Hydroxyl directed: C -arylation: Synthesis of 3-hydroxyflavones and 2-phenyl-3-hydroxy pyran-4-ones under transition-metal free conditions

Article abstract of DOI:10.1039/c7ob01929g

An efficient, transition-metal free and direct C-arylation of 3-hydroxychromone moieties in the presence of a base, air as an oxidant and arylhydrazines as arylating agents to furnish highly biologically active flavonols or 3-hydroxyflavones has been developed. We have further extended our methodology for the C-arylation of the 5-hydroxy pyran-4-one moiety. The role of the free hydroxyl group towards C-arylation has been delineated.

Full text of DOI:10.1039/c7ob01929g

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DOI: 10.1039/C7OB01929G
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ARTICLE
Hydroxyl directed C-arylation: synthesis of 3-hydroxyflavones and
2-phenyl-3-hydroxy pyran-4-ones under transition-metal free
conditions
Received 00th January 20xx,
Accepted 00th January 20xx
Sayantan Paul, a,b and Asish K. Bhattacharyaa,b*
DOI: 10.1039/x0xx00000x
www.rsc.org/
OH
An efficient, transition-metal free and direct C-arylation of 3-
hydroxychromone moieties in presence of base, air as oxidant and
arylhydrazines as arylating agent to furnish highly biologically
active flavonols or 3-hydroxyflavones has been developed. We
have further extended our methodology for the C-arylation of 5-
hydroxy pyran-4-one moiety. The role of free hydroxyl group
towards C-arylation has been delineated.
MeO
O
OR1
OH
OH
OAc
OH
O
HO
O
O
O
O
III
OH
OMe
OH
OH
O
II
IV, Macaranone
A
B
O
O
A
C
OH
O
OH
O
O
HO
OH
O
HO
O
O
OH
3-Hydroxyflavone
I
OH
OH
O
V, Silycristin A
OH
O
HO
Flavonols or 3-hydroxyflavones (3-HF, I), a unique class of flavonoid
are ubiquitous in nature and are present in various plant families.1
These have been found to be highly biologically active molecules
(Figure 1).2 Compound II was isolated3 from EtOAc extract of the
leaves and twigs of Pistacia atlantica (Anacardiaceae) and shows
antiplasmodial activity against Plasmodium falciparum strain K1
(chloroquine and pyrimethamine resistant) with IC50 value of 3.4
µM. The alcoholic extract of the aerial parts of Nervili fordii
(Orchidaceae) afforded compound III which was found to be active
(IC50 16.8 µM) against NO production in lipopolysaccharide-
stimulated murine macrophage (RAW264.7).4 Macaranone A IV
active against (IC50 6.9 µM) human liver cancer cell line (HepG2) was
isolated from EtOAc extract of the leaves of Macaranga sampsonii
(Euphorbiaceae).5 Silychristin V and silybin VI found in the fruits of
Silybum marianum were found to possess radical scavenging and
inhibition of lipoperoxidation activities.6 Saggenone D VII was
isolated from the root bark of white mulberry tree, Morus alba L.
(Moraceae) and shows inhibitory activities against influenza A virus
and Streptococcus pneumoniae with IC50 values of 3.1 μM and 31.6
μM respectively.7 Recently, flavonols based Ru(II) metal drugs have
been developed as anticancer agents.8
VII, Sanggenon
C
O
O
OH
OH
HO
O
O
HO
HO
OH
OH
OH
O
VI, Silybin
Figure
hydroxyflavones (3-HF)
1
Representative bioactive compounds containing the 3-
synthesis of various biologically active aromatic compounds. The
most favoured method for C–H functionalization/activation being
the use of transition-metal catalysed reactions.9 However,
transition-metal catalysed reactions have their own limitations such
as high cost of the catalysts and harsh reaction conditions etc.10 The
synthesis of 3-hydroxyflavones is presently being carried out using
Algar-Flynn-Oyamada (AFO) reaction,11 which requires longer
reaction time and the product is formed in less yield. Therefore,
development of a reaction for the synthesis of 3-hydroxyflavones
using transition-metal free C-arylation of 3-hydroxychromones is
highly desirable.
Arylating reagents such as reactive aryl radical species formed via
denitrogenation of arylhydrazines12 for the C-arylation could be an
alternative method to transition-metal catalysed C-arylation over
other arylating sources.10,13 It is reported that arylhydrazines furnish
arenes with the release of N2 under oxidative conditions however,
in the presence of base, formation of arenes is much faster.13b We
envisioned that direct C-arylation of 3-hydroxychromone moiety
could be achieved using arylhydrazines as aryl radical source under
basic condition. Initially, we reacted chromone 1a, our model
substrate with p-tolyl hydrazine hydrochloride 2a in DMSO with
K2CO3 as base at room temperature in open flask. It was presumed
In recent years, C–H functionalization or activation to form C–C
bond via cross-coupling reactions has been of great interest for the
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that the aryl radical would form and react with the double bond respectively. Having optimized the reaction conditions for the C-2
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between C-2,3 to afford the corresponding C-arylated product arylation of 3-hydroxychromone 1d, we theDnOsIt:u1d0i.e10d3t9h/Ce7sOcBo0p1e92a9nGd
(Scheme 1). The reaction however, resulted in the formation of generality of this developed methodology by reacting various 3-
hydrazone 3aa rather than the expected C-arylated product. The hydroxychromones 1d-f with arylhydrazines 2a-i to furnish flavonol
formation of hydrazone 3aa suggests that the hydrazine 2a 3da-3fi (Table 1). Reaction of arylhydrazine having electron-
immediately reacted with the carbonyl of chromone before aryl donating groups such as methyl, dimethyl and methoxy furnished 3-
radical could be formed under the basic reaction condition. We hydroxyflavones in very good yields whereas arylhydrazines
opined that the double bond between C-2,3 may not be reactive, as possessing electron-withdrawing groups such as chloro 2b, bromo
compared to the carbonyl functionality of the chromone hence we 2f or fluoro 2g afforded the desired product in good yields. It is
introduced a formyl group at C-3. However, the reaction of 3-formyl pertinent to mention here that phenylhydrazines bearing halides
chromone 1b with 2a under the same reaction conditions also lead such as chloro 2b, bromo 2f or fluoro 2g were well tolerated by this
to the formation of hydrazone 3ba. We also studied the reaction methodology and can be further utilized for synthesis of hybrid
with compound 1c bearing a hydroxymethyl group at the C-3 molecules. However, reaction of 3-hydroxychromones 1d-f with
position.14 However, even after 12 h, neither traces of the C- arylhydrazines bearing strong electron-withdrawing groups such as
arylated product nor the hydrazone formation was observed 4-CN, 3-NO2 or 4-NO2 didn’t furnish any C-arylated product and the
instead starting material 1c was recovered unreacted while starting materials 3-hydroxychromones remained unreacted
hydrazine 2a forms an inseparable mixture. The relatively less (Scheme 2).
