Selective alkylation of amines with alcohols by Cp*- iridium(III) half-sandwich complexes

Article abstract of DOI:10.1021/ol303075h

[Cp*Ir(Pro)Cl] (Pro = prolinato) was identified among a series of Cp*-iridium half-sandwich complexes as a highly reactive and selective catalyst for the alkylation of amines with alcohols. It is active under mild conditions in either toluene or water without the need for base or other additives, tolerates a wide range of alcohols and amines, and gives secondary amines in good to excellent isolated yields.

Full text of DOI:10.1021/ol303075h

ORGANIC
LETTERS
2013
Vol. 15, No. 2
266–269
Selective Alkylation of Amines with
Alcohols by Cp*ÀIridium(III)
Half-Sandwich Complexes
Alexander Wetzel,†,‡ Simone Wockel,†,‡ Mathias Schelwies,‡ Marion K. Brinks,‡
€
Frank Rominger,§ Peter Hofmann,†,§ and Michael Limbach*,†,‡
CaRLa À Catalysis Research Laboratory, Im Neuenheimer Feld 584, 69120 Heidelberg,
Germany, BASF SE, Synthesis & Homogeneous Catalysis, Carl-Bosch-Straße 38, 67056
Ludwigshafen, Germany, and Organisch-Chemisches Institut,
€
Ruprecht-Karls-Universitat Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg,
Germany
michael.limbach@basf.com
Received November 8, 2012
ABSTRACT
[Cp*Ir(Pro)Cl] (Pro = prolinato) was identified among a series of Cp*Àiridium half-sandwich complexes as a highly reactive and selective catalyst
for the alkylation of amines with alcohols. It is active under mild conditions in either toluene or water without the need for base or other additives,
tolerates a wide range of alcohols and amines, and gives secondary amines in good to excellent isolated yields.
Since Grigg et al.1 reported [RhH(PPh3)4] to be one of
the first well-defined homogeneous catalysts for metal-
catalyzed N-alkylations of amines with alcohols in 1981, this
hydrogen-transfer process was established as a versatile,
highly selective, and environmentally benign route to
amines:2 it starts from readily available reactants and gives
water as a single side product.3 Indeed, numerous catalysts
based on iridium,4 ruthenium,5 and other transition metals6
have been developed and already are applied industrially,
e.g., in the kilogram-scale synthesis of a glycine transporter
type 1 inhibitor.7
† CaRLa À Catalysis Research Laboratory.
Soluble complexes based on iridium catalyze the forma-
tion of secondary or tertiary amines with high selectivity,
e.g., Fujita’s and Yamaguchi’s [Cp*IrCl2]2,8 Crabtree’s9
and Peris’10 Ir(III)ÀNHC complexes, or even [Ir(COD)Cl]2
‡ BASF SE.
§
€
Ruprecht-Karls-Universitat Heidelberg.
(1) Grigg, R.; Mitchell, T. R. B.; Sutthivaiyakit, S.; Tongpenyai, N.
J. Chem. Soc., Chem. Commun. 1981, 611–612.
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CatChem 2010, 2, 1192–1207. (b) Oro, L. A.; Claver, C. Iridium Com-
plexes in Organic Synthesis: Wiley-VCH: Weinheim, 2009. Own
contributions: (c) Cao, P.; Cabrera, J.; Padilla, R.; Serra, D.; Rominger, F.;
Limbach, M. Organometallics 2012, 31, 921–929. (d) Lavy, S.; Miller,
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A. C.; Maytum, H. C.; Watson, A. J. A.; Williams, J. M. J. J. Am. Chem.
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K.; Michalik, D.; Hollmann, D.; Neubert, L.; Beller, M. ChemSusChem
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r
10.1021/ol303075h
Published on Web 01/03/2013
2013 American Chemical Society

