Silver-Catalyzed, N-Formylation of Amines Using Glycol Ethers

Article abstract of DOI:10.1021/acs.joc.0c01552

A silver-catalyzed protocol was found to afford the N-formylation of amines in moderate-to-good yields. Ethylene glycol-derived, oligomeric ethers were found to function as the formylating agent, with 1,4-dioxane affording the best results. This reaction does not require the use of stoichiometric activating reagents, and avoids the use of explosive reagents or toxic gases, such as CO, as the C1 synthon. Mechanistic studies indicate a single-electron transfer-based pathway. This work highlights the ability of silver to participate in unexpected reaction pathways.

Full text of DOI:10.1021/acs.joc.0c01552

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Note
Silver-Catalyzed, N-Formylation of Amines Using Glycol Ethers
Bradley Hunter King, Michelle Liann Wang, Kate A Jesse, Guneet Kaur,
Brianna Tran, Ryan Walser-Kuntz, Robert George Iafe, and Anna G. Wenzel
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01552 • Publication Date (Web): 25 Sep 2020
Downloaded from pubs.acs.org on September 26, 2020
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The Journal of Organic Chemistry
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Silver-Catalyzed, N-Formylation of Amines Using Glycol Ethers
†
†
†
†
†
Bradley H. King, Michelle L. Wang, Kate A. Jesse, Guneet Kaur, Brianna Tran, Ryan Walser-
⸸
‡
*,†
Kuntz, Robert G. Iafe, Anna G. Wenzel
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†
Keck Science Department, Scripps, Claremont McKenna, and Pitzer Colleges, Claremont, California, 91711, United States
University of Michigan, Ann Arbor, MI 48109, United States
⸸
‡ Department of Chemistry and Biochemistry, California State University, San Marcos, California, 92078, United States
Supporting Information Placeholder
ABSTRACT: A silver-catalyzed protocol was found to afford the N-formylation of amines in moderate-to-good yields. Ethylene
glycol-derived, oligomeric ethers were found to function as the formylating agent, with 1,4-dioxane affording the best results. This
reaction does not require the use of stoichiometric activating reagents, and avoids the use of explosive reagents or toxic gases, such
as CO, as the C1 synthon. Mechanistic studies indicate a single-electron transfer-based pathway. This work highlights the ability of
silver to participate in unexpected reaction pathways.
Copper, silver, and gold—so called “coinage metals”—have a
vibrant history as three of the seven metals of alchemy. While
Scheme 1. Unexpected N-formylation of cyclic urea 1.
1
we became interested in exploring the origins and scope of this
N-formylation reaction. Such an exercise possesses a broader
utility in that N-formyl amines serve as versatile building blocks
copper has long been used for organometallic chemistry and
organic synthesis, the use of homogeneous gold and silver
catalysis is relatively new, and the special catalytic activity and
wide utility of these complexes have become increasingly
recognized.
2
3
4
1
0
in organic and bimolecular synthesis. Current methods for the
N-formylation of amines include reactions utilizing
1
1
stoichiometric activating agents and catalytic reactions that
In addition to being a catalyst in its own right, silver complexes
are frequently used for the purpose of halide abstraction in non-
aqueous systems.5 In particular, silver-mediated halogen
abstraction is regularly employed for the in-situ generation of
use either CO or CO
2
as the carbonyl synthon.1 A report by
2,13
Glorius and coworkers in 2013 described the N-formylation of
amines using a ruthenium N-heterocyclic carbene complex to
14
12c,15
catalyze the dehydrogenation of methanol. DMF
and
6
cationic gold species from a gold catalyst precursor. In this
16
DMSO have also functioned as N-formylation synthons.
capacity, we recently embarked on a research project to explore
the development of gold(I) catalysts for the hydroamination of
olefins. While testing out new complexes against an established
Many of these methods utilize harsh reaction conditions and
1
7
18
highly toxic or unstable reagents, while others require
rigorously anhydrous, inert reaction conditions.1
4,19
Recent
7
method, we observed an unexpected result (Scheme 1). After
1
3a
efforts have striven to move to more eco-friendly media.
heating for 24 h, the reaction failed to produce the desired
hydroamination product 3; instead, the N-formylated product 4
was obtained in 12% isolated yield. Further investigation found
that 4 formed alongside 3 in varying amounts when other
gold(I)/silver complex systems were used. For example, the
In 2018, Wang and coworkers reported the use of tert-butyl
hydroperoxide (TBHP; 3 equiv) to convert ethers—such as 1,4-
dioxane—into C1 synthons for the N-formylation of primary
2
0
amines. Although advantageous that metal was not required
for formylation to occur, this method failed to N-formylate both
heterocyclic and secondary amines. In addition, the use of
TBHP at elevated temperatures (90 ºC) with highly flammable
reaction of
butylphosphino))-1,1'-biphenyl]-Au(I) (10 mol%) activated
with AgSbF (10 mol%), afforded a 49% yield of 4.
1
with 1-octene using chloro[2-(di-t-
6
2
1
solvents poses a significant safety and toxicity hazard.
