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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
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Graphical Abstract Microwave-assisted Thio-Pinner Reaction Scope and Limitation 2
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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 1990s. 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
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Introduction The Pinner reaction, what is it? A way to form amidine functions (Pinner, A. Ber. 1855, 18, 2845-52) 4
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5 The Pinner reaction is interesting because the amidine function is present in various pharmaceutical specialties
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6 The amidine function is also present in some heterocyclic moieties, namely benzimidazole imidazole
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7 The Pinner reaction is highly useful but … certainly not green Is it possible to avoid use of HCl and to improve the conditions ?
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8 Results and discussion An alternative have been proposed:
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9 The proposed procedure is interesting BUT limited This is a multi-component one-pot reaction that does not require HCl less than 10 examples
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10 Our experiments confirmed that the thio-Pinner reaction can be applied from aliphatic nitriles
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11 Our experiments confirmed that the thio-Pinner reaction can be applied from electron-deficient (hetero)aromatic nitriles
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12 Our experiments confirmed that the thio-Pinner reaction can be applied from electron-rich (hetero)aromatic nitriles
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13 Our experiments confirmed that the source of ammonia can be NH 3 (g), AcONH 4 but also NH 4 Cl (NH 4 ) 2 CO 3 NH 3 in isopropanol
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14 Our experiments confirmed that N-substituted amidines can also be prepared by using primary or secondary aliphatic amines
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15 Our experiments confirmed that cyclic amidines can also be prepared by using diamines
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16 Our experiments confirmed that cyclic amidines can also be prepared by using aminoacetaldehyde dimethylacetal
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17 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
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18 Some examples:
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19 CONCLUSION The microwave-assisted thio-Pinner reaction is A useful multi-component one-pot reaction Numerous nitriles can be involved Various sources of ammonia can be used As well as amines and diamines It can be carried out in a few minutes
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20 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
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Ackowledgments We are grateful to the FNRS (Belgium) for a financial support. 21
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