Asymmetric Organocatalytic Synthesis of Bisindoles – Scope and Derivatizations

Article abstract of DOI:10.1002/ejoc.201701502

Starting from 3-vinylindoles and glyoxolate imines, we created a library of diverse 4,6-bis(1H-indole-3-yl)piperidine 2-carboxylates by using 10 mol-% of a chiral phosphoric acid. Utilising electron-withdrawing groups on the starting material during the r

Full text of DOI:10.1002/ejoc.201701502

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Title: Asymmetric organocatalytic synthesis of Bisindoles - Scope and
Derivatizations
Authors: Christina Retich and Stefan Bräse
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10.1002/ejoc.201701502
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Asymmetric organocatalytic synthesis of Bisindoles – Scope and
Derivatizations
Christina Retich,[a] and Stefan Bräse*[a, b]
Abstract: Starting from 3-vinylindoles and glyoxolate imines we
created library of diverse 4,6-bis(1H-indole-3-yl)piperidine
Due to the fact that 3-vinylindole can act as a diene in the
a
Diels-Alder reaction with various electrondeficient olefins[9] or can
[9a, 10]
2-carboxylates using 10 mol% of a chiral phosphoric acid. Utilising
electron withdrawing groups on the starting material during the
reaction led to the formation of Povarov-type structures, which
extended the previous library of molecules. Furthermore we could
demonstrate that consecutive reactions like reductions, cross
coupling reactions or click reactions on bisindoles are feasible.
be utilized in the synthesis of carbazoles,
it is a versatile
building block for the synthesis of heterocycles. In the last few
years, the first asymmetric organocatalytic reactions of
3-vinylindoles including thiourea-catalyzed reactions with
maleimides or indolones, were reported.[11] When reacted with
electron-rich arylamines the reactivity of 3-vinylindole can be that
of a dienophile, furnishing Povarov-type products.[12] Although
Ricci et al. could trap the intermediate which was
a
bisindole-piperidine-hybrid by an excess of 3-vinylindole
(5.00 equiv.), they focused mainly on the asymmetric Povarov
reaction.
Introduction
Bisindole alkaloids such as nortopsentins (1)[1] and dragmacidins
(2)[2] (Figure 1) are widely found in nature, exhibiting various
interesting biological activities. Many compounds of marine origin
bear two isolated indoles on one heterocycle. Nortopsentins and
their analogs exhibit antitumor,[1d, 3] antiproliferative, antifungal[4]
and antiplasmodial[5] activities. Besides, dragmacidins show
phosphatase inhibitory,[6] antiviral,[7] and antitumor[8] effects.
Recently we developed
a
powerful three-component,
enantioselective, and organocatalytic synthesis of 4,6-bis(1H-
indole-3-yl)piperidine 2-carboxylates (5) utilizing easily accessible
3-vinylindoles (3) and imino esters (4) and a chiral phosphoric
acid (Scheme 1).[13] The reaction proceeds within 1 h and
diastereosectively at room temperature, building three new bonds
and three new stereogenic centers in one step.
Scheme 1. Racemic synthesis of bisindole (rac)-5aa with imino ester 4a and
3-vinylindole 3a.
The mechanism of the bisindole formation is shown in Scheme 2.
After the first addition of one equivalent 3-vinylindole (3a) to the
imino ester 4a, the second molecule of 3a is able to attack the
stabilized intermediate. An intramolecular ring closure of 6 finally
yields (rac)-5aa as product. To proceed the reaction, a free NH
group on the indole moiety is necessary, as in previous studies
with N-methylated derivatives no product could be isolated.[13]
Figure 1. Structures of nortopsentins (1) and dragmacidins (2) represent
alkaloids which contain two isolated indole moieties.
[a]
[b]
C. Retich, Prof. Dr. S. Bräse
Karlsruhe Institute of Technology, Institute of Organic Chemistry
Fritz-Haber-Weg 6, 76131 Karlsruhe (Germany)
phone: +49 721 608 43218, fax: +49 721 608 48581
e-mail: braese@kit.edu
homepage: https://www.ioc.kit.edu/braese/
Prof. Dr. S. Bräse
Karlsruhe Institute of Technology, Institute of Toxicology and
Genetics
Hermann-von-Helmholtz-Platz 1
76344 Eggenstein-Leopoldshafen (Germany)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.2017xxxxx.
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Figure
2
shows the synthesized building blocks for the
multicomponent reaction.
Scheme 2. Mechanism for the formation of (rac)-5aa.
Figure 2. Synthesized heterocycles and their yields.
Based on our preliminary work we report the synthesis of several
bisindoles bearing new substitution patterns and heterocycles to
study the scope of the reaction. Furthermore we will perform
consecutive reactions on selected bisindoles.
Imino esters (Figure 3) were prepared according to an established
procedure.[18]
Results and Discussion
Starting material synthesis
3-Vinylindoles (3) and 3-vinylbenzothiophene (9) were
synthesized via Wittig reaction (Scheme 3).[11a]
Scheme 3. Synthesis of 3-vinylindoles (3) and 3-vinylbenzothiophene (9). a
methyltriphenylphophonium iodide, n-BuLi, THF, –50 °C
→ 0 °C; then
indole-3-carboxaldehyde (7)/bezothiophene-3-carboxaldehyde (8), NaHMDS,
THF, –30 °C → rt., 1-5 h, 34–95%.
3-Vinylbenzofuran (10) was synthesized in four steps starting with
benzofuran-3(2H)-one according to
a
literature known
procedure.[14] Another heterocycle which should be introduced
during the three-component reaction is 4-vinyl-1H-imidazole (11).
We obtained the compound after decarboxylation of urocanic acid
by distillation in vacuo.[15] 3-Vinyl-1H-indazole (12) was
synthesized out of 3-bromo-1H-indazole via Stille coupling.[16]
3-vinyl-1H-pyrrole (13) was obtained in five steps out of
commercially available pyrrole.[17]
Figure 3. Synthesized imino esters and their yields.
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In previous work it was envisioned that chiral thiourea catalysts,
Previous studies are confirmed by entries 1-7 (Table 1). At this
point the unsubstituted 3-vinylindole (3a) was used to perform the
reaction. In this case the highest yield was obtained with a chloro
substituted imino ester (4h) – but only for the racemic reaction
(entry 5). Continuously high yields were reported for the racemic
and asymmetric reaction for the fluoro substituted imino ester (4g)
cumulated for both diastereomers (entry 4). Surprisingly the
usage of a methyl substituted imino ester (4b) led to high yields
for the racemic as well as for the asymmetric reaction (entry 2).
For the entries 1–7 we could prove that the addition of the catalyst
increased the yield of the bisindoles.
The results for the reaction with 5-fluoro-3-vinyl-1H-indole (3e)
and 6-fluoro-3-vinyl-1H-indole (3f) are shown in entries 13–16
(Table 1). Thereby we can note high yields for every substitution
during the asymmetric reaction. The racemic reaction with a
methoxy substituted imino ester (4e) yielded 9.8% (entry 15) and
10% (entry 13). Both yields could be improved through an addition
of a phosphoric acid catalyst up to 64%.
would be able to interact strongly with an imine via H-bond
19]
catalysis.[11,
But employing these catalysts did not lead to
satisfying results. There was almost no enantioinduction
(7.5% ee) observed and the yields were mostly diminished
compared to those without applying any catalyst.[13] Therefore we
chose another widely used catalyst class in organic chemistry –
chiral phosphoric acids, also used by Ricci et al. in the
aforementioned paper.[12] Having found an efficient catalyst
(Figure 4) for the enantioselective reaction, we accomplished the
synthesis according to
comparable yields.[20]
a literature known procedure in
Furthermore,
7-methyl-3-vinyl-1H-indole
we
investigated
(3b)
the
(entries
reaction
8–10)
of
a
and
5-bromo-3-vinyl-1H-indole (3h) with the corresponding imino
esters (entries 24–27). The yields of the obtained bisindoles are
not as high as the previously reported yields. But it was important
to functionalize the products with functional groups like methoxy
(4e, entry 27) or ethynyl (4c, entry 8 and 26) to expand the
substrate spectrum.
Further functionalizations were accomplished while using
5-nitrile-3-vinyl-1H-indole (3c) and 4-nitro-3-vinyl-1H-indole (3d)
(entries 11, 12) as starting material. Conclusively the yields for the
asymmetric reaction were also higher than for the racemic one.
Entries 21 and 24 show significantly low yields during the
asymmetric synthesis while using 14(R). In these cases we used a
preparative TLC as purification method and could observe that
some derivatives were not stable throughout the purification
process via preparative TLC. Furthermore a long purification
process, as it is common for preparative TLC was unfortunately
not suitable for all of the bisindoles and led to lower yields. In
general we detected that methoxy substituted bisindoles 5de, 5ee,
5fe, 5ge, 5he do not lead to high yields and are not stable, even
while storing under inert atmosphere at –18 °C.
Furthermore it is interesting to mention, that there was no
successful reaction while using imino esters with a substitution
pattern on the R1 and R2 position – only imino ester 4k reacted to
the desired bisindole. In addition we tried to investigate further
derivatives of the bisindoles by changing the CO2Et-group to
CO2Bn, CO2Me or CF3 or using pyridine as a heterocyle instead
of the aromatic ring. Unfortunately none of the attempts was
successful.
Figure 4. Catalysts (R)-14 and (S)-14.
(Asymmetric) Reaction between 3-vinylindoles (3) and
glyoxalate imines (4)
The synthesis of various bisindole-derivatives was accomplished
by applying one equivalent of an imino ester and two equivalents
of 3-vinylindole. Table 1 shows the synthesized bisindoles in a
non-catalyzed racemic and also catalyzed asymmetric reaction
procedure. The yields in table 1 refer to the 2 diastereomers (F1
and F2) that could be isolated for some bisindoles.
Entries 17–23 (Table 1) show the results while using a chloro
substituted vinylindole (3g) during the reaction. Thereby a fluoro
substituted imino ester (4g) led to the highest yields, either in a
racemic or asymmetric reaction. In general, the yields are good
except of entry 19. We could only isolate 8.4% of the desired
product during the racemic reaction. However the addition of the
phosphoric acid as a catalyst (14) led to an increase of the yield
to 36% or rather 64%. Considering the results of entries 17–23
we can record that electron withdrawing groups on R2 lead to
higher yields.
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Table 1. Racemic and asymmetric synthesis of bisindole derivatives.
Entry
R2/2’
R3
R4
R5
R6
R7
product
Yield[a] [%]
Yield[a] [%]
cat-(S)-14
Yield[a] [%]
cat-(R)-14
F1 F2
rac
F1
F2
F1
F2
[b]
[b]
1
2
3
4
5
6
7
H
H
H
H
H
H
H
H
CH3
N(CH3)2
F
Cl
Br
I
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
5aa
5ab
5ad
5ag
5ah
5ai
69(A)
57(B)
17(A)
29(A)
36(B)
28(A)
22(B)
-
-
-
57(A)
57(A)
43(A)
56(A)
50(A)
49(A)
46(A)
18(A)
16(A)
26(A)
28(A)
49(A)
40(B)
79(B)
46(A)
56(A)
39(B)
22(B)
38(A)
-
-
[b]
[b]
[b]
21(A)
16(A)
29(A)
[b]
[b]
-
-
[b]
[b]
[b]
-
-
-
5aj
28(B)
11(A)
15(A)
[b]
[b]
[b]
8
9
10
H
H
Cl
Ethynyl
Cl
OH
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
5bc
5bh
5bk
18(B)
33(A)
25(A)
-
29(A)
50(A)
27(A)
-
47(A)
30(B)
62(A)
-
17(A)
25(A)
-
-
[b]
[b]
[b]
[b]
-
-
[b]
[b]
[b]
11
12
H
H
CH3
OCH3
H
NO2
CN
H
H
H
H
H
5cb
5de
12(B)
13(A)
-
33(A)
24(A)
-
46(B)
37(B)
-
[b]
[b]
[b]
-
-
-
[b]
[b]
13
14
15
16
H
H
H
H
OCH3
H
OCH3
Cl
H
H
H
H
F
H
F
F
F
H
H
H
H
5ee
5fa
5fe
5fh
10(A)
58(A)
9.8(A)
37(A)
-
37(A)
51(A)
64(A)
51(A)
39(A)
19(A)
30(B)
32(B)
36(B)
30(B)
-
[b]
[b]
H
H
H
-
-
[b]
[b]
[b]
-
-
-
[b]
-
20(A)
19(B)
[b]
[b]
[b]
17
18
19
20
21
22
23
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
5ga
5gb
5ge
5gg
5gh
5gi
28(A)
41(B)
8.4(A)
53(A)
44(A)
41(A)
48(A)
-
67(A)
42(A)
36(A)
57(A)
92(A)
35(A)
47(A)
-
32(A)
67(B)
64(A)
67(A)
29(B)
47(A)
39(A)
-
[b]
[b]
[b]
CH3
OCH3
F
Cl
Br
-
-
-
[b]
[b]
[b]
-
-
-
41(A)
43(A)
23(A)
23(A)
32(A)
[b]
[b]
-
-
41(A)
15(A)
[b]
[b]
[b]
OH
5gk
-
-
-
[b]
[b]
[b]
24
25
26
27
H
H
H
H
H
CH3
Ethynyl
OCH3
H
H
H
H
Br
Br
Br
Br
H
H
H
H
H
H
H
H
5ha
5hb
5hc
5he
67(A)
28(A)
10(B)
23(A)
-
42(A)
24(A)
30(A)
28(B)
-
7.9(B)
34(A)
57(A)
36(A)
-
[b]
[b]
[b]
-
-
-
[b]
[b]
[b]
-
-
-
[b]
[b]
[b]
-
-
-
[a] Isolated yields. Method A: column chromatography; Method B: preparative TLC. [b] not found/traces (<5%).
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Relative and absolute configuration
We observed the appearance of two fractions with different
polarities for most of the synthesized bisindoles. The less polar
fraction (Fraction 1) has an Rf = 0.30 (cyclohexane/EtOAc 2:1)
and the more polar fraction (Fraction 2) has an Rf = 0.10
1
(cyclohexane/EtOAc 2:1). The isolated fractions differ in H and
13C NMR spectra through the chemical shifts and split of the
signals of the piperidine ring. The characterization approves that
two diastereomers were synthesized which vary in their polarity
and so could be separated through column chromatography.
The relative configuration was identified through NOE correlations
(Figure 5). In previous work we could prove through NOE
correlation experiment, X-ray crystallography and electronic
Scheme 4. Postulated mechanism for the formation of the Povarov product
(rac)-16de.
After first addition of the 3-vinylindole 3d to the imine 4e to form
the intermediate 15, the aromatic phenyl ring proceeds a
nucleophilic attack at position 4 to give the Povarov product
(rac)-16de. Table 2 shows the synthesized products.
circular dichroism (CD) spectrum the appearance of the shown
[13]
(2S,4S,6S) configuration.
Therefore we performed a NOE
correlation with fraction 2 of bisindole 5gg. This spectrum showed
some interesting correlations between protons which lead to the
conclusion that as in fraction 1 both indole-3-yl groups are
standing in the equatorial position. In contrast to fraction 1 the
ethyl ester group is also standing in the equatorial position leading
to a (2R,4S,6S) configuration of this diastereomer (Figure 5).
Table 2. Racemic and asymmetric synthesis of Povarov products.
Entry
1
R1
H
R2
product
Yield[a]
[%]
rac
Yield[a]
[%]
cat-(S)
Yield[a]
[%]
cat-(R)
Figure 5. Configurations of bisindole 5gg, above: experimentally determined
1,3-
16af
60
90
66
NOE correlations; below: Configurations of F1 and F2.
Dioxolyl
4-CH3
4-OCH3
4-CH3
1,3-
2
3
4
5
5-CN
4-NO2
5-Cl
16cb
16de
16gb
16gf
80
63
47
99
56
49
-
51
63
-
Substitution effects – the Povarov product
5-Cl
99
80
Dioxolyl
A close observation of the entries 11 and 12 (Table 1) shows a
significant decrease in the yields compared to other entries. This
[a] Isolated yield.
could be explained by the appearance of a competing reaction –
21]
the Povarov reaction.[12,
Scheme 4 shows the postulated
mechanism for the formation of the Povarov product.
Entries 1–5 (Table 2) demonstrate that the Povarov products
could be obtained in good to very good yields in racemic as well
as in asymmetric reactions. The reaction between
a
5-chloro-3-vinyl-1H-indole (3g)/ 3-vinyl-1H-indole (3a) and an
imino ester containing an electron withdrawing like an
1,3-dioxolylring (4f) only leads in both reactions (racemic and
asymmetric) to the formation of the Povarov product in very good
yields (entries 1 and 5). Comparable to the bisindole synthesis,
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entry 1 (Table 2) shows an increase in the yield during the
asymmetric reaction. Unfortunately this observation cannot be
transferred to the other entries of table 2. The conclusion is that
the synthesis of bisindoles is a catalytic reaction in contrast to the
Povarov reaction which proceeds also non-catalytical, which is
obvious while comparing the yields of the enantiomeric catalysts.
To confirm our assumption we analysed entry 4 (table 2). In this
case we obtained the Povarov product (rac)-16gb during the
racemic reaction. While performing the reaction with the
phosphoric catalyst we isolated the corresponding bisindole
(cat)-5gb (entry 18, table 1). Furthermore, entry and 3 (table 2)
and entry 12 (table 1) demonstrate a reaction of a 3-vinylindole
3d with an electron withdrawing group reacting with an
electronrich imine 4e. In contrast to the Povarov product, where
the yields did not change by modifying the racemic conditions to
asymmetric ones (63%), the yields of the bisindoles increased
through the addition of the catalyst from 13% to 37%.
Derivatisation of Bisindoles
Previously synthesized heterocycles 3-vinylbenzothiophene (9),
3-vinylbenzofuran
(10),
4-vinyl-1H-imidazole
(11)
and
3-vinyl-1H-indazole (12) could not be implemented in the
bisindole synthesis – even by changing the electron character of
the imines.
Scheme 6. Synthesis of a bisindole with different substituted 3-vinylindoles.
After a successful synthesis of 3-vinyl-1H-pyrrole (13) we
analyzed its reactivity during a racemic bispyrrole synthesis
(Scheme 5).
However this reaction did not lead to the formation of the desired
product (cat)-5bik. Product (cat)-5bk was synthesized – a
bisindole with the same heterocycles on the piperidine ring.
Furthermore we tried to investigate consecutive reactions with 3
types of bisindoles – the completely unsubstituted one ((rac)-5aa)
and the ethynyl ((rac)-5bc)/bromo ((rac)-5ai) substituted on the
imine position (Scheme 7).
Scheme 5. Racemic reaction of 3-vinyl-1H-pyrrole (13) with imine 4a.
As described in Scheme 5 we could obtain the Povarov product
18 instead of the desired bispyrrole 17. The Povarov product
(rac)-18 could be isolated in 77% yield. Because of the lower
resonant energy of pyrrole, the nucleophilic attack of the phenyl
ring in position 4 proceeds faster than the addition of the second
molecule 3-vinyl-1H-pyrrole (13).
An introduction of two different indole moieties on one piperidine
ring was impossible to perform. We chose two indoles, which
differ significantly in their polarity, for the reaction (Scheme 6).
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products. Their activity towards various test organisms is currently
under investigation. Subsequently we could also prove that it is
possible to perform consecutive reactions (reduction, cross
coupling and click reaction) with selected bisindoles.
Experimental Section
For information concerning the measurements and working
techniques as well as the analytical data of all the other
compounds please use our supporting information.
Ethyl (2S,4S,6S) 4,6 bis(1H indol 3 yl) 1 phenylpiperidine-2-
carboxylate (5aa): This compound was synthesized following the
GP C with 3-vinylindole (3a, 28.6 mg, 0.200 mmol, 2.00 Equiv.)
and ethyl 2-(phenylimino)acetate (4a, 17.7 mg, 0.100 mmol,
1.00 Equiv.) in 3.0 mL dichloromethane. The crude product was
purified by preparative TLC (cyclohexane/ethyl acetate = 3:1) to
give 5aa as a yellow oil (cat-(R): 18.5 mg, 39.8 µmol, 40%;
cat-(S): F1: 26.6 mg, 57.3 µmol, 57%, F2: 8.40 mg, 18.1 µmol,
18%).
The racemic compound was obtained following GP C with
3-vinylindole (3a, 309 mg, 2.16 mmol, 2.00 Equiv.) and ethyl
2-(phenylimino)acetate (4a, 191 mg, 1.08 mmol, 1.00 Equiv.)
without a catalyst in 30 mL dichloromethane. The product 5aa
was obtained after column chromatography (cyclohexane/ethyl
acetate = 2:1) as a colorless oil (345 mg, 0.744 mmol, 69%).
fraction 1 (F1): Rf = 0.48 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 1.19–1.24 (m, 3H, CH2CH3),
2.16–2.30 (m, 1H, NCHCHH), 2.38–2.51 (m, 2H, CHHCHCO2Et,
3
4
NCHCHH), 2.65 (dq, J = 13.2, J = 2.6 Hz, 1H, CHHCHCO2Et),
3.36 (tt, 3J = 12.5, 3J = 3.1 Hz, 1H, CH2CHCH2), 4.05–4.12 (m, 1H,
CHHCH3), 4.13–4.23 (m, 1H, CHHCH3), 4.82 (dd, 3J = 5.6,
3J = 2.3 Hz, 1H, NCHCO2Et), 5.65 (dd, 3J = 11.2, 3J = 3.6 Hz, 1H,
NCHCInd), 6.63–6.71 (m, 1H, CHAr), 6.92–7.04 (m, 5H, CHAr),
7.06–7.11 (m, 1H, CHAr), 7.15 (dd, 3J = 6.4, 3J = 2.2 Hz, 2H, CHAr),
7.22 (ddd, 3J = 9.7, 3J = 7.6, 4J = 1.1 Hz, 3H, CHAr), 7.37 (d,
3J = 8.0 Hz, 1H, CHAr), 7.62 (d, 3J = 8.0 Hz, 1H, CHAr), 7.88–7.96
Scheme 7. Derivatisation of the bisindoles (rac)-5aa/ai/bc. Synthesis:
a
p-tolylboronic acid, potassium phosphate, Pd(OAc)2, Sphos, argon atmosphere,
degassed THF/H2O = 3:1, 80 °C, 16 h, 57%; b LiAlH4, Et2O, argon atmosphere,
reflux, 6 h, 31%; c Acetyl-2,3,4,6-tetra-O-acetyl-D–galactopyranosylazide, 1 M
CuSO4 × 5 H2O, 1 M sodium ascorbate, t-BuOH/H2O = 1:1, 70 °C, 16 h, traces.
