Ugi-based approaches to quinoxaline libraries

Article abstract of DOI:10.1021/co500036n

An expedient and concise Ugi-based unified approach for the rapid assembly of quinoxaline frameworks has been developed. This convergent and versatile method uses readily available commercial reagents, does not require advanced intermediates, and exhibits

Full text of DOI:10.1021/co500036n

Research Article
pubs.acs.org/acscombsci
Ugi-Based Approaches to Quinoxaline Libraries
Jhonny Azuaje,†,§ Abdelaziz El Maatougui,†,§ Xerardo García-Mera,§ and Eddy Sotelo*,†,‡,§
†Center for Research in Biological Chemistry and Molecular Materials (CIQUS), ‡Institute of Industrial Pharmacy, and §Department
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 unified
approach for the rapid assembly of quinoxaline frameworks has
been developed. This convergent and versatile method uses
readily available commercial reagents, does not require
advanced intermediates, and exhibits excellent bond-forming
efficiency, thus exemplifying the operationally simple synthesis
of quinoxaline libraries.
KEYWORDS: Ugi-based approach, quinoxaline libraries, operationally simple synthesis
reaction outcomes that are influenced by the electronic and
steric effects of substituents. Moreover, the use of unsymmetri-
cally substituted precursors (e.g., o-phenylenediamines or
benzofurazan N-oxides) leads to regioisomeric mixtures of
quinoxalines.
INTRODUCTION
■
Quinoxalines have long attracted significant attention due to
their prolific bioactivity profiles (Figure 1). The quinoxaline
unit is featured in therapeutic agents,1 pharmacologically active
derivatives,2 agrochemicals3 and natural occurring compounds4
[e.g., vitamins (such as riboflavin), alkaloids, or antibiotics
(such as echinomycin, actinomycin and leromycin)]. Accord-
ingly, quinoxaline chemotypes are recognized as privileged
scaffolds5 and frequently employed as bioisosters of other
heterocyclic cores (e.g., quinoline, quinazoline or pteridine). In
addition to its bioactivity profile, molecular architectures that
incorporate the quinoxaline framework have demonstrated the
potential of this unit in diverse areas of materials science6 (e.g.,
electroluminescent materials, dyes, organic semiconductors and
chemical switches). The different applications notwithstanding,
synthetic methodologies that target this chemotype remain
somewhat scarce,7 a situation that is evident on considering the
limited skeletal and functional diversity of the available
quinoxaline libraries.8
The recent emergence of multicomponent reactions
(MCR)13 has provided novel approaches that expand the
compendium of methods to assemble libraries of heterocyclic
compounds.13 A few MCR-based methods targeting quinoxa-
lines (Figure 3) have been described,14−17 with relevant
examples exploiting the reactivity of isocyanides in the
Ugi,14,17 Ugi-Smiles,15 or Van Leusen16 reactions. As the
demand of privileged heterocyclic collections for drug discovery
programs remains a priority, particularly libraries of under-
represented chemotypes (e.g., quinoxalines), novel contribu-
tions in this area are highly desirable. As part of our program
aimed at the design of succinct and operationally simple MCR-
based routes to libraries of privileged scaffolds, we report here
an integrated strategy to synthesize novel skeletal and
functionally diverse quinoxaline libraries in a time-efficient
and cost-effective manner.
The classical synthesis of quinoxaline derivatives is carried
out using strategies based on Korner9 and Hinsberg10 methods
̈
(Figure 2); both of these approaches rely on the condensation
of 1,2-arylenediamines with synthons that contain reactive 1,2-
dicarbonyl moieties (e.g., 1,2-diketones, 1,2-ketoesters, or oxalic
acid derivatives).7,11 A useful modification of these synthetic
methods employs 1,2-dicarbonyl compound surrogates (e.g., α-
haloketones, α-hydroxyketones, epoxides, or alkynes).7,11 The
discovery of the Beirut reaction12 (Figure 2), that is, the
cycloaddition between benzofurazan N-oxide and diverse two-
carbon reactive partners (e.g., dienes, enones, enamines, or
enolates derived from ketones, β-diketones, β-ketoesters, etc.),
unveiled an elegant preparative entry to quinoxaline-1,4-
dioxides, which can subsequently be reduced to afford
quinoxaline derivatives (Figure 2). Although existing methods
usually provide satisfactory yields, they do suffer from intrinsic
limitations; for example, narrow substrate scope, the need for
elevated temperatures, expensive and detrimental catalysts, and
RESULTS AND DISCUSSION
■
The Ugi four-component reaction (U-4CR),18 that is, the
condensation of an amine, a carboxylic acid, a carbonyl
component (aldehyde or ketone) and an isocyanide, constitutes
an exceptional preparative tool that has well documented
versatility and robustness for the assembly of heterocyclic
frameworks.19 Among the Ugi-based approaches to target
heterocycles, those that involve the Ugi/deprotect/cyclize
(UDC)20 sequence encompass a highly attractive strategy
that exemplifies the reconciliation of molecular complexity and
experimental simplicity. In the context of a hit optimization
Received: March 1, 2014
Revised: April 6, 2014
© XXXX American Chemical Society
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Figure 1. Representative drug, bioactive, and naturally occurring compounds that feature a quinoxaline scaffold.
