N-C6H4,
2-Thienyl, 2-Furyl, 2-Pyrroyl

SCHEME 88 Synthesis of pyrido[2,3-d:6,5-d0 ]dipyrimidines 153

Mohammadizadeh et al[168] synthesized spiro pyrido
dipyrimidine derivatives 155, 156, and 157 via the reac-
tion of isatin derivatives 5, ninhydrin 138, or
acenaphtoquinone 6 with 6-amino-1,3-dimethyluracil
1 under classical or microwave-assisted solvent-free con-
ditions (Scheme 90).
5 | F U S E D T E T R A CY C L I C SY S T E M
5.1 | Fused [5-6-6-6] systems: Four
heteroatoms
5.2 | Fused [6-5-6-6] systems: One
heteroatom
5.2.1 | Indeno[1,2-b]quinolones
Shirini et al[170] developed an efficient one-pot synthesis
of dihydro-5H-indeno[1,2-b]quinolones derivatives 160 in
good yields from the reaction of aldehydes 1, indandione
122, dimedone 72, and ammonium acetate in the pres-
ence of melamine trisulfonic acid as a catalyst in ethanol
(Scheme 93).

5.1.1 | Pyrazolo[40 ,30 :5,6]pyrido[2,1-a]

phthalazines
0 0
Ghozlan et al[169] reported the synthesis of pyrazolo[4 ,3 -
5,6]pyrimido[2,1-a]phthalazine-9-carbonitrile derivatives
159 via the reaction of pyrazolyl-azaenamine 158 with
arylidenemalononitriles 45 in ethanol in the presence of
piperidine at reflux (Scheme 91).
Compounds 159 were alternatively synthesized by
one-pot, three-components reaction of pyrazolyl-
azaenamine 158 with malononitrile 2 and aldehydes
1 under the same condition (Scheme 92).[169]
5.3 | Fused [6-5-6-6] system: Three
heteroatoms
5.3.1 | Benzo[4,5]imidazo[2,1-b]
quinazolines
Taylor et al[171] reported the synthesis of benzo[4,5]
imidazo[2,1-b]quinazolin-1-one derivatives 162 by the
reaction of aldehydes 1, 2-aminobenzimidazole 161, and
dimedone 72 in the presence of sulfamic acid as a reus-
able, green catalyst in acetonitrile (Scheme 94).
38 ABDELLA ET AL.

SCHEME 89 Synthesis of compounds 154

SCHEME 90 Synthesis of spiro pyrido dipyrimidine derivatives 155, 156, and 157

SCHEME 91 Synthesis of pyrazolo[40 ,30 :5,6]pyrido[2,1-a]phthalazines 159

SCHEME 92 Synthesis of pyrazolo[40 ,30 :5,6]pyrido[2,1-a]phthalazines 159 via a three component reaction

A series of poly(tetrahydrobenzimidazo[2,1-b] Diab et al[172] using a multicomponent reaction of poly-

quinazolin-1(2H)-one) 163 were prepared in good yields by aldehydes with dimedone and 2-aminobenzimidazole 161
ABDELLA ET AL. 39

SCHEME 93 Synthesis of indeno[1,2-b]quinolones 160

SCHEME 94 Synthesis of benzo[4,5]imidazo[2,1-b]quinazolines 162

SCHEME 95 Synthesis of
poly(tetrahydrobenzimidazo
[2,1-b]quinazolinones) 163a-c

SCHEME 96 Synthesis of indeno[20 ,10 :5,6]pyrido[2,3-d]pyrimidines 164

in DMF in the presence of ZnO NPs under microwave irra-
diation as well as under conventional heating (Scheme 95).
5.3.2 | Indeno[20 ,10 :5,6]pyrido[2,3-d]
pyrimidines
The reaction of aldehydes 1 with aminouracil or
thioaminouracil 67 and indandione 122 under different
conditions (Methods A-C) afforded indenopyrido[2,3-d]
pyrimidines derivatives 164 in good yields (Scheme 96,
Table 23).[158,160,161]
Abdelmoniem et al[162] reported the synthesis of spiro
cyclic indeno[20 ,10 :5,6]pyrido[2,3-d]pyrimidine deriva-
tives 165 in good yields from the one-pot, three-
component cyclocondensation reaction of isatin 5,
indandione 122, and aminothiouracil 67 in water in
the presence of PTSA (Scheme 97).
40 ABDELLA ET AL.

