Copper and palladium-catalyzed sequential reactions: One-pot synthesis of isoindolo[2,1-b] isoquinolin-7(5 H)-ones

Article abstract of DOI:10.1039/c9ob00440h

A highly efficient protocol has been developed for the synthesis of diversely substituted isoindolo[2,1-b]isoquinolin-7(5H)-ones through sequential Cu(ii)-catalyzed Sonogashira coupling, intramolecular hydroamidation followed by palladium-catalyzed ligand-free Heck reaction. Good to excellent yields (41-94%) were observed with excellent substrate scope and functional group tolerance. The developed method represents a practical strategy for the construction of bioactive isoindolo[2,1-b]isoquinolin-7(5H)-ones.

Full text of DOI:10.1039/c9ob00440h

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DOI: 10.1039/C9OB00440H
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Copper and palladium-catalyzed sequential reactions: One-pot
synthesis of isoindolo[2,1-b]isoquinolin-7(5H)-ones
Hitesh K. Saini,§,a Shiv Dhiman,§,a Nitesh K. Nandwana,a Krishnan Ranganb and Anil Kumar*a
Received 00th January 20xx,
Accepted 00th January 20xx
A highly efficient protocol has been developed for the synthesis of diversely substituted isoindolo[2,1-b]isoquinolin-7(5H)-
ones through sequential Cu(II)-catalyzed Sonogashira coupling, intramolecular hydroamidation followed by palladium
catalyzed ligand-free Heck reaction. Good to excellent yields (41-94%) were observed with excellent substrate scope and
functional group tolerance. The developed method represents a practical strategy for the construction of bioactive
isoindolo[2,1-b]isoquinolin-7(5H)-ones.
DOI: 10.1039/x0xx00000x
www.rsc.org/
catalyzed
consecutive
Sonogashira
coupling
and
Introduction
The isoindolinone framework is a key structural feature found
in many natural and pharmacologically active compounds. For
example, isoindolinone based natural compounds such as
Lenalidomide,1,
hydroamidation cyclization reactions have been used for the
synthesis of isoindoloquinazolines.21-24 Hu and coworkers
prepared fused isoindolinone heterocyclic derivatives through
palladium-catalyzed cyclization of 1,6-dienes with aryl halides
that involved C–C coupling/C–H functionalization in a one-step
domino reaction.25 Zhang group developed an efficient method
for the synthesis of indolizinones using gem-dibromoolefins
through palladium-catalyzed reaction that involves sequential
one-pot intramolecular C–N bond formation and direct C–H
arylation (Scheme 1a).26 Kim group prepared isoindolo[2,1-
b]isoquinoline derivatives by palladium catalyzed sequential
intramolecular double Heck reactions (Scheme 1b).27 Previously
Kim group reported synthesis of Magallanesine an alkaloid
containing isoindolinone core by employing sequential
intramolecular Heck reaction and Friedel–Crafts acylation
reactions.
2
Aristoyagonine,3
E),
Aristolactams4-6
8
(Goniothalactam,
Piperolactam
Nuevamine,7,
Lennoxamine,9 Magallanesine10 and Rosettacin11 (Figure 1) as
well as synthetic compounds such as isoindolo[2,1-
b]isoquinolin5(7H)-one (topoisomerase I inhibitor)12, 13 (Figure
1) have demonstrated fascinating biological properties.
OMe
O
O
O
O
O
MeO
MeO
MeO
HO
N
N
O
N
Me
N
N
Me
Me
MeO
NH
MeO
O
OMe
NH2
O
MeO
MeO
HO
O
O
Nuevamine
O
Lenalidomide
Piperolactam E
Aristoyagonine
Goniothalactam
O
N
O
O
O
O
OMe
OMe
N
O
O
N
N
i) K2CO3 (3 equiv), Toluene,
70 °C, 5 h
N
N
H
OMe
O
N
O
(a)
O
N
O
N
O
ii) Pd(OAc)2 (10 mol %)
P(2-MeOPh)3 (20 mol %)
120 °C, 12 h
OMe
Isoindolo[2,1-b]isoquinolin-5(7H)-one
Lennoxamine
Magallanesine
Rosettacin
Br
Br
N
topoisomerase I inhibitor
2014
Zhang et al. RSC Adv.
, 4, 51298
O
Figure 1. Selected natural products and bioactive compounds containing isoindolinone
scaffold.
O
I
Br
N
Pd(OAc)2 (10 mol %)
NaHCO3 (2 equiv)
(b)
(c)
(d)
DMF, 110 °C, 5 h
CO2Et
In view of the diverse biological spectrum and unique structural
features of isoindolinones, much efforts have been devoted to
synthesize isoindolinone core and its derivatives by several
research groups.14-17 In recent years, transition metal catalyzed
CO2Et
2016
Kim et al. Tetrahedron Lett.
, 57, 5348
HO
O
O
[CpRhCl2]2, CsOAc
Acetone, rt, 1-3 h
N
OHC
OPiv
N
H
R
sequential reactions,18-20
and more specifically copper-
R
Reddy et al. Org. Lett. 2018, 20, 150
O
i) Cu(OAc)2 H2O, K2CO3
DMF, 130 °C, 1 h
O
N
N
H
§
ii) Pd(OAc)2, Ph3P
130 °C, 2 h
Br
Both authors contributed equally.
Br
a. Mr. HK Saini, Mr. S Dhiman, Mr. NK Nandwana, and Prof. A Kumar
Department of Chemistry, BITS Pilani, Pilani Campus, Pilani, Rajasthan, India
333031, E-mail: anilkumar@pilani.bits-pilani.ac.in.
2017
Kumar et al. Eur. J. Org. Chem.
, 7277
Scheme 1. Synthesis of heterocycle-fused isoindolinone derivatives.
b. Prof. K Rangan
Department of Chemistry, BITS Pilani, Hyderabad Campus, Secunderabad,
Telangana, India 500078.
Reddy group prepared 7-hydroxyisoindolo[2,1-b]isoquinolin-
5(7H)-ones by Rh(III)-catalyzed reaction of 2-alkynyl aldehydes
and N-(pivaloyloxy)benzamides that involve cascade alkyne
Electronic Supplementary Information (ESI) available: [Copies of 1H & 13C NMR,
HRMS spectra and single crystal X-ray data for 4aa, 5aa and 6aa]. See
DOI: 10.1039/x0xx00000x
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insertion/intramolecular amide nitrogen addition to aldehydes the first step resulted in decreased yield of 4aaVwiewitAhrticslleigOhnltinlye
(Scheme 1c).28 Van der Eycken also reported rhodium(III)- increased yield of 6aa (Table 1, entries 7DaOnI:d108.)1.039/C9OB00440H
catalyzed intramolecular insertion of alkyne through C–H
activation of benzamides bearing N-tethered alkynes to
synthesize indolizinones and quinolizinones.29 Recently, our
group also reported an efficient one-pot method of the
synthesis of azepino-fused isoindolinones via sequential
copper-catalyzed Sonogashira coupling, intramolecular
Table 1. Optimization of the reaction conditions.[a]
O
Br
O
O
O
1) Cu-salt, base
solvent, temp
N
N
N
H
N
Br
Br
2) Pd-catalyst
Ph
1a
Ph
4aa
Ph
5aa
Ph
Ph
2a
6aa
% Yield[b]
S.
Cu-catalyst
Pd-catalyst
Base
Solvent
hydroamination and palladium-catalyzed intramolecular direct No.
4aa 5aa 6aa
54 15
arylation reaction (Scheme 1d).30 Herein, we report our results
for the synthesis of isoindolo[2,1-b]isoquinolin-7(5H)-one from
2-bromo-N-(2-bromobenzyl)benzamides through copper-
catalyzed Sonogashira coupling, intramolecular hydroamidation
and subsequent palladium(II)-catalyzed ligand-free Heck
reaction (Scheme 2).
1. Cu(OAc)2·H2O Pd(OAc)2
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
3
2. Cu(OAc)2·H2O Pd(OAc)2/PPh3 K2CO3
32[c] 39 00
3. Cu(OAc)2·H2O Pd(OAc)2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
71
44
40
41
63
68
52
49
46
74
8
9
05
7
4. CuBr
5. CuCl2
6. CuI
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
11
8
5
12
11
05
5
O
7. Cu(OAc)2·H2O[d] Pd(OAc)2
5
i) Cu(OAc)2 H2O, K3PO4
DMF, 120 °C, 2 h
O
Br
N
N
8. Cu(OAc)2·H2O[e] Pd(OAc)2/PPh3 K2CO3
7
R
H
ii) Pd(OAc)2,120 °C, 1 h
R
Br
R = Alkyl, aryl
9. Cu(OAc)2·H2O PdCl2
K2CO3
K2CO3
K2CO3
K2CO3
7
Scheme 2. Synthesis of isoindolo[2,1-b]isoquinolin-7(5H)-one derivatives.
10. Cu(OAc)2·H2O PdCl2(PPh3)2
11. Cu(OAc)2·H2O Pd(PPh3)4
12. Cu(OAc)2·H2O Pd(OAc)2
13. Cu(OAc)2·H2O Pd(OAc)2
14. Cu(OAc)2·H2O Pd(OAc)2
15. Cu(OAc)2·H2O Pd(OAc)2
16. Cu(OAc)2·H2O Pd(OAc)2
17. Cu(OAc)2·H2O Pd(OAc)2
4
7
8
4
6
0
Results and discussion
K2CO3 Toluene
NR[f]
NR[f]
4
Our studies commenced with the reaction of 2-bromo-N-(2-
bromobenzyl)benzamide (1a) and phenylacetylene (2a) under
our previously reported condition for sequential reactions.30
The reaction of 1a and 2a in the presence of Cu(OAc)2·2H2O (10
mol %), K2CO3 (2 equiv.) in DMF for 1 h at 130 C followed by
addition of Pd(OAc)2 (5 mol %) and PPh3 (10 mol %) to the
cooled reaction mixture and heating for additional 2 h at 130 C
resulted in one major product along with two minor products
(Table 1, entry 1). To our surprise, 1H NMR and 13C NMR data of
major product were not consistent with the expected
compound, dibenzo[4,5:6,7]azocino[2,1-a]isoindol-11(9H)-one
(3), but were well in agreement with 12-phenylisoindolo[2,1-
b]isoquinolin-7(5H)-one (4aa) (Scheme 3).