frameworks that incorporate amide groups at position 2 of
the heterocyclic core. Given the limitations of established
methods to access the target structures we decided to assess the
feasibility of an unprecedented Ugi-based approach to quinoxa-
lines (Figure 4). It was envisioned that the Ugi reaction with
glyoxal derivatives (1) and mono-Boc protected phenylenedi-
amines (3) as key precursors would enable the rapid assembly
of adducts 5, which could subsequently be cyclized and, after
removal of the Boc group, afford 1,4-dihydroquinoxalines 6
(Figure 4).
The viability of the proposed pathway was evaluated by
employing phenylglyoxal (1{1}), tert-butyl(2-amino-phenyl)-
carbamate (3{1}), three isocyanides (2{1−3}), and either
propanoic or benzoic acids ((4{1}) and 4{2}) as model
substrates (Figure 5). Equimolar amounts of these precursors
were submitted to the standard U-4CR conditions18 in
methanol at room temperature for 48 h. Analysis of these
reactions confirmed the chemoselectivity of the transforma-
tions, with the Ugi adducts 5 obtained with satisfactory yields
(56−80%). It should be noted that the increasing steric
hindrance present in the varied components [carboxylic acids
(4) or isocyanides (2)] did not affect the reaction behavior or
yield. The resulting Ugi adducts (5) were submitted to a brief
screening to identify the optimal conditions to remove the Boc
group (30% TFA/DCE, 1 M HCl/Ether, 85% H3PO4/H2O).
These experiments demonstrated the superiority of TFA (30%
TFA/DCE at 80 °C, 1 h), which efficiently and rapidly
Figure 2. Classical methods for the synthesis of quinoxaline scaffolds.
program we needed to validate experimentally the in silico
bioactivities predicted for virtual libraries of quinoxaline
Figure 3. Ugi-based multicomponent synthesis of quinoxaline derivatives.14−17
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Figure 4. Proposed synthetic route to quinoxaline derivatives 6.
Figure 5. Diversity elements employed for library synthesis. Arylglyoxals 1{1−4}, isocyanides 2 {1−3}, mono-Boc protected phenylenediamines
3{1−4}, and carboxylic acids 4{1−6}.
promoted the cleavage-cyclization sequence to provide
quinoxalines 6 in yields in the range of 70−86%. Having
established the feasibility of the proposed approach in a
sequential fashion, we focused on the development of a one-pot
assembly of quinoxalines 6. It was gratifying to verify that a
simple work up (see Experimental Procedures) once the Ugi
reaction had finished (TLC monitoring) and subsequent
treatment of the crude Ugi adduct (5) with 30% TFA in
DCE at 80 °C for 1 h delivered targeted quinoxalines (6) with
satisfactory overall yields (Scheme 1). A set of assorted
precursors [Figure 5, carboxylic acids (4), isocyanides (2),
arylglyoxals (1) and mono-Boc protected phenylenediamines
(3)] expecting to modify the electronic, steric and lipo-/
hydrophilic features of the scaffold itself, were submitted to the
previously optimized conditions to evaluate the scope and
robustness of the Ugi-based assembly of 1,4-dihydroquinoxa-
lines documented here (Figure 5). According to the require-
ments of the medicinal chemistry program that inspired the
method development, we focused on the exploration of
structurally diverse carboxylic acids (including alkyl, cycloalkyl,
aryl, and heterocyclic residues at R1).
