Selective iridium-catalyzed alkylation of (hetero)aromatic amines and diamines with alcohols under mild reaction conditions

Article abstract of DOI:10.1002/chem.200802318

A P,N-ligand-coordinated iridium complex has been employed as an efficient catalyst for the selective monoalkylation of (hetero) aromatic amines with alcohols. A significant improvement of this alkylation method has been achieved, such that it can be performed at a temperature of 70°C and with catalyst loadings as low as 0.1 mol% Ir, while still affording excellent yields of secondary amines. Furthermore, the high selectivity of this catalyst for the monoalkylation of aromatic amino functions has been successfully exploited for the alkylation of diamines in both symmetric and non-symmetric fashions, providing a novel and very efficient synthetic tool for the preparation of N,N'-dialkylated aromatic diamines.

Full text of DOI:10.1002/chem.200802318

DOI: 10.1002/chem.200802318
Selective Iridium-Catalyzed Alkylation of (Hetero)Aromatic Amines and
Diamines with Alcohols under Mild Reaction Conditions
Benoꢀt Blank, Stefan Michlik, and Rhett Kempe*[a]
Abstract: A P,N-ligand-coordinated iri-
dium complex has been employed as
an efficient catalyst for the selective
monoalkylation of (hetero)aromatic
amines with alcohols. A significant im-
provement of this alkylation method
has been achieved, such that it can be
performed at a temperature of 708C
and with catalyst loadings as low as
0.1 mol% Ir, while still affording excel-
lent yields of secondary amines. Fur-
thermore, the high selectivity of this
catalyst for the monoalkylation of aro-
matic amino functions has been suc-
cessfully exploited for the alkylation of
diamines in both symmetric and non-
symmetric fashions, providing a novel
and very efficient synthetic tool for the
preparation of N,N’-dialkylated aro-
matic diamines.
Keywords: alkylation
iridium · P,N ligands
· amines ·
Introduction
is an interesting and promising method, since a great variety
of inexpensive alcohols is commercially available and water
is the only by-product of the reaction, rendering the reaction
very atom-economic. Unfortunately, this reaction has a rep-
utation of being rather problematic in terms of catalyst load-
ing and reaction temperature. The first homogeneous cata-
lysts employed for the alkylation of amines with alcohols
were mainly based on ruthenium,[6] as well as rhodium,[7] iri-
dium,[7] and platinum,[8] but were only moderately selective
and needed very high reaction temperatures >1808C. In the
last few years, this type of reaction has again received wide-
spread attention due to the development of a more selective
Ru catalyst by Beller et al. that can be used for the alkyla-
tion of aliphatic amines with primary as well as secondary
alcohols.[9] Another highly efficient Cp*Ir-based catalyst
(Cp*=pentamethylcyclopentadienyl) has been reported by
Fujita et al., which allows the reaction of a great variety of
aromatic as well as aliphatic amines with primary and secon-
dary alcohols and a controlled selectivity in favor of mono-
alkylation.[10] The mechanism of this Ir-catalyzed amination
reaction has also recently been studied by DFT calcula-
tions,[11] affording a better understanding of the reaction
pathways. Significant contributions by Williams et al. have
led to a broadened application scope for the amination of
alcohols[12] and a better understanding of the “borrowing hy-
drogen” mechanism.[13] Following on from this mechanistic
approach, Beller et al. recently reported a very efficient
method for the synthesis of secondary amines starting di-
rectly from aliphatic amines and anilines using the Shvo cat-
alyst.[14] Herein, we present an optimized method for the se-
lective Ir-catalyzed monoalkylation of (hetero)aromatic
Nitrogen-containing molecules and especially amines are a
very important class of compounds. They find widespread
application in both the bulk and fine chemical industries as
basic intermediates, additives, dyes, and agrochemicals, as
well as in the pharmaceutical industry.[1] The development
À
of simple methods for the selective formation of C N bonds
is therefore of great importance. The best known method
for the alkylation of amines is their nucleophilic substitution
reaction with haloalkanes.[2] However, this reaction is only
moderately selective and the mono-, di-, and trialkylated
amines as well as quaternary ammonium salts are obtained.
Therefore, several synthetic protocols for the selective alky-
lation of amines have been developed in the last decades,
such as the reductive amination of carbonyl compounds[3] or
the hydroamination[4] and hydroaminomethylation[5] of C C
À
multiple bonds. However, these methods have certain incon-
veniences. The direct reductive amination of carbonyl com-
pounds is still rather difficult to accomplish and this reaction
is therefore mostly performed in two steps, by reduction of
a previously prepared imine. Compared to the well-estab-
lished intramolecular hydroamination reaction, the intermo-
lecular coupling of alkenes and amines is still very challeng-
ing. Hence, the catalytic alkylation of amines using alcohols
[a] B. Blank, S. Michlik, Prof. Dr. R. Kempe
Lehrstuhl fꢀr Anorganische Chemie II
Universitꢁtsstraße 30, NW I, 95440 Bayreuth (Germany)
Fax : (+49)921-55-2157
E-mail: kempe@uni-bayreuth.de
3790
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 3790 – 3799

FULL PAPER
amines that proceeds efficiently under rather mild condi-
tions, at 708C and with catalyst loadings as low as 0.1 mol%
Ir. Also, a new protocol for the symmetric and nonsymmet-
ric N,N’-dialkylation of diamines with alcohols is reported,
demonstrating the potential of our catalyst towards a broad
scope of substrates.
methyl ether) per mmol of substrate had been added to the
reaction mixture, since this had afforded the best results in
the first solvent screening. However, the quantity used had
not been examined and so our goal here has been to deter-
mine the smallest possible amount of solvent, in anticipation
of higher catalytic activity in a more concentrated reaction
mixture. All optimization studies were carried out with 2-
aminopyridine and benzyl alcohol as model substrates
(Scheme 2).
Results and Discussion
Optimization of the reaction conditions: Recently, we re-
ported on a novel P,N-ligand-stabilized[15] iridium catalyst
for the selective monoalkylation of amines with alcohols.[16]
The complex was generated in situ from [IrClACTHNURGTNEUNG(cod)]2 (cod=
Scheme 2. Model reaction used for the variation of several reaction pa-
rameters.
cis-1,5-cyclooctadiene) and the P,N-ligand Py2NPiPr2 (1)
(Scheme 1). In this first study, the reaction conditions for
Interestingly, the results in Table 1 show that the yield of
the reaction is not significantly dependent on the addition of
diglyme to the reaction mixture, since even the reaction
without the addition of diglyme (entry 7) afforded an excel-
lent yield of the alkylated product. However, the use of
0.2 mL of diglyme was chosen for all further reactions
(entry 6) since incomplete dissolution of the base in the very
small amount of THF from the catalyst stock solutions
could thereby be avoided. Moreover, towards the end of the
reaction, the solution otherwise became very viscous, which
could lead to insufficient stirring.
Scheme 1. In situ formation of the catalyst from [IrClACTHNUGTRENUNG(cod)]2 and P,N-
ligand 1.
the alkylation of anilines were optimized by the screening of
several reaction parameters, such as the addition of base,
the use of different solvents, base/substrate and alcohol/sub-
strate ratios, as well as the catalyst loading. As a result, we
developed a very useful method not only for the selective
monoalkylation of aromatic amines such as aniline, but also
for heteroaromatic substrates such as aminopyridines, which
are usually more difficult to alkylate.[17] In order to further
improve this method for the alkylation of heteroaromatic
substrates, several reaction parameters that had not been
tested before, such as the amount of solvent and the temper-
ature, have now been evaluated with regard to higher cata-
lyst efficiencies as well as milder reaction conditions. In all
former reactions, 1 mL of diglyme (diethylene glycol di-
Table 1. Influence of the volume of solvent.[a]
Volume of solvent (diglyme) [mL]
Yield [%][b]
1
2
3
4
5
6
7
2.0
1.0
0.8
0.5
0.4
0.2
0
77
83
78
83
81
90
85
[a] Reaction conditions: 1.0 mmol 2-aminopyridine, 1.1 mmol benzyl al-
cohol, 1.0 mol% [IrCl(cod)]2, 2.0 mol% Py2NPiPr2 (1), 1.1 mmol KOtBu,
AHCTUNGTRENNUNG
0–2 mL diglyme, 1108C, 24 h. [b] Yield determined by GC analysis with
dodecane as internal standard.
Abstract in German: Ein P,N-Ligand-koordinierter Iridium-
komplex wird als ein effizienter Katalysator fꢀr die selektive
Monoalkylierung von (hetero)aromatischen Aminen mit Al-
koholen beschrieben. Eine signifikante Verbesserung dieser
Alkylierungsmethode wurde erreicht. Bei Temperaturen von
708C und mit Katalysatorbeladungen von bis zu 0.1 mol% Ir
konnten exzellente Ausbeuten fꢀr sekundꢁre Amine erhalten
werden. Weiterhin konnte die hohe Selektivitꢁt des Katalysa-
tors hinsichtlich der Monoalkylierung von aromatischen
Aminogruppen genutzt werden, um Diamine symmetrisch
und unsymmetrisch zu alkylieren. Damit steht ein neues sehr
effizientes Synthesewerkzeug zur Darstellung von N,N’-alky-
lierten aromatischen Diaminen zur Verfꢀgung.
