Novel method for incorporating the CHF2 group into organic molecules using BrF3

Article abstract of DOI:10.1021/ol034051n

(Matrix presented) 2-Alkyl-1,3-dithiane derivatives, easily made from alkyl bromides and the parent 1,3-dithiane, were reacted with BrF₃ to form the corresponding 1,1-difluoromethyl alkanes (RCHF₂) in 60-75% yield. The reaction proceeds well with primary alkyl halides. The limiting step for secondary alkyl halides is the relatively low yield of the dithiane preparation. The two sulfur atoms of the dithiane are essential for the reaction.

Full text of DOI:10.1021/ol034051n

ORGANIC
LETTERS
2003
Vol. 5, No. 5
769-771
Novel Method for Incorporating the
CHF2 Group into Organic Molecules
Using BrF3
Revital Sasson, Aviv Hagooly, and Shlomo Rozen*
School of Chemistry, Raymond and BeVerly Sackler Faculty of Exact Sciences,
Tel-AViV UniVersity, Tel-AViV 69978, Israel
rozens@post.tau.ac.il
Received January 11, 2003
ABSTRACT
2-Alkyl-1,3-dithiane derivatives, easily made from alkyl bromides and the parent 1,3-dithiane, were reacted with BrF3 to form the corresponding
1,1-difluoromethyl alkanes (RCHF2) in 60−75% yield. The reaction proceeds well with primary alkyl halides. The limiting step for secondary
alkyl halides is the relatively low yield of the dithiane preparation. The two sulfur atoms of the dithiane are essential for the reaction.
The difluoromethyl group, CHF2, often contributes special
biological properties to organic molecules. Apart from its
high lipophilicity similar to the CF3 group, CHF2 is able to
act as a hydrogen donor through hydrogen bonding1 and is
actively pursued for enhancing biological activities.2 CHF2
has been used in sugar chemistry,3 incorporated into amino
acids as enzyme inhibitors,4 and plays an important role in
the field of herbicides,5 liquid crystals,6 and most importantly
in many modern anesthetics such as desflurane and isoflu-
rane.7
bonds.11 Some years ago, we developed efficient ways for
replacing ketones and even carboxylic acid carbonyls with
the CF2 group via the reactions of IF and BrF with an array
of hydrazone derivatives12 or thioesters.13 The only type of
carbonyls that failed to react cleanly was aldehydes, where
the formation of the CHF2 group proceeded with very low
yields, the balance consisting of various tars. Recently, we
tried to prepare this moiety from tris(methylthio)alkyl
derivatives, but once again the yields were poor.14 After
further studies, however, we report now a novel and simple
method for the successful construction of this group, starting
from alkyl halides, which are more readily available than
aldehydes, especially in the field of the nonaromatic chem-
istry.
Until today, the most common route for constructing the
CHF2 moiety was the reaction of aldehydes with SF4 and
9
DAST,8 although SeF4 was also used. Other methods
employed the reaction of gem-bistriflate, also an aldehyde
derivative, with Bu4NF10 and the addition of CBr2F2 to double
More than 15 years ago, Katzenellenbogen had shown that
carbonyls, via their 1,3-dithiolanes, can react with the
combination of R2NBr and HF (the so-called [BrF] reagent)
to form the corresponding CF2 derivatives.15 We decided to
examine the reaction of the more versatile dithianes with
BrF3.
* Fax: +972 3 6409293.
(1) Erickson, J. A.; McLoughlin, J. I. J. Org. Chem. 1995, 60, 1626.
(2) Pu, Y. M.; Torok, D. S.; Ziffer, H.; Pan, X. Q.; Meshnick, S. R. J.
Med. Chem. 1995, 38, 4120.
(3) Houlton, S. J.; Motherwell, W. B.; Ross, B. C.; Tozer, M. J.; Williams,
D. J.; Slawin, A. M. Z. Tetrahedron 1993, 49, 8087. Kaneko, S.; Yamazaki,
T.; Kitazume, T. J. Org. Chem. 1993, 58, 2302.
(4) d’Orchymont, H. Synthesis 1993, 961.
(5) Goure, W. F.; Leschinsky, K. L.; Wratten, S. J.; Chupp, J. P. J. Agric.
Food Chem. 1991, 39, 981.
(10) Martinez, G. A.; Barcina, O. J.; Rys, A. Z.; Subramanian, L. R.
Tetrahedron Lett. 1992, 33, 7787.
(6) Kitazume, T.; Ohnogi, T.; Ito, K. J. Am. Chem. Soc. 1990, 112, 6608.
(7) Rozov, L. A.; Huang, C.; Halpern, D. F.; Vernice, G. G. U.S. Patent
5,283,372, 1994. Halpern, D. F.; Robin, M. L. U.S. Patent 4,996,371, 1991.
(8) Middleton, W. J. J. Org. Chem. 1975, 40, 574.
(9) Olah, G. A.; Nojima, M.; Kerekes, I. J. Am. Chem. Soc. 1974, 96,
925.
(11) Gonzales, J.; Foti, C. J.; Elsheimer, S. J. Org. Chem. 1991, 56,
4322.
(12) Rozen, S.; Brand, M.; Zamir, D.; Hebel, D. J. Am. Chem. Soc. 1987,
109, 896.
(13) Rozen, S.; Mishani, E. J. Chem. Soc., Chem. Commun. 1993, 1761.
(14) Hagooly, A.; Ben-David, I.; Rozen, S. J. Org. Chem. 2002, 67, 8430.
10.1021/ol034051n CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/12/2003

