Palladium-Catalyzed Oxidative Cyclocarbonylation of Isoquinolones with CO via C?H/N?H Bond Cleavage: Easy Access to Isoindolo[2,1-b]isoquinoline-5,7-dione Derivatives

Article abstract of DOI:10.1002/adsc.201800347

An efficient and practical synthesis of isoindolo[2,1-b]isoquinoline-5,7-diones through Pd-catalyzed C?H activation/carbonylative annulation of isoquinolones with CO (1 atm) is presented. Deuterium-labeling experiments revealed that the aryl C(sp²)?H bond activation might be the rate-determining step. More interestingly, the title compounds could also be prepared directly from the cascade reaction of N-methoxy benzamides and internal alkynes, as the precursors of isoquinolones, under an atmospheric pressure of carbon monoxide through a Rh/Pd relay catalysis in a user-friendly manner. (Figure presented.).

Full text of DOI:10.1002/adsc.201800347

Title: Palladium-Catalyzed Oxidative Cyclocarbonylation of
Isoquinolones with CO via C-H/N-H Bond Cleavage: Easy Access
to Isoindolo[2,1-b]isoquinoline-5,7-dione Derivatives
Authors: shenghai guo, Fang Wang, Lincong Sun, Xinying Zhang, and
Xuesen Fan
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800347
Link to VoR: http://dx.doi.org/10.1002/adsc.201800347

10.1002/adsc.201800347
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Palladium-Catalyzed Oxidative Cyclocarbonylation of
Isoquinolones with CO via C-H/N-H Bond Cleavage: Easy
Access to Isoindolo[2,1-b]isoquinoline-5,7-dione Derivatives
Shenghai Guo,a,* Fang Wang,a Lincong Sun,a Xinying Zhang,a and Xuesen Fana,*
a
Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, Collaborative Innovation Center of
Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions,
Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan
453007, P. R. China
Fax: (+86)-373-332-6336; e-mail: shguo@htu.cn, xuesen.fan@htu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract: An efficient and practical synthesis of and internal alkynes, as the precursors of isoquinolones,
isoindolo[2,1-b]isoquinoline-5,7-diones
through
Pd- under an atmospheric pressure of carbon monoxide through
catalyzed C-H activation/carbonylative annulation of a Rh/Pd relay catalysis in a user-friendly manner.
isoquinolones with CO (1 atm) is presented. Deuterium-
labeling experiments revealed that the aryl C(sp2)-H bond
Keywords: C-H activation; Cyclocarbonylation; Carbon
activation might be the rate-determining step. More
interestingly, the title compounds could also be prepared
directly from the cascade reaction of N-methoxy benzamides
monoxide; Isoquinolone; Isoindolo[2,1-b]isoquinoline-5,7-
dione
Introduction
Transition metal-catalyzed unreactive C-H bond
activation/functionalization has emerged as one of the
most powerful tools for the construction of various C-
C and C-heteroatom bonds and for the rapid synthesis
of bioactive compounds in modern organic synthesis
as it obviates the need for pre-functionalized
substrates in comparison with the traditional cross-
coupling reactions.[1] To achieve highly site-selective
C-H cleavage and functionalization, the most
frequently used strategy is to install a directing group,
such as amide, ketone, alcohol, carboxylic acid, ester,
nitrogen heterocycle, and others.[2] Recently, NH
isoquinolone unit has emerged as an effective
directing group to enable several oxidative annulation
reactions through transition metal-catalyzed C-H and
N-H bond cleavage, thus leading to the formation of
Scheme
1.
Transition-metal-catalyzed
oxidative
annulations of NH isoquinolones.
directed ortho C-H activation/annulation reactions for
the synthesis of polycyclic isoquinolone derivatives is
highly desirable.
several
isoquinolone-containing
heterocycles
Directing
group-assisted
oxidative
C-H
(Scheme 1). For example, the oxidative annulation of
NH isoquinolones with alkynes has been successfully
applied for the preparation of dibenzo[a,g]quinolizin-
8-one derivatives under the catalysis of Ru, Rh, or Ir
complex.[3] In addition, isoindolo[2,1-b]isoquinolin-
5(7H)-ones could also be obtained through Rh-
catalyzed oxidative coupling of 3-arylisoquinolones
with activated olefins.[4] Recently, Wang et al.
reported an Ir-catalyzed oxidative spirocyclization
reaction of 3-phenylisoquinolones with benzoquinone
to give novel spiro isoquinolone derivatives.[5]
Therefore, the development of more isoquinolone-
carbonylation followed by an intramolecular
annulation reaction with CO as a C1 feedstock
proved to be one of the most promising methods for
the fast construction of a large number of carbonyl-
containing carbocyclic and heterocyclic skeletons.[6]
For example, N-containing functional group-directed
oxidative C-H/N-H carbonylation reactions have been
extensively employed for the preparation of different
five- and six-membered lactam compounds with a
wide range of biological activities.[7] However, as far
as we know, an oxidative C-H carbonylative
cyclization reaction with the use of a NH
1
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10.1002/adsc.201800347
Advanced Synthesis & Catalysis
Table 1. Optimization of reaction conditions for the
synthesis of 2a.[a]
isoquinolone group as a directing group and carbon
monoxide as a carbonyl source to give lactams has
not been reported yet. As a continuation of our recent
study on palladium-catalyzed cyclocarbonylation
reactions,[8] we disclose herein a palladium-catalyzed
NH isoquinolone-directed oxidative cyclocarbonyl-
ation reaction of 3-arylisoquinolin-1(2H)-ones with
CO (1 atm), thus offering a practical and
Yield
(%)[b]
49
81
66
47
0
47
15
61
59
21
6
39
54
51
72
32
59
Entry Catalyst
Oxidant
Base
Solvent
1
PdCl2
AgOTFA
AgOTFA
AgOTFA
Na2CO3 PhCl
Na2CO3 PhCl
Na2CO3 PhCl
Na2CO3 PhCl
Na2CO3 PhCl
Na2CO3 PhCl
Na2CO3 PhCl
Na2CO3 PhCl
Na2CO3 PhCl
straightforward
access
to
isoindolo[2,1-
2
3
Pd(OAc)2
Pd(OTFA)2
b]isoquinoline-5,7-diones, which exhibit potential
fluorescent properties and are usually hard-to-prepare
via the known methods.[9]
4
5
Pd(PPh3)2Cl2 AgOTFA
[Cp*RhCl2]2 AgOTFA
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Cu(OAc)2
Cu(OTf)2
K2S2O8
Results and Discussion
Initially, we chose 3,4-diphenylisoquinolin-1(2H)-
one (1a) as a model substrate to optimize the reaction
parameters for the formation of 2a, including
catalysts, oxidants, bases, and solvents (Table 1).
