Efficient Synthesis of Amines by Iron-Catalyzed C=N Transfer Hydrogenation and C=O Reductive Amination

Article abstract of DOI:10.1002/adsc.201701316

Here we report the catalytic transfer hydrogenation (CTH) of non-activated imines promoted by a Fe-catalyst in the absence of Lewis acid co-catalysts. Use of the (cyclopentadienone)iron complex 1, which is much more active than the classical ‘Kn?lker complex’ 2, allowed to reduce a number of N-aryl and N-alkyl imines in very good yields using iPrOH as hydrogen source. The reaction proceeds with relatively low catalyst loading (0.5–2 mol%) and, remarkably, its scope includes also ketimines, whose reduction with a Fe-complex as the only catalyst has little precedents. Based on this methodology, we developed a one-pot CTH protocol for the reductive amination of aldehydes/ketones, which provides access to secondary amines in high yield without the need to isolate imine intermediates. (Figure presented.).

Full text of DOI:10.1002/adsc.201701316

Title: Efficient Synthesis of Amines by Iron-Catalyzed C=N Transfer
Hydrogenation and C=O Reductive Amination
Authors: Umberto Piarulli, Sofia Vailati-Facchini, Mattia Cettolin,
Xishan Bai, Giuseppe Casamassima, Luca Pignataro, and
Cesare Gennari
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701316
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10.1002/adsc.201701316
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Efficient Synthesis of Amines by Iron-Catalyzed C=N Transfer
Hydrogenation and C=O Reductive Amination
Sofia Vailati Facchini,a,+ Mattia Cettolin,b,+ Xishan Bai,b Giuseppe Casamassima,b Luca
Pignataro,b,* Cesare Gennari,b,* and Umberto Piarullia,*
a
Dipartimento di Scienza e Alta Tecnologia, Università degli Studi dell’Insubria, Via Valleggio, 11 – 22100 Como,
Italy, e-mail: umberto.piarulli@uninsubria.it
Dipartimento di Chimica, Università degli Studi di Milano, Via C. Golgi, 19 – 20133 Milano, Italy
b
e-mail: cesare.gennari@unimi.it; luca.pignataro@unimi.it
These authors contributed equally to this work.
+
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
perfectly atom-economic (H2 is fully incorporated
hydrogenation (CTH) of non-activated imines promoted by into the product), whereas in CTH the hydrogen
Abstract. Here we report the catalytic transfer
a Fe-catalyst in the absence of Lewis acid co-catalysts. Use
of the (cyclopentadienone)iron complex 1, which is much
more active than the classical ‘Knölker complex’ 2,
allowed to reduce a number of N-aryl and N-alkyl imines in
very good yields using iPrOH as hydrogen source. The
reaction proceeds with relatively low catalyst loading (0.5-
donor (iPrOH or Et3N/HCOOH) acts as both solvent
and reductant, forming easy-to-separate by-products
such as acetone or CO2. A number of successful
methodologies for amine synthesis relying on the CH
of imines,[5] nitriles,[6] amides,[7] azides[8] and nitro
groups,[9] or on the CTH of imines/iminium ions[10,11]
have been reported. In most of them noble metals
(such as Ru, Ir, Rh, Pt) are employed, but in recent
years cost and toxicity issues have stimulated the
investigation of alternative approaches, such as metal-
free methodologies[ 12 ] and base metal catalysis.[ 13 ]
Within the latter area, iron appeared particularly
attractive due to its abundancy, low cost and
relatively scarce toxicity.[14] Several Fe-catalysts for
the hydrogenation of imines/iminium ions,[ 15 , 16 ]
nitriles,[17] amides[18] and nitro groups[16] to amines
have been developed. On the contrary, quite
surprisingly, the number of iron catalysts reported for
2
mol%) and, remarkably, its scope includes also
ketimines, whose reduction with a Fe-complex as the only
catalyst has little precedents. Based on this methodology,
we developed a one-pot CTH protocol for the reductive
amination of aldehydes/ketones, which provides access to
secondary amines in high yield without the need to isolate
imine intermediates.
