synthesis of 5,6-dihydrobenzo[1,7]phenanthroline...

102

Chapter 5

Synthesis of 5,6-dihydrobenzo[1,7]phenanthroline and

Quinazolinone heterocycles via reusable catalyst Multi

component reactions

5.1 INTRODUCTION

5.1.1 MULTI COMPONENT REACTIONS

Preparation of an efficient functionalized heterocyclic compound is one of the

important tasks in organic synthesis. Multi component reactions (MCR’s) have

become important method for the rapid construction of heterocyclic compounds

(Fabio et al., 2012; Fleur et al., 2013). These MCR’s are one of the methods address

the challenge for the development of eco-compatible reactions in organic and

medicinal chemistry (Li-Ping et al., 2013; Karen et al., 2010). Multicomponent

reactions leading to formation of nitrogen-containing heterocyclic systems such as

pyridine and pyrimidine have recently been studied (Timoshenkol et al., 2011).

MCR’s generally benefit from other aspects such as atom economy, the use of readily

available starting materials, resource effectiveness and bond-forming efficiency,

which render these reactions useful environmentally friendly alternatives, in keeping

with the greener direction in which organic chemistry is proceeding. The

achievement of making multiple bonds in a one-pot multicomponent coupling

reaction promotes a sustainable synthetic approach to new molecule discovery

(Helmut et al., 2011). In addition, MCR’s are one-pot processes with simpler

experimental conditions that do not require the isolation of intermediates, they are

perfect candidates for combinatorial, automated synthesis and drug discovery (Helmut

et al., 2009).

5.1.1.1 IMPORTANCE OF MULTICOMPONENT REACTIONS

Present-day requirements for new synthetic methods go far beyond the

traditional ones of chemo, regio and stereoselectivity can be summarized as follows:

Use of simple and readily available starting materials

Experimental simplicity

Possibility of automation

Favourable economic factors, including the cost of raw materials, human

resources and energy

Low environmental impact: use of environmentally friendly solvents,

103

atom economy

For this reason, the creation of molecular diversity and complexity from simple and

readily available substrates is one of the major current challenges of organic

synthesis, and hence the devlopment of processes that allow the creation of several

bonds in a single operation has become one of its more attractive goals. The

strategies of MCRs offer significant advantages over conventional linear-type

synthesis for high degree of atom economy, convergence, ease of execution (Roopan

et al., 2010). The achievement of making multiple bonds in a one-pot

multicomponent coupling reaction promotes a sustainable synthetic approach to new

molecule discovery (Bharathi et al., 2014).

Eco-friendly reagents and catalysts are selected medium for green chemical

approaches such as water, supercritical fluids, ionic liquids or solvent-free reactions.

In this context, metal oxide nanoparticles are attractive candidates as solid supports

for the highly active and recyclable catalytic system. Due to their large surface area,

which can carry a high payload of catalytically active species, nanoparticles are

exhibit very high catalytic activity and chemical selectivity under mild conditions

(Roopan et al., 2010). In addition, they can be recovered through a centrifugation or

filtration process and be reused for the next reaction, combining the advantages of

both homogeneous and heterogeneous catalysts. Nowadays nanoparticles have drawn

the attention of scientists, because of their extensive application in the development of

new technologies in the areas of electronics, material sciences, catalyst and medicine

at the nanoscale (Lim et al., 2010; Narayanan et al., 2011). Chemical synthesis

methods lead to presence of some toxic chemical absorbed on the surface that may

have adverse effect in the medical applications. Green synthesis provides

advancement over chemical and physical method as it is cost effective, environment

friendly, easily scaled up for large scale synthesis and in this method there is no need

to use high pressure, energy, temperature and toxic chemicals. Although many

synthetic technologies are present, worldwide the researchers are continuously

searching suitable bio-methods for the synthesis of desired nanoparticles

(Mohanapriya et al., 2008). The development of green processes using agricultural

waste for the synthesis of nanoparticles is evolving into an important branch of

nanotechnology (Kumar et al., 2008; Roopan et al., 2012). The use of

environmentally benign materials like plant leaf extract (Mitta et al., 2013), bacteria

104

(Naveen et al., 2010), fungi (Rajakumar et al., 2012) and enzymes (Parka et al., 2011)

for the synthesis of metal nanoparticles offers numerous benefits of eco-friendliness

and compatibility for pharmaceutical and other biomedical applications as they do not

use toxic chemicals for the synthesis protocol.

Currently, TiO2 nanoparticles have created a new approach for remarkable

applications as an attractive multi-functional material. TiO2 nanoparticles have

unique properties such as higher stability, long lasting, safe and broad-spectrum anti-

biosis (Shi et al., 2012). TiO2 nanoparticles have been especially the center of

attention for their photo-catalytic activities. TiO2 nanoparticles have been used as a

green catalyst in many organic reactions (Tisseh et al., 2012). Among many kind of

heterocyclic, in this chapter includes, Synthesis of Synthesis of 5,6-

dihydrobenzo[1,7]phenanthroline-3-carbonitrile, 5,6-dihydrobenzo[1,7]

phenanthroline and Quinazolinone heterocyclics via reusable catalyst MCR’s

reaction.

During recent years there has been a large investigation on different classes of

phenanthroline compounds, many of which were found to possess an extensive

spectrum of pharmacological activities which is used as a conformationally restricted

analogous (Cheikh et al., 2008). Moreover, phenanthroline derivatives have been

found to possess valuable biological properties, such as anticancer, antibacterial,

antimalarial, and HIV-1 protease inhibitory activities (Hurley et al., 1999; Harlos et

al., 2008; Kumar et al., 2008). There is a scarcity of data concerning the anticancer

activity of 1,10-phenanthroline and its derivatives. 1,10-phenanthroline and 5-amino-

1,10-phenanthroline are studied for antitumor activity (Diana et al., 2009), inhibitory

activity, cytotoxicity, and structure–activity relationship study (Pritam et al., 2012).

Apart from these reports, the studies on phenanthroline and the interaction of

transition metal complexes with DNA continue to attract the attention of researchers

due to their importance in design and development of synthetic drug and DNA foot

printing agent (Maheswari and Palaniandavar., 2004; Yang et al., 2005; Tan et al.,

2007). Phenanthroline complexes of rare-earth elements have attracted the particular

attention of researchers (Sadikov et al., 2009; Bing et al., 1998; Panina et al., 2008;

Uvarova et al., 2012). 1,10-phenanthroline (Bencini and Lippolis., 2010; Brand et al.,

1954), 4,7-phananthroline (Gusak et al., 2004; Gusak et al., 2001; Gusak and kozlov.,

105

2003), 1,7-phenanthroline (Kozlov and Gusak., 2010) have been studied both

synthetically and biologically, Fig 5.1.

Fig 5.1 1, 10- phenanthroline, 5.1 and 5.2, 1, 4- phenanthroline, 5.3 and 5.4, 1, 7-

phenanthroline, 5.5 and 5.6

Unexpected chemical reactions reveal the new kind of chemical pathway and

novel compounds in organic synthesis (Jean et al., 2012; Zhan-Hui et al., 2010;

Mihaly, 2010). Literature survey reveals that the synthesis of pyridine and pyrimidine

analogues can be achieved via Michael reactions (Madhukar et al., 2007). Literature

reveals that Michael addition reactions forms compound contains carbonitrile

functional group in the reaction of α-β-uncaturated ketone with malononitrile

(Kadutskii et al., 2006; Mishriky et al., 2000). At this juncture, we have found that

there is an unexpected Michael addition product in acridine analogous.

Quinazolin-4(1H)-ones was important N-Heterocyclic compounds having

various biological activities (Dabiri et al., 2005). The Friedlander annulation, among

the other methods, is one of the most simple and straight forward approaches for the

synthesis of quinoline derivatives. Varieties of catalysts have been reported for this

purpose. However, almost all of them were used in organic solvents (Chen et al.,

2008; Wang et al., 2008; Roopan et al., 2011). Even several methods have been

reported for the synthesis of 2,3-dihydroquinazolinones (Surpur et al., 2007).

However, these methods suffer from lengthy procedures, yields and vigorous

conditions (Roopan et al., 2008; Mohammadi et al., 2009). Thus, developing versatile

106

approaches to synthesize 2,3-dihydroquinazolin-4(1H)-ones still remains a highly

desired goal in organic synthesis. The importance of this kind of heterocyclic, our

aim is to introduce phenanthroline and Quinazolinone heterocyclics in acridine

system.

