Into the Blue: Ketene Multicomponent Reactions under Visible Light

Article abstract of DOI:10.1021/acs.joc.1c00278

For the first time, a detailed study on the photophysical properties of variously substituted diazoketones and on their photoreactivity under blue LED irradiation was carried out. Despite very limited absorbance in the visible region, we have demonstrated that, independently from their structure, α-diazoketones all undergo a very efficient Wolff rearrangement. Contrarily to the same UV-mediated reaction, where photons can give rise to side processes, in this case, almost all absorbed photons are selective and effective, and the quantum yield is close to 100%. If the rearrangement is carried out in the presence of isocyanides and carboxylic acids/silanols, the photoreactivity is not affected, and the resulting ketenes can afford α-acyloxy- and α-silyloxyacrylamides through two distinct multicomponent reactions, performed both in batch and under continuous flow, with improved selectivity and broader scope. These photoinduced multicomponent reactions can be coupled with other visible-light-mediated transformations, thus increasing the diversity of the molecules obtainable by this approach.

Full text of DOI:10.1021/acs.joc.1c00278

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Into the Blue: Ketene Multicomponent Reactions under Visible Light
Pietro Capurro, Chiara Lambruschini, Paola Lova, Lisa Moni, and Andrea Basso*
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ABSTRACT: For the first time, a detailed study on the photophysical
properties of variously substituted diazoketones and on their photo-
reactivity under blue LED irradiation was carried out. Despite very limited
absorbance in the visible region, we have demonstrated that, independently
from their structure, α-diazoketones all undergo a very efficient Wolff
rearrangement. Contrarily to the same UV-mediated reaction, where
photons can give rise to side processes, in this case, almost all absorbed
photons are selective and effective, and the quantum yield is close to 100%.
If the rearrangement is carried out in the presence of isocyanides and
carboxylic acids/silanols, the photoreactivity is not affected, and the
resulting ketenes can afford α-acyloxy- and α-silyloxyacrylamides through
two distinct multicomponent reactions, performed both in batch and under
continuous flow, with improved selectivity and broader scope. These
photoinduced multicomponent reactions can be coupled with other visible-light-mediated transformations, thus increasing the
diversity of the molecules obtainable by this approach.
pounds, in which only the first was selectively activated by the
absorption of light in the visible region, while the latter diazo
compound remained inactive. This was justified by the authors
by the “lack of appreciable absorbance” of diazocarbonyl
compounds (including phenyldiazoketone) in the visible
region.7
INTRODUCTION
■
Diazocompounds are versatile substrates, able to easily
undergo either carbene generation or Wolff rearrangement to
ketenes, which subsequently undergo various transformations.
Modern chemistry of diazo compounds is dominated by
transition metal catalysis, although photoinduced and thermal
decompositions have also found application.1 Photoinitiated
reactions have experienced a revival of interest due to the
increased understanding of photochemical mechanisms. The
photoinitiated decomposition of diazocompounds is mainly
induced by UV irradiation, and only recently the use of visible
light has been reported by some authors. For example,
Konopelski assembled enantiomerically pure β-lactams from α-
diazo-N-methoxy-N-methyl β-ketoamides, exploiting a UV or
CFL-induced Wolff rearrangement,2 and Burtoloso reported
the use of white LED in the Arndt−Eistert homologation of
simple aliphatic and aromatic diazoketones.3 In these cases,
however, the emission spectra of the light sources were not
correlated with the absorbance spectra of the substrates. On
the other hand, Lu and Xiao used blue LED activation on
various aryl methyl diazoketones,4,5 demonstrating that these
compounds had a discrete absorption in the 410−500 nm
region. Phenyl methyl diazoketone was also employed by Song,
who monitored the Wolff rearrangement under blue LED
These data apparently contradict each other, and a rigorous
study on the absorption spectra of diazoketones and on how
these are correlated to their reactivity is lacking. In our
personal experience, monosubstituted diazoketones 1 display a
UV−vis absorbance spectrum with a maximum at about 250−
300 nm and a negligible absorbance above 400 nm. For this
reason, the ketene three-component reaction (K-3CR)8 and
the silylative ketene three-component reaction (SK-3CR),9
recently developed in our laboratories, were successfully
performed under UV irradiation at 254−360 nm (Scheme
1). These methods, however, had some drawbacks: to prevent
that the same UV radiation-induced double-bond isomer-
ization of the olefinic products 2, the use of additives10 or,
more recently, the employment of flow conditions,11 had to be
introduced. Moreover, competitive absorbance of some
substrates, like those possessing a nitrophenyl or an indole
1
Received: February 4, 2021
Published: April 6, 2021
irradiation by analyzing the H NMR spectra of the reaction
mixture, reporting almost quantitative conversion after 10 h.6
However, the author reported that simple monosubstituted
aromatic α-diazoketones and aliphatic α-diazoketones were
unreactive substrates. Zhou reported blue-light-promoted
cross-coupling of aryldiazoacetates and diazocarbonyl com-
© 2021 The Authors. Published by
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https://doi.org/10.1021/acs.joc.1c00278
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Scheme 1. State of the Art of the Photoinduced Wolff
Rearrangement of Diazocompounds and General Scheme
for the Ketene Three-Component Reaction (K-3CR) and
Sylilative Ketene Three-Component Reaction (SK-3CR)
Reported in the Present Work
Figure 1. List of diazoketones employed in this study.
