An efficient method for the selective iridium-catalyzed monoalkylation of (hetero)aromatic amines with primary alcohols

Article abstract of DOI:10.1002/adsc.200700596

An efficient multi-gram scale synthesis protocol of a variety of P,N ligands is described. The synthesis is achieved in a two-step reaction. First, the amine is deprotonated and subsequently the chlorophosphine is added to yield the corresponding P,N ligand. Deprotonation of the amine is normally achieved with n-BuLi at low temperature, but for the preparation of ligands with a 2,2′-dipyridylamino backbone and phosphines with a high steric demand KH has to be employed in combination with reaction temperatures of 110°C for the salt metathesis step. The reaction of two equivalents of a selected P,N ligand with one equivalent of the iridium complex [IrCl(cod)]2 (cod=1,5-cyclooctadiene) affords P,N ligand-coordinated iridium complexes in quantitative yield. X-Ray single crystal structure analysis of one of these complexes reveals a monomeric five-coordinated structure in the solid state. The iridium complexes were used to form catalysts for the N-alkylation of aromatic amines with alcohols. The catalyst system was optimized by studying 8 different P,N ligands, 9 different solvents and 14 different bases. Systematic variation of the substrate to base and the amine to alcohol ratios as well as the catalyst loading led to optimized catalytic reaction conditions. The substrate scope of the developed catalytic protocol was shown by synthesizing 20 different amines of which 12 could be obtained in isolated yields higher than 90%. A new efficient catalyst system for the selective monoalkylation of primary aromatic and heteroaromatic amines with primary aromatic, heteroaromatic as well as aliphatic alcohols has been established. The reaction proceeds with rather moderate catalyst loadings.

Full text of DOI:10.1002/adsc.200700596

FULL PAPERS
DOI: 10.1002/adsc.200700596
An Efficient Method for the Selective Iridium-Catalyzed
Monoalkylation of (Hetero)aromatic Amines with Primary
Alcohols
Benoît Blank,a Martyna Madalska,a and Rhett Kempea,*
a
Lehrstuhl für Anorganische Chemie II, Universität Bayreuth, 95440 Bayreuth, Germany
Fax : (+49)-921-55-2157; e-mail: kempe@uni-bayreuth.de
Received: December 18, 2007; Published online: March 17, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: An efficient multi-gram scale synthesis tion of aromatic amines with alcohols. The catalyst
protocol of a variety of P,N ligands is described. The system was optimized by studying 8 different P,N li-
synthesis is achieved in a two-step reaction. First, the gands, 9 different solvents and 14 different bases.
amine is deprotonated and subsequently the chloro- Systematic variation of the substrate to base and the
phosphine is added to yield the corresponding P,N amine to alcohol ratios as well as the catalyst loading
ligand. Deprotonation of the amine is normally ach- led to optimized catalytic reaction conditions. The
ieved with n-BuLi at low temperature, but for the substrate scope of the developed catalytic protocol
preparation of ligands with a 2,2’-dipyridylamino was shown by synthesizing 20 different amines of
backbone and phosphines with a high steric demand which 12 could be obtained in isolated yields higher
KH has to be employed in combination with reaction than 90%. A new efficient catalyst system for the se-
temperatures of 1108C for the salt metathesis step. lective monoalkylation of primary aromatic and het-
The reaction of two equivalents of a selected P,N eroaromatic amines with primary aromatic, heteroar-
ligand with one equivalent of the iridium complex omatic as well as aliphatic alcohols has been estab-
[IrCl(cod)]2 (cod=1,5-cyclooctadiene) affords P,N lished. The reaction proceeds with rather moderate
G
ligand-coordinated iridium complexes in quantitative catalyst loadings.
