Concise and scalable asymmetric synthesis of 5-(1-amino-2,2,2- trifluoroethyl)thiazolo[3,2-b][1,2,4]triazoles

Article abstract of DOI:10.1039/c3ob42348d

This study describes asymmetric Mannich-type additions between C-5 lithiated thiazolo[3,2-b][1,2,4]triazoles and enantiomerically pure (S _S)-N-tert-butanesulfinyl-(3,3,3)-trifluoroacetaldimine. Under the optimized conditions, these reactions proceed with good (up to 78%) chemical yields and virtually complete (98 : 2 to >99 : 1 dr) diastereoselectivity. The same stereochemical outcome was obtained using 1.05 g scale of the starting (3,3,3)-trifluoroacetaldimine. The method developed in this work provides concise and generalized access to thiazolo[3,2-b][1,2,4]triazoles containing a chiral (trifluoro)ethylamine group.

Full text of DOI:10.1039/c3ob42348d

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Concise and scalable asymmetric synthesis of
5-(1-amino-2,2,2-trifluoroethyl)thiazolo[3,2-b]-
[1,2,4]triazoles†
Cite this: Org. Biomol. Chem., 2014,
12, 2108
Haibo Mei,a,b Yiwen Xiong,a Chen Xie,a Vadim A. Soloshonok,c,d Jianlin Han*a,b,e and
Yi Pana
This study describes asymmetric Mannich-type additions between C-5 lithiated thiazolo[3,2-b][1,2,4]-
triazoles and enantiomerically pure (SS)-N-tert-butanesulfinyl-(3,3,3)-trifluoroacetaldimine. Under the
optimized conditions, these reactions proceed with good (up to 78%) chemical yields and virtually com-
plete (98 : 2 to >99 : 1 dr) diastereoselectivity. The same stereochemical outcome was obtained using
1.05 g scale of the starting (3,3,3)-trifluoroacetaldimine. The method developed in this work provides
concise and generalized access to thiazolo[3,2-b][1,2,4]triazoles containing a chiral (trifluoro)ethylamine
group.
Received 24th November 2013,
Accepted 29th January 2014
DOI: 10.1039/c3ob42348d
www.rsc.org/obc
Introduction
Heterocyclic compounds are quite commonly found in nature
and have been attracting much attention of organic chemists
for many decades.1 In particular, the thiazolo[3,2-b][1,2,4]tri-
azole fragment is found in many biologically active natural
products.2 Consequently, synthesis and biological study of new
thiazolo[3,2-b][1,2,4]triazole derivatives is currently an active
field of multidisciplinary research.3–5 It was found that the
most promising biologically active types of thiazolo[3,2-b]-
[1,2,4]triazoles usually contain functional chiral moieties.2–5
Accordingly, the development of concise and scalable methods
for asymmetric modification of thiazolo[3,2-b][1,2,4]triazoles is
an important yet challenging goal in synthetic organic and
medicinal chemistry.6–8
Scheme 1 Mannich-type addition reactions between thiazolo[3,2-b]-
[1,2,4]triazoles and chiral CF3-sulfinylimine.
considering our15 and others’16 recent interest in the chem-
istry of (SS)-N-tert-butanesulfinyl-(3,3,3)-trifluoroacetaldimine17
we envisioned a direct, one-step introduction of the pharmaco-
phoric 1-amino-2,2,2-trifluoroethyl moiety onto the thiazolo-
[3,2-b][1,2,4]triazole rings. Herein, we report a study of asym-
metric Mannich-type reactions between C-5 lithiated thiazolo-
[3,2-b][1,2,4]triazoles and (SS)-N-tert-butanesulfinyl-(3,3,3)-
trifluoroacetaldimine. These reactions were found to proceed
with exceptional diastereoselectivity giving rise to virtually one
product in good chemical yields (Scheme 1). The mechanism,
structural generality of this method and its scalability are
discussed.