Table 1. Maximum Absorption and Molar Extinction
Coefficient for Diazoketones 1a−g
ab
,
ac
,
diazoketone
λmax (nm)
εmax
ε450
1a
1b
1c
1d
1e
1f
253
252
307
248
250
301
9600
7600
13500
8300
5200
18400
1.21
0.96
2.29
0.90
0.84
2.11
1.34
1g
268
11100
a
b
Expressed in L mol−1 cm−1. Determined in dichloromethane at
c
0.1−0.05 mM concentration. Determined in dichloromethane at 0.1
M concentration.
moiety, prevented the Wolff rearrangement from occurring,
thus resulting in the failure of the multicomponent reaction.
RESULTS AND DISCUSSION
■
Spectroscopic Studies. Intrigued by the possibility to
perform these multicomponent reactions under less energetic
irradiation, puzzled by the contradictory literature, and aware
of the fact that diazoketones are usually bright yellow solids, we
decided to investigate the possibility to use blue LEDs instead
of UV light to induce the Wolff rearrangement. We selected
and synthesized seven different monosubstituted diazoketones
(Figure 1), both aliphatic and aromatic, with EW and ED
substituents, and determined the UV−vis spectra together with
the molar extinction coefficient at 450 nm (Table 1 and Figure
2). This latter value was much smaller (in the range of 1−2 L
mol−1 cm−1) than the one determined at the λ of maximum
absorbance but was not negligible.
Figure 2. Absorption spectra for diazoketones 1a−g (0.1 M in
dichloromethane) in the region 380−700 nm and overlap with
emission spectrum of blue and green LED.
K-3CR and Quantum Yield Determination. Considering
these results, a solution of diazoketone 1a in dichloromethane
was irradiated at 450 nm with a high-power (1 W of radiant
power) blue LED, and gratifyingly, complete consumption was
observed in a few hours. It is worth noting that no
consumption was observed when low-power blue LED stripes
or high-power green LEDs were used instead. This could in
part explain the contradictory results found in the literature.
We then moved to test a model K-3CR, exposing a mixture of
diazoketone 1a, benzoic acid, and cyclohexyl isocyanide,
dissolved in CDCl3, to irradiation with blue LED and
monitoring the reaction by NMR. Then, 0.05 mmol of
DMSO was added as an internal standard for the integration
reference. Aliquots (100 μL) of the solution were sampled,
diluted in an NMR tube to a total volume of 700 μL of CDCl3,
1
and analyzed via H NMR at defined time intervals. To our
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delight, the reaction proceeded with the desired formation of
product 2a, concomitantly with the consumption of substrate
1a, as illustrated in Figure 3. As expected, no isomerization of
Table 2. Disappearance Rates of Diazoketone 1a and
Formation Rate of the Product 2a for the Model Reaction,
Number of Photons Absorbed by the Reacting Species 1a,
and Quantum Yields (φ−, φK3CR) for the Wolff
Rearrangement and the K-3CR Multicomponent Process,
Respectively
a
a
b
c
d
time [min]
1a [%]
2a [%]
Nphotons
φ−
φK3CR
0
5
10
15
20
25
30
100.0
84.8
74.3
64.8
55.8
46.7
39.7
0.0
9.1
1.24 × 1018
2.60 × 1019
5.00 × 1019
7.29 × 1019
9.47 × 1019
1.15 × 1020
1.35 × 1020
1.05
0.93
0.87
0.84
0.83
0.80
0.89
0.63
0.66
0.66
0.65
0.63
0.61
0.64
18.2
26.5
34.0
40.0
45.6
average values
a
b
Determined by integration of the NMR spectra. Calculated number
of total photons absorbed. Quantum yield for the Wolff rearrange-
ment (value calculated at each time interval). Quantum yield for the
c
d
model K-3CR (value calculated at each time interval).
