De L'

Devant Le

Mme Micheline Draye

M Mohammad Eldakdouki

Mme Emmanuelle Schulz

M Abderrahmane Amgoune

Président M Mahmoud Faraj

Mme Estelle Métay

M Ali

Prof Marc Marc Lemaire

M Ali Alaaeddine

Thèse Pour

Obtenir Le Grade De

Docteur De L'université

D E Lyon

Université De L'

Libanaise

M Mahmoud Faraj

Prof Hachem Ali

Estelle Métay

Christophe Gilbert

Zeinab Elmoussawi

Fatima Rida

Zeina Harkous

Sally Badawi

Najwa Skafi

Ashraf Said

Bilal Maya Dia

A L Asaad

Fatima Yassine

Boris Guicheret

Aurélien Herbinski

Biwen Zhu

Nam Vu

Aubin Charvieux

Dorine Belmessieri

Carole Guyon

Roxan Joncour

Charlotte Gozlan

Elsa Deruer

Souleymane Bah

Tony Cousin

Valentin Cinquin

Hanieh Roueindeji

Planet YOAN Clément Ghiazza

Cherif Adouama

Anne-Sophie Mora

Mariam Attoui

Sanaa Shehayeb

Orsola Beydoun

Marwa Abu Hamdan

Ali Hmayed

Ranin Kawtharani

Layal Harisi

Dipea N,N-Diisopropylethylamine

Ac

Dimethoxyethane Ar

THESE de DOCTORAT

Keywords: Reduction, calcium hypophosphite, ammonium hypophosphite, nitrile, aldehyde, ketone, primary amine, reductive amination, nickel, palladium Réduction, hypophosphite de calcium, hypophosphite d'ammonium, nitrile, aldéhyde, cétone, amine primaire, amination reductrice, nickel, palladium

At the beginning, this work wouldn't have the spirit that it has without the invaluable academic, psychological and support,

" ﺎ ً ﻤ ْ ﻠ ِ ﻋ ﻲ ِ ﻧ ْ د ِ ز ﱠبﱢ ر ﻞ ُ ﻗ َ "و
"Science knows no country, because knowledge belongs to humanity, and is the torch which illuminates the world."

GENERAL INTRODUCTION

The knowledge of chemistry over the last two centuries has contributed to all major advances. Advances in medicine through drug discovery, the role of chemistry in hygiene, building, electronics, cosmetics, perfumes, energy, transportation, and agriculture. Industrialization has led to the development of mass consumption with everincreasing volumes of products produced. On the other hand, the increase in population has led to greater demand of products, thus reducing resources and increasing pollution.

Organic chemistry is currently dependent on the supply of oil and metals. However, the scarcity of these resources leads to an increase in the price of raw materials.

Twenty years ago it was clear that a new paradigm for efficiency in organic synthesis was needed. The introduction of the principles of clean or green chemistry and the underlying concepts of waste minimization, E factors, and atom efficiency provided an answer to this need. Now, twenty years later these concepts are accepted in academic and industrial circles on a worldwide basis. Industrial and academic research has focused on these concepts for the substantial reductions in waste generation by replacing outdated processes employing stoichiometric reagents with greener catalytic alternatives. The next phase of designing a more efficient and sustainable chemical industry will be the successful application of these green catalytic technologies in the efficient synthesis of organic chemicals from renewable resources. 1 These new principles were applied in the development of new tools for the reduction of organic functional groups, one of the most important transformations in chemical industries, which requires the use of hazardous substances, such as aluminum and boron hydrides ( LiAlH 4 , DIBAL-H, Red-Al, NaBH 4 , etc.), which are used in large scale by the chemical industries (2000 to 3000 tons per year), as a source of hydrides in reduction reactions. These hydrides are the subject of numerous books, chapters, reviews and are taught in both theoretical and practical courses in universities and schools. However, despite their efficiency in terms of selectivity and yields, there exist several drawbacks:

They can potentially release hydrogen in a violent manner.

They can react violently with water and air.

The solvents used are often ethers (THF, glymes, diethyl ether, etc.) which are toxic and flammable. 2 Hydrolysis of aluminum and boron hydrides is highly exothermic with hydrogen production, which causes safety problems.

Salts produced during hydrolysis, 3 such as borates or aluminum derivatives are potentially toxic and often considered to be partly responsible for Alzheimer's disease. 4 The salts resulting from the hydrolysis are difficult to separate from the products of the reaction, especially in the case of aluminum salts. A large amount of solvents are required to wash these salts generating significant waste. 5 Therefore, with respect to green chemistry principles, they no longer meet the ecological, economic or social demands and their replacement is an objective.

Catalytic hydrogenation using molecular hydrogen is often preferred for ecological and economic reasons as the amount of waste produced is much lower (principles 2 and 8 of green chemistry). However, using this type of reducing agent is limited by the lack of selectivity, and the harsh reaction conditions (high temperatures and pressures) which require using special and expensive equipment. Reductions using isopropanol as hydrogen donor and solvent at the same time are in equilibrium, shifting the reaction in one direction needs large dilution.

In recent years, hydrosilanes (with a Si-H bond), derived from silicon and whose ultimate waste is silica, have been developed as an interesting alternative to conventional reduction methods. Alkyl-, alkoxy-, and chlorosilanes such as PhSiH 3 , (OEt) 3 SiH and HSiCl 3 were the first studied because they have the advantage of being commercial and easy to prepare. Activated by transition metals or fluorides, they have been used for the reduction of several organic functions. However, despite interesting results, the cost of hydrosilanes, their low vapor pressure, their flammability and their toxicity limit their use on an industrial scale. In addition, some can generate, by redistribution, silane (SiH 4 ) which is a dangerous, toxic, pyrophoric and explosive gas. 6 These drawbacks can probably be overcome by using hydrosiloxanes (having Si-O-Si bonds). In our laboratory, polymethylhydrosiloxane (PMHS) and 1,1,3,3tetramethyldisiloxane (TMDS) were activated by transition metals to reduce a wide variety of organic functions, but these reducers remain too expensive. 7 In our laboratory, during studies dedicated to finding cleaner reducing agents, it was discovered that hypophopshites can selectively reduce some organic functional groups. 8 Actually, hypophosphites are produced on a very large scale, at low price and are known to be non-toxic. Moreover the byporoducts of these reagents are phosphorous derivatives, which are widely used as fertilizers. 9 It was proved that a mixture of sodium hypophosphite and phosphinic acid in the presence of Pd/C in a biphasic water/2-MeTHF system, was able to reduce aromatic and aliphatic nitro groups to anilines and amines. On the other hand, aromatic ketones were selectively reduced into arylmethylenes or alcohols with hypophosphites and Pd/C depending on the selected conditions. An enantioselective version has also been demonstrated, allowing the reduction of (hetero) aromatic ketones. 10 These encouraging results are part of the reason for our interest to study the reducing activity of these reagents in the reduction of other functional groups.

Achieving the aim of this PhD project will prove again the efficiency of hypophosphites as air stable, easy to handle, inexpensive and non-toxic reducing agents. Moreover, it will open the path for the reduction of a wide variety of organic functional groups.

The work of this PhD presented in this thesis is composed of two main parts, briefly explained in the paragraph that follows:

Part one will discuss the reduction of nitriles using calcium hypophosphite and is divided into two distinct sections, the reduction of nitriles into aldehydes and into amines. At the beginning we will discuss general concepts and different methods present in literature for these two reactions. Then, our investigated two methods will be explained. Briefly, in method 1 we associate calcium hypophosphite with nickel acetate in a biphasic medium to produce aldehydes from nitriles. In method 2, the transformation of nitriles into primary amines was performed using calcium hypophosphite in the presence of Pd/C in aqueous medium.

In part two, we present another type of reaction, namely the reductive amination of ketones using ammonium hypophosphite. Similarly, different methodologies present in literature will be discussed, followed by our investigated methodology, where we associate ammonium hypophosphite with Pd/C in n-BuOH.

Part I: Reduction of Nitriles

Using Calcium Hypophosphite PART I. REDUCTION OF NITRILES USING CALCIUM HYPOPHOSPHITE

Introduction

With increasing demand for generic procedures for solution phase chemistry and a broad range of commercially available nitriles, it became desirable to devise an improved protocol for the reduction of surprisingly unreactive cyano group. 11 It has been less investigated so far compared to reductions of C=C, C=O, C=N, and NO 2 bonds. This is primarily due to the high redox potential of nitriles compared to other carboxylic acid derivatives and the low C-CN bond dissociation energy, which leads to undesired reductive decynations, side reactions via fragmentation to aklyl radicals and cyanide anions; and the instability of imine/ iminium intermediates under the reaction conditions, which resulted in alcoholysis, transimination or reductive polymerization pathways. 12 We are interested in two possible pathways: (a) reduction of nitrile to imine which can be hydrolyzed to give the aldehyde; (b) Reduction of the intermediate imine into amine (scheme 1). The selectivity depends on the nature of the reducing agent, nature of catalyst and on the experimental conditions (temperature, time, solvent, additives, etc.).

Scheme 1. General reaction mechanism for the reduction of nitriles.

Although many methods exist today to selectively reduce this function, the search for new processes that are more environmentally friendly, less expensive, more selective and efficient for industrial development is still very important.

In this part, five sections will be discussed. The first debates the different methods from literature for the reduction of nitriles towards aldehydes and amines, the next two will present the work that was carried out in the laboratory for the reduction of nitriles into aldehydes and amines. The fourth will be a conclusion as well will discuss the future perspectives. Finally, the experimental work will be discussed in addition to the characterization data of the isolated products.

Bibliographic data

Reduction of nitriles into aldehydes

Rarely available in nature except in the singular structure of sugars, aldehydes are important intermediates in organic synthesis, but their chemoselective access is a challenging task, because the reaction requires to be stopped at the intermediate imine which is too reactive as mentioned before. Nevertheless selective methods have been found.

Stephen Reduction

Henry Stephen is one of the first researchers who described the reduction of nitriles into aldehydes in 1925. 13 He observed that when aromatic or aliphatic nitriles are added to a solution of stannous chloride (or tin chloride, SnCl 2 ) in saturated diethylether which is then saturated with dry hydrogen chloride, the corresponding imine hydrochloride is obtained. This latter salt, after hydrolysis in warm water, released the corresponding aldehyde in good yield. This conversion of nitriles into aldehydes by the combination of tin chloride/ HCl gas in an organic solvent is known as the " Stephen Reduction".

The Stephen Reduction takes place in three steps (Scheme 2): (1) the nitrile is dissolved in an inert solvent and the solution is then saturated with gaseous hydrochloric acid at 0ºC. The reaction between nitrile and the acid gives an imidoyl chloride 1.

(2) A solution of SnCl 2 / HCl in the reaction solvent is then added and reacted with imidoyl chloride 1 to give an aldimine stannichloride 2 which precipitates in the reaction medium. (3) Hydrolysis of this complex in hot water releases the corresponding aldehyde.

Scheme 2. Mechanism of Stephen reduction. 13 This method is applicable for the reduction of aromatic nitriles leading to average yields of the corresponding aldehydes. Moreover, the yields with aliphatic nitriles are even lower. The reaction is sensitive to steric hindrance and the tolerance to other functional groups is low.

Reduction of nitriles to aldehydes using aluminum hydrides

Lithium Aluminum hydride, LiAlH 4 , is known to be not efficient for the selective reduction of nitriles towards aldehydes, since it is highly reactive and it reacts rapidly on the intermediate imine rather than on nitrile leading to the formation of amine as the major product. [START_REF] Carlier | [END_REF] However, by replacing some of the hydrides with suitable substituents, the selectivity changes towards the aldehyde. A series of lithium aluminum (alkoxy) hydrides such as Li(OEt) 2 AlH 2 , Li(MeO) 3 AlH, Li(n-PrO) 3 AlH, and Li(n-BuO) 3 AlH were studied by H. C. Brown. 15 The best results were obtained with Li(OEt) 3 AlH. Using this reagent, aromatic and aliphatic nitriles 3 have been reduced to the corresponding aldehydes and isolated as hydrazones 4 in higher yields (scheme 3). 15b 18 were developed by N.M Yoon and J. S. Cha to reduce aromatic nitriles to aldehydes at room temperature (Figure 1).

Figure 1.

Structures of aluminum (amino) hydrides 5, 6 and 7. 16,17,18 DIBAL-H has also been used for the successful reduction of nitriles into aldehydes. In a medium containing the nitrile at a very low temperature and in stoichiometric amounts, it leads to iminoaluminate 8, which is finally hydrolyzed to the aldehyde (scheme 4). 19 This method is efficient and applicable on a variety of nitriles including aromatic, aliphatic, α,β-unsaturated nitriles and different derivatives of cyclopropane nitriles. amyl-9-boratabicyclo-[3,3,1] nonane 13 developed by J. S. Cha. 22 2.1.4. Reduction of nitriles into aldehydes using hydrated electrons J. P. Ferris et al. have reported the convenient reduction of nitriles to aldehydes in aqueous media by photochemically generated hydrated electrons. 23 Substituted cyanophenols in the ortho, para and meta positions are the best substrates since they produce electrons themselves. They have demonstrated that the photo-excitation of the ion phenolate 14 gives a hydrated electron. Then it has been suggested that the radical species 15 is formed by the addition of the hydrated electron to the cyanophenolate 14, followed by a rapid proton transfer. The two radical intermediates 16 are supposed to rearrange giving the starting nitrile 14 and the aldimine 17 which hydrolyze to give the aldehyde 18 in moderate yields (scheme 5). For different substrates, the presence of iodide anion is necessary as it is the source of electrons in the reaction medium.

However, the yields remain low.

Scheme 5. Reduction of 4-hydroxybenzonitrile 14 to 4-hydroxybenzaldehyde 18 by photochemically generated hydrated electrons. 23 2.1.5. Reduction of nitriles into aldehydes using aqueous formic acid Aromatic nitriles can be reduced to the corresponding aldehydes using platinum (IV) oxide in aqueous formic acid with good to excellent yields. 24 Formic acid not only serves as a solvent, but also as a hydrogen source in the reaction. Reaction of formic acid with platinum oxide liberates hydrogen and carbon dioxide, 25 and leads to formation of more reactive platinum species capable of reducing nitrile to the corresponding aldimine 19 which is rapidly hydrolyzed to aldehyde (scheme 6). In this reaction system, hydrazine hydrate acts as a reducing agent (reduction of nitrile to imine) and as a reactant where it condenses on the imine to yield the aldazine.

Reduction of nitriles into aldehydes over Ru and Pt-loaded zeolites

Bifunctional zeolite catalysts can be used in the reductive hydrolysis of aromatic nitriles.

For example benzaldehyde is produced selectively using Ru-H-beta catalyst, higher conversion is obtained with Pt-loading over NH 4 -beta. 28 The reaction passes via the intermediate aldimine.

Reduction of nitriles into aldehydes using hydrosilanes

The catalytic hydrosilylation is a suitable tool for the selective reduction of nitriles. It exhibits improved chemo-and regioselectivity under milder conditions compared to conventionally used reducing agents mentioned before. In 1966, R. Calas et al. studied the action of trialkylhydrosilane in the presence of zinc chloride on various nitriles. 29 The major product in the reaction was N-silylimine 24 which is a protected form of aldehyde.

Reactions were carried out under reflux and better yields were obtained in an autoclave.

Under these conditions aliphatic nitriles bearing α-H give better yields than those having no hydrogen at this position (Scheme 8). On the other hand, yields were low with aromatic nitriles.

Scheme 8. Formation of N-silylimine 24 by the reaction of trialkylhydrosilane with nitrile in the presence of ZnCl 2 . 29 In 1970, A. J. Chalk reported the hydrosilylation of α,β-unsaturated nitriles using dimethylchlorosilane HSiClMe 2 in the presence of dicobalt octacarbonyl Co 2 (CO) 8 . 30 For example, with acrylonitrile, the α-adduct was the only product due to the reaction on the carbon-carbon double bond, whereas with methylacrylonitrile 25, 1,4-addition took place to give the N,N-disilylenamine 26 in 20% yield after 6 days (Scheme 9).

Scheme 9.

Hydrosilylation of methacrylonitrile 25 by the HSiClMe 2 /Co 2 (CO) 8 system. 30 In the 1980's, R. J. P. Corriu studied the combination of bis-silanes 27, 28 or 29 (Figure 4) and Fe(CO) 5 for the stoichiometric hydrosilylation of aliphatic nitriles into N,Ndisilylenamines under UV-irradiation. 31 Bis-silanes were also associated with nickel, 32a platinum, 32b and rhodium 32c catalysts to reduce nitriles bearing α-H into cyclic Nsilylenamines and aromatic nitriles into cyclic N-silylimines. Moreover, ruthenium, 33a,b tungsten, 33c,d and molybdenum 33d,e complexes bearing Si-H moiety have been designed

for the stoichiometric hydrosilylation of nitriles but few examples have been published

and yields were low to moderate. Recently, Nikinov and co-workers reported two complexes of molybdenum and ruthenium to catalyze the reduction of nitriles into imines (Figure 5). The molybdenum complex 30 catalyzed slowly the hydrosilylation of benzonitrile in the presence of PhSiH 3 , 34a so that the conversion was complete after 13 days. since it allowed the reduction of aliphatic and aromatic nitriles into N-silylimines at room temperature in good to excellent yields, while preserving any other functional group including ketone, aldehyde, nitro, ether, ester groups and carbon-carbon double bond as well.

Figure 5.

Molybdenum and ruthenium complexes developed by Nikonov. 34 2.1.9. Reduction of nitriles into aldehydes using hydrosiloxanes

Hydrosiloxanes have been considered as a safer alternative for hydrosilanes. Recently our lab reported the first reducing system employing 1,1,3,3-tetramethyldisiloxane (TMDS)

activated by an oxovanadium(V) complex, triisopropoxyvanadium(V) oxide, to reduce nitriles into aldehydes. 35 The reaction proceeds in toluene at 60 ºC with both aromatic and aliphatic nitriles to give the corresponding aldehydes in moderate to good yields (Scheme 10).

Scheme 10.