In this chapter, the unexpected formation of 5,6-dihydrobenzo[1,7]

phenanthroline instead of 5,6-dihydrobenzo[1,7]phenanthroline-3-carbonitrile has

been observed in acridine molecules. Moreover, we also identified Montmorillonite

KSF clay as catalyst to offer regioselective expected products and NaH base as

regioselective formation of unexpected Michael addition products. On the basis of

systematic study, the novel regioselectivity could be assigned by utilization of suitable

catalyst. Further, 2,3-disubstituted dihydroquinazolin-4(1H)-ones have been achieved

via recyclable TiO2 nano catalyst multi component reactions. All Synthesized

compounds were confirmed by FT-IR, 1H-NMR,

13C-NMR and Mass analysis.

5.2 REPORTED SYNTHETIC APPROACH

Kozlov and Gusak., 2010 reported, three-component condensation of 2-

methylquinolin-5-amine, 5.7 with aromatic aldehyde, 5.9 and cyclic β-diketone, 5.8

provides a convenient one-pot procedure for the synthesis of a number of difficultly

accessible methyl-substituted 1,7-phenanthroline derivatives, 5.14.

The formation of benzo[b][1,7]phenanthrolinone system involves initial condensation

of amine, 5.7 with aldehyde, 5.9 to give Schiff base, 5.10, addition of diketone, 5.8 at

the -C=N bond in 5.10, rearrangement of adduct, 5.11 thus formed via elimination of

α-β-unsaturated diketone, 5.12 and its subsequent migration to the aromatic ring (to

the carbon atom in the α-position with respect to the amino group, which possesses

the highest electron density), and intramolecular condensation of rearrangement

product, 5.14.

Kadutskii et al., 2006, reported, 8,9,10,11-Tetrohydrobenzo[a]acridne-11-one,

5.18 reacted with aromatic aldehydes to give the corresponding 10-arylmethylidine-

8,9,10,11-Tetrohydrobenzo[a]acridne-11-ones, 5.19. Further, 5.19 reacted with

malononitrile in the presence of base catalyst led to the formation of polynuclear

partially hydrogenated systems, 2-alkoxy-4-aryl-5,6dihydronaphtho[2,1-j][1,7]

phenanthroline-3-carbonitriles, 5.20.

107

Reagents and conditions: (i) butan-1-ol, reflux, 3-4 h

Reagents and conditions: (ii) ∆ (iii) [o] (iv) ArCHO, aq.KOH (v) CH2(CN)2, 50 %

KOH, EtOH, reflux

Hanaa and Mohamed., 2008, reported anti-inflammatory and analgesic activities

108

of some newly synthesized pyridinedicarbonitrile and benzopyranopyridine

derivatives. The reaction of 1-(2-thienyl or furanyl)-3-(2-hydroxyphenyl)-2-propen-1-

ones, 5.21 with malononitrile in the presence of a sufficient amount of alkoxide anion

was investigated. The hydroxyl group might behave as an active nucleophilic centre,

affording condensed 5H-[1]benzopyrano[3,4-c]pyridine derivatives via double

Michael reaction.

Reagents and conditions: (vi) CH2(CN)2, KOH, EtOH, reflux

Jiuxi Chen and Dengze., 2008, reported 2,3-dihydroquinazolin-4(1H)-ones and

quinazolin-4(3H)-ones have been synthesized in good to excellent yields and high

selectivity by one-pot reaction using isatoic anhydride, 5.28 ammonium acetate, 5.30

and aldehyde, 5.29 in ethanol or in DMSO under mild conditions. The reaction was

109

efficiently promoted by 1 mol % Ga(OTf)3 and the catalyst could be recovered easily

after the reactions and reused without evident loss of reactivity.

Reagents and conditions: (vii) Catalyst, EtOH, CH3CN, H2O, THF, CH3NO2

Zhan-Hui 2010, synthesis of 2,3-dihydroquinazolin-4(1H)-one, 5.34 by three-

component coupling of isatoic anhydride, 5.28 amines, 5.32 and aldehydes, 5.33 were

catalyzed by Magnetic Fe3O4 nanoparticles in water was reported. This methodology

results in the synthesis of a variety of 2,3-dihydroquinazolin-4(1H)-ones in high

yields. The catalyst can be recovered and recycled without a significant loss in the

catalytic activity.

Reagents and conditions: (viii) catalyst, H2O

Yavari and Beheshti., 2011, reported ZnO nanoparticles catalyzed efficient one-

pot three-component synthesis of 2,3-disubstituted quinalolin-4(1H)-ones under

solvent-free conditions. They have developed an efficient ZnO NPs as Lewis acid

catalyst for the synthesis of quinazolinones by a one-pot, three-component

condensation of isatoic anhydride, 5.28 with amines, 5.32 and aldehydes, 5.33 in high

atom economy under solvent-free conditions. The ZnO NPs would act as a catalyst to

activate the substrate molecules. Moreover, the catalyst can be recovered

conveniently and reused for at least three reaction cycles without appreciable loss of

activity.

110

Reagents and conditions: (ix) ZnONP’s (20 mol %), Solvent-free, 70 ⁰C, 3 h

Dabiri et al., 2005, reported an efficient synthesis of mono and disubstituted

2,3-dihydroquinazolin-4(1H)-ones, 5.34 using KAl(SO4)2.12H2O as a reusable

catalyst in water and ethanol. In this method, the use of KAl(SO4)2.12H2O (alum),

which was relatively non-toxican d inexpensive, was at the centre of our study. In the

course of our work on applications of KAl(SO4)2.12H2O in organic reactions, they

have found that it is an effective promoter for the preparation of mono and

disubstituted 2,3-dihydroquinazolin-4(1H)-ones.

Reagents and conditions: (x) alum, H2O & EtOH

Based on the above literature reports, our aim is to introduce phenanthroline and

dihydroquinazoline in acridine system. Following present work describes synthesis of

unexpected 5,6-dihydrobenzo[1,7]phenanthroline and expected 5,6-dihydrobenzo

[1,7]phenanthroline-3-carbonitrile has been observed in acridine molecules. We also

optimized the reaction conditions to get regioselective expected and unexpected

products. Further, 2,3-disubstituted dihydroquinazolin-4(1H)-ones have been

achieved via recyclable TiO2 nano catalyst multi component reactions.

111

5.3PRESENT WORK: RESULTS AND DISCUSSION

Scheme 5.1 Synthesis of 5,6-dihydrobenzo[1,7]phenanthroline-3-carbonitrile, 5.39b

and 5,6-dihydrobenzo[1,7]phenanthroline, 5.36b via MCR’s.

Scheme 5.2 Synthesis of regioselective 5,6-dihydrobenzo[1,7]phenanthroline

derivatives, 5.36a-h

Scheme 5.3 An alternative route for synthesis of 5,6-dihydrobenzo[1,7]

phenanthroline, 5.36b

112

Table 5.1 Summary and physical data of 10-chloro-2-ethoxy-4,12-diphenyl-5,6-

dihydrobenzo [j][1,7]phenanthrolines, 5.36a-h

Compounds 1 2 3 M.P. (°C) Yield (%)a

5.36a -Cl -C6H5 3,4-OCH3 142-144 81

5.36b -Cl -C6H5 4-Cl 236-238 79

5.36c -H -C6H5 4-Cl 163-165 80

5.36d -H -CH3 4-Cl 195-197 76

5.36e -Cl -C6H5 2-Cl 160-162 75

5.36f -Cl -C6H5 2,5-OCH3 138-140 78

5.36g -Cl -C6H5 3-OCH3 146-148 75

5.36h -Cl -C6H5 H 150-152 75

aIsolated yields

Scheme 5.4 Synthesis of 5,6-dihydrobenzo[1,7]phenanthroline-3-carbonitriles,

5.39a,b

113

Scheme 5.5 One pot synthesis of 5,6-dihydrobenzo[1,7]phenanthroline-3-

carbonitriles, 5.39a-d using Montmorillonite KSF catalyst.

