Tandem Hydroaminomethylation Reaction to Synthesize Amines from

Review Cite This: Chem. Rev. 2018, 118, 3833−3861

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Tandem Hydroaminomethylation Reaction to Synthesize Amines from Alkenes Philippe Kalck* and Martine Urrutigoïty* Laboratoire de Chimie de Coordination du CNRS UPR 8241, Composante ENSIACET de l’Institut National Polytechnique de Toulouse, University of Toulouse UPS-INP, 4 allée Emile Monso, 31030 Toulouse Cedex 4, France ABSTRACT: In the context of atom economy and low environmental impact, synthesis of amines by an efficient catalytic process is of great importance to produce these building blocks for fine chemical industry. The one-pot hydroaminomethylation of alkenes is a tandem reaction which involves three successive steps under CO/H2 pressure to perform the catalyzed hydroformylation of the alkene into the corresponding aldehyde followed by its condensation with a N−H function and the catalyzed hydrogenation of the imine/enamine intermediate into the corresponding saturated amine. Rhodium and more recently ruthenium complexes have been designed to combine high conversions of the reactants and chemoselectivity in the expected amines with high regioselectivity in either the linear or the branched amine. The coordination sphere of the metal according to the presence of ligands, temperature, CO/H2 partial pressures, and nature of the solvent is essential for complying with these selectivity requirements. The rate of the hydroformylation step needs to be fast with regard to the hydrogenation step. The role of amines in the coordination sphere and water, presumably in the second sphere, on the mechanism requires some more studies. Similarly, the enantioselective synthesis of amine is not yet achieved directly and interrupted processes or use of asymmetric organo-catalyzed reductive amination are efficient synthetic ways for producing chiral amines. The separation of the catalyst from the organic products by biphasic or (semi-) heterogeneized systems and its recycling have been demonstrated in many cases. The present review provides a report of the state of the art in this autotandem hydroaminomethylation catalysis and should open prospects in the design of less expensive and abundant metal complexes for reaching at low cost similar and even superior performances.

CONTENTS 1. Introduction 1.1. History 1.2. Hydroaminomethylation a Tandem Reaction 2. Mechanism and Selectivity 2.1. Successive Hydroformylation and Hydrogenation Catalytic Cycles 2.2. Operating Conditions: Temperature, CO/H2 Pressure, Ligands, and Substrates 2.2.1. Unmodified Catalysts 2.2.2. Catalysts-Containing Ligands 2.2.3. Asymmetric Catalysis 2.2.4. Hydroaminomethylation of Biosourced Substrates 3. Biphasic Catalysis and Special Activation Conditions 3.1. Biphasic Systems 3.1.1. Aqueous Two-Phase Systems 3.1.2. Ionic Liquid Systems 3.2. Catalysis under Special Activation Conditions 3.2.1. Microwave-Assisted Reactions 3.2.2. Thermomorphic Solvent Systems 3.2.3. Supercritical Systems: scCO2 and scNH3 4. Trends on New Catalysts 4.1. Heterogenized Catalysts © 2018 American Chemical Society

4.2. CO and H2 Surrogates 5. Conclusion Author Information Corresponding Authors ORCID Notes Biographies References

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1. INTRODUCTION 1.1. History

During the period from 1928 to 1944, many studies were performed by Reppe and co-workers at the I.G. Farbenindustrie Aktiengesellschaf t, (conglomerate split after the Second World War to give inter alia Badische Anilin- and Soda-Fabrik, BASF) on the reactivity of acetylene and carbon monoxide to produce organic carbonyl compounds in the presence of transition metal complexes. These studies led directly to an efficient production of acrylic acid from acetylene/CO/H2O catalyzed by the nickel tetracarbonyl complex.1,2 The presence of water in the medium as a hydrogen source is essential for the process and the extension to numerous acetylenic substrates showed the

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Received: November 6, 2017 Published: March 1, 2018 3833

DOI: 10.1021/acs.chemrev.7b00667 Chem. Rev. 2018, 118, 3833−3861

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generality of this reaction, defined in various text books or reviews as carbonylation,2,3 carboxylation,4 and azacarbonylation,5 to produce α,β-unsaturated carboxylic acids. The addition of ammonia in the reaction allowed acrylamide to be produced (eq 1).6

Carbonyl rhodium complexes were further explored. Thus, [Rh6(CO)16] was efficient to catalyze the reaction of pentene with piperidine at 150 °C under 54 bar of CO giving a TON (turnover number) of 70 and a 83% selectivity in N-n-hexylpiperidine.13 Mixed clusters such as [Rh6(CO)16]/[Fe3(CO)12] and [Fe3(CO)12]/[Ru3(CO)12] gave rise to the same activity and even 90% linearity for the Fe/Ru system. Three successive steps occurring during the reaction were proposed (eq 3): (i) hydroformylation of the alkene into the

Synthesis of acrylamide from acetylene, carbon monoxide, and ammonia

Three steps for the aminomethylation of an alkene using the couple carbon monoxide/water Various primary or secondary amines similarly gave rise to Nalkyl and N-dialkyl-amides, in the presence of [Ni(CO)4] at 80−180 °C and 30−35 bar.2 This carbonylation reaction has been extended to ethylene to generate propylamine (eq 2), which further reacted to give Synthesis of propylamine from ethylene, carbon monoxide, and ammonia, involving the water−gas shift reaction corresponding aldehyde, (ii) its condensation with the amine to give the enamine, and (iii) hydrogenation of this enamine into the saturated amine.14 This proposal takes into account the first observation that the reaction of propanal, n-butanal, sec-butanal, or cyclohexanone with ammonia and hydrogen on nickel at high temperature (110−130 °C) produced propyl-, butyl-, and cyclohexylamine in high yields. In this reductive amination reaction, it can be concluded that the aminomethylation reaction involves an aldehyde formed by the alkene hydroformylation.15 Twenty years later, the direct use of the CO/H2 syngas mixture has been tested, in the presence of manganese oxide/zinc chromate and nickel nitrate as hydrogenation-dehydration catalyst.16 Ethylene, ammonia, carbon monoxide, and hydrogen reacted at 350 °C and 590 bar to produce n-propylamine and significant amounts of secondary and tertiary amines. Still in the patents and papers literature, the [Co2(CO)8]/tertiary phosphine catalytic system was claimed to catalyze the transformation of alkenes with ammonia into primary amines17−19 and secondary amines into tertiary amines at 160−220 °C under 35−140 bar of syngas.20,21 The [Rh(H)(CO)(PPh3)3] complex was shown to perform similarly this reaction at 50−200 °C and 60 bar of a CO/H2 (1:2) gas mixture.22 Amines represent important products for bulk chemicals as well as for fine chemistry; this structural function is present in many compounds belonging to agrochemicals, solvents, dyes, monomers for polymerization, functional materials, or biological active compounds. The global amine market is estimated to reach $19.90 billion by 2020 growing at a rate of 8.3% between 2015 and 2020.23 To provide an alternative to multistep classical organic synthetic routes, the present catalytic reaction, called now hydroaminomethylation, is an elegant way to produce them with respect to atom economy and an environmentally benign approach. It is necessary to design catalysts to reach high productivity, high selectivity, long time life, and easy separation from the products to recycle it in good conditions.

dipropyl- and then tripropylamine.7 Along this reaction, the water−gas shift reaction should occur, as demonstrated later. Drastic conditions (T > 300 °C, 150 bar) were required, and large quantities of [Fe(CO)5] were used since inactive iron carbonates were produced. Under the same conditions, ethylene with methylamine mainly provided n-propylmethylamine, like dimethylamine led to n-propyldimethylamine, pyrrolidine giving n-propylpyrrolidine, and propene with dimethylamine producing n-butyldimethylamine.7 Similarly, the secondary [Me(Pr)NH2]+ ammonium compound was directly obtained from the [ethylene/CO/H2O] mixture and [MeNH3]+[CH3COO]− in the presence of [Fe(CO)5].8 Starting from [Me(Pr)NH2]+, [Me(Pr)2NH]+ was produced. This reaction, called aminomethylation, has been extended to higher alkenes to prepare aliphatic primary-, secondary-, or tertiary amines. Thus, cyclohexene reacting with pyrrolidine or dimethylamine, at 170 °C and 140 bar, affords the corresponding tertiary amines with poor yields (6% and traces, respectively). Similar observations were done for dodecenes or tetradecenes with dimethylamine (1.8% yield).9 However, using Rh2O3 as a catalyst precursor under the same conditions allowed 50−80% conversion of higher alkenes to be approached and the bimetallic Rh2O3/[Fe(CO)5] system improved the yields up to 90−94% in aminomethylated products.9 To understand the role of the iron complex, other studies were performed on the reaction of ethylene and piperidine, involving [Fe(CO)5] at 170 °C in the absence of an external source of carbon monoxide. N-Propylpiperidine was produced with a turnover number of 3.3 showing that [Fe(CO)5] plays the role of a reactant providing CO instead of being a catalyst in the modern definition.10 Moreover, the hypothesis that the dihydrido [Fe(H)2(CO)4] complex early proposed by Reppe11 formed in the reaction medium can give the anionic [Fe(H)(CO)4]− species was confirmed, the hydride ligand arising from water. By loss of a CO ligand, the [Fe(H)(CO)3]− tricarbonyl active intermediate was produced.12

1.2. Hydroaminomethylation a Tandem Reaction

In this review, we will focus our attention on the two successive catalytic reactions, generating one C−C and one C−N bond. This one-pot procedure is defined as tandem catalysis.24 The 3834


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Scheme 1. Two Catalytic and the Condensation Steps of the Tandem Catalysis to Produce an Amine from an Alkene and a Secondary Amine

complexes to react α-aminoalkyl radicals with electron deficient alkenes.36 This catalysis has been extended to tris(pyridyl)ruthenium dicationic complexes,37 to have an access after deprotection of N-protected aminomethyltrifluoroborates to primary amines.38 Another hydroaminoalkylation strategy is to perform a “transfer hydrogenative C−C coupling”, which can be regio- and diastereoselective, by reacting a diene with an aminoalcohol in the presence of a ruthenium complex.39−41 Concerning the HAM reaction, it has been reviewed42,43 or analyzed in review chapters dealing with tandem carbonylation reactions involving in the first step the hydroformylation of an alkene.44,45 Recently, a review has exclusively covered studies on the rhodium-catalyzed HAM.46 In the present paper we provide an overview on this powerful and still promising reaction.

