DOI: 10.1002/cctc.201100255 The Catalytic Amination of Alcohols Sebastian Bhn, Sebastian Imm, Lorenz Neubert, Min Zhang, Helfried Neumann, and Matthias Beller*[a]

In this Minireview, the synthesis of amines by the amination of amines are produced in bulk by the chemical industry with alcohols, by means of the so-called borrowing hydrogen meth- this synthetic method. In particular, the recent progress apply- odology, is presented. Compared to other synthetic methodol- ing organometallic catalysts based on iridium, ruthenium, and ogies for the synthesis of amines, these transformations are other metals will be discussed. Notable recent achievements highly attractive because often alcohols are readily available include the conversion of challenging substrates such as diols, starting materials, some of them on a large scale from renewa- the development of recyclable catalysts, milder reaction tem- ble sources. In addition, the amination of alcohols produces peratures, and the direct alkylation of ammonia or its equiva- water as the only by-product, which makes the process poten- lents with alcohols. tially environmentally benign. Already today, lower alkyl

Introduction

The importance of amines Scheme 1. Amination of alcohols with ammonia. Amines are of significant importance for the chemical industry, but also for numerous biological processes. For instance, amino acids and nucleotides constitute essential biological production of lower alkyl amines (Scheme 1).[13] One reason for building blocks and numerous bioactive compounds such as its large scale use is the availability of many alcohols by indus- vitamins, hormones, alkaloids, neurotransmitters, or natural trial processes such as hydroformylation/reduction of olefins toxics contain amino groups.[1] It is, therefore, not surprising, (e.g. 1-propanol, 1-butanol, 2-ethylhexanol), hydration of ole- that numerous amines and their derivatives find application as fins (2-propanol, ethanol), fermentation of sugars (ethanol), or agrochemicals, pharmaceuticals, or food additives. direct production from synthesis gas (methanol). In addition, Since the Haber–Bosch process was implemented in the the amination of alcohols affords water as the only by-product, early 20th century, ammonia has been available on a large scale which is by far less problematic than the salt waste generated and, today, more than 100 million tons are synthesized annual- in the amination of alkyl or aryl halides. ly, consuming 1–2% of the worldwide produced energy![2] The Notably, the reaction temperature and pressure for the in- impact of ammonia for the chemistry of amines arises from dustrial processes using ammonia vary significantly, depending the simple fact that almost every nitrogen atom in synthetic on the substrates and the catalysts. For example, methanol compounds either directly or indirectly comes from ammonia. and ammonia are reacted together at 350–5008C and 15– Although only a minority of the produced ammonia is em- 30 bar using aluminum-based heterogeneous catalysts.[14] ployed in the synthesis of structurally diverse amines, that still Today more than 1 million tons of methylamines are produced results in several million annual tons of amine products.[3] The according to this method. Other heterogeneous catalysts for various applications of these synthetic amines include their alcohol amination are based on tungsten, chromium, nickel, use as solvents, agrochemicals, pharmaceuticals, detergents, cobalt, iron, and copper. Applying such catalysts to current in- fabric softeners, flotation agents, corrosion inhibitors, anti- dustrial processes usually results in a mixture of primary, sec- static additives, lubricants, polymers, varnishes, and dyes.[4] ondary, and tertiary amines. However, the ratio of products can Owing to their importance, a variety of procedures for their be tuned by reaction parameters, such as residence time and synthesis, such as Hofmann alkylation,[5] Buchwald–Hartwig[6] excess of ammonia. In analogy to ammonia, primary or secon- and Ullmann[7] reactions, hydroamination,[8] hydroaminomethy- dary amines can be employed in these transformations to lation,[9] reduction of nitriles,[10] and nitro[11] compounds, or re- obtain secondary or tertiary amines. ductive amination[12] have been developed in the last century. [a] S. Bhn, S. Imm, L. Neubert, Prof. Dr. M. Zhang, Dr. H. Neumann, Prof. Dr. M. Beller Amination of alcohols Leibniz-Institut fr Katalyse an der Universitt Rostock e.V. Among the various known procedures to prepare amines, the Albert-Einstein-Str. 29a, 18059 Rostock (Germany) Fax: (+ 49)381-1281-51113 reaction of ammonia with alcohols is of special industrial im- E-mail: [email protected] portance as it constitutes the most common method for the Homepage: www.catalysis.de

