Reactions of α-imino ketones derived from arylglyoxals with (trifluoromethyl)trimethylsilane; A new route to β-amino-α- trifluoromethyl alcohols

Article abstract of DOI:10.1016/j.jfluchem.2010.07.012

The reactions of α-imino ketones, derived from arylglyoxals, with (trifluoromethyl)trimethylsilane (CF₃SiMe₃) in DME solution, in the presence of catalytic amount of CsF, at room temperature, yield O-silylated β-imino alcohols in the

Full text of DOI:10.1016/j.jfluchem.2010.07.012

Journal of Fluorine Chemistry 131 (2010) 1289–1296
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Reactions of
a-imino ketones derived from arylglyoxals with
(trifluoromethyl)trimethylsilane; a new route to
alcohols
b-amino-a-trifluoromethyl
Grzegorz Mloston a, , Emilia Obijalska a,1, Agnieszka Tafelska-Kaczmarek b, Marek Zaidlewicz b
*
a Department of Organic and Applied Chemistry, University of Lodz, Tamka 12, PL-91-403 Lodz, Poland
b Department of Organic Chemistry, Nicolaus Copernicus University, Gagarina 7, PL-87-100 Torun, Poland
A R T I C L E I N F O
A B S T R A C T
Article history:
The reactions of
a-imino ketones, derived from arylglyoxals, with (trifluoromethyl)trimethylsilane
Received 15 June 2010
(CF3SiMe3) in DME solution, in the presence of catalytic amount of CsF, at room temperature, yield O-
silylated -imino alcohols in the chemoselective manner. Subsequent reduction of these products with
NaBH4 in ethanolic solution leads to the corresponding -(N-alkyl)amino- -trifluoromethyl alcohols in
good to excellent yields. Trifluoromethylation of enantiomerically pure -imino ketones (with Ar = Ph or
Received in revised form 20 July 2010
Accepted 27 July 2010
b
b
a
Available online 11 August 2010
a
p-MeOC6H4), bearing as a chiral auxiliary the PhCH(Me) group attached to the nitrogen atom, yields
mixtures of diastereomeric products in the ratio of ca. 3:2.
Keywords:
Nucleophilic trifluoromethylation
(Trifluoromethyl)trimethylsilane
ß 2010 Elsevier B.V. All rights reserved.
b
a
-Amino alcohols
-Imino ketones
1. Introduction
features, i.e. the synthetic utility of b-amino alcohols and unique
properties of the trifluoromethyl group, results in a growing
interest in the synthesis of amino alcohols bearing the CF3 group
[9]. b-Amino-a-trifluoromethyl alcohols are reported as effective
catalysts in enantioselective reactions and it is well documented
that they are more efficient than their non-fluorinated analogues
Synthesis of fluoroorganic compounds is a challenging topic of
the modern organic chemistry. Especially, the presence of
trifluoromethyl moiety in the target molecule often results in
significant changes of its physical, chemical and biological
properties [1].
[9c].
b-Amino alcohols, modified with fluorinated alkyl chains,
The incorporation of the CF3 group can be conveniently
achieved via nucleophilic addition of (trifluoromethyl)trimethyl-
silane CF3SiMe3, the ‘Ruppert–Prakash reagent’ to electrophilic
double bonds [2]. Trifluoromethylation of aldehydes, ketones [3a–
d] and esters [3e,f], and other carbonyl derivatives [2a,b], with this
extremely useful reagent has been extensively studied. Generally,
imines are less reactive towards CF3SiMe3 than the corresponding
carbonyl analogues. Nevertheless, application of activated imines
were used as attractive building blocks for the preparation of
mimetics of versatile biologically active compounds [9c] as well as
diverse heterocycles with variable ring size [10]. In general, three
main strategies for the synthesis of
b-amino-a-trifluoromethyl
alcohols, are presently known. Historically, the oldest one is the
Henry reaction (nitro-aldol reaction) with subsequent reduction
of the initially formed b-nitro alcohols. Another approach is based
on the ring opening of 2-(trifluoromethyl)oxiranes with primary
or secondary amines, and finally, nucleophilic trifluoromethyla-
[4] or special reaction conditions [5] gave the desired
(trifluoromethyl)amines.
a-
tion of appropriate
a-amino aldehydes with (trifluoromethyl)-
b
-Amino alcohols, both achiral and chiral, are versatile
trimethylsilane has been extensively studied in the past two
decades [9c].
reagents for organic synthesis [6,7] and extremely useful building
blocks for the preparation of diverse, biologically active com-
pounds [8]. Special attention was focused on the enantiomerically
Recently, we reported on the smooth, diastereoselective
additions of CF3SiMe3 to easily available
a-imino ketones 1,
pure
b
-amino alcohols which are used in asymmetric synthesis as
derived from (1R)-camphorquinone, leading to the adducts 2.
chiral auxiliaries or catalysts [6–8]. Combination of two relevant
These products, upon treatment with sodium borohydride, were
smoothly converted into the corresponding
(Scheme 1) [11]. The subsequent reduction of 3 with DIBAL-H
(NaBH4 turned out not to be reactive enough) afforded the
amino- -trifluoromethyl alcohols 4 as single 2-exo,3-exo diaste-
reomers.
b-imino alcohols 3
b
-
* Corresponding author. Tel.: +48 42 635 57 61; fax: +48 42 665 51 62.
a
E-mail address: gmloston@uni.lodz.pl (G. Mloston).
1
Part of the planned PhD Thesis of E. Obijalska, University of Lodz.
0022-1139/$ – see front matter ß 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2010.07.012

[
G. Mloston et al. / Journal of Fluorine Chemistry 131 (2010) 1289–1296
Scheme 1.
[(cShme_2T)ID$F]G
The aim of the present study was the elaboration of a simple
and reproducible protocol for the conversion of readily available
arylglyoxal imines of type 7 into hitherto unknown trifluoro-
methylated
b-amino alcohols 9, potentially useful for further
applications including synthesis of biologically active compounds
and organocatalysis. The key step in the presented method is the
chemoselective addition of CF3SiMe3 to the C55O group and
subsequent reduction of the remaining C55N bond.
Scheme 2.
[(cShme_3T)ID$F]G
2. Results and discussion
Preparation of 1-aryl-2,2-dihydroxyethanones 6a–f was based
on the known oxidation of aryl-methylketones 5a–f using SeO2 in
an aqueous dioxane solution (Scheme 2) [12]. A slightly modified
literature procedure [13] applied for condensation of primary
Scheme 3.
amines with arylglyoxal hydrates 6a–f leads to
a-imino ketones
yield. In this case, the 13C NMR and IR spectra confirmed the
complete conversion of the C55N group. A strong absorption band
located at 3331 cmꢀ1 evidenced the presence of the new N–H
function. In the 1H NMR spectrum the diastereotopic protons of the
CH2 group appeared as an AB-system with two doublets located at
2.87 ppm and 3.39 ppm, correspondingly [14]. Analogous reac-
7a–j (Scheme 2, Table 1). Reactions of arylglyoxals 6 with tert-
butylamine, isopropylamine and (1S)-1-phenylethylamine were
carried out at room temperature in dichloromethane, in the
presence of a dehydrating agent (sodium sulfate). The
a-imino
ketones 7 obtained in these reactions turned out to be quite
unstable compounds, decomposing during the standard purifica-
tion procedure. For this reason they were used directly (as 1H
NMR-pure products) for further conversions. In general, substrates
7 are recommended to be used for the reaction with CF3SiMe3
immediately after preparation. However, the non-enolizable
representatives 7a–f were stable enough and could be kept bellow
0 8C for a longer time, without noticeable decomposition.
First experiments were carried out with 7a in 1,2-dimeth-
oxyethane (DME) using CsF as an initiator. The reaction with
CF3SiMe3 gave a single product, which showed an absorption
signal in the 19F NMR spectrum at ꢀ0.68 ppm. The 13C NMR and IR
spectra proved the presence of the C55N group. The characteristic
1H NMR signal located at 0.19 ppm revealed the presence of the
Me3SiO-group. All spectroscopic data suggested that the expected
1:1 adduct of type 8 (Scheme 3) was formed as a single product in
high yield. Based on our earlier results [11], attempts were made to
reduce the C55N group using NaBH4. In contrast to adducts of type
2, the analogous reaction carried out with 8a in ethanolic solution
at room temperature, afforded after 12 h, in a one-pot procedure,
tions with
same conditions and they yielded desired
omethyl alcohols 9b–j in excellent yields (Table 2).
