A Novel synthesis of 1,3-oxazine-2,4-diones via a simple and efficient reaction of CO2 with 2,3-allenamides

Article abstract of DOI:10.1021/ol9009046

A simple and efficient reaction of CO₂ with 2,3-allenamides under mild conditions (CO₂ balloon without any metal catalyst in the presence of K₂CO₃ or Cs₂CO₃) leads to an efficient synthesis

Full text of DOI:10.1021/ol9009046

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2900-2903
A Novel Synthesis of
1,3-Oxazine-2,4-diones via a Simple and
Efficient Reaction of CO2 with
2,3-Allenamides
Guofei Chen, Chunling Fu, and Shengming Ma*
Laboratory of Molecular Recognition and Synthesis, Department of Chemistry,
Zhejiang UniVersity, Hangzhou 310027, Zhejiang, P. R. China
masm@mail.sioc.ac.cn
Received April 25, 2009
ABSTRACT
A simple and efficient reaction of CO2 with 2,3-allenamides under mild conditions (CO2 balloon without any metal catalyst in the presence of
K2CO3 or Cs2CO3) leads to an efficient synthesis of 1,3-oxazine-2,4-diones. The high reactivity of the allene moiety is crucial for the success
of this transformation since the corresponding reaction of r,ꢀ-unsaturated alkenamides or alkynamides does not occur.
Carbon dioxide is one of the most attractive carbon resources
in organic synthesis as it is highly functionalized, abundant,
economical, and nontoxic; thus, the chemical fixation of CO2
for the synthesis of useful organic chemicals has attracted
more and more attention of scientists from different areas.1
However, due to the thermodynamic and kinetic stability of
CO2, reports on the reaction of CO2 to afford useful organic
products are still limited. Some reactions of nucleophilic
reagents such as alcohols2 and amines3 with CO2 require
high pressure and/or high temperature to afford carbonates
and ureas. Stoichiometric organometallic reagents such as
RMgX,4 RLi,5 RBX2 (with Rh or Cu catalyst),6 and R2Zn
(with Ni catalyst)7 have been used to generate corresponding
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10.1021/ol9009046 CCC: $40.75
Published on Web 06/08/2009
 2009 American Chemical Society

carboxylic acids. Recently it was reported that the reaction
of alkynes, alkenes, or allenes with CO2 under the catalysis
of metallic complexes1,8-11 afforded esters or lactones. Thus,
the efficient chemical fixation of CO2 under mild conditions
is still of high interest. On the other hand, 1,3-oxazine-2,4-
diones are not only an important class of organic intermedi-
ates in organic synthesis12 but also exhibit some biological
activities, for which they are considered as antiulcer agents,
anticonvulsant drugs, herbicides, and plant growth regulators
(Figure 1).13
CO2 to synthesize such products in just one step (Scheme
1).14 However, although there are a few reports on the
Scheme 1
reaction of amides with carbon dioxide, electrochemical
methods15 or stoichiometric strong bases LDA or n-BuLi16
have to be used. Herein, we report a simple and efficient
reaction of CO2 with 2,3-allenamides under mild conditions
(1 atm of CO2 without metal catalyst), which provides a
novel and efficient synthesis of the potentially useful 1,3-
oxazine-2,4-diones.
Initially, we used N-benzyl 4-methyl-2,3-pentadienamide
1a as the substrate to try the reaction. The CO2 gas from a
CO2 balloon was dried by passing through a gas washing
bottle containing concd H2SO4 and released through a relief
needle to the reaction vessel with an outlet. After many
attempts, we were happy to find that 6-isopropyl-1,3-oxazine-
2,4-dione 2a was formed in 73% NMR yield in the presence
of 1.0 equiv of K2CO3 in DMSO at 70 °C for 3 h (entry 3,
Table 1). Some other typical results under different condi-
tions are summarized in Table 1. Among the most commonly
used solvents, DMSO is the best (entries 1-3, Table 1). The
carbonate used is also very important: From Li2CO3 to
Na2CO3 to K2CO3, the reaction rate was accelerated (entries
3, 5, and 6, Table 1). However, the yield of 2a cannot be
improved further by using Cs2CO3 or increasing the dosage
of K2CO3 (entries 4 and 8, Table 1). When K2CO3 was
reduced to 0.5 equiv or the temperature lowered to 60 °C,
the reaction was slower with recovery of 1a within 3 h
(entries 7 and 9, Table 1). Finally, it is fortunate to note that
2a can also be formed in 75% NMR yield by using a CO2
balloon with the relief needle in DMSO to direct CO2 to the
reaction mixture with 1.0 equiv of K2CO3 at 70 °C for 3 h,
which was defined to be our standard reaction conditions
for further study (entry 10, Table 1). Here an outlet is not
necessary, avoiding the continuous release of CO2 to air.
Other bases such as KHCO3, KOH, Et3N, and (i-Pr)2NH were
also tested; however, no better result was afforded (entries
11-14, Table 1). It is noted that when the reaction was
carried out in the presence of K2CO3 under N2 atmosphere,
no product was afforded with 90% recovery of the starting
Figure 1. Some biologically active 1,3-oxazine-2,4-diones.
According to the structure of 1,3-oxazine-2,4-diones, we
envisioned that 2,3-allenamides may be used to react with
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Org. Lett., Vol. 11, No. 13, 2009
2901