Taking into account the remarkable impact of fluorine on
the development of biologically active compounds and
pharmaceuticals,9–14 synthesis of fluorinated thiazolo[3,2-b]-
[1,2,4]triazoles might be of great interest. Therefore,
aSchool of Chemistry and Chemical Engineering, Nanjing University, Nanjing,
210093, China. E-mail: hanjl@nju.edu.cn; Fax: +86-25-83593153;
Tel: +86-25-83593153
Results and discussion
bInstitute for Chemistry & BioMedical Sciences, Nanjing University, Nanjing, 210093,
China
Based on our previous studies of the asymmetric reactions
with N-tert-butylsulfinylimine,15a,b the initial choice of the
reaction conditions was focused on using sulfinylimine 2 with
1.5 equiv. of 6-phenylthiazolo[3,2-b][1,2,4]triazole 1a in the
presence of n-BuLi with THF as a solvent at −78 °C. The reac-
tion proceeded smoothly within 2 hours, affording (entry 1,
Table 1) the desired product 3a in 61% yield. Determination
of the diastereomeric purity by 1H-NMR has revealed two
cDepartment of Organic Chemistry I, Faculty of Chemistry, University of the Basque
Country UPV/EHU, 20018 San Sebastian, Spain
dIKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain
eHigh-Tech Research Institute of Nanjing University, Changzhou, 213164, China
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, full spectroscopic data for compounds 3 and 4 and copies of 1H NMR
and 13C NMR spectra. CCDC 948095. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c3ob42348d
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Table 1 Optimization of the asymmetric Mannich-type addition reaction conditionsa
Entry
Base
1a (equiv.)
Solvent
Time (h)
T (°C)
Yieldb (%)
drc
1
2
3
4
5
6
7
8
n-BuLi
LDA
LiHDMS
(CH3)3COLi
(CH3)3COK
Cs2CO3
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
1.5
1.5
1.5
1.5
1.5
1.5
1.2
1.7
1.7
1.7
1.7
1.7
1.7
1.7
1.7
1.7
1.7
THF
THF
THF
THF
THF
THF
THF
THF
Toluene
Hexane
CH2Cl2
Et2O
THF
THF
THF
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
3
−78
−78
−78
−78
−78
−78
−78
−78
−78
−78
−78
−78
−41
−22
0
61
62
42
Trace
Trace
NRe
40
71
26
27
13
37
72
64
61
66
65
83 : 17
97 : 3
76 : 24
NDd
NDd
—
87 : 13
98 : 2
79 : 21
82 : 18
92 : 8
90 : 10
93 : 7
91 : 9
94 : 6
97 : 3
98 : 2
9
10
11
12
13
14
15
16
17
THF
THF
−78
−78
a Reaction conditions: sulfinylimine (0.5 mmol), base (1.1 equiv. of 1a), solvent (5 mL). b Isolated yields. c Determined by 19F or 1H NMR analysis.
d Not determined. e No reaction.
diastereomeric products (see ESI†) in a ratio of 83 : 17.
