Synthesis and reactions of amino acid-derived benziodazole oxides: New chiral oxidizing reagents

Article abstract of DOI:10.1016/S0040-4039(00)00836-4

The novel benziodazole oxides (3) can be prepared by oxidation of the readily available 2-iodobenzamides (5 or 6) with potassium bromate. Benziodazole oxides can find practical application as selective oxidizing reagents analogous to the widely used Dess-

Full text of DOI:10.1016/S0040-4039(00)00836-4

Tetrahedron Letters 41 (2000) 5299±5302
Synthesis and reactions of amino acid-derived benziodazole
oxides: new chiral oxidizing reagents
Viktor V. Zhdankin,* Jason T. Smart, Peng Zhao and Paul Kiprof
Department of Chemistry, University of Minnesota-Duluth, Duluth, Minnesota 55812, USA
Received 19 May 2000; accepted 23 May 2000
Abstract
The novel benziodazole oxides (3) can be prepared by oxidation of the readily available 2-iodobenzamides
(5 or 6) with potassium bromate. Benziodazole oxides can ®nd practical application as selective oxidizing
reagents analogous to the widely used Dess±Martin periodinane (1) and benziodoxole oxide (2). Preliminary
results indicate that reagents 3 can oxidize primary alcohols to aldehydes, while non-symmetric sul®des are
oxidized to chiral sulfoxides with moderate enantioselectivity. # 2000 Published by Elsevier Science Ltd.
The Dess±Martin periodinane (1) as well as its precursor, benziodoxole oxide 2, have found
wide practical application in organic synthesis as reagents for oxidation of alcohols to carbonyl
compounds.1 Dess±Martin reagent 1 is particularly useful in natural product synthesis as a mild,
selective oxidizer soluble in dichloromethane, chloroform or acetonitrile. Reagent 2 is a cheaper
alternative to Dess±Martin reagent; however, its practical application is limited due to the
potentially explosive nature and insolubility in common solvents.1 Despite these limitations,
benziodoxole oxide 2 was shown to be particularly useful as the reagent for a highly selective
oxidation of alcohols to carbonyl compounds in DMSO.2
We wish to report the preparation, structure, and chemistry of novel cyclic derivatives of penta-
valent iodine, benziodazole oxides 3. In contrast to the analogous benziodoxole oxide 2, compounds
3 are non-explosive and are soluble in dichloromethane and other common non-polar organic
* Corresponding author. Fax: 218 726 7394; e-mail: vzhdanki@d.umn.edu
0040-4039/00/$ - see front matter # 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)00836-4

5300
solvents. These new benziodazole oxides (3) can be conveniently prepared by oxidation of the
readily available 2-iodobenzamides (5 or 6) with potassium bromate or OXONE1 (2KHSO5/
KHSO4/K2SO4). The starting materials, 2-iodobenzamides 5 and 6, are prepared in high yield
from the commercially available 2-iodobenzoyl chloride 4 and natural amino acids or their
methyl esters (Scheme 1).3
Scheme 1.
Oxidation of methyl esters 5 by potassium bromate in aqueous sulfuric acid a€ords products 3
in moderate yields along with benziodoxole oxide 2 as the by-product due to hydrolysis of amides
3 (Scheme 2).4 To minimize the formation of by-product 2, we used milder reaction conditions
compared to the originally reported conditions for the bromate oxidation.5 Amides 6 can be
oxidized to products 3 under similar conditions (Scheme 2), but the yields are generally lower.
The structure of products 3 was elucidated from spectral data in comparison with the previously
reported benziodazoles.6 In addition, the structure of product 3a was theoretically investigated by
ab initio molecular orbital calculations (Fig. 1).7 According to the calculations, the molecule is
planar with the alkyl group R and the oxygen atom of IˆO out of plane. The geometry around
the iodine atom resembles a typical see-saw structure derived from a trigonal bipyramidal
electron pair geometry.
Scheme 2.

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Figure 1. Calculated structure of benziodazole oxide 3a at the HF/LANL2DZ level of theory. Selected bond lengths
and angles: I±N 2.02 A, I±C 2.13 A, I±O 2.13 A; C±I±O 155.1ꢀ
Derivatives of phenylalanine (5d and 6d) form only products of decomposition under bromate
oxidation reaction conditions. We have found, however, that 6d can be oxidized by the commercially
available oxidizer OXONE1 instead of potassium bromate. Oxidation of 2-iodobenzamide 6d by
OXONE1 in distilled water a€ords benziodazole oxide 3d in a moderate yield (Scheme 2).8
We expect that benziodazole oxides and their derivatives can ®nd practical application as
selective, chiral oxidizing reagents in organic synthesis. Preliminary results indicate that compounds
3 can selectively oxidize primary alcohols to aldehydes similarly to benziodoxoles 1 and 2. For
example, reagent 3d slowly reacts with benzyl alcohol in chloroform at 50ꢀC a€ording benzaldehyde
1
as the only product detected by H NMR. This reaction can be accelerated in the presence of
catalytic amount of tri¯uoroacetic acid. Under similar conditions, reagents 3 oxidize organic
sul®des to sulfoxides in almost quantitative yield. Oxidation of non-symmetric sul®des a€ords
chiral sulfoxides with moderate enantioselectivity (Scheme 3).
Scheme 3.

