Unusual tandem oxidative C-C bond cleavage and acetalization of chalcone epoxides in the presence of iodine in methanol

Article abstract of DOI:10.1055/s-0033-1339134

An unusual reaction of chalcone epoxides is observed where chalcone epoxides on heating with iodine in methanol leads to α,α- dimethoxyacetophenones, through C-C bond cleavage followed by acetalization of the formyl group. The process occurs through ring

Full text of DOI:10.1055/s-0033-1339134

LETTER
▌1591
letter
Unusual Tandem Oxidative C–C Bond Cleavage and Acetalization of
Chalcone Epoxides in the Presence of Iodine in Methanol
C–C Bond Cleavage in Chalcone Epoxides
Balaso G. Jadhav, Shriniwas D. Samant*
Department of Chemistry, Institute of Chemical Technology, Matunga, Mumbai 400019, India
Fax +91(22)33611020; E-mail: samantsd@yahoo.com; E-mail: sd.samant@ictmumbai.edu.in
Received: 16.03.2014; Accepted after revision: 28.04.2014
hypervalent iodine reagents.11 A few catalytic systems
have also been described for the cleavage. For example,
molecular O2/DMSO with bismuth(III) ligands2 affords
carboxylic acids, instead of aldehydes and ketones. Only
Abstract: An unusual reaction of chalcone epoxides is observed
where chalcone epoxides on heating with iodine in methanol leads
to α,α-dimethoxyacetophenones, through C–C bond cleavage fol-
lowed by acetalization of the formyl group. The process occurs
through ring opening of the chalcone epoxide by methanol to form one method of cleavage of α-methyl styrene epoxides us-
ing sodium molybdate/H2O2,8 with HMPT or TDPT in a
biphasic system of dichloromethane and acidified water,
β-methoxy alcohol, cleavage of the C–C bond in the latter to form
α-ketoaldehyde, and acetalization of the formyl group to give the
product. The protocol provides direct access to α,α-dimethoxyace-
affords the corresponding aldehydes. The reaction has
tophenones from chalcone epoxides.
been reported electrochemically.2 Literature survey shows
that epoxides which are used for the oxidative cleavage
Key words: oxidative cleavage, chalcone epoxides, iodine, α,α-
dimethoxyacetophenones, acetals, α-ketoaldehydes
are those bearing hydrogen, alkyl, or aryl on the oxirane
ring.2 However, such a C–C bond cleavage of α,β-epoxy-
ketones is not reported, though it may provide α-keto al-
Reactions of epoxides are interesting due to the presence
dehydes which are difficult to prepare by other methods.
of a strained oxirane ring in them. The most common
Herein we report our serendipitous observation of oxida-
reactions involve opening of the oxirane ring to form 1,2-
tive cleavage of α,β-epoxy ketones (chalcone epoxides) to
α,α-dimethoxy acetophenones using iodine in refluxing
methanol. To our surprise α,α-dimethoxy acetophenones
were the sole products in the reaction. The reaction pro-
disubstituted compounds.1 Another type of reaction in-
volves breaking of the C–O bond of epoxides followed by
rearrangement of the skeleton to form carbonyl com-
pounds with the same number of carbons as epoxides.1 On
ceeded through ring opening of the chalcone epoxide by
the other hand, cleavage of the C–C bond in epoxides fol-
methanol to form β-methoxy alcohol, cleavage of the C–
C bond in the latter to form α-ketoaldehyde, and acetaliza-
tion of the formyl group to give the product. Chalcone ep-
lowed by oxidation, that is, oxidative cleavage of epox-
ides, is not that common and reported to require
uncommon reagents and drastic conditions. However, this
oxides were prepared from chalcones using hydrogen
process has a potential to serve as an effective and selec-
peroxide and sodium hydroxide in methanol.12
tive alternative to oxidative cleavage of olefins which em-
We were interested in the reaction of trifunctional deriva-
tive 2, which can be obtained from 1 through methanoly-
sis (Scheme 1). While attempting to prepare 2a (R1 = R2 =
R3 = H) in good yield, without any side product, 1a (R1 =
ploys very hazardous reagents like OsO4, ozone, etc.
Oxidative cleavage of epoxides has been attempted using
2
HIO4 or H5IO6,3 Pb(OAc)4,4 CAN,5 Na2Cr2O7·2H2O,6
PyCrO(O2)2,7 PyMoO(O2)2,8 alkaline H2O2,9 NaIO4,10 and
R2
O
OMe
R2
O
O
I2 (5 mol%)
I2 (2.0 equiv)
R3
reflux
OH
R1
R1
R3
MeOH
r.t.
1
2
R2
O
R2
O
OMe
OMe
H
O
R1
R1
4
3
Scheme 1 Oxidative cleavage of chalcone epoxides to α,α-dimethoxyacetophenones using iodine in methanol
SYNLETT 2014, 25, 1591–1595
Advanced online publication: 03.06.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339134; Art ID: st-2014-b0231-l
© Georg Thieme Verlag Stuttgart · New York

