Indolylglycines Backbones in the Synthesis of Enantiopure 3,3-Spiroindolenines, Indolyl Tetracyclic Hemiaminals, and 3-Indolyl-maleimides Frameworks

Article abstract of DOI:10.1002/ejoc.201900814

This paper describes the synthesis of novel N-substituted 3-indolylglycines (3IGs), in high yields and optical purity via three-component Mannich reaction (3CR) of indole and free glyoxylic acid in the presence of primary and secondary aliphatic amines. By using this efficient approach, a series of racemic 3-indolylglycines (3IGs) as well as the optically pure (S)-3-indolylglycine ((S)-3IG) in multigram synthesis using (R-1-phenylethylamine ((R)-α-PEA) as chiral pool were synthetized. In parallel investigations, 3IGs were used as the starting material for the highly stereoselective synthesis of spiroindolenines bearing three controlled contiguous stereogenic centers. Despite our expectations, the N-chloroacetyl esters of 3IGs did not provide the expected spiroindolenine derivatives but led us to the discovery of a new methodology for the preparation of 3-indolylmaleimides (3IMs); compounds known for their broad range of important biological and fluorescence activities.

Full text of DOI:10.1002/ejoc.201900814

A Journal of
Accepted Article
Title: Indolylglycines backbones in the synthesis of enantiopure 3,3-
spiroindolenines, indolyl tetracyclic hemiaminals and 3-indolyl-
maleimides frameworks
Authors: Jozef Markus, Branislav Ferko, Dušan Berkeš, Ján Moncol,
Ata Martin Lawson, Mohamed Othman, and Adam Daïch
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900814
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900814
Supported by

10.1002/ejoc.201900814
European Journal of Organic Chemistry
FULL PAPER
Indolylglycines backbones in the synthesis of enantiopure 3,3-
spiroindolenines, indolyl tetracyclic hemiaminals and 3-indolyl-
maleimides frameworks
Jozef Markus,[a] Branislav Ferko,[a] Dušan Berkeš,*[a]Ján Moncol,[b] Ata Martin Lawson,[c] Mohamed
Othman,[c] and Adam Daïch*[c]
‡ Dedicated to the memory of our colleague Prof. Dr. Ing. František Považanec who passed away in his hometown on 20 April 2017.
Abstract: This paper describes the synthesis of novel N-substituted
3-indolylglycines (3IGs), in high yields and optical purity via three-
component Mannich reaction (3CR) of indole and free glyoxylic acid
in the presence of primary and secondary aliphatic amines. By using
this efficient approach, a series of racemic 3-indolylglycines (3IGs)
as well as the optically pure (S)-3-indolylglycine ((S)-3IG) in
multigram synthesis using (R-1-phenylethylamine ((R)--PEA) as
chiral pool were synthetized. In parallel investigations, 3IGs were
used as the starting material for the highly stereoselective synthesis
of spiroindolenines bearing three controlled contiguous stereogenic
centers. Despite our expectations, the N-chloroacetyl esters of 3IGs
did not provide the expected spiroindolenine derivatives but led us to
the discovery of a new methodology for the preparation of 3-
indolylmaleimides (3IMs); compounds known for their broad range of
important biological and fluorescence activities.
broad range of biological potential,[5] not only as protein kinase
inhibitors,[6] but also as promising agents in anticancer therapy.[7]
In addition, representative of 3-indolylmaleimides (3IMs)
subfamily such as compound 6 (SB-216763, Figure 1)[8] can be
useful in modern optoelectronics because of its high
fluorescence activity.[8]
Introduction
Aza-heterocyclic systems probably constitute the largest and
most varied family of organic compounds. The indole nuclei
belonging to this family occupy a privileged place as the most
frequent ring present in the bioactive natural compounds as well
as the highest reliable source to provide new molecules with
both pharmaceutical and industrial importance.[1] In particular,
spirocyclic indolenines 1, 2 and 3 (Figure 1)[2] are among the
best studied classes, due to their therapeutic potential and
versatility to act as precursors for other important heterocyclic
systems including carbazoles, oxindoles and more.[3] Another
important class of compounds bearing an indole subunit are bis-
indolylmaleimides (BIMs) 4 and 5 (Figure 1)[4] which possess a
Figure 1. Examples of naturally occurring alkaloids such as spiroindolenines
(1,2,3) and bis-indolylmaleimide (BIM; 4,5) and unnatural 3-indolylmaleimide
(3IM) derivative 6 (SB-216763).
Because of these interesting properties, the synthetic
strategies for these compounds is a matter of interest. In this
light, we present herein the strategy for the preparation of
optically pure spiroindolenine derivatives, their tetracyclic
hemiaminals and 3-indolylmaleimides (3IM) from enantiopure N-
substituted 3-indolylglycines (3IGs).
3IGs have attracted great attention as nonproteinogenic acids
and serve as important synthetic intermediates in drug
development, natural products as well as peptide mimetics.
Several synthetic approaches for the synthesis of 3IGs have
been reported in recent years all based on the use of substituted
indole.[9-13] They rely on a small number of strategies, based on
asymmetric catalysis, chiral auxiliary-mediated induction[9-11,13]
and racemic approaches[12] followed exclusively in the latter
case by an enzymatic resolution.[12a]
[a] Dr. J. Markus, Ing. B. Ferko, Assoc. Prof. D. Berkeš
Department of Organic Chemistry, Slovak University of Technology,
Radlinského 9, 81237 Bratislava, Slovakia
E-mail: dusan.berkes@stuba.sk
http://nic.savba.sk/sav/inst/chem/chempap.html
[b] Assoc. Prof. J. Moncol
Department of Inorganic Chemistry, Slovak University of Technology,
Radlinského 9, 81237 Bratislava, Slovakia
ORCID Jan Moncol: orcid.org/0000-0003-2153-9753
[c] Dr. A. M. Lawson, Dr. M. Othman, Prof. A. Daïch
Normandie Univ., UNILEHAVRE, FR 3038 CNRS, URCOM, 76600
Le Havre, France. EA 3221, INC3M CNRS-FR 3038, UFR ST,
BP: 1123, 25 rue Philipe Lebon, F-76063 Le Havre Cedex, France
E-mail: adam.daich@univ-lehavre.fr
ORCID Adam Daïch: orcid.org/0000-0002-6942-0519
https://urcom.niv-lehavre.fr/spip.php?article102
Supporting information for this article is given via a link at the end of
the document. See DOI: 10.1039/x0xx00000x
However, only a few methods are capable to provide an
efficient synthesis of highly enantioenriched α-3IGs. The most
frequent synthetic approach used is the asymmetric Friedel-
Crafts α-aminoalkylation using racemic glyoxylate imines and
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900814
European Journal of Organic Chemistry
FULL PAPER
chiral Lewis or Brönsted acids (Routes IV, Figure 2).[9a-d]
Sporadic approaches using chiral nitrones (Route II, Figure 2)[10]
and an asymmetric oxidative heterocoupling reaction of a chiral
nickel(II) complex (Route III, Figure 2)[11] with indoles (Is) as
carba-nucleophiles were reported.
Furthermore, diastereoselective synthesis based on chiral
imines can also be applied (Route I, Figure 2).[9e-g] A three-
component aminoalkylation of indole moiety in greener racemic
version using glyoxylic acid ((Route VI (R = H), Figure 2)[12e,13a]
or in asymmetric version using chiral amine and ethyl glyoxylate
(Routes VII and VIII (R = Et), Figure 2)[13b,c] were also reported. It
is worth noting that implementation of chiral centre from chiral
amines via diastereoselective approach is usually high and the
enantiomeric purity of the ultimate 3IGs can be improved mostly
via crystallization.[9] In parallel, an interesting ‘four-step’
sequence using a chiral N-Boc-oxazolidine-3-indole as a key
reagent was also developed recently (Route V, Figure 2).[9h]
starting materials (Route IX (R = H), Figure 2). To date, free
glyoxylic acid utilization in indolylglycines synthesis is rare. The
application of Petasis reaction[13b] is an successful example of
such a transformation; however, the indolylboronic acids, often
more difficult to obtain, are required as starting materials.
Ghandi’s recent work describes the synthesis of 3IGs,[13a] which
uses water as solvent in greener context, though is limited only
to primary amines. Thus, the Mannich’s 3CR approach for the
elaboration of enantiopure 3IGs, in which both primary and
secondary amines are transferred under very mild reaction
conditions in high optical purity is a matter of interest.
Results and Discussion
Our study was initiated by the synthesis of racemic α-3IGs by
three-component Mannich type reaction of indole, free glyoxylic
acid and amines. The optimization of the reaction conditions was
accomplished through N-benzyl amine as a model substrate.
Interestingly enough, when we examined the various reaction
conditions including the molar scale, used solvent, reaction time
and concentration for the reaction yield, the addition order of the
reactant seemed to be an important factor. From these attempts,
a significant improvement of the reaction yield, when indole (7)
and benzyl amine (8a) were mixed first followed by addition of
glyoxylic acid (9) with vigorous stirring was achieved. The
optimized results are summarized in the Table 1.
Table 1. Optimization of the reaction conditions for the three-component
Mannich type reaction (3CR) of indole (7), N-benzyl amine (8a) and free
glyoxylic acid 9.[a,b]
7
8a
9
Product 10a
Entry
Solvent
C (M) t (h)
(equiv.) (equiv.)
(equiv.)
1
1
1
1
1.5
1.3
1.2
1.2
1.1
Yield (%)[d]
1
2
3
4
5
6
7
1
1
1
1
1
1
1
1
1
1.5
1.1
1.1
1.1
2
1.3
1.3
1.3
1.1
EtOH
EtOH
i-PrOH
EtOH
EtOH
EtOH
MeOH
MeOH
MeOH
1.2
0.7
0.4
0.7
0.7
0.5
0.4
0.4
0.25
2
2
2
2
2
2
2
2
1
58
44
29
68
85
90
91
91
92
8
9[c]
[a] All reactions were performed at room temperature (25 °C). [b] Reactions
were performed on 2 mmol scale. [c] Reaction was performed on 5 mmol
scale. [d] Isolated yields
Figure 2. Classical methods used for the synthesis of N-substituted 3-
indolylglycines (3IGs) (Routes I-VIII) and our Mannich’s 3CR one (Route IX).
With the optimized reaction conditions in hand, we examined
the scope of the Mannich’s 3CR with a series of primary and
secondary aliphatic amines as well as amino alcohol. As
highlighted in Table 2, the production of the expected derivatives
10 is effective with yields ranging from 75% up to 93% and with
the reaction times ranging from 1 hour up to 4 hours depending
on the used amines. The Mannich’s 3CR resulting products (±)-
Based on both Mannich’s 3CR type[13] and our contribution on
the elaboration of conformationally constrained homophenyl-
alanines using crystallization-induced asymmetric transformation
(CIAT) technology,[14] in this contribution we report the direct
three-component aminoalkylation (3CR) of indole moiety using
glyoxylic acid hydrate and primary or secondary amines as
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900814
European Journal of Organic Chemistry
FULL PAPER
10a-f are easily isolated from the reaction mixture by simple
filtration as white solids. The series of racemic 3IGs obtained are
summarized in Table 2.
the d.r. ratios while the reaction time increased. After the
addition of the free glyoxylic acid (9) the reaction turned to
homogeneous mixture (entries 1-6). Precise tuning of reaction
conditions using methanol (entries 8-12) allowed us to isolate
the major (R,S)-diastereomer in excellent diastereomeric purity
(d.r > 99:1) by simple filtration of precipitated methanolic solvate
from the reaction mixture (entries 12 and 13). In both cases,
changing the quantity of the starting indole (7, 20 mmol up to
100 mmol) had no influence on either d.r ratio or reaction yield.
Moreover, the diastereoselective nucleophilic additions to the
N-substituted chiral imines derived from glyoxylic acid were
recently studied by Ender´s[15] and Sigh´s[16] groups. Based on
this, a putative model of stereoinduction in the addition of indole
to the zwitterionic intermediate was proposed (Scheme 1).
Table 2. Mannich’s 3CR type reaction leading to 3IGs derivatives (±)-10a-f,
from indole (7), amine (8a-f) and free glyoxylic acid (9).
Entry
R1 group
R2 group Solvent
t (h) (±)-10
Yield (%)
1
2
3
4
5
6
Bn
Me
H
H
H
H
MeOH
MeOH
MeOH
EtOH
MeOH
MeOH
1
2
1
2
2
2
(±)-10a
(±)-10b
(±)-10c
(±)-10d
(±)-10e
(±)-10f
92
82
93
88
90
75
2-Ph(CH2)2
Allyl
2-hydroxyethyl H
Bn Me
Next, we examined various conditions for the preparation of
optically pure (S)-3-indolylglycine ((S)-3IG). For this purpose,
various reaction conditions were explored by using cost-effective
(R)-phenylethylamine (11) ((R)--PEA) as chiral pool (Table 3).
Table 3. Optimization of the reaction conditions en-route to the preparation
of pure (S)-3-indolylglycine ((S)-3IG) via the (R,S)-diastereomer 12a.
Scheme 1. Plausible mechanism leading to (R,S)-diastereomer 12a.
The relative and absolute configuration of the new stereogenic
centre was determined by X-ray. The suitable single crystal
12a∙MeOH for X-ray analysis was obtained by crystallization
from the mixture of MeOH/Et2O (Figure 3).[17]
Entry 11 (equiv.) 9 (equiv.) Solvent
C (M) t (h) Yield(%)[h] d.r[g]
1
1.3
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.2
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
EtOH
MeOH
THF
1.2
2
2
2
90[a]
93[a]
89[a]
92[a]
75[a]
87[a]
56[b]
95[c]
63[d]
60[d]
58[d]
52[d]
52[d]
62:38
67:33
78:22
80:20
82:18
78:22
75:25
77:23
90:10
94:6
2
3
1
1
0.3
2
4
THF
4[e]
4[f]
2
5
THF
6
Dioxane 0.25
7
8
9
10
11
12
13
MeCN
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
025
1.3
0.8
0.7
0.7
0.5
0.5
2
2
2
1.5
1
95:5
>99:1
>99:1
1.5
1.5
Reactions were carried using 1 equiv. of indole (7) at room temperature (25
°C) unless otherwise noted. Reactions were performed on 2 mmol scale
(entries 1-7), 10 mmol (entries 8-11), 20 mmol (entry 12), 100 mmol (entry
13). [a] After evaporation of solvent, 12a was isolated by trituration with Et2O.
[b] Product 12a was isolated by simple filtration. [c] After evaporation of
solvent, 12a was isolated by trituration with acetonitrile. [d] Reaction mixture
was seeded with crystals of pure diastereomer and 12a was isolated by
filtration from reaction mixture. [e] Reaction was carried out at -5 °C. [f]
Reaction was carried out at -30 °C. [g] (R,S)-diastereomer 12a : (R,R)-
diastereomer 12b ratio (HPLC). [h] Isolated yields
Figure 3. Molecular structure of the pure (R,S)-diastereomer 12a∙MeOH (salt
form) which was used to provide pure (S)-3-indolylglycine ((S)-3IG) (15).
In order to evaluate the impact of the nucleophile size on the
reaction stereochemistry outcome, Mannich’s 3CR was also
carried out with 2-methylindole (13) as starting material. By
analogy (Scheme 2), using standard conditions, the expected
product 14 was isolated in similar 49% yield and in high d.r.
(>99:1).
By using ethanol and methanol as the reaction solvent (entries
1,2, Table 3), the product 12a was obtained in d.r. excess of
62:38 and 67:33 in favour of the (R,S)-diastereomer. With
lowering the reaction temperature, no change was observed in
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900814
European Journal of Organic Chemistry
FULL PAPER
CTH (Catalytic Transfer Hydrogenation).[20] Simply by using
TEAF (triethylammonium formate) as hydrogen source in
combination with Pd/C in MeOH, we prepared the enantiomeric
pure (S)-3IG (15) in 80% yield and high optical purity (>99.8%
ee) (Scheme 3). This significantly decreased hydrogenolysis of
the C-N bond of the amino acid (1-3%) and prevented
racemization of the optically pure (S)-3IG (15).