Having successfully lowered the amount of added solvent
to a fifth of the original quantity, we proceeded to deter-
mine the optimal catalyst loading for this reaction, since cat-
alyst cost is a very important aspect for the application of a
catalyst in organic synthesis (Table 2).
Screening of the catalyst loading showed that in the range
from 2.0 to 0.1 mol% Ir (entries 1–5) the yield of the prod-
uct remained relatively constant and that even with
0.05 mol% Ir (entry 6) a satisfactory yield could still be ob-
tained. As expected, a higher concentration of the reaction
mixture increased the efficiency of the catalyst and there-
fore 0.1 mol% Ir was determined as a minimum for all fur-
ther reactions. Interestingly, the reaction also took place to
Chem. Eur. J. 2009, 15, 3790 – 3799
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3791

R. Kempe et al.
Table 2. Reduction of the catalyst loading.[a]
mol% Ir[b]
only been obtained with 2 mol% of catalyst, it was of inter-
est to determine whether the reduction of the solvent quan-
tity could also be beneficial for the alkylation of anilines.
Therefore, a further screening of the catalyst loading was
performed with aniline and benzyl alcohol under the above
optimized reaction conditions (Table 4). As expected, the
Yield [%][c]
1
2
3
4
5
6
7
2.0
1.0
0.6
0.2
0.1
0.05
0
90
87
92
85
90
74
10
Table 4. Reduction of the catalyst loading for the alkylation of anilines.[a]
[a] Reaction conditions: 1.0 mmol 2-aminopyridine, 1.1 mmol benzyl al-
cohol, 0–1.0 mol% [IrCl(cod)]2, 0–2.0 mol% Py2NPiPr2 (1), 1.1 mmol
AHCTUNGTRENNUNG
KOtBu, 0.2 mL diglyme, 1108C, 24 h. [b] Catalyst loading in mol% Ir.
[c] Yield determined by GC analysis with dodecane as internal standard.
mol% Ir[b]
Yield [%][c]
1
2
3
4
5
6
2.0
1.0
0.6
0.4
0.2
0.1
97
96
93
87
71
38
some extent when no catalyst was used, affording about
10% of the alkylated product (entry 7). Lastly, the tempera-
ture for this alkylation reaction was also re-evaluated. Most
recent protocols from the literature need elevated tempera-
tures of at least 1108C in order to alkylate amines with alco-
hols.[9,10,12,16] A lower reaction temperature would not only
be beneficial from a technical point of view, but would also
allow the use of more sensitive substrates that would decom-
pose at higher temperatures. In previously conducted reac-
tions, decomposition of chloro-substituted benzyl alcohols
had been observed at 1108C, leading to a partial loss of the
chlorine atom in the final product. Also, the reaction of 4-
(trifluoromethyl)benzyl alcohol with 2-aminopyridine could
not be performed, since the starting materials easily decom-
posed. The effect of varying the temperature on the alkyla-
tion of 2-aminopyridine with benzyl alcohol is summarized
in Table 3. These results show that the reaction could readily
[a] Reaction conditions: 1.0 mmol aniline, 1.1 mmol benzyl alcohol, 0.05–
1.0 mol% [IrCl(cod)]2, 0.1–2.0 mol% Py2NPiPr2 (1), 1.1 mmol KOtBu,
0.2 mL diglyme, 708C, 24 h. [b] Catalyst loading in mol% Ir. [c] Yield de-
AHCTUNGTRENNUNG
termined by GC analysis with dodecane as internal standard.
optimized reaction conditions for 2-aminopyridine could
also be applied for the alkylation of anilines. However, the
results presented in Table 4 clearly show that anilines are
less reactive compared to heteroaromatic amines and that
catalyst loadings of at least 0.6 mol% Ir have to be em-
ployed (entry 3) to achieve full conversion of the substrate
and excellent yields of the product. It seems that the catalyst
is very sensitive to electronic effects, since electron-rich ali-
phatic amines cannot be alkylated at all, whereas the cata-
lytic activity increases with decreasing electron density on
the amine, heteroaromatic substrates therefore being most
efficiently alkylated. Moreover, this catalytic system is the
first reported to be highly efficient for the alkylation of het-
eroaromatic amines with alcohols, because these substrates
can lead to the deactivation of other catalysts due to their
strong coordinating potential. Deprotonated aminopyridines
are a well described class of ligands.[18,19]
Table 3. Influence of the temperature.[a]
T [8C]
Yield [%][b]
1
2
3
4
5
110
90
70
50
25
95
94
93
69
55
[a] Reaction conditions: 1.0 mmol 2-aminopyridine, 1.1 mmol benzyl al-
cohol, 0.05 mol% [IrCl(cod)]2, 0.1 mol% Py2NPiPr2 (1), 1.1 mmol
AHCTUNGTRENNUNG
In summary, the efficiency of our catalytic system has
been further increased through reduction of the amount of
solvent and as a result catalyst loadings as low as 0.1 mol%
Ir and milder reaction temperatures of only 708C may be
applied. The optimal reaction conditions for the alkylation
of aromatic amines with alcohols are now: 1.0 mmol amino-
pyridine, 1.05 mmol alcohol, 1.1 mmol KOtBu, 0.2 mL di-
KOtBu, 0.2 mL diglyme, 25–1108C, 24 h. [b] Yield determined by GC
analysis with dodecane as internal standard.
be performed at just 708C (entry 3), affording the same re-
sults as at higher temperatures (entries 1 and 2). The effi-
ciency of the catalytic system significantly decreases when
the reaction is performed at 508C, but moderate yields of
the product could nevertheless be obtained even at room
temperature. The above studies showed our catalyst to be
especially efficient for the alkylation of heteroaromatic sub-
strates such as aminopyridines, which prompted us to deter-
mine whether the mild reaction conditions and the low cata-
lyst loadings were restricted to aminopyridines, or whether
they could also be applied for the alkylation of anilines.
Since in our first study full conversions of the latter had
glyme, 0.05 mol% [IrClACHTNUGTRNE(GNU cod)]2, 0.1 mol% Py2NPiPr2 (1), re-
action temperature: 708C, time: 24 h.
Based on these optimized reaction conditions, the general
applicability of this method for the monoalkylation of 2-
aminopyridine with various substituted benzylic as well as
aliphatic alcohols is presented in Table 5.
These results show that under the optimized reaction con-
ditions (hetero)aromatic amines can be efficiently alkylated
with a variety of substituted benzyl alcohols bearing func-
3792
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 3790 – 3799

Selective Monoalkylation of Amines with Alcohols
FULL PAPER
Table 5. Iridium-catalyzed N-alkylation of 2-aminopyridine with several
loading of 0.6% Ir, affording the secondary amine 2e in
75% yield (entry 5), which had hitherto not been possible
due to decomposition of the starting material. Besides para-
substituted benzyl alcohols, ortho-substituted benzyl alco-
hols are also well tolerated and, with a slightly higher cata-
lyst loading of 0.3 mol% Ir, the reaction with 2-methylben-
zyl alcohol readily afforded the secondary amine 2g in 90%
yield (entry 7). The more sterically hindered substrate 2-me-
thoxybenzyl alcohol also afforded the corresponding amine
2 f in excellent yield (entry 6). The need for a higher catalyst
loading and a longer reaction time with this substrate can be
rationalized in terms of increased steric demand of the
ortho-methoxy group compared to the smaller ortho-methyl
group. In all of the reactions discussed thus far, substituted
benzyl alcohols that innately favor the deprotonation of the
alcohol function due to their electron-withdrawing nature
were employed. Hence, the reaction was also performed
with 1-butanol (entry 8) as a general example that the
method can also be used with aliphatic alcohols, even
though this required a higher catalyst loading of 2 mol% Ir
and a longer reaction time of 48 h due to the electron-donat-
ing nature of the alkyl backbone and hence decreased pro-
clivity for deprotonation of the alcohol.
alcohols.[a]
mol% Ir[b]
Alcohol
Product
Yield
[%][c]
1
2
0.1
93
89
0.2
0.1
0.2
3
4
86
71
5
6
7
0.6
0.8
0.3
75
Alkylation of diamines with alcohols: One of the outstand-
ing properties of the present catalyst is its high selectivity
for monoalkylation of (hetero)aromatic amines. There are,
of course, other recently developed catalytic systems that
provide good selectivity in favor of the monoalkylation of
primary amines, but in most cases the alcohol cannot be
added in excess, since this would favor the formation of the
tertiary amine. On the contrary, with the present catalyst, no
dialkylation of the amino function to afford the tertiary
amine could be observed in any reaction, irrespective of the
amount of alcohol or base added, even with high catalyst
loadings and after very long reaction times (Scheme 3).
92[d]
90
8
2.0
83[d]
[a] Reaction conditions: 1.0 mmol 2-aminopyridine, 1.05 mmol alcohol,
[IrCl(cod)]2, Py2NPiPr2 (1), 1.1 mmol KOtBu, 0.2 mL diglyme, 708C, 24 h.
