SYNTHESIS OF SOME NEW BIOLOGICAL ACTIVE PYRIMIDINE-FUSED HETEROCYCLES AND ALSO PREPARATION, CHARACTERIZATION AND CATALYTIC APPLICATIONS OF TWO NOVEL MAGNETIC NANO-ORGANOCATALYSTS BASED ON AMINO ACIDS IN MULTICOMPONENT REACTIO

Table of Contents

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CHAPTER ONE: INTRODUCTION

1.1.Organocatalysis. 2

1.2.Supported Organocatalysts. 5

1.3.Supported Amino acids as a Recoverable Organocatalysts. 6

1.4.Nanocatalysis and Magnetic Nanocatalysts. 11

1.5. Magnetic Core-Shell Nanoparticles. 14

1.6. A Brief Literature Review on Applicatin of Magnetic Core-Shell Nanoparticles as a Catalyst Supports in Organic Reactions. 15

1.7. Heterocyclic Chemistry. 18

1.7.1. Importance of Heterocyclic Compounds in Life and Industry. 18

1.8.Multicomponent Reactions. 21

1.9. Pyrimidine-fused Heterocycles (PFHs). 22

1.9.1. Synthesis of Pyrimidine-fused Heterocycles (PFHs) via Multicomponent Reactions  23

1.10.Xanthene: Preparation and Applications. 26

1.11.Bis (indolyl) methanes: Synthesis, Methodology and Biological Importance  30

1.12. Chromenes: Preparation and Applications. 34

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CHAPTER TWO: EXPERIMENTAL

2.1.General Information. 40

2.2.Synthesis of New Library of Hydrophilic Substituted Pyrimidine-Fused Heterocycles Carbohydrates Analogues. 41

2.3.General Procedure for Preparation of Heterocyclic
Pyrimidine-Fused Analogues Using Carbohydrates as a
Reagent (compounds 1a–k). 41

2.4.Physical and Spectroscopic Data for Compounds (1a–k). 42

2.4.1.5-((1S,2R,3R,4R)-1,2,3,4,5-pentahydroxypentyl)-10-phenyl-5,10-dihydropyrido[2,3-d:6,5-d’]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (1a). 42

2.4.2.10-(4-methoxyphenyl)-5-((1S,2R,3R,4R)-1,2,3,4,5-pentahydroxypentyl)-5,10-dihydropyrido[2,3-d:6,5-d’]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (1b)  43

2.4.3.10-benzyl-5-((1S,2R,3R,4R)-1,2,3,4,5-pentahydroxypentyl)-5,10-dihydropyrido[2,3-d:6,5-d’]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (1c). 44

2.4.4.10-(4-hydroxyphenyl)-5-((1S,2R,3R,4R)-1,2,3,4,5-pentahydroxypentyl)-5,10-dihydropyrido[2,3-d:6,5-d’]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (1d)  45

2.4.5.10-(4-ethoxyphenyl)-5-((1S,2R,3R,4R)-1,2,3,4,5-pentahydroxypentyl)-5,10-dihydropyrido[2,3-d:6,5-d’]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (1e)  46

2.4.6.10-(2-methoxyphenyl)-5-((1S,2R,3R,4R)-1,2,3,4,5-pentahydroxypentyl)-5,10-dihydropyrido[2,3-d:6,5-d’]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (1f)  47

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2.4.7.5-((1S,2R,3S,4R)-1,2,3,4,5-pentahydroxypentyl)-10-phenyl-5,10-dihydropyrido[2,3-d:6,5-d’]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (1g). 48

2.4.8.10-(4-methoxyphenyl)-5-((1S,2R,3S,4R)-1,2,3,4,5-pentahydroxypentyl)-5,10-dihydropyrido[2,3-d:6,5-d’]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (1h)  49

2.4.9.10-(4-methoxyphenyl)-5-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-5,10-dihydropyrido[2,3-d:6,5-d’]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (1i)  50

2.4.10.10-phenyl-5-((1R,2R,3R,4R)-1,2,4,5-tetrahydroxy-3-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)pentyl)-5,
10-dihydropyrido[2,3-d:6,5-d’]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (1j)  51

2.4.11.10-(4-methoxyphenyl)-5-((1R,2R,3R,4R)-1,2,4,5-
tetrahydroxy-3-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)pentyl)-5,10-dihydropyrido[2,3-d:6,5-d’]dipyrimidine-2,4,6,8
(1H,3H,7H,9H)-tetraone (1k). 52

2.5.General Procedure for Synthesis of Pyrano[2,3-d:6,5-d’]
dipyrimidine Derivative (compound 2). 53

2.5.1.5-((1R,2S,3S,4S)-1,2,3,4,5-pentahydroxypentyl)-5,9-
dihydro-2H-pyrano[2,3-d:6,5-d’]dipyrimidine-2,4,6,8(1H,3H,7H)-tetraone (2)  53

2.6.General Procedure for Preparation of Heterocyclic Pyrimidine-
Fused Analogues Using Helicin as a sugar-based Reagent in Multicomponent Reaction (compound 3). 54

2.7.Physical and Spectroscopic Data for Compound 3. 54

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2.7.1.5-(2-((3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)phenyl)-5,9-
dihydro-2H-pyrano[2,3-d:6,5-d’]dipyrimidine-2,4,6,8(1H,3H,7H)-tetraone (3)  54

2.8.General Procedure for the Synthesis of Heterocyclic
Pyrimidine-Fused Analogues Using Acetylated Sugar in
the Multicomponent Reaction (compounds 4a & 4b). 55

2.9.Physical and Spectroscopic Data for Compounds (4a &4b). 56

2.9.1.(1S,2R,3R,4R)-1-(2,4,6,8-tetraoxo-10-phenyl-1,2,3,4,5,6,7,8,9,10-decahydropyrido[2,3-d:6,5-d’]
dipyrimidin-5-yl)pentane-1,2,3,4,5-pentayl
pentaacetate (4a). 56

