Silver-catalyzed incorporation of carbon dioxide into o-alkynylaniline derivatives

Article abstract of DOI:10.1021/ol303534w

Benzoxazine-2-one derivatives are important heterocycle structures because of their various pharmaceutical activities, though their synthetic methods had been limited. In some cases, toxic reagents, such as phosgene or carbon monoxide, are required. It was found that a silver catalyst successfully promoted the incorporation of CO₂ into o-alkynylanilines to afford the corresponding benzoxazine-2-ones bearing Z exo-olefin via 6-exo-dig cyclization at the activated C-C triple bond.

Full text of DOI:10.1021/ol303534w

ORGANIC
LETTERS
2013
Vol. 15, No. 4
848–851
Silver-Catalyzed Incorporation of Carbon
Dioxide into o-Alkynylaniline Derivatives
Tomonobu Ishida, Satoshi Kikuchi, Tatsuyuki Tsubo, and Tohru Yamada*
Department of Chemistry, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama,
223-8522, Japan
yamada@chem.keio.ac.jp
Received December 25, 2012
ABSTRACT
Benzoxazine-2-one derivatives are important heterocycle structures because of their various pharmaceutical activities, though their synthetic
methods had been limited. In some cases, toxic reagents, such as phosgene or carbon monoxide, are required. It was found that a silver catalyst
successfully promoted the incorporation of CO2 into o-alkynylanilines to afford the corresponding benzoxazine-2-ones bearing Z exo-olefin via
6-exo-dig cyclization at the activated CꢀC triple bond.
Benzoxazine-2-one derivatives have attracted much atten-
tion as some of the most important heterocycle structures in
pharmaceutical science; for example, one derivative bearing
an exo-olefin, 4-ylidene-1,4-dihydro-2H-3,1-benzoxazine-2-
one 1, were reported active as osteoclast differential induction
inhibitors or anti-inflammatory agents, as well as osteoclasis
inhibitors and antirheumatic agents.1 The analogues of
1, 4-alkylsubstituted 1,4-dihydro-2H-3,1-benzoxazine-2-one
derivatives 2, also indicated biological behaviors with a
modest progesterone receptor (PR) agonist activity, which
have been applied used for contraceptives and hormone
therapy, often in combination with estrogen.2ꢀ5 Efavirenz
(SUSTIVA), composed of the benzoxazine-2-one system, is
the first anti-HIV drug approved by the FDA in the United
States.6 In spite of the importance of the benzoxazine-2-one
components, their methods in organic synthesis have been
limited. Several preparative reactions employing phosgene,1,6ꢀ9
carbon monoxide,10,11carbonyldiimidazole,5 or a hyperva-
lent iodine compound12 were reported for the synthesis of
the 4-alkyl-substituted benzoxazine-2-one derivatives. The
synthetic reaction for benzoxazine-2-ones containing exo-
olefin 1has been only rarely reported in which their scope was
limited and toxic phosgene must be employed.1,8 Carbon
dioxide is regarded as safe, easy handled, and reasonable C1
resource especially for constructing carbonyl functionalities
as an alternative to the use of toxic chemical reagents.
(1) Nakatsuka, M.; Okada, S.; Shimano, K.; Watanabe, S.; Suzuki,
Y.; Nishikaku, F. Sumitomo Pharmaceuticals Co., Ltd. PCT Int. Appl.
WO98/42688, 1998.
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Cohen, J.; Marschke, K. B.; Mais, D. Bioorg. Med. Chem. Lett. 2001,
11, 2747–2750.
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R.; Lundeen, S.; Marschke, K. B.; Zhang, Z. J. Med. Chem. 2002, 45,
4379–4382.
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V. A.; Miller, L. L.; Ullrich, J. W.; Winneker, R.; Wrobel, J.; Zhang, P.;
Zhang, Z.; Zhu, Y. Bioorg. Med. Chem. Lett. 2002, 12, 3487–3490.
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We recently reported that carbon dioxide could be
employed in the presence of a silver salt13 to efficiently
afford the cyclic carbonates, oxazolidinones, and lactones
(7) Testa, E.; Fontanella, L. Farmaco, Ed. Sci. 1966, 21, 549–557.
r
10.1021/ol303534w
Published on Web 01/31/2013
2013 American Chemical Society

