Gold(I)-Catalyzed Intramolecular SEAr Reaction: Efficient Synthesis of Isoxazole-Containing Fused Heterocycles

Article abstract of DOI:10.1021/acs.orglett.7b03760

Intramolecular electrophilic aromatic substitution (S_EAr) reaction at the 5-position of isoxazoles was achieved. The electron-donating heteroatoms (N and O) at the 4-position of isoxazoles, which can be readily prepared based on our originally developed synthetic procedure, and a cationic gold(I) catalyst are essential for the intramolecular S_EAr reaction to synthesize isoxazole-containing fused heterocycles. Structurally diverse isoxazolopyridines 6 and isoxazolopyrans 9, including base-labile 3-unsubstituted derivatives, were synthesized in good to high yields. The addition of N-phenylbenzaldimine as a hydrogen acceptor improved yields in the synthesis of isoxazolopyridines. Furthermore, synthesis of the tetracyclic fused ring system 12 was achieved by tandem cyclization from the corresponding diyne 11.

Full text of DOI:10.1021/acs.orglett.7b03760

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Gold(I)-Catalyzed Intramolecular SEAr Reaction: Efficient Synthesis of
Isoxazole-Containing Fused Heterocycles
Taiki Morita, Shintaro Fukuhara, Shinichiro Fuse, and Hiroyuki Nakamura*
Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, 4259 Nagatsuta-cho,
Midori-ku, Yokohama 226-8503, Japan
S
* Supporting Information
ABSTRACT: Intramolecular electrophilic aromatic substitution (SEAr)
reaction at the 5-position of isoxazoles was achieved. The electron-
donating heteroatoms (N and O) at the 4-position of isoxazoles, which
can be readily prepared based on our originally developed synthetic
procedure, and a cationic gold(I) catalyst are essential for the
intramolecular SEAr reaction to synthesize isoxazole-containing fused
heterocycles. Structurally diverse isoxazolopyridines 6 and isoxazolopyrans 9, including base-labile 3-unsubstituted derivatives,
were synthesized in good to high yields. The addition of N-phenylbenzaldimine as a hydrogen acceptor improved yields in the
synthesis of isoxazolopyridines. Furthermore, synthesis of the tetracyclic fused ring system 12 was achieved by tandem cyclization
from the corresponding diyne 11.
Scheme 1. Synthetic Approaches to Isoxazole-Containing
Fused Heterocyclic Compound I
soxazole is one of the most important frameworks in
Ipharmaceuticals and agrochemicals; in fact, the isoxazole
ring ranks 33rd among the 351 ring systems found in marketed
drugs.1 Not surprisingly, isoxazole-containing fused heterocyclic
systems are frequently found in biologically active compounds
such as anti-inflammatory agent 1,2 phosphodiesterase inhibitor
for treating neurological and psychiatric disorders 2,3 CYP17
inhibitor for treating prostate cancer 3,4 and antimicrobial and
anti-inflammatory agent 45 (Figure 1). Therefore, developing
efficient synthetic methods for this class of compounds is an
urgent issue in pharmaceutical chemistry as well as agro-
chemistry.
Conventional synthetic approaches to isoxazole-containing
fused heterocycles I (Scheme 1) include isoxazole ring formation
of multisubstituted heterocycles II (approach A),6 heterocycle
formation of multisubstituted isoxazoles III (approach B),7 and
heterocycle formation at the 4-position of isoxazoles IV
(approach C).8 On the other hand, heterocycle formation at
the 3- or 5-position of isoxazole V has scarcely been developed,
although intramolecular cyclization at the position adjacent to
the heteroatom is a conventional synthetic approach to other
fused heterocycles. Because 3- and/or 5-unsubstituted isoxazoles
are labile even under mild basic conditions, deprotonation at the
3- or 5-position followed by electrophilic trapping is not
applicable to direct functionalization of isoxazoles.9 In addition,
electrophilic aromatic substitution (SEAr) of isoxazoles is also
difficult due to their poor nucleophilicity.9 Indeed, SEAr reactions
at the 3- or 5-position have never been reported. Only one
example of isoxazole-containing fused heterocycle synthesis via a
reaction at the 5-position of isoxazole was reported by Paoli and
Figure 1. Examples of biologically active isoxazole-containing fused
heterocycles.
