Oxidative Amidation of Amines in Tandem with Transamidation: A Route to Amides Using Visible-Light Energy

Article abstract of DOI:10.1021/acs.joc.0c01222

A methodology is reported for preparing amides using amines as an acyl source. The protocol involves the visible-light-promoted oxidative amidation of amines with pyrazole to synthesize N-acyl pyrazoles followed by transamidation. By combining photoredox catalysis with oxoammonium cations in the presence of sodium persulfate as a terminal oxidant, the N-acyl pyrazoles could be prepared efficiently and effectively using blue LEDs. The transamidation step was performed without the need to purify the N-acyl pyrazole intermediate, and a range of amides were generated in good to excellent yields.

Full text of DOI:10.1021/acs.joc.0c01222

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Article
Oxidative Amidation of Amines in Tandem with
Transamidation: A Route to Amides using Visible-Light Energy
Jyoti Nandi, Matthew Vaughan, Arturo Leon Sandoval, Joshua Paolillo, and Nicholas E. Leadbeater
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01222 • Publication Date (Web): 15 Jun 2020
Downloaded from pubs.acs.org on June 16, 2020
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Oxidative Amidation of Amines in Tandem with Transamidation: A Route to
Amides using Visible-Light Energy
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Jyoti Nandi, Matthew Z. Vaughan, Arturo León Sandoval, Joshua M. Paolillo, and Nicholas E. Leadbeater*
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Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, Connecticut 06269, United States
nicholas.leadbeater@uconn.edu
ABSTRACT
A methodology is reported for preparing amides using amines as an acyl source. The protocol involves the
visible-light promoted oxidative amidation of amines with pyrazole to synthesize N-acyl pyrazoles,
followed by transamidation. By combining photoredox catalysis with oxoammonium cations in the
presence of sodium persulfate as a terminal oxidant, the N-acyl pyrazoles could be prepared efficiently
and effectively using blue LED light. The transamidation step was performed without the need to purify
the N-acyl pyrazole intermediate, and a range of amides were generated in good to excellent yield.
INTRODUCTION
Amides are ubiquitous in biological systems, as well as the motif being found in pharmaceuticals,
agrochemicals, and polymers.1-3 In addition, transformation of an amide bond can afford an array of
synthetically important functionalities including imines, aldehydes, amides, nitriles, and oximes.4-6 As a
result, simple and effective routes to amides are highly sought after both in academic and industrial
settings. The traditional way to synthesize amides involves the coupling of amines with activated
carboxylic acids.7 However, the pre-functionalization steps required can make the overall synthetic route
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inefficient. The metal-catalyzed direct amidation of carboxylic acids with amines has also been
investigated but frequently requires the use of elevated temperature and continuous removal of water.7a
More recently, visible-light energy has been used as a mild and powerful tool to construct amide bonds
from aldehydes. However, the methods either require chlorinated reagents, such as BrCCl3 and N-
chlorosuccinimide, chlorinated solvents, or pre-functionalization steps.8
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The direct conversion of alcohols to amides by reaction with amines is an attractive alternative. This
amidation strategy can be conducted either through a dehydrogenative or an oxidative pathway (Scheme
1a). In the case of the former, the first step of the process involves the extrusion of hydrogen and is
performed under reflux conditions and / or in the presence of a strong base.9-12 The tandem oxidative
pathway (TOP) can be performed using milder conditions.13 Both processes involve the intermediacy of
an aldehyde and, as a result, the obvious starting materials are alcohols. To our knowledge, the conversion
of amines to amides by means of a TOP approach has not been explored to date (Scheme 1b).14-16 A wide
array of amines are commercially available or else simple to prepare. In addition, they can be synthesized
in the form of a salt by treating with an acid, often making them easier to isolate and purify compared to
the corresponding alcohol. As such, amines prove valuable starting materials in industrial applications, for
example in the drug-discovery process.16
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Amidation of alcohols
(a)
4
5
Dehydrogenative Pathway
OH
NR'R"
6
7
8
9
O
O
cat. [M]
R
cat. [M]
-H2
NHR'R"
O
R
OH
-H2
R
R
R
R
NR'R"
NR'R"
M= Ru, Rh, Ag
Tandem Oxidative Pathway (TOP)
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OH
NR'R"
cat. [M]
O2
cat. [M]
O2
NHR'R"
R
O
R
OH
M= Cu, Au or Au/Co
Unexplored pathway: Tandem Oxidative Amidation of amines
(b)
O
cat. [M]
oxidant
H2O
cat. [M]
R
R
NH
O
R
NH2
R
NR'2
oxidant, NHR'2
Scheme 1. Amidation of alcohols and amines
In the field of oxidation chemistry, our group has demonstrated the oxidative amidation of alcohols and
aldehydes using a range of azoles as the amine source to furnish N-acyl azoles.17 As well as being of interest
themselves, N-acyl azoles are considered as activated amides and can participate in transamidation
reactions and other functional-group interconversions.18-20 A metal-free, environmentally benign, and
recyclable oxidant, 4-acetamido-2,2,6,6 tetramethylpiperidine-1-oxoammonium tetrafluoroborate
(AcNH-TEMPO+BF4 , 1) has been used for this oxidative transformation (Scheme 2a).21 However, the
-
demand for a super-stoichiometric quantity of the oxidant 1 limits the synthetic utility of the method.
Photoredox catalysis has become an attractive tool in synthetic chemistry because of the ability to forge
new bonds under very mild conditions by garnering visible-light energy.22-25 To address the limitation of
the oxoammonium cation-mediated oxidation reactions, we devised a dual catalytic system by merging
photoredox catalysis with the pro-oxidant of 1, ACT (AcNH-TEMPO, 2). As part of this, 2 participates in a
single electron transfer (SET) process with the oxidized photocatalyst to form the active oxoammonium
cation oxidant, 1, in-situ which in turn performs the desired oxidation by hydride transfer. The application
of this strategy allowed us to perform the oxidative amidation of aldehydes with azoles in a catalytic
setting. In addition, we could extend this method to a one-pot two-step oxidative amidation of alcohols
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by means of in-situ generation of aldehydes from alcohols (Scheme 2b).20 To illustrate the synthetic
applicability of our developed dual catalytic system, our group has explored other oxidative
transformations by using visible-light energy.26-28
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NHAc
a. Stoichiometric pathway
1
(2.5-5 eq.)
N
O
pyridine (2.25 eq.)
DCM, rt
BF4
H
N
R
OH
O
O
1
Y
or
Z
R
azole
R
NHAc
N-acyl azoles
(1.2-1.5 eq.)
Y, Z: CH or N
b. Catalytic pathway
2
Ru(bpy)3(PF6)2 (2 mol%), (20 mol%)
N
O
Na2S2O8 (2.2-5 eq.), pyridine (2.5-5 eq.)
MeCN, blue LEDs, rt
2
Scheme 2. Oxidative amidation of alcohols and aldehydes to afford N-acyl azoles
Inspired by our earlier work on photoamidation, we decided to turn our attention to the development of
a TOP route for the visible-light promoted oxidative amidation of amines with pyrazole to synthesize
N-acyl pyrazoles. We would use Ru(bpy)3(PF6)2 as the photocatalyst in conjunction with a catalytic amount
of 2 in the presence of a terminal oxidant such as sodium persulfate. The oxidation of the amine starting
material to the corresponding imine would be followed by hydrolysis to the aldehyde by a residual amount
of water in the system.29-30 Alternatively, an amine can be independently oxidized to an imine/aldehyde
by the sulfate radical anion in combination with the photocatalyst, Ru(bpy)3(PF6)2.31 Once generated via
either pathway, the aldehyde would engage in a second oxidation event with pyrazole to yield the desired
N-acyl pyrazole product. Finally, the N-acyl pyrazole could be coupled with different amines to afford a
wide variety of amides by means of a transamidation reaction. Overall, this two-step oxidative route in
tandem with transamidation would provide access to amides by the oxidation of amines via the
intermediacy of N-acyl azoles and could feasibly be performed in a one-pot approach (Scheme 3).
