Chromium-Catalyzed Alkylation of Amines by Alcohols

Article abstract of DOI:10.1002/anie.202001704

The alkylation of amines by alcohols is a broadly applicable, sustainable, and selective method for the synthesis of alkyl amines, which are important bulk and fine chemicals, pharmaceuticals, and agrochemicals. We show that Cr complexes can catalyze this C?N bond formation reaction. We synthesized and isolated 35 examples of alkylated amines, including 13 previously undisclosed products, and the use of amino alcohols as alkylating agents was demonstrated. The catalyst tolerates numerous functional groups, including hydrogenation-sensitive examples. Compared to many other alcohol-based amine alkylation methods, where a stoichiometric amount of base is required, our Cr-based catalyst system gives yields higher than 90 % for various alkyl amines with a catalytic amount of base. Our study indicates that Cr complexes can catalyze borrowing hydrogen or hydrogen autotransfer reactions and could thus be an alternative to Fe, Co, and Mn, or noble metals in (de)hydrogenation catalysis.

Full text of DOI:10.1002/anie.202001704

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Accepted Article
Title: Chromium Catalyzed Alkylation of Amines by Alcohols
Authors: Rhett Kempe, Fabian Kallmeier, Robin Fertig, and Torsten
Irrgang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202001704
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http://dx.doi.org/10.1002/ange.202001704

10.1002/anie.202001704
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Chromium Catalyzed Alkylation of Amines by Alcohols
Fabian Kallmeier, Robin Fertig, Torsten Irrgang and Rhett Kempe*
Dedicated to Marlies Schilling
[*]
F. Kallmeier, Dr. T. Irrgang, Prof. Dr. R. Kempe
Inorganic Chemistry II – Catalyst Design
University of Bayreuth
95440 Bayreuth (Germany)
E-mail: kempe@uni-bayreuth.de
Supporting information for this article is given via a link at the end of the document.
Abstract: The alkylation of amines by alcohols is a broadly
applicable, sustainable, and selective method for the synthesis of
alkyl amines, which are important bulk and fine chemicals,
pharmaceuticals, or agrochemicals. Here we report that Cr
complexes can catalyze this C-N bond formation reaction. We
synthesized and isolated 35 examples of alkylated amines. Thirteen
previously undisclosed products could be obtained, and the use of
amino alcohols as alkylating agents could be demonstrated. The
catalyst tolerates numerous functional groups, among them
hydrogenation sensitive examples. In comparison to many other
alcohol-based amine alkylation protocols where a stoichiometric
amount of base is required, our Cr based catalyst system permits
product isolation with yields higher than 90 % for various alkyl
amines with a catalytic amount of base only. Our study indicates that
Cr complexes can catalyze borrowing hydrogen or hydrogen auto-
transfer reactions and, thus, could be an alternative to Fe, Co and
Mn or noble metals in (de)hydrogenation catalysis.
The alkylation of amines by alcohols can proceed via the
borrowing hydrogen or hydrogen auto-transfer (BH/HA)
mechanism (Figure 1, top). The alcohol is dehydrogenated by
transferring a proton and a hydride to the catalyst with the
hydride binding to the metal and the proton becoming accepted
by the ligand or support. The so formed carbonyl compound can
undergo a Schiff base reaction1 with an amine or ammonia and
the resulting imine becomes reduced by transferring the hydride
and the proton to it and recycling the catalyst. This amine
alkylation is a green or sustainable reaction since alcohols are
employed2 and it permits the selective alkylation of amines.3 The
reaction was discovered by Winans and Adkins4 in 1932 and the
Figure 1. Top: Alkylation of amines by alcohols via borrowing hydrogen or
hydrogen auto-transfer ([M] {transition} metal catalyst). Middle: Key
development of homogeneous 3d metal catalyst for the alkylation of amines by
alcohols. Bottom: Chromium based precatalyst used in this report.
