Enantioselective N -Alkylation of Nitroindoles under Phase-Transfer Catalysis

Article abstract of DOI:10.1055/s-0039-1690751

An asymmetric phase-transfer-catalyzed N -alkylation of substituted indoles with various Michael acceptors was studied. Acidities of nitroindoles were determined in acetonitrile by UV-Vis spectrophotometric titration. There was essentially no correlation between acidity and reactivity in the aza-Michael reaction. The position of the nitro group on the indole ring was essential to control the stereoselectivity of the reaction. Michael adducts were obtained in high yields and moderate enantioselectivities in the reaction between 4-nitroindole and various Michael acceptors in the presence of cinchona alkaloid based phase-transfer catalysts. In addition to outlining the scope and limitations of the method, the geometries of the transition states of the reaction were calculated.

Full text of DOI:10.1055/s-0039-1690751

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–M
paper
A
en
D. Trubitsõn et al.
Paper
Synthesis
Enantioselective N-Alkylation of Nitroindoles under Phase-Transfer
Catalysis
Dmitri Trubitsõna
Jevgenija Martõnovaa
Kristin Erkmana
Andrus Metsalaa
Br
N
Jaan Saameb
OH
NO2
NO2
Kristjan Kõsterb
Ivar Järvinga
Ivo Leitob
(5 mol%)
N
N
N
H
O
R1
Tõnis Kanger*a
0
0
0
0-0
0
0
1-5
3
3
9-
9
6
8
2
+
O
Rb2CO3 (1.3 equiv)
H2O (1.4 equiv)
toluene, r.t.
up to 75% ee
R1
a Department of Chemistry and Biotechnology, Tallinn University
of Technology, 12618 Tallinn, Estonia
tonis.kanger@taltech.ee
b Institute of Chemistry, University of Tartu, 50411 Tartu, Estonia
R2
N-selective alkylation
R2
Received: 26.09.2019
F
Accepted after revision: 04.11.2019
Published online: 26.11.2019
COOH
DOI: 10.1055/s-0039-1690751; Art ID: ss-2019-t0554-op
Abstract An asymmetric phase-transfer-catalyzed N-alkylation of sub-
stituted indoles with various Michael acceptors was studied. Acidities of
nitroindoles were determined in acetonitrile by UV-Vis spectrophoto-
metric titration. There was essentially no correlation between acidity
and reactivity in the aza-Michael reaction. The position of the nitro
group on the indole ring was essential to control the stereoselectivity of
the reaction. Michael adducts were obtained in high yields and moder-
ate enantioselectivities in the reaction between 4-nitroindole and vari-
ous Michael acceptors in the presence of cinchona alkaloid based
phase-transfer catalysts. In addition to outlining the scope and limita-
tions of the method, the geometries of the transition states of the reac-
tion were calculated.
OH
OH
N
N
COOH
F
fluvastatin
prevention of cardiovascular disease
antidiabetic properties
N
NHMe
Key words asymmetric catalysis, heterocycles, Michael addition,
organocatalysis, phase-transfer catalysis
serotonin reuptake inhibitor
Figure 1 Examples of biologically active N-alkylated indoles
Indole and its derivatives are very important scaffolds in
medicinal chemistry,1 being among the most prevalent ring
system in small molecule drugs.2 N-Substituted indole de-
rivatives are used more seldom but there are still examples
of biologically active pharmaceutical compounds contain-
ing this structural moiety (Figure 1).3 The direct functional-
ization of the indole ring system has been an active area of
research for decades.4 The most widely exploited reaction is
an electrophilic aromatic substitution at the C3 position.5
Recently, methods have been developed for the direct elec-
trophilic reactions at the C2 position via a transition-metal-
catalyzed C–H activation.6 At the same time, the enantiose-
lective N-alkylation of indole remains underdeveloped. The
aromaticity of the indole ring and, correspondingly, low
nucleophilicity of the nitrogen atom make it challenging.
Mainly transition-metal-catalyzed reactions have been
applied for the enantioselective N-addition to indole deriv-
atives.7 Only limited methodologies have been developed by
employing asymmetric organocatalytic strategies for N-al-
kylation. Chiral phosphoric acids were applied as catalysts
for the synthesis of N-substituted indoles (Scheme 1a).8 In
these examples strong electrophiles are generated under
acidic conditions or the simultaneous activation of the elec-
trophile and nucleophile takes place. Alternatively, under
basic conditions an intramolecular N-alkylation led to the
formation of tricyclic products via phase-transfer catalysis
(Scheme 1b).9 The introduction of an electron-withdrawing
group reduces the pKa value of the indole and increases the
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–M
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
D. Trubitsõn et al.
Paper
Synthesis
NHCO2Me
NHCO2Me
a
chiral phosphoric acid
+
N
N
N
H
NBoc
2018, You et al.
O
NHBoc
NHBoc
+
NH
Ph
OH
chiral phosphoric acid
N
R
N
H
Ph
NH
2018, Zhong et al.
O
OH
R
Ph
R'
chiral phosphoric acid
R'
+
N
N
R''HN
H
Ph
2017, Sun et al.
Ar
R''HN
Ar
b
X
O
X
O
phase-transfer catalysis
N
NR
N
H
NR
R2O2C
R2O2C
2008, Bandini et al.
c
H
O
aminocatalysis
CHO
+
N
N
H
CHO
Ar
Ar
2010, Wang et al.
Scheme 1 Organocatalytic enantioselective N-alkylation of indole derivatives
nucleophilicity of the N1 position, enabling an aminocata-
lytic intramolecular aza-Michael/aldol cascade reaction of
2-formyl-substituted indole, also affording tricyclic prod-
ucts in high enantio- and regioselectivities (Scheme 1c).10
In this article, we studied the dependence of the N–H
acidity versus the position of the electron-withdrawing
group on the indole ring; the synthetic potential of it was
further harnessed to access enantiomerically pure indole
derivatives via an aza-Michael reaction.11
Our initial studies focused on the reaction of 3-cyanoin-
dole (1) with trans-crotonophenone 2. An EWG on the third
position of the indole ring increases the acidity of the N–H
proton and protects the most reactive C3 position. Recently,
Yang et al. published a non-asymmetric method consisting
of a potassium hydroxide catalyzed intermolecular aza-Mi-
chael addition of indole derivatives to aromatic enones.12
We studied an asymmetric phase-transfer-catalyzed (PTC)
version of it. A library of different phase-transfer catalysts
based on cinchona alkaloids was screened (Table 1).
the steric effect of the substituents of the ammonium salts
I–III derived from cinchonidine on the reaction was stud-
ied. Almost full conversion of the starting compounds 1 and
2 was achieved in the case of benzyl-, naphthyl-, and
anthracenyl-substituted catalysts (Table 1, entries 1–3).
There was a clear dependence of the steric effect of the cat-
alyst on the enantioselectivity of the reaction. Sterically
more demanding catalysts afforded higher enantioselectivi-
ties but they remained modest (in the best case 42% ee; en-
try 3). Catalyst IV demonstrated the same conversion and
quite similar stereoselectivity as the anthracenyl-substitut-
ed catalyst III (entry 4). Due to the low solubility of the am-
monium salt V in toluene, the conversion and ee of product
3 were low (entry 5). The replacement of the bromide anion
in catalyst I by the tetrakis[3,5-bis(trifluoromethyl)phe-
nyl]borate (BARF) anion dramatically affected the reaction
rate and enantioselectivity (entry 6). The influence of the
hydrogen-bond donor of the catalyst was essential.13 Pro-
tecting the OH group as an allyl ether (catalyst VII) provid-
ed full conversion of the starting materials but the product
was racemic (entry 7). The thiourea derived catalyst VIII
afforded the opposite enantiomer 3 with low selectivity
(entry 8). The obtained results were unsatisfying, and
The model reaction was performed at room tempera-
ture in toluene in the presence of an enantiomerically pure
catalyst (20 mol%) and potassium carbonate as a base. First,
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–M

