Niacin as a Potent Organocatalyst towards the Synthesis of Quinazolines Using Nitriles as C–N Source

A Journal of

Accepted Article

Title: Niacin as a Potent Organocatalyst towards the Synthesis of

Quinazolines using Nitriles as C-N Source

Authors: Raghuram Gujjarappa, Nagaraju Vodnala, Velma Ganga

Reddy, and Chandi C Malakar

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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901651

Link to VoR: http://dx.doi.org/10.1002/ejoc.201901651

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Niacin as a Potent Organocatalyst towards the Synthesis of

Quinazolines using Nitriles as C-N Source

Raghuram Gujjarappa,^[a]Nagaraju Vodnala,^[a]Velma Ganga Reddy,^[b]and Chandi C. Malakar*^[a]

g]

Abstract: An efficient and cost-effective Vitamin-B₃-catalyzed

protocol towards the synthesis of diversely substituted quinazolines

is illustrated using 2-aminobenzylamines and nitriles as substrates.

An organocatalytic transformation has been investigated where

nitrile plays a role of C-N bond donor. The developed approach is

applicable on a wide range of 2-aminobenzylamines and nitriles for

the synthesis substituted quinazolines in high yields with a broad

functional group tolerance.

reactions.^[9c-e,

More interestingly, few reports towards the

synthesis of substituted quinazolines are known using the

concept of organocatalysis.^[2a-c]It is noteworthy that, 2-

aminobenzylamines or 2-aminobenzyl alcohols are largely

explored for synthesis of these structurally unique molecules by

employing aldehydes, alkyl alcohols and alkyl amines as C1

synthon under metal-catalyzed, non-metal-catalyzed and

organocatalyzed reaction conditions.^[2a-c,

9-10]

The previously

reported methods have their significance in obtaining broad

range of quinazolines along with certain limitations such as

restricted applicability of protocol, harsh reaction conditions and

harmful by-products.

Introduction

The role of an organocatalyst in the field of synthetic organic

chemistry is impeccable and irreplaceable because of its unique

way of actions in chemical transformations.^[1-2]The contribution

of these organocatalysts for synthesizing wide variety of N-

2]

heterocycles is noticeable.^[1i,

Owing to their biological

importance, immense research work has been performed for the

betterment of available protocols towards the synthesis of

diverse range of N-heterocycles.^[2-3]Among these distinctive

class of N-heterocycles, quinazoline scaffolds have marked their

presence because of their biological and medicinal importance

such as anticancer, antibacterial, antitubercular and antiviral

activities.^[4]The quinazoline scaffolds found their recognition as

FDA-approved marketed drugs to treat lung cancer (afatinib,

erlotinib and gefitinib),^[5]breast cancer (lapatinib)^[6]and other life

threatening diseases.^[7]Quinazolines have also been well-known

for their medicinal activities possessed by naturally occurring

quinazoline alkaloids.^[8]On realizing the significance of these N-

heterocyclic moieties, a large number of reports have appeared

over the past decades by addressing the issues of previous

9]

reports and for their betterment (Scheme 1).^[2b-c,

These

chemical transformations were realized using metal catalysts

such as Mn, Ni, Cu, Ru, Rh, Ir and Pt utilizing varieties of

starting materials.^{[9a, f, h-j, 10]}In recent times, chemists have also

came across the synthesis of quinazolines by utilizing non-

catalytic methods such as DDQ, IBX, PIDA and CsOH mediated

Scheme 1. Approaches towards the synthesis of 2-substituted quinazolines.

However, there have been limited numbers of reports on

using nitrile as a source of C-N bond.^{[9e, h-j, 10k, p]}In most of the

cases, nitrile has been used as a C-N bond donor along with 2-

aminobenzyl alcohol under metal-catalyzed reaction conditions

or with 2-aminobenzylamines as C1 synthon under non-metal-

catalyzed reaction conditions. There are no reports available

pertaining the use of nitrile as a C-N bond donor along with 2-

aminobenzylamines under organocatalyzed reaction conditions.

In continuation of our research work in developing efficient

protocol towards the synthesis of wide range of N-heterocycles

using organocatalysis,^{[2c, i-j]}we have described an efficient and

cost-effective Vitamin-B₃-catalyzed protocol towards the

synthesis of substituted quinazolines by employing 2-

aminobenzylamines and nitriles as a C-N bond donor.

[a]

[b]

R. Gujjarappa, N. Vodnala, Dr. C. C. Malakar

Department of Chemistry

National Institute of Technology Manipur

Langol, Imphal - 795004, Manipur, India

E-mail: chdeepm@gmail.com, cmalakar@nitmanipur.ac.in

Homepage: https://chdeepm.wixsite.com/mysite

Dr. V. G. Reddy

Centre for Advanced Materials & Industrial Chemistry (CAMIC),

School of Science

RMIT University

GPO Box 2476, Melbourne, 3001, Australia

Supporting information for this article is given via a link at the end of

the document.

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Results and Discussion

With the objective of designing an efficient organocatalytic

platform towards the synthesis of quinazolines, we began our

experimental studies by taking 2-aminobenzylamine (1a) and

benzonitrile (2a) as our model substrates. We intended to start

Table 1. Optimization of organocatalytic conditions for the reaction of 1a with

2a.^[a]

our proceedings by screening the previously known

i-j]

organocatalysts^[2c,

for the successful conversion of 2-

aminobenzylamine (1a) and benzonitrile (2a) into 2-

phenylquinazoline (3aa). Initially, the reaction of 2-

aminobenzylamine (1a) and benzonitrile (2a) was carried out

using 30 mol% thiourea as an organocatalyst in DMSO as

solvent at 110 °C for 24 h (Table 1, Entry 1). Under thiourea-

catalyzed reaction condition, 28% of reaction yield was observed.

Next, we focused on using pyridine based organocatalysts for

this chemical transformation. In this process, we have screened

organocatalysts like 3-nitropyridine, 2-picolinic acid, isonicotinic

acid and vitamin-B₃(Entries 2-5). Gratifyingly, all the

organocatalysts were performed well to deliver the desired

product 3aa in the range of 66-86%. The maximum yield of 3aa

was observed when 30 mol% of vitamin-B₃was used as an

organocatalyst in DMSO at 110 °C for 24 h (Entry 5). After

obtaining the highest yield using vitamin-B₃, we were fascinated

in carrying out the reaction under UV-light (Entry 6). To our

disappointment, we did not observe any product formation under

UV-light, rather starting materials were recovered. Further, the

reaction of 2-aminobenzylamine (1a) and benzonitrile (2a) were

performed using 30 mol% of vitamin-B₃in different solvents such

as DMF, DMA, dioxane, THF and H₂O at 110 °C for 24 h

(Entries 7-11). The reaction yields were not further improved by

using solvents other than DMSO. Next, we carried out the

reaction of 1a and 2a under different amounts of organocatalysts

(Entries 12-13). It was observed that decreasing the catalysts

loading to 20 mol% will affect the yield by 18% and increasing

the catalysts load to 40 mol% did not alter the reaction yield. It is

to be noted that, 30 mol% catalysts is optimum to realize this

chemical transformation. In continuation, we also carried out the

reaction of 1a and 2a under different reaction temperature

(Entries 14-15). It was observed that the decrease in

temperature had affected the reaction yield and increase in

temperature gave similar yield of the product. Moreover, the

reaction of 1a and 2a for different time period delivered

unsatisfactory results (Entries 16-18). Having performed an

extensive optimization of the reaction conditions, it was

observed that the highest yield of 2-phenylquinazoline (3aa) was

acquired when the reaction of 2-aminobenzylamine (1a) and

benzonitrile (2a) was carried out using 30 mol% vitamin-B₃in

DMSO at 110 °C for 24 h (Entry 5).

Entry

1

Catalyst (mol %)

Thiourea (30)

Conditions

3aa % Yield^[b]

DMSO, air, 110 °C, 24 h

DMSO, air, UV, 24 h

28

74

66

79

86

0^[c]

73

63

60

42

15

68

85

86

78

64

75

80

2

3-nitropyridine (30)

2-picolinic acid (30)

Isonicotinic acid (30)

Vitamin-B₃(30)

Vitamin-B₃(20)

Vitamin-B₃(40)

Vitamin-B₃(30)

3

4

5

6

7

DMF, air, 110 °C, 24 h

DMA, air, 110 °C, 24 h

dioxane, air, 110 °C, 24 h

THF, air, 110 °C, 24 h

H₂O, air, 110 °C, 24 h

DMSO, air, 110 °C, 24 h

DMSO, air, 120 °C, 24 h

DMSO, air, 100 °C, 24 h

DMSO, air, 110 °C, 16 h

DMSO, air, 110 °C, 20 h

DMSO, air, 110 °C, 30 h

8

9

10

11

12

13

14

15

16

17

18

[a] Unless otherwise indicated: All reactions were performed using 1.0 mmol

1a and 1.0 mmol 2a in 2 mL solvent. [b] Isolated yields. [c] Starting materials

were recovered.

Further, the scope of the reaction conditions were

extended by utilizing polycyclic aromatic nitriles 2q-s, hetero-

aromatic nitriles 2t-u, alkenyl nitriles 2v-w and aliphatic nitriles

2x-y to access broad range of 2-substituted quinazolines 3aq-ay

in 64-82% isolated yield (Scheme 3).

After developing an organocatalytic protocol towards the

efficient conversion of various aryl and alkyl nitriles into

quinazolines, we intended to screen varieties of substituted 2-

aminobenzylamines under the developed reaction conditions. To

implement this objective, 2-aminobenzylamines 1b-f with

electron donating and electron withdrawing functional groups

After realizing the best optimized reaction conditions

towards the synthesis of quinazoline, we performed reactions of

wide range of aryl nitriles 2a-p bearing electron rich as well as

electron poor functional groups with 2-aminobenzylamine 1a to

access diversified quinazoline derivatives. The reaction

conditions showed superior tolerance over electron donating OH,

Me, OMe as well as electron withdrawing F, Cl, Br, NO₂, CF₃,

CO₂Me functional groups by delivering desired quinazolines in

up to 98% isolated yield (Scheme 2).

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were examined to obtain

quinazolines 3 in high isolated yields (Scheme 4).

a

wide range of substituted

group which is stopping the intermediate to undergo

intramolecular cyclization under organocatalyzed reaction

conditions. We assume, in case of 2-aminobenzylamines, the

imine intermediate may facilitates intramolecular cyclization to

obtain 2-substituted quinazolines.

Scheme 2. Scope of aryl nitriles towards the synthesis of 2-substituted

quinazolines.

Scheme 4. Scope of 2-aminobenzylamines towards the synthesis of 2-

substituted quinazolines.

Scheme 5. Reaction of 2-aminobenzyl alcohol 4a to access 2-substituted

quinazolines.

Scheme 3. Further scope of aryl nitriles towards the synthesis of 2-substituted

quinazolines.

Next, we focused on establishing a plausible reaction

mechanism for this organocatalytic process by considering the

difference in reactivity of 2-aminobenzylamines and 2-

aminobenzyl alcohols. To gain further insight of the reaction

mechanism, we carried out control experiments by varying

different reaction parameters. Firstly, we carried out the reaction

of 2-aminobenzylamine (1a) and benzonitrile (2a) separately

under the developed reaction conditions. Surprisingly, the

reaction of 2-aminobenzylamine (1a) gave 2-(quinazolin-2-

yl)aniline (3az) in 62% isolated yield, which is the self-cyclized

product (Scheme 6, Eq. 1). It is believed that, 2-

aminobenzylamine (1a) getting in situ oxidized to 2-

aminobenzaldehyde (6a) followed by condensation with another

molecule of 2-aminobenzylamine (1a) and subsequent oxidation

Having realized an organocatalytic pathway to access

diverse range of substituted quinazolines by utilizing substituted

2-aminobenzylamines and nitrile derivatives, we were

determined to extend scope of the reaction to 2-aminobenzyl

alcohols. In this process, we carried out the reaction of 2-

aminobenzyl alcohol (4a) with 4-chlorobenzonitrile (2i) under the

standard conditions. To our disappointment, the reaction did not

undergo completion to deliver 2-substituted quinazoline 3ai,

rather it stopped at an intermediate stage 5aa which was

confirmed by NMR data. Intermediate 5aa on treatment with

copper-catalyzed reaction conditions,^[10a]delivered the desired

product 3ai in 48% isolated yield (Scheme 5). The probable

reason can be asserted to the electronic nature of aldehyde

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delivered the 2-(quinazolin-2-yl)aniline (3az). In another

experiment, the reaction of benzonitrile (2a) under standard

conditions yielded only starting material (Scheme 6, Eq. 2). We

suspected that, 2-aminobenzylamine (1a) and benzonitrile (2a)

could lead to the formation of 2-aminobenzaldehyde (6a) and

benzamide (7a) respectively and subsequent condensation

followed by oxidation to furnish 2-phenylquinazoline (3aa). As

the above reaction did not have sufficient proofs on reaction

mechanism, we decided to carry out the reaction of 2-

aminobenzylamine (1a) and benzamide (7a) under standard

conditions (Scheme 6, Eq. 3). Again, it was observed that, 2-

aminobenzylamine (1a) is getting self-cyclized to 2-(quinazolin-

2-yl)aniline 3az in higher proportion with only 5% of the desired

3aa. The starting material benzamide (7a) was inactive which

was isolated in 35% yield. The possibility of the reaction

pathway via 2-aminobenzaldehyde (6a) and benzamide (7a)

intermediates was ruled out due to above negative results.^[9f]

check the probability of reaction pathway (Scheme 6, Eq. 5 and

6). The isolated yields of the reaction were drastically reduced

under the influence of radical scavenger, which confirms the

radical pathway of the reaction.

