Multicomponent reaction of benzyl halides: Synthesis of [1,2,4]triazolo/benzimidazolo quinazolinones

Article abstract of DOI:10.1080/00397911.2016.1140784

We demonstrated a simple, highly efficient, one-pot method to construct triazolo/benzimidazolo quinazolinones through a cascade of oxidation, Knoevenagel condensation, and Michael addition followed by cyclization and dehydration. This protocol tolerates e

Full text of DOI:10.1080/00397911.2016.1140784

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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Multicomponet Reaction of Benzyl Halides:
Synthesis of [1,2,4]Triazolo/Benzimidazolo
Quinazolinones
Mallappa Beerappa & Kalegowda Shivashankar
To cite this article: Mallappa Beerappa & Kalegowda Shivashankar (2016): Multicomponet
Reaction of Benzyl Halides: Synthesis of [1,2,4]Triazolo/Benzimidazolo Quinazolinones,
Synthetic Communications
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Date: 29 January 2016, At: 00:14

Multicomponet reaction of benzyl halides: Synthesis of [1,2,4]triazolo/benzimidazolo
quinazolinones
1
1
Mallappa Beerappa , Kalegowda Shivashankar
1
P.G. Department of Chemistry, Central College Campus, Bangalore University,
Bangalore, Karnataka, India
Corresponding author K. Shivashankar E-mail: shivashankark@gmail.com
Supplemental data for this article can be accessed on the publisher’s website.
Abstract
We demonstrated a simple and highly efficient new one-pot method to construct
triazolo/benzimidazolo quinazolinones through a cascade of oxidation, Knoevenagel
condensation and Michael addition followed by cyclization and dehydration. This
protocol tolerates easily available benzyl halides, 2-amino benzimidazole/3-amino-1,2,4-
triazole and α-hydroxy C-H acids as starting materials using trimethyl amine N-oxide in
ethanol. To the best of our knowledge, this is the first example of synthesis of
triazolo/benzimidazolo quinazolinones directly from benzyl halides in one pot. Simple
procedure, environmental friendly, mild reaction condition and high yield are the
attractive features of this method.
KEYWORDS: Quinazolinone, Triazole, Benzimidazole, Trimethyl amine N-oxide and
Multi component reaction
1

INTRODUCTION
Multi-component reactions (MCRs) have been refined in recent years as powerful and
necessary tools in synthetic organic and medicinal chemistry. This powerful tool
combines both the environmental and economic aspects of organic chemistry that are
essential for industrial and academic applications. MCRs offer remarkable advantages
like convergence, reduction in the number of workup, operational simplicity, separation
and purification process, hence minimize waste production and rendering the green
[
1-5]
transformations.
The synthesis of quinazolinone analogues is a significant synthetic reaction in organic
chemistry as these scaffolds are found to be a very important core structure in various
[
6,7]
[8,9]
natural products
and a wide range of biologically active synthetic compounds.
Many commercially available drugs (Fig. 1) including Ispinesib (anticancer),
Dacomitinib (anticancer), Methaqualone (antimalarial), Albaconazole (antifungal
activity), Balaglitazone (antidiabetic and hypolipidimic property) and Anagrelide (for the
[10]
treatment of essential thrombocytosis) are derived from quinazolinone core entities.
[
11]
Quinazolinone moieties exhibit a variety of biological activities such as antitumor,
[
12]
[13]
[14]
[15]
[16]
antiviral, anticancer, antileishmanial, antimicrobial, anti-inflammatory,
[
17]
[18]
[19]
[20]
antitubercular, antimalarial, antifungal and antibiotic.
Hence, the synthesis of
quinazolinone has evoked much interest, as a result of which a variety of synthetic
[
21-23]
methodologies have been reported.
The most important approaches are (i) one-pot
condensation of aromatic aldehydes, 2-amino benzimidazole/3-amino-1, 2, 4-triazole and
2