Table 1. Examination of Various Metal Salts
Scheme 1. Postulation Reaction Mechanism of
o-Alkynylaniline and CO2
entry
metal salt
none
yielda (%)
1
0
0
2
Pd(OAc)2
RhCl2(PPh3)3
PtCl2
3
0
4
0
5
CuBr
0
6
AuCl
0
7b
8
AuCl3
0
AuCl/AgNO3
AgNO3
30
97
97
with a Z exo-olefin from the corresponding alkyne deriva-
tives. In these reactions, the silver catalyst effectively
activates the CꢀC triple bond14 to afford the 5-exo-dig
cyclized products in high yield. A DFT calculation study15
supported these mechanisms. Therefore, when o-alkyny-
laniline derivatives 3 are used as the starting substrates for
the silver-catalyzed carbon dioxide incorporation reaction,
the desired benzoxazine-2-one derivatives bearing the Z
exo-olefin 4 would be obtained via the 6-exo-dig cycliza-
tion on the activated CꢀC triple bond (Scheme 1). We now
report a new synthetic method to produce benzoxazine-
2-one derivatives possessing the Z exo-olefin in the pre-
sence of a silver catalyst from o-alkynylanilines and carbon
dioxide.
9
10
AgOAc
a Isolated yield. b The reaction was carried out at 80 °C.
reaction and several metal salts were initially examined on
the reaction of o-alkynylaniline derivative 3a (Table 1).
The reaction did not proceed in the absence of metal
salts (entry 1). When palladium(II),16aꢀc rhodium(II),16d
platinum(II),16e,f and copper(I) salt,16g,h which would be
expected to activate the CꢀC triple bond effectively, were
investigated, no product formed and the starting material
was recovered (entries 2ꢀ5). Although gold(I)16i,j and
gold(III)16k salts did not work for this reaction (entries 6
and 7), the cationic gold(I) salt (AuCl with AgNO3) could
catalyze this reaction to afford the corresponding benzox-
azine-2-one derivative in 30% yield (entry 8). The silver
salts were also examined on this reaction, and conse-
quently, it was found that they were the most effective
catalysts for this reaction to produce the corresponding
products in excellent yields (entries 9 and 10). Other silver
salts were examined, and it was found that most of them
could catalyze this reaction (Table S1, Supporting
Information), so that AgNO3 was chosen as a standard
catalyst. The benzoxazepin-2-one derivative which might
be generated via the 7-endo-dig cyclization was not de-
tected at all.
Based on previous research, we thought that the activa-
tion of CꢀC triple bond would be the key step for this
(8) Visser, C. M.; Kellogg, R. M. Bioorg. Chem. 1977, 6, 79–88.
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(13) (a) Yamada, W.; Sugawara, Y.; Cheng, H.-M.; Ikeno, T.;
Yamada, T. Eur. J. Org. Chem. 2007, 2604–2607. (b) Yoshida, S.; Fukui,
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786–787. (d) Kikuchi, S.; Sekine, K.; Ishida, T.; Yamada, T. Angew.
Chem., Int. Ed. 2012, 51, 6989–6992.
In the presence of AgNO3 (10mol%) andDBU(1.0equiv)
in DMSO under pressurized (1.0 MPa) carbon dioxide,17
the CO2 incorporation reaction of the o-alkynylaniline 3a
was carried out. The corresponding benzoxazine-2-one 4a
was obtained in excellent yield (Table 2, entry 1). Various
o-alkynylaniline derivatives were then subjected to the
present reaction conditions. The N-alkyl o-alkynylaniline
derivatives could also be transformed into the corres-
ponding products in excellent yields (entries 2ꢀ4). The
o-alkynylanilines with p-substitution 3e, 3f, and 3g were
easily converted into the corresponding 6-substituted
(14) Rhee, J. U.; Krische, M. J. Org. Lett. 2005, 7, 2493–2495.
(15) Kikuchi, S.; Yoshida, S.; Sugawara, Y.; Yamada, W.; Cheng, H.
ꢀM.; Fukui, K.; Sekine, K.; Iwakura, I.; Ikeno, T.; Yamada, T. Bull.
Chem. Soc. Jpn. 2011, 84, 698–717.
(16) (a) Inoue, Y.; Itoh, Y.; Yen, I. F.; Imaizumi, S. J. Mol. Catal.
1990, 60, L1–L3. (b) Bacchi, A.; Chiusoli, G. P.; Costa, M.; Gabriele, B.;
Righi, C.; Salerno, G. Chem. Commun. 1997, 1209–1210. (c) Shi, M.;
Shen, Y. M. J. Org. Chem. 2002, 67, 16–21. (d) Ton, X.; Li, D.; Zhang,
Z.; Zhang, X. J. Am. Chem. Soc. 2004, 126, 7601–7607. (e) Oh, C. H.;
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Eur. J. Org. Chem. 2006, 1636–1647. (g) Rayle, H. L.; Roemmele, R. C.;
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^
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(17) Other reaction conditions were also investigated. The results are
summarized in the Supporting Information.
Org. Lett., Vol. 15, No. 4, 2013
849

