Caiyou
Chen
a,
Xiu-Qin
Dong
*a and
Xumu
Zhang
*ab
aCollege of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, P. R. China. E-mail: xumu@whu.edu.cn; xiuqindong@ whu.edu.cn
bDepartment of Chemisty, South University of Science and Technology of China, Shenzhen, 518000, P.R. China
First published on 5th July 2016
Hydroaminomethylation is a perfect reaction for converting alkenes into valuable amines with high atom economy in the presence of the syngas and amines. Significant progress has been made in the past decades; however, there still remain challenges for the control of chemo- and regioselectivity concurrently. Rhodium has proved to be a better metal in hydroaminomethylation for higher activity in hydroformylation and hydrogenation steps. Although promising results were shown by unmodified rhodium catalysts, phosphine ligand modified rhodium complexes generally displayed better activity and regioselectivity. Among the phosphorus ligands developed, tetraphosphorus ligands exhibited much better regioselectivity due to their stronger chelating ability. Apart from the phosphorus ligands, carbene and nitrogen-containing ligands have also been developed which showed good activity due to the promotion of the hydrogenation step. Although non-enantioselective hydroaminomethylation reactions have been intensively studied, reports on asymmetric hydroaminomethylation are rare. Direct asymmetric hydroaminomethylation is very challenging and only reaction systems with two different catalysts showed promising results.
Some terms like cascade, domino, and tandem reaction are often used to describe the hydroaminomethylation reaction.4 The one-pot hydroaminomethylation reaction involves the succession of three steps. In the first step, the alkenes are converted into the linear or branched aldehydes (hydroformylation), which react with the primary or secondary amines present in the reaction medium to give the enamines or imines in the second step (condensation). The last step involves the hydrogenation of the enamine or imine intermediates to give the final amine products (hydrogenation) (Scheme 1).
Although hydroaminomethylation is a perfect reaction for the preparation of amines, there still remain challenges. The main difficulty is that chemoselectivity and regioselectivity should be controlled concurrently to give amines efficiently. As a matter of fact, side reactions are often observed which can occur with the reaction intermediates. For example, the aldehyde intermediate formed in the reaction system can undergo the aldol reaction to give non-desired products. Furthermore, byproducts like alkanes and alcohols can be observed due to the hydrogenation of the alkene substrates and the aldehyde intermediates. Although hydroaminomethylation is a challenging issue, recent years have seen considerable progress.
Hydroaminomethylation was first discovered by Reppe et al. at BASF, who found that acetylenic compounds reacted with carbon monoxide in the presence of ammonia and water, and the amine products were obtained.5 However, this reaction required a stoichiometric amount of Fe(CO)5 as the catalyst and the reaction conditions were harsh (T > 300 °C, pressure up to 150 bar). Owing to the low efficiency of iron catalysts for hydroaminomethylation, efforts have been made to develop new cobalt catalysts and the subsequent studies have proved that cobalt catalysts are superior and that hydroaminomethylation can proceed under catalytic conditions. The first cobalt-catalyzed hydroaminomethylation employed ethylene and ammonia under high pressure and temperature (40–75 MPa, 170–262 °C) to afford propylamine and dipropylamine, and dipropylamine was shown to be the major product.6 It was further found that the reaction can be conducted under relatively lower pressure by using the cobalt precursor Co2(CO)8 modified with phosphine ligands.7 However, low selectivity was observed in the hydroaminomethylation of terminal olefins with ammonia in the presence of syngas. In addition to cobalt catalysts, manganese and nickel carbonyl complexes were also shown to enable the hydroaminomethylation to proceed in a catalytic way under harsh conditions.8 Nowadays, rhodium, ruthenium and iridium precursors modified with certain ligands have been shown to be much better catalysts for hydroaminomethylation under mild reaction conditions, which makes hydroaminomethylation an ideal way for the preparation of amines. Among the metals used in hydroaminomethylation, rhodium was found to be more active and selective in catalyzing both the hydroformylation and the hydrogenation steps. The development of hydroaminomethylation has already been summarized in several reviews.8,9 The main emphasis of this review is to cover the recent studies on the rhodium-catalyzed hydroaminomethylation. Catalysts based on other metals will not be discussed herein. Moreover, the current review will emphasize ligand effects and the development of ligands for hydroaminomethylation will be discussed in detail.