reactivity of compound 1c could be attributed to the strong six-
membered intramolecular hydrogen bonding. These observations
Table 1 Substrate scopea,b
led us to reason for a suitable group, which would direct C-
arylation. We then studied the reaction of 3-hydroxychromone 1d14
O
O
Ar
O
O
MeCN, NEt2H
open air, rt, 4 h
+
with 2a under the basic condition presuming that hydroxyl group at
C-3 may enhance the reactivity of the double bond. Indeed, our
surmise was proved correct with the formation of C-2 arylated
product 3da in 32% yield (Scheme 1).
ArNHNH2.HCl
OH
OH
R
R
2a-i
3da-3fi
1d-f
Cl
O
O
O
O
O
O
O
OH
OH
OH
OH
O
O
8 h
3db (73%)
3da (78%)
3dc (80%)
3dd (79%)
R = H
Cl
F
Br
N
NH
O
O
O
O
OH
OH
OH
OH
O
O
O
O
3eb (64%)
3aa (72%)
3dg (76%)
3df (70%)
3de (81%)
OMe
NHNH2.HCl
O
O
O
O
O
O
8 h
DMSO, K2CO3
open air, rt
+
OH
OH
OH
MeO
OH
R = CHO
R
O
3ec (82%)
O
O
O
3eh (82%)
3fa (88%)
3ed (74%)
O
O
N
NH
1a R = H
2a
O
O
1b R = CHO
1c R = CH2OH
3ba (55%)
MeO
OH
MeO
OH
12 h
O
O
No reaction
3fi (72%)c
3fe (76%)
R = CH2OH
NHNH2.HCl
aReaction conditions: 3-Hydroxychromone 1d-f (0.25 mmol), 2a-i (0.375
mmol, 1.5 equiv.), diethyl amine (0.875 mmol, 3.5 equiv.), in MeCN (3 mL) at
rt under open air; bIsolated yield of pure product with respect to 1d-f (in
parenthesis); Phenyl hydrazine (2i) used as free base, diethyl amine (0.625
mmol, 2.5 equiv.).
O
O
DMSO, K2CO3
+
OH
open air, rt
12 h
OH
c
O
O
3da (32%)
2a
1d
Scheme
chromones.
1 Primary studies on C-arylation of differently substituted
After studying the C-arylation reactions of 3-hydroxychromones 1d-
f, we further wished to investigate the scope and generality of this
methodology on differently substituted pyran-4-one moiety. In this
regard, kojic acid 4 ideally suits our requirement as it has a core
structure of pyran-4-one moiety bearing suitably oriented hydroxyl
as well as hydroxymethyl group as substituents on two different
double bonds (Figure 2). Recently, the 2-arylated thio pyrone based
Ru(II) drugs have also been reported as cytotoxic agents which can
be easily derived from C-arylated kojic acid.15
With the desired product in hand, we optimized our reaction
conditions by varying base, solvent, oxidant and equivalence of
hydrazine on the outcome of this reaction (Table S1, see SI).
Optimized condition was obtained (Table S1, entry 7, see SI) when
diethyl amine (3.5 equiv.) and 4-tolylhydrazine hydrochloride (1.5
equiv.) corresponding to 3-hydroxychromone 1d were reacted,
2 | J. Name., 2012, 00, 1-3
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NHNH2.HCl
products or decomposition of reaction mixtures was witnessed
(Scheme 3).
View Article Online
DOI: 10.1039/C7OB01929G
O
MeCN, NEt2H
open air, rt, 4 h
+
No reactions
NHNH2.HCl
O
R
OH
R2
OH
MeCN, NEt2H
O
R1
+
Complex reaction mixtures/
decomposition
open air, rt, 6 h
R2
HO
1d R = H
2l R1 = NO2; R2 = H
2m R1 = CN; R2 = H
2n R1 = H; R2 = NO2
1e R = Me
1f R = OMe
1g R = Cl
O
R1
4
2l R1 = NO2; R2 = H
2m R1 = CN; R2 = H
2n R1 = H; R2 = NO2
Scheme 2 C-arylation reactions of substituted 3-hydroxychromones with
various electron-withdrawing substituents.
Scheme 3 C-arylation reactions of kojic acid 4 with various electron-
withdrawing substituents.
O
HO
Next, we turned our attention towards the role of hydroxyl group
present on chromone on the course of C-arylation reaction as
observed in Scheme 1, that why only in the presence of hydroxyl
group C-arylation takes place. In this context, we protected the free
hydroxy group of 1d as -OMe 1g, -OBn 1h or -OPMB 1i groups,
respectively. Individual reaction of compound 1g, 1h or 1i with
various arylhydrazines 2a, 2b, 2d and 2f, respectively in acetonitrile
and diethyl amine didn’t furnish neither any C-arylated product nor
any hydrazone product instead starting materials were recovered as
such even after 48 hours (Scheme 4a). Similar fact was also
observed (Scheme 4b) when various arylhydrazines 2a, 2b, 2d, 2f
and 2i failed to react with the protected kojic acid derivatives 4a, 4b
and 4c. This signifies that the attack of aryl radical is not feasible if
the hydroxyl group is protected and thus underlying the necessity of
free hydroxyl group for the reaction to take place. Next we turned
our attention on kojic acid 4 as it has another functionalisable site
(next to hydroxymethyl group) for C-arylation. We treated
compound 4 with excess of phenyl hydrazine 2i assuming that the
bi-arylated product should form however, only mono C-arylated
product 5i was obtained with no traces of formation of bi-arylated
product (Scheme 4c). Hence, the role of free hydroxyl group on the
C-arylation reaction was evident. Further, the role of hydroxymethyl
group present in 4 on the product formation, if any was studied.
