Microwave assisted rapid synthesis of phenoxazines and benzopyridoxazines

Article abstract of DOI:10.1080/00397911.2020.1849723

A facile protocol for the synthesis of phenoxazines and benzopyridoxazines by Smiles rearrangement have been demonstrated in short reaction time under microwave irradiation. The control experiments suggest that a reaction proceeds through Smiles rearrangement followed S_NAr ring closure by in situ cascade process. In our present work, both the electron donating and electron withdrawing groups were tolerant and provided a corresponding phenoxazine/benzopyridoxazine in good to moderate yields.

Full text of DOI:10.1080/00397911.2020.1849723

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Microwave assisted rapid synthesis of
phenoxazines and benzopyridoxazines
Kavitha Anchan , Nagaswarupa H. Puttappa , Baburajan Poongavanam &
Sujit Kumar Sarkar
To cite this article: Kavitha Anchan , Nagaswarupa H. Puttappa , Baburajan Poongavanam
& Sujit Kumar Sarkar (2020): Microwave assisted rapid synthesis of phenoxazines and
benzopyridoxazines, Synthetic Communications, DOI: 10.1080/00397911.2020.1849723
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https://doi.org/10.1080/00397911.2020.1849723
Microwave assisted rapid synthesis of phenoxazines and
benzopyridoxazines
Kavitha Anchana,b, Nagaswarupa H. Puttappaa,c, Baburajan Poongavanamb, and
Sujit Kumar Sarkarb
b
aResearch and Development Centre, Bharathiar University, Coimbatore, India; Discovery Chemistry,
c
Syngene International Limited, Bangalore, India; Department of studies in chemistry, Davangere
University, Davangere, India
ABSTRACT
ARTICLE HISTORY
Received 26 July 2020
A facile protocol for the synthesis of phenoxazines and benzopyri-
doxazines by Smiles rearrangement have been demonstrated in
short reaction time under microwave irradiation. The control experi-
ments suggest that a reaction proceeds through Smiles rearrange-
ment followed SNAr ring closure by in situ cascade process. In our
present work, both the electron donating and electron withdrawing
groups were tolerant and provided a corresponding phenoxazine/
benzopyridoxazine in good to moderate yields.
KEYWORDS
Benzopyridoxazines; micro-
wave irradiation;
phenoxazines; smiles
rearrangement; SNAr
cyclization
GRAPHICAL ABSTRACT
Introduction
Phenoxazines and benzopyridoxazines are 6/6/6 fused tricyclic heterocycles which are
gaining attention of researchers as they exhibit biological properties and are used as
building blocks in medicinal chemistry.[1] N-substituted analogues of phenoxazines are
less toxic modulators of multidrug resistant (MDR) in cancer cells.[2] Derivatives of
phenoxazines have been used as visible light absorbing reducing organic photoredox
catalysts (PCs).[3] Owing to their photophysical properties,[4] they have been applied as
dyes in dye-sensitized solar cells[5] and chemosensors.[6] A block copolymer comprised
of polyfluorene (PF) and polytriarylamine (PTAA) functionalized with substituted phe-
noxazines are finding a place in electroluminescent applications.[7]
CONTACT Baburajan Poongavanam
baburajan29@gmail.com; Nagaswarupa H. Puttappa
nagaswarupa77@gmail.com
Discovery Chemistry, Syngene International Limited, Bangalore 560099, India.
Supplemental data for this article can be accessed on the publisher’s web.
ß 2020 Taylor & Francis Group, LLC