K2CO3
K3PO4
tBuOK
Cs2CO3
MeCN
DMF
DMF
DMF
76
8
0
41
5
0
0
6
[a]Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), Cu-catalyst (10 mol %),
base (1.0 mmol), solvent (4 mL) at 120 C, 2 h followed by Pd-catalyst (5 mol
%), 120 C, 1 h. [b]Isolated yields. [c]Reaction was performed at 90 C. [d]20
mol % Cu(OAc)2·H2O was used. [e]30 mol % Cu(OAc)2·H2O was used. fReaction
was performed at reflux. NR = No reaction.
We then investigated other palladium sources including PdCl2,
PdCl2(PPh3)2 and Pd(PPh3)4 and identified Pd(OAc)2 as the most
efficient catalyst (Table 1, compare entry 3 with entries 9-11).
Further investigation showed that the reaction was slightly
more efficient under air atmosphere as compared to nitrogen
atmosphere, indicating that oxygen might play an important
role in the reaction. Different solvents were screened, and DMF
proved to be the optimal solvent (Table 1, compare entry 3 with
entries 12-14). From the screening of different bases such as
O
O
O
Br
i) Cu(OAc)2 H2O, K2CO3
DMF, 120 °C, 2 h
N
N
N
H
+
Br
ii) Pd(OAc)2,PPh3, 130 °C, 1 h
3
Ph
4aa
1a
2a
Scheme 3. The reaction of 2-bromo-N-(2-bromobenzyl)benzamide and phenylacetylene.
Encouraged by initial results, we decided to optimize the
reaction conditions for the synthesis of 4aa by varying the
catalyst, solvent, and base. The results are summarized in Table
1. A slight increment in the yield of 4aa was observed when
Pd(OAc)2 was added without external PPh3 ligand (Table 1, entry
3). This result indicates that the palladium catalyzed Heck
coupling may be proceeding through Pd(II) and not through
Pd(0). Screening of different copper catalysts revealed
Cu(OAc)2·H2O to be ideal, providing 4aa in 71% yield (Table 1,
entry 3). The use of other copper salts such as CuCl2, CuBr, and
CuI failed to afford the desired product 4aa in satisfactory yields
(Table 1, entries 4-6). Increasing amount of copper catalyst in
t
K2CO3, K3PO4, BuOK, and Cs2CO3 (Table 1, entries 3, 15-17),
K3PO4 was found the most suitable base for this transformation
which is in agreement with the first report on ligand-free
Pd(OAc)2 catalyzed Heck reaction.31
The structure of the major product 4aa (CCDC No 1853630) was
unambiguously confirmed by single crystal X-ray analysis
(Figure 2). The other two minor products were 3-benzylidene-
2-(2-bromobenzyl)isoindolin-1-one (5aa) and 3-benzylidene-2-
(2-(phenylethynyl)benzyl)-isoindolin-1-one
(6aa).
The
structures of both 5aa (CCDC No 1853080) and 6aa (CCDC
1853081) were also unambiguously confirmed by single crystal
X-ray analysis (Figure 2).
2 | J. Name., 2012, 00, 1-3
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4aa
5aa
6aa
Next, the scope of diversely substituted 2-VbierwoAmrticole-NOn-(li2ne-
bromobenzyl)benzamides was exploreDdOI(:T1a0b.1l0e39/3C)9. OAB0t04fi4r0sHt,
benzamides (1b-e) with either electron donating or electron
withdrawing substituents on amide ring reacted smoothly with
phenylacetylene (2a) to give corresponding products 4ba-ea in
good to excellent yields (56-92%). Next, benzamides (1b-e) with
a substituent on amide ring were treated with differently
substituted alkynes (2a-e) to give corresponding isoindolo[2,1-
b]isoquinolin-7(5H)-ones (4bb-ee) in moderate to excellent (41-
94%) yields. No obvious electronic effect was observed for
substitution at the C-3 position of benzamide, however
benzamide with a 4-fluoro substituent on amide ring (1e)
resulted in the highest yield. Good yield from fluorine
substituted substrate provides an opportunity for further
functionalization.32 Benzamide 1f and 1g bearing 3,4-dimethoxy
and 3,4-dioxomethylene groups, respectively, in the benzyl ring
reacted well with different alkynes (2a-f) to give corresponding
products (4fa-gc) in moderate to good yield. Finally, 2-bromo-
N-(2-bromobenzyl)-5-nitrobenzamide (1h) with nitro group on
the benzene ring was allowed to react with 2a under standard
optimized conditions. However, desired product (4ha) was not
observed and only isoindolinone intermediate, 3-benzylidene-
2-(2-bromobenzyl)-6-nitroisoindolin-1-one (5ha) was obtained
in 28% yield.
Figure 2. ORTEP diagram for 4aa, 5aa and 6aa.
With the optimized condition in hand, the scope of the
sequential reaction was investigated by using a variety of 2-
bromo-N-(2-bromobenzyl)benzamides and terminal alkynes
(Table 2). The results listed in Table 2 indicated that
ethynylbenzenes (2b-d) with activating groups such as methyl,
methoxy, and n-propyl on the phenyl ring reacted smoothly
with 1a to give corresponding products 4ab-ad in reasonably
good (67-91%) yields.
Ethynylbenzenes with a sterically hindered tert-butyl group (2e)
and fluoro group (2f) on reaction with 1a yielded the respective
products 4ae and 4af in 49% and 44% yields, respectively.
Ortho-substituted ethynylbenzenes (2g) on reaction with 1a
also yielded corresponding product 4ag in 42% yield.
Unfortunately, ethynylbenzene with highly deactivating groups
on the phenyl ring such as 1-ethynyl-4-nitrobenzene (2h) was
unsuccessful under similar reaction conditions. 2-
Ethynylthiophene also participated in this reaction to give
corresponding product 4ai in 68% yield. Interestingly, in
addition to ethynylbenzenes, aliphatic alkynes such as pent-1-
yne (2j), hex-1-yne (2k) and hept-1-yne (2l) also reacted with 1a
to afford the corresponding compounds (4aj-al) in moderate to
excellent (53-93%) yields. In case of aliphatic alkynes, the one-
pot reaction was sluggish and thus final product was obtained
in two-step reaction by first isolating the isoindolinone
intermediate (5aj-al) and then cyclizing using Pd(OAc)2 under
standard conditions.
Table 3: Scope of 2-bromo-N-(2-bromobenzyl)benzamides for
the synthesis of isoindolo[2,1-b]isoquinolin-7(5H)-ones.[a,b]
O
O
Br
i) Cu(OAc)2.H2O, K3PO4
DMF, 120 °C, 2 h
R1
N
N
R1
R2
H
R
Br
ii) Pd(OAc)2, 120 °C, 1 h
R
1a-g
R2
4ba-ha
2a-k
O
O
O
O
MeO
Me
Cl
N
N
N
N
F
4ca
4cb
4cc
4cd
, X = H, 66%
4da
4db
4de
, X = H, 60%
, X = Me, 45%
, X = t-Bu, 41%
4ea
, 92%
4ba
4bb
X
, X = Me, 73%
, X = OMe, 45%
, X = n-Pr, 44%
, X = H, 56%
, X = Me, 62%
X
X
Table 2: Scope of alkynes for the synthesis of isoindolo[2,1-
O
O
O
O
N
O2
N
OMe
OMe
b]isoquinolin-7(5H)-ones.a,b
O
O
N
N
N
F
O
O
Br
i) Cu(OAc)2.H2O, K3PO4
DMF, 120 °C, 2 h
N
R
N
H
R
4fa, X = H
, 80%
4fb, X = Me
4fc, X = OMe, 63%
Br
ii) Pd(OAc)2, 120 °C, 1 h
, 87%
Me
OMe
4gc
2a-k
1a
4aa-ak
4eb
, X = Me, 94%
4ee
, X = t-Bu, 49%
4ff, X = F
4ha, 0%c
, 72%
, 41%
O
O
O
N
O
a]Reaction conditions: 1 (0.5 mmol), 2 (1.0 mmol), Cu(OAc)2·H2O (10 mol %), K3PO4
(1.0 mmol), DMF (4 mL), 120 C, 2 h followed by addition of Pd(OAc)2 (5 mol %) at
rt, 120 C, 1 h. [b]Isolated yields. [c]Isoindolinone intermediates (5ha) was obtained
in 28% yield.
N
N
N
4aa
, 76%
O
4ab
4ad
, 91%
O
, 67%
O
4ac
, 82%
O
Me
OMe
Pr
N
In order to check the feasibility of the developed method for
scale-up, a gram scale reaction of 1a (2.7 mmol, 1.01 g) and 2a
(5.5 mmol, 0.56 g) was performed. The reaction proceeded
smoothly to give 4aa in 69% isolated yield.
N
N
N
OMe
4ae
, 49%
O
4af, 44%
tBu
c
NO2
, 0%
4ag
4ah
, 42%
F
O
O
O
A set of control experiments was performed to elucidate the
N
N
N
N
mechanism for the sequential reaction. Firstly, the reaction of 1a and
2a under optimized conditions in the absence of Pd(OAc)2 gave 5aa
and 6aa in 77% and 4%, respectively (Scheme 4a). Further, when
isolated 5aa was treated with Pd(OAc)2 in the presence of K3PO4 in
DMF for 2 h at 130 C, cyclized product 4aa was obtained in 80% yield
(Scheme 4b). Lowering temperature for the reaction of 1a and 2a to
90 C resulted in a decrease in the yield of 4aa but an increase in the
S
Pent
Bu
Pr
d
4ai
, 68%
d
d
4aj
, 93%
4ak
, 70%
d
4al,
53%
[a]Reaction conditions: 1 (0.5 mmol), 2 (1.0 mmol), Cu(OAc)2·H2O (10 mol %), K3PO4 (1.0
mmol), DMF (4 mL), 120 C, 2 h followed by addition of Pd(OAc)2 (5 mol %) at rt, 120 C,
1 h. [b]Isolated yields. [c]Isoindolinone intermediates (5ah) was obtained in 15% yield.
[d]Isolated yields from corresponding isoindolinone intermediates (5aj-5al).