yield. X-Ray single crystal structure analysis of one
of these complexes reveals a monomeric five-coordi-
nated structure in the solid state. The iridium com- Keywords: alkylation; amines; aminopyridines; iridi-
plexes were used to form catalysts for the N-alkyla- um; P,N ligands; primary alcohols
Introduction
able and the selectivity of the reaction can be con-
trolled with the catalyst. The first homogeneous cata-
Nitrogen-containing molecules and especially amines lysts for this reaction were introduced by Grigg
are intermediates and products of enormous impor- et al.[5] and Watanabe et al.[6] in 1981. Most of them
tance for chemical and life science applications. In the required very high reaction temperatures and the
last decade, catalytic amine syntheses such as, for in- scope of applicable substrates was rather limited. To
stance, Pd-catalyzed aminations of aryl halides,[1] hy- the present day, catalytic systems employing rutheni-
droaminations[2] and hydroaminomethylations[3] have um,[7] rhodium,[8] platinum[9] and iridium,[8,10,11] com-
received particular attention and many new applica- plexes have been reported for the alkylation of pri-
tions have emerged due to the broadening of the mary amines with alcohols. In the last few years, re-
scope of these methods. A well-known method for the search has mainly been focussed on ruthenium-cata-
preparation of N-alkylamines is the reaction of lyzed N-alkylation reactions and has helped to extend
amines with alkyl halides.[4] Such reactions are diffi- the applicability of this reaction towards a broad
cult to run selectively due to increasing nucleophilici- range of substrates.[12,13,14] However, the selective alky-
ty/reactivity of the amine after the first alkylation lation of aromatic amines with primary and secondary
step. The alkylation of primary amines with alcohols alcohols remains challenging. In this regard, Fujita
is an attractive and promising alternative since the et al. reported an interesting system for the N-alkyla-
starting materials are inexpensive and readily avail- tion of amines with alcohols catalyzed by a Cp*Ir
Adv. Synth. Catal. 2008, 350, 749 – 758
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Benoît Blank et al.
FULL PAPERS
complex
(Cp*=pentamethylcyclopentadienyl tion and abbreviation scheme of the P,N ligands syn-
anion)[11,15] and inspired us to develop an easily acces- thesized and used in this study are presented in
sible iridium-based catalyst system. Herein, we report Scheme 1.
on novel P,N ligand coordinated iridium complexes
and the use of these compounds as catalysts for the ligand (1b and 1c) with one equivalent of [IrCl
N-alkylation of (hetero)aromatic amines with primary (cod=1,5-cyclooctadiene) in CH2Cl2 affords P,N
The reaction of two equivalents of a selected P,N
ACHTREUNG
alcohols.
ligand-coordinated iridium complexes in quantitative
yields (Scheme 2).
An X-ray single-crystal structure analysis of 2 re-
vealed a monomeric five-coordinated structure in the
solid state. Selected bond lengths and angles as well
as the molecular structure of 2 are given in Figure 1.
The P,N ligand forms a five-membered ring in addi-
Results and Discussion
Ligand/Catalyst Synthesis
P-Functionalized aminopyridines were reported to be tion to cyclooctadiene and Cl ligand coordination.
effective ligands for a variety of transition metal-cata- The coordination geometry of the metal is distorted
lyzed coupling reactions.[16,17] These P,N ligands are bi- square pyramidal with the chlorine atom as the axial
dentate, form strongly bonded five-membered che- ligand. The base is defined by P1, N1 and the centres
lates and are modular due to extensive variations of of the two olefinic cyclooctadiene bonds. We were
the substituents at the amino as well as the phospho- surprised not to find examples of structural similarity.
rus centres. These ligands were so far essentially pre- To our best knowledge, no iridium complex stabilized
À À
pared in situ from the corresponding amine and chlor- by a N P Cl donor set and two additional olefinic
ophosphine precursors for combinatorial screen- bonds has yet been reported. However, complexes
ings.[16] Thus, within this study we first developed effi- containing phosphorus (mono- and bidentate), nitro-
cient multi-gram scale synthesis protocols for these li-
gands. The synthesis is achieved in a two-step
reaction. First, the amine is deprotonated and subse-
quently the chlorophosphine is added to yield the cor-
responding P,N ligand. Deprotonation of the amine is
normally achieved with n-BuLi at low temperature,
but for the preparation of ligands with a 2,2’-dipyrid-
ylamino backbone and phosphines with a high steric
demand, for instance, tert-butyl substituents, KH has
to be employed in combination with reaction temper-
atures of 1108C to obtain a full conversion. The reac-
Figure 1. Molecular structure of monomeric [(Py2NPCy2)Ir-
À
G
À
À
À
Ir1 2.118(3), P1 Ir1 2.3024(11), Cl1 Ir1 2.5707(10), C1 Ir1
2.112(4), C2 Ir1 2.157(4), C5 Ir1 2.137(4), C6 Ir1 2.153(4),
À
C1 C2 1.427(6), C5 C6 1.406(7), N1 Ir1 P1 80.57(10), P1
Ir1 Cl1 96.52(4), N1 Ir1 Cl1 85.31(9), C1 Ir1 C2
À
39.04(17), C5 Ir1 C6 38.26(17), C1 Ir1 N1 88.03(16), C2
Ir1 Cl1 98.48(13), C6 Ir1 P1 89.45(12), C5 Ir1 Cl1
82.71(13).
Scheme 1. Synthesis of the used P,N ligands.
Scheme 2. Synthesis of 2 (R=cyclohexyl) and 3 (R=isopropyl).
