4.1 INTRODUCTIONshodhganga.inflibnet.ac.in/bitstream/10603/42026/17/17_chapter 4.pdfreaction,...

Chapter 4

© Mayur Vinodrao Khedkar, Institute of Chemical Technology (ICT), Mumbai, India

167

4.1 INTRODUCTION

Isoindole-1,3-diones commonly known as phthalimides, are key structural units of a

variety of biologically important compounds many of which are pharmaceutically

significant. The drug thalidomide [2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione],

was originally developed as a sedative, an alternative to barbiturates, but was

withdrawn from the market in the 1960’s, because it displayed teratogenic properties

(Karimi et al., 2001). The isoindole-1,3-dione N-phthaloyl-L-glutamicacid is a

selective glutamate receptor agonist (Nagasawa et al., 1980), while 1,8-naphthalimide

is known for its cytotoxicity against the growth of human cancer cultured cells (Hall

et al., 1994). Some isoindole-1,3-dione derivatives are active in reducing the growth

of colon adenocarcinoma, osteosarcoma and KB nasopharynx (Hall et al., 1995).

Isoindole-1,3-diones are also known for their antiviral (Balzarini et al., 2003), anti-

inflammatory (Meng et al., 2007), Chk1 inhibitory (Henon et al., 2007), sedative

(Eger et al., 1990), bactericidal and fungicidal properties (Chavan and Pai, 2007).

They also find important applications as synthetic intermediates in the dyes (Steffanut

et al., 2007), pesticides (Pawar et al., 2002) and polymer industries (Chae and Kim,

2007; Chen et al., 2007).

Due to their biological, pharmaceutical and industrial importance, the

synthesis of isoindole-1,3-diones have received considerable attention in the literature.

The most common method reported in the literature for the synthesis of isoindole-1,3-

diones involves the reaction of a phthalic acid anhydride with amine (Scheme 4.1)

(Barooah, 2006; Lima et al., 2002).

Scheme 4.1 Isoindole-1,3-dione synthesis by conventional method.

This conventional protocol is only applicable to organic compounds having

anhydride moiety, further more protocol is limited to synthesis of N-substituted

isoindole-1,3-diones from simple aryl amines and not applicable to heterocyclic

primary amines. Hence, there is need of a protocol which can synthesize variety of

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N-substituted isoindole-1,3-dione from various organic compounds other than

anhydrides and variety of aryl/alkyl amines in one step.

In recent years, several new methodologies for the synthesis of isoindole-1,3-

diones using transition metal catalysts have been emerged. Generally, palladium-

catalyzed aminocarbonylation reactions are widely used for the synthesis of acyclic

amides. Recent advancement in the aminocarbonylation reactions has made it possible

to synthesize cyclic amides through carbonylative cyclization of o-halo aryls such as

o-halo amides, o-dihalo aryls, o-halo esters (Omae, 2011) (Figure 4.1).

Figure 4.1 Transition metal catalyzed carbonylative cyclization of

o-halo aryls for the synthesis of isoindole-1,3-diones.

The palladium-catalyzed carbonylative cyclization reaction is a convenient

method for the regioselective synthesis of carbonyl containing compounds. In this

context, in 1979 Mori et al. reported palladium-catalyzed protocol for carbonylative

cyclization reaction of o-bromobenzamides in presence of carbon monoxide (CO)

(Scheme 4.2). The developed protocol was applied for the synthesis of range of cyclic

imides, such as phthalimide, N-acetylisoindolinone, N-acetylisoquinolone and

quinolone.

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Scheme 4.2 Carbonylative synthesis of N-substituted isoindole-1,3-diones

from o-halo benzamide.

After this report on palladium catalyzed carbonylative synthesis of isoindole-

1,3-diones, various o-haloaryl derivatives including o-dihalo benzene, o-halo benzoate

and o-halo benzamide have been used as a starting material for the synthesis of

isoindole-1,3-diones derivatives.

In 1991, Perry and Turner reported synthesis of isoindole-1,3-diones from o-

dihalo aryl, carbon monoxide and aromatic amines (Scheme 4.3). This methodology

provides a very convenient one-step approach to this important class of heterocycles.

The reaction was optimized by examining the effect of catalyst type and loading,

solvent, CO pressure, temperature, concentration, base and applied for the synthesis of

various isoindole-1,3-diones.

Scheme 4.3 Carbonylative cyclization of o-dihalo aryls for the synthesis

of N-substituted isoindole-1,3-diones.

Buchwald et al. (2008) reported carbonylative cyclization of o-bromo

benzoates for the synthesis of isoindole-1,3-diones (Scheme 4.4). Pd(OAc)2 was used

as a catalyst in presence of bidentated Xantphos ligand. The protocol was applied for

synthesis of different substituted isoindole-1,3-diones.

Scheme 4.4 Carbonylative cyclization of o-bromo benzoates.

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Similar protocol was developed by Worlikar and Larock (2008), using

monodentated triphenyl phosphine (PPh3) ligand for the synthesis of 2-substituted

isoindole-1,3-diones by the one-step palladium catalyzed aminocarbonylation of o-

halobenzoate (Scheme 4.5). They employed Pd(OAc)2/PPh3 as a catalyst in the

presence of 1 atm. CO pressure for 24 h. The Methodology tolerated number of

functional groups including alcohol, ketone, methoxy, nitro groups, and works well

for both aliphatic and aromatic primary amines.

Scheme 4.5 Carbonylative synthesis of N-substituted isoindole-1,3-diones

from o-halobenzoate.

CO free approach for the carbonylative cyclization of methyl-2-iodobenzoate

for the synthesis of substituted isoindole-1,3-diones was developed by Begouin and

Queiroz (2009) (Scheme 4.6). Palladacycle catalyst with tBu3PHBF4 as ligand in

presence of [Mo(CO)6] as a solid CO source was used for the transformation. Range

of N-substituted isoindoline-1,3-dione were synthesized from methyl-2-iodobenzoate.

Scheme 4.6 CO free carbonylative cyclization for synthesis of N-substituted

isoindoline-1,3-diones.

Nickel-catalyzed CO free approach for the synthesis of isoindole-1,3-diones

using isocyanates with 2-iodobenzoate was developed by Hsieh and Cheng (2005)

(Scheme 4.7). This was the first report that explored isocyanates as a CO source for

carbonylative cyclization of 2-iodobeznoate with good tolerance of functional groups.

But protocol was limited for o-iodoester derivatives and required longer reaction time

upto 36 hours.

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Scheme 4.7 Nickel-catalyzed synthesis of substituted isoindole-1,3-dione

using isocyanates.

Lee and Cho (2012) developed carbonylative cyclization reaction of β-bromo-

α,β-unsaturated carboxylic acid with aliphatic amines (Scheme 4.8). PdCl2(PPh3)2 was

used as a catalyst in the presence of MeCN as solvent and 10 atm. CO pressure. But

the protocol was applicable to aliphatic amines only.

Scheme 4.8 Carbonylative cyclization of β-bromo-α,β-unsaturated carboxylic acid.

In 2009, Inoue et al. reported ruthenium-catalyzed carbonylative cyclization at

ortho C-H bonds in aromatic amides leading to isoindole-1,3-diones (Scheme 4.9).