ACHTUNGTRENNUNG
[b] Catalyst loading in mol% Ir. [c] Isolated yield. [d] 48 h.
Scheme 3. High selectivity of the catalyst for monoalkylation of amines.
tional groups in their para (entries 2–5) or ortho positions
(entries 6 and 7), affording the expected secondary amines
2a–h in yields ranging from 71 to 93%. Both electron-with-
drawing (entries 4 and 5) and electron-donating substituents
(entries 2, 3, 6, and 7) are well tolerated. However, in the
case of 4-chlorobenzyl alcohol the catalyst loading had to be
increased to 0.2 mol% Ir, otherwise a full conversion could
not be observed, not even after a prolonged reaction time of
48 h. Loss of the chlorine atom in the final product, resulting
in the formation of unwanted benzylpyridin-2-ylamine, did
not occur, a fact that can certainly be attributed to the
milder reaction temperature of 708C. For the first time, it
was also possible to perform the alkylation reaction with 4-
(trifluoromethyl)benzyl alcohol, albeit with a higher catalyst
Hence, it was of interest to determine whether this selec-
tivity for the monoalkylation of primary aromatic amino
functions could be used for the N,N’-dialkylation of di-
AHCTUNGTREGaNNNU mines. Only very few synthetic procedures for the prepara-
tion of such compounds can be found in the literature,
which variously require very high reaction temperatures (up
to 2508C),[20] previous protection of the amino groups and
subsequent treatment with alkyl halides,[21] or a reductive
amination pathway.[22] In most cases, these transformations
are either not selective or have to be performed in several
steps and thus lack general applicability towards a broad
range of substrates. The reaction of 2,6-diaminopyridine
Chem. Eur. J. 2009, 15, 3790 – 3799
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3793

R. Kempe et al.
Table 7. Ir-catalyzed alkylation of 2,6-diaminopyridine with various alcohols.[a]
with two equivalents of benzyl alcohol was chosen as a
model reaction. Since the alkylation of both amino functions
of the substrate is more demanding than that of simple ami-
nopyridines, the reaction time was increased to 48 h and the
catalyst loading was re-examined. The results of this study
are summarized in Table 6.
mol%
Ir[b]
Alcohol
Product
Yield
[%][c]
Table 6. Determination of the optimal catalyst loading for the alkylation
of 2,6-diaminopyridine.[a]
1
2
3
0.6
0.6
0.6
94
90
97
mol% Ir[b]
4a Yield [%][c]
3a Yield [%][c]
1
2
3
4
5
6
7
8
2.0
1.0
0.8
0.6
0.5
0.4
0.3
0.2
0.1
0
0
1
1
1
8
13
15
23
48
1
89
86
84
81
76
75
66
58
20
0
4
5
6
7
0.6
0.6
1.4
1.4
87
93
82
86
9
10
[a] Reaction conditions: 1.0 mmol 2,6-diaminopyridine, 2.1 mmol benzyl
alcohol, 0–1.0 mol% [IrCl(cod)]2, 0–2.0 mol% Py2NPiPr2 (1), 2.2 mmol
AHCTUNGTRENNUNG
KOtBu, 0.2 mL diglyme, 708C, 48 h. [b] Catalyst loading in mol% Ir.
[c] Yield determined by GC analysis with dodecane as internal standard.
As is evident from the results in Table 6, it is possible to
selectively monoalkylate both amino functions of the di-
ACHTUNGTRENNUNGamine, affording the corresponding product 3a in excellent
yield. However, as expected, this reaction needs slightly ele-
vated catalyst loadings in order to obtain full conversions.
Moreover, the reaction occurs in two separate alkylation
steps since, depending on the catalyst loading, the unilateral-
ly monoalkylated diamine 4a is observed as a by-product.
The use of 0.6 mol% Ir represents a good compromise be-
tween catalyst loading and yield of the dialkylated diamine
(Table 6, entry 4). In order to demonstrate the general ap-
plicability of this method, 2,6-diaminopyridine was reacted
with several substituted benzyl- as well as aliphatic alcohols,
affording the symmetrically N,N’-dialkylated diamines 3a–i
in excellent yields (Table 7).
8
9
0.6
0.8
90
88[d]
[a] Reaction conditions: 1.0 mmol 2,6-diaminopyridine, 2.1 mmol alcohol,
[IrCl(cod)]2, Py2NPiPr2 (1), 0.2 mL diglyme, 0.35 mL THF, 2.2 mmol KOtBu,
708C, 48 h. [b] Catalyst loading in mol% Ir. [c] Isolated yield. [d] 4.0 mmol
AHCTUNGTRENNUNG
methanol.
First, 2,6-diaminopyridine was reacted with benzyl alcohol
(entry 1), which afforded N,N’-dibenzylpyridine-2,6-diamine
(3a) in 94% yield. Next, several substituted benzyl alcohols
were employed (entries 2–7), and, as determined before for
the alkylation of 2-aminopyridine (Table 5), both electron-
donating (entries 2 and 3) and electron-withdrawing
(entry 4) substituents in the para position are well-tolerated,
these reactions affording the dialkylated products in yields
ranging from 87 to 97%. The excellent yield in the case of
the reaction of 4-methoxybenzyl alcohol with 2,6-diamino-
pyridine (entry 3) can be attributed to the limited solubility
of N,N’-bis(4-methoxybenzyl)pyridine-2,6-diamine (3c) in
THF and diglyme; the product precipitates from the solu-
tion, thereby shifting the reaction equilibrium in its favor.
Furthermore, benzyl alcohols bearing substituents in the
meta position may also be used in this reaction, affording
excellent yields of the alkylated product (entry 5). However,
in the case of ortho-substituted benzyl alcohols, for example
with 2-methylbenzyl alcohol (entry 7) or 2-methoxybenzyl
alcohol (entry 6), the reaction is more difficult and the cata-
lyst loading had to be raised to 1.4 mol% Ir. Substituents in
the ortho position have a higher steric demand and probably
hamper the coordination of the imine to the catalyst and the
transfer of the hydride to the latter. As is evident from en-
tries 6 and 7, the reaction of 2-methylbenzyl alcohol with
2,6-diaminopyridine affords a better yield than that of 2-me-
3794
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 3790 – 3799

Selective Monoalkylation of Amines with Alcohols
FULL PAPER
thoxybenzyl alcohol, since the methoxy group has a slightly
greater steric demand compared to the methyl group. No
such differentiation is observed when these substituents are
in the meta or para positions.
In addition, aliphatic alcohols could also be employed as
substrates for this reaction. As a first example the reaction
was performed with 1-butanol, which afforded N,N’-dibutyl-
pyridine-2,6-diamine (3h) in 90% yield (entry 8). Methanol
was also used for the alkylation reaction (entry 9), since the
selective methylation of amines is of great synthetic interest.
This interest stems from the fact that highly toxic and carci-
nogenic methyl iodide is usually employed as the methylat-
ing agent, which leads to non-selective methylation of di-
ACHTUNGTRENNUNGamines. As shown in entry 9, it is possible to selectively di-
methylate 2,6-diaminopyridine using methanol with a cata-
lyst loading of 0.8 mol% Ir, affording 3i in 88% yield. The
excess of methanol used for this reaction was to ensure its
good availability as a reagent because it might be in a state
of reflux at a reaction temperature of 708C. However, due
to the high selectivity of the catalyst for monoalkylation,
this excess of methanol did not present a problem.
Figure 1. Time–conversion plot for the reaction of 2,6-diaminopyridine
with benzyl alcohol. Reaction conditions: 4.0 mmol 2,6-diaminopyridine
~
&
*
( : 4a, : 3a), 8.4 mmol benzyl alcohol ( ), 0.3 mol% [IrClACHTUNGTRENNUNG(cod)]2,
0.6 mol% Py2NPiPr2 (1), 0.8 mL diglyme, 4.4 mL THF, 8.8 mmol KOtBu,
708C, 53 h. Conversion and yields determined by GC analysis with do-
decane as internal standard.
As stated before, the Ir-catalyzed dialkylation of diamines
with alcohols is a two-step reaction, in which the starting di-
amine is first monoalkylated on one side and then the
second amino function is alkylated. The possibility of non-
symmetrically alkylating diamines with different alcohols
without having to first protect one amino group would be
even more interesting than the preparation of symmetrically
dialkylated substrates. The reaction was therefore repeated
with exactly one equivalent of alcohol with the aim of selec-
tively obtaining the unilaterally alkylated diamine 4a
(Scheme 4). However, 4a could only be obtained in 57%
led to a 54% isolated yield of 4a (Scheme 4). However, it is
interesting to see that the alkylation of the second amino
group is not kinetically inhibited, but that the favored reac-
tion of 2,6-diaminopyridine with the alcohol in the first
hours of the reaction is merely due to a higher concentra-
tion of starting material compared to that of the steadily
forming intermediate 4a. The alcohol was hence employed
as the limiting substrate and the reaction was performed
with an excess of the diamine. The addition of two equiva-
lents of 2,6-diaminopyridine to only one equivalent of
benzyl alcohol successfully led to a quantitative yield of N-
benzylpyridine-2,6-diamine (4a) (Scheme 5).