TABLE 23 Percent yields of compounds 164

Method R1 Yield Reference

A 4-Br-C6H4, 4-Cl-C6H4, 4-F-C6H4, 3-O2N-C6H4, 60%-90% Verma et al[161]
4-Me-C6H4, 5-Br-2-HO-C6H4, 2-Thienyl, i-
Propyl
B R2 = Me,Y = O, R1 = 4-Cl-C6H4, 4-Me-C6H4, 87%-90% Khurana et al[158]
4-O2N-C6H4, 3-O2N-C6H4
C R2 = Me, Y = O, R1 = C6H5, 4-O2N-C6H4 90%-94% Nemati and Saeedirad[160]

SCHEME 97 Synthesis of spiro cyclic indeno[20 ,10 :5,6]pyrido [2,3-d]pyrimidine derivatives 165

SCHEME 98 Synthesis of tetrahydrobenzo[a]xanthen-11-ones 166

5.4 | Fused [6-6-6-6] systems: One 5.5.2 | Dihydrochromeno[30 ,40 :5,6]pyrano

heteroatom [2,3-b]pyridines

5.4.1 | Tetrahydrobenzo[a]xanthen- Olyaei et al[180] reported the synthesis of 8,10-diamino-

11-ones
The reaction of aldehydes 1 with β-naphthol 129 and
dimedone 72 under different conditions (Methods A-F)
afforded 8,9,10,12-tetrahydro benzo[a]xanthen-11-ones
166 in good yields (Scheme 98, Table 24).[173–178]
6-oxo-6,7-dihydrochromeno[30 ,40 :5,6]pyrano[2,3-b]pyri-
dine-9-carbonitrile derivatives 168 in good yields by the
reaction of aldehydes 1, 4-hydroxycoumarin 100, and
2-aminoprop-1-ene-1,1,3-tricarbonitrile 111 in the pres-
ence of guanidine hydrochloride as an organocatalyst
under solvent-free conditions (Scheme 100).

5.5 | Fused [6-6-6-6] systems: Three 6 | FUSED P ENTA-CYCLIC

heteroatoms SYSTEM

5.5.1 | Benzo[5,6]chromeno[2,3-d] 6.1 | Fused [6-5-6-5-6] systems: One

pyrimidines heteroatom

Benzo[5,6]chromeno[2,3-d]pyrimidine-9,11(5H,8H)- 6.1.1 | Diindeno[1,2-b:20 ,10 -e]pyridines

diones 167 were synthesized by the reaction of aldehydes
1, β-naphthol 129, and 6-amino-1,3-dimethyluracil 67 in Sadeghi et al[62] developed an efficient one-pot procedure
the presence of InCl3 under solvent-free condition for the synthesis of diindeno[1,2-b:20 ,10 -e]pyridine-
(Scheme 99).[179] 10,12-dione derivaties 169 by the reaction of aldehydes
ABDELLA ET AL. 41

