Novel method of tetramic acid synthesis: Silver-catalyzed carbon dioxide incorporation into propargylic amine and intramolecular rearrangement

Article abstract of DOI:10.1021/ol500806u

Tetramic acid derivatives have been studied as biologically active heterocycle structures for pharmaceutical or agricultural chemicals. Conventional preparative approaches often require highly functionalized starting materials and harsh heating conditions in basic media. The present report provides a conceptually new synthetic strategy for the synthesis of tetramic acid derivatives from easily available propargylic amines and carbon dioxide with a silver salt and DBU under mild reaction conditions.

Full text of DOI:10.1021/ol500806u

Letter
pubs.acs.org/OrgLett
Novel Method of Tetramic Acid Synthesis: Silver-Catalyzed Carbon
Dioxide Incorporation into Propargylic Amine and Intramolecular
Rearrangement
Tomonobu Ishida, Ryo Kobayashi, and Tohru Yamada*
Department of Chemistry, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, 223-5822, Japan
S
* Supporting Information
ABSTRACT: Tetramic acid derivatives have been studied as
biologically active heterocycle structures for pharmaceutical or
agricultural chemicals. Conventional preparative approaches
often require highly functionalized starting materials and harsh
heating conditions in basic media. The present report provides
a conceptually new synthetic strategy for the synthesis of
tetramic acid derivatives from easily available propargylic amines and carbon dioxide with a silver salt and DBU under mild
reaction conditions.
etramic acid structures are found in natural products
T
known for their biological activity. For example, reuter-
icyclin inhibits Gram-positive bacteria,1 and discodermide
inhibits the growth of Candida fungi.2 In addition, spirote-
tramat has been used as an agricultural chemical.3 Therefore,
much effort has been expended on the preparation of tetramic
acid derivatives.4 Most have been synthesized through intra-
molecular cyclization via conventional Dieckmann condensa-
tion (Scheme 1, eq 1)5 or amidation (eq 2).6 These are
Scheme 2. Previous Works: Carbon Dioxide Incorporation
into Alkynyl Amine Derivatives
Scheme 1. Conventional Preparation of Tetramic Acid
established strategies for preparing tetramic acids. However,
highly derivatized starting materials are required and the
reaction conditions involve high heat in basic media. Therefore,
new synthetic alternatives are needed. Recent studies have
investigated intramolecular aza-anti-Michael addition,7 enantio-
selective cyclization through samarium(II) iodide mediated
coupling,8 reductive cyclization with samarium(II) iodide,9 and
oxidative cyclization with hypervalent iodine compounds.10
Recently, we reported a transformation of o-alkynylaniline
derivatives into 4-hydroxyquinolin-2(1H)-one derivatives via
silver-catalyzed alkyne activation and a curious intramolecular
rearrangement (Scheme 2, eq 3).11 The proposed reaction
mechanism involved generation of the corresponding ben-
zoxazin-2-one through silver-catalyzed alkyne activation12
followed by intramolecular rearrangement with C−O bond
cleavage triggered by deprotonation of the amide with DBU as
a base. In mechanistic studies, isotopic labeling experiments
with C18O2 strongly suggested that the corresponding quinoline
compound contained 1 equiv of carbon dioxide. In addition, a
possible isocyanate intermediate was detected by in situ IR
spectroscopy.
Received: March 18, 2014
Published: April 16, 2014
© 2014 American Chemical Society
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Letter
This rearrangement was expected to be applicable to five-
membered ring compounds to enable synthesis of tetramic acid
derivatives from the corresponding primary propargylic amines.
We have already reported a carbon dioxide fixation reaction
involving propargylic amines which affords the corresponding
oxazolidinone in the presence of a silver catalyst without any
base (Scheme 2, eq 4).13 Conducting the reaction in the
presence of an appropriate base and silver catalyst would be
expected to generate an oxazolidinone that could undergo a
similar rearrangement to produce the corresponding tetramic
acid derivatives under mild reaction conditions from simple and
common starting substrates (Scheme 3). The present report
ing oxazolidinone and propargylic amine were consumed and
transformed into the desired tetramic acid in 94% yield (Table
1, entry 6). Moreover, carbon dioxide pressure could be
reduced from 1.0 MPa to atmospheric pressure (0.1 MPa), and
the reaction also proceeded in easily handled MeCN, instead of
DMSO, without any loss of product yield (Table 1, entries 7
and 8). Single crystal X-ray analysis confirmed the structure of
compound 2a as the targeted tetramic acid derivative after
transformation of 2a into 2a′ by methylation with diazo-
methane (Figure 1).14
Scheme 3. This Work: Silver-Catalyzed Carbon Dioxide
Incorporation into Primary Propargylic Amines with
Intramolecular Rearrangement
Figure 1. Single crystal X-ray analysis for 2a′. Thermal ellipsoids are
shown at the 50% probability level. The compound 2a′ was prepared
by methylation of 2a with diazomethane.