Figure 3. NMR study of the model reaction.
K-3CR and SK-3CR in Batch and Flow. A series of K-
3CR and SK-3CR was then performed, employing different
combinations of diazoketones, isocyanides, and carboxylic
acids/triphenylsilanol (Scheme 2). Test experiments, reported
in the Supporting Information, excluded a change in the
absorption profile around 450 nm when moving from pure
diazoketone to the multicomponent mixtures. The results are
shown in Figure 4. As expected from the absorption spectra
(Figure 2), all of the diazoketones employed in this study gave
the Wolff rearrangement with comparable reactivity, inde-
pendently from their structure. This remarkable result is in
contrast with what was previously reported.6
The advantages of the present methodology, in comparison
with the UV-induced multicomponent reactions, are reported
in Table 3. Clearly, E/Z selectivity dramatically improved by
using a less energetic radiation. In fact, beside an overall yield
that remained substantially unchanged, double bond isomer-
ization was completely suppressed in most cases. The only
exception is compound 2d obtained by the reaction of
diazoketone 1g with benzoic acid and cyclohexyl isocyanide. In
this case, however, another advantage is evident: the
bathochromic effect of the nitro group in diazoketone 1g
prevented the UV-mediated Wolff rearrangement from
occuring, as the absorbance of the aromatic ring overlapped
the one of the diazoketone moiety. The use of blue LED,
instead, allowed the K-3CR to take place cleanly with
compound 2d isolated in 86% yield. The poor E/Z selectivity,
in this case, was the result of the same bathochromic effect on
the olefinic product, with the ability to cause double bond
isomerization even under visible light.
The multicomponent reactions could be performed both in
batch and under continuous flow conditions, and in this latter
case, another advantage resulted from the possibility to
perform in flow not only the K-3CR but, for the first time,
also the SK-3CR, as this was unsuccessful employing UV
radiation. The continuous flow apparatus was built in-house
with the same high-power blue LEDs, and full details are given
in the Supporting Information.
Further Visible Light Transformations. α-Substituted
acrylamides 2 have been demonstrated to be valuable synthons
for the synthesis of heterocycles12 and natural products.13
Having established this new methodology, we then moved to
the double bond of acrylamide 2a was observed, as this was
found to occur only under UV irradiation. The reaction was
performed and monitored twice: the first run was sampled
every 15 min up to the complete disappearance of diazoketone
1a (120 min); the second run was sampled every 5 min for 30
min. Integration of selected, noninterfered signals with respect
to that of the internal standard (DMSO) allowed us to
calculate the rate of disappearance of the starting reagents (1a,
benzoic acid, and cyclohexyl isocyanide) and the rate of
formation of product 2a. The quantum yields for the Wolff
rearrangement (disappearance of the diazoketone 1a) and for
the multicomponent step (formation of 2a) were determined
by measurement, in parallel, of the absorbed photons
employing a fiber-based optical setup built ad hoc. The photon
flow from the LED system was collected using an integrating
sphere opportunely placed around the reaction vial and
connected to a CMOS spectrometer (with a resolution of
1.4 nm) with an optical fiber. The estimation of the emitted
number of photons was allowed by a precise calibration of the
setup response using a calibrated white light source (see
Supporting Information for additional details). From the
results reported in Table 2, the quantum yield for the
formation of product 2a remains constant in the first 30 min of
analysis, with an average value of 64%. The quantum yield for
the disappearance of 1a, on the other hand, decreases over
time, with a starting value of 100% after 5 min and an average
value of 89% over the first 30 min. This can be explained with
the accumulation, in the reaction mixture, of absorbing
impurities deriving from phenylketene, which subtract a
small portion of photons to 1a. The quantum yield for the
formation of 2a, on the other hand, is not affected by these
impurities, as the interaction of the ketene with the other two
reagents is the rate-limiting step of the process; thus, there is
always an excess of ketene in the solution. The diazoketone
disappearance quantum yield was found to be much higher
than the one determined with UV (Wood’s lamp) irradiation,
namely, 28%.11 These results demonstrate that, despite a very
low molar extinction coefficient, the absorbed photons almost
exclusively promote the Wolff rearrangement, resulting in a
greatly improved efficiency of the present methodology.