The hydroxymethyl group was protected as OBn by reported
literature procedure.16 Treatment of compound 4d with 2a in
acetonitrile and diethyl amine furnished mono C-arylated product 6
in 74% yield (Scheme 4d). This proves that hydroxymethyl group
has no role on the course of reaction.
OH
O
Figure 2 Structure of kojic acid 4.
We carried out C-arylation of kojic acid
4 with various
arylhydrazines 2a-k to synthesize C-arylated kojic acid derivatives
5a-5k. Interestingly, all the studied arylhydrazines 2a-k on reaction
with kojic acid 4 furnished C-arylated products in very good yields
(Table 2).
Table 2 Substrate scopea,b
O
Ar
O
O
OH
+
MeCN, NEt2H
open air, rt, 6 h
OH
ArNHNH2.HCl
HO
HO
O
5aa-5ak
2a-k
4
Cl
O
O
O
O
O
O
O
OH
OH
OH
OH
HO
HO
HO
HO
O
5aa (75%)
5ab (68%)
5ac (76%)
5ad (78%)
Br
F
MeO
OH
O
O
O
O
OH
OH
OH
HO
HO
HO
HO
O
O
O
O
5ae (77%)
5af (65%)
5ag (74%)
5ah (73%)
Cl
Cl
Cl
Cl
O
O
O
O
O
OH
OH
OH
Cl
HO
HO
HO
O
5ai (72%)c
5ak (62%)
5aj (44%)
aReaction conditions: Kojic acid 4 (0.25 mmol), 2a-k (0.375 mmol, 1.5
equiv.), diethyl amine (0.875 mmol, 3.5 equiv.), in MeCN (3 mL) at rt under
b
open air; Isolated yield of pure product with respect to 4 (in parenthesis);
cPhenyl hydrazine (2i) used as free base, diethyl amine (0.625 mmol, 2.5
equiv.).
The product yield pattern was also found to be in tandem with 3-
hydroxychromone when reacted with arylhydrazines bearing
electron-donating and electron-withdrawing groups, respectively.
However, reaction of kojic acid 4 with arylhydrazines bearing strong
electron-withdrawing groups such as 4-CN, 3-NO2 and 4-nitro didn’t
furnish any C-arylated product instead a complex mixture of
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NEt2H, O2
O
O
O
O
Ar
Ar-NHNH2
Ar
N2
+
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DOI: 10.1039/C7OB01929G
MeCN, NEt H X
2
+
ArNH2NH2
(a)
Ar
open air, rt
48 h
OR
OR
Ar
O
Simultaneous cleavage of O-H
bond and attack of aryl radical
Keto-enol
O
O
H
O
O
Ar
tautomerism
1g R = Me
1h R = Bn
O
Ar = p-Tolyl, p-chloro, 2,5-dimethyl or p-bromo
OH
O
O
1i R = PMB
O
H
C-arylated product
No reaction
Ar
Non-cleavage of O-R bond does not
O
O
Ar
O
H
O
HO
(b)
facilitates the attack of aryl radical X
HO
MeCN, NEt H X
2
+
ArNHNH2
open air, rt
O
OR
48 h
OR
R
O
O
O
R = Me, Bn, PMB
O
Not formed
Ar = p-Tolyl, p-chloro, 2,5-dimethyl and p-bromo or pheny
4a R = Me
4b R = Bn
4c R = PMB
Scheme 6 Plausible mechanism of C-arylation on 3-hydroxychromone and 5-
hydroxy pyran-4-one.
OH
NHNH2
O
Ph
O
O
Ph
O
HO
HO
(c)
+
MeCN, NEt2H
open air, rt, 6 h
Ph
OH
OH
OH
Conclusions
O
O
2i (excess up
to 10 equiv.)
4
(not formed even
in traces)
5i
(formed)
In summary, we have developed a mild and efficient transition-
metal free method for C-arylation of 3-hydroxychromone and
5-hydroxy pyran-4-one using arylhydrazines as arylating source
and air as an oxidant under basic reaction conditions. The
unequivocal role of hydroxyl group in the formation of C-
arylated product has been delineated. We also feel that
present protocol will be useful for several such types of
desired C-arylations essential for total synthesis of natural and
unnatural products.
OBn
NHNH2.HCl
O
O
BnO
(d)
MeCN, NEt2H
open air, rt, 4 h
+
OH
OH
O
O
4d
2a
6 (74%)
Scheme 4 Studies towards the role of free hydroxyl and hydroxymethyl
group in C-arylation.
In order to prove C-arylation of 3-hydroxychromone and pyran-4-
one taking place via free radical reaction, we carried out an ideal
reaction of 2,5-dimethyl phenylhydrazine hydrochloride 2d with
kojic acid 4 in presence of radical scavenger TEMPO under our
optimised reaction condition, which furnished the sole product 7
without any trace of C-arylated product. It proves that C-arylation
of 3-hydroxychromone and pyran-4-one takes place via free radical
mechanism (Scheme 5).
Experimental section
General Information. All melting points were recorded on a Büchi
melting point apparatus in open capillaries and are uncorrected.
Flash chromatography was performed with CombiFlash R 200i
equipped with UV/VIS and ELSD (Isco Teledyne Inc., USA) using
RediSep® pre-packed column (SiO2). 1H NMR spectra were
recorded on a Bruker 200, 400 or 500 MHz spectrometer and 13C
NMR spectra were recorded at 50, 100 or 125 MHz, respectively.
Chemical shifts are reported as δ values (ppm) relative to residual
solvent peak of Methanol-D4 or CDCl3. HRMS (ESI) was recorded on
an Orbitrap (quadrupole plus ion trap) and TOF mass analyzer.
Petroleum ether and ethyl acetate were distilled by usual methods.
All the starting materials and dried solvent such as DMF and DCM
were purchased and used without further drying.
f
NHNH2.HCl
O
OH
+
MeCN, NEt2H
+
4
N
HO
open air, rt
10 min
O
recovered unreacted
No C-arylation obseved
O
2d
4
Isolated product
7 (71%)
Scheme 5 Radical trapping experiment with TEMPO.
Synthesis of 3aa and 3ba.
