Access to indole- and pyrrole-fused diketopiperazines via tandem Ugi-4CR/intramolecular cyclization and its regioselective ring-opening by intermolecular transamidation

Article abstract of DOI:10.1021/jo3018704

An efficient approach for the synthesis of indole- and pyrrole-fused diketopiperazines has been developed. This protocol involves the Ugi four-component reaction (U-4CR) followed by an intramolecular cyclization of the Ugi products at room temperature to

Full text of DOI:10.1021/jo3018704

Article
pubs.acs.org/joc
Access to Indole- And Pyrrole-Fused Diketopiperazines via Tandem
Ugi-4CR/Intramolecular Cyclization and Its Regioselective Ring-
Opening by Intermolecular Transamidation
Shashi Pandey,† Shahnawaz Khan,† Awantika Singh,‡ Harsh M. Gauniyal,‡ Brijesh Kumar,‡
and Prem M. S. Chauhan*,†
‡
†Medicinal and Process Chemistry Division, Sophisticated Analytical Instrument Facility, CSIR-Central Drug Research Institute,
Lucknow, 226 001, India
S
* Supporting Information
ABSTRACT: An efficient approach for the synthesis of indole- and pyrrole-fused diketopiperazines has been developed. This
protocol involves the Ugi four-component reaction (U-4CR) followed by an intramolecular cyclization of the Ugi products at
room temperature to afford the desired products in good to excellent yields. In addition, it is interesting to report the subsequent
regioselective ring-opening of diketopiperazine unit occurring via an intermolecular transamidation reaction under mild
condition, resulting in the formation of highly functionalized indole-2-carboxamides and pyrrole-2-carboxamides.
64821, and WIN 6474522 contain heterofused DKP fragments
INTRODUCTION
■
(Figure 1).
Multicomponent reactions1 (MCRs, especially isocyanide based
Due to the immense significance of these DKPs, cost-
multicomponent reactions I-MCRs2) have attracted consid-
effective and diversity-oriented synthesis is warranted. Although
erable attention from the synthetic organic chemistry
several synthetic protocols for the preparation of these DKPs
community owing to their utility in rapid construction of
are available in the literature,23 either they are not cost-effective
structurally diverse, complex, and biologically relevant mole-
or they lack the feature of diversity within the same molecular
cules from simple precursors. Moreover, these MCRs are highly
flexible, often (chemo and/or regio) selective, convergent,
operationally simple, and atom-efficient, not only providing
molecular diversity and complexity in resulting molecules but
framework. The structural diversity can be generated by the use
of MCRs . In this context, the Ugi reaction had been extensively
utilized for the construction of 2,5 DKPs24 as well as hetero-
fused DKPs.25−28
also capable of providing scaffolds with appropriate function-
In the recent past, Kaim et al. reported the synthesis of fused
tricyclic 2,5 DKP by Ugi reaction followed by Pictet-Spengler,25
Hulme et al. reported the tetrazole-fused ketopiperazine
through Ugi reaction followed by intramolecular cyclization,26
and Krasavin and co-worker reported 2,3-dihydropyrazino[1,2-
a]indole-1,4-diones via a one-pot, two-step procedure involving
Ugi reaction followed by microwave-assisted cyclization.27 Very
recently, Orru et al. reported the elegant synthesis of fused-
DKPs by a tandem biocatalysis/Ugi/Pictet−Spengler-type
cyclization sequence.28 Although the above procedures for
preparation of monocyclic as well as polycyclic DKPs present
an efficient approach to expand the structural diversity, they still
suffer from the limitation of multistep synthesis, prolonged time
alities suitable for further transformations.3
Recently, IMCR coupled with postchemical transformations
such as condensation,4 ring-closure metathesis,5 cycloaddition,6
macrolactonization,7 and so forth in preorganized structures has
emerged as a promising strategy for the creation of highly
diverse heterocyclic scaffolds.8
Among the various bioactive heterocyclic molecules,
Diketopiperazines (DKPs) constitute a unique class of
compounds as a “privileged” scaffold present in many natural
products and are responsible for a wide range of biological
activities9,23b as antitumor,10 antiviral,11 antifungal,12 antibacte-
rial,13 and antihyperglycemic agents,14 GABA-ergic,15 serotoni-
nergic 5-HT1A16 and oxytocin receptors,17 and so forth.
Several natural products such as Gliotoxin,18 Glionitrin B,19
Spirotryprostatin A,20 Demethoxyfumitremorgine C,21 WIN
Received: August 30, 2012
Published: October 12, 2012
© 2012 American Chemical Society
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Figure 1. Example of some biologically active natural products containing “fused- DKP” scaffolds.
Scheme 1. Synthesis of Indole- and Pyrrole-Fused DKPs
Scheme 2. Synthesis of Highly Diverse 1H-Indole-2-carboxamides and 1H-Pyrrole-2-carboxamides
period, stringent reaction conditions including refluxing or
microwave conditions, and low yield. Clearly, there is an urgent
need to develop an alternative procedure for the simple and
rapid synthesis of heteroaryl-fused DKPs.
As a part of our continuing interest in the development of a
novel strategy for synthesis of biologically important N-
heterocyclic scaffolds29 and encouraged by skeletal diversity
provided by IMCRs,30 herein we report a mild and efficient
protocol for the synthesis of heteroaryl-fused DKPs via Ugi-
4CR followed by intramolecular cyclization in one-pot
operation (Scheme 1).
Moreover, we also report the further transformation of these
fused-DKPs to densely functionalized 1H-indole-2-carboxa-
mides and 1H-pyrrole-2-carboxamides resulting from regioslec-
tive ring-opening of DKPs unit via intermolecular trans-
amidation with various primary amines under mild reaction
conditions (Scheme 2). To the best of our knowledge, this is
the first example of a regioselectivity transamidation reaction of
heterofused diketopiperazines under mild conditions.
RESULTS AND DISCUSSION
■
Initially, glycine ester (1), 4-chlorobenzaldehyde (2), tert-butyl
isocyanide (3), and 1H-indole-2-carboxylic acid (4) in
equimolar amounts were chosen as a model substrate to
establish the feasibility of the strategy and to optimize the
reaction conditions including bases and solvents (Table 1). It
was found that when the reaction was carried out without any
base only normal Ugi product (5) was obtained in low yield of
45% even after 24 h (Table 1, entry 1). Then, we carried out
this model reaction by employing a variety of bases (Table 1,
entries 2−6). In the presence of base, the desired cyclized
product (6a) was obtained. We reasoned that addition of base
not only neutralized the glycine methyl ester hydrochloride, but
also accelerated the cyclization step. While examining the effect
of bases, 1.1 mmol of Et3N was found to be effective as base
(Table 1, entry 3); however, DIPEA, KOH, and K2CO3 gave
inferior results (Table 1, entries 2, 5, and 6). Next, we carried
out reaction with 2 mmol of Et3N; the reaction was very
sluggish and furnished a mixture of products with the formation
of (6a) in 60% isolated yield (Table 1, entry 10). To see the
effect of solvents, we examined our reaction in different solvent
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a
Table 1. Optimization of reaction conditions for the synthesis of indole-fused DKPs
b
entry
base (mmol)
solvent
time
yield of 6a
c
1
2
-
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
24 h
60 min
50 min
24 h
7 h
Nr
DIPEA (1.1)
Et3N (1.1)
DBU(1.1)
KOH (1.1)
K2CO3(1.1)
Et3N (1.1)
Et3N (1.1)
Et3N (1.1)
Et3N (2)
82%
90%
20%
80%
84%
80%
30%
70%
60%
3
4
5
6
3 h
7
2 h
8
THF
24 h
2 h
9
CH2Cl2
MeOH
10
50 min
a
Reaction conditions: Glycine methyl ester as HCl salt (1 mmol), 4-chlorobenzaldehyde (1 mmol), tert-butyl isocyanide (1 mmol), and 1H-indole-
b
c
2-carboxylic acid (1 mmol) in 3 mL solvent at room temperature . Isolated yield. Nr uncyclized Ugi product (5) was obtained .
systems as depicted in (Table 1). When the reaction solvent
was changed from MeOH to EtOH and CH2Cl2, a significant
reduction in isolated product yields of 80% and 70%,
respectively, were observed (Table 1, entries 7 and 9). This
suggests that, among the solvent systems examined, MeOH is
the favored solvent system for this reaction.
With the success of our strategy, we wish to expand the scope
of the reaction by employing the 1H-pyrrole-2-carboxylic acid
instead of 1H-indole-2-carboxylic acid under optimized reaction
conditions as described earlier, which afforded the required
pyrrole-fused DKPs in 75−82% yields, and results were
summarized in Table 3.
Additionally, to examine the effect of a substituent on the
heterocyclic scaffold on the reaction sequence we synthesized
3-iodo-1H-indole-2-carboxylic acid and 3,4,5-tribromo-1H-
pyrrole-2-carboxylic acid by following the method reported in
the literature31 and applied our protocol; in the case of 3-iodo-
1H-indole-2-carboxylic acid, the reaction went smoothly,
resulting in product 6aa (Table 2, entry-27). Moreover, we
believe that this iodo substitution can be further utilized for
various palladium and copper catalyzed coupling reactions as
Suzuki-miyuara, Heck, Sonogashira reactions. However, with
3,4,5-tribromo-1H-pyrrole-2-carboxylic acid reaction failed to
yield desired product.