in combination with a phosphine ligand.11 However, although
single base-free systems are known,12,13 harsh reaction
conditions (temperature >100 °C) and activation by in-
organic bases is crucial for high catalytic activity.
Fujita’s dicationic complex [Cp*Ir(NH3)3][I]2 (1) (Scheme1)
is highly active in the alkylation of aqueous NH3 and amines
in water.12c On the other hand, DFT calculations of Eisenstein
and Crabtree suggest that 3 forms from [Cp*IrCl2]2 and
K2CO3.
been used in catalysis.19 Their application for catalytic
N-alkylation of amines with alcohols has no precedent.
Cp*Àiridium complexes 2aÀe (Cp* = η5-C5Me5, cf.
Scheme 2) were synthesized in CH3CN from [Cp*IrCl2]2,
the corresponding amino acid, and K2CO3 in good yields
(70À80%).16 Remarkably, they are stable under air at
ambient temperature for months. While those complexes
with achiral κ2-N,O-glycinato ligands (2a16b and 2c) form
enantiomers, the metal as well as the N-atom of the
sarcosinato ligand in [Cp*Ir(Sar)Cl] (2b)15c are chiral.
Scheme 1. Aminoacidato Ligands in the Cp*ÀIridium-
Scheme 2. Preparation and Structure of 2aÀea
Catalyzed Alkylation of Amines with Alcohols
The κ2-carbonato ligand is supposed to stabilize the
newly generated 16-electron iridiumÀalkoxy intermediate
as an electron donor.14 Thus, we envisaged a compromise of
both approaches, i.e., aminoacidates, to be suitable ligands
leading to high catalytic activity paired with high selectivity.
Cp*Ir(III) half-sandwich complexes of type 2 bearing either
R-,15,16 β-aminoacidato,17 or even peptide-derived ligands18
have been known for decades, but they have only scarcely
a Solid-state (X-ray) molecular structure of 2a; ellipsoids drawn at the
50% probability level. Two independent molecules are present in the
unit cell. Hydrogen atoms omitted for clarity.20
Thus, 2b forms diastereomers (ratio 4:1),15a such as
[Cp*Ir(Val)Cl] (2d)16b and [Cp*Ir(Pro)Cl] (2e),15i which
bearstereogeniccentersatthemetal and in the backboneof
the chiral amino acids (S)-valine and (S)-proline (1:1 and 6:1,
respectively). Crystals of 2a suitable for X-ray analysis were
grown from CH2Cl2 layered with n-pentane (Scheme 2). The
geometry at the metal is that of a three-legged piano stool. The
two angles ClÀIrÀO and ClÀIrÀN are slightly smaller than
the ideal value of 90°, and the NÀIrÀO angle is even below
that (ca. 78°), similar to the analogous complex of valine.16a
In toluene at 140 °C the reaction of 1-octylamine and
1-hexanol catalyzed by [Cp*Ir(Gly)Cl] (2a) (2 mol %) gave
besides the desired hexyloctylamine (4) an almost equiva-
lent amount of dioctylamine (5) resulting from amine
homocoupling (Table 1, a),21 accompanied by small
amounts of the tertiary amines 6 and 7 (ratio 45:44:4:7).
At 95 °C the selectivity for the desired amine 4 increased
to >90%, and only minor amounts of byproducts 5À7
formed (Table 1, bÀd).22
(8) (a) Fujita, K.-i.; Enoki, Y.; Yamaguchi, R. Tetrahedron 2008, 64,
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2003, 44, 2687–2690. (e) Fujita, K.-i.; Yamamoto, K.; Yamaguchi, R.
Org. Lett. 2002, 4, 2691–2694.
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Incarvito, C. D.; Crabtree, R. H. Organometallics 2008, 28, 321–325.
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3790–3799. (b) Sakaguchi, S.; Yamaga, T.; Ishii, Y. J. Org. Chem. 2001,
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Taylor, J. E.; Williams, J. M. J. Org. Process Res. Dev. 2010, 14, 1046–
1049. (b) Kawahara, R.; Fujita, K.-i.; Yamaguchi, R. Adv. Synth. Catal.
2011, 353, 1161–1168. (c) Kawahara, R.; Fujita, K.-i.; Yamaguchi, R.
J. Am. Chem. Soc. 2010, 132, 15108–15111.
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At 75 °C, conversion dropped significantly (Table 1, e),
and not even an excess of 1-hexanol prevented the forma-
tion of small amounts of byproducts at 95 °C (Table 1, f).
Remarkably, 2a is quite soluble in water, and here its
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Organometallics 2000, 19, 2273–2280. (f) Carmona, D.; Lahoz, F. J.;
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Organometallics 1995, 14, 3669–3682. (h) Grotjahn, D. B.; Groy, T. L.
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(20) Selected bond lengths (A) and angles (deg): IrÀCl 2.4177(6)/
2.4143(7), IrÀO 2.0992(18)/2.0998(18), IrÀN 2.120(2)/2.129(2), ClÀIrÀO
86.96(5)/85.25(6), ClÀIrÀN 83.95(6)/85.02(6), OÀIrÀN 78.48(7)/78.39(8).
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J. M. J. Angew. Chem., Int. Ed. 2009, 48, 7375–7378.
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benzyl alcohol (2 mol % 2a, 140 °C, 24 h) yielded mostly tertiary amines
(NH4BF4: 49% conv, 77% Bn3N; NH4OAc: 81% conv, 100% Bn3N;
urea: 69% conv, 26% Bn2NH, 40% Bn3N).
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Org. Lett., Vol. 15, No. 2, 2013
267

