Synthesis of heterocycles and fused heterocycles catalyzed by nanomaterials

Abstract

This review focuses, on the application of nanomaterials as heterogeneous catalysts for the synthesis of different heterocyclic systems. We pay special attention to the specific synthesis of such systems in an organized manner with respect to the type of the heterocyclic systems.

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Ahmed H. M. Elwahy

Ahmed H. M. Elwahy was born in 1963 in Giza, Egypt. He graduated from Cairo University, Egypt in 1984 then he carried out his M.Sc. and Ph.D. studies in 1988 and 1991, respectively, at Cairo University in the field of organic synthesis. He was awarded the Alexander von Humboldt research fellowship in 1998–2000 and in 2003, 2005, 2009, 2010 and 2012 with Prof. Klaus Hafner, at TU-Darmstadt, Germany. In 1997 he promoted to Associate Professor and in 2002 he was appointed as a full Professor of Organic chemistry at Cairo University. In 2001 he received the Cairo University Award in Chemistry and in the same year he received the State-Award in Chemistry. He published around 80 scientific papers in distinguished international journals.

Mohamed R. Shaaban

Mohamed R. Shaaban was born in 1971 in Cairo, Egypt. He graduated from Cairo University, Egypt in 1992 then he joined Professor Ahmad M. Farag's research group. He received his Ph.D. in 2001 at Tokyo Institute of Technology, Japan. In 2001 he was promoted to a Lecturer of Organic Chemistry at Cairo University and continued his research work on organic synthesis as well as on palladium catalyzed C–C cross-couplings. In 2009 he was promoted to Associate Professor of Organic chemistry, and in 2014 he was promoted to Professor of Organic chemistry Faculty of Science, Cairo University.

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1. Introduction

Heterocycles are an important class of compounds, making up more than half of all known organic compounds. Heterocycles are present in a wide variety of drugs, most vitamins, many natural products, biomolecules, and biologically active compounds, including antitumor, antibiotic, anti-inflammatory, antidepressant, antimalarial, anti-HIV, antimicrobial, antibacterial, antifungal, antiviral, antidiabetic, herbicidal, fungicidal, and insecticidal agents. They have also been frequently found as a key structural unit in synthetic pharmaceuticals and agrochemicals. Most of the heterocycles possess important applications in materials science such as dyestuff, fluorescent sensor, brightening agents, information storage, plastics, and analytical reagents. Heterocycles are also of considerable interest because of their synthetic utility as intermediates, protecting groups, chiral auxiliaries, organic catalysts, and metal ligands in asymmetric catalysts.^1–3

The intellectual challenge to invent concise, elegant and conceptually novel synthetic routes to heterocyclic systems has become a steadily increasing driving force both in academia and industry. Therefore, extensive efforts have been directed to develop new and efficient synthetic strategies for these compounds. Among a variety of synthetic protocols, recent researches have been focused on establishment of catalytic approaches to synthesize heterocycles from easily accessible precursors under mild reaction conditions.

In this respect, chemists have made considerable achievements during the twentieth century in heterogeneous catalysis.⁴ Heterogeneous catalysis have the advantage of easy removal of catalyst materials and possible use of high temperatures. Heterogeneous catalysts of metals are composed of two major components: the active metal particles and the support. Typical supports are Al₂O₃, SiO₂, MgO, Fe₂O₃, TiO₂, CeO₂, and many others.⁵ The most widely used conventional method for preparing metal catalysts is the wet impregnation method.⁶ One area of catalysis that is developing at a rapid pace is nano-catalysis.⁷

Nanomaterial-based catalysts are usually heterogeneous catalysts broken up into metal nanoparticles (NPs) in order to speed up the catalytic process. Metal nanoparticles have a higher surface area so there is increased catalytic activity because more catalytic reactions can occur at the same time. Nanoparticles catalysts can also be easily separated and recycled with more retention of catalytic activity than their bulk counterparts.⁸ These catalysts can play two different roles in catalytic processes: they can be the site of catalysis or they can act as a support for catalytic processes.⁹ They are typically used under mild conditions to prevent decomposition of the nanoparticles at extreme conditions.¹⁰

Many experimental studies on nanocatalysts have focused on correlating catalytic activity with particle size. In addition, many other factors such as geometry, composition, oxidation state, and chemical/physical environment can play a role in determining NP reactivity. There are many reviews on the multiple NP synthetic modes,¹¹ and here we will not systematically detail this aspect per se.

In continuation of our interest in reviewing the different approaches for the synthesis of heterocyclic systems,^12–16 this review focuses, on the application of nanomaterials as heterogeneous catalyst for the synthesis of heterocyclic systems. A number of other reviews^17,18 that have appeared, concerning this matter, did not pay special attention to the specific synthesis of such systems in an organized manner with respect to the type of the heterocyclic systems.

The fused heterocycles mentioned in this review are classified according to the type of the ring system. In order to prevent ambiguity, the fused ring systems are determined according to the following criteria:

(a) The presence or the absence of bridgehead nitrogen.

(b) Number of atoms in each ring (including carbon and hetero atoms) starting with the number of atoms in the ring taken as a prefix.

(c) The number of heteroatoms in each ring. 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. Specific synthesis of heterocycles catalyzed by nanomaterials

2.1. Synthesis of five-membered heterocycles

2.1.1. Five-membered rings with one heteroatom.
2.1.1.1. Furan. Cano et al. used commercially available nano-powder magnetite as an excellent catalyst for the addition of acid chlorides 1 to internal and terminal alkynes 2, yielding the corresponding chlorovinyl ketones in good yields. The use of the iridium impregnated on magnetite catalyst permits the integration of the chloroacylation process with a second dehydrochlorination annulation process to yield, in one-pot, 3-aryl-2,5-dialkylfurans 3a–e in good yields, independently of the nature of the starting reagents, and including the heteroaromatic ones (Scheme 1, Table 1).¹⁹

Scheme 1

Table 1 One-pot synthesis of 3-aryl-2,5-dialkylfurans 3a–e

Entry	Ar	R	Product	Yield^a (%)
a Isolated yield after column chromatography.
1	C6H5	^nPr	3a	88
2	C6H5	Me	3b	91
3	4-ClC6H4	^nPr	3c	76
4	4-MeOC6H4	^nPr	3d	94
5	2-Thienyl	^nPr	3e	74

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Cao et al. reported the regioselective synthesis of α-carbonylfurans 6a–r from a range of electron-deficient alkynes 4a–f and 3-substituted 2-yn-ols 5a–h The reaction proceeded using 10 mol% nano-Cu₂O in N,N-dimethylformamide at 50 °C (Scheme 2, Table 2, Method A).²⁰

Scheme 2

Table 2 Regioselective synthesis of α-carbonylfurans 6a–v

Entry	R^1	R^2	R^3	Method	Product	Yield (%)
1	OEt	C6H5	H	A	6a	71
2	OEt	C6H5	Me	A	6b	67
3	OEt	C6H5	C6H5	A	6c	63
4	OEt	C6H5	3-MeC6H4	A	6d	68
5	OEt	C6H5	4-MeOC6H4	A	6e	65
6	OEt	C6H5	4-O2NC6H4	A	6f	66
7	OEt	C6H5	2-Pyridyl	A	6g	69
8	4-MeC6H4	C6H5	2-Thienyl	A	6h	62
9	4-MeC6H4	4-MeC6H4	H	A	6i	67
10	4-MeC6H4	4-MeC6H4	Me	A	6j	73
11	OEt	4-MeC6H4	C6H5	A	6k	70
12	C6H5	Me	Me	A	6l	60
13	C6H5	C6H5	H	A	6m	68
14	C6H5	C6H5	C6H5	A	6n	73
15	C6H5	C6H5	Me	A	6o	71
16	C6H5	C6H5	4-MeOC6H4	A	6p	71
17	C6H5	C6H5	4-O2NC6H4	A	6q	67
18	C6H5	C6H5	2-Thienyl	A	6r	61
19	OEt	C6H5	C≡C–C6H5	B	6s	42
20	C6H5	C6H5	C≡C–C6H5	B	6t	45
21	OEt	OEt	C≡C–C6H4-5-Me	B	6u	49
22	OMe	OMe	C≡C–C6H5	B	6v	51

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Furthermore, 2,4,5-trisubstituted 3-ynylfurans 6s–v were obtained in 42–51% yield by nano-Cu₂O-catalyzed reaction of alkynes 4 and 5-arylpenta-2,4-diyn-1-ols 5 (Scheme 2, Table 2, entries 19–22, Method B).²⁰

Tekale et al. have successfully developed an efficient protocol for the one-pot three-component synthesis of 3,4,5-trisubstituted furan-2(5H)-ones 10a–l from aldehydes 7a–h, amines 9a–e and dimethylacetylene dicarboxylate (DMAD) 8 using nano-crystalline ZnO as a reusable heterogeneous catalyst. The catalyst can be recycled several times with consistent catalytic activity (Scheme 3, Table 3).²¹

Scheme 3

Table 3 One-pot three-component synthesis of 3,4,5-trisubstituted furan-2(5H)-ones 10a–l

Entry	R^1	R^2	Product	Yield (%)
1	C6H5	C6H5	10a	94
2	C6H5	4-MeC6H4	10b	95
3	4-MeOC6H4	C6H5	10c	88
4	C6H5	4-FC6H4	10d	84
5	4-ClC6H4	C6H5	10e	89
6	2-ClC6H4	C6H5	10f	87
7	3-MeOC6H4	C6H5	10g	85
8	4-MeC6H4	C6H5	10h	84
9	C6H5	4-^iPrC6H4	10i	88
10	C6H5	2-FC6H4	10j	84
11	2,4-Cl2C6H3	2-FC6H4	10k	85
12	2,4-(MeO)2C6H3	C6H5	10l	83

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The plausible mechanism for the ZnO nanoparticle catalyzed synthesis of furan 2(5H)-ones 10a–l suggests initially the formation of enamine from amine 9 and DMAD by ZnO promotion. ZnO polarizes the carbonyl group of aldehyde 7 to form polarized adduct which reacts with the enamine followed by cyclization with the elimination of methanol molecule to afford the corresponding furan-2(5H)-ones 10a–l.

2.1.1.2. Pyrrole. Hosseini-Sarvari et al. reported an environmentally benign method for the preparation of N-substituted pyrroles 12a–l from one-pot condensation reaction of 2,5-dimethoxytetrahydrofuran 11 with amines 9 in the presence of nano sulfated titania (Fig. 1) under solvent-free conditions (Scheme 4, Table 4, Method A).²² As shown in Table 4, aromatic amines with electron-donating groups or electron-withdrawing groups are both effective in the Clauson–Kaas reaction, giving desired pyrroles 12a–l in high yield.

Fig. 1 Structure of nano sulfated titania.

Scheme 4

Table 4 Preparation 12a-bm of N-substituted pyrroles 12a-bm

Entry	R	Method	Product	Yield (%)
1	3-MeC6H4	A	12a	98
2	4-MeC6H4	A	12b	90
3	2-EtC6H4	A	12c	98
4	3-MeOC6H4	A	12d	95
5	2-HOC6H4	A	12e	90
6	3-HOC6H4	A	12f	95
7	4-HOC6H4	A	12g	95
8	2-HO-5-MeC6H3	A	12h	95
9	4-NCC6H4	A	12i	95
10	2-F3CC6H4	A	12j	95
11	4-BrC6H4	A	12k	95
12	4-H2NC6H4	A	121	90
13	–CH2C6H5	B	12m	92
14	–CH(Me)C6H5 (S)	B	12n	90
15	–CH(Me)C6H5 (R)	B	12o	90
16	–(CH2)3C6H5	B	12p	86
17	C6H5	B	12q	88
18	3-EtOOCC6H4	B	12r	85
19	2-MeOCC6H4	B	12s	82
20	Pyridyl–CH2–	B	12t	78
21	NHOCC6H5	B	12u	72
22	–OCC6H5	B	12v	NR
23	NH-4-O2NC6H4	B	12w	NR
24	^iBu	B	12x	90
25		B	12y	84
26	–(CH2)3OH	B	12z	86
27	–(CH2)3NH2	B	12aa	85
28	–(CH2)3NH2	B	12ab	72
29	C6H5	C	12ac	95
30	3-HOC6H4	C	12f	93
31	2-MeOC6H4	C	12ad	85
32	4-MeOC6H4	C	12ae	96
33	4-EtOC6H4	C	12af	96
34	2-MeC6H4	C	12ag	89
35	4-MeC6H4	C	12b	94
36	3,4-Me2C6H3	C	12ah	96
37	2,5-Me2C6H3	C	12ai	90
38	2,6-Me2C6H3	C	12aj	87
39	2,6-^iPr2C6H3	C	12ak	75
40	4-^tBuC6H4	C	12al	92
41	2-FC6H4	C	12am	81
42	4-FC6H4	C	12an	82
43	2,4-F2C6H3	C	12ao	85
44	3,4-F2C6H3	C	12ap	90
45	3-ClC6H4	C	12aq	86
46	4-ClC6H4	C	12ar	87
47	3-Cl-4-MeC6H3	C	12as	92
48	3-Cl-4-FC6H3	C	12at	89
49	2,4,5-Cl3C6H2	C	12au	88
50	2-BrC6H4	C	12av	82
51	3-BrC6H4	C	12aw	85
52	4-BrC6H4	C	12k	88
53	4-IC6H4	C	12ax	89
54	2-O2NC6H4	C	12ay	80
55	4-O2NC6H4	C	12az	85
56	4-AcC6H4	C	12ba	89
57	3-F3CC6H4	C	12bb	84
58	4-F3CC6H4	C	12bc	83
59	4-EtOOCC6H4	C	12bd	90
60	2-Naphthyl	C	12be	93
61	2-(4-Bromonaphthyl)	C	12bf	95
62	2-Fluorenyl	C	12bg	93
63	2-Pyridyl	C	12bh	71
64	6-Picolyl	C	12bi	70
65	2-Pyrimidyl	C	12bj	85
66	2-(5-Methylbenzthiazolyl)	C	12bk	80
67	NH–COC6H4	C	12u	90
68	CO-4-H2NC6H4	C	12bl	92
69	4-NH2C6H4	C	12l	94
70	2-(5-Aminonaphthyl)	C	12bm	100

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There are many Lewis and Brønsted acid sites in the sulfated metallic oxides. The superacidity of these materials is attributed to the Brønsted acid sites, created or already existing, whose acidity is increased by the presence of neighboring strong Lewis acid sites. The strength of these Lewis acid sites is due to an inductive effect exercised by sulfate on the metallic cation, which becomes more deficient in electrons,²³ as seen in the Fig. 1. Thus, nano sulfated titania represents a novel type of Lewis acid catalyst.

Polshettiwar and Varma prepared nano-organocatalyst (Fig. 2) by supporting totally benign and naturally abundant glutathione on magnetic nanoparticles. The catalyst showed excellent activity for microwave-assisted synthesis of N-substituted pyrroles 12m–ab by the reaction of a variety of amines 9 with tetrahydro-2,5-dimethoxyfuran 11 (Scheme 4, Table 4, Method B). The rates were essentially the same for both the aliphatic or aromatic nature of the amines, showing the high activity of the catalyst.²⁴

Fig. 2 Nano-organocatalyst obtained by supporting glutathione on magnetic nanoparticles.

Ma et al. reported a facile approach to prepare magnetic nanoparticle-supported antimony catalyst (Fe₂O₃@SiO₂–Sb–IL, Fig. 3). This catalyst exhibited excellent catalytic efficiency in Clauson–Kaas reaction of amines 9 to 2,5-dimethoxytetrahydrofuran 11 in aqueous medium to afford the corresponding N-substituted pyrroles 12b, 12f, 12k, 12l, 12u and 12ac–bm (Scheme 4, Table 4, Method C).²⁵

Fig. 3 Structure of magnetic nanoparticle-supported antimony catalyst.

N-Substituted pyrroles 14a–g have also been prepared from one-pot Paal–Knorr condensation of 2,5-diketone 13 and the appropriate aromatic amine 9 using nano-crystalline sulfated zirconia (SZ) as the catalyst in ethanol at moderate temperature (Scheme 5, Table 5).²⁶

Scheme 5

Table 5 Synthesis of N-substituted pyrroles 14a–g

Entry	R	Product	Yield (%)
1	C6H5	14a	94
2	4-ClC6H4	14b	90
3	4-BrC6H4	14c	85
4	4-O2NC6H4	14d	90
5	C6H5CH2NH2	14e	81
6	4-MeC6H4	14f	90
7	4-MeOC6H4	14g	86

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Li et al. reported one-pot three-component synthesis of multisubstituted pyrroles 17a–av by the reaction of amines 9, nitroolefins 16 and 1,3-dicarbonyl compounds 15 catalyzed by novel magnetic nano-CoFe₂O₄ supported Sb ([CoFe₂O₄@SiO₂–DABCO–Sb], Fig. 4), (Scheme 6, Table 6). The magnetic heterogeneous catalyst could be easily recovered using an external magnet and reused many times without significant loss of catalytic activity.²⁷

Fig. 4 Structure of magnetic nano-CoFe₂O₄ supported Sb ([CoFe₂O₄@SiO₂–DABCO–Sb]).

Scheme 6

Table 6 Synthesis of multisubstituted pyrroles 17a–av

Entry	R^1	R^2	R^3	R^4	Ar	Product	Yield (%)
1	C6H5	Me	Me	H	C6H5	17a	93
2	C6H5	Me	Me	Me	C6H5	17b	80
3	C6H5	Me	Me	Me	4-MeC6H4	17c	87
4	C6H5	Me	Me	Me	4-FC6H4	17d	86
5	C6H5	Me	Me	Me	2-ClC6H4	17e	75
6	C6H5	Me	Me	Me	3-ClC6H4	17f	78
7	C6H5	Me	Me	Me	4-ClC6H4	17g	85
8	C6H5	Me	Me	Me	4-O2NC6H4	17h	75
9	C6H5	Me	Me	Me	2-Furyl	17i	88
10	C6H5	Me	Me	Me	2-Thienyl	17j	82
11	C6H5	Me	Me	Me	2-Naphthyl	17k	47
12	C6H5	Me	Me	Et	C6H5	17l	80
13	C6H5	Me	Me	Et	4-MeC6H4	17m	80
14	C6H5	Me	Me	Et	2-Furyl	17n	76
15	C6H5	Me	Me	Et	2-Thienyl	17o	78
16	4-^tBuC6H4	Me	Me	H	C6H5	17p	92
17	2-Naphthyl	Me	Me	H	C6H5	17q	75
18	4-Fluorenyl	Me	Me	H	C6H5	17r	80
19	4-MeC6H4	Me	Me	Me	C6H5	17s	82
20	4-MeOC6H4	Me	Me	Me	C6H5	17t	88
21	4-FC6H4	Me	Me	Me	C6H5	17u	82
22	4-CIC6H4	Me	Me	Me	C6H5	17v	75
23	2-BrC6H4	Me	Me	Me	C6H5	17w	70
24	3-BrC6H4	Me	Me	Me	C6H5	17x	72
25	4-BrC6H4	Me	Me	Me	C6H5	17y	77
26	4-F3CC6H4	Me	Me	Me	C6H5	17z	51
27	4-F3COC6H4	Me	Me	Me	C6H5	17aa	85
28	2-Furyl-CH2	Me	Me	Me	C6H5	17ab	90
29	2-Fluorenyl	Me	Me	Me	C6H5	17ac	73
30	Allyl	Me	Me	Me	C6H5	17ad	91
31	Bn	Me	Me	Me	C6H5	17ae	90
32	C6H5CH2CH2	Me	Me	Me	C6H5	17af	92
33	C6H5CH(CH3)–	Me	Me	Me	C6H5	17ag	87
34	^cPr	Me	Me	Me	C6H5	17ah	89
35	^cPn	Me	Me	Me	C6H5	17ai	72
36	^nPr	Me	Me	Me	C6H5	17aj	88
37	^nBu	Me	Me	Me	C6H5	17ak	86
38	C6H5	Me	OMe	Me	C6H5	17al	82
39	C6H5	Me	OEt	Me	C6H5	17am	85
40	C6H5	Me	O(CH2)2OMe	Me	C6H5	17an	80
41	C6H5	41	O-Allyl	Me	C6H5	17ao	78
42	C6H5	Et	OMe	Me	C6H5	17ap	76
43	C6H5	Me	OCMe3	Me	C6H5	17aq	83
44	C6H5	Me	OCH2CH(CH3)2	Me	C6H5	17ar	81
45	2-Furyl-CH2	Me	Me	Et	C6H5	17as	89
46	Bn	Me	Me	Et	C6H5	17at	86
47	^cPr	Me	Me	Et	C6H5	17au	82
48	^nPr	Me	Me	Et	C6H5	17av	83

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Sabbaghan and Ghalaei et al. reported a simple procedure for synthesis of polysubstituted pyrroles 20a–m by the three-component reaction of amines 9, phenacyl bromide 18 and dialkyl acetylenedicarboxylates 19 under solvent free conditions using nano structures of ZnO as catalyst (Scheme 7, Table 7).²⁸

Scheme 7

Table 7 Synthesis of polysubstituted pyrroles 20a–m

Entry	R^1	R^2	R^3	Product	Yield (%)
1	Et	C6H5	COOMe	20a	90
2	Et	C6H5	COOEt	20b	88
3	Bn	C6H5	COOMe	20c	90
4	Bn	C6H5	COOEt	20d	94
5	4-ClC6H2–CH2–	C6H5	COOEt	20e	92
6	4-MeC6H2–CH2–	C6H5	COOEt	20f	86
7	^nHexyl	C6H5	COOMe	20g	92
8	^nHexyl	C6H5	COOEt	20h	86
9	Et	4-MeOC6H4	COOEt	20i	75
10	Et	4-ClC6H4	COOMe	20j	78
11	C6H5	C6H5	COOEt	20k	0
12	4-MeOC6H5	C6H5	COOEt	20l	0
13	^nHexyl	COOEt	COOMe	20m	0

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ZnO nano particles catalyze the reaction through its Lewis acid sites (Zn²⁺) and Lewis basic sites (O²⁻).^29,30 In this reaction, the Zn²⁺ sites are interacting with carbonyl groups in acetylenic compound and phenacyl bromide and Lewis basic sites [O²⁻ ] taking up a proton from the generated enamine to give the pyrrole structure.

