Copper-catalyzed C(sp3)-oh cleavage with concomitant c-c coupling: Synthesis of 3-substituted isoindolinones

Article abstract of DOI:10.1021/jo502446k

Copper(II) trifluoromethanesulfonate (Cu(OTf)₂) efficiently catalyzes the C-C coupling of 3-hydoxyisoindolinones with a variety of aryl-, heteroaryl-, and alkenylboronic acids to furnish C(3) aryl-, heteroaryl-, and alkenyl-substituted isoindolinones. The coupling reactions work smoothly in 1,2-dicholoroethane (DCE) reflux, to effect both inter- and intramolecular versions. This is the first report on C(sp³)-OH cleavage with concomitant C-C coupling. The photolabile 2-nitrobenzyl protecting group is most appropriate for promotion of the coupling reaction and for deprotection. The tetracyclic ring motif of the alkaloid neuvamine was prepared by applying the newly developed copper-catalyzed C-C coupling.

Full text of DOI:10.1021/jo502446k

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Article
Copper catalyzed C(sp3)-OH cleavage with concomitant
C-C coupling: Synthesis of 3-substituted isoindolinone
H. Surya Prakash Rao, and Avula Veera Bhadra Rao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502446k • Publication Date (Web): 08 Jan 2015
Downloaded from http://pubs.acs.org on January 11, 2015
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Copper catalyzed C(sp3)-OH cleavage with concomitant C-C coupling:
Synthesis of 3-substituted isoindolinones
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H. Surya Prakash Rao,* A. Veera Bhadra Rao
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Department of Chemistry, Pondicherry University, Pondicherry – 605 014. India
E.mail: hspr.che@pondiuni.edu.in; Telephone: +914132654411; Fax: +914132656230
http://www.pondiuni.edu.in/
Graphical Abstract
Abstract: Copper(II) trifluoromethanesulfonate (Cu(OTf)2) efficiently catalyzes CꢀC coupling of
3ꢀhydoxyisoindolinones with a variety of aryl/heteroaryl/alkenyl boronic acids to furnish C(3)
aryl/heteroaryl/alkenyl substituted isoindolinones. The coupling reactions work smoothly in 1,2ꢀ
dicholoroethane (DCE) reflux, to effect both interꢀ and intraꢀmolecular versions. This is the first
report on C(sp3)ꢀOH cleavage with concomitant CꢀC coupling. Photolabile 2ꢀnitrobenzyl
protecting group is most appropriate to promote the coupling reaction and for the deprotection.
Tetracyclic ring motif of the alkaloid neuvamine was prepared by applying newly developed
copper catalyzed CꢀC coupling.
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Introduction
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Unlike indole, its isomer, isoindole (2Hꢀisoindole) is not a common structural element in
natural products.1 However, bioactive molecules built around isoindole structure are considered
privileged due their multifarious medicinal properties.2 Amongst isoindoles, the C(3) substituted
isoindolinones occur as a part structure in a few alkaloids. Representative examples of such
isoindole alkaloids are nuevamine 1, the first known isoindoloisoquinoline alkaloid and
lennoxamine 2, an isoindolobenzazepine alkaloid, both of which have been isolated from
Berberis darwinii (Figure 1).3 Pestalachloride A 3, an antifungal alkaloid isolated from an
endophytic fungus Pestalotiopsis adust4 and taliscanine 4, an antiparkinson alkaloid isolated
from the rhizomes of Aristolochia taliscana,5 are other examples of alkaloids with C(3)
substituted isoindole structure (Figure 1). Besides medicinally important alkaloids listed above,
some central nervous system (CNS) active drug candidates like (S)ꢀpazinaclone 5 and (R)ꢀPD
172939 66 possess C(3) substituted isoindole structure (Figure 1). Apart from these two drug
candidates, the C(3)ꢀsubstituted isoindolinones exhibit varied biological activities that include
antipsychotic,7 antihypertensive,8 antiulcer9 and anxiolytic10 properties. In view of importance of
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isoindolinones, there have been hectic synthetic efforts towards these coveted structures.11
O
NH
O
MeO
OMe
N
N
O
O
OH
HO
O
N
O
N
N
MeO
MeO
N
O
NH
Cl
NH
N
MeO
OMe
Cl
N
O
HO
OMe
Me
O
Me
Cl
Me
O
O
O
O
Me
Me
OMe
3 (Pestalachloride A)
4 (Taliscanine)
5 ((S)ꢀPazinaclone)
6 ((R)ꢀPD 172939)
1 (Nuevamine)
2 (Lennoxamine)
Figure 1. Examples of naturally occurring (1 ꢀ 4) and biologically active (5 and 6) C(3)
substituted isoindolinones
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The C(3) substituted isoindolinones 9 can be viewed as derivatives of phthalimide.
Generally they have been synthesized from their hydroxy counterparts 7 by SN1 substitution at
hydroxy carbon with electron rich aromatic compounds (carbon nucleophiles; Scheme 1). Due to
poor leaving ability of the hydroxy group, strong protic acids like triflic acid,12 trifluoroacetic
acid,13 conc. H2SO4, 14 conc. HCl15 or Lewis acids like Bi(OTf)3,16 Sn(NTf2)4,17 IrꢀSn3 bimetallic
complexes, 18 gold catalysts19 have been employed to generate iminium ion 8, for quenching with
electronꢀrich aromatic compounds or nucleophiles. Such reactions are generally conducted on 7
having a nitrogen protecting group (PG). Indeed, most of the researchers till date took recourse
to robust benzyl as nitrogen PG, but benzyl group is difficult to remove without destroying the
isoindolinone ring. Overall, existing methods are beleaguered with several drawbacks like
requirement of (i) concentrated protic acids or Lewis acids, (ii) electron rich aromatic
compounds to quench acyl iminium ion and (iii) protecting group that cannot be removed
without affecting the isoindolinone ring. Thus, there is a need to discover conditions for facile
replacement of the hydroxyl group in 7 with electron deficient aromatic, heteroaromatic, or
alkenyl groups through CꢀC coupling without going through acyl iminium ion 8. Furthermore,
there is a need for a PG on nitrogen of the isoindolinone ring, which can be removed under nonꢀ
hydrogenating, neutral and milder reaction conditions. Towards this goal, we resolved to develop
suitable copperꢀcatalyzed CꢀC coupling reactions and suitable PG for synthesis of C(3)
substituted isoindolinones.
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Scheme 1. The existing method for substitution of the OH group in 7 to form 9 and the proposed
method for replacement of the OH group in 7 with aryl groups through CꢀC coupling
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In recent years, organic synthesis involving transition metal catalyzed CꢀC coupling, via
substitution of halides or its congeners involving organometallic intermediates is responsible for
paradigm shift in synthetic planning from classical acidꢀbase to coupling pathways.20 Although
palladium catalysts have been in forefront of the emergence of CꢀC bond coupling reactions,
high cost and extreme toxicity of the metals even in trace quantities, forced researchers to look
for alternatives.21 In this quest, copper catalysts have emerged as viable alternatives. Advantages
of copper catalyst include (i) variable oxidation states of copper (+1, +2 and +3), (ii) solubility of
many copper salts in organic solvents, (iii) low cost, benchꢀtop availability and airꢀ stability, (iv)
environmental and biocompatibility.22 Of late, copper catalyzed cross coupling reactions have
become practicable choice for building CꢀO, CꢀS and CꢀN bonds (for example ChanꢀLamꢀEvans
Coupling).23 The Cu catalyzed CꢀC coupling reactions, however, are yet to become well
established for CꢀC coupling, possibly due to low yields and harsh reaction conditions (e.g.