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A. KAVITHA ET AL.
Figure 1. Structures of few phenoxazine containing RTAs.
Block copolymers with phenoxazine cores help in improving the efficiency of polymer
light emitting diodes (PLEDs).[8] Recently, Pratt and his group reported that phenoxazines
have considerably greater reactivity (by up to 2 orders of magnitude) when compared to
diphenylamine and phenothiazine RTAs (Figure 1) which are commonly used as antioxi-
dants.[9] General methods to prepare phenoxazines involve Smiles rearrangements, transi-
tion metal-catalyzed coupling reactions and nucleophilic substitution reactions. Among
these, Smiles rearrangement reactions offer high degree of diversity to synthesize complex
molecules.[10] Phenothiazines which are one of the privileged scaffolds in medicinal
chemistry are generally prepared by using a base mediated via Smiles rearrangements of N-
(2-((2-nitrophenyl)thio)phenyl)acetamide/N-(2-((2-bromophenyl)thio)phenyl)acetamide.[11]
Unlike phenothiazines, the phenoxazines were less explored. In Scheme 1, some of the pro-
tocols to synthesize phenoxazines and benzopyridoxazines are depicted. Eastmond et al.
reported a base-catalyzed synthesis of cyanophenoxazines by cyano activated fluoro dis-
placement reactions via Smiles rearrangement (Scheme 1a).[12] Yang et al. developed a pal-
ladium catalyzed double N-arylation using di(2-bromoaryl)ethers and primary amines
(Scheme 1b).[13] Bolm and his group reported a transition metal-free direct N-arylation to
synthesize phenoxazines/benzopyridoxazines by intramolecular cyclization for Iodo precur-
sor (Scheme 1c).[14] However, the reaction was unsuccessful with bromo precursor. Pratt
et al. reported copper-mediated synthesis of phenoxazines/benzopyridoxazines from Iodo
diphenyl ethers (Scheme 1d).[15] Eregowda et al. reported the synthesis of phenoxazines
from bromo diphenyl ethers under Ullmann condition at higher temperature for longer
duration (Scheme 1e).[16] Recently, Olofsson et al. reported the metal-free synthesis of
N-acetylphenoxazines by o-arylation of phenol with unsymmetrical diaryliodonium salt
followed by intramolecular N-arylation.[17] All these method of synthesis involve either
activated substrate (EWG) or transition metal-mediated conditions are required with lim-
ited substrate scopes. Also, de-protection (acetyl, formyl) steps are required to get the free
NH-phenoxazines. Thus, developing a metal free and general route to synthesize the skel-
eton of free NH- phenoxazines and benzopyridoxazines derivatives directly are useful to
further derivatize the various N-substituted analogues.
Our present work (Scheme 1f) involves microwave promoted rapid short time synthe-
sis of phenoxazines/benzopyridoxazines derivatives starting from a commercially avail-
able starting material or easily synthesized precursors.
Results and discussion
Initial attempts to develop the methodology of phenoxazine and benzopyridoxazine was
carried out with N-acetyl diphenyl ether (compound 5a), which could be easily synthe-
sized in a 3 step protocol starting from 1-fluoro-2-nitrobenzene with 2-bromo phenol
as shown in Scheme 2.[14] Base mediated nucleophilic displacement of compound 2a
with compound 1a resulted in 1-bromo-2-(2-nitrophenoxy)benzene 3a with 89% yield

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Scheme 1. Synthesis of phenoxazines and benzopyridoxazines.
Scheme 2. Synthesis of key intermediate N-(2-(2-bromophenoxy)phenyl)acetamide (5a).

