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Fluorine reactivity in difluoromethylimidazoles
Journal of Fluorine Chemistry 127 (2006) 980–982 www.elsevier.com/locate/fluor
Short communication
Fluorine reactivity in difluoromethylimidazoles Edward Tuan, Kenneth L. Kirk * Laboratory of Bioorganic Chemistry, National Institute of Diabetes, and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 02892, United States Received 21 February 2006; received in revised form 21 March 2006; accepted 22 March 2006 Available online 2 May 2006
Abstract A difluoromethyl substituent attached directly to an imidazole ring is very reactive toward basic hydrolysis. A correlation of rate of fluoride loss with increasing pH is consistent with a mechanism that involves initial ionization of the imidazole NH, formation of an intermediate azafulvene by loss of HF, and reaction of the intermediate with solvent water. # 2006 Elsevier B.V. All rights reserved. Keywords: Imidazoles; Fluoride loss; Base sensitivity
1. Background We have carried out extensive research with ring-fluorinated imidazoles, indoles, and catecholamines in our laboratory. The rewarding biological properties of these compounds prompted us several years ago to consider the possibility of extending this work to side-chain fluorinated analogues of biologically important aromatic and heteroaromatic amines and amino acids. However, initial efforts to make analogues such as betafluorodopamine or tyramine by deoxyfluorination of the corresponding protected ethanolamine with DAST were unsuccessful. For example, treatment of 2-(3-benxyloxyphenyl)-2-hydroxyethylamine (1) with DAST produced the bfluoroamine 2. Unfortunately, all efforts to remove the benzyl group to give b-fluoro meta-tyramine led to defluorination (Scheme 1) [1]. Precedence for this failure is seen in the report by McCarthy and co-workers who found that a-fluorophenylacetonitriles bearing a strongly electron donating group on the aromatic ring could not be reduced to the fluorinated phenyl ethyl amine [2]. We abandoned attempts to make side-chain fluorinated catecholamines and tyramines, recognizing that the ease of HF elimination from these phenolic systems would make isolation highly improbable. Both 2-trifluoromethylimidazoles [3,4] and 4-trifluoromethylimidazoles [5] are subject to base-induced loss of HF
* Corresponding author. Tel.: +1 301 496 2610; fax: +1 301 402 4182. E-mail address: [email protected] (K.L. Kirk). 0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jfluchem.2006.03.014
with generation of difluoroazafulvene intermediates [5–9], similar to the chemical behavior of phenolic benzotrifluorides [10] and certain other trifluoromethyl-substituted heteroaromatic rings [11,12]. Whereas this chemistry can be used to generate other imidazole derivatives [6–8], the rate of HF loss at physiological pH is too slow to expect any biological consequences of this transformation (t1/2 = 124 d at pH 7.4, 30 8C) [6]. As described above, we had failed in our attempts to prepare phenolic amines substituted with fluorine on the benzylic position. In light of this, and as an extension of our work with trifluoromethyl-substituted imidazoles, we turned our attention to a series of imidazoles (e.g. histamines) and indoles (e.g. tryptamines) with fluorine substituted on the side-chain carbon atom attached to the heteroaromatic ring (the ‘‘benzylic’’ position). We expected these to be more stable than the similarly substituted phenolic amines but more reactive than the trifluoromethyl-substituted heteroaromatics. Reactive fluorine on the side-chain would be proximal to the locus of enzymatic processing, potentially providing useful tools. For example, if suitably reactive we felt these compounds could function as effective inhibitors of pyridoxal-dependent enzymes such as decarboxylases. In a closely related example, Woolridge and Rokita prepared 6-(difluoromethyl)tryptophan to probe the mechanism of tryptophanase-catalyzed beta-elimination of indole from tryptophan [13]. With these considerations in mind, we prepared several examples of these analogues [14–17]. In initial attempts to utilize these compounds as biochemical probes, we discovered that a b,b-difluorinated tryptamine
E. Tuan, K.L. Kirk / Journal of Fluorine Chemistry 127 (2006) 980–982
981
Scheme 1.
