Organic Chemistry Portal
Reactions >> Name Reactions

Further Information

Related Reactions
Synthesis of 3,4-dihydroisoquinolines

Bischler-Napieralski Reaction
Bischler-Napieralski Cyclization

The Bischler-Napieralski Reaction allows the synthesis of 3,4-dihydroisoquinolines from the β-ethylamides of electron-rich arenes using condensation reagents such as P2O5, POCl3 or ZnCl2.

Mechanism of the Bischler-Napieralski Reaction

According to detailed studies by Fodor and Nagubandi (Tetrahedron 1980, 36, 1279. DOI), the Bischler-Napieralski Reaction involves an initial dehydration step of the amide followed by a cyclization. Fodor was able to prepare stable imidoyl salts at room temperature that formed nitrilium salts upon mild heating, whereas the Bischler-Napieralski Reaction required elevated temperatures to form dihydroisoquinolines. A mechanism that includes nitrilium salts also accounts the occurrence of styrenes as side products as will be explained later.

In the dehydration, reagents such as PCl5, POCl3, SOCl2, ZnCl2 can be used to promote loss of the carbonyl oxygen. Use of POCl3 leads first to formation of imidoyl phosphates in which phosphate is a good leaving group. Use of P2O5 or addition of P2O5 to a reaction with POCl3 leads to pyrophosphates, which are even better leaving groups.

For the cyclization, an activated arene is needed to effect ring closure at reflux temperature if the solvent is toluene. Alternatively, xylene can be used, and microwave-assisted chemistry in superheated solvents is also a viable solution.

One of the most important side reactions is the retro-Ritter reaction forming styrenes, which is also evidence for nitrilium salts as intermediates:

In this example, the formation of a conjugated system favors the retro-Ritter reaction. A possible solution is the use of the corresponding nitrile as solvent, which shifts the equilibrium to the left side, but some nitriles (R' ≠ Me) can be expensive. Another solution was recently presented by Larsen using oxalyl chloride to form an N-acyliminium intermediate, so that elimination of the amide group as the nitrile is avoided.

R. D. Larsen, R. A. Reamer, E. G. Corley, P. Davis, E. J. J. Grabowski, P. J. Reider, I. Shinkai, J. Org. Chem., 1991, 56, 6034-6038.

In the following recently published procedure by Movassaghi, Tf2O is used in the presence of 2-chloropyridine to provide a mild cyclodehydration reaction. Here the authors suggest that electrophilic activation of N-alkylamides may lead to a transient highly electrophilic nitrilium ion (or pyridinium adduct) that is trapped by the arene ring.

M. Movassaghi, M. D. Hill, Org. Lett., 2008, 10, 3485-3488.

The two-step procedure reported by Larsen and the method described by Movassaghi allow the transformation of a broad range of substrates into 3,4-dihydroisoquinolines and the use of milder conditions. Some more procedures can be found in the Recent Literature section.

Recent Literature

A Versatile Cyclodehydration Reaction for the Synthesis of Isoquinoline and β-Carboline Derivatives
M. Movassaghi, M. D. Hill, Org. Lett., 2008, 10, 3485-3488.

A Very Mild Access to 3,4-Dihydroisoquinolines Using Triphenyl Phosphite-Bromine-Mediated Bischler-Napieralski-Type Cyclization
D. Vaccari, P. Davoli, C. Ori, A. Spaggiari, F. Prati, Synlett, 2008, 2803-2806.

Strategies and Synthetic Methods Directed Toward the Preparation of Libraries of Substituted Isoquinolines
E. Awuah, A. Capretta, J. Org. Chem., 2010, 75, 5627-5634.

A modified Bischler-Napieralski procedure for the synthesis of 3-aryl-3,4-dihydroisoquinolines
R. D. Larsen, R. A. Reamer, E. G. Corley, P. Davis, E. J. J. Grabowski, P. J. Reider, I. Shinkai, J. Org. Chem., 1991, 56, 6034-6038.

The first Bischler-Napieralski cyclization in a room temperature ionic liquid
Z. M. A. Judeh, C. B. Ching, J. Bu, A. McCluskey, Tetrahedron Lett., 2002, 43, 5089-5091.