A new and efficient method for the synthesis of α,α- dihaloketones by oxyhalogenation of alkynes using oxone-KX (X = Cl, Br, or I)

Article abstract of DOI:10.1016/j.tetlet.2013.05.072

A simple and efficient method for the preparation of α,α- dichloroketones, α,α-dibromoketones, and α,α- diiodoketones by oxyhalogenation of alkynes using oxone and KX (X = Cl, Br, or I) is described.

Full text of DOI:10.1016/j.tetlet.2013.05.072

Accepted Manuscript
A new and efficient method for the synthesis of α,α-dihaloketones by oxyhalo‐
genation of alkynes using Oxone ® -KX (X=Cl, Br or I)
Sridhar Madabhushi, Raveendra Jillella, Kishore Kumar Reddy Mallu, Kondal
Reddy Godala, Venkata Sairam Vangipuram
PII:
S0040-4039(13)00840-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.05.072
TETL 42972
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
10 April 2013
14 May 2013
17 May 2013
Please cite this article as: Madabhushi, S., Jillella, R., Mallu, K.K.R., Godala, K.R., Vangipuram, V.S., A new and
efficient method for the synthesis of α,α-dihaloketones by oxyhalogenation of alkynes using Oxone ® -KX (X=Cl,
Br or I), Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.05.072
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Graphical Abstract
A new and efficient method for the synthesis of α,α-dihaloketones by oxyhalogenation of
alkynes using Oxone®-KX (X=Cl, Br or I)
Sridhar Madabhushi, Raveendra Jillella, Kishore Kumar Reddy Mallu, Kondal Reddy Godala
and Venkata Sairam Vangipuram
1

A new and efficient method for the synthesis of α,α-dihaloketones by oxyhalogenation of
alkynes using Oxone®-KX (X=Cl, Br or I)
Sridhar Madabhushi,* Raveendra Jillella, Kishore Kumar Reddy Mallu, Kondal Reddy Godala
and Venkata Sairam Vangipuram
Fluoroorganics Division, Indian Institute of Chemical Technology, Hyderabad-500607, India
Abstract: A simple and efficient method for the preparation of α, α-dichloroketones, α, α-
dibromoketones and α, α-diiodoketones by oxyhalogenation of alkynes using oxone® and KX(X
=Cl, Br or I) is described.
Keywords: oxone®, potassium halide, oxyhalogenation, alkynes, α, α-dihaloketones.
α,α-Dihaloketones are important intermediates for synthesis of heterocycles,1 unsaturated acids
and ynols,2 and also useful in cyclopropanation reactions.3 These compounds are generally
obtained in poor yields by halogenation of α-methyl ketones with bromine or chlorine.4 In recent
years, oxyhalogenation of alkynes has emerged as an important reaction for the preparation of
α,α-dihaloketones. Shreeve et al.5 have prepared α,α-dibromoketones by oxybromination of
alkynes with KBr using Selectfluor® as an oxidant. In another study, Floris et al.6 have achieved
oxybromination of alkynes with KBr using hydrogen peroxide as an oxidant and (NH4)2MoO4 as
the catalyst. In this method, α,α-dibromoketones were formed in moderate yields along with a
mixture of other products. Recently, Li and co-workers7 studied oxyhalogenation of alkynes
.
using N-halosuccinimide as the halogen source and FeCl3 6H2O as the oxidant. In this reaction,
N-halosuccinimide is required in stoichiometric quantity and this gives mixtures, as succinimide
is invariably produced as a byproduct. Recently, Itoh and co-workers8 reported a photochemical
approach for oxybromination by aerobic photooxidation of alkynes using 48% aqueous HBr and
*Corresponding author. Tel.: +91 40 27191772; fax: +91 40 27160387.
E-mail address: smiict@gmail.com (S. Madabhushi).
2