2.9.2.(1S,2R,3R,4R)-1-(10-(4-methoxyphenyl)-2,4,6,8-
tetraoxo-1,2,3,4,5,6,7,8,9,10-decahydropyrido[2,3-d:6,5-d’]
dipyrimidin-5-yl)pentane-1,2,3,4,5-pentayl
pentaacetate (4b). 57

2.10.General Procedure for Synthesis of Heterocyclic
Pyrimidine-Fused Analogues Using Glucosamine as a Sugar-
Based Reagent in the Multicomponent Reaction with Aldehyde and Barbituric acid (compounds 5a-f). 58

2.11.Physical and Spectroscopic Data for Compounds (5a-f). 58

2.11.1.5-(p-tolyl)-10-((3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-5,10-dihydropyrido[2,3-d:6,5-d’]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (5a). 58

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2.11.2.5-(4-nitrophenyl)-10-((3R,4R,5S,6R)-2,4,5-
trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)
-5,10-dihydropyrido[2,3-d:6,5-d’]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (5b)  59

2.11.3.4-(2,4,6,8-tetraoxo-10-((3R,4R,5S,6R)-2,4,5-trihydroxy
-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-1,2,3,4,5,6,7,8,9,10-decahydropyrido[2,3-d:6,5-d’]
dipyrimidin-5-yl )benzonitrile (5c). 60

2.11.4.5-(3-hydroxy-4-methoxyphenyl)-10-((3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)
-5,10-dihydropyrido[2,3-d:6,5-d’]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (5d)  61

2.11.5.5-(4-bromophenyl)-10-((3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-5,10-dihydropyrido[2,3-d:6,5-d’]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (5e). 62

2.11.6.5-(4-(methylthio)phenyl)-10-((3R,4R,5S,6R)-2,4,
5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-5,10-dihydropyrido[2,3-d:6,5-d’]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (5f). 63

2.12.General Procedure for One-pot Synthesis of PFHs Using
Aliphatic Amine as Reagent (compounds 6a-d). 63

2.13.Physical and Spectroscopic Data for Compound (6a-d). 64

2.13.1.10-butyl-5-(3-hydroxy-4-methoxyphenyl)-5,
10-dihydropyrido [2,3-d:6,5-d’]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (6a)  64

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2.13.2 5-(3-hydroxy-4-methoxyphenyl)-10-(3-hydroxypropyl)
-5, 10-dihydropyrido[2,3-d:6,5-d’]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (6b)  65

2.13.3. 5-(3-hydroxy-4-methoxyphenyl)-10-(2-hydroxyethyl)
-5,10-dihydropyrido[2,3-d:6,5-d’]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (6c)  66

2.13.4.10-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)
-5- (3-hydroxy-4-methoxyphenyl)-5,10-dihydropyrido
[2,3-d:6, 5-d’]dipyrimidine-2,4,6,8(1H,3H,7H,9H)
-tetraone (6d). 67

2.14.General Procedure for Preparation of Heterocyclic
Pyrimidine-Fused Analogues Using 4,4′-oxydianiline
Reagent in Multicomponent Reaction (compounds 7a-e). 67

2.15.Physical and Spectroscopic Data for Compounds (7a-e). 68

2.15.1.10-(4-(4-aminophenoxy)phenyl)-5-(1,2,3,4,5-pentahydroxypentyl)-5,10-dihydropyrido[2,3-d:6,5-d’]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (7a)  68

2.15.2.10-(4-(4-aminophenoxy)phenyl)-5-((1S,2R,3S,4R)-1,2,3,4,5-pentahydroxypentyl)-5,10- dihydropyrido[2,3-d:6,5-d’]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (7b)  69

2.15.3.10-(4-(4-aminophenoxy)phenyl)-5-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-5,10-dihydropyrido[2,3-d:6,5-d’]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (7c)  70

2.15.4.10-(4-(4-aminophenoxy)phenyl)-5-((1S,2S,3R,4R)-1,2,4,5-tetrahydroxy 3-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)pentyl)-5,10-dihydropyrido[2,3-d:6,5-d’]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (7d). 71

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2.15.5.10-(4-(4-aminophenoxy)phenyl)-5-((1S,2S,3R,4R)
-1,2,4,5-tetrahydroxy-3-(((2R,3R,4S,5S,6R)-3,4,
5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran
-2-yl)oxy)pentyl)-5,10-dihydropyrido[2,3-d:6,5-d’]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (7e). 72

2.16.Synthesis of Pyrimidine-Fucsed Derivatives Amino acid
Analogues. 73

2.17. General Procedure for Synthesis of New Class of
Pyrimidine- Fused Amino acid Analogues Using
Multicomponent Reaction of Amino acids, β-Dicarbonyl Compounds and Aldehydes  73

2.18.Physical and Spectroscopic Data for Compound (8a-s). 74

2.18.1.2-(5-(4-cyanophenyl)-2,4,6,8-tetraoxo-1,3,4,5,6,7,8,
9-octahydropyrido[2,3-d:6,5-d’]dipyrimidin-10(2H)-yl)-
3-(1H-imidazol-4-yl)propanoic acid (8a). 74

2.18.2.2-(5-(3-hydroxy-4-methoxyphenyl)-2,4,6,8-tetraoxo-1,3,4,5,6,7,8,9-octahydropyrido[2,3-d:6,5-d’]dipyrimidin-10(2H)-yl)-3-(1H-imidazol-4-yl)propanoic acid (8b). 75

2.18.3.2-(5-(4-bromophenyl)-2,4,6,8-tetraoxo-1,3,4,5,6,7,8,9-octahydropyrido[2,3-d:6,5-d’]dipyrimidin-10(2H)-yl)-3-
(1H-imidazol-4-yl)propanoic acid (8c). 76