Table 5.2 Physical data of expected dihydrobenzo[1,7]phenanthroline-3-carbonitriles,

5.39a-d

Compounds 1 2 3 M.P. ( ⁰C) Yield (%)a

5.39a -Cl -C6H6 3,4-OCH3 162-164 81

5.39b -Cl -C6H6 4-Cl 210-212 78

5.39c -H -C6H6 4-Cl 231-233 81

5.39d -H -CH3 4-Cl 230-232 72

aIsolated yields

Scheme 5.6 A plausible reaction mechanism for the formation of unexpected

dihydrobenzo[1,7]phenanthroline, 5.36b and expected dihydrobenzo

[1,7]phenanthroline-3-carbonitrile, 5.39b

114

Scheme 5.7 Synthesis of 2,3-disubstituted 2,3-dihydroquinazolin-4(1H)-ones, 5.42a-g

Table 5.3 Summary of 2,3-dihydroquinazolin-4(1H)-ones, 5.42a-g

Compounds M.P ( ⁰C)

aYield %

5.42a

156-158 98

5.42b

164-166 91

5.42c

200-202 95

5.42d

178-180 97

5.42e

138-140 94

5.42f

164-165 93

5.42g

153-155 96

aIsolated yields

MCR’s have been carried out by following synthetic strategy. 7-chloro-9-

phenyl-3,4-dihydroacridin-1(2H)-one, 1.33 reacted with 4-cholorobenzaldehyde,

1.44e and malononitrile, 3.35 are carried out with various base catalyst Scheme 5.1

afforded the expected 10-chloro-4-(4-chlorophenyl)-2-ethoxy-12-phenyl-5,6-

dihydrobenzo[j][1,7] phenanthroline-3-carbonitrile, 5.39b and unexpected 10-chloro-

115

4-(4-chlorophenyl)-2-ethoxy-12-phenyl-5,6-dihydrobenzo[j][1,7]phenanthroline,

5.36b.

Table 5.4 Optimization of base mediated Michael addition reaction

Entrya Base (Equiv) Solvent (1:1)

Yield (%)b

5.39b 5.36b

1 K2CO3 (1) EtOH/water - -

2 K2CO3 (3) EtOH/water Tracec -

3 K2CO3 (5) EtOH/water 30 Tracec

4 K2CO3 (6) EtOH/water 30 5

5 Na2CO3 (10) EtOH/water 37 5

6 KOH (20) EtOH 53 9

7 NaOH (20) EtOH 55 17

8 Na (20) EtOH 57 19

9 NaH (5) EtOH 55 24

10 NaH (1) EtOH/benzene 43 27





15 NaH (6) EtOH/benzene Tracec 73



18 Montmorillonite

KSF (100 mg) EtOH 87 -

19 Montmorillonite


20 Montmorillonite


a All reactions were carried out in 1 mmol of (1:1:1) equiv of reactants (1.33, 1.44e

and 3.35) and 5 mL of solvent unless otherwise noted. bisolated yield,

c TLC.

The results are summarized in Table 5.1. Under the optimized reaction

condition, the base catalyst is varied from mild inorganic base to strong bases, Table

5.4.

The Michael reaction of β-functionalized or α,β-unsaturated ketones with

malononitrile has been described. In Table 5.1, optimization of base catalyst is

summarized. 1 equivalent of K2CO3 (Table 5.1, entry 1) in ethanol and water (1:1)

medium shows no reaction. 3 equivalent of K2CO3 (Table 5.1, entry 2) in ethanol

and water (1:1) medium yields the trace amount of expected compound, 5.39b. 5

116

equivalent of K2CO3 (Table 5.1, entry 3) in ethanol and water (1:1) medium yields

the 30 % of expected compound, 5.39b and trace amount of unexpected compound,

5.36b. Further, increasing the order of base catalyst (Table 5.1, entries 4-14) yields

are moderate amount of expected compound, 5.39b and less amount of unexpected

compound, 5.36b. Our aim is to optimize the reaction conditions to get unexpected

compound, 5.36b regiospecifically. Due to the nature of base, the reaction conditions

vary from mild base to strong base. A strong base NaH plays major role to get

unexpected product, 5.36b. The solvents also influence the yield of the products.

NaH in EtOH and benzene (1:1) ratio (Table 5.1, entries 10-17) increase the yield of

unexpected compound, 5.36b and decreas the yield of expected compound, 5.39b.

The optimized conditions are NaH in EtOH/benzene (Table 5.1, entry 16) have given

78 % of yield. Further increasing the amount of base, the yield % of the products

were neither increased nor altered. The next goal of the work is to get the expected

Michael product, 5.39b regiospecifically. In this concern, we carried out the reaction

in Montmorillonite KSF clay catalyst instead of above mentioned bases (Table 5.1,

entries 18-20) which yields regiospecifically 5,6-dihydrobenzo[1,7]phenanthroline-3-

carbonitrile, 5.39b Michael addition product.

The structure of compounds, 5.39b and 5.36b were confirmed by 1H NMR,

13C NMR and mass spectrometry. The unexpected compound, 5.36b was supported

by X-ray crystallography ORTEP Figure 5.2 diagram.

Fig 5.2 ORTEP diagram for compound, 5.36b

117

Table 5.5 Crystallographic data of 10-chloro-4-(4-chlorophenyl)-2-ethoxy-12-phenyl

5,6-dihydrobenzo[j][1,7]phenanthroline, 5.36b

Empirical formula C30 H22 Cl2 N2 O

Formula weight 497.40

Temperature 293(2) K

Wavelength 0.71073 A

Crystal system, space group Monoclinic, P21/c

Unit cell dimensions a = 11.3697(2) A α = 90 º.

b = 28.8078(5) A β = 98.4130(10) º.

c = 15.2132(3) A γ = 90 º.

Volume 4929.25(16) A3

Z, Calculated density 8, 1.340 Mg/m3

Absorption coefficient 0.290 mm-1

F(000) 2064

Crystal size 0.35 x 0.30 x 0.30 mm

Theta range for data collection 2.21- 25.00 º.

Limiting indices -13<=h<=13, -25<=k<=34, -18<=l<=18

Reflections collected / unique 45391 / 8675 [R(int) = 0.0351]

Completeness to theta = 25.00 º 99.9 %

Absorption correction Semi-empirical from equivalents

Max. and min. Transmission 0.9568 and 0.9021

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 8675 / 0 / 632

Goodness-of-fit on F2 1.021

Final R indices [I > 2sigma(I)] R1 = 0.0379, wR2 = 0.0888

R indices (all data) R1 = 0.0599, wR2 = 0.1025

Extinction coefficient 0.0024(2)

Largest diff. peak and hole 0.257 and -0.333 e.A-3

118

Earlier in the literature, the Michael addition offers the expected carbonitrile

product. In this present study, our aim is to focus synthesis of regioselectively

unexpected product, 5.36b and expected compound, 5.39b in various 5,6-

dihydrophenthroline analogues.

From our optimized condition Scheme 5.2, we are utilized various (E)-2-

benzylidene-7-chloro-9-phenyl-3,4-dihydroacridin-1(2H)-one derivatives, 5.35 are

reacted with malononitrile, 3.35 in presence of NaH as a strong base (Table 5.1,

entries 15-17) to get regioselective unexpected products 5.36a-h. Physical data of all

synthesized compounds, 5.36a-h are summarized in Table 5.1.

Further, we have investigated the substrate scope of the two transformations.

The results are shown in further scheme and the regiochemical outcomes of the

reactions are examined. The mode of addition reactions influences the organic

transformation, solvent and catalyst (Christopher and Rachel., 1998). In this concern,

we tried to get regioselective 5,6-dihydrobenzo[1,7]phenanthroline, 5.36b from 7-

chloro-9-phenyl-3,4-dihydroacridin-1(2H)-one, 1.33. We synthesized an intermediate

2-(4-chlorobenzylidene)malononitrile, 5.37 using 4-cholorobenzaldehyde, 1.44e and

malononitrile, 3.35 in ethanol refluxed for 8 h. The intermediate, 5.37 were further

treated with 7-chloro-9-phenyl-3,4-dihydroacridin-1(2H)-one, 1.33 using an

optimized condition (Table 5.1, entry 15) results that unexpected compound, 5.36b

Scheme 5.3.

Expected 5,6-dihydrobenzo[1,7]phenanthroline-3-carbonitrile, 5.39b was

regioselectivelly synthesized through another alternative chemical pathway Scheme

5.4. However, these methods are suffered from some limitation such as low yield,

poor regioselectivity and prolonged reaction time (Gopal et al., 2012). Therefore, we

required to develop mild, economical and complementary synthetic approach. To

overcome this problem we utilized Montmorillonite KSF clay as catalyst, Scheme

5.5. In this case (E)-2-benzylidene-7-chloro-9-phenyl-3,4-dihydroacridin-1(2H)-one,

5.35a,b reacted with malononitrile, 3.35 in presence of Montmorillonite KSF as

catalyst containing 10 mL of ethanol yields 5,6-dihydrobenzo[1,7]phenanthroline-3-

carbonitrile, 5.39a,b. The Montmorillonite KSF as a catalyst for the optimized

reaction conditions are represented in Table 5.4. The recyclability of catalyst is

studied up to 3 cycles. The results are specified in Table 5.6.