In order to check the scope and limitations of our protocol,
reactions of CF3SiMe3 with -imino ketones 7a–c were tested in
a
-imino ketones 7b–j were carried out applying the
b
-amino- -trifluor-
a
a
absence of the fluoride anion as an activator; instead other
catalysts were applied (Table 2). Thus, the experiments performed
in DMF solution, in the presence of K2CO3, or in DMSO solution
˚
using molecular sieves 4 A, yielded the corresponding adducts 8 in
comparable amounts to the reactions carried under ‘classical’
conditions. It is worth mentioning that compounds 9e–f can be
considered as a modified (‘trifluoromethylated’) type of 1-amino 2-
(benzofuran-20-yl)ethan-2-ols, known as anti-hypertensive agents
and
The diastereoselective version of nucleophilic trifluoromethy-
lation of -imino ketones 7k–l, bearing a chiral auxiliary on the
b-blockers [8a,b].
a
nitrogen atom, was also studied (Scheme 4, Table 3).
Table 2
b
-amino-a-trifluoromethyl alcohol 9a (Scheme 3, Table 2) in 90%
Two-step synthesis of
b-amino-a-trifluoromethyl alcohols 9.
Entry
Substrate
Catalyst
Solvent
9 Yield [%]
Table 1
Synthesis of
a-imino ketones 7 from arylglyoxals hydrates.
1
2
7a
7a
7a
7b
7b
7b
7c
7c
7c
7d
7e
7f
CsF
K2CO3
–
DME
DMF
DMSO
DME
DMF
DMSO
DME
DMF
DMSO
DME
DME
DME
DME
DME
DME
DME
90
81
75
73
70
75
82
76
84
89
70
74
72
69
78
72
Product
R
Ar
7 Yield [%]a
3
7a
7b
7c
7d
7e
7f
t-Bu
Ph
93
89
91
86
83
81
93
92
95
92
93
95
4
CsF
K2CO3
–
t-Bu
p-MeOC6H4
p-NO2C6H4
p-CF3C6H4
Benzofuran-2-yl
7-Et-benzofuran-2-yl
Ph
5
t-Bu
6
t-Bu
7
CsF
K2CO3
–
t-Bu
8
t-Bu
9
7g
7h
7i
i-Pr
10
11
12
13
14
15
16
CsF
CsF
CsF
CsF
CsF
CsF
CsF
i-Pr
p-MeOC6H4
p-NO2C6H4
p-CF3C6H4
Ph
i-Pr
7j
i-Pr
7g
7h
7i
7k
7l
(S)-CH(Me)Ph
(S)-CH(Me)Ph
p-MeOC6H4
7j
a
For crude product.

[
G. Mloston et al. / Journal of Fluorine Chemistry 131 (2010) 1289–1296
1291
Scheme 4.
[(ig._1)TD$FIG]
Fig. 1. Comparison of the 1H NMR spectra of racemate and isolated enantiomers of 9k recorded after addition of 1 equiv. of (ꢀ)-(S)-(tert-butyl)(phenyl)phosponothioic acid (10).
Table 3
Diastereoselectivity of CF3SiMe3 additions to enantiomerically pure
a-imino ketones 7k–l.
Entry
Substrate
Conditions
kat.
d.r.a
9 Yield [%]b
Solvent
Temp.
1
2
3
4
7k
7k
7k
7l
CsF
–
DME
DMSO
DME
DME
r.t.
6:4
75
70
68
78
r.t.
6:4
CsF
CsF
ꢀ50 8C
r.t.
6.5:3.5
6:4
a
19
On the basis of F NMR of crude (2R/2S, 10S)-8.
These reactions were carried out under typical conditions, using
cesium fluoride as a catalyst. In both cases, the 19F NMR spectra
taken for crude reaction mixtures revealed the presence of
diastereomers formed in the ratio of ca. 3:2.
The mixtures of diastereomers (2R,10S)-9k–l and (2S,10S)-9k–l
were separated by column chromatography and the enantiomeric
purity of the isolated fast- and slow-fractions2 was proved by the 1H
NMR experiments with (S)-(tert-butyl)phenyltiophosphonic acid
(10) [15] used as a chiral solvating agent. In each experiment only
one set of signals of the corresponding salt was observed (Fig. 1).
In an independent experiment the mixture of diastereomers 9k
subsequently, both racemic isomers were separated chromato-
graphically. In each case, the 1H NMR spectrum of fast-(rac)-9k and
slow-(rac)-9k, registered in the presence of chiral solvating agent
(S)-10, displayed well separated sets of signals attributed to the in
situ formed mixtures of two salts of the corresponding enantio-
mers (Fig. 1).
The obtained results show that the nucleophilic trifluoro-
methylation of enolizable
a-imino ketones 7k–l, derived from
aryloglyoxal, proceed with no racemization of the 1-phenylethyl
substituent. In extension of the results discussed in this paper, the
slow-isomer of 9l was used in another work for a cyclization
reaction with phosgene yielding selectively the corresponding 1,3-
oxazolidin-2-one derivative [10]. The absolute configuration of
both stereogenic centers in this compound was determined by X-
ray crystallography as (5R,10S)-, evidencing thereby the same
absolute configuration [(2R,10S)-] in the slow-9l (minor product)
was also prepared starting with racemic
a-imino ketone 7k and
2
Denotation of slow- and fast-isomer results from the polarity of separated
products; slow-9k,l relate to the more polar diastereoisomers and fast-9k,l to the
less polar ones.

1292
G. Mloston et al. / Journal of Fluorine Chemistry 131 (2010) 1289–1296
[10]. By analogy, the same configuration was attributed to the
more polar product bearing phenyl substituent, i.e. slow-9k.
In order to examine the influence of the reaction conditions on
anhydrous Na2SO4 over 1 h, at room temperature. Then, drying
agent was filtered off and next solvent was evaporated to dryness
(room temperature bath). Crude products were used for further
reactions with no purification.
the stereochemical outcome, the enantiomerically pure
a-imino
ketone 7k was also reacted with CF3SiMe3 in DMSO, in the absence
of the fluoride anion. In this case the ratio of diastereomeric amino
alcohols 9k, obtained after reduction of the initially formed adduct,
was practically unchanged (Table 3). Similarly, another experi-
ment with trifluoromethylation of 7k at low temperature (ꢀ50 8C)
in DME solution, under fluoride catalysis, did not result in a
noticeable change of the d.r. value.
2-(tert-Butylimino)-1-phenylethanone (7a). Yield: 1.05 g (93%).
Orange colored, viscous oil. 1H NMR (600 MHz, CDCl3):
d 1.33 (s,
9H, C(CH3)3), 7.45–7.46 (m, 2 arom. H), 7.56–7.58 (m, 1 arom. H),
8.02 (s, 1H, CH55N), 8.19–8.21 (m, 2 arom. H). 13C NMR (150 MHz,
CDCl3):
arom. CH), 135.3 (1 arom. C), 154.3 (CH55N), 191.6 (C55O). IR (KBr):
3070w, 2971s, 2932m, 2904m, 2871m, 1663vs (C55O), 1598s
d 29.1 (C(CH3)3), 59.2 (C(CH3)3), 128.2, 130.7, 133.3 (5
v
(C55N), 1578m, 1448s, 1365m, 1286s, 1230m, 1179w, 1068w,
1024w, 901w, 762w cmꢀ1. ESI-MS: m/z (rel. int.) 190 (38, [M+1]+),
212 (100, [M+23]+).
3. Conclusions
A new, simple and efficient method for the synthesis of a series
2-(tert-Butylimino)(40-methoxyphenyl)ethanone (7b). Yield:
0.98 g (89%). Yellow colored, viscous oil. 1H NMR (200 MHz,
of new
b-amino-a-trifluoromethyl alcohols of type 9, based on
inexpensive and readily accessible starting materials, was elabo-
rated. In most of the described cases, products 9 were obtained in
high yields and could be purified by standard procedures. They can
be considered as new, attractive building blocks for the synthesis of
other fluorinated organic compounds, e.g. trifluoromethylated
heterocyclic compounds [10].
