LiBr/β-CD/IBX/H2O-DMSO: A new approach for one-pot biomimetic regioselective ring opening of chalcone epoxides to bromohydrins and conversion to 1,2,3-triketones

Article abstract of DOI:10.1080/00397911.2017.1315537

Highly regioselective ring cleavage of chalcone epoxides to bromohydrins has been carried out in good yields with LiBr in the presence of β-CD using DMSO-H₂O as solvent system. The ring-opened product, i.e., bromohydrin, was well adapted to IBX-mediated oxidation in such a fashion that the bromohydrins are transformed to their corresponding 1,2,3-triketones in moderate-to-good yields in one pot.

Full text of DOI:10.1080/00397911.2017.1315537

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
LiBr/β-CD/IBX/H2O-DMSO: A New Approach for
One Pot Biomimetic Regioselective Ring Opening
of Chalcone Epoxides to Bromohydrins and
Conversion to 1,2,3-Triketones
Nishant Verma, Sumit Kumar & Naseem Ahmed
To cite this article: Nishant Verma, Sumit Kumar & Naseem Ahmed (2017): LiBr/β-CD/IBX/
H2O-DMSO: A New Approach for One Pot Biomimetic Regioselective Ring Opening of Chalcone
Epoxides to Bromohydrins and Conversion to 1,2,3-Triketones, Synthetic Communications, DOI:
10.1080/00397911.2017.1315537
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1315537
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Date: 20 April 2017, At: 07:47

LiBr/β-CD/IBX/H2O-DMSO: A New Approach for One Pot Biomimetic
Regioselective Ring Opening of Chalcone epoxides to Bromohydrins and
Conversion to 1,2,3-Triketones
Nishant Verma1, Sumit Kumar1,2, Naseem Ahmed1
1Department of Chemistry, Indian Institute of Technology Roorkee, Uttarakhand, India,
2Department of Chemistry, Central University of Haryana, Jant-Pali, Mahendergarh,
India
Corresponding author: Sumit Kumar and Naseem Ahmed, E-mail:
skjangraa90@gmail.com, nasemfcy@iitr.ac.in
Abstract
Highly regioselective ring cleavage of chalcone epoxides to bromohydrins has been
carried out in good yields with LiBr in presence of β-CD using DMSO-H2O as solvent
system. The ring opened product i.e. bromohydrin were well adapted to IBX mediated
oxidation in such a fashion that the bromohydrins are transformed to their corresponding
1,2,3-triketones in moderate to good yields in one-pot.
GRAPHICAL ABSTRACT:
KEYWORDS: Chalcone epoxide, Bromohydrin, β-Cyclodextrin, IBX, Triketones
1. INTRODUCTION
Chalcone epoxides are important and versatile synthetic intermediates used as starting
material in different organic transformations to form the molecules of pharmaceutical
importance.[1] Due to ring strain in epoxides, they go through easy intra- and
1

intermolecular nucleophilic addition reaction resulting into the formation of various
regio- and stereo-selective synthons under mild catalytic conditions.[2–5]
vic-Halohydrins are valuable precursors in various useful synthetic transformations such
as in the synthesis of halogenated marine bioactive natural products.[6, 7] The ring
cleavage of oxiranes to form halohydrins are usually executed with elemental halogens,[8]
hydrogen halides,[9] Lewis acids[10] and metal halides.[11] However, many of the reported
methods are limited by unsatisfactory yields, side products formation, long reaction
times, competing rearrangements, harsh reaction conditions and low regioselectivity.
1,2,3-Tricarbonyls have gained attention among the organic chemists ever since the first
synthesis of diphenyl triketone in 1890 by von Pechmann and de Neufville.[12] Rubin, and
Wasserman[13] have widely studied the chemistry of these compounds. vic-Tricarbonyl
compounds are the key structural building blocks in biologically active natural products,
[14] such as the potent immunosuppressant FK-506, [14a-c] Rapamycin, [14d] and 29-
demethoxyrapamycin, [14e] protease inhibitor molecules and other biologically active
compounds[15] in synthetic organic chemistry. Vicinal tricarbonyl compounds,
characterized by the highly electrophilic nature of the central carbonyl group, can be
easily attacked by variety of nucleophiles. Several methods have been reported for their
synthesis but many of these involve additives, extra steps to synthesize precursors and
also require strong oxidizing agents to complete this reaction.[12, 13] Moreover, some of
them suffer from low conversions and poor selectivity. Hence, there is still scope for a
generally applicable and mild method, preferably using through supramolecular catalysis
2