119

A plausible reaction mechanism as outlined in scheme 5.6. The investigation

of these two transformations are carried out as per the reported method using

cyclohexanone and α-tetralone analogous (El-Bain et al., 2006; Misheiky et al., 2000).

The result reveals that corresponding carbonitrile functional group contain expected

Michael product.

Table 5.6 Recyclability of Montmorillonite KSF catalyst

Run Amount (mg) Yield (%)

1 250 90

2 230 89

3 220 88

In quinazolin synthesis, we isolated the 2,3-dihydro-3-methyl-2-

phenylquinazolin-4(1H)-one analogues, 5.42a-g by column chromatography in > 90

% yield. These products were characterized using FT-IR, 1H,

13C NMR and mass

analyses. Analysis results are given in experimental section. In FT-IR, compound,

5.42a showed peaks at 3452 cm-1

, corresponding to –NH stretching, 3265 cm-1

for –

NCH3, and 1622 cm-1

for the –C=O group. In proton NMR, the singlet at δ 2.88

corresponds to methyl protons (–CH3), the peak at δ 4.48 is corresponding to –NH

proton, peak at δ 5.71 is corresponding to –CH proton and peaks at δ 6.52–7.97

belong to aromatic protons. In 13

C NMR, the methyl group appears at δ 32, –CH

group appears at δ 74, aromatic carbons appears at a δ 114–145 and –C=O appears at

δ 163. We optimized the reaction with various amount (mol %) of TiO2 NPs.

Catalyst concentration plays a major role in the product yields. It was observed that

increasing the loading of the catalyst from 2 to 5 mol % gave an improved yield of 91

% of the product Table 5.7. Further increase of catalyst loading leads to lower

reaction yields because the products tend to be absorbed on the catalyst.

120

Table 5.7 Optimization of the amount of TiO2 NPs in the synthesis of 2,3-dihydro-3-

methyl-2-(4-(dimethylamino)phenyl)quinazolin-4(1H)one, 5.42b

In order to elucidate the role of the solvents, various solvents were used in

order to evaluate the scope and limitation of the reaction. After screening different

solvents, it was found that TiO2 NPs catalyzed quinazolinone synthesis is not only

faster, but also resulted in better yields under solvent free conditions Table 5.8. In

general, the polar protic solvents (EtOH and water) result in good yields. The aprotic

solvents (CHCl3 and DCM) give the lowest yield. The dielectric constant measures

the solvent’s ability to reduce the field strength of the electric field surrounding a

charged particle immersed in it.

The protic solvents have higher dielectric constant values compared with

aprotic (non-polar) solvents. The protic (polar) solvents that can donate proton easily

can form hydrogen bonds with the reactants. These could be the reasons that we are

getting better yields in protic solvents than in aprotic solvents.

In Table 5.9, catalytic activities are optimized at deferent time interval (room

temperature, 30 min and 1h). The reaction were carried out in the absence of catalyst

(Table 5.9, entry 1), and in the presence of silicagel (Table 5.9, entry 2), amberlite

(Table 5.9, entry 3), montmorillonite KSF (Table 5.9, entry 4), Al2O3-acetic (Table

5.9, entry 5), montmorillonite K10 (Table 5.9, entry 6), Commercial metal oxide

such as ZnO2 (Table 5.9, entry 7), PbO2 (Table 5.9, entry 8), TiO2 (Table 5.9, entry

9) and

Entry Catalyst (mol %) Yield GC-MS (%)

5.42 b

1 2 49.68

2 3 54.53

3 4 76.42

4

5

5

6

91.86

89.47

121

Table 5.8 Effect of solvent for the synthesis of 2,3-dihydro-3-methyl-2-(4-

(dimethylamino)phenyl)quinazolin-4(1H)one, 5.42b

Table 5.9 Selection of catalyst for the synthesis of 2,3-dihydro-3-methyl-2-(4-

(dimethylamino)phenyl)quinazolin-4(1H)one, 5.42b

a

GC-MS identification

Entry Solvent Time

(min)

Yield GC-MS (%)

5.42b

1. DCM 90 36.76

2. CHCl3 60 40.54

3. EtOH 45 73.64

4. H2O 30 76.05

5. Solvent free 30 91.86

Entry Catalyst Time (min) Yield GC-MS (%)

a

5.42b

1 Without catalyst 30 45.90

2 Silica Gel 30 49.60

3 Amberlite 30 54.53

4 Montmorillonite KSF 30 87.63

5 Acidic alumina 30 80.67

6 Montmorillonite K10 30 80.16

7 Commercial ZnO2 30 66.92

8 Commercial PbO2 30 55.21

9 Commercial TiO2 30 80.20

10 TiO2 NPs 30 91.86

122

TiO2 NPs (Table 5.9, entry 10). In the presence of TiO2 NPs the obtained

yield is 91 % at 30 min.

Table 5.10 Literature comparison of yield and conditions with our present work.

S.No Conditions Yield (%) References

1 Alum, H2O, reflux, 1 h 65

Chen et al., 2008

2 Alum, EtOH, reflux, 4 h 78

3 Ga(OTf)3, EtOH, 70 °C, 1 h 79 Wang et al., 2008

4 Zn(PFO)2, H2O/EtOH (1:3), reflux, 6 h 82 Reddy et al., 2007

5 Amberlyst 15, solvent-free, MW, 3 min 81 Roopan et al., 2007

6 SSA, H2O, 80 °C, 4.5 h 85

Dabiri et al., 2008

7 SSA, solvent-free, 80 °C, 5 h 80

8 [bmim]BF4-, 70 °C, 1.5 h 80 Dabiri et al., 2007

9 Fe3O4 NPs, H2O, reflux, 2 h 84 Zhang et al., 2010

10 ZnO NPs, solvent-free, 70 °C, 3 h 88 Yavari et al., 2011

11 Copolymer-PTSA, EtOH, 5 h 88 Saffari-Teluri et al., 2010

12 Chiral phosphoric acid, CHCl3, RT, 24 h 94 Dao-Juan et al., 2012

13 Alum, EtOH, reflux, 7 h 93 Mohammadi et al., 2009

14 Al(MS)3.H2O, EtOH:H2O (1:1), reflux,

30 min 88 Song et al., 2012

15 TiO2 NPs, Solvent free, 70 0C, 30 min 98 Present Work

All other catalyst shows moderate yield at 30 min, furthermore we increased

the time duration from the result we found that decreasing the yield % after 30 min.

Hence the optimized condition was fixed at 30 min for synthesizing, 3-dihydro-3-

methyl-2-phenylquinazolin-4(1H)-one analogues, 5.42a-g. Compound, 5.42b shows

123

91.86 % conversion by using the TiO2 NPs. In Table 5.10, the catalytic activity of the

synthesized TiO2 NPs, to catalyse the formation of compound, 5.42a is compared

with other reported catalyst. In most cases, the TiO2 NPs are comparable or better

than other catalysts.

A possible mechanism for this reaction was shown in scheme 5.8. It has been

conceivable that TiO2 NPs are coordinated to the oxygen atom of the carbonyl groups

in different stages of the reaction activating them for the nucleophilic attack of the

amine and amide nitrogen atoms. The high surface area to volume ratio of TiO2 NPs

is mainly responsible for their catalytic properties.

Scheme 5.8 Plausible mechanism for the synthesis of 2,3-dihydro-3-methyl–2–phenyl

quinazolin-4(1H)-ones, 5.42a-g using TiO2 NPs

124

5.4 CONCLUSION

In conclusion, we have developed the first example of regioselective 5,6-

dihydrobenzo[1,7]phenanthrolines, 5.36b using NaH as base in Michael addition

reaction. The expected 5,6-dihydrobenzo[1,7]phenanthroline-3-carbonitriles, 5.39b

was obtained by Montmorillonite KSF clay as catalyst. These data have lead to the

development of an alternative and straight forward mechanistic pathway for Michael

addition reaction. This report provides an easy method for direct access to

regioselective expected and unexpected compounds. Further, we have successfully

synthesized the TiO2 nanoparticles using aqueous A. squamosa peel extract. These

synthesized TiO2 nanoparticles were characterized using UV, XRD and TEM.

