[Hydroxy(tosyloxy)iodo]benzene mediated α-azidation of ketones

Article abstract of DOI:10.3390/11070523

Reaction of various ketones with [hydroxy(tosyloxy)iodo]benzene (HTIB) followed by treatment of the α-tosyloxy ketones thus generated in situ with NaN₃ offers a one-pot procedure for the synthesis of α-azido ketones. The HTIB used in this conversion may also be generated in situ by using iodosobenzene in combination with p-toluene-sulphonic acid.

Full text of DOI:10.3390/11070523

Molecules 2006, 11, 523-527
molecules
ISSN 1420-3049
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Short Communication
[
Hydroxy(tosyloxy)iodo]benzene Mediated α-Azidation of
Ketones
Om Prakash *, Kamaljeet Pannu, Richa Prakash and Anita Batra
Department of Chemistry, Kurukshetra University, Kurukshetra, Haryana, India
*
Author to whom correspondence should be addressed; Fax: (+91) 1744 238277; e-mail:
dromprakash50@rediffmail.com
Received: 20 August 2005; in revised form: 10 March 2006 / Accepted: 12 March 2006 / Published:
1
4 July 2006
Abstract: Reaction of various ketones with [hydroxy(tosyloxy)iodo]benzene (HTIB)
followed by treatment of the α-tosyloxy ketones thus generated in situ with NaN offers a
3
one-pot procedure for the synthesis of α-azido ketones. The HTIB used in this conversion
may also be generated in situ by using iodosobenzene in combination with p-toluene-
sulphonic acid.
Keywords: Hypervalent iodine, α-azido ketones, [hydroxy(tosyloxy)iodo]benzene,
iodosobenzene.
Introduction
The application of organohypervalent iodine reagents is a fertile and attractive field in organic
synthesis [1]. Of the various hypervalent iodine reagents, iodobenzene diacetate (IBD) [2] and
hydroxy(tosyloxy)iodo]benzene (HTIB) (Koser’s reagent) [3] have been found to be more versatile
[
than other reagents such as iodosobenzene (IOB), etc. The relatively lesser utility of IOB is due to its
polymeric nature [4], which makes it insoluble in common solvents. To overcome such difficulties,
combination reagents were developed. For example, the utility of IOB is greatly enhanced when it is
combined with acids [5], bases [6] or salts [7]. These reactions are thought to proceed via generation in
situ of the I(III) species 4 (Scheme 1). Continuing our investigations on the use of I(III) reagents, we

Molecules 2006, 11
524
now report a one pot α-azidation of ketones using HTIB or the combination reagent [(PhIO) +
n
p-TsOH] [8] and NaN3.
Scheme 1
OX
(PhIO)n + XY
Ph
I
Y
4
Results and Discussion
Based on previous reports on the use of [hydroxy(tosyloxy)iodo]benzene (HTIB) [9] in one-pot
syntheses of α-functionalized ketones, we first attempted the azidation of 1a using HTIB. Accordingly,
acetophenone (1a) was oxidized with one equivalent of HTIB in acetonitrile and subsequently the
α-tosyloxy ketone 2a generated in situ was treated with sodium azide. The reaction resulted in the
formation of the corresponding α-azido acetophenone 3a in 80% yield (Method A, Scheme 2). In order
to study the scope of this approach, various ketones 1b-1g were subjected to α−azidation using one
equivalent of HTIB and NaN to afford the corresponding α−azido ketones 3b-3g in yields ranging
3
from 69% to 81% (Table 1).
Scheme 2
O
O
O
2
R
2
R
Method A
or
2
R
1
R
1
R
1
R
Method B
N
3
OTs
1
2
3
Method A: (i) HTIB/ CH CN, reflux 2 h; (ii) NaN , rt, 2-3 h
3
3
Method B: (i) (PhIO)
n
3 3
+ p-TsOH/CH CN, reflux 2 h; (ii) NaN , rt, 2-3 h
In another important development, we established that it is possible to use a combination of
iodosobenzene and p-toluenesulphonic acid [(PhIO)n + p-TsOH] in place of HTIB. This combination
reagent generates HTIB in situ, which then reacts with ketones 1 to give the intermediary α-tosyloxy
ketones 2 (Method B).
It is evident from the results summarized in Table 1 that Method A and Method B work equally
well, although Method B is more convenient than Method A as the former avoids the preparation of
HTIB. It is to be mentioned that the reported preparation of HTIB consists of two steps starting from
iodosobenzene [10,11] (Scheme 3).

