Cobalt-Catalyzed Regioselective Carboamidation of Alkynes with Imides Enabled by Cleavage of C-N and C-C Bonds

Article abstract of DOI:10.1021/acs.orglett.0c00875

Through the oxidative addition of cobalt into the N-C(O) bond of phthalimide and the subsequent decarbonylation, we describe an efficient cobalt-catalyzed intermolecular decarbonylative carboamidation of alkynes. High regioselectivities have been achieved for unsymmetrical alkynes (including aryl-alkyl or aryl-aryl) to deliver polysubstituted isoquinolones. To facilitate step economy, a three-component decarbonylative carboamidation of alkynes with phthalic anhydrides and amines has been demonstrated using the current cobalt catalysis.

Full text of DOI:10.1021/acs.orglett.0c00875

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Letter
Cobalt-Catalyzed Regioselective Carboamidation of Alkynes with
Imides Enabled by Cleavage of C−N and C−C Bonds
Xiang-Ting Min, Ding-Wei Ji, Hao Zheng, Bing-Zhi Chen, Yan-Cheng Hu, Boshun Wan,
and Qing-An Chen*
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ABSTRACT: Through the oxidative addition of cobalt into the
N−C(O) bond of phthalimide and the subsequent decarbon-
ylation, we describe an efficient cobalt-catalyzed intermolecular
decarbonylative carboamidation of alkynes. High regioselectivities
have been achieved for unsymmetrical alkynes (including aryl−
alkyl or aryl−aryl) to deliver polysubstituted isoquinolones. To
facilitate step economy, a three-component decarbonylative
carboamidation of alkynes with phthalic anhydrides and amines
has been demonstrated using the current cobalt catalysis.
he activation of σ-bonds via oxidative addition with
transition metals is a fundamental step in organometallic
Scheme 1. Activation of σ-Bond via Cobalt Catalysis
T
chemistry. Therefore, the development of novel transition
metal catalytic systems for facilitating such a process is one of
the leading edge efforts in catalysis.1 Compared with the widely
used noble metals, the earth-abundant first-row transition
metals have gained particular attention in recent years owing to
their relatively lower cost and toxicity2a,b,c as well as greater
sustainability. Among them, cobalt catalysis has emerged as a
powerful tool and substantial progress has been achieved in
this area.2d,e For example, cobalt-catalyzed C(sp2)−H
activation via oxidative addition has been well established
(Scheme 1a, eq 1).3,4 However, the oxidative addition of cobalt
with C−C bonds is generally limited to strained rings, such as
benzocyclobutenones5a and methylenecyclopropanes,5b,c and
others6 (Scheme 1a, eq 2). Furthermore, the C−N activation
of amide under cobalt catalysis is rare. In 2017, Danoun and
co-workers described the first cobalt-catalyzed activation of N-
Boc-amides (twisted amides) to form esters for the first time7
(Scheme 1a, eq 3). Despite advances in the transition metal
catalyzed decarbonylation of amide,8 the cobalt-catalyzed
decarbonylative coupling of imides requiring both C−N and
C−C bond cleavages remains undiscovered (Scheme 1a, eq 4).
On the other hand, catalytic multicomponent reaction, due
to its rapid construction of multiple new bonds in one step, has
received much attention over the past decades.9 We envisioned
phthalimide derivatives could be formed in situ from the
condensation of phthalic anhydrides with amines (Scheme 1b).
Subsequently, the aryl-cobalt intermediate generated from
activating its C−N and C−C bonds will undergo migratory
insertion into alkynes to give substituted isoquinolones
(Scheme 1b). The challenges for this strategy include the
following: (a) facile CO insertion into the C−Co bond makes
it difficult to dissociate CO from cobalt;10,11 (b) competitive
decarbonylative homocoupling12 and protolysis13 due to
production of water in the three-component reaction; (c)
regiocontrol in the carboamidation of unsymmetrical alkynes.