Table 2 Scope of thiazolo[3,2-b][1,2,4]triazoles for the asymmetric
Attempts to separate these two CF3-containing products by additiona
column chromatography have failed, indicating insufficient
difference in the physicochemical properties of the diastereo-
mers. The fact that the separation of diastereomeric products
is problematic has added an extra challenge to this work as
only complete diastereoselectivity in these additions could
render this method synthetically useful. Thus, systematic
optimization was carried out to improve both the yield and,
most importantly, the diastereoselectivity. First, the effect of a
base used in these reactions was investigated. It was found
that strong bases could give good results while the weak ones
could not even catalyze the reaction (entries 2–6). LDA was
found to be the best choice, providing for an acceptable yield
and the desired high diastereoselectivity (62% yield and 97 : 3
dr, entry 2). Next, the loading amount of 6-phenylthiazolo-
[3,2-b][1,2,4]triazole 1a was examined. The experiments have
revealed that the use of 1.7 equiv. of 1a leads to the high yield
and excellent diastereoselectivity (71% yield and 98 : 2 dr,
entry 8). Reducing the amount of 1a resulted in an obvious
decrease in both yield and diastereoselectivity (entry 7). The
solvent was found to have a significant effect on the stereo-
chemical outcome (entries 9–12), and THF was finally confirmed
to be the best choice. Furthermore, temperature was also
found to be an important factor in these reactions. Elevated
reaction temperature brought a slight decrease in both yield
and diastereoselectivity (entries 13–15). Finally, the screening
of the reaction time demonstrated that this transformation
could be reasonably completed within 2 hours. Thus, extend-
ing the reaction time resulted in a noticeable decrease in the
Entry
Substrate
R
Product
Yieldb (%)
drc
98 : 2
>99 : 1
>99 : 1
98 : 2
>99 : 1
99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
1
2
3
4
5
6
7
8
9
10
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
71
73
74
72
66
70
73
78
68
40
3-ClC6H4
3-BrC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeC6H4
3,4-Cl2C6H3
2-Naphthyl
Me
1j
3j
a Reaction conditions: sulfinylimine (0.5 mmol), 1 (0.85 mmol), LDA
(0.94 mmol), THF (5 mL). b Isolated yields. c Determined by 19F NMR
analysis.
yield, although it has almost no effect on the diastereo-
selectivity (entry 17).
Having optimized the reaction conditions, our next goal
was to examine the scope of these reactions using available
thiazolo[3,2-b][1,2,4]triazoles (Table 2). Under the standard
reaction conditions, all tested substrates reacted smoothly
pointing to generality of this method. As shown in Table 2, the
diastereoselectivity of the reactions was excellent, producing
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Scheme 2 Example of a large-scale asymmetric synthesis of com-
pound 3a.
virtually single diastereomer 3. Variation of substituents on
the aromatic ring showed no significant effect on either chemi-
cal yield or diastereoselectivity. Both electron-deficient (entries
2–6) and electron-rich (entry 7) aryl-substituted thiazolo[3,2-b]-
[1,2,4]triazoles gave equally good stereochemical outcome. In
particular, thiazolo[3,2-b][1,2,4]triazoles with a di-substituted
aromatic ring 1h or naphthyl substituted 1i were also well
tolerated in this reaction affording products 3h, i in good
yields and with excellent diastereoselectivity (entries 8 and 9).
In the case of alkyl substituted derivative 1j the reaction yield
was noticeably lower; however, the corresponding product 3j
was isolated as a single diastereomer (entry 10).
Fig. 2 Proposed mechanism for the asymmetric Mannich-type
addition.
Finally, we tested this newly developed method for its repro-
ducibility and efficiency on a gram scale. As one can see from
Scheme 2, the reaction conducted under the standard con-
ditions using 1.05 g of sulfinylimine 2 afforded the target
product 3a with good yield (68%) and diastereoselectivity
(94 : 6 dr). Diastereomerically pure 3a can be prepared by crys-
tallization of the crude product. Thus, only a slight decrease in
the yield and diastereoselectivity was detected as compared to
the best result obtained on a 0.10 g scale. Consequently, this
approach can be reliably used for relatively large scale syn-
thesis of various fluorinated chiral thiazolo[3,2-b][1,2,4]triazole
derivatives allowing for systematic biological studies of these
new compounds.
Scheme 3 Conversion of 3a to free chiral primary amine 4.
corresponding products were assigned by analogy, based on
similarity of their chiroptic properties and spectral data.
Consistent with the literature data,18 the asymmetric
Mannich-type addition reactions of thiazolo[3,2-b][1,2,4]tri-
azoles to sulfinylimine 2 are suggested to proceed via a non-
chelated transition state model. Thus, the lithiated thiazolo-
[3,2-b][1,2,4]triazoles preferably approach the imine double
bond from the less hindered face, occupied by the lone pair of
electrons on sulphur, to afford the major diastereomer (Fig. 2).