Table 1. Optimization of Reaction Conditions
selectivityb (%)
entry catalyst temp (°C) conva,b (%) time (h)
4
5
6
7
a
b
c
2a
2a
2a
2a
2a
140
120
110
95
100
100
100
100
54
12
17
20
24
24
24
24
24
24
45 44
83 12
82 12
4
3
2
1
0
2
1
0
0
7
2
4
2
0
1
1
0
0
d
e
94
100
95
3
0
2
2
0
0
75
fc 2a
gd 2a
95
100
100
29
95
96
h
i
[Cp*IrCl2]2
glycine
95
100
0
95
0
a 1-Octylamine, 1-hexanol (each 1.0 mmol), 2a (2 mol %), toluene
(0.3 mL). b Determined by GC. Conversion of 1-octylamine. c 1-Hexanol
(2.0 mmol). d Solvent water (0.1 mL).
Figure 1. Ligand influence on catalyst activity of 2aÀe. Condi-
tions: 1-octylamine, 1-hexanol (each 1.0 mmol), 2aÀe (2.0 mol %),
toluene (0.3 mL), 95 °C. Conversion of alcohol monitored by
NMR (internal standard biphenyl).
activity and selectivity were as high as in an organic solvent
(Table 1, g). Thus, to the best of our knowledge, 2a is the
first Cp*ÀIr(III) complex that catalyzes this reaction with
high activity in organic as well as aqueous media without
additives and at temperatures below 100 °C. In compar-
ison, Fujita’s and Yamaguchi’s state-of-the-art catalyst
[Cp*IrCl2]2 was much less active under these conditions
and glycine itself did not give any conversion (Table 1, h, i).
Under optimized conditions, 2bÀe were highly selective
(>90%) toward the secondary amine (Figure 1) and
within this group of catalysts [Cp*Ir(Pro)Cl] (2e) showed
especially high activity. R-Substituents at the aminoacidato
ligand diminished the catalyst’s reactivity, cf. [Cp*Ir(Val)Cl]
(2d) vs 2a. On the other hand, N-alkylation activated the
complex to a certain degree, and so 2b is more active than 2a.
The substrate scope of [Cp*Ir(Pro)Cl] (2e) is quite
broad: N-alkylanilines 8aÀf formed in excellent isolated
yields (83À99%, cf. Table 2) as did the secondary benzy-
lamines 8g and 8h and the aliphatic amines 8i,j. Bulky
aminesturnedout tobemorechallenging(R = cyclohexyl,
t-Bu), and even at 150 °C and prolonged reaction time in
toluene (72 h) the secondary amines 8k and 8l did only
form in poor yield (23 and <10%).
Compound 2e was generally applicable and gave the
secondary amines 8mÀq in high isolated yields (72À94%).
Similarly, a wide variety of electron-rich (R1 = 4-OMe/
MeC6H4À) as well as electron-poor anilines (R1 = 4-F/Cl/
CO2MeC6H4À) with benzyl alcohols led to secondary
benzylamines 8rÀz in high to excellent isolated yields
(79À100%), both in toluene and water (Table 2). Notably,
N-benzyl-4-fluoroaniline (8v), a motif found in many
biologically active compounds, formed in almost quanti-
tative yield from benzyl alcohol and 4-fluoroaniline.7
Substituents in the 4-position of the benzyl alcohols were
of minor influence (isolated yields 8xÀz >90%). The
yields obtained in water were again comparable or even
slightly better than those in toluene.
Remarkably, 2e also catalyzes the 2-fold amination of diols
and with benzylamine in very good yields (89À94%) in a one-
pot reaction to form the heterocycles N-benzylpyrrolidine
(9a), N-benzylpiperidine (9b), and N-benzylazepane (9c),
even in water (Table 3).
For all those substrates, overalkylation to the tertiary
amines turned out to be favored at elevated temperature and
prolonged reaction time (cf. Table 1): within 36 h at 130 °C,
the tertiary amines 10aÀe formed cleanly from a series of sec-
ondary amines and 1-hexanol (yields 84À90%, cf. Table 4).
Wefinallywereabletorealize the one-pot synthesisof an
unsymmetrical tertiary amine by subsequent alkylation of
a primary amine by two different alcohols (Scheme 3). Thus,
benzylamine was first alkylated with 1-butanol at 100 °C for
24 h in the presence of 2e. Subsequently, 1-hexanol was
added and the temperature was increased to 130 °C for
further 24 h to finally isolate 11 in 77% yield over two steps.
The course of the reactions on a molecular level might
follow the generally accepted hydrogen-borrowing
mechanism.7a,8a,12c,14 The formation of N-benzylaniline
in 81% yield within 24 h from aniline, benzaldehyde, the
hydrogen donor iPrOH and 2e is in accord with this
pathway (Scheme 4a), as was the futile alkylation of aniline
with tBuOH that bears no β-H.
Surprisingly, the reduction of N-benzylideneaniline with
i-PrOH and 2e gave N-benzylaniline in virtually quantita-
tive yield (Scheme 4b), although we would have expected
considerable product inhibition as reported for other
Cp*Ir complexes.7a,8a,12c,14 The ease of this transformation
(4 h, 85 °C) suggests this is not necessarily the rate-
determining step in the catalytic cycle and does not occur
in the coordination sphere of iridium. Alternatively, the
simultaneous proton transfer from the aminoacidato li-
gand and a hydrido-iridium complex to the imine through
268
Org. Lett., Vol. 15, No. 2, 2013