1592
B. G. Jadhav, S. D. Samant
LETTER
R2 = R3 = H) was reacted with excess of pure methanol. The effect of the quantity of iodine on the reaction is given
The reaction did not take place in the absence of any cat- in Table 2. Maximum yield of 4a was obtained with 2.0
alyst. While attempting different catalysts, particularly equivalents of iodine; increasing the time did not increase
Lewis acids, we found that a catalytic amount of iodine the yield of 4a further. The reaction was also carried out
was highly beneficial, and 2a was obtained in excellent in EtOH as solvent in the presence of iodine (2.0 equiv) at
yield. The reaction was studied in detail using different reflux for nine hours. The reaction took place in the same
quantities of iodine (Table 1). The reaction of 1a with 5 manner and gave the expected product (α,α-diethoxy ace-
mol% of iodine in excess of methanol at room tempera- tophenone) in 85% yield. However, other alcohols, 1-pro-
ture provided 2a in 95% yield in two hours. Compound 2a panol and 2-propanol, afforded a mixture of products
was characterized by 1H NMR spectroscopy which from which we could not isolate the desired products.
showed a 3:1 syn/anti ratio in accordance with the litera-
A plausible mechanism of the formation of α,α-dime-
thoxyacetophenones 4 from chalcone epoxides 1 is given
in Scheme 2. In excess of methanol the epoxide ring in 1
is opened, in the presence of iodine functioning as a Lewis
ture.13 Increase in quantity of iodine resulted only in the
decrease in the reaction time with no effect on the yield or
the syn/anti ratio of 2a.
acid, to form β-methoxy alcohol 2. Such a kind of ring
Table 1 Effect of Concentration of Iodine on the Methanolysis of
opening of epoxides is known.13 Alcohols are known to
Chalcone Epoxide 1a to β-Methoxy Alcohol 2aa
react with bromine and iodine to form hypobromites and
hypoiodites.14 Iodine, present in 2.0 equivalents, may re-
act with the hydroxyl group in 2 to form a hypoiodite 5.
The I–O bond in the hypoiodite is very weak and under-
goes homolysis. The hypoiodite 5 may undergo homoly-
sis with iodine radical to form oxyradical 6 which would
undergo C–C bond cleavage to form α-keto aldehyde 3
and radical 7. The latter may form benzyl methyl ether 8
through hydrogen abstraction from HI. To support the
mechanism we treated 2a separately with 2.0 equivalents
of iodine in excess methanol. In this reaction 4a was
formed. Thus, the reaction goes through the intermediate
2.
Entry
Iodine (mol%) Time (h)
Yield of 2a (%)b syn/anti
1
2
3
5
10
20
2
95
95
95
3:1
3:1
3:1
1.2
0.5
a Reaction conditions: 1a (1 mmol), I2, MeOH (3 mL), 25 °C.
b Isolated yield.
Surprisingly, we noticed that when 1a, in boiling metha-
nol, was treated with a larger quantity of iodine (0.5
equiv), it underwent an unusual reaction and gave 4a
(20%) along with 2a (70%; Table 2, entry 4). Compound
4a was separated by column chromatography and was
identified as α,α-dimethoxyacetophenone by HRMS and
IR and 1H NMR spectroscopy.
••
MeOH
••
O
O
OMe
Ar2
O
OMe
Ar2
MeOH
+ I2, – HI
Ar1
Ar2
Table 2 Reaction of 1a in Methanol in the Presence of Increasing
Ar1
Ar1
Amounts of Iodinea
O
OH
O
I2
I
2
Entry
Iodine
(mol%)
Time
(h)
Yield of 4a Yield of 2a
1
5
(%)b
(%)b
•
+ I, – I2
1
2
3
4
5
6
7
8
9
5
10
12
12
12
12
12
12
10
12
12
–
95
95
95
70
40
20
–
O
OMe
Ar2
O
–
OMe
H
O
Ar1
Ar1
+
20
–
•
Ar2
O
O
•
3
50
20
50
70
85
85
85
7
6
100
150
200
250
300
OMe
OMe
Ar1
3
2 MeOH
+
– H2O
4
–
•
–
OMe
Ar2
+
I
7
HI
+
a Reaction conditions: 1a (1 mmol), I2, MeOH (3 mL), reflux.
b Isolated yield.
8
Scheme 2 Proposed mechanism of the formation of α,α-dimethoxy-
acetophenones from chalcone epoxides via β-methoxy alcohols
Synlett 2014, 25, 1591–1595
© Georg Thieme Verlag Stuttgart · New York

