Base mediated spirocyclization of quinazoline: One-step synthesis of spiro-isoindolinone dihydroquinazolinones

Article abstract of DOI:10.1039/c9ra09567e

A novel approach for the spiro-isoindolinone dihydroquinazolinones has been demonstrated from 2-aminobenzamide and 2-cyanomethyl benzoate in the presence of KHMDS as a base to get moderate yields. The reaction has been screened in various bases followed by solvents and a gram scale reaction has also been executed under the given conditions. Based on the controlled experiments a plausible reaction mechanism has been proposed. Further the substrate scope of this reaction has also been studied.

Full text of DOI:10.1039/c9ra09567e

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Base mediated spirocyclization of quinazoline:
one-step synthesis of spiro-isoindolinone
dihydroquinazolinones†
Cite this: RSC Adv., 2020, 10, 9486
Rapolu Venkateshwarlu,ab V. Narayana Murthy,a Krishnaji Tadiparthi,c
Satish P. Nikumbh,a Rajesh Jinkala,a Vidavalur Siddaiah,b M. V. Madhu babu,a
a
Hindupur Rama Mohana and Akula Raghunadh
*
A novel approach for the spiro-isoindolinone dihydroquinazolinones has been demonstrated from 2-
aminobenzamide and 2-cyanomethyl benzoate in the presence of KHMDS as a base to get moderate
yields. The reaction has been screened in various bases followed by solvents and a gram scale reaction
has also been executed under the given conditions. Based on the controlled experiments a plausible
reaction mechanism has been proposed. Further the substrate scope of this reaction has also been studied.
Received 24th November 2019
Accepted 19th February 2020
DOI: 10.1039/c9ra09567e
rsc.li/rsc-advances
Because of their strong potent biologically activity, heterocyclic reactions, electrophilic and radical cyclization, metal-catalysed
compounds have been a constant source of inspiration for the reactions and various electrochemical procedures.6
invention of new drugs especially for pharmaceutical and agro
Previously, a number of metal catalyzed reactions have also
chemical industries.1 Indeed, investigation of novel methods been reported for the spiroannulations.7 Among all, Nishimura
for the synthesis of various natural products and heterocycles et al. developed an Ir(I) catalyzed [3 + 2] annulation of benzo-
has always been a challenging task in modern organic chem- sultam and N-acylketimines with 1,3-dienes via C–H activation
istry. Amid all, spiro based scaffolds have been found to be very for the synthesis of aminocyclopentene derivatives. Further,
interesting because of their structural diversity. In spite of their Xingwei Li et al. developed a Rh(III)-catalysed [3 + 2] annulation
intrinsic structures and immense biological activity there is of cyclic N-sulfonyl or N-acyl ketimines with activated alkenes
a tremendous demand for the chemistry of spiro-isoindolinone for the preparation of various spirocyclic compounds.8 Recently
dihydroquinazolinones.2 Indeed, nitrogen containing hetero- Yangmin Ma et al. developed a one pot nano cerium oxide
cyclic compounds like spiro-oxindole, spiro-isoindoline, spiro- catalyzed synthesis of spiro-oxindole dihydroquinazolinone
isoindolinone are playing a signicant role in medicinal derivatives (Scheme 1).5c However, development of these type of
chemistry and synthetic transformations.3 Moreover these novel compounds is always challenging and more attractive.
compounds present in many natural products as a core unit like Indeed, to the best of our knowledge there are no reports for the
Lennoxamine, Zopiclone, Taliscanine and Pazinaclone (Fig. 1). synthesis of spiro-isoindolinone dihydroquinazolinones. This
In addition, many unnatural spiro-isoindolinones show signif- led us to give more attention to study these compounds.
icant biological activities acting as anti HIV-1, antiviral, anti-
In continuation of our earlier efforts9 for the synthesis of
leukemic, anesthetic and antihypertensive agents.4,5 Notably, various dihydroquinazolinones, herein we would like to report
the spiro-isoindolinone dihydroquinazolinone unit has been KHMDS mediated synthesis of novel spiro-isoindolinone dihy-
found to be a combination of two potent pharmacophore units droquinazolinones. We envisioned the retro synthetic pathway
of dihydroquinazolinone and spiro-isoindolinone. Inspite of for these compounds, as depicted in Scheme 2. Accordingly
their remarkable biological activity afore mentioned, various these compounds could be synthesised from 2-amino-
methods have been developed for their synthesis like lithiation benzamide
and
methyl-2-cyanobenzoate
or
ethyl-2-
approaches, base mediated protocols, Diels–Alder and Wittig cyanobenzoate.