obtained α,α- dibromoketones in 17-84% yields. Most of the studies on oxyhalogenation of
alkynes are limited to preparation of α,α-dibromoketones and they also suffer from one or more
disadvantages such as poor yields, application of expensive or toxic chemicals and formation of
mixture of products. Hence, studies for development of more convenient and efficient methods
for oxyhalogenation of alkynes into α,α-dihaloketones are highly desirable.
Potassium peroxymonosulfate or oxone®, which is commercially available in the form of a triple
salt 2KHSO5·KHSO4·K2SO4, is an important and widely used oxidant in organic synthesis for a
variety of transformations such as oxidation of alkenes to epoxides,9 thioethers to sulfones,10
aldehydes to carboxylic acids11 and tertiary amines to amine oxides.12 In addition, oxone® is also
known to promote bromination,13 hydroxybromination14 and benzylic oxidation15 reactions with
reagents such as NH4Br and KBr. To the best of our knowledge, studies on transformation of
alkynes into α,α-dihaloketones using oxone® as the oxidant are so far not reported in literature.
Herein, we report, a simple and efficient method for the preparation of a variety of α,α-
dichloroketones (79-98%), α,α-dibromoketones (77-99%) and α,α-diiodoketones(5-52%)) by
oxyhalogenation of alkynes with a potassium halide using oxone® as the oxidant as shown in
Scheme 1.
Scheme 1: Oxyhalogenation of alkynes with oxone-KX
In our preliminary experiments, we examined the scope of oxone® mediated oxyhalogenation of
an alkyne using phenylacetylene, which was reacted with a variety of halogen sources such as
3

aq. HCl, NH4Cl, NaCl, KCl, aq. HBr, NH4Br, KBr, KI, N-chlorosuccinimide in the presence of
oxone® in acetonitrile- water and the results are shown in Table 1.
Table 1: A study of various halogen sources for conversion of phenyacetylene into α,α-
dihaloacetophenone using oxone® as the oxidant.
In the above study, best results were observed with potassium halides. For example, the reaction
with oxone®-KCl gave 2,2-dichloro-1-phenylethanone in 98% yield (entry 4, Table 1), reaction
with oxone®-KBr gave 2,2-dibromo-1-phenylethanone in 99% yield (entry 7, Table 1) and the
reaction with oxone® -KI gave 2,2-diiodo-1-phenylethanone in 52% yield (entry 10, Table 1).
These oxyhalogenation reactions were found to proceed well in acetonitrile and water and no
reaction was observed in the absence of water.
In our study, rapid exothermic reaction was observed when oxone® was mixed with KX (KCl,
KBr or KI) in water. In our observation, α, α-dihaloketone formed in high yield under controlled
reaction temperatures. For example, in the above study, we obtained 2,2-dichloro-1-
phenylethanone and 2,2-dibromo-1-phenylethanone in good yields when reaction temperatures
o
were kept below 50 C. In oxyiodination reaction of phenylacetylene with oxone®-KI, we
obtained 2,2-diiodo-1-phenylethanone in good yield when reaction temperature was maintained
o
below -10 C. In these reactions, exothermicity was conveniently controlled with slow
(dropwise) addition of water to the reaction mixture, i.e., to the mixture of phenylacetylene,
potassium halide and oxone® in acetonitrile, at room temperature.
4

Next, using the above optimized reaction procedures, we studied oxychlorination and
oxybromination and oxyiodination reactions of a variety of alkynes 1a-j with oxone®-KCl,
oxone®-KBr and oxone®-KI respectively in acetonitrile and water.16
In this study,
oxychlorination and oxybromination of alkynes 1a-j gave corresponding α,α-dichloroketones
2a-j in 79-98% yields and α,α-dibromoketones 3a-j in 77-99% yields respectively. However, in
oxyiodination reactions of alkynes 1a-j, we obtained mixtures of α,α-diiodoketones 4a-j (5-52%)
and 1,2-diiodo alkenes 5a-j (47-94%) as shown in Table 2.
Table 2: Oxyhalogenation of alkynes using oxone® -KX
The plausible mechanism for the formation of α,α-dihaloketones by reaction of oxone®-KX
system with an alkyne is shown in Scheme 2. Here, in the initial step, oxone® and KX react in
water to give hypohalous acid (HOX).17 Next, hypohalous acid converts into dihalo monoxide
(X2O)18 and reacts with alkyne to give a cyclic alkyne-halonium ion complex, which collapses
into more stable vinyl carbocation and undergoes nucleophilic addition reaction with XO-
producing α, α-dihaloketone as shown in Scheme 2. Here, the terminal alkyne undergoes
nucleophilic(XO-) addition reaction with Markovnikov’s regiochemistry as 2o vinyl carbocation
is more stable than 1o vinyl carbocation.19 In this mechanism, alkyne-bromonium ion complex
collapses to 2o vinyl carbocation, which is being stabilized by the hyperconjucation or electron
releasing inductive effect of the adjacent R group(alkyl or aryl).
Scheme 2: Plausible mechanism for conversion of an alkyne into a α, α-dihaloketone
5

