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 350–500 8C 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.
Albert-Einstein-Str. 29a, 18059 Rostock (Germany)
Among the various known procedures to prepare amines, the
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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 M. Beller et al.

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 (> 200 8C) 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. SN alcohol amination using an iron catalyst by Saito.
Heterogeneous catalysts for alcohol amination have
been known since the first half of the twentieth cen-
Although the reaction temperature is high (200 8C), some allylic tury,[25] but no homogeneously catalyzed version was
alcohols have been successfully converted at 100 8C. 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
(Scheme 5), using [RuCl2(PPh3)3] as the catalyst.[27] 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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The Catalytic Amination of Alcohols

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 180 8C 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*Cl2]2 and K2CO3 in 2002,[29] a series of novel catalysts for
Scheme 8. [IrCp*I2]2 catalyzed N-alkylations with alcohols by Williams.
the N-alkylation of amines using alcohols under milder condi-
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
protocol by changing the base to NaHCO3.[33] 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 110 8C (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
hols in the presence of [IrCp*Cl2]2.[34] 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.

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 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 C H activation of the
aromatic ring.
The group of Crabtree has developed an iridium
complex bearing an N-heterocyclic carbene 32. It was
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
of alcohols and diols using the iridium pincer complex 49.[47, 48] 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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The Catalytic Amination of Alcohols

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 C H-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-
Scheme 17. N-Alkylations by alcohols using [Ru(p-cymene)Cl2]2 by Williams. alyzed by hydrated RuCl3 and dppf 57.[61] 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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 M. Beller et al.

amines reported by the group of Ramn. Here, also

heptanol 86 was converted with 2-aminopyridine 36
in the presence of [Cu(OAc)2] (Scheme 24).[15b, d] 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 160 8C and an excess of K2CO3 were
Scheme 20. N- and C-3-Dialkylation of cyclic amines with alcohols by Bruneau.
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
20 8C 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-
droxide catalyst Ru(OH)x/Al2O3,[62] anilines were selectively N-
monoalkylated to give secondary amine products for example,
3, 81, or 82.[63] In contrast to that, Ru(OH)x/TiO2[64] catalyzes the
formation of tertiary amines such as 83, 84, or 85 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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The Catalytic Amination of Alcohols

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 (200 8C), 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 Ag6Mo10O33 for al-
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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 M. Beller et al.

(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)x/TiO2 Scheme 35. Amination of alcohols and subsequent deprotection of the resulting secon-
system.[65] 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).

1860 www.chemcatchem.org  2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ChemCatChem 2011, 3, 1853 – 1864
The Catalytic Amination of Alcohols

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-
(PPh3)3] and Xantphos[85] 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

ChemCatChem 2011, 3, 1853 – 1864  2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemcatchem.org 1861
 M. Beller et al.

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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