Multicomponent assembly of diverse pyrazin-2(1 H)-one chemotypes

Article abstract of DOI:10.1021/jo4003163

An expedient and concise Ugi-based approach for the rapid assembly of pyrazin-2(1H)-one-based frameworks has been developed. This convergent approach encompasses skeletal, functional and stereochemical diversity, exhibiting an unusually high bond-forming efficiency as well as high structure and step economies. The method involves the use of readily available commercial reagents and is an example of the reconciliation of structural complexity with operational simplicity in a time- and cost-effective manner.

Full text of DOI:10.1021/jo4003163

Article
pubs.acs.org/joc
Multicomponent Assembly of Diverse Pyrazin-2(1H)‑one
Chemotypes
Jhonny Azuaje,1,2 Abdelaziz El Maatougui,1,2 Jose M. Perez-Rubio,1,2 Alberto Coelho,1,2
́
́
Franco Fernandez,2 and Eddy Sotelo1,2,*
́
1Center for Research in Biological Chemistry and Molecular Materials (CIQUS).
2Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, Santiago de Compostela, 15782,
Spain.
S
* Supporting Information
ABSTRACT: An expedient and concise Ugi-based approach
for the rapid assembly of pyrazin-2(1H)-one-based frameworks
has been developed. This convergent approach encompasses
skeletal, functional and stereochemical diversity, exhibiting an
unusually high bond-forming efficiency as well as high
structure and step economies. The method involves the use
of readily available commercial reagents and is an example of
the reconciliation of structural complexity with operational
simplicity in a time- and cost-effective manner.
ones remain clearly insufficient.10 Therefore, the development
of integrated approaches to enable the straightforward assembly
Owing to their prolific bioactivity, pyrazines − and particularly
of pyrazin-2(1H)-one chemotypes remains a methodological
their 2-oxo-derivatives [pyrazin-2(1H)-ones] − are recognized
challenge.
INTRODUCTION
■
as valuable scaffolds in drug discovery.1 These chemotypes,
Within the framework of a project aimed at the concise
which are featured in natural products,2 bioactive compounds3
assembly of privileged scaffolds, we considered the feasibility of
and in several therapeutic agents (Figure 1),1 have proven to be
an isocyanide-based multicomponent approach to deliver highly
particularly versatile for scaffolding strategies.4 In addition to
substituted pyrazin-2(1H)-ones (7). The Ugi-based approach
the bioactivity issue, the reactivity of the 2-azadiene system of
to 2,5-diketopiperazines is an established method,11 but very
the pyrazin-2(1H)-one core provides elegant access to diverse
few reports have described MCR-based methods to access
molecular architectures.5 While pyridazin-2(1H)-ones appear
pyrazin-2(1H)-ones.12 Despite their efficiency, existing meth-
frequently in bioactive molecules, synthetic methodologies
ods have limited scope and reduced flexibility in that they do
targeting this structural platform are somewhat limited.6
not allow the assembly of diverse pyrazin-2(1H)-one-based
The early synthesis of these systems involved the
scaffolds. The pathway proposed here, which follows the Ugi/
condensation of α-diketones with α-aminoamides,6 an
Deprotect/Cyclize (UDC)13 strategy, is shown in Scheme 1.
approach that has very limited scope and generally produces
We envisaged that the Ugi four-component reaction (U-
mixtures of regioisomers. Incisive work by Hoornaert,7 three
4CR)14 employing glyoxals (1) and N-Boc protected amino
decades ago, unveiled the most widely employed preparative
acids (4) as key bifunctional precursors would afford Ugi
entry to pyrazin-2(1H)-ones, wherein an α-aminonitrile is
adducts 5. Subsequent cleavage of the protecting group and
treated with HX and oxalyl halide to afford N-1,C-6-
cyclization would furnish 3,4-dihydropyrazin-2(1H)-ones (6)
disubstituted-3,5-dihalopyrazin-2(1H)-ones. The different re-
that could be easily aromatized to provide the target structures
activities of the halogens on the heterocycle enables the
7. Herein, we report an integrated step- and structure-economic
sequential functionalization of these positions,8 usually employ-
de novo U-4CR-based procedure that enables the straightfor-
ing metal-catalyzed cross-coupling reactions.9 Despite its
ward assembly of different chemotypes derived from the
versatility and efficiency, Hoornaert’s method has intrinsic
pyrazin-2(1H)-one scaffold in a time- and cost-effective
limitations7 [e.g., it requires strongly acidic conditions that are
manner.
not compatible with sensitive functional groups, it involves the
manipulation of hazardous cyanide sources, requires prolonged
reaction times and the reaction outcome is influenced by the
electronic and steric effects of substituents]. Furthermore, the
subsequent decoration of the heterocyclic core often involves
RESULTS AND DISCUSSION
The feasibility of the proposed sequence relies heavily on the
chemoselectivity of the U-4CR employing glyoxals (1) as well
■
multiple steps, involving the use of expensive reagents, additives
and metallic catalysts. In a similar fashion, the synthetic
Received: February 25, 2013
methods targeting functionalized 3,4-dihydropyrazin-2(1H)-
© XXXX American Chemical Society
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Figure 1. Representative alkaloids, drugs and bioactive compounds derived from the pyrazine scaffold.
Scheme 1. Proposed synthetic route to pyrazin-2(1H)-ones
Scheme 2. Ugi-based assembly of pyrazin-2(1H)-ones and their 3,4-dihydro-analogues
as the reactivity profile of the Ugi adducts 5. Phenylglyoxal
(1a), benzylisonitrile (2a), benzylamine (3a) and a set of N-
Boc protected amino acids (4a−c) were selected as model
substrates (Scheme 2). Equimolar amounts of these substrates
were submitted to the standard U-4CR conditions, in methanol
at room temperature for 48 h. Excellent chemoselectivity was
observed, thus confirming the low reactivity of the ketone
moiety of the phenylglyoxal during U-4CR. This process gave
Ugi adducts 5 satisfactorily and the reaction behavior did not
seem to be sensitive to the increasing steric hindrance present
in the amino acid partner (4a−c, R3  H, Me, Bn). Inspection
of reagents and conditions to cleave the Boc group in the
adducts 5 confirmed the feasibility of the proposed pathway in
a shorter sequence, while simultaneously revealing remarkable
facets of this chemistry that highlight its scope and versatility in
terms of the rapid generation of molecular diversity (Scheme
2).
Among the reagents evaluated, TFA-mediated cleavage (30%
TFA/DCE at 80 °C, 2 h) under aerobic conditions proved to
be particularly attractive, directly affording target pyrazin-
2(1H)-ones 7 in satisfactory yields (Scheme 2). Under these
conditions 3,4-dihydropyrazin-2(1H)-ones (6) undergo an
oxidative aromatization, thus avoiding the use of oxidants or
catalytic dehydrogenation. The search for alternative cleavage
conditions revealed that 3,4-dihydropyrazin-2(1H)-ones (6)
could be satisfactorily obtained by treatment of compounds 5
with 2N HCl/ether (0 °C, 0.5 h) or H3PO4 (room
temperature). We next turned to the U-4CR-based one-pot
assembly of pyrazinone derivatives 6 or 7. After monitoring the
Ugi reaction and judging it complete, the solvent was
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Scheme 3. Ugi-Based Assembly of pyrazin-2(1H)-one derivatives (6 and 7)
evaporated and the crude adduct 5 was treated with either TFA
in DCE or HCl/ether (Scheme 2). Gratifyingly, both methods
delivered pyrazin-2(1H)-ones 7 or 3,4-dihydropyrazin-2(1H)-
ones (6) with satisfactory overall yields.
