Copper-Catalyzed [4+2]-Cycloadditions of Isoxazoles with 2-Alkynylbenzaldehydes To Access Distinct α-Carbonylnaphthalene Derivatives: C(3,4)-versus C(4,5)-Regioselectivity at Isoxazoles

Article abstract of DOI:10.1021/acscatal.9b02323

Cu(II)-catalyzed [4+2]-cycloadditions occur between Cu-benzopyryliums and substituted isoxazoles with the regioselectivity on the C(3,4)-carbons of isoxazoles. We postulate that a prior coordination of isoxazoles with Cu(OAc)₂ increases the ?-bond character of the C(3,4) carbons to become an effective 2?-donor. In this reaction sequence, 3,5-disubstituted isoxazoles yield α,?-dicarbonylnaphthalenes whereas, 5-substituted isoxazoles deliver α,?-dicarbonyl-β-aminonaphthalenes. For unsubstituted isoxazole, its cycloaddition chemoselectivity is switched to the C(4,5)-addition regioselectivity to yield α-carbonyl-?-cyanonaphthalene derivatives.

Full text of DOI:10.1021/acscatal.9b02323

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Letter
Copper-catalyzed [4+2]-Cycloadditions of Isoxazoles with 2-
Alkynyl Benzaldehydes to Access Distinct #-Carbonylnaphthalene
Derivatives: C(3,4)- versus C(4,5)-Regioselectivity at Isoxazoles
Sovan Sundar Giri, and Rai-Shung Liu
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b02323 • Publication Date (Web): 15 Jul 2019
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ACS Catalysis
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Copper-catalyzed [4+2]-Cycloadditions of Isoxazoles with 2-Alkynyl
Benzaldehydes to Access Distinct -Carbonylnaphthalene Deriva-
tives: C(3,4)- versus C(4,5)-Regioselectivity at Isoxazoles
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Sovan Sundar Giri and Rai-Shung Liu*
Frontier Research Centre on Fundamental and Applied Sciences of Matters, Department of Chemistry, National
Tsing-Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu, Taiwan 30013, R.O.C.
KEYWORDS. Cycloaddition, benzopyrylium, isoxazole, C(3,4)-carbons, 2π-donor.
ABSTRACT: Cu(II)-catalyzed [4+2]-cycloadditions occur between Cu-benzopyryliums and substituted isoxazoles with the
regioselectivity on the C(3,4)-carbons of isoxazoles. We postulate that a prior coordination of isoxazoles with Cu(OAc)2
increases the -bond character of the C(3,4) carbons to become an effective 2 donor. In this reaction sequence, 3,5-
disubstituted isoxazoles yield -dicarbonylnaphthalenes whereas, 5-substituted isoxazoles deliver -dicarbonyl--
aminonaphthalenes. For unsubstituted isoxazole, its cycloaddition chemoselectivity is switched to the C(4,5)-addition
regioselectivity to yield -carbonyl--cyanonaphthalene derivatives.
Metal-catalyzed cycloadditions emerge as powerful
tools to construct complicated carbocyclic and heterocy-
clic frameworks.1 Aromatic heterocycles such as furans are
well documented to serve as 4π-2 or 2π-donors3 to under-
go catalytic cycloadditions with -bond motifs or 1,n-
dipoles. Apart from furans, isoxazoles are appealing 4π- or
2π-donors in catalytic cycloadditions,4,5 which are acces-
sible to valuable nitroxy (N-O)-containing heterocycles.6
In the context of 2π-systems, the C(4,5)-carbons of furans
and isoxazoles are the exclusive sites for the cycloaddi-
tions without no exception (eq 1).3,5a-d The large C(3,4)
distances7 in furan (1.431 Å) and isoxazole (1.425 Å) show
small -bond character that renders difficult their C(3,4)-
cycloadditions. Eq 2 shows one example between a [4+2]-
cycloaddition of furan and gold-containing benzopy-
rylium, in which the furanyl C(2,3) carbons are the reac-
tion sites.3h Herein, we sought to develop novel cycload-
ditions at the C(3,4)-carbons of furans or isoxazoles, gen-
erating carbonyl ylide intermediates (I, eq 1).8 In chemical
reactivity, we envisage that isoxazoles are typically repre-
sented by the structure (VI, eq 5) whereas the other reso-
nance form VI’ is generally less significant. This reactivity
pattern can be altered when isoxazole is complexes with
an electrophilic catalyst to form M-VI’. To realize this
hypothesis, this work discloses Cu-catalyzed [4+2]-
cycloadditions of substituted isoxazoles with benzopy-
ryliums (III),9 in which the C(3,4) carbons of isoxazoles
are activated by Cu(II) to serve effectively as 2-donors,
naphthalene derivatives bearing useful amine, cyano and
carbonyl functionalities, further manifesting the synthetic
utility.
