Copper(0)/PPh3-Mediated Bisheteroannulations of o-Nitroalkynes with Methylketoximes Accessing Pyrazo-Fused Pseudoindoxyls

Article abstract of DOI:10.1021/acs.orglett.0c02180

A copper(0)/PPh3-mediated cascade bisheteroannulation reaction of o-nitroalkynes with methylketoximes has been developed that provides viable access to a diverse range of pyrazo-fused pseudoindoxyl compounds. Synthetically useful functional groups including sensitive C-I bonds are compatible with this system. Mechanistic studies suggest a reaction cascade involving sequential PPh3-mediated deoxygenative cycloisomerization and copper-catalyzed [3 + 2] pyrazo-annulation.

Full text of DOI:10.1021/acs.orglett.0c02180

pubs.acs.org/OrgLett
Letter
Copper(0)/PPh3‑Mediated Bisheteroannulations of o‑Nitroalkynes
with Methylketoximes Accessing Pyrazo-Fused Pseudoindoxyls
Huanxin Meng,† Zhenhua Xu,† Zhonghua Qu, Huawen Huang,* and Guo-Jun Deng*
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ABSTRACT: A copper(0)/PPh3-mediated cascade bisheteroan-
nulation reaction of o-nitroalkynes with methylketoximes has been
developed that provides viable access to a diverse range of pyrazo-
fused pseudoindoxyl compounds. Synthetically useful functional
groups including sensitive C−I bonds are compatible with this
system. Mechanistic studies suggest a reaction cascade involving
sequential PPh3-mediated deoxygenative cycloisomerization and
copper-catalyzed [3 + 2] pyrazo-annulation.
itrogen-containing heterocycles are privileged core
cycloisomerization of o-nitroalkynes was ingeniously designed
Nskeletons that continually constitute key units of to initiate cascade reactions in both intramolecular and
intermolecular manners. Hence, transformations involving o-
nitroalkyne cycloisomerization followed by nucleophilic
addition (Figure 2a),5 1,3-dipolar cycloaddition (Figure 2b),6
numerous naturally occurring alkaloids and pharmacologically
active compounds. Specifically, pseudoindoxyls featuring the
2,2-disubstituted indolin-3-one core structure appear in diverse
pharmaceutical agents such as Halichrome A, LipidGreen,
Cephalinone, isatisine A, and Duocarmycins A, etc. (Figure
1).1 Consequently, the development of synthetic methods for
pseudoindoxyl formation has drawn considerable interest in
molecular synthesis.2
Figure 2. Pseudoindoxyl formation by cascade cycloisomerization
reactions of o-nitroalkynes.
and radical addition (Figure 2c)7 have been achieved to
provide viable access to diverse pseudoindoxyls. Of them,
stereoselectivity of the quaternary carbon could also be
successfully controlled.5a,6a,c With the well-established imino
radical formation from ketoximes to construct nitrogen-
containing heterocycles,8 we proposed a cascade reaction
involving o-nitroalkyne cycloisomerization and subsequent
radical addition/pyrazole annulations through copper-medi-
ated N−N bond formation. The key challenge of this domino
transformation should be to capture the formal conflict
between the initial reductive cycloisomerization and the
Figure 1. Valuable indolin-3-one molecules.
Indole oxidation to indol-3-ols followed by a semipinacol
rearrangement provides a powerful route to 2,2-disubstituted
indolin-3-ones.3 In the past decade, a number of mild and
sustainable oxidative systems have been developed to enable
effective methods for this event.4 Alternatively, the intra-
molecular cyclization of o-nitroalkynes is also a viable strategy
for the construction of pseudoindoxyl compounds under
generally redox-neutral reaction systems, which was actually
pioneered more than one century ago. Given the development
of mild transition metal catalysis in the last few decades,
Received: July 1, 2020
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© XXXX American Chemical Society
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A