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So far, to the best of our knowledge, no homogeneously also known as the hydrogen auto transfer process.[19,23] Here, catalyzed alcohol amination is employed on industrial scale, the alcohol is activated by oxidation to give an aldehyde or but significant academic work has been performed in recent ketone, which then undergoes a condensation reaction with years. In this respect, a number of additional nitrogen nucleo- the amine nucleophile. Subsequent hydrogenation of the re- philes, such as sulfonamides,[15] amides,[16] or carbamides,[16b] sulting imine with the initially generated hydrogen yields the have been also studied in their reactions with alcohols. After a desired amine product. The terms borrowing hydrogen and short mechanistic and historical introduction, the recent devel- hydrogen auto transfer relate to the fact, that the catalyst “bor- opments in the field of N-alkylation reactions with alcohols by rows” hydrogen and “auto” transfers it to the modified (ami- the borrowing hydrogen methodology will be given. The two nated) aldehyde or ketone. The mechanism of this process is most important catalyst metals for such transformations, iridi- related to a transfer hydrogenation reaction, but has an impor- um and ruthenium, shall be discussed in more detail, while an tant advantage. In contrast to the hydrogenation of an imine overview is given concerning other catalyst metals. Applica- using an alcohol as a hydrogen donor, the oxidized alcohol is tions of ammonia or its equivalents will also be discussed. no longer waste, but acts as a substrate. Thus, a much higher atom economy[24] is achieved. The overall transformation essentially involves a reductive Mechanistic considerations amination as one part. When comparing reductive amination By 1901, the alkylation of aniline with sodium alkoxides had and alcohol amination, it should be noted that in reductive been described.[17] This represents the first coupling of amines aminations side reactions, such as aldol condensation, can with alcohols and proves that alcohol amination does not nec- easily occur, owing to the high concentration of the reactive essarily require a transition metal catalyst. In fact, the necessary aldehyde. By employing alcohols via borrowing hydrogen in- hydrogen transfer can be catalyzed by base in a Meerwein– stead, the corresponding aldehyde is only present in small Pondorf–Verley-type reaction.[18] Unfortunately, these transfor- amounts, since it is generated and consumed in situ, conse- mations usually require high temperatures (>2008C) or very quently, such side reactions can be diminished. long reaction times.[19] In addition, N-alkylation reactions with Depending on substrates and conditions, identification of alcohols can be catalyzed by acid. Such SN type alcohol amina- the exact operating reaction mechanism of an alcohol amina- tions usually require benzylic, propargylic, or allylic alcohols,[20] tion can be very challenging. Here, deuteration experiments but a very recent example demonstrates that even non-activat- may help to distinguish between acid- or base-catalyzed alco- ed alcohols, such as 1-octanol 1 or 2-undecanol, can be con- hol aminations and those proceeding by a borrowing hydro- verted with aniline 2 to give the N-alkyl anilines (e.g. 3)in gen mechanism. Furthermore, the presence of intermediates good yields;[21] an interesting example is shown in Scheme 2. such as ketones or imines indicates oxidation and suggests a borrowing hydrogen mechanism. Additional informa- tion may result from the substrate scope of a given protocol, as tertiary alcohols cannot be oxidized and another amination mechanism must take place.

Brief historical introduction Scheme 2. S alcohol amination using an iron catalyst by Saito. N Heterogeneous catalysts for alcohol amination have been known since the first half of the twentieth cen- Although the reaction temperature is high (2008C), some allylic tury,[25] but no homogeneously catalyzed version was alcohols have been successfully converted at 1008C. reported before 1981, when Grigg and co-workers applied

Another possible activation pathway for alcohol amination is [RhH(PPh3)4] for the N-alkylation of pyrrolidine and primary the so-called borrowing hydrogen methodology[22] (Scheme 3) amines, such as butylamine 6, with primary alcohols (e.g. 5) (Scheme 4).[26] In addition, they demonstrated that ruthenium-

Scheme 4. Rhodium-catalyzed N-alkylation of amines by Grigg.