A magnetic nanoparticle CoFe₂O₄ supported molybdenum catalyst ([CoFe₂O₄@SiO₂-PrNH₂-Mo(acac)₂]), (Fig. 5), was prepared and found to be a highly active and efficient catalyst for a one-pot synthesis of polysubstituted pyrroles 22a–aq via a four-component reaction of aldehydes 7, amines 9, 1,3-dicarbonyl compounds 15 and nitromethane 21 (Scheme 8, Table 8). The catalyst could be easily recovered by simple magnetic decantation and reused five times without significant loss of activity.³¹

Fig. 5 Structure of a magnetic nanoparticle CoFe₂O₄ supported molybdenum catalyst ([CoFe₂O₄@SiO₂-PrNH₂-Mo(acac)₂]).

Scheme 8

Table 8 One-pot synthesis of polysubstituted pyrroles 22a–aq

Entry	R^1	R^2	R^3	R^4	Product	Yield (%)
1	C6H5	Me	Me	C6H5	22a	90
2	4-MeOC6H4	Me	Me	C6H5	22b	86
3	4-MeC6H4	Me	Me	C6H5	22c	92
4	4-FC6H4	Me	Me	C6H5	22d	90
5	4-ClC6H4	Me	Me	C6H5	22e	80
6	4-BrC6H4	Me	Me	C6H5	22f	82
7	4-O2NC6H4	Me	Me	C6H5	22g	50
8	4-F3COC6H4	Me	Me	C6H5	22h	80
9	1-Naphthyl	Me	Me	C6H5	22i	48
10	2-Fluorenyl	Me	Me	C6H5	22j	83
11	Allyl	Me	Me	C6H5	22k	88
12	Bn	Me	Me	C6H5	22l	90
13	4-MeC6H4–CH2–	Me	Me	C6H5	22m	91
14	4-FC6H4–CH2–	Me	Me	C6H5	22n	87
15	C6H4–CH2–CH2–	Me	Me	C6H5	22o	91
16	4-HOC6H4–CH2–CH2–	Me	Me	C6H5	22p	90
17	^cPr	Me	Me	C6H5	22q	90
18	^cPn	Me	Me	C6H5	22r	86
19	^nPr	Me	Me	4-FC6H4	22s	90
20	C6H5	Me	Me	4-(Me2)CHOC6H4	22t	81
21	C6H5	Me	Me	4-FC6H4	22u	87
22	C6H5	Me	Me	4-ClC6H4	22v	86
23	C6H5	Me	Me	4-BrC6H4	22w	85
24	C6H5	Me	Me	4-O2NC6H4	22x	83
25	C6H5	Me	Me	4-F3CC6H4	22y	85
26	C6H5	Me	Me	2-Furyl	22z	60
27	C6H5	Me	Me	2-Thienyl	22aa	71
28	C6H5	Me	Me	1-Naphthyl	22ab	80
29	4-MeC6H4–CH2–	Me	Me	2-Thienyl	22ac	80
30	4-FC6H4	Me	Me	2-Thienyl	22ad	75
31	4-FC6H4	Me	Me	2-(5-Methylthienyl)	22ae	78
32	4-ClC6H4	Me	Me	2-(5-Methylthienyl)	22af	70
33	2-Fluorenyl	Me	Me	2-(5-Methylthienyl)	22ag	80
34	Bn	Me	Me	2-Thienyl	22ah	80
35	C6H4–CH2–CH2–	Me	Me	4-MeC6H4	22ai	88
36	C6H4–CH2–CH2–	Me	Me	4-FC6H4	22aj	89
37	C6H4–CH2–CH2–	Me	Me	3-F3CC6H4	22ak	85
38	^cPr	Me	Me	4-^tBuC6H4	22al	88
39	C6H5	Me	OMe	C6H5	22am	80
40	C6H5	Me	OEt	C6H5	22an	82
41	C6H5	Me	O(CH2)2OMe	C6H5	22ao	80
42	C6H5	Me	O-Allyl	C6H5	22ap	78
43	C6H5	Et	OMe	C6H5	22aq	80

---

2.1.2. Five-membered rings with two heteroatoms.
2.1.2.1. Pyrazole. Emtiazi et al. developed a convenient and direct approach for the preparation of pyrazole derivatives 24a–q in good yields by condensing 1,3-diketones 15 and hydrazines 23 in the presence of nano-silica sulfuric acid. Investigation was made of a series of aromatic hydrazines bearing either electron-donating or electron-withdrawing groups on the aromatic ring (Scheme 9, Table 9, Method A). The substitution group on the phenyl ring did not affect the reaction significantly neither in the product yield nor in the reaction rate.³²

Scheme 9

Table 9 Preparation of pyrazole derivatives 24a–y by Methods A and B

Entry	R^1	R^2	R^3	R^4	Product	Method	Yield (%)
1	2,4-(O2N)2–C6H3	Me	H	Me	24a	A	85
2	2,4-(O2N)2–C6H3	C6H5	H	Me	24b	A	92
3	2,4-(O2N)2–C6H3	C6H5	H	C6H5	24c	A	92
4	2,4-(O2N)2–C6H3	Me	Cl	Me	24d	A	89
5	C6H5	C6H5	H	C6H5	24e	A	93
6	C6H5	Me	Cl	Me	24f	A	93
7	H	C6H5	H	Me	24g	A	87
8	4-BrC6H4	Me	Cl	Me	24h	A	94
9	4-BrC6H4	C6H5	H	C6H5	24i	A	90
10	4-BrC6H4	C6H5	H	Me	24j	A	92
11	4-MeC6H4	C6H5	H	C6H5	24k	A	87
12	4-MeC6H4	C6H5	H	Me	24l	A	89
13	4-MeOC6H4	C6H5	H	C6H5	24m	A	74
14	4-MeOC6H4	C6H5	H	Me	24n	A	88
15	4-MeC6H4SO2	Me	H	Me	24o	A	83
16	4-MeC6H4SO2	C6H5	H	C6H5	24p	A	83
17	4-MeC6H4SO2	C6H5	H	Me	24q	A	84
18	C6H5	Me	H	Me	24r	B	96
19	C6H5	Me	Cl	Me	24s	B	80
20	C6H5	Me	Et	Me	24t	B	84
21	4-ClC6H4	Me	H	Me	24u	B	82
22	4-ClC6H4	Me	Cl	Me	24v	B	78
23	4-ClC6H4	Me	Et	Me	24w	B	84
24	C6H5CO	Me	H	Me	24x	B	88
25	2-Furoyl	Me	H	Me	24y	B	84

---

Various hydrazines and hydrazides reacted also efficiently with 1,3-diketones in the presence of supported glutathione on magnetic nanoparticles (Fig. 2) under microwave irradiation to give the pyrazoles 24r–y in good yields (Scheme 9, Table 9, Method B).²⁴

2.1.2.2. Imidazole. Nano-SnCl₄·SiO₂ as a solid Lewis acid has been synthesized by the reaction of nano-SiO₂ and SnCl₄. The catalyst has been found to be an extremely efficient catalyst for the preparation of 2,4,5-trisubstituted imidazoles 26 via three-component reactions of benzyl 25, aldehydes 7 and ammonium acetate under mild conditions (Scheme 10, Table 10, Method A). Furthermore, the catalyst could be recovered conveniently and reused for at least three times.³³

Scheme 10

Table 10 Preparation of 2,4,5-trisubstituted imidazoles 26a–ad by Methods A–G^a

Entry	R^1	R^2	Product	Method	Yield (%)
a In Method B MW yields% were indicated between parentheses.
1	C6H5	H	26a	A	95
2	4-MeC6H4	H	26b	A	83
3	4-O2NC6H4	H	26c	A	96
4	4-ClC6H4	H	26d	A	95
5	2-MeOC6H4	H	26e	A	80
6	4-MeOC6H4	H	26f	A	85
7	2-ClC6H4	H	26g	A	89
8	2,4-Cl2C6H4	H	26h	A	91
9	4-BrC6H4	H	26i	A	92
10	2-O2NC6H4	H	26j	A	87
11	3-O2NC6H4	H	26k	A	93
12	2-BrC6H4	H	26l	A	90
13	C6H5	H	26a	B	85(96)
14	4-MeC6H4	H	26b	B	87(99)
15	3-MeC6H4	H	26m	B	76(95)
16	4-MeC6H4	H	26b	B	82(98)
17	4-ClC6H4	H	26d	B	78(95)
18	3-ClC6H4	H	26n	B	83(95)
19	4-BrC6H4	H	26i	B	88(93)
20	3-BrC6H4	H	26o	B	78(95)
21	2-Naphthyl	H	26p	B	77(94)
22	2,4-Cl2C6H3	H	26q	B	79(94)
23	2-Thienyl	H	26r	B	75(95)
24	3-O2NC6H4	H	26k	B	85(93)
25	4-Me2NC6H4	H	26s	B	77(96)
26	2-HOC6H4	H	26t	B	85(93)
27	3-HOC6H4	H	26u	B	90(93)
28	C6H5	H	26a	C	90
29	4-Me2NC6H4	H	26s	C	91
30	4-MeOC6H4	H	26f	C	92
31	2-MeOC6H4	H	26e	C	89
32	2-ClC6H4	H	26g	C	88
33	4-ClC6H4	H	26d	C	89
34	2,4-Cl2C6H3	H	26q	C	84
35	4-BrC6H4	H	26i	C	89
36	2-O2NC6H4	H	26j	C	85
37	3-O2NC6H4	H	26k	C	87
38	4-O2NC6H4	H	26c	C	89
39	4-MeC6H4	H	26b	C	—
40	C6H5	H	26a	D	95
41	4-MeOC6H4	H	26f	D	90
42	3-MeOC6H4	H	26v	D	92
43	4-ClC6H4	H	26d	D	96
44	3-MeOC6H4	H	26v	D	98
45	2-Naphthyl	H	26p	D	98
46	3-MeOC6H4	H	26v	D	98
47	C6H5	OMe	26w	D	95
48	4-MeOC6H4	OMe	26x	D	90
49	2-Naphthyl	OMe	26y	D	95
50	3-MeOC6H4	F	26vz	D	98
51	2-Naphthyl	F	26aa	D	98
52	C6H5	H	26a	E	87
53	4-ClC6H4	H	26d	E	92
54	4-BrC6H4	H	26i	E	81
55	4-O2NC6H4	H	26c	E	80
56	4-HOC6H4	H	26ab	E	82
57	4-MeC6H4	H	26b	E	93
58	4-MeOC6H4	H	26f	E	85
59	C6H5	H	26a	F	100
60	4-ClC6H4	H	26d	F	99
61	4-MeOC6H4	H	26f	F	98
62	4-HOC6H4	H	26ac	F	80
63	4-Me2NC6H4	H	26s	F	93
64	3-O2NC6H4	H	26k	F	87
65	2-HOC6H4	H	26t	F	80
66	C6H5	H	26a	G	98
67	3-O2NC6H4	H	26k	G	79
68	4-MeC6H4	H	26b	G	88
69	2-ClC6H4	H	26g	G	95
70	4-ClC6H4	H	26d	G	86
71	3,4-Cl2C6H3	H	26ad	G	83
72	4-MeOC6H4	H	26f	G	85
73	2-MeOC6H4	H	26e	G	78

---

Safari and Zarnegar also synthesized trisubstituted imidazoles 26 in high yield in the presence of sulphamic acid functionalized magnetic Fe₃O₄ nanoparticles (SA–MNPs, Fig. 6) as a novel solid acid catalyst. The reaction proceeds via a three component reaction of benzil 25, aromatic aldehyde 7 and ammonium acetate under solvent-free classical heating conditions or using microwave irradiation (Scheme 10, Table 10, Method B). The heterogeneous catalyst could be recovered easily and reused many times without significant loss of catalytic activity.³⁴

Fig. 6 Structure of sulphamic acid functionalized magnetic Fe₃O₄ nanoparticles.

Nano-TiCl₄·SiO₂ has been found to be an extremely efficient catalyst for the preparation of 2,4,5-trisubstituted imidazoles 26 via similar three-component reactions (Scheme 10, Table 10, Method C). Nano-TiCl₄·SiO₂ as a solid Lewis acid has been synthesized by reaction of nano-SiO₂ and TiCl₄.³⁵

Zarnegar and Safari prepared chitosan-coated Fe₃O₄ nanoparticles (Fe₃O₄@CS, Fig. 7) through in situ co-precipitation of Fe²⁺ and Fe³⁺ ions via NH₄OH in an aqueous solution of chitosan and investigated their catalytic activity in the synthesis of 2,4,5-trisubstituted imidazoles 26 by a similar one-pot reaction (Scheme 10, Table 10, Method D).³⁶

Fig. 7 Structure of chitosan-coated Fe₃O₄ nanoparticles.

Teimouri and Chermahini reported a synthesis of 2,4,5-trisubstituted imidazoles 26 by a similar three components cyclocondensation reaction using nano-crystalline sulfated zirconia (SZ) as catalyst in ethanol at moderate temperature (Scheme 10, Table 10, Method E). It can be seen that electron donating and electron withdrawing groups does not show any difference on the reaction yields.³⁷

Sulfonic acid functionalized SBA-15 nanoporous material (SBA-Pr–SO₃H) with a pore size of 6 nm was found to be a green and effective solid acid catalyst in the one-pot synthesis of 2,4,5-trisubstituted imidazoles 26 under solvent-free conditions (Scheme 10, Table 10, Method F).³⁸

Keivanloo et al. used boehmite nanoparticles (AlOOH NPs) as a highly active and green catalyst for the synthesis of highly substituted imidazoles 26 under solvent-free conditions (Scheme 10, Table 10, Method G).³⁹

Teimouri and Chermahinib reported a versatile and efficient synthesis of 1,2,4,5-tetrasubstituted imidazoles 27 in high yields by four component cyclocondensation of benzyl 25, aniline 9, ammonium acetate and various aromatic aldehydes 7 using nano-crystalline sulfated zirconia (SZ) as a catalyst in ethanol at moderate temperature (Scheme 11, Table 11, Method A).³⁷

Scheme 11

Table 11 Synthesis of 1,2,4,5-tetrasubstituted imidazoles 27a–ay by Methods A–F

Entry	R^1	R^2	R^3	Method	Product	Yield (%)
1	C6H5	C6H5	H	A	27a	87
2	4-ClC6H4	C6H5	H	A	27b	92
3	4-BrC6H4	C6H5	H	A	27c	85
4	4-O2NC6H4	C6H5	H	A	27d	76
5	4-HOC6H4	C6H5	H	A	27e	85
6	4-MeC6H4	C6H5	H	A	27f	87
7	4-MeOC6H4	C6H5	H	A	27g	80
8	4-ClC6H4	C6H5	H	B	27b	100
9	4-ClC6H4	Bn	H	B	27h	100
10	4-MeOC6H4	C6H5	H	B	27g	97
11	4-MeC6H4	C6H5	H	B	27f	99
12	4-MeC6H4	Bn	H	B	27i	95
13	4-Me2NC6H4	Bn	H	B	27j	99
14	3-O2NC6H4	C6H5	H	B	27k	95
15	3-MeOC6H4	Bn	H	B	27l	84
16	C6H5	C6H5	H	C	27a	94
17	C6H5	Bn	H	C	27m	92
18	4-O2NC6H4	4-MeC6H4	H	C	27n	80
19	4-ClC6H4	C6H5	H	C	27b	85
20	4-MeC6H4	Bn	H	C	27i	75
21	4-MeC6H4	C6H5	H	C	27f	91
22	4-ClC6H4	4-O2NC6H4	H	C	27o	79
23	4-O2NC6H4	Bn	H	C	27p	81
24	4-MeC6H4	Bn	H	C	27i	87
25	4-ClC6H4	Bn	H	C	27h	82
26	4-MeOC6H4	C6H5	H	C	27g	92
27	4-MeOC6H4	Bn	H	C	27q	93
28	C6H5	Me	H	C	27r	80
29	C6H5	C6H5	H	D	27a	82
30	C6H5	Bn	H	D	27m	84
31	C6H5	^cHexyl	H	D	27s	64
32	C6H5	Et	H	D	27t	70
33	4-ClC6H4	C6H5	H	D	27b	81
34	4-ClC6H4	Bn	H	D	27h	79
35	2-ClC6H4	Bn	H	D	27u	83
36	4-HOC6H4	Bn	H	D	27v	68
37	4-MeC6H4	C6H5	H	D	27f	73
38	4-MeC6H4	Bn	H	D	27i	91
39	4-MeC6H4	^cHexyl	H	D	27w	75
40	3-MeOC6H4	Bn	H	D	27l	91
41	2-O2NC6H4	Bn	H	D	27x	86
42	^iPr	Bn	H	D	27y	60
43	C6H5	C6H5	H	E	27a	94
44	C6H5	Bn	H	E	27m	96
45	4-MeC6H4	C6H5	H	E	27f	86
46	4-ClC6H4	C6H5	H	E	27b	92
47	C6H5	3-ClC6H4	H	E	27z	93
48	4-O2NC6H4	C6H5	H	E	27d	78
49	C6H5	^cHexyl	H	E	27s	89
50	C6H5	4-O2NC6H4	H	E	27aa	80
51	C6H5	^nPr	H	E	27ab	88
52	C6H5	MeOCH2CH2–	H	E	27ac	90
53	C6H5	^iPr	H	E	27ad	85
54	C6H5	^nBu	H	E	27ae	86
55	C6H5	2-THF–CH2–	H	E	27af	78
56	4-O2NC6H4	3,4-Me2C6H3	H	F	27ag	96
57	3-O2NC6H4	3,4-Me2C6H3	H	F	27ah	96
58	4-NCC6H4	3,4-Me2C6H3	H	F	27ai	94
59	4-MeOC6H4	4-MeC6H4	H	F	27aj	94
60	3-O2NC6H4	3-MeC6H4	H	F	27ak	95
61	4-BrC6H4	4-MeOC6H4	H	F	27al	94
62	3-O2NC6H4	3-MeOC6H4	H	F	27am	91
63	4-NCC6H4	4-MeC6H4	H	F	27an	92
64	4-MeOC6H4	3,4-Me2C6H3	H	F	27ao	88
65	4-O2NC6H4	Bn	Cl	F	27ap	96
66	4-O2NC6H4	3,4-Me2C6H3	Cl	F	27aq	97
67	3-O2NC6H4	3,4-Me2C6H3	Cl	F	27ar	97
68	4-O2NC6H4	3,4-Me2C6H3	Me	F	27as	85
69	^nPr	^cHexyl	H	F	27at	78
70	4-BrC6H4	^cHexyl	H	F	27au	95
71	4-MeOC6H4	^cHexyl	H	F	27av	89
72	4-Pyridyl	3,4-Me2C6H3	H	F	27aw	83
73	3-O2NC6H4	3-O2NC6H4	H	F	27ax	91
74	4-ClC6H4	3,4-Me2C6H3	H	F	27ay	97

---

Ziarani et al. used sulfonic acid functionalized SBA-15 nanoporous material (SBA-Pr–SO₃H) with a pore size of 6 nm as an effective catalyst in the synthesis of a variety of tetrasubstituted imidazoles 27 (Scheme 11, Table 11, Method B).³⁸

Montazeri et al. reported also a four-component synthesis of 1,2,4,5-tetrasubstituted imidazoles 27 using nano Fe₃O₄ as magnetically recyclable catalyst under solvent free conditions (Scheme 11, Table 11, Method C).⁴⁰

Mirjalili et al. applied nano-TiCl₄ ·SiO₂ (Fig. 8) as an efficient catalyst for synthesis of 1,2,4,5-triphenylimidazoles 27 with good to excellent yields via a similar four-component reaction (Scheme 11, Table 11, Method D).⁴¹

Fig. 8 Structure of nano-TiCl₄·SiO₂.

Keivanloo et al. reported the synthesis of 1,2,4,5-tetrasubstituted imidazoles 27 catalyzed by oboehmite nanoparticles (AlOOH NPs) under solvent-free conditions (Scheme 11, Table 11, Method E). The results show that the reactions are equally facile with both electron donating and electron-withdrawing substituents present on both the aromatic aldehydes 7 and aromatic amines 9, resulting in good-to high yields of the corresponding imidazoles 27. Aliphatic amines also reacted efficiently, affording the desired products in 78–90% yield.³⁹

Ray et al. prepared a porous silica nano particle (PSNP-CA, Fig. 9), by post synthesis grafting of COOH functionalized organosilane on porous silica nano particle by using surface hydroxyl groups as anchor point. This catalyst was found to promote the chemoselective synthesis of 1,2,4,5-tetrasubstituted imidazole 27 in water during a similar four multi-component reaction (Scheme 11, Table 11, Method F).⁴²

Fig. 9 Structure of functionalized organosilane on porous silica nano particle.

