KOH/DMSO: A basic suspension for transition metal-free Tandem synthesis of 2,3-dihydroquinazolin-4(1H)-ones

Article abstract of DOI:10.1016/j.tetlet.2019.05.030

A novel protocol for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones from 2-aminobenzamides and aldehyde derivatives catalyzed by KOH/DMSO suspension has been developed. The present transition metal free methodology is operationally simple, scalable and varieties of 2,3-dihydroquinazolin-4(1H)-one derivatives were obtained in good to excellent yields in short reaction times.

Full text of DOI:10.1016/j.tetlet.2019.05.030

Accepted Manuscript
KOH/DMSO: A Basic Suspension for Transition Metal-Free Tandem Synthesis
of 2,3-Dihydroquinazolin-4(1H)-ones
Apurba Dutta, Krishnaiah Damarla, Ankur Bordoloi, Arvind Kumar, Diganta
Sarma
PII:
S0040-4039(19)30477-0
https://doi.org/10.1016/j.tetlet.2019.05.030
TETL 50802
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 March 2019
15 May 2019
17 May 2019
Please cite this article as: Dutta, A., Damarla, K., Bordoloi, A., Kumar, A., Sarma, D., KOH/DMSO: A Basic
Suspension for Transition Metal-Free Tandem Synthesis of 2,3-Dihydroquinazolin-4(1H)-ones, Tetrahedron
Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.05.030
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KOH/DMSO: A Basic Suspension for
Transition Metal-Free Tandem Synthesis of
2,3-Dihydroquinazolin-4(1H)-ones
Leave this area blank for abstract info.
Apurba Duttaa, Krishnaiah Damarlab, Ankur
Bordoloic, Arvind Kumarb and Diganta Sarma*a
# Transition metal free catalys
# Mild reaction conditions
Me2SO
KOH
Basic Suspension
R= Aryl, Heteroaryl
Up to 99% yield
22 examples
O
O
O
NH2
NH2
R
H
NH
N
R
H

1
Tetrahedron Letters
journal homepage: www.elsevier.com
KOH/DMSO: A Basic Suspension for Transition Metal-Free Tandem Synthesis of
2,3-Dihydroquinazolin-4(1H)-ones
Apurba Duttaa, Krishnaiah Damarlab, Ankur Bordoloic, Arvind Kumarb and Diganta Sarma*a
a Department of Chemistry, Dibrugarh University, Dibrugarh-786004, Assam, India E-mail: dsarma@dibru.ac.in.
b AcSIR, Salt and Marine Chemicals Division, CSIR-Central Salt and Marine Chemicals Research Institute, Bhavnagar 364002, India.
cNano catalysis, Catalytic Conversion and Process Division, CSIR-Indian Institute of Petroleum, Mohkampur, Dehradun-248005
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A
novel protocol for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones from 2-
aminobenzamides and aldehyde derivatives catalyzed by KOH/DMSO suspension has been
developed. The present transition metal free methodology is operationally simple, scalable and
varieties of 2,3-dihydroquinazolin-4(1H)-one derivatives were obtained in good to excellent
yields in short reaction times.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Base
Metal free
Scalable
Tandem synthesis
Introduction
metal based catalysts such as sulfamic acid,15 zirconium
chloride,16 Sc(OTf)3,17 NH4Cl,18 p-TsOH,19 CuCl2,20 and
In the last few decades, synthesis of valuable organic
molecules by using principles of green chemistry has become
more demanding and interesting for organic chemists. Reactions
which proceed via green reaction medium in the absence of
expensive reagents and hazardous chemicals as well as produce
minimum waste are considered as ideal reactions.1 In organic
synthesis, transition metal free protocols are considered as more
economical than metal mediated reactions as the latter has many
disadvantages such as high cost of metal catalysts, possibility of
metal contamination in final products etc. Hence, an enormous
number2 of transition metal-free approaches have been developed
over the past decades and chemists are now focusing on this area
to develop more advantageous methods than the existing ones.