two catalysts can be distinct and noninterfering species, so that orthogonal tandem catalysis is operating. When a single catalyst precursor provides the two mechanistically distinct catalytic cycles, the reaction belongs to autotandem catalysis.24,25 In both situations, the two catalytic processes occur simultaneously. Scheme 1 summarizes the different steps occurring in the tandem hydroaminomethylation (HAM) reaction. The first catalytic cycle relates to the hydroformylation reaction to transform an alkene with syngas (CO/H2 1:1) into the linear and branched aldehydes (l and b). These two products react in situ with primary or secondary amine present in the medium to give by condensation the corresponding hydroxylamines which by loss of water provide the enamines or the iminiums, which are in equilibrium with the enamines. The second catalytic cycle operates their reduction by hydrogenation producing the final saturated amines. However, this HAM reaction is not the only catalytic reaction to obtain amines of large interest by an atomeconomical route. Indeed, the direct addition of an N−H function on CC double bond, called hydroamination, also involves a catalytic pathway, even if it is characterized by high reaction barrier due to negative entropic values. Several recent reviews have appeared.26−28 This reaction will not be considered in the present review. Recent works on the synthesis of amines are related to the C−H activation of a methyl group in the α-position of the N− H bond (CH3−NH-R) which reacts with an alkene, providing a new carbon−carbon bond formation. Catalysis concerns the Htransfer on one carbon atom of the alkene and the bonding of CH2−NH-R on the second one. Interestingly, high yields in branched amine can be obtained (b/l > 99:1). Titanium and tantalum complexes29−32 are excellent catalysts for this socalled “hydroaminoalkylation” reaction, which can be inter- or intramolecular. These C−C condensations are related to the hydroamination reactions33−35 providing amines with the same carbon atoms number contributed by the initial amine and alkene. Photoredox catalysis allows also the hydroaminoalkylation reaction to be performed using tris(pyridyl)iridium cationic

2. MECHANISM AND SELECTIVITY 2.1. Successive Hydroformylation and Hydrogenation Catalytic Cycles

The rhodium-catalyzed hydroformylation reaction of an alkene involves mainly the [Rh(H)(CO)2L2] precursor in which L is a phosphine ligand and more interestingly L2 a diphosphine ligand.47 Under the reaction conditions this resting state produces the [Rh(H)(CO)L2] square-planar active species, which coordinates the alkene substrate (RCHCH2). Transfer of the hydride ligand on the CC double bond leads to a linear- or a branched-alkyl species, coordination of one CO followed by its migratory insertion produces a square-planar acyl species, and then oxidative addition of dihydrogen gives rise to the two last intermediates isomeric species of the catalytic cycle [Rh(H)2(COCH2CH2R)(CO)L2] or [Rh(H)2(COCH(R)CH3)(CO)L2]. Release of the aldehyde by reductive elimination of one hydride and the acyl group regenerates the active species. Scheme 2 shows the main steps of the hydroformylation reaction represented for the linear aldehyde. Then the produced aldehydes immediately react with the primary or secondary amine present in the medium to afford the corresponding enamine and iminium intermediates, the 3835


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nature of the ligands, and thus the coordination sphere, is crucial for providing a good hydrogenation activity and eventually a high enantioselectivity.51,52 Actually two catalytic cycles can be considered. It is admitted that the neutral [Rh] active species reacts with dihydrogen by an oxidative addition reaction to give the [Rh(H)2] dihydride. Then, after coordination of the enamine giving [Rh(H)2(enamine)], a hydride transfer occurs to generate the corresponding alkyl species. Reductive elimination of the alkyl group and the hydride ligand leads to the final amine and restores the [Rh] active species. Since recent studies on the hydrogenation of enamines have demonstrated that a cationic intermediate involving an iminium ion is involved,51 a cationic [Rh]+ active species can be considered with a Rh-η2-dihydrogen complex that transfers a proton to the nitrogen atom of the enamine followed by addition of the rhodium-hydride. Recent investigations carried out under HAM reaction conditions, have evidenced an equilibrium between the neutral [Rh(H)(CO)2L2] and the cationic [Rh(CO)(X)L2]+ species, which exists to simultaneously perform the tandem reaction.53 A simplified representation of this equilibrium is shown in Scheme 4. DFT calculations have allowed the deprotonation of

Scheme 2. Main Steps in the Catalytic Cycle of the Hydroformylation Reaction of a Terminal Alkenea

Scheme 4. Equilibrium between the Neutral Hydride Species and the Cationic Square-Planar Complex Involving Protonation and Reductive Elimination of H2

a

The cycle is restricted to the linear product).

linear aldehyde being largely more reactive than the branched one in this condensation reaction.47 Hydrogenation of these two intermediates leading to the expected amines has been reviewed,48−51 and the mechanism analyzed in the literature allows the second catalytic cycle displayed in Scheme 3 to be proposed. It is devoted to the RCHCHNR1R2 enamine hydrogenation, showing the main catalytic steps involving the neutral or cationic rhodium active species, represented as [Rh] and [Rh]+ for simplification. Along this catalytic cycle, the

the cationic dihydride to be identified by the amine present in the medium to restore the neutral hydride active species in the hydroformylation reaction.53,54 In order to avoid the hydrogenation of the alkene into alkane or the aldehyde into the corresponding alcohol, and even the formation of acetals, the hydroformylation step should be faster. As the reactivity of the primary or secondary amine is rapid, the hydrogenation step of the iminium/enamine is ratedetermining. To obtain very efficient catalytic systems, and thus

Scheme 3. Two Catalytic Cycles of the Hydrogenation Reaction in the Presence of a Neutral or a Cationic Rhodium Complexa

a

Only the (Z)-enamine is represented. 3836


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Scheme 5. Hydroaminomethylation Reactions Leading to Difenidol and Fluspirilene

Scheme 6. Synthesis of Alimemazine from 10-Allyl-10H-phenothiazine, Etymemazine from 10-(2-Methylallyl)-10Hphenothiazine, and Trimipramine from 5-Allyl-10,11-dihydro-5H-dibenzo[b,f]azepine

2.2.1. Unmodified Catalysts. After the pioneering studies using Rh2O39 and [Ru3(CO)12],55 the [Rh2(μ-Cl)2(COD)2] complex (COD = 1,5-cyclooctadiene) represents an interesting precursor to generate under CO/H2 pressure (50−120 bar) an active rhodium carbonyl species. After the COD and Cl ligands are removed, the active species is presumably [Rh(H)(CO)3] producing amines in good to excellent yields.56 For instance, to get 4,4-diarylbutylamines, a class of therapeutically interesting molecules, a synthetic route was proposed via a regioselective hydroaminomethylation sequence of 1,1-diaryl-2-propen-1-ols in the presence of piperidine derivatives, leading to 4-amino-1,1-diaryl-1-butanols. Dehydration of these aminoalcohols and hydrogenation of the unsaturated resulting intermediates led to the desired final amines. Several 4-amino-1,1-diaryl-1-butanols, including the antihistaminic agent Difenidol or the Fluspirilene precursor, were thus obtained in excellent yields using the [Rh2(μCl)2(COD)2] precursor in 1,4-dioxane as shown in Scheme 5.56 Similarly, secondary and tertiary naphthylpropylamines have been prepared in high yields starting from 2-vinylnaphthalene57

fast reaction rates and high chemo-, regio-, and eventually enantioselectivity, it is necessary to design the catalyst complex with its complete coordination sphere and the operating conditions, adapted for each couple of alkene/amine substrates. However, in any case the relative two catalytic steps should privilege the hydroformylation rate. 2.2. Operating Conditions: Temperature, CO/H2 Pressure, Ligands, and Substrates

To reach good yields in amines, this tandem reaction is generally performed in the 90−130 °C temperature and 30−60 bar ranges of CO/H2, considered as medium pressure. These experimental conditions are somewhat more severe than those used for the hydroformylation reaction alone, which is consistent with a rate-determining step in the hydrogenation reaction of imines/enamines. The CO/H2 composition depends on the experimental procedures and can generally vary from 1:1 to 1:5. Introduction of ligands, mainly phosphorus-containing ligands, in the coordination sphere of the metal has significant effects on the selectivity of the reaction. 3837


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Scheme 7. Hydroaminomethylation of Bis(methallyl)silanes, Bis(methallyl)ethers, and Bis(methallyl)amines

Scheme 8. Synthesis of a Cryptand by HAM of (N-Acetyl)bis(methylallyl) and the Polyazamacrocycle (before Synthesized by HAM of an α,ω-Bis(methylallyl)dialkene and the α,ω-HN(CH2Ph)(CH2)3NH(CH2Ph) Diamine)