Then to understand the plausible reaction mechanism, we

were inspired to carry out the reaction of 2-aminobenzylamine

(1a) ([M]⁺= 122.1, [M + H]⁺= 123.1) and 4-methoxybenzonitrile

(2f) ([M]⁺= 133.1, [M + H]⁺= 134.1) under standard reaction

conditions. The course of the reaction was investigated and

examined by liquid chromatography-mass spectrometry (LC-MS)

after an interval of 5 h, 10 h and 15 h. The mass-spectroscopic

data revealed that the mechanism proceeds via the formation of

intermediate D ([M]⁺= 252.9) to obtain the desired product 3af

([M]⁺= 236.1) (details of mass spectra are given in Figure S1,

SI).

Scheme 7. Proposed organocatalytic reaction pathway.

With this much information, we proposed a plausible

reaction mechanism based on the experimental and literature

evidences (Scheme 7).^{[2c, j]}According to the proposed reaction

mechanism, catalytic amounts of hydrogen peroxide is

generated by aerial oxidation.^[2c]Next, catalytic amounts of A₁

and A₂were also generated by the successive oxidation of

vitamin-B₃by H₂O₂and air. The in situ generated A₂abstract a

proton for 1a via radical pathway leading to the formation of

amine radical B. Subsequently, amine radical B undergo

oxidation in presence of A₂to give imine intermediate C,

followed by nucleophilic addition on 4-methoxybenzonitrile (2f)

resulting in an amidine embedded imine intermediate D ([M]⁺=

252.9). Finally, nucleophilic attack of amidine nitrogen on to

imine carbon leads to the intermediate E, which on

Scheme 6. Control experiments to establish plausible reaction mechanism.

Next, we carried out the reaction of 1a and 2a using

standard reaction conditions under nitrogen atmosphere

(Scheme 6, Eq. 4). The reaction conditions furnished a complex

reaction mixture with only 18% of desired product 3aa. Hence, it

was cleared that the reaction conditions requires a sufficient

amount of oxygen to accomplish the desired chemical

transformations. Additionally, we also carried out the reaction of

1a and 2a under standard reaction conditions with added radical

dehydroamination

afforded

the

desired

2-(4-

methoxyphenyl)quinazoline (3af) ([M]⁺= 236.1) (Scheme 7).

scavenger TEMPO (2,2,6,6-Tetramethylpiperidine 1-oxyl) to Conclusions

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A 10 mL reaction vial was charged with a mixture of 2-aminobenzyl

alcohol (1a) (1.0 mmol, 123 mg), 4-chlorobenzonitrile (2i) (1.0 mmol,

137.6 mg), DMSO (2 mL) and Vitamin-B₃(0.3 mmol, 37 mg). The

reaction vial was then heated at 110 °C for 24 h. After completion of the

reaction (progress was monitored by TLC; SiO₂, Hexane/EtOAc = 4:1),

the mixture was diluted with ethyl acetate (15 mL) and water (20 mL) and

extracted with ethyl acetate (3 × 10 mL). The combined organic layers

were washed with brine (3 × 10 mL) and dried over anhydrous Na₂SO₄.

The solvent were removed under reduced pressure and the crude

products were purified by column chromatography using silica gel (100-

200 mesh) with hexane/EtOAc (4:1) as the eluent to obtain the

intermediate 5aa in 54% yield (140 mg).

In conclusion, we have presented an organocatalytic protocol to

obtain

quinazolines

from

2-aminobenzylamines

and

benzonitriles as substrates. The reaction conditions were

perceived using catalytic amounts of Vitamin-B₃as an

organocatalyst in presence DMSO as solvent under aerial

oxygen. The reaction conditions were implemented on a wide

range of 2-aminobenzylamines and benzonitriles to obtain

quinazolines in moderate to good yields. Additionally, we have

also carried out a series of control experiments to know insight

into the reaction mechanism. A probable reaction mechanism

was depicted based on the evidences obtained from control

experiments and mass-spectroscopy.

Further, the intermediate 5aa (0.5 mmol, 130 mg), L-proline (0.2 mmol,

23 mg), Cs₂CO₃(1.5 mmol, 489 mg) and DMF (5 mL) were charged in a

reaction flask, the mixture was stirred for 30 min under nitrogen

atmosphere at room temperature, and then CuI (0.1 mmol, 19 mg) was

added. After a 30 min-stirring under the same condition, reaction

temperature was raised to 110 °C for 24 h. After completion of the

reaction (progress was monitored by TLC; SiO₂, Hexane/EtOAc = 4:1),

the resulting solution was cooled to room temperature and filtered, and

the inorganic salts were removed. The filtrate was concentrated with the

aid of a rotary evaporator, and the residue was purified by column

chromatography on silica gel to provide the desired product 3ai in 48%

yield (58 mg).

Experimental Section

General Method: The starting material 2-amino-4-methylbenzylamine

(1b) was prepared using previously reported method^[11]and all other

starting materials were purchased from commercial suppliers (Sigma-

Aldrich, Alfa-Aesar, SD fine chemicals, Merck, HI Media, Ambinter) and

were used without further purification unless otherwise indicated. All

reactions were performed in a 10 mL reaction vial with magnetic stirring.

Solvents used in extraction and purification were distilled prior to use.

Thin-layer chromatography (TLC) was performed on TLC plates

purchase from Merck. Compounds were visualized with UV light (λ = 254

nm) and/or by immersion in KMnO₄staining solution followed by heating.

Products were purified by column chromatography on silica gel,

100 - 200 mesh. Melting points were determined in open capillary tubes

on EZ-Melt automated melting point apparatus and are uncorrected. IR

spectra were measured on Perkin-Elmer Spectrum One (FT-IR

spectrometer) using potassium bromide pellets. All the compounds were

fully characterized by ¹H and ¹³C NMR and further confirmed by EI-

HRMS analysis. All HRMS are recoreded in EI-QTOF method and LC-

MS are recorded in APCI method in acetonitrile solvent. ¹H (¹³C) NMR

spectra were recorded at 400 (100) MHz on a Brucker spectrometer

Experimental Procedures and Analytical Data of Synthesized

Compounds 3aa-az and 3ba-fl.

Preparation of 2-Phenylquinazoline (3aa)

According to the general procedure, reaction between 2-

aminobenzylamine (1a) (1.0 mmol, 122 mg) and benzonitrile (2a) (1.0

mmol, 103 mg) were performed using Vitamin-B₃(0.3 mmol, 37 mg) to

obtain the desired 2-phenylquinazoline (3aa) in 86% (177 mg) yield as

yellow solid (Scheme 2).

using CDCl₃and DMSO-d₆as a solvent. The H and ¹³C chemical shifts

1

2-Phenylquinazoline (3aa)^[2c](Scheme 2): Yellow solid, R_f= 0.60 (SiO₂,

Hexane/EtOAc = 4:1); m.p = 101-102 °C (Lit^[2c]100-102 °C); ¹H NMR

(400 MHz, CDCl₃): δ = 9.48 (s, 1H; 4-H), 8.63 (d, ³J = 8.0 Hz, 2H; 12-H),

8.11 (d, ³J = 8.2 Hz, 1H; 8-H), 7.94-7.88 (m, 2H; 5-H and 7-H), 7.62 (t, ³J

= 7.8 Hz, 1H; 6-H), 7.58-7.48 (m, 3H; 13-H, and 14-H) ppm; ¹³C NMR

(100 MHz, CDCl₃) δ = 161.07 (C-2), 160.54 (C-4), 150.8 (C-9), 138.0 (C-

11), 134.20 (C-7), 130.7 (C-14), 128.7 (C-8), 128.67 (C-13), 128.63 (C-

12), 127.33 (C-6), 127.17 (C-5), 123.64 (C-10) ppm; HRMS (EI-QTOF,

[M + H]⁺): calculated for C₁₄H₁₁N₂: 207.0922; found: 207.0919.

were referenced to residual solvent signals at _H/C7.26/77.28 (CDCl₃)

and _H/C2.51 /39.50 (DMSO-d₆) relative to TMS as internal standards.

Coupling constants J [Hz] were directly taken from the spectra and are

not averaged. Splitting patterns are designated as s (singlet), d (doublet),

t (triplet), q (quartet), m (multiplet), overlapped and br (broad).

General Experimental Procedure for the Synthesis of Quinazolines

3aa-az and 3ba-fl Using Nitriles 2a-y.

A

10 mL reaction vial was charged with

a

mixture of 2-

Preparation of 2-(Quinazolin-2-yl)phenol (3ab)

aminobenzylamines 1a-f (1.0 mmol), nitriles 2a-y (1.0 mmol), DMSO

(2 mL) and Vitamin-B₃(0.3 mmol, 37 mg). The reaction vial was then

heated at 110 °C for 24 h. After completion of the reaction (progress was

monitored by TLC; SiO₂, Hexane/EtOAc = 4:1), the mixture was diluted

with ethyl acetate (15 mL) and water (20 mL) and extracted with ethyl

acetate (3 × 10 mL). The combined organic layers were washed with

brine (3 × 10 mL) and dried over anhydrous Na₂SO₄. The solvent were

removed under reduced pressure and the crude products were purified

by column chromatography using silica gel (100-200 mesh) with

hexane/EtOAc (4:1) as the eluent to obtain the desired products 3aa-az

or 3ba-fl in high isolated yields.

According to the general procedure, reaction between 2-

aminobenzylamine (1a) (1.0 mmol, 122 mg) and 2-hydroxybenzonitrile

(2b) (1.0 mmol, 119 mg) were performed using Vitamin-B₃(0.3 mmol, 37

mg) to obtain the desired 2-(quinazolin-2-yl)phenol (3ab) in 77% (171

mg) yield as pale yellow solid (Scheme 2).

2-(Quinazolin-2-yl)phenol (3ab)^[2c](Scheme 2): Pale yellow solid, R_f=

0.60 (SiO₂, Hexane/EtOAc = 4:1); m.p = 135-136 °C (Lit^[2c]136-137 °C);

¹H NMR (400 MHz, CDCl₃): δ = 13.31 (s, 1H; 17-H), 9.48 (s, 1H; 4-H),

8.66 (d, ³J = 8.0 Hz, 1H; 8-H), 8.02-7.91 (m, 3H; 5-H_,7-H and 16-H), 7.64

(t, ³J = 8.0 Hz, 1H; 6-H), 7.41 (t, ³J = 8.0 Hz, 1H; 14-H), 7.08 (d, ³J = 8.0

General Experimental Procedure for the Synthesis of 2-(4-

Chlorophenyl)quinazoline (3ai) Using 2-Aminobenzyl Alcohol (4a).

3

Hz, 1H; 13-H), 7.01 (t, J = 8.0 Hz, 1H; 15-H) ppm; ¹³C NMR (100 MHz,

CDCl₃) δ = 161.80 (C-2), 160.91 (C-4), 160.55 (C-12), 148.17 (C-9),

135.08 (C-16), 133.31 (C-7), 129.74 (C-14), 127.63 (C-8), 127.50 (C-5),

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127.12 (C-6), 123.06 (C-10), 119.16 (C-15), 119.14 (C-11) 117.92 (C-13)

ppm; HRMS (EI-QTOF, [M + H]⁺): calculated for C₁₄H₁₁N₂O : 223.0871;

found: 223.0868.