Received: March 9, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00875
© XXXX American Chemical Society
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A

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a
Herein, we report a cobalt-catalyzed intermolecular decarbon-
ylative carboamidation of alkynes to form substituted
isoquinolones (Scheme 1b).
Scheme 2. Scope of the Alkynes
The two-component decarbonylative carboamidation of
alkyne 2a with phthalimide derivative 1a was initially
investigated (Table 1). After careful evaluation of the reaction
a
Table 1. Selected Optimization Studies
b
entry
deviation from standard condition
none
without CoI2
3aa/3aa′ yield (3aa)
c
1
2
14.3
−
92%
NR
3
without Ag2CO3
−
NR
4
5
6
7
8
9
10
11
12
13
14
15
16
without P(2-MeOC6H4)3
4.0
−
−
28%
NR
NR
61%
56%
8%
35%
33%
80%
Co(PMe3)4 instead of CoI2
Co2(CO)8 instead of CoI2
Co(PPh3)3Cl instead of CoI2
Co(dppe)Cl2 instead of CoI2
Cp*Co(CO)I2 instead of CoI2
PPh3 instead of P(2-MeOC6H4)3
P(2-furyl)3 instead of P(2-MeOC6H4)3
Xantphos instead of P(2-MeOC6H4)3
Ag2O instead of Ag2CO3
8.9
5.7
−
5.6
3.7
5.0
8.3
−
c
86%
14%
NR
AgOAc instead of Ag2CO3
TBHP instead of Ag2CO3
AgOAc and TBHP instead of Ag2CO3
−
8.0
52%
a
All reactions were performed on 0.10 mmol scale. See Supporting
b
Information for full details. Determined by 1H NMR analysis.
a
Isolated yield of the major regioselective isomer.
c
Isolated yield.
conditions, isoquinolone 3aa was formed in 92% yield with
14:1 (3aa/3aa′) regioselectivity using CoI2/P(2-MeOC6H4)3
as the metal/ligand combination and Ag2CO3 as the oxidant
(entry 1). Control experiments were subsequently conducted
to understand the role of each reagent. In the absence of the
cobalt catalyst or Ag2CO3, no desired product was observed
(entries 2−3). Both the reactivity and regioselectivity
decreased in the absence of P(2-MeOC6H4)3 (entry 4).
Interestingly, the reaction did not proceed with Co0 precursors
(entries 5−6). The use of a CoI or CoII precursor, such as
Co(PPh3)3Cl and Co(dppe)Cl2, slightly lowered the yields
(entries 7−8) (see Table S1). Probably due to the lack of
available coordination sites, the employment of high valent
Cp*Co(CO)I2 as the catalyst precursor gave only an 8% yield
of 3aa (entry 9). Other monodentate phosphine ligands, such
as PPh3 or P(2-furyl)3, led to inferior results (entries 10−11).
The bidentate ligand Xantphos could also promote this
transformation but in slightly diminished yield (entry 12).
The use of Ag2O instead of Ag2CO3 as the oxidant also gave
isoquinolone 3aa in a good yield (entry 13). However, the use
of either AgOAc or TBHP as the oxidants significantly
inhibited the reaction, thus suggesting both the oxidant and
silver ion are important for generating the active intermediate
(entries 14−16).
isoquinolone derivatives (3aa−3af) with high yields and
regioselectivities. Cyclopropyl, ester, and alkoxy groups were
well tolerated. For aryl−alkyl alkynes bearing indoles, good
yields and excellent regioselectivities were observed (3ag−
3ah). The regioselectivity for this unsymmetrical alkyne
carboamidation was confirmed by X-ray analysis of 3ah. A
series of symmetrical diarylacetylenes were also compatible
with this protocol, giving the corresponding products in good
to excellent yields (3ai−3an). A heterocycle, such as
thiophene, was well tolerated under the cobalt catalysis
(3ao). It is interesting to note that, in the case of the
unsymmetrical aryl−aryl alkyne with a slight difference in the
electronic property of the two aryl substituents, the annulation
delivered 3,4-diaryl substituted isoquinolone 3ap with excellent
regioselectivity (>20:1).