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Table 3. Comparison of K-3CR and SK-3CR Performed
with Blue LED and under UV Irradiation (without
a
Additives) in Terms of Yield and E/Z Selectivity
batch conditions
product
blue LED
UV (300 nm)
2b
2c
2d
2e
82% (100:0)
88% (100:0)
86% (57:43)
73% (100:0)
65% (71:29)
56% (66:34)
37% (56:44)
flow conditions
2l
65% (100:0)
77% (100:0)
68% (100:0)
43% (100:0)
50% (67:33)
46% (97:3)
2b
2g
2l
a
For UV reactions, yields are referred to as the major isomer.
continuous flow conditions (Scheme 3, top).14 In the second
set of experiments, we coupled the SK-3CR with a photoredox
Scheme 3. Coupling SK-3CR with Other Visible-Light-
a
Mediated Processes
Figure 4. K-3CR and SK-3CR products with diazoketones 1a−g. The
given yield is that of the isolated product after column
chromatography.
a
Reagents and conditions: (a) Umemoto II (2 equiv), [Ru(bpy)3]Cl2
(1 mol %), MeCN (0.01 M), blue LED, flow 1.5 mL h−1, 32%; (b) 4-
methoxyphenyl diazonium tetrafluoroborate (1 equiv), [Ru(bpy)3]Cl2
(1 mol %), acetone (0.01 M), blue LED, flow 3 mL h−1, 75%.
Scheme 2. K-3CR and SK-3CR with Diazoketones 1a−g
generation of an acetonyl radical.15 The reaction was
performed on the crude mixture derived from the synthesis
of 2g and was performed under continuous flow conditions,
affording 1,4-diketone 4 in an overall 40% yield, based on two
steps (Scheme 3, bottom). Although this transformation was
performed as a separate step, the use of the crude mixture of
the SK-3CR and of a flow system demonstrates, in principle,
that, with the proper equipment, this synthetic route can be
performed within the same reactor in one operation.
CONCLUSION
■
In conclusion, a rigorous study on the absorption properties of
7 structurally different diazoketones has demonstrated that the
Wolff rearrangement can occur under blue LED irradiation,
independently of their structure, and that the process is more
efficient than the one performed under UV irradiation, due to
the higher selectivity of the less energetic photons. The Wolff
rearrangement has been exploited in two distinct multi-
component reactions, namely, K-3CR and SK-3CR, affording
the desired products with complete E/Z selectivity and even in
explore the possibility to couple the multicomponent reactions
with visible-light-mediated functionalization of the resulting
products. The first reaction we explored was a trifluoromethy-
lation, which was first attempted on substrate 2f with
trifluoromethylsulfonyl chloride in the presence of eosin Y
under green LED irradiation, unsuccessfully; eventually, the
synthesis of 3 was achieved using Umemoto II reagent and Ru
photoredox catalysis with blue light, both in batch and under
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13C{1H} NMR: δ 167.7, 161.2, 160.2, 139.4, 134.2, 132.5, 130.4,
129.6, 129.2, 128.7, 124.0, 121.7, 115.0, 113.4, 55.3, 48.2, 41.9, 32.7,
25.5, 24.9. HRMS (ESI) m/z: [M + H]+ calcd for C24H28NO4,
394.2018; found, 394.2012.
those cases where the UV mediated process failed. The
reactions are complete in a few hours, and quantum yields are
remarkably high. We are currently applying the present
approach in other transformations involving ketenes, in
particular, on [2+2] cycloadditions, and we will report the
results in due course.
(Z)-3-(Butylamino)-3-oxo-1-phenylprop-1-en-2-yl 2-(3-
methoxyphenyl)acetate 2c. Yellow oil. Rf = 0.27 (EtOAc/PE 3:7).
Yield: 88% (97 mg). 1H NMR: δ 7.43−7.29 [m, 7H], 7.00−6.89 [m,
3H], 5.52 [t br, J = 5.1, 1H], 3.81 [m, 5H], 3.13 [q, J = 6.9, 2H],
1.33−1.14 [m, 4H], 0.88 [t, J = 6.9, 3H]. 13C{1H} NMR: δ 167.8,
162.3, 160.3, 139.4, 134.2, 132.5, 130.4, 129.6, 129.3, 128.8, 124.2,
121.7, 115.0, 113.6, 55.4, 42.0, 39.6, 31.5, 20.1, 13.9. HRMS (ESI) m/
z: [M + H]+ calcd for C22H26NO4, 368.1862; found, 368.1852.