5
6
groups of Grigg
and Watanabe
introduced the first
Herein we report that chromium complexes can catalyze the
alkylation of amines by alcohols. We synthesized and isolated
35 examples of alkyl amines in yields up to 94%. Thirteen
previously undisclosed products could be obtained and the
selective C-N bond formation employing amino alcohols as the
alkylating agent could be demonstrated. Our catalyst tolerates
numerous functional groups, among them hydrogenation
sensitive examples. We only use a catalytic amount of base and
a mechanism following the BH/HA concept is very likely.
homogeneous catalysts. The development of catalysts of
abundantly available metals to mediate chemical transformation
typically associated with rare noble metals is a similarly
important green or sustainable approach and may permit the
observation of yet unknown selectivity patterns. We recently
summarized the progress made in developing 3d metal catalysts
for C−N and C−C bond formation reactions with alcohols using
the BH/HA concept7 and discovered that chromium catalysts
have not been reported to the best of our knowledge.
Homogeneous catalysts of 3d metals for the alkylation of amines
by alcohols via BH/HA have been discovered by the groups of
Feringa and Barta (Fe), 8 our group (Co), 9 and Beller and
coworkers (Mn).10 Interestingly, these and related complexes
have also been used to catalyze a variety of dehydrogenation
reactions.11
Five Cr(III) precatalysts Cr-Ia-e and the corresponding Cr(II)
precatalysts (Cr-IIa-e) were synthesized first (Figure 2, for the
full synthetic procedure please see supporting information [SI]).
Cr-If and Cr-IIf were synthesized according to literature
12
procedures by Kirchner and coworkers.
The molecular
structure of Cr-Id (which turned out to be the precatalyst of the
1
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Table 1. Catalyst screening for the N-alkylation of aniline[a]
most active catalyst system, vide infra) was confirmed by X-ray
crystal structure analysis (XRD). The magnetic susceptibility µeff
was determined by SQUID measurements to be 3.9 which is
fully consistent with a Cr(III) center.
Entry
1
Precatalyst
Cr-Ia
Yield[b] [%]
21
24
29
2
Cr-Ib
3
Cr-Ic
N1
Cl3
Cr1
P1
P2
Cl1
4
Cr-Id
52 (97[c]
)
Cl2
5
Cr-Ie
18
15
23
35
22
58
31
1
6
Cr-If
Figure 2. Synthesis of the complexes used in this study and molecular
structure of Cr-Id. Thermal ellipsoids at 50 % probability, solvent molecules
and C-H atoms omitted for clarity. Selected bond lengths [Å] and angles [°]:
Cr1-N1 2.086(3), Cr1-P1 2.4492(11), Cr1-P2 2.4520(11), Cr1-Cl1 2.3085(11),
Cr1-Cl2 2.2877(11), Cr1-Cl3 2.3055(11), P1-Cr1-P2 158.56(4), N1-Cr1-Cl2
179.29(9), Cl3-Cr1-Cl1 173.64(4).
7
Cr-IIa
Cr-IIb
Cr-IIc
Cr-IId
Cr-IIe
Cr-IIf
8
9
10
11
12
The reaction of aniline with benzyl alcohol was chosen as a
model reaction and the different complexes tested for their
activity at a catalyst loading of 5 mol% (Table 1). Electron
donating substituents at the triazine core do not significantly
influence the outcome of the reaction (Table 1, entries 1-3 and
7-9), however, the electron withdrawing substituent in Cr-Id and
Cr-IId leads to a two-fold increase in product yield (Table 1,
entries 4 and 10). Notably, switching from a triazine to a pyridine
backbone decreases product formation; the effect being more
pronounced in Cr(II) than Cr(III) complexes (Table 1, entries 6
and 12). Despite giving the best yield so far (Table 1, entry 10),
the result for Cr-IId could not be further increased, which is in
contrast to the Cr(III) analogue Cr-Id (Table 1, entry 4). If the
reaction was run with a slight excess of benzyl alcohol (1.2
equivalents) in 1,4-dioxane under ambient pressure, the product
3a was almost quantitatively obtained using only 3 mol% of Cr-
Id (see SI for screening reactions).
[a] Reaction conditions: 5 mol% precatalyst (50 µmol), 0.5 equiv KOtBu (0.5
mmol, 56 mg), 0.5 mL xylenes (mixture of isomers), 1 equiv benzyl alcohol (1
mmol, 104 µL) and 1 equiv aniline (1 mmol, 91 µL), 150 °C oil bath, 18 h; [b]:
Yield determined by GC-analysis using n-dodecane as internal standard; [c]:
3 mol% Cr-Id (30 µmol), 0.5 equiv. KOtBu (0.5 mmol, 56 mg), 0.5 mL 1,4-
dioxane, 1.2 equiv benzyl alcohol (1.2 mmol, 125 µL) and 1 equiv aniline (1
mmol, 91 µL), 150 °C oil bath, 18 h, bubble counter with backflow protection.