(R1, R3, R5, R6) of the heterocyclic core (Scheme 3). The yields
obtained range from 32 to 78%, with reported values referred to
the overall yield of the three (or four) synthetic steps involved
(U-4CR, deprotection, cyclization, aromatization), thus indicat-
ing excellent yields for each simple step. The method proved to
be broadly successful with all variable components (1−4).
Excellent reactivity profiles were found for tested N-Boc
protected amino acids, the success of which enables the
introduction of significant structural and stereochemical
diversity (Scheme 3). A similar fashion was observed for the
amine partner (including alkyl, aryl and heterocyclic deriva-
tives). Different aryl and heteroaryl fragments, as well the bulky
neighboring tert-butyl group or cyclopropyl residue, are
successfully introduced at position 5 through the glyoxal
precursor (1), while the sequence fails when using
pyruvaldehyde, which does not conserve the chemoselectivity
profile exhibited by its hindered analogues during the U-4CR. It
is apparent from the results in Scheme 3 that the process is
highly successful not only to introduce functional diversity but
also stereochemical diversity at position 3 of the heterocyclic
scaffold. Thus, the use of enantiopure N-Boc amino acids (4)
successfully afforded enantiomerically pure 3,4-dihydropyrazin-
2(1H)-ones (6). It was verified that 6 were isolated in good
yields and also without racemization at the stereocenter (ee
>95%), as determined by chiral HPLC analysis. It should be
Once the feasibility of the proposed pathway had been
validated, the scope and robustness of this five-step one-pot de
novo pyrazin-2(1H)-one synthesis was evaluated (Scheme 3) by
considering a diverse range of commercially available glyoxals
(1), isocyanides (2), amines (3) and either racemic or
enantiopure N-Boc protected amino acids (4). Although the
primary aim of this work was the development of a general and
robust high-throughput synthetic method to assemble diversely
decorated pyrazin-2(1H)-ones (7), we decided to briefly
evaluate the synthesis of some representative enantiopure 3,4-
dihydropyrazin-2(1H)-ones (6).
The results in Scheme 3 enable a preliminary assessment of
the exploratory power of this conceptual and experimentally
simple strategy. Two remarkable features of the methodology
reported here concern its outstanding bond-forming efficiency
and step economy, which allow compounds 6 and 7 to be
assembled in a one-pot process that involves the formation of
four or five new bonds, respectively. It can be seen that this
approach enables the rapid de novo assembly of pyrazin-2(1H)-
ones (7) and their 3,4-dihydro analogues (6), while allowing
the incorporation of highly diverse residues at variable positions
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Scheme 4. Ugi-Based assembly of pyrazin-2(1H)-ones unsubstituted at position 1
Scheme 5. Ugi-based assembly of pyrazine derivatives 11 and 13
pointed that while 3,4-dihydropyrazin-2(1H)-ones (6) are
stable at the solid state, they spontaneously aromatize on
standing in solution (e.g., CDCl3, DMSO-d6 or MeOH) for
more than 72h. Accordingly, chiral HPLC determinations were
performed employing freshly prepared 3,4-dihydropyrazin-
2(1H)-one solutions.
In an effort to broaden the exploratory power of the method,
the assembly of pyrazin-2(1H)-ones unsubstituted at position 1
of the heterocyclic backbone (8) was assessed (Scheme 4).
Although several authors have reported successful U-4CR with
ammonia,15 our attempts with model reagents failed. The use of
2,4-dimethoxy-benzylamine as an ammonia surrogate during
the U-4CR (Scheme 4), enabled us to overcome this drawback.
It was anticipated that the acidic conditions required for the
deprotection-cyclization-aromatization sequence would pro-
mote concomitant cleavage of the 2,4-dimethoxybenzyl residue,
directly affording 8. The viability of the proposed pathway was
evaluated for phenylglyoxal, some representative amino acids
and isocyanides. It was found that the one-pot sequence
performed quite well, successfully delivering the desired
pyrazin-2(1H)-ones (8) in yields in the range 56−74%.
To further evaluate the generality of the newly developed
strategy, its effectiveness in the assembly of novel chemotypes
derived from the 3,4-dihydropyrazin-2(1H)-one scaffold was
assessed (Scheme 5). We particularly focused on the assembly
of 3,3-disubstituted-3,4-dihydropyrazin-2(1H)-ones (11) and
4-substituted-3,4-dihydropyrazin-2(1H)-ones (12). With this
aim in mind glycine Boc derivatives 9 and 10a−b were
submitted to U-4CR conditions and subsequently deprotected
(Scheme 5). These substrates showed different reactivity
profiles.
For example, the sterically hindered substrate 9 exhibited
remarkable performance during the UDC sequence, thus
enabling the straightforward assembly of hitherto unknown
3,3-dimethyl-3,4-dihydropyrazin-2(1H)-ones (11). As can be
seen (Scheme 5), the transformations retain the efficiency and
excellent scope previously observed. In sharp contrast to the
results described above, the analytical and spectroscopic data
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phase HPLC analysis employing freshly prepared 3,4-dihydropyrazin-
2(1H)-one solutions.
obtained for compounds isolated from the UDC-based
sequence employing glycine derivatives 10 (Scheme 5) revealed
that the products obtained were not the desired 12, but rather
4-alkyl-pyrazin-2,3-diones (13). The structural assignment
within the series (see Supporting Information) was comple-
mented by X-ray crystallography data obtained on a
monocrystal of one representative compound (Compound
13d).16
Analysis of the Ugi adduct intermediate for compound 13d
corroborated the performance of U-4CR, confirming that
compounds 13 are produced during the deprotection-
cyclization sequence. The evaluation of milder methods to
cleave the protecting group afforded pyrazin-2,3-diones 13
irrespective of the reagent or conditions employed, thus
evidencing the robustness of the pathway delivering these
structures. Although it is premature to put forward a
mechanistic proposal, the previously experienced tendency to
aromatize of 6 strongly supports the occurrence of an oxidative
pathway mediated by highly reactive 2(1H)pyrazinoium salts. A
preliminary exploration of the transformation revealed the
efficiency, broad scope and robustness of the identified pyrazin-
2,3-(1H,4H)-dione synthesis, which afforded compounds 13 in
satisfactory yields (64−74%). To the best of our knowledge,
the pathway reported herein constitutes the first direct
preparative method for the straightforward assembly of
diversely decorated pyrazin-2,3-(1H,4H)-diones.
In summary, we report a U-4CR-based approach that
provides an integrated and straightforward entry to several
chemotypes derived from the pyrazin-2(1H)-one scaffold. This
convergent and versatile method, which exhibits an unusually
high bond-forming efficiency as well as structure and step
economies, presents broad substrate scope and excellent
functionality tolerance. This approach enables the rapid
assembly of diverse pyrazin-2(1H)-one-based frameworks
encompassing skeletal, functional and stereochemical diversity.
In addition, the method involves the use of readily available
commercial reagents and operationally simple synthetic
protocols and does not require advanced intermediates,
anhydrous solvents or transition metal catalysts. This approach
therefore exemplifies the reconciliation of structural complexity
and operational simplicity in an environmentally friendly and
time- and cost-effective manner.
General procedure for the one-pot synthesis of 3,4-
dihydropyrazin-2(1H)-ones 6 and pyrazin-2(1H)-ones 7. A
mixture of the glyoxal derivative (1.0 mmol), the amine (1.0 mmol),
the isocyanide and the protected aminoacid (1.0 mmol) in MeOH (3
mL) was submitted to orbital stirring at room temperature for 48 h.