Enantiomerically pure imino ketones 7k,l containing a chiral
auxiliary, derived from 1-phenylethylamine, undergo nucleophilic
trifluoromethylation, followed by the reduction of the C55N bond,
producing in both cases comparable mixtures (ca. 3:2) of the
CDCl3): d 1.33 (s, 9H, C(CH3)3), 3.88 (s. 3H, OCH3), 6.94, 8.25 (2d,
3JH,H = 9.0 Hz, 4 arom. H), 7.99 (s, 1H, CH55N). 13C NMR (50 MHz,
CDCl3): 28.9 (C(CH3)3), 59.3 (C(CH3)3), 113.4, 113.5, 132.9, 133.1 (4
arom. CH), 154.6.1, 154.5 (2 arom. C), 163.8 (CH55N), 190.0 (C55O).
IR (KBr):
v 2970s, 2933m, 2903m, 2841m, 1656vs (C55O), 1601vs
(C55N), 1574s, 1509s, 1460m, 1419m, 1365m, 1312s, 1258vs,
1172vs, 1115w, 1030s, 949w, 841s, 810m, 777w cmꢀ1. ESI-MS: m/z
(rel. int.) 164 (100), 220 (44, [M+1]+), 242 (44, [M+23]+).
2-(tert-Butylimino)(40-nitrophenyl)ethanone (7c). Yield: 1.06 g
(91%). Yellow crystals, m.p. 70ꢀ74 8C (crude). 1H NMR (200 MHz,
corresponding diastereomeric
b
-amino-
a
-trifluoromethyl alco-
CDCl3): d 1.33 (s, 9H, C(CH3)3), 8.00 (s, 1H, CH55N), 8.27–8.41 (m, 4
hols 9k and 9l, respectively.
arom. H). 13C NMR (50 MHz, CDCl3):
(C(CH3)3), 123.1, 131.8 (4 arom. CH), 140.5, 154.2 (2 arom. C),
154.2 (CH55N), 190.0 (C55O). IR (KBr): 3117w, 2975m, 2937w,
d 28.8 (C(CH3)3), 59.5
4. Experimental
v
2871m, 2899w, 1666vs (C55O), 1603s (C55N), 1524vs, 1478w,
1364m, 1344vs, 1287s, 1230m, 1104w, 1010w, 951w, 905w, 863m,
754m cmꢀ1. ESI-MS: m/z (rel. int.) 179 (100), 193 (38), 235 (47
[M+1]+), 257 (15, [M+23]+).
2-(tert-Butylimino)-1-[40-(trifluoromethyl)phenyl]ethanone
(7d). Yield: 1.10 g (86%). Yellow colored, viscous oil. 1H NMR
4.1. General experimental procedures
Melting points were determined on a Melt-Temp. II apparatus
(Aldrich) in capillaries and are uncorrected. The 1H, 13C{1H} and 19
F
NMR spectra were recorded in CDCl3 with TMS or CCl3F as the
internal standards using Bruker AC-200 or Bruker ARX-300 spectro-
meters. Assignments of signals in 13C NMR spectra were made on the
basisofDEPT135experiments. TheIRspectraweremeasured usinga
NEXUS FT-IR spectrophotometer. The MS spectra (CI, EI, ESI) were
obtained using LKB-2091, Finnigan MAT-95, or Bruker Esquire LC
spectrometers. OpticalrotationsweremeasuredonaPERKIN-ELMER
(700 MHz, CDCl3):
3JH,H = 8.4 Hz, arom. H), 8.01 (s, 1H, CH55N). 13C NMR
(175 MHz, CDCl3):
d 1.34 (s, 9H, C(CH3)3), 7.72, 8.34 (2d,
4
d
28.9 (C(CH3)3), 59.5 (C(CH3)3), 123.7 (q,
3
1JC,F = 271.2 Hz, CF3), 125.1 (q, JC,F = 3.5 Hz, 2 arom CH), 130.9 (2
2
arom. CH), 134.3 (q, JC,F = 31.7 Hz, 1 arom. C), 138.1 (1 arom. C),
154.2 (CH55N), 190.6 (C55O). 19F NMR (235 MHz, CDCl3):
d
ꢀ63.7 (s,
2974vs, 2935m, 2907m, 2873w, 1671vs (C55O),
1639m (C55N), 1578w, 1509w, 1464w, 1411s, 1366m, 1325vs,
241 MC spectropolarimeter for
l
= 589 nm. Elemental analyseswere
CF3). IR (film): v
performed in the Microanalytical Laboratory of the Centre of
Molecular and Macromolecular Studies PAS in Lodz.
1287vs, 1230s, 1170vs, 1131vs, 1111vs, 1063s, 1017s, 904w cmꢀ1
.
ESI-MS: m/z (rel. int.) 206 (28), 230 (100, [M+1]+), 252 (89,
[M+23]+).
4.2. Materials
2-(tert-Butylimino)-1-(benzofuran-20-yl)ethanone (7e). Yield:
0.95 g (83%). Yellow crystals, m.p. 109–110 8C (crude). 1H NMR
Commercial acetophenone (5a), p-methoxyacetophenone (5b),
p-nitroacetophenone (5c), p-(trifluoromethyl)acetophenone (5d),
sodium borohydride, were purchased from Sigma–Aldrich. Benzo-
furan-2-ylmethylketone (5e) and 7-ethylbenzofuran-2-ylmethylk-
etone (5f) were prepared according to the known protocol [8c]. 2,2-
Dihydroxyarylethan-2-ones 6a–f were prepared according to the
published procedure [12]. Dimethoxyethane (DME) was dried over
sodium benzophenone and they were freshly distilled prior to the
use. Dimethylsulfoxide (DMSO) was dried over CaH2, dimethylfor-
mamide (DMF) over CaSO4 and both distilled under reduced
(300 MHz, CDCl3):
7.59–7.63, 7.73–7.76 (4m, 4 arom. H), 7.97 (s, 1H, CH55N), 8.20 (d,
4JH,H = 0.9 Hz, 1 arom. H) ppm. 13C NMR (175 MHz, CDCl3):
29.0
d 1.35 (s, 9H, C(CH3)3), 7.28–7.33, 7.45–7.51,
d
(C(CH3)3), 59.3 (C(CH3)3), 112.5, 119.5, 123.8, 123.9, 128.7 (5 arom.
CH), 127.2, 150.2, 155.8 (3 arom. C), 153.9 (CH55N), 180.5 (C55O)
ppm. IR (KBr):
v 2974m, 2929w, 2900w, 2868w, 1655vs (C55O),
1608m (C55N), 1549s, 1474w, 1362w, 1303w, 1236w, 1210w,
1165s, 1146s, 1069m, 1028w, 933w, 843w, 804w, 756s cmꢀ1. ESI-
MS: m/z (rel. int.) 206 (27), 230 (100, [M+1]+), 252 (89, [M+23]+).
2-(tert-Butylamino)-1-(70-ethylbenzofuran-20-yl)ethanone
˚
pressure and stored over activated molecular sieves 4 A.
(7f). Yield: 1.04 g (81%). Brownish crystals, m.p. 67–68 8C (crude).
4.3. Syntheses of
a
-imino ketones 7a–l
1H NMR (300 MHz, CDCl3):
d 1.35 (s, 9H, C(CH3)3), 1.36 (t,
3
3JH,H = 7.8 Hz, 3H, CH2CH3), 3.02 (q, JH,H = 7.8 Hz, 2H, CH2CH3),
1
2
4.3.1. General procedure
7.22–7.33 (m, 2 arom. H), 7.58 (dd, JH,H = 1.5 Hz, JH,H = 7.5 Hz, 1
arom. H), 7.98 (s, 1H, CH55N), 8.15 (s, 1 arom CH55N). 13C NMR
Aryl-2,2-dihydroxyethanones 6a–f (5 mmol) and the corre-
sponding amine (5.05 mmol) were dissolved in methylene chloride
(5 ml) and the solution was stirred magnetically, in the presence of
(75 MHz, CDCl3):
d 14.0 (CH2CH3), 22.7 (CH2CH3), 29.0 (C(CH3)3),
59.3 (C(CH3)3), 119.9, 121.1, 124.0, 127.6 (4 arom. CH), 126.9,

G. Mloston et al. / Journal of Fluorine Chemistry 131 (2010) 1289–1296
1293
129.0, 150.0 (3 arom. C), 154.0 (1 arom. CH), 154.6 (CH55N), 180.6
(C55O). IR (KBr): 2968s, 2929w, 2897w, 1657vs (C55O), 1635s
(C55N), 1554s, 1488w, 1360w, 1353m, 1314m, 1212w, 1169s,
1071w, 966w, 904w, 849m, 745m cmꢀ1. ESI-MS: m/z (rel. int.) 202
(89), 258 (100, [M+1]+), 280 (59, [M+23]+).
