Ru-Catalyzed [3 + 2] Cycloaddition of Nitrile Oxides and Electron-Rich Alkynes with Reversed Regioselectivity

Article abstract of DOI:10.1021/acs.orglett.1c00273

Polarity reversal ("umpolung") of a functional group can override its inherent reactivity and lead to distinct bond-forming modes. Herein we describe a rarely studied cycloaddition between nitrile oxides and electron-rich alkynes with reversed regioselect

Full text of DOI:10.1021/acs.orglett.1c00273

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Letter
Ru-Catalyzed [3 + 2] Cycloaddition of Nitrile Oxides and Electron-
Rich Alkynes with Reversed Regioselectivity
Qiang Feng, Hai Huang, and Jianwei Sun*
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ABSTRACT: Polarity reversal (“umpolung”) of a functional group
can override its inherent reactivity and lead to distinct bond-
forming modes. Herein we describe a rarely studied cycloaddition
between nitrile oxides and electron-rich alkynes with reversed
regioselectivity, leading to the useful 4-heterosubstituted isoxazoles.
The use of a ruthenium catalyst completely overrides the inherent
polarity of nitrile oxides. This reversed regioselectivity was also
observed for their reactions with a range of electron-deficient
alkynes.
olarity reversal (“umpolung”) is a powerful strategy that
enables a functional group to reverse its polarity and
thermal conditions. A mild catalytic protocol with high
regiocontrol remains undeveloped.
P
override its inherent reactivity, resulting in a distinct bond-
forming mode.1 In the past half century or so, this concept has
underwent significant development.1a A number of functional
groups can exhibit this type of umpolung by either
stoichiometric or catalytic manipulation, among which the
carbonyl group is probably the most studied. For example, a
carbonyl group can be rendered nucleophilic by converting
into dithiane or other acyl anion equivalents by means of
cyanide or N-heterocyclic carbene catalysis (Scheme 1a).
Recently, Deng and co-workers have also demonstrated an
elegant example of organocatalytic asymmetric umpolung of
imine functionality.1j Despite such impressive progress in the
studies of umpolung reactivity, functional groups capable of
umpolung are rather limited. Moreover, the majority of current
catalytic examples are based on organocatalysis. The develop-
ment of metal-catalyzed umpolung reactions remains in high
demand.
Nitrile oxide is a versatile functionality that can participate in
various dipolar cycloaddition reactions for the synthesis of a
wide range of heterocycles.2−4 In particular, its cycloaddition
with terminal alkynes to form isoxazoles has been well-
studied.3−5 However, cycloaddition of nitrile oxides is
relatively difficult to control regarding chemoselectivity and
regioselectivity, which is partly due to the typical requirement
for in situ generation of this reactive nitrile oxide intermediate
and its facile dimerization.2,6
The innate reactivity of nitrile oxide normally engages the
oxygen motif as the nucleophilic site and the carbon as the
electrophilic unit.2−7 Therefore, the regioselectivity of their
thermal [3 + 2] cycloaddition with polarized alkynes is
inherently governed by matching the well-defined polarity of
the alkyne triple bond (Scheme 1b). Thus, in the few thermal
reactions with electron-rich alkynes (e.g., thioalkynes, yn-
amines), the 5-heterosubstituted isoxazoles were formed as the
major regiosiomer (Scheme 1b).7 However, 4-heterosubsti-
tuted isoxazoles, the opposite regioisomer, are important
subunits in biologically active molecules that lack efficient
access (e.g., I−III, Scheme 1c).8 Thus, the development of
such an efficient cycloaddition process with reversed
regioselectivity would be highly useful.
In continuation of our interest in electron-rich alkynes,
particularly for cycloaddition,9 we began this study with
internal thioalkyne 1a as the model substrate.10 N-Hydrox-
ybenzimidoyl chloride 2a was employed as the model
precursor for the in situ generation of nitrile oxide in the
presence of base Et3N. In the absence of a catalyst, the reaction
using DCE as solvent did not lead to any isoxazole formation
(Table 1, entry 1). Instead, dimerization of the nitrile oxide
was observed as the major pathway. Next, we evaluated various
transition-metal-based catalysts that proved effective for similar
cycloadditions.2−8 While most of these catalysts still led to only
Nevertheless, significant progress has been achieved. For
example, Fokin and co-workers have pioneered copper- and
ruthenium-catalyzed systems that provided complementary
regioselectivity for terminal alkynes and haloalkynes.3a−c,4f In
contrast, cycloaddition of nitrile oxides with electron-rich
alkynes have not been systematically studied.7 Current
sporadic examples mostly focus on terminal ones under
Received: January 24, 2021
Published: March 22, 2021
https://doi.org/10.1021/acs.orglett.1c00273
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2431−2436
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structure of 3a was confirmed by X-ray crystallography. After
further considerable efforts in screening various ruthenium-
based catalysts, we were able to identify [CpRu]-based
catalysts CpRu(MeCN)3PF6 and CpRu(cod)Cl as the superior
catalysts, giving essentially the same yields (entries 11−12).
The commercially more accessible catalyst CpRu(MeCN)3PF6
was used for further optimization.