Scheme 2. Mannich’s 3CR type reaction leading to 3IGs derivative 14 from 2-
methylindole (13), (R)--PEA (11) and free glyoxylic acid (9).
The relative and absolute configuration of the new stereogenic
centre in the pure product 14 was also determined by
crystallographic analysis. The suitable single-crystal of 14∙MeOH
for X-ray diffraction was obtained by crystallization from the
mixture of MeOH/Et2O (Figure 4).[18]
Scheme 3. Preparation of the enantiopure (S)-3IG (15) by highly selective N-
debenzylation of (R,S)-diastereomer 12a.
Subsequently, we established a practical two-step sequence
consisting of a highly diastereoselective Mannich’s 3CR and a
highly chemoselective N-debenzylation to form optically pure
amino acids via CTH on multigram scale. Next, we decided to
demonstrate the high potential of the enantiopure (S)-3IG as
starting material for the elaboration of three families of new
compounds such as spiroindolenines, indolyl tetracyclic
hemiaminals and 3IMs by exploring the well-known high
nucleophilic reactivity of the indole C3-position[1,21] towards both
CSP2 and CSP3 electrophilic centers.
Figure 4. Molecular structure of the pure (R,S)-diastereomer 14∙MeOH
isolated in the saltf form as MeOH solvate.
From the observations raised while verifying the literature, we
found that simple route for the preparation of enantiomeric pure
N-substituted 3IGs 12a and 14 is still not a guarantee that these
derivatives could be easily transferred to corresponding optically
pure amino acids. There are several known protocols for the
preparation of optically pure N-substituted 3IGs[9,13b,c] (see
Figure 2 and corresponding comments along the text) but only a
few of them describe how to remove the protecting group in
order to isolate corresponding free amino acids.[9b,11] This
important challenge was thoroughly investigated as a rare
example by Hiemstra’s group[9b] in one of his work dedicated to
optically pure free amino acids. This concretely proceeded by
deprotection of 2-nitrophenylsulfenyl or triphenylmethylsulfenyl
group by cleavage of N-S linkage under acidic conditions (TFA
in DCM) which turned out to be more complicated in the latter
case.[9b] No N-debenzylation was discussed in these reports.
Standard conditions for N-debenzylation (e.g., Pd/C, MeOH,
H2 1.1 bar, r.t for 24 h)[19] leads to partial hydrogenlytic bond
breaking of C-N of the amino acid fragment. This gives the 3-
indolylacetic acid (16) as a side reaction product (estimated to
10-15% of the mixture by HPLC) which considerably
complicates the isolation of the free amino acid (S)-3IG (16)
(Scheme 3).
Thus having the suitable synthon 12a for spirocyclization,[21]
we examined the intramolecular Michael addition with maleic
anhydride using indole nucleophilicity.[21] Initial acylation
experiments were attempted starting from methanolic solvate of
the 3-IG (R,S)-12a, but due to its low solubility, further
optimization was necessary (Scheme 4). To resolve this problem,
the methanolic solvate of 3-IG (R,S)-12a, was converted to the
anhydrous triethylammonium salt which showed high solubility in
DCM. The latter was hence easily acylated in this medium with
the maleic anhydride forming the unstable N-acylated-3-IG 18,
which underwent spontaneous cyclization furnishing spirocyclic
indolenine derivative 19 (Scheme 4).
Furthermore, the acylation and intramolecular Michael addition
occured in one-pot, without isolation of unstable intermediate 18
whereas the pure spiroindolenine derivative 19 was isolated in
80% yield from (R,S)-17. This cascade reaction is highly
stereoselective and only one stereoisomer of spirocyclic
indolenine derivative 19 was confirmed by NMR and HPLC
analysis of the reaction mixture (see SI Part). The absolute
stereochemistry of the product (R,S)-19 was determined from
the structure of spirocyclic indoline 20, which was prepared by
the reduction of 3H-indole derivative 19 with NaBH4 in the
mixture of acetic acid and DCM 1:5 in 70% yield. Based on NMR
measurements (gHMBC, gCOSY, NOESY and HSQC) the
To overcome this problem, after numerous attempts we found
the optimized conditions for the selective N-debenzylation using
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900814
European Journal of Organic Chemistry
FULL PAPER
absolute configuration on the new stereogenic centers was
determined as (2’S,3’S,4’R) (Scheme 4).
cell eradication.[27] The reactions proceeded as SN2 alkylations
[26d]
by displacement of halide (Heathcock reaction)
associated mostly with aza-Prins type cyclization.[25-27]
which is
Scheme 5. Intramolecular alkylation of N-chloroacetyl-3-indolylglycines D into
spiro-compounds E.
At the beginning, attempts with free amino acids 10a, 10b or
enatiopure (R,S)-12a failed due to intramolecular nucleophile
substitution of chloride with carboxylate anion and the following
hydrolysis of six-membered ring lactone. To bypass this problem,
we decided to prepare 3-indolyglycinols and use them as a
starting substrates for desired spirocyclization. This is to
measure the effect of the R group on the cyclization step as well
as the stereochemistry outcome hoping to establish the
generality and versatility of the process. Thus, reduction of
prepared N-alkyl substituted 3-IGs 10a,b and (R,S)-12a with
LAH leads to the formation of 3-indolyglycinols which were used
without further purification in the next step to form N-
chloroacetyl-3-indolyglycinols 22a-c in 53-75% yield (Scheme 6).
To avoid the hypothetic undesired side reaction of chloride
intramolecular substitution with alcohol, the latter free alcohols
22a-c were protected with silyl protecting group to provide 23a-c
in 87% up to 93% yield.
Scheme 4. Two-steps preparation from (R,S)-diastereomer 12a of the
optically pure spirocyclic indolenine derivative 19 and its reduction and
oxidation into indoline and oxindole derivatives 20 and 21, respectively.
Since the reduction of spiroindolenine 19 went smoothly, we
persueded to test the oxidation reaction of the imine function of
product (R,S)-19 which would likely lead to enantiopure aza-
spirannic compounds belonging to spiro-oxindole series.[23] This
family of compounds is fundamental due to the great abundance
of alkaloids bearing this pattern, with important biological
activities including the inhibition of p53-MDM2 interaction useful
in targeted cancer therapy.[24] For this perspective, the
compound (R,S)-19 was refluxed in water, forming a hemiaminal,
followed by its oxidization with dichromic acid in the presence of
sulfuric acid to provide spirooxindole derivative (R,S)-21 in 49%
yield (Scheme 4).
Having established the capacity of indole-3-branched
containing substituents to provide cascade process in forming
spirooxindole derivatives, we sought to demonstrate the
potential of N-chloroacetyl derivative of 3-IGs as suitable
3
substrates for intramolecular indole C3 position-Csp alkylation to
form the spiro moiety (Scheme 5).
It is noteworthy that, although intermediates D (Scheme 5)
containing functionalized -haloacetamides appear to be trivial
substrates, intriguingly only a few of them were engaged in the
intramolecular cyclization reactions. On the other hand, the
papers devoted to them are all concerned with the synthesis of
the indolic Aspidosperma alkaloids, such as (-)-Vindorosine[25]
and more broadly the Strychnos alkaloids[26] which showed
significant MDR reversal activity potentially important for cancer
Scheme 6. Synthesis of N-chloroacetyl-3-indolylglycinols 22a-c and N-
chloroacetyl-O-protected 3-indolylglycinols 23a-c.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900814
European Journal of Organic Chemistry
FULL PAPER
The reaction conditions for the base induced intramolecular
alkylation of 23 with indole C3-position were optimized using
optically pure N-chloroacetyl-O-protected 3-indolylglycinol (23c).
relative configuration of new stereogenic center C5a was
determined to be R by NOESY NMR analysis and configuration
on spirocyclic carbon C10b was also confirmed to be S (see SI
Part) as determined by X-ray analysis for product 25a (Figure 5).
Table 4. Optimization of the reaction conditions for spirocyclization of the
enantiopure acetamide 23c into 24c.
Entry
Base
Base (Equiv.) Solvent
t (h)
T (°C) Yield(%)[b]
1
2
3
4
5
6
7
8
NaH
NaH
NaH
t-BuOK
t-BuOK
t-BuOK
NaHMDS
LiHMDS
K2CO3
DBU
1.1
1.1
1.1
1.5
1.5
1.5
2
2
5
2
2
THF
THF
Et2O
THF
THF
DMF
THF
THF
MeCN
THF
THF
0.5
1
rt
0
rt
rt
0
rt
rt
rt
68
68
52
53
52
8
0.5
0.5
0.5
0.5
0.5
1
24
24
24
52
44
35
9
10
11
reflux
rt
rt
[a]
-
[a]
LiOH
-
[a] Only the decomposition of the reaction substrate was observed. [b] Isolated
yields
Scheme 7. Synthesis of spiroindolenine derivatives 24a-c and their tetracyclic
hemiaminals 25a-c.
The various reaction conditions were optimized including base,
solvent, reaction time, temperature and the results are
summarized in Table 4. From the latters, both the nature and the
quantity relative to the substrate 23c of the base seem to be
pivotal for the successful reaction and NaH (1.1 equiv.) in dry
THF at room temperature for 30 minutes (entry 1) seems to be
the best formulation used (Table 4). Interestingly, the reaction
failed with DBU (entry 10) and LiOH (entry 11) in THF at room
temperature even with up to 2 equivalents of the base and the
reaction time prolonged to 24 hours. It is noteworthy that the
reaction is highly stereoselective and in all cases only one
diastereomer of spirocylic product 24c was observed. Related
result with allyl group instead of CH2OTBS was published by us
recently using the same base in THF, but the d.r. of the
spiroindolenine obtained was only of 91:9.[28] Furthermore, due
to the high steric hindrance of N-chloroacetyl function and O-silyl
protecting group configuration, the NMR spectrum of 24c is a
mixture of rotamers (see Supporting Information for details).
The optimized reaction conditions obtained for 24c were
applied in the synthesis of 24a,b using racemic N-benzyl and N-
methyl substituted derivatives 23a and 23b, respectively. The
intramolecular alkylation occurs with high diastereoselectivity,
whereas only one diastereomer from the reaction mixture was
isolated (d.r. > 99:1). Moreover, deprotection of silyl group with
TBAF at room temperature according to classical procedure
from spiroindolenine derivatives 24a-c afforded the free alcohol
which underwent spontaneously an intramolecular cyclization to
form the tetracyclic hemiaminals 25a-c ranging from 78% to
84% yield. These results clearly demonstrate only very low
impact of the N-substituted moiety on the spirocyclization profile
but none on the stereochemistry reaction outcome. Finally, the
Figure 5. Molecular structure of 25b.[29]
We next worked to establish the generality and versatility of
the synthetic approach depicted in the Scheme 7 with N-
chloroacetyl-3-indolylglycinols 22a-c which proved to be suitable
substrates for spirocyclization after alcohol protection. The
behavior of N-chloroacetyl esters of 3-indolylglycines 26a-c
substituted by benzyl, methyl or chiral -phenylethyl groups on
the nitrogen amide atom were examined under the same
cyclization conditions.
Scheme 8. Cyclization of N-chloroacetyl esters of 3-indolylglycines 26a-c into
the unexpected 3-indolylmaleimides 28.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900814
European Journal of Organic Chemistry
FULL PAPER
Despite our expectations, the methylesters of chloroacetyl
indolylglycines 26a-c under basic conditions did not provide the
expected spiroindolenine derivatives 27a-c. We were able to
isolate unknown fluorescence compounds as major products in
low yields under the reaction conditions for spirocyclization used
above. Comparing their physical and chemical properties with
pertinent literature, the structure of unknown products was
determined to be 3-indolylmaleimides (3IMs) 28, which possess
overcome this problem, the use of an excess of propylene oxide
as hydrogen chloride scavenger drastically improved the
isolation and overall yields of the reaction. Finally, the
optimization of reaction conditions for 3IMs was carried out with
methyl acetate 26ba.
To increase the reaction yields, we investigated the type and
amount of the base in various polar aprotic solvents. Since the
lower temperature did not seem to affect the overall yields of the
reactions, all the reactions were performed at room temperature.
When the reaction was carried out in DMF and dioxane instead
of THF, only lower yields were observed. Among the various
screening bases, NaH was the most effective and the further
crucial parameter was its quantity. In fact, when the reaction was
treated with 2.2 equiv. of NaH the 100% conversion was
achieved in just 10 minutes and the overall yield after the
purification of N-methyl 3IM 28ba (Table 5, entry 2) was
improved to 95%. Having established the optimal conditions, we
thus generalized the new process by preparing five mono-
substituted 3IMs in yields ranging from 73% up to 95%.
Curiously, two 2-disubstituted 3IMs (Table 5, Entries 3 and 4)
were formed with lower yields which did not exceed 32% (28bb)
and 55% (28bc), respectively.
a
very interesting broad range of pharmacological and
fluorescence activities (Scheme 8).[8,30]
Scheme 9. Cyclization of N-chloroacetyl esters of 3-indolylglycines 26a-c into
the unexpected 3-indolylmaleimides 28 starting from amino acids 10a-b,12a.
Table 5. Preparation of N-substituted 3IMs 28 via amino esters 29 and
chloroacetamides 26.
Entry
R
R2
Yield (%) Products Yield (%) Yield (%)
29
73
53
-
26 & 28
26
28
1
2
3
4
5
6
7
Bn
Me
Me
Me
H
H
Cl
Me
H
aa
ba
bb
bc
ca
da
ea
94
75
86
87
94
80
70
87
95
32
55
83
79
73
-
(R)-PhEt[a]
PhEt
Allyl
86
75
72
H
H
Scheme 10. Proposed mechanism of the base-mediated formation of 3IMs 28.
[a] The reaction was realized in chiral series with commercially available (R)-α-
Me-b
Cl
PEA.
Based on the precedent results, a plausible mechanism for the
base-mediated ring-opening ring closure (RORC) of N-
chloroacetyl esters of 3IGs 26 was proposed through the
To the best of our knowledge, this approach for the synthesis
of 3IMs 28 starting form chloroacetamide ester of type 26 is
unprecedented in the published research. We thus decided to
investigate and optimize the reaction conditions for this domino
process. First, we had to find specific reaction conditions for
successful esterification of 3IGs in racemic and chiral forms,
respectively 10 and 12, since these derivatives are very
sensitive in acidic solution. For the preparation of methylesters
of 3IGs 29 we used the mixture of methanolic HCl solution in
combination with 2,2-dimethoxypropane which was carried out
at rt (Scheme 9). The next step was the chloroacetylation of
prepared methylesters of 3IGs 29 which was realized by analogy
as for 3-indolylglycinols 22a-c with chloroacetyl chloride and
triethylamine. This method leads to the expected
chloroacetylated esters of type 26 which were obtained in low
yields due to isolation problems during the work-up. To
formation of β-lactam intermediate
argument agrees with the González-Muniz
G
(Scheme 10). This
group’s
investigations of similar base-assisted intramolecular alkylation
of N-benzyl-N-chloroacetyl amino acid derivatives.[31] Thus
formation of the dianion species F, from 3IGs 26 which required
2 equivalents of base, undergoes an intramolecular nucleophilic
substitution to furnish the indol-3-yl β-lactam system
G
according to the reported observations. The shift of electron
pairs of these unstable intermediates induces the opening of the
β-lactam strained ring giving the corresponding intermediate H.
