An unexpected rearrangement-hydration reaction sequence of 2H-chromenes to dihydrochalcones under catalysis of HAuCl4

Article abstract of DOI:10.1016/j.tetlet.2012.08.117

2-Aryl-2H-chromenes in aqueous DCM medium under catalysis of HAuCl ₄ are converted into 3-(2-hydroxyaryl)-1-arylpropan-1-ones through hydration-rearrangement reaction sequence in very good yield. The key step probably involves the [1,5] hydride shift followed by the hydrolysis under the reaction condition. The notable advantages of this method are operational simplicity and ease of isolation of products and also provide a pathway to convert the chalcone into DHCs with the transposition of carbonyl group. 2012 Elsevier Ltd. All rights reserved.

Full text of DOI:10.1016/j.tetlet.2012.08.117

Tetrahedron Letters 53 (2012) 6321–6325
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An unexpected rearrangement-hydration reaction sequence of
2H-chromenes to dihydrochalcones under catalysis of HAuCl4
⇑
Gourhari Maiti , Utpal Kayal, Rajiv Karmakar, Rudraksha N. Bhattacharya
Department of Chemistry, Jadavpur University, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Aryl-2H-chromenes in aqueous DCM medium under catalysis of HAuCl4 are converted into 3-(2-
hydroxyaryl)-1-arylpropan-1-ones through hydration-rearrangement reaction sequence in very good
yield. The key step probably involves the [1,5] hydride shift followed by the hydrolysis under the reaction
condition. The notable advantages of this method are operational simplicity and ease of isolation of prod-
ucts and also provide a pathway to convert the chalcone into DHCs with the transposition of carbonyl
group.
Received 26 July 2012
Revised 27 August 2012
Accepted 28 August 2012
Available online 1 September 2012
Keywords:
2H-Chromenes
Ó 2012 Elsevier Ltd. All rights reserved.
Dihydrochalcones
Hydration-rearrangement sequence
HAuCl4
The development of new reactions for the synthesis of diverse
molecular frameworks is a challenging task in the field of modern
synthetic chemistry. To generate new chemical entities in an effi-
cient manner is pivotal in medicinal chemistry, chemical biology
and among others. Flavonoids received attention as dietary constit-
uents of potential importance to health. Effects are thought to be
due to their antioxidant properties and the involvement in biolog-
ical pathways.1 Dihydrochalcones (DHCs), the reduced form of
chalcones are a family of flavonoids containing two aromatic rings
joined by three carbon spacers, widely distributed in nature and
are used as important intermediates for the synthesis of many nat-
ural products and pharmaceutical drugs.2 Some of the natural and
synthetic dihydrochalcones as well as glucoside derivatives of
dihydrochalcone were found to show diverse biological activities,
such as antimicrobial,3 anti-HIV-I protease,4 antileishmanial,5 anti-
malarial6 and anticancer activity.7 Flavonoid moiety has also re-
ceived much attention as dietary constituents of potential
importance to health and as food sweeteners (neohesperidin).8
Mostly, DHCs are synthesized through the reduction of chalcone
so obtained by Claisen–Schmidt condensation reaction or through
the alkaline reduction of a corresponding flavanone.9 These widely
used procedures not only require the complete protection of all
phenolic functionalities but also long reaction time in order to
achieve the high yield. Recently, Wagner and coworkers reported
a concise Pd-mediated Heck-type reaction as an alternative route
to DHCs.10
Recently, direct acylation of aryl chloride with palladium-
pyrrolidine co-catalysts and also double arylation of allyl alcohols
via a one-pot Heck arylation-isomerization–acylation cascade were
reported.11 Although Friedel–Crafts acylation, of phenols with
dihydrocinnamic acids provided a direct route to certain dihydr-
ochalcones, a more general synthetic approach is the chemoselec-
tive reduction of conjugated enones that is the double bond of the
appropriate chalcones by catalytic hydrogenation.12 Selective
reduction of chalcone to DHCs by using ultrasound and zinc—acetic
acid solution has also been reported.13 Although, numerous routes
to the DHCs are known in the literature, DHCs having substituents
on both the rings, specially containing hydroxyl and halogens are
not prevalent.
In continuation to our effort to explore the chemistry of the
flavonoids14 and their biological importance prompted us to devel-
op a simple, general and efficient alternative method towards the
synthesis of highly substituted DHCs. Moreover, to the best of
our knowledge, there is no report in the literature on the conver-
sion of chromenes into DHCs by gold (III) catalysed rearrangement
hydration reaction sequence.
Very recently, flavenes are reported in the literature that they
undergo dimerization (Scheme 1) on treatment with catalysts like
methanol-acid (10 M HCl, TFA or glacial AcOH) and FeCl3ꢀ6H2O.15
Interestingly, instead of expected dimerization reaction, we got
the ring opening product on treatment with gold (III) catalyst in
wet DCM.
Herein, we wish to report a novel synthetic transformation of
2-aryl-2H-chromenes into 3-(2-hydroxyaryl)-1-arylpropan-1-ones
through rearrangement hydration reaction sequence under
⇑
Corresponding author. Fax: +91 33 2414 6223.
E-mail address: ghmaiti123@yahoo.co.in (G. Maiti).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.117

