Catalytic Formal Hydroamination of Allylic Alcohols Using Manganese PNP-Pincer Complexes

Article abstract of DOI:10.1002/adsc.202100081

Several manganese-PNP pincer catalysts for the formal hydroamination of allylic alcohols are presented. The resulting γ-amino alcohols are selectively obtained in high yields applying Mn-1 in a tandem process under mild conditions. (Figure presented.).

Full text of DOI:10.1002/adsc.202100081

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DOI: 10.1002/adsc.202100081
Catalytic Formal Hydroamination of Allylic Alcohols Using
Manganese PNP-Pincer Complexes
Leandro Duarte de Almeida,a Florian Bourriquen,a Kathrin Junge,a,* and
Matthias Bellera,*
a
Leibniz-Institut für Katalyse e.V., Albert-Einstein-Str. 29a, 18059 Rostock, Germany,
Fax: +49 381-1281-5000
E-mail: kathrin.junge@catalysis.de; matthias.beller@catalysis.de
Manuscript received: January 20, 2021; Revised manuscript received: March 5, 2021;
Version of record online: March 17, 2021
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100081
© 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH. This is an open access article under the
terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
Abstract: Several manganese-PNP pincer catalysts
for the formal hydroamination of allylic alcohols are
presented. The resulting γ-amino alcohols are
selectively obtained in high yields applying Mn-1 in
a tandem process under mild conditions.
Keywords: hydroamination; allylic alcohol; manga-
nese; amine; pincer complex
Nitrogen containing compounds, including γ-amino
alcohols, show many interesting biological properties
and thus find numerous applications as agrochemicals
and pharmaceuticals (Scheme 1a). In general, the
formation of CÀ N bonds continues to be a relevant
topic in many organic syntheses and has numerous
implementations in the chemical industry.[1] Among the
various methodologies known in this area, direct
hydroamination reactions are particularly appealing as
they are in line with the green chemistry principles due
to the 100% atom efficiency and the good availability
of substrates.[2] In the past, a plethora of different
catalyst systems and metals have been utilized for
olefin hydroamination as outlined in several excellent
reviews.[3]
Due to the significance of CÀ N bond formations,
many research groups have focussed on the develop-
ment of new methodologies in this field, especially in
recent years using earth-abundant 3d metals.[4]
Amongst these metals, manganese has attracted in-
creasing attention.[5] Due to its broad range of
Scheme 1. Importance of γ-amino alcohols and catalyst systems
for carbon-nitrogen bond formation.
oxidation states, manganese complexes present valua-
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Table 1. Manganese-catalysed allyl alcohol hydro-amination.[a]
ble features for (redox) catalysis (Scheme 1b). Indeed,
Milstein and co-workers reported the use of a
MnÀ PNN pincer complex for the aza-Michael addition
of amines and unsaturated nitriles.[6] The same group
also realised the dehydrogenative coupling of amines
with methanol to formamides utilising a MnÀ PNP
pincer catalyst.[7] In a similar vein, our group devel-
oped the first N-alkylation of amines with primary
alcohols using MnÀ PNP catalysts.[8] In addition,
Hultzsch and co-workers reported the N-alkylation of
amines with secondary alcohols using a manganese
PN3-pincer catalyst.[9] Primary amines could also be
coupled with diols to obtain cyclic imines[10a] or
pyrroles.[10b]
Besides the recent publications of CÀ N bond
formation with manganese catalysts,[11] so far none of