Scheme 9. Hydroaminomethylation Reaction of the 1,4-Bis(2-methyl-allyloxy)-benzene with N,N′-Dibenzyl-butyl-1,4-diamine (n = 3) or N,N′-Dibenzyl-hexyl-1,4-diamine (n = 5)

l/b ratio values range from 66:34 to 28:72 according to the heteroatom nature. On the contrary, the bis(methallyl) compounds only give the l/l products, the yields depending on the heteroelement (Scheme 7). The di- or triamines characterized by linear carbon chain between the nitrogen atoms possess a potential biological activity.63 Oxa- and azamacroheterocyclic systems are of interest for various applications due to their selective binding properties toward ions and neutral molecules and also as valuable building-blocks for the synthesis of natural products. Azamacroheterocyclic systems were synthesized starting from ready available dialkenes and diamines via the ring-closing bis(HAM) reaction.64,65 This method allows for wide variations in ring size, heteroatom, and substitution patterns to obtain various macroheterocyclic products. In addition, when Nbenzyl-substituted macrocyclic systems are obtained, the synthesis of cryptands can be accomplished by subsequent hydrogenolysis of the benzyl group and further bis(HAM) with α,ω-dialkenes (Scheme 8). The application of this procedure in the synthesis of azamacroheterocycles containing hydroquinone, 1,1′-biphenyl, or (S)-1,1′-binaphthol units was successfully conducted since relatively high yields (59−78%) are gained.66 When the reaction involves bis-methylallylphenyl ethers and N-benzyl-

or secondary and tertiary N-carbazolylisopropylamines from Nvinylcarbazole.58 The (S)-3-(2-methyl-4-morpholinobutyl)-4-phenyloxazolidin-2-one compound was synthesized from (S)-3-(2-methylallyl)-4-phenyloxazolidin-2-one and morpholine.59 The catalytic conditions involve 0.3−0.5% mol of rhodium precursor under a 50−80 bar CO/H2 (1:1 to 1.5:1) pressure at 120 °C. The reaction proceeds slowly since 99% yield was reached after 2−3 days. Allylic ethers or silanes and even amines can be transformed to generate γ- or δ-amino functionalized ethers, silanes, and amines in high yields into a mixture of linear and branched isomers.60 This procedure is a powerful pathway to prepare biological products such as alimemazine, etymemazine, as well as trimipramine (Scheme 6).61 The regioselectivity into these branched isomers is due to the presence of the nitrogen atom which coordinates to the rhodium center during the hydroformylation step and plays a directing-group role.62 By extension of this reaction, various di- or triamines were obtained from ethers, silanes or amines containing diallyl fragments. The synthesis is carried out with [Rh2(μCl)2(COD)2] catalyst precursor at 120 °C under 100 bar CO/H2 (1:1).63 The nonsubstituted allyl systems afford mixtures of l/l, l/b, and b/b products with morpholine. The 3838


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Scheme 10. HAM of N-Methylallylphtalimide with Benzylamine, Deprotection of the Benzyl Group by Hydrogenation on Pd/C at Room Temperature and further HAM with One Equivalent of N-Methylallylphtalimide

Scheme 11. Selected Diphosphine Ligands with Their Bite Angle Values and the Yield in the Linear Amine Starting from Pent2-ene and Piperidine

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2.2.2. Catalysts-Containing Ligands. 2.2.2.1. Phosphorus-Containing Ligands. The catalytic phosphine-containing rhodium systems are well-known to be efficient in the hydroformylation reaction.47,74,75 The active species can be generated either by synthesis of the [RhCl(CO)(PPh3)2],22 [RhH(CO)(PPh3)3],22,76 [Rh(NBD)(PMe2Ph)3]+,76−78 and [Rh2(μ-S-tBu)2(CO)2(PPh3)2]79,80 complexes or by adding in situ phosphine ligands either to the [Rh2(μ-Cl)2(COD)2], [Rh(COD)2]+, and [Rh(acac)(CO)2] precursors. Diphosphine ligands play a special role in this reaction due to the stabilization of the intermediate pentacoordinated [RhH(CO)(alkene)L2] species. Particularly interesting are the bulky diphosphine ligands, such as Naphos (L1),81 Iphos (L2),82,83 Xantphos (L3),84 and di-t-Bu-Xantphenoxaphos (L4) 85 (Scheme 11) added to [Rh(COD)2]BF4, which transform terminal aliphatic alkenes into the corresponding linear aldehydes with l/b reaching 99:1. These diphosphines are characterized by a large bite angle (111−123°).84,86 The steric hindrance of the ligands also allows converting an internal alkene into large amounts of the terminal aldehyde (l/b = 96:4) due to the isomerization reaction of the carbon−carbon double bond. The succession of the hydride transfer to the coordinated internal CC double bond and the β-H elimination produces mainly the linear alkyl-rhodium species, which is further carbonylated into the terminal aldehyde. Thus, these catalytic systems have been examined in the HAM reaction to provide attractive regioselectivity in linear amines up to 99:1% for terminal alkenes.87−90 The Xantphos L3 ligand (Scheme 11) introduced in the rhodium coordination sphere of [Rh(acac)(CO)2] allows dendritic perallylated polyglycerols and morpholine to be converted into the corresponding dendritic polyamines, with a high selectivity in the linear isomers.91 However, when the autoclave is charged with all of the reactants the l/b ratio is close to 1:1. So, the hydroformylation reaction is first carried out and then the amine is introduced and the second catalytic step performed still under CO/H2 pressure, where the l/b ratio reaches 93:7. Presumably, the coordination of morpholine to the rhodium metal center induced this absence of regioselectivity in the hydroformylation step. Other ligands similar to L4 (Scheme 11), with small variations in the electronic properties, have been prepared and previously tested in the hydroformylation reaction of transoct-2-ene85 and tested in the HAM of pent-2-ene. The bite angle has a significant influence on the regioselectivity of the reaction since for L5 the l/b ratio is 81:19 and for L6 89:11, presumably due to higher rate of β-H elimination of the branched- compared to the linear-alkyl intermediate induced by ligand steric effects in the [Rh(alkyl)(CO)(L5 or L6)] intermediate species. However, a too large bite angle as 131.2° for L7 induces a decrease in the regioselectivity (79:21), probably because the rate of β-H elimination from the linear alkyl intermediate is also increased. In the HAM reaction, similar observations are done in the production of linear amines L5 and L6 giving l/b = 69:31 and 73:27 and L7 only 51:49.90 To combine high activity and selectivity, the electronic and steric properties of the ligands have a decisive influence. It is well-known that the P(OR)3 phosphite ligands afford high activities in rhodium-catalyzed hydroformylation. Indeed, their weaker σ-donor and stronger π-acceptor properties than PR3 ligands facilitate the dissociation of a CO ligand from the metal center.92 In addition, bulky diphosphites allow to reach high l/b regioselectivity. Introduction of pyrrolyl substituents results in

diamine units (Scheme 9) two new stereogenic centers are created. The final products obtained as a mixture of enantiomers and diastereomers are difficult to separate. The use of ether derived(S)-1,1′-binaphthol revealed no stereocontrol during hydroformylation under the catalytic conditions used. These azamacrocycles can be considered as ligands for asymmetric catalysis when they are synthesized by HAM of methylallyl diolefins containing chiral units (tartaric acid derivatives) and diamines.67 This procedure is less efficient than the stepwise hydroformylation-reductive amination sequence as only 32% of the 1:1 mixture of the azamacrocycle diastereoisomers is achieved in comparison with 86% in the second case. Encouraging results in preliminary studies were reported on the coordination chemistry of these ligands with zinc and rhodium metal centers. To build complex scaffolds such as polyamine dendrimers, the HAM reaction is revealed to be a powerful procedure starting from benzylamine as an ammonia equivalent in order to circumvent the direct ammonia alkylation. Further debenzylation generates a NH function used in a second HAM reaction to produce a symmetric tertiary amine as shown for instance in Scheme 10.68,69 The same reaction performed with urea, as an ammonia source, at 80 bar CO/H2 (1:1), 120 °C for 2 days, gave the expected amine in an one-step procedure with 78% yield.69 The preparation of polyamine dendrimers is conducted according to the strategy in which methallyl-modified dendrons are attached to the polyamine core through HAM. The procedure provides a rapid assembly of dendrimers with any desired molecular weight in only a very few steps.70 The [Ru3(CO)12] precursor is able to catalyze the HAM reaction using water as the source of hydrogen through the water−gas shift (WGS) reaction, which converts CO/H2O into CO2/H2, using the appropriate conditions. Syntheses are conducted in N-methyl-2-pyrrolidone/H2O mixture under 40 bar CO pressure at 130 °C for 20 h in the presence of a large excess of K2CO3. Terminal CC bonds of various alkenes, dienes, styrene or allylbenzenes were converted into the corresponding amines with yields as high as 92% and linearity ranging from 90 to 99%, except for styrene (30%). Due to this high selectivity 4-vinylcyclohexene and β-citronellene were exclusively transformed into the terminal amines. Whereas oct2-ene provides a large linear selectivity due to the isomerization reaction, no reaction occurs with cyclohexene (99.8:0.2%), but the hydrogenation activity decreased leading to a lower chemoselectivity of 25%. Conversely, more acidic media (toluene/ phenol) gave high activities, but side-reactions like aldol condensation were favored.93 The tetraphosphoroamidite L14 ligand and its derivatives (Scheme 13),93,94 built on a biphenyl moiety, are known to produce unprecedented regioselectivities in the hydroformylation of styrene and its substituted derivatives,95 as well as terminal96 and internal alkenes,97,98 into the corresponding linear aldehydes. Indeed, 3-phenylpropanal was reached with l/ b = 95.5:4.5 ratio, 3-(2,4,6-trimethylphenyl)propanal with 99:1, and nonanal with 99.5:0.5. For the HAM reaction of styrene, almost the same regioselectivity was obtained, although the l/b ratio is lower with a chemoselectivity significantly reduced due to the presence of large amounts of ethylbenzene.99 The