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R
NH
O
hv
O
NHR'2
pyrazole
5
6
7
H2O
N
ACT
Na2S2O8
Ru
R
NH2
R
N
R
NR'2
R
O
8
9
Tandem Oxidative Pathway (TOP)
Transamidation
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Scheme 3. Proposed strategy for preparing amides using amines as an acyl source
RESULTS AND DISCUSSION
We embarked on reaction optimization studies for the photoamidation of amines to N-acyl-pyrazoles by
using our previously developed conditions for the photoamidation of alcohols and aldehydes as a starting
point.20 A test reaction was performed using benzylamine (3a) as a model substrate, with Ru(bpy)3(PF6)2
(2 mol%) as the photocatalyst, ACT (2, 20 mol%) as the primary oxidant, sodium persulfate (5 eq.) as the
secondary oxidant, and pyridine (5 eq.) as base. The reaction mixture was exposed to blue LED light.
During the optimization studies, a number of side-products were observed. While the corresponding
nitrile was the major off-target product formed, we also observed benzaldehyde, benzoic acid, and the
homo-coupled imine. These are commonly observed in a TOP involving amines and often this impurity
profile makes the optimization process challenging.13,14a The use of pyrazole (1.5 eq.) as a non-oxidizable
N-coupling partner for the amidation of benzylamine afforded 86% of the N-acyl pyrazole product, 4a and
9% of the nitrile, 4b (Table 1, entry 1). The replacement of pyrazole with imidazole resulted in no
amidation product being formed. Instead, benzaldehyde and benzoic acid were obtained (entry 2). This
can be explained by the higher basicity of imidazole relative to pyridine resulting in the formation of the
non-nucleophilic imidazolium ion in place of acyl pyridinium ion, this preventing the amidation step to
yield the N-acyl imidazole. Turning focus to the quantity of pyrazole used, reducing from 1.5 eq. to 1.1 eq.
resulted in a drop-in product yield from 86% to 75% whereas increasing the pyrazole loading to 3.5 eq.
had no significant effect in outcome (entries 3 and 4). Next, we screened alternative photocatalysts,
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namely [Ir(dtbbpy)(ppy)2]PF6 and 9-mesityl-10-methylacridinium tetrafluoroborate in lieu of
Ru(bpy)3(PF6)2. Neither of these resulted in an improvement in product conversion (entries 5 and 6).
Returning to Ru(bpy)3(PF6)2 but changing the light source from blue LEDs to white LEDs showed a very
slight diminution in the effectiveness (entry 7) indicating that the former was optimal for this
photoreaction. Next, we varied the ACT loading, firstly reducing from 20 mol% to 12 mol%, and then
increasing to 30 mol%. Where the former resulted in less product, the latter showed a slight increase in
conversion to 4a (entries 8 and 9), in light of which we opted to remain at an ACT loading 20 mol%.
Increasing the photocatalyst loading from the original 2 mol % to 4 mol% showed no change in outcome
(entry 10). However, the reducing in the photocatalyst loading to resulted in an appreciable drop in
conversion to 4a from 86% to 81% (entry 11). Changing the persulfate salt from sodium to potassium
reduced the conversion to 4a down to 26% (entry 12). While 5 equiv of sodium persulfate is required for
the methodology, as a mild and an inexpensive terminal oxidant it has been used previously in these
amounts in other photocatalytic reactions in order to obtain optimal results.20,28,33
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We next investigated the effect of varying the base used in the reaction. Of the pyridine bases screened,
those bearing substituents at the 2- and 6-position led predominantly to benzaldehyde formation (entries
13 and 14) whereas bases with no substitution at these positions yielded 4a as the major product (entries
1 and 15). This structural dependence of pyridine bases suggests that amidation of benzaldehyde occurs
via the formation of an acyl pyridinium ion followed by attack of pyrazole to afford the N-acyl pyrazole,
4a. The formation of the acyl pyridinium intermediate is also suggested by our previous reports and other
literature on oxidative functionalization of alcohols and aldehydes.17,32 The use of strong bases such as
DABCO, DBU and DMAP significantly reduced the formation of the acyl pyrazole product (entries 16-18),
this being in line with the fact that tertiary amines can cause the reductive quenching of the excited
2+
photocatalyst [Ru(bpy)3 ]* leading to reduction of organic functionalities instead of oxidation reactions.
While a mineral base, Cs2CO3, resulted in partial oxidation of the benzylamine, the homo-coupled imine
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was observed as the major product (entry 19). We concluded that pyridine is the ideal choice for the
desired transformation. While 5 equiv of pyridine is required for the methodology, it is noteworthy that
it is a multifaceted reagent in our system. It activates the aldehyde via the formation of an N-acyl
pyridinium ion, sequesters any acid generated in the reaction, and avoids the inhibition of the oxidation
reaction by preventing protonation of the amine starting material and aldimine intermediate.17, 20, 28-30
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We next probed the effects of two operational changes. Firstly, placement of a vent needle in the top of
the otherwise sealed reaction vessel, and secondly addition of a catalytic amount of lithium
tetrafluoroborate as an additive, the latter being previously reported to activate imines and aldehydes in
similar reactions.34 While individually these modifications did not have a noticeable impact on outcome
(entries 20 and 21), when used in tandem a significant increase in product conversion was observed (entry
22). These final changes then provided us with optimized conditions for the transformation and a 91%
conversion to 4a. Of note, other lithium salts were less effective; both lithium sulfate and lithium
perchlorate gave lower conversion to the desired product (86% and 75% respectively). Using lithium
persulfate as a simple replacement for the mix of sodium persulfate and lithium tetrafluoroborate was
not a viable option given that Li2S2O8 is not commercially available.
We concluded our optimization studies by performing a series of control experiments. These confirmed
that the photocatalyst, ACT and light are essential for the successful outcome of the transformation. In
their absence, benzaldehyde is observed as the major product (entries 23-25). Removal of sodium
persulfate from the reaction resulted in the formation of 95% of homo-coupled imine, 4c, indicating that
the terminal oxidant is required to achieve complete oxidation of 3a to 4a (entry 26).
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Table 1: Optimization of reaction conditions for the conversion of amines to N-acyl pyrazolesa
O
N
N
NH2
Ru(bpy)3(PF6)2, ACT
Na2S2O8, pyridine
N
HN
N
N
7
8
blue LEDs, rt, MeCN, 24 h
3a
4a
4b
4c
9
entry pyrazole eq. Ru(bpy)3(PF6)2 eq.