Next, selective decarbonylative annulation of phthalimide
derivatives with alkynes that also bear phthalimides groups,
which are widely embedded in pharmaceuticals and bio-
logically active molecules such as thalidomide14 were tested
(Scheme 3). Selective C−N activation in the presence of four
amide bonds on two structurally similar substrates (1a and
2q−2s) may pose a challenge for the cobalt catalysis.
Satisfactorily, the tested alkynes were compatible with this
protocol, providing isoquinolones bearing phthalimide groups
in high yields and regioselectivities (>20:1, 3aq−3ar).
Furthermore, isoquinolone 3as with multiple N-heterocycles
was isolated in moderate yield and regioselectivity. To
demonstrate the scalability of this methodology, the reaction
With the optimal conditions in hand, the substrate scope for
the Co-catalyzed carboamidation of alkynes with phthalimides
was investigated (Scheme 2). A variety of unsymmetrical aryl−
alkyl alkynes underwent carboamidation smoothly to deliver
B
https://dx.doi.org/10.1021/acs.orglett.0c00875
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a
the substrates of such motifs. The regioselective annulations of
3-amino substituted phthalimides 1b and 1c were successfully
demonstrated. Moreover, it was found that the free NH on 1b
and 1c plays an important role in the regiocontrol, because
formation of its tautomer may hinder the oxidative addition of
the adjacent carbonyl moiety with cobalt.16a,b,d The reaction of
3-chlorophthalimide 1d with alkyne 2i afforded cycloadduct
5di in 60% yield, the product of which is difficult to synthesize
via C−H activation owing to steric hindrance.17 Phthalimides
such as 1e, 1f, 1g, 1h were also compatible with the process,
providing the corresponding products 4ei, 4fi, 4gi, 4ga, 4ha in
acceptable yields. 8-Amino-5-methoxyquinoline (MQ) can be
used instead of 8-aminoquinoline for its ease of cleavage.18
Mechanistically, we sought to probe the aryl−cobalt
intermediates resulting from the oxidative addition of a low-
valent cobalt into the N−C(O) bond of imides and the
subsequent decarbonylation (eqs 5−8). Interestingly, the
Scheme 3. Selective Activation Among Four Amide Bonds
a
Isolated yield of the major regioselective isomer.
of 1a with 2q was successfully performed on 2.0 mmol of
starting materials, which afforded 0.862 g of 3aq (85% yield).
After exploring the scope of the alkynes, an array of
phthalimide derivatives were examined (Scheme 4). 3-Amino
substituted phthalimides are prevalent motifs in drugs15 and
fluorescent probes;16a−c thus, it would be of interest to modify
a
Scheme 4. Scope of the Phthalimides
decarbonylative homocoupling product 6a can be obtained
in 35% yield in the absence of alkynes.12 The addition of
stoichiometric H2O prevents the formation of 6a (eq 5). When
1i and 2a were treated with the standard conditions, the
corresponding cyclization product was not detected, and
instead, decarbonylative product 6b was obtained in 45% yield.
The use of external water as an additive gave product 6b in
90% yield (eq 6). Full incorporation of deuterium at the site of
decarbonylation (6c) in the presence of D2O suggested that
water was the proton source for this reaction (eq 7).13 To gain
insight into the role of the oxidant, the gas phase of the
reaction mixture was analyzed by GC-MS (eq 8). Silver oxide
(Ag2O) was used instead of Ag2CO3 to avoid the background
decarboxylation of Ag2CO3 (eq 8). Carbon dioxide (CO2) was
detected as the major gas component, which suggested that the
oxidant played a role as a CO scavenger in the cobalt-catalyzed
decarbonylation.
