Synthesis of quaternary carbon-centered indolo[1,2-a]quinazolinones and indazolo[1,2-a]indazolonesviaC-H functionalization

Article abstract of DOI:10.1039/d0cc07419e

An unprecedented Ru(ii)-catalyzed Csp²-H bond activation and annulation reaction of phenylindazolones with diaryl-substituted alkynes and dialkyl-substituted alkynes provided efficient routes for the construction of all-carbon quaternary-centered indolo[1,2-a]quinazolinones and quaternary carbon-centered indazolo[1,2-a]indazolones, respectively. The indolo[1,2-a]quinazolinones were fomedviaCsp²-H activation, alkyne insertion and a 1,2-phenyl shift. Indazolo[1,2-a]indazolones were formed through a cascade reactionviathe formation of exocyclic double bonds containing indolo[1,2-a]quinazolinones.

Full text of DOI:10.1039/d0cc07419e

View Article Online
View Journal
ChemComm
Chemical Communications
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: K. Gogoi, B. R.
Bora, G. Borah, B. Sarma and S. Gogoi, Chem. Commun., 2021, DOI: 10.1039/D0CC07419E.
Volume 54
This is an Accepted Manuscript, which has been through the
Number
January 2018
Pages 1-112
1
4
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Chemical Communications
rsc.li/chemcomm
Accepted Manuscripts are published online shortly after acceptance,
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
shall the Royal Society of Chemistry be held responsible for any errors
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
S. J. Connon, M. O. Senge et al.
Conformational control of nonplanar free base porphyrins:
towards bifunctional catalysts of tunable basicity
rsc.li/chemcomm

Please do not adjust margins
Page 1 of 5
ChemComm
View Article Online
DOI: 10.1039/D0CC07419E
COMMUNICATION
Synthesis of Quaternary Carbon Centered Indolo[1,2-
a]quinazolinones and Indazolo[1,2-a]indazolones via C-H
Functionalization
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Kongkona Gogoi†, Bidisha R. Bora†, Geetika Borah§, Bipul Sarma‡, and Sanjib
Gogoi†,*
An unprecedented Ru(II)-catalyzed Csp2-H bond activation and heterocycles.5 Very recently, Perumal and co-workers used
annulation reaction of phenylindazolones with diaryl substituted phenylindazolones to perform Rh(III)-catalyzed activation of
alkynes and dialkyl substituted alkynes provided efficient routes Csp2-H bond followed by direct alkyne annulation to synthesize
for the construction of all-carbon quaternary centered indolo[1,2- indazolo[1,2-a]cinnolines (Scheme 1, eq 1).5d In our continuous
a]quinazolinones and quaternary carbon centered indazolo[1,2-
a]indazolones, respectively. The indolo[1,2-a]quinazolinones were
fomed via the Csp2-H activation, alkyne insertion and 1,2-phenyl
shift pathways. The indazolo[1,2-a]indazolones were formed
through a cascade reaction via the formation of exocyclic double
bond containing indolo[1,2-a]quinazolinones.
Indoloquinazolinones are known to exhibit wide range of
bioactivities such as anticancer, antibacterial, antifungal etc.1
Figure 1. Examples of bioactive indolo[1,2-a]quinazolinones
and pyrazolo[1,2-a]indazolone
Among
the
indoloquinazolinones,
the
indolo[1,2-
effort to develop novel metal-catalyzed C-H bond
functionalization reactions,6 herein, we describe a novel Ru(II)-
catalyzed Csp2-H activation and annulation reaction of
phenylindazolones with aryl/heteroaryl substituted alkynes.
