Manganese-Catalyzed Selective Hydrogenative Cross-Coupling of Nitriles and Amines to Form Secondary Imines

Article abstract of DOI:10.1002/adsc.202100285

Manganese complexes with tridentate PNN ligands have been synthesized as catalysts for hydrogenative cross-coupling reaction of nitriles and amines to form secondary imines. This reaction afforded a variety of unsymmetrical secondary imines in good yields with excellent selectivity. Investigation of catalyst intermediates indicated that an amido manganese complex may be the active catalyst species for this reaction. (Figure presented.).

Full text of DOI:10.1002/adsc.202100285

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DOI: 10.1002/adsc.202100285
Very Important Publication
Manganese-Catalyzed Selective Hydrogenative Cross-Coupling of
Nitriles and Amines to Form Secondary Imines
Xiao-Gen Lia and Qi-Lin Zhoua,*
a
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071,
People’s Republic of China
Tel: 0086–22-23500011
E-mail: qlzhou@nankai.edu.cn
Manuscript received: March 5, 2021; Revised manuscript received: April 9, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100285
complex can catalyze hydrogenative cross-coupling
reaction of nitriles with amines to form secondary
Abstract: Manganese complexes with tridentate
PNN ligands have been synthesized as catalysts for
imines selectively under mild reaction conditions. In
hydrogenative cross-coupling reaction of nitriles
addition, Prechtl et al.[5] achieved similar selectivity
and amines to form secondary imines. This reaction
afforded a variety of unsymmetrical secondary
imines in good yields with excellent selectivity.
with a PNP-Ru catalyst.
Earth-abundant metals such as iron,[6] cobalt,[7]
nickel,[8] and manganese[9] have been used to catalyze
Investigation of catalyst intermediates indicated that
nitrile hydrogenation, but only a few of these metals
an amido manganese complex may be the active
can selectively catalyze hydrogenative cross-coupling
catalyst species for this reaction.
reaction of nitriles with amines to form secondary
imines. For example, Milstein et al. reported that a
PNN-Fe catalyst shows high selectivity for this
Keywords: Manganese complex; Hydrogenative
reaction in 2017 (Scheme 1).[6e] Although this work
cross-coupling; Nitrile; Amine; Secondary imine
represents a breakthrough, the yields of reactions of
aliphatic nitriles are low. As part of our ongoing
research on catalytic hydrogenation of carboxylic
The imine functional group is present in a variety of
compounds including pharmaceuticals and is widely
used in organic synthesis.[1] Aldimines are commonly
prepared by condensation reactions between aldehydes
and amines.[2] However, because of the intermediate
valence of aldehydes, they are not readily available,
and thus their utility for imine synthesis is limited. In
recent years, considerable effort has been devoted to
seeking alternative methods for preparing imines
efficiently and economically.[3] Among the newly
developed methods, catalytic hydrogenative cross-
coupling reactions of nitriles and amines have high
potential applicability for organic synthesis because
these substrates are readily available bulk chemicals,
and hydrogenation is an environmentally friendly
reaction. However, the huge challenge with these
reactions is that the selectivity is very poor, since many
by-products could be formed in the reaction. In
attempts to overcome this challenge, researchers have
Scheme 1. Catalysts for Hydrogenative Cross-Coupling of
Nitriles and Amines.
developed several efficient catalysts (Scheme 1). For
example, Milstein et al.[4] reported that a PNN-Ru
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derivatives,[10] we herein report a protocol for highly Treatment of ligands 1 with Mn(CO)5Br in toluene
selective manganese-catalyzed hydrogenative cross- resulted in manganese complexes 2 in 80–93% yields
coupling of nitriles and amines to form secondary (Scheme 2).
imines.
Hydrogenative cross-coupling reaction of benzoni-
We began by synthesizing a variety of manganese trile (3a) and n-heptylamine (4a) in nPrOH was carried
complexes (PNN-Mn, 2) containing a biphenylamino- out to evaluate the performance of catalysts 2
phosphine-pyridine ligand. PNN-type tridentate ligands (Table 1). When 1 mol% of 2a was used as the catalyst
1 were synthesized in high yield by Suzuki coupling of and 10 mol% of NaOtBu was used as a base in PrOH,
n
2-bromophenyldiphenyl-phosphines and 2-aminophe- (E)-N-heptyl-1-phenylmethanimine was obtained in
°
nylboronic acid, followed by condensation reaction 53% yield after 40 h at 80 C under 40 atm of hydrogen
between the coupling products and 2-pyridinecarbox- (entry 1). The reaction showed excellent selectivity,
aldehydes (for details, see Supporting Information). yielding only the desired secondary imine (5a).