TABLE 24 Percent yields of compounds 166

Method R1 Yield Reference

A (X = 5-O2N, R1 = 4-Cl-C6H4), (X = 3-MeO, 90%-92% Balou et al[173]
R1 = 3-HO-C6H4)
B (X = H, R1 = C6H5, 4-Me-C6H4, 4-MeO-C6H4, 85%-94% Mohamadpour et al[174]
3-MeO-C6H4, 4-HO-C6H4, 4-O2N-C6H4, 3-O2N-
C6H4, 4-Cl-C6H4, 2-Cl-C6H4, 4-Br-C6H4, 3-Br-
C6H4, 4-F-C6H4)
C (X = H, R1 = 4-Cl-C6H4, 2-Cl-C6H4, 4-Br-C6H4, 77%-93% Maleki et al[175]
4-F-C6H4, 4-O2N-C6H4, 3-O2N-C6H4, 4-MeO-
C6H4, 4-HO-C6H4, 2-HO-C6H4, 2,4-Cl2-C6H3)
D (X = H, R1 = C6H5, 3-Cl-C6H4, 4-Cl-C6H4, 2,3-Cl2- 86%-93% Moosavi-Zare[176]
C6H3, 2,4-Cl2-C6H3, 2-Br-C6H4, 3-Br-C6H4, 4-Br-
C6H4, 3-O2N-C6H4, 4-O2N-C6H4, 3-HO-C6H4,
2-Me-C6H4, 3-Me-C6H4, 4-MeO-C6H4)
E (X = H, R1 = C6H5, 3-Br-C6H4, 4-Br-C6H4, 2-Cl- 83%-97% Sonei et al[177]
C6H4, 3-Cl-C6H4, 4-Cl-C6H4, 4-F-C6H4, 3-Me-
C6H4, 4-Me-C6H4, 4-MeO-C6H4, 2-HO-C6H4,
4-HO-C6H4, 4-NC-C6H4, 4-O2N-C6H4, 3-O2N-
C 6H 4)
F (X = H, R1 = C6H5, 2-Me-C6H4, 3-Me-C6H4, 51%-95% Nasseri et al[178]
4-Me-C6H4, 2-Cl-C6H4, 3-Cl-C6H4, 4-Cl-C6H4,
2-O2N-C6H4, 3-O2N-C6H4, 4-O2N-C6H4, 2-MeO-
C6H4, 3-MeO-C6H4, 4-MeO-C6H4)

SCHEME 99 Synthesis of benzo[5,6]chromeno[2,3-d]pyrimidinediones 167

SCHEME 100 Synthesis of dihydrochromeno[30 ,40 :5,6]pyrano[2,3-b]pyridines 168

1 and indandione 122 in the presence of ammonium ace- 6.2 | Fused [6-6-6-5-6] systems: One
tate and nanoparticles SiO2-BF3 under solvent-free condi- heteroatom
tion (Scheme 101).
Spiro[diindeno[1,2-b:20 ,10 -e]pyridine-11,30 -indoline] 6.2.1 | Benzo[g]indeno[1,2-b]quinolines
trione derivatives 170a and 170b were synthesized by the
one-pot cyclocondensation reaction between ninhydrin Khaligh et al[182] has reported an efficient method for
138 or isatin 5 and indandione 122 in acetic acid in the the synthesis of 12-aryl-12-hydro-5H-benzo[g]indeno[2,
presence of ammonium acetate (Scheme 102).[181] 1-b]quinoline-6,11,13-trione derivatives 171 by the
42 ABDELLA ET AL.

SCHEME 101 Synthesis of diindeno[1,2-b:20 ,10 -e]pyridines 169

SCHEME 102 Synthesis of spiro[diindeno[1,2-b:20 ,10 -e]pyridine-11,30 -indoline]triones 170

SCHEME 103 Synthesis of 5H-benzo[g]indeno[2,1-b]quinolinetriones 171

SCHEME 104 Synthesis of benzo[f]indeno[1,2-b]chromenes 172

reaction of aldehydes 1, 2-hydroxynaphthalene-1, 6.3 | Fused [6–6-6-6-6] systems: One

