Synthesis of Chiral Bis(3-indolyl)methanes Bearing a Trifluoromethylated All-Carbon Quaternary Stereocenter via Nickel-Catalyzed Asymmetric Friedel-Crafts Alkylation Reaction

Article abstract of DOI:10.1021/acs.joc.0c00336

Bis(3-indolyl)methanes are well-known natural products with a broad range of important biological functions including cancer cell growth inhibition and antimicrobial activity. Incorporation of a trifluoromethyl group is known to have a profound effect on the parent compound's biological activities. Here, an efficient method for the synthesis of chiral trifluoromethylated bis(3-indolyl)methanes via a catalytic asymmetric Friedel-Crafts (F-C) alkylation reaction has been established. Both enantiomers of the catalysis products can be obtained by tuning the chiral substituents of the catalyst. With 5 mol % of the Ni(II)/(imidazoline-oxazoline) complex as the catalyst, the F-C reaction of indoles with β-CF3-β-(3-indolyl)nitroalkenes proceeded well to afford a series of chiral bis(3-indolyl)methanes bearing a trifluoromethylated all-carbon quaternary stereocenter in generally good yields with excellent enantioselectivities (up to 98% yield and 94% ee). Furthermore, by interchanging the indole moieties of the two reactants, indole vs β-CF3-β-(3-indolyl)nitroalkene in the F-C reaction, both enantiomers of a given trifluoromethylated bis(3-indolyl)methane were obtained with high enantioselectivities (89-94% ee) upon removal of the indole N-protecting group in the F-C products. The current work represents the first general catalytic enantioselective approach to the important class of trifluoromethylated bis(3-indolyl)methanes.

Full text of DOI:10.1021/acs.joc.0c00336

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Article
Synthesis of Chiral Bis(3-indolyl)methanes Bearing a
Trifluoromethylated All-Carbon Quaternary Stereocenter via
Nickel-catalyzed Asymmetric Friedel-Crafts Alkylation Reaction
Wen-Jing Zhu, Jun-Fang Gong, and Mao-Ping Song
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00336 • Publication Date (Web): 06 Jul 2020
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Synthesis of Chiral Bis(3-indolyl)methanes Bearing a
Trifluoromethylated All-Carbon Quaternary Stereocenter via
Nickel-catalyzed Asymmetric Friedel-Crafts Alkylation Reaction
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Wen-Jing Zhu, Jun-Fang Gong, and Mao-Ping Song
College of Chemistry, Henan Key Laboratory of Chemical Biology and Organic Chemistry,
Green Catalysis Center, Zhengzhou University, Zhengzhou 450001, People’s Republic of
China
ABSTRACT: Bis(3-indolyl)methanes are well known natural products with a broad range
of important biological functions including cancer cell growth inhibition and anti-microbial
activity. Incorporation of a trifluoromethyl group is known to have a profound effect on the
parent compound’s biological activities. Here an efficient method for the synthesis of chiral
trifluoromethylated bis(3-indolyl)methanes via a catalytic asymmetric Friedel-Crafts (F-C)
alkylation reaction has been established. Both enantiomers of the catalysis products can be
obtained by tuning the chiral substituents of the catalyst. With 5 mol% of the
Ni(II)/(imidazoline-oxazoline) complex as the catalyst, the F-C reaction of indoles with
β-CF -β-(3-indolyl)nitroalkenes proceeded well to afford
a
series of chiral
3
bis(3-indolyl)methanes bearing a trifluoromethylated all-carbon quaternary stereocenter in
generally good yields with excellent enantioselectivities (up to 98% yield and 94% ee).
Furthermore, through interchanging the indole moieties of the two reactants, indole vs
β-CF -β-(3-indolyl)nitroalkene in the F-C reaction, both enantiomers of a given
3
*
Tel./Fax: (+86)-371-6776-3869. E-mail: gongjf@zzu.edu.cn (J.-F. Gong) or mpsong@zzu.edu.cn (M.-P.
Song).
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trifluoromethylated bis(3-indolyl)methane were obtained with high enantioselectivities
(89-94% ee) upon removal of the indole N-protecting group in the F-C products. The
current work represents the first general catalytic enantioselective approach to the important
class of trifluoromethylated bis(3-indolyl)methanes.
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INTRODUCTION
The heterocyclic bis(3-indolyl)methane (3,3-BIM) compounds, in which two 3-indolyl
units are joined together by a simple or a substituted methylene bridge, have been
1
increasingly gaining research interests. This is largely due to a number of studies reporting
a broad range of biological functions for BIMs, including cancer cell growth inhibition,2
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anti-inflammation, anti-fungal activity, and regulation of cell differentiation. BIMs have
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also been found able to act as colorimetric sensors. These reported various biological
activities apparently aroused from the differences in the structures of those functionally
tested BIMs. Thus, design and synthesis of new BIM compounds particularly the new
chiral BIMs are then imperative to understand and expand structural basis for the
therapeutically important BIMs.
A number of strategies have been successfully developed for the synthesis of
bis(3-indolyl)methanes.1,7 Nonetheless, enantioselective approaches to the chiral BIMs are
rather limited.8,9 Among these reports, the catalytic asymmetric Friedel-Crafts (F-C)
alkylation reaction10 especially organo-catalyzed F-C reaction accounts for the dominant
approach. Thus, in the presence of chiral phosphoric acids8a,d,f or chiral imidodiphosphoric
acids8b,c,e as the catalysts, several indole-containing electrophiles including
(3-indolyl)methanamines,8a
trimethylsilyl-protected
3-arylindolylmethanols,8b
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8c
8d,e
8f
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-hydroxy-indolyloxindoles, 3-vinylindoles
as well as 3-indolylsulfamidates reacted
smoothly with indoles to give structurally diverse chiral BIMs in generally high yields with
good to excellent enantioselectivities.
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On the other hand, it has been reported that organic compounds bearing a
trifluoromethylated tertiary or quaternary stereogenic carbon center play a unique and
significant role in pharmaceutical, agochemical and materials sciences.11 In particular,
introduction of a trifluoromethylated stereogenic carbon center has a profound effect on the
biological activities of the parent compounds. Therefore, chiral trifluoromethylated
bis(3-indolyl)methanes12 containing a trifluoromethylated carbon stereocenter may have
novel and interesting biological functions, and it is highly desirable to develop efficient
methods for the synthesis of these compounds.
We have previously demonstrated that Co(II), complexed with chiral hybrid
(
imidazoline-oxazoline) ligand derived from 2,2-dimethylmalonic acid, was an effective
and highly stereoselective catalyst for enantioselective Michael addition of 2-acetyl
1
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azaarenes to β-CF -β-aryl(indole) nitroalkenes. In view of the high efficiency of the
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(
imidazoline-oxazoline) ligand in the above Co-catalyzed enantioselective transformations,
we expected that this type of ligand could also perform well in asymmetric Friedel-Crafts
alkylation reaction involving β-CF -β-disubstituted nitroalkenes. In the current report, we
3
extended our previous work by using chiral Ni(II)/(imidazoline–oxazoline) complex to
catalyze asymmetric F-C reaction of indoles with β-CF -β-(3-indolyl)nitroalkenes (Scheme
3
1
).14 A variety of chiral trifluoromethylated bis(3-indolyl)methanes bearing a
trifluoromethylated all-carbon quaternary stereocenter were thus obtained in high yields
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and enantioselectivities. The current work represents the first example of synthesis of
biologically relevant chiral trifluoromethylated BIMs. In addition, we found that upon
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removal of the indole N-protecting group (R ) in the F-C products, both enantiomers of a
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given trifluoromethylated bis(3-indolyl)methane could be generated with high
enantioselectivities.
Scheme 1. Ni-catalyzed Asymmetric Friedel-Crafts Alkylation Reaction of Indoles
with β-CF -β-(3-indolyl)nitroalkenes
3
F3C
NO2
R1
F3C
R3
R1
NO2
Ni(ClO4)2 6H O/L1
2
N
R2
+
N
H
N
R3
p-Tol
N
H
N
O
R2
N
N
Ph
Ph
L1
RESULTS AND DISCUSSION
We began our investigations by choosing indole 1a and the N-Ts-protected
β-CF -β-(3-indolyl)nitroalkene 2a as reactants for the F-C reaction (Table 1). The reaction
3
of 2a with 1.5 equivalent of 1a was first carried out in the presence of 5 mol% of
o
Ni(ClO ) ·6H O and 6 mol% of chiral imidazoline-oxazoline ligand L1 in toluene at 80 C
4
2
2
for 12 h. Under the above stated conditions the reaction proceeded efficiently to produce
the expected trifluoromethylated bis(3-indolyl)methane 3aa in a 97% yield with 90% ee
(entry 1). In the absence of ligand L1 the product 3aa was not detected which suggested the
crucial role of the ligand for the reaction (entry 2). Then potential of the other three Lewis
acids was examined. It was found that the use of Ni(OTf) , Zn(OTf) or Zn(ClO ) ·6H O as
2
2
4 2
2
Lewis acid resulted in marked decrease in both yield and enantioselectivity of 3aa (8‒34
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yields with 48‒77% ee, entries 3‒5). Subsequently, the reaction temperature was optimized.