Indeed, in order to understand the reaction conditions, we
have commenced the reaction by taking 2-amino-N-hexyl-
benzamide (2) and methyl-2-cyanobenzoate (3) as a model
substrates. However, in the initial phase of reaction optimisa-
tion, we have screened the reaction in different bases (Fig. 2)
and to our delight amongst all the bases KHMDS, LiHMDS and
NaHMDS were amenable to get moderate yields. However the
reaction had not progressed at low temperatures (5 ꢀC) and
aTechnology Development Centre, Custom Pharmaceutical Services, Dr. Reddy's
Laboratories Ltd., Hyderabad 500049, India
bDepartment of Organic Chemistry and FDW, Andhra University, Visakhapatnam
530045, India. E-mail: raghunadha@drreddys.com
cDepartment of Chemistry, CHRIST (Deemed to be University), Hosur Road, Bengaluru
560029, India
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra09567e
9486 | RSC Adv., 2020, 10, 9486–9491
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
Fig. 1 Some biologically active spiro-isoindolinone and quinazolinone units.
could improve the yield at room temperature. Moreover the Incontinuation, the reaction was futile when the reaction was
reaction underwent complete conversion with 1.5 equivalents of carried out in DIPEA, DBU, K2CO3 and Cs2CO3. Subsequently,
t
base. Further, the reaction was also executed with ethyl-2- the reaction in NaOMe and BuOK produced exclusively the
cyanobenzoate and could replicate the same yield. hydrolysis product (4) of methyl-2-cyanobenzoate (Table 1). To
Scheme 1 Different strategies for the synthesis of quinazolinone units.
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 9486–9491 | 9487

View Article Online
RSC Advances
Paper
Scheme 2 Retro synthetic approach for the synthesis of quinazolinone unit.
Fig. 3 Solvent screening in the presence of KHMDS.
Fig. 2 Base screening in 1,4-dioxane.
circumvent this problem the reaction has also been screened in
various solvents.
Gratifyingly, among all the solvents 1,4-dioxane, THF and
1,2-dimethoxyethane were found to get good to moderate yields.
Whereas, other solvents like DCM ended up with non-polar
spots where as in toluene unknown polar impurity was
observed. However, there is no reaction progress observed in
Table 1 Optimisation of the base-mediated spiroannulationa
Entry
Base
Solvent
1jb (%)
Cyano benzoic acid (4)(%)
1
2
3
4
5
6
7
KHMDS
NaHMDS
NaOMe
tBuOK
KHMDS
KHMDS
LiHMDS
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
THF
60
58
—
—
40
60
55
4
3
60
60
5
1,2-DME
1,4-Dioxane
5
5
a
Reaction conditions: KHMDS (1 M, 1.5 mmol), 2-amino-benzamide (1 mmol) and methyl-2-cyanobenzoate (1.5 mmol) in 1,4-dioxane (10 mL).
Isolated yield.
b
9488 | RSC Adv., 2020, 10, 9486–9491
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
Table 2 Substrate scope of the reactiona
a
Reaction conditions: KHMDS (1 M, 1.5 mmol), 2-amino-benzamide (1 mmol) and methyl/ethyl-2-cyanobenzoate (1.5 mmol) in 1,4-dioxane (10
mL).
the presence of triuoroacetic acid as well as in BF3$Et2O as predicted (Scheme 3). Indeed, to gain insight into the mecha-
a solvent (Fig. 3). nism a series of control experiments have been executed under
With the optimized conditions in hand, we have explored the the similar reaction conditions. Initially the reaction has been
applicability of our reaction with various substrates by taking carried out without base and both the starting materials were
various groups like alkyl, cyclopropyl, cyclohexyl, cycloheptyl, intact. Further the reaction without 2-aminobenzamide resulted
benzyl, naphthyl, furan and to our delight all the substrates hydrolysis product. To explore further, the reaction has also
were well tolerated under the aforementioned optimal condi- been executed on a 10 gram-scale for the synthesis of 1j and has
tions (Table 2). The only limitation of this reaction is successfully been demonstrated under the aforementioned
substituted cyanobenzoate.
optimized conditions.
Based on the aforementioned studies and the literature
The Scheme 3 describes a plausible mechanism for the
reports, a plausible mechanism for this reaction has been preparation of compound 1. Initially, KHMDS will abstract N–H
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 9486–9491 | 9489

View Article Online
RSC Advances
Paper
Scheme 3 Plausible mechanisms for the synthesis of spiro-isoindolinone dihydroquinazolinones.
proton of amide and nucleophilic nitrogen will attack the cya-
nobenzoate to get imine intermediate 6 and 7, which on
S. V. Shishkina, O. V. Shishkin and C. O. Kappe, J. Comb.
Chem., 2006, 8, 427.
subsequent cyclization lead to the formation of 8 and 9. Finally, 2 (a) K. Ding, Y. Lu, Z. Nikolovska-Coleska, G. Wang, S. Qiu,
the compounds 8 and 9 underwent cyclization to get the spiro-
isoindolinone dihydroquinazolinone 1.
