Synthesis of α-trifluoromethyl-α-hydroxycarboxylate dervatives and their phosphorus-containing analogs with the use of fluorinated diazo compounds

Article abstract of DOI:10.1134/S1070428010050015

Approach was developed underlain by the use of fluorinated diazocompounds to the synthesis of derivatives of α-trifluoromethyl-α- hydroxycarboxylic acids and their phosphorus-containing analogs, α-trifluoromethyl-α-hydroxyphosphonic acids. Methyl 2-diazo-3,3,3-trifluoropropionate and diethyl 1-diazo-2,2,2- trifluoroethylphosphonate under the action of catalytic quantities of dirhodium tetraacetate Rh₂(OAc)₄ easily inserted into the O-H bond leading to the formation of the corresponding products in high yields. Pleiades Publishing, Ltd., 2010.

Full text of DOI:10.1134/S1070428010050015

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 5, pp. 619−623. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © I.D. Titanyuk, D.V. Vorob’eva, S.N. Osipov, I.P. Beletskaya, 2010, published in Zhurnal Organicheskoi Khimii, 2010,
Vol. 46, No. 5, pp. 631−635.
Synthesis of α-Trifluoromethyl-α-hydroxycarboxylate
Dervatives and Their Phosphorus-ContainingAnalogs
with the Use of Fluorinated Diazo Compounds
I. D. Titanyuka, D. V. Vorob’evab, S. N. Osipovb, and I. P. Beletskayaa
aLomonosov Moscow State University, Moscow, 119992 Russia
e-mail: i-titan@yandex.ru
bNesmeyanov Institute of Organoelemental Compounds,
Russian Academy of Sciences, Moscow
Received January 11, 2009
Abstract—Approach was developed underlain by the use of fluorinated diazocompounds to the synthesis of
derivatives of α-trifluoromethyl-α-hydroxycarboxylic acids and their phosphorus-containing analogs, α-
trifluoromethyl-α-hydroxyphosphonic acids. Methyl 2-diazo-3,3,3-trifluoropropionate and diethyl 1-diazo-2,2,2-
trifluoroethylphosphonate under the action of catalytic quantities of dirhodium tetraacetate Rh2(OAc)4 easily
inserted into the O–H bond leading to the formation of the corresponding products in high yields.
DOI: 10.1134/S1070428010050015
this class are haptenes in the enzyme-catalyzed formation
of antibodies, they also exhibit activity as inhibitors of
various proteolytic enzymes, wide range of physiological
activity, in particular, antibacterial and antitumor ones [6].
The introduction of fluorine or fluoroalkyl moieties into
molecules of biologically active compounds is an
important process in the development of new efficient
drugs [1–4]. A special attention is attracted by the
synthesis of trifluoromethyl-containing derivatives due to
the unique properties of the trifluoromethyl group
(hydrophobic character, high electronegativity, steric bulk)
positively affecting the transport characteristics of the
potential drugs. Besides the presence of a fluorine atom
provides a possibility of monitoring the chemical
surrounding of the fluorine-containing groups, of the
conformational analysis, and of the study of metabolic
processes by 19F NMR spectroscopy. These unique
features facilitated the fast development of the chemistry
of biologically active organofluorine compounds, in
particular, fluorinated α-hydroxy acids and their
derivatives.
The phosphonic group (PO32–) is the common structural
fragment for a wide range of biologically active
compounds and pharmaceuticals. Phosphonic acids and
their derivatives are important analogs of the
corresponding carboxylic acids. Their synthesis and
biological activity is in the center of the interest of organic
and pharmaceutical chemistry [5]. Many compounds of
It was shown previously that the simultaneous
introduction of the trifluoromethyl and carboxylate or
dialkylphosphonate groups was easily performed with the
help of the corresponding trifluoromethylated carbenes,
..
..
like CF3CO2R [7] or CF3CP(O)(OR)2 [8]. The carbenes
were formed from the appropriate diazo compounds under
the action of catalytic quantities of derivatives of transition
metals.