(m, 1H, CHAr), 9.84 (sbr, 1H, NH), 10.00 (sbr, 1H, NH) ppm; 13
C
The derivatization experiments shown in Scheme 7 were
successful. Product 19 was obtained via a Suzuki cross coupling
reaction using p-tolylbronic acid in 57% yield. The reduction of
(rac)-5aa was realized with LiAlH4 in 31% yield. The provided
sugar azide could be successfully introduced in a Click-reaction.
Product 21 could be obtained in 24% yield.
NMR (100 MHz, acetone-d6, 25 °C, TMS): δ = 14.4 (+, CH2CH3),
20.6 (+, CH2CHCH2), 36.9 (–, CHCH2), 43.4 (–, CHCH2), 52.8 (+,
NCHCInd), 60.6 (–, CH2CH3), 65.7 (+, NCHCO2Et), 112.0 (+, CHAr),
112.3 (+, CHAr), 119.1 (+, CHAr), 119.2 (+, CHAr), 119.3 (+, CHAr),
119.8 (Cq, CAr), 120.4 (Cq, CAr), 120.7 (+, CHAr), 121.0 (+, CHAr),
121.8 (+, CHAr), 122.1 (+, CHAr), 122.2 (+, CHAr), 123.7 (+, CHAr),
125.3 (+, 2 × CHAr), 126.9 (Cq, CAr), 127.6 (Cq, CAr), 128.2 (+, 2 ×
CHAr), 137.7 (Cq, CAr), 137.9 (Cq, CAr), 151.9 (Cq, CAr), 173.7 (Cq,
CO2Et) ppm; IR (ATR): 푣̃ = 3410, 2932, 2540, 1697, 1595, 1492,
1455, 1336, 1245, 1176, 1093, 1023, 931, 845, 810, 740, 696,
581, 477, 424 cm-1; MS (FAB, 3-NBA): m/z (%): 464 (64) [M+H]+,
390 (69), 347 (43); HRMS (FAB, 3-NBA): calcd for C30H30O2N3
[M+H]+: 464.2333; found: 464.2334.
Conclusions
In conclusion, we could create a diverse library of bisindoles
based on previous investigations on the powerful
three-component,
enantioselective,
and
organocatalytic
synthesis of 4,6-bis(1H-indole-3-yl)piperidine 2-carboxylates.
Furthermore we could observe a formation of an interesting side
product – the Povarov product – while using electron withdrawing
groups on the starting material. Both products are highly
functionalized and they resemble medicinally interesting natural
fraction 2 (F2): Rf = 0.33 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 0.81 (t, 3J = 7.1 Hz, 3H,
CH2CH3), 2.14 (q, 3J = 12.3 Hz, 1H, NCHCHH), 2.20–2.31 (m, 2H,
CHHCHCO2Et, NCHCHH), 2.38 (q, 3J = 12.3 Hz, 1H,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701502
European Journal of Organic Chemistry
FULL PAPER
3
3
CHHCHCO2Et), 3.31 (tt, 3J = 12.5, 3J = 3.6 Hz, 1H, CH2CHCH2),
1H, NCHCO2Et), 4.63 (dd, J = 11.1, J = 2.9 Hz, 1H, NCHCInd),
3.73 (q, 3J = 7.1 Hz, 2H, CH2CH3), 3.97 (dd, 3J = 11.0, 3J = 2.9 Hz, 6.79 (d, J = 8.1 Hz, 2H, CHAr), 6.97–7.15 (m, 7H, CHAr), 7.19–
3
3
3
1H, NCHCO2Et), 4.53 (dd, J = 11.0, J = 2.9 Hz, 1H, NCHCInd),
7.25 (m, 2H, CHAr), 7.38 (d, 3J = 8.0 Hz, 1H, CHAr), 7.71 (d,
3J = 8.0 Hz, 1H, CHAr), 8.00–8.06 (m, 1H, CHAr), 9.76 (sbr, 1H,
NH), 10.02 (sbr, 1H, NH) ppm; 13C NMR (100 MHz, acetone-d6,
25 °C, TMS): δ = 14.2 (+, CH2CH3), 20.8 (+, CH3), 27.5 (+,
CH2CHCH2), 38.4 (–, CHCH2), 42.8 (–, CHCH2), 60.4 (–, CH2CH3),
61.4 (+, NCHCInd), 69.9 (+, NCHCO2Et), 112.0 (+, CHAr), 112.3 (+,
CHAr), 118.8 (Cq, CAr), 119.1 (+, CHAr), 119.3 (+, CHAr), 119.5 (+,
CHAr), 120.5 (Cq, CAr), 121.1 (+, CHAr), 121.2 (+, CHAr), 121.8 (+,
CHAr), 122.1 (+, CHAr), 124.0 (+, CHAr), 127.4 (Cq, CAr), 127.6 (Cq,
CAr), 127.8 (+, 2 × CHAr), 129.2 (+, 2 × CHAr), 134.9 (Cq, CAr),
137.7 (Cq, CAr), 137.9 (Cq, CAr), 149.5 (Cq, CAr), 172.9 (Cq,
CO2Et) ppm; IR (ATR): 푣̃ = 3408, 2921, 2851, 1723, 1696, 1618,
1509, 1456, 1338, 1224, 1176, 1094, 1030, 815, 738, 582, 548,
477, 423 cm-1; MS (FAB, 3-NBA): m/z (%): 477 (50) [M]+, 271 (73),
192 (100), 154 (78), 147 (76), 91 (83); HRMS (FAB, 3-NBA): calcd
for C31H31O2N3 [M]+: 477.2411; found: 477.2411.
3
6.71 (t, J = 7.3 Hz, 1H, CHAr), 6.82–6.98 (m, 7H, CHAr), 7.06–
7.11 (m, 4H, CHAr), 7.25 (d, 3J = 8.0 Hz, 1H, CHAr), 7.58 (d,
3J = 8.0 Hz, 1H, CHAr), 7.85–7.90 (m, 1H, CHAr), 9.65 (sbr, 1H,
NH), 9.90 (sbr, 1H, NH) ppm.
Ethyl 4,6-bis(1H-indol-3-yl)-1-(4-tolyl)piperidine-2-carboxylate
(5ab): This compound was synthesized following the GP C with
3-vinylindole (3a, 28.6 mg, 0.200 mmol, 2.00 Equiv.) and ethyl
2-((4-tolyl)imino)acetate (4b, 19.1 mg, 0.100 mmol, 1.00 Equiv.)
in 3.0 mL dichloromethane. The product 5ab was obtained after
column chromatography (cyclohexane/ethyl acetate = 2:1) as a
yellow oil in two fractions (cat-(R): 37.9 mg, 79.0 µmol, 79%;
cat-(S): F1: 27.2 mg, 56.9 µmol, 57%, F2: 7.40 mg, 15.5 µmol,
16%).
The racemic compound was obtained following GP C with
3-vinylindole (3a, 28.6 mg, 0.200 mmol, 2.00 Equiv.) and ethyl
2-((4-tolyl)imino)acetate (4b, 19.1 mg, 0.100 mmol, 1.00 Equiv.)
without a catalyst in 3.0 mL dichloromethane. The product 5ab
was obtained after column chromatography (cyclohexane/ethyl
acetate = 2:1) as a yellow oil (27.0 mg, 56.6 μmol, 57%).
Ethyl 4,6-bis(1H-indol-3-yl)-1-(4-(dimethylamino)-
phenyl)piperidine-2-carboxylate (5ad): This compound was
synthesized following the GP C with 3-vinylindole (3a, 28.6 mg,
0.200 mmol,
2.00 Equiv.)
and
ethyl
2-((4-
dimethylaminophenyl)imino)acetate (4d, 22.0 mg, 0.100 mmol,
1.00 Equiv.) in 3.0 mL dichloromethane. The product 5ad was
obtained after column chromatography (cyclohexane/ethyl
acetate = 2:1) as a yellow oil in two fractions (cat-(R): F1: 23.4 mg,
46.2 µmol, 46%, F2: 10.6 mg, 20.9 µmol, 21%; cat-(S): F1:
21.6 mg, 42.6 µmol, 43%, F2: 12.9 mg, 25.5 µmol, 26%).
fraction 1 (F1): Rf = 0.41 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 1.22 (t, 3J = 7.1 Hz, 3H,
CH2CH3), 2.04 (s, 3H, CH3), 2.17–2.28 (m, 1H, NCHCHH), 2.38–
2.49 (m, 2H, CHHCHCO2Et, NCHCHH), 2.63 (dq, 3J = 13.2,
3
3
3J = 2.6 Hz, 1H, CHHCHCO2Et), 3.37 (tt, J = 12.5, J = 3.0 Hz,
1H, CH2CHCH2), 4.04–4.11 (m, 1H, CHHCH3), 4.13–4.24 (m, 1H,
The racemic compound was obtained following GP C with
3-vinylindole (3a, 28.6 mg, 0.200 mmol, 2.00 Equiv.) and ethyl
3
3
CHHCH3), 4.74 (dd, J = 5.6, J = 2.3 Hz, 1H, NCHCO2Et), 5.65
(dd, 3J = 11.3, 3J = 3.6 Hz, 1H, NCHCInd), 6.76 (d, 3J = 8.2 Hz, 2H,
2-((4-dimethylaminophenyl)imino)acetate
(4d,
catalyst in 3.0 mL
3J = 5.6, 3J = 2.3 Hz, 2H, CHAr), 7.23 (dd, 3J = 6.9, 3J = 1.5 Hz, 1H, dichloromethane. The product 5ad was obtained after column
22.0 mg,
CHAr), 6.93–7.04 (m, 3H, CHAr), 7.06–7.12 (m, 3H, CHAr), 7.14 (dd, 0.100 mmol, 1.00 Equiv.) without
a
3
3
CHAr), 7.37 (d, J = 8.0 Hz, 1H, CHAr), 7.62 (d, J = 8.0 Hz, 1H,
CHAr), 7.91–7.97 (m, 1H, CHAr), 9.81 9.98 (sbr, 1H, NH), 9.98 9.98
(sbr, 1H, NH) ppm; 13C NMR (100 MHz, acetone-d6, 25 °C, TMS):
δ = 14.7 (+, CH2CH3), 20.6 (+, CH3), 27.5 (+, CH2CHCH2), 37.0 (–,
CHCH2), 43.4 (–, CHCH2), 52.8 (+, NCHCInd), 60.5 (–, CH2CH3),
65.9 (+, NCHCO2Et), 112.0 (+, CHAr), 112.3 (+, CHAr), 119.1 (+,
CHAr), 119.2 (+, CHAr), 119.3 (+, CHAr), 119.9 (Cq, CAr), 120.4 (Cq,
CAr), 120.8 (+, CHAr), 121.1 (+, CHAr), 121.7 (+, CHAr), 122.1 (+,
CHAr), 123.7 (+, CHAr), 125.4 (+, 2 × CHAr), 126.9 (Cq, CAr), 127.6
(Cq, CAr), 128.9 (+, 2 × CHAr), 131.3 (Cq, CAr), 137.7 (Cq, CAr),
137.9 (Cq, CAr), 149.4 (Cq, CAr), 173.8 (Cq, CO2Et) ppm; IR (ATR):
푣̃ = 3395, 3347, 2920, 2851, 1708, 1618, 1509, 1452, 1339, 1274,
1209, 1188, 1094, 1040, 1007, 933, 848, 816, 741, 673, 615, 592,
561, 515, 466, 423 cm-1; MS (EI, 70 eV): m/z (%): 477 (46) [M]+,
404 (24), 337 (29), 307 (28), 271 (49), 192 (53), 154 (100), 136
(67), 118 (35), 91 (26); HRMS (EI): calcd for C31H31O2N3 [M]+:
477.2411; found: 477.2414.
chromatography (cyclohexane/ethyl acetate = 2:1) as a yellow oil
(8.38 mg, 16.5 µmol, 17%).
fraction 1 (F1): Rf = 0.28 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 1.23 (t, 3J = 7.1 Hz, 3H,
CH2CH3), 2.22 (q, 3J = 12.6 Hz, 1H, NCHCHH), 2.37–2.48 (m, 2H,
CHHCHCO2Et, NCHCHH), 2.54–2.62 (m, 1H, CHHCHCO2Et),
2.71 (s, 6H, N(CH3)2), 3.41 (tt, 3J = 12.5, 3J = 3.0 Hz, 1H,
CH2CHCH2), 4.04–4.11 (m, 1H, CHHCH3), 4.13–4.24 (m, 1H,
CHHCH3), 4.57 (d, 3J = 3.8 Hz, 1H, NCHCO2Et), 5.68 (dd,
3J = 11.1, 3J = 2.6 Hz, 1H, NCHCInd), 6.41 (d, 3J = 8.8 Hz, 2H,
CHAr), 6.94–7.04 (m, 3H, CHAr), 7.06–7.15 (m, 5H, CHAr), 7.22 (dd,
3
3
3J = 6.3, J = 2.4 Hz, 1H, CHAr), 7.37 (d, J = 8.0 Hz, 1H, CHAr),
7.62 (d, 3J = 8.0 Hz, 1H, CHAr), 7.96 (dd, 3J = 6.1, 3J = 2.4 Hz, 1H,
CHAr), 9.77 (sbr, 1H, NH), 9.98 (sbr, 1H, NH) ppm; 13C NMR
(100 MHz, acetone-d6, 25 °C, TMS): δ = 14.7 (+, CH2CH3), 27.5
(+, CH2CHCH2), 37.0 (–, CHCH2), 40.9 (+, N(CH3)2), 43.6 (–,
CHCH2), 52.9 (+, NCHCInd), 60.4 (–, CH2CH3), 66.2 (+,
NCHCO2Et), 112.0 (+, CHAr), 112.3 (+, CHAr), 113.0 (+, 2 × CHAr),
119.0 (+, CHAr), 119.3 (+, 2 × CHAr), 120.1 (Cq, CAr), 120.6 (Cq,
CAr), 120.9 (+, CHAr), 121.0 (+, CHAr), 121.6 (+, CHAr), 122.1 (+,
CHAr), 123.7 (+, CHAr), 126.7 (+, 2 × CHAr), 127.1 (Cq, CAr), 127.6
fraction 2 (F2): Rf = 0.26 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 0.96 (t, 3J = 7.1 Hz, 3H,
CH2CH3), 2.08 (s, 3H, CH3), 2.19–2.30 (m, 1H, NCHCHH), 2.30–
2.42 (m, 2H, CHHCHCO2Et, NCHCHH), 2.44–2.54 (m, 1H,
CHHCHCO2Et), 3.43 (tt, 3J = 12.1, 3J = 3.5 Hz, 1H, CH2CHCH2),
3.86 (q, 3J = 7.1 Hz, 2H, CH2CH3), 4.03 (dd, 3J = 11.2, 3J = 2.8 Hz, (Cq, CAr), 137.7 (Cq, CAr), 137.9 (Cq, CAr), 141.9 (Cq, CAr), 147.2
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701502
European Journal of Organic Chemistry
FULL PAPER
3
(Cq, CAr), 174.2 (Cq, CO2Et) ppm; IR (ATR): 푣̃ = 3408, 3053, 2922,
2851, 1720, 1695, 1613, 1514, 1455, 1338, 1246, 1223, 1173,
1113, 1092, 1038, 1022, 1010, 945, 818, 764, 739, 694, 580, 552,
476, 423 cm-1; MS (FAB, 3-NBA): m/z (%): 506 (100) [M]+, 271
(51), 147 (57); HRMS (FAB, 3-NBA): calcd for C32H34O2N4 [M]+:
506.2676; found: 506.2675.
3J = 3.5 Hz, 1H, NCHCInd), 6.71 (t, J = 8.8 Hz, 2H, CHAr), 6.92–
7.04 (m, 3H, CHAr), 7.07–7.11 (m, 1H, CHAr), 7.14 (d, 3J = 2.3 Hz,
1H, CHAr), 7.18 (d, 3J = 2.3 Hz, 1H, CHAr), 7.21–7.25 (m, 3H,
3
3
CHAr), 7.38 (d, J = 8.0 Hz, 1H, CHAr), 7.62 (d, J = 8.0 Hz, 1H,
CHAr), 7.93 (d, J = 7.3 Hz, 1H, CHAr), 9.86 (sbr, 1H, NH), 10.00
3
(sbr, 1H, NH) ppm; 13C NMR (100 MHz, acetone-d6, 25 °C, TMS):
δ = 14.7 (+, CH2CH3), 27.5 (+, CH2CHCH2), 36.9 (–, CHCH2), 42.2
(–, CHCH2), 53.1 (+, NCHCInd), 60.7 (–, CH2CH3), 65.9 (+,
NCHCO2Et), 112.0 (+, CHAr), 112.3 (+, CHAr), 114.5 (+, CHAr),
114.7 (+, CHAr), 119.2 (+, 2 × CHAr), 119.3 (+, CHAr), 119.4 (Cq,
CAr), 120.3 (Cq, CAr), 120.8 (+, CHAr), 121.1 (+, CHAr), 121.8 (+,
CHAr), 122.2 (+, CHAr), 123.9 (+, CHAr), 126.8 (Cq, CAr), 127.2 (+,
CHAr), 127.3 (+, CHAr), 127.6 (Cq, CAr), 137.7 (Cq, CAr), 137.9 (Cq,
CAr), 148.2 (Cq, CAr), 159.6 (Cq, d, 1J = 235.6 Hz, CF), 173.6 (Cq,
CO2Et) ppm; 19F NMR (376 MHz, acetone-d6, 25 °C): δ = –
fraction 2 (F2): Rf = 0.18 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 0.97 (t, 3J = 7.1 Hz, 3H,
CH2CH3), 2.23 (q, 3J = 12.3 Hz, 1H, NCHCHH), 2.28–2.39 (m, 2H,
CHHCHCO2Et, NCHCHH), 2.45 (q, 3J = 12.3 Hz, 1H,
CHHCHCO2Et), 2.72 (s, 6H, N(CH3)2), 3.40 (tt, 3J = 12.3,
3
3J = 3.5 Hz, 1H, CH2CHCH2), 3.86 (q, J = 7.1 Hz, 2H, CH2CH3),
3.98 (dd, 3J = 11.3, 3J = 2.7 Hz, 1H, NCHCO2Et), 4.58 (dd,
3
3J = 11.1, J = 2.8 Hz, 1H, NCHCInd), 6.33–6.40 (m, 2H, CHAr),
6.97–7.04 (m, 4H, CHAr), 7.05–7.12 (m, 3H, CHAr), 7.18–7.23 (m,
2H, CHAr), 7.37 (d, 3J = 8.0 Hz, 1H, CHAr), 7.71 (d, 3J = 7.9 Hz, 1H, 127.8 ppm; IR (ATR): 푣̃ = 3409, 2923, 2851, 2539, 1697, 1504,
CHAr), 8.02–8.08 (m, 1H, CHAr), 9.72 (sbr, 1H, NH), 10.01 (sbr,
1H, NH) ppm; 13C NMR (100 MHz, acetone-d6, 25 °C, TMS):
δ = 14.4 (+, CH2CH3), 27.5 (+, CH2CHCH2), 38.5 (–, CHCH2), 40.7
(+, N(CH3)2), 43.0 (–, CHCH2), 60.3 (–, CH2CH3), 61.7 (+,
NCHCInd), 70.5 (+, NCHCO2Et), 112.0 (+, CHAr), 112.3 (+, CHAr),
112.7 (+, 2 × CHAr), 119.0 (+, CHAr), 119.1 (Cq, CAr), 119.3 (+,
CHAr), 119.5 (+, CHAr), 120.6 (Cq, CAr), 121.2 (+, CHAr), 121.3 (+,
CHAr), 121.7 (+, CHAr), 122.1 (+, CHAr), 123.9 (+, CHAr), 127.5 (Cq,
CAr), 127.6 (Cq, CAr), 128.6 (+, 2 × CHAr), 137.7 (Cq, CAr), 137.9
(Cq, CAr), 141.2 (Cq, CAr), 149.2 (Cq, CAr), 173.0 (Cq, CO2Et) ppm;
IR (ATR): 푣̃ = 3400, 3054, 2921, 2850, 1722, 1695, 1612, 1515,
1456, 1339, 1245, 1177, 1095, 1028, 1010, 950, 855, 817, 740,
581, 549, 477, 425 cm-1; MS (FAB, 3-NBA): m/z (%): 506 (100)
[M]+, 271 (62), 132 (87); HRMS (FAB, 3-NBA): calcd for
C32H34O2N4 [M]+: 506.2676; found: 506.2676.
1454, 1337, 1246, 1210, 1175, 1093, 1010, 932, 832, 815, 739,
708, 581, 565, 549, 476, 424 cm-1; MS (FAB, 3-NBA): m/z (%):
482 (14) [M]+, 271 (23), 196 (32), 154 (44), 137 (43), 109 (35), 97
(67), 95 (100); HRMS (FAB, 3-NBA): calcd for C30H28O2N3F [M]+:
481.2160; found: 481.2158.
fraction 2 (F2): Rf = 0.24 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 0.83 (t, 3J = 7.1 Hz, 3H,
CH2CH3), 2.06–2.17 (m, 1H, NCHCHH), 2.16–2.31 (m, 2H,
CHHCHCO2Et, NCHCHH), 2.40 (q, 3J = 12.4 Hz, 1H,
CHHCHCO2Et), 3.31 (tt, 3J = 12.2, 3J = 3.4 Hz, 1H, CH2CHCH2),
3.74 (q, 3J = 7.1 Hz, 2H, CH2CH3), 3.94 (dd, 3J = 11.2, 3J = 2.7 Hz,
3
3
1H, NCHCO2Et), 4.45 (dd, J = 11.2, J = 2.7 Hz, 1H, NCHCInd),
3
6.60 (t, J = 8.8 Hz, 2H, CHAr), 6.83–6.99 (m, 5H, CHAr), 7.08–
7.13 (m, 4H, CHAr), 7.25 (d, 3J = 8.0 Hz, 1H, CHAr), 7.58 (d,
3J = 8.0 Hz, 1H, CHAr), 7.82–7.88 (m, 1H, CHAr), 9.68 (sbr, 1H,
NH), 9.91 (sbr, 1H, NH) ppm; 13C NMR (100 MHz, acetone-d6,
25 °C, TMS): δ = 14.3 (+, CH2CH3), 34.3 (+, CH2CHCH2), 38.3 (–,
CHCH2), 42.5 (–, CHCH2), 60.6 (–, CH2CH3), 61.8 (+, NCHCInd),
69.7 (+, NCHCO2Et), 112.2 (+, CHAr), 112.3 (+, CHAr), 114.9 (+,
CHAr), 115.1 (+, CHAr), 118.3 (Cq, CAr), 119.2 (+, CHAr), 119.4 (+,
CHAr), 119.5 (+, CHAr), 120.4 (Cq, CAr), 121.0 (+, CHAr), 121.3 (+,
CHAr), 121.9 (+, CHAr), 122.1 (+, CHAr), 124.1 (+, CHAr), 127.3 (Cq,
CAr), 127.6 (Cq, CAr), 129.9 (+, CHAr), 130.0 (+, CHAr), 137.7 (Cq,
CAr), 137.9 (Cq, CAr), 148.2 (Cq, CAr), 159.6 (Cq, d, 1J = 235.6 Hz,
CF), 172.8 (Cq, CO2Et) ppm; 19F NMR (376 MHz, acetone-d6,
25 °C): δ = –123.5 ppm.