In the present study, though we did not observe formation of 1,2-dichloroalkene and 1,2-
dibromoalkene in oxychlorination and oxybromination reactions, we observed formation 1,2-
diiodoalkene as a side product in oxyiodination reaction of an alkyne with oxone®-KI. Here, it
appears that I2O is less stable when compared to Cl2O and Br2O at temperatures below -10 oC.
Thermal splitting of I2O can generate iodine,20 which readily reacts with an alkyne to give a 1,2-
diiodoalkene.21
In conclusion, this work describes the first study of application of oxone® as an oxidant for
oxyhalogenation of alkynes into α, α-dihaloketones. In this study, a simple and efficient method
was shown for efficient conversion of a variety of alkynes into α, α-dichloroketones, α, α-
dibromoketones and α, α-diiodoketones under mild conditions.
Acknowledgment: R.J., K.K.R.M., K.R.G. are thankful to CSIR, New Delhi for the financial
support in the form of Senior Research Fellowship. V.S.V. is thankful the Director, IICT for the
financial support in the form of Senior Project Assistantship.
Supplementary data: Supplementary data (experimental procedures, characterization data and
1H &13C NMR spectra of the compounds) associated with this article could be found in the
support information.
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7

11. Travis, B. R.; Sivakumar, M.; Hollist, G. O.; Borhan, B. Org.Lett. 2003, 5, 1031-1034.
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1401-1405.
15. Moriyama, K.; Takemura, M.; Togo, H. Org. Lett. 2006, 14, 2414-2417.
16. A typical procedure for preparation of α,α-dichlorketons and α,α-dibromoketones: 1-
Ethynyl-4-methylbenzene 1b (0.5 g, 4.3 mmol), KBr (1.0 g, 8.6 mmol), oxone® (5.3 g, 8.6
mmol) and acetonitrile (10 mL) were taken into a 100 mL round bottomed flask and stirred at
room temperature. Next, water (5 mL) was added dropwise to the mixture. With addition of
water, exothermic reaction was observed and temperature of the reaction mixture increased to
o
50 C. After completion of the reaction (TLC), reaction mixture was diluted with water (10
mL) and extracted with ethyl acetate (3x15 mL). The combined organic layers were washed
with brine, dried over anhyd. Na2SO4 and concentrated under reduced pressure. Purification
of the crude product by normal column chromatography (silica gel 60-120 mesh, n-hexane)
furnished 2,2-dibromo-1-p-tolylethanone 3b (1.22 g, 97%) as a pale yellow solid (m.p. 96-98
o
1
oC; lit.22 97-99 C), which was characterized by the following spectral data: H NMR (300
MHz, CDCl3): δ = 7.98 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 6.69 (s, 1H), 2.44 (s,
3H); 13C NMR (75 MHz, CDCl3): δ = 185.5, 145.6, 129.7, 129.5, 128.0, 39.9, 21.7; IR (neat):
υ 3012, 2932, 1708, 1423, 1282, 993, 748, 682 cm-1; Elemental Analysis: C, 37.14; H,
2.775%; Calcd: C, 37.04; H, 2.76%;
A typical procedure for preparation of α,α-diiodoketones: 1-Ethynyl-4-methylbenzene 1b
(0.5 g, 4.3 mmol), KI (1.4 g, 8.6 mmol), oxone® (5.3 g, 8.6 mmol) and acetonitrile (10 mL)
8