It can be observed from Scheme 1 that the method proved to
be broadly successful, providing the target structures with yields
ranging from 57% to 77%. It should be pointed out that the
reported values (Scheme 1) refer to the overall yield of the
synthetic steps involved (U-4CR, deprotection and cyclization),
thus indicating excellent yields for each simple step. The
information contained in Scheme 1 also supports the excellent
reactivity and chemoselectivity profile obtained for all
components (Figure 5, compounds 1−4) in a process that
allowed the incorporation of diverse residues at variable
positions (R1, R2, Ar, R6, R7) of the heterocyclic core (Scheme
1). A remarkable feature of the de novo 1,4-dihydroquinoxaline
assembly documented here concern its bond-forming efficiency,
which allows compounds 6 to be obtained in an experimentally
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Scheme 1. Ugi-Based Assembly of 1,4-Dihydroquinoxalines 6
simple and covergent one-pot process that involves the
formation of four new bonds.
and isocyanides (Scheme 2a), led us to evaluate the viability of
a similar approach with phenylglyoxal derivatives (1) used as
the carbonyl partner (Scheme 2b). The feasibility of the
proposed pathway, which should afford 2-carboxamidoquinoxa-
lines 9, would be heavily dependent on the availability of the
isocyanide to rapidly attack (α-addition) the initially formed
iminium ion (10) (Scheme 2b). The U-3CR process would
generate an Ugi adduct (11) that should render 9 following the
In an effort to broaden the versatility of the approach
outlined in Scheme 1, we decided to assess its applicability for
the assembly of other quinoxaline chemotypes (Scheme 2).
The recently developed acid-catalyzed Ugi three-component
synthesis (U-3CR)17 of 2-aminoquinoxalines (7), which
involves the reaction of aldehydes, o-phenylenediamines (8)
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Scheme 2. Proposed Direct Ugi-Based Assembly of 2-Carboxamidoquinoxalines 9
Figure 6. Proposed Ugi-based route to quinoxalines 9.
cyclization-aromatization sequence (Scheme 2b). Phenylglyoxal
(1{1}), benzyl isocyanide (2{1}) and o-phenylenediamine
(8{1}) were employed as model substrates to assess the
practicality of the transformation (Scheme 2c). The reactions
were tested under the acidic conditions (HCl) described by
Krasavin17a and also on neutral media. These experiments
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Scheme 3. U-3CR-Based Assembly of Quinoxalines 9
revealed that, irrespective of the experimental conditions, the
isolated product was not the desired 2-carboxamidoquinoxaline
9 (or its 1,4-dihydroderivative 12), but rather the 2-phenyl-
quinoxaline 13. The experimental behavior outlined above was
observed consistently irrespective of the experimental param-
eters modified (e.g., isocyanide equivalents, acid employed,
solvent or temperature). The reaction outcome, which reflects
the inability of the isocyanide to intercept the iminiun ion
intermediate (10), confirms that monoprotonation of the
phenylenediamine does not effectively prevent the cyclo-
condensation pathway to afford 13. Alternative efforts to access
2-carboxamidoquinoxaline 9 by the direct reaction of benzyl
isocyanide (2a) and 13, or its N-benzoylquinoxalinium salt,21
also failed (Scheme 2c).
The results described in Scheme 2 highlight the convenience
of using mono-Boc protected phenylenediamines (3) as key
precursors during the projected pathways. In an effort to
overcome the aforementioned failures, and inspired by a recent
paper22 describing an Ugi three-component reaction (U-3CR)
that employs catalytic amounts (10 mol %) of phenyl-
phosphinic acid (14) to transform an amine, an aldehyde,
and an isocyanide into a α-amino amide, it was envisioned that
a conceptually simple U-3CR-based assembly of quinoxalines 9
could be developed. The designed pathway (Figure 6), which
follows the UDC strategy,20 utilizes three of the reactive
partners previously employed for the synthesis of the 1,4-
dihydroquinoxalines 6 (Figure 5, precursors 1−3), with
phenylphosphinic acid being critical to protonate the in situ
generated imine and, in particular, to enable a water molecule
to intercept the electrophilic nitrilium ion. Such a sequence
(Figure 6) would afford α-aroyl aminoacetamides 15 and
subsequent acid-mediated cleavage and cyclization would afford
the 1,4-dihydroquinoxalines 12. Finally, aromatization of 12
would generate 2-carboxamidoquinoxalines 9.
