A Highly Active PN3 Manganese Pincer Complex Performing N-Alkylation of Amines under Mild Conditions

Article abstract of DOI:10.1021/acs.orglett.9b00832

A highly active Mn(I) catalyst based on a nonsymmetric PN³-ligand scaffold for the N-alkylation of amines with alcohols utilizing the borrowing hydrogen methodology is reported. A broad range of anilines and the more challenging aliphatic amines were alkylated with primary and secondary alcohols. Moreover, the combination of low catalyst loadings and mild reaction conditions provides high efficiency for this atom-economic transformation.

Full text of DOI:10.1021/acs.orglett.9b00832

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
3
A Highly Active PN Manganese Pincer Complex Performing
N‑Alkylation of Amines under Mild Conditions
†
‡
,†
Leonard Homberg, Alexander Roller, and Kai C. Hultzsch*
†
University of Vienna, Faculty of Chemistry, Institute of Chemical Catalysis, Wah
̈
ringer Straße 38, 1090 Vienna, Austria
‡
University of Vienna, Faculty of Chemistry, X-ray Structure Analysis Center, Wah
̈
ringer Straße 42, 1090 Vienna, Austria
*
S Supporting Information
ABSTRACT: A highly active Mn(I) catalyst based on a
3
nonsymmetric PN -ligand scaffold for the N-alkylation of
amines with alcohols utilizing the borrowing hydrogen
methodology is reported. A broad range of anilines and the
more challenging aliphatic amines were alkylated with primary
and secondary alcohols. Moreover, the combination of low
catalyst loadings and mild reaction conditions provides high
efficiency for this atom-economic transformation.
itrogen-containing compounds are of significant im-
portance in many fields of chemistry. Applications range
Since 2016, various Mn(I) pincer complexes that utilize
metal−ligand cooperation (MLC) in borrowing hydrogen and
dehydrogenative condensation processes have been reported in
N
from multiton-scale agrochemicals to fine chemicals and
11
12
13
1
pioneering contributions from Milstein, Beller, Kempe,
pharmaceuticals. In order to meet the insatiable demand,
6d,e,14
15
16
17
Kirchner,
Sortais, Rueping, and others. Interest-
atom-efficient processes utilizing benign starting materials are
2
ingly, secondary alcohols as substrates were only used in the
being sought. Over the past four decades, a number of
11g,13a,14a,16b,17d
dehydrogenative synthesis of heterocycles.
The
homogeneous catalysts for the N-alkylation using alcohols have
3
direct alkylation of amines with secondary alcohols is more
been developed, with the majority of these catalyst systems
2
4
prevailing for noble metal catalysts, Knoelker type iron
being based on precious metals, such as Ru and Ir. Recently,
6
a,c,f
18
complexes,
and enzymatic transformations, whereas it
the emphasis in catalysis research has shifted in favor of more
7b
5
remains challenging for cobalt catalysts and was not reported
for manganese-based systems (Figure 2).
abundant and cheaper base metals for catalysis, in particular,
6
7
on catalyst systems based on Fe and Co. Generally, the
application of the base metal Mn in catalysis is also highly
Most direct alkylations have been reported for anilines, while
more nucleophilic benzyl amines pose a challenge for Mn
catalysts. Dehydrogenative coupling reactions providing
8
desirable, thanks to its high availability as the third most
9
abundant transition metal after Fe and Ti in the earth’s crust.
11a
aldimines were reported in the initial work of Milstein and
However, Mn-based catalysts for hydrogen transfer and
borrowing hydrogen processes, including N-alkylation of
amines, have attracted attention only very recently (Figure
5
,10
1
).
6f,7b
Figure 2. Secondary alcohols as substrates for direct N-alkylations.
Received: March 6, 2019
Figure 1. Recently developed manganese systems for N-benzylation
12a,13d
of anilines.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00832
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
were further investigated by the groups of Kirchner and
Letter
6d
temperature to the same species C upon addition of base under
identical conditions.
