Copper-catalysed synthesis of 3-hydroxyisoindolin-1-ones from benzylcyanide 2-iodobenzamides

Article abstract of DOI:10.1039/c9ob02329a

An efficient one-pot two-step sequential reaction for the synthesis of biologically active 3-hydroxyisoindolin-1-one derivatives from 2-iodobenzamide derivatives and various substituted benzyl cyanides in the presence of CuCl and cesium carbonate in DMSO is reported. Furthermore, 3-hydroxyisoindolinone derivatives possessing bromo substituents were obtained from 2-iodobenzamide and 2-bromobenzyl cyanide substrates in two steps. Benzyl cyanide has been successfully used for the first time as a benzoyl synthon for the synthesis of 3-hydroxyisoindolin-1-ones. Interestingly, the mechanism of formation of 3-hydroxyisoindolin-1-ones is a novel pathway that involves carbon degradation followed by ring contraction.

Full text of DOI:10.1039/c9ob02329a

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Copper-catalysed synthesis of 3-hydroxyisoindolin-
1-ones from benzylcyanide 2-iodobenzamides†
Cite this: DOI: 10.1039/c9ob02329a
Veerababurao Kavala, Chen-Yu Wang, Cheng-Chuan Wang, Prakash Bhimrao Patil,
ChiaChi Fang, Chun-Wei Kuo and Ching-Fa Yao
*
An efficient one-pot two-step sequential reaction for the synthesis of biologically active 3-hydroxyiso-
indolin-1-one derivatives from 2-iodobenzamide derivatives and various substituted benzyl cyanides in
the presence of CuCl and cesium carbonate in DMSO is reported. Furthermore, 3-hydroxyisoindolinone
derivatives possessing bromo substituents were obtained from 2-iodobenzamide and 2-bromobenzyl cyanide
substrates in two steps. Benzyl cyanide has been successfully used for the first time as a benzoyl synthon for
the synthesis of 3-hydroxyisoindolin-1-ones. Interestingly, the mechanism of formation of 3-hydroxyisoindo-
lin-1-ones is a novel pathway that involves carbon degradation followed by ring contraction.
Received 28th October 2019,
Accepted 6th January 2020
DOI: 10.1039/c9ob02329a
rsc.li/obc
Kim and Zhao research groups individually disclosed the syn-
thesis of 3-hydroxyisoindolinone derivatives starting from
Introduction
3-Hydroxyisoindolin-1-one derivatives are important constitu- benzamide derivatives via tandem metal-catalyzed oxidative
ents of natural products and are pharmaceutically active build- acylation of secondary benzamides with aldehydes and an
ing blocks in medicinal chemistry, as shown in Fig. 1.1 intramolecular cyclization strategy using Rh9 and Pd10 cata-
Molecules that contain the 3-hydroxyisoindolin-1-one core are lysts, respectively. Recently, Shen and coworkers reported base-
known to exhibit a wide range of activities such as anti- promoted cascade C–C coupling/N-α-sp3C–H hydroxylation for
microbial and antitumor activities and act as inhibitors of the synthesis of 3-hydroxyisoindolinone derivatives.11
protein–tyrosine phosphatase and HIV-1 integrase.2 Besides, Subsequently other methods were also reported.12 The need
anticonvulsant and antihypertensive drugs3 contain the for expensive metal catalysts, additional oxidants, and harsh
3-hydroxyisoindolin-1-one core. Furthermore, 3-hydroxyisoin- reaction conditions is the limitation of these protocols.
dolinone derivatives are also important surrogates for the syn- Therefore, an efficient protocol that addresses these issues is
thesis of various products.4
As a result, continuous efforts have been directed towards derivatives.
the development of efficient methods for the synthesis of Benzyl cyanide is a versatile reagent which plays multiple
3-hydroxyisoindolin-1-one derivatives. literature survey roles in reactions by functioning as a nucleophile, cyanating
highly desirable for the synthesis of 3-hydroxyisoindolinone
A
revealed that the most common method for the synthesis of
3-hydroxyisoindolinone derivatives is the selective addition of
organometallic reagents such as RMgX, RLi, and R2Zn to
phthalimide derivatives.5 The other methods for their syn-
thesis from phthalimides include photodecarboxylative
addition of carboxylates6 and reductive coupling with alde-
hydes and ketones (Fig. 2).7
Liu et al.8 introduced a green protocol for the synthesis of
3-hydroxyisoindolinone derivatives from 2-(ethynyl)benzoic
acids and primary amines using a phase transfer catalyst in
the presence of water under microwave conditions. Later, the
Department of Chemistry, National Taiwan Normal University, 88, Sec. 4, Ting-Zhou
Road, Taipei-116, Taiwan, Republic of China. E-mail: cheyaocf@ntnu.edu.tw
†Electronic supplementary information (ESI) available. CCDC 1945018–1945020.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c9ob02329a
Fig. 1 Representative natural products and biologically active com-
pounds that contain the 3-hydroxyisoindolin-1-one core.
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reaction by replacing the nitrogen atmosphere with an open
atmosphere at the same temperature for 24 h. The reaction
produced 35% of the expected product (3aa). Encouraged by
this result, we screened various conditions to improve the yield
of the desired product while maintaining the same sequence
of conditions (initially the reaction was conducted under a
nitrogen atmosphere until the formation of the intermediate,
then the nitrogen balloon was removed and the reaction was
conducted in an open atmosphere). In this regard, firstly, we
increased the amount of the base in the reaction (Table 1,
entries 2 and 3). We found that the reaction resulted in a
better yield with 3 equiv. of Cs2CO3. Next, we optimized the
amount of benzyl cyanide in the reaction (Table 1, entries
4–6). The use of 1.5 equiv. of benzyl cyanide in the reaction
gave better yield compared with the use of a higher amount of
benzyl cyanide. Furthermore, no marked improvement in the
yield of the desired product was observed when the reactions
were performed at 80 °C and 100 °C (Table 1, entries 7 and 8).
Next, we screened different bases such as K2CO3, K3PO4, TEA,
Fig. 2 Known synthetic route for accessing 3-hydroxyisoindolin-1-one
derivatives.
agent and benzoyl protecting group. Moreover, the use of and DBU for use in this reaction. The reactions afforded a low
benzyl cyanide as a nucleophile13 and cyanating agent14 is well yield of the product with these bases (Table 1, entries 9–12).
documented in the literature. Furthermore, several reports are After an extensive screening of parameters like the ratio of
available on the use of benzyl cyanide as a benzoyl synthon for reagents, bases, solvents, and temperature, the product yield
the protection of amine and alcohol groups.15 Previously, we reached only 47%.
reported that benzyl cyanide acts as a nucleophile as well as a
cyanating agent in the same reaction by slight modification of
the reaction conditions.16
Table 1 Optimization studies
As part of our interest in developing fascinating protocols
for the synthesis of biologically active heterocycles using
2-iodobenzamides,17 very recently, we reported the synthesis of
benzopyridoindolone derivatives via a one-pot copper-cata-
lyzed tandem reaction of 2-iodobenzamide and 2-iodobenzyl-
cyanide derivatives.18 When we replaced 2-iodobenzyl cyanide
2a
(eq.)
Temp.
(°C)
Yieldb
(%)
with 2-bromobenzylcyanide in the reaction, we obtained two
products in which the first product corresponded to the benzo-
fused pyridoindolone derivative. The other one was an
unknown product, which was characterized by NMR and mass
spectral data. From the spectral data, it was found that the
unknown product was a 3-hydroxyisoindolinone derivative.