Next, to further explore the synthetic potential of these
highly diverse DKPs we treated fused DKPs with different
amines leading to the formation of densely functionalized 1H-
indole-2-carboxamides and 1H-pyrrole-2-carboxamides via
intermolecular transamidation. It is noteworthy that carbox-
amide is omnipresent in numerous biological and synthetic
polymers, as well as being extensively utilized for the
preparation of pharmaceuticals and agrochemicals, and in
synthetic organic chemistry.32 Furthermore, 1H-indole-2-
carboxamide and 1H-pyrrole-2-carboxamide templates are
present in natural products,33 as well as in numerous
biologically active compounds associated with a wide range of
biological activity as fibrinogen receptor antagonists,34 glycogen
phosphorylase inhibitors,35 inhibitors of human LDL copper-
induced peroxidation,36 potent Bcl-2/Bcl-xL inhibitors,38 and
allosteric modulators of the Cannabinoid CB1 receptor,40 as
well as anti-HIV-1 activity37 and antiviral activity against
With the optimized conditions established above for the
synthesis of (6a), we decided to probe the generality of the
reaction to construct indole-fused DKP derivatives. The
reaction appears to be versatile, and 27 compounds 6(a−z)
and 6aa were synthesized in 70−90% yield (Table 2, entries 1−
27) by treating aldehydes, amino acid esters as amine input,
two different isocyanides, and 1H-indole-2-carboxylic acid.
The protocol was effective with aromatic aldehydes having
either electron-withdrawing or electron donating groups. It is
noteworthy that the reactions of halo-substituted benzalde-
hydes proceeded in shorter time. In the case of ortho-
substituted aldehydes, the reaction time was significantly
longer, which is likely due to its steric properties (Table 2,
entries 19 and 20). The furan-2-carbaldehyde, as a hetero-
aromatic aldehyde, was used in this reaction and gave moderate
yield (Table 2, entry 14). We have also examined the alicyclic
ketones to survey the scope and generality of our methodology;
the reaction of alicyclic ketones with 1H-indole-2-carboxylic
acid, glycine methyl ester, and tert-butyl isocyanide went
smoothly, and products were obtained in good yields (Table 2,
entries 21 and 22).
The structure of the products 6(a−z) and 6aa were deduced
from their IR, HRMS, 1H NMR, and 13C NMR spectra.
Furthermore, the disappearance of two characteristic peaks, that
is, the singlet of three protons of -OCOCH3 of amino ester
(around δ 3.8 ppm) and singlet of -NH proton of indole
1
(around δ 9.7 ppm) in H NMR, confirmed the formation of
cyclized product (see the Experimental Section).
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Table 2. Synthesis of Indole-Fused DKPs by Utilizing Ugi-4CR
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Table 2. continued
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Table 2. continued
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Table 2. continued
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Table 2. continued
a
Reaction conditions: Amino acid methyl ester as HCl salt (1 mmol), Et3N (1.1 mmol), corresponding aldehydes (1 mmol), isocyanide (1 mmol),
b
and 1H-indole-2-carboxylic acid (1 mmol) in 3 mL methanol at room temperature. Isolated yield.
virulent neurotropic alphaviruses,39 thus remaining target
structures of interest to synthetic chemists.
with fused DKPs in ethanol at reflux (Table-4). Thus, the above
transformation provides a novel, mild, and efficient approach
for the synthesis of biologically relevant, densely functionalized
indole 2-carboxamides.
For the synthesis of these 1H-indole-2-carboxamides and 1H-
pyrrole-2-carboxamides, initially we treated the indole-fused
DKP (6a) and benzyl amine in ethanol under reflux. The
progress of the reaction was monitored by TLC, and after 4 h,
we observed the complete disappearance of (6a) followed by
the emergence of a new spot on TLC (Scheme 3).
The synthesized product was well-characterized as 9a by
their IR, HRMS, 1H NMR, and 13C NMR spectra. The
molecular formula of product 9a was suggested to be
C30H31ClN4O3 by the HRMS peak (M + H)+ at 531.2153.
Moreover, the appearance of a characteristic sharp singlet of
−NH proton of indole at around δ 9.58 ppm further confirms
the formation of 9a.
It is also interesting to note that regioselectivity was observed
during the intermolecular transamidation reaction on 6a.
Remarkably, apart from 9a, two other structures 10 and 11
could also form; however, 9a was formed exclusively. This
regioselectivity may be due to the higher electrophilicity of
carbonyl carbon of amide (marked with *) as compared to the
other two in 6a (Scheme 4).
Furthermore, the series of highly substituted indole 2-
carboxamides and pyrrole 2-carboxamides 9(a−h) were easily
obtained in good to excellent yield by treating various amines
CONCLUSION
■
In summary, we have developed the most concise, mild, and
efficient strategy to construct the highly functionalized indole-
and pyrrole-fused DKPs via tandem Ugi-4CR/intramolecular
cyclization in good to excellent yields. The operational
simplicity, mild reaction condition, and high efficiency nature
make this synthetic strategy highly attractive and promising for
the construction of heteroaryl-fused DKPs, which are of
considerable interest as potential biologically active compounds
or pharmaceuticals. In addition, we have also described the mild
protocol for the synthesis of pharmacologically active highly
diverse 1H-indole-2-carboxamides and 1H-pyrrole-2-carboxa-
mides, which involves the reigioselective intermolecular trans-
amidation under mild reaction condition. Biological screening
of synthesized compounds are currently under progress in our
laboratory and will be reported in due course.
EXPERIMENTAL SECTION
General Procedure for the Preparation of Compound 5. To a
stirred solution of glycine methyl ester hydrochloride (1 mmol) in
■
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Table 3. Synthesis of Pyrrole-Fused DKPs by Utilizing Ugi-4CR
a
Reaction conditions: Glycine methyl ester as HCl salt (1 mmol), Et3N (1.1 mmol), benzaldehydes (1 mmol), isocyanide (1 mmol), and 1H-
b
pyrrole-2-carboxylic acid (1 mmol) in 3 mL methanol at room temperature. Isolated yield.
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Scheme 3. Synthesis of Indole 2-Carboxamide Derivative by Ring-Opening of DKP Unit via Intermolecular Transamidation
Scheme 4. Three Possibilities for the Formation of Products (9−11) by Regioselective Intermolecular Transamidation
methanol (3 mL) were added successively 4-chlorobenzaldehyde (1
mmol), 1H-indole-2-carboxylic acid 4 (1 mmol), and tert-butyl
isocyanide (1 mmol). The mixture was stirred at room temperature
for 24 h. After completion of the reaction, solvent was evaporated at
reduced pressure and purified through column chromatography
(eluent: CHCl3/MeOH) using 100−200 mesh silica gel to afford
the desired product.
of time as indicated in Table 2. The progress of the reaction was
monitored by TLC. After completion of the reaction, solvent was
evaporated at reduced pressure and purified through column
chromatography (eluent: CHCl3/MeOH) using 100−200 mesh silica
gel to afford the desired product 6(a-z) and 6aa.
N-tert-Butyl-2-(4-chlorophenyl)-2-(1,4-dioxo-3,4-dihydro-
pyrazino[1,2-a]indol-2(1H)-yl) acetamide (6a). White solid; Yield
90% (381 mg); Mp: 238−239 °C; IR (KBr) νmax: 3423, 3338, 1716,
[tert-Butylcarbamoyl-(4-chloro-phenyl)-methyl]-(1H-indole-2-
carbonyl)-amino]-acetic Acid Methyl Ester (5). White solid; Mp
180−181 °C; Yield 45% (205 mg); IR (KBr) νmax: 3433, 3015, 1729,
1
1640, 1570 cm−1; H NMR (300 MHz, CDCl3) δ = 8.41 (d, 1H, J =
8.0 Hz), 7.71 (d, 1H, J = 7.7 Hz), 7.52−7.47 (m, 2H), 7.43−7.36 (m,
5H), 6.33 (s, 1H), 5.69 (s, 1H), 5.04 (d, 1H, J = 19.4 Hz), 3.91 (d, 1H,
J = 19.4 Hz), 1.38 (s, 9H); 13C NMR (75 MHz, CDCl3) δ = 167.6,
161.7, 156.7, 135.4, 134.7, 132.0, 130.9, 129.5, 128.9, 128.1, 128.0,
125.3, 122.4, 116.5, 114.9, 58.5, 52.1, 49.0, 28.6; HRMS (ESI TOF
(+)) calcd for [C23H22ClN3O3 + H+] 424.1422; found 424.1423.
2-(4-Bromophenyl)-N-tert-butyl-2-(1,4-dioxo-3,4-dihydro-
pyrazino[1,2-a]indol-2(1H)-yl) acetamide (6b). White solid; Yield
86% (402 mg); Mp: 235−236 °C; IR (KBr) νmax: 3423, 3304, 1722,
1
1661 cm−1; H NMR (300 MHz, CDCl3) δ = 9.69 (s, 1H), 8.64 (s,
1H), 7.69 (d, 1H, J = 7.3 Hz), 7.59 (d, 1H, J = 7.7 Hz), 7.45−7.29 (m,
4H), 7.25−7.20 (m, 1H), 7.15 (t, 1H, J = 7.4 Hz), 7.04 (s, 1H), 6.39
(s, 1H), 4.09 (d, 1H, J = 16.2 Hz), 3.74 (s, 3H), 3.35 (d, 1H, J = 16.2
Hz), 1.49 (s, 9H); 13C NMR (75 MHz, CDCl3) δ = 171.7, 168.3,
165.3, 136.1, 135.0, 133.7, 130.9, 130.4, 128.0, 127.8, 126.4, 125.2,
122.7, 120.6, 111.7, 106.9, 67.6, 52.6, 52.2, 46.9, 28.5; HRMS (ESI
TOF (+)) calcd for [C24H26ClN3O4 + H+] 456.1685; found 456.1689.
