Copper(II)-catalyzed synthesis of pyrazinones from α-Azido-N- allylamides under an oxygen atmosphere

Article abstract of DOI:10.1055/s-0030-1261185

A copper(II)-catalyzed reaction of -azido-N-allylamide synthetic under an oxygen atmosphere resulted in the formation of 2-formyl pyrazinones. The present transformation was characterized by the following steps: 1) 1,3-dipolar cycloaddition of the azido part onto the intramolecular alkene to give bicyclic aziridine intermediates; 2) further copper(II)-catalyzed oxygenation-oxidation of the aziridines to give 2-formyl pyrazinones. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1261185

LETTER
2167
Copper(II)-Catalyzed Synthesis of Pyrazinones from a-Azido-N-allylamides
under an Oxygen Atmosphere
S
a
ynthesis of Py
i
n
es from
a
-A
e
N
-allylamide
Z
s
hang,a Jian-Yuan Lee,a Naomi Yamazaki,b Shunsuke Chiba*a
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
21 Nanyang Link, 637371, Singapore
Fax +6567911961; E-mail: shunsuke@ntu.edu.sg
Department of Chemistry, Tohoku University, Aoba-ku, Sendai, 980-8578, Japan
b
Received 13 May 2011
•
Abstract: A copper(II)-catalyzed reaction of a-azido-N-allylamide
synthetic under an oxygen atmosphere resulted in the formation of
2-formyl pyrazinones. The present transformation was character-
ized by the following steps: 1) 1,3-dipolar cycloaddition of the azi-
do part onto the intramolecular alkene to give bicyclic aziridine
intermediates; 2) further copper(II)-catalyzed oxygenation–oxida-
tion of the aziridines to give 2-formyl pyrazinones.
O
O
O
[CuIII]
N
+N2
–N
cat. Cu(OAc)2
K3PO4
N
NR2
N
N
DMF, 80 °C
under O2
(1 atm)
R1
R2
R1
R2
R1
O
O
O
Key words: pyrazinone, organic azides, 1,3-dipolar cycloaddition,
copper, oxygen
Scheme 1 Copper-catalyzed synthesis of azaspirocyclohexadien-
ones
Pyrazine derivatives are attractive compounds due to their
potential biological property in pharmaceutical domains.1
Classically, pyrazine frameworks were constructed by
self-condensation of 2-amino carbonyl compounds2 or
condensation between 1,2-dicarbonyl compounds and
1,2-diamines.3 Although other types of synthetic ap-
proaches towards pyrazines have been developed,4 versa-
tile methodologies to construct pyrazines with selective
control of substitution patterns using readily accessible
building blocks are still needed. Herein, we report cop-
per(II)-catalyzed synthesis of 2-formyl pyrazinones from
readily available a-azido-N-allylamides under an O2 at-
mosphere.
O
Me
Me
N
N
Me
+N2
–N
Me
Ph
O
Cu(OAc)2 (20 mol%)
K3PO4 (1 equiv)
2a 42%
+
N
DMF, 80 °C, 4 h
under O2 (1 atm)
Ph
O
N
H
O
1a
N
Me
Ph
O
We have recently reported a copper(II)-catalyzed synthe-
sis of azaspirocyclohexadienones from a-azido-N-aryl-
amides under an O2 atmosphere.5 The transformation was
carried out by a sequence of denitrogenative formation of
iminyl copper species from a-azido-N-arylamides and
their imino-cupration with an intramolecular benzene ring
on the amido nitrogen followed by consecutive formation
of C–O bonds, where molecular oxygen was a prerequi-
site for achieving the present catalytic cyclization and that
one of the oxygen atoms of O2 was found to be incorpo-
rated into the cyclohexadienones (Scheme 1).
Me
3a 18%
Scheme 2 A reaction of a-azido-N-phenyl-N-allylamide 1a
In order to obtain pyrazinones 3 as the sole product as well
as to elucidate the reaction mechanism of this pyrazinone
formation, our study was commenced with the reaction of
a-azido-N-allylamide 1b, which was subjected to 20
mol% of Cu(OAc)2 in the presence of K2CO3 at 80 °C un-
der an O2 atmosphere (Scheme 3). The reaction proceeded
smoothly to afford pyrazinone 3b in 62% yield.7 The
structure of 3b was secured by the X-ray crystallographic
analysis.8 When the reaction of 1b was conducted under a
N2 atmosphere, only dihydropyrazinone 49 was isolated in
14% yield, which indicated that molecular oxygen is es-
sential for the formation of a formyl group (Scheme 3).
