Direct Reductive Amination of Camphor Using Iron Pentacarbonyl as Stoichiometric Reducing Agent: Features and Limitations

Article abstract of DOI:10.1002/ejoc.202001087

The method of direct reductive amination of camphor and fenchone was proposed. The most effective reducing agent is iron carbonyl. No ligands or solvents are needed. The stereochemistry of the corresponding products was determined by HMBC, HSQC, and NOESY

Full text of DOI:10.1002/ejoc.202001087

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Direct reductive amination of camphor using iron pentacarbonyl
as stoichiometric reducing agent: features and limitations
Authors: Oleg I. Afanasyev, Artemy R. Fatkulin, Pavel N. Solyev, Ivan
Smirnov, Artem Amangeldyev, Sergey E. Semenov, and
Denis Chusov
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001087
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0
1/2020

European Journal of Organic Chemistry
10.1002/ejoc.202001087
COMMUNICATION
Direct reductive amination of camphor using iron pentacarbonyl
as stoichiometric reducing agent: features and limitations
[
a]
[a]
[b]
[c]
[c]
Oleg I. Afanasyev, Artemy R. Fatkulin, Pavel N. Solyev, Ivan Smirnov, Artem Amangeldyev,
[
c]
[a]
Sergey E. Semenov, and Denis Chusov*
[
a]
A.R. Fatkulin, Dr. O.I. Afanasyev, Dr. D. Chusov
A.N.Nesmeyanov Institute of Organoelement Compounds of Russian Academy of Sciences,
8 Vavilova St., 119991 Moscow, Russian Federation
2
E-mail: denis.chusov@gmail.com
[
b]
c]
Dr. P.N. Solyev
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences
32 Vavilova St., 119991 Moscow, Russian Federation
[
Ivan Smirnov, Artem Amangeldyev, Sergey E. Semenov
Moscow South-Eastern School named after V.I. Chuikov (Moscow Chemical Lyceum),
4
Tamozhenniy proezd, 111033 Moscow, Russian Federation
Supporting information for this article is given via a link at the end of the document.
Abstract: The method of direct reductive amination of camphor and
fenchone was proposed. The most effective reducing agent is iron
carbonyl. No ligands or solvents are needed. The stereochemistry of
the corresponding products was determined by HMBC, HSQC, and
NOESY spectra. The limitations of the method were shown. The
reaction of camphor with primary amines led to exclusively exo
product, while the reaction of fenchone led to exclusively endo product.
The reaction of camphor with cyclic amines led to the mixture of endo
and exo isomers.
There is no universal approach, and almost every manuscript
reports some particular protocol different from others.
Terpenoids are an irreplaceable class of natural products as well
as chemical motifs. The camphoryl group is an important moiety
in the structure of chiral ligands for asymmetric synthesis catalysis
or it can be used as an auxiliary group in asymmetric
synthesis.[
1][2][3][4][5][6]
The usage of fenchone based molecules for
asymmetric catalysis and synthesis is less common because of
the difficulty of fenchone modifications due to steric hindrance.[7,8]
Camphor is
a readily available starting molecule for the
preparation of different compounds with biological activity. For
example, camphor diimines demonstrate antiviral activity.[9][10][11]
Fenchonyl amine-based molecules are potential therapeutic
agents for the treatment of Alzheimer’s disease.[12]
Amines are a crucial class of organic compounds with multiple
academic and industrial applications. There are a plethora of
synthetic approaches towards amines synthesis and
modifications,[13] reductive amination being one of the most
powerful and useful methods. Literature analysis revealed that the
production of 21% of the most popular and commercially
successful drug substances can be achieved using the reductive
amination in one or multiple steps.[14]
However, the reductive amination of camphor and fenchone
remains a challenge. A standard approach to reductive amination
with amines other than ammonia and methylamine includes two
steps: preparation of azomethines or Schiff bases in the presence
of strong Lewis acids and their reduction with more or less
conventional reducing agents (Scheme 1, a).[15] The synthesis of
fenchonyl amines is even more challenging. Hydroxylamine or
formamide are the largest molecules that can be added to
fenchone, so the synthesis of amines requires up to four steps.[16]
Scheme 1. Reductive amination of camphor
In most cases, the first stage of this process requires quite harsh
conditions. For example, the preparation of a Schiff base from
camphor and 1-phenylethylamine requires 5-10 days of heating
at 150°C.[17][18] Schiff bases of other primary amines could be
prepared under similarly harsh conditions.[1][2][19][20][21][11][22]
Preparation of enamines is possible using titanium tetrachloride
[23]
as a catalyst. The reduction also might be challenging. Sodium
borohydride or sodium cyanoborohydride was described as
suitable for this goal in several reports.[17][18][19][20] Several other
reports describe the application of a combination of sodium
borohydride with nickel or cobalt chlorides.