Table 1. Optimization of Reaction Conditions for the Reaction
of N-Benzyl-4-methyl-2,3-pentadienamide 1a with Carbon
Dioxidea
Table 2. Reaction of Different 2,3-Allenamides with Carbon
Dioxidea
1
isolated yield
NMR yield
of 2a (%)
recovery of
1a (%)
entry
R1
Me
Me
Me
Et
R2
R3
R4
of 2 (%)
entry
base
solvent
1
2b
3c
4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Et
Bn (1a)
Bn (1a)
Bn (1a)
Bn (1b)
Bn (1c)
Bn (1d)
allyl (1e)
propargyl (1f)
n-Bu (1g)
Ph (1h)
H (1i)
75 (2a)
70 (2a)
64 (2a)
80 (2b)
64 (2c)
49 (2d)
47 (2e)
58 (2f)
48 (2g)
0d
33 (2i)
55 (2i)
59 (2j)
76 (2k)
70 (2l)
92 (2m)
94 (2n)
78 (2o)
1
2
3
4
5
K2CO3
K2CO3
K2CO3
Cs2CO3
Na2CO3
Li2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KHCO3
KOH
DMF
DMA
4
17
73
69
32
13
72
70
55
75
25
16
5
90
77
0
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
5
i-Bu
Ph
0
6
56
83
6
0
34
0
21
20
50
70
90
7
Me
Me
Me
Me
Me
Me
n-C5H11
Me
Me
Me
Me
6
8
7b
8c
9
10
11
12e
13
14
15
16
17f
18f
9d
10e
11e
12e
13e
14e
15e,f
H (1i)
Bn (1j)
Bn (1k)
n-C7H15 Bn (1l)
H
H
Me Me
Me Et
Bn (1m)
Bn (1n)
Bn (1o)
Et3N
(i-Pr)2NH
K2CO3
3
0
-(CH2)5-
Me
a The reaction was carried out using 0.2-0.4 mmol of 1 and 1.0 equiv
of K2CO3 in DMSO with a CO2 balloon at 70 °C for 3 h unless otherwise
stated. b The reaction was conducted in the presence of 10 mol % of K2CO3
with a reaction time of 12 h. c The reaction was conducted using 5.0 mmol
of 1a and a glass pipe instead of the relief needle. d Compound 1h was
recovered in 74% yield. e The reaction was conducted at 60 °C. f Cs2CO3
(1.0 equiv) was used.
a The reaction was carried out using 0.2 mmol of 1a, and the yields
were determined by 1H NMR analysis with mesitylene as the internal
standard. b K2CO3 (0.5 equiv) was used. c K2CO3 (2.0 equiv) was used.
d The reaction was conducted at 60 °C. e The reaction was conducted in a
closed vessel without an outlet. f The reaction was carried out under N2
atmosphere.
material 1a, which indicated that the CO2 unit in the product
2a was from the CO2 gas, not the carbonate base (entry 15,
Table 1). The structure of 2a was further confirmed by the
X-ray diffraction study (Figure 2).17
R1 or R2 can be an alkyl and phenyl group. Allenamides
with bulkier substituents such as isobutyl and phenyl groups
gave the corresponding products 2c and 2d in relatively lower
yields (entries 5 and 6, Table 2). The substituent R4 on the
nitrogen atom of 2,3-allenamides may be allyl, propargyl,
alkyl, or hydrogen (entries 7-9 and 11-12, Table 2).
However, when N-phenyl-substituted 2,3-allenamide 1h was
applied, no reaction occurred with 74% recovery of the
starting material (entry 10, Table 2). The reaction of 1i should
be conducted at 60 °C since the reaction at 70 °C afforded
2i in only 33% yield (entries 11 and 12, Table 2). 4-Mono-
substituted and 2,4-disubstitued 2,3-allenamides can form the
corresponding products in moderate to good yields (entries
13-15, Table 2). 2,4,4-Trisubstituted 2,3-allenamides 1m,
1n, and 1o gave 2m, 2n, and 2o in good to excellent yields.
It is noted that 1.0 equiv of Cs2CO3 was required in the
reaction of 2,3-allenamides 1n and 1o since the starting
materials were not consumed completely under the standard
reaction conditions (entries 17 and 18, Table 2). When we
conducted the reaction with a catalytic amount of K2CO3
(10 mol %), the product 2a could also be formed in 70%
yield with a much longer reaction time (12 h) (entry 2, Table
2). Using a glass pipe instead of the relief needle, the reaction
can also be conducted using 5.0 mmol (1.0 g) of 1a to form
2a in 64% yield (entry 3, Table 2).
Figure 2. ORTEP representation of 2a.
Some typical results of different 2,3-allenamides under the
optimized conditions are listed in Table 2. The substituent
(17) Crystal data for compound 2a: C112H120N8O24, MW ) 1962.16,
monoclinic, space group P2(1)/c, final R indices [I > 2σ(I)], R1 ) 0.0355,
wR2 ) 0.0876; R indices (all data), R1 ) 0.0389, wR2 ) 0.0903; a )
6.2715(2) Å, b ) 11.4983(4) Å, c ) 34.2480(11) Å, R ) 90°, ꢀ )
90.7310(10)°, γ ) 90°, V ) 2469.48(14) Å3, T ) 173(2) K, Z ) 1,
reflections collected/unique 27845/4366 (Rint ) 0.0195), number of observa-
tions [I > 2σ(I)] 4005, parameters: 329. Supplementary crystallographic
data have been deposited at the Cambridge Crystallographic Data Centre,
CCDC 722623.
It should be noted that the reaction of N-benzyl but-2(E)-
enamide 3a and N-benzyl hept-2-ynamide 3b under the same
2902
Org. Lett., Vol. 11, No. 13, 2009