According to the general procedure, reaction between 2-

aminobenzylamine (1a) (1.0 mmol, 122 mg) and 4-methoxybenzonitrile

(2f) (1.0 mmol, 133 mg) were performed using Vitamin-B₃(0.3 mmol, 37

mg) to obtain the desired 2-(4-methoxyphenyl)quinazoline (3af) in 91%

(215 mg) yield as pale yellow solid (Scheme 2).

Preparation of 4-(Quinazolin-2-yl)phenol (3ac)

2-(4-Methoxyphenyl)quinazoline (3af)^[2c](Scheme 2): Pale yellow

solid, R_f= 0.63 (SiO₂, Hexane/EtOAc = 4:1); m.p = 88-89 °C (Lit^[2c]89-

According to the general procedure, reaction between 2-

aminobenzylamine (1a) (1.0 mmol, 122 mg) and 4-hydroxybenzonitrile

(2c) (1.0 mmol, 119 mg) were performed using Vitamin-B₃(0.3 mmol, 37

mg) to obtain the desired 4-(quinazolin-2-yl)phenol (3ac) in 79% (175

mg) yield as white solid (Scheme 2).

3

91 °C); ¹H NMR (400 MHz, CDCl₃): δ = 9.42 (s, 1H; 4-H), 8.58 (dt, J =

3

8.0 Hz, 2H; 12-H), 8.04 (d, J = 8.6 Hz, 1H; 8-H), 7.91-7.85 (m, 2H; 5-H

3

and 7-H), 7.57 (t, J = 8.0 Hz, 1H; 6-H), 7.03 (d, J = 8.0 Hz, 2H; 13-H),

3.90 (s, 3H; 15-H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 161.81 (C-2),

160.84 (C-4), 160.36 (C-14), 150.80 (C-9), 134.0 (C-11), 130.7 (C-7),

130.2 (C-12), 128.4 (C-8), 127.10 (C-6), 126.8 (C-5), 123.30 (C-10),

113.95 (C-13), 55.37 (C-15) ppm; HRMS (EI-QTOF, [M + H]⁺): calculated

for C₁₅H₁₃N₂O: 237.1027; found: 237.1024.

4-(Quinazolin-2-yl)phenol (3ac)^[9d](Scheme 2): White solid, R_f= 0.60

(SiO₂, Hexane/EtOAc = 4:1); m.p = 131-133 °C (Lit^[9d]130-132 °C); ¹H

NMR (400 MHz, CDCl₃): δ = 9.42 (s, 1H; 15-H), 9.31 (s, 1H; 4-H), 8.50 (d,

3

³J = 8.0 Hz, 2H; 12-H), 8.03 (d, J = 8.2 Hz, 1H; 8-H), 7.92-7.88 (m, 2H;

5-H and 7-H), 7.59 (d, ³J = 8.0 Hz, 1H; 6-H), 6.98 (d, ³J = 8.0 Hz, 2H; 13-

H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 162.0 (C-2), 160.5 (C-4), 160.34

(C-14), 150.0 (C-9), 134.5 (C-11), 130.51 (C-7), 128.31 (C-12), 128.31

(C-8), 127.32 (C-6), 126.9 (C-5), 123.30 (C-10), 115.65 (C-13) ppm;

HRMS (EI-QTOF, [M + H]⁺): calculated for C₁₄H₁₁N₂O : 223.0871; found:

223.0868.

Preparation of 2-(4-Fluorophenyl)quinazoline (3ag)

According to the general procedure, reaction between 2-

aminobenzylamine (1a) (1.0 mmol, 122 mg) and 4-fluorobenzonitrile (2g)

(1.0 mmol, 121 mg) were performed using Vitamin-B₃(0.3 mmol, 37 mg)

to obtain the desired 2-(4-fluorophenyl)quinazoline (3ag) in 76% (170

mg) yield as white solid (Scheme 2).

Preparation of 2-(4-Methylphenyl)quinazoline (3ad)

2-(4-Fluorophenyl)quinazoline (3ag)^[2c](Scheme 2): White solid, R_f=

0.60 (SiO₂, Hexane/EtOAc = 4:1); m.p = 131-132 °C (Lit^[2c]130-131 °C);

¹H NMR (400 MHz, CDCl₃): δ = 9.46 (s, 1H; 4-H), 8.62 (d, ³J = 8.0 Hz,

2H; 12-H), 8.07 (d, ³J = 8.0 Hz, 1H; 8-H), 7.95-7.90 (m, 1H, 5-H and 7-H),

According to the general procedure, reaction between 2-

aminobenzylamine (1a) (1.0 mmol, 122 mg) and 4-methylbenzonitrile

(2d) (1.0 mmol, 117 mg) were performed using Vitamin-B₃(0.3 mmol, 37

mg) to obtain the desired 2-(4-methylphenyl)quinazoline (3ad) in 88%

(193 mg) yield as pale yellow solid (Scheme 2).

3

7.62 (t, J = 8.0 Hz, 1H; 6-H), 7.20 (d, ³J = 8.0 Hz, 2H; 13-H) ppm; ¹³C

NMR (100 MHz, CDCl₃) δ = 165.93 (C-2), 164.4 (C-4), 160.36 (d, J = 32

Hz, C-14), 150.74 (C-9), 134.26 (C-11), 130.7 (C-7), 130.63 (C-12),

128.56 (J = 262 Hz), 127.25 (d, J = 12 Hz, C-12), 123.5 (C-10), 115.6 (d,

J = 21 Hz, C-13) ppm; HRMS (EI-QTOF, [M + H]⁺): calculated for

C₁₄H₁₀FN₂: 225.0828; found: 225.0825.

2-(4-Methylphenyl)quinazoline (3ad)^[2c](Scheme 2): Pale yellow solid,

R_f= 0.65 (SiO₂, Hexane/EtOAc = 4:1); m.p = 105-106 °C (Lit^[2c]105-

107 °C); ¹H NMR (400 MHz, CDCl₃): δ = 9.45 (s, 1H; 4-H), 8.50 (td, ³J =

3

8.0 Hz, 2H; 12-H), 8.07 (d, J = 8.6 Hz, 1H; 8-H), 7.94-7.87 (m, 2H; 5-H

and 7-H), 7.59 (dt, ³J = 8.0 Hz, 1H; 6-H), 7.34 (d, ³J = 8.0 Hz, 2H; 13-H),

2.45 (s, 3H; 15-H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 161.26 (C-2),

160.56 (C-4), 150.9 (C-9), 141.0 (C-11), 135.4 (C-7), 134.2 (C-14), 129.5

(C-8), 128.68 (C-13), 128.66 (C-12), 127.25 (C-6), 127.17 (C-5), 123.65

(C-10), 21.65 (C-15) ppm; HRMS (EI-QTOF, [M + H]⁺): calculated for

C₁₅H₁₃N₂: 221.1079; found: 221.1076.

Preparation of 2-(2-Chlorophenyl)quinazoline (3ah)

According to the general procedure, reaction between 2-

aminobenzylamine (1a) (1.0 mmol, 122 mg) and 2-chlorobenzonitrile (2h)

(1.0 mmol, 137.6 mg) were performed using Vitamin-B₃(0.3 mmol, 37

mg) to obtain the desired 2-(2-chlorophenyl)quinazoline (3ah) in 71%

(171 mg) yield as yellow solid (Scheme 2).

Preparation of 2-(2,6-Dimethoxyphenyl)quinazoline (3ae)

2-(2-Chlorophenyl)quinazoline (3ah)^[2c](Scheme 2): Yellow solid, R_f=

0.62 (SiO₂, Hexane/EtOAc = 4:1); m.p = 66-67 °C (Lit^[2c]67-68 °C); ¹H

NMR (400 MHz, CDCl₃): δ = 9.54 (s, 1H; 4-H), 8.14 (d, ³J = 8 Hz, 1H; 8-

H), 8.02-7.94 (m, 2H; 5-H and 7-H ), 7.86-7.80 (m, 1H; 13-H), 7.71 (t, ³J =

7.8 Hz, 1H; 6-H), 7.57-7.52 (m, 1H; 16-H), 7.45-7.37 (m, 2H; 14-H and

15-H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 161.92 (C-2), 160.27 (C-4),

150.36 (C-9), 138.19 (C-11), 134.52 (C-7), 132.96 (C-12), 131.84 (C-14),

130.6 (C-13), 130.4 (C-16), 128.66 (C-8), 128.16 (C-6), 127.22 (C-5),

According to the general procedure, reaction between 2-

aminobenzylamine

(1a)

(1.0 mmol,

122

mg)

and

2,6-

dimethoxybenzonitrile (2e) (1.0 mmol, 163 mg) were performed using

Vitamin-B₃(0.3 mmol, 37 mg) to obtain the desired 2-(2,6-

dimethoxyphenyl)quinazoline (3ae) in 74% (197 mg) yield as pale yellow

solid (Scheme 2).

2-(2,6-Dimethoxyphenyl)quinazoline (3ae)^[2c](Scheme 2): Pale yellow

solid, R_f= 0.60 (SiO₂, Hexane/EtOAc = 4:1); m.p = 59-60 °C (Lit^[2c]58-

126.94 (C-15), 123.31 (C-10) ppm; HRMS (EI-QTOF, [M

calculated for C₁₄H₁₀ClN₂: 241.0532; found: 241.0530.

+

H]⁺):

3

59 °C); ¹H NMR (400 MHz, CDCl₃): δ = 9.46 (s, 1H; 4-H), 8.11 (d, J =

8.0 Hz, 1H; 8-H), 7.94-7.88 (m, 2H; 5-H and 7-H), 7.83 (d, ³J = 6.8 Hz,

2H; 13-H), 7.62 (dt, ³J = 8.0 Hz, 1H; 6-H), 6.64 (dt, ³J = 8.0 Hz, 1H; 14-H),

3.94 (s, 6H; 15H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 161.12 (C-2),

160.64 (C-4), 160.42 (C-12), 150.66 (C-9), 140.0 (C-7), 134.22 (C-14),

128.7 (C-8), 127.44 (C-6), 127.16 (C-5), 123.73 (C-10), 106.27 (C-13),

103.93 (C-11), 55.65 (C-15) ppm; HRMS (EI-QTOF, [M + H]⁺): calculated

for C₁₆H₁₅N₂O₂: 267.1134; found: 267.1132.

Preparation of 2-(4-Chlorophenyl)quinazoline (3ai)

According to the general procedure, reaction between 2-

aminobenzylamine (1a) (1.0 mmol, 122 mg) and 4-chlorobenzonitrile (2i)

(1.0 mmol, 137.6 mg) were performed using Vitamin-B₃(0.3 mmol, 37

mg) to obtain the desired 2-(4-chlorophenyl)quinazoline (3ai) in 83% (200

mg) yield as pale yellow solid (Scheme 2).

Preparation of 2-(4-Methoxyphenyl)quinazoline (3af)

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2-(4-Chlorophenyl)quinazoline (3ai)^[2c](Scheme 2): Pale yellow solid,

R_f= 0.62 (SiO₂, Hexane/EtOAc = 4:1); m.p = 131-133 °C (Lit^[2c]130-

132 °C); ¹H NMR (400 MHz, CDCl₃): δ = 9.46 (s, 1H; 4-H), 8.58 (dt, ³J =

7.74-7.67 (m, 2H; 6-H and 7-H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ =

160.74 (C-2), 158.7 (C-4), 150.60 (C-9), 148.86 (C-13), 139.9 (C-16),

134.56 (C-7), 134.2 (C-11), 129.52 (C-15), 128.77 (C-8), 128.07 (C-6),

127.2 (C-5), 125.01 (C-10), 123.96 (C-14), 123.6 (C-12) ppm; HRMS (EI-

QTOF, [M + H]⁺): calculated for C₁₄H₁₀N₃O₂: 252.0773; found: 252.0770.