further delivering -dicarbonylnaphthalenes 3 and -
dicarbonyl--aminonaphthalenes 5 respectively (eq 3). In
the case of unsubstituted isoxazole, the chemoselectivity
The importance of this new catalysis is the one-pot syn-
is switched to C(4,5)-carbons to deliver -carbonyl--
thesis of 2-carbonyl-3-aminonaphthalene derivatives 5
cyanonaphthalene products 8 (eq 4). Importantly, this
that are structural cores for several bioactive molecules
catalytic system is accessible to three distinct
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ACS Catalysis
(Figure 1, I-IV).10 Rifampicin is used as an antitubercular
Page 2 of 8
one byproducts 3a” was obtained in 30% yield (see
agent10a
while
PI-083(NSC45382)10b
and
(-)-N-
Scheme s1, SI) whereas less acidic Cu(acac)2 gave unreact-
ed 1a and an alkyne hydration 3a-H in 38% and 8% yields
respectively. CuI was entirely catalytically inactive (en-
tries 2-4). With Cu(OAc)2 (10 mol %) in toluene and chlo-
robenzene, the yields of the desired product 3a were 63%
and 46% respectively (entry 5-6). Other solvents such as
DCE, acetonitrile and THF were inappropriate for this
new reaction (entries 7-9). With a 15 mol % loading of
Cu(OAc)2, our target 3a was isolated in 72% yield (entry
10). We also tested other catalysts such as
IPrAuCl/AgNTf2, Zn(OTf)2 and PtCl2, each at 10-20 mol %
loading, but our target 3a was not produced at all (entries
11-13). In the case of gold catalyst, one hydrative dimeriza-
tion of compound 1a occurred to give 3b”/3c” was isolated
in 15% and 20% as depicted in SI (Scheme s1). The molec-
ular structure of compound 3a was inferred from its rela-
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8
methylguattescidine10c serve as anticancer agents. Com-
pound IV is in phase-1 clinical trial under code name
S23906-1 for its potent cytotoxic effects.10d Notably, chem-
ical derivations of compounds 5 afford new polyaromatic
molecules that have the same structural cores as several
bioactive molecules (vide infra).
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tive 3n11 and the H NOE spectra matched well with this
1
proposed structure.
We assessed the generality of these new reactions be-
tween 2-alkynyl benzaldehydes 1 and 3,5-disubstituted
isoxazoles 2; the results are summarized in Table 2. For 2-
alkynyl benzaldehydes 1b-1c bearing various 4-
phenylalkynyl groups (R1 = 4-XC6H4, X = OMe and Cl),
their reactions with 3,5-dimethyl isoxazole 2a afforded
Figure 1. Representative bioactive molecules.
Table 1 summarizes the optimized conditions for cata-
lytic cycloadditions of 2-(phenylethynyl)benzaldehyde 1a
with 3,5-dimethylisoxazole 2a and with varied copper
catalysts. Heating this mixture (1a/2a = 1:2) in hot
Table 2. Catalytic Synthesis of α,γ-Dicarbonyl Naph-
thalenes
Table 1. [4+2]-Cycloadditions Over Various Copper
salts
yieldb (%)
catalyst
(mol%)a
T[°C]
/t[h]
entry
solvent
3a-
H
1a
3a’ 3a
1
2
CuCl2(10)
toluene
toluene
toluene
toluene
toluene
PhCl
DCE
ACN
THF
toluene
110/ 24
110/ 20
110/ 24
110/ 24
110/ 16
120/ 16
80/ 24
80/ 24
70/ 24
110/ 7
20
--
--
--
8
--
--
15
20
27
--
8
13
--
--
--
14
7
--
--
--
9
55
21
14
--
63
46
12
8
Cu(OTf)2(10)
Cu(acac)2(10)
CuI(10)
Cu(OAc)2(10)
Cu(OAc)2(10)
Cu(OAc)2(10)
Cu(OAc)2(10)
Cu(OAc)2(10)
Cu(OAc)2(15)
3
4
5
6
7
8
9
10
38
96
--
--
55
52
95
--
--
72
IPrAuCl/
AgNTf2(10)
a
b
11
DCE
80/15
--
9
--
--
1 = 0.3 M. Product yields are reported after separation
from silica column.
