Recent developments in the reduction of aromatic and aliphatic nitro

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Recent developments in the reduction of aromatic and aliphatic nitro compounds to amines. Manuel Orlandi, Davide Brenna, Reentje Harms, Sonja Jost, and Maurizio Benaglia Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00205 • Publication Date (Web): 21 Jul 2016 Downloaded from http://pubs.acs.org on December 19, 2017

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Organic Process Research & Development

Recent developments in the reduction of aromatic and aliphatic nitro compounds to amines. Manuel Orlandi,a Davide Brenna,a Reentje Harms,b Sonja Jost,b Maurizio Benaglia,a* a

Dipartimento di Chimica, Università degli Studi di Milano, via Golgi 19, 20133 Milano, Italy;

Tel. +390250314171; Fax: +390250314159; e mail: [email protected] b

DexLeChem GmbH, c/o CoLaborator, Building S141, Muellerstr. 178, 13353 Berlin, Germany.

Tel. +493046065383 E-mail: [email protected]

ACS Paragon Plus Environment


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Abstract: The reduction of the nitro group represents a powerful and widely used transformation that allows to introducing an amino group in the molecule. New synthetic strategies for complex functionalized molecular architectures are deeply needed, including highly efficient and selective nitro reduction methods, tolerant of a diverse array of functional moieties and protecting groups. Since chiral amino groups are ubiquitous in a variety of bioactive molecules such as alkaloids, natural products, drugs and medical agents, the development of reliable catalytic methodologies for the nitro group reduction is attracting an increasing interest also in the preparation of enantiomerically pure amines. In this context, the modern reduction methods should be chemoselective and respectful of the stereochemical integrity of the stereogenic elements of the molecule. The review will offer an overview of the different possible methodologies available for this fundamental transformation, with a special attention on the most recent contributions in the field, especially in the last ten years: hydrogenations, metal dissolving and hydride transfer reductions, catalytic transfer hydrogenations and metal-free reductions. The main advantages or limitations for the proposed methods will be briefly discussed, highlighting in some cases the most important features of the presented reduction methodologies from an industrial point of view. Keywords: nitro reduction, hydrogenation, chemoselectivity, trichlorosilane, amines.



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Contents

1. Introduction 2. Hydrogenation with H2 2.1 Heterogeneous catalytic systems 2.2. Homogeneous catalytic systems 2.3 Water/gas shift reactions 3. Catalytic transfer hydrogenation 4. Hydride transfer reductions 5. Metal dissolving reductions 6. Metal-free reduction methods 7. Outlook and perspective


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1. Introduction The formation of amines through the reduction of nitro-groups represents a fundamental transformation in organic chemistry which is frequently used in the synthesis of pharmaceuticals, agrochemicals, dye intermediates and pigments as well as for a variety of fine and specialty chemicals.1 The most simple aromatic amine, aniline, was formerly produced on industrial scale by treating nitrobenzene with iron in the presence of small amounts of hydrochloric acid. This process known as Béchamp reduction for the synthesis of aniline and iron oxide pigments is today mainly replaced by the catalytic hydrogenation of nitrobenzene. Analogously, considering other important compounds for polyurethane chemistry as for example 2,4 and 2,6 diamino benzenes, these isocyanate precursors are obtained through the hydrogenation of the corresponding dinitrotoluenes.2 A wide variety of highly functionalized and chiral nitro derivatives which can act as immediate precursors for the corresponding chiral amines are further accessible via several synthetic routes. Nitro olefins can serve as Michael acceptors in conjugate addition or Morita-Baylis-Hillman reactions and as dienophiles in Diels-Alder reactions.3,4,5,6,7,8 Asymmetric examples of conjugate addition reactions followed by nitro reduction comprise inter alia the synthesis of the pyrrolidine core of the Endothelin-A Antagonist ABT-546 and the pyrrolidinone comprising Rolipram, an inhibitor of (PDE)IV, a cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase, active in the treatment of depression.9,10 Nitroalkanes provide further a source for stabilized carbanion nucleophiles which can be used in the construction of new carbon-carbon bonds with haloalkanes, aldehydes (Henry reaction) and Michael acceptors.11,12 Besides the classic Henry reaction, several additional methods emerged for the preparation of nitro olefins using homogeneous or heterogeneous catalysis. The direct nitration of olefinic C-H bonds, the ipso-nitration of aryl α,β-unsaturated carboxylic acids or vinylboronic acids and the palladium-catalyzed multidehydrogenative cross-coupling reactions of (hetero-)arenes with nitroethane for the synthesis of β-(hetero-)aryl nitroethylenes are emphasized in this context.13 A still rare example for a stereoselective Henry reaction in API synthesis was also recently investigated targeting building blocks for the antitumor agent bengamide, but catalyst loading and diastereoselectivity still leave room for further optimization in this system.14 The enantioselective synthesis of the β-adrenoceptor agonist (-)-denopamine was successfully achieved, exploiting a catalytic, asymmetric nitro-aldol reaction and subsequent hydrogenation of the nitro group. Although the catalytic Henry reaction proceeds in this case with a modest turnover number, yield and enantioselectivity are already quite promising for practical application.15 The introduction of an amino-group offers a well-known plethora of further bond forming opportunities and only a few selected examples are here remembered. Since the discovery of the transformation of aromatic amines to diazonium salts as early as 1858 by Griess, several prominent name reactions



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evolved over time around these valuable intermediates. These salts present a useful starting point for various stoichiometric and/or catalytic carbon-halogen, carbon-oxygen, carbon-sulfur, carboncarbon or carbon-boron bond forming reactions.16 The well-known Buchwald-Hartwig cross coupling protocols further allow the inter- or intramolecular Pd-catalyzed formation of carbon-nitrogen bonds between aryl halides or trifluoromethanesulfonates and 1° or 2° aliphatic or aromatic amines, imides and amides.17 New synthetic strategies for complex functionalized molecular architectures may be designed in the future, based on novel highly chemoselective nitro reduction methods which need to tolerate the presence of a diverse array of functional moieties and protecting groups. Additionally, innovative catalytic reduction protocols are further desired from the environmental point of view. The present review will focus only on the most recent developments of this widely used and long time known transformation.

2. Hydrogenation Molecular hydrogen not only is a bright fuel of the future, but also is widely used today in fundamental chemical reactions.18 One of the most relevant industrial transformation that involves the use of hydrogen is the reduction of nitro groups. The hydrogenation of aromatic nitro compounds is in many cases the method of choice for the production of the corresponding aniline derivatives.

