Visible-Light Photocatalytic Functionalization of Isocyanides for the Synthesis of Secondary Amides and Ketene Aminals

Article abstract of DOI:10.1021/acs.joc.0c01946

A new visible light-induced photocatalytic protocol enabling the formation of secondary amides from electron-poor organic bromides and isocyanides was developed. In addition, the in situ interception of ketenimine intermediates with nitrogen nucleophiles such as amines, hydrazines, and TMSN3 afforded, in a one-pot two-step procedure, valuable scaffolds such as ketene aminals, pyrazolones, and tetrazoles. Mechanistic evidence confirmed a radical pathway where isocyanides acted as radical geminal acceptors generating key imidoyl radical species.

Full text of DOI:10.1021/acs.joc.0c01946

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Article
Visible-Light Photocatalytic Functionalization of Isocyanides for the
Synthesis of Secondary Amides and Ketene Aminals
Rolando Cannalire, Jussara Amato, Vincenzo Summa, Ettore Novellino, Gian Cesare Tron,
and Mariateresa Giustiniano*
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ABSTRACT: A new visible light-induced photocatalytic protocol
enabling the formation of secondary amides from electron-poor
organic bromides and isocyanides was developed. In addition, the in
situ interception of ketenimine intermediates with nitrogen nucleo-
philes such as amines, hydrazines, and TMSN3 afforded, in a one-pot
two-step procedure, valuable scaffolds such as ketene aminals,
pyrazolones, and tetrazoles. Mechanistic evidence confirmed a radical
pathway where isocyanides acted as radical geminal acceptors
generating key imidoyl radical species.
Scheme 1. Photocatalytic Synthetic Protocol Developed for
the Synthesis of Amides and Amidines
INTRODUCTION
■
The amide bond is one of the most important linkages in
biological molecules and is present in 25% of marketed drugs.1
Synthetic methods to achieve amide bond formation conven-
tionally rely on coupling of carboxylic acids with amines in the
presence of stoichiometric or excess condensing agents,2
whereas catalytic procedures exploiting boric acid and boron-
based reagents as well as transition-metal-catalyzed3 and N-
heterocyclic carbine-catalyzed oxidative couplings of aldehydes
with amines4 represent less conventional approaches. On the
other hand, photoredox catalysis is emerging as a powerful tool
for chemists as it allows us to exploit visible-light-absorbing
photocatalysts, which upon electron or energy transfer
processes are able to sensitize organic molecules and trigger
a photochemical reaction.5−8 In this context, some visible-
light-mediated strategies have been reported,9−11 and in
particular, the ability of isocyanides to act as geminal radical
acceptors to yield amides was recently demonstrated by Rohe
et al. describing the UV-light generation of alkyl radicals from
bromoalkanes in the presence of a dimeric gold(I) photoredox
catalyst.12 Following our interest in the study of isocyanides as
radical acceptors,13 we envisaged that visible-light photoredox
generation of C-centered radicals from simple precursors such
as bromoalkanes, followed by a somophilic isocyanide
insertion, could advantageously lead to amide derivatives
(Scheme 1, path A). During the preparation of this article,
Huang et al. reported a nickel-catalyzed aminocarbonylation of
alkyl iodides with isocyanides, which, however, was limited to
tertiary isocyanides and aliphatic iodines.14
As an added value, the protocol herein reported enabled a
photoinduced multicomponent one-pot-two-step synthesis of
ketene aminals. Indeed, the treatment of strong α-acidic
starting alkyl bromides (such as diethyl bromomalonate) under
standard reaction conditions afforded valuable ketenimines
intermediates, which were intercepted in situ with both
aliphatic and aromatic amines (Scheme 1, path B).
Received: August 31, 2020
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© XXXX American Chemical Society
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A

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Ketene aminals, structurally related to amidines, behave as
bioisosteres of thiourea, amidine, and guanidine moieties, with
improved pharmacokinetic properties, as shown in histamine
H2-receptor antagonists (e.g., ranitidine)15 and FXa inhib-
itors.16 Their synthesis is usually accomplished in three
reaction steps starting from an isothiocyanate17 (Scheme 2)
the obtainment of unsymmetrical trisubstituted products is still
considered a challenging task.
RESULTS AND DISCUSSION
■
We preliminarily explored the feasibility of amides’ formation
by reacting ethyl bromoacetate 1 (1.5 equiv) and tert-butyl
isocyanide 2 as test substrates, in the presence of fac-Ir(ppy)3
(1%) as the photocatalyst, Na2CO3 as the base (1.5 equiv), in
acetonitrile, and in the presence of H2O (20 equiv) (Table 1
entry 1).
Scheme 2. Literature-Reported Synthesis of Disubstituted
Ketene Aminals
After 20 h under blue light-emitting diodes (LEDs)
irradiation (30 W), at room temperature, we were able to
isolate the desired product 7a in a fair 54% yield. In order to
improve the reaction yield, the equivalents of the starting alkyl
halide, the catalyst, the equivalents and the nature of the base,
and different amounts of water were screened. The addition of
a sacrificial electron donor, such as diazabicyclo[2.2.2]octane
(DABCO) (1 equiv), led to a dramatic drop in the yield
(Table 1entry 2), while the use of the same amount of
DABCO (1 equiv) along with the 2-fold increase of both
bromide 1 and Na2CO3 led to an excellent yield of 97% (Table
1entry 3). Interestingly, a comparable high yield (96%) was
obtained halving both DABCO, 1, and Na2CO3 (Table 1
entry 4). Ruthenium-based catalysts proved to be unable to
promote the reaction both in the presence and in the absence
of DABCO (Table 1entries 5−7). Similarly, when the
reaction was performed with photoactive organic dyes, such as
Eosin Y and Rose Bengal, only starting materials were
detectable (Table 1entries 8−10). Attempted further
and is associated with several drawbacks such as the use of
toxic and hazardous reagents (e.g., molecular iodine and
sodium hydride) and the need for cooling (0 °C) or refluxing
the reaction mixture. Even more importantly, starting from an
isothiocyanate limited this synthetic approach to disubstituted
ketene aminals with both nitrogen atoms bearing one
substituent, whereas the use of formamidinium salts can lead
to tetrasubstituted symmetrical ketene aminals.18 Accordingly,
a
Table 1. Optimization of Reaction Conditions
a
entry
equiv of 1
PC
DABCO (equiv)
base (equiv)
H2O (equiv)
20
yield (%)
b
b
b
b
1
2
3
4
5
6
7
8
1.5
1.5
3
fac-Ir(ppy)3 (1%)
fac-Ir(ppy)3 (1%)
fac-Ir(ppy)3 (1%)
fac-Ir(ppy)3 (1%)
Ru(bpy)3(PF6)2 (1%)
Ru(bpy)3·6H2O (1%)
Ru(bpy)3PF6 (1%)
eosin Y (5%)
eosin Y (5%)
rose bengal (1%)
fac-Ir(ppy)3 (1%)
fac-Ir(ppy)3 (1%)
fac-Ir(ppy)3 (1%)
fac-Ir(ppy)3 (1%)
fac-Ir(ppy)3 (1%)
fac-Ir(ppy)3 (1%)
fac-Ir(ppy)3 (1%)
fac-Ir(ppy)3 (1%)
fac-Ir(ppy)3 (1%)
fac-Ir(ppy)3 (1%)
fac-Ir(ppy)3 (1%)
fac-Ir(ppy)3 (1%)
Na2CO3 (1.5)
Na2CO3 (1.5)
Na2CO3 (3)
Na2CO3 (1.5)
Na2CO3 (1.5)
Na2CO3 (1.5)
Na2CO3 (1.5)
Na2CO3 (1.5)
Na2CO3 (1.5)
54
traces
97
1
1
0.5
0.5
0.5
20
20
20
20
20
20
20
20
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1
96
traces
traces
traces
b
c
b
c
b
c
d
0.5
ND
ND
ND
d
9
e f
,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
b
c
0.33
0.33
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
Na2CO3 (1)
Na2CO3 (1)
20
55
b
b
b
b
b
f
c
1
MeCN/H2O 1:1
MeCN/H2O 1:1
MeCN/H2O 1:3
100%
73
c
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
Na2CO3 (1.5)
Na2CO3 (1.5)
Na2CO3 (1.5)
Na2CO3 (1.5)
Na2CO3 (1.5)
Na2CO3 (1.5)
Na2CO3 (1.5)
84
c
78
62
ND
98%
ND
ND
25%
96%
46%
ND
20
20
20
20
20
20
20
g
h
Na2HPO4 (1.5)
Na2HPO4 (1.5)
Na2CO3 (1.5)
a
b
c
d
e
f
Compound 2 0.25 mmol in MeCN 0.1 M. Degassing by freeze−pump−thaw. Yield by 1H NMR. Green LED 16 W. EtOAc as the solvent. No
g
h
degassing under an Ar atmosphere. Open flask. Under a O2 atmosphere.