involving cyclodextrins due to the fine tuning of their physicochemical properties which
is continuously attaining importance in the contemporary organic transformations. These
reactions do not produce any toxic waste products. Cyclodextrins are cyclic
oligosaccharides having hydrophobic cavities and exert micro-environmental effects in
catalyzing reactions through non-covalent hydrogen bonding forming reversible host–
guest complexes just like in enzymes. [16] In our previous study,[16b, 18a] we have developed
one-pot deprotection of THP/MOM ethers and concomitant oxidative cleavage of
epoxides to form 1,2,3 triketones using β-Cyclodextrin/IBX. In continuation of our recent
studies with β-CD/IBX[18] we conceived the possibility of converting chalcone
epoxides[21] to their corresponding tricarbonyl compounds in a simple manner.
Previous work: [17, 18a]
This work:
3

To our delight, herein, we devise that LiBr/β-CD in water can be conveniently utilized to
achieve the conversion of chalcone epoxides[21] to their corresponding bromohydrins in
good to excellent yields under mild reaction conditions. Further, we establish that this
methodology can be conveniently combined with the alcoholic oxidation and oxidative
debromination reaction of bromohydrins by IBX in DMSO to access 1,2,3-triketones in
one pot.
This reaction was conducted by the in situ formation of the epoxide-β-CD complex
followed by the nucleophilic attack of LiBr and stirring at room temperature to afford the
corresponding bromohydrins in respectable yields. Indeed, we imagined this
bromohydrins could be readily converted to their corresponding triketones in the same
pot.
2. RESULTS AND DISCUSSION
2.1 Chemistry
We visualized that the IBX mediated conversion of bromohydrins to the vic-tricarbonyls
could be readily adapted to one-pot transformations by capitalizing on the LiBr-mediated
conversion of epoxides in H2O:DMSO to the corresponding bromohydrins. Thus, the
4

chalcone epoxides were converted to bromohydrins with LiBr/β-CD in water, and the
latter were subjected to IBX-mediated oxidation into the same pot. The chalcone
epoxides were prepared by following the literature procedure.[18a]
From the results as shown in Table 1, in our preliminary study toward the development of
this methodology, a prototype reaction was carried out by treating substrate 1a with LiBr
(1.2 mmol) and β-CD in DMSO at room temperature and only a small conversion of 1a
to 2a was obtained even with prolonged reaction time (Table 1, entry 1, 25%). On the
contrary, the yield of 2a was enhanced abruptly when only water was used as a solvent
(Table 1, entry 2, 82%). This is because of a lower solubility of β-CD in the DMSO than
in the water. But, with the introduction of 1.2 mmol of LiBr and β-cyclodextrin as a
supramolecular host along with 2.5 mmol of IBX in the reaction, to our delight, a small
conversion of 1a to 3a was obtained to afford the product 3a in 24% (Table 1, entry 3).
The role of β-CD in this reaction may be that it complexes with the epoxide assisting the
nucleophilic attack by LiBr, expedites the solubility of IBX in water and conducts the
reaction smoothly. Surprisingly, the 4a was obtained as the sole product[20] when only
H2O was used as a solvent (Table 1, entry 4, 80%). This suggests that DMSO is acting as
an oxidant and found indispensable for the transformation of bromo to carbonyl
functionality. During the exploratory studies conducted, this model reaction was
attempted by examining the relative proportions of H2O:DMSO. Among the proportions
of H2O:DMSO, (1:1) was found to be the best solvent system affording the highest yield
(89%) of 3a in the shortest reaction time (10 h) (Table 1, entry 7). Since, the v/v ratio of
H2O:DMSO employed can be as low as 1:1; therefore, the 1:1 v/v of H2O:DMSO solvent
5

system was used in the standard conditions. For instance, on taking 3:1 of solvent ratio
(H2O:DMSO), product 3a was obtained in 69% yield (Table 1, entry 5). It is also
remarkable that decreasing the H2O:DMSO ratio to 2:1 or 1:1 resulting into the
enhancement of the product yield of 3a to 78 and 89% respectively. The present
optimized synthesis of 3a involves stirring a mixture of 1a, LiBr and β-CD at rt for 5 h in
H2O:DMSO (1:1) followed by the addition of IBX and stirring for a further 5–8 h at rt to
afford triketones 3a in consistently good yields (89%).
After getting optimization conditions in hand, we have extended the procedure to a
variety of chalcone epoxides, which are tabulated in Table 2 and 3. They were easily
converted into their respective bromohydrins and triketones in excellent yields (79-91%).
A mechanistic description of this transformation is depicted in Fig. 1. A plausible
mechanism for the transformation of chalcone epoxides to triketones is proposed in
Scheme 1. The role of β-CD seems to be not only to activate epoxide (I) by hydrogen
bonding, but also to encourage highly effective ring opening by LiBr due to inclusion
complex formation, thus assisting the hydrolysis to form bromohydrin (II). The
transformation of (II) to (III) was almost imperceptible without the added IBX. This
clearly shows the role of IBX in the conversion of (II) to (III). Upon monitoring of the
reaction without added IBX, it is expected the formation of a salt resulting from the
attack of DMSO (Kornblum oxidation) on (II). Its decomposition to (III) did not occur
until IBX was not added which in turn generate product (V) via intermediates (IV).
Compound (V) can be easily converted to (VI) through further oxidation with IBX.[19]
6