3

8.0 Hz, 2H; 12-H), 8.07 (d, J = 8.2 Hz, 1H; 8-H), 7.95-7.90 (m, 2H; 5-H

and 7-H), 7.63 (dt, ³J = 8.0 Hz, 1H; 6-H), 7.50 (dt, ³J = 8.0 Hz, 2H; 13-H)

ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 160.56 (C-2), 160.06 (C-4), 150.71

(C-9), 136.85 (C-14), 136.53 (C-11), 134.29 (C-7), 129.91 (C-13), 128.85

(C-12), 128.62 (C-8), 127.5 (C-6), 127.2 (C-5), 123.64 (C-10) ppm;

HRMS (EI-QTOF, [M + H]⁺): calculated for C₁₄H₁₀ClN₂: 241.0532; found:

241.0530.

Preparation of 2-(4-Nitrophenyl)quinazoline (3am)

According to the general procedure, reaction between 2-

aminobenzylamine (1a) (1.0 mmol, 122 mg) and 4-nitrobenzonitrile (2m)

(1.0 mmol, 148 mg) were performed using Vitamin-B₃(0.3 mmol, 37 mg)

to obtain the desired 2-(4-nitrophenyl)quinazoline (3am) in 70% (176 mg)

yield as yellow solid (Scheme 2).

Preparation of 2-(2-Bromo-4-methylphenyl)quinazoline (3aj)

According to the general procedure, reaction between 2-

aminobenzylamine (1a) (1.0 mmol, 122 mg) and 2-bromo-4-

methylbenzonitrile (2j) (1.0 mmol, 196 mg) were performed using

Vitamin-B₃(0.3 mmol, 37 mg) to obtain the desired 2-(2-bromo-4-

methylphenyl)quinazoline (3aj) in 75% (224 mg) yield as yellow solid

(Scheme 2).

2-(4-Nitrophenyl)quinazoline (3am)^[9d](Scheme 2): Yellow solid, R_f=

0.64 (SiO₂, Hexane/EtOAc = 4:1); m.p = 214-216 °C (Lit^[9d]215-217 °C);

¹H NMR (400 MHz, CDCl₃): δ = 9.50 (s, 1H; 4-H), 8.80 (d, J = 8.0 Hz, 1H;

13-H), 8.36 (d, ³J = 8.0 Hz, 1H; 12-H), 8.12 (d, ³J = 8.0 Hz, 1H; 8-H),

8.03-7.97 (m, 2H; 5-H and 7-H), 7.69 (t, ³J = 8.0 Hz, 1H; 6-H) ppm; ¹³C

NMR (100 MHz, CDCl₃) δ = 160.71 (C-2), 159.75 (C-4), 150.60 (C-9),

149.17 (C-14), 143.83 (C-11), 134.62 (C-7), 129.38 (C-12), 128.85 (C-8),

128.33 (C-6), 127.2 (C-5), 123.87 (C-13), 123.76 (C-10) ppm; HRMS (EI-

QTOF, [M + H]⁺): calculated for C₁₄H₁₀N₃O₂: 252.0773; found: 252.0770.

2-(2-Bromo-4-methylphenyl)quinazoline (3aj)^[2c](Scheme 2): Yellow

solid, R_f= 0.65 (SiO₂, Hexane/EtOAc = 4:1); m.p = 50-51 °C (Lit^[2c]49-

3

50 °C); ¹H NMR (400 MHz, CDCl₃): δ = 9.52 (s, 1H; 4-H), 8.12 (d, J =

7.2 Hz, 1H; 8-H), 8.00-7.93 (m, 2H; 5-H and 7-H), 7.71-7.66 (m, 2H; 6-H

and 16-H), 7.57 (s, 1H; 13-H), 7.25 (d, ³J = 7.9 Hz, 1H; 15-H), 2.41 (s,

3H; 17-H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 162.8 (C-2), 160.15 (C-

4), 150.3 (C-9), 140.86 (C-11), 137.26 (C-14), 134.32 (C-13), 134.2 (C-7),

131.6 (C-16), 128.62 (C-15), 128.3 (C-8), 127.92 (C-6), 127.14 (C-5),

123.23 (C-10), 121.7 (C-12), 20.97 (C-17) ppm; HRMS (EI-QTOF, [M +

H]⁺): calculated for C₁₅H₁₂BrN₂: 299.0183; found: 299.0180.

Preparation of 2-(3-(Trifluoromethyl)phenyl)quinazoline (3an)

According to the general procedure, reaction between 2-

aminobenzylamine

(1a)

(1.0 mmol,

122

mg)

and

3-

(trifluoromethyl)benzonitrile (2n) (1.0 mmol, 171 mg) were performed

using Vitamin-B₃(0.3 mmol, 37 mg) to obtain the desired 2-(3-

(trifluoromethyl)phenyl)quinazoline (3an) in 76% (208 mg) yield as white

solid (Scheme 2).

Preparation of 2-(2-Nitrophenyl)quinazoline (3ak)

According to the general procedure, reaction between 2-

aminobenzylamine (1a) (1.0 mmol, 122 mg) and 2-nitrobenzonitrile (2k)

(1.0 mmol, 148 mg) were performed using Vitamin-B₃(0.3 mmol, 37 mg)

to obtain the desired 2-(2-nitrophenyl)quinazoline (3ak) in 72% (181 mg)

yield as yellow solid (Scheme 2).

2-(3-(Trifluoromethyl)phenyl)quinazoline (3an) (Scheme 2): White

solid, R_f= 0.60 (SiO₂, Hexane/EtOAc = 4:1); m.p = 108-110 °C; IR (KBr)

ν = 2925, 1541, 1459, 1260, 752 cm^-1; ¹H NMR (400 MHz, CDCl₃): δ =

9.49 (s, 1H; 4-H), 8.93 (d, J = 3.6 Hz, 1H; 12-H), 8.83 (dt, J = 8.0 Hz, 1H;

3

16-H), 8.12 (ddd, J = 8.2, 2.2, 1.2 Hz, 1H; 14-H), 7.98-7.93 (m, 2H; 5-H

and 15-H), 7.76 (d, ³J = 8.0 Hz, 1H; 8-H), 7.68-7.64 (m, 2H; 6-H and 7-H)

ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 160.66 (C-2), 159.57 (C-4), 150.68

(C-9), 138.82 (C-11), 134.41 (C-16), 131.68 (C-7), 131.27 (q, J = 32 Hz,

C-11), 130.95 (C-15), 129.1 (C-8), 128.73 (C-6), 127.79 (C-5), 127.20 (C-

10), 127.07 (q, J = 11 Hz, C-12), 125.50 (q, J = 16 Hz, C-14), 123.84 (C-

17) ppm; HRMS (EI-QTOF, [M + H]⁺): calculated for C₁₅H₁₀F₃N₂:

275.0796; found: 275.0792.

2-(2-Nitrophenyl)quinazoline (3ak)^[2c](Scheme 2): Yellow solid, R_f=

0.60 (SiO₂, Hexane/EtOAc = 4:1); m.p = 94-95 °C (Lit^[2c]95-96 °C); ¹H

NMR (400 MHz, CDCl₃): δ = 9.44 (s, 1H; 4-H), 8.13 (dd, ³J = 7.8 Hz, 1H;

3

8-H), 8.08 (d, J = 8.6 Hz, 1H; 16-H), 7.99-7.93 (m, 2H; 13-H and 15-H),

7.90 (d, ³J = 8.0 Hz, 1H; 14-H), 7.75-7.67 (m, 2H; 5-H and 7-H), 7.60 (td,

³J = 8.2 Hz, 1H; 6-H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 160.55 (C-2),

159.7 (C-4), 150.4 (C-12), 150.0 (C-9), 134.66 (C-15), 133.63 (C-16),

132.3 (C-7), 131.9 (C-14), 130.2 (C-8), 128.65 (C-6), 128.4 (C-5), 127.3

(C-11), 124.2 (C-10), 123.5 (C-13) ppm; HRMS (EI-QTOF, [M + H]⁺):

calculated for C₁₄H₁₀N₃O₂: 252.0773; found: 252.0770.

Preparation of 2-(4-(Trifluoromethyl)phenyl)quinazoline (3ao)

According to the general procedure, reaction between 2-

aminobenzylamine

(1a)

(1.0 mmol,

122

mg)

and

4-

Preparation of 2-(3-Nitrophenyl)quinazoline (3al)

(trifluoromethyl)benzonitrile (2o) (1.0 mmol, 171 mg) were performed

using Vitamin-B₃(0.3 mmol, 37 mg) to obtain the desired 2-(4-

(trifluoromethyl)phenyl)quinazoline (3ao) in 73% (200 mg) yield as pale

yellow solid (Scheme 2).

According to the general procedure, reaction between 2-

aminobenzylamine (1a) (1.0 mmol, 122 mg) and 3-nitrobenzonitrile (2l)

(1.0 mmol, 148 mg) were performed using Vitamin-B₃(0.3 mmol, 37 mg)

to obtain the desired 2-(3-nitrophenyl)quinazoline (3al) in 73% (183 mg)

yield as pale yellow solid (Scheme 2).

2-(4-(Trifluoromethyl)phenyl)quinazoline (3ao)^[2c](Scheme 2): Pale

yellow solid, R_f= 0.64 (SiO₂, Hexane/EtOAc = 4:1); m.p = 135-136 °C

(Lit^[2c]136-137 °C); ¹H NMR (400 MHz, CDCl₃): δ = 9.36 (s, 1H; 4-H),

8.75 (d, ³J = 8.0 Hz, 2H; 12-H), 8.50 (d, ³J = 8.0 Hz, 1H; 8-H), 7.83 (d, ³J

= 8.0 Hz, 2H; 13-H), 7.74 (m, 2H; 5-H and 7-H), 7.62 (d, ³J = 8.0 Hz, 1H;

6-H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 160.61 (C-2), 159.60 (C-4),

150.65 (C-9), 141.31 (C-11), 134.37 (C-7), 132.11 (q, J = 32 Hz, C-14),

128.82 (C-8), 128.77 (C-6), 127.86 (C-5), 127.16 (C-12), 125.57 (C-10),

2-(3-Nitrophenyl)quinazoline (3al)^[2c](Scheme 2): Pale yellow solid, R_f

= 0.64 (SiO₂, Hexane/EtOAc = 4:1); m.p = 101-103 °C (Lit^[2c]101-

1

102 °C); H NMR (400 MHz, CDCl₃): δ = 9.52-9.50 (m, 2H; 4-H and 12-

3

H), 8.99 (dt, J = 8.0 Hz, 1H; 16-H), 8.36 (ddd, J = 8.0, 2.4, 1.2 Hz, 1H;

14-H), 8.14 (d, ³J = 8.0 Hz, 1H; 8-H), 8.00-7.95 (m, 2H; 5-H and 15-H),

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125.52 (q, J = 3.2 Hz, C-13), 123.84 (C-15) ppm; HRMS (EI-QTOF, [M +

H]⁺): calculated for C₁₅H₁₀F₃N₂: 275.0796; found: 275.0792.

Preparation of 2-(Anthracen-9-yl)quinazoline (3as)

According to the general procedure, reaction between 2-

aminobenzylamine (1a) (1.0 mmol, 122 mg) and 9-athracenecarbonitrile

(2s) (1.0 mmol, 153 mg) were performed using Vitamin-B₃(0.3 mmol, 37

mg) to obtain the desired 2-(anthracen-9-yl)quinazoline (3as) in 71%

(217 mg) yield as yellow solid (Scheme 3).

Preparation of Methyl 4-(quinazolin-2-yl)benzoate (3ap)

According to the general procedure, reaction between 2-

aminobenzylamine (1a) (1.0 mmol, 122 mg) and methyl 4-cyanobenzoate

(2p) (1.0 mmol, 161 mg) were performed using Vitamin-B₃(0.3 mmol, 37

mg) to obtain the desired methyl 4-(quinazolin-2-yl)benzoate (3ap) in

80% (211 mg) yield as brown solid (Scheme 2).