General Procedure for the Preparation of Compound 6(a-
w). To a solution of amino ester hydrochloride (1 mmol) in methanol
(3 mL) was added triethylamine (1.1 mmol), and the resulting
solution was stirred at room temperature for 10 min. To the stirred
solution were successively added corresponding aldehdye (1 mmol),
1H-indole-2-carboxylic acid 4 (1 mmol), and isocyanide (1 mmol).
The mixture was stirred at room temperature for the specified period
1
1626, cm−1; H NMR (300 MHz, CDCl3) δ = 8.41 (d, 1H, J = 7.9
Hz), 7.71 (d, 1H, J = 7.6 Hz), 7.59 (d, 2H, J = 7.7 Hz), 7.49 (s, 2H),
7.41−7.30 (m, 3H), 6.31 (s, 1H), 5.67 (s, 1H), 5.04 (d, 1H, J = 19.3
Hz), 3.91 (d, 1H, J = 19.5 Hz), 1.38 (s, 9H); 13C NMR (50 MHz,
DMSO-d6) δ = 167.7, 162.4, 155.8, 134.3, 133.9, 131.7, 131.3, 129.0,
128.7, 127.5, 125.0, 122.6, 121.6, 115.6, 113.2, 58.0, 50.7, 49.5, 28.3;
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Table 4. . Synthesis of 1H-Indole-2-Carboxamide and 1H-Pyrrole-2-Carboxamide Derivatives via Regioselective Intermolecular
Transamidation
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Table 4. continued
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Table 4. continued
a
b
Reaction conditions: Fused diketopiperazine (1 mmol), amine (1.2 mmol) in 5 mL ethanol at reflux. Isolated yield.
1
HRMS (ESI TOF (+)) calcd for [C23H22BrN3O3 + H+] 468.0917;
found 468.0918.
N-tert-Butyl-2-(1,4-dioxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-
yl)-2-(4-fluorophenyl) acetamide (6c). White solid; Yield 82% (334
mg); Mp: 216−218 °C; IR (KBr) νmax: 3496, 3301, 1722, 1627 cm−1;
1H NMR (300 MHz, CDCl3) δ = 8.34 (d, 1H, J = 8.1 Hz), 7.64 (d,
216 °C; IR (KBr) νmax: 3488, 3368, 1713, 1643 cm−1; H NMR (300
MHz, CDCl3) δ = 8.40 (d, 1H, J = 7.9 Hz), 7.70 (d, 1H, J = 7.5 Hz),
7.50−7.47 (m, 2H), 7.39−7.35 (m, 1H), 7.31−7.22 (m, 4H), 6.33 (s,
1H), 5.64 (s, 1H), 5.00 (d, 1H, J = 19.6 Hz), 3.91 (d, 1H, J = 19.6 Hz),
2.37 (s, 3H), 1.38 (s, 9H); 13C NMR (50 MHz, CDCl3) δ = 168.2,
162.0, 156.6, 139.2, 134.6, 130.3, 129.9, 129.5, 128.9, 128.4, 127.7,
125.2, 122.3, 116.4, 114.6, 59.1, 51.9, 49.1, 28.6, 21.1; HRMS (ESI
TOF (+)) calcd for [C24H25N3O3 + H+] 404.1969; found 404.1969.
N-tert-Butyl-2-(1,4-dioxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-
yl)-2-(4-ethylphenyl) acetamide (6h). White solid; Yield 76% (317
1H, J = 7.6 Hz), 7.44−7.39 (m, 2H), 7.38−7.29 (m, 3H), 7.09 (t, 2H, J
= 8.4 Hz), 6.27 (s, 1H), 5.62 (s, 1H), 4.97 (d, 1H, J = 19.5 Hz), 3.84
(d, 1H, J = 19.5 Hz), 1.31 (s, 9H); 13C NMR (50 MHz, CDCl3) δ =
167.9, 161.8, 156.6, 134.6, 131.5, 131.3, 129.4, 128.9, 128.2, 127.9,
125.3, 122.3, 116.5, 116.4, 116.1, 114.8, 58.4, 52.0, 49.0, 28.6; HRMS
(ESI TOF (+)) calcd for [C23H22FN3O3 + H+] 408.1718; found
408.1718.
N-tert-Butyl-2-(4-chloro-3-fluorophenyl)-2-(1,4-dioxo-3,4-
dihydropyrazino[1,2-a]indol-2 (1H)-yl)acetamide (6d). White solid;
Yield 82% (362 mg); Mp: 228−229 °C; IR (KBr) νmax: 3428, 3021,
1639 cm−1; 1H NMR (300 MHz, CDCl3) δ = 8.42 (d, 1H, J = 8.2 Hz),
7.72 (d, 1H, J = 7.7 Hz), 7.53−7.44 (m, 3H), 7.42−7.29 (m, 2H), 7.19
(d, 1H, J = 8.2 Hz), 6.31 (s, 1H), 5.74 (s, 1H), 5.05 (d, 1H, J = 19.4
Hz), 3.94 (d, 1H, J = 19.4 Hz), 1.39 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ = 167.1, 161.5, 156.8, 134.7, 134.2, 134.1, 131.5, 128.9,
128.1, 127.9, 125.8, 125.7, 125.4, 122.4, 117.9, 117.6, 116.5, 115.2,
58.1, 52.2, 49.02, 28.6; HRMS (ESI TOF (+)) calcd for
[C23H21ClFN3O3 + Na+] 464.1148; found 464.1139.
mg); Mp: 186−187 °C; IR (KBr) νmax: 3336, 1716, 1642 cm−1; H
1
NMR (300 MHz, CDCl3) δ = 8.41 (d, 1H, J = 8.1 Hz), 7.71 (d, 1H, J
= 7.7 Hz), 7.50−7.45 (m, 2H), 7.40−7.38 (m, 1H), 7.34−7.24 (m,
4H), 6.34 (s, 1H), 5.60 (s, 1H), 5.01 (d, 1H, J = 19.6 Hz), 3.92 (d, 1H,
J = 19.6 Hz), 2.71 (q, 2H, J = 7.5 Hz), 1.38 (s, 9H), 1.28 (t, 3H, J = 7.6
Hz); 13C NMR (75 MHz, CDCl3) δ = 168.1, 162.1, 156.6, 145.6,
134.7, 130.6, 129.6, 129.0, 128.9, 128.5, 127.8, 125.3, 122.4, 116.5,
114.7, 59.2, 52.1, 49.1, 28.6, 28.5, 15.34; HRMS (ESI TOF (+)) calcd
for [C25H27N3O3 + H+] 418.2125; found 418.2122.
N-tert-Butyl-2-(1,4-dioxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-
yl)-2-(4-methoxyphenyl) acetamide (6i). White solid; Yield 79% (331
mg); Mp: 194−195 °C; IR (KBr) νmax: 3359, 3188, 1715, 1639, cm−1;
1H NMR (300 MHz, CDCl3) δ = 8.41 (d, 1H, J = 8.1 Hz), 7.71 (d,
1H, J = 7.7 Hz), 7.51−7.46 (m, 2H), 7.40−7.32 (m, 3H), 6.96 (d, 2H,
J = 8.5 Hz), 6.31 (s, 1H), 5.58 (s, 1H), 4.99 (d, 1H, J = 19.6 Hz), 3.92
(d, 1H, J = 19.7 Hz), 3.83 (s, 3H), 1.38 (s, 9H); 13C NMR (50 MHz,
CDCl3) δ = 168.3, 162.1, 160.1, 156.5, 134.6, 130.9, 128.9, 128.4,
127.7, 125.2, 122.3, 116.4, 114.6, 58.9, 55.3, 51.9, 49.0, 28.6; HRMS
(ESI TOF (+)) calcd for [C24H25N3O4 + H+] 420.1918; found
418.1917.
N-tert-Butyl-2-(1,4-dioxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-
yl)-2-(3,4,5-trimethoxy phenyl) acetamide (6j). White solid; Yield
82% (393 mg); Mp: 235−236 °C; IR (KBr) νmax: 3384, 1646 cm−1;
1H NMR (300 MHz, CDCl3) δ = 8.43 (d, 1H, J = 8.1 Hz), 7.72 (d,
1H, J = 7.5 Hz), 7.50−7.47 (m, 2H), 7.41 (t, 1H, J = 7.4 Hz), 6.63 (s,
2H), 6.26 (s, 1H), 5.60 (s, 1H), 5.08 (d, 1H, J = 19.6 Hz), 3.98 (d, 1H,
J = 19.7 Hz), 3.87 (s, 3H), 3.85 (s, 6H), 1.39 (s, 9H); 13C NMR (50
MHz, DMSO-d6) δ = 168.3, 162.7, 155.7, 153.0, 137.4, 133.9, 130.1,
129.2, 128.7, 127.5, 125.0, 122.6, 115.7, 113.0, 106.4, 60.0, 58.8, 55.8,
50.7, 49.5, 28.3; HRMS (ESI TOF (+)) calcd for [C26H29N3O6 + H+]
480.2129; found 480.2126.
