Synthesis of Enantioenriched Phthalide and Isoindolinone Derivatives from 2-Formylbenzoic Acid

Article abstract of DOI:10.1055/s-0036-1589404

Transformations of 2-formylbenzoic acid provide direct access to a series of heterocyclic organic compounds such as phthalides and isoindolinones. Here, we use (+)-cinchonine as a catalyst in conjunction with nonafluoro-tert-butanol as a hydrogen-bond donor to afford enantiomerically enriched acylated 3-hydroxyphthalides with up to 99% yield and 90% ee through dynamic kinetic resolution. Moreover, various 3-alkoxyphthalides as well as 2-alkyl-3-hydroxy-1-isoindolinones were synthesized from 2-formylbenzoic acid.

Full text of DOI:10.1055/s-0036-1589404

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–L
paper
A
D. Niedek et al.
Paper
Synthesis
Synthesis of Enantioenriched Phthalide and Isoindolinone Deriva-
tives from 2-Formylbenzoic Acid
O
Dominik Niedek
Dynamic Kinetic
Resolution
R = H, Alkyl, Ph, O-Alkyl
Sören M. M. Schuler
Christian Eschmann
Raffael C. Wende
Alexander Seitz
Felix Keul
O
(+)-cinchonine (10 mol%)
chlorobenzene, –10 °C
5–99% yield; up to 90% ee
11 examples
R
O
O
O
O
R = Me, Et, iPr, Allyl
One-Pot Reaction
OH
CHO
O
DMAP (10 mol%)
1) Tf2O (2.0 equiv)
2) R–OH (10.0 equiv)
63–84% yield
4 examples
Peter R. Schreiner*
OR
O
Institute of Organic Chemistry, Justus-Liebig University Giessen,
Heinrich-Buff-Ring 17, 35392 Giessen, Germany
prs@uni-giessen.de
Amidation/Cyclization
R = (Cy-)Alkyl, Ar, Alkynyl
1) SOCl2, 4 h, reflux
2) R–NH2 (2.0 equiv)
N
R
33–79% yield
4 examples
This manuscript is dedicated to Prof. Dieter Enders on the
occasion of his 70th birthday and for his seminal contributions
to organic chemistry.
OH
Received: 28.07.2016
Accepted after revision: 05.10.2016
Published online: 03.11.2016
particular have been comprehensively reported6–15 because
of their important role in the synthesis of biologically active
compounds, natural products, and pharmaceuticals.16–26
3-Phthalideyl alkanoates, which can be obtained from FBA
through reaction with carboxylic anhydrides under re-
flux,2,5 were employed as precursors of arylspiroketals,27
building blocks for polyaromatics,28 as reagents for the
phthalidation of heteroarenes,11 and also as building blocks
for antitumor agents,29 β-lactam antibiotics,30 and orally
active opioid peptides.31 In case of the enantiopure com-
pound, the phthalide core could act as an auxiliary for fur-
ther functionalization of the carbonyl group of the ester to
generate, for example, enantiomerically enriched tertiary
alcohols. Furthermore, these compounds may be applied as
chiral acylating reagents.32–35
DOI: 10.1055/s-0036-1589404; Art ID: ss-2016-t0535-op
Abstract Transformations of 2-formylbenzoic acid provide direct ac-
cess to a series of heterocyclic organic compounds such as phthalides
and isoindolinones. Here, we use (+)-cinchonine as a catalyst in con-
junction with nonafluoro-tert-butanol as a hydrogen-bond donor to af-
ford enantiomerically enriched acylated 3-hydroxyphthalides with up to
99% yield and 90% ee through dynamic kinetic resolution. Moreover,
various 3-alkoxyphthalides as well as 2-alkyl-3-hydroxy-1-isoindoli-
nones were synthesized from 2-formylbenzoic acid.
Keywords acylation, chiral auxiliary, cinchona alkaloids, dynamic ki-
netic resolution, organocatalysis
Since its discovery in 1886,1 2-formylbenzoic acid 1a
(FBA) or its tautomeric form 3-hydroxyphthalide 1b
(Scheme 1) (ring-chain tautomerism) was often described
as a useful precursor in organic synthesis.2 The atypical
chemical behavior that fits neither to an aldehyde nor to a
carboxylic acid, and especially the unexpected high reactiv-
ity of this compound toward nucleophiles as well as elec-
trophiles, are probably the main reasons for the great atten-
tion it has received.2,3 The cyclized tautomeric form 1b of 2-
formylbenzoic acid is considerably favored in almost all sol-
vents. The only exception is pure sulfuric acid, in which the
open-chain aldehyde is preferred.3 The reactivity of 1 was
previously described to be comparable to that of an acyl
chloride. Thus, under appropriate conditions 1a/1b reacts
with a series of nucleophiles, such as alcohols, thiols, pri-
mary as well as secondary amines, amides, ureas, carba-
mates, but also with electrophilic carboxylic anhydrides af-
fording 3-substituted phthalides.2,4,5 The synthesis of the
phthalide core in general and 3-substituted derivatives in
O
O
solvent
OH
O
OH
O
1a
1b
Scheme 1 Equilibrium of 2-formylbenzoic acid 1a and its tautomeric
form 3-hydroxyphthalide 1b
There are some transition-metal-catalyzed approaches
to prepare 3-phthalideyl alkanoates.6–7,36 However, the de-
sired products are generally obtained as racemic mixtures.
To our knowledge, there is only one example of a dynamic
kinetic resolution (DKR) employing a chiral 4-(N,N-dimeth-
ylamino)pyridine (DMAP) derived catalyst and isobutyric
anhydride. By using 1b, the acylated product (S)-2c formed
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

B
D. Niedek et al.
Paper
Synthesis
We first observed the unexpected reactivity and behav-
ior of the formyl group of the FBA while trying to convert its
aldehyde functionality into a trifluoromethyl ketone with
the Ruppert–Prakash reagent by following a known proto-
col.51 After work-up and purification, we isolated a small
amount of a single cyclic product that was identified as 3-
ethoxyphthalide (3b; see Figure 3 below).
O
O
DMAP* (1 mol%)
(iPrCO)2O, Et3N
O
O
tBuOMe, r.t., 8 h
O
OH
O
1b
(S)-2c
>99% (40% ee)
Inspired by the previously reported DKR,37 we envis-
aged the development of an enantioselective synthesis of 3-
substituted phthalides employing a chiral catalyst. We
chose (–)-cinchonidine 4b as catalyst, acetic anhydride as
an inexpensive and readily available electrophile and, refer-
ring to our established π–methylhistidine based acylation
concept,52–56 toluene as solvent. Under these conditions at
0 °C, product 2a formed in 83% yield with 28% ee (Table 1,
entry 1). Based on this promising result, we optimized the
reaction conditions and tested the pseudoenantiomer of 4b
(+)-cinchonine (4a), (+)-quinidine (5a), (–)-quinine (5b),
(+)-dihydroquinidine (6a), and (–)-dihydroquinine (6b) as
well as some chiral thioureas developed by Soós (7),57
Takemoto (8),58 and Nagasawa (9) (Figure 1) as further cata-
lysts.59
Scheme 2 Dynamic kinetic resolution of FBA using a chiral DMAP-
derived catalyst (labeled DMAP*)
in quantitative yield with moderate selectivity (40% ee;
Scheme 2).37,38
Besides the phthalides, 3-substituted isoindolinones are
also important building blocks in organic synthesis.39,40
There are several applications described, for example, in the
synthesis of pharmaceutically active agents or natural
products.41–45 Especially the synthesis of 2-alkyl-3-hy-
droxy-1-isoindolinones starting from N-alkylphthalimides
is described in detail.46–50 Again, to our knowledge, no
strategy starting from readily available FBA and the desired
amine to perform an amidation/cyclization process has
been reported. This strategy is advantageous compared
with the reduction of N-alkylphthalimides. Amines and FBA
are readily available starting materials and the substrate
scope could be appreciably improved. Moreover, the re-
action can be performed in one pot and with much better
atom economy.
The best results were obtained with a catalytic amount
of (+)-cinchonine (4a; Table 1, entry 9); a stoichiometric
amount of catalyst 4a led to lower yields and selectivities
(entries 8 and 9). Consequently, we selected 10 mol% 4a
and 2.0 equiv Ac2O for further investigations. To improve
OMe
OMe
OH
OH
OH
N
N
N
N
N
N
4a
5a
6a
OMe
OMe
N
N
N
OH
OH
OH
N
N
N
4b
5b
6b
N
CF3
CF3
F3C
F3C
S
S
CF3
CF3
S
S
OMe
NH HN
NH
HN
N
N
CF3
F3C
N
N
H
H
H
H
N
N
7
8
9
Figure 1 Employed chiral catalysts
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

