An efficient one-pot route for the Synthesis of functionalized Quinazoline

Derivatives

Abstract: An efficient acid catalysed method for the synthesis of functional quinazolines, in

this protocol involves the condensation of three components in the one pot reaction condition,

phenacybromides, ammonium acetate and aminoacetophenones using the acetic acid as a

catalyst, in this procedure aminoacetophenones was utilised for the development of imine was

the ancestor for the produced quinazolines derivatives, the condensation of reactants to form

C-N bonds via acid catalysed method, therefore, we synthesised a library of 12 compounds

was produced by this protocol.

Graphical abstract

Keywords:

* Corresponding authors.

E-mail addresses:

Introduction

Quinazolines are the nitrogen containing heterocyclic compounds and they are treated as

functional structural molecules and it plays a key role in the area of medicinal 1-3 and

pharmacological as well as DPP-4 inhibitor4 for treating type-II diabetes, 5-HT2A receptor5

and active therapeutic agents6,7 and these quinazolines are Naturally occurring biologically
active substances due its ever present nature and to develop biologically active and privileged

scaffolds8 these Quinazoline scaffolds having excellent pharmacological properties such as anti

cancer9, antimalarial10, antituberculosis11, anti hypertensive12 and anti-inflammatory13

synthesis and development of new derivatives of quinazolines, apart form this method some of

the known procedures are reported previously, those are used by the involvement of simple

amines, amides and amino acids14 recently some methods reports with using Ir, Pt, Pd and CuI

all these synthetic routes are successfully capable but it has some drawbacks such as usage of

high amount of strong oxidising agents15 like DDQ, NaClO, MnO2 and there a straight forward

statement apart from the previously reported methods, drawbacks like usage of costly

chemicals synthesis such as harsh reaction conditions 16, including time and reaction work up

procedures

Figure 1. Marketed anticancer drugs of quinazolines derivatives

Herein focused to the development of quinazoline derivatives by using very passionate and

successful route i.e. environmentally ecofriendly method.

Synthesis of Quinazoline Derivatives with optimizing conditions

Results and discussions

Chemistry:

Initially, we intended to utilize the reported method by Cho et al.ref for the acid catalysed

condensation of phenacylbromide, ammonium acetate and aminoacetophenones in the

prescence of acetic acid to obtain the (4-methylquinazolin-2-yl)(phenyl)methanone analogues

as they demonstrate outstanding anticancer properties.

To the stirred reaction mass of aminoacetophenones 1eq and phenacylbromide 1.2 eq in ethanol

water (1:3) was added acetic acid 2 mol% and the reaction mixture was allowed to stir at reflux

for 4. After the reaction was complete, the reaction progress was monitered by TLC, then the

reaction solvent was evaporated in a vacuum and the residue was extracted with ethyl

acetate/water. The organic layer was separated, dried over anhydrous Na2SO4 and evaporated

to yield a crude product which was purified through silica gel column chromatography using

ethyl acetate/hexane.

Table-1 Synthesised derivatives of quinazoline via acetic acid method

Table-1 Optimization reaction conditions

Entry Catalyst T (OC)/ t (h) Solvent Yield of 3a (%)

1 -- RT/12 ethanol 27
2 -- RT/6 methanol 23
3 acetic acid RT/6 water 29
4 acetic acid RT/12 hexane 10
5 acetic acid RT/12 water 15

6 acetic acid RT/12 acetonitrile 60

7 acetic acid RT/8 Ethanol/water 70

8 acetic acid RT/12 Ethanol/water 81

9 acetic acid reflux/4 Ethanol/water 90

Conclusion

In conclusion we have developed a simple, robust and efficient method for the synthesis of

functionalized quinazolines by using a acetic acid catalysed condensation of

aminoacetophenones, amoniumacetate and phenacylbromide in healthy metal free reaction

conditions, this method does not required any environmental harsh reaction condition and it is

applicable for the all the insightful substituents of the reactants. It is the suitable method for

development of new route for the synthesis of biologically and pharmaceutically active

quinazoline derivatives.
General procedure for the synthesis of (4-phenylquinazolin-2-yl) methanone Derivatives