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Elevating temperature to 90 C was detrimental to the enantioselectivity though an
o
excellent yield could still be achieved (entry 6). In contrast, lowering temperature to 70 C
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was beneficial for the enantioselectivity which improved from 90% ee to 92% ee while the
yield dropped noticeably from 97% to 70% (entry 7). Further lowering the temperature to
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0 °C did not lead to a further improvement in enantioselectivity and the yield decreased
o
drastically to 28% (entry 8). Therefore, 70 C was considered to be an appropriate reaction
o
temperature. At the temperature of 70 C, a yield of 90% or above could be obtained when
the concentration of substrate 2a was changed from 0.1 M (mol/L) to 0.2 M (entry 9) or
0
.13 M (entry 10). Unfortunately, the enantioselectivity reduced to 88% ee. We also tested
reactions in different solvents and found toluene to be an optimal solvent and superior to at
least DCE and CH CN (entries 11 and 12). Changing the ratio of 1a and 2a from 1.5:1 to
3
1
:1 did not give better results, either (entry 13). Gratifyingly, a length of 24 hours appeared
to be sufficient to provide the optimal yield and enantioselectivity (93% yield with 92% ee,
entry 14 vs 7). Thus, under the conditions as shown in entry 14 the performance of the
other chiral ligands L2–L9 was investigated and compared. The ligands L2-L4, which are
the same type as ligand L1, gave 3aa in much lower yields and/or enantioselectivity
(entries 15-17). Interestingly, in the presence of the ligands L2 and L3 the major
enantiomer of the product 3aa possesses the opposite absolute configuration to that
obtained with ligand L1. In particular, the ligand L2 containing additional phenyl groups
afforded a promising enantioselectivity of 82% though the yield was somewhat moderate
(entry 15). The structurally very related four bis(oxazoline) ligands L5-L8 also showed
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inferior stereocontrol compared with ligand L1 (entries 18-21). Among them, good
enantioselectivity could be achieved with ligands L5 and L6. Ligands L5, L7 and L8
behaved similarly to their corresponding analogues L1, L3 and L4. By contrast, ligand L6
performed very differently from its analogue L2 (entry 19 vs 15). In the presence of ligand
L6 the major enantiomer of 3aa has the opposite absolute configuration to that obtained
with ligand L2. In addition, in the presence of the bis(imidazoline) ligand L9 the reaction
did not occur (entry 22). Therefore, the ligand L1 was ideal for the catalysis. Importantly,
when the reaction was conducted under air, 3aa was produced without any loss of
enantioselectivity though the yield showed somewhat decrease (entry 23 vs 14). This result
indicates that the synthesis of chiral trifluoromethylated bis(3-indoyl)methanes via
Ni(II)-(imidazoline-oxazoline) complex-catalyzed Friedel-Crafts reaction can be carried out
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without the need for strictly exclusion of air.
Table 1. Optimization of Reaction Conditionsa
F3C
NO2
F3C
LA (5 mol %)
NO2
Ts
N
L
(6 mol %)
+
o
N
Solvent, T C
N
N
H
Ts
H
1a
2a
3aa
t-Bu
p-Tol
p-Tol
p-Tol
N
O
O
O
N
N
R2
R2
R2
R2
N
N
N
N
N
N
R1
R1
R1
R1
Ph
Ph
1
2
1
2
L9
L1 R = Ph, R = H
L5 R = Ph, R = H
1
2
1
2
L2 R = R = Ph
L6 R = R = Ph
1
2
1
2
L3 R = Bn, R = H
L7 R = Bn, R = H
1
2
1
2
L4 R = t-Bu, R = H
L8 R = t-Bu, R = H
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o
b
c,d
entry
L
LA
Ni(ClO ) ·6H O
solvent
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCE
T ( C) time (h) yield (%) ee (%)
1
2
3
4
5
6
7
8
9e
L1
/
80
80
80
80
80
90
70
60
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
12
12
12
12
12
12
12
12
12
12
12
12
12
24
24
24
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24
24
24
24
97
n.d.
17
90
--
4 2
2
Ni(ClO ) ·6H O
4
2
2
1
1
1
1
1
1
1
1
1
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2
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2
2
2
2
2
2
2
3
3
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3
3
3
3
3
3
3
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4
4
4
4
4
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4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
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9
0
1
2
3
4
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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
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L9
L1
Ni(OTf)2
Zn(OTf)2
60
48
77
88
92
87
88
88
76
--
8
Zn(ClO ) ·6H O
34
4
2
2
Ni(ClO ) ·6H O
98
4
2
2
Ni(ClO ) ·6H O
70
4
2
2
Ni(ClO ) ·6H O
28
4
2
2
Ni(ClO ) ·6H O
90
4
2
2
1
0f
Ni(ClO ) ·6H O
92
4
2
2
1
1
1
2
Ni(ClO ) ·6H O
13
4 2
2
Ni(ClO ) ·6H O
CH CN
trace
53
4
2
2
3
1
3g
Ni(ClO ) ·6H O
Toluene
90
92
-82
-22
8
4
2
2
1
4
Ni(ClO ) ·6H O Toluene
93
4 2
2
15
Ni(ClO ) ·6H O
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
48
4
2
2
1
1
6
7
Ni(ClO ) ·6H O
63
4
2
2
Ni(ClO ) ·6H O
trace
96
4
2
2
18
Ni(ClO ) ·6H O
89
85
-18
6
4
2
2
1
2
2
2
9
0
1
2
Ni(ClO ) ·6H O
69
4
2
2
Ni(ClO ) ·6H O
61
4
2
2
Ni(ClO ) ·6H O
15
4 2
2
Ni(ClO ) ·6H O
n.d.
81
--
4
2
2
2
3h
Ni(ClO ) ·6H O
92
4
2
2
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aReaction conditions unless noted otherwise: 1a (0.3 mmol), 2a (0.2 mmol), Lewis acid
o
b
(
LA) (5 mol%), L (6 mol%), solvent (2.0 mL), T C, Ar. Isolated yield. n.d.: Not detected.
c
d
Determined by chiral HPLC. The absolute configuration of 3ja was determined to be R
according to the X-ray crystal diffraction analysis (vide infra). That of 3aa was assigned to
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4
5
6
7
8
9
0
e
f
g
h
be R by analogy. Toluene (1.0 mL). Toluene (1.5 mL). 1a:2a = 1:1. Under air.
Upon the optimized reaction conditions being determined as described above (Table 1,
entry 14), we next investigated the scope of indole and nitroalkene substrates. As shown in
Scheme 2, a list of substituted indoles 1b-1l were used in the F-C reaction to react with the
N-Ts-protected nitroalkene 2a, resulting in chiral trifluoromethylated BIM derivatives
3
ba-3la with diverse structures in generally good yields with good to excellent
enantioselectivities (81-93% ee). It appears that both the reactivity (yield) and the
enantioselectivity are affected by the position and electronic property of the substituent on
the indole. In the case of 4-F substituted indole 1b, the reactivity and stereoselectivity
reduced apparently which might be likely due to the strong electron-withdrawing property
of the fluorine and steric hindrance at the 4-position. In other cases, a reaction time longer
than 24 h was usually necessary to ensure good yields, indicating that the reactivity of 1c-1l
was also lower than indole 1a. In comparison with indoles containing an
electron-withdrawing group such as F, Cl and Br, indoles with electron-donating group
such as Me and OMe exhibited obviously higher reactivity. On the other hand, a clear trend
for the effect of the substituent on the reaction enantioselectivities could not be obtained.
Besides the N-Ts-protected nitroalkene 2a, the N-Boc-protected nitroalkene 2a′ was also a
suitable reactant for the current F-C reaction though it was unreactive in the related
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Co(II)-catalyzed Michael addition.13b The reactions of 2a′ with indole 1a and indoles
containing electron-donating group at 5-, 6- and 7-positions proceeded equally well to
afford the corresponding chiral BIMs (3aa′-3la′) with a C-CF stereogenic center in good
3
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
yields with high enantioselectivities (84-94% ee). Roughly, the reaction yields were lower
than those with the N-Ts-protected nitroalkene 2a while the enantioselectivities were
slightly higher instead. Unfortunately, the indole with electron-withdrawing group such as
5
-F reacted poorly with N-Boc-protected nitroalkene 2a′ and only trace amount of the
product 3ca′ was formed.
