Pharmacomodulation of Positions Two & Four of Nucleus Five

Al Saadi et al (2019): Pharmacomodulation using palladium catalyze November 2019 Vol. 22(7)

Pharmacomodulation of positions two & four of nucleus five-nitroimidazole by using palladium catalyze

Noor Thamer Abbas Al Saadi 1* Marwah Thamer Abbas Al Saadi1, Zina Tahsin Ali1

1. College of pharmacy, Almuthanna University

*Corresponding Author: Dr. Noor Thamer Abbas Al Saadi, College of pharmacy, Almuthanna University

Abstract:

Cross-coupling reactions consist of reactions between an electrophilic organic species such as a halide or a pseudohalide (triflate, tosylate, mesylate) (R1-X) and an organometallic reagent (R2-M; M = Mg, Li, Cu, Zn, Al, B and Si). These reactions are catalyzed by a metal transition complex based on nickel or palladium, and result in the formation of new CClO.sub.2 bonds. Many cross-coupling reactions have thus been developed in about twenty years, by varying the nature of the electrophile, organometallic reagent and transition metal (Scheme 1). The most commonly used coupling reactions involve palladium as a transition metal, and the diversity of these reactions is based on the type of organometallic used, based on aluminum, zinc or zirconium (Negishi coupling), [1] boron (Suzuki coupling), [2] magnesium (Kumada coupling), [3] tin (Stille coupling) , [4] or silicon (coupling of Hiyama) .[5] The development of this type of reaction allowed Richard Heck, Ei-ichi Negishi and Akira Suzuki to be awarded the Nobel Prize for Chemistry in 2010.[1].

Key words: Pharmacomodulation, nitromidazole, palladiumcatalyz, cross-coupling, reactions

How to cite this article: Al Saadi NTA, Al Saadi MTA, Ali ZT (2019): Pharmacomodulation of positions two & four of nucleus five-nitroimidazole by using palladiumcatalyz, Ann Trop Med Pub Health; 22: S202. DOI: http://doi.org/10.36295/ASRO.2019.22072

Introduction

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Al Saadi et al (2019): Pharmacomodulation using palladium catalyze November 2019 Vol. 22(7)

Since its discovery in 1805 by Wollaston, the use of palladium has developed in different fields such as the manufacture of medical equipment, as a substitute for steel, and especially in chemical synthesis.127 Following the fortuitous discovery of Walter Hafner in which ethylene exposed to oxygen and palladium on carbon led to the production of acetaldehyde, the interest of palladium in the synthesis of organic compounds was highlighted. This discovery was exploited in an industrial process, the Wacker process (Scheme 1). [6]

Figure 1: Wacker Process

The first product from an oxidative addition between PdO- (PPh3) 4 and an aryl halide was obtained by Fitton et al. in 1968.129 In the same period, it was demonstrated by Tsuji that the nucleophilic substitutions on the allylic substrates possessing a leaving group could be catalyzed by palladium, via an π-allyl palladium intermediate complex (Scheme). The regeneration of palladium at oxidation state 0 at the end of the cycle suggests the possibility of a catalytic cycle, which is new for the time.

Figure 2: Reaction of tsuji-Trots, subsequently the number of reactions catalyzed by palladium has multiplied

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Al Saadi et al (2019): Pharmacomodulation using palladium catalyze November 2019 Vol. 22(7)

The Heck reaction makes it possible to form a coupling between a halogenated derivative and an alkene. After demonstrating the formation of a C-C bond between an organomercuric derivative and an alkene in 1968, he became interested in developing a new method with a halogenated derivative, in order to abstain from highly toxic organomercurics (Scheme 3).

The Kumada-Corriu reaction consists of a coupling between an alkyl or aryl Grignard reagent and an aryl or vinyl halogenated derivative, most often catalysed by nickel, although some publications have reported the use of palladium.

