Visible-light-driven catalytic oxidation of aldehydes and alcohols to nitriles by 4-acetamido-tempo using ammonium carbamate as a nitrogen source

Article abstract of DOI:10.1039/c9ob01918a

A mild and efficient route to prepare nitriles from aldehydes by combining photoredox catalysis with oxoammonium cations is reported. The reaction is performed using ammonium carbamate as the nitrogen source. The practicality of the method is increased by the extension of the dual catalytic system to one-pot two-step conversion of alcohols to nitriles.

Full text of DOI:10.1039/c9ob01918a

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PAPER
Visible-light-driven catalytic oxidation of
aldehydes and alcohols to nitriles by 4-acetamido-
TEMPO using ammonium carbamate as a nitrogen
source†
Cite this: Org. Biomol. Chem., 2019,
17, 9182
Jyoti Nandi
and Nicholas E. Leadbeater
*
Received 1st September 2019,
Accepted 28th September 2019
A mild and efficient route to prepare nitriles from aldehydes by combining photoredox catalysis with
oxoammonium cations is reported. The reaction is performed using ammonium carbamate as the nitro-
gen source. The practicality of the method is increased by the extension of the dual catalytic system to
one-pot two-step conversion of alcohols to nitriles.
DOI: 10.1039/c9ob01918a
rsc.li/obc
ologies in a catalytic setting. The visible-light harvesting cata-
lyst, Ru(bpy)3(PF6)2 oxidizes the pro-oxidant, 1b to generate the
Introduction
Compounds bearing the nitrile functionality are ubiquitous in active oxidant, AcNH-TEMPO+ in situ that enables the oxidative
nature and also are key pharmaceuticals and agrochemicals.1–4 modulation of different functionalities without the need of
In addition, nitriles are valuable precursors to the synthesis of superstoichiometric quantities of the oxoammonium
nitrogen-containing functional groups and heterocycles.5 cation.18,24,25 We have recently reported the oxidation of alde-
Common routes to prepare nitriles include substitution reactions hydes to nitriles by employing this dual catalytic system using
with cyanide sources and dehydration of amides and oximes.6–10 ammonium persulfate, (NH4)2S2O8, as both the terminal
These methods rely on toxic reagents and harsh reaction con- oxidant and nitrogen source (Scheme 1a). Pyridine is used as a
ditions, often limiting their synthetic applicability.
base, and activated molecular sieves employed to sequester
The direct oxidation of aldehydes using nitrogen serves as any water in the reaction mixture and thereby prevent competi-
an alternative and often more efficient way to synthesize tive formation of the corresponding carboxylic acid product.
nitriles, the reason being the easy accessibility and safe hand- The methodology does have limited substrate scope. In
ling of aldehydes.11–13 To this end, the oxoammonium salt addition, reactions have to be performed at 50 °C under moist-
4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium
ure-free conditions, and the protocol could not be extended to
tetrafluoroborate (AcNH-TEMPO+BF4−, 1a) and its precursor, alcohols as substrates.18
ACT (AcNH-TEMPO, 1b) have been employed in the oxidation
As a continuation of our interest in photoredox catalysis, we
of aldehydes to nitriles.14,15 Of the nitrogen sources reported next wanted to explore the applicability of our dual catalytic
for this transformation, ammonium salts are most favored due system to the preparation of amides from aldehydes. In a test
to their stability and lower toxicity relative to other sources like
hexamethyldisilazane (HMDS). However, these protocols often
involve a combination of elevated temperatures, anhydrous
conditions, or an inert atmosphere.16–18
Photoredox catalysis is growing at an incredible pace as a
tool in the preparative organic synthetic community because it
provides access to valuable chemical bonds in extremely mild
conditions with very low catalyst loadings.19–23 This has
motivated us to combine photoredox catalysis with oxoammo-
nium cations to develop oxidative functionalization method-
Department of Chemistry, University of Connecticut, 55 North Eagleville Road,
Storrs, Connecticut 06269, USA. E-mail: nicholas.leadbeater@uconn.edu
†Electronic supplementary information (ESI) available: Experimental details and
Scheme 1 Photo-oxidation of aldehydes by an ACT/Ru(bpy)3(PF6)2 dual
spectral characterization. See DOI: 10.1039/c9ob01918a
catalytic system.