With regard to the rhodium-catalyzed hydroaminomethylation, Eilbracht et al. contributed many efforts in the last decade. In 2000, Eilbracht et al. conducted an interesting hydroaminomethylation reaction with unmodified [Rh(COD)Cl]2 as the catalyst.11 The Rh(I)-catalyzed hydroaminomethylation of dienes in the presence of primary amines or secondary α,ω-diamines was applied to the synthesis of a variety of macroheterocyclic rings (2). As shown in Scheme 3, starting from (hetero)diallylic systems, 12- to 36-membered polyheterocycles were obtained in up to 56% yield. In addition, it was found that the macrocyclic systems 3 thus obtained can be debenzylated and that the resulting macrocyclic diamines undergo a second ring-closing bis(hydroaminomethylation) to give cryptand systems 4.
In 2004, Eilbracht et al. conducted the hydroaminomethylation of 1,1-diaryl-allyl-alcohols with unmodified [Rh(COD)Cl]2 as the catalyst.12 Hydroaminomethylation of 1,1-diaryl-allyl-alcohols provides a new access to 4,4-diarylbutylamines, which possess therapeutic activity and are commercially available therapeutic agents as exemplified by the antihistaminic agent difenidol 5 and fluspirilene 7 (Scheme 4).12 It was found that the hydroaminomethylation of 1,1-diaryl-allyl-alcohols proceeded smoothly with [Rh(COD)Cl]2 as the catalyst. As shown in Scheme 4, difenidol (5) and the fluspirilene precursor 6 were obtained in almost quantitative yield. Starting from 6, fluspirilene (7) can be easily obtained.
Later, in 2009, Eilbracht et al. continued work on hydroaminomethylation with unmodified [Rh(COD)Cl]2 as the catalyst.13 An efficient preparation of chiral polyamino alcohols (PAA) via the hydroaminomethylation of chiral N-olefinic oxazolidinones with different amines followed by hydrolysis was reported. As shown in Scheme 5, the hydroaminomethylation of chiral N-olefinic oxazolidinones proceeded smoothly in the presence of the unmodified catalyst [Rh(COD)Cl]2 to give the amine products 8a–c in high yields. The subsequent hydrolysis gave the desired chiral amino alcohols 9a–c readily. Based on these results, the dendritic chiral PAAs (Mw = 1300–1400 g mol−1) were also synthesized efficiently through a multifold hydroaminomethylation/hydrolysis procedure. Interestingly, the obtained chiral PAAs were investigated as ligands in the ruthenium-catalyzed asymmetric transfer hydrogenation of acetophenone to 1-phenyl alcohol.
In 1999, Beller et al. described a selective hydroaminomethylation of olefins with ammonia to form linear primary and secondary aliphatic amines in a two phase system.14L1 (Scheme 6) was utilized as the ligand for its high water solubility. A high yield with moderate regioselectivity was observed in the hydroaminomethylation of terminal olefins with ammonia. Later, in 2005, Whiteker et al. used the phosphite ligand L2 (Scheme 6) in the hydroaminomethylation of 1-pentene with piperidine.15 Excellent amine selectivity was observed (100%); however, the regioselectivity was low.
In the hydroaminomethylation reaction, fine tuning of the electronic and steric properties of the ligand is necessary to combine higher activity and selectivity. Recently, efforts have been made into the systematic investigation of monophosphorus ligands for hydroaminomethylation. Urrutigoïty et al. compared three class of phosphorus(III) ligands in hydroaminomethylation: phosphines, phosphites and phospholes (Scheme 6).16 The hydroaminomethylation (HAM) of estragole, a biorenewable starting material available from essential oils of various plants, was reported for the first time. Di-n-butylamine was used as the amine counterpart and the corresponding amines (10a–c) were obtained in high yields (Scheme 7). The monophospholes TPP (L3), DBP (L4) and PPP (L5) were employed for the first time as ancillaries for hydroaminomethylation and proved to be promising options for a more efficient manner of promoting the reductive amination than the classic PPh3 ligand and resulted in less side products than the systems with phosphite (L2).
In 2011, Clarke et al. investigated ligand effects in the rhodium-catalyzed hydroaminomethylation of styrene with the ligands L6–L8.17 In the course of their studies, it was found that fluorinated mono-phosphines L6 and L7 were more active than their more electron-donating counterpart L8 in the enamine hydrogenation step of the reaction, which is in contrast with the widely held view that alkene hydrogenation activity increases with ligand donor strength. The subsequent DFT calculations comparing the reaction pathways for a simple alkene and a representative enamine showed that the rate-determining step changes from the first insertion into the Rh–H bond for but-2-ene to the final reductive elimination step from the Rh–hydride–alkyl species in the enamine hydrogenations.
