Iodobenzene-catalyzed synthesis of α-azidoketones and α-thiocyanatoketones from aryl ketones with MCPBA as a cooxidant

Article abstract of DOI:10.1002/jccs.201000023

Iodobenzene-catalyzed synthesis of α-azidoketones and α-thiocyanatoketones from aryl ketones with MCPBA as a cooxidant is described. The method is simple, rapid and practical, generating α-azidoketones and α-thiocyanatoketones from the aryl ketone without

Full text of DOI:10.1002/jccs.201000023

Journal of the Chinese Chemical Society, 2010, 57, 149-152
149
Communication
Iodobenzene-Catalyzed Synthesis of a-Azidoketones and
a-Thiocyanatoketones from Aryl Ketones with MCPBA as a Cooxidant
Ya-Li Changa (
Huey-Min Wangb,* (
Iou-Jiun Kangc (
), Chi-Lin Chunga (
), Rei-Sheu Houb (
) and Ling-Ching Chena,* (
), Fang-Wen Wua (
),
),
)
aGraduate Institute of Pharmaceutical Sciences, College of Pharmacy, Kaohsiung Medical University,
Kaohsiung 807, Taiwan, R.O.C.
bChung Hwa College of Medical Technology, Tainan 717, Taiwan, R.O.C.
cDivision of Biotechnology and Pharmaceutical Research, National Health Research Institutes,
Miaoli County 350, Taiwan, R.O.C.
Iodobenzene-catalyzed synthesis of a-azidoketones and a-thiocyanatoketones from aryl ketones
with MCPBA as a cooxidant is described. The method is simple, rapid and practical, generating a-azido-
ketones and a-thiocyanatoketones from the aryl ketone without isolation of a-tosyloxyketones in good to
excellent yields.
Keywords: Hypervalent iodine; a-Azidoketones; a-Thiocyanatoketones; Poly(ethylene golycol).
INTRODUCTION
a-Azidoketones are versatile organic intermediate
are mainly prepared from the reaction of a-haloketones
with thiocyanate ion in various organic solvents.11 How-
ever, all of the known preparation methods for both a-
azidoketones and a-thiocyanatoketones suffered from one
or more limitations as regards tedious reaction procedure,
long reaction times, and relatively low yields. Moreover,
invariably all of the reported reactions were conducted in
volatile toxic organic solvents.
Poly(ethylene golycol) (PEG),12 a biologically ac-
ceptable polymer used extensively in drug delivery and in
bioconjugates as tools for diagnostics has been used as a
solvent medium support for various transformations.13 In
recent times ionic liquids have been in the forefront of re-
search, and several publications and reviews have already
appeared.14 Even though ionic liquids offer some advan-
tages, the tedious preparation of ionic liquids (and raw ma-
terials for ionic liquids) and their environmental safety is
still debated. Compared with PEG, however, toxicity and
environmental burden data of ionic liquids are for the most
part unknown. Furthermore, the cost of ionic liquids is of-
ten more expensive than that of PEG.15 To date some of the
more important reactions have been carried out and investi-
gated in PEG, for example, Heck reaction,16 catalytic hy-
drogenations,17 asymmetric dihydroxylation reaction,18
Baylis-Hillman reaction,19 Biginelli reaction,20 Suzuki-
Miyaura reaction, Stille cross-coupling reaction,21 Wacker
for the synthesis of biologically important heterocyclic
compounds which include oxazoles, pyrroles, and pyra-
zines.1 Synthetically useful intermediates such as a-amino
ketones,2 a-azido-b-hydroxy ketones,3 and b-amino alco-
hols also have been prepared from a-azidoketones.4 The
synthesis of a-azidoketones can be commonly achieved by
azide-halogen exchange reactions of a-haloketones.5 In
addition, a-azidoketones have been successfully prepared
from reaction of sodium azide with a-tosyloxy ketones by
treatment with surfactant pillared clays6 and triphase catal-
ysis under ultrasound irradiation7 in organic solvents such
as chloroform or acetonitrile. Very recently, a-azidoke-
tones have been prepared from a-diazoketones in the pres-
ence of sodium azide and cerium(III) chloride heptahy-
drate.8 On the other hand, synthesis of a-azidoketones di-
rectly starting from ketones has been by far less explored.
To our best knowledge, the only previous example of a-
azidation of ketones was reported from our group by the re-
action of a-(p-nitrobenzenesulfonyl)oxy ketone intermedi-
ates with sodium azide in acetonitrile.9 a-Thiocyanato-
ketones can serve as valuable precursors for the prepara-
tion of many valuable heterocyclic compounds and many
protocols have been developed for its preparations.10 In
similar to the a-azidoketones, the a-thiocyanatoketones