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Table 1 Optimization of the ACT/Ru(bpy)3(PF6)2 dual catalytic system
to synthesize nitriles using ammonium carbamate as the nitrogen
sourcea
reaction using 4-methoxybenzaldehyde, 2a as a test substrate,
ammonium carbamate (NH4CO2NH2) as the nitrogen source
and acetonitrile/water as solvent mix we hoped to form 4-meth-
oxybenzamide as the product (Scheme 1b). Ammonium carba-
mate has been shown to act as an ammonia source and indeed
is more stable and less expensive on molar basis than
ammonia itself.26 We posited that the in situ generated
ammonia could react with the aldehyde starting material and
then water in the solvent mixture could hydrolyse the resultant
imine to form the amide instead of another oxidation of the
imine to afford the nitrile. However, the reaction afforded the
corresponding nitrile in 90% isolated yield (95% conversion).
It was noteworthy that the reaction was performed at room
temperature in the presence of water and the yield of nitrile
was significantly higher than that from our previous protocol.
This encouraged us to probe the reaction further and deter-
mine whether it was applicable to other aldehydes and if the
substrate scope could be extended beyond the aromatic
examples that were reported in our previous work. This was
indeed the case and the methodology could also be expanded
to the one-pot two-step oxidation of alcohols to nitriles. We
report our results here.
Conversion
(%)
Entry Reaction conditionsb
1
Ru(bpy)3(PF6)2, ACT, pyridine, NH4CO2NH2,
acetonitrile/water (95 : 5 v/v)
95
2
Ru(bpy)3(PF6)2, ACT, pyridine, NH4CO2NH2,
acetonitrile
77
37
33
12
76
27
86
86
32
17
3
Ru(bpy)3(PF6)2, ACT, pyridine, NH4CO2NH2,
dichloromethane/water (95 : 5 v/v)
Ru(bpy)3(PF6)2, ACT, pyridine, NH4CO2NH2,
dimethylformamide/water (95 : 5 v/v)
Ru(bpy)3(PF6)2, ACT, pyridine, NH4CO2NH2,
toluene/water (95 : 5 v/v)
Ru(bpy)3(PF6)2, ACT, DBU, NH4CO2NH2,
acetonitrile/water (95 : 5 v/v)
Ru(bpy)3(PF6)2, ACT, DMAP, NH4CO2NH2,
acetonitrile/water (95 : 5 v/v)
Ru(bpy)3(PF6)2, ACT, 2,6-lutidine, NH4CO2NH2,
acetonitrile/water (95 : 5 v/v)
4
5
6
7
8
9
Ru(bpy)3(PF6)2, ACT, pyridine (1.5 eq.),
NH4CO2NH2, acetonitrile/water (95 : 5 v/v)
(Ir[dF(CF3)PP]2 (dtbpy))PF6, ACT, pyridine,
NH4CO2NH2, acetonitrile/water (95 : 5 v/v)
Eosin Y, ACT, pyridine, NH4CO2NH2, acetonitrile/
water (95 : 5 v/v)
10
11c
12c
13
14
15
16
17
18
19
20
21
22
23
24
25
Results and discussion
9-Mesityl-10-methylacridinium BF4−, ACT, pyridine, 6
Our test reaction performed using 2a as a model aldehyde,
ammonium carbamate (4 eq.) as the nitrogen source and
acetonitrile/water (95 : 5 v/v) led to a 95% conversion to the
desired nitrile, 3a, when employing Ru(bpy)3(PF6)2 (2 mol%)
as the photocatalyst, ACT (20 mol%, 1b) as the primary
oxidant, ammonium persulfate (2.2 eq.) as the secondary
oxidant, pyridine (2.5 eq.) as base, and blue LED strips as the
light source. The reaction was complete after 24 h at room
temperature (Table 1, entry 1). Our first parameter in the
optimization stage was the solvent. Changing from a 95 : 5 v/v
mix of acetonitrile/water to pure acetonitrile had a deleterious
effect on conversion, showing the importance of water (entry
2). This can be attributed to the increased solubility of the two
ammonium salts, (NH4)2S2O8 and NH4CO2NH2, in the aceto-
nitrile/water solvent mix. The replacement of acetonitrile with
