Large-scale Mannich-type reactions of (SS)-N-tert- butanesulfinyl-(3,3,3)-trifluoroacetaldimine with C-nucleophiles

Article abstract of DOI:10.1016/j.jfluchem.2014.06.015

Here we describe the first attempts to scale up five addition reactions between (S_S)-N-tert-butanesulfinyl-(3,3,3)-trifluoroacetaldimine 6 with C-nucleophiles derived from ketones (two examples), glycine Schiff base and heterocycles (two examples). In all cases studied, the observed stereochemical outcome of the scaled up (5.0-25.0 mmol) reactions was lower as compared with the original 0.5 mmol scale. However, the observed worsening of yields and diastereoselectivity was not identical and depended on the reaction conditions and reaction mechanisms. In general, scaling up of the reactions conducted at ambient temperatures presented no problems while the low-temperature (-78 °C) processes would require special equipment to provide strict maintenance of the reaction temperature to obtain the desirable outcome. Importantly, using procedures described here, series of biologically relevant compounds containing 2,2,2-trifluoro-1-(amino)ethyl [CF₃CH(NH₂)-] pharmacophore unit can be prepared in enantiomerically pure form on up to 5 g scale, allowing their systematic biological studies.

Full text of DOI:10.1016/j.jfluchem.2014.06.015

Journal of Fluorine Chemistry 165 (2014) 67–75
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Large-scale Mannich-type reactions of
(SS)-N-tert-butanesulfinyl-(3,3,3)-trifluoroacetaldimine
with C-nucleophiles
c,d,
Chen Xie a, Haibo Mei a, Lingmin Wu a, Jianlin Han a,b, , Vadim A. Soloshonok
*
*
,
Yi Pan a
a School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination, Nanjing University, Nanjing, 210093, China
b Institute for Chemistry & BioMedical Sciences, Nanjing University, Nanjing, 210093, China
c Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, 20018 San Sebastian, Spain
d IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain
A R T I C L E I N F O
A B S T R A C T
Article history:
Here we describe the first attempts to scale up five addition reactions between (SS)-N-tert-
butanesulfinyl-(3,3,3)-trifluoroacetaldimine with C-nucleophiles derived from ketones (two
Received 6 May 2014
6
Received in revised form 11 June 2014
Accepted 14 June 2014
Available online 20 June 2014
examples), glycine Schiff base and heterocycles (two examples). In all cases studied, the observed
stereochemical outcome of the scaled up (5.0–25.0 mmol) reactions was lower as compared with the
original 0.5 mmol scale. However, the observed worsening of yields and diastereoselectivity was not
identical and depended on the reaction conditions and reaction mechanisms. In general, scaling up of the
reactions conducted at ambient temperatures presented no problems while the low-temperature
(ꢀ78 8C) processes would require special equipment to provide strict maintenance of the reaction
temperature to obtain the desirable outcome. Importantly, using procedures described here, series of
biologically relevant compounds containing 2,2,2-trifluoro-1-(amino)ethyl [CF3–CH(NH2)-] pharmaco-
phore unit can be prepared in enantiomerically pure form on up to 5 g scale, allowing their systematic
biological studies.
Keywords:
CF3-imine
Large-scale
Mannich reaction
Trifluoromethyl-amino compounds
Biologically active compounds
ß 2014 Published by Elsevier B.V.
1. Introduction
of the recent achievements in this area is the development of new
drug Odanacatib (2) (Fig. 1) awaiting approval for treatment for
Considering the unprecedented growth in the number of
marketed fluorine-containing drugs, the development of synthetic
methodology for preparation of organofluorine compounds is
currently an extremely active research subject [1]. In particular,
the recent upsurge in the development of trifluoromethylation
methods is driven by the apparent pharmaceutical potential of CF3-
containing drugs. However, most of the research in this area focuses
on installation of CF3-group onto aromatic, heteroaromatic and sp2
carbon species [2]. Thus, preparation of more structurally complex
compounds, possessing aliphatic CF3-group along with other
functional groups, still presents a significant synthetic challenge.
For example, 2,2,2-trifluoro-1-(amino)ethyl [CF3–CH(NH2)-] struc-
tural feature 1 (Fig. 1), has attracted considerable interest as a
pharmacophore unitinthe design ofbioactivecompounds [3,4]. One
osteoporosis and bone metastasis [5].
Methodological choice for preparation of CF3–CH(NH2)-phar-
macophore unit 1 is rather limited including trifluoromethylation
of imines 3 (Scheme 1) [6], reductive amination of ketones 4 [7]
and additions of C-nucleophiles to imines 5 [8]. Among these
methods, the reductive amination is by far most general and
practical being used for large-scale preparation of Odanacatib 2 [5].
Of particular synthetic potential is the biomimetic version of a
reductive amination using base-catalyzed 1,3-azomethine–azo-
methine isomerization [9,10] (Scheme 2).
Motivated by this limited choice of synthetic methodology, it
was envisioned that chiral (S)-N-tert-butylsulfinyl-3,3,3-trifluor-
oacetaldimine (R)- or (S)-6 can serve as a universal reagent for
generalized preparation of various types of compounds 1 [11].
Considering this quite stimulating synthetic potential of imine 6,
large-scale synthesis of both enantiomers of (R)- and (S)-6 was
developed rendering these compounds relatively inexpensive and
commercially available [12]. Since 2011, our and other groups have
been actively studying chemistry of CF3-imine-6 discovering its
*
Corresponding authors. Tel.: +34 943015177; fax: +34 943015270.
E-mail addresses: hanjl@nju.edu.cn (J. Han),
vadym.soloshonok@ehu.es (V.A. Soloshonok).
http://dx.doi.org/10.1016/j.jfluchem.2014.06.015
0022-1139/ß 2014 Published by Elsevier B.V.

68
C. Xie et al. / Journal of Fluorine Chemistry 165 (2014) 67–75
Me
relevant compounds pharmaceuticals [14]. Accordingly, fluorine-
containing derivatives of these compounds have been attractive
targets for synthetic chemists for quite some time [15]. Application
F
Me
N
CF3
R
CF3
NH2
CN
of imines 6 for preparation of
a-CF3-b-keto-amines of type 8
N
(Table 1), through addition reactions with Li-enolates 7, was
shown to be quite generalized affording compounds 8 in 42–87%
yields and good-to-excellent diastereoselectivity (74/26 to >99/1)
[16]. In particular, under optimized reaction conditions, imine (S)-
6 readily reacted with acetophenone derived enolate 7 giving rise
to the addition product (Ss)(S)-8 in 84% yield and excellent (99/1)
diastereoselectivity (Table 1, entry 1) [16].
