Constructing the OCF2O moiety using BrF3

Article abstract of DOI:10.1021/jo801116n

(Chemical Equation Presented) A general preparation for aromatic and aliphatic, cyclic as well as linear, symmetric and asymmetric difluoromethylenedioxy derivatives is described. The alcohols were reacted with thiophosgene to give thiocarbonates, which in turn were reacted with BrF ₃. The fluorination step is complete in seconds with moderate to high yields under mild conditions.

Full text of DOI:10.1021/jo801116n

Constructing the OCF2O Moiety Using BrF3
Youlia Hagooly and Shlomo Rozen*
School of Chemistry, Tel-AViV UniVersity, Tel-AViV 69978, Israel
rozens@post.tau.ac.il
ReceiVed May 22, 2008
A general preparation for aromatic and aliphatic, cyclic as well as linear, symmetric and asymmetric
difluoromethylenedioxy derivatives is described. The alcohols were reacted with thiophosgene to give
thiocarbonates, which in turn were reacted with BrF3. The fluorination step is complete in seconds with
moderate to high yields under mild conditions.
Introduction
lithium batteries and capacitors,6 and optical fibers such as
bis(alkoxy)difluoromethane possess good thermal stability, high
glass transition temperatures, and low dielectric constants.7
Only a few reactions leading to difluoroethers have been
reported,8 and even fewer are specifically designed for con-
structing the difluorodiether group (OCF2O). Aromatic deriva-
tives of this type have been prepared mainly by reacting various
nucleophilic fluoride reagents (e.g., HF, AgF, SbF3, Bu4NH2F3)
with either dichlorodioxomethylene derivatives or thiocar-
bonates.9,10 However, only few leads to alicyclic derivatives
could be found.7,11 The lack of a general method for preparing
a wide spectrum of symmetric and asymmetric difluorometh-
ylenedioxy (OCF2O) compounds is conspicuous.
For the past 15 years, we have investigated various halogen
fluoride reagents, such as IF and BrF, as nucleophilic fluorinating
agents.12 One of the most successful reagents of this group
proved to be bromine trifluoride (BrF3), especially in construct-
ing the CF213 and the CF314,15 moieties at various sites in organic
molecules. The main feature of the mechanism governing most
There is a continuous effort to develop new fluorine-
containing compounds, as is evident from the thousands of
books, publications, reviews and journals devoted to this subject.
It is enough to say that this interest has spread to all fields of
chemistry from energy-related issues, materials, and agriculture
to biologically interesting compounds.
Among the numerous fluorine-containing compounds, the
ones possessing trifluoromethyl and difluoromethylene groups
are of special value for many medicinal and industrial uses.1
The important trifluoromethoxy group and its positive influence
on various organic compounds are also well documented.2 The
properties of the difluoromethylenedioxy group (OCF2O), on
the other hand, has remained relatively unexplored. Recently,
however, it is becoming a focus of interest due to its special
contributions in pharmaceuticals.3,4 For instance, a series of
novel 2-aminothio phenecarboxamide derivatives containing the
OCF2O moiety have been developed as potential chemothera-
peutic agents for cancer treatment.5 Also, dioxolane derivatives
with this group were found to be suitable for use in secondary
(5) Brennan, C.; Kluender, C. E.; Wickens, P.; Enyedy, I. J.; Hong, Z.; Jones,
B.; Kumarasinghe, E. S.; Chuang, C.; Phillips, B.; Dixon, J. PCT Int. Appl.
WO 2006023707, 2006.
(1) Feiring, A. E. In Organofluorine Chemistry: Principles and Commercial
Applications; Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.; Plenum: New York,
London, 1994; pp 339-372.
(6) Nakano, T.; Shiono, K. Ger. Offen. DE 19700656, 1997.
(7) Yang, Y.; Mikes, F.; Koike, Y.; Okamoto, Y. Macromolecules 2004, 37,
7918–7923.
(8) (a) Bunnelle, W. H.; McKinnis, B. R.; Narayanan, B. A. J. Org. Chem.
1990, 55, 768–770. (b) Rozen, S.; Mishani, E. J. Chem. Soc., Chem. Commun.
1993, 1761–1762.