This journal is © The Royal Society of Chemistry 20xx
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yield of 5aa (Scheme 4c). Reaction of 1a with 2a using Pd(OAc)2 and
PPh3 after 5 h yielded only isoindolinone intermediate 5aa in 30%
yield (Scheme 4d). Similarly, reaction of 1a with 2a on simultaneous
addition of Cu(OAc)2·H2O and Pd(OAc)2 under standard reaction
conditions also resulted in the formation of 5aa in 55% yield and
desired product 4aa was not observed in this reaction. These results
indicate that the reaction proceeds through 5aa, Pd(OAc)2 is
essential for the Heck coupling and sequential reaction conditions
are more appropriate for this transformation.
Conclusions
View Article Online
DOI: 10.1039/C9OB00440H
In summary, we have developed a novel and efficient process
involving copper-catalyzed Sonogashira coupling,
intramolecular hydroamidation and palladium-catalyzed Heck
reaction for the preparation of isoindolo[2,1-b]isoquinolin-
7(5H)-ones derivatives. This unified approach provided
isoindolo[2,1-b]isoquinolin-7(5H)-ones in moderate to excellent
yields with broad substrate scope and functional group
compatibility.
O
Br
O
O
Cu(OAc)2.H2O (10 mol %)
K3PO4 (2 equiv)
N
H
N
N
Br
Experimental
General methods
(a)
Br
1a
DMF, 120 °C, 2 h
Ph
Ph
Ph
Ph
5aa
6aa,
4%
2a
All reagents and solvents were purchased from commercial
sources and used without further purification. Melting points
were measured using an automatic capillary point apparatus
and are uncorrected. The thin layer chromatography (TLC) was
performed on 0.25 mm silica gel 60-F254 and a UV-lamp was used
as a visualizing agent. Column chromatography was performed
using silica gel (100-200 mesh) and hexane and ethyl acetate
were used as eluents. The 1H and 13C NMR spectra were
obtained on 400 MHz and 100 MHz spectrometer. Coupling
constant and chemical shifts were reported in Hertz (Hz) and
parts per million (ppm) respectively, relative to the internal
standard of tetramethylsilane (TMS). IR spectroscopy was
performed as a neat sample on an FT-IR instrument and values
are expressed in cm-1. The HRMS were analyzed by electrospray
ionization (ESI) method on a Q-TOF LC-MS spectrometer.
Representative procedure for the synthesis of 2-bromo-N-(2-
bromobenzyl)benzamides (1)
2-Bromobenzoic acid (1.0 mmol), triethylamine (1.7 mL, 2.5
mmol), 3-bis(dimethylamino)methyliumyl-3H-benzotriazol-1-
oxide hexafluorophosphate (HBTU) (2.8 g, 1.5 mmol) and DMF
(15 mL) were added to a 50 mL round bottom flask. The round
flask was covered with rubber septum, stirred at 0 C for 30
minutes and added (2-bromoaryl)methanamine (1.2 mmol).
Reaction temperature was brought to room temperature and
stirred for overnight. After completion of the reaction as
indicated by thin layer chromatography, water (20 mL) was
added to the reaction mixture. The quenched reaction mixture
was washed with ethyl acetate (2 × 20 mL). Collected organic
layer was dried over anhydrous Na2SO4 and organic solvent was
evaporated on rotatory evaporator. The residue obtained was
O
O
N
Pd(OAc)2 (5 mol %)
K3PO4 (2 equiv)
N
(b)
Br
DMF, 120 °C, 2 h
Ph
Ph
4aa
5aa
, 80%
O
Br
O
O
N
i) Cu(OAc)2.H2O (10 mol %)
K3PO4 (2 equiv), DMF, 90 oC, 2h
N
N
H
Br
(c)
Br
1a
Ph
ii) Pd(OAc)2 (5 mol %),
DMF, 90 °C, 2 h
Ph
Ph
2a
4aa
5aa
1a
Ph
5aa
2a
i) Pd(OAc)2 (5 mol %), PPh3 (2 equiv)
ii) Cu(OAc)2.H2O (10 mol %), Pd(OAc)2 (5 mol %),
K3PO4 (2 equiv), DMF, 120 oC, 5h
30%
55%
(d)
Scheme 4. Control experiments.
Based on the experimental evidence and literature reports, a
plausible mechanism of the sequential copper and palladium
catalyzed reaction has been proposed in scheme 5. It is believed
that Cu(II) initially interacts with alkyne to give copper acetylide
as the starting point of the catalytic cycle33 which then on
oxidative addition reaction with 1 gives intermediate A (Scheme
5). Reductive elimination with the assistance of base
intermediate A leads to the formation of Sonogashira product
B. Finally, intermediate B undergoes 5-exo-dig cyclization to
give isoindolinone intermediate 5.21-24 The mechanism for the
second step is not clear. It is expected that the reaction
proceeds via Pd(II)/Pd(IV) cycle, however involvement of
Pd(0)/Pd(II) cycle cannot be ruled out at this stage. It is
proposed that the intermediate 5 on reaction with Pd(OAc)2
leads to the formation of a transient palladacycle C31 which then
undergoes intramolecular oxidative addition to generate the
Pd(IV) species D. Base-promoted elimination of the acetate ion
from D followed by reductive elimination leads to the product 4
with regeneration of Pd(II) species to complete the catalytic
cycle.
purified
by
silica
gel
chromatography
using
hexane/ethylacetate (9:1 v/v) as eluent.
2-Bromo-N-(2-bromobenzyl)benzamide (1a). Off-white solid
(1.2 g, 68%); MP 131-133 C; IR (nujol): 3263, 1643, 1591,
1541, 1315, 1026, 742, 699 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.59 (dt, J = 8.0, 1.2 Hz, 2H), 7.56 – 7.52 (m, 2H), 7.37 – 7.31 (m,
2H), 7.28 (td, J = 7.5, 1.8 Hz, 1H), 7.19 (td, J = 7.7, 1.7 Hz, 1H),
6.57 (s, 1H), 4.73 (d, J = 6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
167.4, 137.4, 136.8, 133.4, 132.8, 131.4, 130.6, 129.7, 129.4,
127.8, 127.6, 123.8, 119.3, 44.4; HRMS (ESI/Q-TOF) calcd for
C14H12Br2NO 367.9280, found 367.9264 [M+H]+, 369.9242
[M+2+H]+, and 371.9224 [M+4+H]+.
R
O
2
Copper catalyzed
Hydroamidation
O
Br
O
Br
Cu
O
Br
N
Br
Reductive
elimination
N
N
N
R
H
H
H
III
(5-exo-dig cyclization)
R
Br
Cu
1
5
L
R
R
Br
Pd(OAc)2
B
A
O
O
O
O
Oxidative
addition
Br
N
R
N
N
-AcOH
AcO
Pd
-Pd(OAc)Br
Pd
OAc
OAc
R
R
Br
O
Me
4
D
C
Scheme 5. Proposed mechanism.
4 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
2-Bromo-N-(2-bromobenzyl)-5-methylbenzamide (1b). Off- (nujol): 3282, 2974, 1635, 1477, 1429, 1238, 1035, 925, 684
View Article Online
-1
1
DOI: 10.1039/C9OB00440H
white solid (1.3 g, 71%); MP 129-131 C; IR (nujol): 3261, 1637, cm ; H NMR (400 MHz, CDCl3) δ 7.60 (dd, J = 8.0, 0.8 Hz, 1H),
1539, 1305, 1033, 837, 754, 557 cm-1; 1H NMR (400 MHz, CDCl3) 7.57 (dd, J = 7.6, 1.6 Hz, 1H), 7.38 (td, J = 7.5, 1.2 Hz, 1H), 7.29
δ 7.59 (dd, J = 8.0, 1.0 Hz, 1H), 7.55 (dd, J = 7.6, 1.5 Hz, 1H), 7.44 (td, J = 8.0, 1.6 Hz, 1H), 7.06 (s, 1H), 7.03 (s, 1H), 6.47 (bs, 1H),
(d, J = 8.2 Hz, 1H), 7.38 (d, J = 1.9 Hz, 1H), 7.34 (td, J = 7.5, 1.1 6.00 (s, 2H), 4.65 (d, J = 6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
Hz, 1H), 7.20 (td, J = 7.7, 1.6 Hz, 1H), 7.08 (dd, J = 8.2, 1.8 Hz, 167.4, 147.6, 137.3, 133.5, 131.4, 130.0, 129.7, 127.6, 121.4,
1H), 6.54 (s, 1H), 4.74 (d, J = 6.0 Hz, 2H), 2.32 (s, 3H); 13C NMR 119.3, 112.7, 110.8, 110.6, 101.9, 44.3 HRMS (ESI/Q-TOF) calcd
(100 MHz, CDCl3) δ 167.7, 137.8, 136.8, 136.7, 133.2, 132.8, for C15H12Br2NO3 411.9178, found 411.9164 [M+H]+, 413.9144
132.3, 130.6, 130.4, 129.4, 127.8, 123.9, 115.8, 44.4, 20.8; [M+2+H]+, and 415.9125 [M+4+H]+.
