Palladium-Catalyzed Inert C?H Bond Activation and Cyclocarbonylation of Isoquinolones with Carbon Dioxide Leading to Isoindolo[2,1-b]isoquinoline-5,7-Diones

Article abstract of DOI:10.1002/adsc.201900305

A palladium-catalyzed inert C?H bond activation and cyclocarbonylation of isoquinolones leading to isoindolo[2,1-b]isoquinoline-5,7-diones under 1 atm of carbon dioxide has been developed. This transformation features high regio- and chemo-selectivity, step-economy, and good functional group tolerance. Most of the corresponding products were obtained in moderate to good yields. It offers an alternative approach for the synthesis of useful diverse isoindolo[2,1-b]isoquinoline-5,7-dione derivatives. (Figure presented.).

Full text of DOI:10.1002/adsc.201900305

Title: Palladium-Catalyzed Inert C-H Bond Activation and
Cyclocarbonylation of Isoquinolones with Carbon Dioxide
Leading to Isoindolo[2,1-b]isoquinoline-5,7-diones
Authors: Kelu Yan, Junbin Jin, Yong Kong, Bin Li, and Baiquan Wang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900305
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10.1002/adsc.201900305
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Palladium-Catalyzed Inert CH Bond Activation and
Cyclocarbonylation of Isoquinolones with Carbon Dioxide
Leading to Isoindolo[2,1-b]isoquinoline-5,7-diones
Kelu Yan,a Junbin Jin,b Yong Kong,b Bin Li,a and Baiquan Wanga,c,*
a
State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071,
People’s Republic of China
Fax: (+86)-22-23504781; e-mail: bqwang@nankai.edu.cn
SINOPEC Research Institute of Petroleum Engineering, Beijing 100101, People’s Republic of China
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
b
c
Sciences, Shanghai 200032, People’s Republic of China
Received: ((will be filled in by the editorial staff))
Dedicated to the 100th anniversary of Nankai University.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
CO2 fixation. Recently, a series of breakthroughs in
the transition-metal-catalyzed C–H carboxylation of
(hetero)arenes with CO2 were accomplished.[5] In
these examples, the substrates are mainly limited to
Abstract:
A
palladium-catalyzed inert CH bond
activation and cyclocarbonylation of isoquinolones leading
to isoindolo[2,1-b]isoquinoline-5,7-diones under 1 atm of
carbon dioxide has been developed. This transformation
features high regio- and chemo-selectivity, step-economy,
and good functional group tolerance. Most of the
corresponding products were obtained in moderate to good
yields. It offers an alternative approach for the synthesis of
terminal
alkyne,
polyhalogenated
aromatic
hydrocarbons, and heterocyclic rings which possess
an acidic C–H bond. However, subsequent reports
have shown that these substrates can react with CO2
in the presence of Cs2CO3, LiOtBu, or other bases,
even without adding any transition-metal catalysts.[6]
Moreover, for the inert C–H bonds, only few Rh(I),[7]
Rh(II),[8] and Pd(II)[9] catalyzed carboxylations with
CO2 have been reported. It can be seen that the
utilization of CO2 still exists a series of challenges
need to be solved and it remains in its initial
development stage. Therefore, there is still an urgent
need to develop new substrates and establish new
methods in the fixation of CO2.
useful
diverse
isoindolo[2,1-b]isoquinoline-5,7-dione
derivatives.
Keywords: CH activation; carbon dioxide; palladium;
isoquinolones; isoindolo[2,1-b]isoquinoline-5,7-diones
Carbon dioxide (CO2) is an inexpensive, nontoxic,
abundant, and renewable feedstock which can be
used as the ideal one-carbon (C1) building block to
produce fuels, materials, and commodity chemicals.[1]
However, it is challenging to utilize CO2 under mild
reaction conditions because of its thermodynamic
stability and kinetic inertness.[2] In the past few
decades, novel reagents and various strategies have
been developed in promoting the conversion of CO2
into value-added chemicals.[3-9] However, under
transition-metal-free conditions, the site selectivity of
several carboxylations of arene substrates with CO2 is
determined by the most nucleophilic site of the arenes
and it is difficult to overcome the electronic biases in
this type of reactions.[4] In comparison with the
transition-metal-free reactions, transition-metal-
catalyzed C–H bond activation/functionalization has
flourished as a powerful and atom-economical tool to
construct C–C and C–heteroatom bonds as it obviates
the need for pre-functionalized substrates.[10] This
strategy has also been employed in the reactions of
An isoquinolone moiety is an important structural
unit, which frequently occurs in various natural
products and synthetic compounds.[11-14] Recently,
Scheme 1. Palladium-catalyzed cyclocarbonylation of
isoquinolones
1
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10.1002/adsc.201900305
Advanced Synthesis & Catalysis
NH isoquinolone unit has emerged as an effective
directing group to construct isoquinolone-containing
heterocycles through transition metal-catalyzed C–H
and N–H bond activation. Li[12] and our group[13] have
reported several oxidative annulations of NH
74% yield. In addition, different solvents were
investigated, and DMF was discovered to be more
suitable for this transformation (entries 7, 910).