Scheme 13. Tetraphosphoroamidite L14 and Tetraphosphine L15 Ligands

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Scheme 14. Selected Bis(imine)phosphine L16−L18 and dppf L19 Ligands

reaction of methallylic alcohols with various amines. The protection of the alcohol function with o-diphenylphosphinobenzoic acid (o-DPPBA) induced the substrate-directed diastereoselective HAM reaction.111 Otherwise, the intramolecular reaction of aminoalkenes produces the corresponding cycloamines using mono- or bisphosphites, such as Biphephos (L20), containing very crowded bulky aryl substituents (Scheme 16).112,113 This L20 ligand also generates with [Rh(acac)(CO)2] an efficient catalytic system to perform the HAM reaction of 3-allyl-2-methylquinazolin-4(3H)-one with arylhydrazines.114 Similarly, the [Rh(acac)(CO)2]/diphosphite L21 catalytic system allows the highly regioselective synthesis of two biologically active targets to be performed,115,116 the antiarrhythmia ibutilide117 and the antidepressant aripiprazole118 (Scheme 17). These two products are obtained at 28 bar CO/ H2 (1/1), 75 °C, in THF, with 55% and 67% yields, respectively. A recent report deals with the synthesis of the two other structurally related antihistamine drugs, Terfenadine and Fexofenadine (Scheme 18),119 under similar reaction conditions. High regioselectivity in the linear product is reached in the presence of L21, higher than those observed with the monodentate phosphite ligand L22. The catalytic system proved to be tolerant toward various functional groups present in the substrates and to require milder conditions than systems involving diphosphine ligands without any noticeable hydrolysis. In a similar approach, the hindered diphosphite ligand Biphephos L20 introduced in the rhodium coordination sphere, induced a high l/b (87:13) selectivity in the functionalization of the chiral (S)-4-benzyl-3-(allyl)oxazolidin-2-one substrate.59 In this case, the reaction was conducted in two separate steps: first

pressure and temperature conditions used (pCO/pH2 = 5:25 bar; 60 °C) since maintaining a low temperature is particularly important to favor the branched amine. This high regioselectivity was also observed with [Rh2Cl2(μ-diphosphinite)(COD)2] (Scheme 15) for styrene and dipentylamine (l/b = 9:91).107 Scheme 15. Dirhodium Complex Resulting from the Coordination of a Diphosphinite Ligand to [Rh2(μCl)2(COD)2]

Although phosphite ligands lead to higher reaction rates than phosphines in the hydroformylation reaction92 and some of them give attractive results in the hydrogenation of dimethyl itaconate or methyl (Z)-N-acetylaminocinnamate, particularly in its chiral version,108−110 they have been for a long time considered as unsuitable and not able to promote the HAM reaction, due to their sensitivity to hydrolysis.88 However, a few studies report this reaction using such ligands. The [Rh(acac)(CO)2]/4 P(OPh)3 catalytic system has been used for the Scheme 16. Bulky Phosphite Ligands

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Scheme 17. Synthesis of Ibutilide and Aripiprazole

Scheme 18. Synthesis of Terfenadine and Fexofenadine

Scheme 19. Hydroformylation of (S)-4-Benzyl-3-(2-methylallyl)oxazolidin-2-one

Scheme 20. Synthesis of a Chiral Diaminoalcohol by Condensation of the Major Aldehyde Isomer of Scheme 19 with Piperazine under Hydroformylation Conditions Followed by Hydrolysis

and l/b ratio of 99:1 and for styrene 88% and 60:40 in the corresponding diamines. Moreover, starting from methyl undec-10-enoate or undec-10-enol the corresponding α,ωdiester or α,ω-diol were synthesized in 70% yield with l/b ratios of 72:28 and 70:30, respectively. 2.2.2.2. Mixed Phosphorus−Nitrogen Ligands. Various hybrid aminophosphine ligands have been synthesized giving rise during the catalytic cycle either to the κ2-P,N or the κ1-P coordination mode due to the lability of the nitrogen atom. The resulting vacant position can have a beneficial effect on the substrate coordination for its activation. The reactivity of [Rh(COD)(P−N)]+ cationic complexes (Scheme 22) containing the o-diphenylphosphino-[N-(2hydroxyethyl)-N-methyl]aniline L23 ligand and its 2-methoxyethyl analogue L24 was tested in the reaction of styrene and

the hydroformylation reaction to privilege the formation of the linear aldehyde (Scheme 19) and then piperazine or 1-(3,5bis(piperazin-1-yl)methyl)benzyl)piperazine was added to transform mainly the major aldehyde isomer (87%) for producing the dendritic polyalcohol amines with yields of 92% and 80%, respectively (Scheme 20). The [Rh(acac)(CO)2]/L20 catalytic system allows the corresponding diamine to be produced in a one-pot procedure in the reaction involving piperazine and oct-1-ene (Scheme 21).120 Operating at 120 °C and a pCO/pH2 = 17:23 bar syngas pressure, a 80% yield in 1,4-dinonylpiperazine was obtained with a l/b = 77:23 ratio. These good results in this bis-HAM reaction encouraged the authors to explore other substrates such as hex-1-ene or dodec-1-ene under the optimized reaction conditions. Interestingly 3,3-dimethylbut-1-ene gave 87% yield 3843


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Scheme 21. Double-Hydroaminomethylation of Oct-1-ene with Piperazine

Scheme 23. 2-(Dicyclohexyl-phosphino)-1-(2-methoxyphenyl)-1H-imidazole L25 Ligand

[Rh2(μ-Cl)2(COD)2] and the bidentate N-donor ligand giving rise to the cationic [Rh(COD)(L26)]+ rhodium species associated with the anionic [RhCl2(COD)]− moiety. The same reaction carried out under CO pressure results in the substitution of the 1,5-cyclooctadiene ligand by CO ligands to give the corresponding carbonyl [Rh(CO) 2 (L26)][RhCl2(CO)2] species (Scheme 24). As shown in previous studies, this complex displays high activity and regioselectivity in hydroformylation of various substituted-styrene substrates under mild conditions.127 The access to 1,2,3,4-tetrahydroquinolines, which are of great interest for the preparation of pharmaceuticals and agrochemicals, is possible via the catalyzed intramolecular HAM of 2-isopropenylanilines.119 The best reaction conditions led to 98% yield of the final isolated tetrahydroquinolines (Scheme 25) although this synthesis requires a large catalyst load of 5−7.5 mol % and a long reaction time of 48 h. Interestingly, seven-membered 2benzazepines and 1-benzazepines, known for their biological activity,119 have been also synthesized.128 Two synthetic approaches were considered: the first one starting from isopropenylamines (path A, Scheme 25) and the second one from 2-isopropenylbenzaldehyde and aniline derivatives into a one-pot process (path B, Scheme 25). In both cases, similar high yields up to 98% are obtained.119,126 In path B, the first step is the reductive amination of the aldehyde moiety with the aniline derivative, followed by the intramolecular HAM of the alkene function. This catalytic system gives an access to a novel atom economy procedure to prepare in a one-pot reaction 2benzazepines and tetrahydroquinolines. The bis-pyrazolylmethane ligands, particularly bis(dimethylpyrazolyl)methane L27, coordinated to rhodium provides the cationic [Rh(L27)(CO)2]BF4 complex (Scheme 26) giving a good activity for oct-1-ene and diethylamine in the HAM reaction.129 Under mild conditions (12 bar CO/H2 (1:1), 80 °C, 6 h), 85% yield in amines was reached with 62:38 l/b ratio, the only byproducts being internal octenes (15%). Substituting one CO ligand with PPh3 leads to the [Rh(L27)(CO)(PPh3)]BF4 complex, which improved the l/b ratio to 72:28. The introduction of the triphenylphosphine ligand results in this higher l/b ratio since the stronger hydridic character of the Rh−H bond promotes the formation of the linear alkyl moiety in the hydride transfer step to the alkene coordinated to the metal center. However, the system is slower, since the yield in amines is only 35%. 2.2.2.4. Carbene Ligands. N-Heterocyclic carbene (NHC) ligands coordinated to transition metals provide effective catalysts in a wide variety of reactions, and the role of NHC ligands in metal-catalyzed carbonylation reactions has been recently highlighted.130−132 These ligands possess strong electron-donating properties so that the resulting rhodium complexes induce high chemoselectivity, especially avoiding the

Scheme 22. L23 and L24 P−N Ligands and the Corresponding Cationic [Rh(COD)(P−N)][BF4] Rhodium Complexes

morpholine. These complexes are known to be very regioselective catalysts for the hydroformylation of styrene to obtain the branched aldehyde (around 94.3% after 22 h, at 40 °C and 100 bar).121 Operating at somewhat higher temperatures (60−100 °C), the reaction converted all of the styrene and morpholine reactants with 85.5% selectivity in the branched amine. Noteworthy, the use of the 1,4-dioxane/ THF solvent mixture promoted these attractive results, whereas the 1,4-dioxane/dichloromethane mixture led to extensive polymerization and side-reactions.122 Similarly, 2-phosphino-substituted imidazole ligands have been synthesized to coordinate a ruthenium metal center from [Ru3CO12]. The results obtained for oct-1-ene and oct-2-ene are promising since, at 130 °C and under 60 bar pressure, l/b ratios as high as 96:4 were attained from the terminal alkene and 83:17 from the internal one in the presence of piperidine.123 This reaction is quite general because the same reactivity is observed when various alkenes and amines are implied. The catalytic system involving the L25 ligand (Scheme 23) generates for styrene around the same quantities of linear and branched products (45:55), the operating conditions being somewhat the same (60 bar, CO/H2 = 1:5, 130 °C, 20 h). Conversely, the reaction of α-methylstyrene and allylbenzene led to better regioselectivity in the linear amine (l/b = 99:1 and 88:12, respectively), but with lower yields (55 and 84%). 2.2.2.3. Dinitrogen Ligands. After the first observation that the [Rh+(COD)(η6-PhBPh3)−] zwitterionic complex is active for the HAM reaction of styrene to provide mainly the branched methylated amine,124 the cationic rhodium complex coordinated by N,N,N′,N′-tetramethylethylenediamine (TMEDA, L26) can carry out the reaction of 2-isopropenylanilines, and more generally isopropenylamines, to produce 1,2,3,4-tetrahydroquinolines125 and 2,3,4,5-tetrahydro-1H-2benzazepines.126 The catalytic precursor is synthesized from 3844


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Scheme 24. Hydroaminomethylation of 2-Isopropenylanilines