Keywords: hydrogenation; iron; amination; homogeneous
catalysis; imines
19
, 20 ]
the CTH of imines is very limited.[
(Cyclopentadienone)iron complexes were used to
achieve the direct amination of alcohols with a
Amines are a very common and important class of
organic compounds, broadly used for the synthesis of
bioactive compounds, dyes, fibers and materials.[1 ]
The main methodologies for their preparation involve
a reduction as the key step, with imines (either pre-
isolated or formed in situ), iminium ions, nitriles,
amides, nitro groups, azides as typical substrates.[2]
On the lab scale, this transformation is often
performed using boron- and aluminum-derived
hydrides (e.g., NaBH4, NaBH3CN, LiAlH4), metal
salts (e.g., SnCl2) or phosphorus compounds (e.g.,
PPh3) as stoichiometric reductants. However, the use
of these reducing agents involves formation of a
stoichiometric amount of salts or other by-products,
with associated environmental costs. For this reason,
catalytic hydrogenation (CH)[3] and catalytic transfer
hydrogenation (CTH)[4] can be considered much more
attractive from an industrial point of view. These
methodologies employ cheap reducing agents and
present less problems of waste disposal: CH is
[
21 , 22 ]
‘hydrogen borrowing’ strategy,
that is
mechanistically related to CTH.[23]
Scheme 1. Preliminary tests of pre-catalysts 1 and 2 in the
CTH of a ketimine.
1
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10.1002/adsc.201701316
Advanced Synthesis & Catalysis
In recent years, our research group has been active in is able to promote ketimine CTH only in the presence
the field of C=O reductions, mainly using of a substantial amount of Lewis acid.[19a,20]
(cyclopentadienone)iron complexes.[24,25] Building on Encouraged by the promising result obtained with
this expertise, we report here our efforts to develop an pre-catalyst 1, we set to optimize the reaction
efficient Fe-catalytic methodology for the transfer conditions using two different model substrates, i.e.
hydrogenation of non-activated N-aryl and N-alkyl ketimine S1 and aldimine S2. Catalyst loading,
imines. In a preliminary experiment, we tested concentration and temperature were varied as shown
complex 1, recently developed in our group,[24a] and in Table 1.
the classical ‘Knölker complex’ 2[26] in the CTH of N- Conversions were determined by 1H NMR analysis of
(1-phenylethylidene)-p-anisidine S1 (Scheme 1).
the crude reaction mixtures, as only reduction product
Pre-catalytic complexes 1 and 2 were activated by de- and/or staring material signals were visible in the
complexation of one CO ligand in the presence of spectra. With ketoimine S1, the initial substrate
Me3NO.[15b,e,g,h,21a,d,24] This activation step was found concentration (C0,sub.) has a remarkable influence on
to be delicate and crucial to achieve reproducibility. the conversion, and 0.25 M was found to be the
Under optimized conditions, the pre-catalyst was optimal value (Table 1, entry 2 vs. entries 1 and 3).
dissolved in iPrOH (Cprecat. = 0.1 M or higher) and Lowering the catalyst loading to 2 mol% did not
reacted with Me3NO for 20 min at r.t., before adding impact on conversion (Table 1, entries 4-5), whereas
the substrate and heating. The catalyst derived from 1 at 1 mol% and at 0.5 mol% the reaction was sluggish
proved substantially more active than the one derived (Table 1, entries 6 and 8). Increasing the temperature
from 2 (97% vs. 2% yield, Scheme 1). This difference (100 °C; Table 1, entries 7, 9, 10) restored high
in activity is dramatic and more pronounced than that conversion when 1 mol% of catalyst loading was used
observed in the CH and CTH of ketones.[24a]
(Table 1, entry 7), while proved ineffective with
lower loadings (Table 1, entries 9, 10). As expected,
aldimine S2 was found to be more reactive than
ketimine S1, giving full conversion with 5 mol%
catalyst loading, irrespective of C0,sub. (Table 1, entries
11-13). Experiments run at 2 mol% confirmed that
0.25 M is the optimal C0,sub. value (Table 1, entries 14
vs. 15). Further lowering the catalyst loading down to
0.5% led to a less pronounced decrease of the rate
than in the case of S1 (Table 1, entries 16 and 18 vs. 6
and 8), and full conversion was restored by running
the reaction at 100 °C (entries 17 and 19, TON up to
200). At 0.1 mol% catalyst loading, the conversion
dropped to 17% (Table 1, entry 20).