ACT eq. Na2S2O8 eq. pyridine eq. 4ab (%) 4bb (%)
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1
2c
1.5
1.5
1.1
3.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.04
0.01
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
NA
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.12
0.30
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
NA
5
5
86
0
9
2
5
5
3
5
5
75
85
45
2
12
7
4
5
5
5d
6e
7f
5
5
17
<1
11
12
9
5
5
5
5
82
77
89
86
81
26
23
12
75
-
8
5
5
9
5
5
10
11
12
13
14
15
16
17
18
19
20g
21h
22i
23
24
25j
26
5
5
5
5
5
8
K2S2O8
5
24
10
22
4
5
5
2,6-lutidine
collidine
5
3,5-lutidine
5
DABCO
-
5
DBU
10
<1
-
3
5
DMAP
3
5
Cs2CO3
trace
9
5
5
5
5
5
5
5
5
86
86
91
6
5
8
5
9
5
3
0.02
0.02
0.02
5
20
-
3
0.20
0.20
5
-
NA
-
-
aReaction conditions: 3a (0. 5 mmol, 1 eq.), pyridine (5 eq.), pyrazole (1.5 eq.), Ru(bpy)3(PF6)2 (0.02 eq.), ACT (0.20 eq.), Na2S2O8
(5 eq.) in MeCN (1 mL, 0.5 M) for 24 h, irradiating with blue LEDs. bConversions are determined by GCMS. cImidazole was used in
place of pyrazole, expected product was N-acyl imidazole. d[Ir(dtbbpy)(ppy)2]PF6 was used in place of Ru(bpy)3(PF6)2. e9-mesityl-
10-methylacridinium tetrafluoroborate was used in place of Ru(bpy)3(PF6)2. fWhite LEDs were used in place of blue LEDs.gReaction
vial was equipped with a vent needle. h30 mol% of anhydrous LiBF4 was added. iReaction was performed with both a vent needle
and the addition of 30 mol% anhydrous LiBF4. jPerformed in absence of light.
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To study the effect of the nitrogen base and also the lithium ion on the formation of the intermediate acyl
pyridinium ion via the nucleophilic attack on benzaldehyde, quantum chemical calculations were
performed using Gaussian 16.35 The method involved geometry optimization and vibrational frequency
calculations in the gas phase at the B3LYP/6-31+g(d,p) level of theory, and B3LYP/6-31+g(d,p) for the
transition states.36 This study showed that the lithium ion reduces the energy barrier for the nucleophilic
attack of pyridine on the carbonyl group of benzaldehyde in comparison to the sodium ion by 4.3 kcal/mol
(Figure 1a). Next, we also calculated energies for the attack of different nitrogen bases on the lithium-
bound benzaldehyde. Pyridine bases bearing substituents in the 2- and 6-positions, such as 2,6-lutidine
and collidine, showed a higher activation enthalpy than that of the less sterically-encumbered analogues,
pyridine and 3,5-lutidine (Figure 1b). These computational results supported our experimental results,
where the amidation reaction was found to be faster with more nucleophilic bases than the sterically-
encumbered ones (Table 1, entries 1 and 13-15). Furthermore, the direct attack of pyrazole in place of
pyridine showed a higher energy barrier which was also borne out by experimental results. A reaction
with 6.5 equivalents of pyrazole in the absence of pyridine resulted in a significant drop in the selectivity
for the amidation process with the formation of 46% of benzaldehyde, 19% benzoic acid, and 15% N-acyl
pyrazole (4a). All these results provide evidence for the formation of the acyl pyridinium ion via the
nucleophilic attack of pyridine on the lithium-activated aldehyde followed by reaction of pyrazole with
the acyl pyridinium ion to afford the N-acyl pyrazole.
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Li
H
Li
H
O
O
N
N
5
6
7
Li
H
O
Li
H
Li
O
O
H
H
N
N
N
N
Li
H
N
O
O
8
9
Na
17.0
15.1
11.1
Na
O
H
O
16.6
14.3
H
Li
H
N
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N
N
10.7
10.6
Li
O
H
H
6.3
N
8.5
5.2
5.2
N
Energy
Energy
6.3
3.9
Li
Li
N
N
O
O
O
O
H
H
N
Na
Li
H
N
H
H
N
O
O
1.9
0
0
Li
Li
H
N
Li
N
N
O
+
H
H
N
N
N
N
(a)
(b)
Figure 1: Reaction profiles for the reaction of benzaldehyde (a) with pyridine in the presence of sodium
and lithium ions, and (b) with different pyridine bases and pyrazole in the presence of a lithium ion
After establishing the optimized conditions for the synthesis of N-acyl pyrazoles, we investigated the
substrate scope of the methodology in tandem with a transamidation reaction. Our motivation for this
comes about from the fact that while N-acyl pyrazoles are of interest in their own right, they also serve as
valuable intermediates for the generation of more conventional amides. Initially, a series of benzylamines
bearing different substituents were screened in the photoamidation with pyrazole to afford N-acyl
pyrazoles. The crude acyl pyrazole products were obtained by simple filtration of the reaction mixture
with diethyl ether through a fritted funnel followed by the removal of the solvent. The filtration step is
necessary to avoid the subsequent oxidation of the amine coupling partner in the transamidation step,
either by the photocatalyst or the oxoammonium cation. Cyclohexylamine was selected as the initial
amine coupling partner for the transamidation of N-acyl pyrazole products to afford amides, 5a-5j. The
results are summarized in Table 2. The transamidation step was performed using acetonitrile as the
solvent. In the case of benzylamine (3a), the desired amide 5a was obtained in 69% isolated yield over
both steps. While the addition of triethylamine in the transamidation step did not further improve the
overall yield of 5a, a slight increase to 70% was observed when molecular sieves were added.20,37 With this
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modification in hand, a range of substituted benzylamines were screened for the TOP in tandem with
transamidation under our optimized conditions, in each case the desired cyclohexylamide product (5c-5j).
These included representative ortho, meta-, and para-substituted benzylamines, along with a poly-
substituted example. At this juncture, we also wanted to see if we could reduce the reaction time for the
first step; the formation of the acyl pyrazole intermediate. We performed the step using benzylamine (3b)
for 16 h instead of 24 h, and then concatenated this with the transamidation with cyclohexylamine.
Instead of the 63% isolated yield obtained over both steps when performing the first step for 24 h, we
obtained a 59% yield when reducing the reaction time to 16 h. This confirmed that the full 24 h for the
first step is required for optimal results. We also explored the expansion of the methodology to aliphatic
amines, however they were not found to be amenable to our methodology. In the case of n-butylamine
as a test case, we found that the reaction led to off-target oxidation events. The success of benzyl-
functionalized substrates but the failure of aliphatic examples leads us to believe that the benzyl group
activates the α-carbon of the benzyl amines to undergo hydride transfer and facilitates the process by
which the aminium radical cation undergoes hydrogen-atom transfer (HAT) to form the aldimine. The lack
of success of oxidation in the case of aliphatic substrates is not unprecedented; the oxidation of amines
with sodium periodate and TEMPO is not applicable for non-benzylic amines.6
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Table 2: Substrate scope of benzylamines for the conversion to cyclohexylamides by means of a
concatenated photoamidation and transamidation protocola,b
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6
7
NH2
O
O
pyrazole (1.5 eq.), pyridine (5 eq.)
LiBF4 (30 mol%), ACT (20 mol%)
N
NH2
MeCN (1M)
N
N
R
R
R
H
Ru(bpy)3(PF6)2 (2 mol%), Na2S2O8 (5 eq.)
blue LEDs, rt, MeCN (0.5 M), 24 h
3 Å M.S., 16 h
3
crude after
filteration
(3 eq.)