This is an interesting result where the six-membered ring con-
tracts to a five-membered ring through one carbon degra-
dation. Hence, we envisioned that the investigation of this
reaction would be very useful as 3-hydroxyisoindolinone
derivatives exhibit a variety of biological activities. Moreover,
the reaction of 2-bromobenzylcyanide and 2-iodobenzamide
produced two products, and we speculate that the use of
benzyl cyanide instead of 2-bromobenzyl cyanide would give
single product as it can avoid the formation of benzofused
pyridoindolone.
Entrya
Catalyst
Ligand
Base (eq.)
1
2
3
4
5
6
7
8
1.2
1.2
1.2
1.5
2
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuI
CuBr
CuSO4
Cu(OAc)2
CuCl2
CuCl
CuCl
CuCl
No
No
No
No
No
No
No
No
No
No
No
No
L1
L2
L3
L1
L1
L1
L1
L1
No
L1
L1
Cs2CO3 (2)
Cs2CO3 (3)
Cs2CO3 (4)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
K2CO3 (3)
K3PO4 (3)
DBU (3)
60
60
60
60
60
60
80
100
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
35
45
36
40
47
45
41
25
24
35
30
24
45
30
28
44
33
20
26
20
50
78
52
2.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
9
10
11
12
13
14
15
16
17
18
19
20
21c
22c
23c,d
TEA (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
To test this hypothesis, we initiated the reaction of 2-iodo-
N-benzylbenzamide (1a) and benzyl cyanide (2a) in the pres-
ence of CuI and Cs2CO3 (2 equiv.) at 60 °C in DMSO for
20 min under a nitrogen atmosphere. The reaction produced
a Reaction conditions: (1) 1a (1 mmol), 2a, catalyst (10 mol%), ligand
(20 mol%), base, DMSO, temp., N2; (2) air, 60 °C. b NMR yields.
c Additional amount of Cs2CO3 was added after the formation of the
intermediate. d The second step under O2.
3-amino-2-benzyl-4-phenylisoquinolin-1(2H)-one
which
remained unchanged even after 12 h. However, without isolat-
ing the aminoisoquinolinone compound, we continued the
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Table 2 Scope and limitation when using various cyanide derivativesa,b
To improve the yield of the product, we performed the reac-
tion using different ligands such as L-proline (L1), 1,10-phe-
nanthroline (L2), and 8-hydroxyquinoline (L3). With proline,
the reaction afforded the corresponding product in 45% yield
(Table 1, entry 13) while a poor yield of the product was
obtained with 1,10-phenanthroline and 8-hydroxyquinoline
(Table 1, entries 14 and 15). Next, we screened other copper
catalysts such as CuI, CuBr, CuSO4, Cu(OAc)2 and CuCl2 along
with CuCl (Table 1, entries 16–20). Among the copper catalysts
used in this reaction, CuCl was found to be the best catalyst
for this conversion. Next, we conducted the reaction by adding
an additional amount of cesium carbonate (2 equiv.) after the
formation of the intermediate. The reaction produced 50% of
the desired product. When the reaction was carried out in the
presence of L-proline with the addition of 2 more equivalents
of cesium carbonate, 78% of the corresponding 3-hydroxyiso-
lindolinone derivative was produced (Table 1, entry 22). Next,
we conducted the reaction in the presence of oxygen. To our
surprise, the reaction provided the desired product in 52%
yield, which is less than that obtained in an open atmosphere.
The optimized conditions for the reaction were 10 mol% of
CuCl, 20 mol% of L-proline and 3 equiv. of cesium carbonate
in DMSO at 60 °C under a nitrogen atmosphere until the for-
mation of the intermediate (3-aminoisoquinolinone derivative)
and the reaction was continued by the addition of 2 more
equivalents of cesium carbonate in an open atmosphere in
one pot. Later we examined the scope of the methodology by
fixing 2-iodo-N-benzylbenzamide (1a) and changing the substi-
tuents on the benzyl cyanide substrate, as shown in Table 2.
The reaction of 1a and unsubstituted benzyl cyanide pro-
duced its corresponding 3-hydroxyisoindolin-1-one product
(3aa) in 63% yield. Next, Benzyl cyanide bearing moderate elec-
tron-donating groups such as Me and t-Bu afforded the
a Reaction conditions: 1 (1 mmol), 2 (1.1 eq.), CuCl (10 mol%), Cs2CO3
(3 eq.), DMSO (2 mL) heated at 60 °C under N2 until the formation of
the intermediate, which was confirmed by TLC; the reaction was con-
tinued by the addition of two more equiv. of Cs2CO3 at the same temp-
erature in an open atmosphere in one pot. b Isolated yield.
desired products (3ab and 3ac) in moderate yields, whereas good yield. Then, we examined the reactions of 2-iodobenza-
benzyl cyanide containing strong electron-donating groups mide substrates containing N-phenethyl, N-phenylbutyl,
such as OMe and OCH2O furnished the corresponding pro- N-ethylmethoxy, N-ethylindolyl and N-ethylmorphinyl substitu-
ducts (3ad and 3ae) in low yields. On the other hand, electron- ents. Good yield of the products was obtained in the case of
withdrawing groups such as Cl, F, Br, dichloro, and CF3 on the N-phenethyl (3ea), N-phenylbutyl (3fa), and N-ethylmethoxy
benzyl cyanide substrate work well in producing the desired (3ga) substrates. Moderate yields of the 3-hydroxyisoindolin-1-
products (3af, 3ag, 3ah, 3ai, 3aj, and 3ak) in good to excellent one derivatives were obtained with N-ethylindolyl (3ha) and
yields. The reaction of benzyl cyanide containing strong elec- N-ethylmorphinyl (3ia) substrates. Furthermore, we tested the
tron-withdrawing groups with 2-iodo-N-benzylbenzamide gave reactions of various substituted 2-iodobenzamide substrates
a poor yield of the desired product (3al). When using ethylcya- with benzyl cyanide. Halogens such as 5-bromo, 3-chloro, and
noacetate and malanonitrile, we did not obtain the desired 5-fluoro substituted 2-iodobenzamide derivatives readily par-
products. However, with ethylcyanoacetate, the reaction ticipated in the reaction to furnish the corresponding 3-hydro-
afforded 2-benzyl-1,3-dioxo-1,2,3,4-tetrahydroisoquinoline-4- xyisoindolinone derivatives 3ja, 3ka and 3la, respectively, in
carbonitrile while with malanonitrile, 3-amino-2-benzyl-1-oxo- good yields. On the other hand, the substrates containing elec-
1,2-dihydroisoquinoline-4-carbonitrile was obtained.
tron-donating groups such as methoxy, dimethoxy, and
Next, we were interested in checking the scope of the proto- methylenedioxy groups afforded the corresponding products
col by fixing the benzyl cyanide substrate and varying the (3ma, 3na, and 3oa) in moderate yields.
N-alkyl substituents of the starting material 2-iodobenzamide
under the optimized reaction conditions (Table 3).