Based on the above observations, a plausible mechanism of C-
arylation of 3-hydroxychromone and pyran-4-one moieties has
been delineated in Scheme 6. Presumably, at first the aryl hydrazine
forms aryl radical in presence of base and atmospheric oxygen with
the elimination of N2.17 The breaking of O-H bond facilitates the
attack of aryl radical on C-2 position. The proton at C-2 further then
undergoes a keto-enol tautomerism to furnish the desired C-
arylated product. This concludes that the possible keto-enol
tautomerism in 3-hydroxychromones and pyran-4-ones is the real
driving force for the position specific C-arylations.
In 10 ml round bottom flask, compound 1a/1b (0.25 mmol, 1
equiv.) was dissolved in DMSO (3 mL) at rt. Then p-tolyl hydrazine
hydrochloride 2a (48 mg, 0.30 mmol, 1.2 equiv.) was added to the
round bottom flask followed by addition of potassium carbonate
(104 mg, 0.75 mmol, 3.0 equiv.). The reaction was stirred in open
air and monitored by TLC. After complete consumption of 1a/1b,
the reaction mixture was diluted with water (20 mL), extracted with
ethyl acetate (3×15 mL) and washed with brine (2×10 mL). The
organic layer was dried over anhydrous Na2SO4and the solvent was
concentrated under reduced pressure to furnish a residue, which
was purified by flash chromatography (RediSep SiO2 column, 12 g)
using pet ether-ethyl acetate as eluent (9:1 to 4:1) to furnish
3aa/3ba respectively.
4 | J. Name., 2012, 00, 1-3
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(4H-Chromen-4-ylidene)-2-(p-tolyl)hydrazine (3aa): Yellow solid (46 148.1, 138.4, 135.4, 134.6, 133.6, 131.4, 130.9, 130.2, 129.8, 125.6,
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+
mg, 72%); m.p. 133–137 ˚C; Rf = 0.35 (PE/EtOAc, 4:1); 1H NMR 124.7, 121.3, 118.5, 21.0, 19.7; HRMS: mD/zOIf:o1r0.1C0137H9/1C5O7O3 B(0M19+2H9)G:
(CDCl3, 200 MHz): δ 12.06 (s, 1H), 8.21–8.19 (m, 2H), 7.94 (dd, J = calcd 267.1016, found 267.1017.
8.0, 1.6 Hz, 1H), 7.56–7.48 (m, 1H), 7.39–7.36 (m, 4 H), 7.09–7.05 2-(2,4-Dimethylphenyl)-3-hydroxy-4H-chromen-4-one
(3de):
(m, 1H), 7.01–6.92 (m, 1H), 2.30 (s, 3H); 13C NMR (CDCl3, 50 MHz): δ Yellow solid (53 mg, 81%); m.p. 199–201 ˚C; Rf = 0.48 (PE/EtOAc,
192.2, 162.7, 142.2, 138.0, 136.0, 131.2, 130.4, 130.2, 119.8, 119.1, 4:1); 1H NMR (CDCl3, 400 MHz): δ 8.29 (dd, J = 8.2, 1.8 Hz, 1H), 7.71–
118.6, 21.1; LCMS (ESI): m/z 250.1for C16H14N2O2 (M)+
7.67 (m, 1H), 7.52–7.49 (m, 2H), 7.44–7.41 (m, 1H), 7.18–7.15 (m,
3-((2-(p-tolyl)hydrazono)methyl)-4H-chromen-4-one (3ba): Yellow 2H), 6.52 (brs, 1H), 2.40 (s, 3H), 2.37 (s, 3H); 13C NMR (CDCl3, 100
1
solid (38 mg, 55%); m.p. 117–119 ˚C; Rf = 0.38 (PE/EtOAc, 4:1); H MHz): δ 173.3, 155.9, 148.1, 140.8, 138.4, 137.6, 133.6, 131.7,
NMR (CDCl3, 200 MHz): δ 12.04 (s, 1H), 8.44 (s, 1H), 8.16 (s, 1H), 129.8, 127.2, 126.6, 125.6, 124.6, 121.3, 118.5, 21.5, 20.1; HRMS:
7.92 (dd, J = 8.0, 1.5 Hz, 1H), 7.64–7.60 (m, 2H), 7.56–7.48 (m, 1H), m/z for C17H15O3 (M+H)+: calcd 267.1016, found 267.1014, m/z for
7.32–7.28 (m, 2H), 7.07 (dd, J = 8.5, 0.9 Hz 1H), 7.01–6.93 (m, 1H), C17H14O3Na (M+Na)+: calcd 289.0835, found 289.0834.
2.41 (s, 3H); 13C NMR (CDCl3, 50 MHz): δ 192.2, 162.7, 142.2, 138.0, 2-(4-Bromophenyl)-3-hydroxy-4H-chromen-4-one (3df): Yellow
136.9, 136.0, 131.2, 130.4, 130.2, 123.2, 120.1, 119.7, 119.1, 118.6, solid (54 mg, 70%); m.p. 242–244 ˚C (decomposition); Rf = 0.42
1
21.1; HRMS: m/z for C17H15O2N2 (M+H)+: calcd 279.1128, found (PE/EtOAc, 4:1); H NMR (CDCl3, 400 MHz): δ 8.27–8.24 (m, 1H),
279.1121.
8.16–8.14 (m, 2H), 7.75–7.70 (m, 1H), 7.69–7.66 (m, 2H), 7.62–7.59
General Procedure for the Synthesis of 3da–3fi.
(m, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.12 (brs, 1H); 13C NMR (CDCl3, 100
In a 10-ml round bottom flask, compound 1d–f (0.25 mmol, 1 MHz): δ 173.5, 155.4, 143.9, 138.6, 133.9, 131.9, 130.0, 129.2,
equivalent) was dissolved in acetonitrile (3 mL) at rt. Then aryl 125.5, 124.7, 120.6, 118.3; HRMS: m/z for C15H10O3Br (M+H)+: calcd
hydrazine hydrochloride 2a–i (0.375 mmol, 1.5 equiv.) was added to 316.9808, found 316.9808.
the round bottom flask followed by addition of diethyl amine (90 2-(4-Fluorophenyl)-3-hydroxy-4H-chromen-4-one (3dg): Yellow
1
µL, 0.875 mmol, 3.5 equiv.). The reaction was stirred in open air and solid (48 mg, 76%); m.p. 163–165 ˚C; Rf = 0.43 (PE/EtOAc, 4:1); H
monitored by TLC. After complete consumption of starting material, NMR (CDCl3, 200 MHz): δ 8.32–8.17 (m, 3H), 7.76–7.68 (m, 1H),
the reaction mixture was concentrated under reduced pressure and 7.61–7.56 (m, 1H), 7.47–7.42 (m, 1H), 7.27–7.18 (m, 2H), 7.07 (brs,
the residue was purified by flash chromatography (RediSep, SiO2 1H); 13C NMR (CDCl3, 50 MHz): δ 173.4, 166.1, 161.1, 155.4, 144.1,
column, 12 g) using ethyl acetate-pet ether as eluent (0→1:49) to 138.2, 133.8, 130.1, 129.9, 127.3, 125.5, 124.6, 118.2, 116.0, 115.6;
furnish corresponding 3da–3fi.