derivative rapidly lost fluorine under the conditions for enzyme catalysis [18]. We thus felt an important prelude to any future biological studies would be the acquisition of information on the chemical stability of these new indole and imidazole derivatives. HF loss leading to formation of monofluoro azafulvene intermediates was suspected, based on the precedents of HF loss from an aromatic or heteroaromatic trifluoromethyl groups cited above. Indeed, Middleton and Bingham reported that attempts to prepare a,a-difluoroindoleacetic acid by basic hydrolysis of an N-acetyl ethyl ester derivative led to loss of fluorine and regeneration of a carbonyl group [19]. Detailed kinetic studies have been carried out with trifluormethylimidazoles [6,20], and Woolridge and Rokita examined the kinetics of hydrolysis of 6-(difluoromethyl)tryptophan [13]. We have found no detailed examination of hydrolysis of the difluoromethyl group attached directly to the heterocyclic ring. Our intent to study the rate of fluoride loss from these indole derivatives was thwarted by the discovery that all available samples stored as solid salts in the cold had lost fluorine with formation of carbonyl derivatives. Fortunately our imidazole samples were still viable, so we undertook an examination of the reactivity of these with respect to fluoride loss. This report describes the results of this examination of lability of 2difluoromethylimidazole (1) [15], 4-difluoromethylimidazole (2) [15] and difluorohistidinol (3) [17] (Scheme 2) at physiologic and higher pH values.
2. Kinetic and analytical methods The rates of fluoride loss were followed spectrophotometrically in solution at various pH values. For reactions carried out at pH values greater than 9.4 bicarbonate buffers prepared from 0.05 M NaHCO3 and 0.1 M NaOH were used; for pH values less than 9.4 buffers prepared with varying concentrations of 0.1 M tris(hydroxymethyl)aminomethane (tris) and 0.1 M HCl were used. For each compound, the peak absorbance wavelength of the product solution was first determined by allowing reactions to proceed to completion in each buffer solution. The UV spectra were measured on a Beckman DU 640 spectrophotometer with peak absorbance wavelength being determined for each buffer system used. The rate of conversion of each compound to its product in basic conditions was determined by monitoring the change in intensity of the uv maximum with time. The temperature of the sample was maintained at 30 8C using a constant temperature water bath. 3. Results Reactions with 2-difluoromethylimidazole (1) were monitored either at 283 nm (tris buffer) or 296 nm (bicarbonate buffer). Reactions of 4-difluoromethylimidazole (2) and difluorohistidinol (3) were monitored at 255 nm (tris buffer) or 260 nm (bicarbonate buffer). The reactions followed apparent first order kinetics. In order to investigate product formation, the same reaction (CF2-imidazole in base) was performed on preparative amounts of 2- and 4-difluormethylimidazoles. After isolation, 1H NMR spectra of the products showed the expected aldehydic proton signal at 9.8 ppm. However, there was evidence for additional higher molecular weight products in the mass spectrum. Further analysis of products has not been done at this time. The rates of reaction of the CF2-imidazoles in basic solution as determined above are summarized in Table 1. Although the
Scheme 2.
Table 1 Kinetic data for hydrolysis difluoromethyl-substituted imidazoles pH
2-Difluoromethyl-1H-imidazole 1
kobsd (s ) 7.40 8.50 9.04 9.48 10.00 10.15 10.22 10.32 10.43
1
t1/2 (s)
7.15 10 8.71 10 1.80 10 1.03 10 2.80 10 3.84 10 3.99 10
5
5.20 10
2
4 3 2 2 2 2
kobsd (s ) 3
9.69 10 7.96 102 3.85 102 67.2 24.8 18.0 17.4 13.3
b,b-Difluorohistidinol
4-Difluoromethyl-1H-imidazole
5
7.84 10 1.16 10 3 3.10 10 3 8.35 10 3 3.1 10 2 4.79 10 2 7.34 10 2 1.01 10
kobsd (s 1)
t1/2 (s)
1
3
8.85 10 5.98 10 2 2.24 10 2 83.0 22.3 14.5 9.45 6.8
t1/2 (s) 5
3.80 104 2.93 103 5.95 102 2.39 102 83.2 62.1
2
40.2 23.5
1.82 10 2.37 10 4 1.17 10 3 2.9 10 3 8.3 10 3 1.11 10 2 1.72 10 2.95 10
2
982
E. Tuan, K.L. Kirk / Journal of Fluorine Chemistry 127 (2006) 980–982
Scheme 3.