19,20,21

The reduction of nitroarenes, in the absence of substituents that are “hydrogen sensitive”, is carried out with catalytic methodologies on industrial scale. The most relevant problem in the use of heterogeneous catalysts for the nitro reduction is the presence of other reducible functionalities in the molecules.22 In the last decades, the research in this field focused on the development of catalysts for highly chemoselective hydrogenations of nitro groups.

2.1 Heterogeneous catalytic systems In this paragraph a large number of catalysts involving the use of nanoparticles will be described; .the reactivity of those systems is strongly influenced by different parameters, such as size, shape and nature of the support of the nanoparticles. However, since the focus of this review is on the analysis and the comparison of the performances of different systems in the nitro reduction, the morphological aspects of the catalytic particles will be not discussed in detail. One interesting example of selective catalytic reduction of nitro compounds was reported in 2004 by Higginson et al (Scheme 1).23 The hydrogenation of three different pharmaceutical nitro-containing molecules was performed using High-Throughput Experimentation (HTE) methods. The authors decided to use this strategy because the selectivity in these reactions is influenced by various factors: the catalyst, the presence of additives and the reaction conditions. In order to find the best ACS Paragon Plus Environment

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reaction setting for every substrate they performed a huge number of tests. After the screening, the reduction of nitro groups in all the compounds was achieved with excellent chemoselectivity. Reaction selectivity is a common issues in the hydrogenation of nitro compounds bearing other functional groups such as halogens and residues that can go under hydrogenolysis. Higginson reported the selective reduction of the following compounds: A, that was reduced without any loss in optical purity; B, bearing a benzydryl amine which was well tolerated and C, which was reduced without any trace of dehalogenation. Scheme 1. Chemoselective heterogeneous catalytic hydrogenation. X

CO2H

2

R

R

HN Ph

N N

1

R

NO2

5% Pt/C, EtOAc/H2O y(%) 68-90

A

N

O2N

Ph R 5% Pd/BaSO4, MeOH y(%) not reported

O2N

B

R

Cl N

N

5% Ir/C, MgO, THF y(%) 99

C

They run 264 reactions in the initial screening, using multiple High-Pressure Units and a Quick Screen workstation. To find the best catalyst and the best reaction parameters for every substrate, by reducing all the side reactions, the authors have screened sixteen different heterogeneous catalysts, five different solvents and three different additives in all the possible combinations. Only two catalysts (Pd/C, Pd/Al2O3) were efficient for the reduction of all the three compounds. Moreover, no solvents were compatible with all the reactions, and any additive was not general. The authors also reported a scale up for the preparation of compound A: 35 grams of nitro compound were reduced without any loss in selectivity. This intensive screening required to find the experimental set up of choice shows that a general heterogeneous catalyst able to selectively reduce the nitro group is still needed. Indeed, different substrates with different hydrogen sensitive groups very often require extended optimization studies in order to find the correct reaction conditions. An example of a large scale nitro reduction was reported by Gallagher and co-workers,24 during the study for the preparation of a drug candidate with several sensitive functional groups (Scheme 2).



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Scheme 2. Chemoselective heterogeneous catalytic hydrogenation.

After the screening of different suitable reduction methods, they found that some stoichiometric protocols, efficiently employed on a laboratory scale, suffered from several problems during the scale up process. In particular, during the nitro reduction the formation of different byproducts was observed, the most abundant being the hydroxylamine. Thus, the only efficient methodology on a multi-kilogram scale was found to be the use of commercially available Ni catalyst under hydrogenating conditions (see Scheme 2). A very active research field in the last decades was the preparation of different supported nanoparticles in order to improve the reactivity, the recoverability and the selectivity of heterogenous catalysts. Nanosized materials feature unique properties: the high surface to volume ratio of nanoparticles compared to bulkier materials generally results in an extremely high catalytic activity and often improved selectivity. One of the first examples of selective and efficient catalyst based on nanoparticles for the nitro reduction, was reported by Corma and Serna, in 2006.25 Gold nanoparticles supported on TiO2, of Fe2O3, catalyzed the chemoselective hydrogenations of functionalized nitroarenes under very mild conditions and without the accumulation of dangerous hydroxylamines. The system is compatible with alkenes, aldehydes, nitriles and amides. In 200726 the authors, combining kinetics, in situ IR spectroscopy and quantum chemical calculations, clarified the reaction mechanism. Also the cooperation between the support and the gold catalyst was rationalized and the improved selectivity of the system was explained. In particular, the nitro group is coordinated to the support of the gold nanoparticles. Such coordination keeps the nitro group closer to the active metal, thus increasing the selectivity of the catalyst. In 2008 Katam and co-workers27 developed an efficient heterogeneous catalysts, based on nanocrystalline Magnesium Oxide-stabilized Palladium(0), prepared from commercial available NAPMg-PdCl4 in only two steps and quantitative yield. This catalyst was successfully applied in the reduction of aliphatic and aromatic nitro groups under mild conditions. The catalyst was recovered quantitatively by simple filtration and was reused for several cycles without any loss in the catalytic


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activity. Halogens, alkoxy-groups, aldehydes, ketones were tolerated and the yields were always very high (Scheme 3). Scheme 3: Nanocrystalline Mg oxide Pd(0) stabilized nitro reduction

Almost simultaneously28 a different system based on Platinum and Palladium nanoparticles supported on carbon nanofibers (CNF’s) was developed and used in the reductions of nitroarenes. The nanosized platinum particles dispersed on plateled-type CNF were found to be very efficient in the selective reductions of functionalized nitroarenes. Halogen-substituted nitroarenes were reduced with excellent yields and a very good selectivity. This catalyst was also able to selectively reduce nitro groups in the presence of terminal alkenes, nitriles, amides, esters and benzylic alcohols. The selectivity of the catalyst is strongly related to the orientation of the graphite layers of the support: the perpendicular( CNF-P) and the stacked obliquely ones (CNF-H) afforded the best results. In 2009 Shi reported the preparation of a catalyst for heterogeneous hydrogenation of nitrobenzenes over recyclable Pd(0) nanoparticles stabilized by polyphenol-grafted collagen fibers.29 This type of catalyst showed a good activity in the reduction of nitroarenes compared to the corresponding catalyst supported on inorganic materials; however, a quite poor selectivity was observed and the reduction of 4-nitrochlorobenzene occurs only with 48% yield. In 2011, in a very interesting study by Kasparian et al.,30 a chemoselective reduction of nitro groups in the presence of activated heteroaryl halides was achieved via a catalytic hydrogenation with a commercially available sulfided platinum catalyst. Using this catalyst the authors were able to avoid the test of different additives in order to prevent the dealogenation of the pyridine ring. The high chemoselectivity of the catalyst, according to the author, is due to the poisoning activity of the sulfur that hampers the more active sites of the platinum surface. Notably, only with the iodide derivatives, the formation dangerous hydroxylamine intermediate was observed (Scheme 4).



