Direct electrophilic monofluoromethylation

Article abstract of DOI:10.1021/ol702500u

Monofluoromethyl derivatives of various nucleophiles have been synthesized using a new electrophilic monofluoromethylating reagent developed. The S-(monofluoromethyl)diarylsulfonium tetrafluoroborate has been shown to be effective for the introduction of an electrophilic monofluoromethyl group into C, S, O, N, and P nucleophiles. This methodology has been expanded for the synthesis of various biologically important compounds.

Full text of DOI:10.1021/ol702500u

ORGANIC
LETTERS
2008
Vol. 10, No. 4
557-560
Direct Electrophilic
Monofluoromethylation
G. K. Surya Prakash,* Istvan Ledneczki, Sujith Chacko, and George A. Olah*
Loker Hydrocarbon Research Institute and Department of Chemistry,
UniVersity of Southern California, Los Angeles, California 90089-1661
gprakash@usc.edu; olah@usc.edu
Received October 12, 2007
ABSTRACT
Monofluoromethyl derivatives of various nucleophiles have been synthesized using a new electrophilic monofluoromethylating reagent developed.
The S-(monofluoromethyl)diarylsulfonium tetrafluoroborate has been shown to be effective for the introduction of an electrophilic
monofluoromethyl group into C, S, O, N, and P nucleophiles. This methodology has been expanded for the synthesis of various biologically
important compounds.
Compounds with monofluoromethyl moiety have a consider-
able importance in the field of medicinal chemistry. The
volatile, monofluorinated anaesthetic Sevoflurane, with one
of the fastest onset and offset ability, has attained a great
significance in the modern anaesthesiology.1 Monofluoro-
acetic acid is known to disrupt the Krebs cycle,2 and
fluoromethylated amino acids were recognized as potent
suicide inhibitors of the enzymatic decarboxylation reaction.3
According to the isostere-based drug design, there are
numerous examples4 of various biologically active mono-
fluoromethylated compounds. In spite of these facts, the
number of monofluoromethylation methods is relatively
small. Besides the first published direct electrophilic mono-
fluoromethylation using fluoromethanol,5 only the fluoro-
methyl halides and triflate4d,6 (usually 18[F]-labeled) were
used, mainly to synthesize 18[F]-labeled radiopharmaceuti-
cals. Recently, Hu et al. presented CH2ClF7 as an indirect
electrophilic monofluoromethylating reagent. Nucleophilic
monofluoromethylation methods using synthetic equivalent
of fluoromethide species such as magnesium benzyl fluo-
(4) Some examples: (a) Parent, E. E.; Carlson, K. E.; Katzenellenbogen,
J. A. J. Org. Chem. 2007, 72, 5546. (b) Simeon, F. G.; Brown, A. K.;
Zoghbi, S. S.; Patterson, V. M.; Innis, R. B.; Pike, V. W. J. Med. Chem.
2007, 50, 3256. (c) Silhar, P.; Pohl, R.; Votruba, I.; Hocek, M. Org. Biomol.
Chem. 2005, 3, 3001. (d) Gerus, I. I.; Kolomeitsev, A. A.; Kolycheva, M.
I.; Kukhar, V. P. J. Fluorine Chem. 2000, 105, 31.
(1) (a) Hiyama, T. Organofluorine Compounds; Springer: Berlin, 2000.
(b) Kudzma, L. V.; Huang, C. G.; Lessor, R. A.; Rozov, L. A.; Afrin, S.;
Kallashi, F.; McCutcheon, C.; Ramig, D. J. Fluorine Chem. 2001, 111, 11.
(2) Kun, E.; Dummel, R. J. Methods Enzymol. 1969, 13, 623.
(3) (a) Kollonitsch, J.; Perkins, L.; M. Patchett, A. A.; Doldouras, G.
A.; Marburg, S.; Duggan, D. E.; Maycock, A. L.; Aster, S. D. Nature 1978,
274, 906. (b) Welch, J. T. Tetrahedron 1987, 43, 3123.
(5) Olah, G. A.; Pavlath, A. Acta Chim. Acad. Sci. Hung. 1953, 3, 425-
429.
(6) (a) Zhang, M.-R.; Ogawa, M.; Furutsuka, K.; Yoshida, Y.; Suzuki,
K. J. Fluorine Chem. 2004, 125, 1879. (b) Zheng, L.; Berridge, M. S. Appl.
Radiat. Isotopes 2000, 52, 55. (c) Iwata, R.; Pascali, C.; Bogni, A.;
Furumoto, S.; Terasaki, K.; Yanai, K. Appl. Radiat. Isotopes 2002, 57, 347.
(7) Zhang, W.; Zhu, L.; Hu. J. Tetrahedron 2007, 63, 10569.
10.1021/ol702500u CCC: $40.75
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Published on Web 01/17/2008

