Diversity oriented synthesis of β-carbolinone and indolo-pyrazinone analogues based on an Ugi four component reaction and subsequent cyclisation of the resulting indole intermediate

Article abstract of DOI:10.1039/c5ra27090a

A one-pot domino multicomponent reaction for the rapid, integrated and versatile synthesis of highly functionalized β-carbolinones (9a-9ab) and indolo-pyrazinones (10a-10ab) has been established. The reaction involves an Ugi-four component reaction of ind

Full text of DOI:10.1039/c5ra27090a

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Diversity oriented synthesis of β-carbolinone and indolo-pyrazinone
analogues based on an Ugi four component reaction and subsequent
cyclisation of the resulting indole intermediate
a
Pooja Purohit, Anand Kumar Pandey, Brijesh Kumar, and Prem M. S. Chauhan*
a
b
a
a
b
Medicinal and Process Chemistry Division, Sophisticated Analytical Instrument Facility, CSIR-
Central Drug Research Institute, Lucknow-226031, India
Corresponding Author: Phone No: 0522-2771940, Extn: 4659, 4660, Fax: 91-522-2771941; Email:
*
Premsc58@hotmail.com, prem_chauhan_2000@yahoo.com
Graphical Abstract:
Abstract: One pot domino multicomponent reaction for a rapid, integrated and versatile
synthesis of highly functionalized β-carbolinones (9a-9ab) and indolo-pyrazinones (10a-
10ab) has been established. The reaction involves an Ugi-four component reaction of indole
2-carboxylic acid (1 or 16a-c), aryl or alkyl aldehyde (6a-p), isocyanide (3a-e), and
aminoacetaldehyde dimethyl acetal (7) followed by in situ acid-mediated
deprotection/activation/electrophilic cyclisation/and aromatisation. The products were
obtained from Ugi adducts in good to excellent yield within short periods of 20-30 min at
room temperature (35 ºC). The potential of the methodology is proved by development of a

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diverse library of heterocyclic compounds with point and skeletal diversity. Moreover, the
synthesis has also been accomplished using N-substituted derivatives of indole 2-carboxylic
acid that delivers highly diverse N-substituted β-carbolinones (18a-l) heterocycles of
medicinal importance.
Keywords: Indole, Ugi reaction, β-carbolinone, pyrazinone, cyclisation
Introduction: Much attention has been drawn in the recent years towards the isocyanide
based multi component reactions (IMCRs), especially the Ugi-four component reaction (Ugi-
1
CR), the Ugi-three component reaction (Ugi-3CR), and the Passerni reaction due to their
2
3
4
ability to generate diverse heterocycles for medicinal chemistry. Aside from the vast array of
more traditional methods, the Ugi-4CR offers a powerful and atom-economical way to
construct functionalized molecular architecture from readily available starting materials such
4
as aldehydes, amines, isocyanides, and carboxylic acids. These MCRs are of particular
interest due to their mild reaction conditions, operational simplicity, atom economy, wide
5
functional group tolerance, and are ideal for achieving environmentally friendly reactions.
The combination of multicomponent reactions (MCRs) with post-condensation modifications
via various ring-forming reactions has proven to be a powerful tool for accessing novel
heterocyclic scaffolds. However the post modifications of Ugi products are generally
restricted to a single chemical reaction which limits its scope in diversity oriented synthesis
6
of complex molecules. Thus, the new domino Ugi/cyclisation reactions, which allowed the
rapid construction of elaborate or highly functionalized heterocyclics in one single operation,
7,8
has always been welcomed by the scientific community.
In recent decades, indole precursors have found extensive applications as a key component in
multi component processes as they provide additional diversity and functionalization to
9
product library. Indole nucleus containing natural product such as ß-carboline, ß-

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carbolinone, spirooxindoles etc., are not limited to privileged structures that have the ability
10
to bind with several receptors else the attractive scaffolds for drug discovery. Indole
heterocyclic, ß-carboline core containing natural products and related synthetic derivatives
have found extensive application in medicinal chemistry as antitumour, antimalarial,
1
1
antileishmanial, anticancer, and other life style related diseases. It occurs in numerous
natural products from fungi, bacteria, and plant isolates. Some of the examples have been
shown (Fig. 1) like tetrahydro-β-carboline derivatives (I) having antitumour activity through
12
inhibition of transforming growth factor beta (TGF-β). Likewise, Evodiamine (II), a
12
quinazolinocarboline alkaloid from chinese herb and levendamycin (III), isolated from the
12
fermentation broths of Streptomyces lavendulae, shows excellent antitumour activity. 6-
Methoxy-1,2,3,4-tetrahydro-β-carboline (pinoline) (IV) is believed to have a major role as an
12
europrotective and in the regulation of adrenal gland. Racemic spirotetrahydro β-carboline-
based spiroazepine indole (V) has also been recently shown to exhibit antiplasmodial
12
activity.
Figure 1: Biologically active natural and synthetic therapeutic agents containing ß-carboline
core.

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A pyrido-1-one annulated indole derivative, the ß-carbolinone ring systems is a common
motif plays a prominent role in organic and medicinal chemistry, such as affinity for the
13
benzodiazepine receptor, antileukemic, and central nervous system depressing properties.
Further, the ß-carbolinone ring containing natural product strychnocarpine is a well-known
14
muscle relaxant and a 5-hydroxytryptamine receptor stimulant. Beside having significant
medicinal values, ß-carbolinone heterocyclics have been less explored and, only a few
methods for their syntheses have been reported in the literature. Among these are the first
solid phase and liquid phase syntheses of ß-carbolinones with the generation of four points
15
diversity for various hydrophobic and hydrophilic groups by Wen-Ren Li el al. Later in
2008, Padwa et al., reported the preparation of a series of ß-carbolinones in single step
1
2c
starting from N-propargyl indole-2-carboxamides.
Moreover, Pyrazinones derivatives are found alone and/or embedded with several privilege
heterocyclics which displays prominent biological activity and are featured in several
16
naturally occurring molecules and synthetic derivatives. We have also been interested in the
synthesis of indole fused pyrazinone heterocycles due to their significance in chemical
15
biology. In pursuit of a protocol for preparing functionalized ß-carbolinones (9) and indolo-
pyrazinones (10) with diverse pharmacological properties, we envisioned the four component
Ugi-MCR/post cyclisation approach using preorganised substrates. The scaffolds 9 and 10
illustrate the flexibility and complexity which is achieved in single operation and at the same
time results in the combination of two the most bioactive rings indole and pyrido-2-one.
Indeed, our group has long had an interest in discovering new synthetic strategies utilising the
17
Ugi MCR/post modification approaches for accessing biologically important heterocycles.
Very recently, we reported the synthesis of biologically important indole diketopiperazine (5)
analogues via four component Ugi reaction and
Scheme 1: Synthesis of indole fused diketopiperazines (5)

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17
subsequent ring opening leading to a library of dipeptides (Scheme 1). In this continuation,
we next directed our efforts towards the reaction of the Ugi precursors indole-2-carboxylic
acid (1) or N-substituted indole-2-carboxylic acid (16a-c), aryl or alkyl aldehyde (6a-p), and
isocyanide (3), aminoacetaldehyde dimethyl acetal (7), and their subsequent
deprotection/activation/electrophilic cyclisation/aromatisation at room temperature (35 ºC) to
afford diverse set of ß-carbolinones (9) in good to excellent yield along with small amount of
indolo-pyrazinones (10) (Scheme 2). It is noteworthy that, the new protocol avoids the use of
any transition metal catalyst, thereby excluding their contamination during synthesis,
18
favourable for biological screening.
Scheme 2: Synthesis of ß-carbolinones and indolo-pyrazinones derivative from Ugi
precursors

