Synthesis of 2,3-Diarylisoindolin-1-one by Copper-Catalyzed Cascade Annulation of 2-Formylbenzonitriles, Arenes, and Diaryliodonium Salts

Article abstract of DOI:10.1021/acs.joc.7b02035

A three-component cascade cyclization was developed to synthesize 2,3-diarylisoindolin-1-one by using 2-formylbenzonitrile, arenes, and diaryliodonium salts. The process underwent copper-catalyzed tandem C-N/C-C bond formation, producing isoindolin-1-one derivatives in good to excellent yields.

Full text of DOI:10.1021/acs.joc.7b02035

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Article
Synthesis of 2,3-Diaryl Isoindolin-1-one by Copper-Catalyzed Cascade
Annulation of 2-Formylbenzonitriles, Arenes and Diaryliodonium Salts
Li Liu, Shu-Hua Bai, Yang Li, Li-Xun Wang, Yang Hu, Hui-Ling Sung, and Jian Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02035 • Publication Date (Web): 03 Oct 2017
Downloaded from http://pubs.acs.org on October 4, 2017
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The Journal of Organic Chemistry
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Synthesis of 2,3-Diaryl Isoindolin-1-one by Copper-Catalyzed
Cascade Annulation of 2-Formylbenzonitriles, Arenes and
Diaryliodonium Salts
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Li Liu,‡ Shu-Hua Bai,† Yang Li,† Li-XunWang,† Yang Hu,† Hui-Ling Sung,§ and Jian Li *,†
†School of Pharmaceutical Engineering & Life Sciences, Changzhou University, Changzhou, 213164, China
‡ School of Petrochemical Engineering, Changzhou University, Changzhou, 213164, China
§ Division of Preparatory Programs for Overseas Chinese Students, National Taiwan Normal University, Linkou, 24449,
Taiwan
Supporting Information
OTf
O
CHO
N
I
R2
R1
R2
R3
R1
N
Cu(OAc)2 5 mol%
DCE, 110 o
R4
C
R4
35 examples, up to 99% yield
one-pot cascade ( C-N & C-C bond-forming event )
readily available substrates
simple conditions
[
]
A three-component cascade cyclization was developed to synthesize 2,3-diarylisoindolin-1-one by using 2-formylbenzonitrile,
arenes and diaryliodonium salts. The process underwent copper-catalyzed tandem C-N / C-C bonds formation, producing
isoindolin-1-one derivatives in good to excellent yields.
Scheme 1. Synthesis of nitrogen-containing heterocycles by
cyclization of o-cyanobenzene and diaryliodonium salts
ꢀ
INTRODUCTION
Aryl nitriles are undoubtedly one of the most valuable
structural motifs in organic synthesis,1 due to the versatility of
conversion to other functional groups2 and nitrogen-containing
heterocycles.3 Chen and co-workers demonstrated convenient
protocols for synthesis of nitrogen-containing heterocycles
from aryl nitriles and diaryliodonium salts, using the concept
of aromatic electrophile generation via the intermediacy of
Cu(III) species described by Gaunt et al.4,5 Very Recently,
Novák reported a copper-catalyzed reaction for the synthesis
of iminobenzoxazine derivatives from ortho-cyanoanilides and
diaryliodonium triflates via the formation of the C-N and C-C
bonds.6 All the reactions produced an activation of a nitrile
group with a copper catalyst and generated N-aryl nitrilium
cation in situ, then the N-phenylnitrilium intermediate would
be attacked by group R followed by tandem ring closure to
give final heterocycle product (Scheme 1).6,7 Inspired by this
cyclization concept, we chose aldehyde as the group R in the
ortho position and the reaction should provide new
heterocycle through similar cyclization path.
R2
C
OTf
R2
N
R2
R1
R1
I
Cu Cat.
R3
R1
R4
N
R3
R3
N
Previous Work
R
OTf
OTf
R
I
I
NH
N
HN
N
R
R
R
R
2 equiv.
R
0.5 equiv.
10% Cu(OTf)2
DCE, 65 o
N
20% Cu(OTf)2
NH2
N
DCE, 110 o
C
C
H2N
Ar
N
N
O
O
Ar Cu(III)
N
H
R
N
R
Our Previous Work
OTf
OTf
O
O
I
I
Ar1
Ar2
Ar1
Ar2
N
Ar1
Ar
Ar1
N
Ar
CHO
(3 equiv)
(1 equiv)
CuI (5mol%)
DCE, 80 o
N
Ar
Cu(OTf)2 (5mol%)
DCE, 110 o
Ar2
O
C
N
C
Ar
I
This Work
OTf
Isoindolin-1-ones is an important structural scaffolds
commonly found in pharmaceuticals and natural products.8
Furthermore, 2,3-substituted isoindolin-1-ones show great
significance in many biologically active molecules,9 such as
Pagoclone,10 anxiolytic drug, is related to better-known drugs
as the sleeping medication zopiclone. Therefore, how to
synthesize the isoindolin-1-ones efficiently is an interesting
O
N
CHO
N
I
R2
R1
R2
R3
R1
Cu Cat.
R4
R4
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Page 2 of 8
yield.
theme in organic chemistry and drug discovery. As a result,
numerous methods for the construction of the isoindolin-1-
ones have been developed rapidly in recent decades.11
However, most of these methods suffer from certain
limitations with respect to the substrate scope, yield, or
apparative requirements, and are not suitable for the
preparation of compound libraries. Recently, we reported a
cascade cyclization mode for the construction of isoindolin-1-
one scaffolds with diaryliodonium salts.12 As a result of
ongoing project, we herein report a three-component cascade
cyclization to synthesize 2,3-substituted isoindolin-1-one by
using readily available substrates including of 2-
formylbenzonitrile, arenes and diaryliodonium salts. The
reaction proceeded smoothly with copper catalysts through the
formation of the C-N bond and C-C bond in cascade
annulation reaction (Scheme 1).
1
2
3
4
5
6
7
8
Delightedly, the desired product 4a was collected in 82%
yield in the presence of 10% CuI (Table 1, entry 5). To our
surprise, the reaction finished in only 2 hours. Other Lewis
acids such as FeCl3 and CoCl2 were not suitable for this
transformation. The screening of copper-catalysts showed that
Cu(OAc)2 was the most efficient for this reaction, 89% yield
of 4a was obtained (entry 12). To improve the yield of 4a, we
adjusted the temperature and found that 4a was obtained in
lower yield at 80 oC. Further screening of the solvents, such as
MeCN, DMF, THF, 1,4-dioxane and toluene, DCE was found
to be the best solvent.
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Table 2. Diaryliodonium salts scopea,b
O
R1
ꢀ
RESULTS AND DISCUSSION
At the outset, we selected 2-formylbenzonitrile 1a, 1,3,5-
N
OTf
Me
Cu(OAc)2 (5mol%)
DCE, 110oC
CHO
CN
Me
I
R1
R2
Me
Me
Me
trimethylbenzene 2a and di-p-chloroliodoniumtriflate 3a as
model substrates to investigate the feasibility for this three-
component reaction. Without catalyst the reaction did not
3
1a
4
2a
Me
O
O
OTf
I
OTf
N
Cl
N
F
o
I
work in DCE at 110 C overnight (Table 1, entry 1). Some
Me
Me
Me
Me
F
F
Cl
Cl
proton acids such as TfOH, PTSA and CF3COOH were
employed as the catalysts, negative results were obtained
under the same conditions above.