Scheme 2. Substrate Scope of the Reactiona
F3C
NO2
Ni(ClO4)2 6H O (5 mol%)
R1
F3C
2
R1
NO2
R3
R2
L1 (6 mol%)
N
+
N
o
Toluene, 70 C
H
N
R3
N
H
3
3
1
2 R = Ts or Boc
R2
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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
R1
F3C
R1
NO2
NO2
NO2
NO2
F3C
F3C
F3C
Ts
Ts
R1
Ts
Ts
N
N
N
N
N
N
H
N
H
R1
N
H
H
1
b
1
69%, 91% eec
1
1
3
3
aa R = H, 93%, 92% ee
3ca R = F,
3da R = Cl, 87%, 93% eec
3ha R = Cl, 58%, 83% ee
3ka R = Me, 85%, 81% ee
ba R1 = F, 69%, 88% eec
1
1
1
3ia R = Me, 91%, 90% ee
3la R = OMe, 63%, 93% ee
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
1
b
3
ea R = Br, 75%, 92% ee
3ja R = OMe, 90%, 88% ee
1
3fa R = Me, 95%, 90% ee
1
3
ga R = OMe, 94%, 89% ee
R1
NO2
NO2
NO2
NO2
F3C
F3C
F3C
F3C
Boc
Boc
Boc
Boc
N
N
R1
N
N
N
H
N
H
N
R1
N
H
H
1
traced
1
3ca' R = F,
3ia' R = Me, 80%, 93% ee
1
3
aa' 74%, 91% eeb
3ka' R = Me, 75%, 84% ee
fa' R = Me, 88%, 94% eeb
1
1
R = OMe, 82%, 91% eeb
1
3
3ja'
3la' R = OMe, 41%, 93% ee
1
3ga' R = OMe, 86%, 93% ee
NO2
NO2
NO2
NO2
N
F3C
F3C
F3C
F3C
Ts
N
Ts
N
Ts
N
Ts
N
H
F
N
H
N
R2
N
H
H
R2
R2
ab 66%, 93% eee
2
68%, 89% eee
74%, 87% eec
2
e
f
3ak R = Me, 93%, 93% eee
al R = OMe, 87%, 93% eee
2
3
3ac R = F,
3ai R = Me, 96%, 94% ee
ae R2 = Br,
2
3
3
3ai R = Me, 84%, 94% ee
2
3
2
c
af R = Me,
89%, 86% ee
2
c
3ag R = OMe, 91%, 92% ee
2
e
3
am R = CO Me, 98%, 92% ee
2
NO2
NO2
Me
NO2
MeO
NO2
F3C
F3C
F3C
F3C
Boc
Boc
Ts
Ts
N
N
N
N
N
H
N
N
H
N
H
H
Me
af' 14%, 90% eee
MeO
Me
3gf 68%, 85% eee
Me
3fg 92%, 90% eee
3
3ai' 20%, 82% eee
Me
NO2
NO2
NO2
F3C
F3C
Me
F3C
Ts
Ts
N
N
Me
Boc
N
N
H
N
H
N
H
Me
Me
Me
3
fi 97%, 91% eec
3ii 93%, 92% eec
3
fi' 40%, 90% eee
a
Reaction conditions: 1 (0.3 mmol), 2 (0.2 mmol), Ni(ClO ) ·6H O (5 mol%), L1 (6 mol%),
4
2
2
o
toluene (2.0 mL), Ar, 70 C for 36 h. Yields are of the isolated products. The ee values were
determined by chiral HPLC. The absolute configurations of the products 3 were assigned to
b
c
be R by analogy based on the X-ray crystal diffraction analysis of 3ja. For 24 h. For 48 h.
d
e
f
For 72 h. For 60 h. 1a (6.0 mmol), 2i (4.0 mmol), Ni(ClO ) ·6H O (5 mol%), L1 (6
4
2
2
o
mol%), toluene (40.0 mL), Ar, 70 C for 84 h.
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A wide range of substituted nitroalkenes were also tested under the optimal reaction
conditions (Scheme 2). The N-Ts-protected nitroalkenes 2b-2l with various substituents on
the indole ring were well tolerated, giving the desired chiral trifluoromethylated BIMs
3ab-3al in 66-98% yields with 86-94% ee. The substituents include electron-withdrawing
groups (F, Br and COOMe) and electron-donating group (Me and OMe) at 4-, 5-, 6- or
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
7
-position of indole ring. For the reactions of N-Boc-protected nitroalkenes 2f′ and 2i′
bearing 5- or 6-Me on the indole ring with indole 1a, good to excellent enantioselectivities
3af′ and 3ai′, 90% and 82% ee, respectively) were obtained. However, the yields were
(
rather low (< 20%). Notably, good results could still be achieved when both indole and the
N-Ts-protected nitroalkene were substituted with electron-donating group such as Me and
OMe (3fg, 3gf, 3fi and 3ii, 68-97% yields with 85-92% ee). Lastly, 5-Me indole 1f was
subjected to the reaction with N-Boc-protected nitroalkene 2i′, which afforded the product
3
fi′ in 40% yield with 90% ee. Overall, the N-Boc-protected nitroalkenes exhibited lower
reactivity than the corresponding N-Ts-protected nitroalkenes especially when they
contained substituent on the indole ring.
From the above investigations it can be seen that the current method tolerates various
substituents which are located at 4-, 5-, 6- or 7-position of indole ring in both the indole and
the nitroalkene, providing a series of chiral trifluoromethylated BIMs with structural
diversity. In particular, some substituents such as F, Cl, Br and COOMe in the obtained
BIM compounds can be easily utilized for further transformations to produce more new
trifluoromethylated BIMs.
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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
To further explore the practical potential of the method established above, the synthesis
reaction for the chiral CF -containing BIM 3ai from indole 1a and the nitroalkene 2i was
3
carried out at a gram-scale level under the optimal conditions with a reaction time of 84 h
(Scheme 2). The target product 3ai was isolated in a yield of 84% (1.81g) without any loss
of enantioselectivity (94% ee).
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
Besides the gram scale synthesis, we next conducted a series of transformation reactions
of the F-C products (Scheme 3). First, under a strong acidic condition, the N-Boc protecting
group in the product 3fa′ was successfully removed according to previously reported
1
5
method, giving the corresponding product (S)-4a in 77% yield with 93% ee (Scheme 3a).
Similarly, removal of the Boc group in the product 3af′ afforded (R)-4a, the enantiomer of
(
S)-4a (Scheme 3a). Subsequently, three additional pairs of enantiomeric
trifluoromethylated BIMs 4b-4d were obtained by removing the N-Ts protecting group in
the products 3 in the presence of cesium carbonate as previously reported (Scheme 3b).13b,16
In all cases, the corresponding enantiomers 4 were prepared in good yields without loss of
enantioselectivity. Furthermore, as shown in Scheme 3c, the NO group of (R)-4c was
2
readily reduced to NH by NaBH /NiCl ·6H O in methanol at room temperature. The
2
4
2
2
expected tryptamine derivative 5 was obtained in a yield of 74% with an enantioselectivity
of 94% ee.
Scheme 3. Transformations of the Products 3
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NO2
N
NO2
NO2
NO2
N
CF3
CF3
CF3
CF3
Boc
Boc
TFA
NH
NH
TFA
CH2Cl2, rt, 1 h
CH Cl , rt, 1 h
(a)
2
2
N
H
N
H
N
H
N
H
3
fa' 94% ee
(S)-4a 77%, 93% ee
(R)-4a 73%, 89% ee
3af' 90% 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
NO2
N
NO2
CF3
NO2
CF3
NO2
N
R1
CF3
R1
CF3
Ts
Ts
Cs2CO3
NH
NH
2 3
Cs CO
THF/CH3OH
0 oC, 12 h
THF/CH OH
(b)
3
N
H
N
H
N
H
N
H
50 oC, 12 h
5
R2
R2
3
3
ga R1 = 5-OMe, 89% ee
ia R1 = 6-Me, 90% ee
3la R1 = 7-OMe, 93% ee
(S)-4b 89%, 89% ee
(S)-4c 84%, 90% ee
(S)-4d 70%, 93% ee
(R)-4b 92%, 92% ee
(R)-4c 87%, 94% ee
(R)-4d 75%, 93% ee
3ag R2 = 5-OMe, 92% ee
3ai R2 = 6-Me, 94% ee
3al R2 = 7-OMe, 93% ee
NO2
NH2
NH
CF3
CF3
NH
NiCl2 6H2O, NaBH4
MeOH, rt, 1 h
(
c)
N
N
H
H
(R)-4c 94% ee
5 74%, 94% ee
The absolute configurations of the F-C reaction product 3ja and the transformed product
4a from 3fa' were determined by X-ray crystallographic analysis to be R and S, respectively
(
see Figures S1 and S2 in the Supporting Information). Based on the stereochemical
outcomes and the previously reported studies,14a one possible pathway for the formation of
R)-3 was then proposed accordingly. As depicted in Scheme 4, the imidazoline-oxazoline
(
ligand L1 first coordinates to the Ni(II) center in a N,N-bidentate fashion, thereby
generating a chiral Ni(II) complex that in turn acts as an efficient Lewis acid catalyst. Next,
1
,3-binding of the nitroalkene 2a to the Ni(II) catalyst through NO group results in
2
activation of the nitroalkene. To avoid unfavorable steric repulsions between the indole 1j
and the phenyl group of chiral ligand L1, the Si-face attacking of the indole 1j at the
β-position of the nitroalkene occurs preferentially, whereby the (R)-isomer of 3ja is formed.
Scheme 4. Possible Stereochemical Pathway
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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
p-Tol
p-Tol
N
O
N
O
N
O
N
N
O
N
Ph
Ni
N
Ph
Ni
N
O
O
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
OMe
N
N
Ts
CF3
Ts
CF3
N
H
MeO
N
H
Re face approach
Si face approach
disfavored
favored
(
R)-3ja
(S)-3ja
CONCLUSION
In summary, we have developed a highly enantioselective Friedel-Crafts alkylation reaction
of indoles with β-CF -β-(3-indolyl)nitroalkenes catalyzed by Ni(II)/
imidazoline-oxazoline) complex. A series of bis(3-indolyl)methane derivatives containing
a
3
(
a trifluoromethylated all-carbon quaternary stereocenter have been prepared in high yields
with excellent enantioselectivities. Our work established for the first time an
enantioselective synthesis method for chiral trifluoromethylated BIMs with a feasible way
to obtain both enantiomers.