describes a novel method for the synthesis of tetramic acids,
which relies on silver-catalyzed carbon dioxide incorporation,
followed by an intramolecular rearrangement.
Further optimization of the reaction conditions was
performed (Table 2). When reaction temperatures were
Previous reports11,12 have indicated that choosing the
appropriate base is crucial for this reaction. Therefore, various
bases were examined for suitability for the reaction (Table 1).
Table 2. Conditions Optimization
Table 1. Preliminary Experiment: Screening for Bases
a
yield (%)
entry
temp (°C)
base (equiv)
time (h)
2a
3a
94
b
1
10
20
30
40
50
60
60
2.0
2.0
1.0
1.0
1.0
1.0
2.0
2.0
121
67
48
48
24
24
4
0
a
yield (%)
c
2
0
90
52
22
17
trace
0
entry
base
2a
3a
98
3
4
5
6
7
31
59
58
95
92
96
1
2
3
4
5
6
K2CO3
KOH
tBuOK
Et3N
0
0
83
0
97
0
89
d
DIPEA
DBU
0
91
8
60
24
0
a
b
c
94
95
95
trace
trace
trace
Isolated yield. 1.0 equiv of DBU was added after 84 h passed. 1.0
b
d
7
bc
,
DBU
equiv of DBU was added after 31 h passed. Loading of AgNO3 was
reduced to 0.5 mol %.
8
DBU
a
b
c
Isolated yield. Pressure of CO2 is 0.1 MPa. MeCN was used as a
solvent instead of DMSO.
reduced from 60 °C to 10 or 20 °C, only the corresponding
oxazolidinone was obtained in high yield without generation of
tetramic acid, despite an excess amount of DBU and a longer
reaction time (Table 2, entries 1 and 2). Reactions at 30, 40,
and 50 °C afforded the corresponding tetramic acid; however,
oxazolidinone also remained (Table 2, entries 3−5). Con-
sequently, the reaction should be conducted at 60 °C to afford
the desired product in high yield (Table 2, entry 6). These
results suggest that the rate-determining step of the reaction is
rearrangement of oxazolidinone triggered by deprotonation of
the amide. Reaction in the presence of 2.0 equiv of DBU was
In the presence of inorganic bases such as K2CO3, KOH, and t-
BuOK, the starting substrate was consumed completely,
although the corresponding tetramic acid was not obtained;
instead, the intermediate oxazolidinone was obtained in high
yield (Table 1, entries 1−3). When triethylamine or DIPEA
was used as a weak base, the corresponding product was not
produced, but oxazolidinone was generated in 89% or 91%
yield, respectively (Table 1, entries 4 and 5). When the
sufficiently strong organic base DBU was used, the correspond-
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Letter
completed in just 4 h (Table 2, entry 7). Under the present
reaction conditions, the catalyst loading could be reduced to 0.5
mol % (Table 2, entry 8) to produce the corresponding
tetramic acid in excellent yield.
The optimized reaction conditions were applied to reactions
involving various primary propargylic amine derivatives (Table
3). In the presence of 0.5 mol % of AgNO3 and 2.0 equiv of
on phenyl group 1c as an electron-withdrawing group at the
para-position, the reaction proceeded quickly to produce the
corresponding tetramic acid derivative 2c in 90% yield (Table
3, entry 3). An electron-donating methyl group 1d or methoxy
group 1e also was used as a substituent on the phenyl group at
the para-position. Both reacted with carbon dioxide and were
converted into the corresponding products 2d and 2e,
respectively, in good yields (Table 3, entries 4 and 5).
Heterocyclic groups also were investigated as substituents R1.