Recently, we started to experiment with bromine trifluo-
ride, a reagent known for a long time and yet practically
ignored by organic chemists. This “ban” was a result of
bromine trifluoride’s violent reactivity toward many organic
solvents such as hexane, acetone, ethers, and the like. The
fact that it could be safely employed in solvents such as
CHCl3, CFCl3, and CCl4 was overlooked. We have shown,
however, that this reagent can be of help in many organic
transformations such as difficult bromination of deactivated
aromatic rings,16 transformations of carbonyls to the CF2
group17 and of nitriles to the corresponding CF3 compounds,18
oxidation of alcohols to acyl fluorides,19 synthesis of
trifluoromethyl ethers,20 construction of trifluoromethyl al-
kanes,14 and more.21 Most of the above transformations were
made possible because of the tendency of the electrophilic
bromine in BrF3 to complex itself around basic heteroatoms,
especially sulfur. Such complexation brings the naked and
efficient nucleophilic fluorides near the potential reaction
center and reduces the prospects of undiscriminating radical
brominations and fluorinations.
take place during the reactions with dithianes when tertiary
centers are present. We found that the reaction around the
sulfur atoms is by far the dominant one. No tertiary
fluorination was observed with the dithiane of 2,6-dimethyl-
octane (8), which behaved as expected to produce the 1,1-
difluoro-4,8-dimethylnonane (9). The polycyclic core of
compounds such as 1-ethyladamantane and 1-ethylnorbor-
nane had been unintentionally fluorinated in the past with
BrF3. Their corresponding dithianes 10 and 11, however,
react satisfactorily to form the corresponding difluoromethyl
derivatives 12 and 13 in 55 and 65% yields, respectively.
Cyclic 1,3-dithiane (1) is available either commercially
or through a simple synthesis. Its lithium salt is also readily
accessible and reacts with alkyl halides to form the corre-
sponding 2-alkyl-1,3-dithianes.22
When 2-decane-1,3-dithiane (2) was reacted for 1-2 min
under mild conditions with BrF3,23 we were able to isolate
the yet unknown 1,1-difluoroundecane (3) in 75% yield.24
Similarly, dodecyl bromide, through its dithiane derivative
4, was converted to 1,1-difluorotridecane (5).10 Bis-dithiane
derivatives also work as demonstrated by the bis-dithiane
of 1,10-dibromodecane 6, which was converted in good yield
to the previously unknown 1,1,12,12-tetrafluorododecane (7).
The fluorine atoms in bromine trifluoride can in certain
cases act as electrophiles25 and substitute tertiary hydrogens
similarly to F2.26 It was of interest to see if such processes
(15) Sondej, S. C.; Katzenellenbogen, J. A. J. Org. Chem. 1986, 51,
3508.
(16) Rozen, S.; Lerman, O. J. Org. Chem. 1993, 58, 239.
(17) Rozen, S.; Mishani, E.; Bar- Haim, A. J. Org. Chem. 1994, 59,
2918.
(18) Rozen, S.; Rechavi, D.; Hagooly, A. J. Fluorine Chem. 2001, 111,
161.
(19) Rozen, S.; Ben-David, I. J. Fluorine Chem. 1996, 76, 145.
(20) Ben-David, I.; Rechavi, D.; Mishani, E.; Rozen, S. J. Fluorine Chem.
1999, 97, 75.
Placing the CHF2 group on a secondary site is somewhat
more problematic. The limiting factor of the whole reaction
in these cases is the construction of the appropriate dithiane
since the basic lithium derivative of 1 may induce an
elimination of the secondary bromine. The best procedure
found in the literature for making such dithianes consists of
coupling the Grignard derivative of the secondary alkyl halide
(21) Rozen, S.; Ben-David, I. J. Org. Chem. 2001, 66, 496.
(22) For the general procedure for preparing the 2-alkyl-1,3-dithiane
derivatives, see: Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231.
(23) Preparation and Handling of BrF3. Although commercially
available, we prepare our own BrF3 by simply passing 0.58 mol of pure
fluorine through 0.2 mol of bromine placed in a copper reactor and cooled
to 0-10 °C. At this temperature, the higher oxidation state, BrF5, will not
form in any appreciable amount (Stein, L. J. Am. Chem. Soc. 1959, 81,
1269); however, we always use a small excess of bromine, thereby keeping
the reagent from disproportionation to BrF5. The product can be stored in
Teflon containers indefinitely. BrF3 is a strong oxidizer and tends to react
Very exothermically with water and oxygenated organic solVents. Work using
BrF3 should be conducted in a well Ventilated area, and caution and
common sense should be exercised. General Procedure for Reaction of
2-Alkyl-1,3-dithianes with BrF3. The 2-alkyl-1,3-dithianes (1 mmol) were
dissolved in 10-15 mL of dry CFCl3. About three mmols of BrF3 were
dissolved in the same solvent, cooled to 0 °C and added dropwise to the
solutions of dithianes. The reaction mixture was then washed with saturated
aqueous Na2S2O3 until colorless. The aqueous layer was extracted with CH2-
Cl2 and the organic layer dried over MgSO4. Evaporation of the solvent
followed by purification by flash chromatography gave the target difluoro
products.
(24) The spectral properties of the known and referenced products are
in full agreement with the properties described in the literature. Those
properties, as well as the microanalysis of all new difluoromethyl products
(oils) presented in this work, are in excellent agreement with their structures.
The main characteristic features of 3, 7, 9, 12, and 13 are as follows: 1H
NMR δ 5.78-5.81 ppm (1 H, tt, J1 ) 57 Hz, J2 ) 5 Hz), 19F NMR: -116
ppm (dt, J1 ) 57 Hz, J2 ) 17 Hz); 13C NMR δ 117-118 (t, J ) 239 Hz),
32-34 ppm (t, J ) 20 Hz). 17: 1H NMR 5.6 ppm (1 H, td, J1 ) 57 Hz,
J2 ) 4 Hz); 19F NMR δ -125 (1 F, ddd, J1 ) 275 Hz, J2 ) 57 Hz, J3 )
17 Hz), -122.6 ppm (1 F, ddd, J1 ) 275 Hz, J2 ) 57 Hz, J3 ) 13 Hz); 13
C
NMR δ 119.4 (t, J ) 242 Hz), 37.2 (t, J ) 19 Hz), 29.7 (t, J ) 4 Hz), 12.1
ppm (t, J ) 5 Hz).
(25) Boguslavskaya, L. S.; Kartashov, A. V.; Chuvatkin, N. N. Zh. Org
Khim. (English translation) 1989, 25, 1835.
(26) Rozen, S.; Gal, C. J. Org. Chem. 1987, 52, 2769. Rozen, S.; Gal,
C. J. Org. Chem. 1987, 52, 4928.
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Org. Lett., Vol. 5, No. 5, 2003