The reaction was carried out using Ru3(CO)12 as catalyst, 10 atm. CO, 7 atm. ethylene

as a hydrogen acceptor and toluene as a solvent at 160 °C for 24 h. A wide variety of

functional groups, including methoxy, amino, ester, ketone, cyano, chloro, bromo

substituted aromatic amides were screened to afford corresponding substituted

phthalimides. But the protocol was limited to the amides having N-substituted

pyridin-2-ylmethylamine moiety, because pyridine moiety supports intramolecular

CH activation.

Scheme 4.9 Ruthenium-catalyzed carbonylation of substituted aromatic amides.

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Recently Du et al. (2011) succeed in oxidative carbonylation of simple

benzamides using Rhodium catalyst. Range of N-substituted benzamides derivatives

were screened for the oxidative carbonylation using RhCp*(MeCN)3(SbF6)2 catalyst

and Ag2CO3 oxidant (Scheme 4.10).

Scheme 4.10 Rhodium-catalyzed synthesis of substituted isoindole-1,3-diones.

The literature reports reveals that, o-diiodoaryls, o-dibromoaryls, 2-

halobenzoates and substituted benzamide were explored as a starting material for the

carbonylative synthesis of isoindole-1,3-diones, however comparatively inexpensive

substrate like o-halobenzoic acid was not explored. Furthermore, All the reported

protocols on carbonylative synthesis of N-substituted isoindole-1,3-dione have some

common drawbacks like requirement of harsh reaction conditions, the use of

ruthenium/rhodium metal catalysts along with high catalyst loading, longer reaction

time upto 24 h and lower substrate compatibility which limits their applications.

Therefore, there was a need of an active and viable catalytic protocol for the

carbonylative synthesis of N-substituted isoindole-1,3-dione, by using inexpensive o-

halobenzoic acid as a substrate which could operate under milder reaction conditions.

It is well known that, aryl bromide derivatives are difficult substrates to

carbonylate, due to the fact that the oxidative insertion of Pd(0) into a C-Br bond is

less facile. Few protocols for simple aminocarbonylation of bromoaryl were reported

but require harsh reaction conditions (Buckwald et al., 2008). Hence, the synthesis of

this important class of imides (isoindole-1,3-diones) from relatively less reactive

starting materials like o-bromobenzoic acids is a challenging task. Thus, there is a

need to develop an efficient protocol for the synthesis of N-substituted isoindole-1,3-

diones from this inexpensive starting material.

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4.2 CARBONYLATIVE CYCLIZATION OF O-BROMOBENZOIC ACID AND

PRIMARY AMINES.

In this context, for the first time carbonylative cyclization of o-halo benzoic acid for

carbonylative synthesis of N-substituted isoindole-1,3-dione using Pd(OAc)2/1,1'-

bis(diphenylphosphino)ferrocene (dppf) as a catalytic system have been developed

(Scheme 4.11). The developed protocol is general in nature and applied for the

synthesis of wide variety of aliphatic and aromatic N-substituted isoindole-1,3-diones.

Scheme 4.11 Carbonylative cyclization of o-halobenzoic acid for the synthesis

of N-substituted isoindole-1,3-diones.

4.2.1 RESULTS AND DISCUSSION

A series of experiments were performed in order to optimize the reaction conditions

for carbonylative cyclization reaction of o-bromobenzoic acid with aniline as a model

reaction in the presence of Pd(OAc)2 as a catalyst. Various reaction parameters such

as effect of ligand, catalyst loading, solvent, base, temperature and time were studied

and the results obtained are summarized in Table 4.1 and Table 4.2.

The initial reaction was carried out in the absence of ligand but no desired

product was obtained (Table 4.1, entry 1). Noting the importance of the ligand in the

reaction, various phosphine ligands were screened with the aim of increasing the yield

of the corresponding product (Figure 4.2). Monodentated phosphine ligand like

triphenyl phosphine (L1) provided poor yield of N-phenylisoindole-1,3-dione (Table

4.1, entry 2), therefore various bidentated phosphine ligands (L2-L6) were screened

(Table 4.1, entries 3-7). Bidentated phosphine ligands like 1,1-

bis(diphenylphosphino)methane (dppm), 1,1-bis(diphenylphosphino)ethane (dppe)

and 1,1-bis(diphenylphosphino)propane (dppp) were found ineffective for the reaction

(Table 4.1, entries 3-5).

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Figure 4.2 Phosphine ligands screened for the carbonylative cyclization

reaction of o-iodobenzoic acid with aniline.

Sterically hindered phosphine ligand like Xantphos (L5) provided moderate

yield of the N-phenylisoindole-1,3-dione. The results obtained using Xantphos as a

ligand, encouraged to examine the effect of other sterically hindered bisphosphine

ligands on the product yield. Hence, hindered phosphine ligand containing bulky

ferrocene ring i.e. 1,1'-Bis(diphenylphosphino)ferrocene ligand (dppf) was screened,

which provided maximum yield of N-phenylisoindole-1,3-dione, hence used for

further studies (Table 4.1, entry 7).

With dppf (L6) as the ligand of choice, the effect of catalyst loading on

reaction outcome was studied. Reaction was carried out using 5 mol% of palladium

provided 85% yield of N-phenylisoindole-1,3-dione. When catalyst concentration was

increased from 5 mol% to 10 mol%, slight increase in the yield of N-phenylisoindole-

1,3-dione was observed (Table 4.1, entries 7-8). Whereas, on decreasing the amount

of catalyst up to 2.5 mol%, provided lower yield of N-phenylisoindole-1,3-dione

(Table 4.1, entry 9). Thus, 5 mol% Pd(OAc)2 and dppf (L6) as a ligand was used for

further optimization studies.

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Table 4.1 Ligand and catalyst loading study for the carbonylative cyclization of

o-bromobenzoic acid with anilinea

Entry Catalyst Catalyst

loading (mol%)

Ligand Yield

(%)b

1 Pd(OAC)2 5 - 0

2 Pd(OAC)2 5 L1 20

3 Pd(OAC)2 5 L2 10

4 Pd(OAC)2 5 L3 5

5 Pd(OAC)2 5 L4 15

6 Pd(OAC)2 5 L5 65

7 Pd(OAC)2 5 L6 85

8 Pd(OAC)2 10 L6 90

9 Pd(OAC)2 2.5 L6 60

a Reaction conditions: o-bromobenzoic acid (1 mmol), aniline (1.5 mmol), Pd(OAc)2

(5 mol%), DABCO (2 mmol), toluene (10 mL), CO pressure 1 atm., time (10 h). b Yield based on GC analysis.

Thus, using Pd(OAc)2/dppf as a preferred catalyst, the effect of various

reaction parameters like effect of solvent, base, temperature and time was investigated

on reaction of o-bromobenzoic acid with aniline (Table 4.2, entries 1-11). Initially

effect of solvent on reaction outcome was studied. The polar solvents like N,N-

dimethyl formamide (DMF), acetonitrile (ACN) and water afforded lower yield of

desired product (Table 4.2, entries 1-3), whereas anisole provided moderate yield of

the N-phenylisoindole-1,3-dione (Table 4.2, entry 4). But it was observed that, the

reaction was more favourable using toluene as a solvent (Table 4.2, entry 5).