NMR (600 MHz, CDCl3):
d
1.64 (d, 3JH,H = 6.6 Hz, 3H, CH3), 3.87 (s,
3
v
OCH3), 4.59 (q, JH,H = 6.6 Hz, 1H, CH), 6.93–6.96 (m, 2 arom. H),
7.27–7.31 (m, 1 arom. H), 7.36–7.39 (m, 2 arom. H), 7.41–7.43 (m, 2
arom. H), 8.10 (s. 1H, CH55N), 8.27–8.30 (m, 2H, 2 arom. H). 13C
NMR (150 MHz, CDCl3):
126.6, 127.3, 128.6, 133.5 (9 arom. CH), 128.1, 143.5, 158.4 (3
arom. C), 164.0 (CH55N), 189.1 (C55O). IR (KBr): 3084w, 3060w,
3030w, 2972m, 2931w, 2866w, 1658s (C55O), 1598vs (C55N),
1573w, 1510m, 1453w, 1371w, 1261vs, 1173s, 1026m, 843m cmꢀ1
ESI-MS: m/z 266 (100, [Mꢀ1]+). [
d 24.5 (CH3), 55.3 (OCH3), 70.5 (CH), 113.6,
2-(Isopropylimino)-1-phenylethanone (7g). Yield: 0.81 g (93%).
Yellow colored viscous oil. 1H NMR (600 MHz, CDCl3):
d
1.31 (d,
v
3JH,H = 6.0 Hz, 6H, CH(CH3)2), 3.62 (dsept., 3JH,H = 6.6 Hz,
4JH,H = 0.6 Hz, 1H, CH(CH3)2), 7.44–7.47 (m, 2 arom. H), 7.56–
.
4
7.59 (m, 1 arom. H), 8.07 (d, JH,H = 0.6 Hz, 1H, CH55N), 8.19–8.21
a]D = +40 (c = 1.0).
(m, 2 arom. H). 13C NMR (150 MHz, CDCl3):
d
23.6 (CH(CH3)2), 62.2
(CH(CH3)2), 128.3, 130.6, 133.4 (5 arom. CH), 135.2 (1 arom. C),
156.9 (CH55N), 191.0 (C55O). IR (film): 3069w, 3028w, 2971s,
4.4. Synthesis of
b-amino-a-trifluoromethyl alcohols 9
v
2930m, 2869s, 1663vs (C55O), 1598s (C55N), 1578m, 1448s, 1381w,
1362w, 1317m, 1286vs, 1180w, 1143m, 1065w, 1026w, 944w,
853m cmꢀ1. ESI-MS: m/z (rel. int.) 167 (33), 176 (100, [M+1]+), 198
(7, [M+23]+).
4.4.1. Reactions of
a-imino ketones 7 with
(trifluoromethyl)trimethylsilane
Method A—a general procedure. A solution of the corresponding
a
-imino ketone 7a–l (1 mmol) in anhydrous DME (1.5 ml), was
2-(Isopropylimino)-1-(40-methoxyphenyl)ethanone
(7h).
placed in a dry, two-necked flask, equipped with septum and a tube
filled with anhydrous CaCl2. Next, catalytic amount 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 three times with CH2Cl2. The
organic layers were combined and dried over anhydrous Na2SO4.
After filtration, the solvents were evaporated and the crude, oily
products 8a–l were used for further reactions without purification.
Method B—a general procedure. A solution of the corresponding
Yield: 0.94 g (92%). Yellow colored, viscous oil. 1H NMR
3
(200 MHz, CDCl3):
d
1.31 (d, JH,H = 6.3 Hz, 6H, CH(CH3)2), 3.60
3
(sept., JH,H = 6.3 Hz, 1H, CH(CH3)2), 3.87 (s, 3H, OCH3), 6.94, 8.23
(2d, JH,H = 8.8 Hz, 4 arom. H). 13C NMR (50 MHz, CDCl3):
3
d 23.4
(CH(CH3)2), 55.2 (OCH3), 61.9 (CH(CH3)2), 113.5, 132.8 (4 arom.
CH), 127.9, 157.9 (2 arom. C), 163.8 (CH55N), 189.2 (C55O). IR (film):
v
2970vs, 2933s, 2868m, 1656vs (C55O), 1598vs (C55N), 1572s,
1509s, 1464s, 1421s, 1362m, 1315s, 1258vs, 1173s, 1143m, 1116w,
1070w, 1028s, 957w, 856m cmꢀ1. ESI-MS: m/z (rel. int.) 164 (93),
178 (20), 206 (100, [M+1]+), 228 (25, [M+23]+).
a
-imino ketone 7a–c (1 mmol) in 1.5 ml of anhydrous DMF was
2-(Isopropylimino)-1-(40-nitrophenyl)ethanone (7i). Yield:
placed in a dry two-necked flask equipped with septum and a tube
filled with anhydrous CaCl2. Next, catalytic amount of freshly dried
K2CO3 and (trifluoromethyl)trimethylsilane (0.17 ml, 157 mg,
1.1 mmol) were added. The reaction solution was stirred
magnetically at room temperature and after ca. 3 h was quenched
with water (5 ml). The mixture was extracted three times with
CH2Cl2. The organic layers were separated, combined and dried
over anhydrous Na2SO4. After filtration, the solvents were
evaporated and the crude oily products 8a–c were used for further
reactions without purification.
1.05 g (95%). Yellow crystals, m.p. 28ꢀ34 8C (crude). 1H NMR
3
(600 MHz, CDCl3):
d
1.31 (d, JH,H = 6.6 Hz, 6H, CH(CH3)2), 3.66
3
4
(dsept., JH,H = 6.6 Hz, JH,H = 0.6 Hz, 1H, CH(CH3)2), 8.07 (d,
4JH,H = 0.6 Hz, 1H, CH55N), 8.27–8.30, 8.37–8.39 (2m, 4 arom. H).
23.5 (CH(CH3)2), 62.2 (CH(CH3)2),
123.2, 131.7 (4 arom. H), 139.9, 150.3 (2 arom. C), 156.7 (CH55N),
196.2 (C55O). IR (KBr): 2973w, 2933w, 2872w, 1661m (C55O),
13C NMR (150 MHz, CDCl3):
d
v
1601m (C55N), 1523vs, 1467w, 1345s, 1317w, 1288m, 1147w,
1109w, 1014w, 952w, 866w cmꢀ1. ESI-MS: m/z (rel. int.) 179 (40),
203 (16), 218 (70), 221 (100, [M+1]+).
2-(Isopropylimino)-1-[40-(trifluoromethyl)phenyl]ethanone
(7j). Yield: 0.94 g (92%). Yellow colored, viscous oil. 1H NMR
Method C—a general procedure. A solution of the corresponding
a
-imino ketone 7a–c (1 mmol) in anhydrous DMSO (2.0 ml) an
˚
freshly activated molecular sieves 4 A were placed in a dry, two-
necked flask equipped with septum and a tube filled with
anhydrous CaCl2. Next, (trifluoromethyl)trimethysilane (0.17 ml,
157 mg, 1.1 mmol) was added drop-wise and the reaction solution
was stirred magnetically at room temperature for ca. 3 h. After this
time, a portion of water (5 ml) was added and the mixture was
extracted three times with CH2Cl2. The organic layers were
combined and dried over anhydrous Na2SO4. After filtration, the
solvents were evaporated and the crude, oily products 8a–c were
used for further reactions without purification.
