Benign catalysis with zinc: Atom-economical and divergent synthesis of nitrogen heterocycles by formal [3 + 2] annulation of isoxazoles with ynol ethers

Article abstract of DOI:10.1039/c8gc02051e

Herein, we disclose an efficient zinc-catalyzed formal [3 + 2] annulation of isoxazoles with ynol ethers under exceptionally mild reaction conditions, leading to the atom-economical and divergent synthesis of 2-alkoxyl 1H-pyrroles and 3H-pyrroles, respect

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PAPER
Benign catalysis with zinc: atom-economical and
divergent synthesis of nitrogen heterocycles by formal
[3+2] annulation of isoxazoles with ynol ethers
Cite this: DOI: 10.1039/x0xx00000x
Xin-Qi Zhu,a Han Yuan,a Qing Sun,b Bo Zhou,a Xiao-Qin Han,a Zhi-Xin Zhang,a Xin Lu*b
and Long-Wu Ye*a,c
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
Herein, we disclose an efficient zinc-catalyzed formal [3+2] annulation of isoxazoles with ynol
ethers under exceptionally mild reaction conditions, leading to the atom-economical and
divergent synthesis of 2-alkoxyl 1H-pyrroles and 3H-pyrroles, respectively. Importantly, this
zinc-catalyzed protocol demonstrates the dramatically divergent reactivity from the relevant
platinum catalysis, where the formal [4+2] annulation of isoxazoles with ynol ethers was
involved. In addition, theoretical calculations provide further evidence for the feasibility of the
www.rsc.org/
proposed reaction mechanism, especially the distinct selectivity
.
Introduction
thioethers has traditionally been far less exploited despite being
readily accessed and robust.9,10 Very recently, our group
disclosed that zinc could effectively catalyze the reaction of
isoxazoles with thioynol ethers to afford β-keto enamides, and
an unprecedented 1,2-sulfur migration was presumably
involved.11 Inspired by these results and our continuing effort
on the use of heterosubstituted alkynes for heterocycle
synthesis,12 we envisioned that the reaction of isoxazoles with
ynol ethers might also be achieved by this zinc catalysis. Herein,
we wish to report the realization of such a zinc-catalyzed
formal [3+2] annulation of isoxazoles with ynol ethers, leading
to the atom-economical and divergent synthesis of 2-alkoxyl
1H-pyrroles and 3H-pyrroles, respectively (Scheme 1b). And
Isoxazoles, as masked 1,3-dicarbonyl equivalents, have proven
to be versatile building blocks and pivotal intermediates for the
efficient construction of various valuable heterocycles.1 As a
result, numerous methods have been developed based on
isoxazoles in recent years.2 However, the relevant reactions of
isoxazoles with alkynes have seldom been explored3-7 probably
due to the relatively weak nucleophilicity of isoxazoles. In 2015,
our group reported the first catalytic reaction of isoxazoles with
alkynes, and this protocol has been utilized into the synthesis of
various 2-aminopyrroles through a gold-catalyzed formal [3+2]
annulation of isoxazoles with ynamides involving a presumable
α-imino gold carbene intermediate.3 Interestingly, a formal
[4+2] annulation of isoxazoles with ynol ethers occurred
instead in the presence of platinum as catalyst, and the
corresponding α-imino platinum carbene was presumably
generated (Scheme 1a).4 Such a protocol has also been well
exploited by Hashmi,5 Liu6 and others,7 and various efficient
gold-catalyzed annulations have been established, allowing the
facile synthesis of a range of valuable heterocycles. Despite
these findings, these catalytic annulations have been mostly
limited to noble-metal catalysts. Therefore, the exploration of
non-noble metal-catalyzed protocol for such a generation of α-
imino metal carbenes is highly desirable, not only for making
this protocol more practical, but also because it may result in a
selectivity switch for the assembly of diverse heterocycles.
