Synthesis of Isoindolinones by Pd-Catalyzed Coupling between N-Methoxybenzamide and Styrene Derivatives

Article abstract of DOI:10.1021/acs.joc.6b01696

An atom-economical protocol for a tandem process involving Fujiwara-Moritani-aza-Wacker reactions has been developed for the Pd-catalyzed coupling between N-methoxy benzamide and styrene derivatives. The generality of the methodology was demonstrated by the synthesis of a library of 25 3-benzylidene isoindolinones in moderate to good yields. A further 40 3-benzyl derivatives were obtained by telescoping the process with a catalytic hydrogenation reaction.

Full text of DOI:10.1021/acs.joc.6b01696

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Article
Synthesis of isoindolinones by Pd-catalyzed coupling
between N-methoxybenzamide and styrene derivatives
Changkun Xia, Andrew J. P. White, and King Kuok (Mimi) Hii
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01696 • Publication Date (Web): 05 Aug 2016
Downloaded from http://pubs.acs.org on August 10, 2016
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Synthesis of isoindolinones by Pd-catalyzed coupling between N-methoxybenzamide
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and styrene derivatives
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Changkun Xia,† Andrew J. P. White and King Kuok (Mimi) Hii*
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Department of Chemistry, Imperial College London, Exhibition Road, South Kensington, London SW7
2AZ, U.K. *Eꢀmail: mimi.hii@imperial.ac.uk.
†Current affiliation: School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang,
212013, China.
Table of Contents graphic
Abstract: An atomꢀeconomical protocol for a tandem process involving FujiwaraꢀMoritaniꢀazaꢀWacker
reactions has been developed for the Pdꢀcatalyzed coupling between Nꢀmethoxy benzamide with styrene
derivatives. The generality of the methodology was demonstrated by the synthesis of a library of
twentyꢀfive 3ꢀbenzylidene isoindolinones in moderate to good yields. A further twentyꢀtwo 3ꢀbenzyl
derivatives were obtained by telescoping the process with a catalytic hydrogenation reaction.
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Introduction
3ꢀBenzylꢀsubstitutedꢀisodolinones (I) constitute a family of privileged pharmacophores (Fig. 1) with
significant therapeutic potentials, such as glycine transporter (GlyT1) inhibitors (Abbvie),1 and
aldosterone synthase (CYP11B2 or CYP11B1) inhibitors (Hoffmannꢀla Roche).2 The subꢀstructure is
also found in many natural products, including isoindolobenzazepine alkaloids (e.g. lennoxamine3), and
aristolactam alkaloids (including piperolactams4), known to have potent antiꢀtumor activities.5
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Figure 1. Biologically active 3ꢀbenzylꢀsubstituted isoindolinones (I) and natural products containing the
subꢀstructure.
Scheme 1. Proposed route for assembling I.
Conceptually, structure I can be constructed in two steps: By a FujiwaraꢀMoritani (FM) reaction
between benzamide and styrene derivatives, followed by an intramolecular azaꢀWacker reaction
(Scheme 1); the resultant product 2 can then be subjected to catalytic hydrogenation to yield the target
structure. The FM reaction between a benzamide derivative and an alkene can be achieved using Rh,6
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Ru7 and Ir8 catalysts. However, using these catalysts, the reaction terminates at the formation of the
acyclic compound (1). In contrast, both reactions can be effected in tandem under Pd catalysis to give
the Nꢀheterocycle 2as the final product. This was first reported independently by the research groups of
Wrigglesworth et al9 and Li et al in 2011,10 when Pd(OAc)2 were used to catalyze the coupling between
Nꢀmethoxybenzamides with activated alkenes containing electronꢀwithdrawing substituents, i.e. R =
CO2R, CONR2, SO2Ph, COR. One example using styrene as the alkene reactant was reported to afford
the 2ꢀbenzylidene derivative (R = Ph, 2aa) in a moderate yield (≤50%); notably, no further examples of
other conjugated alkenes were provided. In this work, we have modified the catalytic protocol to widen
the scope of this methodology to a wide range of styrene derivatives (Z = Ar), with the aim of
synthesizing a library of 3ꢀbenzyl substituted isoindolinones (analogues of compound I) for biological
evaluation (Scheme 2).
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Scheme 2. Modification of the tandem FMꢀazaꢀWacker reactions for the synthesis of I.
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Results and discussion
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NꢀMethoxybenzamide and styrene were initially employed as model substrates in the evaluation of
reaction parameters (Table 1). Following the reported procedure by Li et al,10 palladium(II) acetate was
employed as a catalyst precursor with 2 equivalents of the oxidant (benzoquinone, BQ), and the reaction
was performed in acetic acid at 100 °C. This afforded the expected product 2aa in 27% yield (entry 1).
This was lower than the reported yields of 46%, which may be due to the prolonged reaction time (48 h
vs 10 h). Subsequent studies at lower reaction temperatures did not lead to any improvement (entry 2),
and the addition of TFA only has a marginally beneficial effect under these conditions (entry 3). By
increasing the amount of oxidant and styrene, the product yield may be improved (entry 4), which also
allowed the reaction time to be shortened (entry 5).
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Notably, attempt to lower the amount of oxidant from 2 equivalents to 1 equivalent adversely
affected the reaction, even in the presence of O2 (entry 6), i.e. we were unable to replicate the 50% yield
achieved by using 20 mol% of BQ, as reported by Wrigglesworth et al.9 The need to use an excess of
BQ is a significant issue; apart from poor atomꢀeconomy, benzoquinone is also genotoxic,11 which may
interfere with subsequent biological testing should any residue remain in the product. Therefore,
although a reasonable yield (69%) can be achieved using this oxidant, it was decided that a safer
alternative should be sought. With this in mind, a number of more benign oxidants were evaluated,
including potassium and ammonium persulfates, as well as tertꢀbutyl perbenzoate (Table S1, Supporting
information). The use of these strong oxidants was found to be incompatible with the benzamide
substrates, causing them to decompose at temperatures >50 ºC. After some further investigation, we
were able to identify O2/20 mol% Cu(OAc)2 as a good replacement of benzoquinone, delivering 2aa at a
slightly elevated temperature of 90 °C (entries 7ꢀ8); in this case, the beneficial effect of TFA was more
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pronounced (entries 8 vs 9), as it suppressed the competitive hydrolysis of Nꢀmethoxybenzamide under
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Table 1. Initial evaluation of reaction parameters.a
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Entry
1
[O]b
x
y
z
T (ºC)
t (h)
48
Yieldc (%)
27
BQ (2)
2
ꢀ
3
100
2
BQ (2)
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2
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ꢀ
3
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BQ (2)
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ꢀ
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BQ (2.5)
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BQ (2.5)
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BQ (1), O2
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Cu(OAc)2 (0.2), O2
Cu(OAc)2 (0.2), O2
Cu(OAc)2 (0.2), O2
Cu(OAc)2 (0.2), O2
1.5
1.5
1.5
1.5
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1
aGeneral conditions: Reactions were performed using Nꢀmethoxyꢀbenzamide as the limiting reagent (0.3
b
mmol). More results are listed in Tale S1 (Supporting information). Equiv indicated in parenthesis.
cIsolated yield after column chromatography.
In earlier work,9,10 2aa was reported to be formed exclusively as an Eꢀisomer. In the present
study, however, it was obtained as a mixture of isomers, irrespective of the oxidant or reaction
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conditions, typically in a ratio of approximately 2:1. This was established by integrating the methoxy
proton resonance at 4.1 and 3.5 ppm, respectively. The configuration isomers were subsequently
separated by column chromatography, and the E-configuration of the major isomer was confirmed by
Xꢀray crystallography (Figure S1, Supporting Information). In the solid state structure, the pendant
phenyl is twisted outꢀofꢀplane from the isoindolinone ring, in order to avoid unfavourable interactions
between the ortho H’s.
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Under these reaction conditions, polymerization of styrene is a minor competitive process. However, the
NMR spectrum of the reaction mixture contained additional resonance peaks, indicating the presence of
a persistent side product (ca. 20%), identified by a distinct 1H NMR singlet signal at 8.51 ppm. A small
amount of this impurity was isolated. Its 1H NMR spectrum, with the accompanying mass ion (MH+) of
176, are consistent with the formation of the 6ꢀmembered Nꢀmethoxy isoquinolinone 3 (Scheme 3).12
The formation of this unexpected side product is attributed to the formation of the minor Zꢀisomer of
1aa, which undergoes 6ꢀendo-trig cyclization in the subsequent azaꢀWacker reaction (antiꢀaddition). In
the absence of an accessible βꢀhydride, the putative intermediate (A) undergoes a synꢀcoplanar βꢀphenyl
elimination to afford compound 3. Such βꢀaryl elimination processes involving CꢀC cleavage are rare;
known only to occur in reactions involving sterically bulky arylmethanols.13
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Scheme 3. Competitive formation of side product 3.
Next, the generality of the catalytic methodology was tested. Using the new protocol, a small library of
twentyꢀfive new 3ꢀbenzylidene isoindolinone derivatives was constructed from readilyꢀavailable
benzamide and styrene derivatives (Table 2). Reaction yields are moderate to good, ranging between 49ꢀ
72%. In general, better yields were obtained with styrene derivatives bearing electronꢀwithdrawing
substituents. Again, in all cases, a mixture of E/Zꢀisomers was obtained, typically in a 2:1 ratio in favor
of the Eꢀisomer. The Eꢀconfiguration is favored when 2ꢀmethylꢀ or 2ꢀmethoxyꢀsubstituted Nꢀmethoxyꢀ
benzamides (entries 13ꢀ21) were used as substrates; particularly in combination with 2ꢀvinyl
naphthalene (entries 5, 11, 16 and 21).