Isolated instances were published concerning the
application of methyl-2-diazo-3,3,3-trifluoropropionate (I)
to the insertion into the O–H bond by examples of amino
acids [9] and phenol [10]. We considerably extended the
applicability of this reaction bringing into this process
various classes of hydroxyl-containing substrates, like
carboxylic acids, aliphatic alcohols, phenols, and
substituted amino acids. The chemical process was
carried out with the catalysis by Rh2(OAc)4 (2–3 mol%).
This catalyst is widely used in the chemistry of diazo
compounds for it makes it possible to perform the
reactions under mild conditions providing a high yield of
619

TITANYUK et al.
Table (Contd.)
620
Scheme 1.
O
O
ROH, 1 mol%
Rh2(OAc)4
CF3
CF3
OMe
OMe
Benzene, Δ
N2
OR
IIа_IId
I
V
V
V
R = Bz (a), Ph (b), Bn (c), PhtNCH(s-Bu)C(O) (d).
Scheme 2.
(1) CbzNH2, MS 5
(2) TFAA_Py
O
(3) HP(O)(OEt)2,
OEt
OEt
F3C
P
F3C
OH Me3SiCl
NHCbz
OEt
III, 75%
O
P
O
P
OEt
OEt
OEt
OEt
H2, Pd/C
MeOH
F3C
F3C
i-PrONO
CHCl3
V
V
NH2
N2
IV, 100%
V, 70%
Products of insertion into O–H bond of diazo compounds I
and V
10
11
V
the final products. In all studied cases we isolated insertion
products IIa–IId in high yields (see Scheme 1, Table,
runs nos. 1–4).
I
We formerly prepared a phosphorus analog of
compound I, diethyl 1-diazo-2,2,2-trifluorophosphonate
(V), the first representative of fluorinated α-diazophos-
phonates [8]. We report here on the complete procedure
of its synthesis. The method includes four simple stages:
(1) The condensation of commercially available
trifluoroacetic aldehyde ethylhemiacetal with benzyl
carbamate; (2) diethyl phosphite addition to formed in
situ fluoral N-benzyloxycarbonylimine in the presence of
trimethylchlorosilane; (3) removal of Cbz-protection from
diethyl aminophosphonate III in conditions of catalytic
hydrogenation; (4) diazotization of α-aminophosphonate
(IV) with isopropyl nitrite (Scheme 2).
I
I
V
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SYNTHESIS OF α-TRIFLUOROMETHYL-α-HYDROXYCARBOXYLATE DERVATIVES
621
In developing the key diazotization stage we tested
the classic procedures like the treatment of compound
IV with sodium nitrite in various mineral acids
(hydrochloric, sulfuric) or in acetic acid. However in all
studied events the yield of the target diazo compound did
not exceed 25%. The best result was obtained by treating
aminophosphonate IV with isopropyl nitrite. In this case
we isolated trifluoromethyldiazophosphonate V in the
analytically pure state in 70% yield. The product turned
out to be stable light-yellow liquid boiling at 47–50°C
(1 mm Hg). The developed synthesis of the new diazo
compound was successfully scaled to 50 g.
carried out on silica gel Merck 60 (230–400 mesh
ASTM).
Synthesis of Diethyl 1-diazo-2,2,2-trifluoro-
ethylphosphonate
1-(Benzyloxycarbonylamino)-2,2,2-trifluoro-
ethanol [11]. To a solution of 20 g (132 mmol) of benzyl
carbamate, 21 g (146 mmol) of trifluoroacetaldehyde
ethylhemiacetal, and 6.6 g (61 mmol) of triethylamine in
200 ml of anhydrous CH2Cl2 was added 100 g of
molecular sieves 5 A, and the reaction mixture was left
standing at room temperature for 14 days. Then 100 ml
of ethyl acetate was added, the molecular sieves were
filtered off and thoroughly washed with ethyl acetate.
The organic solutions were combined, the solvent was
evaporated, the residue was recrystallized from CH2Cl2.