After the successful application of the one-pot reaction con-
ditions to various benzyl cyanide substrates, we then turned
When N-methyl and N-isopropyl substituents were used in our attention to utilize 2-bromobenzyl cyanide. To obtain the
the reactions, the desired products (3ba and 3ca) were isolated 3-hydroxyisoindolin-1-one derivative from this reaction, we per-
in 65 and 52% yields, respectively. The reaction works well formed the reaction in two steps, wherein we performed the
with N-phenyl, producing the corresponding product (3da) in reaction of 2-bromobenzylcyanide and 2-iodobenzamide
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Table 3 Scope and limitation when using substituted 2-iodobenzamide
derivativesa,b
Table 4 Scope and limitation when using substituted 2-iodobenzamide
derivatives and 2-bromobenzylcyanide substratesa,b,c
a Reaction conditions: 1 (1 mmol), 2 (1.1 eq.), CuCl (10 mol%), Cs2CO3
(3 eq.), DMSO (2 mL) heated at 60 °C under N2 until the formation of
the intermediate, which was confirmed by TLC; the reaction was con-
tinued by the addition of two more equivalents of Cs2CO3 at the same
temperature in an open atmosphere in one pot. b Isolated yield.
a Reaction conditions: 1 (1 mmol), 2 (1.1 eq.), CuCl (10 mol%), Cs2CO3
(3 eq.), DMSO (2 mL) heated at 60 °C under N2 until the formation of
the intermediate. Then the reaction was stopped with water and
extracted with EA. The crude mixture was treated with two equiv. of
Cs2CO3 at 60 °C in an open atmosphere (reaction conducted in two
steps). b Isolated yield. c In all the cases, we observed the benzopyri-
doindole derivative as a side product in 10–15% yield.
derivatives at 60 °C until the complete consumption of the
amide component. Later the reaction was quenched to remove
the copper salt. After the workup, the crude reaction mixture
was again reacted with cesium carbonate in DMSO at the same
temperature to obtain the corresponding hydroxyisoindolin-1-
one derivative. It is important to note that the reaction invol-
ving 2-bromobenzyl cyanide substrates did not require the
L-proline ligand for the formation of intermediate 3-aminoiso- ents on the benzyl cyanide substrate as shown in Table 4. A
quinolinone derivatives. Furthermore, in the presence of moderate yield of the desired product is obtained using the
L-proline, a greater amount of the benzopyridoindole derivative OMe substituent on the 2-bromobenzyl cyanide substrate and
was formed as a side product. Under modified conditions, we 3,4-dimethoxy-2-bromobenzyl cyanide and 3,4-methylenedioxy-
investigated the reactions of various substituted 2-iodobenza- 2-bromobenzyl cyanide substrates gave the desired products
mides and 2-bromobenzylcyanides (Table 4). The results are 3ap and 3aq in yields of 40% and 45%, respectively.
shown in Table 4. The reaction of various N-substituted-2-iod- Dibromobenzyl cyanide produced the desired product 3ar in
benzamide substrates such as N-phenyl, N-benzyl and good yield.
N-ethylphenyl 2-iodobenzamide with 2-bromobenzyl cyanide
We thought of two plausible pathways for the formation of
furnished the corresponding hydroxyisoindolin-1-one deriva- 3-hydroxyisoindolin-1-one from 2-iodo-N-methylbenzamide
tives (3an, 3en, and 3fn) in good yields. Under the present and benzyl cyanide (Scheme 1).
reaction conditions, halo substituted 2-iodobenzamide sub-
Initially, the formation of the 3-amino isoquinolinone inter-
strates reacted smoothly to afford the desired products (3kn, mediate occurs in the presence of CuCl and a base (the isoqui-
3ln, and 3mn) in good yields. However, the electron-donating nilone intermediate was isolated and characterized). In the
group substituted 2-iodobenzamide substrates produced the first pathway, intermediate [A] generates iminium salt [B] in
corresponding products (3nn and 3pn) in slightly lower yields the presence of a base, which undergoes ring opening to
compared to the electron-withdrawing group substituted afford cyano intermediate 2-(cyano(phenyl)methyl)-N-methyl-
2-iodobenzamides. Later the reaction scope was examined by benzamide [C]. Next, intramolecular cyclization occurs by the
fixing 2-iodo-N-benzylbenzamide and changing the substitu- loss of a cyanide ion to afford 2-methyl-3-phenylisoindolin-1-
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Scheme 1 Plausible mechanistic pathways for the reaction.
one (D), which upon reaction with oxygen in the presence of a
base furnishes peroxide intermediate [E].11 Next, the peroxide
intermediate decomposes to afford the 3-hydroxyisoindolin-1-
one derivative (3). Another possibility is that after the for-
mation of 2-(cyano(phenyl)methyl)-N-methylbenzamide inter-
mediate [C], it reacts with oxygen in the presence of a base to
produce peroxide intermediate [F], which subsequently decom-
poses to afford intermediate [G]. Further, intermediate [G]
affords intermediate [H] by the elimination of a cyanide ion,
which subsequently undergoes intramolecular cyclization to
afford the desired product 3.
Scheme 2 Reaction of 3-aminoisoquinolinone with cesium carbonate
under an argon atmosphere.
To check for the suitable pathway among the proposed
pathways, we carried out a few controlled experiments.
Initially, the intermediate (3-aminoisoquinolinone) was iso-
lated and then it was subjected to the reaction in d6-DMSO in
the presence of Cs2CO3 in an NMR tube. The reaction was
monitored constantly. It was observed that the NH2 peak dis-
appeared in the 1H NMR spectrum as soon as the base was
added. This indicates the formation of intermediate [B].
Moreover, the proton NMR spectrum showed only two sets of
protons, one corresponding to the final product and the other
corresponding to intermediate B. We did not find any other
products during the 1H NMR experiment of the reaction of
intermediate [A] (see NMR experiment results in the ESI, page
S56†).
Scheme 3 Reaction of 2-benzyl-3-phenylisoindolin-1-one.
various substituted benzyl cyanides in the presence of CuCl
and cesium carbonate in DMSO is reported. Furthermore, we
also reported the synthesis of 3-hydroxyisoindolinone deriva-
tives and benzofused pyridoindolone from 2-iodobenzamide
and 2-bromobenzyl cyanide substrates by altering the reac-
tion conditions. Benzyl cyanide has been successfully used
for the first time as a benzoyl synthon for the synthesis of
3-hydroxyisoindolin-1-ones. Also, the proposed mechanism
for the formation of 3-hydroxyisoindolin-1-ones is a novel
pathway that involves carbon degradation followed by ring
contraction.
The reaction of intermediate A and cesium carbonate was
conducted under an argon atmosphere. Intermediate
A
remained unchanged even after 12 h (Scheme 2), whereas in
open air, the reaction afforded the 3-hydroxyisoindolinone
derivative (3a) in 80% yield.
Next we synthesized 2-benzyl-3-phenylisoindolin-1-one
using a known procedure and it was treated with cesium car-
bonate in DMSO at 60 °C in an open atmosphere. The reaction
produced 3-hydroxy-N-benzyl-isoindolin-1-one (3aa) in 74%
yield (Scheme 3).
Experimental section
General information
Based on these observations, we cannot rule out either of
two possibilities proposed in Scheme 1. However, under an
argon atmosphere, the 3-aminoisoquinolinone derivative did Reagents and solvents were purchased from various commer-
not produce 2-benzyl-3-phenylisoindolin-1-one derivative. cial sources and were used directly without any further purifi-
Hence, we speculate that pathway 1 is a more plausible cation, unless otherwise stated. Column chromatography was
mechanistic pathway for the formation of product 3.
performed using 63–200 mesh silica gel. 1H and 13C NMR
In conclusion, an efficient one-pot two-step sequential spectra were recorded at 400/500/600 and 100/125/150 MHz,
reaction for the synthesis of biologically active 3-hydroxyi- respectively. Chemical shifts are reported in parts per million
soindolin-1-one derivatives from 2-iodobenzamide and (δ) using TMS and chloroform or DMSO-d6 as internal stan-
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dards and coupling constants are expressed in hertz. Melting
points were recorded using an electro thermal capillary
Spectral data
melting point apparatus and are uncorrected. HRMS spectra Known compounds 3aa,11 3ak,9 3al, 3ba, 3ca, 3da.11
were recorded using ESI-TOF or ESI-Neg mode. The
starting 2-iodobenzamide derivatives 1 and benzyl cyanide
2-Benzyl-3-hydroxy-3-(p-tolyl)isoindolin-1-one (3ab)
derivatives 2 were synthesized following previously reported Yield 74% (244 mg); pale yellow solid. Mp: 166.0–168.0 °C (EA/
methods.
hexane). 1H-NMR (400 MHz, CDCl3) δ 7.76–7.74 (m, 1H),
7.47–7.40 (m, 2H), 7.25–7.24 (m, 1H), 7.21–7.13 (m, 7H),
7.08–7.06 (m, 2H), 4.70 (d, J = 14.98 Hz, 1H), 4.02 (d, J = 14.98
Hz, 1H), 3.43 (s, 1H), 2.32 (s, 3H); 13C-NMR (100 MHz, CDCl3)
δ 168.0, 149.4, 138.4, 138.3, 135.5, 132.9, 130.4, 129.6, 129.3,
128.9, 128.3, 127.2, 126.4, 123.6, 122.9, 91.9, 43.2, 21.3; HRMS
(ESI-neg) m/z calcd for C22H18NO2 (M− − H) 328.1338, found
328.1334.
