View source for Leimgruber–Batcho indole synthesis

The '''Leimgruber–Batcho indole synthesis''' is a series of [[organic reaction]]s that produce [[indole]]s from o-nitro[[toluene]]s '''1'''.{{Ref|BatchoPatent}}{{Ref|Batch1985}}{{Ref|Clark1984}} The first step is the formation of an [[enamine]] '''2''' using N,N-dimethylformamide dimethyl acetal and [[pyrrolidine]].{{Ref|Maehr1981}} The desired indole '''3''' is then formed in a second step by [[Redox|reductive]] cyclisation.

[[File:Leimgruber-Batcho Indole Scheme.png|center|500px|The Leimgruber-Batcho indole synthesis]]

In the above scheme, the reductive cyclisation is effected by [[Raney nickel]] and [[hydrazine]].  [[palladium on carbon|Palladium-on-carbon]] and [[hydrogen]], [[stannous chloride]], [[sodium dithionite|sodium hydrosulfite]]{{Ref|Garcia1974}}, or [[iron]] in [[acetic acid]]{{Ref|Ponticello1979}} are also effective [[reducing agent]]s.

==Reaction mechanism==
In the initial enamine formation, [[dimethylamine]] (a gas) is displaced by pyrrolidine from the dimethylformamide dimethylacetal, producing a more reactive [[reagent]]. The mildly acidic hydrogens of the [[methyl]] group in the nitrotoluene can be [[deprotonation|deprotonated]] under the basic conditions, and the resultant [[carbanion]] attacks to produce the enamine shown, with loss of [[methanol]]. The sequence can also be performed without pyrrolidine, via the N,N-dimethyl enamine, though reaction times may be much longer in some cases. In the second step the [[nitro compound|nitro group]] is reduced to -NH<sub>2</sub> using [[hydrogen]] and a Raney nickel catalyst, followed by cyclisation then [[elimination reaction|elimination]] of the pyrrolidine. The hydrogen is often generated [[in situ]] by the spontaneous decomposition of [[hydrazine]] hydrate to H<sub>2</sub> and [[Nitrogen|N<sub>2</sub>]] in the presence of the nickel.

The reaction is a good example of a reaction that was widely used in industry before any procedures were published in the mainstream scientific literature. Many indoles are [[Pharmacology|pharmacologically active]], so a good indole synthesis is important for the [[pharmaceutical industry]]. The process has become a popular alternative to the [[Fischer indole synthesis]] because many starting [[Arene substitution patterns|ortho-]]nitrotoluenes are commercially available or easily made. In addition, the reactions proceed in high [[chemical yield]] under mild conditions.  

The intermediate enamines are electronically related to [[push–pull olefin]]s, having an [[electron-withdrawing]] nitro group [[conjugated system|conjugated]] to an electron-donating group. The extended conjugation means that these compounds are usually an intense red color.

==Variations==

===Dinitrostyrene reductive cyclization===
The reductive cyclization of dinitrostyrenes ('''2''') has proven itself effective when other more common methods have failed.{{Ref|Chen2001}}

[[File:Dinitrostyrene Reductive Cyclization.png|center|600px|An example of a dinitrostyrene reductive cyclization]]

Most of the standard reduction methods listed above are successful with this reaction.

==See also==
*[[Bartoli indole synthesis]]
*[[Fischer indole synthesis]]
*[[Reissert indole synthesis]]
==References==
# {{Note|BatchoPatent}} Batcho, A. D.; Leimgruber, W. {{US patent|3732245}} & {{US patent|3976639}}
# {{Note|Batch1985}} Batcho, A. D.; Leimgruber, W. ''[[Organic Syntheses]]'' '''1985''', ''63'', 214–220. ([https://web.archive.org/web/20120204222708/http://www.orgsyn.org/orgsyn/prep.asp?prep=cv7p0034 Article])
# {{Note|Clark1984}} Clark, R. D.; Repke, D. B. ''Heterocycles'' '''1984''', ''22'', 195–221. (Review)
# {{Note|Maehr1981}} Maehr, H.; Smallheer, J. M. ''[[J. Org. Chem.]]'' '''1981''', ''46'', 1753. ({{doi|10.1021/jo00321a053}})
# {{Note|Garcia1974}} Garcia, E. E.; Fryer, R. I. ''J. Heterocycl. Chem.'' '''1974''', ''11'', 219.
# {{Note|Ponticello1979}} Ponticello, G. S.; Baldwin, J. J. ''J. Org. Chem.'' '''1979''', ''44'', 4003. ({{doi|10.1021/jo01336a065}})
# {{Note|Chen2001}} Chen, B.-C.; Hynes, Jr., J.; Randit, C. R.; Zhao, R.; Skoumbourdis, A. P.; Wu, H.; Sundeen, J. E.; Leftheris, K. ''Heterocycles'' '''2001''', ''55'', 951-960.
{{Organic reactions}}
{{DEFAULTSORT:Leimgruber-Batcho indole synthesis}}
[[Category:Indole forming reactions]]
[[Category:Carbon-heteroatom bond forming reactions]]
[[Category:Name reactions]]