3
(600 MHz, CDCl3):
d
1.31 (d, JH,H = 6.6 Hz, 6H, CH(CH3)2), 3.65
3
4
(dsept., JH,H = 6.6 Hz, JH,H = 0.6 Hz, 1H, CH(CH3)2), 7.72 (d,
3JH,H = 8.4 Hz, 2 arom. H), 8.32 (dq, JH,H = 8.4 Hz, JH,F = 1.2 Hz, 2
3
4
arom. H), 8.52 (d, JH,H = 0.6 Hz, 1H, CH55N). 13C NMR (150 MHz,
4
CDCl3):
d
23.5 (CH(CH3)2), 62.2 (CH(CH3)2), 123.6 (q,
3
1JC,F = 271.7 Hz, CF3), 125.2 (q, JC,F = 3.0 Hz, 2 arom CH), 131.0 (2
2
arom. CH), 134.4 (q, JC,F = 33.2 Hz, 1 arom. C), 138.0 (1 arom. C),
156.8 (CH55N), 190.1 (C55O). IR (film):
v 2974s, 2934w, 2872m,
1671s (C55O), 1618w (C55N), 1578w, 1468w, 1411m, 1383w,
1325vs, 1285s, 1171s, 1131vs, 1111s, 1077s, 1062s, 1017m,
958w, 858m, 845m cmꢀ1. ESI-MS: m/z (rel. int.) 202 (49), 226
(22), 244 (100, [M+1]+).
2-{10-[(10S)-10-Phenylethyl]imino}phenylethanone (7k). Yield:
1.11 g (94%). Orange colored semi-solid material. 1H NMR
4.4.2. Reduction of adducts 8a–l with sodium borohydride—a general
procedure
To a magnetically stirred solution of the corresponding adduct
8a–l in EtOH (3 ml), sodium borohydride (228 mg, 6 mmol) was
added in small portions while cooling the reaction flask in ice-bath.
When the evolution of hydrogen was complete, the mixture was
stirred at room temperature over next 12 h. After this time the
solvent was evaporated and the solid residue was treated with a
portion of water (ca. 10 ml), and subsequently extracted with
CH2Cl2. The organic layers were combined, dried over anhydrous
Na2SO4. After filtration, the solvents were evaporated and the
crude products were purified by distillation in vacuum or
crystallized.
3
(300 MHz, CDCl3):
d
1.64 (d, JH,H = 6.6 Hz, 3H, CH3), 4.61 (q,
3JH,H = 6.6 Hz, 1H, CH), 7.27–7.49 (m, 7H, 7 arom. H), 7.57–7.62 (m,
1H, 1 arom. H), 8.12 (s. 1H, CH55N), 8.21–8.24 (m, 2H, 2 arom. H).
24.6 (CH3), 70.6 (CH), 126.6, 127.4,
128.3, 128.7, 130.7, 133.5 (10 arom. CH), 135.1, 143.4 (2 arom. C),
158.1 (CH55N), 190.9 (C55O). IR (KBr): 3085w, 3061w, 3029w,
13C NMR (75 MHz, CDCl3):
d
v
2973m, 2927w, 2866w, 1663vs (C55O), 1598s (C55N), 1578w,
1493m, 1488s, 1370w, 1286s, 1179w, 1070w, 1026w, 960w, 762m
cmꢀ1. ESI-MS: m/z 236 (100, [Mꢀ1]+). [
a]D = +10 (c = 1.0).
2-{10-[(10S)-10-Phenylethyl]imino}-4-methoxyphenylethanone
(7l). Yield: 1.11 g (94%). Orange colored, semi-solid material. 1H
3-(tert-Butylamino) 1,1,1-trifluoro-2-phenylpropan-2-ol (9a).
Crude product was purified by distillation in Kugel–Rohr apparatus

1294
G. Mloston et al. / Journal of Fluorine Chemistry 131 (2010) 1289–1296
at 100 8C/0.08 Pa. Yield: 196–236 mg (75–90%) (see Table 2).
Colorless crystals, m.p. 30–32 8C. 1H NMR (300 MHz, CDCl3):
1.09
(s, 9H, C(CH3)3), 2.87 (dq, JH,H = 12.9 Hz, JH,F = 1.2 Hz 1H, CH2),
3.39 (d, 2JH,H = 12.9 Hz, 1H, CH2), 5.74 (br. s, 1H, OH) [16], 7.33–7.43
(m, 3 arom. H), 7.57–7.62 (m, 2 arom. H) ppm. 13C NMR (75 MHz,
filtration trough neutral Al2O3 plug (hexane/CH2Cl2 1:1) and
subsequently recrystallized from hexane. Yield: 210 mg (70%).
d
2
4
Colorless crystals, m.p. 45–48 8C (hexane). 1H NMR (700 MHz,
2
CDCl3):
d
1.13 (s, 9H, C(CH3)3), 3.22, 3.29 (2d, JH,H = 12.6 Hz, 2H,
CH2), 6.97 (s, 1H, 1 arom. H), 7.25–7.27, 7.31–7.34, 7.51–7.53,
CDCl3):
2JC,F = 27.5 Hz, Cq), 127.6 (q, JC,F = 286.1 Hz, CF3), 126.0, 128.1,
128.2 (5 arom. CH), 138.0 (1 arom. C). 19F NMR (188 MHz, CDCl3):
ꢀ94.3 (s, CF3). IR (KBr): 3449m,br (OH), 3331s (NH), 2976m,
2938w, 1636w, 1451w, 1397w, 1369w, 1271m, 1231w, 1208w,
1159vs, 1126w, 1075w, 1059w, 1016w, 974w, 747m, 707s cmꢀ1
d
28.9 (C(CH3)3), 46.4 (CH2) 50.5 (C(CH3)3), 72.8 (q,
7.60–7.61 (4m, 4 arom. H). 13C NMR (175 MHz, CDCl3):
(C(CH3)3), 44.3 (CH2) 51.2 (C(CH3)3), 72.1 (q, JC,F = 29.9 Hz, Cq),
106.8, 111.8, 121.7, 123.4, 125.0 (5 arom. CH), 125.2 (q,
1JC,F = 285.3 Hz, CF3), 128.0, 154.1, 155.5 (3 arom. C). 19F NMR
d
29.4
1
2
d
v
(235 MHz, CDCl3):
d
ꢀ79.3 (s, CF3). IR (KBr):
v 3358m.br (OH),
.
3129m (NH), 2962s, 2934m, 2899m, 2870m, 1618w, 1484m, 1455s,
1407m, 1369s, 1354m, 1302m, 1268s, 1252s,1210s, 1175vs,
1164vs, 1093m, 1064s, 1017m, 944s, 939w, 860m, 756s, 726m,
699m, 654w cmꢀ1. ESI-MS: m/z (rel. int.) 228 (27), 302 (100,
[M+1]+), 324 (27, [M+23]+). Anal. Calcd. for C15H18F3NO2 (301.31):
C, 59.79; H, 6.02. Found: C, 60.08; H, 6.20.
ESI-MS: m/z (rel. int.) 188 (55), 206 (100), 262 (47, [M+1]+), 284 (9,
[M+23]+). Anal. Calcd. for C13H18F3NO (261.23): C, 59.76; H, 6.94;
N, 5.36. Found: C, 59.78; H, 6.90; N, 5.46.
3-(tert-Butylamino) 1,1,1-trifluoro-2-(40-methoxyphenyl)pro-
pan-2-ol (9b). Crude product was distilled in Kugel–Rohr appara-
tus at 110 8C/0.08 Pa as a thick oil, which at room temperature
forms a semi-solid material. Yield: 206–219 mg (70–75%) (see
3-(tert-Butylamino)
2-(70-ethylbenzofuran-20-yl)-1,1,1-tri-
fluoropropan-2-ol (9f). Crude product was purified by filtration
trough neutral Al2O3 plug (hexane/CH2Cl2 1:1) and subsequently
crystallized. Yield: 244 mg (74%). Colorless crystals, m.p. 23–25 8C
Table 2). Colorless crystals, m.p. 37–40 8C. 1H NMR (300 MHz,
2
CDCl3):
d
1.09 (s, 9H, C(CH3)3), 2.86 (dq, JH,H = 12.6 Hz,
4JH,F = 0.9 Hz, 1H, CH2), 3.34 (d, JH,H = 12.9 Hz, 1H, CH2), 3.82 (s,
3H, OCH3), 6.89–6.94 (m, 2 arom. H), 7.48–7.53 (m, 2 arom. H). 13
NMR (75 MHz, CDCl3): 29.0 (C(CH3)3), 46.4 (CH2), 50.6 (C(CH3)3),
55.2 (OCH3), 72.7 (q, JC,F = 27.5 Hz, Cq), 113.6, 127.4, 127.5 (4
arom. CH), 125.8 (q, 1JC,F = 285.7 Hz, CF3), 130.0, 159.6 (2 arom. C).