H
H
O
1
2
MeO2S
Odanacatib
Fig. 1. 2,2,2-Trifluoro-1-(amino)ethyl pharmacophore 1 and new drug Odanacatib
2.
Quite unexpectedly, scaling up this procedure from 0.5 to 5.0
and 25 mmol of starting imine (S)-6 resulted in noticeable
worsening of all major reaction factors, including chemical yield
and diastereoselectivity. As shown in the original work, the
stereochemical outcome of this Mannich addition is very sensible
to the reaction temperature. Thus, the observed gradual decrease
in the diastereoselectivity (entries 1, 2, 3) may indicate the
problem with maintenance of ꢀ78 8C, required for the optimal
stereoselectivity. For example, the diastereomeric ratio of 83/17
was obtained for 0.5 mmol reaction conducted at 0 8C [16].
Nevertheless, the target (Ss)(S)-8 was isolated via column
chromatography as a white solid in a reasonably good yield
(61%) and markedly improved diastereoselectivity (97:3 dr).
Thus prepared addition product (Ss)(S)-8 was deprotected to
R
R'
-CF3
-R (Nu)
-R (Nu)
F3C
N
N
R
R
3
5
R
CF3
NH2
Reductive
amination
O
S
CF3
1
F3C
N
O
(S)-6
4
Scheme 1. Synthetic approach for preparation of pharmacophore unit 1.
O
CF3
O
S
O
CF3
NH2
furnish
b-keto-amine (S)-9. Conducting this large-scale (3.21 g)
1) aq HCl, MeOH, r.t., 8h
2) Et3N, CH2Cl2, r.t., 1h
process under the same conditions used previously for 0.5 mmol
scale reaction, afforded amine (S)-9 in 86% isolated yield, which is
quite agreeable with the 90% yield obtained on the 0.5 mmol scale
[16].
N
H
(Ss)(S)-8
10 mmol scale
(S)-9
86% yield
Scheme 2. Large-scale (3.21 g) deprotection of product 8 to free amine 9.
2.2. Addition of glycine Schiff base esters to sulfinylimine (S)-6
reactivity and mode of the asymmetric induction [13]. Justifiably,
as it is always proper for the original research, all these reported
data have been acquired using about 100 mg imine 6 scale. Taking
into account that the ultimate goal in standing the chemistry of
imine 6 is the synthesis of compounds with potentially new and
useful biological properties, one may agree that the target
compounds have to be prepared on gram scale to provide for
their systematic biological studies. To this goal, we initiated a
special project aiming at scaling up previously reported processes
to estimate their practicality and limitations.
Our next goal was preparation of a,b-(diamino)acids, an
important type of polyfunctional natural and tailor-made amino
acids [17] with some specific biological properties [18]. Reports on
asymmetric synthesis of fluorinated derivatives of
a,b-(diami-
no)acids are rare [19] and their biological properties still await
investigation. Therefore it was quite motivating to explore the
application of imines 6 for large-scale preparation of enantio-
merically pure 2,3-diamino-4,4,4-trifluorobutanoic acid. Previous-
ly we reported that reactions of imine (S)-6 with glycine Schiff
base/methyl ester 10 easily take place at ambient temperatures in
the presence of organic or medium-strength inorganic bases
(Table 2) [20]. Under the optimized conditions (THF, r.t., Cs2CO3)
(entry 1) the target addition product (Ss)(S)-11 was isolated in both
excellent yield (98%) and diastereomeric purity(dr 99/1).
2. Results and discussion
2.1. Addition of ketone-derivative enolates to sulfinylimine (S)-6.
Using the same conditions but scaling up the amount of the
starting (sulfinyl)imine (S)-6 from 1.0 mmol (entry 1) to 10.0 mmol
(entry 2) and 25.0 mmol (entry 3) resulted in a gradual decrease in
b
-Keto-amino compounds and the related g-amino alcohols are
very important intermediates in preparation of various biologically
Table 1
Reactions of imine (S)-6 (0.5–25.0 mmol) with Li-enolate 7.
OLi
O
CF3
O
S
O
S
1) THF, -78 oC
2) aq NH4Cl
+
N
H
F3C
(S)-6
N
7
(Ss)(S)-8
Entry
Scale of the reaction (mmol sulfinylimine)
Time (h)
Yield (%)
dr
99:1
1
2
3
0.5
5.0
2
84
74
61a
2.5
4
95:5
25.0
82:18
a
Isolated yield of product 8 in diastereomeric ratio of 97/3.

C. Xie et al. / Journal of Fluorine Chemistry 165 (2014) 67–75
69
Table 2
Reactions of imine (S)-6 (1.0–25.0 mmol) with glycine Schiff base 10.
O
S
CF3
O
O
O
S
Cs2CO3 (10 mol %)
THF, r.t.
N
H
OCH3
Ph
Ph
N
+
OCH3
N
CF3
N
Ph
Ph
(S)-6
10
(Ss)(2S,3S)-11
Entry
Scale of the reaction (mmol sulfinylimine)
Time (h)
Yield (%)
Isomer ratio
1
2
3
1.0
10.0
25.0
1
1
1
98
95
86
99:1
99:1
>99:1
O
S
CF3
O
1) 0.3 N TFA/CH2Cl2
0-20 oC, 24h
O
S
CF3
O
N
H
OCH3
Ph
N
H
OCH3
N
2) Et3N, r.t., 1h
NH2
Ph
(Ss)(2S,3S)-12
(Ss)(2S,3S)-11
10 mmol scale (4.55 g)
79% yield
Scheme 3. Chemo-selective deprotection of the
a-amino group in 11 giving rise to product 12.
the isolated yield of product (Ss)(2S,3S)-11 from 98% to 95% and
86%, respectively. However, the diastereoselectivity of the reac-
tions remained constantly perfect 99/1. While the loss in the
chemical yield was disappointing, the observed reproducibility in
the diastereoselectivity rendered, in our opinion, this scaling up
process rather encouraging. Obviously, one of the reasons for this
successful outcome is that the process can be conducted under
operationally convenient conditions [21], without recourse to
controlled low temperatures, specially dried solvents or air/water-
sensitive reagents.