After completion of the reaction, CH2Cl2 (3 mL) and PS-p-TsOH (2.0
mmol) were added. The reaction mixture was submitted to orbital
stirring at room temperature until complete consumption of the
unreacted isocyanide (30−60 min). The polystyrene-supported
reagent was filtered off and successively washed [3 times (5 mL)]
with MeOH, AcOEt and CH2Cl2. Evaporation of the solvents from the
filtrate afforded a residue, which was treated with HCl 2N in ether
(and stirred at room temperature for 1h) to afford 6 or 30% TFA in
DCE (and heated to 80 °C for 1h) to afford 7. The solution was then
treated with saturated NaHCO3. After extraction with ethyl acetate,
the organic phase was dried (Na2SO4) and evaporated under reduced
pressure to afford an oily residue that was purified by chromatographic
methods on silica gel using hexane/AcOEt mixtures.
General procedure for the one-pot synthesis of pyrazin-
2(1H)-ones 8. A mixture of the glyoxal derivative (1.0 mmol), 2,4-
dimethoxybenzylamine (1.0 mmol), the isocyanide and the protected
aminoacid (1.0 mmol) in MeOH (3 mL) was submitted to orbital
stirring at room temperature for 48 h. After completion of the reaction,
CH2Cl2 (3 mL) and PS-p-TsOH (2.0 mmol) were added. The
reaction mixture was submitted to orbital stirring at room temperature
until complete consumption of the unreacted isocyanide (30−60 min).
The polystyrene-supported reagent was filtered off and successively
washed [3 times (5 mL)] with MeOH, AcOEt and CH2Cl2.
Evaporation of the solvents from the filtrate afforded a residue,
which was treated with 30% TFA in DCE (10 mL) and heated to 80
°C for 2h. The solution was then treated with saturated NaHCO3.
After extraction with ethyl acetate, the organic phase was dried
(Na2SO4) and evaporated under reduced pressure to afford an oily
residue that was purified by chromatographic methods on silica gel
using hexane/AcOEt mixtures.
N,1-dibenzyl-6-oxo-3-phenyl-1,4,5,6-tetrahydropyrazine-2-car-
boxamide (6a). yield 66%, 262.8 mg, white powder (EtOH, mp 158−
160 °C); 1H NMR (300 MHz, CDCl3) δ (ppm): 7.60 (d, J = 7.5 Hz,
2H), 7.50 − 7.09 (m, 11H), 6.86 (dd, J = 6.7, 2.8 Hz, 2H), 6.26 (t, J =
5.4 Hz, 1H), 5.28 (d, J = 15.0 Hz, 1H), 5.17 (s, 1H), 4.67 (d, J = 20.8
Hz, 1H), 4.55 − 4.39 (m, 1H), 4.30 (dd, J = 14.9, 6.2 Hz, 1H), 4.21 −
4.00 (m, 2H); 13C NMR (75 MHz, CDCl3) δ (ppm): 167.4, 164.9,
161.0, 137.0, 135.7, 135.2, 131.1, 129.8, 129.0, 128.7, 128.6, 128.2,
128.1, 127.6, 127.2, 127.1, 61.6, 48.4, 43.8; HRMS (CI) m/z calcd. for
C25H23N3O2 [M+H]+: 398.1869, found: 398.1856.
EXPERIMENTAL SECTION
(R)-N,1-dibenzyl-5-methyl-6-oxo-3-phenyl-1,4,5,6-tetrahydropyr-
■
1
azine-2-carboxamide (6b). yield 72%, 297.2 mg, pale yellow oil; H
Commercially available starting materials and reagents were purchased
and used without further purification from freshly opened containers.
Polystyrene-supported p-toluenesulfonic acid was purchased from
commercial sources. All solvents were purified and dried by standard
methods. Organic extracts were dried with anhydrous Na2SO4. The
reactions were monitored by TLC and purified compounds each
showed a single spot. Unless stated otherwise, UV light and/or iodine
vapor were used for the detection of compounds. The synthesis and
purification of all compounds were accomplished using the equipment
routinely available in organic chemistry laboratories. Most of the
preparative experiments were performed in coated vials on an organic
synthesizer with orbital stirring. Purification of isolated products was
carried out by column chromatography. Compounds were routinely
characterized by spectroscopic and analytical methods. Melting points
were determined on a melting point apparatus and are uncorrected.
The chemical structures of the obtained compounds were charac-
terized by nuclear magnetic resonance spectroscopy (1H and 13C) and
high-resolution mass spectra (HRMS). Unless otherwise quoted,
NMR spectra were recorded in CDCl3. Chemical shifts are given as δ
values against tetramethylsilane as internal standard and J values are
given in Hz. The enantiomeric excesses were determined by chiral-
NMR (300 MHz, CDCl3) δ (ppm): 7.56 (d, J = 6.3 Hz, 2H), 7.43 −
7.11 (m, 13H), 6.86 − 6.73 (m, 1H), 6.04 (t, J = 5.9 Hz, 1H), 5.15
(dd, J = 20.1, 1.8 Hz, 1H), 4.35 − 4.22 (m, 1H), 4.15 − 4.03 (m, 2H),
3.95 (d, J = 15.2 Hz, 1H), 1.65 (d, J = 7.4 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ (ppm): 170.0, 165.0, 160.9, 136.3, 135.3, 130.9, 129.0,
128.9, 128.8, 128.6, 128.1, 128.0, 127.7, 127.6, 127.3, 127.1, 62.2, 48.1,
43.9, 20.4; HRMS (CI) m/z calcd. for C26H25N3O2 [M+H]+:
412.2025, found: 412.2007.
(R)-N,1,5-tribenzyl-6-oxo-3-phenyl-1,4,5,6-tetrahydropyrazine-2-
1
carboxa-mide (6c). yield 78%, 380.7 mg, pale yellow oil; H NMR
(300 MHz, CDCl3) δ (ppm): 7.77 − 7.64 (m, 1H), 7.65 − 7.48 (m,
2H), 7.41 − 7.29 (m, 5H), 7.23 (dtd, J = 10.6, 7.6, 4.9 Hz, 6H), 7.10 −
6.92 (m, 4H), 6.93 − 6.80 (m, 1H), 6.61 − 6.45 (m, 1H), 5.79 (t, J =
5.8 Hz, 1H), 5.15 (d, J = 4.2 Hz, 1H), 5.02 − 4.84 (m, 2H), 4.61 (ddd,
J = 6.6, 4.3, 1.9 Hz, 1H), 4.21 (d, J = 5.8 Hz, 2H), 3.78 − 3.49 (m,
2H); 13C NMR (75 MHz, CDCl3) δ (ppm): 168.4, 164.9, 159.8,
138.4, 137.0, 135.3, 131.0, 130.3, 129.2, 128.9, 128.7, 128.5, 128.3,
128.0, 127.9, 127.6, 127.3, 127.1, 126.6, 126.2, 62.7, 48.4, 43.8, 38.3;
HRMS (CI) m/z calcd. for C32H29N3O2 [M+H]+: 488.2338, found:
488.2363.
E
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(R)-N,1-dibenzyl-3-(tert-butyl)-5-methyl-6-oxo-1,4,5,6-tetrahy-
128.6, 128.6, 128.4, 128.3, 128.2, 127.9, 127.7, 124.3, 47.5, 44.2, 21.5;
HRMS (EI) m/z calcd. for C26H23N3O2 [M]+: 409.1790, found:
409.1791.
dropyrazine-2-carboxamide (6d). yield 57%, 223.6 mg, white powder
1
(EtOH, mp 147−149 °C); H NMR (250 MHz, CDCl3) δ (ppm):
7.46 − 7.05 (m, 10H), 5.87 (s, 1H), 5.12 (d, J = 14.7 Hz, 1H), 4.63 (s,
1H), 4.35 − 4.18 (m, 3H), 4.18 − 3.99 (m, 1H), 1.74 − 1.51 (m, 3H),
1.00 (s, 9H); 13C NMR (75 MHz, CDCl3) δ (ppm): 172.3, 171.3,
165.9, 137.2, 135.7, 128.9, 128.8, 128.3, 128.2, 127.9, 127.8, 60.4, 57.1,
49.1, 43.9, 39.3, 28.1, 18.0. HRMS (ESI- FIA-TOF) m/z calcd. for
C24H29N3O2 [M+H]+: 392.2333, found: 392.2337.
