Reissert synthesis

The Reissert synthesis of indoles has found much success with o-nitrotoluenes, but has been tried for the s5nithesis of azaindoles in only a few cases. Herz and Murty first reported unsuccessful attempts at base-catalyzed condensation of ethyl oxalate with 4-nitro-3-picoline and its Y-oxide (45). No conditions were reported. Later, 

Badger and Rao reported that the treatment of the iV -oxide (45) with potassium ethoxide and ethyl oxalate in ethanol at room temperature gave none of the expected pyruvate but a little of the bispicolyl (46). It had been shown in 1954 that 2- and 4-picoline 1-oxides readily condensed with ethyl oxalate to give the pyruvates in good yield. The electron-attracting influence of the iV-oxide is known to make the 

2- and 4-methyls more acidic, as in the case with the picolines themselves. It was expected that 3-nitro-2- or 3-nitro-4-picolines should give better results. Preliminary trials with these compounds and with 

3- nitro-2-picoline 1-oxide failed. Recently, however, Prydman et al. reported the successful realization of this reaction. 2-Methoxy- 

5-nitro-4-picoline was treated with ethyl oxalate and potassium ethoxide to give the pyruvate (47) in 93 % yield. Hydrogenation with palladium on carbon gave the 6-azaindole-2-carboxylate (48) in 85 % yield. Rapoport states that potassium ethoxide was found to be the most effective catalyst, and that the reaction has been extended to a large number of 4- and 6-azaindoles, with and without the alkoxy group. 

---

There are many other indole syntheses but we will give a brief mention to only one other and that is because it allows the synthesis of indoles with a different substitution pattern in the benzene ring. If you like names, you may call it the Reissert synthesis, and this is the basic reaction. 

The ester products we have been using so far can be hydrolysed and decarboxylated by the mechanism described in the last chapter if a free indole is required. In any case, it is not necessary to use diethyl oxalate as the electrophilic carbonyl compound. The strange antibiotic chuangxinmycin (which you met in Chapter 32) was made by a Reissert synthesis using the acetal of DMF as the electrophile. Here is part of the synthesis. 

General application of the Reissert synthesis does not seem likely, although it may prove to be quite useful for the synthesis of 4- and 6-azaindoles. The nitropicolines are fairly readily available from existing pyridine reactions. 

---