Stereospecific N-acylation of indoles and corresponding microwave mediated synthesis of pyrazinoindoles using hexafluoroisopropanol

Article abstract of DOI:10.1016/j.tet.2021.132017

We envisioned a facile construction of diversified pyrazinoindoles by using 1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) as the solvent and catalyst, hence eliminating metal catalyzed routes for its development. The process is facilitated by HFIP that has emerged as a powerful tool for development of novel fused heterocycles. This cascade approach blends the asymmetric N-acylation with consecutive intramolecular cyclisation via Pictet-Spengler reaction as an efficient tool forming overall two stereogenic centers. Our approach deals with incorporation of L-amino acid on substituted indoles to provide the chiral N-acylated indole precursor followed by cyclisation to access pyrazinoindole derivatives in high enantiomeric excess up to >99% in good to excellent yields, which have great potential as molecular scaffolds in drug discovery. We have also described the mechanistic course of the reaction based on density functional theory.

Full text of DOI:10.1016/j.tet.2021.132017

Tetrahedron 84 (2021) 132017
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereospecific N-acylation of indoles and corresponding microwave
mediated synthesis of pyrazinoindoles using hexafluoroisopropanol
,
Aarushi Singh a, Snigdha Singh a b, Shubham Sewariya a, Nidhi Singh a, Prashant Singh c,
, f, *
Ajay Kumar d, Rakeshwar Bandichhor e, Ramesh Chandra a
a Laboratory of Drug Discovery and Development, Department of Chemistry, University of Delhi, Delhi, 110007, India
b Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, United Kingdom
c Department of Chemistry, Atma Ram Sanatan Dharma (ARSD) College, University of Delhi, New Delhi, 110021, India
d Department of Chemistry, Indian Institute of Technology (IIT), Delhi, 110016, India
e Dr. Reddy’s Laboratories, Limited, Innovation Plaza, IPDO Bachupally, Hyderabad, 500090, India
f Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We envisioned
a
facile construction of diversified pyrazinoindoles by using 1,1,1,3,3,3-
Received 30 November 2020
Received in revised form
31 January 2021
Accepted 5 February 2021
Available online 15 February 2021
Hexafluoroisopropanol (HFIP) as the solvent and catalyst, hence eliminating metal catalyzed routes for
its development. The process is facilitated by HFIP that has emerged as a powerful tool for development
of novel fused heterocycles. This cascade approach blends the asymmetric N-acylation with consecutive
intramolecular cyclisation via Pictet-Spengler reaction as an efficient tool forming overall two stereo-
genic centers. Our approach deals with incorporation of L-amino acid on substituted indoles to provide
the chiral N-acylated indole precursor followed by cyclisation to access pyrazinoindole derivatives in
high enantiomeric excess up to >99% in good to excellent yields, which have great potential as molecular
scaffolds in drug discovery. We have also described the mechanistic course of the reaction based on
density functional theory.
Keywords:
Hexafluoroisopropanol
Stereospecific
Pictet-spengler reaction
Microwave
© 2021 Elsevier Ltd. All rights reserved.
1. Introduction
Pyrazinoindoles are known to possess wide spectrum of biological
activities including receptor agonist, CNS depressant, protein ki-
Heterocycles bearing stereocenters are common structural
motifs in biologically active compounds [1] and over the year’s
various innovative synthetic methods for their synthesis have been
reported [2,3]. Approaches to synthesize nitrogen-containing
functionalities are of great importance [4,5], not only form the
view point of significant functional group but also owing to their
vast structural assortments to act as a versatile precursor in various
organic reactions [6]. Amongst the widely distributed fused indole
heterocycles in various alkaloids and natural product synthesis,
pyrazinoindoles are attractive targets for synthetic organic chem-
ists due to their biological activity and ubiquitous structural motifs
in natural products [7,8]. The enantiomerically reinforced indole-
based heterocycles have a crucial role in medicinal chemistry.
nase C inhibitor, antibacterial [9e12]. The most common laboratory
method used for the synthesis of these indole-based heterocyclic
scaffolds involves Pictet-Spengler reaction [13]. The Pictet-Spengler
cyclisation [14e17] provides an efficient synthetic method for the
synthesis of privileged pharmacophores [17] such as tetrahydro-b-
carbolines, tetrahydroisoquinolines or other polyheterocycles
[18e20].
Conventionally, the pyrazinoindoles was accessed by Nayak
et al. [21] from substituted allylamines and indole-2-
carboxaldehyde via saponification followed by Curtius rearrange-
ment. Recently, Wani et al. [22] described an elegant approach for
the synthesis of pyrazinoindoles via base mediated ring opening of
aziridine with 3-methyl indole followed by BF3$OEt2, MgSO4 cata-
lyzed cyclisation. However, applicability of these approaches ad-
dresses some issue related to multistep procedure, harsh reaction
condition, use of catalyst, thereby limiting their applicability in
synthetic chemistry. These challenges are often compounded by
socio-economic consequences, however advances in synthetic
* Corresponding author. Dr. B.R. Ambedkar Center for Biomedical Research,
University of Delhi, Delhi, 110007, India.
E-mail addresses: rameshchandragroup@gmail.com, acbrdu@hotmail.com
(R. Chandra).
https://doi.org/10.1016/j.tet.2021.132017
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

A. Singh, S. Singh, S. Sewariya et al.
Tetrahedron 84 (2021) 132017
organic chemistry offer a realistic means to access such bioactive
scaffolds. Despite these elegant developments, exploration of new
methods that enables direct access to novel fused indoles from
readily available cheap feed stocks would remain highly desirable.
Microwave assisted chemistry has provided an alternate
method to conventional synthesis and it is rapidly growing field for
organic chemist due to short reaction time, higher yields, high
purity products [23]. In the past decade, use of catalyst has
exhibited large capacity of complex molecules with good tolerance
of functional groups. Although, the use of hexafluoroisopropanol in
organic synthesis has become a powerful tool for the development
of multicyclic scaffolds [24], and therefore we have eliminated the
use of harsh reaction conditions with use of this solvent [25].