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Scheme 4. Sulfided platinum as catalyst for hydrogenation of heteroaryl nitro compounds.

In 2011 many catalysts based on metallic nanoparticles have been reported. Nishihara et al.31 developed an efficient catalyst for the reduction of nitro groups based on dendrimer-stabilized Fe/Rh nanoparticles. The dendrimer matrices serve as supporting material to prevent nanoparticles from aggregating and to provide a desired chemical interface between the nanoparticles and the reaction media. Indeed, they developed a more efficient catalyst system for the hydrogenation of simple nitroarenes under relatively mild conditions, in comparison to previously reported Rh/dendrimer nanoparticles.32 Then, Pagliaro et al.,33 reported the synthesis of a new series of platinum catalysts able to catalyze the selective reduction of nitroarenes. The catalyst is nanostructured platinum (0) entrapped within an organosilica matrix. The trapped nanoparticles are stable and proved to be efficient in the nitro reduction, affording the product generally in yields; the catalysts could be reused up to seven times in the standard reaction conditions without loss in chemical activity. The catalyst also shows an excellent chemoselectivity: indeed, the nitro group can be selectively reduced under mild conditions when other reducible groups such as carbonyls, amides, and esters are present in the molecule. Also the presence of halogens on the aromatic ring is well tolerated; for para substitution the selectivity is >99% with F, 87% for Cl, 80% for Br but only 50% for I. However, the presence of a cyano group is not tolerated In 2011 a new supported catalyst on Nitrogen-doped Carbon Nanofibers, was used as efficient and chemoselective promoter for hydrogenation of nitroarenes by Naghashima and co-workers34 The addition of nitrogen containing compounds as a catalyst poison, shows a reduction in the reaction rate, but also suppresses possible side reactions, and leads to more chemoselective nitro reduction. This catalyst shows a very good selectivity: the transformation of the aromatic nitro group occurs in the presence of halogens, cyano, esters, conjugated double bonds, and benzylic substituents without any erosion in chemical yields.


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An impressive breakthrough was done by Beller and co-workers in 2013.35 They reported an iron catalyst based on Fe2O3 which is synthesized by the controlled pyrolysis of iron-phenanthroline (FePhen) complexes on carbon. The scope of the catalyzed hydrogenation is wide; indeed, a large number of nitroarenes were reduced in good to excellent yields (86-99%) with excellent chemoselectivity, even when bearing sensitive groups such as: carbonyls, halogens, carboxylic derivatives, solfones and carbon-carbon multiple bonds. Furthermore, in order to demonstrate the utility of the method the authors performed a scale up to a gram scale for some appealing substrates. During the synthesis of the catalyst, by means of the pyrolysis of the Fe-Phen complexes on the carbon support, the formation of FeNX centers occurs. Those centers are formed only at 800 °C and they govern the activity of the catalyst, in fact the material supported on carbon shows no activity without the pyrolysis treatment. Moreover, the size of the nanoparticle seems to be important with respect to the generated active centers.



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2.2.

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Homogeneous catalytic systems

In this chapter, homogeneously catalyzed nitro reductions by the use of molecular H2 as reducing agent are discussed. Lately, he research has specially focused on catalysts working in aqueous biphasic systems. The chemoselective hydrogenation of substituted nitroarenes using a water soluble iron complex (FeSO47H2O + EDTANa2) was reported by Chaudhari et al in 2004. 36 In this case, the reactions are performed in a biphasic media, while neat substrate and product respectively forms a water immiscible organic phase. Exemplarily, 4-Nitrochlorobenzene is reduced in very good yield (96.2%) whereas the reduction method is tolerating also amine, keto, and cyano groups. For some substrates (p-nitro anisole, p-nitrobenzoic acid and p-nitrobenzyl nitrile) lower selectivities were observed, assuming formation of azo and hydrazo derivatives through high reaction temperatures (150 °C). The aqueous phase was recycled five times (overall TON 6665), without observing any loss in the catalyst activity and selectivity of aniline. The use of water as solvent is very useful for the catalyst recovering and is considered also safer for temperature control when running exothermic reactions. Shi and co-workers37 synthesized Pd nanoparticles by the use of bayberry tannin (BT). It’s an amphiphilic water-soluble polymer, that allows for efficient mass transfer of hydrophobic nitro arenes dissolved in ethyl acetate- to the catalyst in the aqueous phase due to a decrease of the interfacial tension (comparable to a surfactant). Reactions were carried out at 20 bar and 50 °C. The polymeric catalyst was reused three times by simple extraction of the organic phase without loss in activity (TOFs: 300-360 h-1). Meijboom et al.38 developed an eco-friendly process by the use of RuCl3 and Phenanthroline, where the catalyst was prepared by stirring precatalyst and ligand in an ethanolic aqueous solution overnight. The reduction process has been optimized by a screening of parameters like metal to ligand ratio, temperature, pressure and solvents. Thereby, the best solvent was found to be water in the reduction of Nitrobenzene at 160°C and 27.5 bar. The reactions work nicely (TOFs approx. 100 h-1) for differently substituted Nitrobenzenes, like methoxy-derivatives (Y=98%),alcoxy substituted compounds (4-OH, 99% yield, as well as 3,4-OH, 98% yield), carboxylic acid (Y=84%, Sel=99%) and aldehyde (99% yield). Beller et al.39 developed a thermally stable ligand P[PhPPh2]3 that has been employed, after catalyst formation with Fe(BF4)26H2O (in situ), in the reduction of Nitroarenes at 20 bar and 120°C (Scheme 5). Different functional groups are tolerated such as halogens in meta and para positions, terminal and internal double bonds, esters, ketones and ethers. Also the reduction of nitro group on heterocyclic substrates have been investigated; in this case one additional equiv. of TFA was needed to prevent coordination of the heterocyclic N atom to the catalyst. Interestingly, azobenzenes were not observed ACS Paragon Plus Environment

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but the catalytic hydrogenation of diazobenzene afforded full conversion assuming that both pathways (direct and via coupling of hydroxylamine and nitrosobenzene) can be plausible. Scheme 5. Iron-phosphine complexes mediated hydrogenation of nitroarenes.