When 1a was treated with PdCl2 (10 mol %),
AgOTFA (2.0 equiv.), and Na2CO3 (0.5 equiv.) in
AgOAc
10
11[c]
12
13
14
15
16
17
18
19
20
21
22[d]
23[e]
24[f]
25[g]
26[h]
27
28
29
Cu(OTFA)2 Na2CO3 PhCl
O2
BQ
Na2CO3 PhCl
Na2CO3 PhCl
K2CO3
K3PO4
DBU
AgOTFA
AgOTFA
AgOTFA
AgOTFA
AgOTFA
AgOTFA
AgOTFA
AgOTFA
AgOTFA
AgOTFA
AgOTFA
AgOTFA
AgOTFA
AgOTFA
AgOTFA
PhCl
PhCl
PhCl
o
chlorobenzene (2 mL) at 120 C for 15 h under an
atmospheric pressure of CO, the oxidative
cyclocarbonylation reaction proceeded smoothly and
afforded the desired 12-phenylisoindolo[2,1-
b]isoquinoline-5,7-dione (2a) in 49% yield (entry 1).
The structure of 2a was unambiguously confirmed by
X-ray analysis (see the Supporting Information). To
improve the efficiency, different catalysts such as
DABCO PhCl
TEA PhCl
Na2CO3 toluene 50
Na2CO3 xylene
Na2CO3 DMSO
Na2CO3 DMF
Na2CO3 PhCl
Na2CO3 PhCl
Na2CO3 PhCl
Na2CO3 PhCl
Na2CO3 PhCl
Na2CO3 PhCl
Na2CO3 PhCl
PhCl
25
0
0
60
38
80
68
79
0
Pd(OAc)2,
Pd(OTFA)2,
Pd(PPh3)2Cl2,
and
[Cp*RhCl2]2 were screened (entries 2-5). Among
them, Pd(OAc)2 exhibited the highest catalytic
activity (81%). With Pd(OAc)2 as the catalyst, we
also examined the effect of other oxidants including
Cu(OAc)2, Cu(OTf)2, K2S2O8, AgOAc, Cu(OTFA)2,
O2, and BQ on this oxidative cyclocarbonylation
reaction (entries 6-12), and AgOTFA was proved to
be the best oxidant (entries 2 vs. 6-12). Next, five
other inorganic and organic bases were also tested
(entries 13-17), however, all of them were less
effective than Na2CO3 (entries 13-17 vs. 2). In
addition, with the use of toluene, o-xylene, DMSO,
and DMF as the reaction solvents, decreased yields of
2a were observed (entries 18-21). Changing the
amount of Pd(OAc)2, AgOTFA, or Na2CO3 failed to
improve the yield of 2a (entries 22-26). In following
studies, it was also found that, without Pd(OAc)2, this
reaction failed to afford 2a (entry 27). Besides, in the
absence of AgOTFA or Na2CO3, the formation of 2a
was suppressed obviously (entries 28-29). Finally,
Pd(OAc)2
Pd(OAc)2
4
55
AgOTFA
[a]The reactions were run with 1a (0.4 mmol), CO (1 atm),
catalyst (0.04 mmol), oxidant (0.8 mmol), base (0.2 mmol),
solvent (2 mL), 120 oC, 15 h. [b]Isolated yield. [c]CO:O2=2:1.
[d]With Pd(OAc)2 (0.02 mmol). [e]With AgOTFA (0.4
mmol). [f]With AgOTFA (1.2 mmol). [g]With Na2CO3 (0.08
mmol). [h]With Na2CO3 (0.4 mmol).
diones 2b-2i in 65-82 yields, and no obvious
electronic and steric effects was observed. Besides
isoquinolones (1a-1i), other fused pyridones (1j-1n)
were also proved to be good substrates and
underwent this carbonylative annulation reaction
smoothly to give the corresponding products in
reasonable to good yields. For example, with two
naphtho-fused pyridones as reactants, the Pd-
catalyzed cyclocarbonylation reactions could afford
the desired pentacyclic lactam products 2j and 2k in
74% and 52% yields, respectively. When furo- and
thieno-fused pyridones were employed, the reactions
could also yield the expected carbonylated products
2l-2n in 68%-81% yields. In addition, we also
investigated the Pd-catalyzed reaction of alkyl
substituted pyridone with CO (1 atm), and it turned
out that the reaction proceeded smoothly to afford 2o
o
when the reaction was carried out at 100 or 140 C,
2a was obtained in 52% or 80% yield.
With the optimized reaction conditions (Table 1,
entry 2) in hand, we next studied the scope and
limitation of this Pd-catalyzed NH isoquinolone-
directed oxidative cyclocarbonylation reaction
forming isoindolo[2,1-b]isoquinoline-5,7-diones (2).
As demonstrated in Table 2, both electron-donating
and electron-withdrawing R1 attached on 6-, 7-, and
8-positions of isoquinolones (1) were well compatible
with the optimized reaction conditions to give the
corresponding isoindolo[2,1-b]isoquinoline-5,7-
2
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10.1002/adsc.201800347
Advanced Synthesis & Catalysis
in 74% yield by increasing the loading of Pd catalyst
and the reaction time. Next, the effect of different R2
was examined. The results suggested that
isoquinolone substrates (1) with a methyl, fluoro, or
chloro group on the para-, meta-, or ortho-position of
the 3-phenyl moiety took part in this reaction to
afford 2p-2t, and it was observed that p- and m-
substituted substrates provided much higher yields
than o-substituted one (2p-2s vs. 2t), suggesting that
the steric hindance of R2 affected the efficiency of
63% yield. To further expand the substrate scope, the
cyclocarbonylation reactions of 4-methyl substituted
and 4-unsubstituted isoquinolones (1v-1z) were also
tried, to our delight, these reactions proceeded
smoothly to furnish the desried products 2v-2z in 60-
80% yields.