Example of the reduction of nitriles to aldehydes by TMDS. 35 2.1.10. Reduction of nitriles to aldehydes by hypophopshites

In the sixties, Staskun was the first to report the reduction of nitriles into aldehydes with hypophosphites and Raney-nickel as a catalyst in water/acetic acid/ pyridine solution (Scheme 11). 36 These conditions were thereafter widely applied to the reduction of aliphatic, 37 aromatic 38 and heteroaromatic 39 nitriles. As an example, Gosh used these conditions to reach compound 33, which was an intermediate in the total synthesis of (+)-Jasplakinolide. 40 The chemoselectivity of this reaction is well represented by the reduction of compound 34 into 35 for which no dehalogenation was observed. 41 Moreover, the reduction could be performed in the presence of a heteroaromatic ring, as in the transformation of 36 to 37 with 90% yield. 42

Scheme 11. Examples of the reduction of nitriles to aldehydes by hypophosphites. 40,41,42 2.2. Reduction of nitriles into amines Amines are valuable compounds that are present in many agrochemicals and drugs. In addition, many other industrially relevant products, such as dyes, detergents, solvents, additives or antifoaming agents contain amines in their structure. [START_REF] Lawrence | Amines: Synthesis Properties and Application[END_REF] More specifically, primary amines are highly relevant, owing to their straightforward functionalization. [START_REF] Camurlu | [END_REF] The reduction of nitrile to primary amine is usually accompanied with the formation of secondary and tertiary amines as by-products of the reaction (Scheme 12). The formation of the secondary amine 41 is due to the nucleophilic attack of the amine 39 previously formed on the intermediate imine 38. The elimination of ammonia leads to the secondary imine 40, which is then reduced to the secondary amine 41. Furthermore, the latter secondary amine 41 can also react with the imine 38 to result in the tertiary amine 42 in the same manner.

Scheme 12. Reduction of nitriles to amines and possible side reactions.

The selectivity of the respective amines depends on the structure of the substrate, the nature and the amount of the catalyst, basic and acidic additives, the reaction medium, and other reaction parameters. Among these factors, the nature of the catalyst appears to be the most important for determining the selectivity. Apparently, there are two possibilities to improve the chemoselectivity towards the primary amine: (1) a low concentration of the imine 38 is desirable to suppress formation of the secondary amine 41 and (2) the equilibrium between 38 and 40 should be shifted towards 39 by the addition of ammonia or an appropriate base. 45 2.2.1. Reduction of nitriles into amines using aluminum hydrides Among the metal hydrides used for the reduction of nitriles to amines are aluminum hydrides such as LiAlH 4 , NaAlH 4 , AlH 3 and Red-Al. [START_REF] Trost | Comprehensive Organic Synthesis[END_REF] For example, P. R. 48 The milder sodium borohydride is generally not strong enough to reduce cyano group, however, its behavior change upon association with transition metal salts, such as nickel, 49 and cobalt. 50 For example, in the presence of catalytic amount of nickel chloride, NaBH 4 reduces aromatic, aliphatic and (hetero) aromatic nitriles 45 to amines at r. 6), were able to reduce nitriles into the corresponding amines by refluxing in THF. 51 However, these aminoboranes are not able to reduce nitriles in the presence of other functional groups including aldehydes, ketones, epoxides and esters. Singaram. 51

Reduction of nitriles into amines by catalytic hydrogentation

Catalytic hydrogenations are of great importance in organic synthesis and play a key role in the production of numerous bulk products and intermediates in the chemical industry.

From an ecological point of view, reductions using molecular hydrogen as reducing agent represent one of the most efficient and atom-economical transformations. [START_REF] Rylander | Catalytic Hydrogenation in Organic Synthesis[END_REF] In general, heterogeneous catalysts are well established in the hydrogenation of non-demanding polar functional groups, which often takes place at high temperatures and/or pressures. [START_REF] Pritchard | [END_REF] The complementary development of well-defined homogeneous complexes that allow for selective reduction under milder conditions also constitute a cutting-edge endeavor in modern catalyst design. 54 2.2.3.1.Heterogeneous catalysis 2.2.3.1.1. Raney Nickel and cobalt catalysts Among various metallic catalysts, nickel and cobalt have been widely used for the hydrogenation of nitriles to primary amines. In general, cobalt catalysts are supposed to be more selective than nickel in the formation of primary amines, although nickel catalysts are usually more active than cobalt ones. [START_REF] Nishimura | Handbook of Heterogeneous Catalytic Hydrogenation for Organic Synthesis[END_REF] For example the reduction of nitrile 50 gave amine 51 in 88% yield after 25 min. using Raney cobalt in ethanol-ammonia at 125-150°C and under 20 Mpa (200 bar) (Scheme 15). [START_REF] Reeve | [END_REF] Recently in 2016, Beller group developed a new heterogeneous cobalt catalyst system supported on α-Al 2 O 3 for the reduction of aromatic as well as aliphatic nitriles to primary amines under mild conditions. 57

Scheme 15. Reduction of nitrile 50 to primary amine 51 by heterogeneous catalytic hydrogenation using Raney-Co. [START_REF] Reeve | [END_REF] With respect to Raney nickel, the most widely used reaction at the industrial level is the reduction of adiponitrile in the presence of Raney nickel to give either 1,5-hexanediene, 58 (synthesis of nylon-6,6) or 6-aminohexanenitrile, 59 (synthesis of caprolactam, precursor of nylon-6). 19). 66 Aromatic, heteroaromatic and alkyl nitriles were reduced using these systems.

Scheme 19. Hydrogenation of nitriles using ruthenium/DPPF or PPh 3 systems. 66 Furthermore, the same group performed the selective hydrogenation of aromatic nitriles by applying a combination of the ruthenium precursor 53 in the presence of SIMesBF 4 56

and additional base (Scheme 20). 67

Scheme 20. Hydrogenation of aromatic nitriles using Ru/carbine-catalyzed system. 67 It should be noted that the presence of base t-BuOK increases the selectivity of the reaction towards primary amine and strongly inhibits the formation of secondary amines.

Ruthenium hydride complexes were also developed for the reduction of nitriles to amines. 68

Rhodium catalysts

In 1979, Yoshida, Okano, and Otsuk explored rhodium(I) hydrides for the first time for the selective hydrogenation of nitriles to the corresponding primary amines under ambient conditions. 69 For example RhH[P(i-Pr) 3 ] 3 57 proved to hydrogenate aromatic and aliphatic nitriles to give the corresponding primary amines with excellent yields up to 99% (Scheme 21).

Scheme 21. Hydrogenation of nitriles using rhodium catalyst. 69 It is noted that complexes with other precious metals including Ir 70 and Re 71 have been used for this type of hydrogenation as well.

Iron catalysts

Nowadays one of the major goals in catalysis is the replacement of previously mentioned precious metals by inexpensive and less toxic non-noble metals. 72 In 2014, Beller group reported an aliphatic PNP-pincer based iron catalyst 58 for the hydrogenation of nitriles to primary amines. 73 Two years later, D. Milstein and co-workers developed another novel iron complex 59 (Figure 7) based on a novel PNP pincer ligand as well. 74

Figure 7. Fe based catalysts for homogeneous hydrogenation of nitriles to primary amines. 73,74 Complex 59 in the presence of NaBHEt as the hydrogen donor in the presence of 2% KOH. 81 In this reaction N-isoproplidene amine 68 formed as a result of the condensation between the primary amine arising from nitrile reduction and acetone resulting from the oxidation of 2-propanol during CTH reaction (Scheme 24). The N-isopropylidene amine 68 is then hydrolyzed to primary amine with dilute HCl and isolated as hydrochloride salt. Actually, the presence of KOH suppresses the reduction of 68 into symmetrical amine.

Scheme 24. Catalytic transfer hydrogenation of aliphatic nitriles using 2-propanol/Ni-Raney. 81 In 2013, Beller and co-workers explored CTH of aromatic and aliphatic nitriles to the corresponding primary amines using 2-butanol as a hydrogen donor. 82 The same group, later studied the CTH of (hetero)aryl nitriles to amines using ammonium formate (NH 4 HCO 2 ) in the presence of Pd/C. 83 2.2.6. Reduction of nitriles to amines using hydrosilanes For the first time, Corriu and co-workers reported transition metal catalyzed hydrosilylation of nitriles using Wilkinson's catalyst. 84 In the presence of Wilkinson Catalyst. 84 In 1985, T. Murai group developed a system using HSiMe 3 (10 equiv.) C. Fernandes explored the reduction of a wide range of aromatic nitriles bearing different functional groups using PhSiH 3 (300 mol%) and ReIO 2 (PPh 3 ) 2 (10 mol%) as a catalytic system. 90 In addition to metal catalysis, a convenient approach is the use of fluoride ions as an activator for the hydrosilylation. Tetra-n-butylammonium fluoride (TBAF) is considered to be a useful catalyst candidate since it offers a highly nucleophilic fluoride anion as an activator for the hydrosilylation. For example in 2013, Beller group studied the hydrosilylation of aromatic nitriles using TBAF 79 (Scheme 27). 91

Scheme 27. Reduction of aromatic nitriles using PhSiH 3 /TBAF system. 91 Unfortunately, using this approach to reduce aliphatic nitriles and heterocyclic nitriles such as, 3-thiophene carbonitrile and picolinonitrile did not yield the desired product.

Another example of the metal-free silylative reduction of nitriles is the use of B(C 6 F 5 ) 3 /Et 2 SiH 2 system developed by S. Chang and co-workers (Scheme 28). 92 The use of sterically bulky silane such as Et 3 SiH allowed only the partial reduction leading to Nsilylimines.

Scheme 28. Reduction of aromatic nitriles using Et 2 SiH 2 /B(C 6 F 5 ) 3 system. 92 2.2.7. Reduction of nitriles to amines using hydrosiloxanes

The most studied hydrosiloxanes are the long-chain polymer polymethylhydrosiloxane (PMHS) 80 and the shortest 1,1,3,3-tetramethyldisiloxane (TMDS) 81 mentioned before in the reduction of nitriles to aldehydes (Figure 8). Two efficient systems TMDS-Ti(OiPr) 4 , 93 and PMHS-Ti(OiPr) 4 , 93b were developed in our laboratory for the reduction of aliphatic and aromatic nitriles to the corresponding primary amines. The synthetic approach was straight forward and provided primary amines as hydrochloride salt in almost quantitative yields. For example nitrile 82 was reduced to primary amine 83 in 90% isolated yield using both systems (Scheme 29).

However, the reaction with PMHS 80 was faster than in case of TMDS 81.

Scheme 29. Reduction of nitrile 82 to primary amine 83 using TMDS or PMHS in the presence of Ti(OiPr) 4 . 93 Furthermore, PMHS-Ti(OiPr) 4 reducing system reduced dinitriles 84 into the corresponding saturated N-heterocycles 85 (Scheme 30). 93b

Scheme 30. Reduction of dinitriles 84 into saturated N-heterocycles 85 with the reducing system PMHS-Ti(OiPr) 4 . 93b

Another methodology was developed in our group for the reduction of aromatic nitriles to amines with TMDS 80 in the presence of catalytic quantity of copper triflate (Cu(OTf) 2 ) (Scheme 31). 94

Scheme 31. Reduction of nitriles to primary amines using TMDS and Cu(OTf) 2 in 2-MeTHF or in 1,2,3-TMP. 94 The reaction is highly solvent dependent and the best results were found in 1,2,3-Trimethoxypropane 86 (1,2,3-TMP). Good results were also observed with 2-MeTHF, even if the selectivity for the desired primary amine was sometimes lower.

Reduction of nitriles to amines using hypophosphites

The reduction of nitriles into amines using hypophosphites was mentioned as the result of formation of an undesired product observed by Johnstone during the cleavage of aromatic ethers with sodium hypophopshite and Pd/C. 95 Another example is the reduction of nitrile 87 to primary amine 88 using sodium hypophosphite in the presence of Raney nickel and in a mixture of water/acetic acid/ pyridine, however, the yield was as low as 22% (Scheme 32). 96

Scheme 32. Reduction of nitrile 87 to primary amine 88 using sodium hypophosphite. 96

Conclusion

Numerous synthetic tools are available in literature for the selective reduction of nitrile function. Aluminum and boron hydrides are effective, but several drawbacks exist such as their use in combination with toxic and flammable solvents, dangerous workup, production of hazardous and toxic metal salts as secondary products, as wellas being substrate dependent.

Molecular hydrogen remains the ideal reducer. Effective and selective homogeneous as well as heterogeneous catalysts have been developed. However, no universal catalyst exists, and no general method is available, so that each type of substrate needs optimization. Moreover the workup of such reactions requires specific apparatus that holds high pressure.

The single electron transfer and catalytic transfer hydrogenation makes it possible to overcome the limitations of hydrogenation, but these conditions remain ineffective on several substrates.

Hydrosilylation reactions have also been reported to convert nitriles to either Nsilylimine or to N,N-disilylenamine (protected forms of aldehyde) or to N,N-disilylamine (protected form of amine). Other methods allow the isolation of unprotected amines.

However, such methods utilize reagents that are often too expensive, must be used in excess, toxic, flammable, and can release in some cases SiH 4 which is dangerous pyrophoric gas. Another limitation is their use in association with toxic metals and expensive ligands in some cases. These drawbacks can probably be overcome by using hydrosiloxanes, but the limitation in such cases is also the relative high cost of the silicon reagents.

Finally, few examples have been reported for the reduction of nitriles to aldehydes using hypophosphites, and only one example is available for their reduction towards the amine but in a very low yield.

Results and discussion

Previous results in the laboratory

Marc Baron has developed during his PhD work the synthesis of tetrahydro-β-carbolines including the reduction of nitroindoles to provide non-natural tryptamines. 8 For example 35), where the corresponding alcohols were isolated in moderate to excellent yields (39-95%). 10

Scheme 35. Reduction of aromatic and aliphatic ketones using sodium hypophosphite. 10 On the basis of these encouraging results, an enantioselective version has been developed using RuCl(p-cymene)[(R,R)-TsDPEN] 94 (4 mol%) as a catalyst, in a glycerol/2-MeTHF biphasic solvent mixture (Scheme 36). 10 The reaction allowed the reduction of (hetero)aromatic ketones to alcohols in moderate to excellent chemo-and enantioselectivities (22-97% ee).

Scheme 36. Enantioselective reduction of ketones using sodium hypophosphite. 10 Moreover, aromatic ketones were reduced either to alcohols or alkanes using hypophosphites with Pd/C. 11 The study of the reaction parameters revealed the importance of the acidity of the reaction medium, the temperature as well as the catalyst loading. The determining factor for the selectivity towards alcohol is the addition of tetrabutylammonium chloride (TBAC) (7 mol%) The deoxygenation reaction to obtain the alkane was maintained in the presence of NaH 2 PO 2 .H 2 O (3 equiv.), H 3 PO 2 (1 equiv.), Pd/C (10 mol%) in H 2 O/CPME at 100°C for 5h (Scheme 37, method B). The reaction was generally faster in comparison to that using ruthenium catalyst.

Objective

After obtention of these results, it seems very interesting to study the reductive ability of these types of reagents in the presence of other functionalities. Our aim is to develop easy, versatile and green methods, particularly for the reduction of nitriles into aldehydes and amines. Herein, we report our investigated methodologies in details.

Reduction of nitriles to aldehydes

Feasibility and optimization of reaction conditions a. Screening of different hypophosphites

In order to confirm the feasibility of the reduction of the group nitrile by hypophosphite, benzonitrile 95 was used as a model substrate. The first tests were carried out using nickel chloride as a catalyst, since we are interested in using non-precious metal catalysts due to their abundance and low price. Initially, the reducing activity of different hypophosphites was studied in the presence of an additive tris(dioxa- In this case it is important to mention that the color of the reaction mixture changes from green which is the color of Ni(II) species to dark grey the color of Ni (0) species. Other hypophosphites were also tested in this reaction including sodium hypophosphite

(NaH 2 PO 2 .H 2 O), ferric hypophosphite [Fe(H 2 PO 2 ) 3 ]
and hypophosphorous acid (H 3 PO 2 ).

However, we didn't observe any conversion with no change in the color of the reaction mixture. As a result, Ca(H 2 PO 2 ) 2 was the only one to show reactivity in this transformation, so it was choosed for further studies to optimize reaction conditions. On the other hand, the change in the color of the reaction mixture from green to dark grey is an evidence that a reaction took place.

b. Screening of different catalysts

While trying to improve the conversion, we decided to increase the temperature to 100°C, and to use K 2 CO 3 as a basic additive instead of TDA in the presence of different metal catalysts (Table 1). As we mentioned before in the bibliographic part, nitriles in reductive conditions can afford several products in different ratios depending on the reaction conditions. Increasing the temperature and using 40 mol% of K 2 CO 3 in the presence of NiCl 2 .6H 2 O, makes it possible to increase the conversion up to 68%, and to increase the GC ratio of benzaldehyde 97 to 46% (Table 1, entry 1).

c. Screening of different nickel catalysts

On the basis of these results, where only nickel catalyst yielded the desired aldehyde 97, the catalytic activity of different nickel complexes was tested in the same reaction conditions ( catalyst was Ni~65 wt.% on Si/Al, after 24h the conversion was complete, but we didn't obtain benzaldehyde 97, instead benzylalcohol 98, benzamide 101 and dibenzylamine 102 were the products in this reaction. It seems that this reaction is too fast, so several reactions were followed. We observed that after 1h the conversion was complete leading to 35% of 97. After 30 min the conversion reaches 62%, giving 79% of benzaldehyde 97

(Table 2, entry 10). It is clear that Ni~65 wt.% on Si/Al is efficient with high reactivity, however the chemoselectivity should be improved. Moreover, the appearance of a green color at the end of the reaction reveals a lack of stability of this catalyst in these reaction conditions.

This series of experiments revealed that the nature of nickel precursor is very important in determining the conversion and the selectivity towards the desired product.

Ni(OAc) 2 .4H 2 O showed the best reactivity in this reaction.

d. The nature of catalytic species

It is important to mention that a control experiment in the absence of calcium hypophosphite and base did not lead to any conversion, thus confirming that the hypophosphite and the base are crucial for the formation of Ni (0) species, and eventually for the reduction of nitrile to aldehyde.

A recent work done in 2012 reported the synthesis of nickel nanoparticles (NiNPs) by the reduction of less toxic nickel precursor Ni(OAc) 2 .4H 2 O, using sodium hypophosphite NaH 2 PO 2 .H 2 O under microwave irradiation in the presence of propylene glycol as a solvent (Figure 9). 97 It was mentioned that the formation of NiNPs depended on PO 2 ]/[NaOH] molar ratios. More NaOH leds to an increase in the pH of the reaction solution and thereby to a decrease in the free energy required to form NiNPs as per Nernst equation:

[Ni 2+ ]/[NaH 2
Ni 2+ + 2OH -+2H 2 PO 2 - Ni + 2HPO 2 -+ 2H 2 O.
Such decrease in the free energy would have resulted in large number of nuclei and thus particles. On the other hand, higher concentration of NaH 2 PO 2 .H 2 O introduced more phosphorous into the system, thus increasing the chances of Ni-P compounds formation instead of pure Ni. Here arises the second role of the base in the medium, where it helps in releasing phosphorous species into the system to form pure NiNPs.

e. Screening of basic additives

It is known that the solubility of Ca(H 2 PO 2 ) 2 in water is low in comparison to the solubility of other hypophosphite derivatives (Table 3). Therefore lower concentrations of calcium hypophosphite were used in our study. Experiments showed that the amount of Ca(H 2 PO 2 ) 2 could be reduced to 1 equiv. instead of 2.5 equivalents with improved conversions. 4.