Furthermore, via this general approach, two possible orien-
tations of the thiazolo[3,2-b][1,2,4]triazole anions A and B are
possible. Considering obvious steric interactions of the
CF3 group and the substituent R in B, it is most likely that the
transition state A might be preferred.
To determine the absolute configuration of products 3, we
took advantage of good crystallinity of compound 3a and con-
ducted its crystallographic analysis (Fig. 1). As shown in Fig. 1,
the absolute configuration of the newly generated chiral center
in this process is R. The absolute configurations of other
As the final task of this work, we studied an example of the
chiral auxiliary removal and preparation of compound 4 with
free amino function. Using relatively common conditions,15a,b
such as treatment of 3a with aqueous HCl in methanol
(Scheme 3), the target amine 4 was obtained in high isolated
yield of 86%.
Conclusions
In summary, we have demonstrated that the asymmetric
Mannich-type addition reactions between lithium-derived
imidazo[2,1-b]thiazoles and CF3-sulfinylimine 2 occur with
Fig. 1 ORTEP diagram showing compound (SS)(R)-3a.
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reasonably good yields and excellent diastereoselectivity. These (m, 1 H), 3.92 (s, 1 H), 1.30 (s, 9 H). 13C NMR (CDCl3,
reactions are reproducible on a relatively large scale and can 100 MHz): δ = 156.4, 155.9, 134.2, 133.9, 132.4, 131.0, 128.2,
be reliably used for preparation of various thiazolo[3,2-b]- 127.8, 125.0 (q, J = 281.0 Hz), 123.5, 119.0, 57.0, 54.8 (q, J =
[1,2,4]triazoles containing a chiral 1-amino-2,2,2-trifluoroethyl 32.0 Hz), 22.5. 19F NMR (CDCl3, 376 MHz): δ = −73.7. HRMS
group for systematic biological studies.
[M
480.9974.
3d: white solid, mp 61–63 °C, [α]2D5 +107.9 (c 0.25, CHCl3).
+
H+]: calcd for [C16H17BrN4OF3S2] 480.9979, found
General information
All imine addition reactions were performed in oven-dried 1H NMR (CDCl3, 400 MHz): δ = 8.18 (s, 1 H), 7.73–7.76 (m,
vials under a N2 atmosphere. Solvent THF was dried and dis- 2 H), 7.26–7.31 (m, 2 H), 5.25–5.30 (m, 1 H), 3.91 (s, 1 H), 1.29
tilled prior to use. Thiazolo[3,2-b][1,2,4]triazoles 1 were syn- (s, 9 H). 13C NMR (CDCl3, 100 MHz): δ = 165.4 (d, J = 251.0 Hz),
thesized according to the literature.8 Sulfinylimine 2 was 156.4, 156.0, 134.7, 131.9 (d, J = 9.0 Hz), 125.0 (q, J = 280.0 Hz),
obtained from Accela ChemBio Co., Ltd. LDA (2 M in THF) was 122.0 (d, J = 3.0 Hz), 118.1, 117.0 (d, J = 22.0 Hz), 57.0, 54.8 (q,
from Aldrich. These and other chemicals were used as J = 32.0 Hz), 22.4. 19F NMR (CDCl3, 376 MHz): δ = −73.8,
obtained from commercial sources without further purifi- −107.9. HRMS [M
cation. Flash chromatography was performed using silica gel 443.0599, found 443.0598.
60 (200–300 mesh). Thin layer chromatography was carried out
3e: white solid, mp 67–69 °C, [α]2D5 +68.1 (c 0.23, CHCl3). 1H
+
Na+]: calcd for [C16H16N4OF4S2Na]
on silica gel 60 F-254 TLC plates of 20 cm × 20 cm. Melting NMR (CDCl3, 400 MHz): δ = 8.18 (s, 1 H), 7.70 (d, J = 8.0 Hz,
points are uncorrected. Values of optical rotation were 2 H), 7.59 (d, J = 8.0 Hz, 2 H), 5.25–5.30 (m, 1 H), 3.92 (s, 1 H),
measured on a Rudolph Automatic Polarimeter A21101. 1H, 1.29 (s, 9 H). 13C NMR (CDCl3, 100 MHz): δ = 156.4, 156.0,
13C and 19F NMR spectra were recorded on
a Bruker 137.4, 134.5, 131.0, 129.9, 125.0 (q, J = 281.0 Hz), 124.3, 118.3,
AVANCE400M spectrometer. HRMS spectra were recorded 57.0, 54.7 (q, J = 32.0 Hz), 22.4. 19F NMR (CDCl3, 376 MHz): δ =
using a Micromass GCT (TOF MS EI+).