N,1,5-tribenzyl-6-oxo-3-phenyl-1,6-dihydropyrazine-2-carboxa-
mide (7c). yield 65%, 315.4 mg, white powder (EtOH, mp 166 − 167
1
°C); H NMR (300 MHz, CDCl3) δ (ppm): 7.42 − 7.33 (m, 2H),
7.31 − 7.23 (m, 2H), 7.23 − 6.81 (m, 14H), 6.44 − 6.24 (m, 2H), 5.29
(s, 2H), 5.14 (t, J = 5.4 Hz, 1H), 4.08 (s, 2H), 3.87 (d, J = 5.4 Hz,
2H); 13C NMR (75 MHz, CDCl3) δ (ppm): 161.7, 159.6, 154.3,
137.0, 136.2, 136.1, 135.5, 131.2, 130.6, 129.7, 129.4, 128.6, 128.6,
128.40, 128.3, 128.1, 127.9, 127.7, 126.6, 125.2, 124.4, 47.6, 44.2, 40.5;
HRMS (EI) m/z calcd. for C32H27N3O2 [M]+: 485.2103, found:
485.2101.
(R)-5-((1H-imidazol-4-yl)methyl)-1-benzyl-N-(tert-butyl)-6-oxo-3-
phenyl-1,4,5,6-tetrahydropyrazine-2-carboxamide (6e). yield 32%,
1
142.2 mg, white powder (EtOH, mp 223−224 °C); H NMR (300
MHz, CDCl3) δ (ppm): δ 7.65 − 7.52 (m, 2H), 7.52 − 7.27 (m, 8H),
7.23 − 7.12 (m, 2H), 6.92 (s, 1H), 5.22 (d, J = 15.1 Hz, 1H), 5.06 (s,
1H), 4.96 (s, 1H), 4.44 (td, J = 5.7, 1.7 Hz, 1H), 4.29 (d, J = 15.1 Hz,
1H), 3.51 (dd, J = 5.7, 3.7 Hz, 2H), 1.05 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ (ppm): 169.6, 163.1, 162.1, 135.9, 135.4, 134.4, 131.2,
129.1, 129.0, 128.2, 128.0, 127.1, 125.8, 62.9, 61.9, 52.2, 49.4, 28.2;
HRMS (CI) m/z calcd. for C26H29N5O2 [M+H]+: 444.2400, found:
444.2393.
1-benzyl-N-(tert-butyl)-5-methyl-6-oxo-3-phenyl-1,6-dihydropyr-
azine-2-carboxamide (7d). yield 58%, 217.6 mg, white powder
1
(EtOH, mp 191 − 192 °C); H NMR (300 MHz, CDCl3) δ (ppm):
7.66 − 7.49 (m, 2H), 7.47 − 7.18 (m, 8H), 5.47 (s, 2H), 4.97 (s, 1H),
2.56 (s, 3H), 0.92 (s, 9H); 13C NMR (75 MHz, CDCl3) δ (ppm):
161.0, 158.6, 155.1, 136.8, 136.1, 131.6, 131.3, 128.8, 128.6, 128.4,
128.1, 128.0, 127.9, 52.6, 48.1, 27.9, 21.6; HRMS (EI) m/z calcd. for
C23H25N3O2 [M]+: 375.1947, found: 375.1949.
(R)-5-((1H-indol-3-yl)methyl)-1-benzyl-N-(tert-butyl)-6-oxo-3-
phenyl-1,4,5,6-tetrahydropyrazine-2-carboxamide (6f). yield 38%,
1-benzyl-N-(tert-butyl)-5-isobutyl-6-oxo-3-phenyl-1,6-dihydro-
1
187.6 mg, white powder (EtOH, mp 289−290 °C); H NMR (300
pyrazine-2-carboxamide (7e). yield 66%, 275.4 mg, white powder
1
MHz, CDCl3) δ (ppm): 7.64 − 7.28 (m, 8H), 7.24 − 7.06 (m, 3H),
7.04 − 6.90 (m, 1H), 6.67 (dd, J = 8.5, 6.9 Hz, 2H), 6.44 (d, J = 7.6
Hz, 2H), 5.56 (d, J = 15.4 Hz, 1H), 4.41 (dd, J = 5.5, 1.6 Hz, 1H), 4.16
(s, 1H), 3.89 (d, J = 15.5 Hz, 1H), 3.38 (dd, J = 15.9, 1.6 Hz, 1H), 3.26
(dd, J = 15.9, 5.4 Hz, 1H), 1.01 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ (ppm): 170.1, 168.0, 138.6, 136.0, 135.5, 133.0, 129.3, 128.3, 128.2,
126.9, 126.9, 126.7, 124.7, 122.8, 120.1, 118.8, 111.2, 109.2, 67.6, 57.1,
54.5, 51.0, 47.4, 28.0; HRMS (ESI-FIA-TOF) m/z calcd. for
C31H32N4O2 [M+H]+: 493.2604, found: 493.2609.
(EtOH, mp 144 − 145 °C); H NMR (300 MHz, Chloroform-d) δ
(ppm): 7.64 − 7.52 (m, 2H), 7.48 − 7.14 (m, 8H), 5.47 (s, 2H), 5.01
(s, 1H), 2.82 (dd, J = 7.0, 5.2 Hz, 2H), 2.32 (dt, J = 13.5, 6.8 Hz, 1H),
1.06 − 0.98 (m, 6H), 0.93 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
(ppm): 160.9, 160.6, 154.8, 136.6, 136.0, 131.2, 130.9, 128.8, 128.6,
128.5, 128.3, 127.8, 127.6, 52.4, 47.8, 42.6, 27.7, 26.7, 22.7; HRMS
(EI) m/z calcd. for C26H31N3O2 [M]+: 417.2416, found: 417.2415.
1-benzyl-N-(tert-butyl)-5-(2-(methylthio)ethyl)-6-oxo-3-phenyl-
1,6-dihydro-pyra-zine-2-carboxamide (7f). yield 52%, 240.8 mg,
white powder (EtOH, mp 120 − 121 °C); 1H NMR (300 MHz,
CDCl3) δ (ppm): 7.65 − 7.54 (m, 2H), 7.47 − 7.16 (m, 8H), 5.47 (s,
2H), 5.02 (s, 1H), 3.24 (dd, J = 7.6, 6.7 Hz, 2H), 2.98 (dd, J = 7.8, 7.0
Hz, 2H), 2.18 (s, 3H), 0.93 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
(ppm): 160.8, 158.7, 154.5, 136.4, 135.8, 131.6, 130.9, 128.6, 128.5,
128.4, 128.3, 127.7, 127.6, 52.4, 47.9, 33.4, 30.6, 27.6, 15.3; HRMS
(ESI-FIA-TOF) m/z calcd. for C25H29N3O2S [M+H]+: 436.2053,
found: 436.2057.