HRMS (ESI/Q-TOF) calcd for C15H14Br2NO 381.9437, found Synthesis of 2-bromo-N-(2-bromobenzyl)-5-nitrobenzamide
381.9421 [M+H]+, 383.9399 [M+2+H]+, and 385.9381 [M+4+H]+. (1h). 2-Bromo-5-nitrobenzoic acid (0.60 mmol) and Mukaiyama
2-Bromo-N-(2-bromobenzyl)-5-methoxybenzamide
(1c). reagent34 (0.73 mmol) and THF were added to a 50 mL round
White solid (1.1 g, 64%); MP 125-127 C; IR (nujol): 3296, 1645, bottom flask and stirred at room temperature under inert
1533, 1286, 1230, 1045, 808, 752, 599 cm-1; 1H NMR (400 MHz, atmosphere. Triethylamine (0.169 mL, 1.2 mmol) was added
CDCl3) δ 7.57 (dd, J = 8.0, 0.9 Hz, 1H), 7.53 (dd, J = 7.6, 1.4 Hz, dropwise to the reaction mixture and stirred. After 10 min (2-
1H), 7.43 (d, J = 8.8 Hz, 1H), 7.32 (td, J = 7.5, 1.0 Hz, 1H), 7.18 bromoaryl)methanamine (0.73 mmol) was added dropwise and
(td, J = 7.8, 1.6 Hz, 1H), 7.11 (d, J = 3.1 Hz, 1H), 6.82 (dd, J = 8.8, reaction mixture was heated up to reflux for 4 h under inert
3.1 Hz, 1H), 6.69 (s, 1H), 4.71 (d, J = 6.0 Hz, 2H), 3.79 (s, 3H); 13
C
atmosphere. After completion of the reaction, evaporated the
NMR (100 MHz, CDCl3) δ 167.1, 158.9, 137.9, 136.8, 134.2, THF and viscous residue was extracted with 30% ethyl acetate-
132.8, 130.5, 129.3, 127.8, 123.8, 117.9, 114.9, 109.4, 55.6, hexane (20 mL × 2). Collected the organic layer, concentrated it
44.4; HRMS (ESI/Q-TOF) calcd for C15H14Br2NO2 397.9386, found and subjected to purification by column chromatography using
397.9372 [M+H]+, 399.9353 [M+2+H]+, and 401.9333 [M+4+H]+. hexane/ethyl acetate (9:1 v/v) as eluent.
2-Bromo-N-(2-bromobenzyl)-5-chlorobenzamide (1d). Off- Off-white solid (60 mg, 24%); MP 203-205 C; IR (nujol): 3255,
white solid (1.0 g, 60%); MP 180-182 C; IR (nujol): 3250, 1637, 1635, 1527, 1450, 1350, 1033, 756, 732 cm-1;1H NMR (400 MHz,
1541, 1454, 1301, 1035, 813, 756, 599 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 2.7 Hz, 1H), 8.14 (dd, J = 8.7, 2.7 Hz, 1H),
CDCl3) δ 7.60 (dd, J = 8.0, 1.2 Hz, 1H), 7.56 – 7.52 (m, 3H), 7.35 7.81 (d, J = 8.8 Hz, 1H), 7.62 (dd, J = 8.0, 1.0 Hz, 1H), 7.56 (dd, J
(td, J = 7.5, 1.1 Hz, 1H), 7.28 – 7.25 (m, 2H), 7.21 (td, J = 7.8, 1.6 = 7.6, 1.5 Hz, 1H), 7.37 (td, J = 7.5, 1.1 Hz, 1H), 7.23 (td, J = 7.8,
Hz, 1H), 6.53 (bs, 1H), 4.74 (d, J = 6.0 Hz, 2H); 13C NMR (100 MHz, 1.6 Hz, 1H), 6.55 (bs, 1H), 4.78 (d, J = 6.0 Hz, 2H); 13C NMR (100
CDCl3) δ 166.0, 138.7, 136.5, 134.6, 133.9, 132.9, 131.4, 130.8, MHz, CDCl3) δ 165.1, 147.1, 138.8, 136.2, 134.7, 133.0, 131.0,
129.8, 129.5, 127.9, 123.9, 117.2, 44.5; HRMS (ESI/Q-TOF) calcd 129.8, 128.0, 126.7, 125.6, 124.6, 124.0, 44.7; HRMS (ESI/Q-
for C14H11Br2ClNO 401.8890, found 401.8873 [M+H]+, 403.8852 TOF) calcd for C14H9Br2N2O3 410.8985, found 410.9005 [M-H]-,
[M+2+H]+, and 405.8833 [M+4+H]+.
412.8986 [M+2-H]-, and 414.8966 [M+4-H]-.
2-Bromo-N-(2-bromobenzyl)-4-fluorobenzamide (1e). Off- Representative procedure for the synthesis of isoindolo[2,1-
white solid (1.2 g, 69%); MP 160-162 C; IR (nujol): 3261, 1639, b]isoquinolin-7(5H)-ones
1598, 1541, 1481, 1305, 1261, 1026, 754, 692 cm-1;1H NMR (400 A clean, oven-dried 10 mL round bottom flask was charged with
MHz, CDCl3) δ 7.61 – 7.54 (m, 2H), 7.51 (dd, J = 7.6, 1.5 Hz, 1H), 2-bromo-N-(2-bromobenzyl)benzamide (1a) (185 mg, 0.5
7.34 – 7.30 (m, 2H), 7.19 (td, J = 7.7, 1.6 Hz, 1H), 7.06 (td, J = 8.3, mmol), phenyl acetylene (2a) (102 mg, 1.0 mmol), Cu(OAc)2·H2O
2.5 Hz, 1H), 6.67 (s, 1H), 4.70 (d, J = 6.0 Hz, 2H); 13C NMR (100 (10 mg, 10 mol %) and K3PO4 (212 mg, 1.0 mmol) in DMF (4 mL).
MHz, CDCl3) δ 166.5, 162.9 (d, J = 254.8 Hz), 136.7, 133.6 (d, J = Resulting solution was stirred at 120 C for 2 h then Pd(OAc)2 (6
3.6 Hz), 132.8, 131.4 (d, J = 8.9 Hz), 130.6, 129.4, 127.8, 123.8, mg, 5 mol %) was added at ambient temperature in one pot
120.7 (d, J = 24.7 Hz), 120.0 (d, J = 9.7 Hz), 114.9 (d, J = 21.3 Hz), fashion and continued the reaction mixture for another 1 h at
44.5; HRMS (ESI/Q-TOF) calcd for C14H11Br2FNO 385.9186, 120 C. On completion, the reaction mass was cooled to room
found 385.9164 [M+H]+, 387.9144 [M+2+H]+, and 389.9125 temperature, diluted with water 30 mL and extracted into
[M+4+H]+.
EtOAc (2 × 30 mL). The combined organic layers were dried over
2-Bromo-N-(2-bromo-4,5-dimethoxybenzyl)benzamide (1f). anhydrous Na2SO4 and evaporated to dryness. The crude
Off-white solid (1.1 g, 53%); MP 147-149 C; IR (nujol): 3283, residue was purified by column chromatography
1
1636, 1541, 1408, 1315, 852, 659 cm-1; H NMR (400 MHz, (EtOAc/hexanes = 2:3 v/v) to obtain 4aa in 76% (118 mg) yield.
CDCl3) δ 7.60 (dd, J = 8.0, 0.9 Hz, 1H), 7.56 (dd, J = 7.6, 1.7 Hz, 12-Phenylisoindolo[2,1-b]isoquinolin-7(5H)-one (4aa). Yellow
1H), 7.38 (td, J = 7.5, 1.1 Hz, 1H), 7.30 (dd, J = 7.8, 1.8 Hz, 1H), solid (118 mg, 76%); MP 245-247 C; IR (nujol):  1689, 1450,
7.10 (s, 1H), 7.04 (s, 1H), 6.46 (s, 1H), 4.69 (d, J = 6.0 Hz, 2H), 1396, 1355, 756, 694 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.91 (d,
3.90 (s, 3H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.4, J = 7.6 Hz, 1H), 7.61 – 7.59 (m, 3H), 7.45 – 7.41 (m, 3H), 7.33 –
149.2, 148.6, 137.5, 133.4, 131.4, 129.6, 129.0, 127.6, 119.3, 7.30 (m, 1H), 7.26 – 7.24 (m, 2H), 7.20 (t, J = 7.3 Hz, 1H), 6.91 (d,
115.4, 113.8, 113.5, 56.2, 56.2, 44.1; HRMS (ESI/Q-TOF) calcd J = 7.7 Hz, 1H), 6.39 (d, J = 7.9 Hz, 1H), 5.26 (s, 2H);13C NMR (100
for C16H16Br2NO3 427.9491, found 427.9472 [M+H]+, 429.9453 MHz, CDCl3) δ 166.3, 135.1, 134.7, 132.6, 131.1, 130.5, 130.5,
[M+2+H]+, and 431.9434 [M+4+H]+.
129.6, 129.3, 129.1, 128.8, 128.6, 128.0, 127.7, 126.6, 126.2,
2-Bromo-N-((6-bromobenzo[d][1,3]dioxol-5-yl)methyl)-
123.2, 122.9, 119.4, 43.1; DEPT-135 (100 MHz, CDCl3) δ 131.1,
benzamide (1g). Brown solid (0.56 g, 27%); MP 152-154 C; IR 130.6, 129.4, 128.8, 128.6, 128.1, 127.7, 126.6, 126.2, 123.2,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Organic & Biomolecular Chemistry
Page 6 of 11
ARTICLE
Journal Name
122.9, -43.1; HRMS (ESI/Q-TOF) calcd for C22H16NO 310.1226, 5-(2-Methoxyphenyl)-10,10a-dihydro-11H-benzo[b]fluoren-
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found 310.1219 [M+H]+.
12-(p-Tolyl)isoindolo[2,1-b]isoquinolin-7(5H)-one
11-one (4ag). Yellow solid (72 mg, 42%); MP 193-194 C; IR
DOI: 10.1039/C9OB00440H
(4ab). (nujol):  1682, 1489, 1465, 1242, 1018, 941, 756 cm-1; 1H NMR
Yellow solid (147 mg, 91%); MP 231-233 C; IR (nujol):  1697, (400 MHz, CDCl3) δ 7.91 (d, J = 7.6 Hz, 1H), 7.58 (td, J = 8.0, 1.6
1458, 1365, 1355, 756, 694 cm-1; 1H NMR (400 MHz, DMSO) δ Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.32 – 7.24 (m, 4H), 7.20 – 7.14
7.81 (d, J = 7.5 Hz, 1H), 7.50 (td, J = 7.5, 0.7 Hz, 1H), 7.44 (t, J = (m, 3H), 6.86 (d, J = 7.6 Hz, 1H), 6.51 (d, J = 8.0 Hz, 1H), 5.27 (d,
6.4 Hz, 1H), 7.40 (td, J = 7.8, 1.0 Hz, 1H), 7.33 – 7.29 (m, 3H), J = 5.7 Hz, 2H), 3.72 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.3,
7.23 (t, J = 7.5 Hz, 1H), 6.77 (d, J = 7.7 Hz, 1H), 6.39 (d, J = 7.8 Hz, 158.2 134.9, 132.2, 132.1, 131.1, 130.6, 130.3, 129.6, 129.2,
1H), 5.16 (s, 2H), 2.48 (s, 3H); 13C NMR (100 MHz, DMSO) δ 128.7, 127.9, 127.6, 126.5, 125.8, 123.5, 122.9, 122.8, 121.4,
165.5, 138.5, 134.7, 132.6, 132.0, 131.9, 130.5, 130.3, 129.7, 116.2, 111.6, 55.7, 43.2.