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Selective Iridium-Catalyzed Monoalkylation of (Hetero)aromatic Amines
FULL PAPERS
Table 1. Influence of substrate/base ratio.[a]
gen, sulfur or carbene donors in such an arrangement
are known.[18] The Ir Cl distance in 2 [2.571(1) Š]
À
Entry
Base
Substrate:Base
Yield [%][b]
À
matches the average value of the Ir Cl bond in these
compounds (2.57 Š).
1
2
3
4
5
6
7
K2CO3
K2CO3
K2CO3
KO-t-Bu
KO-t-Bu
KO-t-Bu
KO-t-Bu
1:1
2:1
5:1
50:1
5:1
2:1
1:1
2
2
1
1
29
78
92
NMR studies of 2 and 3 reveal a similar structure
in solution. Two separate signal sets for the pyridyl
moieties most likely for the coordinating as well as
non-coordinating were observed. At room tempera-
ture, the isopropyl groups of 3 exhibit only broad
1H NMR signals that can easily be resolved into the
corresponding multiplets at lower temperatures
(À208C). These results are indicative of the dynamic
behaviour of the isopropyl groups of 3 in solution and
underline the crowded nature of the compound.
[a]
Reaction conditions: 0.50 mmol aniline, 0.50 mmol benzyl
alcohol, 5.0 mol% [IrCl(cod)]2, 10.0 mol% PyMeNPPh2
AHCTREUNG
(1e), 0.01–0.50 mmol base, 1 mL toluene, 1108C, 24 h.
Yield determined by GC analysis with dodecane as inter-
nal standard.
[b]
Catalytic Studies
Table 2. Solvent screening.[a]
Based on the pioneering work of Fujita et al., where
[Cp*IrCl2]2 was employed as a catalyst for the alkyla-
tion of aromatic amines with several primary and sec-
ondary alcohols,[11,15] we chose to determine the cata-
lytic potential of iridium-P,N complexes for such reac-
tions. The alkylation of aniline with alcohols has
proved to be challenging with ruthenium-based cata-
lysts and often affording mixtures of mono- and di-
Entry
Solvent
Temperature
Yield [%][b]
1
2
3
4
5
6
7
8
9
Toluene
DMF
1108C
1108C
1108C
1108C
1108C
1108C
1108C
708C
36
60
42
86
2
Dioxane
Diglyme
DMSO
Pyridine[c]
DME
0
62
77
0
A
THF
Et3N[c]
1108C
aniline with benzyl alcohol as a model reaction
(Scheme 3). In general, the screening reactions were
performed using 0.5 mmol of substrates at 1108C for
24 h and the catalyst was prepared in situ from stock
[a]
Reaction conditions: 0.50 mmol aniline, 0.50 mmol benzyl
alcohol, 1.0 mol% [IrCl(cod)]2, 2.0 mol% PyMeNPPh2
(1e), 0.50 mmol KO-t-Bu, 1 mL solvent, 24 h.
Yield determined by GC analysis with dodecane as inter-
nal standard.
AHCTREUNG
[b]
[c]
solutions of [IrCl(cod)]2 and P,N ligand.
N
Reaction without KO-t-Bu.
Optimization of the Reaction Conditions
of base still led to full conversion of the amine, but to
First, the influence of the substrate/base ratio using a mixture of alkylated amine as well as the corre-
various amounts of K2CO3 under the same reaction sponding imine.
conditions as in the literature was studied.[15] The re-
In order to optimize the reaction conditions the cat-
sults (Table 1, entries 1–3) exhibit only very low yields alyst loading was lowered from 10 to 2 mol% and sev-
(1–2%) of the expected benzylated aniline. Therefore eral organic solvents were screened (Table 2). The
K2CO3 was exchanged with the stronger and better highest yields were obtained in diglyme (86%) or
soluble base KO-t-Bu. The results of these reactions THF (77%) (Table 2, entries 4 and 8). Alkaline sol-
(Table 1, entries 4–7) show that KO-t-Bu is much vents such as pyridine and triethylamine were also
more effective and leads to better yields. Surprisingly, used (Table 2, entries 6 and 9), but without further ad-
full conversion of the amine into benzylphenylamine dition of KO-t-Bu. In both cases no conversion of was
could only be obtained when stoichiometric amounts observed.
of base were employed. Interestingly, use of 50 mol%
In a next step various organic and inorganic bases
were examined in order to determine the best reac-
tion conditions and see if the results obtained with
KO-t-Bu could be improved. The results summarized
in Table 3 show that only a few bases led to accepta-
ble conversions and yields. In most cases only poor
conversions were achieved and the corresponding
imine was obtained as a by-product, except in the run
Scheme 3. Model reaction used to optimize the reaction con-
ditions for the alkylation of aromatic amines.
with KN(SiMe3)2 where more undefined by-products
A
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751

Benoît Blank et al.