2.3 Water/gas shift reaction Herein, we present some recent papers related to the water/gas shift reaction in the nitro reduction illustrated in Scheme 6, including also some discussion on the proposed mechanisms which are not fully understood and are still under study. Scheme 6. Water/Gas Shift reaction (WGS) and reaction principle for NO2 reduction Ar-NO2 + 3CO + H2O ---- Ar-NH2 + 3CO2 In 1994 Nomura40 reported about the use of triruthenium dodecacarbonyl (Ru3(CO)12) in the presence of amine bases, like triethylamine or diisopropylamine, in the reduction of aromatic nitro derivatives. Typical reaction conditions and tested functional groups are shown in Scheme 7.

Scheme 7. WGS reaction and the reduction of nitroarenes with ruthenium catalysts.



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Herein, very high turnover number of 10000 were obtained by increasing the temperature and pressure from 150°C, 20 bar (TON 1500) to 180°C and 50 bar. Interestingly, in the reaction of benzonitrile (under reduction conditions) no production of CO2 and H2 was observed. It’s assumed that the reduction of aromatic Nitro compounds is not followed by hydrogenation with H2 from the WGSR but by either decarboxylation of isocyanates in water or intramolecular hydrogen transfer. When the reactions were carried out in not aqueous solutions, the byproducts nitrosobenzene and azobenzene were detected. The reduction of nitrobenzene using [Rh(CO)4]- (either as a K+, Cs+ or (PPh3)2N+ salt) in absence of any other ligands was investigated by Cenini and Ragaini in water. 41 The best Rh salt seems to be the (PPh3)2N+. By using a catalyst amount of 0.1 mol%, aniline is obtained from nitrobenzene with 95% yield and without detectable amount of any byproducts (99%. In the reduction of nitro benzene, TOFs of 3900 h-1 have been obtained on 250 mmol scale (0.42 mol/l), and even the reused catalyst showed an excellent performance in three consecutive runs. When the reductions were run without water, no conversion could be observed; the reduction under molecular hydrogen (1 bar) in ethanol/water showed also no conversion, what is contradictory to “real” WGSR. Very recently, the Beller group44 developed and investigated cobalt oxide nanoparticles, encapsulated on carbon and doped with nitrogen. This inexpensive and earth abundant catalyst could be reused after centrifugation, washing and drying after each run. The reductions have been ACS Paragon Plus Environment

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performed on gram scale (0.24 mol/l) in THF/water (10:1 v/v) with a broad tolerance of functional groups like halogens (Br, I, Cl) and ester with very high selectivities for the corresponding amines. In Table 1 some metal catalyzed nitro reduction method by hydrogenation are reported and compared. The table summarizes, among others, for each method (i) the reaction conditions and results (solvent, temperature, and yield), (ii) possible substrates (aliphatic, aromatic, both), (iii) the functional group tolerance with respect to other reducible moieties, and (iv) whether the reducing agent is commercially available. Table 1. Comparison between some metal catalyzed nitro reductions with hydrogen NO2a

H2 source

Catalyst

mol%

Solv.

t (h)

T (°C)

P (atm)

H2 (g)

Au/TiO2

0.23-1.14

Tol.

0.5-6

100-140

9-25

x

H2 (g)

Au/Fe2O3

0.39-4.30

Tol.

1-9.5

100-140

10-25

x

H2 (g)

Pd-MgO

1.48

THF

1-3

RT

nde

x

H2 (g)

Pd/CNF-P

0.001

AcOEt

4

RT

10

x

H2 (g)

Pd(0)-EGCG0.2-CF

0.12

EtOH

3-4

37

10

x

f

Ar.

Functional group toleranceb

Al. C=O CO2R CN x

x

x

x

x

x

x

x

Pt(S)/C

0.1

THF

8-42

37

3

x

H2 (g)

Rh32Fe28 TPP-DPA

0.3

MeOH

10

RT

1

x

H2 (g)

Pt/N-CNF-H

1-3

AcOEt

6

RT

7-10

x

x

H2 (g)

FeSO4 ·7H2O EDTANa2

0.07

H2O

2-9

150

27

x

x

0.2

H2O

160

27

x

x

2-5

t-AmOH

120

20

x

x

H2 (g) H2 (g)

RuCl3+ Phen

[FeF(L2)][BF4] h

WGSR

g

2

Ru3(CO)12

0.03

EtOH/H2O

2

150

20

x

WGSR

[Rh(CO)4] (PPh3)2N

0.1

H2O

1.5

200

60-80

x

WGSRh

Au/Fe(OH)3

1.5g

EGEEi/H2O

1.5-6

100

15

x

h

h

WGSR

Au/TiO2

1

EtOH/H2O

1-5

25

1-5

x

WGSR

Co3O4+Phenj@C

2

THF/H2O

24

125

30+30k

x

x

x

H2 (g)

j

x

x x

Av.

Hal OBn C=C C≡C

x

Cc, 8-9

x

nd 8-9

x

x

x

N

12

C

13

N

14

N

15 19

C

Cl

C x

Br, Cl

Cl, Br

x

x

x

x

x

x

x

x

x

x

a

11

Cl

x x

N

x

x

x

10

x

x

x

N

x

x

x

Ref

x

x

x

d

x

N

21

C

23

C

24

N

25

c

N

26

N

44

Suitability for the reduction of aromatic (Ar) or aliphatic (Al) nitro groups. bx = tolerated; the absence of signs stands for unavailable information or for poor tolerance. cSupplied by the World Gold Council. dN/C = not (N) or commercially (C) available; eThe reduction was performed using a hydrogen balloon. fThis catalyst was used for the reduction of heteroaromatic nitro compounds. hWGSR= water gas shift reaction. i2-Ethoxyethanol. g wt.-%, jPhenanthroline, k 30 bar CO and 30 bar N2



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3. Catalytic transfer hydrogenation

