Synthesis of unsymmetrical pyrazines based on ?±-diazo oxime ethers

Article abstract of DOI:10.1021/ol5034173

Synthesis of unsymmetrically substituted pyrazines has been a challenge. The reactivity of ?±-imino carbenoids derived from ?±-diazo oxime ethers has been exploited for pyrazine synthesis, in which the reaction of ?±-diazo oxime ethers with 2H-azirines provides highly substituted pyrazines in good to excellent yields.

Full text of DOI:10.1021/ol5034173

Letter
pubs.acs.org/OrgLett
Synthesis of Unsymmetrical Pyrazines Based on α‑Diazo Oxime
Ethers
Nicole S. Y. Loy,† Sunggak Kim,† and Cheol-Min Park*,‡
†Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637616, Singapore
‡Department of Chemistry, UNIST, UNIST-gil 50, Ulsan 689-798, Korea
S
* Supporting Information
ABSTRACT: Synthesis of unsymmetrically substituted pyrazines
has been a challenge. The reactivity of α-imino carbenoids derived
from α-diazo oxime ethers has been exploited for pyrazine synthesis,
in which the reaction of α-diazo oxime ethers with 2H-azirines
provides highly substituted pyrazines in good to excellent yields.
yrazines are an important class of N-heterocycles found in
diverse bioactive natural products and therapeutic agents.
alkenylation of pyrazines has been reported, although substrates
are limited to symmetrical disubstituted pyrazines due to
regioselectivity.8 Multistep synthesis of tetrasubstituted pyr-
azines has been reported by using nickel-catalyzed cross-coupling
of chloropyrazines with alkyl zinc reagents followed by Friedel−
Crafts acylation.9
Given the limitations of current methods, we were prompted
to develop the synthesis of unsymmetrical pyrazines. α-Diazo
oxime ethers have been demonstrated to serve as an excellent
precursor for α-imino carbenoids, of which their synthetic utility
has been explored in the synthesis of various N-heterocycles.10
Among our earlier works, we have shown that activation of 2H-
azirines by reacting with vinyl carbenoids leads to the formation
of pyridines via electrocyclization of 3-azatrienes.10d We
envisioned that this strategy could be extended to the synthesis
of pyrazines by employing α-diazo oxime ethers.
P
Examples include the potassium-sparing diuretics amiloride and
triamterene, which are used in the management of hypertension
and congestive heart failure. Further, pyrazine derivatives
pyrazinamide and morinamide are antibacterial drugs used to
treat tuberculosis. The pyrazine moiety is also found in
varenicline, which stimulates nicotine receptors more weakly
than nicotine, and it is used to treat people addicted to smoking.
Despite their broad utility, efficient synthetic methods for
pyrazines are primarily limited to symmetrical pyrazines. For
example, the condensation of α-amino ketones allows an efficient
synthesis for pyrazines; however, this approach gives rise to
mixtures of regioisomeric pyrazines when two different α-amino
ketones are employed. A similar problem is encountered when
1,2-diamines and 1,2-diketones are reacted.1
Likewise, dimerization of nitrile ylides derived from azirines
and dehydrogenative dimerization of 1,2-amino alcohols provide
symmetrical pyrazines.2 Efforts have been made to develop a
synthesis of unsymmetrical pyrazines. In the pioneering work,
Buchi reported electrocyclization-based synthesis of pyrazines,
although examples were limited by simple methyl- or ethyl-
substituted pyrazines.3 N−H insertion of α-amino acid-derived
primary amides with α-keto carbenoids followed by cyclization to
give pyrazines has been reported.4
An alternative approach involving substitution of pyrazine
cores has also been developed.5 Despite its harsh reaction
conditions, direct lithiation allows introduction of various
substitutions on pyrazine cores.6 Halide-substituted pyrazines
have been employed in palladium-catalyzed cross-coupling
reactions to functionalize the cores.7 Zirconium-mediated
Our initial efforts to realize the transformation commenced by
screening different metal complexes with α-diazo oxime ether 1a
and 2H-azirine 2a in 1,2-dichloroethane (DCE) at 90 °C and
subsequently heating to 150 °C to ensure complete cyclization
(Table 1).
Unlike the reaction of vinyl carbenoids and azirines, in which
Rh-based catalysts showed superior activity while Cu catalysts
were completely inactive,10d Rh catalysts failed to give pyrazine
4a (Table 1, entries 1 and 2). Among the copper complexes
screened, Cu(OAc)2 and Cu(acac)2 showed promising results
Received: November 25, 2014
© XXXX American Chemical Society
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DOI: 10.1021/ol5034173
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Letter
a
a
Table 1. Optimization of Pyrazine Synthesis
Scheme 1. Scope of 2H-Azirines for Pyrazine Synthesis
b
entry
catalyst
solvent
DCE
yield (%)
1
Rh2(OAc)4
Rh2(esp)2
2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
toluene
3
Cu(OAc)2
30
55
64
50
60
87
83
79
4
Cu(acac)2
5
Cu(OTf)2
6
[Cu(OTf)]2·PhH
Cu(tfacac)2
Cu(hfacac)2
Cu(hfacac)2
Cu(hfacac)2
7
8
9
10
chlorobenzene
a
Reaction conditions: 1a (0.36 mmol), 2a (0.3 mmol), solvent (0.15
b