HRMS: m/z for C15H10FO3 (M+H)+: calcd 257.0608, found 257.0603.
3-Hydroxy-2-(p-tolyl)-4H-chromen-4-one (3da): Yellow solid (48 mg, 2-(4-Chlorophenyl)-3-hydroxy-6-methyl-4H-chromen-4-one (3eb):
1
78%); m.p. 190–192 ˚C; Rf = 0.44 (PE/EtOAc, 4:1); H NMR (CDCl3, Yellow solid (45 mg, 64%); m.p. 210 ˚C (decomposition); Rf = 0.40
1
500 MHz): δ 8.25 (d, J = 8.0 Hz, 1H), 8.16–8.14 (m, 2H), 7.70 (t, J = (PE/EtOAc, 4:1); H NMR (CDCl3, 500 MHz): δ 8.23–8.21 (m, 2H),
7.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.41 (t, J = 7.4 Hz, 1H), 7.34–7.33 8.03 (s, 1H), 7.55–7.48 (m, 4H), 7.04 (brs, 1H), 2.49 (s, 3H); 13C NMR
(m, 2H), 7.05 (brs, 1H), 2.43 (s, 3H); 13C NMR (CDCl3, 125 MHz): δ (CDCl3, 125 MHz): δ 173.3, 153.8, 138.5, 136.1, 135.3, 134.7, 129.7,
173.4, 155.4, 145.4, 140.6, 138.2, 133.5, 129.4, 128.3, 127.7, 125.4, 129.0, 128.9, 124.6, 120.3, 118.0, 20.9; HRMS: m/z for C16H12O3Cl
124.5, 120.7, 118.3, 21.6; HRMS: m/z for C16H13O3 (M+H)+: calcd (M+H)+: calcd 287.0469, found 287.0473.
253.0859, found 253.0857, m/z for C16H12O3Na (M+Na)+: 275.0679, 3-Hydroxy-6-methyl-2-(o-tolyl)-4H-chromen-4-one (3ec): Yellow
1
found 275.0674.
solid (54 mg, 82%); m.p. 187–188 ˚C; Rf = 0.44 (PE/EtOAc, 4:1); H
2-(4-Chlorophenyl)-3-hydroxy-4H-chromen-4-on (3db): Yellow solid NMR (CDCl3, 500 MHz): δ 8.07 (brs, 1H), 7.60 (d, J = 7.9 Hz, 1H),
1
(49 mg, 73%); m.p.197–199 ˚C; Rf = 0.42 (PE/EtOAc, 4:1); H NMR 7.52–7.50 (m, 1H), 7.44–7.40 (m, 2H), 7.38–7.32 (m, 2H), 6.47 (brs,
(CDCl3, 400 MHz): δ 8.25–8.20 (m, 3H), 7.73–7.69 (m, 1H), 7.58 (d, J 1H), 2.49 (s, 3H), 2.40 (s, 3H); 13C NMR (CDCl3, 125 MHz): δ 173.2,
= 8.7 Hz, 1H), 7.50–7.48 (m, 2H), 7.42 (t, J = 7.8 Hz, 1H); 13C NMR 154.3, 147.6, 138.3, 137.7, 135.0, 134.6, 130.8, 130.4, 130.1, 129.8,
(CDCl3, 100 MHz): δ 173.5, 155.4, 143.9, 138.6, 136.3, 134.0, 129.6, 125.7, 124.6, 120.9, 118.2, 21.0, 20.1; HRMS: m/z for C17H15O3
129.1, 129.0, 125.6, 124.8, 120.7, 118.4; HRMS: m/z for C15H10O3Cl (M+H)+: calcd 267.1016, found 267.1017.
(M+H)+: calcd 273.0313, found 273.0312, m/z for C15H9O3ClNa 2-(2,4-Dimethylphenyl)-3-hydroxy-6-methyl-4H-chromen-4-one
(M+Na)+: 295.0132, found 295.0129.
(3ee): Yellow solid (52 mg, 74%); m.p. 250 ˚C (decomposition); Rf =
3-Hydroxy-2-(o-tolyl)-4H-chromen-4-one (3dc): Yellow solid (50 mg, 0.47 (PE/EtOAc, 4:1); 1H NMR (CDCl3, 400 MHz): δ 8.07 (s, 1H), 7.51–
1
80%); m.p. 189–191 ˚C; Rf = 0.44 (PE/EtOAc, 4:1); H NMR (CDCl3, 7.49 (m, 2H), 7.42–7.40 (m, 1H), 7.18–7.15 (m, 3H), 6.45 (brs, 1H),
500 MHz): δ 8.30 (d, J = 8.0 Hz, 1H), 7.72–7.69 (m, 1H), 7.61 (d, J = 2.50 (s, 3H), 2.41 (s, 3H), 2.37 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ
7.6 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.45–7.41 (m, 2H), 7.37–7.33 (m, 173.1, 154.2, 147.9, 140.6, 138.2, 137.5, 135.0, 134.5, 131.6, 129.7,
2H), 6.53 (brs, 1H), 2.41 (s, 3H); 13C NMR (CDCl3, 125 MHz): δ 173.3, 127.2, 126.5, 124.6, 120.9, 118.2, 21.4, 21.0, 20.0; HRMS: m/z for
155.9, 147.8, 138.4, 137.7, 133.6, 130.9, 130.4, 130.0, 129.8, 125.8, C18H17O3 (M+H)+: calcd 281.1172, found 281.1175.
