Novel ring transformation of mesoionic oxazoles into 2(1H)-pyrazinones by the reaction with TosMIC

Article abstract of DOI:10.1016/j.tetlet.2013.06.018

Treatment of mesoionic 1,3-oxazolium-5-olates with TosMIC in the presence of a base causes a novel ring transformation affording 2(1H)-pyrazinones in moderate yields. The origin of C-2 carbonyl oxygen in the product was elucidated to be molecular oxygen, based on ¹⁸O-labeling experiments.

Full text of DOI:10.1016/j.tetlet.2013.06.018

Tetrahedron Letters 54 (2013) 4418–4421
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel ring transformation of mesoionic oxazoles
into 2(1H)-pyrazinones by the reaction with TosMIC q
Ryosuke Saijo a, Ken-ichi Kurihara a, Kazuki Akira a, Hidemitsu Uno b, Masami Kawase a,
⇑
a Faculty of Pharmaceutical Sciences, Matsuyama University, Matsuyama, Ehime 790-8578, Japan
b Department of Chemistry and Biology, Graduate School of Science and Engineering, Ehime University, Matsuyama 790-8577, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of mesoionic 1,3-oxazolium-5-olates with TosMIC in the presence of a base causes a novel ring
transformation affording 2(1H)-pyrazinones in moderate yields. The origin of C-2 carbonyl oxygen in the
product was elucidated to be molecular oxygen, based on 18O-labeling experiments.
Received 22 March 2013
Revised 27 May 2013
Accepted 6 June 2013
Available online 13 June 2013
R1
COCF3
R1
R2
R2
Ts
N
O
O ,
2
DBU
TsCH2N C,
- CO2
Keywords:
2-Pyrazinone
TosMIC
N
O
O
N
Mesoion
Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
Ring transformation of heterocyclic compounds is an important
area of chemistry from both theoretical and practical viewpoint.1,2
Such processes may provide interesting synthetic routes to deriva-
tives that are not easily accessible by other methods.
Mesoionic compounds have become useful and versatile syn-
thons en route to varied and functionalized heterocyclic systems.3
Their reactivity stems from their masked 1,3-dipolar character,
thus interacting with a wide range of dipolarophiles in cycloaddi-
tion reactions. One useful class of these mesoionic compounds is
1,3-oxazolium-5-olates, commonly known as münchnones.4 De-
spite significant interest in these mesoionic heterocycles, their
transformation to another ring system via a nucleophilic reaction
has received relatively little attention.
In principle, the addition of nucleophiles to 1 can a priori be
expected to occur at three different positions (C-2, C-5, or COCF3).
Previously, we reported that reactions of mesoionic with
1
N-nucleophiles such as amidines, ammonia, phenylhydrazine, and
aminomalonate proceeded, depending on the nature of the nucleo-
philes and the reaction conditions.5 Generally, these reactions occur
via the initial attack of the N-nucleophiles on the C-2 position of the
ring. On the other hand, it is shown that O-nucleophiles such as
H2O, EtOH, and AcOH attack at C-5 of 1.6 Recently, reactions of
phosphorus- or sulfur-ylides are found to attack the C-2 position
of 1, affording pyrrole derivatives.7p-Toluenesulfonylmethyl isocy-
anide (TosMIC) is a versatile, widely applicable reagent bearing an
active methylene group and readily forms a stabilized, nucleophilic
carbanion, which will react with a variety of electrophiles, such as
aldehydes, ketones, and imines.8 This class of reagent has most
commonly been used in heterocyclic ring construction, in particu-
lar, of oxazole, pyrrole, and imidazole moieties.
Mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates (1) are eas-
ily prepared from N-acyl-N-alkylglycines (2) in a one step through
the cyclodehydration by trifluoroacetic anhydride followed by tri-
fluoroacetylation at C-4 position of an intermediary mesoionic 1,3-
oxazolium-5-olates (Eq. (1)).5
We report herein a novel type of ring transformation of meso-
ionic oxazoles 1 into 2(1H)-pyrazinones 3 via an initial attack of
TosMIC on the C-2 position of the ring.