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To the best of our knowledge, this is first report for such Ugi-4CR of indole 2-carboxylic
acid, aminoacetaldehyde dimethyl acetal, aryl aldehyde, and isocyanide and/or subsequent
cyclisation under acidic medium.
Result and Discussion: As part of our on-going research on Ugi MCRs, we studied the
reaction of indole-2-carboxylic acid (1), 3,4-dimethoxy benzaldehyde (6a),
aminoacetaldehyde dimethyl acetal (7), and tertiary butyl isocyanides (3a) in methanol for 6h
at rt (35 ºC), that resulted in the formation of Ugi adduct 8a as the major product. The
methanol was removed in vacuo and further reaction was performed directly by stirring of
3 3 2
Ugi adduct 8a in CH CN under BF .OEt (2.0 equiv.) for 60 min. at rt (35 ºC), which
furnished the cyclised product 9a and 10a, albeit in lower yields (entry 1, Table1).
The products 9a and 10a were isolated from column chromatography and characterised by
1
13
20
IR, HRMS, H NMR and C NMR spectra (see supporting information). To identify the
optimal reaction conditions for the domino reaction, we checked different catalysts, solvents
and temperatures and the results of this study are depicted in Table 1.
Table1:Optimisation of reaction condition for synthesis of ß-carbolinone and indolo-
a
pyrazinonederivatives.

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MeO OMe HN
N
CHO
OMe
O
NC
MeOH
COOH
MeO
N
NH2
OMe
6 h
H
N
OMe
OMe
O
OMe
H
1
6a
7
3a
8a
reagent, rt
solvent
HN
OHN
O
O
N
N
N
N
H
O
OMe
MeO
MeO
OMe
9a
10a
b
Yield
Entry
Reagents (equiv)
Solvents
Time (min)
9
a
10a
10
1
2
3
4
5
6
7
8
9
BF
BF
3
3
.OEt
.OEt
2
2
(1.0)
(1.0)
MeOH
60
60
22
45
24
52
66
72
79
73
47
46
CH
3
CN
11
AlCl
3
(1.0)
Toluene
Toluene
60
Traces
TFA (0.2)
TFA (0.2)
TFA (0.5)
TFA (1.0)
TFA (1.0)
TFA (1.0)
TFA (1.0)
120
120
45
8
8
CH
3
CN
CH CN
3
8
CH
3
CN
20
11
8
THF
DCM
20
45
7
10
Chloroform
45
7

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1
1
1
1
1
1
1
1
1
2
2
1
2
3
4
5
6
7
8
9
0
1
TFA (2.0)
PTSA (0.2)
PTSA (1.0)
MSA(1.0)
CH CN
3
20
120
20
78
52
10
8
9
8
7
-
CH CN
3
CH
CH
CH
CH
3
3
3
CN
CN
CN
CN
72
30
69
TFMSA (1.0)
30
57
c
HClO
4
(1.0)
3
60
UN
d
d
e
Acetic acid
Acetic acid (5.0)
-
-
60
UN
UN
NR
-
Toluene
60
-
CH
CH
CH
3
3
3
CN
CN
CN
>120
60
-
f
TFA (1.0)
TFA (1.0)
65
7
7
g
15
45
a
Reaction conditions: step 1: indole 2-carboxylic acid (1) (1 mmol), 3, 4-dimethoxy benzaldehyde (6a) (1
mmol), aminoacetaldehyde dimethyl acetal (7) (1.1 mmol), tertiary butyl isocyanide (3a) (1.1 mmol) in 3 mL
solvent, reaction time 6h, rt (35 C). Step 2: substrate Ugi adducts 8a (1 mmol), TFA (1.0 equiv.), solvent (2
mL), rt (35 C), reaction time (20 min.), Isolated yield. unidentified mixture. reaction temperature (rt (35 ºC)
and/or 90 C). no reaction. reaction temperature (0 ºC). reaction temperature (75 ºC).
̊
b
c
d
̊
e
f
g
̊
The one step one pot reaction of Ugi/cyclisation reaction using MeOH was unsuccessful
since the reaction generates additional impurities in the reaction mixture, restricting the use of
MeOH as solvent for promoting cyclisation (entry 1, Table 1). To obtain the desired product
(9a and 10a), we tested the reaction using different Brønsted and Lewis acids which is
depicted in Table 1. In our initial efforts, using BF .OEt with CH CN solvent does not leads
3
2
3
any significant change in yield of desired products (entry 2, Table 1). Performing the
cyclisation with AlCl in toluene generates inseparable reaction mixture (entry 3, Table 1).
3
Next, we examine a set of Brønsted acids in different solvents (entries 4–19, Table 1) where,

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triflouro acetic acid (TFA) (entry 7, Table 1), p-toluene sulphonic acid (PTSA) (entry 13,
Table 1), and/or methanesulphonic acid (MSA) (entry 14, Table 1) seemed promising for
cyclisation of Ugi product. It may be due to the acidic strength of TFA (pKa ~-0.25), PTSA
(pKa ~-2.58) and, MSA (pKa ~-2.60) are good enough to enhance the electrophilicity of the
oxo-group for intramolecular cyclisation via C-3 or N-1 position of indole ring consequently
good yield of cyclisation. However, in case of triflouromethanesulphonic acid (TFMSA, pKa
~
-14.0) (entry 15, Table 1) and/or perchloric acid (HClO4, pKa ~-10.0) (entry 16, Table 1),
being highly acidic in nature may protonate the N-1 of indole ring and thus reduce the
nucleophilicity of C-3 carbon of indole ring thus the lower yield of cyclisation. In other hand,
the acid (like CH COOH, pKa ~+4.76) having high pKa value i.e. weak acidic strength is not
3
enough to enhance the electrophilicity of oxo-group therefore low feasibility of cyclisation
(entry 17 and 18, Table 1).
Due to the volatile nature of TFA (72 ̊C ) and easily removed by evaporation without
neutralization or extraction in organic solvents, is the reagent of choice which prompted us to
further optimize the reaction condition using TFA. Therefore, further refinement was limited
to varying the solvent and temperature. We also investigated the amount of TFA required for
this reaction and it was observed that with decreasing the amount of catalyst, the yields also
decreased (entries 5-7, Table 1). It is observed that further increase of the catalyst loading to
2.0 equiv. has no obvious influence on the reaction (entry 11, Table 1). Subsequently, the
effect of solvent was examined where DCM, and/or CHCl showed no superiority to toluene
3
as solvents but in THF and/or CH
reaction time (compare entries 4, 7, 8, 9, 10, Table 1). When the reaction was carried out
using 1.0 equivalent of TFA in CH CN, a complete disappearance of starting materials was
3
CN a good yield of product was observed with reduction in
3
observed while attaining the highest yield of 9a and 10a (79% and 11% yield respectively,
entry 7, Table 1). As predicted, the reaction did not work at all without cyclizing reagent