Received: December 3, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03760
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
co-workers.10 They reported a Diels−Alder reaction between
α,β-unsaturated hydrazone and 4-nitro-3-phenylisoxazole to
provide isoxazolopyridine. Therefore, the development of
efficient synthetic methods for I, which cannot be readily
synthesized by other approaches, remains important. We
recently reported the first practical and high-yielding SEAr
reaction of isoxazole at its 4-position.11 The reaction enables us
to conduct the synthesis of I through approach D. In this paper,
we wish to report the first synthesis of isoxazole-containing fused
heterocycles via cationic gold(I)-catalyzed SEAr reaction at the 5-
position of isoxazoles (Scheme 1).
particular, the best yield was observed when combinations of
RuphosAuCl and AgSbF6 (entry 14) and JohnphosAuCl and
AgSbF6 (entry 15) were used. As described later, the reaction of
5a to form 6a included (1) a cyclization step and (2) an oxidative
aromatization step. We speculated that acceleration of the (2)
oxidative aromatization step was necessary to improve the yield
of 6a. However, the addition of oxidants such as tBuO2H,
(tBuO)2, DDQ, or O2 did not improve the yield of 6a (entries
16−19). We supposed that the use of a hydrogen acceptor would
accelerate the oxidation; thus, N-phenylbenzaldimine (7)13 was
employed on the basis of this assumption. Expectedly, 6a was
obtained in 84% yield (entry 20). In addition, the amount of
catalyst could be reduced from 20 to 5 mol % without decreasing
the yield of 6a (entry 21). It should be noted that the cationic
gold(I) catalyst did not lose its Lewis acidity in the presence of a
stoichiometric amount of Lewis base, imine 7, in the reaction
process. The use of Ph3PAuCl in the presence of 7 decreased the
yield of 6a (entry 22), suggesting that the steric bulkiness of the
Johnphos ligand might prevent the approach of 7 to the cationic
gold atom. The combination of JohnphosAuCl with AgOTf and
AgNTf2 resulted in poor reaction yields (14% and 30%,
respectively). Since 3-unsubstituted isoxazolopyridine could
not be synthesized via approach A due to its instability,6a the
established intramolecular SEAr reaction is useful for con-
struction of 3-unsubstituted isoxazolopyridines.
We first employed 4-(1-phenylpropargylamino)isoxazole 5a
as a substrate for investigating isoxazole-containing fused
heterocycle formation (Table 1). We anticipated that the
Table 1. Catalyst Screening for Intramolecular SEAr Reaction
of 5a
a
entry
catalysts
additive
yield (%)
1
ZnCl2
ZnBr2
ZnI2
0
7
2
3
0
Thus, we next examined the scope and limitations of this
reaction. The substrate scope and limitations were examined by
using the optimized conditions (Table 1, entry 21) as shown in
Table 2. Alkyl-substituted alkynes 5b−d afforded the corre-
4
CuCl2
CuBr2
0
5
b
6
Cu(OTf)2
0
g
7
[Cp*RhCl]2
0
8
[Ir(cod)(PCy3)(Py)]PF6
Ph3PAuCl/AgSbF6
0
Table 2. Scope and Limitations of Intramolecular SEAr
Reaction of 5
9
50
16
31
51
41
54
10
11
12
13
14
15
16
17
18
19
IPrAuCl/AgSbF6
CyJohnphosAuCl/AgSbF6
XphosAuCl/AgSbF6
tBuXphosAuCl/AgSbF6
RuphosAuCl/AgSbF6
JohnphosAuCl/AgSbF6
JohnphosAuCl/AgSbF6
JohnphosAuCl/AgSbF6
JohnphosAuCl/AgSbF6
JohnphosAuCl/AgSbF6
JohnphosAuCl/AgSbF6
c
54
tBuO2H
(tBuO)2
47
37
56
50
a
entry
5
R1
R2
R3
6
yield (%)
1
5b
5c
5d
5e
5f
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
Me
6b
6c
6d
6e
6f
79
84
85
71
70
74
38
0
DDQ
2
npentyl
O2 (1 atm)
3
tBu
d
f
20
7
7
7
84
4
4-MeC6H4
d
e
f
21
JohnphosAuCl/AgSbF6
87
f
5
4-OMeC6H4
d
e
22
Ph3PAuCl/AgSbF6
60
6
5g
5h
5i
3-OMeC6H4
6g
6h
6i
a
NMR yield using 1,1,2-trichloroethane as an internal standard.