5
8
9
O
O
O
O
N
N
N
H
N
H
H
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H
Me
MeO
Ph
5a
5b
5c
5d
(68%)
(70%)
(63%)
(54%)
O
O
O
N
N
H
N
H
H
F3C
Cl
F
5e
5f
5g
(74%)
(72%)
(73%)
O
O
O
Cl
N
H
N
H
N
H
F
Br
F
5h
5i
5j
(72%)
(65%)
(70%)
aReaction conditions for the photoamidation step: 3 (1 mmol, 1 eq.), pyridine (5 eq.), pyrazole (1.5 eq.), anhydrous LiBF4 (0.30
eq.), Ru(bpy)3(PF6)2 (0.02 eq.), ACT (0.20 eq.), Na2S2O8 (5 eq.) in MeCN (1 mL, 0.5 M) for 24 h with a vent needle on top and
irradiated with blue LEDs; reaction conditions for the transamidation step: cyclohexylamine (3 eq.), MeCN (1 M), 3 Å M.S. (220
mg) for 16 h. bOverall isolated yields.
Moving beyond cyclohexylamine, we wanted to explore a range of amines in the transamidation step
(Table 3). We examined various acyclic primary and secondary amines, using
p-trifluoromethylbenzylamine as the progenitor to the N-acyl pyrazole intermediate (5k-5n). In each case
a greater than 70% isolated yield was obtained over the two steps. A cyclic amine, piperidine was
amenable to this tandem oxidative route (5o), as was benzylamine, a more challenging nucleophile (5p).
Next, we moved our attention to substituted amines including those bearing methoxy and trifluoromethyl
substituents along with tryptamine (5q-5s). The respective transamidation products were obtained in
good yield in good to fair yields. A synthetically important amide, N-adamantylbenzamide, 5t, was also
synthesized using the protocol; the amide being previously employed in iridium-catalyzed C-H amination
reaction.38 To test the generality of the method, an electron rich azole, p-tolyl-N-pyrazole was also used
as the N-acyl intermediate. Employing N-butylamine and benzylamine in the transamidation step, the
desired products 5u and 5v were obtained in good yields.
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The plausible mechanism of the oxidation of amines with our developed dual catalytic system of
ACT/Ru(bpy)3(PF6)2 is outlined in Figure 2. The following possible sequence of steps are proposed based
on our previously published mechanism20 and leverages prior art and electrochemical data: (a) excitation
of the photocatalyst, RuII complex to *RuII upon irradiation with blue light; (b) oxidative quenching of *RuII
to RuIII by the terminal oxidant, Na2S2O8 via single-electron transfer; disproportionation of the persulfate
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-
•-
ox
ion to generate a sulfate anion (SO4 ) and a sulfate radical anion (SO4 ); (c) oxidation of the ACT (2) (E1/2
red
[ACT/ACT+] = 0.61 V vs. SCE) to form the primary oxidant, ACT+ (1) in situ by the RuIII (E1/2 [RuIII/RuII] =
1.29 V vs. SCE)29,39 regenerating the photocatalyst, RuII; (d) formation of the aldimine 7 and the N-acyl
pyridinium ion 8 by hydride-transfer to ACT+ (1) affording the hydroxylamine 6; (e) regeneration of the
ACT (2) from 6 via hydrogen-atom transfer (HAT) to the SO4•- radical anion.
The proposed mechanism of the reaction also allows us to account for the five equivalents of pyridine and
sodium persulfate required for the reaction. In the case of pyridine, one equiv is required to facilitate
hydride transfer in the oxidation of the amine substrate to the aldimine intermediate, one equiv is needed
to form the N-acyl pyridinium ion en-route to the N-acyl pyrazole product, two equiv are consumed in the
comproportionation of 6 and 1 to 2, and the final equivalent avoids protonation of the amine substrate
during the course of the reaction. In the case of sodium persulfate, one equiv is required for the overall
oxidation of the amine starting material to the aldimine intermediate by either converting hydroxylamine
6 to 2 or oxidizing the aminium radical cation to the aldimine via HAT. A second equivalent of sodium
persulfate is needed for the overall oxidation of the aldehyde intermediate to the N-acyl pyrazole by
converting 6 to 2 by HAT. A further 2 equiv are consumed in resetting the ACT cycle by converting 6 and
1, formed in a comproportionation reaction, back to 2. The final equivalent of sodium persulfate is needed
to help compensate for its partial solubility in the acetonitrile solvent used, and thereby allow us to
achieve full oxidation of the amine starting material to the N-acyl pyazole product.17, 21, 30, 31
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Table 3: Substrate scope of transamidation coupling partner in a concatenated photoamidation and
transamidation protocola,b
O
O
pyrazole (1.5 eq.), pyridine (5 eq.)
LiBF4 (30 mol%), ACT (20 mol%)
N
NHRR' (3 eq.), MeCN (1M)
3 Å M.S., 16 h
NH2
N
NHRR'
R
R
R
Ru(bpy)3(PF6)2 (2 mol%), Na2S2O8 (5 eq.)
blue LEDs, rt, MeCN (0.5 M), 24 h
3
crude after
filteration
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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40
41
42
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45
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49
50
51
52
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O
O
O
O
N
H
N
N
Ph
N
H
H
H
6
F3C
F3C
F3C
F3C
5l
(72%)
O
5k
5m
5n
(76%)
O
(73%)
O
(75%)
O
F
Ph
N
N
F
N
N
H
H
H
MeO
F
F3C
F3C
F3C
F3C
5o (
5p
5q
5r
66%)
O
(73%)
O
(69%)
O
(68%)
O
N
Ph
H
NH
N
H
N
H
NH
Me
2
F3C
Me
F3C
5s (
5t
5u
5v
(66%)
76%)
(33%)
(64%)
aReaction conditions for the photoamidation step: 3 (1 mmol, 1 eq.), pyridine (5 eq.), pyrazole (1.5 eq.), anhydrous LiBF4 (0.30
eq.), Ru(bpy)3(PF6)2 (0.02 eq.), ACT (0.20 eq.), Na2S2O8 (5 eq.) in MeCN (1 mL, 0.5 M) for 24 h with a vent needle on top and
irradiated with blue LEDs; reaction conditions for the transamidation step: coupling amine (3 eq.), MeCN (1 M), 3 Å M.S. (220 mg)
for 16 h. bOverall isolated yields.
Figure 2: Plausible reaction mechanism for the conversion of the amines to N-acyl pyrazoles.
1
Oxidation reaction by hydride transfer to
+
RR
SO4
AcHN
N
oxidation reaction by
hydride transfer
1
OH
6
H2O
N
R
NH
HAT
-
R
NH2
R
O
HSO4
- NH3
R
H
Li
6
7
ACT cycle
N
H
AcHN
N
AcHN
N
O
1
2
O
H
N
N
R
NH2
R
R
NH2
NH
1
N
R
N
R
O
SET
N
N
N
-
SO4
2 HSO4
Li
R
O
Li+
RuII
O
RuIII
R
O
6
2-
SO4
8
N
H
SO4
photocatalytic cycle
2-
SO4
SET
*RuII
2-
S2O8
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CONCLUSIONS
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In summary, we have presented a two-step one-pot methodology for the generation of amides using
amines as an acyl source. The protocol involves the visible-light promoted oxidative amidation of amines
with pyrazole to synthesize N-acyl pyrazoles, followed by transamidation. Employing a dual catalytic
system of ACT (AcNH-TEMPO, 2) and Ru(bpy)3(PF6)2 in the presence of a terminal oxidant such as sodium
persulfate, the N-acyl pyrazoles could be prepared efficiently and effectively using blue LED light. The
transamidation step was performed without the need to purify the N-acyl pyrazole intermediate, and a
range of amides were generated in good to excellent yield.