General procedure for the one-pot synthesis of
3-hydroxyisoindolinone derivatives from benzylcyanide and
2-iodobenzamide derivatives
A 25 mL round-bottom flask was charged with 3 mL of DMSO,
followed by 2-iodobenzamide derivative 1 (1 mmol), copper(I)
chloride (0.15 mmol), proline (0.3 mmol), benzyl cyanide
derivative 2 (2 mmol), and cesium carbonate (3 mmol). The
reaction mixture was stirred at 60 °C until the complete con-
sumption of 2-iodobenzamide to form an intermediate, as evi-
denced by TLC. Then, 2 mmol of additional cesium carbonate
was added and the reaction was continued in an open atmo-
sphere at the same temperature until the completion of the
reaction, as evidenced by TLC. Then, the mixture was cooled
down to room temperature and ice/water was added to it. The
reaction mixture was extracted with ethyl acetate (3 × 20 mL).
The organic layer was separated, dried over anhydrous MgSO4
and filtered and the dried organic layer was then concentrated
to give the crude product. The resulting residue was further
purified by flash column chromatography using 1 : 5 ethyl
acetate/hexane on silica gel.
2-Benzyl-3-(4-(tert-butyl)phenyl)-3-hydroxyisoindolin-1-one (3ac)
Yield: 60% (223 mg); pale yellow solid. Mp: 194.4–196.3 °C
1
(EA/hexane). H-NMR (400 MHz, CDCl3) δ 7.77 (d, J = 6.92 Hz,
1H), 7.49–7.41 (m, 2H), 7.29–7.27 (m, 1H), 7.25–7.19 (m, 4H),
7.17–7.10 (m, 5H), 4.66 (d, J = 16.0 Hz, 1H), 4.10 (d, J = 16.0
Hz, 1H), 1.28 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ 168.1,
151.5, 149.4, 138.2, 135.3, 132.9, 130.5, 129.6, 129.0, 128.2,
127.0, 126.2, 125.4, 123.5, 123.0, 91.8, 43.1, 34.7, 31.5; HRMS
(ESI-neg) m/z calcd for C25H24NO2 (M− − H) 370.1807, found
370.1806.
2-Benzyl-3-hydroxy-3-(4-methoxyphenyl)isoindolin-1-one (3ad)
Yield: 45% (155 mg); white solid. Mp: 176.3–177.3 °C (EA/
hexane). 1H-NMR (400 MHz, CDCl3) δ 7.79–7.77 (m, 1H),
7.49–7.42 (m, 2H), 7.26–7.20 (m, 5H), 7.19–7.14 (m, 3H),
6.79–6.77 (m, 2H), 4.73 (d, J = 14.98 Hz, 1H), 4.05 (d, J = 14.98
Hz, 1H), 3.78 (s, 3H), 3.13 (s, 1H); 13C-NMR (100 MHz, CDCl3)
δ 168.0, 159.8, 149.4, 138.4, 132.9, 130.4, 130.4, 129.6, 128.9,
General procedure for the synthesis of 3-hydroxyisoindolinone
derivatives from 2-bromobenzylcyanide and 2-iodobenzamide
derivatives
A 25 mL round-bottom flask was charged with 3 mL of DMSO, 128.3, 127.9, 127.2, 123.6, 122.9, 113.9, 91.8, 55.5, 43.1; HRMS
followed by 2-iodobenzamide derivative 1 (1 mmol), copper(I) (ESI-neg) m/z calcd for C22H18NO3 (M− − H) 344.1287, found
chloride (0.15 mmol), 2-bromobenzyl cyanide derivative 2 344.1295.
(2 mmol), and cesium carbonate (3 mmol) under a nitrogen
atmosphere. The reaction mixture was stirred at 60 °C until the
complete consumption of 2-iodobenzamide to form the inter-
3-(Benzo[d][1,3]dioxol-5-yl)-2-benzyl-3-hydroxyiso indolin-1-one
(3ae)
mediate, as evidenced by TLC. Then, the reaction mixture was Yield: 40% (143 mg); pale yellow solid. Mp: 203.2–205.0 °C
quenched with saturated ammonium chloride solution and (EA/hexane). 1H-NMR (400 MHz, CDCl3) δ 7.82–7.80 (m, 1H),
extracted with ethyl acetate. The organic layer was separated, 7.51–7.43 (m, 2H), 7.28–7.24 (m, 3H), 7.22–7.16 (m, 3H),
dried over anhydrous MgSO4 and filtered and the dried 6.92–6.89 (dd, J = 8.12, 1.76 Hz, 1H), 6.72–6.69 (m, 2H),
organic layer was then concentrated to give the crude inter- 5.92–5.91 (m, 2H), 4.77 (d, J = 15.00 Hz, 1H), 4.10 (d, J = 15.00
mediate. The crude intermediate product was dissolved in Hz, 1H), 2.90 (s, 1H); 13C-NMR (100 MHz, CDCl3) δ 167.9,
DMSO and 2 mmol of cesium carbonate was added. The 149.2, 148.0, 147.9, 138.4, 133.0, 132.3, 130.4, 129.8, 128.9,
reaction mixture was stirred at 60 °C in an open atmosphere 128.4, 127.3, 123.7, 122.8, 120.3, 108.2, 107.3, 101.4, 91.7, 43.1.
until the completion of the reaction, as evidenced by TLC. HRMS (ESI-neg) m/z calcd for C22H16NO4 (M− − H) 358.1079,
Then the reaction mixture was cooled down to room tempera- found 358.1072.
ture and ice/water was added to it. The reaction mixture was
extracted with ethyl acetate (3 × 20 mL). The organic layer was
2-Benzyl-3-(3-chlorophenyl)-3-hydroxyisoindolin-1-one (3af)
separated, dried over anhydrous MgSO4 and filtered and the Yield: 87% (315 mg); white solid. Mp: 197.8–199.7 °C (EA/
dried organic layer was then concentrated to give the crude hexane). 1H-NMR (400 MHz, CDCl3) δ 7.77–7.75 (m, 1H),
product. The resulting residue was further purified by flash 7.51–7.43 (m, 2H), 7.33 (s, 1H), 7.26 (d, J = 7.60 Hz, 1H),
column chromatography using 1 : 5 ethyl acetate/hexane on 7.21–7.18 (m, 1H), 7.15–7.10 (m, 7H), 4.59 (d, J = 14.96 Hz,
silica gel.
