Nitroepoxides as versatile precursors to 1,4-diamino heterocycles

Article abstract of DOI:10.1021/ol500444z

Nitroepoxides are easily transformed into 1,4-diamino heterocycles such as quinoxalines and pyrazines by treatment with 1,2-benzenediamines and ammonia, respectively. Additionally, related saturated heterocycles, such as piperazines and tetrahydroquinoxalines, can be accessed by treatment with 1,2-diamines and a reducing agent. These transformations are efficient, provide access privileged, bioactive structures, and produce minimal waste.

Full text of DOI:10.1021/ol500444z

Letter
pubs.acs.org/OrgLett
Nitroepoxides as Versatile Precursors to 1,4-Diamino Heterocycles
Andreu Vidal-Albalat, Santiago Rodríguez, and Florenci V. Gonzalez*
́
̀ ̀ ́
Departament de Química Inorganica i Organica, Universitat Jaume I, Castello, Spain
S
* Supporting Information
ABSTRACT: Nitroepoxides are easily transformed into 1,4-
diamino heterocycles such as quinoxalines and pyrazines by
treatment with 1,2-benzenediamines and ammonia, respec-
tively. Additionally, related saturated heterocycles, such as
piperazines and tetrahydroquinoxalines, can be accessed by
treatment with 1,2-diamines and a reducing agent. These
transformations are efficient, provide access privileged,
bioactive structures, and produce minimal waste.
iamino heterocycles, such as quinoxalines, tetrahydroqui-
Dnoxalines, piperazines, and pyrazines, find numerous
applications in medical and material science. For example,
quinoxaline derivatives have been reported as anticancer,1
antiviral,2 antibacterial,3 and antiinflammatory agents4 and as
kinase inhibitors5 and antibiotics.6 In addition, the quinoxaline
moiety has been recently incorporated in materials with
interesting properties such as solar cells.7 Compounds
containing the pyrazine heterocycle find numerous applications
in materials science,8 medicinal chemistry,9 compounds that are
responsible for the flavor and aroma of several foodstuffs and
wines,10 and compounds with herbicidal activity.11 Recently,
tetrasubstituted pyrazines have been discovered as semi-
ochemicals in orchids.12 Compounds that possess a tetrahy-
droquinoxaline system have been studied as potent cholesteryl
ester transfer protein inhibitors,13 anticonvulsants,14 potassium
channel openers,15 and anti-HIV agents.16 The piperazine
moiety has been classified as a “privileged scaffold” in medicinal
chemistry17 and is frequently found in many natural products as
well as being a large class of biologically active compounds
(Figure 1).
A common method for the preparation of the aforemen-
tioned heterocycles is the condensation of 1,2-dicarbonyl
compounds with 1,2-diamines.18 General synthetic approaches
to differently substituted 1,2-dicarbonyl compounds are usually
step intensive and typically involve redox approaches. A
convergent route could potentially involve the use of carbonyl
anion synthons, but again, the oxidation states of the initial
product require modification. Although interesting approaches
have been reported to circumvent this limitation,19 we
envisaged that nitroepoxides could be convenient and enabling
starting materials for the preparation of 1,4-diamino hetero-
cycles.
Nitroepoxides are an underdeveloped class of compounds
with wide potential for use in chemical synthesis.20 These
interesting small molecules can be easily prepared through the
straigthforward epoxidation of nitroalkenes, which in turn are
readily accessed from a standard nitroaldol/Henry reaction
(Figure 1). We previously reported the derivatization of
Figure 1. Reaction design for heterocycles.
nitroepoxides into vicinal diamines by treatment with an
amine and then a reductive agent,21 and we now report the
transformations of nitroepoxides into heterocycles with two
nitrogen atoms. Our strategy revolves around the reaction
between nitroepoxide and 1,2-diamine to afford an α-
iminoamine intermediate (Figure 1). This key intermediate
Received: February 11, 2014
Published: March 3, 2014
© 2014 American Chemical Society
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Letter
can be processed in two ways: the exposure to air produces the
oxidized aromatic heterocycle while the in situ addition of a
reducing agent directly accesses the saturated analogue.
Scheme 1. Synthesis of Piperazines 3a−c
We began our studies of the preparation of quinoxalines by
combining nitroepoxide 1a with 1,2-benzenediamine (1.5
equiv) in 1,2-dichloroethane. We were pleased to see that the
reaction afforded quinoxaline 2a (Table 1, entry 1) under very
a
Table 1. Synthesis of Quinoxalines
