Gold-Catalyzed Michael-Type Reactions and [4 + 2]-Annulations between Propiolates and 1,2-Benzisoxazoles with Ester-Directed Chemoselectivity

Article abstract of DOI:10.1021/acs.orglett.8b02663

This work reports gold-catalyzed reactions between 1,2-benzisoxazoles and propiolate derivatives with ester-controlled chemoselectivity. For ethyl propiolates 1′, their gold-catalyzed reactions afforded Michael-type products 4, whereas tert-butyl propiola

Full text of DOI:10.1021/acs.orglett.8b02663

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Gold-Catalyzed Michael-Type Reactions and [4 + 2]-Annulations
between Propiolates and 1,2-Benzisoxazoles with Ester-Directed
Chemoselectivity
Yashwant Bhaskar Pandit, Rajkumar Lalji Sahani, and Rai-Shung Liu*
Frontier Research Centers of Matter Science and Technology and Department of Chemistry, National Tsing Hua University,
Hsinchu, Taiwan, R.O.C.
S
* Supporting Information
ABSTRACT: This work reports gold-catalyzed reactions
between 1,2-benzisoxazoles and propiolate derivatives with
ester-controlled chemoselectivity. For ethyl propiolates 1′,
their gold-catalyzed reactions afforded Michael-type products
4, whereas tert-butyl propiolates 1 preferably underwent [4 +
2]-annulations, further yielding 6H-1,3-oxazin-6-one deriva-
tives 3.
1,2-Benzisoxazoles (2)1 and anthranils (2′)2 are structurally
related nitroxy containing heterocycles that are the structural
cores of bioactive or naturally occurring molecules. With Au(I)
and Pt(II) catalysts, these two nitroxy heterocycles can serve as
nucleophiles to attack π-alkynes at the nitrogen or oxygen atoms,
enabling further access to molecules of useful complexity.3−5
Nevertheless, the reported examples focus intensively on
anthranils 2′3,4 whereas there are few examples on 1,2-
benzisoxazoles 2.5 We have recently reported gold-catalyzed
[5 + 2]-annulations of anthranils 2′ with propiolate derivatives 1
via an O-attack route, which yielded quinoline oxides efficiently
(eq 1).4a The reaction chemoselectivity was surprisingly varied
catalyzed reactions of 1,2-benzisoxazoles 2 on propiolate
derivatives 1 and 1′,6 but the chemoselectivity was controlled
by the esters of propiolates 1 and 1′. For ethyl propiolates 1′,
their gold-catalyzed reactions with 1,2-benzisoxazoles 2 afforded
Michael-type products 4, whereas tert-butyl propiolates 1
preferably underwent [4 + 2]-annulations with 1,2-benzisox-
azoles 2, further yielding 6H-1,3-oxazin-6-one derivatives 3 (eq
3). A plausible mechanism to rationalize the two reaction routes
is presented herein.
Table 1 shows an optimization of [4 + 2]-annulation product
3 using various gold and other catalysts. Our initial tests between
tert-butyl propiolate 1 and 1,2-benzisoxazole 2 (1.2 equiv) were
run with LAuCl/AgNTf2 catalysts in hot dichloroethane (DCE,
80 °C) (L = PPh3, P(OPh)3, and P(t-Bu)2(o-biphenyl), leading
to an 82−95% recovery of starting 1a (entries 1−3); herein,
target 3a was found in a small proportion (10%) in one instance.
The use of IPrAuCl/AgNTf2 greatly increased the yield of 3a up
to 77% (entry 4). A change of silver salts as in entries 5−6 (AgX,
X = OTf and SbF6) gave compound 3a in small yields (7−58%,
entries 5−6); the poor reactivity of OTf− might be attributed to
its good binding with inactive 2a (entry 7). IPrAuCl/AgNTf2 in
varied solvents gave 3a in yields, as follows: 48% in toluene, 35%
in MeCN, and 15% in 1,4-dioxane (entries 8−10) The structural
elucidation of 3a was confirmed with X-ray diffraction (CCDC-
1862119).