N-tert-Butyl-2-(3,4-dichlorophenyl)-2-(1,4-dioxo-3,4-dihydro-
pyrazino[1,2-a]indol-2(1H)-yl) acetamide (6e). White solid; Yield
84% (385 mg); Mp: 218−220 °C; IR (KBr) νmax: 3417, 3311, 1725,
1
1677, 1628 cm−1; H NMR (300 MHz, CDCl3) δ = 8.42 (d, 1H, J =
8.1 Hz), 7.72 (d, 1H, J = 7.8 Hz), 7.55−7.50 (m, 4H), 7.42−7.37 (m,
1H), 7.31−7.29 (m, 1H), 6.30 (s, 1H), 5.77 (s, 1H), 5.06 (d, 1H, J =
19.4 Hz), 3.94 (d, 1H, J = 19.4 Hz), 1.39 (s, 9H); 13C NMR (50 MHz,
CDCl3) δ = 167.9, 161.5, 156.8, 134.7, 133.6, 131.4, 131.1, 128.8,
128.6, 128.1, 127.9, 125.4, 122.4, 116.4, 115.2, 57.9, 52.2, 49.0, 28.6;
HRMS (ESI TOF (+)) calcd for [C23H21Cl2N3O3 + H+] 458.1033;
found 458.1033.
N-tert-Butyl-2-(1,4-dioxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-
yl)-2-phenylacetamide (6f). White solid; Yield 86% (335 mg); Mp:
1
228−229 °C; IR (KBr) νmax: 3335, 3015, 1716, 1642 cm−1; H NMR
(300 MHz, CDCl3) δ = 8.41 (d, 1H, J = 8.0 Hz), 7.71 (d, 1H, J = 7.7
Hz), 7.49−7.36 (m, 8H), 6.37 (s, 1H), 5.61 (s, 1H), 5.04 (d, 1H, J =
19.6 Hz), 3.91 (d, 1H, J = 19.6 Hz), 1.39 (s, 9H); 13C NMR (50 MHz,
CDCl3) δ = 168.0, 161.9, 156.6, 134.6, 133.5, 129.5, 129.3, 129.2,
128.9, 128.3, 127.8, 125.2, 122.3, 116.4, 114.7, 59.3, 52.0, 49.1, 28.6;
HRMS (ESI TOF (+)) calcd for [C23H23N3O3 + H+] 390.1812; found
390.1813.
N-tert-Butyl-2-(1,4-dioxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-
yl)-2-(naphthalen-1-yl) acetamide (6k). White solid; Yield 84% (369
mg); Mp >240 °C; IR (KBr) νmax: 3305, 3084, 1725, 1653 cm−1; H
1
NMR (300 MHz, DMSO-d6) δ = 8.24−8.21 (m, 2H), 8.04−7.91 (m,
3H), 7.84 (d, 1H, J = 8.07 Hz), 7.65−7.48 (m, 6H), 7.43−7.38 (m,
1H), 7.01 (s, 1H), 4.88 (d, 1H, J = 19.0 Hz), 3.49 (d, 1H, J = 19.9 Hz),
N-tert-Butyl-2-(1,4-dioxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-
yl)-2-p-tolylacetamide (6g). White solid; Yield 80% (323 mg); Mp:
10223
dx.doi.org/10.1021/jo3018704 | J. Org. Chem. 2012, 77, 10211−10227

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Article
1.31 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ = 168.5, 161.2, 154.3,
133.0, 130.9, 130.6, 128.8, 128.3, 126.6, 126.4, 125.7, 124.9, 124.8,
122.7, 118.4, 117.6, 115.0, 54.5, 50.2, 48.6, 27.8; HRMS (ESI TOF
(+)) calcd for [C27H25N3O3 + H+] 440.1969; found 440.1969.
N-tert-Butyl-2-(1,4-dioxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-
yl)-2-(4-methoxnaphthalene-1-yl)acetamide (6l). White solid; Yield
78% (366 mg); Mp >240 °C; IR (KBr) νmax: 3449, 3307, 1716, 1697
cm−1; 1H NMR (300 MHz, CDCl3) δ = 8.35 (d, 2H, J = 7.7 Hz), 7.89
(d, 1H, J = 7.5 Hz), 7.70 (d, 1H, J = 7.8 Hz), 7.60−7.52 (m, 4H),
7.48−7.42 (m, 1H), 7.38−7.33 (m, 1H), 6.93 (s, 1H), 6.87 (d, 1H, J =
8.1 Hz), 5.60 (s, 1H), 5.00 (d, 1H, J = 19.7 Hz), 4.06 (s, 3H), 3.65 (d,
1H, J = 19.7 Hz), 1.41 (s, 9H); 13C NMR (50 MHz, CDCl3) δ =
169.0, 162.1, 156.7, 156.4, 134.6, 132.7, 129.0, 128.5, 128.1, 127.7,
125.8, 125.2, 123.0, 122.4, 120.8, 116.4, 114.6, 102.9, 56.0, 55.6, 52.1,
49.2, 28.6; HRMS (ESI TOF (+)) calcd for [C28H27N3O4 + Na+]
492.1894; found 492.1892.
N-tert-Butyl-2-(1,4-dioxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-
yl)acetamide (6m). White solid; Yield 70% (219 mg); Mp: 203−205
°C; IR (KBr) νmax: 3520, 3379, 1724, 1656 cm−1; 1H NMR (300 MHz,
CDCl3) δ = 8.46 (d, 1H, J = 8.3 Hz), 7.72 (d, 1H, J = 7.7 Hz), 7.55−
7.48 (m, 2H), 7.43−7.40 (m, 1H), 5.89 (s, 1H), 4.62 (s, 2H), 4.08 (s,
2H), 1.36 (s, 9H); 13C NMR (75 MHz, CDCl3) δ = 166.2, 161.2,
156.6, 134.9, 128.9, 128.1, 128.0, 125.4, 122.5, 116.5, 114.9, 53.1, 51.8,
50.4, 28.7; HRMS (ESI TOF (+)) calcd for [C17H19N3O3 + H+]
314.1499; found 314.1497.
(ESI TOF (+)) calcd for [C24H22F3N3O3 + H+] 458.1686; found
458.1685.
N-tert-Butyl-2-(1,4-dioxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-
yl)-2-(4-nitrophenyl) acetamide (6r). White solid; Yield 82% (356
1
mg); Mp >240 °C; IR (KBr) νmax:3306, 3077, 1724, 1676 cm−1; H
NMR (300 MHz, CDCl3) δ = 8.39 (d, 1H, J = 8.1 Hz), 8.29 (d, 2H, J
= 8.5 Hz), 7.71−7.63 (m, 3H), 7.53−7.48 (m, 2H), 7.42−7.37 (m,
1H), 6.48 (s, 1H), 6.03 (s, 1H), 5.11 (d, 1H, J = 19.3 Hz), 3.92 (d, 1H,
J = 19.3 Hz), 1.40 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ = 167.0,
162.3, 155.9, 147.3, 142.6, 134.0, 130.3, 129.2, 128.9, 128.6, 128.5,
127.6, 125.0, 123.8, 122.6, 115.6, 113.3, 58.3, 50.9, 49.7, 28.3; HRMS
(ESI TOF (+)) calcd for [C23H22N4O5 + Na+] 457.1482; found
457.1458.
N-tert-Butyl-2-(1,4-dioxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-
yl)-2-(2-fluorophenyl) acetamide (6s). White solid; Yield 78% (318
1
mg); Mp: 229−231 °C; IR (KBr) νmax: 3433, 1629, 1548 cm−1; H
NMR (300 MHz, CDCl3) δ = 8.41 (d, 1H, J = 8.1 Hz), 7.70 (d, 1H, J
= 7.6 Hz), 7.58−7.53 (m, 1H), 7.51−7.35 (m, 4H), 7.25−7.23 (m,
1H), 7.18−7.11 (m, 1H), 6.58 (s, 1H), 5.76 (s, 1H),), 5.02 (d, 1H, J =
19.5 Hz), 3.94 (d, 1H, J = 19.4 Hz), 1.38 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ = 167.4, 161.8, 156.3, 134.7, 131.5, 131.4, 131.1, 131.1,
128.9, 128.2, 127.8, 125.2, 124.8, 124.8, 122.3, 120.9, 120.8, 116.4,
116.3, 116.1, 114.8, 53.8, 52.0, 49.3, 28.6; HRMS (ESI TOF (+)) calcd
for [C23H22FN3O3+ H+] 408.1718; found 408.1699.
2-(2-Bromophenyl)-N-tert-butyl-2-(1,4-dioxo-3,4-
dihydropyrazino[1,2-a]indol-2(1H)-yl) acetamide (6t). White solid;
Yield 81% (379 mg); Mp: 226−228 °C; IR (KBr) νmax: 3429, 3282,
N-tert-Butyl-2-(1,4-dioxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-
yl)-2-(furan-2-yl) acetamide (6n). White solid; Yield 70% (265 mg);
1
1
3077, 1714, 1678, 1640; H NMR (300 MHz, CDCl3) δ = 8.41 (d,
Mp: 200 °C; IR (KBr) νmax: 3488, 3410, 3314, 1644 cm−1; H NMR
1H, J = 8.1 Hz), 7.70−759 (m, 3H), 7.47−7.30 (m, 5H), 6.39 (s, 1H),
5.79 (s, 1H), 4.88 (d, 1H, J = 19.4 Hz), 3.75 (d, 1H, J = 19.4 Hz), 1.39
(s, 1H); 13C NMR (75 MHz, CDCl3) δ = 167.9, 161.8, 156.3, 134.7,
133.9, 132.8, 131.2, 130.9, 129.1, 128.3, 128.1, 127.8, 125.9, 125.3,
122.4, 116.5, 114.8, 60.1, 52.2, 49.6, 28.6. HRMS (ESI TOF (+)) calcd
for [C23H22BrN3O3 + H+] 468.0917; found 468.0919.