imidazolate anion is likely the reactive species, the observed rates [k (s 1)] are not corrected for relative degrees of ionization. The reactions at higher pH values were too rapid to measure and this prevented determination of limiting rates. In addition, attempts to calculate kinetic pKa values based on the available data were not successful. Thus, a more thorough kinetic analysis of this process was not attempted. The results nonetheless are quite revealing from a practical point of view, and the calculated t1/2 at each pH value is given in Table 1. 4. Discussion Loss of fluorine, initiated by formation of the imidazolate ion, is expected to proceed with formation of an azafulvene intermediate. Further reaction with solvent produces the carbonyl product (Scheme 3). Although we have not analyzed the product mixtures, there is NMR evidence for formation of carbonyl containing product, along with apparent subsequent decomposition products. Basic solutions of the compounds rapidly darken. Despite this, good apparent first order kinetics of decomposition were observed. For our research purposes, the instability of these compounds under basic conditions in itself is a highly relevant observation that we wish to reveal. We have evaluated the results of this study from two points of view. First, with respect to the practical issue of utility of the compounds we have prepared for biological studies, it is clear that any such studies will need to take into account the extreme sensitivity of the difluoromethyl substituent appended to an imidazole ring. It is obvious that any studies in basic solution will be difficult. The half-lives at pH values near physiologic values are slightly less than 3 h for 2-difluoromethyl- and 4difluoromethylimidazole and slightly less than 11 h for diflourohistidinol. The corresponding values at the highest pH measured (10.4) are 13, 10 and 23 s, respectively. A second consideration stems from previous work with trifluoromethylimidazoles. The basic hydrolysis of 2-trifluormethylimidazole previously has been examined in detail [6,20]. At pH 7.4 (308) the calculated t1/2 of 2-trifluoromethylimidazole is 2970 h or about 124 d, based on a kinetic pKa of 10.11 [6]. At pH 10.4 the t1/2 = 8.73 h, compared to t1/2 = 13 s for 2difluoromethylimidazole. Particularly in view of the fact that there will be a greater proportion of imidazolate anion present at a given pH value for trifluoromethylimidazole relative to the less acidic difluoromethylimidazole, this represents a far slower rate of carbon–fluorine bond breaking in the former species. It is well documented that a-fluorination greatly increases C–F bond strengths [21].
5. Summary We have demonstrated the high reactivity of diflouormethylsubstituted imidazoles under basic conditions. The relatively short half-life of these compounds at pH 7.4 suggests that biological evaluation of these analogues will be difficult. Although we have yet to examine the corresponding indoles, we assume from limited experience with these compounds that a similar situation pertains. The relatively slow reaction reported for the trifluoromethyl-substituted imidazoles illustrates the stabilizing effect of a-fluorination on a C–F bond. Acknowledgements This research was supported by the Intramural Research Program of the NIH, NIDDK. E. Tuan is grateful for support from the NIH summer student program. References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]
[15] [16] [17] [18] [19] [20] [21]
