Transition metal free regio-selective C-H hydroxylation of chromanones towards the synthesis of hydroxyl-chromanones using PhI(OAc)2 as the oxidant

Article abstract of DOI:10.1039/c7cc08588e

The chromanone scaffold is considered as a privileged structure in drug discovery. Herein, we report a highly efficient PhI(OAc)₂ mediated regioselective, direct C-H hydroxylation of chromanones. This method offers easy access to substituted 6-hydroxy chromanones in moderate to good isolated yields, thus paving the way for their pharmaceutical studies.

Full text of DOI:10.1039/c7cc08588e

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DOI: 10.1039/C7CC08588E.
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DOI: 10.1039/C7CC08588E
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Transition Metal Free Regio-selective C-H Hydroxylation of
Chromanones towards the Synthesis of Hydroxyl-Chromanones
using PhI(OAc)2 as Oxidant
Received 00th January 20xx,
Accepted 00th January 20xx
N.Viswanadh,ac Ganesh S. Ghotekar,ac Mahesh B. Thoke,a R.Velayudham,a Aslam C. Shaikh,ac M.
DOI: 10.1039/x0xx00000x
Karthikeyanbc and M. Muthukrishnan*ac
www.rsc.org/
Abstract: The chromanone scaffold is considered as privileged for the synthesis of corresponding hydroxylated products.9 Later,
structure in drug discovery. Herein, we report a highly efficient research group of Dong and Rao, independently developed a
PhI(OAc)2 mediated regioselective, direct C−H hydroxylation of carbonyl group directed Pd-catalyzed ortho-hydroxylation of
chromanones. This method offers an easy access to substituted 6- arenes. 10 Similarly, the group of Sun 11 and Guin 12 developed
hydroxy chromanones in moderate to good isolated yields, thus palladium catalysed pyridyl-directed homogeneous hydroxylation of
paves the way for their pharmaceutical studies.
the aryl C−H bond in which TBHP was used as a sole oxidant. By
using oxime ether as a directing group, Jiao and co-workers
reported an efficient Pd-catalyzed, directed ortho C−H
hydroxylation of arenes.13 In 2013, Ackermann and co-workers
reported ruthenium catalysed site selective C-H oxygenation with
weakly-coordinating aromatic ketones as well as aldehyde. 14
Mizuno et al. reported divanadium-substituted phospho-tungstate
catalysed unique chemo- and regio-selective hydroxylation of
arenes with aqueous H2O2.15 Very recently, Maiti and co-workers
Chromones are privileged structural motifs; they are ubiquitous
in plethora of natural products and pharmaceutically important
compounds. They display exceedingly diverse range of biological
activities such as antitumor, antioxidant, antibacterial, and anti-
inflammatory properties.1 Incorporation of hydroxyl functionality
into a chromone moiety (either natural or synthetically) often
compliment with better activity profile than the parent molecules.2
Therefore, the regio and chemo selective introduction of hydroxyl
into chromone framework especially chromanones3 and related
complex molecules received considerable attention.4 However, late
stage and selective introduction of hydroxyl into C-6 position of
chromanones is unknown in the literature. Importantly, many
chromanone molecules possessing C-6 oxygenation pattern are
found to be biologically significant (Figure 1).5,6
reported the scope of template assisted palladium catalysed direct
16
meta-hydroxylation/acetoxylation strategy.
Despite these
significant progresses, regio- and chemo-selective direct C-H
hydroxylation of complex heterocyclic scaffolds in the absence of
directing group remains a challenge. Therefore, a practical and
efficient approach for regio-/chemo-selective direct C−H
hydroxylation under mild reaction condition is highly desirable.
In recent years, C-H bond functionalization, in particular selective
oxidation of aromatic C-H bonds has emerged as a powerful tool in
organic synthesis.7 , 8 This approach is extermely useful in the
synthesis of various therapeutically active agents and natural
products, as it conveniently provides the functionality that is
required in the final target molecule or facilitating subsequent
chemical transformations. Transition metal catalyzed C-H
hydroxylation were accomplished with the assistance of directing
groups such as pyridine, carbonyl, ketoxime, or amide, and mostly
utilizing palladium, rhodium, or ruthenium as catalysts (Scheme 2a).
For instance, Sanford and co-workers disclosed their seminal work
on palladium catalysed directed C−H acetoxylation of ketoxime
ether substrates with PhI(OAc)2 or oxone/AcOH oxidative system
Figure 1. Representative examples of biologically significant C-6
hydroxylated chromanones
a.Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr.
