New β-amino-α-trifluoromethyl alcohols and their exploration in the synthesis of trifluoromethylated imidazole derivatives

Article abstract of DOI:10.1016/j.jfluchem.2011.07.016

Racemic and enantiomerically pure β-amino-α-trifluoromethyl alcohols were obtained via sequential nucleophilic trifluoromethylation of selected α-imino ketones, derived from arylglyoxals, and subsequent removal of the MeO or Ph(Me)CH substituent, respecti

Full text of DOI:10.1016/j.jfluchem.2011.07.016

Journal of Fluorine Chemistry 132 (2011) 951–955
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
New
b
-amino-
a
-trifluoromethyl alcohols and their exploration in the
synthesis of trifluoromethylated imidazole derivatives
a,
Grzegorz Mloston , Emilia Obijalska a, ,1, Heinz Heimgartner b
*
*
´
a
´
´
´
Department of Organic and Applied Chemistry, University of Ło´dz, Tamka 12, PL-91-403 Łodz, Poland
b Institute of Organic Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
A R T I C L E I N F O
A B S T R A C T
Article history:
Racemic and enantiomerically pure
b
-amino-
a
-trifluoromethyl alcohols were obtained via sequential
-imino ketones, derived from arylglyoxals, and
Received 24 June 2011
Received in revised form 16 July 2011
Accepted 18 July 2011
nucleophilic trifluoromethylation of selected
a
subsequent removal of the MeO or Ph(Me)CH substituent, respectively, located at the N-atom. The
obtained products, containing a primary amino group, were used for the synthesis of imidazole N-oxides
bearing a trifluoromethyl group as a part of the N(1)-alkyl chain. Imidazole N-oxides with an electron-
withdrawing ester group at C(4) underwent spontaneous isomerization under the reaction conditions,
and the corresponding imidazol-2-ones derivatives were isolated as final products.
ß 2011 Elsevier B.V. All rights reserved.
Available online 23 July 2011
Keywords:
Nucleophilic trifluoromethylation
(Trifluoromethyl)trimethylsilane
b-Amino alcohols
Imidazole N-oxides
1. Introduction
their synthesis is based on the condensation of a-hydroxyimino
ketones 4 with formaldehyde and a corresponding primary amine
(Scheme 2).
The importance of
b-amino-a-trifluoromethyl alcohols is well
established, and our recent review summarizes methods of their
synthesis as well as applications for the preparation of hetero-
cycles and biologically active compounds [1]. The elaboration of
simple and efficient methods for their synthesis is a challenging
task. Particular attention is focused on amino compounds, which
In a previous paper, we showed that the primary amine can be
replaced by a
b-amino alcohol and the imidazole N-oxide obtained
in this case contains a
b
-hydroxyalkyl residue at N(1) [7e].
The goal of the present study was the elaboration of a method
for the preparation of amino alcohols of type 2 with a primary
amino group (R55H) via nucleophilic trifluoromethylation [8] of
properly selected arylglyoxalimines. Furthermore, the obtained
-amino-a-trifluoromethyl alcohols should be used as starting
materials for the synthesis of new imidazole N-oxides 3, bearing a
contain the trifluoromethyl group in a-position [2]. Very likely, the
same relationship is valid for trifluoromethylated imidazole
derivatives, with the CF3 group attached directly to C(2) [3] of
the imidazole ring or in a side chain attached to N(1) [4].
Regioselective nucleophilic trifluoromethylation of imines 1
derived from arylglyoxals with subsequent reduction of the C55N
bond was described as a convenient protocol for the preparation of
b
OH
Ar
OSiMe3
NR
CF3SiMe3
r.t.
NaBH4
NR
NHR
Ar
F3C
Ar
F3C
O
EtOH, r.t.
b
-amino-a-trifluoromethyl alcohols 2 with a secondary amino
2
group [5] (Scheme 1). These products were applied for the
preparation of aziridines as well as five- and six-membered O,N-
heterocycles [6].
1
Scheme 1.
The synthesis and reactivity of 2-unsubstituted imidazole N-
oxides 3 are of current interest as they are useful building blocks for
the preparation of diverse imidazole derivatives, including enan-
tiomerically pure compounds [7]. The straightforward method for
O-
R2
R3
R2
R3
NOH
O
N+
[R1-NH2 + CH2O]
+
N
R1
* Corresponding authors. Tel.: +48 42 635 57 61; fax: +48 42 665 51 62.
E-mail addresses: gmloston@uni.lodz.pl (G. Mloston´ ),
emiliaobijalska@gmail.com (E. Obijalska).