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Table 2. Tandem reaction between Nꢀmethoxybenzamide and styrene derivatives.a
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Entry Ar1, Ar2
Product Yield (%)b E/Z
1
Ph, Ph
2aac
2abc
2ac
2ad
2ae
2af
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68
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2/1
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Ph, 4ꢀClꢀPh
2.1/1
2/1
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Ph, 4ꢀFꢀPh
4
Ph, 4ꢀMeꢀPh
5/1
5
Ph, 2ꢀNap
2.3/1
2.4/1
1.9/1
1.9/1
1.5/1
1.9/1
3.5/1
1.8/1
2.7/1
3.1/1
2.9/1
3.5/1
2.5/1
4.3/1
3.1/1
4.2/1
3.7/1
1.9/1
1.7/1
1.8/1
1/0
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Ph, 4ꢀCF3ꢀPh
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4ꢀMeꢀPh, Ph
2da
2dbc
2dc
2dd
2de
2df
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4ꢀMeꢀPh, 4ꢀClꢀPh
4ꢀMeꢀPh, 4ꢀFꢀPh
4ꢀMeꢀPh, 4ꢀMeꢀPh
4ꢀMeꢀPh, 2ꢀNap
4ꢀMeꢀPh, 4ꢀCF3ꢀPh
2ꢀMeꢀPh, Ph
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2ga
2gbc
2gd
2ge
2gf
2ꢀMeꢀPh, 4ꢀClꢀPh
2ꢀMeꢀPh, 4ꢀMeꢀPh
2ꢀMeꢀPh, 2ꢀNap
2ꢀMeꢀPh, 4ꢀCF3ꢀPh
2ꢀMeOꢀPh, Ph
2ha
2hbc
2hd
2he
2ibc
2id
2ꢀMeOꢀPh, 4ꢀClꢀPh
2ꢀMeOꢀPh, 4ꢀMeꢀPh
2ꢀMeOꢀPh, 2ꢀNap
4ꢀMeOꢀPh, 4ꢀClꢀPh
4ꢀMeOꢀPh, 4ꢀMeꢀPh
4ꢀMeOꢀPh, 4ꢀCF3ꢀPh
4ꢀCF3ꢀPh, 4ꢀClꢀPh
2if
2jbc
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aReaction conditions: Nꢀmethoxybenzamide (0.3 mmol, 1 equiv), styrene (0.9 mmol, 3 equiv),
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Pd(OAc)2 (0.015 mmol, 5 mol%), Cu(OAc)2·2H2O (0.06 mmol, 20 mol%), acetic acid (1.5 mL),
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trifluoroacetic acid (TFA, 0.3 mmol, 1 equivalent), O2 balloon, 90 °C. Isolated yield obtained after
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column chromatography, E:Z ratio indicated in parenthesis. Characterized by NMR spectroscopy after
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column chromatography.
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In some cases, the E/Z isomers may be separated by column chromatography for characterization
purposes these include 2aa, 2ab, 2db, 2gb, 2hb, 2ib and 2jb). In other cases, the isomeric mixture was
directly subjected to hydrogenation reactions over Pd/C in a telescoped process, affording twentyꢀtwo
novel 2ꢀbenzylꢀsubstituted isoindolinones (Fig. 2). The hydrogenation reaction is known to proceed well
in high yields for similar benzylideneisoindolidinones, when the exocyclic alkene contains an electronꢀ
withdrawing ester group.9,14 In the present case, the reduction of arylꢀsubstituted 2required slightly
elevated temperatures of between 40ꢀ50 °C. This was attributed to the twisted alkene moiety observed
in the Xꢀray crystal structure (See Supporting Information), sterically hindering the accessibility to
surfaceꢀadsorbed hydrides. Under these conditions, the substrate may be reduced further to the Nꢀ
demethoxylated product 4’. Interestingly, the outcome of the catalytic hydrogenation process is rather
dependent upon the nature of the pendant aryl group. Notably, 4’ was obtained as the major product
when the aryl group contains fluorinated substituents. Conversely, the yields of chloroꢀsubstituted
compounds (4ab, 4gb, 4db and 4ib) were also affected by the competitive dehalogenation of the
chloride during the catalytic hydrogenation process. In this part of the work, Xꢀray crystallographic
structures of reduced 4aa and 4aa’ were obtained (Figures S2 and S3, Supporting Information),
providing additional information of their structure features that may be useful for fragmentꢀbased
discovery.
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Figure 2. Reduced isoquinolines synthesized via telescoped steps (reported yields were calculated over
two steps). Ratio of 4:4’ is indicated in parenthesis.
Conclusion
The scope of the Pdꢀcatalyzed tandem FujiwaraꢀMoritani (FM)ꢀintramolecular azaꢀWacker cyclisation
has been substantially expanded to styrene derivatives, replacing the use of excess genotoxic
benzoquinone by benign O2, in the presence of Cu(OAc)2 as coꢀcatalyst. By telescoping the process with
catalytic hydrogenation, a series of 3ꢀbenzylꢀsubstituted isoindolinones can be prepared from readily
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available Nꢀmethoxybenzamide and styrene derivatives in two synthetic operations. The methodology
has good generality, providing access to >40 novel isoindolinone structures containing either a
benzylidene or a benzyl substituent at positionꢀ3.
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Experimental Section
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General Experimental Methods.
Unless otherwise stated, all precursors were obtained from commercial suppliers and used as received
without purification. Solvents were dried by passing through the columns of molecular sieves in a
solvent purification system. All reactions were carried out in ovenꢀdried glassware. Reaction
temperatures are reported as the temperature of the bath/heating block surrounding the vessel unless
otherwise stated. Analytical thin layer chromatography was performed on silica plates. Visualization
was accomplished with UV light (254 nm), and/or KMnO4 staining solutions followed by heating.
Column chromatography was performed on flash silica gel (40ꢀ63 mesh).1H and 13C NMR spectra were
recorded at ambient temperature (25 °C) on spectrometers. Residual protic solvents were used as an
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internal standard and C resonances were referenced to the deuterated carbon. Chemical shifts (δ) are
reported in ppm. Monoisotopic values for chlorinated compounds were reported and calculated using
the major isotope (35Cl).
Single crystals of Eꢀ2aa, 4aa and 4’aa suitable for Xꢀray crystallography was obtained as needles by
recrystallization from EtOAc and hexane at room temperature. Selected crystals were centered on an Xꢀ
ray crystal structural data were collected using a diffractometer equipped with a CCD detector and a
graphite monochromated Mo Kα radiation (λ = 0.71073 Å). The data collection routine, unit cell
refinement, and data processing were carried out with the program CrysAlis.15 Structures were solved
by the direct method and refined by fullꢀmatrix leastꢀsquares methods with SHELXLꢀ97 programs.16 Xꢀ
ray crystal data and structure refinement parameters were listed in Table S2 (Supporting information).
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The data were deposited at the CCDC database, with the reference numbers 1472315ꢀ1472317 for Eꢀ
2aa, 4aa, and 4’aa, respectively.
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NꢀMethoxy benzamide derivatives (precursors for the catalytic reaction) were prepared from
commercially available benzoyl chloride and Oꢀmethylhydroxylamine, by a published procedure.17 The
characterization data of these compounds are entirely consistent with the literature values.17
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General procedure for the tandem Fujiwara-Moritani-aza-Wacker reaction. A reduced volume
Radley’s reaction tube was charged with a stir bar, the appropriate styrene (0.9 mmol, 3 equiv), and Nꢀ
methoxybenzamide (0.3 mmol, 1 equiv) derivatives, Pd(OAc)2 (0.05 equiv) and Cu(OAc)2·2H2O (0.2
equiv) and acetic acid (1.5 mL) at room temperature. The tube was evacuated briskly under vacuum and
recharged with oxygen three times. The O2 atmosphere in the tube was maintained by connecting a
balloon of O2 to the reaction tube through a needle pierced through the septum. The reaction vessel was
then placed in an aluminum heating block heated to 90 ºC and stirred. The reaction was monitored by
TLC until the starting material was consumed. The reaction mixture was concentrated under vacuum
and the residue was subjected directly to column chromatography using petroleum ether/EtOAc (6/1) as
the eluent. A selection of the Zꢀ and Eꢀisomer may be collected as separate fractions for characterization
purposes, or as a combined fraction for the telescoped process.
The reaction can be successfully replicated on larger scale using Nꢀmethoxybenzamide (136 mg, 0.9
mmol, 1 equiv), styrene (281 mg, 2.7 mmol, 3 equiv), Pd(OAc)2 (0.05 equiv) and Cu(OAc)2·2H2O (0.2
equiv), TFA (1 equiv), and acetic acid (4.5 mL). Following column chromatography, 43 mg (19%) of
the Zꢀ isomer and 91 mg (40%) of the Eꢀisomer were isolated separately.
Catalytic hydrogenation of 2 to 4. A mixture of Z/Eꢀ2 was dissolved in anhydrous methanol (10 mL)
in a Radley’s reaction tube. 10 wt% Pd/C was added to this mixture before the system was then sealed
with a cap and a balloon of hydrogen attached via a needle pierced through the septum. The reaction
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vessel was placed in the aluminum block and the mixture was stirred and heated between 40ꢀ50 ºC for 2
h. The reaction mixture was filtered through Celite and the filtrate concentrated to give a yellow solid
which was then purified by flash column chromatography (petroleum ether /EtOAc, 4/1).
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(Z)-3-Benzylidene-2-methoxyisoindolin-1-one, Z-2aa. Light yellow solid (15 mg, 0.059 mmol, 20%).