Thus far, we have established an efficient access to
isoindolo[2,1-b]isoquinoline-5,7-diones (2) through
Pd-catalyzed oxidative cyclocarbonylation of
isoquinolones (1). As most of 1 were prepared
through Rh-catalyzed oxidative annulation of readily
obtainable N-methoxy benzamides with internal
alkynes,[10] we were then interested in whether 2
could be synthesized directly from the cascade
reaction of N-methoxy benzamides with internal
alkynes and CO (1 atm) through a Rh/Pd relay
this
C-H
activation/carbonylation
reaction
significantly. It is also noteworthy that, with m-
methyl substituted isoquinolone (1q), this reaction
provided two regioisomers 2q and 2q' in 72% and
4% yields, respectively. In addition, when 3,4-
di(thiophen-2-yl)isoquinolin-1(2H)-one (1u) was
subjected to the optimized conditions, the
corresponding tetracyclic lactam (2u) was obtained in
catalysis. To check this
hypothesis,
N-
methoxybenzamide (3a) was firstly treated with
Table 2. Scope for the synthesis of isoindolo[2,1-b]isoquinoline-5,7-dione derivatives (2)[a],[b]
[a]Reaction conditions: 1 (0.4 mmol), CO (1 atm), Pd(OAc)2 (0.04 mmol), AgOTFA (0.8 mmol), Na2CO3 (0.2 mmol), PhCl
o
(2 mL), 120 C. [b]Isolated yields. [c]Pd(OAc)2 (0.08 mmol), 30 h. [d]Another regioisomer 2q' (4%). [e]1t (88%) was
recovered.
3
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10.1002/adsc.201800347
Advanced Synthesis & Catalysis
Scheme 2. One-pot two-step synthesis of 2a through a Rh/Pd relay catalysis.
diphenylacetylene (4a, 1.1 equiv.) in the presence of
with 4a and CO (1 atm) very well to provide the
corresponding isoindolo[2,1-b]isoquinoline-5,7-
[Cp*RhCl2]2 (2.5 mol %) and CsOAc (0.3 equiv.) at
o
60 C for 16 h in PhCl, which is the best solvent for
diones 2a-2i in moderate to good yields. In addition,
we also investigated the reactions of different alkynes
(4) with 3a and CO (1 atm), and it was found that a
series of Me-, F-, and Cl-substituted diarylacetylenes
(4) proved to be good substrates and underwent this
cascade reaction smoothly to give the expected
products 2p-2s. With 1,2-di(thiophen-2-yl)ethyne and
asymmetric 1-phenylpropyne, this cascade reactions
could also give rise to the corresponding products 2u
and 2v in 50% and 45 yields, respectively. Finally,
we also attempted to synthesize 12-unsubstituted
the subsequent cyclocarbonylation reaction. Then,
Pd(OAc)2 (10 mol %), AgOTFA (2.0 equiv.), and
Na2CO3 (0.5 equiv.) were added to the reaction
mixture, and the resulting mixture was stirred at 120
oC for 15 h under CO (1 atm). To our delight, the
envisioned one-pot two-step reaction proceeded
smoothly under a Rh/Pd relay catalysis to afford 2a in
a total yield of 73% (Scheme 2).
Next, the substrate scope for this one-pot two-step
synthesis of 2 was studied in detail, and the results
are listed in Table 3. It turned out that various N-
methoxy benzamides (3) with either electron-
donating groups (CH3- and CH3O-) or electron-
withdrawing groups (F-, Cl-, and Br-) on the para-,
meta-, or ortho-position of the phenyl ring reacted
isoindolo[2,1-b]isoquinoline-5,7-dione
(2w)
by
changing internal alkynes to phenylacetylene. After
several trials, it turned out that phenylacetylene could
not react with either N-OMe- or N-OPiv-benzamide
under the catalysis of Rh-complex to give the key
intermediate 4-unsubstituted isoquinolone (1w).
Accordingly, 2w could not be obtained. In following
Table 3. Scope for the one-pot two-step synthesis of 2[a]
studies,
it
was
found
that,
when
trimethyl(phenylethynyl)silane was employed as a
surrogate of phenylacetylene, this one-pot two-step
cascade reaction worked well. As shown in Scheme 3,
treatment
of
N-OPiv-benzamide
with
trimethyl(phenylethynyl)silane in the presence of
[Cp*RhCl2]2 (0.5 mol %) and CsOAc (2.0 equiv.) in
PhCl at room temperature for 16 h could afford the
isoquinolone intermediate (1aa),[11] which then
underwent a detrimethylsilylation and oxidative
cyclocarbonylation cascade under the optimized
reaction conditions for the synthesis of 2a (Table 1,
entry 2) to provide the target product (2w) in a total
yield of 68%.
Scheme 3. One-pot synthesis of isoindolo[2,1-
b]isoquinoline-5,7-dione (2w).
To gain some insight into the reaction mechanism
for the Pd-catalyzed oxidative cyclocarbonylation of
isoquinolones (1) with CO (1 atm), we carried out
three deuterium-labeling experiments as shown in
Scheme 4. First, treatment of the monodeuterated
isoquinolone [D1]-1w with CO (1 atm) under the
optimized conditions for 3 h afforded [D1]-2w and
2w (0.6:0.4) as an inseparable mixture in a total yield
of 22% (Scheme 4, Eq. 1). Second, an intermolecular
competitive experiment by using an equimolar
mixture of 1w and [D5]-1w was also performed under
the standard conditions, and it was observed that a
[a]Reaction conditions: (1) 3 (0.4 mmol), 4 (0.44 mmol),
CsOAc (0.12 mmol), [Cp*RhCl2]2 (0.01 mmol), PhCl (2
o
mL), 60 C, 16 h; (2) CO (1 atm), Pd(OAc)2 (0.04 mmol),
o
AgOTFA (0.8 mmol), Na2CO3 (0.2 mmol), 120 C, 15 h.
[b]Isolated yields.
4
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10.1002/adsc.201800347
Advanced Synthesis & Catalysis
mixture of 2w and [D4]-2w (0.71:0.29) was obtained
in a total yield of 19% (Scheme 4, Eq. 2). Third,
parallel reactions of 1w and [D5]-1w were also
performed under the standard conditions for 3 h, and
2w and [D4]-2w were obtained in 16% and 6% yields,
respectively (Scheme 4, Eq. 3). Based on the above
results, the intra-, intermolecular, and parallel KIE
(kinetic isotopic effect) values are 1.5, 2.45, and 2.67,
suggesting that the aromatic C(sp2)-H bond activation
might be the rate-determining step.
b]isoquinoline-5,7-diones via the Pd-catalyzed
oxidative double C-H/N-H bond cleavages of NH
isoquinolone
derivatives
followed
by
the
cyclocarbonylation with the use of CO (1 atm) as a
carbonyl source. Based on the preliminary
mechanistic studies, significant kinetic isotopic
effects (KIE) were observed, suggesting that the
aromatic C(sp2)-H bond activation might be involved
in
the
rate-determining
step
of
this
cyclocarbonylation reaction. In addition, we also
disclosed a more practical procedure for the
preparation of isoindolo[2,1-b]isoquinoline-5,7-
diones starting from the NH isoquinolone’s
precursors, N-methoxy benzamides and internal
alkynes, and carbon monoxide (1 atm) via a Rh/Pd
relay catalysis. Further development of more
transition-metal-catalyzed oxidative annulations of
NH isoquinolones with other reagents is currently
underway in our laboratory.