Phenylglyoxal (1{1}), benzylisocyanide (2{1}), and tert-
butyl(2-amino-phenyl)carbamate (3{1}) were selected to
explore the viability of the transformation under the conditions
described by Pan and List22 [10 mol % of phenylphosphinic
acid (14), toluene at 80 °C, 12−24 h]. Nevertheless, these
experiments were unsuccessful and the targeted Ugi adduct
(15) was not detected. Attempts to modify the reaction
behavior by changing the experimental conditions [e.g., solvent
(dioxane, chloroform or DMF), temperature (50, 70 °C) or
reaction times (3−48 h)] proved fruitless. The only parameter
that was able to modify the reaction performance was the
amount of phenylphosphinic acid (14) employed in the
transformation, with the best results obtained on changing
from a catalytic to a stoichiometric procedure. The use of 1
equiv of phenylphosphinic acid (14) during the projected U-
3CR (toluene, 80 °C, 24 h) directly afforded the N-benzyl-3-
phenyl-1,4-dihydroquinoxaline-2-carboxamide (9{1,1,1})
(41%), together with 2-phenylquinoxaline 13 (26%). This
result provides evidence that, under stoichiometric conditions,
14 is able to cleave the Boc group within the Ugi adduct (15)
and also in the starting tert-butyl(2-amino-phenyl)carbamate
(1{1}) or the corresponding iminium ion intermediate. Slight
modifications of the experimental conditions [e.g., lowering the
temperature (80 to 60 °C) and reaction times (24 to 8 h)]
negated the side pathways to 13. These changes allowed the
Ugi adduct (15{1,1,1}) to be isolated as the main product
F
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(58%) together with small amounts (5−7%) of cyclized
quinoxaline derivative (12{1,1,1}). Hydrolytic cleavage (30%
TFA/DCE) of the crude reaction mixture promoted a
deprotection-cyclization sequence that led to N-benzyl-3-
phenyl-1,4-dihydroquinoxaline-2-carboxamide 12{1,1,1}
(52%). It should be noted that 1,4-dihydroquinoxalines 12
are unstable compounds that easily aromatize (either
spontaneously or during chromatographic purification).
Accordingly, it was decided to treat the crude reaction mixture
after Boc cleavage with a mild oxidant to exclusively obtain
quinoxalines 9. Brief exposure (0.5−1 h) of the reaction
mixture with MnO2 (3 equiv) provided the target 2-
carboxamidoquinoxalines 9 in satisfactory yields. Once the
feasibility of the proposed method had been established for a
model system, and having identified a set of experimental
conditions that afforded quinoxaline 9{1,1,1}, the scope of the
method was briefly assessed by employing representative
compounds of precursors 1−3 (Figure 5) as well as two
novel mono-Boc protected phenylenediamines [3{5} and
3{6}]. All reactions were performed in a one-pot fashion.
After monitoring the multicomponent reaction and judging it
complete, the solvent was evaporated and the crude adduct
(15) was submitted to the cleavage-cyclization-aromatization
sequence (Scheme 3). A preliminary assessment of the
efficiency and scope of the convergent and experimentally
simple three-component quinoxaline synthesis documented
here is provided in Scheme 3. It can be observed that the yields
obtained range from 51 to 69%, with the reported values
referred to the overall yield of the three synthetic steps involved
(U-3CR, deprotection, cyclization and aromatization). It can
also be seen from Scheme 3 that the reaction proved to be
successful with all variable components (1−3), thus enabling
the heterocyclic core to be decorated with different residues.
In summary, we report here two novel Ugi-based approaches
that provide an integrated and straightforward entry to novel
quinoxaline-based libraries encompassing skeletal and func-
tional diversity. This convergent and versatile method, which
uses readily available commercial reagents and does not require
advanced intermediates or anhydrous solvents, exhibits high
bond-forming efficiency; thus exemplifying the operationally
simple synthesis of quinoxaline libraries in a time-efficient and
cost-effective manner.
nuclear magnetic resonance spectroscopy (1H and 13C) and
high-resolution mass spectroscopy (HRMS). Unless otherwise
stated 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.
General Procedure for the One-Pot Synthesis of 1,4-
Dihydroquinoxalines 6. A mixture of the glyoxal derivative
(0.5 mmol), the monoprotected phenylenedediamine (0.5
mmol), the isocyanide (0.5 mmol) and the carboxylic acid (0.5
mmol) in MeOH (2 mL) was submitted to orbital stirring at
room temperature for 48 h. After completion of the reaction,
CH2Cl2 (3 mL) and PS-p-TsOH (1.0 mmol) were added. The
reaction mixture was submitted to orbital stirring at room
temperature until the unreacted isocyanide had been consumed
(0.5 h). The polystyrene-supported reagent was filtered off and
successively washed [3 × 5 mL] with MeOH, EtOAc, and
CH2Cl2. The solvents were evaporated from the filtrate to
afford an oily residue, which was dissolved in DCE (10 mL)
and then treated with 30% TFA and stirred at 80 °C for 1−3 h.