Thereafter, various organic and inorganic bases were screened with the aim of

obtaining a higher yield of desired product (Table 4.2, entries 5-8). Triethylamine

(Et3N) and DABCO were found to be compatible bases while inorganic bases like

K2CO3 and Cs2CO3 provided a poor yield of N-phenylisoindole-1,3-dione. As

DABCO provided maximum yield of the N-phenylisoindole-1,3-dione, hence was

Chapter 4


176

considered for further study (Table 4.2, entry 5). Next the effect of temperature on

reaction outcome was studied, the reaction was carried out at different temperatures

ranging from 90-110 °C, addressing 100 °C as an optimum reaction temperature

(Table 4.2, entries 5 and 9-10). When reaction time was decreased, lower yield of the

N-phenylisoindole-1,3-dione was obtained (Table 1, entry 11). Hence, the best

optimized reaction parameters were; o-bromobenzoic acid (1 mmol), aniline (1.5

mmol), Pd(OAc)2 (5 mol%), dppf (10 mol%) and DABCO (2 mmol) in 10 mL toluene

at 100 °C under 1 atm. CO pressure for 10 h.

Table 4.2 Optimization of carbonylative cyclization of o-bromobenzoic acida

Entry Solvent Base Temp

(°C)

Yield

(%)b

Effect of solvent

1 DMF DABCO 100 40

2 ACN DABCO 100 5

3 Water DABCO 100 0

4 Anisole DABCO 100 60

5 Toluene DABCO 100 85

Effect of solvent

6 Toluene Et3N 100 60

7 Toluene K2CO3 100 10

8 Toluene Cs2CO3 100 15

Effect of temperature and time



11c Toluene DABCO 100 75

a Reaction conditions: o-bromobenzoic acid (1 mmol), aniline (1.5 mmol), Pd(OAc)2

(5 mol%), dppf (10 mol%), 1 atm. CO pressure, time (10 h). b Yield based on GC analysis.

c Reaction time 8 h.

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177

After obtaining best reaction conditions in hand, the scope of the present

reaction system on various aromatic primary amines for synthesis of diverse N-

substituted isoindole-1,3-dione was examined (Table 4.3). The model system under

optimized reaction conditions with aniline furnishes 83% isolated yield of N-phenyl

isoindole-1,3-dione (Table 4.3, entry 1). Methyl substituted o-bromobenzoic acid gave

79% yield of 5-methyl-2-phenylisoindoline-1,3-dione (Table 4.3, entry 2).

Thereafter, the scope of the reaction using various substituted aromatic

primary amines containing electron donating or electron withdrawing groups was

studied. Reaction of o-bromobenzoic acid with 4-methoxyaniline, 4-chloroaniline and

4-methylaniline provided 85%, 86% and 79% yield of the desired product

respectively (Table 4.3, entries 3-5). The reaction of sterically hindered ortho

substituted aryl amines like 2-methoxyaniline and 2-methylaniline provided excellent

yield of 2-(2-methoxyphenyl)isoindoline-1,3-dione and 2-(2-

methylphenyl)isoindoline-1,3-dione respectively (Table 43, entries 6-7). 2-

aminobenzonitrile provided 76% yield of 2-(1,3-dioxoisoindolin-2-yl)benzonitrile

(Table 4.3, entry 8). Amine having bulky 2-(trifluoromethyl) group for example 2-

(trifluoromethyl)aniline and 3-(trifluoromethyl)aniline provided 70% and 79% yield

of corresponding N-substituted phthalimide derivative (Table 4.3, entries 9-10).

Table 4.3 Carbonylative cyclization of o-bromobenzoic acid with different aromatic

primary aminesa

Entry o-bromobenzoic

acid

Amine Product Yield

(%)b

1

83

2

79

3

85

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178

4

86

5

79

6

90

7

89

8

76

9

70

10

79

a Reaction conditions: o-bromobenzoic acid (1 mmol), aromatic amine (1.5 mmol),

Pd(OAc)2 (5 mol%), dppf (10 mol%), DABCO (2 mmol), toluene (10 mL), 1 atm.

CO pressure, 100 °C, time (10 h). b Isolated yield.

In order to extend the scope of the developed protocol, optimized reaction

conditions were then applied to the carbonylative cyclization reaction of aliphatic

(acyclic/cyclic) primary amines (Table 4.4). Reaction of o-bromobenzoic acid with

long chain amine like n-butylamine, hexylamine and heptylamine react smoothly

providing excellent yield of the corresponding product (Table 4.4, entries 1-3).

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Table 4.4 Carbonylative cyclization of o-bromobenzoic acid with different aliphatic

primary aminesa

Entry o-bromobenzoic

acid

Amine Product Yield

(%)b

1

98

2

89

3

88

4

91

5

98

6

90

7

N

O

O

88

8

N

O

O

89

a Reaction conditions: o-bromobenzoic acid (1 mmol), aliphatic amine (1.5 mmol),

Pd(OAc)2 (5 mol%), dppf (10 mol%), DABCO (2 mmol), toluene (10 mL), 1 atm.

CO pressure, 100 °C, time (10 h). bIsolated yield.

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Sterically hindered tert-butyl amine furnished 91% yield of 2-(tert-

butyl)isoindoline-1,3-dione (Table 4.4, entry 4). Benzylamine provided excellent

yield of 2-benzylisoindoline-1,3-dione (Table 4.4, entry 5).

Encouraged by these results, various primary amines containing cyclic carbon

chain were screened. Cyclohexylamine and cyclopentylamine provided 90% and 88%

yield of 2-cyclohexylisoindoline-1,3-dione and 2-cyclopentylisoindoline-1,3-dione

respectively (Table 4.4, entries 6-7). Strained ring containing primary amine like

cyclopropylamine was also well tolerated providing 89% yield of 2-

cyclopropylisoindoline-1,3-dione (Table 4.4, entry 8).

Thus, the developed protocol proved to be general for the carbonylative

cyclization reaction of o-bromobenzoic acid with various structurally and

electronically different aromatic and aliphatic primary amines providing good to

excellent yield of the desired N-substituted isoindole-1,3-diones.

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181

4.2.2 PLAUSIBLE REACTION MECHANISM OF CARBONYLATIVE CYCLIZATION

Carbonylative cyclization of o-halobenzoic acid reaction proceeds through a

mechanism that involves three distinctive steps: (1) Oxidative addition of palladium

(2) CO insertion (3) Base-catalyzed cyclization (Scheme 4.12).

Initially, palladium catalyst undergoes oxidative addition into carbon halogen

bond to give aryl palladium intermediate (I). Subsequent migratory insertion of CO

into the metal-alkyl bond of aryl palladium intermediate (I) gives the corresponding

acylpalladium complex (II). The acylpalladium complex (II) then attacked by

nucleophile i.e. amine to give intermediate (III) leaving Pd(0), which again goes in to

the cycle. Later, intermediate (III) in the presence of base gives anionic intermediate

(IV), which then cyclized to produce intermediate (V), which then reductively

eliminate to give the corresponding isoindole-1,3-diones product (VI).

Scheme 4.12 Plausible reaction mechanism of carbonylative cyclization

reaction of o-halobenzoic acid.