Ethyl 4,6-bis(1H-indol-3-yl)-1-(4-fluorophenyl)piperidine-2-
carboxylate (5ag): This compound was synthesized following the
GP C with 3-vinylindole (3a, 28.6 mg, 0.200 mmol, 2.00 Equiv.)
and ethyl 2-((4-fluorophenyl)imino)acetate (4g, 19.5 mg,
0.100 mmol, 1.00 Equiv.) in 3.0 mL dichloromethane. The product
5ag
was
obtained
after
column
chromatography
(cyclohexane/ethyl acetate = 2:1) as a yellow oil in two fractions
(cat-(R): F1: 27.1 mg, 56.2 µmol, 56%, F2: 7.70 mg, 16.0 µmol,
16%; cat-(S): F1: 27.1 mg, 56.2 µmol, 56%, F2: 13.7 mg,
28.4 µmol, 28%).
The racemic compound was obtained following GP C with
3-vinylindole (3a, 28.6 mg, 0.200 mmol, 2.00 Equiv.) and ethyl
2-((4-fluorophenyl)imino)acetate (4g, 19.5 mg, 0.100 mmol,
1.00 Equiv.) without a catalyst in 3.0 mL dichloromethane. The
product 5ag was obtained after column chromatography
(cyclohexane/ethyl acetate = 2:1) as a yellow oil in two fractions
(F1: 14.0 mg, 29.1 μmol, 29%; F2: 14.2 mg, 29.4 μmol, 29%).
Ethyl 4,6-bis(1H-indol-3-yl)-1-(4-chlorophenyl)piperidine-2-
carboxylate (5ah): This compound was synthesized following the
GP C with 3-vinylindole (3a, 28.6 mg, 0.200 mmol, 2.00 Equiv.)
and ethyl 2-((4-chlorophenyl)imino)acetate (4h, 21.2 mg,
0.100 mmol, 1.00 Equiv.) in 3.0 mL dichloromethane. The product
5ah
was
obtained
after
column
chromatography
(cyclohexane/ethyl acetate = 2:1) as a yellow oil (cat-(R): 19.7 mg,
39.4 µmol, 39%; cat-(S): F1: 24.9 mg, 50.0 µmol, 50%, F2:
24.4 mg, 49.0 µmol, 49%).
The racemic compound was obtained following GP C with
3-vinylindole (3a, 28.6 mg, 0.200 mmol, 2.00 Equiv.) and ethyl
2-((4-chlorophenyl)imino)acetate (4a, 21.2 mg, 0.100 mmol,
1.00 Equiv.) without a catalyst in 3.0 mL dichloromethane. The
crude product was purified by preparative TLC (cyclohexane/ethyl
fraction 1 (F1): Rf = 0.39 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 1.23 (t, 3J = 7.1 Hz, 3H,
CH2CH3), 2.25 (q, 2J = 12.5 Hz, 1H, NCHCHH), 2.39–2.50 (m, 2H,
2
3
CHHCHCO2Et, NCHCHH), 2.66 (dq, J = 13.2, J = 2.5 Hz, 1H,
CHHCHCO2Et), 3.36 (tt, 3J = 12.5, 3J = 2.9 Hz, 1H, CH2CHCH2),
4.04–4.14 (m, 1H, CHHCH3), 4.15–4.25 (m, 1H, CHHCH3), 4.72
3
3
3
(dd, J = 5.6, J = 2.2 Hz, 1H, NCHCO2Et), 5.61 (dd, J = 11.3,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701502
European Journal of Organic Chemistry
FULL PAPER
acetate = 4:1) to give 5ah as a yellow oil (18.0 mg, 36.0 µmol,
36%).
(cyclohexane/ethyl acetate = 3:1) as a yellow oil (cat-(R): 12.0 mg,
22.1 µmol, 22%; cat-(S): 26.5 mg, 48.9 µmol, 49%).
The racemic compound was obtained following GP C with
3-vinylindole (3a, 100 mg, 1.40 mmol, 2.00 Equiv.) and ethyl
2-((4-bromophenyl)imino)acetate (4i, 179 mg, 0.698 mmol,
1.00 Equiv.) without a catalyst in 10 mL dichloromethane. The
product 5ai was obtained after column chromatography
(cyclohexane/ethyl acetate = 3:1) as a yellow oil (108 mg,
0.198 mmol, 28%).
fraction 1 (F1): Rf = 0.51 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 1.24 (t, 3J = 7.1 Hz, 3H,
CH2CH3), 2.24 (q, 2J = 12.5 Hz, 1H, NCHCHH), 2.40–2.49 (m, 2H,
CH2CHCO2Et), 2.69 (q, 2J = 12.5 Hz, 1H, NCHCHH), 3.32 (tt,
2J = 12.5, 3J = 3.1 Hz, 1H, CH2CHCH2), 4.02–4.09 (m, 1H,
CHHCH3), 4.17–4.24 (m, 1H, CHHCH3), 4.83 (dd, 3J = 5.6,
3J = 2.3 Hz, 1H, NCHCO2Et), 5.57 (dd, 3J = 11.3, 3J = 3.6 Hz, 1H,
NCHCInd), 6.94–6.98 (m, 3H, CHAr), 6.97–7.04 (m, 2H, CHAr),
Rf = 0.28 (cyclohexane/EtOAc 3:1); 1H NMR (400 MHz, acetone-
3
3
7.06–7.10 (m, 1H, CHAr), 7.14 (d, J = 2.4 Hz, 1H, CHAr), 7.18–
d6, 25 °C, TMS): δ = 1.25 (t, J = 7.1 Hz, 3H, CH2CH3), 2.24 (q,
7.26 (m, 4H, CHAr), 7.38 (d, 3J = 7.9 Hz, 1H, CHAr), 7.62 (d,
3J = 7.9 Hz, 1H, CHAr), 7.90 (d, 3J = 7.9 Hz, 1H, CHAr), 9.90 (sbr,
1H, NH), 10.01 (sbr, 1H, NH) ppm; 13C NMR (100 MHz, acetone-
d6, 25 °C, TMS): δ = 14.7 (+, CH2CH3), 27.5 (+, CH2CHCH2), 36.8
(–, CHCH2), 43.1 (–, CHCH2), 53.0 (+, NCHCInd), 60.8 (–,
CH2CH3), 65.5 (+, NCHCO2Et), 112.1 (+, CHAr), 112.3 (+, CHAr),
119.2 (+, CHAr), 119.3 (+, 2 × CHAr), 120.2 (Cq, CAr), 120.7 (+,
CHAr), 121.1 (+, CHAr), 121.9 (+, CHAr), 122.2 (+, CHAr), 123.9 (+,
CHAr), 126.6 (Cq, CAr), 126.7 (Cq, CAr), 126.9 (+, 2 × CHAr), 127.6
(Cq, CAr), 128.1 (+, 2 × CHAr), 137.7 (Cq, CAr), 137.9 (Cq, CAr),
150.9 (Cq, 2 × CAr), 173.5 (Cq, CO2Et) ppm; IR (ATR): 푣̃ = 3400,
2929, 1724, 1696, 1596, 1490, 1455, 1369, 1337, 1275, 1246,
1177, 1091, 1009, 932, 819, 766, 740, 671, 581, 503, 477,
424 cm-1; MS (FAB, 3-NBA): m/z (%): 498 (15) [M]+, 381 (15), 271
(56), 212 (66), 153 (57), 137 (56), 97 (63), 95 (100); HRMS (FAB,
3-NBA): calcd for C30H29O2N335Cl [M+H]+: 498.1943; found:
498.1941.
3J = 12.6 Hz, 1H, NCHCHH), 2.40–2.49 (m, 2H, CHHCHCO2Et,
3
3
NCHCHH), 2.69 (dq, J = 13.2, J = 3.0 Hz, 1H, CHHCHCO2Et),
3.32 (tt, 3J = 12.5, 3J = 3.0 Hz, 1H, CH2CHCH2), 4.07–4.15 (m, 1H,
CHHCH3), 4.17–4.25 (m, 1H, CHHCH3), 4.84 (dd, 3J = 5.6,
3J = 2.3 Hz, 1H, NCHCO2Et), 5.56 (dd, 3J = 11.3, 3J = 3.6 Hz, 1H,
NCHCInd), 6.93–7.04 (m, 3H, CHAr), 7.06–7.12 (m, 3H, CHAr),
7.13–7.15 (m, 2H, CHAr), 7.16 (t, 4J = 1.7 Hz, 1H, CHAr), 7.19 (d,
3
3J = 2.4 Hz, 1H, CHAr), 7.24 (d, J = 7.6 Hz, 1H, CHAr), 7.37 (d,
3
3J = 7.9 Hz, 1H, CHAr), 7.62 (d, J = 7.9 Hz, 1H, CHAr), 7.90 (d,
3J = 7.6 Hz, 1H, CHAr), 9.90 (sbr, 1H, NH), 10.01 (sbr, 1H,
NH) ppm; 13C NMR (100 MHz, acetone-d6, 25 °C, TMS): δ = 14.7
(+, CH2CH3), 27.5 (+, CH2CHCH2), 36.8 (–, CHCH2), 43.0 (–,
CHCH2), 53.0 (+, NCHCInd), 60.8 (–, CH2CH3), 65.5 (+,
NCHCO2Et), 112.1 (+, CHAr), 112.3 (+, CHAr), 114.3 (Cq, CAr),
116.9 (+, CHAr), 119.2 (+, CHAr), 119.3 (+, CHAr), 119.3 (Cq, CAr),
120.2 (Cq, CAr), 120.7 (+, CHAr), 121.1 (+, CHAr), 121.9 (+, CHAr),
122.2 (+, CHAr), 123.9 (+, CHAr), 126.6 (Cq, CAr), 127.5 (Cq, CAr),
127.8 (+, CHAr), 131.0 (+, CHAr), 131.9 (+, CHAr), 132.4 (+, CHAr),
137.7 (Cq, CAr), 137.9 (Cq, CAr), 151.4 (Cq, CAr), 173.4 (Cq,
CO2Et) ppm.
fraction 2 (F2): Rf = 0.32 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 0.98 (t, 3J = 7.1 Hz, 3H,
CH2CH3), 2.21–2.31 (m, 1H, NCHCHH), 2.35 (dq, 2J = 13.0,
3J = 3.0 Hz, CHHCHCO2Et), 2.43 (dq, 2J = 13.0, 3J = 3.0 Hz,
CHHCHCO2Et), 2.48–2.58 (m, 1H, NCHCHH), 3.45 (tt, 2J = 12.2,
Ethyl 4,6-bis(1H-indol-3-yl)-1-(4-iodophenyl)piperidine-2-
3
3J = 3.6 Hz, 1H, CH2CHCH2), 3.90 (q, J = 7.1 Hz, 2H, CH2CH3),
carboxylate (5aj): This compound was synthesized following the
GP C with 3-vinylindole (3a, 28.6 mg, 0.200 mmol, 2.00 Equiv.)
and ethyl 2-((4-iodophenyl)imino)acetate (4j, 30.3 mg,
0.100 mmol, 1.00 Equiv.) in 3.0 mL dichloromethane. The product
4.10 (dd, 3J = 11.0, 3J = 2.9 Hz, 1H, NCHCO2Et), 4.63 (dd,
3
3J = 11.0, J = 2.9 Hz, 1H, NCHCInd), 6.99–7.05 (m, 5H, CHAr),
7.06–7.11 (2H, CHAr), 7.18–7.26 (m, 4H, CHAr), 7.38 (d,
3
3J = 8.0 Hz, 1H, CHAr), 7.71 (d, J = 8.0 Hz, 1H, CHAr), 7.98 (dd,
5aj
was
obtained
after
column
chromatography
3
3J = 5.4, J = 3.7 Hz, 1H, CHAr), 9.83 (sbr, 1H, NH), 10.04 (sbr,
(cyclohexane/ethyl acetate = 2:1) as a colorless oil in two
fractions (cat-(R): F1: 22.6 mg, 38.3 µmol, 38%, F2: 8.60 mg,
14.6 µmol, 15%; cat-(S): F1: 26.8 mg, 45.5 µmol, 46%, F2:
6.30 mg, 10.7 µmol, 11%).
The racemic compound was obtained following GP C with
3-vinylindole (3a, 28.6 mg, 0.200 mmol, 2.00 Equiv.) and ethyl
2-((4-iodophenyl)imino)acetate (4j, 30.3 mg, 0.100 mmol,
1.00 Equiv.) without a catalyst in 30 mL dichloromethane. The
crude product was purified by preparative TLC (cyclohexane/ethyl
acetate = 4:1) to give 5aj as a yellow oil in two fractions (F1:
13.1 mg, 22.1 µmol, 22%, F2: 16.3 mg, 27.6 µmol, 28%).
1H, NH) ppm; 13C NMR (100 MHz, acetone-d6, 25 °C, TMS):
δ = 14.3 (+, CH2CH3), 34.0 (+, CH2CHCH2), 38.1 (–, CHCH2), 42.2
(–, CHCH2), 60.7 (–, CH2CH3), 61.4 (+, NCHCInd), 69.0 (+,
NCHCO2Et), 112.1 (+, CHAr), 112.3 (+, CHAr), 118.2 (Cq, CAr),
119.3 (+, CHAr), 119.4 (+, CHAr), 119.5 (+, CHAr), 120.4 (Cq, CAr),
120.9 (+, CHAr), 121.3 (+, CHAr), 121.9 (+, CHAr), 122.1 (+, CHAr),
124.2 (+, CHAr), 127.3 (Cq, CAr), 127.6 (Cq, CAr), 128.6 (+,
2 × CHAr), 129.4 (+, 2 × CHAr), 130.3 (Cq, CAr), 137.7 (Cq, CAr),
137.9 (Cq, CAr), 151.0 (Cq, CAr), 172.8 (Cq, CO2Et) ppm.
Ethyl (2S,4S,6S)-4,6-bis(1H-indol-3-yl)-1-(4-bromophenyl)-
piperidine-2-carboxylate (5ai): This compound was synthesized
following the GP C with 3-vinylindole (3a, 28.6 mg, 0.200 mmol,
2.00 Equiv.) and ethyl 2-((4-bromophenyl)imino)acetate (4i,
25.6 mg, 0.100 mmol, 1.00 Equiv.) in 3.0 mL dichloromethane.
The product 5ai was obtained after column chromatography
fraction 1 (F1): Rf = 0.49 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 1.25 (t, 3J = 7.1 Hz, 3H,
CH2CH3), 2.23 (q, 2J = 12.5 Hz, 1H, NCHCHH), 2.39–2.50 (m, 2H,
CHHCHCO2Et, NCHCHH), 2.69 (dq, J = 13.3, J = 2.6 Hz, 1H,
CHHCHCO2Et), 3.31 (tt, 2J = 12.4, 3J = 3.0 Hz, 1H, CH2CHCH2),
4.07–4.15 (m, 1H, CHHCH3), 4.16–4.25 (m, 1H, CHHCH3), 4.85
2
3
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701502
European Journal of Organic Chemistry
FULL PAPER
3
3
3
(dd, J = 5.6, J = 2.3 Hz, 1H, NCHCO2Et), 5.55 (dd, J = 11.3,
0.100 mmol, 1.00 Equiv.) without
a
catalyst in 3.0 mL
3J = 3.7 Hz, 1H, NCHCInd), 6.93–6.98 (m, 1H, CHAr), 7.00–7.05 (m, dichloromethane. The crude product was purified by preparative
3H, CHAr), 7.06–7.11 (m, 1H, CHAr), 7.13 (d, 3J = 2.1 Hz, 1H,
TLC (cyclohexane/ethyl acetate = 3:1) to give 5bc as a yellow oil
(9.12 mg, 18.0 µmol, 18%).
3
CHAr), 7.19 (d, J = 2.1 Hz, 1H, CHAr), 7.22–7.30 (m, 3H, CHAr),
7.34–7.41 (m, 2H, CHAr), 7.61 (d, 3J = 7.8 Hz, 1H, CHAr), 7.89 (d,
3J = 7.8 Hz, 1H, CHAr), 9.90 (sbr, 1H, NH), 10.00 (sbr, 1H,
NH) ppm; 13C NMR (100 MHz, acetone-d6, 25 °C, TMS): δ = 14.7
(+, CH2CH3), 27.5 (+, CH2CHCH2), 36.8 (–, CHCH2), 43.1 (–,
CHCH2), 52.8 (+, NCHCInd), 60.8 (–, CH2CH3), 65.4 (+,
NCHCO2Et), 84.7 (Cq, CI), 112.1 (+, CHAr), 112.3 (+, CHAr), 119.2
(+, CHAr), 119.3 (Cq, CAr), 119.4 (+, 2 × CHAr), 120.2 (Cq, CAr),
120.7 (+, CHAr), 121.1 (+, CHAr), 121.9 (+, CHAr), 122.2 (+, CHAr),
123.8 (+, CHAr), 126.6 (Cq, CAr), 127.5 (Cq, CAr), 127.6 (+,
2 × CHAr), 137.1 (+, 2 × CHAr), 137.7 (Cq, CAr), 137.8 (Cq, CAr),
152.0 (Cq, CAr), 173.4 (Cq, CO2Et) ppm; IR (ATR): 푣̃ = 3402, 2922,
1722, 1694, 1581, 1483, 1455, 1337, 1246, 1177, 1093, 1009,
952, 818, 740, 651, 581, 477, 424 cm-1; MS (FAB, 3-NBA): m/z
(%): 589 (7) [M]+, 304 (46), 271 (57), 109 (59), 95 (100); HRMS
(FAB, 3-NBA): calcd for C30H28O2N3127I [M]+: 589.1221; found:
589.1219.
Rf = 0.47 (cyclohexane/EtOAc 2:1); 1H NMR (400 MHz, acetone-
d6, 25 °C, TMS): δ = 1.24 (t, J = 7.0 Hz, 3H, CH2CH3), 2.22 (q,
3
3J = 12.2 Hz, 1H, NCHCHH), 2.37 (s, 3H, CH3), 2.39–2.44 (m, 2H,
CHHCHCO2Et, NCHCHH), 2.46 (s, 3H, CH3), 2.66–2.73 (m, 1H,
CHHCHCO2Et), 3.29 (tt, 3J = 12.9, 3J = 2.5 Hz, 1H, CH2CHCH2),
3.37 (s, 1H, CH), 4.06–4.15 (m, 1H, CHHCH3), 4.17–4.24 (m, 1H,
3
3
CHHCH3), 4.92 (dd, J = 5.5, J = 2.2 Hz, 1H, NCHCO2Et), 5.55
(dd, 3J = 11.1, 3J = 3.7 Hz, 1H, NCHCInd), 6.80 (d, 3J = 6.7 Hz, 1H,
CHAr), 6.84–6.97 (m, 4H, CHAr), 7.06–7.12 (m, 2H, CHAr), 7.13–
7.22 (m, 3H, CHAr), 7.45 (d, 3J = 7.4 Hz, 1H, CHAr), 7.72 (d,
3J = 7.4 Hz, 1H, CHAr), 9.85 (sbr, 1H, NH), 9.96 (sbr, 1H,
NH) ppm; 13C NMR (100 MHz, acetone-d6, 25 °C, TMS): δ = 14.7
(+, CH2CH3), 16.8 (+, CH3), 16.9 (+, CH3), 27.5 (+, CH2CHCH2),
36.8 (–, CHCH2), 43.0 (–, CHCH2), 53.0 (+, NCHCInd), 60.9 (–,
CH2CH3), 65.1 (+, NCHCO2Et), 77.3 (+, CH), 84.7 (Cq, CCH),
115.1 (Cq, CAr), 117.0 (+, CHAr), 118.3 (+, CHAr), 119.6 (+, CHAr),
119.7 (+, CHAr), 120.0 (Cq, CAr), 120.7 (Cq, CAr), 120.8 (+, CHAr),
121.2 (Cq, CAr), 121.5 (Cq, CAr), 122.6 (+, CHAr), 122.8 (+, CHAr),
123.4 (+, CHAr), 124.6 (+, 2 × CHAr), 126.3 (Cq, CAr), 127.2 (Cq,
CAr), 132.1 (+, 2 × CHAr), 137.1 (Cq, CAr), 137.3 (Cq, CAr), 152.8
(Cq, CAr), 173.5 (Cq, CO2Et) ppm; IR (ATR): 푣̃ = 3401, 3278, 2923,
2853, 2100, 1724, 1695, 1602, 1508, 1435, 1370, 1342, 1291,
1244, 1175, 1108, 1061, 1021, 940, 829, 782, 746, 645, 571, 533,
476, 408 cm-1; MS (FAB, 3-NBA): m/z (%): 516 (31) [M+H]+, 299
(42), 202 (64), 95 (100); HRMS (FAB, 3-NBA): calcd for
C34H34O2N3 [M+H]+: 516.2646; found: 516.2647.
fraction 2 (F2): Rf = 0.36 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 1.00 (t, 3J = 7.1 Hz, 3H,
CH2CH3), 2.22–2.32 (m, 1H, NCHCHH), 2.34–2.46 (m, 2H,
CHHCHCO2Et, NCHCHH), 2.46–2.57 (m, 1H, CHHCHCO2Et),
3.44 (tt, 3J = 11.9, 3J = 3.8 Hz, 1H, CH2CHCH2), 3.91 (q,
3
3
3J = 7.1 Hz, 2H, CH2CH3), 4.12 (dd, J = 10.9, J = 3.1 Hz, 1H,
NCHCO2Et), 4.66 (dd, 3J = 11.0, 3J = 3.1 Hz, 1H, NCHCInd), 6.98–
7.04 (m, 5H, CHAr), 7.06–7.11 (m, 2H, CHAr), 7.19–7.26 (m, 2H,
3
CHAr), 7.30–7.40 (m, 3H, CHAr), 7.70 (d, J = 7.9 Hz, 1H, CHAr),
7.96–7.99 (m, 1H, CHAr), 9.83 (sbr, 1H, NH), 10.03 (sbr, 1H,
NH) ppm; 13C NMR (100 MHz, acetone-d6, 25 °C, TMS): δ = 14.3
(+, CH2CH3), 27.5 (+, CH2CHCH2), 37.9 (–, CHCH2), 42.1 (–,
CHCH2), 60.7 (–, CH2CH3), 61.0 (+, NCHCInd), 68.6 (+,
NCHCO2Et), 89.1 (Cq, CI), 112.2 (+, CHAr), 112.3 (+, CHAr), 118.3
(Cq, CAr), 119.3 (+, CHAr), 119.4 (+, CHAr), 119.5 (+, CHAr), 120.4
(Cq, CAr), 120.9 (+, CHAr), 121.3 (+, CHAr), 121.9 (+, CHAr), 122.1
(+, CHAr), 124.2 (+, CHAr), 127.2 (Cq, CAr), 127.6 (Cq, CAr), 129.7
(+, 2 × CHAr), 137.7 (+, 2 × CHAr), 137.9 (Cq, CAr), 138.4 (Cq, CAr),
152.1 (Cq, CAr), 172.9 (Cq, CO2Et) ppm; IR (ATR): 푣̃ = 3402, 2922,
2851, 1723, 1693, 1583, 1486, 1456, 1337, 1246, 1178, 1094,
1005, 812, 739, 654, 581, 476, 423 cm-1; MS (FAB, 3-NBA): m/z
(%): 589 (7) [M]+, 304 (27), 271 (31), 154 (21), 133 (100), 95
(57); HRMS (FAB, 3-NBA): calcd for C30H28O2N3127I [M]+:
589.1221; found: 589.1220.