EXPERIMENTAL SECTION
General Procedures. Solvents were dried with standard methods and freshly distilled
prior to use if needed. The imidazoline-oxazoline ligands L1–L4,13 the bis(oxazoline)
ligands L5 and L7,17 the bis(oxazoline) ligand L6, the bis(imidazoline) ligand L9, as
18
19
2
0
well as β-CF -β-(3-indolyl)nitroalkenes 2 were prepared according to the literature
3
methods. All other chemicals including the bis(oxazoline) ligand L8 were used as
1
13
1
purchased. All reactions that required heating were heated using an oil bath. H, C{ H},
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and 19F NMR spectra were recorded on a Bruker DPX-400 spectrometer with CDCl or
3
DMSO-d as the solvent and TMS as an internal standard. HRMS were determined on a
6
Waters Q-Tof Micro MS/MS System ESI spectrometer. The enantiomeric excesses of (R)-
and (S)-enantiomers were determined by HPLC analysis over a chiral column with a UV
detector. The absolute configuration of the major enantiomer was assigned by X-ray
diffraction analysis. Melting points were measured on a WC-1 instrument and uncorrected.
Optical rotations were recorded on a PerkinElmer 341 polarimeter.
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
Synthesis of β-CF -β-(3-indolyl)nitroalkenes. The nitroalkenes 2 were synthesized
3
2
0
according to the procedure reported by Kang, He, and Liu. The analytical data of the new
nitroalkenes are given as follows.
(E)-Tert-butyl 5-methyl-3-(3,3,3-trifluoro-1-nitroprop-1-en-2-yl)-1H-indole-1-carboxylate
(2f′). With petroleum ether/EtOAc (50/1) as eluent; yellow solid (1.50 g, 81%); mp:
o
1
1
06.2–108.1 C. H NMR (400 MHz, CDCl ): δ 8.05 (d, J = 8.5 Hz, 1H), 7.79 (s, 1H), 7.66
3
(d, J = 1.2 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.01 (s, 1H), 2.42 (s, 3H), 1.68 (s, 9H);
1
3
1
C{ H} NMR (100 MHz, CDCl ): δ 148.9, 140.2 (q, J = 6.2 Hz), 133.4, 133.2, 129.8 (q,
3
C–F
JC–F = 32.7 Hz), 127.8, 127.02, 126.98, 122.1 (q, JC–F = 274.2 Hz), 118.9, 115.4, 106.9,
1
9
+
8
5.0, 28.1, 21.4; F NMR (376 MHz, CDCl ): δ -66.8; HRMS (ESI) m/z: [M + Na] calcd
3
for C H F N O Na 393.1038; Found 393.1038.
1
7
17
3
2
4
(E)-Tert-butyl 6-methyl-3-(3,3,3-trifluoro-1-nitroprop-1-en-2-yl)-1H-indole-1-carboxylate
(2i′). With petroleum ether/EtOAc (50/1) as eluent; yellow solid (1.55 g, 84%); mp:
o
1
1
7
09.2–111.5 C. H NMR (400 MHz, CDCl ): δ 8.05 (s, 1H), 7.75 (s, 1H), 7.66 (s, 1H),
3
1
3
1
.11 (s, 2H), 2.49 (s, 3H), 1.69 (s, 9H); C{ H} NMR (100 MHz, CDCl ): δ 149.0, 140.1
3
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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
(
q, JC–F = 6.3 Hz), 135.8, 135.4, 129.8 (q, JC–F = 32.7 Hz), 126.5, 125.2, 122.1 (q, JC–F =
2
74.3 Hz), 118.6, 116.0, 107.1, 85.0, 28.1, 21.9; 19F NMR (376 MHz, CDCl ): δ -66.7;
3
+
HRMS (ESI) m/z: [M + Na] calcd for C H F N O Na 393.1038; Found 393.1039.
1
7
17
3
2
4
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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0
1
2
3
4
5
6
7
8
9
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General Procedure for the Catalytic Friedel-Crafts alkylation Reaction. To a
Schlenk tube were added Ni(ClO ) ·6H O (3.7 mg, 0.010 mmol) and the ligand L1 (5.1 mg,
4
2
2
0
.012 mmol) under argon atmosphere. Toluene (2.0 mL) was then added through a syringe.
o
The resulting mixture was stirred at 70 C for 1 h, after which the indole 1 (0.3 mmol) and
the nitroalkene 2 (0.2 mmol) were added successively. The mixture was stirred at 70 °C
until the reaction was completed (monitored by TLC). The solvent was evaporated under
vacuum and the residue was purified by chromatography on silica gel plates to afford the
product 3. The corresponding racemic products were prepared by the reaction of indole
(0.15 mmol) and nitroalkene (0.10 mmol) in the presence of 20 mol% of Cu(OAc) and 10
2
mol% Cs CO in toluene (1.0 mL) at 100 °C for 12 h.
2
3
Procedure for the Gram-Scale Experiment. To a Schlenk tube were added
Ni(ClO ) ·6H O (73.1 mg, 0.20 mmol) and the ligand L1 (101.6 mg, 0.24 mmol) under
4
2
2
argon atmosphere. Toluene (40 mL) was then added through a syringe. The resulting
o
mixture was stirred at 70 C for 1 h, after which indole 1a (702.9 mg, 6.0 mmol) and the
nitroalkene 2i (1697.6 mg, 4.0 mmol) were added successively. The mixture was stirred at
70 °C for 84 h. The solvent was evaporated under vacuum and the residue was purified by
column chromatography on silica gel (petroleum ether/EtOAc, 20/1) to afford the product
3
ai (1.81 g, 84% yield, 94% ee).
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(
R)-1-Tosyl-3-(1,1,1-trifluoro-2-(1H-indol-3-yl)-3-nitropropan-2-yl)-1H-indole
(3aa).
With petroleum ether/EtOAc (3/1) as eluent; white solid (97.6 mg, 93%); mp: 110.1‒111.7
oC. The enantiomeric excess was determined on a Daicel Chiralpak IC column with
n-hexane/2-propanol (90/10) and flow rate 1.0 mL/min and detected at a UV wavelength of
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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7
8
9
0
2
54 nm. Retention times: 12.6 min (major), 14.2 min (minor), 92% ee. [α]D20 = -5 (c 0.14,
1
CH Cl ). H NMR (400 MHz, CDCl ): δ 8.38 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.87 (s, 1H),
2
2
3
7
.78 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.2 Hz, 1H), 7.29‒7.27 (m, 3H), 7.21‒7.17 (m, 1H),
7
.10‒7.06 (m, 1H), 6.88‒6.85 (m, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.68‒6.62 (m, 2H), 5.55 (d,
J = 11.4 Hz, 1H), 5.40 (d, J = 11.4 Hz, 1H), 2.38 (s, 3H); 13C{ H} NMR (100 MHz,
CDCl ): δ 145.5, 136.2, 135.1, 134.8, 130.1, 128.9, 126.9, 126.5, 125.9 (q, J = 283.7 Hz),
1
3
C–F
1
5
25.4, 125.1, 124.1, 123.5, 122.7, 120.9, 120.3, 119.9, 116.0, 113.8, 111.7, 107.8, 77.3,
1
9
1.0 (q, JC–F = 28.2 Hz), 21.6; F NMR (376 MHz, CDCl ): δ -69.5; HRMS (ESI) m/z:
3
+
[
M+Na] calcd for C H F N O NaS 550.1024; Found 550.1024.
2
6
20
3
3
4
(R)-4-Fluoro-3-(1,1,1-trifluoro-3-nitro-2-(1-tosyl-1H-indol-3-yl)propan-2-yl)-1H-indole
(
3ba). With petroleum ether/EtOAc (2/1) as eluent; white solid (74.8 mg, 69%); mp:
o
1
13.0‒114.6 C. The enantiomeric excess was determined on a Daicel Chiralpak IC column
with n-hexane/2-propanol (85/15) and flow rate 1.0 mL/min and detected at a UV
wavelength of 254 nm. Retention times: 6.6 min (major), 7.5 min (minor), 88% ee. [α]D20
=
1
+28 (c 0.24, CH Cl ). H NMR (400 MHz, CDCl ): δ 8.56 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H),
2
2
3
7
1
1
.85 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.29‒7.27 (m, 3H), 7.24‒7.17 (m, 2H), 7.01 (dd, J =
.8, 8.7 Hz, 1H), 6.88 (t, J = 7.6 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.74 (s, 1H), 5.49 (d, J =
1
3
1
1.4 Hz, 1H), 5.42 (d, J = 11.4 Hz, 1H), 2.33 (s, 3H); C{ H} NMR (100 MHz, CDCl ): δ
3
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55.3 (d, JC–F = 244.0 Hz), 145.4, 139.0 (d, JC–F = 10.6 Hz), 135.1, 134.6, 130.0, 128.5,
26.9, 126.5, 126.1 (q, JC–F = 284.3 Hz), 125.4, 124.9, 123.6 (d, JC–F = 8.4 Hz), 123.5,
21.2, 117.6, 114.4 (d, JC–F = 19.2 Hz), 113.6, 108.2 (d, JC–F = 3.5 Hz), 106.8 (d, JC–F = 3.4
0
1
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9
Hz), 106.1 (d, JC–F = 22.1 Hz), 78.3 (d, JC–F = 10.2 Hz), 51.2 (q, JC–F = 28.1 Hz), 21.6; F
+
NMR (376 MHz, CDCl ): δ -68.6, -114.1; HRMS (ESI) m/z: [M+Na] calcd for
3
C H F N O NaS 568.0930; Found 568.0928.