reaction conditions did not occur with 100% and 78%
recovery of the starting materials, respectively, which shows
the importance of the high reactivity of the allene moiety
for this transformation (Scheme 2).
Scheme 3
Scheme 2
DMSO at 70 °C for 3 h using a CO2 balloon in the presence
of K2CO3 or Cs2CO3, which leads to an efficient synthesis
of 1,3-oxazine-2,4-diones. As a result of usefulness of the
products12,13 and the efficient reaction of carbon dioxide,
the reaction may have potentials in organic and medicinal
chemistry. Further studies in this area are being pursued in
our laboratory.
Based on these facts, a rationale for this reaction is
depicted in Scheme 3. The 2,3-allenamide 1 would lose a
proton under the basic conditions to form intermediate M1,
which to some extent may attack the carbon atom in carbon
dioxide to form the intermediate M2. Subsequently, the
oxygen anion in the intermediate M2 would attack the central
carbon atom in the allene moiety to drive the equilibrium
between 1, M1, and M2 to generate the delocalized allylic
intermediate M3,18 which undergoes protonolysis to form
product 2 with the CdC bond in the six-membered ring.
In conclusion, we have developed a very mild protocol
for chemical transformation of carbon dioxide by conducting
its reaction with the readily available 2,3-allenamides19 in
Acknowledgment. Financial support from the Major State
Basic Research and Development Program (2009CB825300)
and Project for Basic Research in Natural Science Issued by
Shanghai Municipal Committee of Science (No. 08dj1400100).
S.M. is a Qiu Shi Adjunct Professor at Zhejiang University.
We thank Mr. Guobi Chai in this group for reproducing the
results presented in entries 2, 6, and 9 in Table 2.
Supporting Information Available: Typical experimental
procedure and analytical data for all products not listed in
the text. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) For a review on the nucleophilic hydrohalogenation of electron-
deficient allenes, see: Ma, S.; Li, L. Synlett 2001, 1206.
(19) 2,3-Allenamides may be easily available from propargylic alcohols
in two steps, see: (a) Ma, S.; Xie, H. J. Org. Chem. 2002, 67, 6575. (b)
Ma, S.; Xie, H. Tetrahedron 2005, 61, 251.
OL9009046
Org. Lett., Vol. 11, No. 13, 2009
2903