and iridium-based catalysts were active for such transforma- tions. At the same time, Watanabe et al. reported the N-alkyla- tion of aniline 2 with simple alcohols, such as 1-propanol 8 [27] (Scheme 5), using [RuCl2(PPh3)3] as the catalyst. In the follow-

ing years, [RuCl2(PPh3)3] and other systems were applied in a Scheme 3. Borrowing hydrogen in the amination of alcohols. number of alcohol aminations.[19] With just a few exceptions,[28]

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Most protocols using [IrCp*Cl2]2 require a base and DFT cal- culations have indicated that the coordinated base is part of the catalytically active species.[35] In this respect, the applica-

tion of the similar [IrCp*I2]2 catalyst by the group of Williams is remarkable. They showed that the catalyst was active in the Scheme 5. Ruthenium-catalyzed dialkylation of aniline by Watanabe. coupling of amines (e.g. 17, 19) and alcohols such as 18 in the absence of base (Scheme 8).[36] The reaction conditions were temperatures of about 1808C were required and the proce- dures were usually limited to structurally simple primary alcohols.

Iridium-based Catalysts Since Fujita and co-workers first studied the combination of [IrCp*Cl ] and K CO in 2002,[29] a series of novel catalysts for 2 2 2 3 Scheme 8. [IrCp*I ] catalyzed N-alkylations with alcohols by Williams. the N-alkylation of amines using alcohols under milder condi- 2 2 tions have been developed. For example, [IrCp*Cl2]2 has been applied in a number of alcohol amination reactions[30] includ- comparable to Fujita’s protocol. Interestingly, the reaction was ing cyclization reactions of diols with amines[31] and amination run in water. The authors further demonstrated, that the cata- of secondary alcohols.[32] In 2008, Fujita et al. improved the lyst requires polar solvents and the application of ionic liquids [33] protocol by changing the base to NaHCO3. Hence, a range was found to be beneficial for the synthesis of tertiary of primary and secondary amines was N-alkylated with primary amines.[37] and secondary alcohols at a comparatively mild temperature By treatment of [IrCp*I2]2 with aqueous ammonia in metha- of 1108C (Scheme 6) and the obtained yields were in general nol, Fujita and co-workers prepared a water-soluble dicationic catalyst 23. It was recently applied in the synthesis of secon- dary (e.g. 22) and tertiary amines (e.g. 26) from primary or sec- ondary alcohols, as well as secondary amines (Scheme 9).[38]

Scheme 6. Amination of alcohols using [IrCp*Cl2]2 by Fujita. good to excellent. The possibility to convert secondary alco- Scheme 9. Amination of alcohols using a water-soluble iridium complex by hols and the tolerance of functional groups, such as cyano Fujita. (10), nitro (11), or methoxycarbonyl (12) groups, should also be highlighted. The stability of the catalytic system is remarkable, as the trans- Very recently, Cumpstey, Martin-Matute, and co-workers re- formations were carried out under air and in water. Further- ported the N-alkylation of carbohydrate-based amines by alco- more, the authors were able to phase separate the catalyst [34] hols in the presence of [IrCp*Cl2]2. For instance, 13 was con- and reuse it three times without significant loss of activity. verted with 14 to give the amine-linked pseudodisaccaride 15 In 2009, Ishii et al. reported the N-heterocyclization of naph- (Scheme 7). Notably, a secondary hydroxyl group within 14 thylamine 27 with 1,3-propanediol 28 to give benzoquinoline was tolerated. This method represents the first amination of 29 (Scheme 10). In the presence of IrCl3 and using BINAP as carbohydrates. the ligand, 1,2- and 1,3-diols were converted into benzoquino- lines and benzoindoles in moderate to excellent yields.[39] The

Scheme 7. Formation of an amine linked pseudodisaccaride by Cumpstey and Martin-Matute. Scheme 10. N-Heterocyclization of naphtylamines by Ishii.