(300 MHz, CDCl3) δ = 8.46 (d, 1H, J = 8.1 Hz), 7.73 (d, 1H, J = 8.0
Hz), 7.52 (s, 3H), 7.43−7.38 (m, 1H), 6.65 (s, 1H), 6.47 (s, 1H), 6.39
(s, 1H), 5.72 (s, 1H), 4.95 (d, 1H, J = 19.5 Hz), 4.11 (d, 1H, J = 19.4
Hz), 1.39 (s, 9H); 13C NMR (75 MHz, CDCl3) δ = 165.5, 161.8,
156.4, 146.9, 144.0, 134.7, 128.9, 128.1, 127.9, 125.3, 122.4, 116.4,
114.9, 112.5, 110.8, 54.0, 52.1, 49.3, 28.5; HRMS (ESI TOF (+)) calcd
for [C21H21N3O4 + H+] 380.1605; found 380.1600.
2-(4-Chlorophenyl)-N-cyclohexyl-2-(1,4-dioxo-3,4-dihydro-
pyrazino[1,2-a]indol-2(1H)-yl) acetamide (6o). White solid; Yield
86% (387 mg); Mp >240 °C; IR (KBr) νmax: 3246, 3084, 3021, 1717,
1643 cm−1; 1H NMR (300 MHz, CDCl3 +TFA-d1) δ = 8.40 (d, 1H, J
= 8.1 Hz), 7.77 (d, 1H, J = 7.7 Hz), 7.61−7.55 (m, 2H), 7.48−7.36
(m, 5H), 6.42 (s, 1H), 4.94 (d, 1H, J = 19.7 Hz), 4.08 (d, 1H, J = 19.5
Hz), 3.87 (br s, 1H), 1.92−1.88 (m, 2H), 1.73−1.60 (m, 3H), 1.37−
1.16 (m, 6H); 13C NMR (75 MHz, CDCl3+TFA-d1) δ = 168.5, 168.4,
161.9, 158.2, 136.6, 134.9, 130.9, 130.1, 129.8, 129.3, 128.9, 126.5,
126.2, 123.0, 117.7, 116.6, 59.9, 49.9, 49.4, 32.3, 32.2, 25.09, 24.4;
HRMS (ESI TOF (+)) calcd for [C25H24ClN3O3 + H+] 450.1579;
found 450.1573.
N-Cyclohexyl-2-(1,4-dioxo-3,4-dihydropyrazino[1,2-a]indol-
2(1H)-yl)-2-(naphthalen-1-yl) acetamide (6p). White solid; Yield
80% (372 mg); Mp >240 °C; IR (KBr) νmax: 3427, 3288, 3020, 1720,
1642 cm−1. 1H NMR (300 MHz, CDCl3+TFA-d1) δ = 8.32 (d, 1H, J =
8.1 Hz), 8.03−7.94 (m, 2H), 7.84−7.82 (m, 1H), 7.78 (d, 1H, J = 7.7
Hz), 7.69−7.56 (m, 6H), 7.48−7.43 (m, 1H), 7.22 (s, 1H), 4.93 (d,
1H, J = 20.0 Hz), 3.87 (br s, 1H), 3.76 (d, 1H, J = 20.0 Hz), 1.95 (s,
2H), 1.73−1.61 (m, 3H), 1.39−1.16 (m, 6H); 13C NMR (75 MHz,
CDCl3+TFA-d1) δ = 169.8, 162.6, 158.2, 134.9, 134.1, 131.4, 131.3,
129.5, 129.4, 128.9, 128.3, 128.2, 127.0, 126.9, 126.4, 126.3, 125.4,
123.1, 121.6, 118.0, 116.6, 57.3, 50.1, 49.4, 32.3, 32.2, 25.1, 24.4;
HRMS (ESI TOF (+)) calcd for [C29H27N3O3 + Na+] 488.1945;
found 488.1933.
N-tert-Butyl-2-(1,4-dioxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-
yl)-2-(4-(trifluoromethyl) phenyl)acetamide (6q). White solid; Yield
83% (379 mg); Mp: 231−232 °C; IR (KBr) νmax: 3481, 3314, 1721,
1652 cm−1; 1H NMR (300 MHz, CDCl3) δ = 8.41 (d, 1H, J = 8.1 Hz),
7.72−7.69 (m, 3H), 7.59 (d, 2H, J = 8.0 Hz), 7.52−7.48 (m, 2H),
7.42−7.37 (m, 1H), 6.43 (s, 1H), 5.82 (s, 1H), 5.09 (d, 1H, J = 19.4
Hz), 3.89 (d, 1H, J = 19.4 Hz), 1.39 (s, 9H); 13C NMR (50 MHz,
CDCl3) δ = 167.3, 161.5, 156.8, 137.6, 134.7, 129.8, 128.8, 128.1,
127.9, 126.3, 125.4, 122.4, 116.4, 115.2, 58.5, 52.2, 49.1, 28.6; HRMS
N-tert-Butyl-1-(1,4-dioxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-
yl)cyclopentanecarboxamide (6u). White solid; Yield 78% (286 mg);
1
Mp: 208 °C; IR (KBr) νmax: 3401, 2961, 1708, 1644, 1578 cm−1; H
NMR (300 MHz, CDCl3) δ = 8.43 (d, 1H, J = 8.1 Hz), 7.70 (d, 1H, J
= 7.6 Hz), 7.54−7.49 (m, 1H), 7.42−7.37 (m, 2H), 6.47 (s, 1H), 4.58
(s, 2H), 2.67−2.63 (m, 2H), 2.06−2.01 (m, 2H), 1.78−1.77 (m, 4H),
1.34 (s, 9H); 13C NMR (75 MHz, CDCl3) δ = 171.1, 161.7, 157.9,
134.3, 129.0, 127.8, 125.3, 122.3, 116.2, 114.5,73.1, 51.2, 50.9, 35.5,
28.5, 22.5; HRMS (ESI TOF (+)) calcd for [C21H25N3O3 + Na+]
390.1788; found 390.1786.
N-tert-Butyl-1-(1,4-dioxo-3,4-dihydropyrazino[1,2-a]indol-2(1H)-
yl)cyclohexanecarboxamide (6v). White solid; Yield 80% (305 mg);
1
Mp: 224−226 °C; IR (KBr) νmax: 3422, 1748, 1614, 1580 cm−1; H
NMR (300 MHz, CDCl3) δ = 8.42 (d, 1H, J = 8.1 Hz), 7.69 (d, 1H, J
= 7.7 Hz), 7.53−7.48 (m, 1H), 7.40−7.36 (m, 2H), 6.19 (s, 1H), 4.60
(s, 2H), 2.37−2.31 (m, 2H), 2.14−2.11 (m, 2H), 1.69 (br s, 2H),
1.57−1.52 (m, 4H), 1.36 (s, 9H); 13C NMR (50 MHz, CDCl3) δ =
171.8, 162.0, 158.5, 134.2, 129.3, 129.1, 127.7, 125.3, 122.3, 116.2,
114.5, 66.0, 51.3, 49.8, 32.5, 28.6, 25.3, 22.7; HRMS (ESI TOF (+))
calcd for [C22H27N3O3 + H+] 382.2125; found 382.2123.
N-tert-Butyl-2-(3-(4-hydroxybenzyl)-1,4-dioxo-3,4-dihydro-
pyrazino[1,2-a]indol-2(1H)-yl) acetamide (6w). White solid; Yield
70% (293 mg); Mp: 230−231 °C; IR (KBr) νmax: 3433, 2962, 1636,
1517 cm−1; 1H NMR (300 MHz, CDCl3) δ = 9.10 (s, 1H), 8.34−8.29
(m, 2H), 7.72−7.67 (m, 2H), 7.54−7.49 (m, 1H), 7.39 (t, 1H, J = 7.5
Hz), 7.08 (s, 1H), 6.70 (d, 2H, J = 8.2 Hz), 6.34 (d, 1H, J = 8.2 Hz),
4.75 (s, 1H), 4.58 (d, 1H, J = 16.1 Hz), 3.88 (d, 1H, J = 16.1 Hz),
3.28−3.10 (m, 2H),1.28 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ =
165.9, 164.5, 155.7, 155.2, 133.1, 129.5, 128.0, 128.0, 126.9, 124.4,
123.5, 121.9, 114.9, 114.3, 111.8, 63.3, 49.9, 46.2, 28.0; HRMS (ESI
TOF (+)) calcd for [C24H25N3O4 + H+] 420.1918; found 420.1921.
N-tert-Butyl-2-(3-methyl-1,4-dioxo-3,4-dihydropyrazino[1,2-a]-
indol-2(1H)-yl)acetamide (6x). White solid; Yield 75% (245 mg);
1
Mp: 174−175 °C; IR (KBr) νmax: 3431, 2970, 1711, 1640, 1570; H
NMR (300 MHz, CDCl3) δ = 8.45 (d, 1H, J = 8.2 Hz), 7.72 (d, 1H, J
= 7.7 Hz), 7.55−7.48 (m, 2H), 7.43−7.38 (m, 1H), 6.42 (s, 1H), 4.57
10224
dx.doi.org/10.1021/jo3018704 | J. Org. Chem. 2012, 77, 10211−10227

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Article
(q, 1H, J = 7.0 Hz), 4.23 (m, 2H), 1.76 (d, 3H, J = 7.0 Hz), 1.34 (s,
9H); 13C NMR (75 MHz, CDCl3) δ = 167.3, 165.0, 156.8, 134.9,
129.0, 128.1, 127.7, 125.4, 122.5, 116.5, 114.8, 60.1, 51.5, 50.3, 28.6,
19.9; HRMS (ESI TOF (+)) calcd for [C18H21N3O3 + H+] 328.1656;
found 328.1656.