Ulmann coupling).24 With the advent of organoboron reagents, copper catalyzed CꢀC coupling
reactions are becoming feasible on a variety of substrates.25 Organoboranes are stable, exhibit
higher functionalꢀgroup tolerance and commercially available or easy to prepare.26 We have
recently demonstrated facile copper catalyzed Csp3ꢀCsp2 cross coupling reactions of
organoboron reagents with 4Hꢀchromenes having C(4) SMe group to furnish a variety of 4–arylꢀ
4Hꢀchromenes.27 In continuation of this study, we present herein the copper catalyzed
intermolecular/intramolecular coupling reaction of isoindolinol 7 with aryl/heteroaryl/alkenyl
boronic acids for facile synthesis of C(3) substituted isoindolinones (Scheme 1). Although some
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examples of Pd(II) or Ni(0) catalyzed cross coupling of organoboron reagents with activated
benzylic hydroxyl are known,28 ours is the first report on such cross coupling involving free
benzylic hydroxyl group, arylboronic acid and a copper catalyst.
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Results and discussion
Our initial efforts were directed towards unearthing a suitable copper catalyst and
reaction conditions for coupling of Nꢀbenzyl protected 3ꢀhydroxyisoindolinꢀ1ꢀone 7a and
phenylboronic acid 12a to furnish 2ꢀbenzylꢀ3ꢀphenylisoindolinꢀ1ꢀone 10a (Table 1). Following
our experience,27 as a first attempt, we employed Cu(OAc)2.H2O in 10 mol% in dichloromethane
(DCM) reflux but the reaction provided 10a in less than 5% yield. The yield rose to 45% when
the reaction was conducted in higher boiling dichloroethane (DCE) reflux (entry 1). The yield
gradually rose to a plateau of about 85% with increased catalytic loading (entries 2 and 3).
Alternate Cu(II) catalysts like Cu(CF3COO)2.H2O, Cu(acac)2, CuCl2.2H2O, CuBr2, CuSO4.5H2O
and CuO (entries 4ꢀ9) did not provide desired 10a in better yield. However, in the genre of
Cu(II) catalysts, 10 mol% of copper(II) trifluoromethane sulfonate (Cu(OTf)2) provided the best
yield (86%) after chromatographic purification of the product (entry 10). Lesser amounts of
catalytic loading (5 mol%) was not sufficient to complete the transformation in reasonable time
(entry 12) and higher amount of catalytic loading (20 mol%) did not improve the yield further.
Moreover, we made certain that Cu(OTf)2 catalysis was not due to minor triflic acid impurity, by
conducting the reaction in the presence of sodium carbonate as the buffering agent (entry 11). In
reality, the yield perceptibly rose to 92% in the presence of 0.5 equivalents of Na2CO3 indicating
that minor amount of TfOH, which is inevitable in commercial Cu(OTf)2 may actually impede
the reaction. Furthermore, a run with 10 mol% of TfOH alone was conducted to convincingly
rule out the possibility of TfOH being responsible for the reaction as a Brønsted acid. As
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anticipated, the reaction did not proceed to provide 10a (entry 13). The copper(I) salts like CuCl,
CuBr, CuI, Cu2O or stable copper(I) complexes like CuBrSMe2, Cu(PPh3)3Br, copper(I)ꢀ
thiopheneꢀ2ꢀcarboxylate (CuTC) or Cu(I)ꢀ3ꢀmethylsalicylate (CuMeSal) did not promote the
coupling (entries 14ꢀ21) indicating that copper(I) species may not be involved in the reaction.
Low yield obtained in the cases of CuCl, CuBr, CuTC, CuMeSal can be attributed to Cu(II)
impurities or facile switch of Cu(I) to Cu(II). Notably, there was no reaction when palladium(II)
catalyst (Pd(OAc)2, entry 22) or palladium(0) catalyst (Pd2(dba)3, entry 23) was employed in
presence or absence of a base. To evaluate if Cu(OTf)2 catalysis is due to its Lewis acidic nature,
we conducted the reaction in presence of catalytic amounts of similar borderline Lewis acids29
such as Sc(OTf)3, Fe(OTf)3, Zn(OTf)2 and Yb(OTf)3 but the reactions did not work (entries 24ꢀ
27).
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Table 1. Optimization conditions of coupling reactions conducted in DCE reflux in presence of
different catalysts
Entry Catalyst
Time (h) mol (%) Yield (%)
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3
Cu(OAc)2.H2O
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10
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85
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Cu(OAc)2.H2O
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Cu(OAc)2 H2O
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Cu(CF3COO)2.H2O
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Cu(acac)2
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10
5
48
16
25
nr
nr
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92
64
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nr
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CuCl2.2H2O
7
CuBr2
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8
CuSO4.5H2O
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CuO
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Cu(OTf)2
Cu(OTf)2, Na2CO3 (0.5 equiv)
4
Cu(OTf)2
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TfOH
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10
10
10
5
CuCl
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12
12
12
12
12
12
6
CuBr
CuI
Cu2O
Cu(I)BrSMe2
Cu(PPh3)3Br
CuTC
CuMeSal
Pd(OAc)2, Na2CO3 (1 equiv)
Pd2(dba)3 Na2CO3 (1 equiv)
Sc(OTf)3
8
5
12
12
12
12
10
10
10
10
Fe(OTf)3
Zn(OTf)2
Yb(OTf)3
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nr = no reaction
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As an alternative to DCE we screened some common solvents and changed reaction
parameters to decipher best conditions. Of the alternate solvents investigated such as toluene
(42%), tetrachloroethane (TCE; 76%), acetonitrile (28%) and dioxane (48%), none of them
worked as good as DCE (92%). The transformation worked best under an atmosphere of nitrogen.
Under oxygen atmosphere the yield of 10a was only 16% indicating that the reaction does not go
through oxygen mediated catalyst regeneration. Surprisingly, metal complexing and organic
solvent solubilising ligands like PPh3 (34%) or phenanthroline (42%) actually decreased the
yield of 10a.
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Next, we looked into the reactivity of two derivatives of phenylboronic acids, namely,
phenylboronic acid pinacol ester 12b and potassium phenyltrifluoroborate 12c towards the
coupling reaction, since both of the reagents have been employed previously in place of
phenylboronic acid with concomitant advantages (Scheme 2).30 We, however, found that in such
runs there is not much difference in the yield of 10a over the reaction when phenylboronic acid
was employed. As a result, because of easy availability, we chose to go ahead with phenyl
boronic acids for further studies.
O
O
NBn
X
Cu(OTf)2 (10 mol%)
Na2CO3 (0.5 equiv)
NBn
DCE, reflux
6-10 h, 78-91%
OH
7a
12b-c
10a
O
O
12b: X =
(91%, 6 h); 12c: X = BF3K (78%, 10 h).
B
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Scheme 2. Scope of Cuꢀcatalyzed cross coupling of aryl boronic acid derivatives with 2ꢀbenzylꢀ
3ꢀhydroxyisoindolinone 7a.