2.18.4.3-(1H-imidazol-4-yl)-2-(5-(4-nitrophenyl)-2,4,6,8
-tetraoxo-1,3,4,5,6,7,8,9-octahydropyrido[2,3-d:6,5-d’]dipyrimidin-10(2H)-yl)propanoic acid (8d). 77

2.18.5.2-(9-(4-cyanophenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl)acetate (8e). 78

2.18.6.2-(3,3,6,6-tetramethyl-9-(4-nitrophenyl)-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin 10(9H)-yl)acetate (8f). 79

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2.18.7.2-(9-(4-fluorophenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl)acetate (8g). 80

2.18.8.2-(3,3,6,6-tetramethyl-1,8-dioxo-9-p-tolyl-1,2,3,4,5,6,
7,8-octahydroacridin-10(9H)-yl)acetic acid (8h). 81

2.18.9.2-(9-(4-bromophenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl)acetic acid (8i). 82

2.18.10.2-(3,3,6,6-tetramethyl-9-(4-(methylthio)phenyl)-1,
8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl)
acetic acid (8j). 83

2.18.11.2-(9-(4-chlorophenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl)acetic
acid (8k). 84

2.18.12.2-(9-(3-hydroxy-4-methoxyphenyl)-3,3,6,6-
tetramethyl-1, 8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10
(9H)-yl)acetic acid (8l). 85

2.18.13.2-(9-(4-tert-butylphenyl)-3,3,6,6-tetramethyl-1,8-
dioxo-1,2,3,4,5,6,7,8 octahydroacridin-10(9H)-yl) acetic
acid (8m). 86

2.18.14.2-(5-(3-hydroxy-4-methoxyphenyl)-2,4,6,8-tetraoxo-1,3,4,5,6,7,8,9-octahydropyrido[2,3-d:6,5-d’]
dipyrimidin-10(2H)-yl)-3-mercaptopropanoic acid (8n). 87

2.18.15.2-(5-(4-cyanophenyl)-2,4,6,8-tetraoxo-1,3,4,5,6,7,8,9-octahydropyrido[2,3-d:6,5-d’]dipyrimidin-10(2H)-yl)-3
-(4-hydroxyphenyl)propanoic acid (8o). 88

2.18.16.2-(5-(4-cyanophenyl)-2,4,6,8-tetraoxo-1,3,4,5,6,7,8,9-octahydropyrido[2,3-d:6,5-d’]dipyrimidin-10(2H)-yl)
succinic acid (8p). 89

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2.18.17.2-(5-(4-cyanophenyl)-2,4,6,8-tetraoxo-1,3,4,5,6,7,8,9-octahydropyrido[2,3-d:6,5-d’]dipyrimidin-10(2H)-yl)pentanedioic acid (8q). 90

2.18.18.2-(5-(4-cyanophenyl)-2,4,6,8-tetraoxo-1,3,4,5,6,7,8,9-octahydropyrido[2,3-d:6,5-d’]dipyrimidin-10(2H)-yl)-5-guanidinopentanoic acid (8r). 91

2.18.19.2-(5-(4-chlorophenyl)-2,4,6,8-tetraoxo-1,3,4,5,6,7,8,9-octahydropyrido[2,3-d:6,5-d’]dipyrimidin-10(2H)-yl)-5-guanidinopentanoic acid (8s). 92

2.18.20.(3-(5-(3-hydroxyphenyl)-2,4,6,8-tetraoxo-1,3,4,5,6,7,
8,9-octahydropyrido[2,3-d:6,5-d’]dipyrimidin-10(2H)-yl)propanoyl)histidine (8t)  93

2.18.21.(3-(5-(4-cyanophenyl)-2,4,6,8-tetraoxo-1,3,4,5,6,7,8,9-octahydropyrido[2,3-d:6,5-d’]dipyrimidin-10(2H)-yl)propanoyl)histidine (8u). 94

2.18.22.(3-(5-(3-hydroxy-4-methoxyphenyl)-2,4,6,8-tetraoxo-1,3,4,5,6,7,8,9-octahydropyrido[2,3-d:6,5-d’]dipyrimidin-10(2H)-yl)propanoyl)histidine (8v)  95

2.18.23.5-(((R)-1-((carboxymethyl)amino)-3-mercapto-1-
oxopropan-2-yl)amino)-2-(5-(4-nitrophenyl)-2,4,6,8-
tetraoxo-1,3,4,5,6,7,8,9-octahydropyrido[2,3-d:6,5-d’]dipyrimidin-10(2H)-yl)-5-oxopentanoic acid (8w). 96

2.18.24.5-(((R)-1-((carboxymethyl)amino)-3-mercapto-1-
oxopropan-2-yl)amino)-2-(5-(4-cyanophenyl)-2,4,6,8-
tetraoxo-1,3,4,5,6,7,8,9-octahydropyrido[2,3-d:6,5-d’]dipyrimidin-10(2H)-yl)-5-oxopentanoic acid (8x). 97

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2.19.General Procedure For Synthesis of Pyrimidine-Fused Amino
acid Analogues Using Carbohydrate as a Polyhydroxy
Aldehydes Component (compounds 9a-e). 98

2.20.Physical and Spectroscopic Data for Compounds (9a-e). 98

2.20.1. (3-(2,4,6,8-tetraoxo-5-((1R,2S,3S,4S)-1,2,3,4,5-pentahydroxypentyl)-1,3,4,5,6,7,8,9-octahydropyrido
[2,3-d:6,5-d’]dipyrimidin-10(2H)-yl)propanoyl)
histidine (9a). 98

