Supramolecular synthesis of selenazoles using selenourea in water in the presence of β-cyclodextrin under atmospheric pressure

Article abstract of DOI:10.1021/jo062421q

Selenazoles were synthesized from α-bromo ketones and selenourea in the presence of β-cyclodextrin in water at 50 °C under atmospheric pressure.

Full text of DOI:10.1021/jo062421q

the application of Hantzsch procedure.6,7 The methods available
have a number of drawbacks such as the use of anhydrous
Supramolecular Synthesis of Selenazoles Using
Selenourea in Water in the Presence of
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â-Cyclodextrin under Atmospheric Pressure†
solvents, inert atmosphere, basic conditions, longer reaction,
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and low yields in the presence of water. Apart from this,
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selenourea is air and light sensitive. Thus, in view of these
shortcomings, there is a need to develop a mild and ecofriendly
synthetic methodology for these high value compounds by
replacing organic solvents, most of which are flammable, toxic,
or carcinogenic, with water using a recyclable activator as a
M. Narender, M. Somi Reddy, V. Pavan Kumar,
V. Prakash Reddy, Y. V. D. Nageswar, and K. Rama Rao*
Organic Chemistry DiVision-I, Indian Institute of Chemical
Technology, Uppal Road, Hyderabad 500-007, India
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part of green chemical approach.
Water is a cheap, nontoxic, and most readily available reaction
medium, making it an environmentally and economically
drkrrao@yahoo.com
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attractive solvent. However, the fundamental problem in
performing reactions in water is that many organic substrates
are hydrophobic and are insoluble in water. In our efforts to
develop biomimetic approaches through supramolecular cataly-
ReceiVed NoVember 24, 2006
14
sis and also to overcome some of the drawbacks in the existing
methodologies for the synthesis of 2-amino-1,3-selenazoles from
R-bromo ketones, we report herein, for the first time, the
aqueous-phase synthesis of selenazoles from R-bromo ketones
and selenourea in the presence of â-cyclodextrin (Scheme 1).
Cyclodextrins are cyclic oligosaccharides possessing hydro-
phobic cavities. They are torus-like macro-rings made up of
Selenazoles were synthesized from R-bromo ketones and
selenourea in the presence of â-cyclodextrin in water at 50
C under atmospheric pressure.
°
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glucopyranose units. As a consequece of the C1 conformation
of the glucopyranose units, all secondary hydroxyl groups are
situated on one of the two edges of the ring, whereas all primary
ones are placed on the other edge. The C-2-OH group of one
glucopyranoside unit forms a hydrogen bond with C-3-OH group
of the adjacent glucopyranose unit. Thus, the side where the
secondary hydroxyl groups are situated, the diameter of the
cavity is larger than on the side with the primary hydroxyls,
1
Selenazoles have been extensively studied as synthetic tools,
2
as well as for their biological significance. Among them, 1,3-
selenazoles are of pharmacological relevance due to their
antibiotic and cancerostatic activity. A prominent example is
the C-glycosyl selenazofurin with antibacterial activity. 2-Amino-
,3-selenazoles are also good superoxide anion-scavengers. A
3
3a
4
1
number of synthetic routes have been developed for the
selenium-containing heterocyclic compounds because of their
interesting reactivities. These have been prepared mainly by
(
6) (a) Larsen, R. 1,3-Selenazoles. In ComprehensiVe Heterocyclic
Chemistry II; Kartritzky, A., Rees. C. W., Scriven, E. F. V., Eds.; Elsevier
Science: Oxford, 1996; Vol. 3, Chapter 8. (b) Koketsu, M.; Nada, F.;
Ishihara, H. Synthesis 2002, 195. (c) Kaminski, R.; Glass, R. S.; Skowronska,
A. Synthesis 2001, 1308. (d) Koketsu, M.; Fukuta, Y.; Ishihara, H.
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P. Synthesis 2003, 1215.
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†
IICT communication no. 061226.
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1) (a) Casar, Z.; Majcen-Le, A.; Marechal; Lorey, D. New J. Chem.
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75. (c) Duddeck, H.; Bradenahl, R.; Stefaniak, L.; Jazwinski, J.; Kamienski,
B. Magn. Resonance Chem. 2001, 39, 709. (d) Archer, S.; McGarry, R. J.
Heterocyclic Chem. 1982, 19, 1245.
(2) (a) Park, Y.-J.; Koketsu, M.; Kim, J. M.; Yeo, J.-H.; Ishihara, H.;
Lee, K.-G.; Kim, S. Y.; Kim, C.-K. Biol. Pharm. Bull. 2003, 26, 1657. (b)
Koketsu, M.; Choi, S. Y.; Ishihara, H.; Lim, B. O.; Kim, H.; Kim, S. Y.
Chem. Pharm. Bull. 2002, 50, 1594. (c) Li, H.; Hallows, W. H.; Punzi, J.
S.; Marquez, V. E.; Carell, H. L.; Pankiewicz, K. W.; Watanabe, K. A.;
Goldstein, B. M. Biochemistry 1994, 33, 23. (d) Goldstein, B. M.; Leary,
J. F.; Farley, B. A.; Marquez, V. E.; Levy, P. C.; Rowley, P. T. Blood
(8) (a) Koketsu, M.; Kogami, M.; Ando, H.; Ishihara, H. Synthesis 2006,
0031. (b) Geisler, K.; Kunzler, A.; Below, H.; Bulka, E.; Pfeiffer, W.-D.;
Langer, P. Synthesis 2004, 0097. (c) Koketsu, M.; Imogawa, M.; Mio, T.;
Ishihara, H. J. Heterocycl. Chem. 2005, 42, 831.
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3) (a) Goldstein, B. M.; Kennedy, S. D.; Hennen, W. J. J. Am. Chem.
(12) (a) OECD (Organization for Economical Cooperation and Develop-
ment) Workshop on Sustainable Chemistry, 1998. (b) Anastas, P. T.; Warner,
J. C. Green Chemistry: Theory and Practice; Oxford University Press:
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J. J. Promoting Green Chemistry Initiatives, in Environm. Sci. Technol.
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(13) (a) Jaeger, D. A.; Frey, M. R. J. Org. Chem. 1982, 47, 311-315.
(b) Jaeger, D. A.; Jamrozik, J.; Golich, T. G.; Clennan, M. W.; Mohebalian,
J. J. Am. Chem. Soc. 1989, 111, 3001-3006. (c) Jaeger, D. A.; Sayed, Y.
M.; Dutta, A. K. Tetrahedron Lett. 1990, 31, 449-450.
Soc. 1990, 112, 8265 and references cited therein. (b) Shafiee, A.;
Khashayarmanesh, Z.; Kamal, F. J. Sci., Islamic Repub. Iran 1990, 1, 11.
c) Shafiee, A.; Shafaati, A.; Khamench, B. H. J. Heterocycl. Chem. 1989,
6, 709. (d) For cancerostatic activity of 1,3-selenazoles, see: Srivastava,
P. C.; Robins, R. K. J. Med. Chem. 1983, 26, 445. (e) Also see: Shafiee,
A.; Mazloumi, A.; Cohen, V. J. J. Heterocycl. Chem. 1979, 16, 1563.
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C. W., Scriven, E. F. V., Eds.; Pergamon: London, 1996; Vols. 1-11. (b)
Back, T. G. Organoselenium Chemistry: A Practical Approach; Oxford
University Press: Oxford, 1999. (c) Wirth, T. Organoselenium Chemistry.
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23, 8408.
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0.1021/jo062421q CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/01/2007
J. Org. Chem. 2007, 72, 1849-1851
1849