Traceable amount of 2a was obtained. The yield was not increased
even when the reaction was carried out at 60 °C. The reaction was
carried out for 3 h at 60 °C. The amount of catalyst was 5 mol %.
Isolated yield. DCE = 1,2-dichloroethane, Tf = trifluoromethane-
sulfonyl, Cp* = 1,2,3,4,5-pentamethylcyclopentadienyl, cod = 1,5-
cyclooctadiene, IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-yli-
dene, CyJohnphos = 2-(dicyclohexylphosphino)biphenyl, Xphos = 2-
dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, BuXphos = 2-di-
t-butylphosphino-2′,4′,6′-triisopropylbiphenyl, Ruphos = 2-dicyclohex-
ylphosphino-2‘,6‘-diisopropoxybiphenyl, Johnphos = (2-biphenyl)di-t-
butylphosphine. DDQ = 2,3-dichloro-5,6-dicyano-p-benzoquinone.
7
4-CF3C6H4
b
c
8
H
d
9
5j
4-MeC6H4
4-ClC6H4
npentyl
H
Ph
Ph
Ph
Ph
6j
82
79
71
53
e
f
g
10
11
12
5k
5l
6k
6l
5m
6m
a
Isolated yield.
t
sponding isoxazolopyridines 6b−d in good to high yields
regardless of the steric bulkiness of the R2 group (Table 2,
entries 1−3). Aryl-substituted alkynes with electron-donating
groups 5e−g afforded good yields (entries 4−6), whereas
electron-withdrawing 4-CF3C6H4-substituted alkyne 5h resulted
in a decreased yield (entry 7). No reaction was observed when
terminal alkyne 5i was used as a substrate (entry 8), revealing that
a substituent at the terminal position of alkynes is essential for the
current intramolecular SEAr reaction. The 3-alkyl or 3-aryl-
substituted isoxazoles 5j−l also underwent the intramolecular
nitrogen atom at the 4-position would enhance the nucleophil-
icity of the isoxazole ring. Zinc catalysts (entries 1−3), copper
catalysts (entries 4−6), a rhodium catalyst (entry 7), and an
iridium catalyst (entry 8) did not afford product 6a in satisfactory
yields. On the other hand, cationic gold(I) catalysts12 afforded 6-
endo cyclization product 6a in 16−54% yields (entries 9−15). In
B
DOI: 10.1021/acs.orglett.7b03760
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
SEAr reaction to afford the corresponding isoxazolopyridines 6j−
l in high yields regardless of the electronic factor of the R1 groups.
Substrate 5m, which has a methyl group at the propargylic
position, was also converted to the corresponding 6m in 53%
yield (entry 12).
Scheme 2. Deuterium-Labeling Study
We then turned our attention to the intramolecular SEAr
reaction of 4-propargyloxyisoxazoles 8, which have a less
electron-donating oxygen atom at the 4-position. Our previously
developed procedure enabled us to prepare 8 readily.11 The
results are summarized in Table 3. The intramolecular SEAr
results indicate that imine 7 acts as an acceptor of hydrogen to
assist the oxidative aromatization step in the reaction pathway as
expected.