2.20.2. (3-(2,4,6,8-tetraoxo-5-((1R,2S,3R,4R)-1,2,3,4,5-pentahydroxypentyl)-1,3,4,5,6,7,8,9-octahydropyrido
[2,3-d:6,5-d’]dipyrimidin-10(2H)-yl)propanoyl)histidine
(9b). 99

2.20.3.(3-(2,4,6,8-tetraoxo-5-((1S,2S,3R)-1,2,3,4-
tetrahydroxybutyl)-1,3,4,5,6,7,8,9-octahydropyrido
[2,3-d:6,5-d’]dipyrimidin-10(2H)-yl)propanoyl)
histidine (9c). 100

2.20.4.(3-(2,4,6,8-tetraoxo-5-((1R,2R,3R,4R)-1,2,4,5-
tetrahydroxy-3-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)
pentyl)-1,3,4,5,6,7,8,9-octahydropyrido[2,3-d:6,5-d’]dipyrimidin-10(2H)-yl)propanoyl)histidine (9d). 101

2.20.5.(3-(2,4,6,8-tetraoxo-5-((1R,2R,3R,4R)-1,2,4,5-tetrahy
droxy-3-(((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)pentyl)-1,3,4,5,6,7,8,9-octahydropyrido[2,3-d:6,5-d’]dipyrimidin-10(2H)-yl)propanoyl)histidine (9e). 102

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2.21.General Procedure For Synthesis of Four-compounent
Reaction Pyrimidine-Fused Amino acid Analogues
Using Four-Compounent Reaction (compounds 10a-c). 103

2.22.Physical and Spectroscopic Data for Compound (10a-c). 103

2.22.1.2-(8,8-dimethyl-2,4,6-trioxo-5-p-tolyl-1,2,3,4,6,7,8,9-octahydropyrimido[4,5-b]quinolin-10(5H)-yl)-3-mercaptopropanoic acid (10a). 103

2.22.2.2-(5-(4-tert-butylphenyl)-8,8-dimethyl-2,4,6-trioxo-1,2,3,4,6,7,8,9-octahydropyrimido[4,5-b]quinolin-10
(5H)-yl)-3-hydroxybutanoic acid (10b). 104

2.22.3.2-(8,8-dimethyl-5-(4-(methylthio)phenyl)-2,4,6-trioxo-1,2,3,4,6,7,8,9-octahydropyrimido[4,5-b]quinolin-10
(5H)-yl)-3-hydroxybutanoic acid (10c). 105

2.23.General Procedure for One-pot Synthesis of 9-
(1H-indol-3-yl)-xanthen-4-(9H)-ones via the Reaction
of O-methyl protected/unprotected Salicyaldehydes,
Indoles and β-Dicarbonyl Compounds Using
Trimethylsilyl Iodide. 106

2.24.General Procedure for the Synthesis of L-proline-Modified Magnetic Nanoparticles (LPMNPs). 106

2.24.1.Preparation of Fe₃O₄ Nanoparticles. 106

2.24.2.Preparation of Fe₃O₄@SiO₂ Nanoparticles. 107

2.24.3.Synthesis of Vinyl Magnetic Nanoparticle (VMNP). 107

2.24.4.Synthesis of MNP-Oxiran (MNPO). 107

2.24.5.Synthesis of L-proline Magnetic Nanoparticles
(LPMNPs) Catalyst 108

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2.25.General procedure for the LPMNP-Catalyzed
Multicomponent Synthesis of 9-(1H-indol-3-yl)-2,
2-dimethyl- 2,3-dihydro-1H-xanthen-4(9H)-one
(compound 11a-y). 109

2.26.Physical and Spectroscopic Data for 9-(1H-indol-3-yl)
-xanthen-4-(9H)-one Derivatives for Compound 11a-y. 110

2.26.1.9-(1H-indol-3-yl)-3,3-dimethyl-3,4-dihydro-
2H-xanthen-1(9H)-one (11a). 110

2.26.2. 3,3-dimethyl-9-(2-methyl-1H-indol-3-yl)-3,4-
dihydro-2H-xanthen-1(9H)-one (11b). 111

2.26.3. 9-(5-bromo-1H-indol-3-yl)-3,3-dimethyl-3,4-dihydro-2H-xanthen-1(9H)-one (11c)  111

2.26.4.6-hydroxy-9-(1H-indol-3-yl)-3,3-dimethyl-3,4-dihydro-
2H-xanthen-1(9H)-one (11d). 112

2.26.5.6-hydroxy-3,3-dimethyl-9-(1-methyl-1H-indol-3-yl)-3,
4-dihydro-2H-xanthen-1(9H)-one (11e). 113

2.26.6.9-(1H-indol-3-yl)-3,4-dihydro-2H-xanthen-1(9H)
-one (11f). 113

2.26.7.9-(1-methyl-1H-indol-3-yl)-3,4-dihydro-2H-xanthen-1
(9H)-one (11g). 114

2.26.8.9-(2-methyl-1H-indol-3-yl)-3,4-dihydro-2H-xanthen-1
(9H)-one (11h). 115

2.26.9.6-hydroxy-9-(1H-indol-3-yl)-3,4-dihydro-2H-xanthen-1
(9H)-one (11i). 115

2.26.10.6-hydroxy-9-(1-methyl-1H-indol-3-yl)-3,4-dihydro-2H-xanthen-1(9H)-one (11j)  116

2.26.11.9-(5-bromo-1H-indol-3-yl)-3,4-dihydro-2H-xanthen-1(9H)-one (11k)  117

Content                                                                                                                 Page

2.26.12.5-(1H-indol-3-yl)-1H-chromeno[2,3-d]pyrimidine-2,4(3H,5H)-dione (11l)  117

2.26.13.5-(1H-indol-3-yl)-1H-chromeno[2,3-d]pyrimidine-2,4(3H,5H)-dione (11m)  118