romalonates,8 fluoromethyl phenyl sulfone,9 and 1-fluorobis-
(phenylsulfonyl)methane10 were also reported.
of R-fluoro sulfides, without isolation, it was oxidized to
the corresponding sulfoxide using N-bromosuccinimide. The
subsequent Friedel-Crafts type reaction of compound 5 with
1,2,3,4-tetramethylbenzene (6) initiated by trifluoromethane-
Our group has recently developed the first electrophilic
difluoromethylating agent (direct “+CF2H” group transfer),
which can build difluoromethyl group into several O, N, P
nucleophiles.11 As a continuation of our work, we now
disclose the results of the synthesis and use of a new
electrophilic monofluoromethylation reagent (for direct
“+CH2F” transfer), namely S-monofluoromethyl-S-phenyl-
2,3,4,5-tetramethylphenylsulfonium tetrafluoroborate (7).
Our aim was to prepare the tetrafluoroborate salt of the
S-(monofluoromethyl)diarylsulfonium cation (Scheme 1). At
-
sulfonic anhydride and followed by treatment of BF4 salt
afforded the S-monofluoromethyl-S-phenyl-2,3,4,5-tetra-
methylphenylsulfonium tetrafluoroborate (7) in good yield
(Scheme 1, route c).
In some cases, to overcome the difficulty of the separation
of the desired product from the byproduct phenyl tetra-
methylphenyl sulfide (13) by column chromatography, we
also prepared the solid-phase bound S-monofluoromethyl-
sulfonium tetrafluoroborate salt (9), using cross-linked
polystyrene resin (8).
Scheme 1. Preparation of S-Monofluoromethyl-S-phenyl-
2,3,4,5-tetramethylphenylsulfonium Tetrafluoroborate (7) and the
Solid-Phase Bound S-Monofluoromethylsulfonium
Tetrafluoroborate Reagent (9)
Since the CH2F moiety in the reagent contains hydrogens,
the most crucial characteristic is its stability toward bases.
Comparing the features of our new reagent (7) to the di-11
and trifluoromethyl analogues,14 we should emphasize that
its stability is similar to S-(trifluoromethyl)diphenylsulfonium
tetrafluoroborate. In contrast with the CF2H reagent, com-
pound 7 is a solid, non-sensitive to moisture and its
preparation does not require an inert atmosphere.
Decomposition of the reagent was not observed and both
the triflate and tetrafluoroborate salts are stable. The
increased stability is due to the decreased acidity of the
hydrogens in the CH2F group. However, since the CH2F
group contains only one electron-withdrawing fluorine atom,
the carbon is less electrophilic and its greater stability enables
it to react with more substrates than the difluoromethyl
analogue. The new material can be stored in a refrigerator
for months without any decrease in activity and it remains
stable for days standing in dry CH2Cl2 and CH3CN solutions.
It reacts with MeOD yielding fluoromethyl methyl ether and
decomposes in DMF and THF. With the aim of efficiently
synthesizing monofluoromethylated salts of nitrogen and
phosphorus nucleophiles, we tested primary, secondary, and
tertiary amines, indole, pyridine, and 4-dimethylaminopyri-
dine, several substituted imidazoles and some triarylphos-
phines as substrates. Burton et al. have reported the synthesis
of the monofluoromethyltriphenyl phosphonium salts.15a
These compounds are very effective reagents to introduce
fluoromethyl moiety into a substrate.15b A few methods6a,16
have also been reported on the preparation of the mono-
fluoromethylated quaternary salts of triethylamine. Among
the tested nitrogen nucleophiles only the tertiary amines and
imidazoles provided the expected monofluoromethylated
first, we attempted to prepare the monofluoromethyl phenyl
sulfoxide (5) with the direct fluorination of methyl phenyl
sulfoxide (1) using Selectfluor and sodium hydride or
butyllithium, but our efforts were unsuccessful (Scheme 1,
route a). As an alternative, we tried the fluorination of phenyl
methyl sulfide (2) with Selectfluor followed by oxidation.
After separation, the yield was lower than we expected
(25%)12 (Scheme 1, route b). Finally, we chose the nucleo-
philic substitution (SRN1) reaction of the liquefied CH2FCl
with sodium thiophenolate (3) for the preparation of mono-
fluoromethyl sulfide (4).13 Having realized the unstable nature
(13) Hine, J.; Porter, J. J. J. Am. Chem. Soc. 1960, 82, 6178.
(14) (a) Yagupolskii, L. M.; Kondratenko, N. Y.; Timofeeva, G. N.
Zh. Org. Khim. 1984, 20, 115. (b) Umemoto, T.; Ishihara, S. J. Am.
Chem. Soc. 1993, 115, 2156. (c) Umemoto, T.; Adachi, K. J. Org. Chem.
1994, 59, 5692. (d) Yang, J. J.; Kirchmeier, R. L.; Shreeve, J. M. J. Org.
Chem. 1998, 63, 2656. (e) Ma, J. A.; Cahard, D. J. Org. Chem. 2003, 68,
8726.
(15) (a) Burton, D. J.; Wiemers, D. M. J. Fluorine Chem. 1985, 27, 85.
(b) Roversi, E.; Scopelliti, R.; Solari, E.; Estoppey, R.; Vogel, P.; Brana,
P.; Menendez, B.; Sordo, J. A. Chem. Commun. 2001, 1214.
(16) (a) Brauer, D. J.; Burger, H.; Grunwald, M.; Pawelke, G.; Wilke, J.
Z. Anorg. Allg. Chem. 1986, 537, 63. (b) Bohme, H.; Hilp, M. Chem. Ber.
1970, 103, 104. (c) Dimitrov, A.; Pfeifer, D.; Jonetal, U.; Rudiger, St.;
Seppelt, K. J. Fluorine Chem. 1997, 82, 143.
(8) Palmer, T. US5101068, 1992.
(9) (a) Li, Y.; Hu, J. Angew. Chem., Int. Ed. 2005, 44, 5882. (b) Li, Y.;
Ni, C.; Liu, J.; Zhang, L.; Zheng, J.; Zhu, L.; Hu, J. Org. Lett. 2006, 8,
1693. (c) Liu, J.; Li, Y.; Hu, J. J. Org. Chem. 2007, 72, 3119.
(10) (a) Fukuzumi, T.; Shibata, N.; Sugiura, M.; Yasui, H.; Nakamura,
S.; Toru, T. Angew. Chem., Int. Ed. 2006, 45, 4973. (b) Mizuta, S.; Shibata,
N.; Goto, Y.; Furukawa, T.; Nakamura, S.; Toru, T. J. Am. Chem. Soc.
2007, 129, 6394. (c) Prakash, G. K. S.; Chacko, S.; Alconcel, S.; Stewart,
T.; Mathew, T.; Olah, G. A. Angew. Chem., Int. Ed. 2007, 46, 4933.
(11) Prakash, G. K. S.; Weber, C.; Chacko, S.; Olah, G. A. Org. Lett.
2007, 9, 1863.
(12) Lal, G. S. J. Org. Chem. 1993, 58, 2791.
558
Org. Lett., Vol. 10, No. 4, 2008