Moreover, the hydrogen bonding ability of HFIP along with its
enhanced acidity has played an integral part in boosting the reac-
tivity. Whilst scrutiny of various solvent for the cyclisation, HFIP
plays a vital role in stimulating cyclisation of pyrazinoindoles
through microwave mediated synthesis. The use of HFIP as a sol-
vent for the cyclisation came out as a result of strenuous optimi-
zation of various acid catalysts rather than
a pre-planned
investigation [26]. Several examples are known in the literature for
the use of HFIP as a solvent but it sometimes plays a dual role where
HFIP has deeper significance under the reaction protocol apart from
its use as a solvent without using additional acid catalyst [27e29].
In spite of lacking proper explanation regarding the role of HFIP in
the reaction mechanism, this work would pave the way for efficient
development of indole-based scaffolds.
Considering the shortcomings in the existing procedures to
access these for the synthesis of pyrazinoindoles and pioneering
achievements of pyrazinoindoles in the field of medicinal chemis-
try [30e32]. The enantioselective N-acylation of indole has been a
grueling task owing to the innate high nucleophilicity at C-3 posi-
tion and feeble acidity of the NeH bond of the indole nucleus.
Therefore, the identification of safe, efficacious, and ecologically
sound strategies to achieve the N-acylation of indole accounts for
an imperative challenge. Interestingly, HFIP promoted cyclisation
has eliminated the use of lewis acid catalyst, Brønsted acid and led
to the streamlined synthesis of pyrazinoindoles in excellent yields.
Following a discussion of the existing state of the art, we aim to
develop operationally straightforward, one pot, metal-free and an
efficient microwave assisted route to access diastereomeric pyr-
azinoindole derivatives 4 using HFIP as a solvent via Pictet-Spengler
reaction.
Fig. 1. Previous work and our finding.
in presence of acetic acid [35], which was easily coupled with N-boc
protected amino acid using common coupling reagents. After
obtaining the desired coupled product 2(aec), we aromatized our
indoline nucleus using DDQ that afforded our desired precursor
3(aec), which was purified using column chromatography and
obtained in good yields [36] (Scheme 1).
We started to optimize our final step with the reaction of N-boc
protected amine 3a and 4-nitro benzaldehyde to obtain cyclized
product 4a as depicted in Table 1. We first commenced our reaction
by deprotection of the boc protected chiral amines followed by the
reaction of chiral amine (1.0 equiv.) and benzaldehyde (1.0 equiv.)
in presence of PTSA (1.2 equiv.) as catalyst in DCE at rt for 2 h to
obtain 4a but unfortunately no product formation was observed
(Table 1, entry 1). Then, amine (1.0 equiv.) & benzaldehyde (1.0
equiv.) was subjected to 20% acetic acid in MeOH at rt, but we
couldn’t see product formation even during reflux.
2. Result and discussion
In 2006, Tiwari group [33] reported the stable one-pot synthesis
of pyrazinoindole from indolyl ethylamine by reacting with alde-
hydes in presence of lewis acids. Another appealing route to Pyr-
azinoindole was reported by Padwa group [34] via the gold-
catalyzed intramolecular reaction of alkynes (Fig. 1). A third
approach, disclosed by the Wani group, again features the con-
struction of pyrazinoindole via base mediated ring opening of
aziridines Inspired by these findings, we started our synthesis using
readily available feedstock to access pyrazinoindoles.
2.1. Optimization of reaction conditions
Thereafter we charged our reaction vial with amine, benzalde-
hyde and dissolved in DCM at rt in presence of AlCl3 and catalytic
amount of benzotriazole for 12 h and the corresponding pyr-
azinoindole derivative 4a was formed in 18% yield (Table 1, entry 3).
To improve the reaction yield, we altered reaction parameters like
lewis acid, solvent, temperature and screening of solvents which
could led us to HFIP. Due to outstanding feature of HFIP, it could
Our synthetic journey commenced with N-acylation of 3-methyl
indole by incorporating amino acids. To achieve an efficient route
for N-acylation of 3-methyl indole, several conditions were
screened. During the initial attempt, 3-methyl indole was coupled
with N-boc protected amino acid using different coupling reagent.
To access pyrazinoindoles, we reduced indole/3-methyl indole to
indoline/3-methyl indoline 1(a,b) using sodium cyanoborohydride
2

A. Singh, S. Singh, S. Sewariya et al.
Tetrahedron 84 (2021) 132017
Scheme 1. Synthesis of N-acylated chiral amines 3(aec) from Indoles and L-amino acids.
Table 1
Optimization of the one-pot reaction to access pyrazinoindole 4a.
Entry
Reaction Conditions
Product 4a (%)
1.
2.
3.
4.
5.
6.
7.
20%TFA in DCM; PTSA (1.2 equiv.), DCE, rt/reflux, 2e12 h
20%TFA in DCM; MeOH, Acetic acid (20 mol%), rt/reflux, 2e12 h
20%TFA in DCM; cat. amt. AlCl3, Benzotriazole (1.0 equiv.), DCM, rt, 12 h
20%TFA in DCM; cat. amt. AlCl3, Benzotriazole (1.0 equiv.), DCM, 60 ꢀC, 12 h
HFIP, rt, 24 h
NRa
NRa
18%
NRa
NRa
80
HFIP, reflux, 12 h
HFIP, 60e65 ꢀC, MW, 40 min
92
a
NR: no reaction.
easily perform the deprotection of the N-Boc group, simultaneously
performs cyclisation [37]. Therefore HFIP at refluxing temperature
for 12 h yielded 80% product as a single diastereomer (Table 1, entry
6). Encouraged by this result, the similar conditions were employed
under microwave irradiation for 40 min which led to improved
yield (Table 1, entry 7).
product. However, it is important to note that electron withdrawing
groups on the aryl aldehyde significantly facilitate the reaction; the
final products were obtained in high yields (Scheme 2, entries 1e4,
6). The reaction was found less sensitive to substitution at all ring
positions of the aryl aldehyde, with the shortest reaction times
observed for para substituted aryl aldehydes (entry 1).
The result of a brief survey of the generality & scope of this one-
pot process with chiral amine and aryl aldehyde are summarized in
Table 1. The final product was characterized using spectroscopic
data and further using X-ray crystal analysis, as depicted in Scheme
2.