2.26.14.5-(2-methyl-1H-indol-3-yl)-1H-chromeno[2,3-d]
pyrimidine-2,4(3H,5H) dione (11n). 119

2.26.15. 5-(1H-indol-3-yl)-2-thioxo-2,3-dihydro-1H-chromeno
[2,3-d]pyrimidin-4(5H)-one (11o). 119

2.26.16. 6-hydroxy-9-(1H-indol-3-yl)-3,3-dimethyl-3,4-
dihydro-2H-xanthen-1(9H)-one (11p). 120

2.26.17. 7-bromo-5-(1H-indol-3-yl)-1,5-dihydro-2H-chromeno
[2,3-d]pyrimidine-2,4(3H)-dione (11q). 121

2.26.18. 7-bromo-9-(1H-indol-3-yl)-3,3-dimethyl-2,3,4,9-
tetrahydro-1H-xanthen-1-one (11r). 121

2.26.19. 5-(1H-indol-3-yl)-7-nitro-1,5-dihydro-2H-chromeno
[2,3-d]pyrimidine-2,4(3H)-dione (11s). 122

2.26.20. methoxy-3,3-dimethyl-9-(1-methyl-1H-indol-3-yl)
-3,4-dihydro-2H-xanthen-1(9H)-one (11t). 122

2.26.21. 9-(5-bromo-1H-indol-3-yl)-6-methoxy-3,3-dimethyl-3,
4-dihydro-2H-xanthen-1(9H)-one (11u). 123

2.26.22. 6-methoxy-3,3-dimethyl-9-(2-methyl-1H-indol-3-yl)-3,
4-dihydro-2H-xanthen-1(9H)-one (11v). 124

2.26.23. 6-methoxy-9-(1-methyl-1H-indol-3-yl)-3,4-dihydro-2H-xanthen-1(9H)-one (11w)  124

2.26.24. 9-(1H-indol-3-yl)-6-methoxy-3,4-dihydro-2H-xanthen-1
(9H)-one (11x). 125

2.26.25. 6-methoxy-9-(2-methyl-1H-indol-3-yl)-3,4-dihydro-2H-xanthen-1(9H)-onee (11y)  126

Content                                                                                                                 Page

2.27. General Procedure for the Synthesis of Bis(indolyl)methane Derivatives in the Presence of the LPMNP Catalyst 126

2.28. Physical and Spectroscopic Data for compound (12a-n). 127

2.28.1. 3-((1H-indol-3-yl)(phenyl)methyl)-1H-indole (12a) []. 127

2.28.2. 2-(Di(1H-indol-3-yl)methyl)phenol (12b) []. 127

2.28.3. 4-(Di(1H-indol-3-yl)methyl)phenol (12c) []. 128

2.28.4. 3-(Di(1H-indol-3-yl)methyl)phenol (12d). 128

2.28.5. 3-((1H-indol-3-yl)(4-methoxyphenyl)methyl)
-1H-indole (12e) [122]. 129

2.28.6. 5-(Di(1H-indol-3-yl)methyl)-2-methoxyphenol (12f) []. 130

2.28.7. 3-((1H-indol-3-yl)(p-tolyl)methyl)-1H-indole (12g) []. 130

2.28.8. 3-((3,4-Difluorophenyl)(1H-indol-3-yl)methyl)
-1H-indole (12h). 131

2.28.9. 3-(Di(1H-indol-3-yl)methyl)benzonitrile (12i) []. 131

2.28.10. 3-((1H-indol-3-yl)(3-nitrophenyl)methyl)-1H-indole
(12j) []. 132

2.28.11. 3-((1H-indol-3-yl)(4-nitrophenyl)methyl)-1H-indole
 (12k) [126]. 132

2.28.12. 3-((1H-indol-3-yl)(2-nitrophenyl)methyl)-1H-indole
 (12l) [128]. 133

2.28.13. 3-((2-Chlorophenyl)(1H-indol-3-yl)methyl)-1H-indole
(12m) [126]. 133

2.28.14. 3-((4-Chlorophenyl)(1H-indol-3-yl)methyl)-1H-indole
(12n) [126]. 134

2.29. General Procedure for the Synthesis of L-Cysteine-Modified
Magnetic Nanoparticles (LCMNPs). 134

Content                                                                                                                 Page

2.30. General Procedure for the Synthesis of 2-amino-4H-chromene
-3-Carbonitrile Derivatives Using a Multicomponent Reaction
and in the Presence of LCMNP Catalyst 135

2.31. Physical and Spectroscopic Data for Compound (13a-s). 135

2.31.1. 2-amino-4-(1H-indol-3-yl)-4H-chromene-3-
carbonitrile (13a). 135

2.31.2. 2-amino-4-(1-methyl-1H-indol-3-yl)-4H-
chromene-3-carbonitrile (13b). 136

2.31.3. 2-amino-4-(2-methyl-1H-indol-3-yl)-4H-
chromene-3-carbonitrile (13c). 137

2.31.4. 2-amino-4-(5-bromo-1H-indol-3-yl)-4H-
chromene-3-carbonitrile (13d). 137

2.31.5. 2-amino-4-(5-methoxy-1H-indol-3-yl)-4H-
chromene-3-carbonitrile (13e). 138

2.31.6. 2-amino-4-(1H-indol-3-yl)-6-methoxy-4H-
chromene-3-carbonitrile (13f). 138

2.31.7. 2-amino-6-methoxy-4-(1-methyl-1H-indol-3-yl)-
4H-chromene-3-carbonitrile (13g). 139

2.31.8. 2-amino-6-methoxy-4-(2-methyl-1H-indol-3-yl)-
4H-chromene-3-carbonitrile (13h). 140

2.31.9. 2-amino-4-(5-bromo-1H-indol-3-yl)-6-methoxy-4H-
chromene-3-carbonitrile (13i). 140