Table 1. Optimization of the reaction conditionsa
3a
3b
4a, 89% Me
Me
4b
, 72%
O
O
OTf
OTf
N
Br
N
Me
I
I
Me
Me
Me
Me
Me
Me
Br
Br
3d
3c
4d
, 94%
O
Me
Me
4c
, 99%
O
OTf
OTf
N
CF3
N
OMe
I
I
Me
Me
Me
F3C
CF3
MeO
OMe Me
3f
3e
Me
Me
4f
, 76%
4e, 90%
Entry
Catalyst
T (
℃
)
Solvent
Yield (%) b
O
O
OTf
Me
OTf
N
Ph
I
110
110
110
110
110
110
110
N
1
2
--
TfOH
PTSA
TFA
DCE
DCE
--
--
I
Me
Me
Ph
Me
3h
Me
Me
Me
3g
Me
, 96%
Me
, 60%
3
DCE
--
4h
4g
O
N
OTf
4
DCE
--
Me
COOEt
I
Me
5
CuI
DCE
82
--
EtOOC
Me
Me
Me
6
FeCl3
CoCl2
Cu(OTf)2
CuBr
CuBr2
DCE
3i
4i
, 84%
Me
7
DCE
--
O
O
OTf
N
OMe
N
NO2
8
110
110
110
DCE
75
77
82
85
89
53
--
I
Me
Me
Me
Me
9
DCE
MeO
NO2
3j
4j, 23%
4e,
Me
77%
Me
10
DCE
O
N
O
OTf
11 [Cu(CH3CN)4]PF6 110
DCE
NO2
N
I
Me
Me
12
13
14
15
16
17
18
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
110
80
DCE
Me
NO2
Me
4g, 62%
3k
DCE
4j, 20% Me
Me
a Reaction condition: 1a (0.5 mmol), 2a (1.0 mmol), 3 (0.6 mmol)
and Cu(OAc)2 (10mol%) in DCE (2.0 mL), 110oC, 2 h. b Isolated
yield.
110
110
110
110
110
MeCN
DMF
THF
--
trace
58
48
1,4-Dioxane
Toluene
Under the optimal conditions, the substrate scope of
diaryliodonium salts 3 was investigated in this reaction (Table
2). Diaryliodonium salts could be easily prepared according to
the literature.13 To our delight, the reaction displayed excellent
functional group tolerance, symmetric diaryliodonium salts
a
Reaction condition: 1a (0.5 mmol), 2a (1.0 mmol), 3a (0.6
mmol) and catalyst (10 mol%) in DCE (2.0 mL), 110oC, 2 h.
Isolated
b
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ed yield.
with a variety of substituents involving fluoro, chloride,
1
2
3
4
5
6
7
8
bromide, methyl, methoxyl and CF3 group on the aromatic
ring all worked well with 2-formylbenzonitrile 1a and 1,3,5-
trimethylbenzene 2a, providing the corresponding 2,3-
diarylisoindolin-1-one in up to 99% yield (Table 2). The
structure of the resulting 4b was unequivocally confirmed
using X-ray diffraction.14 It is noteworthy that the electron-
donating group substrates show higher activity than
withdrawing group substrates (4d, 4e vs 4f). Moreover,
unsymmetrical diaryliodonium salts were proven to be suitable
substrates, which underwent a similar process toward 4 in
good to excellent yields (Table 2, 4h-4j). Interestingly, the
higher the steric hindrance on one of the aryl groups of
diaryliodonium salts, the more pronounced chemselectivity
favoring is observed, 4h was the only one product in the
reaction, the same phenomenon occurred in 4i. With the aim to
explore the electronic nature of the substituents on the
neighboring aryl group of the salts, unsymmetrical
diaryliodonium salts 3j and 3k were tested. The reaction of 3j
is conducted towards the formation of 4e and 4j in 77/23 ratio,
showing that Ar2IOTf bearing electron-donating substituents
favor the transformation.
After exploring the applicability of diaryliodonium triflates,
we surveyed the scope of 2-formylbenzonitrile and arenes in
this copper-catalyzed annulation (Table 3). The scope and
generality of the reaction were explored by treating different
benzene derivatives. Benzene was used to give the
corresponding product 4aa in 67% yield. Various mono-
9
substituted
benzene
derivatives,
including
toluene,
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ethylbenzene, cumene, tert-butylbenzene and anisole were
examined in the reaction, giving the desired products in 41-
99% yields (4ab-4af). Notably, when anisole was employed,
the final product 4af was obtained as
a mixture of
regioisomers (ortho/para = 26/73). Besides, the disubstituted
and trisubstituted benzenes also worked efficiently, affording
2,3-diarylisoindolin-1-one in up to 99% yield (4ag-4am).
Furthermore, 1-methylnaphthalene and 2-methylthiophene
were also appropriate partners for this reaction. Interestingly,
estrone 3-methyl ether 15 was proven to be a suitable substrate,
which underwent
a similar three-component cyclization
process toward complex steroid compound 4ap in 81% yield.
Disappointingly, arenes with electron-withdrawing group,
such as nitrobenzene, (trifluoromethyl)benzene, did not
proceed under standard conditions. Next, the scope of 2-
formylbenzonitrile was probed. 2-formylbenzonitrile with
fluoro, bromide and chloride group on the aromatic ring gave
the desired product 4ba-4be in 84-99% yields. The position of
substituted groups had less influence on the reaction, such as
fluoro group on 5-, 6- and 7-position of 2-formylbenzonitrile
(4ba, 4bb and 4bc), which proceeded smoothly to generate the
products in good to excellent yields. In addition, electron-
donating and electron-withdrawing groups at 5- positions of 1
also afforded products 4bg and 4bh in synthetically useful
yields (80% and 51%).
Table 3. Arene and 2-formylbenzonitrile scopea,b
Scheme 2. Preliminary mechanistic studies
O
OTf
I
NH
Me
CHO
CN
Br
Br
Me
Cu(OAc)2 (5 mol%)
DCE, 110 o
Me
Cu(OAc)2 (5 mol%)
DCE, 110oC
Me
no reaction
C
Me
1a
2a
Me
9% yield
5,
O
OTf
N
Br
CHO
CN
I
CuI (5 mol%)
DCE, 80 o
Br
N
O
C
Br
6,
52% yield
3c
1a
Preliminary mechanistic experiments were conducted to
gain insights into the transformation (Scheme 2). Interestingly,
2-formylbenzonitrile 1a reacted with mesitylene 2a under the
standard conditions to produce 3-mesitylisoindolin-1-one 5 in
only 9% yield;16, 17 next, treatment 5 with diaryliodonium salts
3c under standard conditions, the reaction did not afford the
final product 4c. In another parallel reaction, polycycle prod-
uct 6 was obtained in 52% yield from the reaction of 1a and
diaryliodonium salts 3c. The results indicated that the reaction
was not initiated by the reaction of 2-formylbenzonitrile 1a
a
Reaction condition: 1 (0.5 mmol), 2 (1.0 mmol), 3c (0.6 mmol)
and Cu(OAc)2 (10 mol%) in DCE (2.0 mL), 110 oC, 2 h. b Isolat-
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diaryliodonium salt 3 (0.6 mmol), Cu(OAc)2 (0.025 mmol,
10mol%) in DCE (2 mL) was stirred at 110 ºC for 2 hours.
After completion of the reaction (observed on TLC), the sol-
vent was evaporated under reduced pressure to obtain the
crude mixture. The residues was purified by silica-gel column
chromatography (Ethyl acetate/Petroleum ether = 1/4 - 1/2) to
afford the pure product 4. The obtained product was analyzed
by 1H NMR, 13C NMR and HRMS.
and aromatic ring, 2-formylbenzonitrile 1a was activated first
1
2
3
4
5
6
7
8
by diaryliodonium salts in the presence of copper.