This intermediate, after peptide coupling by addition/elimination
process, delivers (I). The deprotonation/protonation under acid-
base equilibrium of the latter furnishes ultimately the isolated
product 28 containing both indole and maleimide rings.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900814
European Journal of Organic Chemistry
FULL PAPER
on a Varian Unity Inova 300 MHz (300 MHz for 1H, 75 MHz for 13C) or
Varian 600 VNMRS (600 MHz for 1H, 150 MHz for 13C) spectrometers.
Chemical shifts are cited with respect to Me4Si as internal (1H and 13C)
standard, or residual solvent peak. The chemical shifts are given in parts
per million (ppm). High-resolution mass spectra (HRMS) were recorded
on a Thermo Scientific Orbitrap Velos mass spectrometer with a heated
electrospray ionisation (HESI) source. The mass spectrometer was
operated with full scan (50–2000 amu) in positive or negative FT mode
(at a resolution of 100000). The analyte was dissolved in MeOH and
infused via syringe pump at a rate of 5 mL/min. The heated capillary was
maintained at 275 °C with a source heater temperature of 50 °C, and the
sheath, auxiliary and sweep gases were at 10, 5 and 0 units, respectively.
The source voltage was set to 3.5 kV.
Conclusions
In summary, we have developed a new three component
Mannich type reaction of indole and glyoxylic acid in the
presence of primary and secondary aliphatic amines in
moderate to high yields. This provides a straightforward access
to racemic N-substituted-3-indolylglycines in multigram scale.
We also presented optically pure derivative of (S)-3-
indolylglycine with cost effective (R)-1-phenylethylamine as
chiral auxiliary which was successfully transformed to the
enantiopure amino acid (S)-3-indolylglycine both in high yield
and enantiomeric purity >99%ee.
The optically pure derivatives of (S)-3-indolylglycine were used
as valuable platforms for the synthesis of more complex
spirocyclic derivatives, such as substructures of the bioactive
indole alkaloids including spiroindolenines, spirooxindoles and
spirocyclic indolines. Three derivatives of indolyl tetracyclic
hemiaminals were synthesized from N-chloroacetyl O-protected
3-indolyglycinols, whereas in all cases only one stereoisomer
was observed. Finally, a novel approach for the preparation of
2-(Benzylamino)-2-(1H-indol-3-yl)acetic acid (10a). To the stirred
solution of indole (590 mg; 5 mmol) and benzylamine (589 mg; 5.5 mmol)
in 10 mL of methanol at 0 °C was added solution of glyoxylic acid
monohydrate (506 mg; 5.5 mmol) dissolved in 10 mL of MeOH. The
reaction mixture was stirred at room temperature for 1 hour. The
precipitated product was filtered off, washed with MeOH and Et2O and
dried. The corresponding 2-(benzylamino)-2-(1H-indol-3-yl)acetic acid
(10a) was obtained as white solid (1.29 g, 92 %), m.p = 202-206 °C
(lit.[13] m.p = 205-207 °C). 1H NMR (300 MHz, NaOD/D2O) δ = 7.58 (d, J =
7.8 Hz, 1H); 7.40 (d, J = 8.1 Hz, 1H); 7.25-7.0 (m, 8H); 4.40 (s, 1H); 3.63
(d, J = 12.8 Hz, 1H), 3.54 (d, J = 12.8 Hz, 1H). 13C NMR (75 MHz,
NaOD/D2O) δ = 180.1, 139.0, 136.1, 128.6, 128.5, 127.2, 125.8, 124.0,
121.7, 119.2, 118.9, 113.3, 111.7, 58.9, 50.6. HRMS (HESI): m/z [M+H]+
calculated for C17H17N2O2 (281.12900), found 281.12845.
compelling
indolylmaleimides
derivatives,
the
pivotal
intermediates for pharmacological compounds, was described in
only three steps from N-substituted-3-indolylglycines. Ultimately,
we also proposed the plausible mechanism for cyclization of N-
chloroacetyl esters of 3-indolyglycines to form maleimide ring
through the formation of β-lactam intermediate.
2-(1H-Indol-3-yl)-2-(methylamino)acetic acid (10b). To the stirred
solution of indole (5.9 g; 50 mmol) and methylamine (27.5 mL 2M/MeOH;
55 mmol) in 50 mL of MeOH at 0 °C was added solution of glyoxylic acid
monohydrate (5.06 g; 55 mmol) dissolved in 50 mL of MeOH. The
reaction mixture was stirred at room temperature for 2 hours. The
precipitated product was filtered off, washed with MeOH and Et2O and
dried. The corresponding 2-(1H-indol-3-yl)-2-(methyl-amino)acetic acid
(10b) was obtained as white solid (8.42 g, 82 %), m.p = 197-200 °C
(lit.[13] m.p = 198-200 °C). 1H NMR (300 MHz, NaOD/D2O) δ = 7.74 (ddd,
J = 7.8, 1.3, 0.8 Hz, 1H), 7.51 (ddd, J = 8.0, 1.3, 0.8 Hz, 1H), 7.32 (bs,
1H), 7.23 (ddd, J = 8.4, 7.1, 1.3 Hz, 1H), 7.16 (ddd, J = 8.3, 7.1, 1.3 Hz,
1H), 4.38 (d, J = 0.6 Hz, 1H), 2.33 (s, 3H). 13C NMR (75 MHz,
NaOD/D2O) δ = 180.0, 136.1, 125.6, 124.0, 121.8, 119.3, 118.9, 112.9,
111.8, 61.5, 32.9. HRMS (HESI): m/z [M+H]+ calculated for
C11H13N2O2 (205.09770), found 205.09715.
Experimental Section
Crystallographic data: Data collection and cell refinement of
12a∙MeOH, 14∙MeOH and 25b were made by Stoe StadiVari
diffractometer using HPAD detector Pilatus3R 300K microfocused source
Xenocs Genix3D Cu HF. The structure were solved by program
SUPERFLIP or SHELXT,[32] and refined by full-matrix least-squares
procedures with CRYSTALS (ver. 14.61) or SHELXL (ver. 2018/3).[33]
The structures were drawn using OLEX2 package.[34] Absolute structures
were determined for 12a∙MeOH by Hooft method[35a] implemented in
CRYSTALS (y = -0.09(8)),[35b] and for 14∙MeOH using Parsons[35c] and
Hooft[35a] methods (x = 0.03(3), y = 0.06(3)). The molecule 25b is full
disordered in two stastical positions with occupancy factors 0.533(8) and
0.467(8) (See ESI). The disordered molecules are modeled using SAME
instruction, and structure model has been refined using SHELXL's
commands RIGU and EADP. Full crystallographic data have been
deposited with the Cambridge Crystallographic Data Centre (CCDC n°:
1912329, 1912330 and 1912331). Copies of the data can be obtained
free of charge at the following address: http://www.ccdc.cam
2-(1H-Indol-3-yl)-2-(phenethylamino)acetic acid (10c). To the stirred
solution of indole (1.18 g; 10 mmol) and phenylethylamine (1.332 g; 11
mmol) in 20 mL of methanol at 0 °C was added solution of glyoxylic acid
monohydrate (1.01 g; 11 mmol) dissolved in 5 mL of MeOH. The reaction
mixture was stirred at room temperature for 1 hour. The precipitated
product was filtered off, washed with MeOH and Et2O and dried. The
corresponding 2-(1H-indol-3-yl)-2-(phenethyl-amino)acetic acid (10c)
was obtained as white solid (2.74 g, 93 %), m.p = 209-211 °C. 1H NMR
(300 MHz, D2O/NaOD): δ = 7.49 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 8.1 Hz,
1H), 7.19 – 6.72 (m, 8H), 4.38 (s, 1H), 2.58 – 2.37 (m, 4H). 13C NMR (75
MHz, D2O/NaOD): δ = 179.9, 139.7, 136.1, 128.5, 128.4, 126.0, 125.8,
124.0, 121.6, 119.1, 118.8, 113.2, 111.7, 59.6, 47.5, 34.9. HRMS (HESI):
m/z [M+H]+ calculated for C18H18N2O2 (295.1446), found 295.1440.
General Remarks: Most of the commercially available chemicals were
purchased from Sigma-Aldrich, Alfa Aesar or from any other commercial
sources with high purity and were used without further purification. All
solvents were distilled before use. Thin layer chromatographic (TLC)
studies were performed on pre-coated silica gel 60 F 254 on aluminum
sheets (Merck KGaA). The compounds were visualized by UV
fluorescence and by dipping the plates in an aqueous H2SO4 solution of
cerium sulfate/ammonium molybdate followed by charring with a heat
gun. Melting points were obtained using a Stuart SMP30 apparatus and
are uncorrected. Optical rotations were measured with a JASCO P-2000
2-(Allylamino)-2-(1H-indol-3-yl)acetic acid (10d). To the stirred
solution of indole (1.18 g; 10 mmol) and allylamine (0.632 g; 11 mmol) in
30 mL of ethanol at 0 °C was added solution of glyoxylic acid
monohydrate (1.01 g; 11 mmol) dissolved in 5 mL of EtOH. The reaction
mixture was stirred at room temperature for 2 hours. The precipitated
polarimeter and are given in units of 10–1 deg.cm2.g–1. H (600 MHz and
1
300 MHz) and 13C (150 MHz and 75 MHz) NMR spectra were obtained
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900814
European Journal of Organic Chemistry
FULL PAPER
product was filtered off, washed with EtOH and Et2O and dried. The
the reaction mixture was left to sit for 1 hour at room temperature. The
precipitated product was filtered off and dissolved in MeOH (200 mL).
Insoluble residue was filtered off and to the filtrate was added Et2O (200
mL) and mixture was left to sit for 1 hour. The corresponding (R)-2-(1H-
indol-3-yl)-2-(((R)-1-phenylethyl)amino)acetic acid (12b) were obtained
by filtration as white crystals (3.5 g, 11%; d.r 99:1), m.p = 157-159 °C.
corresponding 2-(allylamino)-2-(1H-indol-3-yl)acetic acid (10d) was
1
obtained as white solid (2.04 g, 88 %), m.p = 185-186 °C. H NMR (300
MHz, D2O/NaOD): δ = 7.83 – 7.65 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 8.0 Hz,
1H), 7.32 (s, 1H) 7.30 – 7.10 (m, 2H), 5.94 (ddt, J = 16.5, 10.3, 6.2 Hz,
1H), 5.27 - 5.14 (m, 2H), 4.48 (s, 1H), 3.27 (ddt, J = 13.8, 6.0, 1.4 Hz,
1H), 3.16 (ddt, J = 13.8, 6.4, 1.3 Hz, 1H). 13C NMR (75 MHz,
D2O/NaOD): δ = 179.3, 136.1, 134.3, 125.7, 124.4, 121.8, 119.3, 118.9,
117.9, 112.3, 111.8, 58.7, 49.2. HRMS (HESI): m/z [M+H]+ calculated for
C13H14N2O2 (231.1133), found 231.1129.
25
[α]D = -77° (MeOH c 0.34). 1H NMR (300 MHz, NaOD/D2O) δ = 7.44 –
7.29 (m, 7H), 7.18 (s, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.02 (t, J = 7.5 Hz,
1H), 4.17 (s, 1H), 3.83 (q, J = 6.5 Hz, 1H), 1.33 (d, J = 6.6 Hz, 3H).13C
NMR (75 MHz, NaOD/D2O) δ = 180.5, 144.0, 135.9, 128.7, 127.5, 127.3,
125.9, 123.4, 121.7, 119.1, 118.6, 113.6, 111.6, 56.2, 48.7, 22.7.
2-(2-Hydroxyethylamino)-2-(1H-indol-3-yl)acetic acid (10e). To the
stirred solution of indole (590 mg; 5 mmol) and ethanolamine (336 mg;
5.5 mmol) in 10 mL of MeOH at 0 °C was added solution of glyoxylic acid
monohydrate (506 mg; 5.5 mmol) dissolved in 10 mL of MeOH. The
reaction mixture was stirred at room temperature for 2 hours. The
precipitated product was filtered off, washed with MeOH and Et2O and
dried. The corresponding 2-(2-hydroxyethylamino)-2-(1H-indol-3-yl)acetic
acid (10e) was obtained as white solid (1.05 g, 90 %), m.p = 180-183 °C.
1H NMR (300 MHz, D2O/NaOD): δ = 7.76 – 7.72 (m, 1H), 7.50 – 7.45 (m,
1H), 7.32 (s, 1H), 7.26 – 7.10 (m, 2H), 4.47 (d, J = 0.5 Hz, 1H), 3.74 –
3.58 (m, 2H), 2.82 – 2.55 (m, 2H). 13C NMR (75 MHz, D2O/NaOD): δ =
180.3, 136.1, 125.7, 123.9, 121.8, 119.2, 118.9, 113.4, 111.8, 60.5, 60.0,
48.5. HRMS (HESI): m/z [M+H]+ calculated for C12H15N2O3 (235.10827),
found 235.10772.
(S)-2-(2-Methyl-1H-indol-3-yl)-2-(((R)-1-phenylethyl)amino)acetic acid
(14). To the stirred solution of 2-methylindole (655 mg; 5 mmol) and (R)-
α-phenylethylamine (667 mg; 5.5 mmol) in 50 mL of MeOH at 0 °C was
added solution of glyoxylic acid monohydrate (506 g; 5.5 mmol) dissolved
in 25 mL of MeOH. After 10 minutes the reaction mixture was seeded
with crystals of the pure (R,S)-diastereomer and stirred at room
temperature for 1 hour. The precipitated product was filtered off, washed
with MeOH, Et2O and dried. The corresponding (S)-2-(2-methyl-1H-indol-
3-yl)-2-(((R)-1-phenylethyl)amino)acetic acid (14) was obtained as white
solid (759 mg, 49 %; d.r 99:1), m.p = 147-149 °C. [α]D25 = +88° (MeOH c
0.2). 1H NMR (600 MHz, NaOD/D2O) δ = 7.63 (bd, J = 7.8 Hz, 1H), 7.34
(bd, J = 7.9 Hz, 1H), 7.24 (m, 2H), 7.18 (m, 1H), 7.11 (m, 1H), 7.09 –
7.03 (m, 3H), 4.29 (s, 1H), 3.46 (q, J = 6.6 Hz, 1H), 1.91 (s, 3H), 1.18 (d,
J = 6.7 Hz, 3H).13C NMR (151 MHz, NaOD/D2O) δ = 182.6, 147.4, 138.3,
138.1, 131.5, 129.9, 129.8, 123.5, 121.9, 121.3, 113.8, 111.2, 59.6, 26.4,
13.4. HPLC: column WATERS SPHERISORB ODS1, 250x4.6 mm, 5 μm;
mobile fase: MeCN/H2O 2:7 (1% TEA, 1% H3PO4); flow: 1.0mL/min;
detection UV 210 nm; major (S,R)-diastereomer t = 13.9 min; minor
(R,R)-diastereomer t = 11.2 min. HRMS (HESI): m/z [M+H]+ calculated
for C19H21N2O2 (309.15975), found 309.16036.
2-(benzyl(methyl)amino)-2-(1H-indol-3-yl)acetic (10f). To the stirred
solution of indole (590 mg; 5 mmol) and N-methylbenzylamine (667 mg;
5.5 mmol) in 10 ml of methanol at 0°C was added solution of glyoxylic
acid monohydrate (506 mg; 5.5 mmol) dissolved in 10 ml of methanol.