2
6
19
4
3
4
(R)-5-Fluoro-3-(1,1,1-trifluoro-3-nitro-2-(1-tosyl-1H-indol-3-yl)propan-2-yl)-1H-indole
(3ca). With petroleum ether/EtOAc (2/1) as eluent; white solid (75.7 mg, 69%); mp:
o
103.6‒105.8 C. The enantiomeric excess was determined on a Daicel Chiralpak IC column
with n-hexane/2-propanol (85/15) and flow rate 1.0 mL/min and detected at a UV
wavelength of 254 nm. Retention times: 6.9 min (major), 7.9 min (minor), 91% ee. [α]D20
=
1
+
4 (c 0.35, CH Cl ). H NMR (400 MHz, CDCl ): δ 8.53 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H),
2
2
3
7
.86 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 2.5 Hz, 1H), 7.27 (d, J = 8.2 Hz, 2H),
7.24–7.17 (m, 2H), 6.89–6.85 (m, 1H), 6.82–6.75 (m, 2H), 6.24 (dd, J = 2.1, 10.1 Hz, 1H),
1
3
1
5
.47 (d, J = 11.4 Hz, 1H), 5.39 (d, J = 11.4 Hz, 1H), 2.34 (s, 3H); C{ H} NMR (100 MHz,
CDCl ): δ 157.6 (d, J = 234.5 Hz), 145.9, 135.1, 134.5, 132.7, 130.3, 128.7, 126.7, 126.6,
3
C–F
1
25.9 (d, JC–F = 10.2 Hz), 125.8 (q, JC–F = 283.9 Hz), 125.6, 125.2, 123.5, 120.8, 115.3,
13.9, 112.5 (d, JC–F = 9.7 Hz), 111.5 (d, JC–F = 26.3 Hz), 107.9 (d, JC–F = 4.7 Hz), 104.9 (d,
1
1
9
JC–F = 24.9 Hz), 77.2, 50.9 (q, JC–F = 28.3 Hz), 21.6; F NMR (376 MHz, CDCl3): δ -69.4,
-
122.1; HRMS (ESI) m/z: [M+Na]+ calcd for C H F N O NaS 568.0930; Found
26 19 4 3 4
5
68.0929.
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(
R)-5-Chloro-3-(1,1,1-trifluoro-3-nitro-2-(1-tosyl-1H-indol-3-yl)propan-2-yl)-1H-indole
(
3da). With petroleum ether/EtOAc (2/1) as eluent; white solid (98.2 mg, 87%); mp:
o
1
07.6‒108.4 C. The enantiomeric excess was determined on a Daicel Chiralpak IC column
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
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
with n-hexane/2-propanol (95/5) and flow rate 1.0 mL/min and detected at a UV
wavelength of 254 nm. Retention times: 30.3 min (major), 35.9 min (minor), 93% ee. [α]D20
1
=
+105 (c 0.32, CH Cl ). H NMR (400 MHz, CDCl ): δ 8.56 (s, 1H), 7.91 (d, J = 8.4 Hz,
2
2
3
1
H), 7.67 (d, J = 8.3 Hz, 2H), 7.55 (s, 1H), 7.27‒7.17 (m, 4H), 7.11 (d, J = 8.1 Hz, 1H),
7
.07‒7.02 (m, 1H), 6.97‒6.92 (m, 2H), 6.52 (dd, J = 7.6, 12.1 Hz, 1H), 5.71‒5.62 (m, 2H),
2.38 (s, 3H); 13C{ H} NMR (100 MHz, CDCl ): δ 145.7, 135.0, 134.62, 134.56, 130.4,
1
3
1
1
28.5, 126.8, 126.4, 126.0, 125.8 (q, JC–F = 284.0 Hz), 125.7, 125.2, 123.5, 123.3, 120.9,
19
19.3, 115.1, 113.7, 112.9, 107.6, 77.2, 51.0 (q, JC–F = 28.3 Hz), 21.6; F NMR (376 MHz,
+
CDCl ): δ -69.3; HRMS (ESI) m/z: [M+Na] calcd for C H ClF N O NaS 584.0635;
3
26 19
3
3
4
Found 584.0634.
(R)-5-Bromo-3-(1,1,1-trifluoro-3-nitro-2-(1-tosyl-1H-indol-3-yl)propan-2-yl)-1H-indole
(
3ea). With petroleum ether/EtOAc (2/1) as eluent; white solid (90.7 mg, 75%); mp:
o
1
06.7‒108.2 C. The enantiomeric excess was determined on a Daicel Chiralpak IC column
with n-hexane/2-propanol (90/10) and flow rate 1.0 mL/min and detected at a UV
wavelength of 254 nm. Retention times: 10.4 min (major), 12.9 min (minor), 92% ee. [α]D20
1
= +26 (c 0.28, CH Cl ). H NMR (400 MHz, CDCl ): δ 8.47 (s, 1H), 7.94 (d, J = 8.4 Hz,
2
2
3
1
1
1
H), 7.83 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.31‒7.29 (m, 3H), 7.23‒7.16 (m, 3H), 6.98 (s,
H), 6.93‒6.89 (m, 1H), 6.81 (d, J = 8.1 Hz, 1H), 5.51 (d, J = 11.5 Hz, 1H), 5.43 (d, J =
1
3
1
1.5 Hz, 1H), 2.35 (s, 3H); C{ H} NMR (100 MHz, CDCl ): δ 145.6, 134.94, 134.89,
3
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34.6, 130.4, 128.4, 127.0, 126.8, 126.5, 125.9, 125.74 (q, JC–F = 284.0 Hz), 125.69, 125.2,
23.4, 122.4, 120.9, 115.0, 113.8, 113.7, 113.2, 107.6, 77.1, 51.0 (q, JC–F = 28.1 Hz), 21.7;
1
19
+
F NMR (376 MHz, CDCl ): δ -69.2; HRMS (ESI) m/z: [M+Na] calcd for
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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7
8
9
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C H BrF N O NaS 628.0129; Found 628.0128.
2
6
19
3
3
4
(R)-5-Methyl-3-(1,1,1-trifluoro-3-nitro-2-(1-tosyl-1H-indol-3-yl)propan-2-yl)-1H-indole
(3fa). With petroleum ether/EtOAc (2/1) as eluent; white solid (103.2 mg, 95%); mp:
o
1
12.2‒113.6 C. The enantiomeric excess was determined on a Daicel Chiralpak IC column
with n-hexane/2-propanol (92/8) and flow rate 1.0 mL/min and detected at a UV
wavelength of 254 nm. Retention times: 15.4 min (major), 19.4 min (minor), 90% ee. [α]D20
1
=
+28 (c 0.21, CH Cl ). H NMR (400 MHz, CDCl ): δ 8.26 (s, 1H), 7.95 (d, J = 8.4 Hz,
2
2
3
1
H), 7.86 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.27‒7.24 (m, 2H), 7.21‒7.12 (m, 3H),
.92‒6.85 (m, 2H), 6.79 (d, J = 8.1 Hz, 1H), 6.65 (s, 1H), 5.59 (d, J = 11.5 Hz, 1H), 5.39 (d,
6
13
1
J = 11.4 Hz, 1H), 2.33 (s, 3H), 2.07 (s, 3H); C{ H} NMR (100 MHz, CDCl ): δ 145.5,
3
135.0, 134.9, 134.6, 130.1, 129.6, 128.8, 126.9, 126.3, 125.9 (q, JC–F = 284.0 Hz), 125.5,
1
2
25.0, 124.6, 124.5, 123.4, 121.1, 119.5, 115.8, 113.7, 111.3, 107.3, 77.2, 51.2 (q, JC–F
=
19
+
8.3 Hz), 21.6, 21.5; F NMR (376 MHz, CDCl ): δ -69.3; HRMS (ESI) m/z: [M+Na]
3
calcd for C H F N O NaS 564.1181; Found 564.1181.
27 22
3
3
4
(R)-5-Methoxy-3-(1,1,1-trifluoro-3-nitro-2-(1-tosyl-1H-indol-3-yl)propan-2-yl)-1H-indole
(3ga). With petroleum ether/EtOAc (2/1) as eluent; white solid (104.8 mg, 94%); mp:
o
1
06.1‒108.2 C. The enantiomeric excess was determined on a Daicel Chiralpak IC column
with n-hexane/2-propanol (88/12) and flow rate 1.0 mL/min and detected at a UV
wavelength of 254 nm. Retention times: 11.1 min (major), 12.8 min (minor), 89% ee. [α]D20
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8
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1
=
+45 (c 0.28, CH Cl ). H NMR (400 MHz, CDCl ): δ 8.35 (s, 1H), 7.94 (d, J = 8.4 Hz,
2 2 3
1
H), 7.90 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.3 Hz, 2H), 7.21‒7.16 (m, 3H),
6
.88‒6.84 (m, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.72 (dd, J = 2.4, 8.9 Hz, 1H), 6.19 (s, 1H),
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
1
3
1
5.52 (d, J = 11.4 Hz, 1H), 5.37 (d, J = 11.4 Hz, 1H), 3.25 (s, 3H), 2.34 (s, 3H); C{ H}
NMR (100 MHz, CDCl ): δ 154.1, 145.5, 134.9, 134.8, 131.3, 130.2, 128.8, 127.0, 126.3,
3
1
26.0, 125.9 (q, JC–F = 283.8 Hz), 125.1, 124.6, 123.4, 121.1, 115.4, 113.5, 113.0, 112.3,
1
9
1
07.4, 102.0, 77.3, 55.3, 51.0 (q, JC–F = 28.3 Hz), 21.6; F NMR (376 MHz, CDCl ): δ
3
+
-
69.5; HRMS (ESI) m/z: [M+Na] calcd for C H F N O NaS 580.1130; Found 580.1130.