[
24]
α-hydroxy C-H acids (ii) three-component reaction of 2-amino benzamides, aryl
[
25]
halides, and isocyanides (iii) one-pot reaction with o-amino benzamides and primary
[
26]
alcohols (iv) cascade synthesis of phenylamino substituted quinazolinones from urea
[
27]
derivatives and tert-butyl isocyanide [v] oxidative radical skeletal rearrangement
[
28]
induced by oxygen (vi) synthesis of quinazolinone and quinazoline from aerobic
[
29]
oxidative C(sp3)−H amination/C−N cleavage. Other methods have also been
[
30]
developed within the last three decades. In the past years, a few methods have
described the one-pot multicomponent synthesis of quinazolinones based on catalysts
[31]
[32]
[33]
[34]
[35]
such as NH SO H, thiamine hydrochloride, CuCl, chitosan, nafion-H®,
2
3
[36]
[37]
[38]
Mg-Al-CO3, silica gel and H P W O ·18H O from the reaction of aromatic
6
2
18
6
2
aldehydes, 2-amino benzimidazole/3-amino-1,2,4-triazole and α-hydroxy C-H acids.
Nevertheless, these methods have some significant limitations like restricted to
benzaldehyde, harsh reaction conditions, required long reaction time, tedious work-up,
low yields, use of metal and moisture sensitive catalysts. Hence, the development of a
simple and high yielding environmentally kind procedure for the one-pot multicomponent
synthesis of quinazolinone analogues is still reasonable.
As part of our continuing efforts on the development of new methods for the construction
[39]
of biologically active compounds, we have reported synthesis of pyran-based
heterocycles via one-pot reaction of benzyl halides, α-hydroxy C-H acids and active
[
40]
methylene compounds. Herein, we investigated a new and straightforward approach
for the synthesis of triazolo/benzimidazolo quinazolinones which involved an in situ
oxidation of benzyl halides with trimethyl amine N-oxide in to corresponding aldehydes,
3

which they undergo a three-component reaction with α-hydroxy C-H acids and 2-
aminobenzimidazole/3-amino-1,2,4-triazole without addition of any other catalyst. The
wider scope and synthetic utility of trimethyl amine N-oxide for the synthesis of
heterocyclic compounds in one pot has not been explored even though this reagent has
[
41,42]
been used as an oxidizing agent
. This procedure developed the known reaction using
[
43]
the novel methodology, while not limiting one of the substrates to an aldehyde.
RESULTS AND DISCUSSION
To set up the optimal reaction conditions for the construction of quinazolinone analogues,
our preliminary experiments were focused on a one-pot reaction involving 3-cyanobenzyl
bromide (1 equiv), 2-amino benzimidazole (1 equiv), and dimidone (1 equiv) in the
presence of trimethyl amine N-oxide (2 equiv) as an oxidizing agent. For a low hazard
and eco-friendly process, ethanol is used as a preferred solvent for all the optimization
o
experiments. The reactions were performed heating at 70 C. It was found that the yield
of the product was relatively superior. However, the yield decreased when the reaction
o
proceed to room temperature or over 70 C. Based on above results, a reaction of 3-
cyanobenzyl bromide (1 equiv), 2-amino benzimidazole (1 equiv) and dimidone (1 equiv)
o
in the presence of trimethyl amine N-oxide (2 equiv) stirring in ethanol at 70 C was
considered as a standard and a model reaction (Scheme 1) to optimize the reaction
[44]
conditions for the one-pot synthesis of other triazolo/benzimidazolo quinazolinones.
In order to evaluate the effect of organic solvents to optimize the reaction conditions
using trimethyl amine N-oxide as an oxidizing agent for the synthesis of quinazolinone
4