(L28)] rhodium complex (Scheme 27) efficiently catalyzes the reaction of aliphatic and cyclic alkenes or vinylarenes such as 1(4-methylphenyl)styrene or 1-(2-pyridyl)styrene with piperidine (Scheme 28). This catalyst achieves good activity and chemoselectivity in THF at 60 bar CO/H2 pressure (1:5), 95− 105 °C, during 12−16 h.136 The modest regioselectivity observed is similar to that obtained during the hydroformylation reaction with the l/b ratio close to 33:67 at complete oct-1-ene conversion whatever the bulky substituents present on the ligand.104,105,132−134,139,140 The key role of the carbene complex is to catalyze the hydroformylation reaction with no excess of ligand, avoiding the formation of hydrogenated byproducts (octane or nonanol), contrary to the phosphorus-containing ligands, which leave very easily the rhodium coordination sphere under a CO pressure. Turnover frequencies (TOF) as high as 3540 h−1 can be obtained with the L30 tetrazole-based carbene complex (Scheme 27).140 The species generated during this step, presumably a rhodiumhydride one, is also active to hydrogenate the imine/enamine intermediate. With these carbene ligands, special attention has been devoted to the access to 3,3-diarylpropylamines of pharmaceutical interest, whose catalytic pathway can be achieved by either the hydroformylation/reductive amination sequence104,141 or by the HAM reaction.105,142 Starting from 1,1-diarylethenes, regioselectivity in linear amines is excellent due to the steric hindrance of the two aryl substituents. In the presence of 0.1% mol of [RhCl(COD)(L28)] catalyst, in toluene, at 60 bar CO/H2 (1:5), 125 °C, and 24 h, various biologically active antihistaminic pheniramines are obtained in good to moderate yields (Scheme 29). Some of them are synthesized through this unprecedented one-pot reaction sequence.143

Scheme 25. Synthesis of 2-Benzazepines via Intra- or Intermolecular HAM Reactions

Scheme 26. Cationic [Rh(L27)(CO)(CO or PPh3)]BF4 Rhodium Complexes

isomerization of the terminal CC double bond and high regioselectivity in the production of linear aldehydes during the hydroformylation step, especially when carbenes and phosphorus-containing ligands are simultaneously coordinated.133−135 The HAM reaction has been recently described using carbene ligands.136−138 The 1,3-dimesitylimidazol-2-ylidene (Imes, L28) ligand is particularly interesting, since the [RhCl(COD)-

Scheme 27. N-Heterocyclic Carbene Ligands and the Corresponding Rhodium(I) Complexes

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Scheme 28. Hydroaminomethylation with the [RhCl(COD)(L28)] Rhodium−Carbene Complex

Scheme 29. Biological Active Pheniramines (Yields in %) Synthesized with the [RhCl(COD)(L28)] Rhodium−Carbene Catalyst

Scheme 30. Chelating Dicarbenes Ligands L31−L36 to Operate the HAM Reaction with High Selectivity in the Branched Amine

1:24, in the presence of the 3,3′[1,2-phenylenebis(methylene)]bis(1-methyl-1H-imidazole) L31 ligand. Extension to piperidine, N-phenylpiperidine, and N-methylpiperidine for the reaction with chloro-, methyl-, or methoxy-styrene gives rise to a good regioselectivity in the branched resulting amine. 2.2.3. Asymmetric Catalysis. As a significant number of bioactive145,146 and pharmaceutical147 nitrogen-containing compounds are chiral, the HAM reaction represents a powerful

The introduction of chelating dicarbene ligands (Scheme 30) in the coordination sphere of rhodium, starting from [Rh2(μCl)2 (COD)2 ], to presumably produce in the catalytic conditions the [RhCl(CO)(dicarbene)] complex, allows high branched/linear ratios to be induced for the resulting amines.144 It is necessary to adjust the operating conditions. Conversion of 98% can be reached for styrene and morpholine, at 69 bar of CO/H2 (1:1), 80 °C in CH2Cl2, and the l/b ratio is 3846


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tool for their straightforward synthesis.148 In the case of styrene, the lack of enantioselectivity was observed at the end of the HAM reaction, in spite of various chiral diphosphine ligands introduced in the coordination sphere of neutral or cationic rhodium complexes.149 DFT calculations highlight that the two energetic pathways for the (E)- and (Z)-enamine hydrogenation, calculated for the styrene/piperidine asymmetric HAM reaction, present the same energy (−12.2 and −12.8 kcal.mol−1, respectively). Moreover, the reductive elimination of the hydride and alkylamine ligands from the rhodium coordination sphere is the rate-limiting step.149 Thus, another strategy has been explored for obtaining chiral amines. A recent report describes that styrene and its derivatives can be converted into β-chiral amines with significant enantioselectivity combining metal- and organocatalysts.150 Indeed, the [Rh(acac)(CO)2]/P(p-MeOC6H4)3 catalytic system operates under 11 bar CO/H2 pressure, in the presence of the Hantzsch ester (1,4-dihydro-2,6-dimethyl3,5-pyridinedicarboxylate), as a hydride source, and the chiral TRIP phosphoric acid (3,3′-bis(2,4,6-triisopropylphenyl)-1,1′binaphtyl-2,2′-diyl hydrogen phosphate) for the asymmetric induction during the hydrogenation of the imine intermediate (Scheme 31). The reaction proceeds slowly (3 days) with good

hemiacetal after 2−3 days reaction time (Scheme 32). Then, after CO/H2 depressurization, either an oxidant (pyridinium chlorochromate, PCC) is added to give the pyrrolidinones or a reductant (HSiEt3 and BF3·OEt2) to generate pyrrolidines. Enantiomeric excesses as high as 95% are gained. This strategy has been applied to synthesize the pyrrolidine precursor of Vernakalant,154 an antiarrhythmic agent, and Enablex,155 which is a muscarinic receptor antagonist (Scheme 32). 2.2.4. Hydroaminomethylation of Biosourced Substrates. Biomass has the potential to serve as a sustainable source of energy and organic carbon substrates. As the production of chemicals from renewable materials represent innovative strategies, the extension of the HAM reaction to the conversion of natural resources has also great potential. Therefore, the reaction has been studied on monoterpenes and unsaturated fatty acids. 2.2.4.1. Hydroaminomethylation of Monoterpenes. Limonene is one of the major constituent of the essential oil extracted from citrical plants.156 It is functionalized with secondary amines like diethylamine and morpholine in 81− 93% yields, and the linear product is exclusively obtained owing to the steric hindrance of the isopropenyl group.157 The catalytic conditions are 80 bar of CO/H2 (1:1), 80 °C, and 20 h in the presence of the dimer [Rh2(μ-Cl)2(COD)2] catalyst. The reaction gives an easy access to growth regulators for tobacco plants. Seven other (R)-(+)-limonene-derived amines were synthesized in good isolated yields.158 Alkylated amines (npropylamine, isopropylamine, and benzylamine), cyclic amines (piperidine, piperazine, and morpholine), and an aromatic one (aniline) were used. In order to decrease the long reaction time for completion (sometimes 48 h), the authors report improvements in the HAM protocol in splitting the process into two catalytic steps: hydroformylation (under a CO/H2 mixture) and hydrogenation after condensation with the amine (only H2). Depending on the amine used as a substrate, the total reaction time is between 10 and 24 h. Higher selectivity is reached for the products of the reactions with secondary amines (79 to 89% isolated yield). The products have been tested against Leishmania(V) braziliensis and some of them (the resulting amines from n-propylamine and aniline) present better in vitro activity than the standard drug pentamidine. Two promising new anti-Trypanosomia cruzi limonene derivatives have also been identified (the resulting amines from aniline and piperazine).159 In the goal to transform natural products extracted from renewable crops in large amounts into useful, or potentially useful, new chemicals, the HAM reaction of limonene, camphene, β-pinene,160 and eugenol161 has been carried out in the presence of di-n-butylamine, morpholine, and n-butylamine to obtain the corresponding homologous amines. Moderate to good yields (73−94%) were reached using [Rh2(μ-OMe)2(COD)2] as catalytic precursor in the presence or not of phosphines as ancillary ligands in toluene at 80 °C under 60 bar of CO/H2 pressure. The regioselectivity of the reaction is strongly induced by the substrate itself, and the amine group is almost exclusively present in the α-carbon position (Scheme 33). The unmodified rhodium catalyst is very efficient for the HAM transformation of terpenes, notably camphene in which double bond isomerization is not a competitive reaction. To prevent isomerization the addition of the triphenylphosphine P(C6H5)3 ligand is necessary but decreases the enamine/imine hydrogenation rate. Bulkier tribenzylphosphine P(CH2C6H5)3 gives better results; its greater steric hindrance probably

Scheme 31. Asymmetric HAM Reaction Combining a Rhodium Complex and the Chiral TRIP Phosphoric Acid, the Hantzsch Ester Being the Hydrogen Source

to excellent isolated yields and enantioselectivities ranging from 79 to 91%.150 This protocol is adapted from the asymmetric organo-catalyzed reductive amination of aldehydes via dynamic kinetic resolution (DKR).151 This reaction needs large amounts of Hantzsch ester as a hydrogen source for the reduction of the imine, since it does not operate in the presence of dihydrogen. This report represents the first direct HAM reaction of styrene. An extension of this reaction to various styrene and aniline derivatives also gives excellent enantioselectivities, using the [Rh(acac)(CO)2]/(R,R)-Ph-BPE catalytic system and a chiral phosphoric acid.152 A chiral intramolecular version of the HAM reaction is described following an interrupted approach to synthesize pyrrolidines and pyrrolidinones.153 Indeed, starting from a protected 3-substituted allyl-amine, large quantities of the [Rh(acac)(CO)2]/(S,R)-(N-Bn)-Yanphos catalytic system (substrate/catalyst = 20) are used under 20 bar (CO/H2 = 1:1) at 70 °C to produce the stable chiral five-membered cyclic 3847