2
7
22
3
3
5
(R)-6-Chloro-3-(1,1,1-trifluoro-3-nitro-2-(1-tosyl-1H-indol-3-yl)propan-2-yl)-1H-indole
(
3ha). With petroleum ether/EtOAc (2/1) as eluent; white solid (65.2 mg, 58%); mp:
o
1
11.5‒113.4 C. The enantiomeric excess was determined on a Daicel Chiralpak IC column
with n-hexane/2-propanol (85/15) and flow rate 1.0 mL/min and detected at a UV
wavelength of 254 nm. Retention times: 6.7 min (major), 7.6 min (minor), 83% ee. [α]D20
=
1
-4 (c 0.23, CH Cl ). H NMR (400 MHz, CDCl ): δ 8.46 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H),
2
2
3
7
.87 (s, 1H), 7.78 (d, J = 8.1 Hz, 2H), 7.32‒7.25 (m, 4H), 7.20 (t, J = 7.8 Hz, 1H), 6.86 (t, J
7.7 Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H), 6.48 (d, J = 8.9 Hz, 1H), 6.40 (d, J = 8.7 Hz, 1H),
=
1
3
1
5
.48 (d, J = 11.4 Hz, 1H), 5.37 (d, J = 11.4 Hz, 1H), 2.39 (s, 3H); C{ H} NMR (100 MHz,
CDCl ): δ 145.6, 136.5, 135.1, 134.7, 130.1, 128.8, 128.6, 126.9, 126.5, 125.7 (q, J
=
C–F
3
284.0 Hz), 125.3, 124.5, 124.1, 123.6, 121.2, 120.8, 120.7, 115.7, 113.9, 111.5, 108.2, 77.4,
1
9
5
0.8 (q, JC–F = 28.3 Hz), 21.6; F NMR (376 MHz, CDCl ): δ -69.6; HRMS (ESI) m/z:
3
+
[
M+Na] calcd for C H ClF N O NaS 584.0635; Found 584.0634.
2
6
19
3
3
4
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(
R)-6-Methyl-3-(1,1,1-trifluoro-3-nitro-2-(1-tosyl-1H-indol-3-yl)propan-2-yl)-1H-indole
(
3ia). With petroleum ether/EtOAc (2/1) as eluent; white solid (99.0 mg, 91%); mp:
o
1
13.2‒114.5 C. The enantiomeric excess was determined on a Daicel Chiralpak IC column
0
1
2
3
4
5
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7
8
9
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1
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
with n-hexane/2-propanol (87/13) and flow rate 1.0 mL/min and detected at a UV
wavelength of 254 nm. Retention times: 9.6 min (major), 11.5 min (minor), 90% ee. [α]D20
1
=
-6 (c 0.32, CH Cl ). H NMR (400 MHz, CDCl ): δ 8.23 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H),
2
2
3
7
1
.86 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 7.21‒7.17 (m, 2H), 7.11 (s,
H), 6.89‒6.85 (m, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 6.46 (d, J = 8.4
Hz, 1H), 5.53 (d, J = 11.4 Hz, 1H), 5.38 (d, J = 11.4 Hz, 1H), 2.39 (s, 3H), 2.32 (s, 3H);
1
3
1
C{ H} NMR (100 MHz, CDCl ): δ 145.3, 136.6, 135.1, 134.8, 132.6, 130.1, 128.9, 126.9,
3
1
26.5, 125.8 (q, JC–F = 283.8 Hz), 125.0, 123.4, 123.2, 122.3, 120.9, 119.6, 116.0, 113.9,
1
9
1
11.4, 107.8, 77.3, 51.0 (q, JC–F = 28.1 Hz), 21.6, 21.5; F NMR (376 MHz, CDCl ): δ
3
+
-
69.5; HRMS (ESI) m/z: [M+Na] calcd for C H F N O NaS 564.1181; Found 564.1179.
2
7
22
3
3
4
(R)-6-Methoxy-3-(1,1,1-trifluoro-3-nitro-2-(1-tosyl-1H-indol-3-yl)propan-2-yl)-1H-indole
(
3ja). With petroleum ether/EtOAc (2/1) as eluent; white solid (100.2 mg, 90%); mp:
o
2
36.4‒238.6 C. The enantiomeric excess was determined on a Daicel Chiralpak IC column
with n-hexane/2-propanol (85/15) and flow rate 1.0 mL/min and detected at a UV
wavelength of 254 nm. Retention times: 10.0 min (major), 12.0 min (minor), 88% ee. [α]D20
1
= -12 (c 0.82, CH Cl ). H NMR (400 MHz, DMSO-d ): δ 11.28 (s, 1H), 7.95–7.92 (m, 4H),
2
2
6
7
.53 (s, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.21 (t, J = 7.6 Hz, 1H), 6.88 (t, J = 7.5 Hz, 1H), 6.77
(
d, J = 2.2 Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H), 6.15 (d, J = 8.8 Hz, 1H), 5.96 (dd, J = 2.2, 8.8
Hz, 1H), 5.86 (d, J = 12.3 Hz, 1H), 5.79 (d, J = 12.3 Hz, 1H), 3.64 (s, 3H), 2.39 (s, 3H);
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1
C{ H} NMR (100 MHz, DMSO-d ): δ 155.1, 145.7, 137.0, 134.3, 133.8, 130.3, 128.8,
6
1
1
26.8 126.0 (q, JC–F = 283.5 Hz), 125.4, 125.0, 123.5, 123.3, 120.8, 119.4, 116.7, 113.3,
09.3, 105.8, 94.4, 77.2, 54.9, 49.8 (q, JC–F = 27.6 Hz), 21.0; 19F NMR (376 MHz,
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
+
DMSO-d ): δ -68.9; HRMS (ESI) m/z: [M+Na] calcd for C H F N O NaS 580.1130;
6
27 22
3
3
5
Found 580.1131.
(
R)-7-Methyl-3-(1,1,1-trifluoro-3-nitro-2-(1-tosyl-1H-indol-3-yl)propan-2-yl)-1H-indole
(3ka). With petroleum ether/EtOAc (2/1) as eluent; white solid (92.2 mg, 85%); mp:
o
1
13.6‒115.3 C. The enantiomeric excess was determined on a Daicel Chiralpak IC column
with n-hexane/2-propanol (90/10) and flow rate 1.0 mL/min and detected at a UV
wavelength of 254 nm. Retention times: 12.6 min (major), 14.6 min (minor), 81% ee. [α]D20
1
=
-1 (c 0.31, CH Cl ). H NMR (400 MHz, CDCl ): δ 8.31 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H),
2
2
3
7
.85 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.28‒7.16 (m, 4H), 6.88‒6.85 (m, 2H), 6.78 (d, J =
.1 Hz, 1H), 6.59‒6.53 (m, 2H), 5.55 (d, J = 11.4 Hz, 1H), 5.40 (d, J = 11.4 Hz, 1H), 2.41
8
1
3
1
(s, 3H), 2.37 (s, 3H); C{ H} NMR (100 MHz, CDCl ): δ 145.4, 135.8, 135.1, 134.8, 130.1,
3
1
28.9, 126.9, 126.5, 125.9 (q, JC–F = 283.8 Hz), 125.1, 124.9, 123.9, 123.5, 123.2, 121.0,
20.7, 120.5, 117.7, 116.0, 113.8, 108.3, 77.2, 51.1 (q, JC–F = 28.1 Hz), 21.6, 16.5; 19
1
F
+
NMR (376 MHz, CDCl ): δ -69.4; HRMS (ESI) m/z: [M+Na] calcd for C H F N O NaS
3
27 22
3
3
4
5
64.1181; Found 564.1180.
(R)-7-Methoxy-3-(1,1,1-trifluoro-3-nitro-2-(1-tosyl-1H-indol-3-yl)propan-2-yl)-1H-indole
(3la). With petroleum ether/EtOAc (2/1) as eluent; white solid (70.3 mg, 63%); mp:
o
1
09.9‒111.9 C. The enantiomeric excess was determined on a Daicel Chiralpak IC column
with n-hexane/2-propanol (92/8) and flow rate 1.0 mL/min and detected at a UV
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6
wavelength of 254 nm. Retention times: 26.1 min (major), 29.8 min (minor), 93% ee. [α]D20
1
=
+6 (c 0.20, CH Cl ). H NMR (400 MHz, CDCl ): δ 8.61 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H),
2
2
3
7
.85 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H), 7.21‒7.16 (m, 2H),
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
6.88‒6.85 (m, 1H), 6.77 (d, J = 8.1 Hz, 1H), 6.57 (t, J = 7.8 Hz, 1H), 6.50 (d, J = 7.6 Hz,
1
3
1
1
H), 6.27 (d, J = 8.0 Hz, 1H), 5.54 (d, J = 11.4 Hz, 1H), 5.38 (d, J = 11.4 Hz, 1H), 3.89 (s,
13
1
H), 2.37 (s, 3H); C{ H} NMR (100 MHz, CDCl ): δ 146.1, 145.3, 135.1, 134.8, 130.0,
3
28.9, 127.0, 126.9, 126.6, 126.5, 125.9 (q, JC–F = 283.9 Hz), 125.0, 123.6, 123.4, 121.0,
20.8, 116.0, 113.8, 112.5, 108.4, 102.3, 77.2, 55.3, 51.0 (q, JC–F = 28.3 Hz), 21.6; 19
F
+
NMR (376 MHz, CDCl ): δ -69.5; HRMS (ESI) m/z: [M+Na] calcd for C H F N O NaS
3
27 22
3
3
5
5
80.1130; Found 580.1128.