(9) Saint-Jalmes, L. J. Fluorine Chem. 2006, 127, 85–90.
(10) Guidotti, J.; Schanen, V.; Tordeux, M.; Wakselman, C. J. Fluorine Chem.
2005, 126, 445–449.
(11) Kuroboshi, M.; Hiyama, T. Synlett 1994, 251–252.
(12) (a) Hebel, D.; Rozen, S. J. Org. Chem. 1988, 53, 1123. (b) Rozen, S.;
Mishani, E.; Bar-Haim, A. J. Org. Chem. 1994, 59, 2918–2918.
(2) Leroux, F.; Jeschkle, P.; Schlosser, M. Chem. ReV. 2005, 105, 827–856.
(3) Zhu, G.; Gandhi, V. B.; Gong, J.; Thomas, S.; Woods, K. W.; Song, X.;
Li, T.; Diebold, R. B.; Luo, Y.; Liu, X.; Guan, R.; Klinghofer, V.; Johnson,
E. F.; Bouska, J.; Olson, A.; Marsh, K. C.; Stoll, V. S.; Mamo, M.; Polakowski,
J.; Campbell, T. J.; Martin, R. L.; Gintant, G. A.; Penning, T. D.; Li, Q.;
Rosenberg, S. H.; Giranda, V. L. J. Med. Chem. 2007, 50, 2990–3003.
(4) Su, J.; Tang, H.; McKittrick, B. A.; Burnett, D. A.; Zhang, H.; Smith-
Torhan, A.; Fawzi, A.; Lachowicz, J. Bioorg. Med. Chem. Lett. 2006, 16, 4548–
4553.
6780 J. Org. Chem. 2008, 73, 6780–6783
10.1021/jo801116n CCC: $40.75 2008 American Chemical Society
Published on Web 08/12/2008

Constructing the OCF2O Moiety Using BrF3
reactions with BrF3 involves the complexation of the soft acidic
bromine with a soft base (e.g., sulfur or nitrogen atoms) in the
target molecule. The fluorides in this reagent then react
selectively with the activated carbon, forming the desired
products, while minimizing unwanted destructive radical side
reactions.16 These reactions helped us, among other things, to
construct the OCF2Cl group,17 and we present here a route
leading to a general synthesis of the OCF2O moiety.
To produce asymmetric bis(alkoxy)difluoromethane deriva-
tives, a stepwise process was required. The reaction between
1-octanol (1d), Et3N and thiophosgene provided octyl chlo-
rothioformate (5d),22 which then was added to a methanol
solution, forming the asymmetric precursor O-methyl-O-oc-
tylthiocarbonate (6d) in 80% yield. The reaction of 6d with
BrF3 led to 1-(difluoro(methoxy)methoxy)octane (7d), which
if not specially protected hydrolyzed, as did 3c, to methyl octyl
carbonate (8d)23 in 80% yield (Scheme 2). When instead of
octanol, trichloroethanol was used, forming O-methyl-O-2,2,2-
trichloroethylthiocarbonate (6e) via 2,2,2-trichloroethyl chlo-
rothioformate (5e),20 the reaction with BrF3 led to a new and
hydrolytically stable 1,1,1-trichloro-2-(difluoro(methoxy)me-
thoxy)ethane (7e) in 90% yield (Scheme 2).
Results and Discussion
The reaction of 2 molar equiv of 2-nitrophenol (1a) with 1
molar equiv of thiophosgene in the presence of sodium
hydroxide formed O,O-bis(2-nitrophenyl)thiocarbonate (2a).18
Despite the tendency of aromatic rings to be brominated by the
strong electrophilic bromine in BrF3, the fluorination on the
carbon bonded to the sulfur atom in 2a was much faster.19 The
new bis(2-nitrophenoxy)difluoromethane (3a) was thus formed
in 80% yield (Scheme 1).