were taken into a 100 mL round bottomed flask and the mixture was cooled to -10 oC using a
salt-ice bath. Next, water (5 mL) was added drop wise to the mixture and after completion of
the reaction (TLC), the reaction mixture was diluted with water (10 mL) and extracted with
ethyl acetate (3x15 mL). The combined organic layer was washed with brine, dried over
anhydrous Na2SO4 and concentrated under reduced pressure. Purification of the crude
product by normal column chromatography (silica gel 60-120 mesh, n-hexane) furnished 2,2-
o
diiodo-1-p-tolylethanone 4b (0.86 g, 52%) as a pale yellow solid (m.p. 75-77 C) and (E)-
(1,2-diiodovinyl)benzene 5b (0.76 g, 47%) as a pale yellow oil. Spectral data obtained for 4b
and 5b are as follows:
o
1
2,2-diiodo-1-p-tolylethanone(4b): pale yellow solid, m.p. 75-77 C; H NMR (300 MHz,
13
CDCl3): δ = 7.93 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 6.50 (s,1H), 2.44 (s,3H); C
NMR (75 MHz, CDCl3): δ = 187.8, 145.3, 129.5, 129.6, 125.8, 21.7, -28.2; IR (KBr): υ 3036,
2925, 1718, 1456, 1262, 968, 801 cm-1.
1
(E)-1-(1,2-diiodovinyl)-4-methylbenzene(5b): yellow oil, H NMR (CDCl3 300 MHz,): δ=
7.25(d, J = 8.1 Hz, 2H), 7.20(s, 1H), 7.15(d, J = 7.9 Hz, 2H), 2.34 (s, 3H); 13C NMR (75
MHz, CDCl3): δ = 145.2, 131.0, 129.9, 115.3, 99.4, 81.7, 20.5; IR (neat): υ 3063, 3012, 2948,
2851, 1416, 1201, 1152, 989, 789 cm-1.
17. Swain, C. G.; Crist, D. R. J. Am. Chem. Soc. 1972, 94, 3195-3200.
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9

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2001, p.442.
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10

Scheme 1: Oxyhalogenation of alkynes with Oxone-KX
2KHSO5 + KX
2HOX
KOH + HOX + K2S2O8
X2O + H2O
R
O
X+ OX
X
X
X
X
XO
R
XO
R
R
H
X2O
H
R
H
H
H
 
dihaloketone
Scheme 2: Plausible mechanism for conversion of an alkyne into a α,α-dihaloketone

Table 1: A study of various halogen sources for conversion of phenyacetylene into a α,α-
dihaloacetophenone using oxone® as the oxidant.
S.No.
1
Halogen
source
Product
Reaction
time (min)
% yielda
66
50% Aq. HCl
60
60
60
10
60
60
2
3
4
5
6
7
8
NH4Cl
75
80
98
50
60
NaCl
KCl
48% Aq. HBr
NH4Br
KBr
15
-
99
-
N. R.
9
KI
KI
20
20
99
99
3:1
1:1
10b
aIsolated yields; breaction temperature = -10 oC.
1

Table 2: Oxyhalogenation of alkynes using Oxone® -KX
Entry
Alkyne 1
2
3
4/5
% yielda Reaction % yielda Reaction % yielda Reaction
Time
(min)
10
Time
(min)
15
Time
(min)
20
a
b
c
98
96
94
99
97
95
51/48
52/47
5/94
15
30
15
30
25
120
d
96
10
97
30
48/50
20
e
f
90
79
20
30
92
82
20
30
50/45
45/52
25
20
g
h
87
89
15
20
90
94
20
25
48/49
46/50
20
25
i
j
86
80
30
30
89
77
30
30
44/48
42/54
25
30
aIsolated yields. All products gave satisfactory 1H&13C NMR, IR and Mass spectral data.
2