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EXPERIMENTAL SECTION
General Considerations. NMR Spectra (1H-, 13C-, and 19F-) were performed at 300 K on a Brüker DRX-400
400 MHz spectrometer. 1H-NMR spectra were referenced either to residual CHCl3 (7.26 ppm) in CDCl3 or
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to residual DMSO-d5 (2.50 ppm) in DMSO-d6. C-NMR spectra were referenced either to CDCl3 (77.16
ppm) or to DMSO-d6 (39.52 ppm). 19F-NMR spectra were referenced to hexafluorobenzene (-164.9 ppm).
High-resolution mass spectra were collected on an Applied Biosystems QSTAR Elite equipped with an
electrospray ionization (ESI) source, calibrated using Agilent LC/MS tuning mix. Reactions were monitored
by an Agilent Technologies 7820A Gas Chromatograph attached to a 5975 Mass Spectrometer, 1H-NMR,
and/or by TLC on silica gel plates (60Å porosity, 250 μm thickness). TLC analysis was performed using
permanganate stain, p-anisaldehyde stain, and/or UV light. Flash chromatography and silica plugs utilized
Dynamic Adsorbents Inc. Flash Silica Gel (60Å porosity, 32-63 µm). Quantum chemical calculations were
performed using Gaussian 16.35 The method used for the calculations of the systems involve geometry
optimization and vibrational frequency calculations in gas phase at the B3LYP/6-31+g(d,p) level of theory
and B3LYP/6-31+g(d,p) for the transition states.36 Gibbs free energies in solution are obtained the sum of
electronic and thermal free energies. Stationary points were characterized by frequency calculations at
298 K, with structures at energy minima showing no negative frequencies and transition-states showing
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one negative frequency. All energy values shown are in kcal mol-1. Molecular figures were generated using
CYLView.
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Chemicals. The 4-acetamido-TEMPO (ACT, 2) and the photocatalyst, Ru(bpy)3(PF6)2 were prepared in
laboratory by literature protocols.21,39a All the amines employed were purchased from commercial
suppliers and distilled before use if required.
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Photochemistry. LEDs were configured as outlined in the “Photochemical Reactor Design” section of
previous articles.39b A fan was employed to ensure reactions remained at or near rt when using LEDs. The
LED-based photoreactors are designed with LED strips (Blue LEDs: 39.4 inch strips, 470 nm blue light,
32918 mcd ft-1), power supply (12V DC power supply - 60 Watt), connectors (LC2 Locking male connector
CPS adapter cable), clip fan (2-Speed clip fan, 6-inch), Pyrex crystallizing dishes (150  75 mm), aluminum
foil, and duct tape. The light components were purchased from SuperBright LEDs.
Typical Procedure for the optimization of the photoamidation step without LiBF4.
To a 2-dram reaction vial equipped with a stir-bar was added Ru(bpy)3(PF6)2 (8.6 mg, 0.02 eq.), ACT (21
mg, 0.20 eq.), and acetonitrile (MeCN, 0.5 mL). The vial was charged with pyridine (198 mg, 5 eq.) and
pyrazole (51 mg, 1.5 eq.), and the contents stirred for 2-3 min. Benzylamine (3a, 54 mg, 0.5 mmol, 1 eq.)
and Na2S2O8 (sodium persulfate, 595 mg, 5 eq.) were added to the vial followed by a further aliquot of
acetonitrile (0.5 mL). The vial was sealed with a cap and a piece of parafilm. The reaction mixture was
irradiated in the blue LED reactor for 24 h unless noted otherwise. The temperature of the reaction
mixture was maintained at approximately room temperature by using a fan positioned over the light set-
up. Upon completion of the irradiation step, the reaction mixture was quenched with ethyl acetate
(EtOAc) and product mixtures were analyzed by GC-MS.
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Typical Procedure for the optimization of the photoamidation step with LiBF4.
5
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To a 4-dram reaction vial equipped with a stir-bar was added the benzylamine (3a, 54 mg, 0.5 mmol, 1
eq.), pyridine (198 mg, 5 eq.), pyrazole (51 mg, 1.5 eq.), MeCN (0.5 mL), and anhydrous LiBF4 (14 mg, 0.30
eq.), and the mixture stirred for 5 min. The vial was then charged with ACT (21 mg, 0.20 eq.), Ru(bpy)3(PF6)2
(8.6 mg, 0.02 eq.) and Na2S2O8 (595 mg, 5 eq.), and a further aliquot of acetonitrile (0.5 mL). The vial was
sealed with a cap and the contents irradiated in the blue LED reactor for 24 h unless noted otherwise. The
temperature of the reaction mixture was maintained at approximately room temperature by using a fan
positioned over the light set-up. Upon completion of the irradiation step, the reaction mixture was
quenched with EtOAc and product mixtures were analyzed by GC-MS.
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Typical Procedure for concatenating photoamidation and transamidation.
Stage One: To a 4-dram reaction vial equipped with a stir bar was added the benzylamine (3, 1 mmol, 1
eq.), pyridine (395 mg, 5 eq.), pyrazole (102 mg, 1.5 eq.), MeCN (1 mL), and anhydrous LiBF4 (28 mg, 0.30
eq.), and the mixture stirred for 5 min. The vial was then charged with ACT (43 mg, 0.20 eq.), Ru(bpy)3(PF6)2
(17 mg, 0.02 eq.), and Na2S2O8 (1.190 g, 5 eq.) and a further aliquot of acetonitrile (1 mL). The vial was
sealed with a septum cap and a vent needle (0.5 mm × 16 mm) placed through the septum on the vial.
The contents of the vial were irradiated in the blue LED reactor for 24 h. Upon completion of the
irradiation step, the reaction mixture was quenched with anhydrous diethyl ether (Et2O) and the vial
contents filtered through a coarse-porosity fritted glass funnel. The solvent was then removed in vacuo
to afford the crude N-acyl pyrazole that was used directly in the next step.
Stage Two:
To a 50-mL round bottom flask equipped with a stir-bar was added the crude acyl pyrazole in acetonitrile
(0.5 mL) and the mixture allowed to stir for 2 min. After this time, activated 3Å molecular sieves (220 mg),
coupling amine (3 eq.), and a further aliquot of acetonitrile (0.5 mL) was added to the flask. The flask was
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then sealed with a septum and the reaction mixture stirred for 16 h at room temperature. The reaction
was quenched with EtOAc and the contents of the flask transferred to a separatory funnel and diluted
with aqueous 0.5 M HCl (100 mL). The layers were separated, and the aqueous layer was extracted with
EtOAc (3 × 50 mL). The combined organic layers were washed with 0.5 M HCl (2 × 50 mL), saturated
aqueous sodium bicarbonate (NaHCO3, 2 × 50 mL), deionized water (50 mL), and brine (100 mL). The
organic layer was dried over sodium sulfate (Na2SO4) and the solvent was removed in vacuo to afford the
crude amide, 5. Further purification was accomplished by silica plug.