The reaction mixture was stirred at RT for 1 hour. The precipitated
product was filtered off, washed with methanol and diethyl ether and
dried. The corresponding 2-(benzyl(methyl)amino)-2-(1H-indol-3-yl)acetic
1
(11f). was obtained as white solid (1.10 g, 75 %), m.p = 184-189 °C. H
(S)-2-Amino-2-(1H-indol-3-yl)acetic acid (15). The acid 12a (6.53 g; 20
mmol) was dissolved in dry methanol (300 mL) and TEAF (6.48 g; 15
mmol). To the suspension was added 10% Pd/C (1.31 g; 20 wt%) and
the reaction mixture was stirred under athmosphere of Argon for 24 h at
room temperature. The catalyst was filtered off and washed with hot
MeOH (200 mL). The filtrate was reduced to the approximately 50 mL
and was sonicated for about 10 minutes. The mixture was left to sit for 24
h in freezer and the precipitated product was filtered off, washed with
MeOH, Et2O and dried. The corresponding (S)-2-amino-2-(1H-indol-3-
yl)acetic acid (15) was obtained as white solid (3.06 g, 80 %; ee 99.8%),
NMR (300 MHz, D2O/NaOD): δ = 7.73 (d, J = 7.8 Hz, 1H), 7.49 (d, J =
8.0 Hz, 1H), 7.42 (s, 1H), 7.38 – 7.09 (m, 7H), 4.33 (s, 1H), 3.72 (d, J =
12.8 Hz, 1H), 3.55 (d, J = 12.7 Hz, 1H), 2.15 (s, 3H)13C NMR (75 MHz,
D2O/NaOD): δ = 177.4, 135.5, 133.6, 127.8, 125.9, 124.9, 124.8, 123.1,
119.4, 117.0, 109.5, 109.3, 64.6, 56.0, 36.7. HRMS (HESI): m/z [M+H]+
calculated for C18H19N2O2 (295.14410), found 295.14420
(S)-2-(1H-Indol-3-yl)-2-(((R)-1-phenylethyl)amino)acetic acid (12a). To
the stirred solution of indole (11.7 g; 100 mmol) and (R)-α-
phenylethylamine (13.4 g; 110 mmol) in 100 mL of MeOH at 0 °C was
added solution of glyoxylic acid monohydrate (10.3 g; 110 mmol)
dissolved in 100 mL of MeOH. After 10 minutes the reaction mixture was
seeded with crystals of the pure (R,S)-diastereomer and stirred at room
temperature for 1.5 hour. The precipitated product was filtered off,
washed with MeOH (50 mL) and Et2O (50 mL) and dried. The
25
m.p = 199-202 °C, [α]D = +109° (H2O c 0.2). 1H NMR (300 MHz,
NaOD/D2O) δ = 7.69 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.27 (s,
1H), 7.20 (t, J = 7.5 Hz, 1H), 7.12 (t, J = 7.4 Hz, 1H), 4.60 (s, 1H). 13C
NMR (75 MHz, NaOD/D2O) δ = 181.7, 136.2, 125.2, 123.4, 121.8, 119.2,
118.9, 115.8, 111.8, 53.0. HRMS (HESI): m/z [M+H]+ calculated for
C10H10N2O2 (191.08205), found 191.08148. HPLC: column CROWNPAK
CR (+) fy Daicel Chem. Ind. Ltd. 150x4 mm; Mobile phase: aqueous
solution of HClO4 (pH 2.0)/methanol = 1000/15; flow: 1.2 mL/min,
corresponding
(S)-2-(1H-indol-3-yl)-2-(((R)-1-phenylethyl)amino)acetic
acid (12a) was obtained as white solid (17 g, 52 %; d.r 99:1), m.p = 150-
152 °C. [α]D25 = +96° (MeOH c 0.2). 1H NMR (300 MHz, NaOD/D2O) δ =
7.49 (d, J = 7.9 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.31 – 7.08 (m, 7H),
7.01 (t, J = 7.5 Hz, 1H), 4.30 (s, 1H), 3.57 (q, J = 6.6 Hz, 1H), 1.22 (d, J =
6.7 Hz, 3H). 13C NMR (75 MHz, NaOD/D2O) δ = 180.0, 144.3, 136.1,
128.6, 127.2, 126.9, 125.9, 124.2, 121.6, 119.0, 118.9, 113.1, 111.7,
54.6, 48.7, 22.1. HRMS (HESI): m/z [M+H]+ calculated for C19H22N2O3
(295.14465), found 295.14410. HPLC: column WATERS SPHERISORB
ODS1, 250x4.6 mm, 5 μm; mobile fase: MeCN/H2O 2:7 (1% TEA, 1%
H3PO4); flow: 1.0mL/min; detection UV 210 nm; major (R,S)-
diastereomer t = 12.6 min; minor (R,R)-diastereomer t = 10.9 min.
detection UV 210 nm; (R)-enantiomer tR = 9.2 min. (S)-enantiomer tR
=
17.8 min.
Triethylammonium (S)-2-(1H-indol-3-yl)-2-(((R)-1-phenylethyl)amino)
acetate (17). The acid 12a (3.26 g; 10 mmol) was dissolved in
acetonitrile (50 mL). To the suspension was added TEA (10 mL) and the
reaction mixture was refluxed for 10 minutes. The hot mixture was filtered
off and left to slowly crystallize at room temperature approximately for 30
minutes. After cooling at room temperature, the reaction mixture was left
to sit in the freezer for 12 hours. The precipitated crystals were filtered off,
washed with dry Et2O and dried. The corresponding triethylammonium
(S)-2-(1H-indol-3-yl)-2-(((R)-1-phenylethyl)amino) acetate (17) were
(R)-2-(1H-Indol-3-yl)-2-(((R)-1-phenylethyl)amino)acetic acid (12b).
To the residue filtrate of the reaction 12a was added Et2O (200 mL) and
25
obtained as crystals (3.45 g, 87 %), m.p = 134-136 °C, [α]D
=
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900814
European Journal of Organic Chemistry
FULL PAPER
+72°( MeOH c 0.2). 1H NMR (300 MHz, D2O) δ = 7.59 (d, J = 7.9 Hz, 1H),
7.49 (d, J = 8.1 Hz, 1H), 7.45 – 7.18 (m, 7H), 7.12 (t, J = 7.5 Hz, 1H),
4.45 (s, 1H), 3.76 (q, J = 6.7 Hz, 1H), 3.05 (q, J = 7.3 Hz, 6H), 1.37 (d, J
= 6.7 Hz, 3H), 1.20 (t, J = 7.3 Hz, 9H).13C NMR (75 MHz, D2O) δ = 182.1,
146.5, 139.0, 131.6, 130.4, 129.9, 128.7, 127.4, 124.7, 122.1, 121.9,
115.3, 114.7, 60.4, 57.9, 49.3, 24.5, 11.1. HRMS (HESI): m/z [M+H]+
calculated for C24H33N3O2 (396.26510), found 396.26455.
N-Benzyl-2-chloro-N-(2-hydroxy-1-(1H-indol-3-yl)ethyl)acetamide
(22a). To the suspension of LAH (3.6 g; 93.5 mmol) in THF (100 mL) was
added 10a (5 g; 17.8 mmol) under virgous stirring and the reaction
mixture was refluxed for 4 hours. After completion of the reaction, the
mixture was cooled down (ice-bath) and was slowly quenched with 5N
solution of KOH (20 mL). The formed clear layer was separated, and the
residue was washed several times with Et2O. The collected organic
layers were dried over anhydrous MgSO4, filtered off and evaporated
yielding a crude product (4.3 g; 91%) which was used to the next step
without further purification. To the solution of crude product (4.13 g; 15.5
mmol) and TEA (3.24 mL; 23.25 mmol) in DCM (60 mL) at 0 °C was
slowly added the solution of chloracetylchloride (1.35 mL; 17.05 mmol) in
DCM (15 mL). The reaction mixture was stirred for 1 hour at 0 °C and
then was quenched with saturated solution of NaHCO3 and extracted
with EtOAc (2x75 mL). The collected organic layers were dried over
anhydrous MgSO4, filtered off, evaporated and the residue was purified
by column chromatography (EtOAc/DCM 2:3) yielding a product as
a colourless solid (3.98 g, 75%), m.p = 112-117 °C. 1H NMR (600 MHz,
DMSO)-Major rotamer δ =11.10 (s, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.38 –
7.32 (m, 2H), 7.12 – 7.06 (m, 2H), 7.05 – 6.98 (m, 3H), 6.91 – 6.87 (m,
2H), 5.38 (dd, J = 8.6, 5.0 Hz, 1H), 5.24 (t, J = 5.1 Hz, 1H-OH), 5.04 (d, J
= 13.4 Hz, 1H), 4.60 (d, J = 13.3 Hz, 1H), 4.38 (m, 1H), 4.19 (d, J = 15.6
Hz, 1H), 3.93 – 3.86 (m, 2H). 13C NMR (151 MHz, DMSO)-Major rotamer
δ = 167.1, 138.8, 136.0, 127.4, 126.8, 126.6, 125.8, 124.3, 119.0, 118.7,
111.5, 109.6, 61.3, 56.3, 45.3, 43.1. 1H NMR (600 MHz, DMSO)-Minor
rotamer δ =11.02 (s, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.38 – 7.30 (m, 2H),
7.17 – 7.13 (m, 3H), 7.05 – 6.97 (m, 4H), 6.16 (dd, J = 8.1, 5.8 Hz, 1H),
4.93 (t, J = 5.5 Hz, 1H-OH), 4.46 (d, J = 17.9 Hz, 1H), 4.41 (m, 1H), 4.08
(2'S,3R,4'R)-4'-(Carboxymethyl)-5'-oxo-1'-((R)-1-phenylethyl)spiro-
[indole-3,3'-pyrrolidine]-2'-carboxylic acid (19). 17 (791 mg; 2 mmol)
was dissolved in DCM (10 mL). Subsequently was added maleic
anhydride (216 mg; 2.2 mmol) and the reaction mixture was stirred at
room temperature for 24 hours. The DCM was evaporated, and the
residue was purified by column chromatography (DCM/AcOH 5:1). The
product was isolated as a yellowish solid (630 mg, 80%, d.r 99:1), m.p =
141-143 °C, [α]D25 = +187° (EtOAc c 0.2). 1H NMR (600 MHz, DMSO) δ =
12.54 (s, 1H), 7.88 (s, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.45 – 7.36 (m, 5H),
7.36 – 7.30 (m, 2H), 7.27 (t, J = 7.2 Hz, 1H), 5.45 (q, J = 6.9 Hz, 1H),
3.81 – 3.78 (m, 1H), 3.36 (s, 1H), 2.36 (dd, J = 16.4, 7.6 Hz, 1H), 1.46 (m,
4H).13C NMR (151 MHz, DMSO) δ = 172.9, 172.6, 171.5, 155.7, 139.7,
133.4, 129.3, 128.7, 127.8, 127.2, 126.7, 123.5, 120.8, 62.5, 58.0, 50.2,
42.9, 29.8, 16.1. HRMS (HESI): m/z [M+H]+ calculated for C22H20N2O5
(393.14505), found 393.14450.
(2'S,3S,4'R)-4'-(Carboxymethyl)-5'-oxo-1'-((R)-1-phenylethyl)spiro-
[indoline-3,3'-pyrrolidine]-2'-carboxylic acid (20). The carboxylic acid
19 (500 mg; 1.26 mmol) was dissolved in DCM (20 mL) and AcOH (2
mL). The mixture was cooled down to -10 °C and during 10 minutes was
added NaBH4 (95 mg; 2.52 mmol) portionwise. The reaction mixture was
stirred for 30 minutes at -10 °C and then was quenched with water (8 mL).
The DCM was evaporated and the precipitated product was filtered off
and washed with water (5 mL). The product was isolated as a white solid
(350 mg, 70%, d.r 99:1), m.p = 258-262 °C, [α]D25 = +118° (MeOH c 0.2).
1H NMR (600 MHz, CD3OD/CDCl3) δ = 7.41 – 7.30 (m, 5H), 7.10 (d, J =
7.5 Hz, 1H), 7.03 (t, J = 7.4 Hz, 1H), 6.67 (t, J = 7.4 Hz, 1H), 6.60 (d, J =
7.8 Hz, 1H), 5.54 (q, J = 7.2 Hz, 1H), 4.03 (dd, J = 7.4, 6.1 Hz, 1H), 3.86
(s, 1H), 3.31 (d, J = 10 Hz, 1H), 2.63 – 2.54 (m, 2H), 2.30 (dd, J = 16.2,
5.8 Hz, 1H), 1.49 (d, J = 7.3 Hz, 3H). 13C NMR (151 MHz, CD3OD/CDCl3)
δ = 176.6, 175.0, 173.8, 153.8, 140.6, 130.4, 129.8, 129.1, 128.3, 126.7,
124.8, 119.8, 111.4, 64.8, 56.3, 55.7, 51.5, 44.0, 31.3, 16.3. HRMS
(HESI): m/z [M+H]+ calculated for C22H22N2O5 (395.16070), found
395.16015.
(d, J = 13.9 Hz, 1H), 4.04 (d, J = 13.9 Hz, 1H), 3.89 – 3.79 (m, 2H). 13
C
NMR (151 MHz, DMSO)-Minor rotamer δ = 166.9, 138.5, 135.9, 128.3,
126.9, 126.5, 126.0, 121.4, 118.9, 118.6, 111.5, 110.7, 60.8, 52.6, 46.0,
43.1. HRMS (HESI): m/z [M+H]+ calculated for C19H20ClN2O2 (343.12133),
found 343.12093.
2-Chloro-N-(2-hydroxy-1-(1H-indol-3-yl)ethyl)-N-methylacetamide
(22b). Following the analogy as for 22a, from reduction of carboxylic acid
10b, crude substrate (4.3 g; 22.6 mmol) delivered compound 22b and
was purified by column chromatography (EtOAc/MeOH 20:1) yielding a
1
product as a white solid (3.19 g, 53%), m.p = 146-147 °C. H NMR (600
MHz, DMSO)-Major rotamer δ =11.05 (s, 1H), 7.45 (d, J = 7.9 Hz, 1H),
7.40 – 7.34 (m, 2H), 7.13 – 7.06 (m, 1H), 6.98 – 6.95 (m, 1H), 5.97 (dd, J
= 8.8, 5.4 Hz, 1H), 4.84 (t, J = 5.7 Hz, 1H-OH), 4.45 (d, J = 13.5 Hz, 1H),
4.35 (d, J = 13.5 Hz, 1H), 3.97 – 3.89 (m, 2H), 2.70 (s, 3H). 13C NMR
(151 MHz, DMSO)-Major rotamer δ =166.1, 136.0, 126.7, 123.7, 121.4,
118.8, 118.7, 111.4, 110.6, 59.9, 51.3, 43.0, 28.9. 1H NMR (600 MHz,
DMSO)-Minor rotamer δ =11.15 (s, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.40 –
7.34 (m, 2H), 7.13 – 7.06 (m, 1H), 7.02 – 6.99 (m, 1H), 5.24 (dd, J = 8.7,
4.9 Hz, 1H), 5.21 (t, J = 5.5 Hz, 1H-OH), 4.91 (d, J = 13.4 Hz, 1H), 4.50
(d, J = 13.3 Hz, 1H), 3.88 – 3.81 (m, 2H), 2.53 (s, 3H). 13C NMR (151
MHz, DMSO)-Minor rotamer δ =166.6, 136.2, 126.2, 123.7, 121.4, 119.0,
118.7, 111.6, 109.8, 60.1, 55.8, 42.8, 27.9. HRMS (HESI): m/z [M+H]+
calculated for C13H16ClN2O2 (267.09003), found 267.08954.
(2'S,3R,4'R)-4'-(Carboxymethyl)-2,5'-dioxo-1'-((R)-1-phenylethyl)-
spiro[indoline-3,3'-pyrrolidine]-2'-carboxylic acid (21). The carboxylic
acid 19 (200 mg; 0.51 mmol) was mixed with water (30 mL) and the
result mixture was refluxed for about 10 minutes until the formation of
clear solution. The reaction mixture then was placed to the oil bath
(heated to 80 °C) and 0.0001 M solution of H2SO4 was added (10 mL).
