Synthesis of heterocyclic compounds based on isatin through 1, 3-dipolar cycloaddition reactions

This review gives an overview of the advances in the use of isatin in the synthesis of various heterocyclic compounds via 1,3-dipolar cycloaddition reactions during the period from 2000 to 2011.


Introduction
The biological and pharmacological properties of isatin and its derivatives have led to extensive use of these compounds as key intermediates in organic synthesis. 1Isatin is a core constituent of many alkaloids 2 and drugs 3 as well as dyes, 4 pesticides and analytical reagents.Literature surveys reveal that various derivatives of isatin possess diverse activities such as antibacterial, 5 antifungal, 6 antiviral, 7 anti-HIV, 8 anti-mycobacterial, 9 anticancer, 10 anti-inflammatory 11 and anticonvulsant activities. 12urthermore, isatins with their multifunctionality and diversity of transformations are synthetically versatile substrates and many efforts have been made toward the synthesis of these compounds.
1,3-Dipolar cycloaddition, also known as the Huisgen reaction, 13 is regarded as one of the most attractive methods for the formation of pharmacologically important five-membered Nheterocyclic compounds.1,3-Dipolar cycloaddition of ylidic species such as azomethine ylides with dipolarophiles provides an efficient and convergent approach for constructing pyrrolidine rings which are classes of compounds with significant biological activities.
Considering isatin as an important building block in organic synthesis, and since there is a wide range of reactions that include isatin in the synthesis of heterocyclic compounds, in the present review the focus is on applications of isatin in 1,3-dipolar cycloaddition reactions from reports that have been published after 2000.

Scheme 1
The synthesis of spiropyrrolizidine oxindoles 8 containing two ester groups or two amide groups has been reported.In this reaction maleates or maleamides 7 act as dipolarophiles (Scheme 2). 15

Scheme 4
β-Nitrostyrene 9 was also used in reaction with non-stabilized azomethine ylides generated from isatin 1 with sarcosine 17, resulting in the formation of a series of spiro-oxindolonitropyrrolidines 18 in good yields (Scheme 5). 19

Scheme 5
The [3+2]-cycloaddition reaction of 3-acetylcoumarins 19 with azomethine ylides in toluene under reflux for 18 h afforded chromene bearing novel spiropyrrolidine-oxindoles 20.The products 21 were surprisingly obtained when the reactions were carried out in methanol under reflux conditions for 15 h (Scheme 6). 20The results show that the reaction in methanol was accompanied by deacetylation, presumably by nucleophilic attack of methanol at the COMe group.

Scheme 6
Chen and coworkers published a study of reactions of isatin, α-amino acids and 1,4naphthoquinone 22 using ultrasound in methanol at about 40 °C to afford a series of 3spiro[pyrrolidino-oxindoles] derivatives 23 (Scheme 7). 21

Scheme 7
Dipolarophiles 24 and 25 derived from galactose have been reacted with azomethine ylides generated from isatin and secondary amino acids to give the corresponding spiroglycoheterocycles 26-29 in good yields (Scheme 8). 22

Scheme 10
A synthetic route for the preparation of a novel class of dicyano-functionalised spiropyrrolidine 37 and spiropyrrolizidine 38 from the reaction of various arylidenemalononitrile Knoevenagel adducts 36 with non-stabilized azomethine ylides generated from isatin and α-amino acids (sarcosine/N-phenylglycine/proline) has been developed (Scheme 11). 25The reactions were carried out under both conventional heating and ultrasonic irradiation conditions.

Scheme 16
This reaction was also carried out with L-proline 6 in place of sarcosine (Scheme 17). 31

Scheme 20
The cycloaddition reaction of azomethine ylides generated by the reaction of isatin and sarcosine, with the olefinic bond of Baylis-Hillman adducts 69 gave the corresponding cycloadducts 70 as single regioisomers as disclosed by Raghunathan and coworkers (Scheme 21). 35

Scheme 23
Investigations by Pardasani and coworkers have shown that the oxazolidinone compound 78, was derived from the condensation of isatin with L-proline, while in the presence of a dipolarophile, the intermediate iminium species 76 underwent decarboxylation to give the azomethine ylide 79 which subsequently underwent 1,3-dipolar cycloaddition reactions to give spiro-polycyclic compounds 80 and 81 (Scheme 24).38

