Phosphotungstic acid mediated, microwave assisted solvent-free green synthesis of highly functionalized 2?-spiro and 2, 3-dihydro quinazolinone and 2-methylamino benzamide derivatives from aryl and heteroaryl 2-amino amides

Article abstract of DOI:10.1016/j.tetlet.2018.12.011

Phosphotungstic acid has been found as green catalyst for the synthesis of spiro and cyclized quinazolinones and 2-amino substituted carboxamide under microwave irradiation and solvent-free condition has been developed. The scope of the reaction has been demonstrated for a variety of aldehydes and ketones with O-amino amides such as 2-amino-benzamide, 2-amino-5-iodo benzamide, 3-aminothiophene-2-carboxamide, 3-aminobenzofuran-2-carboxamide and 2-aminopyridine-3-carboxamides. The reaction afforded spiro-, cyclized quinazolinones and 2-amino substituted carboxamide derivatives within few minutes of irradiation in excellent yield. Plausible mechanism for the formation of products is provided. Synthetic utility of 1′H-spiro[fluorene-9,2′-quinazolin]-4′(3′H)-one 3a has been demonstrated by synthesis of 1,4-di(1′H-spiro[fluorene-9,2′-quinazolin]-4′(3′H)-one) buta-1,3-diyne 12, 1′-((1-benzyl-1H-1,2,3-triazol-4-yl) methyl)-1′H-spiro[fluorene-9,2′-quinazolin]-4′(3′H)-one 13 and 1′-phenyl-1′H-spiro[fluorene-9,2′-quinazolin]-4′(3′H)-one 14 under standard protocols.

Full text of DOI:10.1016/j.tetlet.2018.12.011

Accepted Manuscript
Phosphotungstic Acid Mediated, Microwave Assisted Solvent-Free Green Syn-
thesis of Highly Functionalized 2ˈ-Spiro and 2, 3-dihydro Quinazolinone and 2-
Methylamino benzamide Derivatives from Aryl and Heteroaryl 2-Amino
amides
Motakatla Novanna, Sathananthan Kannadasan, Ponnusamy Shanmugam
PII:
S0040-4039(18)31444-8
https://doi.org/10.1016/j.tetlet.2018.12.011
TETL 50474
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 October 2018
30 November 2018
4 December 2018
Please cite this article as: Novanna, M., Kannadasan, S., Shanmugam, P., Phosphotungstic Acid Mediated,
Microwave Assisted Solvent-Free Green Synthesis of Highly Functionalized 2ˈ-Spiro and 2, 3-dihydro
Quinazolinone and 2-Methylamino benzamide Derivatives from Aryl and Heteroaryl 2-Amino amides, Tetrahedron
Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.12.011
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Tetrahedron Letters
Phosphotungstic Acid Mediated, Microwave Assisted Solvent-Free Green
Synthesis of Highly Functionalized 2ˈ-Spiro and 2, 3-dihydro Quinazolinone and
2-Methylamino benzamide Derivatives from Aryl and Heteroaryl 2-Amino
amides
Motakatla Novannaa, Sathananthan Kannadasana* and Ponnusamy Shanmugamb*
aDepartment of Chemistry, School of Advanced Sciences, VIT, Vellore-632014, Tamil Nadu, India; E mail: kannadasan.s@vit.ac.in
bOrganic and Bio-Organic Chemistry Division, Council of Scientific and Industrial Research (CSIR)-Central Leather Research Institute (CLRI), Adyar, Chennai-
600020, India; Fax: (+) 91-44-24911589; Phone: (+91)-44-24437130; E-mail: shanmu196@rediffmail.com
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Abstract: Phosphotungstic acid has been found as green catalyst for the synthesis of spiro- and
cyclized quinazolinones and 2-amino substituted carboxamide under microwave irradiation and
solvent-free condition has been developed. The scope of the reaction has been demonstrated for
a variety of aldehydes and ketones with O-amino amides such as 2-amino-benzamide, 2-amino-
5-iodo benzamide, 3-aminothiophene-2-carboxamide, 3-aminobenzofuran-2-carboxamide and 2-
aminopyridine-3-carboxamides. The reaction afforded spiro-, cyclized quinazolinones and 2-
amino substituted carboxamide derivatives within few minutes of irradiation in excellent yield.
Plausible mechanism for the formation of products is provided. Synthetic utility of 1'H-
spiro[fluorene-9,2'-quinazolin]-4'(3'H)-one 3a has been demonstrated by synthesis of 1,4-di(1'H-
spiro[fluorene-9,2'-quinazolin]-4'(3'H)-one) buta-1,3-diyne 12, 1'-((1-benzyl-1H-1,2,3-triazol-4-
yl) methyl)-1'H-spiro[fluorene-9,2'-quinazolin]-4'(3'H)-one 13 and 1'-phenyl-1'H-spiro[fluorene-
9,2'-quinazolin]-4'(3'H)-one 14 under standard protocols.
Available online
Keywords:
Phosphotungstic acid
Quinazolinones
Aminoamides
Click chemistry
Eglinton coupling
Benzyne reaction
@ 2015 Elsevier Ltd. All rights reserved.
1. Introduction
as drug discovery, chemo-, regio- and stereo selective
synthesis and multistep reactions. Development of solvent
Heteropoly acids (HPAs) are heterogeneous green solid
acid catalyst extensively used in organic synthesis.1 The
advantages of HPAs catalysts are eco-friendly, easy to handle,
low toxicity and economical. Among the HPAs,
phosphotungstic acid (H3PW12O40) (HPW) with Keggin-type
structure stands out as an efficient catalyst due to its high
acidic strength2 and thermal stability.3 HPW has also been
proved as effective and versatile catalyst in many organic
reactions4 include Aldol reaction, aza-Diels-Alder reaction,
Beckman rearrangement, Claisen-Schmidt reaction, Friedel-
Crafts acylation, Fries rearrangement, Mannich reaction and
alcoholysis, oxidation and azidation of alcohols, dehydration
of carbohydrates, esterification and trans esterification
reactions. Particularly, the HPW has been employed as
catalyst in the synthesis of coumarins,5 naphthyridinones,6
pyridones7 and quinolones.8
free/solid-state10 green chemistry synthesis is current interest
of chemists due to environmental concerns.
Figure
1
Quinazolinone cores in natural products and
pharmaceuticals
Quinazolinones11 have been extensively used as antitumor,
antihypertensive, anticonvulsants, antiviral, antimicrobial,
antifungal, anti-inflammatory activity and a number of natural
products with quinazolinone backbone prone to exhibit
prominent bioactivities (Figure 1).12 Hence a number of
methods have been developed to synthesize quinazolinones
using transition metals such as copper,13 iridium,14
manganese,15 silver,16 vanadium17 and cyanuric chloride,18
Non-conventional chemical synthesis using microwave9
irradiation has been developed as a tool for one of the green
chemistry techniques. Microwave assisted organic reactions
have an advantage of exposure to specific thermal effects that
leads to the selective absorption of microwave energy and
hence speed up the reaction and higher yields. Microwave
method simplifies conventionally tedious research areas such

