New iridium catalysts for the efficient alkylation of anilines by alcohols under mild conditions

Article abstract of DOI:10.1002/chem.201001871

The synthesis of eight new iridium complexes containing anionic P,N ligands is described. These complexes have been investigated as catalysts for amine alkylation reactions, resulting in a highly active catalyst for the selective monoalkylation of anilines with primary alcohols, under mild reaction conditions. Nearly quantitative conversion was observed at 70 °C with a catalyst loading as low as 0.05 mol % iridium. Selective amine alkylation: The synthesis of eight new iridium complexes containing anionic P,N ligands (see image) is described. These new complexes were used as highly active catalysts for the selective monoalkylation of anilines with primary alcohols, and gave nearly quantitative conversion under mild reaction conditions.

Full text of DOI:10.1002/chem.201001871

FULL PAPER
DOI: 10.1002/chem.201001871
New Iridium Catalysts for the Efficient Alkylation of Anilines by Alcohols
under Mild Conditions
Stefan Michlik and Rhett Kempe*[a]
Abstract: The synthesis of eight new iridium complexes containing anionic P,N li-
gands is described. These complexes have been investigated as catalysts for amine
alkylation reactions, resulting in a highly active catalyst for the selective
monoalkylation of anilines with primary alcohols, under mild reaction conditions.
Keywords: alcohols · alkylation ·
anilines · iridium · N,P ligands
ACHTUNGTRENNUNG
Nearly quantitative conversion was observed at 708C with a catalyst loading as
low as 0.05 mol% iridium.
Introduction
usually requires a stoichiometric amount of base. Both of
these observations were not fully understood by us and we
became interested in obtaining a more detailed insight into
how the catalyst operates within an HA/BH scenario. The
observations made led to a new class of catalysts that oper-
ates very efficiently under mild conditions.
P,N-ligand-stabilised iridium complexes are efficient cata-
[1–3]
[4]
À
À
lysts for selective C N
and C C coupling reactions in-
volving the borrowing-hydrogen (BH)[5] or hydrogen-auto-
transfer (HA)[6] catalysis protocols.[7] These protocols pro-
ceed for Ir-complex-catalysed amine alkylations as shown in
Scheme 1 and have been developed into efficient synthetic
methods by (for instance) the groups of Beller,[8] Grigg,[9]
Fujita,[10] Williams[8a,11] and Yus,[12] as well as by us.[1–4]
Results and Discussion
The P,N-ligand-based Ir catalyst system developed by us is
Detection of the catalytically active species in aminopyri-
dine alkylation reactions: In previous work, it has been
shown that our catalyst system is highly active in the alkyl-
especially active in the alkylation of aminopyridines[2,3] and
AHCTUNGTRENNUNG
ation of 2-aminopyridines with primary alcohols.[2,3] There-
fore, 2-aminopyridine (1.0 equiv), alcohol (1.1 equiv) and
KOtBu were reacted, at 708C, in the presence of the Ir cata-
lyst (0.1 mol%; Scheme 2). Under these conditions, N-(2-
pyridyl)benzylamine was isolated in a very good yield of up
to 93%.[2]
However, these mild reaction conditions could not simply
be transferred to the alkylation of anilines. For these com-
pounds it was necessary to increase the catalyst loading to
0.6 mol% iridium to obtain comparable results. It was con-
Scheme 1. The metal-complex catalysed borrowing-hydrogen or hydro-
gen-autotransfer protocol to selectively alkylate amines ([Ir]=iridium
complex).
[a] 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
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001871.
Scheme 2. Alkylation of aminopyridines under mild conditions.
Chem. Eur. J. 2010, 16, 13193 – 13198
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
13193

cluded that the presence of aminopyridines may change the
nature of the catalyst. NMR experiments were carried out
to investigate whether the catalyst reacts with the
aminopyriACHTUNGTRENNUNGdine substrate. Stoichiometric amounts of 2-ami-
nopyridine and KOtBu were added to catalyst 1, under
equivalent conditions to the catalysis experiments
Scheme 3. The reaction of 1 with 2-aminopyridine, in the presence of
KOtBu.