150 J. Chin. Chem. Soc., Vol. 57, No. 2, 2010
Chang et al.
reaction,22 and asymmetric aldol reaction,23 etc.
Table 1. Synthesis of a-azidoketones and a-thiocyanatoketones
(3)
Hypervalent iodine(III) reagents have been used ex-
tensively in organic synthesis due to their low toxicity,
ready availability and easy handling.24 Recently, iodoben-
zene-catalyzed efficient a-tosyloxylation of ketones with
m-chloroperbenzioc acid (MCPBA) and p-toluenesulfonic
acid (PTSA) was reported to give the corresponding a-
tosyloxy ketones.25 Here, as a part of our efforts to develop
greener organic reaction procedure,26 we would like to re-
port PhI-catalyzed a-tosyloxylation of aryl ketones to pre-
pare a-azidoketons and a-thiocyanatoketones in PEG-400
without isolation of a-tosyloxyketones in good to excellent
yields (Scheme I). Recently, study on the synthetic use of
organic catalysts has become important, due to their less
toxicity than that of organometallic catalysts.
Yield (%) of 3
Product
Ar
R
X=N3
X=SCN
a
b
c
d
e
f
C6H5
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
C6H5
H
H
86
81
79
77
80
82
85
78
85
84
80
75
83
84
82
80
H
H
H
H
g
h
Me
H
2-Furyl
i
2-Thienyl
H
H
83
84
81
86
j
2-Naphthyl
Table 2. Effect of solvent on the nucleophilic substitution of a-
tosyloxy ketone intermediate with sodium azide to form
2-azidoacetophenone (3a)
RESULTS AND DISCUSSION
As shown in Scheme I, our experiments involving a
one-pot procedure for the preparation of a-azidoketones
(3) by nucleophilic substitution reactions of a-tosyloxy-
ketones intermediates (2) with the azide anion in PEG-400
at room temperature was successful. The results are sum-
marized in the Table 1. When the reaction was conducted in
the classical molecular solvent, such as acetonitrile, the
preparation of 2-azidoacetophenone (3a) needs refluxing
for 2 h; however, in PEG-400, the reaction took place at
room temperature for 0.5 h and gave a higher yield (Table
2). Next, we have also examined the nucleophilic substitu-
tion reactions of a-tosyloxy ketone intermediates with
thiocyanate ion. The reactions worked well to give the cor-
responding a-thiocyanatoketones with equal efficiencies
to the cases of a-azidation reactions.
Reaction
Reaction Time Yield
Entry
Solvent
Temperature ° )
(h)
(%)
1
2
3
MeCN
[Bmim] PF6
PEG-400
80
40
25
2
75
80
86
0.5
0.5
of ketone to provide a-tosyloxyketone intermediates (2).
Nucleophilic substitution reaction of 2 with azide anion
and thiocyanate ion gave the corresponding a-azidoke-
tones and a-thiocyanatoketones (3).
In conclusion, we have described a novel and effi-
cient method for the synthesis of a-azidoketones and a-
thiocyanatoketones using PEG-400 as reaction medium.
The important features of this procedure are enhanced re-
action rate, mild reaction condition, high yield and green
aspects such as avoiding hazardous organic solvents, toxic
catalysts and waste, ease of recovery and reuse of this novel
A plausible reaction pathway for the present reaction
is shown in Scheme II. Thus, PhI is oxidized by MCPBA in
the presence of PTSA to generate [hydroxyl(tosyloxy)-
imdo]benzene in situ, which then reacts with the enol form
Scheme I