During the course of the study on substrate scope for this
azaspirocyclohexadienone synthesis, it was found that the
reaction of a-azido-N-phenyl-N-allylamide 1a delivered
azaspirodienone 2a in 42% yield along with 18% yield of
2-formyl pyrazinone 3a that might be formed via formal
imino-oxygenation of the C=C bond6 (Scheme 2).
We next examined the generality of this catalytic synthe-
sis of 2-formyl pyrazinones 3 (Table 1).10,11 By varying
substituent R1, electron-rich aryl rings could be intro-
duced in good to moderate yields (entries 1–4). This pro-
cess could keep C–Cl and C–Br bonds intact (entries 5–7),
SYNLETT 2011, No. 15, pp 2167–2170
Advanced online publication: 12.08.2011
DOI: 10.1055/s-0030-1261185; Art ID: D14511ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
1

2168
L. Zhang et al.
LETTER
Scheme 3 Reactions of a-azido-N-allyl-N-benzylamide 1b
while the reaction was sluggish when R1 is a 2-chlorophe- In order to confirm the reaction pathway of this pyrazino-
nyl moiety (entry 6). The substrate 1j bearing a 4- ne formation, a-azido-N-allylamide 1b were first treated
cyanophenyl group as R1 provided the desired pyrazinone with one equivalent of NaOMe to generate the transient
3j only in 17% yield. The alkyl group as R1 was not viable N-H imine species,12 which was then subjected to 20
for this transformation (entry 9). In addition to a benzyl mol% of Cu(OAc)2 at 80 °C under an O2 atmosphere
group on the amino nitrogen as R2, 4-methoxybenzyl, and (Scheme 5). In this case, only a-keto amides 6 and 713
methyl groups could be employed (entries 10 and 11). were isolated in 41% and 4% yields, respectively, without
Moreover, a bulky 2,6-dimethylphenyl moiety could be formation of any pyrazinone 3b, suggesting that the imi-
installed for selective synthesis of N-aryl pyrazinone 3n nyl copper species is not involved in the reaction course.
without azaspirocyclohexadienone formation.
It was speculated that formation of pyrazinone 3 was ini-
tiated by the azido-alkene 1,3-dipolar cycloaddition reac-
tion.14 Based on this hypothesis, a-azido-N-allylamide 1b
was heated in refluxing toluene, which resulted in the 1,3-
dipolar cycloaddition to provide bicyclic aziridine B via
denitrogenative fragmentation of putative triazoline
A.15,16 Upon removal of toluene from the reaction system
under reduced pressure, resulting aziridine B was subject-
ed to 20 mol% of Cu(OAc)2 in DMF solution at 80 °C un-
der an O2 atmosphere, which delivered pyrazinone 3b in
48% yield (Scheme 6).
It is noteworthy that the reaction in the presence of a
Wittig stabilized ylide (Ph3P=CHCO2Me) provided 2-al-
kenyl pyrazinone 5 in 60% yield via one-pot alkenylation
of the resulting 2-formyl pyrazinone 3 (Scheme 4).
+N2
–N
Cu(OAc)2 (20 mol%)
K2CO3 (1 equiv)
N
Ph
+
CO2Me
(1 equiv)
Ph3P
DMF, 80 °C, 5 h
under O2 (1 atm)
O
Cl
Based on these results, a proposed reaction pathway of the
formation of pyrazinone 3b was shown in Scheme 7. Af-
ter generation of bicyclic aziridine B via 1,3-dipolar azi-
do-alkene cycloaddition, single-electron oxidation of B
with Cu(OAc)2 might form radical cation C, which under-
went deprotonation followed by ring opening of the aziri-
dine ring to generate primary alkyl radical D. Resulting
radical D was converted into copper peroxy species E by
trapping molecular oxygen. Elimination of copper hy-
droxide from E afforded 2-formyl dihydropyrazinone F,
that would be further oxidized under the present reaction
conditions to give pyrazinone 3b.