2.3. Addition of indanone-derivative enolates to sulfinylimine (S)-6
With these rather successful results we turned again to low-
temperature reactions of imine (S)-6 (1.0–25.0 mmol) with
indanone-derivative enolates. Interest in these reactions was
motivated by the fact that indanone derived fluorine-containing b-
amino ketones are unknown type of compounds. However,
one may envision that combination of indanone skeleton with
CF3–CH(NH2)-pharmacophore unit might result in derivatives of
pharmaceutical importance.
The product (Ss)(2S,3S)-11, obtained as a white solid (4.55 g,
10 mmol, entry 3, 86% yield, >99:1 dr) was chemo-selectively
Previously we reported that the addition reaction between
imine (S)-6 and indanone-derived Li-enolate, conducted on
deprotected (Scheme 3) to free the
a
-amino group giving rise to
1.0 mmol scale [22], resulted in b-amino-ketone (Ss)(2S,3S)-14
diastereomerically pure product 12.
isolated in 94% yield and 99/1 dr (Table 3, entry 1).
Product (Ss)(S)-12 possesses
a
-free and
b
-protected amino
Reproducing this reaction on 5.0 mmol scale (entry 2) resulted
in 8% decrease in the chemical yield, while the diastereoselectivity
was intact (99/1). Further fivefold increase of the reaction scale
groups and therefore can be used for selective incorporation of this
type of fluorinated amino acid into peptides through one or
another amino functionality.
(entry 3) gave b-amino-ketone (Ss)(2S,3S)-14 in 79% yield and 94/6
Table 3
Reactions of imine (S)-6 (1.0–25.0 mmol) with indanone-derivative enolates.
CF3
O
S
O
O
N
H
LDA (20 mol %)
THF, -78 oC
S
+
N
CF3
O
(S)-6
13
(Ss)(2S,3S)-14
Entry
Scale of the reaction (mmol sulfinylimine)
Time (h)
Yield (%)
Isomer ratio
1
2
3
1.0
5.0
4
5
6
94
86
79
99:1
99:1
94:6
25.0

70
C. Xie et al. / Journal of Fluorine Chemistry 165 (2014) 67–75
CF3
CF3
O
S
C-nucleophiles derived from heterocyclic compounds. For in-
stance, the imidazo[2,1-b]thiazole moiety features prominently in
numerous natural as well as synthetic biologically active
compounds [24]. However, its fluorinated derivatives containing
amino functionality have not been described.
1) aq HCl, MeOH, r.t., 8h
N
NH2
H
2) Et3N, CH2Cl2, r.t., 1h
O
O
(Ss)(2S,3S)-14
(2S,3S)-15
Recently, we reported that imine (S)-6 can be reacted with Li-
nucleophile derived from imidazo[2,1-b]thiazole 16 to furnish new
family of potentially biologically interesting compounds of type 17
(Table 4) [25]. The original addition procedure conducted on
0.5 mmol scale gave rise to the product (Ss)(S)-17 in 70% yield and
perfect diastereoselectivity (>99/1) (entry 1). Delightfully, scaling
up the reaction by 10 fold gave virtually the same yield and
stereochemical outcome (entry 2). On the other hand, further
increase of the reaction scale, to 25.0 mmol of imine (S)-6, resulted
in slightly reduced yield 65% (entry 3) but noticeably worsened
diastereoselectivity. This outcome was quite similar to the results
obtained in 0.5 mmol scale reaction conducted at 0 8C [25]. The
data obtained, clearly suggested that the stereochemical outcome
of this large-scale reaction is critically sensitive to strict-
controlling the reaction temperature and may be improved by
using appropriate low-temperature equipment.
10 mmol scale (3.33 g)
82% yield
Scheme 4. Deprotection of (Ss)(S)-14 (3.33 g, 10.0 mmol) to free
15.
b-amino-ketone
diastereomeric ratio. Taking into account that this reaction was
conducted at ꢀ78 8C, the obtained stereochemical outcome was
rather encouraging. It should be pointed out that further
purification of the product (Ss)(2S,3S)-14, from 94/6 dr to
diastereomerically pure state (>99/1 dr) can be achieved simply
by washing the crude product with hexane/ethyl acetate mixture
(4:1). It should be noted that in this reaction, due to the formation
of two new stereogenic centers, up to four diastereomerically
products can be expected. Since the process is conducted at ꢀ78 8C
and therefore may be sensitive to the reaction temperature, the
observed stereochemical outcome for scaled up reactions is rather
impressive. The reason for still high stereoselectivity might be in
the reaction mechanism. In particular, considering importance of
the geometric homogeneity of reaction species for the stereo-
chemical outcome of the addition reactions [23], one may suggest
that the results obtained in the reaction with indanone is due to its
rigid cyclic structure and the formation of geometrically homoge-
neous enolates.
Nevertheless, the product (Ss)(S)-17 was obtained in diaster-
eomerically pure state via column chromatography and depro-
tected to free amine (S)-18 (Scheme 5). Again, the isolated yield
(87%) of amine (S)-18 was just a bit lower than that (91%) obtained
on the 0.5 mmol scale reaction (Scheme 6).
2.5. Addition of thiazolo[3,2-b] [1,2,4]triazole-derived nucleophiles to
sulfinylimine (S)-6
Diastereomerically pure 3.33 g of product (Ss)(S)-14 was
deprotected under the standard conditions (MeOH/HCl) furnishing
free
b
-amino-ketone 15 in 82% yield (Scheme 4). Though the yield
The thiazolo[3,2-b][1,2,4]triazole structural fragment is found
in biologically active natural products [26]. Like in the discussed
above case of imidazo[2,1-b]thiazoles, fluorinated amino-deriva-
tives of thiazolo[3,2-b][1,2,4]triazoles are virtually unknown
compounds.
of (S)-15 on the much smaller 0.5 mmol scale was 87%, it seems
that this stage presents no problems for further scaling up of this
procedure.
2.4. Addition of imidazo[2,1-b]-thiazole-derived nucleophiles to
sulfinylimine (S)-6
We demonstrated that the nucleophile derived from heterocy-
cle 19 can be cleanly added to imine (S)-6 resulting the
corresponding addition products (Ss)(S)-20 (Table 5) [27]. In the
small-scale reactions (0.5 mmol, entry 1) amine (Ss)(S)-20 was
obtained in 71% yield and good 98/2 dr. Gradual increase of the
With these results in hand, we decided to focus the rest of
this study on the addition reactions between imine (S)-6 with
Table 4
Addition reactions between imine (S)-6 (0.5–25.0 mmol) with imidazo[2,1-b]-thiazole-derived nucleophiles 16.