Yield [%][b]
FULL PAPERS
Table 3. Base screening.[a]
Table 4. Ligand screening.[a]
Entry
Base
Yield [%][b]
Entry
Ligand
1
2
3
4
5
6
7
8
KO-t-Bu
K3PO4
K2CO3
Na2CO3
NaOAc
KOAc
Cs2CO3
AgF3OAc
79
37
0
0
0
<1
12
<1
48
59
0
20
0
67
1
2
3
4
5
6
7
8
9
PyMeNPPh2 (1e)
PyMeNPCy2 (1f)
68
67
67
79
66
66
81
77
34
PyMeNP
ACHTREUNG
PyMeNP
ACHTREUNG
Py2NPPh2 (1a)
Py2NPCy2 (1b)
Py2NP
ACHTREUNG
Py2NP
ACHTREUNG
9
KN
NaN
Mg(OEt)2
KOSiMe3
(i-Pr)2Et
KH
R
without ligand
10
11
12
13
14
ACHTREUNG
[a]
Reaction conditions: 0.50 mmol aniline, 0.50 mmol benzyl
alcohol, 1.0 mol% [IrCl(cod)]2, 2.0 mol% ligand,
AHCTREUNG
AHCTREUNG
0.50 mmol KO-t-Bu, 1 mL diglyme, 1108C, 24 h.
Yield determined by GC analysis with dodecane as inter-
nal standard.
N
ACHTREUNG
[b]
[a]
Reaction conditions: 0.50 mmol aniline, 0.50 mmol benzyl
alcohol, 1.0 mol% [IrCl(cod)]2, 2.0 mol% PyMeNPPh2
AHCTREUNG
whether the amount of KO-t-Bu could be reduced
without loss of performance. When catalytic amounts
of base were employed (Table 5, entries 1–3) only
poor conversions were observed as well as the forma-
tion of the corresponding imine as a major by-prod-
(1e), 0.50 mmol base, 1 mL diglyme, 1108C, 24 h.
Yield determined by GC analysis with dodecane as inter-
nal standard.
[b]
were observed. KO-t-Bu was once again found to be uct. The same result was obtained when 50 mol% of
the best base, leading to best conversions and highest base were introduced, affording good conversions, but
yield of benzylphenylamine (Table 3, entry 1). The re- also mostly imine as by-product (Table 5, entry 4).
action with KH or NaN(SiMe3)2 also led to satisfying The highest yields were obtained when stoichiometric
G
results (Table 3, entries 10 and 14), but the yields amounts of KO-t-Bu were used and it also seems that
using other bases were much lower. For example, a 10% excess of base is necessary to form the product
K2CO3, Na2CO3, NaOAc, KOAc, AgF3OAc, Mg- quantitatively (Table 5, entry 6).
A
G
Finally, in order to obtain 100% conversion (GC)
and thus to allow optimized product isolation, the in-
It was of special interest to us to know how impor- fluence of the amine/alcohol ratio on the N-alkylation
tant the influence of the P,N ligand is for the outcome reaction was studied. Our investigations showed that
of the reaction and to determine a trend of reactivity a large excess of alcohol leads to decreasing yields
for the different ligands. Therefore, screening of all (Table 6, entries 2–4), whereas a 10% excess of alco-
the mentioned ligands described in Scheme 1 was ac- hol (Table 6, entry 5) is beneficial in order to achieve
complished. The results show that all ligands have an full conversion and to decrease the amount of corre-
activating influence on the metal centre, as the ob- sponding imine.
tained yields were significantly higher compared to
the reaction without ligand (Table 4, entry 9). Three
ligands were found to be very activating (Table 4, en-
tries 4, 7, 8) since they afforded yields from 77% up
to 81%. All these ligands contain electron-donating
i-Pr or t-Bu substituents on the phosphorus centre
and hence provide a strong basicity of the latter.