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With the optimized conditions in hand, we evaluated generality of 3ꢀarylisoindolinone
synthesis and outcome of the reaction as a consequence of electron density of the aromatic ring
(Scheme 3). We conducted coupling between 2ꢀbenzylꢀ3ꢀhydroxyisoindolinone 7a and three
more aryl boronic acids, namely 4ꢀtrifluoromethylphenylboronic acid 12d having highly
electronꢀwithdrawing C4ꢀCF3 group, 4ꢀmethoxyphenylboronic acid 12e having highly electronꢀ
donating C4ꢀOMe group and furanꢀ2ꢀboronic acid 12f in which boronic acid is on an electron
rich heteroaromatic ring. Each reaction provided corresponding 3ꢀarylisoindolinones 10b-d in
good to excellent yield. Among the three boronic acids 12d-f, the reaction with furanꢀ2ꢀboronic
acid 12f provided lowest yield (78%) and the reaction took longer time (12 h) reflecting sluggish
nature of the reactant in coupling reactions.31 The isoindolinone 10a was characterized by
spectral (IR, 1H NMR, 13C NMR and DEPTꢀ135) and analytical data. A singlet at about δ 5.0
ppm assignable to C(3)H in the 1H NMR spectrum of 2ꢀbenzylꢀ3ꢀphenylisoindolinꢀ1ꢀones 10a is
the diagnostic signal. Spectral and analytical data of 10b-d compared well with those of 10a.
Scheme 3. Scope of Cuꢀcatalyzed cross coupling of different arylboronic acids with 2ꢀbenzylꢀ3ꢀ
hydroxyisoindolinone 7a.
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Having stabilized reaction conditions for the copper catalyzed cross coupling of 7a and
aryl boronic acids 12, it was our next endeavor to remove the benzyl PG in 10a so that the
isoindolinone motif gets exposed. As anticipated, selective reductive removal of the PG proved
to be difficult as there are two benzylic positions in 10a, both of which were getting reductively
cleaved under hydrogenation conditions resulting in destruction of isoindolinone motif. As an
alternative, we placed 4ꢀmethoxybenzyl group (PMB) on nitrogen 7b with an intention of
selectively removing under oxidative conditions (Scheme 4).32 Regrettably, coupling reaction
between 7b and phenylboronic acid 12a was not efficient. Surprisingly, when palladium
sensitive allyl 7c or propargyl 7d33 were placed on nitrogen there was no reaction to provide
anticipated 10f-g respectively. It is possible that 7c-d and Cu(OTf)2 combine to provide stable
complexes. Gratifyingly, when we employed photolabile 2ꢀnitrobenzyl (NB) PG34 on
isoindolinone motif (7e) the coupling worked best to provide product 10h in excellent yield
within 3 h.
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Scheme 4. Scope of Cuꢀcatalyzed cross coupling in presence of different protecting groups
(PGs).
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To understand the reaction mechanism of Csp3ꢀCsp2 coupling and to rule out the
possibilities of nucleophilic substitution, we conducted two reactions on 3ꢀhydroxyisoindolinone
7a in THF; one with PhMgBr, a hard nucleophile and the other with 2(PhMgBr)CuI,35 a soft
nucleophile. Both the reactions did not provide the substitution product 10a ruling out
possibilities of a nucleophilic substitution. As noted in Table 1 (entries 10 and 11) TfOH
impurity in Cu(OTf)2 or TfOH (entry 13) impede the reaction by engineering towards generation
of Nꢀacyl iminium ion intermediates, instead of channeling the reactant 7 towards coupling
pathways. Based on the evidences so far accumulated, possible mechanism was depicted and
shown in Scheme 5. First and important step is the insertion of copper into fragile carbonꢀboron
bond to provide reactive intermediate PhCu(OTf) 13.36 The intermediate 13 then enters into the
catalytic cycle to react with 3ꢀhydroxyisoindolinone 7 to provide the intermediate 14. Crucial Cꢀ
C coupling with concomitant CꢀO bond cleavage then takes place on 14 to provide the product
10 and copper(II) species 15. The reaction of 15 with arylboronic acid 12 regenerates 13 and
stable boric acid. Throughout the catalytic cycle copper remains in the oxidation state of +2.
Interaction of copper(II) species with the C(3) hydroxy group in the intermediate 14 could reflect
its Lewis acid characteristics. Driving force for coupling reaction is the formation of stable CꢀC
bond in 10 and CuꢀO bond in 15, at the cost of ArꢀCu and CꢀOH bonds. Although metal salt
solubilizing ligands like PPh3 and phenanthroline helped dissolution of Cu(OTf)2 in DCE,
decreased yield of the desired product 10 (vide supra) indicates that ligand bound copper catalyst
is sterially hindered to allow formation of 14.
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Scheme 5. Plausible mechanism for copper mediated formation of 3ꢀsubstituted isoindolinones
10.
To demonstrate scope of the coupling reaction, a range of arylboronic acids 12d-p were
reacted with 3ꢀhydroxyꢀ2ꢀ(2ꢀnitrobenzyl)isoindolinꢀ1ꢀone 7e under optimized conditions to
realize fourteen 2ꢀ(2ꢀnitrobenzyl)ꢀ3ꢀarylisoindolinꢀ1ꢀones 10i-u (Table 2). The arylboronic acids
12d-p were selected with a view of their structural diversity and potential binding to biological
targets. High efficiency of crossꢀcoupling was observed regardless of the presence of strongly
electronꢀwithdrawing (12d, 12gꢀh to 10i, 10lꢀm), mildly electron withdrawing (12i-k to 10n-p),
strongly electron donating (12e to 10j) or mildly electron donating (12l-m to 10q-r) nature of the
substitution in the aryl ring. Notably, the crossꢀcoupling reaction worked well even with orthoꢀ
substituted boronic acids (12n-p to 10s-u) indicating that the cross coupling is not highly
sensitive to the steric bulk on the aryl ring. Boronic acid on an electronꢀrich heterocyclic ring,
namely, furanꢀ2ꢀboronic acid 12f participated in the coupling with 7e to furnish isoindolinone
10k. However, the coupling did not work with thiopheneꢀ2ꢀboronic acid, pyridineꢀ3ꢀboronic acid
and quinoloneꢀ3ꢀboronic acid indicating that the reaction is sensitive to boronic acids that
contain coordinating sites. The copper mediated cross coupling between 3ꢀhydroxyisoindolinꢀ1ꢀ
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one 7e and alkenyl boronic acids 12q-r to furnish alkenyl substituted isoindolinones 10v-w took
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Table 2. Scope of Cuꢀcatalyzed cross coupling of 2ꢀnitrobenzyl protected 3ꢀ
hydroxyisoindolinone 7e with different aryl/heteroaryl/alkenyl boronic acids.
Entry
1
R
Substrate Product Time (h) Yield (%)
4ꢀCF3C6H4
4ꢀMeOC6H4
2ꢀFuryl
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10
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77
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91
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10l
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12i
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3,5ꢀF2C6H3
4ꢀClC6H4
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10n
10o
10p
10q
10r
10s
10t
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7
3ꢀClC6H4
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12j
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4ꢀBrC6H4
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12k
12l
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4ꢀMeC6H4
3ꢀMeC6H4
2,3ꢀ(OMe)2C6H3
2,5ꢀ(OMe)2C6H3
2,6ꢀ(OMe)2C6H3
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12m
12n
12o
12p
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10u
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nꢀHexꢀ1ꢀenyl
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12q
12r
10v
Styreneyl
10w
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After demonstrating feasibility of synthesis of different C(3)substituted isoindolinones
10h-w with NB as Nꢀprotecting group, our next task was to cleave photoꢀlabile NB, so that free
isoindole moiety gets exposed. We irradiated dilute (10ꢀ2 M) CH3CN:H2O (1:1) solutions of four
selected isoindolinones namely, 10h, 10j, 10l and 10o, with 4 × 3 µW LED lamps emitting at
370 nm (see supplementary information for an image of the inꢀhouse built reactor).37 The
photochemical cleavage reaction was clean and took place within 4 h to provide deprotected
products 11a-d in excellent yield (Scheme 6). The photo cleavage was facile on substrates
having aryl ring with electronꢀdonating (10j) or electronꢀwithdrawing (10l, 10o) substituent’s.