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Scheme 32. Access to the Synthesis of Chiral Pyrrolidinone and Pyrrolidine, Frameworks Found in Drugs (Examples of Vernakalant and Enablex) and Natural Products

alized on the disubstituted double bond of the 1,3-diene moiety (the 3-methylene moiety; Scheme 34) by the [Rh2(μCl)2(COD)2]/bis(diphenylphosphino)ethane (dppe) catalytic system in the presence of HNMe2. The resulting product is the 3-ethyl enamine, and it is necessary to use Pd/C to hydrogenate in a second reaction the enamine function to obtain the C11 amine. Then CH3I is added to produce the corresponding quaternary ammonium.163 To develop this approach, this procedure is applied to β-farnesene, another terpene of industrial importance. The four resulting diethyl- or dimethyl-quaternary ammonium iodides present similar critical micelle concentrations to that of known long-chain cationic surfactants, like dodecyltrimethylammonium bromide and cetyltrimethylammonium bromide (CTAB). 2.2.4.2. Hydroaminomethylation of Unsaturated Fatty Acids. Hydrolysis of fats and oils gives rise to even-numbered aliphatic carboxylic acids and coproduces glycerol. The C-18 oleic acid in which the CC double bond is in the ninth position is widely produced from many crops. Similarly linoleic acid (two CC bonds in positions 9 and 12) and linolenic acid (three CC bonds in positions 9, 12, and 15) can be obtained, as well as their corresponding esters after direct transesterification. The HAM reaction of ethyl oleate has been recently explored with hexylamine, benzylamine, aspartic acid diethyl ester, valinol, and morpholine.164 The reaction proceeds in toluene or 1,4-dioxane at 140 °C for 20 h under 100 bar CO/H2 pressure in the presence of [Rh2(μ-Cl)2(COD)2] precatalyst. High yields are obtained, in the range of 91−99% except for aspartic acid diethyl ester (68%). However, diisopropylamine gives only 5% of the final amine, since the hydrogenation step converts the two aldehyde regioisomers into the corresponding alcohols. Interestingly, two equivalents of oleic ester with the

Scheme 33. Hydroaminomethylation of Limonene, Camphene, and β-Pinene

disfavors the formation of the less active bis-ligand−metal species [Rh(H)(CO)2L2] in the catalytic cycle.160,161 Concerning estragole, an allyl-benzene derivative, the HAM reaction involving phosphole ligands and butylamine results in the formation of the two linear and branched corresponding amines, with almost no double bond isomerization. These ligands give a good compromise between good chemoselectivity and activity.162 All of the products formed except the final amine obtained from limonene and morpholine are new, and products derived from limonene have potential bioactivity as growth regulators in tobacco plants.157 Myrcene (7-methyl-3-methylene-1,6-octadiene) a triunsaturated monoterpene, has been selected for the synthesis of renewable surfactants. It is selectively and exclusively function3848


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Scheme 34. HAM Reaction of the 3-Methylene Moiety of β-Myrcene to Give the Enaminea

a

Further hydrogenation on Pd/C and methylation with CH3I provides the quaternary terpenylammonium iodide.

Scheme 35. Double HAM Reaction Involving Ethyl Oleate and Hexylamine

Scheme 36. Cascade HAM and HHM of the CC Double Bond of Trioleina

a

Only one chain has been represented.170 Three representative functionalized trioleins are drawn. 3849


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Scheme 37. Water-Soluble Mono and Diphosphine Ligands

3. BIPHASIC CATALYSIS AND SPECIAL ACTIVATION CONDITIONS In the context of sustainable chemistry, in terms of ecological and economical requirements, the synthesis of fine chemicals catalyzed by transition metal complexes needs highly efficient recycling of the catalyst. It is thus necessary to perform its separation from the organic products in conditions where it can be reused with no loss of metal or ligands. The biphasic approach allows satisfying this issue.

primary hexylamine results in the formation of the tertiary amine after a double HAM reaction (Scheme 35).164,165 Extension of this reaction in using S-(−) or R-(+)-pyrrolidine-2-carboxylic acid or proline in methanol allows the HAM reaction to be combined with an esterification giving rise to a diester, an interesting biopolymer precursor. Thermomorphic solvent systems (see section 3.2.2) involving linear alkanes as the second solvent result in yields as high as 95% in the two expected regioisomers and the separation of the catalyst with a leaching reduced to several ppm.166,167 After interesting observations that aminoalcohols transform Δ16 steroids into the corresponding hydroxyl-aminomethyl derivatives,168 oleyl alcohol and diethylamine are transformed into the resulting aminoalcohol which is separated in a thermomorphic process.169 Recently, synthesis of novel amino-hydroxylated triglycerides from biobased unsaturated triolein has been reported, resulting from the one-pot HAM/Hydrohydroxymethylation (HHM) cascade sequence in the presence of dibutylamine (Scheme 36).170 Indeed, the ligand-free [Rh(acac)(CO)2] rhodium catalyst produces, via HAM, tertiary amines which act as ligands of Rh species capable of hydrogenating the remaining formyl groups (produced in the hydroformylation step) into alcohols. Generally, the resulting triglycerides contain two dibutylaminomethyl and one hydroxymethyl group. Special achievement of this work lies also in the possibility of varying the proportion of aminomethyl and hydroxymethyl groups (determined by MALDI-TOF/TOF spectrometry) grafted onto the triglyceride fatty chain via an accurate control of the experimental conditions.170,171 The resulting amino-hydroxylated triglycerides represent building blocks whose applications could be of major interest in polymer chemistry.

3.1. Biphasic Systems

3.1.1. Aqueous Two-Phase Systems. Performing the HAM reaction in an aqueous two-phase system is an interesting approach to separate the catalyst from the organic products. It is necessary to overcome the mass transport limitations of the substrate to the aqueous catalyst-containing phase, even if the reaction presumably occurs in the interphase region.172 Several methods are proposed to face the problem, like the use of amphiphilic ligands, surfactants, or cosolvents. After early studies on the direct synthesis of primary amines from alkenes and ammonia at high pressures, with deceiving catalytic performances using cobalt systems,173,17,19 a new approach has been conducted in biphasic media.174 The major challenge is to avoid the side reactions producing mainly secondary and even tertiary amines. Experiments performed with the sodium salts of the monodentate tris-sulfonatedtriphenylphosphine (TPPTS, L37) and sulfonated bidentate BINAS (L38) ligands (Scheme 37) led to attractive results provided a high molar phosphorus to rhodium ratio (P/Rh = 425 and 140, respectively) is maintained to keep the [Rh(H)(CO)L2] hydroformylation active species in the aqueous phase.175,176 However, such a strategy significantly reduces the hydrogenation rates. To offset this loss of activity, the iridium [Ir2(μ-Cl)2(COD)2] complex, known to be a more efficient hydrogenation catalyst in the presence of a phosphorus ligand, is added.174 Thus, a dual transition metal catalytic system is built. Starting from pent-1-ene and ammonia with an 3850


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8:1 NH3/alkene ratio, higher selectivity with respect to the primary amine is obtained by lowering the polarity of the organic solvent moving from methyltertiobutylether (MTBE) to anisole or toluene. In these conditions, a better extraction of the hydrophobic primary amine from the aqueous phase occurs. The reactivity of NH3 with aldehydes leads to the preferential formation of the primary amines with regard to the secondary ones. In the toluene/water system, the primary to secondary amine ratio is 82:18 instead of 69:31 in MTBE/water.174 Another solution is to add Na2SO4 in the aqueous phase to improve the ionic strength difference between the two phases, as previously observed in the hydroformylation reaction when addition of the Li2SO4, Na2SO4, Cs2SO4, or Al2(SO4)3 salts introduces a strong electrolyte character in the water phase, so that the activation barrier for the dissociation of a TPPTS ligand in the rhodium coordination sphere is higher and promotes the presence of [Rh(H)(CO)(L37)2] over [Rh(H)(CO)2(L37)].177 Interestingly, the use of ammonium salts of primary and secondary amines and a large excess of the TPPTS ligand (P/Rh = 64) allows a 99% selectivity in linear amines in the HAM reaction of oct-1-ene in water to be reached.178 Thus, the addition of either organic or inorganic acids appears to be an efficient way to avoid the aldol condensation and to promote the intermediate enamine hydrogenation. The functionalization of long chain alkenes is also of great interest, because of the highly industrial importance of the resulting aliphatic tertiary amines.179 Thus, the HAM of high alkenes using water-soluble phosphine ligands with the dual rhodium/iridium catalytic system has also been explored.180−182 To improve the solubility of these alkenes in water, a cationic surfactant, cetyltrimethylammonium bromide (CTAB), can be introduced. This strategy has already been used in the hydroformylation reaction under the same conditions and the formation of micelles results in higher reaction rates and l/b aldehyde ratios.183 Due to its steric hindrance the BISBIS (L39) diphosphine ligand184,185 is particularly interesting since the regioselectivity in linear amines is significantly improved. In solvent-free media, attractive results are observed at 130 °C under 30 bar CO/ H2 (1:1). Several parameters, especially the cationic surfactant CTAB concentration, the P/Rh, and amine/alkene molar ratios are optimized for the reaction. The best results are obtained with P/Rh and amine/alkene ratios of 30 and 4, respectively to gain 91% conversion, 46% selectivity in amines and l/b ratio of 94:6. The [RhH(CO)(L39)] complex in the presence of CTAB allows for instance to gain a l/b ratio around 99:1 when P/Rh = 3.7.182 The combination of [RhCl(CO)(L37)2] and [IrCl(CO)(L37)2] under the same catalytic conditions leads to a 67% chemoselectivity in the expected amines.180 These results confirm that the iridium catalyst plays a more active role in the hydrogenation step of the reaction. To overcome the mass transfer limitations, an efficient micellar approach186 has been developed.187 Indeed the use of the amphiphilic triphenylphosphine functionalized poly(2oxazoline) macroligands L41 (Scheme 38) with the phosphine moieties covalently linked to the hydrophobic part of a mixed block copolymer, allows the authors to perform the HAM reaction of oct-1-ene with dimethylamine and the separation of the resulting products. The key role of these amphiphilic ligands is to produce a highly active species concentration inside the hydrophobic core of the micelles formed in the aqueous media. Even at 150 °C, where the rhodium catalyst is still stable, 22% yield in amine is observed with l/b ratio of

Scheme 38. Amphiphilic Triphenylphosphine L41 Functionalized Poly(2-oxazoline) Macroligands