C
D. Trubitsõn et al.
Paper
Synthesis
Table 1 Catalyst Screening for the Reaction between 3-Cyanoindole
and trans-Crotonophenonea
therefore a more systematic study of substituted indoles
was performed. Nitroindoles were the compounds of choice
because of their possible interaction with the phase-trans-
fer catalyst.14
CN
First, the acidities of the nitrosubstituted indoles were
determined (Table 2). As expected, nitroindoles and 3-
cyanoindole behave in acetonitrile as weak acids, with pKa
values in the range of 22–30, thus being by their acid
strength approximately between benzoic acid15 and
phenol.16 By acid strength, the nitroindoles fall into two
distinct groups – the ones with nitro group on the five-
membered ring (pKa between 22 and 24) and the ones with
the nitro group on the six-membered ring (pKa between 27
and 30). The reason is evidently the good match between
the electron-withdrawing abilities of the nitro group on the
one hand and the vicinity of the nitro group to the acidity
center in the five-membered ring, as well as the overall
higher electron density in the five-membered ring. The
strongest of the nitroindoles – 3-nitroindole – benefits from
highly efficient resonance stabilization of the negative
charge in the anion via conjugation of the nitro group with
the acidity center.
In the following reactions, commercially available 4-ni-
troindole was used as a model compound. It was found that
under similar conditions applied to 3-cyanoindole the reac-
tion with 4-nitroindole in the presence of catalyst III was
more selective (Table 3, entry 1). The reaction rate was in-
creased when rubidium carbonate was used as a base, af-
fording the N-alkylated product in 95% yield within 5 hours
without any decrease in enantioselectivity (entry 2, 65%
ee). An aqueous solution of rubidium carbonate decreased
the rate of the reaction substantially and for the full conver-
sion a reaction time of 24 hours was needed (entry 3). The
enantiomeric purity of the product was increased to 74% by
lowering the temperature of the reaction to –20 °C (entry
5). Cesium carbonate induced a less selective reaction (en-
try 6).
O
CN
N
catalyst (20 mol%)
3
∗
O
+
K2CO3 (1.3 equiv)
toluene, r.t.
N
H
2
1
Br
Br
N
Br
OH
N
N
OH
OH
N
N
N
II
III
I
NO2
O
N
Br
Br
OH
BARF
OH
N
N
OH
N
N
N
IV
V
VI
Br
Br
N
N
H
H
O
N
N
CF3
O
S
CF3
N
N
VIII
VII
During the optimization of the reaction conditions the
effect of water on the reaction rate was revealed. Small
amounts of water could significantly affect the rate of the
reactions catalyzed by the quaternary ammonium salts.17
The balance between the amount of water and amount of
phase-transfer catalyst was screened (for the full optimiza-
tion process, see the Supporting Information). It was found
that both low concentrations and high concentrations of
water decreased the reaction rate. With the optimum water
concentration the amount of the catalyst III was decreased
to 5 mol%. Increasing the amount of trans-crotonophenone
from 1.2 equivalents to 2.1 equivalents afforded the N-al-
kylated 4-nitroindole 5a in a reasonable time (5 h), high
yield (95%), and moderate ee (69%).
Entry
Catalyst
Time (h)
Conv. (%)b
ee (%)c
1
2
3
4
5
6
7
8
I
18
18
16
16
16
18
16
20
98
99
83
80
26
5
18
26
42
36
4
II
III
IV
V
VI
VII
VIII
6
99
29
rac
–28
a Reaction conditions: 1 (1.2 equiv), 2 (1 equiv), catalyst (20 mol%), base
(1.3 equiv), r.t.
b Conversion determined by 1H NMR of crude mixture.
c Determined by chiral HPLC analysis of the sample obtained by preparative
TLC.
Next, the influence of the position of the nitro group on
the aza-Michael reaction was studied under the optimal
conditions (Table 4). It was found that the most reactive
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–M

D
D. Trubitsõn et al.
Paper
Synthesis
Table 2 Results of pKa Measurements in Acetonitrile
NO2
NO2
CN
4
3
O2N
5
NO2
R
2
N
N
N
N
N
H
N
N
H
N
O2N
6
H
H
H
H
H
H
7
NO2
a
Acid (A)
Reference acid (Ra)
pKa(Ra)
pKa
pKa(A)
Assigned pKa(A)
2-nitroindole
3-nitroindole
4-nitroindole
2-nitrophenol
22.85
23.53
22.85
23.53
26.96
28.1
–0.80
–0.10
0.10
23.65
23.63
22.75
22.79
27.84
27.8
23.64
9-MeO2C-fluorene
2-nitrophenol
22.77
27.8
9-MeO2C-fluorene
(4-MeC6F4)(C6H5)CHCN
5-nitroindole
0.74
–0.88
0.28
5-nitroindole
6-nitroindole
(4-MeC6F4)(C6H5)CHCN
(4-MeC6F4)(C6H5)CHCN
4-nitroindole
26.96
26.96
27.83
28.1
–1.12
–0.85
0.14
28.08
27.81
27.69
29.8
28.1
27.7
7-nitroindole
5-nitroindole
–1.74
–2.21
1.88
29.9
26.0
6-nitroindole
27.74
28.11
26.96
26.14
29.95
29.99
26.03
25.96
9-C6F5-fluorene
3-cyanoindole
(4-MeC6F4)(C6H5)CHCN
(C6F5)(C6H5)CHCN
0.93
0.18
a pKa(Ra) – pKa(A)
derivatives were 4- and 5-nitroindoles (entries 1 and 3), but
the former was more selective (69% and 38% ee, respective-
ly). Also, 3- and 6-nitroindoles were less attractive sub-
strates, affording products in low enantioselectivities (en-
tries 2 and 4). In the case of 2- and 7-nitroindole, no reac-
tion was detected during 24 hours, most probably because
of steric reasons (entries 5 and 6). The obtained results
show that the position of the nitro group is essential in de-
termining the enantioselectivity and it participates in the
transition state. Comparison of Tables 2 and 4 reveals that
there is essentially no correlation between acidity and reac-
tivity in the aza-Michael reaction. There is, however, a con-
nection between reactivity and steric hindrance: the least
reactive are 2- and 7-nitroindole, where the nitro groups
are spatially closest to the acidity center.
The scope of the reaction was studied with the most se-
lective 4-nitroindole 4a (Scheme 2). Various ,-unsaturat-
ed carbonyl compounds 2a–l, unsaturated ester 2m, and ni-
trostyrene 2n were used as Michael acceptors. It was found
that aromatic and heteroaromatic enones were the most re-
active and selective starting compounds, affording products
within 5 hours in moderate to high yields and moderate to
good enantioselectivities. Neither electron-withdrawing
(4b), nor electron-donating groups (4c) in the phenyl ring
influenced the reaction substantially. The heteroaromatic
furyl substituent did not affect the reaction enantioselec-
tivity, and product 6d was obtained in high yield. Steric hin-
drance in the -position of the enone decreased the reac-
tion rate, as demonstrated in experiments with the vinyl-
substituted enones 2e and 2f.
Table 3 Optimization of the Reaction between 4-Nitroindole (4a) and
trans-Crotonophenone (2)a
NO2
NO2
O
N
5a
catalyst III (20 mol%)
∗
O
+
base (1.3 equiv)
toluene, r.t.
N
H
4a
2
Entry
Base
Time
21 h
Yield (%)b
95
ee (%)c
1
K2CO3
65
65
64
70
74
54
2
Rb2CO3
5 h
92
95
97
97
95
3
5 M aq Rb2CO3
Rb2CO3
24 h
24 h
6 d
4d
5e
6
Rb2CO3
Cs2CO3
18 h
a Reaction conditions: 4a (0.1 mmol, 1 equiv), 2 (2.1 equiv), catalyst III (20
mol%), Rb2CO3 (1.3 equiv), r.t.
b Isolated yield.
c Determined by chiral HPLC analysis.
d Reaction at 5 °C.
e Reaction at –20 °C
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–M

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D. Trubitsõn et al.
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Synthesis
The absolute stereochemistry of compound 6c was un-
ambiguously assigned by single-crystal X-ray diffraction
(Figure 2). The configurations of other compounds in the
series were assigned by analogy.
To our disappointment, the reaction had limitations
that could be divided into two categories: either the reac-
tion proceeded, but racemic products were formed (6h, 6i,
6j), or there was no reaction (starting compounds 2k–n).
Sterically more hindered aliphatic cyclic ketone 2h and
trans-chalcone 2i provided racemic products with lower re-
action rates compared to the model compound 2a. It was
assumed that the long reaction time gave rise to a nonselec-
tive background reaction, leading to racemic products. In
the case of the 1,4-diketone 6j, racemization of the -posi-
tion of the carbonyl group through enolization under basic
conditions is most probable. The reaction did not proceed
NO2
NO2
O
catalyst III (5 mol%)
R1
R2
+
Rb2CO3 (1.3 equiv)
H2O (1.4 equiv)
toluene, r.t.
O
N
N
H
R2
4a
2a–n
6a–j
R1
NO2
NO2
NO2
NO2
N
N
N
N
O
O
O
O
O
6a 67%
ee = 59%
5 h
6b 74%
ee = 73%
5 h
6c 83%
6d 90%
ee = 63%
5 h
ee = 75%a
5 h
Br
O2N
MeO
NO2
NO2
NO2
N
N
N
O
O
O
6e 80%
ee = 64%
24 h
6f 82%
ee = 59%
24 h
6g 96%
ee = 69%
5 h
NO2
NO2
NO2
N
N
N
O
O
O
O
6h 65%
ee = rac
24 h
6i 35%
ee = rac
48 h
6j 60%
ee = rac
24 h
NO2
NO2
NO2
NO2
N
H
N
N
N
4a
H
H
4a
H
4a
NO2
4a
+
+
+
O
+
O
O
2n
H
O
2l
2k
2m
no reaction
24 h
no reaction
24 h
no reaction
24 h
no reaction
24 h
Scheme 2 The reaction scope and limitations. Reagents and conditions: 4a (0.1 mmol, 1 equiv), 2a–n (2.1 equiv), catalyst III (5 mol%), Rb2CO3
(1.3 equiv), H2O (1.4 equiv), under argon atmosphere; all yields are isolated yields; ee values were determined by chiral HPLC analysis; a 90% ee was
obtained after a single recrystallization.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–M