On the basis of the above-discussed optimization, we
selected C0,sub. = 0.25 M, 2 mol% loading of 1, and T =
100 °C as conditions for investigating the substrate
scope. The screening was carried out on preparative
scale (2 mmol), and isolated yields were assessed for
each product (Table 2). Delightfully, excellent yields
(83% to quantitative) were obtained with all
substrates, with the single exception of the -
tetralone-derived ketimine S12 (Table 2, entry 12),
which was only partially reduced (57% yield).
Particularly remarkable are the results obtained with
the sterically encumbered imines such as S6 (Table 2,
entry 6), S9 (entry 9), S10 (entry 10) and S11 (entry
11).
Table 1. Imine CTH promoted by pre-catalyst 1:
optimization of the reaction conditions.[a]
Cat. loading
[mol%]
#
Sub.
C0,sub. [M] Conv. [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
S1
S1
S1
S1
S1
S1
S1
S1
S1
S1
S2
S2
S2
S2
S2
S2
S2
S2
S2
S2
5
5
5
2
2
1
1
0.5
0.5
0.1
5
5
5
2
2
1
1
0.5
0.5
0.1
0.40
0.25
0.13
0.40
0.25
0.25
0.25
0.25
0.25
0.25
0.40
0.25
0.13
0.40
0.25
0.25
0.25
0.25
0.25
0.25
72
97
89
71
>99
8
88[c]
4
16[c]
0[c]
>99
>99
>99
90
>99
74
As a further challenge, we investigated a reductive
amination methodology involving the synthesis of the
imine and its catalytic transfer hydrogenation (CTH)
in one pot. This kind of protocol, pioneered by
Renaud and co-workers in the case of imine catalytic
hydrogenation (CH),[15b,e,h] would make imine
isolation and purification unnecessary, and thus
extend the substrate scope to imines that cannot be
readily isolated (e.g., those derived from aliphatic
carbonyl compounds).
>99[c]
28
>99[c]
17[c]
[a]
Reaction conditions: 1/Me3NO = 1:2, T = 70 °C, 18 h,
solvent: iPrOH.
Determined by 1H-NMR of the crude reaction mixture.
Reaction run at 100 °C.
[b]
[c]
Moreover, these results confirm what reported by
Zhao and co-workers for their pre-catalyst (precursor
of the same catalytic species as pre-catalyst 2), which
2
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10.1002/adsc.201701316
Advanced Synthesis & Catalysis
Table 2. Substrate scope evaluation in the CTH promoted Table 3. CTH-based reductive amination of aldehydes and
by pre-catalyst 1.[a] ketones promoted by pre-catalyst 1.[a]
#
1
Product
Yield [%][b]
>99
Yield
[%][b]
Yield
[%][b]
#
1
Substrate
#
7
Substrate
P13
P14
P15
P16
P17
2
3
4
5
93
74
75
90
99
98
2
3
4
99[c]
99
8
99
99
83
9
6
7
80[c]
60[c]
P1
99
10
P18
[a]
Reaction conditions: S/amine/1/Me3NO = 100:150:5:5;
C0,sub.= 0.25 M (0.5 mmol). Imine formation and catalyst
activation were performed in different pots.
Isolated yields.
Imine formation was performed in the presence of TFA
(10 mol%), which was then quenched with DIPEA (15
mol%) before adding the activated catalyst.
5
99
95
11
12
99
57
[b]
[c]
6
PMP = p-methoxyphenyl.
[a]
Reaction conditions: substrate/1/Me3NO = 100:2:4,
C0,sub.= 0.25 M (0.5 mmol), T = 100 °C, 18 h, solvent:
iPrOH.
Isolated yields.
1 mol% catalyst loading, substrate/1/Me3NO = 100:1:2.