Scheme 4. Reaction of 2,6-diaminopyridine with one equivalent of benzyl
alcohol to afford the mono-N-alkylated product (4a) and the N,N’-dialky-
lated product (3a).
Scheme 5. Preparation of N-benzyl-pyridine-2,6-diamine (4a) using an
excess of 2,6-diaminopyridine.
yield, along with the N,N’-dialkylated product 3a (19%) as
well as unreacted starting material (20%), rendering a one-
pot preparation of nonsymmetrically dialkylated diamines
impossible. To gain a better understanding of this reaction, a
kinetic experiment was performed in which the composition
of the reaction mixture was monitored over time by gas
chromatography (Figure 1).
This experiment clearly showed that under the given cir-
cumstances it is not possible to obtain compound 4a in
yields higher than 60%, since its formation reaches a maxi-
mum after around 6 h. At the same time, around 20% of 4a
has already reacted with another equivalent of alcohol to
afford the dialkylated product 3a. This corroborates the ear-
lier finding that the reaction with one equivalent of alcohol
With the ability to selectively alkylate only one amino
group of the diamine, as shown in Scheme 5, and due to the
excellent selectivity of the catalyst for the monoalkylation
of amines, this method could be further employed to synthe-
size nonsymmetrically substituted diamines by treating the
monoalkylated product 4a with a different alcohol. To the
best of our knowledge, no simple protocol has been report-
ed in the literature that can be used for the selective prepa-
ration of such nonsymmetrically alkylated compounds with-
out the need for several protection and deprotection steps
of the amino functions. Therefore, this iridium-catalyzed
two-step synthesis, in which one of the amino functions is
first monoalkylated and then, after purification, the monoal-
kylated intermediate is further reacted with any other alco-
Chem. Eur. J. 2009, 15, 3790 – 3799
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3795

R. Kempe et al.
hol, leading to a nonsymmetrically substituted diamine, rep-
resents a great synthetic improvement. Table 8 shows some
examples that demonstrate the general applicability of this
synthetic method, in which the initially prepared compound
4a was reacted with an equivalent of another alcohol, af-
Conclusion
In summary, we have developed an efficient and mild Ir-cat-
alyzed protocol for the N-alkylation of (hetero)aromatic
amines with alcohols, which proceeds at a reaction tempera-
ture of only 708C and with catalyst loadings as low as
0.1 mol% Ir. Compared to the known protocols from the lit-
erature, which require temperatures in the range 110–1508C
and catalyst loadings of 2–6 mol%, these are the mildest re-
action conditions ever reported for the alkylation of amines
with alcohols. Furthermore, we have been able to exploit
the selectivity of our catalyst system for the monoalkylation
of amines for the preparation of symmetrically as well as
nonsymmetrically N,N’-dialkylated diamines, providing the
first simple and general protocol for the preparation of
these compounds. Further investigations aimed at gaining a
better understanding of the selectivity of the catalyst as well
as the reaction mechanism are currently underway in our
laboratories.
fording the expected nonsymmetrically diACTHNUTRGNEaNUG lkylated diamines
5a–d.
Table 8. Ir-catalyzed N-alkylation of N-benzyl-pyridine-2,6-diamine with
various alcohols.[a]
mol%
Ir[b]
Alcohol
Product
Yield
[%][c]
1
2
0.4
0.4
95
94
Experimental Section
General considerations: All reactions were carried out under a dry argon
or nitrogen atmosphere, using standard Schlenk and glove box tech-
niques. Non-halogenated solvents were distilled over sodium/benzophe-
none and halogenated solvents over P2O5. Diglyme was dried over molec-
ular sieves. Deuterated solvents were obtained from Cambridge Isotope
Laboratories and stored over molecular sieves. All chemicals were pur-
chased from commercial sources in purities >97% and were used with-
out further purification. In the case of 2,6-diaminopyridine, the dark
black unpurified compound was used only for the screening reactions
whereas the recrystallized compound was used for all further reactions.
NMR spectra were obtained using a Varian INOVA 300 or a Varian
INOVA 400 spectrometer at 298 K. Chemical shifts are reported in ppm
relative to the deuterated solvent. Elemental analyses were performed
on a Vario Elementar EL III. GC analyses were performed on an Agilent
6890N Network GC system equipped with a HP-5 column (30 mꢃ
0.32 mmꢃ0.25 mm). Flash column chromatography was performed on
silica gel 60 (0.040–0.063 mm) from Merck; all eluting solvents were
freshly distilled prior to use.
3
4
0.8
0.5
97
98[d]
[a] Reaction conditions: 1.0 mmol N-benzylpyridine-2,6-diamine (4a),
1.1 mmol alcohol, [IrCl(cod)]2, Py2NPiPr2 (1), 1.1 mmol KOtBu, 0.2 mL
diglyme, 0.35 mL THF, 708C, 48 h. [b] Catalyst loading in mol% Ir.
ACHTUNGTRENNUNG
[c] Isolated yield. [d] 2.0 mmol methanol.
The above results further demonstrate that para-, meta-,
and ortho-substituted benzyl alcohols can readily be em-
ployed for the alkylation of N-benzylpyridine-2,6-diamine
(4a), affording dialkylated products in yields of up to 97%.
Generally, the alkylation of the second amino function of di-
amines is slightly more difficult and therefore the optimal
catalyst loadings determined for the alkylation of 2-amino-
pyridine could not directly be adopted, since with these
quantities only incomplete conversions were observed. This
might be due to a higher steric demand of the substrate,
which renders the coordination to the catalyst more difficult
and therefore reduces the activity of the catalyst. In the case
of ortho-substituted benzyl alcohols (entry 3), this becomes
even more apparent since a catalyst loading of 0.8 mol% Ir
had to be employed to obtain full conversion of the sub-
strate. As a final example, methanol was used as the alkylat-
ing agent and the corresponding N-benzyl-N’-methylpyri-
dine-2,6-diamine (5d) was obtained in 98% yield (entry 4).
Typical procedure for the Ir-catalyzed alkylation of (di)amines with alco-
hols: Stock solutions of [IrClACHTUNGTRENUNG(cod)]2 and Py2NPiPr2 were mixed in a
Schlenk tube. The (di)amine (1.00 equiv), the alcohol (1.05 equiv or
2.1 equiv for diamines), and diglyme (200 mL) were then added. Finally,
KOtBu (1.10 equiv or 2.20 equiv for diamines) was dissolved in the reac-
tion mixture, the reaction tube was tightly closed, and the contents were
stirred at 708C for the mentioned time. The reaction mixture was then
cooled to room temperature, quenched with water (2 mL) and diethyl
ether (7–8 mL), and subsequently extracted with diethyl ether (3ꢃ
20 mL). The combined organic layers were washed with brine (15 mL),
dried over Na2SO4, and filtered, and the solvent was removed in vacuo.
Finally, the residue was purified by column chromatography and dried in
vacuo.
Benzylpyridin-2-yl-amine (2a):[23] [IrCl
ACTHNUTRGENUN(G cod)]2 (80 mL, 0.0005 mmol,
0.00625m in THF) was combined with Py2NPiPr2 (80 mL, 0.001 mmol,
0.0125m in THF). The substrates were added and the reaction was al-
lowed to proceed for 24 h at 708C. Column chromatography (pentane/di-
ethyl ether, 1:1) yielded 2a (161 mg, 0.88 mmol, 88%). 1H NMR
(400 MHz, CDCl3): d=8.05 (ddd, J=3.9, 1.1, 0.9 Hz, 1H), 7.39–7.24 (m,
6H), 6.56 (ddd, J=7.1, 5.1, 0.9 Hz, 1H), 6.34 (d, J=8.4 Hz, 1H), 4.99
(brs, 1H), 4.46 ppm (d, J=5.9 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d=158.6, 148.1, 139.1, 137.5, 128.6, 127.3, 127.1, 113.1, 106.7, 46.3 ppm.
3796
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 3790 – 3799

Selective Monoalkylation of Amines with Alcohols
FULL PAPER
(4-Methylbenzyl)pyridin-2-ylamine
(2b):[16]
[IrCl
G
(160 mL,
63.6, 44.6, 19.2 ppm; elemental analysis calcd (%) for C13H14N2 (198.3): C
78.75, H 7.12, N 14.13; found: C 78.70, H 7.27, N 14.09.
Butylpyridin-2-ylamine (2h):[24] [IrCl
ACTHNUTRGNEN(UG cod)]2 (160 mL, 0.01 mmol, 0.0625m
0.001 mmol, 0.00625m in THF) was combined with Py2NPiPr2 (160 mL,
0.002 mmol, 0.0125m in THF). The substrates were added and the reac-
tion was allowed to proceed for 24 h at 708C. Column chromatography
(pentane/diethyl ether 1:1) yielded 2b (177 mg, 0.89 mmol, 89%).