Having established optimal reaction conditions, the addressable
substrate scope was evaluated using different primary alcohols
(Table 2). The screening substrate 3a was isolated in 85 % yield.
Substrates containing methyl (3b), methoxide (3c) and
thiomethyl (3e) groups were synthesized in slightly better yields
of 88 to 93 %. The use of (4-benzyloxy)benzyl alcohol furnished
product 3d in 90 % yield without any signs of cleavage of the
benzyloxy group. Next, a series of electron rich, N,N-dialkyl-
substituted para-aminobenzyl alcohols were tested and the
resulting products 3f and 3g were isolated in 89 and 84 % yield,
respectively. The previously undisclosed product 3h, containing
a piperazine moiety could be isolated almost quantitatively
(94 %). Heteroaromatic alcohols furnished the pyridine
derivative 3i and thiophene derivative 3j in 90 and 81 % yield,
respectively. Furthermore, halide-substituted benzyl alcohols
reacted smoothly giving the products 3k-o in 62 to 92 % yield.
Notably, the strong electron withdrawing nitrile group was
tolerated and the corresponding product 3p was obtained in
52 % yield. Employing 2-phenylethanol instead of a benzylic
alcohol, resulted in a decrease in yield to 61 % (3q).
2
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Table 2. Substrate scope regarding primary alcohols[a]
Table 3. Substrate scope regarding the amine[a]
.
[a] 3 mol% Cr-Id (30 µmol), 0.5 equiv. KOtBu (0.5 mmol, 56 mg), 0.5 mL 1,4-
dioxane, 1.2 equiv alcohol (1.2 mmol) and 1 equiv aniline (1 mmol, 91 µL),
150 °C oil bath, 18 h, bubble counter with backflow protection. Yields refer to
isolated product; [b]: new compound; [c]: 5 mmol scale.
Next, the substrate scope regarding the amine was evaluated
(Table 3). For this purpose, a series of para-substituted anilines
was tested. First, 4-methylaniline was reacted under standard
conditions and furnished 5a in 89 % yield. Next, radical-reaction
and hydrogenation-sensitive substrates were tested. To our
delight, cyclopropanes, double, and triple bonds did not undergo
undesired reactions, therefore furnishing 5b-d in very agreeable
yields of 77 to 93 %. A substrate containing an electron donating
methoxide group was converted as efficiently as substrates
containing electron withdrawing groups like halides, leading to
the isolation of 5e-h in similar yields of 84 to 92 %. The
synthesis of 5g could be easily scaled up to 10 mmol scale,
furnishing 2.20 grams (75 %) of product. Product 5i, containing
the strongly electron withdrawing nitrile group could be isolated
in 46 % yield. Lastly, a series of N-heterocyclic amines was
subjected to catalytic N-alkylation. Aminopyridine 5j and
aminoquinoline 5k were synthesized in respectable yields of 88
and 78 %, respectively. The five-membered heteroaromatic
aminopyrazole reacted smoothly, affording 5m in 79 % yield.
Lastly, 4,6-dicyclopropylpyrimidin-2-amine, which can easily be
prepared from alcohols and guanidine by a one-pot procedure,13
was reacted with para-methoxybenzyl alcohol and furnished
product 5n in a satisfying 85 % yield.
[a] 3 mol% Cr-Id (30 µmol), 0.5 equiv. KOtBu (0.5 mmol, 56 mg), 0.5 mL 1,4-
dioxane, 1.2 equiv 4-methoxybenzyl alcohol (1.2 mmol, 149 µL) and 1 equiv
amine (1 mmol), 150 °C oil bath, 18 h, bubble counter with backflow
protection. Yields refer to isolated product; [b]: new compound; [c]: 10 mmol
scale.
Concluding from the Hammett study (See SI), electron deficient
anilines react faster with alcohols. Therefore, we hypothesized
that a selective reaction with unprotected amino benzyl alcohol
should occur readily (Table 4). Indeed, the reaction between 4-
bromoaniline with 3-aminobenzyl alcohol furnishes 8a in 75 %
yield of isolated material. The yield is significantly affected by
using 3-bromoaniline (Table 4; 8b, 34 %), which is consistent
with our findings from the Hammett study, as the position of the
electron withdrawing group in conjugation with the amine is
pivotal. With an additional chlorine substituent in meta-position,
8c can be obtained in a similar yield to 8a. Amino alcohols
containing an additional methyl group gave similar results,
indicating that the selectivity should arise from electronic factors
rather than steric considerations.
