Access to nitriles from aldehydes mediated by an oxoammonium salt

Article abstract of DOI:10.1002/anie.201412256

A scalable, high yielding, rapid route to access an array of nitriles from aldehydes mediated by an oxoammonium salt (4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate) and hexamethyldisilazane (HMDS) as an ammonia surrogate has been developed. The reaction likely involves two distinct chemical transformations: reversible silyl-imine formation between HMDS and an aldehyde, followed by oxidation mediated by the oxoammonium salt and desilylation to furnish a nitrile. The spent oxidant can be easily recovered and used to regenerate the oxoammonium salt oxidant.

Full text of DOI:10.1002/anie.201412256

Angewandte
Chemie
DOI: 10.1002/anie.201412256
Synthetic Methods
Access to Nitriles from Aldehydes Mediated by an Oxoammonium
Salt**
Christopher B. Kelly, Kyle M. Lambert, Michael A. Mercadante, John M. Ovian,
William F. Bailey,* and Nicholas E. Leadbeater*
Abstract: A scalable, high yielding, rapid route to access an
array of nitriles from aldehydes mediated by an oxoammo-
nium salt (4-acetylamino-2,2,6,6-tetramethylpiperidine-1-
oxoammonium tetrafluoroborate) and hexamethyldisilazane
(HMDS) as an ammonia surrogate has been developed. The
reaction likely involves two distinct chemical transformations:
reversible silyl-imine formation between HMDS and an
aldehyde, followed by oxidation mediated by the oxoammo-
nium salt and desilylation to furnish a nitrile. The spent oxidant
can be easily recovered and used to regenerate the oxoammo-
nium salt oxidant.
to converting readily accessible functionalities (e.g. aldehydes
and alcohols) into nitriles. The most typical approach is to use
hydroxylamine to form an oxime followed by a dehydration
reaction.[7] Again, scalability is limited because of the inherent
instability of hydroxylamine. An attractive alternative is to
perform direct oxidative nitrile synthesis by exposure of an
alcohol or aldehyde to ammonia and an oxidant. This
transformation has been accomplished both stoichiometri-
cally[8] and catalytically[9]
Recently we engaged in an investigation probing the use
of the oxoammonium salt 4-acetylamino-2,2,6,6-tetramethyl-
piperidine-1-oxoammonium tetrafluoroborate (Bobbittꢀs
Salt; 1a) for oxidative amidation of 2a. We initially attempted
to use our previously optimized reaction conditions for the
oxidative esterification of aldehydes (Figure 1a),[10a] but
instead replacing hexafluoroisopropanol (HFIP) by hexame-
thyldisilazane (HMDS) as the coupling partner (Figure 1b).
HMDS was employed as a nitrogen source since no appreci-
able reaction occurs upon exposure of HMDS to 1a, unlike
with aqueous ammonia. Rather than obtaining amidation, we
serendipitously discovered a route to rapidly and efficiently
access the nitrile 3a (Figure 1c), albeit a process that was
exothermic. Given the advantages of oxoammonium salt
T
he nitrile group is a highly useful motif to synthetic organic
chemists and it can be readily converted into various valuable
heterocycles and functional groups such as amines, amides,
carboxylic acids, or esters.[1] Additionally, nitriles are prized in
their own right as they commonly appear in fine chemicals
and can be found in a number of pharmaceutical and
agrochemical compounds.[1,2] The most common approach
to the preparation of nitriles involves substitution reactions of
organic halides with a cyanide source.[1] While a very practical
and inexpensive route, utilization of toxic cyanide can prove
problematic on scale up. Alternatively, some organic cyanide
sources have been explored with great success.[3] Rather than
incorporating the nitrile functionality directly, various nitro-
gen-containing functionalities can be converted into nitriles.