M). Isolated yields. esp = α,α,α′,α′-tetramethyl-1,3-benzenedipropi-
onate, tfacac = trifluoroacetylacetonate, hfacac = hexafluoroacetylacet-
onate.
providing the desired product albeit in low yields, 30% and 55%,
respectively (Table 1, entries 3 and 4). A comparison was made
between Cu(II) and Cu(I) for their efficiency, showing the
superior activity of Cu(II) (Table 1, entries 5 and 6). The
electronic effect of ligands was clearly observed from the series of
reactions employing Cu(OTf)2, Cu(tfacac)2, and Cu(hfacac)2;
the most electron-deficient Cu(hfacac)2 emerged as the catalyst
of choice providing the pyrazine in 87% (Table 1, entries 5, 7, and
8). Reactions in different solvents including toluene and
chlorobenzene gave comparable yields (83% and 79%,
respectively, Table 1, entries 9 and 10).
a
Reaction conditions: 1 (0.36 mmol), 2 (0.3 mmol), DCE (0.15 M).
With the optimized conditions in hand, we turned our
attention to the substrate scope of the reaction. To assess
electronic and steric influences in the formation of unsym-
metrical pyrazines, we first surveyed various 2H-azirines by
reacting with α-diazo oxime ethers 1a and 1b (Scheme 1). The
transformation is generally well tolerated and provides the
corresponding pyrazines in good yields. Electronic effect of 2H-
azirines on the reaction was examined by substitution of the
phenyl group of 2H-azirine 2a, revealing broad tolerance for both
electron-donating and -withdrawing groups (4ab−ad). The
reaction with 2H-azirine 2d bearing ortho-substitution also
smoothly proceeded to give 4ad indicating marginal steric
influence. The feasibility of access to fully substituted pyrazines
was examined by employing disubstituted 2H-azirine 2h.
Gratifyingly, pseudosymmetric tetrasubstituted pyrazine 4ah
was obtained in 68% yield, which may serve as a useful
intermediate allowing for selective derivatization of the ester
groups. Additional 2H-azirines were examined for the
introduction of different types of substituents. While the reaction
of 2-alkyl substituted 2H-azirine 2i provided the corresponding
pyrazine 4ai in good yield, that of 2-phenyl-2H-azirine 2j was
sluggish to give 4aj in 42% yield, presumably due to steric
hindrance between the two phenyl groups. Consistent with the
broad tolerability of the reaction with diazo compound 1a, 1b
bearing phenyl substitution also efficiently participated in the
reaction providing the corresponding pyrazines in good yields
(4bb−bi).
The reported yields in parentheses are of the isolated products.
Scheme 2. Scope of Diazo Compounds for Pyrazine
a
Synthesis
a
Reaction conditions: 1 (0.36 mmol), 2a (0.3 mmol), DCE (0.15 M).
The reported yields in parentheses are of the isolated products.
Encouraged by these results, we further explored the substrate
scope by employing α-diazo oxime ethers with various
substituents of electronic and steric characteristics (Scheme 2).
The electronic effect examined by substituting the phenyl group
of 2H-azirine with electron-donating and -withdrawing groups
(1b, 1c, and 1d) clearly revealed the efficiency of the reaction in
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DOI: 10.1021/ol5034173
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the order of 4-methoxyphenyl, phenyl, and 4-nitrophenyl (76%,
67%, and 51% for 4ca, 4ba, and 4da, respectively). Both primary
and secondary alkyl-substituted diazo compounds showed good
conversion providing the corresponding pyrazines 4ea, 4fa, and
4ga in yields of 77%, 76%, and 80%, respectively. 1,1′-
Biheteroaryl derivatives are useful moieties that are frequently
found in many bioactive molecules. As shown in Scheme 1, this
type of pyrazines 4ha and 4ia could be readily synthesized in 65%
and 63% yields. In addition to ester groups, keto-substituted
pyrazines could be synthesized by employing the corresponding
α-diazo oxime ethers (4ja, 60%).
ACKNOWLEDGMENTS
■
This work was supported by a UNIST grant (1.130063.01) and
National Research Foundation of Korea (NRF) grants (2014-
011165, Center for New Directions in Organic Synthesis, and
NRF-2014R1A2A2A01006060) funded by the Korean govern-
ment and Nanyang Technological University.
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Scheme 3. Proposed Reaction Mechanism
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azine formed via electrocyclization of 3 rapidly isomerizes to 1,4-
dihydropyrazine, and spontaneous elimination of MeOH
provides pyrazine 4. This mechanistic pathway is consistent
with the observed regiochemistry of pyrazines.
In summary, we have developed a novel synthesis of
unsymmetrical pyrazines via the reaction of α-diazo oxime
ethers with 2H-azirines via electrocyclization of 1,4-diazahexa-
trienes. This method proves sufficiently general to provide
various unsymmetrically substituted pyrazines.
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures and characterization data. This
material is available free of charge via the Internet at http://pubs.
acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: cmpark@unist.ac.kr.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/ol5034173
Org. Lett. XXXX, XXX, XXX−XXX