Scheme 1. Introduction to Umpolung of Nitrile Oxides for
Cycloaddition with Electron-Rich Alkynes
Next, different solvents were compared (entries 13−16).
Although protic solvents were less effective, the aprotic polar
solvent MeCN could slightly improve the efficiency (entry 16).
Finally, the use of a lower concentration further improved the
reaction yield to 92% (entry 17). It is worth noting that this
reaction exhibited complete regioselectivity opposite to the
thermal condition.
With the optimized conditions, we examined the reaction
scope. As shown in Table 2, a diverse range of internal
a
Table 2. Reaction Scope
a
Table 1. Condition Optimization
b
entry
catalyst
solvent
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
yield (%)
1
2
3
4
5
6
7
8
−
<5
<5
<5
<5
<5
<5
<5
55
14
31
79 (76)
80
75
23
65
CuSO4·5H2O
Ni(cod)2
Pd(PPh3)4
Rh(cod)Cl2
[Ir(cod)Cl2]2
Ru(cod)Cl2
Cp*Ru(cod)Cl
Cp*Ru(PPh3)2Cl
Cp*Ru(MeCN)3PF6
CpRu(MeCN)3PF6
CpRu(cod)Cl
CpRu(MeCN)3PF6
CpRu(MeCN)3PF6
CpRu(MeCN)3PF6
CpRu(MeCN)3PF6
CpRu(MeCN)3PF6
9
10
11
12
13
14
15
16
c
THF
MeOH
1,4-dioxane
MeCN
a
Reaction scale: 1 (0.2 mmol), 2 (0.3 mmol), Et3N (0.3 mmol),
b
c
84
92
MeCN (4.0 mL). Isolated yield. Run at 5.0 mmol scale.
d
17
MeCN
a
b
Reaction scale: 1a (0.1 mmol), 2a (0.15 mmol). Yield was based on
thioalkynes participated smoothly in the mild intermolecular
cycloaddition reactions to provide the 3,4,5-trisubstituted
isoxazoles bearing a 4-sulfenyl group with good to excellent
efficiency (entries 1−17). Both aliphatic and aromatic
substituents on the thioalkynes were suitable substrates.
Moreover, electron-donating and electron-withdrawing groups
on the thioalkynes did not show obvious influence on the
1H NMR analysis of the crude mixture using mesitylene as the
internal standard. Isolated yield. Run at 0.05 M concentration.
c
d
dimerization of the nitrile oxide (entries 2−7), we were
pleased to find that the [Cp*Ru]-based system could lead to
isoxazole 3a, albeit with low efficiency (entries 8−10). The
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reaction efficiency. A thiophene heterocycle could also be
successfully incorporated in the isoxazole product. In addition,
this protocol was also amenable to various hydroximoyl
chlorides with different electronic properties, including an
alkenyl-substituted example (entries 18−22). The reaction was
equally efficient at gram scale (entry 10). Moreover, all these
reactions produced only one regioisomer.
In addition to electron-rich alkynes, we were also curious
about whether this selectivity switch is general toward electron-
deficient alkynes. For direct comparison, we set up both
thermal (uncatalyzed) and ruthenium-catalyzed reactions for
the same pair of substrates (Table 4). Indeed, a complete
Table 4. Regioselectivity Switch on Electron-Deficient
a
Intrigued by the above success with thioalkynes, we further
extended this protocol to other electron-rich alkynes. Indeed,
direct use of the above standard conditions for the reaction
between ynol ether 4a (R1 = m-tolyl) and hydroximoyl
chloride 2a could give the desired isoxazole 5a, but only with
moderate efficiency (42% NMR yield; see the Supporting
Information (SI) for details). The low yield was mainly due to
the competing dimerization of the nitrile oxide. Next, we
further optimized the conditions (see the SI for details). By
replacing the solvent with 1,4-dioxane, the reaction yield could
be improved to 75%. As solvents can influence the reaction
rates of the desired cycloaddition and the competing
dimerization of nitril oxide differently, the superior perform-
ance of 1,4-dioxane in this case might originate from the
change in this rate comparison. Next, various ynol ethers and
nitrile oxide precursors were examined, and they all provided
the desired 4-alkoxyl isoxazoles with moderate to good yields
(Table 3). Again, only one regioisomer was observed in these
Alkynes
a
Table 3. Reaction of Ynol Ethers
a
Condition A: alkyne (0.2 mmol), 2a (0.5 mmol), Et3N (0.5 mmol),
and Et2O (8 mL), rt, 48 h; Condition B: standard conditions as
shown in Table 2, except that THF was used as solvent. Isolated yield.
b
c
Run with MeCN as solvent. The alkyne was recovered.
a
Reaction scale: 4 (0.2 mmol), 2 (0.3 mmol), Et3N (0.3 mmol), 1,4-
b
dioxane (4.0 mL). Isolated yield.
switch of regioselectivity was also observed with all these
electron-poor alkynes, including alkynyl sulfone, ester, ketone,
aldehyde, and phosphonate.11 Under thermal conditions
(condition A), the matched innate polarity of the two partners
led to isomers 8 bearing the electron-withdrawing group on the
4-position.4 In contrast, with Ru-catalysis, isoxazoles 9 with the
electron-withdrawing group on the 5-position were uniformly
generated with high efficency and regio ratio (rr). These results
indicate that the Ru-catalyzed umpolung reactivity of nitrile
oxides is indeed general.