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4.3 CONCLUSION

In conclusion, for the first time a simple, efficient, catalytic system for

carbonylative cyclization of o-bromobenzoic acid for the synthesis of N-

substituted isoindole-1,3-diones have been developed.

The present protocol sounds promising alternative to the conventional

methodologies for synthesis of several N-substituted isoindole-1,3-diones for

simple, inexpensive o-halobenzoic acid derivative.

The protocol works under milder reaction condition like requires atmospheric

CO pressure, lower catalyst loading and less reaction time.

The reaction system was optimized with respect to various parameters and

enabled carbonylative cyclization reaction of variety aromatic and aliphatic

primary amines affording excellent yield of corresponding products.

Thus we believe that, simple reaction procedures, greater substrate

compatibility along with good to excellent yields of desired products, making

the developed protocol an important supplement to the existing methods.

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4.4 EXPERIMENTAL

4.4.1. General: All chemicals were purchased from Lancaster (Alfa-Aesar), Sigma

Aldrich, S. D. fine chemical and commercial suppliers. Gas chromatography (GC)

analysis was carried out on Perkin-Elmer Clarus 400 GC equipped flame ionization

detector with a capillary column (Elite-1, 30 m × 0.32 mm × 0.25 μm) using the

external standard method. The 1H NMR spectra were recorded on Varian-300/500

MHz FT-NMR spectrometer in CDCl3 using TMS as the internal standard. Chemical

shifts are reported in parts per million (δ) relative to tetramethylsilane as the internal

standard. J (coupling constant) values were reported in hertz. Proton splitting patterns

are described as s (singlet), d (doublet), t (triplet), and m (multiplet).

4.4.2. General procedure for synthesis of substituted isoindole-1,3-dione: To a 100

mL stainless steel autoclave, o-bromobenzoic acid (1 mmol), amine (1.5 mmol),

Pd(OAc)2 (5 mol%), dppf (10 mol%), toluene (10 mL) and DABCO (2 mmol) were

added. The autoclave was closed, purged three times with carbon monoxide,

pressurized with 1 atm. of CO and then heated at 100 °C for 10 h. After completion of

reaction, the reactor was cooled to room temperature and remaining CO gas was

carefully vented then the reactor opened and reaction mixture was filtered, vessel was

thoroughly washed with ethyl acetate (2 x 5 mL) to remove any traces of product and

catalyst if present. The filtrate obtained was evaporated under vacuum to give crude

product which was purified by column chromatography (silica gel, 60-120 mesh;

petroleum ether/ethyl acetate, 95:05) to afford the desired product with high purity.

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4.5 Carbonylative cyclization of o-halobenzoic acids for synthesis of N-

substituted isoindole-1,3-dione using polymer supported Palladium N-

heterocyclic carbene as an efficient, heterogeneous and reusable catalyst.

In the previous section, the first report on carbonylative cyclization reaction of o-

bromobenzoic acid with primary amines by using efficient homogeneous

Pd(OAc)2/dppf catalytic system have been explained. Although, the above protocol

has wide applications for synthesis of various N-substituted isoindole-1,3-dione, still

the protocol suffers from some drawbacks such as use of homogeneous non-recyclable

catalyst. It is well known that, in the case of homogenous catalysts, catalyst-product

separation is difficult and also lacks catalyst reusability. It is known that, such toxic

palladium based impurities creates considerable problems in the case of

pharmaceutical products as the purity of the product is of enormous importance. In

addition, the used phosphine ligands are toxic and air/moisture sensitive.

Hence, suitable efforts to anchor such homogeneous palladium complex are

necessary, which can overcome such limitation of catalyst-product separation and

recycle. Furthermore, previous protocol showed unreactivity towards heterocyclic

amines, thus, invites development of new general methodologies for the synthesis of

N-substituted isoindole-1,3-diones. To overcome these issues in the development of an

efficient, economical and facile protocol with an additional advantage of catalyst

recyclability endows heterogeneous catalysis as an emerging alternative to the earlier

reported homogeneous protocols.

Another major concern in palladium catalyzed reactions is the replacement of

air/moisture sensitive phosphine ligand, without compromising with yield of desired

product. In this regards, recently N-heterocyclic carbene ligands (NHC) have emerged

as an attractive alternative to phosphine ligands because of their effective binding

ability to transition metal irrespective of their oxidation states (Herrmann, 2002).

Furthermore, the NHC ligands have also shown excellent air/moisture stability and

have higher dissociation energies than those of other ligands which have been

quantified by theoretical calculations for different metals (Schwarz et al., 2000).

Therefore, the complex of the NHC and transition metal is much stronger, as well as

being chemically and thermally more inert towards cleavage than that of other metal

Chapter 4


185

complexes. Therefore, researchers are exploring NHC ligands for different organic

transformations (Byun and Lee, 2004).

Another attractive feature of the NHC ligands is that, along with transition

metal they can easily bound to the polymeric solid support (polymer/resin). And this

polymer-supported metal-N-heterocyclic carbene (PS-M-NHC) complex offers

various advantages such as reuse of expensive transition metals and ligands with a

possibility to prevent the contamination of ligand residue on products. Hence, various

groups have studied the application of polymer supported palladium-NHC complex

(PS-Pd-NHC) as a catalyst for various organic transformations including Suzuki

coupling reactions (Tandukar and Sen, 2007; Gomann et al., 2009) carbonylative

Suzuki coupling (Qureshi et al., 2011) and hydrogenation reaction (Bagal et al., 2011).

However, to the best of our knowledge; no such polymer-supported reusable catalytic

system has been explored for carbonylative cyclization of o-halobenzoic acid to

synthesize wide variety of isoindole-1,3-dione.

4.5.1 RESULTS AND DISCUSSION

The present work describes an efficient, heterogeneous recyclable protocol for

carbonylative cyclization of o-halobenzoic acid using PS-Pd-NHC as a catalyst under

atmospheric CO pressure (Scheme 4.13). The methodology offers synthesis of various

aromatic, aliphatic and heterocyclic N-substituted phthalimides with good to excellent

yield. The protocol is advantageous due to the ease in handling of the catalyst and

simple workup procedure with effective catalyst recyclability.

Scheme 4.13 Carbonylative cyclization of o-halobenzoic acid and

o-halobenzoate using PS-Pd-NHC complex.

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186

The ease of preparation of complex, indefinite shelf life, stability towards air

and compatibility with various hindered and functionalized aryl/heteroaryl amines

makes it an ideal complex for the synthesis of N-substituted isoindole-1,3-dione.

4.5.2 Preparation of polymer supported palladium-N-heterocyclic carbene complex

(PS-Pd-NHC):

Preparation of polymer supported palladium-N-heterocyclic carbene complex (PS-Pd-

NHC) is a two step process. The first step involves the preparation of resin supported

ionic liquid from the reaction of Merrifield’s peptide resin and N-methyl imidazole. In

the second step resin supported ionic liquid reacts with the Pd(OAc)2 in aqueous

solution of Na2CO3 to give the corresponding PS-Pd-NHC complex (Figure 4.3).

Figure 4.3 Preparation of polymer supported palladium-N-heterocyclic carbene

complex (PS-Pd-NHC).