3
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Table 4. Alkylation of anilines using 3-aminobenzyl alcohols[a]
[a]: 3 mol% Cr-Id (30 µmol), 0.5 equiv. KOtBu (0.5 mmol, 56 mg), 0.5 mL 1,4-
dioxane, 1.2 equiv aminobenzyl alcohol (1.2 mmol) and 1 equiv amine (1
mmol), 150 °C oil bath, 18 h, bubble counter with backflow protection. Yields
refer to isolated product; [b]: new compound; (EWG = electron withdrawing
group).
Finally, preliminary mechanistic experiments were conducted.
The mercury drop test shows no influence of mercury on the
yield of the model reaction (65 % without mercury, 69 % at 225
mol% Hg-loading) indicating that the active catalyst is likely to be
homogeneous in nature. This is further supported by the partial
inhibition of the reaction by the phosphine oxide OPPh3 (0.3
mol% OPPh3: 56 % of 3a). The activation of Cr-Id was then
examined by addition of KOtBu to the complex using IR
spectroscopy. The complex exhibits a broad NH resonance at
3214 cm-1 which gradually disappears upon the addition of base.
We concluded that a doubly deprotonated species could act as
the active catalyst, which is similar to our recent findings with a
Mn catalyst.14 Then, the dehydrogenation and hydrogenation
step of the proposed BH/HA cycle were examined. 18 % alcohol
were consumed in a closed flask and 27 % were consumed
when the same reaction was run using a bubble counter with
backflow protection for pressure equalization. Afterwards, the
ability of the catalyst to hydrogenate the intermediate imine was
probed. Employing 5 mol% Cr-Id and 50 mol% KOtBu, 26 %
amine product 3a was observed. To gain insight into the nature
of the rate determining step, a Hammett study was conducted. It
could be observed that electron donating groups like Me and
OMe lead to a decreased reaction rate. On the other hand,
increased reaction rates are obtained for anilines with electron
withdrawing groups like Cl, Br and styrene. This leads to the
assumption that the rate determining step could likely be the
hydride transfer to the imine, since electron withdrawing groups
at the aniline can cushion the build-up of negative charge during
hydride transfer.
Figure 3. Top: IR spectroscopy of Cr-Id after activation with 2 equivalents of
KOtBu and reaction with benzyl alcohol (normalized); Bottom: Poisoning and
hydrogenation experiments.
In summary we established evidence that Cr complexes can
mediate (de)hydrogenation catalysis. The catalytic N-alkylation
of amines by alcohols was explored since it is an important and
green or sustainable C-N bond formation reaction. The
chromium complexes we use as precatalysts are inexpensive
and easy to synthesize. Our catalyst system mediates the
alkylation of amines under conditions comparable to other
homogeneous 3d metal catalysts with the noteworthy exception
that only sub-stoichiometric quantities of base are required. In
total, 35 amines (13 of which have not been described in
literature so far) have been synthesized and isolated in yields up
to 94 %. The catalyst system tolerates functional groups such as
Aryl-I, CN and other hydrogenation sensitive groups like benzyl
ether, alkene and alkyne and converts unprotected amino benzyl
alcohols efficiently. The active catalyst is likely to be of
homogeneous nature as indicated by poisoning experiments.
The Hammett study indicates that the rate determining step is
most likely the hydride transfer to the imine. Furthermore, a
borrowing hydrogen or hydrogen autotransfer mechanism is very
likely.
Acknowledgements
4
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We thank Tobias Schwarz for X-ray analysis, Hannah Kurz for
the
SQUID
measurements
and
the
Deutsche
Forschungsgemeinschaft DFG KE 756/29-1 for financial support.
Keywords: alcohols • amine alkylation • borrowing hydrogen
chromium • hydrogen autotransfer
5
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Entry for the Table of Contents
Easily accessible Cr complex catalyse the alkylation of amines by alcohols, a sustainable or green C-N formation reaction following
the borrowing hydrogen or hydrogen autotransfer concept. The work indicates that Cr complexes can mediate (de)hydrogenation
catalysis.
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6
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