B
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Figure 1. Reaction scope (standard reaction conditions as in Table 1, entry 17 performed on a 0.25 mmol scale).
optimization of reaction conditions (Table 1entries 11−16)
led to decreased yields. Very interestingly, the quantitative
yield (Table 1entry 4) was retained also without rigorous
degassing under an inert atmosphere (Ar balloon) (entry 17).
The presence of the inorganic base Na2CO3 was also essential
(Table 1entry 20), while it can be efficiently replaced by
Na2HPO4 (Table 1entry 21) but not by NaH2PO4 (Table
1entry 22), indicating that at least a base with pKa > 7 is
required to retain high yields. Finally, the photoredox nature of
the transformation was undoubtedly demonstrated (Table 1
entry 23).
C
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By adopting the optimized reaction conditions (Table 1
entry 17), we then investigated the generality of this
transformation by evaluating a variety of isocyanides and
both alkyl and aryl bromides as alkyl and aryl radical
precursors, respectively. As depicted in Figure 1, keeping
ethyl bromoacetate 1 constant, excellent yields (4−7, 86−
99%) were obtained by reacting different aliphatic primary,
secondary, and tertiary isocyanides, regardless the presence of
either cyclic or linear bulky α-branched substituents. Yet,
aromatic isocyanides (ArNC) were less efficient substrates
affording aryl amides 8 and 9 in moderate yields. Remarkably,
by changing the alkyl bromide counterpart (e.g., diethyl 2-
bromomalonate 10), both electron-rich and electron-poor aryl
isocyanides afforded compounds 11−15 in moderate to high
yields (30−85%). On the other hand, reaction of aliphatic
isocyanides under standard conditions led to the quantitative
formation of the ketenimine 16. We reasoned that its
formation could depend on the strength of the inorganic
base. Thus, different weaker bases such as NaHCO3,
Na2HPO4, and NaH2PO4 were screened, with NaH2PO4
(pKa = 2.1) able to afford amide 17, although in a moderate
yield of 44%. Still, this reoptimized reaction conditions proved
to be general as compounds 18 and 19 were obtained in 68
and 70% yields, respectively.
Further experiments indicated that the outcome of the
reaction was strongly influenced by the electronic nature of the
bromide reagent. Actually, the presence of an electron-
withdrawing group demonstrated to be essential, as 2-
bromoacetophenone 20 gave products 21−23 in excellent
yields, while more electron-rich alkyl bromides failed to give
the desired amides. Still, aryl bromides with strong electron-
withdrawing substituents in the ortho position such as 2′-
bromoacetophenone 24 afforded the corresponding amides
25−27, while deactivated bromobenzene did not react at all.
Finally, the switch from the ester moiety of alkyl bromide 1 to
a cyano-functional group in 28, albeit still exerting an electron-
withdrawing effect, showed to be detrimental (29).
To further demonstrate the preparative utility of this
methodology, a scale-up synthesis of 3 was successfully carried
out (76% yield) by using 2.5 mmol of tBuNC 2 under the
standard reaction conditions (Scheme 3A). Noteworthy,
performing the reaction under sunlight irradiation provided
the target compound 3 in a good 73% yield (Scheme 3B).
As depicted in Figure 1, diethyl bromomalonate 10 and
tBuNC 2 quantitatively afforded the ketenimine 16 under our
reaction conditions in presence of Na2CO3. As a matter of fact,
there are few methods reported in the literature to produce
such compounds, and Zhu and co-workers19 recently
published the thermal palladium-catalyzed reaction of α-
haloketones with isocyanides using toluene as the solvent.
We herein provide a mild photocatalytic protocol in a green
solvent system and at room temperature. Moreover, the
relatively stable ketenimines can be intercepted in situ by
different nucleophiles, thereby acting as a chemical platform
for divergent synthesis. Thus, we decided to explore such
reactivity in a multicomponent one-pot two-steps procedure.
After the starting tBuNC 2 and diethyl bromomalonate 10
were converted into ketenimine 16, an amine was added in
situ, while kept under stirring without further irradiation
overnight, to afford the corresponding ketene aminal.20 As
shown in Figure 2, both aliphatic and aromatic amines proved
to be competent substrates (ketene aminals 30−35). Besides
tBuNC, secondary and primary isocyanides such as cyclohexyl-
Scheme 3. (A) Scale-Up Reaction; (B) Natural Sunlight-
Induced Reaction
and n-pentylisocyanide also proved to be suitable substrates as
shown with products 37 and 38 (75 and 80% yield,
respectively; Figure 2).
Furthermore, the in situ-generated ketenimine could be
considered as a linchpin to gain access to diversely function-
alized heterocycles such as pyrazolones and tetrazoles (Scheme
4). Actually, the addition of phenylhydrazine in situ led to
product 39 in a 66% overall yield through a domino
nucleophilic addition/intramolecular transamidation, while
the use of TMSN3 afforded, via a [3 + 2] cycloaddition, the
tetrazole derivative 40 in good yield (50% overall yield).
A plausible mechanism for the reaction entails an oxidative
quenching cycle (Figure 3).6,20 Under visible-light irradiation,
the photocatalyst fac-Ir(ppy)3 undergoes a metal-to-ligand
charge transfer populating the excited state IrIII* (E(IrIV/IrIII*
= −1.73 V vs SCE)),21 which is quenched by bromoalkane 1
(ERED(1/1•− = −1.08 V vs SCE)),22,23 generating IrIV and the
corresponding alkyl radical I• after loss of a bromide anion.
Subsequently, I• is able to give a somophilic insertion into the
isocyanide 2 to form the imidoyl radical II•. The latter can be
oxidized to nitrilium ion III by the IrIV catalyst generated in the
first step (E(IrIV/IrIII = +0.77 V vs SCE))21 (path A, Figure 3).