HomiBhabha Road, Pune - 411 008, India, E-mail: m.muthukrishnan@ncl.res.in.
b.Division of Chemical Engineering and Process Development, CSIR-National
Chemical Laboratory, Dr. HomiBhabha Road, Pune - 411008, India.
c. Academy of Scientific & Innovative Research (ACSIR), CSIR-NCL Campus, Pune,
India.
As part of our long standing interest in synthesis-cum-structural
modifications of privileged chromone scaffolds for various biological
applications,17 we sought to develop a robust protocol for the
synthesis of hydroxylated chromanones in a regioselective manner.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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the desired C-6 oxygenated product (entries 5-9), and PhI(OAc)2
Herein, we disclose our findings of novel, metal free and
regioselective (C-6) C-H hydroxylation of chromanones using
hypervalent iodine as an oxidant and TFA/H2O system as a solvent.
To the best of our knowledge, there is no report on late stage
induction of C-H hydroxylation at C-6 position of chromanone
scaffold is available (Scheme 2b).
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appears to be the best. Improvement in the yield was observed
DOI: 10.1039/C7CC08588E
upto 48%, when the temperature was increased to 120 °C for 12 h
(entry 10). To our surprise, the formation of desired product has
been improved to 70% when 1.2 equiv of PhI(OAc)2was used (entry
11). Further incresearing the equiv of PhI(OAc)2unable to enhance
the yield (entry 12). In the absence of H2O, the yield of C-6
oxygenation product has dropped down (entry 13). The PhI(OAc)2 is
crucial for the reaction; in absence of PhI(OAc)2 failed to form
desired C-6 oxygeantion product ( entry 14).
Table2.Scope of C6 C−H hydroxylation of chromanonesa,b
Scheme 2. Regioselective C−H hydroxylation previous work and this
work.
Table 1. Optimization of reaction conditionsa,b
Entry
Oxidant
Conditions
Yield (%)
6a
1
2
3
4
5
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
AcOH/H2O, 100°C, 12 h
TCA/H2O, 100°C, 12 h
TFA/H2O, 100°C, 12 h
TFA/TFAA/H2O, 100°C, 12 h
12
<5
35
20c
28
PhI(CF3CO2)2 TFA/H2O, 100°C, 12 h
6
7
8
9
10
11
12
13
14
K2S2O8
(tBuO)2
(BnO)2
Selectfluor
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
-
TFA/H2O, 100°C, 12 h
TFA/H2O, 100°C, 12 h
TFA/H2O, 100°C, 12 h
TFA/H2O, 100°C, 12 h
TFA/H2O, 120°C, 12 h
TFA/H2O, 120°C, 12 h
TFA/H2O, 120°C, 12 h
TFA, 120°C, 12 h
20
<5
<5
<5
48
70d
68e
28
TFA/H2O, 120°C, 12 h
<5f
aReaction conditions: 0.11 mmol 5a, 0.11 mmol oxidant, solvent (1
b
c
ml (1:1). Isolated yields. Formation of 6a’ observed in 16% yield.
d1.2 Equiv of PhI(OAc)2 was used. 1.5 Equiv of PhI(OAc)2 was used.
e
fReaction was conducted without PhI(OAc)2. Ac = acetyl, TCA =
trichloroacetic acid, TFA
trifluoroaceticanhydride.
=
trifluoroacetic acid, TFAA
=
We initiated our optimization studies with spiro[chromane-2,1'-
cyclohexan]-4-one (5a) as a model substarte (Table 1). Initally,
treatment of 5a with PhI(OAc)2 in AcOH/H2O (1:1) as a mixture of
solvent at 100 °C, we observed the formation of C-6 oxygenation
product 6a in 12% yield. The structure of 6a was unambiguously
confirmed by single crystal anaylsis as well as 2D NMR
spectroscopy. Intrigued by this interesting observation several
reaction conditions were tried, the TFA/H2O mixture in 1:1 ratio was
found to be better, yielding the desired product in 35% yield ( entry
3). Next we investigated the influence of various oxidants on C-6
hydroxylation of chromanones. Oxidants such as PhI(CF3CO2)2,
K2S2O8, (tBuO)2, (BnO)2 and Selectfluor were not efficient to afford
aReaction conditions: 0.37 mmol 5a, 0.44 mmol oxidant, TFA:H2O (1
ml (1:1). bIsolated yields. cNo formation of desired product.