F
D. Trubitsõn et al.
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Synthesis
Table 4 Effect of the Position of the Nitro Group on Nitroindole 4 on the Aza-Michael Reactiona
O
O2N
4
3
5
N
catalyst III (5 mol%)
+
∗
O2N
O
2
Rb2CO3 (1.3 equiv)
H2O (1.4 equiv)
toluene, r.t.
N
H
6
7
4a–f
2
5a–f
argon
Entry
Product
NO2 position
Time (h)
Yield (%)b
ee (%)c
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
4
3
5
6
2
7
5
5
92
65
95
82
nrd
nrd
69
42
38
35
–
5
5
24
24
–
a Reaction conditions: 0.1 mmol scale, 1 equiv of 4a–f, 2.1 equiv of 2, 5 mol% of catalyst III, 1.3 equiv of Rb2CO3 and 1.4 equiv of H2O under argon atmosphere.
b Isolated yield.
c Determined by chiral HPLC analysis.
d nr = no reaction.
with (2E,4E)-1-phenylhexa-2,4-dien-1-one (2k), croton-
aldehyde (2l), phenyl (E)-but-2-enoate (2m), and -nitro-
styrene (2n).
Generally, aromatic ketones were the best substrates for
the N-alkylation of nitroindoles. The obtained results sug-
gested the importance of – interactions in the transition
state. To gain insight into the reaction mechanism, compu-
tational studies were conducted based on the density func-
tional M062X/def2SVP method. In order to assess noncova-
lent interactions, a Natural Bond Orbital (NBO) analysis was
performed using the M062X/def2TZVP method (for calcula-
tion details and NBO energies, see the Supporting Informa-
tion). In the ternary complex INT1-S a strong hydrogen
bond between the deprotonated N atom of indole 4a and
the hydroxyl group of catalyst III, together with the – in-
teractions between the quinolone ring of the catalyst III
and indole 4a, form (Figure 3A). Distortion of the complex
leads to the intermediate (INT2-S) with reorganized geome-
try: a hydrogen bond forms between the nitro group of in-
dole and the hydroxyl of the catalyst (Figure 3B). The inter-
mediate forms a product via a bond-forming step (TS1)
(distance between Michael acceptor and donor site is 2.28
Figure 2 X-ray crystal structure of compound 6c (CCDC 1923379)
Figure 3 Optimized geometries of intermediates and transition state: A: INT1-S; B: INT2-S; C: TS1-S
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–M

G
D. Trubitsõn et al.
Paper
Synthesis
Å) (Figure 3C). Throughout the reaction, – interactions
remain important.
Indole derivatives 1, 4a, 4c, 4d, and 4f were purchased from Fluo-
rochem Ltd and used as received. 2-Nitroindole (4e)24 and 3-nitroin-
dole (4b)25 were prepared according to literature procedures and the
analytical data matched those in the literature.
We have revealed here a systematic study of the N-al-
kylation of nitroindoles. It was found that a Cinchona alka-
loid-derived PTC reaction with various Michael acceptors
led exclusively to aza-Michael adducts in high yields and
moderate to good enantioselectivities. The acidity of the N–H
proton was not the decisive factor in determining the reac-
tivity and selectivity of the reaction. Instead, the position of
the nitro group on the indole ring plays a crucial role in the
reaction.
Synthesis of Unsaturated ,-Enones 2 and 2a–n
(E)-1-Phenylbut-2-en-1-one (2)26
To a 1 M solution of phenylmagnesium bromide in THF (25 mL, 25
mmol) in THF (75 mL) crotonaldehyde (2.07 mL, 25 mmol) was added
dropwise at 0 °C under argon. The mixture was stirred for 45 min at
the same temperature and then quenched with sat. aq NH4Cl (25 mL).
The organic solvent was removed under reduced pressure and aq
NH4Cl (20 mL) was added. The reaction mixture was extracted with
EtOAc (5 × 50 mL). The organic phase was dried with MgSO4, filtered,
and concentrated to dryness under reduced pressure to provide a yel-
low oil. The Grignard product was dissolved in DCM (40 mL) and
MnO2 (21.7 g, 250 mmol, 10 equiv) was added under vigorous stir-
ring. The reaction mixture was stirred overnight. The mixture was fil-
tered through a pad of Celite, washed with DCM, and purified by col-
umn chromatography (silica gel, 2–10% EtOAc–PE).
All commercially available reagents were used without further purifi-
cation. All air- or moisture-sensitive reactions were carried out under
an argon atmosphere using oven-dried glassware. The reactions were
monitored by TLC with silica-gel-coated aluminum plates (Merck 60
F254) and visualized with KMnO4, anisaldehyde, vaniline, or ninhy-
drine stain. Yields refer to chromatographically purified products. 1H
NMR spectra were recorded on a Bruker Avance III instrument at 400
MHz and are reported in ppm () referenced to the residual solvent
signal (CDCl3:  = 7.26; CD3OD,  = 3.31). 13C NMR spectra were re-
corded at 101 MHz and are reported in parts per million () refer-
enced to the residual solvent signal (CDCl3:  = 77.16; CD3OD:  =
49.00). HRMS spectra were recorded with an Agilent Technologies
6540 UHD Accurate-Mass Q-TOF LC/MS spectrometer by using AJ-ESI
ionization. IR spectra were recorded on a Bruker Tensor 27 FT-IR spec-
trophotometer. Optical rotations were obtained with an Anton Paar
GWB Polarimeter MCP500 at 20 °C in CHCl3 and are calibrated with
pure solvent as a blank. Chiral HPLC was performed by using Chiral-
pak AD-H (250 × 4.6 mm), Chiralcel OJ-H (250 × 4.6 mm), or Chiralcel
OD-H (250 × 4.6 mm) columns. Column chromatography was per-
formed on a preparative purification system with silica gel Kieselgel
40–63 m. The measured melting points are uncorrected. All crystal-
line products are obtained from chloroform. Purchased chemicals and
solvents were used as received. DCM was distilled over phosphorus
pentoxide. PE has a boiling point of 40–60 °C. The reactions were per-
formed under air without additional moisture elimination unless
stated otherwise.
Yield: 1.988 g (54%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 7.96–7.89 (m, 2 H), 7.58–7.51 (m, 1 H),
7.49–7.43 (m, 2 H), 7.07 (dq, J = 15.3, 6.8 Hz, 1 H), 6.91 (dq, J = 15.3,
1.6 Hz, 1 H), 2.00 (dd, J = 6.8, 1.6 Hz, 3 H).
Analytic data were in agreement with the literature data.
2-En-1-ones 2a,c–f,k by Wittig Reaction; General Procedure
The aldehyde (1.2 equiv) was added to the mixture of phosphonium
ylide (1 equiv) in DCM (0.2 M). The reaction was monitored by TLC.
Upon completion of the reaction, the DCM was evaporated to give a
solid residue that was triturated with hexane. The solid triphenyl-
phosphine oxide was filtered off and the hexane layer was dried over
Na2SO4, filtered, and concentrated to dryness under reduced pressure.
The crude mixture was purified by column chromatography (silica
gel).
(E)-1-(4-Bromophenyl)but-2-en-1-one (2a)
Following the general procedure, starting from 1-(4-bromophenyl)-2-
(triphenyl-5-phosphaneylidene)ethan-1-one (1.75 g, 3.8 mmol) and
acetaldehyde (256 L, 4.56 mmol), the mixture was stirred for 7 d.
The title compound was obtained after purification by column chro-
matography (silica gel, 1–6% EtOAc–PE).
Acidity Measurements
UV-Vis spectrophotometric titration was used to determine the acidi-
ty (pKa values) of the nitroindoles and 3-cyanoindole in acetonitrile.
Measurements were carried out in a glovebox, applying a method de-
scribed earlier.15 The argon atmosphere (5.0) as the environment for
all experiments was kept dry and oxygen-free (both contents below 1
ppm) and only freshly prepared solutions in MeCN (H2O < 5 ppm)
were used. UV-Vis spectra were collected on Agilent Cary 60 and
PerkinElmer Lambda 12 spectrophotometers using an external cell
compartment inside the glovebox. CF3SO2OH and EtN=P2(dma)5 (or
tert-butyliminotri(pyrrolidino)phosphorane) solutions in MeCN were
used as acidic and basic titrants, respectively. In titration experiments
the concentration of the indoles and reference acids were in the range
of 10–5 to 10–4 M.
Yield: 611 mg (71%); white crystals.
1H NMR (400 MHz, CDCl3):  = 7.83–7.75 (m, 2 H), 7.64–7.56 (m, 2 H),
7.08 (dq, J = 15.3, 6.9 Hz, 1 H), 6.86 (dq, J = 15.3, 1.6 Hz, 1 H), 2.00 (dd,
J = 6.9, 1.6 Hz, 3 H).
Analytic data were in agreement with the literature data.27
(E)-1-(4-Methoxyphenyl)but-2-en-1-one (2c)
Following the general procedure starting from 1-(4-metoxyphenyl)-
2-(triphenyl-5-phosphaneylidene)ethan-1-one (1.97 g, 4.8 mmol)
and acetaldehyde (326 L, 5.8 mmol), the mixture was stirred for 7 d.
The title compound was obtained after purification by column chro-
matography (silica gel, 1–10% EtOAc–PE).
Phase-transfer catalysts I–III,18 VII,18 IV,19,20 V,21 VI,22 and VIII23 were
prepared by corresponding literature procedures and the
Yield: 700 mg (83%); colorless oil.
Analytical data matched those in the literature.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–M