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(
entry 19, Table 1). We have also done the Ugi post cyclisation reaction at lower temperature
0 ºC) which delivered the low yield of regioisomers in longer time (entry 20, Table 1). It is
(
noteworthy that, at a reaction temperature of 75 ºC, the yield of the desired product was
decreased significantly (entry 21, Table 1).
The scope and limitations of this one pot domino Ugi/cyclisation process (entry 7, Table 1),
were next examined by employing diverse aromatic/heteroaromatic (HetAr)/aliphatic
aldehydes appended with various substituents (6a-i, Table 2). The complete list of the
synthesized compounds (9a-9ab and 10a-10ab) with corresponding starting materials is
given in the supporting information (S-Table 1). It is interesting to note that in all cases
whether aromatic aldehydes with electron-withdrawing and/or electron-donating groups were
used, products were obtained with minimal variation in isolated yields (Table 2; 58−79%).
The presented protocol shows extensive evaluation of the transformation that not only reveals
novel reactivity facets and expanded scope of the method but also provides ß-carbolinone and
indolo-pyrazinone chemotypes featuring unexplored functional, skeletal, and fusion patterns
of indole heterocycles. We have synthesized several ß-carbolinone and indolo-pyrazinone
derivatives containing halogens such as flouro, chloro, bromo based on their role in
introducing lipophilicity in molecules in medicinal chemistry (entry 4, Table 2 and see
supporting information; Table 1). The 4-nitro benzaldehyde (6c) with a strong electron
withdrawing substituent also provides the cyclized product in good yield (entry 3, Table 2).
Sterically hindered 1-naphthaldehyde (6f) with tertiary butyl isocyanide (3a) provides the
cyclized products in 74% yield (entry 6, Table 2). Further, 4-Hydroxy benzaldehyde (6e) and
n-pentyl carbon aldehyde (6g) were also used as aldehyde sources for extensively evaluating
the chemoselectivity profile of the transformation. The 1, 4-terephthalaldehyde has also
demonstrated usefulness for domino Ugi/cyclisation reactions, leading to the bis analogue of
21
β-carbolinone as the major product in good yield (entries 12, Table 2). Inspired by the

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22
biological activity of marinocarboline A-D containing the β-carboline nucleus, we have
utilised a indole 3-carboxaldehyde precursor, which delivered β-carboline (inseparable from
reaction mixture) and indolo-pyrazinone polyheterocycles in relatively lower yield (entry13,
Table 2). However, we were unable to obtain any product from ketones under the optimized
conditions which limits this methodology for such substrates. Cyclohexyl isocyanide (3b),
1,1,3,3-tetramethyl butyl isocyanide (3c), 4-methoxyphenyl isocyanide (3d), and n-pentyl
isocyanide (3e) were also used as isocyanides for diversification in the products library.
Table 2:One pot, Two Step Synthesis of ß-carbolinones (9a-m) and indolo-pyrazinones
a
10a-m) derivative .
(
Cyclised product
b
entry
Starting material
Yield%
9
10
1

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O HN
2
O
N
N
10b,9
3
COOH
MeO
NH2
N
H
1
OMe
CHO
7
4
NC
3a
6d
Cl
HN
O
N
5
N
H
O
OH
9
e,72
6
Cy
HN
O
N
O
7
N
H
9g,72

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HN
O
N
8
N
H
O
9
h,69
9
1
0
1
1
1
2

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1
3
a
Reaction conditions: step 1: indole 2-carboxylic acid (1) (1 mmol), aryl or alkyl aldehyde (6a-i) (1 mmol),
aminoacetaldehyde dimethyl acetal (7) (1.1 mmol), alkyl or aryl isocyanide (3a-e) (1.1 mmol) in 3 mL solvent
at rt (35 C). Step 2: substrate Ugi adducts 8a-m (1 mmol), TFA (1.0 equiv.), CH CN (2 mL), reaction time (20-
0 min.), rt (35 ºC), Isolated yield. Inseparable from reaction mixture.
̊
3
b
c
3
A proposed mechanism of the TFA-mediated domino reaction for both of the cyclised
product 9a and 10a is depicted in Figure 2. The first step is the general Ugi reaction which
includes continuous stirring of Ugi precursors for 4-6h at rt (35 ºC).The second step includes
a domino deprotection, activation, and electrophilic cyclisation followed by aromatisation for
product formation. Based on a literature survey, we envisaged that such a transformation can
23
only occur under acid medium. The Ugi precursor, subjected to TFA for protonation
involves the conversion of acetal to aldehyde first, which then forms an oxonium ion 11. This
oxonium ion 11 has two nucleophilic centres indole N-1 and indole C-3 which can attack to
the positive carbon. Out of the two possibilities, the most nucleophilic site is indole C-3,
which attacks first and provides the cyclised intermediate 12. This intermediate 12 afforded
the desired product 9a in good yield with removal of methanol, presumably because of the
acidic conditions employed. The product 10a is found as a minor side product via
intermediate 13, and results from the involvement of indole N-1 site in cyclisation.

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Figure 2: Plausible mechanism for product formation
Further, we have extended the substrate scope of this domino reaction by introducing N-
substituted indole-3-carboxylic acids as a carboxylic acid component. The desired N-
substituted indole-2-carboxylic acids (16a-c) were achieved in good yield only in three steps
starting from indole-2-carboxylic acid. Prior to N-functionalization, the substrate 1 was
protected through ester formation with thionyl chloride/ethanol leading to indole-2-
carboxylic ethyl ester 14. This intermediate 14 is reacted with corresponding alkyl or benzyl

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or propargyl halide in presence of NaH in DMF providing N-substituted indole-2-carboxylic
ethyl ester 15a-c. This is followed by hydrolysis with KOH in equimolar ratios of
2
THF:MeOH:H O solvent providing the salt of the carboxylic acid which upon neutralisation
with dilute hydrochloric acid (pH=2) provided the desired Ugi precursor N-substituted
indole-2-carboxylic acid (16a-c) in moderate to good yield (see supporting information,
Scheme 1).
Once these N-substituted indole-2-carboxylic acids (16a-c) were in hand, they were subjected
to domino Ugi 4CR/cyclisation reaction together with an aryl aldehyde (6a or 6b or 6d or 6e
or 6h or 6j), aminoacetaldehyde dimethyl acetal (7), and isocyanides (3a-c) under our
optimised reaction conditions. Interestingly, all the N-substituted indole-2-carboxylic acids
were successfully transformed into the desired N-substituted ß-carbolinone analogues (18a-l)
in excellent yield. Moreover, we found that in all cases products were obtained with minimal
variation in isolated yield. We have also notice that cyclisation reaction of Ugi adduct of N-
substituted precursors were achieved in lesser time (15-20 min) compared to that of the Ugi
product derived from 1H-indole-2-carboxylic acid (20-30 min), which may be due to indole
ring activation from the substituents (alkyl, benzyl and propargyl groups). The input of
propargyl group over the N-1 position of indole allows a further diversification point on
carbolinone heterocycle (entry 9-12, Table 3), which could be highly desirable for structural
and biological activity assessments. These propargyl linked carbolinones can be further
24
elaborated using various reactions for eg. [3+2]-click reactions, aldehyde/alkyne/secondary
2
amine coupling reactions, Sonogashira reactions and many other cyclisation reactions .
5
26
27
Table 3: Synthesis of N-substituted ß-carbolinone analogues (18a-l) from Ugi/post
a
cyclisation approach.