129.7, 129.6, 129.4, 128.5, 128.2, 127.4, 125.9, 123.1, 123.1, 12-(Thiophen-2-yl)isoindolo[2,1-b]isoquinolin-7(5H)-one (4ai).
119.3, 43.1, 21.5; HRMS (ESI/Q-TOF) calcd for C23H18NO Yellow solid (106 mg, 68%); MP 251-253 C; IR (nujol):  1689,
324.1383, found 324.1379 [M+H]+.
12-(4-Methoxyphenyl)isoindolo[2,1-b]isoquinolin-7(5H)-one
1519, 1458, 1111, 779, 694 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.92 (d, J = 7.5 Hz, 1H), 7.63 (dd, J = 5.2, 1.0 Hz, 1H), 7.47 (t, J =
(4ac). Yellow solid (139 mg, 82%); MP 229-231 C; IR (nujol):  7.2 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.31 – 7.22 (m, 4H), 7.15 (dd,
1
1689, 1512, 1365, 1242, 763, 694 cm-1; H NMR (400 MHz, J = 3.4, 1.0 Hz, 1H), 7.10 (d, J = 7.4 Hz, 1H), 6.57 (d, J = 7.8 Hz,
CDCl3) δ 7.90 (d, J = 7.6 Hz, 1H), 7.42 (td, J = 7.5, 0.6 Hz, 1H), 7.33 1H), 5.23 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 166.4, 135.4,
– 7.27 (m, 5H), 7.20 (td, J = 7.8, 1.8 Hz, 1H), 7.14 – 7.11 (m, 2H), 134.4, 133.0, 132.8, 131.4, 129.5, 129.3, 129.2, 128.7, 128.1,
6.95 (d, J = 7.6 Hz, 1H), 6.51 (d, J = 7.9 Hz, 1H), 5.23 (s, 2H), 3.96 127.9, 127.8, 127.6, 126.5, 125.8, 123.4, 123.0, 111.3, 43.0;
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.3, 159.7, 134.8, 132.9, HRMS (ESI/Q-TOF) calcd for C20H14NOS 316.0791, found
131.7, 131.1, 130.7, 129.5, 129.2, 128.7, 128.0, 127.7, 126.9, 316.0787 [M+H]+
126.6, 126.2, 123.2, 122.9, 119.2, 114.7, 55.4, 43.1; HRMS 12-Propylisoindolo[2,1-b]isoquinolin-7(5H)-one (4aj). Yellow
(ESI/Q-TOF) calcd for C23H18NO2 340.1332, found 340.1326 solid (127 mg, 93%); MP 142-144 C; IR (nujol):  1681, 1519,
[M+H]+.
1458, 1087, 817, 756, 694 cm-1;1H NMR (400 MHz, CDCl3) δ 7.99
(d, J = 7.5 Hz, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.66 (t, J = 7.5 Hz, 1H),
12-(4-Propylphenyl)isoindolo[2,1-b]isoquinolin-7(5H)-one
(4ad). Yellow solid (118 mg, 67%); MP 146-148 C; IR (nujol):  7.56 – 7.52 (m, 2H), 7.36 (t, J = 7.3 Hz, 1H), 7.32 – 7.26 (m, 2H),
1689, 1519, 1458, 1072, 694 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.11 (s, 2H), 3.02 (t, J = 8.12 Hz, 2H), 1.83 –1.74 (m, 2H), 1.19 (t,
7.91 (d, J = 7.6 Hz, 1H), 7.44 – 7.39 (m, 3H), 7.32 – 7.29 (m, 3H), J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.8, 134.7, 131.7,
7.28 – 7.24 (m, 2H), 7.20 (t, J = 7.4 Hz, 1H), 6.94 (d, J = 7.6 Hz, 131.5, 130.1, 129.89, 129.86, 128.5, 128.0, 127.8, 126.8, 123.7,
1H), 6.42 (d, J = 7.9 Hz, 1H), 5.26 (s, 2H), 2.77 (t, J = 7.8 Hz, 2H), 123.4, 123.2, 119.5, 43.0, 28.8, 22.5, 14.4; HRMS (ESI/Q-TOF)
1.87 – 1.74 (m, 2H), 1.06 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, calcd for C19H18NO 276.1383, found 276. 1379 [M+H]+.
CDCl3) δ 166.3, 143.1, 134.8, 132.8, 132.1, 131.0, 130.4, 130.3, 12-Butylisoindolo[2,1-b]isoquinolin-7(5H)-one (4ak). Yellow
129.5, 129.4, 129.2, 128.7, 128.0, 127.7, 126.5, 126.3, 123.2, solid (100 mg, 70%); MP 163-165 C; IR (nujol):  1681, 1519,
122.9, 119.6, 43.1, 37.9, 24.5, 13.8; HRMS (ESI/Q-TOF) calcd for 1458, 1095, 763, 694 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.99 (d,
C25H22NO 352.1696, found 352.1691 [M+H]+.
12-(4-(Tert-butyl)phenyl)isoindolo[2,1-b]isoquinolin-7(5H)-
J = 7.5 Hz, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H),
7.57 – 7.53 (m, 2H), 7.39 – 7.29 (m, 3H), 5.12 (s, 2H), 3.06 (t, J =
one (4ae). Off-white solid (90 mg, 49%); MP 258-260 C; IR 8 Hz, 2H), 1.63 (m, 4H), 1.07 (t, J = 7.2 Hz, 3H); 13C NMR (100
(nujol):  1689, 1519, 1458, 1111, 756, 694 cm-1; 1H NMR (400 MHz, CDCl3) δ 165.8, 134.7, 131.7, 131.5, 130.0, 129.90, 129.88,
MHz, CDCl3) δ 7.90 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 8.3 Hz, 2H), 128.5, 128.0, 127.8, 126.8, 123.7, 123.4, 123.2, 119.7, 43.0,
7.42 (td, J = 7.5, 0.7 Hz, 1H), 7.34 – 7.29 (m, 3H), 7.28 – 7.24 (m, 31.3, 26.6, 23.2, 14.0; HRMS (ESI/Q-TOF) calcd for C20H20NO
2H), 7.20 (td, J = 7.8, 1.5 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H), 6.40 (d, 290.1539, found 290.1535 [M+H]+.
J = 7.9 Hz, 1H), 5.25 (s, 2H), 1.47 (s, 9H); 13C NMR (100 MHz, 12-Pentylisoindolo[2,1-b]isoquinolin-7(5H)-one (4al). Yellow
CDCl3) δ 166.3, 151.7, 134.8, 132.8, 131.8, 131.1, 130.4, 130.1, solid (80 mg, 53%); MP 91-93 C; IR (nujol):  1681, 1519, 1465,
129.5, 129.1, 128.7, 128.0, 127.7, 126.5, 126.3, 126.1, 123.2, 1288, 765, 694 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 7.6
122.8, 119.6, 43.1, 34.8, 31.5; HRMS (ESI/Q-TOF) calcd for Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.68 – 7.64 (m, 1H), 7.55 (d, J =
C26H24NO 366.1852, found 366.1848 [M+H]+.
7.6 Hz, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.36 (td, J = 7.9, 1.6 Hz, 1H),
12-(4-Fluorophenyl)isoindolo[2,1-b]isoquinolin-7(5H)-one
7.32 – 7.26 (m, 2H), 5.10 (s, 2H), 3.04 – 3.00 (m, 2H), 1.78 – 1.70
(4af). Yellow solid (72 mg, 44%); MP 202-204 C; IR (nujol):  (m, 2H), 1.61 – 1.54 (m, 2H), 1.51 – 1.42 (m, 2H), 0.98 (t, J = 7.2
1689, 1512, 840, 779, 694 cm-1;1H NMR (400 MHz, CDCl3) δ 7.92 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.8, 134.7, 131.7, 131.6,
(d, J = 7.6 Hz, 1H), 7.45 (d, J = 7.2 Hz, 1H), 7.42 – 7.38 (m, 2H), 129.94, 129.90, 129.87, 128.5, 128.0, 127.8, 126.8, 123.7, 123.4,
7.33 – 7.27 (m, 5H), 7.21 (t, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 123.2, 119.8, 43.0, 32.3, 28.9, 26.9, 22.6, 14.1; HRMS (ESI/Q-
1H), 6.43 (d, J = 7.6 Hz, 1H), 5.25 (s, 2H); 13C NMR (100 MHz, TOF) calcd for C21H22NO 304.1696, found 304.1692 [M+H]+.
CDCl3) δ 166.3, 162.9 (d, J = 248.1 Hz), 134.6, 132.5, 132.4 (d, J 9-Methyl-12-phenylisoindolo[2,1-b]isoquinolin-7(5H)-one
= 8.0 Hz), 131.2, 130.9, 130.9, 129.6, 129.1, 129.0, 128.2, 127.8, (4ba). Yellow solid (90 mg, 56%); MP 242-244 C; IR (nujol): 
1
127.0, 126.7, 126.0, 123.0 (d, J = 3.6 Hz), 118.2, 116.5 (d, J = 21.4 1689, 1519, 1489, 1365, 763, 702 cm-1; H NMR (400 MHz,
Hz), 43.1; HRMS (ESI/Q-TOF) calcd for C22H15FNO 328.1132, CDCl3) δ 7.70 (s, 1H), 7.60 – 7.56 (m, 3H), 7.42 – 7.39 (m, 2H),
found 328.1128 [M+H]+.