4
A. KAVITHA ET AL.
Table 1. Optimization of reaction conditions for the synthesis of phenoxazine.
Yield
(%)a
(6a:6aa)
Temp.
Entry
Base
Solvent
[ꢁC]
Time [min]
1
2
3
4
5
6
7
8
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
DMF
DMF
DMF
DMF
DMSO
130
130
100
150
150
130
130
150
150
150
155
155
30
60
30
30
30
30
30
30
30
30
15
5
17:07
12:0
traces
28:0
11:0
09:0
00-0
00-0
32:0
NMP
Toluene
Xylene
DMF
DMF
DMF
9
10
11
12
Cs2CO3
Cs2CO3
Cs2CO3
67:0
83:0
DMF
48:27b
Reaction condition: 5a (0.5 mmol), base (1.0 mmol), 2 mL solvent in MW heating. aYield of isolated products by column
chromatography. b0.5 mmol (1.0 equiv.) of base was used.
(step-1). Which then taken for nitro reduction under SnCl2ꢀH2O condition to provide
the quantitative amine intermediate 4a (step-2). We attempted the direct intra molecu-
lar cyclization of amine 4a to get the phenoxazine 6a by using different bases in differ-
ent solvents at 100–180 ꢁC, were unsuccessful. As we have observed either unreacted
starting material or decomposed starting material. Further to favor cyclization over the
Smiles rearrangement,[18] we converted free amine 4a to the corresponding N-acetyl
diphenyl ether 5a by acetylation (step-3).
Optimization of the cyclization reaction was carried out using N-(2-(2-bromophenox-
y)phenyl)acetamide 5a as model substrate to get 10H-phenoxazine 6a or N-acetyl-phe-
noxazine 6aa. First, we chose conventional thermal heating condition (80 ꢁC to 160 ꢁC,
1–14 h) and observed traces of 10H-phenoxazine 6a (<10% isolated yield) and many
unidentified products. Further attempts to increase the yield of the phenoxazine 6a
were unsuccessful (data not shown). Then, we switched to microwave (MW) heating as
the high temperature reactions can be carried out safely in a microwave reactor. The
obtained results are shown in Table 1. To our delight, when we used Na2CO3 as a base
in DMF under microwave irradiation at 130 ꢁC for 30 minutes (Table 1, entry 1) we
obtained 17% of 10H-phenoxazine 6a and 7% of N-acetyl phenoxazine 6aa as product
by isolated yield. Reduced temperature and longer reaction time (Table 1, entries 2 and
3) affected the yield of the 6a negatively. Increasing the reaction temperature to 150 ꢁC,
resulted in slightly increased yield of 6a up to 28% (Table 1, entry 4). We screened mul-
tiple bases and solvents to optimize the yield as shown in Table 1, we found that
Cs2CO3 (2.0 equiv.) base and DMF as solvent under shorter duration (MW, 15 min at
155 ꢁC) resulted in excellent yield (83%) of 10H-phenoxazine 6a (Table 1, entry 11).
Further varying any of the parameters didn’t increase the yield of 6a. When the reaction
was performed with 1.0 equiv. of Cs2CO3 (Table 1, entry 12) we obtained 48% of 6a

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Scheme 3. Control experiment to trap the Smiles product (5aa).
and 27% 6aa. This result showed that the reaction required 2.0 equiv. of base in order
to get the acetyl cleaved free NH phenoxazine 6a as single product.
Although Smiles rearrangements of diaryl ethers bearing secondary amides have been
previously reported,[19] the control experiment was conducted to trap the rearranged
intermediate diphenyl amine 5aa (shown in Scheme 3). Since our optimized reaction
condition (Table 1, entry 11) gave major desired phenoxazine 6a, we just reduced the
reaction duration to 5 min. and identified the Smiles rearranged product 5aa was
formed in 22% along with 34% of cyclized phenoxazine 6a. When the reaction was car-
ried out at 100 ꢁC for 15 min under microwave conditions we obtained the Smiles rear-
ranged product N-(2-bromophenyl)-N-(2-hydroxyphenyl)acetamide 5aa in 78% yield
1
(Scheme 3, step-1). The isolated 5aa was characterized by H-NMR and 13C-NMR.
Further, the N-(2-bromophenyl)-N-(2-hydroxyphenyl)acetamide 5aa was exposed to
the standard reaction condition (Scheme 3, step-2) resulting in the formation of phe-
noxazine 6a in slightly lower yield (68%). Based on this experiment and observation, we
found that the reaction proceeds firstly Smiles rearrangement and forms the diphenyl
amine intermediate 5aa which then undergoes C-O bond formation by intramolecular
nucleophilic substitution (SNAr), subsequently the deacetylation happens under base
and high temperature condition to produces the 10H-phenoxazine 6a.
As shown in Scheme 4, in order to find the feasibility of the same cyclization to get
10H-phenoxazine 6a, the aryloxy acetanilides having different leaving groups X ¼ Cl
(5a0), F (5a00) and I (5a000) were synthesized (following the synthetic sequence in
Scheme 2) and attempted with the optimized reaction condition (Table 1, entry-11).
When X ¼ Cl (5a’) we obtained 85% of product and when X ¼ F (5a00) we obtained 90%
isolated yield of 10H-phenoxazine 6a. Similarly, the poor leaving group X ¼ I (5a000) also
cyclized and yielded 74% yield of 6a. With the optimized condition in hand, we set out
to investigate the scope of the various substituted key intermediates of aryloxy acetani-
lides having different leaving groups (Br, Cl, F and I) and functional groups like
(COOMe, CN, Me, Cl, Br, F) were synthesized (6a–6n) starting with the corresponding
phenol derivatives (1a–1n) and nitro derivatives (2a–2n) by following the Scheme 2
reaction sequence.[14] The results obtained are shown in Table 2. As expected, the cyc-
lization worked well with the ortho, meta and para substituted analogues (6a–6n).
Moreover, it indicates that the efficiency of the reaction toward electron releasing, neu-
tral and electron withdrawing substituted derivatives are well tolerant and provides
good yields of the corresponding phenoxazine derivatives.
The substrates (5a–5h) synthesized from 2-halophenol (1) and substituted nitro
derivatives (2a–2h) provided phenoxazines (6a–6h) in good yields as single isomer. To
further support that the reaction proceeds through Smiles rearrangement, the substi-
tuted aryloxy acetanilides (5i–5n) synthesized from substituted phenols (1i–1n) were
attempted for cyclization, resulting in the formation of rearranged products (6i–6n) in