This reaction proceeds through Csp2-H activation, alkyne
insertion and 1,2-aryl shift to provide an efficient synthetic
method for indolo[1,2-a]quinazolinones (Scheme 1, eq 2). We
a]quinazolinones have attracted considerable attention
recently, owing to their poly(ADP-ribose) polymerase-1 (PARP-
1) and protein kinase CK2 inhibitory activities (Figure 1).2
Therefore, development of novel practical methods to
construct this heterocyclic scaffold is a thrust research area.3
Again, recently, the indazole and indazolone ring fused
heterocycles have emerged as pharmaceutically important
compounds because of their remarkable biological activity.4
Pyrazolo[1,2-a]indazolone and indazolo[1,2-a]indazolone are
two such fused heterocyclic scaffolds which have got much
attention very recently for their bioactivity and interesting
laser activity.4 However, method to construct the indazolo[1,2-
a]indazolone skeleton is not considerably explored. Therefore,
a direct method to synthesize this heterocyclic scaffold using
simple and readily available starting material is highly desired.
Last few decades have witnessed the significant evolution of
metal-catalyzed C-H activation and alkyne annulation reactions
for the step-economic construction of important
Scheme 1. Metal-catalyzed annulation reactions of
phenylindazolone and alkyne
a. †Applied Organic Chemistry, Chemical Sciences & Technology Division, CSIR-North
East Institute of Science and Technology, Jorhat-785006, AcSIR, Ghaziabad-
201002, India, §Department of Chemistry, Dibrugarh University, Dibrugarh-
786004, and ‡Department of Chemical Sciences, Tezpur University, Tezpur-
784028, India, Email: skgogoi1@gmail.com; sanjibgogoi@neist.res.in
Electronic Supplementary Information (ESI) available: Experimental procedures,
spectroscopic data and copies of 1H NMR, 13C NMR and HRMS spectrum of the
synthesized compounds, See DOI:
also report an unprecedented Ru(II)-catalyzed cascade
reaction of phenylindazolones with dialkyl substituted alkynes
for the synthesis of indazolo[1,2-a]indazolones (Scheme 1, eq
2). Notably, these synthetic methods of indolo[1,2-
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 5
COMMUNICATION
Journal Name
a]quinazolinones and indazolo[1,2-a]indazolones afford all- reaction conditions to afford 57-79% VieywiAerltdicsle Onlionef
carbon quaternary carbon-centered and quaternary carbon- indoloquinazolinones 3aa ae
ThenD, OI: 1s0o.1m03e9/D0oCfC074t1h9eE
centered heterocycles. Again, the creation of a new method to representative unsymmetrical aryl group substituted alkynes
construct a quaternary carbon stereo center, which is present 2f were tested with 1a, which afforded 48-67% yields of 3af
in many bioactive molecules has itself been considered as a ah. Similarly, the unsymmetrical alkyne substituted with an
challenging task in organic synthesis.7
aryl and a heteroaryl group 2i provided the desired product 3ai
-
.
-
h
-
Initially, we tested the reaction of phenylindazolone 1a with in 51% yield. Next, the optimized reaction conditions were
alkyne 2a for the synthesis of indoloquinazolinone 3aa (Table applied to study the substrate scope of some of the
SI-1). Among various transition metal complexes tested, the phenylindazolones 1b
[{RuCl2(p-cymene)}2] complex (5 mol %) together with the phenylindazolones substituted with electron-releasing or
additive Cu(OAc)2.H2O produced the highest yield of the electron-withdrawing methyl, methoxy and chloro
product 3aa in tAmOH (38%) (entry 2). Then, to further substituents at 5-position of the fused phenyl ring 1b
improve the yield of 3aa some other additives were tested. provided 57-68% yields of the desired compounds 3ba da. The
-i with alkyne 2a. As shown in Table 1,
-
d
-
Fortunately, the additive CsOAc provided the highest yield sensitive bromo substituted phenylindazolone 1e also
(79%) of the product 3aa (entry 7). Further studies on solvents tolerates the reaction conditions to afford 3ea (58%). Then,
and catalyst loading could not improve the yield of 3aa (entries some of the phenylindazolones possessing electron-releasing
10-15). The highest yielding reaction conditions were then or electron-withdrawing substituents such as methyl, methoxy
applied first to study the substrate scope of diaryl or aryl and chloro on the substituted phenyl ring of phenylindazolone
heteroaryl substituted alkynes 2a
-
i
. As shown in Table 1, the
1f
-
i
were studied with alkyne 2a to provide 53-65% yields of
ia. The annulation reaction of 1i and 2a was
compounds 3fa
-
Table 1. Scope of alkynes (2a ) and phenylindazolones (1a-i)
-
i
highly regioselective, which might be due to the steric effect of
the substituted methyl group. Then, the optimized reaction
conditions were tested for the annulation of dialkyl substituted
alkyne 2j with 1a (Table 2). Notably, instead of providing the
indolo[1,2-a]quinazolinone derivative, this reaction afforded
indazolo[1,2-a]indazolone 4aj in 62% yield. Because of the
Table 2. Scope of dialkyl alkynes (2j-k)
aReaction conditions: 1a (0.1 mmol), 2a (0.1 mmol), catalyst (5 mol %),
additive (0.1 mmol) and tAmOH (3.0 mL) at 95 °C under air for 24 h.