C
D. Niedek et al.
Paper
Synthesis
Table 1 Catalyst Screening
Table 2 Influence of Solvent and Temperature on the Selectivitya
O
O
O
O
catalyst
Ac2O (1.0 equiv)
(+)-cinchonine (10 mol%)
Ac2O (2.0 equiv)
O
O
O
O
solvent, r.t., 24 h
solvent, 24 h
O
O
OH
OH
O
O
1b
2a
1b
(R)-2a
Entry
Catalyst
Yield (%)
ee (%)e
Entry
Solvent
Temp (°C)
ee (%)b
1a
2b
4b
4a
4b
5a
5b
6a
6b
4a
4a
7
83
67
n.d.
53
41
55
59
83
89
74
77
96
28 (S)
28 (R)
28 (S)
20 (R)
18 (S)
20 (R)
20 (S)
28 (R)
36 (R)
24 (S)
20 (R)
2 (R)
1
2
cyclohexane
benzene
r.t.
r.t.
r.t.
r.t.
0
26
33
40
36
43
54
48
67
14
50
60
53
17
71
66
58
59
3b
3
hexafluorobenzenec
toluene
4b
4
5b
5
CH2Cl2
6b
6
chlorobenzene
toluene
0
7b
7
0
8b,d
9c,d
10c,d
11c,d
12c,d
8
n-hexanec
acetonec
0
9
–10
–10
–10
–10
–10
–10
–30
–30
–30
10
11
12
13
14
15
16
17
1,2-DCE
8
chlorobenzene
xylene
9
a Reaction conditions: FBA (1.0 mmol), toluene (15 mL), 4b (1.0 equiv).
b Reaction conditions: FBA (0.3 mmol), anhydrous toluene (4.0 mL), cincho-
na alkaloid (1.0 equiv).
perfluorohexanec
n-hexanec
chlorobenzene
xylene
c Reaction conditions: FBA (0.3 mmol), anhydrous CHCl3 (4.0 mL), catalyst
(10 mol%).
d Ac2O (2.0 equiv).
e Enantiomeric excess determined based on chiral GC analysis without in-
ternal standard.
n-hexanec
a Reaction conditions: FBA (0.3 mmol), 4a (10 mol%), anhydrous solvent
(2.0 mL).
b Enantiomeric excess determined based on chiral GC analysis without inter-
the selectivity, we performed a solvent screening and inves-
tigated the influence of the temperature on the selectivity
(Table 2).
nal standard.
c Distilled solvent used.
The best results were obtained in nonpolar aprotic sol-
vents at low temperatures (Table 2, entries 6, 8, 11, 14, and
15). Given that non-anhydrous n-hexane afforded the high-
est selectivity, we assumed a polar transition state that ne-
cessitates the presence of a hydrogen-bonding donor
(HBD). To support this postulate, the reaction was per-
formed in extra anhydrous n-hexane and defined amounts
of strong HBDs, such as hexafluoroisopropanol (HFIP), tri-
fluoroethanol (TFEA), nonafluoro-tert-butanol (NFTBA), or
pentafluorophenol (PFP) were added (Table 3). To our de-
light, we found an appreciable influence of the hydrogen
donor strength on the selectivity. With increasing acidity of
the additive, the selectivity also increased. The only excep-
tion was PFP, because of its low solubility in n-hexane. In-
terestingly, water also delivered comparable results. Addi-
tion of 25 mol% NFTBA was found to be ideal for our system.
With the optimized reaction conditions in hand, we
started a substrate screening using various electrophiles;
the results are summarized in Figure 2. For the preparative-
scale experiments chlorobenzene was used as solvent, be-
cause of better solubility of the reagents and much shorter
reaction times. The reactions were monitored by TLC in
each case and quenched with methanol upon complete
consumption of the starting material. In cases where the
solubility of the carboxylic anhydrides was low in n-hex-
ane, the selectivities were higher in chlorobenzene (com-
pare 2d and 2f); compounds 2b and 2c quickly racemized
upon heating.
We also developed a Steglich esterification protocol60,61
for the formation of the carboxylic anhydride in situ using a
carbodiimide (in this case N,N′-diisopropyl carbodiimide;
DIC) and the desired carboxylic acid. This provides access to
products for which the corresponding carboxylic anhy-
drides are either not readily available or expensive. Thus,
products 2j and 2k were obtained in moderate yields, but
with rather low selectivity, which is probably due to the ba-
sic character of DIC. For comparison we also used acetic
acid and obtained 2a in 55% yield with 56% ee.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

D
D. Niedek et al.
Paper
Synthesis
O
(+)-cinchonine (10 mol%)
NFTBA (25 mol%)
O
anhydride (2.0 equiv)
O
O
R
n-hexane, –10 °C, 48 h
O
OH
O
1b
2a–k
O
O
O
O
O
O
O
O
O
O
O
O
Ph
Cl
O
O
O
O
O
O
O
O
O
O
O
O
(R)-2a
(R)-2b
(R)-2c
(S)-2d
(R)-2e
(S)-2f
83% eea
60% eea
79% eea
52% eea
79% eea
42% eea
87% (67% ee)b
75% (54% ee)b
65% (54% ee)b
53% (80% ee)b
72% (28% ee)b
99% (78% ee)b
O
O
O
O
O
O
O
O
O
O
O
O
O
O
H
O
O
O
O
O
O
O
O
O
O
(R)-2g
(S)-2h
(S)-2i
(R)-2j
(S)-2k
13% eea
13% eea, d
90% eea,d
2% eea,c
65% eea,c
9% (13% ee)b
16% (11% ee)b,d
28% (52% ee)b,d
<5% (2% ee)b,c
98% (54% ee)b,c
a 0.30 mmol FBA, ee was determined via chiral GC or HPLC without internal standard
b 0.75 mmol FBA, chlorobenzene was used as solvent; yield of isolated product after column chromatography
c carboxylic anhydride was prepared in situ using 2.0 equiv DIC and 4.0 equiv carboxylic acid
d 1.0 equiv alkaloid
Figure 2 Substrate scope of the DKR of 2-formylbenzoic acid
We also investigated other electrophiles including ben-
zyl bromide, benzyl isocyanate, and benzyl isothiocyanate
under our optimized conditions. Unfortunately, we only
isolated (±)-3-phthalideyl (benzyl)carbamate (10; see ex-
perimental section and the Supporting Information) result-
ing from benzyl isocyanate as a racemate. In case of isothio-
cyanate, the reactivity was too low and starting materials
were re-isolated.
We then employed the protocol detailed above in con-
junction with triflic anhydride to introduce a good leaving
group on phthalide 11. This would allow the installation of
a broad variety of substituents on the phthalide core
(Scheme 3).
The lack of selectivity could be caused by rapid uncata-
lyzed formation of 11, which outperforms the DKR by the
catalyst. On the other hand, the nucleophilic substitution it-
self may lead to racemization if SN1 character prevails be-
cause the substitution must exclusively proceed through an
SN2 mechanism to preserve the enantiomeric excess. To
avoid the SN1 reaction, we added only a small excess of the
desired alcohol instead of using the alcohol itself also as
solvent and used polar aprotic dichloromethane, without
success. Nevertheless, the use of FBA, alcohol and DMAP in-
stead of the chiral alkaloid enabled the formation of (±)-3-
O
As we were not able to isolate triflate 11, the nucleo-
phile was added directly after complete consumption of the
starting material (monitored by TLC) without intermittent
purification. To gain deeper insight on the reactivity, we se-
lected primary, secondary, tertiary, and allylic alcohols as
nucleophiles (Figure 3). The desired products 3a–d were
obtained in good yields but as racemic mixtures. By using
tert-butanol the desired product either did not form or was
not stable upon purification.
O
O
Tf2O
Nuc
O
O
O
OTf
OH
Nuc
1b
11
3
Scheme 3 One-pot reaction sequence to yield 3-substituted phtha-
lides
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

E
D. Niedek et al.
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Synthesis
Table 3 Improvement of the Selectivity by Addition of a Hydrogen-
Bond Donora
1) (+)-cinchonine (1.0 equiv)
Tf2O (2.0 equiv)
O
O
2) ROH (10.0 equiv)
O
(+)-cinchonine (10 mol%)
O
O
O
Ac2O (2.0 equiv)
CH2Cl2, –30 °C, 24 h
O
additive
OH
OR
O
n-hexane, –10 °C, 24 h
1b
3a–d
O
OH
O
1b
(R)-2a
ee (%)b
O
O
O
O
Entry
Additive
Amount (equiv)
O
O
O
O
1
2
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
TFEA
NFTBA
PFP
31.7
15.8
2.02
1.01
0.51
0.25
0.13
0.06
0.25
0.25
0.25
0.25
–
4
7
O
O
O
O
3
40
45
63
78
78
45
74
83
72
70
35
3a
63%a
3b
73%a
50% (0% ee)b
3c
3d
77%a
67% (0% ee)b
84%a
37% (0% ee)b
4
66% (0% ee)b
5
a 10 mol% DMAP instead of alkaloid, yield of isolated product after column
chromatography
6
7
b
0.30 mmol FBA, yield of isolated product after column chromatography,
8
ee was determined via chiral GC without internal standard.
9
Figure 3 Screening of alcohols
10
11
12
13
O
O
1) SOCl2, 4 h, reflux
2) RNH2 (2.0 equiv)
H2O
–
O
N R
CH2Cl2, 0 °C
a Reaction conditions: FBA (0.3 mmol), 4a (10 mol%), –10 °C, 24 h, solvent
(2.00 mL in total).
OH
OH
12a–d
b Enantiomeric excess determined based on chiral GC analysis without in-
ternal standard
1b
O
O
alkoxyphthalides in good yields up to 84% under much
milder conditions compared with previously reported pro-
tocols.9,10,62
3-Alkoxyphthalides are building blocks for the synthesis
of, for example 2-alkyl-3-hydroxy-1-isoindolinones 12 (Fig-
ure 4).4,19,63 Notably, their synthesis is also possible directly
from 1b as starting material. After heating 1b to reflux in
SOCl2, the addition of primary amines directly led to sub-
strates 12a–d in moderate yields.
The DKR using 12a–d was not possible as a result of the
very slow isomerization of the stereogenic center. Desired
products 13a–d were obtained as racemic mixtures (see ex-
perimental section and the Supporting Information). Addi-
tion of DBU to accelerate isomerization64,65 also did not en-
able the desired DKR. Note that kinetic resolution of 12a–d
was not observed while monitoring product formation by
chiral GC. Moreover, DKR of 14 yielding acetylated com-
pound 15 was also not successful, which was already re-
ported;37,38 hence, under our catalytic conditions, the
isomerization of such isoindolinones seems to be too slow
compared with the acylation (see experimental section and
the Supporting Information).
N
N
OH
12a
64%a
OH
12b
33%a
O
O
CF3
CF3
N
N
OH
OH
12d
79%a
12c
49%a
a yield of isolated product after column chromatography
Figure 4 Amidation/cyclization of 1b in one pot
In summary, we have demonstrated the synthesis of a
series of compounds related to different chemical classes
starting from 2-formylbenzoic acid (1a). We describe an
optimized protocol for the dynamic kinetic resolution of 1b,
using readily available cinchona alkaloids and anhydrides,
thus yielding the corresponding products in excellent yields
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