−73.8. HRMS [M + H+]: calcd for [C16H17ClN4OF3S2] 437.0484,
found 437.0477.
Typical procedure for asymmetric addition of sulfinylimine
1
3f: white solid, mp 72–74 °C, [α]2D5 +57.3 (c 0.22, CHCl3). H
Into an oven-dried reaction vial flushed with N2 were taken NMR (CDCl3, 400 MHz): δ = 8.18 (s, 1 H), 7.75 (d, J = 8.0 Hz,
compound 1 (0.85 mmol) and anhydrous THF (3.0 mL). The 2 H), 7.63 (d, J = 8.0 Hz, 2 H), 5.25–5.30 (m, 1 H), 3.92 (s, 1 H),
reaction vial was cooled to −78 °C and LDA (2 M in THF, 1.29 (s, 9 H). 13C NMR (CDCl3, 100 MHz): δ = 156.4, 156.0,
0.47 mL) was added dropwise with stirring. After 1 h at −78 °C, 134.6, 132.9, 131.1, 125.8, 125.0 (q, J = 280.0 Hz), 124.8, 118.3,
sulfinylimine 2 (0.5 mmol) dissolved in anhydrous THF 57.0, 54.7 (q, J = 32.0 Hz), 22.4. 19F NMR (CDCl3, 376 MHz): δ =
(2.0 mL) was added dropwise. Stirring was continued at −73.8. HRMS [M + H+]: calcd for [C16H17BrN4OF3S2] 480.9979,
−78 °C for 2 h, then the reaction was quenched with saturated found 480.9980.
NH4Cl (3.0 mL) followed by H2O (5.0 mL) and the mixture was
3g: white solid, mp 142–143 °C, [α]2D5 +74.1 (c 0.52, CHCl3).
brought to room temperature. The organic layer was taken and 1H NMR (CDCl3, 400 MHz): δ = 8.17 (s, 1 H), 7.61 (d, J = 8.0 Hz,
the aqueous layer was extracted with EtOAc (2 × 20 mL). The 2 H), 7.40 (d, J = 8.0 Hz, 2 H), 5.30–5.36 (m, 1 H), 3.88 (s, 1 H),
combined organic layers were dried with anhydrous Na2SO4, 2.44 (s, 3 H), 1.28 (s, 9 H). 13C NMR (CDCl3, 100 MHz): δ =
filtered and the solvent was removed to give the crude product, 156.2, 155.9, 141.4, 135.8, 130.2, 129.4, 125.1 (q, J = 281.0 Hz),
which was purified by a TLC plate (hexane–EtOAc, 1 : 1).
123.0, 117.5, 56.9, 54.9 (q, J = 32.0 Hz), 22.4, 21.5. 19F NMR
3a: white solid, mp 192–193 °C, [α]2D5 +107.3 (c 1.05, CHCl3). (CDCl3, 376 MHz): δ = −73.8. HRMS [M + Na+]: calcd for
1H NMR (CDCl3, 400 MHz): δ = 8.18 (s, 1 H), 7.71–7.74 (m, [C17H19N4OF3S2Na] 439.0850, found 439.0853.