Synthesis of a-Azidoketones and a-Thiocyanatoketones
J. Chin. Chem. Soc., Vol. 57, No. 2, 2010 151
Scheme II
reaction medium.
REFERENCES
1. (a) Majo, V. J.; Perumal, P. T. Tetrahedron Lett. 1997, 38,
6889. (b) Majo, V. J.; Perumal, P. T. J. Org. Chem. 1998, 63,
7136. (c) Horiuchi, C. A.; Kiji, S. Chem. Lett. 1988, 31. (d)
Fan, X.; Zhang, Y. Tetrahedron Lett. 2002, 43, 1863.
2. Jeong, J. U.; Fuchs, P. L. J. Am. Chem. Soc. 1994, 116, 773.
3. (a) Patonay, T.; Hoffman, R. V. J. Org. Chem. 1995, 60,
2368. (b) Patonay, T.; Juhasz-Toth, E.; Benyei, A. Eur. J.
Org. Chem. 2002, 285.
EXPERIMENTAL SECTION
All melting points are uncorrected. The IR spectra
were recorded on a Shimadzu IR-27 G spectrophotometer.
1H NMR and 13C NMR spectra were recorded on a Varian
Unity Plus 400 MHz. Chemical shifts (d) were measured in
ppm with respect to TMS. MS were obtained on a JEOL
JMS D-300 instrument.
4. Takehara, J.; Hashiguchi, S.; Fujii, A.; Inoue, S.-I.; Ikariya,
T.; Noyori, R. Chem. Comm. 1996, 233.
General one-pot procedure for the synthesis of a-
azidoketones (3)
5. Takeuchi, H.; Yanagida, S.; Ozaki, T.; Hagiwara, S.; Eguchi,
S. J. Org. Chem. 1989, 54, 431.
To a mixture of aryl ketone (1) (1.0 mmol), PhI (1.0
mmol), and PSTA·H2O (1.1 mmol) in acetonitrile (20 mL)
was added MCPBA (1.1 mmol) and refluxed for 1 h. After
removal of acetonitrile, then PEG-400 (2 g) was added to
the reaction mixture and was stirred at room temperature
for 0.5 h to complete the reaction. Then the reaction mix-
ture was extracted with EtOAc (3 ´ 5 mL). The extract was
washed with aq sat. NaHCO3 solution once and dried and
the solvent was removed under reduced pressure. The resi-
due was chromatographed on silica gel using a mixture of
ethyl acetate and n-hexane (1:4) as eluent to give 3.
2-Azidoacetophenone (3a)
Oily compound (lit.,27 oil). IR (neat) n: 2104, 1695
cm-1. 1H NMR (CDCl3) d : 4.86 (s, 2H), 7.47-7.52 (m, 2H),
7.62 (t, J = 7.6 Hz, 1H), 7.89-7.91 (m, 2H). 13C NMR
(CDCl3, 100 MHz) d: 58.4, 127.9, 128.9, 134.1, 134.3,
193.1. MS (EI) m/z: 161 (M+), 134, 106, 105.
6. Varma, R. S.; Kumar, D. Catal. Lett. 1998, 53, 225.
7. Varma, R. S.; Naicker, K. P.; Kumar, D. J. Mol. Catal. A:
Chem. 1999, 149, 153.
8. Yadav, J. S.; Subba Reddy, B. V.; Srinivas, M. Chem. Lett.
2004, 33, 882.
9. Lee, J. C.; Kim, S.; Shin, W. C. Synth. Comm. 2000, 30,
4271.
10. (a) Prakash, O.; Rani, N.; Sharma, V.; Moriarty, R. M.
Synlett 1997, 1255. (b) Nair, V.; Nair, L. G.; George, T. G.;
Augustine, A. Tetrahedron 2000, 56, 7607.
11. Schantl, J. G.; Lagoja, I. M. Synth. Comm. 1998, 28, 1451.
12. Harris, J. M.; Zalipsky, S. Poly(Ethylene Glycol): Chemistry
and Biological Applications; ACS Books: Washington D. C.,
1997.
13. (a) Dickerson, T. J.; Reed, N. N.; Janda, K. D. Chem. Rev.
2002, 102, 3325. (b) Ahn, J.-M.; Wentworth, Jr., P.; Janda, K.
D. Chem. Commun. 2003, 480.
14. (a) Welton, T. Chem. Rev. 1999, 99, 2071. (b) Freemoutle,
M. Chem. Eng. News 2000, 78(15), 37. (c) Wassercheid, P.;
Keim, W. Angew. Chem. Int. Ed. 2000, 39, 3772. (d)
Freemoulte, M. Chem. Eng. News 2001, 79(1), 21.
15. Ji, C.; Scott, K. S.; Jonathan, G. H.; Robin, D. R. Green
Chem. 2005, 7, 64.
ACKNOWLEDGEMENT
We gratefully acknowledge the National Council Sci-
ence of Republic of China for financial support of this
work.
16. Chandrasekhar, S.; Narsihmulu, Ch.; Sultana, S. S.; Reddy,
N. R. K. Org. Lett. 2002, 4, 4399.
17. Chandrasekhar, S.; Narsihmulu, Ch.; Sultana, S. S.; Reddy,
N. R. K. Chem. Commun. 2003, 1716.
Received November 12, 2009.
18. Chandrasekhar, S.; Narsihmulu, Ch.; Chandrasekhar, G.;