6322
G. Maiti et al. / Tetrahedron Letters 53 (2012) 6321–6325
Previous work
H+, MeOH
O
This work
HAuCl4 (5 mol-%)
HAuCl4 (5 mol%)
DCM, H2O
R
or
DCM-H2O, rt, 24 h
75 %
O
O
Lewis acid
R1
OH
5a
4a
R1
O
Scheme 3. Synthesis of 3-(2-hydroxyphenyl)-1-propan-1-one.
O
H
O
R1
R
+ isomer
R
R
OH
H
Table 1
Optimization of reaction condition for hydration of 2-(4-methoxyphenyl)-2H-chro-
menea
R1
O
catalyst
Scheme 1. Reaction of 2H-chromene under different conditions.
O
solvent, rt
OH
OMe
OMe
4b
5b
O
R1
Entry
Catalyst
Solvent
Time (h)
Yieldd (%)
R1
O
CHO
R1
c
NaOH
1
2
3
4
5
6
7
8
HAuCl4
HAuCl4
HAuCl4
HAuCl4
HAuCl4
HAuCl4
HAuCl4
HCL
DCM(dry)
CH3CN
DCMb
48
48
24
24
24
24
24
24
24
24
24
24
24
24
24
NaBH4
IPA
c
O
H
O
EtOH-H2O
R2
OH
83
78
53
12
15
25
30
5
4
2
R2
3
DCMb
R2
1
Tolueneb
EtOHb
Scheme 2. Synthesis of chromene derivatives.
THFb
Aq.EtOH
Aq.EtOH
DCMb
9
PTSA
catalysis of HAuCl4 in wet DCM at room temperature in very good
yield. The 2H-chromene derivatives (4) were prepared following
the literature procedure of Claisen–Schmidt condensation of 20-
hydroxyaceto-phenones (1) with various aromatic aldehydes (2)
afforded the o-hydroxychalcones (3), followed by the reduction
with NaBH4 in isopropyl alcohols (IPA) in good yield (Scheme 2).15a
Recently, gold catalysts have emerged as powerful catalysts due
to their efficiency in many chemical transformations.16 Gold nano-
particles are also reported to isomerize alkenes.17 HAuCl4 was gi-
ven importance in the optimization study due to its ability to
polarize carbon–carbon multiple bonds.18 Thus in a preliminary
reaction, 2-(4-metoxyphenyl)-2H-chromene (4a) was treated with
HAuCl4 at room temperature in wet dichloromethane (DCM) for
24 h to furnish 3-(2-hydroxyphenyl)-1-phenylpropan-1-one (5a)
in 75% yield (Scheme 3).
With the encouraging initial result, optimization of the reaction
conditions was studied using various catalyst Bronsted and Lewis
acids and also varieties of solvents. The results are summarized
in Table 1. From Table 1 it is evident that HAuCl4 in DCM was
the best in terms of yield. Ceric ammonium nitrate in acetonitrile
provides the desired product but with slightly lower yield (78%).
The optimum amount of HAuCl4 required was screened and it
was found that on gradually increasing the amount of catalyst to
5 mol %, yield of the reaction increases gradually but beyond
5 mol % there is no significant improvement of the rate as well as
yield of the reaction. It was also observed that instead of addition
of catalyst in one slot, better results were obtained by the addition
of catalyst in two equal portions at a time interval of 12 h. To ex-
plore further the scope of the methodology, we performed a series
of reactions with various 2-aryl-2H-chromenes. The results of our
