Highly Selective Ruthenium-Catalyzed Direct Oxygenation of Amines to Amides

Article abstract of DOI:10.1002/chem.201705601

Reports on aerobic oxidation of amines to amides are rare, and those reported suffer from several limitations like poor yield or selectivity and make use of pure oxygen under elevated pressure. Herein, we report a practical and an efficient ruthenium-catalyzed synthetic protocol that enables selective oxidation of a broad range of primary aliphatic, heterocyclic and benzylic amines to their corresponding amides, using readily available reagents and ambient air as the sole oxidant. Secondary amines instead, yield benzamides selectively as the sole product. Mechanistic investigations reveal intermediacy of nitriles, which undergo hydration to afford amide as the final product.

Full text of DOI:10.1002/chem.201705601

A Journal of
Accepted Article
Title: Highly Selective Ruthenium Catalyzed Direct Oxygenation of
Amines to Amides
Authors: Debabrata Maiti, Goutam Kumar Lahiri, Ritwika Ray, Arijit
Singha Hazari, and Shubhadeep Chandra
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To be cited as: Chem. Eur. J. 10.1002/chem.201705601
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Highly Selective Ruthenium Catalyzed Direct Oxygenation of
Amines to Amides
Ritwika Ray,* Arijit Singha Hazari, Shubhadeep Chandra, Debabrata Maiti,* and Goutam Kumar
Lahiri*[a]
Abstract: Reports on aerobic oxidation of amines to amides are rare,
and those reported suffer from several limitations like poor yield or
selectivity and make use of pure oxygen under elevated pressure.
Here we report a practical and an efficient ruthenium catalyzed
synthetic protocol that enables selective oxidation of a broad range
of primary aliphatic, heterocyclic and benzylic amines to their
corresponding amides, using readily available reagents and ambient
air as the sole oxidant. Secondary amines instead, yield benzamides
selectively as the sole product. Mechanistic investigations reveal
intermediacy of nitriles which undergo hydration to afford amide as
the final product.
Amides are one of the most important class of compounds due
to their versatility as intermediates in organic synthesis and their
applicability as raw materials in polymer industry.[1] Significant
attention has therefore been given towards the development of
viable methods for their synthesis.[2] Among them, direct
oxygenation of the -methylene group of amine to produce
amide is much preferred given the easy accessibility of amines
through a wide variety of chemical transformations.[3] However,
reports on direct oxidation of amines to amides in high yield or
selectivity are rare which is primarily due to higher reactivity of
the NH2-group with respect to the methylene -carbon.[4] With
few exceptions, the reported procedures for -oxygenation of
amines require stoichiometric amount of oxidants such as
tBuOOH,[4a] RuO4,[4b] iodosobenzene,[4c] and PhCO3tBu.[4d] In this
regard, Mizuno and coworkers developed a heterogeneous
system involving a Ru/Al2O3 catalyst for the aerobic oxidation of
primary amines to amides.[4f] However, they performed the
reactions in an autoclave under pressurized oxygen (5 atm) and
at an elevated temperature (130-160 oC). Moreover, the reaction
was non-selective and unwanted side products like nitrile,
aldehyde, carboxylic acid, and imine products were observed
(Scheme 1). Later, an alternate approach was adopted by the
same group where stoichiometric amount of MnO2-based
octahedral molecular sieves (OMS-2) was used to selectively
oxidize amines to amides, however presence of ammonia was
reported to be crucial to achieve the same (Scheme 1).[4g]
Additionally, Milstein and coworkers reported an oxidant free
dehydrogenation of cyclic amine to lactum in presence of a Ru-
derived pincer complex. Nonetheless, such reactions were
responsive only at an elevated temperature.[4q] On the whole,
inability to use ambient air as the oxidant and formation of
multiple products reduces the practicality of these systems.
Scheme 1. An outline of the work.
exhibits excellent selectivity towards amidation without the
formation of any undesired side products. The reaction
conditions are relatively mild and ambient air is the sole oxidant,
which enhance the practicality of this method to a significant
extent. In addition, the method is highly functional group tolerant
and a host of aliphatic, heterocyclic and benzylic amines are
oxygenated in a straightforward manner. The present work also
establishes
a mechanistic pathway involving a hydroxyl-
ruthenium as the active species. Formation of an 18O labeled
amide is also detected spectroscopically.
