Design and synthesis of spirobiisoxazoline dibenzoquinone derivatives via [3?+?2] double 1,3-dipolar cycloaddition reaction

Article abstract of DOI:10.1016/j.tetlet.2018.12.067

“A series of novel spirobiisoxazoline dibenzoquinone derivatives were synthesized starting from 2,5-dimethoxybenzaldehyde in a six-step synthetic sequence”. The key step [3 + 2] double 1,3-dipolar cycloaddition of oxime chloride with allenoate was perform

Full text of DOI:10.1016/j.tetlet.2018.12.067

Accepted Manuscript
Design and Synthesis of Spirobiisoxazoline Dibenzoquinone Derivatives via
[3+2] Double 1,3-Dipolar Cycloaddition Reaction
K. Jones. M. Swapnaja, Satyanarayana Yennam, Murthy Chavali
PII:
S0040-4039(18)31527-2
https://doi.org/10.1016/j.tetlet.2018.12.067
TETL 50530
DOI:
Reference:
Tetrahedron Letters
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6 November 2018
26 December 2018
27 December 2018
Please cite this article as: Swapnaja, K.J., Yennam, S., Chavali, M., Design and Synthesis of Spirobiisoxazoline
Dibenzoquinone Derivatives via [3+2] Double 1,3-Dipolar Cycloaddition Reaction, Tetrahedron Letters (2018),
doi: https://doi.org/10.1016/j.tetlet.2018.12.067
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Design and Synthesis of Spirobiisoxazoline
Dibenzoquinone Derivatives via [3+2] Double
1,3-Dipolar Cycloaddition Reaction
K. Jones. M. Swapnajaa,b, Satyanarayana Yennama*, Murthy Chavalic

Tetrahedron Letters
1
TETRAHEDRON
LETTERS
Pergamon
Design and Synthesis of Spirobiisoxazoline Dibenzoquinone Derivatives
via [3+2] Double 1,3-Dipolar Cycloaddition Reaction
K. Jones. M. Swapnajaa,b, Satyanarayana Yennama*, Murthy Chavalic
a Department of Medicinal Chemistry, GVK Biosciences Pvt. Ltd., Survey Nos: 125(part) & 126, IDA Mallapur, Hyderabad 500076, Indiab
b Division of Chemistry, Department of Sciences and Humanities, Vignan’s Foundation for Science, Technology and Research, Vadlamudi, Guntur 522 213,
India
c MCETRC, Tenali 522 201 Guntur, AP, India
Abstract: “A series of novel spirobiisoxazoline dibenzoquinone derivatives were synthesized starting from 2,5-dimethoxybenzaldehyde
in a six-step synthetic sequence”. The key step [3+2] double 1,3-dipolar cycloaddition of oxime chloride with allenoate was performed
under mild reaction conditions using sodium carbonate at ambient temperature. This is the first innovative synthesis of Spirobiisoxazoline
Dibenzoquinone system where quinone ring is alkylated to isoxazoline moiety.
Spiro compounds are a particular class of naturally
occurring substances characterized by highly pronounced
biological properties [1-2]. Keeping in view of diverse
biological activities associated with spiro heterocyclic
compounds, it was thought to construct a novel system by
the conjugation of these bioactive rings together in a
single molecular framework to see the additive effects
towards their biological activities.
reactivity and high prevalence in the environment. Natural
and synthetic quinone derivatives are well known for
antitumor activity [9]. Many drugs such as daunorubicin,
doxorubicin Fig.2, epirubicin, mitomycin, mitoxantrones,
and saintopin, which are used clinically in the therapy of
solid cancers [10]. The quinone anticancer compounds
undergo enzymatic reduction via one or two electrons to
give the corresponding semiquinone radical or
hydroquinone. These semiquinone and the superoxide
radical anion will generate the hydroxyl radical and which
is the cause of DNA strand breaks [11].
Natural and nonnatural isoxazolines and
spirocyclic isoxazoline derivatives have emerged as
promising drug candidates due to their significant
biological activities [3] resulting in an overall
antiproliferative effect on a variety of cancer cell lines.
The natural product 11-deoxyfistularin-3 [4] contains two
spirocyclic isoxazoline moieties and is cytotoxic toward
estrogen dependent MCF-7 breast cancer cells (LD50= 17
mg/L). Other closely related spirocyclic isoxazoline
natural products such as fistularin-3, [7] psammaplysin A,
[5] exhibits cytotoxic activity and aerothionin,
homoaerothio-nin [6], Fig. 1 are known for antimicrobial
activity. Quinones have attained great interest from a
medical and toxicological perspective due to their unique
In recent years, the strategy employing to design
new bioactive hybrid molecules gained more importance
due to their improved biological activity compared to the
standard drugs. Such dual action compounds, or hybrid
compounds, offer the possibility to overcome the current
resistance and reduce the appearance of new resistant
strains [12]. Based on this hypothesis, previously we have
synthesized quinone five membered phenyl/heterocyclic
hybrids [13-16].
Fig. 1. Spiroisoxazoline Natural Products
Fig. 2. Known Quinone Drugs