Dehydration of amides is one such approach, but often
requires harsh reaction conditions (e.g. P2O5 and high
temperatures).[4] By using a variety of metal- or nonmetal-
based oxidants, primary amines can undergo a double oxida-
tion to afford nitriles.[5,6] More recently, attention has turned
[*] C. B. Kelly,[+] K. M. Lambert,[+] M. A. Mercadante,[+] J. M. Ovian,
Prof. W. F. Bailey, Prof. N. E. Leadbeater
Department of Chemistry, University of Connecticut
55 N. Eagleville Road, Storrs, CT 06269-3060 (USA)
E-mail: william.bailey@uconn.edu
nicholas.leadbeater@uconn.edu
Prof. N. E. Leadbeater
Department of Community Medicine & Health Care
University of Connecticut Health Center, The Exchange
263 Farmington Ave, Farmington, CT 06030 (USA)
[+] These authors contributed equally to this work.
[**] This work was supported by the National Science Foundation
(CAREER Award CHE-0847262 CBK, MAM, NEL) and the University
of Connecticut Office of Undergraduate Research (JMO). Addi-
tionally, we thank Dr. Leon Tilley of Stonehill College for useful
discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201412256.
Figure 1. Serendipitous nitrile formation during oxidative amidation
attempts.
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oxidants, namely that they are environmen-
tally benign, recyclable, and metal-free species
which can facilitate oxidation under extremely
mild reaction conditions, and our interest in
enhancing the profile of oxoammonium salt-
based transformations, we elected to advance
this unusual outcome into a general method-
ology for the direct synthesis of nitriles from
aldehydes.[10]
To understand our unexpected result
better, we systematically examined the role
of each of the reaction components. This study
also served as an opportunity to optimize
reaction conditions. First, to control the
observed exotherm when utilizing the oxida-
tive esterification conditions for this trans-
Figure 2. Reported amine oxidation mediated by 1a and the oxidation of a plausible
mechanistic intermediate.
formation, we decided to conduct the reaction in CH2Cl2. This
solvent served as a thermal sink and no exotherm was
observed at an aldehyde concentration of 0.5m. We quickly
found that pyridine was not essential for nitrile formation as
the reaction proceeded readily in its absence. This observa-
tion eliminated the possibility of an acyl pyridinium inter-
mediate which was posited by Bobbitt et al. as the key
intermediate during oxidative esterification reactions medi-
ated by 1a.[10b] Variation of the loading of 1a and HMDS
provided further critical mechanistic insight. The use of
0.5 equivalents as opposed to 1 equivalents of 1a in the
presence of three equivalents of HMDS gave starkly different
results. In the case of the former, one would expect only to
obtain about 25% conversion into the nitrile because of the
known comproportionation of 1a under basic conditions.[10b]
While this was confirmed by 1H NMR spectroscopy, an
additional 25% of 2a was consumed and the formation of
another compound was observed. This compound was later
identified as the N-(trimethylsilyl)imine
The formation of Me3Si-F was also observed when 2a was
treated with 1a. Use of the perchlorate salt of 1a strictly gave
Me3Si-OH and (Me3Si)2O as the reaction by-products. Next,
HMDS loading was varied. At only 1 equivalent of HMDS
and 2 equivalents of 1a, a 50% conversion into 3a was
achieved, with the remainder being 2a and no intermediate
imine detected. Use of 2 equivalents or more of HMDS gave
sole conversion into 3a.
With these data in hand, we were able to construct
a plausible reaction mechanism (Figure 3). We speculate that
numerous pathways are available for the formation of the N-
trimethylsilyl imine of 2a from HMDS and small amounts
form during the course of the reaction. Rapid oxidation of the
À
imine would forge the remaining C N bond, thus furnishing
the nitrilium ion which, in the presence of the now naked
tetrafluoroborate anion, would decompose to BF3 and Me3Si-
À
F. Given the strength of Si F bond and the computed
exothermic nature of nitrilium deprotonation during our
of 2a. In contrast, use of 1 equivalent of
1a afforded complete consumption of
2a in addition to the formation of equal
amounts of 3a and the imine. By
employing two or more equivalents of
1a, we were able to obtain 3a as the sole
product. The absence of the imine at
higher loadings of 1a suggested to us
that it was the likely reaction intermedi-
ate, and that it was the species under-
going oxidation during the course of the
reaction.
This conclusion was further evi-
denced by a recent report by Wiberg,
Bailey, and co-workers who stated that
oxidation of imines by 1a is highly
favorable and exothermic (Figure 2a).[6]
We confirmed that such imines could be
oxidized with 1a by independently
preparing 4 and subjecting it to our
reaction conditions. We observed
a highly exothermic reaction, with ben-
zonitrile and Me3Si-F being the
observed major products (Figure 2b).