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Letter
following oxidative N−N bond generation in one pot. Herein,
in our systematic studies, we have demonstrated that the mild
oxidative property of ketoxime internal oxidants combined
with copper catalysis could enable the oxidative N−N coupling
in the PPh3-based reductive system (Figure 2d).
Initially, we set up the bisheteroannulation of 1-(cyclo-
propylethynyl)-2-nitrobenzene (1a) and acetophenone oxime
acetate (2a) to screen the reaction conditions (Table 1). In the
cycloisomerization of o-nitroalkynes, found all inferior to PPh3
(entries 13 and 16). The reaction at 90 °C gave the same
efficiency (entry 17), while further lowering to 80 °C led to a
substantial decrease of reactivity (entry 18, 55% yield). Control
experiments revealed that the copper catalyst is a basic
necessity for the bisheteroannulation (entry 19), and the
reaction in the absence of phosphorus reductant with 2.0 equiv
of copper powder worked, albeit in low yield (entry 20). The
reaction carried out under an air atmosphere also significantly
decreased the yield (entry 21). Finally, the 1 mmol scale
reaction featured diminished reactivity to afford 3a in 42%
yield (entry 12).
a
Table 1. Optimization of Reaction Conditions.
With the optimized reaction conditions in hand, we next
probe the substrate scope of the copper-powder-mediated
reductive bisheteroannulation (Figure 3). With respect to
oxime acetates derived from acetophenones, the corresponding
products were generally obtained in moderate yields (3a−3v),
with a broad array of compatible functionalities including alkyl,
alkoxy, halogen, and even nitro. Notably, the C(sp2)−I bond,
which is highly sensitive to the copper-based reductive system,
was well tolerated in the present catalysis (3j), with no
b
catalyst
reductant
(equiv)
temp.
yield 3a
entry
(mol %)
solvent
(°C)
(%)
1
2
3
4
5
6
7
8
CuCl (20)
CuCl (20)
CuCl (20)
CuCl (20)
CuCl (20)
CuBr (20)
CuI (20)
PPh3 (1.0)
PPh3 (1.0)
PPh3 (1.0)
PPh3 (1.0)
PPh3 (1.0)
PPh3 (1.0)
PPh3 (1.0)
CH3CN
toluene
PhCl
o-DCB
DMF
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
26
trace
22
38
15
22
trace
trace
trace
45
CuCl2 (20) PPh3 (1.0)
CuBr2 (20) PPh3 (1.0)
9
10
11
12
13
14
15
Cu (20)
Cu (20)
Cu (50)
Cu (50)
Cu (50)
Cu (50)
PPh3 (1.0)
PPh3 (2.0)
PPh3 (2.0)
PBu3 (2.0)
B2Pin2 (2.0)
51
c
70, 42
64
23
Mo(CO)6
(2.0)
trace
16
17
18
Cu (50)
Cu (50)
Cu (50)
Et3SiH (2.0)
PPh3 (2.0)
PPh3 (2.0)
PPh3 (2.0)
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
100
90
80
90
90
90
52
70
55
ND
11
48
d
19
20
21
Cu (200)
Cu (50)
e
PPh3 (2.0)
a
Reaction conditions: 1a (0.3 mmol), 2a (0.2 mmol), catalyst,
reductant, solvent (1.5 mL), 100 °C, 5 h, under Ar, unless otherwise
b
c
d
e
noted. Isolated yield. 1.0 mmol scale. In the absence of Cu. Under
air.
presence of copper catalyst (CuCl, 20 mol %) and reductant
(PPh3, 1.0 equiv), the reaction performed in CH3CN afforded
the target pseudoindoxyl product 3a in 26% yield (entry 1).
Solvent screening among others featured that ortho-dichlor-
obenzene (o-DCB) was superior to others (entries 2−5),
furnishing 3a in 38% yield (entry 4). Low-polarity media such
as toluene quenched the desired transformation (entry 2).
Other copper catalysts were then tested (entries 6−10). While
CuBr diminished the yield to 22% (entry 6), copper(II) salts
proved catalytically inactive (entries 8 and 9), suggesting a
reduction-initiated cascade process of the bisheteroannulation.
In view of these observations, we rationally employed copper
powder as the catalyst, which therein enhanced the reactivity
to 45% yield (entry 10). Increasing either catalyst loading or
the amount of reductant improved the present reaction, with
combinational use of Cu (50 mol %) and PPh3 (2.0 equiv) to
give the best results (entries 11 and 12, 70% yield). Other
reductants including PBu3, B2Pin2, Mo(CO)6, and Et3SiH,
some of which were successfully used previously for reductive
Figure 3. Substrate scope of the copper-mediated bisheteroannula-
tions.
B
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detection of dehalogenative product. However, nitro-substi-
tuted acetophenone oximes resulted in relatively lower yields
of products (3l, 3q), along with probably formation of anilines
that led to a mixed complex mass. The inhibitory influence of
sterically hindered substrates, i.e., ortho-substituted acetophe-
none oximes, was not observed (3r−3t); therein, the expected
pseudoindoxyl products were generated in similar yields with
para- and meta-substituted reactants. Heteroaryl methylketox-
imes bearing pyridinyl and benzothiophenenyl moieties also
displayed modest reactivities (3w−3y). In correspondence
with acetophenone oximes, naphthyl and phenanthrenyl
substrates were expectedly accommodated with the present
copper catalysis (3z−3ab).
Subsequently, we tested a range of o-nitroalkynes. The
substrates attached with a primary or tertiary alkyl group at the
alkyne moiety dramatically decreased the yield. For example,
the tert-butyl o-nitroalkyne afforded the corresponding product
3ac in only 30% yield. Comparably, diarylacetylenes showed
modest reactivities, thus providing a feasible access to 2-aryl
pseudoindoxyl products (3ad−3ai). The o-nitroalkyne bearing
a thienyl moiety generated the corresponding product in 29%
yield.
The major side product of this bisheteroannulation reaction
was generated by the monocyclization, in which the N−N