ChemCatChem 2011, 3, 1853 – 1864 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemcatchem.org 1855 M. Beller et al. reaction is believed to start with the N-alkylation of naphthylamine 27 by the diol through borrowing hy- drogen amination followed by CÀH activation of the aromatic ring. The group of Crabtree has developed an iridium complex bearing an N-heterocyclic carbene 32.Itwas found to be active in the amination of alcohols with Scheme 11. Iridium NHC complex developed and applied by Crabtree. amines such as aniline 2.[40] However, good yields were only achieved for benzyl alcohol 25 and the re- action required 50 mol% base (Scheme 11). In 2009, the groups of Stephens and Marr com- bined the fermentation of glycerol 33 by Clostridium butyricum to give 1,3-propanediol 28 with an N-alky- lation of aniline 2 using an iridium catalyst 35.[41,42] After fermentation, the aqueous solution containing 1,3-propanediol 28 was transferred to a sealed tube and aniline 2, iridium catalyst 35, toluene and K2CO3 Scheme 12. Combination of biocatalysis and borrowing hydrogen by Stephens and Marr. were added. The following reaction afforded only 20% conversion but the selectivity for the monoami- nated product 34 was reasonable. The protocol is an interesting combination of biocatalysis and chemoca- talysis applying the borrowing hydrogen methodolo- gy. The reaction sequence is illustrated in Scheme 12. The group of Kempe has developed an in situ-gen- erated iridium catalyst for the N-alkylation of anilines and aminopyridines with primary alcohols.[43] The low Scheme 13. Selective amination of 3-amino-1-propanol by Kempe. reactivity of aliphatic amines was used for a selective amination of aminoalcohols.[44] Intramolecular cycliza- tion reactions occurred when five or six membered rings are formed. As an example the reaction of 2- aminopyridine 36 and 3-amino-1-propanol 37 is dis- played in Scheme 13. Kempe et al. further demon- strated this catalyst to be active under comparatively Scheme 14. Alkylation of diamines under mild conditions by Kempe. mild conditions.[45] Although similar amine alkylations are usually performed at about 110 8C, very good yields were achieved at 70 8C using low catalyst load- ings. An example is given in Scheme 14. As aminopyridines showed higher reactivity com- pared to anilines and NMR investigations revealed the replacement of the Py2NPiPr2 (Py=2-pyridyl) ligand 39 by aminopyridines, this motif was recently Scheme 15. Alkylation of anilines with low catalyst loading and temperature by Kempe. applied in the synthesis of an improved molecular- defined catalyst 45.[46] It showed significantly higher performance for the alkylation of anilines with alco- hols than the previously reported system. The highest reactivi- droxyl groups with secondary amines such as diethylamine 46. ty was observed for the reaction of 4-chloroaniline 43 with Good to excellent yields for the monoaminated products (e.g. benzyl alcohol 25 (Scheme 15). However, Kempe’s iridium sys- 51–54) were obtained if an excess of amine was used. Exam- tems have one main drawback: They require stoichiometric ples for this transformation are illustrated in Scheme 16. amounts of base, which lowers the atom efficiency and re- quires aqueous workup. Ruthenium-based Catalysts Bçrner, Andrushko, and co-workers reported the amination [47,48] of alcohols and diols using the iridium pincer complex 49. The combination of [Ru(p-cymene)Cl2]2 with bidentate phos- Here, primary alcohols were converted in moderate to good phine ligands was investigated by the group of Williams. Ini- yields. Again, the addition of base was found to be beneficial. tially, dppf 57 was used as ligand and the authors reported The tolerance of a nitrile functional group within the alcohol successful alkylation of primary and secondary amines with pri- 47 should be highlighted. This protocol was applied to reac- mary alcohols.[49] The protocol was improved by using DPE- tions of ethylene glycol 50 and other diols bearing primary hy- phos 60 as ligand (Scheme 17).[15f] Thus, additional transforma-