28.6; HRMS (ESI TOF (+)) calcd for [C20H23N3O4+ H+] 370.1761;
found 370.1767.
2-(4-Bromophenyl)-N-tert-butyl-2-(1,4-dioxo-3,4-dihydropyrrolo-
[1,2-a]pyrazin-2(1H)-yl) acetamide (8c). White solid; Yield 80% (334
1
mg); Mp: 170−171 °C; IR (KBr) νmax: 3429, 1760, 1634, 1580. H
NMR (300 MHz, CDCl3) δ = 7.47−46 (m, 1H), 7.42−7.31 (m, 4H),
7.14−7.13 (m, 1H), 6.53−6.50 (m, 1H), 6.31 (s, 1H), 5.71 (br s, 1H),
5.03 (d, 1H, J = 19.9 Hz), 3.85 (d, 1H, J = 20.1 Hz), 1.36 (s, 9H); 13C
NMR (50 MHz, CDCl3) δ = 167.9, 161.5, 156.1, 135.3, 132.2, 130.8,
129.6, 125.3, 119.3, 119.0, 115.7, 58.0, 52.2, 48.8, 28.6. HRMS (ESI
TOF (+)) calcd for [C19H20BrN3O3+ H+] 418.0761; found 418.0769.
N-tert-Butyl-2-(1,4-dioxo-3,4-dihydropyrrolo[1,2-a]pyrazin-
2(1H)-yl)-2-(3,4,5-trimethoxyphenyl) acetamide (8d). White solid;
Yield 78% (335 mg); Mp: 215−216 °C; IR (KBr) νmax: 3356, 2931,
2839, 1735 cm−1; 1H NMR (300 MHz, CDCl3) δ = 7.48 (s, 1H), 7.16
(s, 1H), 6.60 (s, 2H), 6.54−6.52 (m, 1H), 6.25 (s, 1H), 5.63 (s, 1H),
5.07 (d, 1H, J = 20.3 Hz), 3.93−3.84 (m, 10H), 1.38 (s, 9H); 13C
NMR (50 MHz, CDCl3) δ = 168.3, 161.7, 155.9, 153.6, 138.4, 128.8,
125.3, 118.9, 118.8, 115.6, 106.4, 60.7, 58.8, 56.1, 51.9, 48.8, 28.5;
HRMS (ESI TOF (+)) calcd for [C22H27N3O6+ H+] 430.1973; found
430.1965.
2-(4-Chlorophenyl)-2-(1,4-dioxo-3,4-dihydropyrazino[1,2-a]-
indol-2(1H)-yl)-N-(2,4,4-trimethylpentan-2-yl)acetamide (6y). White
solid; Yield 86% (412 mg); Mp: 236 °C; IR (KBr) νmax: 3436, 2962,
1
1640, cm−1; H NMR (300 MHz, CDCl3) δ = 8.39 (d, 1H, J = 8.2
Hz), 7.69 (d, 1H, J = 7.7 Hz), 7.50−7.35 (m, 7H), 6.35 (s, 1H), 5.85
(s, 1H), 5.04 (d, 1H, J = 19.4 Hz), 3.94 (d, 1H, J = 19.5 Hz), 1.89 (d,
1H, J = 14.8 Hz), 1.61 (d, 1H, J = 14.8 Hz), 1.46 (d, 1H, J = 12.1 Hz),
0.95 (s, 9H); 13C NMR (75 MHz, CDCl3) δ = 167.1, 161.6, 156.6,
135.3, 134.7, 131.8, 130.9, 129.4, 128.9, 128.1, 127.9, 125.3, 122.4,
116.4, 115.0, 58.7, 56.2, 52.2, 48.9, 31.5, 31,4, 28.9, 28.5; HRMS (ESI
TOF (+)) calcd for [C27H30ClN3O3 + Na+] 502.1868; found
502.1865.
2-(4-Chlorophenyl)-2-(1,4-dioxo-3,4-dihydropyrazino[1,2-a]-
indol-2(1H)-yl)-N-(2-morpholinoethyl)acetamide (6z). White solid;
Yield 70% (336 mg); Mp >240 °C; IR (KBr) νmax: 3430, 2077, 1695,
1652,1580 cm−1; 1H NMR (300 MHz, DMSO-d6) δ = 8.43 (br s, 1H),
8 32 (d, 1H, J = 8.1 Hz), 7.84 (d, 1H, J = 8.1 Hz), 7.56−7.42 (m, 7H),
6.29 (s, 1H), 4.68 (d, 1H, J = 18.8 Hz), 3.96 (d, 1H, J = 18.9 Hz), 3.56
(s, 4H), 3.29−3.27 (m, 2H), 2.38 (s, 1H); 13C NMR (75 MHz,
DMSO-d6) δ = 167.1, 161.8, 155.3, 133.5, 132.9, 132.5, 130.9, 128.6,
128.1, 128.0, 127.0, 124.5, 122.1, 115.1, 112.5, 65.6, 57.9, 56.6, 48.9,
35.3; HRMS (ESI TOF (+)) calcd for [C25H25ClN4O4 + H+]
481.1637; found 481.1620.
N-tert-Butyl-2-(4-chlorophenyl)-2-(1,4-dioxo-3,4-dihydropyrrolo-
[1,2-a]pyrazin-2(1H)-yl) acetamide (8e). White solid; Yield 82% (306
mg); Mp: 176−178 °C; IR (KBr) νmax: 3457, 2970, 1645, 1567 cm−1;
1H NMR (300 MHz, CDCl3) δ = 7.56−7.55 (m, 2H), 7.46−7.45 (m,
1H), 7.29−7.27 (m, 2H), 7.09 (s, 1H), 6.51−6.49 (m, 1H), 6.36 (s,
1H), 5.99−5.96 (m, 1H), 5.05 (d, 1H, J = 20.2 Hz), 3.85 (d, 1H, J =
20.2 Hz), 1.32 (s, 9H); 13C NMR (50 MHz, CDCl3) δ = 167.9, 161.4,
155.9, 132.8, 132.4, 131.0, 125.1, 123.3, 119.2, 118.9, 115.6, 57.9, 51.9,
48.7, 28.5; HRMS (ESI TOF (+)) calcd for [C19H20ClN3O3+ H+]
374.1266; found 374.1259.
N-tert-Butyl-2-(4-chlorophenyl)-2-(10-iodo-1,4-dioxo-3,4-
dihydropyrazino[1,2-a]indol-2(1H)-yl)acetamide (6aa). White solid;
Yield 88% (483 mg); Mp: 230−231 °C; IR (KBr) νmax 3434, 2098,
1
1639, 1549 cm−1; H NMR (300 MHz, CDCl3) δ = 8.39 (d, 1H, J =
General Procedure for the Preparation of Compound 9(a−
h). To a stirred solution of requisite fused diketopiperazine (1 mmol)
in ethanol (5 mL) was added corresponding amine (1.2 mmol), and
the reaction mixture was heated at reflux for 4−8 h. The progress of
the reaction was monitored by TLC. After completion of the reaction,
solvent was evaporated at reduced pressure and purified through
column chromatography (eluent: CHCl3/MeOH) using 100−200
mesh silica gel to afford the desired product 9(a−h).
8.1 Hz), 7.61−7.53 (m, 2H), 7.48−7.37 (m, 5H), 6.46 (s, 1H), 5.93 (s,
1H), 5.09 (d, 1H, J = 19.6 Hz),3.90 (d, 1H, J = 19.6 Hz), 1.38.(s, 9H);
13C NMR (75 MHz, CDCl3 + TFA) δ = 167.5, 160.7, 155.3, 134.1,
133.4, 132.4, 131.9, 130.3, 128.5, 125.2, 122.8, 115.8, 57.4, 51.1, 49.3,
48.4, 28.0; HRMS (ESI TOF (+)) calcd for [C23H21ClIN3O3 + H+]
550.0389; found 550.0371.
General Procedure for the Preparation of Compound 8(a−
e). To a solution of glycine methyl ester hydrochloride (1 mmol) in
methanol (3 mL) was added triethylamine (1.1 mmol), and the
resulting solution was stirred at room temperature for 10 min. To the
stirred solution were added successively corresponding benzaldehdye
(1 mmol), 1H-pyrrole-2-carboxylic acid (1 mmol), and isocyanide (1
mmol). The mixture was stirred at room temperature for the specified
period of time as indicated in Table 3. The progress of the reaction
was monitored by TLC. After completion of the reaction, solvent was
evaporated at reduced pressure and purified through column
chromatography (eluent: CHCl3/MeOH) using 100−200 mesh silica
gel to afford the desired product 8(a−e).