In 2002, Beller et al. reported the selective synthesis of linear amines from internal olefins or olefin mixtures via a catalytic one-pot reaction consisting of an initial olefin isomerization followed by hydroaminomethylation.18 This reaction constitutes an economically attractive and environmentally favorable synthesis of linear aliphatic amines. The use of the cationic rhodium precursor [Rh(COD)2]BF4 with the sterically crowded diphosphine ligands naphos (L9), iphos (L10) and L11 (Scheme 8) were reported for the first time. Among all the ligands tested, it was found that iphos (L10) gave the best result and excellent chemoselectivity and regioselectivity were obtained in the isomerization–hydroaminomethylation of 2-butene (Scheme 9). Later in 2003, the same group found that xantphos 12 was also an excellent ligand for the hydroaminomethylation of a variety of terminal alkenes with different amines.19 Investigation into xantphos type ligands such as L13 and L14 showed that the natural bite angles and steric hindrance of ligands have significant influence on the hydroaminomethylation results.20 It was also found that the regioselectivity for the linear product follows a similar trend to that observed in the hydroformylation of internal alkenes with the use of xantphos ligands. Furthermore, each of the individual steps in hydroaminomethylation was monitored by high-pressure infrared spectroscopy. The results suggest that hydroaminomethylations take place by a sequential isomerization/hydroformylation/amination/hydrogenation pathway.
Apart from the natural bite angles and steric hindrance, the electronic effects of ligands also have a crucial influence on the activity and selectivity of hydroaminomethylation. With the π-acidic ligands coordinated to the metal center, CO dissociation will be facilitated via the trans-effect and the reaction rate will be improved as a consequence in the hydroformylation step.21 Based on this concept, Vogt et al. developed ligands L15 and L16 with an outstanding π-acceptor character by modifying the xanthene backbone with dipyrrolylphosphine,22 which has χ values approaching those of phosphites.23 Accordingly, the bis-[(dipyrrolyl)phosphino]xanthene ligand L15 showed outstanding activities and selectivities with turnover frequencies of 6200 h−1 as well as very high n/i ratios exceeding 200 in the hydroaminomethylation of terminal alkenes. In addition, it was found that the pKa value of the alcohol used in the solvent mixture has a profound effect on the catalytic performance. By using acidic media, the activity was enhanced; on the contrary, less acidic media led to increased regio- and chemoselectivity, as well as an increased degree of double-bond isomerization.
The hydroaminomethylation of styrene provides easy access to arylethylamines, which are a class of pharmaceutically important compounds.24 However, it is a great challenge to obtain the branched amines. In 2005, Beller et al. developed the [Rh(cod)2BF4]/dppf- (L17) catalyzed hydroaminomethylation of aromatic olefins with different amines in the presence of HBF4 with good regioselectivity towards the branched products (Scheme 10).25 The described catalytic system allows the hydroaminomethylation of styrenes under mild conditions.
In 2004, Thiel et al. developed the new bisphosphine ligands L18–L19 (Scheme 8) containing the imine donor functionality in the backbone.26 The new bisphosphine ligands were coordinated to the [(CO)2Rh(μ-Cl)]2 precursor to give the rhodium complexes 11a–b in high yields (Scheme 11). The resulting complexes were characterized by means of 31P NMR, 13C NMR and infrared spectroscopy, which revealed that the two phosphine atoms in rhodium complexes 11a–b are in the trans configuration (Scheme 11). Significant changes were observed in the 31P NMR spectra when the Lewis acid KPF6 or Zn(OTf)2 was added to the solution of the rhodium complexes 11a–b, which proves the existence of secondary interactions between the ligands and the Lewis acids. The rhodium complexes 11a–b were subsequently tested in the hydroaminomethylation of 1-pentene or styrene with piperidine. It was found that the amine selectivity increased evidently with the addition of co-catalyst, due to the easier hydrogenation of the enamine.
In 1999, Saylik et al. first employed the bisphosphite ligand biphephos (L20) (Scheme 12) in intramolecular hydroaminomethylation.29 A range of aminoalkenes (12) were converted to give cyclic amines with a range of medium and large ring sizes in yields up to 85% in the presence of biphephos as a ligand. High regioselectivity was observed for the non-branched products 13 when biphephos was used as the ligand. However, the hydrogenation products (15) of the substrates were also observed (Scheme 13).
Later in 2005, Whiteker et al. developed the highly regioselective synthesis of two biologically active targets, the anti-arrhythmia compound ibutilide (17)30 and the antidepressant aripiprazole (19)31via rhodium-catalyzed hydroaminomethylation with biphephos (L20) as the ligand.32 Under very mild reaction conditions (75 °C, CO/H2 = 14:14 bar), ibutilide (17) and aripiprazole (19) were obtained in moderate yields (Scheme 14). Importantly, the regioselectivity (up to 48:1) was very high when biphephos (L20) was used as the ligand. In 2010, the same group also published the synthesis of the other structurally related antihistamine drugs, terfenadine (21)and fexofenadine (22) (Scheme 15).33 Under similar reaction conditions, terfenadine (21) and fexofenadine (22)were synthesized with high regioselectivities using the bisphosphite ligand L21 (Scheme 15).