SCHEME 2. Formation of Asymmetric
Bis(alkoxy)difluoromethane Derivatives (7d, 7e)
SCHEME 1. Formation of Symmetric Bis(alkoxy/
aryloxy)difluoromethane Derivatives (3)
The stability of the OCF2O group in compounds possessing
electron-withdrawing groups (EWGs), such as 3a, 3b, and 7e,
and the ready hydrolysis of 3c and 7d may be explained by
fluorine hyperconjugation activating the difluoromethylene
toward reaction with the nucleophilic water to form eventually
the dialkyl carbonates 4c and 8d. The presence of an EWG next
to the OCF2O moiety, even on one side of the molecule as in
7e, decreases the hyperconjugation capability and as a result
increases the stability toward hydrolysis. The slow decomposi-
tion of 3c having a somewhat remote oxygen atom at each side
of the difluoromethylenedioxy group reflects an intermediate
behavior (Scheme 3).
Similarly, the reaction of 1 molar equiv of thiophosgene and
2 molar equiv of 2,2,2-trichloroethanol (1b) in the presence of
triethylamine (Et3N) led to O,O-bis(2,2,2-trichloroethyl)thio-
carbonate (2b)20 in 90% yield. The 1-min reaction of this
thiocarbonate with 1 molar equiv of BrF3 afforded the symmetric
bis(2,2,2-trichloroethoxy)difluoromethane (3b) in 90% yield.
The aliphatic (tetrahydrofuran-2-yl)methanol (1c) was also
converted to the corresponding thiocarbonate (2c) and reacted
with BrF3 to form bis(2-tetrahydrofuranylmethoxy)diflu-
oromethane (3c) in 60% yield. Unlike the two previous
examples, however, 3c was accompanied with 20% of bis(2-
tetrahydrofuranylmethyl)carbonate (4c).21 With time, if no
special precautions were taken, 3c was completely hydrolyzed
to 4c (Scheme 1). It should be noted that certain types of
compounds (see below) were also found to be hydrolytically
sensitive, preventing us from obtaining for them analytically
pure samples.
SCHEME 3. Hydrolysis of Difluoromethylenedioxo
Derivatives with No EWG
(13) (a) Hagooly, A.; Sasson, R.; Rozen, S. J. Org. Chem. 2003, 68, 8287–
8289. (b) Rozen, S.; Ben-David, I. J. Org. Chem. 2001, 66, 496–500. (c) Sasson,
R.; Hagooly, A.; Rozen, S. Org. Lett. 2003, 5, 769–771.
(14) Ben-David, I.; Rechavi, D.; Mishani, E.; Rozen, S. J. Fluorine Chem.
1999, 97, 75–78.
(15) (a) Sasson, R.; Rozen, S. Tetrahedron 2005, 61, 1083–1086. (b) Rozen,
S.; Mishani, E. J. Chem. Soc. Chem. Commun. 1994, 2081–2082. (c) Hagooly,
A.; Rozen, S. Chem. Commun. 2004, 594–595.
The protons released during the hydrolysis process and those
originating from the workup serve as catalyst for the decom-
position by forming a hydrogen bond with the leaving fluo-
rides.24 Indeed when compounds such as 7d were quickly
purified and kept under basic condition (MeOH/NaOMe or
MeOH/Et3N), the hydrolysis was retarded.
(16) Rozen, S. Acc. Chem. Res. 2005, 38, 803–812.
(17) Hagooly, Y.; Sasson, R.; Welch, M. J.; Rozen, S. Eur. J. Org. Chem.
2008, 19, 2875–2880.
(18) Frolov, A. F.; Novikova, G. V. Uch. Zap. Yarosl. Tekhnol. Inst. 1957,
2, 115–127; Chem. Abstr. 1960, 54, 496h.
(19) Rozen, S.; Lerman, O. J. Org. Chem. 1993, 58, 239–240.
(20) Fr. Demande FR 2295038, 1976.
(21) Williams, J. L. R.; Reynolds, D. D.; Dunham, K. R.; Tinker, J. F. J.
Org. Chem. 1959, 24, 64–68.
(22) Fikse, M. A.; Bylund, W. E.; Holubowitch, N. E.; Abelt, C. J. Synthesis
2006, 24, 4118–4120.
(23) Tundo, P.; Rossi, L.; Loris, A. J. Org. Chem. 2005, 70, 2219–2224.