Mitra et al. have explored the use of nano In₂O₃ as an effective and versatile catalyst for the synthesis of 4,5-unsymmetrically substituted 1H-imidazoles 26ae-ap in good yields. The reaction was performed by the reaction of varying amidines 28 with a wide range of structurally diverse nitroolefins 29 (Scheme 12, Table 12). As it is evident from Table 12, this procedure is uniformly effective for nitroolefins with different substituents on the benzene ring as well as for aliphatic nitroolefin.⁴³ Based on previous results, the indium(III) catalyst promotes Michael addition of amidine–nitroolefin by activating the double bond.⁴⁴

Scheme 12

Table 12 Synthesis of 4,5-unsymmetrically substituted 1H-imidazoles 26ae–ap

Entry	R^1	R^2	R^3	Product	Yield (%)
1	C6H5	Me	C6H5	26ae	88
2	C6H5	Me	4-MeOC6H4	26af	80
3	C6H5	Me	4-ClC6H4	26ag	70
4	C6H5	Me	4-MeC6H4	26ah	80
5	C6H5	Me	4-BrC6H4	26ai	72
6	C6H5	Me	^iPr	26aj	65
7	C6H5	Me	3,4-CH2O2C6H3	26ak	81
8	C6H5	Me	2-Furyl	26al	79
9	C6H5	Et	C6H5	26am	70
10	3-O2NC6H4	Me	C6H5	26an	75
11	3-O2NC6H4	Me	4-MeOC6H4	26ao	82
12	Me	Me	C6H5	26ap	55

---

2.1.2.3. Thiazole. A magnetically ionic liquid supported on Fe₃O₄@SiO₂ nanoparticles (MNPs@SiO₂–IL, Fig. 10) was synthesized and evaluated as a recoverable catalyst for the one-pot synthesis of 1,3-thiazolidin-4-ones 31a–j in high to excellent yield by the three-component condensation of arylaldehydes 7, anilines 9 and thioglycolic acid 30 under solvent-free conditions (Scheme 13, Table 13).⁴⁵ It can be speculated that the methylimidazolium cation [MIM]⁺ in the MNPs@SiO₂–IL favors the interact on oxygen atom of the carbonyl group of the aldehyde and facilitates the formation of imine intermediate by increasing the electrophilicity of the carbonyl group of the aldehyde.

Fig. 10 Structure of a magnetically ionic liquid supported on Fe₃O₄@SiO₂ nanoparticles.

Scheme 13

Table 13 One-pot synthesis of 1,3-thiazolidin-4-ones 31a–j

Entry	R^1	R^2	Product	Yield (%)
1	C6H5	C6H5	31a	94
2	C6H5	4-MeC6H4	31b	90
3	C6H5	4-ClC6H4	31c	90
4	C6H5	4-O2NC6H4	31d	86
5	4-MeC6H4	4-MeC6H4	31e	93
6	4-MeC6H4	C6H5	31f	88
7	4-ClC6H4	C6H5	31g	95
8	4-O2NC6H4	C6H5	31h	92
9	4-O2NC6H4	4-MeC6H4	31i	90
10	3-O2NC6H4	C6H5	31j	89

---

2.1.3. Five-membered rings with three heteroatoms.
2.1.3.1. Oxadiazole. 4,5,6,7-Tetrahydro-6-((5-substituted-1,3,4-oxadiazol-2-yl)methyl)thieno[2,3-c]pyridines 33a–m have been prepared by subjecting hydrazide compound 32 and different aromatic aldehydes 7 to reflux in ethanol using combined nano (ZnO–TiO₂) (1 mmol each) as a catalyst (Scheme 14, Table 14).⁴⁶

Scheme 14

Table 14 Synthesis of tetrahydrothieno[2,3-c]pyridines 33a–m

Entry	R^1	Product	MW yield (%)	Δ yield (%)
1	4-ClC6H4	33a	96	91
2	C6H5	33b	91	88
3	4-MeOC6H4	33c	95	91
4	C6H5	33d	91	87
5	3,4-(HO)2C6H3	33e	95	91
6	2,6-Cl2C6H4	33f	91	88
7	2,4-(MeO)2C6H3	33g	94	90
8	4-HOC6H4	33h	94	89
9	2-Pyrrolyl	33i	95	87
10	2-Thienyl	33j	94	88
11	4-FC6H4	33k	94	90
12	2,4-Cl2C6H4	33l	92	89
13	2-Pyridyl	33m	95	87

---

2.1.3.2. 1,2,3-Triazole. Kaboudin et al. reported the synthesis of 1,2,3-triazoles 36a–q via a one-pot reaction of arylboronic acids 34 with sodium azide in water at room temperature in the presence of Cu₂–β-CD (CD = cyclodextrin) as a nanocatalyst followed by a click cyclization reaction with alkynes 35 (Scheme 15, Table 15).⁴⁷

Scheme 15

Table 15 Synthesis of 1,2,3-triazoles 36a–q

Entry	Ar	R	Product	Yield (%)
1	C6H5	C6H5	36a	94
2	2-FC6H5	C6H5	36b	94
3	3-O2NC6H4	C6H5	36c	95
4	3,5-F2C6H4	C6H5	36d	96
5	4-MeC6H4	C6H5	36e	94
6	4-MeOC6H4	C6H5	36f	97
7	4-ClC6H5	C6H5	36g	96
8	4-HOC6H4	C6H5	36h	94
9	2-Naphthyl	C6H5	36i	94
10	C6H5	4-MeC6H4	36j	95
11	C6H5	3-NH2C6H4	36k	95
12	C6H5	^nPr	36l	93
13	C6H5	^nBu	36m	89
14	C6H5	^nPn	36n	91
15	C6H5	CH2OH	36o	92
16	C6H5	CH3(CH2)3–CH(OH–)	36p	90
17	C6H5	COOH	36q	94

---

The authors proposed mechanism for Cu₂–β-CD catalyzed in situ azidation of arylboronic acids 34 for the synthesis of 1,2,3-triazoles 36a–q. The reaction is initiated by transmetallation of the aryl group from Boron to copper via the attack of the hydroxide ligand to the oxophilic boron center. The resulting arylcopper intermediate undergoes subsequent reductive azidation to the arylazide compound (Fig. 11). According to literature reports for the Cu-catalyzed azide–alkyne 1,3-dipolar cycloaddition,⁴⁸ the 1,2,3-triazole formation proceeds through attack of the hydroxido ligand of Cu₂–β-CD complex to the terminal hydrogen of acetylene to give copper acetylide. Continuing, coordination of the arylazide to the copper center of the acetylide initiates an azide–alkyne 1,3-dipolar cycloaddition.

Fig. 11 Mechanism for in situ azidation of arylboronic acids for the synthesis of 1,2,3-triazoles catalyzed by Cu₂–β-CD.

Kamal and Swapna developed a new Fe₂O₃ nanoparticle catalyzed three-component reaction for the construction of 2,4,5-trisubstituted-1,2,3-triazoles 39a–x from chalcones 37, sodium azide and aryl halides 38. This tandem three-component reaction involves an oxidative 1,3-dipolar cycloaddition of the chalcone and azide and subsequent regioselective N-2-arylation (Scheme 16, Table 16). Control experiments suggest that atmospheric oxygen acts as the sacrificial oxidant in the reaction. The reaction has good substrate scope and furnishes the products in very good yields. Importantly, the catalyst is easily recoverable and may be reused without any significant loss in catalytic activity.⁴⁹

Scheme 16

Table 16 Synthesis of 2,4,5-trisubstituted-1,2,3-triazoles 39a–x

Entry	R^1	R^2	R^3	X	Product	Yield (%)
1	2-FC6H4	2-FC6H4	2-O2NC6H4	F	39a	92
2	4-FC6H4	3-CF3C6H4	2-O2NC6H4	F	39b	90
3	4-O2NC6H4	C6H5	2-O2NC6H4	F	39c	89
4	3-F-4-ClC6H3	4-FC6H4	2-O2NC6H4	F	39d	80
5	4-CF3C6H4	4-FC6H4	2-O2NC6H4	F	39e	80
6	4-MeC6H4	C6H5	2-O2NC6H4	F	39f	75
7	C6H5	4-MeOC6H4	2-O2NC6H4	F	39g	65
8	4-MeC6H4	3-ClC6H4	2-O2NC6H4	F	39h	70
9	4-MeOC6H4	4-FC6H4	2-O2NC6H4	F	39i	75
10	3-MeO-4-FC6H3	4-FC6H4	2-O2NC6H4	F	39j	72
11	4-MeOC6H4	4-FC6H4	2-F-4-O2NC6H3	F	39k	62
12	4-MeC6H4	3-ClC6H4	2-F-4-O2NC6H3	F	39l	59
13	4-MeOC6H4	4-FC6H4	2,4-(O2N)2C6H3	Cl	39m	70
14	4-MeC6H4	3-ClC6H4	2-O2NC6H4	Cl	39n	68
15	4-^iPrC6H4	C6H5	2-O2NC6H4	F	39o	62
16	2-MeC6H4	C6H5	2-F-4-O2NC6H3	F	39p	69
17	2-MeC6H4	C6H5	2-F-4-O2NC6H3	F	39q	65
18	4-O2NC6H4	C6H5	2-F-4-O2NC6H3	F	39r	86
19	4-FC6H4	4-FC6H4	2-F-2,4-(O2N)2C6H2	F	39s	93
20	2-Thienyl	C6H5	2-O2NC6H4	F	39t	—
21	2-Pyrrolyl	C6H5	2-O2NC6H4	F	39u	—
22	2-MeC6H4	C6H5	2-O2NC6H4	Cl	39v	—
23	4-FC6H4	4-FC6H4	4-O2NPyridyl	Cl	39w	—
24	2-MeC6H4	C6H5	2-MeC6H4	Cl	39x	—

---

Wang et al. prepared nanoparticle-supported tris(triazolyl)–CuBr (Fig. 12), with a diameter of approximately 25 nm and evaluated its catalytic activity in the copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction (Scheme 17, Table 17, Method A). It was found that the procedure can be successfully extended to various organic azides and alkynes to afford the corresponding 1H-1,2,3-triazoles 41a–q.⁵⁰

Fig. 12 Structure of nanoparticle-supported tris(triazolyl)–CuBr.

Scheme 17

Table 17 Synthesis of 2,4,5-trisubstituted-1,2,3-triazoles 41a-bi by Methods A–D^ab

Entry	R^1	R^2	Method	Product	Yield (%)
a .b The dimeric acetylene was the main product.
1	C6H5	C6H13	A	41a	95
2	C6H5	C8H17	A	41b	91
3	C6H5	C18H32	A	41c	82
4	C6H5	C6H5	A	41d	92
5	C6H5	4-MeOC6H4	A	41e	83
6	C6H5	4-IC6H4	A	41f	81
7	C6H5	Bn	A	41g	96
8	4-CHOC6H4	Bn	A	41h	96
9	4-MeOC6H4	Bn	A	41i	94
10	4-NH2OC6H4	Bn	A	41j	92
11	2-Pyridyl	Bn	A	41k	86
12	3-Pyridyl	Bn	A	41l	92
13	C4H9	Bn	A	41m	99
14	C5H11	Bn	A	41n	93
15	HO–C(CH3)	Bn	A	41o	89
16	HO–C(C6H5)	Bn	A	41p	93
17	Ferrocenyl	Bn	A	41q	96
18	C6H5	PhOCH2CH(OH)CH2–	B	41r	93
19	C6H5	2-HOC6H10–	B	41s	92
20	C6H5	CH2=C(Me)COOCH2CH(OH)CH2–	B	41t	83
21	4-ClC6H4OCH2	2,4-Cl2C6H3OCH2CH(OH)CH2–	B	41u	80
22	4-ClC6H4OCH2	4-BnC6H4OCH2CH(OH)CH2–	B	41v	81
23	Me2C(OH)	4-MeOC6H4OCH2CH(OH)CH2–	B	41w	85
24	Me2C(OH)	PhOCH2CH(OH)CH2–	B	41x	91
25	Me2C(OH)	4-MeOC6H4OCH2CH(OH)CH2–	B	41y	93
26	HOCH2	PhOCH2CH(OH)CH2–	B	41z	88
27	BrCH2	4-ClC6H4OCH2CH(OH)CH2–	B	41aa	86
28	–A	4-MeOC6H4OCH2CH(OH)CH2–	B	41ab	90
29	–A	MeCH2CH(OH)CH2–	B	41ac	88
30	–B	4-MeOC6H4OCH2CH(OH)CH2–	B	41ad	93
31	–B	2-C10H7CH2CH(OH)CH2–	B	41ae	92
32	–B	2-HOC6H10–	B	41af	83
33	Ph–C≡CPh	2-HOC6H10–	B	41ag	—
34	–B	C10H7OCH2CH(OH)CH2–	C	41ah	93
35	–B	4-MeOC6H4OCH2CH(OH)CH2–	C	41ai	92
36	–A	4-MeOC6H4OCH2CH(OH)CH2–	C	41aj	83
37	–A	4-Cl-3-MeC6H3OCH2CH(OH)CH2–	C	41ak	80
38	–A	MeCH2CH(OH)CH2–	C	41al	81
39	–C	PhOCH2CH(OH)CH2–	C	41am	85
40	–D	^nBuOCH2CH(OH)CH2–	C	41an	91
41	–D	AllylOCH2CH(OH)CH2–	C	41ao	93
42	4-ClC6H4OCH2	2,4-Cl2C6H3OCH2CH(OH)CH2–	C	41ap	88
43	4-ClC6H4OCH2	4-BnC6H4OCH2CH(OH)CH2–	C	41aq	86
44	4-O2NC6H4OCH2	2-HOC6H10–	C	41ar	90
45	C6H5	PhOCH2CH(OH)CH2–	C	41as	88
46	C6H5	AllylOCH2CH(OH)CH2–	C	41at	87
47	Me2C(OH)	4-BnC6H4OCH2CH(OH)CH2–	C	41au	91
48	Me2C(OH)	PhOCH2CH(OH)CH2–	C	41av	90
49	–E	4-Cl-3-MeC6H3OCH2CH(OH)CH2–	C	41aw	—
50	C6H5	Bn	D	41g	98
51	C6H5	C6H5	D	41ax	97
52	C6H5	Me	D	41ay	92
53	C6H5	C3H7	D	41az	83
54	C6H5	C6H13	D	41ba	95
55	C6H5	C10H24	D	41bb	95
56	C6H5	C12H25	D	41bc	65
57	C6H5	C16H33	D	41bd	62
58	C6H5	C10H20N3	D	41be	60
59	Me2C(OH)	Bn	D	41bf	65
60	Me2C(OH)	C6H5	D	41bg	95
61	Me2C(OH)	C3H7	D	41bh	90
62	Me2C(OH)	C6H13	D	41bi	94

---

Rad et al. reported that the 1,3-dipolar cycloaddition of organic azides with terminal alkynes 35 can be catalyzed by doped nano-sized Cu₂O on melamine formaldehyde resin (nano-Cu₂O MFR) to furnish the corresponding 1,4-disubstituted 1H-1,2,3-triazole adducts 41s–ag in good to excellent yields at room temperature (Scheme 17, Table 17, Method B).⁵¹

Nano copper-doped silica cuprous sulfate (CDSCS), proved also to be a highly efficient heterogeneous catalyst for the regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles derivatives 41g and 41ah–bj. In this synthetic methodology, CDSCS catalyzes 1,3-dipolar Huisgen cycloaddition of different functionalized β-azido alcohols and alkynes in a (1 : 1, v/v) solution of THF/H₂O at room temperature (Scheme 17, Table 17, Method C). The catalyst can be easily prepared and reused for many consecutive runs without a significant decrease in its catalytic reactivity.⁵²

Veerakumar et al. used highly dispersed SiO₂ supported CuNPs (copper nanoparticles, Fig. 13) as a recyclable heterogeneous nanocatalyst to employ the synthesis of 1,4-disubstituted-1,2,3-triazoles 41az–bi via Huisgen 1,3-dipolar cycloaddition reactions of halides 38, alkynes 35, and sodium azide using DMSO as the solvent (Scheme 17, Table 17, Method D). All the reactions proceed smoothly to give 41 in high yield.⁵³

Fig. 13 Structure of highly dispersed SiO₂ supported copper nanoparticles.

Nanoparticle-supported tris(triazolyl)–CuBr, with a diameter of approximately 25 nm has been easily prepared, and its catalytic activity was evaluated in the copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction. The catalyst has been applied for the one-pot synthesis of triazoles 41, through a cascade reaction involving benzyl bromides 38, alkynes 35, and sodium azide (Scheme 18, Table 18, Method A).⁵⁴

Scheme 18

Table 18 One-pot synthesis of 1,2,3-triazoles 41a–dt by Methods A–D

Entry	R^1	R^2	X	Method	Product	Yield (%)
1	C6H5	2-BrC6H4CH2–	Br	A	41bj	88
2	C6H5	3-IC6H4CH2–	Br	A	41bk	87
3	C6H5	4-CNC6H4CH2–	Br	A	41bl	72
4	C6H5	4-O2NC6H4CH2–	Br	A	41bm	90
5	C6H5	3-MeC6H4CH2–	Br	A	41bn	98
6	C6H5	1-Me-4-C6H4triazolyl–	Br	A	41bo	83
7	C6H5	C6H4CH2–	Br	B	41bp	92
8	C6H5	4-HOC6H4CH2–	Br	B	41bq	93
9	C6H5	4-MeOC6H4CH2–	Br	B	41br	91
10	C6H5	3-O2NC6H4	Br	B	41bs	89
11	C6H5	C6H4CH2CH2–	Br	B	41bt	81
12	^nHexyl	C6H4CH2–	Br	B	41bu	72
13	COOEt	C6H4CH2–	Br	B	41bv	84
14	4-MeOC6H4	C6H4CH2–	Br	B	41i	91
15	4-MeC6H4	C6H4CH2–	Br	B	41bw	85
16	4-BrC6H4	C6H4CH2–	Br	B	41bx	78
17	C6H5	^cHexyl	Br	B	41by	70
18	C6H5	C6H4CH2–	Cl	B	41a	88
19	^cHexyl	4-MeOC6H4CH2–	Cl	B	41bz	80
20	C6H5	C6H4CH2–	Br	C	41bp	98
21	C6H5	C6H4CH2–	Cl	C	41ca	99
22	C6H5	4-NCC6H4CH2–	Br	C	41bp	99
23	C6H5	3,5-(MeO)2C6H3CH2–	Br	C	41bp	98
24	C6H5	C6H5CH=CHCH2–	Br	C	41cb	94
25	C6H5	C6H4COCH2–	Cl	C	41cc	82
26	C6H5	EtOOCCH2–	Br	C	41cd	98
27	C6H5	CH3(CH2)8–	I	C	41ce	98
28	C6H5	CH3(CH2)8–	Cl	C	41cf	94
29	C6H5	^cHexyl	Br	C	41cg	93
30	C6H5	Indol-3-yl–CH2CH2–	Br	C	41a	89
31	C6H5OCH2	C6H4CH2–	Br	C	41ch	76
32	N-Phthalimidyl-CH2	C6H4CH2–	Br	C	41ci	84
33	SiMe3	C6H4CH2–	Br	C	41cj	82
34	CH2CH2CH2C≡CH	C6H4CH2–	Br	C	41ck	87
35	C6H5	C6H4CH2–	Br	C	41g	98
36	C6H5	C6H4CH2–	Cl	C	41g	99
37	C6H5	4-NCC6H4CH2–	Br	C	41cbl	99
38	C6H5	3,5-(MeO)2C6H3CH2–	Br	C	41cm	98
39	C6H5	9-Anthracenyl–CH2–	Br	C	41cn	90
40	C6H5	C6H5CH=CHCH2–	Br	C	41co	94
41	C6H5	C6H4COCH2–	Cl	C	41cp	82
42	C6H5	EtOOCCH2–	Br	C	41cq	98
43	C6H5	CH3(CH2)8–	I	C	41cr	98
44	C6H5	CH3(CH2)8–	Cl	C	41cs	91
45	C6H5	^cHexyl	Br	C	41a	93
46	C6H5	Indol-3-yl-CH2CH2–	Br	C	41ct	89
47	C6H5OCH2	C6H4CH2–	Br	C	41cu	76
48	4-MeOC6H4	C6H4CH2–	Br	C	41i	90
49	Pyrid-2-yl	C6H4CH2–	Br	C	41k	92
50	N-Phthalimidyl-CH2	C6H4CH2–	Br	C	41cv	84
51	SiMe3	C6H4CH2–	Br	C	41cw	82
52	(CH2)5CH3	CH3(CH2)8–	I	C	41cx	92
53	(CH2)8CH3	^cHexyl	Br	C	41cy	89
54	3-(HC≡C)C6H4	C6H4CH2–	Br	C	41cz	92
55	(CH2)3C≡CH	C6H4CH2–	Br	C	41da	87
56	None	HC≡C–(CH2)4–	Cl	C	41db	89
57	C6H5	C6H5	N2^+BF4^−	C	41d	85
58	C6H5	4-MeOC6H4	N2^+BF4^−	C	41e	75
59	C6H5	4-MeOCC6H4	N2^+BF4^−	C	41de	71
60	C6H5	4-NCC6H4–	N2^+BF4^−	C	41df	78
61	C6H5	4-O2NC6H4–	N2^+BF4^−	C	41dg	92
62	4-MeOC6H4	4-O2NC6H4–	N2^+BF4^−	C	41dh	88
63	Pyrid-2-yl	4-O2NC6H4–	N2^+BF4^−	C	41di	91
64	4-F3CC6H4	4-O2NC6H4–	N2^+BF4^−	C	41dj	90
65	SiMe3	4-O2NC6H4–	N2^+BF4^−	C	41dk	83
66	C6H5	C6H5	N2^+BF4^−	C	41d	85
67	C6H5	C6H5	NH2	D	41d	90
68	C6H5	4-MeOC6H4	NH2	D	41dl	95
69	C6H5	2-ClC6H4	NH2	D	41dm	64
70	C6H5	3-ClC6H4	NH2	D	41dn	80
71	C6H5	4-ClC6H4	NH2	D	41do	78
72	C6H5	4-MeC6H4	NH2	D	41dp	90
73	C6H5	4-F3CC6H4	NH2	D	41dq	66
74	C6H5	1-Naphthyl	NH2	D	41dr	70
75	(CH2)3CH3	C6H5	NH2	D	41ds	93
76	^cHexyl	C6H5	NH2	D	41dt	89
77	C6H5	C6H5	NH2	D	41d	92
78	C6H5	C6H5	Oxiranyl	C	41d	92

---

A graphene based composite material with c-Fe₂O₃ (Fig. 14) nanoparticles has been synthesized via a simple chemical route and can also serves as an efficient catalyst for one-pot synthesis of a series of 1,4-disubstituted-1,2,3 triazoles 41 via reaction of halides 38, sodium azide and the corresponding alkynes 35 (Scheme 18, Table 18, Method B). It is noticeable that increase of electronic effect in the benzyl moiety increases the yield whereas it decreases with substrates containing electron deficient aromatic halides. The same observation is found when different alkynes are studied.⁵⁵

Fig. 14 Structure of a graphene based composite material with c-Fe₂O₃ nanoparticles.