b
entry
R1, R2
Ph, Me
epoxide
R3
diamine
yield (%)
c
1
1a
1a
1a
1b
1b
1c
1c
1d
1e
1e
H
H
Cl
H
Cl
H
Cl
H
H
Cl
2a
2a
2b
2c
2d
2e
2f
72
86
82
80
75
78
70
80
63
48
2
Ph, Me
3
Ph, Me
4
p-F-Ph, Me
p-F-Ph, Me
p-Me-Ph, Me
p-Me-Ph, Me
p-F-Ph, Et
n-Pr, Me
prepared through reduction of quinoxalines.27 We evaluated a
one-pot process for the preparation of tetrahydroquinoxalines
starting from nitroepoxides (Scheme 2). We initially applied
5
6
7
8
2g
2h
2i
9
Scheme 2. Optimization of Conditions for the Synthesis of
Tetrahydroquinoxaline 4
10
n-Pr, Me
a
Reactions were carried out using nitroepoxide (1.0 equiv) and 1,2-
b
benzenediamine (1.5 equiv) at room temperature for 16 h. Yield of
isolated product. Reaction was performed using 1,2-dichloroethane as
c
a solvent.
mild conditions. In order to improve the yield of the reaction,
other conditions were evaluated. Higher yield was obtained by
using ethanol as a solvent and performing the reaction in the
presence of air22 (Table 1, entry 2). The improvement of the
yield with ethanol as the solvent is most likely due to the higher
solubility of the reactants and to the unreactivity of the solvent
with diamines compared to 1,2-dichloroethane.23 Under these
conditions, the color of the reaction mixture turns an intense
red as an indicator of reaction completion and was general all
cases studied to date. Various nitroepoxides were subjected to
reaction conditions to explore the scope of the process.
Nitroepoxides 1a−d having an aryl group and an alkyl group
gave a higher yield (Table 1, entries 1−8), while compound 1e
having an alkyl group in both positions gave a lower yield
(Table 1, entries 9 and 10).
Following the success of the quinoxaline study, we then
evaluated a one-pot procedure for the preparation of 2,3-
disubstituted piperazines starting from nitroepoxides. Piper-
azines 3a−c were prepared using the same procedure as the
one reported by us for the preparation of diamines21 but using
1,2-ethylenediamine instead of an amine and ethanol as a
solvent instead of 1,2-dichloroethane (eq 1, Scheme 1). The
reaction afforded piperazines 3a−c as a mixture of cis/trans
isomers, with the syn isomer predominating.
the same conditions as mentioned above for the preparation of
piperazines over nitroepoxide 1, but using 1,2-benzenediamine
instead of ethylenediamine. However, the main product of the
reaction was quinoxaline 2a (eq 2, Scheme 2). Tetrahydroqui-
noxaline 4 was obtained when borane−tetrahydrofuran
complex was used as a reductive agent in tetrahydrofuran as a
solvent.28 However, the yield was low, and the main product of
the reaction was quinoxaline 2a (eq 3, Scheme 2). Finally,
nitroepoxide 1a was transformed into tetrahydroquinoxaline 4
in higher yield by treatment with 1,2-benzenediamine in
dichloromethane as a solvent for 48 h and then addition of
borane−tetrahydrofuran complex (4 equiv) (eq 4, Scheme 2).
The stereochemistry of tetrahydroquinoxaline 4 was assigned
by NMR as for piperazines 3a−c.
The stereochemistry of the piperazines 3a−c was assigned by
NMR coupling constants (J2,3 for trans, higher than for cis) and
by NOE experiments (Scheme 1).
Although approaches for the preparation of oxopiperazines24
or 2-substituted piperazines have been reported,25 procedures
for the preparation of 2,3-disubstituted piperazines are scarce.26
Methods for the preparation of tetrahydroquinoxalines suffer
from the same drawbacks as quinoxalines, since they are usually
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Although other approaches have been reported,29 pyrazines
are commonly prepared from α-aminoaldehydes.30 We
envisioned a preparation of pyrazines starting from nitro-
epoxides using dry ammonia in methanol. Ammonia would
attack the nitroepoxide to give an α-amino ketone which could
dimerize to afford a dihydropyrazine intermediate which upon
oxidation could afford pyrazine (Scheme 3). When nitro-
ACKNOWLEDGMENTS
■
This work was financed by the Bancaixa−UJI foundation (P1
1B2011-59 and P1 1B2011-28). A.V.-A. thanks Generalitat
Valenciana for a Ph.D. research grant under the VALi+D
Program. We also thank Serveis Centrals d’Instrumentacio
́
́
Cientifica from Universitat Jaume I for technical support.
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■
S
* Supporting Information
Experimental procedures and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: fgonzale@uji.es.
Notes
The authors declare no competing financial interest.
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Supporting Information).
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