Yield 29 g (88%), colorless crystals. 1H NMR spectrum
(CD3CN), δ, ppm: 5.1 s (2H), 5.45–5.55 m (1H), 5.88–
5.93 m (1H), 7.3 m (5H). 19F NMR spectrum CD3CN),
δ, ppm: –4.5. The spectral data are in agreement with
those formerly published [11].
In the course of further research we found that diazo
compound V readily reacted with alcohols and carboxylic
acids. The reaction completed within 5–10 h at boiling in
benzene in the presence of catalytic quantities (1–
3 mol%) of Rh2(OAc)4 giving the corresponding products
of insertion into the O–H bond VI in good yields (see
Scheme 3, Table, runs nos. 5–11). The character of R
substituent insignificantly affects the process.
The product of insertion in O–H bond of the trifluoro-
acetic acid VIe (see Table, run no. 9) proved to be
hydrolytically unstable; during the purification by column
chromatography it lost the trifluoroacyl group and
converted into the corresponding 2-hydroxy-3,3,3-
trifluoroethylphosphonate.
Diethyl {1-[(benzyloxycarbonyl)amino]-2,2,2-
trifluoroethyl}phosphonate (III) [12]. To a solution
of 26 g(105 mmol)of the above prepared hemiaminal in
200 ml of anhydrous pyridine at –20°C was added 24.1 g
(114 mmol) of trifluoroacetic anhydride. While maintaining
the temperature of the reaction mixture at –20°C
a solution was added of 28.8 g (209 mmol) of diethyl
phosphite in 200 ml of CH2Cl2, and then was added
dropwise 45.3 g (417 mmol) of trimethylchlorosilane. The
mixture was gradually warmed to room temperature and
left overnight at this temperature. The solution obtained
was washed with 10% HCl for pyridine removal, then
with saturated solution of NaHCO3, and dried with
MgSO4. The solvent was evaporated, the residue was
recrystallized from the mixture petroleum ether–ethyl
acetate, 9:1 v/v. Yield 32.4 g (84%), colorless crystals,
mp 53.5–56°C. 1H NMR spectrum (CDCl3), δ, ppm:
Hence we developed a simple preparative method for
the synthesis of derivatives of α-CF3-substituted
hydroxycarboxylates and hydroxyphosphonates by the
reaction of α-CF3-substituted diazocarboxylate I and
diazophosphonate V under the catalysis with Rh2(OAc)4.
A wide range of OH-containing substrates was brought
into the reaction: alcohols, phenols, carboxylic acids, and
substituted amino acids, and the corresponding insertion
products were obtained in good yields.
EXPERIMENTAL
NMR spectra were registered on spectrometers
Bruker AV-300 and AV-400 at operating frequencies
300 and 400 (1H), 75 and 100 (13C), 288 and 376 MHz
(19F) (internal reference CFCl3); 121.5 and 162 MHz
(31P) (external reference H3PO4). All solvents used in
the reactions were dried with appropriate drying agents.
The reaction progress was monitored by TLC on plates
with silica gel Merck 60 F254. Spots were visualized by
UV irradiation or by treating with cerium molibdate in
5% H2SO4 solution. The column chromatography was
Scheme 3.
O
P
O
P
ROH, 1 mol%
Rh2(OAc)4
OEt
OEt
OEt
OEt
CF3
CF3
Benzene, D
N2
OR
VIa_VIg
V
R = Me (a), Et (b), Bz (c),Ac (d), CF3C(O) (e),
BocNHCH(Bn)C(O) (f), Ph (g).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 5 2010

TITANYUK et al.
622
ppm: 3.91 s (3H), 5.74 q (1H, 2J 6.7 Hz), 7.51 t (2H,
2J 8.0 Hz), 7.67 t (1H, 2J 8.0 Hz), 8.14 d (2H, 2J 8.0 Hz).
19F NMR spectrum (CDCl3), δ, ppm: 4.8 s. Found, %:
C 50.45; H 3.50. C11H9F3O4. Calculated, %: C 50.39;
H 3.46.
