Facile oxidation of primary amines to nitriles using an oxoammonium salt

Article abstract of DOI:10.1021/ol503345h

The oxidation of primary amines using a stoichiometric quantity of 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (1) in CH₂Cl₂-pyridine solvent at room temperature or at gentle reflux affords nitriles in good yield under mild conditions. The mechanism of the oxidation, which has been investigated computationally, involves a hydride transfer from the amine to the oxygen atom of 1 as the rate-limiting step.

Full text of DOI:10.1021/ol503345h

Letter
pubs.acs.org/OrgLett
Facile Oxidation of Primary Amines to Nitriles Using an
Oxoammonium Salt
Kyle M. Lambert, James M. Bobbitt, Sherif A. Eldirany, Kenneth B. Wiberg,* and William F. Bailey*
†
†
†
,‡
,†
†Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269, United States
‡Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States
*
S Supporting Information
ABSTRACT: The oxidation of primary amines using a stoichiometric
quantity of 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium
tetrafluoroborate (1) in CH Cl −pyridine solvent at room temperature
2
2
or at gentle reflux affords nitriles in good yield under mild conditions.
The mechanism of the oxidation, which has been investigated
computationally, involves a hydride transfer from the amine to the
oxygen atom of 1 as the rate-limiting step.
mines are acutely sensitive to oxidation, and a host of
Oxidation of primary amines to nitriles using 1 is
A
products may be generated depending on the oxidant. A
particularly challenging oxidation is the conversion of a primary
accomplished as follows: slow addition (syringe pump; 15−
20 mL/h) of an approximately 0.5 M solution of the amine in
dry methylene chloride to a stirred slurry of 4 molar equiv of 1
in dry methylene chloride (150 mL per 10 mmol of amine)
containing 8 molar equiv of dry pyridine followed by stirring
the reaction mixture at room temperature or at gentle reflux
under an atmosphere of nitrogen for a period of time. A simple
extractive workup affords essentially pure nitriles, without the
need for chromatographic purification, in good to excellent
yield as evidenced by the results presented in Table 1.
amine to a nitrile (RCH NH → RCN). This transformation,
2
2
which formally involves a double dehydrogenation, has been
accomplished in a variety of ways including transition-metal
catalyzed dehydrogenation, and aerobic oxidation catalyzed by
transition metals. More recently, catalytic systems for aerobic
oxidation of amines to nitriles have been developed that involve
catalytic quantities of a nitroxide, a base, cuprous iodide, and an
appropriate ligand for the metal. In this connection, we were
intrigued by reports on the oxidation of amines to nitriles by
the oxoammonium cation generated from TEMPO by
electrochemical oxidation.
Herein we report that the oxidation of a primary amine to
the corresponding nitrile may be accomplished expediently, and
in high yield using a stoichiometric quantity of a readily
available oxoammonium salt (1). As detailed below, the
oxidation proceeds under mild conditions using inexpensive
reagents via a well-defined process. Moreover, the reduced
oxidant (2), a stable nitroxide, may be recovered and recycled
using commercial bleach to regenerate the oxoammonium salt.
The oxoammonium salt, 4-acetamido-2,2,6,6-tetramethyl-
piperidine-1-oxoammonium tetrafluoroborate (1), is a stable,
highly crystalline, yellow solid. The salt is commercially
available. Alternatively, it is easily prepared in a few simple
steps from 4-amino-2,2,6,6-tetramethylpiperidine and inexpen-
1
2
3
4
The stoichiometry of the overall process, depicted in Scheme
1
, eq 1, requires explanation. For the stepwise oxidation of the
amine to an aldimine (Scheme 1, eq 2) and then to the nitrile
Scheme 1, eq 3), 2 molar equiv of 1 are required. However, in
5
(
the presence of base, 1 and the hydroxylamine (3) syn-
proportionate (Scheme 1, eq 4) to give 2 molar equiv of
7
nitroxide (2). Thus, a total of 4 molar equiv of 1 are required
for the transformation and the product mixture consists of
nitrile (Table 1), pyridinium tetrafluoroborate, and nitroxide 2.
Although only 4 molar equiv of pyridine would seem to be
required for the transformation, an excess of pyridine was used
so as to avoid protonation of the amine substrate. It is
important to note, as detailed in the Supporting Information,
that the nitroxide may be recovered with 70−80% efficiency
and recycled to give 1.
The results summarized in Table 1 demonstrate that the
oxidation protocol is a robust one. Benzylic and allylic amines
are oxidized more quickly than aliphatic amines, typically 12 h
at room temperature for benzylic amines and 24−36 h at room
temperature for aliphatic amines. Benzylic amines bearing
strongly electron-withdrawing substituents are, however,
oxidized rather slowly (Table 1, entries 7 and 9). Sluggish
6
sive reagents in multimole quantities.
Received: November 18, 2014
©
XXXX American Chemical Society
A
dx.doi.org/10.1021/ol503345h | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Oxidation of Primary Amines to Nitriles (Scheme 1,
eq 1)
Scheme 1. Overall Process
a
rate of 20 mL/h was found to be appropriate for the oxidation
of relatively reactive amines while a slower rate of 15 mL/h was
employed for the oxidation of less reactive substrates such as
aliphatic amines. When the amine is added too quickly to the
oxidant, it reacts fairly rapidly with the aldimine intermediate to
8
give the symmetrical imine (RCHNCH R). Control
2
