The Bischler–Napieralski reaction is an intramolecular electrophilic aromatic substitution reaction that allows for the cyclization of β-arylethylamides or β-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.
Two types of mechanisms have appeared in literature for the Bischler–Napieralski reaction. Mechanism I 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 and conditions
The Bischler–Napieralski 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, also known as 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 100 °C.
Related reactions and variations
Several reactions that are related to the Bischler–Napieralski reaction are known. The Pictet-Spengler reaction proceeds from a β-arylamine via condensation with an aldehyde. The Picter-Gams reaction proceeds from an α-hydroxy-β-phenethylamide and culminates in isoquinoline via condensation instead of dehydrogenation.
There are documented variations on the Bischler–Napieralski 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 β-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 (see references).
- August Bischler, Bernard Napieralski (1893). "Zur Kenntniss einer neuen Isochinolinsynthese". Berichte der Deutschen Chemischen Gesellschaft 26 (2): 1903. doi:10.1002/cber.189302602143.
- Capilla, A. S.; Romero, M.; Pujol, M. D.; Caignard, D. H.; Renard, P. (2001). "Synthesis of isoquinolines and tetrahydroisoquinolines as potential antitumour agents". Tetrahedron 57 (39): 8297. doi:10.1016/S0040-4020(01)00826-2.
- Doi, S.; Shirai, N.; Sato, Y. (1997). "Abnormal products in the Bischler–Napieralski isoquinoline synthesis". J. Chem. Soc., Perkin Trans. 1 (15): 2217. doi:10.1039/a701332i.
- Fodor, G. and Nagubandi, S. (1980). "Correlation of the von Braun, Ritter, Bischler-Napieralski, Beckmann and Schmidt reactions via nitrilium salt intermediates". Tetrahedron 36 (10): 1279. doi:10.1016/0040-4020(80)85039-3.
- Ishikawa, T.; Shimooka, K.; Narioka, T.; Noguchi, S.; Saito, T.; Ishikawa, A.; Yamazaki, E.; Harayama, T.; Seki, H.; Yamaguchi, K. J. (2000). "Anomalous Substituent Effects in the Bischler−Napieralski Reaction of 2-Aryl Aromatic Formamides". Org. Chem. 65 (26): 9143. doi:10.1021/jo0012849.
- Wang, X.-j.; Tan, J.; Grozinger, K. (1998). "A significantly improved condition for cyclization of phenethylcarbamates to N-alkylated 3,4-dihydroisoquinolones". Tetrahedron Lett. 39 (37): 6609. doi:10.1016/S0040-4039(98)01395-1.
- Kitson, S. L. (2007). "Mechanism of the Bischler–Napieralski exocyclic and endocyclic dehydration products in the radiosynthesis of (R)-(-)-[6a-14C]apomorphine". J. Labelled Cmpds. And Radiopharm. 50 (5–6): 290. doi:10.1002/jlcr.1270.
- 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. ISBN 978-3-642-01053-8.