[1][2][11][24]
Some of the
groups use combinations of anhydrous chloroform, anhydrous
1
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European Journal of Organic Chemistry
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methanol, and anhydrous nickel chloride or 20 fold excess of
sodium borohydride with 4 fold excess of nickel chloride. To the
best of our knowledge, no papers describe any general approach
for the direct reductive amination of camphor or fenchone. There
is only one example of camphor direct reductive amination without
an external hydrogen source using carbon monoxide as a
reducing agent.[25] This protocol is very efficient but its application
is limited by the necessity of carbon monoxide and high-pressure
equipment for the reaction setup.
Herein, we tried to find a general approach for the direct reductive
amination of camphor and fenchone. We started with classical
borohydrides as reducing agents. We tried sodium borohydride
and sodium triacetoxyborohydride in the direct reductive
amination of camphor (see SI). However, no desired product was
detected even when camphor and amine were premixed and
heated with titanium(IV) isopropoxide. The only product of this
process was camphoryl alcohol. Since the triacetoxyborohydride
is a more selective reagent we hoped that only C=N double bond
would be reduced. However, when the reaction was performed
with p-anisidine, the Schiff base was detected but there was not
even a trace of the desired amine. When pyrrolidine was chosen
as an amine the desired product was not formed as well.
Balancing efficiency in the reductive amination of sterically
hindered ketones and the convenience of synthetic protocols, iron
pentacarbonyl was selected as a reagent of choice. Iron
pentacarbonyl is an underestimated reagent with a high potential
for use in organic chemistry.[26] It is a multiton industrial compound
being used in iron production. Its price is comparable to the price
of some HPLC solvents, and it is readily available all over the
world. The applicability of iron pentacarbonyl for the reductive
modifications of carbonyl compounds was earlier demonstrated
by our group.[
27][28][29]
In particular, it was found that iron
pentacarbonyl is a very efficient reducing agent in the reductive
amination of highly inert ketones like benzophenone.[29] In
addition, there are a lot of iron-based catalysts applicable in
reductive amination using different reducing agents e.g. silanes,
hydrogen, formates, etc.[30][31][32] Therefore, we concluded that
iron pentacarbonyl could be applied for the reductive amination of
camphor.
Scheme 2. Substrate scope for the reductive amination of camphor and
fenchone. Isolated yields and temperature regimens. The diastereomeric ratio
was determined by GC or by NMR. Detailed experimental conditions with full
characterization of all the resulting products are provided in SI. [ GC yield.
a]
A broad set of amines was investigated. The results are provided
(
Scheme 2, Scheme 5). The developed protocol can be applied
to the reductive amination of camphor with a variety of primary
and secondary aliphatic amines. A principle difference in reactivity
of secondary and primary amines was noted. Cyclic secondary
amines react with camphor leading to the target molecules, and
in most cases, conversion of camphor is almost the same as the
yield of the product. Less nucleophilic amines require a higher
temperature
of
the
reaction:
pyrrolidine
(1a)
and
hydroxypyrrolidine (1b) react at 100°C while less nucleophilic
tetrahydroisoquinoline reacts only at 140°C (1c) and morpholine
2
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European Journal of Organic Chemistry
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COMMUNICATION
requires heating at 160°C (1d). The reaction of morpholine at
140°C leads to 1d only in 40% yield vs. 62% at 160 °C.