Experimental Section
General Information
Isoquinolones (1) were prepared through Rh-catalyzed
oxidative annulation reaction of N-OMe or N-OPiv-
benzamides with internal alkynes.[10-11] [D1]-1w and [D5]-
1w were synthesized through copper-catalyzed cross-
coupling reactions of 2-bromobenzamide with [D1]-
acetophenone and [D5]-acetophenone.[12] Unless noted,
other commercial reagents and solvents were used without
further purification. Melting points were recorded with a
Scheme 4. Deuterium-labeling experiments.
On the basis of the above facts, a plausible
mechanism for the formation of 2 is suggested as
shown in Scheme 5. Initially, the chelation of the
amide group of 1 with CO-ligated PdII species
followed by double N-H/C-H bond cleavages gives
rise to a five-membered palladacycle A. Subsequent
migratory insertion of carbon monoxide into the aryl
C(sp2)-Pd bond of A affords a six-membered PdII-
complex B. And then, intermediate B undergoes a
reductive elimination to provide product 2 and a Pd0-
complex which is then reoxidized to the active PdII-
species by AgOTFA.
1
micro melting point apparatus and uncorrected. The H
NMR spectra were recorded at 400 or 600 MHz. The 13C
NMR spectra were recorded at 100 or 150 MHz. High-
resolution mass spectra (HRMS) were collected in ESI
mode by using a MicrOTOF mass spectrometer. All
reactions were monitored by thin-layer chromatography
(TLC) using silica gel plates (silica gel 60 F254 0.25 mm),
and components were visualized by observation under UV
light (254 and 365 nm).
General Procedure for the Synthesis of Isoindolo[2,1-
b]isoquinoline-5,7-diones
(2)
via
Pd-Catalyzed
Oxidative Cyclocarbonylation.
To a schlenk tube (15 mL) containing a mixture of NH
isoquinolone 1 (0.4 mmol) in chlorobenzene (2 mL) were
added Pd(OAc)2 (0.04 mmol), AgOTFA (0.8 mmol), and
Na2CO3 (0.2 mmol) under CO (1 atm) atmosphere. Next,
o
the resulting mixture was stirred at 120 C for 15 h until
isoquinolone 1 was consumed completely. And then, the
reaction was quenched with NH4Cl and extracted with
dichloromethane. The extract was washed with H2O and
brine and then dried over anhydrous Na2SO4. The solvent
was evaporated under reduced pressure and the crude
product was purified by column chromatography on silica
gel (dichloromethane/ethyl acetate = 10:1) to afford the
corresponding isoindolo[2,1-b]isoquinoline-5,7-dione 2.
12-Phenylisoindolo[2,1-b]isoquinoline-5,7-dione (2a):
Yellow solid (105 mg, 81%), mp >300 oC. 1H NMR
(CDCl3, 600 MHz) δ 6.26 (d, J = 7.8 Hz, 1H), 7.05 (d, J =
7.8 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 7.35-7.37 (m, 3H),
7.44-7.47 (m, 1H), 7.50-7.53 (m, 1H), 7.56-7.58 (m, 3H),
7.91 (d, J = 7.2 Hz, 1H), 8.51 (d, J = 7.2 Hz, 1H); 13C
NMR (CDCl3, 150 MHz) δ 119.8, 123.7, 125.4, 126.5,
127.9, 128.2, 128.5, 129.2, 129.3, 129.8, 129.9, 130.3,
131.5, 133.8, 133.9, 134.3, 135.2, 137.4, 159.8, 165.4.
HRMS (ESI) calcd for C22H13NNaO2 [M + Na]+ 346.0838,
Scheme 5. Proposed mechanism for the formation of 2.
Conclusion
In summary, we have successfully established a
novel and efficient synthetic route to isoindolo[2,1-
found
346.0862.
CCDC-1838542
contains
the
5
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10.1002/adsc.201800347
Advanced Synthesis & Catalysis
supplementary crystallographic data for this compound.
These data can be obtained free of charge from The
4-Chloro-12-phenylisoindolo[2,1-b]isoquinoline-5,7-
o
1
dione (2h): Yellow solid (93 mg, 65%), mp >300 C. H
NMR (CDCl3, 400 MHz) δ 6.26 (d, J = 8.0 Hz, 1H), 7.02
(d, J = 7.6 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.39-7.46 (m,
4H), 7.52 (d, J = 7.6 Hz, 1H), 7.63-7.65 (m, 3H), 7.98 (d, J
= 7.6 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ 118.8, 123.9,
124.1, 125.3, 125.8, 128.3, 129.4, 129.9, 130.2, 130.4,
132.0, 132.2, 133.2, 133.8, 134.4, 134.5, 137.7, 140.4,
157.8, 165.0. HRMS (ESI) calcd for C22H12ClNNaO2 [M +
Na]+ 380.0449, found 380.0446.
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
2-Methyl-12-phenylisoindolo[2,1-b]isoquinoline-5,7-
o
dione (2b): Yellow solid (101 mg, 75%), mp 283-284 C.
1H NMR (CDCl3, 400 MHz) δ 2.35 (s, 3H), 6.28 (d, J = 8.0
Hz, 1H), 6.87 (s, 1H), 7.30-7.34 (m, 2H), 7.40-7.43 (m,
3H), 7.63-7.65 (m, 3H), 7.97 (d, J = 7.6 Hz, 1H), 8.45 (d, J
= 8.0 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ 22.0, 119.9,
123.7, 125.3, 125.5, 126.6, 128.2, 129.2, 129.3, 129.8,
130.4, 131.6, 134.0, 134.3, 135.2, 137.4, 144.8, 159.7,
165.4 (two 13C signals were not observed). HRMS (ESI)
calcd for C23H15NNaO2 [M + Na]+ 360.0995, found
360.1011.
3-Bromo-12-phenylisoindolo[2,1-b]isoquinoline-5,7-
o
1
dione (2i): Yellow solid (122 mg, 76%), mp >300 C. H
NMR (CDCl3, 400 MHz) δ 6.33 (d, J = 7.6 Hz, 1H), 6.98
(d, J = 8.4 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.39-7.42 (m,
2H), 7.45 (t, J = 7.6 Hz, 1H), 7.63-7.68 (m, 4H), 7.98 (d, J
= 7.6 Hz, 1H), 8.68 (d, J = 2.0 Hz, 1H); 13C NMR (CDCl3,
150 MHz) δ 119.1, 123.0, 123.8, 125.5, 128.0, 128.1,
129.2, 129.4, 129.9, 130.1, 130.3, 131.8, 133.3, 134.6,
135.1, 136.2, 136.9, 158.5, 165.1 (one 13C signal was not
observed). HRMS (ESI) calcd for C22H12BrNNaO2 [M +
Na]+ 423.9944, found 423.9943.