Alonso et al. found that copper nanoparticles on activated carbon CuNPs/C can also effectively catalyze the multicomponent synthesis of 1,2,3-triazoles 41 from the reaction of different halides, diazonium salts or amines, with sodium azide and alkynes in water at a low copper loading (Scheme 18, Table 18, Method C).^56,57

The same group used CuNPs/C, at a low catalyst loading (0.5 mol%), to promote the multicomponent synthesis of 1,2,3-triazoles from phenylacetylene, sodium azide and epoxides (Scheme 18, Table 18, Method D, entry 78).^56,57

Alonso et al. applied also a new strategy in which the alkene 42 was directly mixed with the CuNPs/C, dimethyl(methylthio)-sulfonium tetrafluoroborate DMTSF, and NaN₃ in MeCN to produce the corresponding methylsulfanyl azide in only 1 h at room temperature. The subsequent reaction with the alkyne 35 afforded the triazole 41du which represent its synthesis from an alkene 42 in one pot for the first time (Scheme 19).⁵⁶

Scheme 19

2.2. Synthesis of six-membered heterocycles

2.2.1. Six-membered rings with one heteroatom.
2.2.1.1. 4H-Pyran. Commercially available nano-power magnetite or iron(III) oxide have been used as a catalyst in the construction of 4-substituted-4H-pyrans 43a–l from reaction of β-keto esters or other 1,3-dicarbonyl compound 15 with the corresponding aldehyde 7 (Scheme 20, Table 19). The reaction implies a tandem process, involving an aldol condensation, a Michael-type addition, and a dehydrating annulation. The isolated yields of pyrans 43a–l were similar independently of the aromatic aldehyde used, with electron-withdrawing groups, unsubstituted rings, or electron-donating groups being well tolerated.⁵⁸

Scheme 20

Table 19 Synthesis of 4-substituted-4H-pyrans 43a–l

Entry	R^1	Y	R^2	Product^a	Yield (%)
a Reaction carried out using compound 15 (2.5 mmol), 7 (1 mmol), in 3 mL of toluene during 3 h, unless otherwise stated. Yields obtained by Fe2O3 catalysis appeared in paranthesis.
1	Me	OMe	4-BrC6H4	43a	96 (94)
2	Me	OMe	4-NCC6H4	43b	79
3	Me	OMe	Ph	43c	85 (82)
4	Me	OMe	4-MeOC6H4	43d	83
5	Me	OMe	4-HOC6H4	43e	68
6	Me	OMe	2-naphthyl	43f	57
7	Me	OMe	(CH2)5CH	43g	80 (79)
8	Me	OMe	i-Pr	43h	72 (67)
9	Me	OEt	4-BrC6H4	43i	95
10	Me	OEt	4-MeOC6H4	43j	63
11	Me	Me	4-MeOC6H4	43k	75 (64)
12	Me	OMe	4-BrC6H4	43l	91 (79)

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2.2.1.2. Dihydropyridine. 1,4-Dihydropyridine derivatives 44a–o have been prepared efficiently in a one-pot synthesis via Hantzsch condensation using nanosized titanium dioxide as a heterogeneous catalyst. Thus, various aliphatic, aromatic, and heterocyclic aldehydes 7 underwent smooth cyclocondensation with ethyl acetoacetate and ammonium acetate to give 44a–o in good yields (Scheme 21, Table 20, Method A). The present methodology offers several advantages such as excellent yields, short reaction times (30–120 min) environmentally benign, and mild reaction conditions. The catalyst can be readily separated from the reaction products and recovered in excellent purity for direct reuse.⁵⁹

Scheme 21

Table 20 Synthesis 1,4-dihydropyridine derivatives 44a–q by Methods A and B

Entry	Ar	Products	Method	Yield^a (%)
a Isolated yield of the pure product based on aryl aldehyde.
1	C6H5	44a	A	92
2	4-BrC6H4	44b	A	89
3	4-ClC6H4	44c	A	90
4	3-ClC6H4	44d	A	86
5	2-ClC6H4	44e	A	80
6	4-O2NC6H4	44f	A	87
7	4-MeOC6H4	44g	A	81
8	4-HOC6H4	44h	A	93
9	4-CH3C6H4	44i	A	90
10	4-NCC6H4	44j	A	90
11	C6H5–CH=CH	44k	A	86
12	C7H5O	44l	A	92
13	2-Furyl	44m	A	50
14	2-Thienyl	44n	A	90
15	C6H12O	44o	A	95
16	C6H5	44a	B	85
17	4-BrC6H4	44b	B	88
18	4-ClC6H4	44c	B	90
19	4-HOC6H4	44h	B	83
20	4-MeOC6H4	44g	B	90
21	4-MeC6H4	44p	B	92
22	3-O2NC6H4	44q	B	78
23	4-O2NC6H4	44f	B	73

---

Mirzaei and Davoodnia used a microwave-assisted sol–gel method to synthesize nano-sized MgO particles using Mg(NO₃)₂·6H₂O as precursor and deionized water as solvent. The catalytic behavior of the catalyst was investigated in the one-pot synthesis of Hantzsch 1,4-dihydropyridines 44a–c, 44f–h, and 44p, 44q (Scheme 21, Table 20, Method B). The reaction proceeded in good to high yields from the reaction of aromatic aldehydes, ethylacetoacetate, and ammonium acetate.⁶⁰

A reaction mechanism is proposed and postulated that in MgO nanoparticles, there are acid-base bifunctional sites where Mg and O act as a weak Lewis acidic site and relatively high strength Brönsted basic site, respectively. These acid-base bifunctional sites facilitate the formation of arylidene and enamine intermediates that then react to give the final products.

2.2.1.3. Tetrahydropyridine. Eshghi et al. prepared a nanomagnetic organic–inorganic hybrid catalyst (Fe@Si–Gu-Prs, Fig. 15) by the chemical anchoring of Preyssler heteropolyacid (H₁₄[NaP₅W₃₀O₁₁₀]) onto the surface of modified Fe₃O₄ magnetic nanoparticles with guanidine-propyl-trimethoxysilane linker. The catalytical activity of this catalyst in the synthesis of tetrahydropyridine 45a–u was investigated. Thus, reaction of aldehydes 7, amines 9, and ethyl acetoacetate 15 using 0.025 g Fe@Si–GuPrs at room temperature and under solvent-free conditions afforded 45a–u in high yield (Scheme 22, Table 21). The results shown in Table 22 showed that aldehyde 7 and amine 9 compounds with substituents carrying either electron donating or electron-withdrawing groups reacted successfully and gave the expected products in excellent yields following short reaction times.⁶¹

Fig. 15 Structure of a nanomagnetic organic–inorganic hybrid catalyst (Fe@Si–Gu-Prs).

Scheme 22

Table 21 Synthesis of tetrahydropyridines 45a-u

Entry	R^1	R^2	Products	Yield (%)
1	C6H5	C6H5	45a	96
2	C6H5	4-BrC6H4	45b	94
3	C6H5	4-ClC6H4	45c	91
4	4-NCC6H4	C6H5	45d	92
5	4-NCC6H4	4-ClC6H4	45e	95
6	4-MeC6H4	4-MeC6H4	45f	95
7	4-MeC6H4	C6H5	45g	91
8	4-MeC6H4	4-BrC6H4	45h	92
9	4-MeC6H4	4-O2NC6H4	45i	95
10	4-MeC6H4	4-MeC6H4	45j	92
11	3-O2NC6H4	C6H5	45k	90
12	4-MeOC6H4	4-ClC6H4	45l	93
13	4-ClC6H4	4-BrC6H4	45m	90
14	4-ClC6H4	4-MeC6H4	45n	93
15	4-ClC6H4	C6H5	45o	91
16	4-MeOC6H4	4-MeC6H4	45p	92
17	4-MeOC6H4	C6H5	45q	90
18	4-MeOC6H4	4-BrC6H4	45r	94
19	C6H5	4-IC6H4	45s	91
20	4-ClC6H4	4-BrC6H4	45t	92
21	4-NCC6H4	4-BrC6H4	45u	91

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Table 22 One pot synthesis of pyridine dicarbonitriles 47a–r by Methods A and B

Entry	R^1	R^2	Method	Product	Yield^a^b (%)
a Method A Yields were analyzed by GC.b Method B yield refer to those of pure isolated products.
1	C6H5	4-MeC6H4	A	47a	82
2	4-ClC6H4	4-MeC6H4	A	47b	87
3	3-ClC6H4	4-MeC6H4	A	47c	85
4	4-BrC6H4	4-MeC6H4	A	47d	83
5	3-BrC6H4	4-MeC6H4	A	47e	83
6	3-O2NC6H4	4-MeC6H4	A	47f	81
7	4-O2NC6H4	4-MeC6H4	A	47g	82
8	4-MeOC6H4	4-MeC6H4	A	47h	85
9	C6H5	C6H5	B	47i	91
10	C6H5	4-ClC6H4	B	47j	81
11	C6H5	4-MeOC6H4	B	47k	79
12	C6H5	4-MeC6H4	B	47a	84
13	4-MeC6H4	C6H5	B	47l	81
14	4-ClC6H4	C6H5	B	47m	87
15	4-ClC6H4	4-MeC6H4	B	47b	80
16	2-Naphthyl	C6H5	B	47n	79
17	2-Pyridinyl	C6H5	B	47o	89
18	2-Phenylpropanal	C6H5	B	47p	88
19	Me	C6H5	B	47q	90
20	C6H5	n-Bu	B	47r	83

---

2.2.1.4. Pyridine. Pyridine dicarbonitriles 47 have been synthesized in good yields via a one-pot multi-component reaction of aldehydes 7, malononitrile 46, and thiols 30 in the presence of nano-TiO₂ as a catalyst in ethanol (Scheme 23, Table 22, Method A).⁶²

Scheme 23

2-Hydroxyethylammonium sulphonate immobilized on -Fe₂O₃ nanoparticles (-Fe₂O₃-2-HEAS, Fig. 16) was synthesized as a new supported ionic liquid by the reaction of n-butylsulfonated-Fe₂O₃ with ethanolamine. This catalyst also efficiently promoted the synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines 47 in good to high yields under solvent-free conditions (Scheme 23, Table 22, Method B+). The catalyst was easily isolated from the reaction mixture by magnetic decantation using an external magnet and reused at least five times without significant degradation in the activity.⁶³

Fig. 16 Structure of 2-hydroxyethylammonium sulphonate immobilized on -Fe₂O₃ nanoparticles.

2.2.2. Six-membered rings with two heteroatoms.
2.2.2.1. Dihydropyrimidine. The magnetic Fe₃O₄ nanoparticles supported imidazolium-based ionic liquids (MNPs–IILs, Fig. 17), were used as efficient new catalysts for the one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones(thiones) 49a–l. The reaction proceeded via a one-pot cyclocondensation of an aromatic aldehydes 7, β-dicarbonyl compound 15, urea or thiourea 48 in the presence of the magnetic nanocatalysts under microwave irradiation and solvent-free conditions (Scheme 24, Table 23).⁶⁴

Fig. 17 Structure of magnetic Fe₃O₄ nanoparticles supported imidazolium-based ionic liquids.

Scheme 24

Table 23 One-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones(thiones) 49a–l

Entry	R	X	R^1	Product	Time/yield (%) MW^a	Time/yield (%) Δ^b
a Using microwave irradiation.b Under classical heating conditions.
1	Ph	O	OEt	49a	4/97	30/95
2	3-ClC6H4	O	OEt	49b	4/98	25/97
3	4-O2NC6H4	O	OEt	49c	4/98	30/97
4	2-Thienyl	O	OEt	49d	4/98	25/98
5	2-FC6H4	O	OEt	49e	4/97	35/92
6	3,4-(OMe)2C6H3	O	OEt	49f	4/99	20/98
7	4-MeC6H4	S	OEt	49g	4/95	40/90
8	Ph	S	OEt	49h	4/97	35/96
9	2-Thienyl	S	OEt	49i	4/95	25/95
10	Ph	O	Me	49j	4/97	30/95
11	Ph	S	Me	49k	4/96	30/93
12	4-MeC6H4	S	Me	49l	4/95	35/92

---

2.2.2.2. Pyrimidine. 4-Amino-6-aryl-2-phenyl pyrimidine-5-carbonitrile derivatives 50a–m were synthesized through a one-pot, three-component reaction of an aldehydes 7, malononitrile 46 and benzamidine hydrochloride 28, in the presence of magnetic nano Fe₃O₄ particles as a catalyst under solvent-free conditions (Scheme 25, Table 24). The products 50a–m were all prepared with excellent yields at 100 °C in 1–1.5 h. Both aromatic aldehydes with electron donating substituents and electron-withdrawing substituents showed significant reactivity in this process.⁶⁵

Scheme 25

Table 24 Synthesis of 4-aminopyrimidine-5-carbonitrile derivatives 50a–m

Entry	Ar	Product	Yield^a (%)
a Isolated yields.
1	Ph	50a	98
2	4-ClC6H4	50b	96
3	4-BrC6H4	50c	94
4	2,3-DiClC6H3	50d	96
5	2-ClC6H4	50e	96
6	4-NCC6H4	50f	98
7	4-MeC6H4	50g	96
8	2,4-DiClC6H3	50h	96
9	3-O2NC6H4	50i	96
10	4-O2NC6H4	50j	96
11	3-Indolyl	50k	90
12	4-MeCONHC6H4	50l	95
13	4-MeOC6H4	50m	95

---

2.2.2.3. Pyrazine. An iron Schiff base complex was encapsulated in SBA-15 mesoporous silica to afford a Fe(III)-Schiff base/SBA-15 heterogeneous nanocatalyst (Fig. 18) for the synthesis of pyrazines 52a–d from the reaction of the appropriate diamines 51a, 51b with the corresponding 1,2-diketone 25. These reactions proceeded in water with excellent yields (Scheme 26).⁶⁶

Fig. 18 Structure of an iron Schiff base complex encapsulated in SBA-15 mesoporous silica.

Scheme 26

2.3. Synthesis of fused bicyclic systems

2.3.1. Carbocyclic fused heterocycles.
2.3.1.1. Five-membered carbocyclic fused with 6-membered heterocyclic ring: two heteroatoms.
2.3.1.1.1. Cyclopenta[d]pyrimidine. Nano titania-supported sulfonic acid (n-TSA) has been easily prepared from the reaction of nano titania (titanium oxide) with chlorosulfonic acid as sulfonating agent. This catalyst was efficiently used as a heterogeneous catalyst for synthesis of pyrimidinones 54a–s, via three component reaction of aromatic aldehydes 7, cylopentanone 53, urea or thiourea 49a, 49b in solvent-free at 70 °C (Scheme 27, Table 25).⁶⁷

Scheme 27

Table 25 Synthesis of pyrimidinones 54a–s

Entry	Ar	X	Product^a	Time (h)	Yield^b (%)
a Reaction conditions: aromatic aldehyde (1 mmol), cyclopentanone (1 mmol), urea or thiourea (1.2 mmol) in solvent-free at 70 °C.b Isolated yield.
1	C6H5	O	54a	0.75	95
2	2-ClC6H4	O	54b	1.5	86
3	4-ClC6H4	O	54c	1.25	84
4	4-FC6H4	O	54d	1.25	83
5	4-BrC6H4	O	54e	1.25	89
6	4-MeC6H4	O	54f	1	94
7	4-MeOC6H4	O	54g	1	93
8	3-O2NC6H4	O	54h	2.5	83
9	2-Naphthyl	O	54i	1.5	82
10	C6H5	S	54j	1	96
11	2-ClC6H4	S	54k	2	86
12	4-ClC6H4	S	54l	1.5	92
13	4-FC6H4	S	54m	1.6	86
14	4-BrC6H4	S	54n	1.4	89
15	4-MeC6H4	S	54o	1	91
16	4-MeOC6H4	S	54p	1	93
17	3-O2NC6H4	S	54q	3.5	79
18	4-O2NC6H4	S	54r	3	91
19	2-Naphthyl	S	54s	1.5	87

---

2.3.1.2. Six-membered carbocyclic fused with 6-membered heterocyclic ring: one heteroatom.
2.3.1.2.1. Tetrahydro-4H-chromene. Nano magnetic complex lanthanum strontium magnesium oxide La_0.7Sr_0.3MnO₃ (LSMO) has been explored as an efficient and recyclable catalyst to effect the one-pot three-component synthesis of 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromenes 56 by condensation reactions between aromatic aldehydes 7, malononitrile 46 and 5,5-dimethyl-cyclohexane-1,3-dione 55 in EtOH under ultrasound irradiation conditions (Scheme 28, Table 26, Method A).⁶⁸

Scheme 28

Table 26 One-pot three-component synthesis of tetrahydro-4H-chromenes 56a–aa by Methods A–D

Entry	R	Product	Method	Yield (%)
1	C6H5	56a	A	92
2	4-FC6H4	56b	A	96
3	4-ClC6H4	56c	A	97
4	3-O2NC6H4	56d	A	98
5	4-O2NC6H4	56e	A	88
6	4-MeOC6H4	56f	A	5
7	4-MeC6H4	56g	A	87
8	2-ClC6H4	56h	A	83
9	4-HOC6H4	56i	A	92
10	2-O2NC6H4	56j	A	77
11	CH=CHC6H4	56k	A	Trace
12	CH2CH2C6H4	56l	A	Trace
13	C6H5	56a	B	98
14	4-MeOC6H4	56f	B	73
15	4-MeC6H4	56g	B	93
16	4-Me2NC6H4	56m	B	90
17	2-ClC6H4	56h	B	86
18	4-ClC6H4	56c	B	94
19	4-BrC6H4	56n	B	90
20	2-O2NC6H4	56j	B	83
21	3-O2NC6H4	56d	B	98
22	4-O2NC6H4	56e	B	97
23	2-FC6H4	56o	B	90
24	CH3CH2CH2	56p	B	70
25	Furan-2-yl	56q	B	93
26	CH=CHC6H5	56k	B	71
27	C6H5	56a	C	97
28	4-MeOC6H4	56f	C	89
29	4-MeC6H4	56g	C	93
30	4-Me2NC6H4	56m	C	95
31	2-ClC6H4	56h	C	86
32	4-ClC6H4	56c	C	94
33	4-BrC6H4	56n	C	93
34	2-O2NC6H4	56j	C	88
35	3-O2NC6H4	56d	C	95
36	4-O2NC6H4	56e	C	94
37	C6H5	56a	D	94
38	2-ClC6H4	56h	D	97
39	2-BrC6H4	56r	D	94
40	4-ClC6H4	56c	D	98
41	4-BrC6H4	56n	D	96
42	3-ClOC6H4	56s	D	96
43	4-FC6H4	56b	D	98
44	2-ClC6H4	56h	D	96
25	2-O2NC6H4	56j	D	95
46	4-O2NC6H4	56e	D	93
47	4-NCOC6H4	56t	D	95
48	3-HOC6H4	56u	D	90
49	2-Naphthyl	56v	D	97
50	1-Naphthyl	56w	D	92
51	2-Furyl	56x	D	94
52	2-Thienyl	56y	D	96
53	4-OHCC6H4	56i	D	98
54	4-OHCC6H4	56i	D	98
55	Et	56z	D	88
56	^nPr	56aa	D	86

---

Azarifar et al. used nano-titania-supported Preyssler-type heteropolyacid, n-TiO₂/H₁₄[NaP₅W₃₀O₁₁₀] as an efficient and reusable heterogeneous catalyst for the synthesis of highly functionalized 4H-chromenes 56 under ultrasound irradiation conditions (Scheme 28, Table 26, Method B).⁶⁹

The same group reported also the synthesis of highly functionalized 4H-chromenes 56 in the presence of nano-titania sulfuric acid (15 nm TSA) as a heterogeneous catalyst (Scheme 28, Table 26, Method C).⁷⁰

As shown in Table 26, the ease of the reaction is directly related to the substituents attached to the benzene ring and the spatial accessibility of aldehyde 7 as well. The electron withdrawing groups were found to activate the aldehyde toward nucleophilic attack and increase the reaction rate (entry 10, 11).