It is becoming increasingly reported that silver is not an entirely
innocent participant in gold-catalyzed reactions. These so-
called “silver effects” are often the result of either the direct
Table 1. Catalyst and solvent screen for the Ag-catalyzed
a
formylation of 1.
8
involvement of silver in the catalytic cycle or the result of
O
O
O
6
,9
incomplete silver activation of the gold pre-catalyst. In light
of this,
catalyst (10 mol%)
BnN
NH
BnN
N
H
solvent, 100 oC,
24 h
AuCl
S
1
4
O
P
O
N
entry
catalyst
solvent
% yieldb
O
O
O
2
(10 mol%),
Me
O
Bn
AgSbF6 (10 mol%) Bn
Me Bn

N
NH
N
N
N
N
H
5
1
-octene (200 equiv),
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1
,4-dioxane
1
3
4
1
00 oC, 24 h
Not Observed
12% yield

The Journal of Organic Chemistry
Page 2 of 8
O
CHO
NH2
N
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
AgSbF
6
81 (80)c
1
2
H
24
63
O
NH2
NHCHO
2
3
4
5
6
7
8
9
2
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
0
0
0d
48
66
4
none added
AgSbF
AgBF
AgClO
AgNO
AgOTf
AgNTf
NHCHO
6
NH2
3
4
5
6
56
54
71
36
4
MeO
Me
Cl
MeO
Me
Cl
4
NH2
NH2
NHCHO
NHCHO
N
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
57
49
0e
2
1
0
1
AgSbF
AgSbF
AgSbF
AgSbF
AgSbF
AgSbF
AgSbF
AgSbF
6
1
6
6
6
6
6
6
6
1,3-dioxane
dioxolane
12-crown-4
15-crown-5
0
0e
NH2
NH2
12
N
H
1
1
1
1
3
4
5
6
75
O
O
7
CHO
7
NH2
N
H
0
18-crown-6
0
39
O
O
O
CHO
NH
N
N
17
m-xylenef
5, 12, 33
8
9
50
a
Conducted on a 0.1-mmol scale using catalyst (10 mol%) in
respective solvent (0.08 M). GC yields. Isolated yield. Reaction
conducted at 24 C. Reaction conducted at solvent’s boiling point.
1, 5, and 20 equiv of 1,4-dioxane used, respectively.
b
c
d
N
H
40
e
CHO
f
a
Conducted on a 0.5-mmol scale using AgSbF
6
(10 mol%) in
b
1,4-dioxane (0.08 M). Isolated yields.
Herein, we report the silver(I)-catalyzed N-formylation of
amines using ethylene glycol-derived, oligomeric cyclic and
acyclic ethers as the C1 synthon.
acetonitrile as the reaction solvent in the absence of 1,4-dioxane
also failed to afford 4; only starting material decomposition was
observed.
Catalytic N-Formylation. Initial efforts were focused on
determining the origins of the observed formylation activity
using cyclic urea 1 as the model substrate (Table 1). GC yields
Productive product formation appears to require ethylene
glycol-derived, oligomeric ethers as the reaction solvent. There
is literature precedence for the formation of chelating
monomeric or dimeric complexes when silver(I) is added to 1,4-
dioxane, which may play a role in the unique reactivity
observed. In addition to 1,4-dioxane, the use of 12-crown-4
and 15-crown-5 as the reaction solvent afforded formylation
activity (Table 1, entries 13 and 14). However, yields of 4 were
observed to drop precipitously with an increase in crown ether
aperture: no formylation activity was observed when this
reaction was performed in 18-crown-6. This could be due to the
ability of silver to intercalate into the aperture created by larger
22
are reported based on response-factor determination; these
were found to correlate with isolated yields (e.g., entry 1).
Removal of the 1-octene was found to negligibly affect reaction
yields. The exclusion of the gold complex increased reaction
yield to 81% (entry 1). In contrast, no formylated product was
2
4
2
3
observed in the absence of silver complex (entries 2 and 3).
No starting material conversion occurred when the reaction was
conducted at 24 C (entry 4). The formation of 4 was observed
with a variety of silver salts (entries 5-9); the best results were
6
obtained using AgSbF .
2
5
ring sizes, deactivating it as a catalyst. The oligomeric ether
need not be cyclic: diethylene glycol diethyl ether afforded 4 in
Solvent proved to be crucial for formylation activity (Table 1,
entries 10-17). In contrast to the TBHP-promoted reaction,
which performed passably well (47% vs. 60%) using THF in
place of 1,4-dioxane, no formylation activity was observed in
the silver-catalyzed reaction using this solvent (entry 10),
hinting at a distinct reaction mechanism. No formylation
activity was also observed using 1,3-dioxane and dioxolane. It
should be noted that the use of dichloroethane, toluene, m-
xylene, and
3
9% yield (entry 16).