152 J. Chin. Chem. Soc., Vol. 57, No. 2, 2010
Chang et al.
Shyamsunder, T. Tetrahedron Lett. 2004, 45, 2421.
19. Chandrasekhar, S.; Narsihmulu, Ch.; Saritha, B.; Sultana, S.
S. Tetrahedron Lett. 2004, 45, 5865.
Polycoordinated Iodine; VCH: New York, 1992. (h) Kita, Y.;
Tohma, H.; Yakura, T. Trends Org. Chem. 1992, 3, 113. (i)
Stang, P. J. Angew. Chem., Int. Ed. Engl. 1992, 31, 274. (j)
Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123. (k)
Kitamura, T.; Fujiwara, Y. Org. Prep. Proc. Int. 1997, 29,
411.
20. Xia, M.; Wang, Y.-G. Tetrahedron Lett. 2002, 43, 7703.
21. Li, J.-H.; Hu, X.-C.; Liang, Y.; Xie, Y.-X. Tetrahedron 2006,
62, 31.
22. Haimov, A.; Neumann, R. Chem. Commun. 2002, 876.
23. Chandrasekhar, S.; Narsihmulu, Ch.; Reddy, N. R. K.; Sul-
tana, S. S. Tetrahedron Lett. 2004, 45, 4581.
25. (a) Yamamoto, Y.; Togo, H. Synlett 2006, 798. (b) Yamamoto,
Y.; Kawano, Y.; Toy, P. H.; Togo, H. Tetrahedron 2007, 63,
4680.
24. Reviews, see: (a) Banks, D. F. Chem. Rev. 1966, 66, 243. (b)
Varvoglis, A. Chem. Soc. Rev. 1981, 10, 377. (c) Koser, G. F.
In The Chemistry of Functional Groups, Supplement D;
Patai, S.; Rappoport, Z., Eds.; Wiley: New York, 1983;
Cheapter 18 and 25. (d) Varvoglis, A. Synthesis 1984, 709.
(e) Moriaty, R. M.; Prakash, O. Acc. Chem. Res. 1986, 19,
244. (f) Moriarty, R. M.; Vaid, R. K.; Koser, G. F. Synlett
1990, 365. (g) Varvoglis, A. The Organic Chemistry of
26. (a) Lin, P.-Y.; Hou, R.-S.; Wang, H.-M.; Kang, I.-J.; Chen,
L.-C. J. Chin. Chem. Soc. 2009, 56, 455. (b) Cheng, H.-T.;
Hou, R.-S.; Wang, H.-M.; Kang, I.-J.; Lin, P.-Y.; Chen, L.-C.
J. Chin. Chem. Soc. 2009, 56, 632. (c) Lin, P.-Y.; Hou, R.-S.;
Wang, H.-M.; Kang, I.-J.; Chen, L.-C. J. Chin. Chem. Soc.
2009, 56, 683.
27. Takeuchi, H.; Yanagida, S.; Ozaki, T.; Hagiwara, S.; Eguchi,
S. J. Org. Chem. 1989, 54, 431.