Iodine-mediated direct synthesis of 3-iodoflavones

Article abstract of DOI:10.1080/00397911.2018.1440601

Molecular iodine has been used for the regioselective, one pot, direct synthesis of 3-iodoflavones from 2′-allyloxy chalcones, 2′-hydroxy chalcones and flavones. Allyl deprotection, cyclization dehydrogenation and α-iodination of 2′-allyloxychalcones has been achieved in a single step to offer 3-iodoflavones.

Full text of DOI:10.1080/00397911.2018.1440601

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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Iodine-mediated direct synthesis of 3-iodoflavones
Avinash M. Patil, Dayanand A. Kamble & Pradeep D. Lokhande
To cite this article: Avinash M. Patil, Dayanand A. Kamble & Pradeep D. Lokhande (2018):
Iodine-mediated direct synthesis of 3-iodoflavones, Synthetic Communications, DOI:
10.1080/00397911.2018.1440601
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https://doi.org/10.1080/00397911.2018.1440601
Iodine-mediated direct synthesis of 3-iodoflavones
Avinash M. Patil, Dayanand A. Kamble, and Pradeep D. Lokhande
Department of Chemistry, The Centre for Advanced Studies, Savitribai Phule Pune University, Pune,
Maharashtra, India
ABSTRACT
ARTICLE HISTORY
Received 24 November 2017
Molecular iodine has been used for the regioselective, one pot, direct
synthesis of 3-iodoflavones from 20-allyloxy chalcones, 20-hydroxy
chalcones and flavones. Allyl deprotection, cyclization dehydrogena-
tion and α-iodination of 20-allyloxychalcones has been achieved in a
single step to offer 3-iodoflavones.
KEYWORDS
2-Allyloxy chalcone;
3-iodoflavone; chromenone;
deallylation; molecular
iodine
GRAPHICAL ABSTRACT
Introduction
Flavones are available naturally and can also be prepared by chemical syntheses.[1] These
are known to exhibit some of the important bioactivities like COX-2 inhibitors, antiviral,
tyrosine, and protein kinase C inhibition, antitubulin, antihypertensive, anti-inflammatory,
and anticancer.[2] Haloflavones particularly iodoflavones are highly significant in synthetic
organic chemistry.[3] Flavones and their haloderivatives have been studied widely and
intensively in recent decades.[4]
Flavonoids, iodoflavonoids, and iodothioflavonoids are potential intermediates in
diversity oriented synthesis, metal catalyzed coupling reactions[5] and 2,3-diaryl flavonoids.
In general, there are two distinct methods to obtain the 3-iodoflavones, (i) from acyclic
compounds-like chalcones and (ii) from chromones. Both of these reported synthetic
methods suffer from the drawbacks, such as use of unstable and moisture sensitive
reagents, such as ICl[5] and LDA.[6] A transition metal containing activator-like
[8]
cerium(IV) ammonium nitrate (CAN)[7] (Fig. 1) or the strong acid, such as H2SO4 is
needed whereas iodine mediated synthesis has not been explored to its capacity,[9] where
molecular iodine is used as the iodinating reagent. A two-step process (i) α-metallation[3,5]
and (ii) electrophilic iodination[3] is required when unsubstituted flavones are used as
substrates. Therefore, the problem of regioselective iodination and use of multiple synthetic
operations need to be dealt with further. Therefore, owing to the pharmaceutical and
CONTACT Pradeep D. Lokhande
pdlokhande@chem.unipune.ac.in
Department of Chemistry, The Centre for
Advanced Studies, Savitribai Phule Pune University, Pune 411007, Maharashtra, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
© 2018 University Grants Commission, India