Figure 1. Molecular structure of 2a. Selected bond length [ꢃ] and angles
À
À
À
À
[8]: Ir1 N1 2.071(5), Ir1 C1 2.109(6), Ir1 C2 2.140(6), Ir1 C5 2.191(6),
À
À
À
À
Ir1 C6 2.216(6), Ir1 P1 2.2806(15), C1 C2 1.402(9), C5 C6 1.381(9),
À
À
À
P1 N2 1.659(5), N1 C9 1.405(7), P1 C14 1.835(6), N1-Ir1-C1 157.0(2),
N1-Ir1-C2 164.3(2), C1-Ir1-C2 38.5(2), N1-Ir1-C5 95.2(2), N1-Ir1-P1
79.23(14), N2-P1-Ir1 105.53(19), N2-C9-N1 121.7(5).
(Scheme 3). In the 31P NMR spectrum (161 MHz, CD2Cl2,
298 K) only one peak, at d=94.9 ppm, was detected, which
is shifted to higher field in comparison with the chemical
shift of complex 1 (d=110.4 ppm). This observation indi-
cates that complex 1 does react with 2-aminopyridine, in the
presence of a base, to form a new compound. Independent
synthesis of this new compound, complex 2a, through de-
Iridium complexes like 2a, that is, compounds stabilised
by anionic P,N ligands, might be responsible for the en-
hanced activity in alkylation reactions of aminopyridines
and might be a better class of catalyst than complexes like
1, namely, ones stabilised by neutral P,N ligands. To investi-
gate the potential of this “novel” class of Ir catalysts, a small
library of ligands was synthesised from different substituted
2-aminopyridines and 2-aminopyrimidines by reacting them
with chlorodiisoproylphosphane or chlorodiphenylphos-
phane in the presence of a base.
protonation of PyHNP
ACHTUNGTRENNUNG
lowed by the addition of [{IrClAHCNUTGTRENNUNG
diene), led to 2a in 80% isolated yield (Scheme 4).
Scheme 4. Synthesis of 2a.
Crystals suitable for X-ray crystal structure analysis were
obtained from a hexane solution. The molecular structure of
À
2a is shown in Figure 1. In complex 2a, both the Ir1 N1
À
(2.071(5) ꢃ), and the P1 N2 (1.659(5) ꢃ) bond lengths are
slightly shorter than those in complex 1, which contains a
Iridium complexes based upon these ligands were synthes-
ised in two different ways. The first was deprotonation of
the corresponding ligand by nBuLi, followed by the addition
of [{IrClACHTUNGRTENNG(U cod)}2] (0.5 equiv). The resulting LiCl was filtered
off and the solvent removed under vacuum. The more ele-
gant method was a one-step synthesis of the complexes. For
À
À
neutral
P,N-ligand
(Ir1 N1
(2.119(3) ꢃ),
P1 N2
(1.730(3) ꢃ)), because deprotonation of the amino group
means that the electron density is delocalised over the P-N-
C-N backbone. Similar observations have been made by
Woollins and co-workers for platinum and palladium com-
plexes stabilised by deprotonated 2-(diphenylphosphinoami-
no)pyridine (dppap).[13] Seidel already succeeded in 1967 in
synthesising a neutral nickel(II) complex by using the depro-
tonated dppap ligand.[14]
this, the dissolved ligand was added to [{IrOMeACHTUNGTRENNUNG(cod)}2]
(0.5 equiv) and the complex was formed by elimination of
methanol in quantitative yield. Iridium complexes 2a–9a
were synthesised and characterised (Scheme 5).
It is possible that if complexes like 2a are formed under
the catalytic conditions with alkylated aminopyridines, simi-
lar complexes may be formed with anilines. However, no re-
action of complex 1 with aniline in the presence of a base
was observed.
