Iron-Catalyzed Reductive Amination of Aldehydes in Isopropyl Alcohol/Water Media as Hydrogen Sources

Article abstract of DOI:10.1002/adsc.201701619

Reductive amination can be carried in i-PrOH/H₂O as hydrogen sources using commercially available iron carbonyl complexes. Within an aqueous alkaline environment, a hydridocarboferrate is formed and its reducing potential is exploited for hydrogenation of the imine (or iminium ion) obtained in situ from aldehydes or ketones, and primary or secondary amines in almost equimolar ratio. This completely sustainable and hydrogen-free process proceeds at 100 °C using Fe₃(CO)₁₂ as catalyst precursor under convectional heating while Fe₂(CO)₉ gave better results when the reaction was carried out under MW dielectric heating. Both enolizable and non-enolizable aldehydes may be successfully employed in reactions with aliphatic and aromatic amines. (Figure presented.).

Full text of DOI:10.1002/adsc.201701619

Title: An Iron Catalyzed Reductive Amination of Aldehydes in Isopropyl
Alcohol l/Water media as Hydrogen Sources
Authors: Elena Petricci, Niccolò Santillo, Daniele Castagnolo, Elena
Cini, and Maurizio Taddei
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701619
Link to VoR: http://dx.doi.org/10.1002/adsc.201701619

Advanced Synthesis & Catalysis
10.1002/adsc.201701619
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Iron-Catalyzed Reductive Amination of Aldehydes in Isopropyl
Alcohol/Water Media as Hydrogen Sources
a,
a
b
a
Elena Petricci, * Niccolò Santillo, Daniele Castagnolo, Elena Cini, and Maurizio
a,
Taddei *
a
Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena Italy
E-mail: elena.petricci@unisi.it; maurizio.taddei@unisi.it
School of Cancer and Pharmaceutical Sciences, King’s College London, 150 Stamford Street SE1 9NH London UK
b
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######.((Please
delete if not appropriate))
ones,[6] the use of noble metals as catalysts remain
unappealing for industrial and pharmaceutical
processes as shown by the limitations introduced by
regulatory agencies that requires, for API registration,
only small traces (ppm) of noble metals present in final
Abstract. Reductive amination can be carried in i-
PrOH/H O as hydrogen sources using commercially
2
available iron carbonyl complexes. Within an aqueous
alkaline environment, a hydridocarboferrate is formed
and its reducing potential is exploited for hydrogenation
of the imine (or iminium ion) obtained in situ from
aldehydes or ketones, and primary or secondary amines in
almost equimolar ratio. This completely sustainable and
hydrogen-free process proceeds at 100 °C using
[7]
product.
Safer alternatives are represented by
"
green" metals such as Cu, Fe or Zn catalyst. Recently,
Fe catalysis emerged as an appealing field in organic
chemistry due to the iron low toxicity, earth abundance
and low cost. A number of different iron complexes
have been developed to date for the formation of new
Fe
3
(CO)12 as catalyst precursor under convectional
heating while Fe
2
(CO) gave better results when the
9
reaction was carried out under MW dielectric heating.
Both enolizable and non-enolizable aldehydes may be
successfully employed in reactions with aliphatic and
aromatic amines.
[8]
[9]
C-C bond, for carbonylation and cycloadditions
[10]
reactions, nucleophilic substitutions as well as other
[11]
transformations recently reviewed.
While iron
complexes have been widely explored for the
reduction of aldehydes, ketones and imine/iminium
Keywords: amines; iron catalysis; microwave;
reduction; hydrides.
[
12-14]
ions
, Fe catalyzed reductive amination has been
[11c,15-18]
poorly investigated to date.
The research
[16]
[17]
[18]
groups of Piarulli, Renaud and Beller recently
reported different examples of Fe-catalyzed reductive
amination (Scheme 1).