1H), 4.13 (d, J = 14.96 Hz, 1H), 3.62 (s, 1H); 13C-NMR
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(100 MHz, CDCl3) δ 168.2, 148.8, 140.6, 137.7, 134.5, 133.2, HRMS (ESI-neg) m/z calcd for C21H15N2O4 (M− − H) 359.1032,
130.2, 129.9, 129.7, 128.9, 128.6, 128.3, 127.3, 127.1, 124.8, found 359.1029.
123.7, 123.0, 91.1, 43.0; HRMS (ESI-neg) m/z calcd for
3-Hydroxy-2-phenethyl-3-phenylisoindolin-1-one (3ea)
C21H15NO2Cl (M− − H) 348.0791, found 348.0797.
Yield: 69% (228 mg); yellow solid. Mp: 194.0–196.0 °C (EA/
2-Benzyl-3-(4-fluorophenyl)-3-hydroxyisoindolin-1-one (3ag)
hexane). 1H-NMR (400 MHz, CDCl3) δ 7.71–7.69 (d, J = 7.24 Hz,
Yield: 78% (260 mg); pale yellow solid. Mp: 179.5–180.3 °C 1H), 7.47–7.38 (m, 4H), 7.35–7.32 (m, 3H), 7.27–7.25 (m, 1H),
1
(EA/hexane). H-NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.40 Hz, 7.24–7.20 (m, 2H), 7.18–7.14 (m, 1H), 7.07–7.06 (m, 2H),
1H), 7.49 (t, J = 7.42 Hz, 1H), 7.43 (t, J = 7.40 Hz, 1H), 7.24–7.20 3.67–3.60 (m, 1H), 3.45 (s, 1H), 3.19–3.11 (m, 1H), 2.99–2.92
(m, 3H), 7.10–7.05 (m, 5H), 6.86 (t, J = 8.54 Hz, 2H), 4.44 (d, J = (m, 1H), 2.59–2.52 (m, 1H); 13C-NMR (100 MHz, CDCl3) δ
15.0 Hz, 1H), 4.13 (d, J = 15.0 Hz, 1H), 4.25 (s, 1H); 13C-NMR 168.0, 149.2, 139.5, 138.9, 132.9, 130.7, 129.7, 129.0, 128.8,
(100 MHz, CDCl3) δ 168.2, 162.8 (d, JC–F = 247.29 Hz), 149.2, 128.6, 126.5, 126.4, 123.4, 122.9, 91.5, 41.6, 34.8; HRMS (ESI-
138.0, 134.2 (d, JC–F = 2.84 Hz), 133.1, 130.2, 129.8, 128.9, 128.6 neg) m/z calcd for C22H18NO2 (M− − H) 328.1338, found
(d, JC–F = 8.33 Hz), 128.3, 127.2, 123.6, 122.9, 115.2 (d, JC–F
=
328.1341.
21.64 Hz), 91.3, 42.9; HRMS (ESI-neg) m/z calcd for
C21H15NO2F (M− − H) 332.1087, found 332.1078.
3-Hydroxy-3-phenyl-2-(4-phenylbutyl)isoindolin-1-one (3fa)
Yield: 65% (232 mg); white solid. Mp: 133.8–135.2 °C (EA/
hexane). 1H-NMR (400 MHz, CDCl3) δ 7.69 (d, J = 7.24 Hz, 1H),
2-Benzyl-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one (3ah)
Yield: 85% (297 mg); yellow solid. Mp: 195.5–197.2 °C (EA/ 7.50–7.38 (m, 4H), 7.33–7.32 (m, 3H), 7.28–7.22 (m, 3H),
hexane). 1H-NMR (400 MHz, CDCl3) δ 7.74–7.72 (m, 1H), 7.18–7.08 (m, 3H), 3.87 (s, 1H), 3.45–3.38 (m, 1H), 3.00–2.93
7.50–7.42 (m, 2H), 7.24–7.09 (m, 10H), 4.54 (d, J = 14.9 Hz, (m, 1H), 2.49 (t, J = 7.22 Hz, 2H), 1.54–1.44 (m, 3H), 1.38–1.34
1H), 4.09 (d, J = 14.9 Hz, 1H), 3.76 (s, 1H); 13C-NMR (100 MHz, (m, 1H); 13C-NMR (100 MHz, CDCl3) δ 168.1, 149.2, 142.5,
CDCl3) δ 168.2, 148.9, 137.9, 137.0, 134.5, 133.1, 130.2, 129.8, 138.9, 132.8, 130.8, 129.6, 128.6, 128.6, 128.4, 126.4, 125.8,
128.9, 128.5, 128.3, 128.1, 127.2, 123.6, 122.9, 91.3, 42.9; 123.4, 122.9, 91.5, 39.5, 35.6, 29.2, 28.5; HRMS (ESI-neg) m/z
HRMS (ESI) m/z calcd for C21H15NO2Cl (M− − H) 348.0791, calcd for C24H22NO2 (M− − H) 356.1651, found 356.1653.
found 348.0798.
3-Hydroxy-2-(3-methoxypropyl)-3-phenylisoindolin-1-one (3ga)
2-Benzyl-3-(4-bromophenyl)-3-hydroxyisoindolin-1-one (3ai)
Yield: 60% (192 mg); white solid. Mp: 130–132 °C (EA/hexane).
Yield: 82% (323 mg); white solid. Mp: 183.5–185.5 °C (EA/ 1H-NMR (400 MHz, CDCl3) δ 7.79–7.77 (m, 1H), 7.47–7.25 (m,
1
hexane). H-NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.0 Hz, 1H), 8H), 5.10 (s, 1H), 3.83–3.79 (m, 1H), 3.57–3.44 (m, 2H), 3.18 (s,
7.48–7.39 (m, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 3H), 2.97–2.91 (m, 1H), 2.01–1.88 (m, 2H); 13C-NMR (100 MHz,
1H), 7.12–6.96 (m, 7H), 4.45 (d, J = 16.0 Hz, 1H), 4.17 (s, 1H), CDCl3) δ 168.1, 149.6, 139.2, 132.5, 130.3, 129.1, 128.5, 128.3,
4.13 (d, J = 16.0 Hz, 1H); 13C-NMR (100 MHz, CDCl3) δ 167.9, 126.1, 123.1, 122.5, 91.5, 71.3, 58.3, 37.2, 28.1; HRMS
148.6, 137.7, 137.3, 132.9, 130.0, 129.6, 128.7, 128.2, 128.1, (ESI-TOF) m/z calcd for C18H19NO3Na (M + Na)+ 320.163, found
127.0, 123.4, 122.7, 91.1, 42.7; HRMS (ESI-neg) m/z calcd for 320.1264.
C21H16BrNO2 (M− − H) 382.1055, found 382.1047.
3-Hydroxy-2-(2-morpholinoethyl)-3-phenylisoindolin-1-one
2-Benzyl-3-(2,4-dichlorophenyl)-3-hydroxyisoindolin-1-one (3aj) (3ha)
Yield: 87% (335 mg); yellow solid. Mp: 194.0–195.4 °C. Yield: 45% (153 mg); pale yellow solid. Mp: 166.0–168.0 °C
1H-NMR (400 MHz, CDCl3) δ 8.27 (d, J = 8.0, 1H), 7.66–7.61 (m, (EA/hexane). 1H-NMR (400 MHz, CDCl3) δ 9.48 (brs, 1H),
1H), 7.49–7.34 (m, 3H), 7.17 (d, J = 8.0, 1H), 7.11–6.99 (m, 5H), 7.83–7.81 (m, 1H), 7.51–7.39 (m, 4H), 7.38–7.30 (m, 3H), 7.23
6.87 (s, 1H), 4.49 (d, J = 12.0 Hz, 1H), 4.26 (d, J = 12.0 Hz, 1H), (d, J = 8.0 Hz, 1H), 4.17–4.13 (m, 1H), 3.76 (m, 4H), 2.91 (t, J =
4.25 (brs, 1H); 13C-NMR (100 MHz, CDCl3) δ 168.6, 147.1, 13.6 Hz, 1H), 2.76 (t, J = 12.4 Hz, 1H), 2.53–2.34 (m, 5H);
136.5, 135.3, 133.3, 133.2, 132.7, 131.7, 131.0, 130.6, 129.7, 13C-NMR (100 MHz, CDCl3) δ 168.2, 149.6, 140.4, 132.7, 129.5,
128.9, 127.8, 127.0, 126.8, 123.4, 122.1, 89.2, 42.7; HRMS (ESI- 128.9, 128.7, 128.4, 126.2, 123.4, 122.3, 90.0, 66.1, 58.3, 53.0,
neg) m/z calcd for C21H14Cl2NO2 (M− − H) 382.0402, found 35.8; HRMS (ESI-TOF) m/z calcd for C20H23N2O3 (M+H)
382.0405.
