Development of Gold-catalyzed [4+1] and [2+2+1]/[4+2] Annulations between Propiolate Derivatives and Isoxazoles

Article abstract of DOI:10.1002/anie.201610665

Two new gold-catalyzed annulations of isoxazoles with propiolates have been developed. Most isoxazoles follow an initial O attack on the alkyne to afford a [4+1] annulation product. This process results in a remarkable alkyne cleavage of initial propiolates. Unsubstituted isoxazoles proceed through an N attack step to yield formal [2+2+1]/[4+2] annulation products. These two annulation products arise initially from two seven-membered heterocyclic intermediates, which then lead to products.

Full text of DOI:10.1002/anie.201610665

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201610665
German Edition: DOI: 10.1002/ange.201610665
Heterocycles
Development of Gold-catalyzed [4+1] and [2+2+1]/[4+2]
Annulations between Propiolate Derivatives and Isoxazoles
Rajkumar Lalji Sahani and Rai-Shung Liu*
Abstract: Two new gold-catalyzed annulations of isoxazoles
with propiolates have been developed. Most isoxazoles follow
an initial O attack on the alkyne to afford a [4+1] annulation
product. This process results in a remarkable alkyne cleavage
of initial propiolates. Unsubstituted isoxazoles proceed
through an N attack step to yield formal [2+2+1]/[4+2]
annulation products. These two annulation products arise
initially from two seven-membered heterocyclic intermediates,
which then lead to products.
seven-membered heterocyclic intermediates, as depicted in
Equations (3) and (4).
G
old-catalyzed annulations of alkynes with weak nucleo-
philes are powerful tools to access highly functionalized
carbo- or heterocycles.[1] These reactions focus intensively on
electron-rich ynamides,[2] and recently on electron-deficient
propiolates.[3] Isoxazoles are important aromatic heterocycles
which exist in many bioactive molecules.[4] Because of their
easy synthesis, isoxazoles prove to be versatile three-atom
building units in various catalytic annulations,[5–7] thus yield-
ing useful azacycles with molecular complexity. Manning and
Davies reported the first instance in rhodium-catalyzed [3+3]
annulations of isoxazoles with alkenyldiazo species to afford
highly substituted 3-carbonylpyridine derivatives.[5a] In the
context of ynamides, Ye and co-workers report a series of
catalytic [3+2] annulations to access 4-carbonyl-2-amino-
pyrroles [Eq. (1); PG = protecting group].[6] Hashmi and co-
workers reported distinct [3+2] annulations of ynamides with
benzo[c]isoxazoles to form 2-amino-4-carbonylindoles
[Eq. (2)].[7] These annulations involve an N attack to generate
gold iminocarbenes to facilitate aza-Nazarov reactions
[Eqs. (1) and (2)]. We seek new annulations of isoxazoles
with alkynes beyond three-atom building units. This work
reports two distinct annulations between isoxazoles and
propiolates, thus yielding 2,4-dicarbonylpyrroles [Eq. (3)]
and 3,8-dicarbonylimidazo[1,2-a]pyridines [Eq. (4)], respec-
tively. The chemoselectivity depends on the types of initial
isoxazoles. In the new [4+1] annulation, a cleavage of the
alkyne of initial propionates occurred[8,9] with an unexpected
O attack of isoxazoles. Particularly interesting is the trimo-
lecular process in Equation (4), which assembles one discrete
propiolate and two discrete isoxazoles through a formal
[2+2+1]/[4+2] annulation. The attack of isoxazoles follows
a N-attack path. Notably, analysis of our annulation products
suggests that the key intermediates likely involve two distinct
The importance of these new annulations is to provide
facile access to a series of well-known bioactive molecules (I–
VII), as depicted in Figure 1.[10,11] For the 2,4-dicarbonylpyr-
role-containing molecules, sunitinib and RWJ 37868 serve as
tyrosine kinase inhibitor and anticonvulsant agents, respec-
tively, whereas III is a MEK inhibitor.[10] For the 3,8-
dicarbonylimidazo[1,2-a]pyridine representatives, zolpidem
and GSK812397 were used to treat insomnia and HIV
[*] R. L. Sahani, Prof. Dr. R.-S. Liu
Department of Chemistry, National Tsing-Hua University
Hsinchu (Taiwan, ROC)
E-mail: rsliu@mx.nthu.edu.tw
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201610665.
Figure 1. Representative bioactive molecules.
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Table 2: [4+1] annulations with various propiolates and isoxazoles.
infections, respectively, and saripidem and nicopidem were
sedative and anxiolytic agents, respectively.[11]
Table 1 shows the optimization of the [4+1] annulation
product 3a using various gold catalysts. With various LAuCl/
AgNTf2 catalysts [L = P(OPh)3, IPr, PPh3, and P(tBu)2(o-
biphenyl), 5 mol%], our initial tests of the reactions between
the propiolate 1a with isoxazole 2a (2 equiv) in DCE at 358C
Table 1: Reactions over various gold catalysts.