Negishi's work has shown that coupling reactions can be catalyzed by nickel and palladium interchangeably.[1]. On the other hand, even if it is more expensive, palladium makes it possible to obtain better yields when coupling between a nickel and palladium. alkyne and an alkene or an aryl and an alkyne. In addition, palladium complexes are compatible with more functional groups than nickel complexes.

The coupling of Negishi is the first reaction to have allowed the formation of an asymmetric biaryl compound with a good yield. It initially consisted of a cross-

In the same period, Eaborn et al reported the first coupling reaction between an aryl halide and a palladium catalyzed organostannane (Scheme 3). This is the coupling of Stile.[7] Subsequently, the coupling of an organostannane bearing a double bond with an aryl halide was used to synthesize variously substituted ketones.[6,7] The drawbacks of this type of Coupling remains the toxicity of tin derivatives and the low polarity of these compounds rendering them poorly soluble in water. About 10 years later, Hiyama et al. describe the first coupling reaction between an aryl halide and an organosilane activated by a fluorine source such as (Tris (dimethyl) amino) sulfonium difluorotrimethylsilicate (TASF) (Scheme 4). The organosilanes have the advantage of be less toxic than organozinc, boronic or stannane.

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The reactions of Negishi, Kumada, Stille and Suzuki have a very similar mechanism, which differs for the coupling of Heck (Scheme 4). [1]. the only step common to all these reactions is the oxidative addition of the aryl halide to palladium with the degree of oxidation 610, which initiates the catalytic cycle. Many phosphine ligands (Ln) are used to stabilize Pd (0), but various parameters such as size, stoichiometry, and electron effects of the ligand influence the reactivity of the catalyst during the oxidative addition and deoxidation steps. The most commonly used ligand is triphenylphosphine (PPh3), but synthesis and the search for new ligands are very active. In the Heck reaction, the second step consists in the coordination of the alkene with palladium at the oxidation level II, then at its migratory insertion in syn. The regioselectivity of insertion depends on the nature of the alkene, the ligand used and the conditions reaction. The formed organopalladic species then undergoes a hydride beta-elimination to form the corresponding alkene, followed by a reductive elimination in the presence of a base, to regenerate the initial palladium at the oxidation state 0.141 In the other couplings, the second step is a transmetallation of the R1 group of the organometallic on the palladium complex. The last step is a reductive elimination which leads to the regeneration of the Pd (0) palladium catalyst and the creation of a C-C bond. Figure 3: General cycle of palladium-catalyzed coupling reactions. Many advances have been made in the development of palladium-catalyzed couplings that are widely used for drug synthesis in the pharmaceutical industry. The number of industrial processes involving palladium-catalyzed coupling in the synthesis of chemicals or In this work, we focused on Suzuki-Miyaura and Sonogashira couplings due to the diversity of available boronic acids and alkynes and pharmacomodulation with aryl and alkyne groups. Methodology: The results of these reactions are summarized in Table 1. Table 1.Preparation of 1,2-Dialkyl-4- arylsulfonylmethyl-5-nitro-1H-imidazoles and 4-Arylsulfonylmethyl-1-methyl-5-nitro-1H-imidazolesa .

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1. Suzuki-Miyaura coupling A) General In 1979, A. Suzuki and N. Miyaura reported the stereoselective synthesis of aryl (E) -alkenes by reacting 1-alkenylboronan with aryl halides in the presence of a palladium catalyst.[9]. Suzuki-Miyaura Coupling is a reaction between an organoborane derivative and an aryl halide or triflate catalyzed by palladium. This is a widely used method for C-C bond formation (Scheme 20). Although the base more used is sodium carbonate, it can be insufficient in case of sterically highly congested substrate. Other bases can be used to accelerate the transmetallation step and improve the yield of coupling product: (Ba (OH) 2, K 3 PO 4, Cs 2 CO 3, K 2 CO 3, TlOH, KF, CsF, NBu 4 F, NaOH) .[10] Reactivity of the aryl halide towards Suzuki-Miyaura coupling varies with halogen (I> Br> Cl >> F).General reaction of Suzuki-Miyaura. The advantages and disadvantages of this reaction are grouped in:

Stereoselectivity and regioselectivity of possible coupling: The development of Suzuki-Miyaura coupling is constantly evolving with the search for new catalysts to facilitate the coupling of low reactive aryl halides and to improve coupling product yields.[11,12]. A) Mechanism As we mentioned earlier, the mechanistic cycle of the Suzuki-Miyaura coupling reaction is common to other pallado-catalyzed couplings and takes place in 3 steps

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The first step is an oxidative addition of a halogenated derivative (R2-X) to the palladium catalyst Pd (0) to form Pd (II) as an R2-Pd (II) -X complex. Between the first and the second stage, a metathesis phenomenon is observed between the anion of the base (OR-) and the anion bound to palladium (X-) which leads to the R2-Pd (II) -OR derivative. The second step is a transmetallation of the R1 group of the boronic acid on the R2-Pd (II) -OR complex. This step requires that the boronic acid be activated by a base in order to form the corresponding organoborate which makes it possible to increase the nucleophilicity of the R 1 group and to accelerate its transfer to palladium. The third and last stage is a reductive elimination which leads to the regeneration of the Pd (O) palladium catalyst and the creation of a C-C bond (R1-R2). Different catalysts, bases and solvents can be used for the Suzuki-Miyaura reaction, but the combinations significantly influence the yields and selectivity of the reaction. The most commonly used catalyst is Pd (PPh3) 4, but Pd (AcO) 2 and PdCl2 (PPh3) 2 are also good precursors because they are easily reduced in situ to Pd (0). it is desired to carry out a coupling using the least reactive halide, aryl chloride, the use of electron-rich catalysts such as P (t-Bu) 3 and 2- (di-t- butylphosphino) biphenyl accelerate the oxidative addition step, and improves the coupling product yield, including at room temperature. The main bases used are sodium or potassium carbonate, phosphate or hydroxide derivatives (1.5 to 2 equiv.), in aqueous solution, or in suspension in toluene, dioxane, DME or DMF. It has been shown that the reactivity of the bases is as follows: TlOH> Tl2CO3 ~ Ba (OH) 2> NaOH> K3PO4> Na2CO3> NaHCO3 and that the use of a strong base was recommended when the aryl halides or Arylboronic acids were polysubstituted in ortho. The presence of water is generally favorable and makes it possible to accelerate the reaction.

B) Regiselective Suzuki-Miyaura couplings in imidazole series: A large number of metallocatalytic regioselective couplings on polyhalogenated heteroaromatic compounds are reported in the literature and have made it possible to synthesize numerous molecules by introducing a wide variety of substituents. The heterocycles most often studied in palladium- catalyzed regioselective coupling reactions are thiophene, furan, thiazole and imidazole.[14]. The reactivity of Pd (0) to a C-X bond is the same as that of nucleophilic-aromatic substitution reactions (SNAr). The preferential site of a SNAr depends on the C-X binding force that is correlated with the electron density of the carbon. The more a carbon is deficient in electrons, the more it will be eligible for a SNAr.[15]. In the Suzuki-Miyaura reaction, the step of oxidatively adding the halogenated derivative to the palladium catalyst depends on the electronic carbon deficiency carrying the leaving halogen group. This electronic deficit can be correlated with the values of displacements in NMR spectroscopy. Indeed, chemical shifts in NMR are very sensitive to electronic effects and provide important information on the electronic environment of the different parts of a molecule. Data on the regioselectivity of Suzuki-Miyaura coupling of dibromo-imidazoles, extrapolated from chemical shifts in NMR, indicate that the coupling must take place as a priority on carbon in position 2. ©Annals of Tropical Medicine & Public Health S201