Amines represent a wide and important class of
organic compounds, present in almost 40% of the
registered active pharmaceutical principles (APIs) and
[1]
in 20% of commercial agrochemicals. Several
synthetic methodologies for their preparation have
been described so far, among which reductive
amination of carbonyl compounds is the first choice in
fine chemical industries, especially when the
preparation of secondary and tertiary amines is
[2]
required. Reductive amination reactions are based on
the formation of an imine (or an iminium ion)
intermediate from a carbonyl substrate and a
nucleophilic amine followed by a reductive step. The
most common reducing agents employed in this step
are: (i) metal hydrides as NaBH
4
, LiAlH4, or
[3]
NaBH (OAc) used in stoichiometric amounts, (ii)
3
molecular hydrogen (often at high pressure) in the
presence of homogeneous or heterogeneous noble
[4]
metal catalysts (i.e. Pd, Pt, Rh, Ir) or (iii) a hydride
generated from a hydrogen transfer process catalyzed
again by a noble metal. Although catalytic processes
are more sustainable with respect to the non-catalytic
[5]
Scheme 1. State of the art.[16-18]
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201701619
Tailor-made Fe carbonyl complexes in the presence of
2
Table 1. Optimization of reaction conditions.
H
gas (Beller’s method)[ and toluene (a non-
18]
ecofriendly solvent, Beller’s and Piarulli’s methods)
are yet required.[
16,18]
In addition, these approaches
[
13,18]
have been applied mainly to aromatic amines.
Herein, we present an alternative iron catalyzed and
hydrogen free method for the reductive amination of a
wide variety of aromatic and aliphatic aldehydes and
amines. Contrary to previously reported approaches
Convb
En.
Cat.
Reaction conditions
(equiv)
1a
Fe
3
(CO)12 CO (6.8 atm), iPrOH, MW
10
35
80
41
88
32
76
78
60
89
80
52
49
45
85
95
98
where Fe is used to activate H
2
, we were intrigued by
transient
(0.06)
100 °C, 20 min
the possibility to employ
a
2a,c
Fe
3
(CO)12 CO (6.8 atm), iPrOH, MW
hydridocarboferrate, generated from iron carbonyl
complexes in alkaline medium, as the hydrogen source
in the reducing step of reductive amination reactions.
The formation of carbonylhydridoferrates has been the
subject of several studies mainly directed toward their
stoichiometric applications in chemical reduction
reactions.[ Only few reductive processes catalyzed
by hydridocarboferrate have been described, some of
them requiring a CO atmosphere (from 1 to 100
atm).[
(0.06)
100 °C, 20 min
3a,c
Fe
3
(CO)12 CO (1 atm), iPrOH, 100 °C, 12 h
(
0.06)
Fe (CO)
0.06)
Fe (CO)
0.06)
4a,c
2
9
9
CO (1 atm), iPrOH, 100 °C, 12 h
(
5a,c
6c,d
7c,d
8c,d
9c,d
CO (1 atm), iPrOH, MW 100 °C,
20 min
2
19]
(
3 3
Fe (CO)12 PPh (0.4 equiv), TEA (0.4
(
0.2)
Fe
0.2)
Fe
0.2)
Fe
0.2)
Fe
0.2)
Fe (CO)12 DMAP (0.4 equiv), iPrOH, 12 h
0.06)
Fe (CO)12 DMAP (0.4 equiv), iPrOH, 12 h
0.04)
Fe (CO)12 NaOH (1 equiv), iPrOH, 12 h
0.04)
Fe (CO)12 NaOH (0.4 equiv), iPrOH, 12 h
0.06)
Fe (CO)12 NaOH (0.4 equiv), DMAP (0.4
0.04)
equiv), CO (1 atm), iPrOH, 12 h
19a]
3
(CO)12 DMP (0.4 equiv), TEA (0.4
Carbonylhydridoferrate can be easily generated
(
equiv), CO (1 atm), iPrOH, 12 h
starting rom Fe(CO)
5
in alkaline medium as reported
3
(CO)12 DMAP (0.4 equiv), CO (1 atm),
in equation 1.[
19a, 20]
(
iPrOH, 100 °C, 12 h
3
(CO)12 DMAP (0.2 equiv), CO (1 atm),
-
]- + CO
]- has obtained, the reductive
Fe(CO)
5
+ OH  [HFe(CO)
4
Eq 1
(
iPrOH, 12 h
1
1
1
1
1
1
1
1
0c,d
3
(CO)12 DMAP (0.4 equiv), iPrOH, 12 h
Once [HFe(CO)
4
(
potential of the carbonylhydridoferrates might be
exploited in an iron mediated reductive amination
1c,d
2c,d
3c,e
4c,e
5c,e
6c,e
7c,e
3
(
-
where water (the OH source) is the hydrogen donor, a
3
sustainable protocol with a potentially high impact on
amine synthesis.
