Reductive amination catalyzed by iridium complexes using carbon monoxide as a reducing agent

Article abstract of DOI:10.1039/c7ob01005b

Development of novel, sustainable catalytic methodologies to provide access to amines represents a goal of fundamental importance. Herein we describe a systematic study for the construction of a variety of amines catalyzed by a well-defined homogeneous ir

Full text of DOI:10.1039/c7ob01005b

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Smol’yakov, D. A. Loginov and D. Chusov, Org. Biomol. Chem., 2017, DOI: 10.1039/C7OB01005B.
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Reductive Amination Catalyzed by Iridium Complexes Using
Carbon Monoxide as a Reducing Agent
Received 00th January 20xx,
Accepted 00th January 20xx
Alexey P. Moskovets,a Dmitry L. Usanov,b Oleg I. Afanasyev,a Vasilii A. Fastovskiy,a Alexander P.
Molotkov,a Karim M. Muratov,a Gleb L. Denisov,a Semen S. Zlotskii,с Alexander F. Smol'yakov,a,d
Dmitry A. Loginova and Denis Chusov*a,d
DOI: 10.1039/x0xx00000x
www.rsc.org/
Development of novel, sustainable catalytic methodologies to complexes with weakly and strongly bonded ligands with η-1,
provide access to amines represents a goal of fundamental η-2, η-3, η-5 and η-6 coordination types (Scheme 1) as
importance. Herein we describe a systematic study for the potential catalysts. As a result, herein we report the first
construction of a variety of amines catalyzed by a well-defined example of iridium-catalyzed CO-assisted reductive amination.
homogeneous iridium complex using carbon monoxide as a
Complexes
[CpIrI2]2,
[Cp*IrCl2]2,
[CpIr(cod)Br]PF6,
reducing agent. The methodology was shown to be compatible [CpIr(cod)Br][CpIrBr3], [(η5-indenyl)IrI2]2, [(η5-indenyl)IrCp]PF6,
with functional groups prone to reduction by hydrogen or complex [(η5-indenyl)Ir(η-C6H3Me3)](BF4)2 were synthesized by known
hydrides.
procedures.7-10 Cyclooctadienyl complex [CpIr(η3,η2-C8Н11)]PF6
was prepared by the reaction of CpIr(cod) with silver
trifluoroacetate (Scheme 2; anions are omitted in the schemes
for clarity). Probably, this reaction proceeds via intermediate
formation of dication [CpIr(cod)]2+ which undergoes
spontaneous deprotonation to give[CpIr(η3,η2-C8Н11)]+.
Earlier, Maitlis and coworkers synthesized the pentamethyl
Among the transformations which are conventionally classified
as reductions, reductive amination is notable for particularly
high preparative significance, being one of the most
convenient and versatile methods of C-N bond formation.1,2
Notably, a representative screening of publications in the field
of medicinal chemistry demonstrated that reductive amination
is used more frequently than the eight most popular reductive
processes combined,3 which is not surprising in light of the
numerous advantages of this type of transformation, such as
accessibility of starting materials, modular nature and the
possibility of rapid build-up of molecular complexity.
analog
[Cp*Ir(η3,η2-C8Н11)]PF6
by
interaction
of
[Cp*Ir(Me2CO)3]2+ with cyclooctadiene.11
Phosphite complexes [(cod)Ir{P(OR)3}3]PF6 (R = Me, Et)
were unexpectedly formed in the reaction of [CpIr(cod)Br]PF6
with phosphites (Scheme 3). Notably, phosphites play a dual
role in this reaction: they serve both as ligands and reducing
agents. Indeed, there are signals for five-valence phosphorus
species (2.5-30 ppm) along with those for coordinated and free
phosphite (89 and 140 ppm, respectively) in the 31P NMR
spectrum of the reaction mixture. Usually, binding of
cyclopentadienyl ligand to transition metals is considerably
stronger than that of cyclooctadiene. Probably, reduction of
Ir(III) to Ir(I) facilitates substitution of Cp in this case. In
contrast, a similar reaction of [CpIr(cod)Br]PF6 with 2,2′-
bipyridyl, which does not possess reducing ability, leads to
substitution of cyclooctadiene with the formation of [CpIr(2,2′-
bipy)Br]PF6 (Scheme 3).
Our group has recently discovered a catalytic reductive
methodology4 which takes advantage of the deoxygenative
potential of carbon monoxide and does not require an external
hydrogen source unlike the conventional approaches to e.g.
reductive amination.