tetrafluoroborate salts (10, 11) in high yield and with high
selectivity (Table 1).
boxylic acids were reacted in the presence of Cs2CO3 as a
base or the sodium salts of the sulfonic acids were reacted
without using a base (Table 2). Unlike the difluoromethyl
Table 1. Reaction of Tertiary Amines, Imidazoles, and
Triphenylphosphine with 7 Producing the Corresponding
Monofluoromethylated Onium Saltsa
Table 2. Reaction of Sulfonic and Carboxylic Acids with 7 to
the Corresponding Fluoromethyl Estersa
a Values indicate isolated yields. b With solid reagent 9.
analogues, the monofluoromethyl esters of carboxylic acids
(15) were reasonably stable and were isolated in good yields.
One of the convenient new feature of the reagent 7 is that
it reacts with naphthols, phenols, perfluorophenol, thiophenol,
and fluorinated alcohols providing the corresponding mono-
fluoromethyl ethers (16) in high yield and with high
selectivity (Table 3). In these cases, we tested various alkali
carbonates such as sodium, potassium, and cesium carbon-
ates18 with the latter being the base of the choice probably
due to its better solubility in CH3CN. Considering the
corresponding acid dissociation constants of simple alcohols
(pKa ∼15), perfluorinated alcohols (pKa ∼10), phenols (pKa
∼10), carboxylic acids (pKa ∼5), sulfonic acids (pKa ∼0),
it is not surprising that we were unable to perform the
monofluoromethylation of simple alcohols. Although the
a Values indicate isolated yields. b DIAD was used as a co-reagent in
CH2Cl2 as solvent.
Among the tested phosphines only triphenylphosphine
gave the corresponding monofluoromethyl tetrafluoroborate
salt (12) in 31% yield. Modification of different oxygen and
sulfur nucleophiles such as methyl ethers, thioethers, and
methyl esters of sulfonic and carboxylic acids into the
corresponding fluoro analogues is not a straightforward task,
and only a few methods are available for the synthesis of
such compounds.1b,6,17 However, there is no method available
for the preparation of monofluoromethyl alkanesulfonates.
Fluoromethyl esters 14 and 15 were prepared under two
different reaction conditions; either the corresponding car-
(17) (a) Stavber, S.; Zupan, M. Tetrahedron Lett. 1993, 34, 4355. (b)
Ringone, R.; Benneche, T. J. Fluorine Chem. 1999, 95, 121. (c) Schlosser,
M.; Limat, D. Tetrahedron 1995, 51, 5807.
(18) (a) Flessner, T.; Doyle, S. J. Prakt. Chem. 1999, 341, 186. (b) Cella,
J. A.; Bacon, S. W. J. Org. Chem. 1984, 49, 1122. (c) Gisin, B. F. HelV.
Chim. Acta 1973, 56, 1476.
Org. Lett., Vol. 10, No. 4, 2008
559