(
3
We first investigated the possibility to perform a
(
reductive amination using Fe (CO)12 as precursor of
3
3
the hydridodecarboferrate. Following our previous
experience, the reaction of benzaldehyde with p-
anisidine was chosen as the model to explore reaction
conditions. 2-Propanol (i-PrOH) was selected as the
solvent as well as the potential hydride source, while
an excess of the amine was employed to guarantee the
alkaline medium. At first, the reaction was carried out
under CO atmosphere in order to stabilize the expected
catalytic species (Table 1, entry 1). The choice of
(
3
(
equiv), iPrOH, 12 h
Fe
3
(CO)12 NaOH (0.4 equiv), DMAP (0.4
(
0.04)
Fe (CO)
0.06)
equiv), iPrOH/H
NaOH (0.5 equiv), DMAP (0.2
equiv), iPrOH/H O (10:1), MW,
5 min
a] 1 (1 equiv), 2 (2 equiv), Fe complex 0.06 equiv; [b]
2
O (10:1), 12 h
2
9
(
2
1
[
Fe
3
(CO)12 was based on our previous successful
Conversion determined by GC/MS analysis; [c] The
reaction mixture was degassed before irradiation. [d] 1 (1
equiv), 2 (1 equiv), 100 °C. [e] 1 (1.5 equiv), 2 (1 equiv),
microwave-assisted
aminocarbonylation
of
ynamides.[ In the first attempt, p-anisidine 2 was
employed as both the reactant and the base, under
microwave (MW) irradiation. i-PrOH was the solvent
under CO atmosphere (6.8 atm) at 100 °C for 20
9b]
1
00 °C.
minutes and using 0.06 equivalents of Fe (CO)12. Only
3
Interestingly, when Fe
2
(CO) was used as Fe source,
9
a 10% conversion of 2 into product 3 was observed.
The presence of oxygen proved to be detrimental for
the catalytic process; in fact, an improvement in the
yields of 3 was observed when the reaction mixture
was degassed before heating (Table 1, entry 2). A
substantial increment from 35 to 80% conversion was
observed when the reaction was carried out in a sealed
tube charged with 1 atm of CO, and heated for 12 h at
an opposite behavior was observed. Convectional
heating (oil bath) led to 3 with 45% conversion while
8
1
8% conversion was obtained when 2 was reacted for
h at 100 °C under MW dielectric heating (Table 1,
entries 4-5).
Starting from these data, we further investigated the
reductive amination protocol in the presence of
Fe
heating and MW dielectric heating respectively (Table
, entries 6-17). Different solvents, additives and bases
3
(CO)12 or Fe
2
(CO)
9
both under convectional
100° C into an oil bath (Table 1, entries 2-3).
1
were employed and, in order to make the protocol
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201701619
sustainable and atom economic, the starting aldehyde
yield) methods. The scope of the reaction was finally
explored, and the results are summarized in Table 2.
1
and the amine 2 were used in equimolar ratio (for
additional experiments see Table S1). When a 1:1
mixture of PPh and TEA in the presence of Fe
0.2 equiv) and CO (1 atm) was used, the amine 3 was
obtained with 32% conversion in i-PrOH (Table 1,
entry 6). The use of DMAP instead of PPh led to 3
3
3
(CO)12
(
Table 2. Reaction scope.