So far only rhodium and ruthenium complexes were found
to be capable of catalyzing CO-assisted5-6 reductive reactions.
In this work, we tried to expand our knowledge about this type
of processes and tried both iridium(I) and iridium(III)
The structure of [(cod)Ir{P(OMe)3}3]PF6 was determined by X-
ray diffraction (Fig. 1). The Ir−P bonds (2.248−2.317, av. 2.278
Å) in cation [(cod)Ir{P(OMe)3}3]+ are considerably shorter than
those in the previously reported phosphide complex
[(cod)Ir(PMe3)3]+ (2.327−2.379, av. 2.348 Å).12 The strong Ir−P
bonds correlate well with low catalytic activity of
[(cod)Ir{P(OMe)3}3]PF6 in reductive amination reactions (see
bellow). In accordance with the trans-effect, the Ir−cod bonds
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in the phosphite complex (2.182−2.312, av. 2.248 Å) are longer optimization studies. The effect of iodine counterion seems to
than the corresponding bonds in the phosphide analog be general for the iridium complexes. When sodium iodide was
(2.178−2.237, av. 2.207 Å).
added to iridium trichloride the yield increases from 33 to 47%
(Table 1, entries 11-12).
2
Ir
Br
Ir
Ir
–
–
–
PF6
PF6
(BF4 )
2
1
2
3
Ir
–
–
Ir
Ir
PF6
PF6
(MeO)3
P
P(OMe)3
Cl
P(OMe)3
2
4
5
6
Ir
Br
Ir
Figure 1.Cation [(cod)Ir{P(OMe)3}3]+
6with atoms shown as thermal
Br
Ir
Ir
Br
Br
Cl
Cl
Cl
ellipsoids at 50% probability level. Hydrogen atoms are omitted for
clarity. Selected bond lengths (Å):Ir1−C12 2.289(3), Ir1−C13 2.312(3),
Ir1−C16 2.209(3), Ir1−C17 2.182(3), Ir1−P1 2.2691(8), Ir1−P2 2.2480(7),
Ir1−P3 2.3177(8), C12−C13 1.395(5), C16−C17 1.433(4).
2
2
7
8
9
Ir
Ir
Table 1. Catalyst screening in the model reductive amination
reaction.[a]
I
I
I
I
2
2
OMe
1% [Ir]
THF
10
11
OMe
CHO
Scheme 1. Iridium complexes tested as pre-catalysts for the reductive
N
H
30 atm CO
140 oC, 22 h
-CO2
H2N
amination reaction.
12a
Entry
1
Catalyst
Catalyst loading [mol%]
Yield [%]
CF3COOAg
Ir
Ir
–
1
1.0
1.0
1.0
1.0
0.5
1.0
0.5
0.5
1.0
0.5
0.5
1.0
1.0
5
PF6
CF3COOH
KPF6
2
2
8
4
3
3
8
Scheme 2.Synthesis of [CpIr(η3,η2-C8Н11)]+.
4
4
12
14
25
29
28
21
39
57
33
47
5
5
2,2'-bipyridyl
Ir
P(OR)3
N
6
6
Ir
Br
Ir
Br
–
–
PF6
PF6
PF6
N
–
(RO)3
P
P(OR)3
P(OR)3
7
7
2
R = Me (6), Et
8
8
Scheme 3.Reactivity of [CpIr(cod)Br]+.
9
9
10
10
11
12
13
After all the catalysts had been synthesized, we decided to
compare them using p-methylbenzaldehyde and p-anisidine as
model substrates (Table 1). It was found that dimeric
iridium(III) complexes with bridging halide ligands are
considerably more catalytically active than cationic monomeric
species (Table 1, entries 8-11 vs. 1-4). Iridium(I) complexes give
moderate yields (entries 5-7). Superior performance was
observed for complexes of iridium(III) with Cp and halogens
(Table 1, entries 8-10). CyclopentadienylIridium(III) diiodide
was found to provide the best results among the tested metal
complexes (entry 11) and was therefore used for the further
11
IrCl3
IrCl3 + 3NaI
[a] 1:1 ratio of the amine and the aldehyde was employed. 0.2 mmol scale.