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N-cyclohexyl-4-methyl-benzamide (5a).41 The title product was purified by silica plug (a gradient of 90:10
1
to 85:15; hexanes: EtOAc) and was obtained in 70% yield (152 mg) as an off-white solid. H NMR (400
MHz, CDCl3) δ 7.64 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 7.8 Hz, 2H), 6.11 (d, J = 8.1 Hz, 1H), 4.03 – 3.86 (m, 1H),
2.36 (s, 3H), 2.05 – 1.94 (m, 2H), 1.72 (dt, J = 13.4, 3.9 Hz, 2H), 1.62 (dt, J = 12.5, 3.8 Hz, 1H), 1.46 – 1.31
(m, 2H), 1.29 – 1.12 (m, 3H). 13C {1H} NMR (101 MHz, CDCl3) δ 166.6, 141.5, 132.3, 129.2, 126.9, 48.7, 33.3,
25.7, 25.0, 21.5.
N-cyclohexyl-benzamide (5b).41 The title product was purified by silica plug (a gradient of 90:10 to 80:20;
hexanes: EtOAc) and obtained in 63% yield (128 mg) as a yellow crystalline solid. 1H NMR (400 MHz, CDCl3
δ 7.74 (d, J = 7.5 Hz, 2H), 7.44 (t, J = 7.3 Hz, 1H), 7.37 (t, J = 7.5 Hz, 2H), 6.23 (d, J = 8.3 Hz, 1H), 4.00 – 3.89
(m, 1H), 2.07 – 1.87 (m, 2H), 1.77 – 1.68 (m, 2H), 1.66 – 1.57 (m, 1H), 1.44 – 1.31 (m, 2H), 1.30 – 1.10 (m,
3H). 13C {1H} NMR (101 MHz, CDCl3) δ 166.7, 135.2, 131.2, 128.5, 127.0, 48.8, 33.2, 25.6, 25.0.
N-cyclohexyl-4-methoxy-benzamide (5c).41 Modification from the general procedure: 1.5 mL of MeCN
was used for stage two to avoid stirring issue due to the immediate formation of a heavy precipitate. The
title product was purified by silica plug (a gradient of 90:10 to 70:30; hexanes: EtOAc) and obtained in 54%
yield (127 mg) as a yellowish solid. 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz,
2H), 6.18 (d, J = 8.1 Hz, 1H), 3.97 – 3.86 (m, 1H), 3.78 (s, 3H), 2.06 – 1.89 (m, 2H), 1.70 (dt, J = 13.5, 3.8 Hz,
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2H), 1.60 (dt, J = 13.5, 3.6 Hz, 1H), 1.44 – 1.28 (m, 2H), 1.28 – 1.10 (m, 3H). 13C {1H} NMR (101 MHz, CDCl3)
δ 166.2, 162.0, 128.7, 127.4, 113.6, 55.4, 48.7, 33.3, 25.6, 25.0.
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N-cyclohexyl-4-phenyl-benzamide (5d).42 Modification from the general procedure: 4 mL of MeCN and 5
mL of cyclohexylamine were used for stage two. The title product was purified by silica plug (a gradient
of 90:10 to 80:20; hexanes: EtOAc) and obtained in 68% yield (189 mg) as a white solid. 1H NMR (400 MHz,
CDCl3) δ 7.90 – 7.76 (m, 2H), 7.73 – 7.56 (m, 4H), 7.46 (t, J = 7.6 Hz, 2H), 7.38 (t, J = 7.3 Hz, 1H), 6.00 (d, J
= 8.1 Hz, 1H), 4.35 – 3.63 (m, 1H), 2.17 – 1.99 (m, 2H), 1.85 – 1.73 (m, 2H), 1.72 – 1.58 (m, 1H), 1.53 – 1.36
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(m, 2H), 1.32 – 1.18 (m, 3H). C {1H} NMR (101 MHz, CDCl3) δ 166.4, 144.2, 140.2, 133.9, 129.0, 128.1,
127.5, 127.3, 127.3, 48.8, 33.4, 25.7, 25.1.
N-cyclohexyl-4-trifluoromethyl-benzamide (5e).43 The title product was purified by silica plug (90:10;
hexanes: EtOAc) and obtained in 74% yield (201 mg) as a white crystalline solid. 1H NMR (400 MHz, CDCl3)
δ 7.85 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 5.98 (d, J = 7.7 Hz, 1H), 4.15 – 3.80 (m, 1H), 2.10 – 1.99
(m, 2H), 1.77 (dt, J = 13.5, 3.9 Hz, 2H), 1.71 – 1.56 (m, 1H), 1.50 – 1.38 (m, 2H), 1.30 – 1.20 (m, 3H). 13C {1H}
NMR (101 MHz, CDCl3) δ 165.5, 138.5 (d, J = 1.3 Hz), 133.1 (q, J = 32.7 Hz), 127.5, 125.6 (q, J = 3.7 Hz),
123.8 (q, J = 272.6 Hz), 49.2, 33.2, 25.6, 25.0. 19F NMR (376 MHz, CDCl3) δ -66.07 (s, 3F).
N-cyclohexyl-4-chloro-benzamide (5f).41 The title product was purified by silica plug (a gradient of 90:10
to 80:20; hexanes: EtOAc) and obtained in 72% yield (170 mg) as a white solid. 1H NMR (400 MHz, CDCl3)
δ 7.68 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.6 Hz, 2H), 5.96 (d, J = 7.6 Hz, 1H), 4.04 – 3.86 (m, 1H), 2.01 (dt, J =
12.4, 4.0 Hz, 2H), 1.75 (dt, J = 13.5, 3.9 Hz, 2H), 1.69 – 1.60 (m, 1H), 1.48 – 1.35 (m, 2H), 1.28 – 1.16 (m,
3H). 13C {1H} NMR (101 MHz, CDCl3) δ 165.7, 137.6, 133.6, 128.9, 128.4, 49.0, 33.3, 25.7, 25.0.
N-cyclohexyl-4-fluoro-benzamide (5g).41 The title product was purified by silica plug (a gradient of 90:10
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to 80:20; hexanes: EtOAc) and obtained in 73% yield (161 mg) as an off-white solid. H NMR (400 MHz,
CDCl3) δ 7.74 (dd, J = 8.5, 5.3 Hz, 2H), 7.02 (t, J = 8.5 Hz, 2H), 6.28 (d, J = 8.0 Hz, 1H), 4.13 – 3.74 (m, 1H),
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1.96 (dd, J = 12.3, 4.2 Hz, 2H), 1.71 (dt, J = 13.3, 3.8 Hz, 2H), 1.61 (dt, J = 13.0, 3.9 Hz, 1H), 1.44 – 1.28 (m,
2H), 1.28 – 1.10 (m, 3H). 13C {1H} NMR (101 MHz, CDCl3) δ 165.7, 164.7 (d, J = 251.3 Hz), 131.4 (d, J = 3.2
Hz), 129.3 (d, J = 8.9 Hz), 115.6 (d, J = 21.8 Hz), 48.9, 33.3, 25.7, 25.0. 19F NMR (376 MHz, CDCl3) δ -111.88
– -112.04 (m).