COCF3
O
R1
3
4
+
(CF3CO)2O
N
Table 1 shows the results when 4-trifluoroacetyl-1,3-oxazoli-
um-5-olate (1a) was allowed to react with TosMIC in the presence
of base. Various sets of reaction conditions were investigated to
determine the optimum conditions (Table 1). We found that the or-
der in which the reagents are mixed has a profound effect on the
yields. First, the base was added to a solution of 1a and TosMIC
in DMF and the yields were low (Table 1, entries 1–6). However,
the better yields were generally obtained by adding the mesoionic
compound last to the reaction mixture (Table 1, entries 7–10).
-
R2
N
R1
CO2H
O
ð1Þ
5
O
1
R2
2
2
1
q
This is an open-access article distributed under the terms of the Creative
Commons Attribution License, which permits unrestricted use, distribution, and
reproduction in any medium, provided the original author and source are credited.
⇑
Corresponding author. Tel.: +81 89 9267098; fax: +81 89 9267162.
E-mail address: kawase@cc.matsuyama-u.ac.jp (M. Kawase).
0040-4039/$ - see front matter Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.018

R. Saijo et al. / Tetrahedron Letters 54 (2013) 4418–4421
4419
Table 1
Optimization of reaction conditionsa,b
Me
COCF3
Me
Ph
Ph
Ts
N
O
TosMIC, Base
Solvent
N
O
O
N
1a
3a
Entry
TosMIC (n equiv)
Base (x equiv)
Solvent
Condition
Yield (%)
1
2
3
4
5
6
1.2
1.2
2.4
2.4
1.2
1.2
1.5
1.5
1.5
1.5
K2CO3 (2)
tBuOK (2)
tBuOK (4)
tBuOK (4)
NaH (2)
DBU (2)
DBU (2)
MTBD (2)
tBuOK (2)
P4-tBu (2)
Dry MeOH
THF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
rt, 19 h
rt, 17 h
0 °C, 3 h
ꢀ20 °C, 6 h
rt, 3 h
7
33
34
39
9
28
61
58
40
67
rt, 1 h
7c
8c
9c
10c
0 °C, 2 h
0 °C, 2 h
0 °C to rt, 5 h
0 °C to rt, 6 h
DMF
a
Reactions were performed with 1a (1 mmol), TosMIC (n equiv), and base (x equiv) in solvent (5 mL) under an atmosphere of Ar without any precaution to exclude air in
the solvent.
b
Isolated yields.
1a was added after stirring at 0 °C for 1 h.
c
on C2 and N3 of the mesoionic ring on the reaction were investi-
gated. The reaction is efficient in both 3-alkyl- and 3-aryl-substi-
tuted mesoionic compounds (entries 1–4 and 7–9). However,
2-methyl compounds 1e gave slightly lower yields compared to
2-aryl-substituted compounds 1a–d and f–h. In this reaction, sev-
eral polar materials were detected by TLC, but none of them were
characterized. In the case of the reaction of 1e, the yield of 3e im-
proved from 19% to 42% when the reaction was carried out at
ꢀ40 °C (entries 5 and 6). To our disappointment, 2-tert-butyl-
substituted mesoionic compounds 1i and j gave the expected
2-pyrazinones in low yield or not at all (entries 10 and 11), presum-
ably due to the steric hindrance of the tert-butyl group at 2-position
of 1i and j.
Table 2
Reaction of 1a to form 3aa,b
Entry Condition
Yield (%)
of 3a
1
Under Ar atmosphere (the solvent DMF was degassed by 44
sonication under Ar)
2
3
4
5
Under Ar atmospherec
61
59
59
72
Under air (using CaCl2 drying tube)
Under O2 atmosphered
Under O2 atmosphere (with bubbling by O2 in the
solvent through the reaction)
a
A solution of TosMIC (1.5 mmol) and DBU (2 mmol) in DMF (5 mL) was stirred
at 0 °C for 1 h, then 1a (1 mmol) was added to the solution and the reaction mixture
was stirred at 0 °C for 3 h.
b
The structure of 3a was unequivocally confirmed by X-ray dif-
fraction study of single crystals (Fig. 1).11 The 1H NMR spectrum
of 3a exhibited the signal of 3-H at d 8.13 and other products
(3b–i) showed the characteristic 3-H at the same position.