Catalyst development: If catalyst systems based upon 2a–9a
are responsible for the high efficiency of the alkylation reac-
tions of aminopyridines they should do well in the alkylation
of anilines. Since catalyst efficiency depends upon the reac-
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Chem. Eur. J. 2010, 16, 13193 – 13198

Alkylation of Anilines by Alcohols
FULL PAPER
Next, the influence of the base was investigated to deter-
mine whether the results obtained with KOtBu could be im-
proved upon. As can be seen in Table 1, entries B1–B5, only
some bases achieved a reasonable yield. However, the prob-
lem was that with all bases, except NaOtBu and KOtBu
(Table 1, entries B4 and B5), simultaneous to the amine for-
mation, the corresponding imine was also observed. The
better results achieved with KOtBu compared with NaOtBu
are explained by its excellent solubility in diglyme. The
bases used, with the exception of KOtBu, were generally
very poorly soluble in diglyme, which could have caused the
incomplete conversions.
Scheme 5. Synthesis of 2a–9a.
After these optimisations, we were interested to see if the
addition of stoichiometric amounts of base was needed to
allow complete conversion or whether catalytic quantities of
base are sufficient. Therefore, the influence of the substrate/
base ratio was investigated (Table 1, entries C1–C7). The re-
sults shown in Table 1, entries C1–C5, suggest that it is nec-
essary to use a substrate/base ratio of 1:1.1, because only in
this case (Table 1, entry C1) was it possible to obtain com-
plete conversion and an excellent yield (99%) within 24 h.
However, at a base loading of only 10 mol%, it was possible
to achieve a yield of 31% (Table 1, entry C5), which contra-
dicts the aforementioned stoichiometric requirement for
base. For this reason, we investigated whether it is possible
to bring the reaction to complete conversion by the use of
10 mol% of KOtBu. To this end, the reaction time was in-
creased; after 48 h a yield of 45% and after 4 days a yield of
60% were obtained.
To examine the reaction with catalyst 2a in detail, a kinet-
ic experiment for the reaction of aniline with benzyl alcohol
was performed by utilising continuous sampling by gas chro-
matography. As can be seen in Figure 2, it is possible to
come to complete conversion and a very good yield (94%)
with catalytic amounts of base. However, a very long reac-
tion time (ꢀ150 h) and a high catalyst loading (2.0 mol%
iridium) is needed to get this result. Since these reaction
conditions are unfavourable, it is reasonable to use an
tion conditions, these had to be optimised for the new cata-
lyst system. Catalyst 2a was used for the optimisation of the
reaction conditions (Scheme 6).
Scheme 6. The model reaction used for finding the optimum reaction
conditions.
First of all, the influence of the solvent was determined
and various organic solvents were tested. As can be seen
from Table 1, diethylene glycol dimethyl ether (diglyme) ap-
pears to be the most suitable solvent, because complete con-
version and a very good yield (99%) could only be achieved
by using this solvent (Table 1, entry A5). When using THF,
toluene or dimethoxyethane (DME), the yields were sub-
stantially lower (Table 1, entries A2–A4), indicating an in-
hibitory influence of the solvent on the reaction. It was also
observed that the yield of N-phenylbenzylamine remains the
same even with higher catalyst loadings. Interestingly, when
DMSO was used as the solvent, no conversion was observed
(Table 1, entry A1). Unfortunately, in all recent work the
catalyst stock solution was in THF,[1–4] even for the solvent
screenings. Since THF seems to deactivate our catalyst, all
further stock solutions were made in diglyme.
Table 1. Screening of solvent, base and substrate/base ratio.[a]
A
B
C
Solvent
Yield
Base
Yield
[%][b]
Substrate/Base
Yield
[%][b,c]
[%][b,d]
1
2
3
4
5
6
7
DMSO
THF
toluene
DME
n.d.
32
34
50
99
K3PO4
NaOH
KOH
NaOtBu
KOtBu
23
10
9
25
99
1:1.1
1:1.0
1:0.7
1:0.5
1:0.3
1:0.1
1:0
99
72
68
45
36
31
n.d.
diglyme
[a] Reaction conditions: aniline (1.0 mmol), benzyl alcohol (1.1 mmol),
catalyst 2a (0.4 mol%), base (1.1 mmol), solvent (0.2 mL), 708C, 24 h;
n.d.=not determined. [b] Yield determined by GC analysis with dodec-
ane as the internal standard. [c] Catalyst stock solutions were made with
the corresponding solvent. [d] Mean values after three runs.