N-(2-(Benzylamino)-2-oxoethyl)-N-(2-(tert-butylamino)-1-(4-
chlorophenyl)-2-oxoethyl)-1H-indole-2-carboxamide (9a). White
solid; Yield 90% (447 mg); Mp: 126−128 °C; IR (KBr): 3433,
1
2925, 1645 cm−1; H NMR (300 MHz, CDCl3) δ = 9.91 (br s, 1H),
9.58 (s, 1H), 7.64 (d, 1H, J = 7.8 Hz), 7.40 (d, 1H, J = 8.2 Hz), 7.30−
7.23 (m, 8H), 7.14 (d, 3H, J = 7.4 Hz), 6.88 (s, 1H), 5.82 (s, 1H), 5.53
(s, 1H), 4.59−4.37 (m, 3H), 3.72−3.68 (m, 1H), 1.24 (s, 9H); 13C
NMR (75 MHz, CDCl3) δ = 169.2, 164.2, 138.1, 135.9, 131.3, 129.7,
128.4, 127.8, 127.3, 125.3, 122.7, 120.7, 111.6, 107.2, 66.2, 52.0, 50.8,
43.5, 28.3; HRMS (ESI TOF (+)) calcd for [C30H32ClN4O3 + H+]
531.2157; found 531.2153.
N-(2-(tert-Butylamino)-1-(4-chlorophenyl)-2-oxoethyl)-N-(2-(4-
methoxybenzylamino)-2-oxoethyl)-1H-indole-2-carboxamide (9b).
White solid; Yield 84% (471 mg); Mp: 134−136 °C; IR (KBr): 3434,
N-tert-Butyl-2-(1,4-dioxo-3,4-dihydropyrrolo[1,2-a]pyrazin-
2(1H)-yl)-2-(naphthalene-1-yl) acetamide (8a). White solid; Yield
80% (311 mg); Mp > 240 °C; IR (KBr) νmax: 3782, 3313, 2854, 1679,
1
2921, 1647, 1516 cm−1; H NMR (300 MHz, CDCl3) δ = 9.86 (br s,
1
1636, cm−1; H NMR (300 MHz, CDCl3) δ = 7.97−7.89 (m, 3H),
1H), 9.77 (s, 1H), 7.61 (d, 1H, J = 7.6 Hz), 7.39 (d, 1H, J = 8.1 Hz),
7.28−7.21 (m, 5H), 7.12−7.10 (m, 3H), 6.83 (br s, 1H), 6.77 (d, 2H, J
= 8.5 Hz), 5.99 (s, 1H), 5.56 (s, 1H), 4.52−4.27 (m, 3H), 3.73−3.62
(m, 4H), 1.19 (s, 9H); 13C NMR (75 MHz, CDCl3) δ = 169.46, 169.1,
164.3, 158.8, 136.0, 135.7, 131.4, 130.4, 129.6, 127.9, 127.7, 125.2,
122.6, 120.6, 113.8, 111.7, 107.2, 65.99, 55.2, 52.0, 50.8, 42.9, 28.2;
HRMS (ESI TOF (+)) calcd for [C31H33ClN4O4 + H+] 561.2263;
found 561.2257.
7.67 (d, 1H, J = 6.8 Hz), 7.55−7.50 (m, 3H), 7.41−7.40 (m, 1H),
7.20−7.19 (m, 1H), 6.99 (s, 1H), 6.51−6.49 (m, 1H), 5.67 (s, 1H),
5.02 (d, 1H, J = 20.4 Hz), 3.55 (d, 1H, J = 20.4 Hz), 1.40 (s, 1H); 13C
NMR (50 MHz, CDCl3) δ = 168.9, 161.6, 155.7, 133.9, 131.7, 130.2,
129.5, 129.0, 127.9, 127.6, 126.5, 125.3, 125.1, 122.7, 119.0, 118.7,
115.5, 55.7, 52.1, 49.0, 28.6; HRMS (ESI TOF (+)) calcd for
[C23H23N3O3+ H+] 390.1808; found 390.1804.
N-tert-Butyl-2-(1,4-dioxo-3,4-dihydropyrrolo[1,2-a]pyrazin-
2(1H)-yl)-2-(4-methoxyphenyl) acetamide (8b). White solid; Yield
75% (277 mg); Mp: 198−199 °C; IR (KBr) νmax: 3433, 3368, 1723,
1650, 1590 cm−1; 1H NMR (300 MHz, CDCl3) δ = 7.45 (s, 1H), 7.32
(d, 2H, J = 8.2 Hz), 7.16 (s, 1H), 6.95 (d, 2H, J = 7.8 Hz), 6.51 (s,
1H), 6.27 (s, 1H), 4.97 (d, 1H, J = 20.1 Hz), 3.86−3.80 (m, 4H), 1.36
(s, 9H); 13C NMR (75 MHz, CDCl3) δ = 168.4, 161.8, 160.1, 156.0,
130.9, 125.6, 125.4, 119.0, 118.7, 115.6, 114.7, 58.4, 55.3, 52.0, 48.8,
N-(2-(tert-Butylamino)-1-(4-chlorophenyl)-2-oxoethyl)-N-(2-(4-
chlorobenzylamino)-2-oxoethyl)-1H-indole-2-carboxamide (9c).
White solid; Yield 95% (537 mg); Mp: 136−138 °C; IR (KBr):
1
3435, 2918, 1647, 1520 cm−1; H NMR (300 MHz, CDCl3) δ = 9.90
(br s, 1H), 9.72 (s, 1H), 7.61 (d, 1H, J = 7.6 Hz), 7.40 (d, 1H, J = 8.1
Hz), 7.28−7.25 (m, 7H), 7.14−7.08 (m, 2H), 7.02 (br s, 1H), 6.87 (s,
1H), 5.97 (s, 1H), 5.59 (s, 1H), 4.56−4.52 (m, 2H), 4.41 (d, 1H, J =
18.4 Hz), 3.78 (d, 1H, J = 14.8 Hz), 1.19 (s, 9H); 13C NMR (75 MHz,
10225
dx.doi.org/10.1021/jo3018704 | J. Org. Chem. 2012, 77, 10211−10227

The Journal of Organic Chemistry
Article
CDCl3) δ = 169.5, 169.4, 164.1, 136.0, 135.3, 133.5, 131.3, 130.3,
129.7, 129.3, 128.6, 127.8, 126.7, 125.3, 122.7, 120.7, 111.7, 107.1,
65.99, 51.9, 50.8, 41.3, 28.1; HRMS (ESI TOF (+)) calcd for
[C30H30Cl2N4O3 + Na+] 587.1586; found 587.1587.
163.3, 158.7, 153.8, 138.7, 130.5, 129.4, 128.4, 123.6, 122.3, 114.0,
113.7, 110.8, 106.9, 66.4, 60.8, 55.9, 55.1, 51.8, 50.1, 42.7, 28.3; HRMS
(ESI TOF (+)) calcd for [C30H38N4O7 + H+] 567.2813; found
567.2813.
N-(2-(tert-butylamino)-1-(4-chlorophenyl)-2-oxoethyl)-N-(2-(3,4-
dichlorobenzylamino)-2-oxoethyl)-1H-indole-2-carboxamide (9d).
ASSOCIATED CONTENT
■
White solid; Yield 86% (516 mg); Mp: 127−128 °C; IR (KBr) νmax
:
3287, 3062, 2964, 1657, 1608 cm−1; 1H NMR (300 MHz, CDCl3) δ =
10.34 (br s, 1H), 9.57 (s, 1H), 7.64 (d, 1H, J = 7.7 Hz), 7.42−7.39 (m,
2H), 7.35−7.30 (m, 3H), 7.22−7.01 (m, 5H), 6.84 (s, 1H), 5.76 (s,
1H), 5.54 (br s, 1H), 4.55−4.30 (m, 3H), 3.75−3.70 (m, 1H), 1.24 (s,
9H); 13C NMR (75 MHz, CDCl3) δ = 169.7, 169.5, 164.0, 138.5,
135.9, 132.3, 131.2, 130.2, 130.0, 129.8, 127.8, 127.6, 125.4, 122.7,
120.8, 111.6, 107.1, 66.3, 52.1, 50.7, 42.3, 28.2; HRMS (ESI TOF (+))
calcd for [C30H30Cl3N4O3 + H+] 599.1378; found 599.1360.
S
* Supporting Information
Copies of 1H and 13C NMR spectra of selected compounds are
available online. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
N-(2-(tert-butylamino)-2-oxo-1-(3,4,5-trimethoxyphenyl)ethyl)-
N-(2-(4-methoxybenzylamino)-2-oxoethyl)-1H-indole-2-carboxa-
mide (9e). White solid; Yield 82% (505 mg); Mp: 116−119 °C; IR
(KBr): 3450, 2980, 1674, 1520 cm−1; 1H NMR (300 MHz, CDCl3) δ
= 10.12 (br s, 1H), 9.66 (s, 1H), 7.65 (d, 1H, J = 7.4 Hz), 7.42 (d, 1H,
J = 8.1 Hz), 7.31−7.23 (m, 3H), 7.14−7.09 (m, 1H), 6.89 (s, 1H),
6.72 (d, 2H, J = 7.6 Hz), 6.49 (s, 2H), 5.86 (s, 1H), 5.61(s, 1H), 4.48−
4.30 (m, 3H), 3.85−3.65 (m, 13H), 1.29 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ = 170.0, 169.6, 164.0, 158.7, 153.8, 138.9, 135.8, 130.4,
129.4, 128.0, 127.9, 125.1, 122.7, 120.6, 113.7, 111.5, 107.1, 107.0,
66.8, 60.8, 56.0, 55.1, 51.9, 50.4, 42.8, 28.3; HRMS (ESI TOF (+))
calcd for [C34H40N4O7 + H+] 617.2970; found 617.2955.
