A convergent approach to 2-substituted-5-methoxyindoles. Application to the synthesis of melatonin

Quiclet‐Sire, Béatrice; Sortais, Benoît; Zard, Samir Z.

doi:10.1039/b204371h

Cited by 32 publications

(16 citation statements)

References 23 publications

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“…Both practical preparations [57][58][59] and an interesting radical synthesis [60] of melatonin have recently been reported. In the latter, the indoline ring of 5 is formed in a radical step, Fig.…”

Section: Indole Benzo[b]thiophene Benzo[b]furan Benzimidazoles Inmentioning

confidence: 99%

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Synthesis of Compounds as Melatonin Agonists and Antagonists

Garratt¹,

Tsotinis

2007

MRMC

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The functions of melatonin, the hormone of the pineal gland, are of considerable current interest. Synthetic melatonin analogues as agonists and antagonists have been explored in some detail and the molecule can be considered as consisting of an indole core, acting mainly as a spacer, and the 5-methoxyl and 3-amidoethyl side chains acting as the functional components, as originally proposed by Heward and Hadley. This review focuses on the synthetic routes to these melatonin analogues, first of the core, then of the substituents that have been attached to the core, and finally those compounds with restricted conformations and those that are chiral. The importance of the various factors involved in the activity of the compounds as agonist or antagonists is indicated, as is the difference in activity of enantiomers.

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Section: Indole Benzo[b]thiophene Benzo[b]furan Benzimidazoles Inmentioning

confidence: 99%

“…Changing the C-3 substituent to N-1 and the C-5 methoxyl to C-6 gives a series of compounds comparable to melatonin [60][61][62]. 6-Methoxyindole (7) is readily available from 4methoxy-2-nitroaniline (6) in ca.…”

Section: Indole Benzo[b]thiophene Benzo[b]furan Benzimidazoles Inmentioning

confidence: 99%

Synthesis of Compounds as Melatonin Agonists and Antagonists

Garratt¹,

Tsotinis

2007

MRMC

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“…In the course of examining ring closures employingF riedel-Crafts conditions discussed above (Scheme 7), an unexpected conversion of indolines to indoles was observed involving elimination of the mesyl group on the indoline nitrogen. [49] This occurs with electron-rich derivatives such as 107 (Scheme 19). In cold concentrated sulfuric acid, the mesyl group is protonated and then expelled to give indole 111 via intermediates 108-110.T his reaction is not general but nevertheless useful is certains ituations, as shown by examples 111a-d displayed in the lower part of Scheme 19.…”

Section: Indolesbye Limination Of Methanesulfinic Acidmentioning

confidence: 99%

“…Melatonin 111e possesses a5 -methoxy-indole motif andi st hus ideally suited for this approach (Scheme 20). [49] Addition of xanthate 112 to allyl aniline 90 gives adduct 113 and subsequentc yclization furnishes indoline 114.H ydrolysis of the ester with concentrated hydrochlorica cid, followed by Curtius rearrangementm ediated by diphenylphosphoryl azide 115 [50] and treatment of the intermediate isocyanate without isolation with acetic anhydride and acetic acid affords am ixture of acetamide 116 anda cetimide( not shown). The latter is convertedi nto the former by ab riefc ontact with potassium carbonate in methanol.…”

Section: Indolesbye Limination Of Methanesulfinic Acidmentioning

confidence: 99%

The Xanthate Route to Indolines, Indoles, and their Aza Congeners

Zard

2020

Chemistry A European J

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Convergentr outes to av ariety of indolines, indoles, oxindoles, and their aza analogues involving radical additions of xanthates are described. Three approaches are summarized. The first is the least general and relies on the generation of aryl or heteroaryl radicals startingf rom diazonium salts. The second involves radical addition to N-allylanilines followed by ring-closure onto the aromatic core. A large varietyo fi ndolines and azaindolines can thus be obtained and, in many cases, converted into the corresponding indoles and azaindoles by variousm ethods. Thes ynthesiso f novel fluoroazaindolines and fluoroazaindoles by ar are homolytic ipso-substitution of fluorine atoms is particularly noteworthy.T he last approachh inges on the direct modification of indoles by radical addition to the pyrrole subunit of the indolen ucleus. Application of this methodology to the total synthesis of melatonin andt he alkaloids mersicarpine, caulerpine, and the pentacyclic skeleton of tronocarpine is briefly discussed. Mosto ft he compounds described herein would be difficult to obtain by more traditional routes.

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“…Side chain transformations and indole-N-deprotection gave melatonin in around 20% overall yield. Sortais and coworkers 9 have applied their free radical reaction methodology to a route to indolines which was elaborated to give in seven steps a 32% overall yield of melatonin as illusrated in Scheme 8. The first step involved an intermolecular catalytic radical addition of a xanthate to a protected N-allylaniline which was followed by stoichiometric radical formation and indoline ring closure.…”

Section: Melatonin Synthesismentioning

confidence: 99%