We found that the LED lamps as a source of 370 nm light for NB deprotection is far superior
compared to conventional high pressure mercury vapor lamps as LED lamps do not generate heat
and filter to cutꢀoff unwanted light is not required.38
Scheme 6. The cleavage of NB in the presence of UV light (370 nm).
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Finally, we attempted synthesis of tetracyclic lactam system 19 of neuvamine 1 from
arylboronic acid 17 to demonstrate intramolecular version of our newly developed Cu(OTf)2
catalyzed CꢀC coupling reaction (Scheme 7). Starting phthalimide derivative39 16 was prepared
from corresponding amine40 and phthalic anhydride in toluene reflux. The aryl bromide 16 was
converted into the boronic acid derivative 17 by palladiumꢀcatalyzed reaction with
bis(pinacolato)diboron.41 Controlled reduction of one of the carbonyl groups in 17 with sodium
borohydride provided isoindolinꢀ3ꢀol 18 which on treatment with Cu(OTf)2 under our optimized
reaction conditions provided neuvamine framework 19 in excellent yield.
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Scheme 7. Synthesis of neuvamine like molecule 19 via Cuꢀcatalyzed intramoleculer coupling
reaction.
Conclusion
In summary, we described facile Cu(OTf)2 catalyzed Csp3ꢀCsp2 coupling involving 3ꢀ
hydoxyisoindolinones and a variety of aryl/heteroaryl/alkenyl boronic acids to efficiently furnish
C(3) aryl/heteroaryl/alkenyl substituted isoindolinones. This is the first report on copper
catalyzed C(sp3)ꢀOH cleavage with concomitant CꢀC coupling. In this way, we demonstrated
facile substitution of OH group in 3ꢀhydoxyisoindolinones with electron rich, electron deficient
aryl and alkenyl groups with equal facility. We have shown that photolabile 2ꢀnitrobenzyl is the
best Nꢀprotecting group and DCE reflux is the best medium for the transformation. We
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demonstrated both interꢀ and intraꢀmolecular versions through synthesis of twenty four C(3)
substituted isoindolinones and tetracyclic ring motif of the alkaloid neuvamine.
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Experimental section
General experimental methods
Progression of all the reactions was monitored by TLC using hexanes (60ꢀ80 °C boiling mixture)
/ ethyl acetate mixture as eluent. Column chromatography was performed on silica gel (100ꢀ200
mesh) using increasing percentage of ethyl acetate in hexanes. 1HꢀNMR spectra (400 MHz), 13C
NMR (100MHz) and DEPT–135 spectra were recorded for (CDCl3, CDCl3 + CCl4 (1:1) or
DMSOꢀd6) solutions on 400 MHz spectrometer with TMS as internal standard. Coupling
constants J are given in Hz. IR spectra were recorded as KBr pellets on a FTꢀIR spectrometer.
High resolution mass spectra were recorded on quadrupoleꢀtimeꢀofꢀflight (QTOF) mass
spectrometer using electrospray ionization mode. The Xꢀ ray diffraction measurements were
carried out at 298 K on equipped with a graphite monochromator and a MoꢀKα fineꢀfocus sealed
tube (λ = 0.71073 Å). Organic solvents were dried by standard methods. The catalyst Pd2(dba)3
and the alkenyl boronic acids were prepared according to literature procedures.41 Light mediated
deprotection of NB group to generate isoindolinones was carried out using homeꢀbuilt reactor
having four UVꢀLED (3µW) lamps with emission maximum at 370 nm (see supplementary
information for the photograph). Maximum intensity of the LED bulbs as determined using a
intensity and waveꢀlength characterization possible UVꢀvisible spectrometer having resolution of
0.23 nm in the range 200ꢀ1100 (see Figure 3 in the supplementary information).
General procedure for synthesis of 2-benzyl-3-arylisoindolin-1-one 10a-e.
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Synthesis of 2-benzyl-3-phenylisoindolinone 10a: An ovenꢀdried 25 mL twoꢀneck roundꢀ
bottom flask connected to Shlenk line through a condenser was charged with phenylboronic acid
12a (60 mg, 0.5 mmol), Cu(OTf)2 (18 mg, 0.05 mmol) and Na2CO3 (27 mg, 0.25 mmol). The
flask was sealed with a rubber septum, evacuated under vacuum and purged nitrogen gas three
times. Anhydrous dichloroethane (DCE, 2 mL) was added through a syringe and the contents
were stirred for 10 min. 2ꢀBenzylꢀ3ꢀhydroxyisoindolinꢀ1ꢀone 7a (120 mg, 0.5 mmol) in DCE (4
mL) was next added at rt (30 °C) over 5 min. The resulting reaction mixture was refluxed for 4 h
while periodically checking by TLC for completion of reaction. The reaction mixture was then
extracted with dichloromethane (DCM, 2 × 20 mL). The organic layer was washed with water (2
× 20 mL), brine (1 × 10 mL) followed by removal of DCM under reduced pressure. The crude
product was subjected to column chromatography (silica gel, gradient elution with increasing
volume of EtOAc in hexanes) to yield 2ꢀbenzylꢀ3ꢀphenylꢀisoindolinone 10a.
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2-Benzyl-3-phenylisoindolin-1-one 10a: Colourless solid (143 mg, 92% yield) Mp: 135 °C
(reported 136 °C); IR (KBr, cmꢀ1) 3030, 2920, 1695, 1613, 1494, 1464, 1399, 1291, 1075, 1026,
978, 761, 738, 701; 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 6.6 Hz, 11H), 7.50ꢀ7.39 (m, 2H),
7.39ꢀ7.02 (m, 1H), 5.40 (d, J = 14.8 Hz, 1H), 5.24 (s, 1H), 3.73 (d, J = 14.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 168.6 (C), 146.4 (C), 137.1 (C), 136.8 (C), 131.9 (CH), 131.4 (C), 129.2
(CH), 128.8 (2 X CH), 128.5 (CH), 128.4 (CH), 127.8 (CH), 127.6 (CH), 123.8 (CH), 123.2
(CH), 63.6 (CH), 43.9 (CH2); HRMS (ESI) calcd for C21H17NO (M + H) 300.1382, found
300.1382.
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2-Benzyl-3-(4-(trifluoromethyl)phenyl)isoindolin-1-one10b: Colourless solid (167 mg, 88%
yield) Mp: 115 °C; IR (KBr, cmꢀ1) 3064, 3033, 2926, 2861, 1702, 1618, 1494, 1467, 1398, 1327,
1119, 1068, 891, 848, 795, 737, 700, 609; 1H NMR (400 MHz, CDCl3 + CCl4; 1:1) δ 7.95 (d, J =
7.1 Hz, 1H), 7.61 (d, J = 7.8 Hz, 2H), 7.52ꢀ7.37 (m, 2H), 7.28ꢀ7.06 (m, 8H), 5.40 (d, J = 14.9
Hz, 1H), 5.27 (s, 1H), 3.72 (d, J = 14.9 Hz, 1H); 13C NMR (100 MHz, CDCl3 + CCl4; 1:1) 168.4
(C), 145.6 (C), 141.3 (C), 136.8 (C), 132.2 (CH), 131.4 (C), 131.2 (q, J = 32 Hz, C), 128.9 (CH),
128.8 (CH), 128.5 (CH), 128.2 (CH), 127.9 (CH), 126.3 (q, J = 4 Hz, CH), 125.3 (C), 124.2
(CH), 123.1 (CH), 63.0 (CH), 44.1 (CH2); HRMS (ESI) calcd for C22H16F3NONa (M + Na)
390.1082, found 390.1085.