Scheme 14 Highly selective synthesis of ibutilide (17) and aripiprazole (19) via the rhodium-catalyzed hydroaminomethylation. |
Scheme 15 Highly selective synthesis of terfenadine (21) and fexofenadine (22) via the rhodium-catalyzed hydroaminomethylation. |
As the regioselectivity in the hydroaminomethylation was determined by the hydroformylation step, we envisioned the tetraphosphorus ligands tetrabi (L22) and TPPB (L23) will also afford excellent regioselectivities in the hydroaminomethylation. The tetrabi L22a (Scheme 16) was then tested in the hydroaminomethylation of a variety of terminal alkenes and amines. Corresponding to our hypothesis, the tetrabi L22a showed excellent regioselectivities and amine selectivities. Regioselectivity as high as >525:1 (n:i) was obtained in the hydroaminomethylation of 1-hexene with piperidine, which represents the highest among all the reported results. Amine selectivity as high as 99.7% was also observed. Moreover, the rhodium–L22a catalytic system exhibited excellent activities, affording TONs as high as 6930.35
Subsequently, the tetrabi ligands L22 were tested in the isomerization–hydroaminomethylation of internal alkenes.36 Remarkably, a 95.3% amine selectivity and a 36.2 n/i ratio were obtained in the isomerization–hydroaminomethylation of 2-octene with piperidine using the tetrabi ligand at an S/L/Rh ratio of 1000/4/1, and the TON could reach 6837 with an 82.5% amine selectivity and a 39.1 n/i ratio at an S/L/Rh ratio of 10000/12/1. The meta-CF3-Ph substituted ligand L22e (Scheme 16) was found to be the best ligand with up to a 99.2% amine selectivity and 95.6 n/i ratio for 2-pentene (Scheme 18). The tetrabi ligands L22 afforded much better regioselectivity than the other ligands applied in the isomerization–hydroaminomethylation of internal olefins, and these results were also the best among all the reported results.
Encouraged by the excellent results achieved with the tetrabi ligands L22, the tetraphosphoramidite ligands L23 were also employed in the rhodium-catalyzed hydroaminomethylation reactions. It is well-known that the linear-selective hydroaminomethylation of styrenes is very challenging among the different alkenes due to the intrinsic trend to form branched amines. There is no general report on the highly linear selective hydroaminomethylation of styrenes to produce 3-arylpropylamines. Recently, we developed an efficient and unprecedented linear-selective (n/i up to >99:1) rhodium-catalyzed hydroaminomethylation of styrenes with the tetraphosphoramidite ligands L23 as the ligands.37 A very high n:i ratio (up to >99:1) was achieved using Rh(nbd)2SbF6 modified with L23b, which is the highest linear selectivity for the hydroaminomethylation of styrene and its derivatives (Scheme 19). The performance of the present system can be explained by the electron-withdrawing property of the pyrrole moiety and the steric interactions between the more bulky tetraphosphorus ligands and the substrates.
Scheme 19 Highly linear selective hydroaminomethylation of styrenes using the tetraphosphoramidite ligand L23b. |
The ligand effects of the tetraphosphoramidite ligands L23 were investigated in the rhodium-catalyzed regioselective hydroaminomethylation of 1-hexene and 1-pentene with piperidine.38 It was found that the substituents of the diphenylphosphane moiety of the ligands greatly affected the amine selectivity and regioselectivity. The 3,3′,5,5′-tetramethylsubstituted pyrrole-based tetraphosphorus ligand L23e was found to be the best ligand, with up to a 70.9 n/i ratio and 99.5% amine selectivity for 1-pentene and a 31.3 n/i ratio and 97.9% amine selectivity for 1-hexene. Moreover, the 4,4′-dimethyl-substituted ligand L23b also showed excellent reactivity, 99.9% amine selectivity and a 27.7 n/i ratio for the regioselective hydroaminomethylation of 1-pentene.