Figure 2. Time conversion plot for the reaction of aniline with benzyl al-
~
&
*
cohol ( : benzyl alcohol; : aniline; : N-phenylbenzylamine). Reaction
conditions: aniline (4.0 mmol), benzyl alcohol (4.4 mmol), catalyst 2a
(2 mol%), diglyme (1 mL), KOtBu (0.4 mmol) and dodecane (1 mmol)
as an internal standard.
Chem. Eur. J. 2010, 16, 13193 – 13198
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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13195

R. Kempe and S. Michlik
excess of base to accelerate the reaction and to reduce the
catalyst loading.
To determine whether the base is essential for the imine
hydrogenation step or for the activation of the benzyl alco-
hol, imine hydrogenation experiments were carried out with
different base loadings and by using N-benzylidene-
than if the corresponding 2-aminopyrimidines (Table 3, en-
tries 3 and 4) were used. The best catalyst for this reaction
seems to be catalyst 7a (Table 3, entry 6), which achieved a
65% yield at a very low catalyst loading (0.05 mol% iridi-
um).
The final screening was performed on the catalyst loading
to find the minimum catalyst loading necessary to achieve
full conversion and good yields (Table 4). As shown in
Table 4, it was sufficient to use a catalyst loading of
0.1 mol% to obtain a very good yield (92%) for this reac-
tion (Table 4, entry 4). With catalyst 7a, the catalyst loading
can be reduced to approximately 1/6 of the catalyst loading
required when using catalyst 1. If no catalyst is used a con-
version of only 3% is observed (Table 4, entry 6).
ACHTUNGTRENNUNG(phenyl)amine as the starting material to get further insights
Scheme 7. The hydrogenation of benzylideneACTHUNRTGNEUNG(phenyl)amine.
Table 4. Catalyst loading.[a]
into this reaction (Scheme 7). As can be seen from Table 2,
the excess of base is not needed for the hydrogenation of
the imine, since even 10 mol% of base gives complete con-
version and excellent yield (95%; Table 2, entry 2). At
higher base loadings the yield of N-phenylbenzylamine de-
clines (Table 2, entries 3 and 4) and various byproducts are
formed.
Ir loading [%]
Yield [%][b]
Ir loading [%]
Yield [%][b]
1
2
3
0.4
0.3
0.2
99
99
99
4
5
6
0.1
0.05
0.0
92
65
3
[a] Reaction conditions: aniline (1.0 mmol), benzyl alcohol (1.1 mmol),
catalyst 7a, KOtBu (1.1 mmol), diglyme (0.2 mL), 708C, 24 h. [b] Yield
determined by GC analysis with dodecane as the internal standard; mean
values after three runs.
Table 2. The influence of base ratio on the hydrogenation of
benzylideneACHTUNGTRENNUNG
(phenyl)amine.[a]
To confirm the results we achieved for the alkylation of
aniline with benzyl alcohol with catalyst 7a, different aniline
derivatives were reacted with primary alcohols (Table 5). To
compare results, batches were made both with catalyst 7a
and the original catalyst 1 to show the superiority of the
new catalyst system. As can be seen in Table 5, complex 7a
is a significantly better catalyst than 1. All products were
obtained in very good to excellent yields by using complex
7a. The catalyst loadings are very low and the reaction con-
ditions are very mild in comparison with protocols previous-
ly developed for this reaction.[5–12]
Base [mol%]
Conversion [%]
Yield [%][b]
1
2
3
4
0
10
50
10
100
100
100
9
95
90
70
110
[a] Reaction conditions: benzylideneACTHNUTRGNEUNG(phenyl)amine (1.0 mmol), H2
(20 bar), catalyst 2a (0.4 mol%), diglyme (0.2 mL), 708C, 24 h. [b] Yield
determined by GC analysis with dodecane as the internal standard.