A blank experiment was done in the absence of base. After 24h, the color of the reaction persisted at green and no conversion was observed (Table 4, entry 1). This indicated that Ni (II) species were not reduced to Ni (0) which is the real catalyst in the reaction. For all other entries with different bases, the color of the solution changes to dark grey indicating the formation of Ni (0) species. In the presence of K 2 CO 3 (Table 4, entry 2), the conversion increased up to 91% after 24h in comparison to entry 8 of table 2 (with 2,5 equiv. of reducing agent). However, lower GC ratio of benzaldehyde 97 was obtained (29%).

Na 2 CO 3 and CaCO 3 showed similar results with high conversions and moderate yield of 97 reaching 40 and 42%, respectively (Table 4, entries 3 and 4). This is an indication that the counter ion has small effect on the selectivity. When acetates were used as bases, benzaldehyde 97 was the sole product in the reaction but with low conversions (Table 4, entries 6 and 7). a Conv. and GC ratio were determined by gas chromatography.

A reaction with N,N-Diidopropylethylamine (DIPEA) was also performed, leading to a complete conversion after 24 h, but only 5% of 97 was detected (Table 4, entry 8). Even after 7h a mixture of different products was observed with 55% of 97.

It is clear that the type and strength of base is important to have suitable pH in the reaction medium, leading to changes in conversions and selectivities. On the basis of these results, acetates showed better reactivity in terms of GC ratio towards the desired product, though the conversions were low. The optimization was pursued with Ca(OAc) 2 .H 2 O as a base.

f. Screening of different co-solvents

We start thinking how it is possible to increase the conversion while keeping the same selectivity. In fact, benzonitrile is slightly soluble in these aqueous conditions (<0.5 g/100 ml at 22 °C). Therefore, in our route for optimization we were interested in using a co-solvent to the improve the conversion. As a consequence, the reduction of benzonitrile (Table 5). The reaction performed in H 2 O/MeOH solvent mixture led to an increase in the conversion up to 75% after 21h, but with lower yield of benzaldehyde 97 (91%) (Table 5, entry 1). In this case, side reactions occured and led to the formation of benzylalcohol 98, benzamide 101 and dibenzylamine 102 as byproducts. This is evidence that the conversion could be improved in the presence of co-solvent. When EtOH was used as a co-solvent, the rate of the reaction was faster; where benzonitrile 95 was completely converted after 7h to benzaldehyde 97 as the sole product (

h. Effect of concentration of benzonitrile in ethanol

The effect of concentration of benzonitrile in EtOH was also studied and results are represented in Figure 11. As the concentration increases the conversion increases too, till it reaches 100% at 1M. Higher concentration did not lead to any change in conversion. 6. In order to avoid the separation of a complex mixture at the end of the reaction, all reactions were performed several times to determine the time needed for complete conversion avoiding the over reduction into alcohol. Benzonitrile 95 was well reduced in 7h into benzaldehyde 97 as mentioned in the optimization section. However, the isolated yield was only 50% due to the high volatility of 97, which was partially lost during evaporation after treatment of the reaction mixture (Table 6, entry 1). Nitriles bearing an EDG were successfully reduced. For 4hydroxybenzonitrile 104, traces of byproducts were observed resulting from the over reduction, and the corresponding aldehyde 4-hydroxybenzaldehyde 105 was obtained in 93% yield and 90% isolated yield (Table 6, entry 2). However, in case of 2hydroxybenzonitrile 106, where the hydroxyl group is at the ortho position, the reaction required 23h, and afforded 2-hydroxybenzaldehyde 107 in 93% yield (Table 6, entry 3).

The reduction of 4-methoxybenzonitrile 108 also required also a longer reaction time, where pure aldehyde 109 was obtained with 97% isolated yield after 26h (Table 6, entry 4). P-tolunitrile 110 was also reduced to the corresponding aldehyde 111 after 17h in 98% yield (Table 6, entry 5).

The reduction of substrates containing EWG was also performed. For example, ethyl 4cyanobenzoate 112 was completely converted after 7h into ethyl 4-formylbenzoate 113 with 94% isolated yield (Table 6, entry 6). In case of 4-(trifluoromethyl) benzonitrile 114, the reaction was fast,so that after 5h 4-(trifluoromethyl) benzaldehyde 115 was obtained in 93% yield. The alcohol was a byproduct in this reaction (Table 6, entry 7).

With 4-formylbenzonitrile 116, the conversion was not complete reaching 86% after 8h and giving terephthaldehyde 117 in 85% isolated yield (Table 6, entry 8). As the reaction proceeds, the conversion was complete but with the corresponding alcohol as the major product due to the over reduction. The reaction of naphthaline nitriles 118 and 120 afforded the corresponding aldehydes 119 and 121 in 80 and 85% isolated yields.

However the conversions cannot be increased more than 91%, even after long reaction time (Table 6, entries 9 and 10).

The substrate versatility of this method was further demonstrated by the reduction of halogenated aromatic nitriles. For 2-chlorobenzonitrile 122, only 51% of the nitrile was converted after 7h yielding 57% of 2-cholorobenzaldehyde 123 (Table 6, entry 11). It is noted that several byproducts were observed resulting from the over reduction and dehalogenation reactions. Moreover, it is important to mention that complete conversion cannot be attained even after long reaction time, or upon increasing the amount of hypophosphite, or even upon changing the concentration of nitrile 122 in ethanol. On the other hand, the reduction worked better in the presence of bromine substituents 124 and 126 at meta and para positions, with high yields reaching 90% of the corresponding aldehydes (Table 6, entries 12 and 13).

Finally, to check the potential of our investigated method, reactions were employed on the more challenging alkyl chain substituted benzonitriles and aliphatic nitriles including hexanenitrile, octanenitrile, phenylacetonitrile and phenylbutyronitrile. Results showed that complete conversion of nitrile 127, with no selectivity towards the aldehyde. Instead, alcohol 128, diamine 129 as the major product and triamine 130 were observed as shown in scheme 39.

Scheme 39. Reduction of aliphatic nitrile 127 using our investigated methodology.

Limitations of the methodology

For every method, there exist some limitations. For example, in case of 2-cyanopyridine 131 and 2-aminobenzonitrile 132, formation of inactive complexes were observed with blue and offwhite colors respectively (Figure 12). On the other hand, with nitro substituted nitriles, Ni II was not reduced to Ni 0 (no change of color from green to black), thus the reduction did not occur. This was verified by making GC of the reaction mixture. It is expected that nitro group poisons the catalyst.

To confirm this hypothesis, a reaction was performed with nitrobenzene in our optimized conditions; in this case Ni 0 was not formed as well. And as we mentioned in the previous page that the reduction of aliphatic nitriles is considered to be a limitation.

Mechanism

Moving to the mechanistic part, from an experimental point of view, the reduction of nitrile to aldehyde occur when there is modification in the color of the reaction mixture from light green into grey or black. This could be attributed to the reduction of Ni II to Ni 0 by hypophosphite and the formation of nickel nanoparticles as described in literature. 97 While trying to understand the mechanism, a test was done by heating hypophosphite, nickel catalyst and the base in water at 100°C in a sealed tube. After 30 min, the color changed to black, and when we open to add benzonitrile there was a lot of pressure. As expected, after 7h there was no conversion. Mainly this is due to the loss of hydrogen gas. From these observations we expect to have the redox reactions shown in scheme 40.

Scheme 40. Expected redox reactions.

( However, limitations have been noted in case of nitriles bearing nitro and amine groups.

Moreover, aliphatic nitriles were not reduced to the desired aldehyde as well.

For future perspectives, the mechanism should be studied in details concerning the type of intermediates and species present at each stage of the reaction. Moreover, the method could be improved in order to reduce aliphatic and sterically hindered substrates with better isolated yields and on large scale for industrial applications. for 24h. Underr these conditions using, 2.5 mol% of 10 wt.% Pd/C as the catalyst, led to the formation of benzylamine 99 in 98% yield and toluene 133 as a byproduct in 2% yield, which can be obtained via hydrogenolysis (Table 7, entry 1). When changing the amount of catalyst to 1 mol%, only 6% of 99 were obtained. The major product was dibenzylamine 102 with 94% yield (Table 7, entry 2). This could be explained by the slow kinetics of the reaction when the amount of catalyst is low, so that there is more interaction between the intermediate imine and the produced amine.

Although very good results were obtained, it was very important to study the effect of different parameters on the reaction pathway.

b. Screening of different basic additives

At the beginning, the reaction was performed with the same previous conditions but in the presence of two other t bases (Table 8).

). Thus, the best result was observed with complete conversion and excellent selectivity towards the amine by using K 2 CO 3 as the base.

c. Screening of different co-solvents

The effect of the presence of co-solvent in the medium was evaluated next. The results of the reduction of benzonitrile 95 in the mixture of different solvents and water, over 10 wt.% Pd/C (2,5 mol%), in the presence of Ca(H 2 PO 2 ) 2 (2,5 equiv.) and K 2 CO 3 (40 mol%) at 100°C for 7h are given in Table 9. The concentration of 95 in the organic solvent was 1M. 9, entry 5). According to these results, it is favourable to use a simple system with water as the sole solvent.

d. Effect of the amount of base

Finally, the amount of base necessary for the reduction was investigated. Results are given in Table 10. In general, we noticed that decreasing the amount of potassium carbonate K 2 CO 3 does not have any effect on the conversion, whereas it influences the ratio between different products. a Conv. and GC ratio were determined by gas chromatography.

With 20 mol% K 2 CO 3 , the ratio of 99 decreases to 95% and more toluene 133 was formed (Table 10, entry 1). Going down to 10 mol% K 2 CO 3 , 92% of 99 and 8% of 133

were formed (Table 10, entry 2). With no base or with 5 mol% (Table 10, entries 3 and 4) similar results were obtained with ratio 86% of 99. Thus, the base has an important role in shifting the reaction towards primary amine with no byproducts.

Application of methodology on different substrates

After checking all these parameters, the optimal conditions are now in hand. Using 10 wt.% Pd/C and 2,5 equiv. of Ca(H 2 PO 2 ) 2 and 40 mol% K 2 CO 3 in aqueous medium at 100ºC, we investigated the reduction of 10 different nitriles with excellent chemoselectivity to yield the corresponding primary amines within reaction times ranging from 2-23h. After hydrolysis at room temperature with 2M HCl solution in diethylether, pure amines were obtained as their hydrochloride salts. The catalytic system displayed a variety of functional group tolerance, so that aromatic nitriles with electron-withdrawing as well as electron-donating substituents were reduced in good to excellent yields (Table 11). 11, entry 3), the conversion was complete after only 2h, reducing formyl and cyano groups into hydroxyl and amine groups respectively. However it was not possible to determine the corresponding yield by precipitation due to the presence of hydroxyl group. For that reason, the reaction was kept for 16h so that the hydroxyl group was reduced. Derivatives with electron-donating groups including methoxy (108) and methyl groups (110), were also reduced successfully after 22 hours, and the salts ( 140) and ( 141)

were obtained in excellent yields (Table 11, entries 5-6).

Cyano-naphthalene substrates 118 and 120 with cyano groups at different positions were also reduced. In these cases only a GC ratio of 55-56% of the corresponding amines were obtained with methylnaphthalenes as byproducts (Table 11, entries7-8). It should be noted that these percentages cannot be increased even at less reaction times, the formation of the amine and methylnaphthalene are in parallel.

Halogenated derivatives were also reduced (Table 11, entries 9-10). In these cases, dehalogenation reactions were observed followed by the reduction of nitrile to amine.

Other halogenated derivatives at different positions were reduced giving benzylamine at the end of the reaction.

It is noted that this system is efficient in the cyclization of dinitriles. From literature data, this transformation could be realized by hydrogenation catalyzed by Ni, 103 Rh, 104 Pt 105 and Pd 103f, 105a catalysts. Other sources of hydrides such as aluminum and boron hydrides or silanes have been used as well. 106,107 In our laboratory, two systems were reported using TMDS-Ti(Oi-Pr) 4 and PMHS-Ti(Oi-Pr) 4 .These systems were able to reduce dinitriles into the corresponding saturated Nheterocycles, through an intramolecular reductive alkylation reaction as shown in scheme 42. 108 Scheme 42. Formation of saturated N-heterocycles by reduction of dinitriles.

In our case, glutaronitrile 144 was converted into piperidine 145 then to 5-(piperidin-1yl)pentanenitrile 146 under similar reaction conditions, where 3 equivalents of the reducing agent Ca(H 2 PO 2 ) 2 (Scheme 43). This shows that our system is able to cyclize dinitriles into either N-heterocyclic compounds or into substituted N-heterocyclic compounds. However, the reaction conditions should be optimized. On the other hand some limitations exist, in case of aliphatic nitriles the conversions were very low.

Scheme 43. The cyclization of glutaronitrile 144 into5-(piperidin-1-y)pentanenitrile 146 via intermediate 145.

Mechanism

Based on our observations, a mechanism was proposed as detailed in Scheme 44. We propose that reactions take place on the surface of heterogeneous palladium and in solution. At the beginning, we suggest that molecular hydrogen is formed during the interaction of base and calcium hypophosphite in water upon heating. Molecular hydrogen then deposits on the surface of Pd/C, where consequence reduction of benzonitrile to benzylamine occur on the surface of the catalyst passing through benzylimine intermediate. To explain the formation of dibenzylamine, we suggest that when there is less catalyst, the concentration of free imine increases in the solution, since there is less adsorption onto the catalyst surface. This benzylimine reacts with the formed benzylamine and produces dibenzylamine and ammonia.

Scheme 44. Proposed mechanism for the reduction of nitrile into amine and diamine.

Conclusion

The comparison of the results obtained with calcium hypophosphite and the results of Johnstone obtained with sodium hypophosphite during the cleavage of aromatic ethers, 95 showed better conversions as well as better yields in our method.

As a result we have demonstrated that our catalytic system Ca(H 2 PO 2 ) 2 / Pd/C is efficient for the reduction of variety of aromatic nitriles bearing different functional groups where the amount of catalyst change the whole pathway of the reaction. The advantages of the used system lie in the choice of greener reagents and solvents (H 2 O) and the easy workup ( mild, simple, and practical).

Conclusion

In this part, we have developed two methodologies for the reduction of nitriles into aldehydes and amines, using an effective hydrogen donor calcium hypophosphite Ca(H 2 PO 2 ) 2 .

The reduction of nitriles into aldehydes was done in the presence of Ni(OAc) 2 as a catalyst and Ca(OAc) 2 as a basic additive in biphasic medium of ethanol/water. Good yields and good selectivities have been observed, however the reaction is restricted only to aromatic derivatives. More experiments and analysis should be done to improve the substrate versatility and to understand the exact mechanism.

The reduction into amines was done in different conditions, using Pd/C as a catalyst and K 2 CO 3 as a basic additive in aqueous medium. With 2,5 mol% of catalyst the amine is the sole product, changing the amount to 1 mol% the diamine is the major one. This system also allowed the formation of 6-membered saturated heterocycle by the reduction of glutaronitrile. Additional optimization and development steps are therefore required for the cyclization of dinitriles.

Finally, these reactions were performed with non-toxic solvents and an inexpensive reducer Ca(H 2 PO 2 ) 2 . For these reasons these two reducing systems may be of interest in green synthesis. in ethanol= 1M), the tube was then sealed. The reaction mixture was stirred at 920 rpm and heated at 100°C. After the sufficient time for each substrate, the tube was cooled at room temperature, depressurized and an aliquot was taken and extracted with water and diethyl ether for GC analysis to check the conversion of the starting material. The reaction mixture was then diluted by excess of water to remove ethanol and extracted twice with diethylether. The combined organic extracts were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure (800 mbar). After concentration, aldehydes were obtained as oils or solids. If needed a flash chromatography column was done on silica gel by using gradient of different solvents according to the final product. The products were then characterized by NMR spectroscopy and GC-MS.

Experimental part

Typical procedure for the reduction of nitrile into amine

In a sealed tube Ace-Thred #15 indicated above, calcium hypophosphite (425.15mg, 2.5 mmol) was introduced, followed by K 2 CO 3 (55.12 mg, 0.4 mmol). Part II: Direct Reductive Amination of Ketones Using Ammonium Hypophosphite

Introduction

Amines represent an important class of compounds in organic chemistry, especially for the pharmaceutical and agrochemical industries. Numerous methodologies have been reported for the synthesis of amines, including reductive amination (RA) of carbonyl compounds, which is the reaction of aldehydes or ketones with ammonia, primary amines, or secondary amines in the presence of reducing agents to give primary, secondary, or tertiary amines respectively.

The RA of aldehydes and ketones proceeds in several consecutive steps as shown in scheme 45. The reaction between 147 and 148 involves the initial formation of the intermediate carbinol amine 149, which dehydrates to form an imine. Under the reaction conditions which are usually weekly acidic to neutral, the imine is protonated to form an iminium ion 150. 109 Scheme 45. Reductive amination pathway.

Catalytic Leuckart-Wallach-Type reductive amination of ketones

In 1885, Leuckart first described the conversion of certain aldehydes and ketones to the corresponding amines by heating with excess ammonium formate. 111 In 1892, Wallach applied the method to a number of alicyclic and terpenoid ketones, as well as certain aldehydes, and showed it's general application. 112 After this, the reaction was known as Leuckart-Wallach (LW) reaction.

The LW reaction takes place via several steps. At the beginning, ammonium formate dissociates into ammonia and formic acid upon heating, and the produced ammonia condenses on the carbonyl carbon forming carbenium ion which was rearranged into iminium ion. Subsequently, a cyclic transition state was formed with the aid of formic acid, followed by decarboxylation and finally deprotonation to form the corresponding amine (Scheme 46). 111,112,113 Scheme 46. Mechanism of LW reaction. 111,112,113 In 2002, M. Kitamura et al. produces a novel catalytic system facilitating the Leuckart-Wallach-type reaction at lower temperature with chemoselectivity and generality. 114 The reaction is catalysed by Cp*Rh(III) complex (0,005 mol%), in the presence of 5 equiv. HCOONH 4 in methanol at 50-70°C, to give the amines with yields up to 99% (Scheme 47). This method has been applied also to the synthesis of α-amino acids directly from αketo acids. Scheme 47. DRA of acetophenone 154 using Cp*Rh(III) and HCOONH 4 . 114

DRA of ketones using cyanohydridoborate anion

Considerable attention has been devoted to the study of modified boron hydrides as selective reducing agents for organic functional groups. 115,116 In 1970, R. F. Borch et al.

has established that the reduction of the iminium moiety with BH 3 CN -was rapid at pH 6-7, and that the reduction of aldehydes and ketones was negligible in this pH range. Thus, it was conceivable that an aldehyde or ketone could be reductively aminated by simply reacting the carbonyl compound with amine or ammonia at pH~6 in the presence of BH 3 CN -to get the amine, where the pre-equilibrium step that generates the iminium moiety is the rate determining step. 117 For example, when acetophenone 154 was treated with fivefold excess of ammonia in methanol at pH=6 in the presence of LiBH 3 CN, α-phenylethylamine 155 was obtained after 48h in 74% yield (scheme 48). Scheme 48. DRA of 154 in the presence of ammonium acetate and LiBH 3 CN. 117 The literature is replete with publications that document the use of NaBH 3 CN in reductive amination reactions. 118 This reaction can be carried out under mild conditions, and is compatible, in some cases, with many functional groups. However, the processes based on such reducing agents have many limitations, it may require up to fivefold excess of the amine, 117 it is usually slow and sluggish with aromatic ketones and with weakly basic amines, 119 and may result in the contamination of the product with cyanide. 120 The reagent is highly toxic, since it leads to the production of toxic byproducts such as HCN and NaCN.