Sarrafi et al. demonstrated a similar approach for the synthesis of 4H-chromene derivatives 56 in excellent yields using mesoporous silica nanoparticles as a bio-compatible, and recoverable catalyst (Scheme 28, Table 26, Method D).⁷¹

CuFe₂O₄ magnetic nanoparticles were synthesized and recognized as an efficient catalyst for the one-pot synthesis of 4H-chromene derivatives 57 in aqueous medium at mild conditions and in excellent yields. The reaction proceeds via MCR's of dimedone or cyclohexane-1,3-dione, 55 dialkyl acetylenedicarboxylates 8 and malononitrile or ethyl cyanoacetate 46 (Scheme 29, Table 27).⁷²

Scheme 29

Table 27 One-pot synthesis of 4H-chromene derivatives 57a–h

Entry	R^1	R^2	R^3	Product	Time (h)	Yield (%)
1	Me	Et	CN	57a	2	92
2	Me	Et	CO2Et	57b	2.5	88
3	Me	Me	CN	57c	2	91
4	Me	Me	CO2Et	57d	2.5	86
5	H	Et	CN	57e	2	94
6	H	Et	CO2Et	57f	2.5	89
7	H	Me	CN	57g	2	92
8	H	Me	CO2Et	57h	2.5	86

---

Pradhan et al. proposed a possible mechanism (Scheme 3) for this 3 CRs. Thus, Cu²⁺ of CuFe₂O₄ catalyzed the Michael addition reaction of dialkyl acetylene dicarboxylate with alkyl nitrile derivatives (malononitrile and ethyl cyanoacetate) during the formation of the intermediate X. The nucleophilic attack by the intermediate Y at the β position (with respect to nitrile group) of the intermediate X was enhanced by Cu²⁺ may be due to the polarization of the π-electron cloud. Finally, the Lewis acidic Fe³⁺ interacted with enolate intermediate Z which in turn facilitates intramolecular electrophilic cyclization with the formation of the six member ring (P) (Scheme 30).⁷²

Scheme 30

Sarrafi et al. investigated the synthesis of spiro[(4H-chromene)-4,3′-oxindoles] 59a–s by three component reaction of an isatin, malononitrile, and cyclic 1,3-diketones in ethanol at 60 °C using mesoporous silica nanoparticles as a catalyst (Scheme 31, Table 28, Method A).⁷¹

Scheme 31

Table 28 Synthesis of spiro[(4H-chromene)-4,3′-oxindoles] 59a–s by Methods A and B

Entry	R^1	R^2	R	Product	Method	Yield (%)
1	H	H	Me	59a	A	98
2	H	H	H	59b	A	97
3	H	H	Me	59c	A	95
4	H	H	H	59d	A	96
5	H	Bn	Me	59e	A	93
6	H	Bn	H	59f	A	95
7	5-Br	H	Me	59g	A	97
8	5-Br	H	H	59h	A	98
9	5-Me	H	Me	59i	A	95
10	5-Me	H	H	59j	A	94
11	5-O2N	H	Me	59k	A	96
12	5-O2N	H	H	59l	A	97
13	5-Br	H	Me	59e	A	96
14	5-Br	H	H	59h	B	96
15	H	H	H	59d	B	98
16	H	NO2	H	59m	B	94
17	H	Me	H	59n	B	92
18	H	Cl	H	59o	B	97
19	H	Br	H	59p	B	91
20	Me	H	H	59q	B	96
21	H	H	Me	59a	B	97
22	H	NO2	Me	59r	B	93
23	H	Cl	Me	59s	B	90

---

Hosseini-Sarvari and Tavakolian also synthesized spirooxindole derivatives 59 by a one-pot, three-component reaction of 55, 58 and 46 in excellent yield at room temperature under solvent-free conditions in the presence of 10 mol% ZnO nano-rods catalyst by a very simple procedure (using a mortar and the mixture was ground by a pestle at room temperature) (Scheme 31, Table 28, Method B). All of the reactions provided the desired spirooxindole products in excellent yields employing both electron-deficient (entries 2, 4, and 5) and electron-rich (entry 3) isatins as substrates.⁷³

The nano ZnO has Lewis acid (Zn²⁺) and Lewis basic (O²⁻) sites.⁷⁴ In the first step (i) a Lewis acid site (Zn²⁺) is coordinated to O-atom of the C=O group of isatin, resulting in the increase of its reactivity.⁷⁵

2.3.1.3.2. Hexahydroquinoline. Tajbakhsh et al. reported four component reaction of dimedone 55, aldehyde 7, acetoacetic ester 15, and ammonium acetate using a catalytic amount of titanium dioxide nanoparticles to prepare the polyhydroquinoline derivatives 60 in high yields (Scheme 32, Table 29). It can be seen that both electron-rich and electron-deficient aldehydes as well as heterocyclic ones worked well, giving good to excellent yields of the substituted polyhydroquinoline derivatives.⁷⁶

Scheme 32

Table 29 Synthesis of polyhydroquinoline derivatives 60a–s

Entry	R	Product	Yield^a (%)
a Yield refers to isolated products.
1	C6H5	60a	96
2	4-BrC6H4	60b	94
3	3-BrC6H4	60c	90
4	4-ClC6H4	60d	92
5	2-ClC6H4	60e	90
6	3-ClC6H4	60f	90
7	4-(CH3)2NC6H4	60g	80
8	2-MeOC6H4	60h	93
9	2-FC6H4	60i	90
10	4-NO2C6H4	60j	88
11	2-NO2C6H4	60k	82
12	4-MeC6H5	60l	92
13	4-OHC6H5	60m	86
14	C6H5CH=CH	60n	90
15	2-Thienyl	60o	89
16	3-Thienyl	60p	91
17	2-Furyl	60q	90
18	3-Pyridyl	60r	89
19	C4H8O	60s	84

---

The bimetallic ZnFe₂O₄ nanopowder, a dual Lewis acid–base combined catalyst, is found to efficiently catalyze a four component reaction for the synthesis of functionalized tetrahydrospiro[indoline-3,2′-quinoline] derivatives 61a–ae. Thus, reaction of arylamines 9, dialkyl acetylene dicarboxylates 8, isatin derivatives 58 and cyclohexane-1,3-diones 55 in water medium at room temperature afforded 61 in good yields (Scheme 33, Table 30).⁷⁷ A probable mechanism for the formation of 61 depends on the dual role of ZnFe₂O₄ as a Lewis acidic site, as well as basic site.⁷⁸

Scheme 33

Table 30 Synthesis of tetrahydrospiro[indoline-3,2′-quinoline] derivatives 61a-ae

Entry	R^1	R^2	R^3	R^4	R^5	Product	Yield (%)
1	H	H	4-MeC6H4	Me	Me	61a	77
2	H	H	4-MeOC6H4	Et	Me	61b	75
3	H	H	4-BrC6H4	Me	Me	61c	72
4	H	H	4-BrC6H4	Et	Me	61d	73
5	Et	H	4-MeOC6H4	Me	Me	61e	80
6	Et	H	4-ClC6H4	Me	Me	61f	78
7	H	Br	4-MeOC6H4	Me	Me	61g	71
8	Et	Cl	4-MeOC6H4	Et	H	61h	77
9	H	Cl	4-BrC6H4	Me	Me	61i	69
10	Pr	H	4-MeOC6H4	Me	Me	61j	72
11	H	Cl	4-ClC6H4	Et	Me	61k	76
12	Pr	Cl	4-MeOC6H4	Me	Me	61l	81
13	Pr	Cl	4-MeC6H4	Et	Me	61m	72
14	Pr	H	4-ClC6H4	Me	H	61n	70
15	H	H	4-MeOC6H4	Et	H	61o	74
16	Pr	Cl	4-ClC6H4	Me	H	61p	76
17	H	F	4-MeOC6H4	Et	H	61q	78
18	H	Br	4-ClC6H4	Et	Me	61r	73
19	Et	Cl	4-FC6H4	Et	H	61s	79
20	H	Cl	4-MeC6H4	Et	Me	61t	82
21	H	H	3-ClC6H4	Et	Me	61u	67
22	H	H	3-MeOC6H4	Et	Me	61v	70
23	H	Cl	3-ClC6H4	Et	Me	61w	69
24	H	H	4-ClC6H4	Me	Me	61x	77
25	H	Cl	4-MeOC6H4	Me	Me	61y	73
26	H	Cl	C6H5	Me	Me	61z	67
27	H	Cl	4-MeOC6H4	Et	Me	61a	78
28	H	H	4-MeOC6H4	Me	Me	61b	78
29	H	H	C6H5	Me	Me	61c	73
30	H	H	4-ClC6H4	Et	Me	61d	79
31	H	H	4-MeC6H4	Et	Me	61e	82

---

2.3.2. Benzo fused heterocycles.
2.3.2.1. Benzo fused with 5-membered heterocyclic ring: two heteroatoms.
2.3.2.1.1. Benzoxazole. Sarode et al. reported a green and sustainable approach for the synthesis of 2-substituted benzoxazole 63 by using a one pot redox cascade condensation reaction of benzyl amine derivatives 9 and 2-nitrophenols 62, catalyzed by Cu ferrite NPs (Scheme 34, Table 31).⁷⁹ Cu ferrite NPs are magnetically separable, air stable and can be recycled up to fifth cycle without a significant loss in catalytic activity.

Scheme 34

Table 31 Synthesis of 2-substituted benzoxazoles 63a–m

Entry	R-NH2	R^1	Product	R	Yield (%)
1	C6H5CH2–	H	63a	C6H5	92
2	3-HOC6H4CH2–	H	63b	3-HOC6H4	84
3	4-MeOC6H4CH2–	H	63c	4-MeOC6H4	89
4	4-FC6H4CH2–	H	63d	4-FC6H4	85
5	4-BrC6H4CH2–	H	63e	4-BrC6H4	78
6	2-Naphthyl–CH2–	H	63f	2-Naphthyl	90
7	3-Pyridyl–CH2–	H	63g	3-Pyridyl	87
8	3,5-(MeO)2C6H3CH2–	H	63h	3,5-(MeO)2C6H3	81
9	C6H5CH2–	2-Me	63i	C6H5	84
10	C6H5CH2–	3-Cl	63j	C6H5	80
11	C6H5CH2–	3,4-Me2	63k	C6H5	90
12	C6H5CH2–	3-Cl	63l	C6H5	86
13	C6H5CH2–	2-Me-3-Cl	63m	C6H5	83

---

The plausible reaction mechanism depends on the basis that Cu ferrite NPs provide the surface for the simultaneous oxidation and reduction of the reactants.⁸⁰ Benzyl amine on autoxidation forms corresponding benzaldehyde and releases the ammonia which was confirmed by the litmus paper test after the workup of the reaction. Here ammonia acts as a hydrogen source for the reduction of the nitro group of the o-nitro phenol. It reduces to 2-amino phenol which was then condensed with the benzaldehyde and gives the 2-phenylbenzo[d]oxazole (Scheme 35).

Scheme 35

Tang et al. described a one-pot direct synthesis of benzoxazoles 63 using o-nitrophenols 62 and alcohols 64 as the starting materials catalyzed by gold nanoparticles supported on titanium dioxide (Au/TiO₂) (Scheme 36). The products were obtained in good yields and yields are summarized in Table 32 The electronic properties of a series of benzylic alcohols were found to have little influence on the reaction. Reactions with benzylic alcohols bearing both electron-donating groups (Table 32, entries 2–5) and electron-withdrawing groups (Table 32, entries 8–10) in the aromatic ring could effectively afford the desired products in excellent yields. However, the steric hindrance of the substituents had a negative influence on the reaction. Relatively low yields of the corresponding products were obtained when the substituent groups appeared in the ortho-position of the benzene ring (Table 32, entries 6 and 7).⁸¹

Scheme 36

Table 32 One-pot synthesis of benzoxazoles 63a-ag

Entry	R	R^1	Product	Yield (%)
1	C6H5	H	63a	99(90)
2	4-MeC6H4	H	63n	98
3	3-MeC6H4	H	63o	97
4	4-MeOC6H4	H	63p	99(91)
5	3-MeOC6H4	H	63q	91
6	2-MeC6H4	H	63r	81
7	2-MeOC6H4	H	63s	85
8	4-FC6H4	H	63d	95(85)
9	3-FC6H4	H	63t	94
10	4-ClC6H4	H	63u	98
11	4-BrC6H4	H	63e	63/17
12	4-CF3C6H4–	H	63v	70
13	1-Naphthyl	H	63w	95
14	Me	H	63x	52
15	^tBu	H	63y	63(55)
16	^nC5H11	H	63z	56
17	Cyclohexyl	H	63aa	60
18	C6H5	4-Me	63ab	96
19	C6H5	5-Me	63ac	95(84)
20	C6H5	4-MeO	63ad	97
21	C6H5	5-F	63ae	98
22	C6H5	4-F	63af	99
23	C6H5	4-Cl	63ag	95
24	C6H5	H	63a	80(75)

---

The authors suggested a possible mechanism for the reaction as depicted in Scheme 37. First of all, dehydrogenative oxidation of the alcohol 64 to its corresponding carbonyl compound generates the gold-hydride species (b) and 2-nitrophenol (62) is reduced to 2-aminophenol in situ by b. This is the first hydrogen-transfer process. Then, the aldehyde can readily react with 2-aminophenol to afford the corresponding imine (c). c is selectively converted to the intermediate 2-phenyl-2,3-dihydrobenzoxazole (d) under the catalysis of a gold catalyst. Subsequently, d can be rapidly oxidized to the product 63 in the presence of a gold catalyst accompanied by the generation of b and 2-nitrophenol (62) is reduced to 2-aminopheno by b. This is the second hydrogen-transfer process. In the whole catalytic cycle, the alcohol and the intermediate 2-phenyl-2,3-dihydrobenzoxazole are used as reductants (hydrogen donor) once and 2-nitrophenol is used as the oxidant (hydrogen acceptor) twice.⁸¹

Scheme 37

2.3.2.1.2. Benzimidazole. Nasr-Esfahani et al. reported the synthesis of a stable heterogeneous catalyst, Cu(II) containing nanosilica triazine dendrimer (Cu(II)-TD@nSiO₂). This catalyst has been successfully applied for the synthesis of benzimidazoles 65a–k via the condensation of 1,2-phenylenediamines 9 with a wide variety of aromatic, polycyclic and heteroaromatic aldehydes at ambient atmosphere under conventional conditions (Scheme 38, Table 33).⁸²

Scheme 38

Table 33 Synthesis of benzimidazoles 65a–k

Entry	R	R^1	Product	Yield (%)
1	C6H5	H	65a	95
2	4-ClC6H4	H	65b	97
3	2-BrC6H4	H	65c	97
4	4-MeC6H4	H	65d	95
5	3-O2NC6H4	4-Me	65e	89
6	1-Naphthyl	4-Me	65f	93
7	1-Naphthyl	4-Cl	65g	88
8	9-Anthryl	H	65h	92
9	3-Pyridyl	H	65i	91
10	3-Indolyl	4-Me	65j	92
11	2-Thienyl	H	65k	92

---

The same authors has also achieved an efficient synthesis of bis-benzimidazoles 66, from terephthaldialdehyde using this catalytic system (Scheme 39).⁸²

Scheme 39

A highly efficient and selective reaction for the synthesis of 2-substituted benzimidazoles 68 using o-nitroanilines 67 and alcohols 64 as the starting materials catalyzed by Au/TiO₂ has been developed via two hydrogen-transfer processes (Scheme 40, Table 34). This reaction has a good tolerance to air and water, a wide substrate scope, and represents a new avenue for practical C–N and C–O bond formation. More importantly, no additional additives, oxidants and reductants are required for the reaction and the catalyst can be recovered and reused readily.⁸¹

Scheme 40

Table 34 Synthesis of 2-substituted benzimidazoles 68a–f

Entry	R^1	R^2	Product	Yield (%)
1	C6H5	H	68a	78(70)
2	C6H5	Me	68b	84
3	4-MeC6H4	Me	68c	83
4	4-MeOC6H4	Me	68d	86(81)
5	4-FC6H4	Me	68e	86
6	4-ClC6H4	Me	68f	79(70)

---

2.3.2.1.3. Benzothiazole. The Cu(II) containing nanosilica triazine dendrimer (Cu(II)-TD@nSiO₂, Fig. 19) can also be used as an efficient catalyst for the preparation of various benzothiazoles under mild conditions. The reaction proceeded by reaction of the appropriate aromatic aldehydes 7 with 2-aminothiophenol 9 in the presence of a catalytic amount of Cu(II)-TD@nSiO₂ (Scheme 41, Table 35, Method A).⁸²

Fig. 19 Structure of Cu(II) containing nanosilica triazine dendrimer.

Scheme 41

Table 35 Preparation of various benzothiazoles 69a–u by Methods A and B

Entry	Ar	Product	Method	Yield (%)
1	4-ClC6H5	69a	A	97
2	2,4-Cl2C6H3	69b	A	96
3	3,4-(MeO)2C6H3	69c	A	93
4	4-MeC6H4	69d	A	98
5	3-MeOC6H4	69e	A	96
6	3-O2NC6H4	69f	A	87
7	1-Naphthyl	69g	A	93
8	3-Pyridyl	69h	A	92
9	3-indolyl	69i	A	94
10	2-Thienyl	69j	A	92
11	C6H5	69k	B	90
12	2-ClC6H4	69l	B	84
13	4-ClC6H4	69a	B	86
14	2-HOC6H4	69m	B	82
15	4-HOC6H4	69n	B	83
16	4-FC6H4	69o	B	86
17	4-BrC6H4	69p	B	86
18	4-MeC6H4	69d	B	90
19	4-MeOC6H4	69q	B	93
20	2-O2NC6H4	69r	B	81
21	3-O2NC6H4	69f	B	86
22	4-O2NC6H4	69s	B	89
23	2-Naphthyl	69t	B	90
24	Furyl	69u	B	79

---

Rahmani et al. prepared nano titania-supported sulfonic acid (n-TSA) from the reaction of nano titania (titanium oxide) with chlorosulfonic acid as sulfonating agent. This was efficiently used as a heterogeneous catalyst for synthesis of 2-arylbenzothiazoles 69, via reaction of aromatic aldehyde with 2-aminothiophenol in solvent-free at 70 °C (Scheme 41, Table 35, Method B).⁶⁷

Nasr-Esfahani et al. prepared symmetrical bis-benzothiazole 70 in high yield by the reaction of terephthaldialdehyde 7 with two equivalents of 2-aminothiophenol 9 in the presence of a catalytic amount of Cu(II)-TD@nSiO₂ under conventional conditions (Scheme 42).⁸²

Scheme 42

2.3.2.2. Benzo fused with 6-membered heterocyclic ring: one heteroatom.
2.3.2.2.1. 2H-Chromene. A wide range of substituted coumarin derivatives 71a–l were synthesized by refluxing in acetonitrile, ethyl acetoacetate, and ethyl benzoyl acetate 15 with a wide range of structurally diverse phenol derivatives 62 within a short reaction time with a catalytic combination of pyridine dicarboxylic acid as organocatalyst and nanocrystalline ZnO (Scheme 43, Table 36).⁸³

Scheme 43

Table 36 Synthesis of coumarin derivatives 71a–l

Entry	R	R^1	Product	Yield (%)
1	H	Me	71a	90
2	3-OH	Me	71b	93
3	3,5-(OH)2	Me	71c	89
4	3-MeO	Me	71d	93
5	3-OH-2-Me	Me	71e	86
6	3-NH2	Me	71f	89
7	4-O2N	Me	71g	92
8	4-Cl	Me	71h	73
9	3-OH	Ph	71i	88
10	3,5-(OH)2	Ph	71j	85
11	3-MeO	Ph	71k	87
12	3,5-(Me)2	Ph	71l	85

---

2.3.2.2.2. 4H-Chromene. Nano ZnO can serve as an efficient catalyst for the synthesis of 2-amino-4H-benzopyrans 72a, 72b in good yields from methylenemalononitrile, generated in situ from aldehyde 7 and malononitrile 46 and phenols 62a, 62b (Scheme 44).⁸⁴

Scheme 44

Mohammad and Kassaee reported the use of sulfochitosan-coated Fe₃O₄ magnetic nanoparticles (Fe₃O₄@CS–SO₃H NPs, Fig. 20) as a “green” heterogeneous catalyst for preparation of 2-amino-4H-chromen-4-yl phosphonates 72c–k through one-pot, three-component reactions of salicylaldehydes 7, malononitrile 46, and triethyl phosphite in water at room temperature (Scheme 45, Table 37).⁸⁵

Fig. 20 Structure of sulfochitosan-coated Fe₃O₄ magnetic nanoparticles.

Scheme 45

Table 37 Preparation of 2-amino-4H-chromen-4-yl phosphonates 72c–k

Entry	R^1	Product	Yield (%)
1	H	72c	93
2	6-Cl	72d	96
3	6-O2N	72e	92
4	6-Me	72f	95
5	6-Br	72g	97
6	7-MeO	72h	93
7	6,8-Br2	72i	97
8	6,8-Br2	72j	94
9	6-MeO	72k	88

---

2.3.2.3. Benzo fused with 6-membered heterocyclic ring: two heteroatoms.
2.3.2.3.1. Quinoxaline. An iron Schiff base complex was encapsulated in SBA-15 (Santa BArbara No. 15), the most interesting mesoporous silica, to afford a Fe(III)-Schiff base/SBA-15 heterogeneous nanocatalyst (Fig. 21). The latter catalyzed the synthesis of quinoxalines 73a–d with excellent yields from the reaction of o-phenylenediamine with the appropriate 1,2-diketone 25 in water (Scheme 46, Table 38).⁶⁶

Fig. 21 Structure of an iron Schiff base complex encapsulated in SBA-15.