Transfer hydrogenations, unlike conventional hydrogenation methods, does not require any elaborate experimental set-up of high-pressure reactors. The most commonly used reagents for the hydrogen transfer are HCOOH, HCOOH/TEA, HCOONH4, iPrOH, NH2NH2H2O. An efficient, easily-handled procedure in the catalytic transfer reduction of nitroarenes with high chemoselectivities and yields, was reported by Cao and co-workers in 2011.45 The authors use TiO2supported gold nanoparticles in combination with 5 equiv. HCOONH4 as hydrogen source. Thereby, the heterogeneous catalyst is the active species (the hot filtration test confirmed no conversion and in addition no Au was detected by ICP) with a loading of 1 mol% Au. Within 3 hours complete conversion of the starting material nitrobenzene into the desired product in ethanol as solvent, at RT, was achieved. The reduction was also performed in neat water with prolonged reaction time (12 h) but same high selectivity of 99%. Other tolerated functional groups include halide (-F and -Cl yields 90-99%), olefin (98%), nitrile (65%) (in a very recent paper of the same author with formic acid as hydrogen source, a yield of over 99% is obtained),46 methoxy (94%), aldehyde (90%), benzyl alcohol (90%), ketone (99%), ester (98%); dinitrobenzenes were reduced regioselectively (isolated yields 7187%). In Cao’s very recent paper46 aliphatic nitro groups reduction have been also accomplished very efficient: ethylamine, cyclohexylamine and tertbutylamine were obtained in >99% yields, within 4 h in toluene at 60°C, on a 0.2 mol/l scale. Also heteroaromatics were successfully reduced (6Nitroquinoline: yield 99% within 3h). In addition, 7 equiv. HCOONH4 serves as formylating source when the reaction is carried out in the aprotic solvent acetonitrile, leading to formanilides as products. Also the group of Baskaran and co-workers47 has reported the direct synthesis of formanilides from nitro compounds using 10 equiv. HCOONH4 and 10% Pd/C. Gawande et al.48 examined and synthesized Ag@Ni core shell nanocatalyst for the transfer hydrogenation with therefore typical procedure: isopropanol as hydrogen donor and KOH as base. The catalyst was reused 8 times by simple separation with a magnet, with yields approximately equal to 90% for 4-hydroxyamino benzene. Several mono substituted nitro compounds bearing halogen, phenolic alcohol, nitrile, ester or ketone were reduced in high yields (>90%) at 80°C within 3 hours. Beller and co-workers reported about different transfer hydrogenation methods for reduction of nitro compounds. In this contribution the authors used an homogeneous iron complex prepared in situ using Fe(BF4)26 H2O and the tetraphos ligand shown in Scheme 8. 49


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Scheme 8. Iron-phosphine catalyzed transfer hydrogenation of nitroarenes in EtOH

Different reducing agents (e.g. CH3COOH, HCOONa), have been tested but only formic acid was suitable for this transformation. Even the very well-known combination of HCOOH/Et3N gave no conversion (78% to 99%. Furthermore, no hydroxylamines (99%, yield >99%). Singh and co-workers51 reported 2011 about iron phthalocyanine (Pc) catalyzed transfer reduction of nitro arenes in the green solvent mixture ethanol and water. Thereby, the catalytic species is stable towards moisture and temperature. The hydrogen source is NH2NH2H2O (2 equiv), a green reagent despite its toxicity, since in principle after hydrogen transfer, the only byproduct is water and molecular nitrogen. The active catalysts investigated are FeSO47H2O, K4[Fe(CN)6]3H2O and FePc/FeSO47H2O, all of them are very effective in the reduction of 4-nitrobenzonitrile, with excellent yields (>99%) and selectivity (>99%). Furthermore, this synthetic protocol also tolerates different functional groups e.g. halides, acids, esters, keto, hydroxy, benzylic moieties; dinitrobenzenes (o, p, m) showed very high regioselectivity (99%); 3-Nitrostyrene showed either no reaction or complete conversion with bad selectivity depending on the used Fe precursor.



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Kappe et al.52 reported about iron-based transfer hydrogenation of Nitroarenes in a microwave assisted continuous flow reactor at 150-170°C. In this approach different Fe precursor were investigated like Fe(acac)3, FeCl24H2O, FeCl36H2O and Fe(OAc)2 , showing that all of them are efficient. The reducing agent here is hydrate hydrazine (1.8 equiv.) and during catalysis in MeOH or EtOH, Fe3O4 nanocrystals are formed in situ. Thereby it was shown that commercially available Fe3O4 was not active. Furthermore, the in situ generated Fe3O4 nanoparticles (magnetite) could be reused several times. Different substrates were successfully reduced (Yields≥95%) while retaining the functional groups: halogens, alcohols, ethers, amides, esters and amines. Heterocyclic compounds such as quinolines, indoles and pyridines showed also excellent results with yields above 97% for the corresponding amines. The hydrazine approach as reducing agent cannot be used for nitro substrates containing ketone or aldehyde functions because of formation of hydrazone, and also olefinic double bonds will be reduced by the diimide intermediate. The preparation of the intermediate of the fungicide Boscalide was achieved on 0.5 mol/l scale. In general very high TOFs were obtained (3000-12000 h-1) because of short residence times by applying continuous flow. A recent application of this methodology in the synthesis of other industrially relevant nitroarenes was reported also by Kappe and co-workers.53 The nitro reduction of the important intermediates for the synthesis of the muscle relaxant Tizanidine, and for the synthesis of the antibiotic Linezolid have been investigated (Scheme 9). Whereas, the reduction of the Tizanidine intermediate worked excellent (yield 98%) with the standard reaction procedure, the reduction of the Linezolid intermediate needed higher catalyst concentration (3 mol %). In this contribution even aliphatic nitro compounds (linear and branched as well as cyclic, all of them without further functionalities) have been reduced with high conv. >99% and yields ≥96%. Scheme 9. Synthetic applications of Iron nanocrystals as catalysts for the reduction of nitro groups in microwave assisted flow.