Initial studies in air instead of any additional oxygen pressure
with 1a as the catalyst, benzylamine as the model substrate and
toluene as the solvent, afforded a mixture of nitrile and imine
instead of amide (entry 1, Table S1, Supporting Information).
The conversion was also poor. Alternatively, addition of one
equivalent of tBuOK led to the formation of benzamide as a
minor product and benzonitrile as a major one (entry 2, Table
S1). Further screening with an array of solvents (entries 3-13,
Table S1) disclosed the desired amidation in excellent yield and
selectivity with tBuOH as the solvent (entry 13, Table S1). This
further implies the bulkiness of tBuOH being crucial to generate
amides. A variety of other bases was also tested, and highly
basic tBuOK, was found to be the most active one (entries 13-20,
Table S1). In addition, investigation with different metal
precursors, revealed the superiority of the Ru-based catalysts
towards selective formation of amides in high yields (Table S2,
Supporting Information).
Subsequently, the optimized reaction conditions were applied
to a wide variety of primary benzylic amines to assess the scope
and limitations of the present protocol (Table 1). Unsubstituted
benzyl amine afforded benzamide in excellent yield (3a). A
similar observation was made for aryl rings substituted with alkyl
or alkoxy groups at p- and m-positions (3b, 3d, 3e, 3g, and 3q).
Notably, benzylamines substituted with Me- and OMe-groups at
the o-position produced high yielding amides (3c and 3f),
whereas steric factor contributed to relatively low yields of the
same in earlier reports.[4f] Halogenated amines were also
compatible and desired products were formed without any
Recently we reported Ru-catalyzed aerobic oxidation protocols
for the conversion of primary alcohols to aldehydes[5] and
primary amines to nitriles and imines.[6] As a continuation of our
interest in this direction, we sought to develop a catalytic system
which will “selectively” oxygenate amines to amides in “air” and
thereby overcome the difficulties encountered earlier. Here we
report that [RuH(CO)Cl(PPh3)3] (1a) is an efficient catalyst for
the aerobic oxidation of amines to their corresponding amides in
presence of commercially available potassium tert-butoxide
(tBuOK) as the base and tert-butanol (tBuOH) as the solvent
(Scheme 1). In contrast to earlier reports,[4f,g] the present method
[a] R. Ray, A. S. Hazari, S. Chandra, Prof. D. Maiti, Prof. G. K. Lahiri
Department of Chemistry, Indian Institute of Technology Bombay
Powai, Mumbai 400076, India
E-mail: ritwika@chem.iitb.ac.in, dmaiti@chem.iitb.ac.in,
lahiri@chem.iitb.ac.in
Supporting information for this article is given via a link at the end of
the document.
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Table 1. Ru-catalyzed amidation of benzylic amines.[a]
Table 3. Ru-catalyzed amidation of heterocyclic amines.
Unless otherwise stated, yields refer to isolated products.
monooxygenases such as Cytochrome P450[7] and only a very
few synthetic methods are known so far to carry out this
transformation.[8,9] In the present case, this might be attributed to
N-dealkylation of secondary amines followed by amidation of the
dealkylated primary analogue and generation of an alcohol
molecule as the corresponding side product. This is rationalized
on the basis of GC-MS data where for N-dealkylation oxidation
of dibenzylamine (8c), benzamide and benzyl alcohol were
observed as the sole products (no starting amine) which has
also been confirmed from the NMR analysis of the isolated
products, whereas for N-methylbenzylamine (8a) and N-
ethylbenzylamine (8b), respective starting amines and
benzamides were observed (Figure S1, Supporting Information).
Corresponding MeOH and EtOH being small and highly volatile
in nature, were probably beyond the range of detection limit and
hence not observed. However, the exact mechanism still
remains elusive at this point. Tertiary amines were completely
unreactive under identical reaction conditions (not shown) and
therefore predictably selective. Such a chemoselective nature of
the present methodology may be exploited in the selective
amidation of the 1o amine over the 2o or 3o amine in organic
molecules with multiple amine functionalities. Amidation was
equally effective on larger scales. Both, benzylamine (2a) and
piperonyl amine (6d) underwent oxidation on 1 g scales to afford
the desired amides in 84% and 71% yields, respectively (Table
5). Nicotinamide (7a), a precursor to NAD, and with numerous
medicinal uses, could also be produced in excellent yield when
the amidation was performed on the same scale (Table 5).