6
A. KAVITHA ET AL.
Table 2. Synthesis of substituted phenoxazines/benzopyridoxazines.
Entry
1
Substrate 5
Product 6
Yield (%)a
H
N
X = Br, 83
X = Cl, 85
X = F, 90
X = I, 74
O
6a
H
N
2
3
82
88
O
Br
6b
NHAc
H
N
CO2Me
O
O
Br
CO2Me
6c
5c
Br
NHAc
O
4
5
76
Br
5d
X= Br, 77
X= I, 80
NHAc
H
N
Br
O
6
7
73
N
O
6f
N
N
Br
Br
5f
NHAc
H
N
O
72
N
O
6g
Br
5g
(continued)

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7
H
N
8
83
O
CN
6h
9
66
10
11
72
66
12
13
14
75
67
69b
a
Reaction conditions: (5a–5n) (0.5 mmol), Cs2CO3 (1.0 mmol), DMF (10 V) in MW for 15 min. Yield of iso-
lated products. bWe obtained major acetyl phenoxazine (6n) over deacetylated product <10%
(not isolated).
moderate yields. The isolated products were well characterized and verified by 2 D
NMR data (see supporting information). Our attempts to get the single crystals for the
isolated compounds were unsuccessful, as we noticed multi compounds in the same
sample after crystallization. Probably, decomposed due to the solution phase instability
or light sensitivity. In the case of example 6n, we observed major N-acetyl phenoxazine
(69%) over deacetylated product (<10%). Since the reaction condition is quite fast
(15 min.), we could not isolate/detect a Smiles rearranged intermediate for the substrates
(5b–5n). Also, the isolated phenoxazines were confirmed by 2 D NMR by correlating

8
A. KAVITHA ET AL.
Scheme 4. Generality of the cyclization with different leaving groups (5a–5a000).
Scheme 5. Synthesis of 6-bromo-3-chloro-10-methyl-10H-phenoxazine.
with exchangeable NH proton of phenoxazine, we alkylated one of the isolated phenox-
azine 6-bromo-3-chloro-10H-phenoxazine 6i to 6-bromo-3-chloro-10-methyl-10H-phe-
noxazine 7 (Scheme 5) and confirmed as well by methyl group interaction with arene
protons of phenoxazine by 2 D NMR (see supporting information). With this conclu-
sion, we report here that the cyclization reaction proceeds through Smiles/SNAr cas-
cade process.
Conclusion
We have described a general, highly chemo selective and metal free protocol for the
construction of free NH-phenoxazines and benzopyridoxazines from N-acetyl diphenyl
ethers. The optimized reaction condition worked well with the different leaving groups
(F, Cl, Br, I) substituted N-acetyl diphenyl ethers affords the corresponding phenoxa-
zines in moderate to good yields. As supported by trapping a Smiles intermediate (5aa)
and structural confirmation of isolated phenoxazines (6i–6n) by 2 D NMR, we identified
the reaction proceeds through Smiles rearrangement followed by intra molecular SNAr
cyclization. As the protocol involves metal free reaction condition, the substituted aryl
halides (I, Br, Cl) were compatible and provides the free NH-phenoxazine and benzo-
pyridoxazine scaffolds which we can used for further derivatization. Moreover, reaction
requires a very short time and isolated yields are good to moderate irrespective of leav-
ing groups and functional groups were attempted. Since the protocol involves micro-
wave reactor, the high temperature reaction condition is a safe and convenient to adopt
in laboratory scale synthesis.
Experimental section
General
Commercially available high purity grade chemicals were used as received without fur-
ther purification. TLC was performed with aluminum sheets silica gel 60 F254 (Merck)
and products were visualized by UV detection.1H NMR and 13C NMR spectra were

