Reduction of isatin and cyanocinnamate derivatives using the Hantzsch's ester. The mechanism of Hantzsch's ester oxidation has been investigated by semiempirical calculations employing the PM3 Hamiltonian.
The reduction of the methyleneoxindole derivatives has been proposed to occur via hydride transfer from the C-4 position of the ester to the C-3 carbon atom of the exocyclic double bond and via proton transfer from the protonated dihydropyridine intermediate to C-4 Figure 8. Figure 8. Representation of the hydride and proton transfers upon the reduction of methyleneoxindole derivatives.
Scheme 14 shows the reaction conditions for the synthesis of anhydrolycorinone 66 and hippadine 67 alkaloids. Synthesis of anhydrolycorinone 66 and hippadine 67 alkaloids. This synthetic route also produces dehydroanhydro-lycorine 68 , pratosine 69 , assoanine 70 , anhydrolycorinone 71 and oxoassoanine 72 alkaloids Figure 9.
Figure 9. Structures of alkaloids. Synthetic route for the preparation of isatin nucleosides 75 and the corresponding HSV-1 inhibition percentages. Isatin derivatives inhibited both the expression and activity of NOS and COX-2 in macrophage cells, demonstrating their anti-inflammatory activities.
Therefore, these compounds may be useful in the design of new lead compounds for the discovery of drugs with anti-inflammatory and anticancer activities Figure Structures of isatin and aromatic ring substituted derivatives.
Ribeiro et al. Reaction conditions for the synthesis of isatin ketals. Because endogenous isatin acts on the central nervous system CNS ,51 the hypnotic and sedative activities of the isatin ketals shown in Scheme 16 have been evaluated by Zapata-Sudo et al.
To overcome this difficulty, Pinto et al. The cyclisation of isonitrosoacetanilides 79 using BMI. Cyclisation reactions using BMI. NTf2 and HBF4. In the case of 3-substituted isonitrosoacetanilides, the cyclisation step in the Sandmeyer's procedure can generate a mixture of two regioisomers Scheme Almeida et al.
This technique was effective in all cases with the same solvent system hexane:ethylacetate:ethanol:water, Pathway of a formation of 4-substituted-isatins, b formation of 6-substituted-isatins. All products were obtained with excellent yields. The chlorination of aromatic isatin with trichloro-isocyanuric acid TCCA using sulfuric acid as a catalyst was studied by Ribeiro et al.
A continued interest in the preparation of chlorinated isatins led Silva et al. In the presence of sulfuric acid, the isatin aromatic ring was always chlorinated at one or two positions, depending on the amount of TCCA used Scheme 19B. In the presence of acetic acid or acetone, N-chlorinated products were formed because the isatin nitrogen was not replaced by a methyl group or a substituent at position 7.
The reactions of isatins containing electron-withdrawing groups produce only monochlorinated products, except when there is competition from the ipso substitution.
Isatin chlorination with TCCA. The C-3 isatin carbonyl can be removed selectively to yield the corresponding oxindoles because it is more electrophilic than the amide carbonyl C2. This difference in electrophilicity allows the synthesis of oxindoles from isatins using different methodologies to reduce the C-3 carbonyl, e. Oxindole-based compounds 87, 88 and 89 Figure 11 have been shown to inhibit protein kinases via competition with ATP.
For example, these compounds bind to residues in the ATP pocket of the tyrosine kinase intracellular domain of the VEGF receptor, which regulates angiogenesis. Structures of semaxanib 87, SU 88 and sunitinib As part of on-going research on the synthesis of new bioactive substances, Silva et al.
E-products were obtained in the presence of either KOH or morpholine, however, substantially higher yields of the Z-products were noted when morpholine was used as the catalyst. Selectivity reversal was observed in the reactions of the di-substituted 5,7-dichloro 90d and 5,7-dibromo 90f oxindoles in the presence of this catalyst, with the predominant formation of the Z-products.
The position rather than the nature of the substituent determined the outcome of the reaction: dichloro 90e and dibromo 90g derivatives reacted to yield only the Z-products, most likely due to steric effects. Synthesis of ferrocenyl oxindoles.
The effects of the ferrocenyl oxindoles shown in Scheme 20 on the migration of tumour cells MDA-MB breast cancer cells have been investigated using wound healing and Boyden chamber cell migration assays. Additionally, the redox behaviour of all compounds was evaluated by cyclic voltammetry.
The ferrocenyl Fc group was found to be more easily oxidised in the Z isomers than in the E isomers of the oxindoles 93ac and 93gi. Porphyrin indolinone conjugates 97 have been prepared by Menezes et al. Synthesis of porphyrin indolinone conjugates This technique allows the detection of transient ionic species with short lifetimes under mild conditions. The Sandmeyer's method is easily reproduced and can be used in undergraduate experimental classes.