The sensitivity of the silver-catalyzed formylation of 1 to
reaction condition variation was investigated. Entry 1 in Table
has been scaled up to 1 mmol with no diminishment in
reaction yield. Freshly purchased anhydrous, unstabilized 1,4-
dioxane from multiple vendors afforded the same results. To
explore the use of stoichiometric amounts of 1,4-dioxane in lieu
of using it as the reaction solvent, the formylation of 1 was
investigated in m-xylene (Table 1, entry 17). Only a 5%, 12%,
and 33% yield of 4 was obtained when 1, 5, and 20 equivalents
of 1,4-dioxane were used, respectively.
2
0
1
2
6
Table 2. Formylation of primary and secondary amines in
a
1,4-dioxane.
O
AgSbF (10 mol%)
R
6
R
Variation of the amine substrate is outlined in Table 2. In
addition to cyclic urea 1, primary amines could also be
formylated (entries 1-6). Reaction yields (24-71%) were found
to be comparable to those obtained by Wang and coworkers’
NH
N
H
1
,4-dioxane
R'
o
R'
100 C, 24 h
% yieldb
TBHP report. Formylated o-phenylenediamine (entry 6) was
20
entry
amine
product
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The Journal of Organic Chemistry
obtained as its corresponding Schiff base. No conversion was
O
O
O
O
O
O
AgSbF6 (10 mol%)
,4-dioxane,
TEMPO (3 equiv)
N
1
2
3
4
5
6
7
8
9
observed when benzamide was used as the substrate (entry 7).
In marked contrast to the TBHP-promoted formylation,
heterocyclic and secondary amines were tolerated in this
reaction, affording moderate yields (entries 8 and 9).
+
BnN
NH
BnN
N
H
1
1
00 oC, 24 h
4, trace
[6+H]+
1
m/z 244.1907
This reaction proved remarkably tolerant to oxygen. While
reactions were generally set up under argon, it was later found
that stirring the reaction of 1 with 1,4-dioxane and AgSbF (10
6
Scheme 3. Formylation in the presence of the radical
scavenger TEMPO.
mol%) in air for 10 minutes prior to heating afforded no
diminishment in the yield of 4 obtained. More unexpectedly,
bubbling oxygen gas through the reaction mixture for an
equivalent amount of time (10 min) prior to heating also
afforded no change in product yield relative to the reaction set
up under argon. In contrast, reaction exposure to light—which
pressed the radical pathway of a silver-catalyzed, Meerwein
arylation. Interestingly, no diminishment in the yield of 4
relative to the BHT-free reaction was observed.
33
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The radical scavenger TEMPO is also known to suppress Ag-
catalyzed radical processes,
3
4
and there is literature
3
5
precedence for it successfully inhibiting reactions in cases
where BHT was found to have lesser influence. To investigate
this possibility, the reaction of 1 was performed in the presence
of TEMPO (2 equiv relative to 1). While the formylation
product 4 still formed, the reaction yield was cut in half.
Increasing the amount of added TEMPO to 3 equiv relative to
27
is well-known to lead to silver salt decomposition —was found
to be associated with diminished and inconsistent formylation
reaction performance; care was taken to use foil and amber vials
to minimize light contamination.
3
4
Mechanistic Studies. A deuterium isotope study was
performed to confirm that dioxane was the source of the C1
synthon. To do this, the formylation of 1 was performed using
1
led to full reaction suppression (Scheme 3). Analysis of the
crude reaction mixture via high-resolution FAB+ (MBA
matrix) confirmed the presence of the scavenged 1,4-dioxane
radical (6). The presence of 6 in the crude reaction mixture was
also confirmed by GC-MS.
1,4-dioxane-d
this, the reaction yield was observed to precipitously drop from
1% to 2%. Isolation and analysis of the formylated product via
8
as the reaction solvent (Scheme 2). Upon doing
8
high-resolution mass spectrometry confirmed the presence of a
The presence of 6 upon the addition of TEMPO hints that silver
initiates a radical pathway by forming an initial carbon radical
(7; Scheme 4). This type of radical initiation is similar to
mechanisms proposed in related reaction settings.
helps to rationalize the dramatic preference of protio-1,4-
dioxane over its deuterated analog in reaction performance. An
attempt was made to use Ag NMR to visualize the proposed
silver hydride complex; unfortunately, insufficient sensitivity
prevented observation. The observed lack of sensitivity of this
2
reaction to oxygen suggests that the reaction of O with 7, which
has been observed in 1,4-dioxane decomposition studies,
likely does not play a role in the reaction mechanism.
+
monodeuterated product by +ESI (m/z 206.1039 = [M+H] ).
1
H-NMR was used to confirm deuterium placement at the
formyl position (5) and percent incorporation. Interestingly,
despite 99% deuteration of the 1,4-dioxane used, 29% of the
formylated product isolated was found to be the protio-4.
Investigating this further, the reaction of 1 was set up again, this
time using a 50:50 mixture of protio- and deuterated dioxane.