4
3
1
Part of the PhD Thesis of E. Obijalska, University of Ło´dz´, 2011.
Scheme 2.
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.07.016

952
G. Mloston´ et al. / Journal of Fluorine Chemistry 132 (2011) 951–955
.
MeO-NH2 HCl,
AcONa
Ar
OH
Ar
OSiMe3
LiAlH4
CF3SiMe3
OH
F3C
Ar
NH2
F3C
Ar
N
N
O
O
OMe
OMe
MeOH/H2O,
reflux
CsF, DME,
r.t.
THF, r.t.
OH
5a Ar = Ph
5b Ar = 4-MeOC6H4
(rac)-7a
(rac)-7b
6a (90%)
6b (92%)
(rac)-2a (69%)
(rac)-2b (78%)
Scheme 3.
OH
OH
H
S
S
H2/Pd,C
S
N
Ph
NH2
Ar
F3C
Ar
F3C
MeOH, r.t.
Me
(2S,1'S)-2c
(2S,1'S)-2d
(S)-2a (92%)
(S)-2b (81%)
OH
OH
H
R
R
S
H2/Pd,C
N
Ph
NH2
F3C
F3C
Ar
Ar
MeOH, r.t.
Me
(R)-2a (90%)
(R)-2b (77%)
(2R,1'S)-2c
(2R,1'S)-2d
a: Ar = Ph
b: Ar = 4-MeOC6H4
c: Ar = Ph
d: Ar = 4-MeOC6H4
Scheme 4.
b
-hydroxy-
b
-trifluoromethyl substituent at N(1). Moreover,
Another approach suitable for the preparation of amino
alcohols with a primary amino group is the debenzylation of the
initially obtained secondary N-benzylated amines 2. Especially
optically active imidazole N-oxides with this substitution pattern
should be also prepared.
important in this case is the exploration of N-(a-methylbenzyl)
derivatives, which opens access to optically active amino alcohols.
2. Results and discussion
The preparation of optically active amino alcohols 2c,d, synthe-
sized from (S)-
5a,b, has already been reported [5]. The separated diastereo-
isomers were treated with H2/Pd, in methanol at room
temperature to give the enantiomerically pure amino alcohols
(R)-2a, (S)-2a, (R)-2b, and (S)-2b (Scheme 4).
The enantiomeric purity of the obtained chiral amino alcohols
(R)- and (S)-2a and (R)- and (S)-2b was established spectroscopi-
cally by running the 1H- and 19F-NMR spectra in CDCl3 in the
presence of the optically pure (S)-(tert-butyl)(phenyl)phospho-
nothioic acid [9] (see also [5,7f,10].
The synthesis of imidazole derivatives was carried out first with
racemic amino alcohols 2a and 2b using formaldehyde and
diacetyl monooxime (4a). After heating the mixture in boiling
ethanol for 3 h, imidazole N-oxides 3a and 3b were isolated in 70
and 82% yield, respectively (Scheme 5).
a-methylbenzylamine and arylglyoxal hydrates
Searching for suitably substituted arylglyoxalimines, the model
compounds 6, bearing a methoxy group at the N-atom, were
selected. They were obtained by treatment of arylglyoxal hydrates
5a,b with O-methyl hydroxylamine hydrochloride in the presence
of sodium acetate. The subsequent nucleophilic trifluoromethyla-
tion was carried out under typical conditions using an equimolar
amount of CF3SiMe3 (Ruppert-Prakash reagent [8]) in dimethoxy-
ethane (DME) in the presence of catalytic amounts of CsF. The
crude reaction mixtures were examined by 19F-NMR spectroscopy,
which evidenced the presence of only one CF3 signal in each case.
Additionally, the IR and 13C-NMR spectra indicated that the
obtained products contained still the C55N bond, in accordance
with the structure of the O-silylated 1:1 adducts 7 (Scheme 3).
The attempted desilylation/reduction step using NaBH4 [5] led
in both cases to complex mixtures. The alternative protocol with
LiAlH4 in THF gave the expected amino (trifluoromethyl)alcohols
2a,b in 69 and 78% yield, respectively.
C
On the other hand, the same procedure applied for (rac)-2b and
ethyl 2-hydroxyimino-3-oxobutanoate (4b) led to imidazolone
(rac)-8a, which was obtained as the sole product (Scheme 6). Based
O
+
Me
Me
N
OH
Me
Me
NOH
O
NH2
CH2O
Ar
F3C
+
+
N
OH
CF3
EtOH, reflux
Ar
4a
(rac)-3a (70%) Ar = Ph
(rac)-2a
(rac)-2b
(rac)-3b (82%) Ar = 4-MeOC6H4
Scheme 5.