these methodologies include olefin hydroamination. In
the past few years, formal hydroamination of allylic
alcohols has received a lot of attention, with most
publications making use of ruthenium catalysts (Sche-
me 1c). In this respect in 2015, Oe reported a
borrowing hydrogen approach with ruthenium catalysts
Entry Cat. [mol%]
Base [mol%] Yield 3a [%][b]
1
2
3
4
5
6
7
8
Mn-1
Mn-2
Mn-3
Mn-4
Mn-5
Mn-6
Mn-7
Mn-8
K3PO4 [40]
K3PO4 [40]
K3PO4 [40]
K3PO4 [40]
K3PO4 [40]
K3PO4 [40]
K3PO4 [40]
K3PO4 [40]
68
67
0
49
54
64
0
for
synthesising
anti-Markovnikov
γ-amino
alcohols.[12]
Recently, Wang and co-workers employed chiral
ruthenium catalysts – similar to Noyori’s catalysts –
for the asymmetric hydroamination of allylic alcohols
with piperazines.[13] Complementary to these original
publications, the Buchwald group reported a copper-
phosphine catalyst, in conjunction with silanes, to
obtain asymmetric γ-amino alcohols using hydroxyl
amines as nucleophiles.[14] Notably, the only example
using a non-noble metal catalyst for the formal hydro-
0
9[c]
10
11
12
13[d]
14[d]
Ru-MACHO BH3 K3PO4 [40]
Fe-1
Fe-2
34
40
52
71
76
64
81
87
K3PO4 [40]
K3PO4 [40]
K2CO3 [40]
K2CO3 [40]
K2CO3 [20]
K2CO3 [40]
K2CO3 [40]
Mn-1
Mn-1
Mn-1
15[d,e] Mn-1
amination of amines with allylic alcohols was devel- 16[d,f] Mn-1
oped by the Wang group. By applying an iron PNP-
[a] N-Methylaniline 1a (0.5 mmol), allyl alcohol 2a (1 mmol),
catalyst (1 mol%), NaHBEt3 (2 mol%), K3PO4 (40 mol%),
pincer complex as a catalyst, the corresponding anti-
Markovnikov γ-amino alcohols could be obtained in
high yields by a tandem reaction composed of a
°
toluene (2 mL), 18 h, 80 C.
[b] Yields are determined by internal standard.
[c] No NaHBEt3.
dehydrogenation/Michael
addition/hydrogenation
sequence.[15] Inspired by this excellent report and our
previous work on manganese pincer catalysis for
transfer hydrogenation[16] and dehydrogenation reac-
tions,[17]] we decided to evaluate these type of
manganese compounds for the formal hydroamination
of allylic alcohols (Scheme 1d).
[d] Cyclohexane (2 mL).
[e]
°
18 h, 60 C.
[f]
°
24 h, 60 C.
P moiety, a decrease of steric hindrance favoured the
In preliminary experiments, we examined the formation of product 3a, as seen for Mn-1, Mn-5 and
reaction of N-methylaniline (1a) with prop-2-en-1-ol Mn-6. The best result was obtained with catalyst Mn-1
(2a) in the presence of various manganese PNP- (Mn- containing the diethyl moiety, while a negligible
1–6) and NNN-pincer (Mn-7–8) complexes, K3PO4 as difference in catalytic activity was observed for the
base and catalytic amount of sodium borane.[18] As neutral (Mn-1) and cationic (Mn-2) complexes (En-
shown in the Table 1, manganese catalysts bearing a tries 1–2). No reaction took place with the N-methyl
NNN-pincer scaffold were inactive in the catalytic test catalyst Mn-3, which indicates the involvement of the
reaction, while with nearly all manganese PNP-pincer NH-moiety in the catalytic process via metal ligand
complexes the corresponding hydroaminated product cooperation (MLC) (Entry 3).[18a] Applying the com-
3a was formed. A lower yield of 3a was produced mercially available Ru-MACHO BH3 and iron-PNP
using Mn-4, which possess an electron-withdrawing (Fe-1 and Fe-2) catalysts in the model reaction, the
ligand (Entry 4). For electron-donating ligands on the results showed that catalysts Mn-1, Mn-2 and Mn-6
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are more suitable for the formal hydroamination than
ruthenium and iron pincer complexes under the chosen
reaction conditions.
