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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

Graphical Abstract

C N

solvent

C

SR

NHC

N

NH2 SR

R'

H

R'NH2

HS OH

O

HN CH3

O

Microwave-assisted Thio-Pinner Reaction

Scope and Limitation

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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

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Introduction

The Pinner reaction, what is it?

A way to form amidine functions (Pinner, A. Ber. 1855, 18, 2845-52)

C N

HCl (g) / ROH

solvent

C

OR

NH. HCl

solvent

R' NH2

C

N

NH. HCl

R'

H

HCl (g)

C NH C NH

ROH

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The Pinner reaction is interesting because the

amidine function is present in various

pharmaceutical specialties

H N

N

NS

O

CO2H

mecillinamTM

HN

N

otrivinTM

O O

NH2

NH

H2N

HN pentacarinatTM

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N

N

R'

N

N

R'

The amidine function is also present

in some heterocyclic moieties, namely

benzimidazole

imidazole

C N

HCl (g) / ROH

solvent

C

OR

NH. HCl

solvent

R' NH2

C

N

NH. HCl

R'

H

HCl (g)

C NH C NH

ROH

hours to days

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The Pinner reaction

is highly useful but …

certainly not green

Is it possible to avoid use of HCl

and to improve the conditions ?

C N

solvent

C

SR

NH

solvent

R' NH2

C

N

NH

R'

H

HCl (g)

C NH

RSH

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Results and discussion

An alternative have been proposed:

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The proposed procedure is interesting

BUT limited

C N

solvent

C

SR

NH

C

N

NH2 SR

H

H

RSH / NH3

RSH = N-acetylcysteineHS OH

O

HN CH3

O

4 - 48 h35 - 60 °C

This is a multi-component one-pot reactionthat does not require HCl

less than 10 examples

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Our experiments confirmed

that the thio-Pinner reaction can be applied

• from aliphatic nitriles

C N

solvent

C

SR

NHC

N

NH2 SR

H

H

NH3

HS OH

O

HN CH3

O

Boc

HN CN

Boc

HN

NH

O

CN

Boc

HN Boc

HN

NH

O

NH2

NHNH2

NH

70 - 90 % 90 %

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Our experiments confirmed

that the thio-Pinner reaction can be applied

• from electron-deficient (hetero)aromatic nitriles

O2N

CN

N

CN

F3C

CN

N

NH2

HN

F3C O2N

NH2

HN

NH2

HN

70 - 90 % 70 - 80 % 60 - 80 %

C N

solvent

C

SR

NHC

N

NH2 SR

H

H

NH3

HS OH

O

HN CH3

O

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Our experiments confirmed

that the thio-Pinner reaction can be applied

• from electron-rich (hetero)aromatic nitriles

C N

solvent

C

SR

NHC

N

NH2 SR

H

H

NH3

HS OH

O

HN CH3

O

H2N

CN

O

CN

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Our experiments confirmed

that the source of ammonia can be

• NH3 (g), AcONH4

• but also NH4Cl

(NH4)2CO3

NH3 in isopropanol

C N

solvent

C

SR

NHC

N

NH2 SR

H

H

NH3

HS OH

O

HN CH3

O

H

NH

N

H

C

SR

NH

N N

N

H

H H

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Our experiments confirmed

that N-substituted amidines can also be prepared

• by using primary

or secondary aliphatic amines

C N

solvent

C

SR

NHC

N

NH2 SR

H

H

NH3

HS OH

O

HN CH3

O

R"

NH

N

R'

NN CN

methylamine: 85 %ethylamine: 85 %propylamine: 80 %isopropylamine: 75 %butylamine: 80 %hexylamine: 75 %cyclohexylamine: 70 %diethylamine: 75 %

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Our experiments confirmed

that cyclic amidines can also be prepared

• by using diamines

C N

solvent

C

SR

NHC

N

NH2 SR

H

H

NH3

HS OH

O

HN CH3

O

N

N

H

H2N

H2NCNN N 75 %

RSH

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Our experiments confirmed

that cyclic amidines can also be prepared

• by using aminoacetaldehyde dimethylacetal

C N

solvent

C

SR

NHC

N

NH2 SR

H

H

NH3

HS OH

O

HN CH3

O

N

N

H

CN

H3CO

H2N

OCH3

H

N N

N

N

H

CN

O2N O2N

85 %

75 %

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C N

solvent

C

SR

NHC

N

NH2 SR

R'

H

R'NH2

HS OH

O

HN CH3

O

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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Some examples:

N

NH

H2N

H2NCNN N

5 min120 °C60 %RSH

O2N

RSH

AcONH4

O2N

NH2

NH5 min100 °C95 %

RSH

5 min100 °C85 %

O2N O2N

NH

N

H3CO

H2N

OCH3

H

CN

CN

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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

C N

solvent

C

SR

NHC

N

NH2 SR

R'

H

R'NH2

HS OH

O

HN CH3

O

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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

C N

solvent

C

SR

NHC

N

NH2 SR

R'

H

R'NH2

HS OH

O

HN CH3

O

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Ackowledgments

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