NN

Cl-

CH2

NN

CH2Cl

CMPS

+ NMP, 80 oC

12 h

MR-IMZ-Cl

1-methylimidazole

N N

PdOAcAcO

PS-Pd-NHC

H2C

1. Pd(OAc)2, Na2CO3

2. Water/DMF(1:1)

3. 50 oC, 2hr

Chapter 4


187

4.5.3 PS-Pd-NHC catalyzed carbonylative cyclization reaction of o-halobenzoic acid.

A series of experiments were performed in order to optimize the reaction conditions

on carbonylative cyclization reaction of o-iodobenzoic acid with aniline as a model

system in the presence of PS-Pd-NHC as a catalyst (Scheme 4.14).

Scheme 4.14 Carbonylative cyclization of o-halobenzoic acid using

PS-Pd-NHC complex.

Various reaction parameters such as effect of solvent, catalyst loading, base,

temperature and time were studied and the results obtained are summarized in Table

4.5. It was observed that, the nature of solvent affected the yield of reaction. Solvents

like DMF, DMSO provided lower yield of expected product (Table 4.5, entries 1-2).

Whereas, water as a solvent did not provided desired product (Table 4.5, entry 3). As

toluene provided excellent yield (96%) of N-phenyl isoindole-1,3-dione, it was used

for further study (Table 4.5, entry 4). Thereafter effect of catalyst loading was studied,

where increasing initial catalyst loading from 0.5 mol% to 1 mol% has increased the

yield of desired product, while further increase in the amount of catalyst up to 1.5

mol% had no profound effect on the yield of N-phenyl isoindole-1,3-dione (Table 4.5,

entries 4-6). Further, reaction was carried out by using various organic and inorganic

bases (Table 4.5, entries 4 and 7-9). Among the various bases screened, Et3N was

found to be the best base for the present reaction system. In order to examine the

effect of temperature, the reactions was carried out at 80 °C but the lower yield of

N-phenyl isoindole-1,3-dione was observed (Table 4.5, entry 10) while on increasing

reaction temperature up to 100 °C excellent yield of the N-phenyl isoindole-1,3-dione

was observed. A reduced reaction time provided lower yield of N-phenyl isoindole-

1,3-dione (Table 4.5, entry 11), hence further reactions were carried out at 4 h. Hence,

the optimized reaction conditions were: o-iodobenzoic acid (1 mmol), amine (1.5

mmol), PS-Pd-NHC (1 mol %) and Et3N (2 mmol), toluene as a solvent (10 mL), at

100 °C for 4 h.

Chapter 4


188

Table 4.5 Optimization of carbonylative cyclization of o-iodobenzoic acida

Entry PS-Pd-NHC

(mol%)

Solvent Base Temp.

(°C)

Time

(h)

Yield

(%)b

Effect of solvent

1 1 DMF Et3N 100 4 50

2 1 DMSO Et3N 100 4 60

3 1 Water Et3N 100 4 --

4 1 Toluene Et3N 100 4 96

5 1.5 Toluene Et3N 100 4 97

6 0.5 Toluene Et3N 100 4 89

Effect of base

7 1 Toluene DBU 100 4 85

8 1 Toluene DABCO 100 4 90

9 1 Toluene K2CO3 100 4 50

Effect of Temperature and time

10 1 Toluene Et3N 80 4 80

11 1 Toluene Et3N 100 2 90

a Reaction conditions: o-iodobenzoic acid (1 mmol), aniline (1.5 mmol), base (2

mmol), PS-Pd-NHC (1 mol%), solvent (10 ml), CO pressure (1 atm). b Yield based on GC analysis.

It is noteworthy to mention that, the present reaction works under the

atmospheric CO pressure. After obtaining best reaction conditions in hand, the scope

of the present system was examined for the synthesis of diverse N-substituted

isondole-1,3-dione using various aromatic, aliphatic and heterocyclic primary amines,

and the results obtained are summarized in Table 4.6.

The developed system under optimized conditions with o-iodobenzoic acid

and aniline furnished 92% isolated yield of N-phenyl isondole-1,3-dione (Table 4.6,

entry 1). Relatively unreactive o-bromobenzoic acid was screened for synthesis of

isondole-1,3-dione, which provided moderate yield of desired product (55%) after 24

h (Table 4.6, entry 2). Thereafter, various substituted aromatic amines containing

Chapter 4


189

electron donating or electron withdrawing groups were tested for the reaction (Table

4.6, entries 3-9). p-toluidine, p-anisidine and 4-aminoacetophenone reacts with o-

iodobenzoic acid and provided 89%, 90% and 80% yield of desired product

respectively (Table 4.6, entries 3-5). The reaction of sterically hindered ortho

substituted aryl amines like o-toluidine and o-bromoaniline also provided good to

excellent yield of 2-(o-tolyl)isoindoline-1,3-dione and 2-(2-bromophenyl)isoindoline-

1,3-dione under optimized reaction conditions (Table 4.6, entries 6-7). The catalyst

was then subjected for the carbonylation of bulky α-naphthylamine and β-

naphthylamine which provided 89% and 75% of 2-(naphthalen-1-yl)isoindoline-1,3-

dione and 2-(naphthalen-2-yl)isoindoline-1,3-dione respectively (Table 4.6, entries 8-

9).

Encouraged by these results aliphatic amines such as n-butyl amine and benzyl

amine were screened which provided excellent yield of 2-butylisoindoline-1,3-dione

and 2-benzylisoindoline-1,3-dione respectively (Table 4.6, entries 10-11).

To the best of our knowledge heterocyclic N-substituted isoindole-1,3-dione

has not yet been synthesized from o-halobenzoic acid. Considering this various

heterocyclic N-substituted isoindole-1,3-dione were synthesized from different

heterocyclic amines such as 2-aminothiazole, 2-aminobenzothiazole and 5-

methylfurfuryl amine with ease, where all substrates were quite eligible providing

good to excellent yield of the expected products (Table 4.6, entries 12-14).

Table 4.6 Reaction of o-halobenzoic acid with different aromatic, aliphatic and

heterocyclic aminesa

Entry o-halo benzoic acid

derivative

Amine Product Yield

(%)b

1

92

2c

55

3

89

Chapter 4


190

4

90

5

80

6

76

7

81

8

89

9

75

10

91

11

90

12

80

13

76

14

85

a Reaction conditions: o-halobenzoic acid (1 mmol), amine (1.5 mmol), PS-Pd-NHC

(1 mol %), Et3N (2 mmol), toluene (10 mL), CO (1 atm), 100 °C, 4 h. b Isolated yield.


Chapter 4


191

4.5.4 PS-Pd-NHC catalyzed carbonylative cyclization reaction of o-halobenzoate.

Carbonylative cyclization of methyl methyl-2-iodobenzoate was previously reported

in literature by using non recyclable homogeneous palladium catalysts (Worlikar and

Larock, 2008; Buchwald et al., 2008), which requires harsh reaction conditions like

longer reaction time upto 24 h and higher catalyst loading upto 5 mol%.

Hence, to ensure the compatibility of developed protocol, carbonylative

cyclization of o-halobenzoate for the synthesis of isoindole-1,3-diones using PS-Pd-

NHC catalyst under atmospheric CO pressure have been developed (Scheme 4.15).