125.6, 124.6, 121.2, 118.4, 20.1; HRMS: m/z for C16H13O3 (M+H)+: 3-Hydroxy-2-(4-methoxyphenyl)-6-methyl-4H-chromen-4-one
calcd 253.0859, found 253.0862.
2-(2,5-Dimethylphenyl)-3-hydroxy-4H-chromen-4-one
(3eh): Yellow solid (58 mg, 82%); m.p. 256–258 ˚C; Rf = 0.43
(3dd): (PE/EtOAc, 4:1); H NMR (CDCl3, 400 MHz): δ 8.25–8.23 (m, 2H),
1
Yellow solid (52 mg, 79%); m.p. 205–207 ˚C; Rf = 0.48 (PE/EtOAc, 8.02 (brs, 1H), 7.51–7.46 (m, 2H), 7.06–7.04 (m, 2H), 7.00 (brs, 1H),
4:1); 1H NMR (CDCl3, 400 MHz): δ 8.30 (dd, J = 8.2, 1.4 Hz, 1H), 7.53– 3.90 (s, 3H), 2.48 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 173.1, 161.0,
7.51 (m, 1H), 7.46–7.41 (m, 2H), 7.25–7.23 (m, 2H), 6.54 (brs, 1H), 153.6, 145.2, 137.6, 134.8, 134.3, 129.5, 124.5, 123.7, 120.4, 117.9,
2.39 (s, 3H), 2.36 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 173.4, 156.0,
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114.1, 55.4, 20.9; HRMS: m/z for C17H15O4 (M+H)+: calcd 283.0965, C13H13O4 (M+H)+: calcd 233.0808, found 233.0806; m/z
found 283.0966.
C13H12O4Na (M+Na)+: calcd 255.0628, foundD2O5I5:.1006.12043.9/C7OB01929G
3-Hydroxy-6-methoxy-2-(p-tolyl)-4H-chromen-4-one (3fa): Yellow 2-(2,5-Dimethylphenyl)-3-hydroxy-6-(hydroxymethyl)-4H-pyran-4-
1
solid (62 mg, 88%); m.p. 189–191 ˚C; Rf = 0.42 (PE/EtOAc, 4:1); H one (5d): Brown solid (49 mg, 78%); m.p. 130–132˚C; Rf = 0.42
1
NMR (CDCl3, 500 MHz): δ 8.15–8.14 (m, 2H), 7.56 (brs, 1H), 7.52– (PE/EtOAc, 1:1); H NMR (CD3OD, 500 MHz): δ7.27 (s, 1H), 7.19 (s,
7.51 (m, 1H), 7.38–7.28 (m, 3H), 6.98 (brs, 1H), 3.92 (s, 3H), 2.44 (s, 2H), 6.56 (s, 1H), 4.46 (s, 2H), 2.34 (s, 3H), 2.26 (s, 3H); 13C NMR
3H); 13C NMR (CDCl3, 125 MHz): δ 173.0, 156.5, 150.5, 145.2, 140.5, (CD3OD, 125 MHz): δ 177.0, 170.0, 155.5, 143.7, 136.5, 135.8, 132.0,
137.8, 129.4, 128.4, 127.7, 124.3, 121.1, 119.7, 103.8, 56.0, 21.6; 131.6, 131.4, 109.9, 61.6, 21.0, 19.7; HRMS: m/z for C14H15O4
HRMS: m/z for C17H15O4 (M+H)+: calcd 283.0965, found 283.0964.
2-(2,5-Dimethylphenyl)-3-hydroxy-6-methoxy-4H-chromen-4-one
(M+H)+: calcd 247.0965, found 247.0961; m/z for C14H14O4Na
(M+Na)+: calcd 269.0784, found 269.0780.
(3fd): Yellow solid (56 mg, 76%); m.p. 242–244 ˚C; Rf = 0.42 2-(2,4-Dimethylphenyl)-3-hydroxy-6-(hydroxymethyl)-4H-pyran-4-
1
(PE/EtOAc, 4:1); H NMR (CDCl3, 400 MHz): δ 7.61 (brs, 1H), 7.46– one (5e): Brown solid (48 mg, 77%); m.p. 132–134 ˚C; Rf = 0.40
1
7.40 (m, 2H), 7.31–7.29 (m, 1H), 7.27–7.19 (m, 2H), 6.49 (brs, 1H), (PE/EtOAc, 1:1); H NMR (CD3OD, 500 MHz): δ 7.39 (d, J = 7.6 Hz,
3.93 (s, 3H), 2.39 (s, 3H), 2.34 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 1H), 7.16 (s, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.57 (s, 1H), 4.47 (s, 2H),
172.8, 156.5, 151.0, 147.9, 138.0, 135.3, 134.5, 131.2, 130.7, 130.1, 2.36 (s, 3H), 2.30 (s, 3H); 13C NMR (CD3OD, 125 MHz): δ 177.2,
129.8, 124.3, 121.7, 119.8, 103.9, 7.0, 56.0, 20.9, 19.5; HRMS: m/z 170.0, 150.8, 144.0, 141.6, 138.8, 132.3, 131.0, 128.6, 127.5, 110.0,
for C18H17O4 (M+H)+: calcd 297.1121, found 297.1124.
61.6, 21.5, 20.2; HRMS: m/z for C14H15O4 (M+H)+: calcd 247.0965,
3-Hydroxy-6-methoxy-2-phenyl-4H-chromen-4-one (3fi): Yellow found 247.0963; m/z for C14H14O4Na (M+Na)+: calcd 269.0784,
solid (48 mg, 72%)a; m.p. 185–187 ˚C; Rf = 0.40 (PE/EtOAc, 4:1); H found 269.0781.
1
NMR (CDCl3, 200 MHz): δ 8.28–8.23 (m, 2H), 7.57–7.47 (m, 5H), 2-(4-Bromophenyl)-3-hydroxy-6-(hydroxymethyl)-4H-pyran-4-one
7.35–7.28 (m, 1H), 7.04 (brs, 1H), 3.92 (s, 3H); 13C NMR (CDCl3, 50 (5f): Pale yellow solid (49 mg, 65%); m.p. 140–142˚C; Rf = 0.28
MHz): δ 173.1, 156.5, 150.6, 138.2, 131.2, 130.1, 128.6, 127.7, (PE/EtOAc, 1:1);1H NMR (CD3OD, 500 MHz): δ 8.05–8.04 (m, 2H),
124.5, 121.1, 119.8, 103.8, 56.0; HRMS: m/z for C16H13O4 (M+H)+: 7.66–7.64 (m, 2H), 6.54 (s, 1H), 4.53 (s, 2H); 13C NMR (CD3OD, 100
calcd 269.0808, found 269.0801.