A plausible mechanism for the intramolecular SEAr reaction of
4-propargylaminoisoxazoles 5 and 4-propargyloxyisoxazoles 8 is
shown in Scheme 3. First, the alkyne moiety of 5 and 8 would be
Table 3. Scopes of Intramolecular SEAr Reaction of 8
Scheme 3. Plausible Mechanism
a
entry
8
R1
R2
9
yield (%)
1
8a
8b
8c
8d
8e
8f
H
Me
H
9a
9b
9c
9d
9e
9f
70
60
83
85
69
95
64
83
73
54
73
70
61
84
75
88
63
65
50
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3
Me
4
cyclopentyl
tBu
5
6
(CH2)3OTBS
Ph
7
8g
8h
8i
9g
9h
9i
8
4-OMeC6H4
4-CO2EtC6H4
TMS
9
10
11
12
13
14
15
16
17
18
19
8j
9j
8k
8l
NMeTs
Me
9k
9l
4-ClC6H4
4-ClC6H4
3-CF3C6H4
4-FC6H4
4-OMeC6H4
2-thienyl
npentyl
8m
8n
8o
8p
8q
8r
8s
4-CF3C6H4
Ph
npentyl
9m
9n
9o
9p
9q
9r
9s
Me
activated by the cationic gold(I) catalyst to generate intermediate
i. An electron-donating heteroatom-assisted SEAr reaction of
isoxazoles occurs to generate the alkenyl gold intermediate ii.14
In the cyclization of 8 (Z = OH), rearomatization of the isoxazole
ring and protodeauration would provide cyclized product 9. In
contrast, in the case of cyclization of 5 (Z = NH), imine 7
abstracts a proton from ii to rearomatize the isoxazole ring, and
dihydropyridine iii is generated. Then, iminium cation iv accepts
a hydride from iii to generate pyridinium cation v with N-
phenylbenzylamine (10).15 The subsequent protodeauration
provides isoxazolo[4,5-b]pyridines 6 accompanied by regener-
ation of the cationic gold(I) catalyst. We speculate that the
basicity of imine 7 should be insufficient to deactivate the
cationic gold catalyst but sufficient to abstract a proton from ii. In
addition, N-benzyl-protected 5a did not undergo intramolecular
SEAr reaction, revealing that the rearomatization (iii → v) is a
driving force for the formation of 6.
Finally, we applied the current cationic gold(I)-catalyzed
intramolecular SEAr reaction to construct a tetracyclic fused ring
system via tandem cyclization. Diyne 11 was designed and
subjected to the intramolecular SEAr reaction (Scheme 4). To
our delight, the desired tetracyclic product 12 was obtained in
20% yield as shown in Scheme 4. The structure of 12 was
unambiguously confirmed by X-ray crystallographic analysis.16
In conclusion, we demonstrated the first SEAr reaction at the 5-
position of isoxazoles. The electron-donating heteroatoms (N
and O) at the 4-positions of the isoxazoles, which can be readily
prepared based on our originally developed synthetic procedure,
and the sterically bulky cationic gold(I) catalyst are essential for
the intramolecular SEAr reaction for the formation of isoxazole-
Me
Me
npentyl
cyclopentyl
a
Isolated yield. TBS: tert-butyldimethylsilyl. TMS: trimethylsilyl. Ts: p-
toluenesulfonyl.
reaction of 8a proceeded in the presence of a combination of 10
mol % of JohnphosAuCl and 10 mol % of AgSbF6 to afford the
desired 6-endo cyclization product, isoxazolopyran 9a, in 70%
yield (Table 3, entry 1). Interestingly, terminal alkyne 8b also
afforded the corresponding isoxazolopyran 9b in 60% yield,
although terminal alkyne 5i did not undergo the intramolecular
SEAr reaction (Table 3, entry 2, vs Table 2, entry 8). The 3-aryl-
substituted alkynes 8c−q afforded the desired isoxazolopyrans
9c−q in good yields regardless of the electronic factor of the R1
groups (entries 3−17). In addition, various substituents
including alkyl (entries 3−6), aryl (entries 7−9), silyl (entry
10), and sulfonyl amide (entry 11) groups could be employed as
the R2 group. The 3-alkyl-substituted alkynes 8r and 8s also
afforded the desired isoxazolopyrans 9r and 9s (entries 18 and
19), although the observed yields were lower than those of 3-aryl-
substituted alkynes 8c and 8d. Needless to say, these base-
sensitive 3-unsubstituted isoxazolopyrans (9) have never been
synthesized before.