After 10 minutes the solution of 0.0001 M H2CrO4 was added in small
portions during 5-10 minutes. After 1 hour the reaction mixture was
cooled down and was extracted with EtOAc (4x25 mL). The collected
extracts were dry under anhydrous MgSO4, evaporated and the residue
was purified by column chromatography (DCM/AcOH 10:1) yielding
2-Chloro-N-((S)-2-hydroxy-1-(1H-indol-3-yl)ethyl)-N-((R)-1-phenyl-
ethyl)acetamide (22c). Following the analogy as for 22a, from reduction
of carboxylic acid 12a, crude substrate (2.24 g; 8 mmol) delivered
compound 22c and was purified by column chromatography
(Hexanes/EtOAc 2:1) yielding a product as a white solid (1.91 g, 67%),
m.p = 161-162 °C. 1H NMR (300 MHz, CDCl3) δ = 8.45 (bs, 1H), 7.53 (d,
J = 7.8 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.24 (m, 2H), 7.20 – 7.03 (m,
5H), 6.93 (d, J = 2.4 Hz, 1H), 5.00 (q, J = 7.1 Hz, 1H), 4.91 (t, J = 3.8 Hz,
1H), 4.43 (d, J = 16.6 Hz, 1H), 4.29 (d, J = 16.6 Hz, 1H), 4.03 – 3.92 (m,
2H), 1.69 (d, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ = 167.6, 141.0,
136.2, 128.0, 127.3, 127.1, 125.6, 123.9, 122.4, 119.9, 118.5, 113.1,
25
colourless solid (102 mg, 49%, d.r 99:1), m.p = 156-159 °C, [α]D = -
1
10.4°(EtOAc c 0.2). H NMR (600 MHz, DMSO) δ = 12.35 (s, 2H), 10.61
(s, 1H), 7.42 – 7.25 (m, 5H), 7.22 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.4 Hz,
1H), 6.96 (t, J = 7.5 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 5.29 (q, J = 7.0 Hz,
1H), 3.69 (s, 1H), 3.59 (t, J = 6.5 Hz, 1H), 2.55 – 2.41 (m, 1H), 1.85 (dd, J
= 16.1, 6.1 Hz, 1H), 1.45 (d, J = 7.0 Hz, 3H). 13C NMR (151 MHz, DMSO)
δ = 176.3, 172.6, 172.0, 171.3, 142.5, 139.2, 129.3, 128.1, 127.6, 127.4,
124.9, 124.2, 121.9, 109.7, 62.3, 52.8, 50.8, 44.2, 30.4, 17.0. HRMS
(HESI): m/z [M+H]+ calculated for C22H20N2O6 (409.13996), found
409.13941.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900814
European Journal of Organic Chemistry
FULL PAPER
111.6, 69.8, 68.8, 56.5, 53.2, 18.3. HRMS (HESI): m/z [M+H]+ calculated
for C20H22ClN2O2 (357.13698), found 357.13638.
126.7, 126.1, 126.0, 125.3, 125.0, 124.5, 121.5, 121.3, 119.0, 118.9,
118.8, 118.5, 111.5, 111.3, 110.5, 109.1, 62.2(CH2-OTBS, major/minor),
55.9(CH-Ind, major/minor), 52.6(CH-Ph, minor), 51.5(CH-Ph, major),
44.4(CH2-Cl, major), 43.0(CH2-Cl, minor), 25.7, 18.9, 17.8, 17.7, 17.3, -
5.5, -5.6. HRMS (HESI): m/z [M+H]+ calculated for C26H36ClN2O2Si
(471.22346), found 471.22281.
N-Benzyl-N-(2-((tert-butyldimethylsilyl)oxy)-1-(1H-indol-3-yl)ethyl)-2-
chloroacetamide (23a). To the solution of 22a (3.7 g; 10.8 mmol) and
imidazole (1.1 g; 16.1 mmol) in DCM (120 mL) at room temperature was
added solution of TBSCl (2.43 g; 16.1 mmol). The reaction mixture was
stirred for 24 hours and after completition was dilluted with water and
extracted with DCM. The collected organic layers were dried over
anhydrous MgSO4, filtered off and evaporated resulting crude product
which was purified by column chromatography (Et2O/Hexane 1:4). The
product was isolated as a colourless solid (4.32 g, 87 %), m.p = 131-
137 °C. 1H NMR (600 MHz, DMSO)-Major rotamer δ =11.16 (s, 1H), 7.57
(d, J = 8.0 Hz, 1H), 7.44 (d, J = 2.2 Hz, 1H), 7.38 – 7.33 (m, 1H), 7.18 –
6.88 (m, 7H), 5.50 (dd, J = 9.4, 4.1 Hz, 1H), 5.05 (d, J = 13.6 Hz, 1H),
4.65 (d, J = 13.5 Hz, 1H), 4.51 – 4.41 (m, 1H), 4.16 – 3.97 (m, 3H), 0.90
(s, 9H), 0.08 (s, 3H), 0.02 (s, 3H). 13C NMR (151 MHz, DMSO) - Major
rotamer δ =167.1, 138.9, 136.0, 127.5, 126.7, 126.4, 126.0, 124.3, 121.5,
119.0, 118.7, 111.5, 109.0, 62.7, 55.8, 45.1, 43.3, 25.7, 17.8, -5.7, -5.7.
1H NMR (600 MHz, DMSO)-Minor rotamer δ = 11.06 (s, 1H), 7.51 (d, J =
7.9 Hz, 1H), 7.40 (d, J = 1.9 Hz, 1H), 7.38 – 7.33 (m, 1H), 7.18 – 6.88 (m,
7H), 6.19 (dd, J = 8.6, 4.9 Hz, 1H), 4.53 – 4.38 (m, 2H), 4.21 – 3.92 (m,
4H), 0.87 (s, 9H), 0.07 (s, 6H). 13C NMR (151 MHz, DMSO) - Minor
rotamer δ =166.9, 138.4, 136.0, 128.2, 126.8, 126.8, 126.0, 124.2, 121.5,
119.0, 118.5, 111.5, 110.2, 62.3, 52.3, 46.1, 42.9, 25.7, 17.8, -5.5, -5.5.
HRMS (HESI): m/z [M+H]+ calculated for C25H34ClN2O2Si (457.20781),
found 457.20740.
(2'S,3S)-1'-Benzyl-2'-(((tert-butyldimethylsilyl)oxy)methyl)spiro-
[indole-3,3'-pyrrolidin]-5'-one (24a). To the solution of 23a (914 mg; 2
mmol) in THF (10 mL) was added sodium hydride (60% dispersion in
mineral oil 120 mg; 3 mmol) portionwise. The reaction mixture was stirred
for 30 minutes and after completition the solvent was evaporated. The
resulting crude product was purified by column chromatography
(DCM/EtOAc 2:1). The product was isolated as a colourless solid (648
mg, 77 %, d.r 99:1), m.p = 75-81 °C. 1H NMR (600 MHz, CDCl3) δ = 8.29
(s, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.37 – 7.32 (m, 4H), 7.31 – 7.26 (m, 2H),
7.10 (td, J = 7.5, 0.7 Hz, 1H), 7.02 (ddd, J = 7.5, 1.1, 0.6 Hz, 1H), 5.21 (d,
J = 14.6 Hz, 1H), 3.99 (d, J = 14.6 Hz, 1H), 3.89 (dd, J = 11.6, 2.7 Hz,
1H), 3.53 (dd, J = 11.6, 1.9 Hz, 1H), 3.45 (t, J = 2.2 Hz, 1H), 3.25 (dd, J =
16.6, 0.9 Hz, 1H), 2.29 (d, J = 16.6 Hz, 1H), 0.95 (s, 9H), 0.11 (s, 3H),
0.09 (s, 3H). 13C NMR (151 MHz, CDCl3) δ = 173.2, 172.8, 153.9, 143.0,
136.0, 128.8, 128.7, 128.5, 128.0, 126.9, 121.3, 120.5, 63.9, 61.6, 58.6,
44.8, 36.9, 25.8, 18.0, -5.6. HRMS (HESI): m/z [M+H]+ calculated for
C25H33N2O2Si (421.23113), found 421.23044.
(2'S,3S)-2'-(((Tert-butyldimethylsilyl)oxy)methyl)-1'-methylspiro-
[indole-3,3'-pyrrolidin]-5'-one (24b). Following the analogy as for 24a,
substrate 23b (1.7 g; 4.4 mmol) delivered compound 24b and was
purified by column chromatography (DCM/EtOAc 1:1) yielding a product
as a colourless solid (1.1 g, 72%, d.r 99:1), m.p = 106-108 °C. 1H NMR
(600 MHz, CDCl3) δ = 8.31 (s, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.38 (td, J =
7.6, 1.2 Hz, 1H), 7.34 (d, J = 7.4 Hz, 1H), 7.29 – 7.24 (m, 1H), 3.88 (dd, J
= 11.6, 2.6 Hz, 1H), 3.60 (dd, J = 11.6, 2.2 Hz, 1H), 3.54 (t, J = 2.3 Hz,
1H), 3.14 (d, J = 16.5 Hz, 1H), 2.99 (s, 3H), 2.29 (d, J = 16.5 Hz, 1H),
0.92 (s, 9H), 0.11 (s, 3H), 0.08 (s, 3H)13C NMR (151 MHz, CDCl3) δ =
173.3, 173.0, 154.0, 143.0, 128.7, 127.2, 121.5, 120.5, 67.0, 61.6, 58.91,
36.7, 28.1, 25.7, 18.0, -5.6. HRMS (HESI): m/z [M+H]+ calculated for
C19H29N2O2Si (345.19983), found 345.19871.
N-(2-((Tert-butyldimethylsilyl)oxy)-1-(1H-indol-3-yl)ethyl)-2-chloro-N-
methylacetamide (23b). Following the analogy as for 23a, substrate 22b
(797 mg; 2.99 mmol) delivered compound 23b and was purified by
column chromatography (Et2O/Hexane 1:3) yielding
a product as
a colourless solid (1.06 g, 93%), m.p = 155-156 °C. 1H NMR (600 MHz,
DMSO)-Major rotamer δ =11.08 (bs, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.41
(d, J = 2.0 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.10 (m, 1H), 6.97 (t, J = 7.5
Hz, 1H), 6.00 (dd, J = 8.7, 5.1 Hz, 1H), 4.39 (d, J = 13.3 Hz, 1H), 4.35 (d,
J = 13.3 Hz, 1H), 4.14 – 4.07 (m, 1H), 4.00 (dd, J = 10.8, 5.2 Hz, 1H),
2.72 (s, 3H), 0.87 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H). 13C NMR (151 MHz,
DMSO)-Major rotamer δ =166.1, 136.0, 126.7, 123.8, 121.4, 118.9, 118.6,
1
111.4, 110.1, 61.5, 50.8, 42.7, 29.2, 25.8, 17.8, -5.4, -5.5. H NMR (600
(2'S,3S)-2'-(((Tert-butyldimethylsilyl)oxy)methyl)-1'-((R)-1-phenyl-
ethyl)spiro[indole-3,3'-pyrrolidin]-5'-one (24c). Following the analogy
as for 24a, substrate 23c (942.2 mg; 2 mmol) delivered compound 24c
and was purified by column chromatography (Et2O/Hexane 2:1) yielding
a product as a colourless solid (590 mg, 68%, d.r 99:1), m.p = 143-
145 °C. 1H NMR (300 MHz, CDCl3) δ = 8.22 (s, 1H), 7.54 (d, J = 7.7 Hz,
1H), 7.45 – 7.39 (m, 2H), 7.37 – 7.23 (m, 4H), 7.09 (t, J = 7.5 Hz, 1H),
6.96 (d, J = 8.0 Hz, 1H), 5.58 (q, J = 7.2 Hz, 1H), 3.87 (dd, J = 11.4, 3.0
Hz, 1H), 3.55 (dd, J = 11.4, 1.7 Hz, 1H), 3.36 (d, J = 16.3 Hz, 1H), 3.27
(dd, J = 2.9, 1.7 Hz, 1H), 2.16 (d, J = 16.3 Hz, 1H), 1.72 (d, J = 7.3 Hz,
3H), 0.96 (s, 9H), 0.10 (s, 6H). 13C NMR (75 MHz, CDCl3) δ = 172.9,
172.9, 153.6, 143.3, 138.9, 128.8, 128.3, 128.1, 127.8, 126.8, 121.2,
120.4, 64.8, 63.9, 59.3, 51.9, 37.2, 25.7, 18.0, 17.8, -5.7. HRMS (HESI):
m/z [M+H]+ calculated for C26H35N2O2Si (435.24678), found 435.24579.
MHz, DMSO)-Minor rotamer δ =11.20 (bs, 1H), 7.51 (d, J = 7.9 Hz, 1H),
7.42 (d, J = 2.2 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.10 (m, 1H), 7.01 (t, J
= 7.5 Hz, 1H), 5.35 (dd, J = 8.9, 4.6 Hz, 1H), 4.90 (d, J = 13.5 Hz, 1H),
4.49 (d, J = 13.5 Hz, 1H), 4.15 – 4.07 (m, 2H), 2.51 (s, 3H), 0.88 (s, 9H),
0.11 (s, 3H), 0.08 (s, 3H). 13C NMR (151 MHz, DMSO)-Minor rotamer δ
=166.6, 136.1, 126.1, 123.8, 121.5, 119.0, 118.7, 111.6, 109.1, 61.6,
55.2, 43.0, 27.8, 25.7, 17.8, -5.6, -5.6. HRMS (HESI): m/z [M+H]+
calculated for C19H30ClN2O2Si (381.17651), found 381.17592.
N-((S)-2-((Tert-butyldimethylsilyl)oxy)-1-(1H-indol-3-yl)ethyl)-2-
chloro-N-((R)-1-phenylethyl)acetamide (23c). Following the analogy as
for 23a, substrate (762 mg; 2 mmol) delivered compound 23c and was
purified by column chromatography (Et2O/Hexane 1:2) yielding a product
1
as a colourless solid (1.25 g, 89%), m.p = 90-96 °C. H NMR (600 MHz,
DMSO) (mixture of rotamers) δ = 11.19 (bs, 1H-NH, major), 10.97 (bs,
1H-NH-minor), 7.70 (m 1H), 7.60 (m, 1H), 7.40 (m, 3H), 7.15 – 6.62 (m,
12H), 5.48 (m, 1H-CH-Ind), 5.01 (m, 1H-CH-Ph, minor), 4.96 (d, J = 13.7
Hz, 1H-CH2-Cl), 4.62 (m, 1H-CH-Ph, major), 4.56 (d, J = 13.7 Hz, 1H-
CH2-Cl), 4.39 (m, 2H-CH2-OTBS), 4.00 (m, 2H-CH2-OTBS), 1.79 (m, 3H-
CH3-CH, minor), 1.74 (d, J = 5.9 Hz, 3H-CH3-CH, major), 0.92 (s, 9H-Si-
terc-butyl, major), 0.89 (s, 9H-Si-terc-butyl, minor), 0.17 (s, 3H-Si-CH3,
major), 0.15 (s, 3H-Si-CH3-major), 0.09 (m, 6H-Si-CH3x2, minor). 13C
NMR (151 MHz, DMSO) (mixture of rotamers) δ =166.7(C=O, minor),
165.2(C=O, major), 142.1, 141.5, 135.8, 135.4, 128.0, 127.1, 126.9,
(3aS,5aR,10bS)-3-benzyl-3a,4,5a,6-tetrahydro-1H-
pyrrolo[3',2':3,4]furo[2,3-b]indol-2(3H)-one (25a). To the solution of
24a (421 mg; 1 mmol) in THF (5 mL) was added TBAF (379 mg, 1.2
mmol) and the reaction mixture was stirred for 24 hours at room
temperature. After completition of the reaction the solvent was
evaporated, and the resulting crude product was purified by column
chromatography (EtOAc/Hexane 1:1). The product was obtained as
a colourless crystals (254 mg, 83 %, d.r 99:1), m.p = 145-148 °C. 1H
NMR (600 MHz, CDCl3) δ = 7.37 – 7.30 (m, 2H), 7.30 – 7.23 (m, 3H),
7.07 (ddd, J = 7.8, 7.5, 1.3 Hz, 1H), 7.04 (dddd, J = 7.5, 1.3. 0.7, 0.6 Hz,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900814
European Journal of Organic Chemistry
FULL PAPER
1H), 6.74 (td, J = 7.5, 0.9 Hz, 1H), 6.57 (dd, J = 7.8 Hz, 1H), 5.71 (d, J =
3.3 Hz, 1H), 4.99 (d, J = 15.2 Hz, 1H), 4.70 (d, J = 2.9 Hz, 1H), 4.15 (d, J
= 15.1 Hz, 1H), 4.01 (d, J = 10.6 Hz, 1H), 3.83 (d, J = 3.4 Hz, 1H), 3.57
(dd, J = 10.8, 3.4 Hz, 1H), 3.03 (d, J = 17.9 Hz, 1H), 2.87 (d, J = 17.9 Hz,
1H).13C NMR (151 MHz, CDCl3) δ= 172.5, 149.3, 135.7, 129.1, 128.9,
128.0, 127.9, 127.8, 123.5, 119.2, 108.6, 102.0, 70.3, 66.4, 56.7, 45.0,
42.1. HRMS (HESI): m/z [M+H]+ calculated for C19H19N2O2 (307.14465),
found 307.14402
113.1, 111.4, 57.4, 52.1, 51.6. HRMS (HESI): m/z [M+H]+ calculated for
C18H18N2O2 (295.1446), found 295.14471.