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9
recorded on Bruker 300 or 400 MHz and 75 or 100 MHz spectrometer respectively in
CDCl3/CD3OD/DMSO-d6 using TMS as an internal standard. Chemical shifts (d) are
given in ppm relative to TMS. Coupling constants J are reported in Hz and coupling
patterns are described as bs ¼ broad singlet, s ¼ singlet, d ¼ doublet, t ¼ triplet,
dd ¼ doublet of doublet, td ¼ triplet of doublet, q ¼ quartet, m ¼ multiplet. Mass spectra
were recorded on Liquid Chromatography Mass Spectrometry (LCMS) or Ultra
Performance Liquid Chromatography (UPLC). The compounds were isolated by Biotage
Isolera silica gel flash chromatography using silica gel (40–63 lm, 60 Å). Microwave
reactions were carried out using a Biotage Initiator 2.5 microwave synthesizer operating
at 0–400 W irradiation power, at a normal absorption level. Organic solutions were con-
centrated under reduced pressure on a Bu€chi rotary evaporator.
General experimental procedure for the synthesis of phenoxazines/benzopyridoxa-
zines (6a–6n)
A microwave tube equipped with a magnetic stir bar was charged with the correspond-
ing N-acetyl diphenyl ether (5a–5n) (1 mmol), Cs2CO3 (2 mmol) and DMF (20 V). The
resultant reaction mixture was heated at 155 ꢁC for 15 minutes by microwave irradi-
ation. After completion of the reaction, water was added, extracted with ethyl acetate.
The combined organic layer was dried over anhydrous Na2SO4 and the solvent was
removed under vacuum. The residue was then purified by Biotage Isolera silica gel
(40–63 lm, 60 Å) flash column chromatography (hexane/EtOAc, 95:5) to afford the cor-
responding phenoxazines/benzopyridoxazines (6a–6n).
Note: We noticed better recovery in the isolated yields, when the product was isolated
and purified as soon as the reaction completed.
Synthesis of N-(2-bromophenyl)-N-(2-hydroxyphenyl)acetamide (5aa)
A microwave tube equipped with a magnetic stir bar was charged with N-(2-(2-bromo-
phenoxy)phenyl)acetamide (5a) (0.10 g, 0.33 mmol), Cs2CO3 (0.107 g, 0.33 mmol) and
DMF (20 V). The resultant reaction mixture was heated at 100 ꢁC for 15 minutes by
microwave irradiation. After completion of the reaction, water was added, extracted
with ethyl acetate. The combined organic layer was dried with anhydrous Na2SO4 and
the solvent was removed under vacuum. The residue was then purified by Biotage
Isolera silica gel (40–63 lm, 60 Å) flash column chromatography (hexane/EtOAc, 80:20)
to afford N-(2-bromophenyl)-N-(2-hydroxyphenyl)acetamide 5aa 0.078 g (78% yield) as
a off white solid. LCMS (ES þ APCI-MS) calcd. For C14H12BrNO2: 305.01, found
(M þ H)þ ¼ 306.0; 1H-NMR (400 MHz, DMSO-d6): d 10.50 (bs, 1H), 7.70 (d,
J ¼ 7.60 Hz, 1H), 7.48–7.12 (m, 5H), 7.10–6.81 (m, 2H), 1.93 (s, 3H); 13C-NMR
(100 MHz, CDCl3): d 171.99, 150.90, 142.12, 134.25, 130.81, 130.26, 130.18, 129.19,
128.74, 125.69, 123.56, 121.07, 120.51, 23.66; Anal calc. for C14H12BrNO2: C, 54.92; H,
3.95; N, 4.58%; found C, 55.01; H, 2.85; N, 4.39%.
10h-phenoxazine (6a)
Following the general procedure using N-(2-(2-bromophenoxy)phenyl)acetamide 5a
(0.50 g, 1.63 mmol)) provided 0.25 g (83% yield) of the product 6a as a white solid.