Scheme 4.15 Carbonylative cyclization of o-halobenzoate using

PS-Pd-NHC complex.

Representative examples of aliphatic and aromatic amines were screened with

methyl-2-halobenzoate and in all the cases moderate to good yield of desired products

were obtained (Table 4.7, entries 1-5). Reaction of methyl-2-iodobenzoate with

aniline provided 70% isolated yield of N-phenyl isoindole-1,3-dione (Table 4.7, entry

1). Whereas methyl-2-bromobenzoate provided moderate yield of N-phenyl isoindole-

1,3-dione (Table 4.7, entry 2). Reaction of methyl-2-iodobenzoate with p-toluidine

provided 75% yield of the corresponding product (Table 4.7, entry3). Aliphatic amine

like n-butyl amine reacts smoothly with 2-iodobenzoate providing 79% yield 2-

butylisoindoline-1,3-dione (Table 4.7, entry 4). Whereas benzyl amine afforded 80%

yield of respective N-substituted isoindole-1,3-dione (Table 4.7, entry 5).

Chapter 4


192

Table 4.7 Reaction of the o-halobenzoate with different aromatic and aliphatic

aminesa

Entry o-halo benzoate

derivative

Amine Product Yield

(%)b

1

70

2c

45

3

75

4

79

5

80

a Reaction conditions: o-halobenzoate (1 mmol), amine (1.5 mmol), PS-Pd-NHC

(1 mol%), Et3N (2 mmol), toluene (10 mL), CO pressure 1 atm., 100 °C, 6 h. b Isolated yield.


To expand the scope of developed protocol, the catalytic system was extended

for the synthesis of lactone (isobenzofuran-1(3H)-one) via cyclization reaction of o-

iodobenzyl alcohol using PS-Pd-NHC complex as a catalyst under optimized reaction

conditions (Scheme 4.16). The corresponding product, isobenzofuran-1(3H)-one was

obtained with excellent yield (up to 85% yield). This observation and obtained results

thus recommend that, varying the ortho substituent on o-haloaryls would lead to

synthesis of various heterocycles, thus highlighting the wide applicability of

developed protocol.

Chapter 4


193

Scheme 4.16 Carbonylative cyclization for synthesis of lactone using

PS-Pd-NHC complex.

In order to determine whether the catalysis was due to the PS-Pd-NHC

complex or due to a palladium metal that comes off the support at higher temperature

during the reaction and returns back to the support on cooling, a hot filtration test was

performed (Lempers, 1998; Zhao, 2009). Carbonylative cyclization reaction of o-

iodobenzoic acid with aniline was carried out at 100 oC. Then PS-Pd-NHC complex

was filtered off during reaction in a hot condition and the filtrate was allowed to react

further. The catalyst filtration was performed at the 100 oC in order to avoid possible

re-coordination of soluble palladium upon cooling. It was found that, after this hot

filtration, no further reaction occurred. This experimental finding’s suggested that, the

palladium metal did not leached out of complex at elevated temperature during the

progress of reaction. In addition, to reconfirm this observation ICP-AES analysis of

the reaction mixture was carried out, which revealed below detectable level (below

0.01 ppm) of palladium in solution.

In order to make the catalytic system more economical, reusability study of

PS-Pd-NHC catalyst was carried out on the model reaction of o-iodobenzoic acid with

aniline in presence of Et3N as a base in toluene at an atmosphere CO pressure (Figure

4.4). The catalyst exhibited remarkable activity and recyclability for four consecutive

cycles without decreasing activity of the catalyst.

Chapter 4


194

Figure 4.4 Recyclability study of PS-Pd-NHC catalyst.

As a result the developed protocol proved to be general for the carbonylative

cyclization reaction of various structurally and electronically different aryl and

heteroaryl amines with o-halobenzoic acid and o-iodobenzoate, providing good to

excellent yield of the corresponding isoindole-1,3-dione.

0

20

40

60

80

100

1 2 3 4

96 94 92 90

Yie

ld (

%)

Recycle Run

Chapter 4


195

4.6 CONCLUSION

In conclusion, for the first time a simple, efficient, phosphine free and

heterogeneous catalytic system for carbonylative cyclization of o-halobenzoic

acid for the synthesis of N-substituted isoindole-1,3-dione using polymer

supported Palladium N-heterocyclic carbene complex have been developed.

The present heterogeneous protocol sounds promising alternative to the

conventional methodologies for the synthesis of several N-substituted

isoindole-1,3-dione for simple, inexpensive o-halobenzoic acid derivative and

milder reaction condition like, use of atmospheric CO pressure, lower reaction

time.

Catalyst offers practical advantages such as; easy handling, separation from

product and reuse.

The reaction was optimized with respect to various parameters and enabled

carbonylative cyclization reaction of variety aromatic, aliphatic and

heterocyclic amines with o-halobenzoic acid affording excellent yield of

corresponding N-substituted isoindole-1,3-dione.

Protocol was also applied for the carbonylative cyclization of methyl-2-iodo

benzoate.

Catalytic system showed excellent activity and selectivity and effectively

recycled for four consecutive cycles.

The leaching of the Pd metal was examined by hot filtration and ICP-AES

analysis and the obtained result reveals that, there was no palladium metal

leaching.

Furthermore, synthesis of phthalide (isobenzofuran-1(3H)-one) via cyclization

reaction of o-iodobenzyl alcohol using optimized reaction conditions credits

an additional advantage to developed protocol.

Chapter 4


196

4.7 EXPERIMENTAL

4.7.1 General: All chemicals were purchased from Lancaster (Alfa-Aesar), Sigma

Aldrich, S. D. fine chemical and commercial suppliers. Gas chromatography analysis

was carried out on Perkin-Elmer Clarus 400 GC equipped flame ionization detector

with a capillary column (Elite-1, 30 m × 0.32 mm × 0.25 μm) using the external

standard method. A GC/MS-QP 2010 instrument (Rtx-17, 30 m × 25 mm i.d., film

thickness 0.25 μm df) (column flow 2 mL min−1

, 80-240 °C at 10 °C/min rise). The

1H NMR spectra were recorded on Varian-500/300 MHz FT-NMR spectrometer in

CDCl3 using TMS as the internal standard. Chemical shifts are reported in parts per

million (δ) relative to tetramethylsilane as the internal standard. J (coupling constant)

values were reported in hertz (Hz). Proton splitting patterns are described as s

(singlet), d (doublet), t (triplet), and m (multiplet).

4.7.2 Typical procedure for the preparation of polymer supported palladium-N-

heterocyclic carbene complex (PS-Pd-NHC):

Polymer supported palladium-N-heterocyclic carbene complex (PS-Pd-NHC) used

was prepared according to the procedure reported in the literature (Qureshi et al.,

2011). Preparation of PS-Pd-NHC complex is a two step process.

Step-1: Preparation of imidazolium-loaded polymeric support (MR-IMZ-Cl)

In 100 mL round bottom flask were added Chloromethyl polystyrene resin

(CMPS)/Merrifield resin (2 % cross linked, 2.3 mmol Cl/g, Aldrich) 5 g, N-methyl

imidazole (20 mmol) in toluene (50 mL) and refluxed for 24 h. On completion, the

reaction mixture was cooled to room temperature. It was then filtered and the residue

obtained was washed with toluene, 0.1 mol/L HCl, water and methanol sequentially

followed by drying under reduced pressure to afford imidazolium-loaded polymeric

support MR-IMZ-Cl (loading of ionic liquid : 1.67 mmol/g, determined by elemental

analysis). The complex was further characterized by FT-IR to check the attachment of

the ionic liquid. A strong band centred at 1569 cm-1

confirms the attachment of the

imidazole on Merrifield resin.