DRA of ketones using sodium triacetoxyborohydride

Sodium triacetoxy borohydride NaBH(OAc) 3 was presented by Abdel-Magid et al. in 1996, as a general reducing agent for the RA of aldehydes and ketones. This reagent is considered to be mild in comparison to other boron hydride reagents. 121 The effectiveness of this reaction includes aliphatic acyclic and cyclic ketones, aliphatic and aromatic aldehydes, with primary and secondary amines including a variety of weakly basic and non-basic amines. Reaction times vary from 20 min to 10 d depending on the structure of the reactants.

Taking an example, 1,4-dioxaspiro [4.5]decan-8-one 156 was reacted with 1 equiv. of benzylamine in the presence of acetic acid and 1,2-dichloroethane (DCE) as a solvent, using 1,3-1,6 equiv. of NaBH(OAc) 3 at rt and under N 2 atmosphere. The corresponding amine 157 was obtained after 20 min and isolated as an oxalate salt in 92% yield (Scheme 49). 121 Scheme 49. DRA of 156 in the presence of NaBH(OAc) 3 . 121 For the same ketone, the reaction was dependent on the steric and electronic factors associated with the amines. For example, the reaction of 156 with piperidine requires 75 min to give the amine in 66% isolated yield. This method suffers from several drawbacks since NaBH(OAc) 3 is flammable, water-reactive and poorly soluble in the most common organic solvents and has limitations with aromatic and unsaturated ketones. In addition, this reagent has only one available hydride and usually excess (1.5 equiv.) of the reagent are necessary for reaction.

DRA of ketones using sodium borohydride

Sodium borohydride NaBH 4 is an inexpensive reducing agent known to reduce imines and other functionalities, thus limiting its application in broader sense. Moreover, it is understood that the poor electrophilic carbonyls, poor nucleophilic amines, and sterically crowded reactive centers do not favor the completion of imine formation. Thus, it is quite apparent that NaBH 4 alone may not afford excellent yields. For that reason NaBH 4 should be associated with metal catalysts and additives. Literature is full with these examples.

With Brønsted acids

NaBH 4 has been employed with various Brønsted acids (H 2 SO 4 , p-toluenesulfonic acid) in order to facilitate the initial formation of the imine leading to a successful RA without byproducts. 122 However, these are corrosive, toxic and difficult to separate from the reaction solution, so they were substituted by more environmentally friendly solid acids such as heteropolyacids (HIPAs). 123 Other researchers focused on ionic liquids (IL), which have potential as green solvents for several chemical and biochemical transformations. 124 In 2006, Nagaiah et al. Prasad and co-workers made a combination of all these concepts, and reported for the first time the RA of carbonyl compounds using NaBH 4 in the presence of Brønsted acidic IL, in which the Brønsted acidic nature of the IL is responsible for imine formation. 126 Reaction was conducted by adding the amine and carbonyl compound in 1-methyl imidazium tetrafluoroborate ([Hmim][BF 4 ]) 159, which is efficient in various organic transformations, 127 then stirred at 30°C for 30-60 min in order to monitor the conversion of 154 for example to imine, at the end NaBH 4 was added to achieve 82% yield of 160 within 4h (Scheme 51). 126 Using this methodology a series of aldehydes and ketones were reductively aminated in excellent yields. An advantage of the process is the recovery of the IL at the end of the reaction, which is recycled for four consecutive reactions during the RA of benzaldehyde. Another advantage is the selectivity towards imines in the first step of the reaction without the formation of any side product. Scheme 51. RA of aldehydes and ketones using NaBH 4 / 159. 126

With fluorinated chiral auxiliary

Recently, the reduction of N-tert-butylsulfinyl ketimines has attracted much attention and has been applied in the synthesis of many drug candidate. 128,129 The reduction of Nsulfinyl imines was firstly reported by Cozzi 130 and later studied by Ellman. 131,132 Encouragingly, K. Since its discovery in Brown's laboratory in the early sixties, 135 nickel boride (BNi 2 ) has been developed by different research groups as an important catalyst for various transformations. 136 The moistened reagent is non-pyrophoric in nature relative to many metal hydrogenation catalysts. J. C. Sarma and coworkers studied the in situ generation of BNi 2 from NaBH 4 and nickel chloride (NiCl 2 ). 137 During the course of the reaction it was observed that a carbonyl group remains unaffected under appropriate reaction conditions. So it was argued that the system could be suitable for RA of aldehydes and ketones. This was confirmed in 2000, when the group generated BNi 2 and used it for the RA of ketones and aldehydes in the presence of amine. 138 For example, α-ionone 168 was reacted with benzylamine to give 169 in 80% yield (Scheme 54). R. S. Varma and co-workers reported the RA of carbonyl compounds under solvent-free conditions using NaBH 4 -wet clay coupled with MW activation. 141 Clay not only behaves as an acid, but also provides water from its interlayers that is responsible for the acceleration of the reducing ability of NaBH 4 . 142 The synthesis of N-phenyl-p-chlorobenzylamine 171 is representative of the general procedure employed (Scheme 55). A mixture of p-chlorobenzaldehyde 170, aniline and montmorillonite K10 clay were placed in MW oven and irradiated for 2 min, followed by the addition of freshly prepared NaBH 4 -clay and water. The reaction mixture was again irradiated for 30 sec at 65°C to give the corresponding amine 171 in 97% yield. Without this support a poor yield was obtained (~10%). 141 Scheme 55. Reduction of 170 using NaBH 4 -clay under microwave irradiation. 141 2.4.6. With Amberlyst-15

In the past decade, the chemistry of Amberlyst-15 172 (Figure 13) has experienced a rapid development. 143e This growing interest in Amberlyst-15 is mainly due to its mild and highly selective properties, combined with its environmentally benign character and commercial availability. Amberlyst-15 is now routinely used in organic synthesis as other heterogeneous reusable acid catalysts for various selective transformations of simple and complex molecules. In 2010, N. Mahdavi and co-workers reported the DRA of aldehydes and ketones with primary or secondary amines in the presence of NaBH 4 and 172 in THF (method 1), and under solvent-free conditions (method 2). In both methods, the reaction was carried out using an equimolar ratio between carbonyl compound, amine and the reducing agent. 144 For example, the DRA of cyclohexanone 173 using method 1 requires 15 min, whereas it requires 3 min using method 2 to obtain the N-cyclohexylamine 174 in excellent yields Using this methodology, aromatic, aliphatic, cyclic and heterocyclic aldehydes and ketones were reductively aminated with other aromatic and aliphatic primary amines.

Limitations include the reduction with secondary amines and morphine, where reactions led to the formation of alcohols. Moreover acetophenone and β-ionone were not reduced using this method. Scheme 59. RA of benzaldehdye with aniline using boric acid-activated NaBH 4 . 148

With Guanidine hydrochloride

The group of Heydari found an interest in the application of guanidine hydrochloride (Gu.HCl) in water for different organic transformations. 149,150,151 Gu.HCl found applications in the DRA of aldehydes with a variety of primary amines to give the desired products in high isolated yields (81-98%) as shown in Scheme 60. 152 However, using this system α-β-unsaturated ketones were reduced into allyl alcohols and not into amines. Scheme 60. DRA of aldehydes with primary amine using Gu.HCl/NaBH 4 . 152

With Deep eutectic solvent

Recently, deep eutectic solvents (DESs) have emerged. DESs are peers of the conventional ionic liquids (ILs). They have low vapor pressure and flammability. 153 The main difference between these two families of compounds is that ILs are neither biodegradable nor cost-effective, however, DESs are biodegradable, non-toxic, and inexpensive. DESs are easily prepared by combining two components, a hydrogen acceptor (mainly choline chloride) and a hydrogen donor. The easiest component of this family is the combination of choline chloride and urea (ChCl/Urea) which are very cheap and non-toxic compounds. The occurrence of these compounds and their ability to serve as catalysts dates back to 2003. 154 In 2016, the group of Heydari reported the synthesis of secondary amines by the DRA of aldehydes and ketones using the following conditions: aldehyde/ketone (1mmol), MeOH (2 mL), ChCl/urea (50 mg), at rt for 30-60 min. Different derivatives of benzaldehyde, furfural, cinnamaldehyde, acetophenone and phenyl acetophenone were well reduced to the corresponding amines with high isolated yields ranging between 89-98%. 155 For example phenylacetone 184 was reduced with aniline in 60 min to give N-(1phenylpropan-2-yl)aniline 185 in 90% isolated yield (Scheme 61). Scheme 61. DRA of 184 ito 185 using ChCl/urea and NaBH 4 . 155 According to the previously reported ChCl/urea catalyzed reactions, 156 it seems that this reagent catalyze the reaction through the formation of hydrogen bonds with carbonyl compound (Scheme 62). Scheme 62. Formation of hydrogen bond between carbonyl and ChCl/urea. 155 2.4.12. With thiourea and Hantzsch ester Another DRA process that relies on hydrogen bonding for imine activation was reported by D. Menche and co-workers. 157 The complete acid-free reaction is mediated by catalytic amounts of thiourea as a simple and readily modifiable organocatalyst, and uses the Hantzsch ester for transfer hydrogenation. As an example, the DRA of acetophenone 154 with equimolar amounts of p-anisidine 186 and the Hantzsch ester 187 was carried out in the presence of 0,1 equiv of thiourea 188 and 5Å MS at 50°C for 48h. Under these conditions 4-methoxy-N-(1-phenylethyl)aniline 189 was obtained in 88% isolated yield (Scheme 63). Scheme 63. The Hydrogen Bond Catalyzed DRA of 154 in the presence of thiourea/ Hantzsch ester. 157

DRA of ketones using zinc borohydride

To overcome the elevated pressures and the expensive toxic reagents that are accompanied with borohydrides and the LW reaction, reactions with zinc were introduced. The use of zinc borohydride, 166 prepared from sodium borohydride and zinc chloride, as a unique mild reducing agent for the reduction of aldehydes and ketones into the corresponding alcohols has been amply demonstrated in the 1iterature. 167 It has shown a great reactivity in RA reactions as well.

With Zinc borohydride in diethylether

In 1990, H. Kotsuki and co-workers described the reduction of Schiff's bases using 1 equiv. of zinc borohydride in Et 2 O at room temperature to give the corresponding amines in 27-98% isolated yields (Scheme 65). 168 Schiff's bases were prepared by conventional condensation of amines with aldehydes or ketones. Scheme 65. RA of Schiff's bases using Zn(BH 4 ) 2 /Et 2 O. 168 2.6.2. With activated Zinc/acetic acid Few aldehydes and ketones have been reductively aminated albeit in low yields with the simpler and inexpensive zinc amalgam and hydrochloric acid, 169,170 but it has not been generally applied to carbonyl compounds. Moreover, it affects the hydrolysis of various functional groups. 171 In 1991, Miccovic et al. found a simple and efficient method for the preparation of secondary N-alkylarylamines via RA of ketones with primary aromatic amines using zinc dust and AcOH. 172 The reaction proceeded rapidly in the presence of stoichiometric amounts of the reagents being complete in 1-4h, at 60-70°C, where the corresponding secondary amines were afforded in good isolated yields 50-90% (Scheme 66). 172 Scheme 66. DRA of ketones using activated Zn/AcOH. 172 2.6.3. With activated Zinc borohydride/ Zinc chloride In the same context of developing borohydride-based reagent systems for selective transformations, S. Bhattacharyya and co-workers utilized a combination of zinc chloride ZnCl 2 and zinc borohydride Zn(BH 4 ) 2 for the reductive methylation of amines. 173 As a sequel of this work, they presented the DRA of available fluorobenzaldehydes with a number of secondary amines. 174 They demonstrated that one-pot reagent system comprising of ZnCl 2 and NaBH 4 generated Zn(BH 4 ) 2 in situ, which is also an effective alternative making the reaction more simple by avoiding the preparation of Zn(BH 4 ) 2 .

Typically, ZnCl 2 was added to a mixture of secondary amine and fluorobenzaldehyde 192 for example, in anhydrous THF, and the reaction was stirred for 30 min at rt to ensure the formation of the intermediate imine 193. This step was followed by the addition of 1,5 equiv. of either Zn(BH 4 ) 2 or NaBH 4 in anhydrous THF, resulting in tertiary amines 194 as shown in Scheme 67. 174 It is important to mention that this transformation did not take place in the absence of ZnCl 2 , which is functioning as a Lewis-acid to produce iminium ions that are then reduced by zinc borohydride.

DRA of ketones using Decaborane

In 1986, T. Kudo and A. Nose described the selective reduction of imines to the corresponding secondary amines using diborane (B 2 H 6 )-MeOH system. 177 Later in 2000, C. M. Yoon and his group studied the DRA using decaborane (B 10 H 14 ) as a mild reducing agent. For example, acetone 198 was reductively aminated using 1,2 equiv. of p-toluidine 199, 30 mol% of B 10 H 14 in MeOH. The reaction was stirred for 30 min at room temperature under N 2 atmosphere to produce the corresponding amine N-isopropyl-4-methylaniline 200 in 95% isolated yield (Scheme 69). 178 The effectiveness and fast rate of the reaction is resulting from the catalytic activity of decaborane for imine formation, which is known to be the rate determining step. Several examples of aldehydes and ketones were reduced using this method in the presence of variety of aromatic and aliphatic amines. Scheme 69. DRA of acetone 198 using B 10 H 14 . 178 2.8. DRA of ketones using amine boranes Amine boranes are effective reagents to carry out RAs due to their acid stability and functional group compatibility. 179 Amine boranes derived from primary or secondary amines suffer from incorporation of the amine, therefore, are only appropriate for reduction of pre-formed imines. Amine boranes derived from tertiary amines or aromatic amines do not incorporate into the imine intermediate. Another reaction was developed in 1995 by DiMare et al., where in situ RA of aldehydes and ketones were done using methanolic pyr-BH 3 in the presence of 4Å MS. 181 However, this reagent is quite unstable to heat and attempted distillation of the liquid residue at reduced pressures sometimes resulted in violent decompositions. 182 Thus, extreme care is necessary if this reagent is handled in large quantities. Moreover, industrial applications seem problematic, despite the availability of a patented method for purification. 183 2.8.2. With α-picoline-borane α-Picoline-borane (Pic-BH 3 ) is a thermally stable transparent solid that can be stored on a shelf for months without any appreciable loss of the reducing ability in comparison to pyr-BH 3 , as well as cheap and commercially available. Y. Kikugawa and his group showed that the use of this reagent eliminated the problems encountered with the use of previously mentioned reducing agents. The reaction was carried out in MeOH, in H 2 O and in neat conditions in the presence of small amounts of AcOH. 184 For example the DRA of cyclohexanone 173 with aniline was carried out using equimolar amounts of aniline, 173 and pic-BH 3 at room temperature in the presence of traces of AcOH. The results were the similar in three different solvent systems where Ncyclohexylaniline 174 was obtained with 94-95% yield (Scheme 71). Scheme 71. DRA of cyclohexanone 173with pic-BH 3 in three different solvent media. 184

With benzylamine-borane

Between 1960-1980, dimethylamine-borane was used as a reducing agent for two-step RA in glacial AcOH. However, its use has been limited to aryl aldimines derived from substituted anilines. 185 In 2002, M. A. Peterson group discovered that benzylamineborane is an effective reductant for in situ RA of carbonyl compounds. 186 For example, the reduction of 4-phenyl-2-butanone 204 using benzylamine-borane 205 in the presence of stoichiometric amounts of benzylamine (1,1 equiv.) and 4Å MS gave the corresponding N-Benzyl- (1-methyl-3-phenyl)propylamine 206 in 80% isolated yield (scheme 72). Acyclic and conjugated carbonyl compounds underwent successfully the RA with diethylamine and with a series of different amines. It should be noted that without LiClO 4 , the process did not lead to any reduction, but was generally accompanied by products resulting from the reduction of carbonyl group. In some cases, stoichiometric amount of trimethylsilyl chloride (TMSCl) was added as an activator in order to obtain good yields, such as in the case of 4-chlorobenzaldehyde with aniline. 191 2.10. DRA of ketones with silanes and siloxanes 2.10.1. With polymethylhydrosiloxane (PMHS) PMHS has been reported as an air and moisture stable, inexpensive, non-toxic, versatile, and widely used reducing agent in organic synthesis. 192 This reagent has minimal or no reducing ability in the absence of an activator, usually a transition metal catalyst such as Zn(II), 193 Ru(0), 194 and Cu(I-II), 195 or fluoride. 196 Once activated, PMHS becomes a powerful reagent that can effectively perform a wide range of reactions. Scheme 79. DRA of cyclohexanone with 214 using PMHS/Zn-Co-DMC system. 207 Acetophenone was less reactive in this method where it reacted with benzylamine, aniline, m-toluidine and p-anisidine to give the corresponding secondary amines in 52-68% isolated yield. Moreover, the results showed that Zn-Co-DMC is reusable for at least four times with little loss in catalytic activity.

With phenylsilane

Recent literature reports suggested the possibility that diorganotin dihalides could catalyze DRA in the presence of organosilane reductants. 208 In particular, catalysis of both imine formation, 209 and imine reduction with organosilanes, 210 have been separately described.

In 2001, R. Apodaca and W. Xiao, investigated a procedure for the DRA of aldehydes and ketones in the presence of phenylsilane (PhSiH 3 ) as a stoichiometric reductant, and dibutyltin dichloride (Bu 2 SnCl 2 ) as a catalyst (Scheme 80). 211 Reactions with substrates bearing potentially reducible functional groups including aryl iodide, cinnamyl, nitro and benzyloxy gave the anticipated products, without detectable reduction side products.