Synthesized TiO2 nanopowders were used as a catalyst for 2,3-dihydro-3-methyl-2-

phenylquinazolin-4(1H)-one analogues, 5.42a–g synthesis.

5.5 EXPERIMENTAL SECTION

5.5.1 SYNTHESIS OF 5,6-DIHYDROBENZO[1,7]PHENANTHROLINE-3-

CARBONITRILE, AND 5,6- DIHYDROBENZO[1,7]PHENANTHROLINE, 5.36b

VIA MCR’S.

To a solution of 7-chloro-9-phenyl-3,4-dihydroacridin-1(2H)-one 1.33 (1

mmol) was added with 4-chlorobenzaldehyde 1.44e (1 mmol) and malononitrile 3.35

(1 mmol) in presence of base with ethanol (10 ml) refluxed for 5 h at 80 ⁰C. The

reaction was monitored by TLC. After completion of the reaction, reaction mixture

was neutralized with 2N HCl. The precipitate was filtered off, washed with water and

dried. Two different products 5.39b and 5.36b were separated by column

chromatography. For optimization, same reactions were carried out by several times

with different base at various equivalent mole ratio to get unexpected regioselective

product 5.36b.

5.5.2 SYNTHESIS OF REGIOSELECTIVE 5,6-DIHYDROBENZO[1,7]PHENAN

THROLINE, 5.36a-h

A mixture of 40 equivalent (0.96 g) NaH was stirred with a solution contains 5

ml of ethanol and 5 ml of benzene in ice cold condition at 15 min. A mixture of

corresponding (E)-2-benzylidene-7-chloro-9-phenyl-3,4-dihydroacridin-1(2H)-one,

5.35a-h (1 mmol) and malononitrile, 3.35 (1 mmol) were added with a solution

contains NaH base. After addition of the reagents and reactants the reaction mixture

was refluxed for 3 h at 80 ⁰C. The reaction was monitored by TLC. After the

125

completion of the reaction, the reaction mixture was poured into ice cold water and

neutralized with 2N HCl. The precipitate was filtered and washed with water. The

product was purified by column chromatography results that compound, 5.36a-h.

5.5.3. AN ALTERNATIVE ROUTE FOR THE SYNTHESIS OF 5,6-DIHYDRO

BENZO[1,7]PHENANTHROLINE, 5.36b

Intermediate 2-(4-chlorobenzylidene)malononitrile, 5.37 was synthesized by

reacting 4-chlorobenzaldehyde, 1.44e (1 mmol) with malononitrile, 3.35 (1 mmol) in

ethanol refluxed for 8 h. Further, intermediate, 5.37 (1 mmol) was refluxed for 5 h

with 7-chloro-9-phenyl-3,4-dihydroacridin-1(2H)-one, 1.33 (1 mmol) in ethanol

contains 40 equivalent NaH base. The result offers, unexpected regioselective

product, 5.35.

5.5.4 SYNTHESIS OF 5,6-DIHYDROBENZO[1,7]PHENANTHROLINE-3-CARBO

NITRILE, 5.39a,b

(E)-2-benzylidene-7-chloro-9-phenyl-3,4-dihydroacridin-1(2H)-one, 5.35a,b

(1 mmol) and malononitrile, 3.35 (1 mmol) were added with a solution contain 10 ml

of ethanol and catalytic amount of piperidine (2 drops) refluxed for 5 h result

compound, 5.38. Intermediates 5.38 were further refluxed for 3 h at 80 ⁰C in solution

contain 10 % KOH. The completion of reaction was noted by TLC. The reaction was

poured into ice cold water and neutralized with 2N HCl. The product was purified by

column chromatography. The result was offered expected compounds, 5.39a,b.

5.5.5 ONE POT SYNTHESIS OF 5,6-DIHYDROBENZO[1,7]PHENANTHROLINE

-3-CARBONITRILE, 5.39a-d USING MONTMORILLONITE KSF CATALYST

Solution of ethanol (10 mL), (E)-2-benzylidene-7-chloro-9-phenyl-3,4-

dihydroacridin-1(2H)-one, 5.35a-d (1 mmol), malononitrile, 3.35 (1 mmol)

montmorillonite KSF were added and refluxed for 3 h. The completion of reaction

was noted by TLC. Catalyst was recovered and reused for further three times. The

product was purified by column chromatography. The result was offered expected

compounds, 5.39a-d.

Bio-fabricated TiO2 nanoparticles

Biosynthesis of rutile TiO2 nanoparticles (TiO2 NPs) was achieved by a novel,

biodegradable and convenient procedure using fruit peel Annona squamosa aqueous

extract. Rutile TiO2 NPs were characterized using UV, XRD, SEM and TEM studies

(Roopan et al., 2012)

126

5.5.6 GENERAL PROCEDURE FOR SYNTHESIS OF 2,3-DISUBSTITUTED 2,3-

DIHYDROQUINAZOLINE-4-(1H)-ONES, 5.42a-g

A mixture of isatoic anhydride, 5.28 (0.234 g, 2 mmol), methyl amines, 5.40

(68.7 mL, 2 mmol), benzaldehydes 5.41a-g (2 mmol) and TiO2 NPs (5 mol %) was

heated at 70 ⁰C for 30 min. The reaction was monitored by TLC analysis using

petroleum ether-ethyl acetate (1:4, v/v). After the completion of the reaction, the

reaction mixture was cooled to room temperature. The solid residue was dissolved in

hot ethanol and centrifuged to remove the catalyst. Then the filtrate was subjected to

column chromatography eluting with petroleum ether-ethyl acetate (1:4, v/v) to

isolate the desired compounds. The isolated compounds were confirmed by FTIR,

1H,

13C NMR and GC–MS analyses.

The spectral details are as follows,

10-chloro-4-(3,4-dimethoxyphenyl)-2-ethoxy-12-phenyl-5,6-dihydrobenzo[j][1,7]

phenanthroline-3-carbonitrile, 5.39a

Orange solid; M.F: C33H26ClN3O3; Yield 81

%; M.P: 162-164 ⁰C; FT-IR (KBr pellet)

νmax/(cm−1

): 2225 (CN), 1541, 1516 (-C-O-

C); 1H NMR (400 MHz, CDCl3): δ (ppm),

1.06-1.10 (t, J = 6.8 Hz, 3H, -CH3), 2.97- 3.00 (t, J = 6.4 Hz, 2H, -CH2), 3.16-3.19 (t,

J = 6.4 Hz, 2H, -CH2), 3.23-3.29 (q, J =7 Hz, 2H, -CH2), 3.90 (s, 3H, -OCH3), 3.94 (s,

3H, -OCH3), 6.51 (s, 1H), 6.87-6.90 (d, J = 8 Hz, 1H), 6.92-6.96 (d, J = 8 Hz, 2H),

7.29 (s, 1H), 7.39-7.48 (m, 4H), 7.58-7.60 (d, J = 8.8 Hz, 1H), 7.97-8.00 (d, J = 8.8

Hz, 1H); 13

C NMR (400 MHz, CDCl3): δ (ppm), 14.44, 24.56, 29.72, 56.00, 61.21,

110.36, 110.96, 112.09, 121.98, 125.47, 125.83, 2x126.92, 128.00, 128.32, 3x129.26,

129.60, 2x130.15, 130.19, 131.24, 133.77, 138.89, 144.54, 145.40, 148.82, 149.07,

149.20, 151.18, 161.27, 161.34; Exact Mass: 547.17; Found EI-MS: m/z 548.58

[M+1].

10-chloro-4-(4-chlorophenyl)-2-ethoxy-12-phenyl-5,6-dihydrobenzo[j][1,7]phenan

throline-3-carbonitrile, 5.39b

Yellow solid; M.F: C31H21Cl2N3O; Yield 78 %;

M.P: 210-212 ⁰C; FT-IR (KBr pellet)

127

νmax/(cm−1

): 2222 (CN), 1544, 1492 (-C-O-C); 1H NMR (400 MHz, CDCl3) δ (ppm),

1.11-1.14 (t, J = 14.4 Hz, 3H, -CH3), 2.79-2.83 (t, J = 8.25 Hz, 2H, -CH2), 3.19-3.16

(t, J = 13.2 Hz, 2H, -CH2), 3.36-3.31 (q, J = 7.2 Hz, 2H, -CH2), 7.25-7.32 (m, 5H),

7.47-7.52 (m, 5H), 7.98-8.00 (d, J = 8.8 Hz, 2H); 13

C NMR (400 MHz, CDCl3): δ

14.19, 24.38, 33.53, 63.01, 115.02, 125.33, 125.57, 126.11, 2x127.47, 128.60, 129.00,

129.27, 129.54, 3x129.63, 130.13, 130.28, 130.63, 131.27, 132.35, 133.33, 135.82,

138.18, 146.04, 146.56, 153.36, 153.60, 160.52, 161.92; Exact Mass: 521.11; Found

ESI-MS: m/z 522.23 [M+1].