We assessed the scope of these [4 + 2]-annulations using
various tert-butyl propiolates 1b−1k and 1,2-benzisoxazoles
2b−2i; the results are summarized in Scheme 1. Various 4-
phenyl-substituted propiolates 1b−1e (R1 = Cl, Br, CF3, and
Me) were also applicable to deliver 6H-1,3-oxazin-6-one
derivatives 3b−3e in satisfactory yields (74−84%). To our
delight, alkyl-substituted propiolates (1f−1i; R = isopropyl, n-
butyl, cyclopropyl, and cyclohexyl) were also suitable for these
with ynamide 1′ that underwent an N-attack path to implement
[3 + 2]-annulations with anthranils 2′ (eq 2).4b We sought to
achieve new annulations between alkynes and 1,2- benzisox-
azoles 2. Here, we report two feasible reaction paths in the gold-
Received: August 21, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02663
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
C(6)-substituents (Y = Cl, Br, and Me), their gold-catalyzed
reactions furnished compounds 3o−3q in 88−92% yields
(entries 14−16). With naphtho[2,3-d]isoxazole (2h) and 5,7-
dibromo-1,2-benzisoxazole (2i), these annulations proceeded
well, affording compounds 3r and 3s in 90% and 86% yields,
respectively (entries 17−18).
Table 1. [4 + 2]-Annulations with Various Catalysts
Table 2 shows distinct gold-catalyzed reactions of ethyl
propiolate 1a′ with 1,2-benzisoxazole 2a. IPrAuCl/AgNTf2 and
b
yield (%)
temp
time
(h)
entry
catalyst
solvent
DCE
(°C)
1a
3a
a
Table 2. Effect of Ester on Chemoselectivity
1
2
Ph3PAuCl/AgNTf2
80
80
60
60
88
82
0
10
(PhO)3PAuCl/
AgNTf2
DCE
3
4
5
6
7
8
9
10
LAuCl/AgNTf2
IPrAuCl/AgNTf2
IPrAuCl/AgOTf
IPrAuCl/AgSbF6
AgNTf2
IPrAuCl/AgNTf2
IPrAuCl/AgNTf2
IPrAuCl/AgNTf2
DCE
DCE
DCE
DCE
DCE
toulene
MeCN
80
80
80
80
80
100
80
100
60
48
48
60
48
60
60
60
95
0
0
77
7
58
0
48
35
15
78
30
97
35
50
76
b
yield (%)
entry
catalyst
time (h)
1a′
4a
4a′-H
1
2
3
4
5
IPrAuCl/AgNTf2
LAuCl/AgNTf2
LAuCl/AgOTf
LAuCl/AgSbF6
AgNTf2
30
24
30
20
20
0
25
0
60
68
45
80
4
0
14
8
8
0
1,4-dioxane
a
b
1a = 0.16 M, 2a = (1.2 equiv). Product yields are reported after
purification from a silica gel column. L = P(t-Bu)2(o-biphenyl), IPr =
1,3-bis(diisopropylphenyl)imidazole-2-ylidene). DCE = 1,2-dichloro-
ethane.
24
b
96
a
1a′ = 0.11 M, 2a = (1.5 equiv). Product yields are reported after
a b
,
purification from a silica gel column. L = P(t-Bu)2(o-biphenyl). IPr =
1,3-bis(diisopropylphenyl)imidazole-2-ylidene). DCE = 1,2-dichloro-
ethane.
Scheme 1. Scope of [4 + 2]-Annulations
P(t-Bu)2(o-biphenyl)AuCl/AgNTf2 gave ethyl Z-3-phenoxya-
crylate 4a in 60% and 68% yields, respectively (entries 1−2). For
P(t-Bu)2(o-biphenyl)AuCl, various silver salts including AgOTf
and AgSbF6 greatly affected the production of desired 4a with
45% and 80% yields respectively (entries 3−4); in these
instances, we also produced ethyl Z-3-aminoacrylate 4a′-H in
minor proportions (8−14%). Again, AgNTf2 alone was
catalytically inefficient, affording product 4a in only 4% yield
(entry 5).
