One-pot synthesis of α-ketoacetals from aryl methyl ketones in the presence of selenous acid catalyzed by boron trifluoride etherate

Article abstract of DOI:10.1016/j.tetlet.2015.05.087

A simple and efficient one-pot preparation of α-ketoacetals from substituted acetophenones and triethylorthoformate in the presence of H₂SeO₃ and BF₃·Et₂O as catalyst has been developed. The desired products are obtained in good yields by a simple protocol involving neat and mild reaction conditions. The present methodology provides an attractive alternative method for the preparation of α-ketoacetal derivatives.

Full text of DOI:10.1016/j.tetlet.2015.05.087

Accepted Manuscript
One-pot synthesis of α-ketoacetals from aryl methyl ketones in the presence of
selenous acid catalyzed by boron triflouride etherate
Icydora Kharkongor, Bekington Myrboh
PII:
S0040-4039(15)00920-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.05.087
TETL 46359
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
16 April 2015
21 May 2015
22 May 2015
Please cite this article as: Kharkongor, I., Myrboh, B., One-pot synthesis of α-ketoacetals from aryl methyl ketones
in the presence of selenous acid catalyzed by boron triflouride etherate, Tetrahedron Letters (2015), doi: http://
dx.doi.org/10.1016/j.tetlet.2015.05.087
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One-pot synthesis of α-ketoacetals from aryl
methyl ketones in the presence of selenous
acid catalyzed by boron triflouride etherate
Leave this area blank for abstract info.
Icydora Kharkongora and Bekington Myrboha, ∗

1
Tetrahedron Letters
journal homepage: www.els evier.com
One-pot synthesis of α-ketoacetals from aryl methyl ketones in the presence of
selenous acid catalyzed by boron triflouride etherate
Icydora Kharkongora and Bekington Myrboha, ∗
a Centre for Advanced Studies in Chemistry, Department of Chemistry, North-Eastern Hill University, Mawlai, Shillong -793022, India
ARTICLE INFO
ABSTRACT
Article history:
Received
A simple and efficient one-pot preparation of α-ketoacetals from substituted acetophenones and
triethylorthoformate in the presence of H2SeO3 and BF3·Et2O as catalyst has been developed.
The desired products are obtained in good yields by a simple protocol involving neat and mild
reaction conditions. The present methodology provides an attractive alternative method for the
preparation of α-ketoacetals derivatives.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
α-ketoacetals
Selenium
triethylortoformate
reported methods are quite effective, they are often limited by
harsh reaction conditions, the use of expensive starting materials
and requirement of strong bases for carrying out the reactions.
In continuation of our successful studies on the synthetic
.
1. Introduction
The α-ketoacetals are important synthons and constitute an
array of functional groups of great value in synthetic organic
chemistry. The importance of α-ketoacetals in organic synthesis
is their selective functionalization of a keto group over the more
reactive aldehydes, as the latter is protected as an acetal.1 The α-
ketoacetals are key intermediates in the preparation of chiral
cyanohydrins,2,3 alpha hydroxyl esters,4 alpha hydroxyl acetals,5
chiral sulphoxides,6 chiral 1,2-diols7 and nicotine derivates.8 The
α-ketoacetals are also important synthons for the synthesis of
heterocycles.9
utility of selenium and its compounds19 we wish to report here an
alternative convenient and one-pot synthesis of α-ketoacetals
starting from easily available starting materials under mild
reaction conditions (Scheme 1). In the initial reaction, when
acetophenone (1a) (1.0 mmol), triethylorthoformate (2) (2.0
mmol) in the presence of H2SeO3 (0.5 equiv) and BF3·Et2O (1.5
mL) was stirred at room temperature for 24 h, the product 3a was
obtained in 50% yield (Table 1, entry 1). However, after
optimization, the reaction in the presence of 0.7 equiv of H2SeO3
proceeded to afford 3a in 75% within 10 h (Table 1, entry 2).
Further, there was no significant increase in the yield of the
product 3a when 1.0 equiv of H2SeO3 was used (Table 1, entry 3)
A number of methods have been developed for the preparation of
α-ketoacetals. The first classical approach to the preparation of α-
ketoacetals is based on the work of Wohl and Lang.10 Other
methods also includes the acetalization of monoalkyl-substituted
glyoxals with triethylorthoformate,3 treatment of ethyl α,α-
diethoxyacetate with Grignard reagents11 and α,α-dichloroketones
with MeONa.12 Nucleophilic additions on Weinreb amides also
afforded α-ketoacetals.1 The use of selenium dioxide as a catalyst
has also been reported in the conversion of terminal alkynes13 and
methyl aryl ketones14 to α-ketoacetals in the presence of MeOH.
Transformation of methoxystyrenes with Ce(IV) ammonium
nitrate,15 rearrangement of 1,3-dimethoxy-2-alkanones,16
oxidation of arylketones by thallium(III) and halogens17 and
nucleophilic addition to α,α-dialkoxyacetyl chlorides18 are some
of the other methods reported in the literature. Although the
———
Table 1. Optimization of reaction conditionsa
Entry H2SeO3 (equiv)
Time (h)
Yield (%)b
BF3·Et2O (mL)
1
2
3
4
5
0 . 5 (2 equiv of 2)
0 . 7 (2 equiv of 2)
1 . 0 (2 equiv of 2)
1 . 2 (2 equiv of 2)
0 . 7 (1 equiv of 2)
1 . 5
1 . 5
1 . 5
1 . 5
1 . 5
24
5 0
7 5
7 6
7 1
4 7
10
10
12
18
aReaction conditions: 1a (1.0 mmol), 2 (2.0 mmol), H2SeO3 (0.7 equiv),
BF3·Et2O (1.5 mL), neat, rt, time.
bIsolated yields.
∗ Corresponding author. Tel.: +91-364-272-2612; fax: +91-364-255-0076; e-mail: bmyrboh@nehu.ac.in