The pyrazinoindole derivatives were also accessed from L-boc
alanine amino acid, the desired product were obtained here as a
mixture of diastereomers in good yields. The corresponding pyr-
azinoindoles 4(AeE) were synthesized by series of aryl aldehydes
in good yields with diastereomeric ratio up to 2:1. The dr ratios
calculated from 1H NMR spectroscopic technique are summarized
in Scheme 3.
2.2. Substrate scope
With the optimized reaction conditions in hand, we investigated
the substrate scope of reaction using the aryl aldehyde bearing both
electron donating groups (Me, OMe) and electron withdrawing
group (nitro, flouro, chloro, bromo) for the synthesis of various
substituted pyrazinoindoles in good yields.
Interestingly, we found that electron withdrawing substituents
at ortho, para or meta positions of aryl aldehydes (Scheme 2, entries
1e4) and electron-donating (Scheme 2, entry 5) at para position
were well tolerated, producing the cyclized products 4(a-g) &4(a’-
e’) in moderate to good yields. Unfortunately, 4-
methoxybenzaldehyde (Scheme 2, entry 7) was found to be a
poor substrate under these conditions, although elevated temper-
atures and extended reaction times couldn’t acquire the desired
2.3. Mechanism based on DFT calculations
Authors have tried to propose the mechanism for the formation
of the compounds as shown in Scheme 4 based on the DFT
approach using Gaussian 9.0. According to our observation, the
HFIP initiated the reaction by deprotecting the chiral amine and
then free amine attacks on aryl aldehydes generating the corre-
sponding iminium ion, which undergoes cyclisation to give pair of
diastereomers by the rotation of the C]N bond. The boat like
transition state P is bound to attack through C-2 of the indole ring
on the prochiral C]N bond in 6-endo-trig approach via two
pathways re- and si-face intramolecular nucleophilic attack.
Herein, intermediate P is used to understand the re face and si
3

A. Singh, S. Singh, S. Sewariya et al.
Tetrahedron 84 (2021) 132017
while
A
gives an intermediate with
a
free energy change
of ꢁ3.4 kcal/mol showing exothermic character. Further, B and A
gives 4 and 400 with free energy change of 349 and 346 kcal/mol
respectively. Based on DFT calculations, the fast formation of
transition state B (re-face attack) is considered favourable where
bulky 1,3- substituents are there in pseudoequatorial orientation
that avoids the destabilization caused due to 1,3 diaxial in-
teractions, leading to the major 1,3 cis diastereomer 4. On the other
hand the si-face attack produces less favourable species A, due to
destabilization caused by 1,3 diaxial interaction between bulky
groups which explains the formation of minor 1,3 trans diaste-
reomer 4”. However both the diastereomers are formed in case of
X ¼ CH3 due to less steric hindrance in comparison to bulky
X ¼ CH2Ph group which results in the single diastereomeric
product.
Even, the intermediate obtained from B has high HOMO-LUMO
gap than for A, therefore, considered more stable and more reac-
tive. Based on this data, it is proposed that 4 is more favourable than
the 4”
3. Experimental section
3.1. Materials
Solvents and reagents were purchased from commercial sources
and used without purification for the experiments. Reactions using
microwave were run in a closed vial applying a dedicated CEM-
Discover monomode microwave apparatus operating at a fre-
quency of 2.45 GHz with continuous irradiation power from 0 to
300 W (CEM Corporation, P.O. Box 200, Matthews, NC 28106). The
product purity was assayed using thin-layer chromatography (TLC)
on silica get pre-coated plates from Merck. Visualization was done
under UV lamp. Product samples in ethyl acetate were loaded on
TLC plates and developed in Ethyl acetate/Petroleum ether (1:9, v/
v). When slight impurities were detected by iodine vapour/UV light
visualization and ninhydrin stain compounds were further purified
thrice using column chromatography on neutral alumina gel (CDH).
Melting points were determined on Melting point machine
M ꢁ 560 (Buchi). Single crystals of shelx were used as supplied. A
suitable crystal was selected and mounted on a diffractometer. The
crystal was kept at a steady T ¼ 293(2) K during data collection. The
structure was solved and by using Olex2 [38] as the graphical
interface. The model was refined with olex2.refine 1.3-dev [39]
using full matrix least squares minimisation on F2. 1H and 13C nu-
clear magnetic resonance (NMR) spectra were recorded in CDCl3,
DMSO medium on a JEOL ECX-400P NMR at 400 MHz and 100 MHz,
respectively at USIC, University of Delhi, using TMS as an internal
Scheme 2. Scope for the Synthesis of pyrazinoindoles 4a using L-Phenylalanine based
chiral amines 3(a,b).
standard. Chemical shifts are expressed in ppm (d-scale) and
coupling constants (J) in Hz. Splitting patterns are described as
singlet (s), doublet(d), doublet of doublet (dd), triplet (t), quartet (q)
and multiplet (m). The high-resolution mass spectral data was
obtained using a Agilent Technology-6530, Accurate mass, Q-TOF
LCMS spectrometer at USIC, University of Delhi. Optical rotations
were measured on Rudolph Research analytical Autopol II using a
6.0 mL cell with a 100.0 mm path length at 25 ꢀC and are reported
Scheme 3. Scope for the Synthesis of pyrazinoindoles 4a using L-Alanine based chiral
amines 3c.
as [a
]D25 (concentration (c) in gm per 100 mL solvent).
face attack to the major and minor product. In case of re face attack,
P gives B, a transition state is hypothesized with a free energy
change of 5.3 kcal/mol, while in the case of si face attack on P, it
gives another hypothesized transition, A with a free energy change
of 9.9 kcal/mol (Fig. 2). The transition state, B found out to
favourable than A as lesser the free energy change indicate feasi-
bility of the reaction.