Single-crystal X-ray analysis of crystals of complex A
obtained from DME at −35 °C revealed that a unit cell
consisted of two independent molecules of an octahedral PN
1
3d
Kempe. In addition, the preparation of amides from benzyl
amines and aliphatic alcohols via dehydrogenative coupling
11e
was reported recently.
3
Many established Mn(I) catalyst systems for borrowing
hydrogen reactions are based on a symmetric ligand scaffold,
while nonsymmetric variants have been studied less extensively
Mn(I) pincer tricarbonyl cation (Figure 4) as well as
(Figure 3). This shortfall sparked our interest, especially in
terms of modular ligand design supporting an MLC
mechanism.
Figure 4. Molecular structure of cationic species A with thermal
2−
ellipsoids set at 50% probability. The anion [MnBr ] , a second
4
cationic Mn(I) pincer moiety, and all hydrogen atoms, except for the
hydrogen attached to N3a, are omitted for clarity. Selected bond
lengths (Å): Mn1A−P1A = 2.2622(13), Mn1A−N1A = 2.049(4),
Mn1A−N2A = 2.026(3), Mn1A−C1A = 1.799(5), Mn1A−C2A =
1.861(4), Mn1A−C3A = 1.849(4), P1A−N3A = 1.705(4), C1A−
O1A = 1.153(5), C2A−O2A = 1.134(5), C3A−O3A = 1.138(5).
Selected angles (deg): N1A−Mn1A−P1A = 159.85(11), N2A−
Mn1A−P1A = 81.58(10), N2A−Mn1A−N1A = 78.27(14), C1A−
Mn1A−N2A = 177.04(19), C1A−Mn1A−P1A = 96.20(15), C3A−
Mn1A−C2A = 166.98(18), C2A−Mn1A−P1A = 96.33(13), C3A−
Mn1A−P1A = 94.12(15). See the Supporting Information (SI) for
crystallography details.
Figure 3. Selected examples of pincer ligand sets for Mn(I)-catalyzed
borrowing hydrogen and dehydrogenative condensation pro-
11−16
cesses.
The group of Ke conducted DFT calculations for Ru-
catalyzed alcohol dehydrogenation utilizing MLC with differ-
19
ent tridentate ligands. Thus, we identified the bipyridine-
6
iPr
20
based ligand bpy- NH- P (Figure 3) as a promising
candidate for a Mn(I)-based borrowing hydrogen catalyst.
3
6
iPr
Complexation of the PN -pincer ligand bpy- NH- P with
31
[MnBr4]2− as an unexpected anion, which supports the
observation of partial Mn degradation during the complex-
ation. In a separate experiment, crystals of a Mn(II) pincer
complex were obtained at room temperature, but this species
Mn(CO) Br was monitored by P NMR spectroscopy in
5
various solvents, including toluene, benzene, THF, and DME.
The progress of the reaction was accompanied by formation of
a dark orange solution. In toluene, partial complex degradation
became apparent within 24 h in the form of a dark brown
precipitate, possibly due to the poor solubility of the formed
21
was found to be catalytically inactive. This led to the
assumption that Mn(I) is the active species for catalysis and
that during the complexation a partial disproportionation of
Mn(I) can occur. Due to the degradation process in solution,
we performed all reactions with freshly prepared stock
solutions with an in situ prepared precatalyst. Thus, all catalyst
loadings were determined by the employed amount of
intermediates. Complexation in THF-d at 25 °C produced a
8
single species A within 2 h (Scheme 1) observed at 98 ppm in
Scheme 1. Complexation Reaction of Mn(CO) Br with
5
6
iPr
bpy- NH- P
Mn(CO) Br, not taking potential degradation into account.