(hexane). 1H NMR (700 MHz, CDCl3):
d 13 (s, 9H, C(CH3)3), 1.35 (t,
2
C
3JH,H = 7.7 Hz, 3H, CH2CH3) 2.91–2.97 (m, 2H, CH2CH3), 3.21, 3.29
(2d, 2JH,H = 12.6 Hz, 2H, CH2), 6.95 (s, 1 arom. H), 7.17–7.19 (m, 1
arom. H), 7.14, 7.42 (2d, 3JH,H = 7.7 Hz, 2 arom. H) ppm. 13C NMR
d
2
(176 MHz, CDCl3): d 14.3 (CH2CH3), 23.3 (CH2CH3), 29.4 (C(CH3)3),
19F NMR (188 MHz, CDCl3):
d
ꢀ2.5 (s, CF3). IR (KBr):
v
3447m.br
44.3 (CH2) 51.4 (C(CH3)3), 72.2 (q, 2JC,F = 29.9 Hz, Cq), 107.1, 119.3,
1
(OH), 3327m (NH), 2963vs, 2915s, 2891s, 2855s, 1612m, 1515vs,
1455m, 1366m, 1254vs, 1172s, 1158s, 1221s, 1083m, 1035m,
976w, 914w, 874m, 888s, 883m, 734s, cmꢀ1. CI-MS (isobutane): m/
z (rel. int.) 292 (100, [M+1]+). Anal. Calcd. for C14H20F3NO (291.32):
C, 57.72; H, 6.92; N, 4.81. Found: C, 57.98; H, 6.83; N, 4.87.
3-(tert-Butylamino) 1,1,1-trifluoro-2-(40-nitrophenyl)propan-
2-ol (9c). Crude product was preliminarily purified by filtration
trough neutral Al2O3 plug (hexane/CH2Cl2 1:1) and subsequently
crystallized. Yields: 234–257 mg (76–84%) (see Table 2). Colorless
crystals, m.p. 101–104 8C (hexane/CH2Cl2). 1H NMR (300 MHz,
123.6, 124.5 (4 arom. CH), 125.1 (q, JC,F = 287.0 Hz, CF3), 127.7,
128.2, 153.5, 154.2 (4 arom. C). 19F NMR (235 MHz, CDCl3):
d
ꢀ79.4 (s, CF3) ppm. IR (film):
v 3338m.br, 3126m, 3063m, 3032m,
2969vs, 2936m, 2876m, 1716w, 1601w, 1484m, 1464m, 1427m,
1368m, 1277m, 1257m, 1180vs, 1146vs, 1096m, 1052m, 986m,
937w, 870m, 823m, 784m, 707w cmꢀ1. ESI-MS: m/z (rel. int.) 256
(58), 274 (14), 330 (100, [M+1]+), 352 (48, [M+23]+). Anal. Calcd.
for C17H22F3NO2 (329.37): C, 61.99; H, 6.73. Found: C, 61.92;
H, 6.55.
1,1,1-Trifluoro-3-(isopropylamino) 2-phenylpropan-2-ol (9g).
Crude product was purified by filtration trough neutral Al2O3 plug
(hexane/CH2Cl2 9:1). Yield: 178 mg (72%). Colorless, thick oil. 1H
CDCl3):
d 1.09 (s, 9H, C(CH3)3), 1.25 (br. s, 1H, NH), 2.78, 3.47 (2d,
2JH,H = 13.2 Hz, 1H, CH2), 6.00 (br. s, 1H, OH), 7.77–7.80 (m, 2 arom.
H), 8.21–8.26 (m, 2 arom. H). 13C NMR (75 MHz, CDCl3):
(C(CH3)3), 46.5 (CH2) 50.9 (C(CH3)3), 72.9 (q, JC,F = 27.8 Hz, Cq),
125.3 (q, 1JC,F = 286.3 Hz, CF3), 123.4, 127.32, 127.34 (4 arom. CH),
145.3, 148.0 (2 arom. C). 19F NMR (188 MHz, CDCl3):
d
29.0
NMR (700 MHz, CDCl3):
d
1.07, 1.11 (2d, JH,H = 6.3 Hz, 6H,
3
2
2
CH(CH3)2), 2.79–2.83 (m, 1H, CH(CH3)2), 2.94 (dq, JH,H = 13.3 Hz,
4JH,F = 0.7 Hz, 1H, CH2), 3.52 (d, 2JH,H = 13.3 Hz, 1H, CH2), 7.38–7.44
(m, 3 arom. H), 7.64 (d, JH,H = 7.7 Hz, 2 arom H). 13C NMR
3
d
ꢀ1.9 (s, CF3).
IR (KBr):
v
3447m.br (OH), 3320m (NH), 3124w, 2982m, 2964m,
(175 MHz, CDCl3): d 23.0, 23.2 (CH(CH3)2), 49.5 (CH2), 50.8
2
1
1607w, 1523vs, 1397w, 1491w, 1352vs, 1280m, 1273m, 1227m,
1173vs, 1152vs, 1102s, 977w, 897w, 850s, 743w, 703m, cmꢀ1. CI-
MS (isobutane): m/z (rel. int.) 293 (14), 307 (100, [M+1]+). Anal.
Calcd. for C13H17F3N2O3 (306.29): C, 50.98; H, 5.59; N, 8.61. Found:
C, 51.55; H, 5.67; N, 8.91.
3-(tert-Butylamino) 1,1,1-trifluoro-2-[40-(trifluoromethyl)phe-
nyl]propan-2-ol (9d). Crude product was distilled in Kugel–Rohr
apparatus at 100 8C/0.08 Pa; thick oil, forms a semi-solid material
at room temperature. Yield: 291 mg (89%). Colorless crystals, m.p.
(CH(CH3)2), 73.2 (q, JC,F = 26.4 Hz, Cq), 125.8 (q, JC,F = 286.0 Hz,
CF3), 126.2, 128.3, 128.5 (5 arom. H), 138.1 (1 arom. C). 19F NMR
(235 MHz, CDCl3):
d
ꢀ78,9 (s, CF3). IR (film):
v 3340m.br, 3094m,
3064m, 3038m, 2968s, 2934m, 2873m, 1605w, 1497m, 1470m,
1452s, 1387m, 1372m, 1247s, 1215s, 1154vs, 1123s, 1074s, 1045s,
1028m, 983m, 923w, 880w, 766s, 702s cmꢀ1. CI-MS (isobutane): m/
z (rel. int.) 248 (100, [M+1]+). ESI-HRMS: (m/z) for C12H17F3NO
([M+1]+) calcd.: 248.12568. Found: 248.12543.
1,1,1-Trifluoro-3-(isopropylamino) 2-(40-methoxyphenyl)pro-
pan-2-ol (9h). Crude product was purified by filtration trough
neutral Al2O3 plug (hexane/CH2Cl2 9:1). Yield: 175 mg (69%).