3.2. General experimental procedures
3.2.1. General experimental procedure for the synthesis of
compound 1
The 3-methyl indole/indole (1.0 equiv.) is dissolved in acetic
acid, then sodium cyanoborohydride (5.0 equiv.) was added portion
wise at 0 ꢀC and stirred for 3 h at rt under nitrogen atmosphere. The
Further, B gives a transition state with a free energy change of
0.0 kcal/mol indicating its endothermic character of the reaction
4

A. Singh, S. Singh, S. Sewariya et al.
Tetrahedron 84 (2021) 132017
Scheme 4. Plausible Mechanism for Formation of pyrazinoindoles.
completion of reaction was monitored using TLC and the reaction
mixture was washed with saturated aq. NaHCO3to neutral pH. The
resulting solution was extensively extracted by DCM and the
organic solution was washed with brine, dried (Na2SO4) and
concentrated in vacuo to afford 1 as thick oil.
pyrazinoindoles. The completion of reaction was confirmed using
TLC and work up was done by evaporating HFIP twice by adding
DCM on reduced pressure. Further it was washed with saturated
solution of bisulphite to remove excess of aldehyde. Thus crude
obtained was purified using column chromatography on neutral
alumina twice due to the presence of aliphatic impurities, we used
AR grade solvents throughout out our synthesis and compounds
were isolated at 4e6% EtOAc/Hexane to obtain final compounds 4
in fair to good yield.
3.2.2. General experimental procedure for the synthesis of
compound 2(a-c)
EDC.HCl (1.2 equiv.), N, N- diisopropylethylamine (2.5 equiv.)
were added to a solution of compound 1 (1.0 equiv.), L-boc-amino
acid (1.0 equiv.) and HOBt (1.2 equiv.) in dryDMF and stirred for 24 h
at rt under nitrogen. To the reaction mixture added EtOAc and the
organic solution was washed with water and brine, dried (Na2SO4)
and concentrated in vacuo. Purification by column chromatography
(silica gel, Hexane/EtOAc 95:5) afforded pure 2 as a white solid.
3.3. Spectroscopic data
3.3.1. tert-butyl(1-(3-methyl-1H-indol-1-yl)-1-oxo-3-
phenylpropan-2-yl)carbamate 3a
Melting Point: 128e131 ꢀC. 1H NMR (400 MHz, CDCl3)
d 8.40 (d,
J ¼ 7.9 Hz, 1H), 7.48 (d, J ¼ 7.1 Hz, 1H), 7.33 (m, J ¼ 13.7, 7.4, 3.7 Hz,
2H), 7.22e7.16 (m, 4H), 7.12e7.08 (m, 2H), 5.40 (d, J ¼ 8.8 Hz, 1H),
3.15 (m, J ¼ 64.2, 13.8, 6.4 Hz, 2H), 2.21 (s, 3H), 1.40 (s, 9H). 13C NMR
3.2.3. General experimental procedure to access the N-acylated
precursors 3(a-c)
(100 MHz, CDCl3)
d 169.98, 155.15, 135.65, 129.48, 128.59, 127.15,
To the solution of coupling product 2 (1.0 equiv.) in dried THF,
added DDQ (5.0 equiv.) and refluxed for 3e4 h. The completion of
reaction was monitored through TLC and the reaction mixture was
filtrated through Celite and concentrated over vacuo, purified by
column chromatography (silica gel, Hexane/EtOAc 95:5) afforded
pure 3 as a white solid.
125.46, 124.01, 121.20, 119.48, 118.99, 116.83, 80.27, 54.19, 39.68,
28.36, 9.77. HRMS (ESI-TOF) m/z: [MþNa]þ Calcd for C23H26N2O3Na
401.1840; found 401.1859. The enantiomeric excess (ee) was
determined using chiral HPLC analysis (CHIRALPAK IA column,
detection at 254 nm),
n
-hexane/ipropanol
¼
95:5, flow
rate ¼ 1 mL/min, tR (1) ¼ 7.64 min (minor), tR (2) ¼ 8.89 min
(major).
3.2.4. General experimental procedure to access pyrazinoindoles
4(a-g); 4(a’-f’); 4(A-E)
The designed pyrazinoindoles 4 will be synthesized by using
modified Pictet-Spengler reaction. For this, the compound 3(aec)
(1.038 mmol, 1.0 equiv.) was taken in a clean and dried microwave
vial and was charged with minimum amount of HFIP (1 mL) fol-
lowed by addition of aryl aldehydes (1.038 mmol, 1.0 equiv.). The
reaction mixture was set at 60 ꢀC for 40 min to obtain final
3.3.2. tert-butyl(1-(1H-indol-1-yl)-1-oxo-3-phenylpropan-2-yl)
carbamate 3b
Melting Point: 99e102 ꢀC. 1H NMR (400 MHz, CDCl3)
d 8.40 (d,
J ¼ 8.2 Hz, 1H), 7.53 (d, J ¼ 7.6 Hz, 1H), 7.33 (m., J ¼ 34.2, 21.3, 5.4 Hz,
3H), 7.23 (s, 2H), 7.19 (d, J ¼ 6.6 Hz, 2H), 7.08 (d, J ¼ 7.5 Hz, 2H), 6.58
(d, J ¼ 3.8 Hz, 1H), 5.41e5.23 (m, 2H), 3.23 (m, J ¼ 13.7, 6.3 Hz, 1H),
5

A. Singh, S. Singh, S. Sewariya et al.
Tetrahedron 84 (2021) 132017
Fig. 2. DFT approach to understand the feasibility of re-/si-attack and structures of the intermediates and transition states. Color scheme: N: blue; Cl: green; O: red.
3.06 (m, J ¼ 13.8, 6.2 Hz, 1H), 1.39 (s, 9H). 13C NMR (100 MHz, CDCl3)
3.3.4. 3-Benzyl-10-methyl-1-(4-nitrophenyl)-2,3-dihydropyrazino
[1,2-a]indol-4(1H)-one 4a
d
170.50, 155.15, 135.75, 135.57, 130.62, 129.46, 128.66, 127.22,
125.42, 124.27, 121.02, 116.81, 110.17, 80.35, 54.29, 39.65, 28.37.
HRMS (ESI-TOF) m/z: [MþH]þ Calcd for C22H24N2O3 365.1865;
found 365.1851.