2
cationic amberlyst-15 resin,19 clays,20 PTSA,21 starch
7
1:1.2
1.2:1
1:1
HPW (50)
200W
200W
300W
300W
200W
200W
200W
200W
3
3
3
5
3
3
3
3
90
90
90
75
50
80
75
20
sulfate,22 and TFA23 were employed as catalysts. Recently, a
metal free synthesis of quinazolinone has been also reported.24
Despite having various methods to synthesize quinazolinones,
it is limitedly explored using green chemistry protocol and
thus prompted us to explore the prospect of HPW as a green
catalyst. Hence herein we report the HPW catalysed synthesis
of highly functionalized title compounds from various aryl
and heteroaryl amino amides under solvent-free microwave
irradiation.
8
HPW (50)
9
HPW (50)
10
11
12
13
14
1:1
HPW (50)
1:1
H3BO3(50)
MK-10(50)
CeraliteIR120 (50)
1:1
1:1
1:1
aAll the reactions were carried out on a CEM Discover 300 microwave
synthesiser under neat condition; bStandard mode, 50 psi, at 100 C;
cIsolated yield; Optimised condition.
d
Initially, a mixture of 1 equivalent of 2-amino benzamide
(1a) and 1 equivalent of 9H-fluoren-9-one (2a) and 50 w/w
HPW was microwave irradiated (100 Watts) for 2 minutes
afforded 1'H-spiro[fluorene-9,2'-quinazolin]-4'(3'H)-one (3a)
in 30% yield (table 1, entry1). Compound 3a was thoroughly
characterised by spectroscopic and XRD method (Figure 2).25
In order to compare the efficiency of other green acid
catalysts, experiments with boric acid, montmorillonite K10
clay and Ceralite IR 120 were carried out (Table 1, entries 11-
13). However, no comparable yields were obtained. The
reaction without any catalyst afforded only 20% of the
product indicated the necessity of the catalyst in the reaction.
Hence, conditions shown in entry 4 of table 1 were found to
be optimum.
Encouraged by the preliminary results and in order to
demonstrate the scope of the method, the reaction was
elaborated to a variety of aryl and heteroaryl amino amides
1a-e17 and ketones/aldehydes 2a-p (Table 2). The reaction
afforded title compounds 3a-n, 4a-h, 5a, 5b, 6a and 7a in
very good to excellent yields. The results are summarised in
Table 2.
Figure 2 ORTEP diagram of compound 3a (CCDC 1582823)25
Table 2 Scope of the reactiona, b
In order to optimize the reaction condition for the synthesis
of 3a, parameters such as microwave power and irradiation
time, mole ratio of reactants and percentage load of catalyst
were considered. Thus, a reaction of 1:1 ratio of compounds
1a and 2a and 50 W/W of HPA without any solvent was
microwave irradiated at 100 W for 4 min. afforded product 3a
only in 30% yield (Table 1, entry 2). Hence, repeating the
reaction with increased power level 200 W for one minute
afforded increased yield of (50%) 3a (Table 1, entry 3). The
reaction with 200 W PL for 3 minutes improved the yield
substantially to 90%(Table 1, entry 4). To optimise the
catalyst load, reactions with 20 w/w and 100 w/w percent
catalyst afforded 80% and 90% yield of 3a indicates lower
load of catalyst decreased the yield while higher load did not
alter the yield and hence 50 W/W catalyst load is optimum
(Table 1, entries 5 and 6). Increasing the microwave power
level and change of mole ratio of starting materials afforded
the desired product 3a in decreased or no improvement in the
yield (Table 1, entries 7-10).
Table 1 Optimization of synthesis of spiro compound 3aa, b
Entry Substrate
ratio
Catalyst
MW
Irradiation
Time
%
(% W/W)
power
Yield
3ac
30
1a:2a
(Watt) (min.)
1
2
3
4
5
6
1:1
1:1
1:1
1:1
1:1
1:1
HPW (50)
HPW (50)
HPW (50)
HPW (50)
HPW (20)
HPW (100)
100W
100W
200W
200W
200W
200W
2
4
1
3
3
3
30
50
90d
80
90