1H NMR (400 MHz, CDCl3): d=8.10 (ddd, J=5.1, 1.8, 1.1 Hz, 1H), 7.38
(ddd, J=8.5, 6.8, 1.8 Hz, 1H), 7.25 (d, J=8.1 Hz, 2H), 7.14 (d, J=8.1 Hz,
2H), 6.57 (ddd, J=7.1, 4.9, 1.1 Hz, 1H), 6.36 (d, J=8.4 Hz, 1H), 4.83
(brs, 1H), 4.45 (d, J=5.9 Hz, 2H), 2.33 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=158.6, 148.2, 137.4, 136.9, 136.0, 129.3, 127.4,
113.1, 106.7, 46.1, 21.1 ppm.
in THF) was combined with Py2NPiPr2 (160 mL, 0.02 mmol, 0.125m in
THF) in THF instead of diglyme (200 mL). The substrates were added
and the reaction was allowed to proceed for 48 h at 708C. Column chro-
matography (pentane/diethyl ether 1:1) yielded 2h (123 mg, 0.82 mmol,
83%). 1H NMR (400 MHz, CDCl3): d=8.06 (ddd, J=4.8, 1.8, 0.7 Hz,
1H), 7.39 (ddd, J=8.5, 6.9, 1.8 Hz, 1H), 6.53 (ddd, J=7.1, 5.1, 0.9 Hz,
1H), 6.35 (d, J=8.4 Hz, 1H), 4.46 (brs, 1H), 3.23 (td, J=7.0, 5.9 Hz,
2H), 1.59–1.55 (m, 2H), 1.42–1.37 (m, 2H), 0.94 ppm (t, J=7.3 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=159.9, 148.2, 137.3, 112.6, 106.3, 42.0,
31.7, 20.2, 13.9 ppm.
(4-Methoxybenzyl)pyridin-2-ylamine
(2c):[16]
[IrCl
(80 mL,
0.0005 mmol, 0.00625m in THF) was combined with Py2NPiPr2 (80 mL,
0.001 mmol, 0.0125m in THF). The substrates were added and the reac-
tion was allowed to proceed for 24 h at 708C. Column chromatography
(pentane/diethyl ether 2:1) yielded 2c (184 mg, 0.86 mmol, 86%).
1H NMR (400 MHz, CDCl3): d=8.06 (d, J=5.2 Hz, 1H), 7.36 (t, J=
7.2 Hz, 1H), 7.25 (d, J=8.4 Hz, 2H), 6.84 (d, J=6.8 Hz, 2H), 6.55 (t, J=
6.8 Hz, 1H), 6.33 (d, J=8.4 Hz, 1H), 4.84 (brs, 1H), 4.39 (d, J=5.6 Hz,
2H), 3.76 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=159.0, 158.8,
148.4, 137.6, 131.4, 128.9, 114.2, 113.3, 107.0, 55.5, 46.0 ppm.
N,N’-Dibenzylpyridine-2,6-diamine (3a): [IrClACTHNURTGNENG(U cod)]2 (48 mL, 0.003 mmol,
0.0625m in THF) was combined with Py2NPiPr2 (48 mL, 0.006 mmol,
0.125m in THF) in additional THF (160 mL). The substrates were added
and the reaction was allowed to proceed for 48 h at 708C. Column chro-
matography (pentane/diethyl ether 4:1) yielded 3a (271 mg, 0.94 mmol,
94%). 1H NMR (400 MHz, CDCl3): d=7.35–7.16 (m, 11H), 5.72 (d, J=
7.7 Hz, 2H), 4.62 (brs, 2H), 4.43 ppm (d, J=5.9 Hz, 4H); 13C NMR
(100 MHz, CDCl3): d=158.0, 139.7, 139.1, 128.5, 127.4, 127.0, 95.2,
46.3 ppm; elemental analysis calcd (%) for C19H19N3 (289.4): C 78.86, H
6.62, N 14.52; found: C 78.53, H 6.75, N 14.58.
(4-Chlorobenzyl)pyridin-2-ylamine
(2d):[16]
[IrCl
N
(160 mL,
0.001 mmol, 0.00625m in THF) was combined with Py2NPiPr2 (160 mL,
0.002 mmol, 0.0125m in THF). The substrates were added and the reac-
tion was allowed to proceed for 24 h at 708C. Column chromatography
(pentane/diethyl ether 1:1) yielded 2d (155 mg, 0.71 mmol, 71%).
1H NMR (400 MHz, CDCl3): d=8.06 (ddd, J=5.1, 1.8, 0.7 Hz, 1H), 7.36
(ddd, J=8.5, 6.9, 1.8 Hz, 1H), 7.25–7.20 (m, 4H), 6.56 (ddd, J=7.1, 5.1,
0.9 Hz, 1H), 6.31 (dd, J=8.1 Hz, 1H), 4.84 (brs, 1H), 4.44 ppm (d, J=
6.2 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=158.4, 148.2, 137.8, 137.5,
132.9, 128.7, 128.6, 113.4, 106.9, 45.5 ppm.
N,N’-Bis(4-methylbenzyl)pyridine-2,6-diamine (3b): [IrClACTHNUTRGNEUNG(cod)]2 (48 mL,
0.003 mmol, 0.0625m in THF) was combined with Py2NPiPr2 (48 mL,
0.006 mmol, 0.125m in THF) in additional THF (160 mL). The substrates
were added and the reaction was allowed to proceed for 48 h at 708C.
Column chromatography (pentane/diethyl ether 3:1) yielded 3b (286 mg,
0.90 mmol, 90%). 1H NMR (400 MHz, CDCl3): d=7.27 (s, 4H), 7.21 (t,
J=7.87 Hz, 1H), 7.15 (d, J=7.69 Hz, 4H), 5.74 (dt, J=8.05 Hz, 2H),
4.61 (t, J=5.49 Hz, 2H), 4.41 (d, J=5.86 Hz, 4H), 2.36 ppm (s, 6H);
13C NMR (100 MHz, CDCl3): d=158.0, 139.0, 136.6, 136.6, 129.2, 127.4,
95.0, 46.1, 21.1 ppm; elemental analysis calcd (%) for C21H23N3 (317.4): C
79.46, H 7.30, N 13.24; found: C 79.26, H 7.20, N 13.52.
Pyridin-2-yl-(4-trifluoromethylbenzyl)amine (2e): [IrClACTHNUTRGNEUNG(cod)]2 (48 mL,
0.003 mmol, 0.0625m in THF) was combined with Py2NPiPr2 (48 mL,
0.006 mmol, 0.125m in THF). The substrates were added and the reaction
was allowed to proceed for 24 h at 708C. Column chromatography (pen-
tane/diethyl ether 1:1) yielded 2e (189 mg, 0.75 mmol, 75%). 1H NMR
(400 MHz, CDCl3): d=8.09 (ddd, J=5.1, 1.8, 0.7 Hz, 1H), 7.57 (d, J=
8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 7.45–7.35 (m, 1H), 6.57 (ddd, J=
7.3, 5.1, 1.1 Hz, 1H), 6.60 (d, J=8.4 Hz, 1H), 4.99 (brs, 1H), 4.59 ppm
(d, J=5.9 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=158.2, 147.9, 143.5,
137.7, 129.4 (q, J=32.2 Hz), 127.4, 125.5 (q, J=3.6 Hz), 124.2 (q, J=
272.0 Hz), 113.5, 107.0, 45.6 ppm; elemental analysis (calcd (%) for
C13H11N2F3 (252.2): C 61.90, H 4.40, N 11.11; found: C 61.40, H 4.44, N
11.02.
N,N’-Bis(4-methoxybenzyl)pyridine-2,6-diamine (3c): [IrClACTHNUTRGNEUNG(cod)]2 (48 mL,
0.003 mmol, 0.0625m in THF) was combined with Py2NPiPr2 (48 mL,
0.006 mmol, 0.125m in THF) in additional THF (160 mL). The substrates
were added and the reaction was allowed to proceed for 48 h at 708C.
Column chromatography (CH2Cl2/ethyl acetate 60:1) yielded 3c (337 mg,
0.97 mmol, 97%). 1H NMR (400 MHz, CDCl3): d=7.28–7.24 (m, 4H),
7.20 (t, J=7.9 Hz, 1H), 6.85 (ddd, J=9.2, 2.9, 2.6 Hz, 4H), 5.72 (d, J=
7.7 Hz, 2H), 4.58 (t, J=5.3 Hz, 2H), 4.36 (d, J=5.86 Hz, 4H), 3.79 ppm
(s, 6H); 13C NMR (100 MHz, CDCl3): d=158.7, 157.9, 139.1, 131.7, 128.7,
113.9, 95.1, 55.3, 45.8 ppm; elemental analysis calcd (%) for C21H23N3O2
(349.4): C 72.18, H 6.63, N 12.03; found: C 71.98, H 6.60, N 11.86.