[Bmim]PF6.21 Although these methods are very useful but some
of them have limitations such as harsh reaction conditions, use of
expensive reagents, long reaction time and tedious work-up
procedures. Literature revealed that this reaction is mainly carried
out in presence of acid catalyst but in 2014, O. Obaiah et al.
developed
a
methodology for the synthesis of 2,3-
dihydroquinazolin-4(1H)-ones using basic ionic liquid22 as a
catalyst. To the best of our knowledge, this is the only report of
base catalyzed quinazolinone synthesis from 2-aminobenzamide
and carbonyl compounds. Therefore, developing new basic
catalytic systems for the synthesis of 2,3-dihydroquinazolin-
4(1H)-ones from 2-aminobenzamide and carbonyls is expected to
gain a lot of interest among scientific community.
Nitrogen containing heterocycles are found in a plethora of
biological active molecules including natural products. Among
the N-containing heterocyclic molecules quinazolinone scaffold
is a core element of many pharmaceutically active compounds.
Many quinazolinone motifs possess broad range of biological and
therapeutic activities such as antimalarial,3 anticancer,4
antitumor,5 antitubercular,6 anti-HIV,7 anti-inflammatory,8
antiviral,9 antihypertensive,10 and anticonvulsant.11 Therefore,
tremendous efforts have been projected to discover simple and
direct approaches towards the synthesis of quinazolinone
nucleus. There are many approaches available for the synthesis of
these biologically essential quinazolinones,12-14 among them one
of the most popular methods is the cyclocondensation of 2-
aminobenzamide with carbonyl analogues. Recently different
strategies were developed for the synthesis of quinazolinones by
employing different types of acid catalysts as well as transition
O
N
O
O
O
O
NH
N
HO
O
N
S
O
O
N
N
NH
N
O
OH
NH2
Doxazosin
Raltitrexed
O
N
F
O
O
H2N
N
HN
N
Cl
O
S
O
N
N
O
O
O
O
O
NH
N
N
Cl
N
H
NH2
Prazosin
Fenquizone
Gefitinib
Figure 1: Quinazoline containing drug molecules.

2
Tetrahedron Letters
Herein, we have described the results of our systematic study
5
CuNPs/NC
KOH (1 mmol)
DMSO
30 min
99
(20)
to elaborate
a practical and scalable synthesis of 2,3-
Effect of Basic Catalyst
dihydroquinazolin-4(1H)-ones using KOH/DMSO suspension at
room temperature.
6
7
8
9
-
-
-
-
-
-
-
-
-
KOH (1 mmol)
NaOH (1 mmol)
K2CO3 (1 mmol)
Cs2CO3 (1 mmol)
ESP (20 mg)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
-
30 min
99
75
00
70
00
00
00
10
20
Results and discussion
30 min
Our aim was to show the versatile catalysis of our previously
reported CuNPs/NC catalyst23 in 2,3-dihydroquinazolin-4(1H)-
ones synthesis since literature revealed that synthesis of 2,3-
dihydroquinazolin-4(1H)-ones proceeds faster in the presence of
copper source as catalyst. Therefore, we initially performed the
reaction in the presence of CuNPs/NC catalyst taking 2-
aminobenzamide and 4-chlorobenzaldehyde as model substrate.
The reaction was carried out at room temperature in different
solvents but after 24 hours only a trace amount of product was
obtained when DMSO was chosen as solvent (Table 1, entry 1).