quinazolinones 3. The formation of N-substituted amino
amides can be explained based on analogy of imine-iminium
ion isomerization mechanism26 from the imine intermediate A
and iminium ion B under the influence of HPW-microwave
irradiation condition. The formation of iminium ion under
acidic condition is evident26 that subsequently undergoes
isomerization leads to the observed product. However, no
conclusive evidence is available for the mechanism of reduced
product formation and the mechanism discussed is tentative.
To substantiate the mechanistic proposal shown in scheme
1, under optimised conditions, reactions using o-
phenylenediamine 8 and aldehydes 2g and 2i afforded
corresponding reduced products 9a’and 9b’. Herein, the
mechanism for the reduced product formation is explained
invoking a dipole intermediate27d followed by hydride shift.
(Scheme 2).27 However, mono amino compound such as
aniline failed to provide reduced product and imine only
isolated.
______________________________________________________________________________
aAll the reactions were carried out on a CEM Discover 300 microwave
synthesiser under neat condition; bStandard mode, 200 W, 50 psi, 100 C
c
for 3 min; Compound 4d was isolated as trace along with starting amino
e
amide impurity; Increased power (300 W) and extended irradiation time
(15 min.) resulted charred material.
It should be noted that in the case of reactions of biphenyl
and flourene aldehydes 2g, 2i, 2j with amino amides 1a and
1b, along with minor cyclised derivatives, an open chain
major products 3g', 3i', 3j', 4d' and 4f' were observed as main
products. It has been observed that amine substituted products
formed rather than amide substituted products as evidenced
from 13C NMR chemical shift value of amide carbonyl at
 171.7. Accordingly, no change of chemical shift was
observed for amide carbonyl in the isolated product and hence
confirmed amine substituted products. Under optimised
condition, 2-amino-9-flourenone 2o and deactivated Boc
protected 2-amino-9-flourenone 2p was found to be
unsuccessful with amides 1a-d. In order to show reactivity
and diversity of the reactions, amino amides such as 3-
aminobenzofuran-2-carboxamide 1d (position of amine and
amide reverted) and 2-amino pyridine-3-carboxamide 1e with
ketone 2a was examined and the reaction afforded 1H-
spiro[benzofuro[3,2-d] pyrimidine-2,9'-fluoren]-4(3H)-one 6a
and 1'H-spiro[fluorene-9,2'-pyrido[2,3-d]pyrimidin]-4'(3'H)-
one 7a. However, the reaction afforded lower yield of
products upon irradiating with higher power level (250 W)
and duration (10 min.). Further, reaction of 1c with ketone 2a
Scheme 2 Reaction of 2g and 2i with o-phenylenediamine 8
The effectiveness of this methodology was further
scrutinized by a gram scale synthesis of 3a under optimized
reaction condition without notable decrease in the yield
(80 %) (Scheme 3).
Scheme 3 Gram scale synthesis of 3a
afforded
1'H-spiro[fluorene-9,2'-thieno[3,2-d]pyrimidin]-4'
The nature of structural and diversity of the products
obtained prompted us to examine the synthetic utility of the
synthesised quinazolinones, firstly N-alkylation was
considered. Thus, reaction between 3a and propargyl bromide
10a in ACN under the influence of K2CO3 afforded mono
alkylated product 11a in only 10% yield. However, change of
base to NaH and solvent DMF afforded an optimum yield of
11a in 90% yield (Table 3. Entry 4). To our dismay, di
alkylation of 3a was not observed with excess of alkylating
agent, base and prolonged reaction times. Similarly, synthesis
of compounds 11b-c were achieved from the reaction between
3a and alkyl halides 10b and 10c, respectively (Scheme 4).
(3'H)-one 5a and with ferrocene carboxaldehydes 2h an open
chain product 5b was observed as a single product.
To explain the diverse product formation, a plausible
mechanism for the formation of spiro-, cyclised and open
chain products are discussed in Scheme 1.
Table 3 Optimization of synthesis of 11a
Entry
Solvent
CH3CN
CH3CN
DMF
Basea
K2CO3
Et3N
Time (h)
% Yield of 9ab
1
2
3
4
5
24
24
24
1
10
25
50
90
65
Scheme 1 Plausible mechanism for the formation of spiro- and
cyclized quinazolinones and 2-methyl amino benzamide
CaH2
NaH
NaH
DMF
The spiro and cyclised quinazolinone formation may be
explained as under the influence of HPW, initial formation an
THF
1
a2.5 equiv. of base was used in all the reactions, change of equivalents
did not alter the observed product formation and yield; bIsolated yield
imine
intermediate
from
anthranilamide
1
with
ketone/aldehyde 2 subsequently undergoes nucleophilic attack
by the amide nitrogen to yield corresponding spiro or cyclised