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D. Trubitsõn et al.
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Synthesis
1H NMR (400 MHz, CDCl3):  = 7.99–7.90 (m, 2 H), 7.06 (dq, J = 15.2,
6.7 Hz, 1 H), 6.97–6.89 (m, 3 H), 3.87 (s, 3 H), 1.99 (dd, J = 6.8, 1.5 Hz,
3 H).
(E)-1-(4-Nitrophenyl)but-2-en-1-one (2b)
3-Hydroxy-1-(4-nitrophenyl)butan-1-one
Analytic data were in agreement with the literature data.28
To a dry flask under argon was added diisopropylamine (1.4 mL, 10
mmol) in THF (15 mL). The mixture was cooled to –20 °C and 2.5 M
n-BuLi in hexane (4 mL, 10 mmol, 1.05 equiv) was added. The mixture
was stirred for 30 min, cooled to –78 °C, and p-nitroacetophenone (1
equiv) was added. The reaction mixture was stirred for 20 min at –78
°C and acetaldehyde (590 L, 10.5 mmol, 1.1 equiv) was added. After 1
h the mixture was quenched with sat. aq NaHCO3 and warmed to r.t.
The crude mixture was poured into Et2O and washed with H2O, 1% aq
HCl (2 × 50 mL), sat. aq NaHCO3 (2 × 50 mL), and brine (2 × 50 mL). The
organic layer was dried over Na2SO4 and concentrated to dryness un-
der reduced pressure. The crude mixture was purified by column
chromatography (silica gel, 5–30% EtOAc–PE) providing 3-hydroxy-1-
(4-nitrophenyl)butan-1-one; yield: 470 mg (24%).
(E)-1-(Furan-2-yl)but-2-en-1-one (2d)
Following the general procedure starting from 1-(4-furan-2-yl)-2-
(triphenyl-5-phosphaneylidene)ethan-1-one (1.4 g, 3.78 mmol) and
acetaldehyde (255 L, 4.54 mmol), the mixture was stirred for 6 d.
The title compound was obtained after purification by column chro-
matography (silica gel, 2–8% EtOAc–PE).
Yield: 210 mg (41%); white crystals.
1H NMR (400 MHz, CDCl3):  = 7.64–7.57 (m, 1 H), 7.24–7.22 (m, 1 H),
7.22–7.11 (m, 1 H), 6.82 (dq, J = 15.4, 1.7 Hz, 1 H), 6.55 (dd, J = 3.5, 1.7
Hz, 1 H), 1.99 (dd, J = 6.9, 1.7 Hz, 3 H).
Analytic data were in agreement with the literature data.28
1H NMR (400 MHz, CDCl3):  = 8.34–8.29 (m, 2 H), 8.14–8.09 (m, 2 H),
4.54–4.37 (m, 1 H), 3.18–3.12 (m, 2 H), 2.98 (s, 1 H, OH), 1.33 (d, J =
6.4 Hz, 3 H).
(E)-4-Methyl-1-phenylpent-2-en-1-one (2e)
Following the general procedure starting from 1-phenyl-2-(triphenyl-
5-phosphaneylidene)ethan-1-one (1.75 g, 4.6 mmol) and isobutyral-
dehyde (440 L, 4.8 mmol, 1.05 equiv), the mixture was stirred for 6
d. The title compound was obtained after purification by column
chromatography (silica gel, 2% EtOAc–PE).
Analytic data were in agreement with the literature data.31
2b
3-Hydroxy-1-(4-nitrophenyl)butan-1-one (470 mg, 2.25 mmol) was
dissolved in a mixture of DCM (7 mL) and pyridine (1.8 mL) and treat-
ed with mesyl chloride (174 L, 2.25 mmol) under an argon atmo-
sphere for 4 h. H2O (10 mL) was added and reaction mixture was ex-
tracted with DCM (3 × 20 mL). The organic phase was washed with
sat. aq CuSO4 (4 × 30 mL) and brine (2 × 30mL), dried over Na2SO4, and
concentrated to dryness under reduced pressure. The title compound
was obtained after purification by column chromatography (silica gel,
2–10% EtOAc–PE).
Yield: 220 mg (28%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 7.97–7.89 (m, 2 H), 7.59–7.52 (m, 1 H),
7.50–7.42 (m, 2 H), 7.03 (dd, J = 15.5, 6.7 Hz, 1 H), 6.82 (dd, J = 15.5,
1.4 Hz, 1 H), 2.66–2.51 (m, 1 H), 1.14 (d, J = 6.8 Hz, 6 H).
Analytic data were in agreement with the literature data.29
(E)-1-Phenylnon-2-en-1-one (2f)
Yield: 175 mg (41%); white solid.
Following the general procedure starting from 1-phenyl-2-(triphenyl-
5-phosphaneylidene)ethan-1-one (1.1 g, 2.9 mmol) and heptanal
(494 L, 3.5 mmol), the mixture was stirred for 5 d. The title com-
pound was obtained after purification by column chromatography
(silica gel, 1–6% EtOAc–PE).
1H NMR (400 MHz, CDCl3):  = 8.34–8.26 (m, 2 H), 8.07–7.99 (m, 2 H),
7.12 (dq, J = 15.4, 6.9 Hz, 1 H), 6.87 (dq, J = 15.3, 1.7 Hz, 1 H), 2.03 (dd,
J = 6.9, 1.7 Hz, 3 H).
Analytic data were in agreement with the literature data.32
(E)-1-(Naphthalen-2-yl)but-2-en-1-one (2g)
3-Hydroxy-1-(2-naphthalenyl)-1-butanone
Yield: 250 mg (40%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 7.96–7.90 (m, 2 H), 7.59–7.52 (m, 1 H),
7.51–7.42 (m, 2 H), 7.07 (dt, J = 15.4, 6.9 Hz, 1 H), 6.87 (dt, J = 15.4, 1.4
Hz, 1 H), 2.37–2.27 (m, 2 H), 1.58–1.46 (m, 2 H), 1.42–1.21 (m, 6 H),
0.93–0.84 (m, 3 H).
Diisopropylamine (1.37 mL, 9.8 mmol) was dissolved in THF (18 mL)
under argon. The mixture was cooled to –20 °C and 2.5 M n-BuLi in
hexane (3.92 mL, 9.8 mmol) was added; then the mixture was stirred
for 30 min and cooled to –78 °C before 1-(naphthalen-2-yl)ethan-1-
one (1.59 g, 9.3 mmol) was added. The mixture was stirred for 20 min
at –78 °C and acetaldehyde (570 L, 10.26 mmol) was added. The
mixture was stirred for an additional 1 h and was quenched with sat.
aq NaHCO3 and warmed to r.t. The crude mixture was poured into
Et2O, washed with H2O, 1% aq HCl (2 × 50 mL), sat. aq NaHCO3 (2 × 50
mL), and brine (2 × 50 mL). The organic layer was dried over Na2SO4
and concentrated to dryness under reduced pressure. The crude mix-
ture was purified by column chromatography (silica gel, 5–30% EtO-
Ac–PE); this provided 3-hydroxy-1-(2-naphthalenyl)-1-butanone;
yield: 1.788 g (90%).
Analytic data were in agreement with the literature data.29
(2E,4E)-1-Phenylhexa-2,4-dien-1-one (2k)
Following the general procedure starting from 1-phenyl-2-(triphenyl-
5-phosphaneylidene)ethan-1-one (1.1 g, 2.9 mmol) and (E)-but-2-
enal (290 L, 3.5 mmol), the mixture was stirred for 5 d. The title
compound was obtained after purification by column chromatogra-
phy (silica gel, 2–4% EtOAc–PE).
Yield: 250 mg (40%); yellow amorphous solid.
1H NMR (400 MHz, CDCl3):  = 7.96–7.90 (m, 2 H), 7.57–7.51 (m, 1 H),
7.50–7.36 (m, 3 H), 6.87 (dd, J = 15.1, 0.8 Hz, 1 H), 6.40–6.19 (m, 2 H),
1.90 (dd, J = 6.1, 1.0 Hz, 3 H).
1H NMR (400 MHz, CDCl3):  = 8.46 (d, J = 1.7 Hz, 1 H), 8.11–7.80 (m, 4
H), 7.67–7.52 (m, 2 H), 4.53–4.41 (m, 1 H), 3.41 (d, J = 3.0 Hz, 1 H, OH),
3.31 (dd, J = 17.6, 2.8 Hz, 1 H), 3.18 (dd, J = 17.6, 8.9 Hz, 1 H), 1.35 (d,
J = 6.4 Hz, 3 H).
Analytic data were in agreement with the literature data.30
Analytic data were in agreement with the literature data.31
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–M