5
As a starting point, we investigated the N-alkylation of
aniline with benzyl alcohol to form N-benzylaniline (1a) as a
benchmark reaction (Table 1), with the goal of implementing
mild conditions with low catalyst and base additive loadings.
Initially, 3 mol % of catalyst and stoichiometric amounts of
potassium tert-butoxide as a base were used in toluene at 60
°
C, providing 84% conversion in 24 h to a mixture of the
the 31P NMR spectrum.21 This species converted within 24 h
to two, yet unidentified, new species B and B′ observed at 157
and 149 ppm in a 1:1 ratio. Upon addition of either KH or
KOtBu, species A formed a new species C observed at 140
ppm within 5 min at room temperature, which presumably is a
dearomatized complex. Furthermore, a mixture containing
species B and B′ also converged within 5 min at room
desired amine 1a and the imine intermediate 1b in a 98:2 ratio
(Table 1, entry 1). Lowering the catalyst loading to 1 mol % in
a more concentrated reaction mixture improved the conversion
and amine selectivity even as the reaction temperature was
lowered to 50 °C (Table 1, entry 3). As the solvent polarity
was increased, we found slightly higher activity in ethers like
DME, 1,4-dioxane, and THF compared to the commonly used
19
B
DOI: 10.1021/acs.orglett.9b00832
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of Reaction Conditions in the N-
Alkylation of Aniline with Benzyl Alcohol
Scheme 2. Screening of Various Amines in the N-Alkylation
with Benzyl Alcohol
a
a
b
b
c
cat.
base
solvent
(mL)
temp
(°C)
conv
ratioc
no. (mol %)
(equiv)
(%)
1a/1b
1
2
3
4
5
6
7
8
9
1
1
1
1
1
3
1
1
1
1
1
1
0.5
0.25
A (1.0)
A (1.0)
A (1.0)
A (1.0)
A (0.5)
B (0.5)
B (0.4)
B (0.5)
B (0.5)
B (0.5)
B(0.5)
B(0.5)
f
T (1.0)
T (1.0)
T (0.1)
D (0.1)
D (0.1)
D (0.1)
D (0.1)
D (0.1)
D (0.1)
D (0.1)
D (0.1)
D (0.1)
D (0.1)
D (0.1)
60
60
50
50
50
50
50
50
50
50
60
60
80
80
84
78
93
99
79
99
81
80
70
55
3
98:2
99:1
99:1
only 1a
99:1
only 1a
98:2
>99:1
>99:1
99:1
0
1
2
3
4
0.1
d
1
90:10
e
1
0
0
4
1
g
B (0.5)
only 1a
a
General conditions: 1 mmol of aniline, 1 mmol of benzyl alcohol, 1:1
b
ratio ligand to metal precursor, Ar. A ≡ KOtBu, B ≡ KH, T ≡
c
toluene, D ≡ DME. Conversion to 1a and 1b; aniline consumption
d
e
determined by GC−MS. No ligand added. Without metal
a
f
g
General conditions: 1.1 mmol of amine, 1 mmol of benzyl alcohol,
precursor. No base added. Without catalyst.
0
.1 mL of DME, 24 h, 60 °C, Ar. Yields determined by GC−FID with
b c
p-xylene as standard. 36 h. 1% N-(4-ethylphenyl)-1-phenyl-
methanimine, 6% N-benzyl-4-ethylaniline. 100 °C. Partially race-
mized ((R)-2l 84% ee (S)-2l 80% ee).
d
e
2
1
toluene. A screening of different bases to investigate lower
additive loading provided potassium hydride as being more
21
efficient in substoichiometric ratios, though comparatively
2
4
low base loadings (less than 30 mol %) rendered the system
achieved. The sterically more demanding 1-phenylethyl-
22
25
significantly less active. The commonly used base KOtBu
also provided good activity, but overall KH was more efficient
in terms of operating at lower base loadings, lower temper-
ature, and working under almost neat conditions. When the
catalyst loading was lowered to 0.1 mol %, a turnover number
of 550 was achieved with trace amounts of N-phenylbenzimine
amine provided average conversions.