Alternatively, DABCO could act as a sacrificial electron donor
to regenerate the IrIII photocatalyst (path B). The nitrilium ion
III is then intercepted by the bromide anion (path C) to form
imidoyl bromide IV that is eventually hydrolyzed to amide 3.
Alternatively, when diethyl bromomalonate is used as the
starting alkyl bromide, the presence of a stronger acidic α-
hydrogen led to the base-mediated formation of ketenimine 16
(path D).
This mechanistic hypothesis was further supported by
Stern−Volmer quenching experiments (Figure 4). Accordingly,
diethylbromomalonate 10 was able to quench a 4:1 MeCN/
H2O solution of fac-Ir(ppy)3 (Figure 4A), whereas DABCO
showed to be inefficient (Figure 4B), thus indicating a poor
probability of a reductive quenching cycle.
In order to provide further experimental evidences about the
proposed mechanism, we carried out the reaction in the
presence of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO),
capable of behaving as a radical trap; the resulting crude
reaction mixture was analyzed by high-resolution mass
spectrometry (HRMS), and two key radical intermediate−
TEMPO adducts (i.e., with alkyl radical I• and with imidoyl
D
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Figure 2. One-pot two-steps visible light photocatalytic synthesis of amidines (yields are calculated over the two steps).
CONCLUSIONS
Scheme 4. Photocatalytic Generation of Ketenimine 16 and
Its Use as a Chemical Platform
■
In conclusion, by combining easily available starting materials,
such as organic halides and isocyanides, we developed a new
visible light induced photocatalytic protocol enabling the
formation of secondary amides under mild conditions.
A range of electron-poor aliphatic and aromatic halides
smoothly underwent amidation with primary, secondary, and
tertiary aliphatic isocyanides as well as with aromatic ones, thus
demonstrating a wide scope and a good functional group
tolerance. Additionally, the successful in situ interception of
ketenimine intermediates with nitrogen nucleophiles such as
aromatic and both primary and secondary aliphatic amines
provided a new protocol to access challenging unsymmetrical
trisubstituted ketene aminals. Still, ketenimine intermediates
could be used as a chemical platform to synthesize, in a 3-
component-2-steps procedure, valuable drug-like structural
frameworks such as pyrazolones and tetrazoles. In sum, these
applications further validated the robustness of the developed
photoredox catalytic system, which did not interfere with nor
prevented the domino transformations attempted, thus high-
lighting the potential for future progresses in the identification
of new tandem photocatalytic/thermal processes, a valuable
but underexplored class of multicomponent reactions.
EXPERIMENTAL SECTION
General Methods. Commercially available reagents and solvents
were used without further purification. When necessary, the reactions
■
radical II•) were detected (Scheme 5 and Figures S1 and S2,
Supporting Information).
E
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Figure 3. Mechanistic hypothesis.
Figure 4. Fluorescence emission spectra of a fac-Ir(ppy)3 solution (200 μM) in the absence and presence of stepwise addition of (A) diethyl
bromomalonate (10) and (B) DABCO at 20 °C.
Scheme 5. Control Experiment: Reaction Performed in the Presence of TEMPO
were performed in oven-dried glassware under a positive pressure of
dry nitrogen. Photochemical reactions were carried out using a
PhotoRedOx Box (EvoluChem) with a 30 W blue LED (EvoluChem,
model: HCK1012-01-008, wavelength 450 nm, LED: CREE XPE. A
holder suitable for 4 mL scintillation vials (45 × 14.7 mm) has been
fitted with the Schlenk flask: this allows a fixed sample placement
distance from the light source). All NMR spectra were obtained with a
Bruker Avance NEO 400 MHz instrument. Experiments for structure
elucidation were performed in CDCl3 at 25 °C with a RT-DR-BF/
1H-5mm-OZ SmartProbe. High-resolution electrospray ionization
(ESI)-MS spectra were performed on a Thermo LTQ Orbitrap XL
mass spectrometer. The spectra were recorded by infusion into the
ESI source using MeOH as the solvent. Chemical shifts (δ) are
reported in part per million (ppm) relative to the residual solvent
peak. Column chromatography was performed on silica gel (70−230
mesh ASTM) using the reported eluents. Thin layer chromatography
was carried out on 5 × 20 cm plates with a layer thickness of 0.25 mm
(silica gel 60 F254) to monitor the reaction by using UV and/or
KMnO4 as the revelation methods.
General Procedure for the Preparation of Compounds 3−9,
11−16, 21−23, 25−27, and 29 (Method A). To a 4 mL color-less
screw-cap glass vial equipped with a magnetic stir bar were added the
isocyanide (0.25 mmol), Na2CO3 (0.375 mmol, 1.5 equiv), fac-
Ir(ppy)3 (0.0025 mmol, 1% mol), the organobromide (0.375 mmol,
1.5 equiv), and DABCO (0.125 mmol, 0.5 equiv). Then, 2.5 mL
MeCN (0.1 M) and H2O 95 μL (20 equiv) were added into the
reaction vial via a syringe. The resulting mixture was purged with
nitrogen and then stirred under 30 W blue LED irradiation at room
temperature for 20 h. Then, the reaction mixtures were poured into
water, extracted with EtOAc (3 times), the collected organic layers
F
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were washed with 1 N HCl (1 time) and brine (1 time), dried over
dry Na2SO4, and evaporated under vacuum. The reaction crude was
purified by chromatography on silica-gel.
A. The crude material was purified by column chromatography (n-
hexane/ethyl acetate 1:5%) to give the product as a pale yellow oil
(26.5 mg, 45% yield). 1H NMR (400 MHz, CDCl3): δ 9.07 (br s, 1H,
−NH), 7.20−7.16 (m, 2H), 6.79−6.75 (m, 1H), 4.26 (q, J = 7.1 Hz,
2H), 3.45 (s, 2H), 2.30 (s, 6H), 1.32 (t, J = 7.0 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 170.1, 162.7, 138.7, 137.3, 126.3, 117.9,
61.9, 41.5, 29.7, 21.4, 14.1; HRMS (ESI) m/z: calcd [M + H]+ for
General Procedure for the Preparation of Compounds 17−
19 (Method B). To a 4 mL color-less screw-cap glass vial equipped
with a magnetic stir bar were added the isocyanide (0.25 mmol),
NaH2PO4 (0.375 mmol, 1.5 equiv), fac-Ir(ppy)3 (0.0025 mmol, 1%
mol), the organobromide (0.375 mmol, 1.5 equiv), and DABCO
(0.125 mmol, 0.5 equiv). Then, 2.5 mL MeCN (0.1 M) and H2O 95
μL (20 equiv) were added into the reaction vial via a syringe. The
resulting mixture was purged with nitrogen and then stirred under 30
W blue LED irradiation at room temperature for 20 h. Then, the
reaction mixtures were poured into water, extracted with EtOAc (3
times), the collected organic layers were washed with 1 N HCl (1
time) and brine (1 time), dried over dry Na2SO4, and evaporated
under vacuum. The reaction crude was purified by chromatography
on silica-gel.
+
C13H18NO3 , 236.1281; found [M + H]+, 236.1262.