7.31 – 7.24 (m, 2H), 7.18 (td, J = 7.8, 1.4 Hz, 1H), 7.07 (d, J = 8.8
6 | J. Name., 2012, 00, 1-3
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Hz, 1H), 6.89 (d, J = 7.7 Hz, 1H), 6.27 (d, J = 8.0 Hz, 1H), 5.23 (s, 138.2, 132.9, 132.0, 131.3, 130.5, 130.3, 130.0, 128.9, 127.6,
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2H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.4, 139.3, 127.6, 126.5, 125.9, 124.5, 119.3, 118.1,D1O0I5: .160,.150539.7/C, 94O3.B20,024140.5H;
135.2, 132.7, 132.2, 130.6, 129.8, 129.3, 129.1, 128.5, 127.8, HRMS (ESI/Q-TOF) calcd for C24H20NO2 354.1489, found
127.7, 126.6, 126.0, 123.1, 123.0, 118.6, 43.1, 21.6; HRMS 354.1481 [M+H]+.
(ESI/Q-TOF) calcd for C23H18NO 324.1383, found 324.1379 9-Methoxy-12-(4-methoxyphenyl)isoindolo[2,1-b]isoquinolin-
[M+H]+.
7(5H)-one (4cc). Yellow solid (83 mg, 45%); MP 197-199 C; IR
(nujol):  1681, 1512, 1489, 1242, 1026, 771, 725 cm-1; 1H NMR
9-Methoxy-12-phenylisoindolo[2,1-b]isoquinolin-7(5H)-one
(4ca). Brown solid (113 mg, 66%); MP 201-203 C; IR (nujol):  (400 MHz, CDCl3) δ 7.38 (d, J = 2.4 Hz, 1H), 7.33 – 7.30 (m, 2H),
1
1689, 1519, 1489, 1080, 833, 702 cm-1; H NMR (400 MHz, 7.25 (td, J = 7.3, 1.2 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.13 – 7.10
CDCl3) δ 7.62 – 7.57 (m, 3H), 7.43 – 7.40 (m, 2H), 7.38 (d, J = 2.4 (m, 2H), 6.93 (d, J = 7.5 Hz, 1H), 6.84 (dd, J = 8.6, 2.5 Hz, 1H),
Hz, 1H), 7.31 (d, J = 6.8 Hz, 1H), 7.26 (dd, J = 7.4, 1.1 Hz, 1H), 6.40 (d, J = 8.6 Hz, 1H), 5.22 (s, 2H), 3.96 (s, 3H), 3.87 (s, 3H); 13
C
7.19 (t, J = 7.5 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 6.81 (dd, J = 8.6, NMR (100 MHz, CDCl3) δ 166.2, 160.6, 159.7, 133.0, 131.8,
2.5 Hz, 1H), 6.29 (d, J = 8.6 Hz, 1H), 5.24 (s, 2H), 3.87 (s, 3H); 13
131.3, 130.5, 128.9, 127.6, 127.6, 127.1, 126.5, 125.9, 124.5,
C
NMR (100 MHz, CDCl3) δ 166.2, 160.6, 135.2, 132.7, 131.3, 119.4, 117.8, 114.7, 105.6, 55.7, 55.4, 43.2; HRMS (ESI/Q-TOF)
130.7, 130.3, 129.3, 128.9, 128.5, 127.7, 127.5, 126.5, 125.9, calcd for C24H20NO3 370.1438, found 370.1431 [M+H]+.
124.4, 119.4, 118.1, 105.7, 55.7, 43.2; HRMS (ESI/Q-TOF) calcd 9-Methoxy-12-(4-propylphenyl)isoindolo[2,1-b]isoquinolin-
for C23H18NO2 340.1332, found 340.1324 [M+H]+.
9-Chloro-12-phenylisoindolo[2,1-b]isoquinolin-7(5H)-one
7(5H)-one (4cd). Yellow solid (84 mg, 44%); MP 147-149 C; IR
(nujol):  1705, 1519, 1489, 1080, 825, 771 cm-1; 1H NMR (400
(4da). Yellow solid (103 mg, 60%); MP 254-256 C; IR (nujol):  MHz, CDCl3) δ 7.40 (s, 1H), 7.38 – 7.37 (m, 2H), 7.30 (d, J = 8.1
1697, 1543, 1519, 1365, 825, 725, 702 cm-1; 1H NMR (400 MHz, Hz, 3H), 7.25 (td, J = 7.4, 1.2 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 6.93
CDCl3) δ 7.87 (d, J = 1.7 Hz, 1H), 7.60 – 7.59 (m, 3H), 7.41 – 7.39 (d, J = 7.6 Hz, 1H), 6.81 (dd, J = 8.6, 2.5 Hz, 1H), 6.32 (d, J = 8.6
(m, 2H), 7.32 – 7.29 (m, 2H), 7.22 – 7.18 (m, 2H), 6.91 (d, J = 7.7 Hz, 1H), 5.23 (s, 2H), 3.86 (s, 3H), 2.77 (t, J = 7.6 Hz, 2H), 1.85 –
Hz, 1H), 6.28 (d, J = 8.4 Hz, 1H), 5.25 (s, 2H); 13C NMR (100 MHz, 1.75 (m, 2H), 1.06 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3)
CDCl3) δ 164.9, 135.0, 134.7, 132.8, 132.3, 131.3, 131.0, 130.4, δ 166.2, 160.6, 143.0, 132.9, 132.3, 131.3, 130.4, 130.3, 129.3,
129.6, 129.4, 129.0, 128.8, 128.3, 127.8, 126.6, 126.4, 124.3, 128.9, 127.6, 127.6, 126.5, 126.0, 124.4, 119.3, 118.2, 105.6,
123.0, 120.2, 43.2; HRMS (ESI/Q-TOF) calcd for C22H15ClNO 55.7, 43.2, 37.9, 24.5, 13.8; HRMS (ESI/Q-TOF) calcd for
344.0837, found 344.0831 [M+H]+.
C26H24NO2 382.1802, found 382.1792 [M+H]+.
10-Fluoro-12-phenylisoindolo[2,1-b]isoquinolin-7(5H)-one
9-Chloro-12-(p-tolyl)isoindolo[2,1-b]isoquinolin-7(5H)-one
(4ea). Yellow solid (151 mg, 92%); MP 228-230 C; IR (nujol):  (4db). Yellow solid (81 mg, 45%); MP 236-238 C; IR (nujol): 
1
1689, 1519, 1458, 1365, 1157, 702, 648 cm-1;1H NMR (400 MHz, 1697, 1519, 1458, 1365, 825, 709 cm-1; H NMR (400 MHz,
CDCl3) δ 7.88 (dd, J = 8.4, 5.1 Hz, 1H), 7.62 – 7.60 (m, 3H), 7.40 CDCl3) δ 7.87 (d, J = 1.7 Hz, 1H), 7.40 (d, J = 7.8 Hz, 2H), 7.30 –
(dd, J = 6.5, 3.1 Hz, 2H), 7.32 – 7.29 (m, 2H), 7.22 – 7.18 (m, 1H), 7.28 (m, 4H), 7.24 – 7.17 (m, 2H), 6.93 (d, J = 7.7 Hz, 1H), 6.37
7.12 (td, J = 8.7, 2.2 Hz, 1H), 6.91 (d, J = 7.7 Hz, 1H), 6.01 (dd, J = (d, J = 8.4 Hz, 1H), 5.24 (s, 2H), 2.54 (s, 3H); 13C NMR (100 MHz,
9.3, 2.1 Hz, 1H), 5.25 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 165.3, CDCl3) δ 164.9, 138.6, 134.9, 132.9, 132.4, 131.5, 131.2, 131.0,
164.5 (d, J = 249.7 Hz), 136.8 (d, J = 11.0 Hz), 134.4, 132.3, 130.3, 130.2, 130.1, 129.6, 129.1, 128.3, 127.8, 126.6, 126.4, 124.4,
129.7 (d, J = 3.9 Hz), 129.5, 129.2, 128.9, 128.4, 127.8, 126.5 (d, 123.0, 120.3, 43.2, 21.5; HRMS (ESI/Q-TOF) calcd for C23H17ClNO
J = 21.9 Hz), 125.7 (d, J = 1.9 Hz), 124.8 (d, J = 10.0 Hz), 120.5, 358.0993, found 358.0985 [M+H]+.
116.5 (d, J = 24.2 Hz), 110.4, 110.1, 43.2; HRMS (ESI/Q-TOF) 12-(4-(Tert-butyl)phenyl)-9-chloroisoindolo[2,1-b]isoquinolin-
calcd for C22H15FNO 328.1132, found 328.1126 [M+H]+.
9-Methyl-12-(p-tolyl)isoindolo[2,1-b]isoquinolin-7(5H)-one
7(5H)-one (4de). Yellow solid (82 mg, 41%); MP 252-254 C; IR
(nujol):  1697, 1543, 1519, 1458, 1064, 825, 771, 725 cm-1; 1H
(4bb). Yellow solid (106 mg, 62%); MP 253-255 C; IR (nujol):  NMR (400 MHz, CDCl3) δ 7.87 (d, J = 1.7 Hz, 1H), 7.61 – 7.59 (m,
1689, 1519, 817, 763, 709 cm-1;1H NMR (400 MHz, CDCl3) δ 7.71 2H), 7.33 – 7.29 (m, 4H), 7.24 – 7.21 (m, 2H), 6.96 (d, J = 7.6 Hz,
(s, 1H), 7.39 (d, J = 7.8 Hz, 2H), 7.30 – 7.28 (m, 3H), 7.26 – 7.24 1H), 6.29 (d, J = 8.4 Hz, 1H), 5.25 (s, 2H), 1.47 (s, 9H); 13C NMR
(m, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.92 (d, J (100 MHz, CDCl3) δ 164.9, 151.9, 134.9, 132.9, 132.4, 131.5,
= 7.7 Hz, 1H), 6.36 (d, J = 8.0 Hz, 1H), 5.23 (s, 2H), 2.54 (s, 3H), 131.3, 131.0, 130.0, 129.6, 129.1, 128.3, 127.8, 126.6, 126.5,
2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.4, 139.2, 138.2, 126.2, 124.3, 122.9, 120.3, 43.2, 34.9, 31.5; HRMS (ESI/Q-TOF)
132.9, 132.3, 132.2, 132.0, 130.6, 130.4, 130.0, 129.8, 129.1, calcd for C26H23ClNO 400.1463, found 400.1448 [M+H]+.