1Η ΝΜR (CDCl3, 400 MHz): δ 7.87–7.84 (m, 1H), 7.75–7.72 (m, 1H), 7.62 (td, 1H, J = 7.6 Hz, 1.2 Hz),
7.59–7.54 (m, 2H), 7.50 (td, 1H, J= 7.5, 1.0 Hz), 7.39–7.34 (m, 2H), 7.34–7.27 (m, 1H), 6.70 (s, 1H),
3.47 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 162.8, 134.6, 133.2, 132.5, 130.3, 129.5, 129.3, 127.9,
127.8, 126.0, 123.5, 119.5, 107.0, 63.4. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C16H14NO2 252.1024;
Found: 252.1046; [M+H+CH3CN]+ Calcd for C18H17N2O2 293.1290; Found: 293.1334.
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(E)-3-Benzylidene-2-methoxyisoindolin-1-one, E-2aa. Previously reported either as a slightly yellow
oil9 or a pale yellow solid.10 In this work, it is isolated as a colorless solid (30 mg, 0.12 mmol, 40%), mp
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133ꢀ134 °C. H NMR (CDCl3, 400 MHz): δ 7.86–7.81 (m, 1H), 7.50–7.34 (m, 8H), 6.76 (s, 1H), 4.10
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(s, 3H). C NMR (CDCl3, 101 MHz): δ 161.0, 134.5, 132.0, 131.8, 131.4, 129.6, 129.5, 128.8, 128.1,
127.9, 123.4, 123.0, 110.1, 64.3. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C16H14NO2 252.1024;
Found: 252.1029; [M+H+CH3CN]+ Calcd for C18H17N2O2 293.1290; Found: 293.1292.
(Z)-3-(4-Chlorobenzylidene)-2-methoxyisoindolin-1-one, Z-2ab. Light yellow solid (19 mg, 0.067
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mmol, 22%). H NMR (CDCl3, 400 MHz): δ 7.90–7.84 (m, 1H), 7.74–7.71 (m, 1H), 7.64 (td, 1H, J =
7.6, 1.2 Hz), 7.54–7.48 (m, 2H), 7.38–7.30 (m, 4H), 6.62 (s, 1H), 3.51 (s, 3H). Insufficient quantity
obtained for 13C NMR spectroscopy. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C16H13NO2Cl 286.0634;
Found: 286.0635.
(E)-3-(4-Chlorobenzylidene)-2-methoxyisoindolin-1-one, E-2ab. Light yellow solid (40 mg, 0.139
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mmol, 46%). mp 110ꢀ111 °C. H NMR (CDCl3, 400 MHz): δ 7.86–7.83 (m, 1H), 7.51–7.37 (m, 7H),
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6.67 (s, 1H), 4.10 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 161.1, 134.0, 133.0, 132.4, 132.2, 131.2,
130.9, 129.9, 129.1, 128.0, 123.6, 122.9, 108.5, 64.4. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C16NO2H13Cl 286.0634; Found: 286.0630; [M+H+CH3CN]+ Calcd for C18H16N2O2Cl 327.0900; Found:
327.0910.
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(Z)-3-(4-Chlorobenzylidene)-2-methoxy-5-methyl-isoindolin-1-one, Z-2db. Light yellow solid (28
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mg, 0.093 mmol, 31%). H NMR (CDCl3, 400 MHz): δ 7.73 (d, 1H, J = 7.9 Hz), 7.53–7.46 (m, 3H),
7.35–7.30 (m, 3H), 6.58 (s, 1H), 3.48 (s, 3H), 2.50 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 163.1,
143.5, 134.8, 133.6, 131.9, 131.6, 130.9, 130.63, 130.2, 129.0, 128.1, 123.6, 119.9, 105.0, 63.3, 22.3.
HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C17H15NO2Cl300.0791; Found: 300.0800; [M+H+CH3CN]+
Calcd for C19H18N2O2Cl 341.1056; Found: 341.1052.
(E)-3-(4-Chlorobenzylidene)-2-methoxy-5-methyl-isoindolin-1-one, E-2db. Light yellow solid (36
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mg, 0.120 mmol, 40%). mp 137ꢀ139 °C. H NMR (CDCl3, 400 MHz): δ 7.73 (dd, 1H, J= 7.5, 0.9 Hz),
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7.45–7.38 (m, 4H), 7.29–7.26 (m, 2H), 6.62 (s, 1H), 4.08 (s, 3H), 2.31 (s, 3H). C NMR (CDCl3, 101
MHz): δ 161.3, 143.0, 133.9, 133.1, 132.5, 131.5, 130.9, 129.9, 128.1, 125.4, 123.5, 123.4, 123.3,
108.2, 22.3. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C17H15NO2Cl 300.0791; Found: 300.0779;
[M+H+CH3CN]+ Calcd for C19H18N2O2Cl 341.1056; Found: 341.1057.
(Z)-3-(4-Chlorobenzylidene)-2-methoxy-6-methyl-isoindolin-1-one, Z-2gb. Light yellow solid (13
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mg, 0.043 mmol, 15%). H NMR (CDCl3, 400 MHz): δ 7.67–7.68 (m, 1H), 7.62–7.59 (m, 1H), 7.51–
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7.47 (m, 2H), 7.45–7.42 (m, 1H), 7.35–7.30 (m, 2H), 6.55 (s, 1H), 3.49 (s, 3H), 2.47 (s, 3H). C NMR
(CDCl3, 101 MHz): δ 163.1, 140.1, 133.7, 133.6, 131.9, 131.6, 130.2, 128.1, 126.1, 123.8, 119.4, 104.8,
63.3, 21.7. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C17H15NO2Cl 300.0791; Found: 300.0800;
[M+H+CH3CN]+ Calcd for C19H18N2O2Cl 341.1056; Found: 341.1055.
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(E)-3-(4-Chlorobenzylidene)-2-methoxy-6-methyl-isoindolin-1-one, E-2gb. Light yellow solid (42
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mg, 0.14 mmol, 47%). mp 141–142 °C. H NMR (CDCl3, 400 MHz): δ 7.65 (d, 1H, J = 2.7 Hz), 7.45–
7.32 (m, 5H), 7.20 (dd, 1H, J = 8.1, 1.8 Hz), 6.61 (s, 1H), 4.09 (s, 3H), 2.41 (s, 3H). 13C NMR (CDCl3,
101 MHz): δ 161.3, 140.5, 133.8, 133.2,133.1, 132.5, 130.9, 129.0, 128.6, 128.1, 123.8, 122.8, 107.6,
64.3, 21.7. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C17NO2H15Cl 300.0791; Found: 300.0807;
[M+H+CH3CN]+ Calcd for C19H18N2O2Cl 341.1056; Found: 341.1083.
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(Z)-3-(4-Chlorobenzylidene)-2,6-dimethoxy-isoindolin-1-one, Z-2hb. Light yellow solid (14 mg,
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0.044 mmol, 15%). H NMR (CDCl3, 400 MHz): δ 7.63–7.59 (m, 1H), 7.50–7.46 (m, 2H), 7.35–7.30
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(m, 3H), 7.17 (dd, 1H, J = 8.5, 2.5 Hz), 6.50 (s, 1H), 3.89 (s, 3H), 3.49 (s, 3H). C NMR (CDCl3, 101
MHz): δ 163.0, 161.2, 133.5, 131.9, 131.6, 130.0, 128.1, 127.5, 127.0, 121.1, 121.0, 106.3, 104.5, 63.4,
56.0. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C17H15NO3Cl 316.0740; Found: 316.0727;
[M+H+CH3CN]+ Calcd for C19H18N2O3Cl 357.1006; Found: 357.0928.
(E)-3-(4-Chlorobenzylidene)-2,6-dimethoxy-isoindolin-1-one, E-2hb. Light yellow solid (45 mg,
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0.145 mmol, 49%). mp 109–110 °C. H NMR (CDCl3, 400 MHz): δ 7.63–7.59 (m, 1H), 7.50–7.46 (m,
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2H), 7.35–7.30 (m, 3H), 7.17 (dd, 1H, J = 8.5, 2.5 Hz), 6.50 (s, 1H), 3.89 (s, 3H), 3.49 (s, 3H). C
NMR (CDCl3, 101 MHz): δ 161.2, 161.1, 133.7, 133.2, 132.3, 130.8, 129.7, 129.9, 124.3, 123.7, 119.9,
107.0, 106.6, 64.4, 55.8. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C17H15NO3Cl 316.0740; Found:
316.0735; [M+H+CH3CN]+ Calcd for C19H18N2O3Cl 357.1006; Found: 357.1006.
(Z)-3-(4-Chlorobenzylidene)-2,5-dimethoxy-isoindolin-1-one, Z-2ib. Light yellow solid (16 mg,
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0.051 mmol, 17%). mp 140–141 °C. H NMR (CDCl3, 400 MHz): δ 7.80–7.75 (m, 1H), 7.53–7.47 (m,
2H), 7.36–7.31 (m, 2H), 7.18–7.16 (m, 1H), 7.04 (dd, 1H, J = 8.4, 2.2 Hz), 6.56 (s, 1H), 3.93 (s, 3H),
3.48 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 163.8, 163.1, 136.8, 133.7, 131.8, 131.6, 130.3, 128.2,
125.4, 118.7, 116.5, 108.9, 105.1, 104.2, 63.2, 56.0. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
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C17H15NO3Cl 316.0740; Found: 316.0725; [M+H+CH3CN]+ Calcd for C19H18N2O3Cl 357.1006; Found:
357.0992.