(R)-Tert-butyl
3-(1,1,1-trifluoro-2-(1H-indol-3-yl)-3-nitropropan-2-yl)-1H-indole-1-
carboxylate (3aa′). With petroleum ether/EtOAc (3/1) as eluent; white solid (69.7 mg,
o
7
4%); mp: 95.6‒96.9 C. The enantiomeric excess was determined on a Daicel Chiralpak
IC column with n-hexane/2-propanol (96/4) and flow rate 1.0 mL/min and detected at a UV
wavelength of 254 nm. Retention times: 10.8 min (major), 12.1 min (minor), 91% ee. [α]D20
1
=
-9 (c 0.33, CH Cl ). H NMR (400 MHz, CDCl ): δ 8.36 (s, 1H), 8.15 (d, J = 8.2 Hz, 1H),
2
2
3
7
.87 (s, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.25‒7.24 (m, 1H), 7.21‒7.17 (m, 1H), 7.13‒7.09 (m,
H), 7.05 (d, J = 8.2 Hz, 1H), 6.89‒6.84 (m, 2H), 6.79 (d, J = 8.0 Hz, 1H), 5.58 (d, J = 11.3
1
1
3
1
Hz, 1H), 5.48 (d, J = 11.3 Hz, 1H), 1.71 (s, 9H); C{ H} NMR (100 MHz, CDCl ): δ 149.4,
3
1
36.3, 135.3, 128.5, 126.0 (q, JC–F = 285.6 Hz), 125.5, 125.4, 124.7, 124.6, 122.72, 122.68,
20.7, 120.5, 120.1, 115.3, 113.9, 111.6, 108.2, 84.8, 77.4, 51.1 (q, JC–F = 28.2 Hz), 28.2;
1
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F NMR (376 MHz, CDCl ): δ -69.3; HRMS (ESI) m/z: [M+Na]+ calcd for
3
C H F N O Na 496.1460; Found 496.1458.
24 22
3
3
4
(
R)-Tert-butyl
3-(1,1,1-trifluoro-2-(5-methyl-1H-indol-3-yl)-3-nitropropan-2-yl)-1H-
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
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1
2
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4
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0
1
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7
8
9
0
indole-1-carboxylate (3fa′). With petroleum ether/EtOAc (2/1) as eluent; white solid (85.9
o
mg, 88%); mp: 96.1‒98.6 C. The enantiomeric excess was determined on a Daicel
Chiralcel OD-H column with n-hexane/2-propanol (96/4) and flow rate 1.0 mL/min and
detected at a UV wavelength of 254 nm. Retention times: 32.6 min (major), 39.5 min
minor), 94% ee. [α]D20 = +3 (c 0.27, CH Cl ). H NMR (400 MHz, CDCl ): δ 8.23 (s, 1H),
1
(
2
2
3
8.17 (d, J = 8.2 Hz, 1H), 7.84 (s, 1H), 7.23‒7.19 (m, 2H), 7.10 (s, 1H), 6.97‒6.85 (m, 4H),
1
3
1
5
.65 (d, J = 11.4 Hz, 1H), 5.48 (d, J = 11.4 Hz, 1H), 2.25 (s, 3H), 1.71 (s, 9H); C{ H}
NMR (100 MHz, CDCl ): δ 149.5, 135.4, 134.7, 129.7, 128.5, 126.1 (q, J = 283.8 Hz),
3
C–F
1
25.6, 125.3, 124.7, 124.4, 122.7, 120.9, 119.7, 115.3, 114.0, 111.4, 107.6, 84.8, 77.2, 51.3
19
(q, JC–F = 28.1 Hz), 28.2, 21.7; F NMR (376 MHz, CDCl ): δ -69.1; HRMS (ESI) m/z:
3
+
[M+Na] calcd for C H F N O Na 510.1617; Found 510.1616.
2
5
24
3
3
4
(
R)-Tert-butyl
3-(1,1,1-trifluoro-2-(5-methoxy-1H-indol-3-yl)-3-nitropropan-2-yl)-1H-
indole-1-carboxylate (3ga′). With petroleum ether/EtOAc (2/1) as eluent; white solid (86.5
o
mg, 86%); mp: 95.8‒97.6 C. The enantiomeric excess was determined on a Daicel
Chiralpak IA column with n-hexane/2-propanol (90/10) and flow rate 1.0 mL/min and
detected at a UV wavelength of 254 nm. Retention times: 13.7 min (major), 16.3 min
minor), 93% ee. [α]D20 = -14 (c 0.27, CH Cl ). H NMR (400 MHz, CDCl ): δ 8.33 (s, 1H),
1
(
2
2
3
8
.15 (d, J = 8.4 Hz, 1H), 7.88 (s, 1H), 7.23‒7.17 (m, 3H), 6.89‒6.81 (m, 2H), 6.76 (dd, J =
.4, 8.8 Hz, 1H), 6.43 (d, J = 2.0 Hz, 1H), 5.55 (d, J = 11.3 Hz, 1H), 5.46 (d, J = 11.3 Hz,
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5
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13
1
1
1
1
H), 3.50 (s, 3H), 1.70 (s, 9H); C{ H} NMR (100 MHz, CDCl ): δ 154.1, 149.4, 135.4,
3
31.5, 128.6, 126.2, 126.1 (q, JC–F = 283.6 Hz), 125.5, 125.2, 124.8, 122.8, 120.7, 115.3,
19
13.8, 112.4, 112.2, 107.7, 102.8, 84.8, 77.3, 55.7, 51.0 (q, JC–F = 28.3 Hz), 28.2; F NMR
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
+
(376 MHz, CDCl ): δ -69.3; HRMS (ESI) m/z: [M+Na] calcd for C H F N O Na
3
25 24
3
3
5
5
26.1566; Found 526.1564.
(
R)-Tert-butyl
3-(1,1,1-trifluoro-2-(6-methyl-1H-indol-3-yl)-3-nitropropan-2-yl)-1H-
indole-1-carboxylate (3ia′). With petroleum ether/EtOAc (2/1) as eluent; white solid (77.9
o
mg, 80%); mp: 108.3–109.8 C. The enantiomeric excess was determined on a Daicel
Chiralpak IC column with n-hexane/2-propanol (96/4) and flow rate 1.0 mL/min and
detected at a UV wavelength of 254 nm. Retention times: 11.0 min (major), 12.9 min
minor), 93% ee. [α]D20 = -8 (c 0.26, CH Cl ). H NMR (400 MHz, CDCl ): δ 8.23 (s, 1H),
1
(
2 2 3
8
6
.15 (d, J = 8.1 Hz, 1H), 7.86 (s, 1H), 7.23‒7.10 (m, 3H), 6.93 (d, J = 8.3 Hz, 1H),
.89‒6.85 (m, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.70 (d, J = 9.3 Hz, 1H), 5.57 (d, J = 11.3 Hz,
1H), 5.46 (d, J = 11.3 Hz, 1H), 2.34 (s, 3H), 1.71 (s, 9H); 13C{ H} NMR (100 MHz,
CDCl ): δ 149.5, 136.7, 135.3, 132.6, 128.6, 126.0 (q, J = 283.4 Hz), 125.3, 124.7, 123.9,
1
3
C–F
1
2
23.4, 122.7, 122.3, 120.7, 119.7, 115.3, 114.0, 111.5, 108.1, 84.8, 77.4, 51.1 (q, JC–F
=
1
9
+
8.2 Hz), 28.2, 21.5; F NMR (376 MHz, CDCl ): δ -69.3; HRMS (ESI) m/z: [M+Na]
3
calcd for C H F N O Na 510.1617; Found 510.1617.
2
5
24
3
3
4
(R)-Tert-butyl
3-(1,1,1-trifluoro-2-(6-methoxy-1H-indol-3-yl)-3-nitropropan-2-yl)-1H-
indole-1-carboxylate (3ja′). With petroleum ether/EtOAc (2/1) as eluent; white solid (82.4
o
mg, 82%); mp: 106.1‒108.5 C. The enantiomeric excess was determined on a Daicel
Chiralpak IC column with n-hexane/2-propanol (94/6) and flow rate 1.0 mL/min and
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detected at a UV wavelength of 254 nm. Retention times: 12.8 min (major), 14.3 min
1
(
minor), 91% ee. [α]D20 = -20 (c 0.27, CH Cl ). H NMR (400 MHz, CDCl ): δ 8.25 (s, 1H),
2
2
3
8
.15(d, J = 8.1 Hz, 1H), 7.86 (s, 1H), 7.20 (t, J = 8.2 Hz, 1H), 7.15 (d, J = 2.2 Hz, 1H),
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
6.89–6.85 (m, 2H), 6.82‒6.78 (m, 2H), 6.52 (dd, J = 2.3, 8.9 Hz, 1H), 5.53 (d, J = 11.3 Hz,
1
1
H), 5.46 (d, J = 11.3 Hz, 1H), 3.73 (s, 3H), 1.72 (s, 9H); 13C{ H} NMR (100 MHz,
CDCl ): δ 156.5, 149.4, 137.1, 135.3, 128.6, 126.0 (q, J = 283.5 Hz), 125.3, 124.7, 123.1,
3
C–F
1
2
22.7, 120.8, 120.7, 119.9, 115.3, 113.9, 110.6, 108.3, 94.6, 84.8, 77.5, 55.4, 51.0 (q, JC–F
=
19
+
8.2 Hz), 28.2; F NMR (376 MHz, CDCl ): δ -69.4; HRMS (ESI) m/z: [M+Na] calcd for
3
C H F N O Na 526.1566; Found 526.1566.
