Isatins Sandmeyer synthesis

Synthesis of isatin. This synthesis originated with Sandmeyer and was further improved by Marvel and Hiers. " The first step, in which aniline is condensed with chloral hydrate and hydroxylamine hydrochloride to form isonitrosoacetanilide (I) is represented schematically as follows ... 

Although isatins having adjacent carbonyls of very different reactivity— amide vs. ketone—undergo a variety of chenucal reactions [86,87], the focus here is on synthetic transformations to indoles. Accordingly, isatins can be reduced directly to indoles (Scheme 11, equations 1-7) [16,89-93]. Given the availability of isatins from aromatic amines (e.g., Sandmeyer synthesis [86], Gassman synthesis [88]), the reduction of isatins to indoles can be an important alternative to other methods. 

Perhaps the greatest value of the Sandmeyer synthesis is the preparation of isatin scaffolds for the generation of compounds of medicinal interest. The ambiphilic nature of isatin allows it to undergo ring forming reactions to produce a variety of heterocyclic systems. Reaction of isatin 33 with substituted isatoicanhydrides 34 to form indoloquinazoline 35,serves as an example. 

The isatin products from the Sandmeyer synthesis can serve as a source of ortto-arylaminoacids through degradation. Hydrolysis of isatin 42, yielded aminoacid 43, which was converted to the anticancer compound DMXAA (44). ... 

Indole-2,3-dione (isatin), red crystals, mp 204°C, is formed inter alia (cf p. 146) by the oxidation of indigo. A generally applicable synthesis of isatins 126 is the Sandmeyer synthesis, in which isonitrosoacetanilides 125 (easily accessible from primary arylamines, chloral hydrate, and hydroxylamine hydrochloride) are cyclized in acidic medium [195] ... 

Sandmeyer synthesis (isatin) 145 Schmidt-Druey synthesis (pyridazine) 461 Schollkopf synthesis (oxazole) 173 Sharpless-Katsuki epoxidation 24 Shaw synthesis (pyrimidine) 468 Skraup-Doebner-Miller synthesis (quinoline) 400 Smiles rearrangement 446 Sommelet-Hauser rearrangement 136 Staudinger reaction 53 Steglich reagent (DMAP) 348 Stork isoxazole annelation 191... 

Sandmeyer s valuable isatin synthesis involves the removal of sulphur from diphenylthiourea (I) (p. 169) with basic lead carbonate. Hydrogen cyanide is combined with the reactive diphenylcarbodiimide (II) so obtained, and the nitrile (III) produced is converted by means of hydrogen sulphide into tbe thioamide (IV). Concentrated sulphuric acid brings about ring closure and the product is the a-anil of isatin (V). Then, by hydrolysis with dilute sulphuric acid, aniline is removed ... 

The most frequently used synthesis of isatins is the Sandmeyer procedure, which involves the formation of an isonitrosoacetanilide (3) from an aniline (2), chloral hydrate, and hydroxylamine. The isonitroso-... 

The method developed by Sandmeyer is the oldest and the most frequently used for the synthesis of isatin. It consists in the reaction of aniline with chloral hydrate and hydroxylamine hydrochloride in aqueous sodium sulfate to form an isonitrosoacetanilide, which after isolation, when treated with concentrated sulfuric acid, furnishes isatin in >75% overall yield17. The method applies well to anilines with electron-withdrawing substituents, such as 2-fluoroaniline18, and to some heterocyclic amines, such as 2-aminophenoxathine19 (Scheme 1). 

Sandmeyer isonitrosoacetanilide isatin synthesis. Formation of isonitrosoacetodi-phenylamidine by condensation of chloral hydrate, hydroxylamine, and aniline cyclization with concentrated sulfuric acid and quantitative hydrolysis to isatin on dilution. 

SANDMEYER Isatin Synthesis Isatin synthesis from anilines (see 1st edition). 

Other references related to the Sandmeyer isatin synthesis are cited in the literature. ... 

The reactivity of the isatin scaffold allows it to serve as a starting material for diverse applications from medicinal chemistry to total synthesis. At the turn of the 20th century Traugott Sandmeyer reported two methods for the synthesis of this essential building block. 

The Sandmeyer diphenylurea isatin synthesis uses symmetrical diphenylthiourea 1 as a substrate for generation of cyanoformamidine 2, via treatment of 1 with potassium cyanide in the presence of lead carbonate. Reaction of formamidine 2 with ammonium sulfide leads to thioamide 3, which can undergo acid-induced cyclization and hydrolysis to produce isatin (4). Examples of the diphenylurea isatin synthesis in the literature are scarce. This is due to Sandmeyer developing the more practical isonitrosoacetanilide isatin synthesis 16 years later. 

There has been limited mechanistic work regarding the two steps of the Sandmeyer isatin synthesis, although Wang offered a proposal in an earlier summary of the reaction. ... 

Although many of the anilines used in the Sandmeyer isatin synthesis have minimal functionality, examples exist where potentially sensitive motifs can survive the harsh reaction conditions. The 6-azauracil substituted aniline 39 could be converted to isatin 40 en route to the polyheterocyclic compound 41. A trifluoroacetyl protected amine could also be carried through the two-step Sandmeyer sequence to yield the isatin of interest. ... 

To study the conformational changes of tryptophan synthase by N-NMR, indole enriched in A-15 was required. Phillips used a Sandmeyer isatin synthesis starting with A-15-labeled aniline (45) to prepare 46 in good yield... 

Wang, Z. Sandmeyer Isatin Synthesis In Comprehensive Organic Name Reactions and Reagents, 3 V set, Wiley Hoboken, NJ, pp. 2467-2470,2009. 

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