Hydrogen-free reductive amination using iron pentacarbonyl as a reducing agent

Article abstract of DOI:10.1039/c7ob02795h

We developed solvent-free reductive amination without an external hydrogen source using iron pentacarbonyl as a reducing agent. Neither a catalyst nor any other additives were employed. Various types of substrates are suitable for the reaction, including

Full text of DOI:10.1039/c7ob02795h

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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DOI: 10.1039/C7OB02795H
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Hydrogen-Free Reductive Amination Using Iron Pentacarbonyl as
a Reducing Agent
Oleg I. Afanasyev,a Dmitry L. Usanov,b Denis Chusov*,a,c
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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We developed solvent-free reductive amination without an reductant.3 From the economic and ecological points of view,
external hydrogen source using iron pentacarbonyl as a reducing iron pentacarbonyl seemed to be the best choice since
agent. Neither a catalyst nor any other additives were employed. elemental impurities of iron in pharmaceutical products are
Various types of substrates are suitable for the reaction, including much less stringently regulated by the corresponding
those with low reactivity, e.g. benzophenone. Among others, the authorities (e.g. FDA) than most other d-metals due to lower
protocol tolerates bromo-, cyano-, benzyloxy-, pyrimidyl and styryl intrinsic toxicity of iron.5 Moreover production of iron
moieties.
pentacarbonyl exceeds thousands of tons per year and it is the
least expensive metal carbonyl available.6 Iron tetracarbonyl
dihydride is a well-known reducing agent; however, it rapidly
Selective and step-economical syntheses of complex molecules
from starting materials easily available in bulk quantities are
highly important from economic and environmental points of
view. Such protocols should naturally tolerate a variety of
functional groups, so that extra steps of introduction and
removal of protective groups can be avoided. Recently, we
decomposes at temperatures above -20
°
C.7 The sodium salt
is more stable, but is not commercially available and requires
highly basic conditions for the synthesis, which can lead to
narrower substrate scope.4 Herein, we describe the protocol
for reductive amination which employs nothing but starting
materials and iron pentacarbonyl. No solvent or external
hydrogen source is needed.
have developed
a series of methods for hydrogen-free
reductive addition using carbon monoxide1 as a reducing
agent.2 Starting from aldehydes or ketones, this approach can
lead to various classes of compounds, including amines,2b
amides, esters,2e,f pyrrolidines,2a and nitriles.2f These
transformations are usually highly selective and tolerate the
presence of aromatic and aliphatic nitrile groups,2f esters,2c
phenols,2b carboxybenzyl (Cbz),2b trifluoroacetamido2b, N-
benzyl2a, O-benzyl2d, aromatic fluoro-2f, chloro-2d and bromo-
moieties,2a cyclopropanes, and even aromatic nitro-groups.2b
Selectivities of these reductive aminations usually appreciably
exceed those of standard reductive agents, such as sodium
cyanoborohydride.2b The natural limitation for the
employment of these methods in laboratory is the necessity to
use a carbon monoxide cylinder. In this context, we decided to
develop a homogeneous alternative with CO in a chemically
bound form, e.g. using a metal carbonyl complex as a
We chose morpholine and p-tolylaldehyde as model
substrates. In light of the fact that iron pentacarbonyl is a
liquid, improvement of the environmental profile of the
reaction by the use of solvent-free conditions seemed very
interesting. Thus, we heated the reaction components at 90
°
C for 4 hours and did detect formation of product 1a (Table 1,
entry 1). The temperature influence was found to be
important in the range up to 130
°C (Table 1, entry 1-3); at
higher temperatures no significant yield variability was found
(Table 1, entry 3-6). When the amount of the carbonyl was
decreased from three to two equivalents, no significant
changes were observed (Table 1, entry 3 vs. 8). If the amount
of the carbonyl was further decreased, the yield significantly
dropped (Table 1, entry 1 vs. 9-11). When the amount of the
starting amine (see supporting information) was increased to
three equivalents, the yield increased up to 86% with reaction
time of four hours.
With these results in hand, we proceeded to investigation
of the substrate scope of the developed methodology under