12
13
Zn(OTf)2(20)
PtCl2(10)
DCE
DCE
80/20
80/15
66
36
13
15
--
--
--
--
desired 3b-3c in 67% and 55% yields respectively (entries
1-2, Table 2). 2-Thienylalkynyl derivative 1d was also an
applicable substrate to yield compound 3d in 78% yield
(entry 3). Alkylalkynyl derivatives 1e and 1f (R1 = n-butyl
and cyclopropyl) reacted well with 3,5-dimethylisoxazole
2a to deliver the corresponding products 3e-3f in 55-57%
yields (entries 4-5). For 2-alkynyl benzaldehydes 1g-1i
bearing 4-phenyl substituents (X = OMe, Me and Cl),
a
b
1a = 0.3 M. Product yields are reported after separation
from silica column. DCE = 1,2-dichloroethane; ACN = ace-
tonitrile; IPr = 1,3-bis(diisopropylphenyl)-imidazol-2-ylidene.
toluene (110 °C) with CuCl2 (10 mol %) afforded 1-(4-
benzoyl-3-methylnaphthalen-2-yl) ethan-1-one 3a in 55%
yield (entry 1). A switch to Cu(OTf)2 and Cu(acac)2 deliv-
ered desired 3a in only 14-21% yields. For acidic Cu(OTf)2
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ACS Catalysis
their resulting products 3g-3i were obtained in 54-76%
Alkylalkynyl derivatives 1e-1f (R1 = n-butyl and cyclopro-
pyl) afforded desired 5c-5d in reasonable yields (36-68%,
entries 3-4). Similarly, the presence of 4-substituents at
the bridging benzene (X = OMe, Cl; Y = H) in substrates
1g and 1i were compatible with the reactions to afford the
desired products 5e-5f in 69% and 51% yields (entries 5-
6). 5-Phenyl substrates 1j and 1k (Y = Me and Cl) were
also catalytically active to produce compounds 5g and 5h
in 81% and 48% yields (entries 7-8). We tested the reac-
1
yields (entries 6-8). We also tested the reactions on 5-
phenyl derivatives 1j and 1k (Y = Me and Cl), affording
expected products 3j-3k in moderate yields (48-74%, en-
tries 9-10). In the case of benzodioxole-derived species 1l,
its reaction with 3,5-dimethylisoxazole 2a gave compound
3l in 69% yield (entry 11). We varied the 3,5-disubstituents
of isoxazoles 2b, 2c and 2d with large alkyl groups, (R3, R2
= Me, n-Bu; Et, Et and n-Bu, cyclopropyl); their corre-
sponding products 3m-3o were obtained in 58-80% yields
(entries 12-14). The molecular structure of compound 3n
was characterized with X-ray diffraction.11 For 3-
methylisoxazole 2e, its Cu-catalyzed reaction with alde-
hyde 1a afforded compound 3p in 25% yield (entry 15);
this small yield indicates the importance of a C(5)-alkyl
substituent (R2) to stabilize a carbonyl ylide I in eq 1. No-
tably, 5-phenyllisoxazole was inapplicable substrate be-
cause the phenyl is an electron-withdrawing group.
The lack of a C(3)-substituent of isoxazoles greatly af-
fects the reaction chemoselectivity. As shown in Table 3,
we performed Cu-catalyzed reactions with 5-substituted
isoxazoles 4; notably, the chemoselectivity was altered to
deliver distinct β-amino α,γ-dicarbonyl naphthalene
compounds 5 (Table 3). The Cu-catalyzed reaction of 2-
(phenylethynyl)benzaldehyde 1a with 5- methylisoxazole
4a afforded compound 5a in 76% yield whereas its tol-
ylalkynyl analogue 1m gave similar compound 5b in 71%
yield (entries 1-2).