2-(Anthracen-9-yl)quinazoline (3as)^[2c](Scheme 3): Yellow solid, R_f=

0.65 (SiO₂, Hexane/EtOAc = 4:1); m.p = 111-112 °C (Lit^[2c]112-114 °C);

3

¹H NMR (400 MHz, CDCl₃): δ = 9.71 (s, 1H), 9.00 (d, J = 8.0 Hz, 1H; 8-

H), 8.60 (s, 1H; 18-H), 8.21 (d, ³J = 8.0 Hz, 1H; 5-H), 8.12 (d, ³J = 7.2 Hz,

Methyl 4-(quinazolin-2-yl)benzoate (3ap)^[2c](Scheme 2): Brown solid,

R_f= 0.62 (SiO₂, Hexane/EtOAc = 4:1); m.p = 120-122 °C (Lit^[2c]120-

3

1H; 7-H), 8.08 (d, J = 8.6 Hz, 2H; 13-H), 7.81 (t, J = 7.2 Hz, 1H; 6-H),

7.60 (d, ³J = 7.0 Hz, 2H; 16-H), 7.46 (t, ³J = 7.6 Hz, 2H; 15-H), 7.37 (t, ³J

= 7.6 Hz, 2H; 14-H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 163.63 (C-2),

160.84 (C-4), 150.65 (C-9), 134.79 (C-11), 133.59 (C-17), 131.55 (C-7),

130.07 (C-12), 128.84 (C-18), 128.72 (C-6), 128.48 (C-16), 128.43 (C-5),

127.42 (C-8), 126.43 (C-15), 125.69 (C-10), 125.26 (C-14), 125.39 (C-

13) ppm; HRMS (EI-QTOF, [M + H]⁺): calculated for C₂₂H₁₅N₂: 307.1235;

found: 307.1230.

1

3

121 °C); H NMR (400 MHz, CDCl₃): δ = 9.50 (s, 1H; 4-H), 8.70 (d, J =

3

8.1 Hz, 2H; 13-H), 8.21 (d, J = 8.0 Hz, 2H; 12-H), 8.12 (d, J = 8.0 Hz,

3

1H; 8-H), 7.98-7.93 (m; 2H, 5-H and 7-H), 7.67 (t, J = 8.0 Hz, 1H; 6-H),

3.97 (s, 3H; 15-H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 166.95 (C-15),

160.56 (C-2), 160.0 (C-4), 150.67 (C-9), 142.12 (C-11), 134.33 (C-7),

131.7 (C-14), 129.84 (C-12), 128.76 (C-8), 128.5 (C-13), 127.8 (C-6),

127.15 (C-5), 123.75 (C-10) 52.22 (C-16) ppm; HRMS (EI-QTOF, [M +

H]⁺): calculated for C₁₆H₁₃N₂O₂: 265.0977; found: 265.0975.

Preparation of 2-(Pyridin-4-yl)quinazoline (3at)

Preparation of 2-([1,1'-Biphenyl]-4-yl)quinazoline (3aq)

According to the general procedure, reaction between 2-

aminobenzylamine (1a) (1.0 mmol, 122 mg) and 4-pyridinecarbonitrile

(2t) (1.0 mmol, 104 mg) were performed using Vitamin-B₃(0.3 mmol, 37

mg) to obtain the desired 2-(pyridin-4-yl)quinazoline (3at) in 69% (143

mg) yield as pale yellow solid (Scheme 3).

According to the general procedure, reaction between 2-

aminobenzylamine (1a) (1.0 mmol, 122 mg) and 4-cyanobiphenyl (2q)

(1.0 mmol, 179 mg) were performed using Vitamin-B₃(0.3 mmol, 37 mg)

to obtain the desired 2-([1,1'-biphenyl]-4-yl)quinazoline (3aq) in 82% (231

mg) yield as white solid (Scheme 3).

2-(Pyridin-4-yl)quinazoline (3at)^[2c](Scheme 3): Pale yellow solid, R_f=

0.60 (SiO₂, Hexane/EtOAc = 4:1); m.p = 124-126 °C (Lit^[2c]125-127 °C);

¹H NMR (400 MHz, CDCl₃): δ = 9.52 (s, 1H; 4-H), 8.80 (d, J = 4 Hz, 2H;

13-H), 8.46 (d, J = 4 Hz, 2H; 12-H), 8.14 (d, ³J = 8 Hz, 1H; 8-H), 8.00-

7.95 (m, 2H; 5-H and 7-H), 7.71 (d, J = 8 Hz, 1H; 6-H) ppm; ¹³C NMR

(100 MHz, CDCl₃) δ = 160.75 (C-2), 158.90 (C-4), 150.9 (C-13), 150.4

(C-9), 145.40 (C-11), 134.53 (C-7), 128.9 (C-8), 128.3 (C-6), 127.2 (C-5),

124.2 (C-10), 122.4 (C-12) ppm; HRMS (EI-QTOF, [M + H]⁺): calculated

for C₁₃H₁₀N₃: 208.0874; found: 208.0870.

2-([1,1'-Biphenyl]-4-yl)quinazoline (3aq)^[2c](Scheme 3): White solid,

R_f= 0.62 (SiO₂, Hexane/EtOAc = 4:1); m.p = 117-118 °C (Lit^[2c]116-

1

3

117 °C); H NMR (400 MHz, CDCl₃): δ = 9.49 (s, 1H; 4-H), 8.69 (d, J =

3

7.8 Hz, 2H; 12-H), 8.11 (d, J = 8.0 Hz, 1H; 8-H), 7.96-7.91 (m, 2H; 5-H

and 7-H), 7.79 (d, ³J = 8.2 Hz, 2H; 16-H), 7.71 (d, ³J = 7.8 Hz, 2H; 13-H),

7.63 (t, ³J = 8.2 Hz, 1H; 6-H), 7.49 (t, ³J = 8.2 Hz, 2H; 17-H), 7.39 (t, ³J =

8.0 Hz, 1H; 18-H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 160.87 (C-2),

160.52 (C-4), 150.87 (C-9), 143.3 (C-14), 140.66 (C-15), 137.0 (C-11),

134.16 (C-7), 129.06 (C-17), 128.85 (C-12), 128.7 (C-8), 127.7 (C-6),

127.4 (C-16), 127.3 (C-18), 127.2 (C-13), 127.2 (C-5), 123.65 (C-10)

ppm; HRMS (EI-QTOF, [M + H]⁺): calculated for C₂₀H₁₅N₂: 283.1235;

found: 283.1233.

Preparation of 2-(Furan-2-yl)quinazoline (3au)

According to the general procedure, reaction between 2-

aminobenzylamine (1a) (1.0 mmol, 122 mg) and 2-furonitrile (2u) (1.0

mmol, 93 mg) were performed using Vitamin-B₃(0.3 mmol, 37 mg) to

obtain the desired 2-(furan-2-yl)quinazoline (3au) in 64% (125 mg) yield

as yellow solid (Scheme 3).

Preparation of 2-(Naphthalen-1-yl)quinazoline (3ar)

According to the general procedure, reaction between 2-

aminobenzylamine (1a) (1.0 mmol, 122 mg) and 1-cyanonaphthalene

(2r) (1.0 mmol, 153 mg) were performed using Vitamin-B₃(0.3 mmol, 37

mg) to obtain the desired 2-(naphthalen-1-yl)quinazoline (3ar) in 78%

(200 mg) yield as pale yellow solid (Scheme 3).

2-(Furan-2-yl)quinazoline (3au)^[2c](Scheme 3): Yellow solid, R_f= 0.62

(SiO₂, Hexane/EtOAc = 4:1); m.p = 126-128 °C (Lit^[2c]126-127 °C); ¹H

3

NMR (400 MHz, CDCl₃): δ = 9.40 (s, 1H; 4-H), 8.11 (d, J = 7.9 Hz, 1H;

8-H), 7.93-7.90 (m, 2H; 5-H and 7-H), 7.77 (d, ³J = 12 Hz, 1H; 13-H),

3

2-(Naphthalen-1-yl)quinazoline (3ar)^[2c](Scheme 3): Pale yellow solid,

R_f= 0.66 (SiO₂, Hexane/EtOAc = 4:1); m.p = 122-123 °C (Lit^[2c]123-

7.61 (t, J = 8 Hz, 1H; 6-H), 7.51 (d, J = 7.8 Hz, 1H; 15-H), 6.63 (s, 1H;

14-H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 160.72 (C-2), 154.1 (C-4),

152.50 (C-11), 150.42 (C-9), 145.34 (C-13), 134.5 (C-7), 128.36 (C-8),

127.3 (C-6), 127.3 (C-5), 123.26 (C-10), 114.1 (C-14), 112.2 (C-15) ppm;

HRMS (EI-QTOF, [M + H]⁺): calculated for C₁₂H₉N₂O: 197.0714; found:

197.0710.

1

3

124 °C); H NMR (400 MHz, CDCl₃): δ = 9.61 (s, 1H; 4-H), 8.70 (d, J =

8.2 Hz, 1H; 18-H), 8.21-8.17 (m, 2H; 14-H and 15-H), 8.04-7.91 (m, 4H;

3

5-H, 8-H, 12-H and 13-H), 7.71 (t, ³J = 7.8 Hz, 1H; 7-H), 7.64 (t, J = 8.2

Hz, 1H; 17-H), 7.61-7.50 (m, 2H; 6-H and 16-H) ppm; ¹³C NMR (100 MHz,

CDCl₃) δ = 163.45 (C-2), 160.45 (C-4), 150.6 (C-9), 136.22 (C-11), 134.4

(C-20), 134.2 (C-19), 131.2 (C-7), 130.5 (C-8), 129.7 (C-15), 128.7 (C-

14), 128.54 (C-5), 127.84 (C-6), 127.2 (C-16), 126.93 (C-17), 125.95 (C-

18), 125.92 (C-13) 125.35 (C-10), 123.17 (C-12) ppm; HRMS (EI-QTOF,

[M + H]⁺): calculated for C₁₈H₁₃N₂: 257.1078; found: 257.1075.

Preparation of (E)-2-Styrylquinazoline (3av)

According to the general procedure, reaction between 2-

aminobenzylamine (1a) (1.0 mmol, 122 mg) and cinnamonitrile (2v) (1.0

mmol, 129 mg) were performed using Vitamin-B₃(0.3 mmol, 37 mg) to

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obtain the desired (E)-2-styrylquinazoline (3av) in 76% (176 mg) yield as

white solid (Scheme 3).

2-Pentylquinazoline (3ay) (Scheme 3): Pale brown solid, R_f= 0.50

(SiO₂, Hexane/EtOAc = 4:1); IR (KBr) ν = 2960, 2851, 1651, 1577, 1484,

1378, 1230, 750 cm^-1; ¹H NMR (400 MHz, CDCl₃): δ = 9.36 (s, 1H; 4-H),

7.98 (d, ³J = 8.0 Hz, 1H; 8-H), 7.91-7.87 (m, 2H; 5-H and 7-H), 7.60 (t, ³J

= 8.0 Hz, 1H; 6-H), 3.12 (t, ³J = 7.5 Hz, 2H; 11-H), 1.94-1.90 (m, 2H; 12-

H), 1.42-1.38 (m, 4H; 13-H and 14-H), 0.92 (t, ³J = 7.2 Hz, 3H; 15-H)

ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 167.96 (C-2), 160.43 (C-4), 150.37

(C-9), 134.0 (C-7), 127.9 (C-8), 127.1 (C-6), 126.94 (C-5), 123.07 (C-10),

40.06 (C-11), 31.8 (C-12), 28.8 (C-13), 22.6 (C-14), 14.1 (C-15) ppm;

HRMS (EI-QTOF, [M + H]⁺): calculated for C₁₃H₁₇N₂: 201.1391; found:

201.1388.

(E)-2-Styrylquinazoline (3av)^[2c](Scheme 3): White solid, R_f= 0.59

(SiO₂, Hexane/EtOAc = 4:1); m.p = 120-122 °C (Lit^[2c]122-123 °C); ¹H

NMR (400 MHz, CDCl₃): δ = 9.38 (s, 1H 4-H), 8.17 (d, ³J = 20 Hz, 1H;

11-H), 8.01 (d, ³J = 9.0 Hz, 1H; 8-H), 7.92-7.86 (m, 2H; 5-H and 7-H),

3

4

7.68 (d, J = 7.6 Hz, 2H; 14-H), 7.60 (t, ³J = 7.5, J = 1.3 Hz, 1H; 6-H),

7.46-7.32 (m, 4H; 12-H, 15-H and 16-H) ppm; ¹³C NMR (100 MHz,

CDCl₃) δ = 161.26 (C-2), 160.38 (C-4), 150.42 (C-9), 138.84 (C-13),

136.2 (C-12), 134.37 (C-7), 129.17 (C-15), 128.86 (C-14), 128.0 (C-8),

127.77 (C-16), 127.73 (C-6), 127.29 (C-5), 127.27 (C-10), 123.4 (C-11)

ppm; HRMS (EI-QTOF, [M + H]⁺): calculated for C₁₆H₁₃N₂: 233.1078;

found: 233.1075.