Ethyl 4,6-bis(7-methyl-1H-indol-3-yl)-1-(4-chlorophenyl)-piperidin
e-2-carboxylate (5bh): This compound was synthesized following
the GP C with 7-methyl-3-vinylindole (3b, 31.4 mg, 0.200 mmol,
2.00 Equiv.) and ethyl 2-((4-chlorophenyl)imino)acetate (4h,
21.2 mg, 0.100 mmol, 1.00 Equiv.) in 3.0 mL dichloromethane.
The crude product was purified by preparative TLC
(cyclohexane/ethyl acetate = 3:1) to give 5bh as a yellow oil
(cat-(R): 15.6 mg, 29.7 µmol, 30%; cat-(S): 26.2 mg, 49.8 µmol,
50%).
The racemic compound was obtained following GP C with
7-methyl-3-vinylindole (3b, 31.4 mg, 0.200 mmol, 2.00 Equiv.)
and ethyl 2-((4-chlorophenyl)imino)acetate (4h, 21.2 mg,
0.100 mmol, 1.00 Equiv.) without
a
catalyst in 3.0 mL
Ethyl (2S,4S,6S)-4,6-bis(7-methyl-1H-indol-3-yl)-1-(4-ethynylphe
nyl)-piperidine-2-carboxylate (5bc): This compound was
synthesized following the GP C with 7-methyl-3-vinylindole (3b,
dichloromethane. The product 5bh was obtained after column
chromatography (cyclohexane/ethyl acetate = 2:1) as a yellow oil
in two fractions (F1: 17.6 mg, 33.5 µmol, 33%; F2: 8.90 mg,
16.9 µmol, 17%).
31.4 mg,
0.200 mmol,
2.00 Equiv.)
and
ethyl
2-((4-
ethynylphenyl)imino)acetate
(4c, 20.1 mg,
0.100 mmol,
1.00 Equiv.) in 3.0 mL dichloromethane. The product 5bc was
obtained after column chromatography (cyclohexane/ethyl
acetate = 2:1) as a yellow oil (cat-(R): 24.3 mg, 47.1 µmol, 47%;
cat-(S): 14.9 mg, 28.9 µmol, 29%).
The racemic compound was obtained following GP C with
7-methyl-3-vinylindole (3b, 31.4 mg, 0.200 mmol, 2.00 Equiv.)
and ethyl 2-((4-ethynylphenyl)imino)acetate (4c, 20.1 mg,
fraction 1 (F1): Rf = 0.49 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 1.24 (t, 3J = 7.0 Hz, 3H,
CH2CH3), 2.23 (q, 3J = 12.5 Hz, 1H, NCHCHH), 2.37 (s, 3H, CH3),
2.39–2.45 (m, 2H, CHHCHCO2Et, NCHCHH), 2.46 (s, 3H, CH3),
2.68 (dd, 3J =13.2, 4J = 2.7 Hz, 1H, CHHCHCO2Et), 3.30 (tt,
3J = 12.5, 3J = 3.0 Hz, 1H, CH2CHCH2), 4.06–4.12 (m, 1H,
CHHCH3), 4.18–4.24 (m, 1H, CHHCH3), 4.81 (dd, 3J = 5.6,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701502
European Journal of Organic Chemistry
FULL PAPER
3J = 2.3 Hz, 1H, NCHCO2Et), 5.55 (dd, 3J = 11.2, 3J = 3.6 Hz, 1H,
NCHCInd), 6.78–6.88 (m, 2H, CHAr), 6.89–6.93 (m, 2H, CHAr),
6.94–6.99 (m, 2H, CHAr), 7.08–7.15 (m, 2H, CHAr), 7.16 (d,
3J = 2.4 Hz, 1H, CHAr), 7.17–7.22 (m, 1H, CHAr), 7.45 (d,
3J = 7.7 Hz, 1H, CHAr), 7.74 (d, 3J = 7.7 Hz, 1H, CHAr), 9.84 (sbr,
1H, NH), 9.96 (sbr, 1H, NH) ppm; 13C NMR (100 MHz, acetone-
d6, 25 °C, TMS): δ = 14.7 (+, CH2CH3), 16.8 (+, CH3), 16.9 (+,
CH3), 27.5 (+, CH2CHCH2), 36.9 (–, CHCH2), 43.1 (–, CHCH2),
53.1 (+, NCHCInd), 60.8 (–, CH2CH3), 65.5 (+, NCHCO2Et), 116.0
(+, CHAr), 117.0 (+, CHAr), 118.4 (+, CHAr), 119.7 (+, CHAr), 119.8
(Cq, CAr), 120.6 (Cq, CAr), 120.7 (+, CHAr), 121.2 (Cq, CAr), 121.5
(Cq, CAr), 122.6 (+, CHAr), 122.7 (+, CHAr), 123.5 (+, CHAr), 123.9
(+, CHAr), 126.3 (Cq, CAr), 126.6 (Cq, CAr), 126.8 (+, CHAr), 127.2
(Cq, CAr), 128.1 (+, CHAr), 129.6 (+, CHAr), 137.1 (Cq, CAr), 137.3
(Cq, CAr), 150.9 (Cq, CAr), 173.5 (Cq, CO2Et) ppm; IR (ATR):
푣̃ = 3397, 2930, 1725, 1697, 1596, 1490, 1442, 1369, 1343, 1245,
1176, 1091, 1062, 1021, 940, 818, 782, 746, 716, 683, 582 564,
503, 477 cm-1; MS (FAB, 3-NBA): m/z (%): 525 (25) [M]+, 299 (66),
212 (89), 135 (78); HRMS (FAB, 3-NBA): calcd for
C32H32O2N335Cl [M]+: 525.2178; found: 525.2178.
in two fractions (F1: 14.4 mg, 25.0 μmol, 25%; F2: 14.5 mg,
25.0 μmol, 25%).
fraction 1 (F1): Rf = 0.40 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 1.27 (t, 3J = 7.1 Hz, 3H,
CH2CH3), 2.24–2.33 (m, 1H, 1H, NCHCHH), 2.36 (s, 3H, CH3),
2.37–2.45 (m, 2H, CHHCHCO2Et, NCHCHH), 2.46 (s, 3H, CH3),
2.67 (dq, 3J = 13.2, 3J = 2.6 Hz, 1H, CHHCHCO2Et), 3.28 (tt,
3J = 12.5, 3J = 3.1 Hz, 1H, CH2CHCH2), 4.07–4.18 (m, 1H,
CHHCH3), 4.20–4.30 (m, 1H, CHHCH3), 4.71 (dd, 3J = 5.5,
3J = 2.3 Hz, 1H, NCHCO2Et), 5.48 (dd, 3J = 11.1, 3J = 3.8 Hz, 1H,
NCHCInd), 6.79 (d, 3J = 7.0 Hz, 1H, CHAr), 6.85–6.97 (m, 3H,
CHAr), 7.11 (d, 3J = 2.1 Hz, 1H, CHAr), 7.24 (s, 2H, CHAr), 7.28 (d,
3
3J = 2.4 Hz, 1H, CHAr), 7.45 (d, J = 7.4 Hz, 1H, CHAr), 7.77 (d,
3J = 7.9 Hz, 1H, CHAr), 8.10 (sbr, 1H, OH), 9.88 (sbr, 1H, NH),
9.97 (sbr, 1H, NH) ppm; 13C NMR (100 MHz, acetone-d6, 25 °C,
TMS): δ = 14.7 (+, CH2CH3), 16.8 (+, CH3), 16.9 (+, CH3), 27.5 (+,
CH2CHCH2), 36.9 (–, CHCH2), 42.8 (–, CHCH2), 53.4 (+,
NCHCInd), 60.9 (–, CH2CH3), 65.8 (+, NCHCO2Et), 117.0 (+, CHAr),
118.7 (+, CHAr), 119.5 (Cq, 2 × CAr), 119.6 (+, CHAr), 119.7 (+,
CHAr), 120.6 (Cq, CAr), 120.7 (+, CHAr), 121.2 (Cq, 2 × CAr), 121.5
(Cq, CAr), 122.6 (+, CHAr), 122.7 (+, CHAr), 123.8 (+, CHAr), 126.3
(+, 2 × CHAr), 127.2 (Cq, CAr), 137.3 (Cq, 2 × CAr), 144.7 (Cq, CAr),
145.3 (Cq, 2 × CAr), 173.5 (Cq, CO2Et) ppm; IR (ATR): 푣̃ = 3396,
2921, 2852, 1722, 1694, 1613, 1563, 1479, 1404, 1370, 1343,
1294, 1225, 1160, 1132, 1111, 1092, 1019, 943, 857, 826, 784,
748, 711, 655, 584, 540, 516 cm-1; MS (FAB, 3-NBA): m/z (%):
576 (7) [M+H]+, 299 (13), 154 (34), 132 (100), 91 (72); HRMS
(FAB, 3-NBA): calcd for C32H32O3N335Cl2 [M+H]+: 576.1815;
found: 576.1813.
fraction 2 (F2): Rf = 0.31 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 0.98 (t, 3J = 7.1 Hz, 3H,
CH2CH3), 2.20–2.30 (m, 1H, NCHCHH), 2.30–2.45 (m, 5H,
CHHCHCO2Et, NCHCHH, CH3), 2.47 (s, 3H, CH3), 2.48–2.56 (m,
1H, CHHCHCO2Et), 3.42 (tt, 3J = 12.0, 3J = 3.5 Hz, 1H,
CH2CHCH2), 3.90 (q, 3J = 7.1 Hz, 2H, CH2CH3), 4.08 (dd,
3J = 11.1, 3J = 3.0 Hz, 1H, NCHCO2Et), 4.62 (dd, 3J = 11.1,
3J = 2.9 Hz, 1H, NCHCInd), 6.83 (d, 3J = 7.1 Hz, 1H, CHAr), 6.88–
6.97 (m, 3H, CHAr), 6.98–7.04 (m, 2H, CHAr), 7.06 (d, 3J = 2.5 Hz,
1H, CHAr), 7.18 (d, 3J = 2.5 Hz, 1H, CHAr), 7.20–7.25 (m, 2H,
3
3
CHAr), 7.54 (d, J = 7.6 Hz, 1H, CHAr), 7.82 (d, J = 7.6 Hz, 1H,
CHAr), 9.77 (sbr, 1H, NH), 9.99 (sbr, 1H, NH) ppm; 13C NMR
(100 MHz, acetone-d6, 25 °C, TMS): δ = 14.3 (+, CH2CH3), 16.8
(+, CH3), 16.9 (+, CH3), 27.5 (+, CH2CHCH2), 34.1 (–, CHCH2),
38.1 (–, CHCH2), 42.3 (+, NCHCInd), 60.7 (–, CH2CH3), 69.1 (+,
NCHCO2Et), 117.2 (+, CHAr), 118.6 (+, CHAr), 118.7 (Cq, CAr),
119.6 (+, CHAr), 119.7 (+, CHAr), 120.8 (Cq, CAr), 120.9 (+, CHAr),
121.2 (Cq, CAr), 121.4 (Cq, CAr), 122.6 (+, CHAr), 122.7 (+, CHAr),
123.9 (+, CHAr), 126.9 (Cq, CAr), 127.2 (Cq, CAr), 128.6 (+,
2 × CHAr), 129.4 (+, 2 × CHAr), 130.3 (Cq, CAr), 137.1 (Cq, CAr),
137.3 (Cq, CAr), 151.0 (Cq, CAr), 172.8 (Cq, CO2Et) ppm.
fraction 2 (F2): Rf = 0.30 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 1.02 (t, 3J = 7.1 Hz, 3H,
CH2CH3), 2.22 (q, 3J = 12.3 Hz, 1H, NCHCHH), 2.28–2.41 (m, 2H,
CHHCHCO2Et, NCHCHH), 2.37 (s, 3H, CH3), 2.42–2.52 (m, 1H,
CHHCHCO2Et), 2.47 (s, 3H, CH3), 3.42 (tt, 3J = 12.2, 3J = 3.3 Hz,
1H, CH2CHCH2), 3.94 (q, 3J = 7.1 Hz, 2H, CH2CH3), 4.02 (dd,
3J = 11.2, 3J = 2.6 Hz, 1H, NCHCO2Et), 4.60 (dd, 3J = 11.2,
3J = 2.6 Hz, 1H, NCHCInd), 6.83 (d, 3J = 7.1 Hz, 1H, CHAr), 6.87–
6.99 (m, 3H, CHAr), 7.13 (d, 3J = 2.4 Hz, 1H, CHAr), 7.19 (d,
3J = 2.2 Hz, 1H, CHAr), 7.25 (s, 2H, CHAr), 7.53 (d, 3J = 7.6 Hz, 1H,
3
CHAr), 7.82 (d, J = 7.9 Hz, 1H, CHAr), 8.40 (sbr, 1H, OH), 9.83
(sbr, 1H, NH), 10.00 (sbr, 1H, NH) ppm; 13C NMR (100 MHz,
acetone-d6, 25 °C, TMS): δ = 14.3 (+, CH2CH3), 16.8 (+, CH3),
16.9 (+, CH3), 34.2 (+, CH2CHCH2), 38.3 (–, CHCH2), 42.5 (–,
CHCH2), 60.7 (–, CH2CH3), 61.5 (+, NCHCInd), 69.8 (+,
NCHCO2Et), 117.2 (+, CHAr), 118.4 (+, CHAr), 118.5 (Cq, CAr),
119.7 (+, 2 × CHAr), 120.7 (Cq, CAr), 120.9 (+, CHAr), 121.2 (Cq,
CAr), 121.3 (Cq, 2 × CAr), 121.5 (Cq, CAr), 122.6 (+, CHAr), 122.7 (+,
CHAr), 123.9 (+, CHAr), 127.2 (Cq, CAr), 128.8 (+, 2 × CHAr), 137.1
Ethyl 4,6-bis(7-methyl-1H-indol-3-yl)-1-(3,5-dichloro-4-hydroxyph
enyl)–piperidine-2-carboxylate (5bk):
This compound was synthesized following the GP C with
7-methyl-3-vinylindole (3b, 31.4 mg, 0.200 mmol, 2.00 Equiv.)
and ethyl 2-((3,5-dichloro-4-hydroxyphenyl)imino)acetate (4k,
26.2 mg, 0.100 mmol, 1.00 Equiv.) in 3.0 mL dichloromethane.
The product 5bk was obtained after column chromatography
(cyclohexane/ethyl acetate = 2:1) as a yellow oil (cat-(R): 36.6 mg, (Cq, CAr), 137.3 (Cq, CAr), 144.9 (Cq, 2 × CAr), 147.4 (Cq, CAr),
61.8 µmol, 62%; cat-(S): 15.5 mg, 26.9 µmol, 27%).
172.6 (Cq, CO2Et) ppm; IR (ATR): 푣̃ = 3396, 2920, 2851, 2529,
1722, 1611, 1558, 1477, 1371, 1344, 1226, 1161, 1132, 1110,
1093, 1060, 1019, 942, 857, 823, 783, 746, 710, 679, 654, 584,
515, 487 cm-1; MS (FAB, 3-NBA): m/z (%): 576 (7) [M+H]+, 299
(13), 154 (34), 132 (100), 91 (72); HRMS (FAB, 3-NBA): calcd for
C32H32O3N335Cl2 [M+H]+: 576.1737; found: 576.1735.
The racemic compound was obtained following GP C with
7-methyl-3-vinylindole (3b, 31.4 mg, 0.200 mmol, 2.00 Equiv.)
and ethyl 2-((3,5-dichloro-4-hydroxyphenyl)imino)acetate (4k,
26.2 mg, 0.100 mmol, 1.00 Equiv.) without a catalyst in 3.0 mL
dichloromethane. The product 5bk was obtained after column
chromatography (cyclohexane/ethyl acetate = 2:1) as a yellow oil
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701502
European Journal of Organic Chemistry
FULL PAPER
Ethyl (2S,4S,6S)-4,6-bis(5-cyano-1H-indol-3-yl)-1-(4-tolyl)piperid
ine-2-carboxylate (5cb): This compound was synthesized
following the GP C with 5-cyano-3-vinylindole (3c, 33.6 mg,
0.200 mmol, 2.00 Equiv.) and ethyl 2-((4-tolyl)imino)acetate (4b,
19.1 mg, 0.100 mmol, 1.00 Equiv.) in 3.0 mL dichloromethane.
The product 5cb was obtained after column chromatography
TLC (cyclohexane/ethyl acetate = 1:1) to give 5de as a brown oil
(7.70 mg, 10.0 µmol, 13%).
Rf = 0.28 (cyclohexane/EtOAc 1:1); IR (ATR): 푣̃ = 3354, 2927,
1726, 1620, 1508, 1358, 1318, 1249, 1191, 1041, 977, 885, 799,
732, 463 cm-1; MS (FAB, 3-NBA): m/z (%): 584 (24) [M+H]+, 506
(cyclohexane/ethyl acetate = 2:1) as a yellow oil (cat-(R): 24.3 mg, (23), 396 (49), 395 (100); HRMS (FAB, 3-NBA): calcd for
46.0 µmol, 46%; cat-(S): 17.2 mg, 32.6 µmol, 33%).
The racemic compound was obtained following GP C with
5-cyano-3-vinylindole (3c, 33.6 mg, 0.200 mmol, 2.00 Equiv.) and
ethyl 2-((4-tolyl)imino)acetate (4b, 19.1 mg, 0.100 mmol,
1.00 Equiv.) without a catalyst in 3.0 mL dichloromethane. The
crude product was purified by preparative TLC (cyclohexane/ethyl
acetate = 3:1) to give 5cb as a yellow oil (6.10 mg, 11.6 µmol,
12%).
C31H30O7N5 [M]+: 584.2140; found: 584.2138.
Ethyl 4,6-bis(5-fluoro-1H-indol-3-yl)-1-(4-methoxyphenyl)-piperidi
ne-2-carboxylate (5ee): This compound was synthesized
following the GP C with 5-fluoro-3-vinylindole (3e, 32.2 mg,
0.200 mmol,
2.00 Equiv.)
and
ethyl
2-((4-methoxyphenyl)imino)acetate (4e, 20.7 mg, 0.100 mmol,
1.00 Equiv.) in 3.0 mL dichloromethane. The crude product was
purified by preparative TLC (cyclohexane/ethyl acetate = 4:1) to
give 5ee as a yellow oil (cat-(R): 16.0 mg, 30.0 µmol, 30%;
cat-(S): F1: 19.8 mg, 37.4 µmol, 37%; F2: 20.6 mg, 38.9 µmol,
39%).
Rf = 0.18 (cyclohexane/EtOAc 2:1); 1H NMR (400 MHz, acetone-
d6, 25 °C, TMS): δ = 1.23 (t, 3J = 7.1 Hz, 3H, CH2CH3), 2.14–2.26
(m, 1H, NCHCHH), 2.46 (dq, 2J = 13.0, 3J = 3.3 Hz, 1H,
CHHCHCO2Et), 2.52–2.64 (m, 2H, CHHCHCO2Et, NCHCHH),
2.87 (s, 3H, CH3), 3.43 (tt, 2J = 12.5, 3J = 3.5 Hz, 1H, CH2CHCH2),
4.04–4.11 (m, 1H, CHHCH3), 4.16–4.24 (m, 1H, CHHCH3), 4.77
The racemic compound was obtained following GP C with
5-fluoro-3-vinylindole (3e, 32.2 mg, 0.200 mmol, 2.00 Equiv.) and
ethyl
2-((4-methoxyphenyl)imino)acetate
(4e,
20.7 mg,
3
3
3
(dd, J = 5.3, J = 2.6 Hz, 1H, NCHCO2Et), 5.69 (dd, J = 11.4,
3J = 3.5 Hz, 1H, NCHCInd), 6.78 (d, 3J = 8.2 Hz, 2H, CHAr), 7.14 (d,
3J = 8.4 Hz, 2H, CHAr), 7.26 (dd, 3J = 8.4, 4J = 1.5 Hz, 1H, CHAr),
7.37–7.43 (m, 3H, CHAr), 7.47 (d, 3J = 2.3Hz, 1H, CHAr), 7.56 (d,
3J = 8.4 Hz, 1H, CHAr), 8.07 (s, 1H, CHAr), 8.40–8.42 (m, 1H,
CHAr), 10.44 (sbr, 1H, NH), 10.63 (sbr, 1H, NH) ppm; 13C NMR
(100 MHz, acetone-d6, 25 °C, TMS): δ = 14.7 (+, CH2CH3), 20.6
(+, CArCH3), 27.5 (+, CH2CHCH2), 36.4 (–, CHCH2), 43.4 (–,
CHCH2), 52.8 (+, NCHCInd), 60.7 (–, CH2CH3), 65.7 (+,
NCHCO2Et), 102.3 (Cq, CArCN), 102.5 (Cq, CArCN), 113.3 (+,
CHAr), 113.6 (+, CHAr), 120.9 (Cq, CAr), 121.3 (Cq, CAr), 121.4 (Cq,
CAr), 121.5 (Cq, CAr), 124.0 (+, CHAr), 124.5 (+, CHAr), 124.8 (+,
CHAr), 124.9 (+, CHAr), 125.6 (+, 2 × CHAr), 126.5 (Cq, CAr), 126.6
(+, CHAr), 127.0 (+, CHAr), 127.4 (Cq, CAr), 129.0 (+, 2 × CHAr),
131.8 (Cq, CAr), 139.3 (Cq, CAr), 139.4 (Cq, CAr), 149.0 (Cq, CAr),
173.6 (Cq, CO2Et) ppm; IR (ATR): 푣̃ = 3321, 2921, 2851, 2217,
1695, 1616, 1509, 1469, 1438, 1350, 1245, 1223, 1174, 1087,
1020, 936, 920, 882, 804, 697, 640, 578, 477, 418 cm-1; MS (FAB,
3-NBA): m/z (%): 527 (7) [M]+, 321 (57), 133 (100); HRMS (FAB,
3-NBA): calcd for C33H29O2N5 [M]+: 527.2316; found: 527.2318.