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4. Hydride transfer reductions The reductions highlighted herein are characterized by a hydride transfer that can occur either by direct reaction via a catalyst or demands additives. Aluminum hydride is a very classical agent for the direct reduction of nitro groups to aliphatic amines and aromatic azo compounds.54 Other classical reagents as boron hydrides55 and silanes are not reactive to nitro groups due to the less polarized metalloid hydrogen and thus further bond activation is needed. Among the repertoire of available hydride reducing agents, sodium borohydride, organo silanes (RnSiH4-n, n = 1,2,3) and siloxanes are the most desirable compounds due to their inexpensiveness and their lower reducing power that tolerates other “reducible” functional and halide groups. The sodium borohydride mediated reduction of nitro groups is known to be efficiently enhanced by supported nickel (Raney, TiO2, SiO2) Pd/C, and manifold (main and transition) metal salts e.g. CoCl2, FeCl2, SnCl2, CuSO4, Cu(acac)2, Ni(OAc)2, NiCl2, BiCl3 and SbCl3.56 Particularly gold and other coinage and platinum group nanoparticles for the mild NaBH4-activation were increasingly elaborated in the recent years.57 Mazaheri et al. reported that nickel nanoparticles immobilized on zeolites acts as selective catalyst in presence of sodium borohydride for the reduction of nitrobenzene and other aryl nitro derivates which bear functional groups e.g. halogens (Cl, Br, I) in para and meta position, amines, phenolic and benzylic OH. Using a catalyst loading of about 4.25 mol% nickel complete conversion is obtained within 1 to 65 min at r.t. The catalyst was reused 6 times with decreasing yields from 97 to 91% only and Ni leaching of 1%.58 Nickel is also catalytically very active when incorporated as tetrachloronickelate counter ion in an ionic liquid (IL) as [C6(mpy)2][NiCl4]22-.59 The reduction of p-nitrophenol (8 equiv. NaBH4 in presence of 5 mol% IL) to aminophenol was carried out in aqueous solution obtaining 85% yield after 5 min at r.t. The catalyst tolerates several phenols and amines, however, halogen nitrobenzenes react much slower (4 h) and particularly p-chloro and m-iodo nitrobenzene give lower yields of 55 and 65%, respectively. Moreover, C6(mpy)2][NiCl4]22- could be successfully immobilized in polyvinylidene fluoride (PVDF) fiber by electrospinning. The heterogenization enabled a reusability and stability study which was examined on 4-nitrophenol and 0.3 g nanofiber that contained 15 mg (about 3 mol%) C6(mpy)2][NiCl4]22-. Recently, a metal free method for the activation of sodium borohydride was reported by Zeynizadeh et al. Apparently the reagents are activated upon addition of 400 mg/mmol charcoal and the nitroarene is converted to the aniline in very good to excellent yields at 60 °C.60 Historically, the first process applying silanes as hydride source was developed 1957 by Wackerchemie Burghausen, Germany, to avoid the use of aluminum hydrides which were rather laborious to handle on large scale.61

Therefore, polymethylhydrosiloxane (PMHS) was used in



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presence of a hydrogen donor e.g. ethanol and 2–5 mol% (relative to PMHS) dibutyltin dilaurate to reduce carbonyl and nitro compounds to alcohols and amines. PMHS has certain advantages as it is cheap, bench stable and can be produced literally by any silicone manufacturer. In a follow-up work, Dow Corning Corp. published 1973 the catalytic activity of Pd/C and PMHS in ethanol at 40–60°C for the reduction of nitrobenzene to aniline.62 Despite the clear industrial interest, a comprehensive application of silane/siloxane hydride sources started in 1996 when Brinkman and Miles reported in a systematic study the reduction of nitroarenes by means of triethylsilane and Wilkinson’s catalyst (Scheme 10a).63 More recent protocols for silane activation use Pd(OAc)2 (5 mol%) as catalyst.64 Both PHMS and triethylsilane were elaborated as very suitable hydride sources for para- and ortho-toluidine formation in 30 min at r.t. (94% yield, see Scheme 10a). Furthermore, additional amino, hydroxyl, fluoride and nitrile groups are well tolerated in all three possible positions on the phenyl ring, although p-nitrile nitrobenzene reduction results only in 77% yield. Acyls, methyl ethers, even t-butyldimethylsilylether (TBS) are well tolerated, but thioethers deactivate the Pd-catalysts and the yield drops to 10%. Moderate selectivity is observed for dinitrobenzene, p-nitrobenzaldehyde, and 2-nitrothiophene. Addition of fluoride mineral salt (200 mol%, e.g. LiF, NaF, KF, CsF) accelerated the reaction rate drastically due to further silicon activation, and addition of potassium fluoride was found to be optimal. Many nitroarene derivatives were tested and the respective anilines were obtained in good to excellent yields. Unfortunately, this methodology is not suitable for aliphatic nitro compounds because the reaction stops at the hydroxylamine intermediate which is then observed as main product in 31–89% yield (Scheme 10b). Scheme 10. Activation of silane and siloxanes by means of Pd and Rh catalysts.


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Another transition metal catalysts with distinct hydride transfer reactivity are rhenium(V) oxides (ReXO2(PPh3)2; X = halogen). They are well established as hydrosilylation catalysts for a wide range of aldehydes and ketones using particularly Me2PhSiH and typically 60–80 °C reaction temperature. More recently, Fernandes and co-workers showed that oxo-rhenium complexes can also transfer hydrides from silanes to nitrogroups.65 In that study Me2PhSiH, PhSiH3, Et3SiH and PMHS have all been reported to be excellent reducing agents at 110 °C in the presence of both ReIO2(PPh3)2 or ReOCl3(PPh3)2 catalysts. Despite more harsh reaction conditions, satisfactory functional group tolerance is observed; esters are not reduced, but other carbonyls and olefins. At optimized reaction conditions (Me2PhSiH (3.6 eq), ReIO2(PPh3)2 (5 mol%) in toluene at 110°C) a plethora of nitroarenes was converted to the amine in yields between 50 and 98% (Scheme 11a). In contrast, aliphatic of 2phenylnitro ethane gave the nitrile in 38% isolated yield (Scheme 11b). Noteworthy, the method is very suitable for halogen substituted nitroaryls, and the 4-iodo anilines are obtained in good yields with both catalysts (76–86% yield). The 4-fluoroanilines are obtained in excellent yields (about 97%) only if phenylsilane is used instead of dimethylphenylsilane. Scheme 11. Activation of silane by means of oxo-renium complexes.

Modern studies rather focus on the development of cheaper catalyst complexes composed by abundant metals and simple ligand sphere. For example, in 2010 the groups of Beller66 and Lemaire67 reported independently the activation of organosilanes and siloxanes by simple iron complexes, based on a previous work from Nagashima and co-works.68 Lemaire and co-workers showed that 10 mol% iron catalyst, particularly Fe(acac)3, catalyzes the reduction of several nitroarenes in the presence of 4 equiv. of PMHS and TMDS (1,1,3,3tetramethyldisiloxane) in toluene at 90 °C or THF at 60°C, respectively.