SCHEME 1
TABLE 1. Synthesis of Selenazoles in Water in the Presence of
â-Cyclodextrin in Water
since the free rotation of the latter reduces the effective diameter
of the cavity. They bind substrates selectively and catalyze
chemical reactions by supramolecular catalysis involving the
reversible formation of host-guest complexes with the sub-
strates by noncovalent bonding as seen in enzyme complexation
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processes. Complexation depends on the size, shape, and
hydrophobicity of the guest molecule. These attractive features
of cyclodextrins in the biomimetic modeling of chemical
reactions prompted us to investigate the synthesis of a variety
of selenazoles using the substrate-â-cyclodextrin complexes with
selenourea in water.
In general, the reactions were carried out by the in situ
formation of â-cyclodextrin complex of R-bromo ketone in
water at 50 °C, followed by the addition of selenourea and
stirring to give the corresponding selenazoles in almost quantita-
tive yields (86-95%, Table 1). The yields of aromatic R-bromo
ketones (phenacyl bromides) were comparatively higher than
the aliphatic R-bromo ketones (Table 1, entries 9 and 10). When
R-bromoethyl acetoacetate was reacted with selenourea, ethyl
2
8
-amino-4-methyl-1,3-selenazole-5-carboxylate was obtained in
7% yield (Table 1, entry 10). These reactions proceed smoothly
without the formation of any byproducts or rearranged products.
1
All of the products were characterized by H NMR, IR, and
mass spectrometry and compared with the reported data.
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a
All of the products were identified by 1H NMR, IR, and mass
spectrometry and compared with the reported data.16 b Isolated yields after
purification.
â-Cyclodextrin can be easily recovered and reused. These
reactions do take place with R-cyclodextrin (R-CD); however,
â-CD was chosen as the activator since it is inexpensive and
easily accessible. Longer reaction (>12 h) and very low yields
TABLE 2. 1H NMR Studies of â-CD Complexes and Reaction
Mixtures
(25%) were seen in the absence of â-CD; in addition, water
substrate
H3 (δ)
H5 (δ)
solubility problems arise with some compounds. Use of a
catalytic amount of â-CD (0.1 mmol per mole of the substrate)
had no impact on the reaction since the yields of the product
obtained were the same as observed in the absence of â-CD.
These experiments indicate the substantial role of cyclodextrin.
The supramolecular catalysis of the reaction was established
â-CD
4.014
3.947
3.925
3.909
3.902
3.833
3.805
3.792
â-CD-PB
â-CD-PB-selenourea, 20 min
â-CD-PB-selenourea, 40 min
1
through H NMR studies with phenacyl bromide (PB) as a
the phenyl ring of phenacyl bromide included in the hydrophobic
cavity of â-CD. These shifts indicate the formation of an
inclusion complex of phenacyl bromide with â-CD.17 After
addition of selenourea (20 and 40 min), there is a further upfield
shift of the H3 (0.022 ppm) and H5 (0.028 ppm) protons. This
increase in the upfield character of H3 (0.022 ppm) and H5
1
representative example. The H NMR (D2O) of the â-cyclo-
dextrin, â-cyclodextrin-phenacyl bromide complex, and freeze-
dried reaction mixtures of â-cyclodextrin-phenacyl bromide-
selenourea at 20 min and 40 min were studied (Table 2). It has
been observed that there is an upfield shift of H3 (0.067 ppm)
and H5 (0.069 ppm) protons of â-CD in the case of â-CD-PB
complex as compared to â-CD due to the screening effect of
(
0.028 ppm) protons of â-CD as compared to â-CD-phenacyl
bromide complex may be explained by the enhanced aromatic
nature in the phenyl selenazole derivative. Thus, â-cyclodextrin
(
15) Szejtli, J.; Osa, T. In ComprehensiVe Supramolecular Chemistry;
Pergamon Press: New York, 1996; Vol. 3.
16) Geisler, K.; Pfeiffer, W. -D.; Kunzler, A.; Below, H.; Bulka, E.;
Langer, P. Synthesis 2004, 875.
(
(17) (a) Demarco, P. V.; Thakkar, A. L. Chem. Commun. 1970, 2. (b)
D’Souza, Lipkowitz, K. B. Chem. ReV. 1998, 98, 1741-2076.
1
850 J. Org. Chem., Vol. 72, No. 5, 2007