Other additives such as ZnEt2 and AlMe3 gave low
yields or no product under the present reaction
conditions (entries 1112). Finally, we chose the
reaction conditions of entry 7 as the standard
conditions.
isoquinolones
with
alkynes,
olefins,
and
benzoquinones under the catalysis of Ru(II), Rh(III),
or Ir(III). Very recently, Guo and Fan group reported
a palladium-catalyzed oxidative cyclocarbonylation
of isoquinolones with CO leading to isoindolo[2,1-
b]isoquinoline-5,7-dione derivatives (Scheme 1a).[14]
Although this transformation is step-efficient and
atom-economical, the use of highly toxic CO and a
stoichiometric oxidant is inevitable. Therefore, it is
absolutely essential to explore whether inexpensive
and nontoxic CO2 can be employed instead of CO to
With the establishment of the optimized conditions
in hand, we explored the applicability of the scope of
diversely substituted 3,4-diphenylisoquinolin-1(2H)-
ones (1a−1v), and the results are summarized in
Table 2. To our delight, most reactions proceeded
smoothly to afford corresponding products in
moderate to good yields. The cyclocarbonylation of
substituted
3,4-diphenylisoquinolin-1(2H)-ones
synthesize
derivatives. Following our growing interest in
transition-metal-catalyzed C–H bond
activation/functionalization,[13,15] we herein report a
palladium-catalyzed cyclocarbonylation of
isoindolo[2,1-b]isoquinoline-5,7-dione
bearing alkyl, methoxyl, and phenyl groups at the C6-
position afforded corresponding products in good
yields (63–76%, 2a–2g). While, introducing an
electron-withdrawing substituent such as halogen,
cyano, methoxycarbonyl, and trifluoromethyl at the
C6-position of 3,4-diphenylisoquinolin-1(2H)-ones
afforded corresponding products (2h–2l) in moderate
yields (41–54%). The corresponding product 2m was
obtained in only 5% yield, when 2-nitro-12-
phenylisoindolo[2,1-b]isoquinoline-5,7-dione (1m)
with a nitro at the C6-position was employed. This
isoquinolones with CO2 leading to isoindolo[2,1-
b]isoquinoline-5,7-diones.
We initiated our work by treating 3,4-
diphenylisoquinolin-1(2H)-one (1a) (0.2 mmol, 1.0
equiv.) with 1 atm of CO2 in the presence of
Pd(TFA)2 (10 mol%), KOtBu (5.0 equiv.), and ZnMe2
(3 equiv.) in DMF (N,N-dimethylformamide) (2.0 mL) may be because the strong electron-withdrawing
at 150 °C for 20 h, and the desired product 12-
phenylisoindolo[2,1-b]isoquinoline-5,7-dione (2a)
was obtained in 33% yield (Table 1, entry 1). The
effect of catalysts was firstly investigated, which
revealed that Pd(OAc)2 was the most effective
catalyst (36%, entries 14). No product was observed
in the absence of catalyst or base (entries 56). Then,
other bases including LiOtBu and NaOtBu were
tested (entries 2, 78). To our delight, the reaction
employing LiOtBu as the base provided product 2a in
ability of the nitro group reduces the nucleophilic
Table 2. Substrate scope of isoquinolones.[a]
Table 1. Optimization of the reaction conditions.[a]
Entry Catalyst
Base
Solvent Additive Yield[b]
1
2
3
4
5
6
7
8
9
Pd(TFA)2 KOtBu
DMF
DMF
DMF
DMF
DMF
DMF
ZnMe2
ZnMe2
ZnMe2
ZnMe2
ZnMe2
ZnMe2
ZnMe2
ZnMe2
ZnMe2
33
36
29
31
0
0
74
0
Pd(OAc)2 KOtBu
PdCl2
KOtBu
Pd(PPh3)2 KOtBu
-
KOtBu
-
Pd(OAc)2
Pd(OAc)2 LiOtBu DMF
Pd(OAc)2 NaOtBu DMF
Pd(OAc)2 LiOtBu
DMA
42
0
10 Pd(OAc)2 LiOtBu DMSO ZnMe2
11 Pd(OAc)2 LiOtBu
12 Pd(OAc)2 LiOtBu
DMF
DMF
ZnEt2
AlMe3
65
0
[a] Conditions: 1a (0.2 mmol), CO2 (1 atm), catalyst (0.02
mmol), base (1.0 mmol), additive (0.6 mmol), solvent (2
mL), 150 C, 20 h. [b] Isolated yields.