Br
OTf
H
I
O
O
N
H
N
Br
Br
3c
N
O
Cu(OAc)2
I
1a
Br
B
A
Br
9
ꢀ
EXPERIMENTAL DATA OF PRODUCTS
O
O
10
11
12
13
14
15
16
17
18
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22
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O
N
Br
N
Br
2ꢀ(4ꢀChlorophenyl)ꢀ3ꢀmesitylisoindolinꢀ1ꢀone (4a). White
1
Me
H
Me
N
Br
solid (160.5 mg, 89%). MP: 151-153 ºC. H NMR (300 MHz,
CDCl3) δ 7.95-7.92 (m, 1H), 7.51-7.48 (m, 4H), 7.24-7.20 (m,
2H), 7.17-7.14 (m, 1H), 6.93 (s, 1H), 6.58 (s, 1H), 6.46 (s,
1H), 2.65 (s, 3H), 2.19 (s, 3H), 1.62 (s, 3H). 13C NMR (125
MHz, CDCl3) δ 167.8, 143.8, 138.7, 138.0, 137.0, 136.5,
136.4, 132.7, 132.1, 131.8, 130.0, 129.8, 128.9, 123.9, 123.1,
122.4, 61.5, 29.7, 21.3, 20.8, 18.9. HRMS (ESI) calcd for
C23H21ClNO ([M+H]+): 362.1306 found 362.1310.
Me
Me
- H
Me
H
C
Me
4c
Me
D
Me
Me
2a
Figure 1. Proposed reaction mechanism
On the basis of the above experimental results, a reasonable
mechanism suggested that N-aryl nitrilium cation is involved
as shown in Figure 1. First, the reaction of 2-
formylbenzonitrile 1a with diaryliodonium salts 3c gives the
N-aryl nitrilium cation A in the presence of copper catalyst.
Then the phenylnitrilium intermediate A is attacked by the
aldehyde to afford intermediate B, which undergoes an intra-
molecular rearrangement via aza-Michael reaction to give
cation intermediate C. Finally, the aimed product 4c is gener-
ated through the Friedel-Crafts reaction between C and mesit-
ylene 2a.
2ꢀ(4ꢀFluorophenyl)ꢀ3ꢀmesitylisoindolinꢀ1ꢀone (4b). White
crystalline solid (123.6 mg, 72%). MP: 164-166 ºC. 1H NMR
(300 MHz, CDCl3) δ 7.97-7.94 (m, 1H), 7.51-7.44 (m, 4H),
7.18-7.15 (m, 1H), 6.99-6.91 (m, 3H), 6.60 (s, 1H), 6.47 (s,
1H), 2.62 (s, 3H), 2.19 (s, 3H), 1.64 (s, 3H). 13C NMR (125
MHz, CDCl3) δ 167.9, 159.9 (d, J = 242.8 Hz), 144.1, 138.0,
136.9 (d, J = 18.7 Hz), 133.8, 132.6, 131.7, 129.8, 128.5,
123.8 (d, J = 7.5 Hz), 122.4, 115.7 (d, J = 22.5 Hz), 61.9, 21.3,
20.8, 18.9. 19F NMR (282 MHz, CDCl3) δ -116.7. HRMS
(ESI) calcd for C23H21FNO ([M+H]+): 346.1602 found
346.1600.
ꢀ
CONCLUSIONS
In conclusion, we have demonstrated a three-component
2ꢀ(4ꢀBromophenyl)ꢀ3ꢀmesitylisoindolinꢀ1ꢀone (4c). White
solid (199.4 mg, 99%). MP: 150-151 ºC. 1H NMR (300 MHz,
CDCl3) δ 7.94-7.92 (m, 1H), 7.48-7.43 (m, 4H), 7.37-7.34 (m,
2H), 7.16-7.13 (m, 1H), 6.93 (s, 1H), 6.57 (s, 1H), 6.44 (s,
1H), 2.66 (s, 3H), 2.18 (s, 3H), 1.61 (s, 3H). 13C NMR (125
MHz, CDCl3) δ 167.8, 143.8, 138.1, 136.9, 132.8, 131.8,
129.9, 129.1, 128.5, 123.9, 122.9, 122.4, 117.8, 61.4, 21.3,
20.8, 18.9. HRMS (ESI) calcd for C23H21BrNO ([M+H]+):
406.0801 found 406.0803.
cascade cyclization for the construction of 2,3-
diarylisoindolin-1-one with 2-formylbenzonitriles, arenes and
diaryliodonium salts. The transformation proceeds via electro-
philic Ar-Cu(III) activation of cyano group, undergoes C-N/
C-C tandem cyclization into the 2,3-diaryl isoindolin-1-one
core. The developed methodology provides straightforward
access to 2,3-diaryl isoindolin-1-one derivatives in up to 99%
yields. Further applications of these three-component cascade
reactions are ongoing in our laboratory.
3ꢀMesitylꢀ2ꢀpꢀtolylisoindolinꢀ1ꢀone (4d). White solid (159.5
1
mg, 94%). MP: 145-147 ºC. H NMR (300 MHz, CDCl3) δ
ꢀ
EXPERIMENTAL SECTION
8.00-7.97 (m, 1H), 7.52-7.50 (m, 2H), 7.42 (d, J =8.4 Hz 2H),
7.19-7.17 (m, 1H), 7.11 (d, J =8.4 Hz 2H), 6.93 (s, 1H), 6.61
(s, 1H), 6.52 (s, 1H), 2.66 (s, 3H), 2.12 (s, 3H), 2.27 (s, 3H),
1.68 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 167.9, 144.2,
137.7, 137.2, 136.7, 135.2, 134.6, 132.4, 131.7, 129.7, 129.4,
128.4, 123.8, 122.4, 121.9, 61.7, 21.3, 20.9, 20.8, 18.9. HRMS
(ESI) calcd for C24H24NO ([M+H]+): 342.1852 found
342.1855.
General Information. All reactions were carried out under
an airatmosphere condition. Various reagents were purchased
from Aldrich, Acros or Alfa. The diaryliodonium salts 2 were
prepared according literature. Flash column chromatography
was performed using silica gel (200–300 mesh). Analytical
thin-layer chromatography was performed using glass plates
pre-coated with 200–300 mesh silica gel impregnated with a
fluorescent indicator (254 nm). NMR spectra were recorded in
CDCl3 on Bruker NMR-300 (300MHz), NMR-400 (400MHz
and NMR-500 (500MHz) with TMS as an internal reference.
The model of HRMS is BrukermaXis UHR-TOF. The prepa-
ration of 2-formylbenzonitrile derivatives was described ac-
cording to the literature.18
3ꢀMesitylꢀ2ꢀ(4ꢀmethoxyphenyl) isoindolinꢀ1ꢀone (4e). White
solid (159.8 mg, 90%). MP: 138-140 ºC. 1H NMR (300 MHz,
CDCl3) δ 7.94-7.93 (m, 1H), 7.48-7.45 (m, 2H), 7.39-7.37 (m,
2H), 7.15-7.13 (m, 1H), 6.88 (s, 1H), 6.81-6.78 (m, 2H), 6.59
(s, 1H), 6.44 (s, 1H), 3.69 (s, 3H), 2.58 (s, 3H), 2.17(s, 3H),
1.64 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 167.9, 156.9,
144.3, 137.8, 136.8, 132.3, 131.6, 130.8, 129.6, 128.3, 123.8,
122.3, 114.1, 62.0, 55.3, 21.3, 20.8, 18.9. HRMS (ESI) calcd
for C24H24NO2 ([M+H]+): 358.1802found 358.1803.