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(E)-3-(4-Chlorobenzylidene)-2,5-dimethoxy-isoindolin-1-one, E-2ib. Light yellow solid (30 mg,
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0.095 mmol, 32%). mp 151–153 °C. H NMR (CDCl3, 400 MHz): δ 7.79–7.73 (m, 1H), 7.45–7.38 (m,
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4H), 7.01–6.92 (m, 2H), 6.63 (s, 1H), 4.08 (s, 3H), 3.69 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 163.1,
161.4, 134.0, 133.3, 133.1,132.7, 131.6, 130.9, 129.0, 128.1, 125.2, 120.5, 116.1, 108.3, 108.2, 64.3,
55.6. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C17H15NO3Cl 316.0740; Found: 316.0727;
[M+H+CH3CN]+ Calcd for C19H18N2O3Cl 357.1006; Found: 357.0990.
(E)-3-(4-Chlorobenzylidene)-5-trifluoromethyl-2-methoxy-isoindolin-1-one, E-2jb. Colorless solid
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(18 mg, 0.051 mmol, 17%). mp 147–149 °C. H NMR (CDCl3, 400 MHz): δ 7.99–7.97 (m, 1H), 7.79–
7.71 (m, 2H), 7.48–7.40 (m, 4H), 6.80 (s, 1H), 4.13 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 159.6,
134.8, 134.3, 133.9, 132.2, 131.5, 131.3, 130.9, 130.7, 129.3, 126.8, 126.8, 126.8, 126.7, 124.2, 120.1,
120.1, 120.0, 120.0, 110.5, 64.6. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C17H12NO2ClF3 354.0508;
Found: 354.0501; [M+H+CH3CN]+ Calcd for C19H15N2O2ClF3 395.0774; Found: 395.0730.
3-Benzyl-3-hydro-2-methoxy-isoindolin-1-one, 4aa. Colorless solid (24 mg, 0.094 mmol, 31%). mp
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94–95 °C. H NMR (CDCl3, 400 MHz): δ 7.75–7.72 (m, 1H), 7.47–7.36 (m, 2H), 7.26–7.18 (m, 3H),
7.13–7.08 (m, 2H), 6.99–6.96 (m, 1H), 4.98 (dd, 1H, J = 7.6, 4.4 Hz), 3.99 (s, 3H), 3.45 (dd, 1H, J =
13.8, 4.4 Hz), 3.02 (dd, 1H, J =13.8, 7.6 Hz). 13C NMR (CDCl3, 101 MHz): δ 164.6, 141.6, 135.5,
131.7, 130.1, 129.8, 128.5, 128.5, 127.1, 123.8, 123.1, 63.9, 60.4, 37.4. HRMS (ESIꢀTOF) m/z: [M+H]+
Calcd for C16H16NO2 254.1181; Found: 254.1181.
3-Benzyl-2,3-dihydro-isoindolin-1-one, 4’aa. Colorless solid (11 mg, 0.049 mmol, 16%). mp 134–135
°C. 1H NMR (CDCl3, 400 MHz): δ 7.83 (dt, 1H, J = 7.3, 1.0 Hz), 7.53 (td, 1H, J = 7.5, 1.3 Hz), 7.46 (td,
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1H, J = 7.4, 1.0 Hz), 7.34–7.28 (m, 3H, ArꢀH), 7.27 (d, 2H, J = 6.6 Hz), 7.20 (d, 1H, J =1.4 Hz), 7.08
(br s, 1H, NH), 4.81 (dd, 1H, J = 8.5, 5.5 Hz), 3.18 (dd, 1H, J =13.6, 5.5 Hz), 2.87 (dd, 1H, J =13.6, 8.5
Hz).13C NMR (CDCl3, 101 MHz): δ 170.6, 146.9, 137.0, 132.1, 131.8, 129.4, 128.9, 128.4, 127.2,
123.9, 122.8, 58.1, 41.4. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C15H14NO 224.1075; Found:
224.1079; [M+H+CH3CN]+ Calcd for C17H17N2O 265.1341; Found: 265.1236.
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3-(4-Chlorobenzyl)-3-hydro-2-methoxy-isoindolin-1-one, 4ab. Colorless solid (22 mg, 0.076 mmol,
25%). 1H NMR (CDCl3, 400 MHz): δ 7.72–7.69 (m, 1H), 7.47 (td, 1H, J =7.5, 1.3 Hz), 7.39 (ddd, 1H, J
= 8.2, 7.5, 1.0 Hz), 7.18–7.06 (m, 3H), 7.02–6.95 (m, 2H), 4.97 (dd, 1H, J = 6.8, 4.2 Hz), 3.98 (s, 3H),
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3.33 (dd, 1H, J =13.9, 4.2 Hz), 3.11 (dd, 1H, J =13.9, 6.8 Hz). C NMR (CDCl3, 101 MHz): δ 164.4,
141.1, 133.5, 132.9, 131.8, 131.2, 130.1, 128.7, 128.5, 123.9, 122.9,63.8, 59.8, 36.8. HRMS (ESIꢀTOF)
m/z: [M+H]+ Calcd for C16H15NO2Cl 288.0791; Found: 288.0782; [M+H+CH3CN]+ Calcd for
C18H18N2O2Cl 329.1057; Found: 329.1043.
3-(4-Fluorobenzyl)-3-hydro-2-methoxy-isoindolin-1-one, 4ac. Colorless solid (10 mg, 0.036 mmol,
12%). 1H NMR (CDCl3, 400 MHz): δ 7.72 (dt, 1H, J = 7.5, 1.0 Hz), 7.47 (td, 1H, J = 7.5, 1.3 Hz), 7.40–
7.37 (m, 1H), 7.09–7.06 (m, 1H), 7.02–6.99 (m, 2H,), 6.90–6.84 (m, 2H), 4.97 (dd, 1H, J = 6.8, 4.2 Hz),
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3.99 (s, 3H), 3.35 (dd, 1H, J =14.0, 4.2 Hz), 3.12 (dd, 1H, J = 14.0, 6.8 Hz). C NMR (CDCl3, 101
MHz): δ 164.5, 162.0 (d, J = 254 Hz), 141.3, 131.6 (d, J = 8.0 Hz), 131.3, 130.7, 130.2, 128.7, 123.9,
122.9, 115.3 (d, J = 22 Hz), 63.8, 60.0, 36.7. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C16H15NO2F
272.1086; Found: 272.1086; [M+H+CH3CN]+ Calcd for C18H18N2O2F 313.1352; Found: 313.1275.
3-(4-Fluorobenzyl)-2,3-dihydro-isoindolin-1-one, 4’ac. Colorless solid (18 mg, 0.075 mmol, 25%).
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mp 147–149 °C. H NMR (CDCl3, 400 MHz): δ 7.81 (dt, 1H, J = 7.5, 1.0 Hz, ArꢀH), 7.54 (td, 1H,
J=7.5, 1.3 Hz, ArꢀH), 7.50–7.43 (m, 1H, F ArꢀH), 7.38 (d, 1H, J = 6.0 Hz, ArꢀH), 7.29ꢀ7.26 (m, 1H),
7.17–7.10 (m, 2H), 7.01–6.92 (m, 2H), 4.97–4.67 (m, 1H), 3.15 (dd, 1H, J = 13.7, 5.6 Hz), 2.90 (dd, 1H,
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J = 13.7, 7.9 Hz). 13C NMR (CDCl3, 101 MHz): δ 170.9, 162.0 (d, J = 245 Hz), 146.7, 132.4 (d, J = 3.2
Hz), 132.1, 131.8, 131.0 (d, J = 8.1 Hz), 128.5, 124.0, 122.8, 115.6 (d, J = 21.6 Hz), 58.0, 40.4. HRMS
(ESIꢀTOF) m/z: [M+H]+ Calcd for C15H13NOF 242.0981; Found: 242.0983; [M+H+CH3CN]+ Calcd for
C17H16N2OF 283.1247; Found: 283.1242.
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3-Hydro-2-methoxy-3-(4-methylbenzyl)-isoindolin-1-one, 4ad. Colorless solid (26 mg, 0.097 mmol,
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32 %). H NMR (CDCl3, 400 MHz): δ 7.73 (ddd, 1H, J = 7.3, 1.5, 0.8 Hz), 7.47–7.34 (m, 2H), 7.05–
6.95 (m, 5H), 4.95 (dd, 1H, J = 7.7, 4.3 Hz), 3.98 (s, 3H), 3.41 (dd, 1H, J = 13.8, 4.3 Hz), 2.96 (dd, 1H,
J = 13.8, 7.7 Hz), 2.28 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 164.5, 141.7, 136.6, 132.2, 131.7, 130.0,
129.6, 129.1, 128.4, 123.7, 123.1, 63.9, 60.4, 37.3, 21.2. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C17H18NO2 268.1337; Found: 268.1328.
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2,3-Dihydro-3-(4-methylbenzyl)-isoindolin-1-one, 4’ad. Colorless solid (4 mg, 0.017 mmol, 6%). H
NMR (CDCl3, 400 MHz): δ 7.85–7.82 (m, 1H), 7.56 (td, 1H, J = 7.5, 1.2 Hz), 7.49–7.46 (m, 1H), 7.37–
7.34 (m, 1H), 7.18–7.10 (m, 4H), 6.33 (br s, 1H), 4.76 (dd, 1H, J = 9.4, 4.9 Hz), 3.22 (dd, 1H, J =13.6,
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4.9 Hz), 2.72 (dd, 1H, J = 13.6, 9.4 Hz), 2.35 (s, 3H). C NMR (CDCl3, 101 MHz): δ 170.4, 147.0,
137.0, 134.0, 131.9, 129.7, 129.2, 128.5, 124.1, 122.8, 58.3, 41.2, 21.2. HRMS (ESIꢀTOF) m/z: [M+H]+
Calcd for C16H16NO 238.1231; Found: 238.1237; [M+H+CH3CN]+ Calcd for C18H19N2O 279.1497;
Found: 279.1386.