(2-Methoxybenzyl)pyridin-2-ylamine
(2 f):
[IrCl
(64 mL,
0.004 mmol, 0.0625m in THF) was combined with Py2NPiPr2 (64 mL,
0.008 mmol, 0.125m in THF). The substrates were added and the reaction
was allowed to proceed for 48 h at 708C. Column chromatography (pen-
tane/diethyl ether 1:1) yielded 2 f (197 mg, 0.92 mmol, 92%). 1H NMR
(400 MHz, CDCl3): d=8.09 (ddd, J=5.1, 1.8, 0.7 Hz, 1H), 7.37 (ddd, J=
8.6, 7.0, 2.1 Hz, 1H), 7.24 (dd, J=7.8, 1.7 Hz, 1H), 7.24 (dt, J=7.8,
1.6 Hz, 1H), 6.85–6.80 (m, 2H), 6.54 (ddd, J=7.1, 5.1, 0.9 Hz, 1H), 6.40
(d, J=8.4 Hz, 1H), 4.84 (brs, 1H), 4.48 (d, J=6.2 Hz, 2H), 3.84 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=158.9, 157.42, 148.2, 137.3, 128.8,
128.3, 127.1, 120.4, 112.8, 110.2, 106.7, 55.3, 41.7 ppm; elemental analysis
calcd (%) for C13H14N2O (214.3): C 72.87, H 6.59, N 13.07; found: C
72.83, H 6.67, N 13.10.
N,N’-Bis(4-chlorobenzyl)pyridine-2,6-diamine (3d): [IrClACTHNUTRGNEUNG(cod)]2 (48 mL,
0.003 mmol, 0.0625m in THF) was combined with Py2NPiPr2 (48 mL,
0.006 mmol, 0.125m in THF) in additional THF (160 mL). The substrates
were added and the reaction was allowed to proceed for 48 h at 708C.
Column chromatography (pentane/diethyl ether 3:1) yielded 3d (312 mg,
0.87 mmol, 87%). 1H NMR (400 MHz, CDCl3): d=7.25 (m, 8H), 7.18 (t,
J=8.05 Hz, 1H), 5.70 (d, J=7.69 Hz, 2H), 4.61 (t, J=5.67 Hz, 2H),
4.40 ppm (d, J=5.86 Hz, 4H); 13C NMR (100 MHz, CDCl3): d=157.7,
139.1, 138.4, 132.6, 128.6, 128.6, 95.5, 45.5 ppm; elemental analysis calcd
(%) for C19H17N3Cl2 (358.3): C 63.80, H 4.78, N 11.73; found: C 64.05, H
4.72, N 12.06.
N,N’-Bis(3-methylbenzyl)pyridine-2,6-diamine (3e): [IrClACTHNUTRGNEUNG(cod)]2 (48 mL,
(2-Methylbenzyl)pyridin-2-ylamine
(2g):
[IrCl
(cod)]2
(240 mL,
0.003 mmol, 0.0625m in THF) was combined with Py2NPiPr2 (48 mL,
0.006 mmol, 0.125m in THF) in additional THF (350 mL). The substrates
were added and the reaction was allowed to proceed for 48 h at 708C.
Column chromatography (CH2Cl2/ethyl acetate 40:1) yielded 3e (294 mg,
0.93 mmol, 93%). 1H NMR (400 MHz, CDCl3): d=7.28–7.17 (m, 7H),
7.11 (d, J=7.3 Hz, 2H), 5.77 (d, J=8.1 Hz, 2H), 4.67 (t, J=5.7 Hz, 2H),
4.44 (d, J=5.9 Hz, 4H), 2.37 ppm (s, 6H); 13C NMR (100 MHz, CDCl3):
d=158.0, 139.6, 139.1, 138.1, 128.2, 128.1, 127.8, 124.5, 95.0, 46.3,
21.4 ppm; elemental analysis calcd (%) for C21H23N3 (317.4): C 79.46, H
7.30, N 13.24; found: C 79.11, H 7.16, N 13.20.
0.0015 mmol, 0.00625m in THF) was combined with Py2NPiPr2 (240 mL,
0.003 mmol, 0.0125m in THF). The substrates were added and the reac-
tion was allowed to proceed for 24 h at 708C. Column chromatography
(pentane/diethyl ether 1:1) yielded 2g (179 mg, 0.9 mmol, 90%).
1H NMR (400 MHz, CDCl3): d=8.09 (dd, J=4.9, 0.9 Hz, 1H), 7.4 (ddd,
J=8.4, 7.0, 1.8 Hz, 1H), 7.31 (d, J=6.6 Hz, 1H), 7.21–7.15 (m, 3H), 6.58
(ddd, J=7.3, 5.1, 0.7 Hz, 1H), 6.36 (d, J=8.4 Hz, 1H), 4.74 (brs, 1H),
4.45 (d, J=5.5 Hz, 2H), 2.36 ppm (s, 3H); 13C NMR (100 MHz, CDCl3):
d=158.8, 148.4, 137.7, 136.9, 136.5, 130.6, 128.2, 127.6, 126.3, 113.2, 107.0,
Chem. Eur. J. 2009, 15, 3790 – 3799
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3797

R. Kempe et al.
N,N’-Bis(2-methoxybenzyl)pyridine-2,6-diamine (3 f): [IrCl
G
N-Benzyl-N’-(3-methylbenzyl)pyridine-2,6-diamine (5b): [IrClACHTUNGTRENNUNG(cod)]2
(320 mL, 0.002 mmol, 0.00625m in THF) was combined with Py2NPiPr2
(320 mL, 0.004 mmol, 0.0125m in THF). The substrates were added and
the reaction was allowed to proceed for 48 h at 708C. Column chroma-
tography (pentane/diethyl ether 10:1) yielded 5b (285 mg, 0.94 mmol,
94%). 1H NMR (400 MHz, CDCl3): d=7.36–7.14 (m, 9H), 7.07 (d, J=
7.3 Hz, 1H), 5.74 (d, J=7.7 Hz, 2H), 4.65 (brs, 2H), 4.42 (dd, J=18.3,
5.9 Hz, 4H), 2.33 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=158.0,
157.9, 139.7, 139.6, 139.2, 138.2, 128.5, 128.4, 128.2, 127.8, 127.4, 127.0,
124.5, 95.1, 95.1, 46.3, 21.4 ppm; elemental analysis calcd (%) for
C20H21N3 (303.4): C 79.17, H 6.98, N 13.85; found: C 78.60, H 6.91, N
13.83.
0.005 mmol, 0.0625m in THF) was combined with Py2NPiPr2 (80 mL,
0.01 mmol, 0.125m in THF) in additional THF (350 mL). The substrates
were added and the reaction was allowed to proceed for 48 h at 708C.
Column chromatography (pentane/diethyl ether 1:1) yielded 3 f (239 mg,
0.68 mmol, 68%). 1H NMR (400 MHz, CDCl3): d=7.32 (dd, J=7.5,
1.6 Hz, 2H), 7.23 (td, J=8.1, 1.8 Hz, 2H), 7.18 (t, J=7.9 Hz, 1H), 6.89
(ddd, J=14.6, 7.3, 1.1 Hz, 4H), 5.73 (d, J=7.7 Hz, 2H), 4.73 (t, J=
6.2 Hz, 2H), 4.45 (d, J=6.2 Hz, 4H), 3.85 ppm (s, 6H); 13C NMR
(100 MHz, CDCl3): d=158.2, 157.3, 138.9, 128.8, 128.0, 127.7, 120.4,
110.0, 94.8, 55.2, 41.5 ppm; elemental analysis calcd (%) for C21H23N3O2
(349.4): C 72.18, H 6.63, N 12.03; found: C 71.94, H 6.59, N 12.00.
N-Benzyl-N’-(2-methylbenzyl)pyridine-2,6-diamine (5c): [IrClACHTUNGTRENNUNG(cod)]2
N,N’-Bis(2-methylbenzyl)pyridine-2,6-diamine (3g): [IrClACTHNUTRGNEUNG(cod)]2 (80 mL,
(64 mL, 0.004 mmol, 0.0625m in THF) was combined with Py2NPiPr2
(64 mL, 0.008 mmol, 0.125m in THF). The substrates were added and the
reaction was allowed to proceed for 48 h at 708C. Column chromatogra-
phy (pentane/diethyl ether 4:1) yielded 5c (295 mg, 0.97 mmol, 97%).
1H NMR (400 MHz, CDCl3): d=7.37–7.29 (m, 5H), 7.27–7.15 (m, 5H),
5.74 (d, J=8.1 Hz, 2H), 4.64 (brs, 1H), 5.45–4.39 (m, 5H), 2.35 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=158.0, 139.7, 139.1, 137.2, 136.2,
130.3, 128.5, 128.1, 127.4, 127.2, 127.0, 126.0, 95.1, 95.0, 46.4, 44.4,
19.0 ppm; elemental analysis calcd (%) for C20H21N3 (303.4): C 79.17, H
6.98, N 13.85; found: C 78.88, H 6.94, N 13.79.
0.005 mmol, 0.0625m in THF) was combined with Py2NPiPr2 (80 mL,
0.01 mmol, 0.125m in THF) in additional THF (350 mL). The substrates
were added and the reaction was allowed to proceed for 48 h at 708C.
Column chromatography (pentane/diethyl ether 3:1) yielded 3g (223 mg,
0.70 mmol, 70%). 1H NMR (400 MHz, CDCl3): d=7.36–7.31 (m, 2H),
7.24 (t, J=7.9 Hz, 1H), 7.20–7.18 (m, 6H), 5.75 (d, J=8.1 Hz, 2H), 4.47
(brs, 2H), 4.40 (d, J=5.5 Hz, 4H), 2.36 ppm (s, 6H); 13C NMR
(100 MHz, CDCl3): d=158.1, 139.0, 137.2, 136.2, 130.2, 128.0, 127.2,
126.0, 94.9, 44.4, 19.0 ppm; elemental analysis calcd (%) for C21H23N3
(317.4): C 79.46, H 7.30, N 13.24; found: C 79.24, H 7.31, N 13.23.