Scheme 46

Table 38 Synthesis of quinoxalines 73a–d

Entry	R^1	Product	Yield (%)
1	C6H5	73a	99
2	4-FC6H4	73b	99
3	4-MeOC6H4	73c	98
4	Me	73d	99

---

2.3.2.3.2. Quinazoline. Zhang et al. prepared a new heterogeneous catalyst consisting of CuO NPs supported on kaolin and studied its catalytic activity for the synthesis of quinazolines 75. Thus, a series of quinazoline derivatives 75 were synthesized from 2-aminobenzophenones 74 and benzylic amines 9 under mild conditions in good to excellent yields (Scheme 47, Table 39). The employment of a suitable supporting material can not only increase the catalytic activity of CuO NPs but also facilitate the separation between the catalyst and the product.⁸⁶

Scheme 47

Table 39 Synthesis of quinazolines 75a–z

Entry	R^1	R^2	R^3	Product	Yield (%)
1	H	C6H5	C6H5	75a	90
2	H	4-Fluorophenyl	C6H5	75b	88
3	H	4-Bromophenyl	C6H5	75c	83
4	H	p-Tolyl	C6H5	75d	82
5	H	2,5-DiMephenyl	C6H5	75e	71
6	H	Mesityl	C6H5	75f	0
7	H	Et	C6H5	75g	84
8	H	^nBu	C6H5	75h	95
9	H	Hexadecyl	C6H5	75i	78
10	H	^iPr	C6H5	75j	90
11	H	^tBu	C6H5	75k	89
12	H	Cyclopropyl	C6H5	75l	90
13	H	Cyclopropyl	C6H5	75l	74
14	H	C6H5	C6H5	75m	73
15	6-Cl	C6H5	C6H5	75a	85
16	6-Br	C6H5	C6H5	75n	93
17	6,7-DiMe	C6H5	C6H5	75o	63
18	6-Cl	C6H5	C6H5	75p	45
19	H	C6H5	p-Tolyl	75q	89
20	H	C6H5	m-Tolyl	75r	86
21	H	C6H5	o-Tolyl	75s	94
22	H	C6H5	4-Methoxyphenyl	75t	88
23	H	C6H5	Benzo[1,3]dioxol-5-yl	75u	58
24	H	C6H5	4-Chlorophenyl	75v	87
25	H	C6H5	4-Fluorophenyl	75w	91
26	H	C6H5	4-(Trifluoromethyl)phenyl	75x	92
27	H	C6H5	1-Naphthyl	75y	86
28	H	C6H5	2-Furyl	75z	51

---

A postulated reaction pathway is proposed, as shown in Scheme 48. Firstly, CuO NPs may activate 2-aminobenzophenone to generate intermediate I. Meanwhile, benzylic amine can attach to the surface of the CuO NPs to form intermediate II. In the intermediate II, the distance between 2-aminobenzophenone and benzylic amine may be shortened, facilitating the attack of benzylic amine to 2-aminobenzophenone. After attacked by benzylic amine, imine A is formed. A subsequently undergoes an oxidation process and is stabilized by CuO NPs (intermediate III). Intramolecular attack of the amino-group to the imine cation results in intermediate B. Further oxidation of intermediate B gives the quinazoline product.⁸⁶

Scheme 48

Tang et al. developed a highly efficient and selective nitrogen source-promoted reaction for the synthesis of 2,4-disubstituted quinazolines 75 from o-nitroacetophenones 76 and alcohols 64 catalyzed by Au/TiO₂ via a hydrogen-transfer strategy (Scheme 49, Table 40). This reaction has good tolerance to air and water, a wide substrate scope, and represents a new avenue for practical multiple C–N bond formation. More importantly, no additional additive, oxidant and reductant are required in the reaction and the catalyst can be recovered and reused readily. The electronic properties of a series of aromatic alcohols were found to have little influence on the reaction. The reactions could be carried out effectively to afford the desired products with good yields regardless of the electron-donating groups or electron-withdrawing groups at the benzene ring of benzylic alcohols. However, the steric hindrance of the substituents had a negative influence on the reaction.⁸⁷

Scheme 49

Table 40 Synthesis of 2,4-disubstituted quinazolines 75a-ae

Entry	R^1	R^2	R^3	Yield (%)
a Under air.b 150 °C.
1	H	Me	C6H5	99(83)^a
2	H	Me	4-MeC6H4	97(80)^a
3	H	Me	4-MeOC6H4	95
4	H	Me	2-MeOC6H4	54(84)^b
5	H	Me	3,4-(MeO)2C6H3	97
6	H	Me	4-FC6H4	91(81)^a
7	H	Me	3-FC6H4	70
8	H	Me	4-ClC6H4	96
9	H	Me	2-ClC6H4	63(86)^b
10	H	Me	4-BrC6H4	94(85)^a
11	H	Me	4-MeOOCC6H4	36(94)^b
12	H	Me	4-CF3C6H4	31(87)^b
13	H	Me	1-Naphthyl	89
14	H	Me	Me	85(74)^a
15	H	Me	^nPr	76
16	H	Me	^tBu	58
17	H	Me	Cyclohexyl	73
18	H	C6H5	C6H5	74
19	H	4-MeC6H4	C6H5	71
20	H	4-FC6H4	C6H5	76
21	H	4-ClC6H4	C6H5	73
22	H	4-BrC6H4	C6H5	68
23	H	2,4,6-(Me)3C6H2	C6H5	0
24	6-Cl	C6H5	C6H5	73
25	6-Me	Me	C6H5	92
26	6-F	Me	C6H5	94(97)^a
27	7-Cl	Me	C6H5	91
28	H	H	C6H5	53
29	H	^nBu	C6H5	56
30	H	^cPn	C6H5	71
31	H	Hexadecyl	C6H5	68

---

The possible mechanism is depicted in Scheme 50. First of all, dehydrogenative oxidation of the alcohol (64) into the corresponding carbonyl compound (64′) promoted by ammonia, generates the gold-hydride species (b) and 76a′ is reduced into 76b in situ by b. This is the first hydrogen-transfer process and also the rate-limiting step of the reaction. Then, 76b can readily react with 64a′ to afford the corresponding imine (c). Compound c is converted to the intermediate (d) under the catalysis of gold. Subsequently, d can be rapidly oxidized to the product of 75 in the presence of the gold catalyst accompanied with the generation of b. And 76a′ is again reduced into 76b by b. This is the second hydrogen-transfer process. In the whole catalytic cycle, the alcohol 64 and the intermediate d are used as the reductant (hydrogen donor) once and the nitro compound 76a′ is used as the oxidant (hydrogen acceptor) twice.⁸⁷

Scheme 50

2.3.3. Two fused heterocycles.
2.3.3.1. Fused [5-5] systems: two bridgehead nitrogens and one extra heteroatom.
2.3.3.1.1. Pyrazolo[1,2-a][1,2,4]triazole. Azarifar et al. explored the catalytic activity of nano-structured ZnO in the synthesis of pyrazolo[1,2-a][1,2,4]triazole-1,3-dione derivatives 78 via a three-component coupling reaction between aromatic aldehydes 7, malononitrile 46, and 4-aryltriazoles 77 under solvent-free conditions (Scheme 51, Table 41, Method A).⁸⁸

Scheme 51

Table 41 Synthesis of pyrazolo[1,2-a][1,2,4]triazole-1,3-dione derivatives 78a-ai by Methods A–C

Entry	R	X	R^1	Product	Method	Yield (%)
1	C6H5	CN	C6H5	78a	A	90
2	4-ClC6H4	CN	C6H5	78b	A	88
3	C6H5	CN	4-ClC6H4	78c	A	91
4	4-ClC6H4	CN	4-ClC6H4	78d	A	91
5	4-O2NC6H4	CN	4-ClC6H4	78e	A	90
6	4-O2NC6H4	CN	2,4-Cl2C6H4	78f	A	86
7	4-O2NC6H4	CN	4-O2NC6H4	78g	A	71
8	C6H5	CN	4-MeOC6H4	78h	A	84
9	4-O2NC6H4	CN	4-MeOC6H4	78i	A	81
10	C6H5	CN	4-^tBuC6H4	78j	A	80
11	4-O2NC6H4	CN	4-^tBuC6H4	78k	A	75
12	4-Cl-3O2NC6H3	CN	C6H5	78l	A	86
13	2,4,6-(MeO)3C6H2	CN	C6H5	78m	A	78
14	2,3-Cl2C6H4	CN	C6H5	78n	A	91
15	C6H5	CN	C6H5	78a	A	—
16	C6H5	CN	C6H5	78a	B	89
17	4-BrC6H4	CN	C6H5	78o	B	88
18	3-O2NC6H4	CN	C6H5	78p	B	91
19	4-ClC6H4	CN	C6H5	78q	B	86
20	3-BrC6H4	CN	C6H5	78r	B	81
21	2-BrC6H4	CN	C6H5	78s	B	87
22	4-MeC6H4	CN	C6H5	78t	B	90
23	C6H5	COOMe	C6H5	78u	B	83
24	3-O2NC6H4	COOMe	C6H5	78v	B	84
25	4-ClC6H4	COOMe	C6H5	78w	B	85
26	4-O2NC6H4	COOMe	C6H5	78x	B	92
27	4-ClC6H4	COOEt	C6H5	78y	B	82
28	4-O2NC6H4	COOEt	C6H5	78z	B	86
29	4-MeC6H4	COOEt	C6H5	78aa	B	89
30	Ferrocenyl	CN	C6H5	78ab	B	—
31	C6H5	CN	C6H5	78a	C	92
32	4-ClC6H4	CN	C6H5	78b	C	90
33	4-FC6H4	CN	C6H5	78ac	C	92
34	2-ClC6H4	CN	C6H5	78ad	C	88
35	3-ClC6H4	CN	C6H5	78ae	C	94
36	2-O2NC6H4	CN	C6H5	78af	C	88
37	4-O2NC6H4	CN	C6H5	78ag	C	89
38	2,4-Cl2C6H3	CN	C6H5	78ah	C	90
39	3-O2NC6H4	CN	C6H5	78p	C	90
40	4-MeC6H4	CN	C6H5	78t	C	89
41	3-BrC6H4	CN	C6H5	78r	C	93
42	2-BrC6H4	CN	C6H5	78s	C	92
43	4-BrC6H4	CN	C6H5	78o	C	89
44	n-Heptanal	CN	C6H5	78ai	C	—

---

Naeimi et al. also developed an efficient clean method for the synthesis of pyrazolo[1,2-a][1,2,4]triazole derivatives 75 via a one-pot three-component reaction of aromatic aldehydes 7, 77 and 46 in the presence of a catalytic amount of nanocrystalline (NC) magnesium oxide (Scheme 51, Table 41, Method B).⁸⁹

Shaterian and Moradi used a similar approach for the synthesis of 7-amino-1,3-dioxo-1,2,3,5-tetrahydropyrazolo[1,2-a][1,2,4]triazole derivatives 78 by employing magnetic Fe₃O₄ nanoparticles coated by (3-aminopropyl)-triethoxysilane (Fig. 22) as a catalyst for a similar reaction (Scheme 51, Table 41, Method C).⁹⁰

Fig. 22 Structure of magnetic Fe₃O₄ nanoparticles coated by (3-aminopropyl)-triethoxysilane.

2.3.3.2. Fused [5-5] systems: four heteroatoms [2:2].
2.3.3.2.1. Imidazo[4,5-d]imidazole. Nano-sized HZSM-5 zeolite have been used by Vessally et al. as a mild and efficient catalyst for the synthesis of tetrahydroimidazo[4,5-d]imidazole-2,5(1H,3H)dione derivatives 79a–f through reaction between urea 49 and the appropriate dicarbonyl compound 25. The yield of the reaction increases when the time of the reaction reaches 72 h. The amount of catalyst was also reported to increase the reaction yields. HZSM-5 was prepared by ion exchange of ZSM-5 nanozeolite with NH₄Cl, followed by drying and calcination (Scheme 52, Table 42).⁹¹

Scheme 52

Table 42 Synthesis of tetrahydroimidazo[4,5-d]imidazole-2,5(1H,3H)dione derivatives 79a–f

Entry	R^1	R^2	Product	Yield (%)
1	H	H	79a	56
2	Me	Et	79b	67
3	C6H5	C6H5	79c	71
4	4-MeOC6H4	4-MeOC6H4	79d	70
5	Me	Me	79e	67
6	Et	Et	79f	70

---

2.3.3.3. Fused [5-6] systems: one bridgehead nitrogen.
2.3.3.3.1. Indolizine. Albaladejo et al. reported the synthesis of a wide range of indolizines 80a–m in moderate-to-high yields (59–93%) by the reaction of pyridine-2-carbaldehyde 7 secondary amines and arylacetylenes 35 using low catalyst loading (0.5 mol%) of Cu NPs/C (Cu NPs on activated carbon) (Scheme 53, Table 43).⁹²

Scheme 53

Table 43 Synthesis of indolizines 80a–m

Entry	R^1 R^2	R^3	Yield (%)
1	–(CH2)5	C6H5	86
2	–(CH2)2–O–(CH2)2–	C6H5	74
3	Bu,Bu	C6H5	91
4	Me,Bn	C6H5	80
5	Bn,Bn	C6H5	93
6	–(CH2)5	4-MeC6H4	69
7	–(CH2)5	4-F3CC6H4	76
8	–(CH2)5	4-MeOOCC6H4	59
9	–(CH2)5	4-Me2NC6H4	93
10	–(CH2)5	4-MeOC6H4	86
11	–(CH2)5	4-BrC6H4	73
12	Bn,Bn	4-MeC6H4	91
13	Bu,Bu	^nDecyl	64

---

2.3.3.4. Fused [5-6] systems: one bridgehead nitrogen and one extra heteroatom.
2.3.3.4.1. Imidazo[1,2-a]pyridine. Meng et al. developed an efficient and mild heterogeneously CuCl₂/nano-TiO₂-catalyzed aerobic synthesis of imidazo[1,2-a]pyridines 82a–d in good yields with low catalyst loading (0.8 mol%) from 2-aminopyridines 9 and ketones 81 using air as the oxidant in the absence of any ligands and additives. This strategy was compatible with a large range of substrates, including unactivated aryl ketones and unsaturated ketones and went through the C–H bond functionalization mechanism (Scheme 54, Table 44).⁹³

Scheme 54

Table 44 Synthesis of imidazo[1,2-a]pyridines 82a–d

Entry	R^1	R^2	Product	Yield (%)
a Methylphenylketone is used and the product is
1	H	4-MeOC6H4	82a	85
2	H	3-MeOC6H4	82b	84
3	H	2-MeOC6H4	82c	69
4	H	4-MeC6H4	82d	88
5	H	3-MeC6H4	82e	82
6	H	2-MeC6H4	82f	91
7	H	4-ClC6H4	82g	92
8	H	3-ClC6H4	82h	88
9	H	2-ClC6H4	82i	70
10	H	4-BrC6H4	82j	85
11	H	4-Me2NC6H4	82k	72
12	H	4-F3CC6H4	82l	65
13	H	3-F3CC6H4	82m	86
14	H	2-F3C6H4	82n	72
15	H	4-MeOOCC6H4	82o	64
16	H	3-O2NC6H4	82p	81
17	H	4-NCC6H4	82q	90
18	H	2-Furyl	82r	78
19	H	2-Thienyl	82s	86
20	H	2-Pyridyl	82t	74
21	H	2-Thiazolyl	82u	71
22	H	2-Styryl	82v	78
23	H	^a	82w	84
24	3-Me	C6H5	82x	83
25	4-Me	C6H5	82y	80
26	4-Me	4-BrC6H4	82z	78
27	4-CF3	C6H5	82aa	75
28	3-Br-2-Me	C6H5	82ab	61
29	2,4-Br2-6-Me	C6H5	82ac	55
30	3-O2N	C6H5	82ad	—

---

Guntreddi et al. demonstrated the catalytic use of magnetic nano-Fe₃O₄–KHSO₄·SiO₂ for an efficient one pot synthesis of imidazo[1,2-a]pyridines 83 by one pot three-component reaction of 2-aminopyridine 9, aldehyde 7, and alkyne 35 (Scheme 55, Table 45, Method A).⁹⁴

Scheme 55

Table 45 Synthesis of imidazo[1,2-a]pyridines 83a–y by Methods A and B

Entry	R^1	R^2	Method	Product	Yield (%)
1	H	C6H5	A	83a	89
2	H	4-ClC6H4	A	83b	86
3	H	3-ClC6H4	A	83c	84
4	H	4-BrC6H4	A	83d	83
5	H	3-BrC6H4	A	83e	82
6	H	2-BrC6H4	A	83f	83
7	H	4-MeOC6H4	A	83g	75
8	H	4-Me2NC6H4	A	83h	—
9	H	4-MeC6H4	A	83i	79
10	H	4-O2NC6H4	A	83j	69
11	H	2-O2NC6H4	A	83k	65
12	H	Et	A	83l	70
13	H	2-Furyl	A	83m	72
14	H	3-MeO-4-OHC6H4	A	83n	55
15	H	4-ClC6H4	B	83b	90
16	H	C6H5	B	83b	92
17	H	4-MeOC6H4	B	83g	85
18	H	4-BrC6H4	B	83d	90
19	H	4-MeC6H4	B	83i	78
20	H	4-NCC6H4	B	83o	95
21	H	4-F3CC6H4	B	83p	90
22	H	4-FC6H4	B	83q	95
23	H	2-MeC6H4	B	83r	80
24	H	2-ClC6H4	B	83s	87
25	H	3-BrC6H4	B	83e	82
26	H	3-ClC6H4	B	83c	85
27	H	1-Naphthyl	B	83t	78
28	H	2-Furyl	B	83u	90
29	H	^nPr	B	83v	65
30	H	^iPr	B	83w	76
31	3-Me	C6H5	B	83x	82
32	3-Me	C6H5	B	83y	78

---

Tajbakhsh et al. synthesized a magnetically recoverable nano-catalyst based on a biimidazole Cu(I) complex by covalent grafting of biimidazole on chloride-functionalized silica@magnetite nanoparticles, followed by metalation with CuI. The prepared nanocatalyst was also shown to have excellent and green catalytic activity in the synthesis of imidazo[1,2-a]pyridines 83a–y via the one-pot reaction of 2-aminopyridines 9, aldehydes 7 and phenylacetylene 35 in aqueous media (Scheme 55, Table 45, Method B).⁹⁵

Multi-component reaction of various types of aldehydes 7, 2-aminopyridines 9 and trimethylsilyl cyanide was carried out in the presence of MCM-41 supported boron trifluoride (BF₃/MCM-41) as a nanostructured solid acid catalyst for the synthesis of 3-iminoaryl-imidazo[1,2-a]pyridine derivatives 84a–i (Scheme 56, Table 46). MCM-41 nanoparticles were synthesized by a sol–gel method and BF₃/MCM-41 samples with various loading amounts of BF₃ and different calcination temperatures were prepared and characterized by XRD, SEM and FT-IR techniques.⁹⁶

Scheme 56

Table 46 Synthesis of 3-iminoaryl-imidazo[1,2-a]pyridine derivatives 84a–i

Entry	R^1	R^2	Product	Yield (%)
1	H	H	84a	95
2	H	6-Me	84b	75
3	3-Pyridyl	H	84c	85
4	4-Me	H	84d	80
5	4-MeO	H	84e	80
6	4-F	H	84f	80
7	4-Me	6-Me	84g	85
8	2-OH	4-Me	84h	80
9	4-F	6-Me	84i	75

---

Sanaeishoar et al. prepared LaMnO₃ perovskit nanoparticles using a sol–gel method. This perovskite-type oxide as a green and reusable catalyst for the synthesis of imidazo[1,2-a]pyridines 85a–o by the reaction between 2-aminopyridine 9, benzaldehydes 7, and cyclohexyl isocyanide under solvent-free conditions within 1.5 h at 35 °C (Scheme 57, Table 47). The products 85a–o were prepared under solvent free conditions without any additives.⁹⁷

Scheme 57

Table 47 Synthesis of imidazo[1,2-a]pyridines 85a–o

Entry	X	R	Product	Yield (%)
1	H	C6H5	85a	96
2	H	4-MeC6H4	85b	95
3	H	4-ClC6H4	85c	99
4	H	4-Me2NC6H4	85d	94
5	H	2-Fluorenyl	85e	95
6	H	4-MeOC6H4	85f	91
7	H	4-BrC6H4	85g	99
8	H	2-Thiophen	85h	97
9	Me	C6H5	85i	95
10	Me	4-MeC6H4	85j	94
11	Me	2,4-Me2C6H3	85k	91
12	Me	4-ClC6H4	85l	98
13	Me	4-Me2NC6H4	85m	94
14	Me	2-Fluorenyl	85n	94
15	Me	4-BrC6H4	85o	99

---

2.3.3.5. Fused [5-6] systems: three heteroatoms [1:2].
2.3.3.5.1. Pyrrolo[2,3-d]pyrimidine. Paul et al. developed a highly convergent, efficient and practical heteroannulation protocol for the synthesis of a library of uracil fused pyrrole derivatives 87a–i by reactions involving the CuFe₂O₄ nanoparticles catalyzed one-pot three-component domino coupling of 6-aminouracil 86, aldehydes 7 and nitromethane (Scheme 58, Table 48).⁹⁸

Scheme 58

Table 48 Synthesis pyrrolo[2,3-d]pyrimidine 87a–i

Entry	R	R^1	Product	Yield%
1	C6H5	Me	87a	89
2	4-MeOC6H4	Me	87b	92
3	4-FC6H4	Me	87c	88
4	4-MeC6H4	Me	87d	92
5	C6H5	H	87e	91
6	4-MeOC6H4	H	87f	91
7	4-FC6H4	H	87g	86
8	4-MeC6H4	H	87h	88
9	2-Furyl	H	87i	78

---

The Fe³⁺ of the magnetic nanoparticles (CuFe₂O₄) has shown excellent catalytic activity in promoting the Knoevenagel condensation reaction by enhancing the electrophilicity of the aromatic aldehydes 7. The Cu²⁺ of CuFe₂O₄ catalyzes the subsequent Michael addition reaction of the 6-aminouracil 86 to the α,β-unsaturated nitroalkene.

2.3.3.6. Fused [5-6] systems: three heteroatoms [2:1].
2.3.3.6.1. Pyrazolo[3,4-c]pyridine. MCM-41 (Mobil Composition of Matter No. 41) embedded magnetic nanoparticles which was prepared through the formation of MCM-41 in the presence of Fe₃O₄ nanoparticles has been used as a magnetically recoverable catalyst for the synthesis of new series of pyrazolo[3,4-c]pyridine derivatives 89a–p. The reaction proceeded by the reaction of 3,5-dibenzylidenepiperidin-4-one 88 with methylhydrazine, hydrazine hydrate or hydrazine hydrate and subsequent acylation of the bicyclic compounds with acetic anhydride (Scheme 59, Table 49).⁹⁹

Scheme 59

Table 49 Synthesis of pyrazolo[3,4-c]pyridine derivatives 89a–p

Entry	X	R	Product	Yield (%)
1	4-Me	Me	89a	97
2	2,4-Cl2	Me	89b	98
3	4-Br	Me	89c	90
4	4-PhCH2O	Me	89d	95
5	2,3-Cl2	Me	89e	98
6	4-Cl	Me	89f	98
7	4-MeO	Me	89g	90
8	4-F	Me	89h	98
9	4-Me	Me	89i	98
10	4-CN	Me	89j	96
11	4-Cl	COMe	89k	90
12	4-PhCH2O	COMe	89l	90
13	4-CN	COMe	89m	95
14	2,3-Cl2	H	89n	95
15	3-O2N	H	89o	96
16	2,4-Cl2	H	89p	98

---

It is worth mentioning that 3,5-dibenzylidenepiperidin-4-one with electron-withdrawing groups on the phenyl rings induce greater electronic positive charge on the corresponding β-atoms and reacted rapidly whereas electron-rich groups on the phenyl rings require longer reaction times.

A plausible mechanism for the formation of pyrazolo[4,3-c]pyridines 89a–p is shown in Scheme 60. Because of the Lewis acidity property of the Fe³⁺, the intermediate 88 can be formed through the reaction of hydrazine hydrate with activated C=C double bond of 3,5-dibenzylidenepiperidin-4-one 88. Then, the nucleophilic attack of the other NH₂ group on the carbonyl (C=O) moiety gives intermediate (4). Finally, the expected product (5) is afforded by water elimination.