(E)-3-(Cyclohexylamino)-3-oxo-1-(4-nitrophenyl)prop-1-en-2-yl
benzoate (E)-2d. Yellow foam. Rf = 0.61 (EtOAc/PE 1:3). Yield: 49%
(58 mg). 1H NMR: δ 8.25−8.19 [m, 2H], 8.17−8.10 [m, 2H], 7.73−
7.58 [m, 3H], 7.52 [t, J = 7.8 Hz, 2H], 6.74 [s, 1H], 5.82 [d, J = 8.3
Hz, 1H], 3.81 [m, 1H], 1.91−1.77 [m, 2H], 1.68−1.56 [m, 2H],
1.43−0.94 [m, 6H]. 13C{1H} NMR: δ 164.9, 160.9, 147.4, 144.6,
139.1, 134.3, 130.3, 130.0, 128.8, 128.1, 123.6, 121.6, 48.5, 32.4, 25.3,
24.6.HRMS (ESI) m/z: [M + H]+ calcd for C22H22N2O5, 394.1529;
found, 394.1536.
EXPERIMENTAL SECTION
■
General Information. NMR spectra were recorded at 300 MHz
(1H), 75 MHz (13C), and 282 MHz (19F), and the chemical shifts (δ)
are expressed in parts per million relatively to tetramethylsilane
(TMS) as an internal standard (0.00 ppm). Coupling constants are
reported in hertz. NMR acquisitions were performed at 300 K, and
CDCl3 was used as a solvent. HR-MS analyses were carried out on a
Synapt G2 QToF mass spectrometer. MS signals were acquired from
50 to 1200 m/z in ESI positive ionization mode. UV−vis analyses
were performed on a Varian Cary 50 Scan (190−1100 nm) using
quartz cuvettes (Hellma Standard absorption cuvettes in Suprasil
quartz) using nonanhydrous dichloromethane (cutoff ca. 230 nm) as
a solvent, purchased from Sigma-Aldrich, and used without further
purification. Reactions were monitored by TLC. TLC analyses were
carried out on silica gel plates (thickness = 0.25 mm), viewed at UV
(λ = 254 nm) and developed with Hanessian stain (dipping into a
solution of (NH4)4MoO4·4H2O (21 g) and Ce(SO4)2·4H2O (1 g) in
H2SO4 (31 mL) and H2O (469 mL) and warming). Column
chromatography was performed with the “flash” methodology
alternatively using 220−400 mesh silica, grade I alumina, or 60−
100 mesh Florisil. Solvents employed as eluents and for all other
routinary operations, as well as anhydrous solvents and all reagents
used, were purchased from commercial suppliers and employed
without any further purification.
(Z)-3-(Cyclohexylamino)-3-oxo-1-(4-nitrophenyl)prop-1-en-2-yl
benzoate (Z)-2d. Yellow foam. Rf = 0.51 (EtOAc/PE 1:3). Yield: 37%
1
(44 mg). H NMR: δ 8.21−8.10 [m, 4H], 7.78−7.70 [m, 1H], 7.66
[dd, J = 9.0, 0.5 Hz, 2H], 7.61−7.53 [m, 2H], 7.39 [s, 1H], 5.93 [d, J
= 8.2 Hz, 1H], 3.97−3.79 [m, 1H], 1.96 [dd, J = 12.2, 3.7 Hz, 2H],
1.75−1.62 [m, 2H], 1.47−1.07 [m, 6H]. 13C{1H} NMR: δ 163.2,
160.8, 147.4, 142.6, 139.0, 134.8, 130.3, 130.0, 129.2, 127.7, 123.9,
121.3, 48.8, 32.8, 25.4, 24.7. HRMS (ESI) m/z: [M + H]+ calcd for
C22H22N2O5, 394.1529; found, 394.1523.