In the case of primary aliphatic amines, a side transamination
process was noted at elevated temperatures (Scheme 3). Two
molecules of amine react with each other giving the symmetrical
secondary amine and ammonia. This secondary amine reacts
with iron carbonyl giving formamide 4 (the possible mechanism is
provided below on the Scheme 4). Ammonia reacts with camphor
under reductive conditions giving corresponding primary amine,
which also undergoes formylation leading to formamide 3. This
process is negligible at 100°C, but increasing the temperature
increases its role. At 160°C the ratio 3:2 achieves 1:1 and higher.
Scheme 3. Transamination of primary aliphatic amines
100°C is usually enough for amination with the majority of primary
aliphatic amines (1f, 1g, 1i, 1j, 1k, 1l, 1n). In some cases, with
increased sterical hindrance higher temperature is required (1h,
1m). Benzylamine allows the formation of the target product with
64% yield (1h) while 1-naphtylethylamine reacts only with a yield
of 34% under the same conditions. Further increasing of the
temperature leads to the transamination of starting amine, so it
does not improve the yield of the target product. The increased
steric hindrance in ketones results in a significant drop of the yield.
E. g. fenchone might be used as a carbonyl component only at
elevated temperatures and with the low yield (1p). However, to
the best of our knowledge, it is the only example of direct
reductive amination of fenchone.
Noteworthy, these reaction conditions tolerate different functional
groups that might be unstable under strongly acidic conditions
used in the classical approach. For example, the heterocycle (1n)
or the acetal group (1k) are tolerated. The ω-hydroxyl group in the
alkylamine structure is also tolerated, although it slightly
decreases the yield in comparison to a similar substrate without
the hydroxyl group (1l vs. 1f). However, the reaction with 3-
hydroxypyrrolidine leads to essentially the same yield as with
pyrrolidine (1a vs. 1b). This fact could be assigned to the
possibility of complexation of iron with amine as an N,O-bidentate
ligand. The formation of the iron complex with hydroxypyrrolidine
is much less probable compared to a similar complex with 6-
aminohexan-1-ol, thus, the reductive amination with the latter is
less efficient.
Figure 1. Assignment of the structure of 1h.
All tested primary amines react with the selective formation of the
single diastereomer, while cyclic secondary amines usually lead
to the formation of the mixture of two adducts with the ratios from
4:1 to 1.8:1. To determine the structure of these products HMBC,
HSQC, and NOESY spectra were registered for the synthesized
compounds. All the characterization data is provided in SI; as an
example here we describe the structure assignment of 1h.
According to HSQC and HMBC spectra (Figure 1, a, b), the
signals of methyl groups could be assigned: CH
corresponds to signals at 0.92 ppm in the H spectrum and 11.89
ppm in the 13C spectrum. According to HMBC, this methyl group
3
(C10)
1
3
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European Journal of Organic Chemistry
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has cross-peaks with the following signals in the 13C spectrum:
analysis of NMR correlation spectra for all isolated products
revealed that primary amines react with camphor with the
exclusive formation of exo-adducts. Fenchone reacts with
phenylethylamine leading to endo-adduct. Secondary amines
lead to the formation of the mixture of endo- (major) and exo-
(minor) isomers. There is only one exception: the selective
formation of the endo-adduct in the case of 2-(piperazin-1-
yl)pyrimidine (product 1o).
36.78 ppm, 47.45 ppm, and 68.18 ppm. The latter corresponds to
C2, which has a cross-peak with the multiplet at 2.62 ppm in the
1
H spectrum. The signal at 47.45 ppm has a lower intensity in
comparison with other 13C signals, so it should be quaternary
carbon C1. Therefore, the signal at 36.78 ppm corresponds to C6.
This resonance has a cross-peak in the HSQC spectrum with the
multiplet at 1.08 ppm. As we see the definite cross-peak between
signals at 1.08 and 2.62 ppm in the NOESY spectrum (Figure 1,
c), we conclude that the configuration of 1h is exo. Accurate
Scheme 4. The difference in the reductive amination with primary and secondary amines.
This fact indicates the two different ways for the reductive
amination with primary and secondary amines (Scheme 4).