Scheme 27
The chemistry of phosphorus and sulfur ylides has been exploited for the reaction of various bromoallyl derivatives 95 with methyl acrylate, methyl vinyl ketone and N-phenylmaleimide 96 to afford the respective spirocyclic products 97 in good to moderate yields.The reaction of the bromoallyl derivatives of 1-methyl isatins 95 in acetonitrile with Me 2 S, diazo compounds 98, and K2CO3 at room temperature afforded 3-spiropyrazole-2-oxindoles 99 (Scheme 28). 42

Scheme 29
The 1,3-dipolar cycloaddition of stable isatin ketonitrone 106 with various cyclic and acyclic dipolarophiles has been conducted under classical, ionic liquid and solvent-free conditions to give novel spiro[oxindole-isoxazolidine] derivatives 108 and 109 with similar diastereoselectivity (Scheme 30). 44Condensation of isatin 1 or isatin imine 105 with phenylhydroxylamine led to the formation of stable isatin ketonitrones 106 and 107 in high yields.It was found from ROESY and NOE investigations that the configuration of the stable isatin ketonitrone was Z and not E.

Scheme 32
Spiroindoles 121 were prepared readily via a one-pot, 1,3-dipolar cycloaddition reaction of azomethine imines 120 with isatin imines 105 under microwave irradiation and classical heating (Scheme 33).47  By using microwave irradiation, the reaction time was reduced greatly from 9-14 hours to 6-8 min and the yield of the reaction was enhanced by 10-20% compared to the conventional heating method.

Scheme 33
The combination of an α-diazoester 123 and an imine 122 in the presence of a Cu(I) catalyst generated a transient azomethine ylide which underwent a highly diastereoselective cycloaddition with dipolarophile 124 to afford highly substituted spiropyrrolidinyloxindoles 125 in a convergent, three-component assembly reaction (Scheme 34). 48

Scheme 44
Synthesis of novel dispiro pyrrolo/pyrrolizidino ring systems by the cycloaddition of azomethine ylides with the dipolarophile 9-arylidine-fluorene 163 using four different methodologies has been described (Scheme 45). 61A solvent-free microwave-assisted approach gave products with the highest yields in the shortest times.

Scheme 47
Perumal and coworkers employed two dipolarophiles 173 and 174 to yield 175 and 176 respectively, as single products with good yields (Scheme 48). 64

Scheme 50
The reaction of tetrahydroisoquinoline-3-carboxylic acid 140 with 180 and isatin was reported, too.Compound 182 as an alternative dipolarophile, reacted with isatin and 140 in the presence of TiO2-silica catalyst (Scheme 51). 67

Scheme 52
Reaction of azomethine ylides with various p-substituted 2,6-bis(arylmethylidene)cyclohexanones 187 under different conditions, proceeded regioselectively to give novel dispiroheterocycles 188.The products, on subsequent annulation with hydrazine hydrate, afforded 189 in good yields (Scheme 53). 69Replacing benzylamine with sarcosine in this reaction has also been reported. 70The products were screened for their antibacterial and antifungal activity against ten human pathogenic bacteria and four dermatophytic fungi.6a

Scheme 53
(Z)-16-arylidene-estrone derivatives 190 as 2π components were used in reactions with azomethine ylides for the synthesis of hitherto unknown steroidal dispiropyrrolidines 191 (Scheme 54). 71The reactions were carried out using three different sets of conditions.

Scheme 56
Domino reactions of isatin, and sarcosine 74 or phenylglycine, 75 furnishing highly functionalised dispiropyrrolidines 200-203 in moderate yields, have been described.When the reaction was performed with L-proline and congeners it resulted in the dimeric azomethine ylides 204 (Scheme 57). 75These compounds were screened for their antimycobacterial activities.

Scheme 64
Compound 228 as a dipolarophile undergoes regioselective 1,3-dipolar cycloaddition in different reaction conditions to give a new class of complex spiropyrrolidines 229 88 and 230 89 in good yields (Scheme 65).