An insight into the pathway of the reaction was sought by con-
ducting the reaction under an atmosphere of 18O2. The reaction of
Isolated yields.
c
The reaction was performed without any precaution to exclude air in the sol-
vent DMF.
d
The reaction was not performed with bubbling by O2.
1a with TosMIC under 18O2 atmosphere gave a pyrazinone 3a⁄ (18
O
Among the base examined [1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU), phosphazene base (P4 base),9 7-methyl-1,5,7-triazabicy-
clo[4.4.0]dec-5-ene (MTBD), t-BuOK, NaH and K2CO3], DBU, and
P4 base usually gave best results. DBU was elected as the choice
of base for all further reactions due to the cheapness and easy
handling.
content: 67%) in 73% yield (Eq (2)). Thus, the carbonyl group of
amide in compound 3a⁄ contained more than 67% of the 18O
label.12
Me
COCF3
Me
Ph
Ph
Ts
N
18O
18O2, TosMIC, DBU
Next, we investigated the influence of O2 on the outcome of the
reaction (Table 2). The reaction was performed on five kinds of
reaction conditions; (1) under Ar atmosphere in the solvent DMF
degassed by sonication under Ar, (2) under Ar atmosphere without
any precaution to exclude air in the solvent DMF, (3) under air
using CaCl2 drying tube for the protection from moisture, (4) under
O2 atmosphere without bubbling by O2, and (5) under O2 atmo-
sphere with bubbling by O2 throughout the reaction. The O2 pres-
ent in the solvent was enough for completion of the reaction
(entries 2–4). However, the highest yield of product 3a was ob-
tained when the reaction was done under an atmosphere of O2
with bubbling by O2 (entry 5).
N
(2)
O
ð2Þ
DMF
O
N
y. 73%
1a
3a*
A tentative mechanism which accounts for the formation of 3 is
depicted in Scheme 1. Thus, initial nucleophilic attack by the Tos-
MIC anion on C-2 of 1 gave rise to an adduct 4 which is converted
into the intermediate 5 via proton transfer, which may be in equi-
librium with 6. The driving force for the decarboxylation of 6 is
probably due to the electron-donating TosMIC anion and the elec-
tron-withdrawing trifluoromethyl ketone. Subsequent ring closure
by intramolecular nucleophilic attack of the anion 7 to the electro-
philic isocyano carbon may afford 8 which undergoes proton trans-
fer to give 9. Intermediate 9 would be the electron donor to O2.
Thus, formation of free radical-superoxide complex 10, followed
With the optimized conditions in hand,10 the scope of the reac-
tion substrates was investigated. The results are summarized in
Table 3, when the reaction was performed under O2 atmosphere
with bubbling by O2 throughout the reaction. Thus, the substituents

4420
R. Saijo et al. / Tetrahedron Letters 54 (2013) 4418–4421
Table 3
2(1H)-Pyrazinones from various mesoionic oxazoles and TosMICa,b
R1
N
COCF3
R1
R2
Ts
O
TosMIC (1.5eq), DBU (2eq)
DMF
N
O
O
N
R2
3a-i
1a-i
Entry
1
R1
R2
Condition
Product
Yield (%)
1
2
3
4
5
6
7
8
a
b
c
d
e
e
f
g
h
i
Me
Me
Me
Ph
Ph
Ph
Ph
4-BrC6H4
4-MeOC6H4
Ph
Me
Me
Ph
Ph
0 °C, 3 h
0 °C, 5 h
0 °C, 1 h
0 °C, 4 h to rt, 19 h
0 °C, 4 h to rt, 18 h
ꢀ40 °C, 12 h
0 °C, 4.5 h
0 °C, 5 h
0 °C, 5 h
0 °C, 3 h
0 °C, 4.5 h
3a
3b
3c
3d
3e
3e
3f
3 g
3 h
3i
72
70
78
65
19
42
55
53
58
11
0
PhCH2
4-MeOC6H4CH2
PhCH2
Me
Ph
9
10
11
4-MeOC6H4
tBu
tBu
j
3j
a
A solution of TosMIC (1.5 mmol) and DBU (2 mmol) in DMF (5 mL) was stirred at 0 °C for 1 h, then 1 (1 mmol) was added to the solution under an atmosphere of O2 with
bubbling of O2 throughout the reaction.
b
Isolated yields.
by recombination of superoxide with the incipient carbon free
radical, might produce hydroperoxide anion 11. This anion 11
leads to the intermediate 12 which extrudes trifluoroacetate anion
to provide the 2-pyrazinone 3.