study are summarized in Table 2.
10
11
12
13
14
15
Yb(OTf)3
Yb(OTf)3
AuCl3
InCl3
InCl3
Tolueneb
DCMb
8
40
10
7
CH3CNb
DCMb
CAN
CH3CNb
78
a
Reaction conditions: 2-(4-methoxyphenyl)-2H-chromene (0.5 mmol), catalyst
(0.025 mmol), solvent (0.5 mL).
b
Reactions performed with adding a drop of water.
Desired product not formed.
Refers to pure and isolated yield.
c
d
Although, the exact mechanism of this transformation is not
clear at present the plausible mechanism for the reaction has been
proposed in Scheme 4. This involves the formation of C-Au bond
along with a benzylic carbocation which is followed by oxygen in-
duced [1,5]-shift of H to the carbocation centre leading to an oxo-
nium ion intermediate. This type of hydride shift followed by C–C
bond formation are known in the literature.19 It subsequently adds
a molecule of water across carbon–oxygen double bond to form a
cyclic hemiketal which undergoes ring opening along with the
replacement of C-Au bond with C–H bond to furnish the dihydr-
ochalcone motif. It might be mentioned here that Schaus et al.15b
reported the dimerization of 2H-chromenes, proposed a similar
reaction mechanism by studying the reaction of 2-deuterated-
chromene, obtained 3-deuterated-DHC as a by-product with only
6% yield on treatment with FeCl3.
In a separate experiment, 2H-chromene (4a) was treated with
HAuCl4 in DCM and in the presence of two drops of D2O at room
temperature (Scheme 5). Not to our surprise, we found the dihydr-
ochalcone containing mono deuterium at the C-2 position. This
was confirmed by 1H NMR and 13C NMR spectral studies.
The non-deuterated analogue 5a on stirring with DCM–D2O for
24 h under chloroauric acid (HAuCl4) catalysis did not undergo
deuterium exchange reaction with enolizable hydrogen. This
proves that the incorporation of the deuterium was not a simple
exchange of enolizable hydrogen and is in conformity with our
hypothesis involving [1,5]-shift. X-ray crystallographic analysis20
of 5q (Fig. 1) unequivocally proved the position of the carbonyl
group in DHC which also provided a direct evidence of the
structure.
A variety of 2-aryl-2H-chromenes with diverse substitution pat-
terns of electron donating groups in both the rings smoothly
underwent the transformation to give products 5b–t in very good
yields. TLC showed formation of a single product along with some
(2–4%) unreacted 2H-chromene which were recovered by column
chromatography. On the other hand, 2-(2,6-dichlorophenyl)-2H-
chromene (Table 2, entry 21) did not react under similar reaction
condition. This is probably due to steric crowding at C-2, which re-
sists the nucleophilic attack of water molecule. The novelty of the
methodology lies in the unexpected regioselectivity of the
hydrolysis.

