Bischler indole synthesis modifications

Wender and White published a very simple indole ring synthesis that involves the generation of a bis-lithio anion 1 and its reaction with an a-halo carbonyl compound 2, followed by acid- or base-catalyzed dehydration [1,2], The overall transformation is shown in Scheme 1, along with three examples. This chemistry illustrates yet another indole ring synthesis that uses a-halo carbonyl compounds [3]. We will encounter these compounds again with the venerable Bischler indole synthesis in Chapter 23. A summary of several Wender indole ring syntheses is tabulated in Table 1 [1, 2, 4-7], Entry 5 features a directed lithiation method to the bis-lithio nucleophile [5], a modification also described by Wender and White [2], Sainsbury and... 

Despite the vagaries of the mechanism, the Bischler indole synthesis is extremely useful, and several variations are known. Buu-Hoi and colleagues anployed a modified version of this indole synthesis to the preparation of 2-arylindoles [12] and polycyclic indoles [13] (Scheme 2, equation 2). Their modification was to heat the w-ary lamino ketone at 230-250 °C in inert silicone oil. Some indoles... 

Some other modifications of the Bischler indole synthesis have been developed. One such modification is that of Moody and coworkers, who employed rhodium to effect N-H insertion of an a-diazo-p-ketoester to an aniline (Scheme 5, equations 1 and 2) [58-60]. The so-formed arylamino P-ketoester 16 was smoothly converted to indole 17 with the ion-exchange resin Amberlyst 15 or in somewhat lower yield with boron trifluoride etherate [59]. These workers extended the method to the synthesis of A-unsubstituted indoles using the novel A-protecting groups, A-(2-ethoxycarbonylethyl)... 

In 1981, Nordlander demonstrated that acetals 22 can be used as reactants in the Bischler-Mdhlau indole synthesis, providing 2,3-unsubstituted indoles in good yield. Subsequent modification was made by Sundberg in 1984. From 1998 to 2002, Moody and co-workers developed a modified Bischler indole synthesis by using rhodium(II) acetate to catalyze the reaction of N-methylanilines with a-diazo-P-ketoesters via an N-H insertion reaction of a rhodium carbenoid. The resulting a-(A -arylamino)ketones cyclize to give indoles upon treatment with BF3 or an acidic ion exchange resin. ... 

The classical Bischler reaction has received relatively little attention in comparison with other methods for indole synthesis because of the harsh reaction conditions that it requires. The milder modifications involve the use of lithium bromide as a catalyst <2005T77> and a procedure under microwave irradiation conditions <2006SL91>. 

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