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Our group applied the combination of [Ru3(CO)12] and Cata- CXiumPCy 67 [N-phenyl-2-(dicyclohexylphosphanyl)pyrrole] in the N-alkylation of primary amines using primary and secon- dary alcohols.[55] This protocol was further extended to secon- dary amines and secondary alcohols to give tertiary amines, which was at that time a scarcely investigated reaction.[56] In 2009, we demonstrated that this catalyst system is also able to perform the selective monoamination of vicinal diols[57,15f] with secondary amines and anilines.[58] Selective amination at pri- mary hydroxyl groups (products 68, 69) or sterically less hin- dered secondary hydroxyl groups (e.g. 70) was observed Scheme 16. Iridium-catalyzed amination of alcohols and diols by Bçrner and (Scheme 19). Notably, the reaction of p-anisidine did not yield Andrushko. cyclic compounds,[59] but the monoaminated product 68 was formed in reasonable yield. However, in case of ethylene glycol, selective diamination occurred. Bruneau et al. reported a ruthenium-catalyzed N- and C-3-dialkylation of cyclic amines with alcohols.[60] The CÀH-activation was achieved by addition of cam- phorsulfonic acid (CSA). It is believed to support the formation of a cyclic enamine species 76 that can be alkylated by an aldehyde in C-3-position (Scheme 20). Moderate to good yields were achieved converting benzylic alcohols (e.g. 25) with pyrrolidine 71, piperi- dine, or azepane. Hexanol has been shown to be active as well, although the dialkylated product was obtained in moderate yield. Very recently, Deng and co-workers reported the formation of unsymmetrically substituted tertiary amines from primary alcohols and tertiary amines cat- [61] Scheme 17. N-Alkylations by alcohols using [Ru(p-cymene)Cl2]2 by Williams. alyzed by hydrated RuCl3 and dppf 57. The selectiv- ity for the tertiary amine product strongly depended tions such as the formation of tertiary amines (e.g. 59) from primary amines and diols, as well as N-alky- lation of amines with secondary alcohols such as cy- clohexanol 21, could be performed. Very recently, Williams et al. also demonstrated that microwave heating can be used for N-alkylations of amines with alcohols, resulting in much shorter re- action times.[16a] The combination of [Ru(p-cyme- ne)Cl2]2 and DPEphos 60 was successfully employed in all the reactions, previously reported with thermal heating. In 2010, our group and the group of Williams re- Scheme 18. N-Alkylation of indoles using alcohols by Beller and Williams. ported the first homogeneously catalyzed N-alkyla- tion of indoles with alcohols.[50,51] This transformation is remarkable because indole is a poor nucleophile. Activation with base would result in an ambident nu- cleophile that is known to react with alcohols in a C- 3-alkylation.[52] However, in the presence of the Shvo catalyst[53,54] 66 an in situ transfer hydrogenation of indole and the alcohol occurred. The resulting indo- line and aldehyde undergo a condensation reaction and the N-alkylated indole is formed by an intramo- lecular isomerization. Applying primary alcohols, the selectively N-alkylated products (e.g. 63–65) were ob- tained in good to excellent yields (Scheme 18). Scheme 19. Monoamination of vicinal diols by Beller.

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amines reported by the group of Ramn. Here, also heptanol 86 was converted with 2-aminopyridine 36 [15b,d] in the presence of [Cu(OAc)2] (Scheme 24). How- ever, the reaction required stoichiometric amounts of KOtBu and six days reaction time. Successful conversions of primary aliphatic alcohols were also achieved by Prathima et al. employing a copper-aluminum hydrotalcite (CuAl-HT) catalyst. Benzylamine 88 was N-alkylated by heptanol 86 with good yield but 1608C and an excess of K CO were Scheme 20. N- and C-3-Dialkylation of cyclic amines with alcohols by Bruneau. 2 3 required (Scheme 25).[68c] The catalyst was separated from the reaction mixture and was reused five times without losing its reactivity. Shi and co-workers reported an elegant iron oxide immobilized palladium catalyst that was able to per- form the reaction of anilines (e.g. 2) and primary ali- phatic amines with primary benzylic and aliphatic al- cohols such as octanol 1. Notably, a difference of 208C in temperature caused a shift in selectivity from secondary to tertiary amine formation Scheme 21. Formation of unsymmetrically substituted tertiary amines by Deng. (Scheme 26).[69a] on the type and presence of solvent. For instance, conversion of tributylamine 78 and benzylic alcohol 79 afforded product 80 in chlorobenzene, whereas the formation of 77 was favored under neat conditions (Scheme 21). The group of Mizuno investigated heterogeneous ruthenium catalysts for the N-alkylation of primary and secondary amines with primary alcohols. Applying the supported ruthenium hy- [62] droxide catalyst Ru(OH)x/Al2O3, anilines were selectively N- monoalkylated to give secondary amine products for example, [63] [64] 3, 81,or82. In contrast to that, Ru(OH)x/TiO2 catalyzes the formation of tertiary amines such as 83, 84,or85 from aliphat- ic amines and primary alcohols (Scheme 22).[65] The authors also demonstrated, that both catalysts can be separated and reused. This year, Ramn and co-workers reported impregnated ruthenium on magnetite to catalyze the N-alkylation of aro- matic amines such as 36 with primary benzylic alcohols to give secondary amines (Scheme 23).[66] Owing to the magnetic properties of the catalyst, it could be easily separated by a Scheme 22. N-Alkylation of amines using Ru(OH)x/Al2O3 or Ru(OH)x/TiO2 by magnetic field and reused up to ten times. However, only ben- Mizuno. zylic alcohols and aromatic amines have been applied and overstoichiometric amounts (130 mol %) of KOH were required.

