Br?nsted Acid-Catalyzed Asymmetric Friedel-Crafts Alkylation of Indoles with Benzothiazole-Bearing Trifluoromethyl Ketone Hydrates

Article abstract of DOI:10.1021/acs.joc.0c00116

An efficient Br?nsted acid-catalyzed asymmetric Friedel-Crafts alkylation of indoles with benzothiazole-bearing trifluoromethyl ketone hydrates as electrophiles has been developed. The mild organocatalytic reactions proceeded well with low catalyst loading to afford a range of enantioenriched α-trifluoromethyl tertiary alcohols containing both benzothiazole and indole rings with excellent yields and enantioselectivities.

Full text of DOI:10.1021/acs.joc.0c00116

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Article
Brønsted Acid-Catalyzed Asymmetric Friedel–Crafts Alkylation of
Indoles with Benzothiazole-Bearing Trifluoromethyl Ketone Hydrates
Wei Wang, Wenhui Xiong, Jinping Wang, Qiu-An Wang, and Wen Yang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00116 • Publication Date (Web): 02 Mar 2020
Downloaded from pubs.acs.org on March 2, 2020
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Page 1 of 28
The Journal of Organic Chemistry
Brønsted Acid-Catalyzed Asymmetric Friedel–Crafts Alkylation of
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Indoles with Benzothiazole-Bearing Trifluoromethyl Ketone Hydrates
Wei Wang, Wenhui Xiong, Jinping Wang,* Qiu-An Wang,* and Wen Yang*
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College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, People’s
Republic of China
E-mail: yangwen@hnu.edu.cn; wangqa@hnu.edu.cn; jinpingwang1985@126.com
HO OH
HO CF3
N
1
mol% B-H*
DCM, rt
N
R2
CF3
R2
+
S
S
N
NH
R1
R1
H
up to 99% yield, >99% ee
Ar
O
O
O

Excellent efficiency and enantioselectivity
P
OH
 Mild recation conditions and low catalyst loading


Simple operation and easy gram-scale preparation
Ar
Synthesis of enantioenriched
α -trifluoromethyl tertiary alcohols
i
Ar = 2,4,6- Pr C H
6 2
3
with two important heterocycles (benzothiazoles and indoles)
B-H*
ABSTRACT
An efficient Brønsted acid-catalyzed asymmetric Friedel–Crafts alkylation of indoles with
benzothiazole-bearing trifluoromethyl ketone hydrates as electrophiles has been developed. The mild
organocatalytic reactions proceeded well with low catalyst loading to afford a range of enantioenriched
α-trifluoromethyl tertiary alcohols containing both benzothiazole and indole rings with excellent yields
and enantioselectivities.
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INTRODUCTION
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Trifluoromethylated compounds, due to their unique properties, including high electronegativity,
lipophilicity, and metabolic stability, have attracted great attention in the past decades.1,2 Particularly
intriguing are chiral α-trifluoromethyl tertiary alcohols, which are important building blocks for the
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preparation of pharmaceuticals and agrochemicals (Figure 1). The notable examples are efavirenz and
indole-substituted trifluoromethyl alcohol A,3a,e,f which are HIV-1 reverse transcriptase inhibitors.
Asymmetric Friedel−Crafts alkylation of indoles with trifluoromethyl ketones (trifluoroacetophenones
and trifluoropyruvates) is an effective and straightforward access to chiral α-trifluoromethyl tertiary
4
,5
alcohols (Scheme 1a). Although many examples have been reported, most of them suffer high catalyst
loading, harsh conditions, and/or diarylated byproducts. Thus, addressing these shortcomings of this
useful transformation is still in demand. To address these issues, previous reports mostly focus on the
development of new catalytic systems, but rarely start with developing efficient substrates. Herein, we
use benzothiazole-bearing trifluoromethyl ketone hydrates as electrophiles instead of
trifluoroacetophenones and trifluoropyruvates (Scheme 1b).
tBu
O
F3C
HO
HO CF3
F3C
CO2Et HOHN
NHMe
N
H
Cl
O N
2
O
O
O
N
O
N
H
H
Ph
B
Efavirenz
anti-HIV
A
anti-HIV
MMPs inhibitor
Figure 1. Examples of pharmaceuticals containing chiral α-trifluoromethyl tertiary alcohols.
Benzothiazole is an important heterocyclic skeleton frequently found in numerous natural products,
6
pharmaceutical molecules, catalysts, fluorescent probes, and materials. The combination of two
privileged structures, a benzothiazole ring and a trifluoromethyl moiety, for the synthesis of chiral
organic molecules could be of significant importance, especially for new drugs and materials. However,
7
there are just a handful of reports on racemic or achiral synthesis. In this paper, we realize the assembly
of such chiral molecules via an efficient Brønsted acid-catalyzed asymmetric Friedel−Crafts alkylation
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of indoles with benzothiazole-bearing trifluoromethyl ketone hydrates as electrophiles (Scheme 1b).
Notably, the introduction of an electon-deficient benzothiazole ring could bring several benefits. First, it
could significantly enhance the electrophilicity of substrates, solving the problem of low reactivity.
Second, it could help to stabilize the monoarylated adducts, thereby suppressing the formation of
diarylated byproducts. Third, it also gives us a good chance to introduce important benzothiazole
heterocycles into chiral α-trifluoromethyl tertiary alcohols.
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5
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9
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Scheme 1. Asymmetric Friedel–Crafts Alkylation of Indole for α-Trifluoromethyl Tertiary
Alcohols
a) Previous work (well-explored)
HO CF3
O
organocatalysts
or [M] & L
+

R
R
CF3
N
H
NH
R = Ph, CO R'
2
b) This work
HO OH
HO CF3
N
N
CF3
B-H*

+
S
S
N
H
NH
RESULTS AND DISCUSSION
Initially, we readily prepared benzothiazole-bearing trifluoromethyl ketone hydrate 1a in one step by a
8
slightly modified procedure, and directly used it as an electrophile for the catalytic asymmetric
Friedel−Crafts alkylation of indole 2a. In the presence of 5 mol% of chiral phosphoric acid I, we were
pleased to find that the reaction proceeded smoothly in toluene at room temperature to provide the
desired product 3aa with full conversion, albeit with low enantioselectivity (16% ee, Table 1, entry 1).
The initial success avoided the further synthesis of the corresponding unstable ketone 1a’ as an
electrophile. Subsequently, a series of BINOL-derived chiral phosphoric acids II−VI with different
substituents at the 3- and 3’-positions were screened, and the catalyst V was found to be superior,
providing excellent efficiency and moderate enantioselectivity (Table 1, entries 2−6). The screening
results showed that more acidic catalysts III and IV resulted in a handful of diarylated byproduct, while
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less acidic catalyst VI just gave trace conversion. The solvent variation has a dramatic impact on the
reaction outcome (Table 1, entries 7−13). Dichloromethane was identified as the best solvent providing
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higher enantioselectivity (78% ee), while other common solvents, such as THF, Et O, EtOAc, and
2
MeCN, all resulted in very low conversion. To our delight, we tried SPINOL-derived chiral phosphoric
acid VII (STRIP), and full conversion and high enantioselectivity (92% ee) were obtained (Table 1,
entry 14). The use of 5 Å molecular sieves (MS) further increased the enantioselectivity to 98% ee, and
also fulfilled full conversion in a much shorter time (Table 1, entry 15). The enhanced reactivity should
be due to MS-accelerated dehydration of trifluoromethyl ketone hydrate 1a. The reduced catalyst
loading (1 or 2 mol %) resulted in essentially no erosion in efficiency and enantioselectivity, but further
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0
reducing the loading (0.5 mol %) decreased slightly the enantioselectivity (Table 1, entries 16−18).
Table 1. Optimization of Reaction Conditionsa
HO CF3
HO OH
N
5
mol% I-VII

N
CF3
NH
+
S
S
N
solvent (0.1 M), rt
H
1a
2a
3aa
Ar
Ar
I: Ar = 9-anthryl
O
O
O
II: Ar = 9-phenanthryl
III: Ar = 1-pyrenyl
O
O
O
P
P
OH
OH IV: Ar = 3,5-(CF ) C H
6 3
3 2
i
Ar
V: Ar = 2,4,6- Pr C H
3
6
2
Ar
i
VI: Ar = SiPh3
VII: Ar = 2,4,6- Pr C H
3 6
2
entry
catalyst
solvent
toluene
toluene
toluene
toluene
toluene
toluene
THF
time (h)
24
conv. (%)b
100
100
80
ee (%)c
16
1
2
3
4
5
6
7
8
9
I
II
24
25
III
IV
V
24
23
24
70
2
24
95
61
−d
−d
−d
−d
−d
78
48
VI
V
24
<10
<10
<10
<10
<10
100
100
24
V
Et
2
O
24
V
EtOAc
MeCN
DCM
24
10
11
12
V
24
V
24
V
CHCl
3
24
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The Journal of Organic Chemistry
1
3
V
DCE
24
24
2
95
62
1
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9
14
VII
VII
VII
VII
VII
DCM
DCM
DCM
DCM
DCM
100
100
100
100
100
-92
-98
-98
-97
-93
1
5e
1
6e,f
4
17e,g
8e,h
6
1
12
a
Reactions were performed with 1a (0.10 mmol), 2a (0.15 mmol), and catalyst (5 mol%) in solvent
(1.0 mL). Determined by H NMR analysis. Determined by HPLC analysis. Not determined. Run
with 5 Å MS (60 mg). Run with 2 mol% VII. Run with 1 mol% VII. Run with 0.5 mol% VII.
