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reaction. The conditions required for the
Madelung synthesis are quite severe. Fortunately, the aforementioned modifications have been since applied to enhance its practicality, working to decrease the required temperature at which the reaction is performed and increase the desired product yield. For example, when electron-donating are placed on the aromatic ring of the
410:(as organolithium reagents are very strong bases) to extract a hydrogen from both the alkyl substituent and the nitrogen, resulting in a negative charge on both. The synthesis proceeds with a nucleophilic attack of the carbanion on the electrophilic carbonyl carbon of the ester or carboxylic acid. When this occurs, the pi-bond of the
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414:
is converted into a lone pair on the oxygen. These lone pairs are then reconverted back into a pi-bond, resulting in the expulsion of the -OR group. Next, the negatively charged nitrogen performs a nucleophilic attack on the adjacent electrophilic carbonyl carbon, again causing the pi-bond of the
268:
and an electron-withdrawing substituent is substituted at R5, the required temperature for the reaction decreases to approximately 25 °C. Even more impressively, researchers have discovered that the required temperature for the
Madelung synthesis decreases to a temperature range of −20 –
263:
substituents. However, when the R5 substituent is an electron-withdrawing substituent, the yield is increased instead of decreased. Additionally, the efficiency of the reaction is also heavily dependent on the bulkiness of the R6 substituent. The bulkier this group, the less efficient is the
305:. Because this toxin ultimately causes significant economic problems in the livestock industry, understanding how to synthesize and easily decompose alkaloid (-)-penitrem D is of great importance. Nonetheless, the synthesis of such a complex molecule was, by itself, an incredible feat.
214:. After these initial steps, strong base is no longer required and hydrolysis must occur. The negatively charged nitrogen is protonated to regain its neutral charge, and the oxygen is protonated twice to harbor a positive charge in order to become a good
423:
Peterson olefination, ultimately resulting in an elimination reaction which expels a TMSO group and forms a pi-bond in the five-membered ring at the nitrogen atom. Then, keto-enol tautomerism occurs, resulting in the desired product.
230:
was formed, whose electrons are converted into a new pi-bond in the ring system. This allows the pi-bond formed by nitrogen in the preceding step to be converted back into a lone pair on nitrogen to restore nitrogen's neutral charge.
351:
The Smith-modified
Madelung synthesis, also called the Smith indole synthesis, was discovered in 1986 by Amos Smith and his research team. This synthesis employs a condensation reaction of organolithium reagents derived from
136:
step is also required in the synthesis. The
Madelung synthesis is important because it is one of few known reactions that produce indoles from a base-catalyzed thermal cyclization of N-acyl-o-toluidines.
277:(LDA) bases are used, and when tetrahydrofuran is used as the solvent. This particular modification, the use of either of these metal-mediated bases, is termed the Madelung-Houlihan variation.
218:. A lone pair from the nitrogen forms a pi-bond to expel the positively charged leaving group, and also causes the nitrogen to harbor a positive charge. The final step of the reaction is an
419:
atom of the trimethylsilyl (TMS) group, resulting in a tricyclic compound, and a positively charged silicon atom and neutral oxygen atom. The synthesis proceeds through an intramolecular
339:
This synthesis was performed without modification to the
Madelung synthesis, using sodium ethoxide base at a temperature of 320 – 330 °C. This indacene has shown to be an
152:
Variants with other bases or additional substituents are possible, but the method is essentially confined to the preparation of 2-alkinylindoles (not easily accessible through
297:. This reaction served useful in synthesizing, with an 81% yield, the architecturally complex tremorgenic indole alkaloid (-)-penitrem D, a molecule naturally produced by
561:
Chen; Xu Jin; Peng, Desseyn; Janssens, Heremans; Borghs, Geise (2 September 2003). "Synthesis, optical and electroluminescent properties of a novel
Indacene".
526:
Smith, Amos; Kanoh, Ishiyama; Minakawa, Rainier; Hartz, Cho; Cui, Moser (9 July 2003). "Tremorgenic Indole
Alkaloids. The Total Synthesis of (-)-Penitrem D".
476:
Houlihan, William; Parrino, Uike (7 May 1981). "Lithiation of N-(2-Alkylphenyl)alkanamides and
Related Compounds. A Modified Madelung Indole Synthesis".
588:
Smith, Amos; Visnick; Haseltine; Sprengeler (1986). "Organometallic
Reagents in Synthesis: A New Protocol for Construction of the Indole Nucleus".