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Cyclised product
18a-l)
b
Entry
Starting material
Yield%
(
1
.
2
.
3
.
HN
O
N
O
4
.
N
Et
OH
18d

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HN
O
5
.
N
N
O
OMe
OMe
1
8e
6
HN
O
N
7
N
O
18g
8
.
O
NH
9
.
N
N
O
CN
1
8i

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10.
a11
.
12.
a
Reaction conditions: step 1: N-substituted indole 2-carboxylic acid (16a-c) (1 mmol), aryl aldehyde (6a, 6b,
d, 6e, 6h, 6j) (1 mmol), aminoacetaldehyde dimethyl acetal (7) (1.1 mmol), alkyl isocyanide (3a-c) (1.1 mmol)
6
in 3 mL solvent, 4-6h, rt (35
3
̊C ). Step 2: substrate Ugi adducts 17a-l (1 mmol), TFA (1.0 equiv.), CH CN (2
b
mL), reaction time (15-20 min.), rt (35
̊C ), Isolated yield.
Conclusion: In Summary, we have constructed a library of biologically valuable heterocyclic
compounds using domino Ugi/post cyclisation approach in a one pot procedure. Our
methodology is straightforward to execute and useful in the preparation of wide variety of β-
carbolinones and indolo-pyrazinones analogues. In addition, we also applied our protocol to
N-substituted indole 2-carboxylic acid precursors which delivered indole C-3 cyclised β-
carbolinones in excellent yield. The salient feature of our protocol is atom economy,
operational simplicity, high yield and easily available precursors in a very short period of
time. By further elaboration and diversification of the various functionally substituted

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scaffolds, a wide range of structurally and spatially diverse compounds can be produced.We
anticipated that this protocol will open the door for the medicinal chemist to synthesise such
frameworks and test for biological activity.
Experimental Section:
General: Melting points are uncorrected and were determined in capillary tubes on a
precision melting point apparatus containing silicon oil. IR spectra were recorded on an FTIR
-1
1
spectrophotometer and are reported in terms of frequency of absorption (cm ). H NMR
spectra were recorded on a 400 MHz and 500 MHz spectrometer in CDCl or DMSO-d (all
signals are reported in ppm with the internal chloroform signal at 7.26-7.28 ppm, or the
3
6
1
internal DMSO signal at 2.50 ppm as standard). C NMR spectra were recorded on 100 MHz
3
and 125 MHz spectrometers in CDCl or DMSO-d (all signals are reported in ppm with the
3
6
internal chloroform signal at 77.21 ppm, or the internal DMSO signal at 39.51 ppm as
standard). Chemical shifts δ are given in ppm relative to the residual signals of
1 13
tetramethylsilane in CDCl or deuterated solvent CDCl /DMSO-d for H and C NMR
3
3
6
spectrometers. Coupling constants J are reported in hertz (Hz). Multiplicities are reported as
follows: singlet (s), broad (br), doublet (d), triplet (t), quartet (q), and multiplet (m). The
HRMS spectra were recorded as ESI-HRMS on Q-TOF, LC-MS/MS mass spectrometer.
Reaction progress was routinely monitored by thin-layer chromatography (TLC) on precoated
silica gel plates. Column chromatography was performed over silica gel. All the solvents and
chemicals were used as procured from the suppliers.
Experimental procedure:
General Procedure 1.
The Two Step One-Pot Synthesis of ß-carbolinone (9a-9ab) and indolo-pyrazinone (10a-
10ab)analogues:To a mixture of the corresponding aldehyde (6a-p) (1.0 mmol) in MeOH,
aminoacetaldehyde dimethyl acetal (7) (1.1 mmol) was added followed by the addition of

Page 21 of 53
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indole 2-carboxylic acid (1) (1.0 mmol), the isocyanide (3a-e) (1.1 mmol).The reaction was
allowed to run for 4-6 h at room temperature (35 C). The progress of reaction was monitored
̊
by TLC. Once starting material was consumed, the MeOH was (in vacuo) at low temperature
followed by the addition of CH CN. The sticky mass was stirred at rt (35 ºC) for 5 min. To
3
homogenize the reaction mixture, at which point TFA (1.0 equiv.) was added and the mixture
was stirred for 20-30 min. at rt (35 ºC). When the reaction was completed (as determined by
TLC) the reaction solvents was (in vacuo) and directly proceeded for column
chromatography (hexane/AcOEt) using 100-200 mesh silica gel to afford the desired product
9a-9ab and 10a-10ab.
N-(tert-Butyl)-2-(3,4-dimethoxyphenyl)-2-(1-oxo-1H-pyrido[3,4-b]indol-2(9H)-
yl)acetamide (9a). Isolated as a green solid; 79 % yield (342 mg); mp 150-153
̊C ; IR (KBr)
-
1 1
ν
max: 3398, 3019, 1647, 1215, 757 cm ; H NMR (400 MHz, CDCl
3
) δ: 11.00 (s, 1H), 7.93
(d, J= 8 Hz, 1H), 7.63 (d, J= 8.2 Hz, 1H), 7.45 (t, J= 7.8 Hz, 1H), 7.23 (t, J= 7.6 Hz, 1H),
7.18 (d, J= 7.3 Hz, 1H), 7.06 (d, J= 8 Hz, 1H), 6.98 (s, 1H), 6.96 (d, J= 4.9 Hz, 1H), 6.94 (s,
1
3
1
H), 6.90 (d, J= 8.1 Hz, 1H), 6.27 (s, 1H), 3.90 (s, 3H), 3.80 (s, 3H), 1.40 (s, 9H) ppm; C
) δ: 167.6, 156.0, 149.4, 140.1, 128.0, 127.1, 127.0, 126.6, 125.3,
22.2, 121.7, 121.3, 120.0, 112.6, 112.0, 111.3, 101.4, 61.1, 55.8, 52.0, 28.6ppm; HRMS
NMR (100 MHz, CDCl
3
1
+
(
28 3 4
ESI) calcd for [C25H N O ] 434.2080; found 434.2065.
N-(tert-Butyl)-2-(3,4-dimethoxyphenyl)-2-(1-oxopyrazino[1,2-a]indol-2(1H)-
yl)acetamide (10a). Isolated as a yellow solid; 11 % yield (47 mg); mp 90-93
̊C ; IR (KBr)
-
1 1
ν
1
7
1
max: 3393, 2926, 1627, 1068, 762 cm ; H NMR (400 MHz, CDCl
3
) δ: 7.84 (d, J= 8 Hz,
H), 7.63 (d, J= 8.6 Hz, 1H), 7.44 (s, 1H), 7.41 (t, J= 7.5 Hz, 1H), 7.33 (t, J= 7.5 Hz, 1H),
.24 (d, J= 6.2 Hz, 1H), 7.06 (d, J= 8.3 Hz, 1H), 6.94 (d, J= 1.9 Hz, 1H), 6.92 (d, J= 8.4 Hz,
H), 6.63 (s, 1H), 6.55 (d, J= 6.2 Hz, 1H), 5.98 (s, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 1.41 (s,