3-Methyl-12-phenylisoindolo[2,1-b]isoquinoline-5,7-
o
1
dione (2c): Yellow solid (111 mg, 82%), mp >300 C. H
NMR (CDCl3, 400 MHz) δ 2.48 (s, 3H), 6.32 (d, J = 7.6
Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H),
7.38-7.43 (m, 4H), 7.62-7.63 (m, 3H), 7.97 (d, J = 7.6 Hz,
1H), 8.38 (s, 1H); 13C NMR (CDCl3, 150 MHz) δ 21.3,
120.0, 123.5, 125.3, 126.5, 127.7, 128.1, 129.1, 129.2,
129.6, 129.7, 130.3, 130.6, 134.0, 134.3, 135.0, 135.3,
139.0, 159.8, 165.4 (one 13C signal was not observed).
HRMS (ESI) calcd for C23H16NO2 [M + H]+ 338.1176,
found 338.1176.
14-Phenylbenzo[g]isoindolo[2,1-b]isoquinoline-5,7-
o
1
dione (2j): Yellow solid (111 mg, 74%), mp >300 C. H
NMR (CDCl3, 400 MHz) δ 6.33 (d, J = 7.6 Hz, 1H), 7.34
(dt, J = 0.8, 7.6 Hz, 1H), 7.43 (dt, J = 0.8, 7.6 Hz, 1H),
7.49-7.51 (m, 3H), 7.53-7.57 (m, 2H), 7.67-7.70 (m, 3H),
7.74-7.76 (m, 1H), 7.98 (d, J = 7.6 Hz, 1H), 8.03-8.06 (m,
1H), 9.13 (s, 1H); 13C NMR (CDCl3, 150 MHz) δ 120.3,
123.8, 125.1, 125.3, 126.4, 127.5, 128.3, 128.4, 129.1,
129.2, 129.7, 129.78, 129.83, 130.4, 130.6, 131.5, 132.2,
133.3, 134.17, 134.19, 135.3, 135.7, 160.2, 165.3. HRMS
(ESI) calcd for C26H15NNaO2 [M + Na]+ 396.0995, found
396.1008.
4-Methyl-12-phenylisoindolo[2,1-b]isoquinoline-5,7-
o
dione (2d): Yellow solid (96 mg, 71%), mp >300 C. 1H
NMR (CDCl3, 600 MHz) δ 2.97 (s, 3H), 6.26 (d, J = 7.8
Hz, 1H), 6.97 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H),
7.30-7.33 (m, 1H), 7.39-7.42 (m, 4H), 7.62-7.63 (m, 3H),
7.94 (d, J = 7.8 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ
24.1, 120.0, 123.6, 125.16, 125.21, 125.7, 128.4, 129.1,
129.7, 130.4, 131.3, 132.3, 132.8, 134.1, 134.5, 134.7,
138.9, 144.2, 160.7, 165.5 (one 13C signal was not
observed). HRMS (ESI) calcd for C23H15 NNaO2 [M +
Na]+ 360.0995, found 360.0996.
14-Phenylbenzo[f]isoindolo[2,1-b]isoquinoline-7,9-
o
dione (2k): Yellow solid (78 mg, 52%), mp 266-267 C.
1H NMR (CDCl3, 400 MHz) δ 5.84 (d, J = 8.0 Hz, 1H),
6.99-7.03 (m, 1H), 7.18-7.22 (m, 1H), 7.31 (dt, J = 0.8, 7.6
Hz, 1H), 7.38-7.41 (m, 2H), 7.45-7.47 (m, 2H), 7.57-7.64
(m, 3H), 7.76-7.78 (m, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.88
(d, J = 7.6 Hz, 1H), 8.54 (d, J = 8.8 Hz, 1H); 13C NMR
(CDCl3, 150 MHz) δ 120.8, 124.39, 124.40, 125.4, 126.3,
127.4, 127.6, 128.0, 129.3, 129.5, 129.9, 130.1, 130.37,
130.45, 133.1, 134.3, 134.5, 135.9, 137.2, 138.1, 159.6,
165.2 (two 13C signals were not observed). HRMS (ESI)
calcd for C26H16NO2 [M + H]+ 374.1176, found 374.1178.
2-Methoxy-12-phenylisoindolo[2,1-b]isoquinoline-
5,7-dione (2e): Yellow solid (95 mg, 67%), mp 267-268
oC. 1H NMR (CDCl3, 400 MHz) δ 3.76 (s, 3H), 6.31 (d, J =
7.6 Hz, 1H), 6.50 (d, J = 2.0 Hz, 1H), 7.05 (dd, J = 2.0, 8.8
Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.40-7.43 (m, 3H), 7.62-
7.63 (m, 3H), 7.97 (d, J = 7.6 Hz, 1H), 8.51 (d, J = 8.8 Hz,
1H); 13C NMR (CDCl3, 150 MHz) δ 55.5, 110.2, 115.2,
119.6, 121.1, 123.7, 125.3, 128.4, 129.2, 129.8, 129.9,
130.3, 131.5, 132.2, 133.8, 134.2, 135.1, 139.6, 159.4,
164.0, 165.3. HRMS (ESI) calcd for C23H16NO3 [M + H]+
354.1125, found 354.1135.
4-Phenylfuro[3',2':4,5]pyrido[2,1-a]isoindole-9,11-
o
1
dione (2l): Yellow solid (85 mg, 68%), mp >300 C. H
NMR (CDCl3, 600 MHz) δ 6.38 (s, 1H), 6.74 (d, J = 7.8
Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.41 (t, J = 7.2 Hz, 1H),
7.49-7.50 (m, 2H), 7.59-7.61 (m, 3H), 7.74 (s, 1H), 7.96 (d,
J = 7.8 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ 108.0,
116.0, 123.0, 125.7, 128.3, 129.4, 129.5, 129.6, 129.8,
133.0, 133.3, 134.6, 135.0, 135.3, 143.6, 149.8, 151.0,
165.2. HRMS (ESI) calcd for C20H12NO3 [M + H]+
314.0812, found 314.0828.