4-dione 125, and indandione 122 in the presence of heteroatom
poly(4-vinylpyridinium)hydrogen sulfate as a solid
acid catalyst under solvent free condition 6.3.1 | 14H-Dibenzo[a,j]xanthenes
(Scheme 103).
Aryl-14H-dibenzo[a,j]xanthene derivatives 173 were pre-
pared in good yields by the reaction of aldehydes 1 and
6.2.2 | Benzo[f]indeno[1,2-b]chromenes β-naphthol 129 under different conditions (Methods A-D,
Scheme 105, Table 26).[185–188]
Arylbenzo[f]indeno[1,2-b]chromen-12(13H)-one
deivatives 172 were prepared by the one-pot
cyclocondensation reaction of aldehydes 1, β-naphthol 6.3.2 | 5H-Dibenzo[b,i]xanthenes
129, and indandione 122 in the presence of different cata-
lysts and solvents (Methods A and B, Scheme 104, Aryl-5H-dibenzo[b,i]xanthene-5,7,12,14(13H)-tetraones
Table 25).[183,184] 174 were prepared by the reaction of aldehydes 1 and
ABDELLA ET AL. 43

TABLE 25 Percent yields of compounds 172

Method R1 Yield Reference

A C6H5, 4-Cl-C6H4, 4-MeO-C6H4, 4-Me-C6H4, 3,4-Cl2-C6H3, 2-Cl-C6H4, 2,4-Cl2- 96%-85% Ghasemzadeh
C6H3, 4-HO-C6H4, 3-O2N-C6H4, 4-F-C6H4, 4-NC-C6H4 et al[183]
B C 6H 5 91% Sheik and Majid[184]

SCHEME 105 Synthesis of aryl-14H-dibenzo[a,j]xanthene derivatives 173

TABLE 26 Percent yields of compounds 173

1
Method R Yield Reference
A C6H5, 2-Cl-C6H4, 3-Cl-C6H4, 4-Cl-C6H4, 2,4-Cl2-C6H3, 4-F-C6H4, 4-Br-C6H4, 3-Br- 84%-95% Sadeh et al[185]
C6H4, 2-O2N-C6H4, 3-O2N-C6H4
B C6H5, 4-MeO-C6H4, 4-Cl-C6H4, 4-Me-C6H4, 4-Br-C6H4, 4-O2N-C6H4, 2,4-(MeO)2- 75%-84% Soliman and
C6H3, 3,5-(MeO)2-C6H3, 3,4,5-(MeO)3-C6H2 Mubarak[186]
C C6H5, 3-O2N-C6H4, 4-MeO-C6H4, 4-Cl-C6H4, 4-(Me)2CH-C6H4 88%-95% Maleki et al[187]
D C6H5, 4-O2N-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 2-Cl-C6H4, 4-HO-C6H4, 4-Me-C6H4, 88%-96% Tabatabaeian
4-MeO-C6H4, 3,4-(MeO)2-C6H3 and Ali[188]

SCHEME 106 Synthesis of 5H-dibenzo[b,i]xanthenes 174

2-hydroxynaphthalene-1,4-dione 125 under different nanoparticles as a catalyst under ultrasonic irradiation

reaction conditions (Methods A-C, Scheme 106, (Scheme 107).
Table 27).[189–191]

6.4 | Fused [6-6-6-6-6] systems: Two

6.3.3 | 8H-Dibenzo[a,i]xanthenes heteroatom

Safaei-Ghomi et al[192] reported the synthesis of 14-aryl- 6.4.1 | Benzo[f]chromeno[4,3-b]

8H-dibenzo[a,i]xanthene-8,13 (14H)-diones 175 in good chromenes
yields by the reaction of aldehydes 1,
2-hydroxynaphthalene-1,4-dione 125, and β-naphthol 129 Piltan et al[193] reported the synthesis of 7-aryl-benzo[f]
in the presence of Fe3O4/PEG/succinic anhydride chromeno[4,3-b]chromen-6(7H)-ones 176 by the reaction
44 ABDELLA ET AL.