10
A. KAVITHA ET AL.
1
LCMS (ES þ APCI). calcd. For C12H9NO: 183.06, found (M þ H)þ¼ 184.0; H-NMR
(400 MHz, DMSO-d6): d 8.16 (s, 1H), 6.71 (td, J ¼ 1.60, 7.40 Hz, 2H), 6.60–6.53 (m,
4H), 6.44 (dd, J ¼ 1.20, 7.60 Hz, 2H); 13C-NMR (100 MHz, DMSO-d6): d 143.23, 132.88,
124.37, 120.78, 115.52, 113.74. The analytical data are consistent with previ-
ous reports.[20].
Synthesis of 1-(10H-phenoxazin-10-yl)ethan-1-one (6aa)
A microwave tube equipped with a magnetic stir bar was charged with the N-(2-(2-bro-
mophenoxy)phenyl)acetamide 5a (0.155 g, 0.5 mmol), Na2CO3 (0.11 g, 1.0 mmol) and
DMF (20 V). The resultant reaction mixture was heated at 130 ꢁC for 30 minutes by
microwave irradiation. After completion of the reaction, water was added, extracted
with ethyl acetate. The combined organic layer was dried with anhydrous Na2SO4 and
the solvent was removed under vacuum. The residue was then purified by Biotage
Isolera silica gel (40–63 lm, 60 Å) flash column chromatography (hexane/EtOAc, 95:5)
to afford 8 mg (7% yield) of the product 6aa as a white solid; LCMS (ES þ APCI-MS)
1
calcd. For C14H11NO2: 225.08, found (M þ H)þ ¼ 226.2; H-NMR (400 MHz, DMSO-
d6): d 7.62–7.60 (m, 2H), 7.28–7.16 (m, 6H), 2.27 (s, 3H); 13C-NMR (100 MHz, DMSO-
d6): d 169.27, 150.80, 129.69, 127.49, 125.88, 124.05, 117.07, 23.19. The analytical data
are consistent with previous reports.[14]
Synthesis of 6-bromo-3-chloro-10-methyl-10H-phenoxazine (7)
To a stirred solution of 6-bromo-3-chloro-10H-phenoxazine (6i) (0.10 g, 0.34 mmol) in
DMSO (10 V) was added KOH (0.64 mmol) at 0 ꢁC. The resulting solution was stirred
at RT for 15 mins. Then added MeI (0.37 mmol) in one lot. The reaction mixture was
stirred at RT for 18 h. The reaction mixture was diluted with water, extracted with ethyl
acetate. The combined organic layers were washed with water, brine, dried over anhyd-
rous Na2SO4, filtered through a cotton plug and concentrated under reduced pressure.
The resulting crude was purified by Biotage Isolera silica gel (40–63 lm, 60 Å) flash col-
umn chromatography (hexane/EtOAc, 95:5) to afford 0.085 g (81% yield) of 6-bromo-3-
chloro-10-methyl-10H-phenoxazine (7) as a off white solid. LCMS (ES þ APCI-MS)
1
calcd. For C13H9BrClNO: 308.9, found (M þ H)þ ¼ 310.9; H-NMR (400 MHz, CDCl3):
d 6.91 (dd, J ¼ 1.20, 8.20 Hz, 1H), 6.84 (d, J ¼ 2.40, Hz, 1H), 6.83–6.82 (m, 1H), 6.72 (t,
J ¼ 8.00 Hz, 1H), 6.43 (dd, J ¼ 1.20, 8.00 Hz, 1H), 6.41 (d, J ¼ 8.00 Hz, 1H), 3.01 (s, 3H);
13C-NMR (100 MHz, CDCl3): d 145.49, 142.10, 135.81, 133.23, 125.88, 124.85, 124.55,
123.88, 116.17, 112.06, 110.57, 109.48, 31.25; Anal calc. for C13H9BrClNO: C, 50.27; H,
2.92; N, 4.51%; found C, 50.01; H, 3.10; N, 4.68%.
Acknowledgments
The authors are thankful to Dr. Subhendu Kumar Mohanty, Dr. Sathya Shanker and Karthik T.
Pai for their support and encouragement throughout this work. Kavitha is grateful to Syngene
International Ltd, Bangalore, India for analytical support and the permission for higher educa-
tion (Ph.D.).

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11
Funding
, Kavitha is grateful to Syngene International Ltd, Bangalore, India for financial support.
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