2-Benzyl-3-(4-methoxyphenyl)isoindolin-1-one10c: Colourless solid (136 mg, 83% yield) Mp:
124 °C; (reported 124 °C)IR (KBr, cmꢀ1) 3062, 2927, 2872, 1694, 1611, 1527, 1468, 1400, 1344,
1305, 1142, 1094, 858, 790, 738, 702; 1H NMR (400 MHz, CDCl3) δ 7.86ꢀ7.77 (m, 1H), 7.35ꢀ
7.24 (m, 2H), 7.16ꢀ7.11 (m, 3H), 7.06 (d, J = 6.6 Hz, 2H), 6.98ꢀ6.92 (m, 1H), 6.88ꢀ6.69 (m, 4H),
5.25 (d, J = 14.8 Hz, 1H), 5.08 (s, 1H), 3.66 (d, J = 3.8 Hz, 3H), 3.61 (d, J = 14.9 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 168.3 (C), 159.8(C), 146.6 (C), 137.1 (C), 131.8 (CH), 131.3 (C),
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129.0 (CH), 128.6 (CH), 128.3 (CH), 128.2 (CH), 127.5 (CH), 123.5 (CH), 123.1 (CH), 114.4
(CH), 63.0 (CH), 55.2 (CH3), 43.6 (CH2); HRMS (ESI) calcd for C22H20NO2 (M + H) 330.1488,
found 330.1486.
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2-Benzyl-3-(furan-2-yl)isoindolin-1-one10d: Colourless solid (106 mg, 78% yield) Mp: 108
°C; IR (KBr, cmꢀ1) 1693, 1592, 1567, 1529, 1305, 1195, 1072, 743, 708; 1H NMR (400 MHz,
CDCl3) δ 8.00ꢀ7.86 (m, 1H), 7.54ꢀ7.45 (m, 2H), 7.30ꢀ7.19 (m, 6H), 6.29ꢀ6.36 (m, 2H), 5.40 (s,
1H), 5.32 (d, J = 14.9 Hz, 1H), 3.94 (d, J = 14.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.0
(C), 149.1 (C), 143.5 (CH), 143.0 (C), 137.0 (C), 131.8 (CH), 128.79 (CH), 128.72 (CH), 128.3
(CH), 127.5 (CH), 123.8 (CH), 123.0 (CH), 110.5 (CH), 110.0 (CH), 57.0 (CH), 44.2 (CH2);
HRMS (ESI) calcd for C19H15NO2 (M + H) 290.1175, found 290.1776.
2-(4-Methoxybenzyl)-3-phenylisoindolin-1-one 10e: Colourless solid (88 mg, 54% yield)
Mp:132 °C; IR (KBr, cmꢀ1) 3033, 2929, 2835, 1691, 1612, 1512, 1464, 1399, 1246, 1176, 1033,
817, 737, 699; 1H NMR (400 MHz, CDCl3) δ 7.93 (dd, J = 6.0, 2.2 Hz, 1H), 7.51ꢀ7.30 (m, 5H),
7.17ꢀ7.00 (m, 5H), 6.82 (d, J = 8.7 Hz, 2H), 5.34 (d, J = 14.7 Hz, 1H), 5.22 (s, 1H), 3.77 (s, 3H),
3.68 (d, J = 14.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.5 (C), 159.1 (C), 146.4, 136.9 (C),
131.8 (CH), 131.5, 129.8 (CH), 129.27 (C), 129.21 (CH), 128.7 (CH), 128.3 (CH), 127.8 (CH),
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123.7 (CH), 123.2 (CH), 114.1 (CH), 63.5 (CH), 55.3 (CH3), 43.2 (CH2); HRMS (ESI) calcd for
C22H20NO2 (M + H) 330.1488, found 330.1487.
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N NB
O
Synthesis of 3-hydroxy-2-(2-nitrobenzyl)isoindolin-1-one 7e: To a stirred solution of 2ꢀ(2ꢀ
nitrobenzyl)isoindolineꢀ1,3ꢀdione43 (500 mg, 1.77 mmol) in a mixture of tetrahedrofuran and
methanol (5:0.5 mL) sodium borohydride (114 mg, 2.65 mmol) was added during 10 min at ꢀ10
oC.. Resulting mixture was stirred at ꢀ10 °C for 2 h. Subsequently, excess sodium borohydride
was quenched with aqueous 3 N HCl (0.5 mL). Evaporation of solvents on rotary evaporator
resulted in colourless solid which washed with water to provide 3ꢀhydroxyꢀ2ꢀ(2ꢀ
nitrobenzyl)isoindolinꢀ1ꢀone 7e in 88% yield (443 mg). Mp: 98 °C; IR (KBr, cmꢀ1) 3340, 2865,
1681, 1609, 1577, 1525, 1469, 1431, 1344, 1305, 1207, 1060, 961, 925, 858, 788, 748, 728; 1H
NMR (400 MHz, DMSOꢀd6 + CCl4; 1:1) δ 8.07 (d, J = 8.0 Hz, 1H), 7.73ꢀ7.52 (m, 6H), 7.40 (d, J
= 7.2 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 5.78 (d, J = 8.0 Hz, 1H), 5.06 (d, J = 17.3 Hz, 1H), 4.88
(d, J = 17.3 Hz, 1H); 13C NMR (100 MHz, DMSOꢀd6 + CCl4; 1:1) δ 166.6 (C), 147.8 (C), 144.8
(C), 133.5 (CH), 132.9 (C), 132.0 (CH), 131.0 (C), 129.2 (CH), 128.8 (CH), 128.0 (CH), 124.5
(CH), 123.6 (CH), 122.4 (CH), 81.1 (CH), 39.8 (CH2); HRMS (ESI) calcd for C15H12N2O4Na (M
+ Na) 307.0695, found 307.0698.
Synthesis of 2-(2-nitrobenzyl)-3-phenylisoindolin-1-ones 10h-w: The general procedure
described for synthesis of 2ꢀbenzylꢀ3ꢀarylisoindolinꢀ1ꢀone 10a-e was followed for synthesis of 2ꢀ
(2ꢀnitrobenzyl)ꢀ3ꢀphenylisoindolinꢀ1ꢀone 10h-w.