339.1709, found 339.1709.
2-Benzyl-3-hydroxy-3-(4-nitrophenyl) isoindolin-1-one (3al)
2-(2-(1H-Indol-3-yl)ethyl)-3-hydroxy-3-phenylisoindolin-1-one
(3ia)
Yield: 40% (143 mg); yellow solid. Mp: 206.6–208.4 °C (EA/
hexane). 1H-NMR (400 MHz, DMSO-d6) δ 8.05–8.03 (m, 2H), Yield: 50% (183 mg); yellow oil. 1H-NMR (400 MHz, CDCl3)
7.82–7.80 (m, 1H), 7.60–7.57 (m, 2H), 7.54 (s, 1H), 7.49–7.47 δ 8.00 (s, 1H), 7.72–7.70 (d, J = 7.28 Hz, 1H), 7.45–7.36 (m, 5H),
(m, 2H), 7.29–7.27 (m, 1H), 7.13–7.10 (m, 5H), 4.45 (d, J = 15.5 7.36–7.28 (m, 4H), 7.26–7.24 (d, J = 7.36 Hz, 1H), 7.16–7.12 (m,
Hz, 1H), 4.36 (d, J = 15.5 Hz, 1H); 13C-NMR (100 MHz, DMSO- 1H), 7.06–7.02 (m, 1H), 6.89–6.88 (m, 1H), 3.80–3.73 (m, 1H),
d6) δ 166.8, 148.6, 147.4, 147.0, 137.8, 132.9, 130.3, 129.8, 3.60 (s, 1H), 3.31–3.23 (m, 1H), 3.11–3.03 (m, 1H), 2.82–2.75
128.0, 127.8, 127.7, 126.6, 123.3, 122.9, 122.9, 89.9, 42.3; (m, 1H); 13C-NMR (100 MHz, CDCl3) δ 168.3, 149.3, 138.9,
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136.3, 132.8, 130.7, 129.6, 128.7, 128.7, 127.5, 126.5, 123.3, 7-Hydroxy-6-methyl-7-phenyl-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]
122.9, 122.2, 122.0, 119.3, 119.1, 113.4, 111.2, 91.6, 40.6, 24.5; isoindol-5-one (3oa)
HRMS (ESI-neg) m/z calcd for C24H19N2O2 (M− − H) 367.1447,
found 367.1454.
Yield: 62% (176 mg); pale yellow solid. Mp: 226.4–227.9 °C
(EA/hexane). 1H-NMR (400 MHz, CDCl3) δ 7.36–7.31 (m, 5H),
6.88 (s, 1H), 6.71 (s, 1H), 6.03 (s, 1H), 5.98 (s, 1H), 4.09 (brs,
2-Benzyl-6-bromo-3-hydroxy-3-phenylisoindolin-1-one (3ja)
1H), 2.73 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 167.6, 151.8,
Yield: 68% (266 mg); white solid. Mp: 209.8–210.7 °C
(EA/hexane). 1H-NMR (400 MHz, CDCl3) δ 7.80 (s, 1H),
7.60–7.57 (m, 1H), 7.29–7.23 (m, 5H), 7.13–7.11 (m, 6H), 4.64
(d, J = 16.0 Hz, 1H), 4.15 (d, J = 16.0 Hz, 1H), 3.65 (s, 1H);
13C-NMR (100 MHz, CDCl3) δ 166.5, 147.7, 137.5, 137.4, 135.8,
132.1, 128.7, 128.6, 128.5, 128.2, 127.1, 126.5, 126.2, 124.4,
123.7, 91.5, 43.1 HRMS (ESI-neg) m/z calcd for C21H15NO2Br
(M− − H) 392.0286, found 392.0293.
148.9, 144.8, 138.1, 128.6, 128.4, 125.9, 124.1, 103.3, 10.6,
102.1, 90.4, 24.1.
2-Benzyl-3-(2-bromophenyl)-3-hydroxyisoindolin-1-one (3an)
Yield: 70% (276 mg); white solid. Mp: 185.0–187.0 °C. 1H-NMR
(400 MHz, CDCl3) δ 8.37 (dd, J = 7.98, 1.46 Hz, 1H), 7.77–7.75
(m, 1H), 7.50–7.44 (m, 3H), 7.29–7.27 (d, J = 7.36 Hz, 1H),
7.17–7.12 (m, 7H), 4.54 (d, J = 14.9 Hz, 1H), 4.14 (d, J = 14.9
Hz, 1H), 3.44 (s, 1H); 13C-NMR (100 MHz, CDCl3) δ 168.9,
147.3, 136.9, 135.7, 134.8, 132.6, 132.4, 130.4, 130.3, 129.6,
129.1, 127.9, 127.3, 127.0, 123.4, 122.3, 121.6, 90.5, 43.0;
HRMS (ESI-neg) m/z calcd for C21H15NO2Br (M − H) 392.0286,
found 392.0278.
2-Benzyl-6-chloro-3-hydroxy-3-phenylisoindolin-1-one (3ka)
Yield: 67% (235 mg); pale yellow solid. Mp: 202.0–204.4 °C
(EA/hexane). 1H-NMR (400 MHz, CDCl3) δ 7.70 (s, 1H),
7.45–7.42 (m, 1H), 7.31–7.28 (m, 5H), 7.26–7.15 (m, 6H), 4.72
(d, J = 16.0 Hz, 1H), 4.12 (d, J = 16.0 Hz, 1H), 3.26 (brs, 1H);
13C-NMR (100 MHz, CDCl3) δ 166.5, 147.1, 137.7, 137.6, 135.8,
132.9, 132.0, 128.7, 128.6, 128.5, 128.3, 127.2, 126.2, 124.1,
123.5, 91.4, 43.2; HRMS (ESI+) m/z calcd for C21H17NO2Cl (M +
H) 350.0948, found 350.0942.
2-Phenyl-3-(2-bromophenyl)-3-hydroxyisoindolin-1-one (3en)
Yield: 71% (270 mg); white solid. Mp: 247.3–249.5 °C. 1H-NMR
(400 MHz, CDCl3) δ 8.27 (dd, J = 7.98, 1.46 Hz, 1H), 7.84–7.82
(m, 1H), 7.79 (brs, 1H), 7.62–7.59 (m, 2H), 7.56–7.54 (m, 2H),
7.45–7.40 (m, 2H), 7.27–7.23 (m, 2H), 7.22–7.17 (m, 1H),
7.15–7.09 (m, 2H); 13C-NMR (100 MHz, CDCl3) δ 167.2, 147.3,
136.9, 136.4, 134.5, 133.0, 132.4, 130.7, 130.5, 129.6, 128.2,
127.6, 125.7, 124.6, 122.9, 120.0, 91.2; HRMS (TOF-MS-ES-TOF)
m/z calcd for C20H15NO2Br (M− + H) 380.0286, found 380.0287.