b
1
c
d
e
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2
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6
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8
9
0
f
g
h
Table 2. Substrate Scope with Different Indolesa
HO CF3
HO OH
R
N
1 mol% VII
N
CF3
NH
+
S
S
N
DCM (0.1 M)
H
5
Å MS, rt
R
1a
2a-l
3aa-al
entry
R
time (h)
product
3aa
3ab
3ac
yield (%)b
ee (%)c
97
1
2
3
4
5
6
7
8
9
H
10
7
99
99
95
99
75
99
99
99
99
96
99
5-Me
6-Me
7-Me
4-Me
92
8
97
7
3ad
3ae
3af
97
36
6
>99
97
5-OMe
4-OMe
6-F
7
3ag
3ah
3ai
99
12
16
16
16
>99
97
5-Cl
1
0
1
5-Br
3aj
98
1
6-Br
3ak
95
a
Reactions were performed with 1a (0.20 mmol), 2 (0.30 mmol), catalyst VII (1
b
c
mol%), and 5 Å MS (120 mg) in DCM (2.0 mL). Isolated yield. Determined by
chiral HPLC analysis.
Scheme 2. Asymmetric Friedel−Crafts Alkylation with 2-Methylindole and Pyrroles
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HO CF Me
3
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9
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5
5
5
5
5
5
6
HO OH
N
1
mol% VII
N
NH
CF3
+
Me
(a)
S
S
N
DCM (0.1 M)
Å MS, rt
H
5
1a
2l
3al
(97%, 37% ee)
HO CF3
HO OH
0
1
2
3
4
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9
0
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9
0
R
N
VII
N
1 mol%
CF3
+
(b)
S
HN
R
S
N
DCM (0.1 M)
Å MS, rt
H
5
1a
2n-o
R = H 3an (99%, 74% ee)
R = 2,4-Me2 3ao (84%, 76% ee)a
a
o
Run with 5 mol% VII at -20 C
Having established the standard reaction conditions, we next examined the substrate scope of the
catalytic asymmetric Friedel−Crafts reaction. A range of indoles with different substituents at the 4-, 5-,
6
-, or 7- positions proceeded smoothly to afford the corresponding α-trifluoromethyl tertiary alcohols
aa−ak with excellent yields and enantioselectivities (Table 2, entries 1−11). Unfortunately, low
3
enantioselectivity (37% ee) was observed for 2-methylindole 2l, and no reaction occurred for 3-
substituted indoles (Scheme 2a). Pyrroles 2n−o were also viable substrates, but just
good enantioselectivities (74−76% ee) were achieved (Scheme 2b). Subsequently, trifluoromethyl
ketone hydrates 1b−g were tested for this useful transformation (Scheme 3). Hydrates 1b−e with
different groups on the benzothiazole ring proceeded well, furnishing the desired products 3ba−ea with
excellent yields and enantioselectivities. The position and electronic property of substituents did not
affect the process. Hydrate 1f bearing a thiazole ring also gave a comparable result. Benzoxazole-based
hydrate 1g was also a suitable substrate, and the desired product 3ga was obtained in excellent yield
albeit with diminished enantioselectivity (87% ee). Unfortunately, trifluoromethyl ketone hydrates with
other heterocycles, including imidazole, pyridine, and triazole, were infeasible substrates, presumably
because their basicity affected the acid-catalyzed process. Notably, perfluoroethyl ketone hydrate 1h as
a viable substrate provided the corresponding product 3ha with 99% yield and 94% ee (Scheme 4). In
addition, under the standard conditions, we also used trifluoroacetophenone 1i and ethyl
trifluoropyruvate 1j as electrophiles for Friedel−Crafts alkylation of indole. No reaction was observed
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for the former, and the later provided the desired product 1ja with 82% yield but just 6% ee (Scheme 5).
The results show that the introduction of a benzothiazole ring makes a big difference in the reactivity
and stereoselectivity. The benzothiazole ring as an electon-deficient group improves the eletrophilicity
of trifluoromethyl ketone hydrates, and it also results in excellent enantioselectivity presumably because
of the effect of steric hindrance and π–π interaction with indole.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
3
3
3
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5
5
5
5
5
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2
3
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5
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9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 3. Substrate Scope with Different Trifluoromethyl Ketone Hydrates
HO CF3
HO OH
N
1
mol% VII
N
CF3
NH
NH
+
X
X
N
N
DCM (0.1 M)
5Å MS, rt, 6-12 h
H
R
R
1
b-g
2a
3ba-ga
HO CF3
S
HO CF3
HO CF3
N
N
NH
NH
O
S
R
3ga (99%, 87% ee)a
R = 6-OMe 3ba (99%, 97% ee) 3fa (99%, 97% ee)
R = 6-Br
3ca (99%, 97% ee)
R = 6-NO2 3da (99%, 96% ee)
R = 5-Br
3ea (99%, 98% ee)
a
Run with 5 mol% VII
Scheme 4. Asymmetric Friedel−Crafts Alkylation of Indole with Perfluoroethyl Ketone Hydrate
HO C2F5
HO OH
N
1 mol% VII
N
C2F5
NH
+
S
S
N
DCM (0.1 M)
5 Å MS, rt, 12 h
H
1h
2a
3ha (99%, 94% ee)
Scheme 5. Asymmetric Friedel−Crafts Alkylation of Indole with Trifluoroacetophenone and Ethyl
Trifluoropyruvate
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HO CF3
Ph
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
O
standard conditions
NH
+
Ph
CF3
N
no reaction
H
1i
2a
3ia
HO CF3
EtO C
O
standard conditions
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
NH
F3C
CO Et +
2
N
82% yield, 6% ee
H
1j
2a
3ja
To show the synthetic potential of this protocol, we carried out the gram-scale synthesis and product
transformations (Scheme 6 and 7). Notably, in the presence of 0.2 mol% of VII, a gram-scale catalytic
reaction was performed well in quantitative yield with 93% ee, and optically pure product 3aa was
easily obtained by a simple recrystallization from petroleum ether/ethyl acetate. The absolute
configuration of enantiopure (R)-3aa was unambiguously confirmed by single crystal X-ray analysis.
Alcohol 3aa was readily transformed into 4 by protection with chlorotrimethylsilane. Alkylation of 4
with 3-bromoprop-1-yne at the N-position, followed by deprotection in the workup step, provided the
desired product 5 in high yield and with excellent enantioselectivity maintained. The alkyne moiety of 5
can be used to link other functional molecules via a click reaction. Moreover, we tried to convert the
9
benzothiazole ring into a formyl group by a known procedure. When alcohol 3aa and its derivatives
with different protecting groups (TMS, TBS, and Me) were used for this transformation, we all failed to
get the corresponding chiral aldehyde. Instead, the simple ketone 6 was formed with good efficiency.
Scheme 6. The Gram-Scale Catalytic Reaction
HO CF3
HO OH
N
N
0.2 mol% VII
CF3
NH
+
S
S
N
DCM (0.1 M)
H
5
Å MS, rt, 19 h
1a
2a
4.5 mmol
3aa
3.0 mmol
1.04 g, 99%, 93% ee
(81%, >99% ee)
after a simple recrystallization
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Scheme 7. Product Transformations
1
2
3
4
5
6
7
8
9
HO CF3
TMSO CF3
N
N
TMSCl, NaH
NH
NH
S
S
o
THF, 0 C-rt
87% yield, >99% ee
4
3
aa, >99%ee
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
HO CF3
Br
TMSO CF3
N
N
N
NH
S
S
o
NaH, THF, 0 C-rt
9
0% yield, >99% ee
4
5
TMSO CF3
N
O
a) Me OBF , DCM, 4 Å MS
3
4
NH
F3C
S
o
b) NaBH , MeOH, 0 C-rt
4
NH
c) AgNO , MeCN/H O, rt
3
2
6
4
7
6% yield
To understand the mechanism, we carried out some control experiments (Scheme 8). When
trifluoromethyl ketone 1a’ instead of hydrate 1a was subjected to the standard conditions, almost the
same reaction outcome was achieved (99% yield, 97.5% ee). The result showed that the process firstly
underwent the acid-promoted dehydration of hydrate 1a to form ketone 1a’. N-Methyl indole 2m was
also subjected to the standard conditions, but just trace conversion was observed. Under otherwise
identical conditions, 5 mol% of BINOL-derived phosphoric acid V was employed to evaluate the
performance of both indole 2a and N-methyl indole 2m, and 2a provided much higher efficiency and
enantioselectivity than 2m. The results show that the N−H group of indole is the active site of catalyst
through the hydrogen bonding, and plays an important role in both reactivity and stereocontrol.
Scheme 8. Control Experiments
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HO CF3
O
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
N
standard conditions
N
NH
CF3
+
S
S
N
99% yield, 97.5% ee
H
1
a'
2a
3aa
HO CF3
S
HO OH
standard conditions
N
N
Me
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CF3
+
S
N
trace conv.