F
D. Niedek et al.
Paper
Synthesis
(up to 99%) and good enantioselectivities (up to 90% ee).
The products are potential substrates for further syntheses
of complex cyclic core structures.
Synthesis of 2a–i through DKR of 1b; General Procedure C
2-Formylbenzoic acid (1a; 1.0 equiv) and (+)-cinchonine (4a; 0.1
equiv) were dissolved either in n-hexane or chlorobenzene (0.15 M)
and cooled to –10 °C. Carboxylic anhydride (2.0 equiv) was then add-
ed and the mixture was stirred at –10 °C until the starting material
was consumed, which was monitored by TLC. The reaction was
quenched by addition of an excess of MeOH. The resulting mixture
was stirred for 15–30 min at –10 °C, then the solvent was removed
under reduced pressure and the products were purified by column
chromatography.
Chemicals were purchased from commercial suppliers and were used
without further purification. Solvents for column chromatography,
extractions, filtrations, and recrystallizations were distilled prior to
use. Solvents were dried by using standard procedures and they were
stored under Ar and over activated molecular sieves (3 Å or 4 Å) or
sodium. Column chromatography was carried out with silica gel 60 M
(Macherey–Nagel; 0.040–0.063 mm, 230–400 mesh ASTM). TLC was
performed using precoated Macherey–Nagel plastic sheets Polygram®
SIL G/UV254 (Macherey–Nagel; 0.2 mm silica gel layer with fluores-
cent indicator). For visualization, UV light (254 nm) or staining solu-
tions (KMnO4: 2.5 g KMnO4, 8.3 g K2CO3, 250 mL H2O; phosphomolyb-
dic acid: 9.86 g in 250 mL ethanol) were utilized.
Synthesis of 2j–k through DKR of 1b; General Procedure D
Carboxylic acid (4.0 equiv) and DIC (2.0 equiv) were dissolved either
in n-hexane or chlorobenzene (0.15 M) and cooled to –10 °C. After
stirring for 12 h at –10 °C, 2-formylbenzoic acid (1a; 1.0 equiv) and
(+)-cinchonine (4a; 0.1 equiv) were added and the mixture was
stirred at –10 °C until the starting material was consumed, which was
monitored by TLC (up to 48 h). The reaction was quenched by addi-
tion of an excess of MeOH. The resulting mixture was stirred for 15–
30 min at –10 °C, then the solvent was removed under reduced pres-
sure and the products were purified by column chromatography.
All NMR spectra were recorded with Bruker AV 400 spectrometers.
Chemical shifts (δ) are reported in parts per million (ppm) using ei-
ther tetramethylsilane (TMS) or the corresponding residual solvent
signal as internal standard.66 IR spectra were measured with a Bruker
IFS25 spectrometer. HRMS were recorded with a Bruker Micro TOF
LC. Reaction progress and product formation were monitored by GC-
MS with a Hewlett Packard 5890 gas chromatograph equipped with
flame-ionization detector (FID), a Quadrupole-MS Hewlett Packard
MSD 5971 detector (EI, 70 eV) and a DB-5 MS column (30 m × 0.250
mm). Enantioselectivities were determined either by chiral stationary
phase GC analyses with Hewlett Packard 5890 or 6890 gas chromato-
graphs, respectively, or by chiral stationary phase HPLC with a Dionex
system (Dionex P680 HPLC pump, Shodex RI-101 detector). For mea-
surement of melting points, a Krüss KSP1N capillary melting-point
apparatus was utilized using a heating rate of 1 °C min–1. All melting
points were determined at least twice and are uncorrected. Absolute
stereochemistry was determined by VCD with a Bruker PMA 50 spec-
trometer (see the Supporting Information).
Synthesis of (±)-3-Alkoxyphthalides (3a–d); General Procedure E
2-Formylbenzoic acid (1a; 0.045 g (0.30 mmol, 1.0 equiv) and DMAP
(0.004 g, 0.03 mmol, 0.1 equiv) were dissolved in anhydrous CH2Cl2
(2.0 mL; 0.15 M) and cooled to –30 °C. Triflic anhydride (0.172 g,
0.102 mL, 0.60 mmol, 2.0 equiv) was carefully added in one portion
and the mixture was stirred at –30 °C for 5 h. To the resulting clear
yellow solution an excess of the desired alcohol (10 equiv) was added
and the mixture was stirred for 24 h at –30 °C. The colorless clear
solution was allowed to warm to r.t. and the solvent was removed un-
der reduced pressure. The crude products were purified by column
chromatography (n-hexane/EtOAc, 2:1).
Synthesis of 3a–d through DKR of 1b; General Procedure F
2-Formylbenzoic acid (1a; 1.0 equiv) and (+)-cinchonine (4a; 1.0
equiv) were dissolved in CH2Cl2 (0.15 M) and cooled to –30 °C. Triflic
anhydride (2.0 equiv) was subsequently added in one portion and the
reaction mixture was stirred for 8 h at –30 °C until the starting mate-
rial was consumed, which was monitored by TLC. At this point the de-
sired alcohol (10.0 equiv) was added and stirring at –30 °C was con-
tinued overnight. The solvent was removed under reduced pressure
and the products were purified by column chromatography.
Synthesis of 2a–i through Acylation of (±)-3-Hydroxyphthalides;
General Procedure A
2-Formylbenzoic acid (1a; 1.0 equiv) and DMAP (0.1 equiv) were dis-
solved in CH2Cl2 (0.15 M), producing a colorless clear solution. The
desired carboxylic anhydride (2.0 equiv) and triethylamine (1.0
equiv) were subsequently added and the reaction mixture was stirred
at r.t. until complete conversion of the starting material was achieved
(monitored by TLC). The solvent was removed under reduced pres-
sure and the crude products were purified by column chromatogra-
phy (n-hexane/EtOAc, 2:1).
Synthesis of (±)-Isoindolinones 12a–d; General Procedure G
2-Formylbenzoic acid (1a; 1.0 equiv) was heated at reflux in SOCl2 (5–
10 equiv) for 4 h at 100 °C. The remaining SOCl2 was removed in vacu-
um and the obtained solid was dissolved in CH2Cl2 (10 mL). The mix-
ture was cooled to 0 °C and the desired primary amine (2.0 equiv)
was slowly added. The solution was stirred for 24 h at r.t. then the
reaction mixture was diluted with EtOAc (70 mL), washed with citric
acid (0.5 M), sat. aq Na2CO3 solution, and brine. The organic layer was
dried over MgSO4 and the solvent was removed under reduced pres-
sure. The obtained products were used without further purification.
Synthesis of 2j,k through Acylation of (±)-3-Hydroxyphthalides;
General Procedure B
2-Formylbenzoic acid (1a; 1.0 equiv) and DMAP (0.1 equiv) were dis-
solved in CH2Cl2 (0.15 M), producing a colorless clear solution. The
desired carboxylic anhydride was formed in situ by adding carboxylic
acid (4.0 equiv) and carbodiimide (2.0 equiv). The reaction mixture
was stirred at r.t. for 18 h, while the corresponding urea was formed
as a pale-yellow precipitate. The reaction was monitored by TLC.
Upon complete conversion of the starting material, the precipitated
urea was filtered off and the solvent was removed under reduced
pressure. The crude products were purified by column chromatogra-
phy (n-hexane/EtOAc, 2:1).
Acylation of (±)-Isoindolinones 12a–d to give 13a–d; General Pro-
cedure H
The corresponding (±)-isoindolinone (1.0 equiv) and DMAP (0.1
equiv) were dissolved in CH2Cl2 (0.15 M), followed by the addition of
acetic anhydride (2.0 equiv) and triethylamine (1.0 equiv). The reac-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