To the solution of aminoacetophenones 1eq (1mmol) and phenacylbromide 1.2 eq (1mmol)

add acetic acid as a catalyst in ethanol water (1:3) at reflux and the reaction mixture was

allowed to stir at reflux for 4h. After the reaction was complete, the reaction progress was

monitered by TLC, then the reaction solvent was evaporated in a vacuum and the residue was

extracted with ethyl acetate/water. . The organic layer was separated, dried over anhydrous

Na2SO4 and evaporated to yield a crude product which was purified through silica gel column

chromatography using ethyl acetate/hexane.

Experimental section

All chemicals, reagents were purchased from the commercial sources and were used without

further purification. Reactions were monitored by TLC on silica gel glass plate containing 60

GF-254, and visualization was done by UV light and iodine vapor. 1H and 13C NMR spectra

were recorded on Bruker UXNMR/XWIN-NMR (300 MHz) or Innova Varian-VXR-unity

(400, 500 MHz) instruments. Chemical shifts were expressed in parts per million (in ppm)

downfield from TMS expressed as internal standard and coupling constants are expressed in

Hz. 1H NMR spectral data were reported in the following order: multiplicity (s, singlet; brs,

broad singlet; d, doublet; dd, doublet of doublets; t, triplet; m, multiplet), coupling constants in

Hz, and number of protons. ESI mass spectra were recorded on a Micromass Quattro LC using

ESI+ software with capillary voltage 3.98 kV and an ESI mode positive ion trap detector. High

resolution mass spectra were recorded on a QSTAR XL Hybrid MS-MS mass spectrometer.

Melting points were determined with an electro thermal digital melting point apparatus IA9100

and are uncorrected.

Acknowledgements

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(4-methylquinazolin-2-yl)(phenyl)methanone

Light white solid, 126 mg, 89%. Mp 94-96. 1H NMR (400 MHz, CDCl3) δ 8.24 – 8.10 (m,
4H), 7.97 (t, J =8.3 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.7
Hz, 2H), 3.07 (s, 3H).13C NMR (101 MHz, CDCl3) δ 192.16, 169.48, 158.13, 149.00, 135.55,
134.33, 133.50, 131.15,129.88, 129.06, 128.32, 125.13, 124.25, 22.05. HRMS (ESI, m/z):
calcd for C16H13N2O [M + H]+249.1028, found 249.1025.

4-methoxyphenyl)(4-methylquinazolin-2-yl)methanone

White solid, 112 mg, 82%. 1H NMR (500 MHz, CDCl3) δ 8.20 (d, J = 8.3 Hz, 1H), 8.15 (t, J
= 7.8 Hz, 2H), 7.97 (t, J = 7.6 Hz, 1H), 7.75 (t, J = 7.6 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H), 3.89
(s, 3H), 3.07 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 190.70, 170.15, 169.42, 164.04, 149.01,
134.28, 133.61, 129.81, 128.87, 128.42, 125.12, 113.71, 55.56, 22.04. HRMS (ESI, m/z): calcd
for C17H15N2O2 [M + H] + 279.1134, found 279.1130.
(4-methylquinazolin-2-yl)(p-tolyl) methanone

Cream white solid, 98 mg, 77 %. 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.3 Hz, 1H), 8.16
(d, J = 8.4 Hz, 1H), 8.03 (d, J = 8.2 Hz, 2H), 7.96 (t, J = 7.7 Hz, 1H), 7.75 (t, J = 7.1 Hz, 1H),
7.29 (d, J = 8.0 Hz, 2H), 3.06 (s, 3H), 2.44 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 191.83,
169.41, 158.37, 148.97, 144.51, 134.29, 132.97, 131.27, 129.80, 129.07, 128.96, 125.12,
124.18, 21.84. HRMS (ESI, m/z): calcd for C17H15N2O [M + H] + 263.1184, found 263.1180.
(4-chlorophenyl)(4-methylquinazolin-2-yl)methanone