88:12 and TOF of 461 h−1. For the dual rhodium/iridium catalytic system, the best results are obtained with a Rh/Ir ratio of 2:1 at 130 °C, providing a 600 h−1 TOF value, 24% yield in amines with 62% selectivity and l/b ratio of 92:8. Nevertheless, at this temperature, high hydrogenation activity leads to the undesired alkane, which is faster than the formation of the aldehydes. Special shuttles such as cyclodextrins or calixarenes are largely used for the transfer of the organic substrate into the aqueous phase, especially in the hydroformylation of heavy alkenes.176,188 To the best of our knowledge they have only been implemented in the HAM reaction for the HAM/HHM sequence (see section 2.2.4) of triglycerides with the [Rh(acac)(CO)2]/L41/methylated cyclodextrin providing 76:21 alcohol/amine ratio.171 3.1.2. Ionic Liquid Systems. The use of nonaqueous ionic liquids represents another efficient approach to perform catalysis in a two-phase system.189−192 The main advantage of ionic liquids lies in their negligible vapor pressure, thermal stability, and compatibility with organic compounds and organometallic catalysts. After an easy separation of the organic phase, the catalytic system maintained in the ionic liquid phase allows performing successive experiments without loss of activity, most of the time thanks to a reaction-tailored ionic liquid. The HAM of long chain alkenes193 in a series of [RMIm][OTs] ionic liquids (R = n-butyl, octyl, dodecyl, cetyl, Scheme 39) and adding the L39 ligand to the [Rh(acac)(CO)2] rhodium precursor has been studied. In [BuMIm][BF4], three successive runs operated with dodec-1ene result in a dramatic decrease of the conversion rate (from Scheme 39. Ionic Liquids with 1-Alkyl-3-methylimidazolium Cations

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Scheme 40. Biphasic Hydroaminomethylation Starting from a Cationic Rhodium Precursor

Scheme 41. Synthesis of Benzylated α-Amino Acids by Microwave-Assisted HAM Reaction

3.2. Catalysis under Special Activation Conditions

91% to 67%). In addition, large amounts of dodecane and internal dodecenes with a significant loss of the amine selectivity (from 79% to 47%) are observed. A decrease of the regioselectivity in the linear amine is noted, the l/b ratio going from 94:6 to 81:19. Satisfactory results can be achieved provided the ionic liquid counterion is the tosylate TsO− (pCH3C6H4SO3−) anion, presumably because its structure is very close to that of the aryl-sulfonated groups lying on the phosphorus atoms of the water-soluble ligand. Indeed, the conversion and the chemoselectivity remain almost unchanged (up to 90% conversion, chemoselectivity for amine varying from 78 to 64%) along the five recycling experiments. However, the l/b ratio decreases from 97:3 to 86:14, and this phenomenon is probably due to the progressive oxidation of the ligand. The C12 alkyl chain in the methylimidazolium cation ([DMIm][OTs]) gives an ionic liquid medium more consistent with the dodec-1-ene substrate since 86.4% selectivity in amines is gained. When the hydrophobic PPh3 and BISBI ligands, with no sulfonated groups, are used, a catalyst leaching is observed and the recycling experiments do not give satisfactory results. Another attractive catalytic system combining the Sulfoxantphos ligand L40 (Scheme 37) to the [Rh(COD)2]BF4 cationic rhodium complex in 1-methyl-3-pentyl-imidazolium tetrafluoroborate [PMIm][BF4], in the absence of any other organic solvent, provides high chemo- and regioselectivities to linear amines (Scheme 40).194 The good performances of this catalytic system have been observed in the hydroformylation reaction, which is the fast step in the HAM reaction.195 The C7to C13-substituted piperidine derivatives are produced at 125 °C, 36 bar CO/H2 (1:2), and overnight from terminal C6 to C12 alkenes. By adding fresh substrate directly in the autoclave or after removal of the organic layer, the oxidation of the ligand during recycling is avoided keeping good activity, regio-, and chemoselectivity in amines.194 Thus, after five HAM cycles, at almost complete conversion of the terminal alkene, the organic medium contains roughly 8% of isomerized alkenes and the expected amine in 97% selectivity, with the l/b ratio varying from 95:5 to 98:2. ICP analyses show that the rhodium leaching in the organic phase is under the detection limit of 0.09%. The combination of stoichiometric quantity of the [Rh(acac)(CO)2] and [Rh(COD)2]BF4 rhodium catalyst precursors with an excess of L40 (ligand/Rh = 4) increases the reaction rate, even working at 110 °C, keeping the performances described above (l/b close to 98:2).

New protocols using microwaves, thermomorphic solvents, and supercritical CO2 or supercritical ammonia have been introduced to reach high reaction rates and selectivity, still in the context of sustainable chemistry. 3.2.1. Microwave-Assisted Reactions. Recently, microwaves have been shown to assist chemical transformations because of a rapid local heating. The medium must be sufficiently polar in order that the electric field and dielectric relaxation induce a rapid thermal effect, resulting in both a rapid conversion and a satisfactory selectivity.196 Many studies deal with microwave-promoted carbonylations,197 and more recently, microwave-assisted domino hydroformylation-cyclization reactions were reported for the synthesis of cyclic amines of pharmaceutical interest.198 For the synthesis of natural and non-natural amino acids an original method for the microwave-assisted HAM of alkenes199 can be adapted from the conditions of the hydroformylation reaction of the same substrates.200 The catalytic system is based on the direct addition of the sterically hindered Xantphos L3 or Biphephos L20 ligands to the [RhH(CO)(PPh3)3] complex in a 80 mL vial. A 2.7 bar CO/H2 pressure is introduced into the vial, which is submitted to short irradiation (5−30 min, 110 °C, ethanol) in a monomode microwave oven. Several benzylated α-amino acids are produced in yields up to 90%, starting from the protected allylglycine and secondary amines (Scheme 41). The excellent regioselectivity of the reaction can be noted since the linear isomer is exclusively formed. Further microwave irradiation in the presence of Pd/C under 6−7 bar H2 pressure allows the benzyl protective group to be removed to get the final α-amino acids. 3.2.2. Thermomorphic Solvent Systems. Another strategy to overcome the problem of mass transfer limitation operating in only one phase and to separate efficiently the rhodium catalyst is the use of a three-solvent-system as initially demonstrated in the hydroformylation reaction of heavy alkenes.201,202 The reaction occurs at high temperature in a single-phase, and after cooling, a split into two phases allows the separation between the reaction products and the catalyst. The combination of a polar- and a nonpolar immiscible solvent is required and the addition of a third semipolar solvent permits this particular behavior to be reached with a strong temperature dependence. Propylene carbonate (PC, a green solvent) and dodecane or n-hexane can be used in combination with several N-alkylpyrrolidones, 1,4-dioxane, or alkyllactates in the HAM of oct-1-ene with morpholine.203 The experiments performed at 125 °C (CO/H2 8:39 bar) with [Rh2(μ-Cl)2(COD)2] as 3852


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Scheme 42. HAM Reaction of Ethylmethallylamine: Cyclic Amine and Amide Formation

Scheme 43. Various Ligands Derived from Diphenyl-, Triphenylphosphine, and the BINAP L44 Ligand

aim of industrial process intensification, a systematic study for selecting the most efficient solvent for reducing the catalyst leaching shows that ethanol, acetonitrile, and N-methylpyrrolidone are particularly adapted to the reaction involving oct-1-ene and morpholine.204 This thermomorphic tricomponent solvent system has been extended to methyl oleate condensed with 3-(methylamino)propionitrile in acetonitrile/heptane mixture to produce the corresponding amino nitrile ester with relative modest yields (64% at 120 °C, 50 bar). This latter is hydrogenated giving a precursor for polyamide synthesis. Constant activity and similar

rhodium precursor, in the absence of added ligand, provide attractive results in terms of conversion (97%) and amine selectivity (96%). The 485 h−1 TOF is satisfactory after a 2 h reaction time with the PC/n-hexane/1,4-dioxane (1/0.55/1.3) system, but the regioselectivity remains low since the l/b ratio is 58:42. Noteworthy, a 0.7 wt % rhodium loss is observed. Moving toward PC/dodecane/N-alkylpyrrolidones systems, higher l/b ratios up to 75:25 can be obtained, but the rhodium leaching is quite important. A major drawback is that morpholine not only enhances the solubilizing role of the semipolar solvent but also reacts with the polar solvent giving significant amounts of undesired byproducts. Recently, with the 3853


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4. TRENDS ON NEW CATALYSTS

results are observed during three recycling tests, but the rhodium leaching is about 0.9−1.1% in each run.205 3.2.3. Supercritical Systems: scCO2 and scNH3. Instead of using classical solvents, compressed and most of the time supercritical fluids represent an interesting alternative.206 The HAM of ethyl methallylamine can give either a lactam or a cyclic amine, depending on the reaction conditions.207 In supercritical carbon dioxide (scCO2) the cyclic amine is privileged. Indeed, the gases are more soluble in scCO2 and CO2 acts as a protecting group of the amine function of the substrate to prevent the formation of the lactam. Two pathways are proposed to explain the formation of the products (Scheme 42). Once the acyl-rhodium species intermediate is formed, the nucleophilic attack of the nitrogen atom can occur at the carbonyl group leading to the lactam and regenerating the rhodium hydride active species. Alternatively, the oxidative addition of dihydrogen produces a dihydride-rhodium species, from which the reductive elimination releases the aldehyde. The latter reacts with the secondary amine function, giving the expected pyrrolidine through a condensation/hydrogenation sequence. A higher H2 concentration favors the oxidative addition reaction and thus the formation of the pyrrolidine. High-pressure NMR spectroscopic investigations have evidenced the interaction of CO2 with the N−H amino-group of the starting substrate, leading to its protection owing to the reversible formation of a carbamic acid or an ammonium carbamate. The experiments have been performed with the [Rh(hfacac)(COD)] (hfacac = bis(trifluoromethyl)acetylacetonato ligand) complex and the P[(C6H4)-(CH2)2(CF2)5CF3]3 perfluorinated L42 ligand (Scheme 43), which is characterized by a higher solubility in the scCO2 phase. Under a 40 bar CO/H2 (1:1) partial pressure, at 60 °C with a 3:1 P/Rh ratio, the main product remains the lactam (58%), the pyrrolidine being up to 37%. Increasing the hydrogen partial pressure, which makes easier the oxidative addition reaction of H2, results in a higher selectivity in pyrrolidine (18%:64% for CO/H2 = 1:2) although the formation of a heavier product results from the condensation/hydrogenation of two molecules of 4-aminopentanal. An increase of the temperature completely suppresses the lactam formation, but the intermolecular reaction is favored with regard to the intramolecular one (at 80 °C, intra/inter ratio 40%:52%). As mentioned before, the direct use of NH3 is attractive to produce primary amines and its use in aqueous systems has been previously described.174 To be in the supercritical conditions (scNH3), it is necessary to work in the 120−172 °C temperature range under a pressure around 200−250 bar. Due to the presence of water, which is a coproduct of the reaction, the conditions still require higher pressure values, such as 254−274 bar.208 However, operating at 210 bar and 140 °C 80% of oct-1-ene is converted into 60% of primary amine RNH2 (R = C9 alkyl chain) after 16 h using the dual [IrCl(COD)]2/[Rh(acac)(CO)2] catalytic system protonated by acetic acid. The side reactions are limited to 16% of R2NH secondary amine and 4% of octane.209 This represents the highest yields and selectivities achieved from oct-1-ene and ammonia.