Electron-rich heterosubstituted alkynes have attracted
increasing attention from the synthetic community in the past
decade due to their use in the highly efficient and regioselective
construction of valuable heterocycles. However, compared with
the ynamide chemistry,8 the chemistry of alkynyl ethers and
Scheme 1. Transition metal-catalyzed reaction of isoxazoles with ynol ethers
J. Name., 2013, 00, 1-3 | 1
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these N-heterocycles could be readily converted to valuable γ- reaction of isoxazoles with ynol ethers under platinum catalysis
lactams13 via one-pot synthesis and N-acyl 1H-pyrroles, predominantly afforded 2,5-dihydropyridines.4 Variation of the
respectively (Scheme 1b). Importantly, this zinc-catalyzed catalyst’s counteranion by switching Zn(OTf)2 to ZnCl2 and
protocol demonstrates the dramatically divergent reactivity ZnBr2 failed to further improve the yield (Table 1, entries 6–7).
from the relevant platinum catalysis, where the formal [4+2] To our delight, the reaction yield was substantially improved by
annulation of isoxazoles with ynol ethers was involved.4 employing 10 mol % Zn(OTf)2 and 20 mol % NaBArF ,15 and
4
Moreover, theoretical calculations provide further evidence for the desired 2-ethoxypyrrole 3a was formed in 87% yield (Table
the feasibility of the proposed reaction mechanism, especially 1, entry 8). Of note, NaBArF alone could not catalyze this
4
the distinct selectivity. In this paper, we wish to report the annulation (Table 1, entry 9). Gratifyingly, 3a could be
results of our detailed investigations of this zinc-catalyzed obtained at ambient temperature with a yield up to 89% (Table
reaction of isoxazoles with ynol ethers, including substrate 1, entry 10). In addition, the use of 10 mol % ZnCl2 and 20
scope, synthetic applications and mechanistic studies.
mol % NaBArF4 gave silimar yield but requiring longer reaction
time (Table 1, entry 11). Finally, it should be mentioned that
typical gold catalysts such as IPrAuNTf2 and Cy-
Results and discussion
At the outset, we used ynol ether 1a and commercial JohnPhosAuNTf2 could also catalyze this reaction, but resulting
available 3,5-dimethylisoxazole 2a as the model substrates, and in significantly decreased yields (Table 1, entries 12–13).
some of the results are listed in Table 1.14 Although 1a was
Table 2. Reaction of ynol ether 1a with different 3,5-disubstituted isoxazoles
decomposed in the presence of most non-noble metal catalysts
(Table 1, entries 1–4), we were pleased to find that the
treatment of ynol ether 1a and isoxazole 2a with Zn(OTf)2 at 80
oC afforded the corresponding [3+2] annulation product 3a
rapidly in 66% yield (Table 1, entry 5). Notably, the formation
of 2,5-dihydropyridine was not detected in this case, which is
distinctively different from our previous protocol where the
2a
Table 1. Optimization of reaction conditionsa
a Reactions run in vials; [1a] = 0.05 M; isolated yields are reported. b 5 mmol
scale, 5 mol % Zn(OTf)2 and 10 mol % NaBArF4 were used, [1a] = 0.15 M, 5
h. c -10 oC, 20 mol % Zn(OTf)2 and 40 mol % NaBArF4 were used, 12 h.
With the optimized reaction conditions in hand (Table 1,
entry 10), we explored the scope of the reaction using different
isoxazoles. As shown in Table 2, the zinc-catalyzed reaction of
ynol ether 1a with various 3,5-disubstituted isoxazoles
occurred efficiently, affording the desired 2-ethoxypyrroles
2
in
3
moderate to excellent yields. It was found that different dialkyl-
substituted isoxazoles were suitable substrates for this tandem
b
1
a Reaction conditions: [1a] = 0.05 M. Measured by H NMR using diethyl
annulation, and the corresponding 2-ethoxypyrroles 3a
–3e were
phthalate as the internal standard. 20 mol % NaBArF was added. DCE =
1,2-dichloroethane,
bis(trifluoromethyl)phenyl] borate, Ipr
c
4
NaBArF
=
sodium
tetrakis[3,5-
formed in 63–88% yields (Table 2, entries 1–5). In addition, the
4
=
1,3-bis(2,6-diisopropylphenyl) functional groups such as chloride (Table 2, entry 6) and
imidazol-2-ylidene, CyJohnPhos = 2-(dicyclohexylphosphanyl) biphenyl.