A proposed catalytic cycle is depicted in Scheme 5. First,
Co(II) is disproportionated to active Co(I) species A.19
Through an oxidative addition process, Co(I) species A
activates the C−N bond of imides to form Co(III)
intermediate B (from the perspective of ring strained, N−C
activation precedes C−C activation; see the Supporting
Information for details). A subsequent decarbonylation leads
a
b
Isolated yield of the major regioselective isomer. PhCF3 as the
solvent.
C
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component reaction provides a more convenient alternative to
access such cyclic products.17
Scheme 5. Proposed Mechanism
In summary, we have described an efficient Co-catalyzed
intermolecular decarbonylative carboamidation of alkynes via
the cleavage of C−N and C−C bonds of imides. The migratory
insertion of aryl−cobalt species with unsymmetrical alkynes
(including aryl−alkyl or aryl−aryl) occurs in high regiocontrol
to deliver polysubstituted isoquinolones. A three-component
Co-catalyzed decarbonylative carboamidation of alkynes with
phthalic anhydrides and amines has been also demonstrated to
increase step economy. Further application of this strategy to
other amide decarbonylations and detailed mechanistic
investigations are currently ongoing in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00875.
Experimental materials and procedures, NMR of
compounds, and X-ray crystallographic analysis for
compounds 3ap, 3ah, 3aq, and 4ba (PDF)
to the cobalt complex C. As a CO scavenger, the addition of an
external oxidant facilitates the formation of active intermediate
aryl-Co D. In the presence of alkyne 2, intermediate D
undergoes coordination and migratory insertion of the alkyne
to afford seven-membered cobaltacycle E. A final reductive
elimination produces the isoquinolone products and regener-
ates Co(I) catalyst A. In the absence of alkyne 2, aryl-cobalt C
undergoes a homocoupling pathway to yield compound 6a12
or protolysis to yield compound 6c.13
Accession Codes
CCDC 1974651, 1974659, 1974661, 1974675, and 1977034
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.ca-
m.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.
A three-component decarbonylative carboamidation was
accomplished by the use of bulk chemicals phthalic anhydride
7, 8-aminoquinoline 8, and alkynes 2 (Scheme 6). Overall, this
three-component protocol cleaves four existing bonds while
creating three additional new bonds in one pot. Gratifyingly,
under the standard reaction conditions, a series of
representative isoquinolones were obtained in moderate to
high yields (3aa, 3ac, 3af, 3ai, 3ap, 3ah, 3aq, 4ha). Compared
with the traditional C−H activation strategy, this three-
AUTHOR INFORMATION
Corresponding Author
■
Qing-An Chen − Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, China; orcid.org/
0000-0002-9129-2656; Email: qachen@dicp.ac.cn
Authors
Xiang-Ting Min − Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, China; University of
Chinese Academy of Sciences, Beijing 100049, China
Ding-Wei Ji − Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, China; University of
Chinese Academy of Sciences, Beijing 100049, China
Hao Zheng − Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, China; University of
Chinese Academy of Sciences, Beijing 100049, China
Bing-Zhi Chen − Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, China; University of
Chinese Academy of Sciences, Beijing 100049, China
Yan-Cheng Hu − Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, China; orcid.org/
0000-0002-8731-4445
Scheme 6. Three-Component Decarbonylative
a
Carboamidation of Alkynes
Boshun Wan − Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, China; orcid.org/
0000-0002-7001-6214
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00875
Notes
a
Isolated yield of major regioselective isomer.
The authors declare no competing financial interest.
D
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ACKNOWLEDGMENTS
■
We thank Prof. Yong-Gui Zhou (DICP), Prof. Martin
Oestreich (TU Berlin), and Prof. Kevin G. M. Kou (UCR)
for helpful discussions and manuscript revisions. Financial
support from the National Natural Science Foundation of
China (21971234, 21772194, 21572225), Liaoning Revital-
ization Talents Program (XLYC1807181), and the “Thousand
Youth Talents Plan” is acknowledged.
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