Catalysts Based on Other Metals Academic research has not exclusively focused on ruthenium- and iridium-based catalysts. Especially cheap and readily avail- Scheme 23. N-Alkylation of aromatic amines using Ru(OH)3-Fe3O4 by Ramn. able metals such as iron and copper are highly attractive alter- natives for expensive and often toxic heavy metals. In recent years, some reports about N-alkylations of amines have been published employing catalysts based on iron,[18, 67] cop- per,[15b,d,68] palladium,[69] silver,[15a,70] gold,[71] or osmium.[72] They performed well in the conversion of benzylic alcohols, but many of them are also limited to this “most reactive” substrate Scheme 24. Copper-catalyzed N-alkylation of 2-aminopyridine using hepta- class. An exception is the copper-catalyzed N-alkylation of nol by Ramn.

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In 2011, Gusev et al. developed osmium pincer type com- plexes, such as 98, and employed them in the amination of primary amines such as hexylamine 95 with primary alcohols (Scheme 29).[72] Employing 0.1 mol% 98, good yields of the secondary amine products were achieved. The reactions were Scheme 25. Copper-catalyzed N-alkylation of benzylamine by Prathima. performed at very high temperature (2008C), but interestingly the authors observed only traces of tertiary amines.

N-Alkylation of Ammonia or Ammonia Equivalents with Alcohols The application of ammonia as a nucleophile in bor- Scheme 26. Palladium-catalyzed N-alkylation of aniline with octanol by Shi. rowing hydrogen aminations is a long standing goal. Ammonia is a most attractive substrate because it is cheap and might be used with high atom efficien- cy.[73] Thus, the direct synthesis of a symmetrically Interestingly, this protocol does not require base and only substituted secondary or tertiary amine from an alcohol and low catalyst loadings are needed. Notably, in alcohol amina- ammonia requires fewer synthesis steps than the production tions with copper and palladium catalysts it is possible that an of a primary amine followed by an N-alkylation with the corre- alternative mechanism employing transfer hydrogenation sponding alcohol. might be operating. Hence, the initially resulting imine might Clearly, reactions with ammonia gas require pressure equip- be reduced by an intermolecular transfer hydrogenation from ment. Therefore, attempts have been made to use ammonia another amine substrate. equivalents instead for small scale organic synthesis applica- Shi et al. also studied the hybrid material Ag Mo O for al- 6 10 33 tions. In this respect, the group of Mizuno studied the forma- kylation reactions with amines, carboxamides, sulfonamides, tion of secondary and tertiary amines from urea 99 and the and ketones. This unusual catalyst was further shown to be corresponding alcohols employing a reusable heterogeneous active in the coupling of primary aliphatic alcohols, such as ruthenium catalyst.[74] A number of primary alcohols (e.g. 1) decanol 91 with aniline 2 (Scheme 27).[15a] The yield of the sec- were converted selectively into tertiary amines, whereas the re- ondary amine 92 was comparable to his palladium system. action of secondary alcohols such as cyclohexanol 21 afforded secondary amines, owing to steric hindrance of the resulting product (Scheme 30). In both cases, an excess of alcohol was applied.