analogues (Table1), ethanol was replaced with other polar solvents such as THF,
acetonitrile, DMF, water, acetic acid and methanol (entry 4, 6, 7, 8, 9 and 10). The results
showed that using ethanol as the solvent gave the best yield of the respective product
with higher reaction rate (entry 5). The use of non polar solvents such as toluene,
chloroform, dioxane afforded the desired product in traces (entries 1, 2 and 3). Therefore,
ethanol was selected as a suitable medium to run the further reaction trimethyl N-oxide as
a oxidant.
The scope of present protocol was further investigated by the replacement of dimidone
with ethylacetoacetate. To our observation, the reaction underwent successful
condensation under similar reaction conditions to give the corresponding quinazolinone
analogues in excellent yields (Table 2, entries 8, 9). Reactions were also carried out by
replacing 2-amino benzimidazole with 3-amino-1,2,4-triazole. The reaction underwent
smooth cyclisation to give respective quinazolinone derivatives in virtually high yields
(Table 2, entries 10-14). Thereafter, a series of different substituted quinazolinone
analogues were synthesized from different benzyl halides containing electron-
withdrawing and electron-donating groups using trimethyl amine N-oxide in ethanol at 70
o
45
C in high yields (Table 2). In general, the overall yield ranged from 96% for 3,3-
dimethyl-12(4-nitro-phenyl)-1,2,3,4,5,12-hexahydrobenzo [4,5]imidazo[2,1-
b]quinazolin-1-one (4h) (entry 8) to 85% for 6,6-dimethyl-9-(4-hydroxy-phenyl)-5,6,7,9-
tetrahydro-4H-1,2,4-triazolo[5,1-b] quinazolin-8-one (4m) (entry 13).
5

The proposed mechanism (Figure 2) is similar to the well-known mechanism reported in
[
46-49]
the literature.
In the first step, oxidation proceeds via nucleophilic substitution of the
benzyl halide with the oxygen of the trimethyl amine N-oxide to give a N-alkoxy salt.
Afterwards, proton elimination at the carbon carrying the oxygen leads to the formation
of an .aldehyde giving trimethyl amine hydrogen halide salt which in turn would, in the
second step, able to acid catalyse Knoevenagel condensation between aldehyde and α-
hydroxy C-H acid gives the heterodiene. The third step is the Michael addition of the
amino compound on the heterodiene, followed by cyclisation and dehydration in the
presence of acid to afford the desired product.
CONCLUSION
In conclusion, we have developed a new and straight forward methodology for the one
pot synthesis of quinazolinone analogues via trimethyl amine N-oxide catalyzed in situ
oxidation of benzyl halides into benzaldehydes followed by the three component reaction
with α-hydroxy C-H acids and amine compounds. Mild reaction condition, one pot
operation, easy isolation of product and broad functional group tolerance are the main
advantages of this reaction.
EXPERIMENTAL
General Information:
All the reagents were purchased commercially and were used directly without further
purification. The melting points were measured by the open capillary tubes using electric
melting point equipment and are uncorrected. The Infrared (IR) spectra were obtained
6