O
S
1) LDA, THF, -78 oC
2) aq NH4Cl
S
NH
N
+
N
N
CF3
O
S
N
S
N
F3C
(S)-6
16
(Ss)(S)-17
Entry
Scale of the reaction (mmol sulfinylimine)
Time (h)
Yield (%)
dr
1
2
3
0.5
5.0
2
70
69
65
>99:1
>99:1
90:10
2.5
3
25.0
S
NH
H2N
F3C
1) aq HCl, MeOH, r.t., 8h
2) Et3N, CH2Cl2, r.t., 1h
N
N
O
S
N
S
N
F3C
(Ss)(S)-17
10 mmol scale (4.15 g)
(S)-18
87% yield
Scheme 5. Deprotection of (Ss)(S)-17 (4.15 g, 10.0 mmol) to free amine 18.

C. Xie et al. / Journal of Fluorine Chemistry 165 (2014) 67–75
71
1) aq HCl, MeOH, r.t., 8h
HN S
NH2
CF3
N
N
N
N
2) Et3N, CH2Cl2, r.t., 1h
N
N
O
S
S
CF3
(Ss)(S)-20
10 mmol scale (4.02 g)
(S)-21
84% yield
Scheme 6. Deprotection of (Ss)(S)-20 (4.02 g, 10.0 mmol) to free amine (S)-21.
Table 5
Addition reactions between imine (S)-6 (0.5–25.0 mmol) with thiazolo[3,2-b] [1,2,4]triazole-derived nucleophiles 19.
O
S
HN S
CF3
N
N
N
N
1) LDA, THF, -78 oC
2) aq NH4Cl
N
N
+
N
CF3
O
S
S
(S)-6
19
(Ss)(S)-20
Entry
Scale of the reaction (mmol sulfinylimine)
Time (h)
Yield (%)
dr
98:2
1
2
3
0.5
5.0
2
71
68
63
2.5
3
94:6
25.0
90:10
reaction scale to 5.0 (entry 2) and 25.0 mmol (entry 3) of starting
imine (S)-6 led to worsening of the stereochemical outcome.
However, the decrease in chemical yield and diastereoselectivity
was rather moderate and in a line with the other examples
discussed in this study. Importantly, the target product (Ss)(S)-20
was obtained in diastereomerically pure form (63%) via purifica-
tion by column chromatography.
Deprotection of product (Ss)(S)-20 was conducted on 4.02 scale
using standard conditions (MeOH/HCl). The isolated yield of
enantiomerically pure free amine (S)-21 was 84% which is just 2%
lower as compared with 0.5 scale reaction (86%) [27].
optically pure state by washing out the minor diastereomer or
by column chromatography. In this regard, we would like to
emphasize that the development of alternative, nonconventional
methods for optical purifications using SDE [28] (self-dispropor-
tionation of enantiomers) via sublimation [29] or achiral
chromatography [30] should receive due attention. All target
products were deprotected on large scale to free amino
compounds. These room temperature reactions generally pre-
sented no scaling problems and proceeded with close to original
(0.5 scale) chemical yields.
4. Experimental
3. Conclusions
4.1. General
This work describes the first attempt to scale up the addition
reactions between (SS)-N-tert-butanesulfinyl-(3,3,3)-trifluoroa-
cetaldimine 6 with C-nucleophiles derived from ketones, glycine
Schiff base and heterocycles. In all five reactions studied, the
stereochemical outcome of the scaled up (5.0–25.0 mmol)
reactions was lower as compared with 0.5 mmol processes.
However, the observed decrease in yields and diastereoselectivity
is not identical and depends on the original reaction conditions
and reaction mechanisms. For example, scaling up the room
temperature reactions (additions of glycine Schiff base 10,
Table 2) gave the corresponding addition products (Ss)(2S,3S)-
11 comparable to small scale (0.5 mmol) reactions chemical yields
and even better diastereoselectivity. On the other hand low-
temperature (ꢀ78 8C) reactions gave the target product with
noticeably (ꢁ10%) lower yields and stereoselectivity. These data
clearly suggested that special equipment to control and maintain
the reaction temperature must be used to obtain desirable
outcome. Taking advantage of diastereomeric nature of the
resultant products, all target compounds were obtained in
All commercial reagents and solvents were used without
additional purification unless otherwise specified. CF3-Sulfinyli-
mine
6 was obtained from Accela ChemBio Co., Ltd. All
experiments were monitored by thin layer chromatography
(TLC). TLC was performed on pre-coated silica gel plated. Column
chromatography was performed using silica gel 60 (300–400
mesh).
1H NMR (400 MHz), 13C NMR (101 MHz) and 19F NMR
(376 MHz) were measured on a Bruker AVANCE III-400 spectrom-
eter. Chemical shifts are reported in ppm (
tetramethylsilane (TMS, 0.0 ppm) or with the solvent reference
relative to TMS employed as the internal standard (CDCl3,
d) relative to internal
d
d
7.26 ppm). Data are reported as follows: chemical shift (multiplic-
ity [singlet (s), doublet (d), triplet (t), quartet (q), and multiplet
(m)], coupling constants [Hz], integration). Melting points are
uncorrected. Values of optical rotation were measured on a
Rudolph Automatic Polarimeter A21101. HRMS were recorded on a
LTQ-Orbitrap XL (Thermofisher, U.S.A.).

72
C. Xie et al. / Journal of Fluorine Chemistry 165 (2014) 67–75
4.2. Procedure for the addition of ketone-derivative enolates 7 to
sulfinylimine (S)-6 (25 mmol scale)
layers were washed with H2O (2 ꢂ 200 mL) and brine solution
(1 ꢂ 200 mL) and dried over anhydrous Na2SO4, filtered and the
solvent was removed to give the crude product (99:1 dr,
determined by 19F NMR analysis of the crude product), which
was purified by column chromatography (hexanes/EtOAc = 4:1) to
afford the corresponding product 11 as a white solid in 86%
isolated yield with virtually complete diastereoselectivity (>99:1
dr).