(S)-N-benzyl-3-(furan-2-yl)-5-isopropyl-6-oxo-1-propyl-1,4,5,6-
tetrahydro-pyrazine-2-carboxamide (6g). yield 62%, 236.9 mg, white
1
powder, (EtOH, mp 139−140 °C); H NMR (300 MHz, CDCl3) δ
(ppm): 7.47 (d, J = 1.7 Hz, 1H), 7.35 − 7.19 (m, 2H), 7.19 − 7.01 (m,
3H), 6.60 − 6.33 (m, 2H), 5.19 (s, 1H), 4.39 (qd, J = 14.8, 5.7 Hz,
2H), 4.11 (brs, 1H), 3.90 − 3.75 (m, 1H), 2.94 (ddd, J = 14.0, 8.7, 5.7
Hz, 1H), 2.76 (ddq, J = 9.8, 6.8, 3.5, 3.1 Hz, 1H), 1.70 − 1.40 (m, 3H),
1.18 (d, J = 6.9 Hz, 3H), 0.86 (t, J = 7.3 Hz, 3H), 0.79 (d, J = 6.7 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ (ppm): 169.0, 165.3, 150.9,
150.8, 144.0, 137.2, 128.7, 127.7, 127.3, 112.6, 112.1, 65.6, 62.1, 47.6,
43.9, 29.8, 19.9, 16.8, 11.2; HRMS (ESI-FIA-TOF) m/z calcd. for
C22H27N3O3 [M+H]+: 382.2125, found: 382.2121.
N,5-dibenzyl-6-oxo-3-phenyl-1-propyl-1,6-dihydropyrazine-2-
carboxamide (7g). yield 74%, 315.5 mg, white powder (EtOH, mp
1
140 − 142 °C); H NMR (300 MHz, CDCl3) δ (ppm): 7.69 − 7.50
(m, 2H), 7.51 − 7.33 (m, 5H), 7.33 − 7.04 (m, 6H), 6.87 − 6.71 (m,
2H), 5.90 (t, J = 5.7 Hz, 1H), 4.28 (d, J = 5.5 Hz, 2H), 4.18 (s, 2H),
4.06 − 3.72 (m, 2H), 1.97 − 1.54 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ (ppm): 161.8, 159.1, 154.1, 137.1,
(S)-1-benzyl-N-(tert-butyl)-5-isopropyl-6-oxo-3-phenyl-1,4,5,6-
tetrahydro-pyrazine-2-carboxamide (6h). yield 72%, 308.3 mg, white
1
powder (EtOH, mp 124−125 °C); H NMR (300 MHz, CDCl3) δ
(ppm): 7.76 − 7.65 (m, 2H), 7.48 − 7.23 (m, 8H), 5.34 (d, J = 14.9
Hz, 1H), 5.06 (s, 1H), 4.97 (s, 1H), 4.18 (d, J = 15.0 Hz, 1H), 4.08 (s,
1H), 2.90 − 2.75 (m, 1H), 1.26 (d, J = 6.9 Hz, 3H), 1.09 (s, 9H), 0.89
(d, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ (ppm): 168.8,
164.1, 160.3, 136.4, 136.0, 130.66, 129.0, 128.7, 128.3, 128.0, 127.1,
65.8, 62.7, 48.7, 30.0, 28.3, 20.0, 16.9; HRMS (ESI-FIA-TOF) m/z:
Calcd. for C25H31N3O2 [M+Na]+: 428.2308, found: 428.2286.
N,1-dibenzyl-6-oxo-3-phenyl-1,6-dihydropyrazine-2-carboxa-
mide (7a). yield 54%, 213.9 mg, white powder (EtOH, mp 188−190
°C); 1H NMR (300 MHz, CDCl3) δ (ppm): 8.20 (s, 1H), 7.60 − 7.46
(m, 2H), 7.43 − 7.30 (m, 3H), 7.26 (s, 5H), 7.23 − 7.00 (m, 3H), 6.74
− 6.33 (m, 2H), 5.70 (t, J = 5.4 Hz, 1H), 5.42 (s, 2H), 4.05 (d, J = 5.4
Hz, 2H); 13C NMR (75 MHz, CDCl3) δ (ppm): 161.4, 154.6, 149.4,
135.8, 135.4, 132.6, 131.9, 129.7, 129.3, 128.7, 128.6, 128.6, 128.1,
128.0, 127.9, 127.8, 125.8, 47.2, 44.2; HRMS (ESI-FIA-TOF) m/z
calcd. for C25H21N3O2 [M+H]+: 396.1707, found: 396.1692.
136.4, 135.9, 131.4, 130.8, 129.5, 128.8, 128.6, 128.5, 128.4, 128.3,
128.2, 127.8, 126.5, 48.4, 44.4, 40.2, 22.2, 11.3; HRMS (ESI-FIA-
TOF) m/z calcd. for C28H27N3O2 [M+H]+: 438.2176, found:
438.2176.
N-cyclohexyl-6-oxo-3,5-diphenyl-1-propyl-1,6-dihydropyrazine-
2-carboxamide (7h). yield 57%, 237.2 mg, white powder (EtOH, mp
1
230 − 232 °C); H NMR (300 MHz, CDCl3) δ (ppm): 8.31 − 8.13
(m, 2H), 7.55 − 7.38 (m, 2H), 7.34 − 7.13 (m, 6H), 5.41 (d, J = 8.4
Hz, 1H), 3.97 − 3.77 (m, 2H), 3.73 − 3.47 (m, 1H), 1.83 − 1.57 (m,
2H), 1.55 − 0.95 (m, 8H), 0.83 (t, J = 7.4 Hz, 3H), 0.76 − 0.54 (m,
2H); 13C NMR (75 MHz, CDCl3) δ (ppm): 160.9, 153.8, 151.9,
136.5, 135.7, 132.2, 130.1, 129.3, 128.4, 128.3, 128.3, 128.0, 124.5,
48.9, 48.6, 31.9, 25.1, 24.4, 22.2, 11.4; HRMS (EI) m/z calcd. for
C26H29N3O2 [M]+: 416.2333, found: 416. 2336.
N-benzyl-1-methyl-6-oxo-3,5-diphenyl-1,6-dihydropyrazine-2-
carboxamide (7i). yield 56%, 221.3 mg, white powder (EtOH, mp 223
N,1-dibenzyl-5-methyl-6-oxo-3-phenyl-1,6-dihydropyrazine-2-
1
− 224 °C); H NMR (300 MHz, CDCl3) δ (ppm): 8.34 (dt, J = 7.1,
carboxamide (7b). yield 63%, 257.8 mg, white powder (EtOH, mp
1
2.2 Hz, 2H), 7.61 (qd, J = 4.7, 4.2, 2.7 Hz, 2H), 7.38 (dqd, J = 6.5, 4.3,
1.7 Hz, 6H), 7.29 − 7.11 (m, 3H), 6.86 (dq, J = 6.8, 4.2, 3.6 Hz, 2H),
6.19 (t, J = 5.7 Hz, 1H), 4.32 (d, J = 5.6 Hz, 2H), 3.56 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ (ppm): 161.8, 154.1, 151.9, 136.3, 136.0,
135.5, 131.7, 131.1, 130.3, 129.2, 128.7, 128.6, 128.4, 128.1, 128.0,
184 − 185 °C); H NMR (300 MHz, CDCl3) δ (ppm): 7.63 − 7.46
(m, 2H), 7.43 − 7.33 (m, 3H), 7.32 − 7.21 (m, 5H), 7.21 − 7.00 (m,
3H), 6.64 − 6.44 (m, 2H), 5.50 (s, 2H), 5.35 (t, J = 5.6 Hz, 1H), 4.05
(d, J = 5.4 Hz, 2H), 2.57 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
(ppm): 161.8, 158.9, 154.8, 136.3, 136.2, 135.5, 131.3, 130.3, 128.7,
F
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Article
127.8, 127.8, 44.2, 33.3; HRMS (EI) m/z calcd. for C25H21N3O2 [M]+:
395.1634, found: 395.1638.