Moreover, acetophenone was reduced using 10 mol% of Bu 2 SnCl 2 with good yield. Scheme 80. DRA of carbonyl compounds using PhSiH 3 /Bu 2 SnCl 2 system. 211 In 2005, the group of J. J. Kangasmetsa investigated a similar improved procedure using PhSiH 3 (2 equiv.)/ Bu 2 SnCl 2 (0,1 equiv.) in THF, promoted by MW at 100°C for 7 min. Later in 2014, T. Matsumura and M. Nakada discussed the DRA of different carbonyl compounds using Et 3 SiH and catalytic bismuth(III)chloride (BiCl 3 ). The DRA of various aldehydes and ketones including cyclic and acyclic aryl and alkyl as well as heterocyclic, were examined using 3 equiv. Et 3 SiH, 10 mol% BiCl 3 in acetonitrile at rt. 215 Depending on the structures of reacted carbonyl compound and amine, reaction time ranged from 3-48h to give the corresponding products in 13-99% isolated yields (Scheme 82). Scheme 82. DRA of carbonyl compounds using Et 3 SiH/BiCl 3 system. 215 For the mechanism, the group suggested that Bi(0) would be formed by the reaction of This high imine-selectivity indicated that 219 would be a good candidate for DRA. In 1998, the same group presented the use of tin hydrides in the DRA of aldehydes and ketones under mild conditions. 220 Highly chemoselective reactions were achieved for ketone and aldehydes even with co-existence of aryl halides, vinyl halides, hydroxyl group, double bonds and epoxide functionalities. For the mechanism, the group proposed that hydrogen bonding between the imino group and the acidic silanol group exerts the predominant activating effect. A six-membered transition state 222 involving the silanol coordination to tin and hydrogen bonding to the imino group can be invoked, allowing the selective reduction of the imine to proceed smoothly (Scheme 86). 221 Using this method acetophenone was reductively aminated to give the corresponding amine in 45% isolated yield. Scheme 86. Proposed mechanism for the RA of aldehydes using Bu 3 SnH/SiO 2 via the intermediate 227. 221 2.12. DRA of ketones using catalytic hydrogenation Hitherto several chemical reducing agents, have been shown to be valuable for DRA and giving rise to the alkylated amines in good yields. However, from the ecological point of view and taking into account the demand for atom economy, a more promising approach involves the use of molecular hydrogen as a reducing agent. For ketones, taking acetophenone as an example, the DRA was sluggish with incomplete conversion and only 50% selectivity of the amine. An important note, is that the catalytic system was recycled by simple decantation and reused three times without loss of activity. including hydrogenation reactions. 235 The polymer supported palladium-N-heterocyclic carbene (PS-Pd-NHC) 228 offers several advantages like reuse of expensive transition metals and ligand with a possibility to prevent the contamination of ligand residue in synthesized products (Figure 17). Examples for the DRA using sodium borohydride are many, but this reagent needs to be associated with metal catalysts and additives for the reaction to go smoothly and successfully. The major problem in these reactions is the formation of alcohols as byproducts.

Several reagents other than those mentioned above have been utilized in DRA, including borohydride exchange resin, zinc borohydrides, zirconium borohydrides, decaborane, and amine boranes. In these cases, the reactions require filtration, aqueous workup, evaporation orcombination of these techniques prior to purification.

Organic-soluble reducing reagents such as organosilanes and siloxanes have been reported as good alternatives to classical hydrides. However, there exist several drawbacks, where hydrosilanes are expensive, toxic and flammable, and siloxanes such as PMHS are also expensive, they require the association with toxic me.tals and expensive ligands. Tin hydrides were also used, but it is well known that these reagents are harmful to health and environment.

Finally, the most convenient way with a good atom economy is the use of molecular hydrogen involving homogeneous or heterogeneous catalysis, however, high pressures and temperatures are the main disadvantages.

Results and discussion

3.1.Objective

Although literature is full of examples discussing the DRA of aldehydes and ketones, the development of newly improved protocols for performing DRA by using greener and milder reaction conditions is still desirable. As we mentioned in the previous part that hypophosphites are cheap, harmless and non-toxic reagents that have been employed in several organic transformations. However, their use in DRA of carbonyl compounds have not been reported yet. Among the commercially available hypophosphites we focused on ammonium hypophosphite NH 4 PO 2 H 2 , which could play two roles: (1) a direct source of NH 3 , so there is no need to add an extra amine in the reaction mixture; (2) as a reducing agent.

This part will summarize all methodologies found in literature for the RA of aldehydes and ketones. Followed by our investigated method for the DRA of ketones using ammonium hypophosphite in the presence of heterogeneous catalyst, where different reaction parameters were studied, including: ammonium source, time, temperature, type of catalyst, concentration and additives. Heterogeneous catalysis has an advantage since the catalyst can be easily removed at the end of the reaction, so there is possibility for recycling. Moreover, the used supports, for example charcoal and alumina, present a large specific area for hydrogen adsorption.

Feasibility and optimization of reaction conditions

Our investigations started by choosing acetophenone, the challenging aromatic substrate, as a model substrate for DRA, and reactions were followed by GC.

a. Type of ammonium source

In the first part of this manuscript aromatic nitriles were reduced into amines in the presence of Pd/C. Encouraged by these results, the first array of experiments were done using 5wt.% Pd/C, 3 equiv. of ammonium source, in the presence of EtOH at 80 °C for 24h in the presence of a ballon of hydrogen pressure. Three different ammonium sources were tested in order to compare their efficiency as shown in Table 12. Using ammonium hypophsophite (NH 4 PO 2 H 2 ), the conversion of 154 was complete, however only 12% of the desired α-phenylethylamine 155 was obtained, and bis(1-phenylethyl)amine 237 was the major product with 73% GC ratio (Table 12, entry 1). In case of ammonium acetate (NH 4 OAc) the conversion of 154 was lower with 15% of 155 and 75% of ethylbenzene 239 (Table 12, entry 2). In contrast, only 39% conversion was attained in the presence of ammonia, however 25% of 155 were obtained (Table 12, entry 3). According to these results, NH 4 PO 2 H 2 was the best in terms of conversion, so we went forward with this reagent to study other reaction parameters.

b. Screening of different heterogeneous catalysts

In the second array of experiments, the activity of different heterogeneous catalysts was studied in the presence of 5 mol% of the heterogeneous catalyst, 3 equiv. of NH 4 PO 2 H 2 , in a medium of EtOH at 80°C for 24h. Only 5wt.% Pd/C showed acitivity as mentioned before (Table 13, entry 1). In case of Pt/C, Rh/C and Ru/Al 2 O 3 the conversion of 154 was almost negligible (1-5%) (Table 13, entries 2-4). On the other hand, Ru/C did not show any reactivity (Table 13, entry 5).

Therefore, 5 wt.% Pd/C (2,5mol%), n-BuOH and 100°C were chosen to be the best conditions for further studies. 15, entries 1 & 2). This was expected, due to the fact that when the primary amine is formed, there is still starting material to react with. Less reducing agent can also explain the low conversion. However, increasing the amount of NH 4 PO 2 H 2 led to a complete conversion, promoting the formation of primary amine 155 as the major product (Table 15, entries 3 & 4). We hypothesized that adding NaOH to the reaction mixture will facilitate the ammonia releasing and promote the formation of primary amine. However, results showed a drop in the yield of 155 to 34% (Table 16, entry 3). Actually, NaOH helped to produce more water in the system which decreased the rate of the reaction. According to these results, we can conclude that the small quantity of water generated during the condensation step does not have a big impact on conversion or on the yield of the desired product.

However, excess water affects the selectivity of the reaction.

f. Effect of temperature

In order to evaluate the effect of the temperature of the reaction, the reduction of acetophenone 154 was performed using the optimized conditions: NH 4 PO 2 H 2 (5 equiv.), 5 wt.% Pd/C (2,5 mol%) in n-BuOH where [acetophenone]= 0.5M, while varying the temperature as presented in Figure 18. It is clear that upon increasing the temperature, the conversion of the starting material increases, where it reach 100% at 100°C. primary amines were isolated as oxalic acid salts after treatment of the filtrated reaction mixture with oxalic acid (Table 17).

It is important to mention that the time required for the complete conversion of each substrate is not the same, thus the kinetics of each subtstrate was studied by running more that one reaction at different time intervals.

With respect to acetophenone, the corresponding amine oxalic acid salt was isolated in a high yield of 95% (Table 17, entry 1). The reduction of acetophenone derivatives containg -CH 3 , an electron donating group, at para and meta positions was done successfully (Table 17, entries 2 & 3), the corresponding amines 241 and 243 were obtained with 99 and 90% isolated yields respectively, however, the reaction was faster in case of meta positions (Table17, entry 3). 1-Acetylnaphthalene 244 and 2acetylnaphthalene 246 were also reduced under the optimized reaction conditions in very good to excellent yields after 21-22h (Table 17, entries 4 & 5). However, the reduction of 2-octanone 248 needed 28h for complete conversion, where 2-aminooctane 249 was obtained in 96% isolated yield (Table 17, entry 6). The reduction of alpha-tetralone 250 was also performed within 26h, resulting in a good isolated yield of the corresponding amine salt (Table 17, entry 7).

The substrate versatility of this method was further demonstrated by the reduction of cyclohexanone 173 so that cyclohexylamine 252 was obtained in an excellent isolated yield after 28h (Table 17, entry 8). Halogenated acetophenone derivatives were also reduced. In case of 2'bromoacetophenone 253 the reduction was fast within 7h accompanied by dehalogenation reaction, so that α-phenylethylamine 155 was obtained in almost complete isolated yield (Table 17, entry 9). 4'-cholorbenzonitrile 170 was also reduced after 15h, with chlorine group remaining at the end of the reaction (Table 17, entry 10).

Finally, the challenging 4-acetylbenzonitrile 255 was reduced, the system was able to reduce the cyano and keto group at the same time resulting in 1-(4-(aminomethyl)phenyl)ethanamine 256 after 7h with excellent isolated yield (Table 17, entry 11).

3.4.Mechanism

Moving to the mechanistic part, during the analysis of the reaction we observed in GC chromatogram a product formed in significant quantities other than the corresponding amine. By mass spectroscopic analysis, the structure of di-n-butylphosphonate 259 was confirmed. To be sure, a 31 P NMR was done for the crude reaction, two peaks were observed, which means that there are two phosphorous species at the end of the reaction.

By going back to literature it is known that hypophosphite salts can react with alcoholic solvents to form hypophosphite esters. 246 According to these data, we assumed that With respect to the reducing agent, there is two possibilities, the first one is that ammonium hypophosphite acts as a reducing reagent and the formation of 259 is in competition with the reduction. The second one is that ammonium hypophosphite firstly reacts with butanol to form the alkyl phosphonate 259 which can be the real reducing agent. Further experiments should be done to confirm the exact pathway of the reaction.

Scheme 100. Proposed mechanism for the DRA of ketones using NH 4 PO 2 H 2 in n-BuOH.

Conclusion and perspectives

In this part, we have investigated for the first time, the DRA of ketones into amines using ammonium hypophosphite in the presence of Pd/C. After studying the reaction parameters, best results were obtained using 5 equiv. of NH 4 PO 2 H 2 and 2,5 mol% equiv. of 5 wt.% Pd/C in the presence of n-BuOH as a solvent. In these conditions a variety of cyclic, acyclic aliphatic and aromatic ketones were reduced to give the corresponding amines in excellent isolated yields. In this reaction ammonium hypophosphite plays two crucial roles, so that it acts as a source of ammonia in the medium as well as a reducing agent.

For future perspectives, it is important to study the DRA of more challenging substrates, including aliphatic and sterically hindered ketones and aldehydes, and to study the chemoselectivity of this method in the presence of other competitive functional groups.

On the other hand, it is interesting to synthesize hypophosphite esters and to evaluate their reductive ability in different organic transformations. 13 C. 2 Spin-spin coupling constants (J) are given in Hz. The peak patterns are indicated as follows: (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet, and br. for broad).

Experimental Part

GC-MS analyses were performed on a DSQ -Thermofinnigan spectrometer equipped with quadrupole analyzer and a DB-5MS capillary column (30.0 m × 0.25mm × 0.25μm).

The carrier gas was helium, at a flow rate of 1 mL/min. Column temperature was initially

General Conclusion and Perspectives

better in the presence of K 2 CO 3 . Moreover, decreasing the catalyst load to 1 mol%, changes the selectivity towards the diamine.

Scheme 105. Reduction of aromatic nitriles using calcium hypophosphite.

In the second part, the potential of ammonium hypophosphite in reductive amination was studied. In this reaction ammonium hypophosphite plays to roles: as a source of ammonia and as a reducing agent. A variety of aliphatic and aromatic ketones were reductively aminated in the following conditions: ammonium hypophosphite (5 equiv.), 5 wt.% Pd/C (2,5 mol%), in butanol at 100 °C (Scheme 106).

Scheme 106. Reductive amination of ketones in the presence of NH 4 PO 2 H 2 and Pd/C.

Pd Ni

As a result, it has been shown for the first time that calcium and ammonium hypophosphites are potential alternatives for conventional reducing agents.

For future perspectives, it is very important to find the optimized conditions to reduce aliphatic nitriles into aliphatic aldehydes. Moreover, cyclization of dinitriles should be studied in details. On the other hand, reductive amination methodology should be applied on aliphatic and aromatic aldehydes, and it is interesting to study the indirect reductive amination reaction. Finally, the synthesis of hypophosphite esters and studying their reductive ability could be also interesting.

1 .

 1 . Conclusion ................................................................................................................. 3. RESULTS AND DISCUSSION ............................................................................................ 3.1. Objective ...................................................................................................................... 3.2. Feasibility and optimization of reaction conditions ..................................................... 3.3. Application of the methodology on different substrates .............................................. 3.4. Mechanism ................................................................................................................... 3.5. Conclusion and perspectives ........................................................................................ General information ..................................................................................................... 4.2. Typical procedure for the DRA of ketones .................................................................. 4.3. Typical procedure for the isolation of amines as oxalic acid salts............................... 4.4. Characterization data ................................................................................................... GENERAL CONCLUSION AND PERSPECTIVES ............................................................

Figure 2 .

 2 Figure 2. Derivatives of DIBAL-H developd by D. K. An. 21

Figure 3 .

 3 Figure 3. Structures of Thexylbromoborane-methyl sulfide 12 and potassium 9-sec-

Figure 4 .

 4 Figure 4. Structures of Bis-silanes developed by Corriu group. 31

Figure 6 .

 6 Figure 6. Structures of N,N-dialkylaminoborohydrides developed by B.

Scheme 25 .

 25 Scheme 25. Hydrosilylation of aliphatic nitriles 69 using silane 71 and Wilkinson's

Figure 8 .

 8 Figure 8. Structures of PMHS 80 and TMDS 81.

Figure 9 .

 9 Figure 9. Synthesis of NiNPs using sodium hypophosphite under microwave irradiation.97

Figure 11 .

 11 Figure 11. The variation in the conversion of 95 as a function of concentration of benzonitrile in ethanol.

Figure 12 .

 12 Figure 12. Structures of 2-cyanopyridine 131 and 2-aminobenzonitrile 132.

Scheme 41 .

 41 scheme 41.

  Scheme 50. RA of aldehydes and ketones using NaBH 4 / 158.125

Scheme 52 .Scheme 53 .

 5253 Scheme 52. One pot RA of ketone using 161 and NaBH 4 .133

Scheme 54 .

 54 Scheme 54. RA of 168 in the presence of NaBH 4 /NiCl 2 . 138

  143

Figure 13 .

 13 Figure 13. Structure of Amberlyst-15. 143e

( 91 -Scheme 56 .

 9156 Scheme 56. Reduction of 173 using NaBH 4 -172.144

2. 8 . 1 .

 81 Scheme 70. DRA of 154 in the presence of 203 and pyr-BH 3 . 180

Scheme 73 .

 73 Scheme 73. DRA of aldehydes ane ketones with LiClO 4 and (Ppyz)Zr(BH 4 ) 2 Cl 2 . 191

2. 10 Scheme 74 .Scheme 75 .

 107475 Scheme 74. Reduction of imine 207 using PMHS-Tin Catalyst 208.198

  212

  Scheme 81. DRA of 216 using 217 and Et 3SiH. 214

Et 3 Scheme 83 .

 383 Scheme 83. Reduction of imines into amines using Et 3 SiH/ BiCl 3 system.217

Figure 15 .

 15 Figure 15. Structure of Bu 2 SnClH-HMPA. 220

Scheme 85 .

 85 Scheme 84. DRA of 225 to amine 226 using Bu 2 SnClH-HMPA system.220

Figure 17 .Scheme 94 .

 1794 Figure 17. Structure of palladium-N-heterocyclic carbene (PS-Pd-NHC) 234.

Figure 18 .

 18 Figure 18. The variation in the conversion of 154 as a function of temperature.

Figure 19 .

 19 Figure 19. It was obvious that the concentration of 154 in n-BuOH had an effect on the yield of α-phenylethylamine 155.

Figure 19 .

 19 Figure 19. The variation in the conversion of 154 as a function of [acetophenone] in n-BuOH.

NH 4

 4 PO 2 H 2 react with n-BuOH, as a result ammonium hydroxide NH 4 OH and hypophosphite anion were formed. The former dissociates to give ammonia and water, however, the later undergoes alkylation reactions leading to the formation of nbutylphosphinate 257 and di-n-butylphosphonate 259. In the next step, ammonium formed adds to the carbonyl group, leads to the formation of imine intermediate, which was reduced in the presence of Pd/C and reducing agent to the corresponding amine (Scheme 100).

  70 °C for 2 min, then gradually increased to 310 °C at 15 °C/min and finally kept at 310 °C for 10 min. The injector temperature was 220 °C and the transfer line temperature was 280 °C. GC analyses were performed on a Shimadzu Gas Chromatograph GC-2025 equipped with a ZB-5-MS column (30.0 m × 0.25mm × 0.25μm). The carrier gas was N 2 at a flow rate of 1.27 mL/min. Column temperature was initially 70 °C for 2 min, then gradually increased to 280 °C at 15 °C/min and finally kept at 280 °C for 15 min. The injector temperature was 250 °C and for detection a FID was used at 280 °C.4.2.Typical procedure for the DRA of ketonesIn a sealed tube ammonium hypophosphite (415.15mg, 5 mmol) was added, followed by acetophenone (120 mg, 1 mmol) in n-butanol(2 mL, [acetophenone] in n-butanol= 0.5M). pd/C 5wt.% (53 mg, 2.5 mol%) was then added. The tube was sealed and the reaction was stirred at 800 rpm at 100°C. After 24 hours the tube was cooled in cold water and depressurized carrefully. The reaction mixture was dilluted with HCl (2M in H 2 O) and extracted with diethylether. To the acidic aqeous phase an alkaline solution of NaOH (2M in H 2 O) was added until pH=14, an extraction was done twice with diethylether. The obtained organic phase was dried over Na 2 SO 4 . The crude was analyzed in GC and GC-MS.