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N-cyclohexyl-2-fluoro-benzamide (5h).43 The title product was purified by silica plug (90:10; hexanes:
EtOAc) and obtained in 65% yield (143 mg) as an off-white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.08
(td, J = 7.9, 1.9 Hz, 1H), 7.51 – 7.37 (m, 1H), 7.33 – 7.18 (m, 1H), 7.09 (dd, J = 12.2, 8.2 Hz, 1H), 6.60 (s, 1H),
4.11 – 3.95 (m, 1H), 2.07 – 1.98 (m, 2H), 1.78 – 1.68 (m, 2H), 1.67 – 1.58 (m, 1H), 1.51 – 1.36 (m, 2H), 1.34
– 1.20 (m, 3H). 13C {1H} NMR (101 MHz, CDCl3) δ 162.4 (d, J = 3.3 Hz), 160.7 (d, J = 246.8 Hz), 133.1 (d, J =
9.3 Hz), 132.1 (d, J = 2.3 Hz), 124.8 (d, J = 3.3 Hz), 121.7 (d, J = 11.5 Hz), 116.0 (d, J = 24.9 Hz), 48.7, 33.1,
25.7, 24.9. 19F NMR (376 MHz, CDCl3) δ -117.01 – -117.15 (m).
N-cyclohexyl-3-chloro-benzamide (5i).44 The title product was purified by silica plug (a gradient of 90:10
to 85:15; hexanes: EtOAc) and obtained in 70% yield (167 mg) as a yellow solid. 1H NMR (400 MHz, CDCl3)
δ 7.72 (t, J = 1.9 Hz, 1H), 7.61 (dt, J = 7.7, 1.4 Hz, 1H), 7.44 (dt, J = 8.1, 1.5 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H),
6.01 (d, J = 8.1 Hz, 1H), 4.03 – 3.86 (m, 1H), 2.07 – 1.96 (m, 2H), 1.80 – 1.71 (m, 2H), 1.70 – 1.60 (m, 1H),
1.48 – 1.34 (m, 2H), 1.30 – 1.16 (m, 3H). 13C {1H} NMR (101 MHz, CDCl3) δ 165.4, 137.0, 134.7, 131.3, 129.9,
127.4, 125.1, 49.0, 33.2, 25.6, 25.0.
N-cyclohexyl-4-bromo-2-fluoro-benzamide (5j). The title product was purified by silica plug (a gradient of
90:10 to 80:20; hexanes: EtOAc) and obtained in 72% yield (215 mg) as an off-white solid. 1H NMR (400
MHz, CDCl3) δ 7.95 (t, J = 8.4 Hz, 1H), 7.39 (dd, J = 8.5, 1.9 Hz, 1H), 7.29 (dd, J = 11.3, 1.8 Hz, 1H), 6.52 (t, J
= 9.7 Hz, 1H), 4.06 – 3.92 (m, 1H), 2.07 – 1.94 (m, 2H), 1.79 – 1.69 (m, 2H), 1.68 – 1.58 (m, 1H), 1.49 – 1.36
(m, 2H), 1.33 – 1.19 (m, 3H). 13C {1H} NMR (101 MHz, CDCl3) δ 161.5 (d, J = 3.4 Hz), 160.2 (d, J = 250.9 Hz),
133.4 (d, J = 3.0 Hz), 128.4 (d, J = 3.3 Hz), 126.1 (d, J = 10.4 Hz), 120.8 (d, J = 11.8 Hz), 119.6 (d, J = 28.4 Hz),
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48.9, 33.1, 25.7, 24.8. 19F NMR (376 MHz, CDCl3) δ -114.81 (tdd, J = 11.6, 8.3, 2.5 Hz). HRMS (ESI/Q-TOF)
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m/z: [M + H]+ Calcd for C13H16BrFNO 300.0399; Found 300.0432
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N-n-butyl-4-trifluoromethyl-benzamide (5k).13 Modification from the general procedure: 1 M HCl was
used for the work up in place of 0.5 M HCl. The title product was purified by silica plug (a gradient of 95:5
to 90:10; hexanes: EtOAc) and obtained in 76% yield (187 mg) as a yellow crystalline solid. 1H NMR (400
MHz, CDCl3) δ 7.86 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H), 6.30 (s, 1H), 3.46 (td, J = 7.2, 5.7 Hz, 2H), 1.65
– 1.56 (m, 2H), 1.47 – 1.36 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C {1H} NMR (101 MHz, CDCl3) δ 166.4, 138.3
(d, J = 1.3 Hz), 133.2 (q, J = 32.7 Hz), 127.5, 125.7 (q, J = 3.8 Hz), 123.8 (d, J = 272.4 Hz), 40.2, 31.8, 20.3,
13.9. 19F NMR (376 MHz, CDCl3) δ -66.11 (d, J = 3.5 Hz).
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N-n-octyl-4-trifluoromethyl-benzamide (5l).45 Modification from the general procedure: 1 M HCl was used
for the work up in place of 0.5 M HCl. The title product was prepared by silica plug (a gradient of 95:5 to
90:10; hexanes: EtOAc) and obtained in 72% yield (218 mg) as an off-white-solid. 1H NMR (400 MHz, CDCl3)
δ 7.85 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 6.50 (t, J = 5.7 Hz, 1H), 3.43 (q, J = 6.8 Hz, 2H), 1.59 (q, J =
7.3 Hz, 2H), 1.37 – 1.23 (m, 10H), 0.86 (t, J = 6.7 Hz, 3H). 13C {1H} NMR (101 MHz, CDCl3) δ 166.4, 138.3 (d,
J = 1.4 Hz), 133.2 (q, J = 32.7 Hz), 127.5, 125.6 (q, J = 3.7 Hz), 123.8 (q, J = 272.5 Hz), 40.5, 31.9, 29.7, 29.4,
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29.3, 27.1, 22.7, 14.2. F NMR (376 MHz, CDCl3) δ -66.10 (d, J = 5.0 Hz). HRMS (ESI/Q-TOF) m/z: [M +
H]+ Calcd for C16H23F3NO 302.1732; Found 302.1770
N-benzyl-4-trifluoromethyl-benzamide (5m).46 The title product was purified by silica plug (a gradient of
90:10 to 80:20; hexanes: EtOAc) and obtained in 73% yield (205 mg) as a white solid. 1H NMR (400 MHz,
CDCl3) δ 7.90 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 7.41 – 7.30 (m, 5H), 6.42 (s, 1H), 4.66 (d, J = 5.7
Hz, 2H). 13C {1H} NMR (101 MHz, CDCl3) δ 166.2, 137.8, 137.8 (d, J = 1.2 Hz), 133.5 (q, J = 32.7 Hz), 129.0,
128.1, 128.0, 127.6, 125.8 (q, J = 3.8 Hz), 123.8 (q, J = 272.6 Hz), 44.5. 19F NMR (376 MHz, CDCl3) δ -66.15.
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N-(1-methylpropyl)-4-trifluoromethyl-benzamide (5n). The title product was purified by silica plug (a
gradient of 90:10 to 85:15; hexanes: EtOAc) and obtained in 75% yield (183 mg) as a white solid. 1H NMR
(400 MHz, CDCl3) δ 7.84 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 6.16 (d, J = 8.3 Hz, 1H), 4.21 – 4.00 (m,
1H), 1.65 – 1.50 (m, 2H), 1.22 (d, J = 6.6 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H). 13C {1H} NMR (101 MHz, CDCl3) δ
165.8, 138.5 (d, J = 1.3 Hz), 133.1 (q, J = 32.8 Hz), 127.5, 125.6 (q, J = 3.8 Hz), 123.8 (q, J = 272.5 Hz), 47.6,
29.8, 20.5, 10.5. HRMS (ESI/Q-TOF) m/z: [M + H]+ Calcd for C12H15F3NO 246.1106 ; Found 246.1127
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(Piperidin-1-yl)-(4-(trifluoromethyl)phenyl)methanone (5o).13 The title product was purified by silica plug
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(a gradient of 90:10 to 85:15; hexanes: EtOAc) and obtained in 66% yield (169 mg) as a white solid. H
NMR (400 MHz, Chloroform-d) δ 7.65 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 3.71 (s, 2H), 3.28 (s, 2H),
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1.71 – 1.45 (m, 6H). C {1H} NMR (101 MHz, CDCl3) δ 168.8, 140.2 (d, J = 1.5 Hz), 131.4 (q, J = 32.7 Hz),
127.2, 125.6 (q, J = 3.8 Hz), 123.9 (q, J = 272.3 Hz), 48.7, 43.2, 26.6, 25.6, 24.5. 19F NMR (376 MHz, CDCl3)
δ -66.02 (d, J = 5.3 Hz).