(24) (a) Rozen, S.; Mishani, E. J. Chem. Soc. Chem. Commun. 1993, 1761–
1762. (b) Rozen, S.; Rechavi, D.; Hagooly, A. J. Fluorine Chem. 2001, 111,
161–165. (c) Hagooly, A.; Rozen, S. J. Org. Chem. 2004, 69, 7241–7245.
J. Org. Chem. Vol. 73, No. 17, 2008 6781

Hagooly and Rozen
Aromatic rings in general also prevent easy hydrolysis of the
difluoromethylenedioxo containing compounds. We prepared
2,4-dichlorophenylthioformate (5f),25 reacted it with 3-nitro-
phenol, and formed O-2,4-dichlorophenyl-O-2-nitrophenyl-
thiocarbonate (6f) in 80% overall yield. The consecutive reaction
between 6f and BrF3 resulted in the novel asymmetric 1-di-
fluoro-(2,4-dichloro-(2-nitro-phenoxy)-methoxy)-benzene (7f) in
85% yield, which indeed was hydrolytically stable (Scheme 4).
Aryl-alkyl difluoromethylenedioxy compounds could also be
prepared. O-Methyl-O-3-nitrophenylthiocarbonate (6g) was
made from 3-nitrophenyl chlorothioformate (5g)25 and methanol
followed by reaction with BrF3 to form the novel asymmetric
1-(difluoro(methoxy)methoxy)-3-nitrobenzene (7g) in 85% yield.
It should be noted that the nitro group could be reduced by
NaSH to the corresponding hydrolytically stable 3-(difluo-
ro(methoxy)methoxy)aniline (9g), hinting that any aromatic ring
considerably retards hydrolysis. What is more, compounds of
type 9g can serve as entries to a wide range of new and desirable
molecules.
Using the same approach 11l was prepared from 1,2:5,6-bis-
O-(1-methylethylidene)-D-chiro-inositol (10l) and thiophosgene.
The reaction of 11l with BrF3 led to the formation of the novel
and stable 12l obtained in 90% yield. The specific rotation of
12l may indicate that the reaction with thiophosgene and BrF3
did not affect the chiral centers of the molecule. This notion
was supported by experiments with the chiral shift reagent
Pr(fod)3 revealing only one set of peaks indicating the presence
of only one diastereoisomer.
SCHEME 5. Formation of Alkyl-2,2-difluoro-1,3-dioxolane
Derivatives (12)
SCHEME 4. Formation of Asymmetric Bis(aryloxy/
alcoxy)difluoromethane Derivatives (7f, 7g)
Aromatic difluorodioxole derivatives present in some che-
motherapy drugs5 may also be prepared using BrF3. Involving
both hydroxyl groups in the 1,2-dihydroxy-4-nitrobenzene (10m)
in the reaction with thiophosgene formed the 5-nitrobenzo(1,3)
dioxole-2-thione (11m) in high yield. This thiocarbonate was
reacted with BrF3 to form 2,2-difluoro-5-nitrobenzo(1,3)dioxole
(12m)25 in 85% yield (Scheme 6). The nitro group in 12m could
be reduced to the chemically reactive amine and the stable 2,2-
difluorobenzo(1,3)dioxole-5-amine (14m)25 was obtained in
85% yield.
The present method allows construction of cyclic aliphatic
difluorodioxolanes as well. There are only two compounds of
this type reported in the literature,11 which are sensitive to
hydrolysis resulting in the respective carbonates. This happens
also to the 2,2-difluoro-4-propyl-1,3-dioxolane (12h) prepared
from 11h and BrF3. If not kept strictly anhydrous, 12h quickly
hydrolyzed to O,O-(1,2-pentane)carbonate (13h)26 (Scheme 5).
Similar behavior was noted when 2,2-difluoro-4-(methoxy-
methyl)-1,3-dioxolane (12i) was converted to 4-propyl-1,3-
dioxolan-2-one (13i)25 in 75% yield. With mono chloro
substitution the hydrolysis proved to be much slower, as
demonstrated by 2,2-difluoro-4-(chloromethyl)-1,3-dioxolane
(12j) made from 11j.27 It took a few days for this compound to
be transformed to 4-(chloromethyl)-1,3-dioxolan-2-one (13j)25
in 80% yield (Scheme 5). A full stability was achieved when
bromine atoms were attached at each side of the aliphatic
difluorodioxolane, as demonstrated by 2,2-difluoro-4,5-bis(bro-
momethyl)-1,3-dioxolane (12k) obtained in 90% yield from
11k28 and BrF3. This result emphasizes once again the important
role of EWGs near the difluoromethylenedioxy moiety for the
stability of molecules of this type.
