The Leimgruber–Batcho indole synthesis is a series of organic reactions that produce indoles from o-nitrotoluenes1.[1][2][3] The first step is the formation of an enamine2 using N,N-dimethylformamide dimethyl acetal and pyrrolidine.[4] The desired indole 3 is then formed in a second step by reductive cyclisation.
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 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 group is reduced to -NH2 using hydrogen and a Raney nickel catalyst, followed by cyclisation then elimination of the pyrrolidine. The hydrogen is often generated in situ by the spontaneous decomposition of hydrazine hydrate to H2 and N2 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 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 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 olefins, having an electron-withdrawing nitro group conjugated to an electron-donating group. The extended conjugation means that these compounds are usually an intense red color.
Variationsedit
Dinitrostyrene reductive cyclizationedit
The reductive cyclization of dinitrostyrenes (2) has proven itself effective when other more common methods have failed.[7]
An example of a dinitrostyrene reductive cyclization
Most of the standard reduction methods listed above are successful with this reaction.
^ Clark, R. D.; Repke, D. B. Heterocycles1984, 22, 195–221. (Review)
^ Maehr, H.; Smallheer, J. M. J. Org. Chem.1981, 46, 1753. (doi:10.1021/jo00321a053)
^ Garcia, E. E.; Fryer, R. I. J. Heterocycl. Chem.1974, 11, 219.
^ Ponticello, G. S.; Baldwin, J. J. J. Org. Chem.1979, 44, 4003. (doi:10.1021/jo01336a065)
^ Chen, B.-C.; Hynes, Jr., J.; Randit, C. R.; Zhao, R.; Skoumbourdis, A. P.; Wu, H.; Sundeen, J. E.; Leftheris, K. Heterocycles2001, 55, 951-960.
March 14, 2024
leimgruber, batcho, indole, synthesis, series, organic, reactions, that, produce, indoles, from, nitrotoluenes, first, step, formation, enamine, using, dimethylformamide, dimethyl, acetal, pyrrolidine, desired, indole, then, formed, second, step, reductive, cy. The Leimgruber Batcho indole synthesis is a series of organic reactions that produce indoles from o nitrotoluenes 1 1 2 3 The first step is the formation of an enamine 2 using N N dimethylformamide dimethyl acetal and pyrrolidine 4 The desired indole 3 is then formed in a second step by reductive cyclisation The Leimgruber Batcho indole synthesisIn the above scheme the reductive cyclisation is effected by Raney nickel and hydrazine Palladium on carbon and hydrogen stannous chloride sodium hydrosulfite 5 or iron in acetic acid 6 are also effective reducing agents Contents 1 Reaction mechanism 2 Variations 2 1 Dinitrostyrene reductive cyclization 3 See also 4 ReferencesReaction mechanism editIn 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 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 group is reduced to NH2 using hydrogen and a Raney nickel catalyst followed by cyclisation then elimination of the pyrrolidine The hydrogen is often generated in situ by the spontaneous decomposition of hydrazine hydrate to H2 and N2 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 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 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 olefins having an electron withdrawing nitro group conjugated to an electron donating group The extended conjugation means that these compounds are usually an intense red color Variations editDinitrostyrene reductive cyclization edit The reductive cyclization of dinitrostyrenes 2 has proven itself effective when other more common methods have failed 7 nbsp An example of a dinitrostyrene reductive cyclizationMost of the standard reduction methods listed above are successful with this reaction See also editBartoli indole synthesis Fischer indole synthesis Reissert indole synthesisReferences edit Batcho A D Leimgruber W U S patent 3 732 245 amp U S patent 3 976 639 Batcho A D Leimgruber W Organic Syntheses 1985 63 214 220 Article Clark R D Repke D B Heterocycles 1984 22 195 221 Review Maehr H Smallheer J M J Org Chem 1981 46 1753 doi 10 1021 jo00321a053 Garcia E E Fryer R I J Heterocycl Chem 1974 11 219 Ponticello G S Baldwin J J J Org Chem 1979 44 4003 doi 10 1021 jo01336a065 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 Retrieved from https en wikipedia org w index php title Leimgruber Batcho indole synthesis amp oldid 1160082473, wikipedia, wiki, book, books, library,