Melting Point: 138e140 ꢀC. 1H NMR (400 MHz, CDCl3)
d 8.47 (dd,
J ¼ 8.0, 2.8 Hz, 1H), 8.12 (d, J ¼ 5.2 Hz, 2H), 7.50 (d, J ¼ 7.4 Hz, 1H),
7.42e7.32 (m, 4H), 7.30e7.25 (m, 3H), 7.24 (d, J ¼ 3.7 Hz, 3H), 5.57
(s, 1H), 3.73 (s, 1H), 3.45e3.23 (m, 2H), 2.05 (d, J ¼ 3.0 Hz, 3H). 13
C
NMR (100 MHz, CDCl3)
d 168.63, 147.72, 145.91, 136.98, 134.70,
131.32, 130.39, 129.60, 128.82, 128.66, 127.13, 125.50, 124.40, 123.97,
118.68, 116.61, 114.12, 55.65, 52.12, 35.85, 8.61. HRMS (ESI-TOF) m/z:
[MþH]þ Calcd for C25H21N3O3 412.1661; found 412.1648. The
enantiomeric excess (ee) was determined using chiral HPLC anal-
ysis (CHIRALPAK IA column, detection at 254 nm), n-hexane/
3.3.3. tert-butyl(1-(3-methyl-1H-indol-1-yl)-1-oxopropan-2-yl)
carbamate 3c
Melting Point: 101e103 ꢀC. 1H NMR (400 MHz, CDCl3)
d 8.42 (d,
J ¼ 7.9 Hz, 1H), 7.52e7.47 (m, 1H), 7.39e7.33 (m, 1H), 7.31 (dd,
ipropanol ¼ 95:5, flow rate ¼ 1 mL/min, tR (1) ¼ 10.44 min (minor),
25
J ¼ 7.5, 1.1 Hz,1H), 7.29e7.26 (m, 1H), 5.47 (d, J ¼ 8.1 Hz,1H), 5.07 (p,
tR (2) ¼ 12.43 min (major). [
a
]
¼ ꢁ98.98 (c ¼ 0.5, CHCl3).
D
J ¼ 7.1 Hz, 1H) 2.27 (s, 3H), 1.50 (d, J ¼ 7.0 Hz, 3H), 1.44 (s, 9H). 13
C
NMR (100 MHz, CDCl3)
d 171.33, 155.18, 136.14, 131.63, 125.53,
123.99, 121.13, 119.66, 119.02, 116.85, 80.22, 48.95, 28.42, 19.80,
9.85. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for C17H22N2O3 303.1708;
found 303.1702.
3.3.5. 3-Benzyl-10-methyl-1-(2-nitrophenyl)-2,3-dihydropyrazino
[1,2-a]indol-4(1H)-one 4b
Melting Point: 168e170 ꢀC. 1H NMR (400 MHz, CDCl3)
d 8.45 (d,
6

A. Singh, S. Singh, S. Sewariya et al.
Tetrahedron 84 (2021) 132017
J ¼ 8.0 Hz, 1H), 7.81 (dd, J ¼ 7.7, 0.9 Hz, 1H), 7.44 (d, J ¼ 7.5 Hz, 1H),
7.40e7.25 (m, 4H), 7.16 (m, J ¼ 12.9, 5.2 Hz, 3H), 7.08 (d, J ¼ 6.8 Hz,
2H), 6.79 (d, J ¼ 7.4 Hz,1H), 6.07 (s,1H), 3.48 (s,1H), 3.16 (m, J ¼ 21.3,
3.3.10. 3-Benzyl-1-(4-nitrophenyl)-2,3-dihydropyrazino[1,2-a]
indol-4(1H)-one 4a’
Melting Point: 144e146 ꢀC. 1H NMR (400 MHz, CDCl3)
d 8.28 (d,
14.0, 5.9 Hz, 2H), 1.96 (s, 3H). 13C NMR (100 MHz, CDCl3)
d
168.78,
J ¼ 8.6 Hz, 1H), 7.66 (d, J ¼ 1.8 Hz, 1H), 7.43 (d, J ¼ 10.1 Hz, 2H), 7.23
(d, J ¼ 12.0 Hz, 2H), 7.19 (s, 4H), 7.09 (s, 3H), 6.51 (d, J ¼ 3.8 Hz, 1H),
5.30 (d, J ¼ 20.0 Hz, 2H), 3.15 (dd, J ¼ 42.1, 6.4 Hz, 3H). 13C NMR
149.41, 136.78, 134.66, 133.75, 132.57, 131.18, 130.48, 129.88, 129.52,
129.28, 128.80, 127.01, 125.59, 125.39, 124.33, 118.68, 116.62, 114.18,
55.66, 49.35, 35.82, 8.37. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for
(100 MHz, CDCl3) d 170.20, 155.34, 142.39, 136.38, 131.85, 129.66,
25
C
25H21N3O3 412.1661; found 412.1612. [
a
]
¼ ꢁ279.09 (c ¼ 0.5,
129.64, 129.62, 129.60, 129.58, 129.54, 129.52, 129.49, 129.47,
129.45, 129.44, 128.60, 127.51, 127.05, 124.67, 124.33, 117.52, 54.32,
D
CHCl3).
47.87, 40.03. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for C24H19N3O3
25
398.1426; found 398.1499. [
a
]
¼ ꢁ48.13 (c ¼ 0.5, CHCl3).