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DOI: 10.1039/C5RA27090A
1
3
9
1
2
3
H) ppm; C NMR (100 MHz, CDCl ) δ: 167.6, 157.4, 149.4, 132.1, 127.7, 127.4, 127.2,
24.1, 122.6, 122.4, 121.6, 113.3, 111.9, 111.3, 110.5, 105.7, 103.3, 59.2, 55.9, 52.1,
+
] 434.2080; found 434.2065.
8.6ppm; HRMS (ESI) calcd for [C25
H
28
N
3
O
4
N-(tert-Butyl)-2-(1-oxo-1H-pyrido[3,4-b]indol-2(9H)-yl)-2-phenylacetamide(9b). Isolated
as a white solid; 64 % yield (238 mg); mp 123-126
̊
-
1 1
7
8
7
59 cm ; H NMR (400 MHz, CDCl
3
) δ: 10.58 (s, 1H), 7.95 (d, J= 7.9 Hz, 1H), 7.61 (d, J=
.4 Hz, 1H), 7.51 (d, J= 7.3 Hz, 1H), 7.47-7.43 (m, 5H), 7.27 (t, J= 7.5 Hz, 1H), 7.20 (d, J=
1
.4 Hz, 1H),7.03 (d, J= 7 Hz, 1H), 6.96 (s, 1H), 6.07 (bs, 1H), 1.41 (s, 9H) ppm; C NMR
3
(
100 MHz, CDCl ) δ: 167.4, 155.6, 140.3, 135.6, 129.2, 129.1, 129.0, 127.5, 126.8, 126.7,
3
126.1, 121.9, 121.3, 120.3, 112.7, 102.3, 61.9, 52.2, 28.5 ppm; HRMS (ESI) calcd for
+
] 374.1869; found 374.1859.
[
C
23
H
24
N
3
O
2
N-(tert-Butyl)-2-(1-oxopyrazino[1,2-a]indol-2(1H)-yl)-2-phenylacetamide (10b). Isolated
as an orange solid; 9 % yield (33 mg); mp 151-155 C; IR (KBr) νmax: 3422, 3019, 1630, 1215,
̊
-
1 1
7
58 cm ; H NMR (400 MHz, CDCl ) δ: 7.84 (d, J= 7.9 Hz, 1H), 7.62 (d, J= 8.6 Hz, 1H),
3
7.47-7.41 (m, 4H), 7.39 (d, J= 6.7 Hz, 2H), 7.33 (s, 1H), 7.31 (t, J= 7.6 Hz, 1H), 7.24 (d, J= 6
13
Hz, 1H), 6.74 (s, 1H), 6.56 (d, J= 6.1 Hz, 1H), 6.03 (s, 1H), 1.42 (s, 9H) ppm; C NMR (100
MHz, CDCl ) δ: 167.4, 157.4, 135.5, 132.1, 129.1, 128.9, 128.8, 127.7, 127.2, 124.1, 122.6,
22.4, 113.4, 110.4, 105.7, 103.4, 59.2, 52.1, 28.6 ppm; HRMS (ESI) calcd for
3
1
+
23 24 3 2
[C H N O ] 374.1869; found 374.1865.
N-(tert-Butyl)-2-(4-nitrophenyl)-2-(1-oxo-1H-pyrido[3,4-b]indol-2(9H)-yl)acetamide
(9c). Isolated as a yellow solid; 67 % yield (280 mg); mp 120-123
̊
-
1 1
3
1
7
019, 1648, 1215, 769 cm ; H NMR (400 MHz, CDCl
3
) δ: 10.11 (s, 1H), 8.29 (d, J= 8.6 Hz,
H), 8.24 (s, 1H), 8.22 (s, 1H), 7.96 (d, J= 7.9 Hz, 1H), 7.57 (s, 2H), 7.55 (s, 1H), 7.22 (d, J=
.2 Hz, 1H), 7.05 (s, 1H), 7.03 (d, J= 7.1 Hz, 1H), 6.99 (s, 1H), 6.41 (s, 1H), 1.41 (s, 9H)

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1
3
ppm; C NMR (100 MHz, CDCl
3
) δ: 168.8, 166.4, 155.7, 143.2, 141.4, 139.8, 129.8, 129.4,
127.5, 126.1, 125.6, 124.2, 124.0, 121.4, 120.6, 112.4, 102.2, 60.3, 52.4, 28.5 ppm. HRMS
+
(
23 4 4
ESI) calcd for [C23H N O ] 419.1719; found 419.1701.
N-(tert-Butyl)-2-(4-nitrophenyl)-2-(1-oxopyrazino[1,2-a]indol-2(1H)-yl)acetamide (10c).
Isolated as a pale yellow solid; 12 % yield (50 mg); mp 130-133
̊
-
1 1
3
019, 1648, 1215, 770 cm ; H NMR(400 MHz, CDCl
3
) δ: 8.26 (d, J= 8.9 Hz, 2H), 7.83 (d,
J= 8 Hz, 1H), 7.62 (d, J= 8.5 Hz, 3H), 7.43 (t, J= 6.8 Hz, 2H), 7.34 (d, J= 7.8 Hz, 1H), 7.31
1
3
(
s, 1H), 6.88 (s, 1H), 6.64 (d, J= 6.2 Hz, 1H), 6.60 (s, 1H), 1.43 (s, 9H) ppm; C NMR (100
MHz, CDCl ) δ: 166.3, 157.3, 147.9, 142.6, 132.3, 129.5, 127.6, 126.5, 124.7, 124.1, 122.8,
3
122.7, 112.5, 110.5, 106.7, 104.3, 58.3, 52.5, 28.6 ppm; HRMS (ESI) calcd for
+
] 419.1719; found 419.1713.
[
C
23
H
23
N
4
O
4
N-(tert-Butyl)-2-(4-chlorophenyl)-2-(1-oxo-1H-pyrido[3,4-b]indol-2(9H)-yl)acetamide
(9d). Isolated as a white solid; 62 % yield (252 mg); mp 113-116 C̊ ; IR (KBr) νmax: 3400,
-
1 1
3
1
019, 1622, 1215, 757 cm ; H NMR (400 MHz, CDCl ) δ: 11.16 (s, 1H), 7.92 (d, J= 7.8 Hz,
3
H), 7.59 (d, J= 8.5 Hz, 1H), 7.43 (t, J= 7.4 Hz, 2H), 7.23 (t, J= 7.5 Hz, 2H), 7.17 (d, J= 7.4
1
Hz, 2H), 7.13 (s, 2H), 6.97 (d, J= 7.4 Hz, 1H), 6.49 (s, 1H), 1.40 (s, 9H) ppm; C NMR (100
3
MHz, CDCl
3
) δ: 167.2, 156.0, 140.1, 134.7, 130.2, 129.2, 127.0, 126.4, 125.3, 122.1, 121.3,
+
] 408.1479;
120.2, 112.6, 101.8, 60.4, 52.1, 28.6 ppm; HRMS (ESI) calcd for [C23
H
23ClN
3
O
2
found 408.1465.
N-(tert-Butyl)-2-(4-chlorophenyl)-2-(1-oxopyrazino[1,2-a]indol-2(1H)-yl)acetamide
(10d). Isolated as a white solid; 11 % yield (44 mg); mp 135-137 ºC; IR (KBr) νmax : 3400,
-
1 1
3
3
019, 1628, 1215, 757 cm ; H NMR (400 MHz, CDCl ) δ: 7.85 (d, J= 8 Hz, 1H), 7.64 (d,
J= 8.2 Hz, 1H), 7.45 (s, 1H), 7.43 (t, J= 8 Hz, 1H), 7.39 (t, J= 1.1 Hz, 1H), 7.30 (s, 1H), 7.28
s, 1H), 7.26 (d, J= 6.1 Hz, 1H), 6.68 (s, 1H), 6.55 (d, J= 6.1 Hz, 1H), 6.01 (s, 1H), 1.41 (s,
(