1g
CO2Me
MeO2C
N
N
+
N
Ph
N
Ph
O
O
Cl
Cl
(E)-5g 49%
(Z)-5g 11%
Scheme 4 Synthesis of 2-alkenyl pyrazinone
O
N
H
N
+N2
O
O
NaOMe (1 equiv)
Cu(OAc)2 (20 mol%)
H
–N
NH
N
Ph
Ph
N
Ph
+
+
Ph
Ph
Ph
N
Ph
N
Ph
DMF, 0 °C
under N2
DMF, 80 °C, 2.5 h
under O2 (1 atm)
Ph
Ph
O
O
O
6 41%
7 4%
3b 0%
O
O
1b
Scheme 5 Control reactions of a-azido-N-allylamide 1b
Synlett 2011, No. 15, 2167–2170 © Thieme Stuttgart · New York

LETTER
Synthesis of Pyrazinones from a-Azido-N-allylamides
2169
Table 1 Substrate Scope of Synthesis of Pyrazinonesa,b
+N2
–N
[CuII]
N
N
H
O
H
N
+N2
NBn
NBn
NBn
– [CuI]
Cu(OAc)2 (20 mol%)
K2CO3 (1 equiv)
Ph
Ph
Ph
– N2
–N
N
O
O
O
N
1b
C
R2
B
R1
R2
R1
DMF, 80 °C
under O2 (1 atm)
time
[CuII]
O
1
O
3
O
O
•
Entry a-Azido-N-allylamide 1 Time (h) Yield of pyrazinone 3 (%)
O2, [CuI]
N
N
– [CuII]OH
NBn
NBn
O
N
H
– H+
+N2
–N
Ph
Ph
O
E
O
D
N
Ph
R1
Ph
N
R1
H
N
O
H
N
O
O
O
O2, [CuII]
1
2
3
4
5
6
7
8
9
1c R1 = 2-naphthyl
1d R1 = 4-PhC6H4
1e R1 = 3,5-Me2C6H3
1f R1 = 4-MeOC6H4
1g R1 = 4-ClC6H4
1h R1 = 2-ClC6H4
1i R1 = 4-BrC6H4
1j R1 = 4-CNC6H4
1k R1 = Me
2
3
5
6
6
6
4
6
3
3c 65
3d 48
3e 41
3f 43
3g 49
3h 21
3i 57
3j 17
3k 0
NBn
NBn
Ph
Ph
O
F
O
3b
Scheme 7 A proposed catalytic pathway of pyrazinone formation
In summary, copper(II)-catalyzed synthesis of pyrazinone
from a-azido-N-allylamides under an O2 atmosphere has
been exploited. The present transformation is character-
ized by the following multistep sequence: intramolecular
1,3-dipolar cycloaddition of azide part onto an alkene to
give bicyclic aziridine intermediates, followed by cop-
per(II)-catalyzed oxygenation–oxidation of the aziridines
to give 2-formyl pyrazinones. Further investigation on ap-
plication of this methodology for synthesis of other types
of heterocycles are currently under way.
O
H
+N2
–N
N
N
R2
N
Ph
R2
Ph
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
O
O
10
11
12
1l R2 = 4-MeOC6H4CH2
1m R2 = Me
2
19
19
3l 62
3m 47
3n 44
Acknowledgment
1n R2 = 2,6-MeC6H3
This work was supported by funding from Nanyang Technological
University and Singapore Ministry of Education (Academic Re-
search Fund Tier 2: MOE2010-T2-1-009). N.Y. thanks JSPS (Japan
Society for the Promotion of Science) for a predoctoral fellowship.
We thank Dr. Yongxin Li (Division of Chemistry and Biological
Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University) for assistance in X-ray crystal-
lographic analysis.
a Reaction conditions: azides (0.5 mmol), Cu(OAc)2 (20 mol%),
K2CO3 (1 equiv), DMF (0.1 M), 80 °C, O2 atmosphere.
b Isolated yields are recorded above.
N
+N2
–N
N
N
N
Ph
N
Ph
– N2
toluene, 100 °C
under N2
Ph
Ph
References and Notes
O
O
(1) For recent reports on the bioactivity study of substituted
pyrazines and their derivatives, see: (a) Kerekes, A. D.;
Esposite, S. J.; Doll, R. J.; Tagat, J. R.; Yu, T.; Xiao, Y.;
Zhang, Y.; Prelusky, D. B.; Tevar, S.; Gray, K.; Terracina,
G. A.; Lee, S.; Jones, J.; Liu, M.; Basso, A. D.; Smith, E. B.
J. Med. Chem. 2011, 54, 201. (b) Andjelkovic, M. WO
2008,040,651, 2008. (c) Parlow, J. J.; Case, B. L.; Dice, T.