LETTER
C–C Bond Cleavage in Chalcone Epoxides
1593
In order to test the generality of the reaction, chalcone ep- position was favorable for the expected reaction; the reac-
oxides substituted on either ring were subjected to the ox- tion was fast, and 4a was obtained within two hours in
idative cleavage (Table 3).
75% yield. The halogen like Cl at the para position was
slightly helpful (Table 3, entry 9). These observations
supported the mechanism proposed. As the reaction in-
volves initial complexation of iodine with the epoxide
ring, the group on the adjacent phenyl ring may exert sub-
stantial effect on this complexation. The group may also
affect the stability of the C–C bond, which breaks and
forms the product.
The most striking observation was that the substituents
present on the phenyl ring adjacent to the epoxide had a
profound effect on the course of the reaction. As one ex-
treme, the electron-withdrawing CN group at the para po-
sition gave only the β-methoxy alcohol 2b16 and no
further reaction took place. On the other hand, the elec-
tron-donating OMe group (Table 3, entry 10) at the para
Table 3 Oxidative Cleavage of Chalcone Epoxides 1 to α,α-Dimethoxy Acetophenones 4a
Entry
1
Chalcone epoxide 1
Product 4
Time (h)
10
Yield of 4 (%)b
O
O
O
OMe
OMe
85
1a
4a
O
O
O
OMe
OMe
2
3
4
5
6
8
14
12
11
24
85
75
75
75
75
Br
Br
4b
1b
O
O
O
OMe
OMe
1c
4c
O
O
O
OMe
OMe
MeO
MeO
1d
4d
MeO
O
MeO
O
O
OMe
OMe
1e
4e
Cl
O
Cl
O
O
OMe
OMe
Cl
Cl
4f
1f
O
O
O
OMe
OMe
7
8
8
75
75
1g
4g
O
O
O
O
OMe
OMe
O
13
4h
1h
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1591–1595

1594
B. G. Jadhav, S. D. Samant
LETTER
Yield of 4 (%)b
85
Table 3 Oxidative Cleavage of Chalcone Epoxides 1 to α,α-Dimethoxy Acetophenones 4a (continued)
Entry
9
Chalcone epoxide 1
Product 4
Time (h)
O
O
O
OMe
OMe
8
Cl
4a
4a
1i
O
O
O
O
OMe
OMe
10
11
2
75
95
OMe
1j
OMe
O
O
12
OH
CN
CN
2b
1k
a Reaction conditions: chalcone epoxide 1 (1 mmol), I2 (2.0 mmol), MeOH (3 mL), reflux.
b Isolated yield.
The minor effect exhibited by the substituent present on
the phenyl ring adjacent to carbonyl group may be ex-
plained on the basis of participation of the carbonyl oxy-
gen in the complexation of iodine with the epoxy oxygen.
The 2,4-disubstituted phenyl ring took longer time for
completion (Table 3, entry 6). This reaction has a poten-
tial to generate key intermediates α,α-dimethoxy aceto-
phenones which find application in the synthesis15 of
chiral cyanohydrins, nicotine derivatives, chiral sulfox-
ides, α-hydroxy acetals, chiral 1,2-diols, and myretnal-
derived chiral auxillaries.
References and Notes
(1) (a) Parker, R. E.; Isaacs, N. S. Chem. Rev. 1959, 59, 737.
(b) Smith, J. G. Synthesis 1984, 629.
(2) Antoniotti, S.; Dunach, E. Synthesis 2003, 2753; and
references cited therein.
(3) (a) Kim, J.; Matsuyama, S.; Suzuki, T. J. Labelled Compd.
Raiopharm. 2004, 47, 921. (b) Sankaranarayanan, S.;
Chattopadhyay, S. Tetrahedron: Asymmetry 1998, 9, 2627.
(c) Nagarkatti, J. P.; Ashley, K. R. Tetrahedron Lett. 1973,
14, 4599.
(4) (a) Ferreira, J. T. B.; Brocksom, T. J.; Braga, A. L. Quim.
Nova 1982, 5, 4. (b) Brocksom, T. J.; Ferreira, J. T. B.;
Braga, A. L. J. Chem. Res., Synop. 1981, 10, 334.
(5) Roy, S. C.; Adhikari, S. Indian J. Chem., Sect. B: Org.
Chem. Incl. Med. Chem. 1992, 31, 459.
(6) Mandal, A. K.; Borude, D. P. Synth. Commun. 1991, 21, 111.
(7) Curci, R.; Lopez, L.; Troisi, L.; Rashid, K. S. M.; Schaap,
P. A. Tetrahedron Lett. 1998, 29, 3145.
(8) Bonchio, M.; Conte, V.; Di Furia, F.; Modena, G. J. Mol.
Catal. 1991, 71, 159.
(9) (a) Ogata, Y.; Sawaki, Y.; Shimizu, H. J. Org. Chem. 1978,
43, 1760. (b) Hoffman, J. J. Am. Chem. Soc. 1957, 79, 503.
(c) Temple, R. D. J. Org. Chem. 1970, 35, 1275.
(10) Binder, C. M.; Dixon, D. D.; Almaraz, E.; Tius, M. A.;
Singaram, B. Tetrahedron Lett. 2008, 49, 2764.
(11) Miyamoto, K.; Tada, N.; Ochiai, M. J. Am. Chem. Soc. 2007,
129, 2772.
(12) Hasegawa, E.; Ishiyama, K.; Horaguchi, T.; Shimizu, T.
J. Org. Chem. 1991, 56, 1631.
(13) Leitao, A. J. L.; Salvador, J. A. R.; Pinto, R. M. A.; Melo,
M. L. S. Tetrahedron Lett. 2008, 49, 1694.
We have reported an unusual observation of oxidative
cleavage of the C–C bond in chalcone epoxides followed
by acetalization with methanol to form α,α-dimethoxy-
acetophenones, when chalcone epoxides are reacted with
iodine in methanol. To the best of our knowledge, no such
tandem C–C bond cleavage and acetalization is reported
earlier. The reaction goes through β-methoxy alcohol for-
mation. The reaction takes place under very mild condi-
tions. The reaction is an equivalent of a retro-Darzen
reaction. The products are synthetically important inter-
mediates.
Acknowledgment
The author B.G.J. is thankful to UGC-SAP for providing a fellow-
ship.
(14) Beebe, T. R.; Hii, P.; Reinking, P. J. Org. Chem. 1981, 46,
1927.
(15) Ayala-Mata, F.; Barrera-Mendoza, C.; Jimenez-Vazquez,
H. A.; Vargas-Diaz, E.; Zepeda, L. G. Molecules 2012, 17,
13864.
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000083.SunpfgIpi
o
o
nr
i
(16) General Procedure for Oxidative Cleavage of Chalcone
Epoxides to α,α-Dimethoxy Acetophenones
To a solution of an appropriate chalcone epoxide (1.0 mmol)
in MeOH (3 mL) was added iodine (2.0 mmol) in one
Synlett 2014, 25, 1591–1595
© Georg Thieme Verlag Stuttgart · New York