The solution was then treated with saturated NaHCO3. The
product was extracted with ethyl acetate and the organic phase
was dried (Na2SO4) and evaporated under reduced pressure to
afford an oily residue, which was purified by chromatography
on silica gel using hexane/EtOAc mixtures.
N-Benzyl-3-phenyl-1-propionyl-1,4-dihydroquinoxaline-2-
carboxamide 6{1,1,1,1}. Yield: 59%, 116 mg (EtOH, mp 175−
1
176 °C). H NMR (300 MHz, CDCl3) δ (ppm): 8.19−8.07
(m, 2H), 7.62 (dt, J = 7.9, 1.0 Hz, 1H), 7.54−7.46 (m, 3H),
7.39−7.29 (m, 1H), 7.28−7.14 (m, 5H), 6.96−6.80 (m, 2H),
6.69 (s, 1H), 6.36 (t, J = 6.4 Hz, 1H), 4.41 (dd, J = 15.1, 6.7 Hz,
1H), 4.18 (dd, J = 15.1, 5.2 Hz, 1H), 2.75 (dq, J = 16.2, 7.4 Hz,
1H), 2.59 (dq, J = 16.2, 7.3 Hz, 1H), 1.16 (t, J = 7.4 Hz, 3H).
13C NMR (75 MHz, CDCl3) δ (ppm): 174.6, 166.3, 162.2,
138.7, 137.5, 136.4, 131.4, 128.8, 128.5, 128.0, 127.6, 127.5,
127.3, 127.1, 127.1, 126.6, 122.8, 43.3, 27.3, 9.6. HRMS (CI)
m/z calcd. for C25H24N3O2 [M + H]+: 398.1869; found
398.1871.
General Procedure for the One-Pot Synthesis of
Quinoxalines 9. A mixture of the glyoxal derivative (0.5
mmol), the monoprotected phenylenedediamine (0.5 mmol),
the isocyanide (0.5 mmol), and phenylphosphinic acid (0.5
mmol) in dry toluene (3 mL) was submitted to orbital stirring
at 60 °C for 8−10h. After completion of the reaction, CH2Cl2
(3 mL) and PS-p-TsOH (1.0 mmol) were added. The reaction
mixture was submitted to orbital stirring at room temperature
until the unreacted isocyanide had been consumed (0.5 h). The
polystyrene-supported reagent was filtered off and successively
washed [3 × 5 mL] with MeOH, EtOAc and CH2Cl2. The
solvents were evaporated from the filtrate to afford an oily
residue, which was dissolved in DCE (10 mL) and then treated
with 30% TFA and stirred at 80 °C for 1−3 h. The solution was
then treated with saturated NaHCO3. The product was
extracted with ethyl acetate. The organic phase was dried
(Na2SO4) and evaporated under reduced pressure to afford an
oily residue, which was dissolved in THF, treated with MnO2
(3 equiv) and stirred at room temperature for 1 h. The
oxidizing agent was filtered off and successively washed with
DCM, THF and MeOH. The solvents were evaporated to
afford an oily residue, which was purified by chromatography
on silica gel using hexane/EtOAc mixtures.
EXPERIMENTAL PROCEDURES
■
Commercially available starting materials and reagents were
purchased and used without further purification from freshly
opened containers. Monoprotected phenylenediamines (3)
were acquired from commercial sources or obtained following
previously described procedures.23 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 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 determined by
N-Benzyl-3-phenylquinoxaline-2-carboxamide (9{1,1,1}).
1
Yield: 69%, 119 mg (EtOH, mp 188−189 °C). H NMR
(300 MHz, CDCl3) δ (ppm): 8.32−8.00 (m, 2H), 7.98−7.62
G
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S
Detailed experimental procedures, complete description of the
spectroscopic and analytical data of all compounds described,
1
including copies of H NMR, 13C NMR, and HRMS. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel.: ++34-881815732. Fax.: ++34-881815702. E-mail: e.
sotelo@usc.es.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was financially supported by the Galician Govern-
ment (Spain, Project 09CSA016234PR). J.A. thanks FUN-
■
DAYACUCHO (Venezuela) and Diputacio
(Galicia, Spain) for research grants.
́
n da Coruna
̃
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