SCHEME 6. Formation of 2,2-Difluoro-5-nitrobenzo(1,3)-
dioxole and 2,2-Difluorobenzo(1,3)dioxole-5-amine (12m,
14m)
In conclusion, this work describes a general method for the
preparation of aromatic and aliphatic symmetric and asymmetric
bis(alkoxy)difluoromethane and difluorodioxolane derivatives.
We hope that the good yields and the moderate reaction
conditions employing BrF3 will further enrich the chemistry
done with this reagent, which for example is extensively used
(25) These compounds are commercially available.
(26) Rybina, G. V.; Srednev, S. S.; Bobyleva, L. I. Russ. J. Appl. Chem.
2003, 76, 842–843.
(27) Kim, C.; Park, M.; Song, B.; Park, K. Bull. Korean Chem. Soc. 2003,
24, 1371–1373.
(28) Weinstein, B.; Orton, E. U.S. Patent 4,525,540, 1985.
6782 J. Org. Chem. Vol. 73, No. 17, 2008

Constructing the OCF2O Moiety Using BrF3
for preparation of anesthetics.29 If handled properly the work
with BrF3 is straightforward and does not require any special
or complicated equipment.
aqueous layer extracted three times with CH2Cl2, and the combined
organic layers were dried over MgSO4. Evaporation of the solvent
followed by flash chromatography yielded the desired fluorinated
compounds. Below, only a couple of detailed examples are shown.
The rest of the materials are described in Supporting Information.
O,O-Bis(2-nitrophenyl)thiocarbonate (2a).18 Prepared from 2-ni-
trophenol (1a) (2 g) as described in the general procedure in 80%
Experimental Section
General Procedure for the Preparation of O,O-Dialkyl/
diarylthiocarbonates Derivatives. A solution of the appropriate
alcohol (20 mmol) and Et3N (2.8 mL, 20 mmol) in 15 mL of THF
was added dropwise to a stirred solution of 0.8 mL of thiophosgene
(10 mmol) in 15 mL of THF at 0 °C. Stirring was continued for 20
min. The precipitated salt was filtered, and the red liquid evaporated
to provide a crude mixture containing the corresponding symmetric
liquid O,O-dialkylthiocarbonates in 70-90% yield. Purification was
performed using flash chromatography, although no attempt was
made to prepare analytically pure samples. As for the preparation
of nonsymmetric O,O-dialkylthiocarbonate derivatives, a larger
excess of thiophosgene (49.8 mmol) was used at 0 °C. The
corresponding alkyl chlorothioformates were usually obtained in
80-90% yield. They were passed through a flash chromatography
column and added to a mixture of 20 mL of the appropriate alcohol
and 3.5 mL of Et3N. After 1 h of stirring at room temperature, the
solvent was evaporated and the desired product purified by flash
chromatography. In the case of aromatic alcohols, NaOH was used
as a base. For the preparation of O,O-alkyl 1,3-dioxolane-2-thiones,
the appropriate alkyl diols (10 mmol) were dissolved in a solution
of 2.9 g of 4-di(methylamino)pyridine (DMAP) (24 mmol) in 20
mL of CHCl3 and added dropwise to a stirred solution of 0.76 mL
of thiophosgene (10 mmol) in 15 mL of CHCl3.30 The reaction
mixture was stirred during 4 h at room temperature. The layers
were separated, and the organic layer washed with saturated
ammonium chloride followed by saturated NaCl solution and dried
over MgSO4. The desired product was separated by flash
chromatography.
1
yield: 1.2 g, red oil; H NMR 8.21 (2 H, dd, J1 ) 8 Hz, J2 ) 1.5
Hz), 7.78 (2 H, td, J1 ) 8 Hz, J2 ) 1.5 Hz), 7.56-7.46 ppm (4 H,
m); 13C NMR 191.8, 146.5, 141.2, 135.8, 128.3, 126.6, 125.9 ppm.