N-Benzyl-N’-methylpyridine-2,6-diamine (5d): [IrClACTHUNRGTNEUNG(cod)]2 (400 mL,
N,N’-Dibutyl-pyridine-2,6-diamine (3h): [IrClACTHNURTGNENG(U cod)]2 (48 mL, 0.003 mmol,
0.0025 mmol, 0.00625m in THF) was combined with Py2NPiPr2 (400 mL,
0.005 mmol, 0.0125m in THF). The substrates were added and the reac-
tion was allowed to proceed for 48 h at 708C. Column chromatography
(pentane/diethyl ether 1:1) yielded 5d (209 mg, 0.98 mmol, 98%).
1H NMR (400 MHz, CDCl3): d=7.37–7.27 (m, 4H), 7.27–7.21 (m, 2H),
5.72 (dd, J=7.7, 5.5 Hz, 2H), 4.65 (brs, 1H), 4.44 (d, J=5.5 Hz, 2H),
4.30 (brs, 1H), 2.84 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=159.0,
158.0, 139.7, 139.1, 128.5, 127.4, 127.0, 94.8, 94.3, 46.3 ppm; elemental
analysis calcd (%) for C13H15N3 (213.3): C 73.21, H 7.09, N 19.70; found:
C 72.97, H 7.05, N 19.76.
0.0625m in THF) was combined with Py2NPiPr2 (48 mL, 0.006 mmol,
0.125m in THF) in additional THF (350 mL). The substrates were added
and the reaction was allowed to proceed for 48 h at 708C. Column chro-
matography (pentane/diethyl ether 1:1) yielded 3h (199 mg, 0.90 mmol,
90%). 1H NMR (400 MHz, CDCl3): d=7.22 (t, J=7.9 Hz, 1H), 7.22 (d,
J=8.1 Hz, 2H), 4.21 (brs, 2H), 3.16 (q, J=6.95 Hz, 4H), 1.56 (t, J=
7.23 Hz, 4H), 1.41–1.37 (m, 4H), 0.93 ppm (t, J=7.3 Hz, 6H); 13C NMR
(100 MHz, CDCl3): d=158.4, 138.9, 94.0, 42.0, 31.7, 20.2, 13.8 ppm; ele-
mental analysis calcd (%) for C13H23N3 (221.4): C 70.54, H 10.47, N
18.98; found: C 70.99, H 10.59, N 19.13.
N,N’-Dimethylpyridine-2,6-diamine (3i): [IrClACTHNURTGNENG(U cod)]2 (64 mL, 0.004 mmol,
0.0625m in THF) was combined with Py2NPiPr2 (64 mL, 0.008 mmol,
0.125m in THF) in additional THF (350 mL). The substrates were added
and the reaction was allowed to proceed for 48 h at 708C. Column chro-
matography (diethyl ether) yielded 3i (121 mg, 0.88 mmol, 88%).
1H NMR (400 MHz, CDCl3): d=7.27 (t, J=7.9 Hz, 1H), 5.71 (d, J=
8.1 Hz, 2H), 4.31 (brs, 2H), 2.83 ppm (d, J=5.1 Hz, 6H); 13C NMR
(100 MHz, CDCl3): d=159.1, 139.0, 94.0, 29.1 ppm; elemental analysis
calcd (%) for C7H11N3 (137.2): C 61.29, H 8.08, N 30.62; found: C 61.04,
H 8.04, N 30.24.
Acknowledgements
This work was supported by NanoCat an International Graduate Pro-
gram within the Elitenetzwerk Bayern. B.B. is grateful for a Bavarian
Elite Graduation Grant (Graduiertenstipendium nach dem Bayerischen
Elitefçrderungsgesetz).
N-Benzylpyridine-2,6-diamine (4a): [IrClACTHNUTRGEN(UNG cod)]2 (320 mL, 0.002 mmol,
[1] S. A. Lawrence, in Amines: Synthesis, Properties and Applications,
Cambridge University, Cambridge, 2004.
[2] a) M. B. Smith, J. March, Advanced Organic Chemistry, 5th ed.,
Wiley, New York, 2001, p. 499; b) R. N. Salvatore, C. H. Yoon, K. W.
Jung, Tetrahedron 2001, 57, 7785–7811.
0.00625m in THF) was combined with Py2NPiPr2 (320 mL, 0.004 mmol,
0.0125m in THF) in additional THF (160 mL). The substrates were added
and the reaction was allowed to proceed for 24 h at 708C. Column chro-
matography (pentane/diethyl ether 1:1) yielded 4a (207 mg, 0.97 mmol,
97%). 1H NMR (400 MHz, CDCl3): d=7.26–7.17 (m, 4H), 7.16–7.10 (m,
1H), 7.1 (t, J=7.9 Hz, 1H), 5.73 (d, J=7.7 Hz, 1H), 5.65 (d, J=7.7 Hz,
1H), 4.57 (brs, 1H), 4.32 (d, J=5.9 Hz, 2H), 4.07 ppm (brs, 2H);
13C NMR (100 MHz, CDCl3): d=158.1, 157.6, 139.4, 139.4, 128.5, 127.3,
127.1, 97.1, 95.6, 46.4 ppm; elemental analysis calcd (%) for C12H13N3
(199.3): C 72.33, H 6.58, N 21.09; found: C 72.33, H 6.58, N 21.09.
[3] a) E. W. Baxter, A. B. Reitz, Organic Reactions, Vol. 59, Wiley, New
York, 2002, p. 1; b) R. O. Hutchins, M. K. Hutchins, B. M. Trost,
Comprehensive Organic Synthesis, Vol. 8, Pergamon Press, Oxford,
1991 pp. 25–78; c) C. F. Lane, Synthesis 1975, 135–146; d) G. W.
Gribble, Chem. Soc. Rev. 1998, 27, 395–404; e) A. F. Abdel-Magid,
K. G. Carson, B. D. Harris, C. A. Maryanoff, R. D. Shah, J. Org.
Chem. 1996, 61, 3849–3862; f) T. Gross, A. M. Seayad, M. Ahmad,
M. Beller, Org. Lett. 2002, 4, 2055–2058.
[4] a) R. Severin, S. Doye, Chem. Soc. Rev. 2007, 36, 1407–1420;
b) K. C. Hultzsch, D. V. Gribkov, J. F. Hampel, J. Organomet. Chem.
2005, 690, 4441–4452; c) J. F. Hartwig, Pure Appl. Chem. 2004, 76,
507–516; d) S. Doye, Synlett 2004, 1654–1672; e) J. Seayad, A. Till-
ack, C. G. Hartung, M. Beller, Adv. Synth. Catal. 2002, 344, 795–
813; f) M. Beller, C. Breindl, M. Eichberger, C. G. Hartung, J.
Seayad, O. Thiel, A. Tillack, H. Trauthwein, Synlett 2002, 1579–
1594.
N-Benzyl-N’-(4-methylbenzyl)pyridine-2,6-diamine (5a): [IrClACTHNUTRGNE(UNG cod)]2
(320 mL, 0.002 mmol, 0.00625m in THF) was combined with Py2NPiPr2
(320 mL, 0.004 mmol, 0.0125m in THF). The substrates were added and
the reaction was allowed to proceed for 48 h at 708C. Column chroma-
tography (pentane/diethyl ether 10:1) yielded 5a (288 mg, 0.95 mmol,
95%). 1H NMR (400 MHz, CDCl3): d=7.36–7.28 (m, 4H), 7.27–7.17 (m,
4H), 7.12 (d, J=7.7 Hz, 2H), 5.72 (d, J=8.1 Hz, 2H), 4.64 (brs, 2H),
4.41 (dd, J=20.5, 4.0 Hz, 4H), 2.33 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=158.0, 157.9, 139.7, 139.2, 136.7, 136.6, 129.2, 128.5, 127.4,
127.0, 95.1, 95.1, 46.3, 46.1, 21.1 ppm; elemental analysis calcd (%) for
C20H21N3 (303.4): C 79.17, H 6.98, N 13.85; found: C 78.79, H 6.99, N
13.74.
[5] a) K.-S. Mꢀller, F. Koc, S. Ricken, P. Eilbracht, Org. Biomol. Chem.
2006, 4, 826–835; b) L. Routaboul, C. Buch, H. Klein, R. Jackstell,
3798
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 3790 – 3799

Selective Monoalkylation of Amines with Alcohols
FULL PAPER
M. Beller, Tetrahedron Lett. 2005, 46, 7401–7405; c) A. Moballigh,
A. Seayad, R. Jackstell, M. Beller, J. Am. Chem. Soc. 2003, 125,
10311–10318; d) P. Eilbracht, L. Bꢁrfacker, C. Buss, C. Hollmann,
B. E. Kitsos-Rzychon, C. L. T. Rische, R. Roggenbuck, A. Schmidt,
Chem. Rev. 1999, 99, 3329–3365.