[Note- Merrifield resin is a used as a polymer support, because it is a type of

copolymer which is nontoxic, commercially available polymer which resists up to

higher temperature range, more reactive and can be easily recovered from reaction],

Chapter 4


197

Step-2: Preparation of polymer supported palladium-N-heterocyclic carbene complex

with the imidazolium loaded polymeric support (PS-Pd-NHC).

A mixture of the imidazolium loaded polymeric support (MR-IMZ-Cl) (1.0 g, 19.1

mmol/g) and Pd(OAc)2 (0.225 g, 1 mmol) was suspended in DMF (20 mL). To this

suspension an aqueous solution (20 mL) of Na2CO3 (1.06 g, 10.0 mmol) was added.

The mixture was then sonicated at room temperature for 30 min. and agitated in an

orbital shaker at 50 °C for 2 h at 150 rpm. On completion, the reaction mixture was

filtered and the polymeric support was washed vigorously with distilled water (5 × 10

mL), methanol (5 × 10 mL) and dried under reduced pressure to provide PS-Pd-NHC.

The amount of Pd loaded on the polymeric support was determined by using

ICP-AES analysis. The polymer supported palladium-N-heterocyclic carbene complex

(50 mg) was treated with a mixture (25 mL) of hydrochloric acid and nitric acid (1:1,

v/v) at room temperature for 30 min. The orange-coloured solution formed was

filtered, washed with distilled water. The filtrate and washing solution were combined

to determine the amount of Pd by Inductively coupled plasma-atomic emission

spectrometry (ICP-AES) and was found to about 0.29 mmol/g of support.

4.7.3 A typical experimental procedure for carbonylative cyclization of o-halobenzoic

acid with amine.

To a 100 mL stainless steel autoclave, o-halobenzoic acid (1 mmol), amine (1.5

mmol), PS-Pd-NHC (1 mol %), toluene (10 mL) and Et3N (2 mmol) were added. The

autoclave was closed, purged four times with carbon monoxide, pressurized with 1

atm of CO and then heated at 100 °C for 4 h. After completion of reaction, the reactor

was cooled to room temperature and remaining CO gas was carefully vented then the

reactor opened and the reaction mixture was filtered, vessel was thoroughly washed

with ethyl acetate (2 x 5 mL) to remove any traces of product and catalyst if present.

The filtrate obtained was evaporated under vacuum to give the crude product which

was purified by column chromatography (silica gel, 60-120 mesh; petroleum

ether/ethyl acetate, 95:05) to afford the desired product with high purity.

Chapter 4


198

4.7.4 A typical experimental procedure for carbonylative cyclization of o-

halobenzoate with amine.

To a 100 mL stainless steel autoclave, o-halobenzoate (1 mmol), amine (1.5 mmol),

PS-Pd-NHC (1 mol %), toluene (10 mL) and Et3N (2 mmol) were added. The

autoclave was closed, purged four times with carbon monoxide, pressurized with 1

atm of CO and then heated at 100 °C for 6 h. After completion of reaction, the reactor

was cooled to room temperature and remaining CO gas was carefully vented then the

reactor opened and the reaction mixture was filtered, vessel was thoroughly washed

with ethyl acetate (2 x 5 mL) to remove any traces of product and catalyst if present.

The filtrate obtained was evaporated under vacuum to give the crude product which

was purified by column chromatography (silica gel, 60-120 mesh; petroleum

ether/ethyl acetate, 95:05) to afford the desired product with high purity.

4.7.5 Experimental procedure for recycling of PS-Pd-NHC catalyst.

The catalyst obtained after filtration was thoroughly washed with distilled water (3 x 5

mL) and then with methanol (3 x 5 mL) to remove any traces of organic material if

present, and dried under reduced pressure. The dried catalyst was then used for

catalyst recyclability experiment.

4.7.6 General procedure for synthesis of phthalide (Isobenzofuran-1(3H)-one).

To a 100 mL stainless steel autoclave, o-iodobenzyl alcohol (1 mmol), PS-Pd-NHC (1

mol %), toluene (10 mL) and Et3N (2 mmol) were added. The autoclave was closed

and pressurized with 1 atm. of CO and then heated at 100 °C for 4 h. After completion

of reaction, the reactor was cooled to room temperature and remaining CO gas was

carefully vented then the reactor was opened and the reaction mixture was filtered, the

vessel was thoroughly washed with ethyl acetate (2 x 5 mL) to remove any traces of

product and catalyst if present. The product was isolated by column chromatography

(silica gel, 60-120 mesh; petroleum ether/ethyl acetate, 95:05) in 85% yield.

Chapter 4


199

4.8 SPECTRAL DATA

2-Phenylisoindole-1,3-dione

White solid; 1H NMR (500 MHz, CDCl3): δ = 7.99 (dd, J = 5.5, 3.3 Hz, 2H),

7.82 (dd, J = 5.4, 3.5 Hz, 2H), 7.43-7.55 (m, 5H); GC-MS (EI, 70 eV): m/z (%) = 223

(M+, 100), 179 (75), 104 (20), 76 (48), 50 (10).

2-Naphthalen-2-yl-isoindole-1,3-dione

White solid; 1H NMR (500 MHz, CDCl3): δ = 8.00-7.81 (m, 8H), 7.56-7.53

(m, 3H).

2-(4-Methyl-phenyl)-isoindole-1,3-dione

White solid; 1H NMR (500 MHz, CDCl3): δ = 7.95 (dd, J = 5.1, 3 Hz, 2H),

7.78 (dd, J = 5.1, 3 Hz, 2H), 7.54-7.26 (m, 4H), 2.24 (s, 3H); GC-MS (EI, 70 eV): m/z

(%) = 238 (M+, 100), 193 (45), 104(29), 76(39).

2-(4-Methoxy-phenyl)-isoindole-1,3-dione

White solid; 1H NMR (500 MHz, CDCl3): δ = 7.94 (m, 2H), 7.78 (m, 2H),

7.33 (d, J = 8.5 Hz, 2H), 7.02 (d, J = 8.5 Hz, 2H), 3.85 (s, 3H); GC-MS (EI, 70 eV):

m/z (%) = 253 (M+, 100), 238 (65), 210 (18), 209 (16), 130 (12), 106 (20), 76(35).

2-(2-Methyl-phenyl)-isoindole-1,3-dione


7.80 (dd, J = 5.4, 3 Hz, 2H), 7.39-7.22 (m, 4H), 2.22 (s, 3H); GC-MS (EI, 70 eV): m/z

(%) = 238 (M+, 100), 191 (25), 104(26), 76 (45).