4-(4-Chloro-phenyl)-2-ethoxy-12-phenyl-5,6-dihydrobenzo[j][1,7]phenanthroline-3-

carbonitrile, 5.39c

Pale yellow solid; M.F: C31H22ClN3O; Yield 81 %;

mp: 231-233 ⁰C; FT-IR (KBr pellet) νmax/ (cm−1

):

2220 (CN), 1545, 1495 (-C-O-C); 1H NMR (400

MHz, CDCl3) δ (ppm), 1.07-1.04 (t, J = 7.2 Hz, 3H, -

CH3), 2.77-2.74 (t, J = 6.8 Hz, 2H, -CH2), 3.16-3.13 (t, J = 6.6 Hz, 2H, -CH2), 3.32-

3.30 (d, J = 7.2 Hz, 2H, -CH2), 7.32-7.30 (d, J = 7.2 Hz, 2H), 7.57-7.41 (m, 7H), 7.67-

7.65 (d, J = 8.4 Hz, 2H), 7.81-7.77 (t, J = 7.2 Hz, 1H), 8.03-8.01 (d, J = 8 Hz, 1H);

13C NMR (400 MHz, CDCl3): δ 14.42, 24.44, 26.93, 34.17, 61.24, 110.04, 124.93,

125.95, 126.62, 2x127.12, 128.11, 128.43, 128.52, 128.71, 129.51, 3x129.69,

2x130.17, 134.31, 134.41, 137.21, 139.54, 145.61, 147.05, 149.85, 150.01, 160.78,

161.25; Exact Mass: 487.15; Found ESI-MS m/z: 488.2 [M+1].

4-(4-Chloro-phenyl)-2-ethoxy-12-methyl-5,6-dihydro-benzo[j][1,7]phenanthroline-3-

carbonitrile, 5.39d

Pale yellow solid; M.F: C26H20ClN3O; Yield 72 %;

M.P: 230-232 ⁰C; FT-IR (KBr pellet) νmax/ (cm−1

):

2225 (CN), 1549, 1493 (-C-O-C); 1H NMR (400

MHz, CDCl3) δ (ppm), 1.53-1.51 (t, J = 7.2 Hz, 3H, -

CH3), 2.78-2.74 (t, J = 6.8 Hz, 2H, -CH2), 3.11-3.08 (t, J = 6.8 Hz, 2H, -CH2), 3.15 (s,

3H), 4.63-4.57 (q, J = 7 Hz, 2H, -CH2), 7.34-7.32 (d, J = 8 Hz, 2H), 7.54-7.52 (d, J =

8 Hz, 2H), 7.61-7.57 (t, J = 11.4 Hz, 1H), 7.76-7.72 (t, J = 7.6 Hz, 1H), 8.03-8.01 (d,

J = 8.4 Hz, 1H), 8.21-8.19 (d, J = 8.4 Hz, 1H); 13

C NMR (400 MHz, CDCl3): δ 14.66,

128

17.30, 24.66, 33.57, 63.56, 94.57, 115.18, 124.90, 125.89, 126.04, 126.32, 2x128.61,

129.16, 2x129.28, 130.15, 130.32, 133.52, 135.78, 144.73, 147.15, 153.47, 155.11,

159.99, 162.10; Exact Mass: 525.13; Found ESI-MS m/z: 526.2 [M+1].


phenanthroline, 5.36a

White solid; M.F: C32H27ClN2O3; Yield 81


νmax/(cm−1

): 1552, 1477 (-C-O-C); 1H NMR

(400 MHz, CDCl3): δ (ppm), 1.11-1.14 (t, J =

13.6 Hz, 3H, -CH3), 2.88-2.90 (m, 2H, -CH2), 3.16-3.17 (m, 2H, -CH2), 3.32-3.34 (q,

J =6.8 Hz, 2H, -CH2), 3.91 (s, 3H, -OCH3), 3.95 (s, 3H, -OCH3), 6.86 (s, 1H), 6.93-

6.95 (d, J = 8 Hz, 1H), 6.99-7.01 (d, J = 8 Hz, 1H), 7.25-7.27 (d, J = 6 Hz, 1H), 7.44-

7.51 (m, 6H), 7.62-7.64 (d, J = 8.8 Hz, 1H), 7.98-8.00 (d, J = 8.8 Hz, 1H); 13

C NMR

(400 Hz, CDCl3): δ 14.33, 24.69, 33.83, 56.10, 56.25, 62.97, 95.36, 111.35, 112.15,

115.56, 121.80, 125.70, 126.01, 126.18, 127.36, 127.53, 128.67, 129.12, 2x129.53,

130.40, 131.23, 132.36, 138.36, 146.12, 146.41, 149.15, 150.11, 153.14, 154.88,

160.84, 162.07; Exact Mass: 522.17; Found ESI-MS: m/z 523.02 [M+1].

10-chloro-4-(4-chlorophenyl)-2-ethoxy-12-phenyl-5,6-dihydrobenzo[j][1,7]

phenanthroline, 5.36b

Yellow solid; M.F: C30H22Cl2N2O; Yield 79 %;

mp: 236-238 ⁰C; FT-IR (KBr pellet) νmax/(cm−1

):

1544, 1492 (-C-O-C); 1H NMR (400 MHz,

CDCl3): δ (ppm), 1.05-1.09 (t, J = 14.4 Hz, 3H, -

CH3), 2.90-2.93 (t, J = 13.6 Hz, 2H, -CH2), 3.15-3.18 (t, J = 13.2 Hz, 2H, -CH2), 3.32-

3.28 (q, J = 1.6 Hz, 2H, -CH2), 6.46 (s, 1H), 7.38-7.47 (m, 8H), 7.58-7.60 (dd, J = 2.4,

2.4 Hz, 2H), 7.97-7.99 (d, J = 8.8 Hz, 2H); 13

C NMR (400 MHz, CDCl3): δ 14.37,

24.31, 34.05, 61.26, 110.38, 125.08, 125.83, 126.66, 126.93, 2x128.31, 2x128.71,

129.25, 3x129.54, 130.12, 2x130.27, 131.82, 134.36, 137.04, 138.81, 144.69, 145.39,

149.39, 150.06, 161.10, 161.28; Exact Mass: 596.11; Found ESI-MS: m/z 497.26

[M+1].

129

4-(4-Chloro-phenyl)-2-ethoxy-12-phenyl-5,6-dihydro-benzo[j][1,7]phenanthroline,

5.36c

Yellow solid; M.F: C30H23ClN2O3; Yield 80 %; M.P:

163-165 ⁰C; FT-IR (KBr pellet) νmax/ (cm−1

): 1545,

1493 (-C-O-C); 1H NMR (400 MHz, CDCl3) δ (ppm),

1.03-0.99 (t, J = 7.2 Hz, 3H, -CH3), 2.90-2.87 (t, J =

6.6 Hz, 2H, -CH2), 3.12-3.09 (t, J = 6.4 Hz, 2H, -CH2), 3.24-3.19 (q, J = 7.2 Hz, 2H,

-CH2), 6.52 (s, 1H), 7.28-7.26 (d, J = 7.2 Hz, 2H), 7.51-7.38 (m, 7H), 7.57-7.55 (d, J

= 8.4 Hz, 2H), 7.75-7.71 (t, J = 7.4 Hz, 1H), 8.01-7.99 (d, J = 8.4 Hz, 1H); 13

C NMR

(400 MHz, CDCl3) δ14.21, 24.49, 33.63, 62.94, 94.67, 115.17, 124.58, 125.40,

126.40, 127.12, 2x127.44, 128.18, 128.36, 128.65, 129.24, 3x129.50, 130.15, 130.48,

133.46, 135.74, 138.88, 147.50, 147.68, 153.45, 153.84, 160.18, 161.93; Exact Mass:

462.15; Found ESI-MS m/z: 463.3 [M+1].

