Full text of DOI:10.1016/j.tetlet.2018.02.084

Accepted Manuscript
Synthesis of trisubstituted 1,3-oxazin-6-ones via base-catalyzed ring-opening
annulation of cyclopropenones with N-(pivaloyloxy)amides
Takanori Matsuda, Kentaro Yamanaka, Yuki Tabata, Takahiro Shiomi
PII:
S0040-4039(18)30297-1
https://doi.org/10.1016/j.tetlet.2018.02.084
TETL 49769
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
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9 January 2018
26 February 2018
28 February 2018
Please cite this article as: Matsuda, T., Yamanaka, K., Tabata, Y., Shiomi, T., Synthesis of trisubstituted 1,3-
oxazin-6-ones via base-catalyzed ring-opening annulation of cyclopropenones with N-(pivaloyloxy)amides,
Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.02.084
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Synthesis of trisubstituted 1,3-oxazin-6-ones
via base-catalyzed ring-opening annulation
of cyclopropenones with N-
Leave this area blank for abstract info.
(pivaloyloxy)amides
Takanori Matsuda *, Kentaro Yamanaka, Yuki Tabata, Takahiro Shiomi

1
Tetrahedron Letters
journal homepage: www.els evier.com
Synthesis of trisubstituted 1,3-oxazin-6-ones via base-catalyzed ring-opening
annulation of cyclopropenones with N-(pivaloyloxy)amides
Takanori Matsuda *, Kentaro Yamanaka, Yuki Tabata, Takahiro Shiomi
Department of Applied Chemistry, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
The base-catalyzed [3+3]-type annulation between cyclopropenones and N-(pivaloyloxy)amides
is reported. The formal insertion of a 1,3-N,O-dipole into a cyclopropenone C–C bond yields a
six-membered azalactone structure. In the presence of catalytic K2CO3 at 60 °C in THF, the
disubstituted cyclopropenone couples with benzamides, acrylamides, and a phenylacetamide to
produce 2,4,5-trisubstituted 1,3-oxazin-6-ones in 23–99% yield.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
cyclopropenone;
ring opening;
annulation;
amide;
oxazinone
Cyclopropenones have served as versatile building blocks in
the construction of cyclic structures using ring-opening
annulation reactions.1,2 Several such annulation reactions have
been developed for the synthesis of cyclic ketones, lactones,
lactams, and other cyclic compounds. 1,3-Oxazin-6-ones are six-
membered azalactones (aza-α-pyrone) that are often used as
precursors for the synthesis of pyrimidinones3 and other
heterocyclic compounds.4 However, until now, only limited
studies into their synthesis has been carried out.5,6 Previously
reported annulation reactions of cyclopropenones affording 1,3-
oxazin-6-ones used N-(acylimino)pyridinium ylide derivatives,7
functioning as a 1,3-N,O-dipole, as reaction partners (Scheme 1,
a–c).6 Recently, significant attention has been devoted to the use
of N-(acyloxy)benzamides in transition-metal-catalyzed C–H
bond functionalization.8 During our continuing search for new
coupling reactions of cyclopropenones2 and directed C–H bond
activation reactions,9 we found that N-(pivaloyloxy)amides can
act as a 1,3-N,O-dipole equivalent in the annulation reaction with
cyclopropenones to produce 1,3-oxazin-6-ones (Scheme 1, d).
This reaction occurs at 60 °C in THF in the presence of catalytic
K2CO3, is complete within 2 h, and gives trisubstituted 1,3-
oxazin-6-ones in 23–99% yield.
Scheme 1. Formal [3+3]-type annulation of cyclopropenones
affording 1,3-oxazin-6-ones
A
mixture of N-(pivaloyloxy)benzamide (1a)10 and
diphenylcyclopropenone (2a, 1.3 equiv.) was heated at 60 °C in
THF in the presence of 0.5 equivalents of K2CO3 (Scheme 2).
The benzamide 1a reacted completely within 1 h via ring-
opening annulation with 2a, and 2,4,5-triphenyl-1,3-oxazin-6-one
(3aa) was isolated in 95% yield.11 The results showed that the
benzamide 1a, when combined with K2CO3, acts as a surrogate
for N-(benzoylimino)pyridinium ylides, to achieve the same
annulation with greater efficiency than the previous procedures
employing ylides. The reaction using N-hydroxy, N-methoxy,
and N-(tert-butoxycarbonyl)oxy derivatives gave 3aa in 21–49%
yield.12 Similar results were obtained using 0.1 equivalents of
K2CO3;13 however, almost no reaction was observed in the
absence of the base.