1
13
using Agilent Cary 630 FT-IR Spectrophotometer. H NMR (400 MHz) and C NMR
(
100 MHz) spectra were recorded on a Bruker spectrometer using DMSO-d as solvents
6
and tetramethylsilane (TMS) as an internal standard at IISC, Bangalore. The chemical
shifts were given on the δ scale (ppm). The purity of the compounds was checked by thin
layer chromatography (Merck silica gel 60 F254 pre coated aluminium sheets). The CHN
analysis was performed on an Elemental Vario Micro Cube CHN Rapid Analyzer. All the
synthesized compounds gave agreeable elemental study.
Typical Procedure For The Synthesis Of 12(3-Cyanophenyl)-3,3-Dimethyl-
1
,2,3,4,5,12-Hexahydrobenzo[4,5]Imidazo[2,1-B]Quinazolin-1-One (4a)
Trimethyl amine N-oxide (290 mg, 3.0 mmol) was added to a solution of 3-cyanobenzyl
bromide (290 mg, 1.5 mmol), dimidone (210 mg, 1.5 mmol) and 2-aminobenzimidazole
(200 mg, 1.5 mmol) in ethanol (10 mL) in a round-bottomed flask. The resulting reaction
o
mixture was heated at 70 C in an oil bath for 70 min. The progress of the reaction was
monitored by TLC. After completion of the reaction, the reaction mixture was allowed to
cool to room temperature. The solid was collected by filtration at pump, washed with
ethanol and recrystallised from hot ethanol to obtain pure product.
1
2(3-Cyano-Phenyl)-3,3-Dimethyl-1,2,3,4,5,12-Hexahydrobenzo[4,5]Imidazo [2,1-
B]Quinazolin-1-One (4a).
Yield 94%; White solid; mp >300 C; IR (ATR, cm ): 3394 (NH), 2018 (CN), 1660
o
-1
-1 1
(
C=O) cm ; H NMR (400 MHz, DMSO-d ): δ 0.98 (s, 3H, -CH ), 1.04 (s, 3H, -CH ),
6 3 3
2
.22 (m, J = 4.0 Hz, 2H, -CH ), 2.48 - 2.64 (m, J = 4.0 Hz, 2H, -CH ), 6.50 (s, 1H, CH),
2 2,
7

1
3
6
2
1
.94 - 7.92 (m, 8H, Ar-H), 11.18 (s, 1H, NH) ppm; C NMR (100 MHz, DMSO-d ): δ
6
6.7, 28.1, 28.4, 32.2, 49.7, 53.6, 105.3, 109.9, 111.0, 117.0, 118.5, 120.7, 122.0, 129.8,
30.9, 131.5, 141.8, 142.8, 145.0, 150.9, 158.1, 159.1, 192.6 ppm; Anal. Calcd for
C H N O: C, 74.98; H, 5.47; N, 15.21; found: C, 74.82; H, 5.31; N, 15.13.
23
20
4
FUNDING
We wish to acknowledge a grant from the Department of Science and Technology –
Science Engineering Research Board (DST - SERB), New Delhi, India under Fast Track
Young Scientist Scheme [Grant No. SB/FT/CS-028/2013].
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1
2

Table 1. Optimization of solvents for the synthesis (4a)
Entry Solvents Time (min) Yield (%)
1
2
3
4
5
6
7
8
9
1
Toluene
CHCl3
Dioxane
THF
95
95
90
80
70
trace
trace
traces
55
Ethanol
96
Acetonitrile 75
86
DMF
80
80
78
Water
68
Acetic acid 80
Methanol 70
65
0
70
1
3

Table 2. Synthesis of quinazolinone analogues (4a–n)
Ent Benzyl
ry halides
α-
Amine
source
Quinazolinones Ti
Yie Ob Lit.
Hydroxy
C-H acids
me ld
s.
mp
O
R
(mi (%) mp ( C)
O
ef
n)
( C
)
1
70
94
>3
0
0
2
70
92
>3
0
0
3
70
92
>3 >300
[
31]
0
0
1
4

4
75
90
>3 >300
[
31]
0
0
5
70
92
>3 >300
[
31]
0
0
[
6
85
88
>3 >300
5
0]
0
0
7
85
88
>3
0
0
1
5

[
8
70
96
>3 >300
5
1]
0
0
9
70
92
>3
0
0
1
0
65
94
>3
0
0
1
1
70
92
292
1
2
70
92
310 303-
05
3
[
31]
1
6

1
3
80
85
>3 >300
[
31]
0
0
1
4
65
94
>3 307-
309
0
0
[
31]
1
7

Scheme 1. Synthesis of 12(3-cyanophenyl)-3,3-dimethyl-1,2,3,4,5,12-
hexahydrobenzo[4,5]imidazo [2,1-b]quinazolin-1-one (4a).
1
8

Scheme 2. A plausible reaction mechanism for the formation of quinazolinone
derivatives.
1
9

Figure 1. Quinazolinone derived commercially available drugs.
2
0