TABLE 27 Percent yields of compounds 174

Method R1 Yield Reference

A C6H5, 4-Me-C6H4, 4-Br-C6H4, 2-Br-C6H4, 4-MeO-C6H4, 2-MeO-C6H4, 2-O2N- 88%-96% Rasul et al[189]
C6H4, 3-O2N-C6H4, 4-O2N-C6H4, 2-Cl-C6H4, 3-Cl-C6H4, 4-Cl-C6H4
B 4-Br-C6H4, 2-C12H7, 3-MeO-4-HO-C6H3 94%-97% Nemati and Sabaqian[190]
C C6H5, 4-Me-C6H4, 2-MeO-C6H4, 4-MeO-C6H4, 2-HO-C6H4, 3-MeO-4-HO- 86%-94% Liu et al[191]
C6H3, 3-C6H4OC6H4, 2-F-C6H4, 4-F-C6H4, 2-Cl-C6H4, 4-Cl-C6H4, 2-Br-
C6H4, 4-Br-C6H4

SCHEME 107 Synthesis of 8H-dibenzo[a,i]xanthenes 175

SCHEME 108 Synthesis of benzo[f]chromeno[4,3-b]chromenes 176

SCHEME 109 Synthesis of benzo[f]chromeno[3,4-b]quinolines 178

of aldehydes 1, β-naphthol 129, and 4-hydroxycoumarin 3-aminocoumarins 177, and β-naphthol 129 in the pres-
100 in the presence of ZnO nanoparticles under solvent ence of N-tetrabutylammonium tribromide (TBATB) as a
free conditions (Scheme 108). catalyst at reflux (Scheme 109).[194]

6.4.2 | Benzo[f]chromeno[3,4-b] 7 | CONCLUSIONS

quinolines
Heterocycles constitute one of the largest areas of
Arylbenzo[f]chromeno[3,4-b]quinolin-6-ones 178 were research in organic chemistry. They have been the sub-
synthesized by the reaction of aldehydes 1, ject of numerous studies due to their wide range of
ABDELLA ET AL.
applications in different fields. This review gave an over-
view of the new developments over the last decades in
the synthesis of many kinds of heterocycles and their
corresponding fused derivatives utilizing Michael as well
as Hanztch reactions. These heterocycles were found to
exhibit a number of significant biological activities
including, anticancer, anti-inflammatory, antiviral, anti-
oxidant, antibacterial, and antifungal activities. The het-
erocycles mentioned in this review are arranged in an
organized manner with respect to the type of heterocyclic
systems. To the best of our knowledges, no review has
been published related to the synthesis of these scaffolds
so far. Heterocycles reported in this review were prepared
by multicomponent reactions using varieties of starting
materials under catalytic and noncatalytic methods. The
reactions proceeded under conventional or non-
conventional technologies such as microwave or ultra-
sound irradiations. Moreover, the reactions were
performed in organic solvents or under solvent-free condi-
tions. These methods offer very attractive features such
as shorter reaction time and higher yields as compared
with the conventional methods. In many cases and
aiming at extending the scope of the reactions, precursors
containing aromatic aldehydes, ketones, or amines bear-
ing either electron-donating or electron-withdrawing
groups on the aromatic ring were used. However, this
was not found to affect significantly neither on the prod-
uct yield nor on the reaction rate. We hope that this
review will be useful not only for synthetic organic chem-
ists but also for heterocyclic and natural product
researchers who are willing to obtain new derivatives
with various biological activities.
ORCID
Amr M. Abdelmoniem https://orcid.org/0000-0002-
9243-7589
Ismail A. Abdelhamid https://orcid.org/0000-0003-
1220-8370
Ahmed H. M. Elwahy https://orcid.org/0000-0002-3992-
9488
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How to cite this article: Abdella AM,
Abdelmoniem AM, Abdelhamid IA, Elwahy AHM.
Synthesis of heterocyclic compounds via Michael
and Hantzsch reactions. J Heterocyclic Chem. 2020;
1–48. https://doi.org/10.1002/jhet.3883