(Z)-3-(Cyclohexylamino)-3-oxo-1-(thiophen-2-yl)prop-1-en-2-yl
benzoate 2e. Brown solid, mp 129.5−131.5 °C. Rf = 0.32 (DCM/
EtOAc/PE 2:1:7). Yield: 73% (78 mg). 1H NMR: δ 8.29 [dd, J = 8.4,
1.5, 2H], 7.72 [tt, J = 7.5, 1.5, 1H], 7.64 [s, 1H], 7.58 [tt, J = 7.8, 1.5,
2H], 7.33 [dt, J = 5.1, 1.2, 1H], 7.28−7.27 [m, 1H], 7.02 [dd, J = 5.1,
3.7, 1H], 5.80 [d br, J = 7.8, 1H], 3.95−3.82 [m, 1H], 1.97−1.07 [m,
10H]. 13C{1H} NMR: δ 163.9, 161.3, 137.9, 134.9, 134.4, 131.7,
130.7, 129.5, 129.0, 128.6, 127.2, 118.2, 48.7, 33.0, 25.6, 24.8. HRMS
(ESI) m/z: [M + H]+ calcd for C20H22NO3S, 356.1320; found,
356.1322.
Diazoketones 1a−g were synthesized according to literature
procedures,16 and analytical data were in accordance with the
literature.16,17
General Procedure for K-3CR and SK-3CR in Batch. The
desired diazoketone (0.3 mmol, 1 equiv, 0.1 M) and the acidic
component (silanol or carboxylic acid, 0.3 mmol, 1 equiv, 0.1 M)
were added to a vial. The vial was sealed and degassed with argon for
5 min. The solvent (dry DCM, 3 mL) and the isocyanide (0.3 mmol,
1 equiv, 0.1 M) were added; then, the solution was degassed for 5 min
with argon. The mixture was then irradiated at a constant temperature
(below 20 °C) at 450 nm (blue LEDs) under magnetic stirring until
complete consumption of the diazoketone (2 h to overnight) upon
TLC analysis (PE/EtOAc 4:1, UV/Hanessian stain). Purification:
products 2a−e, 2g−i, flash chromatography (SiO2, PE/EtOAc);
products 2f and 2l, precipitation from 2 mL of Et2O (−24 °C
overnight).
General Procedure for K-3CR and SK-3CR in Flow. Prior to
irradiation, the flow apparatus was flushed with nitrogen and
conditioned with dry DCM (including the airtight syringe). The
solution of reactants (see batch conditions above) was loaded into the
loading loop and then eluted at 1 mL h−1 (residence time 3 h) for a
total of 12 h to ensure complete collection of the irradiated solution.
The products were then purified as previously described for the batch
conditions.
(Z)-N-Cyclohexyl-3-phenyl-2-((triphenylsilyl)oxy)acrylamide 2f.
1
White foam. Rf = 0.35 (PE/Et2O = 7:3). Yield: 65% (98 mg). H
NMR: δ 7.57−7.54 [m, 6H], 7.46−7.40 [m, 2H], 7.36−7.28 [m, 9H],
7.07−6.97 [m, 3H], 6.84 [s, 1H], 6.16 [d br, J = 8.2 Hz, 1H], 3.66−
3.52 [m, 1H], 1.65−1.47 [m, 5H], 1.22−0.85 [m, 3H], 0.64−0.47 [m,
2H]. 13C{1H} NMR: δ 163.7, 143.2, 135.6, 134.0, 132.7, 130.5, 129.7,
128.2, 128.0, 127.4, 116.8, 48.4, 32.5, 25.5, 25.0. HRMS (ESI) m/z:
[M + H]+ calcd for C33H34NO2S, 504.2348; found, 504.2367.
(Z)-N-Cyclohexyl-4-phenyl-2-((triphenylsilyl)oxy)but-2-enamide
2g. White solid, mp = 99.1−102.3 °C. Rf = 0.30 (PE/Et2O = 7:3).
1
Yield: 65% (101 mg). H NMR: δ 7.67 [dd, J = 8.0, 1.5 Hz, 6H],
7.54−7.38 [m, 9H] 7.19−7.07 [m, 3H], 6.82 [dd, J = 7.6, 1.8 Hz,
2H], 6.17 [t, J = 7.6 Hz, 1H], 6.16 [d, J = 7.6 Hz, 1H], 3.62−3.59 [m,
1H], 3.15 [d, J = 7.5 Hz, 2H], 1.61−1.49 [m, 5H], 1.30−1.12 [m,
2H], 1.04−0.84 [m, 1H], 0.63−0.36 [m, 2H]. 13C{1H} NMR: δ
162.8, 143.2, 139.5, 135.6, 132.7, 130.9, 128.5 (×2), 128.4, 126.1,
117.9, 48.0, 32.6, 32.3, 25.6, 24.9.HRMS (ESI) m/z: [M + H]+ calcd
for C34H36NO2Si, 518.2510; found, 518.2521.