Scheme 2 summarizes the Michael-type reactions of ethyl
propiolates 1b′−1k′ with 1,2-benzisoxazoles 2b−2i; the former
have the same substituents as those of tert-butyl propiolates 1b−
1k to assess the reaction generality. In most instances, ethyl Z-3-
aminoacrylates 4′-H were not isolated because of their small
yields (<5%), whereas entries 5, 6, and 9 afforded 4f′-H, 4g′-H,
and 4j′-H in significant proportions (8−15%). Various aryl-
substituted propiolates (1b′−1e′, R1 = Cl, Br, CF3, Me)
afforded ethyl phenoxyacrylates 4b−4e in satisfactory yields
(71−82%) using P(t-Bu)2(o-biphenyl)AuCl/AgSbF6 (10 mol
%, entries 1−4). The molecular structure of compound 4c was
confirmed with X-ray diffraction (CCDC-1862120). Alkyl-
substituted propiolates (1f′−1i′; R = isopropyl, n-butyl,
cyclopropyl, and cyclohexyl) were also compatible with these
Michael reactions, delivering ethyl 3-phenoxyacrylates 4f−4i in
67−78% yields (entries 5−8). For alkenyl and 2-thienyl
substituted propiolates 1j′ and 1k′, their resulting products 3j
and 3k were obtained in 69% and 80% yields, respectively
(entries 9−10). These Michael reactions are applicable also to
various 1,2-benzisoxazoles 2b−2g substituted at the C(5) and
C(6) carbons (X = Cl, Br, and Me, Y = H; X = H, Y = Cl, Br, and
Me), delivering 4l−4q in 76−88% yields (entries 11−16).
Naphtho[2,3-d]isoxazole (2r) and 5,7-dibromo-1,2-benzisox-
azole (2s) were amenable to these reactions to generate desired
4r and 4s in 84% and 74% yields, respectively (entries 17−18).
a
b
1a = 0.16 M, 2a = (1.2 equiv). Product yields are reported after
purification from a silica gel column. IPr = 1,3-bis(diisopropyl-
phenyl)imidazole-2-ylidene).
annulations, rendering 6H-1,3-oxazin-6-ones 3f−3i in 64−71%
yields (entries 5−8). For alkenyl and 2-thienyl substituted
propiolates 1j and 1k, their corresponding products 3j and 3k
were obtained in 73% and 92% yields, respectively (entries 9−
10). The substrate scope was further expanded with applicable
1,2-benzisoxazoles 2b−2d substituted at the C(5)-carbon (X =
Cl, Br, Me), delivering desired compounds 3l−3n in 84−94%
yields (entries 11−13). For 1,2-benzisoxazoles 2e−2g bearing
B
DOI: 10.1021/acs.orglett.8b02663
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Organic Letters
Letter
a b
,
a decarboxylation reaction, to give compound 5e in 48% yield.
The molecular structure of compound 5e was confirmed with X-
ray diffraction (CCDC-1862121). With ethyl propiolate 1a′, its
resulting 3-phenoxyacylate 4a and 3-aminoacrylate 4a′-H might
indicate that 2-hydroxy benzonitrile 2a′ was generated as a
common intermediate for the two catalytic reactions.
Scheme 2. Scope of Michael-Type Reactions
We note that only a strong base enables the transformation of
1,2-benzisoxazole 2a into 2-hydroxybenzonitrile 2a′;8 this
preparation was achieved with K2CO3 (eq 4). Nevertheless,
treatment of ethyl propiolate 1a′ with 2-hydroxbenzonitrile 2a′
gave only 3-phenoxyacylate 4a whereas 3-aminoacrylate 4a′-H
was completely absent, which is inconsistent with our
observation in Table 2 (entries 2−4). Furthermore, we observed
that the reaction between tert-butyl propiolate 1a and 2-
hydroxybenzonitrile 2a′ with 5 mol % IPrAuCl/AgNTf2 in hot
DCE (80 °C, 48 h) afforded 6H-1,3-oxazin-6-one derivative 3a
in only 21% yield (eq 6), featuring an efficient route.
a
b
1a′ = 0.11 M, 2a = (1.5 equiv). Product yields are reported after
purification using a silica gel column. L = P(t-Bu)2(o-biphenyl).