In this case, reaction yield was found to increase to 30%, and
only 12% deuterium incorporation was observed. If it is
assumed that the dioxane is the source of all formyl protons, this
would represent a dramatic H vs. D preference. Isotope effects
9
,20,34,36
It also
1
09
37
2
8-30
of this magnitude are rarely observed,
and when they are,
Kinetic investigation using aniline as the substrate found a first-
order rate dependence on the amine. A Hammett plot using
para-substituted anilines found the reaction to be favored by
electron-donating substituents,
nucleophilicity and/or donicity plays a positive role in reaction
performance. To probe the possibility of acidic intermediates,
proton scavengers, such as 2,6-lutidine (1 equiv relative to
amine), were investigated in the reaction with 1. In this
example, reaction yield was observed to drop from 81% to 55%:
proton scav-
they are generally attributed to the role of quantum tunneling in
22
3
1
hydrogen abstraction. This being said, while it is clear from
the deuteration present that a majority of the formyl H arises
from the 1,4-dioxane, it is possible that the urea proton may be
serving to skew H/D ratios to the unexpectedly high ratios
observed.
2
2
which indicates amine
Silver salts are known to undergo single-electron transfer (SET)
processes, which are radical in nature.32 To explore this, the
formylation of 1 with 1,4-dioxane using AgSbF (10 mol%) at
6
100 C was conducted in the presence of radical scavengers.
The addition of 3,5-di-tert-butyl-4-hydroxytoluene (BHT; 2
equiv relative to 1) to the reaction mixture prior to heating was
first investigated. Tang and coworkers have previously reported
that the addition of 1 equiv of this reagent completely sup-
3
8
O
O
O
Ag(I)
+
+
HAg(0)
O
7
O
O
O
O
O
Scheme 4. Proposed initial step of Ag-catalyzed formylation
reaction.
AgSbF6 (10 mol%)
,4-dioxane-d8 (99%),
+
BnN
NH
BnN
N
H
BnN
N
D
1
00 oC, 24 h
1
[5+H]+
m/z 206.1039
1
4
1% yield
engers were not found to have a significant role in promoting
reaction.
4:5 = 29:71
Scheme 2. Deuterium isotope study.
NMR-tube experiments were performed on the reaction of 1
with 1,4-dioxane (20 equiv) in toluene-d to probe for reaction
8
intermediates and side products. Remaining starting material 1
and formylated product 4 were clearly visible via H and
1
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The Journal of Organic Chemistry
Page 4 of 8
1
3
1
C{ H} NMR after 24 h. In repetitions of this experiment, a
broad peak at  4.50 ppm was visible, which may be indicative
minutes total). Accurate mass spectrometric data were obtained
at the Caltech Mass Spectrometry Facility. GC-MS data was
obtained on an Agilent 5973C equipped with an INNOWAX
column according to the following method: 50 °C for 3 min,
followed by an increase of 15 °C per minute until 200 C,
followed by an isothermal hold at 200 °C for 20 minutes (33
minutes total). APCI mass spectral data was obtained using an
Advion Expression Compact Mass Spectrometer (CMS) set to
low temperature/low fragmentation mode.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
9
of the presence of dissolved hydrogen gas. The direct reaction
of dioxane with amine, such as that observed by Guo and
coworkers in their silver(I)-mediated oxidative amination of
ethers, was not observed. There was some preliminary
evidence via GC that oxetane—a byproduct associated with
4
0
1
,4-dioxane degradation—might be present. However, this
could not be confirmed via NMR or LC-HRMS. Other
2
0,41
conceivable reaction byproducts,
dione, carbon monoxide, formaldehyde, glyoxal, 2-
vinyloxy)ethanol, and ethylene, were also not observed via
such as 1,4-dioxane-2,5-
Benzylation
of
2-imidazolidinone
to
prepare
1-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
benzylimidazolidin-2-one (1). A 50-mL, two-necked, round-
NMR. At this point, one could envision computation serving as
a valuable tool for mechanistic insight. Unfortunately,
calculations using the rHF/6-31G* basis set have yet to
converge on a reasonable mechanistic possibility and are
ongoing. To date, a full catalytic cycle has proven elusive.
bottom flask equipped with a stirbar was flame dried and placed
in an inert-atmosphere glovebox (N ). In the glovebox, sodium
2
hydride in mineral oil (60 % w/w, 1.11 g, 27.9 mmol, 1.2 equiv)
was added to the flask. The flask was then capped with rubber
septa, removed from the glovebox, and attached to an oven-
dried condenser under a positive stream of argon. Anhydrous
tetrahydrofuran (THF; 24 mL) was syringed into the flask,
followed by 2-imidazolidinone (2.00 g, 23.2 mmol, 1.0 equiv).