3-Hydro-2-methoxy-3-(2-naphthylmethyl)-isoindolin-1-one, 4ae. Colorless solid (27 mg, 0.088
1
mmol, 29 %). H NMR (CDCl3, 400 MHz): δ 7.83–7.77 (m, 1H), 7.76–7.71 (m, 3H), 7.60–7.56 (m,
1H), 7.48–7.40 (m, 2H), 7.40–7.34 (m, 2H), 7.31–7.23 (m, 1H), 6.98–6.94 (m, 1H), 5.07 (dd,1H, J =7.8,
4.4 Hz), 4.01 (s, 3H), 3.63 (dd, 1H, J =13.9, 7.8 Hz), 3.14 (dd, 1H, J =13.8, 7.8 Hz). 13C NMR (CDCl3,
101 MHz): δ 164.6, 141.6, 133.4, 133.1, 132.5, 131.8, 130.0, 128.6, 128.6, 128.2, 127.8, 126.2, 125.8,
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123.8, 123.2, 63.9, 60.3, 38.8. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C20H18NO2 304.1337; Found:
304.1330.
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2,3-Dihydro-3-(2-naphthylmethyl)-isoindolin-1-one, 4’ae. Colorless solid (12 mg, 0.043 mmol, 14%).
1H NMR (CDCl3, 400 MHz): δ 7.84 (ddd, 3H, J = 8.2, 3.2, 2.1 Hz), 7.80–7.74 (m, 1H), 7.70–7.66 (m,
1H), 7.59–7.45 (m, 4H), 7.37 (ddd, 2H, J = 7.5, 4.5, 1.4 Hz), 6.73 (br s, 1H), 4.89 (dd, 1H, J = 9.1, 5.1
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Hz), 3.38 (dd, 1H, J = 13.6, 5.1 Hz), 2.95 (dd, 1H, J = 13.6, 9.1 Hz). C NMR (CDCl3, 101 MHz): δ
170.5, 147.0, 134.6, 133.6, 132.6, 132.0, 131.9, 128.8, 128.5, 128.1, 127.8, 127.7, 127.2, 126.5, 126.0,
124.1, 122.8, 58.1, 41.8. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C19H16NO 274.1231; Found:
274.1242; [M+H+CH3CN]+ Calcd for C21H19N2O315.1497; Found: 315.1387.
3-(4-Trifluoromethyl-benzyl)-3-hydro-2-methoxy-isoindolin-1-one, 4af. Colorless solid (8 mg, 0.024
mmol, 8%). 1H NMR (CDCl3, 400 MHz): δ 7.74–7.71 (m, 1H), 7.52–7.38 (m, 4H), 7.21–7.17 (m, 2H),
7.12–7.09 (m, 1H), 5.03 (dd, 1H, J = 6.7, 4.2 Hz), 3.99 (s, 3H), 3.42 (dd, 1H, J = 13.9, 4.2 Hz), 3.22
(dd, 1H, J =13.9, 6.7 Hz). 13C NMR (CDCl3, 101 MHz): δ 164.6, 141.0, 139.3, 132.0, 130.2, 130.1,
128.9, 125.3 (q, J = 3.7 Hz), 124.0, 122.8, 63.9, 59.7, 37.3. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C17H15NO2F3 322.1054; Found: 322.1056; [M+H+CH3CN]+ Calcd for C19H18N2O2F3 363.1320; Found:
363.1281.
3-(4-Trifluoromethylbenzyl)-2,3-dihydro-isoindolin-1-one, 4’af. Colorless solid (46 mg, 0.159 mmol,
53%). mp 167ꢀ168 °C. 1H NMR (CDCl3, 400 MHz): δ 7.85–7.71 (m, 2H), 7.59–7.45 (m, 4H), 7.30 (dd,
3H, J = 7.8, 6.2 Hz), 4.88–4.84 (m, 1H), 3.25 (dd, 1H, J = 13.7, 5.7 Hz), 3.02 (dd, 1H, J = 13.7, 7.6 Hz).
13C NMR (CDCl3, 101 MHz): δ 171.0, 146.5, 140.8, 132.1, 132.0, 129.9, 129.6, 129.3, 128.7, 125.6 (q,
J= 3.6 Hz), 124.0, 122.8, 57.7, 40.9. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C16H13NOF3 292.0949;
Found: 292.0950; [M+H+CH3CN]+ Calcd for C18H16N2OF3 333.1214; Found: 333.1068.
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3-Benzyl-3-hydro-2-methoxy-5-methyl-isoindolin-1-one, 4da. Colorless solid (25 mg, 0.093 mmol,
31%). 1H NMR (CDCl3, 400 MHz): δ 7.61 (d, 1H, J = 7.7 Hz), 7.25–7.15 (m, 4H), 7.12–7.07 (m, 2H),
6.79–6.76 (m, 1H), 4.92 (dd, 1H, J = 7.4, 4.5 Hz), 3.94 (s, 3H), 3.40 (dd, 1H, J =13.8, 4.5 Hz), 3.01 (dd,
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1H, J = 13.8, 7.4 Hz), 2.34 (s, 3H). C NMR (CDCl3, 101 MHz): δ 164.9, 142.4, 142.0, 135.6, 129.8,
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129.4, 128.4, 127.3, 127.0, 123.6, 63.8, 60.3, 37.8, 22.1. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C17H18NO2 268.1337; Found: 268.1324.
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3-Benzyl-2,3-dihydro-5-methyl-isoindolin-1-one, 4’da. Colorless solid (15 mg, 0.065 mmol, 22%).
mp 147–148 °C. 1H NMR (CDCl3, 400 MHz): δ 7.71 (d, 1H, J = 7.7 Hz), 7.37–7.26 (m, 4H), 7.24–7.20
(m, 2H), 7.13 (br s, 1H), 6.63–6.60 (m, 1H), 4.73 (dd, 1H, J = 9.1, 5.0 Hz), 3.22 (dd, 1H, J = 13.6, 5.0
Hz), 2.76 (dd, 1H, J = 13.6, 9.1 Hz), 2.44 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 170.0, 147.0, 142. 6,
137.2, 129.5, 129.4, 129.3, 128.9, 127.2, 123.8, 123.3, 58.0, 41.6, 22.1. HRMS (ESIꢀTOF) m/z: [M+H]+
Calcd for C16H16NO 238.1231; Found: 238.1229; [M+H+CH3CN]+ Calcd for C18H19N2O 279.1497;
Found: 279.1414.
3-(4-Chlorobenzyl)-3-hydro-2-methoxy-5-methyl-isoindolin-1-one, 4db. Colorless solid (20 mg,
1
0.066 mmol, 22%). H NMR (CDCl3, 400 MHz): δ 7.60 (d, 1H, J = 7.7 Hz), 7.23–7.14 (m, 3H), 7.02–
6.97 (m, 2H, ArꢀH), 6.92–6.89 (m, 1H), 4.92 (dd, 1H, J = 6.5, 4.3 Hz), 3.95 (s, 3H), 3.29 (dd, 1H, J =
13.9, 4.3 Hz), 3.12 (dd, 1H, J = 14.0, 6.5 Hz), 2.39 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 164.9,
142.7, 141.5, 133.8, 132.9, 131.2, 129.7, 128.5, 127.4, 123.8, 123.3, 63.8, 59.8, 36.9, 22.2. HRMS (ESIꢀ
TOF) m/z: [M+H]+ Calcd for C17H17NO2Cl 302.0947; Found: 302.0933; [M+H+CH3CN]+ Calcd for
C19H20N2O2Cl 343.1213; Found: 343.1199.
3-(4-Fluorobenzyl)-3-hydro-2-methoxy-5-methyl-isoindolin-1-one, 4dc. Colorless solid (21 mg,
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0.073 mmol, 24%). mp 95–96 °C. H NMR (CDCl3, 400 MHz): δ 7.57 (d, 1H, J = 7.8 Hz), 7.18 (ddt,
1H, J = 7.8, 1.5, 0.7 Hz), 7.04–6.96 (m, 2H), 6.91–6.82 (m, 3H), 4.91 (dd, 1H, J = 6.6, 4.3 Hz), 3.94 (s,
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3H), 3.29 (dd, 1H, J = 14.0, 4.3 Hz), 3.10 (dd, 1H, J = 14.0, 6.6 Hz), 2.37 (s, 3H). C NMR (CDCl3,
101 MHz): δ 164.7, 162.0 (d, J = 245 Hz), 142.4, 141.5, 131.3 (d, J = 8.0 Hz), 130.8, 129.4, 127.3,
123.6, 123.3, 115.1 (d, J = 21 Hz), 63.6, 59.8, 36.6, 22.0. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C17H17NO2F 286.1243; Found: 286.1237; [M+H+CH3CN]+ Calcd for C19H20N2O2F 327.1509; Found:
327.1559.
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3-(4-Fluorobenzyl)-2,3-dihydro-5-methyl-isoindolin-1-one, 4’dc. Colorless solid (10 mg, 0.039
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mmol, 13%). mp 191–193 °C. H NMR (CDCl3, 400 MHz): δ 7.69 (d, 1H, J = 7.8 Hz), 7.31–7.24 (m,
1H), 7.19–7.10 (m, 3H), 7.01–6.93 (m, 3H), 4.73 (dd, 1H, J = 8.5, 5.2 Hz), 3.18 (dd, 1H, J = 13.7, 5.2
13
Hz), 2.81 (dd, 1H, J =13.7, 8.5 Hz), 2.45 (s, 3H). C NMR (CDCl3, 101 MHz): δ 170.8, 162.1 (d, J =
245 Hz), 147.2, 142.6, 132.7 (d, J = 3.2 Hz), 130.9 (d, J = 7.9 Hz), 129.6, 129.5, 123.8, 123.3, 115.7 (d,
J = 22 Hz), 57.9, 40.6, 22.1. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C16H15NOF 256.1137; Found:
256.1151; [M+H+CH3CN]+ Calcd for C18H18N2OF 297.1403; Found: 297.1427.