244 − 245 °C); 1H NMR (300 MHz, CDCl3) δ (ppm): 10.02 (s, 1H),
7.68 − 7.32 (m, 5H), 5.59 (d, J = 7.8 Hz, 1H), 3.97 − 3.56 (m, 1H),
2.55 (s, 3H), 1.79 − 0.90 (m, 8H), 0.77 (dtd, J = 13.6, 10.1, 3.8 Hz,
2H); 13C NMR (75 MHz, CDCl3) δ (ppm): 161.4, 159.2, 154.5,
136.0, 132.7, 129.8, 129.6, 129.4, 124.5, 48.8, 31.9, 25.1, 23.9, 20.6;
HRMS (ESI-FIA-TOF) m/z calcd. for C18H21N3O2 [M+H]+:
312.1707, found: 312.1710.
General procedure for the one-pot synthesis of pyrazin-
2(1H)-ones 11. A mixture of the glyoxal derivative (1.0 mmol), the
amine (1.0 mmol), the isocyanide and the protected aminoacid (1.0
mmol) in MeOH (3 mL) was submitted to orbital stirring at room
temperature for 48 h. After completion of the reaction, CH2Cl2 (3
mL) and PS-p-TsOH (2.0 mmol) were added. The reaction mixture
was submitted to orbital stirring at room temperature until complete
consumption of the unreacted isocyanide (30−60 min). The
polystyrene-supported reagent was filtered off and successively washed
[3 times (5 mL)] with MeOH, AcOEt and CH2Cl2. Evaporation of the
solvents from the filtrate afforded a residue, which was treated with
HCl (2N) in ether and stirred at room temperature for 2h. The
solution was then treated with saturated NaHCO3. After extraction
with ethyl acetate, the organic phase was dried (Na2SO4) and
evaporated under reduced pressure to afford an oily residue that was
purified by chromatographic methods on silica gel using hexane/
AcOEt mixtures.
Benzyl 3-(4-benzyl-5-(tert-butylcarbamoyl)-3-oxo-6-phenyl-3,4-
dihydro-pyrazin-2-yl)propanoate (7j). yield 48%, 251.6 mg, pale
1
yellow oil; H NMR (300 MHz, CDCl3) δ (ppm): 7.64 − 7.48 (m,
2H), 7.45 − 7.15 (m, 13H), 5.46 (s, 2H), 5.12 (s, 2H), 5.03 (s, 1H),
3.29 (t, J = 6.8 Hz, 2H), 2.89 (t, J = 6.8 Hz, 2H), 0.95 (s, 9H); 13C
NMR (75 MHz, CDCl3) δ (ppm): 172.9, 160.9, 158.3, 154.4, 136.4,
136.0, 135.8, 131.4, 130.7, 128.6, 128.5, 128.5, 128.4, 128.3, 128.2,
128.1, 127.9, 127.7, 66.2, 52.4, 47.9, 30.0, 28.4, 27.7; HRMS (ESI-FIA-
TOF) m/z calcd. for C32H33N3O4 [M+H]+: 524.2544, found:
524.2540.
N-(tert-butyl)-1-(3-morpholinopropyl)-6-oxo-3-phenyl-1,6-dihy-
dropyrazine-2-carboxamide (7k). yield 41%, 163.7 mg, white powder
1
(EtOH, mp 178 − 179 °C); H NMR (300 MHz, CDCl3) δ (ppm):
8.20 (s, 1H), 7.61 − 7.50 (m, 2H), 7.50 − 7.28 (m, 3H), 6.37 (s, 1H),
4.16 (d, J = 6.8 Hz, 2H), 3.67 − 3.29 (m, 2H), 3.18 (t, J = 7.6 Hz, 2H),
2.89 (s, 4H), 2.36 (t, J = 7.4 Hz, 2H), 1.51 − 1.22 (m, 2H), 1.13 (s,
9H); 13C NMR (75 MHz, CDCl3) δ (ppm): 160.6, 154.9, 148.3,
135.9, 133.1, 132.7, 128.6, 128.5, 128.5, 63.7, 54.8, 52.8, 51.8, 42.9,
27.7, 23.3; HRMS (ESI-FIA-TOF) m/z calcd. for C22H30N4O3 [M
+H]+: 399.2391, found: 399.2386.
N-(tert-butyl)-1-(3-(dimethylamino)propyl)-6-oxo-3-phenyl-1,6-
dihydro-pyrazine-2-carboxamide (7l). yield 42%, 149.8 mg, white
1
powder (EtOH, mp 149 − 151 °C); H NMR (300 MHz, CDCl3) δ
N-(tert-butyl)-3-(4-methoxyphenyl)-1,5,5-trimethyl-6-oxo-1,4,5,6-
tetrahy-dropyrazine-2-carboxamide (11a). yield 56%, 206.2 mg,
white powder (EtOH, mp 118 − 120 °C); 1H NMR (300 MHz,
CDCl3) δ (ppm): 7.35 − 7.28 (m, 2H), 7.26 (s, 1H), 6.92 − 6.83 (m,
2H), 5.11 (s, 1H), 3.81 (s, 3H), 3.21 (s, 3H), 1.68 (s, 6H), 1.02 (s,
9H); 13C NMR (75 MHz, CDCl3) δ (ppm): 169.5, 162.1, 159.8,
129.8, 128.2, 123.6, 113.5, 59.3, 55.4, 51.9, 31.1, 28.1, 27.5, 23.3;
HRMS (ESI-FIA-TOF) m/z calcd. for C19H27N3O3 [M+Na]+:
368.1945, found: 368.1948.
(ppm): 8.21 (s, 1H), 7.67 − 7.50 (m, 2H), 7.50 − 7.29 (m, 3H), 5.73
(s, 1H), 4.16 − 3.97 (m, 2H), 2.45 (t, J = 6.9 Hz, 2H), 2.27 (s, 6H),
2.15 − 1.92 (m, 2H), 1.17 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
(ppm): 160.6, 154.7, 148.5, 136.0, 133.6, 131.8, 128.5, 128.4, 128.3,
56.8, 52.7, 45.2, 45.0, 27.9, 26.2; HRMS (ESI-FIA-TOF) m/z calcd. for
C20H28N4O2 [M+H]+: 357.2285, found: 357.2280.
N-benzyl-1-(4-methoxyphenyl)-6-oxo-3,5-diphenyl-1,6-dihydro-
pyrazine-2-carbo-xamide (7m). yield 43%, 302.7 mg, white powder
1
(EtOH, mp 214 − 216 °C); H NMR (300 MHz, CDCl3) δ (ppm):
8.51 − 8.35 (m, 2H), 7.80 − 7.65 (m, 2H), 7.52 − 7.29 (m, 6H), 7.23
− 7.04 (m, 5H), 6.98 − 6.82 (m, 2H), 6.72 − 6.60 (m, 2H), 6.21 (t, J
= 5.8 Hz, 1H), 4.01 (d, J = 5.7 Hz, 2H), 3.82 (s, 3H); 13C NMR (75
MHz, CDCl3) δ (ppm): 161.0, 160.0, 154.1, 152.9, 136.3, 135.4, 132.0,
130.4, 129.3, 129.0, 128.9, 128.7, 128.5, 128.4, 128.3, 128.1, 128.0,
127.8, 127.6, 127.5, 114.5, 55.4, 43.7; HRMS (ESI-FIA-TOF) m/z
calcd. for C31H25N3O3 [M+H]+: 488.1969, found: 488.1978.