Scheme 3 .

 3 Reduction of nitriles 3 by Li(OEt) 3 AlH and the formation of aldehydes in the form of hydrazones 4.

15b

Aluminum, lithium or sodium (amino) hydrides such as Na(NH 2 ) 3 AlH 5,

16

Li[MeN(CH 2 ) 2 NMe]AlH 2 6

17

and Li[(C 6 H 13 ) 2 N] 3 AlH 7

  20

Scheme 4 .

 4 Example of the selective reduction of nitriles by DIBAL-H.19 Recently, new derivatives of DIBAL-H have been developed by D. K. An and his group for the reduction of nitriles at room temperature. From these derivatives Li[(C 5 H 10 N)(i-Bu) 2 AlH] 921a Li[(Ot-Bu)(i-Bu) 2 AlH] 10 21b and Li[(Oi-Pr)(i-Bu) 2 AlH] 11 (figure2). 21c

Scheme 6 .

 6 Pathway of reduction of nitrile to aldehyde by platinum(IV) oxide in aqueous formic acid via the intermediate aldimine 19.

24

Moreover, for example 4-methoxy benzonitrile was converted to 4-methoxy benzaldehyde by refluxing with Raney nickel in 75% formic acid.

26

2.1.6. Reduction of nitriles into aldehydes using hydrazine hydrate and Raney nickel Hydrazine hydrate and Raney nickel are an effective combination to act as a reducing system. Raney nickel has been associated with different organic and inorganic compounds for this purpose as well. For the reduction of nitriles into aldehydes, in the presence of hydrazine hydrate 20, benzonitrile derivatives 21 were converted to aldazines 22, which are then hydrolyzed to aldehydes 23 (Scheme 7). 27 Scheme 7. Reduction of substituted benzonitriles 21 to aldehydes 23 by the reducing system H 2 N-NH 2 20/ Raney-Ni via aldazines 22.

27

  The cationic ruthenium complex [Cp(iPr 3 P)Ru(NCCH 3 ) 2 ][B(C 6 F 5 ) 4 ] 31 with Me 2 PhSiH shows better activity, 34b

imine 65 led to the formation of an Sm 3+ intermediate 66 which upon subsequent protonation furnished the final product 67 (Scheme 23).

	2.2.3.2.4. Manganese Complexes 2.2.5. Reduction of nitriles to amines by catalytic transfer hydrogenation (CTH)
	Recently in 2016, Beller group described the synthesis and application of manganese Complementary to catalytic hydrogenations with molecular hydrogen, the use of transfer
	pincer complex 60 in the catalytic hydrogenation of aromatic, aliphatic and dinitriles hydrogenation reagents allows for reductions under ambient conditions without the need
	(Scheme 22). 75 for any special high pressure equipment. 79 This is of special interest to organic synthesis
	as well as fine chemical production in batch processes.
	In 2002, D.C. Gowda reported the CTH of nitriles using Raney nickel and hydrazinium
	monoformate (N 2 H 4 .HCOOH) as a hydrogen donor in a medium containing methanol at
	Scheme 22. Hydrogenation of nitriles using Co/61 catalytic system. 76 room temperature. 80 Later in 2003, R. C. Mebane and his group described the CTH of
	aliphatic nitriles to the corresponding primary amines with Raney nickel and 2-propanol
	2.2.4. Reduction of nitriles to amines by single electron transfer (SET)
	Recently, Procter and co-workers described the first reduction of aromatic and aliphatic
	Scheme 21. Hydrogenation of nitriles and dinitriles using manganese complex 60. 75 nitriles to primary amines under single electron transfer conditions using SmI 2 (Kagan's
	reagent) 77 activated by Lewis base. 78 They demonstrated that the reaction proceeds
	through the generation of imidoyl-type radicals 62 which was formed in equilibrium with
	2.2.3.2.5. Cobalt catalysts the imine radical 63. Subsequently, single electron transfer (SET) to the imine radical 63
	3 as a hydride source, and potassium Another non-noble metal is cobalt. In 2017, Beller group developed a new generated a carbamine anion 64, which underwent a protonation resulting in the
	hexamethyldisilazane (KHMDS) as a base, effectively catalyzed the hydrogenation of various heteroaromatic, benzylic and aliphatic nitriles (Scheme 22). 74 Scheme 21. Hydrogenation of nitriles using iron complex 59. 74 cobalt/tetradentate phosphine catalyst system for the synthesis of primary amines from nitriles. 76 Co(acac) 3 in combination with ligand tris[2-(dicyclohexylphosphino) ethyl]phosphine 61 efficiently catalyzed the selective hydrogenation of a wide range of heteroaromatic (Co(acac) 3 4 mol%, 80-120°C, 18h) and aliphatic nitriles (Co(acac) 3 5 mol%, 140°C, 24h) to give the corresponding amines (Scheme 22). Mechanistic investigations indicated a strong dependence on temperature for the formation of the active catalytic species 61. formation of the imine 65. In the next step, a further SET to the Scheme 23. Electron transfer reduction of nitriles using SmI 2 -Et 3 N-H 2 O. 78

  in the presence of NaH 2 PO 2 .H

2 O (4 equiv.), Pd/C (2,5 mol%) in water/2-MeTHF at 60°C for 4 hours (Scheme 37, method A). Scheme 37. Commutative reduction of ketones either to alkanes or alcohols.

11

  3,6-heptyl)amine (TDA) 96, at 80°C in aqueous medium. The use of additives for organic synthesis has become a common tactic to improve the outcome of organic reactions. A first test was carried out at 80°C in H 2 O, with 2.5 equiv. of calcium hypophosphite (Ca(H 2 PO 2 ) 2 ) and 20 mol% of the catalyst NiCl 2 .6H 2 O, in addition to 40 mol% of TDA 96. The reaction progress was followed by GC analysis. In these circumstances, and after 24h we observed 29% conversion of benzonitrile 95, where aldehyde 97 was obtained in 17%, and benzylalcohol 98 in 4%, with 79% of several unknown byproducts (Scheme 1).

Scheme 38. Reduction of benzonitrile using Ca(H 2 PO 2 ) 2 / NiCl 2 .6H 2 O.

Table 1 .

 1 Reduction of benzonitrile 95 with Ca(H 2 PO 2 ) 2 catalyzed by different metal catalysts.

	Entry	Catalyst	Conv. [%] a			GC ratio [%] a
				97	98	99	100	101	102 103
	1	NiCl 2 .6H 2 O (20	68	46	12	-	-	11	5	26
		mol%)
	2	CuCl 2 .2H 2 O (20	6	-	-	-	-	100	-	-
		mol%)
	3	5 wt.% Pd/C (2,5	100	-	-	84	-	2	14	-
		mol%)
	4	10 wt.% Pd/C (2,5	100	-	-	100	-	-	-	-
		mol%)
	5	[RuCl 2 (p-cymene)] 2	98	-	5	-	30	65	-	-
		(2,5 mol%)
	6	10 wt.% Pt/C (2,5	16	-	19	-	81	-	-	-
		mol%)

a Conv. and GC ratio were determined by gas chromatography.

Other products were also obtained including benzylalcohol 98 (12%) resulting from the over reduction reaction of benzaldehyde 97, benzamide 101 (11%) obtained from the hydration reaction of benzonitrile 95, dibenzylamine 102 (5%) and dibenzylimine 103 (26%) resulting from the reductive amination reaction. Another transition metal catalyst copper(II)chloride was evaluated, the results showed a very low conversion of 6%, and benzamide 101 was the only product in this reaction (Table

1, entry 2

). The efficiency of noble metal catalysts in this transformation was evaluated as well. In the presence of 2.5 mol% of 5wt.% Pd/C, benzonitrile 95 was completely converted to give 84% of benzylamine 99, 2% of 101 and 14% of 102 (Table

1

, entry 3). The use of the same amount of 10 wt.% Pd/C, led to complete conversion of 95, giving benzylamine 99 as the sole product in the reaction (Table

1

, entry 4). This reaction will be studied in the second section of this part. The use of 2,5 mol% [RuCl 2 (p-cymene)] 2 showed almost complete conversion of 95 reaching 98%, and promoted the formation of 98, 100 and 101 in 5%, 30% and 65% respectively (Table

1

, entry 5). In case of 10 wt.% Pt/C the conversion was low (Table

1

, entry 6). Other catalysts were also tested including Mg(II), Fe(II) and Co(II) precursors, however, none of these catalysts displayed any activity in the reduction of benzonitrile 95.

Table 2 )

 2 . It is noted that only the GC ratio of benzaldehyde 97 is presented in the table, though other products are formed during the reactions. NiCl 2 .6H 2 O as shown before, gave 68% conversion of benzonitrile 95 and led to the formation of 46% of benzaldehyde 97 after 24h(Table 2, entry 1). 37% conversion was achieved with NiBr 2 after the same reaction time, giving 51% of 97 (Table 2, entry 2). Similar conversion was obtained with NiCp 2 which gave 62% of 97 (Table 2, entry 3). In contrast Ni(acac) 2 was not efficient (Table 2, entry 4). Using Ni(dppe)Cl 2 , the GC Ratio of benzaldehyde 97 decreased to 28% with lower conversion of the benzonitrile 95 (Table 2, entry 5).

Table 2 .

 2 Reduction of benzonitrile 95 with Ca(H 2 PO 2 ) 2 catalyzed by different nickel complexes.

	Entry	Nickel complex	Conv. [%] a	GC ratio of 97 [%] a
	1	NiCl 2 .6H 2 O	68	46
	2	NiBr 2	37	51
	3	NiCp 2	34	62
	4	Ni(acac) 2	4	-
	5	Ni(dppe)Cl 2	22	28
	6	Ni(PPh 3 ) 2 Br 2	51	10
	7	Ni(PPh 3 ) 4	68	16
	8	Ni(OAc) 2 .6H 2 O	76	68
	9	Ni(cod) 2	100	6
	10 b	Ni~65 wt.% on Si/Al	62	79
	Phosphine nickel complexes such as Ni(PPh 3 ) 3 Br 2 and Ni(PPh 3 )4, inducing 51% and 68%
	conversions respectively. However, these two catalysts did not lead to any improvement
	in the selectivity towards 97 (Table 2, entries 6 and 7). The best result was observed in
	the presence of Ni(OAc) 2 .4H 2 O, where the conversion of 95 reached 76%, affording 68%
	of the desired product 97 (Table 2, entry 8). Two Ni (0) catalysts were evaluated. For
	example, Ni(cod) 2 leads to a complete conversion, but a mixture of products was
	observed with only 6% of benzaldehyde 97 (Table 2, entry 9). The other tested Ni (0)

a Conv. and GC ratio were determined by gas chromatography; b reaction time is 30 minutes.

Table 3 .

 3 Solubility of different hypophosphites in water expressed in percentage by weight of the hypophosphite derivative.

	Hypophsophite derivative	Solubility in water ( wt.%)
	Ca(H 2 PO 2 ) 2	13 98
	NH 4 H 2 PO 2	51 99
	NaH 2 PO 2	58 100
	H 3 PO 2	Very soluble 101
	H 3 PO 3	75 101
	Na 2 HPO 3	Very soluble 102

After studying several parameters including the type of hypophosphite, the type of catalyst as well as the reaction temperature, it was important to study the influence of different bases on this transformation. The results of reduction in the presence of 1 equiv.

Ca(H 2 PO 2 ) 2 (1M in H 2 O), 20 mol% Ni(OAc) 2 .4H 2 O and 40 mol% of base at 100°C for 24h are summarized in Table

Table 4 .

 4 Reduction of benzonitrile 95 with Ca(H 2 PO 2 ) 2 catalyzed by Ni(OAc) 2 .4H 2 O in the presence of different bases.

	Entry	Base	Conv. [%] a	GC ratio of 97 [%] a
	1	-	-	-
	2	K 2 CO 3	91	29
	3	Na 2 CO 3	94	40
	4	CaCO 3	97	42
	5	AcOK	73	89
	6	AcONa	18	100
	7	Ca(OAc) 2 .H 2 O	12	100
	8	DIPEA	100	5

  95 was studied in a mixture of different organic solvents and water over 20 mol% Ni(OAc) 2 .4H 2 O, 40 mol% Ca(OAc) 2 .H 2 O and in the presence of 1 equiv. of Ca(H 2 PO 2 ) 2

Table 5 .

 5 Reduction of benzonitrile 95 in the presence of different co-solvents.

	Entry Co-solvent	Time	Conv.[%] a			GC ratio [%] a
			[h]		97	98	101	102	103
	1	MeOH	21	75	91	4	2	3	-
	2	EtOH	7	100	100	-	-	-	-
	3	n-BuOH	7	42	95	3	2	-	-
	4	tert-butanol	7	93	74	13	2	11	-
	5	CPME	7	64	83	6	-	8	3
	6	1,2,3-TMP	7	73	92	8	-	-	-

a Conv. and GC ratio were determined by gas chromatography.

Table 5

 5 BuOH solvent mixture, only 42% conversion was reached after 7h with 95% of 97, traces of 98 and 101 were also observed (Table5, entry 3). When the reaction with tert-butanol and H 2 O was performed over 7h, a conversion of 93% was reached with 74% of97 and 98, 101 and 102 as byproducts (Table 5, entry 4). Using a less polar solvent such as CPME, 64% of 95 were converted to give 83% of 97 and other byproducts (Table5, entry 5). In the presence of 1,2,3-TMP, a conversion of 73% was noted after 7h with 92% yield of benzaldehyde 97(Table 5, entry 6). Over reduction led to the formation of 8% of benzylalcohol 98 as a byproduct. This optimization part reveals the importance of solubilization of the substrate and the reducing agent together in the mixture of solvents. The variation in the conversion of 95 as a function of concentration of Ca(H 2 PO 2 ) 2 in water.

, entry 2). In this case when, EtOH was added a turbid reaction mixture was obtained which means that ethanol acts as a hydrotrope for the solubilization of benzonitrile in water. Conversely, in H 2 O/n-

g. Effect of concentration of Ca(H 2 PO 2 ) 2 in water

In order to evaluate the effect of concentration of calcium hypophosphite in water on the reaction, the reduction of benzonitrile 95 was performed using the optimized conditions:

20 mol% Ni(OAc) 2 .4H 2 O, 40 mol% Ca(OAc) 2 .H 2 O, 1 equiv. Of Ca(H 2 PO 2 ) 2 in biphasic

system of H 2 O/EtOH at 100 °C, where [benzonitrile] in EtOH = 1 M, and varying concentrations of Ca(H 2 PO 2 ) 2 in H 2 O. Results are represented in the graph shown in Figure 10. It was observed that the concentration of calcium hypophosphite has an effect on the conversion of 95 rather than on the GC ratio of benzaldehyde 97. The ideal concentration was 1M, lower concentrations diminished the conversion where it reaches 79% at [Ca(H 2 PO 2 ) 2 ]= 0.4M. When higher concentrations were used, the conversion drops dramatically to 38% at [Ca(H 2 PO 2 ) 2 ]= 2M. It is possible that at higher concentrations, calcium hypophosphite, nickel catalyst and substrate are less soluble.

Figure 10.

Table 6 .

 6 Reduction of aromatic nitriles to aldehydes.

	Entry	Substrate	Aldehyde	Time	Conv.	GC	Isolated
				[h]	[%] a	ratio	yield
						[%] a	[%] b
	1			7	100 100	50
				7	100 93	90
	2
	3			23	93	93	90
	4 c			26	100 100	97

a Conversion and GC ratio of aldehyde were determined by GC; b Isolated yield as hydrochloric acid salt; c [S] in EtOH= 0.66M.

Table 7 .

 7 As mentioned in the previous section, where we discussed the reduction of benzonitrile 95 with Ca(H 2 PO 2 ) 2 catalyzed by different metal catalysts that the reduction using 10 wt.% Pd/C caused the complete conversion of benzonitrile to benzylamine as the sole product (Table1, entry 4). Interested by these results we went forward for studying this It was very clear that the efficiency of the reduction highly depends on the type of the catalyst used. At the same time, the amount of catalyst used can change the whole pathway of the reaction as shown in Table7. Reduction of benzonitrile 95 in the presence of Pd/C. The reduction of benzonitrile 95 was done in the presence of 2,5 equiv. of Ca(H 2 PO 2 ) 2 as the reducing agent, 40 mol% of K 2 CO 3 as a basic additive in aqueous medium at 100°C

	3.4. Reduction of nitriles into amines
	3.4.1. Objective

a Conv. and GC ratio were determined by gas chromatography

Table 8 .

 8 Reduction of benzonitrile 95 in the presence of different bases.

	Entry	Base	Time [h]	Conv. [%] a		GC Ratio [%] a
					99	102	133
	1	K 2 CO 3	24	100	100	-	-
	2	DIPEA	5	99	81	13	6
	3	Ca(OAc) 2 .H 2 O	16	100	64	29	2

a Conv. and GC ratio were determined by gas chromatography Using the string base DIPEA, the reaction was fast with complete conversion after 5h (

Table 8 ,

 8 entry 2). In this case the desired benzylamine 99 was obtained in 81% yield and with 102 and 133 as byproducts. It is noted that even at less reaction time this percentage cannot be increased. Calcium acetate hydrate Ca(OAc) 2 .H 2 O was also tested. The conversion was complete after 16h, however, only 69% of 99 was obtained (

Table 8 , entry

 8entry

Table 9 .

 9 Reduction of benzonitrile 95 in the presence of different co-solvents.

	Entry	Co-solvent	Conv. [%] a		GC Ratio [%] a
				98	99	102	133
	1	EtOH	99	13	52	10	25
	2	n-BuOH	100	-	82	2	16
	3	MeOH	88	42	36	16	6
	4	2-MeTHF	41	12	71	5	12
	5	CPME	100	-	96	-	4

a Conv. and GC ratio were determined by gas chromatography The conversion of 95 was fast and almost complete in H 2 O/EtOH solvent mixture, but a mixture of products was obtained with only 52% of the desired benzylamine 99 (Table

9

, entry 1). Using H 2 O/n-BuOH mixture, the reaction was also faster than that with only water; while complete conversion of 95 was observed after 7h, lower yield of 99 was obtained (

Table 9 ,

 9 entry 2). In a mixture of H 2 O/MeOH the conversion was not complete after 7h (88%), giving only 36% of 99 (Table9, entry 3). In the presence of H 2 O/2-

	MeTHF the conversion was the lowest after 7h in comparison to other co-solvents
	reaching 41% with 71% of 99 (Table 9, entry 4). Using H 2 O/CPME mixture, the reaction
	was very fast leading to a complete conversion after 7h with 96% of 99 and traces of
	toluene 133 (Table

Table 10 .