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D. Trubitsõn et al.
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Synthesis
2g
(S)-3-(3-Nitro-1H-indol-1-yl)-1-phenylbutan-1-one (5b)
3-Hydroxy-1-(2-naphthalenyl)-1-butanone (900 mg, 4.2 mmol) was
dissolved in pyridine (3.2 mL) and treated with mesyl chloride (325
L, 4.2 mmol) under argon for 24 h. After H2O was added to the flask,
the mixture was extracted with Et2O (3 × 50 mL). The organic phase
was washed with sat. aq CuSO4 (4 × 30 mL) and brine (2 × 40 mL),
dried over Na2SO4, and concentrated to dryness under reduced pres-
sure. The crude 4-(naphthalen-2-yl)-4-oxobutan-2-yl methanesul-
fonate and TEA (608 L, 4.2 mmol) were mixed in Et2O (20 mL) over-
night. The crude mixture was concentrated and purified by column
chromatography (silica gel, 1–8% EtOAc–PE), providing product 2g.
Title compound 5b was obtained according to the general procedure
from 3-nitroindole (4b; 16.2 mg, 0.1 mmol) and 2 (30.9 mg, 0.21
mmol). The product was isolated by direct column chromatography
(silica gel; 5–25% EtOAc–PE).
Yield: 20 mg (65%); rose amorphous solid; 42% ee [HPLC (Daicel Chi-
ralpak OD-H, hexane–iPrOH, 90:10, flow rate 1.0 mL/min, T = 25 °C,
 = 254 nm): tR = 41.0 (major), tR = 45.1 (minor)]; []D20 –4.7 (c 0.034,
CHCl3); Rf = 0.4 (PE–EtOAc, 3:1).
IR (KBr): 3128, 1685, 1597, 1525, 1481, 1449, 1379, 1303, 1225, 750,
689 cm–1
1H NMR (400 MHz, CDCl3):  = 8.34–8.26 (m, 2 H), 7.94–7.89 (m, 2 H),
7.63–7.54 (m, 2 H), 7.49–7.44 (m, 2 H), 7.44–7.36 (m, 2 H), 5.42–5.29
(m, 1 H), 3.62 (dd, J = 17.6, 5.4 Hz, 1 H), 3.53 (dd, J = 17.6, 7.5 Hz, 1 H),
1.73 (d, J = 6.8 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 196.0, 136.1, 135.0, 134.1, 129.5, 129.0
(2 C), 128.1 (2 C), 127.8, 124.7, 124.5, 121.14, 121.12, 111.0, 48.9,
45.2, 21.0.
Yield: 480 mg (70%).
1H NMR (400 MHz, CDCl3):  = 8.47–8.42 (m, 1 H), 8.03 (dd, J = 8.6, 1.8
Hz, 1 H), 8.00–7.94 (m, 1 H), 7.94–7.85 (m, 2 H), 7.63–7.51 (m, 2 H),
7.21–7.02 (m, 2 H), 2.05 (dd, J = 6.4, 1.1 Hz, 3 H).
Analytic data were in agreement with the literature data.33
Phenyl (E)-But-2-enoate (2m)
Compound 2m was prepared according to a literature procedure.34
HRMS (ESI): m/z [M + H]+ calcd for C18H17N2O3: 309.1234; found:
309.1228.
Yield: 573 mg (35%); colorless liquid.
1H NMR (400 MHz, CDCl3):  = 7.42–7.34 (m, 2 H), 7.27–7.07 (m, 4 H),
6.05 (dq, J = 15.6, 1.7 Hz, 1 H), 1.96 (dd, J = 6.9, 1.7 Hz, 3 H).
(S)-3-(5-Nitro-1H-indol-1-yl)-1-phenylbutan-1-one (5c)
Title compound 5c was obtained according to the general procedure
from 5-nitroindole (4c; 16.2 mg, 0.1 mmol) and 2 (30.9 mg, 0.21
mmol). The product was isolated by direct column chromatography
(silica gel; 5–25% EtOAc–PE).
N-Alkylation of Nitroindoles; General Procedure
Indole 1 or 4 (0.1 mmol), phase-transfer catalyst III (0.005 mmol), and
Rb2CO3 (0.13 mmol) were loaded in a 1 mL vial. The mixture of com-
pounds was held for 1 h under vacuum. The vial was filled with an
argon atmosphere. Toluene (1 mL), ketone 2 (0.21 mmol), and H2O
(0.14 mmol) were added and the reaction mixture was stirred at r.t.
for 5 h under argon unless stated otherwise. The progress of the reac-
tion was monitored by TLC and NMR spectroscopy. After completion
of the reaction, the reaction mixture was directly purified by column
chromatography to afford pure products 3, 5, or 6.
Yield: 29.3 mg (95%); orange amorphous solid; 38% ee [HPLC (Daicel
Chiralpak AD-H, hexane–iPrOH, 90:10, flow rate 1.0 mL/min, T = 25
20
°C,  = 254 nm): tR = 31.8 (minor), tR = 35.9 (major)]; []D –76.4 (c
0.032, CHCl3); Rf = 0.5 (PE–EtOAc, 3:1).
IR (KBr): 2980, 1685, 1610, 1580, 1470, 1450, 1319, 1219, 1070, 743,
690 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.55 (d, J = 2.3 Hz, 1 H), 8.12 (dd, J = 9.1,
2.3 Hz, 1 H), 7.93–7.84 (m, 2 H), 7.60–7.54 (m, 1 H), 7.51 (d, J = 9.2 Hz,
1 H), 7.48–7.38 (m, 3 H), 6.71 (d, J = 3.4 Hz, 1 H), 5.39–5.26 (m, 1 H),
3.58 (dd, J = 17.3, 6.0 Hz, 1 H), 3.46 (dd, J = 17.3, 7.1 Hz, 1 H), 1.69 (d,
J = 6.9 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 196.7, 141.7, 138.5, 136.4, 133.8, 128.9
(2 C), 128.1 (2 C), 127.7, 127.4, 118.4, 117.4, 109.8, 105.0, 48.3, 45.5,
21.3.
(S)-3-(4-Nitro-1H-indol-1-yl)-1-phenylbutan-1-one (5a)
The reaction time was 24 h. Title compound 5a was obtained accord-
ing to the general procedure from 4-nitroindole (4a; 162.2 mg, 1
mmol) and 2 (307 mg, 2.1 mmol). The product was isolated by direct
column chromatography (silica gel; 5–25% EtOAc–PE).
Yield: 281 mg (91%); orange amorphous solid; 65% ee [HPLC (Daicel
Chiralpak AD-H, hexane–iPrOH, 90:10, flow rate 1.0 mL/min, T = 25
HRMS (ESI): m/z [M + H]+ calcd for C18H17N2O3: 309.1234; found:
309.1232.
20
°C,  = 254 nm): tR = 21.3 (major), tR = 29.9 (minor)]; []D –21.4 (c
0.033, CHCl3); Rf = 0.4 (PE–EtOAc, 3:1).
IR (KBr): 2979, 1685, 1597, 1511, 1498, 1448, 1361, 1332, 1312, 1268,
(S)-3-(6-Nitro-1H-indol-1-yl)-1-phenylbutan-1-one (5d)
755, 735 cm–1
.
Title compound 5d was obtained according to the general procedure
from 6-nitroindole (4d; 16.2 mg, 0.1 mmol) and 2 (30.9 mg, 0.21
mmol). The product was isolated by direct column chromatography
(silica gel; 5–15% EtOAc–PE).
1H NMR (400 MHz, CDCl3):  = 8.12 (dd, J = 8.0, 0.8 Hz, 1 H), 7.91–7.86
(m, 2 H), 7.83 (d, J = 8.2 Hz, 1 H), 7.60–7.54 (m, 1 H), 7.51 (d, J = 3.3 Hz,
1 H), 7.47–7.41 (m, 2 H), 7.31–7.26 (m, 2 H), 5.42–5.31 (m, 1 H), 3.58
(dd, J = 17.3, 5.8 Hz, 1 H), 3.47 (dd, J = 17.3, 7.3 Hz, 1 H), 1.70 (d, J = 6.8
Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 196.8, 140.6, 137.9, 136.4, 133.9, 128.9
(2 C), 128.6, 128.1 (2 C), 123.1, 120.6, 117.8, 116.6, 101.1, 48.2, 42.7,
20.1.
Yield: 25.3 mg (82%); yellow solid; mp 168–170 °C; 35% ee [HPLC
(Daicel Chiralpak OD-H, hexane–iPrOH, 90:10, flow rate 1.0 mL/min, T
= 25 °C,  = 254 nm): tR =16.6 (major), tR = 22.6 (minor)]; []D20 –76.4
(c 0.035, CHCl3); Rf = 0.5 (PE–EtOAc, 3:1).
IR (KBr): 2978, 1684, 1580, 1511, 1495, 1462, 1330, 1219, 1070, 777,
HRMS (ESI): m/z [M + H]+ calcd for C18H17N2O3: 309.1234; found:
309.1227.
730, 689 cm–1
.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–M

