Synthesis of Pyrazole Containing Aromatic Heterocycles


Leah Knight, Danielle Lusebrink, Jake Abel, Steve Farmer




It was discovered long ago1 that 2-methylaniline (1) formed indazole (2) in very low yield when diazotized in acetic acid. Yields were improved when the amine bore an electron-withdrawing substituent. The unexpected conversion of an isoquinoline (3) into a pyrazoloisoquinoline2 (4) without the presence of an electron-withdrawing group suggests that this method could be more versatile than previously thought. The present project explores the scope of this reaction.


As part of this project we will be synthesizing a wide variety of aromatic compounds which contain the pyrazole ring structure. These ring structures are expected to have biological properties because many pyrazole compounds have been shown to be antibiotics, anti-inflammatory agents, and benzodiazepine antagonists. In addition a computation chemistry study will be preformed to better understand this reaction. This will allow future researchers to determine if this reaction will work in their system of interest.


1) Bamberger, E. Ann. Chim. 1899, 305, 289-379.

2) Miller, R. B.; Stowell, J. G.; Dugar, S.; Moock, T. E.; Jenks, C. W.; Farmer, S. C.; Phan, B.; Wujcik, C. E.; Olmstead, M. M. Synthetic studies of the formation of pyrazoloisoquinolines. Tetrahedron 2002, 58, 6061-6067.



Project Goals


My overall research project involves three specific goals:


Goal 1) Determine the ability of aromatic methyl amines to cyclize into a pyrazole ring structure.


Goal 2) To determine the ability of this reaction to form a triazole ring structure.


Goal 3) To study the mechanism of this cyclization using computational chemistry.


Goal 1:


It has been theorized that the protonatable ring nitrogen in isoquinoline allowed this reaction to occur. This leads us to believe we can form a pyrazolo ring in other systems which contain a protonatable ring nitrogen. To investigate this we attempted to synthesize 3 different aromatic heterocyles: 2,3-pyrazoloquinoline (5), 1,2-pyrazolonapthalene (6), 2,3-pyrazolopyridine (7).




Goal 2:


Because of the ease of alkylating various ring nitrogens we are interested in using a differing type of methyl group in this reaction. This leads us to believe we can form a triazole ring system using this reaction. If this reaction works it would lead to a novel synthesis pathway to the trizaole ring system. To investigate this idea we are attempting to synthesize 2 different aromatic heterocyles: 1,2-pyrazoloimidazole (8) and 1,2-pyrazolopyrazole (9).




Goal 3:


Computational Methods

All computational models were generated with the PC Spartan Pro (version 1.0.1) molecular modeling program (Wavefunction, Inc.). Models were minimized with a semiempirical PM3 basis set. To ensure the location of a global minimum, we repeated each modeling experiment. All repeated models were within 0.10 kcal mol-1 of the originals.


Models were made of compounds previously made using this cyclization reaction. These models were used to determine the electronegativites of atoms contained in the molecules using the Milliken scale. A comparison shows a linear correlation between the electronegativite of the diazonium nitrogen and the yield of the corresponding cyclization reaction.



Yield (5 %)


10a X = H, R = H



10b X = H, R = CH3



10c X = Br, R = CH3



10d X = SPh, R = CH3
















This graph shows that a certain nitrogen electronegativity is needed for a high yield to be obtained. Now molecules of interest can be modeled to predict if the cyclization reaction will occur. The results of the modeling shows that all of the proposed molecules save (6) should have the required electronegativity required for this reaction to occur.


Starting material for the proposed molecule


Quinoline (5)


Napthalene (6)


Pyridine (7)


Imidazole (8)


Pyrazole (9)












The results of the computational study show that there is a correlation between the electronegativity of the diazonium nitrogen and the ability of the starting material to form a ring.