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N NB
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2-(2-Nitrobenzyl)-3-phenylisoindolin-1-one10h: Colourless solid (109 mg, 91% yield), Mp:
116 °C; IR (KBr, cmꢀ1) 3062, 2927, 2872, 1694, 1611, 1527, 1468, 1400, 1344, 1305, 1142,
1094, 858, 790, 738, 702; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 6.9 Hz, 2H), 7.54ꢀ7.48 (m,
3H), 7.40ꢀ7.36(m, 2H), 7.30ꢀ7.28 (m, 3H), 7.19ꢀ7.17 (m, 1H), 7.01 (d, J = 4.8 Hz, 2H), 5.40 (d, J
= 17.2 Hz, 1H), 5.40 (s, 1H), 4.50 (d, J = 17.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 169.3
(C), 148.4 (C), 146.4 (C), 136.3 (C), 133.6 (C), 132.7 (CH), 132.4 (CH), 130.8 (C), 130.0 (CH),
129.3 (CH), 129.0 (CH), 128.6 (CH), 128.3 (CH), 127.6 (CH), 125.5 (CH), 123.9 (CH), 123.4
(CH), 65.0 (CH), 41.2 (CH2); HRMS (ESI) calcd for C21H16N2O3Na (M + Na) 367.1059, found
367.1058.
2-(2-Nitrobenzyl)-3-(4-(trifluoromethyl)phenyl)isoindolin-1-one 10i: Colourless solid (134
mg, 92% yield), Mp: 141 °C; IR (KBr, cmꢀ1) 3070, 2935, 2860, 1699, 1617, 1528, 1395, 1326,
1166, 1125, 1067, 854, 790, 734; 1H NMR (400 MHz, CDCl3 + CCl4; 1:1) δ 7.94ꢀ7.89 (m, 2H),
7.56ꢀ7.48 (m, 6H), 7.40ꢀ7.38 (m, 1H), 7.19 (d, J = 8.1 Hz, 2H), 7.15ꢀ7.11 (m, 1H), 5.49 (s, 1H),
5.33 (d, J = 16.0 Hz, 1H), 4.57 (d, J = 16.0 Hz, 1H); 13C NMR (100 MHz, CDCl3 + CCl4; 1:1) δ
169.1 (C), 148.7 (C), 145.8 (C), 140.9 (C), 133.67 (CH), 132.64 (CH), 132.5 (C), 131.5 (C),
131.0 (CH), 130.8 (C), 129.0 (CH), 128.6 (CH), 128.0 (CH), 126.3 (m, CH), 124.9 (CH), 124.3
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(CH), 123.3 (CH), 64.6 (CH), 41.3 (CH2); HRMS (ESI) calcd for C22H15F3N2O3Na (M + Na)
435.0932, found 435.0932.
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3-(4-Methoxyphenyl)-2-(2-nitrobenzyl)isoindolin-1-one 10j: Light yellow solid (93 mg, 77%
yield), Mp: 115 °C; IR (KBr, cmꢀ1) 3071, 2935, 2840, 1695, 1609, 1525, 1466, 1400, 1344,
1304, 1248, 1176, 1107, 1027, 787, 731; 1H NMR (400 MHz, CDCl3) δ 7.97ꢀ7.93 (m, 2H), 7.54ꢀ
7.48 (m, 3H), 7.40ꢀ7.36 (m, 2H), 7.18ꢀ7.16 (m, 1H), 6.92 (d, J = 8.3 Hz, 2H), 6.80 (d, J = 8.3 Hz,
2H), 5.39ꢀ5.35 (m, 2H), 4.48 (d, J = 16.8 Hz, 1H), 3.77 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
169.2 (C), 160.0 (C), 148.4 (C), 146.7 (C), 133.7 (CH), 132.9 (C), 132.3 (CH), 130.9 (C), 129.9
(CH), 129.0 (CH), 128.6 (CH), 128.2 (CH), 127.9 (C), 125.0 (CH), 123.9 (CH), 123.4 (CH),
114.6 (CH), 64.5 (CH), 55.4 (CH3), 41.1 (CH2); HRMS (ESI) calcd for C22H18N2O4 Na (M + Na)
397.1164, found 397.1168.
3-(Furan-2-yl)-2-(2-nitrobenzyl)isoindolin-1-one 10k: Colourless solid (93 mg, 79% yield)
Mp: 140 °C; IR (KBr, cmꢀ1) 1697, 1596, 1577, 1470, 1395, 1343, 1305, 1190, 1080, 858, 786,
750, 702; 1H NMR (400 MHz, CDCl3 + CCl4; 1:1) δ 7.97ꢀ7.93 (m, 2H), 7.61ꢀ7.43 (m, 3H), 7.38ꢀ
7.32 (m, 3H), 7.22 (s, 1H), 6.24 (s, 2H), 5.55 (s, 1H), 5.25 (d, J = 16.9 Hz, 1H), 4.83 (d, J = 16.9
Hz, 1H); 13C NMR (100 MHz, CDCl3 + CCl4; 1:1) δ 168.4 (C), 148.6 (C), 148.2 (C), 143.5
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(CH), 142.8 (C), 133.3 (CH), 132.7 (C), 132.1 (CH), 131.4 (C), 129.5 (CH), 128.9 (CH), 127.9
(CH), 124.7 (CH), 123.9 (CH), 123.2 (CH), 110.5 (CH), 110.2 (CH), 58.3 (CH), 41.5 (CH2);
HRMS (ESI) calcd for C19H14N2O4Na (M + Na) 357.0851, found 357.0851.
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3-(4-Fluorophenyl)-2-(2-nitrobenzyl)isoindolin-1-one 10l: Light yellow solid (116 mg, 91%
yield), Mp: 157 °C; IR (KBr, cmꢀ1) 3071, 2930, 1695, 1607, 1527, 1469, 1397, 1342, 1226,
1158, 1097, 856, 788, 737; 1H NMR (400 MHz, CDCl3) δ 7.94ꢀ7.91 (m, 2H), 7.53ꢀ7.48 (m, 3H),
7.40ꢀ7.35 (m, 2H), 7.16ꢀ7.13 (m, 1H), 7.01ꢀ6.93 (m, 4H), 5.40 (s, 1H), 5.35 (d, J = 16.4 Hz, 1H),
4.50 (d, J = 16.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 169.1 (C), 162.8 (d, J = 241 Hz, C),
148.3 (C), 146.2 (C), 133.6 (CH), 132.5 (C), 132.4 (CH), 132.1 (d, J = 3 Hz, C), 130.7 (C), 130.1
(CH), 129.4 (d, J = 9 Hz, CH), 128.7 (CH), 128.4 (CH), 124.9 (CH), 123.9 (CH), 123.3 (CH),
116.2 (d, J = 22 Hz, CH), 64.2 (CH), 41.0 (CH2); HRMS (ESI) calcd for C21H15FN2O3Na (M +
Na) 385.0964, found 385.0964.
3-(3,5-Difluorophenyl)-2-(2-nitrobenzyl)isoindolin-1-one 10m: Light yellow solid (108 mg,
81% yield), Mp: 167 °C; IR (KBr, cmꢀ1) 1713, 1650, 1574, 1530, 1464, 1409, 1333, 1116, 855,
790, 729; 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 6.8 Hz, 2H), 7.56ꢀ7.51 (m, 3H), 7.45ꢀ7.39
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(m, 2H), 7.18 (d, J = 4.8 Hz, 1H), 6.74 (t, J = 8.5 Hz, 1H), 6.61 (d, J = 5.6 Hz, 2H), 5.41ꢀ5.37
(m, 2H), 4.57 (d, J = 16.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 169.2 (C), 16.3.5 (d, J = 249
Hz, C) 163.4 (d, J = 250 Hz, C), 148.5 (C), 145.3 (C), 140.8 (C), 133.8 (CH), 132.7 (CH), 132.2
(C), 130.54 (C), 130.48 (CH), 129.1 (CH), 128.7 (CH), 125.1 (CH), 124.3 (CH), 123.2 (CH),
110.4 (t, J = 18 Hz, CH), 104.5 (t, J = 25 Hz, CH) 64.2 (CH), 41.3 (CH2); HRMS (ESI) calcd for
C21H14F2N2O3Na (M + Na) 403.0870, found 403.0871.