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Aryl nitriles, carbonic acids, esters, and bromides (for 1,3-dinitrobenze a single nitro groups stays unaffected whereas the other is reduced to the amine) are tolerated well, however, a tested benzaldehyde was reduced to the benzylic alcohol. The activity of the iron catalyst is drastically enhanced by addition of phosphine ligands, as it was shown by Beller and co-workers when reacting 2.5 equiv. phenylsilane with p-bromonitrobenzene. Although the bromoaniline is also observed in the absence of catalyst (5% yield), phosphine (25% yield), or silane (6% yield), the reaction is significantly enhanced by combination of all three components. Optimal reaction conditions were found when the nitrobenzene is refluxed in toluene for 16 h in presence of FeBr2 or FeI2 (10 mol%), 12 mol% PPh3 and 2.5 equiv. of PhSiH3. Variation of the reaction conditions revealed that phenylsilane is by far the best hydride source, and already use of diphenylsilane decreases the yield from 99 to 48%. Methoxy- and ethoxysilanes gave moderate yields about 60-66%, respectively. The influence of the phosphane ligand is somewhat less significant and triphenylphosphine is as good as (4-MeO-Ph)3P and methyldiphenylphosphine (99% yield each); PCy3 gave 95% yield. However, when a bidendate ligand as dppe is used, the yield drops to 28%. Allowing the ligand a higher degree of freedom by lengthening of the linker unit (butane in dppb, or hexane linker in dpph), again good yields were obtained (84–80%). Noteworthy, from an upscaling experiment on 1 gram scale the p-bromoaniline was isolated in 78% yield. The general applicability of the method (on nitroarenes) was elaborated by extensive substrate screening. In that study the catalyst system has been proven suitable for aryl chlorides (99% yield) and iodides (96% yield), but fluorides appear more challenging (42%). Olefins and α,β-unsaturated esters, benzyl alcohols, esters and acyl groups are de facto not affected. Interestingly, while aryl methoxy ethers are tolerated, the analog thioether results only in 50% amine product, according to the HSAB rules probably due to iron sulfur interaction. Park, Lee and Park followed an immobilization approach justifying application of rather expensive but highly effective gold nanoparticles.68b Therefore, a simple synthetic route was developed, starting from FeSO4 and HAuCl4 to Fe2O3/Au nanocomposite, in which several gold nanoparticles averaging 10(±3.6) nm deposited on the surface of the magnetic iron oxide core, thus allowing a convenient separation of the particles and the reaction mixture. In catalytic studies the gold nanocomposite was elucidated as very active in the reduction of nitrobenzene to aniline with several commercially available silanes and already after 5 min quantitative conversion is observed at r.t. when using 0.5 mol% catalyst loading, 4.5 equiv. dimethylphenylsilane, and substrate concentration of 0.1 M in ethanol. A comparable activity – full conversion in 30 min – is observed if 2.25 equiv. of cheap TMDS is used instead. Hence, a subsequent screening of mostly para-functionalized nitroarenes, nitrocychlohexane, and nnitrohexane was performed with TMDS and 1 mol% catalyst loading. In comparison with other ACS Paragon Plus Environment

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catalytic system, the catalysts is extraordinary selective and tolerates all tested functional groups as halogens, benzylalcohol, phenol, ketone, ester, amide, nitrile, benzyl, carbamate, and meta-vinyl (ArR, R = F, Cl, Br, CH2OH, OH, COMe, CONMe2, CN, CHCH2, OBn, NHCBz) many functional groups (see Table 2). Interestingly, the catalyst lacks in activity towards p-bromo-nitrobenzene (40 mol% were needed, 1 h reaction time, 95% yield) and p-nitrobenzyl alcohol (24 h reaction time to obtain 91% yield, 1 mol% catalyst loading) and the selectivity decreases in presence of m-vinyl groups to 90% yield. Unfortunately, more challenging substrates as ortho-substituted congeners, and alkyne or iodine functionalized arenes were not tested. Aliphatic amines (n-hexane and cyclohexane) were formed in about 85% yield. The iron oxide core allowed quantitative magnetically separation and reusing of the catalyst nanocomposite and after 5 cycles of catalyzing the nitrobenzene reduction, aniline is formed in still 90% yield. TEM images of the recovered catalyst revealed that the number of gold particles increases slightly on the iron oxide surface. Noteworthy, no leaching of any gold was observed. An ICP-MS analysis of reaction solutions magnetically separated from the particles indicated de facto no loss of gold (90%) at room temperature in only 30 min. Therefore, 7 equiv. of Zn powder were used and examples are given in which the catalyst was reused ones with almost the same yield (up to 2-3% lower) within the same reaction time.82 The use of Zn/NH4Cl (with 4 equiv. Zn and 3 equiv. NH4Cl) was reported to be effective at room temperature in ionic liquids such as [bmim][PF6] and water (10:1).83 Furthermore, the tolerating functional groups given in the table phenolic hydroxyl group (Y=77%) is also tolerated. The ionic liquid could be reused three times after filtration, evaporation and drying, with high yields for aniline (≥87%). Interestingly, by the use of 3 equiv. ammonium formate and 6 equiv. Zn, azoxybenzene and azobenzene as byproducts are obtained, showing that with this synthetic protocol especially azobenzenes are reduced to their corresponding hydrazobenzenes in high yields (83-98%). Hilmersson et al.84 used SmI2 as an single electron transfer reagent. Herein, the reductions are carried out with a SmI2/H2O/i-PrNH2 mixture to reduce para substituted (2-Nitroethyl)-benzenes (with 6 equiv. SmI2, the yield for the bromo analog was only 60%) and their α,β unsaturated analogs (with 8-10 equiv. SmI2) in which the latter lead to saturated primary amines because of the radical reaction mechanism. Even nitrostyrene undergoes dimerization under electron transfer conditions. Lipshutz reported about a very mild, green and efficient reduction method using the commercially available surfactant TPGS-750-M (2 wt.-%) that forms micelles and thus enables the nitro reduction to primary amines in water with Zn dust (10 equiv.) and ammonium chloride (2 equiv.) as proton source. Additionally, the functionalities compatible with the method and reported in Table 3, include alkenes, alkynes and especially all halogens (4-iodoaniline was obtained in 96% yield). By considering always the E factor, the surfactant can be recycled by remaining in the aqueous phase whereas the product is extracted by a minimum amount of ethyl acetate; reactions were performed at substrate concentrations up to 1.5 M in water. The following table represents an overview of the discussed metal dissolving methods.