Modification of the P-aryl groups of the ligand had no
effect on the yield or selectivity (entries 1 and 2). In
contrast, modification of the pyridine ring markedly
affected both the yield and the selectivity. Catalyst 2f,
which has a 4-NMe2 group on the pyridine ring gave
the highest yield (74%), although the selectivity was
relatively low (entries 3–6). To further improve the
yield and selectivity, we varied other reaction parame-
ters. Screening of other solvents showed that only
n
alcohols were suitable, with PrOH being the best
(entries 6–13). Variation of the base, the amount of
Scheme 2. Synthesis of Manganese Complexes 2.
Table 1. Optimization of Reaction Conditions.[a]
Entry
2
Solvent
Base
Conv. (%)[b]
Yield
Yield
Yield
5a (%)[b]
6 (%)[b]
7 (%)[b]
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2f
2f
2f
2f
2f
2f
2f
2f
2f
2f
2f
2f
2f
nPrOH
nPrOH
nPrOH
nPrOH
nPrOH
nPrOH
MeOH
EtOH
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
KOtBu
54
57
74
52
62
99
58
66
57
37
0
53
53
65
52
59
74
57
62
28
37
0
0
0
3
0
trace
16
0
trace
0
0
0
0
0
17
21
17
13
5
0
0
0
0
0
6
0
0
0
0
0
0
0
6
0
6
4
4
0
9[c]
10
11
12
13
14
15
16
17
18[d]
19[d,e]
iPrOH
nBuOH
THF
Toluene
Hexane
nPrOH
nPrOH
nPrOH
nPrOH
nPrOH
nPrOH
0
0
0
0
99
100
99
96
99
100
72
71
72
71
86
98
NaOEt
NaOMe
Na2CO3
NaOtBu
NaOtBu
0
[a] Reaction conditions: benzonitrile (43 mg, 0.42 mmol), n-heptylamine (48 mg, 0.42 mmol), 2 (0.0042 mmol), base (0.042 mmol),
n
°
H2 (40 atm), PrOH (1.0 mL), heated in an autoclave at 80 C for 40 h.
[b] Conversions and yields were determined by GC with ZB-5MSi column using Ph3N as internal standard.
[c] 8% yield of condensation product of n-heptylamine with PrOH (acetone imine) was observed.
i
[d] 0.84 mmol n-heptylamine was used.
[e]
°
30 atm H2, 70 C, 50 h.
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amine, the temperature, and the H2 pressure revealed amine, and halogen substituents were tolerated (5e–
that the optimal reaction conditions were as follows: 5k, 5n, 5o, 5r). Generally, benzonitriles with an
n
1 mol% of 2f and 2 equiv. of n-heptylamine in PrOH electron-donating group at the para or meta position,
°
under 30 atm of H2 at 70 C for 50 h (entries 14–19). for example, 5b, 5c, 5e, 5n and 5o, showed higher
Under these conditions, the reaction showed a 98% yields than benzonitriles with a halogen atom or an
yield and excellent selectivity.
electron-withdrawing group (5i–5l). The reaction was
With the optimized conditions in hand, we studied also sensitive to steric effects, as indicated by the fact
the scope of the reaction with respect to the nitrile that ortho-methylbenzonitrile (5d) and 1-naphthoni-
(Scheme 3). Benzonitriles bearing ether, thioether, trile (5p) gave relatively low yields. In addition to
aromatic nitriles, aliphatic nitriles also gave high yields
in reactions with n-heptylamine (5s–5w), although the
amount of catalyst had to be increased to 2 mol%.
Next we investigated hydrogenative cross-coupling
reaction of various amines with benzonitrile
(Scheme 4). Amines with primary alkyls worked well
under the optimized reaction conditions, producing the
corresponding imines (5aa–5ah) in 66–98% yields.
Amines with ether, amine, amide, and olefin functional
groups were tolerated. Amines with secondary alkyls
also reacted well to afford the desired imines in
reasonable yields (5ai–5ak, 56–63%). However, the
reaction of the tertiary alkyl amine had a very low
yield (5al, 23%), owing to steric hindrance.
