studied for this transformation, but initial attempts under
standard conditions gave no desired product. Principally,
electrophilic aromatic substitution ipso to the hydroxymeth-
ylene occurred with positive chloride or bromide reagents,
resulting in dihalogenated imidazoles 3a or 3b, respectively.15
In contrast to positive bromine and chlorine, iodine will not
easily undergo electrophilic halogenation reactions.16 How-
ever, iodine has been reported to react stoichiometrically with
amines in the literature to give iminium or nitrosonium
species.17 We therefore speculated it would be inert to
imidazole 1 yet reactive with TEMPO in a catalytic manner.
Results of these experiments compared to other oxidants with
imidazole 1 are shown in Table 1. Various chlorinating and
Table 2. Oxidation of Alcohols with Iodine as a Terminal
Oxidant and Catalytic TEMPO
a Assay yields calculated by HPLC using an external reference standard.
Table 1. TEMPO-Catalyzed Oxidation of Imidazole Alcohol
electron-poor, and heteroaromatic (entries 1-7). In the case
of cinnamyl alcohol, about 5% of the iodinated double bond
was observed and was therefore lower than IBDA (ref 8)
because of this side reaction. A saturated alcohol, cyclohex-
anol, gave an 85% yield of cyclohexanone.
The electon-rich benzothiophene alcohols (entries 5 and
6) gave large amounts of chlorinated ring products when
bleach was used as the terminal oxidant with catalytic
TEMPO. Attempted oxidation using sodium tungstate and
peroxide gave only sulfoxide product.18 With the current
conditions, no sulfur oxidation or ring-iodination was
observed. When I2 was used as a terminal oxidant, however,
a high yield of desired aldehyde was obtained.
a Assay yields calculated by HPLC using an external reference standard.
Representative Oxidation. 2-(n-Butyl)-5-chloro-4-imi-
dazolemethanol (750 mg, 3.98 mmol) was charged into a
100-mL round-bottom flask equipped with a magnetic stir
bar. The solid was then slurried in toluene (10 mL) at 20
°C. An aqueous solution of sodium bicarbonate (1.00 g, 11.94
mmol in 10 mL of deionized water) was prepared and
charged into the toluene slurry at 20 °C. Solid iodine (2.02
g, 7.96 mmol) was then charged in one portion to the alcohol
followed by solid TEMPO (62 mg, 0.398 mmol). The
reaction mixture was then aged overnight (16 h) at 20 °C.
The batch was cooled to 5 °C and diluted with ethyl acetate
(10 mL). The batch was quenched at 5 °C by adding an
aqueous solution of sodium sulfite (501 mg sodium sulfite
in 5 mL if DI water). The quenched reaction mixture was
transferred to a separatory funnel (rinsed with additional ethyl
acetate, 10 mL and DI water, 10 mL), and the aqueous layer
was cut away. The organic layer was then washed with 10
mL of saturated aqueous potassium bicarbonate followed by
10 mL of brine. The washed organic layer was then diluted
to 50 mL. The organic layer was then dried over sodium
sulfate and concentrated in vacuo to a volume of 10 mL. A
mechanical stir bar was added, and the solution was further
concentrated by a stream of nitrogen to a volume of 5 mL.
The batch was seeded with title aldehdye (50 mg), and the
slurry was aged at 20 °C for 30 min. The batch was then
cooled to 5 °C and aged for 30 min. The solids were isolated
brominating reagents gave only traces of desired product with
the major product 3a,b containing halogen. Oxone was slow
to react and gave only small amounts of 2 as a minor product
among several other. In contrast to these reagents, I2 gave a
high yield of 2 in several hours at room temperature with
no 3c observed.
Iodine was an effective oxidant for simple substrates as
well as other troublesome substrates. Table 2 lists examples
tested with these oxidation conditions. The conditions are
general for a variety of substrates including electron-rich,
(13) Larsen, R. D.; King, A. O.; Chen, C. Y.; Corley, E. G.; Foster, B.
S.; Roberts, F. E.; Yang, C.; Lieberman, D. R.; Reamer, R. A.; Tschaen,
D. M.; Verhoeven, T. R.; Reider, P. J.; Young, S. L.; Rossano, L. T.;
Brookes, A. S.; Meloni, D.; Moore, J. R.; Arnett, J. F. J. Org. Chem. 1994,
59, 6391. (b) Shi, Y. J.; Frey, L. F.; Tschaen, D. M.; Verhoeven, T. R.
Synth. Commun. 1993, 23, 2623.
(14) For other syntheses, see: (a) Yamamoto, T.; Hibi, Y.; Ogawa, T.,
Nippon Gohsei, U.S. Patent 5,395,943, March 7, 1995. (b) Griffiths, G. J.;
Hauck, M. B.; Imwinkelried, R.; Kohr, J.; Roten, C. A.; Stucky, G. C. J.
Org. Chem. 1999, 8084.
(15) Characterization data for 3b: 1H NMR (399.87 MHz, CDCl3) δ
11.4 (br s, 1H), 2.74 (t, J ) 8 Hz, 2H), 1.67 (pentet, J ) 8 Hz, 2H), 1.34
(sextet, J ) 8 Hz, 2H), 0.87 (t, J ) 7 Hz, 3H); 13C NMR (100.55 MHz,
CDCl3) δ 149.1, 122.5, 100.4, 30.5, 28.6, 22.2, 13.7. Anal. Calcd for C7H10-
BrClN2: C, 35.40; H, 4.24; N, 11.79. Found: C, 35.88; H, 4.21; N, 11.81.
LR MS calcd 235.9, found 235.9.
(16) For a review of the synthesis of iodoaromatic compounds, see:
Merkushev, E. B. Synthesis 1988, 923.
(17) Encyclopedia of Reagents for Organic Synthesis; Paquette, L., Ed.;
Wiley: New York, 1995; p 2797. (b) Sen, V. D.; Golubev, V. A.; Kosheleva,
T. M. IzV. Akad. Nauk SSSR, Ser. Khim. 1977, 4, 747.
(18) Sato, K.; Aoki, M.; Takagi, J.; Noyori, R. J. Am. Chem. Soc. 1997,
119, 12386.
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