127.7, 127.6, 126.5, 126.0, 123.1, 123.0, 118.7, 43.1, 21.6, 21.5; 10-Fluoro-12-(p-tolyl)isoindolo[2,1-b]isoquinolin-7(5H)-one
HRMS (ESI/Q-TOF) calcd for C24H20NO 338.1539, found (4eb). Yellow solid (160 mg, 94%); MP 287-289 C; IR (nujol): 
338.1531 [M+H]+.
1689, 1512, 1458, 1265, 1072, 763, 702, 640 cm-1; 1H NMR (400
9-Methoxy-12-(p-tolyl)isoindolo[2,1-b]isoquinolin-7(5H)-one
MHz, CDCl3) δ 7.87 (dd, J = 8.3, 5.1 Hz, 1H), 7.42 (d, J = 7.8 Hz,
(4cb). Yellow solid (129 mg, 73%); MP 212-214 C; IR (nujol):  2H), 7.32 – 7.29 (m, 4H), 7.22 – 7.18 (m, 1H), 7.11 (td, J = 8.8,
1689, 1489, 1365, 825, 771 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.2 Hz, 1H), 6.93 (d, J = 7.7 Hz, 1H), 6.11 (dd, J = 9.3, 2.1 Hz, 1H),
7.40 – 7.37 (m, 3H), 7.30 – 7.28 (m, 3H), 7.25 (td, J = 7.4, 1.3 Hz, 5.23 (s, 2H), 2.54 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.3,
1H), 7.18 (td, J = 7.9, 1.1 Hz, 1H), 6.91 (d, J = 7.7 Hz, 1H), 6.83 164.5 (d, J = 249.4 Hz), 138.7, 136.8 (d, J = 11.0 Hz), 132.4, 131.3,
(dd, J = 8.6, 2.5 Hz, 1H), 6.37 (d, J = 8.7 Hz, 1H), 5.23 (s, 2H), 3.87 130.2, 130.1, 129.6 (d, J = 3.9 Hz), 129.2, 128.3, 127.8, 126.6,
(s, 3H), 2.53 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.2, 160.6, 126.5, 125.7 (d, J = 1.8 Hz), 124.8 (d, J = 10.1 Hz), 120.6, 116.4
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(d, J = 24.2 Hz), 110.3 (d, J = 26.0 Hz), 43.2, 21.5; HRMS (ESI/Q- (d, J = 21.4 Hz), 109.8, 109.3, 56.2, 55.9, 43.0; HRMS (ESI/Q-TOF)
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+
TOF) calcd for C23H17FNO 342.1289, found 342.1282 [M+H]+.
12-(4-(tert-Butyl)phenyl)-10-fluoroisoindolo[2,1-
calcd for C24H19FNO3 388.1343, found 388.1330 [M+H] .
12-(4-Methoxyphenyl)-[1,3]dioxolo[4,5-g]isoindolo[2,1-
DOI: 10.1039/C9OB00440H
b]isoquinolin-7(5H)-one (4ee). Yellow solid (94 mg, 49%); MP b]isoquinolin-7(5H)-one (4gc). Brown solid (79 mg, 41%); MP
269-271 C; IR (nujol):  1689, 1458, 1396, 1157, 763, 725, 702 114-116 C; IR (nujol):  1689, 1504, 1458, 1242, 1026, 833, 725
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.87 (dd, J = 8.4, 5.1 Hz, 1H), cm-1;1HNMR (400 MHz, CDCl3) δ 7.89 (d, J = 7.2 Hz, 1H), 7.40 (d,
7.62 (d, J = 8.3 Hz, 2H), 7.33 – 7.29 (m, 4H), 7.23 – 7.19 (m, 1H), J = 7.2 Hz, 1H), 7.31 – 7.25 (m, 3H), 7.11 (d, J = 8.5 Hz, 2H), 6.79
7.11 (td, J = 8.7, 2.2 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 5.96 (dd, J = (s, 1H), 6.47 (d, J = 7.9 Hz, 1H), 6.43 (s, 1H), 5.96 (s, 2H), 5.14 (s,
9.4, 2.2 Hz, 1H), 5.24 (s, 2H), 1.47 (s, 9H); 13C NMR (100 MHz, 2H), 3.96 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.2, 159.8,
CDCl3) δ 165.4, 164.4 (d, J = 249.5 Hz), 152.1, 136.8 (d, J = 11.1 147.5, 147.2, 134.7, 131.6, 131.0, 129.3, 129.2, 128.4, 127.2,
Hz), 132.4, 131.9, 129.9, 129.7 (d, J = 3.9 Hz), 129.2, 128.3, 127.1, 123.6, 122.9, 122.8, 119.3, 114.8, 107.1, 106.5, 101.5,
127.8, 126.6, 126.5, 126.3, 125.6 (d, J = 1.8 Hz), 124.7 (d, J = 10.0 55.4, 43.3; HRMS (ESI/Q-TOF) calcd for C24H18NO4 384.1230,
Hz), 120.7, 116.4 (d, J = 24.2 Hz), 110.3 (d, J = 26.3 Hz), 43.2, found 384.1219 [M+H]+.
34.9, 31.4; HRMS (ESI/Q-TOF) calcd for C26H23FNO 384.1758, 3-Benzylidene-2-(2-bromobenzyl)isoindolin-1-one
(5aa).
White solid (150 mg, 77%); MP 158-160 C; IR (nujol):  1705,
1342, 1111, 948, 748, 694, 624 cm-1; 1H NMR (400 MHz, CDCl3)
found 384.1744 [M+H]+.
2,3-Dimethoxy-12-phenylisoindolo[2,1-b]isoquinolin-7(5H)-
one (4fa). Yellow solid (148 mg, 80%); MP 225-227 C; IR (nujol): δ 7.98 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.70 (td, J = 7.6,
1
 1631, 1512, 1458, 1342, 732, 702 cm-1; H NMR (400 MHz, 1.1 Hz, 1H), 7.59 (td, J = 7.5, 0.8 Hz, 1H), 7.36 (dd, J = 7.9, 1.1 Hz,
CDCl3) δ 7.90 (d, J = 7.6 Hz, 1H), 7.61 – 7.59 (m, 3H), 7.44 – 7.38 1H), 7.24 – 7.20 (m, 1H), 7.17 (td, J = 7.6, 1.1 Hz, 1H), 7.12 (t, J =
(m, 3H), 7.24 (t, J = 7.08 Hz, 1H), 6.83 (s, 1H), 6.41 (s, 1H), 6.38 7.6 Hz, 2H), 7.05 (td, J = 7.9, 1.6 Hz, 1H), 6.93 (dd, J = 8.1, 1.0 Hz,
(d, J = 7.9 Hz, 1H), 5.20 (s, 2H), 3.96 (s, 3H), 3.66 (s, 3H);13C NMR 2H), 6.83 (s, 1H), 6.77 – 6.75 (m, 1H), 4.84 (s, 2H); 13C NMR (100
(100 MHz, CDCl3) δ 166.3, 149.2, 148.2, 135.2, 134.7, 131.0, MHz, CDCl3) δ 168.6, 138.2, 135.6, 134.3, 133.7, 132.3, 132.2,
130.5, 129.3, 129.2, 128.9, 128.6, 128.4, 125.4, 122.8, 122.8, 129.2, 128.7, 128.1, 128.0, 127.9, 127.5, 127.1, 126.5, 123.6,
122.2, 119.6, 109.7, 109.5, 56.2, 55.9, 43.0; HRMS (ESI/Q-TOF) 122.2, 119.6, 107.8, 45.8; HRMS (ESI/Q-TOF) calcd for
calcd for C24H20NO3 370.1438, found 370.1429 [M+H]+.
C22H17BrNO 390.0488, found 390.0487 [M+H]+.
2,3-Dimethoxy-12-(p-tolyl)isoindolo[2,1-b]isoquinolin-7(5H)-
2-(2-Bromobenzyl)-3-(4-nitrobenzylidene)isoindolin-1-one
one (4fb). Yellow solid (166 mg, 87%); MP 209-211 C; IR (nujol): (5ah). Off-white solid (32 mg, 15%); MP 247-249 C; IR (nujol):
 1681, 1512, 1458, 1342, 1103, 763, 696 cm-1; 1H NMR (400  1689, 1512, 1465, 1334, 1103, 848, 817, 702 cm-1; 1H NMR
MHz, CDCl3) δ 7.89 (d, J = 7.6 Hz, 1H), 7.41 – 7.38 (m, 3H), 7.30 (400 MHz, CDCl3) δ 8.03 – 7.95 (m, 3H), 7.83 (d, J = 7.5 Hz, 1H),
(d, J = 8.0 Hz, 2H), 7.28 – 7.24 (m, 1H), 6.82 (s, 1H), 6.47 – 6.44 7.73 (t, J = 7.4 Hz, 1H), 7.64 (t, J = 7.3 Hz, 1H), 7.34 (d, J = 7.8 Hz,
(m, 2H), 5.18 (s, 2H), 3.95 (s, 3H), 3.68 (s, 3H), 2.54 (s, 3H); 13C 1H), 7.19 (t, J = 7.3 Hz, 1H), 7.11 – 7.05 (m, 3H), 6.70 – 6.70 (m,
NMR (100 MHz, CDCl3) δ 166.2, 149.1, 148.2, 138.3, 134.8, 2H), 4.81 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 168.5, 146.9,
132.0, 130.9, 130.2, 130.0, 129.2, 128.9, 128.3, 125.6, 122.9, 141.0, 137.6, 136.0, 134.8, 132.7, 132.6, 130.0, 129.6, 128.6,
122.8, 122.3, 119.6, 109.7, 109.7, 56.2, 56.0, 43.0, 21.5; HRMS 127.9, 127.3, 126.5, 123.9, 123.0, 122.1, 119.8, 104.6, 45.7;
(ESI/Q-TOF) calcd for C25H22NO3 384.1594, found 384.1585 HRMS (ESI/Q-TOF) calcd for C22H16BrN2O3 435.0339, found
[M+H]+.
435.0321 [M+H]+.