*E-mail: Premsc58@hotmail.com, prem_chauhan_2000@
yahoo.com. Tel.: +91 522 2612411; fax: +91 522 2623405.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.P. and S.K. are thankful to University Grant Commission,
New Delhi, for financial support. We also thank to SAIF
division, CDRI, for providing the spectroscopic and analytical
data. CDRI communication no. is 8333.
N-(2-(Benzylamino)-2-oxoethyl)-N-(2-(tert-butylamino)-2-oxo-1-
(3,4,5-trimethoxyphenyl) ethyl)-1H-indole-2-carboxamide (9f).
REFERENCES
White solid; Yield 90% (528 mg); Mp: 210−212 °C; IR (KBr) νmax
:
■
3259, 2919, 1656, 1594 cm−1; 1H NMR (300 MHz, CDCl3) δ = 10.24
(br s, 1H), 9.64 (s, 1H), 7.66 (d, 1H, J = 7.3 Hz), 7.42 (d, 1H, J = 8.0
Hz), 7.32−7.29 (m, 3H), 7.18−7.10 (m, 4H), 6.93 (s, 1H), 6.49 (s,
2H), 5.82 (s, 1H), 5.62 (s, 1H), 4.59−4.37 (m, 3H), 3.85−3.63 (m, 10
H), 1.29 (s, 9H); 13C NMR (75 MHz, CDCl3) δ = 170.1, 169.7, 164.0,
153.9, 138.9, 138.2, 135.9, 128.3, 128.1, 128.0, 127.9, 127.1, 125.2,
122.8, 120.6, 111.5, 107.1, 107.0, 66.8, 60.8, 56.0, 51.9, 43.4, 28.3;
HRMS (ESI TOF (+)) calcd for [C33H38N4O6 + H+] 587.2864; found
587.2853.
(1) For recent reviews, see: (a) Multicomponent Reactions, Zhu, J.,
Bienayme, H., Eds.; Wiley-VCH: Weinheim, Germany, 2005. (b) Zhu,
J. Eur. J. Org. Chem. 2003, 1133. (c) Ramon, D. J.; Yus, M. Angew.
Chem., Int. Ed. 2005, 44, 1602. (d) Simon, C.; Constantieux, T.;
Rodriguez, J. Eur. J. Org. Chem. 2004, 4957. (e) Balme, G.; Bossharth,
E.; Monteiro, N. Eur. J. Org. Chem. 2003, 4101. (f) Jacobi von
Wangelin, A.; Neumann, H.; Gordes, D.; Klaus, S.; Strubing, D.; Beller,
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2002, 9, 2085. (h) Domling, A.; Wang, W.; Wang, K. Chem. Rev. 2012,
112, 3083.
N-(2-(tert-butylamino)-2-oxo-1-(3,4,5-trimethoxyphenyl)ethyl)-
N-(2-(3,4-dichlorobenzyl amino)-2-oxoethyl)-1H-indole-2-carboxa-
mide (9g). White solid; Yield 78% (511 mg); Mp: 205−207 °C; IR
(KBr) νmax: 3277, 2920, 1653, 1591 cm−1; 1H NMR (300 MHz,
CDCl3) δ = 10.51 (br s, 1H), 9.61 (s, 1H), 7.66 (d, 1H, J = 7.8 Hz),
7.43−7.41 (m, 2H), 7.33−7.26 (m, 1H), 7.20−7.08 (m, 3H), 6.89 (s,
1H), 6.50 (s, 1H), 5.80 (s, 1H), 5.62 (br s, 1H), 4.53−4.31 (m, 3H),
3.87−3.69 (m, 10 H), 1.30 (s, 9H); 13C NMR (75 MHz, CDCl3) δ =
170.3, 170.0, 163.8, 154.0, 139.1, 138.6, 135.8, 132.4, 131.1, 130.3,
130.0, 128.0, 127.9, 127.6, 125.4, 122.9, 120.8, 111.5, 107.1, 107.0,
67.2, 60.9, 56.1, 52.2, 50.3, 42.3, 28.3; HRMS (ESI TOF (+)) calcd for
[C33H36Cl2N4O6 + H+] 655.2085; found 655. 2070.
(2) (a) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
(b) Domling, A. Chem. Rev. 2006, 106, 17. (c) Domling, A. Curr. Opin.
Chem. Biol. 2002, 6, 306. (d) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu,
S.; Sreekanth, A. R.; Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003,
36, 899. (e) Ugi, I.; Verner, B.; Domling, A. Molecules 2003, 8, 53.
(3) (a) Trost, B. M. Science 1991, 254, 1471. (b) Tietze, L. F. Chem.
Rev. 1996, 96, 115. (c) Wender, P. A.; Handy, S.; Wright, D. L. Chem.
Ind. 1997, 767. (d) Schreiber, S. L. Science 2000, 287, 1964.
(4) (a) Hulme, C.; Cherrier, M.-P. Tetrahedron Lett. 1999, 40, 5295.
(b) Marcaccini, S.; Pepino, R.; Pozo, M. C.; Basurto, S.; Garcia-
Valverde, M.; Torroba, T. Tetrahedron Lett. 2004, 45, 3999. (c) Corres,
N.; Delgado, J. J.; Garcia-Valverde, M.; Marcaccini, S.; Rodriguez, T.;
Rojo, J.; Torroba, T. Tetrahedron 2008, 64, 2225. (d) For a review,
see: Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51. (e) Borisov,
R. S.; Polyakov, A. I.; Medvedeva, L. A.; Khrustalev, V. N.; Guranova,
N. I.; Voskressensky, L. G. Org. Lett. 2010, 12, 3894.
N-(2-(tert-butylamino)-2-oxo-1-(3,4,5-trimethoxyphenyl)ethyl)-
N-(2-(2-hydroxyethylamino)-2-oxoethyl)-1H-indole-2-carboxamide
(9h). White solid; Yield 78% (421 mg); Mp: 117−119 °C; IR (KBr)
1
νmax: 3443, 2920, 1652 cm−1; H NMR (300 MHz, CDCl3) δ = 9.76
(br s, 1H), 9.49 (s, 1H), 7.69 (d, 1H, J = 7.8 Hz), 7.42 (d, 1H, J = 8.1
Hz), 7.32−7.27 (m, 1H), 7.15−7.10 (m, 1H), 6.92 (s, 1H), 6.62 (s,
1H), 5.87 (s, 1H), 5.51 (s, 1H), 4.42−4.30 (m, 1H), 3.88−3.76 (m, 12
H), 3.52−3.21 (m, 2H), 3.10 (s, 1H), 1.35 (s, 9H); 13C NMR (75
MHz, CDCl3) δ = 170.6, 164.1, 154.0, 139.1, 135.9, 127.9, 125.3,
122.7, 120.8, 111.6, 107.1, 67.2, 61.7, 60.9, 56.3, 52.3, 50.7, 42.9, 28.3.
HRMS (ESI TOF (+)) calcd for [C28H36N4O7 + H+] 541.2657; found
541.2651.
(5) (a) Beck, B.; Larbig, G.; Mejat, B.; Magnin-Lachaux, M.; Picard,
A.; Herdtweck, E.; Domling, A. Org. Lett. 2003, 5, 1047. (b) Sello, J.
̈
K.; Andreana, P. R.; Lee, D.; Schreiber, S. L. Org. Lett. 2003, 5, 4125.
(c) Dietrich, S. A.; Banfi, L.; Basso, A.; Damonte, G.; Guanti, G.; Riva,
R. Org. Biomol. Chem. 2005, 3, 97. (d) Ribelin, T. P.; Judd, A. S.;
Akritopoulou-Zanze, I.; Henry, R. F.; Cross, J. L.; Whittern, D. N.;
Djuric, S. W. Org. Lett. 2007, 9, 5119.
N-(2-(tert-butylamino)-2-oxo-1-(3,4,5-trimethoxyphenyl)ethyl)-
N-(2-(4-methoxybenzyl amino)-2-oxoethyl)-1H-pyrrole-2-carboxa-
mide (9i). White solid; Yield 80% (453 mg); Mp: 122−123 °C; IR
́
(6) (a) Sun, X.; Janvier, P.; Zhao, G.; Bienaymee, H.; Zhu, J. Org.
Lett. 2001, 3, 877. (b) Akritopoulou-Zanze, I.; Gracias, V.; Moore, J.
D.; Djuric, S. W. Tetrahedron Lett. 2004, 45, 3421. (c) Akritopoulou-
Zanze, I.; Gracias, V.; Djuric, S. W. Tetrahedron Lett. 2004, 45, 8439.
(d) De Moliner, F.; Crosignani, S.; Galatini, A.; Riva, R.; Basso, A. ACS
Comb. Sci. 2011, 13, 453. (e) Akritopoulou-Zanze, I.; Whitehead, A.;
Waters, J. E.; Henry, R. F.; Djuric, S. W. Org. Lett. 2007, 9, 1299.
1
(KBr) νmax: 3277, 2920,1653,1591, 1335 cm−1; H NMR (300 MHz,
CDCl3) δ = 10.11 (br s, 1H), 9.88 (s, 1H), 7.26 (d, 1H, J = 10.5 Hz),
6.96 (s, 1H), 6.79 (d, 1H, J = 8.4 Hz), 6.67 (s, 1H), 6.45 (s, 2H), 6.24
(s, 1H), 5.76 (s, 1H), 5.58 (s, 1H), 4.48−4.27 (m, 3H), 3.83−3.63 (m,
13H), 1.31 (s, 9H); 13C NMR (75 MHz, CDCl3) δ = 170.3, 169.8,
10226
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The Journal of Organic Chemistry
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