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Table 3. Comparison between some metal dissolving nitro reductions. c

Method

Solvent

b Functional Group Tolerance NO2 T a d y (%) Av. Ref. (°C) Ar. Al. C=O CO2R CN Hal OBn C=C

Fe/AcOH - Ultrasound

EtOH/H2O

30

65-98

x

x

x

x

Sm/NH4Cl - Ultrasound

MeOH

25

74-90

x

x

x

x

THF

25

60-94

x

H 2O

25

81-95

x

[bmim][PF6]

25

73-93

x

x

H 2O

25

92-99

x

x

SmI2/H2O/i-PrNH2 e

Zn/H2O/Cat z (0.05 mol%) Zn/NH4Cl Zn/NH4Cl/TPGS-750-M a

x

C

80

x

C

81

x

C

84

x

N

82

x

C

83

C

79

x x

x

x

x

x

x

x

b

Range of yields in the reduction of different nitro compounds. Suitability for the reduction of aromatic (Ar) or aliphatic (Al) d nitro groups. x = tolerated; the absence of signs stands for unavailable information or for poor tolerance. C = commercially e available; N = Not commercially available. z = poly[N-(2-aminoethyl)acrylamido]trimethylammonium chloride.

6. Metal-free reduction methods Metal-free reductions of nitro groups are interesting because, per definition, they avoid any metal contamination in the product and make treatment of pure salt/organic waste-streams less problematic. Methodologies that avoid the use of hydrogen (and thus metal catalysts) are in particular attractive since they usually do not require any special reactors working under pressure and risk assessments. Bruce and Perez-Medina were the first who observed already in the 194785 that refluxing nitro compounds in hydriodic acid (57%) resulted in the corresponding amine. The procedure was recently revisited by Toyokuni et al.86 Despite moderate to good yields were obtained in the reduction of simple aromatic nitro compounds, the very harsh reaction conditions and the need for I2 delivered from the reaction environment, render this methodology unsuitable for the synthesis of more functionalized molecules. In 1993,87 Park et al. showed that sodium dithionite Na2S2O4 acted as a single electron transfer reductant in the mild transformation of several nitroarenes into the corresponding anilines. The reaction tolerates a wide range of functional groups including halogens and free phenols, however, is limited to aromatic nitro groups. It has been observed that the reaction was accelerated in the presence of 5 mol% Viologen (1,1’-dialkyl-4,4’-bipyridinium ions) by means of Electron Transfer Catalysis (Scheme 13a).


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Scheme 13. Use of sodium dithionite as nitro reducing agent.

Recently, Romero et al. demonstrated that Na2S2O4 is an eligible reagent for the reduction of quinazolinones88 and benzimidazoles89 (Scheme 13b). However, it is important to note that the scale up presents well known safety issues; dried sodium dithionite bears the risk of violent decomposition upon aqueous, oxidative, or thermal treatment; since explosions have been already reported this chemistry should be handled with precautions.90 The thermodynamic behavior was examined in detail by Oda et al. from Shionogi & Co. Ltd, Japan, for the reduction of o-nitroarylamine in multi-gram scale (Scheme 13b).91 They found in semi-batch experiments a highly exothermic reaction profile, that also depends on the used solvent (influencing the stability of Na2S2O4) and on water content; the reaction is accelerated by water addition, 10% water in Ethanol or DMA appearing to be optimal. Also elemental sulfur (S8) is capable reducing nitro groups in the presence of NaHCO3 in DMF at 130°C. Seven different nitroarenes, included compounds bearing CN, COOR, and Cl substituents, were selectively reduced in quite good yields.92 In 1995, Rüchardt discovered the ability of dihydroanthracene (DHA), xanthene and tetraline to act as reducing agents under harsh reaction conditions. When DHA is warmed up to 230–300°C a radical splitting to HAn• and H• occurs. These radical species are reductants which react with unsaturated compounds (styrenes and fullerenes)93 and with nitro groups.94 This method was successfully evaluated for the reduction of five different nitroarenes giving almost quantitative yields (Scheme 14a); however, it was necessary to use DHA in large excess. The reduction of aliphatic



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nitro compounds is impossible due to denitration, as cyclohexane was the only observed product in the reduction of nitrocyclohexane (Scheme 14b). Scheme 14. Dihydroanthracene as nitro reducing agent.

A major drawback is the use of a highly excessive amount of DHA, that leads to the presence/formation of overstoichiometric amounts of organic side product, e.g. anthracene, thus complicating product isolation and purification. Moreover, due to the high reaction temperature, only extremely stable compounds can be reduced without decomposition. This methodology is unsuitable from an organic synthetic perspective, but might be interesting for simple nitroarenes if DHA and anthracene could be separated/recycled. Other metal-free, catalytic transfer hydrogenations of nitroarenes are known, e.g. it has been found that both mesoporous carbon95 and reduced graphene oxide96 promote the hydrogen transfer from hydrazine to nitrobenzene. Refluxing nitrobenzene for 4 h in neat hydrazine hydrate with 2 wt% graphene oxide gave the aniline in very good yield, unfortunately this method was not tested on more substrates. In contrast, on a broader range of nitroarenes the general suitability of mesoporous carbon catalyst was demonstrated, using a catalyst loading of about 5 wt%, refluxing 3 equiv. hydrazine hydrate in ethanol (0.25 M). In the reduction of meta-, ortho, and para-nitrotoluene, para- and meta-nitrophenol, p-nitroaniline, and p-nitrochlorobenzene good yields were observed for the corresponding anilines (81–93%). In 2008, Giomi et al. reported (2-pyridyl)phenyl methanol (g) to be an effective reagent in the reduction of nitrobenzene and 2-chloro-5-nitropyridine (f) in presence of Michael acceptors. Therefore, methyl acrylate has been identified as efficient acceptor for the observed in situ Michael addition towards secondary amines h and i (see Scheme 15a).


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The major drawbacks of this methodology are the moderate yields (

Recent developments in the reduction of aromatic and aliphatic nitro

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