3-Hydro-2-methoxy-5-methyl-3-(4-methylbenzyl)-isoindolin-1-one, 4dd. Colorless solid (22 mg,
1
0.078 mmol, 26%). H NMR (CDCl3, 400 MHz): δ 7.61 (d, 1H, J = 7.8 Hz), 7.20–7.17 (m, 1H), 7.05–
6.96 (m, 4H), 6.82–6.79 (m, 1H), 4.89 (dd, 1H, J = 7.4, 4.4 Hz), 3.95 (s, 3H), 3.36 (dd, 1H, J =13.8, 4.4
13
Hz), 2.98 (dd, 1H, J =13.8, 7.4 Hz), 2.36 (s, 3H), 2.28 (s, 3H). C NMR (CDCl3, 101 MHz): δ 165.0,
142.4, 142.1, 136.5, 132.4, 129.7, 129.4, 129.1, 127.4, 123.6, 63.8, 60.4, 37.4, 22.1, 21.2. HRMS (ESIꢀ
TOF) m/z: [M+H]+ Calcd for C18H20NO2 282.1494; Found: 282.1485; [M+Na+CH3CN]+ Calcd for
C20H22N2O2Na 345.1579; Found: 345.1548.
2,3-Dihydro-5-methyl-3-(4-methylbenzyl)isoindolin-1-one, 4’dd. Colorless solid (8 mg, 0.031 mmol,
10%). mp 165–166 °C. 1H NMR (CDCl3, 400 MHz): δ 7.72 (d, 1H, J = 7.8 Hz), 7.28 (ddd, 1H, J = 8.4,
1.4, 0.6 Hz), 7.21–7.18 (m, 1H), 7.18– 7.10 (m, 4H), 6.15 (br s, 1H), 4.70 (dd, 1H, J = 9.8, 4.5 Hz),
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3.30–3.15 (m, 1H), 2.64 (dd, 1H, J =13.6, 9.8 Hz), 2.46 (s, 3H), 2.35 (s, 3H). C NMR (CDCl3, 101
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MHz): δ 170.4, 147.5, 142.6, 136.9, 134.3, 129.7, 129.5, 129.4, 129.1, 123.8, 123.2, 58.1, 41.3, 22.1,
21.2. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C17H18NO 252.1388; Found: 252.1400;
[M+H+CH3CN]+ Calcd for C19H21N2O 293.1654; Found: 293.1678.
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3-Hydro-2-methoxy-5-methyl-3-(2-naphthylmethyl)-isoindolin-1-one, 4de. Colorless solid (28 mg,
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0.088 mmol, 29%). H NMR (CDCl3, 400 MHz): δ 7.82–7.71 (m, 3H), 7.64–7.57 (m, 2H), 7.48–7.41
(m, 2H), 7.28–7.25 (m, 1H), 7.18 (ddt, 1H, J = 7.8, 1.5, 0.7 Hz), 6.81–6.78 (m, 1H), 5.01 (dd, 1H, J =
7.5, 4.6 Hz), 3.97 (s, 3H), 3.57 (dd, 1H, J = 13.8, 4.6 Hz), 3.16 (dd, 1H, J = 13.8, 7.5 Hz), 2.31 (s, 3H).
13C NMR (CDCl3, 101 MHz): δ 165.0, 142.5, 142.1, 133.4, 133.3, 132.5, 129.5, 128.6, 128.1, 127.8,
127.7, 127.3, 126.2, 125.8, 123.7, 123.6, 63.9, 60.3, 38.1, 22.1. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd
for C21H20NO2 318.1494; Found: 318.1482.
2,3-Dihydro-5-methyl-3-(2-naphthylmethyl)-isoindolin-1-one, 4’de. Colorless solid (14 mg, 0.048
mmol, 16%). mp 179–180 °C. 1H NMR (CDCl3, 400 MHz): δ 7.83 (dd, 2H, J = 9.0, 2.8 Hz), 7.80–7.75
(m, 1H), 7.72 (d, 1H, J = 7.8 Hz), 7.69–7.66 (m, 1H), 7.53–7.44 (m, 2H), 7.37 (dd, 1H, J = 8.4,1.8 Hz),
7.29 (dd, 1H, J = 7.8, 1.3 Hz), 7.21 (dd, 1H, J = 1.5, 0.8 Hz), 6.51 (br s, 1H), 4.82 (dd, 1H, J = 9.5, 4.7
13
Hz), 3.41 (dd, 1H, J=13.6, 4.7 Hz), 2.87 (dd, 1H, J=13.6, 9.5 Hz), 2.46 (s, 3H). C NMR (CDCl3, 101
MHz): δ 170.5, 147.5, 142.7, 134.8, 133.7, 132.6, 129.6, 129.4, 128.7, 128.0, 127.8, 127.7, 127.2,
126.5, 126.0, 123.9, 123.2, 58.0, 41.9, 22.1. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C20H18NO
288.1388; Found: 288.1378; [M+H+CH3CN]+ Calcd for C22H21N2O 329.1654; Found: 329.1651;
[M+Na+CH3CN]+ Calcd forC22H20N2ONa 351.1473; Found: 351.1459.
3-Benzyl-3-hydro-2-methoxy-6-methyl-isoindolin-1-one, 4ga. Colorless solid (27 mg, 0.102 mmol,
34%). mp 105–106 °C. 1H NMR (CDCl3, 400 MHz): δ 7.54–7.52(m, 1H), 7.25–7.17 (m, 4H), 7.12–7.08
(m, 2H), 6.83 (d, 1H, J = 7.7Hz), 4.92 (dd, 1H, J = 7.6, 4.4 Hz), 3.96 (s, 3H), 3.42 (dd, 1H, J = 13.7, 4.4
Hz), 2.96 (dd, 1H, J = 13.7, 7.6 Hz), 2.35 (s, 3H).13C NMR (CDCl3, 101 MHz): δ 164.7, 138.8, 138.5,
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135.6, 132.6, 132.6, 129.8, 128.4, 126.9, 123.9, 122.8, 63.8, 60.2, 37.8, 21.4. HRMS (ESIꢀTOF) m/z:
[M+H]+ Calcd for C17H18NO2 268.1337; Found: 268.1342; [M+Na+CH3CN]+ Calcd forC19H20N2O2
Na333.1422; Found: 331.1426.
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3-Benzyl-2,3-dihydro-6-methyl-isoindolin-1-one, 4’ga. Colorless solid (17 mg, 0.069 mmol, 23%).
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mp 131–133 °C. H NMR (CDCl3, 400 MHz): δ 7.65–7.62(m, 1H), 7.40–7.26 (m, 4H), 7.25–7.17 (m,
3H), 6.58 (br s, 1H), 4.75 (dd, 1H, J = 9.1, 5.2 Hz), 3.19 (dd, 1H, J = 13.6, 5.2 Hz), 2.78 (dd, 1H, J =
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13.6, 9.1 Hz), 2.44 (s, 3H). C NMR (CDCl3, 101 MHz): δ 170.6, 144.3, 138.5, 137.2, 133.7, 132.9,
132.1, 129.3, 129.0, 127.2, 124.2, 122.5, 57.9, 41.7, 21.5. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C16H16NO 238.1231; Found: 238.1229; [M+H+CH3CN]+ Calcd for C18H19N2O279.1497; Found:
279.1508; [M+Na+CH3CN]+ Calcd forC18H18N2ONa 301.1317; Found: 301.1316.
3-(4-Chlorobenzyl)-3-hydro-2-methoxy-6-methyl-isoindolin-1-one, 4gb. Colorless solid (24 mg,
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0.079 mmol, 26%). H NMR (CDCl3, 400 MHz): δ 7.55–7.52 (m, 1H), 7.29–7.26 (m, 1H), 7.19–7.14
(m, 2H), 7.04–6.92 (m, 3H), 4.93 (dd, 1H, J = 6.9, 4.2 Hz), 3.97 (s, 3H), 3.33 (dd, 1H, J = 13.9, 4.2 Hz),
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3.06 (dd, 1H, J = 13.9, 6.9 Hz), 2.38 (s, 3H). C NMR (CDCl3, 101 MHz): δ 164.58, 138.7, 138.2,
133.6, 132.8, 132.7, 131.1, 130.0, 128.4, 124.1, 122.5, 63.7, 59.6, 36.8, 21.4. HRMS (ESIꢀTOF) m/z:
[M+H]+ Calcd for C17H17NO2Cl 302.0947; Found: 302.0939; [M+H+CH3CN]+ Calcd for C19H20N2O2Cl
343.1213; Found: 343.1205; [M+Na+CH3CN]+ Calcd forC19H19N2O2ClNa 365.1033; Found: 365.1009.
3-Hydro-2-methoxy-5-methyl-3-(4-methylbenzyl)-isoindolin-1-one, 4gd. Colorless solid (40 mg,
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0.142 mmol, 47 %). H NMR (CDCl3, 400 MHz): δ 7.55–7.52 (m, 1H), 7.23–7.21 (m, 1H), 7.05–6.96
(m, 4H), 6.84 (d, 1H, J = 7.8 Hz), 4.89 (dd, 1H, J = 7.8, 4.3 Hz), 3.97 (s, 3H), 3.40 (dd, 1H, J = 13.7, 4.3
13
Hz), 2.90 (dd, 1H, J = 13.7, 7.8 Hz), 2.36 (s, 3H), 2.28 (s, 3H). C NMR (CDCl3, 101 MHz): δ 164.8,
138.9, 138.5, 136.5, 132.6, 132.4, 130.0, 129.6, 129.1, 124.0, 122.9, 63.8, 60.3, 37.4, 21.4, 21.2. HRMS
(ESIꢀTOF) m/z: [M+H]+ Calcd for C18H20NO2 282.1494; Found: 282.1497.
