novel biological activities,13 all of which offer potential for
developing new drug candidates. One of the most common
methods for the synthesis of deoxyfluorocatechols, in
other words, ortho-fluorophenols, is the cationic fluorina-
tion of phenols,14 which introduces a fluorine atom to an
unsubstituted aromatic carbon. For the preparation of
multifunctionalized ortho-fluorophenols, the correspond-
ing phenol precursors are required. However, the prepara-
tion of such phenols is not always easy and/or often
requires many steps. Other preparation methods of them
include the multistep transformation of fluorinated ben-
zene derivatives13a,b,15 and the stepwise transformation of
an ortho-functional group of the phenols to a fluorine
atom, such as BalzꢀSchiemann reaction.16 On the other
hand, direct conversion of a hydroxyl group of catechol
derivatives into a fluorine atom provides a quite different
approach for producing the functionalized ortho-fluoro-
phenols, which is particularly attractive and effective when
the catechols are abundantly available; however, there are
no reports on such transformation.
catechol 1a using NaIO4,18 was treated with bis(2-
methoxyethyl)aminosulfur trifluoride (Deoxofluor,19 6.0
equiv) in CH2Cl2 at room temperature.20 Within 2 h, 2a
was consumed to afford a mixture of difluoroketones (3a
and 4a21 in total 45%) and the difluorophenol 5a (8%)
after SiO2 chromatography. The mixture of 3a and 4a was
then treated with NaBH4 in EtOH in the presence of 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU, 5 equiv) at50°C for
30 min toprovide a separable mixture of6a and 7aafter the
aromatization22 (Scheme 2).
Scheme 2. Initial Examination of the Nucleophilic Displace-
ment of the Catecholic Hydroxyl Group of 1a
Scheme 1. Strategy for the Substitution of One of the Two
Hydroxyl Groups of the Catechols with a Fluorine Atom
We now present the first protocol for the nucleophilic
substitution of one of the two hydroxyl groups of catechols
with a fluorine atom via the Umpolung concept (Scheme 1).17
To examine the feasibility of this strategy, the ortho-
quinone 2a, prepared by the known oxidation of the
The yields of the products (3aꢀ5a) were somehow
related to the polarity of the solvent (in detail, see: SI).
After intensive studies, CHCl3 was disclosed to be one of
the most effective solvents in terms of the reactivity and
total yield. Thus, the reaction gave 3a (43%), 4a (10%),
and 5a (26%, each NMR yield) in 1 h. Diethylaminosulfur
trifluoride (DAST), a similar fluorinating reagent, gave
comparable results (3a: 37%, 4a: 9%, 5a: 32%, each NMR
yield); however, the more thermally stable Deoxofluor
seems to be more favorable.19 3a did not change to 5a
under the stated reaction conditions, which suggested that
3a and 5a were independently generated (for a plausible
reaction mechanism, see: SI).
(13) (a) Kirk, K. L.; Olubajo, O.; Buchhold, K.; Lewandowski, G. A.;
Gusovsky, F.; McCulloh, D.; Daly, J. W.; Creveling, C. R. J. Med.
Chem. 1986, 29, 1982. (b) Claudi, F.; Cardellini, M.; Cingolani, G. M.;
Piergentili, A.; Peruzzi, G.; Balduini, W. J. Med. Chem. 1990, 33, 2408.
(c) Ferrari, F.; Claudi, F. Pharmacol., Biochem. Behav. 1991, 38, 131.
(14) Recent examples, see: (a) Pravst, I.; Iskra, M. P.; Jereb, M.;
Zupan, M.; Stavber, S. Tetrahedron 2006, 62, 4474. (b) Kitevski-
LeBlanc, J. L.; Al-Abdul-Wahid, M. S.; Prosser., R. S. J. Am. Chem.
Soc. 2009, 131, 2054. (c) Sugimoto, Y.; Konoki, K.; Murata, M.;
Matsushita, M.; Kanazawa, H.; Oishi, T. J. Med. Chem. 2009, 52, 798.
(d) May, J. A.; Dantanarayana, A. P.; Zinke, P. W.; McLaughlin, M. A.;
Sharif, N. A. J. Med. Chem. 2006, 49, 318. (e) Curini, M.; Epifano, F.;
Maltese, F.; Marcotullio, M. C.; Tubaro, A.; Altinier, G.; Gonzales,
S. P.; Rodriguez, J. C. Bioorg. Med. Chem. Lett. 2004, 14, 2241. Stavber,
S.; Jereb, M.; Zupan, M. Chem. Commun. 2000, 1323.
When we applied this procedure to various catechols 1,
most of the ortho-quinones 2 were found to be less stable
and gradually decompose during the isolation and purifi-
cation. After intensive examination of various oxidants,
the use of o-chloranil23a or PhI(OAc)223b (each 1.05 equiv)
(15) Weinstock, J.; Gaitanopoulos, D.; Oh, H. J.; Pfeiffer, F. R.;
Karash, C. B.; Venslavsky, J. W.; Sarau, H. M.; Flaim, K. E.; Hieble,
J. P.; Kaiser, C. J. Med. Chem. 1986, 29, 1615.
(16) Kirk, K. L. J. Org. Chem. 1976, 41, 2373.
(17) A contrasing experiments in our hands using cationic fluorine
reagents, such as Selectfluor (1.0 equiv),14a for a catechol 1a at ambient
temperature for 20 min resulted in forming the ortho-quinone 2a in 85%
NMR yield without obtaining any fluoronated products.
(18) Takata, T.; Tajima, R.; Ando, W. J. Org. Chem. 1983, 48, 4764.
(19) (a) Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M.; Cheng,
H. J. Org. Chem. 1999, 64, 7048. (b) Lal, G. S.; Pez, G. P.; Pesaresi, R. J.;
Prozonic, F. M. Chem. Commun. 1999, 215.
(20) Fluorination reactions of R-diketones and R-ketoacids using
either Deoxofluor or DAST were reported, see: (a) Singh, R. P.;
Majumder, U.; Shreeve, J. M. J. Org. Chem. 2001, 66, 6263. (b) Singh,
R. P.; Shreeve, J. M. J. Org. Chem. 2003, 68, 6063.
(21) A few examples of the cationic fluoronation of symmetric
4-alkylphenols were reported to give 4-alkyl-6,6-difluorocyclohexa-
2,4-dienones, see: Stavber, S.; Zupan, M. Synlett 1996, 693.
(22) DBU enhances the aromatization of the initial reduction pro-
ducts, 6,6-difluorocyclohexa-2,4-dienols.
(23) (a) Wriede, U.; Fernandez, M.; West, K. F.; Harcour, D.;
Moore, H. W. J. Org. Chem. 1987, 52, 4485. (b) Jung, M. E.; Perez, F.
Org. Lett. 2009, 11, 2165. (c) Knapp, S.; Sharma, S. J. Org. Chem. 1985,
50, 4996. (d) Fetizon, M.; Balogh, V.; Golfier, M. J. Org. Chem. 1971, 36,
1339.
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