aReaction conditions: 1a (0.1 mmol), 2a (0.1 mmol), catalyst (5 mol %),
additive (0.1 mmol) and tAmOH (3.0 mL) at 95 °C under air for 24 h.
importance
of
indazolo[1,2-a]indazolone
containing
compounds, the scope of the reaction was further studied. The
phenylindazolones possessing substituents either on the fused
symmetrical alkynes possessing various electron-releasing or
electron-withdrawing groups such as methyl, methoxy and
or substituted phenyl ring 1b
,
1d-
g
,1i provided corresponding
fluoro on the phenyl ring of the alkyne (2a
-
e
), endured the
indazolo[1,2-a]indazolones 4bj,4dj-gj,4ij with 2j, albeit with
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 5
ChemComm
Please do not adjust margins
Journal Name
COMMUNICATION
low yields (50-63%). Similarly, another dialkyl substituted of the metal and subsequent C-2 activation generates a seven
View Article Online
DOI: 10.1039/D0CC07419E
alkyne 2k tested for this reaction provided 63% yield of 4ak
The structure of synthesized compounds was determined with metal from
the help of NMR spectroscopy and single X-ray crystallographic and 2j respectively. Then, elimination of a molecule of acetic
studies of compounds 3ab and 4ij 8
The phenyl acetylene, acid from and concomitant 1,2-phenyl group migration
.
membered Ru complex
F. The reductive elimination of the
F
might have generated
G and Gʹ, using alkynes 2a
.
G
trimethyl(phenylethynyl)silane, methyl 3-phenylpropiolate,
1,2-di-o-tolylethyne, 1,2-bis(2-chlorophenyl)ethyne and 1-
octene could not provide corresponding annulated indolo[1,2-
a]quinazolinone derivatives. The practical utility of this
annulation reaction was established by accomplishing a gram-
scale reaction between 1a and 2a which provided 75% yield of
3aa (Scheme 2). Next, to determine the mechanism of this
reaction, some of the control experiments were performed.
The reaction of 1a with 2j in the presence of one equivalent of
TEMPO furnished only 23% yield of 4aj, indicating the
involvement of free radical in the formation of 4aj. Again,
when the reactions between 1a and 2j/2k were stopped in
three hours, without allowing total consumption of the
starting materials, the indolo[1,2-a]quinazolinones 4ajʹ (E
isomer) and 4akʹ (E:Z = 24:1) were formed in 33-36% yields.
These intermediates disappeared once the reactions were
Scheme 2. Gram-scale synthesis and control experiments
allowed to run for longer time. In case of aryl alkyl group
containing alkyne 2l, the intermediate 4alʹ (E isomer) did not
disappear after 24 hours also.8 An experiment performed
under standard conditions using 1a alone and CD3OD (or D2O)
as solvent could not provide the H/D exchanged compound 1a-
D
(Scheme 2). This reaction indicates
a non-reversible
formation of acyclic ruthenium complex as an intermediate.