These ligands are also the most bulky ones and thus
ligand bulkiness may also play an important role in
terms of catalyst efficiency or in terms of the genera-
tion of the catalytically active species. Compared with
Table 5. Influence of substrate/base ratio.[a]
Entry
Base
Substrate:Base
Yield [%][b]
1
2
3
4
5
6
KO-t-Bu
KO-t-Bu
KO-t-Bu
KO-t-Bu
KO-t-Bu
KO-t-Bu
50:1
20:1
10:1
2:1
1:1
1:1.1
1
7
19
79
90
98 (92[c])
the results of Fujita, when only [IrCl(cod)]2 was used
G
[a]
Reaction conditions: 1.00 mmol aniline, 1.10 mmol benzyl
alcohol, 1.0 mol% [IrCl(cod)]2, 2.0 mol% Py2NP(i-Pr)2
(1c), 1.10-0.02 mmol KO-t-Bu, 1 mL diglyme, 1108C,
as the catalyst with 5 mol% K2CO3 in toluene – af-
fording only 3% yield,[15] our results show that the
loading and the nature of the added base play an im-
portant role.
Having optimized important reaction parameters
(solvent, ligand, and base), it was of interest to know
U
ACHTREUNG
24 h.
[b]
[c]
Yield determined by GC analysis with dodecane as inter-
nal standard.
Isolated yield.
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Selective Iridium-Catalyzed Monoalkylation of (Hetero)aromatic Amines
Table 6. Influence of amine/alcohol ratio.[a]
FULL PAPERS
Table 7. Influence of catalyst loading.[a]
Entry
Amine:Alcohol
Yield [%][b]
Entry
Ir loading (mol%)
Yield [%][b]
1
2
3
4
5
1:1
1:2
1:3
1:4
75
68
65
57
1
2
3
4
5
2.0
1.0
0.5
0.25
0
98
82
65
33
4
1:1.1
100
[a]
[a]
Reaction conditions: 0.50 mmol aniline, 0.50-2.50 mmol
benzyl alcohol, 1.0 mol% [IrCl(cod)]2, 2.0 mol%
Py2NP(i-Pr)2 (1c), 0.55 mmol KO-t-Bu, 1 mL diglyme,
1108C, 24 h.
Yield determined by GC analysis with dodecane as inter-
nal standard.
Reaction conditions: 0.50 mmol aniline, 0.55 mmol benzyl
alcohol, [IrCl(cod)]2, Py2NP(i-Pr)2 (1c), 0.55 mmol
KO-t-Bu, 1 mL diglyme, 1108C, 24 h.
Yield determined by GC analysis with dodecane as inter-
nal standard.
G
N
ACHTREUNG
A
G
[b]
[b]
Having determined the best reaction conditions prisingly afforded many non-identifiable side-products
(1.0 equiv. amine, 1.1 equiv. alcohol, 1.1 equiv. and only led to moderate yields (34%) when reacted
KO-t-Bu, diglyme, 1108C and [IrCl(cod)]2 with for 17 h. In order to avoid the decomposition of the
Py2NP(i-Pr)2 (1c), the catalyst loading was varied. product the reaction was also monitored by TLC and
AHCTREUNG
ACHTREUNG
Compared with the results of our first investigation quenched after 3 h when full conversion was ob-
where 10 mol% iridium catalyst had been employed served. By doing so benzyl-(4-trifluoromethyl-
(Table 1), it could be shown that a catalyst loading of phenyl)-amine could be isolated in good yields (67%)
2 mol% is sufficient to obtain excellent yields (Table 8, entry 6).
(Table 7, entry 1) with the optimized reaction condi-
The N-alkylation of amines bearing nitro and ester
tions. However, further reduction of the iridium com- groups was unsuccessful and did not afford the ex-
plex concentration led to a decrease of yield within pected secondary amines. Instead, mainly the degra-
the 24 h time window (Table 7, entries 2–5). Finally, a dation products of the starting materials were ob-
catalyst concentration of 1 mol% [IrCl
A
mol% Py2NP(i-Pr)2 (1c) was found to be optimal.
A
stoichiometric amounts of the strong base KO-t-Bu,
since the catalytic system of Fujita et al. in which
K2CO3 (in catalytic amount) was added as a base per-
fectly tolerates nitro-substituted aromatic amines.[15]
Interestingly, not only the derivatives of aniline but
also the even more deactivated heteroaromatic
N-Alkylation Reactions of Substituted Anilines with
Primary Alcohols
In order to point out the general applicability of this amines could generally be alkylated with benzyl alco-
improved iridium-catalyzed N-alkylation reaction, hol in excellent yields (Table 8, entries 9–11). To our
various substituted aromatic amines were alkylated best knowledge, there is no reported general method
with benzyl alcohol with the above-mentioned opti- for the N-alkylation of aminopyridines with alcohols
mal reaction parameters (Table 8).