G. Mloston´ et al. / Journal of Fluorine Chemistry 132 (2011) 951–955
953
O
H
N
R
N
R
R
NOH
O
OH
EtOH,
reflux
O
4-MeOC6H4
NH2
N
+
+ CH2O
N
OH
CF3
4-MeOC6H4
Me
or
OH
CF3
4-MeO C6H4
Me
Me
F3C
Et2O, r.t.
4b R = CO2Et
4c R = COMe
(rac)-2b
(rac)-8a (30%) R = CO2Et
(rac)-8b (40%) R = COMe
(rac)-3c R = CO2Et
(rac)-3d R = COMe
Scheme 6.
on our earlier observation, the formation of (rac)-8a in this case can
be rationalized by the isomerisation of the initially formed N-oxide
(rac)-3c.
4. Experimental part
4.1. General experimental procedures
In general, 2-unsubstituted imidazole N-oxides bearing an
electron withdrawing substituent at C(4) tend to undergo
spontaneous isomerization to the corresponding imidazolones
already at room temperature [10]. Otherwise, the isomerization
requires heating of the N-oxide [11a], irradiation with UV light
[11b], or treatment with acetic anhydride [7b]. The experiment
with 4b and (rac)-2b was repeated in ether at room temperature,
but also in this case only (rac)-8a was obtained. Similarly, the
reaction performed with 3-hydroxyiminopentane-2,4-dione (4c)
led to imidazolone derivative (rac)-8b (Scheme 6).
General. Melting points were determined on a Melt-Temp. II
apparatus (Aldrich) in capillary and they are uncorrected. The
1H, 13C{1H} and 19F NMR spectra were recorded on Bruker
Avance III 600 or Varian Gemini BB 200 spectrometers using
solvent signals as reference. Assignments of signals in 13C NMR
spectra were made on the basis of HMQC experiments. The IR
spectra were measured using a NEXUS FT-IR spectrophotometer.
The MS spectra (ESI, ESI-HRMS) were obtained using Varian 500-
MS or Bruker Esquire LC spectrometers. Elemental analyses were
performed in the Microanalytical Laboratory of the Centre of
Molecular and Macromolecular Studies PAS in Ło´ dz´. Optical
rotations were measured on a PERKIN-ELMER 241 MC spectro-
Finally, the enantiomerically pure amino alcohols (S)-2a and
(S)-2b were used in the reaction with formaldehyde and 4a in
boiling ethanol. The optically active imidazole N-oxides (S)-3a and
(S)-3b were isolated in 52 and 50% yield.
polarimeter for
l = 589 nm.
4.2. Materials
O
Commercial paraformaldehyde, (trifluoromethyl)trimethylsi-
lane, methoxyamine hydrochloride, lithiumaluminium hydride
(1 M solution in THF) and palladium on charcoal (10%) were
Me
Me
N
N
OH
Ar
CF3
purchased from Sigma–Aldrich.
a-(Hydroxyimino)ketones 4a
[12a], 4b [12b], and 4c [12c], as well as 2,2-dihydroxy-1-
arylethanones 5a,b [13] were prepared according to known
protocols.
(2R/2S,10S)-1,1,1-Trifluoro-3-[1-(1-phenylethyl-ami-
no)]-2-arylpropan-2-ols 2c,d were prepared according to the
published procedure [5]. Dimethoxyethane (DME) and tetrahy-
drofurane (THF) were dried over sodium with benzophenone and
they were freshly distilled prior to their use.
(S)-3a Ar = Ph
(S)-3b Ar = 4-MeOC6H4
3. Conclusions
4.3. Syntheses of
a-(methoxyimino)ketones 6
The presented results show that properly substituted imino
derivatives of arylglyoxals can be used for the nucleophilic
trifluoromethylation with the Ruppert-Prakash reagent and subse-
General procedure.