1.25–1.45 m (6H), 4.1–4.3 m (4H), 4.7–4.9 m (1H), 5.2 d
2
2
(2H, J 12.1 Hz), 6.12 d (1H, J 2 Hz), 7.4 m (5H).
19F NMR spectrum (CDCl3), δ, ppm: 8.2 t (JFP 7.6 Hz).
31P NMR spectrum (CDCl3), δ, ppm: 13.2 q (JFP 6 Hz).
The spectral data are in agreement with those formerly
published [11].
Methyl 2-phenoxy-3,3,3-trifluoropropanoate
1
(IIb). Oily substance. H NMR spectrum (CDCl3), δ,
Diethyl (1-amino-2,2,2-trifluoroethyl)phos-
phonate (IV). To a solution of 31 g (83 mmol) of
benzyloxycarbonyl-substituted aminophosphonate III in
methanol was added 2 g 10% Pd/C, and a weak flow of
hydrogen was bubbled through the solution at room
temperature. After the disappearance of the initial
compound (TLC monitoring) (~12 h) the mixture was
filtered, and the solvent was distilled off. The obtained
oily substance was pure according to NMR data, and
was used in the next study without additional purification.
Yield 19.6 g (100%). 1H NMR spectrum (CDCl3), δ,
ppm: 1.37 t (6H, 2J 7.1 Hz), 2.76 br.s (2H), 3.61 m (1H),
4.18–4.31 m (4H). 19F NMR spectrum (CDCl3), δ, ppm:
6.2 t (JFP 7.8 Hz). 31P NMR spectrum (CDCl3), δ, ppm:
16.5 q (JFP 7.4 Hz).
ppm: 3.90 s (3H), 5.03 q (1H, 2J 6.8 Hz), 6.97 d (2H,
2J 8.0 Hz), 7.12 t (1H, 2J 6.0 Hz), 7.35 d.t (2H, 2J1 8.0,
2J2 6.0 Hz). 19F NMR spectrum (CDCl3), δ, ppm: 3.7 s.
Found, %: C 59.42; H 3.82. C10H9F3O3. Calculated, %:
C 59.29; H 3.87.
Methyl 2-benzyloxy-3,3,3-trifluoropropanoate
1
(IIc). Oily substance. H NMR spectrum (CDCl3), δ,
ppm: 3.85 s (3H), 4.35 q (1H, 2J 6.7 Hz), 4.72 d (1H,
2J 12.0 Hz), 4.85 d (1H, 2J 12.0 Hz), 7.40 s (5H). 19F NMR
spectrum (CDCl3), δ, ppm: 3.8 s. Found, %: C 53.25;
H 4.50. C11H11F3O3. Calculated, %: C 53.23; H 4.47.
1-(Methoxycarbonyl)-2,2,2-trifluoroethyl-N-
phthaloyl-L-isoleucinate (IId) was obtained as a mix-
ture of diastereomers which was separated by column
chromatography.
Diethyl (1-diazo-2,2,2-trifluoroethyl)phos-
phonate (V). To a solution of 19.6 g (83 mmol) of
aminophosphonate IV in 300 ml of anhydrous chloroform
was added dropwise 9.5 g (106 mmol) of isopropyl nitrite
at vigorous stirring within 30 min. After adding about
a half of the isopropyl nitrite the reaction mixture self-
heated to boiling. After the end of addition the stirring
was continued for another 30 min, and the temperature
decreased to ambient. The solvent was evaporated on
a rotary evaporator, the reaction product was distilled in
a vacuum. Yield 13.6 g (70%). Yellow liquid, bp 47–50°C
(1 mm Hg). IR spectrum (KBr), ν, cm–1: 2160, 1150.
1H NMR spectrum (CDCl3), δ, ppm: 1.40 t (6H,
2J 7.1 Hz), 4.15–4.30 m (4H). 13C NMR spectrum
(CDCl3), δ, ppm: 15.9, 63.6, 118.6 m, 124.1 d.q (JCF 271.0,
JCP 12.1 Hz). 19F NMR spectrum (CDCl3), δ, ppm: 23.0.