A possible reaction mechanism is proposed to rationalize the
reactivity and regioselectivity employing electron-rich alkynes
as an example (Scheme 3). We believe that the catalytic cycle
begins with complexation of ruthenium with both alkyne and
nitrile oxide.3c The resulting complex A has several features:
(1) The nitrile oxide coordinates with the carbon center rather
than the oxygen center, presumably due to the relatively soft
nature of ruthenium. (2) The presence of the positive charge
on the nitrogen in A may easily lead to back-donation from the
ruthenium center to form the ruthenium carbene resonance
cases. In addition to thioalkynes and ynol ethers, ynamide 6
could also participate in this cycloaddition but with moderate
regioselectivity, favoring the umpolung 4-amino isoxazole 7
(Scheme 2). The relatively low regioselectivity might be due to
either the lower polarization of the triple bond and/or the
weak coordination ability of sulfinamide unit (vide infra).
Scheme 2. Reaction of Ynamide 6
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such highly functionalized stereodefined aminosufenyl olefins
are useful structural units in bioactive molecules and their
synthesis has been an important topic in organic synthesis.13
In summary, we have developed an efficient [3 + 2]
cycloaddition of nitrile oxides with electron-rich alkynes,
including thioalkynes, ynol ethers, and ynamides. Different
from the thermal condition, the ruthenium-catalyzed protocol
leads to opposite regioselectivity, providing efficient and mild
access to a diverse range of useful 4-heterosubstituted
isoxazoles. The observed excellent regioselectivity could be
explained by the polarization of the alkyne triple bond as well
as the additional complexation of the heteroatom with the
ruthenium. In addition to electron-rich alkynes, the ruthenium-
induced polarity reversal of nitrile oxides was also applied to
the regiodivergent cycloaddition with various electron-deficient
alkynes with high efficiency and selectivity.
Scheme 3. Proposed Mechanism
ASSOCIATED CONTENT
■
structure A′, thus minimizing charge separation. (3) Such a
bonding mode between nitrile oxide and ruthenium alters the
electronic property of the nitrile oxide, leading to subsequent
nucleophilic attack onto the oxygen center, rather than the
original electrophilic carbon center. Next, an oxidative
cyclization step takes place to form Ru-heterocycle B, in
which the more nucleophilic β carbon of the alkyne approaches
the oxygen atom. This step can also be regarded as a Diels−
Alder-type [4 + 2] cycloaddition from the Ru-carbene
resonance structure A′. Finally, a reductive elimination step
forms the product via C and regenerates the active catalyst. For
electron-rich alkynes, there might be additional coordination of
the heteroatom (O, S, or N) on the alkyne to the ruthenium
center, as shown in intermediate B. This interaction may help
stabilize this intermediate and thus enhance the reactivity and
regioselectivity, particularly in the case of thioalkynes.
Aiming to further improve the standard protocol, in which a
base has to be used, we employed 4 Å molecular sieves to
replace the base Et3N to mediate the in situ generation of
nitrile oxide. Gratifyingly, the reaction of 1a and 2a also
proceeded efficiently to form the same product 3a in 72% yield
(Scheme 4).12 Thus, this nearly neutral condition could
provide complementary utility when needed.
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00273.
Experimental procedures and NMR spectra (PDF)
Accession Codes
CCDC 1914523 and 1935590 contain 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.
AUTHOR INFORMATION
■
Corresponding Author
Jianwei Sun − Jiangsu Key Laboratory of Advanced Catalytic
Materials & Technology, School of Petrochemical
Engineering, Changzhou University, Changzhou 213164,
China; Department of Chemistry, The Hong Kong University
of Science and Technology, Kowloon, China; orcid.org/
0000-0002-2470-1077; Email: sunjw@ust.hk
Authors
Scheme 4. Reaction without Et3N
Qiang Feng − Jiangsu Key Laboratory of Advanced Catalytic
Materials & Technology, School of Petrochemical
Engineering, Changzhou University, Changzhou 213164,
China; Department of Chemistry, The Hong Kong University
of Science and Technology, Kowloon, China; orcid.org/
0000-0002-7032-0451
Hai Huang − Jiangsu Key Laboratory of Advanced Catalytic
Materials & Technology, School of Petrochemical
Engineering, Changzhou University, Changzhou 213164,
China
The 4-sulfenyl product 3a could be easily oxidized by
mCPBA to provide sulfone 8a (Scheme 5), whose identity was
confirmed to be the same as that obtained in entry 1 of Table
4. Moreover, the isoxazole product could undergo ring opening
smoothly under Ni-catalyzed hydrogenation conditions to
provide highly functionalized enone 10. It is worth noting that
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00273
Notes
Scheme 5. Product Derivatizations
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the NSFC (22071210,
91956114) and Hong Kong RGC (16302719) and Jiangsu
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