White solid, 101 mg, 74%. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.3 Hz, 1H), 8.15 (d, J
= 8.6 Hz, 1H), 8.12 (d, J = 8.6 Hz, 2H), 7.98 (t, J = 7.7 Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H), 7.47
(d, J = 8.5 Hz, 2H), 3.07 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 190.79, 169.65, 157.50, 148.92,
140.01, 134.46, 133.96, 132.58, 129.88, 129.30, 128.65, 125.16, 124.29, 22.05. HRMS (ESI,
m/z): calcd for C16H12ClN2O [M + H] + 283.0638, found 283.0636.
(4-methylquinazolin-2-yl)(3,4,5-trimethoxyphenyl)methanone

Yellow solid, 118 mg, 86 %. 1H NMR (500 MHz, CDCl3) δ 8.22 (d, J = 8.3 Hz, 1H), 8.17 (d,
J = 8.4 Hz, 1H), 7.99 (t, J = 7.7 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.47 (s, 2H), 3.96 (s, 3H),
3.88 (s, 6H), 3.09 (s, 3H). 13
C NMR (126 MHz, CDCl3) δ 190.77, 169.55, 158.16, 152.86,
148.95, 143.24, 134.45, 130.43, 129.78, 129.11, 125.18, 124.23, 108.91, 61.00, 56.34, 22.04.
HRMS (ESI, m/z): calcd for C19H19N2O4 [M + H]+ 339.1343, found 339.1345.

(3,5-dichlorophenyl)(4-methylquinazolin-2-yl) methanone

White solid, 122 mg, 79 %.1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.20 (dd, J = 18.4, 7.8
Hz, 2H), 8.02 (dd, J = 17.8, 7.4 Hz, 2H), 7.80 (t, J = 7.0 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 3.09
(s, 3H). 13
C NMR (101 MHz, CDCl3) δ 189.62, 169.83, 156.89, 148.93, 138.03, 135.36,
134.58, 133.05, 132.89, 130.42, 130.23, 130.00, 129.56, 125.20, 124.40, 22.10. .HRMS (ESI,
m/z): calcd for C16H11Cl2N2O [M + H]+ 317.0248, found 317.0244.

Phenyl (4-phenylquinazolin-2-yl) methanone

White solid, 116 mg, 75% Mp 120-122. 1H NMR (400 MHz, CDCl3) δ 8.30 – 8.21 (m, 2H),
8.16 (d, J = 7.2 Hz, 2H), 8.05 – 7.95 (m, 1H), 7.85 (s, 2H), 7.76 – 7.68 (m, 1H), 7.66 – 7.45
(m, 6H). 13C NMR (101 MHz, CDCl3) δ 192.06, 169.11, 158.47, 150.82, 136.71, 135.55,
134.37, 133.56, 131.15, 130.40, 130.31, 129.76, 129.13, 128.73, 128.36, 127.27, 122.94.
HRMS (ESI, m/z): calcd for C21H15N2O [M + H]+ 311.1184, found 311.1182.
(4-methoxyphenyl)(4-phenylquinazolin-2-yl) methanone

Brown solid, 132 mg, 78%. Mp 130-132. 1H NMR (500 MHz, CDCl3) δ 8.24 (t, J = 8.1 Hz,
2H), 8.17 (d, J = 8.8 Hz, 2H), 7.99 (t, J = 8.0 Hz, 1H), 7.86 (dd, J = 6.3, 2.8 Hz, 2H), 7.71 (t, J
= 7.8 Hz, 1H), 7.61 – 7.55 (m, 3H), 6.98 (d, J = 8.9 Hz, 2H), 3.89 (s, 3H). 13C NMR (126 MHz,
CDCl3) δ 190.60, 169.03, 164.05, 158.97, 150.81, 136.77, 134.31, 133.59, 130.35, 130.30,
129.66, 128.95, 128.70, 128.45, 127.23, 122.84, 113.74, 55.57. HRMS (ESI, m/z): calcd for
C22H17N2O2 [M + H]+ 341.1290, found 341.1286.
(4-phenylquinazolin-2-yl)(p-tolyl)methanone