A.; Fenton, R. L.; Hayes, M. J.; Jones, D. E.; Neumann, W.
L.; Wood, R. S.; Lachance, R. M.; Girard, T. J.; Nicholson,
N. S.; Clare, M.; Stegeman, R. A.; Stevens, A. M.; Stallings,
1b
A
O
N
H
N
Cu(OAc)2 (20 mol%)
K2CO3 (1 equiv)
N
Ph
N
Ph
DMF, 80 °C, 2 h
under O2 (1 atm)
Ph
Ph
O
O
B
3b 48%
Scheme 6 A stepwise synthesis of pyrazinone 3b
Synlett 2011, No. 15, 2167–2170 © Thieme Stuttgart · New York

2170
L. Zhang et al.
LETTER
chromatography (hexane–EtOAc = 90:10) to afford 2-
formyl pyrazinone 3b (91.8 mg, 0.316 mmol) in 62% yield.
(11) For the synthesis of a-azido-N-allylamides 1 as well as
characterization of all new compounds, see the Supporting
Information.
(12) For generation of imine from a-azido ketones and esters
under the strong basic conditions, see: (a) Manis, P. A.;
Rathke, M. W. J. Org. Chem. 1980, 45, 4952. (b) Edwards,
O. E.; Purushothaman, K. K. Can. J. Chem. 1964, 42, 712.
(13) One of the possibilities of the reaction course for the
formation of deallylated amide 7 is outlined below. It might
commence with radical 1,5-H shift from putative iminyl
copper species to give allylic radical, further oxidation of
which would afford allylic cation species. Addition of water
to the carbocation followed by C–N bond cleavage from
resulting hemiaminal could deliver deallylated amide 7
(Scheme 8). We recently reported similar 1,5-H shift from
iminyl copper species, see: Zhane, L.; Ang, G. Y.; Chiba, S.
Org. Lett. 2011, 13, 1622.
W. C.; Kurumbail, R. G.; South, M. S. J. Med. Chem. 2003,
46, 4050. (d) Yang, C. C.; Jick, S. S.; Jick, H. Arch. Intern.
Med. 2003, 163, 1926. (e) Mack, A.; Salazar, J. O.
Formulary 2003, 38, 582.
(2) (a) Blake, K. W.; Porter, A. E. A.; Sammes, P. G. J. Chem.
Soc., Perkin Trans. 1 1972, 2494. (b) Birkofer, L. Chem.
Ber. 1947, 80, 83.
(3) (a) Bradbury, R. H.; Griffiths, D.; Rivett, J. E. Heterocycles
1990, 31, 1647. (b) Rothkopf, H. W.; Wöhrle, D.; Müller,
R.; Kossmehl, G. Chem. Ber. 1975, 108, 875. (c) Flament,
I.; Stoll, M. Helv. Chim. Acta 1967, 50, 1754.
(d) Muehlmann, F. L.; Day, A. R. J. Am. Chem. Soc. 1956,
78, 242. (e) Weijlard, J.; Tishler, M.; Erikson, A. E. J. Am.
Chem. Soc. 1945, 67, 802.
(4) For recent reports on the synthesis of substituted pyrazines
and their derivatives, see: (a) Modha, S. G.; Trivedi, J. C.;
Mehta, V. P.; Ermolat’e, D. S.; Van der Eycken, E. V.
J. Org. Chem. 2011, 76, 846. (b) Guerra, P. V.; Yaylayan,
V. A. J. Agric. Food Chem. 2010, 58, 12523.
(c) Krishnakumar, B.; Swaminathan, M. J. Organomet.
Chem. 2010, 695, 2572. (d) Adama, I.; Orainb, D.; Meier, P.
Synlett 2004, 2031. (e) Sato, N.; Matsumoto, K.; Takishima,
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3167. (f) Buchi, G.; Galindo, J. J. Org. Chem. 1991, 56,
2605.
[Cu]
H
•
NH
NH
N
NH
[Cu]
NBn
NBn
NBn
NBn
NBn
Ph
Ph
Ph
Ph
(5) Chiba, S.; Zhang, L.; Lee, J.-Y. J. Am. Chem. Soc. 2010,
132, 7266.