Methyl 2-(1H-indol-3-yl)-2-(((R)-1-phenylethyl)amino)acetate (29c).
Following the analogy as for 29b, substrate 12a (589 mg; 2 mmol)
delivered compound 29c and was purified by flash chromatography
(EtOAc/ hexane 1:4). The corresponding methyl 2-(1H-indol-3-yl)-2-(((R)-
1-phenylethyl)amino)acetate (29c) was obtained as yellowish oil (580 mg,
25
D
94 %), [α]
= -114° (MeOH, c = 0,2). 1H NMR (300 MHz, CDCl3): δ =
(3aS,5aR,10bS)-3-methyl-3a,4,5a,6-tetrahydro-1H-pyrrolo[3',2':3,4]-
furo[2,3-b]indol-2(3H)-one (25b). Following the analogy as for 25a,
substrate 24b (318.83 mg; 0.925 mmol) delivered compound 25b and
was purified by column chromatography (Et2O/EtOAc 1:1) yielding a
product as a colourless crystals (179 mg, 84%, d.r 99:1), m.p = 224-
227 °C. 1H NMR (600 MHz, CDCl3) δ = 7.15 – 7.09 (m, 2H), 6.79 (td, J =
7.5, 0.9 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.69 (s, 1H), 4.69 (s, 1H), 4.09
(d, J = 10.6 Hz, 1H), 3.91 (d, J = 3.3 Hz, 1H), 3.71 (dd, J = 10.6, 3.4 Hz,
8.20 (s, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.38 – 7.24 (m, 6H), 7.23 – 7.16 (m,
1H), 7.12 (m, 1H), 7.05 (d, J = 2.4 Hz, 1H), 4.55 (s, 1H), 3.71 (q, J = 6.6
Hz, 1H), 3.59 (s, 3H), 1.34 (d, J = 6.6 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ = 173.8, 144.8, 136.4, 128.4, 127.1, 127.0, 126.0, 123.4, 122.4,
119.9, 119.5, 113.1, 111.3, 55.8, 55.1, 52.1, 24.3. HRMS (HESI): m/z
[M+H]+ calculated for C19H20N2O2 (309.1603), found 309.15984.
Methyl 2-(1H-indol-3-yl)-2-(phenethylamino)acetate (29d). Following
the analogy as for 29b, substrate 10c (4.47 g; 15.18 mmol) delivered
compound 29d and was purified by flash chromatography (EtOAc 100 %).
The corresponding methyl 2-(1H-indol-3-yl)-2-(phenethylamino)acetate
(29d) was obtained as white solid (3.51 g, 75 %), m.p = 98-100 °C. 1H
NMR (600 MHz, CDCl3): δ = 8.20 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.34
(d, J = 8.1 Hz, 1H), 7.29 – 7.24 (m, 2H), 7.19 (m, 4H), 7.15 – 7.09 (m,
2H), 4.73 (s, 1H), 3.68 (s, 3H), 2.97 – 2.79 (m, 4H). 13C NMR (151 MHz,
CDCl3): δ = 173.9, 139.8, 136.3, 128.7, 128.4, 126.2, 126.0, 122.8, 122.4,
120.0, 119.4, 113.2, 111.3, 58.5, 52.1, 49.2, 36.5. HRMS (HESI): m/z
[M+H]+ calculated for C19H20N2O2 (309.1603), found 309.15962.
1H), 2.98 (d, J = 17.8 Hz, 1H), 2.89 (s, 3H), 2.79 (d, J = 17.8 Hz, 1H).13
C
NMR (151 MHz, CDCl3) δ= 172.4, 149.4, 129.2, 128.0, 123.6, 119.3,
108.7, 102.1, 72.7, 66.5, 56.8, 42.1, 27.9. HRMS (HESI): m/z [M+H]+
calculated for C13H15N2O2 (231.11335), found 231.11271.
(3aR,5aS,10bR)-3-((R)-1-Phenylethyl)-3a,4,5a,6-tetrahydro-1H-
pyrrolo[3',2':3,4]furo[2,3-b]indol-2(3H)-one (25c). Following the
analogy as for 25a, substrate 24c (434.65 mg; 1 mmol) delivered
compound 25c and was purified by column chromatography
(Et2O/Hexane 2:1→100:0→ Et2O/AcOEt 2:1) yielding a product as
a colourless crystals (251 mg, 78%, d.r 99:1), m.p = 163-166 °C. 1H NMR
(300 MHz, CDCl3) δ = 7.39 – 7.23 (m, 5H), 7.05 (t, J = 7.7 Hz, 1H), 6.94
(d, J = 7.5 Hz, 1H), 6.72 (t, J = 7.5 Hz, 1H), 6.55 (d, J = 7.7 Hz, 1H), 5.63
(d, J = 3.0 Hz, 1H), 5.51 (q, J = 7.2 Hz, 1H), 4.69 (s, 1H), 3.96 (d, J =
10.3 Hz, 1H), 3.64 (d, J = 4.0 Hz,1H), 3.56 (dd, J = 10.3, 4.0 Hz, 1H),
2.94 (d, J = 17.9 Hz, 1H), 2.85 (d, J = 17.9 Hz, 1H), 1.67 (d, J = 7.2 Hz,
3H). 13C NMR (75 MHz, CDCl3) δ= 172.6, 149.0, 138.6, 128.9, 128.8,
128.7, 127.8, 127.4, 123.3, 119.3, 108.7, 101.7, 69.7, 68.9, 56.5, 51.1,
42.2, 18.0. HRMS (HESI): m/z [M+H]+ calculated for C20H21N2O2
(321.16030), found 321.15967.
Methyl 2-(allylamino)-2-(1H-indol-3-yl)acetate (29e). Following the
analogy as for 29b, substrate 10d (2.3 g; 10 mmol) delivered compound
29e and was purified by flash chromatography (EtOAc/hexane 1:1). The
corresponding methyl 2-(allylamino)-2-(1H-indol-3-yl)acetate (29e) was
obtained as white solid (1.76 g, 72 %), m.p = 91-95 °C. 1H NMR (600
MHz, CDCl3): δ = 8.39 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 8.1
Hz, 1H), 7.22 – 7.11 (m, 3H), 5.93 (ddt, J = 16.5, 10.3, 6.1 Hz, 1H), 5.20
(dd, J = 17.2, 1.5 Hz, 1H), 5.13 (dd, J = 10.2, 1.1 Hz, 1H), 4.75 (s, 1H),
3.71 (s, 3H), 3.32 (dd, J = 13.8, 6.0 Hz, 1H), 3.27 (dd, J = 13.8 Hz, 6.0
Hz, 1H), 2.06 (bs, 1H). 13C NMR (151 MHz, CDCl3): δ = 174.0, 136.3,
136.2, 126.0, 122.9, 122.4, 120.0, 119.3, 116.7, 113.1, 111.4, 57.3, 52.1,
50.4. HRMS (HESI): m/z [M+H]+ calculated for C14H16N2O2 (245.1290),
found 245.12835.
Methyl 2-(1H-indol-3-yl)-2-(methylamino)acetate (29b). The acid 10b
(11.5 g; 56.3 mmol) was dissolved in a mixture of 2M HCl/MeOH (200
mL) and 2,2-dimethoxypropane (200 mL). The reaction mixture was
stirred at room temperature for 48 hours. The reaction mixture was
evaporated under reduced pressure and the residue was extracted with a
mixture of saturated NaHCO3 (50 mL) and DCM (2x100 mL). The
combined extracts were dried over MgSO4, filtered off and evaporated in
vacuum. The residue was purified by flash chromatography
(EtOAc/MeOH 100%→10:1→5:1). The corresponding methyl 2-(1H-
indol-3-yl)-2-(methylamino)acetate (29a) was obtained as white solid (7.3
Methyl
(26ba).
2-(2-chloro-N-methylacetamido)-2-(1H-indol-3-yl)acetate
To the mixture of methyl 2-(1H-indol-3-yl)-2-
(methylamino)acetate (29b) (411.5 mg; 1.88 mmol) and propylene oxide
(1.64. g; 28.2 mmol) in THF (15 mL) at 0 °C was added chloracetyl
chloride (233.6 mg; 2.07 mmol) in THF (5 mL). The reaction mixture was
stirred at room temperature for 30 minutes and concentrated under
reduced pressure. The residue was extracted with DCM and NaHCO3
(aq.), dried over MgSO4, filtered off and evaporated under vacuum. The
crude product was purified by flash chromatography (EtOAc/hexane
1:2→1:1→2:1). The corresponding methyl 2-(2-chloro-N-methyl-
acetamido)-2-(1H-indol-3-yl)acetate (26ba) was obtained as white solid
(415.6 mg, 75%), m.p = 128-130 °C. 1H NMR (CDCl3): δ = 8.77 (bs, 1H),
7.50 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.29 – 7.17 (m, 2H),
7.14 (t, J = 7.5 Hz, 1H), 6.65 (s, 1H), 4.21 (d, J = 12.9, 1H), 4.16 (d, J =
12.9, 1H), 3.77 (s, 3H), 2.89 (s, 3H). 13C NMR (CDCl3): δ = 171.0, 167.3,
136.2, 126.4, 125.0, 122.8, 120.5, 118.6, 111.6, 108.1, 54.1, 52.4, 41.8,
31.7. HRMS (HESI): m/z [M+H]+ calculated for C14H15ClN2O3
(295.08495), found 295.08446
1
g, 60 %), m.p = 76-79 °C. H NMR (300 MHz, CDCl3): δ = 8.69 (s, 1H),
7.74 (d, J = 7.5 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.23 – 7.08 (m, 3H),
4.62 (s, 1H), 3.71 (s, 3H), 2.49 (s, 3H). 13C NMR (75 MHz, CDCl3): δ=
173.9, 136.3, 125.9, 123.0, 122.3, 119.9, 119.1, 112.7, 111.4, 60.1, 52.1,
34.6. HRMS (HESI): m/z [M+H]+ calculated for C12H14N2O2 (219.1133),
found 219.1127.
Methyl 2-(benzylamino)-2-(1H-indol-3-yl)acetate (29a). Following the
analogy as for 29b, substrate 10a (3.52 g; 12.56 mmol) delivered
compound 29a and was purified by flash chromatography (EtOAc/hexane
1:2). The corresponding methyl 2-(benzylamino)-2-(1H-indol-3-yl)acetate
(29b) was obtained as white solid (2.7 g, 73 %), m.p = 90-91 °C. 1H NMR
(300 MHz, CDCl3): δ = 8.28 (bs, 1H), 7.80 – 7.57 (m, 1H), 7.38 – 7.27 (m,
6H), 7.24 – 7.11 (m, 3H), 4.72 (d, J = 0.5 Hz, 1H), 3.84 (d, J = 13.1, 1H),
3.79 (d, J = 13.1, 1H), 3.69 (s, 3H). 13C NMR (75 MHz, CDCl3): δ = 174.0,
139.7, 136.4, 128.4, 128.4, 127.1, 126.0, 123.0, 122.4, 120.0, 119.4,
Methyl
2-(N-benzyl-2-chloroacetamido)-2-(1H-indol-3-yl)acetate
(26aa). Following the analogy as for 26ba, substrate 29a (294.35 mg; 1
mmol) delivered compound 26aa and the crude product was purified by
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900814
European Journal of Organic Chemistry
FULL PAPER
flash
chromatography
(DCM/EtOAc
100%→20:1→10:1).
The
Hz, 1H), 7.93 (dd, J = 7.8, 0.7 Hz, 1H), 7.56 – 7.49 (m, 1H), 7.23 (ddd, J
= 8.1, 7.1, 1.1, 1H), 7.16 (ddd, J = 8.1, 7.1, 1.1, 1H), 3.00 (s, 3H). 13C
NMR (DMSO) δ = 168.6, 166.1, 136.5, 133.4, 131.3, 124.6, 122.6, 122.0,
121.6, 120.6, 112.4, 103.3, 24.4. HRMS (HESI): m/z [M+H]+ calculated
for C13H9ClN2O2 (261.04308), found 261.04265.
corresponding methyl 2-(N-benzyl-2-chloroacetamido)-2-(1H-indol-3-
yl)acetate (26aa) was obtained as white solid (351 mg, 94 %), m.p = 121-
122 °C. 1H NMR (CDCl3): δ = 8.47 (bs, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.34
(d, J = 8.2 Hz, 1H), 7.24 – 7.08 (m, 6H), 6.95 (m, 2H), 6.49 (s, 1H), 4.63
(d, J = 18.0 Hz, 1H), 4.59 (d, J = 17.6 Hz, 1H), 4.05 (d, J = 13.2 Hz, 1H),
3.95 (d, J = 13.2 Hz, 1H), 3.73 (s, 3H). 13C NMR (CDCl3): δ = 171.1,
168.2, 137.0, 136.0, 128.6, 127.3, 126.8, 126.0, 125.7, 122.9, 120.7,
118.7, 111.6, 107.8, 55.2, 52.5, 48.9, 42.3. HRMS (HESI): m/z [M+H]+
calculated for C20H19ClN2O3 (371.11625), found 371.11596.
3-(1H-Indol-3-yl)-1,4-dimethyl-1H-pyrrole-2,5-dione (28bc).To the
mixture of methyl 2-(1H-indol-3-yl)-2-(methylamino)acetate (29b) (1 g;
4.58 mmol) and propylene oxide (3.99 g; 69 mmol) in THF (37 mL) at
0 °C was added 2-chloropropionyl chloride (640 mg; 5.03 mmol) in THF
(12 mL). The reaction mixture was stirred at room temperature for 30
minutes and concentrated under reduced pressure. The residue was
extracted with DCM and NaHCO3 (aq.), dried over MgSO4, filtered off
and evaporated under vacuum. The residue was triturated with hexane
(15 mL) and Et2O (2 mL) and the precipitated product was filtered off,
washed with hexane (10 mL) and Et2O (2 mL). The crude product methyl
2-(2-chloro-N-methylpropanamido)-2-(1H-indol-3-yl)acetate (26bc) (1.23
g, 87 %), m.p = 163-167 °C, was obtained as pale-yellow solid and it was
used without further purification to the next step. HRMS (HESI): m/z
[M+H]+ calculated for C15H17ClN2O3 (309.10060), found 309.10070. 26bc
(308.76 mg; 1 mmol) was dissolved in THF (5 ml) and NaH (88 mg; 2.2
mmol; 60 % dispersion in mineral oil) was added and reaction mixture
was stirred at RT for 10 minutes. The reaction was quenched by diluting
with NaHCO3 (0.5 ml) and DCM (20 mL), dried over MgSO4, filtered off
and evaporated under vacuum. The crude product was purified by flash
chromatography (DCM 100 %). The corresponding 3-(1H-indol-3-yl)-1,4-
dimethyl-1H-pyrrole-2,5-dione (28bc) was obtained as yellow crystalline
Methyl 2-(N-allyl-2-chloroacetamido)-2-(1H-indol-3-yl)acetate (26ea).