bromide (Table 2, entry 7) were well tolerated under this
annulation reaction. Then, different aryl-substituted isoxazoles
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were examined, and the reaction also proceeded well to deliver
the corresponding products 3i 3l in 66-95% yields (Table 2, extended to the reaction of ynol ether 1a with fully substituted
entries 9–12). This reaction was also extended to styryl- isoxazoles , only 3H-pyrroles 4a 4i were formed in mostly
Interestingly, when the scope of the above zinc catalysis was
–
2
–
substituted and heteroaryl-substituted isoxozoles, producing the high yields under similar reaction conditions (Table 4). Of note,
anticipated 3h (70%) and 3m (76%), respectively (Table 2, this reaction could also worked smoothly with heteroaryl-
entries 8 and 13). To further test the practicality of the current substituted and alkyl-substituted isoxazoles, which were further
catalytic system, the reaction was carried out on a gram scale transformed into the desired 4h and 4i in 72% and 33% yields,
(5.0 mmol) in the presence of 5 mol % of Zn(OTf)2 and 10 respectively (Table 4, entries 8–9). Importantly, such a zinc
mol % NaBArF , and the desired 3a was obtained in 83% yield catalysis demonstrates unique reactivity dramatically divergent
4
(1.01 g), thus highlighting the synthetic utility of this from the relevant platinum-catalyzed protocol as only the
transformation (Table 2, entry 1). Importantly, no formal [4+2] formation of 2,5-dihydropyridines was observed under
annulation was observed in all cases. The molecular structure of platinum catalysis.4
3a was further confirmed by X-ray diffraction.16
Table 4. Reaction of ynol ether 1a with different fully substituted isoxazoles
2a
Table 3. Reaction of isoxazole 2a with different ynol ethers 1a
a Reactions run in vials; [1a] = 0.05 M; isolated yields are reported.
Further synthetic transformations of the as-synthesized
products were then explored, as outlined in Scheme 2. For
a
b
example, the treatment of ynol ether 1a with isoxazoles
the optimal reaction conditions, followed by hydrolysis with
MsOH, led to the one-pot synthesis of valuable γ-lactams12 5a
2 under
Reactions run in vials; [1] = 0.05 M; isolated yields are reported. 20
mol % Zn(OTf)2 and 40 mol % NaBArF4 were used. c 17% of ynol ether was
recoveried, 10 h.
–
5c in 66–87% yields. Thus, the ether directing group can be
readily transformed into the useful carbonyl group. Moreover,
3H-pyrrole 4a could be facilely converted into the
corresponding N-acyl-protected 1H-pyrrole 6a in 82% yield via
a presumable intermolecular migration3b or intramolecular
double 1,5-migration of acyl group.17
We then extended the reaction to different ynol ethers
(Table 3). The reaction also proceeded smoothly with a variety
of aryl-substituted ynol ethers to produce the corresponding
2-alkoxylpyrroles in generally good to excellent yields
(Table 3, entries 1–10). Of note, heteroaryl-substituted ynol
ether was also compatible with this transformation, delivering
the desired 3x in 62% yield (Table 3, entry 11). In addition to
ethoxyl ynol ethers, methoxy and phenoxy ynol ethers were
also readily tolerated, leading to the efficient formation of
1
1
3
products 3y–3z in 75–78% yields (Table 3, entries 12–13).