(Z)-N-Cyclohexyl-4-phenyl-2-((triphenylsilyl)oxy)but-2-enamide
2h. Colorless oil. Rf = 0.36 (PE/EtOAc = 4:1). Yield: 71% (109 mg).
1H NMR: δ 7.67−7.60 [m, 6H], 7.52−7.37 [m, 9H], 6.17 [d, J = 8.4
Hz, 1H], 6.01 [t, J = 7.6 Hz, 1H], 3.69−3.50 [m, 1H], 1.79 [q, J = 7.0
Hz, 2H], 1.64−1.45 [m, 4H], 1.31−1.13 [m, 5H], 1.01 [s, 7H], 0.81
[t, J = 7.2 Hz, 3H], 0.64−0.49 [m, 2H]. 13C{1H} NMR: δ 163.1,
142.5, 135.6, 132.9, 130.7, 128.3, 120.0, 47.9, 32.6, 31.7, 29.0, 28.6,
26.4, 25.6, 24.9, 22.7, 14.2. HRMS (ESI) m/z: [M + H]+ calcd for
C33H42NO2Si, 512.2979; found, 512.2983.
(S,Z)-tert-Butyl (5-(Benzylamino)-5-oxo-4-((triphenylsilyl)oxy)-
pent-3-en-2-yl)carbamate 2i. Colorless oil. Rf = 0.24 (PE/EtOAc
= 4:1). [α]D = +20.6 (c 1.0, CHCl3). Yield: 40% (66 mg). 1H NMR: δ
(Z)-3-(Cyclohexylamino)-3-oxo-1-phenylprop-1-en-2-yl ben-
zoate 2a. White solid, mp 163.7−165.2 °C. Rf = 0.34 (DCM/
1
EtOAc/PE 1:1:5.5). Yield: 83% (87 mg). H NMR: δ 8.19 [dd, J =
8.4, 1.5, 2H], 7.68 [tt, J = 7.5, 1.2, 1H], 7.56−7.50 [m, 4H], 7.33 [s,
1H], 7.28−7.24 [m, 3H], 6.03 [d br, J = 8.0, 1H], 3.94−3.81 [m, 1H],
1.97−1.09 [m, 10H]. 13C{1H} NMR: δ 163.7, 161.7, 140.0, 134.3,
132.5, 130.3, 129.6, 129.1, 129.0, 128.7, 128.4, 123.6, 48.6, 32.9, 25.5,
24.8. HRMS (ESI) m/z: [M + H]+ calcd for C22H24NO3, 350.1756;
found, 350.1757.
(Z)-3-(Cyclohexylamino)-3-oxo-1-phenylprop-1-en-2-yl 2-(3-
methoxyphenyl)acetate 2b. White solid, mp 89.0−91.2 °C. Rf =
1
0.27 (DCM/EtOAc/PE 1:1:5.5). Yield: 82% (97 mg). H NMR: δ
7.43−7.25 [m, 7H], 7.00−6.89 [m, 3H], 5.46 [d br, J = 8.4, 1H], 3.80
[s, 3H], 3.79 [s, 2H], 3.76−3.65 [m,1H], 1.77−0.73 [m, 10H].
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Article
7.60 [d, J = 8.1 Hz, 6H], 7.49−7.41 [m, 3H], 7.39−7.32 [m, 6H],
7.28−7.15 [m, 3H], 6.96−6.87 [m, 2H], 6.52 [s, 1H], 5.86 (d, J = 9.7
Hz, 1H), 4.35−3.99 [m, 4H], 1.39 [s, 9H], 0.68 [d, J = 6.4 Hz, 3H].
13C{1H} NMR: δ 163.8, 154.7, 142.5, 137.7, 135.6, 132.3, 130.9,
128.7, 128.4, 128.0, 127.5, 120.2, 79.2, 43.7, 43.3, 28.5, 20.7. HRMS
(ESI) m/z: [M + H]+ calcd for C33H39N2O4Si, 555.2674; found,
555.2671.