1-Aryl-2,2-dihydroxyethanone
6a,b
(5 mmol), methoxyamine hydrochloride (5.05 mmol), and sodium
acetate were dissolved in MeOH/H2O 4:1 (10 ml). The mixture was
gently heated to reflux for 30 min. Then, the mixture was diluted
with a saturated aqueous solution of NaHCO3 and extracted with
CH2Cl2. The combined organic layers were dried over anhydrous
Na2SO4. After filtration, the solutions were evaporated to dryness
(room temperature bath). Products 6, contaminated with ca. 5% (by
1H NMR) of unidentified impurities, were used for further
transformations without purification.
quent treatment with LiAlH4 or reduction/debenzylation lead to
amino- -trifluoromethyl alcohols possessing a primary amino
group. The reduction/debenzylation procedure with the imine
derived from enantiomerically pure (S)- -methylbenzyl-amine
b-
a
a
opens a convenient access to enantiomerically pure trifluoromethy-
lated amino alcohols. Both racemic and enantiomerically pure
amino alcohols 2 can be used as new building blocks for the
preparation of imidazole derivates. Depending on the substitution
2-(Methoxyimino)-1-phenyl)ethanone (6a). Yield: 0.73 g (90%).
pattern of
a-hydroxyimino ketone used in these reactions, either 2-
Pale yellow oil. 1H NMR (600 MHz, CDCl3):
d
4.10 (s, 3H, CH3O),
7.45–7.49 (m, 2 arom. CH), 7.58–7.63 (m, 1 arom. CH), 7.95 (s, 1H,
HC55N), 8.07–8.09 (m, 2 arom. CH). 13C NMR (150 MHz, CDCl3):
63.4 (CH3O), 128.3, 130.1, 133.4 (5 arom. CH), 135.9 (1 arom. C),
147.1 (HC55N), 188.1 (C55O). IR (film): 3061w, 2979m, 2900w,
unsubstituted imidazole N-oxides or the isomeric imidazol-2-ones
were obtained. The structure of the obtained imidazole derivatives
relatestosomeknownbiologicallyactivecompoundsand, therefore,
they may be of interest for future applications.
d
v

954
G. Mloston´ et al. / Journal of Fluorine Chemistry 132 (2011) 951–955
2822w, 1656vs (C55O), 1598s (C55N), 1448s, 1328s, 1278s, 1233m,
1182m, 1036s, 1020s, 926m cmꢀ1
2-(Methoxyimino)-1-(4-methoxyphenyl)ethanone (6b). Yield:
0.89 g (92%). Pale yellow oil. 1H NMR (200 MHz, CDCl3):
3.89,
4.09 (2s, 6H, 2 CH3O), 6.94–6.98 (m, 2 arom. CH), 7.94 (s, 1H,
HC55N), 8.10–8.15 (m, 2 arom. CH). 13C NMR (50 MHz, CDCl3):
55.1, 62.9 (2 CH3O), 113.5, 132.2 (4 arom. CH), 128.5, 146.9 (2
arom. C), 163.8 (HC55N), 185.9 (C55O). IR (film): 3073w, 3000w,
2944w, 1640vs (C55O), 1604vs (C55N), 1511m, 1424w, 1293s,
1260vs, 1186m, 1177m, 1037s, 839s cmꢀ1
4.4.3. Hydrogenolysis of b-amino-N-phenylethyl-a-trifluoromethyl
alcohols 2c,d
.
To a solution of the corresponding amino alcohol (2S, 10S)- or
(2R, 10S)-2c,d (1.0 mmol) in MeOH (2 ml), 10% Pd/C (150 mg) was
added, and the flask was closed with a septum. Then, hydrogen
was bubbled through the mixture via a needle from a rubber
balloon, and the suspension was stirred for ca. 3 h under
atmospheric pressure. Next, the solvent was evaporated under
vacuum, and the products were isolated after filtration through
celite and silica gel pads using a mixture hexane/CH2Cl2 (1:1) as
the eluent.
d
d
v
.
4.4. Synthesis of
b
-amino-
a
-trifluoromethyl alcohols 2
(S)-3-Amino-1,1,1-trifluoro-2-phenylpropan-2-ol ((S)-2a). Yield:
189 mg (92%). Colourless crystals, m.p. 86–88 8C (hexane),
4.4.1. Reactions of
(trifluoromethyl)trimethylsilane – general procedure
A solution of the corresponding -methoxyimino ketone 6a,b
a
-iminoketones 6a,b with
[
a
]
D = +43 (c 1.0, CH2Cl2). Spectroscopic data identical with data
for (rac)-2a.
(R)-3-Amino-1,1,1-trifluoro-2-phenylpropan-2-ol ((R)-2a). Yield:
185 mg (90%). Colourless crystals, m.p. 84–86 8C (hexane), [ D = –
a
(1 mmol) in anhydrous DME (1.5 ml), was placed in a dry, two-
necked flask, equipped with septum and a tube filled with
anhydrous CaCl2. Next, a catalytic amount (3–5 mg) of freshly
dried CsF and (trifluoromethyl)trimethylsilane (0.17 ml, 157 mg,
1.1 mmol) were added. The mixture was stirred at room
temperature for ca. 1 h and subsequently quenched with water
(5 ml). The solution was extracted with CH2Cl2 three times. The
organic layers were combined and dried over anhydrous Na2SO4.