In conclusion, starting from the mesoionic 1 and TosMIC, a new
and efficient synthesis of 1,6-disubstituted 5-tosyl-2(1H)-pyrazi-
nones has been described. The 2(1H)-pyrazinone is an important
privileged scaffold in medicinal chemistry, as well as in several
alkaloids with diverse biological activity, including antitumor and
antiviral properties.14 Therefore, several methods for the synthesis
of 2(1H)-pyrazinones have been described in the literature: (a)
condensation of
tion of
a-aminoamides with a
-diketones,15 (b) condensa-
a
-aminonitrile with oxalyl halides,14c,16 and (c) Ugi four-
component reactions.17 Whereas these methods have proven very
useful for the synthesis of 2(1H)-pyrazinones, they generally in-
volve multistep synthetic operations and/or a hazardous cyanide
Figure 1. X-ray structure drawing of 3a.
O
O
O
O
CF3
NC
R1
O
H
R1
R1
R1
N
CF3
-
R1
+
N
-
CF3
OH
N
-
CF3
TosMIC
N
CF3
-
-
N
R2
O
R2
O
- CO2
O
R2
R2
O
O
O
R2
O
CH
Tos
C
C
Tos
Tos
NC
NC
NC
Tos
7
1
4
5
6
R1
N
R1
N
.
-
R1
N
R1
N
R1
-
O2
O
O
O
H
R2
R2
R2
R2
R2
N
.
O
-
O2
COCF3
H
COCF3
H
COCF3
CF3
-
CF3
Tos
N
Tos
N
O
Tos
N
Tos
N
Tos
N
-
O
8
9
10
11
12
R1
N
R2
O
-
-
CF3CO2
Tos
N
3
Scheme 1. Proposed mechanistic pathway.

R. Saijo et al. / Tetrahedron Letters 54 (2013) 4418–4421
4421
7. (a) Saijo, R.; Hagimoto, Y.; Kawase, M. Org. Lett. 2010, 12, 4776; (b) Saijo, R.;
Kawase, M. Tetrahedron Lett. 2012, 53, 2782.
8. Van Leusen, D.; Van Leusen, A. M. Org. React. 2001, 57, 417.
source that limit the scope of these reactions. Indeed, it is still
desirable to develop an efficient method for the synthesis of
2(1H)-pyrazinones. The present reaction could proceed via an ini-
tial attack of TosMIC anions on the C-2 position of the ring, opening
of the oxazole ring, subsequent cyclization, and autoxidation,
which includes oxygenation, cyclization of the resulting peroxy an-
ion, and oxidative cleavage. This unique ring transformation reac-
tion of mesoionic oxazoles with TosMIC was not anticipated but
the reaction is general as evidenced by the examples indicated in
Table 3. The method appears to be useful and convenient in terms
of the ready accessibility of the starting materials, operational sim-
plicity, and mild condition.
9. P4 base is 1-tert-butyl-4,4,4-tris(dimethylamino)-2,2-bis[tris(dimethylamino)-
phosphoranylidenamido]- 2k5,4k5-catenadi(phosphazene).
10. General procedure for the reactions of 1 with TosMIC: To a stirred solution of
TosMIC (293 mg, 1.50 mmol) in DMF (5 mL) was added DBU (304 mg,
2.00 mmol) at 0 °C, and the mixture was stirred for 1 h under an atmosphere
of O2. To the mixture was added 4-trifluoroacetyl-1,3-oxazolium-5-olate 1
(1.00 mmol) with bubbling of O2 throughout the reaction and the whole was
stirred at 0 °C for an additional several hours. After workup with water, the
mixture was extracted with AcOEt (ꢁ3). The combined organic layers were
washed with brine, dried over anhyd Na2SO4, and evaporated. The residue was
purified by column chromatography (silica gel, hexane/AcOEt = 4:1 to 1:1) to
give product 3.