Propargylic amines with a 2-pyridyl group 1f or a 2-thienyl
group 1g on the alkyne underwent reaction to afford the
corresponding heterocycle products 2f and 2g, respectively, in
high-to-excellent yields (Table 3, entries 6 and 7). Alkynyl
amines with a 1-naphthyl group 1h or a 2-naphthyl group 1i
smoothly afforded the corresponding tetramic acid derivatives
2h and 2i, respectively, in high yields despite steric hindrance
(Table 3, entries 8 and 9). Some substituents on the
propargylic position R2 and R3 as well as on the alkynyl
terminal were examined. Not only cyclohexyl amines like the
model substrate but also the propargylic amine with a dimethyl
group on the propargylic position 1j could be transformed into
the corresponding tetramic acid derivative 2j in 90% yield
(Table 3, entry 10). In addition, propargylic amines with a
monosubstituent on the propargylic position underwent the
reaction. Substituent R2 was replaced with an ethyl group 1k or
phenyl group 1l; both reacted with carbon dioxide to generate
the corresponding products 2k and 2l, respectively, in 92% and
91% yield (Table 3, entries 11 and 12).
Table 3. Substrate Scope of Transformation of Various
Propargylic Amines into Tetramic Acids with Carbon
Dioxide Incorporation and Intramolecular Rearrangement
When propargylic amines with no substitution on the
propargylic position were subjected to the reaction conditions,
none afforded the corresponding tetramic acid derivative;
instead the reactions resulted in complex mixtures. After
optimization, a one-pot procedure was found suitable for these
substrates. In the presence of silver acetate without DBU, the
starting substrate was converted into the corresponding
oxazolidinone by silver-catalyzed carbon dioxide incorporation,
followed by degassing by freeze−deaeration to remove
dissolved carbon dioxide. To the reaction mixture at 25 °C,
1.0 equiv of DBU was added. Conducting this procedure using
the starting substrate 1m yielded the corresponding tetramic
acid 2m in 92% yield. Substrates with a methyl substituent in
the ortho-, meta-, or para-position underwent reaction to
produce the corresponding product 2n, 2o, or, 2p, respectively,
in high yield (Scheme 4).
Scheme 4. One-Pot Carbon Dioxide Incorporation and
a
Intramolecular Rearrangement of Propargylic Amines
a
b
Isolated yield. DMSO was used as a solvent instead of MeCN. 10
c
mol % of AgNO3 and 2.0 equiv of DBU were used. Reaction mixture
was exposed to 1.0 MPa of CO2 without DBU for 1 h, then with added
DBU and stirring for 6 h.
DBU under atmospheric pressure of carbon dioxide in MeCN,
propargylic amine 1a was converted into the corresponding
tetramic acid 2a in 96% yield (Table 3, entry 1). The
propargylic amine with terminal alkyne 1b also afforded the
corresponding product 2b in 49% yield (Table 3, entry 2). The
effects of functional groups on the phenyl ring in substituent
R1 also have been examined.15 When a nitro group was placed
a
The oxazolidinone was isolated instead of the degassing process.
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Letter
(13) Yoshida, S.; Fukui, K.; Kikuchi, S.; Yamada, T. Chem. Lett. 2009,
38, 786−787.
In conclusion, we have successfully developed a new strategy
for the synthesis of tetramic acid derivatives. This reaction
overcame previous obstacles encountered in synthesizing
biologically or agriculturally significant heterocyclic compounds
via alternative methods. A wide variety of substrates were
applicable to the optimized reaction conditions to afford the
corresponding tetramic acid derivatives in satisfactory yields.
The results support a proposed reaction mechanism involving
rearrangement ring opening with generation of an isocyanate
and an enolate as intermediates triggered by deprotonation of
the amide, followed by ring closure and formation of a new
carbon−carbon bond. Further investigations and applications
are currently being examined.
(14) Crystallographic data in this paper have been deposited with
Cambridge Crystallographic Data Centre as supplementary publication
no. CCDC-962553. Copies of the data can be obtained free of charge
via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cam-
bridge Crystallographic Data Centre, 12, Union Road, Cambridge,
CB2 1EZ, UK; fax:+44 1223 336033; or deposit@ccdc.cam.ac.uk).
(15) When propargylic amines containing an alkyl group on the
alkyne were subjected to the present reaction conditions, undesired
side reactions occurred.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and analytical data for new com-
pounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: yamada@chem.keio.ac.jp.
Notes
The authors declare no competing financial interest.
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