S. Shangary, W. Gao, D. Qin, J. Stuckey, K. Krajewski,
P. P. Roller and S. Wang, J. Med. Chem., 2006, 49, 3432; (b)
M. Kitajima, T. Nakamura, N. Kogure, M. Ogawa,
Y. Mitsuno, K. Ono, S. Yano, N. Aimi and H. Takayama, J.
Nat. Prod., 2006, 69, 715; (c) N. Bacher, M. Tiefenthaler,
S. Sturm, H. Stuppner, M. J. Ausserlechner, R. Koer and
G. Konwalinka, Br. J. Haematol., 2006, 132, 615; (d)
T. Mugishima, M. Tsuda, Y. Kasai, H. Ishiyama, E. Fukushi,
J. Kawabata, M. Watanabe, K. Akao and J. Kobayashi, J. Org.
Chem., 2005, 70, 9430; (e) K. Ding, Y. Lu, Z. Nikolovska-
Coleska, S. Qiu, Y. Ding, W. Gao, J. Stuckey, K. Krajewski,
P. P. Roller, Y. Tomita, D. A. Parrish, J. R. Deschamps and
S. Wang, J. Am. Chem. Soc., 2005, 127, 10130; (f) R. Raunak,
V. Kumar, S. Mukherjee, A. K. Poonam Prasad, C. E. Olsen,
S. J. C. Schaeffer, S. K. Sharma, A. C. Watterson,
W. Errington and V. S. Parmar, Tetrahedron, 2005, 61, 5687.
3 (a) A. S. Girgis, Eur. J. Med. Chem., 2009, 44, 91; (b)
G. Periyasami, R. Raghunathan, G. Surendiran and
N. Mathivanan, Eur. J. Med. Chem., 2009, 44, 959; (c)
W. Zhang and G. Mei-Lin, Bioorg. Med. Chem., 2009, 17,
2077; (d) A. Amal Raj, R. Raghunathan, M. R. Sridevi
Kumari and N. Raman, Bioorg. Med. Chem., 2003, 11, 407;
(e) D.-G. Zhu, V. B. Gandhi, J. Gong, Y. Luo, X. Liu, Y. Shi,
R. Guan, S. R. Magnone, V. Klinghofer, E. F. Johnson,
J. Bouska, A. Shoemaker, A. Oleksijew, K. Jarvis, C. Park,
Conclusion
In summary we have successfully synthesized atom economic,
scalable and novel spiro-isoindolinone dihydroquinazolinones
under mild conditions. The substrate scope of the reaction has
been studied to get moderate yields and a possible mechanism
for this reaction is proposed. Further investigation of these
types of model substrates is underway in our laboratory.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
The authors would like to thank Dr. Reddy's Laboratory,
Hyderabad for providing facilities to carry out this work.
References
1 (a) A. Dondoni, A. Massi, S. Sabbatini and V. Bertolasi, J. Org.
Chem., 2002, 67, 6979; (b) V. A. Chebanov, E. A. Muravyova,
S. M. Desenko, V. I. Musatov, I. V. Knyazeva,
9490 | RSC Adv., 2020, 10, 9486–9491
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
R. De. Jong, T. Oltersdorf, Q. Li, S. H. Rosenberga and
RSC Advances
Q. Song, Y. Q. Zhu, L. Qin, Z. Y. Qian and L. Dong, Chem.–
Eur. J., 2014, 20, 16882; (c) J.-R. Huang, L. Qin, Y.-Q. Zhu,
Q. Song and L. Dong, Chem. Commun., 2015, 51, 2844; (d)
S. S. Li, L. Wu, L. Qin, Y. Q. Zhu, F. Su, Y. J. Xu and
L. Dong, Org. Lett., 2016, 18, 4214; (e) T. Nishimura, Y. Ebe
and T. Hayashi, J. Am. Chem. Soc., 2013, 135, 2092; (f)
T. Nishimura, M. Nagamoto, Y. Ebe and T. Hayashi, Chem.
Sci., 2013, 4, 4499; (g) M. B. Zhou, R. Pi, M. Hu, Y. Yang,
R. J. Song, Y. Xia and J. H. Li, Angew. Chem., Int. Ed., 2014,
53, 11338; (h) H. Liu, J. Li, M. Xiong, J. Jiang and J. Wang, J.