A set of control experiments were conducted to reveal the
probable catalytic pathway (Table 6). It was observed that the
reaction was not operational either in absence of the base or the
catalyst (entries 1-2), implying the crucial role of both these
components in the overall transformation. No amide was
detected when the reaction was performed in an aqueous
medium and starting amine was fully recovered at the end of the
reaction (entry 3). This is due to poor solubility of the reacting
components in water. Intermediacy of nitrile was ascertained by
quantitative conversion of benzonitrile to benzamide under
standard protocol (entry 4). It should be noted that although the
same reaction in absence of catalyst underwent clean
conversion to amide, presence of tBuOK was found to have a
significant impact in nitrile hydration, since in its absence amide
Unless otherwise stated, yields refer to isolated products. [a] GC yield.
dehalogenation (3h-3k). The protocol was successfully extended
towards the amidation of benzylic compounds substituted with
moderate to strong electron withdrawing groups (3l-3p, and 3r).
Most notable feature was the excellent selectivity and yield
observed in the oxygenation of the non-activated linear,
branched and cyclic aliphatic primary amines (5a, 5b, 5e-5h,
Table 2). Long chain aliphatic amines substituted with a phenyl
group at the C-terminal also underwent smooth oxidation (5c
and 5d). Oxidation of the N, O, S-containing heterocycles led to
excellent yield of the respective amides (7a-7e, Table 3). This
makes the protocol advantageous over the earlier protocols for
Ru-catalyzed oxidation reactions where heterocyclic substrates
were found to be incompatible or less reactive, probably due to
coordination of the heteroatoms to the metal center.[6]
Interestingly, secondary amines under present conditions
furnished benzamides, albeit in low yields, even in presence of a
higher amount of tBuOK (Table 4). This is a rather unique
feature since metabolic N-dealkylation is an important
biotransformation in nature
which is catalyzed
by
Table 2. Ru-catalyzed amidation of aliphatic amines.
Table 4. Secondary amines produce benzamides.[a]
[a]GC yields are reported with 1,3,5-trimethoxybenzene as the internal
standard. Unless otherwise stated, yields refer to isolated PhCONH2 (3a).
Unless otherwise stated, yields refer to isolated products.
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Table 5. Ru-catalyzed amidation of primary amines on larger scales.
Table 6. Mechanistic investigations.
was formed only in a minute quantity (entries 5-6).[2k] Another
control experiment under anaerobic condition did not detect any
amide formation and thereby established the role of oxygen as
the primary oxidant (entry 7). This was further corroborated by
labeling experiment where the same reaction in presence of 18O2
furnished an O-18 labeled amide which was detected in GC-MS
(m/z for C8H9N(18O) = 137.1; 42% 18O enriched; entry 8, and
Figure S2, Supporting Information). In addition, hydration of
nitrile to amide was found to proceed simply in water (entry 9),
and therefore labeling with H2O18 (H2O18 : tBuOH = 1:20)
detected a labeled amide in GC-MS (m/z for C7H7N(18O) =
123.1; 22% 18O enriched; entry 10, and Figure S3, Supporting
Information). The conversion and the selectivity in the oxidation
of benzylamine was not affected when same reactions were
conducted in presence of stoichiometric amounts of radical
scavengers like TEMPO and galvinoxyl (entries 11-12). Such
observations ruled out the probable involvement of any radical
intermediate in the present catalytic pathway. Kinetic
investigations revealed a first order rate dependence with
respect to consumption of the amine substrate. A small primary
kinetic isotope effect value was observed for the oxidation of
benzylamine by comparing the rate of the protio substrate with
that of the deuterated derivative, kH/kD = 1.02 (Figure 1), which
indicates that CH bond cleavage is not turnover limiting in the
present case.