Into an oven-dried round-bottom flask flushed with N2 were
taken acetophenone (5.11 g, 42.5 mmol) and anhydrous THF
(100 mL). The reaction flask was cooled to ꢀ78 8C and LDA (2 M
in THF, 23.4 mL) was added dropwise with stirring. After 45 min at
ꢀ78 8C, sulfinylimine (S)-6 (5.03 g, 25.0 mmol) dissolved in anhy-
drous THF (50 mL) was added dropwise. Stirring was continued at
ꢀ78 8C for 4 h, then the reaction was quenched withsaturated NH4Cl
(50 mL) followed by H2O (75 mL) and the mixture was brought to
room temperature. The organic layer was taken and the aqueous
layer was extracted with EtOAc (2 ꢂ 100 mL). The combined organic
layers were washed with H2O (2 ꢂ 200 mL) and brine solution
(1 ꢂ 200 mL) and dried with anhydrous Na2SO4, filtered and the
solvent was removed to give the crude product (82:18 dr,
determined by 19F NMR analysis of the crude product), which was
purified by column chromatography (hexanes/EtOAc = 4:1) to afford
the corresponding product 8 as a white solid in 61% isolated yield
with 97:3 dr.
(2S,3S)-methyl
3-((S)-1,1-dimethylethylsulfinamido)-2-
((diphenylmethylene)amino)-4,4,4-trifluorobutanoate
(11).
ꢀ 80.2
White solid (9.79 g, 86% yield), mp 160–161 8C. ½a D25
ꢃ
(c = 1.02, CHCl3). 1H NMR (CDCl3, 400 MHz):
d
= 7.62 ꢀ 7.58 (m,
2H), 7.48 ꢀ 7.43 (m, 4H), 7.39 ꢀ 7.33 (m, 2H), 7.16 ꢀ 7.11 (m, 2H),
5.08 (d, J = 10.7 Hz, 1H), 4.52 ꢀ 4.40 (m, 2H), 3.72 (s, 3H), 1.26 (s,
9H), 13C NMR (CDCl3, 101 MHz):
d = 174.0, 169.0, 138.7, 135.7,
131.2, 129.3, 129.0, 128.8, 128.3, 127.2, 124.5 (q, J = 284.8 Hz),
63.9, 59.8 (q, J = 29.8 Hz), 57.3, 52.9, 22.5, 19F NMR (CDCl3,
376 MHz):
d
= ꢀ72.5.
HRMS
[M + Na+]:
calcd
for
C22H25F3N2O3SNa+: 477.1436, found: 477.1430.
(S)-2-methyl-N-((S)-1,1,1-trifluoro-4-oxo-4-phenylbutan-2-
yl)propane-2-sulfinamide (8). White solid (4.89 g, 61% yield), mp
4.5. Procedure for the chemo-selective deprotection of the a-amino
group in 11 giving rise to product 12 (10 mmol scale)
140–142 8C.
400 MHz):
½
a 2D5 45.8 (c = 0.94, CHCl3). 1H NMR (CDCl3,
+
ꢃ
d
= 7.89 ꢀ 7.93 (m, 2H), 7.63 ꢀ 7.57 (m, 1H),
The product 11 (4.55 g, 10 mmol) was dissolved in CH2Cl2
(100 mL) in a round-bottom flask, and the resulting mixture was
cooled to 0 8C. TFA (3.42 g, 30 mmol) was added dropwise with
stirring, and the reaction was allowed to continue at 20 8C for 24 h
(monitored by TLC). Upon completion, Et3N (6.07 g, 60 mmol) was
added, and the mixture was stirred at r.t. for 1 h. H2O (200 mL) was
then added. The organic layer was separated, washed with H2O
(2 ꢂ 200 mL), dried with anhydrous Na2SO4, and filtered. The
solvent was removed to give the crude product, which was purified
by column chromatography (hexanes/EtOAc = 2:1) to afford the
corresponding deprotection product 12 as a colorless oil in 79%
isolated yield.
7.52 ꢀ 7.45 (m, 2H), 4.61 ꢀ 4.48 (m, 1H), 3.89 (d, J = 8.5 Hz, 1H),
3.70 (dd, J = 17.7, 9.7 Hz, 1H), 3.30 (dd, J = 17.7, 3.1 Hz, 1H), 1.16 (s,
9H), 13C NMR (CDCl3, 101 MHz):
d = 195.0, 136.2, 133.9, 128.9,
128.2, 125.4 (q, J = 281.8 Hz), 57.0, 54.0 (q, J = 30.8 Hz), 38.1, 22.4,
19F NMR (CDCl3, 376 MHz):
C
d
= ꢀ74.3. HRMS [M + Na+]: calcd for
14H18F3NO2SNa+: 344.0903, found: 344.0893.
4.3. Procedure for the large-scale (10 mmol scale) deprotection of
product 8 to free amine 9
The product 8 (3.21 g, 10.0 mmol) and MeOH (100 mL) were
placed in a 250 mL round-bottom flask and aq. HCl (36%, 20 mL)
was added dropwise. The reaction was stirred at r.t. for 8 h, during
which the cleavage was monitored by TLC. Volatiles were removed
under reduced pressure. The residue was dissolved in CH2Cl2
(200 mL) and Et3N (30.36 g, 300 mmol) was added. The mixture
was stirred at r.t. for 1 h, then H2O (200 mL) was added. The organic
layer was taken, washed with H2O (2 ꢂ 200 mL), dried with
anhydrous Na2SO4, filtered and the solvent was removed to give
the crude product, which was purified by column chromatography
(hexanes/EtOAc = 2:1) to afford the corresponding deprotection
product 9 as a white solid in 86% isolated yield.
(2S,3S)-methyl
2-amino-3-((S)-1,1-dimethylethylsulfina-
mido)-4,4,4-trifluorobutanoate (12). Colorless oil (2.28 g, 79%
yield). ½a 2D5
ꢃ
+ 5.20 (c = 0.88, CHCl3). 1H NMR (CDCl3, 400 MHz):
= 4.67 (d, J = 10.5 Hz, 1H), 4.26 ꢀ 4.14 (m, 1H), 4.07 (s, 1H), 3.75
d
(s, 3H), 1.75 (s, 2H), 1.14 (s, 9H), 13C NMR (CDCl3, 101 MHz):
= 171.5, 124.8 (q, J = 284.2 Hz), 58.4 (q, J = 29.3 Hz), 57.2, 53.1,
d
52.9 (d, J = 1.4 Hz), 22.4, 19F NMR (CDCl3, 376 MHz):
d
= ꢀ72.6.
HRMS [M + Na+]: calcd for C9H17F3N2O3SNa+: 313.0804, found:
313.0806.