 10 Influence of the amount of K 2 CO 3 on the reduction of benzonitrile 95.

	Entry	K 2 CO 3 [mol%]	Conv. [%] a		GC Ratio [%] a
				99	102	133
	1	20	100	95	-	5
	2	10	100	92	-	8
	3	5	100	86	-	14
	4	-	100	86	3	11

Table 11 .

 11 Reduction of aromatic nitriles to amines.

	Entry	Nitrile	Amine hydrochloride	Time	Conv.[%] a	GC	Isolated
				[h]		ratio	yield of
						of	salt
						amine	[%] b
						[%] a
	1			22	100	98	96
				4	100	100	>99
	2
	3			16	100	91	89
				4	100	95	93
	4
	5			22	100	96	95
	6			22	100	96	95

a Conversion and GC Ratio were determined by GC; b yield of product isolated as HCl salt; c Pd/C 10wt.% (3 mol%, 0.03 mmol),

H 2 O (3 mL) ([Ca(H 2 PO 2 ) 2 ]= 0.83M).

Benzonitrile derivatives bearing electron-withdrawing substituents at the 4-position such as -NO 2 (135), -CHO (137), and -COOEt (112) were quantitatively reduced with calcium hypophosphite and isolated in the form of hydrochloride salts 136, 138 and 139 respectively (Table

11

, entries 2-4). Noting that in case of 4-formyl benzonitrile 137 (Table

  The pressure tube was closed by a front seal Ace O-rings, Silicone (wall 1.78 mm, I.D. 5.3 mm) provided by Sigma Aldrich (ref: 7855-207).

	GC analyses were performed on a Shimadzu Gas Chromatograph GC-2025 equipped
	with a ZB-5-MS column (30.0 m × 0.25mm × 0.25μm). The carrier gas was N 2 at a flow
	The complete references of the pressure tubes used in the reduction of amines into rate of 1.27 mL/min. Column temperature was initially 70 °C for 2 min, then gradually
	aldehydes are: ACE pressure tubes, #15 Ace-Thred, order code (CAS: 8648-03), length increased to 280 °C at 15 °C/min and finally kept at 280 °C for 15 min. The injector
	(10.2 cm), body O.D. (25.4 mm), capacity (15 mL), pressure rating (150 PSI or 10.3 bar) temperature was 250 °C and for detection a FID was used at 280 °C.
	and ACE pressure tubes, order code (CAS: 8648167), length (10.2 cm), body O.D. (38.1
	mm), capacity (38 mL), pressure rating (150 PSI or 10.3 bar). The pressure tube was 4.2. Procedures
	closed by a back seal PTFE plug 5845 with a 210 O-ring for #15 Ace-Thred in
	FETFETM or silicone, provided by Sigma Aldrich as well. 4.2.1. Typical procedure for the reduction of nitrile into aldehyde
	Silica gel (40-63 micron) was used for column chromatography. Thin layer In a sealed tube Ace-Thred #7 indicated above, Nickel(II)acetate tetrahydrate (49.7 mg,
	chromatography was performed on precoated silica gel 60-F 254 plates. UV light, 2,4-0.2 mmol, 20 mol%) was introduced followed by water (1 mL, [Ca(H 2 PO 2 )
	dinitrophenylhydrzine was used for analysis of the TLC plates.
	All compounds were characterized by spectroscopic data. The nuclear magnetic
	4.1. General information resonance (NMR) spectra were recorded either on a Bruker ALS 300 ( 1 H: 300 MHz, 13 C:
	75 MHz), a DRX 300 ( 1 H: 300 MHz, 13 C: 75 MHz) or a Bruker DRX 400 ( 1 H: 400 MHz,
	All reagents were obtained from commercial sources and used as received without any
	further purification. CuCl 2 , Ca(H 2 PO 2 ) 2 and TDA were purchased from Alfa Aesar ® .
	Ca(H 2 PO 2 ) 2 was placed always in desiccators. Ni(CH 3 CO 2 ) 2 .4H 2 O Assay ≥ 99.0% (KT)
	was purchased from Fluka. 10% Pd/C, 10% Pt/C, 5% Pd/C, [RuCl 2 (p-cymene)] 2 and
	NiCp 2 were purchased from Strem Chemicals. NiBr 2 , Ni (acac) 2 , Ni(ph 3 P) 2 Br 2 , Ni(ph 3 P) 4 ,
	Ni(cod) 2 , Ni~65 wt. % on Si/Al, 2,2'-bipyridine, K 2 CO 3 , N,N-diisopropylethylamine,
	hydrogen chloride solution 2M in diethylether and calcium acetate monohydrate were GC-MS analyses were performed on a DSQ -Thermofinnigan spectrometer equipped
	purchased from Sigma Aldrich. Ni(dppe)Cl 2 was purchased from ACROS. NiCl 2 was with quadrupole analyzer and a DB-5MS capillary column (30.0 m × 0.25mm × 0.25μm).
	purchased from Laurylab. The carrier gas was helium, at a flow rate of 1 mL/min. Column temperature was initially
	70 °C for 2 min, then gradually increased to 310 °C at 15 °C/min and finally kept at 310
	The complete references of the used sealed tubes used in the reduction of nitriles into °C for 10 min. The injector temperature was 220 °C and the transfer line temperature was
	aldehydes are: ACE pressure tubes, Ace-Thred #7, order code (Z564564), length (10.2 280 °C.

cm), body O.D.

(19 mm)

, capacity

(9 mL)

, pressure rating (150 PSI or 10.3 bar). 13 C: 100 MHz) spectrometer, in D 2 O or DMSO-d 6 at 293K. Chemical shifts are reported in parts per million (ppm) and are calibrated on residual solvent peaks: D 2 O 4.79 ppm in 1 H, or DMSO-d 6 2.50 ppm in 1 H and 39.52 ppm in

13

C.

1

Spin-spin coupling constants (J) are given in Hz. The peak patterns are indicated as follows:

(s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet, and br. for broad)

. 2 ]= 1M), the tube was stirred at room temperature. Calcium hypophosphite (170 mg, 1 mmol) was then added followed by calcium acetate monohydrate

(70.4 mg, 0.4 mmol, 40 mol%)

. To this mixture was added the nitrile substrate (1 mmol) and ethanol absolute

(1 mL, [nitrile]

Benzaldehyde [100-52-7] (97) Colorless

	mixture was added benzonitrile (103.12mg, 1 mmol), followed by Pd/C 10 wt.% (26.5
	mg, 2.5 mol%), the tube was then sealed. The reaction mixture was stirred at 800 rpm at
	100°C. After 24 hours the tube was cooled in cold water and pressure was released
	carrefully. The reaction mixture was dilluted with HCl (2M in H 2 O) and extracted with
	diethylether. To the acidic aqueous phase an alkaline solution of NaOH (2M in H 2 O) was
	added until pH=14, an extraction was done twice with diethylether. The obtained organic
	phase was dried over Na 2 SO 4 . The crude was analyzed in GC and GC-MS.
	4.2.3. Typical Procedure for isolation of amines as HCl salts
	HCl (1M in diethylether, 1mL) was added to the extracted organic phase, stirring was
	maintained for 30 minutes at room temperature. The resulting precipitate was filtered and
	washed with diethyl ether then pumped under reduced pressure to dry.
	4.3. Characterization data
	4.3.1. Caharacterization data of isolated aldehydes
	2,5 mL of H 2 O was
	then added ( [Ca(H 2 PO 2 ) 2 ]= 1M), the tube was stirred at room temperature. To this

oil. Eluent for isolation 5:5 pentane/DCM.

1 H NMR (300 MHz, CDCl 3 ): δ

  Hz, CH Ar ),7.91-7.89 (d, 1H, J = 6 Hz, CH Ar ), 7.84-7.82 (d, 1H, J = 6 Hz, CH Ar ), 7.63- 7.47 (m, 3H, 3xCH Ar ) ppm. 13 C NMR (75 MHz, CDCl 3 ): δ 193.58 (C q , CHO), 136.71

	4-Hydroxy benzaldehyde [123-08-0] (105)
	Offwhite powder. Eluent for isolation 9:1 DCM/diethylether. 1 H NMR (300 MHz,
	9.92 (s, 1H, CHO), 7.79-7.77 (d, J=6 Hz, 2H, CH Ar ), 7.53-7.50 (m, 1H, CH Ar ), 7.45-7.40 (m, 2H, CH Ar ) ppm 13 C NMR (75 MHz, CDCl 3 ): δ 192.51 (C q , C-HC=O), 136.51 (C q , C Ar ), 134.57 (C q , C Ar ), 129.85 (2 CH, C Ar ), 129.1 (CH, C Ar ) ppm. GC: retention time: 4.3 min. DMSO-d6): δ 10.59 (s broad, 1 H, OH), 9.78 (s, 1H, CHO), 7.77-7.74 (d, J= 9 Hz, 2H, CH Ar ), 6.94-6.91 (d, J= 9 Hz, 2H, CH Ar ), ppm. 13 C NMR (75 MHz, DMSO-d6): δ 190.96 (C q , C-HC=O), 163.33 (C q , C Ar ), 132.12 (CH, C Ar ), 128.45 (C q , C Ar ), 115.85 (CH, C Ar ) ppm. GC: retention time: 8.7 min. 4-methoxybenzaldehyde [123-11-5] (109) Colorless liquid. 1 H NMR (300 MHz, CDCl 3 ): δ 9.77 (s, 1 H, CHO), 7.74-7.71 (d, J = 9 Hz, 2 H, CH Ar ), 6.91-6.88 (d, J = 9 Hz, 2H, CH Ar ), 3.78 (s, 3H, OCH 3 ) ppm. 13 C NMR (75 MHz, CDCl 3 ): δ 190.93 (C q , C-HC=O), 164.72 (C q , C Ar ), 132.09(2 CH, C Ar ), 130.06 (C q , C Ar ), 114.42 (2 CH, C Ar ), 55.69 (CH 3 ) ppm. GC: retention time: 7.8 min. Terephthaldehyde [623-27-8] (117) White crystals. Eluent for isolation 9:1 pentane/diethylether. 1 H NMR (300 MHz, CDCl 3 ): δ 10.03 (s, 2 H, CHO), 7.95 (s, 4H, CH Ar ) ppm. 13 C NMR (75 MHz, CDCl 3 ): δ 191.62 (2 C q , C-HC=O), 140.15 (2 C q , C Ar ), 130.27 (4 CH, C Ar ) ppm. GC: retention time: 7.4 min. 1-Naphthalaldehyde [66-77-3] (121) Colorless liquid. Eluent for isolation 9:1 DCM/diethylether. 1 H NMR (300 MHz, (CH, C Ar ), 128.53 (CH, C Ar ), 127 (CH, C Ar ), 124.91 (CH, C Ar ) ppm. GC: retention time: 10.1 min. 3-Bromobenzaldehyde [3132-99-8] (125) Yellow liquid. Eluent for isolation 6:4 pentane/DCM. 1 H NMR (300 MHz, CDCl 3 ): δ 9.86 (s, 1 H, CHO), 7.92 (s, 1H, CH Ar ), 7.91-7.63 (m, 2H, CH Ar ), 7.35-7.29 (m, 1H, CH Ar ) ppm. 13 C NMR (75 MHz, CDCl 3 ): δ 190.88 (C q , C-HC=O), 138.12 (C q , C Ar ), 137.44 (CH, C Ar ), 132.49 (CH, C Ar ), 130.76 (CH, C Ar ), 128.51 (CH, C Ar ), 123.51 (C q , C Ar ) ppm. GC: retention time: 7.3 min. 4-Bromobenzaldehyde [1122-91-4] (127) White crystals. Eluent for isolation 6:4 pentane/DCM. 1 H NMR (300 MHz, CDCl 3 ): δ 9.86 (s, 1 H, CHO), 7.65-7.62 (d, 2H, J = 9 Hz, CH Ar ), 7.58-7.55 (d, 2H, J = 9 Hz, CH Ar ) ppm. 13 C NMR (75 MHz, CDCl 3 ): δ 191.17 (C q , C-HC=O), 135.18 (C q , C Ar ), 132.54 (2CH, C Ar ), 131.07 (2 CH, C Ar ), 129.88 (C q , C Ar ) ppm. GC: retention time: 7.4 min. 4.3.2. Characterization data of isolated hydrochloride salts CDCl (CH, C Ar ), 135.32 (CH, C Ar ), 133.76 (C q , C Ar ), 131.42 (C q , C Ar ), 130.56 (CH, C Ar ), 129.1 Phenyl methanammonium chloride (134)

2-Hydroxy benzaldehyde [90-02-8] (107)

Colorless liquid. Eluent for isolation: 9:1 pentane/diethylether. 1 H NMR (300 MHz, CDCl 3 ): δ 10.92 (s, 1 H, OH), 9.80 (s, 1H, CHO), 7.48-7.40 (m, 2H, CH Ar ), 6.95-6.88 (m, 2H, CH Ar ), ppm. 13 C NMR (75 MHz, CDCl 3 ): δ 196.75 (C q , C-HC=O), 161.79 (C q , C Ar ), 137.14 (CH, C Ar ), 133.87 (CH, C Ar ), 120.82 (C q , C Ar ), 119.99 (CH, C Ar ), 117.77 (CH, C Ar ) ppm. GC: retention time: 5.3 min. 2-Naphthalaldehyde [66-99-9] (119) Slight yellow crystalline powder. Eluent for isolation 9:1 DCM/diethylether. 1 H NMR (300 MHz, CDCl 3 ): δ 10.05 (s, 1 H, CHO), 8.22 (s, 1H, CH Ar ), 7.91-7.78 (m, 4H, CH Ar ), 7.57-7.45 (m, 4H, CH Ar ) ppm. 13 C NMR (75 MHz, CDCl 3 ): δ 192.36 (C q , C-HC=O), 136.53 (C q , C Ar ), 134.66 (CH, C Ar ), 134.19 (2 C q , C Ar ), 132.72 (C q , C Ar ), 129.62 (CH, C Ar ), 129.21 (CH, C Ar ), 128.17 (CH, C Ar ), 127.19 (CH, C Ar ), 122.84 (CH, C Ar ) ppm. GC: retention time: 10.2 min. 3 ): δ 10.31 (s, 1 H, CHO), 9.17-9.14 (d, 1H, J = 9 Hz, CH Ar ), 8.02-7.99 (d, 1H, J = 87 9 2-Chlorobenzaldehyde [89-98-5] (123) Colorless Liquid. Eluent for isolation only pentane. 1 H NMR (300 MHz, CDCl 3 ): δ 10.38 (s, 1 H, C-CO-H), 7.83 (s, 1H, CH Ar ), 7.8-7.15 (m, 3H, CH Ar ) ppm. 13 C NMR (75 MHz, CDCl 3 ): δ 189.94 (C q , C-HC=O), 138.10 (C q , C Ar ), 135.25 (CH, C Ar ), 132.64 (C q , C Ar ), 130.76 (CH, C Ar ), 129.52 (CH, C Ar ), 127.43 (CH, C Ar ) ppm. GC: retention time: 6.2 min. 1 H NMR (300 MHz, D 2 O): δ 7.47 (s, 5H), 4.17 (s, 2H) ppm 13 C NMR (75 MHz, D 2 O):

δ 132.

54, 129.17, 128.78, 43.06 ppm. (

4-nitrophenyl)methanammonium chloride (136)

	1 H NMR (300 MHz, D 2 O): δ 7.45-7.41 (m, 2H), 7.39-7.35 (m, 2H), 2.43 (s, 1H) ppm
	13 C NMR (75 MHz, D 2 O): δ 139.65, 130.44, 126.89, 122.59, 20.03 ppm.
	(4-ethylphenyl)methanammonium chloride (138)

  Scheme 87).225 Limitations of the reaction include steric effects that leads to the formation of only traces of desired amine. In addition some functional groups including -CN and-NO 2 did not survive under these reaction conditions. DRA of carbonyl group using Catalysts 223 and 224 in the presence of H 2 . DRA of aldehydes using Pd(PhCN) 2 Cl 2 / BQC system.231

	Advantageously in 2002, the same group reported the DRA of aldehydes and ketones metal complexes under H 2 pressure. 231 The reaction was performed using 1 equiv. of
	using these Rh(I) catalysts 223 and 224. It was the first example of a homogeneously amine, 1 mol% of Pd(PhCN) 2 Cl 2 , 6 mol% of BQC (2,2'-biquinoline-4,4'-dicarboxylic
	catalyzed reductive amination using primary and secondary amines. The reaction took acid dipotassium salt), in aqueous medium at 100°C. After 24h the corresponding amines
	place under mild conditions: amine (1 equiv.), H 2 (50 bar), Catalyst (0,2 mol%) in MeOH were isolated in 44-99% isolated yields (Scheme 91).
	2.12.1. Homogeneous Catalysis Only a few preliminary studies on the homogeneous version of this reaction can be found in the literature in spite of the tremendous progress that homogeneous catalysis has seen over the last decades. 222 2.12.1.1. Rhodium Catalysts 2.12.1.1.1. Rh(I) catalysts based on Chelating diphosphines and diphosphinites Figure 17. (S,S)-f-Binaphane 225. 228 In 2003, the same group investigated the RA or aryl ketones using Ir-f-Binaphane 186 (1,2 equiv.), in the presence of I 2 (10 mol%) and Ti(O-iPr) 4 (1,5 equiv.) as additives under H 2 pressure of 69 bar in DCM at rt for 12h (Scheme 90). 229 at rt for 20h (Scheme 87. good yields and by up to 98% ee. 226 complex as the catalyst. For example, acetophenone 154 was reduced with p-anisidine Scheme 91.
	In 1999, A. Börner and co-workers reported that cationic rhodium(I) complexes
	[Rh(dppb)(cod)]BF 4 223 and [Rh(dpoe)(cod)]BF 4 224 are highly efficient pre-catalysts in the hydrogenation of imines and enamines under mild conditions (Figure 16). 223, 224 2.12.1.1.2. Chloro(1,5-cyclooctadiene)rhodium(I) dimer Scheme 90. Assymetric RA of 154 using Ir-f-Binaphane complex. 229
	In 2002, Beller group presented the first procedure for the selective DRA of aromatic and In 2005, T. Ohta and co-workers have found that [Ir(cod) 2 ]BF 4 is sufficiently effective
	aliphatic carbonyl compounds to primary amines using NH 3 in the presence of water-for the DRA of carbonyl compounds with amines in the presence of H 2 . Yields up to 99%
	soluble transition metal complexes. 227 The DRA or aromatic aldehydes was carried out with an aldehyde, and up to 92% with a ketone were obtained in benzene and toluene
	using: Chloro(1,5-cyclooctadiene)rhodium(I) dimer [Rh(cod)Cl] 2 as the catalyst, solvents, respectively. On the other hand ketones were also reductively aminated using a
	NH 4 OAc (50 mol%) as a co-catalyst, TPPTS (tris sodium salt of meta trisulfonated combination of ionic liquid [Bmim]BF 4 158 as a solvent and [Ir(cod) 2 ]BF 4 as the
	triphenylphosphine) as a ligand, 25% aqueous NH 3 solution (20 mL), H 2 (65 bar) at catalyst. 230
	135°C in THF for 2h. Using this methodology the corresponding amines were reduced
	with 33-86% isolated yields (Scheme 88).
	Figure 16. Rhodium(I) complexes 223 and 224 developed by Börner. 223, 224 2.12.1.3. Palladium Catalysts
	In 2006, A. N. Ajjou and co-workers described the DRA of aliphatic and aromatic
	aldehydes with primary and secondary amines, catalyzed by water-soluble transition

225

In 2003, the same group developed the first highly enantioselective DRA of α-keto acids using a cationic Rh-Deguphos catalyst, where several α-amino acids were produced in

Table 12 .

