Preparative-scale synthesis of 3,3,3-trifluoropropene oxide

Article abstract of DOI:10.1016/j.jfluchem.2007.05.018

Bromination of 3,3,3-trifluoropropene in 20% oleum, followed by treatment with acetic acid furnishes 2-bromo-3,3,3-trifluoropropyl acetate in quantitative yield, which upon acid hydrolysis and cyclization with alkali affords 3,3,3-trifluoropropene oxide (TFPO) in 63% overall yield.

Full text of DOI:10.1016/j.jfluchem.2007.05.018

Journal of Fluorine Chemistry 128 (2007) 1255–1259
www.elsevier.com/locate/fluor
Preparative-scale synthesis of 3,3,3-trifluoropropene oxide
*
P. Veeraraghavan Ramachandran , Kamlesh J. Padiya
Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907-2084, United States
Received 6 April 2007; received in revised form 22 May 2007; accepted 28 May 2007
Available online 2 June 2007
Abstract
Bromination of 3,3,3-trifluoropropene in 20% oleum, followed by treatment with acetic acid furnishes 2-bromo-3,3,3-trifluoropropyl acetate in
quantitative yield, which upon acid hydrolysis and cyclization with alkali affords 3,3,3-trifluoropropene oxide (TFPO) in 63% overall yield.
# 2007 Elsevier B.V. All rights reserved.
Keywords: 3,3,3-Trifluoropropene; 3,3,3-Trifluoropropene oxide; Oxirane; Silver acetate; Bromination; Bromoacetoxylation
1. Introduction
2. Results and discussion
Fluorine substitution in organic molecules often influences
the biological properties of medicinal compounds [1] and the
physical properties of several optoelectronic devices [2]. Hence
the development of new synthetic methodologies for the
preparation of fluoroorganic molecules has attracted synthetic
organic chemists [3]. A large number of chiral and achiral
fluorinated building blocks have been recently developed and
used for the synthesis of fluorinated molecules [4]. Among
them, 3,3,3-trifluoropropene oxide (TFPO, 1) is a very versatile
synthetic intermediate (Scheme 1) that has been extensively
utilized in materials and medicinal chemistry [5,6]. For
example, a series of N,N-disubstituted trifluoro-3-amino-2-
propanols were readily prepared from the ring-opening reaction
of 2-trifluoromethyloxirane with the appropriate N-benzylani-
line and examined for reversible inhibition of cholesteryl ester
transfer protein (CETP) [7]. TFPO is also a precursor for
trifluoropropelene carbonate, an electrolyte for lithium
batteries and fuel cells [8].
Reduction of 3-bromo-1,1,1-trifluoroacetone, followed by
cyclization [9] and treatment of trifluoroacetaldehyde with
diazomethane [10] are procedures available for the preparation
of TFPO (Scheme 2). The bromo-acetoxylation of 3,3,3-
trifluoropropene (TFP, 2) using bromine and mercuric acetate,
followed by conversion to the epoxide also has been reported
(Scheme 2) [11]. The toxicity of the mercuric salts is a
drawback for large-scale applications.
The typical procedures for the conversion of olefins to
oxiranes, such as treatment with peracids and hydrogen
peroxide fail to epoxidize perfluoroalkylethylenes [12].
Attempts to prepare the bromohydrin via hypobromous acid
or treatment with bromine and water in the presence of
mercuric acetate also failed in the case of perfluoroalkylethy-
lenes [12]. Coudures et al. have examined the preparation of
perfluoroalkyl oxiranes from perfluoroalkylethylenes (Scheme
3) [12]. They prepared the oxiranes via the hydrolysis of the
corresponding 2-bromo-2-(perfluoroalkyl)ethyl acetate with
NaOH, followed by cyclization with t-BuOK in tetrahydro-
furan. Later, Chaabouni et al. reported the preparation of the
same perfluoroalkyl epoxides from the corresponding 2-bromo-
2-fluoroalkylethanols using caustic soda in the presence of a
phase transfer catalyst (PTC) or using potassium fluoride in
triethylene glycol (Scheme 4) [13]. Both of these reports,
however, did not examine the preparation of 1.
As part of our ongoing projects involving fluoroorganic
chemistry for the preparation of fluoroalkyl carbonates as non-
aqueous electrolytes, we needed large quantities of TFPO.
Following are the details of a preparative-scale synthesis of
TFPO under mild conditions.
Another approach for the synthesis of 1 is via bromoace-
toxylation of 3,3,3-trifluoropropene using N-bromosuccinimide
and acetic acid, followed by treatment with strong alkali
* Corresponding author. Tel.: +1 765 494 5303; fax: +1 765 494 0239.
E-mail address: chandran@purdue.edu (P.V. Ramachandran).
0022-1139/$ – see front matter # 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2007.05.018