G. Maiti et al. / Tetrahedron Letters 53 (2012) 6321–6325
6323
Table 2
Reaction of 2H-chromene with water under HAuCl4 catalysisa
O
R
HAuCl4
R1
R
O
R1
DCM, H2O, rt, 24 h
OH
5a-t
4a-t
Entry
1
2H-Chromene
Product
Yieldb,c (%)
O
O
4a
75
83
77
OH
5a
O
O
2
3
OH
OH
OH
OMe
OMe
4b
5b
O
OMe
OMe
OMe
OMe
O
4c
5c
O
OMe
OMe
OMe
OMe
O
4
78
4d
5d
OMe
OMe
O
O
O
O
O
O
5
6
74
80
4e
OH
OH
5e
O
O
Cl
F
4f
Cl
F
5f
O
O
7
73
OH
OH
4g
5g
O
O
8
9
61
52
56
62
71
87
4h
5h
O
O
S
O
O
S
OH
OH
4i
5i
O
O
10
11
12
13
14
4j
5j
O
O
4k
OH 5k
O
OMe
OH
OMe
OH
O
OH
4l
5l
O
O
OH
4m
5m
O
O
67
4n
OH
I
I
5n
(continued on next page)

6324
G. Maiti et al. / Tetrahedron Letters 53 (2012) 6321–6325
Table 2 (continued)
Entry
2H-Chromene
Product
Yieldb,c (%)
O
O
15
16
75
OH
4o
5o
O
O
83
4p
OH
OMe
OMe
5p
Cl
O
Cl
O
17
18
77
87
OH
4q
5q
O
Cl
Cl
Cl
O
OH
OH
OMe
4r
OMe
5r
O
Cl
OMe
OMe
OMe
OMe
O
19
20
71
57
4s
OMe
5s
OMe
O
MeO
O
MeO
OH
5t
OMe
OMe
4t
Cl
21d
O
Cl
4u
a
Reaction condition: 2H-Chromene (0.5 mmol), HAuCl4 (0.025 mmol), dichloromethane (0.5 mL) and water (1 drop).
Yields refer to pure and isolated yield. The yields are absolute and not relative to the recovered substrate.
All compounds were characterized by IR, 1H NMR, 13C NMR and HRMS analyses.
No reaction.
b
c
d
AuCl3
AuCl3
H
HAuCl4
Ar
[1,5]
O
O
Ar
O
Ar
O
H2O
AuCl3
O
H
AuCl3
OH2
Ar
OH
Ar
O
Ar
OH
Scheme 4. Plausible mechanistic pathway.
Figure 1. X-ray structure of rotameric 5q molecules in a unit cell.
O
O
hydration cascade reaction sequence under catalysis of HAuCl4 in
very good yield. The notable advantages of this method are opera-
tional simplicity and ease of isolation of products. This method also
provides a pathway to convert the varieties of chalcones into DHCs
with the transposition of carbonyl group.
HAuCl4
HAuCl4
O
DCM,D2O
D
DCM,D2O
O
D
OH
4a
5a
5a'
Scheme 5. Reaction in the presence of D2O.
Acknowledgments
We thank the Department of Chemistry, Jadavpur University for
financial and infrastructural support from UGC-CAS and PURSE-
DST Programme. R.K. and U.K. thank CSIR, New Delhi for awarding
the fellowships.
In conclusion, we have developed a novel and simple methodol-
ogy towards the transformation of 2-aryl-2H-chromenes into
3-(2-hydroxyaryl)-1-arylpropan-1-ones through rearrangement-

G. Maiti et al. / Tetrahedron Letters 53 (2012) 6321–6325
6325
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Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.08.
117.
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20. General experimental procedure for transformation of 2-phenyl-2H-chromene into
3-(2-hydroxyphenyl)-1-phenylpropan-1-one (5a): To
a magnetically stirred
mixture of 2-phenyl-2H-chromene 4a (104 mg, 0.5 mmol) in 0.5 mL dry DCM
and a drop of water in a 5 mL screw capped vial, HAuCl4 (4 mg, 0.012 mmol) as
a catalyst was added and stirred for 12 h at room temperature. Further (4 mg,
0.012 mmol) of HAuCl4 was added and stirred for another 12 h. The progress of
the reaction was monitored by TLC. After completion of the reaction, the
solvent was evaporated under reduced pressure, and crude product was
purified by column chromatography (using 100–200 mesh silica gel) eluting
with 8% ethyl acetate in petroleum ether to afford 5a as a light brown liquid
(113 mg, 0.38 mmol, 75%). IR (KBr):
m = 2360, 1727, 1690, 1608, 1563,
1452 cmꢁ1 1H NMR (300 MHz, CDCl3): d 7.98 (d, J = 7.2 Hz, 2H), 7.58 (t,
.
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J = 7.2 Hz, 2H), 7.54 (t, J = 7.2 Hz, 2H), 7.12 (t, J = 7.2 Hz, 2H), 6.83–6.93 (m, 2H),
3.45 (t, J = 6.0 Hz, 2H), 3.04 (t, J = 6.0 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d = 202.0, 154.5, 136.0, 133.7, 130.5, 128.6, 128.3, 127.9, 127.7, 120.6,
117.4, 40.4, 23.3; HRMS for C15H14O2 [M+H]+: m/z Calcd: 227.1072; Found:
227.1077.