Colorless semi-solid material, m.p. 24–27 8C. 1H NMR (700 MHz,
23–25 8C. 1H NMR (700 MHz, CDCl3):
d 1.09 (s, 9H, C(CH3)3), 2.81,
3.44 (2d, 2JH,H = 12.6 Hz, 2H, CH2), 3.82 (s, 3H, OCH3), 7.66, 7.73 (2d,
3JH,H = 8.4 Hz, 4 arom. H). 13C NMR (75 MHz, CDCl3):
d 29.4
2
(C(CH3)3), 46.9 (CH2) 51.2 (C(CH3)3), 72.2 (q, JC,F = 28.2 Hz, Cq),
CDCl3): d
1.06, 1.10 (2d, 3JH,H = 6.3 Hz, 6H, CH(CH3)2), 2.78–2.83 (m,
1
3
124.3 (q, JC,F = 272.9 Hz, CF3), 125.6 (q, JC,F = 3.5 Hz, 2 arom. H),
1H, CH(CH3)2), 2.93, 3.46 (2d, 2JH,H = 12.6 Hz, 2H, CH2), 3.84 (s, 3H,
OCH3), 6.95, 7.53 (2d, 3JH,H = 9.1 Hz, 4 arom. H). 13C NMR (175 MHz,
1
125.9 (q, JC,F = 285.3 Hz, CF3), 127.0 (2 arom. CH), 131.1 (q,
2JC,F = 33.5 Hz, 1 arom. C), 142.6 (1 arom. C). 19F NMR (235 MHz,
CDCl3): d 23.1, 23.2 (CH(CH3)2), 49.4 (CH2), 50.7 (CH(CH3)2), 55.2
2
1
CDCl3):
d
ꢀ63.2 (s, CF3), –78.7 (s, CF3). IR (KBr):
v
3432m.br, 2971m,
(OCH3), 73.0 (q, JC,F = 27.8 Hz, Cq), 125.8 (q, JC,F = 285.3 Hz, CF3),
113.6, 127.5 (4 arom. CH), 130.4, 159.7 (2 arom. C). 19F NMR
2939w, 2875w, 1622w, 1473w, 1416w, 1369w, 1329vs, 1271w,
1211w, 1170vs, 1130s, 1107s, 1071s, 1019w, 977w, 839w, 735w,
656w cmꢀ1. CI-MS (isobutane): m/z 330 (100, [M+1]+). Anal. Calcd
for C14H17F6NO (329.29): C, 51.07; H, 5.20. Found: C, 51.23; H, 5.46.
(235 MHz, CDCl3):
d
ꢀ79.2 (s, CF3). IR (KBr):
v 3425m.br, 2967m,
2937m, 2873w, 2841w, 1612m, 1516s, 1467m, 1443w, 1387w,
1308m, 1254s, 1158vs, 1106m, 1034m, 983w, 831m cmꢀ1. CI-MS
(isobutane): m/z (rel. int.) 278 (100, [M+1]+). Anal. Calcd. for
C13H18F3NO2 (277.29): C, 56.31; H, 6.54. Found: C, 56.37; H, 6.95.
2-(Benzofuran-20-yl)-3-(tert-butylamino)
1,1,1-trifluoropro-
pan-2-ol (9e). Crude product was preliminarily purified by

G. Mloston et al. / Journal of Fluorine Chemistry 131 (2010) 1289–1296
1295
1,1,1-Trifluoro-3-(isopropylamino) 2-(40-nitrophenyl)propan-
2-ol (9i). Crude product was purified by filtration trough neutral
Al2O3 plug (hexane/CH2Cl2 8:2) and subsequently crystallized.
preliminarily purified mixture of diastereomers: 264 mg (78%).
Separation of diastereomers was performed by column chroma-
tography on silica gel using the mixture of hexane and Et2O
(85:15).
Yield: 228 mg (78%). Yellowish crystals, m.p. 41–44 8C (hexane). 1H
3
NMR (700 MHz, CDCl3):
d
1.06, 1.11 (2d, JH,H = 7.0 Hz, 6H,
Fast-(2S, 10S)-9l (major). Yield: 142 mg (42%). Yellowish semi-
CH(CH3)2), 2.77–2.81 (m, 1H, CH(CH3)2), 2.82, 3.58 (2d,
solid material. 1H NMR (600 MHz, CDCl3):
d
1.36 (d,
3
2
2JH,H = 13.3 Hz, 2H, CH2), 7.80, 8.24 (2d, JH,H = 8.6 Hz, 4 arom.
3JH,H = 6.6 Hz,3H, CH3), 2.82, 3.28 (2d, JH,H = 12.6 Hz, 2H, CH2),
H). 13C NMR (175 MHz, CDCl3):
d
23.0, 23.1 (CH(CH3)2), 49.6 (CH2),
3.68 (q, JH,H = 6.6 Hz,1H, CH), 3.82 (s, 3H, OCH3), 6.90–6.92 (m, 2
3
50.6 (CH(CH3)2), 73.1 (q, 2JC,F = 26.4 Hz, Cq), 125.3 (q,
1JC,F = 287.0 Hz, CF3), 123.4, 127.6 (4 arom. CH), 145.3, 148.0 (2
arom. H), 7.20–7.23 (m, 2 arom. H), 7.29–7.30 (m, 1 arom. H), 7.35–
7.37 (m, 2 arom. H), 7.47–7.49 (2 arom. H). 13C NMR (150 MHz,
arom. C). 19F NMR (235 MHz, CDCl3):
d
ꢀ78.7 (s, CF3). IR (KBr):
3358m.br, 3115w, 2974m, 2873w, 1601m, 1523vs, 1468m, 1454m,
1416m, 1355s, 1306m, 1261m, 1218m, 1161 s, 1122m, 1100m,
v
CDCl3): d 24.2 (CH3), 51.4 (CH2), 55.6 (OCH3), 58.8 (CH), 73.5 (q,
1
2JC,F = 28.7 Hz, Cq), 125.9 (q, JC,F = 285.3 Hz, CF3), 113.9, 126.4,
v
127.7, 129.0 (9 arom. CH), 130.0, 144.5, 160.0 (3 arom. C). 19F NMR
1041m, 1030m, 974w, 873w, 848m, 811w, 699m cmꢀ1. CI-MS
(isobutane): m/z 293 (100, [M+1]+). Anal. Calcd. for C12H15F3N2O3
(292.26): C, 49.32; H, 5.17. Found: C, 49.50; H, 5.15.
(565 MHz, CDCl3):
2935w, 2878w, 1612w, 1514w, 1455w, 1372w, 1261m, 1238m,
1183s, 1160vs, 1173vs, 1150s, 1174vs, 1117m, 1032m, 977w cmꢀ1
ESI-HRMS: (m/z) for C18H21F3NO2 ([M+1]+) calcd.: 340.15189.
d
ꢀ78.8 (CF3). IR (film):
v 3063w, 3034w, 2968w,
.
1,1,1-Trifluoro-3-(isopropylamino) 2-[4-(trifluoromethyl)phe-
nyl]propan-2-ol (9j). Crude product was purified by filtration
trough neutral Al2O3 plug (hexane/CH2Cl2 9:1). Yield: 227 mg (72%).
Found: 340.15172. [
a
]
D = ꢀ45 (c = 1.0).
Slow-(2R,10S)-9l (minor). Yield: 101 mg (30%). Yellowish oil. 1H
Colorless, thick oil. 1H NMR (700 MHz, CDCl3):
d
1.05, 1.10 (2d,
NMR (600 MHz, CDCl3):
d
1.40 (d, JH,H = 6.6 Hz,3H, CH3), 2.90 (d,
3
3JH,H = 6.3 Hz, 6H, CH(CH3)2), 2.76–2.85 (m, 1H, CH(CH3)2), 2.84, 3.53
(2d, 2JH,H = 13.3 Hz, 2H, CH2), 7.65, 7.72 (2d, 3JH,H = 8.4 Hz, 4 arom.