0.05
0.04
0.03
0.02
0.01
0.00
0.05
0.04
0.03
0.02
0.01
0.00
a)
b)
in air to form a oxo-ruthenium species, 1c. This was confirmed
by ESI-MS which detected a peak at at m/z = 669.08 (MH) in
CH3CN corresponding to an oxo species, C37H30(16O)2P2Ru as
was observed earlier (Figure S4, Supporting Information).[5]
Interestingly, such peak was observed only when the sample
was collected from a reaction under standard conditions, but in
absence of tBuOK. In contrast, no such peak was detected
when the sample was collected from a similar reaction in
presence of tBuOK. Since it has already been established that
aerobic condition is essential for the desired transformation
(entries 7-8, Table 6), therefore, it is logical to believe that
tBuOK abstracts the proton from the RuH bond in 1c and
reduces the oxo species to a hydroxyl-ruthenium species, 1d.
Importance of a base for the generation of active ruthenium-
hydroxide species in amine oxidation has also been previously
reported in literature.[4f, 11] However, failure to detect any peak
corresponding to the hydroxyl species in ESI-MS is probably due
to a rapid ligand exchange between 1d and the amine substrate
0
20
40
60
80
100
120
0
20
40
60
80
100
Time (in mins)
Time (in mins)
Figure 1. Kinetic isotope effect data for Ru-catalyzed oxidation of a)
PhCH2NH2 and, b) isotopically labeled PhCD2NH2.
Based on these mechanistic investigations,
a plausible
mechanism for Ru-catalyzed amidation of primary amines has
been depicted in Scheme 2.[10] The catalytic pathway involves an
initial decomposition of one PPh3 ligand from 1a to form a
coordinatively unsaturated complex 1b, which was substantiated
through the detection of free PPh3 or PPh3O in GC or GC-MS
within a couple of minutes before any production of nitrile or
amide. Similar phosphine dissociation was observed in earlier
reports of alcohol and amine oxidations.[5,6] The coordinatively
unsaturated complex, 1b so formed then reacts with the oxygen
() which results in the formation of
a ruthenium-amido
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Scheme 2. Plausible mechanism for Ru-catalyzed amidation.
[5] R. Ray, S. Chandra, D. Maiti, G. K. Lahiri, Chem. Eur.J. 2016, 22, 8814-
8822.
[6] R. Ray, S. Chandra, V. Yadav, P. Mondal, D. Maiti, G. K. Lahiri, Chem.
Commun. 2017, 53, 4006-4009.
[7] P. Hlavica, Drug Metab. Rev. 2002, 34, 451-477.
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to form nitrile () and eliminates the second molecule of water.
These eliminated water molecules in-situ facilitates the hydration
of nitrile under strong basic condition and the desired amide (IV)
is formed as the final product.
[9] In organic synthesis only a few dealkylation reactions are known: a) for
the von Braun reaction, Polonovski demethylation reaction, and others,
see: K. McCamley, J. A. Ripper, R. D. Singer, R. J. Scammells, J. Org.
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In conclusion, we have developed an efficient and sustainable
protocol for the direct oxygenation of primary amines to amides,
with ambient air as the oxidant. Under identical reaction
conditions, secondary amines undergo N-dealkylation process to
give benzamides in each case. Overall, the transformations are
clean and do not produce unwanted byproducts. They proceed
with excellent selectivity and is compatible with diverse amine
substrates ranging from benzylic, aliphatic to heterocyclic
compounds to afford the amides in high yields. This process
should be useful for the diversification of primary amides through
transamidation with different amines.
[11] K. Yamaguchi, N. Mizuno, Top. Catal. 2014, 57, 1196-1207.
Acknowledgements
Financial support received from SERB(SR/NM/NS-1065/2015),
DST and UGC (fellowship to R. R. and A.S. H.), India, are
gratefully acknowledged.
Keywords: amines • direct oxygenation • amides • ambient air •
chemoselective • mechanistic study
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1991, pp. 346–356.
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R.Ray*, A.S. Hazari, S.Chandra, D.
Maiti*, G.K.Lahiri*
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Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
Text for Table of Contents
A practical and an efficient ruthenium catalyzed
synthetic protocol have been developed to realize
selective oxidation of a broad range of primary
aliphatic, heterocyclic and benzylic amines to their
corresponding amides, using readily available
reagents and ambient air as the sole oxidant.
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