0.100 mmol, 1.00 Equiv.) without
a
catalyst in 3.0 mL
dichloromethane. The crude product was purified by preparative
TLC (cyclohexane/ethyl acetate = 4:1) to give 5ee as a yellow oil
(5.40 mg, 10.2 µmol, 10%).
fraction 1 (F1): Rf = 0.38 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 1.10 (t, 3J = 7.1 Hz, 3H,
CH2CH3), 2.06 (q, 3J = 12.5 Hz, 1H, NCHCHH), 2.20–2.37 (m, 2H,
2
3
CHHCHCO2Et, NCHCHH), 2.44 (dq, J = 13.2, J = 2.5 Hz, 1H,
CHHCHCO2Et), 3.18 (tt, 2J = 12.5, 3J = 3.2 Hz, 1H, CH2CHCH2),
3.44 (s, 3H, OCH3), 3.88–3.99 (m, 1H, CHHCH3), 4.01–4.10 (m,
3
3
1H, CHHCH3), 4.49 (dd, J = 5.6, J = 2.3 Hz, 1H, NCHCO2Et),
5.45 (dd, 3J = 11.3, 3J = 3.5 Hz, 1H, NCHCInd), 6.38–6.44 (m, 2H,
CHAr), 6.56–6.66 (m, 1H, CHAr), 6.70–6.80 (m, 1H, CHAr), 7.00–
7.08 (m, 3H, CHAr), 7.11–7.18 (m, 3H, CHAr), 7.21–7.30 (m, 1H,
3
3
CHAr), 7.51 (dd, J = 10.3, J = 2.5 Hz, 1H, CHAr), 9.80 (sbr, 1H,
NH), 10.00 (sbr, 1H, NH) ppm; 13C NMR (100 MHz, acetone-d6,
25 °C, TMS): δ = 14.7 (+, CH2CH3), 27.5 (+, CH2CHCH2), 36.7 (–,
CHCH2), 43.0 (–, CHCH2), 53.1 (+, NCHCInd), 55.2 (+, OCH3),
60.5 (–, CH2CH3), 66.0 (+, NCHCO2Et), 103.9 (+, d, 2J = 23.4 Hz,
2
2
CHAr), 105.7 (+, d, J = 23.7 Hz, CHAr), 110.0 (+, dd, J = 37.6,
2
3
Ethyl (2S,4S,6S)-4,6-bis(4-nitro-1H-indol-3-yl)-1-(4-methoxyphe
nyl)piperidine-2-carboxylate (5de): This compound was
synthesized following the GP C with 4-nitro-3-vinylindole (3d,
2J = 26.4 Hz, CHAr), 113.0 (+, dd, J = 46.7, J = 9.8 Hz, CHAr),
113.5 (+, 2 × CHAr), 114.9 (Cq, CAr), 115.4 (+, CHAr), 120.0 (Cq,
3J = 4.9 Hz, CAr), 120.6 (Cq, 3J = 4.8 Hz, CAr), 121.3 (Cq, CAr),
123.4 (+, CHAr), 124.4 (+, CHAr), 126.0 (+, CHAr), 127.0 (+,
2 × CHAr), 134.4 (Cq, 3J = 4.2 Hz, CAr), 144.8 (Cq, CAr), 149.2 (Cq,
CAr), 155.8 (Cq, CAr), 156.8 (Cq, d, 1J = 236.6 Hz, CF), 159.6 (Cq,
d, 1J = 235.6 Hz, CF), 173.9 (Cq, CO2Et) ppm; 19F NMR (376 MHz,
acetone-d6, 25 °C): δ = –131.3, –131.4 ppm; IR (ATR): 푣̃ = 3379,
2924, 2852, 1718, 1623, 1579, 1507, 1482, 1346, 1259, 1240,
1160, 1091, 1021, 934, 795, 751, 700, 614, 570, 512, 428 cm-1;
MS (FAB, 3-NBA): m/z (%): 529 (13) [M]+, 316 (25), 132 (100),
107 (19), 91 (31); HRMS (FAB, 3-NBA): calcd for C31H29O3N3F2
[M]+: 529.2172; found: 529.2170.
37.6 mg,
0.200 mmol,
2.00 Equiv.)
and
ethyl
2-((4-methoxyphenyl)imino)acetate (4e, 20.7 mg, 0.100 mmol,
1.00 Equiv.) in 3.0 mL dichloromethane. The crude product was
purified by preparative TLC (cyclohexane/ethyl acetate = 1:1) to
give 5de as a brown oil (cat-(R): 21.5 mg, 40.0 µmol, 37%;
cat-(S): 13.7 mg, 23.5 µmol, 24%).
The racemic compound was obtained following GP C with
4-nitro-3-vinylindole (3d, 37.6 mg, 0.200 mmol, 2.00 Equiv.) and
ethyl
0.100 mmol, 1.00 Equiv.) without
dichloromethane. The crude product was purified by preparative
2-((4-methoxyphenyl)imino)acetate
(4e,
20.7 mg,
a
catalyst in 3.0 mL
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701502
European Journal of Organic Chemistry
FULL PAPER
1
fraction 2 (F2): Rf = 0.18 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 0.99 (t, 3J = 7.1 Hz, 3H,
CH2CH3), 2.22 (q, 2J = 12.1 Hz, 1H, NCHCHH), 2.27–2.45 (m, 3H,
CH2CHCO2Et, NCHCHH), 3.43 (tt, 2J = 12.1, 3J = 3.3 Hz, 1H,
CH2CHCH2), 3.60 (s, 3H, OCH3), 3.87 (q, 3J = 7.1 Hz, 2H,
CqCHCF), 151.8 (Cq, 2 × CAr), 159.2 (Cq, d, J = 25.8 Hz, CF),
161.5 (Cq, d, 1J = 26.1 Hz, CF), 173.7 (Cq, CO2Et) ppm; 19F NMR
(376 MHz, acetone-d6, 25 °C): δ = –128.1, –128.5 ppm; IR (ATR):
푣̃ = 3415 (w), 2932 (w), 1697 (m), 1625 (w), 1595 (w), 1553 (w),
1493 (m), 1453 (m), 1342 (w), 1248 (m), 1219 (m), 1177 (m), 1137
(m), 1112 (m), 1090 (m), 1023 (m), 951 (m), 834 (w), 799 (m), 764
3
CH2CH3), 4.02 (dd, J = 11.2, 3J = 2.6 Hz, 1H, NCHCO2Et), 4.59
(dd, 3J = 11.2, 3J = 2.9 Hz, 1H, NCHCInd), 6.50–6.60 (m, 2H, CHAr), (w), 697 (m), 572 (w), 476 (m), 434 (w), 386 (vw) cm-1; MS (EI,
7.08–7.22 (m, 6H, CHAr), 7.30–7.38 (m, 2H, CHAr), 7.89 (d,
4J = 1.7 Hz, 1H, CHAr), 8.12–8.24 (m, 1H, CHAr), 10.00 (sbr, 1H,
NH), 10.27 (sbr, 1H, NH) ppm; 13C NMR (100 MHz, acetone-d6,
25 °C, TMS): δ = 14.3 (+, CH2CH3), 33.9 (+, CH2CHCH2), 38.2 (–,
CHCH2), 42.7 (–, CHCH2), 55.3 (+, OCH3), 60.5 (–, CH2CH3), 61.3
70 eV): m/z (%): 499 (13) [M]+, 178 (50), 135 (100); HRMS (EI):
calcd for C30H27O2N3F2 [M]+: 499.2066; found: 499.2067.
fraction 2 (F2): Rf = 0.20 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 1.72 (t, 3J = 7.1 Hz, 3H,
CH2CH3), 3.03 (q, 3J = 12.2 Hz, 1H, NCHCHH), 3.09–3.20 (m, 2H,
(+, NCHCInd), 70.0 (+, NCHCO2Et), 112.2 (Cq, CAr), 112.3 (Cq, CAr), CHHCHCO2Et, NCHCHH), 3.20–3.30 (m, 1H, CHHCHCO2Et),
113.8 (+, 2 × CHAr), 113.9 (+, CHAr), 114.1 (+, CHAr), 118.6 (Cq,
CAr), 120.3 (Cq, CAr), 122.0 (+, CHAr), 123.1 (+, CHAr), 123.6 (+,
CHAr), 124.4 (+, CHAr), 124.8 (+, CHAr), 125.7 (+, CHAr), 129.1 (+,
2 × CHAr), 129.2 (Cq, CAr), 129.4 (Cq, CAr), 136.3 (Cq, CAr), 136.4
(Cq, CAr), 144.5 (Cq, CAr), 158.0 (Cq, CAr), 172.8 (Cq,
CO2Et) ppm; 19F NMR (376 MHz, acetone-d6, 25 °C): δ = –131.4,
–131.5 ppm.
4.22 (tt, 3J = 11.9, 3J = 3.6 Hz, 1H, CH2CHCH2), 4.64 (q,
3J = 7.1 Hz, 2H, CH2CH3), 4.87 (dd, J = 11.1, J = 2.9 Hz, 1H,
NCHCO2Et), 5.42 (dd, 3J = 11.1, 3J = 2.9 Hz, 1H, NCHCInd), 7.57–
7.67 (m, 3H, CHAr), 7.72–7.81 (m, 3H, CHAr), 7.85 (d, 3J = 2.3 Hz,
3
3
3
3
1H, CHAr), 7.91 (dd, J = 10.0, J = 2.4 Hz, 1H, CHAr), 7.97–8.03
(m, 3H, CHAr), 8.48 (dd, 3J = 8.7, 3J = 5.4 Hz, 1H, CHAr), 8.77 (dd,
3J = 8.7, 3J = 5.4 Hz, 1H, CHAr), 10.66 (sbr, 1H, NH), 10.93 (sbr,
1H, NH) ppm; 13C NMR (100 MHz, acetone-d6, 25 °C, TMS):
δ = 14.2 (+, CH2CH3), 27.5 (+, CH2CHCH2), 33.9 (–, CHCH2), 38.1
(–, CHCH2), 42.4 (+, NCHCInd), 61.1 (–, CH2CH3), 69.3 (+,
NCHCO2Et), 98.1 (+, dd, 2J = 28.8, 2J = 25.7 Hz, 2 × CHAr), 107.6
(+, dd, 2J = 24.4, 2J = 21.5 Hz, 2 × CHAr), 118.7 (Cq, 2 × CAr),
120.2–120.7 (+, m, CHAr), 121.7–122.1 (+, m, 2 × CHAr), 124.1 (Cq,
Ethyl 4,6-bis(6-fluoro-1H-indol-3-yl)-1-phenylpiperidine-
2carboxylate (5fa): This compound was synthesized following the
GP C with 6-fluoro-3-vinylindole (3f, 32.2 mg, 0.200 mmol,
2.00 Equiv.) and ethyl 2-(phenylimino)acetate (4a, 17.7 mg,
0.100 mmol, 1.00 Equiv.) in 3.0 mL dichloromethane. The product
2
5fa
was
obtained
after
column
chromatography
CAr), 124.4 (Cq, CAr), 124.6 (+, d, J = 3.5 Hz, CHAr), 125.7 (+,
(cyclohexane/ethyl acetate = 2:1) as a yellow oil (cat-(R): 16.2 mg, CHAr), 127.8 (+, 2 × CHAr), 128.6 (+, 2 × CHAr), 137.6 (Cq, dd,
32.3 µmol, 32%; cat-(S): F1: 25.4 mg, 50.8 µmol, 51%; F2:
9.40 mg, 18.8 µmol, 19%).
3J = 23.7, 3J = 12.6 Hz, CqCHCF), 151.9 (Cq, 2 × CAr), 159.2 (Cq,
1
1
d, J = 26.1 Hz, CF), 161.5 (Cq, d, J = 26.3 Hz, CF), 172.9 (Cq,
CO2Et) ppm; 19F NMR (376 MHz, acetone-d6, 25 °C): δ = –128.2,
–128.5 ppm; IR (ATR): 푣̃ = 3357, 2924, 1722, 1696, 1626, 1594,
1553, 1493, 1455, 1372, 1342, 1248, 1220, 1177, 1137, 1092,
1027, 951, 834, 799, 771, 698, 602, 476, 434 cm-1; MS (FAB,
3-NBA): m/z (%): 500 (27) [M+H]+, 178 (55), 135 (89); HRMS
(FAB, 3-NBA): calcd for C30H28O2N3F2 [M+H]+: 500.2144; found:
500.2146.
The racemic compound was obtained following GP C with
6-fluoro-3-vinylindole (3f, 32.2 mg, 0.200 mmol, 2.00 Equiv.) and
ethyl 2-(phenylimino)acetate (4a, 17.7 mg, 0.100 mmol,
1.00 Equiv.) without a catalyst in 3.0 mL dichloromethane. The
product 5fa was obtained after column chromatography
(cyclohexane/ethyl acetate = 3:1) as a yellow oil (29.0 mg,
58.0 µmol, 58%).
fraction 1 (F1): Rf = 0.37 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 1.06 (t, 3J = 7.0 Hz, 3H,
CH2CH3), 2.06 (q, 3J = 12.6 Hz, 1H, NCHCHH), 2.23–2.37 (m, 2H,
Ethyl (2S,4S,6S)-4,6-bis(6-fluoro-1H-indol-3-yl)-1-(4-methoxyph
enyl)-piperidine-2-carboxylate (5fe): This compound was
synthesized following the GP C with 6-fluoro-3-vinylindole (3f,
4
CHHCHCO2Et, NCHCHH), 2.48 (dd, 3J =13.4, J = 2.7 Hz, 1H,
32.2 mg,
0.200 mmol,
2.00 Equiv.)
and
ethyl
2-((4-
CHHCHCO2Et), 3.20 (tt, 3J = 12.5, 3J = 3.1 Hz, 1H, CH2CHCH2),
3.89–3.97 (m, 1H, CHHCH3), 3.99–4.07 (m, 1H, CHHCH3), 4.66
methoxyphenyl)imino)acetate (4e, 20.7 mg,
0.100 mmol,
1.00 Equiv.) in 3.0 mL dichloromethane. The crude product was
purified by preparative TLC (cyclohexane/ethyl acetate = 4:1) to
give 5fe as a yellow oil (cat-(R): 19.3 mg, 36.0 µmol, 36%; cat-(S):
33.7 mg, 63.6 µmol, 64%).
3
3
3
(dd, J = 5.6, J = 2.3 Hz, 1H, NCHCO2Et), 5.47 (dd, J = 11.3,
3J = 3.6 Hz, 1H, NCHCInd), 6.52–6.64 (m, 2H, CHAr), 6.71 (ddd,
3J = 9.8, 3J = 8.8, 3J = 2.4 Hz, 1H, CHAr), 6.80–6.86 (m, 3H, CHAr),
6.96–7.08 (m, 5H, CHAr), 7.45 (dd, 3J = 8.7, 3J = 5.4 Hz, 1H, CHAr), The racemic compound was obtained following GP C with
7.78 (dd, 3J = 8.7, 3J = 5.4 Hz, 1H, CHAr), 9.81 (sbr, 1H, NH), 9.98
(sbr, 1H, NH) ppm; 13C NMR (100 MHz, acetone-d6, 25 °C, TMS):
δ = 14.7 (+, CH2CH3), 27.5 (+, CH2CHCH2), 36.7 (–, CHCH2), 43.3
(–, CHCH2), 52.8 (+, NCHCInd), 60.6 (–, CH2CH3), 65.7 (+,
NCHCO2Et), 98.09 (+, dd, 2J = 32.2, 2J = 25.8 Hz, 2 × CHAr),
107.7 (+, dd, J = 24.5, J = 20.1 Hz, 2 × CHAr), 119.8–120.3 (+,
m, 2 × CHAr), 120.6 (Cq, 2 × CAr), 121.5–121.8 (+, m, CHAr), 121.9
(+, CHAr), 123.5 (Cq, 2 × CAr), 124.4 (+, CHAr), 125.4 (+, 2 × CHAr),
128.3 (+, 2 × CHAr), 137.5 (Cq, dd, 3J = 18.2, 3J = 12.5 Hz,
6-fluoro-3-vinylindole (3f, 32.2 mg, 0.200 mmol, 2.00 Equiv.) and
ethyl 2-((4-methoxyphenyl)imino)acetate (4e, 20.7 mg,
0.100 mmol, 1.00 Equiv.) without catalyst in 3.0 mL
a
dichloromethane. The product 5fe was obtained after column
chromatography (cyclohexane/ethyl acetate = 4:1) as a yellow oil
(5.20 mg, 9.81 µmol, 9.8%).
2
2
Rf = 0.37 (cyclohexane/EtOAc 2:1); 1H NMR (400 MHz, acetone-
3
d6, 25 °C, TMS): δ = 1.21 (t, J = 7.0 Hz, 3H, CH2CH3), 2.19 (q,
3J = 12.6 Hz, 1H, NCHCHH), 2.34–2.49 (m, 2H, CHHCHCO2Et,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701502
European Journal of Organic Chemistry
FULL PAPER
3
4
NCHCHH), 2.57 (dq, J =13.2, J = 2.5 Hz, 1H, CHHCHCO2Et),
3.36 (tt, 2J = 12.5, 3J = 2.8 Hz, 1H, CH2CHCH2), 3.58 (s, 3H,
1H, NH) ppm; 13C NMR (100 MHz, acetone-d6, 25 °C, TMS):
δ = 14.7 (+, CH2CH3), 27.5 (+, CH2CHCH2), 36.6 (–, CHCH2), 43.0
OCH3), 4.03–4.12 (m, 1H, CHHCH3), 4.12–4.24 (m, 1H, CHHCH3), (–, CHCH2), 53.0 (+, NCHCInd), 60.9 (–, CH2CH3), 65.5 (+,
4.60 (dd, 3J = 5.6, 3J = 2.2 Hz, 1H, NCHCO2Et), 5.61 (dd,
NCHCO2Et), 98.2 (+, dd, 2J = 25.7, 2J = 22.9 Hz, 2 × CHAr), 107.7
(+, dd, 2J = 24.5, 3J = 8.2 Hz, 2 × CHAr), 116.4 (+, CHAr), 119.5 (Cq,
CAr), 120.1 (+, d, J = 10.3 Hz, CHAr), 120.4 (Cq, CAr), 121.7 (+,
CHAr), 121.8 (Cq, CAr), 123.3 (Cq, CAr), 124.3 (+, CHAr), 124.5 (Cq,
3
3J = 11.3, J = 3.5 Hz, 1H, NCHCInd), 6.51–6.57 (m, 2H, CHAr),
3
3
4
3
6.75 (ddd, J = 9.8, J = 8.9, J = 2.3 Hz, 1H, CHAr), 6.84 (ddd,
3J = 9.8, 3J = 8.9, 4J = 2.3 Hz, 1H, CHAr), 6.95 (dd, 3J = 10.1,
4J = 2.4 Hz, 1H, CHAr), 7.09–7.19 (m, 5H, CHAr), 7.58 (dd, 3J = 8.7, CAr), 126.8 (Cq, CAr), 126.9 (+, 2 × CHAr), 128.1 (+, 2 × CHAr),
3J = 5.4 Hz, 1H, CHAr), 7.93 (dd, 3J = 8.7, 3J = 5.6 Hz, 1H, CHAr),
9.91 (sbr, 1H, NH), 10.10 (sbr, 1H, NH) ppm; 13C NMR (100 MHz,
acetone-d6, 25 °C, TMS): δ = 14.7 (+, CH2CH3), 27.5 (+,
CH2CHCH2), 36.8 (–, CHCH2), 43.3 (–, CHCH2), 53.0 (+,
NCHCInd), 55.2 (+, OCH3), 60.5 (–, CH2CH3), 66.0 (+, NCHCO2Et),
98.1 (+, dd, 2J = 33.8, 2J = 25.7 Hz, 2 × CHAr), 106.2–106.8 (+, m,
137.7 (Cq, t, 3J = 12.5 Hz, CqCHCHF), 150.7 (Cq, CAr), 159.2 (Cq,
d, 1J = 235.2 Hz, CF), 161.6 (Cq, d, 1J = 235.6 Hz, CF),
173.4 ppm; 19F NMR (376 MHz, acetone-d6, 25 °C): δ = –128.0, –
128.3 ppm; IR (ATR): 푣̃ = 3370, 2930, 1697, 1625, 1592, 1554,
1489, 1454, 1370, 1342, 1248, 1219, 1177, 1137, 1090, 1022,
951, 800, 754, 718, 669, 605, 569, 476, 433 cm-1; MS (FAB,
3-NBA): m/z (%): 534 (9) [M]+, 106 (37), 95 (34); HRMS (FAB,
3-NBA): calcd for C30H27O2N335ClF2 [M+H]+: 534.1754; found:
534.1754.
