isatin
{{Distinguish|Pisatin|Anisatin|Amlodipine{{!}}Amlodipine (Istin)}}
{{chembox
| Verifiedfields = changed
| verifiedrevid = 443879827
| ImageFile_Ref = {{chemboximage|correct|??}}
| ImageFile1 = Isatine.svg
| ImageSize1 =
| ImageFile2 = IsatinPowder.jpg
| ImageSize2 =
| PIN = 1H-Indole-2,3-dione
| OtherNames =
|Section1={{Chembox Identifiers
| CASNo = 91-56-5
| CASNo_Ref = {{cascite|correct|CAS}}
| Beilstein = 383659
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 27539
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 6787
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 326294
| EC_number = 202-077-8
| Gmelin = 165206
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = C11129
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 82X95S7M06
| PubChem = 7054
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB02095
| SMILES = O=C2c1ccccc1NC2=O
| InChI=1/C8H5NO2/c10-7-5-3-1-2-4-6(5)9-8(7)11/h1-4H,(H,9,10,11)
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C8H5NO2/c10-7-5-3-1-2-4-6(5)9-8(7)11/h1-4H,(H,9,10,11)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = JXDYKVIHCLTXOP-UHFFFAOYSA-N
}}
|Section2={{Chembox Properties
| Formula = C8H5NO2
| MolarMass = 147.1308 g/mol
| Appearance = Orange-red solid
| Density =
| MeltingPtC = 200
| BoilingPt =
| Solubility =
}}
|Section3={{Chembox Hazards
| MainHazards =
| FlashPt =
| AutoignitionPt =
| GHSPictograms = {{GHS07}}
| GHSSignalWord = Warning
| HPhrases = {{H-phrases|302|315|319|335}}
| PPhrases = {{P-phrases|261|264|270|271|280|301+312|302+352|304+340|305+351+338|312|321|330|332+313|337+313|362|403+233|405|501}}
}}
}}
Isatin, also known as tribulin, is an organic compound derived from indole with formula C8H5NO2. The compound was first obtained by Otto Linné Erdman{{cite journal |last1=Erdmann |first1=Otto Linné |title=Untersuchungen über den Indigo |journal=Journal für Praktische Chemie |date=1840 |volume=19 |issue=1 |pages=321–362|doi=10.1002/prac.18400190161 |url=https://zenodo.org/record/1427782 }} and Auguste Laurent{{cite journal |last1=Laurent |first1=Auguste |title=Recherches sur l'indigo |journal=Annales de Chimie et de Physique |date=1840 |volume=3 |issue=3 |pages=393–434}} 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,{{cite journal |last1=Pinto |first1=A. C. |journal=J. Braz. Chem. Soc.|title=The chemistry of isatins: a review from 1975 to 1999 |date=2001 |volume=12 |issue=3 |page=273|doi=10.1590/S0103-50532001000300002 |doi-access=free }}{{cite journal |last1=Bergman |first1=J. |journal=Tetrahedron|title=The structure and properties of some indolic constituents in Couroupita guianensis aubl |date=1988 |volume=41 |issue=14 |page=2879|doi=10.1016/S0040-4020(01)96609-8 }} and also in humans, as a metabolic derivative of adrenaline.{{cite journal |last1=Chiyanzu |first1=I. |journal=Bioorg. Med. Chem. Lett. |title=Synthesis and evaluation of isatins and thiosemicarbazone derivatives against cruzain, falcipain-2 and rhodesain|date=2003 |volume=13 |issue=20 |pages=3527–30 |doi=10.1016/S0960-894X(03)00756-X |pmid=14505663 }}