Then we carried out the same reaction in presence of different
types of bases (Table 1, entries 2-5). To our delight the yield of
the product was maximum in presence of KOH along with
copper catalyst which gives quantitative yields of product within
30 minutes (Table 1, entry 5). To justify the role of copper, we
performed a reaction without using copper catalyst; unexpectedly
we observed that our desired product was obtained within 30
minutes with 99% yields of product (Table 1, entry 6). This
accidental finding encouraged us to proceed further without
copper catalyst. Then we screened different types of inorganic
bases and among them Cs2CO3 and NaOH give good yields of
products but Cs2CO3 takes longer period of times and NaOH
gives slightly lower yields of product than KOH. We also
screened some organic bases, ionic liquids as well as some basic
water extract of waste materials but no one gave better results
than KOH. After choosing the best base KOH, different types of
solvents were used to check the solvent effects. Water miscible
solvents like DMSO, DMF and DMA (dimethyl acetamide) give
higher yields of product in short reaction time. We have also
performed the reaction in presence of water but it takes longer
times for higher yields of product. Among the solvents we have
screened, DMSO was found to the best in terms of product yields
and reaction time (Table 1, entry 6). Further to optimized the
amounts of KOH different molar solutions of KOH in water were
prepared and 2 mL of those solutions were used for the reaction
along with DMSO as solvent and it was found that 0.2 M KOH
solution (Table 1, entry 23) gives same result as obtained with
using 1 mmol of KOH.
30 min
7
10
10
3
10c
11d
12
WEB (2 ml)
[OMIM]OH (2 ml)
DABCO (1 mmol)
Et3N (1 mmol)
13
DMSO
DMSO
3
14
3
Effect of Solvent
15e
16
17
18
19
-
-
-
-
-
KOH (1 mmol)
KOH (1 mmol)
KOH (1 mmol)
KOH (1 mmol)
KOH (1 mmol)
EG
3
10
45
50
50
85
90
EtOH
H2O
3
DMF
DMA
20 min
20 min
Effect of Concentration of KOH
20
21
22
23
-
-
-
-
KOH (0.01M)
KOH (0.01M)
KOH (0.1M)
-
30 min
30 min
30 min
30 min
10
25
85
95
DMSO
DMSO
DMSO
KOH (0.2M,
0.4 mmol)
24
25
26
-
-
-
KOH (0.2M)
KOH (0.2M)
KOH (0.3M)
DMF
DMA
30 min
30 min
30 min
30
75
95
DMSO
aReaction conditions: 2-Aminobezamide (1 mmol), 4-
chlorobenzaldehyde (1.2 mmol) and others stated in the table
were stirred at room temperature.
bIsolated yield.
cESP: Egg shell powder.
dWEB: Water extract of banana.
eEG: Ethylene glycol.
Table 1 Optimization of the reaction conditionsa
Encouraged by these results, various 2,3-dihydroquinazolin-
4(1H)-ones were synthesized by using KOH/DMSO basic
medium to investigate the scope and generality of our catalytic
system. As shown in Table 2, all the aldehydes examined
provided good to excellent yields of products. It was found that
the aldehydes containing halides as substituent react faster with
2-aminobenzamide and give the corresponding 2,3-
dihydroquinazolin-4(1H)-ones within very short reaction time
(Table 2, entries 1,4-10,19,20). Heterocylic aldehydes were also
condensed with 2-aminobenzamide successfully and the
corresponding 2,3-dihydroquinazolin-4(1H)-ones were obtained
in good yields at short reaction times (Table 2, entries 17,18).
O
O
CHO
Cl
Catalyst
NH2
NH
Solvent, r.t.
NH2
N
H
Cl
Entry
Catalyst
(mg)
Base
Solvent
Time
(h)
Yieldb
(%)
Effect of Catalyst
DMSO
1
CuNPs/NC
(20)
-
24
20
Table 2 Synthesis of 2,3-dihydroquinazolin-4(1H)-onesa
O
O
2
3
4
CuNPs/NC
(20)
CuNPs/NC
(20)
CuNPs/NC
(20)
K2CO3 (1 mmol)
Ca2CO3 (1 mmol)
Cs2CO3 (1 mmol)
DMSO
DMSO
DMSO
24
24
9
30
30
90
0.2 M aq. KOH (2 mL)
DMSO (1 mL), r.t.