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D. Trubitsõn et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3):  = 8.50–8.43 (m, 1 H), 8.00 (dd, J = 8.7, 2.0
Hz, 1 H), 7.93–7.86 (m, 2 H), 7.63 (d, J = 8.7 Hz, 1 H), 7.60–7.49 (m, 2
H), 7.45 (t, J = 7.7 Hz, 2 H), 6.62 (d, J = 3.2 Hz, 1 H), 5.41–5.29 (m, 1 H),
3.62 (dd, J = 17.2, 6.1 Hz, 1 H), 3.50 (dd, J = 17.2, 7.1 Hz, 1 H), 1.71 (d,
J = 6.8 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 196.5, 143.1, 136.4, 134.2, 133.8,
133.5, 130.5, 128.9 (2 C), 128.1 (2 C), 121.0, 115.2, 107.0, 103.1, 48.6,
45.4, 21.4.
(S)-1-(4-Methoxyphenyl)-3-(4-nitro-1H-indol-1-yl)butan-1-one
(6c)
Title compound 6c was obtained according to the general procedure
from 4-nitroindole (4a; 16.2 mg, 0.1 mmol) and (E)-1-(4-methoxy-
phenyl)but-2-en-1-one (2c; 37 mg, 0.21 mmol). The product was iso-
lated by direct column chromatography (silica gel; 3–20% EtOAc–PE).
Yield: 28 mg (83%); yellow crystals; mp 100–104 °C; 75% ee [HPLC
(Daicel Chiralpak AD-H, hexane–iPrOH, 80:20, flow rate 1.0 mL/min,
T = 35 °C, = 254 nm): tR =15.8 (major), tR = 23.6 (minor)]; []D20 –34.3
(c 0.065, CHCl3); Rf = 0.3 (PE–EtOAc, 3:1).
HRMS (ESI): m/z [M + H]+ calcd for C18H17N2O3: 309.1234; found:
309.1226.
IR (KBr): 2976, 1675, 1600, 1575, 1511, 1456, 1361, 1308, 1266, 1171,
(S)-1-(4-Bromophenyl)-3-(4-nitro-1H-indol-1-yl)butan-1-one (6a)
759, 737 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.10 (d, J = 7.9 Hz, 1 H), 7.88–7.79 (m, 3
H), 7.49 (d, J = 3.3 Hz, 1 H), 7.29–7.23 (m, 2 H), 6.91–6.85 (m, 2 H),
5.39–5.28 (m, 1 H), 3.83 (s, 3 H), 3.49 (dd, J = 17.0, 5.8 Hz, 1 H), 3.39
(dd, J = 17.0, 7.3 Hz, 1 H), 1.67 (d, J = 6.8 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 195.2, 164.1, 140.5, 137.9, 130.4 (2 C),
129.5, 128.7, 122.6, 120.6, 117.7, 116.7, 114.0 (2 C), 102.8, 55.7, 48.3,
45.3, 21.4.
Title compound 6a was obtained according to the general procedure
from 4-nitroindole (4a; 16.2 mg, 0.1 mmol) and (E)-1-(4-bromophe-
nyl)but-2-en-1-one (2a; 47.3 mg, 0.21 mmol). Following a modifica-
tion of the general procedure, ketone 2a was added before evacuation
of the system. The product was isolated by direct column chromatog-
raphy (silica gel; 2–15% EtOAc–PE).
Yield: 25.9 mg (67%); orange amorphous solid; 59% ee [HPLC (Daicel
Chiralpak AD-H, hexane–iPrOH, 90:10, flow rate 1.0 mL/min, T = 25
HRMS (ESI): m/z [M + H]+ calcd for C19H19N2O4: 339.1339; found:
339.1341.
20
°C,  =254 nm): tR =27.2 (major), tR = 35.2 (minor)]; []D –25.4 (c
0.050, CHCl3); Rf = 0.4 (PE–EtOAc, 10:1).
CCDC 1923379 contains the supplementary crystallographic data for
6c. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
IR (KBr): 2979, 1686, 1585, 1568, 1511, 1498, 1361, 1331, 1304, 1269,
1105, 790, 737 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.15–8.09 (m, 1 H), 7.82 (d, J = 8.3 Hz, 1
H), 7.76–7.70 (m, 2 H), 7.60–7.54 (m, 2 H), 7.49 (d, J = 3.3 Hz, 1 H),
7.32–7.26 (m, 2 H), 5.40–5.29 (m, 1 H), 3.54 (dd, J = 17.3, 5.9 Hz, 1 H),
3.42 (dd, J = 17.4, 7.2 Hz, 1 H), 1.69 (d, J = 6.8 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 195.7, 140.5, 137.8, 135.0, 132.1 (2 C),
129.5 (2 C), 129.0, 128.4, 122.5, 120.6, 117.7, 116.5, 102.9, 47.9, 45.5,
21.3
(S)-1-(Furan-2-yl)-3-(4-nitro-1H-indol-1-yl)butan-1-one (6d)
Title compound 6d was obtained according to the general procedure
from 4-nitroindole (4a; 16.2 mg, 0.1 mmol) and (E)-1-(furan-2-
yl)but-2-en-1-one (2d; 28.6 mg, 0.21 mmol). Following a modifica-
tion of the general procedure, ketone 2d was added before evacuation
of the system. The product was isolated by direct column chromatog-
raphy (silica gel; 5–25% EtOAc–PE).
HRMS (ESI): m/z [M + H]+ calcd for C18H16N2O3Br: 387.0339; found:
387.0342.
Yield: 26.8 mg (90%); orange crystals; mp 85–90 °C; 63% ee [HPLC
(Daicel Chiralpak AD-H, hexane–iPrOH, 90:10, flow rate 1.0 mL/min,
T = 25 °C,  = 254 nm): tR =19.4 (major), tR = 26.5 (minor)]; []D20 –37.8
(c 0.030, CHCl3); Rf = 0.3 (PE–EtOAc, 3:1).
(S)-3-(4-Nitro-1H-indol-1-yl)-1-(4-nitrophenyl)butan-1-one (6b)
Title compound 6b was obtained according to the general procedure
from 4-nitroindole (4a; 16.2 mg, 0.1 mmol) and (E)-1-(4-nitrophe-
nyl)but-2-en-1-one (2b; 40.1 mg, 0.21 mmol). Following a modifica-
tion of the general procedure, ketone 2b was added before evacuation
of the system. The product was isolated by direct column chromatog-
raphy (silica gel; 3–20% EtOAc–PE).
IR (KBr): 3132, 2980, 1672, 1567, 1511, 1499, 1467, 1361, 1332, 1308,
760, 737 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.08 (dd, J = 8.0, 0.8 Hz, 1 H), 7.78 (d, J =
8.1 Hz, 1 H), 7.54–7.43 (m, 2 H), 7.25–7.20 (m, 2 H), 7.09 (d, J = 3.6 Hz,
1 H), 6.46 (dd, J = 3.6, 1.7 Hz, 1 H), 5.33–5.20 (m, 1 H), 3.41 (dd, J =
16.5, 6.4 Hz, 1 H), 3.26 (dd, J = 16.5, 7.1 Hz, 1 H), 1.64 (d, J = 6.9 Hz, 3
H).
13C NMR (101 MHz, CDCl3):  = 185.8, 152.5, 147.0, 140.6, 137.9,
128.5, 122.6, 120.7, 117.82, 117.78, 116.6, 112.8, 103.0, 48.1, 45.5,
21.4.
Yield: 26.1 mg (74%); yellow solid; mp 64–68 °C; 73% ee [HPLC (Daicel
Chiralpak OD-H, hexane–iPrOH, 70:30, flow rate 0.9 mL/min, T = 35
20
°C,  = 254 nm): tR =23.2 (minor), tR = 49.8 (major)]; []D –40.2 (c
0.041, CHCl3); Rf = 0.5 (PE–EtOAc, 3:1).
IR (KBr): 3109, 2929, 1693, 1603, 1524, 1347, 1318, 1269, 790, 786
cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C16H15N2O4: 299.1026; found:
299.1032.
1H NMR (400 MHz, CDCl3):  = 8.30–8.24 (m, 2 H), 8.16–8.09 (m, 1 H),
8.05–8.00 (m, 2 H), 7.85–7.80 (m, 1 H), 7.50 (d, J = 3.3 Hz, 1 H), 7.33–
7.27 (m, 2 H), 5.45–5.29 (m, 1 H), 3.64 (dd, J = 17.6, 6.0 Hz, 1 H), 3.51
(dd, J = 17.7, 6.9 Hz, 1 H), 1.73 (d, J = 6.8 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 195.3, 150.7, 140.63, 140.61, 137.8,
129.2 (2 C), 128.4, 124.1 (2 C), 122.6, 120.8, 117.9, 116.5, 103.2, 47.9,
46.2, 21.4.
(R)-4-Methyl-3-(4-nitro-1H-indol-1-yl)-1-phenylpentan-1-one
(6e)
The reaction time was 24 h. Title compound 6e was obtained accord-
ing to the general procedure from 4-nitroindole (4a; 16.2 mg, 0.1
mmol) and (E)-4-methyl-1-phenylpent-2-en-1-one (2e; 36.6 mg,
0.21 mmol). The product was isolated by direct column chromatogra-
phy (silica gel; 5–25% EtOAc–PE).
HRMS (ESI): m/z [M + H]+ calcd for C18H16N3O5: 354.1084; found:
354.109.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–M