Org. Chem., 2016, 81, 6093; (i) S. T. Mei, H. W. Liang,
B. Teng, N. J. Wang, L. Shuai, Y. Yuan, Y. C. Chen and
Y. Wei, Org. Lett., 2016, 18, 1088; (j) M. V. Pham and
N. Cramer, Chem.–Eur. J., 2016, 22, 2270.
V. L. Giranda, Bioorg. Med. Chem. Lett., 2006, 16, 3424.
4 (a) N. V. Lakshmi, Y. Arun and P. T. Perumal, Tetrahedron
Lett., 2011, 52, 3437; (b) T. H. Babu, A. A. Joseph,
D. Muralidharan and P. T. Perumal, Tetrahedron Lett., 2010,
51, 994; (c) A. Nandakumar, P. Thirumurugan,
P. T. Perumal, P. Vembu, M. N. Ponnuswamy and
P. Ramesh, Bioorg. Med. Chem. Lett., 2010, 20, 4252; (d)
G. Shanthi, G. Subbulakshmi and P. T. Perumal,
Tetrahedron, 2007, 63, 2057; (e) K. Karthikeyan, R. S. Kumar,
D. Muralidharan and P. T. Perumal, Tetrahedron Lett., 2009,
50, 7175; (f) N. V. Lakshmi, P. Thirumurugan and
P. T. Perumal, Tetrahedron Lett., 2010, 51, 1064; (g)
N. V. Lakshmi, P. Thirumurugan and P. T. Perumal, Synlett,
2010, 6, 955; (h) K. Karthikeyan, P. M. Sivakumar, M. Doble 8 (a) M. Nagamoto and T. Nishimura, Chem. Commun., 2014,
and P. T. Perumal, Eur. J. Med. Chem., 2010, 45, 3446; (i)
K. Karthikeyan, P. T. Perumal, S. Etti and G. Shanmugam,
Tetrahedron, 2007, 63, 10581.
5 (a) A. A. Mohammadi, M. Dabiri and H. Qaraat, Tetrahedron,
2009, 65, 3804; (b) K. Engen, J. Savmarker, U. Rosenstrom,
50, 6274; (b) Y. Ebe, M. Hatano and T. Nishimura, Adv.
Synth. Catal., 2015, 357, 1425; (c) M. Nagamoto,
D. Yamauchi and T. Nishimura, Chem. Commun., 2016, 52,
5876; (d) L. Bingxian, H. Panjie, Z. Ying, L. Yunyun,
B. Dachang and L. Xingwei, Org. Lett., 2017, 19, 5402.
J. Wannbery, T. Lundback, A. Jenmalm-Jensen and 9 (a) V. N. Murthy, N. P. Satish, T. Krishnaji, M. V. Madhubabu,
M. Larhed, Org. Process Res. Dev., 2014, 18, 1582; (c)
J. Zhang, J. Zhao, L. P. Wang, J. Liu, D. C. Ren and
Y. M. Ma, Tetrahedron, 2016, 72, 936.
J. Subba Rao, L. V. Rao and A. Raghunadh, RSC Adv., 2018, 8,
22331; (b) S. P. Kumar, V. N. Murthy, K. R. Ganesh, G. S. Rao,
T. Krishnaji and A. Raghunadh, ChemistrySelect, 2018, 3,
6836; (c) C. Jaganmohan, K. P. V. Kumar, G. S. Reddy,
S. Mohanty, J. Kumar, B. V. Rao, T. Krishnaji and
A. Raghunadh, Synth. Commun., 2018, 48, 168; (d)
M. V. Madhubabu, R. Shankar, S. Satish More,
M. V. Basaveswara Rao, U. K. Syam Kumar and
A. Raghunadh, RSC Adv., 2016, 6, 36599; (e)
R. K. Raghavendra, M. Ramamohan, A. Raghunadh,
B. M. Suresh, K. S. Praveen, D. Kalita, E. Laxminarayana,
B. Prasad and M. Pal, RSC Adv., 2015, 5, 61575.
6 (a) P. Jimonet, A. Boireau, M. Cheve, D. Damour, A. Genevois-
Borella, A. Imperato, J. Pratt, J. C. R. Randle, Y. Ribeill,
J. M. Stutzmann and S. Mignani, Bioorg. Med. Chem. Lett.,
1999, 9, 2921; (b) T. Ullrich, S. Krich, D. Binder, K. Mereiter,
D. J. Anderson, D. Meyer and M. Pyerin, J. Med. Chem.,
2002, 45, 4047; (c) D. Stoermer and C. H. Heathcock, J. Org.
Chem., 1993, 58, 564; (d) J. Auerbach and S. M. Weinreb, J.
Am. Chem. Soc., 1972, 94, 7172.
7 (a) L. Dong, C. H. Qu, J. R. Huang, W. Zhang, Q. R. Zhang and
J. G. Deng, Chem.–Eur. J., 2013, 19, 16537; (b) J. R. Huang,
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 9486–9491 | 9491