Ethyl 3-([1,1′-Biphenyl]-4-ylamino)-3-oxopropanoate (9). The
title compound was prepared following the general procedure method
A. The crude material was purified by column chromatography (n-
hexane/ethyl acetate 1:8%) to give the product as a yellow solid (19.1
1
mg, 27% yield): mp 108−110 °C; H NMR (400 MHz, CDCl3): δ
9.31 (br s, 1H, −NH), 7.69−7.63 (m, 2H), 7.61−7.55 (m, 4H),
7.47−7.41 (m, 2H), 7.38−7.33 (m, 1H), 4.28 (q, J = 7.2 Hz, 2H),
3.50 (s, 2H), 1.34 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 169.0, 161.8, 139.4, 136.4, 135.7, 127.7, 126.5, 126.1,
125.8, 119.3, 60.9, 40.3, 13.0; HRMS (ESI) m/z: calcd [M + H]+ for
Ethyl 3-(tert-Butylamino)-3-oxopropanoate (3). The title com-
pound was prepared following the general procedure method A. The
crude material was purified by column chromatography (n-hexane/
ethyl acetate 1:5%) to give the product as pale-yellow oil (45 mg, 96%
yield; 355.8 mg, 76% for the reaction performed on 2.5 mmol of
+
C17H18NO3 , 284.1281; found [M + H]+, 284.1264.
Diethyl 2-([1,1′-Biphenyl]-4-ylcarbamoyl)malonate (11). The
title compound was prepared following the general procedure method
A. The crude material was purified by column chromatography (n-
hexane/ethyl acetate 1:15%) to give the product as pale-yellow solid
(71.1 mg, 80% yield): mp 113−116 °C; 1H NMR (400 MHz,
CDCl3): δ 9.38 (br s, 1H, −NH), 7.68−7.62 (m, 2H), 7.60−7.55 (m,
4H), 7.46−7.41 (m, 2H), 7.36−7.31 (m, 1H), 4.47 (s, 1H), 4.32 (q, J
= 7.0 Hz, 4H), 1.34 (t, J = 7.1 Hz, 6H); 13C{1H} NMR (100 MHz,
CDCl3): δ 165.8, 159.9, 140.4, 137.8, 136.5, 128.8, 127.6, 127.2,
126.9, 120.5, 63.0, 59.6, 13.9; HRMS (ESI) m/z: calcd [M + H]+ for
1
tBuNC 2). H NMR (400 MHz, CDCl3): δ 6.89 (br s, 1H, −NH),
4.19 (q, J = 7.1 Hz, 2H), 3.21 (s, 2H), 1.35 (s, 9H), 1.27 (t, J = 7.2
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 170.0, 164.0, 61.4,
51.3, 42.2, 28.6, 14.0; HRMS (ESI) m/z: calcd [M + H]+ for
+
C9H18NO3 , 188.1281; found [M + H]+, 188.1273.
Ethyl 3-(Cyclohexylamino)-3-oxopropanoate (4). The title
compound was prepared following the general procedure method A.
The crude material was purified by column chromatography (n-
hexane/ethyl acetate 1:10%) to give the product as a white solid (52.8
+
C20H22NO5 , 356.1492; found [M + H]+, 356.1477.
Diethyl 2-((4-Methoxyphenyl)carbamoyl)malonate (12). The
title compound was prepared following the general procedure method
A. The crude material was purified by column chromatography (n-
hexane/ethyl acetate 1:15%) to give the product as a white solid (23.2
1
mg, 99% yield); H NMR (400 MHz, CDCl3): δ 7.01 (br s, 1H,
−NH), 4.20 (q, J = 7.1 Hz, 2H), 3.81 (ddd, J = 14.4, 10.3, 4.2 Hz,
1H), 3.28 (s, 2H), 1.96−1.84 (m, 2H), 1.75−1.65 (m, 2H), 1.64−
1.55 (m, 2H), 1.44−1.13 (m, 7H); 13C{1H} NMR (100 MHz,
CDCl3): δ 169.8, 163.9, 61.5, 48.1, 41.2, 32.8, 25.5, 24.6, 14.0; HRMS
1
mg, 30% yield); H NMR (400 MHz, CDCl3): δ 9.17 (br s, 1H,
−NH), 7.49−7.43 (m, 2H), 6.90−6.83 (m, 2H), 4.43 (s, 1H), 4.30
(q, J = 8.6 Hz, 4H), 3.80 (s, 3H), 1.34 (t, J = 8.6 Hz, 6H); 13C{1H}
NMR (100 MHz, CDCl3): δ 165.9, 159.7, 156.8, 130.3, 121.9, 114.2,
62.9, 59.5, 55.5, 13.9; HRMS (ESI) m/z: calcd [M + H]+ for
+
(ESI) m/z: calcd [M + H]+ for C11H20NO3 , 214.1438; found [M +
H]+, 214.1430.
Ethyl 3-Oxo-3-(pentylamino)propanoate (5). The title compound
was prepared following the general procedure method A. The crude
material was purified by column chromatography (n-hexane/ethyl
acetate 1:10%) to give the product as colorless oil (43.3 mg, 86%
+
C15H20NO6 , 310.1285; found [M + H]+, 310.1283.
Diethyl 2-((3,4-Dimethoxyphenyl)carbamoyl)malonate (13).
The title compound was prepared following the general procedure
method A. The crude material was purified by column chromatog-
raphy (n-hexane/ethyl acetate 1:15%) to give the product as white
1
yield). H NMR (400 MHz, CDCl3): δ 7.12 (br s, 1H, −NH), 4.20
(q, J = 7.1 Hz, 2H), 3.33−3.23 (m, 4H), 1.63−1.48 (m, 2H), 1.38−
1.21 (m, 7H), 0.90 (t, J = 6.9 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 13C{1H} NMR (101 MHz, CDCl3): δ 169.9, 164.8, 61.5,
41.0, 39.6, 29.0 (2C), 22.3, 14.0 (2C); HRMS (ESI) m/z: calcd [M +
1
solid (72.1 mg, 85% yield): mp 120−122 °C; H NMR (400 MHz,
CDCl3): δ 9.23 (br s, 1H, −NH), 7.32 (d, J = 2.4 Hz, 1H), 6.99 (dd, J
= 8.6, 2.4 Hz, 1H), 6.82 (d, J = 8.6 Hz, 1H), 4.43 (s, 1H), 4.31 (q, J =
7.1, 4H), 3.88 (d, J = 8.2 Hz, 6H), 1.33 (t, J = 7.1 Hz, 6H); 13C{1H}
NMR (100 MHz, CDCl3): δ 165.9, 159.7, 149.0, 146.2, 130.8, 112.1,
111.2, 104.9, 62.9, 59.5, 56.0, 56.0, 13.9; HRMS (ESI) m/z: calcd [M
+
H]+ for C10H20NO3 , 202.1437; found [M + H]+, 202.1423.
Ethyl 3-Oxo-3-((2,4,4-trimethylpentan-2-yl)amino)propanoate
(6). The title compound was prepared following the general procedure
method A. The crude material was purified by column chromatog-
raphy (n-hexane/ethyl acetate 1:4%) to give the product as a white
+
+ H]+ for C16H22NO7 , 340.1390; found [M + H]+, 340.1371.