After the catalyst screening, reactions conditions
such as solvent, base and temperature were optimised
(see ESI). Different polar aprotic solvents were tested,
while oxygen-containing solvents presented low hydro-
amination yields. The most suitable solvent for hydro-
amination of N-methylaniline was cyclohexane provid-
°
ing yields up to 87% at 60 C and 24 h (Entries 13, 15,
16). The best result in the base screening was achieved
in the presence of non-stoichiometric amounts of
simple K2CO3. (Entry 12). Here, a certain amount of
base was found to be crucial to achieve high product
yields. While with 20 mol% of K2CO3 the yield of 3a
dropped down (Entry 14), no further improvements
were achieved with base loading above 40 mol%
(Table S1). These findings agree with the results of the
Wang group demonstrating the beneficial role of base
for the dehydrogenation step of the allylic alcohol.[15]
Next, a series of different amines and N-hetero-
cycles were tested for manganese-catalysed hydro-
amination (Scheme 2). For secondary amines, an
increase of steric bulk for N-substituted anilines led to
decreased yields (products 3a–c and 3e). No hydro-
aminated product was observed for diphenylamine,
which might be related to the high steric hindrance and
decreased nucleophilicity on the nitrogen atom. Fur-
thermore, the substituent position of aromatic amines
played an important role (see products 3f–g). Formal
hydroamination of N-allyl aniline was carried out,
leading to 53% yield of 3i. Different substituents, such
as Br, F, CF3 and OMe were tolerated for allyl alcohol
hydroamination (products 3j–m), whilst the nitro
group-containing substrate was not reactive. Gratify-
ingly, an α-amino alcohol reacted well to provide the
amino diol product 3n under our standard reaction
conditions.
Furthermore, the reaction of N-methyl aniline 1a
and N-methyl toluidine 1h with allyl alcohol 2a were
realized in a 5 mmol scale giving the respective
products in 71% (3a) and 64% (3h) isolated yields
°
after 24 hours at 60 C (SI). Although in both cases
slightly reduced product yields were obtained, the
general practicability of the catalytic protocol could be
successfully demonstrated.
Scheme 2. Manganese catalysed formal hydroamination of allyl
a)
alcohol.
Amine (0.5 mmol), allyl alcohol (1 mmol), Mn-1
Aliphatic secondary amines were also successfully
converted with yields between 58–83% (products 3o–
q). As observed for aromatic amines, reactions of
aliphatic amines were also influenced by steric
hindrance. For primary anilines, hydroamination prod-
(1 mol%), NaHBEt3 (2 mol%), cyclohexane (2 mL), K2CO3
b)
°
(40 mol%), 60 C, 24 h, isolated yields.
NaHBEt3 (4 mol%).
Mn-1 (2 mol%),
ucts were obtained in significantly lower yields (3r– (2a) resulted in the formation of the double hydro-
3v). This trend can be explained by a lower electro- amination product 3w in 58% yield. Given that N-
philicity of the neutral imine intermediate which will heterocycles are very relevant constituents of pharma-
be formed by condensation with 2a according to the ceutical drugs, we carried out several reactions with
previously discussed mechanism.[15] Interestingly, reac- different heterocyclic motifs, such as pyrrolidine,
tion of an aliphatic primary amine with prop-2-en-1-ol piperidine, piperazine, morpholine, and indole. Here,
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product yields of 36–94% were achieved for γ-amino
The natural product cinnamyl alcohol successfully
alcohols with the different heterocycles. In general, underwent hydroamination, too, leading to 30% yield
six-membered heterocycles presented higher reactivity of 5c. This decrease in reactivity in case of product 5c
than five-membered heterocycles for allyl alcohol compared to 5a might be related to the bulkiness of
hydroamination. It is assumed that the lower nitrogen the conjugated phenyl ring, and by the electron
nucleophilicity in case of indole led to a decreased delocalisation of the ring. Furthermore, the symmetric
yield of 3y compared to 3x. For piperazines, no allylic diol but-2-ene-1,4-diol could be selectively
significant differences were observed for various hydroaminated to give product 5d. For the α-sub-
substituted derivatives (products 3aa–ab). In the case stituted alcohol 1-phenyl-2-propen-1-ol (2e), the alco-
of tetrahydroquinolines, the nitrogen position had a hol (5e) as well as the ketone (5e‘) containing
considerable effect on hydroamination yield (products hydroamination product were obtained in 59% and
3ac–ad).