LETTER
portion. The reaction mixture was refluxed for the
C–C Bond Cleavage in Chalcone Epoxides
1595
1H NMR (300 MHz, CDCl3): δ = 3.46 (s, 6 H), 5.16 (s, 1 H),
7.29–7.52 (m, 2 H), 7.63 (d, 1 H, J = 8.1 Hz). 13C NMR (300
MHz, CDCl3): δ = 54.5, 103.4, 127.0, 130.4, 131.1, 133.0,
134.2, 137.8, 195.3.
4-(2-Hydroxy-1-methoxy-3-oxo-3-phenylpropyl)benzo-
nitrile (2b)
Yield 95%; white solid; mp 87–89 °C. FTIR (neat): 3369,
2941, 2823, 2230, 1674 (s), 1597, 1448, 1224, 1114, 830,
736, 690 cm–1. DI-MS: m/z = 282.1 [M + H]+. 1H NMR (300
MHz, CDCl3): δ = 3.24 (s, 3 H), 3.62 (d, 1 H, J = 7.5 Hz),
4.53 (d, 1 H, J = 4.5 Hz), 5.35–5.38 (m, 1 H), 7.24 (d, 2 H,
J = 8.7 Hz), 7.45–7.66 (m, 5 H), 7.84 (d, 2 H, J = 7.2 Hz).
13C NMR (300 MHz, CDCl3): δ = 57.6, 76.6, 85.0, 112.0,
118.5, 128.2, 128.6, 128.8, 131.8, 134.2, 134.6, 142.0,
199.0.
appropriate time (monitored by TLC and visualized with
2,4-dinitrophenyl hydrazine stain). The reaction mixture was
cooled to r.t. MeOH was evaporated under reduced pressure
to obtain an oily residue that was purified by column
chromatography (silica gel, 60–120 mesh size) using 5–10%
EtOAc in PE as an eluent to obtain pure products. Pure
products were identified by IR, 1H NMR, and 13C NMR
spectroscopy and HRMS.
Analytical Data of New Compounds
1-(2,4-Dichlorophenyl)-2,2-dimethoxyethanone (4f)
Yield 75%; oil. FTIR (neat): 2939, 2833, 1707 (s), 1583,
1456, 1276, 1193, 867, 750 cm–1. HRMS: m/z calcd for
C10H10ClO3Na [M + Na]+: 270.9967; found: 271.0039,
273.0010, 274.9986.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1591–1595

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