Preparation of 2-(Quinazolin-2-yl)aniline (3az)

According to the general procedure, reaction of 2-aminobenzylamine (1a)

(1.0 mmol, 122 mg) was performed using Vitamin-B₃(0.3 mmol, 37 mg)

to obtain the desired 2-(quinazolin-2-yl)aniline (3az) in 62% (69 mg) yield

as pale yellow solid (Scheme 6).

Preparation of (E)-2-(4-Methoxystyryl)quinazoline (3aw)

According to the general procedure, reaction between 2-

aminobenzylamine (1a) (1.0 mmol, 122 mg) and 4-methoxycinnamonitrile

(2w) (1.0 mmol, 159 mg) were performed using Vitamin-B₃(0.3 mmol, 37

mg) to obtain the desired (E)-2-(4-methoxystyryl)quinazoline (3aw) in

79% (207 mg) yield as white solid (Scheme 3).

2-(Quinazolin-2-yl)aniline (3az)^[12](Scheme 6): Pale yellow solid, R_f=

0.50 (SiO₂, Hexane/EtOAc = 4:1); m.p = 86-88 °C; ¹H NMR (400 MHz,

CDCl₃): δ = 9.44 (d, ³J = 0.3 Hz, 1H; 4-H), 8.63 (dd, ³J = 8.1 Hz, 1H; 8-H),

8.00-7.98 (m, 1H; 5-H), 7.91-7.86 (m, 2H; 7-H and 16-H), 7.59 (td, ³J =

8.0 Hz, 1H; 6-H), 7.27 (td, ³J = 8.0 Hz, 1H; 14-H), 6.86-6.78 (m, 2H; 13-H

and 15-H), 6.57 (s, br, 2H; 17-H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ =

162.47 (C-2), 159.8 (C-4), 149.6 (C-12), 148.91 (C-9), 134.08 (C-7),

131.77 (C-14), 131.4 (C-16), 127.9 (C-8), 127.17 (C-5), 126.9 (C-6),

122.5 (C-10), 119.0 (C-11), 117.13 (C-15) 116.97 (C-13) ppm; HRMS

(EI-QTOF, [M + H]⁺): calculated for C₁₄H₁₂N₃: 222.1031; found: 222.1028.

(E)-2-(4-Methoxystyryl)quinazoline (3aw)^[2c](Scheme 3): White solid,

R_f= 0.61 (SiO₂, Hexane/EtOAc = 4:1); m.p = 101-102 °C (Lit^[2c]103-

1

3

103 °C); H NMR (400 MHz, CDCl₃): δ = 9.35 (s, 1H; 4-H), 8.12 (d, J =

3

24.0 Hz, 1H; 11-H), 7.98 (d, J = 10.0 Hz, 1H; 8-H), 7.87 (d, J = 7.7 Hz,

2H; 6-H and 7-H), 7.62 (d, J = 8.6 Hz, 2H; 14-H), 7.56 (t, ³J = 7.4 Hz, ⁴J =

3

1.1 Hz, 1H; 5-H), 7.29 (d, J = 20.0 Hz, 1H; 12-H), 6.94 (d, J = 8.0 Hz,

2H; 15-H), 3.85 (s, 3H; 17-H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 160.6

(C-2), 160.56 (C-16), 160.3 (C-4), 150.52 (C-9), 1385.45 (C-12), 134.3

(C-7), 129.23 (C-14), 129.0 (C-13), 127.95 (C-8), 127.3 (C-6), 127.0 (C-

5), 125.54 (C-10), 123.28 (C-11), 114.34 (C-15), 55.4 (C-17) ppm; HRMS

(EI-QTOF, [M + H]⁺): calculated for C₁₇H₁₅N₂O : 263.1184; found:

263.1180.

Preparation of 7-Methyl-2-phenylquinazoline (3ba)

According to the general procedure, reaction between 2-amino-4-

methylbenzylamine (1b) (1.0 mmol, 136 mg) and benzonitrile (2a) (1.0

mmol, 103 mg) were performed using Vitamin-B₃(0.3 mmol, 37 mg) to

obtain the desired 7-methyl-2-phenylquinazoline (3ba) in 80% (176 mg)

yield as colorless solid (Scheme 4).

Preparation of 2-Propylquinazoline (3ax)

According to the general procedure, reaction between 2-

aminobenzylamine (1a) (1.0 mmol, 122 mg) and butyronitrile (2x) (1.0

mmol, 69 mg) were performed using Vitamin-B₃(0.3 mmol, 37 mg) to

obtain the desired 2-propylquinazoline (3ax) in 70% (120 mg) yield as

pale brown solid (Scheme 3).

7-Methyl-2-phenylquinazoline (3ba)^[13](Scheme 4): Colorless solid, R_f

= 0.40 (SiO₂, Hexane/EtOAc = 4:1); m.p = 106-108 °C (Lit^[13]107-

1

109 °C); H NMR (400 MHz, CDCl₃): δ = 9.42 (s, 1H; 4-H), 8.61 (br, dd,

3

³J = 8.0 Hz, 2H; 12-H), 7.92 (s, 1H; 8-H), 7.83 (d, J = 8.0 Hz, 1H; 5-H),

3

7.56-7.50 (m, 3H; 13-H and 14-H), 7.46 (dd, J = 9.0 Hz, 1H; 6-H) ppm;

¹³C NMR (100 MHz, CDCl₃) δ = 160.9 (C-2), 159.9 (C-4), 150.9 (C-9),

145.6 (C-7), 137.8 (C-11), 130.7 (C-14), 129.76 (C-6), 128.68 (C-13),

128.64 (C-12), 127.46 (C-8), 126.9 (C-5), 121.85 (C-10), 22.44 (C-15)

ppm; HRMS (EI-QTOF, [M + H]⁺): calculated for C₁₅H₁₃N₂: 221.1079;

found: 221.1076.

2-Propylquinazoline (3ax)^[2c](Scheme 3): Pale brown solid, R_f= 0.61

(SiO₂, Hexane/EtOAc = 4:1); m.p = 121-123 °C (Lit^[2c]120-122 °C); ¹H

3

NMR (400 MHz, CDCl₃): δ = 9.36 (s, 1H; 4-H), 8.00 (d, J = 8.0 Hz, 1H;

8-H), 7.91-7.90 (m, 2H; 5-H and 7-H), 7.61 (t, ³J = 7.8 Hz, 1H; 6-H), 3.11

3

(t, J = 7.7 Hz, 2H; 11-H), 1.99-1.93 (m, 2H; 12-H), 1.05 (t, J = 7.2 Hz,

3H; 13-H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 167.56 (C-2), 160.33 (C-

4), 150.1 (C-9), 134.0 (C-7), 127.72 (C-8), 127.0 (C-6), 126.9 (C-5),

122.97 (C-10), 41.7 (C-11), 22.2 (C-12), 13.9 (C-13) ppm; HRMS (EI-

QTOF, [M + H]⁺): calculated for C₁₁H₁₃N₂: 173.1078; found: 173.1076.

Preparation of 7-Methyl-2-(4-methoxyphenyl)quinazoline (3bf)

According to the general procedure, reaction between 2-amino-4-

methylbenzylamine (1b) (1.0 mmol, 136 mg) and 4-methoxybenzonitrile

(2f) (1.0 mmol, 133 mg) were performed using Vitamin-B₃(0.3 mmol, 37

mg) to obtain the desired 7-methyl-2-(4-methoxyphenyl)quinazoline (3bf)

in 78% (195 mg) yield as brown gummy solid (Scheme 4).

Preparation of 2-Pentylquinazoline (3ay)

According to the general procedure, reaction between 2-

aminobenzylamine (1a) (1.0 mmol, 122 mg) and hexanenitrile (2y) (1.0

mmol, 97 mg) were performed using Vitamin-B₃(0.3 mmol, 37 mg) to

obtain the desired 2-pentylquinazoline (3ay) in 73% (146 mg) yield as

pale brown solid (Scheme 3).

7-Methyl-2-(4-methoxyphenyl)quinazoline (3bf) (Scheme 4): Brown

gummy solid, R_f= 0.40 (SiO₂, Hexane/EtOAc = 4:1); IR (KBr) ν = 2921,

2834, 1611, 1586, 1556, 1490, 1369, 1231, 1163, 1025 cm^-1; ¹H NMR

(400 MHz, CDCl₃): δ = 7.77 (s, 1H; 4-H), 7.49 (d, J = 8.0 Hz, 1H; 5-H),

7.46 (s, 1H; 8-H), 7.23 (d, ³J = 8.0 Hz, 2H; 12-H), 6.91 (d, ³J = 8.0 Hz,

1H; 6-H), 6.85 (d, ³J = 8.0 Hz, 1H; 13-H), 3.78 (s, 1H; 16-H), 2.44 (s, 1H;

3

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15-H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 160.19 (C-2), 159.67 (C-14),

158.95 (C-4), 149.51 (C-9), 145.33 (C-7), 135.84 (C-11), 129.6 (C-12),

127.9 (C-6), 124.63, 122.5, 119.8, 114.3 (C-13), 55.34 (C-16), 22.22 (C-

15) ppm; HRMS (EI-QTOF, [M

251.1184; found: 251.1180.

According to the general procedure, reaction between 2-amino-5-

methoxybenzylamine (1c) (1.0 mmol, 152 mg) and 4-methylbenzonitrile

(2d) (1.0 mmol, 117 mg) were performed using Vitamin-B₃(0.3 mmol, 37

mg) to obtain the desired 6-methoxy-2-(p-tolyl)quinazoline (3cd) in 82%

(201 mg) yield as colorless solid (Scheme 4).

+

H]⁺): calculated for C₁₆H₁₅N₂O:

Preparation of 7-Methyl-2-(4-chlorophenyl)quinazoline (3bi)

6-Methoxy-2-(p-tolyl)quinazoline (3cd)^[2c](Scheme 4): Colorless solid,

R_f= 0.63 (SiO₂, Hexane/EtOAc = 4:1); m.p = 139-140 °C (Lit^[2c]140-

142 °C);¹H NMR (400 MHz, CDCl₃): δ = 9.35 (s, 1H; 4-H), 8.47 (d, ³J = 8

Hz, 2H; 12-H), 7.98 (d, J = 8.0 Hz, 1H; 8-H), 7.54 (dd, J = 8.0 Hz, 1H;

7-H), 7.33 (d, ³J = 8 Hz, 2H; 13-H), 7.15 (d, ⁴J = 2.8 Hz, 1H; 5-H), 3.97 (s,

3H; 15-H), 2.44 (s, 3H; 16-H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 159.5

(C-2), 158.8 (C-4), 158.1 (C-6), 147.0 (C-9), 140.37 (C-11), 135.4 (C-14),

130.04 (C-8), 129.37 (C-13), 128.13 (C-12), 127.1 (C-7), 124.34 (C-10),

103.94 (C-5), 55.73 (C-15), 21.48 (C-16) ppm; HRMS (EI-QTOF, [M +

H]⁺): calculated for C₁₆H₁₅N₂O: 251.1184; found: 251.1180.

According to the general procedure, reaction between 2-amino-4-

methylbenzylamine (1b) (1.0 mmol, 136 mg) and 4-chlorobenzonitrile (2i)

(1.0 mmol, 137.6 mg) were performed using Vitamin-B₃(0.3 mmol, 37

mg) to obtain the desired 7-methyl-2-(4-chlorophenyl)quinazoline (3bi) in

79% (201 mg) yield as pale yellow solid (Scheme 4).

3

5-Methyl-2-(4-chlorophenyl)quinazoline (3bi)^[13](Scheme 4): Pale

yellow solid, R_f= 0.40 (SiO₂, Hexane/EtOAc = 4:1); m.p = 160-161 °C

(Lit^[13]159-160 °C); ¹H NMR (400 MHz, CDCl₃): δ = 9.48 (s, 1H; 4-H),

8.65 (d, ³J = 8.0 Hz, 2H; 12-H), 8.10 (s, 1H; 8-H), 7.90 (d, ³J = 8.0 Hz,

1H; 5-H), 7.55-7.51 (overlapped, 3H; 6-H and 13-H), 2.65 (s, 1H; 15-H)

ppm; HRMS (EI-QTOF, [M + H]⁺): calculated for C₁₅H₁₂ClN₂: 255.0689;

found: 255.0684.