experiments demonstrated that the imine does not react with 1.
The only byproduct detected in any product mixtures was a
small amount of aldehyde presumably generated by hydrolysis
of the aldimine intermediate by adventitious water present in
9
the reaction mixture. The aldimines derived from the more
reactive benzylic amines were particularly prone to hydrolysis
by trace water present in reaction mixtures. If care is not taken
to dry solvent and reagents (particularly salt 1), the aldehyde
may become a major component of the reaction product.
In an effort to gain some insight into the mechanism of the
oxidation, the reaction was studied computationally at the
B3LYP/6-311+G* level both for the optimizations and for
calculation of the thermal corrections; all of the following data
are for 298 K. The calculated results are of course for the gas
phase, but they would be expected to reasonably represent the
trend in energies for the solution phase. It is very difficult to
calculate free energies in solution since the major thermal
correction for the gas phase results from translation, which in
solution becomes diffusion, a more difficult phenomenon to
model.
The oxidation was modeled using ethylamine as the substrate
and the 2,2,6,6-tetramethylpiperidine-1- oxoammonium cation
+
(
TEMPO ) as the oxidant. The results of these studies are
summarized diagrammatically in Figure 1, and details are
provided in the Supporting Information.
The oxoammonium cation was found to form an
intermediate dipole-stabilized prereaction complex with the
amine (ΔG° = 2 kcal/mol). This was followed by the first
oxidation step involving transfer of a hydride from the α-carbon
+
of the amine to the oxygen of TEMPO and formation of a
a
b
CN bond. The transition state for this process had one
All reactions were conducted on a 10 mmol scale. Time reaction
−1
c
imaginary frequency (1047i cm ) and an activation free energy
mixture was stirred at room temperature or reflux. Isolated yield of
chromatographically pure product. Reaction mixture was heated at
gentle reflux.
‡
d
of ΔG = 15.8 kcal/mol relative to the reactants. The product,
the protonated aldimine, was less stable than the reactants by
ΔG° = 7.8 kcal/mol, but with transfer of the acidic proton to
pyridine, the product aldimine and pyridinium cation are more
stable than the reactants by ΔG° = −1.8 kcal/mol.
oxidations may be accelerated, with little loss in yield, by simply
heating the reaction mixture at gentle reflux (Table 1, entries 9,
1
3, and 14).
The second step of the oxidation was initially modeled by
computing the activation energy for hydride transfer from the
α-carbon of the aldimine to the oxygen of the oxoammonium
The successful oxidation of primary amines to nitriles by 1
requires that the amine dissolved in CH Cl (typically a 0.5 M
solution) be added slowly to the reaction mixture. An addition
2
2
‡
cation. This reaction leads to a high ΔG = 31.8 kcal/mol
B
dx.doi.org/10.1021/ol503345h | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 1. Computed profile (B3LYP/6-311+G*) for the oxidation of primary amines to nitriles.
because it results in a high energy protonated acetonitrile
product. Indeed, the latter is calculated to transfer a proton to
pyridine with ΔG° = −35.5 kcal/mol. Clearly, pyridine must
participate in the oxidation step. This was studied by including
ASSOCIATED CONTENT
■
*
S
Supporting Information
General procedures; product characterization; H, 13C, and 19
NMR spectra of all products; a summary of the calculations,
including computed energies and coordinates. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
F
+
pyridine in the reaction of TEMPO with the aldimine.
Gratifyingly, this three-component situation leads to a pre-
reaction complex (ΔG° = 3.2 kcal/mol relative to reactants)
‡
and a more reasonable activation free energy of ΔG = 15.5
AUTHOR INFORMATION
■
*
*
kcal/mol relative to the three reactants. This transition state
Corresponding Authors
−
1
had one imaginary frequency (1016i cm ). The overall
oxidation of the aldimine to the neutral nitrile was computed
to be exothermic by ΔG° = −14 kcal/mol.
E-mail: William.Bailey@uconn.edu.
E-mail: kenneth.wiberg@yale.edu.
Notes
The mechanism suggested by these computational studies is
analogous to that thought to be responsible for the oxidation of
alcohols by the oxoammonium cation in neutral or acidic
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
1
0
■
solution. Both oxidations involve, as the rate-limiting step,
transfer of a hydride from the substrate to the oxidant. The
development of a partial positive charge on the α-carbon of the
amine in the course of the oxidation nicely accounts for the fact
that benzylic amines bearing electron-withdrawing substituents
react more slowly than those bearing electron-donating groups.
In summary, the oxidation of primary amines at room
temperature using oxoammonium salt 1 in methylene
chloride−pyridine provides an experimentally simple, mild,
and efficient method for the synthesis of nitriles. Moreover, the
progress of the oxidation is easily followed visually. The initial
yellow slurry of 1 progressively develops a deep-red color, as
the concentration of soluble nitroxide 2 in the reaction medium
increases. Upon completion of the oxidation, the methylene
chloride is deep red and a white precipitate of pyridinium
tetrafluoroborate is evident. The color changes associated with
the oxidation are illustrated in the Supporting Information.
This work was supported by a grant from Procter & Gamble
Pharmaceuticals, Mason, OH.
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