2-(2-Bromophenyl)isoindoline-1,3-dione


7.82 (dd, J = 5.5, 2.5 Hz, 2H), 7.75 (d, J = 8 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.38-

7.34 (m, 2H); GC-MS (EI, 70 eV): m/z (%) = 301 (2), 222 (M+, 100), 164 (5), 166 (8),

111 (7), 76 (25). ESI H.R. mass spectrometry: m/z calc. 301.9817 [(C14H9NO2Br)H]+,

measured 301.9823.

Chapter 4


200

2-(4-Acetyl-phenyl)-isoindole-1,3-dione

Pale yellow solid; 1H NMR (500 MHz, CDCl3): δ = 8.13 (d, J = 8.5 Hz, 2H),

8.01 (dd, J = 5.5, 3.5 Hz, 2H), 7.85 (dd, J = 5.5, 3.5 Hz, 2H), 7.65 (d, J = 8.5 Hz, 2H),

2.67 (s, 3H); GC-MS (EI, 70 eV): m/z (%) = 265 (25), 250 (M+, 100), 222 (29), 166

(20), 104 (28), 76 (20).

2-Butyl-isoindole-1,3-dione

Colourless liquid; 1H NMR (300 MHz, CDCl3): δ = 7.84-7.83 (m, 2H), 7.72-

7.71 (m, 2H), 3.69 (t, J = 7.5 Hz, 2H), 1.66 (qt, J = 7.5 Hz, 2 H), 1.36 (qt, J = 7.5 Hz,

2 H), 0.95 (t, J = 7.5 Hz, 3H); GC-MS (EI, 70 eV): m/z (%) = 203 (40), 161 (50), 160

(M+, 100), 133 (20), 130 (22), 105 (14), 77 (29).

2-Benzyl-isoindole-1,3-dione

White solid; 1H NMR (500 MHz, CDCl3): δ = 7.86-7.87 (m, 2H), 7.72-7.73

(m, 2H), 7.45 (d, J = 7.5 Hz, 2H), 7.32-7.34 (m, 3H), 4.87 (s, 2H); GC-MS (EI, 70

eV): m/z (%) = 237 (M+, 100), 219 (50), 208 (21), 104 (60), 91 (10), 77 (35).

2-Thiazol-2-yl-isoindol-1,3-dione


7.85 (dd, J = 5.5, 2 Hz, 2H), 7.83 (d, J = 3.5 Hz, 1H), 7.27 (d, J = 3.5, 1H); GC-MS

(EI, 70 eV): m/z (%) = 230 (M+, 100), 76 (51), 50 (10).

2-(5-Methyl-furan-2-ylmethyl)-isoindole-1,3-dione

Pale yellow solid; 1H NMR (500 MHz, CDCl3): δ = 7.86-7.85 (m, 2H), 7.71-

7.70 (m, 2H), 6.23 (d, J = 3 Hz, 1H), 5.87 (d, J = 2.1 Hz, 1H), 4.80 (s, 2H), 2.24 (s,

3H); GC-MS (EI, 70 eV): m/z (%) = 241(M+, 100), 226 (18), 198 (70), 170 (26), 95

(39), 78 (56).

2-(3-trifluoromethyl)phenyl)isoindoline-1,3-dione


7.83 (dd, J = 5.5, 3.5 Hz, 2H), 7.78 (s, 1H), 7.63-7.70 (m, 3H); GC-MS (EI, 70 eV):

m/z (%) = 291 (M+, 100), 247 (92), 104 (32), 76 (72), 50 (20). ESI H.R. mass

spectrometry: m/z calc. 292.0585 [(C15H9NO2F3)H]+, measured 292.0584.

Chapter 4


201

Isobenzofuran-1(3H)-one

White solid; 1H NMR (500 MHz, CDCl3): δ = 7.94 (d, J = 7.5 Hz, 1H), 7.7 (t,

J = 7 Hz, 1H), 7.51-7.57 (m, 2H), 5.35 (s, 2H); GC-MS (EI, 70 eV): m/z (%) = 134

(31), 105 (M+, 100), 77 (55), 51 (20).

Chapter 4


202

4.8.1 SPECTRAS

Figure 4.5 1H NMR (500 MHz) spectrum of 2-Phenylisoindole-1,3-dione.

Figure 4.6 GC-MS spectrum of 2-Phenylisoindole-1,3-dione.

Chapter 4


203

Figure 4.7 1H NMR (500 MHz) spectrum of 2-Naphthalen-2-yl-isoindole-1,3-dione.

Figure 4.8 1H NMR (500 MHz) spectrum of 2-(4-Methyl-phenyl)-isoindole-1,3-dione.

Chapter 4


204

Figure 4.9 GC-MS spectrum of 2-(4-Methyl-phenyl)-isoindole-1,3-dione.

Figure 4.10 1H NMR (500 MHz) spectrum of 2-(4-Methoxy-phenyl)isoindole-1,3-

dione.

Chapter 4


205

Figure 4.11 GC-MS spectrum of 2-(4-Methoxy-phenyl)isoindole-1,3-dione.

Figure 4.12 1H NMR (300 MHz) spectrum of 2-(2-Methyl-phenyl)isoindole-1,3-

dione .

Chapter 4


206

Figure 4.13 GC-MS spectrum of 2-(2-Methyl-phenyl)isoindole-1,3-dione.

Figure 4.14 1H NMR (500 MHz) spectrum of 2-(2-Bromophenyl)isoindoline-1,3-

dione .

Chapter 4


207

Figure 4.15 GC-MS spectrum of 2-(2-Bromophenyl)isoindoline-1,3-dione.

Figure 4.16

1H NMR (500 MHz) spectrum of 2-(4-Acetyl-phenyl)-isoindole-1,3-

dione.

Chapter 4


208

Figure 4.17 GC-MS spectrum of 2-(4-Acetyl-phenyl)-isoindole-1,3-dione.

Figure 4.18 1H NMR (300 MHz) spectrum of 2-Butyl-isoindole-1,3-dione.

Chapter 4


209

Figure 4.19 GC-MS spectrum of 2-Butyl-isoindole-1,3-dione.

Figure 4.20 1H NMR (500 MHz) spectrum of 2-Benzyl-isoindole-1,3-dione.

Chapter 4


210

Figure 4.21 GC-MS spectrum of 2-Benzyl-isoindole-1,3-dione.

Figure 4.22 1H NMR (500 MHz) spectrum of 2-Thiazol-2-yl-isoindol-1,3-dione.

Chapter 4


211

Figure 4.23 GC-MS spectrum of 2-Thiazol-2-yl-isoindol-1,3-dione.

Figure 4.24 1H NMR (500 Mz) spectrum of 2-(5-Methyl-furan-2-ylmethyl)isoindole-

1,3-dione.

Chapter 4


212

Figure 4.25 GC-MS spectrum of 2-(5-Methyl-furan-2-ylmethyl)isoindole-1,3-dione.

Figure 4.26 1H NMR (500 MHz) spectrum of 2-(3-(trifluoromethyl)phenyl)

isoindoline-1,3-dione.

Chapter 4


213

Figure 4.27 GC-MS spectrum of 2-(3-(trifluoromethyl)phenyl) isoindoline-1,3-dione.

Figure 4.28 1H NMR (500 MHz) spectrum of Isobenzofuran-1(3H)-one.

Chapter 4


214

Figure 4.29 GC-MS spectrum of Isobenzofuran-1(3H)-one.

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