Thus, this zinc-catalyzed formal [3+2] annulation protocol
offers a highly efficient and practical way to construct the 2-
alkoxylpyrroles.
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(via TSD2), though kinetically being the most favorable, is
highly reversible with an activation barrier of only 15.6
kcal/mol for its reverse reaction; 1,2-OEt migration (via TSD1
)
is endothermic and kinetically the most unfavorable. As such,
the formation of formal [3+2] annulation product 3a via 1,5-
cyclization is predominant and thermodynamically controlled,
demonstrating the dramatically divergent reactivity from the
relevant platinum-catalyzed protocol, where only the formation
of formal [4+2] annulation product was observed.14
Conclusions
In summary, we have developed an efficient zinc-catalyzed
formal [3+2] annulation of isoxazoles with ynol ethers under
exceptionally mild reaction conditions, leading to the atom-
economical and divergent synthesis of 2-alkoxyl 1H-pyrroles
and 3H-pyrroles, respectively. Importantly, this zinc-catalyzed
protocol demonstrates the dramatically divergent reactivity
from the relevant platinum catalysis, where the formal [4+2]
annulation of isoxazoles with ynol ethers was involved.
Moreover, the mechanistic rationale for this tandem reaction, in
particular accounting for the distinct selectivity, is well
supported by DFT computations.
Scheme 2. Synthetic applications.
Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (21772161, 21622204, 21572186
and 91545105), the President Research Funds from Xiamen
University (20720180036), NFFTBS (J1310024), and PCSIRT.
Notes and references
a
iChEM, State Key Laboratory of Physical Chemistry of Solid Surfaces
and Key Laboratory for Chemical Biology of Fujian Province, College of
Chemistry and Chemical Engineering, Xiamen University, Xiamen
361005, China.
E-mail: longwuye@xmu.edu.cn
b
iChEM, State Key Laboratory of Physical Chemistry of Solid Surfaces
Scheme 3. Plausible mechanism for zinc-catalyzed reaction of isoxazoles with
ynol ethers. Relative free energies(ΔGDCE) of key intermediates and transition
states were computed at the SMD-M06/6-31G(d,p)/LanL2DZ level of theory in
DCE solvent at 298K. Key bond lengths were shown in italic (unit: Å).
and Fujian Provincial Key Laboratory of Theoretical and Computational
Chemistry, College of Chemistry and Chemical Engineering, Xiamen
University, Xiamen 361005, China.
E-mail: xinlu@xmu.edu.cn
c
On the basis of the above experimental observations and
density functional theory (DFT) calculations,14 plausible
mechanisms for this zinc-catalyzed annulation reaction are
depicted in Scheme 3. Firstly, isoxazole 2a nucleophilically
State Key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032,
China.
†
attacks the Zn(II)-ligated ynol ether
intermediate , which is further converted into the phenyl-
stabilized carbocation intermediate upon cleavage of the
isoxazole N-O bond. Subsequently, the intermediate is
subjected competitively to either intramolecular cyclization or
1,2-OEt migration11 to furnish 5-membered ring intermediate
7-membered ring intermediate D2, and cyanide intermediate D1
respectively. Clearly, 1,5-cyclization (via TSD) is highly
exothermic (∆G = 41.9 kcal/mol) and kinetically accessible
with an activation barrier of only 10.6 kcal/mol; 1,7-cyclization
A to yield the vinyl zinc
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
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C
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,
,
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Graphical Abstract
An efficient zinc-catalyzed formal [3+2] annulation of isoxazoles with ynol ethers under room
temperature has been developed, leading to the atom-economical and divergent synthesis of
2-alkoxyl 1H-pyrroles and 3H-pyrroles, respectively. Importantly, this zinc-catalyzed protocol
demonstrates the dramatically divergent reactivity from the relevant platinum catalysis, where the
formal [4+2] annulation of isoxazoles with ynol ethers was involved.