appears to activate the ketones, solubilize the reactants, and
promote the reaction to completion in decreased reaction.
In conclusion, we have demonstrated for the first time that
selenazole formation can be promoted by â-cyclodextrin in
water. This methodology also overcomes the formation of
unwanted byproducts, low yields, high temperatures, and inert
atmosphere, thus making it a more user-friendly procedure. This
methodology will be a useful addition to the modern synthetic
methodology in the context of a higher demand for eco-
compatible chemical processes and increasing interest in green
chemistry.
dissolved in acetone (1 mL) was added dropwise followed by
selenourea (1.2 mmol) and the mixture stirred at 50 °C until the
reaction was complete (as monitored by TLC) (Table 1). The
mixture was extracted with ethyl acetate, and the extract was
2 4
filtered. The organic layer was dried over anhydrous Na SO , the
solvent was removed under reduced pressure, and the resulting
product was further purified by column chromatography. The
aqueous layer was cooled to 5 °C to recover â-CD by filtration.
Acknowledgment. We thank CSIR, New Delhi, India, for
fellowships to M.N., M.S.R., V.P.K., and V.P.R.
Supporting Information Available: Characterization data for
all compounds including H NMR spectra and IR are provided.
1
Experimental Section
This material is available free of charge via the Internet at
http://pubs.acs.org.
General Procedure for the Synthesis of Selenazoles. â-CD (1
mmol) was dissolved in water (20 mL) by warming to 50 °C until
a clear solution was formed. Then, R-bromo ketone (1 mmol)
JO062421Q
J. Org. Chem, Vol. 72, No. 5, 2007 1851