All products were established on the basis of NMR, FTIR and mass spectrometry (ESI†).
For example, compound 2a, the 1H-NMR spectrum showed the characteristic broad peaks
at δ 3.99 ppm for alcoholic hydroxyl group. The appearance of a broad peak at 3425 cm−1
for the –OH groups in the IR spectrum point out the cleavage of epoxide ring and confirm
the formation of compound 2a. In the IR spectrum of Compound 3a, disappearance of
peak at 3425 cm−1 of hydroxyl group confirm its formation. The appearance of the
carbonyl groups showed stretching frequencies at 1695 and 1645 cm-1. HRMS of 3a
supported a molecular composition of C15H10NaO3 [M+Na]+, representing 11 degrees of
unsaturation. In the 1H NMR spectrum of 3a, disappearance of peaks at δH ppm 5.39 (d, J
= 2 Hz, 1H), 5.24 (d, J = 2H, 1H) and 3.99 (s, 1H, D2O exchangeable) establish its
structure. In 13C NMR spectrum, δc ppm 193.3 and 189.6 confirm the presence of two
types of carbonyl group.
3. CONCLUSIONS
In conclusion, we have devised an elegant and alternative methodology for one pot
conversion of chalcone epoxide to triketones via regioselective bromohydrin using a mild
and eco-friendly catalytic system LiBr/β-CD/IBX in H2O:DMSO solvent system under
supramolecular catalysis. The conversion of chalcone epoxides to the tricarbonyl
compounds described herein establishes a valuable addition to the repertoire of IBX
mediated transformations. Thus, we have revealed the synthesis of highly valuable
synthons bromohydrins, and 1,2,3-triketones directly from the easily accessible chalcone
epoxides in moderate to good yields in one pot operation in a biomimetic fashion.
7

4. EXPERIMENTAL
All the required chemicals were purchased from Merck and Aldrich Chemical Company.
Pre-coated aluminium sheets (silica gel 60 F254, Merck) were used for thin-layer
chromatography (TLC) and spots were visualized under UV light.IR spectra were
recorded with KBr on Thermo Nicolet FT-IR spectrophotometer. 1H NMR and 13C NMR
spectra were recorded respectively on Bruker Spectrospin DPX 500 MHz and Bruker
Spectrospin DPX 125 MHz spectrometer using CDCl3 as a solvent and trimethylsilane
(TMS) as an internal standard. Melting points were performed with Ambassador® and
Digital Melting point apparatus (Nutronics), Popular India. Splitting patterns are
designated as follows; s = singlet, d = doublet, m = multiplet, br = broad. Chemical shift
(δ) values are given in ppm. High-resolution mass spectra (HRMS) were obtained on a
Brüker micrOTOF™-Q II mass spectrometer (ESIMS).
4.1. General Procedure for Synthesis of Compounds
4.1.1. Conversion of Chalcone Epoxides to Bromohydrins (2a, 2b, 2f, 2i, 2k) (Table
2)
A solution of chalcone epoxide (1 mmol) and β-CD (1 mmol) in H2O/DMSO (1:1) (10
mL) were added LiBr (1.2 mmol) and the mixture was stirred at room temperature. As
soon as the starting material disappeared (as monitored by TLC analysis), the reaction
mixture was stirred for the time shown in Table 2. After completion, the reaction mixture
was filtered and extracted with ethyl acetate. The organic layer was dried over anhydrous
Na2SO4 and solvent was removed in vacou. The crude product was subjected to silica gel
8