After filtration, the solvents were evaporated and the crude,
oily products 7a,b were used for further reactions without
purification.
a]
42 (c 1.0, CH2Cl2). Spectroscopic data identical with data for (rac)-
2a.
(S)-3-Amino-1,1,1-trifluoro-2-(4-methoxyphenyl)propan-2-ol
((S)-2b). Yield: 190 mg (81%). Colourless crystals, m.p. 97–99 8C
(hexane/Et2O), [a]D = +28 (c 1.0, CH2Cl2). Spectroscopic data
identical with data for (rac)-2b.
(R)-3-Amino-1,1,1-trifluoro-2-(4-methoxyphenyl)propan-2-ol
((R)-2b). Yield: 181 mg (77%). Colourless crystals, m.p. 98–100 8C
(hexane/Et2O). [a]D = –29 (c 1.0, CH2Cl2). Spectroscopic data
identical with data for (rac)-2b.
4.4.2. Reduction of adducts 7a,b with lithium aluminium hydride –
general procedure
4.5. Syntheses of imidazole derivatives 3 and 8
To a magnetically stirred solution of the corresponding adduct
7a,b in anhydrous THF (3 ml), 1 M solution of LiAlH4 (1.0 ml,
1 mmol) was added dropwise while cooling, and the mixture was
stirred for 12 h at room temperature. After this time, a portion of
water (ca. 5 ml) was added carefully while cooling the reaction
flask in an ice-bath. Next, a solution of saturated aqueous NaOH
and solid KOH were added, and subsequently the products were
extracted with Et2O. The organic layers were combined and dried
over anhydrous Na2SO4. After filtration, the solvents were
evaporated and the crude products were purified by column
chromatography on SiO2.
4.5.1. Reactions of
b
-amino-
a-trifluoromethyl alcohols 2a,b with
paraformaldehyde and
procedure
a
-(hydroxyimino)ketone 4a – general
A
solution of a b-amino-a-trifluoromethyl alcohol 2a,b
(1.0 mmol) and paraformaldehyde (32 mg, 1.05 mmol) in EtOH
was stirred at room temperature for 12 h. The solution was filtered,
a
-(hydroxyimino)ketone 4a (1.1 mmol) was added, and the
mixture was heated to reflux for 6 h. Then, the solvent was
evaporated, the residue was treated with Et2O, and the crystalline
product was separated and washed several times with Et2O. Pure
products were obtained after crystallization from an appropriate
solvent.
3-(4,5-Dimethyl-3-oxido-1H-imidazol-1-yl)-1,1,1-trifluoro-
2-phenyl-propan-2-ol ((rac)-3a). Yield: 210 mg (70%). Colourless
crystals, m.p. 239–241 8C (decomp.; iPr2O/MeOH). 1H NMR
3-Amino-1,1,1-trifluoro-2-phenylpropan-2-ol ((rac)-2a). Yield:
141 mg (69%). Colourless crystals, m.p. 84–86 8C (hexane). 1H
NMR (600 MHz, CDCl3):
d 2.71 (br. s, 2H, OH, NH), 3.04, 3.52 (2d,
2JH,H = 13.2 Hz, 2H, CH2), 7.35–7.41 (m, 3 arom. CH), 7.58–7.59 (m,
2 arom. CH). 13C NMR (150 MHz, CDCl3):
d
45.7 (CH2), 74.3 (q,
(600 MHz, CD3OD):
d 1.96, 2.06 (2s, 6H, 2 CH3), 4.55 (s, 2H,
2JC,F = 27.2 Hz, Cq), 126.0 (q, JC,F = 285.3 Hz, CF3), 126.4, 128.5,
CH2), 7.41–7.44 (m, 3 arom. CH), 7.55–7.57 (m, 2 arom. CH), 7.78 (s,
1
128.7 (5 arom. CH), 137.6 (1 arom. C). 19F NMR (565 MHz, CDCl3):
3388s (O–H), 3095m, 3068m, 2904m,
d
1 CH imidazol). 13C NMR (150 MHz, CDCl3):
d 5.5, 7.1 (2 CH3), 49.6
ꢀ78.3 (s, CF3). IR (KBr):
