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BischlerNapieralski reaction - Wikipedia, the free encyclopedia

BischlerNapieralski reaction
From Wikipedia, the free encyclopedia

The BischlerNapieralski reaction is an intramolecular electrophilic aromatic substitution reaction that allows for the cyclization of -arylethylamides or -arylethylcarbamates. It was first discovered in 1893 by August Bischler and Bernard Napieralski, in affiliation with Basle Chemical Works and the University of Zurich. The reaction is most notably used in the synthesis of dihydroisoquinolines, which can be subsequently dehydrated to isoquinolines.

A general scheme of the Bischler-Napieralski reaction.

Contents
1 Mechanisms 2 General Reaction Reagents/Conditions 3 Related Reactions and Variations 4 See also 5 References

Mechanisms

A mechanism for the Bischler-Napieralski reaction involving an imine-ester intermediate.

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Two types of mechanisms have appeared in literature for the BischlerNapieralski reaction. Mechanism I

A mechanism for the Bischler-Napieralski reaction involving a nitrilium intermediate.

involves a dichlorophosphoryl imine-ester intermediate, while Mechanism II involves a nitrilium ion intermediate (both shown in brackets). This mechanistic variance stems from the ambiguity over the timing for the elimination of the carbonyl oxygen in the starting amide. In Mechanism I, the elimination occurs with imine formation after cyclization; while in Mechanism II, the elimination yields the nitrilium intermediate prior to cyclization. Currently, it is believed that different reaction conditions affect the prevalence of one mechanism over the other (see reaction conditions). In certain literature, Mechanism II is augmented with the formation of an imidoyl chloride intermediate produced by the substitution of chloride for the Lewis acid group just prior to the nitrilium ion. Because the dehydroisoquinoline nitrogen is basic, neutralization is necessary to obtain the deprotonated product.

General Reaction Reagents/Conditions

The BischlerNapieralski reaction is carried out in refluxing acidic conditions and requires a dehydrating agent. Phosphoryl chloride (POCl3) is widely used and cited for this purpose. Additionally, SnCl4 and BF3 etherate have been used with phenethylamides, while Tf2O and polyphosphoric acid (PPA, a.k.a. Eaton's reagent) have been used with phenethylcarbamates. For reactants lacking electron-donating groups on the benzene ring, phosphorus pentoxide (P2O5) in refluxing POCl3 is most effective. Depending on the dehydrating reagent used, the reaction temperature varies from room temperature to 100C.

Related Reactions and Variations

Several reactions that are related to the BischlerNapieralski reaction are known. The Pictet-Spengler reaction proceeds from a -arylamine via condensation with an aldehyde. The Picter-Gams reaction proceeds from an -hydroxy--phenethylamide and culminates in isoquinoline via condensation instead of dehydrogenation. There are documented variations on the BischlerNapieralski reaction whose products differ in virtue of either the structure of the initial reactant, the tailoring of reaction conditions, or both. For example, research done by Doi and colleagues suggests that the presence or absence of electron-donating groups on the aryl portion of en.wikipedia.org/wiki/BischlerNapieralski_reaction 2/4

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BischlerNapieralski reaction - Wikipedia, the free encyclopedia

arylethylamides and the ratio of dehydrating reagents influence the patterns of ring closure via electrophilic aromatic substitution, leading to two possibilities for product (see below). Other research on the variations on the Bischler-Napieralski Reaction have investigated the effects of nitro and acetal aryl groups on product formation (for further information, see references).

An example of mechanistic and product variation in the Bischler-Napieralski reaction. Treatment of N-[2(4-methoxyphenyl)-ethyl]-4methoxybenzamide with POCl3 results in the formation of the normal product, 7-methoxy-1-(4-methoxyphenyl)-3,4-dihydroisoquinoline. Treatment exclusively with P2O5 results in a mixture of the normal product and an unexpected product, 6-methoxy-1-(4methoxyphenyl)-3,4-dihydroisoquinoline. The formation of the abnormal product is attributed to the cyclization via the ipso carbon on the phenyl ring to yield a spiro intermediate.

See also
Pictet-Spengler reaction

References
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BischlerNapieralski reaction - Wikipedia, the free encyclopedia

August Bischler, Bernard Napieralski (1893). "Zur Kenntniss einer neuen Isochinolinsynthese" (http://gallica.bnf.fr/ark:/12148/bpt6k90729g/f756.table). Berichte der Deutschen Chemischen Gesellschaft 26 (2): 1903. doi:10.1002/cber.189302602143 (http://dx.doi.org/10.1002%2Fcber.189302602143). Capilla, A. S.; Romero, M.; Pujol, M. D.; Caignard, D. H.; Renard, P. Tetrahedron 2001, 57, 8297. Doi, S.; Shirai, N.; Sato, Y. J. Chem. Soc., Perkin Trans. 1 1997, 2217. G. Fodor and S. Nagubandi Tetrahedron 1980, 36, 1279. Ishikawa, T.; Shimooka, K.; Narioka, T.; Noguchi, S.; Saito, T.; Ishikawa, A.; Yamazaki, E.; Harayama, T.; Seki, H.; Yamaguchi, K. J. Org. Chem. 2000, 65, 9143. Wang, X.-j.; Tan, J.; Grozinger, K. Tetrahedron Lett. 1998, 39, 6609. Kitson, S. L. J. Labelled Cmpds. and Radiopharm., 2007, 50, 290. Lee, Jie J. (2007). Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications. Berlin, Heidelberg: Springer. doi:10.1007/978-3-642-01053-8 (http://dx.doi.org/10.1007%2F978-3-642-01053-8). ISBN 978-3-642-01053-8. Retrieved from "http://en.wikipedia.org/w/index.php?title=BischlerNapieralski_reaction&oldid=552474925" Categories: Heterocycle forming reactions Name reactions This page was last modified on 27 April 2013 at 21:24. Text is available under the Creative Commons Attribution-ShareAlike License; additional terms may apply. By using this site, you agree to the Terms of Use and Privacy Policy. Wikipedia is a registered trademark of the Wikimedia Foundation, Inc., a non-profit organization.

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