Diethyl 2-((2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)carbamoyl)-
malonate (14). The title compound was prepared following the
general procedure method A. The crude material was purified by
column chromatography (n-hexane/ethyl acetate 1:15%) to give the
1
crystal solid (54.8 mg, 90% yield): mp 53−55 °C; H NMR (400
MHz, CDCl3): δ 6.92 (br s, 1H, −NH), 4.19 (q, J = 7.1 Hz, 2H), 3.21
(s, 2H), 1.75 (s, 2H), 1.42 (s, 6H), 1.28 (7, J = 6.9 Hz, 3H), 1.00 (s,
9H); 13C{1H} NMR (100 MHz, CDCl3): δ 168.5, 162.0, 59.9, 53.7,
49.9, 40.9, 30.1, 29.9, 27.6, 12.5; HRMS (ESI) m/z: calcd [M + H]+
1
product as a white solid (29.5 mg, 35% yield): mp 124−125 °C; H
NMR (400 MHz, CDCl3): δ 9.12 (br s, 1H, −NH), 7.21 (d, J = 2.4
Hz, 1H), 6.94 (dd, J = 8.7, 2.4 Hz, 1H), 6.81 (d, J = 8.7 Hz, 1H), 4.41
(s, 1H), 4.35−4.21 (m, 8H), 1.32 (t, J = 7.1 Hz, 6H); 13C{1H} NMR
(100 MHz, CDCl3): δ 165.8, 159.6, 143.5, 140.8, 130.9, 117.2, 113.8,
110.0, 64.4, 64.3, 62.9, 59.5, 13.9; HRMS (ESI) m/z: calcd [M + H]+
+
for C13H26NO3 , 244.1907; found [M + H]+, 244.1904.
Ethyl 3-(((3s,5s,7s)-Adamantan-1-yl)amino)-3-oxopropanoate
(7). The title compound was prepared following the general procedure
method A. The crude material was purified by column chromatog-
raphy (n-hexane/ethyl acetate 1:5%) to give the product as a white
crystal solid (61 mg, 92% yield). 1H NMR (400 MHz, CDCl3): δ 6.71
(br s, 1H, −NH), 4.19 (q, J = 7.1 Hz, 2H), 3.21 (s, 2H), 2.13−1.98
(m, 9H), 1.68 (s, 6H), 1.28 (t, J = 7.0, Hz, 3H); 13C{1H} NMR (101
MHz, CDCl3): δ 168.7, 162.4, 60.1, 50.8, 41.1, 40.2, 35.1, 28.1, 12.8;
+
for C16H20NO7 , 338.1234; found [M + H]+, 338.1221.
Diethyl 2-((4-Chlorophenyl)carbamoyl)malonate (15). The title
compound was prepared following the general procedure method A.
The crude material was purified by column chromatography (n-
hexane/ethyl acetate 1:15%) to give the product as pale-yellow solid
(65.9 mg, 84% yield); 1H NMR (400 MHz, CDCl3): δ 9.38 (br s, 1H,
−NH), 7.56−7.49 (m, 2H), 7.34−7.28 (m, 2H), 4.44 (s, 1H), 4.31
(q, J = 7.1 Hz, 4H), 1.33 (t, J = 7.1 Hz, 6H); 13C{1H} NMR (100
MHz, CDCl3): δ 165.7, 159.9, 135.8, 129.9, 129.1, 121.4, 63.1, 59.4,
+
HRMS (ESI) m/z: calcd [M + H]+ for C15H24NO3 , 266.1750; found
[M + H]+, 266.1731.
Ethyl 3-((2,6-Dimethylphenyl)amino)-3-oxopropanoate (8). The
title compound was prepared following the general procedure method
G
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Article
+
+
13.9; HRMS (ESI) m/z: calcd [M + H]+ for C14H17ClNO5 ,
HRMS (ESI) m/z: calcd [M + H]+ for C14H20NO2 , 234.1488; found
314.0790; found [M + H]+, 314.0784.
[M + H]+, 234.1476.
Diethyl 2-((tert-Butylimino)methylene)malonate (16). The title
compound was prepared following the general procedure method A.
The crude material was purified was purified by chromatography on
silica-gel (n-hexane/EtOAc 90:10) to provide the title compound 16
2-Acetyl-N-(tert-butyl)benzamide (25). The title compound was
prepared following the general procedure method A. The crude
material was purified by column chromatography (n-hexane/ethyl
acetate 1:10%) to give the product as a white solid (21.9 mg, 40%
1
1
(59.1 mg, 98%) as yellow oil. H NMR (400 MHz, CDCl3): δ 4.19
yield; partial conversion). H NMR (400 MHz, CDCl3): δ 7.70 (d, J
(q, J = 7.1 Hz, 4H), 1.54 (s, 9H), 1.26 (t, J = 7.1 Hz, 6H); 13C{1H}
NMR (100 MHz, CDCl3): δ 165.3 (2C), 63.2, 63.1, 60.0, 30.4, 14.4.
= 7.5 Hz, 1H), 7.60−7.55 (m, 1H), 7.50−7.45 (m, 3H), 1.70 (s, 3H),
1.05 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 201.6, 168.5,
137.2, 132.2, 130.9, 129.7, 127.9, 127.4, 52.0, 29.2, 28.6; HRMS (ESI)
+
HRMS (ESI) m/z: calcd [M + H]+ for C12H20NO4 , 242.1386; found
[M + H]+, 242.1373.
+
m/z: calcd [M + H]+ for C13H18NO2 , 220.1332; found [M + H]+,
Diethyl 2-(tert-Butylcarbamoyl)malonate (17). The title com-
pound was prepared following the general procedure method B. The
crude material was purified by column chromatography (n-hexane/
ethyl acetate 1:10%) to give the product as a white solid (27.0 mg,
220.1322.
2-Acetyl-N-cyclohexylbenzamide (26). The title compound was
prepared following the general procedure method A. The crude
material was purified by column chromatography (n-hexane/ethyl
acetate 1:10%) to give the product as a white solid (30.7 mg, 50%
yield; partial conversion); 1H NMR (400 MHz, CD3OD): δ 7.57 (d, J
= 7.8 Hz, 1H), 7.53−7.45 (m, 3H), 7.38 (dt, J = 7.8, 1.3 Hz, 1H),
3.43−3.33 (m, 1H), 1.95−1.85 (m, 2H), 1.75−1.55 (m, 5H), 1.45−
1.13 (m, 6H); 13C{1H} NMR (100 MHz, CD3OD): δ 167.1, 148.5,
132.00, 131.2, 129.0., 122.1, 89.1, 29.9, 29.8, 26.0, 25.1; HRMS (ESI)
1
44% yield). H NMR (400 MHz, CDCl3): δ 7.10 (br s, 1H, −NH),
4.29−4.20 (m, 5H), 1.37 (s, 9H), 1.30 (t, J = 7.1 Hz, 6H); 13C{1H}
NMR (100 MHz, CDCl3): δ 166.1, 161.0, 62.5, 60.0, 51.7, 28.5, 13.9;
+
HRMS (ESI) m/z: calcd [M + H]+ for C12H22NO5 , 260.1492; found
[M + H]+, 260.1479.