Figure 3. Plausible reaction mechanism.
2
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Table 1: Scope of oxidative formation of nitriles[a].
prior[6] investigation, this step likely explains the
observed highly exothermic character of this
reaction. The known[10b] comproportionation of
1a under basic conditions explains the requirement
for 2 equivalents of 1a and HMDS as well as the
formation of 1b.
By using the mechanism as a guide, we treated
2a with 2.5 equivalents of HMDS and 1a in
CH2Cl2. Additionally, to prevent unwanted side
reactions, 1.1 equivalents of pyridine were added.
While not mechanistically necessary, pyridine is an
excellent means to sequester the BF3 generated
during the course of the reaction. We obtained
complete conversion into 3a after only 1 hour at
room temperature. Isolation of 3a proved simple
and we obtained a 95% yield of 3a (Table 1,
entry 1). Next we turned our attention to survey
the scope of the reaction. The initial focus centered
on aryl aldehydes as a means of assessing the
electronic and steric constraints governing this
reaction. Both electron-rich (entries 1,2,8, and 9)
and electron-poor (entries 3–7) benzaldehyde
derivatives all underwent rapid oxidation and
gave fair to excellent yields of their corresponding
nitriles. Scale-up to a 50 mmol scale proved facile
and neither compromised yield nor changed the
impurity profile (entries 1 and 2). However, on
such scales, thermal moderation was required and
was easily accomplished using a room temperature
water bath.
Entry[a] Aldehyde
Nitrile
t [h] Yield [%][b]
1
1
4
95 (90)[c]
97 (88)[c]
2
3
4
24 75
36 51[d]
5
6
36 69
12 91
The electronic and steric constraints of the aryl
systems had a notable effect both on yield and on
reaction rate. Substrates with electron-rich aryl
rings reached completion at a much faster rate than
those bearing electron-withdrawing groups. In
certain cases (entries 3–5 and 7), we were unable
to achieve complete conversion in less than 36 h
using our optimized reaction conditions. Prema-
ture quenching of the reaction mixture led to
hydrolysis of the intermediate imine, thus dimin-
ishing yield and furnishing the starting aldehyde as
a contaminant (typically < 10% by 1H NMR spec-
troscopy). This contaminant could easily be
removed by simply stirring the crude reaction
mixture overnight in Et2O in the presence of
a commercially available silica-bound amine-based
scavenger.[11] In addition, a known side reaction
involving nitriles and the hydroxylamine 1c
(formed during the reaction; see Figure 3) had
a deleterious effect on yield in very electron-poor
systems (entry 4). Discovered by Endo and co-
workers, hydroxylamines of the tetramethylpiper-
idinyl scaffold react rapidly with electron-poor
nitriles to give amides (Figure 4).[11] Moreover,
Endo found the reaction is significantly accelerated
under basic conditions, thus explaining the
observed amide by-product and hence the greatly
diminished yield of 3d.[11] Interestingly, the steric
constraints of 3g (entry 7) must deter this process
7
24 80
8
4 88
9
12 93
12 88
10
11
12
12 82
12 69
13
2 67
14
15
12 75
1
80
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Table 1: (Continued)
Entry[a] Aldehyde
Wondering whether our protocol could be
extended to aliphatic aldehydes, we initially
screened a representative straight chain example
(entry 16). Aliphatic aldehydes not bearing an a-
substitution were problematic, and is likely due to
their propensity to undergo self-aldol reactions in
the presence of silylated amines.[12] However, by
adding HMDS slowly to the reaction mixture, we
were able to avoid this unwanted side reaction and
maintain good yield (entries 15 and 16). Next,
various aliphatic substrates bearing a-substituents
(entries 17–20), whose synthesis would be imprac-
tical by classical SN2 approaches, were screened.
We were pleased to find that they all formed the
desired nitrile, regardless of substitution pattern.
Unsurprisingly, conformational restriction of the
a-substituents dramatically increases the reaction
rate. Restricted systems (entries 18 and 20)
reached completion rapidly, while unrestricted
examples (entries 17 and 19) were sluggish. This
acceleration in rate is likely due to diminished
steric encumbrance by the a-substituents.