The resulting suspension was stirred at ambient temperature for
A silver(I)-catalyzed N-formylation of amines has been
developed that uses ethylene glycol-derived, oligomeric ethers
as the C1 synthon. Originally found to be catalyzed by residual
silver activator present in gold-catalyzed reactions, given the
synthetic utility of N-formylated amines, this reaction is
meritorious in of itself. Reactions conducted using deuterated
1
h. Benzyl bromide (3.3 mL, 27.9 mmol, 1.2 equiv) was then
pipetted into the reaction mixture dropwise, after which it was
allowed to reflux for 24 h immersed in an oil bath. Upon
completion, the reaction was quenched using deionized water
(60 mL), and the mixture was partitioned with diethyl ether (150
mL) in a 500-mL separatory funnel. The layers were separated,
and the aqueous layer was extracted three times using 60-mL
portions of diethyl ether. The combined organics were rinsed
with brine (60 mL), dried over Na SO , filtered, and
2 4
concentrated. Purification via flash chromatography on silica
gel using 2% MeOH/98% dichloromethane (DCM) to elute
1
,4-dioxane confirmed the ether solvent to be the formylating
agent. Further investigation found this reaction to be radical-
based, tolerate air, and exhibit a substrate scope comparable or
superior to related reactions. Using this readily executed
protocol, heterocyclic, primary, and secondary amines all
afforded the corresponding N-formylated product. While higher
yielding N-formylation methods exist, the intrinsic value of this
work lies in highlighting the ability of silver to participate in
unexpected reaction pathways beyond the traditional role of
halide scavenger, particularly when oligomeric, ethylene
glycol-derived solvents and additives are used.
afforded the product as powdery, white crystals (3.52 g; 34%
43
yield); mp 125 C (lit. mp 124 C). Silica TLC: R
f
= 0.15 (5%
methanol: 95% dichloromethane; UV and KMnO
visualization). Characterization information was found to
4
EXPERIMENTAL SECTION
4
3 1
3
correlate with literature values. H-NMR (500 MHz, CDCl ,
General Information. Anhydrous dichloromethane, toluene,
20 °C) δ 7.35-7.26 (5H, m), 4.54 (1H, br s), 4.37 (2H, s), 3.42-
3.39 (2H, m), 3.32-3.29 (2H, m).
diethyl ether, and tetrahydrofuran were obtained via elution
4
2
through a solvent column drying system and degassed with
argon prior to use. The flash chromatography of compounds
was performed utilizing either silica gel 60 (32-63 micron)
Small-Scale Formylation Protocol. Small-scale reactions (0.1
mmol) in 1,4-dioxane, 15-Crown-5, 12-Crown-4, 1,3-dioxane,
dioxolane, and diethylene glycol diethyl ether employed the
following reaction protocol: to a flame-dried, septum-capped
®
purchased from Bodman Industries or Biotage SNAP KP-SIL
flash cartridges.
vial
(4
mL)
containing
a
stir
bar,
silver
Nuclear magnetic resonance (NMR) spectra were obtained
using a Bruker AVANCETM III 500 US+ NMR spectrometer.
Chemical shifts for protons are reported in parts per million
downfield from tetramethylsilane and are referenced to residual
protium in the NMR solvent (CHCl : δ 7.24; toluene = 2.09).
3
Chemical shifts for carbon are reported in parts per million
downfield from tetramethylsilane and were referenced to the
hexafluoroantimonate(V) (AgSbF ; 3.5 mg, 0.010 mmol, 0.10
6
equiv) was weighed out in the glovebox. The vial was wrapped
in aluminum foil, removed from the glovebox, and placed under
argon. Solvent (1,4-dioxane; 0.5 mL, 5.8 mmol) was added, and
the solution was allowed to equilibrate with stirring for ten
minutes. Meanwhile, a stock solution consisting of the amine
(0.12 mmol), 1,4-dioxane (1.2 mL, 14.0 mmol), and anhydrous
dodecane (14 µL, 0.06 mmol) was made in a separate, flame-
dried vial under argon. A 20-L aliquot of the stock solution
3 8
carbon resonances of the solvent (CDCl : δ 77.23; toluene-d =
2
0.4). Data are represented as follows: chemical shift,
integration, multiplicity (s = singlet, d = doublet, sep = septet,
m = multiplet, br = broad), and coupling constants in Hertz
(Hz). IR spectroscopy was performed using an Avatar 370
FTIR. Gas chromatography (GC) data was acquired on an RTX-
5 column (length = 15 m, ID = 0.25 mm, df = 0.10 m) using a
Shimadzu GC-2010. Unless otherwise specified, GC data were
acquired according to the following method: 50 °C for 3 min,
followed by an increase of 15 °C per minute for 12 minutes,
followed by an isothermal hold at 230 °C for 2 minutes (17
was diluted in dichloromethane (1 mL) for use as a GC T time
0
point. After five minutes of stirring, 1.0 mL of the stock solution
was transferred to the silver-containing reaction vial. The argon
line was removed, and the septum cap was snugly wrapped with
Teflon tape. The reaction mixture was then heated to 100 °C for
24 h in an anodized aluminum block. After 24 h, the reaction
was allowed to cool to ambient temperature. A second, 20-L
aliquot of the reaction mixture was diluted in dichloromethane
(1 mL) for use as a T24h time point.