G
D. Niedek et al.
Paper
Synthesis
tion mixture was stirred at r.t. for 24 h. At this point the solvent was
removed under reduced pressure and the crude products were puri-
fied by column chromatography (n-hexane/EtOAc, 2:1).
13C NMR (100.62 MHz, CDCl3): δ = 175.6 (Cq, C=O), 168.0 (Cq, C=O),
144.6 (Cq, CAr), 134.9 (CHAr), 131.3 (CHAr), 126.6 (Cq, CAr), 125.8 (CHAr),
123.5 (CHAr), 92.7 (CH), 34.0 (CH), 18.7 (CH3), 18.7 (CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C12H12O4Na: 243.0634; found:
243.0632.
(±)-3-Phthalideyl Acetate (2a)
Obtained from 2-formylbenzoic acid (0.045 g, 0.30 mmol) and acetic
anhydride (0.061 g, 0.057 mL, 0.60 mmol) by following General Pro-
cedure A.
(±)-3-Phthalideyl 2,2-Dimethylpropionate (2d)
Obtained from 2-formylbenzoic acid (0.045 g, 0.30 mmol) and pivalic
anhydride (0.112 g, 0.122 mL, 0.60 mmol) by following General Pro-
cedure A.
Yield: 0.050 g (87%, 0.26 mmol); colorless solid; mp 68–69 °C;
Rf = 0.39 (n-hexane/EtOAc, 2:1).
IR (ATR): 2972, 1794, 1767, 1361, 1207, 1043, 960, 940, 880, 857, 751,
Yield: 0.048 g (0.20 mmol, 68%); colorless solid; mp 57–59 °C;
Rf = 0.56 (n-hexane/EtOAc, 2:1).
717, 687, 543 cm–1
.
3
1H NMR (400.13 MHz, CDCl3): δ = 7.91 (d, JH–H = 7.6 Hz, 1 H, CHAr),
IR (ATR): 2976, 2936, 1780, 1747, 1467, 1276, 1122, 1047, 968, 937,
7.74 (dt, 3JH–H = 7.5 Hz, 4JH–H = 1.0 Hz, 1 H, CHAr), 7.64 (t, 3JH–H = 7.3 Hz,
1 H, CHAr), 7.59 (d, JH–H = 7.6 Hz, 1 H, CHAr), 7.41 (s, 1 H, CH), 2.18 (s,
766, 752, 715, 688 cm–1
.
3
3
4
1H NMR (400.13 MHz, CDCl3): δ = 7.92 (td, JH–H = 7.6 Hz, JH–H
=
3 H, CH3).
3
4
1.0 Hz, 1 H, CHAr), 7.74 (dt, JH–H = 7.5 Hz, JH–H = 1.1 Hz, 1 H, CHAr),
13C NMR (100.62 MHz, CDCl3): δ = 169.5 (Cq, C=O), 167.9 (Cq, C=O),
144.3 (Cq, CAr), 134.9 (CHAr), 131.4 (CHAr), 126.5 (Cq, CAr), 125.8 (CHAr),
123.6 (CHAr), 92.7 (CH), 20.9 (CH3).
7.64 (dt, JH–H = 7.5 Hz, JH–H = 1.0 Hz, 1 H, CHAr), 7.55 (qd, JH–H
=
3
4
3
7.6 Hz, 4JH–H = 0.8 Hz, 1 H, CHAr), 7.41 (s, 1 H, CH), 1.23 (s, 9 H, CH3).
13C NMR (100.61 MHz, CDCl3): δ = 177.1 (Cq, C=O), 168.1 (Cq, C=O),
144.7 (Cq, CAr), 134.9 (CHAr), 131.3 (CHAr), 126.7 (Cq, CAr), 125.9 (CHAr),
123.5 (CHAr), 92.9 (CH), 39.1 (Cq), 26.9 (CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C10H8O4Na: 215.0321; found:
215.0325.
Analytic data are identical to those reported in the literature.11
HRMS (ESI): m/z [M + Na]+ calcd for C13H14O4Na: 257.0790; found:
257.0786.
Analytic data are identical to those reported in the literature.11
(±)-3-Phthalideyl Butyrate (2b)
Obtained from 2-formylbenzoic acid (0.045 g, 0.30 mmol) and butyric
anhydride (0.094 g, 0.098 mL, 0.60 mmol) by following General Pro-
cedure A.
(±)-3-Phthalideyl Benzoate (2e)
Obtained from 2-formylbenzoic acid (0.150 g, 1.00 mmol) and benzo-
ic anhydride (0.452 g, 2.00 mmol) by following General Procedure A.
Yield: 0.055 g (83%, 0.25 mmol); colorless solid; mp 53–54 °C;
Rf = 0.47 (n-hexane/EtOAc, 2:1).
Yield: 0.171 g (0.67 mmol, 67%); colorless solid; mp 135–136 °C;
IR (ATR): 2969, 2878, 1768, 1758, 1356, 1285, 1148, 1052, 960, 750,
Rf = 0.47 (n-hexane/EtOAc, 2:1+1% TEA).
717, 686 cm–1
.
IR (ATR): 3010, 1773, 1740, 1360, 1248, 1213, 1081, 1053, 970, 930,
3
1H NMR (400.13 MHz, CDCl3): δ = 7.91 (d, JH–H = 7.6 Hz, 1 H, CHAr),
751, 702, 687, 590 cm–1
.
7.74 (dt, 3JH–H = 7.5 Hz, 4JH–H = 1.1 Hz, 1 H, CHAr), 7.64 (t, 3JH–H = 7.5 Hz,
1H NMR (400.13 MHz, CDCl3): δ = 8.08–8.03 (m, 2 H, CHAr), 8.00–8.03
3
1 H, CHAr), 7.58 (d, JH–H = 7.6 Hz, 1 H, CHAr), 7.44 (s, 1 H, CH), 2.40 (t,
3
4
(m, 1 H, CHAr), 7.77 (dt, JH–H = 7.4 Hz, JH–H = 1.2 Hz, 1 H, CHAr), 7.72–
3
3JH–H = 7.4 Hz, 2 H, CH2), 1.69 (sext, JH–H = 7.4 Hz, 2 H, CH2), 0.97 (t,
3
4
7.65 (m, 3 H, CHAr), 7.61 (tt, JH–H = 7.5 Hz, JH–H = 1.2 Hz, 1 H, CHAr),
7.49–7.42 (m, 2 H, CHAr/CH).
3JH–H = 7.4 Hz, 3 H, CH3).
13C NMR (100.61 MHz, CDCl3): δ = 172.2 (Cq, C=O), 168.0 (Cq, C=O),
144.5 (Cq, CAr), 134.9 (CHAr), 131.3 (CHAr), 126.6 (Cq, CAr), 125.8 (CHAr),
123.6 (CHAr), 92.7 (CH), 35.9 (CH2), 18.2 (CH2), 13.6 (CH3).
13C NMR (100.62 MHz, CDCl3): δ = 168.0 (Cq, C=O), 165.2 (Cq, C=O),
144.6 (Cq, CAr), 135.0 (CHAr), 134.2 (CHAr), 131.5 (CHAr), 130.3 (CHAr),
128.7 (CHAr), 128.5 (Cq, CAr), 126.7 (Cq, CAr), 126.0 (CHAr), 123.9 (CHAr),
93.4 (CH).
HRMS (ESI): m/z [M + Na]+ calcd for C12H12O4Na: 243.0634; found:
243.0636.
HRMS (ESI): m/z [M + Na]+ calcd for C15H10O4Na: 277.0477; found:
277.0467.
Analytic data are identical to those reported in the literature.6
Analytic data are identical to those reported in the literature.6
(±)-3-Phthalideyl 2-Methylpropionate (2c)
Obtained from 2-formylbenzoic acid (0.045 g (0.30 mmol) and isobu-
tyric anhydride (0.094 g, 0.099 mL, 0.60 mmol) by following General
Procedure A.
(±)-3-Phthalideyl Chloroacetate (2f)
Obtained from 2-formylbenzoic acid (0.150 g, 1.00 mmol) and chloro-
acetic anhydride (0.342 g, 2.00 mmol) by following General Proce-
dure A.
Yield: 0.053 g (0.24 mmol, 81%); colorless solid; mp 64–65 °C;
Rf = 0.52 (n-hexane/EtOAc, 2:1).
Yield: 0.216 g (0.95 mmol, 95%); colorless solid; mp 86–87 °C;
IR (ATR): 2973, 2936, 2876, 1758, 1468, 1285, 1122, 1050, 1031, 961,
Rf = 0.38 (n-hexane/EtOAc, 2:1).
938, 751, 715, 688 cm–1
.
IR (ATR): 3002, 2959, 1770, 1607, 1397, 1284, 1147, 1050, 1034, 984,
3
1H NMR (400.13 MHz, CDCl3): δ = 7.91 (d, JH–H = 7.6 Hz, 1 H, CHAr),
963, 949, 922, 885, 870, 789, 748, 715, 688 cm–1
.
7.74 (t, 3JH–H = 7.5 Hz, 1 H, CHAr), 7.64 (t, 3JH–H = 7.5 Hz, 1 H, CHAr), 7.57
1H NMR (400.13 MHz): δ = 7.91 (td, JH–H = 7.6 Hz, JH–H = 1.0 Hz, 1 H,
3
4
3
(d, JH–H = 7.6 Hz, 1 H, CHAr), 7.42 (s, 1 H, CH), 2.63 (m, 1 H, CH), 1.20
3
4
CHAr), 7.77 (dt, JH–H = 7.5 Hz, JH–H = 1.1 Hz, 1 H, CHAr), 7.69–7.61 (m,
2 H, CHAr), 7.44 (s, 1 H, CH), 4.17 (s, 2 H, CH2Cl).
(d, 3JH–H = 7.1 Hz, 6 H, CH3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