2-Fluoro-12-phenylisoindolo[2,1-b]isoquinoline-5,7-
o
1
dione (2f): Yellow solid (101 mg, 74%), mp >300 C. H
NMR (CDCl3, 600 MHz) δ 6.35 (d, J = 8.4 Hz, 1H), 6.75
(d, J = 9.6 Hz, 1H), 7.20 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 7.8
Hz, 1H), 7.42-7.47 (m, 3H), 7.65 (m, 3H), 7.98 (d, J = 7.2
Hz, 1H), 8.57 (t, J = 7.2 Hz, 1H); 13C NMR (CDCl3, 150
MHz) δ 112.5 (d, J = 23.1 Hz, 1C), 116.4 (d, J = 23.0 Hz,
1C), 118.9 (d, J = 3.3 Hz, 1C), 123.9, 124.2, 125.4, 128.2,
129.5, 130.0, 130.2, 130.3, 132.3 (d, J = 11.0 Hz, 1C),
4-Phenylthieno[3',2':4,5]pyrido[2,1-a]isoindole-9,11-
o
1
dione (2m): Yellow solid (92 mg, 70%), mp >300 C. H
132.8, 133.2, 134.5, 134.9, 140.2 (d, J = 9.8 Hz, 1C), 158.8, NMR (CDCl3, 400 MHz) δ 6.56 (d, J = 8.0 Hz, 1H), 6.82
165.1, 166.3 (d, J = 253.8 Hz, 1C). HRMS (ESI) calcd for
(d, J = 5.6 Hz, 1H), 7.34 (dt, J = 0.8, 7.6 Hz, 1H), 7.42 (dt,
J = 0.8, 7.2 Hz, 1H), 7.46-7.48 (m, 2H), 7.60-7.61 (m, 3H),
7.69 (d, J = 4.8 Hz, 1H), 7.96 (d, J = 7.2 Hz, 1H); 13C
NMR (CDCl3, 150 MHz) δ 117.9, 123.2, 125.2, 125.6,
128.0, 129.3, 129.6, 129.7, 129.9, 132.4, 133.5, 134.1,
134.5, 135.1, 135.2, 146.7, 155.7, 165.5. HRMS (ESI)
calcd for C20H12NO2S [M + H]+ 330.0583, found 330.0592.
C22H13FNO2 [M + H]+ 342.0925, found 342.0922.
2-Chloro-12-phenylisoindolo[2,1-b]isoquinoline-5,7-
o
1
dione (2g): Yellow solid (113 mg, 79%), mp >300 C. H
NMR (CDCl3, 400 MHz) δ 6.32 (d, J = 8.0 Hz, 1H), 7.06
(d, J = 1.2 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.41-7.43 (m,
2H), 7.45 (s, 1H), 7.48 (m, 1H), 7.65-7.67 (m, 3H), 7.98 (d,
J = 7.2 Hz, 1H), 8.50 (d, J = 8.4 Hz, 1H); 13C NMR
(CDCl3, 150 MHz) δ 118.6, 123.9, 125.4, 126.0, 126.1,
128.1, 128.7, 129.5, 130.0, 130.27, 130.28, 130.8, 132.8,
133.1, 134.5, 134.9, 138.9, 140.7, 158.9, 165.1. HRMS
(ESI) calcd for C22H13ClNO2 [M + H]+ 358.0629, found
358.0630.
7-Methyl-4-(p-tolyl)thieno[3',2':4,5]pyrido[2,1-
a]isoindole-9,11-dione (2n): Yellow solid (116 mg, 81%),
mp 282-283 oC. 1H NMR (CDCl3, 600 MHz) δ 2.31 (s, 3H),
2.44 (s, 3H), 6.44 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 4.8 Hz,
1H), 7.08 (dd, J = 0.6, 8.4 Hz, 1H), 7.26 (d, J = 7.8 Hz,
2H), 7.31 (d, J = 7.8 Hz, 2H), 7.58 (d, J = 4.8 Hz, 1H),
7.67 (s, 1H); 13C NMR (CDCl3, 150 MHz) δ 21.4, 21.5,
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800347
Advanced Synthesis & Catalysis
117.2, 123.0, 125.3, 125.6, 128.1, 129.6, 130.2, 131.1,
131.9, 132.8, 133.7, 134.9, 135.5, 139.1, 140.5, 147.0,
155.8, 165.7. HRMS (ESI) calcd for C22H15NNaO2S [M +
Na]+ 380.0716, found 380.0716.
11-(Thiophen-2-yl)thieno[2',3':3,4]pyrrolo[1,2-
b]isoquinoline-4,6-dione (2u): Yellow solid (84 mg, 63%),
o
1
mp >300 C. H NMR (CDCl3, 400 MHz) δ 7.22-7.23 (m,
1H), 7.29-7.39 (m, 4H), 7.53 (t, J = 7.6 Hz, 1H), 7.63 (t, J
= 7.6 Hz, 1H), 6.67 (d, J = 5.2 Hz, 1H), 8.54 (d, J = 8.0 Hz,
1H); 13C NMR (CDCl3, 150 MHz) δ 111.3, 121.5, 126.4,
128.2, 128.7, 128.9, 129.5, 129.8, 131.8, 132.7, 133.91,
133.93, 136.7, 137.0, 146.1, 159.0, 160.2 (one 13C signal
was not observed). HRMS (ESI) calcd for C18H9NNaO2S2
[M + Na]+ 357.9967, found 357.9968.
3-Methyl-1-phenylpyrido[2,1-a]isoindole-4,6-dione
o
1
(2o): Yellow solid (85 mg, 74%), mp 144-145 C. H
NMR (CDCl3, 600 MHz) δ 2.15 (d, J = 1.2 Hz, 3H), 6.77
(d, J = 7.8 Hz, 1H), 7.02 (q, J = 1.2 Hz, 1H), 7.29 (dt, J =
1.2, 7.8 Hz, 1H), 7.33-7.37 (m, 3H), 7.44-7.47 (m, 3H),
7.87 (d, J = 7.8 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ
16.5, 120.2, 122.9, 125.6, 127.3, 128.99, 129.04, 129.3,
130.0, 134.1, 134.5, 134.6, 134.8, 136.0, 140.0, 160.3,
165.6. HRMS (ESI) calcd for C19H14NO2 [M + H]+
288.1019, found 288.1021.