Table 2. N-Alkylation of Various Amines with Alcohols by
[Cp*Ir(Pro)Cl] (2e) in Toluene or Watera
Table 4. Preparation of Tertiary Amines 10aÀea
entry
R1
R2
yield of 10aÀeb (%)
entry
R1
R2
yield of 8aÀzb (%)
a
b
c
piperidine
morpholine
Bn
84
87
85
90
88
a
b
c
Ph
n-hexyl
n-hexyl
n-hexyl
n-hexyl
n-hexyl
n-hexyl
n-hexyl
n-hexyl
n-hexyl
n-hexyl
n-hexyl
n-hexyl
n-pentyl
Bn
98c
99c
85c
86c
98c
83c
93c
96c
93c
92c
23c
<10c,f
90c
94c
89c
89c
72c
96c
100c
95c
81c
99c
82c
93c
90c
96c
97d
d
4-OMeC6H4À
4-ClC6H4À
4-CO2MeC6H4À
4-FC6H4À
2,4-Me2C6H4À
Bn
Bn
d
d
e
n-hexyl
n-hexyl
Ph
d
e
f
88d
d
Me
d
a Amine, alcohol (each 1.0 mmol), 2e (2.0 mol %) in toluene (0.3 mL).
g
h
i
92d
d
b Isolated yield.
4-OMeBn
n-octyl
96d
d
j
n-pentyl
cyclohexyl
tBu
ke
le
m
n
o
p
q
r
27d
<10d,f
Scheme 3. Subsequent Alkylation of Primary Amine
d
n-octyl
d
d
n-octyl
n-octyl
phenethyl
cyclohexyl
(CH2)2OMe
Bn
n-octyl
84d
79d
n-octyl
Ph
95d
d
s
4-OMeC6H4À
4-ClC6H4À
4-CO2MeC6H4À
4-FC6H4À
2,4-Me2C6H4À
Ph
Bn
d
t
Bn
u
v
w
x
y
z
Bn
86d
d
Bn
Scheme 4. Preliminary Mechanistic Information
Bn
79d
d
4-OMeBn
4-ClBn
4-CO2MeBn
d
Ph
Ph
94d
a Amine, alcohol (each 1.0 mmol), 2e (2.0 mol %). b Isolated yield.
c In toluene (0.3 mL). d In water (0.1 mL). e 72 h, 150 °C. f GC yield. Bn:
benzyl, Ph: phenyl.
In summary, Cp*Àiridium(III) half-sandwich com-
plexes with aminoacidato ligands are highly active and
selective catalysts for the alkylation of amines with alco-
hols. In contrast to state-of-the-art catalysts, they do not
require basic additives or harsh reaction conditions for
high activity. They work both in an organic solvent and in
water. This opens the door for functionalization of both
highly polar and unpolar substrates.
Table 3. Preparation of N-Heterocycles 9aÀca
entry
n
yield of 9aÀcb (%)
d
a
b
c
1
2
3
94c
89c
91c
d
92d
Acknowledgment. A.W., S.W., P.H., and M.L. work at
CaRLa of Heidelberg University, which is cofinanced by
a Amine, diol (each 1.0 mmol), 2e (2.0 mol %). b Isolated yield. c In
€
Heidelberg University, the state of Baden-Wurttemberg,
toluene (0.3 mL). d In water (0.1 mL).
and BASF SE. Support from these institutions is gratefully
acknowledged.
a six-membered cyclic intermediate is a viable pathway, as
proposed by Carmona et al.23
Supporting Information Available. Experimental de-
tails and spectral characterization. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(23) (a) Carmona, D.; Lamata, M. P.; Oro, L. A. Eur. J. Inorg. Chem.
2002, 2239–2251. (b) Carmona, D.; Viguri, F.; Lamata, M. P.; Ferrer, J.;
Bardaji, E.; Lahoz, F. J.; Garcia-Orduna, P.; Oro, L. A. Dalton Trans.
2012, 41, 10298–10308.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 2, 2013
269