2
Tetrahedron
14
1o (2-thienyl)
3oa (99)
3pa (61)
3qa (98)
3ra (32)
3sa (68)
3ta (80)
3ua (68)
15
16
17
18
19
1p (ferrocenyl)
1q (cinnamyl)
1r (1-phenylvinyl)
1s ((E)-1,2-diphenylvinyl)
1t (cyclohexen-1-yl)
1u (benzyl)
Scheme 2. Reaction of N-(pivaloyloxy)benzamide (1a) and
diphenylcyclopropenone (2a)
20
a
Reagents and conditions: amide 1, cyclopropenone 2a (1.3
equiv.), K2CO3 (0.1 equiv.), THF (0.13 M), 60 °C, 0.5–2 h.
Based on the previously proposed mechanism for the
annulation reaction of 2a using ylides,6 a possible mechanism for
the presented reaction was suggested (Scheme 3). The amide
nitrogen in 1a undergoes conjugate addition to 2a in the presence
of a base. The resulting enolate A releases a pivalate anion during
ring opening, generating (N-acyliminomethyl)ketene B. Finally, a
6π electrocyclization yields the oxazinone 3aa.14
b
Isolated yield.
Next,
several
symmetrical
and
unsymmetrical
cyclopropenones15 were reacted with benzamide 1a and
cinnamamide 1q. While 4-methylphenyl (2b) and 2-thienyl
derivatives (2c) gave 1,3-oxazin-6-ones 3ab, 3ac, and 3qc in
good yields (Entries 1–3), the more electron-rich cyclopropenone
2d afforded the products 3ad and 3qd in unsatisfactory yields
(Entries 4 and 5). Furthermore, the reaction of 1a with 2d failed
to proceed when using K2CO3, but did produce 3ad in 46% yield
using CsOPiv. The reaction of unsymmetrical 2-methyl-3-
phenylcyclopropenone (2e) with 1a and 1q gave the single
isomers 3ae and 3qe, respectively, in excellent yields (Entries 6
and 7).5h,m,16 Dialkylcyclopropenone 2f was found to be an
unsuitable substrate for the reaction: 2 equivalents of 2f were
required to obtain 3af in only 23% yield (Entry 8).11
Scheme 3. Proposed mechanism
Next, the scope and generality of the annulation reaction were
explored (Table 1). The cyclopropenone 2a successfully coupled
with benzamides featuring a range of functional groups (1b–u).
This reaction features good functional group tolerance, with no
obvious electronic or steric effects. Moreover, 1,3-oxazin-6-ones
bearing naphthyl (1l and 1m) and heteroaryl (1n and 1o) groups
at the 2 position were obtained in excellent yields (Entries 11–
14). The reaction of ferrocenyl amide gave 3na in 61% yield
(Entry 15). In addition to aromatic amides, acrylamides (1q–t)
and phenylacetamide (1u) also participated in the annulation to
give their corresponding trisubstituted 1,3-oxazin-6-ones (Entries
16–20).11
Table 2. Substrate scope of cyclopropenonesa
Entry
1
2 (R2, R3)
Time (h) 3 (% yield)b
1
2
3
4c
5
6
7
1a 2b (4-MeC6H4, 4-MeC6H4)
1a 2c (2-thienyl, 2-thienyl)
1q 2c
0.5
0.5
1
3ab (65)
3ac (60)
3qc (94)
3ad (46)
3qd (46)
3ae (92)
3qe (95)
3af (23)
Table 1. Annulation reaction of cyclopropenone 2a with
various amides 1b–ua
1a 2d (4-MeOC6H4, 4-MeOC6H4)
1q 2d
1
1
1a 2e (Me, Ph)
0.5
1
1q 2e
1a 2f (Pr, Pr)d
2
Entry
1
1 (R)
3 (% yield)b
3ba (95)
3ca (97)
3da (99)
3ea (95)
3fa (93)
3ga (97)
3ha (93)
3ia (93)
3ja (98)
3ka (97)
3la (95)
3ma (94)
3na (99)
8
a
Reagents and conditions: amide 1, cyclopropenone 2 (1.3
equiv.), K2CO3 (0.1 equiv.), THF (0.13 M), 60 °C.
1b (4-MeC6H4)
1c (4-MeOC6H4)
1d (4-O2NC6H4)
1e (2-MeC6H4)
1f (3,4-Me2C6H3)
1g (3,4-(MeO)2C6H3)
1h (4-FC6H4)
1i (4-ClC6H4)
1j (4-BrC6H4)
1k (4-IC6H4)
2
b
Isolated yield.
3
c
CsOPiv (0.5 equiv.) was used instead of K2CO3.
4
d
5
2f (2 equiv.) was used.
6
In summary, N-(pivaloyloxy)amides were found to be superior
alternatives to N-(acylimino)pyridinium ylides in the ring-
opening annulation of cyclopropenones. In the presence of
K2CO3 (0.1 equiv.) at 60 °C in THF, disubstituted
cyclopropenones coupled with various amides, including
benzamide and acrylamide derivatives, to afford trisubstituted
1,3-oxazin-6-ones in good yields except for electron-rich
cyclopropenones.
7
8
9
10
11
12
13
1l (1-naphthyl)
1m (2-naphthyl)
1n (2-furyl)
Acknowledgments