2-Benzyl-6-fluoro-3-hydroxy-3-phenylisoindolin-1-one (3la)
Yield: 78% (260 mg); pale yellow solid. Mp: 165.7–167.8 °C
1
(EA/hexane). H-NMR (400 MHz, CDCl3) δ 7.44 (dd, J = 8.0, 4.0
Hz, 1H), 7.33–7.28 (m, 5H), 7.24–7.14 (m, 7H), 4.77 (d, J = 16.0
Hz, 1H), 4.09 (d, J = 16.0 Hz, 1H), 2.97 (brs, 1H); 13C-NMR
(100 MHz, CDCl3) δ 166.5, 163.6 (d, JC–F = 248.3 Hz), 144.5,
137.8 (d, JC–F = 4.4 Hz), 132.6 (d, JC–F = 8.6 Hz), 128.7, 128.6,
128.5, 128.3, 127.2, 126.2, 124.5 (d, JC–F = 8.6 Hz), 120.1 (d, JC–F
= 23.6 Hz), 110.3 (d, JC–F = 23.6 Hz), 91.4, 43.2; HRMS (ESI) m/z
calcd for C21H17NO2F (M + H) 334.1243, found 334.1240.
3-(2-Bromophenyl)-3-hydroxy-2-phenethylisoindolin-1-one
(3fn)
Yield: 67% (273 mg); white solid. Mp: 186–188 °C. 1H-NMR
(400 MHz, CDCl3) δ 8.39 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz,
1H), 7.49–7.40 (m, 3H), 7.39 (t, J = 5.0 Hz, 1H), 7.25–7.21 (m,
3H), 7.03–7.02 (m, 2H), 3.63 (s, 1H), 3.62–3.53 (m, 1H),
3.13–3.00 (m, 2H), 2.58–2.30 (m, 1H); 13C-NMR (100 MHz,
CDCl3) δ 168.9, 147.2, 139.3, 135.8, 134.9, 132.6, 132.5, 130.6,
130.4, 129.6, 128.7, 128.4, 127.5, 126.2, 123.1, 122.3, 121.2,
90.3, 41.4, 34.2; HRMS (TOF-MS-ES+) m/z calcd for
C22H19NO2Br (M + H) 408.0599, found 408.0599.
3-Hydroxy-6-methoxy-2-methyl-3-phenylisoindolin-1-one (3ma)
Yield: 45% (131 mg); pale yellow solid. Mp: 192.2–194.2 °C
(EA/hexane). 1H-NMR (400 MHz, CDCl3) δ 7.37–7.30 (m, 5H),
7.20–7.18 (m, 1H), 6.99–6.96 (m, 2H), 3.94 (s, 1H), 3.79 (s, 3H),
2.76 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 167.6, 160.8, 141.1,
138.2, 131.8, 128.6, 128.4, 125.9, 123.6, 120.0, 106.2, 90.8, 55.6,
55.5, 24.1; HRMS (ESI) m/z calcd for C16H15NO3Na (M + Na)
292.0.0950, found 292.0.0952.
2-Benzyl-6-bromo-3-(2-bromophenyl)-3-hydroxyisoindolin-1-
one (3kn)
2-Benzyl-3-hydroxy-5,6-dimethoxy-3-phenylisoindolin-1-one
(3na)
1
Yield: 71% (335 mg); white solid. Mp: 214.0–216 °C. H-NMR
Yield: 55% (206 mg); white solid. Mp: 205.3–207.2 °C (EA/ (400 MHz, CDCl3) δ 8.36 (dd, J = 8.0, 1.4 Hz, 1H), 7.68 (d, J =
hexane). 1H-NMR (400 MHz, CDCl3) δ 7.31–7.29 (m, 2H), 1.4 Hz, 1H), 7.59 (dd, J = 8.0, 1.2 Hz, 1H), 7.50–7.42 (m, 1H),
7.26–7.24 (m, 3H), 7.20–7.12 (m, 6H), 6.67 (s, 1H), 4.67 (d, J = 7.21–7.19 (m, 1H), 7.14–7.00 (m, 7H), 4.54 (d, J = 16.0 Hz, 1H),
16.0 Hz, 1H), 4.13 (d, J = 16.0 Hz, 1H), 3.89 (s, 3H), 3.78 (s, 4.14 (d, J = 16.0 Hz, 1H), 4.28 (s, 1H); 13C-NMR (100 MHz,
3H), 3.38 (brs, 1H); 13C-NMR (100 MHz, CDCl3) δ 168.0, 153.2, CDCl3) δ 167.8, 146.1, 136.3, 135.7, 134.9, 134.7, 134.2, 130.5,
150.5, 142.6, 138.4, 138.2, 128.5, 128.4, 128.3, 128.1, 126.9, 130.4, 129.1, 127.9, 127.4, 127.1, 126.3, 123.9, 123.7, 121.5,
126.3, 122.6, 105.0, 104.8, 91.2, 56.3, 56.2, 43.0; HRMS (ESI) 90.2, 43.1; HRMS (TOF-MS-ES+) m/z calcd for C21H16NO2Br2
m/z calcd for C23H20NO4 (M− − H) 374.1392, found 374.1390.
(M + H) 471.9548, found 471.9548.
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3-(2-Bromophenyl)-5-fluoro-3-hydroxy-2-phenylisoindolin-1-
one (3ln)
6H), 6.69 (dd, J = 8.0, 4.0 Hz, 1H), 4.49 (d, J = 16.0 Hz, 1H),
4.14 (d, J = 16.0 Hz, 1H), 4.01 (brs, 1H) 3.90 (s, 3H); 13C-NMR
(100 MHz, CDCl3) δ 168.9, 158.9, 147.2, 136.9, 136.7, 135.4,
132.6, 132.4, 129.6, 129.1, 127.9, 127.0, 123.3, 122.3, 116.4,
115.8, 111.7, 90.3, 55.6, 43.0; HRMS (TOF-MS-ES+) m/z calcd
for C22H19NO3Br (M + H) 424.0548, found 424.0550.
Yield: 78% (335 mg); white solid. Mp: 254.0–256.0 °C. 1H-NMR
(400 MHz, DMSO-d6) δ 8.23 (dd, J = 8.0, 1.6 Hz, 1H), 7.94 (brs,
1H), 7.89–7.87 (m, 1H), 7.52–7.50 (m, 2H), 7.45–7.40 (m, 3H),
7.28–7.23 (m, 3H), 7.12 (t, J = 8.0 Hz, 1H), 7.00 ((dd, J = 8.0, 1.6
Hz, 1H); 13C-NMR (100 MHz, CDCl3) δ 166.1, 164.0 (d, JC–F
=
2-Benzyl-3-(2-bromo-4,5-dimethoxyphenyl)-3-
hydroxyisoindolin-1-one (3ap)
249.0 Hz), 150.1 (d, JC–F = 9.0 Hz), 136.3, 136.1, 134.5, 130.7 (d,
JC–F = 9.0 Hz), 128.7, 128.3, 127.6, 125.9, 125.5 (d, JC–F = 9.0
Hz), 124.7, 120.0, 117.2 (d, JC–F = 24 Hz), 109.7 (d, JC–F = 24
Hz), 90.5 (d, JC–F = 2 Hz); HRMS (TOF-MS-ES+) m/z calcd for
C20H14NO2BrF (M− − H) 398.0192, found 398.0194.