Unpublished results from this laboratory. M.E. LeTourneau, J.R. McCarthy, Tet. Lett. 25 (1984) 5227–5230. H. Kimoto, K.L. Kirk, L.A. Cohen, J. Org. Chem. 43 (1978) 3403–3405. D. Owen, R.G. Plevey, J.C. Tatlow, J. Fluorine Chem. 17 (1981) 179–186. J.J. Baldwin, P.A. Kasinger, F.C. Novello, J.M. Sprague, J. Med. Chem. 18 (1975) 895–900. H. Kimoto, L.A. Cohen, J. Org. Chem. 44 (1979) 2902–2906. H. Kimoto, L.A. Cohen, J. Org. Chem. 45 (1980) 3831–3835. D.P. Matthews, J.P. Whitten, J.R. McCarthy, J. Org. Chem. 51 (1986) 3228–3231. Y. Hayakawa, H. Kimoto, L.A. Cohen, K.L. Kirk, J. Org. Chem. 63 (1998) 9448–9454. R.G. Jones, J. Am. Chem. Soc. 69 (1947) 2346–2350. Y. Kobayashi, I. Kumadaki, Y. Hirose, Y. Hanzawa, J. Org. Chem. 39 (1974) 1836–1838. J. Bornstein, S.A. Leone, W.F. Sulllivan, O.F. Bennett, J. Am. Chem. Soc. 79 (1957) 1745–1748. E.M. Woolridge, S.E. Rokita, Biochemistry 30 (1991) 1852–1857. K.L. Kirk, Selective fluorination of biologically important imidazoles and indoles, in: V.A. Soloshonok (Ed.), Fluorine-Containing Synthons, ACS Symposium Series #911, Oxford University Press/American Chemical Society, Washington, DC, 2005, pp. 303–317 (chapter 17). B. Dolensky, K.L. Kirk, Coll. Czech. Chem. Commun. 67 (2002) 1335– 1344. B. Dolensky, G. Nam, W.-P. Deng, J. Narayanan, J. Fan, K.L. Kirk, J. Fluorine Chem. 125 (2004) 501–508. B. Dolensky, J. Narayanan, K.L. Kirk, J. Fluorine Chem. 123 (2003) 95– 99. P. Cole, personal communication. W.J. Middleton, E.M. Bingham, J. Org. Chem. 45 (1980) 2883–2887. S.Z. Cohen, Ph.D. dissertation, The George Washington University, 1984. B.E. Smart, in: R.E. Banks, B.E. Smart, J.C. Tatlow (Eds.), Organofluorine Chemistry, Principles and Commercial Applications, Plenum Press, New York, 1994, pp. 57–88.
Short communication
Fluorine reactivity in difluoromethylimidazoles Edward Tuan, Kenneth L. Kirk * Laboratory of Bioorganic Chemistry, National Institute of Diabetes, and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 02892, United States Received 21 February 2006; received in revised form 21 March 2006; accepted 22 March 2006 Available online 2 May 2006
Abstract A difluoromethyl substituent attached directly to an imidazole ring is very reactive toward basic hydrolysis. A correlation of rate of fluoride loss with increasing pH is consistent with a mechanism that involves initial ionization of the imidazole NH, formation of an intermediate azafulvene by loss of HF, and reaction of the intermediate with solvent water. # 2006 Elsevier B.V. All rights reserved. Keywords: Imidazoles; Fluoride loss; Base sensitivity
1. Background We have carried out extensive research with ring-fluorinated imidazoles, indoles, and catecholamines in our laboratory. The rewarding biological properties of these compounds prompted us several years ago to consider the possibility of extending this work to side-chain fluorinated analogues of biologically important aromatic and heteroaromatic amines and amino acids. However, initial efforts to make analogues such as betafluorodopamine or tyramine by deoxyfluorination of the corresponding protected ethanolamine with DAST were unsuccessful. For example, treatment of 2-(3-benxyloxyphenyl)-2-hydroxyethylamine (1) with DAST produced the bfluoroamine 2. Unfortunately, all efforts to remove the benzyl group to give b-fluoro meta-tyramine led to defluorination (Scheme 1) [1]. Precedence for this failure is seen in the report by McCarthy and co-workers who found that a-fluorophenylacetonitriles bearing a strongly electron donating group on the aromatic ring could not be reduced to the fluorinated phenyl ethyl amine [2]. We abandoned attempts to make side-chain fluorinated catecholamines and tyramines, recognizing that the ease of HF elimination from these phenolic systems would make isolation highly improbable. Both 2-trifluoromethylimidazoles [3,4] and 4-trifluoromethylimidazoles [5] are subject to base-induced loss of HF