Me
1a
2m
3am
HO CF3
S
HO OH
N
5 mol% V
N
R
N
CF3
+
S
N
R
DCM (0.1 M)
5 Å MS, rt
1
a
3aa/am
2a/m
R = H 0.5 h, 100% conv., 86% ee
R = Me 24 h, .95% conv., 40% ee
S
F3C
N
S
O
O
O
O
O
O
O
CF3
P
N
H
H
P
O
O
O
N
H
N
H
π...π interaction
Attack Si-face (favored)
Attack Re-face (unfavored)
Figure 2. Possible transition state model.
Based on the observed results of control experiments and the absolute configuration of 3aa, we
proposed a possible transition state model (Figure 2). First, trifluoromethyl ketone hydrate 1a undergoes
the acid-promoted dehydration to form trifluoromethyl ketone 1a’. Then, the chiral phosphoric acid
catalyst VII acts in a bifunctional fashion. The ketone 1a’ is activated by the acid proton moiety through
the hydrogen bonding. Meanwhile, the phosphoryl oxygen atom as a basic site interacts with indole
through the hydrogen bonding. Considering the steric effect between the catalyst substituent and the
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benzothiazole moiety of ketone, and possible π–π interaction, indole 2a favors the Si-face attack of
ketone to provide the (R)-configured product 3aa.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
CONCLUSIONS
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
In summary, we have developed an efficient Brønsted acid-catalyzed asymmetric Friedel−Crafts
alkylation of indoles with trifluoromethyl ketone hydrates. With a suitable employment of
benzothiazole-bearing trifluoromethyl ketone hydrates as electrophiles, chiral phosphoric acid catalyst
(STRIP), and 5 Å molecular sieve, the present reaction provided a range of enantioenriched α-
trifluoromethyl tertiary alcohols bearing both benzothiazole and indole rings with excellent yields and
enantioselectivities. This protocol features excellent efficiency and enantioselectivity, mild reaction
conditions, low catalyst loading, simple operation, and easy gram-scale preparation. This work
represents a new and rare example of catalytic asymmetric method for chiral molecules bearing a
benzothiazole ring and a trifluoromethyl moiety located at a stereogenic carbon atom, which should be
attractive and potential for drug discovery. Further investigation on catalytic asymmetric reactions with
trifluoromethyl ketone hydrates is underway.
EXPERIMENTAL SECTION
General Information. Column chromatography was performed over silica gel (200-300 mesh)
purchased from Qindao Puke Co., China. All air or moisture sensitive reactions were conducted in oven-
dried glassware under nitrogen atmosphere using anhydrous solvents. Anhydrous dichloromethane,
tetrahydrofuran, and acetonitrile were purchased from Energy Chemical and used as received. ACS
grade 2,2,2-trifluoroacetic anhydride (TFA), Et N, toluene, and 1,2-dichloroethane were purchased from
3
Sinopharm Chemical Reagent Co.,Ltd and used as received. H, 13C, and 19F NMR spectra were
1
collected on a Varian INOVA-400 or a Bruker AV-400 NMR spectrometer using peaks of deuterated
1
13
solvents as an internal standard ( H NMR: CDCl at 7.26 ppm, d6-acetone at 2.05 ppm; C NMR:
3
CDCl at 77.0 ppm, d6-acetone at 206.26 ppm). High resolution mass spectra were collected on a
3
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MALDI Micro MX mass spectrometer. Optical rotations were measured on JASCO P-2000 polarimeter
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
with [α] values reported in degrees; concentration (c) is in 10 mg/mL. The enantiomeric excesses were
D
determined by chiral HPLC using a Shimadzu Prominence LC-20A instrument with a Daicel Chiralcel
OD-H column or a Daicel Chiralpak AD-H or AS-H column.
8
The Synthesis of Ketone Hydrates 1a-h. 1-(Benzo[d]thiazol-2-yl)-2,2,2-trifluoroethane-1,1-diol
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
(
1a). To a solution of benzothiazole (1.35 g, 10.0 mmol) in toluene (20 mL) at -20 C was added
dropwise trifluoroacetic anhydride (2.52 g, 12.0 mmol) over 10 min. The mixture was stirred for 0.5 h,
o
and triethylamine (1.21 g, 12.0 mmol) was slowly added. After stirring at -20 C for overnight, the
resulting reaction mixture was spontaneously warmed to room temperature and stirred 12 h. The solvent
was removed in vacuo, and water (5 mL) was added to form white precipitation, which was dissolved in
ethyl acetate (80 mL). The organic phase was successively washed with 1 M HCl (30 mL), water (30
mL), and brine (30 mL), dried over anhydrous Na SO , and concentrated in vacuo to afford the crude
2
4
product. The pure ketone hydrate 1a was obtained by recrystallization from petroleum ether/ethyl
o
1
acetate (5:1) as a white solid (2.30 g, 92% yield), m.p. 144-146 C. H NMR (400 MHz, d6-acetone) δ
1
3
1
8
.11-8.08 (m, 2H), 7.60 (s, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H) ppm. C{ H} NMR
(
(
100 MHz, d6-acetone) δ 168.8, 153.5, 136.6, 127.1, 126.8, 124.3, 123.4 (q, J = 286.3 Hz), 122.8, 93.2
1
9
+
q, J = 33.0 Hz) ppm. F NMR (376.5 MHz, d6-acetone) δ -83.5 ppm. HRMS (ESI) m/z: [M - H O]
2
Calcd for C H F NOS 230.9966; Found 230.9961.
9
4 3
2
,2,2-Trifluoro-1-(6-methoxybenzo[d]thiazol-2-yl)ethane-1,1-diol (1b) was prepared from 6-
methoxybenzothiazole (0.83 g, 5.0 mmol) according to the above procedure. White solid, m.p. 126-128
o
1
C; 1.01 g, 72% yield. H NMR (400 MHz, d6-acetone) δ 7.94 (d, J = 8.8 Hz, 1H), 7.61 (s, 1H), 7.51 (br
1
3
1
s, 2H), 7.14 (d, J = 8.8 Hz, 1H), 3.88 (s, 3H) ppm. C{ H} NMR (100 MHz, d6-acetone) δ 165.4,
1
9
158.7, 147.3, 137.7, 124.3, 123.0 (q, J = 286.3 Hz), 116.5, 104.1, 92.6 (q, J = 33.0 Hz), 55.5 ppm. F
+
NMR (376.5 MHz, d6-acetone) δ -83.6 ppm. HRMS (ESI) m/z: [M] Calcd for C H F NO S 279.0177;
1
0
8
3
3
Found 279.0169.
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1
-(6-Bromobenzo[d]thiazol-2-yl)-2,2,2-trifluoroethane-1,1-diol (1c) was prepared from 6-
1
2
o
bromobenzothiazole (1.07 g, 5.0 mmol) according to the above procedure. White solid, m.p. 136-138 C;
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
0.45 g, 28% yield. H NMR (400 MHz, d6-acetone) δ 8.32 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.68 (d, J =
13
1
8
1
.4 Hz, 1H), 7.62 (s, 2H) ppm. C{ H} NMR (100 MHz, d6-acetone) δ 169.2, 151.9, 137.8, 129.9,
1
9
25.1, 124.8, 122.6 (q, J = 286.4 Hz), 119.3, 92.5 (q, J = 33.1 Hz) ppm. F NMR (376.5 MHz, d6-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
acetone) δ -83.4 ppm. HRMS (ESI) Calcd for C
9
H3
BrF
3
NOS [M - H O] : 308.9071, Found: 308.9063.
2
2
,2,2-Trifluoro-1-(6-nitrobenzo[d]thiazol-2-yl)ethane-1,1-diol (1d) was prepared from 6-
o
nitrobenzothiazole (1.80 g, 10.0 mmol) according to the above procedure. White solid, m.p. 102-103 C;
1
1
.24 g, 42% yield. H NMR (400 MHz, d6-acetone) δ 9.17 (d, J = 2.4 Hz, 1H), 8.44 (dd, J = 2.4, 9.2 Hz,
1
3
1
1H), 8.28 (d, J = 8.8 Hz, 1H), 7.80 (s, 2H) ppm. C{ H} NMR (100 MHz, d6-acetone) δ 174.9, 156.7,
19
1
45.7, 136.4, 124.4, 122.6 (q, J = 286.5 Hz), 121.7, 119.2, 92.6 (q, J = 33.2 Hz) ppm. F NMR (376.5
+
MHz, d6-acetone) δ -83.5 ppm. HRMS (ESI) m/z: [M - H O] Calcd for C H F N O S 275.9816; Found
2
9
3
3
2
3
275.9818.
1
-(5-Bromobenzo[d]thiazol-2-yl)-2,2,2-trifluoroethane-1,1-diol (1e) was prepared from 5-
o
bromobenzothiazole (1.61 g, 7.5 mmol) according to the above procedure. White solid, m.p. 120-121 C;
1
1
1
1
.84 g, 75% yield. H NMR (400 MHz, d6-acetone) δ 8.24 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.65 (d, J =
1
3
1
2.0 Hz, 1H), 7.61 (s, 2H) ppm. C{ H} NMR (100 MHz, d6-acetone) δ 170.8, 154.5, 135.4, 129.5,
1
9
26.6, 124.2, 123.0 (q, J = 286.4 Hz), 119.9, 92.8 (q, J = 33.3 Hz) ppm. F NMR (376.5 MHz, d6-
+
acetone) δ -83.5 ppm. HRMS (ESI) Calcd for C
9
H5
BrF
3
NO
2
S [M] : 326.9176, Found: 326.9171.