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The Journal of Organic Chemistry
Reaction Performed in 18-crown-6. To a flame-dried vial (4
mL) containing a stir bar, AgSbF (3.5 mg, 0.01 mmol) was
Colorless oil; TLC: R
f
= 0.66 (20% hexanes in 80% ethyl
1
1
2
3
4
5
6
7
8
9
acetate; KMnO visualization); H NMR (500 MHz, CDCl , 20
6
4
3
weighed out in the glovebox. The vial was wrapped in
aluminum foil, removed from the glovebox, and placed under
argon. Next, 18-Crown-6 (1.55 g, 5.9 mmol) was added, and the
vial was heated to 75 °C to liquefy the crown ether, after which
the solution was allowed to equilibrate for ten minutes while
stirring. In a separate, flame-dried vial (4 mL), a stock solution
of 1-(phenylmethyl)-2-imidazolidinone (21.2 mg, 0.12 mmol),
°C) δ 8.06 (1H, s), 3.11 (2H, d, J = 7.6 Hz), 2.97 (2H, d, J = 7.5
Hz), 1.98-1.84 (2H, m), 0.89-0.84 (12H, m).
N-benzylformamide. 24% yield, 16 mg. Characterization
information was found to correlate with literature values.
4
6
4
6
White solid (mp 59-60 C; lit. mp 60-61 C); TLC: R
f
= 0.45
(20% hexanes in 80% ethyl acetate; UV and KMnO
4
1
1
8-Crown-6 (3.71 g, 14.0 mmol), and anhydrous dodecane
3
visualization); H NMR (500 MHz, CDCl , 20 °C) δ 8.24 (0.8H,
(14.0 µL, 0.05 mmol) was created under argon. Similar to the
s), 8.17 (0.2H, d, J = 12.0 Hz), 7.36-7.22 (5H, m), 5.80 (1H, br
s), 4.46 (1.8H, d, J = 5.9 Hz), 4.39 (0.2 H, d, J = 6.5 Hz).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
silver-containing vial, the solution was heated to 75 °C to mix
the contents, after which 2.5 mL was transferred to the vial
containing the silver solution. The reaction vial was then heated
to 100 °C for 24 h in an anodized aluminum block. A 20-L
aliquot of the stock solution was diluted in dichloromethane (1
mL) for use as a GC T time point. After 24 h, the reaction was
0
allowed to cool to ambient temperature. A second, 20-L
aliquot of the reaction mixture was diluted in dichloromethane
N-phenylformamide. 63% yield, 38 mg. Characterization
information was found to correlate with literature values. Tan
4
4
4
4
solid (mp 47 C; lit. mp 46 C); TLC: R
acetate in 60% hexanes; UV and KMnO
NMR (500 MHz, CDCl
.39 (0.5H, s), 8.30 (0.5H, br s), 7.56-7.54 (1H, m), 7.47 (0.5H,
f
= 0.36 (40% ethyl
visualization); H
1
4
3
, 20 °C) δ 8.70 (0.5H, d, J = 11.4 Hz),
8
br s), 7.40-7.32 (2H, m), 7.21-7.09 (2H, m).
(1 mL) for use as a T24h time point.
N-(4-methoxyphenyl)formamide. 56% yield, 42 mg.
General Formylation Protocol. To a flame-dried, septum-
capped, amber scintillation vial (20 mL) containing a stir bar,
Characterization information was found to correlate with
4
4
44
literature values. Tan solid (mp 79-80 C; lit. mp 79-81 C);
TLC: R = 0.22 (40% ethyl acetate in 60% hexanes; UV and
KMnO
6
silver hexafluoroantimonate(V) (AgSbF ; 17 mg, 0.05 mmol,
0
.10 equiv) was weighed out in the glovebox. The vial was
f
1
4
3
visualization); H NMR (500 MHz, CDCl , 20 °C) δ
sealed, removed from the glovebox, and placed under argon.
Solvent (1,4-dioxane; 1.4 mL, 16.4 mmol) was added with
stirring. Meanwhile, a stock solution consisting of the amine
8
7
3
.54 (0.5H, br d, J = 11.6 Hz), 8.30 (0.5H, s), 8.11 (0.5H, br s),
.44-7.41 (1.5H, m), 7.03-7.00 (1H, m), 6.88-6.83 (2H, m),
.78-3.77 (3H, m).
(0.50 mmol, 1.0 equiv) and 1,4-dioxane (4.0 mL, 46.9 mmol)
was made in a separate, flame-dried vial under argon. After five
minutes of stirring, the stock solution was transferred to the
silver-containing reaction vial. Two, 0.3-mL rinses of 1,4-
dioxane were used to ensure complete transfer. The argon line
was removed, and the septum cap was snugly wrapped with
Teflon tape. The reaction mixture was then heated to 100 °C for
24 h in an anodized aluminum block. After 24 h, the reaction
was allowed to cool to ambient temperature. The resulting
mixture was then directly purified via flash chromatography on
silica gel. Note: formylated amines exist as a mixture of two
N-p-tolylformamide. 54% yield, 36 mg. Characterization
information was found to correlate with literature values.