either dichloromethane, dimethylformamide, or toluene
resulted in a dramatic reduction in nitrile formation (entries
3–5). Turning attention to the base, replacing pyridine with
strong bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
NH4CO2NH2, acetonitrile/water (95 : 5 v/v)
Ru(bpy)3(PF6)2 (1 mol%), ACT, pyridine,
NH4CO2NH2, acetonitrile/water (95 : 5 v/v)
Ru(bpy)3(PF6)2, ACT, pyridine, NH4CO2NH2
(1.5 eq.), acetonitrile/water (95 : 5 v/v)
Ru(bpy)3(PF6)2, ACT, pyridine, NH4CO2NH2
(2.5 eq.), acetonitrile/water (95 : 5 v/v)
Ru(bpy)3(PF6)2, ACT, pyridine, NH4CO2NH2
(6.0 eq.), acetonitrile/water (95 : 5 v/v)
Ru(bpy)3(PF6)2, ACT, pyridine, aq. NH3,
acetonitrile/water (95 : 5 v/v)
Ru(bpy)3(PF6)2, ACT, pyridine, HMDS, acetonitrile/ 68
water (95 : 5 v/v)
Ru(bpy)3(PF6)2, ACT, pyridine, NH4CO2NH2,
acetonitrile/water (95 : 5 v/v), 0.25 M
Ru(bpy)3(PF6)2, ACT, pyridine, NH4CO2NH2,
acetonitrile/water (95 : 5 v/v), 0.74 M
Ru(bpy)3(PF6)2 (2 mol%), ACT (10 mol%), pyridine, 86
NH4CO2NH2, acetonitrile/water (95 : 5 v/v)
Ru(bpy)3(PF6)2 (2 mol%), ACT (40 mol%), pyridine, 88
NH4CO2NH2, acetonitrile/water (95 : 5 v/v)
Ru(bpy)3(PF6)2, ACT, pyridine, NH4CO2NH2,
(NH4)2S2O8 (1.5 eq.), acetonitrile/water (95 : 5 v/v)
Ru(bpy)3(PF6)2, ACT, pyridine, NH4CO2NH2,
(NH4)2S2O8 (4.0 eq.), acetonitrile/water (95 : 5 v/v)
Ru(bpy)3(PF6)2, ACT, pyridine, NH4CO2NH2,
acetonitrile/water (95 : 5 v/v), 48 h
86
77
90
93
91
84
95
80
89
95
or 4-dimethylaminopyridine (DMAP) had
a significantly
diminutive effect on the conversion to the nitrile product
(entries 6 and 7). Using 2,6-dimethylpyridine (2,6-lutidine) led
to a slightly lower conversion to 3a as compared to pyridine
(entry 8). Returning to pyridine but decreasing the quantity
from 2.5 eq. to 1.5 eq. had a slightly negative effect on product
conversion (entry 9).
a Reactions performed on 0.5 mmol scale; conversion determined by
integration of signals in the 1H-NMR spectrum. b Conditions changed
from entry 1 are highlighted in bold. c 5 mol% of the photocatalyst was
used rather than 2 mol%.
Next,
a series of photocatalysts including (Ir[dF(CF3)
PP]2(dtbpy))PF6, Eosin Y, and 9-mesityl-10-methylacridinium less than 2 mol% of Ru(bpy)3(PF6)2 came at the cost of product
−
BF4 were screened as replacements for Ru(bpy)3(PF6)2 but all formation, a loading of 1 mol% resulting in a drop in conver-
proved inferior (entries 10–12). Performing the reaction using sion of 9% (entry 13).
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Table 2 Control experiments probing the ACT/Ru(bpy)3(PF6)2 dual
catalytic system to synthesize nitriles using ammonium carbamatea
Focusing attention on the nitrogen source, reducing the
quantity of ammonium carbamate used led to a concomitant
reduction in product conversion (entries 14 and 15).
Increasing the loading above 4 eq. did not have an appreciable
effect (entry 16). Changing the nitrogen source from
ammonium carbamate to aqueous ammonia led to a slight
diminution in product yield but when employing HMDS a sig-
nificant drop in effectiveness was observed (entries 17 and 18).
We did briefly explore other ammonium salts to determine
their efficacy as nitrogen sources. In the case of salts such as
ammonium acetate while the desired nitrile was obtained, this
was accompanied by significant byproduct formation such as
the generation of the corresponding amide. This both reduced
the conversion to the desired nitrile but also complicated
product isolation.