2,2,2-Trifluoro-1-(thiazol-2-yl)ethane-1,1-diol (1f) was prepared from thiazole (0.85 g, 10.0 mmol)
o
1
according to the above procedure. White solid, m.p. 93-95 C; 0.30 g, 15% yield. H NMR (400 MHz,
1
3
1
d6-acetone) δ, 7.83 (s, 1H), 7.74 (s, 1H), 7.40 (br s, 2H) ppm. C{ H} NMR (100 MHz, d6-acetone) δ
1
9
166.4, 142.0, 122.05 (q, J = 286.1 Hz), 122.02, 91.7 (q, J = 33.0 Hz) ppm. F NMR (376.5 MHz, d6-
+
acetone) δ -84.0 ppm. HRMS (ESI) m/z: [M - H O] Calcd for C
5
H2
F3NOS 180.9809; Found 180.9814.
2
1
-(Benzo[d]oxazol-2-yl)-2,2,2-trifluoroethane-1,1-diol (1g) was prepared from benzooxazole (1.19 g,
o
1
1
0.0 mmol) according to the above procedure. White solid, m.p. 120-121 C; 1.01 g, 43% yield. H
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NMR (400 MHz, d6-acetone) δ 7.81 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.63 (br s, 2H), 7.51-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
1
7
.42 (m, 2H) ppm. C{ H} NMR (100 MHz, d6-acetone) δ 160.7, 150.8, 140.0, 126.4, 125.0, 122.3 (q,
1
9
J = 285.9 Hz), 120.5, 111.1, 93.2 (q, J = 33.0 Hz) ppm. F NMR (376.5 MHz, d6-acetone) δ -83.8 ppm.
+
HRMS (ESI) m/z: [M] Calcd for C
9
H6
F NO 233.0300; Found 233.0298.
3
3
1
-(Benzo[d]thiazol-2-yl)-2,2,3,3,3-pentafluoropropane-1,1-diol (1h) was prepared from benzothiazole
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(1.35 g, 10.0 mmol) and 2,2,3,3,3-pentafluoropropanoic anhydride (3.72 g, 12.0 mmol) according to the
o
1
above procedure. White solid, m.p. 81-82 C; 1.01 g, 33% yield. H NMR (400 MHz, d6-acetone) δ
1
3
1
8
.13 (d, J = 8.0 Hz, 1H), 8.08 (q, J = 8.0 Hz, 1H), 7.59 (s, 2H), 7.57-7.51 (m, 2H) ppm. C{ H} NMR
(
100 MHz, d6-acetone) δ 169.0, 153.1, 136.9, 127.1, 126.8, 124.3, 122.8, 119.8 (qt, J = 285.2 Hz, J =
1
2
1
9
43.5 Hz), 112.6 (tq, J = 262.1 Hz, J = 34.9 Hz), 94.3 (t, J = 25.8 Hz) ppm. F NMR (376.5 MHz, d6-
1
2
+
acetone) δ -79.3, -81.9, -118.2, -124.9 ppm. HRMS (ESI) m/z: [M] Calcd for C H F NO S 299.0039;
1
0
6
5
2
Found 298.9996.
.General Procedure for Catalytic Asymmetric Friedel−Crafts Alkylation. To a solution of
trifluoromethyl ketone hydrate 1 (0.20 mmol), and catalyst VII (1 mol%) in dichloromethane (2.0 mL)
was added 5 Å MS (120 mg) and indole or pyrrole 2 (0.30 mmol). After stirring at room temperature for
specified time, the mixture was directly purified by silica gel column chromatography (petroleum
ether/ethyl acetate = 5:1 to 3:1) to afford the desired product 3.
(R)-1-(Benzo[d]thiazol-2-yl)-2,2,2-trifluoro-1-(1H-indol-3-yl)ethan-1-ol (3aa). White solid, m.p.
o
1
33-134 C, 69.1 mg, 99% yield. [α]D10: −53.8 (c = 0.51, acetone). The enantioselectivity was
determined by HPLC analysis (Daicel Chiralpak AD-H column, n-hexane/i-propanol = 80:20, flow rate
o
1
1
.0 mL/min, detection at 254 nm, 35 C): t = 8.7 min (minor), t = 11.1 min (major), 97% ee. H NMR
1 2
(400 MHz, d6-acetone) δ 10.58 (br s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.69 (s,
1H), 7.63 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.09 (t, J = 7.2 Hz, 1H),
1
3
1
6
1
1
.98 (s, 1H), 6.94 (t, J = 7.6 Hz, 1H) ppm. C{ H} NMR (100 MHz, d6-acetone) δ 172.3, 154.0, 137.4,
36.1, 126.8, 126.2, 125.6 (q, J = 285.4 Hz), 125.5, 124.1, 124.0, 122.6, 122.4, 121.3, 120.2, 112.3,
19
11.8, 78.0 (q, J = 30.4 Hz) ppm. F NMR (376.5 MHz, d6-acetone) δ -76.4 ppm. HRMS (ESI) m/z:
+
[M + Na] Calcd for C H F N NaOS 371.0442; Found 371.0485.
1
7
11
3
2
(R)-1-(Benzo[d]thiazol-2-yl)-2,2,2-trifluoro-1-(5-methyl-1H-indol-3-yl)ethan-1-ol (3ab). White solid,
m.p. 182-183 C, 71.7 mg, 99% yield. [α]D10: −98.8 (c = 0.51, acetone). The enantioselectivity was
o
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determined by HPLC analysis (Daicel Chiralpak AD-H column, n-hexane/i-propanol = 80:20, flow rate
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o
1
1.0 mL/min, detection at 254 nm, 35 C): t = 7.1 min (minor), t = 9.0 min (major), 92% ee. H NMR
1
2
(400 MHz, d6-acetone) δ 10.45 (br s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.62 (s,
1
6
H), 7.51 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 7.2 Hz, 2H), 7.29 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H),
13
1
.90 (d, J = 1.6 Hz, 1H), 2.25 (s, 3H) ppm. C{ H} NMR (100 MHz, d6-acetone) δ 172.5, 154.2, 136.3,
136.0, 129.1, 127.0, 126.7, 126.4, 125.75, 125.74 (q, J = 285.3 Hz), 124.3, 124.2, 122.7, 121.2, 112.1,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
9
1
11.4, 78.2 (q, J = 30.5 Hz), 21.6 ppm. F NMR (376.5 MHz, d6-acetone) δ -76.5 ppm. HRMS (ESI)
+
m/z: [M + Na] Calcd for C H F N NaOS 385.0598; Found 385.0608.
1
8
13
3
2
(R)-1-(Benzo[d]thiazol-2-yl)-2,2,2-trifluoro-1-(6-methyl-1H-indol-3-yl)ethan-1-ol (3ac). White solid,
m.p. 145-146 C, 68.6 mg, 95% yield. [α]D10: −51.8 (c = 0.50, acetone). The enantioselectivity was
o
determined by HPLC analysis (Daicel Chiralpak AD-H column, n-hexane/i-propanol = 80:20, flow rate
o
1
1
.0 mL/min, detection at 254 nm, 35 C): t = 12.6 min (minor), t = 15.1 min (major), 97% ee. H NMR
1 2
(400 MHz, d6-acetone) δ 10.43 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.61 (s, 2H),
1
3
1
7
.52-7.45 (m, 3H), 7.23 (s, 1H ), 6.91 (s, 1H ), 6.80 (d, J = 8.4 Hz, 1H), 2.35 (s, 3H ) ppm. C{ H}
NMR (100 MHz, d6-acetone) δ 172.4, 154.0, 137.9, 136.2, 132.1, 126.8, 126.2, 125.6 (q, J = 285.6 Hz),
19
1
24.9, 124.2, 124.0, 122.6, 122.0, 121.1, 112.1, 111.7, 78.0 (q, J = 30.4 Hz), 21.4 ppm. F NMR (376.5
+
MHz, d6-acetone) δ -76.4 ppm. HRMS (ESI) m/z: [M + Na] Calcd for C H F N NaOS 385.0598;
1
8
13
3
2
Found 385.0608.
(R)-1-(Benzo[d]thiazol-2-yl)-2,2,2-trifluoro-1-(7-methyl-1H-indol-3-yl)ethan-1-ol (3ad). White solid,
m.p. 163-164 C, 72.0 mg, 99% yield. [α]D10: −42.1 (c = 0.50, acetone). The enantioselectivity was
o
determined by HPLC analysis (Daicel Chiralpak AD-H column, n-hexane/i-propanol = 80:20, flow rate
o
1
1
.0 mL/min, detection at 254 nm, 35 C): t = 7.7 min (minor), t = 14.0 min (major), 97% ee. H NMR
1 2
(400 MHz, d6-acetone) δ 10.55 (br s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.66 (s,
1H), 7.50 (t, J = 8.0 Hz, 1H), 7.43 (t, J = 8.0 Hz, 2H), 6.96 (s, 1H), 6.89 (d, J = 7.2 Hz, 1H), 6.85 (t, J =
1
3
1
7
1
.2 Hz, 1H), 2.43 (s, 3H) ppm. C{ H} NMR (100 MHz, d6-acetone) δ 172.3, 153.9, 136.9, 136.1,
26.8, 126.2, 125.9, 125.5 (q, J = 285.3 Hz), 125.0, 124.0, 123.0, 122.5, 121.5, 120.4, 119.0, 112.2, 78.0
19
(
q, J = 30.3 Hz), 16.6 ppm. F NMR (376.5 MHz, d6-acetone) δ -76.3 ppm. HRMS (ESI) m/z: [M +
+
Na] Calcd for C H F N NaOS 385.0598; Found 385.0595.