1-Methyl-6-phenyl-5-tosylpyrazin-2(1H)-one (3a): Mp 147ꢀ149 °C (CHCl3–
hexane); IR (KBr) mmax 3057, 1674, 1662, 1487, 1322, 575 cmꢀ1 1H NMR
;
(500 MHz, CDCl3) d: 2.41 (s, 3H, ArCH3), 3.13 (s, 3H, NCH3), 7.21–7.27 (m, 4H,
ArH), 7.51–7.59 (m, 5H, ArH), 8.13 (s, 1H, H-3); 13C NMR (126 MHz, CDCl3) d:
21.5, 33.3, 128.3, 128.6, 128.9, 129.0, 129.4, 130.6, 134.0, 137.3, 144.3, 145.0,
145.8, 155.5. MS m/z: 410 (M+, 5.1), 118 (100). Anal. Calcd for C18H16N2O3S: C,
63.51; H, 4.74; N, 8.23. Found: C, 63.32; H, 5.03; N, 8.09.
Acknowledgement
The study was supported by
Research (C)(Kawase No. 20590114) from the Japan Society for
the Promotion of Science (JSPS).
a Grant-a-Aid for Scientific
11. The structure of 3a was confirmed by X-ray analysis (CCDC no. 832512). The
tosyl moiety is disordered and the ratio is calculated to be 0.674:0.326.
12. The 13C NMR spectrum indicated that 18O had been incorporated on the
carbonyl carbon of amide, based on the observation of 18O-isotope effect13 on
the chemical shift of the carbonyl carbon. MS and IR data also supported this
structure.
References and notes
13. Vederas, J. C. Chem. Soc. 1980, 102, 374.
1. Hajos, G.; Riedl, Z.; Kollenz, G. Eur. J. Org. Chem. 2001, 3405.
2. Van der Plas, H. C. In Ring Transformation of Heterocycles; Academic Press: New
York, 1973; Vols. 1 and 2,
3. Gribble, G. W. Mesoionic Ring Systems In Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Toward Heterocycles and Natural Products; Padwa, A.,
Pearson, W. H., Eds.; John Wiley & Sons: Hoboken, 2002; Vol. 59, p 681. Chapter
10.
4. Gribble, G. W. Mesoionic Oxazoles In The Chemistry of Heterocyclic Compounds
Oxazoles: Synthesis, Reactions, and Spectroscopy Part A; Taylor, E. C., Wipf, P.,
Eds.; John Wiley & Sons: Hoboken, 2003; Vol. 60, p 473.
5. (a) Kawase, M.; Koiwai, H. Chem. Pharm. Bull. 2008, 56, 433; (b) Kawase, M.;
Saito, S.; Kurihara, T. Chem. Pharm. Bull. 2001, 49, 461; (c) Kawase, M.; Saito, S.
Chem. Pharm. Bull. 2000, 48, 410.
14. (a) Mehta, V. P.; Sharma, A. K.; Modha, S. G.; Sharma, S.; Meganathan, T.;
Parmar, V. S.; Van der Eycken, E. J. Org. Chem. 2011, 76, 2920; (b) Ortqvist, P.;
Gising, J.; Ehrenberg, A. E.; Vema, A.; Borg, A.; Karlen, A.; Larhed, M.; Danielson,
U. H.; Sandstrom, A. Bioorg. Med. Chem. 2010, 18, 6512; (c) Pawar, V. G.; De
Borggraeve, U. H. Synthesis 2006, 17, 2799.
15. (a) Tota, Y. A.; Elderfield, R. C. J. Org. Chem. 1942, 7, 313; (b) Karmas, G.; Spoerri,
P. E. J. Am. Chem. Soc. 1952, 74, 1580.
16. (a) Vekemans, J.; Pollers-Wieers, C.; Hoornaert, G. J. J. Heterocycl. Chem. 1983,
20, 919; (b) Gising, J.; Ortqvist, P.; Sandstrom, A.; Larhed, M. Org. Biomol. Chem.
2009, 7, 2809.
17. Azuaje, J.; El Maatougui, A.; Perez-Rubio, J. M.; Coelho, A.; Fernandez, F.; Sotelo,
E. J. Org. Chem. 2013, 78, 4402.
6. Kawase, M.; Koiwai, H.; Kurihara, T. Tetrahedron Lett. 1998, 39, 6189.