4.6. Procedure for the addition of indanone-derivative enolates to
(S)-3-amino-4,4,4-trifluoro-1-phenylbutan-1-one (9). White
sulfinylimine (S)-6 (5 mmol scale)
solid (1.86 g, 86% yield), mp 30–31 8C. ½a D25
ꢀ 55.0 (c = 0.44, CHCl3).
ꢃ
1H NMR (CDCl3, 400 MHz):
d
= 8.00 ꢀ 7.91 (m, 2H), 7.63 ꢀ 7.56 (m,
Into an oven-dried round-bottom flask flushed with N2 were
taken 1-indanone 13 (0.73 g, 5.5 mmol) and anhydrous THF
(25 mL). The reaction flask was cooled to ꢀ78 8C and LDA (2 M
in THF, 0.55 mL) was added dropwise with stirring. After 40 min at
ꢀ78 8C, sulfinylimine 6 (1.01 g, 5.0 mmol) dissolved in anhydrous
THF (10 mL) was pre-cooled to ꢀ78 8C, then added dropwise to the
reaction mixture. Stirring was continued at ꢀ78 8C for 5 h, then the
reaction was quenched with saturated NH4Cl (20 mL), followed by
H2O (50 mL) and the mixture was brought to room temperature.
The organic layers were taken and the aqueous layer was extracted
with EtOAc (2 ꢂ 50 mL). The combined organic layers were washed
with H2O (2 ꢂ 100 mL) and brine solution (1 ꢂ 100 mL) and dried
over anhydrous Na2SO4. The solvent was evaporated, and the crude
mixture was co-concentrated with hexane (99:1 dr, determined by
19F NMR analysis of the crude product). The solid product was
washed with a minimum amount of hexane/ethyl acetate mixture
(8:1) to afford pure product 14 in 86% isolated yield with virtually
complete diastereoselectivity.
1H), 7.52 ꢀ 7.44 (m, 2H), 4.06 ꢀ 3.95 (m, 1H), 3.31 (dd, J = 17.5,
2.7 Hz, 1H), 3.18 (dd, J = 17.5, 9.7 Hz, 1H), 1.61 (s, 2H), 13C NMR
(CDCl3, 101 MHz):
d =196.3, 136.4, 133.8, 128.9, 128.2, 126.6 (q,
J = 280.3 Hz), 50.3 (q, J = 29.8 Hz), 39.4 (d, J = 1.0 Hz), 19F NMR
(CDCl3, 376 MHz):
10H11F3NO+: 218.0787, found: 218.0796.
d
= ꢀ78.2. HRMS [M + H+]: calcd for
C
4.4. Procedure for the addition of glycine Schiff base esters to
sulfinylimine (S)-6 (25 mmol scale)
Sulfinylimine (S)-6 (5.03 g, 25.0 mmol), glycine Schiff base ester
10 (6.97 g, 27.5 mmol) and Cs2CO3 (0.81 g, 2.5 mmol) were
dissolved in THF (125 mL), and the resulting reaction mixture
was stirred at r.t. for 1 h. After the reaction was complete, the
reaction was quenched with saturated NH4Cl (20 mL), followed by
H2O (50 mL). The organic layer was taken and the aqueous layer
was extracted with EtOAc (2 ꢂ 50 mL). The combined organic

C. Xie et al. / Journal of Fluorine Chemistry 165 (2014) 67–75
73
(S)-2-methyl-N-((S)-2,2,2-trifluoro-1-((S)-1-oxo-2,3-dihy-
dro-1H-inden-2-yl)ethyl)propane-2-sulfinamide (14). White
solid (5 mmol scale: 1.44 g, 86% yield, 25 mmol scale: 6.58 g,
THF (100 mL). The reaction flask was cooled to ꢀ78 8C and LDA
(2 M in THF, 19.1 mL) was added dropwise with stirring. After 1 h at
ꢀ78 8C, sulfinylimine 6 (5.03 g, 25.0 mmol) dissolved in anhydrous
THF (50 mL) was added dropwise. Stirring was continued at ꢀ78 8C
for 3 h, then the reaction was quenched with saturated NH4Cl
(50 mL) followed by H2O (75 mL) and the mixture was brought to
room temperature. The organic layer was taken and the aqueous
layer was extracted with EtOAc (2 ꢂ 100 mL). The combined organic
layers were washed with H2O (2 ꢂ 200 mL) and brine solution
(1 ꢂ 200 mL) and dried with anhydrous Na2SO4, filtered and the
solvent was removed to give the crude product (90:10 dr,
determined by 19F NMR analysis of the crude product), which
was purified by column chromatography (hexanes/EtOAc = 2:1) to
afford the corresponding product 17 as a white solid in 65% isolated
yield with virtually complete diastereoselectivity.
79% yield), mp 193–195 8C. ½a D25
ꢃ
ꢀ 104.3 (c = 1.21, CHCl3). 1H NMR
(CDCl3, 400 MHz):
d = 7.76 (d, J = 7.7 Hz, 1H), 7.65 (td, J = 7.6,
1.1 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.41 (t, J = 7.3 Hz, 1H),
4.72 ꢀ 4.61 (m, 1H), 3.44 ꢀ 3.29 (m, 2H), 3.15 ꢀ 3.05 (m, 2H),
0.93 (s, 9H), 13C NMR (CDCl3, 101 MHz):
d = 203.6, 153.4, 136.1,
135.7, 128.0, 126.7, 125.3 (q, J = 282.9 Hz), 124.1, 58.1 (q,
J = 30.5 Hz), 57.2, 47.0, 27.2, 22.3, 19F NMR (CDCl3, 376 MHz):
d
= ꢀ73.1. HRMS [M + Na+]: calcd for C15H18F3NO2SNa+: 356.0908,
found: 356.0906.
4.7. Procedure for the addition of indanone-derivative enolates to
sulfinylimine (S)-6 (25 mmol scale)
(S)-2-methyl-N-((R)-2,2,2-trifluoro-1-(3-methyl-6-phenyli-
midazo[2,1-b]thiazol-2-yl)ethyl)propane-2-sulfinamide (17).
Into an oven-dried round-bottom flask flushed with N2 were
taken 1-indanone 13 (3.63 g, 27.5 mmol) and anhydrous THF
(125 mL). The reaction flask was cooled to ꢀ78 8C and LDA (2 M in
THF, 2.75 mL) was added dropwise with stirring. After 40 min at
ꢀ78 8C, sulfinylimine 6 (5.03 g, 25.0 mmol) dissolved in anhydrous
THF (50 mL) was pre-cooled to ꢀ78 8C, then added dropwise to the
reaction mixture. Stirring was continued at ꢀ78 8C for 6 h, then the
reaction was quenched with saturated NH4Cl (50 mL), followed by
H2O (100 mL) and the mixture was brought to room temperature.