2.31.10. 2-amino-6-methoxy-4-(5-methoxy-1H-indol-3-yl)-
4H-chromene-3-carbonitrile (13j). 141

2.31.11. 2-amino-6-bromo-4-(1H-indol-3-yl)-4H-chromene-
3-carbonitrile (13k). 142

2.31.12. 2-amino-6-bromo-4-(1-methyl-1H-indol-3-yl)-4H-
chromene-3-carbonitrile (13l). 142

Content                                                                                                                 Page

2.31.13. 2-amino-6-bromo-4-(2-methyl-1H-indol-3-yl)-4H-
chromene-3-carbonitrile (13m). 143

2.31.14. 2-amino-6-bromo-4-(5-methoxy-1H-indol-3-yl)-4H-chromene-3-carbonitrile (13n)  144

2.31.15. 2-amino-6-bromo-4-(5-bromo-1H-indol-3-yl)-4H-
chromene-3-carbonitrile (13o). 144

2.31.16. 2-amino-7-hydroxy-4-(1H-indol-3-yl)-4H-
chromene-3-carbonitrile (13p). 145

2.31.17. 2-amino-7-hydroxy-4-(1-methyl-1H-indol-3-yl)-
4H-chromene-3-carbonitrile (13q). 145

2.31.18. 2-amino-7-hydroxy-4-(2-methyl-1H-indol-3-yl)-
4H-chromene-3-carbonitrile (13r). 146

2.31.19. 2-amino-7-hydroxy-4-(5-methoxy-1H-indol-3-yl)-
4H-chromene-3-carbonitrile (13s). 147

2.31.20. 2-amino-4-(4-(dimethylamino)phenyl)-6-methoxy-
4H-chromene-3-carbonitrile (13t). 147

2.31.21. 2-(2-amino-3-cyano-4H-chromen-4-yl)malononitrile
(13u). 148

2.31.22. 2-amino-4H-chromene-3,4-dicarbonitrile (13v). 148

CHAPTER THREE: RESULTS AND DISCUSSION

3.1. Synthesis of New Class of Pyrimidine-Fused Heterocycles
Using Carbohydrates as a Suger-Based Component via Multicomponent Rreaction  150

3.2. Synthesis of New Pyrimidine-Fused Heterocycles Using
Amino acids as an Amine-Based Reagent via
Multicomponent Reaction. 169

Content                                                                                                                 Page

3.3. Me₃SiI as a Multifunctional Agent in One-pot Synthesis of
9-(1H-indol-3-yl)-xanthen-4-(9H)-ones Using Reaction
of O-methyl protected/unprotected Salicyaldehydes,
Indoles and β-Dicarbonyl Compounds. 183

3.4. L-Proline-Modified Magnetic Nanoparticles (LPMNP): As a
Highly Efficient and Reusable Magnetic Organocatalyst for
The One-pot Organocatalytic Reaction. 195

3.4.1. Catalyst Preparation and Characterization. 196

3.5. Synthesis of 9-(1H-indol-3-yl) Xanthen-4-(9H)-ones Under
Mild Conditions Using LPMNP as an Efficient Magnetic Nanoparticle Catalyst 202

3.6. Synthesis of Bis(indolyl)methanes Under Mild Conditions
Using LPMNP as an Efficient Magnetic Nanoparticle
Catalyst 211

3.7. Magnetic Nanoparticles Functionalized with L-Cysteine:
A Novel Magnetically Separable Organocatalyst for One-Pot Synthesis of 2-amino-4H-chromene-3-carbonitrile in Water. 218

3.7.1. Magnetic Nanoparticles Supported L-Cysteine (LCMNP) : Preparation and Characterization. 220

3.7.2. LCMNP Catalytic Application in Synthesis of 2-amino
–4H-chromene-3-carbonitrile Derivatives Using a Multicomponent Reaction  227

References …………………………………………………………………………………………….. 237

APPENDIX: ¹H-NMR, ¹³C-NMR and IR Spectrums of the
Synthesized Compounds. 261

Abstract and Title Page in Persian

List of Tables

Table                                                                                                                     Page

Table 3.1. Optimization of multicomponent reaction between
D-glucose, barbituric acid and aniline. 153

Table 3.2. The products of multicomponent reaction of sugars, amines
and barbituric acids for one-pot synthesis of hydrophilic substituted PFHs under optimized conditions. 155

Table 3.3. The products of multicomponent reaction of
D-glucosamine, aldehydes and barbituric acid. 160

Table 3.4. The products of multicomponent reaction of amine,
isovanillin and barbituric  acid. 162

Table 3.5. The products of multicomponent reaction of 4,4′-
oxydianiline, poly hydroxyl chain aldehyde and
barbituric acid. 165

Table 3.6. Optimization of multicomponent reaction between
histidine, barbituric acid and 4-cyanobenzaldehyde. 171

Table 3.7. The products of multicomponent reaction of sugars,
amines and barbituric acids for the synthesis of
hydrophilic substituted PFHs under optimized
conditions. 173

Table 3.8. The products of multicomponent reaction of peptids,
aldehydes and barbituric acids for the synthesis
of PFHs under optimized conditions. 178

Table                                                                                                                     Page

Table 3.9. The products of multicomponent reaction of peptid,
carbohydrate and barbituric acid for the synthesis
of PFHs under optimized conditions. 179

Table 3.10. The products of four-component reaction of amino
acid, aldehyde, barbituric acid and dimedone for
the synthesis of PFHs under optimized conditions. 181

Table 3.11. Optimization of the reaction between 2-
methoxybenzaldehyde, dimedone and indole. 185

Table 3.12. The Products of three-component reaction between 2-methoxybenzaldehyde, indoles and β-dicarbonyl
compounds. 187