and an iridium catalyst. Merely two ruthenium-based
The results show that electron-donating (Table 8, protocols have been reported for the N-alkylation of
entries 2, 3, 4, 8) as well as electron-withdrawing aminopyridines.[7b,14] However, these protocols have
(Table 8, entries 5, 6, 7) substituents in ortho-, meta- also disadvantages especially the selectivity towards
and para-positions of the aromatic ring are perfectly mono- and dialkylation of the amine. In comparison,
tolerated and most products were isolated in very with our iridium catalyst system, excellent yields of
good to excellent yields. However, the use of a strong monoalkylated 2- and 3-aminopyridines could be ob-
base such as KO-t-Bu has disadvantages concerning tained with lower catalyst loadings.
the tolerance for base-sensitive functional groups. For
The reactions were also carried out with aliphatic
example, the alkylation of 4-aminobenzonitrile had to amines such as benzylamine, n-butylamine and cyclo-
be monitored by thin layer chromatography (TLC). hexylamine, but in all cases low conversions were ob-
However, the alkylation of the aminobenzonitrile is served and almost no product could be detected
very fast and full conversion was obtained after only (Table 8, entries 12, 13, 14). These results show the
20 min. The reaction was then rapidly quenched to necessity of a direct connection of the amino group to
prevent the formation of 4-benzylaminobenzamide, the aromatic ring, in order to obtain a good nucleo-
which forms quantitatively after a few hours.
philic attack at the carbonyl center, fast formation of
The N-alkylation reaction of 4-(trifluoromethyl)- the corresponding imine and hydrogen-transfer from
aniline, carrying a usually very stable CF3 group, sur- the iridium complex to the imine.
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Benoît Blank et al.
FULL PAPERS
Table 8. Catalytic N-alkylation of primary aromatic amines with benzyl alcohol.[a]
[a]
Reaction conditions: 1.00 mmol amine, 1.10 mmol benzyl alcohol, 1.0 mol% [IrCl
G
N
1.10 mmol KO-t-Bu, 1 mL diglyme, 1108C, 17 h (reaction times were not optimized).
Isolated yield.
Reaction time: 3 h.
Reaction time: 20 min.
[b]
[c]
[d]
N-Alkylation of Aminopyridines with Primary
Alcohols
lose its chlorine atom and form N-benzylaminopyri-
dine as by-product. Therefore, the reaction had to be
quenched after four hours when full conversion was
In order to show the general applicability of this obtained and decomposition had not yet started.
method for the alkylation of aminopyridines, a broad The reaction of heteroaromatic alcohols also pro-
scope of substituted benzyl alcohol derivatives as well ceeds efficiently and the corresponding N-alkylated
as aliphatic alcohols and heteroaromatic alcohols aminopyridines were obtained in moderate to good
were employed, selectively affording the monoalkylat- yields (Table 9, entries 5–7). Monitoring of theses re-
ed compounds in good to excellent yields.
actions showed that they are slower than the reactions
The results in Table 9 show that the N-alkylation of with benzyl alcohol derivatives. The reaction of pyri-
aminopyridines with several substituted benzyl alco- din-2-ylmethanol did not afford a full conversion of
hols works perfectly and that electron-donating the starting material even after 17 h and 2-aminopyri-
(Table 9, entries 1, 3, 4) as well as electron-withdraw- dine as well as the corresponding product were pres-
ing (Table 9, entry 2) substituents in ortho- and para- ent in the reaction mixture. To the present day there
positions of the aromatic ring are tolerated. All ob- has been no report for such an N-alkylation reaction
tained products were isolated in good to excellent of heteroaromatic amines with heteroaromatic pri-
yields. However, the reaction of 2-aminopyridine with mary alcohols, except for the N-alkylation of aliphatic
4-chlorobenzyl alcohol (Table 9, entry 2) is more com- amines with several heteroaromatic alcohols using a
plicated due to the fact that the product can partially ruthenium catalyst and higher catalyst loadings.[12]
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Selective Iridium-Catalyzed Monoalkylation of (Hetero)aromatic Amines
FULL PAPERS
Table 9. Catalytic N-alkylation of 2-aminopyridine with various primary alcohols.[a]
[a]
Reaction conditions: 1.00 mmol 2-aminopyridine, 1.10 mmol alcohol, 1.0 mol% [IrCl
G
N
1.10 mmol KO-t-Bu, 1 mL diglyme, 1108C, 17 h (reaction times were not optimized).
Isolated yield.
Reaction time 4 h.
[b]
[c]
[d]
1.6 equiv of MeOH, Yield determined by GC analysis with dodecane as internal standard.