To investigate the role of N-phenylbenzaldimine 7 in the
intramolecular SEAr reaction of 5, a deuterium-labeling study was
carried out as shown in Scheme 2. Deuterated substrates 5a−d
were used for the reaction, and deuterium transfer from the
propargylic position of 5a−d to imine 7 was observed. These
C
DOI: 10.1021/acs.orglett.7b03760
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Scheme 4. Tandem Cyclization of 11 and the X-ray Crystal
Structure of Resulting Tetracyclic Compound 12
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́
ez-Canas, M.; Navarro, G.; Hurst, D. P.; Carrillo-
̃
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isoxazolopyrans 9 including base-labile 3-unsubstituted deriva-
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phenylbenzaldimine as a hydrogen acceptor improved yields in
the synthesis of isoxazolopyridines. Furthermore, synthesis of the
tetracyclic fused ring system 12 was achieved by tandem
cyclization from the corresponding diyne 11. We believe that
the current synthetic approach would be a valuable aid in the
drug discovery process based on isoxazole-containing fused
heterocycles.
́
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03760.
Experimental procedures, mechanistic studies, and char-
acterization and spectral data (PDF)
Accession Codes
CCDC 1579486 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
(9) For recent review on the functionalization of isoxazoles, see: Fuse,
S.; Morita, T.; Nakamura, H. Synthesis 2017, 49, 2351.
(10) Turchi, S.; Giomi, D.; Nesi, R.; Paoli, P. Tetrahedron 1995, 51,
7085.
(11) Morita, T.; Fuse, S.; Nakamura, H. Angew. Chem., Int. Ed. 2016,
55, 13580.
(12) For activation of alkynes by cationic gold(I) catalysts, see:
(a) Dorel, R.; Echavarren, A. M. Chem. Rev. 2015, 115, 9028. (b) Tang,
D.; Chen, Z.; Zhang, J.; Tang, Y.; Xu, Z. Organometallics 2014, 33, 6633.
(c) Nevado, C.; Echavarren, A. M. Chem. - Eur. J. 2005, 11, 3155.
(13) Kuninobu, Y.; Inoue, Y.; Takai, K. Chem. Lett. 2007, 36, 1422.
(14) (a) Zhu, M.; Fu, W.; Zou, G.; Xun, C.; Deng, D.; Ji, B. J. Fluorine
Chem. 2012, 135, 195. (b) Samala, S.; Mandadapu, A. K.; Saifuddin, M.;
Kundu, B. J. Org. Chem. 2013, 78, 6769. (c) Reddy, M. R.; Kumar, G. R.;
Yarlagadda, S.; Reddy, C. R.; Yadav, J. S.; Sridhar, B.; Reddy, B. V. S. RSC
Adv. 2016, 6, 113390. (d) Reetz, M. T.; Sommer, K. Eur. J. Org. Chem.
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(15) de Vries, J. G.; Mrsic, N. Catal. Sci. Technol. 2011, 1, 727.
(16) Thermal elipsoids are set at the 35% probability level. Diffused
peaks were observed in the difference Fourier map that were attributable
to disordered solvent molecules. Attempts to model these disordered
peaks were in vain; therefore, the contribution from the disordered
solvent molecules was subtracted using the PLATON/SQUEEZE
program.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hiro@res.titech.ac.jp.
ORCID
Hiroyuki Nakamura: 0000-0002-4511-2984
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Mr. Yoshihisa Sei (Technical Department, Tokyo
Institute of Technology) for technical assistance with X-ray
crystallographic analysis. T.M. gratefully acknowledges the
financial support by the Japan Society for the Promotion of
Science (JSPS, ID No. 17J02929).
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DOI: 10.1021/acs.orglett.7b03760
Org. Lett. XXXX, XXX, XXX−XXX