[a]
Reaction conditions: 1 (0.2 mmol), CO2 (1 atm),
Pd(OAc)2 (0.02 mmol), LiOtBu (1.0 mmol), ZnMe2 (0.6
mmol), DMF (2 mL), 150 C, 20 h, isolated yields.
2
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10.1002/adsc.201900305
Advanced Synthesis & Catalysis
attack of the nitrogen atom on the substrate to CO2.
When a methyl was placed at the C7 position of 3,4-
diphenylisoquinolin-1(2H)-one, product 2n was
obtained in 72% yield. As expected, the
corresponding product 2o was also obtained smoothly
(54%),
when
the
substrate
8-chloro-3,4-
diphenylisoquinolin-1(2H)-one (1o) with a chloro
substituent at the C8-position was employed.
Meanwhile, the study of substrate with two
substituents at the C5/7-position was also examined
and the corresponding product 2p was obtained in
71% yield. Besides isoquinolones, other fused
pyridones (1q–1r) were also proved to be good
substrates. When 3,4-diphenylbenzo[g]isoquinolin-
1(2H)-one (1q) and 5-methyl-3,4-diphenyl-2,5-
Figure 1. The molecular structure of 2t.
To gain more insight into the mechanism, a series
of experiments have been conducted to probe the
reaction mechanism. A H/D exchange experiment of
1a using 0.2 mL of D2O or CD3OD was performed
under standard conditions, and no H/D exchange was
detected (Scheme 3a). This result indicated that the
cleavage of the relevant C−H bond was an
irreversible process. Then, a deuterium competition
experiment between substrate 1y and 1y-d5 was
performed, and a kinetic isotope effect (KIE) of 2.2
was observed (Scheme 3b). Meanwhile, two parallel
independent reactions of 1y and 1y-d5 illustrated a
KIE of 1.7 (Scheme 3c). Both results indicated that
the C(sp2)–H bond cleavage of this transformation
might be involved in the rate-determining step. In
addition, we performed the intermolecular
competition experiment between electronically
dihydro-1H-pyrido[4,3-b]indol-1-one
(1r)
were
employed as the substrates, the corresponding
products 2q and 2r were obtained in 80% and 77%
yields, respectively. In addition, we also investigated
the palladium-catalyzed cyclocarbonylation of
isoquinolones with different R2 substituents (1s–1x).
The results suggested that isoquinolone substrates
bearing a substituent such as methyl, methoxy,
ethoxycarbonyl, and fluorine at the para-position of
the 3-phenyl moiety took part in this reaction
smoothly and afforded corresponding products (2s–
2w) in 53–81% yields. The cyclocarbonylation of
3,4-di(m-tolyl)isoquinolin-1(2H)-one (1w) with a
methyl at the meta-position of the 3-phenyl moiety
afforded regioselective product 2w in 72% yield, no
other regioisomer of 2w was detected. This indicated
that the reaction is sensitive to the steric hindrance
and favors to form the less hindered product.
However, when substrate 1x which bearing a methyl
group in the ortho-position of the 3-phenyl moiety
was employed, no corresponding product was
observed. This may be due to the steric effect of the
ortho substituent which may affect the coplanarity of
the phenyl ring and the isoquinolinone ring and
depress the C–H activation and cyclocarbonylation.
Furthermore, 3-phenylisoquinolin-1(2H)-one (1y)
derived from an unsymmetrical substituted alkyne
proceeded this reaction smoothly to give product 2y
in 70% yield. No corresponding product was detected
when the isoquinolinone 1z which bearing a C(sp3)–
H reaction site was used as the substrate.
differentiated
3,4-di(p-tolyl)isoquinolin-1(2H)-one
(1s) and 3,4-bis(4-fluorophenyl)isoquinolin-1(2H)-
Next, we explored the synthetic applicability of
this method. As shown in Scheme 2, the gram-scale
reaction successfully afforded 2t in 67% yield (1.03 g)
at standard conditions. This result clearly proved the
practical aspect of this newly developed method.