* Corresponding author. Tel.: +1 301 496 2610; fax: +1 301 402 4182. E-mail address: [email protected] (K.L. Kirk). 0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jfluchem.2006.03.014
with generation of difluoroazafulvene intermediates [5–9], similar to the chemical behavior of phenolic benzotrifluorides [10] and certain other trifluoromethyl-substituted heteroaromatic rings [11,12]. Whereas this chemistry can be used to generate other imidazole derivatives [6–8], the rate of HF loss at physiological pH is too slow to expect any biological consequences of this transformation (t1/2 = 124 d at pH 7.4, 30 8C) [6]. As described above, we had failed in our attempts to prepare phenolic amines substituted with fluorine on the benzylic position. In light of this, and as an extension of our work with trifluoromethyl-substituted imidazoles, we turned our attention to a series of imidazoles (e.g. histamines) and indoles (e.g. tryptamines) with fluorine substituted on the side-chain carbon atom attached to the heteroaromatic ring (the ‘‘benzylic’’ position). We expected these to be more stable than the similarly substituted phenolic amines but more reactive than the trifluoromethyl-substituted heteroaromatics. Reactive fluorine on the side-chain would be proximal to the locus of enzymatic processing, potentially providing useful tools. For example, if suitably reactive we felt these compounds could function as effective inhibitors of pyridoxal-dependent enzymes such as decarboxylases. In a closely related example, Woolridge and Rokita prepared 6-(difluoromethyl)tryptophan to probe the mechanism of tryptophanase-catalyzed beta-elimination of indole from tryptophan [13]. With these considerations in mind, we prepared several examples of these analogues [14–17]. In initial attempts to utilize these compounds as biochemical probes, we discovered that a b,b-difluorinated tryptamine
E. Tuan, K.L. Kirk / Journal of Fluorine Chemistry 127 (2006) 980–982
981
Scheme 1.
derivative rapidly lost fluorine under the conditions for enzyme catalysis [18]. We thus felt an important prelude to any future biological studies would be the acquisition of information on the chemical stability of these new indole and imidazole derivatives. HF loss leading to formation of monofluoro azafulvene intermediates was suspected, based on the precedents of HF loss from an aromatic or heteroaromatic trifluoromethyl groups cited above. Indeed, Middleton and Bingham reported that attempts to prepare a,a-difluoroindoleacetic acid by basic hydrolysis of an N-acetyl ethyl ester derivative led to loss of fluorine and regeneration of a carbonyl group [19]. Detailed kinetic studies have been carried out with trifluormethylimidazoles [6,20], and Woolridge and Rokita examined the kinetics of hydrolysis of 6-(difluoromethyl)tryptophan [13]. We have found no detailed examination of hydrolysis of the difluoromethyl group attached directly to the heterocyclic ring. Our intent to study the rate of fluoride loss from these indole derivatives was thwarted by the discovery that all available samples stored as solid salts in the cold had lost fluorine with formation of carbonyl derivatives. Fortunately our imidazole samples were still viable, so we undertook an examination of the reactivity of these with respect to fluoride loss. This report describes the results of this examination of lability of 2difluoromethylimidazole (1) [15], 4-difluoromethylimidazole (2) [15] and difluorohistidinol (3) [17] (Scheme 2) at physiologic and higher pH values.
