Isoindoloindolones - biological activities and syntheses

This review describes the biological activity and synthesis of structurally and biologically significant isoindoloindolone compounds. The various synthetic reports are mainly described under two headings based on use of palladium chemistry or the Wittig reaction as the key step for the construction of the indole or isoindole ring. Other methods are included in the miscellaneous approaches.


Biological Activity
The derivatives of isoindoloindolone are well known for their specific bioactivity profiles.Isoindoloindolone derivatives are reported as potent ligands of MT 3 . 5The third melatonin binding site, MT 3 , is an enzyme, quinone reductase-2 and not a usual seven transmembrane domains receptor.Hydroxyisoindoloindolone derivative 2a has subnanomolar affinity for the melatonin binding site MT 3 .Chloroisoindoloindolone derivative 2b, amidoisoindoloindolone derivative 2c, and aminoisoindoloindolone 2d show DNA binding ability and non-specific interference with the topoisomerase-I catalytic cycle (Figure 2).Compound 2b also has an antiproliferative effect against HT-29 and L1210 cell lines.Compounds 2c and 2d exhibit inhibitory potency for topoisomerase-II comparable to that of etoposide. 6,7Compound 2e shows moderate binding affinity towards human neurokinin-1 (hNK 1 ) receptors in the central nervous system. 1 The NorA protein is a multidrug resistant efflux in the bacterium Staphylococcus aureus.This has resulted in resistance towards numerous structurally dissimilar antibiotics such as norfloxacin, ethidium bromide, berberine, etc. Isoindoloindolone 1 is used as a precursor in the synthesis of 2-aryl-5-nitroindoles as NorA efflux pump inhibitors. 8,9Isoindoloindolone 1 also exhibit charge-transfer fluorescence with high quantum yields in non polar solvents. 10

Synthetic Strategies
Synthetic strategies of isoindoloindolones have been explored by research groups all over the world for decades (1979-2014) due to their diverse applications.Some of these efficient and remarkable achievements are discussed below.

Palladium catalyzed coupling reactions
2][13][14][15][16][17][18] It was first explored by Itahara in 1979 [11][12][13][14] and was further developed by many other research groups.KOAc as a base in refluxing DMA for the synthesis of isoindoloindolones. 1 DeBoef and coworkers used Cu(OAc) 2 along with Pd(OAc) 2 in refluxing acetic acid in O 2 atmosphere for intramolecular aerobic oxidative coupling of 1-benzoylindoles to give isoindoloindolones. 15lectron rich tethered arenes gave better yields than unsubstituted arenes.Kandukuri and Oestreich used methyl nicotinate as ligand for Pd(OAc) 2 in mesitylene and pivalic acid in O 2 atmosphere for aerobic dehydrogenative double C-H coupling in 1-benzoylindoles to give isoindoloindolones. 16ibino and co-workers prepared isoindoloindolone by employing Suzuki-Miyaura reaction of N-Boc-indole-boronic acid 5 and methyl-o-iodobenzoate 6 to give N-Boc-indole esters 7 followed by deprotection to give prominent precursor 8 and finally base mediated cyclisation to isoindoloindolones (Scheme 2). 19The method was further modified to complete the total synthesis of indoloquinoline alkaloid isocryptolepine.Scheme 2. Hibino's method.Cyclisation of dihalo-N-vinylbenzamide 13 to isoindoloindolone by tandem intramolecular Heck reaction is demonstrated by Dominguez's group taking advantage of difference in reactivity between two halo groups (Scheme 4). 21The required dihalo-N-vinylbenzamide 13 was obtained by condensation of o-bromoarylamine 11 with acetaldehyde followed by benzoylation with o-iodobenzoyl chloride 12. Chemoselective palladation with the iodo group of benzamide 13 to form methylene phthalimide intermediate via 5-exo-trig cyclisation followed by endo cyclisation furnished the isoindoloindolone.The overall yield of the sequence was 35%.Estevez's laboratory reported a copper-mediated intramolecular cyclisation of methyl 2-(2aminophenylethynyl)benzoates 16 to isoindoloindolones (Scheme 5, Table 2). 22This precursor was prepared by double Sonogashira coupling reactions initially between trimethylsilylacetylene and methyl-o-iodobenzoate 6 then subsequently with o-iodoaniline 15.Though the chemistry involved in the synthesis is quite interesting, the low overall yields (6-38%) discourage its application on a larger scale.Ponpandian and Muthusubramanian achieved isoindoloindolone synthesis using copper catalyzed domino sp-sp 2 decarboxylative cross coupling reaction of arylpropiolic acids 17 with o-iodotrifluoroacetanilide 18 and subsequent cyclisation (Scheme 6) in excellent yield. 23owever, the scope of this method to prepare other derivatives was not studied.3). 24This method efficiently demonstrates the utility of isocyanides in C-N or C-C bond construction with N-tert-butyl intermediate 20.Using this method a library of twelve compounds was prepared in good to excellent yield.