3
2 × CHAr), 113.5 (+, 2 × CHAr), 119.6 (+, d, J = 10.3 Hz, CHAr),
120.7 (Cq, CAr), 121.7 (+, d, 4J = 3.5 Hz, CHAr), 121.9 (+, d,
3J = 10.1 Hz, CHAr), 123.6 (Cq, CAr), 124.3–124.5 (+, m, CHAr),
127.0 (+, 2 × CHAr), 137.7 (Cq, dd, 3J = 16.4, 3J = 12.6 Hz,
2 × CqCHCF), 144.8 (Cq, 2 × CAr), 155.7 (Cq, 2 × CAr), 159.2 (Cq,
fraction 2 (F2): Rf = 0.28 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 0.85 (t, 3J = 7.1 Hz, 3H,
CH2CH3), 2.10 (q, 3J = 12.3 Hz, 1H, NCHCHH), 2.16–2.28 (m, 2H,
CHHCHCO2Et, NCHCHH), 2.29–2.41 (m, 1H, CHHCHCO2Et),
3.30 (tt, 3J = 12.1, 3J = 3.6 Hz, 1H, CH2CHCH2), 3.76 (q,
1
1
d, J = 27.6 Hz, CF), 161.5 (Cq, d, J = 27.9 Hz, CF), 173.9 (Cq,
CO2Et) ppm; 19F NMR (376 MHz, acetone-d6, 25 °C): δ = –128.1,
–128.6 ppm; IR (ATR): 푣̃ = 3396, 2923, 2540, 1705, 1623, 1553,
1506, 1486, 1451, 1342, 1217, 1176, 1107, 1026, 953, 829, 798,
609, 571, 471, 435 cm-1; MS (FAB, 3-NBA): m/z (%):(100) [M+H]+,
395 (54), 109 (59), 97 (68); HRMS (FAB, 3-NBA): calcd for
C31H30O3N3F2 [M+H]+: 530.2250; found: 530.2250.
3
3
3J = 7.1 Hz, 2H, CH2CH3), 3.95 (dd, J = 11.1, J = 2.9 Hz, 1H,
NCHCO2Et), 4.47 (dd, 3J = 11.1, 3J = 2.9 Hz, 1H, NCHCInd), 6.66–
6.74 (m, 2H, CHAr), 6.82–6.91 (m, 3H, CHAr), 6.95 (d, 3J = 2.4 Hz,
3
3
1H, CHAr), 6.99 (dd, J = 10.1, J = 2.4 Hz, 1H, CHAr), 7.03–7.11
(m, 3H, CHAr), 7.55 (dd, 3J = 8.7, 3J = 5.4 Hz, 1H, CHAr), 7.83 (dd,
3
Ethyl 4,6-bis(6-fluoro-1H-indol-3-yl)-1-(4-chlorophenyl)-piperidin
e-2-carboxylate (5fh): This compound was synthesized following
the GP C with 6-fluoro-3-vinylindole (3f, 32.2 mg, 0.200 mmol,
2.00 Equiv.) and ethyl 2-((4-chlorophenyl)imino)acetate (4h,
21.2 mg, 0.100 mmol, 1.00 Equiv.) in 3.0 mL dichloromethane.
The crude product was purified by preparative TLC
(cyclohexane/ethyl acetate = 3:1) to give 5fh as a yellow oil in two
fractions (cat-(R): F1: 15.8 mg, 29.6 µmol, 30%; F2: 10.3 mg,
19.3 µmol, 19%; cat-(S): F1: 27.3 mg, 51.1 µmol, 51%; F2:
10.7 mg, 20.0 µmol, 20%).
3J = 8.7, J = 5.5 Hz, 1H, CHAr), 9.80 (sbr, 1H, NH), 10.02 (sbr,
1H, NH) ppm; 13C NMR (100 MHz, acetone-d6, 25 °C, TMS):
δ = 14.2 (+, CH2CH3), 33.8 (+, CH2CHCH2), 37.9 (–, CHCH2), 42.1
(–, CHCH2), 60.7 (–, CH2CH3), 61.2 (+, NCHCInd), 69.0 (+,
NCHCO2Et), 98.1 (+, d, 3J = 9.3 Hz, 2 × CHAr), 107.7 (+, dd,
2J = 24.5, 3J = 7.0 Hz, 2 × CHAr), 118.3 (Cq, 2 × CAr), 120.1–120.6
(+, m, 2 × CHAr), 120.9 (+, CHAr), 123.9 (Cq, CAr), 124.3 (+, CHAr),
124.7 (Cq, CAr), 124.8 (Cq, CAr), 128.7 (+, 2 × CHAr), 129.5 (+,
2 × CHAr), 130.5 (Cq, CAr), 137.6 (Cq, dd, 3J = 17.5, 3J = 12.6 Hz,
1
CqCHCHF), 150.8 (Cq, CAr), 159.23 (Cq, d, J = 235.2 Hz, CF),
The racemic compound was obtained following GP C with
6-fluoro-3-vinylindole (3f, 32.2 mg, 0.200 mmol, 2.00 Equiv.) and
ethyl 2-((4-chlorophenyl)imino)acetate (4h, 21.2 mg, 0.100 mmol,
1.00 Equiv.) without a catalyst in 3.0 mL dichloromethane. The
product 5fh was obtained after column chromatography
(cyclohexane/ethyl acetate = 2:1) as a yellow oil (20.0 mg,
37.4 µmol, 37%).
161.6 (Cq, d, 1J = 235.6 Hz, CF), 172.7 (Cq, CO2Et) ppm; 19F NMR
(376 MHz, acetone-d6, 25 °C): δ = –128.1, –128.3 ppm; IR (ATR):
푣̃ = 3370, 2923, 2852, 1722, 1696, 1626, 1591, 1553, 1489, 1455,
1405, 1371, 1342, 1248, 1221, 1178, 1137, 1090, 1024, 951, 828,
799, 755, 720, 670, 569, 476, 432 cm-1; MS (FAB, 3-NBA): m/z
(%): 534 (9) [M]+, 132 (100); HRMS (FAB, 3-NBA): calcd for
C30H27O2N335ClF2 [M+H]+: 534.1754; found: 534.1755.
fraction 1 (F1): Rf = 0.44 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 1.23 (t, 3J = 7.1 Hz, 3H,
CH2CH3), 2.20 (q, 2J = 12.5 Hz, 1H, NCHCHH), 2.37–2.48 (m, 2H,
CHHCHCO2Et, NCHCHH), 2.65 (dq, J = 13.2, J = 2.6 Hz, 1H,
CHHCHCO2Et), 3.29 (tt, 2J = 12.5, 3J = 3.0 Hz, 1H, CH2CHCH2),
4.05–4.15 (m, 1H, CHHCH3), 4.16–4.25 (m, 1H, CHHCH3), 4.80
Ethyl (2S,4S,6S)-4,6-bis(5-chloro-1H-indol-3-yl)-1phenylpiperidin
e-2-carboxylate (5ga): This compound was synthesized following
the GP C with 5-chloro-3-vinylindole (3g, 35.5 mg, 0.200 mmol,
2.00 Equiv.) and ethyl 2-(phenylimino)acetate (4a, 17.7 mg,
0.100 mmol, 1.00 Equiv.) in 3.0 mL dichloromethane. The crude
product was purified by preparative TLC (cyclohexane/ethyl
acetate = 3:1) to give 5ga as a brown oil (cat-(R): 17.0 mg,
32.0 µmol, 32%; cat-(S): 35.5 mg, 66.7 µmol, 67%).
The racemic compound was obtained following GP C with
5-chloro-3-vinylindole (3g, 39.0 mg, 0.200 mmol, 1.80 Equiv.)
and ethyl 2-(phenylimino)acetate (4a, 21.4 mg, 0.121 mmol,
1.00 Equiv.) without a catalyst in 3.0 mL dichloromethane. The
2
3
3
3
3
(dd, J = 5.6, J = 2.3 Hz, 1H, NCHCO2Et), 5.53 (dd, J = 11.3,
3J = 3.6 Hz, 1H, NCHCInd), 6.74 (ddd, 3J = 9.8, 3J = 8.9,
3J = 2.4 Hz, 1H, CHAr), 6.84 (ddd, J = 9.8, J = 8.9, J = 2.4 Hz,
1H, CHAr), 6.94–7.00 (m, 3H, CHAr), 7.12 (dd, 3J = 10.0,
3J = 2.3 Hz, 1H, CHAr), 7.15 (d, 3J = 1.9 Hz, 1H, CHAr), 7.18–7.24
(m, 3H, CHAr), 7.58 (dd, 3J = 8.7, 3J = 5.5 Hz, 1H, CHAr), 7.88 (dd,
3J = 8.7, 3J = 5.5 Hz, 1H, CHAr), 10.00 (sbr, 1H, NH), 10.12 (sbr,
3
3
3
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701502
European Journal of Organic Chemistry
FULL PAPER
product 5ga was obtained after column chromatography
(cyclohexane/ethyl acetate = 2:1) as a brown oil (16.3 mg,
30.6 µmol, 28%).
4J = 2.0 Hz, 1H, CHAr), 10.03 (sbr, 1H, NH), 10.21 (sbr, 1H,
NH) ppm; 13C NMR (125 MHz, acetone-d6, 25 °C, TMS): δ = 14.7
(+, CH2CH3), 20.6 (+, CArCH3), 33.6 (–, CHCH2), 35.0 (+,
CH2CHCH2), 43.0 (–, CHCH2), 52.8 (+, NCHCInd), 60.6 (–,
CH2CH3), 65.8 (+, NCHCO2Et), 113.4 (Cq, CAr), 113.7 (+, CHAr),
115.5 (Cq, CAr), 118.6 (+, CHAr), 119.4 (+, CHAr), 119.7 (Cq, CAr),
120.4 (+, CHAr), 121.8 (+, CHAr), 122.1 (+, CHAr), 122.2 (+, CHAr),
Rf = 0.35 (cyclohexane/EtOAc 2:1); 1H NMR (400 MHz, acetone-
3
d6, 25 °C, TMS): δ = 1.10 (t, J = 7.1 Hz, 3H, CH2CH3), 2.06 (q,
3J = 12.5 Hz, 1H, NCHCHH), 2.26–2.36 (m, 2H, CHHCHCO2Et,
3
4
NCHCHH), 2.50 (dq, J = 13.2, J = 2.6 Hz, 1H, CHHCHCO2Et),
3.19 (tt, 3J = 12.5, 3J = 3.0 Hz, 1H, CH2CHCH2), 3.88–3.98 (m, 1H, 123.1 (Cq, CAr), 124.7 (Cq, CAr), 125.5 (2 × CHAr), 126.5 (Cq, CAr),
CHHCH3), 4.04–4.11 (m, 1H, CHHCH3), 4.68 (dd, 3J = 5.5,
3J = 2.3 Hz, 1H, NCHCO2Et), 5.47 (dd, 3J = 11.3, 3J = 3.5 Hz, 1H,
127.9 (Cq, CAr), 128.5 (+, CHAr), 128.9 (2 × CHAr), 130.1 (Cq, CAr),
131.6 (Cq, CAr), 149.2 (Cq, CAr), 173.6 (Cq, CO2Et) ppm; IR (ATR):
NCHCInd), 6.55 (t, 3J = 7.3 Hz, 1H, CHAr), 6.78–6.87 (m, 3H, CHAr), 푣̃ = 3386, 2923, 1720, 1617, 1509, 1461, 1370, 1210, 1177, 1098,
6.95 (dd, 3J = 8.6, 3J = 2.0 Hz, 1H, CHAr), 7.06–7.14 (m, 4H, CHAr), 1020, 892, 859, 794, 690, 586, 468, 425, 399 cm-1; MS (EI, 70
3
3
7.16 (d, J = 2.4 Hz, 1H, CHAr), 7.26 (d, J = 8.6 Hz, 1H, CHAr),
eV): m/z (%): 547/546/545 (42/25/100) [M]+, 394 (41), 368 (87),
366 (14), 364 (52), 292 (12), 151 (37); HRMS (EI): calcd for
C31H29O2N335Cl2 [M]+: 545.1631; found: 545.1629.
3
3
7.48 (d, J = 2.0 Hz, 1H, CHAr), 7.81 (d, J = 2.0 Hz, 1H, CHAr),
9.93 (sbr, 1H, NH), 10.09 (sbr, 1H, NH) ppm; 13C NMR (100 MHz,
acetone-d6, 25 °C, TMS): δ = 14.7 (+, CH2CH3), 27.5 (+,
CH2CHCH2), 36.6 (–, CHCH2), 43.0 (–, CHCH2), 52.8 (+,
Ethyl (2S,4S,6S)-4,6-bis(5-chloro-1H-indol-3-yl)-1-(4-methoxyph
NCHCInd), 60.7 (–, CH2CH3), 65.7 (+, NCHCO2Et), 113.3 (+, CHAr), enyl)-piperidine-2-carboxylate (5ge): This compound was
113.7 (+, CHAr), 118.6 (+, CHAr), 119.6 (Cq, CAr), 120.2 (Cq, CAr),
120.3 (+, CHAr), 121.9 (+, CHAr), 122.2 (+, CHAr), 122.5 (+, CHAr),
123.1 (+, CHAr), 124.5 (Cq, CAr), 124.7 (Cq, CAr), 125.5 (+, 2 ×
CHAr), 125.7 (+, CHAr), 127.8 (Cq, CAr), 128.3 (+, 2 × CHAr), 128.7
(Cq, CAr), 136.1 (Cq, CAr), 136.2 (Cq, CAr), 151.7 (Cq, CAr), 173.5
(Cq, CO2Et) ppm; IR (ATR): 푣̃ = 3412, 2927, 1721, 1694, 1596,
1492, 1461, 1370 1340, 1246, 1220, 1175, 1097, 1023, 955, 933,
892, 861, 794, 753, 696, 587, 568, 476, 422 cm-1; MS (FAB,
3-NBA): m/z (%): 532 (9) [M+H]+, 178 (46), 133 (100), 109 (40),
107 (40), 105 (46), 104 (33), 97 (40), 95 (72), 93 (44), 91 (74), 83
(58), 81 (88); HRMS (FAB, 3-NBA): calcd for C30H28O2N335Cl2
[M+H]+: 532.1553; found: 532.1552.
synthesized following the GP C with 5-chloro-3-vinylindole (3g,
35.5 mg, 0.200 mmol, 2.00 Equiv.) and ethyl 2-((4-
methoxyphenyl)imino)acetate (4e, 20.7 mg, 0.100 mmol,
1.00 Equiv.) in 3.0 mL dichloromethane. The product 5ge was
obtained after column chromatography (cyclohexane/ethyl
acetate = 2:1) as a yellow oil (cat-(R): 35.9 mg, 63.8 µmol, 64%;
cat-(S): 20.2 mg, 36.0 µmol, 36%)
The racemic compound was obtained following GP C with
5-chloro-3-vinylindole (3g, 35.5 mg, 0.200 mmol, 2.00 Equiv.)
and ethyl 2-((4-methoxyphenyl)imino)acetate (4e, 20.7 mg,
0.100 mmol, 1.00 Equiv.) without
a
catalyst in 3.0 mL
dichloromethane. The product 5ge was obtained after column
chromatography (cyclohexane/ethyl acetate = 2:1) as a yellow oil
(4.69 mg, 8.35 µmol, 8.4%).
Ethyl (2S,4S,6S)-4,6-bis(5-chloro-1H-indol-3-yl)-1-(4-
tolyl)piperidine-2-carboxylate (5gb): This compound was
synthesized following the GP C with 5-chloro-3-vinylindole (3g,
Rf = 0.41 (cyclohexane/EtOAc 2:1); 1H NMR (400 MHz, acetone-
d6, 25 °C, TMS): δ = 1.25 (t, 3J = 7.1 Hz, 3H, CH2CH3), 2.13–2.26
(m, 1H, NCHCHH), 2.35–2.49 (m, 2H, CHHCHCO2Et, NCHCHH),
2.55–2.63 (m, 1H, CHHCHCO2Et), 3.35 (tt, 2J = 12.5, 3J = 3.1 Hz,
1H, CH2CHCH2), 3.58 (s, 3H, OCH3), 4.03–4.09 (m, 1H, CHHCH3),
35.5 mg,
0.200 mmol,
2.00 Equiv.)
and
ethyl 2-(4-
tolylimino)acetate (4b, 19.1 mg, 0.100 mmol, 1.00 Equiv.) in
3.0 mL dichloromethane. The product 5gb was obtained after
column chromatography (cyclohexane/ethyl acetate = 2:1) as a
yellow oil (cat-(R): 36.4 mg, 66.6 µmol, 67%; cat-(S): 22.8 mg,
41.8 µmol, 42%)
3
4.18–4.25 (m, 1H, CHHCH3), 4.62 (dd, J = 5.6, 3J = 2.3 Hz, 1H,
NCHCO2Et), 5.61 (dd, 3J = 11.3, 3J = 3.5 Hz, 1H, NCHCInd), 6.54–
6.57 (m, 2H, CHAr), 6.95 (dd, 3J = 8.6, 4J = 2.1 Hz, 1H, CHAr), 7.08
4
The racemic compound was obtained following GP C with
5-chloro-3-vinylindole (3g, 35.5 mg, 0.200 mmol, 2.00 Equiv.)
and ethyl 2-(4-tolylimino)acetate (4b, 19.1 mg, 0.100 mmol,
1.00 Equiv.) without a catalyst in 3.0 mL dichloromethane. The
product 5gb was obtained after column chromatography
(cyclohexane/ethyl acetate = 2:1) as a yellow oil (22.5 mg,
41.2 µmol, 41%).
(dd, 3J = 8.6, J = 2.1 Hz, 1H, CHAr), 7.15–7.18 (m, 2H, CHAr),
7.22 (d, 3J = 8.6 Hz, 1H, CHAr), 7.27 (dd, 3J = 6.6, 4J = 2.0 Hz, 2H,
3
4
CHAr), 7.39 (d, J = 8.6 Hz, 1H, CHAr), 7.61 (d, J = 2.0 Hz, 1H,
CHAr), 7.96 (d, 4J = 2.0 Hz, 1H, CHAr), 10.01 (sbr, 1H, NH), 10.21
(sbr, 1H, NH) ppm; 13C NMR (100 MHz, acetone-d6, 25 °C, TMS):
δ = 14.7 (+, CH2CH3), 27.5 (+, CH2CHCH2), 36.8 (–, CHCH2), 43.1
(–, CHCH2), 53.0 (+, NCHCInd), 55.2 (+, OCH3), 60.6 (–, CH2CH3),
66.0 (+, NCHCO2Et), 113.3 (+, CHAr), 113.6 (+, 2 × CHAr), 113.7
(+, CHAr), 118.6 (+, CHAr), 119.6 (Cq, CAr), 120.3 (Cq, CAr), 120.4
(+, CHAr), 121.8 (+, CHAr), 122.2 (+, CHAr), 123.1 (+, CHAr), 124.4
(Cq, CAr), 124.7 (Cq, CAr), 125.8 (+, CHAr), 127.0 (+, 2 × CHAr),
Rf = 0.50 (cyclohexane/EtOAc 2:1); 1H NMR (500 MHz, acetone-
3
d6, 25 °C, TMS): δ = 1.24 (t, J = 7.1 Hz, 3H, CH2CH3), 1.96 (s,
3H, CArCH3), 2.15–2.26 (m, 1H, NCHCHH), 2.34–2.49 (m, 2H,
2
3
CH2CHCO2Et), 2.61 (dq, J = 13.1, J = 2.4 Hz, 1H, NCHCHH),
3.32 (tt, 2J = 12.3, 3J = 3.1 Hz, 1H, CH2CHCH2), 4.01–4.11 (m, 1H, 127.9 (Cq, CAr), 128.7 (Cq, CAr), 136.1 (Cq, CAr), 136.2 (Cq, CAr),
CHHCH3), 4.13–4.26 (m, 1H, CHHCH3), 4.73 (dd, 3J = 5.5,
3J = 2.3 Hz, 1H, NCHCO2Et), 5.60 (dd, 3J = 11.3, 3J = 3.6 Hz, 1H,
NCHCInd), 6.77 (d, 3J = 8.1 Hz, 2H, CHAr), 6.90–6.99 (m, 1H,
CHAr), 7.05–7.13 (m, 3H, CHAr), 7.20–7.30 (m, 3H, CHAr), 7.39 (d,
144.7 (Cq, CAr), 155.8 (Cq, CAr), 173.8 (Cq, CO2Et) ppm; IR (ATR):
푣̃ = 3414, 2931, 1716, 1506, 1461, 1371, 1239, 1176, 1097, 1032,
934, 891, 860, 828, 793, 752, 690, 586, 479, 422 cm-1; MS (FAB,
3-NBA): m/z (%): 563/562/561 (34/38/44) [M]+, 341/339 (65/100),
208 (82), 154 (36), 136 (43), 134 (90), 107 (43), 97 (47), 95 (65),
4
3J = 8.7 Hz, 1H, CHAr), 7.61 (d, J = 2.0 Hz, 1H, CHAr), 7.95 (d,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701502
European Journal of Organic Chemistry
FULL PAPER
81 (68); HRMS (FAB, 3-NBA): calcd for C31H29O3N335Cl2 [M]+:
561.1580; found: 561.1581.
NCHCO2Et), 4.60 (dd, 3J = 11.1, 3J = 2.9 Hz, 1H, NCHCInd), 6.72–
6.81 (m, 2H, CHAr), 6.99 (dd, 3J = 8.6, 3J = 2.1 Hz, 1H, CHAr), 7.08
(dd, 3J = 8.6, 3J = 2.1 Hz, 1H, CHAr), 7.16 (d, 3J = 2.5 Hz, 1H,
3
Ethyl 4,6-bis(5-chloro-1H-indol-3-yl)-1-(4-fluorophenyl)-
piperidine-2-carboxylate (5gg): This compound was synthesized
following the GP C with 5-chloro-3-vinylindole (3g, 35.5 mg,
CHAr), 7.22–7.29 (m, 3H, CHAr), 7.35 (d, J = 2.3 Hz, 1H, CHAr),
3
3
7.40 (d, J = 8.6 Hz, 1H, CHAr), 7.73 (d, J = 2.0 Hz, 1H, CHAr),
3
8.00 (d, J = 2.0 Hz, 1H, CHAr), 10.03 (sbr, 1H, NH), 10.27 (sbr,
0.200 mmol,
fluorophenyl)imino)acetate
1.00 Equiv.) in 3.0 mL dichloromethane. The product 5gg was
obtained after column chromatography (cyclohexane/ethyl
2.00 Equiv.)
(4g,
and
19.5 mg,
ethyl
2-((4-
1H, NH) ppm; 13C NMR (100 MHz, acetone-d6, 25 °C, TMS):
δ = 14.3 (+, CH2CH3), 33.8 (+, CH2CHCH2), 38.1 (–, CHCH2), 42.4
(–, CHCH2), 60.6 (–, CH2CH3), 61.4 (+, NCHCInd), 69.6 (+,
NCHCO2Et), 113.5 (+, CHAr), 113.7 (+, CHAr), 115.0 (+, CHAr),
0.100 mmol,
acetate = 2:1) as a yellow oil in two fractions (cat-(R): F1: 36.7 mg, 115.2 (+, CHAr), 118.2 (Cq, CAr), 118.8 (+, CHAr), 120.2 (Cq, CAr),
66.7 µmol, 67%, F2: 17.7 mg, 32.2 µmol, 32%; cat-(S): 31.3 mg,
56.9 µmol, 57%, F2: 12.4 mg, 22.5 µmol, 23%).