3199–3201; c) S. Bꢁhn, D. Hollmann, A. Tillack, M. Beller, Adv.
Synth. Catal. 2008, 350, 2099–2103; d) D. Hollmann, S. Bꢁhn, A.
Tillack, R. Parton, R. Altink, M. Beller, Tetrahedron Lett. 2008, 49,
5742–5745.
[15] a) T. Schareina, R. Kempe, Angew. Chem. 2002, 114, 1591–1594;
Angew. Chem. Int. Ed. 2002, 41, 1521–1523; b) S. Proch, R. Kempe,
Angew. Chem. 2007, 119, 3196–3199; Angew. Chem. Int. Ed. 2007,
46, 3135–3138.
[16] B. Blank, M. Madalska, R. Kempe, Adv. Synth. Catal. 2008, 350,
749–758.
[17] Y. Watanabe, Y. Morisaki, T. Kondo, T. Mitsudo, J. Org. Chem.
1996, 61, 4214–4218.
[18] For review articles on aminopyridinato ligands, see: a) R. Kempe,
H. Noss, T. Irrgang, J. Organomet. Chem. 2002, 647, 12–20; b) R.
Kempe, Eur. J. Inorg. Chem. 2003, 791–803.
[19] For selected work with very bulky aminopyridinato ligands, please
see: a) N. M. Scott, R. Kempe, Eur. J. Inorg. Chem. 2005, 1319–
1324; b) W. P. Kretschmer, A. Meetsma, B. Hessen, N. M. Scott, S.
Qayyum, R. Kempe, Z. Anorg. Allg. Chem. 2006, 632, 1936–1938;
c) S. M. Guillaume, M. Schappacher, N. M. Scott, R. Kempe, J.
Polym. Sci. Part A: Polym. Chem. 2007, 45, 3611–3619; d) A. M.
Dietel, O. Tok, R. Kempe, Eur. J. Inorg. Chem. 2007, 4583–4586;
e) S. Qayyum, K. Haberland, C. M. Forsyth, P. C. Junk, G. B.
Deacon, R. Kempe, Eur. J. Inorg. Chem. 2008, 557–562; f) G. G.
Skvortsov, G. K. Fukin, A. A. Trifonov, A. Noor, C. Dçring, R.
Kempe, Organometallics 2007, 26, 5770–5773; g) A. Noor, R.
Kempe, Eur. J. Inorg. Chem. 2008, 2377–2381; h) D. M. Lyubov, C.
Dçring, G. K. Fukin, A. V. Cherkasov, A. V. Shavyrin, R. Kempe,
A. A. Trifonov, Organometallics 2008, 27, 2905–2907; i) A. Noor,
F. R. Wagner, R. Kempe, Angew. Chem. 2008, 120, 7356–7359;
Angew. Chem. Int. Ed. 2008, 47, 7246–7249; j) A. Noor, W. P.
Kretschmer, G. Glatz, A. Meetsma, R. Kempe, Eur. J. Inorg. Chem.
2008, 5088–5098; k) W. P. Kretschmer, A. Meetsma, B. Hessen, T.
Schmalz, S. Qayyum, R. Kempe, Chem. Eur. J. 2006, 12, 8969–8978;
l) N. M. Scott, T. Schareina, O. Tok, R. Kempe, Eur. J. Inorg. Chem.
2004, 3297–3304.
[6] a) B.-T. Khai, C. Concilio, G. Porzi, J. Org. Chem. 1981, 46, 1759–
1760; b) Y. Watanabe, Y. Tsuji, Y. Ohsugi, Tetrahedron Lett. 1981,
22, 2667–2670; c) S. I. Murahashi, K. Kondo, T. Hakata, Tetrahedron
Lett. 1982, 23, 229–232; d) A. Arcelli, B.-T. Khai, G. Porzi, J. Orga-
nomet. Chem. 1982, 235, 93–96; e) Y. Watanabe, Y. Tsuji, H. Ige, Y.
Ohsugi, T. Ohata, J. Org. Chem. 1984, 49, 3359–3363; f) Y. Tsuji,
K.-T. Huh, Y. Watanabe, J. Org. Chem. 1987, 52, 1673–1680; g) J. A.
Marsella, J. Org. Chem. 1987, 52, 467–468; h) K.-T. Huh, Y. Tsuji,
M. Kobayashi, F. Okuda, Y. Watanabe, Chem. Lett. 1988, 449–452;
i) S. Ganguly, F. L. Joslin, D. M. Roundhill, Inorg. Chem. 1989, 28,
4562–4564; j) G. Bitsi, E. Schleiffer, F. Antoni, G. Jenner, J. Orga-
nomet. Chem. 1989, 373, 343–352; k) S. Ganguly, D. M. Roundhill,
Polyhedron 1990, 9, 2517–2526; l) T. Kondo, S. Yang, K.-T. Huh, M.
Kobayashi, S. Kotachi, Y. Watanabe, Chem. Lett. 1991, 1275–1278;
m) A. Del Zotto, W. Baratta, M. Sandri, G. Verardo, P. Rigo, Eur. J.
Inorg. Chem. 2004, 524–529.
[7] a) R. Grigg, T. R. B. Mitchell, S. Sutthivaiyakit, N. Tongpenyai, J.
Chem. Soc. Chem. Commun. 1981, 611–612; b) N. Tanaka, M. Hata-
naka, Y. Watanabe, Chem. Lett. 1992, 575–578.
[8] Y. Tsuji, R. Takeuchi, H. Ogawa, Y. Watanabe, Chem. Lett. 1986,
293–294.
[9] a) A. Tillack, D. Hollmann, D. Michalik, M. Beller, Tetrahedron
Lett. 2006, 47, 8881–8885; b) D. Hollmann, A. Tillack, D. Michalik,
R. Jackstell, M. Beller, Chem. Asian J. 2007, 2, 403–410; c) A. Till-
ack, D. Hollmann, K. Mevius, D. Michalik, S. Bꢁhn, M. Beller, Eur.
J. Org. Chem. 2008, 4745–4750.
[10] a) K. Fujita, Z. Li, N. Ozeki, R. Yamaguchi, Tetrahedron Lett. 2003,
44, 2687–2690; b) K. Fujita, T. Fujii, R. Yamaguchi, Org. Lett. 2004,
6, 3525–3528; c) K. Fujita, R. Yamaguchi, Synlett 2005, 560–571;
d) R. Yamaguchi, S. Kawagoe, C. Asai, K. Fujita, Org. Lett. 2008,
10, 181–184; e) K. Fujita, Y. Enoki, R. Yamaguchi, Tetrahedron
2008, 64, 1943–1954; f) A. Pontes da Costa, M. Viciano, M. Sanaffl,
S. Merino, J. Tejeda, E. Peris, B. Royo, Organometallics 2008, 27,
1305–1309.
[20] a) V. Sprinzak, J. Am. Chem. Soc. 1956, 78, 3207–3208; b) J. Bern-
stein, B. Stearns, E. Shaw, W. A. Lott, J. Am. Chem. Soc. 1947, 69,
1151–1158.
[11] D. Balcells, A. Nova, E. Clot, D. Gnanamgari, R. H. Crabtree, O.
Eisenstein, Organometallics 2008, 27, 2529–2535.
[21] a) J. W. Sibert, G. R. Hundt, A. L. Sargent, V. Lynch, Tetrahedron
2005, 61, 12350–12357; b) X. Liu, A. H. Eisenberg, C. L. Stern,
C. A. Mirkin, Inorg. Chem. 2001, 40, 2940–2941.
[22] R. Margalef-Catalµ, C. Claver, P. Salagre, E. Fernandez, Tetrahedron
Lett. 2000, 41, 6583–6588.
[23] P. S. Reddy, S. Kanjilal, S. Sunitha, R. B. N. Prasad, Tetrahedron Lett.
2007, 48, 8807–8810.
[24] Z. Zhang, J. Mao, D. Zhu, F. Wu, H. Chenand, B. Wan, Tetrahedron
2006, 62, 4435–4443.
[12] a) G. Cami-Kobeci, J. M. J. Williams, Chem. Commun. 2004, 1072–
1073; b) G. Cami-Kobeci, P. A. Slatford, M. K. Whittlesey, J. M. J.
Williams, Bioorg. Med. Chem. Lett. 2005, 15, 535–537; c) M. Haniti,
S. A. Hamid, M. J. Williams, Chem. Commun. 2007, 725–727.
[13] M. Haniti, S. A. Hamid, P. A. Slatford, J. M. J. Williams, Adv. Synth.
Catal. 2007, 349, 1555–1575.
[14] a) D. Hollmann, S. Bꢁhn, A. Tillack, M. Beller, Angew. Chem. 2007,
119, 8440–8444; Angew. Chem. Int. Ed. 2007, 46, 8291–8294; b) D.
Hollmann, S. Bꢁhn, A. Tillack, M. Beller, Chem. Commun. 2008,
Received: November 7, 2008
Published online: February 13, 2009
Chem. Eur. J. 2009, 15, 3790 – 3799
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3799