Based on the literature reports and our findings, a possible Scheme 3. Probable mechanism
mechanism for the formation of compounds 3aa and 4aj is affords the final compound 3aa. In the presence of alkyl
proposed (Scheme 3).9 The active Ru(II) catalyst
A
first substituents, elimination of a proton from alkyl side chain of Gʹ
activates C-H bond of 1a irreversibly to form a Ru(II) complex is faster than the elimination of a proton from amide N-H
. Then, alkyne metal coordination, followed by insertion of which results in the formation of Hʹ 4ajʹ). Addition of a
alkyne in between C-Ru bond affords Ru complex . Insertion molecule of oxygen in the exocyclic double bond of Hʹ 4ajʹ),
of the metal in between the weak N-N bond affords a six- followed by elimination of a molecule of water, subsequent N-
membered Ru(IV) complex , which on reductive elimination N bond formation and rearrangement affords Lʹ. Probably, the
B
(
C
(
D
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 5
COMMUNICATION
Journal Name
361, 654; (b) P. Gandeepan, T. Müller, D. Zell, G. Cera, S.
intermediate Jʹ might exist in equilibrium with the
intermediate Kʹ. Because of the presence of the attached
conjugated electron withdrawing keto functionality in Jʹ, the
quaternary nitrogen is more electrophilic and as a result
intramolecular cyclization occurs leading to the formation of
N-N bond. The tautomer Mʹ of Lʹ might generate the tricyclic
intermediate Nʹ on intramolecular cyclization. Then hydroxy
group directed oxidative addition of the metal in the C-C bond
of cyclopropane ring closer to the C=N bond, might afford a six
membered Ru complex Oʹ, which in the presence of acetic acid
View Article Online
Warratz and L. Ackermann, Chem. Rev., 2019, 119, 2192; (c)
Y. Yang, K. Li, Y. Cheng, D. Wan, M.DOLiI:a10n.d103J.9/YDo0uC,C0C7h4e1m9E.
Commun., 2016, 52, 2872; (d) S. Mayakrishnan, Y. Arun, C.
Balachandran, N. Emi, D. Muralidharan and P. T. Perumal,
Org. Biomol. Chem., 2016, 14, 1958; (e) S. Baruah, P. Saikia,
G. Duarah and S. Gogoi, Org. Lett., 2018, 20, 3753.
6
7
8
9
(a) P. P. Kaishap, G. Duarah, B. Sarma, D. Chetia and S.
Gogoi, Angew. Chem., Int. Ed., 2018, 57, 456; (b) S.
Borthakur, S. Baruah, B. Sarma and S. Gogoi, Org. Lett., 2019,
21, 2768.
For the construction of all-carbon quaternary stereocenters,
see: (a) A. Y. Hong and B. M. Stoltz, Eur. J. Org. Chem., 2013,
generates 4aj via intermediate Pʹ
.
2745; (b) J. P. Das and I. Marek, Chem. Commun., 2011, 47
,
In conclusion, we have developed novel routes for the
synthesis of quaternary carbon centered indolo[1,2-
a]quinazolinones and indazolo[1,2-a]indazolones using the
Ru(II)-catalyzed Csp2-H activation and annulation reaction of
readily available phenylindazolones with internal alkynes.
Because of the rapid assemblage of complex skeletons and
simplicity in operation, these methods might be useful for the
synthesis of related heterocyclic scaffolds.
4593.
CCDC 1922253, CCDC 2024912 and CCDC 1922254 contain
the supplementary crystallographic data for 3ab, 4ij and 4alʹ,
respectively. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif.
(a) M. Gulías and J. L. Mascareñas, Angew. Chem., Int. Ed.,
2016, 55, 11000; (b) Z. Zhang, H. Jiang and Y. Huang, Org.
Lett., 2014, 16, 5976; (c) D. Zhao, Z. Shi and F. Glorius,
Angew. Chem., Int. Ed., 2013, 52, 12426; (d) Z. Cheng, W. Jin
and C. Liu, Org. Chem. Front., 2019, 6, 841; (e) C. A. Merlic,
M. M. Miller, B. N. Hietbrink and K. N. Houk, J. Am. Chem.
Soc., 2001, 123, 4904; (f) S. Battula, A. Kumar, A. P. Gupta
and Q. N. Ahmed, Org. Lett., 2015, 17, 5562; (g) T. Tamaki,
Conflicts of interest
“There are no conflicts to declare”.