Entry
Catalyst (mol%)[a]
T [8C]
t [h]
Yield [%][b]
1a
3a
1
2
3
4
5
6
7
8
L’AuCl/AgNTf2 (5)[c]
IPrAuCl/AgNTf2 (5)
PPh3AuCl/AgNTf2 (5)
LAuCl/AgNTf2 (5)[c]
IPrAuCl/AgNTf2 (5)
IPrAuCl/AgNTf2 (10)
IPrAuCl/AgSbF6 (10)
IPrAuCl/AgOTf (10)
IPrAuCl/AgNTf2 (10)[d]
AgNTf2 (10)
35
35
35
35
80
80
80
80
80
80
80
24
24
24
24
24
12
24
24
12
12
12
90
75
85
80
40
–
65
55
–
–
20
traces
traces
55
82
30
40
80
[a] [1a]=0.15m, 2a (1.2 equiv). [b] Product yields are reported after
purification from a silica column.
9
10
11
95
95
–
–
–
the 3-thienyl-substituted analogue 1 f to yield the desired 3 f
in 75%. Alkyl-substituted propiolates (1g–i) proved to very
suitable to such annulations, thus yielding the pyrrole
derivatives 3g–i in 82–95% yields. For the alkenyl substrate
1j, its resulting pyrrole 3j was produced with 45% yield. We
varied the esters of the propiolates as in 1k and 1l, thus
affording the pyrroles 3k (60%) and 3l (85%), respectively.
For varied 3,5-disubstituted pyrroles (2b–d), their annula-
tions yielded the desired compounds 3m–o in 65–80% yields,
thus increasing the sizes of R1 and R2 were more favorable for
the side products 3m’–o’. We prepared one alkynylketone
derivative (1p) which gave the desired 3p in 25% yield,
together with the 2-carbonylpyrrole 3p’ in 45% yield.
[a] [1a]=0.15m, 2a (2 equiv) for entries 1–8 and 10–11. [b] Product
yields are reported for products isolated after purification from a silica
column. [c] L’=P(OPh)3, L=P(tBu)2(o-biphenyl). [d] Used 1.2 equiv of
2a. DCE=1,2-dichloroethane, IPr=1,3-bis(diisopropylphenyl)imid-
azole-2-ylidene), Tf=trifluoromethanesulfonyl.
gave disappointing results except for IPrAuCl/AgNTf2, which
afforded the desired 3a in 20% yield (entries 1–4). At 808C,
IPrAuCl/AgNTf2 gave this annulation product with an
increased yield of about 55% (entry 5). A high loading
(10 mol%) of this gold catalyst increased the yield of 3a up to
82% (entry 6). A change of counter anions with AgSbF6 and
AgOTf gave 3a in 30 and 40% yields, respectively (entries 7
and 8). When a ratio of 2a/1a = 1.2 was used, the yield of 3a
was nearly unaffected to reflect a high atom economy. No
reaction occurred with either AgNTf2 alone or in the absence
of catalyst (entries 10 and 11). The molecular structure of 3a
was inferred from X-ray diffraction studies of their analogues
3b and 3i (see Table 2).[12] An astonishing feature is
a structural rearrangement of 3a, including complete cleavage
The substituent on the isoxazoles could seriously affect
the chemoselectivity of reactions. 5-Methylisoxazole (2e)
followed the known [3+2] annulation [Eq. (1)] to afford the
pyrrole 4q in 72% yield [Eq. (5)]. Its structure was confirmed
1
by H NOE experiments. In contrast, 3-methylisoxazole (2 f)
yielded our new [4+1] annulation species 3r as the major
product [Eq. (6)]. Accordingly, the 5-methyl moiety of
isoxazole impedes the O-attack regioselectivity whereas its
3-methyl suppresses the N-attack pathway, thus reflecting
steric effects.
More striking are the trimolecular reactions of the
unsubstituted isoxazole 2g to afford 3,8-dicarbonylimidazo-
[1,2-a]pyridines (5), as depicted in Table 3. In several
instances, the byproducts 4, as reported in Yeꢀs work
[Eq. (1)],[6a] were isolated in minor proportions (15–27%).
The structure of one compound, 4e, was confirmed by X-ray
diffraction studies.[12] The major products 5 arose from
a trimolecular process, including one discrete propiolate and
two discrete isoxazoles (2g). The molecular structures of 5b
and 5e were determined by X-ray diffraction studies.[12] For
various phenyl-substituted propiolates [R = 4-XC6H4, X = H
=
ꢀ
of initial alkyne moiety to yield a tBuO(O C) C fragment to
construct a pyrrole ring.