N,1-dibenzyl-3-cyclopropyl-5,5-dimethyl-6-oxo-1,4,5,6-tetrahy-
dropyrazine-2-carboxamide (11b). yield 58%, 218.6 mg, white
1
powder (EtOH mp 84 − 85 °C), Yield: 56%. H NMR (300 MHz,
CDCl3) δ (ppm): 7.36 − 7.04 (m, 11H), 5.81 (d, J = 5.8 Hz, 1H), 4.86
(s, 2H), 4.38 (d, J = 5.8 Hz, 2H), 1.72 (td, J = 6.6, 6.0, 2.7 Hz, 1H),
1.62 − 1.53 (m, 1H), 1.47 (s, 7H), 0.63 − 0.57 (m, 1H), 0.57 − 0.51
(m, 1H). 13C NMR (75 MHz, CDCl3) δ (ppm): 169.9, 162.7, 155.7,
137.3, 137.0, 130.2, 128.8, 128.7, 128.5, 128.3, 128.1, 127.8, 127.8,
127.5, 127.1, 127.1, 59.1, 46.5, 44.0, 28.2, 28.1, 23.6, 13.0, 6.7. HRMS
(ESI) m/z calcd. for C24H27N3O2 [M+H]+: 390.2176, found:
390.2178.
1-benzyl-N-cyclohexyl-5-(4-methoxybenzyl)-3-(4-methoxyphen-
yl)-6-oxo-1,6-dihydropyrazine-2-carboxamide (7n). yield 62%, 231.4
1
mg, white powder (EtOH, mp 137 − 139 °C); H NMR (300 MHz,
CDCl3) δ (ppm): 7.33 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.7 Hz, 2H),
7.08 (d, J = 6.3 Hz, 5H), 6.80 − 6.61 (m, 4H), 5.26 (s, 2H), 4.87 (d, J
= 8.1 Hz, 1H), 4.00 (s, 2H), 3.64 (s, 3H), 3.61 (s, 3H), 3.42 − 3.27
(m, 1H), 1.35 − 0.63 (m, 8H), 0.52 − 0.25 (m, 2H); 13C NMR (75
MHz, CDCl3) δ (ppm): 161.1, 159.8, 159.5, 158.3, 154.3, 136.1, 130.8,
130.5, 130.4, 129.6, 129.2, 128.8, 128.5, 128.0, 127.7, 113.9, 113.8,
55.4, 55.2, 48.6, 47.6, 39.5, 31.4, 25.1, 24.1; HRMS (ESI-FIA-TOF)
m/z calcd. for C33H35N3O4 [M+H]+: 538.2700, found: 538.2695.
N-(tert-butyl)-6-oxo-3-phenyl-1,6-dihydropyrazine-2-carboxa-
mide (8a). yield 56%, 152.4 mg, white powder (EtOH, mp 246 − 247
General procedure for the one-pot synthesis of pyrazin-
2(1H)-ones 13. A mixture of the glyoxal derivative (1.0 mmol), the
amine (1.0 mmol), the isocyanide and the protected aminoacid (1.0
mmol) in MeOH (3 mL) was submitted to orbital stirring at room
temperature for 48 h. After completion of the reaction, CH2Cl2 (3
mL) and PS-p-TsOH (2.0 mmol) were added. The reaction mixture
was submitted to orbital stirring at room temperature until complete
consumption of the unreacted isocyanide (30−60 min). The
polystyrene-supported reagent was filtered off and successively washed
[3 times (5 mL)] with MeOH, AcOEt and CH2Cl2. Evaporation of the
solvents from the filtrate afforded a residue, which was treated with
30% TFA in DCE (10 mL) and heated to 80 °C for 1h. The solution
was then treated with saturated NaHCO3. After extraction with ethyl
acetate, the organic phase was dried (Na2SO4) and evaporated under
reduced pressure to afford an oily residue that was purified by
chromatographic methods on silica gel using hexane/AcOEt mixtures.
N-benzyl-4-methyl-5,6-dioxo-3-phenyl-1-propyl-1,4,5,6-tetrahy-
dropyrazine-2-carboxamide (13a). yield 74%, 279.8 mg, white
1
°C); H NMR (300 MHz, CDCl3) δ (ppm): 10.19 (s, 1H), 8.15 (s,
1H), 7.61 − 7.19 (m, 5H), 5.43 (s, 1H), 0.94 (s, 9H); 13C NMR (75
MHz, CDCl3) δ (ppm): 159.0, 154.6, 151.3, 135.6, 133.4, 129.8, 129.7,
129.3, 126.9, 52.3, 27.9; HRMS (ESI-FIA-TOF) m/z calcd. for
C15H17N3O2 [M+H]+: 272.1394, found: 272.1385.
5-benzyl-N-cyclohexyl-6-oxo-3-phenyl-1,6-dihydropyrazine-2-
carboxamide (8b). yield 74%, 278.8 mg, white powder (EtOH, mp
215 − 216 °C); 1H NMR (300 MHz, CDCl3) δ (ppm): 9.99 (s, 1H),
7.59 − 7.38 (m, 7H), 7.36 − 7.14 (m, 3H), 5.58 (d, J = 7.7 Hz, 1H),
4.21 (s, 2H), 3.82 − 3.65 (m, 1H), 1.73 − 1.56 (m, 1H), 1.56 − 1.13
(m, 6H), 1.12 − 0.96 (m, 1H), 0.94 − 0.64 (m, 2H); 13C NMR (75
MHz, CDCl3) δ (ppm): 161.9, 159.2, 154.0, 136.6, 136.0, 132.8, 129.7,
129.6, 129.5, 129.3, 128.4, 126.6, 124.9, 48.8, 39.5, 31.9, 25.1, 23.9;
HRMS (EI) m/z calcd. for C24H25N3O2 [M]+: 387.1947, found:
387.1944.
1
powder (EtOH mp 128 − 129 °C); H NMR (300 MHz, CDCl3) δ
(ppm): 7.60 − 7.30 (m, 6H), 7.22 − 7.07 (m, 4H), 6.95 − 6.80 (m,
1H), 4.26 − 4.11 (m, 2H), 3.78 − 3.53 (m, 2H), 3.04 (s, 3H), 1.94 −
1.56 (m, 2H), 0.98 − 0.75 (m, 3H); 13C NMR (75 MHz, CDCl3) δ
(ppm): 161.1, 155.7, 154.4, 136.9, 130.7, 130.5, 129.8, 129.0, 128.5,
127.8, 127.3, 123.8, 120.4, 48.2, 43.8, 33.6, 21.8, 11.2; HRMS (CI) m/
z calcd. for C22H23N3O3 [M+H]+: 378.1812, found: 378.1816.
N-cyclohexyl-5-methyl-6-oxo-3-phenyl-1,6-dihydropyrazine-2-
carboxamide (8c). yield 68%, 230.8 mg, white powder (EtOH, mp
G
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N-(tert-butyl)-4-methyl-5,6-dioxo-3-phenyl-1-propyl-1,4,5,6-tet-
Kuo, L. C.; Lewis, S. D.; Lucas, B. J.; Yan, Y. Bioorg. Med. Chem. Lett.
2003, 13, 161−164.
rahydropyra-zine-2-carboxamide (13b). yield 67%, 230.6 mg, white
1
powder (EtOH mp 241 − 243 °C); H NMR (300 MHz, CDCl3) δ
(4) (a) De Borggraeve, W. M.; Verbist, B. M. P.; Rombouts, F. J. R.;
Pawar, V. G.; Smets, W. J.; Kamoune, L.; Alen, J.; Van der Eycken, E.
V.; Compernolle, F.; Hoornaert, G. J. Tetrahedron 2004, 60, 11597−
11612. (b) Pawar, V. G.; De Borggraeve, W. M.; Maes, V.; Tourwe, D.
A.; Compernolle, F.; Hoornaert, G. J. Tetrahedron Lett. 2005, 46,
1707−1710.
(ppm): 7.49 (s, 5H), 5.83 (s, 1H), 3.94 − 3.69 (m, 2H), 3.11 (s, 3H),
1.92 − 1.67 (m, 2H), 1.01 (s, 9H), 0.94 (t, J = 7.4 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ (ppm): 160.1, 155.4, 154.3, 130.9, 130.8, 129.7,
128.8, 123.6, 121.2, 51.8, 48.6, 33.6, 27.6, 21.7, 11.3; HRMS (ESI-FIA-
TOF) m/z calcd. for C19H25N3O3 [M+H]+: 344.1969, found:
344.1970.