Thiocarbonate of 1,2:5,6-Bis-O-(1-methylethylidene)-D-chiro-ino-
sitol (11l). was prepared from 1,2:5,6-bis-O-(1-methylethylidene)-
D-chiro-inositol (10l) (1.0 g, 4 mmol) as described in the general
procedure in 90% yield: 1.0 g, white crystals; mp 210.8-211.7
1
°C; H NMR 4.63 - 4.58 (4 H, m), 4.31 (2 H, s), 1.53 (6 H, s),
1.38 ppm (6 H, s); 13C NMR 191.4, 111.3, 83.5, 78.5, 74.2, 27.2,
24.7 ppm.
Bis(2-nitrophenoxy)difluoromethane (3a). was prepared from 2a
(980 mg) as described in the general procedure in 80% yield: 1.2 g,
1
yellow crystals, mp 54 °C; H NMR 7.79 (2 H, dd, J1 ) 8 Hz, J2
) 1.5 Hz), 7.55 (2 H, td, J1 ) 8 Hz, J2 ) 1.5 Hz), 7.43-7.27 ppm
(4 H, m); 13C NMR 120.6 (t, J ) 259 Hz), 142.9, 142.0, 134.2,
127.6, 125.8, 124.1 ppm; 19F NMR -55.5 ppm (s); HRMS (ESI-
Qq TOF) m/z calcd for C13H8N2F2NaO6 349.0242 (MNa)+, found
349.0197 (MNa)+. Anal. Calcd for C13H8F2N2O6: C, 47.86; H, 2.47;
N, 8.58. Found: C, 47.83; H, 2.34; N, 8.30.
Difluoromethylation of 1,2:5,6-Bis-O-(1-methylethylidene)-D-
chiro-inositol (12l). was prepared from 11l (1.0 g) as described in
the general procedure in 90% yield (920 mg); white crystals, mp
141-142 °C; 1H NMR 4.53 (2 H, s), 4.46-4.44 (2 H, m),
4.08-4.07 (2 H, m), 1.52 (6 H, s), 1.36 ppm (6 H, s); 13C NMR
131.0 (t, J ) 248 Hz), 111.3, 80.8, 76.7, 74.7, 27.2, 24.6 ppm; 19
F
NMR -57.7 ppm (2 F, s); HRMS (ESI-Qq TOF) m/z calcd for
C13H19F2O6 309.1144 (MH)+, found 309.1161 (MH)+. Anal. Calcd
for C13H18F2O6: C, 50.65; H, 5.89; F, 12.33. Found: C, 50.83; H,
General Procedure for the Preparation of the Difluoro
Derivatives with BrF3. The appropriate thiocarbonate or the (1,3)-
dioxole-2-thione derivatives were dissolved in 20-25 mL of CHCl3
in glass flask and cooled to 0 °C. The best results were achieved
when the reagent (1 molar equiv) BrF3 was dissolved in a few
milliliters of CFCl3, cooled to 0 °C, and added dropwise at the
same temperature using a glass dropping funnel. The reaction
mixture was then washed with aqueous Na2SO3 till colorless. The
5.92; F, 11.96. [R]25 ) -22 (c 0.9, EtOH).
D
Acknowledgment. This work was supported by the USA-
Israel Binational Science Foundation (BSF), Jerusalem, Israel.
Supporting Information Available: Addition experiment
details, NMR’s spectra of all difluoromethylenedioxo derivatives
and their novel precursor described in this work. This material
is available free of charge via the Internet at http://pubs.acs.org.
(29) (a) Rozov, L. A.; Huang, C.; Halpern, D. F.; Vernice, G. G. U.S. Patent
5,283,372, 1994. (b) Rozov, L. A.; Huang, C. G.; Halpern, D. F.; Vernice, G. G.;
Ramig, K. Tetrahedron: Asymmetry 1997, 8, 3023–3025.
(30) Corey, E. J.; Hopkins, B. Tetrahedron Lett. 1982, 23, 1979–1982.
JO801116N
J. Org. Chem. Vol. 73, No. 17, 2008 6783