Preparation of 6-Methoxy-2-(4-chlorophenyl)quinazoline (3ci)

According to the general procedure, reaction between 2-amino-5-

methoxybenzylamine (1c) (1.0 mmol, 152 mg) and 4-chlorobenzonitrile

(2i) (1.0 mmol, 137.6 mg) were performed using Vitamin-B₃(0.3 mmol,

37 mg) to obtain the desired 6-methoxy-2-(4-chlorophenyl)quinazoline

(3ci) in 76% (205 mg) yield as colorless solid (Scheme 4).

Preparation of 7-Methyl-2-(3-nitrophenyl)quinazoline (3bl)

According to the general procedure, reaction between 2-amino-4-

methylbenzylamine (1b) (1.0 mmol, 136 mg) and 3-nitrobenzonitrile (2l)

(1.0 mmol, 148 mg) were performed using Vitamin-B₃(0.3 mmol, 37 mg)

to obtain the desired 7-methyl-2-(3-nitrophenyl)quinazoline (3bl) in 72%

(191 mg) yield as yellow solid (Scheme 4).

6-Methoxy-2-(4-chlorophenyl)quinazoline (3cd)^[2c](Scheme 4):

Colorless solid, R_f= 0.65 (SiO₂, Hexane/EtOAc = 4:1); m.p = 171-

172 °C (Lit^[2c]172-173 °C);¹H NMR (400 MHz, CDCl₃): δ = 9.30 (s, 1H; 4-

H), 8.50 (d, ³J = 8 Hz, 2H; 12-H), 7.94 (d, ³J = 8.6 Hz, 1H; 8-H), 7.53 (dd,

³J = 8.6 Hz, 1H; 7-H), 7.47 (d, ³J = 8 Hz, 2H; 13-H), 7.10 (d, ⁴J = 2.7 Hz,

1H; 5-H), 3.94 (s, 3H; 15-H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 159.0

(C-2), 158.6 (C-4), 158.54 (C-6), 147.1 (C-9), 136.9 (C-14), 136.55 (C-

11), 130.30 (C-8), 129.73 (C-13), 129.0 (C-12), 127.55 (C-7), 124.73 (C-

10), 104.13 (C-5), 55.97 (C-15) ppm; HRMS (EI-QTOF, [M + H]⁺):

calculated for C₁₅H₁₂ClN₂O: 271.0638; found: 271.0635.

7-Methyl-2-(3-nitrophenyl)quinazoline (3bl) (Scheme 4): Yellow solid,

R_f= 0.40 (SiO₂, Hexane/EtOAc = 4:1); IR (KBr) ν = 2926, 1640, 1524,

1352, 765 cm^-1; ¹H NMR (400 MHz, DMSO-d₆): δ = 9.56 (s, 1H; 4-H),

9.32 (d, J = 3.6 Hz, 1H; 12-H), 8.94 (dt, ³J = 8.0 Hz, 1H; 16-H), 8.32 (ddd,

³J = 8.0, 2.4, 1.2 Hz, 1H; 14-H), 8.02 (s, 1H; 8-H), 7.93-7.87 (m, 2H; 5-H

3

and 15-H), 7.54 (dd, J = 9.0 Hz, 1H; 6-H), 2.59 (s, 3H; 17-H) ppm; ¹³C

Preparation of 6,7-Methylenedioxy-2-phenylquinazoline (3da)

NMR (100 MHz, DMSO-d₆) δ = 161.8 (C-2), 160.2 (C-4), 150.15 (C-9),

145.08 (C-13), 143.68 (C-7), 138.12 (C-16), 133.04 (C-11), 131.09 (C-

15), 129.94 (C-6), 128.53 (C-8), 127.32 (C-12), 126.75 (C-5), 125.8 (C-

10), 122.9 (C-14), 21.78 (C-17) ppm; HRMS (EI-QTOF, [M + H]⁺):

calculated for C₁₅H₁₂N₃O₂: 266.0929; found: 266.0924.

According to the general procedure, reaction between 6-

(aminomethyl)benzo[d][1,3]dioxol-5-amine (1d) (1.0 mmol, 166 mg) and

benzonitrile (2a) (1.0 mmol, 103 mg) were performed using Vitamin-B₃

(0.3 mmol, 37 mg) to obtain the desired 6,7-methylenedioxy-2-

phenylquinazoline (3da) in 79% (198 mg) yield as colorless solid

(Scheme 4).

Preparation of 6-Methoxy-2-phenylquinazoline (3ca)

According to the general procedure, reaction between 2-amino-5-

methoxybenzylamine (1c) (1.0 mmol, 152 mg) and benzonitrile (2a) (1.0

mmol, 103 mg) were performed using Vitamin-B₃(0.3 mmol, 37 mg) to

obtain the desired 6-methoxy-2-phenylquinazoline (3ca) in 79% (186 mg)

yield as colorless solid (Scheme 4).

6,7-Methylenedioxy-2-phenylquinazoline

(3da)^[2c]

(Scheme

4):

Colorless solid, R_f= 0.61 (SiO₂, Hexane/EtOAc = 4:1); m.p = 172-

174 °C (Lit^[2c]172-173 °C);¹H NMR (400 MHz, CDCl₃): δ = 9.15 (s, 1H; 4-

H), 8.53 (d, ³J = 9 Hz, 2H; 12-H), 7.54-7.44 (m, 3H; 13-H and 14-H), 7.33

(s, 1H; 8-H), 7.09 (s, 1H; 5-H), 6.13 (s, 2H; 15-H) ppm; ¹³C NMR (100

MHz, CDCl₃) δ = 160.3 (C-2), 157.7 (C-4), 154.37 (C-9), 150.53 (C-7),

148.5 (C-6), 138.4 (C-11), 130.43 (C-14), 128.8 (C-13), 128.4 (C-12),

120.97 (C-10), 105.23 (C-8), 102.43 (C-6), 102.08 (C-15) ppm; HRMS

(EI-QTOF, [M + H]⁺): calculated for C₁₅H₁₁N₂O₂: 251.0821; found:

251.0818.

6-Methoxy-2-phenylquinazoline (3ca)^[2c](Scheme 4): Colorless solid,

R_f= 0.63 (SiO₂, Hexane/EtOAc = 4:1); m.p = 119-121 °C (Lit^[2c]118-

119 °C);¹H NMR (400 MHz, CDCl₃): δ = 9.38 (s, 1H; 4-H), 8.57 (d, ³J = 8

3

Hz, 2H; 12-H), 8.01 (d, J = 8.2 Hz, 1H; 8-H), 7.58-7.48 (m, 4H; 7-H, 13-

H and 14-H), 7.16 (d, J = 2.8 Hz, 1H; 5-H), 3.98 (s, 3H; 15-H) ppm; ¹³C

NMR (100 MHz, CDCl₃) δ = 159.42 (C-2), 158.83 (C-4), 158.3 (C-6),

147.0 (C-9), 138.116 (C-11), 130.21 (C-14), 130.16 (C-8), 128.6 (C-13),

128.2 (C-12), 127.24 (C-7), 124.5 (C-10), 103.93 (C-5), 55.77 (C-15)

ppm; HRMS (EI-QTOF, [M + H]⁺): calculated for C₁₅H₁₃N₂O: 237.1028;

found: 237.1025.

Preparation of 6,7-Methylenedioxy-2-( p-tolyl)quinazoline (3dd)

According to the general procedure, reaction between 6-

(aminomethyl)benzo[d][1,3]dioxol-5-amine (1d) (1.0 mmol, 166 mg) and

4-methylbenzonitrile (2d) (1.0 mmol, 117 mg) were performed using

Vitamin-B₃(0.3 mmol, 37 mg) to obtain the desired 6,7-methylenedioxy-

Preparation of 6-Methoxy-2-(p-tolyl)quinazoline (3cd)

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European Journal of Organic Chemistry

FULL PAPER

2-( p-tolyl)quinazoline (3dd) in 78% (206 mg) yield as colorless solid

(Scheme 4).

6-Fluoro-2-phenylquinazoline (3ea)^[2c](Scheme 4): Colorless solid, R_f

= 0.66 (SiO₂, Hexane/EtOAc = 4:1); m.p = 137-138 °C (Lit^[2c]138-

140 °C);¹H NMR (400 MHz, CDCl₃): δ = 9.44 (s, 1H; 4-H), 8.59 (dd, ³J =

9 Hz, 2H; 12-H), 8.11 (dd, J = 9.2, 4.8 Hz, 1H; 8-H), 7.68 (td, J = 8.8,

2.8 Hz, 1H; 7-H), 7.58-7.51 (m, 4H; 5-H, 13-H and 14-H) ppm; ¹³C NMR

(100 MHz, CDCl₃) δ = 161.2 (d, J = 250.0 Hz, C-6), 160.1 (C-2), 159.04

(C-4), 148.23 (C-9), 138.0 (C-11), 131.68 (d, J = 12.0 Hz, C-8), 130.97

(C-14), 128.95 (C-13), 128.73 (C-12), 124.81 (d, J = 32.0 Hz, C-7), 124.2

(d, J = 12.0 Hz, C-10), 110.42 (d, J = 29 Hz, C-5) ppm; HRMS (EI-QTOF,

[M + H]⁺): calculated for C₁₄H₁₀FN₂: 225.0828; found: 225.0825.

3

6,7-Methylenedioxy-2-( p-tolyl)quinazoline (3dd)^[2c](Scheme 4):

Colorless solid, R_f= 0.64 (SiO₂, Hexane/EtOAc = 4:1); m.p = 186-

188 °C (Lit^[2c]187-188 °C);¹H NMR (400 MHz, CDCl₃): δ = 9.12 (s, 1H; 4-

3

H), 8.42 (d, J = 9 Hz, 2H; 12-H), 7.32-7.30 (m, 3H; 13-H and 8-H), 7.06

(s, 1H; 5-H), 6.11 (s, 2H; 15-H), 2.43 (s, 2H; 16-H) ppm; ¹³C NMR (100

MHz, CDCl₃) δ = 160.35 (C-2), 157.64 (C-4), 154.28 (C-9), 150.5 (C-7),

148.3 (C-6), 140.60 (C-11), 135.67 (C-14), 129.55 (C-13), 128.35 (C-12),

120.8 (C-10), 105.15 (C-8), 102.36 (C-6), 102.08 (C-15), 21.72 (C-16)

ppm; HRMS (EI-QTOF, [M + H]⁺): calculated for C₁₆H₁₃N₂O₂: 265.0977;

found: 265.0974.

Preparation of 2-(4-Chlorophenyl)-6-fluoroquinazoline (3ei)

According to the general procedure, reaction between 2-amino-5-

fluorobenzylamine (1e) (1.0 mmol, 140 mg) and 4-chlorobenzonitrile (2i)

(1.0 mmol, 137.6 mg) were performed using Vitamin-B₃(0.3 mmol, 37

mg) to obtain the desired 2-(4-chlorophenyl)-6-fluoroquinazoline (3ei) in

73% (189 mg) yield as colorless solid (Scheme 4).

Preparation of 6,7-Methylenedioxy-2-(4-chlorophenyl)quinazoline

(3di)

According to the general procedure, reaction between 6-

(aminomethyl)benzo[d][1,3]dioxol-5-amine (1d) (1.0 mmol, 166 mg) and

4-chlorobenzonitrile (2i) (1.0 mmol, 137.6 mg) were performed using

Vitamin-B₃(0.3 mmol, 37 mg) to obtain the desired 6,7-methylenedioxy-

2-(4-chlorophenyl)quinazoline (3di) in 76% (216 mg) yield as colorless

solid (Scheme 4).

2-(4-Chlorophenyl)-6-fluoroquinazoline (3ei)^[2c](Scheme 4): Colorless

solid, R_f= 0.64 (SiO₂, Hexane/EtOAc = 4:1); m.p = 186-188 °C (Lit^[2c]

187-188 °C);¹H NMR (400 MHz, CDCl₃): δ = 9.41 (s, 1H; 4-H), 8.54 (dd,

3

³J = 9 Hz, 2H; 12-H), 8.08 (dd, J = 9.3, 5.0 Hz, 1H; 8-H), 7.68 (td, J =

8.8, 2.8 Hz, 1H; 7-H), 7.55-7.47 (m, 3H; 5-H and 13-H) ppm; ¹³C NMR

(100 MHz, CDCl₃) δ = 161.25 (d, J = 240 Hz, C-6), 160.12 (C-4), 159.11

(C-4), 148.12 (C-9), 137.2 (C-11), 136.46 (C-14), 131.62 (d, J = 11 Hz,

C-8), 130.0 (C-13), 129.13 (C-12), 124.95 (d, J = 34 Hz, C-7), 124.22 (d,

J = 12 Hz, C-10), 110.46 (d, J = 29 Hz, C-5) ppm; HRMS (EI-QTOF, [M +

H]⁺): calculated for C₁₄H₉ClFN₂: 259.0438; found: 259.0435.