MHz): δ 177.0, 169.8, 146.1, 144.1, 132.9, 131.5, 130.1, 125.0,
109.3, 61.5; HRMS: m/z for C12H10O4Br (M+H)+: calcd 296.9757,
found 296.9752.
abase used (65 µL, 0.625 mmol, 2.5 equiv.)
General Procedure for the Synthesis of 5a–5k.
In a 10 mL round bottom flask, kojic acid 4 (35 mg, 0.25 mmol, 1 2-(4-Fluorophenyl)-3-hydroxy-6-(hydroxymethyl)-4H-pyran-4-one
equiv.) was dissolved in acetonitrile (3 mL) at rt. Then aryl hydrazine (5g): Yellow solid (44 mg, 74%); m.p. 129–131 ˚C; Rf = 0.38
1
hydrochloride 2a–k (0.375 mmol, 1.5 equiv.) was added to the (PE/EtOAc, 1:1); H NMR (CD3OD, 200 MHz): δ 8.24–8.17 (m, 2H),
round bottom flask followed by addition of diethyl amine (90 µL, 7.31–7.22 (m, 2H), 6.58 (s, 1H), 4.57 (s, 2H); 13C NMR (CD3OD, 50
0.875 mmol, 3.5 equiv.). The reaction was stirred in open air and MHz): δ 176.8, 169.5, 130.8, 130.6, 116.7, 116.3, 109.1, 61.4; HRMS:
monitored by TLC. After complete consumption of kojic acid 4, the m/z for C12H10O4F (M+H)+: calcd 237.0558, found 237.0557.
reaction mixture was concentrated under reduced pressure and the 3-Hydroxy-6-(hydroxymethyl)-2-(4-methoxyphenyl)-4H-pyran-4-
residue was purified by flash chromatography (RediSep, SiO2 one (5h): Yellow solid (46 mg, 73%); m.p. 135–136 ˚C; Rf = 0.38
1
column, 12 g) using pet ether-ethyl acetate as eluent (0→1:1, (PE/EtOAc, 1:1); H NMR (CD3OD, 200 MHz): δ 8.11–8.06 (m, 2H),
gradient) to furnish the desired product.
7.05–7.01 (m, 2H), 6.52 (s, 1H), 4.53 (s, 2H), 3.86 (s, 3H); 13C NMR
3-Hydroxy-6-(hydroxymethyl)-2-(p-tolyl)-4H-pyran-4-one (5a): Pale (CD3OD, 50 MHz): δ 169.2, 162.5, 147.9, 142.8, 130.2, 115.1, 109.1,
yellow solid (43 mg, 75%); m.p. 123–125 ˚C; Rf = 0.32 (PE/EtOAc, 61.6, 56.0; HRMS: m/z for C13H13O5 (M+H)+: calcd 249.0757, found
1:1); 1H NMR (CD3OD, 200 MHz): δ 8.01–7.96 (m, 2H), 7.30–7.26 (m, 249.0759.
2H), 6.52 (s, 1H), 4.52 (s, 2H), 2.38 (s, 3H); 13C NMR (CD3OD, 50 3-Hydroxy-6-(hydroxymethyl)-2-phenyl-4H-pyran-4-one (5i): Brown
1
MHz): δ 176.8, 169.4, 147.5, 143.3, 141.3, 130.2, 129.4, 128.3, solid (39 mg, 72%);a m.p. 124–126 ˚C; Rf = 0.30 (PE/EtOAc, 1:1); H
109.0, 61.4, 21.5; HRMS: m/z for C13H13O4 (M+H)+: calcd 233.0808, NMR (CD3OD, 400 MHz): δ 8.12–8.10 (m, 2H), 7.50–7.42 (m, 3H),
found 233.0805; m/z for C13H12O4Na (M+Na)+: calcd 255.0628, 6.54 (s, 1H), 4.54 (s, 2H); 13C NMR (CD3OD, 100 MHz): δ 175.4,
found 255.0623
168.2, 145.7, 142.2, 130.8, 129.4, 128.1, 107.6, 60.0; HRMS: m/z for
2-(4-Chlorophenyl)-3-hydroxy-6-(hydroxymethyl)-4H-pyran-4-one
C12H11O4 (M+H)+: calcd 219.0652, found 219.0651.
(5b): Yellow solid (43 mg, 68%); m.p. 171–173 ˚C; Rf = 0.25 abase used (65 µL, 0.625 mmol, 2.5 equiv.)
1
(PE/EtOAc, 1:1); H NMR (CD3OD, 500 MHz): δ 8.17–8.12 (m, 2H), 3-Hydroxy-6-(hydroxymethyl)-2-(2,4,6-trichlorophenyl)-4H-pyran-
7.55–7.50 (m, 2H), 6.56 (s, 1H), 4.56 (s, 2H); 13C NMR (CD3OD, 125 4-one (5j): White solid (36 mg, 44%); m.p. 128–130 ˚C; Rf = 0.35
1
MHz): δ 175.3, 168.2, 144.5, 142.5, 135.1, 129.5, 128.3, 107.7, 60.0; (PE/EtOAc, 1:1); H NMR (CD3OD, 500 MHz): δ 7.66 (s, 2H), 6.61 (s,
HRMS: m/z for C12H10O4Cl (M+H)+: calcd 253.0262, found 253.0258.
3-Hydroxy-6-(hydroxymethyl)-2-(o-tolyl)-4H-pyran-4-one
1H), 4.47 (s, 2H); 13C NMR (CD3OD, 125 MHz): δ 176.9, 170.8, 144.1,
(5c): 138.7, 138.1, 129.6, 110.5, 61.4; HRMS: m/z for C12H8O4Cl3 (M+H)+:
White solid (45 mg, 76%); m.p. 128–130˚C; Rf = 0.35 (PE/EtOAc, 1:1); calcd 320.9483, found 320.9486.