4.1. Heterogenized Catalysts

Very recently, rhodium nanoparticles have been produced and stabilized by the thermoregulated Ph2P[(CH2CH2O)16CH3] L43 ligand, defined as one kind of nonionic surface-active phosphine ligand, which shows a special property of inversetemperature dependent solubility in water (Scheme 43).210 These catalysts can operate in a mixture of butan-1-ol and water at 40−60 bar for the HAM reaction of oct-1-ene with di-npropylamine.211 Working at 90−120 °C, above the cloud point (CP) of the thermoregulated ligand, the catalyst is transferred from the aqueous phase to the organic phase, containing the substrates. Cooling the system under the CP at room temperature allows separating the products dissolved in the organic phase and the catalyst, going back to the aqueous phase. Similarly, the intermolecular HAM reaction of various alkenes is catalyzed by gold nanoparticles deposited on cobalt oxide Au/Co3O4 at 120 °C and 40 bar of CO/H2.212 Presumably, the cobalt(0) atoms formed through reduction by the hydrogen spillover on the surface of the gold nanoparticles initiate the hydroformylation reaction. Dissolution of some cobalt is proved by its leaching (2.1%) measured after catalysis. Moreover, this reaction is highly dependent on the amine basicity and its relative concentration. Indeed, piperidine, whatever its concentration, poisons the catalyst during the reaction with hex-1-ene, whereas N-methyl- or Nisopropyl-aniline gives rise to the expected amines provided not too large quantities (from 8.8 to 17.5 equiv) are introduced. In addition, mercury poisoning tests resulted in the catalytic activity maintained, although the selectivity in amines is lower.211 Encapsulation of [Rh(H)(CO)(PPh3)3] into the pores of hexagonal mesoporous silica functionalized by aminopropyltrimethoxysilane to coordinate the rhodium metal center gives also solid catalysts.213 The amines (l/b = 73:30−82:18) produced from hex-1-ene and piperidine or morpholine present selectivities ranging from 60 to 65% due to significant isomerization into internal hexenes. Interestingly, the catalyst is recycled four times with no loss of activity. A more efficient heterogeneous catalyst is elaborated from aqueous sodium silicate solutions, addition of NaCl, KF, and KCl to produce a gel before adding titanium dioxide. The mixture is then heated at 200 °C for 42 h. From the two NaETS-4 and Na-ETS-10 solids (exchanged titanosilicates), sodium is exchanged with rhodium providing crystalline RhETS-4 and Rh-ETS-10 solids with large surface area (234m2/g measured by CO2 adsorption).214 These two catalysts are efficient to perform the HAM reaction of hex-1-ene or cyclohexene in the presence of various amines with a complete conversion in 4 h at 100 °C and 68 bar (CO/H2 = 13.5:54) pressure. No hydrogenation of the alkene occurs and the selectivity in amines is close to 100%, except for primary amines leading to ca. 80%. The l/b regioselectivity is 50:50. Presumably, the presence of cationic Rh+ sites and the acidity of the surface explain the good observed chemoselectivity. Increasing the H2/CO ratio favors the conversion and the selectivity in linear amine. Addition of the monodentate PPh3, P(p-CF3−Ph)3 L45 or P(2,4,6-MeO-Ph)3 L46, or bidentate Xantphos L3 and BINAP L44 phosphine ligands (Schemes 11 and 43) reduces the selectivity in amine, but the regioselectivity into linear amine is strongly increased by using the L3 and L44 ligands. The systems remain stable during four runs in the 3854


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recycling with complete conversion. Nevertheless, a slight decrease in activity is observed beyond the fifth cycle.214 A similar heterogenization strategy involves the application of sol−gel immobilized rhodium catalysts.215 A copolymer is prepared from tetramethyl orthosilicate and triethoxyoctylsilane in a solution of ethanol/water, where the [Rh2(μ-Cl)2(COD)2] complex and the [(EtO)3SiCH2CH2]PPh2 ligand L47 (Scheme 43161) in THF are added and the mixture is continuously stirred for 48−96 h until the gelation is complete. After thermal treatment under reduced pressure and washing with dichloromethane to remove the nonimmobilized rhodium complex, a ceramic material is obtained. This solid catalyzes the HAM reaction of styrene with aniline, and high performances into the branched amine (95%) are obtained at 60 °C under 20 bar of CO/H2 (2:1) for 12 h. Nitroanilines can be directly used as “masked anilines” in this reaction with vinylarenes. Under the same conditions, nitrobenzene, 1-chloro-4-nitrobenzene, and 1methyl-4-nitrobenzene, instead of the corresponding anilines, are used and the reaction provides the same performances.215 Semiheterogeneous catalysts are elaborated by grafting the dicarbene L31 ligand which bears triethoxysilanes groups on Fe3O4 magnetic nanoparticles through six Si−O−Fe bonds. Then the [Rh2(μ-Cl)2(COD)2] precursor is introduced to generate the [RhCl(CO)(dicarbene)] complex by treatment with an excess of tBuOK. The active species still induces high b/l ratio for the amines resulting from styrene derivatives and morpholine, although the ratio is somewhat lower than in homogeneous conditions. Indeed this ratio for styrene and morpholine is 16:1 instead of 24:1 in homogeneous conditions, keeping the same 98% yield.144 Application of an external magnetic field allows an easy separation of the nanoparticles from the reaction medium, and after washing them with CH2Cl2 they are reused directly. After four catalytic cycles the performances are maintained, and no leaching in rhodium was analyzed in the solutions. Using supported ionic liquid phase (SILP) materials as microscopically homogeneous, but heterogeneous catalysts, the continuous gas-phase HAM reaction can occur for ethylene and diethylamine catalyzed by [Rh(acac)(CO)2]/Xantphos (L3). ILs of low basicity and lipophilicity result in very selective HAM catalysis, particularly [trimethyl Imidazolium][bis(trifluoromethylsulfonyl)imide] ([MMMIM][NTf2]), on polymer-based spherical activated carbon (PBSAC) supports. Indeed, the TOF is of 520 h−1 and the reaction performed on 18 days allows a total TON of 115 000 with an average selectivity in diethyl(propyl)amine of 99% to be reached.216

30% of linear amine, the main product being 2-(N,Ndimethylaminomethyl)nonane (34%) besides other branched amines. Similar results are observed for various terminal alkenes involving pent-1-ene to hexadec-1-ene, allylbenzene, or vinylcyclohexane. The internal CC double bond of cyclohexene or cycloheptene can also be functionalized but at lower rates.217 Dimethylformamide can also be used as a surrogate of dimethylamine. In the HAM reaction of non-1-ene in DMF the [Rh(acac)(CO)2]/PPh3 catalytic system provides 7% of selectivity in nonyldi(methyl)amine at 40 bar and 80 °C at a complete conversion, or 29% at 150 °C, provided a large excess of PPh3 is introduced (P/Rh = 214). Introduction of [Ru3(CO)12] to perform catalysis, still with DMF, generates a somewhat more active bimetallic catalytic system with 38% of amine obtained at 150 °C.218 The HAM reaction using CO2 instead of CO has been explored through the reverse water−gas shift reaction (RWGS), the CO2/H2 couple producing in situ CO and H2O.219 The reaction requires [Ru3(CO)12] as catalyst, temperatures as high as 160 °C, the presence of LiCl to suppress the alkene hydrogenation and to promote the RWGS, and benzyl(triethyl)ammonium chloride (BTAC) as phase-transfer agent. In these conditions, at 80 bar in toluene, cyclopentene and morpholine give rise to the corresponding amine with 98% yield. The generalization of this procedure allows synthesizing various amines from the couples morpholine/alkenes or cyclopentene/amines. It is also possible to operate in the absence of hydrogen, as earlier demonstrated with a modest activity in the HAM reaction of pent-1-ene and piperidine, by using [Rh6(CO)16] or a mixture of Fe/Rh and Fe/Ru clusters.13 New catalytic systems based on [Ru3(CO)12] with no phosphine ligands have been recently designed.71 The source of hydrogen is H2O through the water−gas shift (WGS) reaction, which converts CO/H2O into CO2/H2. Syntheses are done in N-methyl-2-pyrrolidone/ H2O mixtures under 40 bar CO pressure at 130 °C for 20 h in the presence of a large excess of K2CO3. Terminal CC bonds for various alkenes, dienes, styrene, or allylbenzenes are converted into the corresponding amines with yields as high as 92% and linearity ranging from 90 to 99%, except 30% for styrene. Interestingly, 4-vinylcyclohexene and β-citronellene are transformed into the corresponding terminal amines with high yields and excellent regioselectivity (l/b > 99%). Cyclohexene does not react (

Tandem Hydroaminomethylation Reaction to Synthesize Amines from

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