A 6H-1,3-oxazin-6-one derivative such as 3a was versatile to
react with electron-deficient alkynes in a [4 + 2]-cycloaddition,
accompanied by a loss of CO2 (see Scheme 3).7 Species 3a was
Scheme 4 depicts a mechanism involving an initial N-attack of
1,2-benzisoxazole at gold-π-alkyne A to yield intermediate B;
Scheme 3. Functionalizations with 6H-1,3-Oxazin-6-one
Derivatives
Scheme 4. Effects of Esters on Chemoselectivity
initially acylated to form compound 5a which reacted with
diethyl but-2-ynedioate to yield 2-phenylpyridine derivative 5b.
This method was applicable to the synthesis of related derivative
5c with no prior acylation procedure. A direct reaction between
species 3a and propiolic acid afforded compound 5d in 93%
yield. Finally, treatment of species 3a with DBU (1.2 equiv)
induced an intramolecular Michael reaction to form inter-
mediate In that was subsequently hydrolyzed with water to affect
this N-attack arises from the potent nucleophilicity of the
nitrogen atom. A subsequent cyclization of species B via an ester
attack at the iminium moiety forms six-membered heterocyclic
intermediate C. We envisage that the C−H proton of species C
is acidic because dissociation of this proton enables an
aromatization to form gold-containing 6-alkoxy-1,3-oxazin-1-
ium species D or D′. For species D, a loss of the tert-butyl cation
generates stable gold-containing 6H-1,3-oxazin-6-one derivative
C
DOI: 10.1021/acs.orglett.8b02663
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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E, and, ultimately, the observed product 3a. In the case of
intermediate D′ the ethyl group is chemically stable to undergo
ring cleavage, further yielding a nitrium intermediate F. This
process rationalizes a side product such as 3-aminoacrylate 4a′-
H after hydration of this nitrilium species. A further dissociation
of this nitrilium is expected to form gold-π-alkyne species A and
2-hydroxybenzonitrile 2a′, which react with each other to afford
observed 3-phenoxyacrylate 4a.
In summary, this work reports two distinct reactions between
1,2-benzisoxazoles and propiolate derivatives. For ethyl
propiolates 1′, their gold-catalyzed reactions afford 3-phenox-
yacrylates 4 whereas tert-butyl propiolates 1 preferably undergo
[4 + 2]-nitrile annulations, further yielding 6H-1,3-oxazin-6-one
derivatives 3. Resulting [4 + 2]-annulation products 3 are further
elaborated into useful 2-phenylpyridine derivatives upon
treatment with electron-deficient alkynes. We postulate a
plausible mechanism in which the two propiolates have the
same initial steps to form gold-containing 6-alkoxy1,3-oxazin-1-
ium intermediates, which undergo distinct chemoselectivity as
effected by the alkoxy groups.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b02663.
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Experimental procedures, characterization data, and
copies of 1H and 13C NMR spectra (PDF)
Accession Codes
CCDC 1862119−1862121 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rsliu@mx.nthu.edu.tw.
ORCID
Rai-Shung Liu: 0000-0002-2011-8124
Notes
(9) For gold-catalyzed cycloadditions of alkynes, see selected reviews:
(a) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180−3211. (b) Patil, N. T.;
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Liu, R.-S. Chem. Soc. Rev. 2009, 38, 2269−2281. (d) Muratore, M. E.;
Homs, A.; Obradors, C.; Echavarren, A. M. Chem. - Asian J. 2014, 9,
3066−3082.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank the Ministry of Science and Technology and
the Ministry of Education, Taiwan, for supporting this work.
■
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