Mizuno’s group also reported a Cu(OH)x/Al2O3-catalyzed ver- sion for this reaction.[68b] Under comparable conditions, secon- dary amines were obtained from primary benzylic alcohols in Scheme 27. Silver/molybdenum-catalyzed amination of aliphatic alcohols by Shi. very good yields. In 2007 Williams et al. demonstrated the formation of triben- zylamine 101 from benzyl alcohol 25 and ammonium acetate,

catalyzed by the combination of [Ru(p-cymene)Cl2]2 and dppf In 2010, Cao and co-workers reported the use of a Au/TiO2- VS catalyst (VS=very small particles, 1.8 nm) in the N-alkyla- tion of anilines (e.g. 2) with alcohols (Scheme 28).[71a] High yields were achieved using primary (e.g. 1) as well as secon- dary aliphatic alcohols (e.g. 94) and the catalyst was shown to be reusable. When aliphatic amines were converted with these alcohols, only moderate yields were achieved since self cou- Scheme 29. Osmium-catalyzed N-alkylation of hexylamine by Gusev. pling of the amines occurred.

Scheme 30. Application of urea as an ammonia source in alcohol amination Scheme 28. Gold-catalyzed N-alkylation of aniline by Cao. by Mizuno.

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(Scheme 31).[49b] This was the first application of ammonium cessfully converted into the corresponding tertiary amines salts for the synthesis of tertiary amines from alcohols in ho- with high yields. The reaction times were shorter compared to mogeneous catalysis. Fujita’s iridium system, but an excess of alcohol (5 equiv) was required and no example for the conversion of secondary alco-

hols was described. In addition, Mizuno applied a Cu(OH)x/

Al2O3 catalyst for the synthesis of tribenzylamine 101 from benzyl alcohol 25.[68b] Both systems are shown in Scheme 34. The use of aqueous ammonia or its equivalents is attractive with respect to atom economy and handling, but none of the Scheme 31. Synthesis of tribenzylamine by Williams. reported systems were successfully applied for the synthesis of

Fujita and co-workers also studied the application of ammonium salts for the in situ generation of am- monia and subsequent alkylation using alcohols.[75] In the presence of [IrCp*Cl2]2 and NaHCO3, secondary al- cohols were converted into secondary amines in yields up to 84 %. Interestingly, the product selectivity for the reaction of primary alcohols (e.g. 25, 102) de- Scheme 34. Alkylation of aqueous ammonia with alcohols by Mizuno. pended on the type of alcohol, as well as the kind of ammonium salt (Scheme 32). primary amines. As primary amines are very useful intermedi- ates for further derivatization reactions, the development of novel methods for the synthesis of primary amines is of ongo- ing interest[77] and different procedures applying the borrow- ing hydrogen methodology have been developed. An interest- ing approach is the introduction of an N-nucleophile followed by deprotection. In principle, the N-nucleophile can be consid- ered as an ammonia equivalent. Scheme 32. Alkylation of ammonium salts with alcohols by Fujita. In 2009, the group of Williams reported the coupling of dif- ferent primary alcohols (e.g. 18) with 1-phenylethylamine 17. Unfortunately, alkylation reactions of ammonium salts gener- Addition of Pd/C (10 wt%), ethanol and acid in a hydrogen at- ate stoichiometric amounts of waste salts. In this respect, the mosphere gave primary amines in up to 83% isolated yield application of aqueous ammonia for such transformations is (Scheme 35).[78] Since benzyl groups are removed during the more attractive. Accordingly, Fujita and co-workers applied deprotection step, an alternative route was developed for the their water-soluble dicationic catalyst 23 in the alkylation of synthesis of primary benzylamines from benzylic alcohols. Ap- aqueous ammonia with alcohols. Primary alcohols such as hex- plication of trimethylsilylethanesulfonamide 106 as the N-nu- anol 102 were converted into tertiary amines in very good cleophile followed by in situ deprotection using CsF/DMF re- yields, whereas secondary amines were obtained again in the sulted in primary amine formation with good yields. The syn- amination of cyclohexanol 21 and other secondary alcohols (Scheme 33).[76] Notably, the reaction is not driven by an excess of alcohol, since a 3:1 ratio of al- cohol to ammonia (2:1 in case of secondary alcohols) was applied. Furthermore, the catalyst could be reused three times by addition of dichloromethane followed by phase separation. In 2010 Mizuno and co-workers reported an N-alky- lation of aqueous ammonia using their Ru(OH) /TiO x 2 Scheme 35. Amination of alcohols and subsequent deprotection of the resulting secon- [65] system. Hence, primary alcohols (e.g. 1) were suc- dary amine by Williams.

thesis of benzylamine 88 is displayed in Scheme 36.[78] A similar protocol has recently been published by the group of Yus.[15b,d] For instance, p-toluenesulfona- mide 108 was N-alkylated with benzylic alcohol 25 in an efficient copper-catalyzed reaction followed by deprotection to give the desired benzyl amine 88 Scheme 33. Alkylation of aqueous ammonia with alcohols by Fujita. (Scheme 37).