bond was not formed and workup of the reaction mixture
afforded pseudoindoxyls bearing a ketone moiety. For example,
besides the formation of 3aj, the thienyl reactant also
generated monocyclization product 4c as the side product
(Figure 4). This kind of product was dominant especially when
Figure 5. Control experiments.
Given the above results, a plausible reaction mechanism is
illustrated in Figure 6. Direct nitro deoxygenative reduction by
Figure 6. Possible reaction mechanism.
Figure 4. Formation of pseudoindoxyls 4.
the o-nitroalkynes attached with a primary alkyl. Hence, the
hexyl and octyl substrates afforded pseudoindoxyls 4a and 4b,
respectively, in moderate yields, along with the formation of
bisheteroannulation products in only trace amounts.
PPh3 is impossible in our system.10 Hence, we propose that the
initial step should be the nucleophilic attack of the PPh3 base
to an alkyne moiety, which induces the 5-exo-dig cyclization of
1.11 Then, intramolecular charge transfer of the cyclic
intermediate A leads to the phosphorus ylide B, which
furnishes indol-3-one C via Wittig-type deoxygenation.
Simultaneously, in the presence of copper powder, oxime
acetate 2a results in the imino-copper(II) species D by
oxidative addition of copper(0) into the N−O bond.8b
Subsequently, migration insertion of D across the CN
bond of C occurs to generate the cyclocopper intermediate E,
with the final N−N bond reductive elimination12 producing
the pyrazolo[1,5-a]indolone product 3. We suspect a steric
bulky group is required to push the copper center close to both
nitrogen atoms, hence enabling the N−N bond formation.
Otherwise, the interaction of C and D leads to the formation of
intermediate F by nucleophilic addition. The subsequent
workup of F gives the monocyclic product 4.
Based on the results reported in the literature,5a,6a,7b,9 we
postulated that our copper/PPh3-based system could reduce o-
nitroalkynes to trigger a reductive cycloisomerization reaction,
with then the resultant indol-3-one containing an imine
fragment coupled with methylketoximes to generate the
dihydropyrazole ring. The results of control experiments
suggest this to be rational, with the roles of PPh3 and copper
catalyst clarified to independently work in both reaction steps
(Figure 5a,b). The addition of PPh3 also has an obvious
inhibitory effect on the later [3 + 2] pyrazolannulation that is
expected to be a redox-neutral process. Finally, elusive results
were obtained when conducting the reactions with a radical
scavenger, where an additional 2,2,6,6-tetramethylpiperidine-1-
oxyl (TEMPO) featured no significant influence on the yield,
and by contrast, 3,5-di-tert-butyl-4-hydroxytoluene (BHT)
quenched the transformation (Figure 5c).
In summary, we have developed a viable copper powder/
triphenylphosphine-based reductive system that enables
C
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bisheteroannulation of o-nitroalkynes with methylketoxime
acetates. This protocol provides convenient access to
structurally and pharmacologically significant pseudoindoxyl
compounds with generally moderate yields and tolerates
important functionalities including nitro and iodine being
sensitive to copper-based reductive systems. Mechanistically,
the reaction cascade involves triphenylphosphine-mediated
deoxygenative cyclization and copper-catalyzed [3 + 2] formal
annulations.
Natural Science Foundation of China (2020JJ3032), and the
Collaborative Innovation Center of New Chemical Technol-
ogies for Environmental Benignity and Efficient Resource
Utilization is gratefully acknowledged.
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02180.
1
Experimental procedures, characterization data, and H
NMR and 13C NMR spectra for all new products (PDF)
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AUTHOR INFORMATION
Corresponding Authors
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Guo-Jun Deng − Key Laboratory for Green Organic Synthesis
and Application of Hunan Province, Key Laboratory of
Environmentally Friendly Chemistry and Application of
Ministry of Education, College of Chemistry, Xiangtan
University, Xiangtan 411105, China; orcid.org/0000-0003-
2759-0314; Email: gjdeng@xtu.edu.cn
Huawen Huang − Key Laboratory for Green Organic Synthesis
and Application of Hunan Province, Key Laboratory of
Environmentally Friendly Chemistry and Application of
Ministry of Education, College of Chemistry, Xiangtan
University, Xiangtan 411105, China; orcid.org/0000-0001-
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Huanxin Meng − Key Laboratory for Green Organic Synthesis
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University, Xiangtan 411105, China
Zhenhua Xu − Key Laboratory for Green Organic Synthesis and
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Environmentally Friendly Chemistry and Application of
Ministry of Education, College of Chemistry, Xiangtan
University, Xiangtan 411105, China
Zhonghua Qu − Key Laboratory for Green Organic Synthesis
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Complete contact information is available at:
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Author Contributions
†H.M. and Z.X. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support by the National Natural Science Foundation of China
(21602187, 21871226), the Science and Technology Planning
Project of Hunan Province (2019RS2039), Hunan Provincial
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