1
8
13
3
2
(R)-1-(Benzo[d]thiazol-2-yl)-2,2,2-trifluoro-1-(4-methyl-1H-indol-3-yl)ethan-1-ol (3ae). White solid,
m.p. 207-208 C, 54.7 mg, 75% yield. [α]D10: −10.3 (c = 0.52, acetone). The enantioselectivity was
o
determined by HPLC analysis (Daicel Chiralpak AD-H column, n-hexane/i-propanol = 85:15, flow rate
o
1
1
.0 mL/min, detection at 254 nm, 35 C): t = 7.7 min (minor), t = 11.2 min (major), >99% ee. H NMR
1 2
(400 MHz, d6-acetone) δ 10.65 (br s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.65 (s,
1
H), 7.49-7.40 (m, 2H), 7.29 (d, J = 8.0 Hz, 1H), 6.96 (t, J = 8.0 Hz, 1H), 6.68-6.65 (m, 2H), 2.94 (s,
1
3
1
3H) ppm. C{ H} NMR (100 MHz, d6-acetone) δ 172.2, 153.4, 138.3, 137.3, 131.1, 126.9, 126.5,
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1
26.0 (q, J = 3.8 Hz), 125.9 (q, J = 286.8 Hz), 125.7, 124.2, 122.90, 122.88, 122.7, 111.7, 110.2, 78.1 (q,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
9
+
J = 29.0 Hz), 22.2 ppm. F NMR (376.5 MHz, d6-acetone) δ -74.3 ppm. HRMS (ESI) m/z: [M + Na]
Calcd for C H F N NaOS 385.0598; Found 385.0627.
18 13
3
2
(R)-1-(Benzo[d]thiazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-1H-indol-3-yl)ethan-1-ol (3af). White solid,
m.p. 183.5-184.3 C, 75.4 mg, 99% yield. [α]D10: −93.1 (c = 0.50, acetone). The enantioselectivity was
o
determined by HPLC analysis (Daicel Chiralcel OD-H column, n-hexane/i-propanol = 90:10, flow rate
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
1
1
.0 mL/min, detection at 254 nm, 35 C): t = 13.4 min (major), t = 15.3 min (minor), 97% ee. H NMR
1 2
(400 MHz, d6-acetone) δ 10.45 (br s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.63 (s,
1
H), 7.51 (t, J = 7.2 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.30 (d, J = 9.2 Hz, 1H), 7.09 (s, 1H), 6.95 (s, 1H),
1
3
1
6.73 (d, J = 8.8 Hz, 1H), 3.59 (s, 3H) ppm. C{ H} NMR (100 MHz, d6-acetone) δ 172.5, 154.8, 154.2,
1
1
36.2, 132.7, 127.0, 126.9, 126.4, 126.2, 125.8 (q, J = 285.2 Hz), 124.2, 122.7, 113.0, 112.8, 111.6,
19
03.3, 78.1 (q, J = 30.7 Hz), 55.5 ppm. F NMR (376.5 MHz, d6-acetone) δ -74.5 ppm. HRMS (ESI)
+
m/z: [M + Na] Calcd for C H F N NaO S 401.0548; Found 401.0546.
1
8
13
3
2
2
(R)-1-(Benzo[d]thiazol-2-yl)-2,2,2-trifluoro-1-(4-methoxy-1H-indol-3-yl)ethan-1-ol (3ag). White
solid, m.p. 214-215 C, 74.9 mg, 99% yield. [α]D10: −243.1 (c = 0.51, acetone). The enantioselectivity
o
was determined by HPLC analysis (Daicel Chiralpak AD-H column, n-hexane/i-propanol = 80:20, flow
o
1
rate 1.0 mL/min, detection at 254 nm, 35 C): t = 7.5 min (minor), t = 9.8 min (major), 99% ee. H
1
2
NMR (400 MHz, d6-acetone) δ 10.76 (br s, 1H), 8.12-8.09 (m, 2H), 7.77 (s, 1H), 7.69 (s, 1H), 7.57 (t, J
=
7.6 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.23-7.16 (m, 2H), 6.79 (d, J = 7.2 Hz, 1H), 4.11 (s, 3H) ppm.
1
3
1
C{ H} NMR (100 MHz, d6-acetone) δ 172.6, 154.4, 151.6, 139.6, 136.1, 127.0, 126.9, 126.4, 125.6 (q,
1
9
J = 285.4 Hz), 124.2, 123.9, 122.7, 116.1, 111.2, 107.4, 102.1, 77.4 (q, J = 30.0 Hz), 55.7 ppm. F
+
NMR (376.5 MHz, d6-acetone) δ -72.6 ppm. HRMS (ESI) m/z: [M + H] Calcd for C H F N O S
1
8
14
3
2
2
3
79.0728; Found 379.0735.
(R)-1-(Benzo[d]thiazol-2-yl)-2,2,2-trifluoro-1-(6-fluoro-1H-indol-3-yl)ethan-1-ol (3ah). White solid,
m.p. 110-112 C, 72.6mg, 99% yield. [α]D10: −42.3 (c = 0.50, acetone). The enantioselectivity was
o
determined by HPLC analysis (Daicel Chiralpak AD-H column, n-hexane/i-propanol = 85:15, flow rate
o
1
1
.0 mL/min, detection at 254 nm, 35 C): t = 12.3 min (minor), t = 13.3 min (major), >99% ee. H
1 2
NMR (400 MHz, d6-acetone) δ 10.66 (br s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.69
s, 1H), 7.63 (dd, J = 8.4, 5.6 Hz, 1H), 7.51 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 9.6
(
13
1
Hz, 1H), 7.09 (br s, 1H), 6.78 (t, J = 9.6 Hz, 1H) ppm. C{ H} NMR (100 MHz, d6-acetone) δ 172.1,
160.4 (d, J = 234.8 Hz), 154.1, 137.7, 137.5, 136.2, 127.0, 126.4, 125.6 (q, J = 283.8 Hz), 124.2, 123.1,
1
9
1
22.7, 122.6, 112.2, 108.9 (d, J = 24.4 Hz), 98.3 (d, J = 25.8 Hz), 78.0 (q, J = 30.5 Hz) ppm. F NMR
+
(376.5 MHz, d6-acetone) δ -76.6, -122.5 ppm. HRMS (ESI) m/z: [M + Na] Calcd for C H F N NaOS
1
7
10
4
2
3
89.0348; Found 389.0359.
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(
R)-1-(Benzo[d]thiazol-2-yl)-1-(5-chloro-1H-indol-3-yl)-2,2,2-trifluoroethan-1-ol (3ai). White solid,
m.p. 104-105 C, 76.0 mg, 99% yield. [α]D10: −75.1 (c = 0.50, acetone). The enantioselectivity was
determined by HPLC analysis (Daicel Chiralpak AD-H column, n-hexane/i-propanol = 90:10, flow rate
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o
o
1
1
.0 mL/min, detection at 254 nm, 35 C): t = 17.5 min (minor), t = 19.7 min (major), 97% ee. H NMR
1 2
(
400 MHz, d6-acetone) δ 10.79 (br s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.79 (s,
1H), 7.76 (d, J = 2.4 Hz, 1H), 7.51 (t, J = 7.2 Hz, 1H), 7.44 (t, J = 8.4 Hz, 2H), 7.18 (d, J = 7.4 Hz, 1H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
7
1
=
.10 (t, J = 8.8 Hz, 1H) ppm. C{ H} NMR (100 MHz, d6-acetone) δ 171.7, 153.8, 135.8, 135.7, 127.2,
27.1, 126.7, 126.2, 125.4, 125.2 (q, J = 284.7 Hz), 123.8, 122.5, 122.4, 121.0, 120.6, 113.6, 77.7 (q, J
1
9
+
30.8 Hz) ppm. F NMR (376.5 MHz, d6-acetone) δ -76.7 ppm. HRMS (ESI) m/z: [M + H] Calcd for
C H ClF N OS 383.0233; Found 383.0227.