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Scheme 39. Amination of nonadecane 1,19-diamine with ammonia by Kçckritz.

Scheme 36. Synthesis of benzylamine by means of sulfamidation/deprotec- tion by Williams. secondary amines and oligomers. Notably, the diol was obtained in a two step procedure from high- oleic sunflower oil. Thus, the resulting diamine is de- rived from vegetable oils. The synthesis of primary amines from secondary al- cohols and ammonia was achieved in 2010 inde- pendently by our group[82] and Vogt and co-work- ers.[83] Both groups successfully converted a number of secondary alcohols into the corresponding amines

using the combination of [Ru3(CO)12] and commercial- Scheme 37. Synthesis of benzylamine by means of sulfamidation/deprotection by Yus. ly available CataCXiumPCy 67. Selected results for products (116–118) from our work are given in Scheme 40. In addition, also two benzylic primary al- Although these preparation methods resulted in good to ex- cohols were converted (e.g. product 119), although the ach- cellent yields and can be applied without high pressure equip- ieved yields were lower and more catalyst was required com- ment, the lower atom efficiency resulting from the amination/ pared to the procedure reported by Milstein. deprotection sequence is a drawback. Hence, it was interesting to note that in 2008 Gunanathan and Milstein reported the first selective synthesis of primary amines from alcohols using inexpensive ammonia gas (Scheme 38).[79,80] More specifically, in the presence of a ruthe- nium PNP pincer complex 113, primary benzylic amines such as 110 were synthesized from the corresponding primary alco- hols in good to excellent yields. The conversion of most non- benzylic alcohols, such as 2-phenylethanol, resulted in a mix- ture of primary and secondary amines, which indicates alkyla- tion of phenethylamine 111 by itself or the alcohol. Therefore, Scheme 40. Synthesis of primary amines from ammonia and secondary alco- the reaction times were optimized for these substrates to pre- hols by Beller.

Most recently, our group developed a second gen- eration catalyst system for such transformations.[84] The starting point was the selective diamination of isosorbide 120, which is available from d-glucose on industrial scale. The resulting diamine 121 constitutes a potential building block for novel renewable poly- mers. A broad screening of catalysts and reaction Scheme 38. Synthesis of primary amines from alcohols and ammonia by Milstein. conditions revealed the combination of [Ru(CO)ClH- [85] (PPh3)3] and Xantphos 122 to be most active (Scheme 41). In addition, the system was successfully vent consecutive reactions. The selectivity towards primary applied for the amination of primary and secondary alcohols amines was increased by running the reaction in water or a including diols and hydroxyl-substituted esters. mixture of water and organic solvents. This was explained by In addition, our group employed the combination of hydrolysis of secondary imines. Notably, the reaction requires [Ru3(CO)12] and the bidentate DCPE ligand 126 for the amina- only 0.1 mol% catalyst loading, which indicates the high activi- tion of a-hydroxy amides using aromatic and aliphatic amines ty of the Milstein catalyst. as well as ammonia.[86] The method provides access to a- Very recently, Kçckritz, Martin, and co-workers applied Mil- amino acid amides, a structural motive included in a number stein’s catalyst 113 in the synthesis of nonadecane 1,19-dia- of bioactive compounds. Examples for the application of am- mine 115 from nonadecane 1,19-diol 114 and ammonia monia (products 127–129) are displayed in Scheme 42. (Scheme 39).[81] The reaction afforded only small amounts of

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Acknowledgements

Our work covered in this review was supported by the BMBF and the Deutsche Forschungsgemeinschaft (Leib- niz-price). ZM gives thanks for a grant from the Alexander-Humboldt foundation.

Keywords: alcohols · amines · ammonia · catalysis · transition metals

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