2,3-Dimethoxy-12-(4-methoxyphenyl)isoindolo[2,1-
2-(2-Bromobenzyl)-3-(thiophen-2-ylmethylene)isoindolin-1-
b]isoquinolin-7(5H)-one (4fc). Yellow solid (126 mg, 63%); MP one (5ai). Brownish solid (112 mg, 57%); MP 137-139 C; IR
216-218 C; IR (nujol):  1681, 1512, 1450, 1350, 1103, 771, 725, (nujol):  1697, 1465, 1435, 1342, 1103, 948, 740, 696 cm-1; 1H
696 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 7.5 Hz, 1H), NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.5 Hz, 1H), 7.81 (d, J = 7.8
7.40 (t, J = 7.3 Hz, 1H), 7.34 (d, J = 8.6 Hz, 2H), 7.29 – 7.25 (m, Hz, 1H), 7.69 (td, J = 7.6, 1.1 Hz, 1H), 7.59 (td, J = 7.5, 0.8 Hz, 1H),
1H), 7.13 (d, J = 8.6 Hz, 2H), 6.82 (s, 1H), 6.48 (d, J = 7.9 Hz, 1H), 7.43 (dd, J = 7.9, 1.1 Hz, 1H), 7.22 (dd, J = 5.2, 0.6 Hz, 1H), 7.18
6.46 (s, 1H), 5.18 (s, 2H), 3.97 (s, 3H), 3.95 (s, 3H), 3.69 (s, 3H); (td, J = 7.6, 1.2 Hz, 1H), 7.07 (td, J = 7.9, 1.6 Hz, 1H), 6.84 (dd, J
13C NMR (100 MHz, CDCl3) δ 166.2, 159.7, 149.1, 148.2, 134.8, = 5.1, 3.5 Hz, 1H), 6.77 (dd, J = 7.7, 1.3 Hz, 1H), 6.69 (d, J = 1.0
131.6, 130.9, 129.2, 129.1, 128.3, 127.1, 125.7, 122.9, 122.8, Hz, 1H), 6.55 (dt, J = 3.5, 1.2 Hz, 1H), 5.05 (s, 2H); 13C NMR (100
122.2, 119.3, 114.7, 109.7, 109.6, 56.2, 56.0, 55.4, 43.0; HRMS MHz, CDCl3) δ 168.5, 137.8, 135.8, 135.8, 135.0, 132.4, 132.4,
(ESI/Q-TOF) calcd for C25H22NO4 400.1543, found 400.1531 129.5, 128.2, 128.1, 127.8, 127.3, 127.1, 126.7, 126.3, 123.7,
[M+H]+.
122.2, 119.6, 99.7, 45.7; HRMS (ESI/Q-TOF) calcd for
C20H15BrNOS 396.0052, found 396.0039 [M+H]+.
12-(4-Fluorophenyl)-2,3-dimethoxyisoindolo[2,1-
b]isoquinolin-7(5H)-one (4ff). Yellow solid (140 mg, 72%); MP 2-(2-Bromobenzyl)-3-butylideneisoindolin-1-one (5aj). Off-
229-231 C; IR (nujol):  1681, 1512, 1458, 1350, 1219, 1103, white solid (105 mg, 59%); MP 139-141 C; IR (nujol):  1697,
763, 696 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 7.6 Hz, 1465, 1396, 1342, 979, 763, 740 cm-1; 1H NMR (400 MHz, CDCl3)
1H), 7.44 – 7.40 (m, 3H), 7.34 – 7.28 (m, 3H), 6.83 (s, 1H), 6.41 δ 7.93 (d, J = 7.5 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.64 – 7.60 (m,
(d, J = 7.9 Hz, 1H), 6.36 (s, 1H), 5.19 (s, 2H), 3.96 (s, 3H), 3.68 (s, 2H), 7.51 (td, J = 7.5, 0.9 Hz, 1H), 7.21 (td, J = 7.5, 1.2 Hz, 1H),
3H); 13C NMR (100 MHz, CDCl3) δ 166.2, δ 162.9 (d, J = 248.3 Hz), 7.14 (td, J = 7.8, 1.7 Hz, 1H), 6.86 (dd, J = 7.6, 0.6 Hz, 1H), 5.64
149.3, 148.3, 134.5, δ 132.3 (d, J = 8.0 Hz), 131.13, 131.10, (t, J = 8.2 Hz, 1H), 5.26 (s, 2H), 2.12 (q, J = 7.6 Hz, 2H), 1.37 – 1.26
131.0, 129.3, 128.6, 125.3, 123.0, 122.6, 122.2, 118.3, 116.51 (m, 2H), 0.78 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
8 | J. Name., 2012, 00, 1-3
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168.2, 138.1, 136.4, 133.4, 132.8, 131.9, 128.6, 128.4, 127.7,
127.6, 126.9, 123.4, 121.7, 119.0, 109.8, 45.4, 28.0, 23.6, 13.6;
HRMS (ESI/Q-TOF) calcd for C19H19BrNO 356.0645, found
356.0633 [M+H]+.
Acknowledgments
View Article Online
DOI: 10.1039/C9OB00440H
Financial support from Science and Engineering Research Board
(SERB), New Delhi [Project EMR/2016/002242] to carry out this
work, DST-FIST [SR/FST/CSI-270/2015] for HRMS facility and
BITS Pilani for single crystal XRD facility is highly acknowledged.
HKS, SD, and NKN are grateful to the CSIR, New Delhi for the
senior research fellowship. Authors also thank Dr. Om P. S. Patel
for insightful discussions and critical reading of the manuscript.
2-(2-Bromobenzyl)-3-pentylideneisoindolin-1-one (5ak). Off-
white solid (96 mg, 52%); MP 116-118 C; IR (nujol):  1689,
1465, 1396, 1342, 979, 740, 694 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.93 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.64 – 7.59 (m,
2H), 7.51 (t, J = 7.4 Hz, 1H), 7.22 (td, J = 7.5, 1.0 Hz, 1H), 7.14 (td,
J = 7.7, 1.5 Hz, 1H), 6.86 (d, J = 7.2 Hz, 1H), 5.63 (t, J = 8.1 Hz,
1H), 5.26 (s, 2H), 2.14 (q, J = 7.9 Hz, 2H), 1.30 – 1.13 (m, 4H),
0.77 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.1, 138.1,
136.4, 133.2, 132.8, 131.9, 128.6, 128.4, 127.7, 127.6, 126.8,
123.4, 121.8, 119.0, 110.1, 45.5, 32.5, 25.7, 22.2, 13.7; HRMS
(ESI/Q-TOF) calcd for C20H21BrNO 370.0801, found 370.0786
[M+H]+.
Notes and references
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1
1396, 1396, 1342, 1026, 740, 694 cm-1; H NMR (400 MHz,
CDCl3) δ 7.93 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.64 –
7.59 (m, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.21 (td, J = 7.5, 1.0 Hz, 1H),
7.14 (td, J = 7.7, 1.5 Hz, 1H), 6.86 (d, J = 7.2 Hz, 1H), 5.63 (t, J =
8.1 Hz, 1H), 5.26 (s, 2H), 2.13 (q, J = 7.8 Hz, 2H), 1.33 – 1.22 (m,
2H), 1.21 – 1.08 (m, 4H), 0.82 (t, J = 6.9 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 168.1, 138.1, 136.4, 133.2, 132.8, 131.9, 128.6,
128.4, 127.7, 127.6, 126.8, 123.4, 121.8, 119.0, 110.1, 45.5,
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Light yellow oil (15 mg, 28%); IR (nujol): 1640, 1527, 1458, 1350,
1033, 750, 732 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 2.1 Hz, 9. J. R. Fuchs and R. L. Funk, Org. Lett., 2001, 3, 3923-3925.
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1H), 8.24 (dd, J = 8.6, 2.2 Hz, 1H), 7.64 (dd, J = 7.9, 1.1 Hz, 1H), 7.48
(d, J = 8.7 Hz, 1H), 7.46 – 7.42 (m, 3H), 7.38 – 7.34 (m, 2H), 7.20 (td, J
= 7.7, 1.5 Hz, 1H), 7.06 (d, J = 7.7 Hz, 1H), 6.61 (s, 1H), 5.27 (s, 2H); 13
C
NMR (100 MHz, CDCl3) δ 164.7, 148.4, 139.8, 134.7, 134.4, 133.9,
133.1, 131.3, 129.3, 129.2, 129.0, 128.8, 127.9, 127.6, 126.7, 124.3,
122.4, 119.2, 115.8, 43.8; HRMS (APCI) calcd. for C22H16BrN2O3
435.0339, found 435.0342 [M+H]+ and 437.0323 [M+2+H]+.
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3-Benzylidene-2-(2-(phenylethynyl)benzyl)isoindolin-1-one
(6aa). Off-white solid (9 mg, 4%); MP 109-111 C; IR (nujol): 
1697, 1489, 1334, 1103, 956, 756, 694 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.95 (d, J = 7.5 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.68 (td,
J = 7.6, 1.1 Hz, 1H), 7.56 (td, J = 7.5, 0.8 Hz, 1H), 7.42 – 7.39 (m,
2H), 7.38 – 7.34 (m, 3H), 7.34 – 7.30 (m, 1H), 7.19 – 7.14 (m, 3H),
7.09 (t, J = 7.4 Hz, 2H), 6.97 – 6.93 (m, 2H), 6.81 (s, 1H), 6.74 –
6.70 (m, 1H), 5.10 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 168.8,
138.4, 138.2, 134.4, 134.0, 132.1, 131.8, 131.4, 129.1, 128.8,
128.2, 128.2, 128.1, 128.1, 127.9, 127.4, 126.4, 124.9, 123.6,
123.3, 121.0, 119.5, 107.8, 94.6, 86.5, 44.3; HRMS (ESI/Q-TOF)
calcd for C30H22NO 412.1696, found 412.1698 [M+H]+.
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Conflicts of interest
There are no conflicts to declare.
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DOI: 10.1039/C9OB00440H
O
i) Cu(OAc)2 H2O, K3PO4
O
Br
DMF, 120 °C, 2 h
N
R
N
ii) Pd(OAc)2,120 °C, 1 h
H
R = Alkyl, aryl
R
Br
One-pot sequential reactions
Sonogashira coupling
27 examples
Yield 41-94%
intramolecular hydroamidation
Heck reaction
A highly efficient protocol has been developed for the synthesis of diversely substituted isoindolo[2,1-
b]isoquinolin-7(5H)-ones through sequential Cu(II)-catalyzed Sonogashira coupling, intramolecular
hydroamidation followed by palladium catalyzed ligand free Heck reaction.