Molecules 2006, 11
525
Scheme 3
PhI(OAc)
(
PhIO)
PhI(OH)OTs
n
2
IOB
IBD
HTIB
Table 1. α-Azido ketones 2 prepared according to Scheme 2
a
Yield (%)
1
2
Compound
R
R
Method A
Method B
2
a
H
H
H
H
H
H
80
69
72
78
70
81
81
76
74
70
71
69
71
2
b
4-CH
4-CH
3
3
C
6
H
4
2
c
OC
6
H
4
2
d
6 4
4-BrC H
2
e
4-ClC
H
6 4
H
2
f
CH
3
2
g
-(CH
2
)
4
-
83
a
Yields of isolated pure product based on the amount of ketones 1 used.
Conclusions
In summary, the present study offers a better alternative to the existing methods for the synthesis of
α-azido ketones, which are valuable intermediates for various transformations [12] and are generally
prepared by the reaction of α-halo ketones [12] or α-nosyloxy ketones [13] with sodium azide.
Acknowledgements
We are thankful to Kurukshetra University, Kurukshetra for the award of University Research
Fellowship to Kamaljeet Pannu and DRDO (ERIP/ER/0303447/M/01), New Delhi for the award of
Junior Research Fellowship to Richa Prakash to carry out this work.
Experimental
General
All reagents were purchased from commercial sources and were used without further purification.
Iodosobenzene and HTIB were prepared according to literature procedures [9, 10] starting from
1
iodobenzene. Melting points were taken in open capillaries and are uncorrected. H-NMR spectra were
recorded on a Bruker 300 MHz instrument using TMS as an internal standard. IR spectra were
recorded on a Buck Scientific IR M-500 spectrophotometer.

Molecules 2006, 11
526
Representative one-pot procedure for the preparation of α-azido ketones: α-azidoacetophenone (2-
azido-1-phenylethanone)(3a):
Method A. Using HTIB/ NaN3:
To a solution of acetophenone (1a, 1.20 g, 10 mmol) in acetonitrile (20 mL) was added HTIB (4.13
g, 11 mmol) and the resulting solution was refluxed for 2 h. After cooling to room temperature sodium
azide (1.30 g, 2.0 mmol) was added and reaction mixture was stirred for 2 h. Most of the solvent was
distilled off and the residual mixture was dissolved in CH Cl , washed with cold water and dried over
2
2
Na SO α-Azidoacetophenone (3a) separated out from organic layer after trituration with pet. ether as
2
4.
-1 1
a pale yellow oil (1.28 g). IR (Nujol): 2196, 2100, 1697, 1286 cm ; H-NMR (CDCl
H, aromatic protons), 4.41 (s, 2H, CH ) [12a].
3
): δ 7.36-7.87 (m,
5
2
Similarly, other α-azido ketones 3b-3g were prepared from the corresponding ketones 1b-1g in good
yields (Table 1). The identities of the products were confirmed by comparison of their melting points
and spectral data with those reported in literature.
°
°
2
2
2
-Azido-1-(4-methylphenyl)ethanone (3b): Mp 56-57 C
(
Lit. [12b] mp 58-60 C).
°
°
-Azido-1-(4-methoxyphenyl)ethanone (3c): Mp 67-68 C
(
Lit. [12b] mp 68-71 C).
°
°
-Azido-1-(4-bromophenyl)ethanone (3d): Mp 85-86 C (Lit. [12b] mp 86-87 C).
°
-1
2
-Azido-1-(4-chlorophenyl)ethanone (3e): Mp 65-67 C; IR (KBr): 2918, 2105, 1692, 1591 cm ;
1
H-NMR (CDCl
3
): δ 7.80 (d, J = 7.2 Hz, 2H, aromatic protons), 7.6 (d, J = 7.2 Hz, 2H, aromatic
).
protons), 4.51 (s, 2H, CH
2
-
1
2
1
-Azido-1-phenyl-1-propanone (3f) [12a]: Pale yellow oil; IR (Nujol): 2897, 2115, 2009, 1696 cm ;
3
H-NMR (CDCl ): δ 7.2-7.8 (m, 5H, aromatic protons), 4.6 (q, J = 5.7 Hz, 1H, CH), 1.5 (d, J = 6.2 Hz,
3
3H, CH ).
-1
2
-Azidocyclohexanone (3g) [12d]: Pale yellow oil; IR (Nujol): 2932, 2863, 2105, 1721, 1451 cm ;
1
3 2 4
H-NMR (CDCl ): δ 3.7 (dd, J = 9.7 Hz, 2.8 Hz, 1H, -CH-), 1.5-2.4 (m, 8H, -(CH ) -).
n 3
Method B. Using (PhIO) + p-TsOH/ NaN :
To iodosobenzene (2.20 g, 10 mmol) in acetonitrile (20 mL) was added p-toluenesulphonic acid
(
1.72 g, 10 mmol), the mixture was stirred at room temperature for 5 min. To the resulting suspension,
acetophenone (1a, 1.20 g, 10 mmol) was added and the mixture was refluxed for 2 h. After cooling to
room temperature sodium azide (1.30 g, 2.0 mmol) was added and stirred for 2 h. Usual work up (as
given in Method A) gave 1.24 g of 3a. Compounds 3b-3g were similarly prepared in good yields from
the corresponding ketones 1b-1g (Table 1).

Molecules 2006, 11
527
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