2 H), 7.57–7.62 (m, 3 H), 5.31–5.36 (m, 1 H), 3.91 (s, 1 H), 1.29
3h: white solid, mp 66–68 °C, [α]2D5 +68.3 (c 0.33, CHCl3). 1H
(s, 9 H). 13C NMR (CDCl3, 100 MHz): δ = 156.2, 155.8, 135.5, NMR (CDCl3, 400 MHz): δ = 8.19 (s, 1 H), 7.89 (d, J = 2.0 Hz,
130.9, 129.5, 129.4, 126.0, 125.1 (q, J = 281.0 Hz), 118.1, 56.9, 1 H), 7.69 (d, J = 8.0 Hz, 1 H), 7.63 (dd, J = 2.0, 8.0 Hz, 1 H),
54.9 (q, J = 32.0 Hz), 22.4. 19F NMR (CDCl3, 376 MHz): δ = 5.25–5.30 (m, 1 H), 3.95 (s, 1 H), 1.30 (s, 9 H). 13C NMR
−73.8. HRMS (TOF MS EI+) m/z: calcd for [C16H17N4OF3S2] (CDCl3, 100 MHz): δ = 156.5, 156.0, 135.8, 134.1, 133.1, 131.6,
402.0796, found 402.0785.
131.4, 128.7, 125.7, 124.9 (q, J = 280.0 Hz), 119.1, 57.0, 54.7 (q,
3b: white solid, mp 185–187 °C, [α]2D5 +97.2 (c 0.79, CHCl3). J = 32.0 Hz), 22.5. 19F NMR (CDCl3, 376 MHz): δ = −73.7.
1H NMR (CDCl3, 400 MHz): δ = 8.19 (s, 1 H), 7.75 (d, J = 1.6 Hz, HRMS [M + Na+]: calcd for [C16H15Cl2N4OF3S2Na] 492.9914,
1 H), 7.63–7.66 (m, 1 H), 7.52–7.58 (m, 2 H), 5.27–5.32 (m, found 492.9910.
1 H), 3.93 (s, 1 H), 1.30 (s, 9 H). 13C NMR (CDCl3, 100 MHz):
3i: white solid, mp 166–167 °C, [α]2D5 +59.8 (c 1.13, CHCl3).
δ = 156.4, 156.0, 135.5, 134.0, 131.3, 130.8, 129.6, 127.7, 127.6, 1H NMR (CDCl3, 400 MHz): δ = 8.28 (s, 1 H), 8.21 (s, 1 H), 8.08
125.0 (q, J = 281.0 Hz), 118.9, 57.0, 54.8 (q, J = 32.0 Hz), 22.4. (d, J = 8.0 Hz, 1 H), 8.00 (d, J = 8.0 Hz, 1 H), 7.94 (d, J = 8.0 Hz,
19F NMR (CDCl3, 376 MHz): δ = −73.7. HRMS [M + H+]: calcd 1 H), 7.79 (dd, J = 4.0, 8.0 Hz, 1 H), 7.56–7.64 (m, 2 H),
for [C16H17ClN4OF3S2] 437.0484, found 437.0482.
5.41–5.46 (m, 1 H), 3.94 (s, 1 H), 1.31 (s, 9 H). 13C NMR
3c: white solid, mp 190–191 °C, [α]2D5 +94.5 (c 0.95, CHCl3). (CDCl3, 100 MHz): δ = 156.3, 156.0, 135.7, 134.1, 133.1, 130.1,
1H NMR (CDCl3, 400 MHz): δ = 8.19 (s, 1 H), 7.90 (t, J = 2.0 Hz, 129.5, 128.8, 127.9, 127.8, 127.1, 125.5, 125.1 (q, J = 281.0 Hz),
1 H), 7.68–7.73 (m, 2 H), 7.48 (t, J = 8.0 Hz, 1 H), 5.27–5.32 123.3, 118.2, 57.0, 55.0 (q, J = 32.0 Hz), 22.5. 19F NMR (CDCl3,
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376 MHz):
[C20H19N4OF3S2Na] 475.0850, found 475.0850.
δ = −73.7. HRMS [M +
Na+]: calcd for
Notes and references
3j: white solid, mp 193–194 °C, [α]2D5 +132.3 (c 0.56, CHCl3).