We assessed the scope of reactions using various propio-
lates and 3,5-disubstituted isoxazoles and the results are
summarized in Table 2. Besides the target 3, side products,
such as the 2-carbonylpyrrole 3’, were produced in some
instances. Molecular structures of representative products 3b
and 3i have been confirmed by X-ray diffraction studies.[12]
Various aryl-substituted tert-butyl propiolates (1b–e; R = 4-
XC6H4, X = Br, Cl, OMe, and Me) were also effective
substrates and delivered the [4+1] annulation products 3b–
e in satisfactory yields. The reaction was also compatible with
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We postulate a mechanism in Scheme 1 to rationalize the
[4+1] annulations, and it involves an initial O attack of
isoxazole on the propiolates. We envisage that the vinylgold
fragment of the intermediate B accelerates a ring expansion
to form the seven-membered heterocyclic intermediates C via
gold carbene intermediates (B’) to furnish a [5+2] annulation,
as depicted by the A!C transformation. Gold enolates (C)
enable an intramolecular cyclization to generate the five-
membered azacycle E via intermediates C and C’. A consec-
utive 1,5-acyl shift[13] of E forms F, thus ultimately generating
our observed product 3a through a consecutive 1,5-hydrogen
shift.
Table 3: Cascade [4+1]- and [2+2+1]/[4+2]-annulations.
Scheme 1. A postulated mechanism for 2,4-dicarbonylpyrroles.
[a] [1a]=0.15m, 2g (4.0 equiv). [b] Product yields are reported after
purification from a silica column.
The mechanism of formation of the imidazo[1,2-a]pyr-
idines 5 from 2g is also deducible through an initial [5+2]
annulation, as depicted by the A!C’’ transformation
(Scheme 2). This process involves a distinct N attack of 2g
on A following a stepwise mechanism as for the A!C
transformation. The resulting cyclic 2-azaallenium C’’ is better
represented by the resonance form G, which can be trapped
by a second isoxazole to furnish the [4+2] cycloaddition
species H. An aromatization of this species by a loss of water
forms a-iminogold carbenes (I) which are attacked by the
tethered pyridine to enable a cyclization to yield observed
products 5 via the intermediate J.
Most isoxazoles in this work afford 2,4-dicarbonylpyrroles
(3) from the O-attack pathway, and this process is surprising
because the oxygen atom of isoxazole is relatively weak in
nucleophilicity compare to the nitrogen center. This outcome
might be rationalized if a reversible equilibrium exists
between two heterocyclic intermediates C and G, as only
the former can undergo a ring cleavage to give pyrrole
precursor E. Alternatively, 2g is a potent heterodiene for
undergoing a [4+2] cycloaddition with its corresponding
(1a), Br (1b), and OMe (1d)], their resulting imidazo[1,2-
a]pyridines 5a–c were obtained in 65–72% yield. These
imidazo[1,2-a]pyridine syntheses were additionally compat-
ible with the 3-thienyl-substituted propiolate 1 f and several
alkyl- and alkenyl-substituted propiolates (1h–j, and 1m; R =
cyclopropyl, n-butyl, isopropyl, and 1-methylvinyl) to afford
the desired 5d–h in 61–70% yields. Another ester-like ethyl
cyclopropylpropiolate (1l) was also an applicable substrate to
yield the imidazo[1,2-a]pyridine 5i in 75% yield.
Equations (7) and (8) show the control experiments used
to elucidate the mechanism of formation of 3. In a crossover
experiment [Eq. (7)], only two products, 3i and 3s, were
produced from a 1:1 mixture of 1q and 1i. In the presence of
H2*O (*O = 18O, 3 equiv), the annulation between 1i and 2a
yielded 18O-free 2,4-dicarbonylpyrrole 3i [Eq. (8)], thus
suggesting isoxazole is the oxygen source of its cyclopropyl-
ketone group.
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intermediate G, thus yielding the imidazo[1,2-a]pyridines 5
instead.
In summary, we report two new gold-catalyzed annula-
tions between isoxazoles and propiolates. Most isoxazoles
follow an O-attack pathway to enable [4+1] annulations to
yield 2,4-dicarbonylpyrroles.[14] This process results in a cleav-
age of the alkyne of initial propiolates. Unsubstituted
isoxazole follows an N-attack pathway to effect [2+2+1]/
[4+2] annulations to afford 3,8-dicarbonylimidazo[1,2-a]pyr-
idines. The initial step involves an N-attack regioselectivity.
These resulting azacycles are present in many bioactive
molecules. We postulate that these O and N attacks generate
two seven-membered heterocyclic intermediates initially,
each of which lead to distinct annulation products.
Acknowledgements
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We thank Ministry of Science and Technology, Taiwan for
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Conflict of interest
The authors declare no conflict of interest.
Keywords: annulations · gold · heterocycles ·
reaction mechanisms · structure elucidation
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Manuscript received: November 1, 2016
Final Article published: && &&, &&&&
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Communications
Heterocycles
Plan of attack: Two new gold-catalyzed
annulations of isoxazoles with propio-
lates have been developed, including
[4+1] annulations for most isoxazoles,
and formal [2+2+1]/[4+2] annulations
for unsubstituted isoxazoles. The differ-
ent annulations arise initially from differ-
ent attacks, N or O, by the isoxazoles on
the propiolate.
R. L. Sahani, R.-S. Liu*
&&&& — &&&&
Development of Gold-catalyzed [4+1]
and [2+2+1]/[4+2] Annulations between
Propiolate Derivatives and Isoxazoles
6
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