Additionally, the iridium complexes 2a–9a were tested to
determine what effect substitution at the phosphorus and
the amino skeleton has on the reaction (Table 3). Evidently,
all of the catalysts containing phenyl substituents on the
phosphorus (Table 3, entries 2, 4, 6 and 8) gave better results
than those containing an isopropyl substituent (Table 3, en-
tries 1, 3, 5 and 7), although isopropyl was always favoured
in our earlier work.[1–4] Moreover, it is noted that, by using
2-aminopyridines (Table 3, entries 1 and2, and 5–8) as the
amine skeleton, better activities were generally observed
Conclusion
It was shown that our new catalyst system, based upon
anionic P,N ligands, is highly active towards the alkylation of
aniline with primary alcohols and far surpasses the original
catalyst (based upon a neutral P,N ligand). Furthermore, the
catalysts are characterised by good long-term stability, as
confirmed by kinetic experiments over more than five days.
In addition, ligands and complexes are easily accessible in
very good yields. Further work is directed towards the appli-
Table 3. Catalyst screening.[a]
Catalyst
Yield [%][b]
Catalyst
Yield [%][b]
À
À
cation of these catalysts to selective C N and/or C C cou-
pling reactions using the HA/BH protocol.
1
2
3
4
2a
3a
4a
5a
47
61
36
41
5
6
7
8
6a
7a
8a
9a
40
65
49
53
Experimental Section
[a] Reaction conditions: aniline (1.0 mmol), benzyl alcohol (1.1 mmol),
catalyst (0.05 mol%), KOtBu (1.1 mmol), diglyme (0.2 mL), 708C, 24 h.
[b] Yield determined by GC analysis with dodecane as the internal stan-
dard; mean values after three runs.
General considerations: All reactions were carried out in a dry argon or
nitrogen atmosphere using standard Schlenk or glove box techniques.
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Chem. Eur. J. 2010, 16, 13193 – 13198

Alkylation of Anilines by Alcohols
FULL PAPER
Table 5. Catalytic N-alkylation of aniline derivatives with primary alco-
hols.[a]
General procedure for ligand synthesis (2–9): Arylamine (1.0 equiv)
was dissolved in THF (70–120 mL), triethylamine (1.0 equiv) was
added and the solution was cooled to 08C. Then, the corresponding
chlorophosphane (1.0 equiv) was added dropwise, with a syringe. The
solution was allowed to warm to room temperature and stirred over-
night at 508C. The suspension was filtered through a glass filter frit with
a pad of Celite (4 cm) and washed with THF. The solvent was concen-
trated in vacuo yielding the corresponding ligands as white solids.
Catalyst Amine
loading
Product
Yield [%][b]
Catalyst Catalyst
[mol%]
1
7a
General procedure for complex synthesis (2a–9a): [{IrOMeACHTUNGTRENNUNG(cod)}2]
(0.5 equiv) was suspended in THF (5–25 mL) and subsequently a solu-
tion of the corresponding ligand (1.0 equiv, 2–9) in THF (5 mL) was
added dropwise. A red solution was obtained and, after 30 min, the sol-
vent was removed in vacuo, affording dark red solids in almost quanti-
tative yields.
1
2
0.1
0.2
38
92
29
75
92
98
Synthesis of (5-Me)PyNHPPh2 (7): 5-Methyl-2-aminopyridine
(10.0 mmol, 1.08 g) was suspended in THF (70 mL), triethylamine
(10.0 mmol, 1.4 mL) was added and the solution was cooled to 08C.
Then chlorodiphenylphosphane (10.0 mmol, 1.83 mL) was added drop-
wise, with a syringe. The solution was allowed to warm to room temper-
ature and stirred for 4 d at room temperature and 12 h at 508C. The sus-
pension was filtered over a glass filter frit with a pad of Celite (4 cm)
and washed with THF (50 mL). The solvent was removed in vacuo,
yielding compound 7 as a white solid (9.69 mmol, 97%). 1H NMR
(400 MHz, CD2Cl2, 298 K): d=7.92 (s, 1H), 7.50–7.43 (m, 4H), 7.41–
7.28 (m, 7H), 6.95 (d, J=8.6 Hz, 1H), 5.25 (s, 1H), 2.19 ppm (s, 3H);
13C NMR (100 MHz, CD2Cl2, 298 K): d=147.7, 139.6, 138.8, 131.2 (d,
J=20.9 Hz), 129.1, 128.5 (d, J=6.7 Hz), 123.9, 108.4 (d, J=15.0 Hz),
17.4 ppm; 31P NMR (161 MHz, CD2Cl2, 298 K): d=27.21 ppm; elemen-
tal analysis calcd (%) for C18H17N2P: C 73.96, H 5.86, N 9.58; found: C
73.88, H 5.69, N 9.71.