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Scheme 1. Synthesis of trifluoromethyl alcohols via the ring-opening of TFPO.
Scheme 2. Procedures for the synthesis TFPO.
(Scheme 5) [14]. A patent describes the preparation of fluoro-
homologs of TFPO via the conversion of fluoroalkenes to
halosulfates with bromine/iodine and sulfuric acid, followed by
acid hydrolysis to the corresponding halohydrin [15]. The
cyclization of the halohydrins to epoxides using a large excess
of molten KOH at 140–150 8C is also included in this patent
(Scheme 6) [15b].
Our approach to prepare TFPO was to employ 2-bromo-
3,3,3-trifluoropropyl acetate (3) for the conversion. Initially, we
attempted the bromoacetoxylation of 3,3,3-trifluoropropene (2)
using a series of metal acetates, such as Cu, Ni, Zn, Mn, Fe, and
Ag acetates and bromine with the aim of replacing the toxic
mercuric acetate. This study led to the identification of AgOAc
as a possible alternative to the toxic Hg(OAc)2 (Eq. (1)).
However, the silver salts are not economical for large-scale
applications. All other metals acetates failed to provide any
meaningful yield of 3:
Optically active TFPO [16] has been prepared by the
enzymatic oxidation of 3,3,3-trifluoropropene using Nocardia
carollina [6c], by the reaction of hexafluoropropylene oxide
involving a lengthy procedure [17], asymmetric reduction of
3-bromo-1,1,1-trifluoroacetone [18], and hydrolytic kinetic
resolution (HKR) of racemic TFPO catalyzed by chiral
(salen)Co(III) complex [19].
(1)
To develop a cost-effective procedure for the synthesis of
2-bromo-3,3,3-trifluoropropyl acetate, we examined the
bromoacetoxylation of trifluoropropene in the presence of
Scheme 4. Preparation of perfluoroalkyl oxiranes from 2-bromo-2-(perfluor-
oalkyl)ethyl acetate.
Scheme 3. Reactions of 2-bromo-2-(perfluoroalkyl)ethyl acetate.

P.V. Ramachandran, K.J. Padiya / Journal of Fluorine Chemistry 128 (2007) 1255–1259
1257
Scheme 5. NBS-mediated preparation of 2-bromo-3,3,3-trifluoropropyl acetate and TFPO.
sulfuric acid. Accordingly, the treatment of trifluoropropene
3. Conclusion
with a mixture of bromine and 20% oleum and subsequent
acidolysis of the intermediate bromosulfate with acetic acid
provided 2-bromo-3,3,3-trifluoropropyl acetate 3 in quantita-
tive (>99%) yield.
In summary, we have developed a simple, practical and
high yielding procedure for the preparation of 3,3,3-
trifluoropropene oxide from the olefin. This procedure
also affords 2-bromo-3,3,3-trifluoropropyl acetate in quanti-
tative yields and 2-bromo-3,3,3-trifluoropropan-1-ol in 90%
yields. The cyclization of the bromohydrin to the oxirane,
under very mild conditions, requires only slight excess of
NaOH. The simple preparation of these derivatives and
TFPO should aid in fluoroorganic synthesis. The preparation
of fluoroalkyl carbonates from TFPO will be reported in due
course.
We then attempted the direct conversion of 3 to the oxirane
as reported. While Coudures and coworkers reported the
formation of only the bromohydrin by treatment of 3 with
NaOH, Leramontov and coworkers have reported the cycliza-
tion with a similar alkali treatment. In our hands, repeated
treatment of 3 with 70% aqueous NaOH resulted in a mixture of
oxirane 1 and bromo-olefin 4 in a 4:1 ratio (Eq. (2)). The
proximity of the boiling points of 1 and 4 made their separation
tedious and impractical. Knunyants and coworkers have
reported the exclusive formation of 4 in 50% yield from 3
by treatment with aqueous KOH at 100 8C [20].
4. Experimental
3,3,3-Trifluoropropene was obtained as a gift from Great
Lakes Chemical Corporation (Chemtura). All other chemicals
1
were purchased from Aldrich Chemical Co. The H, 13C and
19F nuclear magnetic resonance (NMR) spectra were plotted on
a Varian Gemini-300 spectrometer (300, 75 and 282 MHz,
respectively) with a Nalorac-quad probe. 1H NMR spectra were
obtained using CDCl3 as the solvent with either tetramethylsi-
lane (TMS, d: 0 ppm) or chloroform (CHCl3, d: 7.2 ppm) as the
internal standard. 19F NMR spectra were recorded in CDCl3
using CFCl3 as the internal standard. 1H NMR data are reported
as chemical shifts (d ppm), multiplicity (s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet), coupling constant (Hz), and
integration. Chromatography was performed on 40–60 mm
silica gel (230–400 mesh). Mass spectra were recorded using a
Hewlett Packard 5989B mass spectrometer/5890 series II gas
chromatograph or a Finnigan mass spectrometer model 4000.
The chemical ionization gas used was isobutene.
(2)
We then resorted to the synthesis of 1 via the bromohydrin 5.
Having achieved a quantitative yield of 3, we decided to employ
this for the preparation of the bromohydrin. Acid hydrolysis of 3
with 16% aqueous sulfuric acid furnished bromohydrin 5 in 90%
yield. Although the conversion of other fluorinated bromohy-
drins using t-BuOK and molten KOH is known [12,15], we were
interested in utilizing milder conditions for the cyclization. After
examining a variety of experimental conditions, we designed a
protocol wherein 20% aqueous NaOH was added to the
bromohydrin at 85 8C, with the concurrent isolation of the
epoxide 1 exclusively in 70% yield (Eq. (3)). The overall yield of
TFPO was 63% from trifluoropropene:
5. Experimental procedure
5.1. Silver acetate-mediated bromo-acetoxylation of TFP:
preparation of 2-bromo-3,3,3-trifluoropropyl acetate (3)
(3)
Silver acetate (16.6 g, 100 mmol) was suspended in acetic
acid (60 mL) taken in a 100 mL a 3-necked round-bottomed
(RB) flask fitted with an addition funnel, a bubbler (TFP inlet
tube) and a dry-ice condenser. 3,3,3-Trifluoropropene (9.6 g,
100 mmol) was bubbled through the AgOAc suspension.
Bromine (8.0 g) was added simultaneously. When all of the
TFP has been added, the solution turned greenish yellow. The
reaction mixture was then stirred for 1 h and filtered. The
greenish yellow precipitate of AgBr was washed with
dichloromethane and washed with 60 mL of water. The
Scheme 6. Preparation of 2-bromo-3,3,3-trifluoropropyl sulfate.