101:
at high temperature. The
Madelung synthesis was reported in 1912 by Walter Madelung, when he observed that 2-phenylindole was synthesized using
630:
427:
57:
312:
Use of the Madelung synthesis in the synthesis of (-)-penitrem D; this picture is just one step in the total synthesis of (-)-penitrem D.
415:
electrophile to be converted into a lone pair on the oxygen. This negatively charged oxygen then performs a nucleophilic attack on the
367:
to yield substituted indoles. This synthesis has proven applicable to a wide variety of substituted anilines, including those with
324:
Another facet through which the Madelung synthesis has served useful is in the synthesis of 2,6-diphenyl-1,5-diaza-1,5-dihydro-s-
398:
to 2-substituted indoles. The Smith indole synthesis is one of the most important modifications to the Madelung synthesis.
308:
153:
625:
460:
620:
503:
Gribble, Gordon (23 March 2000). "Recent developments in indole ring synthesis—methodology and applications".
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156:) because of vigorous reaction conditions. A detailed reaction mechanism for the Madelung synthesis follows.
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substituents higher yields are obtained, and the opposite is true when the aromatic ring has
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226:), which involves the extraction of the other hydrogen that was once benzylic, before the
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to yield N-lithioketamine intermediates. These intermediates then undergo intramolecular
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that may have important applications for low-cost light displays in commercial industry.
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Various techniques have been applied to increase the yield of the desired
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in a heated, airless reaction. Common reaction conditions include use of
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Madelung synthesis of 2,6-diphenyl-1,5-diaza-1,5-dihydro-s-indacene
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The Smith indole synthesis begins by use of two equivalents of an
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Strategic Applications of Named Reactions in Organic Synthesis
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solvents, at temperatures ranging between 200–400 °C. A
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resulting from the benzylic hydrogen extraction performs a
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that causes various muscular and neurological diseases in
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The Madelung synthesis has many important applications in
455:. Burlington, MA: Elsevier Academic Press. p. 270.
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Journal of the Chemical Society, Perkin Transactions 1
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to the amide substituent by a strong base. Next, the
431:Reaction Mechanism for the Smith Indole Synthesis
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402:Reaction mechanism of the Smith indole synthesis
16:Organic chemical reaction for producing indoles
243:Advancements in improving reaction conditions
164:The reaction begins with the extraction of a
82:that produces (substituted or unsubstituted)
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328:, from 2,5-dimethyl-1,4-phenylenediamine.
202:of the amide group. When this occurs, the
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451:Kurti, Laszlo; Czako, Barbara (2005).
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347:The Smith-modified Madelung synthesis
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176:substituent and the extraction of a
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154:electrophilic aromatic substitution
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394:to yield indolinines, which then
206:of the amide is converted into a
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210:, creating a negatively charged
320:The structure of (-)-penitrem D
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180:hydrogen from the substituent
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602:10.1016/S0040-4020(01)90586-1
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478:Journal of Organic Chemistry
341:organic light-emitting diode
238:Madelung synthesis mechanism
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379:groups, and can react with
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22:Madelung indole synthesis
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626:Indole forming reactions
275:lithium diisopropylamide
109:and two equivalents of
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295:industrial chemistry
261:electron-withdrawing
220:elimination reaction
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190:nucleophilic attack
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251:product. When the
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160:Reaction mechanism
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76:Madelung synthesis
596:(11): 2957–2969.
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484:(22): 4511–4515.
257:electron-donating
228:bicyclic compound
222:(specifically an
80:chemical reaction
72:organic chemistry
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58:RXNO:0000511
53:ontology ID
45:Identifiers
27:Named after
590:Tetrahedron
396:tautomerize
273:(BuLi) and
224:E2 reaction
124:as base in
105:-benzoyl-o-
99:strong base
615:Categories
436:References
421:heteroatom
389:heteroatom
383:esters or
352:2-alkyl-N-
134:hydrolysis
303:livestock
287:chemistry
208:lone pair
186:carbanion
168:from the
119:potassium
107:toluidine
548:12837093
385:lactones
357:anilines
326:indacene
197:carbonyl
178:benzylic
170:nitrogen
166:hydrogen
122:alkoxide
417:silicon
373:methoxy
204:pi-bond
192:on the
172:of the
86:by the
84:indoles
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377:halide
375:, and
361:esters
293:, and
249:indole
212:oxygen
200:carbon
126:hexane
115:sodium
97:using
369:alkyl
182:ortho
174:amide
78:is a
544:PMID
457:ISBN
255:has
598:doi
571:doi
567:139
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363:or
359:by
128:or
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70:In
51:RSC
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103:N
93:N
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