Table 3.13. Optimization experiments for the synthesis of 11a. 202

Table 3.14. Three-component coupling between 2-
hydroxybenzaldehydes, indoles, and, β-dicarbonyl
compounds using LPMNP as catalyst in the presence
of ethanol under reflux conditions. 204

Table 3.15. Reusability of the LPMNP catalyst in the reaction of salicylaldehyde, indole and dimedone under optimized condition. 210

Table 3.16. Optimization experiments for one-pot synthesis of
3-((1H-indol-3-yl)(phenyl)methyl)-1H-indole (12a). 212

Table 3.17. Effect of different amount of indole on the
model reaction. 213

Table 3.18.  Synthesis of bis(indol-3-yl)methanes using LPMNP. 214

Table 3.19. Reusability of the LPMNP catalyst in the reaction
of indole and aldehydes for synthesis of bis(indolyl)
methanes in water. 217

Table                                                                                                                     Page

Table 3.20. Optimization study for one-pot synthesis of 2-
amino-4-(1H-indol-3-yl)-4H-chromene-3-carbonitrile
in the presence of LCMNP as catalyst 228

Table 3.21. Synthesis of 2-amino-4-(1H-indol-3-yl)-4H-chromene-3-carbonitrile under optimized condition. 230

List of Figures

Figure                                                                                                                    Page

Figure 1.1. Approaches for organocatalyst immobilization. 6

Figure 1.2. Primary amino acid-derived catalysts. 8

Figure 1.3. Magnetic replaces filter. 13

Figure 1.4. Structures of Haem and Chlorophyll. 19

Figure 1.5. Structure of  Indigo and Strychnine. 19

Figure 1.6. Biologically active pyridine and piperidine-based
heterocycles. 20

Figure 1.7. The structure of fluoresceins and Rhodamines. 26

Figure 3.1. The chemical structure of riboflavin (A). Our retrosynthetic analysis for the synthesis of hydrophilic substituted pyrimidine-fused heterocycles (B). 164

Figure 3.2. Chemical structure of newly synthesized PFH compounds.. 164

Figure 3.3. Inhibitory activity of synthetic compounds against
α-Amylase. 164

Figure 3.4. Inhibitory activity of synthetic compounds against
α-Amylase. 167

Figure 3.5. Comparison of FT-IR spectra of Fe₃O₄, Fe₃O₄@SiO₂,
VMNP, MNPO, L-proline and LPMNP catalyst. 198

Figure                                                                                                                    Page

Figure 3.6. A TEM images of two different positions of LPMNP
catalyst particles (a & b). A SEM image of the LPMNP catalyst (c). A histogram which representing the size distribution of the LPMNP catalyst. 199

Figure. 3.7. A typical TGA curve from LPMNP catalyst (a).
The XRD pattern of LPMNP catalyst (b). The EDX
analysis of the LPMNP catalyst (c). The
vibrating sample magnetometer (VSM) of the LPMNP
catalyst (d). 201

Figure 3.8. Comparison of FT-IR spectra of Fe₃O₄, Fe₃O₄@SiO₂,
VMNP, MNPO, L-Cysteine and LCMNP catalyst. 222

Figure 3.9. EDX spectrum of the LCMNP (a) and The TGA
analysis study of LCMNP material (b). 223

Figure 3.10. The TEM images of LCMNP nanoparticles in different positions (a-c). The particle size distribution of LCMNP nanoparticles (d). 224

Figure 3.11. The SEM images of LCMNP material. 225

Figure 3.12. The vibrating sample magnetometer (VSM) of the
LPMNP catalyst (a) and The X-ray Diffraction
(XRD) pattern of the LCMNP catalyst (b). 226

Figure 3.13. The reusability times of LCMNP catalyst in
one-pot synthesis of 2-amino-4H-chromene-3-
carbonitrile derivatives. 236

List of Schemes

Scheme                                                                                                                  Page

Scheme 1.1. The mechanism of Knoevenagel reaction. 3

Scheme 1.2. The role of DMAP as a organocatalyst. 3

Scheme 1.3. Synthesis of optically active steroid using L-proline
as catalyst. 4

Scheme 1.4. The use of Proline-derived as an active organocatalyst. 4

Scheme 1.5. Mannich reactions. 8

Scheme 1.6. Nano-FGT promoted Paal-Knorr reaction. 9

Scheme 1.7. Silica-supported proline organocatalyst as an efficient
catalyst for aldol condensation. 10

Scheme 1.8. Application of silica-supported L-proline (SSLP)
in the synthesis of spirooxindole derivatives. 11

Scheme 1.9. Synthesis of propargyl amines catalyzed by Fe₃O₄ nanoparticle-supported copper (I). 15

Scheme 1.10. Heck reaction of chloroarenes in the presence of
Pd-PFMN catalyst. 16

Scheme 1.11. Magnetic nanoparticle supported antimony as a
recoverable catalyst for Clauson-Kaas reaction. 17

Scheme 1.12. Biguanide-functionalized Fe₃O₄/SiO₂ magnetic
nanoparticles as an efficient catalyst in domino
Knoevenagel condensation/Michael addition/
cyclization reactions. 17

Scheme                                                                                                                  Page

Scheme 1.13. Multicomponent approach for one-pot synthesis of
PFHs in water using p-toluene sulfunic acid (p-TSA)
as catalyst. 23

Scheme 1.14. One-pot three component reaction for synthesis
of pyrimidine derivatives  in water. 24

Scheme 1.15. Multicomponent reaction for synthesis of triazolo
[1,5-a] pyrimidines. 24

Scheme 1.16. Microwave-assisted multicomponent reaction for
synthesis of thiopyrano-, and pyrano[4,3-d]
pyrimidines derivatives. 24

Scheme 1.17. One-pot synthesis of functionalized pyrido[2,3-d]pyrimidines. 25

Scheme 1.18. Microwave promoted three-component reacation
for the synthesis of dihydropyrido[4,3-d]pyrimidines. 25