Table 2. AgNO3 Catalyzed the Reaction of Several
o-Alkynylaniline Derivatives with CO2
Figure 1. Single-crystal X-ray diffraction analysis for 4b. Thermal
elipsoids are shown at 50% probability.
Scheme 2. Silver-Catalyzed Reactions of Several Primary
o-Alkynylaniline Derivatives with CO2
a Isolated yield. b The reaction was carried out for 35 h. c PMB =
p-methoxybenzyl. d The reaction was carried out for 49 h.
a Silver(II) picolinate was used instead of AgOAc.
products 4e, 4f, and 4g in high yields, respectively (entries
5ꢀ7). The m-substituted o-alknylaniline derivative 3h was
also a good substrate for this reaction, and the correspond-
ing 7-substituted product 4h was obtained in 85% yield
(entry 8). The reactions of the substrates bearing the
terminal alkyne 3i and internal alkyne 3j were smoothly
performed to produce the corresponding products (4i and
4j) in high yields (entries 9 and 10). The substrate having
the 2-pyridyl group on the alkynyl terminal was also
subjected to this catalytic system to afford the correspond-
ing product 4k in excellent yield (entry 11). The geometry of
the exo-olefin in the product 4b was confirmed by an X-ray
diffraction analysis (Figure 1). This result revealed the
product was benzoxazine-2-one containing Z exo-olefin as
the sole compound.18 All other products were suggested to be
the Z-isomer based on NOE experiments. Taking into
account our previous studies, this result would suggest that
the silver catalyst could effectively activate the CꢀC triple
bond during this reaction.
The present catalytic system was successfully applied to
various primary o-alkynylaniline derivatives with carbon
dioxide (Scheme 2). The reactions of the o-alkynylanilines
with a free amino group possessing the phenyl-substituted
alkyne 3l and alkyl-substituted alkyne 3m were catalyzed
(18) Crystallographic data reported in this paper have been deposited
with Cambridge Crystallographic Data Centre as supplementary pub-
lication no. CCDC-983361. Copies of the data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge,
CB2 1EZ, UK; fax: þ44 1223 336033; or deposit@ccdc.cam.ac.uk).
850
Org. Lett., Vol. 15, No. 4, 2013

by AgOAc in the presence of DABCO as a base to generate
the benzoxazine derivatives (4l and 4m) in high yields,
respectively. The substrate bearing the terminal alkyne 3n
was also converted into the corresponding benzoxazine
derivative 4n, but in insufficient yield. The yield of 4n was
improved to 75% when catalyzed by silver(II) picolinate
instead of AgOAc. When the o-alkynylaniline derivatives
with p-methyl and p-fluoro groups (3o and 3p) were
subjected to this catalytic system, the corresponding pro-
ducts (4o and 4p) were obtained in 75% and 61% yields,
respectively. When the reaction of the aniline 3q substi-
tuted with trimethylsilylacetylenyl was carried out, the
corresponding benzoxazine-2-one 4n was obtained in
80% yield, though TMS group was removed.
o-alkynylaniline derivatives to produce a series of benzox-
azine-2-one derivatives containing the Z exo-olefin in high
yields under mild reaction conditions, which were reported
to show various biological activities. Primary as well as
secondary anilines could be used with this catalytic system
to afford the corresponding products in good yields. The
structure of the product was verified by an X-ray diffrac-
tion analysis and NOE experiment to determine the pro-
duct possesses the Z exo-olefin. Further applications for
this silver catalytic system are being investigated.
Supporting Information Available. Experimental proce-
dure and analytical data for new compounds. This material
available free of charge via the Internet at http://pubs.acs.org.
In conclusion, it was revealed that the silver catalyst with
bases could allow the reaction of carbon dioxide with the
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
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