Concentration-dependent reactions of deoxofluor with arylglyoxal hydrates: A new route to polyfluoro ethers

Article abstract of DOI:10.1021/ol016319l

(Equation presented) In concentrated solutions (CH₂Cl₂) at 25°C, arylglyoxal hydrates, ArCOCHO·H₂O (Ar = 3,4-OCH₂O-C₆H₃-, 4-MeO-C₆H₄-, 4-Me-C₆H₄-, 4-F-C₆H₄-, Ph-, S-CH=CH-CH=C-) (2a-f) with Deoxofluor gave fluorinated ethers, ArCF₂CHFOCHFCF₂Ar, (3a-f) in >90% yields as meso/racemic mixtures (～1:1). Under very dilute conditions, mixtures of ArCF₂CHO (major) (4a-f) and ArCF₂CF₂H (6a-f) (minor) were obtained. The structures of 3b (racemic) and 4a (meso) have been confirmed by single-crystal X-ray analysis.

Full text of DOI:10.1021/ol016319l

ORGANIC
LETTERS
2001
Vol. 3, No. 17
2713-2715
Concentration-Dependent Reactions of
Deoxofluor with Arylglyoxal Hydrates: A
New Route to Polyfluoro Ethers
Rajendra P. Singh and Jean’ne M. Shreeve*
Department of Chemistry, UniVersity of Idaho, Moscow, Idaho 83844-2343
jshreeVe@uidaho.edu
Received June 21, 2001
ABSTRACT
In concentrated solutions (CH Cl2) at 25 °C, arylglyoxal hydrates, ArCOCHO‚H O (Ar ) 3,4-OCH O-C H -, 4-MeO-C H -, 4-Me-C H -, 4-F-C H -,
2
2
2
6
3
6
4
6
4
6 4
Ph-, S-CHdCH-CHdC-) (2a−f) with Deoxofluor gave fluorinated ethers, ArCF2CHFOCHFCF2Ar, (3a−f) in >90% yields as meso/racemic mixtures
(∼1:1). Under very dilute conditions, mixtures of ArCF2CHO (major) (4a−f) and ArCF2CF2H (6a−f) (minor) were obtained. The structures of 3b
(racemic) and 4a (meso) have been confirmed by single-crystal X-ray analysis.
Fluorine or a fluorinated group is a highly important
substituent in the field of organic chemistry, most often
bringing about some remarkable changes in the physical,
chemical, and biological properties of new compounds/
materials that make them suitable for diverse applications
in the areas of materials science, agrochemistry, and
industry.1-4 Although a wide variety of methods have been
developed for introducing one or more fluorine atoms into
organic compounds,5 the use of Deoxofluor as a nucleophilic
fluorinating reagent is gaining in popularity.6-8 Utilization
of Deoxofluor in the conversion of a simple system such as
an aldehyde or a ketone into the corresponding difluoro
derivative is well explored,7 but this methodology has not
been extended to polycarbonyl compounds. In our continuing
efforts to introduce fluorine into organic compounds nucleo-
philically,8 we discovered a new route to aryl polyfluorinated
ethers by the reactions of arylglyoxal hydrates with Deoxo-
fluor.
Treatment of 2a (2 mmol) with Deoxofluor (1) (4.5 mmol)
in dichloromethane (3 mL) at room temperature for 4 h
afforded 3a and 4a as a meso and racemic mixture (∼1:1)
(2) For the use of organofluorine compounds in medicinal and biomedical
chemistry, see: (a) Biomedical Frontiers of Fluorine Chemistry; Ojima, I.,
McCarthy, J. R., Welch, J. T., Eds.; ACS Symposium Series 639; American
Chemical Society: Washington, DC, 1996. (b) Organic Chemistry in Med-
icinal Chemistry and Biomedical Applications; Filler, R., Ed.; Elsevier:
Amsterdam, 1993. (c) Welch, J. T.; Eswaraksrishnan, S. Fluorine in
Bioorganic Chemistry; John Wiley and Sons: New York, 1991. (d) Filler,
R.; Kirk, K. Biological Properties of Fluorinated Compounds. In Chemistry
of Organic Fluorine Compounds II: A Critical ReView; Hudlicky, M.,
Pavlath, A. E., Eds.; ACS Monograph 187; American Chemical Society:
Washington, DC, 1995; pp 1011-1022. (e) Elliot, A. J. Fluorinated
Pharmaceuticals. In Chemistry of Organic Fluorine Compounds II:
A
Critical ReView; Hudlicky, M., Pavlath, A. E., Eds.; ACS Monograph 187;
American Chemical Society: Washington, DC, 1995; pp 1119-1125. (f)
Sholoshonok, V. A., Ed. Enantiocontrolled Synthesis of Organo-Fluorine
Compounds: Stereochemical Challenge and Biomedical Targets; John
Wiley and Sons: New York, 1999.
(3) For the use of of organofluorine compounds in agrosciences, see:
(a) Cartwright, D. Recent Developments in Fluorine-Containing Agro-
chemicals. In Organofluorine Chemistry: Principles and Commercial
Applications; Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.; Plenum: New
York, 1994; pp 237-257. (b) Lang, R. W. Fluorinated Agrochemicals. In
Chemistry of Organic Fluorine Compounds II; Hudlicky, M., Pavlath, A.
E., Eds.; ACS Monograph 187; American Chemical Society: Washington,
DC, 1995; pp 1143-1148.
* Tel: 208-885-6215. Fax: 208-885-9146.
(1) For the general applications of organofluorine compounds, see:
Organofluorine Chemistry: Principles and Commercial Applications;
Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.; Plenum: New York, 1994.
10.1021/ol016319l CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/02/2001