We then began to investigate different benzyl alcohols in the
N-alkylation of aniline (Scheme 3). We expected a stronger
influence of the substituents on the rate of the dehydrogen-
ation step in the borrowing hydrogen cycle. Redox-innocent
23
substituents in the meta and para position of the benzyl
alcohol were readily tolerated and provided good to excellent
yields (3a, 3c, 3f). A significant effect was induced by fluorine
substituents in the ortho and para positions, providing only low
conversion under standard conditions. However, when the
reaction was performed at 80 °C for 48 h, good yields were
obtained (3e, 3g). Interestingly, 2-chlorobenzyl alcohol
provided good yields merely by extending the reaction time
(3d). Methyl-substituted benzyl alcohols required prolonged
reaction times (3h−j), suggesting that the +I methyl
substituents reduce activity compared to benzyl alcohol.
Nonactivated linear alcohols showed decent activity as
alkylating substrates, although methanol remained a challeng-
ing substrate under the standard conditions (3l−q). 1-(2-
Hydroxyethyl)piperidine provided only a low yield at standard
conditions, but with elevated temperature slightly increased
yields were obtained (3k).
(1b) as the only side product (Table 1, entry 10). In the
absence of either the metal precursor, the ligand, or the base
additive, no or very low conversion was observed (Table 1,
entries 11−14). A screening of various other metal precursors
showed superior activity of Mn(I) in the N-alkylation
2
1
reaction. Thus, further experiments were conducted with
0
6
.5 mol % catalyst loading and 50 mol % of added base KH at
0 °C in DME as solvent.
Different amines were employed in the first part of a
substrate screening (Scheme 2), including various substituted
anilines as well as more nucleophilic aliphatic amines.
23
Introduction of redox-innocent substituents (2a−i) was
found to have only a slight effect on the reactivity. Halogenated
anilines and toluidines are highly active for N-alkylation with
only slight influences from steric hindrance. It was found that
hydrogenation of a vinyl group was less favored than the
reduction of the imine intermediate, and N-benzyl-4-ethylani-
line was only observed as a minor byproduct of 2j. To the best
of our knowledge, benzylamine, a potential ammonia
surrogate, has not been successfully employed as substrate
In order to implement a broad substrate scope, we also
investigated secondary alcohols which have only been reported
as substrates in Mn(I)-catalyzed dehydrogenative synthesis of
11g,13a,14a,16b,17d
nitrogen heterocycles,
but to the best of our
6d,11a,12a,13d,17i
for amine synthesis using Mn(I) catalysts.
When
knowledge, not in the N-alkylation of amines. Only very low
activity was observed under standard conditions, but at slightly
elevated temperatures N-isopropylaniline was obtained from
used under standard conditions only little activity was
observed, but at elevated temperatures excellent yields were
C
DOI: 10.1021/acs.orglett.9b00832
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Screening of Various Alcohols in the N-
Alkylation of Aniline
2k and 2l, a fair conversion to the desired secondary amine was
observed with a good 9:1 amine to imine ratio (Scheme 5).
a
Scheme 5. Exemplary Preparation of Cinacalcet
In summary, we have established a new Mn(I)-based catalyst
3
system utilizing a bipyridine-based PN -pincer ligand
6
iPr
bpy- NH- P with high activity toward N-alkylation of
different amines with alcohols. We were able to reduce the
additive loading to a half equivalent while using low catalyst
loadings unprecedented in Mn(I) borrowing hydrogen
catalysis. Mild reaction conditions could be implemented for
the alkylation of anilines, which allows reactions to be
performed with temperature-sensitive compounds at 60 °C
instead of 80 °C. The overall milder approach was also
implemented successfully when using different benzyl alcohols
as alkylating agents with the only exemption of fluorinated
substrates. More nucleophilic aliphatic amines and challenging
secondary alcohols were also successfully employed as
substrates. The catalytic system not only works under mild
conditions but, moreover, tolerates higher temperatures when
necessary for challenging substrates. Introducing benzylamine
as a high-yielding substrate provides amination with an
ammonia surrogate after subsequent hydrogenolysis.