The racemic compound was obtained following GP C with
5-chloro-3-vinylindole (3g, 37.3 mg, 0.210 mmol, 1.78 Equiv.)
120.3 (+, CHAr), 122.0 (+, CHAr), 122.2 (+, CHAr), 123.3 (+, CHAr),
124.6 (Cq, CAr), 124.8 (Cq, CAr), 126.0 (+, CHAr), 128.4 (Cq, CAr),
128.7 (Cq, CAr), 129.9 (+, CHAr), 130.0 (+, CHAr), 136.1 (Cq, CAr),
136.2 (Cq, CAr), 148.0 (Cq, CAr), 160.8 (Cq, d, 1J = 238.9 Hz, CF),
172.6 (Cq, CO2Et) ppm; 19F NMR (376 MHz, acetone-d6, 25 °C):
δ = –123.1 ppm; IR (ATR): 푣̃ = 3352, 2923, 1724, 1695, 1504,
1462, 1380, 1247, 1210, 1177, 1095, 1029, 893, 858, 832, 796,
754, 671, 588, 541, 477, 424 cm-1; MS (FAB, 3-NBA): m/z (%):
550 (31) [M+H]+, 341 (30), 339 (46), 221 (36), 207 (36), 196 (65),
154 (37), 149 (64), 147 (94), 137 (31), 136 (38), 133 (80), 123
(30), 122 (43), 119 (37), 109 (45), 107 (40), 105 (40), 97 (54), 95
(81), 93 (57), 91 (67), 85 (57), 83 (89), 80 (100); HRMS (FAB,
3-NBA): calcd for C30H27O2N335Cl2F [M+H]+: 550.1459; found:
550.1458.
and
ethyl 2-((4-fluorophenyl)imino)acetate
(4g,
23.0 mg,
0.118 mmol, 1.00 Equiv.) without
a
catalyst in 3.0 mL
dichloromethane. The product 5gg was obtained after column
chromatography (cyclohexane/ethyl acetate = 2:1) as a yellow oil
in two fractions (F1: 30.7 mg, 55.7 μmol, 53%; F2: 23.9 mg,
43.3 μmol, 41%).
fraction 1 (F1): Rf = 0.32 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 1.25 (t, 3J = 7.1 Hz, 3H,
CH2CH3), 2.21 (q, 3J = 12.5 Hz, 1H, NCHCHH), 2.37–2.50 (m, 2H,
3
3
CHHCHCO2Et, NCHCHH), 2.64 (dq, J = 13.2, J = 2.4 Hz, 1H,
CHHCHCO2Et), 3.32 (tt, 3J = 12.5, 3J = 2.9 Hz, 1H, CH2CHCH2),
4.02–4.13 (m, 1H, CHHCH3), 4.18–4.28 (m, 1H, CHHCH3), 4.73
Ethyl 4,6-bis(5-chloro-1H-indol-3-yl)-1-(4-chlorophenyl)-piperidin
e-2-carboxylate (5gh): This compound was synthesized following
3
3
3
(dd, J = 5.5, J = 2.2 Hz, 1H, NCHCO2Et), 5.57 (dd, J = 11.3,
3J = 3.5 Hz, 1H, NCHCInd), 6.74 (t, 3J = 8.8 Hz, 2H, CHAr), 6.96 (dd, the GP C with 5-chloro-3-vinylindole (3g, 35.5 mg, 0.200 mmol,
3J = 8.6, 4J = 2.0 Hz, 1H, CHAr), 7.09 (dd, 3J = 8.6, 4J = 2.0 Hz, 1H, 2.00 Equiv.) and ethyl 2-((4-chlorophenyl)imino)acetate (4h,
4
CHAr), 7.22–7.28 (m, 4H, CHAr), 7.32 (d, J = 2.0 Hz, 1H, CHAr),
21.2 mg, 0.100 mmol, 1.00 Equiv.) in 3.0 mL dichloromethane.
The crude product was purified by preparative TLC
(cyclohexane/ethyl acetate = 3:1) to give 5gh as a yellow oil
(cat-(R): 16.5 mg, 29.0 µmol, 29%; cat-(S): 52.2 mg, 92.1 µmol,
92%).
The racemic compound was obtained following GP C with
5-chloro-3-vinylindole (3g, 36.4 mg, 0.205 mmol, 2.00 Equiv.)
and ethyl 2-((4-chlorophenyl)imino)acetate (4h, 29.2 mg,
3
4
7.40 (d, J = 8.6 Hz, 1H, CHAr), 7.62 (d, J = 2.0 Hz, 1H, CHAr),
4
7.94 (d, J = 2.0 Hz, 1H, CHAr), 10.10 (sbr, 1H, NH), 10.24 (sbr,
1H, NH) ppm; 13C NMR (100 MHz, acetone-d6, 25 °C, TMS):
δ = 14.7 (+, CH2CH3), 27.5 (+, CH2CHCH2), 36.7 (–, CHCH2), 42.9
(–, CHCH2), 53.0 (+, NCHCInd), 60.8 (–, CH2CH3), 65.8 (+,
NCHCO2Et), 113.4 (+, CHAr), 113.7 (+, CHAr), 114.5 (+, CHAr),
114.8 (+, CHAr), 118.6 (+, CHAr), 119.2 (Cq, CAr), 120.0 (Cq, CAr),
120.3 (+, CHAr), 121.9 (+, CHAr), 122.2 (+, CHAr), 123.1 (+, CHAr),
124.6 (Cq, CAr), 124.7 (Cq, CAr), 125.9 (+, CHAr), 127.3 (+, CHAr),
127.4 (+, CHAr), 127.7 (Cq, CAr), 128.7 (Cq, CAr), 136.1 (Cq, CAr),
136.2 (Cq, CAr), 147.9 (Cq, CAr), 158.8 (Cq, d, 1J = 238.9 Hz, CF),
173.4 (Cq, CO2Et) ppm; 19F NMR (376 MHz, acetone-d6, 25 °C):
δ = –127.4 ppm; IR (ATR): 푣̃ = 3369, 2929, 1696, 1549, 1504,
1461, 1368, 1248, 1210, 1175, 1097, 1022, 934, 892, 862, 833,
795, 754, 690, 588, 478, 423 cm-1; MS (FAB, 3-NBA): m/z (%):
550 (22) [M+H]+, 155 (41), 154 (92), 138 (41), 137 (69), 136 (81),
133 (55), 123 (37), 121 (32), 119 (34), 111 (35), 109 (55), 107
(56), 105 (41), 97 (68), 95 (89), 93 (47), 91 (64), 85 (35), 83 (76),
81 (100); HRMS (FAB, 3-NBA): calcd for C30H27O2N335Cl2F
[M+H]+: 550.1459; found: 550.1461.
0.138 mmol, 1.00 Equiv.) without
a
catalyst in 3.0 mL
dichloromethane. The product 5gh was obtained after column
chromatography (cyclohexane/ethyl acetate = 2:1) as a yellow oil
in two fractions (F1: 34.6 mg, 61.0 μmol, 44%; F2: 33.9 mg,
59.8 μmol, 43%).
fraction 1 (F1): Rf = 0.38 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 1.27 (t, 3J = 7.1 Hz, 3H,
CH2CH3), 2.20 (q, 2J = 12.5 Hz, 1H, NCHCHH), 2.38–2.49 (m, 2H,
2
3
CHHCHCO2Et, NCHCHH), 2.67 (dq, J = 13.2, J = 2.6 Hz, 1H,
CHHCHCO2Et), 3.28 (tt, 2J = 12.5, 3J = 2.9 Hz, 1H, CH2CHCH2),
4.05–4.15 (m, 1H, CHHCH3), 4.18–4.35 (m, 1H, CHHCH3), 4.83
3
3
3
(dd, J = 5.5, J = 2.6 Hz, 1H, NCHCO2Et), 5.54 (dd, J = 11.3,
3J = 3.6 Hz, 1H, NCHCInd), 6.63–6.69 (m, 1H, CHAr), 6.93–7.00 (m,
2H, CHAr), 7.01–7.05 (m, 1H, CHAr), 7.08 (dd, 3J = 8.6, 3J = 2.0 Hz,
1H, CHAr), 7.20–7.28 (m, 3H, CHAr), 7.33 (d, 3J = 2.4 Hz, 1H,
fraction 2 (F2): Rf = 0.13 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 0.97 (t, 3J = 7.1 Hz, 3H,
CH2CH3), 2.18–2.29 (m, 1H, NCHCHH), 2.30–2.39 (m, 2H,
CHHCHCO2Et, NCHCHH), 2.40–2.50 (m, 1H, CHHCHCO2Et),
3.45 (tt, 3J = 12.2, 3J = 3.6 Hz, 1H, CH2CHCH2), 3.88 (q,
3
3
CHAr), 7.40 (d, J = 8.6 Hz, 1H, CHAr), 7.61 (d, J = 2.4 Hz, 1H,
CHAr), 7.91 (d, 3J = 2.4 Hz, 1H, CHAr), 10.13 (sbr, 1H, NH), 10.24
(sbr, 1H, NH) ppm; 13C NMR (100 MHz, acetone-d6, 25 °C, TMS):
δ = 14.7 (+, CH2CH3), 27.5 (+, CH2CHCH2), 36.6 (–, CHCH2), 42.8
3
3
3J = 7.1 Hz, 2H, CH2CH3), 4.07 (dd, J = 11.3, J = 2.6 Hz, 1H,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701502
European Journal of Organic Chemistry
FULL PAPER
(–, CHCH2), 53.0 (+, NCHCInd), 60.9 (–, CH2CH3), 65.5 (+,
NCHCO2Et), 113.5 (+, CHAr), 113.7 (+, CHAr), 116.4 (+, CHAr),
118.6 (+, CHAr), 119.1 (Cq, CAr), 120.0 (Cq, CAr), 120.2 (+, CHAr),
122.0 (+, CHAr), 122.2 (+, CHAr), 123.1 (+, CHAr), 124.6 (Cq, CAr),
124.7 (Cq, CAr), 125.9 (+, CHAr), 126.9 (Cq, CAr), 127.0 (+, CHAr),
127.7 (Cq, CAr), 128.2 (+, CHAr), 128.7 (Cq, CAr), 129.5 (+, CHAr),
136.1 (Cq, CAr), 136.2 (Cq, CAr), 150.7 (Cq, CAr), 173.3 (Cq,
CO2Et) ppm; IR (ATR): 푣̃ = 3367, 2926, 1723, 1695, 1592, 1568,
1489, 1461, 1370, 1340, 1246, 1220, 1176, 1093, 1022, 956, 934,
892, 861, 827, 795, 754, 717, 665, 587, 565, 476, 422 cm-1; MS
(FAB, 3-NBA): m/z (%): 566 (13) [M]+, 339 (38), 135 (85); HRMS
(FAB, 3-NBA): calcd for C30H27O2N335Cl3 [M+H]+: 566.1163;
found: 566.1163.
CH2CH3), 2.19 (q, 3J = 12.5 Hz, 1H, NCHCHH), 2.39–2.49 (m, 2H,
4
CHHCHCO2Et, NCHCHH), 2.67 (dq, 3J =13.2, J = 2.5 Hz, 1H,
CHHCHCO2Et), 3.28 (tt, 3J = 12.6, 3J = 3.0 Hz, 1H, CH2CHCH2),
4.04–4.16 (m, 1H, CHHCH3), 4.19–4.29 (m, 1H, CHHCH3), 4.84
3
3
3
(dd, J = 5.5, J = 2.3 Hz, 1H, NCHCO2Et), 5.53 (dd, J = 11.3,
3J = 3.6 Hz, 1H, NCHCInd), 6.96 (dd, 3J = 8.6, 3J = 2.1 Hz, 1H,
3
CHAr), 7.05–7.20 (m, 5H, CHAr), 7.25 (d, J = 8.8 Hz, 2H, CHAr),
7.33 (d, J = 2.4 Hz, 1H, CHAr), 7.40 (d, J = 8.6 Hz, 1H, CHAr),
3
3
3
3
7.61 (d, J = 1.9 Hz, 1H, CHAr), 7.91 (d, J = 2.4 Hz, 1H, CHAr),
10.13 (sbr, 1H, NH), 10.24 (sbr, 1H, NH) ppm; 13C NMR (100 MHz,
acetone-d6, 25 °C, TMS): δ = 14.7 (+, CH2CH3), 27.5 (+,
CH2CHCH2), 36.6 (–, CHCH2), 42.8 (–, CHCH2), 52.9 (+,
NCHCInd), 60.9 (–, CH2CH3), 65.4 (+, NCHCO2Et), 113.5 (+, CHAr),
113.7 (+, CHAr), 114.6 (Cq, CAr), 118.6 (+, CHAr), 119.1 (Cq, CAr),
120.0 (Cq, CAr), 120.2 (+, CHAr), 122.0 (+, CHAr), 122.2 (+, CHAr),
123.1 (+, CHAr), 124.6 (Cq, CAr), 124.7 (Cq, CAr), 125.9 (+, CHAr),
127.4 (+, 2 × CHAr), 127.6 (Cq, CAr), 128.7 (Cq, CAr), 131.1 (+, 2 ×
CHAr), 136.1 (Cq, CAr), 136.2 (Cq, CAr), 151.1 (Cq, CAr), 173.2 (Cq,
fraction 2 (F2): Rf = 0.18 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 0.83 (t, 3J = 7.1 Hz, 3H,
CH2CH3), 2.17–2.51 (m, 4H, NCHCH2, CH2CHCO2Et), 3.45 (tt,
3J = 12.2, 3J = 3.5 Hz, 1H, CH2CHCH2), 3.90 (q, 3J = 7.1 Hz, 2H,
3
CH2CH3), 4.09 (dd, J = 11.1, 3J = 2.6 Hz, 1H, NCHCO2Et), 4.64
(dd, 3J = 11.0, 3J = 2.4 Hz, 1H, NCHCInd), 6.96–7.11 (m, 4H, CHAr), CO2Et) ppm; IR (ATR): 푣̃ = 3360, 2926, 1695, 1586, 1487, 1461,
7.20–7.24 (m, 2H, CHAr), 7.34 (s, 1H, CHAr), 7.40 (d, 3J = 8.6 Hz,
1369, 1247, 1177, 1098, 1023, 892, 862, 823, 795, 754, 651, 587,
564, 477, 423 cm-1; MS (FAB, 3-NBA): m/z (%): 610 (5) [M+H]+,
3
1H, CHAr), 7.72 (s, 1H, CHAr), 7.98 (d, J = 10.3 Hz, 3H, CHAr),
10.08 (sbr, 1H, NH), 10.30 (sbr, 1H, NH) ppm; 13C NMR (100 MHz, 133 (67), 123 (32), 119 (32), 111 (30), 109 (55), 107 (37), 105
acetone-d6, 25 °C, TMS): δ = 14.3 (+, CH2CH3), 33.7 (+,
(41), 97 (61), 95 (91), 93 (44), 91 (51), 85 (38), 83 (83), 81
CH2CHCH2), 38.0 (–, CHCH2), 42.2 (–, CHCH2), 60.8 (–, CH2CH3), (100); HRMS (FAB, 3-NBA): calcd for C30H27O2N379Br35Cl2
61.0 (+, NCHCInd), 69.1 (+, NCHCO2Et), 113.6 (+, CHAr), 113.8 (+,
CHAr), 118.1 (Cq, 2 × CAr), 118.9 (+, CHAr), 120.3 (+, CHAr), 122.1
(+, CHAr), 122.3 (+, CHAr), 123.4 (+, CHAr), 124.7 (Cq, CAr), 124.8
(Cq, CAr), 126.2 (+, CHAr), 128.4 (Cq, CAr), 128.8 (+, 2 × CHAr),
128.8 (Cq, CAr), 129.6 (+, 2 × CHAr), 130.7 (Cq, CAr), 136.2 (Cq,
CAr), 136.3 (Cq, CAr), 150.9 (Cq, CAr), 172.8 (Cq, CO2Et) ppm; IR
(ATR): 푣̃ = 3292, 2925, 1727, 1662, 1459, 1381, 1222, 1144,
1093, 1011, 981, 893, 851, 796, 757, 671, 625, 425 cm-1; MS
(FAB, 3-NBA): m/z (%): 566 (9) [M+H]+, 133 (100), 109 (29), 107
(25), 105 (27), 97 (32), 95 (50), 93 (27), 91 (41), 83 (46), 81 (55);
HRMS (FAB, 3-NBA): calcd for C30H27O2N335Cl3 [M+H]+:
566.1163; found: 566.1162.
[M+H]+: 610.0658; found: 610.0660.
fraction 2 (F2): Rf = 0.22 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 1.00 (t, 3J = 7.1 Hz, 3H,
CH2CH3), 2.17–2.50 (m, 4H, NCHCH2, CH2CHCO2Et), 3.46 (tt,
3J = 11.9, 3J = 3.6 Hz, 1H, CH2CHCH2), 3.91 (q, 3J = 7.1 Hz, 2H,
3
CH2CH3), 4.11 (dd, J = 11.0, 3J = 2.9 Hz, 1H, NCHCO2Et), 4.66
(dd, 3J = 10.8, 3J = 3.1 Hz, 1H, NCHCInd), 7.00 (dd, 3J = 8.6,
3J = 2.0 Hz, 1H, CHAr), 7.08 (dd, 3J = 8.6, 3J = 2.0 Hz, 1H, CHAr),
7.13–7.28 (m, 6H, CHAr), 7.34 (d, 3J = 2.2 Hz, 1H, CHAr), 7.40 (d,
3
3J = 8.7 Hz, 1H, CHAr), 7.72 (d, J = 1.9 Hz, 1H, CHAr), 7.99 (d,
3J = 1.9 Hz, 1H, CHAr), 10.06 (sbr, 1H, NH), 10.27 (sbr, 1H,
NH) ppm; 13C NMR (100 MHz, acetone-d6, 25 °C, TMS): δ = 14.2
(+, CH2CH3), 27.4 (+, CH2CHCH2), 33.5 (–, CHCH2), 37.7 (–,
CHCH2), 42.2 (+, NCHCInd), 60.8 (–, CH2CH3), 68.9 (+,
NCHCO2Et), 113.5 (+, CHAr), 113.7 (+, CHAr), 118.0 (Cq, CAr),
118.5 (Cq, CAr), 118.8 (+, CHAr), 120.1 (Cq, CAr), 120.2 (+, CHAr),
122.0 (+, CHAr), 122.2 (+, CHAr), 123.3 (+, CHAr), 124.6 (Cq, CAr),
124.8 (Cq, CAr), 126.1 (+, CHAr), 128.3 (Cq, CAr), 128.7 (Cq, CAr),
129.8 (+, 2 × CHAr), 131.8 (+, 2 × CHAr), 136.0 (Cq, CAr), 136.2 (Cq,
CAr), 151.3 (Cq, CAr), 172.7 (Cq, CO2Et) ppm; IR (ATR): 푣̃ = 3292,
2924, 1725, 1697, 1661, 1484, 1461, 1384, 1245, 1176, 1095,
1031, 1008, 893, 858, 795, 755, 718, 658, 621, 539, 476, 423 cm-
1; MS (FAB, 3-NBA): m/z (%): 610 (8) [M+H]+, 154 (37), 147 (52),
137 (34), 136 (41), 133 (43), 123 (34), 121 (30), 119 (30), 111
(34), 109 (59), 107 (43), 105 (37), 97 (73), 95 (96), 93 (43), 91
(50), 85 (51), 83 (93), 81 (100); HRMS (FAB, 3-NBA): calcd for
C30H27O2N379Br35Cl2 [M+H]+: 610.0658; found: 610.0658.
Ethyl 4,6-bis(5-chloro-1H-indol-3-yl)-1-(4-bromophenyl)-piperidin
e-2-carboxylate (5gi): This compound was synthesized following
the GP C with 5-chloro-3-vinylindole (3g, 35.5 mg, 0.200 mmol,
2.00 Equiv.) and ethyl 2-((4-bromophenyl)imino)acetate (4i,
25.6 mg, 0.100 mmol, 1.00 Equiv.) in 3.0 mL dichloromethane.
The product 5gi was obtained after column chromatography
(cyclohexane/ethyl acetate = 2:1) as a yellow oil in two fractions
cat-(R): F1: 28.5 mg, 46.6 µmol, 47%, F2: 9.40 mg, 15.4 µmol,
15%; cat-(S): F1: 21.4 mg, 35.0 µmol, 35%, F2: 25.2 mg,
41.2 µmol, 41%).
The racemic compound was obtained following GP C with
5-chloro-3-vinylindole (3g, 39.0 mg, 0.219 mmol, 1.80 Equiv.)
and ethyl 2-((4-bromophenyl)imino)acetate (4i, 21.4 mg,
0.121 mmol, 1.00 Equiv.) without
a
catalyst in 3.0 mL
dichloromethane. The product 5gi was obtained after column
chromatography (cyclohexane/ethyl acetate = 2:1) as a yellow oil
in two fractions (F1: 26.3 mg, 43.0 μmol, 41%; F2: 14.7 mg,
24.0 μmol, 23%).
fraction 1 (F1): Rf = 0.39 (cyclohexane/EtOAc 2:1); 1H NMR (400
MHz, acetone-d6, 25 °C, TMS): δ = 1.27 (t, 3J = 7.0 Hz, 3H,
Ethyl (2S,4S,6S)-4,6-bis(5-chloro-1H-indol-3-yl)-1-(3,5-dichloro-4
-hydroxyphenyl)–piperidine-2-carboxylate (5gk): This compound
was synthesized following the GP C with 5-chloro-3-vinylindole
(3g, 35.5 mg, 0.200 mmol, 2.00 Equiv.) and ethyl 2-((3,5-dichloro-
4-hydroxyphenyl)imino)acetate (4k, 26.2 mg, 0.100 mmol,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701502
European Journal of Organic Chemistry
FULL PAPER
3
4
1.00 Equiv.) in 3.0 mL dichloromethane. The product 5gk was
obtained after column chromatography (cyclohexane/ethyl
acetate = 2:1) as a yellow oil (cat-(R): 24.1 mg, 39.0 µmol, 39%;
cat-(S): 28.9 mg, 46.8 µmol, 47%)
NCHCHH), 2.64 (dd, J = 13.2, J = 2.6 Hz, 1H, CHHCHCO2Et),
3.32 (tt, 2J = 12.5, 3J = 3.0 Hz, 1H, CH2CHCH2), 4.04–4.10 (m, 1H,
CHHCH3), 4.17–4.25 (m, 1H, CHHCH3), 4.82 (dd, 3J = 5.5,
3J = 2.2 Hz, 1H, NCHCO2Et), 5.61 (dd, 3J = 11.3, 3J = 3.5 Hz, 1H,
NCHCInd), 6.69 (t, 3J = 7.3 Hz, 1H, CHAr), 6.98 (t, 3J = 7.9 Hz, 2H,
CHAr), 7.07 (dd, 3J = 7.9, 4J = 1.8 Hz, 1H, CHAr), 7.16–7.23 (m, 4H,
The racemic compound was obtained following GP C with
5-chloro-3-vinylindole (3g, 35.5 mg, 0.200 mmol, 2.00 Equiv.)
and ethyl 2-((3,5-dichloro-4-hydroxyphenyl)imino)acetate (4k,
26.2 mg, 0.100 mmol, 1.00 Equiv.) without a catalyst in 3.0 mL
dichloromethane. The product 5gk was obtained after column
chromatography (cyclohexane/ethyl acetate = 2:1) as a yellow oil
(32.3 mg, 52.4 µmol, 48%).