2
5
24
3
3
5
(R)-Tert-butyl
3-(1,1,1-trifluoro-2-(7-methyl-1H-indol-3-yl)-3-nitropropan-2-yl)-1H-
indole-1-carboxylate (3ka′). With petroleum ether/EtOAc (2/1) as eluent; white solid (73.5
o
mg, 75%); mp: 110.7‒112.0 C. The enantiomeric excess was determined on a Daicel
Chiralpak IC column with n-hexane/2-propanol (95/5) and flow rate 1.0 mL/min and
detected at a UV wavelength of 254 nm. Retention times: 7.7 min (major), 8.9 min (minor),
1
8
4% ee. [α]D20 = -3 (c 0.36, CH Cl ). H NMR (400 MHz, CDCl ): δ 8.27 (s, 1H), 8.15 (d, J
2
2
3
=
8.0 Hz, 1H), 7.86 (s, 1H), 7.25‒7.18 (m, 2H), 6.93‒6.86 (m, 3H), 6.82–6.79 (m, 2H), 5.60
1
3
1
(
d, J = 11.3 Hz, 1H), 5.49 (d, J = 11.3 Hz, 1H), 2.45 (s, 3H), 1.72 (s, 9H); C{ H} NMR
(
100 MHz, CDCl ): δ 149.4, 135.8, 135.3, 128.5, 126.0 (q, J = 283.6 Hz), 125.3, 125.0,
3
C–F
124.6, 124.3, 123.2, 122.7, 120.7, 120.6, 117.9, 115.3, 113.9, 108.7, 84.7, 77.3, 51.1 (q,
JC–F = 28.1 Hz), 28.2, 16.5; 19F NMR (376 MHz, CDCl ): δ -69.3; HRMS (ESI) m/z:
3
+
[
M+Na] calcd for C H F N O Na 510.1617; Found 510.1616.
2
5
24
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(
R)-Tert-butyl
3-(1,1,1-trifluoro-2-(7-methoxy-1H-indol-3-yl)-3-nitropropan-2-yl)-1H-
indole-1-carboxylate (3la′). With petroleum ether/EtOAc (2/1) as eluent; white solid (40.9
o
mg, 41%); mp: 107.6‒109.4 C. The enantiomeric excess was determined on a Daicel
0
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Chiralpak IA column with n-hexane/2-propanol (97/3) and flow rate 1.0 mL/min and
detected at a UV wavelength of 254 nm. Retention times: 38.2 min (minor), 40.4 min
1
(
major), 93% ee. [α]D20 = -1 (c 0.25, CH Cl ). H NMR (400 MHz, CDCl ): δ 8.58 (s, 1H),
2 2 3
8
2
.15 (d, J = 8.1 Hz, 1H), 7.85 (s, 1H), 7.25‒7.18 (m, 2H), 6.90‒6.86 (m, 1H), 6.82‒6.78 (m,
H), 6.65 (d, J = 8.2 Hz, 1H), 6.56 (d, J = 7.7 Hz, 1H), 5.59 (d, J = 11.3 Hz, 1H), 5.48 (d, J
= 11.3 Hz, 1H), 3.91 (s, 3H), 1.72 (s, 9H); 13C{ H} NMR (100 MHz, CDCl ): δ 149.4,
1
3
1
1
2
46.1, 135.3, 128.5, 127.1, 126.7, 126.0 (q, JC–F = 283.5 Hz), 125.3, 124.7, 124.1, 122.7,
20.9, 120.8, 115.3, 113.9, 112.7, 108.8, 102.3, 84.7, 77.4, 55.3, 51.1 (q, JC–F = 28.2 Hz),
8.2; 19F NMR (376 MHz, CDCl ): δ -69.3; HRMS (ESI) m/z: [M+Na] calcd for
+
3
C H F N O Na 526.1566; Found 526.1567.
2
5
24
3
3
5
(R)-4-Fluoro-1-tosyl-3-(1,1,1-trifluoro-2-(1H-indol-3-yl)-3-nitropropan-2-yl)-1H-indole
(
3ab). With petroleum ether/EtOAc (2/1) as eluent; white solid (72.5 mg, 66%); mp:
o
2
07.5‒209.8 C. The enantiomeric excess was determined on a Daicel Chiralpak IC column
with n-hexane/2-propanol (95/5) and flow rate 1.0 mL/min and detected at a UV
wavelength of 254 nm. Retention times: 15.0 min (major), 17.4 min (minor), 93% ee. [α]D20
1
= -180 (c 0.76, CH Cl ). H NMR (400 MHz, CDCl ): δ 8.32 (s, 1H), 7.86–8.81 (m, 2H),
2
2
3
7
.75 (d, J = 8.4 Hz, 2H), 7.32–7.28 (m, 3H), 7.21–7.15 (m, 1H), 7.11–7.07 (m, 1H), 7.01 (d,
J = 2.2 Hz, 1H), 6.81–6.64 (m, 3H), 5.71 (d, J = 12.0 Hz, 1H), 5.50 (dd, J = 4.4, 12.0 Hz,
1
3
1
1
H), 2.38 (s, 3H); C{ H} NMR (100 MHz, CDCl ): δ 155.0 (d, J = 246.7 Hz), 145.7,
3
C–F
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37.2 (d, JC–F = 9.1 Hz), 136.2, 134.5, 130.2, 127.1 (d, JC–F = 3.2 Hz), 127.0, 126.23 (d,
JC–F = 8.3 Hz), 126.15 (q, JC–F = 284.0 Hz), 125.0, 123.9, 122.5, 120.4, 119.9, 117.7 (d, JC–F
=
18.9 Hz), 114.8 (d, JC–F = 4.2 Hz), 111.7, 110.2, 110.0 (d, JC–F = 17.6 Hz), 109.5, 77.8 (d,
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0
JC–F = 10.3 Hz), 51.0 (q, JC–F = 28.1 Hz), 21.7; 19F NMR (376 MHz, CDCl ): δ -69.1,
3
-
112.2; HRMS (ESI) m/z: [M+Na]+ calcd for C H F N O NaS 568.0930; Found
26 19 4 3 4
5
68.0929.
R)-5-Fluoro-1-tosyl-3-(1,1,1-trifluoro-2-(1H-indol-3-yl)-3-nitropropan-2-yl)-1H-indole
(
(3ac). With petroleum ether/EtOAc (2/1) as eluent; white solid (73.7 mg, 68%); mp:
o
101.5‒103.7 C. The enantiomeric excess was determined on a Daicel Chiralpak IA column
with n-hexane/2-propanol (87/13) and flow rate 1.0 mL/min and detected at a UV
wavelength of 254 nm. Retention times: 25.8 min (minor), 28.3 min (major), 89% ee. [α] 20
D
1
=
+12 (c 0.74, CH Cl ). H NMR (400 MHz, CDCl ): δ 8.45 (s, 1H), 7.93–7.90 (m, 2H),
2
2
3
7
.77 (d, J = 8.3 Hz, 2H), 7.32–7.28 (m, 4H), 7.06 (t, J = 8.0 Hz, 1H), 6.90 (dt, J = 2.5, 8.9
Hz, 1H), 6.61–6.55 (m, 2H), 6.35 (dd, J = 2.2, 9.5 Hz, 1H), 5.50 (d, J = 11.4 Hz, 1H), 5.32
1
3
1
(d, J = 11.3 Hz, 1H), 2.38 (s, 3H); C{ H} NMR (100 MHz, CDCl ): δ 159.2 (d, J
=
3
C–F
2
39.0 Hz), 145.7, 136.2, 134.5, 131.5, 130.2, 130.1 (d, JC–F = 10.2 Hz), 128.0, 126.9, 125.8
(q, JC–F = 283.9 Hz), 125.3, 123.9, 122.8, 120.4, 119.7, 115.9, 114.9 (d, JC–F = 9.5 Hz),
1
13.5 (d, JC–F = 25.6 Hz), 111.8, 107.3, 106.7 (d, JC–F = 25.2 Hz), 77.2, 50.8 (q, JC–F = 28.3
1
9
+
Hz), 21.7; F NMR (376 MHz, CDCl ): δ -69.6, -118.3; HRMS (ESI) m/z: [M+Na] calcd
3
for C H F N O NaS 568.0930; Found 568.0932.
2
6
19
4
3
4
(R)-5-Bromo-1-tosyl-3-(1,1,1-trifluoro-2-(1H-indol-3-yl)-3-nitropropan-2-yl)-1H-indole
(3ae). With petroleum ether/EtOAc (2/1) as eluent; white solid (89.9 mg, 74%); mp:
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