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A. M. PATIL ET AL.
Figure 1. Synthesis of 3-iodoflavones. Note: CAN, cerium(IV) ammonium nitrate; DMSO, dimethyl sulfoxide.
synthetic importance of iodoflavones, development of a direct and regioselective synthetic
method is highly desirable.
Molecular iodine is an economic, safe and easily available reagent for an organic
transformation. Moderate Lewis acidic nature of iodine facilitates it’s usage in organic
synthesis.[10] In continuation to our efforts to explore the iodine chemistry for the new
and useful organic transformations, it was always our priority to minimize the use of metals
and other toxic chemicals used in the synthetic chemistry. Aromatization/dehydrogenation
followed by selective iodination of partially saturated aliphatic rings,[11] O-deallylation,[12]
and oxidative cyclizations[13] have been performed under the metal-free environment.
Specifically, the use of substoichiometric amount of I2 in dimethyl sulfoxide (DMSO)
offered the deallylation of allyl phenyl ethers.[14] But in our recent invention, use of stoi-
chiometric I2 resulted in O-deallylation, and aromatic iodination of allyl phenyl ethers.[15]
Whereas recently the 20-allyloxychalcones and 20-hydroxychalcones unexpectedly offered
the corresponding iodoflavones instead of aromatic iodination using molecular iodine.
This obtained result has been described in the present manuscript.
Results and discussion
As a continuation to our ongoing efforts toward the exploration of the utility of molecu-
lar iodine in the synthetic organic chemistry,[11–15] we thought to examine the response
of 20-allyloxychalcones under some varied reaction conditions using I2/DMSO system.
Accordingly when a 0.5 equiv. of molecular iodine was added to the solution of
20-allyloxychalcone 1a in DMSO solvent and heated at 120 °C for 30 min. we got the
corresponding flavone 3a in 96% yield (Table 1, entry a).[16] We thought to increase
the reaction time under similar stoichiometric conditions, we got mixture of flavone
3a (58%) and 3-iodoflavone 2a (31%) after 6 h (Table 1, entry b). This result prompted

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Table 1. Optimization of the reaction conditions for the synthesis of 3-iodoflavone.
Entry
I2 (equiv.)
Temperature (°C)
Time (h)
Yielda (%) 2a
Yielda (%) 3a
a
b
c
d
e
0.5
0.5
1.0
1.3
1.5
120
120
120
120
120
0.5
6
–
96
58
20
–
31
71
92
92
6
6
6
–
aYield refers to an isolated yield after column chromatography.
DMSO, dimethyl sulfoxide.
us to increase the quantity of I2, accordingly use of 1 equiv. of molecular iodine resulted
in the increased yield (71%) of the 3-iodoflavone 2a and 20% of unsubstituted flavone
3a when stirred for 6 h under the same temp and solvent conditions (Table 1,
entry c). From these obtained results it was evident that increase in the equivalence of
molecular I2 is required further to obtain the desired 3-iodoflavone exclusively. Accord-
ingly, when 1.3 equiv. I2 was used 3-iodoflavone was obtained in excellent yield (92%)
without any traces of unsubstituted flavone (Table 1, entry d). However, further increase
in the quantity of the I2 (1.5 equiv.) did not cause any additional advantage to this
method (Table 1, entry e).
The conversion of 20-benzyloxychalcones[17] to the corresponding flavones is already
known in the literature but, it has not been extended to the preparation of 3-iodoflavones.
We have converted 20-allyloxychalcones to 3-iodoflavones under the optimized reaction
condition (Table 1, entry d). Various 20-allyloxychalcones 1a–l have been examined under
the optimized reaction condition to obtain the corresponding 3-iodoflavones 2a–l in good
to excellent yields (Table 2, entries 1–12). However, there was no particular trend observed
Table 2. Synthesis of 3-iodoflavones from 20-allyloxychalcones.
Entry
1
Substrate
Product
Yield (%)
92
(Continued)

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A. M. PATIL ET AL.
Table 2. Continued.
Entry
2
Substrate
Product
Yield (%)
88
3
85
4
5
87
88
6
7
8
9
91
87
88
89
10
85
(Continued)

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Table 2. Continued.
Entry
11
Substrate
Product
Yield (%)
91
12
85
DMSO, dimethyl sulfoxide.
with respect to yield, in case of activating or deactivating substituents on ring B of the
substrates. The substrate bearing strong electron-withdrawing group like nitrile (–CN) also
offered better yield (85%) of the corresponding iodoflavone. When 20-allyloxychalcone
bearing allyloxy group on ring B was stirred under the optimal reaction condition, offered
the corresponding flavone (monitored using TLC) within 30 min. Continuation of the
same reaction for 6–7 h resulted in the inseparable mixture of compounds. Further increase
in I2 equivalence or reaction hours resulted in more complex products.
With the successful conversion of all the 20-allyloxychalcones to the corresponding
3-iodoflavones, we got curious to check the response of 20-hydroxychalcones under the
same reaction condition. Consequently, usage of unsubstituted 20-hydroxychalcone 4a
produced 3-iodoflavone 2a in 94% yield with a greater ease. But a 10 °C increase in the
reaction temp reduced the reaction time to 2.5–3 h. Therefore, various activated and
deactivated 20-hydroxychalcones 4a–e, m were converted efficiently to obtain the
corresponding 3-iodoflavones 2a–e, m in better yields (Table 3).
Table 3. Synthesis of 3-iodoflavones from 20-hydroxychalcones.
Entry
1
Substrate
Product
Yield (%)
94
2
86
(Continued)