4-(4-Chloro-phenyl)-2-ethoxy-12-methyl-5,6-dihydro-benzo[j][1,7]phenanthroline,

5.36d

Yellow solid; M.F: C25H21ClN2O; Yield 76 %; M.P:

195-197 ⁰C; FT-IR (KBr pellet) νmax/ (cm−1

): 1545,

1495 (-C-O-C); 1H NMR (400 MHz, CDCl3) δ (ppm),

1.47-1.45 (t, J = 6.8 Hz, 3H, -CH3), 2.88-2.85 (t, J =

6.6 Hz, 2H, -CH2), 3.10-3.07 (t, J = 6.6 Hz, 2H, -CH2), 3.16 (s, 3H) 4.50-4.45 (q, J =

7.2 Hz, 2H, -CH2), 6.65 (s, 1H), 7.33-7.31 (d, J = 8.4 Hz, 2H), 7.46-7.44 (d, J = 8 Hz,

2H) 7.57-7.53 (t, J = 7.6 Hz, 1H), 7.70-7.67 (t, J = 7.6 Hz, 1H), 8.02-8.00 (d, J = 8.4

Hz, 1H), 8.19-8.17 (d, J = 8.4 Hz, 1H); 13

C NMR (400 MHz, CDCl3) δ13.83, 16.05,

23.61, 33.08, 60.86, 108.62, 123.65, 124.41, 124.82, 126.06, 2x127.73, 127.88,

127.94, 128.31, 2x129.12, 133.34, 136.23, 141.74, 145.55, 149.18, 150.28, 159.54,

160.33; Exact Mass: 400.13; Found ESI-MS m/z: 401.3 [M+1].

10-chloro-4-(2-chlorophenyl)-2-ethoxy-12-phenyl-5,6-dihydrobenzo[j][1,7]

phenanthroline, 5.36e

White solid; M.F: C30H22Cl2N2O; Yield 75 %; M.P:

160-162 ⁰C; FT-IR (KBr pellet) νmax/(cm−1

): 1546,

1481 (-C-O-C); 1H NMR (400 MHz, CDCl3): δ

130

(ppm), 1.06-1.09 (t, J = 14 Hz, 3H, -CH3), 2.60-2.67 (m, 2H, -CH2), 2.78-2.85 (m,

2H, -CH2), 3.17-3.26 (q, J = 10.4 Hz, 2H, -CH2), 6.41 (s, 1H), 7.34-7.36 (m, 2H),

7.40-7.50 (m, 8H), 7.57-7.60 (d, J = 8.8 Hz, 1H), 7.96-7.98 (d, J = 8.8 Hz, 1H); 13

C

NMR (400 MHz, CDCl3): δ 14.51, 23.90, 34.01, 61.34, 110.94, 125.99, 126.29,

126.73, 127.00, 2x127.08, 128.43, 128.56, 129.44, 129.59, 129.69, 2x129.75, 130.26,

130.35, 130.62, 131.88, 132.98, 137.78, 139.11, 144.75, 145.49, 148.87, 161.28,

161.47; Exact Mass: 496.11; Found ESI-MS: m/z 497.46 [M+1].


phenanthroline, 5.36f

White solid; M.F: C32H27ClN2O3; Yield 78 %;

M.P: 138-140 ⁰C; FT-IR (KBr pellet) νmax/(cm−1

):

1552, 1477 (-C-O-C); 1H NMR (400 MHz,

CDCl3): δ (ppm), 1.11-1.14 (t, J = 12.8 Hz, 3H, -

CH3), 2.88-2.90 (m, 2H, -CH2), 3.17-3.18 (m, 2H,

-CH2), 3.33-3.34 (q, J = 6.4 Hz, 2H, -CH2), 3.91 (s, 3H, -OCH3), 3.95 (s, 3H, -OCH3),

6.86 (s, 1H), 6.93-6.95 (d, J = 8 Hz, 1H), 6.99-7.01 (d, J = 8.4 Hz, 1H), 7.25-7.27 (d,

J = 8 Hz, 1H), 7.44-7.51 (m, 6H), 7.62-7.65 (d, J = 8.8 Hz, 1H), 7.98-8.00 (d, J = 8.8

Hz, 1H); 13

C NMR (400 MHz, CDCl3): δ 14.34, 24.69, 33.88, 56.11, 56.26, 62.99,

95.37, 111.37, 112.17, 115.57, 121.81, 125.70, 126.02, 126.19, 127.37, 127.53,

128.68, 129.13, 2x129.53, 130.41, 131.23, 132.37, 138.37, 146.13, 146.42, 149.17,

150.12, 153.15, 154.89, 160.84, 162.08; Exact Mass: 522.17; Found ESI-MS: m/z

523.02 [M+1].

10-chloro-2-ethoxy-4-(3-methoxyphenyl)-12-phenyl-5,6-dihydrobenzo[j][1,7]

phenanthroline, 5.36g

Yellow solid; M.F: C31H25ClN2O2; Yield 75


νmax/(cm−1

): 1558, 1543, 1442 (-C-O-C); 1H

NMR (400 MHz, CDCl3): δ (ppm), 1.06-1.09

(t, J = 14 Hz, 3H, -CH3), 2.93-2.96 (t, J = 12.8 Hz, 2H, -CH2), 3.15-3.18 (t, J = 12.8

Hz, 2H, -CH2), 3.22-3.28 (q, J = 21.2 Hz, 2H, -CH2), 3.84 (s, 3H, -OCH3), 6.50 (s,

1H), 6.87 (s, 1H), 6.91-6.96 (t, J = 19.2 Hz, 2H), 7.25-7.29 (m, 2H), 7.34-7.41 (m,

131

2H), 7.44-7.46 (m, 3H), 7.57-7.60 (d, J = 8.8 Hz, 1H), 7.97-7.99 (d, J = 9.2 Hz, 1H):

13C NMR (400 MHz, CDCl3): δ 14.54, 24.52, 34.31, 55.47, 61.34, 110.57, 113.77,

114.58, 121.32, 125.59, 125.97, 126.96, 2x127.04, 128.45, 129.43, 129.63, 2x129.72,

130.29, 130.32, 131.88, 139.05, 140.19, 144.71, 145.54, 149.31, 151.37, 159.79,

161.38, 161.46; Exact Mass: 592.16; Found ESI-MS: m/z 492.16 [M+].

10-chloro-2-ethoxy-4,12-diphenyl-5,6-dihydrobenzo[j][1,7]phenanthroline, 5.36h

Brown solid; M.F: C30H23ClN2O; Yield 75 %; M.P:

150-152 ⁰C: FT-IR (KBr pellet) νmax/(cm−1

): 1552,

1477 (-C-O-C); 1H NMR (400 MHz, CDCl3): δ

(ppm), 1.11-1.14 (t, J =14 Hz, 3H, -CH3), 2.81-2.84

(t, J =12 2H, -CH2), 3.15-3.18 (t, J =12, 2H, -CH2), 3.31-3.36 (q, J = 6.8 Hz, 2H, -

CH2), 7.15-7.16 (d, J = 4 Hz, 1H), 7.26-7.28 (d, J = 7.2 Hz, 2H), 7.35-7.36 (d, J = 6.4

Hz, 1H), 7.44-7.50 (m, 8H), 7.62-7.64 (d, J = 8.8 Hz, 1H), 7.98-8.00 (d, J = 8.8 Hz,

1H); 13

C NMR (400 MHz, CDCl3): δ 14.30, 24.47, 33.71, 62.98, 95.33, 115.25,

124.56, 125.57, 126.17, 126.83, 127.50, 128.01, 128.09, 128.44, 128.76, 128.96,

129.11, 129.49, 130.28, 130.36, 131.22, 132.34, 132.69, 135.10, 136.95, 138.35,

146.09, 147.14, 153.15, 155.01; Exact Mass: 562.15; Found ESI-MS: m/z 462.97

[M+].

2,3-dihydro-3-methyl-2-phenylquinazolin-4(1H)one, 5.42a

White powder; M.F: C15H14N2O; Yield 98 %; M.P: 156-158 ⁰C;

FT-IR (KBr pellet) νmax/(cm−1

): 3473 (-NHasym), 3294.42 (-

NHsym), 1631 (-C=O); 1H NMR (400 MHz, CDCl3): δ (ppm),

2.88 (s, 3H, -N-CH3), 4.48 (s, 1H, -NH), 5.71 (s, 1H, -CH), 6.52-

6.54 (d, J = 8 Hz, 1H), 6.82-6.86 (t, J = 7.8 Hz, 1H), 7.25 (m, 5H), 7.95-7.97 (d, J =

7.6 Hz, 2H); 13

C NMR (400 MHz, CDCl3): δ (ppm), 32.08, 74.42, 114.17, 115.81,

119.35, 2x126.91, 2x128.67, 129.22, 129.65, 133.56, 139.55, 145.39, 163.74; Exact

Mass: 238.11; Found GC-MS (m/z) 237.33, 236.23, 235.28, 161.31.