Scheme 1.19. Multicomponent reaction for synthesis of pyrimidine-
fused derivatives. 25

Scheme 1.20. Synthesis of dibenzo xanthene derivatives catalyzed
by heteropolyacid under solvent-free conditions. 27

Scheme 1.21. Simple and efficient procedure for the synthesis
of aryl-5H-dibenzo[b,i]xanthene-5,7,12,14 (13H)-tetraone. 28

Scheme 1.22. One-pot four component formation of tetrahydrobenzo[a]xanthene-11-one and diazabenzo[a]anthracene-9,11-dione derivatives. 28

Scheme 1.23. An efficient one-pot procedure for synthesis of  9-
(1H-indol-3-yl)-xanthen-4-(9H)-ones using L-proline
as catalyst. 29

Scheme                                                                                                                  Page

Scheme 1.24. Synthesis of spiro[indoline-3,9′-xanthene] trione
derivatives in the presence of SBA-15-Pr–SO₃H as
an nano solid acid catalyst. 29

Scheme 1.25. Synthesis of various xanthene derivatives in the
presence of DSIMHS. 30

Scheme 1.26. Formation of bis(indolyl)methane using TPP. 31

Scheme 1.27. AlPW₁₂O₄₀ an efficient catalyst for the preparation
of bis (indoly)methans. 32

Scheme 1.28. Using Tritylchloride for bis(indolyl)methan derivatives. 32

Scheme 1.29. Ionic liquid catalyzed bis(indolyl)methane derivatives. 32

Scheme 1.30. Synthesis of bis(indolyl)methane with Benzyl triphenyl phosphonium bromide. 33

Scheme 1.31. BF₃·Et₂O catalyzed the reaction between indoles and carbonyl compounds. 33

Scheme 1.32. Selective synthesis of bis(indolyl)methane derivatives. 34

Scheme 1.33. A three-component reaction for the the synthesis of 4H-chromene derivatives. 36

Scheme 1.34. Hexadecyldimethylbenzyl ammonium bromide
(HDMBAB) catalyst for one pot formation of
4H-chromenes in aqueous media. 36

Scheme 1.35. Synthesis of chromenes in the presence of 2-hydroxybenzaldehydes. 37

Scheme 1.39. Synthesis of chromene derivatives. 38

Scheme 1.40. Preparation of chromenes catalyzed by sodium
carbonate. 38

Scheme                                                                                                                  Page

Scheme 3.1. Synthesis of pyrimidine-fused heterocycle
carbohydrate analogue using pseudo-four component
coupling reaction. 152

Scheme 3.2. Synthesis of new polyhydroxy substituted PFH
derivatives using lactose as disaccharide. 157

Scheme 3.3. Synthesis of pyrano[2,3-d:6,5-d’]dipyrimidine derivative
under optimized conditions. 158

Scheme 3.4. Helicin as sugar-based reagent in MCR.. 158

Scheme 3.5. Acetylated glucose as a reagent in MCR. 159

Scheme 3.7. Proposed mechanisem for synthesis of pyrimidine-
fused heterocycle in the presence of acid catalyst. 168

Scheme 3.8. Synthesis of pyrimidine-fused heterocycle amino
acid analogue. 170

Scheme 3.9. Synthesis of pyrimidine-fused heterocycle amino acid analogue using one-pot procedure coupling reaction. 170

Scheme 3.10. Proposed mechanisem for synthesis of pyrimidine-
fused heterocycle amino acids analogue. 182

Scheme 3.11. Nucleophilic addition reaction of TMSI to aldehydes. 183

Scheme 3.12. Synthesis of 9-(1H-Indol-3-yl)xanthen-4-(9H)-one derivatives using TMSI as a multifunctional agent. 185

Scheme 3.13. Proposed reaction mechanism for one-pot synthesis
of 9-(1H-indol-3-yl)-xanthen-4-(9H)-ones via reaction
of salicyladehydes, indoles and β-dicarbonyl compounds
in the presence of TMSI. 191

Scheme                                                                                                                  Page

Scheme 3.14 Synthesis of 4H-benzopyrans using reaction of 2-methoxybenzaldehyde and dimedone under optimized conditions. To form 4H-benzopyran product the
reduction and methyl-deprotection roles of TMSI
are needed. 192

Scheme 3.15. Reaction of indole with 2-methoxybenzaldehyde in the presence of TMSI under optimized condition is resulted the productions of bis(indolyl)methanes 11c and 11e.
This reaction confirms the nucleophilic addition
of indole to intermediate F and O. 193

Scheme 3.16. Reaction of 2-methoxybenzaldehyde, dimedone
and 5-nitro-1H-indole under optimized conditions
is resulted the production of 4H-benzopyran V.
This reaction confirms that TMSI acts as a
reducing agent in the presence of week nucleophiles. 194

Scheme 3.17. Synthetic route for the preparation of LPMNP catalyst. 196

Scheme 3.18. Generation of catalytic sites on the MNPs surface
using MNPO substrate. 197

Scheme 3.19. proposed catalytic cycle for the formation of 11a. 209

Scheme 3.20. General strategy for the synthesis of bis(indol-3-yl)
methanes in the presence of LPMNP catalyst. 211

Scheme 3.21. Proposed reaction mechanism for the preparation of bis(indol-3-yl)methanes in the presence of LPMNP
catalyst via iminium formation. 216

Scheme 3.22 The synthetic strategy for the synthesis of LCMNP
material. 220

Scheme                                                                                                                  Page

Scheme 3.23. Synthesis of divers 2-amino-4H-chromene-3-
carbonitrile derivatives. 234

Scheme 3.24. The reaction mechanism for synthesis of 2-
amino-4H-chromene-3-carbonitrile derivatives in the
presence of LCMNP catalyst. 235