12-Methylisoindolo[2,1-b]isoquinoline-5,7-dione (2v):
o
1
Yellow solid (78 mg, 75%), mp 279-280 C. H NMR
(CDCl3, 400 MHz) δ 2.71 (s, 3H), 7.51-7.56 (m, 2H), 7.72-
7.78 (m, 3H), 8.02-8.05 (m, 2H), 8.53 (d, J = 8.0 Hz, 1H);
13C NMR (CDCl3, 150 MHz) δ 13.0, 114.6, 124.1, 124.2,
125.6, 127.8, 128.3, 129.3, 129.5, 131.0, 133.8, 134.7,
135.5, 136.9, 159.6, 165.1 (one 13C signal was not
observed). HRMS (ESI) calcd for C17H11NNaO2 [M + Na]+
284.0682, found 284.0697.
9-Methyl-12-(p-tolyl)isoindolo[2,1-b]isoquinoline-5,7-
o
1
dione (2p): Yellow solid (104 mg, 74%), mp >300 C. H
NMR (CDCl3, 400 MHz) δ 2.39 (s, 3H), 2.54 (s, 3H), 6.29
(d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.16 (d, J =
8.4 Hz, 1H), 7.29 (d, J = 7.6 Hz, 2H), 7.42 (d, J = 8.0 Hz,
2H), 7.49 (t, J = 7.6 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.77
(s, 1H), 8.55 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3, 100
MHz) δ 21.4, 21.5, 119.0, 123.6, 125.3, 126.4, 127.7,
128.1, 128.3, 129.1, 130.2, 130.4, 130.8, 131.7, 132.9,
133.6, 135.5, 137.7, 139.0, 140.5, 159.8, 165.5. HRMS
(ESI) calcd for C24H17NNaO2 [M + Na]+ 374.1151, found
374.1163.
Isoindolo[2,1-b]isoquinoline-5,7-dione (2w):[9a] Yellow
solid (79 mg, 80%), mp 245-246 oC. 1H NMR (CDCl3, 400
MHz) δ 6.92 (s, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.50-7.53 (m,
2H), 7.64 (t, J = 7.6 Hz, 1H), 7.70 (t, J = 7.2 Hz, 1H), 7.77
(d, J = 7.6 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 8.42 (d, J =
8.0 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ 103.6, 120.6,
125.5, 127.5, 127.7, 128.2, 128.5, 129.4, 130.5, 133.9,
134.8, 135.0, 135.6, 159.7, 165.1 (one 13C signal was not
observed). HRMS (ESI) calcd for C16H9NNaO2 [M + Na]+
270.0525, found 270.0532.
10-Methyl-12-(m-tolyl)isoindolo[2,1-b]isoquinoline-
5,7-dione (2q): Yellow solid (101 mg, 72%), mp 236-237
1
oC. H NMR (CDCl3, 400 MHz) δ 2.19 (s, 3H), 2.48 (s,
3H), 6.13 (s, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.21-7.23 (m,
3H), 7.44 (d, J = 7.6 Hz, 1H), 7.49-7.54 (m, 2H), 7.57 (d, J
3-(Trifluoromethyl)isoindolo[2,1-b]isoquinoline-5,7-
dione (2x): Yellow solid (86 mg, 68%), mp > 300 C. H
o
1
= 7.2 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 8.54 (d, J = 7.6 Hz, NMR (CDCl3, 400 MHz) δ 7.04 (s, 1H), 7.66 (t, J = 6.8 Hz,
1H); 13C NMR (CDCl3, 150 MHz) δ 21.5, 22.3, 119.7,
124.3, 125.1, 125.7, 126.5, 127.3, 127.9, 128.3, 129.1,
129.5, 129.8, 130.8, 130.9, 131.5, 133.7, 133.8, 135.7,
137.5, 139.5, 145.4, 159.8, 165.4. HRMS (ESI) calcd for
C24H17NNaO2 [M + Na]+ 374.1151, found 374.1150.
1H), 7.72 (d, J = 8.4 Hz, 1H), 7.80 (t, J = 6.8 Hz, 1H), 7.87
(d, J = 7.6 Hz, 1H), 7.93 (dd, J = 1.6, 8.0 Hz, 1H), 8.07 (d,
J = 7.6 Hz, 1H), 8.78 (s, 1H); 13C NMR (CF3COOD, 150
MHz) δ 108.1, 124.4, 126.5 (q, J = 270.2 Hz, 1C), 129.3,
129.6, 129.7, 129.9, 132.1, 135.0, 135.1, 135.3 (q, J = 33.9
Hz, 1C), 138.5, 139.8, 140.1, 142.5, 165.8, 171.8. HRMS
(ESI) calcd for C17H8F3NNaO2 [M + Na]+ 338.0399, found
338.0401.
9-Fluoro-12-(4-fluorophenyl)isoindolo[2,1-
b]isoquinoline-5,7-dione (2r): Yellow solid (111 mg,
o
1
77%), mp >300 C. H NMR (CDCl3, 400 MHz) δ 6.34-
6.37 (m, 1H), 7.07-7.11 (m, 2H), 7.35 (t, J = 8.4 Hz, 2H),
7.40-7.43 (m, 2H), 7.54 (t, J = 7.6 Hz, 1H), 7.59-7.65 (m,
9-(Trifluoromethyl)isoindolo[2,1-b]isoquinoline-5,7-
dione (2y): Yellow solid (76 mg, 60%), mp 297-298 C.
o
2H), 8.56 (d, J = 7.6 Hz, 1H); 13C NMR (CDCl3, 150 MHz) 1H NMR (CDCl3, 400 MHz) δ 7.03 (s, 1H), 7.50-7.55 (m,
δ 111.8 (d, J = 24.0 Hz, 1C), 117.1 (d, J = 21.9 Hz, 2C),
2H), 7.66 (dt, J = 0.8, 8.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H),
118.7, 122.2 (d, J = 23.0 Hz, 1C), 125.6 (d, J = 7.7 Hz, 1C), 7.92 (d, J = 8.0 Hz, 1H), 8.23 (s, 1H), 8.46 (d, J = 8.0 Hz,
126.4, 127.3, 128.6, 129.1, 129.4 (d, J = 3.3 Hz, 1C), 130.2
(d, J = 8.7 Hz, 1C), 131.0 (d, J = 2.3 Hz, 1C), 132.3 (d, J =
8.7 Hz, 2C), 134.0, 137.1, 159.3, 163.3 (d, J = 248.3 Hz,
1C), 163.5 (d, J = 252.8 Hz, 1C), 163.9 (d, J = 3.3 Hz, 1C)
(one 13C signal was not observed). HRMS (ESI) calcd for
C22H11F2NNaO2 [M + Na]+ 382.0650, found 382.0656.