2,3-dihydro-3-methyl-2-(4-(dimethylamino)phenyl)quinazolin-4(1H)one, 5.42b

White solid; M.F: C17H19N3O; Yield 91 %; M.P: 164-166

⁰C; FT-IR (KBr pellet) νmax/(cm−1

): 3456 (-NHasym), 3298 (-

132

NHsym), 1633 (-C=O); 1H NMR (400 MHz, CDCl3): δ (ppm), 2.82 (s, 3H, -N-CH3),

2.95 (s, 6H, -N-2CH3), 4.47 (s, 1H, -NH), 5.60 (s, 1H, -CH), 6.51-6.53 (d, J = 7.6 Hz,

2H), 6.65-6.57 (d, J = 8 Hz, 2H), 6.79-6.82 (t, J = 7.4 Hz, 1H), 7.20-7.26 (m, 1H),

7.92-7.94 (d, J = 7.6 Hz, 2H); 13

C NMR (400 MHz, CDCl3): δ (ppm), 31.59, 2x40.46,

74.18, 2x112.31, 114.05, 115.81, 118.93, 126.61, 128.07, 2x128.59, 133.31, 145.90,

151.31, 163.98; Exact Mass: 281.15; Found GC-MS (m/z) 281.47, 252.23, 197.83,

191.40, 161.20.

2,3-dihydro-3-methyl-2-(3,4-dimethoxyphenyl)quinazolin-4(1H)one, 5.42c

White solid; M.F: C17H18N2O3; Yield 95 %; M.P: 200-

202 ⁰C; FT-IR (KBr pellet) νmax/(cm−1

): 3460 (-NHasym),

3282 (-NHsym), 1631 (-C=O); 1H NMR (400 MHz,

CDCl3): δ (ppm), 2.83 (s, 3H, -N-CH3), 3.82 (s, 3H, -

OCH3), 3.88 (s, 3H, -OCH3), 4.48 (s, 1H, -NH), 5.66 (s, 1H, -CH), 6.55-6.57 (d, J = 8

Hz, 2H), 6.82-6.84 (t, J = 8.2 Hz, 1H), 6.92-6.94 (d, J = 8 Hz, 1H), 6.99 (s, 1H), 7.24-

7.28 (t, J = 7.6 Hz, 1H), 7.94-7.96 (d, J = 8 Hz, 1H); 13

C NMR (400 MHz, CDCl3): δ

(ppm), 31.48, 2x55.95, 74.22, 109.44, 110.85, 2x113.97, 115.69, 119.19, 119.81,

128.52, 131.72, 133.39, 145.54, 149.59, 150.04, 163.82; Exact Mass: 298.13; Found

GC-MS (m/z) 297.32, 296.16, 295.27, 207.26, 161.24.

2,3-dihydro-3-methyl-2-(2,5-dimethoxyphenyl)quinazolin-4(1H)one, 5.42d

White powder; M.F: C17H18N2O3; Yield 97 %; M.P: 178-180


): 3444 (-NHasym), 3062 (-

NHsym), 1635 (-C=O); 1H NMR (400 MHz, CDCl3): δ (ppm),

3.42 (s, 3H, -N-CH3), 3.77 (s, 3H, -OCH3), 3.81 (s, 3H, -

OCH3), 6.65 (s, 1H, -NH), 6.67 (s, 1H, -CH), 6.92-6.94 (d, J =

8.4 Hz, 1H), 6.99-7.02 (d, J = 11.6 Hz, 1H), 7.26-7.29 (s, 1H), 7.50 (m, 1H), 7.75 (s,

1H), 7.89-7.79(d, J = 8 Hz, 1H), 8.33-8.35 (d, J = 7.6 Hz, 1H); 13

C NMR (400 MHz,

CDCl3): δ (ppm), 32.55, 56.03, 74.22, 112.42, 115.01, 116.50, 120.93, 125.27,

126.82, 127.61, 132.18, 134.26, 147.68, 150.61, 151.15, 154.09, 162.57; Exact Mass:

298.13; Found GC-MS (m/z) 297.22, 269.20, 295.24, 264.25, 161.24.

133

2,3-dihydro-3-methyl-2-(2-nitrophenyl)quinazolin-4(1H)one, 5.42e

Yellow solid; M.F: C15H13N3O3; Yield 94 %; M.P: 138-140 ⁰C;

FT-IR (KBr pellet) νmax/(cm−1

): 3475 (-NHasym), 3307 (-NHsym),

1633 (-C=O); 1H NMR (400 MHz, CDCl3): δ (ppm), 3.01 (s,

3H, -N-CH3), 5.38 (s, 1H, -NH), 6.29 (s, 1H, -CH), 6.48-6.50 (d,

J = 8 Hz, 1H), 6.78-6.82 (t, J = 7.4 Hz, 1H), 7.19-7.23 (t, J = 7.6 Hz, 1H), 7.38-7.40

(d, J = 7.6 Hz, 1H), 7.47-7.51 (t, J = 7.6 Hz, 1H), 7.55-7.59 (t, J = 7.6 Hz, 1H), 7.93-

7.95 (d, J = 7.2 Hz, 1H), 8.10-8.12 (d, J = 8 Hz, 1H); 13

C NMR (CDCl3): δ (ppm),

33.35, 69.41, 114.73, 114.98, 119.27, 126.45, 127.66, 128.45, 129.97, 133.95, 134.70,

134.83, 144.04, 147.80, 163.93; Exact Mass: 283.10; Found GC-MS (m/z) 282.19,

281.17, 234.23, 161.29.

2,3-dihydro-3-methyl-2-(3-nitrophenyl)quinazolin-4(1H)one, 5.42f

Light green solid; M.F: C15H13N3O3; Yield 93 %; M.P:

164-165 ⁰C. FT-IR (KBr pellet) νmax/(cm−1

): 3460 (-

NHasym), 3282 (-NHsym), 1631 (-C=O). 1H NMR (400 MHz,

DMSO-d6): δ (ppm), 2.93 (s, 3H, -N-CH3), 6.06 (s, 1H, -

NH), 6.63-6.70 (dd, J = 7.6 Hz, J = 8 Hz, 2H), 7.20-7.23 (t, J = 7.4 Hz, 1H), 7.51 (s,

1H), 7.65-7.72 (m, 3H), 8.17-8.20 (d, J = 12 Hz, 2H); 13

C NMR (400 MHz, DMSO-

d6): δ (ppm), 32.29, 70.74, 114.30, 114.43, 117.50, 120.99, 123.38, 127.44, 130.40,

132.32, 133.50, 142.96, 145.82, 147.94, 162.41; Exact Mass: 283.13; Found GC-MS

(m/z) 282.29, 281.33, 278.33, 161.31, 121.26.

2,3-dihydro-3-methyl-2-(4-nitrophenyl)quinazolin-4(1H)one, 5.42g

White solid; M.F: C15H13N3O3; Yield 96 %; M.P: 153-155


): 3464 (-NHasym), 3107

(-NHsym), 1707 (-C=O); 1H NMR (400 MHz, DMSO-d6): δ

(ppm), 2.92 (s, 3H, -N-CH3), 6.54 (s, 1H, -NH), 6.74 (s,

1H, -CH), 7.10 (s, 1H), 7.23 (s, 1H), 7.35-7.37 (d, J = 7.2 Hz, 1H), 7.64-7.66 (d, J =

7.2 Hz, 2H), 7.72-7.76 (t, J = 17.2 Hz, 1H), 8.17-8.18 (d, J = 7.6 Hz, 2H); 13

C NMR

(CDCl3): δ (ppm), 42.16, 77.75, 124.07, 125.11, 127.64, 135.70, 136.89, 137.18,

139.94, 143.34, 144.27, 144.82, 155.18, 157.37, 172.73; Exact Mass: 283.13; Found

GC-MS (m/z) 283.25, 207.25, 161.31.

synthesis of 5,6-dihydrobenzo[1,7]phenanthroline...

Documents