In an effort to help chemistry teachers diversify and improve their experimental classes, Silva et al. Conclusion Isatin is a molecule with great synthetic versatility and enormous pharmacological potential that has been intensively investigated by Brazilian research groups.
Several structural modifications of the basic core of this molecule have been made, such as ring and alkyl group addition. These modifications often take advantage of the distinct reactivities of the two carbonyls and the N-H group.
In addition to the synthesis of novel compounds, new methods of obtaining isatins have been explored by Brazilian groups. The high number of citations of the work carried out in Brazil is indicative of the Brazilian contribution to the chemistry of isatins.
The author also thanks Prof. Maria D. References 1. Erdmann, O. Wei, L. Baker, J. Guo, Y. Grougnet, R. Sandmeyer, T. Acta , 2, Gassman, P. Taylor, A. S , Loloiu, G. Marvel, C. Accessed on September 13, Lopes, W. Pinto, A. Zukerman-Schpector, J. C: Cryst. Torisawa, Y. Popp, F.
M; Silva, R. Torres, J. Boechat, N. Bastos, M. Garden, S. Kamano, Y. Zheng, K. Aikawa, K. Nakamura, S. Malkov, A. Chen, J. Luppi, G; Monari, M. Tetrahedron , 62, Humber, L. Katz, A. Figueiredo, G. Gabriel, D. Murakami, Y. Acta Crystallogr. Oliveira, M. Acids , 21, This method is applied mostly well to anilines with electron-withdrawing substituents, such as 2-fluoroaniline5.
Et2O at 90o C. After cooling the reaction mixture, addition of water allows isolation of the respective isatins. This methodology has been proved to be particularly effective for the preparation of benzo-oxygenated isatin derivatives6 7. In this method anilines react with oxalyl chloride to form an intermediate chloro-oxalylanilide which can be cyclized in the presence of a Lewis acid, usually aluminium chloride or BF3.
Et2O, although TiCl4 has also been used to give the corresponding isatin. This method has been used for the synthesis of 1-aryl8 and polycyclic isatins derived from phenoxazine, phenothiazine and dibenzoazepine9 as well as indoline In the case of dimethoxyanilines, spontaneous cyclization to yield dimethoxyisatins in the absence of a Lewis acid has been observed, as exemplified in the synthesis of melosatin A 2 , albeit in very low yield Scheme This method was applied successfully for the synthesis of 5,6-dimethoxyisatin from 4-aminoveratrole whereas the use of 2,4-dimethoxyaniline was less successful11 Scheme The Gassman Procedure A fundamentally different and general procedure developed by Gassman is another option for the synthesis of isatins Two complementary methods for the synthesis of the 3-methylthiooxindoles were developed, and the methodology of choice is dependent upon the electronic effect of substituents bonded to the aromatic ring.
When electron-withdrawing groups are present, the oxindole derivative can be synthesized via N -chloroaniline intermediate, which further reacts with a methyl thioacetate ester to furnish an azasulfonium salt Method 1, Scheme 4. In the case of electron-donating groups that destabilize the N -chloro intermediate, and thus give diminished yields of the azasulfonium salt, a second method of generation of this salt, by reaction of the chlorosulfonium salt with an appropriate aniline, gives better yield of the 3-methylthiooxindoles.Scheme 9. Structures of phenylglyoxamides 15 and mandelamides Physiologically CNS is divided into following parts illustration not visible in this excerpt The human brain has about billion nerve cells, also called neurons.
These modifications often take advantage of the distinct reactivities of the two carbonyls and the N-H group.
Cyclisation reactions using BMI. Chen, J. The fact that convolutamydine A was isolated from this bryozoan in only 8.
This method has been used for the synthesis of 1-aryl8 and polycyclic isatins derived from phenoxazine, phenothiazine and dibenzoazepine9 as well as indoline C: Cryst.
N-Acyl-3,3-difluorooxindoles 21 have been shown by Boechat et al.
Figure 1. Baker, J.
Nova , 31, Figure 9. A continued interest in the preparation of chlorinated isatins led Silva et al. Katz, A. This methodology has been proved to be particularly effective for the preparation of benzo-oxygenated isatin derivatives6 7. Synthesis of porphyrin indolinone conjugates
The Sandmeyer's method is easily reproduced and can be used in undergraduate experimental classes. Structures of isatin and aromatic ring substituted derivatives. Popp, F. Acids , 21, Structures of alkaloids.
Acids , 21, Murakami, Y. Torres, J.