Furthermore, the structure of 2t was further
confirmed by its single-crystal X-ray diffraction
analysis (Figure 1).[16]
Scheme 3. The mechanism study experiments.
Scheme 2. Synthesis of 2t on gram-scale.
3
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10.1002/adsc.201900305
Advanced Synthesis & Catalysis
one (1v) to determine the electronic preference of the
Subsequently, the second CO2 insertion into the O–
Pd bond could form a nine-membered palladacycle
intermediate V. The spiroheterocyclic intermediate
VI is generated by intramolecular nucleophilic
addition of V. Subsequently, the decarbonization
releases lactam product 2a and concomitantly
generates carbonate palladium intermediate VII.
Transmetalation between VII and ZnMe2 would give
the intermediate VIII. Finally, the active catalyst
would be regenerated after an acid−base exchange.
In conclusion, we have successfully developed a
novel and efficient approach to build substituted
isoindolo[2,1-b]isoquinoline-5,7-diones from readily
available isoquinolones and CO2 via palladium-
catalyzed inert CH bond activation. Various
regioselective products were prepared smoothly in
moderate to good yields. Further research on the
reaction mechanism and applications of this method
in the synthesis of more complex heterocycles are in
progress in our laboratory.
1
reaction. The H NMR spectrum of the obtained
products showed that the corresponding products 2s
and 2v were produced in a ratio of 1:0.42, which
indicated that the reaction favored the electron-rich
isoquinolones (Scheme 3d). Considering CO2 can be
converted to CO under certain conditions and then
participates in the carbonylation reaction,[17] 1 atm of
CO was used instead of CO2 to react with 1a in
standard conditions. Product 2a was not detected by
HRMS (Scheme 3e). This result excluded the
possibility of CO, converted from CO2, as the active
carbonylation reagent in this transformation.
Recently, Yu and coworkers reported
a
lactonization reaction of unactivated aryl C–H bond
with CO2. They proposed a mechanism based on the
DFT calculation.[9c] Referring to their work and our
preliminary mechanistic studies,
a
possible
mechanism is proposed for this present catalytic
reaction (Scheme 4). First of all, the combination of
tBuO− ion and CO2 leads to the formation of
hemicarbonate ion. The starting active catalytic
complex hemicarbonate−Pd could be generated after
ligand exchange. At the same time, the proton
exchange between solvated LiOtBu and reactant 1a
could afford the intermediate I. Then, the counter
anion exchange of starting active catalytic complex
Experimental Section
A mixture of isoquinolones (1) (0.2 mmol, 1.0 equiv.),
Pd(OAc)2 (4.5 mg, 0.02 mmol, 10 mol%), LiOtBu (80.0
mg, 1.0 mmol, 5.0 equiv.) were weighed in a Schlenk
sealed tube equipped with a stir bar. The tube was then
evacuated and back-filled with CO2 for 3 times, dry DMF
(2.0 mL) and ZnMe2 (1 M) in toluene (0.6 mL, 0.6 mmol,
3.0 equiv.) were added. The Schlenk tube was sealed at 1
atmospheric pressure of CO2 and the mixture was stirred at
150 C for 20 h. Then, the mixture was cooled to room
temperature, concentrated in vacuo, and the resulting
residue was purified by flash column chromatography on
silica gel with EtOAc/petroleum ether.
with
I
affords tBuOCOOLi and palladium
intermediate II. Then, intermediate II undergo a
concerted-metalation−deprotonation (CMD) process
leads to the palladacycle intermediate III and
tBuOCOOH. According to the previous reports,[18] the
activity of CO2 insertion into the N–Pd bond is higher
than the insertion into the C–Pd bond. So, the next
step of this reaction is the insertion of CO2 into the
N–Pd bond and generation intermediate IV.
Acknowledgements
We thank the National Natural Science Foundation of China (No.
21871151, 21672108) and the Natural Science Foundation of
Tianjin (No. 16JCZDJC31700) for financial support.
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10.1002/adsc.201900305
Advanced Synthesis & Catalysis
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10.1002/adsc.201900305
Advanced Synthesis & Catalysis
COMMUNICATION
Palladium-Catalyzed Inert CH Bond Activation
and Cyclocarbonylation of Isoquinolones with
Carbon Dioxide Leading to Isoindolo[2,1-
b]isoquinoline-5,7-diones
Adv. Synth. Catal. Year, Volume, Page 1 - Page 5
Kelu Yan, Junbin Jin, Yong Kong, Bin Li, and
Baiquan Wang*
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