a
General conditions: 1.1 mmol of aniline, 1 mmol of alcohol, 0.1 mL
of DME, 24 h, 60 °C, Ar. Yields determined by GC−FID with p-
xylene as standard. 36 h. 48 h. 80 °C. 100 °C.
b
c
d
e
aniline and 2-propanol in good yield (3r). Nonsymmetrical
secondary alcohols, such as 2-butanol and 1-phenylethanol,
were also successfully employed as alkylating agents (3s, 3t),
though in the latter case, the phenyl group in α-position of the
alcohol seems to obstruct the reaction by its steric hindrance
and more forcing conditions were required to obtain fair yields.
Cyclohexanol was also successfully converted at elevated
temperatures, providing an average yield (3u).
Aside from screening different substrates, the mild
conditions were successfully applied in a gram scale N-
benzylation of aniline with benzyl alcohol. Since the bench-
mark reaction showed already high productivity at lower
catalyst loading (Table 1, entry 9) and slightly lower additive
loading (Table 1, entry 7), we were able to obtain 1a in
excellent isolated yield (Scheme 4).
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00832.
Experimental details, optimization of catalytic reaction
6
iPr
conditions, NMR spectroscopic data of bpy- NH- P,
complex A and N-alkylated anlines, and crystallographic
data (PDF)
Accession Codes
CCDC 1900349−1900350 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Since the more challenging benzylamine substrates (Scheme
, 2k, 2l) were successfully employed, the synthesis of
2
cinacalcet (4) (Mimpara, Sensipar) was chosen as an
exemplary application. With the nonoptimized conditions of
Scheme 4. Gram-Scale N-Alkylation of Aniline with Benzyl
Alcohol
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: kai.hultzsch@univie.ac.at.
ORCID
Kai C. Hultzsch: 0000-0002-5298-035X
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.9b00832
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
10) (a) Maji, B.; Barman, M. Recent Developments of Manganese
ACKNOWLEDGMENTS
■
Complexes for Catalytic Hydrogenation and Dehydrogenation
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K.; Beller, M. Homogeneous Catalysis by Manganese-Based Pincer
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F.; Kempe, R. Manganese Complexes for (De)Hydrogenation
Catalysis: A Comparison to Cobalt and Iron Catalysts. Angew.
Chem., Int. Ed. 2018, 57, 46−60. (d) Filonenko, G. A.; van Putten, R.;
Hensen, E. J. M.; Pidko, E. A. Catalytic (de)hydrogenation promoted
by non-precious metals - Co, Fe and Mn: recent advances in an
emerging field. Chem. Soc. Rev. 2018, 47, 1459−1483. (e) Gorgas, N.;
Kirchner, K. Isoelectronic Manganese and Iron Hydrogenation/
Dehydrogenation Catalysts: Similarities and Divergences. Acc. Chem.
Res. 2018, 51, 1558−1569. (f) Mukherjee, A.; Milstein, D.
Homogeneous Catalysis by Cobalt and Manganese Pincer Complexes.
ACS Catal. 2018, 8, 11435−11469.
We express our gratitude to Dr. Agnieszka J. Nawara-Hultzsch
and Ms. Natalie Hofmann for assistance in product isolation
and characterization.
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ongoing research.
(24) Attempts to utilize secondary amines, such as N-methylaniline,
morpholine, or piperidine, have been unsuccessful so far.
(25) Partial racemization of the stereocenter of (R)- and (S)-
phenylethylamine was observed during the reaction, indicating that
slow dehydrogenation/hydrogenation of the amine does occur under
these conditions.
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