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P.V. Ramachandran, K.J. Padiya / Journal of Fluorine Chemistry 128 (2007) 1255–1259
combined filtrate was washed with NaHCO3, dried over
anhydrous Na2SO4 and evaporated to yield 7.0 g (60%) of 2-
bromo-3,3,3-trifluoropropyl acetate.
1H NMR (CDCl3, 300 MHz), d ppm: 2.12 (s, 3H), 4. 34–4.56
(m, 3H). 19F NMR; (CDCl3, 282 MHz), d ppm: À7.95 (d,
J = 6.4 Hz).
5.5. Preparation of 3,3,3-trifluoropropene oxide (1)
The bromohydrin (130 g, 0.67 mol) prepared as above was
taken in a 1 L three-necked RB flask fitted with a septum, a
thermometer jacket and a distillation set up and heated, while
stirring, to 85 8C (oil bath temperature 95 8C). Aqueous NaOH
(20%, 200 g) was introduced through the septum via a syringe
and the oxirane 1 was distilled out simultaneously as a colorless
liquid. bp 39–40 8C (Ref. [9]: 39.1–39.3 8C). Yield: 52.7 g
(0.47 mol, 70.2%).
5.2. Oleum-mediated bromo-acetoxylation of TFP:
preparation of 2-bromo-3,3,3-trifluoropropyl acetate
TFP (96 g, 1.0 mol) was bubbled through a mixture of
oleum (800 g) and Br2 (160 g, 1.0 mol) at RT. The rate of
addition of TFP was adjusted such that the temperature of the
reaction mixture was maintained within 12–22 8C. The
mixture was left stirred for 1 h and poured to 1.6 L of acetic
acid and heated with stirring at 100 8C for 1 h. Five hundred
milliliters of water was then added at RT and extracted with
dichloromethane (3Â 500 mL, Caution: dichloromethane
forms the upper layer). The combined organic layers were
washed with saturated NaHCO3, dried over anhydrous Na2SO4
and evaporated to yield 234 g (99.6%) of 2-bromo-3,3,3-
trifluropropyl acetate (3) as a colorless liquid. bp 45–47 8C/
1H NMR (300 MHz, CDCl3), d ppm: 3.38–3.46 (m, 1H),
2.96–3.02 (m, 1H), 2.90–2.94 (m, 1H); 13C NMR (75.5 MHz,
CDCl3), d ppm: 124.5, 120.9, 48.3 (q, J = 41.5 Hz); 19F NMR
(282 MHz, CDCl3), d ppm: À12.62 (d, J = 6.1 Hz).
Acknowledgement
We gratefully acknowledge Chemtura for financial support
and the gift of 3,3,3-trifluoropropene for this research.
References
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