v
(CH2), 76.6 (q, 2JC,F = 27.4 Hz, Cq), 123.2, 124.8, 135.0 (2C imidazole,
1
1603w, 1458m, 1273m, 1196s, 1163vs, 1152vs, 1071m,
942m cmꢀ1. ESI-MS m/z (rel. int.): 206 (45, [M+1]+), 188 (100,
[Mꢀ18 + 1]+). Anal. Calcd. for C9H10F3NO (205.18): C, 51.07; H,
5.14. Found: C, 50.79; H, 5.14.
1 arom. C), 125.2 (q, JC,F = 285.4 Hz, CF3), 126.1, 128.3, 129.0 (5
arom. CH), 126.6 (1 CH imidazol). 19F NMR (565 MHz, CD3OD):
d
ꢀ75.6 (s, CF3). IR (KBr):
v 3153br.m, 3061br.m, 2930w, 2630br.m,
1632w, 1450m, 1444w, 1404m, 1341m, 1267s, 1250s, 1172vs,
1155vs, 1079m, cmꢀ1. ESI-HRMS: Calcd for C14H15F3N2O2Na+
3-Amino-1,1,1-trifluoro-2-(4-methoxyphenyl)propan-2-ol ((rac)-
2b). Yield: 183 mg (78%). Colourless crystals, m.p. 94–96 8C
([M+23]+): m/z 323.09783; found: m/z 323.09778. Calcd for
(hexane/Et2O). 1H NMR (600 MHz, CDCl3):
d
3.03, 3.51 (2d,
C
14H16F3N2O2 ([M+1]+): m/z 301.11584; found: m/z 301.11606.
+
2JH,H = 13.2 Hz, 2H, CH2), 3.82 (s, 3H, CH3O), 6.92–6.93 (m, 2 arom.
(S)-3-(4,5-Dimethyl-3-oxido-1H-imidazol-1-yl)-1,1,1-trifluoro-2-
phenyl-propan-2-ol ((S)-3a). Yield: 190 mg (63%). Colourless
crystals, m.p. 240–242 8C (decomp.; iPr2O/MeOH). [ D = +16.0
(c 1.0, MeOH). Spectroscopic data identical with data for (rac)-3a.
3-(4,5-Dimethyl-3-oxido-1H-imidazol-1-yl)-1,1,1-trifluoro-2-(4-
methoxyphenyl)propan-2-ol ((rac)-3b). Yield: 271 mg (82%). Col-
ourless crystals, m.p. 235–237 8C (decomp.; iPr2O/MeOH). 1H NMR
(600 MHz, CD3OD):
(s, 2H, CH2), 6.93–6.96, 7.43–7.44 (2m, 4 arom. CH), 7.72 (s, 1 CH
imidazol). 13C NMR (150 MHz, CD3OD):
7.1, 8.7 (2 CH3), 51.1
CH), 7.49–7.51 (m, 2 arom. CH). 13C NMR (150 MHz, CDCl3):
d
45.6
2
(CH2), 55.5 (CH3O), 73.9 (q, JC,F = 27.2 Hz, Cq), 113.9, 127.7 (4
arom. CH), 126.0 (q, 1JC,F = 286.8 Hz, CF3), 129.6, 159.9 (2 arom. C).
a]
19F NMR (565 MHz, CDCl3):
d
ꢀ78.7 (s, CF3). IR (KBr):
v 3342s (O–
H), 3312m (N–H), 3017m, 2972m, 2913m, 1692w, 1515s, 1465m,
1305m, 1254s, 1183s, 1154vs, 1112m, 1036m, 960m cmꢀ1. ESI-MS
m/z (rel. int.): 236 (27, [M+1]+), 218 (100, [Mꢀ18 + 1]+). Anal. Calcd
for C10H12F3NO2 (235.21): C, 52.69; H, 4.91. Found: C, 52.68; H,
4.95.
d 1.93, 2.04 (2s, 6H, 2 CH3), 3.80 (s, CH3O), 4.49
d

G. Mloston´ et al. / Journal of Fluorine Chemistry 132 (2011) 951–955
955
(CH2), 55.9 (CH3O), 78.0 (q, 2JC,F = 27.5 Hz, Cq), 115.2, 129.0 (4 arom.
CH), 128.1 (1 CH imidazol), 126.8 (q, JC,F = 285.3 Hz, CF3), 125.2,
125.3, 126.3, 162.0 (2C imidazole, 2 arom. C). 19F NMR (565 MHz,
imidazole, 2 arom. C), 159.4 (C55O), 186.6 (CH3CO). 19F NMR
(565 MHz, DMSO-d6): 3280br.s (N–
H + O–H), 1693vs (C55O), 1636vs (C55O), 1605s, 1514m, 1443m,
1308m, 1254m, 1180s, 1173vs, 1153vs, 1144s, 1111m,
1029m cmꢀ1. ESI-HRMS: Calcd for C16H17F3N2O4Na+ ([M+23]+):
m/z 381.10326; found: m/z 381.10346.