1
7
11
3
2
(
R)-1-(Benzo[d]thiazol-2-yl)-1-(5-bromo-1H-indol-3-yl)-2,2,2-trifluoroethan-1-ol (3aj). White solid,
m.p. 172-173 C, 75.8 mg, 96% yield. [α]D10: −114.1 (c = 0.51, acetone). The enantioselectivity was
o
determined by HPLC analysis (Daicel Chiralpak AD-H column, n-hexane/i-propanol = 85:15, flow rate
o
1
1
.0 mL/min, detection at 254 nm, 35 C): t = 10.5 min (minor), t = 11.6 min (major), 98% ee. H NMR
1 2
(
400 MHz, d6-acetone) δ 10.80 (br s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.91 (s,
1
H), 7.77 (s, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.22 (d, J =
1
3
1
8.8 Hz, 1H), 7.17 (s, 1H) ppm. C{ H} NMR (100 MHz, d6-acetone) δ 171.9, 154.0, 136.2, 136.0,
1
28.0, 127.3, 127.0, 125.4 (q, J = 285.0 Hz), 125.3, 124.1, 124.0, 123.9, 122.7, 114.2, 113.2, 111.6, 77.9
19
q, J = 30.6 Hz) ppm. F NMR (376.5 MHz, d6-acetone) δ -76.7 ppm. HRMS (ESI) m/z: [M + H]+
(
Calcd for C H BrF N OS 428.9707; Found 428.9710.
1
7
11
3
2
(
R)-1-(Benzo[d]thiazol-2-yl)-1-(6-bromo-1H-indol-3-yl)-2,2,2-trifluoroethan-1-ol (3ak). White solid,
m.p. 118-119 C, 84.7 mg, 99% yield. [α]D10: −63.7 (c = 0.52, acetone). The enantioselectivity was
o
determined by HPLC analysis (Daicel Chiralpak AS-H column, n-hexane/i-propanol = 90:10, flow rate
o
1
1.0 mL/min, detection at 254 nm, 35 C): t = 16.6 min (minor), t = 21.8 min (major), 95% ee. H NMR
1
2
(
400 MHz, d6-acetone) δ 10.73 (br s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.73 (s,
1
H), 7.63 (s, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.13 (s, 1H),
13
1
7
.10 (d, J = 8.4 Hz, 1H) ppm. C{ H} NMR (100 MHz, d6-acetone) δ 171.9, 154.0, 138.4, 136.1, 126.9,
126.7, 126.4, 125.5 (q, J = 285.5 Hz), 125.3, 124.1, 123.4, 123.0, 122.6, 115.7, 115.2, 112.2, 77.9 (q, J
1
9
+
=
30.6 Hz) ppm. F NMR (376.5 MHz, d6-acetone) δ -76.6 ppm. HRMS (ESI) m/z: [M + H] Calcd for
C H BrF N OS 428.9707; Found 428.9708.
1
7
11
3
2
(R)-1-(Benzo[d]thiazol-2-yl)-1-(2,6-dimethyl-1H-indol-3-yl)-2,2,2-trifluoroethan-1-ol (3al). White
solid, m.p. 140-142 C, 70.6 mg, 97% yield. [α]D10: −28.5 (c = 0.52, acetone). The enantioselectivity
was determined by HPLC analysis (Daicel Chiralpak AD-H column, n-hexane/i-propanol = 80:20, flow
o
o
1
rate 1.0 mL/min, detection at 254 nm, 35 C): t = 7.9 min (minor), t = 10.3 min (major), 37% ee. H
1
2
NMR (400 MHz, d6-acetone) δ 10.34 (br s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.55
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(
t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.98 (t, J
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
1
= 7.2 Hz, 1H), 6.89 (s, 1H), 6.83 (t, J = 7.6 Hz, 1H), 2.38 (s, 3H) ppm. C{ H} NMR (100 MHz, d6-
acetone) δ 172.5, 152.6, 136.4, 136.3, 135.7, 128.0, 126.8, 126.5, 126.2 (q, J = 285.3 Hz), 124.3, 122.5,
1
9
1
21.2, 120.7, 119.8, 111.0, 107.2, 78.8 (q, J = 30.4 Hz), 13.6 ppm. F NMR (376.5 MHz, d6-acetone) δ
+
-75.9 ppm. HRMS (ESI) m/z: [M + Na] Calcd for C H F N NaOS 385.0598; Found 385.0656.
1
8
13
3
2
(R)-1-(Benzo[d]thiazol-2-yl)-2,2,2-trifluoro-1-(1H-pyrrol-2-yl)ethan-1-ol (3an). White solid, m.p. 84-
5 C, 59.2 mg, 99% yield. [α]D10: -54.2 (c = 0.51, acetone). The enantioselectivity was determined by
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
8
HPLC analysis (Daicel Chiralpak AD-H column, n-hexane/i-propanol = 80:20, flow rate 1.0 mL/min,
o
1
detection at 254 nm, 35 C): t = 8.6 min (minor), t = 27.1 min (major), 74% ee. H NMR (400 MHz,
1
2
d6-acetone) δ 10.50 (br s, 1H), 8.11-8.06 (m, 2H), 7.57 (t, J = 7.6 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.30
1
3
1
(
s, 1H), 6.89 (s, 1H), 6.51 (s, 1H), 6.14 (s, 1H) ppm. C{ H} NMR (100 MHz, d6-acetone) δ 171.1,
54.0, 135.8, 127.0, 126.4, 126.0, 124.7 (q, J = 284.6 Hz), 124.1, 122.6, 120.3, 109.3, 108.6, 76.5 (q, J
1
1
9
+
= 31.2 Hz) ppm. F NMR (376.5 MHz, d6-acetone) δ -78.2 ppm. HRMS (ESI) m/z: [M + Na] Calcd
for C H F N NaOS 321.0285; Found 321.0295.
13
9
3
2
(
R)-1-(Benzo[d]thiazol-2-yl)-1-(3,5-dimethyl-1H-pyrrol-2-yl)-2,2,2-trifluoroethan-1-ol (3ao). The
product was prepared according to the general procedure with minor modification (5 mol% VII & -20
o
C). White solid, m.p. 123-125 C, 58.6 mg, 84% yield. [α]D10: -81.2 (c = 0.51, acetone). The
o
enantioselectivity was determined by HPLC analysis (Daicel Chiralpak AD-H column, n-hexane/i-
o
propanol = 90:10, flow rate 1.0 mL/min, detection at 254 nm, 35 C): t = 6.1 min (major), t = 6.7 min
1
2
1
(minor), 76% ee. H NMR (400 MHz, d6-acetone) δ 9.88 (br s, 1H), 8.10 (d, J = 8.0 Hz, 2H), 7.58 (t, J
=
7.2 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.06 (s, 1H), 5.65 (s, 1H), 2.19 (s, 3H) 1.97 (s, 3H) ppm.
1
3
1
C{ H} NMR (100 MHz, d6-acetone) δ 172.5, 153.8, 135.9, 128.2, 127.0, 126.5, 125.2 (q, J = 286.6
1
9
Hz), 124.2, 122.6, 120.0, 119.0, 110.8, 76.9 (q, J = 31.9 Hz), 12.6, 12.2 ppm. F NMR (376.5 MHz, d6-
+
acetone) δ -77.2 ppm. HRMS (ESI) m/z: [M + Na] Calcd for C H F N NaOS 349.0598; Found
1
5
13
3
2
3
49.0656.
(R)-2,2,2-Trifluoro-1-(1H-indol-3-yl)-1-(6-methoxybenzo[d]thiazol-2-yl)ethan-1-ol (3ba). White
solid, m.p. 155-156 C, 75.1 mg, 99% yield. [α]D10: -7.0 (c = 0.51, acetone). The enantioselectivity was
o
determined by HPLC analysis (Daicel Chiralpak AD-H column, n-hexane/i-propanol = 80:20, flow rate
o
1
1
.0 mL/min, detection at 254 nm, 35 C): t = 10.5 min (minor), t = 13.1 min (major), 97% ee. H NMR
1 2
(400 MHz, d6-acetone) δ 10.56 (br s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.62 (d, J = 8.0 Hz,
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3
H), 7.57 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 6.94 (t, J = 7.2 Hz, 2H), 6.89 (s, 1H),
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
1
.83 (s, 3H) ppm. C{ H} NMR (100 MHz, d6-acetone) δ 169.2, 158.7, 148.2, 137.6, 137.4, 126.2,
125.5 (q, J = 285.2 Hz), 125.4, 124.5, 122.4, 121.3, 120.1, 116.4, 112.2, 111.9, 104.5, 77.4 (q, J = 30.4
19
+
Hz), 55.8 ppm. F NMR (376.5 MHz, d6-acetone) δ -76.7 ppm. HRMS (ESI) m/z: [M + H] Calcd for
C H F N O S 379.0728; Found 379.0730.
1
8
14
3
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(R)-1-(6-Bromobenzo[d]thiazol-2-yl)-2,2,2-trifluoro-1-(1H-indol-3-yl)ethan-1-ol (3ca). White solid,
m.p. 203-204 C, 84.8 mg, 99% yield. [α]D10: -13.5 (c = 0.50, acetone). The enantioselectivity was
o
determined by HPLC analysis (Daicel Chiralpak AD-H column, n-hexane/i-propanol = 80:20, flow rate
o
1
1
.0 mL/min, detection at 254 nm, 35 C): t = 8.8 min (minor), t = 10.8 min (major), 97% ee. H NMR
1 2
(400 MHz, d6-acetone) δ 10.61 (br s, 1H), 8.32 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.73 (s, 1H), 7.66 (t, J
8.0 Hz, 2H), 7.46 (d, J = 8.4 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.08 (s, 1H), 6.98 (t, J = 7.6 Hz, 1H)
=
1
3
1
ppm. C{ H} NMR (100 MHz, d6-acetone) δ 173.4, 153.0, 138.0, 137.5, 130.2, 126.2, 125.6, 125.5 (q,
1
9
J = 285.4 Hz), 125.5, 125.2, 122.6, 121.3, 120.3, 119.4, 112.3, 111.5, 78.0 (q, J = 30.4 Hz) ppm. F
NMR (376.5 MHz, d6-acetone) δ -76.4 ppm. HRMS (ESI) m/z: [M + Na]+ Calcd for
C H BrF N NaO S 450.9527; Found 450.9526.