The organic layers were taken and the aqueous layer was extracted
with EtOAc (2 ꢂ 100 mL). The combined organic layers were
washed with H2O (2 ꢂ 200 mL) and brine solution (1 ꢂ 200 mL)
and dried over anhydrous Na2SO4. The solvent was evaporated, and
the crude mixture was co-concentrated with hexane (94:6 dr,
determined by 19F NMR analysis of the crude product). The solid
product was washed with a minimum amount of hexane/ethyl
acetate mixture (4:1) to afford pure product 14 in 79% isolated
yield with virtually complete diastereoselectivity.
White solid (6.74 g, 65% yield), mp 182–183 8C. ½a D25
ꢃ
+ 153.1
= 7.86 ꢀ 7.82 (m,
(c = 1.04, CHCl3). 1H NMR (CDCl3, 400 MHz):
d
2H), 7.64 (s, 1H), 7.41 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 7.4 Hz, 1H), 5.19
(qd, J = 6.5, 2.1 Hz, 1H), 3.84 (s, 1H), 2.53 (s, 3H), 1.28 (s, 9H), 13C
NMR (CDCl3, 101 MHz):
d = 148.6, 147.7, 133.8, 129.7, 128.7, 127.6,
125.3, 123.9 (q, J = 282.0 Hz), 114.4, 106.2, 56.7, 54.0 (q,
J = 32.6 Hz), 22.4, 12.1, 19F NMR (CDCl3, 376 MHz):
d
= ꢀ74.0.
HRMS [M + Na+]: calcd for C18H20F3N3OS2Na+: 438.0892, found:
438.0894.
4.10. Procedure for the deprotection of product 17 (10 mmol scale) to
free amine 18
The product 17 (4.15 g, 10.0 mmol) and MeOH (100 mL) were
placed in a 250 mL round-bottom flask and aq. HCl (36%, 20 mL)
was added dropwise. The reaction was stirred at r.t. for 8 h, during
which the cleavage was monitored by TLC. Volatiles were removed
under reduced pressure. The residue was dissolved in CH2Cl2
(200 mL) and Et3N (30.36 g, 300 mmol) was added. The mixture
was stirred at r.t. for 1 h, then H2O (200 mL) was added. The organic
layer was taken, washed with H2O (2 ꢂ 200 mL), dried with
anhydrous Na2SO4, filtered and the solvent was removed to give
the crude product, which was purified by column chromatography
(hexanes/EtOAc = 1:1) to afford the corresponding deprotection
product 18 as a white solid in 87% isolated yield.
4.8. Procedure for the deprotection of product 14 (10 mmol scale) to
free
b-amino-ketone 15
The product 14 (3.33 g, 10.0 mmol) and MeOH (100 mL) were
placed in a 250 mL round-bottom flask and aq. HCl (36%, 20 mL)
was added dropwise. The reaction was stirred at r.t. for 8 h, during
which the cleavage was monitored by TLC. Volatiles were removed
under reduced pressure. The residue was dissolved in CH2Cl2
(200 mL) and Et3N (30.36 g, 300 mmol) was added. The mixture
was stirred at r.t. for 1 h, then H2O (200 mL) was added. The organic
layer was taken, washed with H2O (2 ꢂ 200 mL), dried with
anhydrous Na2SO4, filtered and the solvent was removed to give
the crude product, which was purified by column chromatography
(hexanes/EtOAc = 2:1) to afford the corresponding deprotection
product 15 as a white solid in 82% isolated yield.
(R)-2,2,2-trifluoro-1-(3-methyl-6-phenylimidazo[2,1-
b]thiazol-2-yl)ethanamine (18). White solid (2.70 g, 87% yield),
mp 121–122 8C. ½a D25
ꢃ
+ 35.0 (c = 1.14, CHCl3). 1H NMR (CDCl3,
= 7.85 ꢀ 7.80 (m, 2H), 7.58 (s, 1H), 7.40 (t, J = 7.6 Hz,
400 MHz):
d
2H), 7.29 (t, J = 7.4 Hz, 1H), 4.75 (q, J = 6.7 Hz, 1H), 2.43 (s, 3H), 1.98
(br, 2H), 13C NMR (CDCl3, 101 MHz):
= 148.2, 146.9, 133.9, 128.6,
127.4, 126.6, 125.0, 124.9 (q, J = 281.9 Hz), 118.8, 105.8, 51.9 (q,
J = 32.0 Hz), 11.8, 19F NMR (CDCl3, 376 MHz):
[M + H+]: calcd for C14H13F3N3S+: 312.0777, found: 312.0769.
d
d
= ꢀ76.7. HRMS
(S)-2-((S)-1-amino-2,2,2-trifluoroethyl)-2,3-dihydro-1H-
inden-1-one (15). White solid (1.89 g, 82% yield), mp 76–77 8C.
½
a 2D5
ꢃ
ꢀ 58.1 (c = 1.58, CHCl3). 1H NMR (CDCl3, 400 MHz):
d
= 7.75
4.11. Procedure for the addition of thiazolo[3,2-b] [1,2,4]triazole-
derived nucleophiles to sulfinylimine (S)-6 (25 mmol scale)
(d, J = 7.7 Hz, 1H), 7.60 (td, J = 7.6, 1.1 Hz, 1H), 7.49 (d, J = 7.7 Hz,
1H), 7.37 (t, J = 7.2 Hz, 1H), 4.16 ꢀ 4.05 (m, 1H), 3.23 ꢀ 3.18 (m,
2H), 3.04 ꢀ 2.97 (m, 1H), 1.33 (s, 2H), 13C NMR (CDCl3, 101 MHz):
Into an oven-dried round-bottom flask flushed with N2 were
taken thiazolo[3,2-b][1,2,4]triazole 19 (8.55 g, 42.5 mmol) and
anhydrous THF (100 mL). The reaction flask was cooled to ꢀ78 8C
and LDA (2 M in THF, 23.4 mL) was added dropwise with stirring.
