Makosza indole synthesis

Indole Ring Synthesis From Natural Products to Drug Discovery, First Edition. Gordon W. Gribble. 2016 John Wiley Sons, Ltd. Published 2016 by John Wiley Sons, Ltd. 

Some final examples of the Makosza indole synthesis are tabulated in Table 2. Volovenko and colleague report a simple synthesis of 3-substituted-2-amino-5-nitroindoles (entry 1), which were transformed into pyrimido[l,2-fl] indoles upon reaction with p-dicarbonyl compounds [26]. A conventional VNS method was used by Lerman and colleagues to craft 6- and 7-hydroxyindoles via sacrificial chlorine atoms that serve to increase the electrophilicity of the benzene ring toward cyanomethylation. Subsequent transfer hydrogenation (Pd/C/HCO NH ) gives the respective hydroxyindoles (entries 2, 3) [27], The preparation of 3,6-dimethyl-5-methoxyindole by Skibo and coworkers (entry 4) was the starting point in a synthesis 

---

Scheme 3 Macor Applications of the Makosza Indole Synthesis...

MACDONALD Porphynne synthesis 237 MADELUNQ indole synthesis 236 MAKOSZA Vicanoua nudsophilic... 

Reviews published during the reporting period of this chapter include a publication by Makosza detailing the use of vicarious nucleophilic substitution of hydrogen as a tool for the synthesis of indole and quinoline derivatives <01H(54)445>. There also appeared a review of simple indole alkaloids and those with a nonrearranged monoterpenoid unit <01NPR66>. 

In 1910 Robert Pschorr and Gerhard Hoppe reported the synthesis of indole via the reaction of o-nitrophenylace-tonitrile with tin foil and concentrated hydrochloric acid to give initially o-aminophenylacetonitrile. Subsequent treatment with sodium in boiling ethanol afforded indole (Scheme 1, equation 1) [1], The starting o-nitrophenylace-tonitrile was synthesized from o-nitrophenylacetic acid in a few steps. Although this simple synthesis of indole is first attributed to Pschorr and Hoppe, it was Makosza who greatly extended it by means of his vicarious nucleophilic substitution (VNS) of hydrogen as an efficient route to the prerequisite o-nitrophenylacetonitriles, as presented in Chapter 43. 

Chloroform added dropwise at room temp, to a stirred mixture of N-methyl-aniline, aq. 50%-NaOH, benzyltriethylammonium chloride, and, optionally, methylene chloride, and stirring continued 1-2 hrs. -> N-formyl-N-methylaniline. Y 76%. F. e. s. J. Grafe, I. Frohlidi, and M. Muhlstadt, Z. Chem. 14, 434 (1974) s. a. M. Makosza and A. Kacprowicz, Rocz. Chem. 49, 1627 (1975) (Eng) C. A. 84, 43265 N-alkylation with alkyl halides, ibid. 49, 1203 (Eng) C. A. 84, 30793 cf. R. Brehme, Synthesis 1976, 113 with tetrabutylammonium hydrogen sulfate as phase transfer catalyst, indole derivs., cf. A. Barco et al., Synthesis 1976, 124. 

Safety considerations were a driver to change the supply route in the synthesis of AZD1981 where the Makosza reaction was conducted above the flash point of acetone in the presence of air and the product nitro-indole (1, Scheme 8.2) was found to be thermally unstable. Furthermore, the yield in the first stage was low and variable (24 to 48%) impacting the overall cost and throughput. The AZ team developed a scalable, potential commercial route to AZD1981 by use of a Semmler-Wolff aromatisation of 2 to 3 to prepare the indole in 51% overall yield (Scheme 8.3). ... 

---