Isatin, also known as tribulin, is an
organic compound derived from
indole with formula C8H5NO2. The compound was first obtained by Otto Linné Erdman[1] and Auguste Laurent[2] in 1840 as a product from the oxidation of
indigo dye by
nitric acid and
chromic acids.
Isatin is a well-known natural product which can be found in plants of the genus Isatis, in Couroupita guianensis,[3][4] and also in humans, as a metabolic derivative of
adrenaline.[5]
The isatin core is also responsible for the color of “
Maya blue” and “Maya yellow” dyes.[10]
Synthesis
Sandmeyer methodology
The Sandmeyer methodology is the oldest and straightforward way for the synthesis of isatin.[11] The method involves the condensation between
chloral hydrate and a primary arylamine (e.g.
aniline), in the presence of
hydroxylamine hydrochloride, in aqueous
sodium sulfate to form an α‐isonitrosoacetanilide. Isolation of this intermediate and subsequent
electrophilic cyclization promoted by strong acids (e.g.
sulfuric acid) furnishes isatin in >75% yield.
Stolle methodology
The Stolle procedure is considered the best alternative to Sandmeyer methodology for the synthesis of both substituted and unsubstituted isatins.[12] In this case primary or secondary arylamines are condensed with
oxalyl chloride to form a chlorooxalylanilide intermediate which can then cyclize in the presence of a
Lewis acid (e.g.
aluminium trichloride,
titanium tetrachloride,
boron trifluoride, etc.).
Other procedures
More recent approaches to the synthesis of N-substituted isatins involves the direct
oxidation of commercially available, substituted indoles or oxindoles with different
oxidizing agents such as
TBHP,[13]IBX-SO3K,[14]tBuONO[15]etc.
The N-functionalization of the isatin core can be readily obtained by the
deprotonation of the amino moiety, forming the corresponding
sodium or
potassium salt, and subsequent addition of an
electrophile (e.g. alkyl or acyl
halides).
In the field of
organic synthesis,
ring expansions are considered valuable reactions since they allow the obtainment medium-size ring (7-9 atoms) which are difficult to synthesize through "classical" methods.[18]
To date, only few articles concerning the ring expansion of isatin derivatives has been reported.
The first one is an acid-catalyzed one-pot
multicomponent reaction involving isatins, aminouracils, and isooxazolones to form isoxazoquinolines, important
scaffolds in
medicinal chemistry.[19]
In another one-pot
multicomponent reaction, a unique two-carbon expansion has been achieved by reacting isatin with indene-1,3-dione and N-substituted
pyridinium bromide to form dibenzo[b,d]azepin-6-ones.[20]
^Bergman, J. (1988). "The structure and properties of some indolic constituents in Couroupita guianensis aubl". Tetrahedron. 41 (14): 2879.
doi:
10.1016/S0040-4020(01)96609-8.
^Chiyanzu, I. (2003). "Synthesis and evaluation of isatins and thiosemicarbazone derivatives against cruzain, falcipain-2 and rhodesain". Bioorg. Med. Chem. Lett. 13 (20): 3527–30.
doi:
10.1016/S0960-894X(03)00756-X.
PMID14505663.
^Mallamo, J.P. (2006). "Structure-guided identification of novel VEGFR-2 kinase inhibitors via solution phase parallel synthesis". Bioorg. Med. Chem. Lett. 16 (8): 2158–62.
doi:
10.1016/j.bmcl.2006.01.063.
PMID16460933.
^He, Y. (2006). "Design, synthesis, and biological evaluations of novel oxindoles as HIV-1 non-nucleoside reverse transcriptase inhibitors". Bioorg. Med. Chem. Lett. 16 (8): 2109–12.
doi:
10.1016/j.bmcl.2006.01.066.
PMID16464578.
^Sriram, D. (2005). "Synthesis and evaluation of anti-HIV activity of isatin beta-thiosemicarbazone derivatives". Bioorg. Med. Chem. Lett. 15 (20): 4451–5.
doi:
10.1016/j.bmcl.2005.07.046.
PMID16115762.