2. Kinetic and analytical methods The rates of fluoride loss were followed spectrophotometrically in solution at various pH values. For reactions carried out at pH values greater than 9.4 bicarbonate buffers prepared from 0.05 M NaHCO3 and 0.1 M NaOH were used; for pH values less than 9.4 buffers prepared with varying concentrations of 0.1 M tris(hydroxymethyl)aminomethane (tris) and 0.1 M HCl were used. For each compound, the peak absorbance wavelength of the product solution was first determined by allowing reactions to proceed to completion in each buffer solution. The UV spectra were measured on a Beckman DU 640 spectrophotometer with peak absorbance wavelength being determined for each buffer system used. The rate of conversion of each compound to its product in basic conditions was determined by monitoring the change in intensity of the uv maximum with time. The temperature of the sample was maintained at 30 8C using a constant temperature water bath. 3. Results Reactions with 2-difluoromethylimidazole (1) were monitored either at 283 nm (tris buffer) or 296 nm (bicarbonate buffer). Reactions of 4-difluoromethylimidazole (2) and difluorohistidinol (3) were monitored at 255 nm (tris buffer) or 260 nm (bicarbonate buffer). The reactions followed apparent first order kinetics. In order to investigate product formation, the same reaction (CF2-imidazole in base) was performed on preparative amounts of 2- and 4-difluormethylimidazoles. After isolation, 1H NMR spectra of the products showed the expected aldehydic proton signal at 9.8 ppm. However, there was evidence for additional higher molecular weight products in the mass spectrum. Further analysis of products has not been done at this time. The rates of reaction of the CF2-imidazoles in basic solution as determined above are summarized in Table 1. Although the
Scheme 2.
Table 1 Kinetic data for hydrolysis difluoromethyl-substituted imidazoles pH
2-Difluoromethyl-1H-imidazole 1
kobsd (s ) 7.40 8.50 9.04 9.48 10.00 10.15 10.22 10.32 10.43
1
t1/2 (s)
7.15 10 8.71 10 1.80 10 1.03 10 2.80 10 3.84 10 3.99 10
5
5.20 10
2
4 3 2 2 2 2
kobsd (s ) 3
9.69 10 7.96 102 3.85 102 67.2 24.8 18.0 17.4 13.3
b,b-Difluorohistidinol
4-Difluoromethyl-1H-imidazole
5
7.84 10 1.16 10 3 3.10 10 3 8.35 10 3 3.1 10 2 4.79 10 2 7.34 10 2 1.01 10
kobsd (s 1)
t1/2 (s)
1
3
8.85 10 5.98 10 2 2.24 10 2 83.0 22.3 14.5 9.45 6.8
t1/2 (s) 5
3.80 104 2.93 103 5.95 102 2.39 102 83.2 62.1
2
40.2 23.5
1.82 10 2.37 10 4 1.17 10 3 2.9 10 3 8.3 10 3 1.11 10 2 1.72 10 2.95 10
2
982
E. Tuan, K.L. Kirk / Journal of Fluorine Chemistry 127 (2006) 980–982
Scheme 3.
imidazolate anion is likely the reactive species, the observed rates [k (s 1)] are not corrected for relative degrees of ionization. The reactions at higher pH values were too rapid to measure and this prevented determination of limiting rates. In addition, attempts to calculate kinetic pKa values based on the available data were not successful. Thus, a more thorough kinetic analysis of this process was not attempted. The results nonetheless are quite revealing from a practical point of view, and the calculated t1/2 at each pH value is given in Table 1. 4. Discussion Loss of fluorine, initiated by formation of the imidazolate ion, is expected to proceed with formation of an azafulvene intermediate. Further reaction with solvent produces the carbonyl product (Scheme 3). Although we have not analyzed the product mixtures, there is NMR evidence for formation of carbonyl containing product, along with apparent subsequent decomposition products. Basic solutions of the compounds rapidly darken. Despite this, good apparent first order kinetics of decomposition were observed. For our research purposes, the instability of these compounds under basic conditions in itself is a highly relevant observation that we wish to reveal. We have evaluated the results of this study from two points of view. First, with respect to the practical issue of utility of the compounds we have prepared for biological studies, it is clear that any such studies will need to take into account the extreme sensitivity of the difluoromethyl substituent appended to an imidazole ring. It is obvious that any studies in basic solution will be difficult. The half-lives at pH values near physiologic values are slightly less than 3 h for 2-difluoromethyl- and 4difluoromethylimidazole and slightly less than 11 h for diflourohistidinol. The corresponding values at the highest pH measured (10.4) are 13, 10 and 23 s, respectively. A second consideration stems from previous work with trifluoromethylimidazoles. The basic hydrolysis of 2-trifluormethylimidazole previously has been examined in detail [6,20]. At pH 7.4 (308) the calculated t1/2 of 2-trifluoromethylimidazole is 2970 h or about 124 d, based on a kinetic pKa of 10.11 [6]. At pH 10.4 the t1/2 = 8.73 h, compared to t1/2 = 13 s for 2difluoromethylimidazole. Particularly in view of the fact that there will be a greater proportion of imidazolate anion present at a given pH value for trifluoromethylimidazole relative to the less acidic difluoromethylimidazole, this represents a far slower rate of carbon–fluorine bond breaking in the former species. It is well documented that a-fluorination greatly increases C–F bond strengths [21].