1H); 13C NMR (CDCl3, 150 MHz) δ 105.7, 121.2, 123.1 (q,
J = 3.3 Hz, 1C), 123.3 (q, J = 271.2 Hz, 1C), 127.9, 128.3,
128.5, 129.4, 129.7, 131.5 (q, J = 3.3 Hz, 1C), 132.8 (q, J
= 32.9 Hz, 1C), 133.9, 134.3, 135.1, 137.7, 159.5, 163.8.
HRMS (ESI) calcd for C17H8F3NNaO2 [M + Na]+ 338.0399,
found 338.0394.
9-Chloro-12-(4-chlorophenyl)isoindolo[2,1-
Benzo[6,7]isoindolo[2,1-b]isoquinoline-7,9-dione (2z):
Yellow solid (76 mg, 64%), mp >300 oC. 1H NMR (CDCl3,
400 MHz) δ 7.41 (s, 1H), 7.47 (dt, J = 1.2, 8.0 Hz, 1H),
7.58 (d, J = 7.6 Hz, 1H), 7.62-7.67 (m, 2H), 7.70 (dt, J =
1.2, 7.2 Hz, 1H), 7.90-7.94 (m, 3H), 8.42-8.46 (m, 2H);
b]isoquinoline-5,7-dione (2s): Yellow solid (113 mg,
72%), mp 261-262 oC. 1H NMR (CDCl3, 400 MHz) δ 6.34-
6.37 (m, 1H), 7.07-7.10 (m, 2H), 7.36 (t, J = 8.0 Hz, 2H),
7.43-7.46 (m, 2H), 7.50 (t, J = 7.6 Hz, 1H), 7.58-7.62 (m,
2H), 8.50 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3, 150 MHz) 13C NMR (CDCl3, 150 MHz) δ 108.6, 120.4, 124.1, 127.0,
δ 119.0, 124.7, 125.4, 126.3, 127.7, 128.9, 129.5, 129.7,
130.2, 131.0, 131.8, 132.0, 133.1, 134.1, 134.7, 135.7,
136.6, 136.8, 159.4, 163.9. HRMS (ESI) calcd for
C22H11Cl2NNaO2 [M + Na]+ 414.0059, found 414.0061.
127.4, 128.0, 128.2, 128.8, 128.9, 129.0, 129.3, 130.2,
132.0, 132.1, 134.0, 135.8, 136.1, 137.3, 159.7, 165.5.
HRMS (ESI) calcd for C20H11NNaO2 [M + Na]+ 320.0682,
found 320.0679.
11-Chloro-12-(2-chlorophenyl)isoindolo[2,1-
b]isoquinoline-5,7-dione (2t): Yellow solid (11 mg, 7%),
mp 246-247 oC. 1H NMR (CDCl3, 600 MHz) δ 7.01 (d, J =
7.8 Hz, 1H), 7.37-7.41 (m, 2H), 7.44 (t, J = 7.2 Hz, 1H),
7.47-7.51 (m, 2H), 7.55-7.60 (m, 3H), 8.00 (d, J = 7.2 Hz,
1H), 8.57 (d, J = 7.2 Hz, 1H); 13C NMR (CDCl3, 150 MHz)
δ 119.9, 124.2, 126.9, 127.38, 127.43, 129.0, 129.2, 129.9,
130.1, 130.7, 131.2, 131.9, 132.0, 132.5, 133.7, 134.1,
135.4, 136.2, 136.6, 138.1, 159.8, 164.0. HRMS (ESI)
calcd for C22H11Cl2NNaO2 [M + Na]+ 414.0059, found
414.0052.
General Procedure for the One-Pot Two-Step Synthesis
of Isoindolo[2,1-b]isoquinoline-5,7-diones (2) via
a
Rh/Pd Relay Catalysis.
To a schlenk tube (15 mL) containing a mixture of N-
methoxy benzamide 3 (0.4 mmol) and internal alkyne 4
(0.44 mmol) in chlorobenzene (2 mL) were added
[Cp*RhCl2]2 (0.01 mmol) and CsOAc (0.12 mmol). Then,
o
the reaction mixture was stirred at 60 C for 16 h until N-
methoxy benzamide 3 was consumed completely. Next,
Pd(OAc)2 (0.04 mmol), AgOTFA (0.8 mmol), and Na2CO3
7
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10.1002/adsc.201800347
Advanced Synthesis & Catalysis
(0.2 mmol) were added into the above reaction system
under CO (1 atm) atmosphere. After being stirred at 120 oC
for 15 h, the resulting mixture was quenched with NH4Cl
and extracted with dichloromethane. The extract was
washed with H2O and brine and then dried over anhydrous
Na2SO4. The solvent was evaporated under reduced
pressure and the crude product was purified by column
chromatography on silica gel (dichloromethane/ethyl
acetate = 10:1) to afford the corresponding isoindolo[2,1-
b]isoquinoline-5,7-dione 2.
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(1) Intramolecular competitive experiment: The reaction
of [D1]-1w (88.8 mg, 0.4 mmol) was run for 3 h under the
optimized conditions. After isolation and purification, the
products [D1]-2w and 2w were obtained in 21.5 mg (22%),
and the starting material [D1]-1w was recovered in 55.8 mg
(63%). The deuteration rate of the product was determined
by 1H NMR ([D1]-2w:2w = 0.6:0.4).
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mmol) was subjected to the optimized conditions for 3 h.
After isolation and purification, the products 2w and [D4]-
2w were obtained in 19.2 mg (19%). The deuteration rate
1
of the product was determined by H NMR (2w:[D4]-2w =
0.71:0.29).
(3) Parallel experiment: Individual reactions of 1w (44.2
mg, 0.2 mmol) and [D5]-1w (45.2 mg, 0.2 mmol) were
performed under the optimized conditions for 3 h. After
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Acknowledgements
We thank the National Natural Science Foundation of China
(Grants 21202040 and 21572047), Project Funded by China
Postdoctoral Science Foundation (2014M552007 and
2015T80771), the Program for Innovative Research Team in
Science and Technology in University of Henan Province
(15IRTSTHN003), Program for Science and Technology
Innovation Talents in Universities of Henan Province
(15HASTIT005), and the Plan for Scientific Innovation Talents of
Henan Province (184200510012) for financial support.
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Fan, Org. Biomol. Chem. 2017, 15, 3674-3680; c) J.
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Advanced Synthesis & Catalysis
FULL PAPER
Palladium-Catalyzed Oxidative Cyclocarbonylation
of Isoquinolones with CO via C-H/N-H Bond
Cleavage: Easy Access to Isoindolo[2,1-
b]isoquinoline-5,7-dione Derivatives
Adv. Synth. Catal. Year, Volume, Page – Page
Shenghai Guo,* Fang Wang, Lincong Sun, Xinying
Zhang, and Xuesen Fan*
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