24% isolated yields, respectively. This shows that even
Due to the high electron-withdrawing ability of the the ketone intermediates formed after the Michael
tert-butoxycarbonyl (Boc) protecting group, the mono- addition step can be hydrogenated to produce the
hydroaminated product 3af could be selectively corresponding γ-amino alcohol. Finally, we tested
obtained in 88% yield. This example offers many substrates with substituents at the carbon β-position,
possibilities for posterior functionalisation of such γ- and the respective product 5f was obtained in 65%
amino alcohols.
yield. However, the more sensitive bromide-substituted
Next, we also evaluated the scope of allylic alcohol did not react.
alcohols using 1-phenylpiperazine 4a, (Scheme 3) as
In summary, the successful application of a well-
piperazine rings are commonly encountered in many defined manganese PNP-pincer complex in the formal
leading pharmaceuticals.[19] Indeed, several allylic hydroamination of allylic alcohols with primary,
alcohols could be hydroaminated with 1-phenylpiper- secondary amines and N-heterocycles was reported.
azine 4a in yields ranging from 25–82%. Hydro- The corresponding γ-amino alcohols were obtained in
amination yield was not so affected by steric hindrance up to 94% yield in a tandem reaction combining
of a methyl group in the olefin of an allylic alcohol dehydrogenation/Michael addition/hydrogenation se-
(product 5a). However, no reaction took place using 3- quence. The properties of these non-innocent pincer
methyl-but-2-ene-1-ol, which can be attributed to the ligands allowed application of this non-noble metal
difficulty for piperazine to attack this sterically catalyst in organic synthesis with a broad substrate
hindered trisubstituted olefin. On the other hand, an scope.
allylic alcohol containing an endocyclic olefinic bond
gave the desired product 5b in 41% yield.
Experimental Section
Reactions were carried out in a heat-gun dried under vacuum
25 mL Schlenk flask equipped with a magnetic stirring bar. The
catalyst (2.2 mg, 0.005 mmol, [1 mol%] Mn-1) was added
inside a glovebox. Outside the glovebox 0.5 mL of cyclohexane
and 10 μL (1 M solution in toluene) of NaHBEt3 (0.01 mmol,
[2 mol%]) was added and the mixture was stirred for 10 min at
room temperature. After this, N-methylaniline (1a) (54 mg,
0.5 mmol), prop-2-en-1-ol (2a) (59 mg, 1 mmol), K2CO3
(0.2 mmol, [40 mol%]) and 1.5 mL of cyclohexane were added
to Schlenk flask. The flask was inserted in an aluminium block
°
and heated to 60 C for 24 hours. After reaction completion, the
flask was cooled down to room temperature and 3 mL of
CH2Cl2 were added to the mixture for GC analysis. Dodecane
was used as internal standard for GC measurements.
All other hydroamination products were isolated by column
chromatograph and characterised by NMR spectroscopy. For
purification, the reaction mixture was cooled to room temper-
ature, transferred to a round-bottom flask, adsorbed on Celite,
and concentrated under vacuum to obtain a dried powder which
was separated using CombiFlash Rf 200 (Teledyne) equipment.
Product was concentrated under vacuum to obtain product
yield.
Scheme 3. Substrate scope of allylic alcohol formal hydro-
amination. 1-Phenylpiperazine (0.5 mmol), alcohol (1 mmol),
a)
Mn-1 (2 mol%), NaHBEt3 (4 mol%), cyclohexane (2 mL),
°
K2CO3 (40 mol%), 60 C, 24 h, isolated yields.
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Acknowledgements
The authors would like to acknowledge the financial support of
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
– Brasil (CAPES) – Finance Code 001 and the European
Research Council (ERC; project NoNaCat 670986). We thank
the analytical staff of the Leibniz-Institute for Catalysis,
Rostock, for their excellent service. We also acknowledge T.
Leischner, H. Hornke, and D. Leonard (LIKAT) for his
assistance with the manuscript. Open Access funding enabled
and organized by Projekt DEAL.
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Catalytic Formal Hydroamination of Allylic Alcohols Using
Manganese PNP-Pincer Complexes
Adv. Synth. Catal. 2021, 363, 1–6
L. Duarte de Almeida, F. Bourriquen, K. Junge*, M. Beller*