Especially interesting is the fact that our catalyst
In order to understand the high selectivity towards
system described here is not only restricted to benzyl monoalkylation of primary aromatic amines, the N-al-
alcohols but that aliphatic alcohols can also be used kylation of a secondary (aryl,alkyl)-amine was investi-
as alkylating agents, particularly methanol. The reac- gated. However, in the reaction of 2-(methylamino)-
tion of 2-aminopyridine with 1-octanol or 1-butanol pyridine with benzyl alcohol no conversion of the
affords the expected N-alkylated aminopyridines in amine was observed (Scheme 4).[15]
good yields (Table 9, entries 9 and 10). We could also
This result shows that our catalyst is highly selec-
show that our catalyst system is very useful for the se- tive towards monoalkylation in the reaction of pri-
lective N-methylation of aminoarenes (Table 9, mary amines with alcohols and stops after one alkyla-
entry 8), affording good yields of monoalkylated tion of the amine. This selectivity is not a matter of
product without any traces of N,N-dimethylated catalyst deactivation, because no dialkylated amine
amine. Such a selective catalytic monomethylation of was observed even with higher catalyst loadings (10
aminoarenes is difficult as earlier investigations have mol%) and higher loadings of base. This selectivity
shown, because an excess of the alcohol has to be renders our catalytic protocol a useful tool for organic
used, leading to unwanted dimethylated tertiary synthesis because the selective monoalkylation, espe-
amines.[6,7g]
Scheme 4. N-Alkylation of secondary amines with benzyl alcohol.
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Benoît Blank et al.
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12.0 mmol) was added dropwise with a syringe. The yellow
solution was then stirred overnight at room temperature and
subsequently heated to 1008C for 4 days. The clear yellow
solution was filtered on a glass filter frit with a celite pad
(3 cm) and washed with 30 mL toluene. The solvent was re-
moved under vacuum and the resulting brown oil left to
crystallize at À208C. The solid was dried under vacuum
yielding the title compound as a pale brown solid; yield:
3.301 g (87%).
cially the monomethylation, of aromatic amines is dif-
ficult to accomplish.
Conclusions
Summarized, we have developed an efficient protocol
for the synthesis of P-functionalized aminopyridine li-
gands and their iridium complexes as well as an effi-
cient catalytic application of the latter for the alkyla-
tion of primary aromatic and heteroaromatic amines
with primary aromatic, heteroaromatic as well as ali-
phatic alcohols. It is noteworthy that this process is
highly selective towards monoalkylation and proceeds
with rather moderate catalyst loadings.
Py2NP(i-Pr)2 (1c): Following the general procedure em-
G
ployed for the synthesis of 1b, the product was obtained as
an orange/red solid; yield: 3.017 g (87%).
PyMeNPPh2 (1e): Following the general procedure em-
ployed for the synthesis of 1b, the product was obtained as a
beige solid; yield: 3.96 g (90%)..
PyMeNPCy2 (1f): Following the general procedure em-
ployed for the synthesis of 1d, without heating after the ad-
dition of the chlorophosphine, the product was obtained as
a colourless very viscous liquid after distillation; yield:
3.722 g (82%).
Experimental Section
PyMeNP(i-Pr)2 (1g): Following the general procedure
E
General Considerations
employed for the synthesis of 1d, without heating after the
addition of the chlorophosphine, the product was obtained
as a pale yellow liquid after distillation; yield: 2.388 g
(71%)..
Please see Supporting Information.
P,N Ligand Synthesis
PyMeNP(t-Bu)2 (1h): Following the general procedure
employed for the synthesis of 1b, the product was obtained
as a yellow liquid after distillation; yield: 2.42 g (73%).
A
For analytical and spectroscopic data please see Supporting
Information. Py2NPPh2 (1a) was prepared according to the
literature procedure.[16]
Complex Synthesis; General Method
A
N
General Procedure for the Preparation of P-
Functionalized Aminopyridines with n-BuLi
subsequently a solution of P,N ligand (2.0 equiv.) in 5 mL
CH2Cl2 was added dropwise. A red solution was obtained
and after 15 min the solvent was removed under vacuum, af-
fording the complex in quantitative yields. For analytical
and spectroscopic data plase see Supporting Information.
Py2NPCy2 (1b): Di(2-pyridyl)amine (2.47 g, 14.4 mmol) was
suspended in 50 mL hexane and the solution was cooled to
À208C. Then n-BuLi (9.0 mL, 14.4 mmol) was added drop-
wise with a syringe. The reaction mixture was stirred at
À208C for 30 min, allowed to warm to room temperature
and stirred for 2 h. The reaction mixture was cooled to
General Procedure for Screening Reactions
À208C
and
chlorodicyclohexylphosphine
(3.18 mL,
In a pressure tube, stock solutions of [IrCl
(cod)]2 (80 mL,
14.4 mmol) added dropwise with a syringe. The yellow solu-
tion was then left to warm to room temperature and stirred
overnight. The yellow suspension was filtered on a glass
filter frit with a celite pad (3 cm) and washed with 100 mL
pentane. The solvents were concentrated under vacuum to
10 mL and the product was left to crystallize at À208C. The
supernatant solution was decanted, the solid washed with
3 mL cold pentane and subsequently dried under vacuum
yielding the title compound as a beige solid; yield: 3.291 g
(64%).