2
3
4
5
6
7
8
9
tions on various 5-substituted isoxazoles 4b-4d (R2
=
styryl, n-butyl and benzyl), producing compounds 5i-5k
in moderate yields (32-51%, entries 9-11). The molecular
structure of compound 5k was characterized by X-ray
diffraction.11
The reaction chemoselectivity is completely altered when
unsubstituted isoxazole 2f is used to react with model
molecule 1a to afford compounds 8a and 9a in 85% and
8% yields respectively (eq 6); the former arises from a
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typical C(4,5)-cycloaddition whereas the latter follows a
novel C(3,4)-cycloaddition. The molecular structure of
compound 8a was confirmed with X-ray diffraction.11 Ac-
cordingly, the C(3,4)-cycloaddition of isoxazoles relies on
the presence of an alkyl group, especially on the C(5)-
carbon to stabilize a carbonyl ylide I (eq 1).
Table 3. Catalytic Synthesis of β-Amino α,γ-
Dicarbonyl Naphthalenes
Table 4. Cu-Catalyzed Synthesis of -Carbonyl--
cyanonaphthalenes
a
b
1 = 0.3 M. Product yields are reported after separation
from a silica column.
The value of this copper-catalyzed reaction is to provide
distinct naphthalene compounds 8 that are difficult to
prepare from other methods. For all cases, additional by-
products 9, resulting from the C(3,4)-addition in Table 4,
a
b
1 = 0.3 M. Product yields are reported after separation
from a silica column.
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ACS Catalysis
were obtained in minor proportions. We tested the reac-
Page 4 of 8
kinamycin (VII)15b. Benzo[f]quinazolines derivatives have
shown antiproliferative effect on human tumor cell lines,
whereas, fluostatins A is a selective inhibitor of the en-
zyme dipeptidyl peptidase III. Isoprekinamycin is a me-
tabolite isolated from Streptomyces murayaensis.
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tions of isoxazole 2f with 2-alkynylbenzaldehydes 1b-1d
bearing various arylalkynes (R1 = p-OMeC6H4, p-ClC6H4
and 2-thienyl), affording the desired compounds 8b-8d in
satisfactory yields (72-85%, entries 1-3). For alkylalkynyl
derivatives 1e-1f (R1 = n-butyl and cyclopropyl), their re-
sulting products 8e and 8f were in 75% and 48% yields
respectively (entries 4-5). For benzodioxole-derived spe-
cies 1l and 4-substituted phenyl benzaldehydes 1g-1i (X =
OMe, Me and Cl), their resulting cycloaddition products
8g-8j were obtained in 65-87% yields (entries 6-9). We
also prepared 2-(phenylethynyl)acetophenone 1n that
afforded the desired product 8k in 78% yield (entry 10).
The molecular structure of compound 8k was confirmed
with x-ray diffraction.11
We conducted an O18 labeling experiment on a mixture
of reactants 1a and 2a, yielding compound O18-3a bearing
only one O18 atom in ratio O16/O18 = 1.8:1 (eq 7). A loss of
18O content is due to the presence of residual water in this
system. From an analysis of the EI-MS fragmentation (see
SI), two fragments, 245.0962 (O16) and 247.1009 (O18), in
intensity ratio 2.1:1, were detected and assigned to be [M–
MeCO]+. These two fragments indicate that the 18O-atom
was labeled on the phenylketone oxygen of species O18-3a.
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For initial 13C-1a bearing 10 % c-content at the aldehyde,
13
The amine and two ketones of compound 5a enable
various chemical functionalizations. Treatment of this
compound with neat CH(OEt)3 and NH4(OAc)12 pro-
duced 1-phenyl-5-(pyrimidin-4-yl)benzo[f]quinazoline 10a
in 76% yield. The molecular structure of compound 10a
was characterized with X-ray diffraction.11 The oxidation
of compound 5a with oxone13 gave 1-phenylnaphtho[2,1-
c]isoxazol 10b in 66% yield whereas the m-CPBA oxida-
tion delivered β-nitro-α,γ-dicarbonyl naphthalene 10d in
56% yields respectively. NaBH4-reduction of species 10b
produced an ethan-1-ol derivative 10c in 91% yield. Em-
ploying a Sandmeyer reaction14 at -10 °C, compound 5a
was convertible to β-iodo-α,γ-dicarbonyl naphthalene 10e
in 91% yield. Finally, diazotization of 5a induced an in-
it resulting product 13C-3a comprised 13C-content only at
the C(4)-carbon, indicating no carbonyl migration (eq 8).