Following the analogy as for 26ba, substrate 29e (2.12 g; 8.7 mmol)
delivered compound 26ea and the crude product was purified by flash
chromatography (EtOAc/hexane 1:1). The corresponding methyl 2-(N-
allyl-2-chloroacetamido)-2-(1H-indol-3-yl)acetate (26ea) was obtained as
1
a white solid (1.95 g, 70 %), m.p = 95-96 °C. H NMR (CDCl3) δ = 8.75
(bs, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), (m, 1H), 7.26
– 7.19 (m, 2H), 7.14 (ddd, J = 8.0, 7.1, 1.1 Hz, 1H), 6.51 (s, 1H), 5.63 –
5.30 (m, 1H), 5.05 – 4.90 (m, 2H), 4.19 (s, 2H), 3.98 – 3.93 (m, 2H), 3.75
(s, 3H). 13C NMR (CDCl3) δ = 171.2, 167.9, 136.1, 134.1, 126.6, 125.5,
122.9, 120.6, 118.6, 116.8, 111.7, 107.9, 54.7, 52.5, 47.7, 42.0. HRMS
(HESI): m/z [M+H]+ calculated for C16H17ClN2O3 (321.10060), found
321.10033.
3-(1H-Indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione (28ba). To the mixture
of
methyl
2-(2-chloro-N-methylacetamido)-2-(1H-indol-3-yl)acetate
1
solid (132 mg, 55 %) m.p = 174-176 °C. H NMR (DMSO) δ = 11.85 (bs,
(26ba) (295 mg; 1 mmol) in THF (5 mL) was added NaH (80 mg; 2.2
mmol; 60 % dispersion in mineral oil) and the reaction mixture was stirred
at room temperature for 10 minutes. The reaction was quenched by
diluting with NaHCO3 (0.5 ml) and DCM (20 mL), dried over MgSO4,
filtered off and evaporated under vacuum. The crude product was
triturated with EtOAc (5 mL) and the corresponding 3-(1H-indol-3-yl)-1-
methyl-1H-pyrrole-2,5-dione (26aa) was obtained as yellow crystalline
solid by filtration (215 mg, 95%), m.p = 194-197 °C, (lit.[33] m.p = 195-
1H), 7.75 (d, J = 2.7 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.52-7.45 (m, 1H),
7.19 (ddd, J = 8.2, 7.1, 1.2 Hz, 1H), 7.10 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H),
2.96 (s, 3H), 2.11 (s, 3H). 13C NMR (DMSO) δ 172.4, 171.2, 136.3, 133.6,
130.4, 129.0, 125.3, 122.1, 120.8, 120.0, 112.1, 104.5, 23.7, 10.6. HRMS
(HESI): m/z [M+H]+ calculated for C14H12N2O2 (241.09770), found
241.09711.
1
196 °C). H NMR (DMSO): δ = 12.03 (bs, 1H), 8.39 (s, 1H), 7.96 (d, J =
1-Benzyl-3-(1H-indol-3-yl)-1H-pyrrole-2,5-dione (28aa). Following the
analogy as for 28ba, substrate 26aa (501.8 mg; 1.35 mmol) delivered
compound 28aa and the crude product was purified by flash
chromatography (EtOAc/hexane 1:2). The corresponding 1-benzyl-3-(1H-
indol-3-yl)-1H-pyrrole-2,5-dione (28aa) was obtained as yellow crystalline
solid (315 mg, 77 %) m.p = 166-170 °C. 1H NMR (DMSO) δ 12.09 (bs,
1H), 8.41 (bs, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.40
– 7.11 (m, 7H), 6.94 (s, 1H), 4.66 (s, 2H). 13C NMR (DMSO) δ 171.6,
171.3, 139.0, 137.1, 136.7, 131.3, 128.6, 127.3, 127.3, 125.5, 123.1,
121.6, 120.5, 113.9, 112.6, 105.5, 40.5. HRMS (HESI): m/z [M+H]+
calculated for C19H14N2O2 (303.11335), found 303.11290.
7.3 Hz, 1H), 7.52 (d, J = 7.4 Hz, 1H), 7.30-7.15 (m, 2H), 6.85 (s, 1H),
2.92 (s, 3H). 13C NMR (DMSO): δ= 172.0, 171.6, 139.0, 136.7, 131.0,
125.5, 123.1, 121.5, 120.4, 114.1, 112.6, 105.5, 23.4. HRMS (HESI): m/z
[M+H]+ calculated for C13H10N2O2 (227.08205), found 227.08147.
3-Chloro-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione (28bb).To
the mixture of methyl 2-(1H-indol-3-yl)-2-(methylamino)acetate (29b)
(2.48 g; 11.4 mmol) and propylene oxide (9.9 g; 171 mmol) in THF (91
mL) at 0 °C was added dichloroacetyl chloride (1.85 g; 12.54 mmol) in
THF (30 mL). The reaction mixture was stirred at room temperature for
30 minutes and concentrated under reduced pressure. The residue was
extracted with DCM and NaHCO3 (aq.), dried over MgSO4, filtered off
and evaporated under vacuum. The residue was triturated with hexane
(25 mL) and Et2O (5 mL) and the precipitated product was filtered off,
washed with hexane (10 mL) and Et2O (2 mL). The crude product methyl
2-(2,2-dichloro-N-methylacetamido)-2-(1H-indol-3-yl)acetate (26bb) (3.26
g, 86 %), m.p = 157-159 °C, was obtained as pale-yellow solid and it
was used without further purification to the next step. HRMS (HESI): m/z
[M+H]+ calculated for C14H14Cl2N2O3 (329.04597), found 329.04576.
26bb (323.5 mg; 0.98 mmol) was dissolved in THF (5 ml) and NaH (86
mg; 2.12 mmol; 60 % dispersion in mineral oil) was added and reaction
mixture was stirred at RT for 10 minutes. The reaction was quenched by
diluting with NaHCO3 (0.5 ml) and DCM (20 mL), dried over MgSO4,
filtered off and evaporated under vacuum. The crude product was
purified by flash chromatography (DCM 100 %). The corresponding 3-
(R)-3-(1H-Indol-3-yl)-1-(1-phenylethyl)-1H-pyrrole-2,5-dione (28ca).To
the mixture of methyl 2-(1H-indol-3-yl)-2-(((R)-1-phenylethyl)amino)
acetate (29c) (1.87 g; 6.1 mmol) and propylene oxide (5.3 g; 91.5 mmol)
in THF (50 mL) at 0 °C was added chloracetyl chloride (758 mg; 6.71
mmol) in THF (16 mL). The reaction mixture was stirred at room
temperature for 30 minutes and concentrated under reduced pressure.
The residue was extracted with DCM and NaHCO3 (aq.), dried over
MgSO4, filtered off and evaporated under vacuum. The crude product
was triturated with hexane (25 mL) and Et2O (5 mL) and the precipitated
product was filtered off, washed with hexane (10 mL) and Et2O (2 mL).
The raw product methyl 2-(2-chloro-N-((R)-1-phenylethyl)acetamido)-2-
25
(1H-indol-3-yl)acetate (26ca) (2.196 g, 94 %), m.p = 114.4-119 °C, [α]D
= -89 ° (MeOH, c = 0,3) was obtained as a pale-yellow solid and it was
used without further purification to the next step. HRMS (HESI): m/z
[M+H]+ calculated for C21H21ClN2O3 (385.13190), found 385.13168. 26ca
(360.4 mg; 0.94 mmol) was dissolved in THF (4.7 ml) and NaH (83 mg;
2.07 mmol; 60 % dispersion in mineral oil) was added and reaction
chloro-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione
obtained as yellow crystalline solid (82 mg, 32 %) m.p = 204-206 °C,
(lit.[34] m.p = 207°C). 1H NMR (DMSO) δ = 12.15 (bs, 1H), 8.08 (d, J = 3.0
(28bb)
was
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900814
European Journal of Organic Chemistry
FULL PAPER
mixture was stirred at RT for 10 minutes. The reaction was quenched by
diluting with NaHCO3 (0.5 ml) and DCM (20 mL), dried over MgSO4,
filtered off and evaporated under vacuum. The crude product was
purified by flash chromatography (DCM 100 %). The corresponding (R)-
VEGA 1/0489/19. The authors are grateful to the University of
Le Havre Normandie from Normandie University (NU) for
technical help. Crystal structures were solved with the support of
the MSVVaS of the Slovak Republic within the Research and
Development Operational Programme for the project "University
Science Park of STU Bratislava" (ITMS project no.
26240220084) cofounded by the European Regional
Development Fund.
3-(1H-indol-3-yl)-1-(1-phenylethyl)-1H-pyrrole-2,5-dione
(28ca)
was
obtained as yellow crystalline solid (237mg, 83 %) m.p = 162-164 °C,
1
[α]D25 = -9,5 ° ( MeOH, c = 0,3). H NMR (CDCl3) δ = 8.67 (bs, 1H), 8.38
(d, J = 2.9 Hz, 1H), 7.79 – 7.72 (m, 2H), 7.49 (m, 2H), 7.45 – 7.39 (m,
1H), 7.38 – 7.22 (m, 6H), 6.60 (s, 1H), 5.46 (q, J = 7.3 Hz, 1H), 1.89 (d, J
= 7.3 Hz, 3H). 13C NMR (CDCl3) δ = 172.0, 171.6, 140.7, 138.9, 136.2,
130.1, 128.5, 127.5, 127.2, 125.8, 123.7, 122.2, 120.2, 115.6, 112.0,
106.8, 49.2, 17.7. HRMS (HESI): m/z [M+H]+ calculated for C20H16N2O2
(317.12900), found 317.12839.
Keywords: Asymmetric synthesis • Multicomponent Reactions
(MCRs) • Mannich reaction • Indolylglycines • Spiroindolenines •
Indolylmaleimides
3-(1H-Indol-3-yl)-1-phenethyl-1H-pyrrole-2,5-dione (28da). To the
mixture of methyl 2-(1H-indol-3-yl)-2-(phenethylamino)acetate (29d)
(1.06 g; 3.44 mmol) and propylene oxide (3. g; 51.6 mmol) in THF (28
mL) at 0 °C was added chloracetyl chloride (429 mg; 3.8 mmol) in THF (9
mL). The reaction mixture was stirred at room temperature for 30 minutes
and concentrated under reduced pressure. The residue was extracted
with DCM and NaHCO3 (aq.), dried over MgSO4, filtered off and
evaporated under vacuum. The crude product was triturated with hexane
(15 mL) and Et2O (2 mL) and the precipitated product was filtered off,
washed with hexane (10 mL) and Et2O (2 mL). The corresponding methyl
2-(2-chloro-N-phenethylacetamido)-2-(1H-indol-3-yl)acetate (26da) was
obtained as white solid (1.06 g, 80%). m.p = 142-144 °C. HRMS (HESI):
m/z [M+H]+ calculated for C21H21ClN2O3 (385.13190), found 385.13164.
26da (384.86 mg; 1 mmol) was dissolved in THF (5 ml) and NaH (88 mg;
2.2 mmol; 60 % dispersion in mineral oil) was added and reaction mixture
was stirred at RT for 10 minutes. The reaction was quenched by diluting
with NaHCO3 (0.5 ml) and DCM (20 mL), dried over MgSO4, filtered off
and evaporated under vacuum. The crude product was purified by flash
chromatography (DCM 100 %). The corresponding 3-(1H-indol-3-yl)-1-
phenethyl-1H-pyrrole-2,5-dione (28da) was obtained as yellow crystalline
solid (250 mg, 79 %) m.p = 139-142 °C. 1H NMR (DMSO) δ 12.05 (bs,
1H), 8.37 (s, 1H), 7.96 (d, J = 7.4 Hz, 1H), 7.53 (d, J = 7.4 Hz, 1H), 7.34
– 7.06 (m, 7H), 6.84 (s, 1H), 3.70 (t, J = 7.3 Hz, 2H), 2.88 (t, J = 7.3 Hz,
2H). 13C NMR (DMSO) δ 171.7, 171.3, 138.8, 138.4, 136.7, 131.1, 128.7,
128.4, 126.4, 125.5, 123.1, 121.5, 120.4, 113.9, 112.6, 105.4, 38.5, 33.9.
HRMS (HESI): m/z [M+H]+ calculated for C20H16N2O2 (317.12900), found
317.12816.
[1]
a) M. Bandini, A. Eichholzer, Angew. Chem. Int. Ed. 2009, 48, 9608–
9644; b) M. Ishikura, T. Abe, T. Choshi, S. Hibino, Nat. Prod. Rep. 2013,
30, 694–752; c) H. Gao, Q.-L. Xu, M. Yousufuddin, D. H. Ess, L. rti,
Angew. Chem. Int. Ed. 2014, 53, 2701–2705 and the references cited
therein.
[2]
[3]
[4]
a) H. J. n lker, K. R. Reddy, Chem. Rev. 2002, 102, 4303–4427; b) A.
W. Schmidt, K. R. Reddy, H.-J. n lker, Chem. Rev. 2012, 112, 3193–
3328; c) J. Bariwal, L. G. Voskressensky, E. V. Van der Eycken, Chem.
Soc. Rev. 2018, 47, 3831–3848.
a) M. E. Welsch, S. A. Snyder, B. R. Stockwell, Curr. Opin. Chem. Biol.
2010, 14, 347–361; b) C.-X. Zhuo, W. Zhang, S.-L. You, Angew. Chem.
Int. Ed. 2012, 51, 12662–12686; c) C. Zheng, S.-L. You, Nat. Prod.
Rep. 2019, https://doi. 10.1039/c8np00098k.
For interesting examples, see: a) P. D. Davis, C. H. Hill, E. Keech, G.
Lawton, J. S. Nixon, A. D. Sedgwick, J. Wadsworth, D. Westmacott, S.
E. Wilkinson, FEBS Lett. 1989, 259, 61–63; b) G. W. Gribble, S. J.
Berthel, in Studies in Natural Product Chemistry (Ed.: Atta-ur-Rahman),
Elsevier, Amsterdam, 1993, vol. 12, pp. 365–409; c) M. Gaßel, C. B.
Breitenlechner, N. König, H. Huber, R. A. Engh, D. Bossemeyer, J. Biol.
Chem. 2004, 279, 23679–23690 ; d) L. Bouissane, J. P. Sestelo, L. A.
Sarandeses, Org. Lett. 2009, 11, 1285–1288; e) Y.-L. An, Z.-H. Yang,
H.-H. Zhang, S.-Y. Zhao, Org. Lett. 2016, 18, 152–155.
[5]
a) K. Dodo, M. Katoh, T. Shimizu, M. Takahashi, M. Sodeoka, Bioorg.
Med. Chem. Lett. 2005, 15, 3114–3118; b) S. Mahboobi, E. Eichhorn, A.
Popp, A. Sellmer, S. Elz, U. Möllmann, Eur.J. Med. Chem. 2006, 41,
176–191; c) C. Peifer, T. Stoiber, E. Unger, F. Totzke, C. Schächtele, D.
Marmé, R. Brenk, G. Klebe, D. Schollmeyer, G. Dannhardt, J. Med.