D
3.3.6. 3-Benzyl-1-(4-chlorophenyl)-10-methyl-2,3-
dihydropyrazino[1,2-a]indol-4(1H)-one 4c
Melting Point:150e152 ꢀC.1H NMR (400 MHz, CDCl3)
3.3.11. 3-Benzyl-1-(4-(trifluoromethyl)phenyl)-2,3-
dihydropyrazino[1,2-a]indol-4(1H)-one 4b’
d
8.49e8.45 (m, 1H), 7.51e7.46 (m, 1H), 7.39 (dd, J ¼ 7.4, 1.3 Hz, 1H),
7.36 (dd, J ¼ 3.7, 1.6 Hz, 1H), 7.34e7.30 (m, 1H), 7.28 (s, 1H), 7.26 (d,
J ¼ 2.3 Hz, 2H), 7.23 (d, J ¼ 3.6 Hz, 3H), 7.10 (d, J ¼ 8.4 Hz, 2H), 5.49
(s, 1H), 3.79 (d, J ¼ 4.8 Hz, 1H), 3.34 (m, J ¼ 21.1, 13.9, 5.9 Hz, 2H),
Melting Point:132e134 ꢀC. 1H NMR (400 MHz, CDCl3)
d 8.50 (d,
J ¼ 8.0 Hz, 1H), 7.58 (d, J ¼ 8.2 Hz, 2H), 7.50 (d, J ¼ 7.6 Hz, 1H), 7.43
(d, J ¼ 8.2 Hz, 2H), 7.38e7.34 (m, 1H), 7.33e7.30 (m, 3H), 7.29e7.25
(m, 3H), 6.20 (s, 1H), 5.45 (s, 1H), 3.93 (dd, J ¼ 9.1, 4.3 Hz, 1H), 3.32
2.02 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 169.11, 137.23, 130.43,
129.56, 129.48, 129.12, 129.01, 128.92, 128.77, 126.99, 125.16, 124.20,
(m, J ¼ 23.1, 14.0, 6.7 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d 169.03,
118.52, 116.56, 55.42, 52.02, 35.95, 8.51. HRMS (ESI-TOF) m/z:
143.25,137.58,137.02,134.96,129.41,129.22,129.01),128.39,127.23,
[MþH]þ Calcd for C25H21ClN2O 401.1422; found 401.1441.
125.73 (q, Jc-F ¼ 262.7 Hz) 125.14, 124.56, 120.59, 116.58, 106.24,
25
[
a
]
¼ ꢁ41.74 (c ¼ 0.15, CHCl3).
57.81, 52.97, 35.93. 19F NMR (377 MHz, CDCl3)
d
ꢁ64.04. HRMS (ESI-
D
TOF) m/z: [MþH]þ Calcd for C25H19F3N2O 421.1529; found 421.1515.
25
[
a
]
¼ ꢁ31.40 (c ¼ 0.5, CHCl3).
D
3.3.7. 3-Benzyl-10-methyl-1-(4-(trifluoromethyl)phenyl)-2,3
dihydropyrazino[1,2-a]indol-4(1H)-one 4d
Melting Point:140e142 ꢀC.1H NMR (400 MHz, CDCl3)
d
8.48 (d,
3.3.12. 3-Benzyl-1-(4-bromophenyl)-2,3-dihydropyrazino[1,2-a]
J ¼ 8.6 Hz, 1H), 7.53 (dd, J ¼ 8.6 Hz, 3H), 7.40 (dd, J ¼ 7.3, 1.3 Hz,1H),
7.37 (dd, J ¼ 3.9, 1.5 Hz,1H), 7.35e7.32 (m,1H), 7.29 (s,1H), 7.27
(s,3H), 7.23 (s,1H), 7.22 (s,1H), 5.45 (s, 1H), 3.69 (dd, J ¼ 7.7, 4.4 Hz,
1H), 3.35e3.20 (m, 2H), 2.06 (s, 3H). 13C NMR (100 MHz, CDCl3)
indol-4(1H)-one 4c’
Melting Point: 140e142 ꢀC. 1H NMR (400 MHz, CDCl3)
d 8.48 (d,
J ¼ 8.1 Hz,1H), 7.46 (dd, J ¼ 15.5, 8.0 Hz, 3H), 7.38e7.32 (m, 2H), 7.30
(dd, J ¼ 8.5, 1.9 Hz, 3H), 7.28e7.22 (m, 4H), 7.17 (d, J ¼ 8.2 Hz, 2H),
6.17 (s, 1H), 5.33 (s, 1H), 3.95 (dd, J ¼ 8.8, 4.3 Hz, 1H), 3.36 (dd,
J ¼ 14.0, 4.3 Hz, 1H), 3.27 (dd, J ¼ 14.0, 9.0 Hz, 1H). 13C NMR
d
171.30, 137.09, 134.67, 131.97, 130.51, 129.58, 128.77, 128.00 (q,
JCꢁF ¼ 261 Hz), 127.03, 125.72, 125.27, 124.25, 118.55, 116.56, 113.73,
60.50, 21.15, 14.27, 8.52. 19F NMR (377 MHz, CDCl3)
d
ꢁ62.58. HRMS
(100 MHz, CDCl3) d167.59, 136.38, 135.80, 133.81, 130.82, 128.63,
(ESI-TOF) m/z: [MþH]þ Calcd for C26H21F3N2O 435.1684; found
128.28, 128.11, 127.86, 126.12, 123.97, 123.42, 121.38, 119.45, 115.43,
25
435.1678. [
a]
¼ ꢁ96.25 (c ¼ 0.5, CHCl3).
105.14, 56.70, 51.65, 34.71. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for
D
25
C
24H19BrN2O 431.0761; found 431.0751. [
a]
¼ þ27.39 (c ¼ 0.5,
D
CHCl3).
3.3.8. 3-Benzyl-10-methyl-1-(p-tolyl)-2,3-dihydropyrazino[1,2-a]
indol-4(1H)-one 4e
Melting Point: 130e132 ꢀC. 1H NMR (400 MHz, CDCl3)
d
8.48 (d,
3.3.13. 3-Benzyl-1-(2,4-difluorophenyl)-2,3-dihydropyrazino[1,2-a]
indol-4(1H)-one 4d’
J ¼ 7.6 Hz, 1H), 7.48 (d, J ¼ 6.9 Hz, 1H), 7.40e7.31 (m, 2H), 7.30e7.25
(m, 2H), 7.22 (d, J ¼ 7.3 Hz, 3H), 7.07 (d, J ¼ 7.8 Hz, 2H), 6.98 (d,
J ¼ 7.7 Hz, 2H), 5.40 (s, 1H), 3.78 (dd, J ¼ 7.3, 3.6 Hz, 1H), 3.38 (dd,
J ¼ 14.0, 3.6 Hz, 1H), 3.18 (dd, J ¼ 13.8, 8.3 Hz, 1H), 2.31 (s, 3H), 2.03
Melting Point:136e138 ꢀC. 1H NMR (400 MHz, CDCl3)
d 8.48 (d,
J ¼ 8.1 Hz, 1H), 7.50 (dd, J ¼ 14.9, 8.0 Hz, 1H), 7.39 (t, J ¼ 7.5 Hz, 1H),
7.33 (dd, J ¼ 10.6, 6.1 Hz, 5H), 7.26 (d, J ¼ 8.0 Hz, 2H), 6.95e6.81 (m,
2H), 5.84 (s, 1H), 5.37 (s, 1H), 4.14e4.04 (m, 1H), 3.74 (dd, J ¼ 14.0,
2.9 Hz, 1H), 3.11 (dd, J ¼ 13.9, 9.2 Hz, 1H). 13C NMR (100 MHz, CDCl3)
(s, 3H). 13C NMR (100 MHz, CDCl3)
d 169.35, 137.74, 137.40, 135.66,
134.67, 133.08, 130.86, 129.57, 129.48, 128.76, 127.49, 126.94, 124.94,
124.11, 118.47, 116.54, 113.25, 55.41, 52.41, 36.07, 21.20, 8.51. HRMS
d
168.46, 130.69, 130.64, 130.60, 130.54, 129.54, 129.29, 129.04,
(ESI-TOF) m/z: [MþH]þ Calcd for C26H24N2O C26H24N2O 381.1969;
127.16, 124.93, 124.39, 120.47, 116.36, 105.28, 61.97, 51.15, 36.91. 19
F
25
found 381.1961. [
a]
¼ ꢁ102.96 (c ¼ 0.5, CHCl3).
