The document summarizes the Bischler-Napieralski reaction, which involves the cyclization of β-arylethylamides or β-arylethylcarbametes to form dihydroisoquinolines under acidic and dehydrating conditions. The reaction proceeds through a nitrilium ion intermediate and can be used to synthesize alkaloids containing an isoquinoline skeleton. It was first discovered in 1893 and the mechanism involves an initial dehydration followed by an intramolecular electrophilic aromatic substitution. Recent literature has explored modifying conditions and substrates to generate substituted isoquinolines and β-carbolines through this cyclodehydration reaction.

1. Bischler-Napieralski Reaction
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2. Content
•Introduction
•Reagent and condition
•Reaction
•Mechanism
•Evidence for intermediate
•Application
•Recent literature
•Reference

3. Bischler-Napieralski Reaction
• It was first discovered in 1893 by August
Bischler and Bernard Napieralski.
• In1980, Fodor and Nagubandi involves an
initial dehydration step of the amide
followed by cyclization.
August Bischler

4. Reagent and condition
•This reaction is carried out in refluxing acidic conditions and requires a dehydrating agent.
•Depending on the dehydrating reagent used, the reaction temperature varies from room
temperature to 100 °C.
• Phosphoryl chloride (POCl3) is widely used and cited for this purpose.

5. Bischler-Napierlaski Reaction
• Cyclization of β-arylethylamides or β-arylethylcarbametes.
• It is an intramolecular electrophilic aromatic substitution reaction.
• Nitrilium salts as a intermediate.
• The reaction is mostly used in the synthesis of dihydroisoquinolines, which can be
subsequently oxidized to isoquinolines.

6. Reaction
CH3 O
NH
R
1
O
POCl3
Benzene
reflux
CH3
O
N
R
1

7. -OPOCl3
Mechanism
H
+
O
P
O
CH3
O
N
Cl ClR
1
-
CH3
O
N
+
R
1
-
CH3
O
NH
R
1
O
OP
Cl
Cl
Cl
Cl
–
O
P
O
CH3
O
H
N
+
Cl Cl
R
1

8. •For the cyclization, an activated arene is needed to effect ring closure at reflux temperature, the solvent is
toluene. Alternatively, xylene can be used.
CH3
O
N
+
R
1 H
CH3
O
+
N
R
1
OCH3
R
1
N
H
+
-

9. Evidence for intermediate
•One of the most important side reactions is the retro-Ritter reaction forming styrenes, which is
the evidence for nitrilium salts as intermediates.
H H
CH3 O
N
+
R
1
H
+
CH3
O
N
CH3
+
-

10. Application
•This reaction has general applications in the preparation of alkaloids containing an isoquinoline
skeleton.
CH3CH3
O
OH
N
Annoretine

11. 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.

12. Recent literature
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.

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

14. Reference
•Nagubandi, S., & Fodor, G. (1980). The mechanism of the bischler-napieralski reaction.
Journal of Heterocyclic Chemistry, 17(7), 1457–1463. doi:10.1002/jhet.5570170720
•M. B. Smith, J. March in March's Advanced Organic Chemistry, 5Ih ed., John Wiley and Sons,
Inc., New York, 2001, p. 721; W. M. Whaley, T. R. Govindachari, Organic Reactions 6, 12
• Heravi, M. M., Khaghaninejad, S., & Nazari, N. (2014). Bischler– Napieralski Reaction in the
Syntheses of Isoquinolines∗. Advances in Heterocyclic Chemistry, 183–
234. doi:10.1016/b978-0-12-800171-4.00005-6
•Organic chemistry portal

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