Diethyl 2-(Cyclohexylcarbamoyl)malonate (18). The title com-
pound was prepared following the general procedure method B. The
crude material was purified by column chromatography (n-hexane/
ethyl acetate 1:10%) to give the product as a white solid (48.5 mg,
68% yield). 1H NMR (400 MHz, CDCl3): δ 7.17 (d, J = 5.2 Hz, 1H),
4.35−4.19 (m, 5H), 3.88−3.74 (m, 1H), 1.96−1.85 (m, 2H), 1.77−
1.65 (m, 2H), 1.42−1.18 (m, 12H); 13C{1H} NMR (100 MHz,
CDCl3): δ 165.9, 161.1, 62.5, 59.2, 48.5, 32.5, 25.5, 24.4, 13.9; HRMS
+
m/z: calcd [M + H]+ for C15H20NO2 , 246.1488; found [M + H]+,
246.1469.
2-Acetyl-N-pentylbenzamide (27). The title compound was
prepared following the general procedure method A. The crude
material was purified by column chromatography (n-hexane/ethyl
acetate 1:10%) to give the product as colorless oil (17.5 mg, 30%
1
yield; partial conversion). H NMR (400 MHz, CDCl3): δ 7.68 (d, J
+
(ESI) m/z: calcd [M + H]+ for C14H24NO5 , 286.1649; found [M +
= 7.5 Hz, 1H), 7.57−7.53 (m, 2H), 7.49−7.41 (m, 1H), 3.4 (ddd, J =
14.1, 10.3, 5.6 Hz, 1H), 3.25 (ddd, J = 14.1, 10.2, 5.7 Hz, 1H), 2.87
(br s, 1H), 1.82−1.55 (m, 5H), 1.45−1.21 (m, 4H), 0.90 (t, J = 6.9
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 166.8, 148.0, 132.2,
129.5, 123.2, 121.5, 88.8, 38.7, 29.7, 29.6, 29.0, 24.2, 22.4, 14.0;
H]+, 286.1633.
Diethyl 2-(Pentylcarbamoyl)malonate (19). The title compound
was prepared following the general procedure method B. The crude
material was purified by column chromatography (n-hexane/ethyl
acetate 1:10%) to give the product as colorless oil (47.8 mg, 70%
yield). 1H NMR (400 MHz, CDCl3): δ 7.29 (br s, 1H, −NH), 4.38−
4.19 (m, 5H), 3.35-3-25 (m, 2H), 1.60−1.48 (m, 2H), 1.38−1.23 (m,
10H), 0.90 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
165.9, 161.9, 62.6, 59.1, 39.9, 28.9, 28.9, 22.3, 14.0, 13.9; HRMS
+
HRMS (ESI) m/z: calcd [M + H]+ for C14H20NO2 , 234.1488; found
[M + H]+, 234.1477.
N-(tert-Butyl)-2-cyanoacetamide (29). The title compound was
prepared following the general procedure method A. The crude
material was purified by column chromatography (n-hexane/ethyl
acetate 1:10%) to give the product as colou=rless oil (5.3 mg, 15%
+
(ESI) m/z: calcd [M + H]+ for C13H24NO5 , 274.1649; found [M +
H]+, 274.1635.
1
yield). H NMR (400 MHz, CDCl3): δ 5.95 (br s, 1H, −NH), 3.30
(s, 2H), 1.35 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 160.0,
115.0, 51.5, 28.0, 26.6; HRMS (ESI) m/z: calcd [M + H]+ for
C7H13N2O+, 141.1022; found [M + H]+, 141.1021.
N-(tert-Butyl)-3-oxo-3-phenylpropanamide (21). The title com-
pound was prepared following the general procedure method A. The
crude material was purified by column chromatography (n-hexane/
ethyl acetate 5:15%) to give the product as pale-brown oil (54.2 mg,
General One-Pot Two-Steps Procedure for the Preparation
of Compounds (30−35 and 37−40) (Method C). To a 4 mL
colorless screw-cap glass vial equipped with a magnetic stir bar were
added the isocyanide (0.25 mmol), Na2CO3 (0.375 mmol, 1.5 equiv),
fac-Ir(ppy)3 (0.0025 mmol, 1% mol), diethylbromomalonate (0.375
mmol, 1.5 equiv), and DABCO (0.125 mmol, 0.5 equiv). Then, 2.5
mL MeCN (0.1 M) and H2O 95 μL (20 equiv) were added into the
reaction vial via a syringe. The resulting mixture was purged with
nitrogen and then stirred under 30 W blue LED irradiation at room
temperature for 20 h. After turning-off irradiation, the nucleophile
(0.25 mmol) was added, and the reaction mixture was stirred at room
temperature for additional 20−40 h. Then, the reaction mixture was
poured into water, extracted with EtOAc (3 times), the collected
organic layers were washed with brine (1 time), dried over dry
Na2SO4, and evaporated under vacuum. The reaction crude was
purified by chromatography on silica-gel.
1
95% yield). H NMR (400 MHz, CDCl3): δ 8.04−7.97 (m, 2H),
7.63-7-58 (m, 1H), 7.54−7.45 (m, 2H), 6.86 (br s, 1H, −NH), 3.89
(s, 2H), 1.40 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 196.6,
164.7, 136.3, 134.0, 128.8, 128.6, 51.5, 46.7, 28.7; HRMS (ESI) m/z:
+
calcd [M + H]+ for C13H18NO2 , 220.1332; found [M + H]+,
220.1320.
N-Cyclohexyl-3-oxo-3-phenylpropanamide (22). The title com-
pound was prepared following the general procedure method A. The
crude material was purified by column chromatography (n-hexane/
ethyl acetate 5:15%) to give the product as a pale-brown solid (57.0
mg, 93% yield). 1H NMR (400 MHz, CDCl3): δ 8.03−7.98 (m, 2H),
7.62−7.57 (m, 1H), 7.52−7.45 (m, 3H), 7.00 (br s, 1H, −NH), 3.93
(s, 2H), 3.88−3.78 (m, 1H), 1.95−1.85 (m, 2H), 1.75−1.65 (m, 2H),
1.45−1.13 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 196.4,
164.7, 136.2, 133.9, 128.8, 128.6, 48.3, 46.5, 32.8, 25.5, 24.7; HRMS
+
(ESI) m/z: calcd [M + H]+ for C15H20NO2 , 246.1488; found [M +
Diethyl 2-((tert-Butylamino)-((4-methoxyphenyl)amino)-
methylene)-malonate (30). The title compound was prepared
following the general procedure method C. The crude material was
purified by column chromatography (n-hexane/EtOAc 80:20) to give
H]+, 246.1480.
3-Oxo-N-pentyl-3-phenylpropanamide (23). The title compound
was prepared following the general procedure method A. The crude
material was purified by column chromatography (n-hexane/ethyl
acetate 5:15%) to give the product as pale-yellow oil (53.1 mg, 91%
1
the product as pale-brown oil (72.9 mg, 88% yield). H NMR (400
MHz, DMSO-d6): δ 8.25−8.18 (m, 2H), 7.05−6.99 (m, 1H), 6.89−
6.81 (m, 1H), 3.84−3.69 (m, 7H), 1.32 (s, 9H), 1.09 (t, J = 7.1 Hz,
6H); 13C{1H} NMR (100 MHz, DMSO-d6): δ 168.3, 162.8, 156.0,
134.2, 123.9, 114.2, 80.9, 58.6, 55.7, 54.3, 30.4, 14.8; HRMS (ESI) m/
1
yield). H NMR (400 MHz, CDCl3): δ 8.05−7.98 (m, 2H), 7.65−
7.59 (m, 1H), 7.54−7.46 (m, 2H), 7.09 (br s, 1H, −NH), 3.95 (s,
2H), 3.33−2.98 (m, 2H), 1.58−1.49 (m, 2H), 1.39−1.27 (m, 4H),
0.93−0.85 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 196.3,
165.5, 136.2, 134.0, 128.8, 128.6, 45.3, 39.6, 29.9, 29.7, 22.3, 14.0;
+
z: calcd [M + H]+ for C19H29N2O5 , 365.2071; found [M + H]+,
365.2083.