NMR (377 MHz, CDCl3)
d
ꢁ108.72, ꢁ113.86. HRMS (ESI-TOF) m/z:
D
[MþH]þ Calcd for C24H18F2N2O 389.1465; found 389.1459.
25
[
a
]
¼ þ20.34 (c ¼ 0.25, CHCl3).
D
3.3.9. 3-Benzyl-1-(2,4-difluorophenyl)-10-methyl-2,3-
dihydropyrazino[1,2-a]indol-4(1H)-one 4f
Melting Point:134e136 ꢀC. 1H NMR (400 MHz, CDCl3)
d
8.43 (d,
3.3.14. 3-Benzyl-1-(p-tolyl)-2,3-dihydropyrazino[1,2-a]indol-
J ¼ 7.9 Hz, 1H), 7.35e7.26 (m, 3H), 7.21 (dd, J ¼ 16.9, 9.4 Hz, 6H),
6.84e6.73 (m, 2H), 5.34 (s, 1H), 3.95 (dd, J ¼ 8.7, 2.8 Hz, 1H), 3.60
(dd, J ¼ 14.2, 3.0 Hz, 1H), 2.99 (dd, J ¼ 13.9, 9.2 Hz, 1H), 1.47 (s, 3H).
4(1H)-one 4e’
Melting Point: 152e154 ꢀC. 1H NMR (400 MHz, CDCl3)
d 8.49 (d,
J ¼ 8.1 Hz, 1H), 7.51e7.44 (m, 1H), 7.37e7.32 (m, 2H), 7.32e7.27 (m,
4H), 7.15 (dd, J ¼ 19.2, 8.1 Hz, 4H), 6.16 (s, 1H), 5.37 (s, 1H), 4.00 (dd,
J ¼ 9.2, 4.3 Hz, 1H), 3.32- (m, J ¼ 23.4, 14.0, 6.8 Hz, 2H), 2.33 (s, 3H).
13C NMR (100 MHz, CDCl3)
d NMR (101 MHz) d 168.44, 164.11(d,
JCꢁF ¼ 247.1 Hz), 161.62 (d, JCꢁF ¼ 247.1 Hz), 137.46, 134.20, 132.68,
131.30, 129.51, 128.94, 128.89, 127.05, 125.12, 124.06, 118.28, 116.44,
113.03, 112.43, 112.39, 104.01, 61.18, 50.67, 36.79, 8.21. 19F NMR
13C NMR (100 MHz, CDCl3)
d 169.03, 143.25, 137.58, 137.02, 134.96,
129.41,129.22,129.00,128.39,127.23,125.79,125.75,125.72,125.68,
125.14, 124.56, 120.59, 116.58, 106.24, 57.81, 52.97, 35.93, 29.81.
(377 MHz, CDCl3)
Calcd for C25H20F2N2O 403.1624, found 403.1636. [
(c ¼ 0.25, CHCl3).
d
ꢁ111.70, ꢁ115.35. HRMS (ESI-TOF) m/z: [MþH]þ
25
a
]
¼ ꢁ56.99
HRMS (ESI-TOF) m/z: [MþH]þ Calcd for C25H22N2O 367.1810; found
D
25
367.1807. [
a]
¼ ꢁ41.70 (c ¼ 0.5, CHCl3).
D
7

A. Singh, S. Singh, S. Sewariya et al.
Tetrahedron 84 (2021) 132017
3.3.15. 3,10-Dimethyl-1-(4-(trifluoromethyl)phenyl)-2,3-
dihydropyrazino[1,2-a]indol-4(1H)-one 4A
112.17, 111.21, 111.17, 111.01, 110.96, 105.07, 104.81, 104.56, 104.49,
104.24, 103.98, 55.95, 51.26, 50.54, 48.02, 47.99, 16.79, 16.76, 8.45,
Melting Point:100e102 ꢀC. 1H NMR (400 MHz, CDCl3)
d
8.50 (dd,
8.30. 19F NMR (377 MHz, CDCl3)
d
ꢁ109.05, ꢁ109.55, ꢁ113.90,
J ¼ 10.0, 7.9 Hz, 1H), 7.39 (dd, J ¼ 11.6, 4.4 Hz, 1H), 7.33 (dt, J ¼ 16.1,
4.5 Hz, 3H), 7.26e7.19 (m, 2H), 7.14 (s, 1H) 5.12 (s, 1H), 3.85 (q,
J ¼ 6.7 Hz, 1H), 2.40 (s, 3H), 1.56 (d, J ¼ 6.7 Hz, 3H). 13C NMR
ꢁ114.54. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for C19H16F2N2O
327.1309; found 327.1301.