with 2-chloro-1,3-dithiane. The yields of such reactions rarely
exeed 50%,27 but once the product is obtained, the reaction
with BrF3 proceeds as expected. We have prepared 2-cy-
clohexane-1,3-dithiane (14) and eventually obtained the target
molecule of difluoromethylcyclohexane (15)10 in 70% yield.
Similarly, the dithiane derived from 2-bromooctane (16) was
reacted to produce 1,1-difluoro-2-methyloctane (17) in 60%
yield.
decanal 18 with BrF3, no substantial complexation took place
between the soft bromine and the hard oxygen atoms
resulting in radical reactions leading to bromine and fluorine
containing tars. Repeating the reaction with the corresponding
oxothioacetal 19 resulted mainly in the formation of decanal
since the BrF3 could in this case attach itself to the sulfur
atom enabling nucleophilic replacement of the sulfur atom
with oxygen.
It should be noted that the main limitation of using
bromine trifluoride for the construction of the difluoromethyl
group is the presence of an aromatic ring that usually is
susceptible to attacks from the electrophilic bromine of the
reagent.
In conclusion, we hope that this work is an additional step
along the road toward establishing BrF3 as a “legitimate”
reagent for organic chemistry. About 20 years ago, F2 was
also considered a reagent to avoid in organic chemistry, but
today numerous laboratories use it routinely. The present use
of BrF3, converting alkyl halides into difluoromethyl deriva-
tives, may be one more step toward this goal.
Acknowledgment. This work was supported by the Israel
Science Foundation founded by the Israel Academy of
Sciences and Humanities.
Supporting Information Available: Complete 1H NMR,
13C NMR, IR and microanalysis data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
As with all successful BrF3 reactions, the presence of the
heteroatom anchor is essential. Since the bromine atom in
BrF3 is a soft acid, it complexes itself best with soft bases
such as sulfur atoms. Indeed, when we reacted the acetal of
OL034051N
(27) Kruse, C. G.; Wijsman, A.; van der Gen, A. J. Org. Chem. 1979,
44, 1847.
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