NH2
NH2
NH
R1
R1CHO
R
R
N
H

3
O
Yieldb
(%)
CHO
CN
Time
(min)
Entry
R
Aldehydes
Products
NH
O
16
17
18
H
H
H
15
180
35
95
80
95
O
CHO
N
H
NH
CN
1
H
30
95
90
N
H
O
NH
Cl
Cl
O
O
CHO
CHO
N
H
NH
O
O
2
H
120
N
CHO
N
H
NH
CH3
CHO
CH3
N
N
H
NH
O
CHO
3
4
5
H
H
H
120
15
85
99
97
Cl
N
H
NH Cl
19
20
H
H
60
60
80
95
N
H
O
Cl
CHO
CHO
Cl
Cl
NH Cl
O
N
H
NH Cl
F
Cl
N
H
O
CHO
F
O
NH
15
O
N
H
NH
21
22
H
H
180
180
NR
NR
H
H
Br
Br
Br
N
H
O
O
CHO
O
NH
NH
6
7
8
9
H
H
H
H
10
10
15
15
98
99
96
95
H3C
H
N
H
N
H
CH3
Br
O
O
CHO
CHO
Br
NH
NH
180,
90
45,
90c
NH Br
23
Cl
Cl
Cl
N
H
N
H
O
O
CHO
CHO
Cl
NH
120,
45
50,
95c
24
Cl
N
H
N
H
Cl
F
F
F
O
CHO
aReaction conditions: 2-Aminobezamides (1 mmol),
substituted aldehydes (1.2 mmol), 0.2 M aq. KOH (2 mL, 0.4
mmol) in DMSO (1 mL) was stirred at room temperature. NR:
No reaction
NH
N
H
F
O
CHO
F
NH
F
bIsolated Yield.
10
H
15
93
cKOH (0.4 mmol) in DMSO (1 mL) at room temperature.
N
H
O
To demonstrate the synthetic utility of this protocol, three
gram-scale reactions were carried out by using the substrates 1a
(1.36 g, 10 mmol) with 1b (1.69 g, 12 mmol), 1a (2.72 g, 20
mmol) with 1b (3.37 g, 24 mmol) and 1a (4.08 g, 30 mmol) with
1b (5.06 g, 36 mmol) under the standard reaction conditions. As
per our expectation, reactions give the corresponding product 2a
in good yields (75%, 70% and 63% isolated yields respectively).
The graphical representations of the results are shown in Scheme
1.
CHO
NH NO2
NO2
11
12
H
H
30
90
95
90
N
H
O
CHO
NH
NO2
N
H
NO2
CHO
O
NH
O
13
H
45
90
O
O
CHO
N
H
0.2 M aq. KOH (2 mL)
DMSO (1 mL), r.t.
NH2
NH2
NO2
NH
NO2
N
H
S
Cl
NH
Cl
14
15
H
H
60
30
95
95
S
1a
1b
2a
CHO
N
H
O
NH
CHO
N
H

4
Tetrahedron Letters
2.
(a) Sun, C. L.; Shi, Z. J. Chem. Rev., 2014, 114, 9219. (b) Allais,
C.; Grassot, J. M.; Rodriguez, J.; Constantieux, T. Chem. Rev.,
2014, 114, 10829. (c) Roscales, S.; Csaky, A. G. Chem. Soc. Rev.,
2014, 43, 8215.
1a
3.
McLaughlin, N. P.; Evans, P.; Pines, M. Bioorg. Med. Chem.,
2014, 22, 1993.
4.
5.
Shetha, A.; Wijdan, I. A. J. Chem. Pharma. Res., 2013, 5, 42.
Foster, B. A.; Coffrey, H. A.; Morin, M. J.; Rastinejad, F. Science,
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7.
8.
Abid, O. H.; Ahmed, A. H. J. Appl. Nat. Sci., 2013, 2, 11.
Pati, B.; Banerjee, S. J. Adv. Pharm. Edu. Res., 2013, 3, 136.
Saravanan, G.; Pannerselvam, P.; Prakash, C. R. Der Pharmacia
Lett., 2010, 2, 216.
0.2 M aq. KOH (20 ml)
DMSO (10 ml), 30 min
0.2 M aq. KOH (40 ml)
DMSO (20 ml), 30 min
0.2 M aq. KOH (60 ml)
DMSO (30 ml), 30 min
9.