2
Tetrahedron Letters
and further increment to 1.3 equiv of H2SeO3 led to a decrease in
the product yield (Table 1, entry 4). Excess of
triethylorthoformate (2 equiv) is required since the use of
1 equivalent of triethylorthoformate (Table 1, entry 5) resulted in
low yield of the product besides the increase in the reaction time.
O
O
H2SeO3 (0.7eq)
O
BF3 Et2O (1.5 mL)
CH(OCH2CH3)3
R
R
Neat, rt
8-14 h
O
1
2
3
Scheme 1. Synthesis of α-ketoacetals
Table 2. One-pot synthesis of α-ketoacetals (3) via Scheme 1
Entry
Substrate 1 ( Ar/Het)
Time (h)
Product 3b
Yield (%)a
75
O
O
1
C6H5 (1a)
10
O
(3a)
(3b)
2
3
4-ClC6H4 (1b)
4-BrC6H4 (1c)
8
8
90
87
(3c)
(3d)
4
5
4-CH3C6H4 (1d)
2-OCH3C6H4 (1e)
8
8
85
86
(3e)
6
3-OCH3C6H4 (1f)
3-OCH3C6H4 (1f)
3-NO2C6H4 (1h)
4-NO2C6H4 (1i)
3-OHC6H4 (1j)
9
84
80
77
75
76
(3f)
(3g)
(3h)
(3i)
7
9
8
10
10
10
9
10
(3j)
11
4-OHC6H4 (1k)
11
70
(3k)
12
13
3-NHCOCH3C6H4 (1l)
4-NHCOCH3C6H4 (1m)
10
10
80
83
(3l)
(3m)