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A. M. PATIL ET AL.
Table 3. Continued.
Entry
3
Substrate
Product
Yield (%)
87
4
89
5
6
91
89
DMSO, dimethyl sulfoxide.
However, the yield obtained in case of unsubstituted 3-iodoflavones was little higher
compared to substituted 3-iodoflavones. The required 2–3 alkene in 3-iodoflavone already
exists in the acyclic substrates where, aromatic alkynones are used as the starting material[5]
(Fig. 1). But here, in case of 20-allyloxy and 20-hydroxychalcones double bond is generated
after the cyclization step where molecular iodine acts as dehydrogenating reagent.
Although there are a few reports about the preparation of 3-iodoflavones from the
corresponding flavones which use Li, Zn, and cerium metal containing activators, still there
is scope for the use of ecofriendly reagent like molecular I2. As a trial when we examined
flavone 3a under optimized reaction condition, to our delight we got the corresponding
3-iodoflavone 2a with better yield (Table 4, entries 1–6). The reaction time was successfully
Table 4. Synthesis of 3-iodoflavones from flavones.
Entry
1
Substrate
Product
Yield (%)
92
(Continued)

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Table 4. Continued.
Entry
2
Substrate
Product
Yield (%)
89
88
90
3
4
5
6
87
89
DMSO, dimethyl sulfoxide.
reduced to 2–2.5 h just by a 10 °C increase in the temperature and various substrates (3a–d,
m, n) were converted to the corresponding 3-iodoflavones (2a–d, m, n). Various
substitution on ring B could not affect the yields significantly.
Flavone 3n bearing 40-allyloxy group was smoothly converted to 3-iodoflavone 2n (yield
89%) keeping the allyloxy group unaffected on the ring B. Probably, addition of iodine to
activated alkene followed by oxidative cyclization is a preferred process, and the generated
iodine may be interacted with the new alkene bond. Thus, iodine may not be available for
deallylation in B-ring. This selective deallylation reaction could find an application in the
synthesis of some natural products.[18]
All the chalcones were easily prepared by the well-known Claisen–Smidth condensation
of the commercially available 20-hydroxyacetophenones and different substituted
benzaldehydes.[19] 20-allyloxychalcones were prepared by the treatment of allyl bromide
with the 20-hydroxychalcones in K2CO3/DMF condition.[20] Flavones 3a–d, m, n were
prepared by the treatment of corresponding 20-hydroxychalcones with 0.6 equiv. of
molecular iodine in DMSO solvent at 130 °C.[21]
Stirring of 20-allyloxychalcones and 20-hydroxychalcones separately under the
I2-DMSO condition for 0.5 h resulted in the formation of flavones (Table 1, entry a).
Whereas various flavones have been converted in to the corresponding 3-iodoflavones
(Table 4). This observed experimental outcome suggests that this iodination reaction

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A. M. PATIL ET AL.
Figure 2. Probable mechanism for the regioselective iodination of flavones. Note: DMSO, dimethyl
sulfoxide.
proceeds via flavone intermediate. DMSO solvent might be helping in dehydro-
iodination process. The phenolic oxygen facilitates the iodination at 3-position, as
depicted in Fig. 2.
Conclusion
In conclusion, we have developed an iodine mediated direct one pot procedure for the
exclusive synthesis of 3-iodoflavones from 20-allyloxychalcones, 20-hydroxychalcones
and flavones in high yields. Deallylation, cyclization, dehydrogenation, and
iodination reactions occur in one-pot, avoiding the isolation of flavanone and flavone
intermediate. Nonindulgence of ring “A” in the iodination process proves the
regioselectivity of this method. Easy preparation of all the substrates renders this
method more practical. 20-hydroxychalcones are useful where protection is not needed
and 20-allyloxychalcones are useful where protection is needed for the synthesis of
3-iodo-flavones. 3-Iodoflavones are potential candidates to be used for different
couplings and functional transformations.
Acknowledgment
Avinash M. Patil and Dayanand A. Kamble thank CSIR, New Delhi and UGC-DSK for the award of
research fellowships.
Funding
This work was supported by the University Grants Commission, DSK, India [Grant Number F.4-2/
2006 (BSR)/CH/15-16/0079] and Council for Scientific and Industrial Research, India [Grant
Number 09/137(0534)/2012-EMR-I].
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