3
with 76% conversion in iPrOH (Table 1, entry 7).
Additional improvements in the conversion were
observed when DMAP was used without TEA as
reported in entry 8. Lowering down the amount of
DMAP to less than 0.4 equiv, gave the formation of
[a
[b]
Entry
Carbonyl
compd.
Conv.
(Yield %)
Product
]
6
0% of amine 3 together with a 25% of unreacted
9
8%
imine 5 (Table 1, entry 9). Finally, based to the
observation that an increase in the CO pressure did not
have any effect on the conversion, a CO-free reaction
was investigated. Interestingly, under these conditions,
the amine 3 was still formed with 89% conversion
1
(93)
65%
40)
2
3
(
(
Table 1, entry 10). Thus, additional efforts were
undertaken to further optimize the CO-free reaction
Table 1, entries 11-17). With DMAP alone, the
amount of Fe (CO)12 could not be lowered to less than
mol% without a dramatic drop in the conversion
Table 1, entries 11-12). Analogously, replacement of
8
5%
(57)
(
3
9
9%
6
(
4
(95)
DMAP with NaOH decreased the conversion, even
using the higher amount of the iron carbonyl complex
85%
(53)
5
6
(
Table 1, entries 13-14). However, with a correct blend
of aqueous NaOH and DMAP, a final high conversion
of 1 and 2 into amine 3 was observed with both the
iron carbonyl complexes (Table 1, entries 15-17).
However, a strong link between the iron catalyst used
8
2%
(51)
and the heating source exists. In fact, whilst Fe
3
(CO)12
87%
(80)
7
worked well under convectional heating (oil bath,
00 °C 12 h), the safer unvolatile[ Fe
21]
1
2
(CO) gave
9
excellent conversion only under MW dielectric
heating at 100 °C for 10 min. This different behavior
may be related to the different stability interaction with
83%
(60)
8
9
8
0%
MWs: Fe
3
(CO)12 generates local hot spots during MW
(CO) . The behavior of the two
(52%)
heating contrary to Fe
2
9
complexes in microwave rotational spectroscopy is
also very different,[ suggesting a diverse heating
profile during MW irradiation. Looking to the
electrons exchanged during the red-ox process, the
8
0%
22]
1
0
(40)
90%
(65)
-
11
reductive amination requires 2 e for each imine
molecule. As Fe-
3
(CO)12 may potentially transfer a
maximum of 30 e , 1 mole of the metal complex may
process a maximum of 15 moles of imine. Thus, a
catalytic process should require less than 6.7 mol% of
95%
(77)
1
1
2
3
7
6%
Fe
3
(CO)12 or, 9.1 mol% of Fe
2
(CO) . Although a
9
(62)
complete electron exchange is not plausible, the
minimum amount required for high conversion was 4
8
1%
mol% of Fe
3
(CO)12 and 6 mol% of Fe
2
(CO)
9
proving
14
15
(69)
that the reaction is not a stoichiometric iron complex
reduction. Optimized conditions for 98% conversion
of 1 and 2 (equimolar) into amine 3 were 6 mol% of
6
4%
(47)
Fe
2
(CO) , 0.4 equiv of DMAP in i-PrOH/water,
9
alkalinized with 0.4 equiv of NaOH, as solvent and
hydride source, at 100 °C for 15 min under MW
dielectric heating. Following these conditions,
compound 3 was obtained in comparable yields with
4
8%
1
6
(41)
5
(39)
3%
18
16
17
respect to Beller’s (97% yield) and Piarulli’s (99%
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201701619
[
a] Carbonyl compound (1.5 equiv), amine (1 equiv),
Fe (CO) (0.06 equiv), NaOH (0.5 equiv), DMAP (0.2
equiv), i-PrOH/H O (10:1), MW, 100 °C, 15 min. [b]
In conclusion, a sustainable iron catalyzed and
hydrogen free protocol for the reductive amination of
amines and aldehydes has been developed. This
procedure is more sustainable than standard metal
catalyzed reductive amination reaction as it counts on
the catalysis of the biocompatible safe iron carbonyl
2
9
2
Conversion was determined by GC/MS analysis while
yields refer to isolated and fully characterized compounds.
complex with i-PrOH/H O.
