Phosphorylated trifluoroethanols
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
103
presence of Et3N as a catalyst, which leads to phosphoꢀ
nates 3a and 3b (it should be noted that, according to
the 31P NMR spectral data of the reaction mixture, no
Cꢀphosphorylated products are formed upon prolonged
(20 h) reflux of an equimolar mixture of reactants in toluꢀ
ene if the base is absent). A possibility of the phosphonateꢀ
phosphate rearrangement is determined by electronꢀwithꢀ
drawing properties of a substituent on the carbon atom in
the αꢀposition. Thus no phosphonate—phosphate rearꢀ
rangement product 3a, i.e., the corresponding phosphate,
has been detected by us after prolonged (10 h) reflux
of phosphonate 3a either in toluene with Et3N or in DMF
in the presence of CsF. Unlike 3a, the Cꢀphosphorylaꢀ
tion product of trifluoroacetophenone 3b upon reflux
for 3 h in toluene in the presence of Et3N in catalytic
amounts was converted to phosphate 4a, which was isoꢀ
lated in 69% yield (isolation by chromatography yielded
88% of 4a).8
In contrast to trifluoroacetone (2a) and trifluoroaceꢀ
tophenone (2b), hexafluoroacetone (2c) and methyl trifluꢀ
oropyruvate (2d) react exothermically with dimethyl phosꢀ
phite (1a) in the absence of basic catalysis to form a mixꢀ
ture of phosphonate 3c and phosphate 5a (1 : 4) (in Ref. 9,
this ratio was found to be 6 : 94) and phosphonate 3d and
phosphate 6a (1 : 3), respectively. The ratio of products
was determined based on the 31P NMR spectra of the
reaction mixtures. The signals in the 31P NMR spectra of
compounds studied (the Abramov reaction and subsequent
phosphonate—phosphate rearrangement) allowed broadꢀ
ening the synthetic scope of the method under considerꢀ
ation for the preparation of Oꢀphosphorylated 1ꢀsubstiꢀ
tuted 2,2ꢀtrifluoroethanols, which is determined by elecꢀ
tronꢀwithdrawing properties of the αꢀsubstituent in
the trifluoromethyl carbonyl component and, first of all,
by the possibility of the phosphonate—phosphate rearranꢀ
gement of the Abramov reaction product, i.e., phosꢀ
phonate. The presence of an electronꢀwithdrawing subꢀ
stituent on the αꢀC atom of trifluoromethyl ketones is
a decisive prerequisite for the phosphonate—phosphate reꢀ
arrangement.
Experimental
1
H, 19F, 13C, and 31P NMR spectra were recorded on
a Bruker DXP 200 spectrometer (200.13, 188.29, 50.32, and
81.01 MHz, respectively) with tetramethylsilane as an internal
standard, and CF3COOH and 85% aqueous H3PO4 as external
standards.
O,OꢀDimethyl 2,2,2ꢀtrifluoroꢀ1ꢀhydroxyꢀ1ꢀmethylethylꢀ
phosphonate (3a). A solution of trifluoroacetone (2a) (5.0 g,
44.6 mmol), dimethyl phosphite (1a) (4.5 g, 40.9 mmol), and
triethylamine (0.2 g) in benzene (20 mL) was kept for 1 day in
a sealed tube at room temperature, benzene was evaporated, and
the residue was fractionally distilled to yield phosphonate 3a
(4.2 g, 45%), b.p. 90—93 °C (3 Torr), m.p. 47—49 °C.
O,OꢀDimethyl 2,2,2ꢀtrifluoroꢀ1ꢀhydroxyꢀ1ꢀphenylethylphosꢀ
phonate (3b). A solution of trifluoroacetophenone (2b) (1.0 g,
6.2 mmol), dimethyl phosphite (1a) (0.68 g, 6.2 mmol), and
triethylamine (0.2 g) in benzene (10 mL) was kept for 1 day at
room temperature, benzene was evaporated, and the residue was
recrystallized from hexane to yield phosphonate 3b (0.5 g, 30%),
m.p. 138—140 °C.