H
D. Niedek et al.
Paper
Synthesis
13C NMR (100.62 MHz): δ = 167.5 (Cq, C=O), 166.3 (Cq, C=O), 143.5
(Cq, CAr), 135.2 (CHAr), 131.7 (CHAr), 126.3 (Cq, CAr), 126.0 (CHAr), 123.8
(CHAr), 93.5 (CH), 40.5 (CH2Cl).
HRMS (ESI): m/z [M + Na]+ calcd for C13H14O5Na: 273.0739; found:
273.0737.
HRMS (ESI): m/z [M + Na]+ calcd for C10H7ClO4Na: 248.9931; found:
(±)-3-Phthalideyl Formate (2j)
248.9932.
Obtained from 2-formylbenzoic acid (0.074 g, 0.50 mmol), formic
acid (0.092 g, 0.075 mL, 2.00 mmol) and diisopropylcarbodiimide
(0.126 g, 0.155 mL, 1.00 mmol) by following General Procedure B.
(±)-(E)-3-Phthalideyl Crotonate (2g)
Obtained from 2-formylbenzoic acid (0.150 g, 1.00 mmol) and trans-
crotonic anhydride (0.308 g, 0.296 mL, 1.20 mmol) by following Gen-
eral Procedure A.
Yield: 0.037 g (0.21 mmol, 42%); colorless solid; mp 82–84 °C;
Rf = 0.33 (n-hexane/EtOAc, 2:1).
IR (ATR): 2992, 2920, 1772, 1733, 1607, 1467, 1359, 1282, 1213, 1120,
Yield: 0.172 g (0.79 mmol, 79%); colorless solid; mp 52–53 °C;
1046, 986, 962, 919, 743, 714, 686 cm–1
.
Rf = 0.42 (n-hexane/EtOAc, 2:1).
4
1H NMR (400.13 MHz, CDCl3): δ = 8.22 (d, JH–H = 1.0 Hz, 1 H, CHO),
IR (ATR): 3062, 3030, 2985, 1774, 1736, 1642, 1468, 1234, 1207, 1047,
7.95 (d, 3JH–H = 7.5 Hz, 1 H, CHAr), 7.77 (dt, 3JH–H = 7.5 Hz, 4JH–H = 1.1 Hz,
1 H, CHAr), 7.68 (dt, JH–H = 7.6 Hz, JH–H = 1.0 Hz, 1 H, CHAr), 7.62 (d,
3JH–H = 7.6 Hz, 1 H, CHAr), 7.51 (s, 1 H, CH).
13C NMR (100.62 MHz, CDCl3): δ = 167.6 (Cq, C=O), 159.2 (Cq, C=O),
143.9 (Cq, CAr), 135.1 (CHAr), 131.7 (CHAr), 126.5 (Cq, CAr), 126.1 (CHAr),
123.8 (CHAr), 92.2 (CH).
966, 928, 858, 842, 748, 713, 685 cm–1
.
3
4
1H NMR (400.13 MHz): δ = 7.85 (td, JH–H = 7.6 Hz, JH–H = 1.0 Hz, 1 H,
3
4
3
4
CHAr), 7.71 (dt, JH–H = 7.6 Hz, JH–H = 1.2 Hz, 1 H, CHAr), 7.64–7.55 (m,
3
3
2 H, CHAr), 7.43 (s, 1 H, CH), 7.06 (dq, JH–H = 15.6 Hz, JH–H = 6.9 Hz,
3
4
1 H, CHAlkene), 5.82 (qd, JH–H = 15.6 Hz, JH–H = 1.7 Hz, 1 H, CHAlkene),
1.85 (dd, 3JH–H = 6.9 Hz, 4JH–H = 1.8 Hz, 3 H, CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C9H6O4Na: 201.0164; found:
13C NMR (100.62 MHz): δ = 167.9 (Cq, C=O), 164.5 (Cq, C=O), 148.4
(CHAlkene), 144.5 (Cq, CAr), 134.8 (CHAr), 131.2 (CHAr), 126.4 (Cq, CAr),
125.6 (CHAr), 123.7 (CHAr), 121.0 (CHAlkene), 92.7 (CH), 18.2 (CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C12H10O4Na: 241.0477; found:
241.0479.
201.0169.
(±)-3-Phthalideyl Acetoxyacetate (2k)
Obtained from 2-formylbenzoic acid (0.074 g, 0.50 mmol), acetoxy-
acetic acid (0.237 g, 2.00 mmol) and dicyclohexylcarbodiimide (1.0 M
in CH2Cl2, 0.206 g, 1.0 mL, 1.00 mmol) by following General Procedure
B.
Analytic data are identical to those reported in the literature.7
Yield: 0.050 g (0.20 mmol, 40%); colorless oil; Rf = 0.59 (n-hex-
(±)-Ethyl 3-Phthalideyl Carbonate (2h)
ane/EtOAc, 1:1).
Obtained from 2-formylbenzoic acid (0.150 g, 1.00 mmol) and diethyl
dicarbonate (0.324 g, 0.295 mL, 2.00 mmol) by following General Pro-
cedure A.
IR (ATR): 3307, 2932, 2856, 1789, 1751, 1703, 1664, 1522, 1258, 1217,
1162, 1080, 1053, 1013, 976, 800, 754, 732, 687 cm–1
.
3
4
Yield: 0.086 g (0.39 mmol, 39%); colorless oil; Rf = 0.40 (n-hex-
ane/EtOAc, 2:1).
1H NMR (400.25 MHz, CDCl3): δ = 7.94 (td, JH–H = 7.5 Hz, JH–H
=
3
4
1.0 Hz, 1 H, CHAr), 7.76 (dt, JH–H = 7.5 Hz, JH–H = 1.1 Hz, 1 H, CHAr),
7.67 (dt, JH–H = 7.6 Hz, JH–H = 1.0 Hz, 1 H, CHAr), 7.61 (qd, JH–H
3
4
3
=
=
IR (ATR): 2986, 1785, 1756, 1608, 1469, 1363, 1239, 1212, 959, 858,
4
3
7.6 Hz, JH–H = 0.8 Hz, 1 H, CHAr), 7.46 (s, 1 H, CH), 4.74 (d, JH–H
751, 685 cm–1
.
16.4 Hz, 1 H, CH2), 4.64 (d, 3JH–H = 16.4 Hz, 1 H, CH2), 2.17 (s, 3 H, CH3).
1H NMR (400.13 MHz, CDCl3): δ = 8.13–8.09 (m, 1 H, CHAr), 7.96 (dt,
13C NMR (100.65 MHz, CDCl3): δ = 170.3 (Cq, C=O), 167.6 (Cq, C=O),
166.8 (Cq, C=O), 143.8 (Cq, CAr), 135.1 (CHAr), 131.7 (CHAr), 126.4 (Cq,
CAr), 126.0 (CHAr), 123.8 (CHAr), 93.1 (CH), 60.4 (CH2), 20.5 (CH3).
4
3JH–H = 7.5 Hz, JH–H = 1.1 Hz, 1 H, CHAr), 7.89–7.82 (m, 2 H, CHAr), 7.49
(s, 1 H, CH), 4.60–4.46 (m, 2 H, CH2), 1.55 (t, 3JH–H = 7.2 Hz, 3 H, CH3).
13C NMR (100.62 MHz, CDCl3): δ = 167.6 (Cq, C=O), 153.5 (Cq, C=O),
143.4 (Cq, CAr), 134.9 (CHAr), 131.5 (CHAr), 126.4 (Cq, CAr), 125.8 (CHAr),
123.7 (CHAr), 95.3 (CH), 65.4 (CH2), 14.1 (CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C12H10O6Na: 273.0375; found:
273.0382.
HRMS (ESI): m/z [M + Na]+ calcd for C11H10O5Na: 245.0426; found:
245.0424.
(±)-3-Methoxyphthalide (3a)
Obtained by following General Procedure E.
Yield: 0.031 g (0.19 mmol, 63%); colorless solid; mp 44–45 °C;
(±)-tert-Butyl 3-Phthalideyl Carbonate (2i)
Rf = 0.47 (n-hexane/EtOAc, 2:1).
Obtained from 2-formylbenzoic acid (0.150 g, 1.00 mmol) and di-tert-
butyldicarbonate (0.437 g, 0.428 mL, 2.00 mmol) by following Gener-
al Procedure A.
IR (ATR): 2941, 2843, 1763, 1378, 1285, 1212, 1122, 1090, 1056, 920,
897, 744, 713, 687 cm–1
.
3
Yield: 0.152 g (0.61 mmol, 61%); colorless solid; mp 72–73 °C;
Rf = 0.48 (n-hexane/EtOAc, 2:1).
1H NMR (400.13 MHz, CDCl3): δ = 7.89 (d, JH–H = 7.6 Hz, 1 H, CHAr),
3
4
7.71 (dt, JH–H = 7.4 Hz, JH–H = 1.1 Hz, 1 H, CHAr), 7.64–7.53 (m, 2 H,
CHAr), 6.30 (s, 1 H, CH), 3.63 (s, 3 H, CH3).
13C NMR (100.62 MHz, CDCl3): δ = 168.7 (Cq, C=O), 144.8 (Cq, CAr),
134.5 (CHAr), 131.0 (CHAr), 127.4 (Cq, CAr), 125.6 (CHAr), 123.5 (CHAr),
103.2 (CH), 56.9 (CH3).
IR (ATR): 2983, 1785, 1754, 1370, 1249, 1155, 1085, 1052, 961, 843,
783, 745, 685 cm–1
.
1H NMR (400.13 MHz, CDCl3): δ = 7.93–7.89 (m, 1 H, CHAr), 7.74 (dt,
4
3JH–H = 7.3 Hz, JH–H = 1.1 Hz, 1 H, CHAr), 7.67–7.61 (m, 2 H, CHAr), 7.26
(s, 1 H, CH), 1.55 (s, 9 H, CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C9H8O3Na: 187.0371; found:
187.0377.
13C NMR (100.62 MHz, CDCl3): δ = 167.9 (Cq, C=O), 151.6 (Cq, C=O),
143.8 (Cq, CAr), 134.9 (CHAr), 131.5 (CHAr), 126.7 (Cq, CAr), 125.9 (CHAr),
123.8 (CHAr), 94.9 (CH), 84.8 (Cq), 27.8 (CH3).
Analytic data are identical to those reported in the literature.67
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

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D. Niedek et al.
Paper
Synthesis
(±)-3-Ethoxyphthalide (3b)
Yield: 0.016 g (0.06 mmol, 19%); colorless solid; mp 154–157 °C;
Rf = 0.30 (n-hexane/EtOAc, 2:1).
Obtained by following General Procedure E.
IR (ATR): 3294, 3064, 1777, 1717, 1540, 1244, 1126, 1041, 957, 749,
Yield: 0.039 g (0.22 mmol, 73%); colorless solid; mp 70–71 °C;
Rf = 0.49 (n-hexane/EtOAc, 2:1).
700, 687 cm–1
.
3
4
1H NMR (400.13 MHz, CDCl3): δ = 7.89 (td, JH–H = 7.6 Hz, JH–H
=
IR (ATR): 3067, 2974, 2906, 1770, 1605, 1360, 1288, 1203, 1138, 1088,
3
4
1048, 932, 865, 745, 712, 687, 637 cm–1
.
0.9 Hz, 1 H, CHAr), 7.72 (dt, JH–H = 7.5 Hz, JH–H = 1.1 Hz, 1 H, CHAr),
7.65–7.57 (m, 2 H, CHAr), 7.44 (s, 1 H, CH), 7.39–7.27 (m, 5 H, CHAr),
5.29 (br. s, 1 H, NH), 4.45 (d, 3JH–H = 6.0 Hz, 2 H, CH2).
3
1H NMR (400.13 MHz, CDCl3): δ = 7.87 (d, JH–H = 7.5 Hz, 1 H, CHAr),
7.73–7.64 (m, 1 H, CHAr), 7.62–7.50 (m, 2 H, CHAr), 6.36 (s, 1 H, CH),
3.75 (m, 2 H, CH2), 1.31 (t, 3JH–H = 7.1 Hz, 3 H, CH3).
13C NMR (100.62 MHz, CDCl3): δ = 168.1 (Cq, C=O), 154.2 (Cq, C=O),
144.4 (Cq, CAr), 137.5 (Cq, CAr), 134.8 (CHAr), 131.1 (CHAr), 128.9 (CHAr),
128.0 (CHAr), 127.8 (CHAr), 126.8 (Cq, CAr), 125.8 (CHAr), 123.6 (CHAr),
93.9 (CH), 45.4 (CH2).
HRMS (ESI): m/z [M + Na]+ calcd for C16H13NO4Na: 306.0743; found:
306.0742.
13C NMR (100.62 MHz, CDCl3): δ = 168.8 (Cq, C=O), 145.2 (Cq, CAr),
134.5 (CHAr), 130.9 (CHAr), 127.3 (Cq, CAr), 125.5 (CHAr), 123.5 (CHAr),
102.4 (CH), 66.0 (CH2), 15.2 (CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C10H10O3Na: 201.0528; found:
201.0533.
Analytic data are identical to those reported in the literature.15
(±)-3-Hydroxy-2-Propyl-1-isoindolinone (12a)
Obtained from 2-formylbenzoic acid (0.751 g, 5.00 mmol), SOCl2 (3.28
g, 2.00 mL, 27.6 mmol), and propylamine (0.591 g, 0.821 mL, 10.0
mmol) by following General Procedure G.
(±)-3-Isopropoxyphthalide (3c)
Obtained by following General Procedure E.
Yield: 0.049 g (0.25 mmol, 84%); colorless solid; mp 66–67 °C;
Rf = 0.54 (n-hexane/EtOAc, 2:1).
Yield: 0.610 g (3.19 mmol, 64%); colorless solid; mp 90–92 °C;
Rf = 0.17 (n-hexane/EtOAc, 2:1).
IR (ATR): 3064, 2977, 2903, 1756, 1347, 1287, 1212, 1108, 1091, 1063,
IR (ATR): 2992, 1771, 1733, 1467, 1357, 1282, 1213, 1120, 1045, 962,
916, 898, 829, 780, 752, 714, 689 cm–1
.
918, 743, 714, 686, 515 cm–1
.
3
4
1H NMR (400.13 MHz, CDCl3): δ = 7.86 (td, JH–H = 7.5 Hz, JH–H
=
3
4
1H NMR (400.25 MHz, acetone-d6): δ = 7.65 (td, JH–H = 7.4 Hz, JH–H
=
3
4
0.9 Hz, 1 H, CHAr), 7.69 (dt, JH–H = 7.5 Hz, JH–H = 1.1 Hz, 1 H, CHAr),
7.60–7.52 (m, 2 H, CHAr), 6.42 (s, 1 H, CH), 4.23 (hept, JH–H = 6.2 Hz,
1 H, CH), 1.36 (d, JH–H = 6.2 Hz, 3 H, CH3), 1.32 (d, JH–H = 6.2 Hz, 3 H,
CH3).
1.1 Hz, 1 H, CHAr), 7.62–7.59 (m, 2 H, CHAr), 7.55–7.48 (m, 1 H, CHAr),
5.90 (d, 3JH–H = 9.4 Hz, 1 H, CH), 5.39 (d, 3JH–H = 9.5 Hz, 1 H, OH), 3.68–
3.54 (m, 1 H, CH2), 3.45–3.28 (m, 1 H, CH2), 1.83–1.57 (m, 2 H, CH2),
0.93 (t, 3JH–H = 7.4 Hz, 3 H, CH3).
3
3
3
13C NMR (100.62 MHz, CDCl3): δ = 169.0 (Cq, C=O), 145.6 (Cq, CAr),
134.4 (CHAr), 130.8 (CHAr), 127.3 (Cq, CAr), 125.4 (CHAr), 123.5 (CHAr),
101.5 (CH), 73.8 (CH), 23.4 (CH3), 22.3 (CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C11H12O3Na: 215.0684; found:
215.0692.
13C NMR (100.65 MHz, acetone-d6): δ = 167.1 (Cq, C=O), 145.8 (Cq,
CAr), 133.3 (Cq, CAr), 132.5 (CHAr), 130.1 (CHAr), 124.3 (CHAr), 123.2
(CHAr), 82.2 (CH), 41.6 (CH2), 23.3 (CH2), 11.8 (CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C11H13NO2Na: 214.0844; found:
214.0855.
Analytic data are identical to those reported in the literature.62
Analytic data are identical to those reported in the literature.68
(±)-3-(3-Phthalideyloxy)-1-propene (3d)
(±)-2-Cyclohexyl-3-hydroxy-1-isoindolinone (12b)
Obtained by following General Procedure E.
Obtained from 2-formylbenzoic acid (0.300 g, 2.00 mmol), SOCl2 (2.46
g, 1.50 mL, 20.7 mmol), and cyclohexylamine (0.298 g, 0.343 mL, 4.00
mmol) by following General Procedure G.
Yield: 0.044 g (0.23 mmol, 77%); yellow oil; Rf = 0.50 (n-hexane/EtOAc,
2:1).
IR (ATR): 2925, 1765, 1355, 1285, 1056, 922, 891, 748, 714, 689 cm–1
.
Yield: 0.154 g (0.98 mmol, 33%); colorless solid; mp 130–132 °C;
Rf = 0.25 (n-hexane/EtOAc, 2:1).
1H NMR (400.13 MHz, CDCl3): δ = 7.91–7.83 (m, 1 H, CHAr), 7.73–7.66
(m, 1 H, CHAr), 7.63–7.54 (m, 2 H, CHAr), 6.40 (s, 1 H, CH), 6.05–5.92
IR (ATR): 3338, 3257, 2924, 2856, 1656, 1406, 1042, 804, 747, 700,
603, 535 cm–1
.
3
4
(m, 1 H, CHAlkene), 5.38 (qd, JH–H = 17.2 Hz, JH–H = 1.4 Hz, 1 H, CH2,),
3
4
3
1H NMR (400.13 MHz, acetone-d6): δ = 7.67–7.42 (m, 4 H, CHAr), 5.98
5.28 (qd, JH–H = 10.4 Hz, JH–H = 1.3 Hz, 1 H, CH2), 4.42 (tdd, JH–H
=
=
3
4
3
3
3
12.5 Hz, JH–H = 5.4 Hz, JH–H = 1.5 Hz, 1 H, CH2, Alkene), 4.32 (tdd, JH–H
(d, JH–H = 10.1 Hz, 1 H, CH), 5.23 (d, JH–H = 10.2 Hz, 1 H, OH), 3.99–
3.81 (m, 1 H, CH), 2.03–1.76 (m, 6 H, CH2), 1.74–1.62 (m, 1 H, CH2),
1.50–1.12 (m, 3 H, CH2).
12.5 Hz, 3JH–H = 5.4 Hz, 4JH–H = 1.3 Hz, 1 H, CH2,Alkene).
13C NMR (100.62 MHz, CDCl3): δ = 168.7 (Cq, C=O), 145.1 (Cq, CAr),
134.5 (CHAr), 133.0 (CHAlkene), 130.9 (CHAr), 127.3 (Cq, CAr), 125.5
(CHAr), 123.6 (CHAr), 119.9 (CH2,Alkene), 101.4 (CH), 70.8 (CH2).
HRMS (ESI): m/z [M + Na]+ calcd for C11H10O3Na: 213.0522; found:
213.0527.
13C NMR (100.62 MHz, acetone-d6): δ = 168.8 (Cq, C=O), 146.0 (Cq,
CAr), 133.4 (Cq, CAr), 132.4 (CHAr), 130.0 (CHAr), 124.1 (CHAr), 123.1
(CHAr), 81.9 (CH), 52.7 (CH2), 32.8 (CH2), 31.1 (CH2), 26.9 (CH2), 26.8
(CH2), 26.4 (CH2).
HRMS (ESI): m/z [M + Na]+ calcd for C14H17NO2Na: 254.1157; found:
(±)-3-Phthalideyl (Benzyl)carbamate (10)
254.1153.
Obtained from 2-formylbenzoic acid (0.045 g, 1.00 mmol) and ben-
zylisocyanate (0.045 g, 0.040 mL, 0.30 mmol) by following General
Procedure A.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