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DOI: 10.1039/C5RA27090A
1
3
9
3
H) ppm; C NMR (100 MHz, CDCl ) δ: 167.1, 157.3, 134.8, 134.0, 132.2, 130.2, 129.3,
127.6, 126.9, 124.3, 122.6, 113.1, 110.5, 106.0, 103.6, 58.4, 52.2, 28.6 ppm; HRMS (ESI)
+
] 408.1479; found 408.1473.
calcd for [C23
H
23ClN
3
O
2
N-(tert-Butyl)-2-(4-hydroxyphenyl)-2-(1-oxo-1H-pyrido[3,4-b]indol-2(9H)-yl)acetamide
(
9e). Isolated as a white solid; 72 % yield (280 mg); mp 160-163 C
̊
; IR (KBr) νmax : 3400,
-
1 1
3
7
7
1
1
1
3
019, 1647, 1215, 758 cm ; H NMR (400 MHz, DMSO-d ) δ: 9.63 (s, 1H), 8.20 (s, 1H),
6
.98 (d, J= 8 Hz, 1H), 7.54 (d, J= 8.1 Hz, 1H), 7.45-7.39 (m, 2H), 7.27 (d, J= 8.6 Hz, 1H),
.19 (d, J= 7.3 Hz, 1H), 7.14 (d, J= 8.5 Hz, 1H), 6.96 (d, J= 7 Hz, 1H), 6.90 (s, 1H), 6.82 (s,
13
H), 6.80 (s, 1H), 6.78 (s, 1H), 1.29 (s, 9H) ppm; C NMR (100 MHz, CDCl + DMSO-d ) δ:
3
6
68.0, 157.3, 155.8, 139.7, 130.4, 127.1, 126.6, 126.2, 125.4, 122.0, 121.2, 120.0, 115.9,
+
] 390.1818; found
12.2, 101.1, 61.0, 51.6, 28.2 ppm; HRMS (ESI) calcd for [C23
H
24
N
3
O
3
90.1804.
N-(tert-Butyl)-2-(4-hydroxyphenyl)-2-(1-oxopyrazino[1,2-a]indol-2(1H)-yl)acetamide
(
10e). Isolated as a white solid; 12 % yield (47 mg); mp 150-153 C
̊
; IR (KBr) νmax : 3400,
-
1 1
3
019, 1625, 1216, 769 cm ; H NMR (400 MHz, CDCl ) δ: 7.82 (d, J= 8.1 Hz, 1H), 7.61 (d,
3
J= 8.3 Hz, 1H), 7.43 (s, 1H), 7.40 (t, J= 7.6 Hz, 1H), 7.32 (d, J= 7.8 Hz, 1H), 7.27 (d, J= 8.3
Hz, 2H), 7.23 (d, J= 6 Hz, 1H), 6.87 (d, J= 8.5 Hz, 2H), 6.56 (s, 1H), 6.51 (d, J= 6.1 Hz, 1H),
1
3
6
1
5
6
.00 (s, 1H), 1.39 (s, 9H) ppm; C NMR (100 MHz, DMSO-d ) δ: 168.0, 157.9, 156.5,
32.1, 130.6, 127.6, 127.4, 126.7, 124.2, 122.8, 122.5, 116.1, 114.6, 112.0, 105.7, 102.3,
+
8.8, 51.1, 28.8 ppm; HRMS (ESI) calcd for [C H N O ] 390.1818; found 390.1822.
23
24
3
3
N-(tert-Butyl)-2-(naphthalen-1-yl)-2-(1-oxo-1H-pyrido[3,4-b]indol-2(9H)-yl)acetamide
(9f). Isolated as a white solid; 74 % yield (313 mg); mp220-223
̊
-
1 1
3
019, 1647, 1215, 758 cm ; H NMR (400 MHz, CDCl
3
) δ: 10.43 (s, 1H), 8.01-7.96 (m, 2H),
7.91-7.86 (m, 3H), 7.66 (d, J= 2.8 Hz, 1H), 7.63 (d, J= 5.4 Hz, 1H), 7.60 (d, J= 7.7 Hz, 1H),

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7.50-7.45 (m, 1H), 7.44-7.41 (m, 2H), 7.23 (t, J= 7.6 Hz, 1H), 7.04 (d, J= 7.2 Hz, 1H), 6.83
1
3
(
d, J= 7.3 Hz, 1H), 5.96 (s, 1H), 1.44 (s, 9H) ppm; C NMR (100 MHz, CDCl
3
) δ: 167.9,
1
1
55.7, 139.9, 134.1, 131.7, 130.2, 128.9, 127.7, 127.6, 127.2, 126.9, 126.4, 126.3, 125.2,
23.1, 122.3, 121.3, 120.0, 112.6, 101.0, 58.4, 52.2, 28.6s ppm; HRMS (ESI) calcd for
+
C H N O ] 424.2025; found 424.2023.
[
2
7
26
3
2
N-(tert-Butyl)-2-(naphthalen-1-yl)-2-(1-oxopyrazino[1,2-a]indol-2(1H)-yl)acetamide
(10f). Isolated as a white solid; 8 % yield (34 mg); mp 140-143
̊
-
1 1
1
618, 1215, 756 cm ; H NMR (400 MHz, CDCl
3
) δ: 8.00-7.95 (m, 2H), 7.92-7.89 (m, 1H),
7.84 (d, J= 7.8 Hz, 2H), 7.60 (d, J= 7.7 Hz, 1H), 7.56 (s, 1H), 7.54 (d, J= 2.4 Hz, 1H), 7.53 (t,
J= 4 Hz, 2H), 7.38 (t, J= 7 Hz, 1H), 7.32 (d, J= 5.9 Hz, 2H), 7.12 (d, J= 6.2 Hz, 1H), 6.41 (d,
1
J= 6 Hz, 1H), 5.81 (s, 1H), 1.44 (s, 9H) ppm; C NMR (100 MHz, CDCl
3
3
) δ: 167.9, 157.0,
1
1
34.0, 132.0, 131.6, 131.0, 130.2, 128.9, 127.7, 127.1, 126.5, 125.1, 124.1, 123.0, 122.5,
22.4, 113.0, 110.4, 105.6, 103.4, 56.7, 52.2, 28.6 ppm; HRMS (ESI) calcd for
+
] 424.2025, found 424.2022.
[
C
27
H
26
N
3
O
2
N-Cyclohexyl-2-(1-oxo-1H-pyrido[3,4-b]indol-2(9H)-yl)-2-phenylacetamide (9g). Isolated
as a white solid; 72 % yield (287 mg); mp 171-174 ºC; IR (KBr) νmax: 3400, 3019, 2933
-
1 1
1
7
7
3
650, 1215, 759 cm ; H NMR (400 MHz, CDCl ) δ: 10.80 (s, 1H), 7.93 (d, J= 7.9 Hz, 1H),
.58 (d, J= 8.4 Hz, 1H), 7.46 (d, J= 2.5 Hz, 1H), 7.44 (m, 2H), 7.42 (t, J= 1.4 Hz, 2H), 7.406-
.400 (t, J= 1.6 Hz, 1H), 7.21 (d, J= 7.3 Hz, 2H), 7.10 (s, 1H), 6.96 (d, J= 7 Hz, 1H), 6.31 (d,
J= 8 Hz, 1H), 3.94-3.86 (m, 1H), 2.01 (d, J= 12.5 Hz, 1H), 1.93 (d, J= 9.6 Hz, 2H), 1.71-1.65
1
3
(
m, 2H), 1.62-1.57 (m, 1H), 1.39-1.32 (m, 2H), 1.19-1.13 (m, 2H) ppm; C NMR (100 MHz,
DMSO-d ) δ: 167.3, 155.5, 139.9, 137.6, 129.3, 128.9, 128.6, 127.7, 127.3, 126.8, 123.6,
22.2, 121.6, 120.0, 113.0, 99.7, 59.6, 48.5, 32.6, 32.6, 25.6, 24.9 ppm; HRMS (ESI) calcd
6
1
+
26 3 2
for [C25H N O ] 400.2025; found 400.2021.