3ꢀMesitylꢀ2ꢀ[(4ꢀtrifluoromethyl)phenyl]ꢀisoindolinꢀ1ꢀone
(4f). White crystalline solid (149.1 mg, 76%). MP: 163-164 ºC.
1H NMR (300 MHz, CDCl3) δ 7.98-7.95 (m, 1H), 7.74-7.71
General Procedure for preparation of compound 4. A solu-
tion of 2-formylbenzonitrile 1 (0.5 mmol), arene 2 (1.0 mmol),
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(m, 2H), 7.55-7.52 (m, 4H), 7.19-7.17 (m, 1H), 6.96 (s, 1H),
6.59-6.54 (m, 2H), 2.72 (s, 3H), 2.21 (s, 3H), 1.63 (s, 3H). 13
2ꢀ(4ꢀBromophenyl)ꢀ3ꢀ(4ꢀethylphenyl)isoindolinꢀ1ꢀone (4ac):
white solid (116.5 mg, 60%). MP: 116-117 ºC. H NMR (300
1
1
2
3
4
5
6
7
8
C
NMR (125 MHz, CDCl3) δ 168.2, 143.7, 138.2, 136.8, 136.2,
133.1, 131.9, 129.9, 128.7, 126.0, 124.0, 122.5, 120.6, 61.4,
21.3, 20.8, 18.9. 19F NMR (282 MHz, CDCl3) δ -62.2. HRMS
(ESI) calcd for C24H21F3NO ([M+H]+): 396.1570 found:
396.1569.
MHz, CDCl3) δ 7.96-7.93 (m, 1H), 7.58-7.46 (m, 4H), 7.40-
7.37 (m, 2H), 7.25-7.21 (m, 1H), 6.01 (s, 1H), 2.57 (q, J = 7.6
Hz, 2H), 1.16 (t, J = 7.6 Hz, 3H). 13C NMR (125 MHz,
CDCl3) δ 167.9, 145.7, 144.6, 136.8, 134.3, 132.7, 131.8,
130.7, 128.7, 128.6, 126.7, 124.1, 123.6, 123.0, 117.8, 65.3,
28.4, 15.2. HRMS (ESI) calcd for C22H19BrNO ([M+H]+):
392.0645 found 392.0644.
3ꢀMesitylꢀ2ꢀphenylisoindolinꢀ1ꢀone (4g). White solid (97.9
1
mg, 60%). MP: 85-87 ºC. H NMR (300 MHz, CDCl3) δ 7.99-
7.96 (m, 1H), 7.64-7.61 (m, 2H), 7.52-7.49 (m, 6H), 7.40-7.35
(m, 2H), 7.30-7.28 (m, 1H), 7.18-7.16 (m, 1H), 6.94 (s, 1H),
6.59 (s, 1H), 6.55 (s, 1H), 2.69 (s, 3H), 2.19 (s, 3H), 1.68 (s,
3H). 13C NMR (125 MHz, CDCl3) δ 168.0, 144.0, 140.4,
137.8, 137.4, 137.2, 137.1, 136.5, 132.5, 131.8, 129.8, 129.5,
128.7, 128.5, 127.4, 127.1, 126.8, 123.9, 122.4, 121.8, 61.6,
21.4, 20.8. HRMS (ESI) calcd for C23H22NO ([M+H]+):
328.1696 found 328.1700.
2ꢀ(4ꢀBromophenyl)ꢀ3ꢀ(4ꢀisopropylphenyl)isoindolinꢀ1ꢀone
9
1
(4ad). white solid (83.0 mg, 41%). MP: 178-180 ºC. H NMR
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
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26
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29
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31
32
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43
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47
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60
(300 MHz, CDCl3) δ 7.95-7.93 (m, 1H), 7.56-7.48 (m, 4H),
7.41-7.38 (m, 2H), 7.24-7.22 (m, 1H), 7.13-7.09 (m, 4H), 6.02
(s, 1H), 2.87-2.78 (m, 1H), 1.19 (s, 3H), 1.17 (s, 3H). 13C
NMR (125 MHz, CDCl3) δ 167.9, 149.2, 145.7, 136.9, 134.3,
132.6, 132.5, 132.3, 131.8, 130.7, 128.6, 127.3, 126.6, 124.1,
123.6, 123.1, 117.8, 65.2, 33.7, 23.8, 23.7. HRMS (ESI) calcd
for C23H21BrNO ([M+H] +): 406.0801 found 406.0801.
2ꢀ(Biphenylꢀ4ꢀyl)3ꢀmesitylisoindolinꢀ1ꢀone (4h). White sol-
1
id (193.4 mg, 96%). MP: 163-165 ºC. H NMR (300 MHz,
2ꢀ(4ꢀBromophenyl)ꢀ3ꢀ(4ꢀtertꢀbutylphenyl)isoindolinꢀ1ꢀone
(4ae). White solid (192.7 mg, 92%). MP: 210-212 ºC. 1H
NMR (300 MHz, CDCl3) δ 7.96-7.93 (m, 1H), 7.57-7.54 (m,
2H), 7.51-7.46 (m, 2H), 7.41-7.38 (m, 2H), 7.29-7.23 (m, 3H),
7.11-7.08 (m, 2H), 6.02 (s, 1H), 1.25 (s, 9H). 13C NMR (75
MHz, CDCl3) δ 167.9, 151.4, 145.7, 136.9, 133.9, 132.6,
131.9, 130.7, 128.6, 126.3, 126.2, 124.1, 123.6, 123.1, 117.7,
65.1, 34.6, 31.2. HRMS (ESI) calcd for C24H23BrNO
([M+H]+): 420.0958 found 420.0959.
CDCl3) δ 7.99-7.96 (m, 1H), 7.64-7.61 (m, 2H), 7.52-7.49 (m,
6H), 7.40-7.35 (m, 2H), 7.30-7.28 (m, 1H), 7.18-7.16 (m, 1H),
6.94 (s, 1H), 6.59 (s, 1H), 6.55 (s, 1H), 2.69 (s, 3H), 2.19 (s,
3H), 1.68 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 167.9,
144.1, 137.8, 137.2, 136.6, 132.5, 131.8, 129.7, 129.5, 128.8,
128.4, 124.9, 123.8, 122.4, 121.8, 61.6, 21.3, 20.8, 18.9.
HRMS (ESI) calcd for C29H26NO ([M+H]+): 404.2009found
404.2015.
Ethyl 4ꢀ(1ꢀmesitylꢀ3ꢀoxoisoindolinꢀ2ꢀyl)benzene (4i): White
crystalline solid (167.6 mg, 84%). MP: 175-176 ºC. 1H NMR
(300 MHz, CDCl3) δ 7.97-7.94 (m, 3H), 7.69-7.66 (m, 2H),
7.54-7.45 (m, 2H), 7.18-7.16 (m, 1H), 6.95 (s, 1H), 6.55-6.51
(m, 2H), 4.29 (q, J = 7.1 Hz, 2H), 2.71 (s, 3H), 2.18 (s, 3H),
1.61 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz,
CDCl3) δ 168.1, 166.1, 143.7, 141.8, 138.0, 136.7, 136.2,
132.9, 131.9, 130.3, 129.9, 129.2, 128.6, 126.0, 123.9, 122.4,
120.1, 61.4, 60.8, 21.3, 20.7, 18.9, 14.3. HRMS (ESI) calcd
for C26H26NO3 ([M+H]+): 400.1907 found 400.1905.