3
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11. General Procedure for Ring-Opening Annulation of
Cyclopropenones 2 with N-(Pivaloyloxy)amides 1. Preparation of
3aa. A Schlenk tube was charged with N-(pivaloyloxy)benzamide
(1a, 22.1 mg, 0.100 mmol), diphenylcyclopropenone (2a, 26.8 mg,
0.130 mmol), and K2CO3 (1.4 mg, 0.010 mmol), the tube was
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°C for 1 h. After cooling to room temperature, the reaction
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1,3-oxazin-6-one (3aa, 30.6 mg, 0.094 mmol, 94%) as a pale
yellow solid. m.p. 206–207 °C; 1H NMR (301 MHz, CDCl3) δ
7.23–7.36 (m, 8H), 7.47–7.56 (m, 4H), 7.59–7.64 (m, 1H), 8.33–
8.38 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 118.2, 127.9, 128.2,
128.4, 128.5, 128.8, 129.92, 129.94, 130.1, 130.6, 132.6, 133.2,
136.2, 158.8, 160.4, 161.0; HRMS (ESI) calcd for C22H16NO2 [M
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702. 3pa: m.p. 198–199 °C; 1H NMR (301 MHz, CDCl3) δ 4.26
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7.32 (m, 8H), 7.37–7.43 (m, 2H); 13C NMR (75.6 MHz, CDCl3) δ
69.6, 70.2, 72.3, 72.7, 116.0, 127.8, 127.9, 128.4, 129.8, 130.1,
130.6, 133.0, 136.5, 159.3, 161.1, 167.4; HRMS (ESI) calcd for
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1728, 1597, 1535, 702. 3ac: m.p. 200–201 °C; 1H NMR (301
MHz, CDCl3) δ 7.01 (dd, J = 5.0, 4.1 Hz, 1H), 7.16 (dd, J = 3.6,
1.2 Hz, 1H), 7.20 (dd, J = 5.0, 3.7 Hz, 1H), 7.25 (dd, J = 3.9, 1.2
Hz, 1H), 7.51–7.67 (m, 5H), 8.31–8.38 (m, 2H); 13C NMR (126
MHz, CDCl3) δ 107.2, 128.0, 128.3, 128.6, 128.7, 128.9, 129.6,
129.6, 132.76, 132.84, 133.0, 133.5, 139.9, 154.0, 159.9, 161.0;
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Supplementary data associated with this article can be found,
in the online version, at…

5
• A formal [3+3]-type annulation between
cyclopropenones and N-(acyloxy)amides is
developed.
• N-(acyloxy)amides can act as a 1,3-N,O-dipole
equivalent in the annulation reaction to form a six-
membered azalactone.
• The reaction occurs in the presence of catalytic
amounts of K2CO3 at 60 °C in THF.
• Various 2,4,5-trisubstituted 1,3-oxazin-6-ones
was prepared in up to 99% yield.