We concluded our screen of substrates by
studying a,b-unsaturated and propargylic systems
(entries 21–24). Cinnamaldehyde (entry 21) suc-
cessfully converted into its nitrile in excellent
yield. When using the optimized reaction condi-
tions, we initially obtained very low yield of 3v
because of polymerization. By performing the
reaction at a higher dilution, we successfully
converted this aldehyde into its nitrile in good
yield (entry 22), albeit at the expense of a longer
reaction time. Removing the double bond from
conjugation had a deleterious effect on the
reaction, with only polymeric material being
obtained (entry 23). This is likely a consequence
of various Michael additions into the alkene. This
observation is in agreement with the findings of
Endo[11] as well as our own[10a] investigations. In
contrast, a representative conjugated propargylic
Nitrile
t [h] Yield [%][b]
16
1
4
71[e]
72
17
18
2
96
19
20
32 80
1
2
82
86
21
22
12 78[f]
[g]
23
24
–
1
–
79
[a] Reaction conditions unless otherwise noted: aldehyde in CH2Cl2 (10 mmol,
1 equiv, 0.5m), HMDS (25 mmol, 2.5 equiv), pyridine (11 mmol, 1.1 equiv), 1a
(25 mmol, 2.5 equiv) [b] Yield of isolated product. [c] Yield on 50 mmol scale. [d] A
50:50 mixture by volume of Et2O and CH2Cl2 was used as the solvent. [e] HMDS was
added dropwise to the reaction mixture. [f] Reaction was run at 0.1m to prevent
polymerization. [g] Complex mixture observed.
aldehyde rapidly and cleanly converted into its nitrile (3x) in
good yield (entry 24).
To expand the utility of our approach, we investigated
whether alcohols could be converted directly into nitriles
using 1a. Using a two-step, one-pot procedure, we found that
this transformation could indeed be accomplished success-
fully (Figure 5). First, 4-chlorobenzyl alcohol was oxidized to
its aldehyde 2y under basic conditions.[13] Subsequent addi-
tion of HMDS, pyridine, and more 1a provided the nitrile in
excellent yield without the need for isolation and purification
of the intermediate aldehyde.
In summary, a methodology for the conversion of an
aldehyde into a nitrile facilitated by an oxoammonium salt is
described. Using HMDS as a nitrogen source, aldehydes can
be converted into nitriles under mild reaction conditions in
fair to excellent yield. Both the success and the rate of the
reaction are contingent on the formation and subsequent
oxidation of the intermediate N-trimethylsilyl imine. The
reaction is scalable and the spent oxidant can be recovered.
Figure 4. Known reaction of electron-poor nitriles with the hydroxyl-
amine 1c discovered by Endo and co-workers.
as no amide was observed despite being significantly electron
poor. This assertion was further evidenced by the fact that the
para counterpart to 3g (not shown) gave the amide as the
major product.
We next probed whether polycyclic and heterocyclic
systems would be amenable to oxidative nitrile formation.
A representative polycyclic example (entry 10) tolerated our
reaction conditions, thus giving the corresponding nitrile 3j in
excellent yield. Similarly, an array of heterocycles containing
sulfur, oxygen, and nitrogen atoms (entries 11–14) were well-
tolerated, thus affording good to excellent yields of nitriles.
4
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Received: December 21, 2014
Published online: && &&, &&&&
Keywords: aldehydes · cyanides · oxidation ·
.
reaction mechanisms · synthetic methods
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Communications
Synthetic Methods
C. B. Kelly, K. M. Lambert,
M. A. Mercadante, J. M. Ovian,
W. F. Bailey,*
N. E. Leadbeater*
&&&& — &&&&
Access to Nitriles from Aldehydes
Mediated by an Oxoammonium Salt
A serendipitous find: The scalable and
high yielding title reaction is mediated by
4-acetylamino-2,2,6,6-tetramethylpiperi-
dine-1-oxoammonium tetrafluoroborate
and hexamethyldisilazane (HMDS). The
reaction likely involves reversible silyl-
imine formation between HMDS and an
aldehyde, and subsequent oxidation and
desilylation. The spent oxidant can be
easily recycled.
6
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