in 91% isolated yield. Under similar reaction conditions,
various arylglyoxal hydrates (2b-f) were also converted into
aryl polyfluoro ethers (3b-f and 4b-f) in >90% isolated
yields. (Scheme 1). Both the meso (3a-f) and racemic (4a-
Table 1. Reaction of Aryglyoxal Hydratesa with Deoxofluor at
Room Temperature
productsb (% yieldc)
substrate
(as hydrate)
meso
racemic
1a
1b
1c
1d
1e
1f
3a (47)
3b (48)
3c (47)
3d (45)
3e (46)
3f (47)
4a (44)
4b (45)
4c (46)
4d (45)
4e (44)
4f (46)
Scheme 1
a All reactions were carried out with 2 mmol of substrate and 4.5 mmol
of Deoxofluor in 3 mL of dichloromethane. b Meso and racemic products
were separated by flash chromatography and characterized by spectroscopic
analysis. c Isolated.
not formed, but rather difluoro aldehydes or tetrafluoro
derivatives were formed. For example, the reaction of 2a (1
mmol) with Deoxofluor (1) (2.5 mmol) in methylene chloride
(200 mL) at 25 °C for 4 h afforded a mixture of 5a (75%)
and 6a (25%). Under similar reaction conditions, various
arylglyoxal hydrates (2b-f) also gave a mixture of 5b-f as
major and 6b-f as minor (Scheme 2). Reaction of concen-
f) compounds were separated by flash chromatography using
a methylene chloride and pentane mixture (1:2) as an eluting
solvent. Each of the meso compounds gave two sets of
signals in the 19F NMR spectra centered at about -110 ppm
(CF2) (ABX pattern) and -138 ppm (CHF) as a doublet of
multiplets. In the racemic products, the signals due to CF2
were essentially identical to those for the meso cases, but
the signal due to CHF was observed at about -146 ppm as
a doublet of multiplets. In the 13C NMR spectra of meso
and racemic products, a characteristic shift was observed due
to the CHF carbon, i.e., in meso compounds as a doublet of
triplets at about 107 ppm with J ) 238 Hz and in the racemic
species as a doublet of triplets at about 103 ppm with the
same J value as in the case of meso. Finally, the structures
of 3b and 4a have been confirmed by single-crystal X-ray
analysis.
Scheme 2
When the reactions described in Scheme 1 were carried
out under very dilute conditions, aryl polyfluoro ethers were
(4) The ability of fluorine to change the properties of organic molecules
has been discussed extensively elsewhere. For example, see: Smart, B. E.
Characteristics of C-F systems. In Organofluorine Chemistry: Principles
and Commercial Applications; Banks, R. E., Smart, B. E., Tatlow, J. C.,
Eds.; Plenum: New York, 1994; pp 57-82.
(5) For general discussion on the synthesis of organofluorine compounds,
see: (a) Olah, G. A.; Prakash, G. K. S.; Chambers, R. D. Synthetic Fluorine
Chemistry; Wiley and Sons: New York, 1992. (b) Furin, G. G. Synthetic
Aspects of the Fluorination of Organic Compounds; Harwood Academic
Publisher: London, 1991. (c) Furin, G. G. Introduction of Fluorine by N-F
Compounds. In Methods of Organic Chemistry (Houben-Weyl) Organo-
Fluorine Compounds; Georg Thieme Verlag: Stuttgart, New York, 1999;
pp 432-499. (d) Taylor, S. D.; Kotoris, C. C.; Hum, G. Tetrahedron 1999,
55, 12431-12477. (e) McClinton, M. A.; McClinton, D. A. Tetrahedron
1992, 48, 6555-6666. (f) Rozen, S. Chem. ReV. 1996, 96, 1717-1736. (g)
Wilkinson, J. A. Chem. ReV. 1992, 92, 505-519. (h) Rozen, S.; Mishani,
E. J. Chem. Soc., Chem. Commun. 1994, 2081. (i) Rozen, S.; Mishani, E.;
Bar-haim, A. J. Org. Chem. 1994, 59, 2918. (j) Middleton, W. J.; Bingham,
E. M. J. Org. Chem. 1980, 45, 2883-2887. (k) Rozen, S.; Lerman, O.;
Kol, M.; Hebel, D. J. Org. Chem. 1985, 50, 4753-4758.
(6) (a) Lal, G. S.; Pez. G. P. U.S. Patent 6,080,886, 2000. (b) Lal, G. S.;
Pez, G. P.; Pesaresi, R. J.; Projonic, F. M.; Chen, H. J. Org. Chem. 1999,
64, 7048-7054. (c) Lal, G. S.; Labach, E.; Evans, A. J. Org. Chem. 2000,
65, 4830-4832.
(7) Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Projonic, M. J. Chem. Soc.,
Chem. Commun. 1999, 215-216.
trated solutions of nonhydrated aryl glyoxals (7g-i) in
methylene chloride with Deoxofluor produced the tetrafluoro
derivatives (8g-i) in excellent isolated yields, whereas only
trace amounts of difluoro products (9g-i) were found
(Scheme 2).
The reaction mechanism for the formation of difluoro or
tetrafluoro products is similar to that of the reaction between
simple aldehydes and ketones6b,7 with Deoxofluor. The
mechanism for the formation of fluorinated ethers is tenta-
tively described in Scheme 3. Fluorination of the carbonyl
group R to the phenyl or substituted phenyl group likely
occurs first to give A. It is known that Deoxofluor fluorinates
alcohols, ROH, to produce the corresponding fluorinated
derivative, R-F. When the hydrated arylglyoxal (A) reacts,
the formation of a fluorinated alcohol (B) is expected.
Fluorine-containing alcohols with fluorine on the R-carbon
are unstable with respect to loss of HF or can react with HF
under highly concentrated conditions to give an unstable
(8) (a) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56, 7613-7633
and references therein. (b) Singh, R. P.; Majumder, U.; Shreeve, J. M. J.
Org. Chem. 2001, in press. (c) Singh, R. P.; Chakraborty, D.; Shreeve, J.
M. J. Fluorine Chem. 2001, in press.
2714
Org. Lett., Vol. 3, No. 17, 2001