Metal-ligand cooperation, in which both metal and
ligand play catalytic roles, is an important concept in
catalysis.[11] To determine whether the NÀ H moiety of
a)
Scheme 3. Scope of Nitriles.
Reaction conditions: nitriles
a)
(0.42 mmol), n-heptylamine (97 mg, 0.84 mmol), 2f (2.8 mg,
Scheme 4. Scope of Amines. Reaction conditions: benzoni-
0.0042 mmol), NaOtBu (4.0 mg, 0.042 mmol), H2 (30 atm),
trile (43 mg, 0.42 mmol), amines (0.84 mmol), 2f (2.8 mg,
n
°
PrOH (1.0 mL), heated in an autoclave at 70 C for 50 h. Yields
0.0042 mmol), NaOtBu (4.0 mg, 0.042 mmol), H2 (30 atm),
n
°
were determined by GC with ZB-5MSi column using Ph3N or
m-xylene as internal standard.
PrOH (1.0 mL), heated in an autoclave at 70 C for 50 h. Yields
b)
2 mol% catalyst was used,
were determined by GC with ZB-5MSi column using m-xylene
20 atm H2. c) 2 mol% catalyst was used, 10 atm H2.
as internal standard. b) 2 mol% catalyst was used.
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catalyst 2a. In the reaction of benzonitrile with n-
31
heptylamine in CD3OD using 2a as catalyst, P NMR
analysis of the hydrogenation reaction mixture showed
a signal at δP 69.83, which is consistent with that in the
reaction using catalyst Mn-I (for details, see Support-
ing Information). In addition, in the reactions using
catalyst Mn/1a or 2a, ESI-MS analyses of the reaction
mixtures indicated that Mn-I was formed during the
reaction (for details, see Supporting Information).
These results indicate that Mn-I may be the active
catalyst in the reaction.
On the basis of the aforementioned experimental
observations and mechanisms reported in the
literatures,[9a,11,12] we propose that this reaction proceed
via the outer-sphere mechanism shown in Scheme 6.
Treatment of precatalyst 2a with NaOtBu generates
amido manganese complex Mn-I, which reacts with
H2 to form MnÀ H species Mn-II. Subsequently, the
hydride from MnÀ H and the proton from the NÀ H of
Mn-II are transferred to the nitrile, giving the primary
Scheme 5. Investigation of Active Catalyst Species.
the ligand of catalysts 2 was involved in the catalysis, imine intermediate and regenerating catalyst Mn-I.
we synthesized N-methylated ligand 1a–Me (for de- Nucleophilic attack of the amine on the primary imine
tails, see Supporting Information). When 1a–Me intermediate is followed by the release of ammonia to
(2 mol%) was used in the hydrogenative cross- form the secondary imine product.
coupling reaction of benzonitrile and n-heptylamine,
In summary, we have synthesized novel manganese
no imine was formed; whereas the use of ligand 1a catalysts that contain a tridentate PNN ligand and can
produced imine 5a in 91% yield under the same catalyze hydrogenative cross-coupling reaction of
conditions (Scheme 5). These results clearly show that nitriles and amines to form secondary imines. Using
the NÀ H moiety of the ligand was involved in the these catalysts, we synthesized a series of secondary
catalysis.
imines in good yields with excellent selectivity by
To shed more light on the reaction mechanism, we means of reactions of aromatic, aliphatic, and hetero-
prepared amido manganese complex Mn-I to catalyze cyclic nitriles with amines. Investigation of catalyst
the reaction (for details, see Supporting Information). intermediates indicated that amido manganese complex
We found that Mn-I (2 mol%) catalyzed the hydro- Mn-I may be the active catalyst species.
genative cross-coupling reaction of benzonitrile with
n-heptylamine, producing imine 5a in 89% yield,
which was similar to the 85% yield achieved with
Scheme 6. Proposed Mechanism for the Manganese-Catalyzed Hydrogenative Cross-Coupling of Nitriles and Amines to Form
Secondary Imines.
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n
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(B06005) of the Ministry of Education of China for financial
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Manganese-Catalyzed Selective Hydrogenative Cross-
Coupling of Nitriles and Amines to Form Secondary Imines
Adv. Synth. Catal. 2021, 363, 1–6
X.-G. Li, Q.-L. Zhou*