2ꢀ(4ꢀbromophenyl)ꢀ3ꢀ(4ꢀmethoxyphenyl)isoindolinꢀ1ꢀone
(4af). White solid (195.0 mg, 99%). MP: 154-155 ºC. 1H
NMR (300 MHz, CDCl3) δ 7.95-7.93 (m, 1H), 7.52-7.49 (m,
4H), 7.41-7.38 (m, 2h), 7.23-7.20 (m, 1H), 7.10-7.07 (m, 2H),
6.80-6.78 (m, 2H), 5.99 (s, 1H), 3.73 (s, 3H). 13C NMR (75
MHz, CDCl3) δ 167.8, 159.6, 145.8, 136.7, 132.7, 131.8,
130.7, 128.9, 128.6, 128.1, 124.1, 123.8, 122.9, 117.9, 114.5,
64.9, 55.2. HRMS (ESI) calcd for C21H17BrNO2 ([M+H]+):
394.0437 found 394.0437.
2ꢀ(4ꢀBromophenyl)ꢀ3ꢀ(2ꢀmethoxyꢀ5ꢀmethylphenyl)isoindolin
ꢀ1ꢀone (4ag). White solid (201.4 mg, 99%). MP: 190-191 ºC.
1H NMR (300 MHz, CDCl3) δ 7.94-7.91 (m, 1H), 7.63-7.61
(m, 2H), 7.50-7.45 (m, 2H), 7.40-7.37 (m, 2H), 7.32-7.30 (m,
1H), 6.99-6.95 (m, 1H), 6.85-6.73 (m, 1H), 6.65-6.52 (m, 2H),
3.98 (s, 3H), 2.04 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 168.2,
154.9, 146.1, 137.2, 136.2, 131.8, 130.6, 129.8, 128.3, 126.7,
124.8, 123.9, 122.9, 122.6, 117.3, 111.0, 55.8, 20.5. HRMS
(ESI) calcd for C22H19BrNO2 ([M+H]+): 408.0594 found
408.0598.
3ꢀMesitylꢀ2ꢀ(4ꢀnitrophenyl)isoindolinꢀ1ꢀone (4j). White sol-
1
id (42.7 mg, 23%). MP: 261-263 ºC. H NMR (300 MHz,
CDCl3) δ 8.17-8.14 (m, 2H), 7.99-7.97 (m, 1H), 7.82-7.79 (m,
2H), 7.60-7.51 (m, 2H), 7.22-7.19 (m, 1H), 7.00 (s, 1H), 6.59-
6.57 (m, 2H), 2.76 (s, 3H), 2.21 (s, 3H), 1.61 (s, 3H). 13C
NMR (125 MHz, CDCl3) δ 168.3, 143.7, 143.5, 143.4, 138.4,
136.5, 136.0, 133.5, 132.1, 131.4, 130.2, 128.8, 124.6, 122.5,
120.0, 61.5, 21.3, 20.8, 18.9. HRMS (ESI) calcd for
C23H21N2O3 ([M+H]+): 373.1547 found 373.1547.
2ꢀ(4ꢀBromophenyl)ꢀ3ꢀphenylisoindolinꢀ1ꢀone (4aa).19 White
2ꢀ(4ꢀBromophenyl)ꢀ3ꢀ(2,5ꢀdimethoxyphenyl)isoindolinꢀ1ꢀ
one (4ah). White solid (192.4 mg, 91%). MP: 164-165 ºC. H
1
1
solid (120.6 mg, 67%). H NMR (300 MHz, CDCl3) δ 7.98-
7.95 (m, 1H), 7.55-7.48 (m, 4H), 7.41-7.38 (m, 2H), 7.29-7.22
(m, 4H), 7.18-7.14 (m, 2H), 6.05 (s, 1H). 13C NMR (125 MHz,
CDCl3) δ 167.9, 145.5, 137.2, 136.8, 132.7, 131.9, 130.7,
129.3, 128.7, 128.6, 124.2, 123.6, 117.9, 65.4.
NMR (300 MHz, CDCl3) δ 7.93-7.90 (m, 1H), 7.61-7.59 (m,
2H), 7.51-7.45 (m, 2H), 7.40-7.32 (m, 3H), 6.90-6.87 (m, 1H),
6.72-6.65 (m 2H), 6.30 (br, 1H), 3.95 (s, 3H), 3.52 (s, 3H). 13
C
NMR (75 MHz, CDCl3) δ 168.1, 153.9, 151.2, 137.1, 132.6,
131.8, 128.5, 124.0, 122.9, 122.8, 117.4, 113.8, 112.1, 56.2,
55.5. HRMS (ESI) calcd for C22H19BrNO3 ([M+H]+):
424.0543 found 424.0548.
2ꢀ(4ꢀBromophenyl)ꢀ3ꢀpꢀtolylisoindolinꢀ1ꢀone (4ab). White
1
solid (99.9 mg, 53%). MP: 166-167 ºC. H NMR (300 MHz,
CDCl3) δ 7.95-7.92 (m, 1H), 7.54-7.48 (m, 4H), 7.40-7.37 (m,
2H), 7.23-7.21 (m, 1H), 7.07 (s, 4H), 6.00 (s, 1H), 2.27 (s,
3H). 13C NMR (125 MHz, CDCl3) δ 167.9, 145.7, 138.4,
136.8, 134.1, 132.7, 131.8, 129.9, 128.6, 126.7, 124.1, 123.7,
123.0, 117.8, 65.3, 21.2. HRMS (ESI) calcd for C21H17BrNO
([M+H]+): 378.0488 found 378.0488.
3ꢀ(5ꢀBromoꢀ2ꢀmethoxyphenyl)ꢀ2ꢀ(4ꢀbromophenyl)isoindolin
ꢀ1ꢀone (4ai). White solid (162.1 mg, 69%). MP: 140-141 ºC.
1H NMR (400 MHz, CDCl3) δ 7.96-7.93 (m, 1H), 7.58-7.55
(m, 2H), 7.52-7.48 (m, 2H), 7.44-7.41 (m, 2H), 7.31-7.27 (m,
2H), 6.85-6.83 (m, 2H), 6.74 (br, 1H), 4.00 (s, 3H). 13C NMR
(75 MHz, CDCl3) δ 167.9, 156.1, 136.7, 132.7, 132.2, 131.9,
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128.7, 124.2, 122.8, 117.7, 112.9, 56.1. HRMS (ESI) calcd for
2ꢀ(4ꢀBromophenyl)ꢀ3ꢀ((8R,9S,13S,14S)ꢀ3ꢀmethoxyꢀ13ꢀmeth
ylꢀ17ꢀoxoꢀ7,8,9,11,12,13,14,15,16,17ꢀdecahydroꢀ6Hꢀcyclopen
C21H16Br2NO2 ([M+H]+) 471.9542 found 471.9545.
1
2
3
4
5
6
7
8
9
ta[a]phenanthrenꢀ2ꢀyl)isoindolinꢀ1ꢀone (4ap). White solid
(230.8 mg, 81%). MP: 118-120 ºC. H NMR (300 MHz,
3ꢀ(4ꢀBromoꢀ2ꢀmethoxyphenyl)ꢀ2ꢀ(4ꢀbromophenyl)isoindolin
ꢀ1ꢀone (4aj). White solid (230.3 mg, 98%). MP: 157-158ºC.
1H NMR (400 MHz, CDCl3) δ 7.94 (t, J = 5.2 Hz, 1H), 7.58-
7.56 (m, 2H), 7.50 (q, J = 5.5 Hz, 2H), 7.44-7.42 (m, 3H),7.76
(br, 1H), 6.71-6.66 (m, 2H), 3.80-3.72 (m,3H). 13C NMR (75
MHz, CDCl3) δ 167.8, 159.8, 145.2, 136.5, 132.9, 131.9,
128.8, 128.6, 128.1, 127.8, 124.3, 123.7, 122.9, 118.1, 117.7,
115.1, 62.9, 56.5. HRMS (ESI) calcd for C21H16Br2NO2
([M+H]+) 471.9542 found 471.9546.