1H NMR (CD3OD, 500 MHz): δ 7.46–7.45 (m, 1H), 7.39–7.36 (m, 1H), 2-(2,4-Dichlorophenyl)-3-hydroxy-6-(hydroxymethyl)-4H-pyran-4-
7.33–7.31 (m, 1H), 7.29–7.26 (m, 1H), 6.57 (s, 1H), 4.46 (s, 2H), 2.32 one (5k): Yellow solid (44 mg, 62%); m.p. 135–137 ˚C; Rf = 0.35
1
(s, 3H); 13C NMR (CD3OD, 125 MHz): δ 177.0, 170.0, 150.3, 143.8, (PE/EtOAc, 1:1); H NMR (CD3OD, 200 MHz): δ 7.65–7.62 (m, 1H),
138.9, 131.6, 131.3, 126.8, 109.9, 61.5, 20.1; HRMS: m/z for 7.58 (s, 1H), 7.49–7.44 (m, 1H), 6.56 (s, 1H), 4.46 (s, 2H); 13C NMR
(CD3OD, 50 MHz): δ 177.0, 170.4, 138.0, 136.0, 134.2, 131.0, 128.5,
6 | J. Name., 2012, 00, 1-3
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110.1, 61.4; HRMS: m/z for C12H9O4Cl2 (M+H)+: calcd 286.9872,
found 286.9876.
Lai, L. Wan, T. Y. Ho, C. C. Hsieh and P. D. L. CVhieawoA,rAticnletOivnilrinael
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General Procedure for the Synthesis of 6.
In a 10 mL round bottom flask, 6-O-benzylated kojic acid 4d (58 mg,
0.25 mmol, 1 equiv.) was dissolved in acetonitrile (3 mL) at rt. Then
p-tolyl hydrazine hydrochloride 2a (59 mg, 0.375 mmol, 1.5 equiv.)
was added to the round bottom flask followed by addition of diethyl
amine (90 µL, 0.875 mmol, 3.5 equiv.). The reaction was stirred in
open air and monitored by TLC. After complete consumption of 4d,
the reaction mixture was concentrated under reduced pressure and
the residue was purified by flash chromatography (RediSep, SiO2
column, 12 g) using pet ether-ethyl acetate as eluent (4:1, isocratic).
3
4
5
6
6-((Benzyloxy)methyl)-3-hydroxy-2-(p-tolyl)-4H-pyran-4-one
(6):
Yellow solid (59 mg, 74%); m.p. 133–135 ˚C; Rf = 0.40 (PE/EtOAc,
1
4:1); H NMR (CDCl3, 200 MHz): δ 7.97–7.93 (m, 2H), 7.42–7.28 (m,
7H), 6.60 (s, 1H), 4.66 (s, 2H), 4.46 (s, 2H), 2.41 (s, 3H); 13C NMR
(CDCl3, 50 MHz): δ 174.3, 164.2, 145.2, 141.5, 140.2, 136.9, 129.4,
128.7, 128.3, 127.9, 127.7, 126.9, 109.1, 73.2, 67.9, 21.5; HRMS: m/z
for C20H19O4 (M+H)+: calcd 323.1278, found 323.1275, m/z for
C20H18O4Na (M+Na)+: calcd 345.1097, found 345.1091.
7
8
Radical Trapping Experiment: General Procedure for the Synthesis
of 7.
In a 10 mL round bottom flask, kojic acid 4 (71 mg, 0.50 mmol, 1
equiv.), 2,5 dimethyl phenyl hydrazine hydrochloride 2d (86 mg,
0.50 mmol, 1 equiv.), TEMPO (92 mg, 0.60 mmol, 1.2 equiv), was
dissolved in acetonitrile (3 mL) at rt. Then diethyl amine (180 µL,
1.75 mmol, 3.5 equiv.) was added in the reaction medium. The
reaction mixture was stirred in open air and monitored by TLC.
After complete consumption of 2d, the reaction mixture was
concentrated under reduced pressure and the residue was purified
by flash chromatography using pet ether-ethyl acetate as eluent
(50:1, isocratic).
9
10 P. Patil, A. Mimonkar and K. G. Akamanchi, J. Org. Chem.,
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1-(2,5-Dimethylphenoxy)-2,2,6,6-tetramethylpiperidine
(7):
Colourless oil (92 mg, 71%); Rf = 0.85 (PE/EtOAc, 9:1); 1H NMR
(CDCl3, 200 MHz): δ 7.29 (s, 1H), 6.92 (d, J = 7.5 Hz, 1H), 6.57 (d, J =
6.7 Hz, 1H), 2.29 (s, 3H), 2.20 (s, 3H), 1.67–1.40 (m, 6H), 1.25 (s, 6H),
0.99 (s, 6H); 13C NMR (CDCl3, 50 MHz): δ 160.9, 135.8, 129.7, 120.0,
119.6, 114.5, 60.3, 39.7, 32.7, 21.6, 20.8, 17.2, 15.9; HRMS: m/z for
C17H28ON (M+H)+: calcd 262.2165, found 262.2167.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by CSIR XIIth FY Project (CSC0130,
NaPAHA). S.P. thanks CSIR, New Delhi, India for the award of a
Senior Research Fellowship.
14 For synthesis of compound 1c and 1d, see: (a) R. A.
Maturana, J. H. Moya, H. P. Mahana and B. W. López, Synth.
Commun, 2003, 33, 3225; (b) The Baeyer-Villiger Oxidation of
Ketones and Aldehydes, ed. G. R. Krow, Wiley-VCH,
Weinheim, 2004.
Notes and references
1
2
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Journal Name
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Jakupec, W. Kandioller and B. K. Keppler, Dalton Trans.,
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View Article Online
DOI: 10.1039/C7OB01929G
16 M. Raje, N. Hin, B. Duvall, D. V. Ferraris, J. F. Berry, A. G.
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C7OB01929G
Graphical Abstract
Hydroxyl directed C-arylation: synthesis of 3-hydroxyflavones and 2-phenyl-3-hydroxy pyran-4-ones
under transition-metal free conditions
Sayantan Paul and Asish K. Bhattacharya
Hydroxyl assisted, efficient, transition-metal free and direct C-arylation of 3-hydroxychromone and 5-
hydroxy pyran-4-one moieties in presence of base, air as oxidant and arylhydrazines as arylating agent
to furnish highly biologically active 3-hydroxyflavones and 2-phenyl-3-hydroxy pyran-4-ones has been
developed.