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With the optimized reaction condition in hand, we next set out to regioselectivity, the results indicates that para-hyVdireowxAyrtliactleioOnnlinies
DOI: 10.1039/C7CC08588E
explore the scope of regioselective C−H hydroxylation at C6 position more favoured over the ortho hydroxylation with respect to oxygen
of various spiro-chromanones. As shown in Table 2, C-6 (see ESI). As shown in Scheme 4, eq. b, preliminary mechanistic
regioselective oxygenation of chromanones proceeded well to give experiment shows the dual role of TFA/H2O as both the oxygen
the desired products irrespective of substitution patterns at spiro source and the essential factor for the conversion of C-H to C-O
position of chromanones. Both symmetrical and unsymmetrical transformation. When the reaction of 5a was performed using
substituents at spiro position such as methyl-methyl (6b), ethyl- labelled H2O18, the products incorporating O16 and O18 were formed
methyl (6c), ethyl-ethyl (6d), methyl-propyl (6e), methyl-ipropyl (6f) in 6.4:1 ratio, indicating C-6 oxygen is predominantly derived from
and methyl-ibutyl (6g) were compatible, providing C-6 oxygenated TFA over labelled H2O18 (see ESI).
chromanone in moderate to good yield. Introduction of long chain
substitution at spiro position of chromanones did not hamper the
outcome of the reaction, and 6h-6k were obtained in good yield
(52-78%). Spirochromanone bearing six, five and seven membered
ring underwent smooth reaction with PhI(OAc)2 to obtain the
corresponding C-6 oxygenated products 6l, 6m and 6n in 48%, 69%
and 72% yields respectively. Further, the reaction condition is
tolerable at substitution in aryl ring as well (6o-6p, 56-62% yield).
Intersetingly, the simple chromanone also offered the desried
product under optimzed reaction condition (6q, 42% yield).
However, xanthone, coumarin and nitrogen herocycles were failed
to yield the desired product.
Scheme 4. Controlled experiments
Table 3. Scope of 2-alkoxy acetophenonea,b
aReaction conditions: 0.37 mmol 7a, 0.44 mmol oxidant, TFA:H2O (1
c
ml(1:1). bIsolated yields. Reaction leads to the formation of allyl
migrated product (8c’, 20% yield). dNo formation of desired Scheme 5. A plausible mechanism
product.
On the basis of our controlled experiments, a plausible reaction
mechanism is depicted in Scheme 5. The nucleophilic attack of
phenyl ring of chromanone to iodonium species A, leads to the
Next, we found out that our optimized reaction is not only
limited to spirochromanones, it works well with 2-alkoxy aryl
ketones as well. The 2-methoxy, 2-ethoxy and 2-isopropoxy
formation of another iodonium intermediate
C
through
acetophenones also proceeds well for C-6 oxygenation reaction to
form the desired products 8a-8d in moderate yield. The structure of
8d also confirmed by single X-ray crystal analysis. In the case of 2-
allyloxy acetophenone, C-6 oxygented product 8c formed in 15 %
yield; along with allyl migrated product 8c‘ in 20% yield (see ESI).
However,the reaction failed to give desired hydroxylated product in
the case of 2-methoxy benzaldehyde andethyl 2-methoxybenzoate.
Next, we examined the regioselectivity of C−H hydroxylation by
blocking the 6th position of chromanone by methyl/chloro
substituent. However, the reaction leads to the formation of ring
migrated product 10a-10b exclusively (Scheme 4, eq. a).18 Further,
the DFT calculation has been performed to study the
intermediate B. The nucleophilic attack of trifluoroacetate anion on
iodonium salt C generates the intermediate D, which on hydrolysis
to afford the desired product. However, nucelophilic attack of H2O
to intermediate C leading to the product cannot be ruled out at this
stage accoording to our controlled experiment.
It is worthy to mention here that, 6-hydroxy chromanone can be
an important starting point for the synthesis of various biologically
important molecules. As depicted in Scheme 6, Desoky et. al.
reported the synthesis of biologically active compounds 11a-11c,
starting from compound 6b.19 Moody‘s group has also utilised
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compound 6b as a starting material for the synthesis of natural
product (R)-(-)-Pestalotheol D(1).20
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DOI: 10.1039/C7CC08588E
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In conclusion, we have successfully developed
a novel,
regioselective, transition metal free protocol for C-6 hydroxylation
of chromanones. Using this late stage functionalization method, we
synthesized diverse range of 6-hydroxy chromanones in moderate
to good yields. Preliminary mechanistic study reveals that TFA/H2O
solvent system serves as both the critical C-H functionalization
factor and also an oxygen source. It is noteworthy that a wide range
of natural products and biologically active compounds contain a 6
oxo-chromanone framework. This protocol can be easily utilized for
the synthesis of those biologically relevant molecules.
Generous financial supports from CSIR-New Delhi (CSC0108 and
CSC0130) are gratefully acknowledged. VN, GSG and ACS thank UGC
& CSIR-New Delhi for the award of senior research fellowships. We
thank Dr. Rajesh Gonnade, CSIR-NCL for providing single crystal X-
ray diffraction data.
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