1
CDCl3) δ 7.94-7.91 (m, 1H), 7.59 (t, J = 8.7 Hz, 2H), 7.50-
7.45 (m, 2H), 7.42-7.31 (m, 3H), 6.65 (br, 2H), 3.97 (s, 3H),
2.84-2.82 (m, 2H), 2.49-2.41 (m, 1H), 2.02-1.96 (m, 6H),
1.42-1.33 (m, 6H), 0.81-0.78 (m, 3H). 13C NMR (125 MHz,
CDCl3) δ 168.3, 155.1, 137.2, 132.6, 131.8, 128.3, 124.0,
123.3, 122.9, 117.4, 111.3, 55.7, 50.3, 47.9, 43.7, 38.0, 35.8,
31.3, 29.6, 26.3, 25.6, 21.5, 13.8. HRMS (ESI) calcd for
C33H33BrNO3 ([M+H]+): 570.1638 found 570.1627.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2ꢀ(4ꢀBromophenyl)ꢀ3ꢀ(3,4ꢀdimethylphenyl)isoindolinꢀ1ꢀone
(4ak). White solid (132.9 mg, 68%). MP: 180-182 ºC. 1H
NMR (300 MHz, CDCl3) δ 7.96-7.93 (m, 1H), 7.57-7.54 (m,
2H), 7.49-7.45 (m, 2H), 7.41-7.38 (m, 2H), 7.24-7.21 (m, 1H),
7.05-7.02 (m, 1H), 6.94-6.91 (m, 2H), 5.97 (s, 1H), 2.17 (s,
3H), 2.15 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 167.9, 145.8,
137.6, 137.1, 136.9, 134.5, 132.7, 131.8, 130.7, 130.4, 128.5,
127.7, 124.3, 124.1, 123.6, 123.2, 117.7, 65.3, 19.8, 19.5.
HRMS (ESI) calcd for C22H19BrNO ([M+H]+): 392.0645
found 392.0644.
2ꢀ(4ꢀBromophenyl)ꢀ6ꢀfluoroꢀ3ꢀmesitylisoindolinꢀ1ꢀone
(4ba). White solid (209.3 mg, 99%). MP: 170-172 ºC. 1H
NMR (300 MHz, CDCl3) δ 7.60-7.57 (m, 1H), 7.43-7.35 (m,
4H), 7.24-7.18 (m, 1H), 7.14-7.09 (m, 1H), 6.93 (s, 1H), 6.59
(s, 1H), 6.43 (s, 1H), 2.65 (s, 3H), 2.19 (s, 3H), 1.61 (s, 3H).
13C NMR (75 MHz, CDCl3) δ 166.7, 162.9 (d, J = 246.6 Hz),
139.3, 138.3, 136.9, 136.6, 136.4, 134.0 (d, J = 8.6 Hz), 133.4,
131.9, 129.9, 128.6, 124.0 (d, J = 8.3 Hz), 123.1, 120.4 (d, J =
23.5 Hz),118.2, 110.4 (d, J = 23.4 Hz), 61.2, 21.3, 20.8, 18.9.
19F NMR (282 MHz, CDCl3) δ -125.0. HRMS (ESI) calcd for
C23H20BrFNO ([M+H]+): 424.0707 found 424.0709.
3ꢀ{Benzo[d][1,3]dioxolꢀ5ꢀyl}ꢀ2ꢀ(4ꢀbromophenyl)isoindolin
ꢀ1ꢀone (4al). White solid (122.1 mg, 60%). MP: 188-189 ºC.
1H NMR (300 MHz, CDCl3) δ 7.94-7.92 (m, 1H), 7.53-7.50
(m, 4H), 7.42-7.39 (m, 2H), 7.24-7.22 (m, 1H), 6.80-6.70 (m,
2H), 6.47 (d, J = 1.8 Hz, 1H), 5.94 (s, 1H), 5.87 (q, J = 1.4 Hz,
2H). 13C NMR (75 MHz, CDCl3) δ 167.7, 148.5, 147.9, 145.5,
136.7, 136.2, 132.7, 131.9, 130.8, 130.7, 128.7, 124.1, 123.8,
123.3, 122.9, 122.4, 120.9, 117.9, 108.6, 106.5, 101.4, 65.2.
HRMS (ESI) calcd for C21H15BrNO3 ([M+H]+): 408.0230
found 408.0231.
2ꢀ(4ꢀBromophenyl)ꢀ5ꢀfluoroꢀ3ꢀmesitylisoindolinꢀ1ꢀone
(4bb). White solid (184.0 mg, 87%). MP:165-166 ºC. 1H NMR
(400 MHz, CDCl3) δ 7.98-7.96 (m, 1H), 7.43 (s, 4H), 7.22 (t, J
= 8.1 Hz, 1H), 6.96 (s, 1H), 6.86 (d, J = 7.6 Hz, 1H), 6.64 (s,
1H), 6.48 (s, 1H), 2.66 (s, 3H), 2.24 (s, 3H), 1.67 (s, 3H). 13C
NMR (125 MHz, CDCl3) δ 165.8 (d, J =243.9 Hz), 146.3,
138.4, 137.0, 136.4, 131.9, 129.9, 128.5, 128.2, 126.2, 123.0,
118.0, 116.5 (d, J = 8.1 Hz), 109.8 (d, J = 24.1 Hz), 61.2, 21.2,
20.8, 18.9. 19F NMR (282 MHz, CDCl3) δ -112.1. HRMS
(ESI) calcd for C23H20BrFNO ([M+H]+): 424.0707 found
424.0708.
2ꢀ(4ꢀBromophenyl)ꢀ3ꢀ(2,4,6ꢀtrimethoxyphenyl) isoindolinꢀ1ꢀ
1
one (4am). White solid (156.3 mg, 69%). MP: 180-182 ºC. H
NMR (300 MHz, CDCl3) δ 7.92-7.89 (M, 1H), 7.58-7.54 (m,
2H), 7.46-7.44 (m, 2H), 7.37-7.34 (m, 2H), 7.19-7.16 (m, 1H),
6.68 (s, 1H), 6.15 (d, J = 2.3 Hz, 1H), 5.83 (d, J = 2.3 Hz, 1H),
3.97 (s, 3H), 3.72 (s, 3H), 3.28 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 168.1, 161.5, 159.9, 159.5, 145.7, 137.3, 132.7,
131.8, 131.1, 127.9, 127.3, 123.5, 123.0, 122.9, 122.3, 117.0,
104.6, 91.8, 91.4, 90.6, 56.6, 56.2, 55.5, 54.9. HRMS (ESI)
calcd for C23H21BrNO4 ([M+H]+): 454.0648 found 454.0651.
2ꢀ(4ꢀBromophenyl)ꢀ7ꢀfluoroꢀ3ꢀmesitylisoindolinꢀ1ꢀone
(4bc). White solid (196.6 mg, 93%). MP: 186-187 ºC. 1H
NMR (400 MHz, CDCl3) δ 7.48-7.45 (m, 1H), 7.42-7.35 (m,
4H), 7.10 (q, J = 8.9 Hz, 1H), 6.95-6.94 (m, 2H), 6.61 (s, 1H),
6.46 (s, 1H), 2.67 (s, 3H), 2.21 (s, 3H), 1.68 (s, 3H). 13C NMR
(125 MHz, CDCl3) δ 164.6, 158.9 (d, J = 256.3 Hz), 146.6,
138.3, 136.9, 136.6, 136.4 (d, J = 15.3 Hz), 134.6, 131.8 (d, J
= 5.5 Hz), 129.9, 128.7, 123.1, 119.4, 118.5, 118.0, 115.7 (d, J
= 18.6 Hz), 61.2, 21.3, 20.8, 18.9. 19F NMR (282 MHz,
CDCl3) δ -156.9. HRMS (ESI) calcd for C23H20BrFNO
([M+H]+): 424.0707 found 424.0710.