3c (δ 15.34 sept, JP,F = 3.3 Hz) and 3d (δ 16.23 q, JP,F
=
= 3.4 Hz) are in the region characteristic of phosphonates
with the corresponding spinꢀspin coupling constants
JP,F = 3.3 Hz, the signals in the spectra of 5a (δ 1.03 s) and
6a (δ 1.02 s) indicate their phosphate structure. In the
presence of Et3N, the reaction of 1a with 2c and methyl
trifluoropyruvate 2d leads (according to the 31P NMR
spectra of the reaction mixtures) to phosphates 5a and 6a
in virtually quantitative yields. Phosphates 5b and 6b—j
were obtained similarly.
Phosphates 4—6, obtained in 58—90% yields, are colꢀ
orless light liquids, their composition and structures are
established based on data from elemental analysis and 1H,
19F, and 31P NMR spectra. Thus the 31P NMR spectra
exhibit signals in the region δ from –3 to 2, which confirm
the phosphate nature of compounds 4—6.
The inhibitory activity of phosphates 4—6 with respect
to serine esterases enhances with the increase in the elecꢀ
tronꢀwithdrawing properties of αꢀsubstituents in trifluoroꢀ
ethoxy leaving group in the order 4 < 5 < 6; these data will
be published elsewhere. The data from biochemical studꢀ
ies of phosphates 4—6 are in good enough agreement with
the known concepts,10 including those published by us
earlier4,5,11,12 on the optimization of the leaving group
structure in the molecules of organophosphorus serine esꢀ
terase inhibitors.
The yields, boiling points, and spectral characteristics of
phosphonates 3a,b are given in Tables 1 and 2.
O,OꢀDimethyl Oꢀ(2,2,2ꢀtrifluoroꢀ1ꢀphenylethyl) phosphate
(4a). A solution of trifluoroacetophenone (2b) (2 g, 11.5 mmol),
dimethyl phosphite (1a) (1.3 g, 11.8 mmol), and triethylamine
(0.2 g) in toluene (10 mL) was refluxed for 3 h, toluene was
evaporated, the residue was fractionally distilled to yield phosꢀ
phate 4a (2.3 g, 69%). 13C NMR (CDCl3), δ: 55.00 (d, MeO,
JC,P = 5.8 Hz); 55.79 (d, MeO, JC,P = 5.8 Hz); 76.68 (dq, CCF3,
JC,P = 4.3 Hz, JC,F = 33.9 Hz), 123.31 (dq, CF3, JC,F = 280.6 Hz,
JC,P = 9.7 Hz); 128.27 (q, oꢀPh, JC,F = 1.0 Hz); 129.11 (s, mꢀPh);
130.63 (s, pꢀPh); 131.55 (m, ipsoꢀPh).
O,OꢀDialkyl Oꢀ(2,2,2ꢀtrifluoroꢀ1ꢀphenylethyl) phosphaꢀ
tes (4b—j) were obtained similarly to phosphate 4a from dialꢀ
kyl phosphites 1b—j (10.5 mmol), trifluoroacetophenone 2b
(10.5 mmol), and Et3N (0.2 g). The yields, boiling points,
and spectral characteristics of phosphates 4a—j are given in Taꢀ
bles 1 and 2.
O,OꢀDimethyl Oꢀ(1,1,1,3,3,3ꢀhexafluoropropanꢀ2ꢀyl) phosꢀ
phate (5a). A solution of dimethyl phosphite (1a) (3.0 g, 27.3 mmol),
hexafluoroacetone (2c) (5.5 g, 33.1 mmol), and Et3N (0.2 g) in
THF (10 mL) was kept for 1 day in a sealed tube at room temperꢀ
ature, the solvent was evaporated, and the residue was fractionꢀ
ally distilled to obtain phosphate 5a (6.0 g, 80%).
In conclusion, the synthetic potential of the twoꢀstep
reaction of phosphites with αꢀtrifluoromethyl carbonyl