1
d
ꢀ76.1 (s, CF3). IR (KBr):
v
CD3OD):
d
ꢀ77.9 (s, CF3). IR (KBr):
v 3162br.m, 3018br.m, 2845br.w,
2614br.w, 1613m, 1516s, 1444w, 1340w, 1305m, 1250s, 1173vs,
1154vs, 1030m, 841m cmꢀ1. ESI-HRMS: Calcd. for C15H18F3N2O3
+
([M+1]+): m/z 331.12640; found: m/z 331.12662.
(S)-3-(4,5-Dimethyl-3-oxido-1H-imidazol-1-yl)]-1,1,1-trifluoro-
2-(4-methoxyphenyl)propan-2-ol ((S)-3b). Yield: 202 mg (61%).
Colourless crystals, m.p. 234–236 8C (decomp.; iPr2O/MeOH).
[a]D = +13.7 (c 1.0, MeOH). Spectroscopic data identical with data
for (rac)-3b.
Acknowledgement
The authors thank the Polish Ministry for Science and Higher
Education for financial support (Grant # NN204130335) and PD Dr.
L. Bigler, University of Zu¨rich, for ESI-HRMS.
4.5.2. Reactions of
b
-amino-
a
-trifluoromethyl alcohol 2b with
References
paraformaldehyde and
procedure
a
-(hydroxyimino)ketones 4b,c – general
´
[1] G. Mloston, E. Obijalska, H. Heimgartner, J. Fluorine Chem. 131 (2010) 829–843.
[2] (a) J. Liu, J. Hu, Future Med. Chem. 1 (2009) 875–888;
(b) D. O’Hagan, J. Fluorine Chem. 131 (2010) 1071–1081;
(c) A.E. Sorochinsky, V.A. Soloshonok, J. Fluorine Chem. 131 (2010) 127–139;
(d) V.P. Kukhar, A.E. Sorochinsky, V.A. Soloshonok, Future Med. Chem. 1 (2009)
793–819.
A
solution of a b-amino-a-(trifluoromethyl)alcohol 2a,b
(1.0 mmol) and paraformaldehyde (32 mg, 1.05 mmol) in EtOH
was stirred at room temperature for 12 h. Then, the solution was
filtered, 4b or 4c (1.1 mmol) was added, and the mixture was
stirred in room temperature for 48 h. The white precipitate was
filtered off and washed several times with Et2O.
[3] J. Dietrich, V. Gokhale, X. Wang, L.H. Hurley, G.A. Flynn, Bioorg. Med. Chem. 18
(2010) 292–304.
[4] (a) Takeda Pharmacentical Company Ltd., WO 2008/139941 A1, 2008;
(b) Astrazeneca AB, Astrazeneca UK, Ltd., WO 2004/13141 A1, 2004;
(c) Yamanouchi Pharmaceutical Co., Ltd., US 4977175 A1, 1990.
[5] G. Mloston´ , E. Obijalska, A. Tafelska-Kaczmarek, M. Zajdlewicz, J. Fluorine Chem.
131 (2010) 1289–1296.
[6] E. Obijalska, G. Mloston´ , A. Linden, H. Heimgartner, Helv. Chim. Acta 93 (2010)
1725–1736.
[7] (a) G. Mloston´ , T. Gendek, H. Heimgartner, Tetrahedron 56 (2000) 5405–5412;
(b) G. Mloston´ , M. Celeda, G.K.S. Prakash, G.A. Olah, H. Heimgartner, Helv. Chim.
Acta 83 (2000) 728–738;
3-(4-Ethoxycarbonyl-2,3-dihydro-5-methyl-2-oxo-1H-imidazol-
1-yl)-1,1,1-trifluoro-2-(4-methoxyphenyl)propan-2-ol
((rac)-8a).