In conclusion, we have reported the first catalytic
transfer hydrogenation (CTH) of non-activated N-aryl
and N-alkyl imines promoted by a Fe-complex in the
absence of Lewis acid co-catalysts. Thanks to pre-
catalyst 1[24a] – displaying much higher activity than
the classical ‘Knölker complex’ 2 – it was possible to
reduce a number of imines with a cheap reductant
(iPrOH) using a relatively low catalyst loading (0.5-2
mol%). Remarkably, very good yields were obtained
also with non-activated ketimines, whose reduction
with a Fe-complex as the only catalyst has little
precedents.[15a,b,e,h] Based on this CTH methodology, a
reductive amination protocol was also developed,
which leads to the one-pot formation of secondary
amines in high yield, starting from an
aldehyde/ketone and a primary amine.
[b]
[c]
Preliminary tests revealed that successful imine
formation is crucial for the reductive amination
outcome. Indeed, whenever the conversion to imine
was lower than 90% the CTH gave complex mixtures.
Thus, we first optimized the imine synthesis step[27]
(see the Supporting Information). We then carried out
CTH tests by adding the pre-activated catalyst and
iPrOH to the crude imine solution in toluene.
Good to excellent yields were obtained with both
aldehyde and ketone substrates (Table 3). Aromatic
and heteroaromatic aldehydes showed the best
reactivity (Table 3, entries 1-2), but also products P15
and P16 – deriving, respectively, from an aliphatic
and an α,β-unsaturated aldehyde – were isolated in
good yields (entries 3-4). The reaction worked well
also when an aliphatic amine (2-phenylethan-1-
amine) was employed instead of 4-methoxyaniline
Experimental Section
General information
All reactions were performed under argon atmosphere in
(Table 3, entry 5). While ketones were found less pressure-proof Schlenk vessels fitted with a screw cap.
reactive than aldehydes, both the aromatic (Table 3,
entry 6) and the aliphatic substrate (entry 7) gave
synthetically useful yields.
General Procedure for the CTH of pre-formed imines
Pre-catalyst 1 (3.8 mg, 0.010 mmol, 0.02 equiv.) and
Me3NO (1.6 mg, 0.020 mmol, 0.04 equiv.) were dissolved
in dry iPrOH (0.1 mL) and the resulting solution, which
gradually turned from yellow to dark red, was stirred for 20
minutes at r.t.. The imine substrate (0.5 mmol, 1 equiv.)
was added, followed by dry iPrOH (1.9 mL). The reaction
vessel was sealed and stirred in a pre-heated oil bath at
3
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10.1002/adsc.201701316
Advanced Synthesis & Catalysis
100 °C for 18 h. The volatiles were removed and the crude
was purified by flash column chromatography using a
hexane/AcOEt mixture.
[6] For a recent review, see: D. B. Bagal, B. M. Bhanage,
Adv. Synth. Catal. 2015, 357, 883-900.
General Procedure for the reductive amination of
aldimines
[7] For a recent review, see: A. Volkov, F. Tinnis, T.
Slagbrand, P. Trillo, H. Adolfsson, Chem. Soc. Rev.
2016, 45, 6685-6697.
3 Å MS (400 mg), the aldehyde (0.5 mmol, 1 equiv.) and
the amine (0.75 mmol, 1.5 equiv.) were dissolved in dry
toluene (0.5 mL) and the mixture was stirred for 1 h at
100 °C. Meanwhile, in another vessel, pre-catalyst 1 (9.6
mg, 0.025 mmol, 0.05 equiv.) and Me3NO (1.9 mg, 0.025
mmol, 0.05 equiv.) were dissolved in dry iPrOH (0.25 mL).
The activated catalyst solution was dispensed into the
vessel containing the imine, followed by dry iPrOH (1.2
mL). The reaction vessel was sealed and stirred in a pre-
heated oil bath at 100 °C for 18 h. The volatiles were
removed and the crude was purified by flash column
chromatography using a hexane/AcOEt mixture.
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Reduction Methods, Wiley-VCH, 2008, pp. 271-296.
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precious metals, see: a) B. Václavíková Vilhanová, A.
Budinská, J. Václavík, V. Matoušek, M. Kuzma, L.