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In conclusion, the novel benziodazole oxides (3) can be prepared by oxidation of the readily
available 2-iodobenzamides (5 or 6) with potassium bromate. In contrast to the known benz-
iodoxole oxide (2), they are non-explosive and are soluble in dichloromethane and other common
non-polar organic solvents. We expect that benziodazole oxides and their derivatives can ®nd
practical application as selective, chiral oxidizing reagents in organic synthesis.
Acknowledgements
This work was supported by a research grant from the National Science Foundation (NSF/
CHE-9802823). We would also like to thank the Minnesota Supercomputer Institute and the
UMD Digital Imaging Laboratory (DIL) for a generous allocation of computer resources.
References
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3. Representative procedure for the preparation of amides 5: To a stirred, cold (ice-bath) mixture of l-alanine methyl
ester hydrochloride (1.396 g, 10 mmol) in CH2Cl2 (50 ml), triethylamine (2.78 ml, 20.0 mmol) and 2-iodobenzoyl
chloride (2.67 g, 10 mmol) were slowly added. After 2 hours of additional stirring, water (40 ml) was added and
organic layer was separated. The organic layer was washed with 10% hydrochloric acid (50 ml), 5% sodium
hydroxide (2Â25 ml) and dried over anhydrous magnesium sulfate. Solvent was evaporated and resulting yellow
solid was recrystallized from ethylacetate±hexane and dried in vacuum to a€ord 3.3 g (96%) of analytically pure
amide 5a: mp 130±131.5ꢀC; 1H NMR (CDCl3): 7.83 (d, 2H), 7.40 (m, 2H), 6.50 (br.d, 1H, NH), 4.80 (m, 1H), 3.80
(s, 3H), 1.58 (d, 3H). Anal. calcd for C11H12INO3: C, 39.66; H, 3.63; N, 4.20. Found: C, 39.83; H, 3.76; N, 4.25.
4. Representative procedure for preparation of benziodazole oxides 3 by bromate oxidation: To a stirred mixture of 5a
(3.331 g, 10 mmol) in 0.75 M sulfuric acid (150 ml) at 55ꢀC, potassium bromate (2.171 g, 13 mmol) was added over
a 0.5 hour period. The mixture was stirred for 24 hours at 55ꢀC. The resulting solution was cooled to 0ꢀC and the
precipitate was ®ltered. The precipitate was washed with water (100 ml), acetone (75 ml), diethyl ether (50 ml), and
dried in vacuum to yield 2.141 g (64%) of benziodazole oxide 3a: mp 151ꢀC (with decomposition); 1H NMR
(CDCl3): 8.31 (d, 1H), 8.19 (d, 1H), 7.81 (t, 1H), 7.68 (t,1H), 5.00 (q, 1H), 1.68 (d, 3H). Anal. calcd for
C10H8INO4: C, 36.06; H, 2.42; N, 4.21. Found: C, 36.18; H, 2.45; N, 4.30.
5. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4156.
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8. Preparation of benziodazole oxide 3d by OXONE1 oxidation: To a stirred mixture of 6d (1.186 g, 3 mmol) in 75 ml
of distilled water, OXONE1 (5.533 g, 9 mmol) was added all at once. The reaction mixture was warmed to 70±75
oC for 20 min and then stirred at this temperature for 1 hour. The ®nely dispersed suspension was then cooled to
5ꢀC and left at this temperature for 1.5 hours with slow stirring. The white precipitate was then ®ltered, washed
with 100 ml of distilled water, and dried in a vacuum to give 0.158 g (39%) of 3d: mp 134±135ꢀC; 1H NMR
(CDCl3): 8.2 (m, 2H), 7.8±7.6 (m, 2H), 7.4±7.0 (m, 5H), 5.0 (d, 1H, CH), 3.40 (m, 2H, CH2Ph). 13C NMR
(CDCl3): 178.4, 167.2, 135.9, 134.3, 131.4, 130.6, 130.1, 129.6, 129.5, 128.7, 128.1, 120.2, 58.6, 53.5. Anal. calcd for
C16H12INO4: C, 46.97; H, 2.96; N, 3.42. Found: C, 46.75; H, 3.03; N, 3.36.