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3-(4-Chlorophenyl)-2-(2-nitrobenzyl)isoindolin-1-one 10n: Colourless solid (109 mg, 81%
yield), Mp: 151 °C; IR (KBr, cmꢀ1) 1698, 1612, 1526, 1490, 1468, 1395, 1345, 1307, 1088, 789,
748, 719; 1H NMR (400 MHz, CDCl3 + CCl4; 1:1) δ 7.92 (d, J = 7.2 Hz, 2H), 7.52ꢀ7.39 (m, 5H),
7.27ꢀ7.24 (m, 2H), 7.14ꢀ7.12 (m, 1H), 6.98 (d, J = 8.4 Hz, 2H), 5.39 (s, 1H), 5.33 (d, J = 16.4
Hz, 1H), 4.51 (d, J = 16.4 Hz, 1H); 13C NMR (100 MHz, CDCl3 + CCl4; 1:1) δ 169.0 (C), 148.5
(C), 146.0 (C), 135.0 (C), 134.9 (C), 133.5 (C), 132.5 (CH), 132.4 (CH), 130.8 (C), 130.6 (CH),
129.5 (CH), 129.0 (CH), 128.8 (CH), 128.4 (CH), 124.9 (CH), 124.1 (CH), 123.3 (CH), 64.3
(CH), 41.1 (CH2); HRMS (ESI) calcd for C21H15ClN2O3Na (M + Na) 401.0669, found 401.0673.
3-(3-Chlorophenyl)-2-(2-nitrobenzyl)isoindolin-1-one 10o: Colourless solid (118 mg, 88%
yield), Mp: 165 °C; IR (KBr, cmꢀ1) 3063, 2918, 2859, 1697, 1526, 1470, 1396, 1344, 1305,
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7.44ꢀ7.38 (m, 2H), 7.25ꢀ7.15 (m, 3H), 6.98ꢀ6.96 (m, 2H), 5.39 (s, 1H), 5.35 (d, J = 16.8 Hz,
1H),(d, J = 16.8 Hz, 1H); 13C NMR (100 MHz, CDCl3 + CCl4; 1:1) δ 169.1 (C), 148.5 (C), 145.8
(C), 138.6 (C), 135.2 (C), 133.6 (CH), 132.5 (CH), 132.4 (C), 130.7 (C), 130.5 (CH), 130.4
(CH), 129.2 (CH), 128.9 (CH), 128.4 (CH), 127.6 (CH), 125.8 (CH), 124.9 (CH), 124.1 (CH),
123.3 (CH), 64.5 (CH), 41.2 (CH2); HRMS (ESI) calcd for C21H15ClN2O3Na (M + Na)
401.0669, found 401.0664.
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3-(4-Bromophenyl)-2-(2-nitrobenzyl)isoindolin-1-one 10p: Colourless solid (126 mg, 85%
yield), Mp: 114 °C; IR (KBr, cmꢀ1) 1697, 1613, 1526, 1469, 1396, 1344, 1306, 1072, 1011, 788,
745; 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.1 Hz, 2H), 7.54ꢀ7.49 (m, 3H), 7.42ꢀ7.37 (m,
4H), 7.15ꢀ7.13 (m, 1H), 6.91 (d, J = 7.0 Hz, 2H), 5.38ꢀ5.34 (m, 2H), 4.51 (d, J = 16.8 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 169.2 (C), 148.5 (C), 145.9 (C), 135.5 (C), 133.7 (CH), 132.5
(CH), 132.4 (2C, C,CH), 130.7 (C), 130.3 (CH), 129.3 (CH), 128.8 (CH), 128.5 (CH), 125.0
(CH), 124.1 (CH), 123.3 (CH), 123.0 (C), 64.4 (CH), 41.2 (CH2); HRMS (ESI) calcd for
C21H15BrN2O3Na (M + Na) 445.0164, found 445.0162.
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2-(2-Nitrobenzyl)-3-(p-tolyl)isoindolin-1-one 10q: Colourless solid (113 mg, 89% yield), Mp:
135 °C; IR (KBr, cmꢀ1) 1696, 1609, 1527, 1468, 1400, 1345, 1305, 1200, 1158, 1095, 858, 787,
734, 706; 1H NMR (400 MHz, CDCl3 + CCl4; 1:1) δ 7.92 (d, J = 6.9 Hz, 2H), 7.59ꢀ7.30 (m, 5H),
7.20ꢀ7.03 (m, 3H), 6.89 (d, J = 7.7 Hz, 2H), 5.38ꢀ5.33 (m, 2H), 4.45 (d, J = 16.8 Hz, 1H), 2.31
(s, 3H); 13C NMR (100 MHz, CDCl3 + CCl4; 1:1) δ 169.0 (C), 148.5 (C), 146.6 (C), 138.7 (C),
133.5 (CH), 133.2 (C), 132.9 (C), 132.2 (CH), 131.0 (C), 130.1 (CH), 129.9 (CH), 128.5 (CH),
128.1 (CH), 127.6 (CH), 124.9 (CH), 123.9 (CH), 123.4 (CH), 64.7 (CH), 41.0 (CH2), 21.3
(CH3); HRMS (ESI) calcd for C22H18N2O3Na (M + Na) 381.1215, found 381.1215.
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2-(2-Nitrobenzyl)-3-(m-tolyl)isoindolin-1-one 10r: Colourless solid (109 mg, 86% yield), Mp:
129 °C; IR (KBr, cmꢀ1), 3049, 2922, 1694, 1609, 1578, 1526, 1469, 1397, 1342, 1304, 1200,
1095, 857, 787, 770, 730, 706; 1H NMR (400 MHz, CDCl3 + CCl4; 1:1) δ 7.93ꢀ7.91 (m, 2H),
7.53ꢀ7.47 (m, 3H), 7.40ꢀ7.35 (m, 2H), 7.18ꢀ7.13 (m, 2H), 7.08ꢀ7.06 (m, 1H), 6.81 (d, J = 7.6 Hz,
1H), 6.77 (s, 1H), 5.38 (d, J = 16.8 Hz, 1H), 5.35 (s, 1H), 5.49 (d, J = 16.8 Hz, 1H), 2.25 (s, 3H);
13C NMR (100 MHz, CDCl3 + CCl4; 1:1) δ 169.2 (C), 148.4 (C), 146.4 (C), 139.0 (C), 136.1 (C),
133.5 (CH), 132.8 (C), 132.3 (CH), 130.9 (C), 130.0 (CH), 129.7 (CH), 129.1 (CH), 128.5 (CH),
128.2 (CH), 128.0 (CH), 124.9 (CH), 124.8 (CH), 123.9 (CH), 123.4 (CH), 65.0 (CH), 41.1
(CH2), 21.4 (CH3); HRMS (ESI) calcd for C22H18N2O3Na (M + Na) 381.1215, found 381.1214.