It looks like a red-orange powder, and it is usually employed as building block for the synthesis of a wide variety of biologically active compounds including antitumorals,{{cite journal |last1=Mallamo |first1=J.P. |journal=Bioorg. Med. Chem. Lett.|title=Structure-guided identification of novel VEGFR-2 kinase inhibitors via solution phase parallel synthesis |date=2006 |volume=16 |issue=8 |pages=2158–62 |doi=10.1016/j.bmcl.2006.01.063 |pmid=16460933 }} antivirals,{{cite journal |last1=He |first1=Y. |journal=Bioorg. Med. Chem. Lett.|title=Design, synthesis, and biological evaluations of novel oxindoles as HIV-1 non-nucleoside reverse transcriptase inhibitors |date=2006 |volume=16 |issue=8 |pages=2109–12 |doi=10.1016/j.bmcl.2006.01.066 |pmid=16464578 }} anti-HIVs,{{cite journal |last1=Sriram |first1=D. |journal=Bioorg. Med. Chem. Lett.|title=Synthesis and evaluation of anti-HIV activity of isatin beta-thiosemicarbazone derivatives |date=2005 |volume=15 |issue=20 |pages=4451–5 |doi=10.1016/j.bmcl.2005.07.046 |pmid=16115762 }} and antituberculars.{{cite journal |last1=Bin-Jubair |first1=F.A.S.|title= Anti-Tubercular activity of Isatin and Derivatives |journal=Int. J. Res. Pharm. Sci. |date=2010 |volume=1 |page=113}}
The isatin core is also responsible for the color of “Maya blue” and “Maya yellow” dyes.{{cite journal |last1=Vuzquez de Agredos-Pascual |first1=M.L. |journal=Angew. Chem. Int. Ed.|title=From Maya Blue to "Maya Yellow": A Connection between Ancient Nanostructured Materials from the Voltammetry of Microparticles |date=2011 |volume=50 |issue=25 |pages=5741–4 |doi=10.1002/anie.201100921 |pmid=21557419 }}
Synthesis
=Sandmeyer methodology=
The Sandmeyer methodology is the oldest and straightforward way for the synthesis of isatin.{{cite journal |last1=Sandmeyer |first1=T. |title=Über Isonitrosoacetanilide und deren Kondensation zu Isatinen |journal=Helv. Chim. Acta |date=1919 |volume=2 |page=234|doi=10.1002/hlca.19190020125 |url=https://zenodo.org/record/1426793 }} 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.{{cite journal |last1=Stollé |first1=R. |title=Über N-substituierte Oxindole und Isatine |journal=J. Prakt. Chem. (In German) |date=1922 |volume=105 |issue=1 |pages=137–148|doi=10.1002/prac.19221050111 |url=https://zenodo.org/record/1428064 }} 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,{{cite journal |last1=Ji |first1=S.J. |journal=Org. Lett. |title=I2/TBHP-Catalyzed Chemoselective Amination of Indoles |date=2014 |volume=16 |pages=3094–3097}} IBX-SO3K,{{cite journal |last1=Kirsch |first1=S.F. |journal=Synthesis|title=Synthesis of Isatins through Direct Oxidation of Indoles with IBX-SO3K/NaI |date=2015 |volume=47 |issue=13 |pages=1937–1943|doi=10.1055/s-0034-1380517 }} tBuONO{{cite journal |last1=Wei |first1=W.T. |journal=Synlett|title=Synthesis of Indoline-2,3-diones by Radical Coupling of Indolin-2-ones with tert-Butyl Hydroperoxide |date=2018 |volume=29 |issue=2 |pages=215–218|doi=10.1055/s-0036-1589106 }} etc.
Reactivity
The presence of an aromatic ring, a ketone and a γ-lactam moiety, gives to isatin the rare potential to be used as both an electrophile and a nucleophile: indeed, it undergoes an enormous number of reactions, such as N-substitutions, electrophilic aromatic substitution at positions C-5 and C-7 of the phenyl ring, nucleophilic additions onto the C-3 carbonyl group, chemoselective reductions, oxidations, ring-expansions and spiro-annulations. Because of this unique reactivity, isatin is considered one of the most valuable building blocks in organic synthesis.
=''N''-Substitution=
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).