Krishnan, S. K.; Ganguly, S.; Veerasamy, R.; Jan, B. Eur. Rev.
Med. Pharmacol. Sci., 2011, 15, 673.
10. Chern, J.; Tao, P.; Wang, K.; Gutcait, A.; Liu, S.; Yen, M.; Chien,
S.; Rong, J. J. Med. Chem., 1998, 41, 3128.
Scheme 1: Gram scale synthesis
11. Patel, N. B.; Patel, V. N.; Patel, H. R.; Shaikh, F. M.; Patel, J. C.
Acta Pol. Pharma.: Drug Research, 2010, 67, 267.
12. (a) Moore, J. A.; Sutherland, G. J.; Sowerby, R.; Kelly, E. G.;
Palermo S.; Webster, W. J. Org. Chem., 1969, 34, 887; (b) Cai, G.
P.; Xu, X. L.; Li, Z. F.; Weber, W. P.; Lu, P. J. Heterocycl. Chem.,
2002, 39, 1271; (c) Connolly, D. J.; Cusack, D.; O’sullivan T. P.;
Guiry, P. J. Tetrahedron, 2005, 61, 10153.
13. (a) Shi, D. Q.; Rong, L. C.; Wang, J. X.; Wang, X. S.; Tu, S. J.;
Hu, H. W. Chem. J. Chin. Univ., 2004, 25, 2051; (b); (c) Shi, D.
Q.; Rong, L. C.; Wang, J. X.; Zhuang, Q. Y.; Wang X. S.; Hu, H.
W. Tetrahedron Lett., 2003, 44, 3199; (c) Shi, D. Q.; Shi, C. L.;
Wang, J. X.; Rong, L. C.; Zhuang Q. Y.; Wang, X. S. J.
Heterocycl. Chem., 2005, 40, 173.
14. (a) Dabiri, M.; Salehi, P.; Otokesh, S.; Baghbanzadeh, M.;
Kozehgarya G.; Mohammadi, A. A. Tetrahedron Lett., 2005, 46,
6123; (b) Salehi, P.; Dabiri, M.; Zolfigol M. A.; Baghbanzadeh,
M. Synlett, 2005, 1155; (c) Baghbanzadeh, M.; Salehi, P.; Dabiri
M.; Kozehgarya, G. Synlett, 2006, 344.
15. Rostami, A.; Ashkan Tavakoli, A. Chin. Chem. Lett., 2011, 22
1317.
16. Abdollahi-Alibeik, M.; Shabani, E. Chin. Chem. Lett., 2011, 22,
1163.
Plausible mechanism of the reaction:
Based on the above results, a plausible reaction mechanism
has been proposed for this protocol (Scheme 2). The reaction was
initiated with the formation of Schiff base intermediate between
aldehyde and 2-aminobezamide in the presence of KOH/DMSO
suspension. Then delocalisaztion of the lone-pair on nitrogen
atom to the elctrophilic carbon atom followed by the abstraction
of the proton by the hydroxide ion of the KOH/DMSO
suspension resulted in the formation of cyclized product with a
negative centre on nitrogen atom. Finally, protonation takes place
from the water molecule which was released in the previous step
and give the desired 2,3-dihydroquinazolin-4(1H)-one.
OH
H
O
N
O
O
O
N
NH
R
H
NH2
NH2
NH2
R
R
17. Chen, J. X.; Wu, H. Y.; Su, W. K. Chin. Chem. Lett., 2007, 18,
536.
18. Shaabani, A.; Maleki, A.; Mofakham, H. Synth. Commun., 2008,
38, 3751.
(KOH DMSO)
H2O
19. Cheng, R.; Guo, T.; Zhang-Negrerie, D.; Du, Y.; Zhao, K.
Synthesis, 2013, 45, 2998.
20. Abdel-Jalil, R. J.; Voelter, W.; Saeed, M. Tetrahedron Lett., 45,
2004, 3475.