2
Non-enolizable aldehydes (precursors of products 3-
1
1) gave acceptable to good yields of the
corresponding secondary and tertiary amines (Table 2).
The only exception was represented by the less
nucleophilic p-fluoro aniline, although compound 4
was isolated in 40 % yield (Table 2, entry 2).
Enolizable aldehydes could be also used in this
reaction leading to products 12-14 with good
conversions (Table 2, entries 10-12). Particularly,
compound 13 was obtained in comparable yields with
respect to Renaud’s17 protocol. The reaction
conditions are compatible with the presence of a
double bond (Table 2, entry 13) and an aqueous
solution of formaldehyde can be used for methylation
of a primary amine (Table 2, entry16). Ketones react
also although with low conversion/yield (Table 2,
entries 15 and 17). As expected, the reaction follows
the general trend of reductive amination that occurs
with better yields when non-enolizable carbonyl
compounds and electronrich aromatic amines were
employed. All the reaction in Table 2 were performed
using Fe
2
(CO)
9
under MW dielectric heating. Reaction
(CO)12 (0.04 equiv) under
yields using Fe
3
convectional heating are reported in SI.
Before the proposal of a convincing mechanism, the
possibility of a radical process was excluded as the
reaction worked well in the presence of radical
scavenger BHT. Then, a study on deuterium
Scheme 2. Proposed reaction mechanism (exemplified with
Fe(CO)
5
)
incorporation was carried out with D
SI). Maximum deuterium incorporation (93%) was
observed when both deuterated reagents were
employed, while with H O and i-PrODd a 20% of the
deuterated amine was obtained. Although D O (or
2
O and i-PrODd
8
(
The scope of the reaction is wide, and the protocol may
be applied to both aliphatic and aromatic amines as
well as to enolizable and non-enolizable aldehydes.
Finally, the reaction can be carried out in short reaction
times and the products can be isolated after simple
filtration on a silica pad.
2
8
2
-
OD ) seems to be the major hydride source, i-PrOH
was oxidized to acetone, identified in the final reaction
mixture. On the other hand, DMAP seems to be also
required for a high yield reductive amination.
Based on these observations, the proposed mechanism
is described in Scheme 2. In a first step, the Fe
carbonyl and NaOH react generating the
Experimental Section
carbonylhydridoferrate
intermediate
A
with
General
methoxyphenyl)benzylamine (3): MW dielectric heating.
in a MW tube, under N atmosphere and under stirring,
Fe (CO) (29 mg, 0.08 mmol) is solubilized in a mixture of
i-PrOH (2.5 ml) and water (0.25 ml). The mixture is
degassed by sonication bubbling N for 3 min. NaOH (40
mg, 1 mmol) is added and the mixture left under stirring for
minutes. benzaldehyde (212 mg, 2 mmol), p-anisidine
procedure
to
obtain
N-(4-
concurrent elimination of a molecule of CO
2
(step i in
Scheme 1). The active catalyst A transfers the hydride
ion to the in situ formed imine B that is immediately
2
2
9
protonated by H O producing the expected amine C
2
2
and NaOH (step ii). At the same time, DMAP yields
complex D, which reacts with NaOH, regenerating A
and DMAP N-oxide (step iii). DMAP is finally
recycled through a (Fe catalyzed) reduction mediated
5
(
246 mg, 2 mmol) and DMAP (49 mg, 0.4 mmol) are added
to the reaction mixture. The tube is then inserted in a MW
cavity and heated for 15 minutes at 100 °C, using a
maximum power of 150 W (max internal pressure set at 250
by i-PrOH, thus producing acetone and H O (steps iv
2
psi). After cooling, the mixture is diluted with CH
2
Cl
2
, dried
and v). This mechanism agrees with the results of the
deuterium incorporating experiments and with a final
redox balance utilizing i-PrOH as reducing agent (the
scheme relating to the mechanism with deuterated
reagents is reported in SI).