Scheme 2. Synthesis of Biologically and Pharmaceutically
Table 3. Reaction of Phenols, Naphthols, and Alcohols with 7
to the Corresponding Fluoromethyl Ethersa
Important Monofluoromethyl and Fluorinated Derivativesa
b
a Values indicate isolated yield. With solid reagent 9.
Of the various carbon nucleophiles containing hydrogen
with the proper acidity, only a few proved to be suitable
precursors to form C-C bond with reagent 7 (Table 4).
In conclusion, we have developed the first practical
electrophilic monofluoromethylating reagent and succesfully
transferred the monofluoromethyl group to various nucleo-
philes including C, N, O, S, and P nucleophiles. We have
also applied this methodology for the synthesis of various
biologically and pharmaceutically important compounds.
Table 4. Reaction of Carbon Nucleophiles with Reagent 7a
a Values indicate isolated yields. b With solid reagent 9. c Yield based
on fluorobenzene as internal standard. d Not stable.
sodium salt of the 1,3,5-trimethylbenzyl alcohol was prepared
but the conjugate anion being a strong base destroyed the
reagent. In contrast, the conjugate base of the hexafluoro-
propan-2-ol compounds (pKa ∼8-9) are stabilized by the
trifluoromethyl groups and possess decreased basicity, and
consequently, the expected products could be prepared (Table
3, entries 8 and 9). Considering oxygen nucleophiles, it can
be stated that the pKa of the compound should be at least 10
or less for a successful monofluoromethylation reaction.
a X, Y, Z ) electron-withdrawing groups. b Values indicate isolated
yields. c It is not separated from the unreacted starting material, yield based
on fluorobenzene as internal standard.
Our observations that the reagent is capable of reacting
with hydroxy compounds prompted us to prepare the
monofluoromethylated derivatives of the major estrogen
hormone estradiol (17), the analgesic acetaminophene (18),
the fluorinated analogues of papaverine (19), and quinidine
alkaloids (20) (Scheme 2). In the case of oxygen nucleo-
philes, we have already discussed the importance of the
required acidity of the substrate to avoid the decomposition
of the electrophilic reagent. Having considered this fact,
we extended the use of our reagent for carbon nucleophiles
also.
Acknowledgment. Support of our work by the Loker
Hydrocarbon Research Institute is gratefully acknowledged.
Supporting Information Available: General experimen-
tal procedure and spectroscopic data of all of the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL702500U
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Org. Lett., Vol. 10, No. 4, 2008