Yield: 125 mg (30%). Colourless crystals, m.p. 196–198 8C
(decomp.). 1H NMR (600 MHz, DMSO-d6):
d 1.23 (t, JH,H = 7.2 Hz,
3
3H, CH3CH2), 2.22 (s, 3H, CH3), 3.76 (s, CH3O), 4.17 (t, 3JH,H = 7.2 Hz,
2
3H, CH3CH2), 4.21, 4.32 (2d, 2H, JH,H = 15.6 Hz, 2H, CH2), 6.95–
6.96, 7.52–7.54 (2m, 4 arom. CH), 7.58 (s, 1H, OH), 10.92 (s, 1H,
(c) G. Mloston´ , M. Jasin´ ski, A. Linden, H. Heimgartner, Helv. Chim. Acta 89 (2006)
1304–1316;
(d) G. Mloston´ , J. Roman´ ski, M. Jasin´ ski, H. Heimgartner, Tetrahedron: Asymme-
try 20 (2009) 1073–1080;
(e) M. Jasinski, G. Mloston, P. Mucha, A. Linden, H. Heimgartner, Helv. Chim. Acta
90 (2007) 1765–1780;
NH). 13C NMR (150 MHz, DMSO-d6):
d 9.9 (CH3), 14.2 (CH3CH2),
46.7 (CH2), 55.1 (CH3O), 60.0 (CH3CH2), 76.7 (q, 2JC,F = 27.4 Hz, Cq),
1
125.3 (q, JC,F = 286.8 Hz, CF3), 113.6, 128.1 (4 arom. CH), 127.7,
´
´
127.9 131.5, 154.6 (2C imidazole, 2 arom. C), 159.5 (CH3CH2CO2
and C55O). 19F NMR (565 MHz, DMSO-d6):
d
ꢀ76.4 (s, CF3). IR (KBr):
3280br.s (N–H + O–H), 1693vs (C55O), 1636vs (C55O), 1605s,
1514m, 1443m, 1308m, 1254m, 1180s, 1173vs, 1153vs, 1144s,
´
´
(f) P. Mucha, G. Mloston, M. Jasinski, A. Linden, H. Heimgartner, Tetrahedron:
Asymmetry 19 (2008) 1600–1607;
v
(g) G. Mloston´ , M. Jasin´ ski, H. Heimgartner, Eur. J. Org. Chem. (2011) 2542–2547.
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2633–2644;
(b) G.K.S. Prakash, M. Mandal, J. Fluorine Chem. 112 (2001) 123–131;
(c) R.P. Singh, J.M. Shreeve, Tetrahedron 56 (2000) 7613–7632;
(d) G.K.S. Prakash, A.K. Yudin, Chem. Rev. 97 (1997) 757–786.
[9] J. Omelan´ czuk, M. Mikołajczyk, Tetrahedron: Asymmetry 7 (1996) 2687–2694.
[10] M. Jasin´ ski, G. Mloston´ , A. Linden, H. Heimgartner, Helv. Chim. Acta 91 (2008)
1916–1933.
1111m, 1029m cmꢀ1 ESI-HRMS: Calcd. for C17H19F3N2O5Na+
.
([M+23]+): m/z 411.11383; found: m/z 411.11384.
3-(4-Acetyl-2,3-dihydro-5-methyl-2-oxo-1H-imidazol-1-yl)-
1,1,1-trifluoro-(4-methoxphenyl)propan-2-ol
155 mg (40%). Colourless crystals, m.p. 222–225 8C (decomp.).
1H NMR (600 MHz, DMSO-d6):
2.25, 2.26 (2s, 6H, CH3 + CH3CO),
3.76 (CH3O), 4.23, 4.35 (2d, 2H, 2JH,H = 15.0 Hz, 2H, CH2), 6.95–6.97,
7.53–7.55 (2m, 4 arom. CH), 7.51 (s, 1H, OH), 10.89 (s, 1H, NH). 13
NMR (150 MHz, DMSO-d6): 10.5 (CH3), 28.1 (CH3CO), 46.3 (CH2),
((rac)-8b).
Yield:
d
[11] (a) R. Bartnik, W.E. Hahn, G. Mloston´ , Rocz. Chem. 51 (1977) 49–57;
´
(b) R. Bartnik, G. Mloston, Rocz. Chem. 51 (1977) 1747–1750.
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(b) I.R. Correˆa Jr., P.J.S. Moran, Tetrahedron 55 (1999) 14221–14232;
(c) X.-H. Cai, H.-J. Yang, G.-L. Zhang, Synthesis (2005) 1569–1571.
C
d
2
1
55.1 (CH3O), 76.6 (q, JC,F = 27.2 Hz, Cq), 125.2 (q, JC,F = 288.3 Hz,
¨
[13] (a) G. Fodor, O. Kova´cs, J. Am. Chem. Soc. 71 (1949) 1045–1048;
CF3), 113.5, 127.6 (4 arom. CH), 118.8, 127.5, 131.2, 153.7 (2C
(b) C. Rioux-Lacoste, C. Viel, Bull. Soc. Chim. Fr. (1974) 2463–2470.