File:Isatin N-alkylation, acylation.jpg
On the other hand, N-arylation is usually achieved by cross-coupling reactions with aryl halides using copper or palladium catalysts.{{cite journal |last1=Coppola |first1=Gary M. |title=Arylation of isatins. A direct route to -arylisatoic anhydrides |journal=Journal of Heterocyclic Chemistry |date=September 1987 |volume=24 |issue=5 |pages=1249–1251 |doi=10.1002/jhet.5570240503}}{{cite journal |last1=Majumder |first1=Arpi |last2=Gupta |first2=Ragini |last3=Mandal |first3=Mrinmay |last4=Babu |first4=Madhu |last5=Chakraborty |first5=Debashis |title=Air-stable palladium(0) phosphine sulfide catalysts for Ullmann-type C–N and C–O coupling reactions |journal=Journal of Organometallic Chemistry |date=April 2015 |volume=781 |pages=23–34 |doi=10.1016/j.jorganchem.2014.11.018}}
=Ring expansion=
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.{{cite journal |last1=Donald |first1=James R. |last2=Unsworth |first2=William P. |title=Ring-Expansion Reactions in the Synthesis of Macrocycles and Medium-Sized Rings |journal=Chemistry - A European Journal |date=3 July 2017 |volume=23 |issue=37 |pages=8780–8799 |doi=10.1002/chem.201700467|pmid=28295709 |url=http://eprints.whiterose.ac.uk/114123/1/CEJ_SuRE_medium_ring_paper_accepted_article_manuscript.docx }}
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.{{cite journal |last1=Poomathi |first1=Nataraj |last2=Mayakrishnan |first2=Sivakalai |last3=Muralidharan |first3=Doraiswamy |last4=Srinivasan |first4=Rajagopal |last5=Perumal |first5=Paramasivan T. |title=Reaction of isatins with 6-amino uracils and isoxazoles: isatin ring-opening vs. annulations and regioselective synthesis of isoxazole fused quinoline scaffolds in water |journal=Green Chemistry |date=2015 |volume=17 |issue=6 |pages=3362–3372 |doi=10.1039/c5gc00006h}}
File:Isatin ring expansion.jpg
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.{{cite journal |last1=Shi |first1=Rong-Guo |last2=Wang |first2=Xiao-Hua |last3=Liu |first3=Ruzhang |last4=Yan |first4=Chao-Guo |title=Two-carbon ring expansion of isatin: a convenient construction of a dibenzo[b,d]azepinone scaffold |journal=Chemical Communications |date=2016 |volume=52 |issue=37 |pages=6280–6283 |doi=10.1039/c6cc00525j|pmid=27079548 |s2cid=36547699 }}
=''C-2''/''C-3'' nucleophilic addition=
Isatin suffers nucleophilic addition on carbonyls at C-2 and C-3 positions. The regioselectivity of the process strongly depends both on the substrate (properties of the substituents on the isatin core, especially those bonded to the nitrogen atom) and the reaction conditions (solvent, temperature etc.). In some cases the nucleophilic addition could be followed by secondary reactions (e.g. cyclization, ring expansion, ring opening etc.)