over dry Na SO , filtered and the solvent removed under
2 4
vacuum. The residue is dissolved into dimethoxyethane (5
mL) and passed through a short path of silica. Evaporation
of the solvent gave product 3 (429 mg, 93% yield), m.p. 48-
[
23]
5
0°C, lit m.p. 49-50 °C.
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201701619
2
Convectional heating: in a sealed tube, under N atmosphere
Pizzetti, A. Russo, E. Petricci, Chem. Eur. J., 2011, 17,
3
and under stirring, Fe (CO)12 (60 mg, 0.12 mmol) is
4
523-4528; c) M. D. Greenhalgh, A. S. Jones, S. P.
solubilized in a mixture of i-PrOH (2.5 ml) and water (0.25
ml). The mixture is degassed by sonication bubbling N for
Thomas, P. Stephen , ChemCatChem, 2015, 7, 190-222.
[10] a) D. Toulemon, B. Pichon, C. Leuvrey, S. Zafeiratos,
V. Papaefthimiou, X. Cattoen, S. Begin-Colin, Chem.
Mater., 2013, 25, 2849-2854; b) S. J. Perez, M. Purino,
P. O. Miranda, V. S. Martin, I. Fernandez, J. I. Padron,
Chem. Eur. J., 2015, 21, 15211-15217; c) J. M. Hoyt, V.
A. Schmidt, A. M. Tondreau, P. J. Chirik, Science, 2015,
2
3
min. NaOH (40 mg, 1 mmol) is added and the mixture left
under stirring for 5 minutes. benzaldehyde (212 mg,, 3
mmol), p-anisidine (246 mg, 2 mmol) and DMAP (49 mg,
0
.4 mmol) are added to the reaction mixture. The reaction
mixture is heated under stirring for 12 h at 130 °C (external
bath temperature, internal temperature previously
determined for these conditions 100 °C). After cooling, the
2 2 2 4
mixture is diluted with CH Cl , dried over dry Na SO ,
3
49, 960-963; d) M.-N. Zhao, L. Yu, R.-R. Hui, Z.-H.
Ren, Y.-Y. Wang, Z.-H. Guan, ACS Catal. 2016, 6,
473–3477.
filtered and the solvent removed under vacuum. The residue
is dissolved into dimethoxyethane (5 mL) and passed
through a short path of silica. Evaporation of the solvent
gave product 3 (387 mg, 91% yield), m.p. 48-50°C.
3
[
11] a) B. Plietker, Iron catalysis in organic chemistry:
reactions and applications, Wiley-VCH, Weinheim,
2
008; b) C. Bolm, J. Legros, J. Le Paih, L. Zani, Chem.
Acknowledgements
Rev. 2004, 104, 6217-6254; c) C. P. Casey, J. B. Johnson
J. Am. Chem. Soc., 2005, 127, 1883–1894; d) C. P.
Casey, H. Guan J. Am. Chem. Soc., 2007, 129, 5816–
Dipahrma Francis srl (Milan, I) is gratefully acknowledged for
financial support. EP thanks italian Ministero dell'Istruzione,
dell'Università e della Ricerca (MIUR) for financial support
5
817; e) C. P. Casey, H. Guan J. Am. Chem. Soc., 2009,
131, 2499-2507; f) A. Fürstner, Angew. Chem. Int. Ed.,
009, 48, 1364-1367; g) K. Junge, K. Schrꢀder, M.
(
PRIN2015LZE994). MIUR is also acknowledged for financial
support through the program “Dipartimenti di Eccellenza - 2018-
022”.
2
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Huang, M. Arndt, K. Gooßen, H. Heydt, L. J. Gooßen,
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UPDATE
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