Chem. 2006, 49, 1271–1281; d) D. E. Levy, D.-X. Wang, Q. Lu, Z.
Chen, J. Perumattam, Y.-J. Xu, A. Liclican, J. Higaki, H. Dong, M.
Laney, B. Mavunkel, S. Dugar, Bioorg. Med. Chem. Lett. 2008, 18,
2390–2394; e) M. E. McDonnell, H. Bian, J. Wrobel, G. R. Smith, S.
Liang, H. Ma, A. B. Reitz, Bioorg. Med. Chem. Lett. 2014, 24, 1116–
1121; f) E. Pereira, A. Youssef, M. El-Ghozzi, D. Avignant, J. Bain, M.
Prudhomme, F. Anizon, P. Moreau, Tetrahedron Lett. 2014, 55, 834-–
837.
1-Allyl-3-(1H-indol-3-yl)-1H-pyrrole-2,5-dione (28ea). Following the
analogy as for 28ba, substrate 26ea (352.85 mg; 1.1 mmol) delivered
compound 28ea and the crude product was purified by flash
chromatography (DCM 100 %). The corresponding 1-allyl-3-(1H-indol-3-
yl)-1H-pyrrole-2,5-dione (28ea) was obtained as yellow crystalline solid
(196.5 mg, 73 %) m.p = 154-155 °C. 1H NMR (DMSO) δ = 12.06 (bs, 1H),
8.40 (d, J = 2.6 Hz, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H),
7.35 – 7.09 (m, 2H), 6.93 (s, 1H), 5.92 – 5.78 (m, 1H), 5.17 – 5.04 (m,
2H), 4.12 – 4.06 (m, 2H). 13C NMR (DMSO) δ = 171.4, 171.1, 138.9,
136.7, 132.9, 131.2, 125.5, 123.1, 121.5, 120.4, 116.0, 113.9, 112.6,
105.5, 39.2. HRMS (HESI): m/z [M+H]+ calculated for C15H12N2O2
(253.09770), found 253.09721.
[6]
[7]
a) M. F. Denning, Y. Wang, B. J. Nickoloff, T. Wrone-Smith, J. Biol.
Chem. 1998, 273, 29995–30002; b) A. Basu, Mol. Pharmacol. 1998, 53,
105–111; c) D. Brehmer, K. Godl, B. Zech, J. Wissing, H. Daub, Mol.
Cell. Proteomics 2004, 3, 490–500; d) G. Szanda, P. Koncz, A. Rajki,
A. Spät, Cell Calcium 2008, 43, 250–259.
a) G. H. Zhu, B. C. Y. Wong, M. C. Eggo, S. T. Yuen, K. C. Lai, S. K.
Lam, Dig. Dis. Sci. 1999, 44, 2020–2026; b) Z. Han, P. Pantazis, T. S.
Lange, J. H. Wyche, E. A. Hendrickson, Cell Death Differ. 2000, 7,
521–530; c) R. T. Snowden, X. M. Sun, M. J. S. Dyer, G. M. Cohen,
Leukemia 2003, 17, 1981–1989; d) B. Pajak, A. Turowska, A.
Orzechowski, B. Gajkowska, Apoptosis 2008, 13, 509–522.
Acknowledgements
B.F is thankful to Dr. Oľga Caletková for valuable discussions
during solving and interpreting the NMR spectra and to Dr.
Michal Šoral for measuring the complex rotamer NMR-spectra.
This research was supported by Slovak Research and
Development Agency under contract No. APVV-16-0258 and
[8]
a) C.-W. Chiu, T. J. Chow, C.-H. Chuen, H.-M. Lin, Y.-T. Tao, Chem.
Mater. 2003, 15, 4527–4532; b) M. Nakazono, S. Nanbu, A. Uesaki, R.
Kuwano, M. Kashiwabara, K. Zaitsu, Org. Lett. 2007, 9, 3583–3586; c)
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900814
European Journal of Organic Chemistry
FULL PAPER
M. Nakazono, A. Jinguji, S. Nanbu, R. Kuwano, Z. Zheng, K. Saita, Y.
Oshikawa, Y. Mikuni, T. Murakami, Y. Zhao, S. Sasaki, K. Zaitsu, Phys.
Chem. Chem. Phys. 2010, 12, 9783–9793; d) Y. S. Lee, Z. Lin, Y. Y.
Chen, C. Y. Liu, T. J. Chow, Org. Electron. 2010, 11, 604–612; e) A. C.
Schmöle, A. Brennführer, G. Karapetyan, R. Jaster, A. Pews-Davtyan,
R. Hübner, S. Ortinau, M. Beller, A. Rolfs, M. J. Frech, Bioorg. Med.
Chem. 2010, 18, 6785–6795.
Narendra Babu, G. R. Srinivasa, D. C. Santhosh, D. Channe Gowda, J.
Chem. Res. 2004, 66-67.
[21] For recent review on spirocyclization, see: J. Bariwal, L. G.
Voskressensky, E. V. Van der Eycken, Chem. Soc. Rev. 2018, 47,
3831–3848.
[22] For example, see: S. Lakhdar, M. Westermaier, F. Terrier, R. Goumont,
T. Boubaker, A. R. Ofial, H. Mayr, J. Org. Chem. 2006, 71, 9088–9095.
[23] For general review on spiro-oxindole compounds, see: a) A. Ding, M.
Meazza, H. Guo, J. W. Yang, R. Rios, Chem. Soc. Rev. 2018, 47,
5946–5996; b) M. J. James, P. O’Brien, R. J. K. Taylor, W. P.
Unsworth, Chem. Eur. J. 2016, 22, 2856–2881; c) J. M. Smith, J.
Moreno, B. W. Boal, N. K. Garg, Angew. Chem. Int. Ed. 2015, 54, 400–
412; d) C. Tsukano, Y. Takemoto, Heterocycles 2014, 89, 2271–2302;
e) E. M. Carreira, T. C. Fessard, Chem. Rev. 2014, 114, 8257–8322.
[24] For recent examples, see: a) A. K. Gupta, M. Bharadwaj, A. Kumar, R.
[9]
a) M. Johannsen, Chem. Commun. 1999, 2233–2234; b) M. J. Wanner,
P. Hauwert, H. E. Schoemaker, R. D. de Gelder, J. H. Van Maarseveen,
H. Hiemstra, Eur. J. Org. Chem. 2008, 180–185; c) H. Ube, S. Fukuchi,
M. Terada, Tetrahedron: Asymmetry 2010, 21, 1203–1205; d) X.-W.
Wang, Y.-Z. Hua, M.-C. Wang, J. Org. Chem. 2016, 81, 9227–9234; e)
B. Jiang, Z.-G. Huang, Synthesis 2005, 2198–2204; f) T. Andreassen, L.
K. Hansen, O. R. Gautun, Eur. J. Org. Chem. 2008, 4871–4876; g) D.-
U. Ji, M.-H. Xu, Chem. Commun. 2010, 46, 1550–1552; h) K. Goswami,
I. Duttagupta, S. Sinha, J. Org. Chem. 2012, 77, 7081–7085.
Mehrotra,
Top.
Curr.
Chem.
2017,
375,
3.
[10] M. L. Murat-Onana, C. Berini, J.-N. Denis, J.-F. Poisson, F. Minassian,
N. Pelloux- Léon, Eur. J. Org. Chem. 2014, 3773–3776.
[11] D. Lin, J. Wang, X. Zhang, S. Zhou, J. Lian, H. Jiang, H. Liu, Chem.
Commun. 2013, 49, 2575–2577.
https://doi.org/10.1007/s41061-016-0089-0; b) C. Sheng, G. Dong, Z.
Miao, W. Zhang, W. Wang, Chem. Soc. Rev. 2015, 44, 8238–8259.
[25] W. Chen, X.-D. Yang, W.-Y. Tan, X.-Y. Zhang, X.-L. Liao, H. Zhang,
Angew. Chem. Int. Ed. 2017, 56, 12327–12331.
[12] a) A. Janczuk, W. Zhang, W. Xie, S. Lou, J.-P. Cheng, P. G. Wang,
Tetrahedron Lett. 2002, 43, 4271–4274; b) N. Sakai, J. Asano, Y.
Shimano, T. Konakahara, Tetrahedron 2008, 64, 9208–9215; c) K.
Goswami, I. Duttagupta, S. Sinha, J. Org. Chem. 2012, 77, 7081–7085;
d) Z. Xu, X. Yu, X. Feng, M. Bao, Beilstein J. Org. Chem. 2012, 8,
1564–1568; e) Li, J.-T.; Sun, S.-F.; Sun, M.-X. Ultrason. Sonochem.
2011, 18, 42-44; f) Xie, L.-H.; Cheng, J.; Luo, Z.-W.; Lu, G. Tetrahedron
Lett., 2018, 59, 457-461.
[26] a) C. N. Teijaro, S. Zhao, P. Kokkonda, R. B. Andrade, Org. Lett. 2015,
47, 1547–1556; b) G. Sirasani, R. B. Andrade, Org. Lett. 2011, 13,
4736–4737; c) G. Sirasani, T. Paul, W. Jr. Dougherty, S. Kassel, R. B.
Andrade, J. Org. Chem. 2010, 75, 3529–3532; d) G. Sirasani, R. B.
Andrade, Org. Lett. 2009, 11, 2085–2088.
[27] S. Munagala, G. Sirasani, P. Kokkonda, M. Phadke, N. Krynetskaia, P.
Lu, F. J. Sharom, S. Chaudhury, M. D. M. Abdulhameed, G. Tawa, A.
Wallqvist, R. Martinez, W. Childers, M. Abou-Gharbia, E. Krynetskiy, R.
B. Andrade, Bioorg. Med. Chem. 2014, 22, 1148–1155.
[13] For Mannich’s 3CR type in this area, see: a) M. Ghandi, A. Taheri,
Molecules 2009, 14, 1056–1061; b) B. Jiang, C.-G. Yang, H.-H. Gu,
Tetrahedron Lett. 2001, 42, 2545-–2547; c) Q. Kang, Z.-A. Zhao, S.-L.
You, Tetrahedron 2009, 65, 1603–1607.
[28] M. Šoral, J. Markus, J. Doháñošová, S. Šoralová, D. Dvoranová, A.
Chyba, J. Moncol, D. Berkeš, T. Liptaj, J. Mol. Struct. 2017, 1128, 230–
238.
[14] A. olarovič, D. Berkeš, P. Baran, F. Považanec, Tetrahedron Lett.
2005, 46, 975–978 and the refrences cited therein.
[29] Crystal Data for C13H14N2O2 (25b) (M =230.26 g/mol): monoclinic,
space group P21/c (no. 14), a = 11.2021(4) Å, b = 7.1357(3) Å, c =
13.7312(6) Å, β = 99.688(3)°, V = 1081.95(8) Å3, Z = 4, T = 100 , μ(Cu
α) = 0.788 mm-1, Dcalc = 1.414 g/cm3, 14722 reflections measured
(8.006° ≤ 2Θ ≤ 143.356°), 2079 unique (Rint = 0.0597, Rsigma = 0.0538)
which were used in all calculations. The final R1 was 0.0401 (I>2.0σ(I))
and wR2 was 0.0965 (all data). CCDC no. 1912331.
[15] D. Enders, M. Seppelt, T. Beck, Adv. Synth. Catal. 2010, 352, 1413–
1418.
[16] N. Singh, R. D. Anand, S. Trehan, Tetrahedron Lett. 2004, 45, 2911–
2913.
[17] Crystal
g/mol): monoclinic, space group P21 (no. 4), a = 11.1461(2) Å, b =
6.29540(10) Å, c = 12.2120(2) Å, β = 101.096(2)°, V =
840.89(3) Å3, Z = 2, T = 100 K, μ(Cu Kα) = 0.709 mm-1, Dcalc
1.289 g/cm3, 34703 reflections measured (7.38° ≤ 2Θ ≤ 143.04°), 2897
unique (Rint 0.0135, Rsigma 0.0051) which were used in all
Data for
C19H22N2O3 (12a∙MeOH)
(M =326.40
[30] For recent review, see: T. Janosik, A. Rannug, U. Rannug, N.
Wahlström, J. Slätt, J. Bergman, Chem. Rev. 2018, 118, 9058–9128.
[31] G. Gerona-Navarro, M. A. Bonache, R. Herranz, M. T. García-López, R.
González-Muñiz, Synlett 2000, 9, 1249–1252.
=
=
=
[32] a) L. Palatinus, G. Chapuis, J. Appl. Crystallogr. 2007, 40, 786–790; b)
G. M. Sheldrick, Acta Crystallogr. 2015, A71, 3–8.
calculations. The final R1 was 0.0315 (I>2.0σ(I)) and wR2 was 0.0810
(all data). CCDC no. 1912329.
[33] a) P. W. Betteridge, J. R. Carruthers, R. I. Copper, K. Prout, D. Watkin,
J. J. Appl. Crystallogr. 2003, 36, 1487–1487; b) G. M. Sheldrick, Acta
Crystallogr. 2015, C71, 3-8.
[18] Crystal
Data for
C20H24N2O3 (14∙MeOH)
(M =340.41
g/mol):
orthorhombic, space group P212121 (no. 19), a = 8.5965(3) Å, b =
10.2518(2) Å, c = 21.7025(5) Å, V = 1912.8963(9) Å3, Z = 4, T = 295 K,
μ(Cu α) = 0.642 mm-1, Dcalc
[34] O. Dolomanov, L. J. Bourhis, R. I. Gildea, J. A. K. Howard, J. Appl.
Crystallogr. 2009, 42, 339–341.
=
1.182 g/cm3, 107332 reflections
measured (8.148° ≤ 2Θ ≤ 143.238°), 3713 unique (Rint = 0.0269,
Rsigma = 0.0108) which were used in all calculations. The final R1 was
0.0325 (I>2.0σ(I)) and wR2 was 0.0905 (all data). CCDC no. 1912330.
[19] See for example, see: C. Cheng, J. Sun, L. Xing, J. Xu, X. Wang, Y. Hu,
J. Org. Chem. 2009, 74, 5671–5674 and the references cited therein.
[20] a) S. Ram, L. D. Spicer, Tetrahedron Lett. 1987, 28, 515–516; b) M. J.
Tike, V. V. Mahajani, Chem. Eng. J., 2006, 123, 31–41; c) S. N.
[35] a) R. W. W. Hooft, L. H. Straver, A. L. Spek, J. Appl. Crystallogr. 2008,
41, 96–103; b) R. I. Cooper, D. J. Watkin, H. D. Flack, Acta Crystallogr.
2016, C72, 261–267; c) S. Parsons, H. D. Flack, T. Wagner, Acta
Crystallogr. 2013, B69, 249–259.
[36] J. Bergman, E. Desarbre, E. Koch, Tetrahedron 1999, 55, 2363–2370.
[37] D. S. Cochin, M. I. Tranchepain, Org. Biomol. Chem. 2009, 7, 706–716.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900814
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
FULL PAPER
Spiroindolenine Systems
J. Markus, B. Ferko, D. Berkeš,* J.
Moncol, A. M. Lawson, M. Othman, and
A. Daïch*
Page No. – Page No.
A series of racemic and enantiopure 3-indolylglycines (3IGs), in high yields and
optical purity were reported via the simple and efficacious Mannich’s 3CR of
indole, free glyoxylic acid and primary or secondary aliphatic amines. A
multigram synthesis using (R)-PEA as chiral auxiliary was realized and the
resulting 3IGs were used to provide enantiopure 3,3-spiroindolenines, indolyl
tetracyclic hemiaminals and 3-indolylmaleimides in an unexpected pathway.
Indolylglycines backbones in the
synthesis
spiroindolenines, indolyl tetracyclic
hemiaminals and 3-indolyl-
maleimides frameworks
of
enantiopure
3,3-
This article is protected by copyright. All rights reserved.