0.005 mmol, 0.0625M in THF) and Py2NP(i-Pr)2 (1c) (80 mL,
AHCTREUNG
0.01 mmol, 0.125M in THF) were mixed. Then aniline
(45.9 mL, 0.50 mmol), benzyl alcohol (56.8 mL, 0.55 mmol)
and 1 mL diethylene glycol dimethyl ether (diglyme) as sol-
vent were added. Last, KO-t-Bu (0.56 g, 0.55 mmol) was dis-
solved in the reaction mixture and the pressure tube was
fitted with a Teflonꢁ cap and stirred at 1108C for 24 h. The
reaction mixture was cooled to room temperature. Then
water (15 mL), diethyl ether (15 mL) and dodecane
(56.8 mL, 0.25 mmol) were added. After stirring, an aliquot
of the organic phase was analyzed by gas chromatography.
General Procedure for the Preparation of P-
Functionalized Aminopyridines with KH
General Procedure for the N-Alkylation Reactions
Py2NP
(t-Bu)2 (1d): Potassium hydride (0.48 g, 12.0 mmol)
In a pressure tube, stock solutions of [IrCl
U
was suspended in 30 mL toluene and the solution was
cooled to À408C. Then di(2-pyridyl)amine (2.05 g,
12.0 mmol), dissolved in 30 mL toluene was added dropwise
with a dropping funnel. The reaction mixture was stirred at
À208C for 30 min, allowed to warm to room temperature
and stirred overnight. Then the reaction mixture was cooled
to À208C and chloro-di-tert-butylphosphine (2.3 mL,
0.01 mmol, 0.0625M in THF) and Py2NP(i-Pr)2 (1c) (160 mL,
ACHTREUNG
0.02 mmol, 0.125M in THF) were mixed. Then the amine
(1.00 equiv.), the alcohol (1.10 equiv.) and 1 mL diethylene
glycol dimethyl ether (diglyme) as solvent were added. Last,
KO-t-Bu (1.10 equiv.) was dissolved in the reaction mixture
and the pressure tube was fitted with a Teflonꢁ cap and
stirred at 1108C for 17 h. The reaction mixture was cooled
756
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Selective Iridium-Catalyzed Monoalkylation of (Hetero)aromatic Amines
FULL PAPERS
to room temperature and all volatiles were removed under
vacuum. Then water (40 mL) was added to the residue and
extracted with diethyl ether (3”20 mL). The combined or-
ganic layers were washed with brine (15 mL), dried over
Na2SO4, filtered and the solvent removed under vacuum. Fi-
nally, the residue was purified by column chromatography.
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Crystallographic Data
The X-ray crystal structure analysis of 2 was performed by
using a STOE-IPDS II equipped with an Oxford Cryo-
stream low-temperature unit. Structure solution and refine-
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WinGX.[21] Crystal system: triclinic, space group: P1, lattice
¯
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constants
ACHTREUNG
a=100.393(5), b=96.344(5), g=94.013(5),
V
1545.66(17), crystal size [mm]: 0.35”0.32”0.15, 1calcd.
[gcmÀ3]: 1.694, m [mmÀ1] (Mo-Ka): 4.656, T [K]: 173(2), q
range [8]: 1.37–26.13, no. of unique refl.: 5822, no. of obsd.
refl. [I>2s(I)]: 5104, no. of parameters: 352, wR2 (all data):
0.0626, R value [I>2s(I)]: 0.0298. CCDC 670063 (com-
pound 2) contains the supplementary crystallographic data
for this publication. These data can be obtained free of
charge at www.ccdc.cam.uk/data_request/cif (or from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; Fax: + 44–1223–336–033; e-
mail: deposit@ccdc.cam.ac.uk).
Supporting Information
Detailed synthesis and characterization data of all ligands,
complexes and products.
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This work was also supported by NanoCat, an International
Graduate Program within the Elitenetzwerk Bayern. BB
thanks for a Bavarian Elite Graduation Grant (Graduierten-
stipendium nach dem Bayerische Elitefçrderungsgesetz) and
MM for an ERASMUS grant.
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