1
7
10
3
2
2
(R)-2,2,2-Trifluoro-1-(1H-indol-3-yl)-1-(6-nitrobenzo[d]thiazol-2-yl)ethan-1-ol (3da). Yellow solid,
m.p. 158-160 C, 78.0 mg, 99% yield. [α]D10: -2.9 (c = 0.51, acetone). The enantioselectivity was
o
determined by HPLC analysis (Daicel Chiralpak AD-H column, n-hexane/i-propanol = 80:20, flow rate
o
1
1
.0 mL/min, detection at 254 nm, 35 C): t = 11.6 min (minor), t = 14.6 min (major), 96% ee. H NMR
1 2
(400 MHz, d6-acetone) δ 10.62 (br s, 1H), 9.09 (s, 1H), 8.34 (d, J = 9.2 Hz, 1H), 8.15 (d, J = 8.8 Hz,
1
6
H), 7.72 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.25 (s, 1H), 7.09 (t, J = 7.6 Hz, 1H),
1
3
1
.95 (t, J = 7.2 Hz, 1H) ppm. C{ H} NMR (100 MHz, d6-acetone) δ 178.9, 157.6, 145.9, 137.4, 136.5,
126.0, 125.6, 125.3 (q, J = 285.3 Hz), 124.5, 122.6, 122.0, 121.1, 120.3, 119.5, 112.3, 111.0, 78.3 (q, J
19
+
=
30.8 Hz) ppm. F NMR (376.5 MHz, d6-acetone) δ -76.3 ppm. HRMS (ESI) m/z: [M + Na] Calcd
for C H F N NaO S 416.0293; Found 416.0287.
1
7
10
3
3
3
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(
R)-1-(5-Bromobenzo[d]thiazol-2-yl)-2,2,2-trifluoro-1-(1H-indol-3-yl)ethan-1-ol (3ea). White solid,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
m.p. 166-167 C, 85.0 mg, 99% yield. [α]D10: -101.1 (c = 0.50, acetone). The enantioselectivity was
o
determined by HPLC analysis (Daicel Chiralpak AD-H column, n-hexane/i-propanol = 80:20, flow rate
o
1
1
.0 mL/min, detection at 254 nm, 35 C): t = 9.3 min (minor), t = 11.9 min (major), 98% ee. H NMR
1 2
(
400 MHz, d6-acetone) δ 10.66 (br s, 1H), 8.24 (s, 1H), 8.09 (d, J = 6.8 Hz, 1H), 7.77 (s, 1H), 7.66 (dd,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
J = 8.0 Hz, J = 14.4 Hz, 2H), 7.50 (d, J = 8.0 Hz, 1H), 7.17-7.14 (m, 2H), 7.02 (t, J = 7.6 Hz, 1H) ppm.
1
2
1
3
1
C{ H} NMR (100 MHz, d6-acetone) δ 174.6, 155.2, 137.4, 135.2, 129.2, 126.6, 126.1, 125.6, 125.4 (q,
1
9
J = 285.4 Hz), 124.2, 122.6, 121.2, 120.3, 119.9, 112.3, 111.5, 78.0 (q, J = 30.6 Hz) ppm. F NMR
+
(
376.5 MHz, d6-acetone) δ -76.4 ppm. HRMS (ESI) m/z: [M + Na] Calcd for C H BrF N NaO S
17 10
3
2
2
450.9527; Found 450.9526.
o
(R)-2,2,2-Trifluoro-1-(1H-indol-3-yl)-1-(thiazol-2-yl)ethan-1-ol (3fa). White solid, m.p. 108-110 C,
5
9.2 mg, 99% yield. [α]D10: -6.0 (c = 0.51, acetone). The enantioselectivity was determined by HPLC
analysis (Daicel Chiralpak AD-H column, n-hexane/i-propanol = 90:10, flow rate 1.0 mL/min, detection
o
1
at 254 nm, 35 C): t = 16.2 min (minor), t = 17.3 min (major), 97% ee. H NMR (400 MHz, d6-
1
2
acetone) δ 10.51 (br s, 1H), 7.81 (d, J = 1.6 Hz, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.61 (s, 1H), 7.54 (d, J =
8
.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 6.73 (s, 1H) ppm.
1
3
1
C{ H} NMR (100 MHz, d6-acetone) δ 171.1, 143.3, 137.4, 126.2, 125.5 (q, J = 285.1 Hz), 125.4,
1
9
1
21.8, 121.4, 121.2, 120.0, 112.2, 112.1, 77.56 (q, J = 30.5 Hz) ppm. F NMR (376.5 MHz, d6-acetone)
+
δ -76.9 ppm. HRMS (ESI) m/z: [M + Na] Calcd for C H F N NaOS 321.0285; Found 321.0326.
13
9
3
2
(S)-1-(Benzo[d]oxazol-2-yl)-2,2,2-trifluoro-1-(1H-indol-3-yl)ethan-1-ol (3ga). The product was
prepared according to the general procedure with minor modification (5 mol% VII). White solid, m.p.
o
2
15-216 C, 65.9 mg, 99% yield. [α]D10: -43.8 (c = 0.51, acetone). The enantioselectivity was
determined by HPLC analysis (Daicel Chiralpak AD-H column, n-hexane/i-propanol = 80:20, flow rate
o
1
1
.0 mL/min, detection at 254 nm, 35 C): t = 11.6 min (major), t = 14.9 min (minor), 87% ee. H NMR
1 2
(
400 MHz, d6-acetone) δ 10.62 (br s, 1H), 7.82-7.81 (m, 1H), 7.65 (s, 1H), 7.61-7.58 (m, 2H), 7.45 (d, J
=
8.0 Hz, 1H), 7.42-7.40 (m, 2H), 7.10 (t, J = 7.6 Hz, 1H), 6.96 (t, J = 8.0 Hz, 1H), 6.86 (s, 1H) ppm.
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1
3
1
C{ H} NMR (100 MHz, d6-acetone) δ 163.1, 151.3, 141.0, 137.4, 126.7, 126.1, 125.7, 125.5, 125.3 (q,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
9
J = 284.3 Hz), 122.5, 121.1, 120.8, 120.3, 112.3, 111.5, 110.5, 75.6 (q, J = 31.7 Hz) ppm. F NMR
+
(376.5 MHz, d6-acetone) δ -77.3 ppm. HRMS (ESI) m/z: [M + Na] Calcd for C H F N NaO
1
7
11
3
2
2
3
55.0670; Found 355.0725.
(
R)-1-(Benzo[d]thiazol-2-yl)-2,2,3,3,3-pentafluoro-1-(1H-indol-3-yl)propan-1-ol (3ha). White solid,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
m.p. 147-148 C, 85.0 mg, 99% yield. [α]D10: -45.1 (c = 0.50, acetone). The enantioselectivity was
o
determined by HPLCanalysis (Daicel Chiralpak AD-H column, n-hexane/i-propanol = 85:15, flow rate
o
1
1
.0 mL/min, detection at 254 nm, 35 C): t = 10.9 min (minor), t = 11.8 min (major), 94% ee. H NMR
1 2
(
400 MHz, d6-acetone) δ 10.63 (s, 1H), 8.05 (t, J = 7.6 Hz, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.84 (d, J =1.0
1
3
1
Hz, 1H), 7.52-7.40 (m, 3H), 7.20 (s, 1H), 7.13 (t, J = 9.6 Hz, 1H), 7.03 (t, J = 9.6 Hz, 1H) ppm. C{ H}
NMR (100 MHz, d6-acetone) δ 172.3, 153.6, 137.1, 135.6, 126.4, 126.0, 125.8, 125.7, 123.6, 122.1,
1
21.49, 121.46, 119.82, 119.80 (qt, J = 286.8 Hz, J = 36.1 Hz), 114.5 (tq, J = 263.6 Hz, J = 34.2 Hz),
1 2 1 2
1
9
111.9, 111.2, 78.1 (t, J = 25.1 Hz) ppm. F NMR (376.5 MHz, d6-acetone) δ -78.0 (s, 3F), -117.5 (d, J
+
=
274.5 Hz, 1F), -119.1 (d, J = 274.8 Hz, 1F) ppm. HRMS (ESI) m/z: [M] Calcd for C H F N OS
1
8
11
5
2
3
98.0512; Found 398.0498.
The Gram-Scale Preparation of 3aa. To a solution of trifluoromethyl ketone hydrate 1 (748 mg, 3.0
mmol), and catalyst VII (4.3 mg, 0.006 mmol, 0.2 mol%) in dichloromethane (30.0 mL) was added 5 Å
MS (1.80 g) and indole (527 mg, 0.30 mmol), and the reaction mixture was stirred at room temperature
for 19 h. Upon completion (monitored by TLC), the mixture was filtered through celite, and washed
with dichloromethane (3 × 10 mL). The filtrate was concentrated under reduced pressure, and the
residue was purified by silica gel column chromatography to afford the desired product 3aa as a white
solid (1.04 g, 99% yield, 93% ee). The pure enantiomer was obtained by a simple recrystallization from
o
petroleum ether/ethyl acetate (5:1) as a white solid (846 mg, 81% yield, >99% ee). m.p. 134-135 C.
