Microwaveassisted ThioPinner Reaction Scope and Limitation Loic Tessier

Microwave-assisted Thio-Pinner Reaction Scope and Limitation Loic Tessier and Jean Jacques Vanden Eynde * University of Mons – UMONS, Laboratory of organic chemistry, B-7000 Mons, Belgium * Corresponding author: jean-jacques. vandeneynde@ex. umons. ac. be 1

Microwave-assisted Thio-Pinner Reaction Scope and Limitation Graphical Abstract 2

Abstract: The amidine function constitutes the active pharmacophore of several drugs and is present in many molecules under the forms, i. a. , of imidazolines and imidazoles. However preparation of amidine-containing derivatives is often restricted by tedious experimental protocols. For example, the Pinner reaction, the most popular procedure, requires long reaction times, use of gaseous hydrochloric acid under anhydrous conditions, and two well defined steps. An important improvement was briefly developed by Lange et al. at the end of the 1990 s. The alcohol was replaced by an odorless thiol (N-acetyl cysteine) whose pronounced nucleophilic character enabled to avoid the presence of the inorganic acid. In addition the intermediate thioimidate does not need to be isolated. Our combined interest in green chemistry, heterocyclic synthesis, and identification of novel drug candidates led us to revisit that thio-Pinner reaction. In that way we have been able to demonstrate that it can advantageously be performed under microwave irradiation and can be readily extended to the synthesis of imidazolines and imidazoles. Keywords : N-acetyl cysteine; amidine; imidazole; microwave; Pinner reaction 3

Introduction The Pinner reaction, what is it? A way to form amidine functions (Pinner, A. Ber. 1855, 18, 2845 -52) 4

The Pinner reaction is interesting because the amidine function is present in various pharmaceutical specialties 5

The amidine function is also present in some heterocyclic moieties, namely benzimidazole 6

The Pinner reaction certainly not green is highly useful but … Is it possible to avoid use of HCl and to improve the conditions ? 7

Results and discussion An alternative have been proposed: 8

The proposed procedure is interesting BUT limited less than 10 examples This is a multi-component one-pot reaction that does not require HCl 9

Our experiments confirmed that the thio-Pinner reaction can be applied • from aliphatic nitriles 10

Our experiments confirmed that the thio-Pinner reaction can be applied • from electron-deficient (hetero)aromatic nitriles 11

Our experiments confirmed that the thio-Pinner reaction can be applied • from electron-rich (hetero)aromatic nitriles 12

Our experiments confirmed that the source of ammonia can be • NH 3 (g), Ac. ONH 4 • but also NH 4 Cl (NH 4)2 CO 3 NH 3 in isopropanol 13

Our experiments confirmed that N-substituted amidines can also be prepared • by using primary or secondary aliphatic amines 14

Our experiments confirmed that cyclic amidines can also be prepared • by using diamines 15

Our experiments confirmed that cyclic amidines can also be prepared • by using aminoacetaldehyde dimethylacetal 16

Our experiments confirmed that reaction times, normally ranging from 4 to 48 hours at 35 -60 C • can be reduced to a few minutes when experiments are performed under microwave irradiation 17

Some examples: 18

CONCLUSION The microwave-assisted thio-Pinner reaction is ü A useful multi-component one-pot reaction ü Numerous nitriles can be involved ü Various sources of ammonia can be used ü As well as amines and diamines ü It can be carried out in a few minutes 19

In the next future, in order to recycle N-acetylcysteine, we shall bind it to various auxiliairies, namely • Solid supports • Soluble polymers • Task specific ionic liquids 20

Ackowledgments We are grateful to the FNRS (Belgium) for a financial support. 21