J
D. Niedek et al.
Paper
Synthesis
(±)-2-[3,5-Bis(trifluoromethyl)phenyl]-3-hydroxy-1-isoindoli-
none (12c)
(±)-2-Cyclohexyl-3-oxo-1-isoindolinyl Acetate (13b)
Obtained from 12b (0.048 g, 0.20 mmol) and acetic anhydride (0.042
Obtained from 2-formylbenzoic acid (0.300 g, 2.00 mmol), SOCl2
(2.460 g, 1.50 mL, 20.7 mmol), and 3,5-bis(trifluoromethyl)aniline
(0.458 g, 0.312 mL, 4.00 mmol) by following General Procedure G.
g, 0.039 mL, 0.40 mmol) by following General Procedure H.
Yield: 0.020 g (0.07 mmol, 36%); colorless oil; Rf = 0.51 (n-hex-
ane/EtOAc, 2:1).
Yield: 0.353 g (0.98 mmol, 49%); colorless solid; mp 127–129 °C;
Rf = 0.50 (n-hexane/EtOAc, 2:1).
IR (ATR): 3401, 2932, 2856, 1739, 1707, 1400, 1372, 1231, 1207, 1182,
1167, 1125, 1009, 937, 803, 753, 697 cm–1
.
IR (ATR): 3400, 3062, 1786, 1745, 1530, 1469, 1388, 1279, 1187, 1162,
1H NMR (400.13 MHz, CDCl3): δ = 7.81–7.75 (m, 1 H, CHAr), 7.56–7.48
(m, 3 H, CHAr), 7.11 (s, 1 H, CH), 4.02 (tt, 3JH–H = 12.1 Hz, 3JH–H = 3.7 Hz,
1 H, CH), 2.14 (s, 3 H, CH3), 2.06–1.96 (m, 1 H, CH2), 1.90–1.77 (m, 3 H,
CH2), 1.75–1.32 (m, 5 H, CH2), 1.28–1.08 (m, 1 H, CH2).
1148, 1119, 1093, 1076, 870, 701, 683 cm–1
.
1H NMR (400.13 MHz, acetone-d6): δ = 7.99–7.68 (m, 6 H, CHAr), 7.63
(s, 1 H, CHAr), 7.48 (d, 3JH–H = 11.0 Hz, 1 H, CH), 7.28–7.21 (m, 1 H, OH).
13C NMR (100.62 MHz, acetone-d6): δ = 169.2 (Cq, C=O), 167.9 (Cq,
C=O), 149.9 (Cq, CAr), 148.1 (CHAr), 146.1 (CHAr), 136.4 (CHAr), 135.4
(CHAr), 133.1 (q, 2JC–F = 34.1 Hz, Cq, CArCF3), 132.2 (CHAr), 131.7 (CHAr),
128.5 (Cq, CAr), 126.2 (CHAr), 125.9 (CHAr), 124.8 (CHAr), 124.7 (CHAr),
115.2. (CH), 113.1 (CHAr), 87.0 (CF3), 86.5 (CF3) (both tautomeric
forms).
13C NMR (100.65 MHz, CDCl3): δ = 171.1 (Cq, C=O), 167.9 (Cq, C=O),
141.5 (Cq, CAr), 132.4 (Cq, CAr), 132.3 (CHAr), 130.3 (CHAr), 123.8 (CHAr),
123.6 (CHAr), 81.9 (CH), 52.1 (CH2), 32.0 (CH2), 30.9 (CH2), 26.0 (CH2),
25.6 (CH2), 21.5 (CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C16H19NO3Na: 296.1268; found:
296.1270.
HRMS (ESI): m/z [M + Na]+ calcd for C16H9F6NO2Na: 384.0435; found:
384.0430.
(±)-2-[3,5-Bis(trifluoromethyl)phenyl]-3-oxo-1-isoindolinyl Ace-
tate (13c)
(±)-3-Hydroxy-2-(2-propynyl)-1-isoindolinone (12d)
Obtained from 12c ( 0.073 g, 0.20 mmol) and acetic anhydride (0.042
Obtained from 2-formylbenzoic acid (0.300 g, 2.00 mmol), SOCl2 (2.46
g, 1.50 mL, 20.7 mmol), and propargylamine (0.166 g, 0.193 mL, 3.00
mmol) by following General Procedure G.
g, 0.039 mL, 0.40 mmol) by following General Procedure H.
Yield: 0.016 g (0.04 mmol, 20%); colorless solid; mp 126–127 °C;
Rf = 0.61 (n-hexane/EtOAc, 2:1).
Yield: 0.294 g (1.57 mmol, 79%); colorless solid; mp 154–155 °C;
Rf = 0.15 (n-hexane/EtOAc, 2:1).
IR (ATR): 3314, 3124, 1744, 1728, 1708, 1620, 1564, 1475, 1388, 1274,
1123, 1107, 1084, 1017, 885, 758, 700, 681, 664 cm–1
.
IR (ATR): 3267, 2914, 2122, 1680, 1614, 1422, 1268, 1044, 752, 699,
1H NMR (400.13 MHz, CDCl3): δ = 8.22–8.15 (m, 2 H, CHAr), 7.94 (dt,
651, 594 cm–1
.
4
3JH–H = 7.4 Hz, JH–H = 1.2 Hz, 1 H, CHAr), 7.78–7.59 (m, 5 H, CHAr/CH),
1H NMR (400.13 MHz, CDCl3/MeOH-d4): δ = 8.00–7.41 (m, 5 H,
2.11 (s, 3 H, CH3).
2
4
CH/CHAr), 5.94 (br. s, 1 H, OH), 4.60 (dd, JH–H = 17.6 Hz, JH–H = 2.6 Hz,
1 H, CH2), 4.02 (dd, 2JH–H = 17.6 Hz, 4JH–H = 2.6 Hz, 1 H, CH2), 2.26–2.19
(m, 1 H, CH).
13C NMR (100.65 MHz, CDCl3): δ = 170.8 (Cq, C=O), 166.8 (Cq, C=O),
2
140.1 (Cq, CAr), 138.3 (Cq, CAr), 134.1 (CHAr), 132.8 (q, JC–F = 33.0 Hz,
Cq, CArCF3), 131.2 (CHAr), 131.1 (Cq, CAr), 124.6 (CHAr), 124.3 (CHAr),
13C NMR (100.62 MHz, CDCl3/MeOH-d4): δ = 166.9 (Cq, C=O), 144.1
(Cq, CAr), 135.1 (Cq, CAr), 132.6 (CHAr), 131.2 (CHAr), 129.9 (CHAr), 123.5
(CHAr), 98.5 (CH), 81.0 (Cq), 71.9 (CH), 28.6 (CH2).
123.1 (q, 1JH–H = 291.9 Hz, CF3), 118.9 (CHAr), 80.8 (CH), 20.8 (CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C18H11F6NO3Na: 426.0535; found:
426.0537.
HRMS (ESI): m/z [M + Na]+ calcd for C11H9NO2Na: 210.0531; found:
210.0536.
(±)-3-Oxo-2-(2-propynyl)-1-isoindolinyl Acetate (13d)
Obtained from 12d (0.105 g, 0.56 mmol) and acetic anhydride (0.042
g, 0.039 mL, 1.12 mmol) by following General Procedure H.
(±)-3-Oxo-2-propyl-1-isoindolinyl Acetate (13a)
Obtained from 12a (0.050 g, 0.26 mmol) and acetic anhydride (0.053
g, 0.049 mL, 0.52 mmol) by following General Procedure H.
Yield: 0.046 g (0.20 mmol, 36%); colorless solid; mp 97–98 °C;
Rf = 0.42 (n-hexane/EtOAc, 2:1).
Yield: 0.015 g (0.06 mmol, 24%); colorless solid; mp 92–93 °C;
Rf = 0.35 (n-hexane/EtOAc, 2:1).
IR (ATR): 3259, 2963, 2927, 2120, 1737, 1714, 1619, 1422, 1232, 1142,
1013, 750, 690, 670, 595, 527 cm–1
.
IR (ATR): 3258, 2971, 2927, 2875, 1664, 1600, 1459, 1408, 1317, 1056,
1H NMR (400.13 MHz, CDCl3): δ = 7.89–7.78 (m, 1 H, CHAr), 7.63–7.47
797, 742, 691, 591 cm–1
.
(m, 3 H, CHAr), 7.15 (s, 1 H, CH), 4.63 (dd, 2JH–H = 17.7 Hz, 4JH–H = 2.5 Hz,
1H NMR (400.25 MHz, CDCl3): δ = 7.83–7.79 (m, 1 H, CHAr), 7.59–7.48
1 H, CH2), 4.09 (dd, JH–H = 17.7 Hz, JH–H = 2.5 Hz, 1 H, CH2), 2.26 (t,
1 H, 4JH–H = 2.5 Hz, CH), 2.17 (s, 3 H, CH3).
2
4
3
3
(m, 3 H, CHAr), 7.01 (s, 1 H, CH), 3.71 (ddd, JH–H = 13.9 Hz, JH–H
=
=
2
3
3
8.6 Hz, JH–H = 7.0 Hz, 1 H, CH2), 3.24 (ddd, JH–H = 14.0 Hz, JH–H
13C NMR (100.62 MHz, CDCl3): δ = 171.1 (Cq, C=O), 167.1 (Cq, C=O),
141.1 (Cq, CAr), 132.9 (Cq, CAr), 131.5 (CHAr), 130.5 (CHAr), 124.3 (CHAr),
124.0 (CHAr), 80.9 (CH), 77.8 (Cq), 72.4 (CH), 30.0 (CH2), 28.6 (CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C13H11NO3Na: 252.0638; found:
252.0638.
8.5 Hz, 2JH–H = 5.5 Hz, 1 H, CH2), 2.17 (s, CH3), 1.76–1.57 (m, 2 H, CH2),
0.94 (t, 3JH–H = 7.4 Hz, 3 H, CH3).
13C NMR (100.65 MHz, CDCl3): δ = 171.3 (Cq, C=O), 168.0 (Cq, C=O),
141.1 (Cq, CAr), 132.4 (Cq, CAr), 132.3 (CHAr), 130.4 (CHAr), 123.9 (CHAr),
123.7 (CHAr), 81.3 (CH), 42.1 (CH2), 21.7 (CH3), 21.2 (CH2), 11.5 (CH3).
HRMS (ESI): m/z [M–Ac+Na]+ calcd for C11H13NO2Na: 214.0838;
found: 214.0839.
(±)-2-Acetyl-3-hydroxy-1-isoindolinone (14)
o-Phthalaldehyde (2.68 g, 20.0 mmol, 1.0 equiv) and acetamide (1.18
g, 20.0 mmol, 1.0 equiv) were suspended in distilled water (150 mL),
then NaOH (0.112 g, 2.80 mmol, 0.14 equiv) dissolved in distilled wa-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