K
D. Trubitsõn et al.
Paper
Synthesis
Yield: 26.9 mg (80%); orange amorphous solid; 64% ee [HPLC (Daicel
13C NMR (101 MHz, CDCl3):  = 196.7, 140.5, 137.9, 135.9, 133.7,
132.5, 130.0, 129.7, 129.0, 128.8, 128.7, 127.9, 127.2, 123.5, 122.7,
120.6, 117.8, 116.7, 102.9, 48.3, 45.8, 21.5.
Chiralpak AD-H, hexane–iPrOH, 90:10, flow rate 1.0 mL/min, T = 25
20
°C,  = 254 nm): tR =17.3 (major), tR = 20.8 (minor)]; []D –31.9 (c
0.037, CHCl3); Rf = 0.7 (PE–EtOAc, 3:1).
HRMS (ESI): m/z [M + H]+ calcd for C22H19N2O3: 359.1390; found:
IR (KBr): 2966, 1686, 1597, 1565, 1512, 1499, 1448, 1361, 1327, 1302,
359.1389.
1273, 758, 737 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.16–8.07 (m, 1 H), 7.88 (d, J = 8.2 Hz, 1
H), 7.86–7.79 (m, 2 H), 7.58–7.50 (m, 1 H), 7.45–7.36 (m, 3 H), 7.32–
7.23 (m, 2 H), 5.00–4.90 (m, 1 H), 3.67 (dd, J = 17.3, 8.4 Hz, 1 H), 3.55
(dd, J = 17.3, 4.3 Hz, 1 H), 2.38–2.23 (m, 1 H), 1.09 (d, J = 6.6 Hz, 3 H),
0.74 (d, J = 6.6 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 196.9, 140.5, 139.1, 136.5, 133.7,
129.2, 128.9 (2 C), 128.1 (2 C), 122.2, 120.6, 117.7, 117.2, 103.0, 58.4,
42.0, 34.2, 20.4, 19.4.
3-(4-Nitro-1H-indol-1-yl)cyclohexan-1-one (6h)
The reaction time was 24 h. Title compound 6h was obtained accord-
ing to the general procedure from 4-nitroindole (4a; 16.2 mg, 0.1
mmol) and cyclohex-2-en-1-one (2h; 20.2 mg, 0.21 mmol). The prod-
uct was isolated by direct column chromatography (silica gel; 5–30%
EtOAc–PE).
Yield: 16.8 mg (65%); yellow amorphous solid; racemic [HPLC (Daicel
Chiralpak AD-H, hexane–iPrOH, 90:10, flow rate 1.0 mL/min, T = 25
°C,  = 254 nm): tR1 = 23.2, tR2 = 26.8]; Rf = 0.1 (PE–EtOAc, 3:1).
HRMS (ESI): m/z [M + H]+ calcd for C20H21N2O3: 337.1547; found:
337.1543.
IR (KBr): 2952, 1713, 1512, 1498, 1449, 1362, 1333, 1307, 1284, 792,
757 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.15 (d, J = 8.0 Hz, 1 H), 7.68 (d, J = 8.2
Hz, 1 H), 7.47 (d, J = 3.3 Hz, 1 H), 7.36–7.27 (m, 2 H), 4.80–4.70 (m, 1
H), 2.99–2.87 (m, 1 H), 2.87–2.74 (m, 1 H), 2.62–2.32 (m, 3 H), 2.30–
2.12 (m, 2 H), 1.91–1.76 (m, 1 H).
13C NMR (101 MHz, CDCl3):  = 207.2, 140.8, 137.6, 128.2, 122.8,
120.9, 118.0, 116.0, 103.2, 54.7, 48.4, 40.9, 31.7, 22.3.
(S)-3-(4-Nitro-1H-indol-1-yl)-1-phenylnonan-1-one (6f)
The reaction time was 24 h. Title compound 6f was obtained accord-
ing to the general procedure from 4-nitroindole (4a; 16.2 mg, 0.1
mmol) and (E)-1-phenylnon-2-en-1-one (2f; 45.4 mg, 0.21 mmol).
The product was isolated by direct column chromatography (silica
gel; 2–15% EtOAc–PE).
Yield: 31.0 mg (82%); orange amorphous solid; 59% ee [HPLC (Daicel
Chiralpak AD-H, hexane–iPrOH, 95:5, flow rate 1.0 mL/min, T = 25 °C,
 = 254 nm): tR =19.4 (major), tR = 22.4 (minor)]; []D20 –12.2 (c 0.064,
CHCl3); Rf = 0.6 (PE–EtOAc, 4:1).
HRMS (ESI): m/z [M + H]+ calcd for C14H15N2O3: 259.1077; found:
259.1081.
3-(4-Nitro-1H-indol-1-yl)-1,3-diphenylpropan-1-one (6i)
IR (KBr): 3106, 2928, 2856, 1685, 1597, 1580, 1361, 1323, 1274, 755,
The reaction time was 48 h. Title compound 6i was obtained accord-
ing to the general procedure from 4-nitroindole (4a; 16.2 mg, 0.1
mmol) and (2E)-1,3-diphenylprop-2-en-1-one (2i; 43.7 mg, 0.21
mmol). Following a modification of the general procedure, ketone 2i
was added before evacuation of the system. The product was isolated
by direct column chromatography (silica gel; 5–25% EtOAc–PE).
737 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.12 (dd, J = 8.0, 0.8 Hz, 1 H), 7.89–7.82
(m, 3 H), 7.59–7.51 (m, 1 H), 7.48–7.38 (m, 3 H), 7.32–7.24 (m, 2 H),
5.26–5.15 (m, 1 H), 3.58 (dd, J = 17.3, 6.7 Hz, 1 H), 3.46 (dd, J = 17.3,
6.1 Hz, 1 H), 2.08–1.92 (m, 2 H), 1.35–0.97 (m, 8 H), 0.81 (t, J = 6.9 Hz,
3 H).
13C NMR (101 MHz, CDCl3):  = 197.1, 140.8, 138.9, 136.6, 134.0, 129.1
(2 C), 129.0, 128.3 (2 C), 122.6, 120.9, 117.9, 117.0, 103.3, 52.8, 45.0,
36.1, 31.8, 29.1, 26.4, 22.8, 14.3.
Yield: 13.0 mg (35%); yellow solid; mp = 79–83 °C; racemic [HPLC
(Daicel Chiralpak OD-H, hexane–iPrOH, 70:30, flow rate 1.0 mL/min,
T = 35 °C,  = 254 nm): tR1 = 15.7, tR2 = 33.4]; Rf = 0.3 (PE–EtOAc, 3:1).
IR (KBr): 3063, 1685, 1596, 1580 1521, 1497, 1448, 1361, 1329, 1296,
HRMS (ESI): m/z [M + H]+ calcd for C23H27N2O3: 379.2016; found:
753, 737, 697 cm–1
.
379.2021.
1H NMR (400 MHz, CDCl3):  = 8.12 (dd, J = 8.0, 0.8 Hz, 1 H), 7.98–7.90
(m, 2 H), 7.76 (d, J = 8.2 Hz, 1 H), 7.63–7.56 (m, 1 H), 7.51–7.44 (m, 3
H), 7.36–7.18 (m, 7 H), 6.50–6.43 (m, 1 H), 4.07 (dd, J = 17.4, 7.8 Hz, 1
H), 3.95 (dd, J = 17.4, 6.1 Hz, 1 H).
(S)-1-(Naphthalen-2-yl)-3-(4-nitro-1H-indol-1-yl)butan-1-one
(6g)
Title compound 6g was obtained according to the general procedure
from 4-nitroindole (4a; 16.2 mg, 0.1 mmol) and (E)-1-(naphthalen-2-
yl)but-2-en-1-one (2g; 41.2 mg, 0.21 mmol). Following a modifica-
tion of the general procedure, ketone 2g was added before evacuation
of the system. The product was isolated by direct column chromatog-
raphy (silica gel; 3–20% EtOAc–PE).
13C NMR (101 MHz, CDCl3):  = 195.8, 140.6, 139.7, 138.4, 136.3,
134.0, 129.6 (2 C), 129.3 (2 C), 129.0, 128.5, 128.2 (2 C), 126.4 (2 C),
123.0, 121.0, 117.9, 117.1, 103.0, 55.7, 43.9.
HRMS (ESI): m/z [M + H]+ calcd for C23H19N2O3: 371.1390; found:
371.1387.
Yield: 34.2 mg (96%); orange amorphous solid; 69% ee [HPLC (Daicel
2-(4-Nitro-1H-indol-1-yl)-1,4-diphenylbutane-1,4-dione (6j)
Chiralpak AD-H, hexane–iPrOH, 90:10, flow rate 1.0 mL/min, T = 25
The reaction time was 24 h. Title compound 6j was obtained accord-
ing to the general procedure from 4-nitroindole (4a; 16.2 mg, 0.1
mmol) and (E)-1,4-diphenylbut-2-ene-1,4-dione (2j; 49.6 mg, 0.21
mmol). Following a modification of the general procedure, ketone 2i
was added before evacuation of the system. The product was isolated
by two sequential column chromatography procedures (silica gel;
first: 3–20% EtOAc–PE; second: 50% DCM–PE).
20
°C,  = 254 nm): tR =27.8 (major), tR = 42.4 (minor)]; []D –87.9 (c
0.032, CHCl3); Rf = 0.5 (PE–EtOAc, 3:1).
IR (KBr): 2979, 1680, 1626, 1565, 1510, 1498, 1469, 1361, 1331, 1302,
1269, 756, 737 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.37 (d, J = 1.7 Hz, 1 H), 8.12 (dd, J = 8.0,
0.8 Hz, 1 H), 7.97–7.81 (m, 5 H), 7.64–7.52 (m, 3 H), 7.39–7.19 (m, 2
H), 5.47–5.36 (m, 1 H), 3.70 (dd, J = 17.2, 5.8 Hz, 1 H), 3.61 (dd, J =
17.1, 7.2 Hz, 1 H), 1.74 (d, J = 6.8 Hz, 3 H).
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–M