not form polyfluoro ethers even when water is present in
the reaction mixture.
Scheme 3
In summary, a new application of Deoxofluor to give
polyfluoro ethers is reported. Depending on the concentration
of the reaction solution and the degree of hydration of the
arylglyoxal, fluorinated ethers or tetrafluoro and difluoro
derivatives are selectively produced. Further studies of
Deoxofluor with other substrates are continuing.
Acknowledgment. This work was supported by the
National Science Foundation (CHE-9720365) and by the
Petroleum Research Fund, administered by the American
Chemical Society. We are particularly grateful to Dr. G. S.
Lal of Air Products and Chemical, Inc. for the gift of
Deoxofluor. We thank Drs. G. Knerr and A. Blumenfeld for
measuring HRMS and NMR spectra, respectively. We are
grateful to Professors Richard V. Williams, Paul. D. Arm-
strong, and James H. Cooley for helpful discussions.
intermediate C. A second molecule of the fluorinated alcohol
(B) attacks at the highly nucleophilic carbon of C, which
results in the formation of an intermediate D. Under acidic
conditions (HF), the formation of ether E is not surprising
(Scheme 3). As a result of the presence of Deoxofluor,
fluorination of the carbonyl group R to the phenyl or
substituted phenyl group could also occur later in the process.
Under very dilute conditions, if appropriate nucleophiles are
not available, the intermediates B, C, and D easily decom-
pose. It should be noted that nonhydrated aryl glyoxals do
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 3a-f, 4a-
f, 9g-i; crystal data and structure refinements, atomic
coordinates, bond lengths, bond angles, anisotropic displace-
ment parameters, hydrogen coordinates, and ORTEP draw-
ings for 3b and 4a. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL016319L
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