After 1 h at ꢀ78 8C, sulfinylimine (5.03 g, 25.0 mmol) dissolved in
anhydrous THF (50 mL) was added dropwise. Stirring was
continued at ꢀ78 8C for 3 h, then the reaction was quenched with
saturated NH4Cl (50 mL) followed by H2O (75 mL) and the mixture
was brought to room temperature. The organic layer was taken and
the aqueous layer was extracted with EtOAc (2 ꢂ 100 mL). The
combined organic layers were washed with H2O (2 ꢂ 200 mL) and
d
= 204.9, 154.1, 136.3, 135.3, 127.7, 126.7, 126.7 (q, J = 281.5 Hz),
124.1, 52.6 (q, J = 29.4 Hz), 47.3, 26.4 (d, J = 0.7 Hz), 19F NMR
(CDCl3, 376 MHz):
C
d
= ꢀ76.2. HRMS [M + H+]: calcd for
11H11F3NO+: 230.0793, found: 230.0778.
4.9. Procedure for the addition of imidazo[2,1-b]-thiazole-derived
nucleophiles to sulfinylimine (S)-6 (25 mmol scale)
Into an oven-dried round-bottom flask flushed with N2 were taken
imidazo[2,1-b]-thiazole 16 (9.11 g, 42.5 mmol) and anhydrous

74
C. Xie et al. / Journal of Fluorine Chemistry 165 (2014) 67–75
brine solution (1 ꢂ 200 mL) and dried with anhydrous Na2SO4,
filtered and the solvent was removed to give the crude product
(90:10 dr, determined by 19F NMR analysis of the crude product),
which was purified by column chromatography (hexanes/
EtOAc = 2:1) to afford the corresponding product 20 as a white
solid in 63% isolated yield with virtually complete diastereoselec-
tivity.
and the Fundamental Research Funds for the Central Universities
(Nos. 1107020522 and 1082020502). The Jiangsu 333 program (for
Pan) and Changzhou Jin-Feng-Huang program (for Han) are also
acknowledged.
Appendix A. Supplementary data
(S)-2-methyl-N-((R)-2,2,2-trifluoro-1-(6-phenylthiazolo[3,2-
b][1,2,4]triazol-5-yl)ethyl)propane-2-sulfinamide (20). White
Supplementary material related to this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.jfluchem.2014.06.015.
solid (6.35 g, 63% yield), mp 188–189 8C. ½a D25
ꢃ
+ 111.0 (c = 0.98,
CHCl3). 1H NMR (CDCl3, 400 MHz):
d = 8.14 (s, 1H), 7.69 (dd, J = 7.7,
1.8 Hz, 2H), 7.59 ꢀ 7.52 (m, 3H), 5.30 (qd, J = 6.3, 2.4 Hz, 1H), 4.01
References
(s, 1H), 1.25 (s, 9H), 13C NMR (CDCl3, 101 MHz):
d
= 156.3, 156.0,
135.7, 131.0, 129.6, 129.5, 126.0, 123.7 (q, J = 282.4 Hz), 118.0,
57.0, 54.7 (q, J = 32.4 Hz), 22.5, 19F NMR (CDCl3, 376 MHz):
d
[1] (a) J. Wang, M. Sa´nchez-Rosello´, J.L. Acen˜a, C. del Pozo, A.E. Sorochinsky, S. Fustero,
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425.0688, found: 425.0681.
4.12. Procedure for the deprotection of product 20 (10 mmol scale) to
free amine 21
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The product 20 (4.02 g, 10.0 mmol) and MeOH (100 mL) were
placed in a 250 mL round-bottom flask and aq. HCl (36%, 20 mL)
was added dropwise. The reaction was stirred at r.t. for 8 h, during
which the cleavage was monitored by TLC. Volatiles were removed
under reduced pressure. The residue was dissolved in CH2Cl2
(200 mL) and Et3N (30.36 g, 300 mmol) was added. The mixture
was stirred at r.t. for 1 h, then H2O (200 mL) was added. The organic
layer was taken, washed with H2O (2 ꢂ 200 mL), dried with
anhydrous Na2SO4, filtered and the solvent was removed to give
the crude product, which was purified by column chromatography
(hexanes/EtOAc = 1:1) to afford the corresponding deprotection
product 21 as a white solid in 84% isolated yield.
[2] (a) T. Furuya, A.S. Kamlet, T. Ritter, Nature 473 (2011) 470;
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(R)-2,2,2-trifluoro-1-(6-phenylthiazolo[3,2-b][1,2,4]triazol-
5-yl)ethanamine (21). White solid (2.52 g, 84% yield), mp 106–
(b) R. Filler, Y. Kobayashi, Y.L. Yagulpolskii, Organofluorine Compounds in Me-
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108 8C. ½a 2D5
ꢃ
ꢀ 3.8 (c = 1.23, CHCl3). 1H NMR (CDCl3, 400 MHz):
d
= 8.15 (s, 1H), 7.69 ꢀ 7.62 (m, 2H), 7.60 ꢀ 7.56 (m, 3H), 4.86 (q,
J = 6.6 Hz, 1H), 1.95 (br, 2H), 13C NMR (CDCl3, 101 MHz):
155.2, 132.5, 130.6, 129.4, 129.2, 126.6, 124.7(q, J = 282.2 Hz), 122.8,
d = 155.9,
[4] (a) J.L. Acen˜a, A. Simo´n-Fuentes, S. Fustero, Curr. Org. Chem. 14 (2010) 928;
(b) J. Han, A.E. Sorochinsky, T. Ono, V.A. Soloshonok, Curr. Org. Synth. 8 (2011)
281;
52.3 (q, J = 31.9 Hz), 19F NMR (CDCl3, 376 MHz):
d
= ꢀ75.8. HRMS
[M + H+]: calcd for C12H10F3N4S+: 299.0573, found: 299.0580.
(c) K.V. Turcheniuk, V.P. Kukhar, G.V. Roeschenthaler, J.L. Acena, V.A. Soloshonok,
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´
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Table of contents
Sorochinsky, Synthesis (2011) 3045;
(f) A.E. Sorochinsky, V.A. Soloshonok, J. Fluor. Chem. 131 (2010) 127;
O
S
CF3
O
S
(C-nucleophiles)
+
R
O
F3C
N
R
N
H
C-nucleophiles =
good chemical yields
O
OLi
excellent diastereoselectivities
Ph
N
OCH3
0.5, 5.0 and 25 mmol scale reaction
Ph
N
N
N
S
N
N
S
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793.
Acknowledgment
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We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (No. 21102071)

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