K
D. Niedek et al.
Paper
Synthesis
ter (5 mL) was slowly added by using a syringe. The resulting clear
solution was stirred at r.t. for 12 h. The precipitate was filtered off,
washed with distilled water and recrystallized from acetonitrile to
give 1-(1,3-dihydroxy-2-isoindolinyl)-1-ethanone (16).
Acknowledgment
We thank Dr. Dennis Gerbig for the VCD analysis, Cesare Savarino for
synthesizing starting materials, and the analytical department for all
spectroscopic and spectrometric measurements.
Yield: 0.809 g (4.19 mmol, 21%); colorless solid.
1H NMR (400.25 MHz, DMSO-d6): δ = 7.49–7.35 (m, 4 H, CHAr), 6.34 (d,
3
3JH–H = 9.5 Hz, 1 H, CHAr), 6.19 (d, JH–H = 7.4 Hz, 1 H, CHAr), 6.14 (d,
Supporting Information
3JH–H = 9.5 Hz, 1 H, CHAr), 6.09 (d, 3JH–H = 7.5 Hz, 1 H, CHAr), 2.20 (s, 3 H,
CH3).
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1589404.
S
u
p
p
o
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g
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rmoaitn
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u
p
p
ortiInfogrmoaitn
13C NMR (100.65 MHz, DMSO-d6): δ = 170.3 (Cq, C=O), 140.0 (Cq, CAr),
139.5 (Cq, CAr), 129.1 (CHAr), 129.0 (CHAr), 123.8 (CHAr), 123.7 (CHAr),
82.6 (CH), 80.6 (CH), 22.4 (CH3).
References
Analytic data are identical to those reported in the literature.69–71
(1) Racine, S. Ber. Dtsch. Chem. Ges. 1886, 19, 778.
(2) Wheeler, D. D.; Young, D. C.; Erley, D. S. J. Org. Chem. 1957, 22,
547.
Compound 16 (0.600 g, 3.10 mmol, 1.0 equiv) was dissolved in boiling
distilled water (25.0 mL), then Na2Cr2O7·2 H2O (0.600 g, 2.01 mmol,
0.65 equiv) and some drops of concentrated H2SO4 were added. After
heating under vigorous stirring to 110 °C, the resulting dark mixture
was slowly cooled to r.t. and allowed to stand for 12 h to give 14 after
filtration, washing with cold water, and drying in vacuum.
(3) Kagan, J. J. Org. Chem. 1967, 32, 4060.
(4) Aksjonova, K.; Belyakov, S.; Liepinsh, E.; Boman, A.; Lundstedt,
T.; Lek, P.; Trapencieris, P. Synthesis 2012, 44, 2200.
(5) Csende, F. ARKIVOC 2006, (vi), 174.
(6) Cho, C. S.; Baek, D. Y.; Shim, S. C. J. Heterocycl. Chem. 1999, 36,
289.
(7) Cho, C. S.; Baek, D. Y.; Kim, H.-Y.; Shim, S. C.; Oh, D. H. Synth.
Commun. 2000, 30, 1139.
(8) Cho, C. S.; Kim, J. U.; Choi, H.-J. J. Organomet. Chem. 2008, 693,
3677.
Yield: 0.260 g (1.36 mmol, 44%); colorless fine needles; mp 150–
152 °C (Lit.70 163.0–164.5 °C).
IR (ATR): 1721, 1690, 1604, 1466, 1424, 1357, 1271, 1053, 963, 791,
748, 695, 642, 582 cm–1
.
1H NMR (400.25 MHz, DMSO-d6): δ = 11.31 (s, 1 H, CHO), 7.86–7.75
3
(m, 5 H, CHAr), 7.67–7.59 (m, 2 H, CHAr), 7.02 (d, JH–H = 7.7 Hz, 1 H,
CH), 7.46 (d, 3JH–H = 7.7 Hz, 1 H, OH), 2.52 (s, 3 H, CH3) (both tautomer-
(9) Cho, C. S.; Lim, D. K.; Kim, T.-J.; Shim, S. C. J. Chem. Res. 2002,
550.
ic forms).
(10) Shim, S. C.; Lee, D. Y.; Jiang, L. H.; Kim, T. J.; Cho, S.-D. J. Hetero-
cycl. Chem. 1995, 32, 363.
(11) Nandakumar, M.; Sankar, E.; Mohanakrishnan, A. K. Synlett
2014, 25, 509.
(12) Sueki, S.; Wang, Z.; Kuninobu, Y. Org. Lett. 2016, 18, 304.
(13) Renzetti, A.; Nakazawa, H.; Li, C.-J. RSC Adv. 2016, 6, 40626.
(14) Zhang, H.; Zhang, S.; Liu, L.; Luo, G.; Duan, W.; Wang, W. J. Org.
Chem. 2010, 75, 368.
(15) Knepper, K.; Ziegert, R. E.; Bräse, S. Tetrahedron 2004, 60, 8591.
(16) Loughlin, W. A.; Jenkins, I. D.; Henderson, L. C.; Campitelli, M.
R.; Healy, P. C. J. Org. Chem. 2008, 73, 3435.
(17) Broadhurst, M. J.; Hassall, C. H. J. Chem. Soc., Perkin Trans. 1
1982, 2227.
(18) Bates, M. A.; Sammes, P. G.; Thomson, G. A. J. Chem. Soc., Perkin
Trans. 1 1988, 3037.
(19) Maslat, A. O.; Al-Hamdany, R.; Fataftah, Z.; Mahrath, A. J.;
Abussaud, M. J. Toxicol. Environ. Chem. 2003, 85, 149.
(20) Brimble, M. A.; Caprio, V. E.; Johnston, A. D.; Sidford, M. H. Tet-
rahedron Lett. 2000, 41, 3955.
(21) Sperry, J.; Liu, Y.-C.; Brimble, M. A. Org. Biomol. Chem. 2010, 8,
29.
13C NMR (100.65 MHz, DMSO-d6): δ = 169.8 (Cq, C=O), 169.2 (Cq,
C=O), 166.4 (Cq, C=O), 144.4 (Cq, CAr), 134.6 (CHAr), 134.3 (CHAr), 132.6
(Cq, CAr), 130.0 (CHAr), 129.5 (Cq, CAr), 124.3 (CHAr), 123.9 (CHAr), 122.9
(CHAr), 79.7 (CH), 25.1 (CH3) (both tautomeric forms).
HRMS (ESI): m/z [M + Na]+ calcd for C10H9NO3Na: 214.0480; found:
214.0481.
(±)-2-Acetyl-3-oxo-1-isoindolinyl Acetate (15)
Compound 14 (0.050 g, 0.26 mmol, 1.0 equiv) and DMAP (0.003 g,
0.03 mmol, 0.1 equiv) were dissolved in CH2Cl2 (2.0 mL) followed by
the addition of acetic anhydride (0.053 g, 0.049 mL, 0.52 mmol, 2.0
equiv) and triethylamine (0.026 g, 0.036 mL, 1.0 equiv). The mixture
was stirred at r.t. for 24 h, then the solvent was removed under re-
duced pressure to give 15 after column chromatography (n-hex-
ane/EtOAc, 2:1).
Yield: 0.036 g (0.15 mmol, 59%); colorless solid; mp 123–124 °C;
Rf = 0.44 (n-hexane/EtOAc, 2:1).
IR (ATR): 2922, 1732, 1702, 1474, 1434, 1375, 1358, 1275, 1227, 1213,
1024, 970, 763, 695, 598 cm–1
.
3
4
1H NMR (400.13 MHz, CDCl3): δ = 7.88 (td, JH–H = 7.7 Hz, JH–H
=
(22) da Silva Maia, A. F.; Siqueira, R. P.; de Oliveira, F. M.; Ferreira, J.
G.; da Silva, S. F.; Caiuby, C. A. D..; de Oliveira, L. L.; de Paula, S.
O.; Souza, R. A. C.; Guilardi, S.; Bressan, G. C.; Teixeira, R. R.
Bioorg. Med. Chem. Lett. 2016, 26, 2810.
(23) Gong, W.; Zhou, Y.; Li, X.; Gao, X.; Tian, J.; Qin, X.; Du, G. Mole-
cules 2016, 21, 549.
1.0 Hz, 1 H, CHAr), 7.72–7.67 (m, 4 H, CHAr), 2.65 (s, 3 H, CH3), 2.11 (s,
3 H, CH3).
13C NMR (100.62 MHz, CDCl3): δ = 170.2 (Cq, C=O), 170.0 (Cq, C=O),
166.5 (Cq, C=O), 140.9 (Cq, CAr), 135.1 (CHAr), 131.0 (CHAr), 130.3 (Cq,
CAr), 125.1 (CHAr), 124.8 (CHAr), 78.9 (CH), 25.2 (CH3), 20.9 (CH3).
(24) Mal, D.; Ghosh, K.; Jana, S. Org. Lett. 2015, 17, 5800.
(25) Beck, J. J.; Chou, S.-C. J. Nat. Prod. 2007, 70, 891.
(26) Karmakar, R.; Pahari, P.; Mal, D. Chem. Rev. 2014, 114, 6213.
(27) Brimble, M. A.; Caprio, V.; Johnston, A. D.; Sidford, M. Synthesis
2001, 855.
HRMS (ESI): m/z [M]+ calcd for C12H11NO4: 233.0688; found:
233.0699.
Analytic data are identical to those reported in the literature.72
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