Later, in 2006, the same group prepared a variety of novel rhodium–carbene complexes for hydroaminomethylation.42 Starting from [Rh(cod)Cl]2 and 1,3-dimesitylimidazole-2-ylidenes, the corresponding rhodium–carbene complexes 24–28 were prepared in 82–95% yields (Scheme 21). The rhodium–carbene complexes 24–28 were then tested in the hydroaminomethylation of 1,1-diphenylethylenes. Hydroaminomethylation of 1,1-diphenylethylenes will give 3,3-diarylpropylamines (pheniramines), which represent the well-known first-generation family of H1 antihistaminic agents. The biological activity of 3,3-diarylpropylamines can be tuned from antiallergic to choleretic, antipyretic, coronardilatic, and antispasmodic by varying the amine core (Scheme 22).43 Synthesis of 3,3-diarylpropylamines has attracted immense interest, and a variety of methods have been reported via rhodium-catalyzed hydroaminomethylation.44 However, the reported methods often suffered from long reaction time, high catalyst loading, and low catalyst activity. The novel rhodium–carbene complexes showed promising results for the synthesis of the bioactive 3,3-diarylpropylamines via the hydroaminomethylation reaction. Better activity (TOF up to 288 h−1) was achieved compared with any previously reported procedure for the hydroaminomethylation of 1,1-diphenylethylenes. In the presence of 0.1 mol% of the catalyst, the corresponding 3,3-diarylpropylamines were obtained in high yield and selectivity.42
In 2007, Alper et al. developed the hydroaminomethylation of 2-isopropenylanilines and isopropenylamines to produce 1,2,3,4-tetrahydroquinolines catalyzed by the cationic rhodium complex 33a coordinated by N,N,N′,N′-tetramethylethylendiamine (TMEDA).46 This intramolecular hydroaminomethylation is highly regioselective and gives the 1,2,3,4-tetrahydroquinolines in up to over 98% yield (Scheme 24b) albeit with a relatively high catalyst loading. The catalytic precursor was synthesized from [{RhCl(COD)}2] and the bidentate nitrogen-containing ligands, which afforded the cationic [Rh(COD)(TMEDA)]+ rhodium species associated to the anionic [RhCl2(COD)] moiety (32). The carbonyl rhodium species [Rh(CO)2(TMEDA)]-[RhCl2(CO)2] 33 were obtained under a CO atmosphere (Scheme 24a).47 This rhodium carbonyl complex also showed high activity and regioselectivity in the hydroformylation of various substituted styrenes under mild conditions.47
Later, in 2008 and 2010, the nitrogen-containing ligands modified rhodium carbonyl species 33 were applied by the same group to the synthesis of the seven-member-ring 2-benzazepines 34,48 which have proven to be interesting for their biological activity.49 Two synthetic routes for the synthesis of the seven-member-ring 2-benzazepines 34 were described (Scheme 25). The first route is the intramolecular hydroaminomethylation starting from isopropenylamines or allylanilines. The second route is the intermolecular hydroaminomethylation starting from 2-isopropenylbenzaldehyde and aniline derivatives. The two synthetic routes both gave the desired biologically active seven-member-ring 2-benzazepines 34 in similar high yields. Interestingly, it was found that the solvent had a significant influence on the regioselectivity.
Scheme 25 Two synthetic routes for the synthesis of seven-membered-ring 2-benzazepines via hydroaminomethylation. |
Although direct asymmetric hydroaminomethylation is extremely challenging due to the unavoidable racemization of the chiral iminium or imine intermediates, it is still possible to get the chiral amine products if the racemic iminium or imine intermediates can be hydrogenated in an enantioselective way with an appropriate chiral catalyst (Scheme 27).51 Recently, Xiao et al. reported the asymmetric hydroaminomethylation of styrenes using dual metal and organo-catalysts.51 In this dual metal and organo-catalytic system, the non-chiral rhodium catalyst modified with P(4-MeOC6H5)3 is responsible for the non-enantioselective hydroformylation giving the branched aldehyde with high regioselectivity, and the chiral organo-catalyst is responsible for the enantioselective hydrogenation of the iminium or the imine intermediates. Based on the studies of List et al.,52 a chiral phosphoric acid TRIP (36) was selected as the second catalyst and the Hantzsch ester (HEH) 35 was selected as the hydrogen source (Scheme 28), due to the excellent performance of this catalytic system in asymmetric reductive amination reactions.52 A variety of styrene derivatives were converted to the chiral amines via asymmetric hydroaminomethylation with the dual metal and organo-catalyst. Good to excellent yields (up to 87%) and ee (up to 91%) were obtained (Scheme 28). Although this hydroaminomethylation was non-direct and needed an equivalent amount of Hantzsch ester as the hydrogen source for the hydrogenation of the iminium or imine intermediates, this method is attractive and represents the first asymmetric hydroaminomethylation.
Footnote |
† This review is for celebrating the 75th birthday of Prof. Barry Trost. |
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