Scheme 60

2.3.3.6.2. Imidazo[4,5-b]pyridine. Rai et al. reported unprecedented version of the Ugi three-component coupling reaction, in which isocyanides 91 react with unprotected aldoses 90 as biorenewable aldehyde components 7 and acyclic amidines 28 as amine components. The reaction proceeds through [4 + 1] cycloaddition of a conjugated imine intermediate with the isocyanide 91 followed by dehydrative ring transformation of the resulting 4-amino-5-(polyhydroxyalkyl)imidazole to afford imino sugarannulated imidazoles 92a–f and 93a–f in excellent yields (86–95%). The procedure is performed in one pot in the presence of a nanoclay (K-10) catalyst, and can be expeditiously effected under solvent-free microwave-irradiation conditions (Scheme 61, Table 50).¹⁰⁰

Scheme 61

Table 50 Synthesis of imino sugarannulated imidazoles 92a–f and 93a–f

Entry	R^1	R^2	Product	Time^a (min)	Yield^b (%)
a Time required for completion of the reaction as indicated by TLC.b Yield of isolated and purified products.
1	Ph	Ph	92a	12	91
2	Ph	Bn	92b	15	88
3	Me	Ph	92c	12	90
4	Me	Bn	92d	12	89
5	4-ClC6H4	Ph	92e	14	94
6	4-ClC6H4	Bn	92f	12	92
7	Ph	Ph	93a	15	91
8	Ph	Bn	93b	15	90
9	Me	Ph	93c	15	90
10	Me	Bn	93d	12	86
11	4-ClC6H4	Ph	93e	13	92
12	4-ClC6H4	Bn	93f	12	95

---

2.3.3.7. Fused [6-5] systems: three heteroatoms [1:2].
2.3.3.7.1. Dihydropyrano[2,3-c]pyrazole. Nano magnetic complex lanthanum strontium magnesium oxide La_0.7Sr_0.3MnO₃ (LSMO) has been explored as an efficient and recyclable catalyst to effect the one-pot three-component synthesis of 1,4-dihydropyrano[2,3-c]pyrazol-5-yl cyanide 95 by condensation reactions between aromatic aldehydes 7, malononitrile 46 and 3-methyl-1-phenyl-2-pyrazolin-5-one 94 in EtOH under ultrasound irradiation conditions (Scheme 62, Table 51, Method A).⁶⁸

Scheme 62

Table 51 Synthesis of 1,4-dihydropyrano[2,3-c]pyrazol-5-yl cyanide 95a–r by Methods A–C

Entry	Ar	Product	Method	Time (min)	Yield (%)
1	Ph	95a	A	11	89
2	4-FC6H4	95b	A	5	95
3	4-ClC6H4	95c	A	6	92
4	3-ClC6H4	95d	A	8	88
5	4-BrC6H4	95e	A	11	87
6	3-O2NC6H4	95f	A	5	90
7	4-O2NC6H4	95g	A	6	91
8	2,4-Cl2C6H3	95h	A	11	88
9	3-EtO-4-HOC6H3	95i	A	14	86
10	4-PhC6H4	95j	A	9	91
11	2-Naphthyl	95k	A	11	90
12	4-HOCC6H4	95l	A	10	86
13	PhCH=CH	95m	A	80	Trace
14	PhCH2CH2	95n	A	80	Trace
15	Ph	95a	B	15	97
16	4-MeOC6H4	95o	B	30	83
17	4-MeC6H4	95p	B	20	93
18	2-ClC6H4	95q	B	30	86
19	3-ClC6H4	95d	B	15	91
20	4-ClC6H4	95c	B	15	95
21	4-BrC6H4	95e	B	20	90
22	4-PhC6H4	95j	B	15	90
23	4-OHCC6H4	95l	B	10	83
24	3-O2NC6H4	95f	B	10	98
25	4-O2NC6H4	95g	B	10	97
26	2-FC6H4	95r	B	10	90
27	2-Naphthyl	95k	B	12	92
28	Ph	95a	C	15	96
29	4-MeOC6H4	95o	C	25	85
30	4-MeC6H4	95p	C	15	92
31	2-ClC6H4	95q	C	20	88
32	3-ClC6H4	95d	C	15	96
33	4-ClC6H4	95c	C	10	95
34	4-BrC6H4	95e	C	15	92
35	4-PhC6H4	95j	C	15	87
36	4-OHCC6H4	95l	C	10	87
37	3-O2NC6H4	95f	C	10	97
38	4-O2NC6H4	95g	C	5	97
39	2-FC6H4	95r	C	5	91

---

Azarifar et al. reported also the synthesis of highly functionalized 1,4-dihydropyrano[2,3-c]pyrazole derivatives 95 from the ultrasound promoted reactions between 7, 45 and 94 in the presence of nano-titania-supported Preyssler-type heteropolyacid (n-TiO₂/H₁₄[NaP₅W₃₀O₁₁₀]) as an efficient and reusable heterogeneous catalyst (Scheme 62, Table 51, Method B).⁶⁹

Nano-titania sulfuric acid (15 nm TSA) was also used as an efficient and reusable heterogeneous catalyst to furnish the synthesis of 95 in high to excellent yields by a similar ultrasound promoted reactions (Scheme 62, Table 51, Method C).⁷⁰

A four-component reaction of hydrazine hydrate or phenyl hydrazine 23, ethyl 3-alkyl-3-oxo propanoate 15, aldehydes 7 and malononitrile 46 has been performed in the presence of nanosized magnesium oxide as a highly effective heterogeneous base catalyst to produce of 6-amino-3-alkyl-4-aryl-5-cyano-1,4-dihydropyrano[2,3-c]pyrazole derivatives 96 in excellent yields and in a short experimental time. This method is simple and rapid for focusing a pyrano ring with a pyrazole ring (Scheme 63, Table 52, Method A).¹⁰¹

Scheme 63

Table 52 Synthesis of 1,4-dihydropyrano[2,3-c]pyrazole derivatives 96a–x by Methods A and B

Entry	R	R^1	Ar	Product	Method	Yield (%)
1	H	Me	C6H5	96a	A	97
2	H	Me	2-ClC6H4	96b	A	93
3	H	Me	4-ClC6H4	96c	A	97
4	H	Me	3-BrC6H4	96d	A	90
5	H	Me	4-O2NC6H4	96e	A	90
6	H	Me	4-MeOC6H4	96f	A	89
7	Ph	Me	C6H5	96g	A	95
8	Ph	Me	4-MeC6H4	96h	A	93
9	Ph	Me	4-MeOC6H4	96i	A	90
10	Ph	Me	4-ClC6H4	96j	A	96
11	Ph	Me	2,4-Cl2C6H3	96k	A	92
12	Ph	Me	4-BrC6H4	96l	A	88
13	Ph	Pr	4-ClC6H4	96m	A	92
14	Ph	^iPr	4-ClC6H4	96n	A	93
15	Ph	^iPr	2,4-Cl2C6H3	96o	A	95
16	H	Me	C6H5	96a	B	96
17	H	Me	3-MeO-4-HOC6H3	96p	B	81
18	H	Me	4-ClC6H4	96j	B	93
19	H	Me	4-MeOC6H4	96i	B	89
20	H	Me	4-O2NC6H4	96e	B	87
21	H	Me	2,4-Cl2C6H3	96k	B	85
22	H	Me	4-BrC6H4	96l	B	86
23	H	Me	3-BrC6H4	96d	B	86
24	H	Me	2-ClC6H4	96b	B	85
25	H	Me	2-O2NC6H4	96q	B	82
26	H	Me	2,4-Cl2C6H3	96k	B	87
27	H	Me	4-FC6H4	96r	B	87
28	H	Me	4-MeC6H4	96h	B	85
29	H	Me	2,5-(MeO)2C6H3	96s	B	85
30	H	Me	3,4-(MeO)2C6H3	96t	B	82
31	H	Me	3,4,5-(MeO)3C6H2	96u	B	84
32	H	Me	4-HOC6H4	96v	B	81
33	H	Me	4-Me2NC6H4	96w	B	81
34	H	Me	3-O2NC6H4	96x	B	92

---

Shaterian and Azizi et al. reported also a convenient and efficient solvent-free procedure for preparation of 6-amino-4-aryl-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles 96 by a similar four component reaction in the presence of a catalytic amount of titanium dioxide nano-sized particles (Scheme 63, Table 52, Method B).¹⁰²

Pradhan et al. synthesized CuFe₂O₄ magnetic nanoparticles and reported their use as an efficient catalyst for the one-pot synthesis of dihydropyrano[2,3-c]pyrazole derivatives 97a–k at mild conditions and in excellent yields. The four component reaction (4CRs) of a wide variety of substituted hydrazine derivatives 23, ethyl acetoacetate 15, dialkyl acetylenedicarboxylates 8 and alkyl nitrile derivatives 46 (malononitrile and ethyl cyanoacetate) gave the targeted dihydropyrano[2,3-c]pyrazoles 97a–k in good yield (Scheme 64, Table 53).⁷²

Scheme 64

Table 53 Synthesis of dihydropyrano[2,3-c]pyrazole derivatives 97a–k

Entry	R^1	R^2	R^3	Product	Yield (%)
1	C6H5	Et	CN	97a	95
2	4-O2NC6H4	Et	CN	97b	90
3	4-BrC6H4	Et	CN	97c	94
4	4-NCC6H4	Et	CN	97d	94
5	H	Et	CN	97e	97
6	C6H5	Me	COOEt	97f	93
7	4-O2NC6H4	Me	COOEt	97g	98
8	4-BrC6H4	Me	COOEt	97h	92
9	4-NCC6H4	Me	COOEt	97i	92
10	H	Me	COOEt	97j	96
11	H	Et	COOEt	97k	85

---

2.3.3.8. Fused [5-7] systems: four heteroatoms [2:2].
2.3.3.8.1. Pyrazolo[3,4-e][1,4]thiazepine. Nano n-propylsulfonated γ-Al₂O₃ is easily prepared by the reaction of nano γ-Al₂O₃ with 1,3-propanesultone. This reagent can be used as an efficient catalyst for the synthesis of spiro[indoline-3,4-pyrazolo[3,4-e][1,4]thiazepine]diones 100a–p by a four-component condensation reaction of 3-aminocrotononitrile 98, phenylhydrazine 23, isatin 58 and 2-mercaptoacetic acid 99 in aqueous media (Scheme 65, Table 54). This method consistently has the advantages of excellent yields and short reaction times. Further, the catalyst can be reused and recovered several times.¹⁰³

Scheme 65

Table 54 Synthesis of spiro[indoline-3,4-pyrazolo[3,4-e][1,4]thiazepine]diones 100a–p

Entry	R^1	R^2	R^3	Product	Time (h)	Yield (%)
1	H	H	H	100a	5	91
2	H	H	Me	100b	5	92
3	H	5-Cl	Me	100c	8	88
4	H	5-Br	H	100d	8	87
5	H	5-F	H	100e	5	90
6	H	5-F	Me	100f	5	93
7	H	5-Me	H	100g	7	87
8	H	5-Me	Me	100h	7	86
9	Me	H	H	100i	6	90
10	Me	H	Me	100j	6	92
11	H	5-O2N	H	100k	10	Trace
12	H	5-O2N	Me	100l	10	Trace
13	H	6-Cl	H	100m	7	91
14	H	6-Cl	Me	100n	8	88
15	H	6-Br	H	100o	7	88
16	H	6-Br	Me	100p	8	90

---

2.3.3.9. Fused [6-6] systems: one bridgehead heteroatom and one extra atom.
2.3.3.9.1. Pyrido[1,2-c]pyrimidine. Yadav and Rai have developed nanoclay-catalyzed unprecedented three component [3 + 2 + 1] coupling protocol for an expeditious synthesis of pharmaceutically relevant multifunctionalized fused pyrimidines 103, 105 in excellent yields (79–92%) with high trans-diastereoselectivity (>94%) using unprotected aldoses as a biorenewable aldehyde component 7, an active methylene building block 2-phenyl-1,3-oxazol-5-one (101), and amidines/guanidine 28 (Scheme 66, Table 55). The reaction proceeds under solvent-free MW irradiation conditions via initial formation of the protected benzoylamine derivatives 102 and 104, respectively, followed by acid hydrolysis.¹⁰⁴

Scheme 66

Table 55 Synthesis of pyrido[1,2-c]pyrimidines 103 and 105

Entry	R	Product	Time (min)	Yield (%)	trans/cis Ratio
1	Me	103a	10	89	98 : 2
2	NH2	103b	10	79	95 : 5
3	H	103c	12	88	97 : 3
4	Ph	103d	10	92	96 : 4
5	4-O2NC6H4	103e	11	90	96 : 4
6	4-H2NC6H4	103f	10	83	98 : 2
7	Me	105a	11	86	96 : 4
8	NH2	105b	12	89	95 : 5
9	H	105c	10	91	97 : 3
10	Ph	105d	12	89	95 : 5
11	4-O2NC6H4	105e	10	82	98 : 2
12	4-H2NC6H4	105f	10	90	96 : 4
13	Me	103a	4	45	95 : 5
14	Me	105a	6	52	95 : 5

---

2.3.3.10. Fused [6-6] systems: three heteroatoms [1:2].
2.3.3.10.1. Pyrido[2,3-d]pyrimidine. The magnetic nanoparticles supported silica sulfuric acid (Fe₃O₄@SiO₂–SO₃H) was used as an efficient catalyst for the synthesis of pyrido[2,3-d]pyrimidines 106a, 106b by reacting 6-amino-1,3-dimethyl uracil 86 with ethylacetoacetate 15 and various substituent benzaldehydes 7 in water (Scheme 67). The desired products 106a, 106b were obtained in excellent yields irrespective of the presence of an electron withdrawing or releasing substituent. The catalyst was readily recovered using an external magnet and could be reused several times without significant loss of reactivity.¹⁰⁵

Scheme 67

2.3.3.10.2. Pyrido[2,3-b]pyrazine. Malakooti reported the synthesis of pyrido[2,3-b]pyrazines 108a–c catalyzed by a heterogeneous nanocatalyst Fe(III)-Schiff base/SBA-15 from the reaction of 2,3-diaminopyridine 107 with the appropriate 1,2-diketone 25 (Scheme 68). These reactions proceeded in water with excellent yields.⁶⁶

Scheme 68

2.3.3.10.3. Pyrido[3,4-b]pyrazine. The same authors reported the synthesis of pyrido[3,4-b]pyrazines 110a–c from the reaction of 3,4-diaminopyridine 109 with the appropriate 1,2-diketone 25 under similar reaction conditions and using the same nano-catalyst (Scheme 69).⁶⁶

Scheme 69

2.4. Synthesis of fused tricyclic systems

2.4.1. Fused [5-6-6] system: one bridgehead heteroatom.
2.4.1.1. Pyrrolo[1,2-a]quinoline. Albaladejo et al. reported the synthesis of a wide range of pyrrolo[1,2-a]quinolines in moderate-to-high yields (59–93%) by the reaction of quinoline-2-carbaldehyde (111) with secondary amines and phenylacetylene (35) using low catalyst loading (0.5 mol%) of Cu NPs/C (Cu NPs on activated carbon) (Scheme 70, Table 56).⁹²

Scheme 70

Table 56 Synthesis of pyrrolo[1,2-a]quinolones 112a–f

Entry	R	Product	Yield (%)
1	C6H5	112a	82
2	C6H5	112b	92
3	4-MeC6H4	112c	84
4	4-CF3C6H4	112d	79
5	4-MeOC6H4	112e	84
6	4-BrC6H4	112f	72

---

2.4.2. Fused [5-6-6] system: two bridgehead heteroatoms.
2.4.2.1. Pyrazolo[2,1-b]phthalazine. Kiasat et al. developed an efficient, and high yielding one-pot protocol for the synthesis of 2H-pyrazolo[2,1-b]phthalazinedione derivatives 115 by three-component coupling of phthalhydrazide 113, acetylacetone 15 and some aromatic aldehydes 7 in ecofriendly neat conditions promoted by nano-γ-alumina sulforic acid (Scheme 71, Table 57, Method A).¹⁰⁶

Scheme 71

Table 57 Synthesis of 2H-pyrazolo[2,1-b]phthalazinedione derivatives 115a–s by Methods A–C

Entry	R	R^1	R^2	Product	Method	Yield (%)
a Product is the bis-derivative:
1	C6H5	COMe	Me	114a	A	88
2	4-ClC6H4	COMe	Me	114b	A	60
3	4-MeOC6H4	COMe	Me	114c	A	81
4	4-O2NC6H4	COMe	Me	114d	A	77
5	4-NCC6H4	COMe	Me	114e	A	70
6	2-ClC6H4	COMe	Me	114f	A	67
7	C6H5	CN	NH2	114g	B	90
8	2-ClC6H4	CN	NH2	114h	B	89
9	3-ClC6H4	CN	NH2	114i	B	91
10	4-O2NC6H4	CN	NH2	114j	B	87
11	4-FC6H4	CN	NH2	114k	B	93
12	4-MeC6H4	CN	NH2	114l	B	86
13	2-BrC6H4	CN	NH2	114m	B	90
14	3-MeOC6H4	CN	NH2	114n	B	87
15	4-Pyridyl	CN	NH2	114o	B	86
16	3-Pyridyl	CN	NH2	114p	B	90
17	2-Naphthyl	CN	NH2	114q	B	91
18	3-OHC-C6H4	CN	NH2	114r	B	88^a
19	2,4-Cl2C6H3	CN	NH2	114s	B	92
20	2,3-Cl2C6H3	CN	NH2	114t	B	91
21	C6H5	COMe	Me	114a	C	85
22	4-O2NC6H4	COMe	Me	114d	C	88
23	4-NCC6H4	COMe	Me	114e	C	87
24	4-ClC6H4	COMe	Me	114b	C	84

---

The catalytic activity of nano-structured ZnO has also been explored in the synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones 114 via a three-component coupling reaction between 113, 15, and 7 (Scheme 71, Table 57, Method B).⁸⁸ Almost all the reactions proceeded smoothly in relatively short reaction times (8–20 min) to afford the respective 1H-pyrazolo[1,2-b]phthalazine-5,10-diones 4a–n in high yields (86–93%).

Kiasat and Davarpanah prepared Fe₃O₄@silica sulfuric acid core–shell nanocomposite (Fig. 23) and investigated its catalytic activity in the synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives 114 (Scheme 71, Table 57, Method C). The attractive features of this method are simple procedure, cleaner reaction, use of reusable catalyst, easy workup and performing multicomponent reaction under solvent free conditions.¹⁰⁷

Fig. 23 Structure of Fe₃O₄@silica sulfuric acid core–shell nanocomposite.

Shaterian and Mohammadnia reported an efficient, one-pot procedure for preparation of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives 116a–ab from four-component condensation reaction of hydrazine monohydrate 23, phthalic anhydride 115, malononitrile or ethyl cyanoacetate 46 and aromatic aldehydes 7 in the presence of magnetic Fe₃O₄ nanoparticles coated by (3-aminopropyl)-triethoxysilane (Fig. 24) as catalyst under mild, ambient, and solvent-free conditions (Scheme 72, Table 58). The magnetic Fe₃O₄ nanoparticles coated by (3-aminopropyl)-triethoxysilane can be recovered and reused several times without loss of activity.¹⁰⁸

Fig. 24 Structure of magnetite–sulfuric acid (Fe₃O₄·SO₃H) magnetic nanoparticles.

Scheme 72

Table 58 Synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives 116a-ab

Entry	ArCHO	X	Product	Time (min)	Yield (%)
1	C6H5CHO	CN	116a	19	92
2	2-ClC6H4CHO	CN	116b	15	93
3	3-ClC6H4CHO	CN	116c	16	90
4	4-ClC6H4CHO	CN	116d	15	93
5	4-FC6H4CHO	CN	116e	17	89
6	2-O2NC6H4CHO	CN	116f	14	91
7	4-BrC6H4CHO	CN	116g	15	92
8	3-BrC6H4CHO	CN	116h	16	89
9	3-ClC6H4CHO	CO2Et	116i	23	88
10	2-O2NC6H4CHO	CO2Et	116j	21	89
11	3-O2NC6H4CHO	CO2Et	116k	22	91
12	4-O2NC6H4CHO	CO2Et	116l	21	89
13	4-BrC6H4CHO	CO2Et	116m	22	90
14	2,6-Cl2C6H3CHO	CN	116n	14	92
15	2,4-Cl2C6H3CHO	CN	116o	15	91
16	2,3-Cl2C6H3CHO	CN	116p	16	93
17	2-MeOC6H4CHO	CN	116q	14	90
18	3-MeOC6H4CHO	CN	116r	16	92
19	2,4,6-(MeO)3C6H2CHO	CN	116s	17	91
20	2,6-(MeO)2C6H3CHO	CN	116t	16	93
21	5-MeC6H4CHO	CN	116u	16	92
22	4-F3CC6H4CHO	CN	116v	16	90
23	2,6-Cl2C6H3CHO	CO2Et	116w	22	89
24	2,4-Cl2C6H3CHO	CO2Et	116x	21	88
25	2,3-Cl2C6H3CHO	CO2Et	116y	23	89
26	2-MeOC6H4CHO	CO2Et	116z	22	90
27	4-F3CC6H4CHO	CO2Et	116aa	22	89
28	n-Heptanal	CN	116ab	10 h	Trace

---

2.4.3. Fused [6-6-5] system: two heteroatoms [1:1].
2.4.3.1. Chromeno[4,3-b]pyrrole. Paul et al. reported a highly convergent, efficient and practical heteroannulation protocol for the synthesis of a library of coumarin fused pyrrole derivatives 118a–k Thus, one-pot three-component domino coupling of 4-aminocoumarin 117, aldehydes 7 and nitromethane catalyzed by CuFe₂O₄ magnetic nano particles resulted in highly substituted of 118 in good yields (Scheme 73, Table 59).⁹⁸

Scheme 73

Table 59 Synthesis of chromeno[4,3-b]pyrroles 118a–k

Entry	R	Product	Yield (%)
1	C6H5	118a	87
2	4-MeO	118b	95
3	4-F	118c	85
4	4-Me	118d	87
5	3-O2N	118e	80
6	4-Cl	118f	85
7	3-HO-4-MeO	118g	84
8	4-O2N	118h	85
9	2,4-Cl2	118i	90
10	4-Br	118j	87
11	2-Thienyl	118k	81

---

2.4.4. Fused [6-6-6] systems: one heteroatoms.
2.4.4.1. Octahydro-1H-xanthene. Poly(4-vinylpyridine)-supported nanoparticles of copper(I) iodide(P4VPy–CuI) have been reported as a new, efficient and recyclable catalyst for the synthesis of 1,8-dioxooctahydroxanthenes 119a–t from the reaction of cyclic 1,3-dicarbonyl compounds 55 (dimedone and 1,3-cyclohexadione) with aldehydes 7 under solvent-free conditions (Scheme 74, Table 60).¹⁰⁹ This catalyst can be recovered by simple filtration and recycled up to 10 consecutive runs without losing of its efficiency.