column chromatography using hexane:EtOAc (90:10) to yield the products (2a, 2b, 2f, 2i,
2k).
4.1.2. The One-Pot Conversion of Chalcone Epoxides To 1,2,3-Triketones (3a-P)
(Table 3)
A solution of chalcone epoxide (1 mmol) and β-CD (1 mmol) in H2O/DMSO (1:1) (10
mL) were added LiBr (1.2 mmol) and the mixture was stirred at room temperature. As
soon as the starting material disappeared (as monitored by TLC analysis), IBX (2.5
mmol) was introduced into the same pot and the reaction mixture was stirred for the time
shown in Table 3. After completion, the reaction mixture was filtered and extracted with
ethyl acetate. The crude product was subjected to silica gel column chromatography
using hexane : EtOAc (85 : 15) to yield the products. The product obtained was heated at
100-120 oC for 6 h under reduced pressure in nitrogen atmosphere to give VTCs.
4.2. Characterization
4.2.1.1. 3-Bromo-2-Hydroxy-1,3-Diphenylpropan-1-One (2a)
Light yellow solid, mp 90-92 oC; 1H NMR (500 MHz, CDCl3, ppm): δ 7.89 (d, J = 8.5
Hz, 2H), 7.66-7.63 (m, 1H), 7.54-7.50 (m, 4H), 7.37-7.29 (m, 3H), 5.39 (d, J = 2 Hz,
1H), 5.24 (d, J = 2H, 1H), 3.99 (s, 1H, D2O exchangeable).13C NMR (125 MHz, CDCl3,
ppm): δ 199.3, 139.0, 135.4, 133.7, 132.5, 131.2, 129.9, 129.4, 127.9, 75.3, 56.4. IR
(KBr, cm-1): 3425, 2948, 1640, 1599, 1582. HRMS (ESIMS) for C15H13BrNaO2(M+Na)+
Anal. calcd. 326.9991; found 326.9989.
9

1,3-Diphenylpropane-1,2,3-Trione (3a)
Light yellow solid, mp 67-73 oC; 1H NMR (500 MHz, CDCl3, ppm): δ 8.08 (dd, J = 2,
8.4 Hz, 4H), 7.71-(t, J = 7.4 Hz, 2H), 7.57 (t, J = 7.8 Hz, 4H).13C NMR (125 MHz,
CDCl3, ppm): δ192.2, 179.8, 135.7, 132.4, 130.3, 129.3. IR (KBr, cm-1): 1695, 1645.
HRMS (ESIMS) for C15H10NaO3 (M+Na)+ Anal. calcd. 261.0522; found 261.0520.
ACKNOWLEDGEMENT
The authors wish to express their gratitude to DST New Delhi for providing HRMS,
NMR facility and CSIR, New Delhi for awarding SRF to S.K and N. V.
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13

Table 1. Optimization of reaction conditions.b
Entry
H2O:DMSO
(v/v)
IBX (eq.)
Time (h) Yield (%)c
2a
15
71
-
3a
-
4a
-
1
2
3
4
5
6
7
0:100
100:0
0:100
100:0
3:1
0
15
8
0
-
-
2.5
2.5
2.5
2.5
2.5
15
15
18
18
10
15
-
-
--
-
79
-
60
71
81
2:1
-
-
1:1
-
-
bReaction was carried out on 1 mmol scale; cisolated yield.
14

Table 2. Conversion of chalcone epoxides to bromohydrins.a
Entry Chalcone epoxide
1
bromohydrin ketone (2a-s)
Time (h) Yield (%)b
6
92
91
89
88
90
92
92
87
2
3
4
5
6
7
8
6
7
7
5.5
6.5
6
6
15

9
6
88
89
88
91
86
85
87
10
11
12
13
14
15
7
6
7
7.5
7.5
8
16
17
18
7.5
7
85
82
83
7
16

19
5
83
Reaction conditions: Chalcone epoxide (1 mmol), β-CD (1 mmol), LiBr (1.2 mmol), H2O
(10 mL). bGC Yield.
17

Table 3. Transformation of chalcone epoxides to 1,2,3- triketones.a
Entry Chalcone epoxide
1
Triketones (3a-p)
Time (h) Yield (%)b
10
10
10
81
75
76
2
3
4
5
6
7
8
11
9.5
11
11
10
74
78
74
79
81
18

9
10
11
11
78
79
77
10
11
12
13
14
15
16
17
18
11
11
12
11
11
10
11
80
76
74
75
77
75
72
19

19
8
76
aReaction conditions: Chalcone epoxide (1 mmol), β-CD (1 mmol), LiBr (1.2 mmol),
IBX (2.5 mmol), H2O:DMSO (10 mL). bisolated yield.
20

Scheme 1. Mechanism for the oxidation of chalcone epoxides to tricarbonyl compounds.
21

Figure 1. Mechanistic Rationale of LiBr/β-CD induced transformation of chalcone
epoxide to bromohydrin
22