Solvent screening revealed ethereal solvents and alcohols as
the optimum media for the reaction (see SI). To avoid any
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H(R2)
R4
possibility of hydrogen transfer reaction we chose
tetrahydrofuran as a solvent instead of isopropanol. The
H
O
1 mol% [CpIrI2]2
N
R1
R1
N
R3
R4
30 atm CO, THF
150 oC, 20 h
H(R2)
R3
Table 2.Temperature and pressure influence for the model reductive
amination reaction.[a]
OMe
Ph
OMe
N
O
Ph
N
NH
12a, 72% (58%)
H
12b, 68% (55%)
12c, 92% (75%)
OMe
Catalyst
Ph
O
N
N
Entry
Solvent[b]
T, °C
P, bar
loading
[mol%]
Yield [%][c]
Cl
O
N
H
Cl
Ph
Ph
1
2
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
140
150
160
150
150
150
150
150
150
130
140
150
50
50
50
60
50
30
20
10
5
1.0
1.0
1.0
0.5
0.5
0.5
0.5
0.5
0.5
1.0
1.0
1.0
49
54
57
39
37
34
11
9
12d
12e
, 68% (30%)
12f
, 64% (51%)
, 92% (92%)
COOEt
Cl
COOEt
Ph
3
4
NH
NH
NH
5
12g
12h
12i
dr
, 82% (74%)
, 70% (54%)
, 96% (84%), 1.5:1
6
OMe
CF3
OMe
Ph
7
Ph
N
F3C
8
O
NH
NH
9
2
12j, 69% (62%)
12k, 45% (30%)
12l, 60% (41%)
10b
11b
12b
50
50
50
67
67
72
OMe
N
Cl
N
PMP
Cl
N
H
[a] 1.5:1 ratio of the amine and the aldehyde was employed. 0.1 mmol scale [b]
2:1 ratio of the amine and the aldehyde was employed. 22h. [c] yields were
determined by GC.
12m, 96% (96%)
12n, 62% (53%)
12o, 93% (78%)
Scheme 4. Substrate scope of reductive amination catalyzed by CpIrI2
in the presence of carbon monoxide. Yields were determined by NMR
with an internal standard. Isolated yields are given in parentheses.
temperature studies showed no significant trend at
temperatures higher than 140 °C (Table 2, entries 1-3). The
pressure had almost no influence on the reaction outcome
above 30 bar, which can be explained by the supercritical
nature of carbon monoxide (Table 2, entry 4-7). When the
pressure was decreased from 30 to 20 bar the reaction rate
was significantly lower (Table 2, entry 6 vs. 7). Nonetheless,
the reaction still proceeded to some extent even at the
pressure of as low as 5 bar (Table 2, entry 9). The yield
becomes significantly higher at amine to aldehyde ratio of 2:1
(Table 2, entry 10-12). Comparison iridium catalysis with our
previous data clearly shows that for the most nucleophilic
amines rhodium still represents the best choice. For ruthenium
catalyzed reactions with nucleophilic aliphatic amines, N-
formamide was detected as a side product; no such byproduct
was found in case of iridium catalysis.
CpIrnLm
CO
O
R1 R2
R4
N
R1
R4
R3
HO
R1
+
R4
N
CO
Irn
H
R3
R2
R2
N
R3
CpLm
H
CO
R4
H
OH
Irn+2
OC
R4
LmCp Irn+2
N
LmCp
N
R3
R1
R2
R1
R3
R2
O
H
O
LmCp Irn+2
R4
R3
O=C=O
With the optimized conditions in hand, we turned to
investigation of the scope of the developed methodology
(Scheme 4). We found that chlorinated cyclopropanes could
react with amines without any erosion of either cyclopropane
N
R1
R2
Scheme 5. Plausible mechanism.
rings or halogen substitution (12f, 12n). The stability of the
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2012, 14, 2371; (h) N.K. Pahadi, M. Paley, R. Jana, S.R.
dioxalane moiety was also successfully validated (12e). N-
benzyl moiety, which is usually fragile under various reductive
conditions, remained fully intact in our system. Both aromatic
and aliphatic amines are suitable for the reaction, and both
primary and secondary amines can be used.
Waetzig, J.A. Tunge J. Am. Chem. Soc., 2009, 131, 46, 16626.
(i) J.P. Patel, A.-H. Li, H. Dong, V.L. Korlipara, M.J. Mulvihill,
Tetrahedron Lett., 2009, 50, 44, 5975.
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S. D. Roughley, A. M. Jordan, J. Med. Chem. 2011, 54, 3451.