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2,3-Dihydro-6-methyl-3-(4-methylbenzyl)-isoindolin-1-one, 4’gd. Colorless solid (7 mg, 0.027 mmol,
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9%). H NMR (CDCl3, 400 MHz): δ 7.65–7.63 (m, 1H), 7.38–7.33 (m, 1H), 7.22 (d, 1H, J = 7.8 Hz),
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7.17–7.10 (m, 4H), 6.36 (br s, 1H), 4.72 (dd, 1H, J = 9.3, 5.0 Hz), 3.20–3.14 (m, 1H), 2.70 (dd, 1H, J
=13.6, 9.3 Hz), 2.44 (s, 3H), 2.35 (s, 3H).13C NMR (CDCl3, 101 MHz): δ 170.5, 144.4, 138.5, 136.9,
134.2, 132.9, 132.1, 129.7, 129.2, 124.2, 122.5, 58.1, 41.3, 21.5, 21.2. HRMS (ESIꢀTOF) m/z: [M+H]+
Calcd for C17H18NO 252.1388; Found: 252.1393; [M+H+CH3CN]+ Calcd for C19H21N2O 293.1654;
Found: 293.1649; [M+Na+CH3CN]+Calcd forC19H20N2ONa 315.1473; Found: 315.1470.
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3-Hydro-2-methoxy-6-methyl-3-(2-naphthylmethyl)-isoindolin-1-one, 4ge. Colorless solid (34 mg,
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0.107 mmol, 36%). H NMR (CDCl3, 400 MHz): δ 7.82–7.72 (m, 3H), 7.60–7.53 (m, 2H), 7.47–7.41
(m, 2H), 7.31–7.24 (m, 2H), 7.18 (ddd, 1H, J = 7.9, 1.7, 0.8 Hz), 6.81 (d, 1H, J = 7.7 Hz), 5.02 (dd, 1H,
J = 7.9, 4.5 Hz), 3.99 (s, 3H), 3.62 (dd, 1H, J = 13.8, 4.5 Hz), 3.09 (dd, 1H, J = 13.8, 7.9 Hz), 2.34 (s,
3H). 13C NMR (CDCl3, 101 MHz): δ 164.8, 138.9, 138.6, 133.4, 133.3, 132.7, 132.5, 129.9, 128.6,
128.1, 127.8, 127.7, 126.2, 125.8, 124.1, 122.9, 63.9, 60.2, 38.1, 21.4. HRMS (ESIꢀTOF) m/z: [M+H]+
Calcd for C21H20NO2 318.1494; Found: 318.1495.
2,3-Dihydro-6-methyl-3-(2-naphthylmethyl)-isoindolin-1-one, 4’ge. Colorless solid (6 mg, 0.020
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mmol, 7%). mp 159–160 °C. H NMR (CDCl3, 400 MHz): δ 7.88–7.76 (m, 3H), 7.71–7.63 (m, 2H),
7.53–7.45 (m, 2H), 7.42–7.33 (m, 2H), 7.25 (d, 1H, J = 7.7 Hz), 6.42 (br s, 1H), 4.84 (dd, 1H, J = 9.4,
5.0 Hz), 3.37 (dd, 1H, J = 13.6, 5.0 Hz), 2.90 (dd, 1H, J =13.6, 9.4 Hz), 2.45 (s, 3H). 13C NMR (CDCl3,
101 MHz): δ 170.5, 144.3, 138.6, 134.8, 133.7, 133.0, 132.6, 132.1, 128.8, 128.1, 127.9, 127.7, 127.3,
126.5, 126.0, 124.3, 122.5, 58.0, 42.0, 21.5. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C20H18NO
288.1388; Found: 288.1400; [M+H+CH3CN]+ Calcd for C22H21N2O 329.1653; Found: 329.1673;
[M+Na+CH3CN]+ Calcd forC22H20N2ONa 351.1473 Found: 351.1480.
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3-(4-Trifluoromethyl-benzyl)-3-hydro-2-methoxy-6-methyl-isoindolin-1-one, 4gf. Colorless solid
(23 mg, 0.069 mmol, 23%).1H NMR (CDCl3, 400 MHz): δ 7.54–7.51 (m, 1H), 7.47–7.43 (m, 2H), 7.28
(ddd, 1H, J = 7.7, 1.7, 0.8 Hz), 7.21–7.16 (m, 2H), 6.96 (d, 1H, J = 7.8 Hz), 4.98 (dd, 1H, J = 6.8, 4.3
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Hz), 3.97 (s, 3H), 3.44–3.36 (m, 1H), 3.17 (dd, 1H, J = 13.8, 6.8 Hz), 2.37 (s, 3H). C NMR (CDCl3,
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101 MHz): δ 164.7, 139.5, 139.0, 138.2, 132.9, 131.0, 130.2, 130.1, 125.3 (q, J = 3.6 Hz), 124.3, 124.2,
122.6, 63.8, 59.6, 37.4, 21.5. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C18H17NO2F3 336.1211; Found:
336.1205; [M+H+CH3CN]+ Calcd for C20H20N2O2F3 377.1477; Found: 377.1468.
3-(4-Trifluoromethyl-benzyl)-2,3-dihydro-6-methyl-isoindolin-1-one, 4’gf. Colorless solid (27 mg,
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0.087 mmol, 30%). H NMR (CDCl3, 400 MHz): δ 7.63–7.60 (m, 1H), 7.56 (d, 2H, J = 7.9 Hz), 7.37
(ddd, 1H, J =7.8, 1.7, 0.8 Hz), 7.32 (d, 2H, J = 8.0 Hz), 7.20 (d, 1H, J = 7.7 Hz), 6.89 (s, 1H), 4.79 (dd,
1H, J = 8.3, 5.3 Hz), 3.25 (dd, 1H, J = 13.6, 5.3 Hz), 2.91 (dd, 1H, J = 13.6, 8.3 Hz), 2.44 (s, 3H).13C
NMR (CDCl3, 101 MHz): δ 170.8, 143.8, 141.1, 138.9, 133.1, 132.1, 129.8, 125.8 (q, J = 3.7 Hz),
125.6, 124.4, 122.4, 57.5, 41.3, 21.5. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C17H15NOF3306.1105;
Found: 306.1115; [M+H+CH3CN]+ Calcd for C19H18N2OF3 347.1371; Found: 347.1367.
3-Benzyl-3-hydro-2,6-dimethoxy-isoindolin-1-one, 4ha. Colorless solid (21 mg, 0.072 mmol, 23%).
mp 100–101 °C. 1H NMR (CDCl3, 400 MHz): δ 7.25–7.19 (m, 3H), 7.12–7.08 (m, 2H), 6.97 (dd, 1H, J
= 8.4, 2.5 Hz), 6.83 (dt, 1H, J = 8.4, 0.6 Hz), 4.91 (ddd, 1H, J = 7.7, 4.3, 0.7 Hz), 3.98 (s, 3H), 3.79 (s,
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3H), 3.43 (dd, 1H, J = 13.7, 4.3 Hz), 2.95 (dd, 1H, J = 13.7, 7.7 Hz). C NMR (CDCl3, 101 MHz):
δ 164.5, 160.0, 135.4, 133.7, 131.2, 129.7, 128.4, 126.9, 124.1, 119.8, 106.6, 63.8, 60.0, 55.6, 37.8.
HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C17H18NO3 284.1286; Found: 284.1276.
3-Benzyl-2,3-dihydro-6-methoxy-isoindolin-1-one, 4’ha. Colorless solid (23 mg, 0.091 mmol, 29%).
1H NMR (CDCl3, 400 MHz): δ 7.39–7.28 (m, 4H), 7.26–7.21 (m, 3H), 7.11 (dd, 1H, J = 8.3, 2.5 Hz),
6.15 (br s, 1H), 4.71–4.75 (m, 1H), 3.86 (s, 3H), 3.22 (dd, 1H, J = 13.4, 5.0 Hz), 2.72 (dd, 1H, J = 13.5,
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9.4 Hz). C NMR (CDCl3, 101 MHz): δ 170.1, 160.2, 139.1, 137.1, 133.2, 129.1, 128.9, 127.2, 123.5,
120.3, 106.5, 57.6, 55.7, 41.7. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C16H16NO2 254.1181; Found:
254.1179; [M+H+CH3CN]+ Calcd for C18H19N2O2 295.1446; Found: 295.1449; [M+Na+CH3CN]+ Calcd
for C18H18N2O2Na 317.1266; Found: 317.1256.
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3-Hydro-2,5-dimethoxy-3-(4-methylbenzyl)-isoindolin-1-one, 4hd. Colorless solid (33 mg, 0.111
mmol, 37 %). 1H NMR (CDCl3, 400 MHz): δ 7.23 (d, 1H, J = 2.4Hz), 7.05–6.95 (m, 5H), 6.85–6.82 (m,
1H), 4.88 (ddd, 1H, J = 7.8, 4.2, 0.7 Hz), 3.98 (s, 3H), 3.79 (s, 3H), 3.39 (dd, 1H, J =13.7, 4.2 Hz), 2.90
(dd, 1H, J =13.7, 7.8 Hz), 2.28 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 164.6, 160.1, 136.5, 133.9,
132.3, 131.3, 129.7, 129.2, 124.2, 119.8, 106.6, 63.9, 60.1, 55.7, 37.5, 21.2. HRMS (ESIꢀTOF) m/z:
[M+H]+ Calcd for C18H20NO3 298.1443; Found: 298.1452.