 12 DRA of 154 using different ammonium sources.

	Entry	Ammonium	Conv. [%] a			GC ratio [%] a
		source		155	237	238	239	by-products
	1	NH 4 PO 2 H 2	100	12	73	1	2	12
	2	NH 4 OAc	91	15	7	-	75	3
	3	NH 3	39	25	35	40	-	-

a Conv. and GC ratio were determined by gas chromatography.

Table 14 .

 14 DRA of acetophenone 154 using NH 4 PO 2 H 2 in different reaction conditions.In the next step, we studied the effect of the amount of hypophosphite NH 4 PO 2 H 2 on the DRA of 154, according to Table15. Decreasing the amount of NH 4 PO 2 H 2 to 1 and 2

	Entry	Pd/C	Solvent	T [°C] Conv.			GC Ratio [%] a
		[mol%]			[%] a	155 237	238	239	byproducts
	1	5	EtOH	80	100	12	73	1	2	12
	2	5	n-BuOH	100	100	35	60	5	-	-
	3	2,5	n-BuOH	100	100	45	55	-	-	-
	4	2,5	CPME	100	55	-	40	25	35	-
	5	2,5	1,2,3-TMP	100	36	-	86	14	-	-
	6	2,5	2-MeTHF	100	32	-	68	19	13	-
	d. Effect of amount of NH 4 PO 2 H 2

a Conv. and GC ratio were determined by gas chromatography. equivalents favoured the formation of secondary amine 237, with lower conversions (Table

Table 15 .

 15 Effect of the amount of NH 4 PO 2 H 2 on the DRA of acetophenone 154. Conv. and GC ratio were determined by gas chromatography. b molecular sieves 3 Å.

	Entry	Additive [mol%]	Conv.			GC ratio [%] a
			[%] a	155	237	238	239	byproduct
	1	CaH 2 / 0.6 mol%	100	70	1	-	-	29
	2	MS b / 20 mol%	100	56	13	2	27	2
	3	NaOH/ 250 mol%	100	34	55	2	8	1
	a

Table 17 .

 17 Direct reductive amination of ketones using ammonium hypophosphite and Pd/C.

	Entry	ketone	amine	Time	Conv.	GC	Isolated
				[h]	[%] a	ratio	yield
						[%] a	[%] b
				24	100 100	95
				24	100 100	99
				7	100 100	90
				22	100	98	80
				21	100 100	99
				28	100 100	96
				26	90	90	85
				28	100 100	99

a Conversion and GC Ratio were determined by GC; b yield of products isolated as oxalic acid salt.

  4.1. General informationAll reagents were obtained from commercial sources and used as recieved without any furthur purification. Ammonium hypophosphite 97%, NaOH, Molecular sieves 3Å and oxalic acid were purchased from Sigma Aldrich. Pd/C 5wt.%, Ru/C 5wt.%, Ru/Al 2 O 3 5%, Rh/C 5% and Pt/C 5% were purchased from Strem Chemicals. Calcium hydride 90-95% was purchased from Alfa Aesar. The complete references of the pressure tubes are: ACE pressure tubes, #15 Ace-Thred, order code (CAS: 8648-03), length (10.2 cm), body O.D. (25.4 mm), capacity (15 mL), pressure rating (150 PSI or 10.3 bar) and ACE pressure tubes, order code (CAS: 8648167), length (10.2 cm), body O.D. (38.1 mm), capacity (38 mL), pressure rating (150 PSI or 10.3 bar). The pressure tube was closed by a back seal PTFE plug 5845 with a 210 O-ring for #15 Ace-Thred in FETFETM or silicone. All compounds were characterized by spectroscopic data. The nuclear magnetic resonance (NMR) spectra were recorded either on a Bruker ALS 300 ( 1 H: 300 MHz, 13 C: 75 MHz), a DRX 300 ( 1 H: 300 MHz, 13 C: 75 MHz) or a Bruker DRX 400 ( 1 H: 400 MHz, 13 C: 100 MHz) spectrometer, in D 2 O at 293K or DMSO-d 6 at 343 K . Chemical shifts are reported in parts per million (ppm) and are calibrated on residual solvent peaks: D 2 O 4.79 ppm in 1 H, or DMSO-d 6 2.50 ppm in 1 H and 39.52 ppm in

H NMR (300 MHz, DMSO): δ 6.56-6.52 (m,

2H),6.38-6.33 (m, 2H), 3.06 (s, 2H),

Acknowledgements

This work was carried out in the laboratory Catalyse, Synthèse et Environnement (CASYEN), in the group of Marc Lemaire within l'Institut de Chimie et Biochimie

, I would like to thank the EDST research platforms at the Lebanese University for the technical experimental help. I would like to thank particularly: Dr. Eric Da SILVA and Dr.

Subsequent reduction of this iminium ion produces the amine 151 as the final product.

However, there are some reports that provide evidence suggesting a direct reduction of the carbinol amine 149 as a possible pathway leading to 151. 110 The choice of the reducing agent is very critical to the success of the reaction, since it must reduce selectively the intermediate imine to amine, and not to produce the corresponding alcohol 152 or secondary amine 153 according to scheme 45.

The reductive amination reaction is described as a direct reaction when the carbonyl compound and the amine are mixed with the proper reducing agent without prior formation of the intermediate imine or iminium salt. A stepwise or indirect reaction involves the preformation of the intermediate imine followed by the reduction in a separate step.

In literature, there exist many methods for this type of reaction. However, there is a big demand for new environmentally friendly methods which are more practical and less expensive.

In this part, different methods from literature for the RA of aldehydes and ketones to form amines will be discussed. Then, we will explain our new investigated method, finishing with a conclusion, perspectives and experimental section.

Bibliographic data

A powerful route to synthesize amines is the RA of carbonyl groups using ammonia or amine to form the imine intermediate, which is then reduced to amine. This reaction is attractive in organic synthesis because ketones and aldehydes can be transformed, in one reaction vessel, directly to the corresponding secondary or primary amine, without isolation of the intermediary imine or hydroxyl amine. Herein, we reported the literature data concerning this type of reaction. Initially, the group studied the RA of benzaldehyde with aniline using 179 and NaBH 4 , they showed that the yield of the desired amine is dependent on time and mixing order, so that when benzaldehyde was mixed firstly with aniline for 10 min, and the resulting mixture was then grounded with NaBH 4 and 179, the reaction afforded 94% of 182 and only 6% of 183. P-toluene sulfonic acid monohydrate 180 and benzoic acid 181 showed the same result (Scheme 59).

Notably, the amount of thiourea 188 added have no significant influence on the reaction rate where similar results were obtained using 1, 0.5 or 0.1 equivalents. However, in its absence the amine 189 was not observed, proving its crucial influence as an organocatalyst. 157 Finally, NaBH 4 was associated with many other reagents such as ZnCl 2 , 158 ZrCl 4 , 159 and carbon-based solid acid (CBSA). 160

DRA of ketones using Borohydride Exchange Resin

In 1977, Borohydride Exchange Resin (BER) was introduced by Gibson and Baily. 161 Later N. M. Yoon and co-workers reported that BER is an interesting chemoselective reducing agent for carbonyl compounds in alcoholic solvents. 162,163 Several other significant applications were also presented. 164 The group have shown that BER is a good alternative to cyanoborohydrides and NaBH(OAc) 3 since it is non-toxic and less expensive in comparison to these reagents.

In 1993, N. M. Yoon et al. reported The reaction was employed under neutral conditions, and was effective in both protic and aprotic solvents including THF, DCM and MeOH. Moreover, it did not involve production of any toxic byproduct. Aliphatic and aromatic ketones were successfully reduced with this method, as well as aromatic aldehydes. However, the reaction was less effective with hindered ketones. 187 Finally, E. R. Burkhardt and B. M. Coleridge designed a liquid aromatic amine borane 5ethyl-2-methylpyridine borane (PEMB). 188 The advantageous properties of PEMB including liquid physical state, the thermal stability at ambient temperatures, and the slow reaction with protic solvents made it an attractive replacement for other amine boranes in reduction reactions. 189 2.9. DRA of ketones using zirconium borohydride-piperazine Heydari group used zirconium borohydride-piperazine complex (Ppyz)Zr(BH 4 ) 2 Cl 2 , which is air and thermally stable, in the selective reduction of various important functionalities. 190 These results promoted the group to study the RA of aldehydes and ketones using this reagent in the presence of 5 mol% lithiumperchlorate (LiClO 4 ) as a Lewis acid (Scheme 73). 191

PMHS-Zinc(II)triflate

In 2010, S. Enthaler investigated the DRA of aldehydes in the presence of variety of amines, using PMHS being activated with Lewis acid. 203,204 Simple zinc(II) triflate [Zn(OTf) 2 ] (5 mol%) was applied as the hydrosilylation catalyst for the reduction of the in situ formed imine by condensation of an aldehyde with an amine (1 equiv.), in the presence of PMHS in THF at 60°C for 24h (scheme 78). Broad functional group tolerance was achieved, giving the corresponding amines in 58-97% isolated yield. Under these conditions acetophenone was not reduced. The easy synthetic procedure, high thermal stability and specific surface area gave DMC high importance as a catalyst in organic synthesis. 205 Since Lewis-acid catalysts have been demonstrated to be one of the best catalysts for RA as mentioned before, DMC would be ideal catalysts in this transformation, since they are considered to be heterogeneous water tolerant Lewis acids. 206 In 2016, H. Kim et al. proved the effectiveness of DMC in DRA of aldehydes and ketones. The group tested several metal combination of double metal cyanide, among which zinc and cobalt metal combination was found to be highly active in comparison with other metal combinations. Thus, Zn-Co-DMC catalyst was synthesized and used in the DRA of carbonyl groups. 207 For example, the DRA of cyclohexanone 173 with m-Scheme 88. DRA of aromatic aldehydes using [Rh(cod)Cl] 2 /TPPTS in the presence of NH 3 and H 2 . 227 Aliphatic aldehydes were also reductively aminated in similar conditions either with [Rh(cod)Cl] 2 /TPPTS or by using the bimetallic [Rh(cod)Cl] 2 /[Ir(cod)Cl] 2 catalyst at 145°C in toluene for 10h. In this case the corresponding amines were obtained in lower yields (45-47%), this is due to the formation of secondary amines as well as aldol condensation products in considerable amounts (Scheme 89). Scheme 89. DRA of aliphatic aldehydes using different catalytic systems in the presence of NH 3 and H 2 . 227 Although high selectivity and yields toward aromatic primary amines were achieved, high pressures and temperatures is one of the disadvantages of this reaction. On the other hand, the yields of aliphatic primary amines from aliphatic aldehydes were still poor.

Iridium Catalysts

In 2001, the group of X. Zhang developed a chiral ligand, f-Binaphane 225 (Figure 17), that has shown excellent reactivities and enantioselectivities for Ir-catalyzed asymmetric hydrogenation of acyclic imines (up to 99% ee). 228 Scheme 93. DRA of carbonyl compounds using PS-Pd-NHC in the presence of H 2 . 236 It is important to mention that the catalyst complex 228 was effectively recycled up to six consecutive cycles with maintenance of appreciable catalytic activity.

Palladium on Carbon

The DRA of carbonyl compounds with NH 3 and H 2 is an alternative route to produce primary amines in practical production. However, one-pot amination of carbonyl compounds with NH 3 generally suffers from a main issue that the chemoselectivity is relatively poor, as the initially-generated amines are more nucleophilic than ammonia itself, thus often resulting in a mixture of products of primary, secondary, and tertiary amines. 237 The first catalyzed amination of aldehydes or ketones using NH 2.12.2.4. Core-shell Fe@Pd/C catalyst In the effort to develop heterogeneous recyclable catalyst system for DRA using environmental-friendly molecular hydrogen, N. M. Patil and B. M. Bhanage reported core-shell Fe@Pd/C as a versatile catalyst for the DRA of carbonyl compounds with primary and secondary amines in aqueous reaction media. For example, cyclohexanone 173 was reductively aminated with morpholine 231 using 1 mol% of Fe@Pd/C catalyst, 30 bar of H 2 pressure at 80°C for 8h in 15 mL of water. The corresponding amine 232 was obtained in 92% isolated yield (Scheme 96). 247 Scheme 96. DRA of cyclohexanone with 239 using Fe@Pd/C in the presence of H 2 . 247 2.12.2.5. Supported Ru Catalyst In 2005, Bodis and co-workers used carbon supported group VIII noble metals (Pt, Pd, Rh and Ru) as catalysts for the DRA of butyraldehyde with NH 3 . It was found that Rh and Ru catalysts were active and selective in the production of primary amine under 50 bar of H 2 pressure, while Pt and Pd catalysts favored the secondary amine formation. 248 In 2015, X. Chen, S. Han and co-workers presented the DRA of aldehydes with NH 3 over Ru based catalysts. For example, n-heptaldehyde 233 was reductively aminated to 94% GC yield of 1-heptylamine 234 over Ru/γ-Al2O3 in the presence of gaseous NH 3 and H 2 pressure (Scheme 97). 249 A variety of aliphatic and aromatic aldehydes were reduced using this method. Scheme 97. DRA of 233 using Ru/γ-Al2O3 in the presence of H 2 and NH 3 . 249 Ru supported on θ-Al2O3 gave similar results. Other purely basic and relative acids supports were tested, however, only amphoteric supports showed good results.

Platinum Catalyst

In 2011, M. E. Domine and co-workers designed metal catalysts based on Pt and Pd nanoparticles supported on structured microporous Beta Zeolites and mesoporous MCM-41 materials, as well as specially designed γ-Al2O3 samples. 250 These metal/solid acid composites were applied as efficient catalysts under mild reaction conditions in the selective DRA of ketones to produce substituted amines and N-heterocycles. Pt/Al-Beta catalyst possess the best catalytic activity, with amine selectivity up to 95%. For example, cyclohexanone 173 was mixed with 1equiv. of piperidine 235 in the presence of 30-50 mg of solid catalyst under H 2 pressure of 5 bars at 100°C (Scheme 98). Scheme 98. DRA of 173 using Pt/Al-Beta catalyst in the presence of H 2 . 250 2.12.2.7. Palladium and Ruthenium black catalysts Another work was done using palladium and ruthenium by S. Yada and co-workers for the RA of acetophenone, (+)-camphor, and 5α-cholestan-3-one over Ru and Pd metals as well as their carbon supported catalysts. 251 Alcohols were obtained as by-products, but this was effectively depressed by adding ammonium chloride NH 4 Cl as an additive. 252 For example, when acetophenone 154 was reductively aminated with Pd black without any addtitive, the alcohol was the sole product. However, upon adding NH 4 Cl the corresponding amine α-phenylethylamine 155 was obtained with82% selectivity (Scheme 99). 251 Scheme 99. DRA of 154 using Pd black/NH 4 Cl system in the presence of H 2 and NH 3 . 251 Although of all these interesting results using molecular hydrogen, this reaction still has the limitation of requirement of high pressures and in some cases high temperatures.

2.13.Conclusion

Indeed, during the last decades several reductive amination protocols to synthesize amines from carbonyl compounds are present in literature.

The DRA using cyanoborohydrides and sodium triacetoxyborohydride, offers the advantages of simplicity, wide availability of substrates, mild reaction conditions, and tolerance to other functional groups. However, the former is highly toxic and generates The best result was obtained in the presence of 5 equiv. of the ammonium hypophosphite, in which the conversion of 154 was complete, and α-phenylethylamine 155 was obtained as the sole product assisted by GC (Table 15, entry 5). Moving up to 6 equiv. the mixture starts to turn thick with no conversion (Table 15, entry 6).

e. The effect of additives

Although optimal conditions were in hand, but we also investigated the effect of adding an additive in the reaction mixture according to Table 16. During the condensation step between NH 3 and ketone, H 2 O is released which can hinder the reaction by limiting the equilibrium between the starting material and the imine group. Therefore calcium hydride (CaH 2 ), a well-known desiccant, was added to react with water to form hydrogen thus increasing the reduction rate. However, results showed a decrease in the yield of 155 (70%) after 24h (Table 16, entry 1). MS were also tried as drying additives, however, only 56% of 155 was obtained (Table 16, entry 2).

GENERAL CONCLUSION AND PERSPECTIVES

The purpose of this work was to replace boron and aluminum hydrides by air-stable, easy-to-handle, less expensive and less toxic reducing agents, that are selective and compatible with other functional groups.

In the laboratory, hydrosiloxanes associated with different metals have been used for the reduction of a wide variety of organic functions.

Among the available reagents meeting these criteria, sodium hypophosphite, calcium and magnesium hydrides, which have been used in our laboratory for the reduction of ketones to alcohols and alkanes, as well as in reductive amination and reductive alkylation reactions.

Based on these results, respecting the principles of green chemistry, such as the minimization of waste, the use of renewable materials and catalysts, my thesis project focuses on the study of new reducing systems based on hypophosphites in order to reduce new organic functions.

Taking the advantage of solubility of hypophosphites in water, the reduction of nitriles to aldehydes using calcium hypophosphite was carried out in two-phase water/ethanol medium, in the presence of Ca(OAc) 2 and Ni(OAc) 2 at 100°C (Scheme 105). The reaction allowed the reduction of aromatic nitriles to the corresponding aldehydes with good yields and good selectivities.

The reduction of aromatic nitriles catalyzed by different catalysts led to different products at the end of the reaction in each case. In the presence of 10 wt.% Pd/C, primary amine was the sole product. Thus, the determining factor for the selectivity towards aldehyde or amine is the type of catalyst. Variety of aromatic nitriles were reduced with the following optimized conditions: calcium hypophosphite (2,5 equiv.), 10 wt.% Pd/C (2,5 mol%), K 2 CO 3 (40 mol%) at 100°C in aqueous medium (Scheme 105). The reaction is generally