[
α]D10: −56.8 (c = 0.50, acetone). The enantioselectivity was determined by HPLC analysis (Daicel
Chiralpak AD-H column, n-hexane/i-propanol = 80:20, flow rate 1.0 mL/min, detection at 254 nm, 35
oC): t = 11.6 min (major), >99% ee.
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(
R)-2-(2,2,2-Trifluoro-1-(1H-indol-3-yl)-1-((trimethylsilyl)oxy)ethyl)benzo[d]thiazole (4). Under
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o
N , to a stirring suspension of NaH (24.0 mg, 0.60 mmol, 60% wt) in dry THF (4 mL) at 0 C was added
2
dropwise 3aa (104.5 mg, 0.30 mmol, >99% ee) in dry THF (2.0 mL), and the mixture was stirred at
room temperature for 1 h. Then TMSCl (0.15 mL, 1.20 mmol) was added dropwise, and the mixture
was stirred for another 3 h. Upon completion, the reaction was quenched with water (1 mL) and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
saturated NH Cl aqueous solution (5 mL) at 0 C. The mixture was extracted with EtOAc (15 mL × 2),
4
and the combined organic layers were washed with brine (10 mL), dried over anhydrous Na SO , and
2
4
concentrated under reduced pressure. The residue was purified by flash column chromatography on
silica gel (petroleum ether/ethyl acetate = 10:1 to 5:1) to afford the desired product 4 as a white solid,
o
10
m.p. 195-197 C, 109.5 mg, 87% yield. [α]
D
: +20.2 (c = 0.50, acetone). The enantioselectivity was
determined by HPLC analysis (Daicel Chiralpak AD-H column, n-hexane/i-propanol = 98:2, flow rate
o
1
1
.0 mL/min, detection at 254 nm, 35 C): t
1
= 18.3 min (minor), t
2
= 19.9 min (major), >99% ee. H
NMR (400 MHz, CDCl ) δ 9.82 (s, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.46-7.38 (m,
3
13
1
2
H), 6.96 (d, J = 7.6 Hz, 2H), 6.88 (t, J = 7.2 Hz, 1H), 6.83-6.76 (m, 2H), 0.02 (s, 9H) ppm. C{ H}
NMR (100 MHz, CDCl ) δ 174.6, 153.4, 136.4, 135.7, 126.1, 125.5, 125.2, 125.0, 124.1 (q, J = 286.4
3
1
9
Hz), 123.2, 122.1, 121.8, 119.7, 119.5, 111.7, 109.9, 79.4 (q, J = 30.4 Hz), 0.9 ppm. F NMR (376.5
+
MHz, CDCl ) δ -74.2 ppm. HRMS (ESI) m/z: [M] Calcd for C20
H
19
F N OSSi 420.0939; Found
3
3
2
4
20.0938.
R)-1-(Benzo[d]thiazol-2-yl)-2,2,2-trifluoro-1-(1-(prop-2-yn-1-yl)-1H-indol-3-yl)ethanol
(
(5).
o
Under N , to a stirring suspension of NaH (18.0 mg, 0.45 mmol, 60% wt) in dry THF (4 mL) at 0 C
2
was added dropwise 4 (63.0 mg, 0.15 mmol) in dry THF (2 mL), and the mixture was stirred at room
temperature for 1 h. Then 3-bromo-1-propyne (53.5 mg, 0.45 mmol) was added dropwise, and the
resulting reaction mixture was spontaneously warmed to room temperature and stirred for another 3 h.
o
Upon completion, the reaction was quenched with water (5 mL) at 0 C, and stirred for 2 h at room
temperature. The mixture was extracted with EtOAc (10 mL × 2), and the combined organic layers were
washed with brine (10 mL), dried over anhydrous Na SO , and concentrated under reduced pressure.
2
4
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The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate =
0:1 to 5:1) to afford the desired product 5 as colorless oil, 52.0 mg, 90% yield. [α]D10: -8.7 (c = 0.50,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
acetone). The enantioselectivity was determined by HPLC analysis (Daicel Chiralpak OD-H column, n-
o
hexane/i-propanol = 95:5, flow rate 1.0 mL/min, detection at 254 nm, 35 C): t = 19.6 min (minor), t =
1
2
1
2
4.0 min (major), >99% ee. H NMR (400 MHz, CDCl ) δ 8.14 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.0 Hz,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
H), 7.61 (s, 1H), 7.59-7.52 (m, 2H), 7.43 (t, J = 7.2 Hz, 2H), 7.27 (t, J = 7.6 Hz, 1H), 7.08 (t, J = 3.6
1
3
1
Hz, 1H), 5.19 (s, 1H), 4.89 (d, J = 2.4 Hz, 2H), 2.47 (t, J = 2.4 Hz, 1H) ppm. C{ H} NMR (100 MHz,
CDCl ) δ 169.2, 151.6, 136.5, 136.2, 126.7 (q, J = 2.7 Hz), 126.4, 126.2, 125.9, 124.1 (q, J = 285.1 Hz),
3
1
9
1
23.7, 122.8, 121.8, 120.9, 120.8, 110.5, 109.8, 77.0 (q, J = 31.1 Hz), 76.9, 74.3, 36.1 ppm. F NMR
+
(376.5 MHz, CDCl ) δ -76.3 ppm. HRMS (ESI) m/z: [M] Calcd for C H F N OS 386.0701; Found
3
20 13
3
2
3
86.0697.
,2,2-Trifluoro-1-(1H-indol-3-yl)ethanone (6). The mixture of 4 (168.2 mg, 0.40 mmol), 4 Å MS
2
(750 mg), and anhydrous dichloromethane (5.0 mL) was stirred at room temperature for 10 min, and
then Me OBF (184.9 mg, 1.25 mmol) was added. After stirred for 2 h, another batch of Me OBF
3
4
3
4
(184.9 mg, 1.25 mmol) was added. Upon completion (monitored by TLC), the reaction was
concentrated without filtering off the molecular sieves to give the crude benzothiazolium salt. It was
redissolved in MeOH (5.0 mL), and cooled to 0 °C. Then NaBH (1.25 mmol) was added in portions.
4
Upon completion (monitored by TLC), the mixture was diluted with acetone (5 mL), filtered through a
pad of Celite, and concentrated to give the crude benzothiazoline. To a vigorously stirred solution of the
crude benzothiazoline in CH Cl (1.5 mL) and CH CN (7.5 mL) were added H O (0.90 mL) and AgNO
3
2
2
3
2
(254.8 mg, 1.5 mmol). Upon completion (monitored by TLC), and the reaction was quenched with 1 M
phosphate buffer (0.5 mL, pH = 7). After stirred for 15 min, the reaction mixture was diluted with 1 M
phosphate buffer (12.5 mL, pH 7) and partially concentrated to remove CH CN. The suspension was
3
extracted with EtOAc (15 mL × 2), and the combined organic layers were dried over Na SO , filtered
2
4
through a pad of Celite, and concentrated under reduced pressure. The residue was purified by flash
column chromatography on silica gel (petroleum ether/ethyl acetate = 10:1 to 5:1) to afford the desired
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o
1
product 6 as a yellow solid, m.p. 210-211 C, 70.0 mg, 76% yield. H NMR (400 MHz, d6-acetone) δ
1
2
3
4
5
6
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1.68 (s, 1H), 8.42 (s, 1H), 8.32 (d, J = 7.2 Hz, 1H), 7.63 (t, J = 5.6 Hz, 1H), 7.36 (t, J = 2.8 Hz, 2H)
1
3
1
ppm. C{ H} NMR (100 MHz, Acetone) δ 175.3 (q, J = 34.1 Hz), 137.6, 137.2 (q, J = 5.0 Hz), 127.0,
19
1
7
25.2, 124.2, 122.4, 118.0 (q, J = 289.2 Hz), 113.4, 110.6 ppm. F NMR (376.5 MHz, d6-acetone) δ -
2.9 ppm.
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ASSOCIATED CONTENT
The Supporting Information is available free of charge on the ACS Publications website at DOI:
1
0.1021/acs.joc.xxxxxx.
1
13
19
Copies of H, C, and F NMR spectra, X-ray crystallographic data of 3aa (PDF)
X-ray crystallographic data of 3aa (CIF).
AUTHOR INFORMATION
Corresponding Author
*
E-mail: yangwen@hnu.edu.cn
*E-mail: wangqa@hnu.edu.cn
E-mail: jinpingwang1985@126.com
*
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We are grateful for the financial support from the National Natural Science Foundation of China (Grant
No. 21702055) and Youth Foundation of Hunan University (Grant No. 531107050885).
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(
OH
OH
N
X
Et N
H O
2
N
X
3
R
+ (CF3CO)2O
R
toluene
CF3
15-75% yield
(
9) Yu, J.; Wu, Z.; Zhu, C. Efficient Docking–Migration Strategy for Selective Radical Difluoromethylation of
Alkenes. Angew. Chem., Int. Ed. 2018, 57, 1715617160.
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