2ꢀ(4ꢀBromophenyl)ꢀ3ꢀ(5ꢀmethylthiophenꢀ3ꢀyl)isoindolinꢀ1ꢀ
1
one (4an). White solid (101.5 mg, 53%). MP: 165-167 ºC. H
NMR (300 MHz, CDCl3) δ 7.96-7.94 (m, 1H), 7.60-7.47 (m,
6H), 7.38-7.37 (m, 1H), 6.85 (d, J = 3.4 Hz, 1H), 6.54-6.53
(m, 1H), 6.26 (s, 1H), 2.34 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 167.0, 144.9, 141.2, 137.7, 136.4, 132.7, 131.9,
130.6, 129.0, 127.1, 124.8, 124.6, 124.2, 123.1, 118.5, 61.4,
15.4. HRMS (ESI) calcd for C19H15BrNOS ([M+H]+):
384.0052 found 384.0049.
2ꢀ(4ꢀBromophenyl)ꢀ5ꢀchloroꢀ3ꢀmesitylisoindolinꢀ1ꢀone
1
(4bd). White solid (184.3 mg, 84%). MP: 92-94 ºC. H NMR
(400 MHz, CDCl3) δ 7.84 (d, J = 7.4 Hz, 1H), 7.46-7.34 (m,
5H), 7.13-7.12 (m, 1H), 6.94 (s, 1H), 6.60 (s, 1H), 6.42 (s,
1H), 2.64 (s, 3H), 2.19 (s, 3H), 1.63 (s, 3H). 13C NMR (125
MHz, CDCl3) δ 166.7, 145.4, 139.1, 138.4, 136.9, 136.5,
136.4, 133.4, 131.9, 130.5, 130.0, 129.3, 128.3, 125.2, 122.9,
118.1, 61.1, 21.3, 20.8, 18.9. HRMS (ESI) calcd for
C23H20BrClNO ([M+H]+): 440.0411 found 440.0413.
2ꢀ(4ꢀBromophenyl)ꢀ3ꢀ(4ꢀmethylnaphthalenꢀ1ꢀyl) isoindolinꢀ
1ꢀone (4ao). White solid (145.2 mg, 68%). MP: 235-236 ºC.
1H NMR (300 MHz, CDCl3) δ 8.52 (d, J = 8.4 Hz, 1H ), 8.12
(d, J = 8.4 Hz, 1H), 7.97 (d, J = 7.4 Hz, 1H), 7.79 (t, J = 7.0
Hz, 1H), 7.69-7.59 (m, 3H), 7.48-7.45 (m, 2H),7.35-7.32 (m,
3H), 7.10-7.08 (m, 1H), 7.03 (s, 1H), 6.98-6.95 (m, 1H), 2.62
(s, 3H). 13C NMR (125 MHz, CDCl3) δ 168.3, 145.8,
137.1,134.9, 133.4,132.6, 131.8, 131.7,131.1, 130.7, 130.6,
130.5, 128.6, 126.9, 126.7, 125.9, 125.7, 125.2, 124.4, 122.7,
122.4, 117.3, 60.1, 19.6. HRMS (ESI) calcd for C25H19BrNO
([M+H]+): 428.0645 found 428.0650.
2ꢀ(4ꢀBromophenyl)ꢀ5ꢀbromoꢀ3ꢀmesitylisoindolinꢀ1ꢀone
(4be). White solid (238.5 mg, 99%). MP: 125-126 ºC. 1H
NMR (300 MHz, CDCl3) δ 7.82 (d, J = 8.1 Hz, 1H), 7.66-7.63
(m, 1H), 7.41 (s, 4H), 7.31 (s, 1H), 6.95 (s, 1H), 6.63 (s, 1H),
6.46 (s, 1H), 2.65 (s, 3H), 2.22 (s, 3H), 1.65 (s, 3H). 13C NMR
(125 MHz, CDCl3) δ 166.9, 145.6, 138.5, 137.0, 136.6, 136.4,
132.1, 132.0, 131.9, 131.1, 130.0, 128.3, 127.5, 125.7, 123.1,
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The Journal of Organic Chemistry
16, 597. (c) Fleming, F. F.; Yao, L.; Ravikumar, P. C.; Funk, L.;
118.2, 61.1, 21.3, 20.8, 18.9. HRMS (ESI) calcd for
C23H20Br2NO ([M+H]+): 483.9906 found 483.9908.
Shook, B. C. J. Med. Chem. 2010, 53, 7902. (d) Kleemann, A.; Engel,
J.; Kutscher, B.; Reichert, D. Pharmaceutical Substances Syntheses
Patents Applications; Georg Thieme: Stuttgart, 2001. 4th ed.
(2) (a) Rappoport, Z. The Chemistry of the Cyano Group; Inter-
science Publishers: London, 1970. (b) Kukushkin, V. Y.; Pombeiro,
A. J. L. Chem. Rev. 2002, 102, 1771. (c) Anbarasan, P.; Schareina, T.;
Beller, M. Chem. Soc. Rev. 2011, 40, 5049.
(3) (a) Stuk, T. L.; Assink, B. K.; Bates, R. C.; Erdman, D. T.; Fedij,
V.; Jennings, S. M.; Lassig, J. A.; Smith, R. J.; Smith, T. L. Org.
Process Res. Dev. 2003, 7, 851. (b) Chen, M.; He, M.; Zhou, X.;
Huang, L.; Ruan, Y.; Huang, P. Tetrahedron 2005, 61,1335. (c) Shi-
rasaka, T.; Kunitake, T.; Tsuneyoshi, I. Brain Res. 2009, 1300, 105.
(d) Favor, D. A.; Powers, J. J.; White, A. D.; Fitzgerald, L. W.; Grop-
pi, V.; Serpa, K. A. Bioorg. Med. Chem. Lett. 2010, 20, 5666. (e) D.
Augner, D. C. Gerbino, N. Slavov, J. M. Neudorfl, H. G. Schmalz.
Org. Lett. 2011, 13, 5374. (f) Habibi, D.; Nasrollahzadeh, M.; Sahe-
bekhtiari, H.; Parish, R. V. Tetrahedron, 2003, 69, 3082.
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2ꢀ(4ꢀBromophenyl)ꢀ3ꢀmesitylꢀ5ꢀphenoxyisoindolinꢀ1ꢀone
(4bf). White solid (186.7 mg, 75%). MP: 194-195 ºC. 1H NMR
(300 MHz, CDCl3) δ 7.78 (d, J = 8.3 Hz, 1H), 7.35-7.24 (m,
6H), 7.06 (t, J = 7.2 Hz, 1H), 6.92-6.90 (m, 3H), 6.81-6.73 (m,
2H), 6.52 (s, 1H), 6.34 (s, 1H), 2.51 (s, 3H), 2.10 (s, 3H), 1.61
(s, 3H). 13C NMR (125 MHz, CDCl3) δ 167.3, 161.8, 155.8,
146.3, 138.1, 137.0, 136.4, 131.8, 130.0, 129.9, 128.9, 126.7,
125.6, 124.4, 122.9, 119.6, 118.2, 117.7, 112.1, 61.2, 21.2,
20.8, 18.9. HRMS (ESI) calcd for C29H25BrNO2 ([M+H]+):
498.1063 found 498.1057.