(6) Wang, H.; Wang, Y.; Liang, D.; Liu, L.; Zhang, J.; Zhu, Q.
Angew. Chem. Int. Ed. 2011, 50, in press; DOI: 10.1002/
anie.201100362.
(7) Other bases, such as K3PO4 and NaOAc exhibited similar
reactivity, while MgO was not a viable catalyst for this
transformation.
O
O
O
O
HO
O
NH
H
N
H2O
Bn
Ph
Ph
O
O
7
(8) The structures of 3b and 3i were secured by X-ray
crystallographic analysis (see Supporting Information). The
supplementary crystallographic data of these molecules are
contained in CCDC 824717 and 824717, respectively. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
conts/retrieving.html.
(9) Dihydropyrazinone 4 might be formed from the proposed
primary alkyl radical D (in Scheme 7) by hydrogen
abstraction from the solvent DMF. For the process of
hydrogen abstraction from the solvent DMF: (a) Minisci,
F.; Citterio, A.; Vismara, E.; Giordano, C. Tetrahedron
1985, 41, 4157. (b) Palla, G. Tetrahedron 1981, 37, 2917.
(10) General Procedure for the Cu(II)-Catalyzed Synthesis of
Pyrazinones from a-Azido-N-allylamides
Scheme 8
(14) For recent reports on the azido-alkene 1,3-dipolar
cycloaddition reaction, see: (a) Hui, B. W.-Q.; Chiba, S.
Org. Lett. 2009, 11, 729. (b) Nair, V.; Suja, T. D.
Tetrahedron 2007, 63, 12247. (c) Feldman, K. S.; Iyer, M.
R.; López, C. S.; Faza, O. N. J. Org. Chem. 2008, 73, 5090.
(d) Zhou, Y.; Murphy, P. V. Org. Lett. 2008, 10, 3777.
(e) Kim, S.; Lee, Y. M.; Lee, J.; Lee, T.; Fu, Y.; Song, Y.;
Cho, J.; Kim, D. J. Org. Chem. 2007, 72, 4886. (f) Huang,
X.; Shen, R.; Zhang, T. J. Org. Chem. 2007, 72, 1534.
(g) Feldman, K. S.; Iyer, M. R.; Hester, D. K. II. Org. Lett.
2006, 8, 3116. (h) Feldman, K. S.; Iyer, M. R. J. Am. Chem.
Soc. 2005, 127, 4590; and references cited therein.
To a solution of N-allyl-2-azido-N-benzyl-2-phenyl-
acetamide (1b, 156.1 mg, 0.510 mmol) in DMF (5.1 mL)
were added Cu(OAc)2 (18.9 mg, 0.104 mmol) and K2CO3
(70.4 mg, 0.509 mmol), and the mixture was stirred at 80 °C
for 2 h under an O2 atmosphere (1 atm). After cooling to r.t.,
the solid was filtered through a Celite pad. To the mixture,
1 M aq HCl was added, and the organic materials were
extracted twice with Et2O. The combined extracts were then
washed with H2O, brine, and dried over MgSO4. Filtration
and removal of the solvent under reduced pressure afforded
a crude mixture, which was subjected to flash column
(15) For reports on the mechanism of the elimination of
dinitrogen from triazoline intermediates with heterolytic
cleavage of the N–N bond, see: (a) Shea, K. J.; Kim, J.-S.
J. Am. Chem. Soc. 1992, 114, 4846. (b) Wladkowski, B. D.;
Smith, R. H. Jr.; Michejda, C. J. J. Am. Chem. Soc. 1991,
113, 7893; and references cited therein.
(16) A radical pathway via homolytic cleavage of the N–N bond
of triazoline intermediates is proposed, see: (a) Broeckx,
W.; Overbergh, N.; Samyn, C.; Smets, G.; L’abbé, G.
Tetrahedron 1971, 27, 3527. (b) Feldman, K. S.; Iyer, M.
R.; Hester, D. K. II. Org. Lett. 2006, 8, 3116. (c) Feldman,
K. S.; Iyer, M. R. J. Am. Chem. Soc. 2005, 127, 4590.
Synlett 2011, No. 15, 2167–2170 © Thieme Stuttgart · New York