[[File:Isatin nuclophilic addition.jpg|thumb|center|950px|Example of solvent-dependent nucleophlic addition to isatin{{cite journal |last1=Bergman |first1=Jan |last2=Stålhandske |first2=Claes |last3=Vallberg |first3=Hans |title=Studies of the Reaction between Indole-2,3-diones (Isatins) and Secondary Aliphatic Amines. |journal=Acta Chemica Scandinavica |date=1997 |volume=51 |pages=753–759 |doi=10.3891/acta.chem.scand.51-0753|url=http://actachemscand.org/pdf/acta_vol_51_p0753-0759.pdf |doi-access=free }}
]]
=Oxidation=
The oxidation of isatin using hydrogen peroxide (Baeyer–Villiger oxidation) or chromic anhydride yields isatoic anhydride,{{cite journal |last1=Reissenweber |first1=Gernot |last2=Mangold |first2=Dietrich |title=Oxidation of Isatins to Isatoic Anhydrides and 2,3-Dioxo-1,4-benzoxazines |journal=Angewandte Chemie International Edition in English |date=March 1980 |volume=19 |issue=3 |pages=222–223 |doi=10.1002/anie.198002221}}{{cite journal |last1=Yang |first1=Shuangshuang |last2=Li |first2=Xishuai |last3=Hu |first3=Fangfang |last4=Li |first4=Yinlong |last5=Yang |first5=Yunyun |last6=Yan |first6=Junkai |last7=Kuang |first7=Chunxiang |last8=Yang |first8=Qing |title=Discovery of Tryptanthrin Derivatives as Potent Inhibitors of Indoleamine 2,3-Dioxygenase with Therapeutic Activity in Lewis Lung Cancer (LLC) Tumor-Bearing Mice |journal=Journal of Medicinal Chemistry |date=25 October 2013 |volume=56 |issue=21 |pages=8321–8331 |doi=10.1021/jm401195n|pmid=24099220 }}{{cite journal |last1=Bao |first1=Yajie |last2=Yan |first2=Yizhe |last3=Xu |first3=Kun |last4=Su |first4=Jihu |last5=Zha |first5=Zhenggen |last6=Wang |first6=Zhiyong |title=Copper-Catalyzed Radical Methylation/C–H Amination/Oxidation Cascade for the Synthesis of Quinazolinones |journal=The Journal of Organic Chemistry |date=20 April 2015 |volume=80 |issue=9 |pages=4736–4742 |doi=10.1021/acs.joc.5b00191|pmid=25849218 }} a compound widely used either in herbicide products and in medicinal chemistry. The use of peroxydisulfuric acid gives rise to 1,4‑benzoxazine compounds.
=Dimerization=
Dimerization of isatin with KBH4 in methanol yields Indirubin.{{cite journal |last1=Wang |first1=Cuiling |last2=Yan |first2=Jiaxu |last3=Du |first3=Mo |last4=Burlison |first4=Joseph A. |last5=Li |first5=Chi |last6=Sun |first6=Yanni |last7=Zhao |first7=Danqing |last8=Liu |first8=Jianli |title=One step synthesis of indirubins by reductive coupling of isatins with KBH 4 |journal=Tetrahedron |date=May 2017 |volume=73 |issue=19 |pages=2780–2785 |doi=10.1016/j.tet.2017.03.077}} This represents the indigo pigment's red component and a highly effective cytotoxic compound.
=Reduction=
Reduction of the non-amide carbonyl group obviously occurs to give oxindole, respectively.
See also
References
{{reflist}}
Reviews
- {{cite book|doi=10.1016/S0065-2725(08)60127-0|volume=18|pages=1–58|year=1975|last1=Popp|first1=Prank D.|title=Advances in Heterocyclic Chemistry Volume 18 |chapter=The Chemistry of Isatin |isbn=9780120206186}}
- {{cite journal |last1=Silva |first1=Joaquim F. M. da |last2=Garden |first2=Simon J. |last3=Pinto |first3=Angelo C. |title=The chemistry of isatins: a review from 1975 to 1999 |journal=Journal of the Brazilian Chemical Society |date=June 2001 |volume=12 |issue=3 |pages=273–324 |doi=10.1590/S0103-50532001000300002|doi-access=free }}
- {{cite journal|doi=10.1134/S1070428009110013|title=New isatin derivatives|journal=Russian Journal of Organic Chemistry|volume=45|issue=11|pages=1583|year=2009|last1=Mesropyan|first1=E. G.|last2=Avetisyan|first2=A. A.|s2cid=97341279}}
- {{cite journal |last1=Varun |first1=Varun |last2=Sonam |first2=Sonam |last3=Kakkar |first3=Rita |title=Isatin and its derivatives: a survey of recent syntheses, reactions, and applications |journal=MedChemComm |date=2019 |volume=10 |issue=3 |pages=351–368 |doi=10.1039/C8MD00585K|pmid=30996856 |pmc=6438150 }}
External links
- {{cite EB1911 |wstitle=Isatin |volume=14 |pages=865–866 |short=1}}