M. Ohashi and S. Ogoshi, Angew. Chem., Int. Ed., 2011, 50
,
12067; (h) S. Ogoshi, M. Nagata and H. Kurosawa, J. Am.
Chem. Soc., 2006, 128, 5350; (i) M. Lin, F. Li, L. Jiao and Z.-X.
Yu, J. Am. Chem. Soc., 2011, 133, 1690.
Acknowledgment
The authors thank SERB and CSIR New Delhi for financial
support via the GPP-0367 (CRG/2019/00l898) and OLP 2038
projects. B. R. Bora thanks DST for the INSPIRE-SRF fellowship.
We are grateful to the Director, CSIR-NEIST for his keen
interests.
References
1
(a) R. Rohini, P. M. Reddy, K. Shankera, A. Hu and V.
Ravinder, Eur. J. Med. Chem., 2010, 45, 1200; (b) A. K.
Bhattacharjee, D. J. Skanchy, B. Jennings, T. H. Hudson, J. J.
Brendle and K. A. Werbovetz, Bioorg. Med. Chem., 2002, 10
,
1979; (c) C.-W. Jao, W.-C. Lin, Y.-T. Wu and P.-L. Wu, J. Nat.
Prod., 2008, 71, 1275.
(a) D. V. Ferraris, J. Med. Chem., 2010, 53, 4561; (b) K.
Zimmermann, R. Portmann and D. F. Rigel, U. S. Patent
6964960, 2005; (c) E. Vangrevelinghe, K. Zimmermann, J.
Schoepfer, R. Portmann, D. Fabbro and P. Furet, J. Med.
Chem., 2003, 46, 2656.
2
3
4
For example, see: (a) T. Abe, Y. Takahashi, Y. Matsubara and
K. Yamada, Org. Chem. Front., 2017, 4, 2124; (b) H. Jiang, J.
Yang, X. Tang and W. Wu, J. Org. Chem., 2016, 81, 2053; (c)
S. Badigenchala and G. Sekar, J. Org. Chem., 2017, 82, 7657
and references cited therein.
(a) Y. Xu, M. Shen, X. Zhang and X. Fan, Org. Lett., 2020, 22
,
4697; (b) X. Wu and H. Ji, J. Org. Chem., 2018, 83, 4650; (c) Z.
Yang, Z. Song, L. Jie, L. Wang and X. Cui, Chem. Commun.,
2019, 55, 6094; (d) C. K. Mahesha, S. K. Mandal and R.
Sakhuja, Asian J. Org. Chem., 2020, 9, 1199; (e) J. Zhou, L.
Zhang, J. Chen, J. Chen, C. Yin and C. Yu, Tetrahedron Lett.,
2020, 61, 152350; (f) H. Tomioka, A. Okuno, T. Sugiyama and
S. Murata, J. Org. Chem., 1995, 60, 2344; (g) E. C. Breinlinger,
A. Burchat, J. D. Dietrich, M. Friedman, D. Ihle, D. Kinsman, K.
Mullen, A. T. Osuma, A. Vasudevan and N. S. Wilson,
US20180215764A1; (h) W. E. Conrad, R. Fukazawa, M. J.
Haddadin and M. J. Kurth, Org. Lett., 2011, 13, 3138.
5
For recent reviews and examples, see: (a) G. Duarah, P. P.
Kaishap, T. Begum and S. Gogoi, Adv. Synth. Catal., 2019,
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
ChemComm
View Article Online
DOI: 10.1039/D0CC07419E
A cascade, Ru(II)-catalyzed annulative transformation of phenylindazolones and alkynes into
indolo[1,2-a]quinazolinones and indazolo[1,2-a]indazolones is reported.
R4
R4
R1
O
N
O
O
O
R4
R3
N
R3
R1
NH
R1
R3
N
R3
R4
N
N
Ru(II)
CsOAc
Ru(II)
CsOAc
R2
R2
R2
(R3, R4 = aryl, heteroaryl)
(R3, R4 = alkyl)
17 examples
8 examples