We performed our reactions at a concentration of 0.5 M in
aldehyde 2a. Operating in a more dilute solution lowered the
conversion to nitrile, but performing the reaction at 0.74 M
was possible with no negative effect (entries 19 and 20). This
therefore allowed for process intensification. In assessing
other parameters, decreasing either the catalyst loading of 1b
or the quantity of ammonium persulfate had a negative effect
on product conversion (entries 21–24). Extending the reaction
time from 24 h to 48 h did not increase product conversion
(entry 25). Alternative light sources, terminal oxidants, reaction
atmosphere (oxygen enriched and anaerobic), and solvent
compositions were also evaluated but none proved superior to
those used initially (ESI, Tables S1 and S2†).
As anticipated, the reaction also works with the addition of
4-acetamido-2,2,6,6-tetramethylpiperidine-N-hydroxylamine
and 1a at the start of the reaction in place of 1b;18,24 albeit
with a sluggish rate of the nitrile formation in the case of the
latter (ESI, Table S1†). Our optimized conditions therefore
comprised of a 0.74 M solution of aldehyde in acetonitrile/
water (95 : 5 v/v), ammonium carbamate (4 eq.) as the nitrogen
source, Ru(bpy)3(PF6)2 (2 mol%) as the photocatalyst, ACT
(20 mol%, 1b) as the primary oxidant, ammonium persulfate
(2.2 eq.) as the secondary oxidant, pyridine (2.5 eq.) as base,
and blue LED strips as the light source, running the reaction
for 24 h at room temperature.
Entry
Omitted component
Conversion (%)
1
2
3
4
5
6
None
Light
95
0
0
Ru(bpy)3(PF6)2
(NH4)2S2O8
AcNH-TEMPO (ACT, 1b)
NH4CO2NH2
0
11b
23
a Reactions performed on the 0.5 mmol scale; conversion determined
by integration of signals in the 1H-NMR spectrum. b Mixture of
unreacted aldehyde, nitrile, and other oxidized products was observed
including carboxylic acid, amide along with unidentified products in
GC-MS.
mation (entry 6), but is in no way as effective in this role as
ammonium carbamate.18
With optimized conditions in hand, we investigated the
substrate scope of the methodology. A range of para-substi-
tuted benzaldehydes with both electron-donating and electron-
withdrawing groups were first screened, all of them affording
the desired nitriles in moderate to high yield (Table 3, 3a–e).
Likewise, ortho- and meta-substituted analogs were well-toler-
ated (3f–h) as were representative polysubstituted benzal-
dehydes and one polycyclic example (3i–m). The rate of nitrile
formation for 3,4-(methylenedioxy)benzaldehyde (3k) was very
sluggish and running the reaction for an extended time (48 h)
did not further improve conversion to the nitrile product.
Isolated yields of nitriles 3d and 3h, prepared from 4-cyano-
Table 3 Scope of the ACT/Ru(bpy)3(PF6)2 dual catalytic system to syn-
thesize nitriles from aldehydes using ammonium carbamatea
We next performed a series of control experiments to
confirm that all the components play an essential role in the
reaction. We removed individual components from our opti-
mized conditions (Table 2, entry 1). No conversion to product
was observed in the absence of light or photocatalyst showing
that the transformation is indeed a photocatalytic process
(entries 2 and 3). The same was true if ammonium persulfate
was omitted, this showing the key role of this component as a
terminal oxidant (entry 4). The elimination of nitroxide (1b)
resulted in a mixture of oxidized products, including nitrile,
amide, and carboxylic acid along with several unidentified
byproducts and unreacted aldehyde (entry 5).18 With no
addition of ammonium carbamate, a 23% conversion of nitrile
was obtained. The reason that some product was formed in
this case is because the ammonium persulfate can generate
ammonia in situ to serve as a nitrogen source for nitrile for-
a Reactions performed on 1 mmol scale; all yields are isolated yields
after purification. b Ran for 18 h instead of 24 h.
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Table 4 Scope of the ACT/Ru(bpy)3(PF6)2 dual catalytic system to syn-
thesize nitriles from alcohols using ammonium carbamatea
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was financially supported by the University of
Connecticut. We thank undergraduate student, Mason
L. Witko (University of Connecticut) for his contributions to
the experimental part of this research work.
a Reactions performed on 1 mmol scale; all yields are isolated yields
after purification. b Ran for 48 h instead of 24 h; 24 h gave 60% iso-
lated yield of 3t.
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This journal is © The Royal Society of Chemistry 2019