6,7-Methylenedioxy-2-(4-chlorophenyl)quinazoline (3di)^[2c](Scheme

4): Colorless solid, R_f= 0.65 (SiO₂, Hexane/EtOAc = 4:1); m.p = 222-

224 °C (Lit^[2c]223-225 °C);¹H NMR (400 MHz, CDCl₃): δ = 9.14 (s, 1H; 4-

3

H), 8.49 (d, J = 9 Hz, 2H; 12-H), 7.47 (d, J = 8 Hz, 2H; 13-H), 7.32 (s,

1H; 8-H), 7.11 (s, 1H; 5-H), 6.17 (s, 2H; 15-H) ppm; ¹³C NMR (100 MHz,

CDCl₃) δ = 159.3 (C-2), 157.74 (C-4), 154.53 (C-9), 150.52 (C-7), 148.7

(C-6), 136.93 (C-14), 136.62 (C-11), 129.77 (C-13), 129.0 (C-12), 121.1

(C-10), 105.2 (C-8), 102.5 (C-6), 102.15 (C-15) ppm; HRMS (EI-QTOF,

[M + H]⁺): calculated for C₁₅H₁₀ClN₂O₂: 285.0431; found: 285.0428.

Preparation of 7-Fluoro-2-phenylquinazoline (3fa)

According to the general procedure, reaction between 2-amino-4-

fluorobenzylamine (1f) (1.0 mmol, 140 mg) and benzonitrile (2a) (1.0

mmol, 103 mg) were performed using Vitamin-B₃(0.3 mmol, 37 mg) to

obtain the desired 7-fluoro-2-phenylquinazoline (3fa) in 75% (149 mg)

yield as off-white solid (Scheme 4).

Preparation of 6,7-Methylenedioxy-2-(3-nitrophenyl)quinazoline (3dl)

According to the general procedure, reaction between 6-

(aminomethyl)benzo[d][1,3]dioxol-5-amine (1d) (1.0 mmol, 166 mg) and

3-nitrobenzonitrile (2l) (1.0 mmol, 148 mg) were performed using

Vitamin-B₃(0.3 mmol, 37 mg) to obtain the desired 6,7-methylenedioxy-

2-(3-nitrophenyl)quinazoline (3dl) in 74% (218 mg) yield as yellow solid

(Scheme 4).

7-Fluoro-2-phenylquinazoline (3fa)^[14](Scheme 4): Off-white solid, R_f

= 0.60 (SiO₂, Hexane/EtOAc = 4:1); ¹H NMR (400 MHz, CDCl₃): δ = 9.43

(s, 1H; 4-H), 8.63-8.60 (m, 1H; 12-H), 7.94 (dd, ³J = 8.0 Hz, 1H; 5-H),

7.71 (d, ³J = 8.0 Hz, 1H; 6-H), 7.58-7.49 (m, 3H; 8-H and 13-H), 7.38 (td,

³J = 9.0 Hz, 1H; 14-H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 166.06 (d, J

= 272 Hz, C-7), 161.8 (C-2), 159.93 (C-4), 152.44 (d, J = 19 Hz, C-9),

137.55 (C-11), 131.03 (C-14), 129.8 (d, J = 14 Hz, C-5), 128.76 (C-13),

128.72 (C-12), 120.9 (C-10), 118.0 (d, J = 34 Hz, C-6), 112.5 (d, J = 27

Hz, C-8) ppm; HRMS (EI-QTOF, [M + H]⁺): calculated for C₁₄H₁₀FN₂:

225.0828; found: 225.0824.

6,7-Methylenedioxy-2-(3-nitrophenyl)quinazoline (3dl) (Scheme 4):

Yellow solid, R_f= 0.40 (SiO₂, Hexane/EtOAc = 4:1); IR (KBr) ν = 3050,

2160, 1613, 1524, 1350, 768 cm^-1; ¹H NMR (400 MHz, DMSO-d₆): δ =

9.42 (s, 1H; 4-H), 9.33 (d, J = 0.3 Hz, 1H; 12-H), 8.89 (dt, ³J = 8.0 Hz,

1H; 16-H), 8.37 (ddd, ³J = 8.0, 2.4, 1.2 Hz, 1H; 14-H), 7.85 (t, ³J = 8.0 Hz,

1H; 15-H), 7.54 (s, 1H; 8-H), 7.49 (s, 1H; 5-H), 6.32 (s, 2H; 17-H) ppm;

¹³C NMR (100 MHz, CDCl₃) δ = 159.5 (C-2), 156.06 (C-4), 149.81 (C-9),

148.94 (C-7), 146.95 (C-6), 136.94 (C-16), 134.58 (C-11), 130.09 (C-15),

127.53, 124.0 (C-12), 123.87 (C-10), 108.71 (C-8), 103.57 (C-5), 102.07

(C-17) ppm; HRMS (EI-QTOF, [M + H]⁺): calculated for C₁₅H₁₀N₃O₄:

296.0671; found: 296.0666.

Preparation of 7-Fluoro-2-(3-nitrophenyl)quinazoline (3fl)

According to the general procedure, reaction between 2-amino-4-

fluorobenzylamine (1f) (1.0 mmol, 140 mg) and 3-nitrobenzonitrile (2l)

(1.0 mmol, 148 mg) were performed using Vitamin-B₃(0.3 mmol, 37 mg)

to obtain the desired 7-fluoro-2-(3-nitrophenyl)quinazoline (3fl) in 71%

(191 mg) yield as white solid (Scheme 4).

Preparation of 6-Fluoro-2-phenylquinazoline (3ea)

According to the general procedure, reaction between 2-amino-5-

fluorobenzylamine (1e) (1.0 mmol, 140 mg) and benzonitrile (2a) (1.0

mmol, 103 mg) were performed using Vitamin-B₃(0.3 mmol, 37 mg) to

obtain the desired 6-fluoro-2-phenylquinazoline (3ea) in 77% (173 mg)

yield as colorless solid (Scheme 4).

7-Fluoro-2-(3-nitrophenyl)quinazoline (3fl) (Scheme 4): White solid,

R_f= 0.50 (SiO₂, Hexane/EtOAc = 4:1); IR (KBr) ν = 3061, 2160, 1623,

1550, 1380, 1349, 1140, 1020, 768 cm^-1; ¹H NMR (400 MHz, CDCl₃): δ =

9.49 (s, 1H; 4-H), 9.48 (s, 1H; 12-H), 8.96 (d, ³J = 8.0 Hz, 1H; 16-H), 8.37

(d, ³J = 8.0 Hz, 1H; 14-H), 8.02 (dd, ³J = 8.0 Hz, 1H; 5-H), 7.77-7.69 (m,

2H; 6-H and 8-H), 7.46 (td, ³J = 9.0 Hz, 1H; 15-H) ppm; ¹³C NMR (100

10.1002/ejoc.201901651

European Journal of Organic Chemistry

FULL PAPER

MHz, CDCl₃) δ = 166.25 (d, J = 272 Hz, C-7), 160.23 (C-2), 159.5 (C-4),

152.5 (d, J = 18 Hz, C-9), 148.9 (C-13), 139.46 (C-16), 134.37 (C-11),

129.94 (d, J = 14 Hz, C-5), 129.65 (C-15), 125.38 (C-14), 123.8 (C-12),

121.26 (C-10), 118.9 (d, J = 34 Hz, C-6), 112.7 (d, J = 27 Hz, C-8) ppm;

HRMS (EI-QTOF, [M + H]⁺): calculated for C₁₄H₉FN₃O₂: 270.0678; found:

270.0674.

2017, 15, 2307-2340; r) Q. Ren, M. Li, L. Yuan, J. Wang, Org. Biomol.

Chem. 2017, 15, 4731-4749; s) F. Vetica, P. Chauhan, S. Dochain, D.

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see: t) A. K. Khatana, V. Singh, M. K. Gupta, B.

A Tiwari,

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Lett. 2018, 20, 6372-6375; v) V. D. G. Oliveira, M. F. D. C. Cardoso, L.

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Preparation of 4-Chloro-N-(2-formylphenyl)benzimidamide (5aa)

[2]

a) B. Han, C. Wang, R.-F. Han, W. Yu, X.-Y. Duan, R. Fang, X.-L. Yang,

Chem. Commun. 2011, 47, 7818-7820; b) J. Ma, Y. Wan, C. Hong, M.

Li, X. Hu, W. Mo, B. Hu, N. Sun, L. Jin, Z. Shen, Eur. J. Org. Chem.

2017, 3335-3342; c) R. Gujjarappa, S. K. Maity, C. K. Hazra, N.

Vodnala, S. Dhiman, A. Kumar, U. Beifuss, C. C. Malakar, Eur. J. Org.

According to the general procedure, reaction between 2-aminobenzyl

alcohol (1a) (1.0 mmol, 123 mg) and 4-chlorobenzonitrile 2i (1.0 mmol,

137.6 mg) were performed using Vitamin-B₃(0.3 mmol, 37 mg) to obtain

the desired 4-chloro-N-(2-formylphenyl)benzimidamide (5aa) in 54% (140

mg) yield as yellow solid (Scheme 2).

Chem.

2018,

4628-4638;

d)

S.

B.

Bhagat,

V.

N.

Telvekar, Synlett 2018, 29, 874-879; e) G.-L. Wu, Q.-P. Wu,

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4-Chloro-N-(2-formylphenyl)benzimidamide (5aa) (Scheme 5): Yellow

solid, R_f= 0.55 (SiO₂, Hexane/EtOAc = 4:1); IR (KBr) ν = 3458, 3309,

2916, 2850, 2710, 2160, 1730, 1620, 1590, 1352, 764 cm^-1; ¹H NMR

(400 MHz, CDCl₃): δ = 12.11 (s, 1H; 1-NH), 10.00 (d, J = 4.0 Hz, 1H; 4-

H), 8.93 (d, ³J = 8.0 Hz, 1H; 5-H), 8.02 (d, ³J = 8.0 Hz, 1H; 13-H), 7.75

(dd, J = 8.0 Hz, 1H; 7-H),7.69 (td, ³J = 8.0 Hz, 1H; 6-H), 7.51 (dt, J =

8.0 Hz, 1H; 12-H), 7.30 (td, ³J = 8.0 Hz, 1H; 8-H) ppm; ¹³C NMR (100

MHz, CDCl₃) δ = 196.04 (C-4), 165.07 (C-2), 141.1 (C-9), 138.62 (C-14),

136.51 (C-7), 136.26 (C-5), 132.73 (C-6), 129.19 (C-12), 128.96 (C-13),

123.3, 122.0, 120.0 (C-8) ppm; HRMS (EI-QTOF, [M + H]⁺): calculated

for C₁₄H₁₂ClN₂O: 259.0638; found: 259.0630.

3

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CCM appreciate Science and Engineering Research Board

(SERB), New Delhi and NIT Manipur for financial support in the

form of research grant (ECR/2016/000337). We sincerely thank

Prof. Anil Kumar, Vikki N. Shinde and Shiv Dhiman from BITS

Pilani for sample analysis and research support. RG and NV

grateful to Ministry of Human Resource and Development

(MHRD), New Delhi for fellowship support.

Keywords: Vitamin-B₃-catalyzed • Organocatalysis • Nitrile • C-

N Source • Quinazolines

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Entry for the Table of Contents

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N-Heterocycles, Organocatalysis

Raghuram Gujjarappa, Nagaraju

Vodnala, Velma Ganga Reddy and

Chandi C. Malakar*

Page No. – Page No.

An organocatalyzed protocol has been described for the comprehensive synthesis

of 2-substituted quinazolines using nitriles as C-N Source. The developed reaction

conditions holds good for wide range of substrates by giving the desired products in

excellent yields.

Niacin as a Potent Organocatalyst

towards the Synthesis of

Quinazolines using Nitriles as C-N

Source

Article Doi

Niacin as a Potent Organocatalyst towards the Synthesis of Quinazolines Using Nitriles as C–N Source

DOI: 10.1002/ejoc.201901651

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