3
4
0.05
0.2
33
81
5
6
0.2
0.4
54
48
98
91
Synthesis of [{(5-Me)PyNHPPh2}IrACHTUNTRGENNUG(cod)] (7a): [{IrOMeACHTUNGTRENNUNG(cod)}2]
(1.2 mmol, 795 mg) was dissolved in THF (20 mL) and a solution of
compound 7 (2.4 mmol, 701 mg) dissolved in THF (5 mL) was subse-
quently added dropwise. A red solution was obtained and, after 30 min,
the solvent was removed in vacuo and the residue was recrystallised
from hexane/THF (3:1), yielding red crystals (1.03 mmol, 86%).
1H NMR (400 MHz, CD2Cl2, 298 K): d=7.59 (ddd, J=10.8, 7.3, 1.7 Hz,
4H), 7.41–7.36 (m, 6H), 7.23 (s, 1H), 7.04 (dt, J=8.9, 2.4 Hz, 1H), 6.88
(d, J=8.9 Hz, 1H), 4.94 (s, 2H), 3.54 (s, 2H), 2.25–2.19 (m, 4H), 2.02 (s,
3H), 2.04–1.94 ppm (m, 4H); 13C NMR (100 MHz, CD2Cl2, 298 K): d=
143.8 (d, J=2.7 Hz), 140.7 (d, J=2.9 Hz), 138.4 (d, J=0.6 Hz), 137.8 (d,
J=0.5 Hz), 132.5 (d, J=12.2 Hz), 130.5 (d, J=2.3 Hz), 128.8 (d, J=
10.3 Hz), 116.6, 116.4 (d, J=0.5 Hz), 115.9 (d, J=0.6 Hz), 95.32, 91.7 (d,
J=13.4 Hz), 60.4, 33.5, 29.5, 17.3 ppm; 31P NMR (161 MHz, CD2Cl2,
298 K): d=72.54 ppm; elemental analysis calcd (%) for C26H28IrN2P: C
52.78, H 4.77, N 4.73; found: C 52.83, H 4.86, N 4.72.
7
8
0.2
0.2
73
52
97
98
[a] Reaction conditions: amine (1.0 mmol), benzyl alcohol (1.1 mmol),
KOtBu (1.1 mmol), diglyme (0.2 mL), 708C, 24 h. [b] Yield determined by
GC analysis with dodecane as the internal standard.
Halogenated solvents were dried over P2O5 and non-halogenated solvents
were dried over sodium benzophenone ketyl. Deuterated solvents were
ordered from Cambridge Isotope Laboratories, vented, stored over mo-
lecular sieves and distilled. All chemicals were purchased from commer-
cial sources with a purity over 97% and used without further purification,
with the exception of aniline, which was distilled before use in the screen-
ing reactions. NMR spectra were performed by using an INOVA
400 MHz spectrometer at 298 K. Chemical shifts are reported in ppm rel-
ative to the deuterated solvent. Elemental analysis was carried out on a
Vario elementar EL III. GC analyses were carried out on an Agilent
6890N Network GC system equipped with an HP-5 column (30 mꢄ
0.32 mmꢄ0.25 mm).
Acknowledgements
This work was supported by NanoCat, an International Graduate Pro-
gram within the Elitenetzwerk Bayern.
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closed with a Teflon cap and stirred at 708C for 24 h. The reaction mix-
ture was cooled to room temperature and quenched by the addition of
water (2 mL). Then, diethyl ether (10 mL) and dodecane (1.0 mmol,
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tube, the catalyst stock solution (200 mL, 0.02 m) in diethyl glycol dimeth-
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solvent (0.2 mL) and base (1.1 mmol) were combined.
Chem. Eur. J. 2010, 16, 13193 – 13198
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R. Kempe and S. Michlik
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Published online: October 7, 2010
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