2JH,H = 12.6 Hz, 1H, CH2), 3.29 (dq, 2JH,H = 12.6 Hz, 4JH,F = 1.2 Hz 1H,
CH2), 3.81 (s, 3H, CH3), 3.83 (q, 3JH,H = 6.6 Hz,1H, CH), 6.90–6.91 (m,
2 arom. H), 7.23–7.24 (m, 2 arom. H), 7.26–7.29 (m, 1 arom. H),
7.34–7.36(m, 2 arom. H), 7.45–7.46 (m, 2 arom. H). 13C NMR
H). 13C NMR (75 MHz, CDCl3):
d
23.4, 23.5 (CH(CH3)2), 49.9 (CH2),
51.0 (CH(CH3)2), 73.4 (q, 2JC,F = 26.4 Hz, Cq), 124.3 (q, 1JC,F = 271.2 Hz,
3
1
CF3), 125.6 (q, JC,F = 3.5 Hz, 2 arom. CH), 125.8 (q, JC,F = 287.0 Hz,
CF3), 127.0 (2 arom. CH), 131.1 (q, 2JC,F = 31.7 Hz, 1 arom. C), 142.5 (1
(150 MHz, CDCl3): d 23.1 (CH3), 50.1 (CH2), 54.37 (OCH3), 57.4
2
1
(CH), 73.0 (q, JC,F = 27.2 Hz, Cq), 124.8 (q, JC,F = 285.3 Hz, CF3),
112.9, 125.5, 126.6, 126.8, 127.9 (9 arom. CH), 128.6, 143.3, 158.9
arom. C). 19F NMR (235 MHz, CDCl3):
IR (film):
d
ꢀ63.2 (s, CF3), – 78.8 (s, CF3).
v
3343m.br, 2970s, 2936m, 2875m, 1932w, 1622m, 1471m,
(3 arom. C). 19F NMR (565 MHz, CDCl3):
d
ꢀ78.6 (CF3). IR (film):
v
1417m, 1388m, 1329vs, 1248s, 1166vs, 1128vs 1106vs, 1070vs,
1044m, 1018s, 984m, 923w, 838s, 790w cmꢀ1. CI-MS (isobutane): m/
z (rel. int.) 316 (100, [M+1]+). Anal. Calcd for C13H15F6NO (315.26): C,
49.53; H, 4.88. Found: C, 49.74; H, 4.85.
3343m (NH), 3063w, 3028w, 2966m, 2934m, 2840m, 1896w,
1611s, 1583m, 1515s, 1465m, 1403m, 1375m, 1305s, 1281s,
1254vs, 1174vs, 1158vs, 1031s, 969m cmꢀ1. ESI-HRMS: (m/z) for
18H21F3NO2 ([M+1]+) calcd.: 340.15189. Found: 340.15163.
D = ꢀ13 (c = 1.0).
C
[a]
(2R/2S)-1,1,1-Trifluoro-3-{10-[(10S)-10-phenylethylamino]}-2-
phenylpropan-2-ol ((2R/2S,10S)-9k). Total yield of preliminarily
purified mixture of diastereomers: 210–232 mg (68–75%) (see
Table 3). Separation of diastereomers was performed by column
chromatography on silica gel using mixture of hexane and Et2O
(85:15).
Acknowledgment
The authors thank the Polish Ministry for Science and Higher
Education for a grant (Grant # N N204 130335) (G.M. and E.O.).
Fast-(2S,10S)-9k (major). Yield: 123 mg (40%). Yellowish oil. 1H
1.27 (d, 3JH,H = 6.6 Hz,3H, CH3), 2.74 (dq,
References
NMR (600 MHz, CDCl3):
d
4
2
2JH,H = 13.2 Hz, JH,F = 1.2 Hz 1H, CH2), 3.23 (d, JH,H = 13.2 Hz, 1H,
[1] (a) R.D. Chambers, Fluorine in Organic Chemistry, Blackwell, Oxford, 2004;
(b) P. Kirsh, Modern Fluoroorganic Chemistry, Wiley-VCH, Weinheim, Germany,
2004;
3
CH2), 3.57 (q, JH,H = 6.6 Hz,1H, CH), 7.07–7.12 (m, 2 arom. H),
7.17–7.21 (m, 1 arom. H), 7.26–7.34 (m, 5 arom. H), 7.46–7.47 (m, 2
arom. H). 13C NMR (150 MHz, CDCl3):
d 23.92 (CH3), 51.2 (CH2),
´
´
(c) J.-P. Begue, D. Bonnet-Delpon, Bioorganic and Medicinal Chemistry of
58.6 (CH), 73.5 (q, 2JC,F = 27.2 Hz, Cq), 125.6 (q, 1JC,F = 286.8 Hz, CF3),
126.3, 127.5, 128.3, 128.5, 128.8 (10 arom. CH), 137.8, 144.2 (2
Fluorine, Wiley, Hoboken, NJ, 2008;
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arom. C). 19F NMR (565 MHz, CDCl3):
d
ꢀ78.4. IR (film):
v 3344m
(NH), 3063m, 3030m, 2929m, 2872m, 1956w, 1495s, 1451vs,
1404m, 1376m, 1305m, 1280m, 1242s, 1177vs, 1155vs, 1074m,
1029m, 998m, 899w cmꢀ1. ESI-HRMS: (m/z) for C17H19F3NO
([M+1]+) calcd.: 310.14133 Found: 310.14137. [
a
]D = ꢀ54 (c = 1.0).
Slow-(2R,10S)-9k (minor). Yield: 83 mg (27%). Yellowish oil. 1H
NMR (600 MHz, CDCl3):
d
1.39 (d, 3JH,H = 6.6 Hz,3H, CH3), 2.88 (dq,
4
2
2JH,H = 12.6 Hz, JH,F = 1.2 Hz 1H, CH2), 3.31 (d, JH,H = 12.6 Hz, 1H,
(c) G.K.S. Prakash, C. Panja, H. Vaghoo, V. Surampudi, R. Kultyshev, M. Mandal, G.
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Int. Ed. 37 (1998) 820–821;
3
CH2), 3.82 (q, JH,H = 6.6 Hz,1H, CH), 7.20–7.22 (m, 2 arom. H),
7.24–7.27 (m, 1 arom. H), 7.32–7.38 (m, 5 arom. H), 7.50–7.52 (2
arom. H). 13C NMR (150 MHz, CDCl3):
(CH), 73.8 (q, JC,F = 28.7 Hz, Cq), 125.5 (q, JC,F = 283.8 Hz, CF3),
d
24.0 (CH3), 50.9 (CH2), 58.2
(f) K. Funabiki, A. Shibata, H. Iwata, K. Hatano, Y. Kubota, K. Komura, M. Ebihara,
M. Matusi, J. Org. Chem. 73 (2008) 4694–4697.
2
1
126.2, 126.3, 127.4, 128.3, 128.5, 128.8 (10 arom. H), 137.4, 144.0
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590;
(2 arom. C). 19F NMR (565 MHz, CDCl3):
d
ꢀ78.2. IR (film):
v 3344m
(NH), 3063m, 3030m, 2969m, 2929m, 2872m, 1956w, 1495m,
1451s, 1403m, 1376m, 1302s, 1278s, 1243s, 1174vs, 1155vs, 1074s,
1026m, 998m, 919w cmꢀ1. ESI-HRMS: (m/z) for C17H19F3NO
(d) G.K.S. Prakash, M. Mandal, G.A. Olah, Org. Lett. 3 (2001) 2847–2850;
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([M+1]+) calcd.: 310.14133 Found: 310.14130. [
(2R/2S)-1,1,1-Trifluoro-3-{10-[(10S)-10-phenylethylamino]}-2-
(400-methoxyphenyl)propan-2-ol ((2R/2S,10S)-9l). Total yield of
a]
D = ꢀ32 (c = 1.0).
[5] (a) A. Dilman, D.E. Arkhipov, V.V. Levin, P.A. Belyakov, A.A. Korlyukov, M.I.
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1296
G. Mloston et al. / Journal of Fluorine Chemistry 131 (2010) 1289–1296
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(2008) 1676–1683.
¨
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[6] For reviews, see:
[14] It is worth mentioning that the first of these two signals appears as a dq, but the
second one as a doublet. Additional splitting of the more shielded signal, located at
2.87 ppm might results from trough-space interaction of one of the CH2 protons
with CF3 moiety. The same phenomenon has not been observed in all other amino
alcohols of type 9. In some instances, e.g. 9e–f, only broadening of the more
deshielded signals, were observed. Additionally, for compounds 9e–f the ob-
served difference of chemical shifts is smaller. As the result, the low resolved
spectra of both compounds showed only one, broad pseudo-singlet.
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´
´
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[16] (a) Signals related to dynamic NH and/or OH protons have not been always
registered in the 1H NMR spectra of amino alcohols 9;
(b) In the IR spectra, absorption bands related to the N-H and/or O-H stretching
bonds could not be always found. Very likely, this effect results from strong inter-
and intramolecular H-bonding in compounds 8.
´
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