5. Summary We have demonstrated the high reactivity of diflouormethylsubstituted imidazoles under basic conditions. The relatively short half-life of these compounds at pH 7.4 suggests that biological evaluation of these analogues will be difficult. Although we have yet to examine the corresponding indoles, we assume from limited experience with these compounds that a similar situation pertains. The relatively slow reaction reported for the trifluoromethyl-substituted imidazoles illustrates the stabilizing effect of a-fluorination on a C–F bond. Acknowledgements This research was supported by the Intramural Research Program of the NIH, NIDDK. E. Tuan is grateful for support from the NIH summer student program. References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]
[15] [16] [17] [18] [19] [20] [21]
Unpublished results from this laboratory. M.E. LeTourneau, J.R. McCarthy, Tet. Lett. 25 (1984) 5227–5230. H. Kimoto, K.L. Kirk, L.A. Cohen, J. Org. Chem. 43 (1978) 3403–3405. D. Owen, R.G. Plevey, J.C. Tatlow, J. Fluorine Chem. 17 (1981) 179–186. J.J. Baldwin, P.A. Kasinger, F.C. Novello, J.M. Sprague, J. Med. Chem. 18 (1975) 895–900. H. Kimoto, L.A. Cohen, J. Org. Chem. 44 (1979) 2902–2906. H. Kimoto, L.A. Cohen, J. Org. Chem. 45 (1980) 3831–3835. D.P. Matthews, J.P. Whitten, J.R. McCarthy, J. Org. Chem. 51 (1986) 3228–3231. Y. Hayakawa, H. Kimoto, L.A. Cohen, K.L. Kirk, J. Org. Chem. 63 (1998) 9448–9454. R.G. Jones, J. Am. Chem. Soc. 69 (1947) 2346–2350. Y. Kobayashi, I. Kumadaki, Y. Hirose, Y. Hanzawa, J. Org. Chem. 39 (1974) 1836–1838. J. Bornstein, S.A. Leone, W.F. Sulllivan, O.F. Bennett, J. Am. Chem. Soc. 79 (1957) 1745–1748. E.M. Woolridge, S.E. Rokita, Biochemistry 30 (1991) 1852–1857. K.L. Kirk, Selective fluorination of biologically important imidazoles and indoles, in: V.A. Soloshonok (Ed.), Fluorine-Containing Synthons, ACS Symposium Series #911, Oxford University Press/American Chemical Society, Washington, DC, 2005, pp. 303–317 (chapter 17). B. Dolensky, K.L. Kirk, Coll. Czech. Chem. Commun. 67 (2002) 1335– 1344. B. Dolensky, G. Nam, W.-P. Deng, J. Narayanan, J. Fan, K.L. Kirk, J. Fluorine Chem. 125 (2004) 501–508. B. Dolensky, J. Narayanan, K.L. Kirk, J. Fluorine Chem. 123 (2003) 95– 99. P. Cole, personal communication. W.J. Middleton, E.M. Bingham, J. Org. Chem. 45 (1980) 2883–2887. S.Z. Cohen, Ph.D. dissertation, The George Washington University, 1984. B.E. Smart, in: R.E. Banks, B.E. Smart, J.C. Tatlow (Eds.), Organofluorine Chemistry, Principles and Commercial Applications, Plenum Press, New York, 1994, pp. 57–88.