^Bin-Jubair, F.A.S. (2010). "Anti-Tubercular activity of Isatin and Derivatives". Int. J. Res. Pharm. Sci. 1: 113.
^Vuzquez de Agredos-Pascual, M.L. (2011). "From Maya Blue to "Maya Yellow": A Connection between Ancient Nanostructured Materials from the Voltammetry of Microparticles". Angew. Chem. Int. Ed. 50 (25): 5741–4.
doi:
10.1002/anie.201100921.
PMID21557419.
^Ji, S.J. (2014). "I2/TBHP-Catalyzed Chemoselective Amination of Indoles". Org. Lett. 16: 3094–3097.
^Kirsch, S.F. (2015). "Synthesis of Isatins through Direct Oxidation of Indoles with IBX-SO3K/NaI". Synthesis. 47 (13): 1937–1943.
doi:
10.1055/s-0034-1380517.
^Wei, W.T. (2018). "Synthesis of Indoline-2,3-diones by Radical Coupling of Indolin-2-ones with tert-Butyl Hydroperoxide". Synlett. 29 (2): 215–218.
doi:
10.1055/s-0036-1589106.
^Coppola, Gary M. (September 1987). "Arylation of isatins. A direct route to -arylisatoic anhydrides". Journal of Heterocyclic Chemistry. 24 (5): 1249–1251.
doi:
10.1002/jhet.5570240503.
^Poomathi, Nataraj; Mayakrishnan, Sivakalai; Muralidharan, Doraiswamy; Srinivasan, Rajagopal; Perumal, Paramasivan T. (2015). "Reaction of isatins with 6-amino uracils and isoxazoles: isatin ring-opening vs. annulations and regioselective synthesis of isoxazole fused quinoline scaffolds in water". Green Chemistry. 17 (6): 3362–3372.
doi:
10.1039/c5gc00006h.
^Shi, Rong-Guo; Wang, Xiao-Hua; Liu, Ruzhang; Yan, Chao-Guo (2016). "Two-carbon ring expansion of isatin: a convenient construction of a dibenzo[b,d]azepinone scaffold". Chemical Communications. 52 (37): 6280–6283.
doi:
10.1039/c6cc00525j.
PMID27079548.
S2CID36547699.
^
abReissenweber, Gernot; Mangold, Dietrich (March 1980). "Oxidation of Isatins to Isatoic Anhydrides and 2,3-Dioxo-1,4-benzoxazines". Angewandte Chemie International Edition in English. 19 (3): 222–223.
doi:
10.1002/anie.198002221.
^Yang, Shuangshuang; Li, Xishuai; Hu, Fangfang; Li, Yinlong; Yang, Yunyun; Yan, Junkai; Kuang, Chunxiang; Yang, Qing (25 October 2013). "Discovery of Tryptanthrin Derivatives as Potent Inhibitors of Indoleamine 2,3-Dioxygenase with Therapeutic Activity in Lewis Lung Cancer (LLC) Tumor-Bearing Mice". Journal of Medicinal Chemistry. 56 (21): 8321–8331.
doi:
10.1021/jm401195n.
PMID24099220.
^Bao, Yajie; Yan, Yizhe; Xu, Kun; Su, Jihu; Zha, Zhenggen; Wang, Zhiyong (20 April 2015). "Copper-Catalyzed Radical Methylation/C–H Amination/Oxidation Cascade for the Synthesis of Quinazolinones". The Journal of Organic Chemistry. 80 (9): 4736–4742.
doi:
10.1021/acs.joc.5b00191.
PMID25849218.
^Wang, Cuiling; Yan, Jiaxu; Du, Mo; Burlison, Joseph A.; Li, Chi; Sun, Yanni; Zhao, Danqing; Liu, Jianli (May 2017). "One step synthesis of indirubins by reductive coupling of isatins with KBH 4". Tetrahedron. 73 (19): 2780–2785.
doi:
10.1016/j.tet.2017.03.077.
Mesropyan, E. G.; Avetisyan, A. A. (2009). "New isatin derivatives". Russian Journal of Organic Chemistry. 45 (11): 1583.
doi:
10.1134/S1070428009110013.
S2CID97341279.