H
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1
Diethyl 2-((tert-Butylamino)-((4-chlorophenyl)amino)-
methylene)-malonate (31). The title compound was prepared
following the general procedure method C. The crude material was
purified by column chromatography (n-hexane/EtOAc 80:20) to give
the product as pale brown oil (40.8 mg, 80% yield). H NMR (400
1
MHz, CDCl3): δ H NMR (400 MHz, CDCl3): δ 10.84 (br s, 1H),
9.58 (br s, 1H), 7.07−6.99 (m, 2H), 6.88−6.80 (m, 2H), 4.18 (q, J =
7.1 Hz, 4H), 3.80 (s, 3H), 2.74 (dt, J = 7.0, 5.2 Hz, 2H), 1.50−1.38
(m, 2H), 1.31 (t, J = 7.1 Hz, 6H), 1.25−1.12 (m, 4H), 0.83 (t, J = 6.9
Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 171.5, 163.6, 156.8,
133.0, 124.5, 114.4, 78.1, 59.7, 55.5, 45.4, 29.4, 28.8, 22.2, 14.4, 13.9;
1
the product as pale-brown oil (55.3 mg, 60% yield). H NMR (400
MHz, DMSO-d6): δ 8.23−8.16 (m, 2H), 7.38−7.24 (m, 2H), 6.89−
6.83 (m, 2H), 3.75 (q, J = 7.1 Hz, 4H), 1.33 (s, 9H), 1.04 (t, J = 7.1
Hz, 6H); 13C{1H} NMR (100 MHz, DMSO-d6): δ 168.3, 168.0,
134.2, 123.9, 122.0, 114.2, 80.9, 58.8, 54.3, 30.4, 14.8; HRMS (ESI)
+
HRMS (ESI) m/z: calcd [M + H]+ for C20H31N2O5 , 379.2227;
found [M + H]+, 379.2214.
+
m/z: calcd [M + H]+ for C18H26ClN2O4 , 369.1575; found [M + H]+,
Ethyl 5-(tert-Butylamino)-3-oxo-2-phenyl-2,3-dihydro-1H-pyra-
zole-4-carboxylate (39). The title compound was prepared following
the general procedure method C. The crude material was purified by
column chromatography (CH2Cl2/MeOH 98:2) to give the product
369.1565.
Diethyl 2-((tert-Butylamino)-((4-methoxybenzyl)amino)-
methylene)-malonate (32). The title compound was prepared
following the general procedure method C. The crude material was
purified by column chromatography (CH2Cl2/MeOH 99:1) to give
the product as a white solid (85.2 mg, 90% yield): mp 158−160 °C;
1H NMR (400 MHz, CDCl3); δ 8.05 (br s, 1H), 7.46 (br s, 1H),
1
as an orange solid (50.0 mg, 66% yield): mp 80−82 °C. H NMR
(400 MHz, CDCl3): δ 1H NMR (400 MHz, DMSO-d6): δ 7.80 (br s,
1H), 7.65−7.55 (m, 2H), 7.48−7.40 (m, 2H), 7.20−7.10 (m, 1H),
4.18 (q, J = 6.9 Hz, 2H), 1.30−1.18 (m, 12H); 13C{1H} NMR (101
MHz, DMSO-d6): δ 165.8, 163.1, 151.6, 139.5, 129.0 (2C), 120.1,
59.0, 52.0, 50.3, 29.5, 15.0; HRMS (ESI) m/z: calcd [M + H]+ for
7.22−7.15 (m, 2H), 6.90−6.82 (m, 2H), 4.33 (d, J = 5.1 Hz, 2H),
4.15 (q, J = 7.1 Hz, 4H), 3.80 (s, 3H), 1.34 (s, 9H), 1.27 (t, J = 7.1
Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 170.3, 166.4, 159.2,
130.2, 129.2, 114.2, 80.7, 59.7, 55.3, 54.7, 50.7, 30.6, 14.4; HRMS
+
C16H22N3O3 , 304.1655; found [M + H]+, 304.1655.
Diethyl 2-(1-(tert-Butyl)-1H-tetrazol-5-yl)malonate (40). The title
compound was prepared following the general procedure method C.
The crude material was purified by column chromatography (hexane/
EtOAc 8:2) to give the product as a white solid (35.5 mg, 50% yield):
mp 50−51 °C; 1H NMR (400 MHz, CDCl3): δ 4.29−4.20 (m, 5H),
1.37 (s, 9H), 1.30 (t, J = 7.1 Hz, 6H); 13C{1H} NMR (101 MHz,
CDCl3): δ 166.1, 161.0, 62.5, 60.0, 51.7, 28.5, 13.9; MS (ESI) m/z:
+
(ESI) m/z: calcd [M + H]+ for C20H31N2O5 , 379.2227; found [M +
H]+, 379.2224.
Diethyl 2-((tert-Butylamino)-(cyclohexylamino)methylene)-
malonate (33). The title compound was prepared following the
general procedure method C. The crude material was purified by
column chromatography (CH2Cl2/MeOH 97:3) to give the product
+
calcd [M + H]+ for C12H21N4O4 , 285.15; found [M + H]+, 285.00;
1
as a white solid (80.0 mg, 94% yield): mp 154−156 °C; H NMR
HRMS analysis for compound 40 gave peaks derived from
fragmentation of tetrazole ring, as described in literature.24
Stern−Volmer Fluorescence Quenching Experiments. Fluo-
rescence titration experiments were performed at 20 °C on a FP-8300
spectrofluorometer (Jasco) equipped with a Peltier temperature
controller system (Jasco PCT-818). A sealed quartz cuvette with a
path length of 1 cm was used. Titrations were carried out by stepwise
addition of diethyl bromomalonate (10) or DABCO to the cell
containing a fixed concentration of fac-Ir(ppy)3 solution (200 μM) in
MeCN/H2O (4:1). The Ir(III) complex was excited at 450 nm, and
emission spectra were recorded between 460 and 650 nm at 100 nm/
min scan speed. Both excitation and emission slit widths were set at 5
nm.
(400 MHz, CDCl3): δ 8.01 (br s, 1H), 7.86 (d, J = 8.6 Hz, 1H), 4.15
(q, J = 7.1 Hz, 4H), 3.53−3.44 (m, 1H), 2.00−1.93 (m, 2H), 1.78−
1.70 (m, 2H), 1.35 (s, 9H), 1.32−1.13 (m, 12H); 13C{1H} NMR
(100 MHz, CDCl3): δ 170.9, 166.0, 81.6, 59.6, 55.5, 54.8, 33.3, 30.4,
+
25.5, 25.0, 14.4; HRMS (ESI) m/z: calcd [M + H]+ for C18H33N2O4 ,
341.2434; found [M + H]+, 341.2421.