Yield: 40% (181 mg); white solid. Mp: 202.3–203.7 °C. 1H-NMR
(400 MHz, CDCl3) δ 7.91 (s, 1H), 7.61–7.59 (d, J = 7.40 Hz, 1H),
7.48–7.45 (t, J = 7.44 Hz, 1H), 7.40–7.37 (t, J = 7.34 Hz, 1H),
7.20–7.18 (d, J = 7.44 Hz, 1H), 7.10–7.06 (m, 5H), 6.65 (s, 1H),
4.43 (d, J = 14.8 Hz, 1H), 4.17 (d, J = 14.8 Hz, 1H), 4.30 (s, 1H),
4.02 (s, 3H), 3.78 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 169.1,
149.7, 148.2, 147.8, 137.1, 132.8, 132.5, 129.7, 129.3, 128.0,
127.8, 127.1, 123.5, 122.5, 117.6, 113.4, 112.2, 90.5, 56.5, 56.3,
43.1; HRMS (ESI-neg) m/z calcd for C23H19NO4Br (M− − H)
452.0497, found 452.0491.
3-(2-Bromophenyl)-5-chloro-3-hydroxy-2-phenylisoindolin-1-
one (3mn)
Yield: 80% (332 mg); white solid. Mp: 262–264 °C. 1H-NMR
(400 MHz, CDCl3) δ 8.23 (dd, J = 8.0, 2.0 Hz, 1H), 7.96 (brs,
1H), 7.85 (d, J = 8.0 Hz, 1H), 7.65 (dd, J = 8.0, 2.0 Hz, 1H),
7.52–7.50 (m, 2H), 7.45–7.42 (m, 2H), 7.27–7.19 (m, 4H),
7.15–7.09 (m, 1H); 13C-NMR (100 MHz, CDCl3) δ 166.1, 149.2,
137.7, 136.2, 134.6, 131.2, 130.8, 130.7, 130.0, 128.3, 127.7,
126.0, 124.8, 124.7, 122.4, 120.0, 90.7; HRMS (TOF-MS-ES+)
m/z calcd for C20H14NO2ClBr (M− + H) 413.9896, found
413.9897.
2-Benzyl-3-(6-bromobenzo[d][1,3] dioxol-5-yl)-3-
hydroxyisoindolin-1-one (3aq)
1
Yield: 45% (197 mg); white solid. Mp: 214–216.0 °C. H-NMR
(400 MHz, CDCl3) δ 7.87 (s, 1H), 7.70 (d, J = 4.0 Hz, 1H),
7.50–7.44 (m, 2H), 7.18–7.13 (m, 6H), 6.70 (s, 1H), 6.04 (dd, J =
8.0, 1.6 Hz, 1H), 4.54 (d, J = 16.0 Hz, 1H), 4.14 (d, J = 16 Hz,
1H), 3.61 (s, 1H); 13C-NMR (100 MHz, CDCl3) δ 168.7, 148.5,
147.5, 147.3, 137.1, 132.6, 132.3, 129.6, 129.0, 128.0, 127.1,
123.3, 122.1, 114.5, 112.6, 110.4, 102.0, 90.4, 43.0; HRMS
(TOF-MS-ES+) m/z calcd for C22H17NO4Br (M + H) 438.0341,
found 438.0346.
2-Benzyl-3-(2-bromophenyl)-3-hydroxy-6-methoxyisoindolin-1-
one (3nn)
Yield: 58% (246 mg); white solid. Mp: 192.0–194.0 °C. 1H-NMR
(400 MHz, CDCl3) δ 8.36 (dd, J = 8.0, 1.2 Hz, 1H), 7.45 (t, J = 8.0
Hz, 1H), 7.29–7.27 (m, 1H), 7.18–7.16 (m, 7H), 7.02–7.01 (m,
1H), 7.00–6.98 (m, 1H), 4.58 (d, J = 14.9 Hz, 1H), 4.26 (d, J =
14.9 Hz, 1H), 3.84 (s, 3H), 3.44 (s, 1H); 13C-NMR (100 MHz,
CDCl3) δ 168.7, 161.1, 139.4, 137.0, 135.7, 134.8, 134.2, 130.4,
130.2, 129.1, 127.9, 127.3, 127.0, 123.2, 121.5, 119.8, 106.8,
90.5, 55.6, 43.2; HRMS (TOF-MS-ES+) m/z calcd for
C22H19NO3Br (M + H) 424.0548, found 424.05449.
2-Benzyl-3-(2,5-dibromophenyl)-3-hydroxyisoindolin-1-one
(3ar)
Yield: 64% (301 mg); white solid. Mp: 213–215 °C. 1H-NMR
(400 MHz, CDCl3) δ 8.52 (d, J = 4.0 Hz, 1H), 7.66 (dd, J = 8.0,
1.2 Hz, 1H), 7.48–7.43 (m, 2H), 7.22 (dd, J = 8.0, 1.2 Hz, 1H),
7.17 (d, J = 8.0 Hz, 1H), 7.10–7.05 (m, 5H), 7.00 (d, J = 4.0 Hz,
1H), 4.35 (d, J = 16.0 Hz, 1H), 4.26 (brs, 1H); 4.25 (d, J = 16.0
Hz, 1H), 13C-NMR (100 MHz, CDCl3) δ 168.9, 146.7, 137.7,
136.4, 136.0, 133.4, 133.1, 132.8, 132.3, 129.9, 129.1, 127.9,
127.1, 123.4, 122.3, 121.4, 120.2, 89.8, 42.9; HRMS
(TOF-MS-ES+) m/z calcd for C21H16NO2Br2 (M + H) 471.9548,
found 471.9550.
6-Benzyl-7-(2-bromophenyl)-7-hydroxy-6,7-dihydro-5H-[1,3]
dioxolo[4,5-f]isoindol-5-one (3pn)
Yield: 60% (263 mg); white solid. Mp: 209–211 °C. 1H-NMR
(400 MHz, CDCl3) δ 8.32 (dd, J = 8.0, 4.0 Hz, 1H), 7.44–7.40 (m,
1H), 7.29 (dd, J = 8.0, 1.6 Hz, 1H), 7.13–7.05 (m, 6H), 6.99 (s,
1H), 6.55 (s, 1H), 5.99 (t, J = 1.4 Hz, 2H), 4.44 (d, J = 16 Hz,
1H), 4.14 (d, J = 16 Hz, 1H), 4.06 (s, 1H); 13C-NMR (100 MHz,
CDCl3) δ 168.6, 151.8, 149.1, 143.0, 139.9, 135.6, 134.8, 134,
136.9, 135.7, 134.8, 130.4, 130.2, 129.1, 127.9, 127.3, 126.9,
126.6, 121.5, 103.2, 103.0, 102.1, 89.7, 43.1; HRMS
(TOF-MS-ES+) m/z calcd for C22H17NO4Br (M + H) 438.0341,
found 438.0339.
Conflicts of interest
There are no conflicts to declare.
2-Benzyl-3-(2-bromo-5-methoxyphenyl)-3-hydroxyisoindolin-1-
one (3ao)
Acknowledgements
Yield: 50% (212 mg); white solid. Mp: 194.0–196.0 °C. 1H-NMR Financial support from the Ministry of Science and
(400 MHz, CDCl3) δ 7.96 (d, J = 1.6 Hz, 1H), 7.66 (d, J = 8.0 Hz, Technology of the Republic of China (MOST 106-2113-M-003-
1H), 7.47–7.39 (m, 2H), 7.29 (d, J = 8.0 Hz, 1H), 7.13–7.10 (m, 007) and Instrumentation Centre at National Taiwan Normal
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University is gratefully acknowledged. The authors are grateful
to Ms Hsiu-Ni Huang, Ms Chiu-Hui He and Mr Ting-Shen Kuo
for providing HRMS, NMR spectra and crystallographic data,
respectively.
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