We also tested the reaction on 18O-1a bearing 25% 18O
content at its aldehyde, but its corresponding product 3a
contained no 18O-oxygen (eq 9).
tramolecular
cyclization
to
give
6-acetyl-11H-
benzo[a]fluoren-11-one 10f in 73% yield.
Scheme 1. Functionalization of One Representative
Compound 5a
Structural analysis of major products 3 or 5 indicates
that the C(3,4)-cycloadditions of isoxazoles 2 are viable
routes. A plausible mechanism is provided in Scheme 2.
Only unsubstituted isoxazole 2f (R1 = R2 = H) undergoes a
typical C(4,5)-cycloaddition (eq 6). We postulate that
Cu(OAc)2 first reacts with an isoxazole to form a complex
pair Cu-2, in which the C(3,4) bond has significant -
bond character, as shown the resonance structure Cu-2’.
An initial [4+2]-cycloaddition9 between Cu-containing
benzopyrylium A and species Cu-2 generates species B, of
which the oxonium group is attacked by water according
to an 18O-labeling experiment (eqs 7 and 9). This hydroly-
sis reaction is expected to yield species C that undergoes
dehydration to give unsaturated oxonium species D. We
postulate that the positive charge of species E locates
mainly at the benzylic carbon so that cleavage of the N-O
bond is initiated by an attack of water at the amino N-H
moiety, yielding species E for those isoxazoles 2 bearing
R2 = alkyl. An elimination of NH2OH from species E is
expected to form products 3. For C(5)-substituted isoxa-
The value of these derivation reactions provides highly
matchable cores of selected bioactive molecules such as
benzo[f]quinazolines (V), 15a fluostatins A(VI) and isopre-
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ACS Catalysis
zole 4 (R2 = H), the corresponding C(3,4)-isoxazole cy-
cloaddition affords intermediate D’ that can induce cleav-
age of a N-O bond to produce the observed products 5
through a loss of Cu(OAc)2 and a proton transfer. The
proposed complex pair Cu-2 also rationalizes the distinct
behavior of unsubstituted isoxazole 2f (eq 6), for which
formation of a complex with Cu(OAc)2 is difficult because
an alkyl group to enhance the nitrogen basicity is lacking.
Experimental procedures, characterization data, crystallog-
1
raphy data, and H NMR and 13C NMR for representative
1
2
3
4
5
6
7
compounds (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
8
9
Prof. Rai-Shung Liu
*E-mail: rsliu@mx.nthu.edu.tw
Scheme 2. A Plausible Reaction Mechanism
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ORCID
Rai-Shung Liu: 0000-0002-2011-8124
Notes
The authors declare no conflict of interest.
ACKNOWLEDGMENT
We thank the Ministry of Education (MOE106N506CE1) and
the Ministry of Science and Technology (MOST107-3017-F-
007-002),Taiwan,for financial support of this work.
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unsubstituted isoxazole 2f arises from the C(4,5)-
cycloadditions. Following a similar path, an initial [4+2]-
cycloaddition between Cu-benzopyrylium A and isoxazole
generates species G that subsequently undergoes a Cu-
assisted deprotonation through intermediate H, yielding
species I and ultimately the observed product through an
aromatization.
In summary, this work reports the first success for Cu-
catalyzed [4+2]-cycloadditions16 of benzopyryliums with
substituted isoxazoles, in which the regioselectivity of
isoxazoles occurs on the C(3,4)-carbons. This chemoselec-
tivity is astonishing because the C(3,4) bond of isoxazoles
has little -bond character. We postulate that a prior
bonding of isoxazoles with Cu(OAc)2 activates the C(3,4)
bond via an increased -bond character. In this reaction
sequence, 2,5-disubstituted isoxazoles afford -
dicarbonylnaphthalenes whereas 5-substituted isoxazoles
afford -dicarbonyl--aminonaphthalenes. In the case
of unsubstituted isoxazole, a typical C(4,5)-addition regi-
oselectivity is observed with formation of -ketonyl--
cyanonaphthalenes. The use of one 2-alkynyl benzalde-
hyde to access three distinct classes of highly functional-
ized naphthalene products highlights the synthetic utility.
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