Primary amine reacts with camphor via the Schiff base formation
and water release. Then this intermediate undergoes reduction by
4
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European Journal of Organic Chemistry
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iron carbonyl hydride complex. The re face attack is hindered by
two methyl groups in the camphoryl moiety, therefore, the si face
attack is preferred leading to the selective formation of the exo-
adduct.
The amination of fenchone has an opposite selectivity. Si face
attack is hindered by -CH
preferred as this side is shielded by only one CH
Therefore selective formation of endo-adduct is observed.
2
CH
2
- fragment, while re face attack is
2
group.
In the case of secondary amines, there are two possible
hemiaminal intermediates reversibly forming from camphor and
amine. The exo-hemiaminal is less stable due to the sterical
hindrance, so, the major intermediate is the endo-hemiaminal. Its
deoxygenation with iron carbonyl leads to the preferable
formation of the endo-adduct. In the case of reaction with the
bulky secondary amine 2-(piperazin-1-yl)pyrimidine the sterical
hindrance is very high and the exo-adduct is not formed in any
detectable quantities.
We suppose that in the case of secondary and primary amines
there is a different mechanism of reduction with the iron carbonyl.
In both cases at the beginning of the reaction iron carbonyl reacts
with an amine (Scheme 4). Such transformations are described in
the papers of Bulkin et al.[33–35] According to these reports, the
amine reacts with iron carbonyl leading to the intermediate
formation of compound A. In the absence of water it decomposes
to the iron carbonyl amine complex and the corresponding
formamide. This iron carbonyl amine complex serves as a
deoxygenating agent for the hemiaminal. In the presence of water
Scheme 5. Limitations of iron carbonyl promoted reductive amination of
camphor
To sum up, the direct reductive amination of camphor and
fenchone with iron carbonyl as a reducing agent has been
investigated. The scope and limitations of this approach were
described, the stereochemistry was confirmed. The sterically
hindered fenchone can be used as the starting material but the
yield of the product is low. This protocol allows reductive
amination with primary and cyclic secondary aliphatic amines
leading to the formation of camphorylamines with moderate to
good yields. In the case of secondary amines, a mixture of
diastereomers forms with endo-isomer as a major, while primary
aliphatic amines lead to the selective formation of exo-isomers.
(
side product of Schiff base formation in the case of primary
amines) A is transformed to the tetracarbonylhydridoferrate (in
the absence of inorganic hydroxides this process was described
by Bulkin et al. [33–35] or by Yamashita et al.[36]; in the presence of
NaOH or KOH it is a well-known process (Hieber reaction)) which
is a well-known reducing agent able to reduce Schiff base to the
amine.[37]
However, the developed protocol has some limitations (Scheme
Acknowledgements ((optional))
5). It cannot be applied for amination with aromatic amines, even
with electron-donating groups: product 2a was formed in a very
low yield even under heating at 200°C. The reason is a reduced
nucleophilicity of these compounds. Another type of amines that
cannot be introduced to this reaction is secondary acyclic amines.
Diethylamine and methyl benzylamine do not react with camphor
under these conditions (2b, 2c): camphor has been recovered
from these reaction mixtures. Very high sterical hindrance is also
a limitation. Tert-butylamine does not react with camphor under
the standard conditions. Reductive amination with ammonia and
its synthetic equivalents is also impossible under these conditions.
Gaseous ammonia on its own or formed in situ by the
decomposition of ammonia carbonate does not react with
camphor.
The work was financially supported by the Russian Science
Foundation (grant # 16-13-10393). NMR studies were performed
with the financial support from the Ministry of Science and Higher
Education of the Russian Federation using the equipment of the
Center for molecular composition studies of INEOS RAS. HPLC-
HRMS studies conducted by Dr. Pavel N. Solyev were supported
by the Program of fundamental research for state academies for
2013−2020 (No. 01201363818)
Keywords: reductive amination • camphor • fenchone • iron
carbonyl • no external hydrogen source
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Entry for the Table of Contents
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The direct reductive amination protocol of camphor and fenchone was developed. Scope and limitations of this protocol were studied.
Primary amines react with high selectivity while secondary cyclic amines lead to a mixture of endo-(major) and exo-(minor) adducts
with a good to moderate yields.
Key topic: Camphor amination
Institute and/or researcher Twitter usernames: @chusovgroup
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