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In fact, the hydrogen carried by the carbon at position 2 of the non-brominated parent compound has the highest chemical shift in NMR (Scheme 4), so it is theoretically the most electron-deficient carbon-

2. Figure 4: 1H NMR chemical shift of hydrogen carried by the carbons of the imidazole nucleus These results are consistent with those observed by Kawasaki et al. in 1994 during the total synthesis of nortopsentin, a marine alkaloid. They reported that the most reactive position of 2, 4, 5- tribromoimidazole towards the Suzuki-Miyaura coupling was position 2, followed by position 5. To functionalize these two positions, they operated by one-pot methodology. [16,17]. This leads us to propose that the addition of a nitro group (electro-attractor) at the 5-position of 2,4- dibromoimidazole would modulate the regioselectivity of this coupling by depleting the electron density of the neighboring carbon 4 which would thus become more reactive. The study of this hypothesis will be developed in the second part of this chapter. d) Applications of Suzuki-Miyaura coupling in medicinal chemistry Suzuki-Miyaura coupling is widely used in the pharmaceutical industry and in research laboratories for the synthesis of drugs and the search for new molecules.155 It is found in the industrial synthesis of a marketed and well-known antihypertensive drug: the losartan (Scheme 5):Using Suzuki-Miyaura coupling in losartan synthesis The synthesis of a key intermediate of an anti-depressant drug (SB-245570) whose development was stopped in 2000 in the UK also involved a Suzuki-Miyaura coupling The search for new catalysts that are inexpensive, stable and recyclable, making it possible to work in very mild reaction conditions, appears as a new challenge.

D) Applications of Suzuki-Miyaura coupling in 5-nitroimidazole series.

The first coupling of Suzuki-Miyaura on a nitroimidazole was reported by our team in 2009. A library of 18 new 5-nitroimidazoles were thus synthesized from a coupling of Suzuki-Miyaura on 4-bromo-1,2 dimethyl-5-nitro-1H-imidazole .

More recently, a Suzuki-Miyaura coupling reaction has been described on 4-bromo-2-methyl-5-nitro-1- phenethyl-1H-imidazole with good yields of coupling products . to study the influence of the nitro group, this coupling was tested under the same conditions, on the same starting material after reduction of the nitro group, but the coupling product was not observed. Iaroshenko et al. most of them observed the polymerization of the starting compound, probably because of the instability of the aminoimidazole formed.

The Suzuki-Miyaura coupling is one of the most frequently used palladium-catalyzed couplings for the synthesis of new molecules with therapeutic potential due to the large number of commercial boronic acids, the mild reaction conditions, the high tolerance of this reaction to many groups, and the low

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toxicity of boron compared to 70 other metals like tin. The diversity of available catalysts makes it possible to influence the regioselectivity of the reaction and to improve the yields of coupling products with low reactive starting materials such as aryl chloride. While there are many applications, only a few Suzuki-Miyaura couplings have been reported in the 5-nitroimidazole series. In the current state of our knowledge, no regioselective coupling has been performed on a polyhalogenated 5-nitroimidazole. We will explore this responsiveness in the second part of this chapter.

3. Coupling of Sonogashira

A) General

The first cross-coupling reaction between an aryl halide and an acetylenic derivative resulting in the synthesis of disubstituted alkynes was described in 2016 by chemists RD Stephens and CE Castro.164 The disadvantage of this reaction was the use of very explosive copper acetylide. In 1975, Sonogashira et al. have described the synthesis of symmetrical alkynes by reacting acetylene gas with aryl iodides or vinyl bromides, in the presence of catalytic amount of palladium Pd (PPh3) 2Cl2 and CuI.[18] copper iodide. The main advantage of the Sonogashira reaction compared to that of Castro- Stephens is the formation of the organocuprate in situ, making it possible to use catalytic amounts of copper and to overcome the risk of explosion of copper acetylides. The Sonogashira reaction makes it possible to obtain di-substituted alkynes, by reaction between an aryl or vinyl halide and a terminal alkyne, in the presence of a catalytic amount of copper and palladium salt [19].

