Bartoli-indole synthesis

7-Substituted indoles from the reaction of ort/jo-substituted nitroarenes and vinyl Grignard reagents. 

Bartoli, G. Leardini, R. Medici, A. Rosini, G. J. Chem. Soc., Perkin Trans. 1 1978, 892. Giuseppe Bartoli is a professor at the Universita di Bologna, Italy. 

Bartoli indole synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J. Eds. Wiley Sons Hoboken, NJ, 2005, 100-103. (Review). 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 10, Springer-Verlag Berlin Heidelberg 2009 

692-696. Giuseppe Bartoli is a professor at the Universita di Bologna, Italy. 

Bartoli, G. Palmieri, G. Bosco, M. Dalpozzo, R. Tetrahedron Lett. 1989, 30, 2129-2132. 

7-Substituted indoles fiom the reaction of or/Ao-snbstituted nitroarenes and vinyl Grignaid reagents. 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 12, Springer International Publishing Switzerland 2014 

The reaction of the o-substituted nitrobenzene 1 with 3 moles of the vinyl magnesium halide 2 gives the 7-substituted indole 3 as the major product. 

In 1989, Bartoli reported that vinylmagnesium bromide reacted with 2-nitrotoluene (4) at -40 C in THF to furnish 7-methylindole (5) in 67% yield. The reaction process also proceeded well with other 2-substituted nitrobenzenes. However, the 3- or 4-substituted nitrobenzenes provided either no indole products or indoles in poor yield.  

The Bartoli process has been employed effectively in the synthesis of 7-substituted indoles including 7-alkoxy (15), 7-alkyl (18) , and 7-formal indoles (21). Although the yields are only moderate, this process does provide a simple entry into indoles which were heretofore difficult to obtain. 

Dobbs then modified the approach to prepare indoles devoid of substituents at position 7 by employing a blocking group. Treatment of a range of o- 

Recently, the Bartoli indole synthesis was extended to solid supports. In contrast to the earlier reports in the liquid phase, o,o-unsubstituted nitro analogs (see 25) prove to be useful substrates. In addition, fluoro/chloro substituted nitro derivatives are well tolerated, which typically undergo nucleophilic substitution under Bartoli conditions in the liquid phase. 

Invented merely 20 years ago in 1989, the Bartoli indole synthesis refers to the formation of 7-substituted indoles from the reaction of ort/io-substituted nitroarenes and excess of vinyl Grignard reagents.  

The mechanism for the Bartoli indole synthesis, postulated by Bartoli et al. based on experimental evidence, is rather unique. As shown below, 

The Bartoli indole synthesis has found utility in medicinal chemistry despite its infancy. For instance, the nitro-diarylether ketone was protected as a ketal and treated with vinylmagnesium bromide to afford the indole derivative. The resulting phenyl-indolyl ether is an intermediate for preparing serotonin (5HT) receptor ligands for treatment of nervous system disorders. Specifically, the diphenyl ether ligands exhibited activity as 5HT2 antagonists. 

On the other hand, the benzhydryl proteeted 7-hydroxy indole is also the key intermediate in the synthesis of a 7-carboxyindolylglycine derivative, proposed as a putative mGluRl receptor antagonist. Using the Gilmore s modification of the Bartoli indole synthesis, the protected nitro-phenol was converted into 7-hydroxy indole in 44% yield. 

Following these early investigations on the Bartoli indole synthesis, several research groups made use of this reaction to great effect as a starting point in natural product synthesis despite the inherent low to modest yields. Stolz employed the Bartoli synthesis to prepare 7-benzyloxy-4-bromoindole (33% yield from 2-benzyloxy-5-bromoni-(robenzene and vinylmagnesium bromide) in the first total synthesis of the marine bis-indole ( )-dragmacidin D [24]. 

1 to more than a dozen carbomethoxyindoles 2. As we have already seen in the Bartoli reaction, the main products are the corresponding reduced anilines. Pirrung and colleagues described a modification of the Bartoli indoli-zation that entails a six-fold excess of vinylmagnesium bromide in a solvent mixture of THF and dimethoxyethane (DME) and the addition of the nitrobenzene 3 to the Grignard. This method was used to prepare 7-alkylindoles 4 (equation 2) [43], 

Even though the yields of indoles from the Bartoli synthesis are usually below 50%-60%, and ort/to-substitu-tion to the nitro group is mandatory, this methodology is extraordinarily powerful for constructing indoles with substitution in the benzene ring. 

The short synthesis of the pyrrolophenanthridone alkaloid hippadine was accomplished by D.C. Harrowven and co-workers. The key step of the synthetic sequence was the Ziegler modified intramolecular Ullmann biaryl coupling between two aryl bromides. One of the aryl halides was 7-bromoindole which was prepared using the Bartoli indole synthesis. The second aryl bromide was connected to 7-bromoindole via a simple A/-alkylation. 

Several heterocycles were prepared from dehydroabietic acid, and their antiviral properties were evaluated in the laboratory of B. Gigante. Dehydroabietic acid was first esterified, then brominated. Nitrodeisopropylation was achieved using a mixture of nitric acid and sulfuric acid. The resulting o-bromo nitroarene was treated with excess vinyl Grignard reagent to obtain the corresponding methyl-12-bromo-13,14b-pyrrolyl-deisopropyl dehydroabietate. 

Deoxygenation of alcohols by means of radical scission of their corresponding thiocarbonyl intermediates. 

Nitric oxide radical is a stable, and therefore, long-lived radical 

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The Bartoli indole synthesis [24] is an excellent method for preparing 7-bromoindole (21) [29a, 30]. 

Baeyer-Villiger oxidation, 83 Bartoli indole synthesis, 80 bauerine B, 196... 

The total synthesis of (-)-fuchsiaefoline was accomplished in the laboratory of J.M. Cook using the Larock indole synthesis to prepare the key precursor 7-methoxy-D-tryptophan in enantiopure form. The propargyl-substituted Schollkopf chiral auxiliary was reacted with 2-iodo-6-methoxyaniline in the presence of 2 mol% Pd(OAc)2 to give the expected indole in good yield. Interestingly, the Bartoli indole synthesis gives /-substituted indoles only in moderate yield. 

Bartoli indole synthesis Formation of 7-substituted indoles from ortho-substituted nitro- or nitrosoarenes. 40... 

Knepper, K., Braese, S. Bartoli Indole Synthesis on Solid Supports. Org. Lett. 2003, 5, 2829-2832. 

Related reactions Bartoli indole synthesis, Larock indole synthesis, Madelung indole synthesis, Nenitzescu indole synthesis ... 

A review of the Bartoli indole synthesis (type Ilac cyclization) has appeared <05COC163>. The Bartoli indole synthesis involves the addition of vinyl Grignards to nitroarenes. 

A modified Bartoli indole synthesis, the condensation of nitroarenes with a vinyl Grignard, was utilized to prepare a precursor to the pyrrolobenzoxazine natural product CJ-12662 <04JOC7875>. 

Bartoli indole synthesis (reaction of vinyl magnesium halides with o-substituted nitroarenes) 05COC163. 

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