Červený, Eur. J. Org. Chem. 2017, 2017, 5131-5134;
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Y. Lan, Y. Zhao, Angew. Chem. Int. Ed. 2016, 55,
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General Procedure for the reductive amination of
ketimines
3 Å MS (400 mg), the ketone (0.5 mmol, 1 equiv.), the
amine (0.75 mmol, 1.5 equiv.) and TFA (4 μL, 0.05 mmol,
0.1 equiv., dispensed as a stock solution in toluene) were
dissolved in dry toluene (final total volume: 0.5 mL) and
stirred for 2 h at 100 °C. Meanwhile, in another vessel, pre-
catalyst 1 (9.6 mg, 0.025 mmol, 0.05 equiv.) and Me3NO
(1.9 mg, 0.025 mmol, 0.05 equiv.) were dissolved in dry
iPrOH (0.25 mL). Freshly distilled DIPEA (13 μL, 0.075
mmol, 0.15 equiv.) and then the activated catalyst solution
were dispensed into the vessel containing the imine,
followed by dry iPrOH (1.2 mL). The reaction vessel was
sealed and stirred at 100 °C for 18 h. The volatiles were
removed and the crude was purified by flash column
chromatography using hexane/AcOEt mixture.
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Acknowledgements
L. P. thanks the Dipartimento di Chimica, Università degli Studi
di Milano, for financial support (Piano di Sostegno alla Ricerca
2015-2017 – Action B). We thank Prof. Albrecht Berkessel for
inspiring discussions.
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2017, 71, 580-585; b) A. Quintard, J. Rodriguez,
Angew. Chem. Int. Ed. 2014, 53, 4044-4055; Angew.
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[26] H.-J. Knölker, J. Heber, C. H. Mahler, Synlett 1992,
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[27] Condensation of benzaldehyde and acetophenone with
4-methoxyaniline was monitored by 1H-NMR.
Reaction in toluene for 1 h in the presence of 3 Å
molecular sieves (MS) allowed quantitative aldimine
synthesis, whereas high-yielding ketimine formation
required also the presence of trifluoracetic acid (TFA,
10 mol%). In the latter case, excess N,N-
diisopropylethylamine (DIPEA, 15 mol%) had to be
added after imine formation to neutralize TFA (which
would otherwise cause partial degradation of the
catalyst). For further details, see the Supporting
Information.
[20] Mezzetti et al.,[19b] Morris et al.,[19c-e] and Beller et
al.[19f] developed chiral PNNP-FeII complexes (either
pre-isolated or generated in situ) promoting the
enantioselective CTH of pro-chiral C=N bonds. The
scope of these methodologies is limited to activated
N-(diphenylphosphinyl)-imines, while N-aryl and N-
alkyl imines were apparently unreactive. Very
recently, Zhao et al. reported that N-aryl and N-alkyl
imines can be reduced by iPrOH in the presence of a
(cyclopentadienone)iron complex, provided that a
Lewis acid [e.g., 10 mol% Fe(acac)3] is used as co-
catalyst.[19a]
[21] a) T. J. Brown, M. Cumbes, L. J. Diorazio, G. J.
Clarkson, M. Wills, J. Org. Chem. 2017, 82, 10489-
10503; b) T. Yan, B. L. Feringa, K. Barta, ACS Catal.
2016, 6, 381-388; c) H.-J. Pan, T. W. Ng, Y. Zhao,
Chem. Commun. 2015, 51, 11907-11910; d) A. J.
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17, 1086-1089; e) T. Yan, B. L. Feringa, K. Barta,
Nat. Commun. 2014, 5, 5602.
[22] The scope of these methodologies is limited to
primary alcohols, while secondary alcohols – which
form α-branched secondary amines –react only in the
presence of large amounts of a Lewis acid co-catalysts
(e.g., 40 mol% AgF).[21c]
[23] For recent reviews on the ‘hydrogen borrowing’
approach, see: a) F. Huang, Z. Liu, Z. Yu, Angew.
Chem. Int. Ed. 2016, 55, 862-875; b) A. Quintard, J.
Rodriguez, ChemSusChem 2016, 9, 28-30; c) J. M.
5
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10.1002/adsc.201701316
Advanced Synthesis & Catalysis
COMMUNICATION
Efficient Synthesis of Amines by Iron-Catalyzed
C=N Transfer Hydrogenation and C=O Reductive
Amination
Adv. Synth. Catal. Year, Volume, Page – Page
Sofia Vailati Facchini, Mattia Cettolin, Xishan Bai,
Giuseppe Casamassima, Luca Pignataro, Cesare
Gennari, Umberto Piarulli
6
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