This reaction has many advantages and disadvantages which are summarized in Table 2.146 This method has become the most used for the synthesis of arylacetylenes and conjugated enynes.166 Advantages Disadvantages:

- Reaction at room temperature

- Use of catalytic amount of copper

- Commercial copper salts

- Does not require solvents and reagents to be completely anhydrous

- The base can serve as a solvent

- Works equally well on small and large quantities

- The stereochemistry of the starting compound is retained in the final product

-The difference in reactivity as a function of the halides allows the regioselective couplings (I ≈ OTf> Br >> Cl).

- synthesis on complex substrates secondary reactions:

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- If alkyne substituted by electron-attracting groups Michael's addition

- Propargylic alkyne substituted by electron-withdrawing groups - rearrangement to the corresponding allyne

- Increase of temperature in case of very congested substrates little reactive secondary reactions Avantages et inconvénients du couplage de Sonogashira

B) Reaction Mechanism

The catalytic cycle of the Sonogashira coupling reaction involves 3 steps common to other palladium- catalyzed coupling reactions [20].

The first step is an oxidative addition of the halogenated derivative (R1-X) to the palladium catalyst Pd (0) to form Pd (II) as an R1-Pd (II) -X complex.

The second step is a transmetallation of the R2 group of the organocuprate on the complex R1-Pd (II) - X. This step first requires the conversion of the alkyne to copper acetylide in the presence of a base and a copper salt.

The last step is a reductive elimination which leads to the regeneration of the palladium catalyst Pd (0) and to the creation of a link.

The exact mechanism of copper / palladium co-catalysis is not fully understood, but these two metals appear to be involved in two distinct catalytic cycles.

Most of the synthetic routes involving a Sonogashira coupling use PdCl2 (PPh3) 2 and CuI in the presence of amine as co-catalyst. The development of more reactive palladium catalysts, making it possible to dispense with co-catalysis with copper, appears as a new challenge.166 Indeed, the presence of copper requires being in an inert atmosphere because in basic medium and in the presence of oxygen, the homo-coupling of the alkyne to itself can take place according to the Hay / Glaser reaction

C) Coupling applications of Sonogashira

Coupling of Sonogashira is involved in many routes of synthesis of natural products such as (-) Heliannuol E, 168 mapicine169 and N1999A2170 with antibiotic properties .

D) Imidazole series applications

The reactivity of imidazoles with Sonogashira coupling has been studied by several teams.

This coupling was carried out in particular on brominated imidazoles at the 4-position. In the 2,5- imidazole dicarboxamide series (Scheme 35), the yields of coupling product were less than 50% whereas in series 1-methyl-2- phenyl-1H-imidazole-5-carbaldehyde (Scheme 36), they reached 83%.

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In 2016, Yamaguchi et al. used the Sonogashira coupling in imidazopyridine series . They obtained 43 new imidazopyridines with good yields between 50 and 99%, using variously substituted alkynes.

The application of Sonogashira has been reported by Mutel et al. in 2002 More recently, our team synthesized a series of 21 novel 5-nitroimidazoles by coupling Sonogashira to 1,2-dimethy l-5-nitro- 1H-1. imidazole with good yields (40 to 98%) (Scheme 39). This method tolerates a large number of variously substituted alkynes (acetylenic alcohol, aliphatic terminal alkyne and aryl acetylene).[22,23].

Conclusion

Coupling Sonogashira is a coupling widely used in the pharmaceutical industry and in the development of new therapeutic molecules. The mild reaction conditions and the large number of "tolerable" functional groups make it one of the most used palladium-catalyzed couplings. There are some examples of Sonogashira coupling on an imidazole nucleus, of which only two are on a nitrated imidazole. In the second part of this chapter, we will discuss the synthesis of new 5-nitroimidazoles by Sonogashira coupling.

Reference

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