47,48
48
Tan solid (mp 51-52 C; lit. mp 51-53 C); TLC: R
f
= 0.27
(40% ethyl acetate in 60% hexanes; UV and KMnO
4
1
3
visualization); H NMR (500 MHz, CDCl , 20 °C) δ 8.65 (0.5H,
d, J = 11.5 Hz), 8.46 (0.5H, br s), 8.36 (0.5H, s), 7.58 (0.5H, br
s), 7.46-7.43 (1H, m), 7.28-7.13 (2H, m), 7.02-7.00 (1H, m),
2
.36 (3H, m, 3H).
N-(4-chlorophenyl)formamide. 71% yield, 55 mg.
Characterization information was found to correlate with
1
rotamers observable by H NMR.
48,49
48
literature values.
06 C); TLC: R
3
UV and KMnO visualization); H NMR (500 MHz, CDCl , 20
White solid (mp 104-105 C; lit. mp 104-
3
-Benzyl-2-oxoimidazolidine-1-carbaldehyde
(4).
Crude
1
f
= 0.28 (40% ethyl acetate in 60% hexanes;
reaction was purified via flash-column chromatography on
silica gel using 40% ethyl acetate in hexanes as the eluent to
afford the product in 80% isolated yield (82 mg) as a viscous,
1
4
°C) δ 8.63 (0.3H, d, J = 10.7 Hz), 8.36 (0.7H, s), 7.97 (0.5H, br
s), 7.49-7.47 (1H, m), 7.33-7.27 (2H, m), 7.03-7.00 (1H, m).
yellow oil. GC yield: 81%. TLC: R
f
= 0.21 (1:1 ethyl acetate in
–
1
hexanes; UV visualization); IR (thin film, cm ) 1734 (s), 1691
1
1H-benzo[d]imidazole. 36% yield, 21 mg. Characterization
information was found to correlate with literature values.
White solid (mp 170-173 C; lit. mp 172-173 C); TLC: R
(s) 1353 (m), 1260 (m); H NMR (500 MHz, CDCl
3
, 20 °C) 
4
4
9.02 (1H, s), 7.42-7.28 (5H, m), 4.51 (2H, s), 3.80-3.77 (2H, m),
4
4
1
3
1
f
=
3
1
.42-3.39 (2H, m); C{ H} NMR (125 MHz, CDCl
60.4, 154.8, 135.2, 129.0, 128.3, 128.2, 47.4, 41.4, 37.0;
[M+H] 205.0977, found m/z:
3
, 20 °C) 
0
.43 (10% methanol in 90% dichloromethane; UV and KMnO
4
1
3
visualization); H NMR (500 MHz, CDCl , 20 °C) δ 8.04 (1H,
HRMS (EI) calcd. for C11
05.0974.
13 2 2
H N O
s), 7.65 (1H, br s), 7.29 (2H, d, J = 3.1 Hz), 7.28 (2H, d, J = 3.1
Hz).
2
Piperidine-1-carbaldehyde. 50% yield, 28 mg. Characterization
44,45
Formylation of 1 on a 1-mmol Scale. To a flame-dried, septum-
capped, amber scintillation vial (20 mL) containing a stir bar,
silver hexafluoroantimonate(V) (AgSbF
information was found to correlate with literature values.
Colorless oil; TLC: R
f
= 0.27 (20% hexanes in 80% ethyl
1
6
; 34 mg, 0.10 mmol,
acetate; KMnO visualization); H NMR (500 MHz, CDCl , 20
4
3
0
.10 equiv) was weighed out in the glovebox. The vial was
°C) δ 7.99 (1H, s), 3.46 (2H, t, J = 5.7 Hz), 3.28 (2H, t, J = 5.6
Hz), 1.68-1.64 (2H, m), 1.58-1.49 (4H, m).
sealed, removed from the glovebox, and placed under argon.
Solvent (1,4-dioxane; 2.8 mL, 32.8 mmol) was added with
stirring. Meanwhile, a stock solution consisting of the amine
(1.0 mmol, 1.0 equiv) and 1,4-dioxane (8.0 mL, 93.8 mmol) was
made in a separate, flame-dried vial under argon. After five
N,N-diisobutylformamide. 40% yield, 31 mg. Characterization
4
5
information was found to correlate with literature values.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
minutes of stirring, the stock solution was transferred to the
Page 6 of 8
the solvent. Solution 1 consisted of a known amount (e.g., 0.158
mmol) of formylated amine, while Solution 2 contained
anhydrous dodecane (32.0 µL, 0.158 mmol) or tetradecane in
the case of p-Cl-aniline. From these two solutions, five, 10-mL
calibration standards were generated by combining the
dodecane and formylated solutions in ratios of 2:1, 1:1, 1:2, 1:3,
and 1:4 and normalizing the volumes to 10 mL using
chloroform. These mixtures were analyzed via GC. Actual peak
area ratios of formylated amine to dodecane were plotted
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
silver-containing reaction vial. Two, 0.6-mL rinses of 1,4-
dioxane were used to ensure complete transfer. The argon line
was removed, and the septum cap was snugly wrapped with
Teflon tape. The reaction mixture was then heated to 100 °C for
2
4 h in an anodized aluminum block. After 24 h, the reaction
was allowed to cool to ambient temperature. The resulting
mixture was then directly purified via flash chromatography on
silica gel to afford 4 in 81% yield (166 mg).