the optimized reaction conditions (Figure 1).
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Table 1 Investigation of the effects of the amount of iron well and furnished product 1n in 89% yield without the need
pentacarbonyl and temperature on reductive amination.
for any chromatographic isolation (Scheme 1).
Figure 1 Studies on the substrate scope.
O
N
O
O
O
N
N
N
Entrya
Fe(CO)5, eq.
T, °C
90
yield % b
14
Br
OMe
1
2
3
3
OBn
110
130
150
160
180
130
130
130
130
130
26
1a
, 86%
1b
, 70%
1c
1d
, 92%
, 77%
3
3
41
O
O
4
3
40
N
N
5
3
41
N
6
3
44
O
O
1e
, 75%
1f
1g
, 85%
, 75%
7
5
51
8
2
44
N
N
9
1
24
HN
N
N
N
N
10
11
0.5
0.2
15
11
a
0.2 mmol scale. 1.5 eq. of morpholine were used. Yields were
1i, 78%b
1j, 85%c
1k, 87%d
1h
, 88%
determined by GC. Tol = p-methylphenyl.
A wide range of aldehydes could be successfully employed,
including those containing various functional groups prone to
N
N
N
reduction by dihydrogen. For example, benzyloxy moiety (1b)
,
aromatic bromides (1c) and aromatic nitriles (1l) can be
tolerated. Aliphatic aldehydes are known to undergo self-aldol
reaction catalyzed by amines (especially secondary aliphatic
amines);8 however, under our reaction conditions reductive
amination product 1d was isolated in excellent yield. Whereas
ketones are usually much less reactive in reductive amination,
CN
c
e
c
1l
1m
1n
, 70%
, 72%
, 69%
a
Solvent-free conditions. 3 equivalents of Fe(CO)5 and amine were
employed. 4 h at 130 °С. b 2 equivalents of amine were employed. 140
°С. c Room temperature. 12 hours. d 140 °С. e 90 °С. 12 hours.
our methodology worked well with aliphatic ketones 1e-f
.
Acetophenone could be converted into product 1h with
isolated yield of 88%. Moreover, even as unreactive ketone as
2-adamantanone 1g successfully furnished the product in 85%
yield. Besides morpholine, other type of tested amines
underwent the desired transformation 1i-k in high yields. The
optimum reaction temperature was clearly dependent on the
nucleophilicity of the starting amine. For piperazine and
pyrrolidine the reaction proceed well even at room
Scheme 1 Scaled-up synthesis of N-adamantyl-pyrrolidine at
room temperature.
temperature (1j, 1l, 1k). Other type of amines also could react
at room temperature; however the reaction time should be
more than 4 hours. We were surprised to found that even
benzophenone could be successfully employed: after 12 hours
In conclusion, we have showed that the concept of
hydrogen-free reductive amination can be expanded to metal
carbonyls as reducing agents, which can lead to the more
selective approaches in organic synthesis. The synthetic value
of the developed methodology was demonstrated by efficient
preparation of a representative range of amines including
clean gram-scale synthesis not requiring chromatographic
purification. The reaction proceeds well even in case of poorly
reactive ketones such as benzophenone.
at 90
°C product 1m was isolated in 69% yield. The protocol is
so mild that we isolated compound 1n without any side
reactions on the styryl moiety.
The scalability and preparative utility of the developed
methodology was exemplified on the synthesis of N-
adamantylpyrrolidine. Despite the lower intrinsic reactivity of
2-adamantanone with respect to less sterically challenged
substrates, a gram-scale reaction with pyrrolidine proceeded
2 | J. Name., 2012, 00, 1-3
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We gratefully thank Professor Terent`ev A.O. and Dr. Vil` V. for (7) (a) Krumholz, P.; Stettiner, H. M. A. J. Am. Chem. Soc. 1949, 71, 9,
the inspiring us to work with iron carbonyl. This work was 3035; (b) Rittmeyer, P.; Wietelmann, U. In Ullmann’s Encyclopedia of
supported by the Russian Foundation for Basic Research (15-03- Industrial Chemistry; Wiley-VCH Verlag GmbH & Co. KGaA, 2000
02548). D.C. thanks the Ministry of Education and Science of the (8) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007,
Russian Federation (Agreement number 02.a03.21.0008). The 107, 12, 5471.
contribution of Center for molecule composition studies of INEOS
RAS is gratefully acknowledged.
Notes and references
1
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(5) www.fda.gov US Pharmacopeia general chapter <231>.
(6) The carbonyls can be purchased from Sigma-aldrich. Fe(CO)5 231
USD/kg (0.23 USD/g); Mn2(CO)10 109 USD/50g (2.18 USD/g); Mo(CO)6
1322 USD /500 g (2.64 USD/g); Co2(CO)8 1532 USD/500g (3.06 USD/g);
W(CO)6 456 USD/100g (4.56 USD/g); Cr(CO)6 498 USD/100g (4.98 USD/g).
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