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19
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25
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2ꢀ(4ꢀBromophenyl)ꢀ3ꢀmesitylꢀ5ꢀmethoxyisoindolinꢀ1ꢀone
(4bg). Liquid (170.0 mg, 78%). 1H NMR (400 MHz, CDCl3) δ
7.84 (d, J = 7.8 Hz, 1H), 7.37 (m, 4H), 6.98 (dd, J = 8.4, 1.9
Hz, 1H), 6.91 (s, 1H), 6.58 (s, 2H), 6.36 (s, 1H), 3.77 (s, 3H),
2.64 (s, 3H), 2.19 (s, 3H), 1.65 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ 167.7, 163.8, 146.2, 137.9, 137.1, 136.4, 131.8,
129.8, 1239.3, 125.4, 124.7, 122.8, 117.5, 115.1, 107.2, 61.2,
55.7, 21.3, 20.8, 18.9. HRMS (ESI) calcd for C24H23BrNO2
([M+H]+): 436.0907 found 436.0901.
(4) (a) Wang, Y.; Chen, C.; Peng, J.; Li, M. Angew. Chem., Int. Ed.
2013, 52, 5323. (b) Peng, J.; Chen, C.; Wang, Y.; Lou, Z.-B.; Li, M.;
Xi, C.; Chen. H. Angew. Chem., Int. Ed. 2013, 52, 7574. (c) Wang, Y.;
Chen, C.; Zhang, S.; Lou, Z.; Su, X.; Wen, L.; Li. M. Org. Lett. 2013,
15, 4794. (d) Guo, W.; Li, S.; Tang, L.; Li, M.; Wen, L.; Chen. C.
Org. Lett. 2015, 17, 1232.
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Am. Chem. Soc. 2013, 135, 5332. (b) Walkinshaw, A. J.; Xu, W.;
Suero, M. G.; Gaunt, M. J. J. Am. Chem. Soc. 2013, 135, 12532. (c)
Zhang, F.; Das, S.; Walkinshaw, A. J.; Casitas, A.; Taylor, M.; Suero,
M. G.; Gaunt, M. J. J. Am. Chem. Soc. 2014, 136, 8851. (d) Cahard,
E.; Male, H. P. J.; Tissot, M.; Gaunt, M. J. J. Am. Chem. Soc. 2015,
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6228.
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M.; Hodkinson, C. C.; Northfield, C. J.; Page, M. I. Bioorg. Med.
Chem. Lett. 2000, 10, 1629. (b) Jagtap, P. G.; Southan, G. J.; Baloglu,
E.; Ram, S.; Mabley, J. G.; Marton, A.; Salzman, A.; Szabo, C.
Bioorg. Med. Chem. Lett. 2004, 14, 81.
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Wustrow, D. J.; Zoski, K. T.; Whetzel, S. Z.; Corbin, A. E.; Pugsley,
T. A.; Heffner, T. G.; Wise, L. D. Bioorg. Med. Chem. Lett. 1998, 8,
1499. (b) Kanamitsu, N.; Osaki, T.; Itsuji, Y.; Yoshimura, M.; Tsu-
jimoto, H.; Soga, M. Chem. Pharm. Bull. 2007, 55, 1682. (c) Alonso,
N.; Caamaño, O.; Romero-Duran, F. J.; Luan, F.; Cordeiro, N. D. S;
Yañez, M.; González-Díaz, H.; García-Mera, X. ACS Chem. Neuroꢀ
sci. 2013, 4, 1393. (d) Byrne, A. J.; Barlow, J. W.; Walsh, J. J.
Bioorg. Med. Chem. Lett. 2011, 21, 1191. (e) Vieth, M.; Cummins, D.
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R.; Gago, F. J. Med. Chem. 1998, 41, 836.
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Fedij, V.; Jennings, S. M.; Lassig, J. A.; Smith, R. J.; Smith. T. L.
Org. Process Res. Dev. 2003, 7, 851. (b) Shirasaka, T.; Kunitake, T.;
Tsuneyoshi. I. Brain Res. 2009, 1300, 105. (c) Favor, D. A.; Powers,
J. J.; White, A. D.; Fitzgerald, L. W.; Groppi, V.; Serpa. K. A. Bioorg.
Med. Chem. Lett. 2010, 20, 5666.
(11) (a) Knepper, K.; Ziegler, R. E.; Bräse, S. Tetrahedron 2004, 60,
8591. (b) Guo, Z.; Schultz, A. G.; J. Org. Chem. 2001, 66, 2154. (c)
Zhou, Y.; Zhai, Y.; Li, J.; Ye, D.; Jiang, H.; Liu, H. Green Chem.
2010, 12, 1397. (d) Wang, Z.; Feng, C.; Xu, M.; Lin, G. J. Am. Chem.
Soc. 2007, 129, 5336. (e) Fujioka, M.; Morimoto, T.; Tsumagari, T.;
Tanimoto, H.; Nishiyama, Y.; Kakiuchi, K. J. Org. Chem. 2012, 77,
2911. (f) Das, S.; Addis, D.; Knöpke, L. R.; Brückner, A.; Junge, K.;
Beller, M. Angew. Chem., Int. Ed. 2011, 50, 9180; Angew. Chem.
2011, 123, 9346. (g) Bhakuni, B. S.; Yadav, A.; Kumar, S.; Patel, S.;
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2015, 17, 4479. (i) Verma, A.; Meenakshi, S. P.; Kumar, A.; Yadav,
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Comm. 2015, 51, 1371.
2ꢀ(4ꢀBromophenyl)ꢀ3ꢀmesitylꢀ5ꢀnitroisoindolinꢀ1ꢀone
(4bh). White solid (114.7 mg, 51%). MP: 213-214 ºC. H
1
NMR (400 MHz, CDCl3) δ 8.81 (d, J = 1.6 Hz, 1H), 8.42 (dd,
J = 8.3, 2.0 Hz, 1H), 7.46-7.42 (m, 4H), 7.36 (d, J = 8.3 Hz,
1H), 6.98 (s, 1H), 6.65 (s, 1H), 6.59 (s, 1H), 2.68 (s, 3H), 2.24
(s, 3H), 1.64 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 165.6,
149.7, 148.7, 138.9, 136.9, 136.6, 136.1, 133.7, 132.1, 130.2,
127.6, 123.2, 119.6, 118.8, 61.7, 21.4, 20.8, 19.0. HRMS
(ESI) calcd for C23H20BrN2O3 ([M+H]+): 451.0652 found
451.0648.
ꢀ
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website. Characterization of products (copies of
1H, 13C, and 19F NMR spectra) (PDF).
X-ray data for 4b, 4i, 4ah, 4al and 4ao. (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: lijianchem@cczu.edu.cn
ORCID
Jian Li: 0000-0001-6713-1302
Notes
The authors declare no competing financial interest.
ꢀ
ACKNOWLEDGMENT
We are grateful to National Natural Science Foundation of China
(21402013), the Natural Science Foundation of Jiangsu Province
(BK20140259), Jiangsu Key Laboratory of Advanced Catalytic
Materials and Technology (BM2012110) and Advanced Catalysis
and Green Manufacturing Collaborative Innovation Center.
ꢀ
REFERENCES
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(14) CCDC 153320 (4b), CCDC 153321 (4i), CCDC 153322 (4ah),
CCDC 1539491 (4al) and CCDC 1539492 (4ao), contain the supple-
mentary crystallographic data for this paper.
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