L
D. Niedek et al.
Paper
Synthesis
(28) Hamura, T.; Hosoya, T.; Yamaguchi, H.; Kuriyama, Y.; Tanabe,
M.; Miyamoto, M.; Yasui, Y.; Matsumoto, T.; Suzuki, K. Helv.
Chim. Acta 2002, 85, 3589.
(29) Kamata, S.; Haga, N.; Matsui, T.; Nagata, W. Chem. Pharm. Bull.
1985, 33, 3160.
(52) Müller, C. E.; Wanka, L.; Jewell, K.; Schreiner, P. R. Angew. Chem.
Int. Ed. 2008, 47, 6180.
(53) Hrdina, R.; Müller, C. E.; Wende, R. C.; Wanka, L.; Schreiner, P. R.
Chem. Commun. 2012, 48, 2498.
(54) Hofmann, C.; Schuler, S. M. M.; Wende, R. C.; Schreiner, P. R.
Chem. Commun. 2014, 50, 1221.
(55) Hofmann, C.; Schümann, J. M.; Schreiner, P. R. J. Org. Chem.
2015, 80, 1972.
(56) Wende, R. C.; Seitz, A.; Niedek, D.; Schuler, S. M. M.; Hofmann,
C.; Becker, J.; Schreiner, P. R. Angew. Chem. Int. Ed. 2016, 55,
2719.
(57) Vakulya, B.; Varga, S.; Csámpai, A.; Soós, T. Org. Lett. 2005, 7,
1967.
(30) Marchand-Brynaert, J.; Laub, R.; De Meester, F.; Frêre, J.-M. Eur.
J. Med. Chem. 1988, 23, 561.
(31) Ogawa, T.; Araki, M.; Miyamae, T.; Okayama, T.; Hagiwara, M.;
Sakurada, S.; Morikawa, T. Chem. Pharm. Bull. 2003, 51, 759.
(32) Grasa, G. A.; Singh, R.; Nolan, S. P. Synthesis 2004, 971.
(33) Lee, J. H.; Han, K.; Kim, M.-J.; Park, J. Eur. J. Org. Chem. 2010, 999.
(34) Kubota, M.; Yamamoto, T.; Yamamoto, A. Bull. Chem. Soc. Jpn.
1979, 52, 146.
(35) Romanski, J.; Nowak, P.; Kosinski, K.; Jurczak, J. Tetrahedron Lett.
2012, 53, 5287.
(58) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125,
12672.
(36) Nudelman, A.; Ruse, M.; Aviram, A.; Rabizadeh, E.; Shaklai, M.;
Zimrah, Y.; Rephaeli, A. J. Med. Chem. 1992, 35, 687.
(37) Yamada, S.; Yamashita, K. Tetrahedron Lett. 2008, 49, 32.
(38) Yamada, S.; Noguchi, E. Tetrahedron Lett. 2001, 42, 3621.
(39) Speck, K.; Magauer, T. Beilstein J. Org. Chem. 2013, 9, 2048.
(40) Smith, K.; El-Hiti, G. A.; Hegazy, A. S.; Kariuki, B. Beilstein J. Org.
Chem. 2011, 7, 1219.
(59) Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Tetrahe-
dron Lett. 2004, 45, 5589.
(60) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17, 522.
(61) Hrdina, R.; Müller, C. E.; Schreiner, P. R. Chem. Commun. 2010,
46, 2689.
(62) Matsuda, T.; Suzuki, K.; Abe, S.; Kirikae, H.; Okada, N. Tetrahe-
dron 2015, 71, 9264.
(41) Zhuang, Z.-P.; Kung, M.-P.; Mu, M.; Kung, H. F. J. Med. Chem.
1998, 41, 157.
(63) Chiurato, M.; Routier, S.; Troin, Y.; Guillaumet, G. Eur. J. Org.
Chem. 2009, 3011.
(42) Agouridas, V.; Capet, F.; Couture, A.; Deniau, E.; Grandclaudon,
P. Tetrahedron: Asymmetry 2011, 22, 1441.
(64) Yagishita, F.; Ishikawa, H.; Onuki, T.; Hachiya, S.; Mino, T.;
Sakamoto, M. Angew. Chem. Int. Ed. 2012, 51, 13023.
(65) Steendam, R. R. E.; Kulka, M. W.; Meekes, H.; van Enckevort, W.
J. P.; Raap, J.; Vlieg, E.; Rutjes, F. P. J. T. Eur. J. Org. Chem. 2015,
7249.
(66) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62,
7512.
(67) Qu, H.; Chi, C. Org. Lett. 2010, 12, 3360.
(68) Dempster, R. K.; Luzzio, F. A. Tetrahedron Lett. 2011, 52, 4992.
(69) DoMinh, D.; Stern, M. H.; Giannini, D. D.; Kelts, L. W. Tetrahe-
dron 1983, 39, 1667.
(43) Comins, D. L.; Schilling, S.; Zhang, Y. Org. Lett. 2005, 7, 95.
(44) More, V.; Rohlmann, R.; Mancheno, O. G.; Petronzi, C.; Palombi,
L.; Rosa, A. D.; Mola, A. D.; Massa, A. RSC Adv. 2012, 2, 3592.
(45) Heaney, H.; Shuhaibar, K. F. Synlett 1995, 47.
(46) Ding, G.; Li, C.; Shen, Y.; Lu, B.; Zhang, Z.; Xie, X. Adv. Synth.
Catal. 2016, 358, 1241.
(47) Brewster, J. H.; Fusco, A. M.; Carosino, L. E.; Corman, B. G. J. Org.
Chem. 1963, 28, 498.
(48) Lixin, W.; Jiyu, W.; Fan, Y.; Jianfeng, S.; Wen, W. Lett. Org. Chem.
2008, 5, 26.
(70) Reynolds, R. D.; Conboy, R. J. J. Org. Chem. 1965, 30, 2251.
(71) Reynolds, R. D.; Arendsen, D. L.; Guanci, D. F.; Wickman, R. F.
J. Org. Chem. 1970, 35, 3940.
(49) Ding, G.; Lu, B.; Li, Y.; Wan, J.; Zhang, Z.; Xie, X. Adv. Synth. Catal.
2015, 357, 1013.
(50) Cabrero-Antonino, J. R.; Sorribes, I.; Junge, K.; Beller, M. Angew.
Chem. Int. Ed. 2016, 55, 387.
(72) Sharfuddin, M.; Narumi, A.; Iwai, Y.; Miyazawa, K.; Yamada, S.;
Kakuchi, T.; Kaga, H. Tetrahedron: Asymmetry 2003, 14, 1581.
(51) Romney, D. K.; Miller, S. J. Org. Lett. 2012, 14, 1138.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L