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DOI: 10.1039/C5RA27090A
N-Cyclohexyl-2-(1-oxopyrazino[1,2-a]indol-2(1H)-yl)-2-phenylacetamide (10g). Isolated
as a white solid; 12 % yield (48 mg); mp 170-173
̊
-
1 1
1
215, 757 cm ; H NMR (400 MHz, CDCl
3
) δ: 7.83 (d, J= 8.1 Hz, 1H), 7.63 (d, J= 8.3 Hz,
1H), 7.46-7.38 (m, 7H), 7.33 (d, J= 7.6 Hz, 1H), 7.25 (d, J= 6 Hz, 1H), 6.80 (s, 1H), 6.62 (d,
J= 5.8 Hz, 1H), 6.26 (d, J= 8 Hz, 1H), 3.90-3.87 (m, 1H), 2.03 (d, J= 12.5 Hz, 1H), 1.96 (d,
J= 12.4 Hz, 1H), 1.75-1.68 (m, 2H), 1.64-1.59 (m, 1H), 1.44-1.34 (m, 2H), 1.25-1.14 (m, 3H)
1
ppm; C NMR (100 MHz, CDCl
3
3
) δ: 167.2, 157.4, 135.3, 132.1, 129.1, 128.8, 127.7, 127.1,
124.1, 122.6, 122.4, 113.4, 110.5, 105.8, 103.5, 59.0, 48.9, 32.8, 32.7, 25.4, 24.7 ppm; HRMS
+
(
26 3 2
ESI) calcd for [C25H N O ] 400.2025; found 400.2022.
2-(1-Oxo-1H-pyrido[3,4-b]indol-2(9H)-yl)-2-phenyl-N-(2,4,4-trimethylpentan-2-
yl)acetamide (9h). Isolated as a green solid; 69 % yield (296 mg); mp 110-113
̊C ; IR (KBr)
-
1 1
ν
max : 3418, 3019, 1648, 1215, 757 cm ; H NMR (400 MHz, CDCl
3
) δ: 10.85 (s, 1H), 7.94
(d, J= 7.9 Hz, 1H), 7.59 (d, J= 8.1 Hz, 1H), 7.48-7.42 (m, 3H), 7.41 (t, J= 7.4 Hz, 3H), 7.25-
7.21 (m, 1H), 7.04 (s, 1H), 6.98 (d, J= 7.2 Hz, 1H), 6.17 (s, 1H), 1.85 (d, J= 14.5 Hz, 1H),
1
3
1
.66 (d, J= 14.8 Hz, 1H), 1.49 (s, 3H), 1.46 (s, 3H), 0.90 (s, 9H) ppm; C NMR (100 MHz,
) δ: 167.0, 156.0, 140.1, 135.9, 129.1, 128.9, 128.7, 127.2, 127.0, 126.4, 125.1, 122.2,
21.2, 120.1, 112.7, 101.6, 61.6, 56.1, 52.2, 31.3, 28.9, 28.5 ppm; HRMS (ESI) calcd for
CDCl
3
1
+
[
27 32 3 2
C H N O ] 430.2495; found 430.2483.
2-(1-Oxopyrazino[1,2-a]indol-2(1H)-yl)-2-phenyl-N-(2,4,4-trimethylpentan-2-
yl)acetamide (10h). Isolated as a white solid; 8 % yield (34 mg); mp 160-163
̊C ; IR (KBr)
-
1 1
ν
1
2
6
max : 3323, 3019, 1617, 1215, 757 cm ; H NMR (400 MHz, CDCl
3
) δ: 7.85 (d, J= 8.1 Hz,
H), 7.63 (d, J= 8.6 Hz, 1H), 7.48 (t, J= 8 Hz, 3H), 7.43 (t, J= 3 Hz, 1H), 7.41 (t, J= 2.4 Hz,
H), 7.40 (d, J= 3.2 Hz, 1H), 7.32 (d, J= 7.4 Hz, 1H), 7.25 (d, J= 6.2 Hz, 1H), 6.68 (s, 1H),
.58 (d, J= 6.1 Hz, 1H), 5.94 (s, 1H), 1.91 (d, J= 14.8 Hz, 1H), 1.63 (d, J= 14.7 Hz, 1H), 1.51
1
3
(
3
s, 3H), 1.47 (s, 3H), 0.95 (s, 9H) ppm; C NMR (100 MHz, CDCl ) δ: 167.0, 157.3, 135.2,

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1
5
4
32.1, 129.1, 128.9, 128.8, 127.7, 127.1, 124.1, 122.6, 122.4, 113.3, 110.5, 105.8, 103.5,
+
] 430.2495; found
9.5, 56.2, 52.1, 31.4, 29.0, 28.6 ppm; HRMS (ESI) calcd for [C27
H
32
N
3
O
2
30.2493.
N-(4-Methoxyphenyl)-2-(1-oxo-1H-pyrido[3,4-b]indol-2(9H)-yl)-2-phenylacetamide (9i).
Isolated as a yellow solid; 46 % yield (194 mg); mp 180-183 C; IR (KBr) νmax: 3401, 3019,
̊
-
1
1
6
1
1
6
1
1
644, 1215, 758 cm ; H NMR (400 MHz, DMSO-d ) δ: 10.60 (s, 1H), 8.00 (d, J= 8 Hz,
H), 7.57-7.54 (m, 3H), 7.50-7.38 (m, 7H), 7.20 (t, J= 8 Hz, 1H), 7.07 (s, 1H), 6.98 (s, 2H),
13
6
.93-6.89 (m, 2H), 3.72 (s, 3H) ppm; C NMR (100 MHz, DMSO-d ) δ: 166.8, 156.0, 155.6,
39.9, 136.6, 132.2, 129.6, 129.4, 129.4, 127.39, 127.32, 126.95, 123.8, 122.1, 121.7, 121.2,
+
] 424.1661;
20.1, 114.4, 113.0, 100.0, 60.9, 55.6 ppm; HRMS (ESI) calcd for [C26
22
H N
3
O
3
found 424.1656.
N-(4-Methoxyphenyl)-2-(1-oxopyrazino[1,2-a]indol-2(1H)-yl)-2-phenylacetamide (10i).
Isolated as a pink solid; 11 % yield (46 mg); mp 160-163 C; IR (KBr) νmax : 3392, 1623,
̊
-
1 1
1
7
1
3
1
5
403, 1215, 765 cm ; H NMR (400 MHz, CDCl ) δ: 8.54 (s, 1H), 7.82 (d, J= 8 Hz, 1H),
3
.63 (d, J= 8.5 Hz, 1H), 7.53 (d, J= 9 Hz, 4H), 7.43 (t, J= 4.0 Hz, 5H), 7.33 (d, J= 7.5 Hz,
H), 7.30 (ds, J= 4.5 Hz, 2H), 7.06 (s, 1H), 6.85 (d, J= 8.9 Hz, 1H), 6.67 (d, J= 6.1 Hz, 1H),
13
.78 (s, 3H) ppm; C NMR (100 MHz, CDCl ) δ: 166.4, 157.6, 156.6, 134.7, 132.1, 130.7,
3
29.2, 128.9, 127.7, 126.9, 124.3, 122.6, 122.5, 121.7, 114.1, 113.2, 110.5, 106.2, 103.6,
+
] 424.1661; found 424.1663.
9.8, 55.4 ppm; HRMS (ESI) calcd for [C26
H
22
N
O
3 3
2-(1-Oxo-1H-pyrido[3,4-b]indol-2(9H)-yl)-N-pentyl-2-phenylacetamide (9j). Isolated as a
yellow solid; 72 % yield (279 mg); mp 110-113
̊
-
1 1
7
57 cm ; H NMR (400 MHz, CDCl
3
) δ: 9.91 (s, 1H), 7.94 (d, J= 7.7 Hz, 1H), 7.57 (d, J=
8.4 Hz, 1H), 7.49 (d, J= 7 Hz, 1H), 7.45-7.40 (m, 5H), 7.27 (t, J= 7.3 Hz, 1H), 7.21 (d, J= 7.5
Hz, 1H), 7.00 (s, 1H), 6.95 (d, J= 7.4 Hz, 1H), 6.32 (s, 1H), 3.40-3.30 (m, 2H), 1.55 (t, J= 8.0
1
3
Hz, 2H), 1.30-1.27 (m, 4H), 0.88 (t, J= 6.9 Hz, 3H) ppm; C NMR (100 MHz, DMSO-d ) δ:
6