21. Chen, J.; Su, W.; Wu, H.; Liu, M.; Jin, C. Green Chem., 2007, 9,
972.
22. Obaiah, O.; Kebbahalli, N. N.; Goravanahalli, R. M.;
Chottanahalli, P. S.; Kanchugarakoppal, R. S.; Kempegowda, M.
Eur. J. Chem., 2014, 5, 671.
O
O
H2O
OH
NH
NH
N
R
N
H
R
Scheme 2: Plausible reaction mechanism
Conclusion
In summary, we have succeeded in developing a simple and
eco-friendly methodology for synthesis of 2,3-dihydroquinazolin-
4(1H)-ones catalyzed by KOH/DMSO suspension at room
temperature. With the ease of procedure, the use of easily
accessible and inexpensive substrates, short reaction times and
utility for the synthesis of a wide range of derivatives made this
protocol very attractive. We believe that this greener and cost
effective process finds application in the synthesis of
quinazolinone containing pharmaceutical compounds.
23. Dutta, A.; Chetia, M.; Ali, A. A.; Bordoloi, A.; Gehlot, P. S.;
Kumar, A.; Sarma, D. Catal. Lett., 2019, 149, 141.
24. Typical experimental procedure: 2-Aminobezamides (1 mmol)
and substituted aldehyde (1.2 mmol) and 0.2 M solution of KOH
in water (2 mL) in DMSO (1 mL) were stirred at room
temperature. The progress of the reaction was monitored by TLC
under UV light. After completion of the reaction the mixture was
extracted with ethyl acetate (3 x 10 mL) and washed with water (3
x 10 mL). The combined extract was dried over anhydrous
Na2SO4. The filtrate was concentrated under reduced pressure. The
product was purified by column chromatography over silica gel
using n-hexane/ethyl acetate (3:1 v/v) as eluent to get the purified
product. The products were then characterized by ESI-MS, 1H
NMR and 13C NMR spectra.
Acknowledgments
DS is thankful to DBT, New Delhi, India for a research grant [No.
BT/PR24684/NER/95/810/2017]. AD thanks DBT, New Delhi for
Research Fellowship. The financial assistance of UGC-SAP
programme to the Department of Chemistry, Dibrugarh University is
also gratefully acknowledged.
Supplementary Material
1
General Information, Experimental and Analytical data, H
and 13C NMR spectra and characterisation data of all the
synthesised compounds are available as Supplementary
Information
References and notes
1.
Sheldon, R. A.; Arends, I.; Hanefeld, U. Green Chemistry and
Catalysis; Wiley-VCH: Weinheim, Germany, 2007.

5
KOH/DMSO: A Basic Suspension for
Transition Metal-Free Tandem Synthesis
of 2,3-Dihydroquinazolin-4(1H)-ones
Apurba Dutta,a Krishnaiah Damarla,b Ankur
Bordoloic Arvind Kumarb and Diganta Sarma*a
aDepartment of Chemistry, Dibrugarh University,
Dibrugarh-786004, Assam, India,
E-mail: dsarma22@gmail.com
bAcademy of Scientific and Innovative Research
(AcSIR)-Central Salt and Marine Chemicals
Research Institute Council of Scientific and
Industrial Research (CSIR) G. B. Marg,
Bhavnagar, 364002, Gujarat, India
cNano catalysis, Catalytic Conversion and Process
Division, CSIR-Indian Institute of Petroleum,
Mohkampur, Dehradun-248005
# Transition metal free catalys
# Mild reaction conditions
Me2SO
KOH
Basic Suspension
R= Aryl, Heteroaryl
Up to 99% yield
22 examples
O
O
O
NH2
NH2
R
H
NH
N
R
H
Highlights:
 Transition metal free catalyst is the major
advantage of the present strategy.
 Synthesis of 2,3-dihydroquinazolin-4(1H)-
ones using basic suspension as catalyst.
 Scalable synthesis of the method is
important from industrial perspective.
 Broad substrate scope of products with good
to excellent yields.