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(b) P.N. Kolesnikov, D.L. Usanov, E.A. Barablina, V.I. Maleev,
D. Chusov, Org. Lett. 2014, 16, 5068. (c) P.N. Kolesnikov, N.Z.
Yagafarov, D.L. Usanov, V.I. Maleev, D. Chusov, Org. Lett.
2015, 17, 173. (d) N.Z. Yagafarov, P.N. Kolesnikov, D.L.
Usanov, V.V. Novikov, Y.V. Nelyubina, D. Chusov, Chem.
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Surprisingly, ketones are even more suitable for this reaction.
Only when hexane-2,5-dione was used as a starting material
exclusive formation of N-PMP-2,5-dimethylpyrrole 12m was
detected. When naphtylethylamine was used together with
benzylacetone the product of 1.5:1 dr was obtained (12i).
Based on our previous studies we suggest
a plausible
5
6
For the recent examples of using carbon monoxide for nitro
group reductive transformation see H.-Q. Li, X. Liu, Q. Zhang,
mechanism of the process (Scheme 5). The reaction between
an amine and a carbonyl compound leads to the formation of a
hemiaminal. The oxidative addition of iridium complex to C-O
bond of the heminal leads to a new complex. After an attack of
hydroxyl group on the coordinated CO and elimination of CO2,
the iridium hydride complex should be formed. Reductive
elimination then leads to the formation of the product and
regeneration of the catalytic species.
S.-S. Li, Y.-M. Liu, H.-Y. He, Y. Cao, Chem. Comm., 2015, 51
11217.
,
For the state-of-the-art examples of reductive application CO
in the water-gas shift reaction in organic chemistry see: (a)
S.E. Denmark, M.Y.S. Ibrahim A. Ambrosi, ACS Catalysis 2017,
7
, 1, 613; (b) A. Ambrosi, S.E. Denmark, Angew. Chem. Int.
Ed. 2016, 55, 12164; (c) J. W. Park, Y. K. Chung, ACS Catal.
2015, , 4846; (d) S.E. Denmark, Z.D. Matesich, J. Org. Chem.
5
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He K. N. Fan, Angew. Chem. Int. Ed., 2009, 48, 9538; (g) J.
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Conclusions
In summary, we have found a new type of catalyst which can
provide atom-economical reductive amination of aldehydes
and ketones. The methodology takes advantage of the unique
deoxygenative potential of carbon monooxide and does not
require an external hydrogen source, which enables full
compatibility with a range of functional groups prone to
reduction (e.g. N-benzyl, dioxalane, halo-, cyclopropanes).
Cao, S. Liu, Y.D. Wang, Chinese Journal of Catalysis, 2016, 37
,
1669; (j) J. Ni, L. He, Y.M. Liu, Y. Cao, H.Y. He, K.N. Fan, Chem.
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H.-Y. He, K.N. Fan, Chem. Commun., 2010, 46, 1553.
For the recent examples of metal carbonyl as the source of
carbon monoxide see: (a) N. Jana, F. Zhou, T.G. Driver, J. Am.
Chem. Soc., 2015. 137,21, 6738; (b) F. Zhou, D.S. Wang, T.G.
Driver, Adv. Synth. Catal., 2015. 357, 16-17, 3463.
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C. White, A. Yates, P. M. Maitlis, Inorg. Synth. 1992, 29, 228.
Notes and references
10 D. A. Loginov, A. M. Miloserdov, Z. A. Starikova, P. V.
Petrovskii, A. R. Kudinov, Mendeleev Commun. 2012, 22, 192.
11 A.A. Chamkin, A.M. Finogenova, Yu.V. Nelyubina, J. Laskova,
‡We thank the Russian Academy of Sciences (P-8 grant), the
Russian Foundation for Basic Research (grant No. 15-03-02548
A) and the Council of the President of the Russian Federation
(Grant for Young Scientists No. МК-520.2017.3) for the financial
support. D.A.L. gratefully acknowledges support of the Russian
Foundation for Basic Research (project 16-33-60140 mol_а_dk).
D.C. and A.F.S. thanks the Ministry of Education and Science of
the Russian Federation (Agreement number 02.a03.21.0008).
The contribution of Center for molecule composition studies of
INEOS RAS is gratefully acknowledged.
A.R. Kudinov, D.A. Loginov, Mendeleev Commun. 2016, 26
491.
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For selected recent papers on reductive amination see: (a) H.
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