Scheme 74

Table 60 Synthesis of 1,8-dioxooctahydroxanthenes 119a–t

Entry	ArCHO	R	Time (min)	Product	Yield (%)
1	C6H5CHO	Me	13	119a	88
2	2-O2NC6H4CHO	Me	15	119b	89
3	3-O2NC6H4CHO	Me	10	119c	89
4	4-O2NC6H4CHO	Me	7	119d	90
5	2-ClC6H4CHO	Me	10	119e	90
6	4-ClC6H4CHO	Me	8	119f	90
7	4-FC6H4CHO	Me	10	119g	88
8	4-MeC6H4CHO	Me	12	119h	87
9	2-MeOC6H4CHO	Me	25	119i	87
10	4-MeOC6H4CHO	Me	28	119j	85
11	3,4-(MeO)2C6H3CHO	Me	36	119k	86
12	4-NCC6H4CHO	Me	14	119l	85
13	4-HOC6H4CHO	Me	35	119m	86
14	C6H5CHO	H	12	119n	90
15	4-BrC6H4CHO	H	9	119o	90
16	4-ClC6H4CHO	H	8	119p	91
17	4-MeOC6H4CHO	H	30	119q	86
18	4-NCC6H4CHO	H	12	119r	90
19	3-BrC6H4CHO	H	8	119s	87
20	3-MeOC6H4CHO	H	30	119t	88

---

2.4.4.2. Decahydroacridine. Dam et al. developed an efficient, high yielding, expeditious method for the synthesis of decahydroacridine derivatives 120a–n via an one-pot multi-component condensation of dimedone 55, aldehydes 7, and ammonium acetate in water using Fe₃O₄@SiO₂ nanoparticles as a recyclable heterogeneous catalyst. This method takes advantage of the fact that water, a green solvent is used in combination with Fe₃O₄@SiO₂ nanoparticles as catalyst which can be easily recovered magnetically and reused for further runs (Scheme 75, Table 61, Method A).¹¹⁰ The nature and position of substitution in the aromatic ring did not affect the reactions much. The reaction was tried with aliphatic aldehydes, ketones, and furfuraldehyde but no desired product 120a–n was formed after 5 h of refluxing.

Scheme 75

Table 61 Synthesis of decahydroacridine derivatives 120a–n by Methods A and B

Entry	Ar	Product	Method	Yield (%)
1	4-ClC6H4	120a	A	92
2	4-BrC6H4	120b	A	89
3	4-NCC6H4	120c	A	93
4	4-O2NC6H4	120d	A	95
5	2-O2NC6H4	120e	A	94
6	2-ClC6H4	120f	A	90
7	4-MeOC6H4	120g	A	85
8	4-MeC6H4	120h	A	82
9		120i	B	90
10		120j	B	87
11		120k	B	81
12		120l	B	78
13		120m	B	83
14		120n	B	86

---

Fekri et al. reported also an efficient, three component synthesis of novel class of decahydroacridine derivatives 120a–n from reaction between the appropriate aldehydes 7, dimedone 55 and ammonium acetate in the presence of nano Fe₃O₄ as a recyclable catalyst under ultrasonic irradiation (Scheme 74, Table 61, Method B).¹¹¹

2.4.4.3. 3H-Benzo[f]chromene.
2.4.4.4. 2H-Benzo[g]chromene. 2H-Benzo[h]chromen-2-one 122 and 2H-benzo[g]chromen-2-one derivatives 124 were synthesized by refluxing in acetonitrile of ethyl acetoacetate or ethyl benzoyl acetate 15, with each of α-naphthol 123 and β-naphthol 121 with a catalytic combination of pyridine dicarboxylic acid as organocatalyst and nanocrystallin ZnO (Scheme 76).⁸³

Scheme 76

2.4.4.5. 4H-Benzo[h]chromene.
2.4.5.1. 1H-benzo[f]chromene. Kumar et al. found that nanosized magnesium oxide can easily catalyze three-component condensation reaction of aldehydes 7, malononitrile 46, and α-naphthol 123 in water–PEG to afford the corresponding 4H-Benzo[h]chromenene 125a–f in high yields at room temperature (Scheme 77, Table 62, Method A). The greener protocol was found to be fairly general and the catalyst was reused in subsequent reactions with consistent activity.¹¹²

Scheme 77

Table 62 Synthesis of 4H-Benzo[h]chromenene 125a–f by Methods A and B

Entry	R	Method	Product	Yield^a%
a Yield in methanol between paranthes.
1	Ph	A	125a	86(96)
2	4-MeOC6H4	A	125b	85(95)
3	3-O2NC6H4	A	125c	92(96)
4	4-O2NC6H4	A	125d	93(97)
5	4-ClC6H4	A	125e	86(89)
6	2-Furyl	A	125f	84(87)
7	4-O2NC6H4	B	125g	98
8	Ph	B	125a	85
9	4-HOC6H4	B	125h	85
10	4-MeOC6H4	B	125b	50
11	4-ClC6H4	B	125e	95
12	3-ClC6H4	B	125i	75
13	2-ClC6H4	B	125j	80
14	2-Thiophenyl	B	125k	90
15	2-Furyl	B	125f	60

---

Hosseini-Sarvari et al. used nano ZnO as an efficient catalyst for the synthesis of 2-amino-4H-chromenes 125a, 125b, 125e, 125f, 125g–k from methylenemalononitrile, generated in situ from aldehyde 7 and malononitrile 46 and naphthol 123 (Scheme 77, Table 62, Method B).⁸⁴

Hosseini-Sarvari et al. also used nano ZnO to catalyze the reaction of various naphthalenediols 126, 128, 130, 132, 134 with aldehydes 7 and malononitrile 46 to produce 4H-benzo[h]chromene 127 and 129 (Scheme 78) and 1H-benzo[f]chromene 131, 133, and 135 (Scheme 79).⁸⁴

Scheme 78

Scheme 79

2.4.5. Fused [6-6-6] system: two heteroatoms [1:1].
2.4.5.1. Dihydropyrano[3,2-c]chromene. CuFe₂O₄ magnetic nanoparticles were synthesized and recognized as an efficient catalyst for the one-pot synthesis of pyrano[3,2-c]coumarin derivatives 137a–d in aqueous medium at mild conditions and in excellent yields. The reaction proceeds via MCR's of 4-hydroxycoumarin 136, dialkyl acetylenedicarboxylates 8 and malononitrile or ethyl cyanoacetate 46 (Scheme 80, Table 63).⁷²

Scheme 80

Table 63 Synthesis of pyrano[3,2-c]coumarin derivatives 137a–d

Entry	R^1	R^2	Product	Yield (%)
1	Et	CN	137a	90
2	Et	CO2Et	137b	87
3	Me	CN	137c	88
4	Me	CO2Et	137d	84

---

Lashgari et al. applied sulfonic acid functionalized SBA-15 (SBA-Pr–SO₃H) as a new nanoporous solid acid catalyst in the green one-pot three-component synthesis of spirooxindole-4H-pyrans 138a–i via condensation of isatins 58, malononitrile or methyl cyanoacetate or ethyl cyanoacetate 46, and 4-hydroxycoumarin 136 in water solvent (Scheme 81, Table 64).¹¹³

Scheme 81

Table 64 One-pot three-component synthesis of spirooxindole-4H-pyrans 138a–i

Entry	R	X	Product	Time (min)	Yield (%)
1	H	CN	138a	15	90
2	Cl	CN	138b	20	85
3	Br	CN	138c	20	78
4	H	CO2Me	138d	20	75
5	Cl	CO2Me	138e	20	78
6	Br	CO2Me	138f	35	75
7	H	CO2Et	138g	30	83
8	Cl	CO2Et	138h	30	91
9	Br	CO2Et	138i	35	84

---

2.4.6. Fused [6-6-6] system: three heteroatoms [2:1].
2.4.6.1. Tetrahydropyrimido[4,5-b]quinoline. Nemati and Saeedirad used magnetic nanoparticles supported silica sulfuric acid (Fe₃O₄@SiO₂–SO₃H) as an efficient catalyst for the synthesis of pyrimido[4,5-b]quinolines 139a–i by reacting 6-amino-1,3-dimethyl uracil 86 with dimedone 55 and various substituent benzaldehydes 7 in water (Scheme 82, Table 65).¹⁰⁵ The desired products were obtained in excellent yields irrespective of the presence of an electron withdrawing or releasing substituent. The catalyst was readily recovered using an external magnet and could be reused several times without significant loss of reactivity.

Scheme 82

Table 65 Synthesis of pyrimido[4,5-b]quinolines 139a–i

Entry	Ar	Product	Time (min)	Yield (%)
1	Ph	139a	30	92
2	4-MeOC6H4	139b	40	86
3	3-BrC6H4	139c	35	90
4	4-O2NC6H4	139d	25	92
5	3-O2NC6H4	139e	30	90
6	2-ClC6H4	139f	35	81
7	4-ClC6H4	139g	25	92
8	4-FC6H4	139h	30	89
9	2-Thiophene	139i	35	87

---

2.4.7. Fused [6-6-6] system: five heteroatoms [2:1:2].
2.4.7.1. Pyrimido[5′,4′:5,6]pyrido[2,3-d]pyrimidine. The magnetic nanoparticles supported silica sulfuric acid (Fe₃O₄@SiO₂–SO₃H) was successfully used as an efficient catalyst for the synthesis of pyrimido[5′,4′:5,6]pyrido[2,3-d]pyrimidine 140 by reacting 6-amino-1,3-dimethyl uracil 86 with 6-amino-1,3-dimethylbarbituric acid and various substituent benzaldehydes 7 in water (Scheme 83).¹⁰⁵ The desired products were obtained in excellent yields irrespective of the presence of an electron withdrawing or releasing substituent.

Scheme 83

2.4.8. Fused [6-6-7] system: two heteroatoms.
2.4.8.1. Tetrahydro-1H-dibenzo[b,e][1,4]diazepine. Maleki and Kamalzare et al. developed a new efficient, and green procedure for the synthesis of benzodiazepine derivatives 141a–l in high yields via a one-pot, three-component reaction of o-phenylenediamine 9, dimedone 55, and different aldehydes 7 at room temperature by using a magnetic recyclable Fe₃O₄@chitosan composite nanocatalyst (Scheme 84, Table 66).¹¹⁴

Scheme 84

Table 66 Synthesis of benzodiazepine derivatives 141a–l

Entry	Ar	Product	Yield (%)
1	4-O2NC6H4	141a	94
2	3-O2NC6H4	141b	89
3	4-ClC6H4	141c	91
4	2-ClC6H4	141d	90
5	2,4-Cl2C6H3	141e	96
6	4-HOC6H4	141f	88
7	2-HOC6H4	141g	85
8	4-MeC6H4	141h	91
9	4-Me2NC6H4	141i	94
10	2-Thienyl	141j	85
11	2-Furyl	141k	87
12	2-Pyridyl	141l	84

---

2.5. Synthesis of fused tetracyclic systems

2.5.1. Fused [6-5-5-6] systems: three heteroatoms [1:2].
2.5.1.1. Tetrahydroindeno[1,2-b]pyrazolo[4,3-e]pyridine. Mohammad et al. reported the synthesis of fused azo-linked pyrazolo[4,3-e]pyridines 144a–f, and 145a–c from indan-1,3-dione 142 and 3-amino-5-methylpyrazole 143, using nano-Fe₃O₄ in water as an effective and reusable catalyst (Scheme 85, Table 67).¹¹⁵ It is important to point out the fact that when 3-amino-5-methylpyrazole (143), indan-1,3-dione (142) and azo-linked benzaldehyde containing electron releasing substituents 7g–i were refluxed for required reaction time, the reaction leads to the formation of the aromatized pyrazolopyridine 145g–i, but in the case of using azo-linked aldehydes containing electron withdrawing substituents 7a–f, just pyrazolopyridine 144a–f were observed.

Scheme 85

Table 67 Synthesis of fused azo-linked pyrazolo[4,3-e]pyridines 144a–f and 145a–c

Entry	Ar	Product	Time (min)	Yield (%)
1	4-IC6H4	144a	5	75
2	4-O2NC6H4	144b	8	83
3	2-Me-4-O2NC6H4	144c	8	75
4	2-ClC6H4	144d	5	83
5	3-ClC6H4	144e	5	95
6	4-ClC6H4	144f	5	84
7	Ph	145a	2	86
8	4-MeC6H4	145b	1	79
9	4-MeOC6H4	145c	1	87

---

2.5.2. Fused [6-5-6-6] systems: two bridgehead heteroatoms.
2.5.2.1. Dihydro-2H-indazolo[2,1-b]phthalazine. Kiasat et al. developed a simple and efficient one-pot protocol for the synthesis of 2H-indazolo[2,1-b]phthalazinetrione derivatives 146 by three-component coupling of phthalhydrazide 113, dimedone 55 and some aromatic aldehydes 7 in ecofriendly neat conditions promoted by nano-γ-alumina sulfuric acid (Scheme 86, Table 68, Method A).¹⁰⁶

Scheme 86

Table 68 One-pot synthesis of 2H-indazolo[2,1-b]phthalazinetrione derivatives 146a-ab by Methods A–C

Entry	R^1	R^2	Method	Product	Yield (%)
a The product was:
1	C6H5	Me	A	146a	88
2	4-ClC6H4	Me	A	146b	90
3	4-O2NC6H4	Me	A	146c	94
4	4-HOC6H4	Me	A	146d	85
5	4-NCC6H4	Me	A	146e	92
6	3-FC6H4	Me	A	146f	90
7	3-ClC6H4	Me	A	146g	90
8	3-MeC6H4	Me	A	146h	88
9	4-MeC6H4	Me	A	146i	86
10	4-MeOC6H4	Me	A	146j	85
11	2-O2NC6H4	Me	A	146k	90
12	C6H5	Me	B	146a	93
13	2-MeC6H4	Me	B	146l	91
14	4-MeC6H4	Me	B	146i	90
15	3-MeOC6H4	Me	B	146h	87
16	4-MeOC6H4	Me	B	146j	89
17	3,4-(MeO)2C6H3	Me	B	146m	88
18	3-BrC6H4	Me	B	146n	85
19	2-ClC6H4	Me	B	146o	87
20	4-ClC6H4	Me	B	146b	93
21	2,4-(Cl)2C6H3	Me	B	146p	91
22	4-FC6H4	Me	B	146q	90
23	2-O2NC6H4	Me	B	146k	82
24	3-O2NC6H4	Me	B	146r	86
25	4-O2NC6H4	Me	B	146c	83
26	2-Naphthyl	Me	B	146s	84
27	C6H5	H	B	146t	86
28	4-Me	H	B	146u	88
29	4-MeOC6H4	H	B	146v	90
30	4-O2NC6H4	H	B	146w	83
31	4-FC6H4	H	B	146x	89
32	3-HOCC6H4	Me	B	146y	80^a
33	C6H5	Me	C	146a	85
34	4-ClC6H4	Me	C	146b	98
35	4-MeOC6H4	Me	C	146j	94
36	4-O2NC6H4	Me	C	146c	72
37	4-MeC6H4	Me	C	146i	70
38	4-CC6H4	Me	C	146e	89
39	4-F3CC6H4	Me	C	146z	78
40	4-NO2NC6H4	Me	C	146c	87
41	4-ClC6H4	Me	C	146b	70
42	3-O2NC6H4	Me	C	146r	83
43	4-BrC6H4	Me	C	146aa	80
44	4-EtOC6H4	Me	C	146ab	70

---

Kiasat and Davarpanah prepared Fe₃O₄@silica sulfuric acid core–shell nanocomposite and investigated its catalytic activity also in the synthesis of 2H-indazolo[2,1-b]phthalazine-1,6,11-trione derivatives 146 by a similar one-pot three component reaction (Scheme 86, Table 68, Method B).¹⁰⁷

Rostami et al. also applied N-propylsulfamic acid supported onto magnetic Fe₃O₄ nanoparticles (MNPs-PSA) as an efficient and magnetically recoverable catalyst for the synthesis of 2H-Indazolo[2,1-b]phthalazine-1,6,11(13H)-trione 146 from a similar one-pot three-component reaction (Scheme 86, Table 68, Method C).¹¹⁶

The same authors have developed this synthetic method for the preparation of bis-2H-indazolo[2,1-b]phthalazine-trione 146 derivative in a 2 : 1.1 : 2 molar ratio of phthalhydrazide to isophthaladehyde and dimedone (Table 68, entry 32).¹¹⁶

2.5.3. Fused [6-5-6-6] systems: three heteroatoms [1:2].
2.5.3.1. Indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine. Nemati and Saeedirad used magnetic nanoparticles supported silica sulfuric acid (Fe₃O₄@SiO₂–SO₃H) as an efficient catalyst for the synthesis of indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine 147a, 147b by reacting 6-amino-1,3-dimethyl uracil 86 with 1,3-indanedione 142 and various substituent benzaldehydes 7 in water (Scheme 87).¹⁰⁵

Scheme 87

2.6. Synthesis of fused pentaacyclic systems

2.6.1. Fused [6-6-6-6-6] systems: one heteroatom.
2.6.1.1. 14H-Dibenzo[a,j]xanthene. Novel magnetite–sulfuric acid (Fe₃O₄·SO₃H) magnetic nanoparticles MSA-MNP 1 and MSA-MNP 2 catalysts (Fig. 24) were prepared by the direct reaction of chlorosulfonic acid with magnetite nanoparticles and were shown to exhibit remarkable catalytic performance in the solvent-free synthesis of mono-, bis-, and tris-14H-dibenzo[a,j]xanthen-14-ylarenes 148a–g, 149, 150, and 152a, 152b. The reactions were performed by the reaction of 2-naphthol with benzaldehyde derivatives (Scheme 88), terephthalaldehyde, isophthalaldehyde (Scheme 89) or trialdehydes 151a and 151b (Scheme 90), respectively, in the presence of 0.1 g MSA-MNP 2 under solvent-free conditions.¹¹⁷

Scheme 88

Scheme 89

Scheme 90

2.6.2. Fused [6-6-6-6-6] systems: three heteroatoms [1:1:1].
2.6.2.1. Dichromeno[4,3-b:3′,4′-e]pyridine. Dam et al. reported an efficient, high yielding method for the synthesis of dichromeno[4,3-b:3′,4′-e]pyridine derivatives 153a–g via an one-pot multi-component condensation of 4-hydroxycoumarine 136, aldehydes 7, and ammonium acetate in water using Fe₃O₄@SiO₂ nanoparticles as a recyclable heterogeneous catalyst (Scheme 91, Table 69).¹¹⁰ The nature and position of substitution in the aromatic ring did not affect the reactions much.

Scheme 91

Table 69 Synthesis of dichromeno[4,3-b:3′,4′-e]pyridine derivatives 153a–g

Entry	Ar	Product	Yield (%)
1	4-ClC6H4	153a	88
2	4-BrC6H4	153b	86
3	4-NCC6H4	153c	90
4	4-FC6H4	153d	87
5	2-ClC6H4	153e	88
6	2-BrC6H4	153f	88
7	4-MeC6H4	153g	82

---

2.7. Synthesis of miscellaneous fused systems

2.7.1. 8,9-Dihydroacenaphtho[1,2-b]pyrazine.

2.7.2. Acenaphtho[1,2-e]pyrido[3,4-b]pyrazine.

2.7.3. Acenaphtho[1,2-e]pyrido[2,3-b]pyrazine.

2.7.4. Dibenzo[f,h]pyrido[3,4-b]quinoxaline. Malakooti et al. reported the synthesis of fused pyrazines and fused pyrido[2,3-b]pyrazines 154–157 from the reaction of the diaminopyridines with the appropriate 1,2-diketone 25 in the presence of an iron Schiff base complex encapsulated in SBA-15 mesoporous silica [Fe(III)-Schiff base/SBA-15] as heterogeneous nanocatalyst (Schemes 92–95). These reactions proceeded in water with excellent yields.⁶⁶

Scheme 92

Scheme 93

Scheme 94

Scheme 95

3. Conclusions

Heterocycles are found in many natural products, pharmaceuticals, organic materials, and in numerous functional molecules. They are especially important in chemical and pharmaceutical industries. Therefore, the ongoing interest for developing new versatile and efficient syntheses of heterocyclic systems has always been a challenge in the synthetic community. They can be synthesized by a variety of synthetic approaches.

This review compiles the literatures on the application of nanomaterials in heterocyclic synthesis. The fused heterocycles mentioned in this review are arranged in an organized manner with respect to the type of heterocyclic systems.

In most of the reactions the spent catalyst can be easily separated from the reaction mixture. It can also be reused without noticeable change in its catalytic activity. Magnetic nanomaterials can be easily recovered by simple magnet, therefore it makes the catalyst more efficient.

We hope that this review will be useful not only for organic synthetic and organometallic chemists, but also for heterocyclic and natural product synthetic chemists.

Acknowledgements

Prof. Dr Ahmed H. M. Elwahy thanks the Alexander von Humboldt Foundation for a research fellowship. He is also greatly indebted to Prof. K. Hafner, University of Darmstadt for his continuous help and generous support.

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