(5) (a) Kaval, N.; Ermolat’ev, E.; Appukkuttan, P.; Dehaen, D.;
Kappe, C. O.; Van der Eycken, E. J. Comb. Chem. 2005, 7, 490−502.
(b) Tutonda, M. G.; Vandenberghe, S. M.; Van Aken, K. J.; Hoornaert,
G. J. J. Org. Chem. 1992, 57, 2935−2937.
N-benzyl-4-ethyl-5,6-dioxo-3-phenyl-1-propyl-1,4,5,6-tetrahydro-
pyrazine-2-carboxamide (13c). yield 64%, 250.8 mg, white powder
1
(EtOH mp 198 − 199 °C); H NMR (300 MHz, CDCl3) δ (ppm):
7.51 − 7.35 (m, 5H), 7.24 − 7.14 (m, 3H), 6.92 − 6.67 (m, 2H), 6.07
(t, J = 6.0 Hz, 1H), 4.12 (d, J = 4.3 Hz, 2H), 3.88 − 3.68 (m, 2H), 3.63
(q, J = 7.0 Hz, 2H), 1.89 − 1.64 (m, 2H), 1.03 (t, J = 7.0 Hz, 3H), 0.89
(t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ (ppm): 161.2,
155.1, 154.7, 137.0, 130.8, 130.2, 129.8, 128.8, 128.4, 127.9, 127.3,
123.2, 120.7, 48.2, 43.8, 40.9, 21.8, 13.2, 11.2; HRMS (ESI-FIA-TOF)
m/z calcd. for C23H25N3O3 [M+H]+: 392.1969, found: 392.1971.
N-(tert-butyl)-4-ethyl-5,6-dioxo-3-phenyl-1-propyl-1,4,5,6-tetra-
hydropyra-zine-2-carboxamide (13d). yield 70%, 250.7 mg, colorless
(6) (a) Pawar, V. G.; De Borggraeve, W. M. Synthesis 2006, 2799−
2814. (b) Japp, F. R.; Knox, A. J. Chem. Soc. 1905, 87, 701−707.
(c) Tota, Y. A.; Elderfield, R. C. J. Org. Chem. 1942, 7, 313−319.
(7) Vekemans, J.; Pollers-Wieers, C.; Hoornaert, G. J. J. Heterocycl.
̈
Chem. 1983, 20, 919−923.
(8) (a) Li, G.; Smith, D.; Krishnananthan, S.; Hartz, R. A.; Dasgupta,
B.; Ahuja, V.; Schmitz, W. D.; Bronson, J. J.; Mathur, A.; Barrish, J. C.;
Chi Chen, B. Org. Process Res. Dev. 2012, 16, 156−159. (b) Gembus,
́
V.; Janvier, S.; Lecouve, J. P.; Gloanec, P.; Marsais, F.; Levacher, V.
1
crystals (EtOH mp 267 − 269 °C); H NMR (300 MHz, CDCl3) δ
Eur. J. Org. Chem. 2010, 3583−3586.
(ppm): 7.49 (s, 3H), 7.26 (s, 2H), 5.67 (s, 1H), 3.90 − 3.75 (m, 2H),
3.67 (q, J = 7.1 Hz, 2H), 1.90 − 1.70 (m, 2H), 1.13 − 0.86 (m, 15H);
13C NMR (75 MHz, CDCl3) δ (ppm): 160.4, 155.1, 154.2, 131.4,
130.9, 129.9, 128.9, 123.1, 121.0, 52.1, 48.7, 41.2, 27.9, 22.0, 13.5, 11.6;
HRMS (ESI-FIA-TOF) m/z calcd. for C20H28N3O3 [M]+: 358.2125,
found: 358.2121.
(9) (a) Modha, S. G.; Trivedi, J. C.; Mehta, V. P.; Ermolat’ev, D. S.;
Van der Eycken, E. V. J. Org. Chem. 2011, 76, 846−856. (b) Mehta, V.
P.; Modha, S. G.; Van der Eycken, E. V. J. Org. Chem. 2010, 75, 976−
979. (c) Kaval, N.; Singh, B. K.; Ermolat’ev, D. S.; Claerhout, S.;
Parmar, V. S.; Van der Eycken, J.; Van der Eycken, E. J. Comb. Chem.
2007, 9, 446−453.
(10) (a) Ohtsuka, Y. J. Org. Chem. 1976, 41, 629−633. (b) Hirano,
H.; Tada, M. J. Heterocycl. Chem. 1981, 18, 905−908. (c) Peng, H.;
Carrico, D.; Thai, V.; Blaskovich, M. A.; Bucher, C.; Pusateri, E. E.;
Sebti, S. M.; Hamilton, A. D. Org. Biomol. Chem. 2006, 4, 1768−1784.
(11) (a) Rhoden, C. R. B.; Rivera, D. G.; Kreye, O.; Bauer, A. K.;
Westermann, B.; Wessjohann, L. A. J. Comb. Chem. 2009, 11, 1078−
1082. (b) Hulme, C.; Peng, J.; Louridas, B.; Menard, P.; Krolikowski,
P.; Kumar, N. V. Tetrahedron Lett. 1998, 39, 8047−8050.
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures and copies of H and 13C
1
NMR spectra for all compounds and crystallographic
information files (CIF) of compound 13d. This material is
available free of charge via the Internet at http://pubs.acs.org.
(12) (a) Faggi, C.; García-Valverde, M.; Marcaccini, S.; Pepino, R.
Synthesis 2003, 1553−1558. (b) El Kaim, L.; Grimaud, L.;
Purumandla, S. R. J. Org. Chem. 2011, 76, 4728−4733. (c) Basso,
A.; Banfi, L.; Guanti, G.; Riva, R.; Tosatti, P. Synlett 2011, 2009−2012.
AUTHOR INFORMATION
Corresponding Author
*Corresponding author: Tel.: ++34-881815732 Fax.: ++34-
881815702, e-mail: e.sotelo@usc.es
Notes
■
Domling, A.; Katrin, I. Synthesis 2005, 662−667.
̈
(13) (a) Liu, A.; Su, H.; Zhou, G.; Zhang, W.; Yan, B. J. Comb. Chem.
2009, 11, 1083−1093. (b) Xu, Z.; Dietrich, J.; Shaw, A. Y.; Hulme, C.
Tetrahedron Lett. 2010, 51, 4566−4569.
The authors declare no competing financial interest.
(14) (a) Multicomponent Reactions, Zhu, J., Bienayme, H., Ed., Wiley-
ACKNOWLEDGMENTS
■
VCH, Weinheim, 2005. (b) Domling, A. Chem. Rev. 2006, 106, 17−89.
̈
This work was financially supported by the Galician Govern-
ment (Spain), Project: 09CSA016234PR. J. A. thanks
FUNDAYACUCHO (Venezuela) for a predoctoral grant.
(c) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.;
Keating, T. A. Acc. Chem. Res. 1996, 29, 123−131.
(15) (a) Thompson, M. J.; Chen, B. J. Org. Chem. 2009, 74, 7018−
7093. (b) Pick, R.; Bauer, M.; Kazmaier, U.; Hebach, C. Synlett 2005,
757−760.
REFERENCES
■
(16) The Supporting Information contains the crystallographic
information files (CIF) of compound 13d. Additional information can
be obtained free of charge from The Cambridge Crystallographic Data
Centre (CCDC 906542).
(1) Kleemann, A., Engel, J., Kutscher, B., Reichert, D., Pharmaceutical
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