4
mechanism for the formation of products is provided.
Synthetic utility of 1'H-spiro[fluorene-9,2'-quinazolin]-
4'(3'H)-one 3a has been demonstrated by synthesis of highly
functionalized heterocycles such as 1,4-di(1'H-spiro[fluorene-
9,2'-quinazolin]-4'(3'H)-one) buta-1,3-diyne 12, 1'-((1-benzyl-
1H-1,2,3-triazol-4-yl)
methyl)-1'H-spiro[fluorene-9,2'-
quinazolin]-4' (3'H)-one 13 and 1'-phenyl-1'H-spiro[fluorene-
9,2'-quinazolin]-4'(3'H)-one 14 under standard reaction
protocols.
Funding Information
Scheme 4 N-alkylation of 3a by propargyl bromide 10a, methyl
iodide 10b and 1, 10-dibromodecane 10c
M. N. thanks UGC (New Delhi) for the award of RGNF. PS
thanks financial supports from the DST (New Delhi) vide
Grant No. SB/EMEQ-044/2014.
Further, the spiro derivative 11a was explored synthetically
through Eglinton28coupling afforded structurally unique 1,3-
diyne derivative 12 in 80% yield and Click29 reaction afforded
triazole derivative 13 in 75% yield (Scheme 5).
Acknowledgment
P.S. thanks the Director, CSIR-CLRI and S. K. thanks the
Chancellor, VIT-Vellore for providing infrastructure facilities
Supplementary Material
Supplementary data (detailed experimental procedure,
characterization of the products and copies of spectra are
provided) associated with this article can be found, in the
online version.
References and Notes
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Scheme 5 Synthetic transformation of 11a to 1,3-diyne derivative
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Scheme 7 Mechanism for the formation of compound 14
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6
Highlights
 Spiro-quinazolinones were synthesized
using phosphotungstic acid (HPW) as
catalyst.
 The method is optimized under HPW
catalyst, neat and microwave irradiation.
 The catalytic efficiency of HPW was
compared with Mont. K10 clay and boric
acid.
 The scope of the reaction is demonstrated.
 Tentative mechanism and synthetic utility
has been demonstrated.

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Phosphotungstic Acid Mediated, Microwave Assisted Leave this area blank for abstract info.
Solvent-Free Green Synthesis of Highly Functionalized
2ˈ-Spiro and 2, 3-dihydro Quinazolinone and
2-Methylamino benzamide Derivatives from Aryl and Heteroaryl 2-Amino amides
Motakatla Novannaa, Sathananthan Kannadasana* and Ponnusamy Shanmugamb*