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3-(2,3-Dimethoxyphenyl)-2-(2-nitrobenzyl)isoindolin-1-one 10s: Light yellow colour solid
(113 mg, 79% yield), Mp: 122; °C. IR (KBr, cmꢀ1) 3066, 2937, 2837, 1697, 1605, 1522, 1465,
1399, 1263, 1141, 1027, 858, 788, 730; 1H NMR (400 MHz, CDCl3 + CCl4; 1:1) δ 7.84ꢀ7.80 (m,
2H), 7.42ꢀ7.36 (m, 4H), 7.30ꢀ7.26 (m, 1H), 7.10ꢀ7.08 (m, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.56 (d,
J = 8.0 Hz, 1H), 6.27 (s, 1H), 5.25ꢀ5.21 (m, 2H), 4.47 (d, J = 17.6 Hz, 1H), 3.75 (s, 3H), 3.61 (s,
3H); 13C NMR (100 MHz, CDCl3 + CCl4; 1:1) δ 168.7 (C), 149.6 (C), 149.5 (C), 148.5 (C),
146.4 (C), 133.2 (CH), 132.7 (C), 132.1 (CH), 130.8 (C), 130.2 (CH), 128.4 (CH), 128.3 (C),
128.0 (CH), 124.6 (CH), 123.7 (CH), 123.2 (CH), 120.5 (CH), 111.4 (CH), 109.9 (CH), 64.8
(CH), 55.75 (CH3), 55.71 (CH3), 40.8 (CH2); HRMS (ESI) calcd for C23H20N2O5Na (M + Na)
427.1270, found 427.1269.
3-(2,5-Dimethoxyphenyl)-2-(2-nitrobenzyl)isoindolin-1-one 10t: Colourless solid (116 mg,
81% yield), Mp: 130 °C; IR (KBr, cmꢀ1) 3002, 2936, 2836, 1694, 1526, 1468, 1340, 1280, 1218,
1047, 856, 789, 748; 1H NMR (400 MHz, CDCl3 + CCl4; 1:1) δ 7.93 (d, J = 6.8 Hz, 2H), 7.50ꢀ
7.46 (m, 3H), 7.36ꢀ7.28 (m, 3H), 6.78ꢀ6.72 (m, 2H), 6.17 (s, 1H), 6.03 (s, 1H), 5.38 (d, J = 16.8
Hz, 1H), 5.57 (d, J = 16.8 Hz, 1H), 3.70 (s, 3H), 3.58 (s, 3H); 13C NMR (100 MHz, CDCl3 +
CCl4; 1:1) δ 169.3 (C), 153.9 (C), 151.9 (C), 148.4 (C), 146.4 (C), 133.4 (CH), 133.3 (C), 132.1
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(CH), 131.4 (C), 129.7 (CH), 128.3 (CH), 127.9 (CH), 125.3 (C), 124.7 (CH), 123.9 (CH), 123.4
(CH), 114.4 (CH), 112.8 (CH), 111.9 (CH), 57.4 (CH), 55.8 (CH3), 55.5 (CH3), 41.2 (CH2);
HRMS (ESI) calcd for C23H20N2O5Na (M + Na) 427.1270, found 427.1273.
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3-(2,6-Dimethoxyphenyl)-2-(2-nitrobenzyl)isoindolin-1-one 10u: Colourless solid (93 mg,
74% yield), Mp: 154 °C; IR (KBr, cmꢀ1) 2933, 2831, 1693, 1528, 1462, 1392, 1284, 1217, 1032,
853, 783, 747; 1H NMR (400 MHz, CDCl3) δ 7.98ꢀ7.94 (m, 2H), 7.51ꢀ7.47 (m, 3H), 7.41ꢀ7.22
(m, 3H), 6.53 (s, 1H), 6.47ꢀ6.26 (m, 2H), 5.98 (s, 1H), 5.38 (d, J = 17.0 Hz, 1H), 4.54 (d, J =
17.1 Hz, 1H), 3.76 (s, 3H), 3.68 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.4 (C), 161.1 (C),
158.9 (C), 148.3 (C), 146.8 (C), 133.5 (C), 133.5 (CH), 132.1 (CH), 131.5 (C), 129.3 (CH),
128.2 (CH), 127.8 (CH), 124.7 (CH), 123.7 (CH), 123.4 (CH), 116.4 (C), 105.3 (CH), 98.4 (2 ×
CH), 57.1 (CH), 55.4 (CH3), 55.3 (CH3), 41.2 (CH2); HRMS (ESI) calcd for C23H20N2O5Na (M
+ Na) 427.1270, found 427.1275.
(E)-2-(2-Nitrobenzyl)-3-styrylisoindolin-1-one 10v: Viscous solid (82 mg, 63% yield). IR
(KBr, cmꢀ1) 3058, 3028, 2960, 2927, 2869, 1696, 1609, 1527, 1469, 1402, 1345, 1305, 1149,
1084, 970, 857, 751, 698; 1H NMR (400 MHz, CDCl3 + CCl4; 1:1) δ 7.95 (dd, J = 8.2, 1.2 Hz,
2H), 7.90 (dd, J = 6.7, 1.0 Hz, 2H), 7.59ꢀ7.49 (m, 6H), 7.44 (d, J = 6.8 Hz, 2H), 7.37 (t, J = 7.5
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Hz, 4H), 7.28ꢀ7.26 (m, 2H), 7.26ꢀ7.23 (m, 3H), 6.75 (d, J = 15.7 Hz, 1H), 5.71 (dd, J = 15.7, 9.2
Hz, 1H), 5.31 (d, J = 16.8 Hz, 1H), 4.99 (d, J = 9.2 Hz, 1H), 4.91 (d, J = 16.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3 + CCl4; 1:1) δ 168.7 (C), 148.7 (C), 144.8 (C), 136.6 (C), 135.6 (CH), 133.6
(CH), 133.3 (C), 132.2 (CH), 131.5 (C), 130.2 (CH), 129.0 (CH), 128.8 (CH), 128.7 (CH), 128.3
(CH), 126.9 (CH), 125.1 (CH), 125.0 (CH), 124.2 (CH), 123.5 (CH), 64.2 (CH), 41.3 (CH2);
HRMS (ESI) calcd for C23H18N2O3Na (M + Na) 393.1215, found 393.1215.
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(E)-3-(Hex-1-en-1-yl)-2-(2-nitrobenzyl)isoindolin-1-one 10w: Viscous solid (103 mg 84%). IR
(KBr, cmꢀ1) 2958, 2928, 2864, 1767, 1696, 1613, 1467, 1401, 1343, 1304, 1223, 1148, 1099,
1049, 974, 857, 789, 731; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.1 Hz, 1H), 7.89 (d, J =
7.4 Hz, 1H), 7.59ꢀ7.47 (m, 3H), 7.43ꢀ7.32 (m, 3H), 5.95ꢀ5.82 (m, 1H), 5.28 (d, J = 17.0 Hz, 1H),
5.05ꢀ4.99 (m, 1H), 4.90 (d, J = 17.0 Hz, 1H), 4.79 (d, J = 9.2 Hz, 1H), 2.06ꢀ2.00 (m, 2H), 1.30ꢀ
1.25 (m, 4H), 0.86 (t, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.8 (C), 148.5 (C),
145.2 (C), 139.2 (CH), 133.6 (CH), 133.3 (C), 132.1 (CH), 131.3 (C), 129.7 (CH), 128.6 (CH),
128.1 (CH), 125.6 (CH), 124.9 (CH), 123.9 (CH), 123.3 (CH), 64.2 (CH), 41.0, 31.9 (CH2), 30.9
(CH2), 22.1 (CH2), 13.9 (CH3); HRMS (ESI) calcd for C21H22N2O3Na (M + Na) 373.1528, found
373.1528.
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