N-phenyl-4-trifluoromethyl-benzamide (5p).46 The title product was purified by silica plug (90:10;
hexanes: EtOAc) and obtained in 73% yield (193 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ
10.45 (s, 1H), 8.15 (d, J = 8.1 Hz, 2H), 7.91 (d, J = 8.1 Hz, 2H), 7.84 – 7.75 (m, 2H), 7.37 (t, J = 7.8 Hz, 2H),
7.13 (t, J = 7.4 Hz, 1H). 13C {1H} NMR (101 MHz, DMSO-d6) δ 164.4, 138.8, 138.8 (d, J = 1.6 Hz), 131.3 (q, J
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= 31.9 Hz), 128.7, 128.6, 125.4 (q, J = 3.7 Hz), 124.0, 123.9 (q, J = 272.5 Hz), 120.4. F NMR (376 MHz,
DMSO-d6) δ -63.65.
N-(2-methoxyethyl)-4-(trifluoromethyl)benzamide (5q). The title product was purified by silica plug (a
gradient of 85:15 to 70:30; hexanes: EtOAc) and obtained in 69% yield (171 mg) as an off-white solid. 1H
NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 6.62 (s, 1H), 3.66 (q, J = 5.1 Hz,
2H), 3.56 (dd, J = 5.6, 4.5 Hz, 2H), 3.38 (s, 3H). 13C {1H} NMR (101 MHz, CDCl3) δ 166.3, 138.0 (d, J = 1.3 Hz),
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133.3 (q, J = 32.7 Hz), 127.6, 125.7 (q, J = 3.8 Hz), 123.8 (q, J = 272.4 Hz), 71.1, 59.0, 40.0. 19F NMR (376
MHz, CDCl3) δ -66.12. HRMS (ESI/Q-TOF) m/z: [M + H]+ Calcd for C11H13F3NO2 248.0898; Found 248.0908
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N-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)benzamide (5r).47 The title product was purified by silica plug
(90:10; hexanes: EtOAc) and obtained in 68% yield (184 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ
7.89 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.1 Hz, 2H), 6.65 (s, 1H), 4.13 (qd, J = 8.9, 6.3 Hz, 2H). 13C {1H} NMR (101
MHz, CDCl3) δ 166.6, 136.6, 134.1 (q, J = 32.9 Hz), 127.8, 126.0 (q, J = 3.8 Hz), 124.2 (d, J = 278.4 Hz), 123.6
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(d, J = 272.7 Hz), 41.4 (q, J = 34.9 Hz). F NMR (376 MHz, CDCl3) δ -66.26, -75.39 (t, J = 9.0 Hz). HRMS
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N-(2-(1H-Indol-3-yl)ethyl)-4-(trifluoromethyl)benzamide (5s).48 The title product was purified by silica
plug (a gradient of 90:10 to 80:20; hexanes: EtOAc) and obtained in 76% yield (251 mg) as a yellow solid.
1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.86 (t, J = 5.6 Hz, 1H), 8.06 (d, J = 8.1 Hz, 2H), 7.85 (d, J = 8.1
Hz, 2H), 7.60 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 2.3 Hz, 1H), 7.13 – 7.04 (m, 1H), 7.03 –
6.95 (m, 1H), 3.67 – 3.53 (m, 2H), 3.00 (t, J = 7.5 Hz, 2H). 13C {1H} NMR (101 MHz, DMSO-d6) δ 165.0, 138.5
(d, J = 1.4 Hz), 136.3, 131.0 (q, J = 31.8 Hz), 128.1, 127.3, 125.3 (q, J = 3.9 Hz), 122.7, 122.6, 120.9, 118.3,
118.2, 111.8, 111.4, 40.4, 25.0. 19F NMR (376 MHz, DMSO-d6) δ 266.25.
N-(1-adamantyl)-4-(trifluoromethyl)benzamide (5t).49 Modification from the general procedure: 3 mL of
MeCN was used for stage two. The title product was purified by silica plug (a gradient of 99:1 to 95:5;
hexanes: EtOAc) and was obtained in 33% yield (107 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.80
(d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.2 Hz, 2H), 5.83 (s, 1H), 2.12 (s, 9H), 1.72 (s, 6H). 13C {1H} NMR (101 MHz,
DMSO-d6) δ 165.6, 139.6 (d, J = 1.3 Hz), 133.0 (q, J = 32.7 Hz), 127.4, 125.7 (q, J = 3.8 Hz), 128.9 – 119.5
(m), 52.9, 41.9, 36.6, 29.7. 19F NMR (376 MHz, CDCl3) δ -66.07. HRMS (ESI/Q-TOF) m/z: [M - H]- Calcd for
C18H14F3N2O 331.1058; Found 331.1014
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N-n-butyl-4-methyl-benzamide (5u).13 The title product was purified by silica plug (a gradient of 90:10
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to 80:20; hexanes: EtOAc) and obtained in 64% yield (122 mg) as a yellow viscous liquid. H NMR (400
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MHz, CDCl3) δ 7.65 (d, J = 7.8 Hz, 2H), 7.19 (d, J = 7.8 Hz, 2H), 6.31 (s, 1H), 3.42 (q, J = 6.7 Hz, 2H), 2.37 (s,
3H), 1.57 (p, J = 7.3 Hz, 2H), 1.44 – 1.33 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H). 13C {1H} NMR (101 MHz, CDCl3) δ
167.6, 141.7, 132.1, 129.2, 127.0, 39.9, 31.9, 21.5, 20.3, 13.9.
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N-benzyl-4-methyl-benzamide (5v).14a The title product was purified by silica plug (a gradient of 90:10 to
80:20; hexanes: EtOAc) and obtained in 66% yield (148 mg) as an off-white crystalline solid. 1H NMR (400
MHz, CDCl3) δ 7.69 (d, J = 7.9 Hz, 2H), 7.40 – 7.27 (m, 5H), 7.22 (d, J = 7.8 Hz, 2H), 6.49 (s, 1H), 4.63 (d, J =
5.6 Hz, 2H), 2.39 (s, 3H). 13C NMR {1H} (101 MHz, CDCl3) δ 167.4, 142.1, 138.5, 131.7, 129.3, 128.9, 128.0,
127.7, 127.1, 44.2, 21.6.
ASSOCIATED CONTENT
Supplementary Information
Complete Citation for Gaussian 16; Energy values for transition-state and ground states; Coordinates for
transition-state and ground states; and 1H, 13C, and 19F NMR spectra of synthesized compounds.
ACKNOWLEDGMENTS
The University of Connecticut is thanked for funding. We thank Dr. Adam Graichen (University of
Connecticut) for obtaining HRMS of novel compounds and Dr. Fabrizio Politano (University of Connecticut)
for helpful discussions.
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