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DOI: 10.1039/C5RA27090A
168.2, 155.5, 139.9, 137.3, 129.4, 129.1, 128.8, 127.5, 127.3, 126.8, 123.6, 122.1, 121.7,
120.1, 112.9, 99.8, 59.9, 39.2, 28.98, 28.92, 22.2, 14.3 ppm; HRMS (ESI) calcd for
+
] 388.2025, found 388.2026.
[
C
24
H
26
N
3
O
2
2-(1-Oxopyrazino[1,2-a]indol-2(1H)-yl)-N-pentyl-2-phenylacetamide (10j). Isolated as a
yellow solid; 11 % yield (42 mg); mp 125-127
̊
-
1 1
cm ; H NMR (400 MHz, CDCl
3
) δ: 7.85 (d, J= 8 Hz, 1H), 7.64 (d, J= 8.3 Hz, 1H), 7.45 (s,
2H), 7.43 (d, J= 7.6 Hz, 4H), 7.39 (d, J= 4.6 Hz, 1H), 7.34 (t, J= 7.4 Hz, 1H), 7.26 (d, J= 6
Hz, 1H), 6.77 (s, 1H), 6.59 (d, J= 6 Hz, 1H), 6.17 (bs, 1H), 3.43-3.30 (m, 2H), 1.58 (t, J= 8.0
1
3
Hz, 2H), 1.34-1.29 (m, 4H), 0.91 (t, J= 6.8 Hz, 3H) ppm; C NMR (100 MHz, CDCl ) δ:
3
168.0, 157.4, 135.0, 132.1, 129.1, 128.8, 127.7, 127.3, 127.1, 124.2, 122.6, 122.5, 113.2,
110.5, 106.0, 103.5, 59.1, 39.9, 29.0, 29.0, 22.2, 13.9 ppm; HRMS (ESI) calcd for
+
] 388.2025; found 388.2018.
[
C
24
H
26
N
3
O
2
N-Cyclohexyl-2-(1-oxo-1H-pyrido[3,4-b]indol-2(9H)-yl)hexanamide (9k). Isolated as a
white solid; 13 % yield (49 mg); mp 220-223
̊
-
1 1
cm ; H NMR (400 MHz, DMSO-d
6
) δ: 11.91 (s, 1H), 8.22 (d, J= 8 Hz, 1H), 8.03 (d, J= 7.8
Hz, 1H), 7.53 (d, J= 8.2 Hz, 1H), 7.48 (d, J= 7.2 Hz, 1H), 7.43 (t, J= 7.1 Hz, 1H), 7.20 (t, J=
7
1
1
.2 Hz, 1H), 7.06 (d, J= 7.3 Hz, 1H), 5.69-5.65 (m, 1H), 3.55-3.52 (m, 1H), 2.05-2.00 (m,
H), 1.91-1.86 (m, 1H), 1.76 (d, J= 9.3 Hz, 1H), 1.66 (bs, 3H), 1.55 (d, J= 12.1 Hz, 1H),
.33-1.26 (m, 2H), 1.24-1.15 (m, 4H), 1.13-1.08 (m, 3H), 0.83 (t, J= 8 Hz, 3H) ppm; poor
+
]
solubility so carbon is not clear; HRMS (ESI) calcd for [C23
80.2334.
H
30
N
3
O
2
380.2338; found
3
N-Cyclohexyl-2-(1-oxopyrazino[1,2-a]indol-2(1H)-yl)hexanamide (10k). Isolated as a
yellow solid; 11 % yield (42 mg); mp 150-153 C; IR (KBr) νmax: 3413, 3018, 2931, 1627,
215, 757 cm ; H NMR (400 MHz, CDCl ) δ: 7.85 (d, J= 7.9 Hz, 1H), 7.69 (d, J= 8.4 Hz,
̊
-1 1
1
3

Page 29 of 53
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DOI: 10.1039/C5RA27090A
1H), 7.45 (t, J= 8 Hz, 2H), 7.37 (t, J= 6.1 Hz, 1H), 7.33 (d, J= 7.6 Hz, 1H), 6.78 (d, J= 5.9
Hz, 1H), 6.20 (d, J= 8.2 Hz, 1H), 5.44 (t, J= 7.8 Hz, 1H), 3.78-3.69(m, 1H), 2.20-2.11 (m,
1H), 1.96-1.86 (m, 2H), 1.80 (t, J= 12.0 Hz, 2H), 1.66 (t, J= 20.0 Hz, 3H), 1.41-1.31 (m, 3H),
1
.27-1.23 (m, 2H), 1.21-1.06 (m, 3H), 0.92 (t, J= 6.8 Hz, 3H) ppm; C NMR (100 MHz,
3
1
CDCl ) δ: 168.5, 157.4, 132.1, 127.7, 127.1, 124.3, 122.6, 111.1, 110.5, 106.7, 103.5, 55.5,
3
+
30 3 2
48.5, 32.8, 32.7, 27.8, 25.4, 24.7, 24.6, 22.3, 13.8 ppm; HRMS (ESI) calcd for [C23H N O ]
380.2338; found 380.2335.
N-Cyclohexyl-2-(4-(2-(cyclohexylamino)-2-oxo-1-(1-oxo-1H-pyrido[3,4-b]indol-2(9H)-
yl)ethyl)phenyl)-2-(1-oxo-1H-pyrido[4,3-b]indol-2(5H)-yl)acetamide (9l). Isolated as a
white solid; 58 % yield (418 mg); mp 200-203
̊
-
1 1
cm ; H NMR (500 MHz, DMSO-d
6
) δ: 11.99 (s, 2H), 8.61-8.58 (m, 1H), 7.98 (d, J= 8.2 Hz,
2
H), 7.84-7.80 (m, 1H), 7.54 (d, J= 8.5 Hz, 2H), 7.43 (t, J= 7.7 Hz, 3H), 7.38 (d, J= 9.2 Hz,
H), 7.35 (d, J= 9.4 Hz, 2H), 7.32(t, J= 3.9 Hz, 1H), 7.19 (t, J= 7.7 Hz, 1H), 7.10 (t, J= 7.4
2
Hz, 2H), 6.97 (s, 1H), 6.96 (d, J= 3.7 Hz, 2H), 3.67-3.59 (m, 2H), 1.82 (d, J= 10.9 Hz, 2H),
1
3
1
.75 (d, J= 10.3 Hz, 2H), 1.63-1.52 (m, 6H), 1.29-1.19 (m, 4H), 1.16-1.09 (m, 6H) ppm; C
NMR (100 MHz, DMSO-d ) δ: 167.0, 155.5, 139.9, 129.9, 129.2, 127.4, 127.2, 126.6, 123.6,
22.4, 122.1, 121.5, 119.9, 112.9, 106.2, 99.8, 59.0, 48.6, 32.6, 25.6, 24.9s ppm; HRMS
6
1
+
(
45 6 4
ESI) calcd for [C44H N O ] 721.3502; found 721.3475.
N-(tert-Butyl)-2-(1H-indol-3-yl)-2-(1-oxopyrazino[1,2-a]indol-2(1H)-yl)acetamide (10m).
Isolated as a brown solid; 12 % yield (49 mg); mp 160-163
̊
-
1 1
1
650, 1215, 769 cm ; H NMR (400 MHz , CDCl
3
) δ: 8.92 (s, 1H), 8.21 (s, 1H), 7.96 (d, J= 8
Hz, 1H), 7.55 (d, J= 3.7 Hz, 2H), 7.54 (d, J= 2.8 Hz, 1H), 7.41 (s, 1H), 7.35 (d, J= 6.8 Hz,
2
6
1
H), 7.20 (t, J= 5.8 Hz, 1H), 7.16 (t, J= 8.0 Hz, 2H), 7.02 (t, J= 7.7 Hz, 1H), 6.69 (s, 1H),
1
3
.50 (s, 1H), 6.33 (t, J= 5.5 Hz, 1H), 1.33 (s, 9H) ppm; C NMR (100 MHz, CDCl ) δ: 172.0,
3
59.7, 136.2, 131.6, 126.9, 126.7, 124.3, 124.0, 123.0, 122.7, 122.1, 121.9, 119.4, 119.1,