2,3-Dihydro-6-methoxy-3-(4-Methylbenzyl)-isoindolin-1-one, 4’hd. Colorless solid (8 mg, 0.029
mmol, 10%). mp 147–148 °C. 1H NMR (CDCl3, 400 MHz): δ 7.31 (d, 1H, J = 2.4 Hz), 7.21 (d, 1H, J =
8.3Hz), 7.17 –7.08 (m, 5H), 6.37 (br s, 1H), 4.74–4.65 (m, 1H), 3.86 (s, 3H), 3.20–3.11 (m, 1H), 2.71
(dd, 1H, J = 13.6, 9.2 Hz), 2.35 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 170.3, 160.3, 139.4, 136.9,
134.1, 133.3, 129.7, 129.2, 123.7, 120.3, 106.6, 77.5, 77.2, 76.8, 57.9, 55.8, 41.3, 21.2. HRMS (ESIꢀ
TOF) m/z: [M+H]+ Calcd for C17H18NO2 268.1337; Found: 268.1344; [M+H+CH3CN]+ Calcd for
C19H21N2O2 309.1603; Found: 309.1613; [M+Na+CH3CN]+ Calcd for C19H20N2O2Na 331.1422 Found:
331.1424.
3-Hydro-2,6-dimethoxy-3-(2-naphthylmethyl)-isoindolin-1-one, 4he. Colorless solid (35 mg, 0.105
mmol, 35%). 1H NMR (CDCl3, 400 MHz): δ 7.83–7.71 (m, 3H), 7.58 (d, 1H, J = 1.8 Hz), 7.48–7.40 (m,
2H), 7.30–7.20 (m, 3H), 6.93 (dd, 1H, J = 8.4, 2.5Hz), 6.81 (dt, 1H, J = 8.3, 0.6 Hz), 5.01 (ddd, 1H, J =
7.9, 4.4, 0.7 Hz), 4.01 (s, 3H), 3.77 (s, 3H), 3.61 (dd, 1H, J = 13.7, 4.4 Hz), 3.09 (dd, 1H, J = 13.7, 7.9
Hz). 13C NMR (CDCl3, 101 MHz): δ 164.7, 160.1, 133.8, 133.4, 133.2, 132.5, 131.3, 128.6, 128.1,
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127.8, 127.7, 126.2, 125.8, 124.2, 119.9, 106.7, 63.9, 60.1, 55.7, 38.2. HRMS (ESIꢀTOF) m/z: [M+H]+
Calcd for C21H20NO3 334.1443; Found: 334.1428; [M+H+CH3CN]+ Calcd for C23H23N2O3 375.1708;
Found: 375.1662.
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2,3-Dihydro-6-methoxy-3-(2-naphthylmethyl)-isoindolin-1-one, 4’he. Colorless solid (8 mg, 0.026
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mmol, 9%). mp 212–215 °C. H NMR (CDCl3, 400 MHz): δ 7.89–7.76 (m, 3H), 7.68 (d, 1H, J = 1.7
Hz), 7.55–7.45 (m, 2H), 7.38 (dd, 1H, J = 8.4, 1.8 Hz), 7.33 (d, 1H, J = 2.4 Hz), 7.25–7.20 (m, 1H),
7.11 (dd, 1H, J = 8.3, 2.5Hz), 6.43 (br s, 1H), 4.83 (ddd, 1H, J = 9.2, 5.1, 0.9 Hz), 3.86 (s, 3H), 3.36 (dd,
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1H, J = 13.6, 5.1 Hz), 2.91 (dd, 1H, J = 13.6, 9.2Hz). C NMR (CDCl3, 101 MHz): δ 170.3, 160.4,
139.3, 134.7, 133.7, 133.3, 132.6, 128.8, 128.1, 127.9, 127.7, 127.2, 126.6, 126.1, 123.7, 120.4, 106.7,
57.8, 55.8, 42.0. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C20H18NO2 304.1337; Found: 304.1333;
[M+Na+CH3CN]+ Calcd for C20H17NO2Na 326.1157; Found: 326.1151.
3-(4-Chlorobenzyl)-3-hydro-2,5-dimethoxy-isoindolin-1-one, 4ib. Colorless solid (18 mg, 0.057
mmol, 19%). 1H NMR (CDCl3, 400 MHz): δ 7.65 (d, 1H, J = 8.4Hz), 7.22–7.16 (m, 2H), 7.07–7.01 (m,
2H), 6.91 (dd, 1H, J = 8.4, 2.3 Hz), 6.59–6.46 (m, 1H), 4.90 (dd, 1H, J = 7.0, 4.4 Hz), 3.96 (s, 3H), 3.78
(s, 3H), 3.33 (dd, 1H, J = 13.9, 4.4 Hz), 3.07 (dd, 1H, J = 13.9, 7.0 Hz). 13C NMR (CDCl3, 101 MHz):
δ 165.1, 162.9, 143.5, 133.8, 133.0, 131.2, 128.6, 125.6, 122.4, 114.8, 108.3, 63.9, 60.0, 55.7, 37.1.
HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C17H17NO3Cl 318.0896; Found: 318.0905.
3-Hydro-2,5-dimethoxy-3-(4-methylbenzyl)-isoindolin-1-one, 4id. Colorless solid (25 mg, 0.084
mmol, 28%). 1H NMR (CDCl3, 400 MHz): δ 7.66 (d, 1H, J = 8.4 Hz), 7.08–6.99 (m, 4H), 6.90 (dd, 1H,
J = 8.4, 2.3 Hz), 6.41–6.38 (m, 1H), 4.86 (dd, 1H, J = 8.0, 4.4 Hz), 3.96 (s, 3H), 3.72 (s, 3H), 3.42 (dd,
1H, J = 13.7, 4.4 Hz), 2.91 (dd, 1H, J = 13.7, 8.0 Hz), 2.29 (s, 3H). 13C NMR (CDCl3, 101 MHz):
δ 165.2, 162.8, 144.1, 136.6, 132.5, 129.7, 129.2, 125.3, 122.3, 115.0, 108.3, 64.0, 60.6, 55.6, 37.5,
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21.2. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C18H20NO3 298.1443; Found: 298.1437;
[M+Na+CH3CN]+ Calcd for C20H22N2O3Na 361.1528; Found: 361.1526.
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2,3-Dihydro-5-methoxy-3-(4-methylbenzyl)-isoindolin-1-one, 4’id. Colorless solid (10 mg, 0.037
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mmol, 12%). mp 181–182 °C. H NMR (CDCl3, 400 MHz): δ 7.74 (d, 1H, J = 8.4 Hz), 7.19–7.09 (m,
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4H), 6.98 (dd, 1H, J = 8.4, 2.2Hz), 6.81–6.76 (m, 1H), 6.31 (br s, 1H), 4.69 (dd, 1H, J = 9.2, 5.1 Hz),
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3.84 (s, 3H), 3.15 (dd, 1H, J = 13.5, 5.1 Hz), 2.74 (dd, 1H, J = 13.5, 9.2 Hz), 2.34 (s, 3H). C NMR
(CDCl3, 101 MHz): δ 170.3, 163.0, 149.4, 136.9, 134.0, 129.7, 129.2, 125.4, 124.5, 115.1, 107.6, 58.0,
55.7, 41.3, 21.2. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C17H18NO2 268.1337; Found: 268.1344;
[M+H+CH3CN]+ Calcd for C19H21N2O2 309.1603; Found: 309.1610; [M+Na+CH3CN]+ Calcd for
C19H20N2O2Na 331.1422 Found: 331.1451.
3-(4-Trifluoromethyl-benzyl)-3-hydro-2,5-dimethoxy-isoindolin-1-one 4if. Colorless solid (45 mg,
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0.128 mmol, 43%). H NMR (CDCl3, 400 MHz): δ 7.62 (d, 1H, J = 8.4 Hz), 7.45 (d, 2H, J = 8.0 Hz),
7.21 (d, 2H, J = 8.0 Hz), 6.89 (dd, 1H, J = 8.5, 2.3 Hz), 6.51 (d, 1H, J = 2.3 Hz), 4.94 (dd, 1H, J =6.8,
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4.4 Hz), 3.94 (s, 3H), 3.75 (s, 3H), 3.39 (dd, 1H, J =14.0, 4.4 Hz), 3.17 (dd, 1H, J = 14.0, 6.8 Hz). C
NMR (CDCl3, 101 MHz): δ 165.1, 163.0, 143.3, 139.5, 130.2, 125.6, 125.3 (q, J= 3.6 Hz), 125.0, 122.2,
115.0, 108.2, 63.9, 59.8, 55.6, 37.5. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C18H17NO3F3 352.1160;
Found: 352.1154; [M+H+CH3CN]+ Calcd for C20H20N2O3F3 393.1426; Found: 393.1397.
3-(4-Trifluoromethyl-benzyl)-2,3-dihydro-5-methoxy-isoindolin-1-one, (4’if). Colorless solid (8 mg,
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0.024 mmol, 8%). mp 142–143 °C. H NMR (CDCl3, 400 MHz): δ 7.75 (d, 1H, J = 8.4 Hz), 7.63–7.57
(m, 2H), 7.38–7.33 (m, 2H), 7.00 (dd, 1H, J = 8.5, 2.2 Hz), 6.80–6.75 (m, 1H), 6.32 (br s, 1H), 4.94 (dd,
1H, J = 10.9, 2.4 Hz), 3.85 (s, 3H), 3.27 (dd, 1H, J = 13.6, 5.1 Hz), 2.89 (dd, 1H, J =13.6, 8.8 Hz). 13C
NMR (CDCl3, 101 MHz): δ 170.3, 163.2, 148.8, 141.1, 129.8, 125.9 (q, J = 3.6 Hz), 125.6, 124.4,
115.2, 107.7, 57.3, 55.8, 41.5. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C17H15NO2F3 322.1055;
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