Diethyl 2-((tert-Butylamino)-(morpholino)methylene)malonate
(34). The title compound was prepared following the general
procedure method C. The crude material was purified by column
chromatography (CH2Cl2/MeOH 95:5) to give the product as a
1
white solid (72.2 mg, 88% yield): mp 156−158 °C; H NMR (400
MHz, CDCl3): δ 6.12 (br s, 1H), 4.10 (d, J = 7.1 Hz, 4H), 3.80−3.71
(m, 4H), 3.42−3.30 (m, 4H), 1.35 (s, 9H), 1.27 (t, J = 7.1 Hz, 6H);
13C{1H} NMR (101 MHz, CDCl3): δ 168.0 (2C), 77.2, 66.2, 59.3,
56.0, 49.8, 30.3, 14.7; HRMS (ESI) m/z: calcd [M + H]+ for
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01946.
■
+
C16H29N2O5 , 329.2071; found [M + H]+, 329.2058.
sı
Diethyl 2-((tert-Butylamino)-(piperidin-1-yl)methylene)-
malonate (35). The title compound was prepared following the
general procedure method C. The crude material was purified by
column chromatography (CH2Cl2/MeOH 95:5) to give the product
HRMS spectra for TEMPO quenching experiments;
references for NMR data of known compounds; and
copies of 1H and 13C NMR spectra for all the
compounds reported in the experimental section
(PDF)
1
as a white solid (40.8 mg, 50% yield): mp 155−157 °C; H NMR
(400 MHz, CDCl3): δ 5.69 (br s, 1H), 4.10 (q, J = 7.1 Hz, 4H),
3.40−3.33 (m, 4H), 1.37 (s, 9H), 1.32−1.14 (m, 12H); 13C{1H}
NMR (101 MHz, CDCl3): δ 167.7 (2C), 77.3, 58.7, 55.8, 50.2, 30.2,
+
25.3, 24.3, 14.8; HRMS (ESI) m/z: calcd [M + H]+ for C17H31N2O4 ,
327.2278; found [M + H]+, 327.2269.
AUTHOR INFORMATION
Corresponding Author
■
Diethyl 2-((Cyclohexylamino)-((4-methoxyphenyl)amino)-
methylene)-malonate (37). The title compound was prepared
following the general procedure method C. The crude material was
purified by column chromatography (hexane/EtOAc 80:20) to give
Mariateresa Giustiniano − Department of Pharmacy,
University of Naples Federico II, 80131 Napoli, Italy;
orcid.org/0000-0002-6856-414X;
1
the product as pale-brown oil (40.8 mg, 75% yield). H NMR (400
MHz, CDCl3): δ 10.70 (br s, 1H), 9.34 (d, J = 8.6 Hz, 1H), 7.04−
6.96 (m, 2H), 6.82−6.73 (m, 2H), 4.10 (q, J = 7.1 Hz, 4H), 3.73 (s,
3H), 2.92−2.77 (m, 1H), 1.67−1.56 (m, 2H), 1.55−1.44 (m, 2H),
1.37−1.15 (m, 10H), 1.10−1.00 (m, 2H); 13C{1H} NMR (101 MHz,
CDCl3): δ 171.6, 162.8, 157.0, 133.0, 124.6, 114.4, 78.6, 63.2, 59.7,
55.5, 52.2, 42.4, 32.6, 25.4, 24.3, 14.4, 13.9; HRMS (ESI) m/z: calcd
Email: mariateresa.giustiniano@unina.it
Authors
Rolando Cannalire − Department of Pharmacy, University of
Naples Federico II, 80131 Napoli, Italy
Jussara Amato − Department of Pharmacy, University of Naples
Federico II, 80131 Napoli, Italy; orcid.org/0000-0001-
6096-3544
Vincenzo Summa − Department of Pharmacy, University of
Naples Federico II, 80131 Napoli, Italy
+
[M + H]+ for C21H31N2O5 , 391.2227; found [M + H]+, 391.2213.
Diethyl 2-(((4-Methoxyphenyl)amino)-(pentylamino)-
methylene)-malonate (38). The title compound was prepared
following the general procedure method C. The crude material was
purified by column chromatography (hexane/EtOAc 80:20) to give
I
https://dx.doi.org/10.1021/acs.joc.0c01946
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
E.; Schumacher, W. A.; Rendina, A. R.; Bozarth, J. M.; Peterson, T. L.;
Zhang, G.; Zahler, R. Ketene Aminal-Based Lactam Derivatives as a
Novel Class of Orally Active FXa Inhibitors. Bioorg. Med. Chem. Lett.
2005, 15, 5453−5458.
(17) Resch, S.; Schneider, A.-R.; Beichler, R.; Spera, M. B. M.;
Fanous, J.; Schollmeyer, D.; Waldvogel, S. R. Naphthyridine
Derivatives as a Model System for Potential Lithium-Sulfur Energy-
Storage Applications. Eur. J. Org. Chem. 2015, 933−937.
(18) De Meijere, A.; Schaumann, E. Category 3, Compounds with
Four and Three Carbon Heteroatom Bonds Three Carbon--Heteroatom
Bonds: Ketene Acetals and Yne--X Compounds; George Thieme Verlag,
2006.
Ettore Novellino − Department of Pharmacy, University of
Naples Federico II, 80131 Napoli, Italy; orcid.org/0000-
0002-2181-2142
Gian Cesare Tron − Department of Drug Science, University of
Piemonte Orientale, 28100 Novara, Italy
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01946
Notes
The authors declare no competing financial interest.
(19) Mamboury, M.; Wang, Q.; Zhu, J. α-Oxo-Ketenimines from
Isocyanides and α-Haloketones: Synthesis and Divergent Reactivity.
Chem.Eur. J. 2017, 23, 12744−12748.
ACKNOWLEDGMENTS
■
̀
Financial support from Universita degli Studi di Napoli
(20) For literature about Pd or Cu triggered coupling of isocyanides
leading to imidines see for example: (a) Saluste, C. G.; Whitby, R. J.;
Furber, M. Palladium-catalysed synthesis of imidates, thioimidates and
amidines from aryl halides. Tetrahedron Lett. 2001, 42, 6191−6194.
(b) Yan, X.; Liao, J.; Lu, Y.; Liu, J.; Zeng, Y.; Cai, Q. Pd-Catalyzed
One-Pot Synthesis of Polysubstituted Acrylamidines from Isocya-
nides, Diazo Compounds, and Imines. Org. Lett. 2013, 15, 2478−
2481.
̀
“Federico II” and Universita del Piemonte Orientale, Novara,
Italy is acknowledged. R.C. acknowledges MIUR-Ministero
̀
dell’Istruzione, dell’Universita e della Ricerca (Italian Ministry
of Education, University and Research), PON R&I 2014-2020-
AIM (Attraction and International Mobility), project
̀
AIM1873131Num. Attivita 2Linea 2.1.
(21) Arias-Rotondo, D. M.; McCusker, J. K. The Photophysics of
Photoredox Catalysis: A Roadmap for Catalyst Design. Chem. Soc.
Rev. 2016, 45, 5803−5820.
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J. Org. Chem. XXXX, XXX, XXX−XXX