White solid, 121 mg, Mp 194-196. 1H NMR (400 MHz, CDCl3) δ 8.29 – 8.21 (m, 2H), 8.06

(d, J = 8.1 Hz, 2H), 7.99 (t, J = 8.2 Hz, 1H), 7.85 (dd, J = 6.4, 2.9 Hz, 2H), 7.72 (t, J = 7.5 Hz,

1H), 7.62 – 7.56 (m, 3H), 7.30 (d, J = 8.0 Hz, 2H), 2.44 (s, 3H). 13C NMR (126 MHz, CDCl3)

δ 191.72, 178.72, 169.04, 158.77, 150.83, 144.54, 136.77, 134.28, 133.00, 131.29, 130.35,
130.31, 129.75, 129.11, 128.99, 128.70, 127.24, 122.90, 21.86. HRMS (ESI, m/z): calcd for

C22H17N2O [M + H]+ 325.1341, found 325.1337.

(4-chlorophenyl)(4-phenylquinazolin-2-yl)methanone

Red solid, 133 mg, 80%. Mp 144-146. 1H NMR (500 MHz, CDCl3) δ 8.24 (d, J = 7.8 Hz, 2H),
8.15 (d, J = 8.3 Hz, 2H), 8.01 (t, J = 7.4 Hz, 1H), 7.85 (d, J = 3.5 Hz, 2H), 7.74 (t, J = 7.5 Hz,
1H), 7.59 (s, 3H), 7.48 (d, J = 8.3 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 190.69, 169.21,
157.85, 150.78, 140.04, 136.60, 134.49, 134.00, 132.57, 130.50, 130.28, 129.77, 129.37,
128.76, 128.70, 127.29, 122.97. HRMS (ESI, m/z): calcd for C21H14ClN2O [M + H]+
345.0795, found 334.0787.
quinazolin-2-yl)(3,4,5-trimethoxyphenyl)methanone

Yellow solid, 118 mg, 86 %. 1H NMR (500 MHz, CDCl3) δ 8.22 (d, J = 8.3 Hz, 1H), 8.17 (d,
J = 8.4 Hz, 1H), 7.99 (t, J = 7.7 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.47 (s, 2H), 3.96 (s, 3H),
3.88 (s, 6H), 3.09. 13
C NMR (126 MHz, CDCl3) δ 190.77, 169.55, 158.16, 152.86, 148.95,
143.24, 134.45, 130.43, 129.78, 129.11, 125.18, 124.23, 108.91, 61.00, 56.34.

4-methylphenyl)(4-methylquinazolin-2-yl)methanone

White solid, 105 mg, 82%. 1H NMR (500 MHz, CDCl3) δ 8.20 (d, J = 8.3 Hz, 1H), 8.15 (t, J
= 7.8 Hz, 2H), 7.97 (t, J = 7.6 Hz, 1H), 7.75 (t, J = 7.6 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H), 3.18
(s, 3H), 3.07 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 190.70, 170.15, 169.42, 164.04, 149.01,
134.28, 133.61, 129.81, 128.87, 128.42, 125.12, 113.71, 55.56, 22.45. 22.01
(3,5-dichlorophenyl)(quinazolin-2-yl) methanone

White solid, 95 mg, 81 %.1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.20 (dd, J = 18.4, 7.8
Hz, 2H), 8.02 (dd, J = 17.8, 7.4 Hz, 2H), 7.80 (t, J = 7.0 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 3.09
(s, 3H). 13
C NMR (101 MHz, CDCl3) δ 189.62, 169.83, 156.89, 148.93, 138.03, 135.36,
134.58, 133.05, 132.89, 130.42, 130.23, 130.00, 129.56, 125.20, 124.40, 22.19. .
1H NMR 4A

C13 NMR-4A
1HNMR-4B

C13 NMR-4B

1H NMR-4C
C13 NMR-4C
1H NMR-4D

C13NMR-4D
1H NMR-4E

C13 NMR-4E
1H NMR-4F

C13 NMR-4F
1H NMR-4G

13C-NMR-4G
1H NMR-4H

C13 NMR-4H
C13 NMR-4I