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Tetrahedron Letters
In this rationale, we are encouraged to discover
an efficient double 1,3-dipolar cycloaddition of allenoates
with nitril-imines for the construction of
rarely addressed new class of spirobiisoxazoline
derivatives by double 1,3-dipolar cycloaddition reaction
and the conjugates of these new molecules with
biologically active quinones. Herein we have designed
and synthesized spirobiisoxazoline dibenzoquinone
derivatives as new hybrid molecules to identify more
potent biologically active compounds.
spirobidihydropyrazoles. [23] Recently Xinye Shang et al.
addressed the double 1,3-dipolar cycloaddition involved
DABCO combined with Et3N, 2-substituted buta-2,3-
dienoates reacted with oxime chlorides to afford
spirobiisoxazolines.[24]
Several cycloaddition reactions were reported to
approach isoxazoline and spiroisoxazoline skeleton over
the years. [17] The strategy based on the cycloaddition of
nitrile oxide, has been revealed to be very feasible and
trustworthy by many research groups. [18] Whereas, in
the above reports, limited reaction partners (alkenes) were
reacted with nitrile oxides to construct the isoxazoline
frameworks [19] and very few reports were addressed the
formation of spirocyclic biisoxazolines via intramolecular
double 1,3-dipolar cycloaddition of dienes. [20].
Therefore, evolving further approaches is still highly
desirable.
Many cycloaddition reactions of allenoates
described the formation of only carbon-carbon double
bond.[21] Zecchiet al. reported the minor formation of
spirobiisoxazoline from the cycloaddition between nitrile
oxide and substituted allene. [22] Guoet al. have reported
Herein we are interested to develop a mild, simple
“thermal
free”
methodology
to
synthesize
spirobiisoxazolines by inorganic base (Na2CO3) mediated
double “1, 3 dipolar” cycloaddition reaction at room
temperature for easy workup and isolation in very good
yield. Further, a literature survey reveals no report on the
synthesis of spirobiisoxazoline with dibenzoquione novel
nucleus yet so far. As part of our ongoing program to
develop efficient compounds and robust methods for the
preparation of biologically relevant molecules from
readily available building blocks, which are novel yet
resemble known biological activity by virtue of the
presence of some critical structural features, we have
developed a facile, simple and mild methodology for the
synthesis of novel spiro biisoxazoline dibenzoquinone
derivatives.
Scheme1. Synthesis of Spirobiisoxazoline Dibenzoquinone Derivatives (8a-8m).
Scheme 2. Plausible mechanism of double 1,3 Dipolar cycloaddition reaction

Tetrahedron Letters
3
16). An enhancement of the yield was achieved when the
reaction was carried out in DCM with Na2CO3 (60%) at
RT for 48h. After that, the reaction with K2CO3 in CHCl3
gave good yield (52%), the yields with remaining systems
were not desirable. The reaction with NaOH as base is
poor yielding. The base catalyzed hydrolysis of compound
5 gave the key intermediate carboxylic acid derivative 6
(90%), which was subjected to amide coupling with
various aliphatic, aromatic, acyclic and cyclic, primary/
secondary amines. Acid amine coupling was carried out
by using HATU as coupling reagent, which afforded
corresponding mide derivatives (7a-7o) in 80-95% yield,.
These amide derivatives (7a-7o) upon oxidation with
ceric ammonium nitrate in ACN/Water at 0 oC resulted in
spirobiisoxazoline dibenzoquinone derivatives (8a-8l) as
yellow solids with very good yield (70-90%) (Fig.3).
However, quinones (8m, 8n and 8o) obtained with some
of the amides m (pyrrolidine) n (4-methoxybenzyl), o (3-
For the synthesis of spirobiisoxazoline
dibenzoquinone compounds 8a-8l, (Scheme 1)
commercially available 2,5-dimethoxybenzaldehyde (1)
was reacted hydroxylamine hydrochloride in MeOH at
reflux afforded oxime 2 (89%). Oxime 2 was treated with
NCS in DCM afforded oxime chloride which on further
treatment with allenoate
4
resulted dimethoxy
spirobiisoxazoline 5. Therefore, a reactive intermediate
nitrile oxide could be easily generated in situ from oxime
chloride in the presence of Na2CO3 in DCM and the nitrile
oxide was expected to react with allenoate to furnish the
desired dimethoxy spirobiisoxazoline 5 (Scheme 2) as
diastereomeric mixture (9:1, 60 %) by [3+2] by double
1,3-dipolar cycloaddition. In this investigation, the
reaction of oxime chloride precursor with allenoate 4
was chosen as the model reaction with the use of Na2CO3
as the base in dichloromethane at RT for 48 h to give the
corresponding product spirobiiosxazoline 5 in 60% yield
(Table 1, entry 5). Further investigation was carried out to
optimise reaction condition by taking the combination of
different solvents such as ACN, DCM, CHCl3 and THF
with different bases like Na2CO3, K2CO3, Cs2CO3 and
NaOH. The results clearly indicated that the reaction
media played an important role in the process (entries 1–
o
pyridyl) were found to be unstable even at 0 C and thus
we were unsuccessful in isolating these compounds. The
synthesized stable compounds (8a-8l) were well
characterized by “IR, 1H NMR, 13C NMR & HRMS
specromerty”.
Fig. 3. Spirobiisoxazoline Dibenzoquinone Derivatives (8a-8l)