AUTHOR INFORMATION
■
Corresponding Author
Andrea Basso − Dipartimento di Chimica e Chimica
̀
Industriale, Universita degli Studi di Genova, 16146 Genova,
Italy; orcid.org/0000-0002-4700-1823; Phone: +39-
010-353-6117; Email: andrea.basso@unige.it
(Z)-N-Cyclohexyl-3-(4-methoxyphenyl)-2-((triphenylsilyl)oxy)-
acrylamide 2l. White foam. Rf = 0.41 (PE/EtOAc = 4:1). Yield: 65%
(104 mg). 1H NMR: δ 7.64−7.26 [m, 17H], 6.80 [s, 1H], 6.52 [d, J =
8.8 Hz, 2H], 6.13 [d, J = 8.3 Hz, 1H], 3.72 [s, 3H], 3.67−3.49 [m,
1H], 1.66−1.44 [m, 5H], 1.31−1.09 [m, 2H], 1.01−0.84 [m, 1H],
0.64−0.48 [m, 2H]. 13C{1H} NMR: δ 163.9, 159.0, 141.9, 135.7,
132.9, 131.1, 130.5, 128.1, 126.6, 116.5, 113.5, 55.3, 48.3, 32.5, 25. 6,
25.0. HRMS (ESI) m/z: [M + H]+ calcd for C34H36NO3Si, 534.2459;
found, 534.2467.
Procedure for the Synthesis of Compound 3 in Flow.
Product 2f (0.06 mmol, 1 equiv, 0.01M), Umemoto II reagent (0.12
mmol, 2 equiv), and Ru(bipy)3Cl2 (1 mol %) were dissolved in
acetonitrile (6 mL) under stirring. The solution was degassed with Ar
for 5 min, then loaded into the 6 mL loading loop, and eluted at 1.5
mL h−1 (residence time 2 h) for a total of 12 h to ensure complete
collection of the irradiated solution. The collected solution was
evaporated under reduced pressure; then, the crude was dissolved in
EtOAc and washed twice with water and once with brine. The
combined organic layers were dried over anhydrous Na2SO4 and then
eventually purified by flash chromatography (SiO2, PE → PE/EtOAc
10:1) to afford 6 mg of the desired product (32% yield).
Authors
Pietro Capurro − Dipartimento di Chimica e Chimica
Industriale, Universita degli Studi di Genova, 16146 Genova,
Italy
Chiara Lambruschini − Dipartimento di Chimica e Chimica
Industriale, Universita degli Studi di Genova, 16146 Genova,
Italy
Paola Lova − Dipartimento di Chimica e Chimica Industriale,
Universita degli Studi di Genova, 16146 Genova, Italy
Lisa Moni − Dipartimento di Chimica e Chimica Industriale,
Universita degli Studi di Genova, 16146 Genova, Italy;
̀
̀
̀
̀
orcid.org/0000-0001-5149-2963
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00278
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript
N-Cyclohexyl-4,4,4-trifluoro-2-oxo-3-phenylbutanamide 3. Col-
orless oil. 1H NMR: δ 7.46−7.34 [m, 5H], 6.76 [br s, 1H], 5.69 [q, J
= 8.8 Hz, 1H], 3.74−3.51 [m, 1H], 1.92 [d, J = 12.1 Hz, 2H], 1.79−
1.61 [m, 2H], 1.41−1.09 [m, 6H]. 13C{1H} NMR: δ 189.9, 157.3,
130.2, 129.4, 129.2, 127.6, 53.2 [q, J = 28.1 Hz], 48.9, 32.5, 25.2, 24.6
(CF3 is not visible). 19F NMR (decoupled) δ −66.5. HRMS (ESI) m/
z: [M + H]+ calcd for C16H18F3NO2, 313.1290; found, 313.1279.
Procedure for the Synthesis of Compound 4 in Flow. 4-
Methoxybenzenediazonium tetrafluoroborate (0.20 mmol, 1 equiv,
0.01 M), crude product 2g (assumed 0.20 mmol, 1 equiv) and
Ru(bipy)3Cl2(1 mol %) were dissolved in acetone (20 mL) under
stirring. The solution was degassed with Ar for 5 min, then loaded
into the 20 mL loading loop, and eluted at 3 mL h−1 (residence time 1
h) for a total of 10 h to ensure complete collection of the irradiated
solution. Prior to irradiation, the flow apparatus was flushed with
nitrogen and conditioned with degassed acetone (including the
airtight syringe). The collected solution was evaporated under
reduced pressure and purified by flash chromatography (SiO2, PE/
EtOAc 4:1) to afford 47 mg of the final product (75% yield).
3-Benzyl-N-cyclohexyl-2,5-dioxohexanamide 4. Colorless oil. Rf
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.B. would like to thank Dott. Riccardo Loddo for help with
performing preliminary experiments.
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00278.
Photochemical equipment, UV−vis characterization of
diazoketones 1a−g, determination of the quantum yield,
and copies of NMR spectra (PDF)
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