(100 MHz, CDCl3)
d 169.79, 169.73, 138.12, 136.51, 134.43, 134.36,
4. Conclusion
134.22, 133.58, 133.56, 132.68, 131.30, 130.57, 130.46, 130.18, 129.22,
129.21, 128.87, 125.14, 125.08, 124.15, 123.95, 118.49, 118.30, 116.53,
116.38, 113.35, 113.33, 60.50, 58.36, 52.25, 50.31, 16.73, 16.67, 8.86,
In conclusion, we have identified a simple route to generate
enantiomerically pure pyrazinoindoles from chiral amines, aryl
aldehydes and HFIP that plays dual role under the reaction. A one-
pot, highly enantioselective Pictet-Spengler reaction was used to
direct the synthesis under microwave-assisted approach. A plau-
sible mechanism for role of HFIP as a solvent and catalyst supported
by DFT calculations has also been discussed, which explains the
preferential formation of the 1,3 cis diastereomer via fast formation
transition state B (free energy change of 5.3 kcal/mol) by favoured
8.45. 19F NMR (377 MHz, CDCl3)
d
ꢁ62.58, ꢁ62.59. HRMS (ESI-TOF)
m/z: [MþH]þ Calcd for C20H17F3N2O 359.1373; found 359.1376.
3.3.16. 3,10-Dimethyl-1-(4-nitrophenyl)-2,3-dihydropyrazino[1,2-
a]indol-4(1H)-one 4B
Melting Point: 128e130 ꢀC. 1H NMR (400 MHz, CDCl3)
d
8.48e8.40 (m, 1H), 8.23 (d, J ¼ 8.7 Hz, 1H), 8.15 (d, J ¼ 8.8 Hz, 1H),
7.63 (d, J ¼ 8.7 Hz, 1H), 7.54e7.39 (m, 2H), 7.38e7.22 (m, 3H) 5.49 (s,
re face attack. Noticeably derivatives incorporated with
alanine amino acid lead to the formation of products with excellent
stereospecificities (de, ee>99%), however, in case of -alanine amino
L-phenyl-
1H), 3.89 (q, J ¼ 6.7 Hz, 1H), 2.10 (s, 3H), 1.47 (d, J ¼ 6.9 Hz, 3H). 13
C
NMR (100 MHz, CDCl3)
d 170.46, 169.79, 139.12, 137.51, 134.63,
L
134.46, 134.20, 133.88, 133.56, 132.68, 131.30, 130.57, 130.46, 130.18,
129.25, 129.22, 128.97, 125.14, 125.08, 124.15, 123.95, 118.49, 118.30,
116.53,116.38,113.36,113.32, 60.52, 58.38, 52.27, 50.33,16.83,16.69,
8.96, 8.48. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for C19H17N3O3
336.1348; found 336.1342.
acid the products were obtained as diastereomers with dr up to 2:1
in good yields. A defined library was synthetically accessed that
consist of both electron donating and electron withdrawing sub-
stituents in order to compare between the effect of the nature of
substituent on the biological activity and we are under investiga-
tion of their in vitro, in vivo activity against various antibacterial
strains. From the antibacterial activities reported in literature, it is
clear that many of these scaffolds could serve as an inspiration for
development of novel antibacterial chemical entities.
3.3.17. 1-(4-chlorophenyl)-3,10-dimethyl-2,3-dihydropyrazino[1,2-
a]indol-4(1H)-one 4C
Melting Point: 128e130 ꢀC. 1H NMR (400 MHz, CDCl3)
d
8.49e8.40 (m,1H), 7.39 (dd, J ¼ 9.0, 2.8 Hz,3H), 7.37e7.35 (m, 1H),
7.34 (dd, J ¼ 7.3, 1.6 Hz, 1H), 7.29 (dt, J ¼ 8.9, 1.9 Hz, 1H), 7.20 (d,
J ¼ 8.5 Hz, 1H), 5.31 (s, 1H), 4.11 (q, J ¼ 7.1 Hz, 1H), 2.05 (s, 3H), 1.54
Declaration of competing interest
(d, J ¼ 4.1, 2.6 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 170.46, 169.79,
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
139.12, 137.51, 134.63, 134.46, 134.20, 133.88, 133.56, 132.68, 131.30,
130.57, 130.46, 130.18, 129.25, 129.22, 128.97, 125.14, 125.08, 124.15,
123.95, 118.49, 118.30, 116.53, 116.38, 113.36, 113.32, 60.52, 58.38,
55.93, 52.27, 50.33, 16.83, 16.69, 8.96, 8.49. HRMS (ESI-TOF) m/z:
[MþH]þ Calcd for C19H17ClN2O 325.1107; found 325.1102.
Acknowledgment
RC and AS are thankful to DST-SERB (EEQ/2016/000489) for
providing financial assistance for conducting research. RC would
like to acknowledge University of Delhi for providing support and
necessary facilities to carry out research work. AS is thankful to
OLEX2 crystallographic software for solving XRD data. NS and SS
are grateful to CSIR for providing the fellowship. Snigdha Singh is
thankful to ICMR (45/66/2018-PHA/BMS/OL) for providing Senior
research fellowship.
3.3.18. 3,10-Dimethyl-1-(p-tolyl)-2,3-dihydropyrazino[1,2-a]indol-
4(1H)-one 4D
Melting Point:106e108 ꢀC. 1H NMR (400 MHz, CDCl3)
d
8.54e8.47 (m, 1H), 7.43e7.37 (m, 1H), 7.37e7.28 (m,3H), 7.24e7.18
(m, 1H), 7.17e7.11 (m, 2H), 5.12 (s, 1H), 3.86 (q, J ¼ 6.7 Hz, 1H), 2.40
(s, 3H), 2.34 (s, 3H), 1.56 (d, J ¼ 6.8 Hz, 3H). 13C NMR (101 MHz,
CDCl3)
d 170.58, 170.08, 138.45, 137.81, 137.49, 136.33, 135.96,
135.04, 134.92, 134.62, 134.24, 133.29, 133.14, 131.51, 130.81, 129.72,
129.51, 129.29, 128.63, 127.72, 124.88, 124.05, 123.85, 121.89, 121.79,
121.69, 119.14, 118.88, 118.43, 118.23, 116.50, 116.37, 115.91, 113.23,
113.10, 111.04, 58.78, 55.97, 52.74, 50.29, 21.36, 21.18, 16.79, 16.70,
8.87, 8.46. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for C20H20N2O
305.1654; found 305.1648.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132017.
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[1,2-a]indol-4(1H)-one 4E
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