L
D. Trubitsõn et al.
Paper
Synthesis
Yield: 22.6 mg (60%); yellow amorphous solid; racemic [HPLC (Daicel
Chiralpak OD-H, hexane–iPrOH, 70:30, flow rate 1.0 mL/min, T = 35
°C,  = 254 nm): tR1 = 11.1, tR2 = 20.8]; Rf = 0.7 (PE–EtOAc, 3:1).
References
(1) For a recent review, see: Ciulla, M. G.; Kumar, K. Tetrahedron
Lett. 2018, 59, 3223.
(2) Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med. Chem. 2014,
57, 5845.
(3) For reviews of pharmaceutically active indole derivatives, see:
(a) Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev.
2010, 110, 4489. (b) Sravanthi, T. V.; Manju, S. L. Eur. J. Pharm.
Sci. 2016, 91, 1. (c) Singh, T. P.; Singh, O. M. Mini-Rev. Med. Chem.
2018, 18, 9.
IR (KBr): 3063, 1680, 1596, 1580, 1516, 1502, 1359, 1332, 1293, 1230,
760, 737, 688 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.15 (dd, J = 8.0, 0.8 Hz, 1 H), 8.00–7.88
(m, 5 H), 7.63–7.57 (m, 1 H), 7.57–7.50 (m, 1 H), 7.50–7.44 (m, 2 H),
7.43 (d, J = 3.3 Hz, 1 H), 7.42–7.34 (m, 3 H), 7.28 (dd, J = 3.4, 0.8 Hz, 1
H), 6.74 (dd, J = 8.1, 5.0 Hz, 1 H), 4.33 (dd, J = 17.8, 8.1 Hz, 1 H), 3.53
(dd, J = 17.8, 5.0 Hz, 1 H).
13C NMR (101 MHz, CDCl3):  = 196.6, 194.2, 140.9, 137.6, 135.9,
134.7, 134.4, 134.1, 130.7, 129.1 (2 C), 129.0 (2 C), 128.6 (2 C), 128.3
(2 C), 123.3, 121.6, 118.2, 116.2, 104.3, 55.9, 40.7.
HRMS (ESI): m/z [M + H]+ calcd for C43H19N2O4: 399.1339; found:
399.1347.
(4) For reviews, see: (a) Bandini, M.; Eichholzer, A. Angew. Chem.
Int. Ed. 2009, 48, 9608. (b) Dalpozzo, R. Chem. Soc. Rev. 2015, 44,
742. (c) Chen, J.-B.; Jia, Y.-X. Org. Biomol. Chem. 2017, 15, 3550.
(5) (a) Fan, Y.; Kass, S. R. J. Org. Chem. 2017, 82, 13288. (b) Liu, L.;
Ma, H.; Xiao, Y.; Du, F.; Qin, Z.; Li, N.; Fu, B. Chem. Commun.
2012, 48, 9281. (c) Wu, K.; Jiang, Y.-J.; Fan, Y.-S.; Sha, D.; Zhang,
S. Chem. Eur. J. 2013, 19, 474.
(6) (a) Zhou, Y.; Li, C.; Yuan, X.; Zhang, F.; Liu, X.; Liu, P. Org. Biomol.
Chem. 2019, 17, 3343. (b) Chaudhary, B.; Diwaker, M.; Sharma,
S. Org. Chem. Front. 2018, 5, 3133. (c) Sandtorv, A. H. Adv. Synth.
Catal. 2015, 357, 2403.
(7) (a) Trost, B. M.; Osipov, M.; Dong, G. J. Am. Chem. Soc. 2010, 132,
15800. (b) Sevov, C. S.; Zhou, J. S.; Hartwig, J. F. J. Am. Chem. Soc.
2014, 136, 3200. (c) Trost, B. M.; Gnanamani, E.; Hung, C.-I.
Angew. Chem. Int. Ed. 2017, 56, 10451. (d) Ye, Y.; Kim, S.-T.;
Jeong, J.; Baik, M.-H.; Buchwald, S. L. J. Am. Chem. Soc. 2019, 141,
3901.
(8) (a) Zhang, L.; Wu, B.; Chen, Z.; Hu, J.; Zeng, X.; Zhong, G. Chem.
Commun. 2018, 54, 9230. (b) Cai, Y.; Gu, Q.; You, S.-L. Org.
Biomol. Chem. 2018, 16, 6146. (c) Chen, M.; Sun, J. Angew. Chem.
Int. Ed. 2017, 56, 4583. (d) Cai, Q.; Zheng, C.; You, S.-L. Angew.
Chem. Int. Ed. 2010, 49, 8666.
(S)-1-(4-Oxo-4-phenylbutan-2-yl)-1H-indole-3-carbonitrile (3)
Title compound 3 was obtained according to the general procedure
from 3-cyanoindole (1; 14.2 mg, 0.1 mmol) and (E)-1-phenylbut-2-
en-1-one (2; 30.9 mg, 0.21 mmol). The product was isolated by direct
column chromatography (silica gel; 5–25% EtOAc–PE).
Yield: 27.4 mg (95%); white solid; mp 59–61 °C; 42% ee [HPLC (Daicel
Chiralpak OJ-H, hexane–iPrOH, 80:20, flow rate 1.0 mL/min, T = 25 °C,
 = 254 nm): tR = 41.7 (major), tR = 46.2 (minor)]; []D20 –19.6 (c 0.033,
CHCl3); Rf = 0.4 (PE–EtOAc, 3:1).
IR (KBr): 3121, 2217, 1685, 1597, 1580, 1530, 1461, 1449, 1361, 1288,
1214, 1184, 744, 689 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.92–7.86 (m, 2 H), 7.79–7.71 (m, 2 H),
7.63–7.51 (m, 2 H), 7.49–7.40 (m, 2 H), 7.39–7.26 (m, 2 H), 5.39–5.26
(m, 1 H), 3.58 (dd, J = 17.4, 5.4 Hz, 1 H), 3.47 (dd, J = 17.4, 7.6 Hz, 1 H),
1.71 (d, J = 6.8 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 196.4, 136.3, 135.0, 134.0, 132.0, 129.0
(2 C), 128.11 (2 C), 128.06, 124.0, 122.4, 120.2, 116.0, 111.0, 86.6,
48.8, 45.2, 21.0.
(9) (a) Bandini, M.; Eichholzer, A.; Tragni, M.; Umani-Ronchi, A.
Angew. Chem. Int. Ed. 2008, 47, 3238. (b) Bandini, M.; Bottoni,
A.; Eichholzer, A.; Miscione, G. P.; Stenta, M. Chem. Eur. J. 2010,
16, 12462.
(10) Hong, L.; Sun, W.; Liu, C.; Wang, L.; Wang, R. Chem. Eur. J. 2010,
16, 440.
HRMS (ESI): m/z [M + H]+ calcd for C19H17N2O: 289.1335; found:
289.1325.
(11) For our previous articles on aza-Michael reactions, see: (a) Žari,
S.; Kudrjashova, M.; Pehk, T.; Lopp, M.; Kanger, T. Org. Lett.
2014, 16, 1740. (b) Metsala, A.; Žari, S.; Kanger, T. ChemCatChem
2016, 8, 2961. (c) Žari, S.; Metsala, A.; Kudrjashova, M.; Kaabel,
S.; Järving, I.; Kanger, T. Synthesis 2015, 47, 875. (d) Kriis, K.;
Melnik, T.; Lips, K.; Juhanson, I.; Kaabel, S.; Järving, I.; Kanger, T.
Synthesis 2017, 49, 604.
(12) Yang, J.; Li, T.; Zhou, H.; Li, N.; Xie, D.; Li, Z. Synlett 2017, 28,
1227.
(13) For PTC with hydrogen bond donors, see: Wang, H. Catalysts
2019, 9, doi: 10.3390/catal9030244.
Funding Information
The authors thank the Estonian Ministry of Education and Research
(grant nos. IUT 19-32, IUT 19-9, IUT 20-14, PRG399, and PUT 1468)
and the Centre of Excellence in Molecular Cell Engineering (2014-
2020.4.01.15-0013) for financial support. This work has been partial-
ly supported by ASTRA ‘TUT Institutional Development Programme
for 2016-2022’ Graduate School of Functional Materials and Technol-
ogies (2014-2020.4.01.16-0032).
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8)
(14) Gomez-Bengoa, E.; Linden, A.; López, R.; Múgica-Mendiola, I.;
Oiarbide, M.; Palomo, C. J. Am. Chem. Soc. 2008, 130, 7955.
(15) Kütt, A.; Leito, I.; Kaljurand, I.; Sooväli, L.; Vlasov, V. M.;
Yagupolskii, L. M.; Koppel, I. A. J. Org. Chem. 2006, 71, 2829.
(16) Raamat, E.; Kaupmees, K.; Ovsjannikov, G.; Trummal, A.; Kütt,
A.; Saame, J.; Koppel, I.; Kaljurand, I.; Lipping, L.; Rodima, T.;
Pihl, V.; Koppel, I. A.; Leito, I. J. Phys. Org. Chem. 2013, 26, 162.
(17) Sasson, Y.; Bilman, N. J. Chem. Soc., Perkin Trans. 2 1989, 2029.
(18) Denmark, S. E.; Weintraub, R. C. Heterocycles 2011, 82, 1527.
(19) Nicolaou, K. C.; Liu, G.; Beabout, K.; McCurry, M. D.; Shamoo, Y.
J. Am. Chem. Soc. 2017, 139, 3736.
Acknowledgment
The authors thank Dr Marina Kudrjashova for her assistance in NMR
studies and Dr Aleksander-Mati Müürisepp for IR spectra.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690751.
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u
p
p
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n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
(20) Bernal, P.; Fernández, R.; Lassaletta, J. M. Chem. Eur. J. 2010, 16,
7714.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–M

M
D. Trubitsõn et al.
Paper
Synthesis
(21) Wang, X.; Lv, J.; Liu, L.; Wang, Y.; Wu, Y. J. Mol. Catal. A: Chem.
2007, 276, 102.
(28) Manjolinho, F.; Grünberg, M. F.; Rodríguez, N.; Gooßen, L. J. Eur.
J. Org. Chem. 2012, 4680.
(22) He, Z.; Yang, X.; Jiang, W. Org. Lett. 2015, 17, 3880.
(23) Reitel, K.; Kriis, K.; Järving, I.; Kanger, T. Chem. Heterocycl.
Compd. 2018, 54, 929.
(24) Pelkey, E. T.; Gribble, G. W. Tetrahedron Lett. 1997, 38, 5603.
(25) Cheng, Q.; Zhang, F.; Guo, Y.-L.; You, S.-L. Angew. Chem. Int. Ed.
2018, 57, 2134.
(26) (a) Therkelsen, F. D.; Hansen, A.-L.; Pedersen, E. B.; Nielsen, C.
Org. Biomol. Chem. 2003, 1, 2908. (b) Chen, S.-j.; Lu, P.-G.; Cai, C.
RSC Adv. 2015, 5, 13208.
(27) Oare, D. A.; Henderson, M. A.; Sanner, M. A.; Heathcock, C. H.
J. Org. Chem. 1990, 55, 132.
(29) Khopade, T. M.; Warghude, P. K.; Mete, T. B.; Bhat, R. G. Tetrahe-
dron Lett. 2019, 60, 197.
(30) Liu, D.-N.; Tian, S.-K. Chem. Eur. J. 2009, 15, 4538.
(31) Berti, F.; Bincoletto, S.; Donati, I.; Fontanive, G.; Fregonesea, M.;
Benedetti, F. Org. Biomol. Chem. 2011, 9, 1987.
(32) Al-Masum, M.; Liu, K.-Y. Tetrahedron Lett. 2011, 52, 5090.
(33) Pan, G.-F.; Zhu, X.-Q.; Guo, R.-L.; Gao, Y.-R.; Wang, Y.-Q. Adv.
Synth. Catal. 2018, 360, 4774.
(34) Bentley, S. C.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J.
E. Org. Lett. 2011, 13, 2544.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–M