Wittig reactions
Boutin and co-workers have developed a sequence involving Wittig olefination of onitrobenzaldehyde 21 with in situ phosphorane formed from the phosphonium salt 22 to give nitroarene 23. 5 The nitro group was reduced by catalytic hydrogenation in the presence of Raney Ni followed by base hydrolysis of the amino-lactone 24 to give the indole acid 25 (Scheme 8).
The acid was then converted into isoindoloindolones by refluxing in toluene in presence of p-TSA.Six isoindoloindolone derivatives with substituents on both the rings were prepared using this four-step protocol in overall yields of 32-58% (Table 4).Our group has developed a two-step route to 6H-Isoindolo[2,1-a]indol-6-ones starting from o-nitrobenzaldehydes 26. 25 The methodology involves Wittig reaction followed by tandem reductive cyclization-lactamization (Scheme 9).Various substituted o-nitrobenzaldehydes were subjected to Wittig reaction with the phosphorane formed from the benzylic phosphorus salt 27 to obtain the corresponding substituted ethyl 2-(2-nitrostyryl)benzoates 28.These were then subjected to tandem reductive cyclisation -lactamization using PPh 3 in refluxing diphenyl ether.The corresponding isoindoloindolones were obtained in good overall yields.(Table 5) The flexibility of this method was demonstrated by synthesizing a series of isoindoloindolones with electron-donating groups like methoxy, dimethoxy, trimethoxy, and methylenedioxy, as well as electron-withdrawing groups like chloro.

Miscellaneous approaches
Griffiths and his group 26 developed a novel route to isoindoloindolones using o-(Nphthaloyl)benzoic acids 34 (Scheme 11, Table 7).The process involves formation of acid chlorides followed by reaction with triethyl phosphite to give tetracyclic-β-keto phosphonates 35 via a carbon-carbon bond forming reaction involving phosphonate anion.This ketoamide phosphonate 35 on reduction with NaBH 4 furnished the required isoindoloindolones in 31-44 % overall yields.A metal free synthesis of isoindoloindolone was reported by Wang's group using dibenzocyclohepten-5-one 41 as starting material (Scheme 14). 32This method involves Beckmann rearrangement of the oxime 42 to the lactam 43 using TFA, followed by bromination and intramolecular cyclisation of dibromodihydrodibenzoazocin-6-one 44 to yield isoindoloindolone.

Conclusions
The synthesis of isoindoloindolones has been extensively studied on account of their diverse biological applications.The methods use different approaches for constructing the indole or isoindole ring.Palladium-catalyzed cyclisation to the indole C-2 is widely used in assembling the isoindole ring.The Wittig reaction was also explored in a few approaches for assembling the indole ring.Clean and high yielding general strategies are required for making newer analogues for biological testing.

a
Isolated yields.

a
Calculated over 3 steps.

a
Isolated yields.

28 a
Calculated over 4 steps

a
Calculated over 2 steps.

a
Calculated over 3 steps.

Table of Contents
Dinnell et al. used Pd(PPh 3 ) 4 as catalyst and

Table 1 .
Finally Pd catalyzed intramolecular Heck C-C coupling gave isoindoloindolones.Various derivatives with substituents on both aryl rings were prepared efficiently (Table1) in moderate to good yields.The yields of 7-methyl and 10-chloro-11-methyl derivatives of 1 were somewhat low.Bao's method for isoindoloindolones 20 1 Scheme 3. Bao's method.Bao's group20reported a synthesis of isoindoloindolones through one-pot sequential Cu catalyzed C-N coupling and Pd catalyzed C-H activation reaction (Scheme 3).This two-step one-pot synthesis uses o-gem-dibromovinylanilines 9 as a starting material for benzoylation with benzoyl chloride and simultaneous intramolecular Buchwald-Hartwig C-N coupling with CuBr catalyst to give N-benzoylated 2-bromoindole 10.