4
4
CHAr), 7.25 (d, J = 2.1 Hz, 1H, CHAr), 7.28 (d, J = 2.1 Hz, 1H,
3
4
CHAr), 7.36 (d, J = 8.6 Hz, 1H, CHAr), 7.77 (d, J = 2.1 Hz, 1H,
CHAr), 8.10 (d, 4J = 2.1 Hz, 1H, CHAr), 10.08 (sbr, 1H, NH), 10.25
(sbr, 1H, NH) ppm; 13C NMR (100 MHz, acetone-d6, 25 °C, TMS):
δ = 14.7 (+, CH2CH3), 27.5 (+, CH2CHCH2), 36.7 (–, CHCH2), 43.0
(–, CHCH2), 52.7 (+, NCHCInd), 60.7 (–, CH2CH3), 65.6 (+,
NCHCO2Et), 112.2 (Cq, CBr), 112.3 (Cq, CBr), 113.9 (+, CHAr),
114.2 (+, CHAr), 119.5 (Cq, CAr), 120.1 (Cq, CAr), 121.8 (+, CHAr),
122.5 (+, CHAr), 123.0 (+, CHAr), 123.4 (+, CHAr), 124.5 (+, CHAr),
Rf = 0.28 (cyclohexane/EtOAc 2:1); 1H NMR (400 MHz, acetone-
3
d6, 25 °C, TMS): δ = 1.30 (t, J = 7.1 Hz, 3H, CH2CH3), 2.23 (q,
3J = 12.5 Hz, 1H, NCHCHH), 2.33–2.52 (m, 2H, CHHCHCO2Et,
3
3
NCHCHH), 2.67 (dq, J = 13.1, J = 2.5 Hz, 1H, CHHCHCO2Et),
3.27 (tt, 3J = 12.5, 3J = 2.9 Hz, 1H, CH2CHCH2), 4.07–4.18 (m, 1H, 124.8 (+, CHAr), 125.5 (+, 2 × CHAr), 125.6 (+, CHAr), 128.3 (+,
CHHCH3), 4.22–4.33 (m, 1H, CHHCH3), 4.76 (d, 3J = 2.3 Hz, 1H,
NCHCO2Et), 5.48 (dd, 3J = 11.3, 3J = 3.5 Hz, 1H, NCHCInd), 6.97
(dd, 3J = 8.6, 3J = 2.1 Hz, 1H, CHAr), 7.08 (dd, 3J = 8.6,
3J = 2.1 Hz, 1H, CHAr), 7.23–7.28 (m, 4H, CHAr), 7.40 (d,
2 × CHAr), 128.5 (Cq, CAr), 129.4 (Cq, CAr), 136.4 (Cq, CAr), 136.5
(Cq, CAr), 151.7 (Cq, CAr), 173.5 (Cq, CO2Et) ppm; IR (ATR):
푣̃ = 3413, 2923, 2852, 1720, 1596, 1492, 1457, 1370, 1245, 1219,
1176, 1094, 1021, 954, 933, 882, 793, 750, 695, 583, 563, 477,
420 cm-1; MS (FAB, 3-NBA): m/z (%): 623/622/621 (46/64/57)
[M+H]+, 594 (100); HRMS (FAB, 3-NBA): calcd for
C30H28O2N379Br2 [M+H]+: 620.0543; found: 620.0543.
3
3J = 8.6 Hz, 1H, CHAr), 7.43 (d, J = 2.4 Hz, 1H, CHAr), 7.61 (d,
3J = 1.9 Hz, 1H, CHAr), 7.94 (d, 3J = 1.9 Hz, 1H, CHAr), 8.13 (sbr,
1H, OH), 10.16 (sbr, 1H, NH), 10.24 (sbr, 1H, NH) ppm; 13C NMR
(100 MHz, acetone-d6, 25 °C, TMS): δ = 14.7 (+, CH2CH3), 27.5
(+, CH2CHCH2), 36.6 (–, CHCH2), 42.6 (–, CHCH2), 53.3 (+,
Ethyl (2S,4S,6S)-4,6-bis(5-bromo-1H-indol-3-yl)-1-(4-tolyl)piperid
NCHCInd), 61.0 (–, CH2CH3), 65.6 (+, NCHCO2Et), 113.5 (+, CHAr), ine-2-carboxylate (5hb): This compound was synthesized
113.7 (+, CHAr), 118.6 (+, CHAr), 118.8 (Cq, CAr), 120.0 (Cq, CAr),
120.3 (+, CHAr), 121.3 (Cq, CAr), 122.1 (+, CHAr), 122.2 (+, CHAr),
123.1 (+, CHAr), 124.7 (Cq, CAr), 124.8 (Cq, CAr), 126.1 (+, CHAr),
126.3 (+, 2 × CHAr), 127.6 (Cq, CAr), 128.7 (Cq, CAr), 136.2 (Cq,
CAr), 136.3 (Cq, CAr), 144.8 (Cq, CAr), 145.0 (Cq, 2 × CAr), 173.3 (Cq,
CO2Et) ppm; IR (ATR): 푣̃ = 3389, 2926, 1693, 1565, 1481, 1461,
1249, 1176, 1098, 1022, 939, 893, 859, 795, 750, 692, 587, 477,
422 cm-1; MS (FAB, 3-NBA): m/z (%): 616 (4) [M+H]+, 165 (23),
154 (21), 136 (25), 133 (100), 109 (29), 107 (28), 105 (26), 97
(33), 95 (49), 93 (26), 91 (37), 85 (20), 83 (43), 81 (54); HRMS
(FAB, 3-NBA): calcd for C30H26O3N335Cl4 [M+H]+: 616.0723;
found: 616.0721.
following the GP C with 5-bromo-3-vinylindole (3h, 44.4 mg,
0.200 mmol, 2.00 Equiv.) and ethyl 2-((4-tolyl)imino)acetate (4b,
19.1 mg, 0.100 mmol, 1.00 Equiv.) in 3.0 mL dichloromethane.
The product 5hb was obtained after column chromatography
(cyclohexane/ethyl acetate = 2:1) as a yellow oil (cat-(R): 21.7 mg,
34.2 µmol, 34%; cat-(S): 15.2 mg, 24.0 µmol, 24%).
The racemic compound was obtained following GP C with
5-bromo-3-vinylindole (3h, 44.4 mg, 0.200 mmol, 2.00 Equiv.)
and ethyl 2-((4-tolyl)imino)acetate (4b, 19.1 mg, 0.100 mmol,
1.00 Equiv.) without a catalyst in 3.0 mL dichloromethane. The
product 5hb was obtained after column chromatography
(cyclohexane/ethyl acetate = 2:1) as a yellow oil (17.4 mg,
27.5 μmol, 28%).
Ethyl (2S,4S,6S)-4,6-bis(5-bromo-1H-indol-3-yl)-1-phenylpiperidi
ne-2-carboxylate (5ha): This compound was synthesized
following the GP C with 5-bromo-3-vinylindole (3h, 44.4 mg,
0.200 mmol, 2.00 Equiv.) and ethyl 2-(phenylimino)acetate (4a,
17.7 mg, 0.100 mmol, 1.00 Equiv.) in 3.0 mL dichloromethane.
The product 5ha was obtained after column chromatography
Rf = 0.35 (cyclohexane/EtOAc 2:1); 1H NMR (400 MHz, acetone-
3
d6, 25 °C, TMS): δ = 1.26 (t, J = 7.1 Hz, 3H, CH2CH3), 2.06 (s,
3H, CH3), 2.10–2.22 (m, 1H, NCHCHH), 2.38–2.48 (m, 2H,
3
3
CHHCHCO2Et, NCHCHH), 2.62 (dq, J = 13.2, J = 2.5 Hz, 1H,
CHHCHCO2Et), 3.32 (tt, 3J = 12.5, 3J = 3.0 Hz, 1H, CH2CHCH2),
4.03–4.11 (m, 1H, CHHCH3), 4.16–4.28 (m, 1H, CHHCH3), 4.73
3
3
3
(cyclohexane/ethyl acetate = 3:1) as a yellow oil (cat-(R): 4.62 mg, (dd, J = 5.6, J = 2.3 Hz, 1H, NCHCO2Et), 5.61 (dd, J = 11.3,
7.43 µmol, 7.9%; cat-(S): 25.9 mg, 41.8 µmol, 42%).
3J = 3.5 Hz, 1H, NCHCInd), 6.79 (d, 3J = 8.2 Hz, 2H, CHAr), 7.06–
7.13 (m, 3H, CHAr), 7.18–7.23 (m, 2H, CHAr), 7.25 (d, 3J = 2.2 Hz,
1H, CHAr), 7.28 (d, 3J = 2.4 Hz, 1H, CHAr), 7.36 (d, 3J = 8.6 Hz, 1H,
The racemic compound was obtained following GP C with
5-bromo-3-vinylindole (3h, 44.4 mg, 0.200 mmol, 2.00 Equiv.)
and ethyl 2-(phenylimino)acetate (4a, 17.7 mg, 0.100 mmol,
1.00 Equiv.) without a catalyst in 3.0 mL dichloromethane. The
product 5ha was obtained after column chromatography
(cyclohexane/ethyl acetate = 3:1) as a yellow oil (41.4 mg,
66.6 µmol, 67%).
3
3
CHAr), 7.77 (d, J = 1.8 Hz, 1H, CHAr), 8.12 (d, J = 1.8 Hz, 1H,
CHAr), 10.07 (sbr, 1H, NH), 10.25 (sbr, 1H, NH) ppm; 13C NMR
(100 MHz, acetone-d6, 25 °C, TMS): δ = 14.8 (+, CH2CH3), 20.6
(+, CH3), 27.5 (+, CH2CHCH2), 36.7 (–, CHCH2), 43.1 (–, CHCH2),
52.8 (+, NCHCInd), 60.6 (–, CH2CH3), 65.8 (+, NCHCO2Et), 112.2
(Cq, CAr), 112.3 (Cq, CAr), 113.8 (+, CHAr), 114.2 (+, CHAr), 119.6
(Cq, CAr), 120.1 (Cq, CAr), 121.7 (+, CHAr), 122.9 (+, CHAr), 123.5
(+, CHAr), 124.4 (+, CHAr), 124.8 (+, CHAr), 125.5 (+, 3 × CHAr),
Rf = 0.45 (cyclohexane/EtOAc 2:1); 1H NMR (400 MHz, acetone-
3
d6, 25 °C, TMS): δ = 1.25 (t, J = 7.1 Hz, 3H, CH2CH3), 2.19 (q,
3J = 12.5 Hz, 1H, NCHCHH), 2.38–2.48 (m, 2H, CHHCHCO2Et,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701502
European Journal of Organic Chemistry
FULL PAPER
128.6 (Cq, CAr), 129.0 (+, 2 × CHAr), 129.4 (Cq, CAr), 131.6 (Cq,
CAr), 136.4 (Cq, CAr), 136.5 (Cq, CAr), 149.2 (Cq, CAr), 173.6 (Cq,
CO2Et) ppm; IR (ATR): 푣̃ = 3416, 2921, 2851, 1719, 1694, 1611,
1565, 1509, 1457, 1369, 1337, 1246, 1219, 1175, 1094, 1020,
955, 934, 882, 818, 792, 751, 719, 671, 582, 475, 419 cm-1; MS
(FAB, 3-NBA): m/z (%): 636 (43) [M+H]+, 429 (45), 192 (69), 133
(63), 118 (46), 95 (73), 89 (100); HRMS (FAB, 3-NBA): calcd for
C31H32O2N379Br2 [M+H]+: 636.0856; found: 636.0857.
obtained after column chromatography (cyclohexane/ethyl
acetate = 2:1) as a yellow oil (cat-(R): 23.7 mg, 36.4 µmol, 36%;
cat-(S): 18.4 mg, 28.3 µmol, 28%).
The racemic compound was obtained following GP C with
5-bromo-3-vinylindole (3h, 44.4 mg, 0.200 mmol, 2.00 Equiv.)
and ethyl 2-((4-methoxyphenyl)imino)acetate (4e, 20.7 mg,
0.100 mmol, 1.00 Equiv.) without
a
catalyst in 3.0 mL
dichloromethane. The product 5he was obtained after column
chromatography (cyclohexane/ethyl acetate = 3:1) as a yellow oil
(14.9 mg, 22.9 μmol, 23%).
Ethyl (2S,4S,6S)-4,6-bis(5-bromo-1H-indol-3-yl)-1-(4-ethynylphe
nyl)piperidine-2-carboxylate (5hc): This compound was
synthesized following the GP C with 5-bromo-3-vinylindole (3h,
Rf = 0.33 (cyclohexane/EtOAc 2:1); 1H NMR (400 MHz, acetone-
3
d6, 25 °C, TMS): δ = 1.26 (t, J = 7.1 Hz, 3H, CH2CH3), 2.18 (q,
44.4 mg,
0.200 mmol,
2.00 Equiv.)
and
ethyl
3J = 12.5 Hz, 1H, NCHCHH), 2.34–2.49 (m, 2H, CHHCHCO2Et,
3
3
2-((4-ethynylphenyl)imino)acetate (4c, 20.1 mg, 0.100 mmol,
1.00 Equiv.) in 3.0 mL dichloromethane. The product 5hc was
obtained after column chromatography (cyclohexane/ethyl
acetate = 2:1) as a yellow oil (cat-(R): 36.5 mg, 56.6 µmol, 57%;
cat-(S): 19.2 mg, 29.7 µmol, 30%).
The racemic compound was obtained following GP C with
5-bromo-3-vinylindole (3h, 44.4 mg, 0.200 mmol, 2.00 Equiv.)
and ethyl 2-((4-ethynylphenyl)imino)acetate (4c, 20.1 mg,
NCHCHH), 2.59 (dq, J = 13.1, J = 2.5 Hz, 1H, CHHCHCO2Et),
3.34 (tt, 3J = 12.4, 3J = 3.0 Hz, 1H, CH2CHCH2), 3.58 (s, 3H,
OCH3), 4.00–4.10 (m, 1H, CHHCH3), 4.16–4.27 (m, 1H, CHHCH3),
4.62 (dd, 3J = 5.5, 3J = 2.2 Hz, 1H, NCHCO2Et), 5.61 (dd,
3
3J = 11.3, J = 3.4 Hz, 1H, NCHCInd), 6.51–6.58 (m, 2H, CHAr),
7.07 (dd, 3J = 8.6, 3J = 1.9 Hz, 1H, CHAr), 7.13–7.22 (m, 4H, CHAr),
7.26 (dd, 3J = 6.5, 3J = 2.2 Hz, 2H, CHAr), 7.36 (d, 3J = 8.6 Hz, 1H,
3
3
CHAr), 7.76 (d, J = 1.8 Hz, 1H, CHAr), 8.12 (d, J = 1.8 Hz, 1H,
CHAr), 10.06 (sbr, 1H, NH), 10.25 (sbr, 1H, NH) ppm; 13C NMR
(100 MHz, acetone-d6, 25 °C, TMS): δ = 14.8 (+, CH2CH3), 27.5
(+, CH2CHCH2), 36.8 (–, CHCH2), 43.1 (–, CHCH2), 53.0 (+,
NCHCInd), 55.2 (+, OCH3), 60.6 (–, CH2CH3), 66.0 (+, NCHCO2Et),
112.2 (Cq, CAr), 112.3 (Cq, CAr), 113.6 (+, 2 × CHAr), 113.8 (+,
CHAr), 114.2 (+, CHAr), 119.6 (Cq, CAr), 120.2 (Cq, CAr), 121.7 (+,
CHAr), 122.9 (+, CHAr), 123.5 (+, CHAr), 124.4 (+, CHAr), 124.8 (+,
CHAr), 125.6 (+, CHAr), 127.0 (+, 2 × CHAr), 128.6 (Cq, CAr), 129.4
(Cq, CAr), 136.4 (Cq, CAr), 136.5 (Cq, CAr), 144.7 (Cq, CAr), 155.8
(Cq, CAr), 173.7 (Cq, CO2Et) ppm; IR (ATR): 푣̃ = 3413, 2923, 2851,
2549, 1703, 1506, 1457, 1370, 1337, 1239, 1175, 1095, 1032,
0.100 mmol, 1.00 Equiv.) without
a
catalyst in 3.0 mL
dichloromethane. The crude product was purified by preparative
TLC (cyclohexane/ethyl acetate = 3:1) to give 5hc as a yellow oil
(6.18 mg, 10.0 µmol, 10%).
Rf = 0.31 (cyclohexane/EtOAc 3:1); 1H NMR (400 MHz, acetone-
3
d6, 25 °C, TMS): δ = 1.14 (t, J = 7.0 Hz, 3H, CH2CH3), 2.05 (q,
3J = 12.4 Hz, 1H, NCHCHH), 2.23–2.38 (m, 2H, CHHCHCO2Et,
3
4
NCHCHH), 2.55 (dd, J =13.3, J = 2.7 Hz, 1H, CHHCHCO2Et),
3.15 (tt, 3J = 12.4, 3J = 2.8 Hz, 1H, CH2CHCH2), 3.25 (s, 1H, CH),
3.94–3.99 (m, 1H, CHHCH3), 4.08–4.14 (m, 1H, CHHCH3), 4.80
3
3
3
(dd, J = 5.5, J = 2.3 Hz, 1H, NCHCO2Et), 5.41 (dd, J = 11.3,
3J = 3.7 Hz, 1H, NCHCInd), 6.95–7.00 (m, 2H, CHAr), 7.02–7.12 (m, 934, 883, 860, 828, 793, 752, 709, 671, 582, 481, 420 cm-1; MS
6H, CHAr), 7.18 (d, 3J = 2.4 Hz, 1H, CHAr), 7.23 (d, 3J = 8.6 Hz, 1H, (FAB, 3-NBA): m/z (%): 651 (55), [M]+, 429 (54), 208 (100); HRMS
3
3
CHAr), 7.64 (d, J = 1.8 Hz, 1H, CHAr), 7.92 (d, J = 1.9 Hz, 1H,
CHAr), 10.01 (sbr, 1H, NH), 10.12 (sbr, 1H, NH) ppm; 13C NMR
(100 MHz, acetone-d6, 25 °C, TMS): δ = 14.8 (+, CH2CH3), 27.5
(+, CH2CHCH2), 36.5 (–, CHCH2), 42.7 (–, CHCH2), 52.9 (+,
NCHCInd), 61.0 (–, CH2CH3), 65.1 (+, NCHCO2Et), 77.5 (+, CH),
84.7 (Cq, CCH), 112.3 (Cq, CAr), 112.4 (Cq, CAr), 113.9 (+, CHAr),
114.2 (+, CHAr), 115.4 (+, CHAr), 119.1 (Cq, CAr), 119.9 (Cq, CAr),
121.7 (+, CHAr), 123.0 (+, CHAr), 123.2 (+, CHAr), 124.6 (+, CHAr),
124.7 (+, 2 × CHAr), 124.8 (Cq, CAr), 125.6 (+, CHAr), 128.3 (Cq,
CAr), 129.4 (Cq, CAr), 132.1 (+, 2 × CHAr), 136.4 (Cq, CAr), 136.5
(Cq, CAr), 152.5 (Cq, CAr), 173.2 (Cq, CO2Et) ppm; IR (ATR):
푣̃ = 3282, 2924, 2851, 2100, 1721, 1693, 1601, 1564, 1503, 1457,
1368, 1247, 1220, 1176, 1094, 1021, 933, 883, 835, 793, 752,
664, 582, 535, 476, 420 cm-1; MS (FAB, 3-NBA): m/z (%): 646
(15) [M+H]+, 429 (17), 202 (39), 132 (100); HRMS (FAB, 3-NBA):
calcd for C32H30O2N379Br2 [M+H]+: 646.0699; found: 646.0699.
(FAB, 3-NBA): calcd for C31H29O3N379Br2 [M]+: 651.0555; found:
651.0553.
Acknowledgements
We gratefully acknowledge the Jürgen-Manchot Stiftung
(fellowship to C. Retich) for the financial support. We also thank
Dr. Sabilla Zhong for her previous work in this field.
Keywords: Bisindole • Heterocycles • Asymmetric •
Organocatalytic • Cross Coupling • Click-reaction • Reduction
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enyl)piperidine-2-carboxylate (5he): This compound was
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44.4 mg,
0.200 mmol,
2.00 Equiv.)
and
ethyl
2-((4-methoxyphenyl)imino)acetate (4e, 20.7 mg, 0.100 mmol,
1.00 Equiv.) in 3.0 mL dichloromethane. The product 5he was
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701502
European Journal of Organic Chemistry
FULL PAPER
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H. Enoki, Y. Umemoto, M. Sakamoto, Tetrahedron Lett. 2002, 43, 4245-
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701502
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Various novel bisindole derivatives
with different substitution patterns
providing an easy access to a library
of biological active compounds were
synthesized. Electron withdrawing
groups on the starting material led to
the formation of Povarov-type
C. Retich, S. Bräse,
Page No. – Page No.
Asymmetric organocatalytic
synthesis of Bisindoles – Scope and
Derivatizations
structures. Furthermore we could
successfully demonstrate that
consecutive reactions like cross
couplings, reductions or even click
reactions on bisindoles are feasible.
This article is protected by copyright. All rights reserved.