31P (CDCl3), δ, ppm: 9.23.
Insertion into O–H bond catalyzed with
Rh2(OAc)4. General procedure. To a solution of 1.0 mmol
of diazo compound I or V in 3 ml of anhydrous benzene
was added 1.0–1.5 mmol of hydroxyl-containing
compound and 1 mol% of dirhodium tetraacetate. The
mixture was boiled for 3–5 h (TLC monitoring), thereafter
the solvent was distilled off on a rotary evaporator. The
residue was subjected to chromatography on silica gel
(eluent ethyl acetate–petroleum ether, 1:5 v/v).
Diastereomer A. Oily substance, [α]D25 –13.4°
1
(c 1.37, CHCl3). H NMR spectrum (CDCl3), δ, ppm:
2
0.89 t (3H, CH3, J 7.2 Hz), 1.09 m (1H, CH2), 1.15 d
2
(3H, CH3, J 7.9 Hz), 1.59 m (1H, CH2), 2.58 m (1H,
2
CH), 3.85 s (3H, OCH3), 4.85 d (1H, CHN, J 8.1 Hz),
5.41 q (1H, CHCF3, 2J 6.9 Hz), 7.76 m (2Harom), 7.88 m
(2Harom). 19F NMR spectrum (CDCl3), δ, ppm: 4.78.
Mass spectrum: m/z 401 [M]+.
Diastereomer B. Oily substance, [α]D25 –3.5° (c 0.86,
CHCl3). 1H NMR spectrum (CDCl3), δ, ppm: 0.87 t (3H,
CH3, 2J 7.4 Hz), 1.07 m (1H, CH2), 1.14 d (3H, CH3,
2J 6.8 Hz), 1.60 m (1H, CH2), 2.62 m (1H, CH), 3.75 s
2
(3H, OCH3), 4.83 d (1H, CHN, J 8.7 Hz), 5.56 q (1H,
2
CHCF3, J 7.2 Hz), 7.77 m (2Harom), 7.90 m (2Harom).
19F NMR spectrum (CDCl3), δ, ppm: 4.88. Found, %:
C 52.32; H 4.89; N 3.69. C17H18F3NO6. Calculated, %:
C 52.44; H 4.62; N 3.60.
Diethyl (1-methoxy-2,2,2-trifluoroethyl)phos-
1
phonate (VIa). Oily substance. H NMR spectrum
2
(CDCl3), δ, ppm: 1.38 t (6H, J 7.0 Hz), 3.65 s (3H),
3.78–3.9 m (1H), 4.2–4.3 m (4H). 19F NMR spectrum
(CDCl3), δ, ppm: 6.7 t (JFP 8.5 Hz). 31P NMR spectrum
(CDCl3), δ, ppm: 11.8 q (JFP 8.9 Hz). Found, %: C 33.75;
H 5.75. C7H14F3O4P. Calculated, %: C 33.61; H 5.64.
Methyl 2-benzoyloxy-3,3,3-trifluoropropanoate
(IIa). Oily substance. H NMR spectrum (CDCl3), δ,
Diethyl (2,2,2-trifluoro-1-ethoxyethyl)phos-
phonate (VIb). Oily substance. H NMR spectrum
1
1
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SYNTHESIS OF α-TRIFLUOROMETHYL-α-HYDROXYCARBOXYLATE DERVATIVES
623
(CDCl3), δ, ppm: 1.28 t (2J 7.1 Hz), 1.38 t (6H, 2J 7.1 Hz),
4.88–5.0 m (1H), 7.05–7.15 m (3H), 7.4–7.5 m (2H).
19F NMR spectrum (CDCl3), δ, ppm: 7.10 t (JFP 8.2 Hz).
31P NMR spectrum (CDCl3), δ, ppm: 10.6 q (JFP 8.9 Hz).
Found, %: C 46.27; H 5.21. C12H16F3O4P. Calculated,
%: C 46.16; H 5.17.
The study was carried out under a financial support
of the Russian Foundation for Basic Research (grant
no. 07-03-00833).