2
2
against observed peak area ratios.
NMR Tube Formylation of 1-Benzylimidazolidin-2-one. To an
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
oven-dried, J-Young tube in the glovebox, AgSbF
(1.4 mg,
ASSOCIATED CONTENT
Supporting Information
6
0.004 mmol, 0.1 equiv) was carefully added. The tube was
wrapped in foil, capped with a small septum, removed from the
glovebox, and placed under argon via a small needle inlet. To a
flame-dried, 4-mL vial under argon, 1-benzylimidazolidin-2-
one (8.5 mg, 0.048 mmol, 1.0 equiv) was added, followed by
The Supporting Information is available free of charge on the ACS
Publications website.
Full experimental details, GC response factor plots, and
NMR, IR, and mass spectra (PDF)
FAIR Data is available as Supporting Information for Publication
and includes the primary NMR FID files for compound 4, as well
as crude reactions and isotope studies related to the reaction of 1 to
prepare 4.
m-toluene-d (0.61 mL) and 1,4-dioxane (82 L, 0.96 mmol, 20
8
equiv). This solution was then transferred to the silver-
containing, J-Young tube via a mini cannula. The J-Young tube
was stoppered, and the contents mixed. The tube was then
immersed in an oil bath at 100 ºC for 24 h, after which time the
1
reaction was analyzed via H NMR.
AUTHOR INFORMATION
Corresponding Author
8
Reactions performed in 1,4-dioxane-d . To a flame-dried,
septum-capped vial (4 mL) containing a stir bar, silver
* Email: awenzel@kecksci.claremont.edu.
Notes
The authors declare no competing financial interest.
hexafluoroantimonate(V) (AgSbF ; 3.5 mg, 0.010 mmol, 0.10
6
equiv) was weighed out in the glovebox. The vial was wrapped
in aluminum foil, removed from the glovebox, and placed under
argon. Solvent (1,4-dioxane-d (99% deuterated); 1.0 mL, 11.7
8
ACKNOWLEDGMENT
mmol) was added with stirring. After 5 minutes, 1-
benzylimidazolidin-2-one (17.6 mg, 0.10 mmol, 1.0 equiv) and
anhydrous dodecane (4.5 µL, 0.02 mmol, 0.2 equiv) were
added. A 20-L aliquot of this solution was diluted in
This work was supported by a grant from the National Science
Foundation (#1566124). S. C. Virgil and M. Shahgholi are thanked
for mass spectral assistance. D. Van der Velde is acknowledged for
Ag NMR assistance. A. McNeil, M. Morales, S. McCarty, J.
Rieland, and J. Wilson are thanked for valuable scientific
discussions.
0
dichloromethane (1 mL) for use as a GC T time point. The
argon line was removed, and the septum cap was snugly
wrapped with Teflon tape. The reaction mixture was then
heated to 100 °C for 24 h in an anodized aluminum block. After
REFERENCES
2
4 h, the reaction was allowed to cool to ambient temperature.
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of
3-benzyl-2-oxoimidazolidine-1-carbaldehyde
was
determined by GC. This reaction was repeated a second time,
affording the same 2% GC yield of 3-benzyl-2-
oxoimidazolidine-1-carbaldehyde. The reactions were
combined and directly purified via flash chromatography on
silica gel to isolate 3-benzyl-2-oxoimidazolidine-1-
(
2) Copper, Silver and Gold in Catalysis; Haruta, M.; Souma, Y., Eds.;
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carbaldehyde (1 mg). Analysis via H NMR found the product
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to be 29% protio/71% deuterated. HRMS (EI+) calcd. for
C H11DN O [M+H] 206.1039, found m/z: 206.1032.
11 2 2
The reaction was repeated using 0.5 mL 1,4-dioxane and 0.5
mL 1,4-dioxane-d as the reaction solvent. GC analysis of the
24h aliquot revealed 30% yield of 3-benzyl-2-
8
T
a
oxoimidazolidine-1-carbaldehyde. This reaction was duplicated
to afford a 28% yield of 3-benzyl-2-oxoimidazolidine-1-
carbaldehyde. Product from the first and second reactions was
isolated to afford 6 mg and 5 mg, respectively. H-NMR
analysis found only 8% deuterium incorporation into the formyl
position.
1
(4) (a) Lo, V. K.-Y.; Chan, A. O.-Y.; Che, C.-M. Gold and Silver
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Generation of GC Response Factors. To generate GC
calibration curves for formylated amines, two stock solutions
were made up in volumetric flasks (10 mL) using chloroform as
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The Journal of Organic Chemistry
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2
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4
5
6
7
8
9
(
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Hydroamination of Ethylene and 1-Alkenes with Cyclic Ureas
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2
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
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O
AgSbF6 (10 mol%)
R
R
NH
N
H
1
00 oC, 24 h
R'
R'
24-81% yield
n
O
O
n = 2, 4, 5
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