3
14
15
16
2-furanyl (1n)
12
14
12
10
65
55
66
70
(3n)
(3o)
(3p)
5-methyl-2-furanyl (1o)
2-thiophenyl (1p)
2-naphthyl (1q)
17
(3q)
aIsolated yields
bProducts were fully characterized by recording their 1H, 13C NMR, IR, Mass and elemental analyses.
The advantages and limitations of this methodology were
investigated by reacting triethylorthoformate (2) with various
substituted aryl methyl ketones (1a-q) in the presence of 0.7
equiv of H2SeO3 and BF3·Et2O (1.5 mL) to give 2,2-diethoxy-1-
phenylethanones (3a-q, Scheme 1).
nucleophilic attack by the lone pair of oxygen atom of the
triethylorthoformate leading to the formation of the product (3).
In summary, we have devised a one-pot method for the
synthesis of α-ketoacetals via the intermediary of H2SeO3 and
BF3·Et2O. The reaction proceeds efficiently at ambient
temperature and ordinary reaction conditions. In the present
methodology we were able to highlight a viable alternative
method involving the use of H2SeO3 and BF3·Et2O in a neat
reaction to furnish the 2,2-diethoxy-1-phenylethanones in good
yields in comparison to some of the earlier reported methods
involving expensive metal catalysts14,16 and strong bases.1,10
From the results obtained it may be noted that irrespective of
the presence of electron withdrawing or releasing substituents in
the ortho-, meta- or para-positions, the reactions proceeded fairly
smoothly to afford the desired products in good to excellent
yields (Table 2, 3a–q). Interestingly, electron poor aromatic
ketones such as 3-nitrobenzaldehyde (1h), and 4-
nitrobenzaldehyde (1i) also furnished 2,2-diethoxy-1-
phenylethanones (3h-i) in high yields (Table 2, entries 8-9). The
scope of this methodology was further extended to the reaction of
heteroaryl or fused aromatic methyl ketones with
triethylorthoformate (2). The same reaction trend was observed in
the case of 1-(2-furanyl)ethanone (1n), 5-methyl-(2-
furanyl)ethanone (1o), 1-(2-thiophenyl)ethanone (1p) to give the
corresponding 2,2-diethoxy-1-(heteroaryl)ethanones (3n-p, 55-
66%) while 1-(2-naphthyl)ethanone (1q) afforded 2,2-diethoxy-
1-(naphthalen-2-yl)ethanones (3q) in 70% yields (Table 1,
entries 14-17).
Acknowledgments
I.K. thanks the University Grants Commission for Rajiv
Gandhi National Fellowship, SAIF NEHU, CDRI Lucknow and
IISC Bangalore for spectral analysis. The author gratefully
acknowledges financial assistance from the Council of Scientific
and Industrial Research, Government of India (Project No.
02(0102)/12/EMR-II)
References and notes
Notably, substituted acetophenones bearing the N-acetyl
group at meta- and para-positions (1l, 1m) also furnished the
product in good yields (Table 1, entries 12-13). The reaction goes
to completion in each case as the starting ketone is completely
consumed. Besides the isolated product, no other products could
be isolated except for the usual unidentifiable impurities. All the
products obtained were fully characterized by 1H NMR, 13C
NMR, IR, Mass and elemental analyses.
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O
O
O
O
H
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HO
OH
R
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R
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3
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Scheme 2. Probable Mechanism
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electrophilic centre at the α-carbon of
6 resulting in a

4
Tetrahedron
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completion of the reaction was monitored by thin layer
chromatography. The reaction mixture was diluted with ethyl
acetate and filtered through a celite bed. The celite was washed
with ethyl acetate. The combined filtrate was washed with
saturated aqueous sodium hydrogen carbonate solution, water (10
mL), and brine (10 mL). The organic layer was separated, dried
with anhydrous Na2SO4 and concentrated. The compound was
purified by column chromatography on silica gel using ethyl
acetate and hexane as eluent.
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20. General experimental procedure: A mixture of aryl methyl ketones
(1 equiv), triethylorthoformate (2 equiv) and selenous acid (0.7
equiv) was stirred in an ice salt mixture (-5oC) followed by the
dropwise addition of BF3·Et2O (49%, 1.5 mL). The reaction was
allowed to stand at room temperature for 8-14 hours. The
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