1H NMR (CDCl3, 400 MHz): δ = 8.18 (s, 1 H), 5.23–5.28 (m,
1 H), 3.91 (s, 1 H), 2.65 (s, 3 H), 1.29 (s, 9 H). 13C NMR (CDCl3,
100 MHz): δ = 156.0, 155.8, 131.6, 125.2 (q, J = 280.0 Hz),
116.4, 56.9, 54.1 (q, J = 32.0 Hz), 22.4, 11.5. 19F NMR (CDCl3,
376 MHz): δ = −74.0. HRMS (TOF MS EI+) m/z: calcd for
[C11H15N4OF3S2] 340.0639, found 340.0633.
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Reaction of large scale application study
In an oven-dried round-bottom flask flushed with N2 were
taken compound 1a (8.5 mmol) and anhydrous THF
(20.0 mL). The reaction flask was cooled to −78 °C and LDA
(2 M in THF, 4.7 mL) was added dropwise with stirring. After
1 h at −78 °C, sulfinylimine 2 (5 mmol) dissolved in anhydrous
THF (10.0 mL) was added dropwise. Stirring was continued
at −78 °C for 2.5 h, then the reaction was quenched with
saturated NH4Cl (10.0 mL) followed by H2O (15.0 mL) and the
mixture was brought to room temperature. The organic
layer was taken and the aqueous layer was extracted with
EtOAc (2 × 30 mL). The combined organic layers were dried
with anhydrous Na2SO4, filtered and the solvent was removed
to give the crude product, which was purified by column
chromatography (hexane–EtOAc, 1 : 1).
Conversion of 3a affording free chiral primary amine 4
3a (0.5 mmol) and MeOH (5.0 mL) were placed in a 25 mL
round-bottom flask and aq. HCl (36%, 1 mL) was added. The
reaction was stirred at r.t. for 8 h, during which time the clea-
vage was monitored by TLC. Volatiles were removed under
reduced pressure. The residue was dissolved in CH2Cl2
(10.0 mL) and Et3N (15 mmol) was added. The reaction was
stirred at rt for 1 h and then H2O (10.0 mL) was added. The
organic layer was taken, washed with H2O (2 × 10 mL), dried
with anhydrous Na2SO4, filtered and the solvent was removed
to give the crude product, which was purified by a TLC plate
(hexane–EtOAc, 1 : 1).
4: white solid, mp 105–106 °C, [α]2D5 −2.6 (c 0.61, CHCl3). 1H
NMR (CDCl3, 400 MHz): δ = 8.15 (s, 1 H), 7.64–7.68 (m, 2 H),
7.57–7.60 (m, 3 H), 4.84–4.89 (m, 1 H), 1.94 (s, 2 H). 13C NMR
(CDCl3, 100 MHz): δ = 156.0, 155.3, 132.6, 130.7, 129.5, 129.3,
126.7, 126.2 (q, J = 280.0 Hz), 122.7, 52.6 (q, J = 32.0 Hz). 19F
NMR (CDCl3, 376 MHz): δ = −75.8. HRMS (TOF MS EI+) m/z:
calcd for [C12H9N4F3S] 298.0500, found 298.0510.
14 (a) J. L. Aceña, A. E. Sorochinsky and V. A. Soloshonok, Syn-
thesis, 2012, 1591–1602; (b) K. Mikami, S. Fustero,
M. Sánchez-Roselló, J. L. Aceña, V. A. Soloshonok and
A. E. Sorochinsky, Synthesis, 2011, 3045–3079.
Acknowledgements
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (no. 21102071) 15 (a) H. Mei, Y. Xiong, J. Han and Y. Pan, Org. Biomol. Chem.,
and the Fundamental Research Funds for the Central Univer-
sities (no. 1107020522 and no. 1082020502). The Jiangsu 333
program (for Pan) and Changzhou Jin-Feng-Huang program
(for Han) are also acknowledged.
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