2
3.83 q (2H, J 7.1 Hz), 3.86–4.0 m (1H), 4.17–4.3 m
(4H). 19F NMR spectrum (CDCl3), δ, ppm: 6.55 t
(JFP 8.5 Hz). 31P NMR spectrum (CDCl3), δ, ppm: 12.0 q
(JFP 8.9 Hz). Found, %: C 36.50; H 6.15. C8H16F3O4P.
Calculated, %: C 36.37; H 6.10.
Diethyl (2,2,2-trifluoro-1-benzoyloxyethyl)-
phosphonate (VIc). Oily substance. 1H NMR spectrum
(CDCl3), δ, ppm: 1.35 d.t (6H, 2J1 1.8, 2J2 7.1 Hz), 4.15–
4.31 m (4H), 5.88–6.0 m (1H), 7.48–7.58 m (2H), 7.63–
7.73 m (1H), 8.12–8.19 m (2H). 19F NMR spectrum
(CDCl3), δ, ppm: 6.6 t (JFP 7.4 Hz). 31P NMR spectrum
(CDCl3), δ, ppm: 9.7 q (JFP 7.4 Hz). Found, %: C 46.07;
H 4.81. C13H16F3O5P. Calculated, %: C 45.89; H 4.74.
Diethyl (2,2,2-trifluoro-1-acetoxyethyl)phos-
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1
phonate (VId). Oily substance. H NMR spectrum
(CDCl3), δ, ppm: 1.40 d.t (6H, 2J1 2.7, 2J2 7.1 Hz), 2.23 s
(3H), 4.20–4.32 m (4H), 5.65–5.8 m (1H). 19F NMR
spectrum (CDCl3), δ, ppm: 7.2. 31P NMR spectrum
(CDCl3), δ, ppm: 9.8 q (JFP 7.4 Hz). Found, %: C 34.62;
H 5.11. C8H14F3O5P. Calculated, %: C 34.54; H 5.07.
Diethyl [2,2,2-trifluoro-1-(trifluoroacetyloxy)-
ethyl]phosphonate (VIe). Yield 86% as shown by
1
1H NMR spectrum. H NMR spectrum (CDCl3), δ, ppm:
1.45 t (6H, 2J 7.1 Hz), 4.25–4.45 m (4H), 5.75–5.85 m
(1H). 19F NMR spectrum (CDCl3), δ, ppm: 7.3 t
(JFP 7.1 Hz), 3.25 C (3H). 31P NMR spectrum (CDCl3),
δ, ppm: 6.6.
2,2,2-Trifluoro-1-(diethoxyphosphoryl)ethyl-N-
(tert-butoxycarbonyl)-L-phenylalaninate (VIf). Oily
substance. Diastereomers mixture in the ratio 1:1.
1H NMR spectrum (CDCl3), δ, ppm: 1.35–1.45 m (6H),
1.45 s (9H), 3.1 d.d.d (1H, 2J1 4.1, 2J2 6.4, 2J3 14.0 Hz),
2
2
3.28 d.t (1H, J1 5.5, J2 14.0 Hz), 4.20–4.37 m (4H),
4.78 m (1H), 4.98 m (1H), 5.68–5.83 m (1H), 7.20–7.30
m (2H), 7.30–7.41 m (3H). 19F NMR spectrum (CDCl3),
δ, ppm: 7.63 t (JFP 7.3 Hz), 7.84 t (JFP 7.3 Hz), 1:1.
31P NMR spectrum (CDCl3), δ, ppm: 8.7 q (JFP 7.4 Hz),
9.3 q (JFP 7.4 Hz). Found, %: C 49.51; H 6.21; N 2.75.
C20H29F3NO7P. Calculated, %: C 49.70; H 6.00; N 2.90.
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Diethyl (1-phenoxy-2,2,2-trifluoroethyl)phos-
phonate (VIg). Oily substance. H NMR spectrum
(CDCl3), δ, ppm: 1.40 t (6H, 2J 7.1 Hz), 4.2–4.4 m (4H),
1
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 5 2010