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Tetrahedron Letters
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Table 1. Optimization of reaction conditions
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Sl.No
Solvent
Conditions
Yield
1
ACN
ACN
ACN
Na2CO3, RT, 64h
Cs2CO3, RT, 48h
K2CO3, RT, 48h
32%
22%
32%
2.
3
[9] R. P. Hertzberg, P. B. Dervan, Biochemistry, 23 (1984) 3934-
3945.
4
ACN
NaOH, RT, 48h
10%
[10] R. Martinez, L. Chacon-Garcia, Curr. Med. Chem.12 (2005)
127-151.
5
DCM
Na2CO3, RT, 48h
60%
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Chem. 29 (1986) 1381-1384.
[12] X. LWang, K. Wan, C. H. Zhou, Eur. J. Med. Chem.45 (2010)
4631-4639.
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Shree, Satyanarayana Yennam; Tetrahedron Letters 53 (2012)
4108–4113.
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Chavali, Y.Poornachandra, C.Ganesh Kumar, Krubakaran
Muthusamy, Venkatesh Babu Jayaraman, Premkumar
Arumugam, Sridhar Balasubramanian, Kiran Kumar Sriram
European Journal of Medicinal Chemistry. 117, (2016) 85-98.
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Jayashree Anireddy., Tetrahedron Letters., 57, (2016),
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Rekula, Challa Gangu Naidu, Yamini Bobde, Balaram Ghosh.,
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[17] (a) C. B. Tripathi and S. Mukherjee, Angew. Chem. Int. Ed.,52
(2013) 8450; (b) M. Gao, Y. Li, Y. Gan and B. Xu, Angew.
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Middleton, A. D. Todora, B. J. Kastern, S. R. Koski, A.
Maskaev, Org. Lett., 15 (2013) 4010.
6
7
DCM
DCM
DCM
CHCl3
CHCl3
CHCl3
CHCl3
THF
Cs2CO3, RT, 48h
K2CO3, RT, 48h
NaOH, RT, 48 h
Na2CO3, RT, 48h
Cs2CO3, RT, 48 h
K2CO3, RT, 48h
NaOH, RT, 48h
Na2CO3, RT, 48h
Cs2CO3, RT, 48h
25%
48%
15%
40%
28%
52%
12%
25%
10%
8
9
10
11
12
13
14
THF
15
16
THF
THF
K2CO3, RT, 48h
NaOH, RT, 48h
10%
traces
In conclusion we synthesized a series of novel
spirobioxazoline dibenzoquinone derivatives via [3+2]
double 1, 3 dipolar cycloaddition reaction. Hence
quinones of spirobiisoxazoline scaffolds are featured in a
range of natural and synthetic products with wide-
reaching biological activities and useful synthetic
intermediates for organic synthesis, spirobiisoxazoline
dibenzoquinone based compounds have the ability to
become drugs of immense use.
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Org. Lett. 13 (2011) 2966.
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(2017) 4714.
[24] Xinye Shang, Kun Liu, Zhongyin ZhanG, Pengfei Li and
Wenjun Li.; Org. Biomol. Chem.16 (2018) 895.
Acknowledgements
Authors are grateful to GVK Biosciences Pvt. Ltd. for
the financial support and encouragement. Help from the
analytical department for the analytical data is
appreciated. We thank Dr. Sudhir Kumar Singh for his
invaluable support and motivation.
References
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1137-1140.

Tetrahedron Letters
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Research Highlights
 Novel spirobiisoxazoline dibenzoquinone derivatives were synthesized.
 [3+2] Double 1,3-dipolar cycloaddition was performed using allenoate and nitrile oxide.
 The new molecules were successfully separated and characterized.